PMID- 20827104 TI - Coccidioidal meningitis: clinical presentation and management in the fluconazole era. AB - Despite the advent of new antifungal agents, coccidioidal meningitis (CM) remains a difficult-to-treat condition with significant morbidity and mortality. In this study we directly compare the clinical presentation and management of patients with Coccidioides immitis meningitis in the azole era (after 1980) to that of a cohort of patients from the pre-azole era. We reviewed 30 CM cases seen at 3 Los Angeles hospitals between the years 1993 to 2008 ("2008 cohort") and compared them to 31 patients ("1980 cohort") described by Bouza et al in a previous study. The demographics and clinical presentation of patients in the 2008 cohort were similar to those of the 1980 cohort except for a higher incidence of Hispanic patients (2008: 53% vs. 1980: 6%) and a greater percentage of patients with underlying, predisposing clinical conditions (2008: 66% vs. 1980: 32%). Ten patients in the 2008 cohort had human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), a condition not reported in the earlier study. Laboratory findings were similar between the 2 groups except for a lower incidence of peripheral leukocytosis and eosinophilia in the 2008 group.There were marked differences in drug treatment between the 2 eras. In the 2008 cohort, 29 patients received fluconazole therapy: 13 were treated with fluconazole monotherapy, and 16 received a combination of fluconazole and intravenous amphotericin B. Although almost all patients (29/31) in the 1980 cohort received intrathecal amphotericin B, only 3 patients in the 2008 study received amphotericin B via this route. With respect to complications of CM, a similar percentage of patients in each cohort developed complications such as stroke and hydrocephalus. The 2008 cohort (40%) had similar mortality compared to patients in the 1980 study (39%); survivors in both groups experienced significant impairment of activities of daily living. Although recommended as first-line therapy for CM, azole-based therapies are not curative and do not necessarily prevent complications associated with the disease.CM remains a serious illness with a high rate of morbidity and mortality. Immunocompromised individuals, especially those with HIV/AIDS, are at special risk for CM and represent a greater share of the overall population with this condition. Despite the clear advantages of azole treatment in CM, new therapeutic approaches are needed to provide definitive cure and to reduce the need for long-term suppressive therapy. PMID- 20827105 TI - Impact of traditional hospital strain of methicillin-resistant Staphylococcus aureus (MRSA) and community strain of MRSA on mortality in patients with community-onset S aureus bacteremia. AB - Community-associated methicillin-resistant Staphylococcus aureus (MRSA) has become an important pathogen in community and nosocomial infections. The impact of these emerging MRSA strains on mortality in adult patients with community onset S aureus bacteremia remains uncertain. We defined community strain MRSA (CoSt-MRSA) and hospital strain MRSA (HoSt-MRSA) according to the results of staphylococcus cassette chromosome mec (SCCmec) molecular typing: CoSt-MRSA isolates had SCCmec type IV or V genes, and HoSt-MRSA isolates had SCCmec type I, II, or III genes. We quantitatively evaluated the impact of the MRSA strain on mortality in patients with CoSt-MRSA or HoSt-MRSA bacteremia by comparison with mortality in patients with methicillin-susceptible S aureus (MSSA) bacteremia.We studied an observational cohort of 500 patients with MSSA bacteremia, 111 patients with CoSt-MRSA, and 133 patients with HoSt-MRSA bacteremia from January 1, 2001, through December 31, 2007. The 90-day cumulative probability of survival in patients with MSSA, CoSt-MRSA, and HoSt-MRSA bacteremia was 71%, 70%, and 55%, respectively (p = 0.014, by Wilcoxon rank-sum test).Compared to patients with MSSA bacteremia, patients with HoSt-MRSA bacteremia were associated with an increased risk of mortality in the first multivariate analysis model adjusting for all potential confounders (hazard ratio [HR], 1.525; 95% confidence interval [CI], 1.091-2.131), in the second model adjusting for all confounders except acute severity of bacteremia (HR, 1.489; 95% CI, 1.071-2.070), and in stratified analysis in patients with low Charlson comorbidity scores (score 0-2) (HR, 3.093; 95% CI, 1.507-6.350).Compared to patients with MSSA bacteremia, patients with CoSt-MRSA bacteremia did not show significant differences in mortality rate in the 2 multivariate analysis models (first model: HR, 1.106; 95% CI, 0.748-1.637; second model: HR, 1.028; 95% CI, 0.697-1.516) or in stratified analysis (HR, 1.092; 95% CI, 0.539-2.214).In conclusion, using MSSA as reference, traditional hospital strain MRSA had a higher impact on bacteremia mortality than community strain MRSA. PMID- 20827106 TI - Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study. AB - Few studies have addressed the association between polypharmacy and hip fracture using population data. We conducted a population-based case-control study to investigate whether polypharmacy increases the risk for hip fracture in the elderly. We used insurance claims data from the Taiwan Bureau of National Health Insurance, a universal insurance program with a coverage rate of more than 98% of the population in Taiwan. We identified 2328 elderly patients with newly diagnosed hip fracture during the period 2005-2007. We randomly selected 9312 individuals without hip fracture to serve as the control group. Patient characteristics, drugs prescribed by physicians, and all types of hip fracture were ascertained. The odds ratio (OR) of hip fracture in association with the number of medications used per day in previous years was assessed.We found that patients were older than controls, predominantly female, and more likely to use 5 or more drugs (22.2% vs. 9.3%, p < 0.0001). The OR of hip fracture increased with the number of medications used per day and with age. Multivariate logistic regression analysis revealed that the overall OR for patients using 10 or more drugs was 8.42 (95% confidence interval [CI], 4.73-15.0) compared with patients who used 0-1 drug per day. However, age-specific analysis revealed that the risk for hip fracture was 23 times greater for patients aged > or = 85 years who used 10 or more drugs than for those aged 65-74 years who used 0-1 drug after controlling for covariates (OR, 23.0; 95% CI, 3.77-140).We conclude that the risk of hip fracture in older people increases with the number of medications used, especially in women. Age interacts with the daily medications for the risk of hip fracture. PMID- 20827107 TI - Outcomes in biopsy-proven lupus nephritis: evaluation of 190 white patients from a single center. AB - We describe the natural history of lupus nephritis (LN) in a historical cohort of 190 white patients with the diagnosis of biopsy-proven LN followed in a single reference center.We evaluated 670 patients with systemic lupus erythematosus (SLE) consecutively followed in our department from 1970 until 2006. All patients fulfilled the 1997 revised criteria for the classification of SLE. White patients (Spanish-born) with biopsy-proven LN were selected as the study population.The cohort included 190 patients (170 female patients and 20 male) with a mean age at LN diagnosis of 31 years. Renal biopsy revealed type I LN in 8 (4%) patients, type II in 33 (17%), type III in 46 (24%), type IV in 72 (38%), type V in 28 (15%), and type VI in 3 (2%) patients. Induction remission was achieved in 85% of patients with types I and II, 78% with type III, 70% with type IV, and 32% of patients with type V. After a mean follow-up of 2391 patient-years, 62 (33%) patients developed chronic renal failure and 18 (9%) evolved to end-stage renal disease. Adjusted multivariate Cox regression analysis identified male sex (hazard ratio [HR], 4.33) and elevated creatinine at LN diagnosis (HR, 5.18) as independent variables for renal failure. Survival was 92% at 10 years of follow up, 80% after 20 years, and 72% after 30 years.Our results suggest that biopsy proven LN in white patients has an excellent prognosis. Ethnicity should be considered a key factor when evaluating the prognosis and therapeutic response to different agents in patients with LN. PMID- 20827108 TI - Late-onset neutropenia after rituximab treatment: case series and comprehensive review of the literature. AB - Rituximab is a chimeric monoclonal antibody against CD20 that is used mainly for the treatment of CD20-positive lymphoma. Recently, its use has been expanded to include treatment of other nonmalignant diseases such as rheumatologic diseases and autoimmune cytopenia. Correlating with the increased use of rituximab has been an increased number of reports of its late adverse effects. One of these is late-onset neutropenia (LON). Most investigators define LON as grade III-IV neutropenia occurring 3-4 weeks after the last treatment with rituximab, in the absence of an alternative explanation for the neutropenia.We report 6 cases of LON identified in our institution. Four patients were treated for diffuse large B cell lymphoma, and 2 patients for follicular lymphoma. Median patient age was 68 years (range, 33-83 yr); LON appeared after a median interval of 77 days (range, 42-153 d) and lasted for a median of 5 days (range, 1-45 d). Five of the 6 patients presented with infectious complications, and 4 patients experienced recurrent episodes of neutropenia. One patient presented with LON and concomitant subacute pulmonary disease that was attributed to rituximab therapy.In addition to our own case series we present a systematic review of the literature, which we performed to compile data to describe better the syndrome of LON. Systematic studies, case series, and case reports were extracted. Most studies dealing with LON are retrospective by design and are limited by the heterogeneous populations included in the analysis. The incidence of LON is generally reported to be in the range of 3%-27%. Data regarding populations at risk are not consistent, and in some instances are conflicting.Patients considered at increased risk of LON include patients after autologous stem cell transplantation, patients treated for acquired immunodeficiency syndrome (AIDS)-related lymphoma, and patients treated with purine analogues. Patients who received previous cytotoxic treatment as well as those treated with more intensive chemotherapy or with chemotherapy in combination with radiotherapy are also considered to be at risk of LON. In addition, advanced stages of disease and having received multiple doses of rituximab are risk factors for LON.The mechanism of LON is poorly understood. Direct toxicity is very unlikely. Some speculate that there may be an infectious etiology involved, as well as an antibody-mediated process, but these ideas have not been substantiated. The concept of a lymphocyte subpopulation imbalance leading to LON has been presented based on the demonstration of T-LGL in peripheral blood and bone marrow of patients with LON. Perturbations in stromal derived factor-1 and in the BAFF cytokine have also been discussed as potential players in the pathogenesis of LON. A recent study correlated specific polymorphism in the immunoglobulin G Fc receptor FCgammaRIIIa 158 V/F with increased rates of LON.The clinical significance of LON is important because it may affect treatment strategies. Of note, infectious complications are not very frequent and not very severe. Pooling data from the major retrospective studies reveals an infection rate of 16.9%. Most infections were mild and resolved promptly. One death occurred from infection during neutropenia. Repeated episodes of LON are not uncommon, but it is so far impossible to identify those patients at risk of these relapsing episodes of LON. Re-treatment with rituximab after LON may result in recurrent episodes, but the implications and risks are uncertain at the present time. The role of growth factors once LON appears is ill defined, and the decision to use them should be made on a case-by-case basis. PMID- 20827109 TI - Campylobacter bacteremia: clinical characteristics, incidence, and outcome over 23 years. AB - Campylobacter is a very rare cause of bloodstream infection, although it has been found relatively frequently in patients infected with human immunodeficiency virus (HIV). The impact of highly active antiretroviral therapy (HAART) and new forms of immunosuppression on the incidence of Campylobacter bacteremia has not been sufficiently assessed. In this study we analyzed the incidence and microbiologic and clinical characteristics of Campylobacter bacteremia over 23 years.We reviewed the clinical records of all patients who had Campylobacter bacteremia from 1985 to 2007. Available strains were reidentified using universal polymerase chain reaction (PCR).During the study period, there were 71 episodes of Campylobacter bacteremia in 63 patients (0.24% of all bloodstream infections), and the incidence remained stable (mean, 0.06/1000 admissions per year and 0.47/100,000 inhabitants per year). Median age was 52 years (interquartile range, 31.25-72.5 yr), and 82% of patients were male. The underlying conditions included liver disease (21/64, 32.8%), HIV infection (15/64, 23.4%), malignancy (7/64, 10.9%), solid organ transplantation (2/64, 3%), hypogammaglobulinemia (10/64, 15.6%), and other (18/64, 31.2%). Twelve patients shared more than 1 underlying condition. Campylobacter bacteremia was community acquired in 81% of the episodes. The origin of the bloodstream infection was abdominal (43.5%), primary (26%), or extraintestinal (31%: respiratory 15%, cellulitis 4.8%, urinary 8%, other 3%). C jejuni was recovered in 66% of cases, C fetus in 19%, and C coli in 12%.Universal PCR was performed on 14 available strains. Molecular and conventional identification matched in 8 isolates. In contrast, molecular methods classified as C fetus (n = 2) and C jejuni (n = 1) 3 strains formerly identified only to genus level as Campylobacter species. In another 3 isolates, molecular identification was not consistent with the phenotypic identification (C fetus identified as C jejuni).Complications appeared in 23.9% of patients. Quinolone resistance was observed in 50% of the isolates. Only 37.8% of patients received appropriate empirical therapy. Mortality was 16.4%, although it was higher in HIV infected patients than uninfected patients (33% vs. 10%; p = 0.04), in cases of hospital-acquired Campylobacter bacteremia compared with community-acquired cases (38.5% vs. 9.4%; p = 0.02), and in the presence of complications compared with patients without complications (100% vs. 0%; p < 0.001). The incidence of recurrence was 5% (3 patients with humoral immunodeficiency). There was a higher proportion of HIV-infected patients among patients with Campylobacter bacteremia in the pre-HAART era (1985-1996) than in the HAART era (1997-2007)-27.5% (11/40) vs. 14.3% (4/28)-although the difference was not statistically significant. Debilitating diseases such as chronic obstructive pulmonary disease emerged as predisposing conditions in the HAART era (0% before HAART era vs. 14.3% in HAART era; p = 0.032).Campylobacter bacteremia is no longer a significant disease of HIV-positive patients on HAART, but often affects other immunocompromised patients as well. Campylobacter bacteremia has an extraintestinal origin in as many as 31% of cases, and humoral immunodeficiency must be sought in patients with recurrent episodes. Quinolones should not be considered for empirical therapy. PMID- 20827110 TI - The spectrum of invasive pneumococcal disease at an adult tertiary care hospital in the early 21st century. AB - Despite widespread pneumococcal vaccination of children and adults, invasive pneumococcal disease (IPD) remains prominent. Using our database of all Streptococcus pneumoniae infections at the Veterans Affairs Medical Center, Houston, Texas, since 2000, we reviewed cases of IPD, defined as the isolation of pneumococci from any normally sterile body site. In 136 cases, the mean age of patients was 63 years; 43% were African American, a higher proportion than the 30% served by our hospital. One hundred sixteen patients (85%) had pneumonia, of whom 3 also had empyema. Seven had bacteremia with no apparent source, 5 meningitis, 5 spontaneous bacterial peritonitis, 3 septic arthritis, 2 endocarditis, and individual patients had osteomyelitis and/or localized abscesses. One hundred twenty-one patients (89%) had > or =1 underlying condition associated with susceptibility to pneumococcal infection, and another 8 (6%) were aged >65 years old. Thus only 5% of patients lacked a condition for which 23 valent pneumococcal polysaccharide vaccine (PPV23) is recommended. Fifty-five percent had been vaccinated; similar proportions of vaccine serotypes infected previously vaccinated and nonvaccinated patients. All but 2 isolates were fully susceptible to penicillin and cefotaxime as currently defined. Consistent with substantial replacement of infecting serotypes since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), none of the predominant infecting serotypes was included in PCV7, although all except for 6A were contained in PPV23. The overall mortality at 30 days was 16% and was similar in vaccinated and nonvaccinated subjects. IPD causes a wide spectrum of disease. Mortality is substantial. PPV23 is clearly not fully protective. PMID- 20827111 TI - Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. AB - Culture of Tropheryma whipplei, the agent of Whipple disease (WD), was achieved in our laboratory in 2000, allowing new perspectives for the diagnosis of this disease and for the description of other potential clinical manifestations caused by this microorganism. Since 2000, we have developed new tools in our center in Marseille, France, to optimize the diagnosis of T whipplei infections. Classic WD was characterized by positive periodic acid-Schiff performed on duodenal biopsy. In the absence of duodenal histologic involvement, localized infections were defined by specific positive T whipplei polymerase chain reaction (PCR) results obtained using samples of other tissues and body fluids. The physicians in charge of patients were asked to complete a questionnaire. A total of 215 diagnoses were performed or confirmed and, among these, 142 patients with sufficient clinical data were included.Herein, we report epidemiologic data, clinical manifestations, and diagnostic tools of T whipplei infections. In the 113 patients with classic WD, the main symptom was arthralgia (88/113, 78%), which explains the many cases misdiagnosed as inflammatory rheumatoid disease (56/113, 50%). Frequently immunosuppressive treatments, more recently including tumor necrosis factor inhibitor, had been previously prescribed (50%) and were often responsible for more rapid clinical progression (43%). Sometimes a short course of antibiotics improved the clinical status.Endocarditis was the second most frequent manifestation of T whipplei, with 16 cases. The clinical picture of this entity corresponds to cardiovascular involvement with acute heart failure (50%) occurring without fever (75%) or previous valvular disease (69%). Neurologic symptoms were the third major manifestation. Other localized infections such as adenopathy, uveitis, pulmonary involvement, or joint involvement were sporadic. Infection with T whipplei resulted in multifaceted conditions. Some localized infections due to this agent have recently been reported and may correspond to emerging entities. Patients with inflammatory rheumatoid disease must be systematically interviewed to determine the efficacy of previous immunosuppressive and antibiotic therapies. PMID- 20827112 TI - Long-term central venous catheter salvage in patients with Bacillus bacteremia. PMID- 20827114 TI - The causal relationship between the use of black cohosh-containing products and hepatotoxicity. PMID- 20827115 TI - The effects of St. John's wort on hot flashes. PMID- 20827116 TI - Phantom limb pain: theories and therapies. AB - BACKGROUND AND OBJECTIVE: Since the beginning of the conflicts in Iraq and Afghanistan, there has been a dramatic increase in the number of military service members with single and multiple-limb amputations. Phantom limb pain (PLP) frequently develops in these individuals. As a result, identifying the best methods to treat PLP is critical. The review highlights areas of inquiry related to phantom pain, with a focus on PLP. REVIEW SUMMARY: This review discusses phantom sensations and phantom pain that arise after amputation of a body part, and summarizes the differences between the 2 conditions. Characteristics of PLP are also discussed, including the onset, duration, and location of PLP. Theories explaining the etiology and presence of PLP are reviewed, along with the numerous treatment options reported in the published data for such pain, including the use of mirrors for treating pain. We conclude with a description of one military hospital's experiences with PLP. CONCLUSIONS: Although more research has been done in previous years, this review identifies the need for continuing investigations. The etiology of PLP needs to be determined through more vigorous investigation, and a focus must be placed on defining treatment options in addition to mirror therapy that will improve the quality of life of those who suffer from this condition. PMID- 20827117 TI - Peripheral nervous system manifestations of Sjogren syndrome: clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies. AB - Sjogren syndrome is among the most common autoimmune diseases affecting adults in the United States, and is frequently regarded as an immune-mediated exocrinopathy exclusively causing dry eyes and dry mouth. However, as a systemic rheumatic disease, there can be various "extraglandular" complications. The eclectic permutation of peripheral nervous system (PNS) syndromes which occur in Sjogren patients are among the most common and severe extraglandular complications. This review article highlights the evaluation, differential diagnosis, immunopathogenic mechanisms, and potential treatment options of these PNS complications encountered by neurologists. The sensory neuropathies constitute the most frequent PNS complication. Sjogren patients can suffer from severe neuropathic pain, with small-fiber neuropathy causing lancinating or burning pain which can disproportionately affect the proximal torso or extremities, and the face (ie, in a "non-length-dependent distribution"). The technique of skin biopsy, assessing for the intraepidermal nerve fiber density of unmyelinated nerves, provides a useful technique for neurologists to diagnose small-fiber neuropathies, especially when there is such a non-length-dependent distribution. Other diagnostic techniques (ie, electromyography/nerve-conduction studies, evoked potentials, nerve and muscle biopsy) may be useful in specific subtypes of neuropathies. A rational approach to treatment requires a careful appraisal of the clinical subtype of the neuropathy, as well as a familiarity with such discriminating immunopathogenic mechanisms. The application of the traditional armamentarium used for neuropathic pain can be especially challenging. Sjogren patients can suffer from debilitating fatigue, sicca symptoms, and autonomic findings; as such manifestations can be complications of various neuropathic agents, neurologists should understand how to minimize such iatrogenic complications. Therefore, this article will empower neurologists to more effectively collaborate with rheumatologists, in the diagnosis and treatment of Sjogren patients with PNS complications. PMID- 20827118 TI - Asymmetric cortical degenerative syndromes: an integrated approach to clinical and imaging review. AB - BACKGROUND: The term asymmetric cortical degenerative syndromes (ACDSs) refers to any brain afflictions that result in selective atrophy, particularly with an asymmetric pattern. Regardless of the etiology, the resulting compromised profile reflects the affected topography, which correlates with the clinical findings, more than any specific neuropathologic entity. REVIEW SUMMARY: ACDS can represent a diagnostic challenge, because of an overlap of clinical manifestations, especially in the early stages. Magnetic resonance techniques are useful to understand nuclear medicine studies and to confirm areas of focal atrophy by providing anatomic details and allowing an accurate correlation with several different clinical settings. CONCLUSIONS: This article demonstrates a practical neuroradiologic approach for ACDS, including optimized imaging analysis (magnetic resonance and nuclear medicine studies), which correlates their patterns with clinical and pathologic findings of the most relevant disorders. PMID- 20827119 TI - Promotion of residents' diagnostic accuracy of early ischemic infarct on nonenhanced brain computed tomography with a modified window setting. AB - BACKGROUND: To assess the effect of a modified window width and center level setting in promoting residents' interpretation of acute ischemic infarct on nonenhanced brain computed tomography (CT). METHODS: Nonenhanced brain CT images of 11 acute ischemic infarct patients were mixed with 11 control patients. Twelve residents reviewed the randomized images on standard setting (window width and center level of 80 and 30) and then on a modified setting (window width and center level of 40 and 40). RESULTS: There was significant elevation of sensitivity, positive predictive rate, and negative predictive rate (P < 0.05, Paired-Samples test) but no significant difference in specificity. CONCLUSION: The radiology department of hospitals with picture archiving and communication system may suggest that a modified brain CT setting according to individual CT scanner and scanning parameters accompany the standard settings to assist residents in the detection of acute ischemic infarct. It is a simple, economic, and effective method, which is worthy of more attention. PMID- 20827120 TI - Current status of neurology grand rounds. AB - OBJECTIVE: We sought to compare the current status of Neurologic Grand Rounds (NGRs) in training programs with the status observed in Medical Grand Rounds. METHODS: A survey was sent to 124 departments of neurology in the United States that are accredited by the American Council of Graduate Medical Education via an online Web tool. We collected data regarding the attendance, objectives, format, educational structure, and perceived changes and trends over time. RESULTS: Seventy-five (60%) surveys were returned: 10% were completed by the department chairperson, 4% by the chief resident, and 54% by another faculty member. NGRs were offered by 99% of the programs surveyed, and 95% of the programs conduct NGRs accredited for Continuing Medical Education. Almost all of the respondents agreed that the education of faculty, house staff, and full-time faculty was very important. Ninety-three percent of the programs hold clinical case presentations, and 60% have patients in attendance for the presentation. Programs reported that the quality, importance, and educational value of NGRs had either not changed or had increased over time (94%, 91%, and 89%, respectively). CONCLUSION: NGRs continue to be an important component of neurology residency training programs. The results of our survey were comparable to those obtained by others studying Medical Grand Rounds. Objectives, components, attendance, format, changes, and trends were also similar. PMID- 20827121 TI - Efficacy of nebivolol and amitriptyline in the prophylaxis of cyclic vomiting syndrome: a case report. AB - BACKGROUND: Cyclic vomiting syndrome (CVS) is an episodic disorder with recurrent attacks of nausea and vomiting. The exact cause of the disorder is still unclear. It was first described in children but may affect patients of any age. The syndrome is frequently misdiagnosed, and patients receive redundant investigations and treatments. Patients are referred finally to a neurologist because of the differential diagnosis of abdominal migraine or abdominal epilepsy. CASE REPORT: We present a 18-year-old girl with episodic nausea and vomiting attacks who was diagnosed as CVS. The attacks regressed with combination treatment with amitriptyline and nebivolol. CONCLUSION: CVS has no specific diagnostic test and the diagnosis is based on history, clinical presentation and exclusion of other possible causes with similar presentation. The syndrome has a strong association with migraine; treatment options may also overlap. Treatment is still based on case series and reports. Here, we aim to present the clinical features as well as treatment response of a patient with CVS. PMID- 20827122 TI - Rapid progression of amyotrophic lateral sclerosis in an acromegalic patient after surgical resection of a growth hormone-producing pituitary adenoma. AB - INTRODUCTION: Insulin-like growth factor-1 (IGF-1) promotes the survival of neurons, mediates neuritic growth, and in 1 clinical trial human recombinant IGF 1 delayed the progression of functional impairment and decline of health-related quality of life in patients with amyotrophic lateral sclerosis (ALS). CASE REPORT: We describe a case of a 65-year-old woman with a 2-year history of symptoms and signs of acromegaly because of a pituitary microadenoma. The patient posed a challenging diagnostic dilemma because of the presence of dysarthria, which was initially considered as the consequence of acromegaly. After octreotide long-acting release (LAR) treatment, the patient underwent uneventful pituitary surgery. Although postoperative evaluation indicated a cure of acromegaly, progressive bulbar symptoms developed, which were followed by upper limb weakness and muscle atrophy. Neurologic investigations confirmed the diagnosis of ALS and riluzole therapy was given. One year after surgery growth-hormone deficiency was diagnosed, but a trial with human recombinant growth hormone failed to produce any significant improvement. Two years after surgery the patient died of a sudden respiratory arrest. Histopathologic examination of the brain and spinal cord confirmed the diagnosis of ALS. CONCLUSIONS: This is the first report showing a rapid progression of ALS after a surgical cure of coexisting acromegaly presumably because of cessation of high endogenous IGF-I levels. PMID- 20827123 TI - Granulocytic sarcoma mimicking HSV encephalitis. AB - INTRODUCTION: Granulocytic sarcomas, or chloromas, are extramedullary collections of immature granulocytes. Central nervous system involvement is rare and of those cases described, most are complications of acute myelogenous leukemia. CASE REPORT: A 40-year-old man with chronic myelogenous leukemia presented with seizure and encephalopathy. Magnetic resonance imaging of the brain revealed temporal T2 hyperintensities with gyriform cortical enhancement. Cerebrospinal fluid showed mild pleocytosis and elevated protein. Electroencephalography demonstrated periodic lateralized epileptiform discharges. Acyclovir was initiated for herpes simplex encephalitis, however, follow-up MRI showed extension of the lesion. MR spectroscopy suggested tumor, confirmed by brain biopsy. Postradiation MRI showed a significant decrease in lesion size. CONCLUSION: Granulocytic sarcoma can present as intraparenchymal cerebral lesions in patients with chronic myelogenous leukemia and may mimic herpes simplex encephalitis. PMID- 20827124 TI - Multifocal strokes as the initial manifestation of metastatic tumors. AB - Patients with cancer are hypercoagulable and at a significant risk for ischemic stroke, but rarely present with stroke as the first manifestation of an underlying malignancy. We report on 2 patients with bihemispheric, multiterritorial infarctions in the absence of a cardioembolic source. PMID- 20827125 TI - Do antiepileptic drugs increase the risk of suicidality in adult patients with epilepsy?: a critically appraised topic. AB - BACKGROUND: The US Food and Drug Administration (FDA) released an alert in 2008 regarding an increased risk of suicidality in patients taking antiepileptic drugs (AEDs). The analysis that prompted this blanket warning has since been criticized for multiple flaws, and its relevance to patients with epilepsy is unclear. OBJECTIVE: To critically assess current evidence regarding the risk of suicidality in adult patients with epilepsy taking commonly prescribed AEDs as monotherapy. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario, structured question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of epilepsy. RESULTS: A structured literature search led to selection of one article providing the highest level of evidence currently available to answer our clinical question: a recent cohort study. The primary results of this study were based on comparisons of several AEDs to topiramate as a reference drug for any indication (including epilepsy), and identified gabapentin, lamotrigine, oxcarbazepine, tiagabine, and valproate as increasing risk of suicidality. A secondary analysis using carbamazepine as the reference drug failed to show statistically significant differences. A subgroup analysis of patients with epilepsy revealed an increased risk of suicidality in patients taking gabapentin as compared with those taking carbamazepine (relative risk, 13.92; 95% confidence interval, 1.82-106.38). CONCLUSION: Evidence of increased suicidality in patients taking AEDs for epilepsy is sparse. On the basis of this critical appraisal, gabapentin is one drug that may increase risk of suicide attempts and completions in these patients. PMID- 20827126 TI - National Case Management Week 2010--the stories you star in. PMID- 20827127 TI - A new era for case management: field research makes the case for case managers in care coordination. PMID- 20827128 TI - Speaking up in case management, part II: implementing speaking up behaviors. AB - OBJECTIVES: Case managers will occasionally witness colleagues from their own or other healthcare disciplines providing care in ways that frankly deviate from or violate standards of care, rules, regulations, policies, and procedures. This article discusses the case manager's ethical obligation to speak up in such instances, as well as lists strategies and techniques that facilitate and enhance professional communications around "speaking up." PRIMARY PRACTICE SETTINGS: All case management work environments. FINDINGS/CONCLUSIONS: When healthcare professionals practice in ways that deviate from established policies, procedures, rules, regulations, and standards of care, they jeopardize the safety and welfare of their clients and, often, their employing institutions. Unfortunately, professionals often remain silent about such errors and deviations for fear that they might suffer retaliation if they speak up or because they do not anticipate a constructive or positive organizational response. Nevertheless, organizations and employees who recognize the value of speaking up can use a variety of strategies described in this article that enable speaking up to become a professional and organizational reality. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Because they practice in the midst of multidisciplinary care, case managers have a marked opportunity to witness any number of practice standards being ignored or violated. Case managers need to develop communication skills and organizational savvy regarding how to approach and remedy such situations, especially when deviations from standards of care have become routine or "normalized." Critical elements in speaking up include cultivating a method to discern the moral perils of remaining silent, learning communication techniques to conduct emotionally challenging conversations, and building organizational leadership that recognizes the value of speaking up and supports safe harbors for employees who speak up appropriately. PMID- 20827131 TI - Battling the uncompensated care spiral: outcomes from a single institution assisting uninsured hospitalized patients to obtain health insurance. AB - PURPOSE OF STUDY: The purpose of this research was to evaluate the effectiveness of financial counseling services in assisting uninsured patients receive financial assistance and medical insurance. PRIMARY PRACTICE SETTING: A single, nonprofit 400+-bed, inner-city, acute care facility in the Mountain West. METHODOLOGY AND SAMPLE: A retrospective, medical record review design was used. Records for any uninsured patients admitted as inpatients to the hospital were considered for the study. A sample of 50 records was selected by evaluating every 21st patient from a chronological list of 1,070 possible records of all uninsured patients admitted to the facility during the months of May through July 2006. A tool was created for this study and used by the principal investigator (H.B.) to abstract specific points of data from each patient record. The research was approved by the university institutional review board. Descriptive statistical analyses were then performed to determine trends. RESULTS: Financial counseling at this institution aided 55% of uninsured patients to obtain health insurance. Because insurance was obtained for previously uninsured patients, the institution was reimbursed a total of $865,350. The institution was left with a total of $388,291 in uncompensated care. Patients younger than 18 years and patients admitted to labor and delivery or newborn nursery units obtained insurance coverage more often than other patients. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Insurance counseling for uninsured hospital patients has proven to be effective. The patient benefits from the counseling by obtaining insurance and the hospital benefits by receiving more financial reimbursement for services given. Case managers have a great opportunity to help their uninsured patients by offering insurance counseling. Case managers should familiarize themselves with all possible health insurance options so that they can advise and guide patients through these application processes. PMID- 20827132 TI - Is it noncompliance, or are the barriers insurmountable? PMID- 20827134 TI - Objective behavioral assessment: the missing link in case management decision making. PMID- 20827135 TI - Discharging the ventilator-dependent patient to home--part 1. PMID- 20827136 TI - Drusen, an old but new frontier. PMID- 20827137 TI - Adherence to recommendations of the age-related eye disease study in patients with age-related macular degeneration. AB - PURPOSE: The purposes of this study were to determine the rate of adherence to the recommendations of the Age-Related Eye Disease Study (AREDS) regarding vitamin supplement use among patients with age-related macular degeneration (AMD) at a tertiary retina center and to identify factors associated with adherence. METHODS: Consecutive patients with a history of AMD were administered an in person survey designed to assess use of vitamin supplementation as well as to investigate factors that may influence supplementation use patterns. A retina specialist performed dilated funduscopic examinations and categorized patients' AMD severity according to the AREDS classification system. The main outcome measure was rate of adherence to AREDS recommendations. RESULTS: Sixty-four patients with AMD completed the survey. Sixty-three percent of patients met AREDS criteria for vitamin supplementation. Of those patients who met the criteria, only 43% reported taking AREDS vitamins in the recommended dosages. Among patients using AREDS vitamins as recommended, 100% were return patients to the tertiary retina center and reported a retina specialist as the primary recommendation source for supplement use. Of patients who met AREDS criteria for vitamin supplementation but were not taking vitamins as per AREDS recommendations, 87% were new patients to the retina service and 75% reported that vitamin supplementation had never been recommended to them. CONCLUSION: Patients with intermediate or advanced AMD in at least one eye show a low adherence rate to the AREDS recommendations for vitamin supplementation. PMID- 20827138 TI - Prospective one-year study of ranibizumab for predominantly hemorrhagic choroidal neovascular lesions in age-related macular degeneration. AB - PURPOSE: To determine the safety and effect of ranibizumab on predominantly hemorrhagic choroidal neovascular lesions due to age-related macular degeneration. METHODS: Seven subjects with predominantly hemorrhagic choroidal neovascular lesions were treated with intravitreal injections of ranibizumab at baseline, Month 1, and Month 2. Additional monthly injections were given through Month 11 at the discretion of the examiner for a potential maximum of 12 injections. RESULTS: At 12 months, the median visual acuity letter score was 30 (Snellen equivalent: 20/250), with a median change from baseline to last follow up of +7 letters. Three of 7 subjects (43%) gained 2 or more lines of vision, while no subject lost 2 or more lines. The median change in OCT central subfield thickness from baseline to Month 12 was -109 microm, with a mean of -120 +/- 158 microm. Two eyes had retinal pigment epithelial tears. No ocular adverse events or systemic adverse events were reported related to the usage of ranibizumab. CONCLUSION: With no subject losing 2 or more lines of visual acuity over 12 months and no new safety concerns identified, these predominantly hemorrhagic lesions treated with ranibizumab appeared to have a better visual acuity outcome than the natural history controls of the submacular surgery trials. While the study is limited by few cases enrolled, the results suggest that ranibizumab is able to penetrate through the subretinal hemorrhage to affect the underlying hemorrhagic choroidal neovascular lesion and the natural history. PMID- 20827140 TI - Relationship between fasting glucose and retinopathy for diagnosis of diabetes: results from a population-based study in urban and rural China. AB - PURPOSE: The purpose of this study was to assess the relationship between the fasting plasma glucose cutoff of 7 mmol/L and the presence of retinopathy in a population in China. METHODS: The Beijing Eye Study 2006 is a population-based study, which included 3,251 subjects aged >or= 45 years. By using fundus photographs, retinopathy was assessed according to the Early Treatment of Diabetic Retinopathy Study. RESULTS: The correlation between fasting plasma glucose concentration and retinopathy suggested a continuous relation instead of a uniform glycemic threshold for prevalent retinopathy. For the diabetes plasma glucose concentration cutoffs of 7.0 mmol/L, 5.6 mmol/L, and 7.8 mmol/L to differentiate between subjects with or without retinopathy, the sensitivities were 18.8%, 44.0%, and 15.4%, respectively, and the specificities were 94.3%, 73.8%, and 96.6%, respectively. After excluding subjects with known diabetes and/or subjects on antidiabetic treatment, the sensitivities of diabetes plasma glucose concentration cutoffs of 7.0 mmol/L, 5.6 mmol/L, and 7.8 mmol/L to differentiate between subjects with or without retinopathy were 7.9%, 34.2%, and 6.3%, respectively, and the specificities were 96.5%, 77.1%, and 98.1%, respectively. CONCLUSION: Confirming a recent study from Australian and North American populations, the results suggest that also for the Chinese population, a uniform glycemic threshold for prevalent retinopathy does not exist. PMID- 20827139 TI - Photodynamic therapy with verteporfin in polypoidal choroidal vasculopathy: results after 3 years of follow-up. AB - PURPOSE: The purpose of this study was to evaluate the efficacy of verteporfin photodynamic therapy on the treatment of polypoidal choroidal vasculopathy. METHODS: A prospective, nonrandomized institutional study was conducted involving 42 eyes of 38 patients with newly diagnosed symptomatic polypoidal choroidal vasculopathy treated exclusively with photodynamic therapy. Twenty-seven eyes completed 3 years of follow-up. Subjects were observed every 3 months with evaluation of best-corrected visual acuity (BCVA), retinography, and fluorescein and indocyanine green angiography. Treatment was given whenever the patient exhibited subfoveal exudation on fluorescein angiography. RESULTS: Mean BCVA was 0.91 +/- 0.33 logarithm of the minimum angle of resolution on the initial visit and 0.93 +/- 0.39 on the 36-month visit. Patients were submitted to an average of 3.19 treatment sessions. On the final evaluation at 36 months, 14.8% of the treated eyes improved their BCVA by at least 0.3 logarithm of the minimum angle of resolution, 74.1% had no significant loss of BCVA, and 25.9% lost >or=0.3 logarithm of the minimum angle of resolution. Recurrences were frequent (59.3% of the eyes at 3 years of follow-up), responded well to retreatment, and were not associated with additional BCVA loss. CONCLUSION: Photodynamic therapy remains a good option for management of polypoidal choroidal vasculopathy. After 3 years, approximately three fourths of the treated eyes had no significant loss of vision, and 14.8% showed significant improvement in visual acuity. PMID- 20827141 TI - Risk factors for the development of transient hypotony after silicone oil removal. AB - PURPOSE: The purpose of the study was to determine the incidence, duration, and risk factors for postoperative transient hypotony after pars plana silicone oil removal. METHODS: This was a retrospective, noncomparative, interventional case series. The records of 89 eyes of 89 patients who underwent pars plana silicone oil removal with at least 6 months of follow-up were reviewed. Postoperative transient hypotony was defined as an intraocular pressure of <6 mmHg occurring within 1 week of surgery, which recovered within 4 months after surgery. RESULTS: Transient hypotony occurred in 35 of 89 eyes (39.3%). Thirty-three eyes recovered within 1 week after surgery. The logistic regression model, including age, number of previous pars plana vitrectomies, number of intraoperative endolaser applications, extent of remaining posterior proliferative vitreoretinopathy and the degree of proliferative vitreoretinopathy removal, number of preoperative antiglaucoma ophthalmic solutions, duration of postoperative anterior chamber inflammation, axial length, preoperative intraocular pressure, and duration of oil tamponade, showed that only axial length was significantly associated with the development of postoperative transient hypotony (odds ratio = 1.385, P = 0.023). CONCLUSION: Transient hypotony frequently developed after silicone oil removal, and most cases recovered within 1 week postoperatively. Patients with a long axial length had increased odds of developing transient hypotony after silicone oil removal. PMID- 20827142 TI - Microperimetric changes after intravitreal triamcinolone acetonide injection for macular edema due to central retinal vein occlusion. AB - PURPOSE: The purpose of this study was to evaluate the effect of intravitreal triamcinolone acetonide on macular function in cases of macular edema because of central retinal vein occlusion. METHODS: Twelve eyes of 12 patients with central retinal vein occlusion were included in this study. In each eye, at baseline and 1, 3, and 6 months after intravitreal triamcinolone acetonide injection, logarithm of the minimum angle of resolution visual acuity, macular sensitivity, fixation stability and fixation location by MP-1 microperimetry, and foveal thickness by optical coherence tomography were assessed. RESULTS: Patients' ages ranged from 50 to 75 years (mean +/- SD, 59 +/- 8 years). All patients were classified as nonischemic. At 1, 3, and 6 months, the mean foveal thickness had decreased from 453 +/- 108 microm to 254 +/- 40.3 microm, 297 +/- 90 microm, and 320 +/- 82 microm and the mean retinal sensitivity had increased from 5.5 +/- 3.3 dB to 9.4 +/- 3.5 dB, 7.8 +/- 3.3 dB, and 7.2 +/- 4.2 dB, respectively. At baseline, fixation was stable in one, relatively unstable in six, and unstable in five eyes. However, 6 months after intravitreal triamcinolone acetonide injection, fixation was stable in 8, relatively unstable in 3, and unstable in one. At baseline, in eyes with macular edema, fixation location was predominantly central in 2, poor central in 4, and predominantly eccentric in 6. And 6 months after treatment, fixation location was predominantly central in 8, poor central in 3, and predominantly eccentric in 1. CONCLUSION: In eyes with macular edema in central retinal vein occlusion, a short-term improvement in retinal sensitivity and fixation properties can be achieved by intravitreal triamcinolone acetonide injection. PMID- 20827143 TI - Retinitis pigmentosa associated with asteroid hyalosis. AB - BACKGROUND: Asteroid hyalosis (AH) is a condition in which cream-colored or white spherical particles are suspended in the vitreous body. Asteroid hyalosis is considered not to cause decreased vision or any other visual symptoms except in rare cases. There have been a few reports of AH in patients with retinitis pigmentosa (RP). METHODS: To assess the prevalence of AH in patients with RP, 320 patients with typical forms of RP were studied. One patient was offered a standard three-port vitrectomy, and the spherical particles obtained from her vitrectomy sample were analyzed using an energy-dispersive x-ray spectrometer. RESULTS: Ten patients (two men and eight women) developed AH. Among them, four had bilateral AH and two had rapidly increasing vitreous opacity that led to decreased vision. One patient was a 48-year-old woman with progressive AH in the left eye. After treatment with a vitrectomy, her vision improved from 0.4 to 0.8. The spherical particles were composed of mainly calcium and phosphorus. CONCLUSION: The prevalence of AH in RP was higher than in previous reports, and we encountered two rare cases of progressive AH with decreased vision. We conclude that AH might lead to decreased vision in patients with RP. PMID- 20827144 TI - The new lens holder for Peyman-Wessels-Landers 132D upright vitrectomy lens. PMID- 20827145 TI - New sutureless contact lens ring system for vitrectomy using cannula system. PMID- 20827146 TI - Cirrus HD-OCT high definition imaging is another tool available for visualization of the choroid and provides agreement with the finding that the choroidal thickness is increased in central serous chorioretinopathy in comparison to normal eyes. PMID- 20827148 TI - Intravitreal bevacizumab injection for central serous chorioretinopathy. PMID- 20827150 TI - We congratulate the authors for publishing their data on bilateral consecutive intravitreal injections administered in their office. PMID- 20827152 TI - Bevacizumab compared with macular laser grid photocoagulation for cystoid macular edema in branch retinal vein occlusion. PMID- 20827154 TI - In their patient, as in our patient, vitreous specimens were culture negative. PMID- 20827155 TI - Prevention of vision loss after cataract surgery in diabetic macular edema with intravitreal bevacizumab: a pilot study. PMID- 20827157 TI - An Asian scenario of ROP is much different from the often quoted Western literature, and it was heartening to see the authors identify and diligently record the numerous risk factors mentioned in the study. PMID- 20827160 TI - Is Kaposi's sarcoma occurring at higher CD4 cell counts over the course of the HIV epidemic? AB - We evaluated longitudinal rates of Kaposi's sarcoma and trends in CD4 cell counts at the time of Kaposi's sarcoma diagnosis during the HIV epidemic (1985-2008). Although rates of Kaposi's sarcoma have decreased, cases are now occurring at higher CD4 cell counts over time, with more than one-third of cases diagnosed in 2002-2008 occurring at CD4 cell counts of at least 350 cells/MUl. These data support future studies evaluating the impact of highly active antiretroviral therapy initiation at higher CD4 cell counts to further reduce Kaposi's sarcoma. PMID- 20827161 TI - In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572. AB - In this study of nine clinical isolates obtained from integrase inhibitor-naive HIV-2-infected patients, the median EC50 value for the new integrase inhibitor S/GSK1349572 was 0.8 nM (range 0.2-1.4), and is similar to HIV-1 reference strains. We found a seven-, 13- and 18-fold increase in EC50 values to S/GSK1349572 for the HIV-2 double (T97A + Y143C; G140S + Q148R) and triple (G140T + Q148R + N155H) mutants, respectively, obtained from two raltegravir-experienced patients. PMID- 20827162 TI - Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AB - OBJECTIVE: To determine whether raltegravir-containing antiretroviral therapy (ART) intensification reduces HIV levels in the gut. DESIGN: Open-label study in HIV-positive adults on ART with plasma HIV RNA below 40 copies/ml. METHODS: Seven HIV-positive adults received 12 weeks of ART intensification with raltegravir alone or in combination with efavirenz or darunavir. Gut cells were obtained by upper and lower endoscopy with biopsies from duodenum, ileum, colon, and rectum at baseline and 12 weeks. Study outcomes included plasma HIV RNA, HIV DNA and RNA from peripheral blood mononuclear cells (PBMC) and four gut sites, T-cell subsets, and activation markers. RESULTS: Intensification produced no consistent decrease in HIV RNA in the plasma, PBMC, duodenum, colon, or rectum. However, five of seven participants had a decrease in unspliced HIV RNA per 10 CD4(+) T cells in the ileum. There was a trend towards decreased T-cell activation in all sites, which was greatest for CD8(+) T cells in the ileum and PBMC, and a trend towards increased CD4(+) T cells in the ileum. CONCLUSION: Most HIV RNA and DNA in the blood and gut is not the result of ongoing replication that can be impacted by short-term intensification with raltegravir. However, the ileum may support ongoing productive infection in some patients on ART, even if the contribution to plasma RNA is not discernible. PMID- 20827163 TI - The erythrocyte sedimentation rate in HIV: a neglected parameter? PMID- 20827164 TI - Pregnancy in HIV vertically infected adolescents and young women: a new generation of HIV-exposed infants. AB - BACKGROUND: Vertically infected individuals are reaching childbearing age and the new generation of HIV-exposed infants is coming to pediatric care. METHODS: Chart review of pregnancies among HIV vertically infected adolescents and young women. RESULTS: Fifteen pregnancies were reviewed. Girls had HIV diagnosis at median age 10.1 years (range 1.3-20). They started sexual life at median age 15 years (range 13-19); median age at pregnancy was 16.9 years (range 14-21.5); 36.4% had presented an AIDS-defining clinical event; have been followed for median 8.5 years (range 2.9-15.8) and had used median two antiretroviral regimens (range 0 7). Fourteen (93.3%) received antiretroviral drugs during pregnancy; median CD4 cell count during pregnancy was 394 (range 117-651) cells/MUl and median viral load was 4800 copies/ml (range 50-100 000); 54% had undetectable viral load near delivery. All patients delivered by elective c-section. Median birth weight was 2650 g (range 2085-3595), median length was 47.3 cm (range 42-51) and median gestational age 38 weeks (range 37-39). All newborn received zidovudine for 6 weeks of life and none was breastfed. Fourteen (93%) infants were considered HIV uninfected; one was lost to follow-up. CONCLUSIONS: This group of adolescents seems to have sexual behavior similar to that of HIV-uninfected. Since this is an experimented antiretroviral population, new drugs may be necessary for adequate viral suppression to avoid HIV mother-to-child transmission. Follow-up of this third generation of HIV-exposed infants needs to be addressed within HIV adolescent care. PMID- 20827165 TI - Clinical presentation and prognosis of the 2009 H1N1 influenza A infection in HIV 1-infected patients: a Spanish multicenter study. AB - OBJECTIVE: The aim of the study was to describe the clinical presentation and prognosis in HIV-1-infected patients with hospital admission and pandemic influenza A 2009 (H1N1) confirmed, and compare this data with those of a general population. DESIGN: : This is a prospective study in nature. METHODS: All adult patients admitted to 13 hospitals in Spain with confirmed influenza A 2009(H1N1) virus infection by real-time reverse transcriptase PCR assay or culture from June 12 to November 10, 2009 were recruited and followed up until 1 month after discharge. In the HIV group risk factors for HIV infection, AIDS criteria, last CD4 cell count and viral load, and antiretroviral therapy and pneumococcal vaccines were collected. RESULTS: Five hundred and eighty-five patients were recruited, 26 with HIV-1 infection and 559 non-HIV. The HIV patients had a long term well controlled infection with a median CD4 cell count 503 cells/MUl and 84% with undetectable viral load, although more frequently they had chronic liver and chronic obstructive pulmonary disease. No significant differences were observed about reported symptoms and physical findings on hospital admission. About 50% of patients in both groups present radiological infiltrates and 30% present respiratory failures. Practically all the patients in both groups received influenza antiviral therapy and in each group 80% received antibacterial therapy. No differences were observed in clinical outcomes. CONCLUSION: In HIV patients, well controlled on HAART, the pandemic influenza virus AH1N1 had a similar clinical outcome and prognosis to that of non-HIV patients. PMID- 20827167 TI - Survival analysis in infectious disease research: describing events in time. AB - Survival analysis methods can be used in infectious disease research to describe the occurrence and timing of clinical or other events subject to censoring and truncation. Here, the survival, hazard, and cumulative hazard functions are defined and simple nonparametric estimators are provided using an illustrative example of survival after AIDS diagnosis. An understanding of these foundational measures is central for an informed use of the survival analysis methods common in infectious disease research. PMID- 20827166 TI - Maternal and nenonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance. AB - OBJECTIVE: Viral resistance occurs with a high frequency after single-dose nevirapine. We aimed to evaluate the tolerance and resistance profiles of a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) given to HIV-1-infected delivering women and their newborns. DESIGN: An open-label phase I/II trial in Cambodia, Cote d'Ivoire and South Africa. METHODS: HIV-1 infected pregnant women received zidovudine from the enrollment until the beginning of labor, when single-dose nevirapine and two tablets of TDF/FTC were given. One daily tablet of TDF/FTC was then administered for 7 days postpartum. All infants received single-dose nevirapine with single-dose TDF (13 mg/kg) and single-dose FTC (2 mg/kg) and 1 week of zidovudine. Mothers and infants were followed for 2 months. Serious adverse events, kinetic of maternal plasma HIV-1 RNA, pediatric HIV infection and genotypic resistance and viral subtype were assessed. RESULTS: Thirty-six HIV-1-infected pregnant women were enrolled: median age 28 years (interquartile range: 26-31 years), median CD4 cell count 462 cells/MUl (interquartile range: 376-632) and median HIV-1 RNA 3.7 log10 copies/ml (interquartile range: 2.95-4.11). Two infants had clinical serious adverse events, including one who died (neonatal sepsis). One transient grade 3 neutropenia and two grade 3/4 hyperbilirubinemia were also reported in neonates. One HIV pediatric in-utero infection was diagnosed (2.8%; 95% confidence interval 0-15.4%). Genotypic viral resistance to nevirapine was detected in one mother out of 34 (2.9%) at one month postpartum, but was also detectable at enrollment. CONCLUSION: The combination of TDF/FTC to delivering women and their neonates appears well tolerated and to minimize the occurrence of nevirapine viral resistance. PMID- 20827168 TI - Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: a randomized clinical trial. AB - OBJECTIVE: The Simplification of antiretroviral therapy with Tenofovir Emtricitabine or Abacavir-Lamivudine trial (STEAL) study randomized HIV participants to switch existing nucleoside reverse transcriptase inhibitors (NRTI) to either abacavir/lamivudine (ABC/3TC; n = 179) or tenofovir/emtricitabine (TDF/FTC; n = 178). An increased risk in cardiovascular disease (CVD) was reported (hazard ratio 7.7, P = 0.048) in ABC/3TC recipients compared with TDF/FTC in the STEAL study. The impact of ABC/3TC treatment on a range of CVD and inflammatory biomarkers was explored. DESIGN AND METHODS: Biomarkers were assessed at 0, 12, 24, and 48 weeks to examine: inflammation - high sensitive C-reactive protein, amyloid-P, amyloid-A, interleukin 6, interleukin 10, interferon alpha, and macrophage migration inhibitory factor; coagulation - D-dimer and fibrinogen; platelet function - soluble P-selectin; endothelial function - vascular cell adhesion molecule 1 and intercellular adhesion molecule 1; renal function - cystatin C. The primary endpoint was the difference between arms for mean change from baseline to week 12. Secondary analyses were differences between groups for mean change from baseline to weeks 24 and 48, time-weighted change from baseline to week 48, and changes to week 12 stratified by Framingham CVD risk score at baseline. RESULTS: Sera were available from 330 (92%) of 357 participants. At baseline, all biomarkers were similar between treatment arms and when stratified for baseline NRTI exposure. There were no significant differences between treatment arms in the mean change from baseline to week 12 for any biomarkers. No consistent between-group differences were seen in the secondary analyses that could suggest one pathophysiological pathway. CONCLUSION: A thorough examination of selected biomarkers associated with cardiovascular morbidity and mortality did not reveal associations with the use of ABC/3TC relative to use of TDF/FTC. PMID- 20827169 TI - Endothelial progenitor cell trafficking in human immunodeficiency virus-infected persons. AB - OBJECTIVE: Human immunodeficiency virus (HIV)-infected people exhibit a high incidence of vascular diseases. Since in the general population the high cardiovascular risk has been associated with an impaired endothelial cell function, we investigated circulating endothelial progenitor cells in HIV positive patients. DESIGN: We evaluated circulating colony-forming unit endothelial cell (CFU-EC) and endothelial colony-forming cell (ECFC) progenitors in 14 antiviral therapy-naive HIV-positive patients, in comparison with 15 normal controls. METHODS: CFU-EC and ECFC derived from peripheral blood mononuclear cells from HIV-infected and HIV-uninfected individuals were recovered and evaluated for HIV genome presence by PCR. Vascular endothelial growth factor (VEGF) and apolipoprotein B mRNA-editing enzyme catalytic polypeptide like (APOBEC) subunits expression were evaluated in infected colonies by real-time PCR. RESULTS: We found that circulating CFU-EC but not ECFC were significantly reduced in HIV-positive patients and that proviral HIV DNA was detectable only in CFU-EC but not in ECFC. Furthermore, the expression of APOBEC subunits was significantly lower in CFU-EC than in circulating monocytes. Accordingly, the CFU EC displayed a high content of proviral DNA copies, suggesting that these cells have a high sensitivity to the HIV infection. CONCLUSIONS: Although HIV does not affect the 'true endothelial progenitor' compartment, it infects and strongly depletes circulating endothelial progenitors with hematopoietic signature. We unravel a novel pathogenetic mechanism by which HIV infection might cause vascular diseases. PMID- 20827171 TI - Control of HIV replication in astrocytes by a family of highly conserved host proteins with a common Rev-interacting domain (Risp). AB - OBJECTIVE: In human astrocytes, restriction of HIV replication involves inhibition of HIV Rev activity. We previously identified a Rev-interacting human protein fragment (16.4.1) that can reduce Rev activity. The 16.4.1 sequence is contained in a group of highly similar host cell proteins, which we call the Risp family. Here we investigate whether the Risp family is connected to HIV replication in astrocytes. METHODS: Cell/tissue lysates were analyzed for Risp expression by western blot with various anti-Risp antibodies. The interaction of astrocytic Risp members with Rev was investigated by affinity chromatography. Astrocytes were transfected with expression plasmids containing cDNAs encoding full-length Risp or the isolated 16.4.1 region for Risp overexpression or with siRNAs designed for Risp knock-down. Rev activity was investigated with a Rev reporter assay. RNA levels were quantified by real-time RT-PCR, HIV Gag levels by p24ELISA. RESULTS: Expression of the Risp family was demonstrated in human brain tissues and astrocytes. Astrocytes were shown to produce Risp family members that interact with Rev. Production of HIV Gag proteins and Rev-dependent RNAs in persistently infected astrocytes increased upon Risp knock-down and decreased upon Risp overexpression. Risp knock-down increased Rev activity and raised proportions of Rev proteins in the nucleus of astrocytes. CONCLUSION: Our results link the Risp family to restriction of HIV production and inhibition of Rev activity in astrocytes. We conclude that the Risp family represents a novel family of host factors that can control HIV replication and may be important for the containment of HIV infection in brain reservoirs. PMID- 20827172 TI - Association of a patent foramen ovale with myocardial infarction and pulmonary emboli in a peripartum woman. AB - Peripartum myocardial infarction is uncommon but devastating in young women. Although it is generally associated with arterial dissection, pregnancy-induced hypercoagulable state can also be a major contributor. Association of patent foramen ovale (PFO) adds to this potential risk. A 29-year-old postpartum female presented with worsening chest pressure, shortness of breath and syncope. She was hypotensive and tachycardic. A ventilation perfusion imaging displayed high probability for pulmonary emboli. With elevated cardiac enzymes and echocardiogram showing wall motion abnormalities, patient underwent percutaneous coronary angioplasty for a midvessel thrombus in the left anterior descending artery. Further workup showed a thrombus straddling into the left atrium via a PFO and a deep venous thrombus in the right iliac vein. Hormonal changes in pregnancy are noted to place young women in a hypercoagulable state. Screening for PFO in this group of patients with timely intervention might prevent a major systemic event caused by paradoxical embolus. PMID- 20827170 TI - Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229. AB - BACKGROUND: Lipoatrophy is prevalent on thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). A pilot trial showed that uridine (NucleomaxX) increased limb fat. METHODS: A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week 48. The study was powered to detect 400-g difference between arms at week 48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences. RESULTS: The 165 participants were 91% men, 62% white; median age 49 years, CD4 cell count 506 cells/MUl, and limb fat 3037 g; 81% had HIV-1 RNA 50 copies/ml or less; 76% were on zidovudine (ZDV). Baseline characteristics were similar between groups. Only 59% completed 48 weeks of treatment; however, only three participants (one on uridine) discontinued due to toxicity (diarrhea). In intent to treat, there was no difference for changes in limb fat between treatments at week 24 or week 48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4 vs. -0.8%, P = 0.01) at week 24 but not at week 48 (1.8 vs. 3.8%, P = 0.93). Similar results were seen when limiting the analysis to patients with at least 80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial anthropometrics, fasting lipids, trunk fat, CD4 cell count, or HIV RNA. CONCLUSIONS: We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week 48 was not due to changes in adherence or reduction in sample size. Uridine was well tolerated and did not impair virologic control. PMID- 20827173 TI - A preclinical therapeutic schedule optimizing docetaxel plus estramustine administration in prostate cancer. AB - Androgen-dependent and castration-resistant prostate cancer (PC) is usually sensitive to docetaxel chemotherapy. Nevertheless, docetaxel resistance frequently appears after several cycles of treatment, raising the problem of salvage treatment for docetaxel-resistant PC patients. Although the combination of docetaxel and estramustine prolongs metastasis-free and overall survival of patients with androgen-independent PC, the use of this modality remains limited in elderly patients or patients with several comorbidities, especially vascular disease or gastrointestinal toxicity, because of unacceptable toxicity including venous thrombosis. The aims of this study were therefore (i) to evaluate the in vivo efficacy of estramustine combined with docetaxel since initial tumor growth and following the appearance of docetaxel resistance in the androgen-dependent human PC xenograft PAC120, and (ii) to evaluate the efficacy of estramustine in six human androgen-independent PC models derived from PAC120. In docetaxel resistant tumor-bearing mice, estramustine alone induced a TGD2 of 18 days, whereas the combination of docetaxel and estramustine induced a TGD2 of 50 days (P<0.05) with no significantly different overall survival of mice treated by docetaxel and estramustine since day 1 or since the onset of resistance to docetaxel. Among the six human androgen-independent tumors treated with estramustine alone, two highly sensitive models, two intermediate responding tumors, and two resistant models were observed. Altogether, these results suggest that estramustine should be combined with docetaxel in PC patients, but the use of this treatment could be limited, particularly in elderly patients, to docetaxel-resistant cases. PMID- 20827174 TI - Validation of the TRANSTEK TMB-988 wrist blood pressure monitor for home blood pressure monitoring according to the International protocol. AB - OBJECTIVE: To evaluate the accuracy of the TRANSTEK TMB-988 for home blood pressure monitoring according to the International Protocol of the Working Group on Blood Pressure Monitoring of the European Society of Hypertension. METHOD: Device evaluation was done in 33 participants (16 men and 17 women) with a mean+/ SD age of 58.2+/-11.8 years (range 32-80 years). Blood pressures [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were sequentially measured using mercury sphygmomanometer (by two trained observers) and alternately measured by the test device (by one supervisor). RESULTS: In phase 1, a total of 33, 42, and 44 of SBP differences and 40, 43 and 45 of DBP differences were within 5, 10 and 15 mmHg, respectively. In phase 2.1, 68, 93, and 97 of SBP differences and 75, 92 and 98 of DBP differences were within 5, 10 and 15 mmHg. The difference between the device and the mean of two observers was -0.6+/-5.0 mmHg for SBP and 0.2+/-5.8 mmHg for DBP, respectively. In phase 2.2, for SBP and DBP, respectively, 27 and 26 participants had at least two of their three differences with 5 mmHg, and there were two participants who did not have any difference within 5 mmHg for both SBP and DBP. CONCLUSION: The TRANSTEK TMB-988 successfully passed all the phases and is recommended for home use in adults. PMID- 20827175 TI - A new technique for simultaneous validation of two manual nonmercury auscultatory sphygmomanometers (A&D UM-101 and Accoson Greenlight 300) based on the International protocol. AB - INTRODUCTION: Auscultatory nonmercury manual devices seem good alternatives for the mercury sphygmomanometers in the clinic and for research settings, but individual internal validation of each device is time-consuming. The aim of this study was to validate a new technique capable of testing two devices simultaneously, based on the International protocol of the European Society of Hypertension. METHODS: The concept of the new technique is to measure blood pressure alternatively by two observers using a mercury sphygmomanometer and by two observers using the A&D UM-101 and Accoson Greenlight 300 devices, connected by Y-tube to obtain simultaneous readings with both nonmercury devices. Thirty three participants were enrolled (mean age 47.2+/-14.0 years). Nine sequential blood pressure measurements were performed for each participant. RESULTS: Both devices passed phase 1 using 15 participants. In phase 2.1 (n=33), on a maximum of 99 measurements, the Accoson device produced 81/95/99 measurements within 5/10/15 mmHg for systolic blood pressure (SBP) and 87/98/99 for diastolic blood pressure (DBP). The A&D device produced 86/96/99 for SBP and 94/99/99 for DBP. In phase 2.2 (n=33), 30 participants had at least 2 out of 3 SBP obtained with Accoson device within 5 mmHg of the mercury device, as compared with 29 of 33 participants with the A&D device. For DBP, this was 33 of 33 participants for both devices. CONCLUSION: Both the nonmercury devices passed the International protocol. The new technique of simultaneous device testing using a Y-tube represents a time saving application of the International protocol. PMID- 20827176 TI - Is very low dose hydrochlorothiazide combined with candesartan effective in uncontrolled hypertensive patients? AB - BACKGROUND: It is controversial whether the combination of very low dose hydrochlorothiazide (HCTZ) and an angiotensin receptor blocker (ARB) is effective in lowering blood pressure (BP). OBJECTIVES: The aim of this study was to evaluate the antihypertensive effect and the safety of an ARB and a very low dose of HCTZ in hypertensive patients. METHODS: This is an observational study. We examined 41 hypertensive patients who were treated with candesartan or another ARB at a standard dose but whose home BP was still greater than or equal to 135/85 mmHg. No patients were taking diuretics at baseline. Clinic and ambulatory BP (ABP) measurement and blood/urine analyses were performed at baseline and in the 2nd to 3rd month after treatment. All patients were either maintained at or switched to 8 mg candesartan, and then 6.25 mg HCTZ was added. Other concomitant drugs were not changed throughout the study period. RESULTS: A total of 41 individuals (age 62.7+/-12.7 years, 61% male) completed the protocol. The add-on treatment of HCTZ significantly lowered clinic and ABPs for both systolic and diastolic BP. The BP reduction was particularly pronounced in sleep BP. In addition, the rate of nondippers decreased from 48.8 to 36.6%, but the rates of dippers (39.0-43.9%) and extreme-dippers (12.2-19.5%) increased. Serum uric acid increased significantly, but the other metabolic measures were not changed by the combination therapy. CONCLUSION: Adding a very low dose of HCTZ (6.25 mg) to an ARB was very effective in lowering clinic and ABP, particularly for night-time BP. PMID- 20827177 TI - A unique presentation of 22q13 deletion syndrome: multicystic kidney, orofacial clefting, and Wilms' tumor. PMID- 20827178 TI - Epicutaneous/transcutaneous allergen-specific immunotherapy: rationale and clinical trials. AB - PURPOSE OF REVIEW: IgE-mediated allergies, such as allergic rhinoconjunctivitis and asthma, have become highly prevalent, today affecting up to 35% of the population in industrialized countries. Allergen immunotherapy (also called hyposensitization therapy, desensitization or allergen-specific immunotherapy), the administration of gradually increasing amounts of an allergen, either subcutaneously or via the sublingual or oral route is effective. However, only few allergy patients (<5%) choose immunotherapy, as treatment duration is over years and because allergen administrations are associated with local and in some cases even systemic allergic side effects due to allergen accidentally reaching the circulation. Therefore, ideally the allergen should be administered to a site that contains high numbers of potent antigen-presenting cells in order to enhance efficacy and shorten treatment duration, and ideally that site should also be nonvascularized in order to prevent both systemic distribution of the allergen and systemic allergic side effects. The epidermis, a nonvascularized multilayer epithelium that contains high numbers of potent antigen-presenting Langerhans cells, could therefore be an interesting administration route. RECENT FINDINGS: We have recently reintroduced transcutaneous or epicutaneous allergen-specific immunotherapy (EPIT) as treatment option for IgE-mediated allergies. This method was found efficacious and safe. Few applications of allergens using skin patches with a treatment duration of a few weeks were sufficient to achieve lasting relief. SUMMARY: This review gives an overview on the history, the rationale, and the mechanisms of transcutaneous/epicutaneous immunotherapy. PMID- 20827179 TI - Evolving focus on diastolic dysfunction in patients with coronary artery disease. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize recent studies of coronary artery disease (CAD) and diastolic dysfunction. RECENT FINDINGS: Myocardial ischemia slows ventricular relaxation and can impair ventricular distensibility resulting in diastolic dysfunction apparent as abnormal left ventricular (LV) filling dynamics that can be recognized noninvasively. As such, the development of diastolic dysfunction during stress testing may improve the recognition of CAD. The noninvasive recognition of diastolic dysfunction indicates a poor prognosis in patients with an acute coronary syndrome and chronic CAD. Patients with heart failure with preserved ejection fraction (HFpEF) frequently have CAD, and it may contribute to the heart failure. SUMMARY: Myocardial ischemia produces diastolic dysfunction. The evaluation of diastolic dysfunction has diagnostic and prognostic roles in the management of CAD. CAD is a frequent and important comorbidity of HFpEF. PMID- 20827180 TI - Evolving concepts on benefits and risks associated with therapeutic strategies to raise HDL. AB - PURPOSE OF REVIEW: To provide an update on high-density lipoprotein (HDL) biology and emerging new HDL-based therapies for athero-thrombosis. RECENT FINDINGS: Atherosclerotic cardiovascular disease remains a major public health threat despite a significant decline over the past three decades. Although current medical therapies, specifically low-density lipoprotein lowering with statins, reduce cardiovascular events by about 25-35%, a substantial residual risk remains, leading to a search for additional therapeutic interventions. In this regard, HDL has emerged as one important target because of epidemiologic evidence linking HDL levels inversely to cardiovascular events, known vascular protective actions of HDL and experimental and clinical research supporting athero protective actions of HDL. However, complexities of HDL composition, particle size, and metabolism have suggested that HDL functionality, and how HDL is increased, may be important determinants of its protective effects. SUMMARY: Thus the possibility that HDL modification could address the residual risk has brought renewed focus on an old HDL-raising drug, niacin, and a number of newer strategies to exploit the vascular benefits of HDL. PMID- 20827181 TI - Hospital safety climate surveys: measurement issues. AB - PURPOSE OF REVIEW: Organizational safety culture relates to behavioural norms in the workplace and is usually assessed by safety climate surveys. These can be a diagnostic indicator on the state of safety in a hospital. This review examines recent studies using staff surveys of hospital safety climate, focussing on measurement issues. RECENT FINDINGS: Four questionnaires (hospital survey on patient safety culture, safety attitudes questionnaire, patient safety climate in healthcare organizations, hospital safety climate scale), with acceptable psychometric properties, are now applied across countries and clinical settings. Comparisons for benchmarking must be made with caution in case of questionnaire modifications. Increasing attention is being paid to the unit and hospital level wherein distinct cultures may be located, as well as to associated measurement and study design issues. Predictive validity of safety climate is tested against safety behaviours/outcomes, with some relationships reported, although effects may be specific to professional groups/units. Few studies test the role of intervening variables that could influence the effect of climate on outcomes. SUMMARY: Hospital climate studies are becoming a key component of healthcare safety management systems. Large datasets have established more reliable instruments that allow a more focussed investigation of the role of culture in the improvement and maintenance of staff's safety perceptions within units, as well as within hospitals. PMID- 20827182 TI - Helicobacter pylori infection and current clinical areas of contention. AB - PURPOSE OF REVIEW: The indication for Helicobacter pylori (H. pylori) eradication has been extended to few extragastroduodenal diseases. Scientific rigor needs to be applied as the list of clinical manifestations potentially related to H. pylori has disproportionally grown to its scientific evidence. Some potential beneficial aspects of H. pylori in allergic diseases and in the context of obesity are critically addressed in this review. The main challenge, however, continues to be the prevention of gastric cancer by H. pylori eradication. Strategies for identification of individuals and populations at risk are reported as well. A final aspect is dedicated to novel treatment regimens for overcoming the increasing treatment failures with proton pump inhibitor-based triple standards. RECENT FINDINGS: H. pylori infection is associated with some extragastric diseases such as idiopathic thrombocytic purpura and iron deficiency anemia that benefit from eradication therapy. The inverse relation of H. pylori prevalence and the increase in allergies and obesity, as reported from epidemiological studies, has prompted research for elucidating potential underlying pathophysiological mechanisms. Strategies for gastric cancer prevention include serological screening, which allow adopting eradication therapy in individuals at high risk. New treatments for H. pylori include sequential, bismuth-based quadruple and nonbismuth-based quadruple therapies. SUMMARY: The main clinical challenge remains prevention of H. pylori-related diseases by effective treatment and screening procedures. PMID- 20827183 TI - Multidisciplinary management of gastric cancer. AB - PURPOSE OF REVIEW: The treatment of gastric cancer has been rapidly evolving with the emergence of new cytotoxic drugs and targeted biologic agents. The purpose of this review is to provide an update in the treatment of localized and metastatic gastric cancer. RECENT FINDINGS: Although the overall incidence of gastric cancer has been declining in the United States, the disease continues to be a devastating problem worldwide. Complete surgical resection offers the chance of cure for localized gastric cancer. However, local and distant recurrences are common. Adjuvant chemoradiation with 5-fluorouracil/leucovorin significantly improves disease-free survival and overall survival as demonstrated by the US Intergroup INT-116 study. Most recently, the UK Medical Research Council Adjuvant Gastric trial showed survival benefit with perioperative chemotherapy. Preoperative chemotherapy and chemoradiation have also been explored in several small randomized studies with encouraging results. However, this approach needs to be further confirmed in a large randomized phase III study. Finally, novel molecular targeting agents have been incorporated into the multimodality treatment and shown promising response rate and progression-free survival. SUMMARY: Gastric cancer remains one of the most clinically challenging cancers among all gastrointestinal malignancies. Mutimodality approach clearly offers survival benefit over surgery alone. In the United States, preoperative chemoradiation or postoperative adjuvant chemoradiation is widely practiced in major centers. PMID- 20827184 TI - Natural killer cells and tumor control. AB - PURPOSE OF REVIEW: After hematopoietic cell transplantation (HCT) donor-derived natural killer (NK) cells kill tumor cells to prevent relapse and mediate other beneficial clinical effects including control of infections without inducing graft-vs.-host disease (GVHD). Understanding the determinants of NK cell alloreactivity and function will support improvements in the design of HCT and adoptive cellular therapies. RECENT FINDINGS: Refinements to the model of NK cell education or licensing have been made which will inform strategies to develop functional alloreactive NK cells for therapeutic use. Differences in NK cell function have been shown to be dependent on the nature of the stimuli. Recent advances have been made in our understanding of the role of activating NK receptors on education and outcome after HCT. The use of adoptively transferred NK cells to treat hematopoietic malignancies has been expanding. New approaches to modulate target sensitivity to NK cell-mediated killing are under development. SUMMARY: NK cells play an important role in the therapeutic efficacy of HCT, with effects on control of infections, GVHD, engraftment and relapse prevention. Recent advances in our understanding of NK cell biology will support improvements in our ability to exploit NK cells to treat cancer. PMID- 20827185 TI - Red blood cell alloimmunization from an African perspective. AB - PURPOSE OF REVIEW: Red blood cell (RBC) alloimmunization occurs when individuals are exposed to erythrocytes that express blood group antigens different from their own. Consequences of alloimmunization include hemolytic disease of the fetus and newborn and hemolytic transfusion reactions, with potentially serious morbidity and mortality. Patients who formed antibodies showed a four to five times increased risk for additional alloantibodies upon further transfusion exposure and may be at increased risk for transfusion reactions. In view of the main transfusion indications in Africans (e.g. malaria and pregnancy), the lifetime risk of exposure to multiple transfusion events is substantial, stressing the need for information on RBC alloimmunization in African transfusion recipients. RECENT FINDINGS: Three cross-sectional studies on RBC alloimmunization from two African countries of Uganda and Malawi showed that 1-6% of transfused patients possessed clinically relevant RBC antibodies. SUMMARY: Regarding RBC compatibility testing for transfusion, ABO/D typing is mandatory in African settings but complete crossmatches are not routinely performed. Despite the limited data on posttransfusion alloimmunization, a complete crossmatch for patients with past transfusions could be recommended. However, more information on blood group distribution in Africans and RBC alloimmunization rates and specificity is needed to consider immunoprophylaxis for hemolytic disease, pretransfusion testing, and preventive strategies to avoid transfusion-induced alloimmunization. PMID- 20827186 TI - Defining genetic risk for graft-versus-host disease and mortality following allogeneic hematopoietic stem cell transplantation. AB - PURPOSE OF REVIEW: This review explores what is known about the genetics of hematopoietic stem cell transplantation (HCT) and how genetic polymorphism affects risk of graft-versus-host disease (GVHD) and mortality. RECENT FINDINGS: Genetic variation found across the human genome can impact HCT outcome by causing genetic disparity between patient and donor and modifying gene function. Single nucleotide polymorphism (SNP) and structural variation can result in mismatching for cellular peptides known as histocompatibility antigens. At least 25-30 polymorphic genes are known to encode functional histocompatibility antigens in mismatched individuals, but their individual contribution to clinical GVHD is unclear. HCT outcome may also be affected by polymorphism in donor or recipient. Association studies have implicated several genes associated with GVHD and mortality, however results have been inconsistent most likely due to limited sample size, and differences in racial diversity and clinical covariates. New technologies using DNA arrays genotyping for a million or more SNPs promise genome-wide discovery of HCT-associated genes, however adequate statistical power requires study populations of several thousand patient-donor pairs. SUMMARY: Available data offers strong preliminary support for the impact that genetic variation has on risk of GVHD and mortality following HCT. Definitive results however await future genome-wide studies of large multicenter HCT cohorts. PMID- 20827187 TI - High-dose cyclophosphamide for graft-versus-host disease prevention. AB - PURPOSE OF REVIEW: Administration of high-dose cyclophosphamide after transplantation inhibits both graft rejection and graft-versus-host disease (GvHD) in mouse models of allogeneic blood or marrow transplantation (alloBMT). This strategy has recently been adapted to human transplantation. RECENT FINDINGS: The safety and efficacy of high-dose posttransplantation cyclophosphamide, when given in combination with tacrolimus and mycophenolate mofetil, was first demonstrated after nonmyeloablative conditioning and allografting using human leukocyte antigen (HLA)-mismatched related donors. Further analysis shows that increasing HLA disparity does not worsen overall outcome. High-dose posttransplantation cyclophosphamide was also found to be effective as sole prophylaxis of acute and chronic GvHD after HLA-matched alloBMT. SUMMARY: Taking advantage of the differential susceptibility of proliferating, alloreactive T cells over nonproliferating, nonalloreactive T cells to high-dose cyclophosphamide, and owing to the drug's stem cell sparing effects, this novel strategy provides a unique opportunity to optimize GvHD prophylaxis after HLA-matched alloBMT and increase the use of HLA-mismatched related donors. Well tolerated and effective mismatched related alloBMT provides access to essentially everyone, such as patients with sickle cell anemia, in need of the procedure. PMID- 20827188 TI - Unrelated stem cell transplantation for patients with multiple myeloma. AB - PURPOSE OF REVIEW: The role of allogeneic stem cell transplantation (SCT) in treatment of myeloma patients is still controversial. Meanwhile, the numbers of unrelated SCT for hematological diseases in Europe are higher than for human leukocyte antigen (HLA)-identical sibling transplantations, but in multiple myeloma only 39% of the allogeneic transplantations are performed from unrelated donors and only a minority were done within prospective clinical trials. RECENT FINDINGS: The few published data of unrelated SCT in multiple myeloma reported a higher treatment-related mortality for standard myeloablative conditioning in comparison to reduced-intensity conditioning. Despite the heterogeneous patient selection in the trial, lower nonrelapse mortality and improved survival can be achieved by careful donor selection (10/10 HLA-alleles, male donor). Natural killer-alloreactivity might play a role, but conclusive data are lacking. Transplantation in more advanced or refractory patients is associated with an inferior outcome. The results of an unrelated SCT seem to be comparable to those of HLA-identical siblings, but a direct comparison is lacking so far. SUMMARY: Unrelated SCT in multiple myeloma is feasible, but prospective clinical trials using unrelated stem cell donors are urgently needed to define the role of an unrelated SCT in multiple myeloma in the era of novel agents. PMID- 20827189 TI - New molecular and surrogate biomarker-based tests in the diagnosis of bacterial and fungal infection in febrile neutropenic patients. AB - PURPOSE OF REVIEW: Prompt diagnosis of infection in febrile neutropenia hosts with hematological malignancy is essential in directing therapy. We highlight experience using modern molecular and biomarker-based methods to diagnose bacterial and fungal bloodstream infections and invasive aspergillosis in these patients. RECENT FINDINGS: Nucleic acid amplification-based strategies are used to detect and identify pathogens from blood cultures or from blood/clinical specimens; the latter are more likely to influence clinical management. Advances in DNA extraction include standardization of isolation of Aspergillus DNA from blood. Broad-range and/or multiplex PCR generally have greater clinical utility than pathogen-specific assays. However, Aspergillus-PCR assays are useful in confirming/excluding disease and monitoring high-risk patients for invasive aspergillosis. Commercial real-time PCR/peptide nucleic acid fluorescent in-situ hybridization systems, used as adjuncts to blood cultures, to detect bacteria and fungi in blood cultures (or blood), are as sensitive as culture and enable earlier institution of targeted therapy. Yet there are no data indicating that molecular detection of bacterial/fungal pathogens influences patient outcomes. Positive serum Aspergillus galactomannan and 1,3-beta-D-glucan tests are useful biomarkers in the diagnosis/screening of fungal infection, and have potential as measures of response to antifungal therapy. Serum procalcitonin levels can help differentiate infectious, from noninfectious, fever. Combined molecular and nonmolecular testing likely offers optimal diagnostic accuracy. SUMMARY: Numerous PCR-based and biomarker tools are available for the diagnosis and screening of infection in febrile neutropenia hosts. The optimal approach remains to be resolved by prospective studies examining the impact of one or more of tests on patient outcomes. PMID- 20827190 TI - Chronic aspergillus infections of the respiratory tract: diagnosis, management and antifungal resistance. AB - PURPOSE OF REVIEW: Chronic pulmonary aspergillosis (CPA) is a relatively rare, slowly progressive pulmonary syndrome due to Aspergillus spp. that requires specific knowledge in terms of disease entity, diagnosis, management and azole resistance. This review focuses on the recent understanding of CPA entity and the emergence of azole resistance in CPA. RECENT FINDINGS: Due to complexities related to patients' background and limited pathological evidence, the disease entity of CPA was incomprehensive and numerous names were previously used. The disease entities and nomenclature of subtypes of CPA have recently been proposed, though previous literature had grouped several different forms of CPA together. Recent advances in the methodology of susceptibility testing have indicated increasing azole resistance in Aspergillus spp. CPA is potentially involved in producing azole resistance and associated with poor response to azoles. SUMMARY: As there are few publications regarding CPA, there are still many unanswered questions. However, updating of disease entity will promote the clinical and basic research in this field. Moreover, the emergence of antifungal drug resistance of Aspergillus is becoming a major concern. Thus, more evidence and research regarding drug resistance are required to improve the outcome of CPA. PMID- 20827191 TI - Modified phospholipids as anti-inflammatory compounds. AB - PURPOSE OF REVIEW: Oxidized phospholipids (OxPLs) are abundantly found at sites of inflammation and are considered to play an active role in the modulation of the immune response. Whereas most studies attributed a proinflammatory role to OxPLs, recent studies demonstrate that some products of phospholipid oxidation may in fact exhibit anti-inflammatory properties. This study summarizes the proinflammatory and anti-inflammatory properties of OxPLs and sheds light on the therapeutic potential of OxPL derivatives or analogs for treatment of chronic inflammatory disorders. RECENT FINDINGS: OxPLs may inhibit activation of several Toll-like receptors and can epigenetically reduce the capacity of dendritic cells to function as mature, fully functional immunostimulatory cells. These data demonstrate that OxPLs can induce anti-inflammatory effects. Moreover, VB-201, an orally available synthetic phospholipid analog of the Lecinoxoid family, was found to attenuate inflammation in various preclinical animal models and is currently employed in a phase II clinical trial in psoriasis. SUMMARY: Chemical or biological modifications of phospholipids yield various products, some of which may exhibit anti-inflammatory properties. Identification of such species and generation of more stable/potent anti-inflammatory OxPL variants may represent a novel approach for the treatment of immune-mediated diseases such as psoriasis, atherosclerosis, multiple sclerosis and rheumatoid arthritis. PMID- 20827192 TI - Non-HDL C equals apolipoprotein B: except when it does not! AB - PURPOSE OF REVIEW: Whether national guidelines should incorporate apolipoprotein B (apoB) into clinical practice is one of the most important and contentious decisions they must face. Canada has chosen to do so. What Europe and America decide remains to be seen. RECENT FINDINGS: Obviously, the results of the major epidemiological studies and clinical trials should be major drivers of decisions about guidelines. Such evidence clearly indicates that apoB is superior to LDL C as a marker of risk and an index of the adequacy of therapy but is mixed as to whether apoB is superior to non-HDL C. In this paper, we demonstrate that the issue is more complicated than it appears: that even if non-HDL C and apoB are equal predictors of vascular risk (which we do not believe is the case), this is not due to the VLDL C that is included in non-HDL C but rather reflects the fact that non-HDL C is a 'backwards' measure of apoB - that is, non-HDL C provides an indirect estimate of LDL particle number. Moreover, equal predictive power in groups does not mean that markers have equal predictive power in individuals. We also list multiple clinical circumstances when non-HDL C and apoB lead to different clinical decisions because the real test of markers is when they differ, not when they agree. SUMMARY: Thus, our conclusion is that apoB and non HDL C are equal - except when they are not. Because apoB allows greater specificity of diagnosis and therapy, it re-establishes the primacy of individuals over groups as the objects of our study and our care and that may be its most important contribution to clinical lipidology. PMID- 20827193 TI - Weight loss: a neglected intervention in the management of chronic kidney disease. AB - PURPOSE OF REVIEW: Obesity is being increasingly implicated as an independent risk factor for the development of chronic kidney disease (CKD), raising the question whether reversing obesity can be utilized as a mainstay or an adjunct therapy for CKD and possibly for its prevention. The purpose of this review is to examine the impact of treatment of obesity on renal outcomes. RECENT FINDINGS: Many observations have pointed to improvement in renal parameters following weight loss. In fact, both surgical and nonsurgical approaches appear to be effective at reducing blood pressure and proteinuria. Weight loss has also been shown to lower glomerular filtration rate (GFR) in obese patients, not an insignificant benefit considering that intra-glomerular hypertension and the subsequent hyperfiltration in the setting of obesity might be a main driver for the development of CKD. SUMMARY: Urinary protein excretion, blood pressure, and GFR improve with surgical and nonsurgical weight loss interventions. Whether improvements in these surrogate outcomes after weight loss actually translate into a reduction in the risk of CKD or amelioration in the rate of progression of established CKD is yet to be determined. PMID- 20827194 TI - Blood pressure management in hemodialysis: what have we learned? AB - PURPOSE OF REVIEW: To review recent developments in the field of hypertension in hemodialysis patients. RECENT FINDINGS: Despite the fact that hypertension is the most common complication of end-stage kidney disease, no evidence-based blood pressure (BP) targets exist for hemodialysis patients. There is growing evidence that outcomes are better predicted by out-of-office BP values, such as home or ambulatory BP monitoring. Intradialytic hypertension is associated with increased risk of death or hospitalization, and is probably mediated by volume overload. BP management should focus on volume control: dry weight 'probing' is well tolerated and effective in lowering BP, as are other strategies that minimize expansion of the extracellular fluid volume, such as avoidance of hypernatric dialysate. We discuss each of these issues in our review. SUMMARY: Modest advances in the understanding of hypertension have occurred in the past 2 years. Clinical trials that focus on BP targets and treatment choices are essential to guide future practice. PMID- 20827195 TI - Management options for cast nephropathy in multiple myeloma. AB - PURPOSE OF REVIEW: This article reviews the relevance of the following areas to the contemporary management of cast nephropathy in multiple myeloma: immunoassays that quantify immunoglobulin free light chain (FLC), novel chemotherapy agents and high cut-off (protein-permeable) haemodialysis, which are under evaluation in patients with cast nephropathy and multiple myeloma. RECENT FINDINGS: Clonal serum FLC can be measured with high sensitivity and specificity and used to rapidly screen for cast nephropathy. A sustained decrease in serum FLC levels within 3 weeks of starting treatment is associated with renal recovery; novel chemotherapy agents can maximize this early response. Although plasma exchange does not produce clinical benefit, pilot studies of high cut-off haemodialysis show high efficacy for serum FLC removal. SUMMARY: If a patient with cast nephropathy and severe acute kidney injury remains dialysis-dependent, the prognosis is poor. A prompt diagnosis and commencement of effective chemotherapy is a critical determinant of renal recovery. A randomized controlled trial of high cut-off haemodialysis in patients with cast nephropathy, who all receive bortezomib-based chemotherapy, is underway. PMID- 20827196 TI - Preemptive transplantation and the transplant first initiative. AB - PURPOSE OF REVIEW: Preemptive kidney transplant (PKT) is the focus of a new initiative, 'Transplant First'. This initiative focuses on increasing patient transition to transplantation prior to the need for dialysis. This review will evaluate the benefits of PKT and means to accomplish this goal. RECENT FINDINGS: Outcomes data show PKT significantly improves long-term survival for the recipient and the allograft. In addition quality of life is improved. This also holds true for children and particularly for adolescents. In 2008, 5.7% of incident patients with end-stage renal disease were placed on the waiting list before beginning dialysis and 0.8% underwent preemptive living donor transplant before wait listing. If patients are evaluated before starting dialysis and are acceptable candidates, up to 40% will receive a preemptive transplant. Recent articles stress that patients want information from their physician; important impediments to PKT remain provider and patient education, insurance coverage and patient reluctance to ask for living donation. SUMMARY: Preemptive transplant saves lives. Increased education focused on providers, patients and entire communities is key, as is an increase in living donation. Furthermore, to maximize the impact of transplant first, increased living donor protections and immunosuppression coverage for the life of the allograft are essential. PMID- 20827197 TI - Traditional molecular markers and response to adjuvant endocrine or trastuzumab based therapies. AB - PURPOSE OF REVIEW: The accurate assessment of traditional molecular markers is essential to inform the choice of the adjuvant systemic treatments for patients with breast cancer. Extensive research efforts have been made to explore whether it is also possible to predict the actual response to the different therapeutic options based on the expression of these markers. RECENT FINDINGS: Endocrine responsiveness of breast cancer has been eventually defined according to the expression of estrogen receptors in at least 1% of invasive tumor cells. The quantitative evaluation of estrogen receptors, progesterone receptors (PgR) and Ki-67 labeling index may help in selecting patients with estrogen receptor positive and HER2-negative tumors who can be spared or may benefit from the addition of chemotherapy to endocrine therapy. Guideline recommendations for an optimal testing of estrogen receptors and PgR have been issued to assist pathologists in the accurate assessment of these markers. Progress has also been made in the identification of candidate patients to HER2-targeted therapies and in the prediction of response to trastuzumab. SUMMARY: Traditional molecular markers play a major role in the selection of candidate patients to systemic interventions, but they are of limited value in predicting their actual response to the different treatments, especially when the markers are evaluated individually. PMID- 20827198 TI - Obsessive-compulsive spectrum disorders: still in search of the concept-affirming boundaries. AB - PURPOSE OF REVIEW: Controversy exists about the diagnostic grouping of obsessive compulsive spectrum disorders (OCSDs) - conditions that are to some extent related to obsessive-compulsive disorder (OCD). This review will re-examine OCSDs in light of the currently available evidence. RECENT FINDINGS: It appears that OCSDs will not constitute a separate nosological group and, if this term is accepted, OCSDs may be grouped together with the anxiety disorders. Much needs to be done to refine the criteria for membership in the OCSDs. In contrast to previous proposals, only a few disorders may be included in the spectrum. The most likely candidates for membership are body dysmorphic disorder and hoarding disorder, if the latter becomes an independent condition. Mixed, but relatively strong, support for inclusion also exists for Tourette's disorder and trichotillomania. SUMMARY: The concept of OCSDs is largely a product of an unbridled nosographical activity, resulting from a selective focus on the similar clinical features and an oversight of the important differences. While the links between some of the putative OCSDs seem important, the question remains as to whether the introduction of the spectrum to a diagnostic and classification system would significantly improve our understanding of these links. PMID- 20827199 TI - Internet-delivered psychotherapy for depression in adults. AB - PURPOSE OF REVIEW: The rapidly growing number of published research papers attests to the increasing interest in Internet-delivered psychotherapy (iPT). The present article reviews the current status of iPT for the treatment of adults with symptoms of depression. RECENT FINDINGS: Randomized controlled trials have confirmed the efficacy of guided iPT in treating people with diagnosed or elevated symptoms of depression with equivalent results obtained by programs based on cognitive behavioural or problem solving models. With guidance, effect sizes are comparable to those obtained in face-to-face psychotherapy and low intensity interventions are as effective as those with higher levels of therapist contact. On current evidence, entirely self-guided programs appear to have fewer benefits, but deliver tangible benefits to completers. SUMMARY: Recent studies indicate the utility of iPT. Large-scale trials are needed to evaluate optimal strategies for disseminating iPT. Future studies should independently replicate findings and efforts are required to educate patients and health professionals about iPT. PMID- 20827200 TI - Clinically amyopathic dermatomyositis. AB - PURPOSE OF REVIEW: Clinically amyopathic dermatomyositis (CADM) is a unique subset of dermatomyositis, with typical skin manifestations of dermatomyositis but little or no evidence of myositis. This review focuses on updates on epidemiology, clinical manifestations, and autoantibody profiles in patients with CADM. RECENT FINDINGS: A population-based survey of dermatomyositis conducted in the United States revealed that overall age-adjusted and sex-adjusted incidence of CADM was 2.08 per 1 million persons. CADM consisted of approximately 20% of dermatomyositis. In general, late-onset myositis was infrequent. There was no apparent difference in frequency of internal malignancy or interstitial lung disease between CADM and classic dermatomyositis. However, anecdotal and retrospective case reports from eastern Asia showed a relatively high incidence of rapidly progressive interstitial lung disease, which is often fatal, in patients with adult-onset and juvenile-onset CADM. Finally, RNA helicase encoded by melanoma differentiation-associated gene 5 was identified as an autoantigen recognized by anti-CADM-140 antibody, which is associated with CADM and rapidly progressive interstitial lung disease. SUMMARY: CADM is a distinct clinical entity with unique clinical features and autoantibody profiles different from classic dermatomyositis. PMID- 20827201 TI - Interstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls. AB - PURPOSE OF REVIEW: To present the latest findings regarding interstitial lung disease (ILD) in idiopathic inflammatory myopathies, focusing on the phenotype of ILD and auto-antibodies, pathogenesis and treatment. RECENT FINDINGS: Interstitial lung disease is a common manifestation of myositis and different phenotypes of ILD associate with various clinical or serological phenotypes. Thus, antisynthetase antibodies are strongly associated with ILD, especially for non-Jo-1 (anti-PL-7 and anti-PL-12) where the association approaches 90-100%. A rare form of ILD with a very poor prognosis, acute and rapidly progressive lung disease, is strongly associated with clinically amyopathic dermatomyositis (CADM) and a novel - anti-CADM-140 auto-antibody. A combination of anti-Jo-1 and anti SSA/Ro antibodies is another marker of severe pulmonary involvement. The use of immunossuppresive therapy in myositis-associated ILD is based on clinical experience, and a few new case reports indicate beneficial effect of tacrolimus in antisynthetase syndrome and rituximab in resistant or acute forms of lung disease but further studies are needed. SUMMARY: Interstitial lung disease is a common manifestation of myositis. Auto-antibody profile seems to determine the frequency, course and severity of lung disease. New biological therapies such as rituximab show promising results in resistant and acute lung disease but controlled trials are needed. PMID- 20827202 TI - Targeting tyrosine kinases: a novel therapeutic strategy for systemic sclerosis. AB - PURPOSE OF REVIEW: This article reviews the current evidence and rationale for the use of tyrosine kinase inhibitors as potential therapeutic interventions for systemic sclerosis. RECENT FINDINGS: The signaling cascades of the profibrotic cytokines transforming growth factor-beta and platelet-derived growth factor utilize tyrosine kinases. Preclinical studies have suggested potential efficacy of tyrosine kinase inhibitors in fibrosing disorders. Imatinib, dasatinib, and nilotinib treatment of scleroderma and normal fibroblasts leads to decreased production of extracellular matrix proteins in an in-vitro model. Several murine models demonstrate decreased skin thickening with tyrosine kinase inhibition. Case reports and one open-label trial suggest potential efficacy of imatinib in diffuse systemic sclerosis, although adverse events are common. One controlled and several uncontrolled trials are ongoing, and their results will better define the role of tyrosine kinase inhibition in the treatment of this disorder. SUMMARY: Tyrosine kinase inhibition as a potential strategy for the treatment of systemic sclerosis has been gaining more widespread interest based on preclinical data and open-label experiences. Large, multicenter, double-blind, randomized controlled trials are needed to assess the efficacy and safety of this approach in this complex disease. PMID- 20827203 TI - Mitochondrial pathology in immune and inflammatory myopathies. AB - PURPOSE OF REVIEW: Acquired immune and inflammatory myopathies (IIMs) are typically subdivided into dermatomyositis, polymyositis and inclusion body myositis. However, many types of IIMs do not fit well into this scheme. Several myopathologic and autoantibody features of IIMs, that are not considered in standard classifications, are useful for defining individual disorders. We will review one set of myopathologic features that occur in some IIMs, mitochondrial abnormalities, and consider its diagnostic, treatment-related and pathogenic implications. RECENT FINDINGS: Myopathologic changes that indicate mitochondrial disorders are often widespread in regions of muscle fiber abnormality in dermatomyositis. They distinguish dermatomyositis with vascular pathology from other inflammatory myopathies with skin changes that have prominent perimysial connective tissue lesions, but no mitochondrial, abnormalities. Mitochondrial abnormalities in scattered muscle fibers occur in sporadic inclusion body myositis and clinically similar disorders. Mitochondrial abnormalities in scattered nonnecrotic muscle fibers in IIM biopsies predict a poor response to immunosuppression. SUMMARY: Muscle biopsy, including evaluation of mitochondrial stains, is important for the correct diagnosis of inflammatory myopathies. By recognizing the full range of distinctive myopathologic changes in the diverse group of IIMs, the clinician can improve diagnostic accuracy and apply appropriate treatment. PMID- 20827204 TI - Malignancy and myositis: novel autoantibodies and new insights. AB - PURPOSE OF REVIEW: Currently available data support the idea that inflammatory myopathies, particularly dermatomyositis, are paraneoplastic diseases. Cancer screening is usually recommended in patients with these conditions, but there is no consensus regarding how and how often screening should be performed. This review will address recent advances in our understanding of the relationship between cancer and myositis and describe new data regarding the best approach for cancer screening in myositis patients. RECENT FINDINGS: A newly described autoantibody to a 155-kDa nuclear protein, identified as transcription intermediary factor 1-gamma (TIF1-gamma), has proven useful for cancer screening in patients with dermatomyositis. Occult tumor detection by PET/computed tomography (PET/CT) seems to be a good alternative to broad conventional screening. A combination of both methods, detection of autoantibodies against p155 and PET/CT study, may be the best approach to ascertain the presence of occult malignancy in patients with dermatomyositis. SUMMARY: Advances in immunology and imaging techniques are increasing the accuracy of occult malignant cancer detection in dermatomyositis patients. Nevertheless, the diagnosis of cancer in this population remains elusive in some cases. Further investigation is needed to improve our knowledge of the link between myositis and cancer. PMID- 20827205 TI - Statin myopathy: a review of recent progress. AB - PURPOSE OF REVIEW: Statins are commonly prescribed lipid-lowering medications that significantly reduce the risk of cardiovascular events. However, they can have myotoxic effects ranging in severity from myalgias to rhabdomyolysis. This review focuses on recent progress in defining the clinical features and mechanism(s) of statin-induced myopathy. RECENT FINDINGS: Although severe myotoxicity is a very rare event, most recent studies suggest that myalgias and relatively low-level muscle damage may occur in a substantial number of patients treated with statins. Those taking medications that increase serum statin concentrations are at greater risk for severe muscle side-effects, as are those with a polymorphism in the gene encoding a hepatic statin transporter. Although the mechanism of muscle damage remains to be fully elucidated, a number of in vitro studies suggest that inhibition of protein prenylation may underlie the myotoxic effects of statins, possibly through the induction of pro-apoptotic pathways. In addition, recent reports have indicated that statins may trigger an immune-mediated necrotizing myopathy with many features of polymyositis. SUMMARY: Severe myopathy is a rare and generally self-limited side-effect of statin medications. However, myalgias are much more common and limit their use in many patients. Recent evidence also suggests that statins are associated with the development of a unique form of immune-mediated myopathy. Awareness of this newly described entity is important, as these patients may require immunosuppressive therapy. PMID- 20827206 TI - Novel therapeutic approaches for inclusion body myositis. AB - PURPOSE OF REVIEW: This review will highlight recent advances in developing strategies to accelerate muscle regeneration and to slow muscle degeneration in myositis, focusing primarily on inclusion body myositis (IBM). RECENT FINDINGS: Therapies for accelerating muscle regeneration, primarily through inhibition of myostatin, have shown promise in the laboratory and are now entering clinical trials. Recent studies have implicated autophagy, a key cellular process involved in clearance of ubiquitinated aggregates, in the pathogenesis of familial and sporadic inclusion body myositis (sIBM). IBM has joined a growing list of diseases known as TDP-43 proteinopathies, in which this protein becomes mislocalized to the cytoplasm; however, it is unclear whether these protein aggregates or others are pathogenic in this disease. SUMMARY: New discoveries of biomarkers in sIBM and new insights into the pathogenesis of familial IBM are opening novel therapeutic pathways for these disorders. In particular, drugs that stimulate autophagy, already in development for cancer and neurodegenerative diseases, are candidates for clinical trials. These disease-specific therapies combined with novel therapies to accelerate muscle regeneration hold promise for future therapy for this devastating disease. PMID- 20827208 TI - Management of anterior urethral stricture: an evidence-based approach. AB - PURPOSE OF REVIEW: To provide a review of the latest evidence on the management of anterior urethral strictures. RECENT FINDINGS: A continuing role exists for urethrotomy or dilatation in the management of urethral strictures as first-line therapy in selected patients. In those patients with bulbar strictures who fail or are not suitable for these procedures, an anastomotic urethroplasty, and if not feasible a substitution urethroplasty using either a flap or oral mucosal graft either by a dorsal, lateral or ventral onlay approach should be considered. For penile strictures, a ventral onlay procedure using skin can be considered except in cases of lichen sclerosis when an onlay procedure utilizing oral mucosa provides the best results using either a one-stage or two-stage approach. SUMMARY: Various options exist for the management of anterior urethral stricture disease. The 'reconstructive ladder' has served to guide urologists over the years. The selection of the correct procedure should be patient-centred and based on the latest evidence. PMID- 20827207 TI - IFN-gamma and IL-17: the two faces of T-cell pathology in giant cell arteritis. AB - PURPOSE OF REVIEW: Granuloma formation in giant cell arteritis (GCA) emphasizes the role of adaptive immunity and highlights the role of antigen-specific T cells. Recent data demonstrate that at least two separate lineages of CD4 T cells participate in vascular inflammation, providing an important clue that multiple disease instigators may initiate pathogenic immunity. RECENT FINDING: IFN-gamma producing Th1 cells and IL-17-producing Th17 cells have been implicated in GCA. Patients with biopsy-positive GCA underwent two consecutive temporal artery biopsies, one prior to therapy and one while on corticosteroids. In untreated patients, Th1 and Th17 cells co-existed in the vascular lesions. Following therapy, Th17 cells were essentially lost, whereas Th1 cells persisted almost unaffected. In the peripheral blood of untreated patients Th17 frequencies were increased eight-fold, but normalized with therapy. Blood Th1 cells were doubled in frequency, independent of therapy. Corticosteroids functioned by selectively suppressing IL-1beta, IL-6 and IL-23-releasing antigen-presenting cells (APCs), disrupting induction of Th17 cells. SUMMARY: At least two distinct CD4 T-cell subsets promote vascular inflammation in GCA. In early disease, APCs promote differentiation of Th17 as well as Th1 cells. Chronic disease is characterized by persistent Th1-inducing signals, independent of IL-17-mediated inflammation. More than one disease instigator may trigger APCs to induce multiple T-cell lineages. Cocktails of therapies will be needed for appropriate disease control. PMID- 20827209 TI - An update on surgery for pelvic organ prolapse. AB - PURPOSE OF REVIEW: The surgical management of pelvic organ prolapse continues to evolve. Recent advancements in techniques and materials have increased the available treatments for pelvic organ prolapse. A current understanding of the benefits and limitations offered by recently introduced materials and techniques is essential to their proper application. RECENT FINDINGS: Current surgical therapies for prolapse now include augmentation with synthetic mesh, which may also be utilized as part of a 'kit'. In addition, both laparoscopic and robot assisted techniques have been developed to address apical vaginal prolapse. Both the use of synthetic mesh and laparoscopic and robotic techniques should continue to be subjected to appropriate scrutiny to assess their long-term success and complications. SUMMARY: While the introduction of novel approaches to pelvic organ prolapse provide further options when considering appropriate therapy, the application of these materials and techniques should be examined with scientific rigor and should demonstrate both a significant benefit and low morbidity prior to widespread adoption. With continued research, we hopefully will be able to identify the ideal approaches and repairs to achieve optimal patient outcomes. PMID- 20827210 TI - Xenon anaesthesia for spinal cord tumour excision in a patient with dilated cardiomyopathy. PMID- 20827211 TI - In-vitro contracture testing for susceptibility to malignant hyperthermia: can halothane be replaced? AB - BACKGROUND: Malignant hyperthermia is a potentially lethal inherited hypermetabolic syndrome that develops in susceptible individuals following administration of depolarising neuromuscular relaxants or volatile anaesthetics. Genetic analysis can only confirm a diagnosis of malignant hyperthermia in about 70%, and in the remainder an in-vitro contracture test, with halothane and caffeine, on muscle obtained from open muscle biopsy is required to establish the diagnosis. As the licence for clinical use of halothane expired in 2005, its continuing availability is in doubt. More modern volatile anaesthetics such as enflurane, isoflurane, desflurane and sevoflurane are less potent triggers of malignant hyperthermia in humans and pigs. The aim of this study was to investigate whether these agents can be considered possible substitutes for halothane in a modified in-vitro contracture test. METHOD: With institutional review board approval and prior written consent, muscle bundles of 30 patients with a personal or family history of malignant hyperthermia were investigated. Of these, 13 were diagnosed malignant hyperthermia susceptible and 17 nonsusceptible. Surplus muscle was tested with increasing concentrations of enflurane, isoflurane, desflurane and sevoflurane. RESULTS: There were no differences in weight, length or predrug tension of the muscle bundles. At increasing concentration, all volatile anaesthetics except sevoflurane induced significantly greater contractures in malignant hyperthermia susceptible compared to malignant hyperthermia nonsusceptible muscle. In malignant hyperthermia susceptible muscle bundles, halothane led to significantly higher contractures compared to the other investigated substances. CONCLUSION: Halothane was the strongest discriminator for malignant hyperthermia in the in-vitro contracture tests. It remains the ideal substance for diagnostic testing and cannot simply be replaced by other agents in this test. PMID- 20827212 TI - Pre-operative evaluation using therapeutic intensity scoring. AB - BACKGROUND AND OBJECTIVE: A Pre-operative Therapeutic Intensity Score (P-TIS) was developed to quantify intensity of pre-operative care. Its association with post operative ICU admission was explored. METHODS: P-TIS assigns 1-4 points to therapeutic interventions and diagnostic procedures based on care intensity. P TIS was evaluated using elective (n = 716) and emergency (n = 289) surgery patients entering the post-anaesthesia care unit (PACU) or directly admitted to ICU. RESULTS: P-TIS has chronic (interventions >48 h before surgery, e.g. chronic dialysis therapy: 3 points, oral antibiotics: 1 point) and acute (interventions within 48 h of surgery, e.g. intra-aortic balloon: 4 points, urinary catheter insertion: 1 point) components. Acute P-TIS provided quantitative information, not provided by other methods, about care intensity immediately before surgery. High acute P-TIS were observed in elective patients with high chronic P-TIS and ASA classifications (3 and 4) and emergency surgery and trauma. The higher acute P-TIS, the more likely emergency patients are to receive post-operative ICU rather than intermediate or routine floor care (odds ratio 1.18, P < 0.001). Adding surgical complexity improved acute P-TIS's ability to predict post operative ICU care in elective patients. CONCLUSION: P-TIS quantifies the intensity of chronic and acute pre-operative care. Acute P-TIS predicted receipt of post-operative ICU care, especially in emergency surgery. PMID- 20827213 TI - Effect of fasting during Ramadan on serum lithium level and mental state in bipolar affective disorder. AB - The Muslims fast every year during the month of Ramadan. A fasting day can last 12-17 h. The effects of fasting on serum lithium levels and the mood changes in patients suffering from bipolar affective disorder during Ramadan are not well studied. We aimed to compare the serum lithium levels, side effects, toxicity and mental state in patients suffering from bipolar affective disorder and on prophylactic lithium therapy before, during and after Ramadan. Sixty-two patients meeting the International Classification of Diseases, Tenth Revision, Research Diagnostic Criteria of bipolar affective disorder receiving lithium treatment for prophylaxis were recruited in a tertiary care teaching hospital in Peshawar, Pakistan. Serum lithium, electrolytes, Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were assessed at three points, 1 week before Ramadan, midRamadan and 1 week after Ramadan. The side effects and toxicity were measured by a symptoms and signs checklist. There was no significant difference in mean serum lithium levels at three time points (preRamadan=0.45+/-0.21, midRamadan=0.51+/-0.20 and postRamadan=0.44+/-0.23 milli equivalents/litre, P=0.116). The scores on HDRS and YMRS showed significant decrease during Ramadan (F=34.12, P=0.00, for HDRS and F=15.6, P=0.000 for YMRS). The side effects and toxicity also did not differ significantly at three points. In conclusion, the patients who have stable mental state and lithium levels before Ramadan can be maintained on lithium during Ramadan. Fasting in an average temperature of 28 degrees C for up to 12 h per day did not result in elevated serum lithium levels or more side effects and did not have adverse effects on mental state of patients suffering from bipolar affective disorder. PMID- 20827214 TI - Psychometric properties of the Fatigue Severity Scale in polio survivors. AB - The objective of this study was to evaluate by means of classical test theory and Rasch analysis the scaling characteristics and psychometric properties of the Fatigue Severity Scale (FSS) in polio survivors. A questionnaire,consisting of five general questions (sex, age, age at time of acute polio, sequelae of polio, and new symptoms), the FSS, and three questions from the Visual Analog Scale questions on fatigue was sent to all 196 polio survivors at the Institute for Rehabilitation in Ljubljana. Responses were assessed in terms of Cronbach's a, item-to-total correlation, factor analysis, and Rasch analysis. Of the128 (65.3%) valid questionnaires returned, those presenting no missing values were used for subsequent analyses (n = 117). The FSS showed good internal consistency: Cronbach's a was greater than 0.95,item-to-total correlation ranged from 0.68 to 0.88. A reduction from seven to three rating categories was necessary to comply with criteria for correct category function. Item difficulty estimates spanned from - 0.91to + 1.09 logits. No item bias was found for sex and age.The internal consistency of FSS was high and its item separation reliability good, indicating a satisfactory replicability of item placement in other samples. In conclusion, Rasch analysis enabled us to confirm the validity of FSS (in its 8-item version, without item 1) as a measure of the severity and impact of physical symptoms of fatigue in polio survivors, so providing a useful starting point for further studies aimed at examining additional psychometric aspects and confirming the appropriateness of the simplification of its rating categories. PMID- 20827215 TI - Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. AB - BACKGROUND: The effects of immunologic and virologic factors on acute myocardial infarction (AMI) rates in patients with HIV are unclear. METHODS: HIV-infected patients in a US healthcare system were assessed for AMI. RESULTS: Of 6517 patients with HIV, 273 (4.2%) had an AMI. In a model adjusting for cardiovascular risk factors, antiretroviral medications, and HIV parameters, CD4 count less than 200/mm (odds ratio, 1.74; 95% confidence interval, 1.07 to 2.81; P = 0.02) predicted AMI. Increased HIV viral load was associated with AMI accounting for cardiovascular disease risk factors and antiretroviral medications but was not significant when CD4 count was considered. CONCLUSIONS: Immunologic control appears to be the most important HIV-related factor associated with AMI. PMID- 20827216 TI - Treatment interruption in a primary care antiretroviral therapy program in South Africa: cohort analysis of trends and risk factors. AB - OBJECTIVE: To investigate antiretroviral treatment (ART) interruption in a long term treatment cohort in South Africa. METHODS: All adults accessing ART between 2004 and 2009 were included in this analysis. Defaulting was defined as having stopped all ART drugs for more than 30 days. Treatment interrupters were patients who defaulted and returned to care during the study, whereas loss to follow-up was defined as defaulting and not returning to care. Kaplan-Meier estimates and Poisson regression models were used to analyze rates and determinants of defaulting therapy and of treatment resumption. RESULTS: Overall rate of defaulting treatment was 12.8 per 100 person-years (95% confidence interval: 11.4 to 14.4). Risk factors for defaulting were male gender, high baseline CD4 count, recency of ART initiation, and time on ART. The probability of resuming therapy within 3 years of defaulting therapy was 42% (event rate = 21.4 per 100 person years). Factors associated with restarting treatment were female gender, older age, and time since defaulting. CONCLUSIONS: Defaulting treatment need not be an irreversible event. Interventions to increase retention in care should target men, less immunocompromised patients, and patients during the first 6 months of treatment. Resumption of treatment is most likely within the first year of interrupting therapy. PMID- 20827217 TI - Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors. AB - OBJECTIVE: Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. METHODS: Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. RESULTS: Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. CONCLUSIONS: Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated. PMID- 20827218 TI - HIV intervention for providers study: a randomized controlled trial of a clinician-delivered HIV risk-reduction intervention for HIV-positive people. AB - Clinician-delivered prevention interventions offer an opportunity to integrate risk-reduction counseling as a routine part of medical care. The HIV Intervention for Providers study, a randomized controlled trial, developed and tested a medical provider HIV prevention training intervention in 4 northern California HIV care clinics. Providers were assigned to either the intervention or control condition (usual care). The intervention arm received a 4-hour training on assessing sexual risk behavior with HIV-positive patients and delivering risk reduction-oriented prevention messages to patients who reported risk behaviors with HIV-uninfected or unknown-status partners. To compare the efficacy of the intervention versus control on transmission risk behavior, 386 patients of the randomized providers were enrolled. Over six-months of follow-up, patients whose providers were assigned the intervention reported a relative increase in provider patient discussions of safer sex (OR = 1.49; 95% CI = 1.06 to 2.09), assessment of sexual activity (OR = 1.60; 95% CI = 1.05 to 2.45), and a significant decrease in the number of sexual partners (OR = 0.49, 95% CI = 0.26 to 0.92). These findings show that a brief intervention to train HIV providers to identify risk and provide a prevention message results in increased prevention conversations and significantly reduced the mean number of sexual partners reported by HIV positive patients. PMID- 20827219 TI - Right coronary artery originating from the left anterior descending artery. PMID- 20827220 TI - Right atrium compression by a renal cyst: a tomographic diagnosis. PMID- 20827221 TI - Dietary protein and risk of hypertension in a Dutch older population: the Rotterdam study. AB - BACKGROUND: Several observational studies suggest an inverse association of protein with blood pressure (BP). However, little is known about the role of dietary protein from specific sources in BP. METHOD: We examined the relation between several types of dietary protein (total, plant, animal, dairy, meat, grain, fish, soy, and nut) and incident hypertension in 2241 participants from the Rotterdam Study, aged at least 55 years, who were free of hypertension at baseline. Hazard ratios, with 95% confidence intervals (CIs), for incident hypertension during 6 years of follow-up were obtained per standard deviation (SD) of energy-adjusted intake of protein. Hazard ratios were adjusted for age, sex, body mass index (BMI), baseline systolic blood pressure (SBP) smoking, educational level, alcohol, intake of carbohydrates, other nutrients, and other types of protein (if applicable). We conducted stratified analyses by age (cut off 70 years), sex, and BMI (cut-off 25 kg/m). RESULTS: The risk of hypertension in the total cohort (1113 cases) was not related to intake of total protein or types of protein (all hazard ratios ~1.00 per SD). Sex and BMI did not significantly modify the associations of dietary protein with hypertension. In 559 participants aged at least 70 years, the intake of animal protein was positively related to risk of hypertension (hazard ratio 1.37 per SD, 95% CI 1.09 1.72). For participants aged below 70 years no association was found (hazard ratio 0.92, 95% CI 0.81-1.06). CONCLUSION: Total dietary protein or types of protein are not related to incident hypertension in this older population. In the more aged, however, high intake of animal protein may increase the risk of hypertension, which warrants further investigation. PMID- 20827222 TI - Magnetic resonance imaging of hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a genetically inherited disease with a wide spectrum of phenotypic presentations. It is crucial to establish an early diagnosis and identify patients at high risk for sudden death. Cardiac magnetic resonance can provide subclinical diagnosis, quantification of severity of known disease, risk stratification, and assessment of response to therapy for HCM. This pictorial review summarizes the main magnetic resonance appearances of HCM and its differential diagnosis. PMID- 20827223 TI - Downregulation of miR-125b in metastatic cutaneous malignant melanoma. AB - This study aimed to identify microRNA species involved in the earliest metastatic event in cutaneous malignant melanoma (MM). Samples from 28 patients with MM [stage T2 (tumor), M0 (distant metastasis)] were grouped by the presence of micrometastasis in the sentinel lymph nodes (N0/N1). Melanoma cells were harvested from primary, cutaneous MM tumors by laser-capture microdissection, and microRNA expression profiles were obtained by the microarray technique. Results were validated by quantitative reverse transcription PCR. We found that miR-125b was downregulated in the primary cutaneous melanomas that produced early metastases (T2, N1, M0) compared with the sentinel lymph node-negative (T2, N0, M0) melanomas. MiR-125b has earlier been found to be downregulated in other tumor types and in atypic naevi compared with the common acquired naevi. In conclusion, miR-125b may be involved in an early progression of cutaneous MM. PMID- 20827224 TI - Centrally administered nesfatin-1 inhibits feeding behaviour and gastroduodenal motility in mice. AB - Nesfatin-1 was recently identified as a peptide with anorexigenic effects that is localized in the hypothalamus and adipocytes. Not much is known about the effect of nesfatin-1 on gut motility. Food intake was measured after intracerebroventricular administration of nesfatin-1 in food-deprived mice. Antral and duodenal motility was assessed by using a manometric method in conscious fed mice. We found that centrally administered nesfatin-1 decreased food intake and inhibited gastroduodenal motility in mice. These results suggest that nesfatin-1 influences gut motility and feeding behaviour. PMID- 20827225 TI - A novel way to make transient-VEPs a better predictor of human binocular integration. AB - To establish an electrophysiological marker of binocular vision, visual evoked potentials were recorded in normal observers for whom interocular refraction differences were induced with converging lenses under five dioptre conditions. Patterns of binocular interaction were categorized (facilitation, averaging or suppression) by comparing monocular and binocular responses. Quantitative and continuous indexes of binocular integration were also calculated (binocular response minus the sum of monocular responses). Results indicated that patterns of interaction were not optimal to account for stereoscopic performance. The latter was, however, best explained by binocular integration indexes. This study shows evidence of predicting binocular vision based on a novel index that allows continuous quantification of binocular transient-visual evoked potential responses. PMID- 20827227 TI - Comparison of 18F-FDG and 11C-choline PET/CT for detecting recurrences in patients with nonsquamous cell head and neck malignancies. AB - OBJECTIVE: The aim of this retrospective study was to evaluate the usefulness of F-fluorodeoxyglucose (FDG) and C-choline positron emission tomography (PET)/computed tomography (CT) for detecting recurrences of nonsquamous cell head and neck malignancies after chemotherapy and radiotherapy. METHOD: Fourteen patients (10 men and four women; mean age: 53.7 +/- 14.5 years) with advanced nonsquamous cell head and neck malignancies other than squamous cell carcinoma were recruited. F-FDG and C-choline PET/CT examinations were performed in all the patients after chemotherapy and radiotherapy. The PET/CT images were evaluated using a visual analysis and a region-based analysis. After the posttreatment PET/CT examination, all the patients underwent further surveillance using the conventional imaging methods. RESULTS: Recurrences were eventually confirmed in eight patients after the posttreatment PET/CT examination. The region-based analysis showed that the maximum standardized uptake values for F-FDG and C choline were strongly correlated with each other (R=0.84). The C-choline PET/CT clearly detected the lesions in two patients, one with severe diabetes mellitus and one with a brain lesion. CONCLUSION: The abilities of F-FDG and C-choline PET/CT to detect lesions were almost the same in this study. In addition, choline has a superior potential for imaging skull base and intracranial lesions because the normal brain is not choline avid. PMID- 20827226 TI - EMR-3: a potential mediator of invasive phenotypic variation in glioblastoma and novel therapeutic target. AB - Epidermal growth factor module-containing mucin-like hormone receptor-3 (EMR-3) is a G-protein coupled receptor with unknown ligand and cellular function. Upregulation of EMR-3 in glioblastoma (GBM) multiforme is associated with poor survival. We investigated the expression patterns and functional significance of EMR-3 in GBM using immunohistochemistry, western blot, reverse transcription PCR, and small interfering RNA knockdown in proliferation and invasion assays. EMR-3 is variably expressed in primary human GBM tissues and cell lines. Knocking down EMR-3 has no impact on cellular proliferation, but decreases cellular invasion by greater than 3-fold. EMR-3 is a potential mediator of cellular invasion in GBM. Given the poor survival associated with high levels of EMR-3 expression in glioma patients, our results provide impetus to explore EMR-3 as a potential therapeutic target. PMID- 20827228 TI - 111In-DTPA-Biotin uptake by Staphylococcus aureus. AB - The potential of indium-111 labelled diethylenetriaminepentaacetic acid alpha,omega-bis(biocytinamide) (In-DTPA-Biotin) as a specific tracer in nuclear medicine imaging of vertebral osteomyelitis has been shown in a large series of consecutive patients. Biocytin is known to serve as a biotin source for a number of different microorganisms and quantitative studies on staphylococci indicated that on a molar basis biocytin seemed to have an activity equal to that of biotin. In this study, we evaluated the possibility of an illicit transport of In DTPA-Biotin in cultures of Staphylococcus aureus on continued incubation for 24 h. Radiolabelled biocytin was prepared as described earlier and the stability and radiochemical purity was assessed in vitro for 24 h after labelling. Our data seem to demonstrate a passive transport of In-DTPA-Biotin into the cells of the microorganisms. PMID- 20827229 TI - Traumatic hypovolemic shock: halt the downward spiral. PMID- 20827230 TI - HPV-related cancer: An equal opportunity danger. PMID- 20827231 TI - Providing optimal care for children with developmental disorders. PMID- 20827232 TI - Diagnosing diabetes with A1C: implications and considerations for measurement and surrogate markers. PMID- 20827234 TI - Evidence-based patient safety advisory for ambulatory surgery. PMID- 20827233 TI - Generation of novel pharmacogenomic candidates in response to methotrexate in juvenile idiopathic arthritis: correlation between gene expression and genotype. AB - OBJECTIVES: Little is known about the mechanisms of efficacy of methotrexate (MTX) in childhood arthritis, or genetic influences upon response to MTX. The aims of this study were to use gene expression profiling to identify novel pathways/genes altered by MTX and then investigate these genes for genotype associations with response to MTX treatment. METHODS: Gene expression profiling before and after MTX treatment was performed on 11 children with juvenile idiopathic arthritis (JIA) treated with MTX, in whom response at 6 months of treatment was defined. Genes showing the most differential gene expression after the treatment were selected for single nucleotide polymorphism (SNP) genotyping. Genotype frequencies were compared between nonresponders and responders (ACR Ped70). An independent cohort was available for validation. RESULTS: Gene expression profiling before and after MTX treatment revealed 1222 differentially expressed probes sets (fold change >1.7, P<0.05) and 1065 when restricted to full responder cases only. Six highly differentially expressed genes were analyzed for genetic association in response to MTX. Three SNPs in the SLC16A7 gene showed significant association with MTX response. One SNP showed validated association in an independent cohort. CONCLUSION: This study is the first, to our knowledge, to evaluate gene expression profiles in children with JIA before and after MTX, and to analyze genetic variation in differentially expressed genes. We have identified a gene, which may contribute to genetic variability in MTX response in JIA, and established as proof of principle that genes that are differentially expressed at mRNA level after drug administration may also be good candidates for genetic analysis. PMID- 20827236 TI - Improving the evaluation and management of the ambulatory and office-based surgical patient. PMID- 20827237 TI - Evidence-based patient safety advisory: patient selection and procedures in ambulatory surgery. AB - Despite the many benefits of ambulatory surgery, there remain inherent risks associated with any surgical care environment that have the potential to jeopardize patient safety. This practice advisory provides an overview of the preoperative steps that should be completed to ensure appropriate patient selection for ambulatory surgery settings. In conjunction, this advisory identifies several physiologic stresses commonly associated with surgical procedures, in addition to potential postoperative recovery problems, and provides recommendations for how best to minimize these complications. PMID- 20827238 TI - Evidence-based patient safety advisory: liposuction. AB - Liposuction is considered to be one of the most frequently performed plastic surgery procedures in the United States, yet despite the popularity of liposuction, there is relatively little scientific evidence available on patient safety issues. This practice advisory provides an overview of various techniques, practices, and management strategies that pertain to individuals undergoing liposuction, and recommendations are offered for each issue to ensure and enhance patient safety. PMID- 20827239 TI - Evidence-based patient safety advisory: patient assessment and prevention of pulmonary side effects in surgery. Part 1. Obstructive sleep apnea and obstructive lung disease. AB - Obstructive sleep apnea and obstructive lung disease may increase a patient's risk of perioperative pulmonary complications. This practice advisory provides an overview of the preoperative steps that should be performed to ensure appropriate patient selection and the safety of patients with these conditions. Also discussed are recommendations for perioperative management and strategies for minimizing complications. PMID- 20827240 TI - Evidence-based patient safety advisory: patient assessment and prevention of pulmonary side effects in surgery. Part 2. Patient and procedural risk factors. AB - Several factors may increase a patient's risk for perioperative pulmonary complications. This practice advisory provides an overview of the preoperative steps that should be performed to ensure appropriate patient selection and patient safety with regard to pulmonary complications. Procedural and patient related risk factors are discussed, as are recommendations for perioperative management and strategies for minimizing complications. PMID- 20827241 TI - Evidence-based patient safety advisory: malignant hyperthermia. AB - As more and more routine plastic surgery procedures move from the hospital to outpatient surgery facilities, plastic surgeons must be aware of the risk factors for life-threatening events that might occur in this setting. This awareness includes recognition of the signs and symptoms and the management of a rare but life-threatening condition, malignant hyperthermia. This article reviews the current understanding of the concepts pertinent to malignant hyperthermia diagnosis and treatment in the outpatient setting and current standards and recommendations for physicians and support personnel regarding malignant hyperthermia preparedness in office-based surgery and anesthesia. PMID- 20827242 TI - Evidence-based patient safety advisory: blood dyscrasias. AB - Rarely, patients with blood disorders may seek to undergo plastic surgery. Although plastic surgeons are not expected to diagnose or manage blood disorders, they should be able to recognize which patients are suitable for surgery and which should be referred to a hematologist before a procedure. This practice advisory provides an overview of the perioperative steps that should be completed to ensure appropriate care for patients with blood disorders. PMID- 20827243 TI - Successful transplantation of single kidneys from pediatric donors weighing less than or equal to 10 kg into standard weight adult recipients. AB - BACKGROUND: The outcomes of single kidneys transplanted from pediatric donors into standard adult recipients (>60 kg) are unknown. Furthermore, the outcomes of single kidneys transplanted from pediatric donors less than or equal to 10 kg are also unknown. METHODS: We retrospectively compared 27 recipients of single kidneys from pediatric donors younger than or equal to 5 years with 69 recipients of adult cadaveric kidneys. RESULTS: The mean pediatric kidney recipient weight was 69 kg. Two-year patient and graft survival in pediatric kidney recipients was 100% and 92.5% respectively, compared with 98.5% and 89.8% in adult kidney recipients (P=NS). Mean time (days) to achieve creatinine less than 3 mg/dL was 14+/-9 compared with 14+/-20 in adult kidney recipients (P=NS). Estimated glomerular filtration rate at discharge, 6, 12, 18, and 24 months was equivalent in both cohorts. Stratifying pediatric kidney recipients by donor weight, there were no differences in acute rejection or graft loss in recipients of kidney from donors less than or equal to 10 kg (n=11; mean weight=8.85 kg), but there was a higher incidence of delayed graft function (7 of 11 vs. 1 of 16; P=0.002). Estimated glomerular filtration rate at discharge, 6, 12, 18, and 24 months was equivalent in both cohorts. CONCLUSIONS: Single pediatric kidneys from donors younger than or equal to 5 years can be transplanted into standard adult recipients without compromising outcomes. Transplanting single kidneys from pediatric donors less than or equal to 10 kg into standard adult recipients is associated with an increased risk of delayed graft function; however, this does not compromise 2-year graft survival or function. PMID- 20827244 TI - [Sonographic aspects in the study of endometrial receptivity in women undergoing in vitro fertilization]. AB - AIM: The embryo implant is the limiting step of the reproductive process about the phenomena involved in the determinism of endometrial receptivity. Some aspects of ultrasound could help us in this regard. The aim of this study was to test the relationship between three ultrasound parameters such as endometrial pattern, subendometrial vascularization, and uterine artery pulsatility index with success rates of in-vitro fertilization (IVF) and with pregnancy rates. METHODS: Twenty-four women candidates for IVF in 2009 were enrolled. A transvaginal ultrasound was performed two-four hours before the embryo transfer to assess differences in the endometrial pattern, subendometrial vascularization, and uterine artery pulsatility index with reference to the group of pregnant and non-pregnant women. RESULTS: Pregnant women most often reveal a trilaminar pattern, a subendometrial vascularization with vessels that penetrate the outer hyperechoic edge of endometrium, and a low-medium uterine artery pulsatility index compared to the group of non-pregnant patients. CONCLUSION: All three studied parameters seem to correlate in the determinism of endometrial receptivity. This leads us to conclude that a trilaminar pattern supported by a correct vascularization and by uterine artery pulsatility index of less than three are good predictors of implant. Their evaluation before subjecting the patient to the embryo transfer may help to increase the pregnancy rate. PMID- 20827245 TI - [Outcome of pregnancy for immigrant women: a retrospective study]. AB - AIM: Italy is experiencing a continuous increase in female immigration and, as a consequence, the number of births by immigrant mothers. The objective of our study was therefore to compare indices for maternal-foetal wellbeing as regards immigrant as opposed to autochthonous pregnant women. METHODS: An analysis was made of CEDAP data from 2001 to 2008 concerning parturients at Udine Obstetric and Gynaecological Clinic, DRG clinical data for 2008 and clinical records for 2008 of foreign parturients: the focus was on which geographical area they came from, hypertensive and metabolic symptoms during pregnancy, maternal serology, gestational period up to childbirth, weight at birth, Apgar index, duration of hospitalisation for the mother and infant. RESULTS: The study covered 13,352 women of whom 2,139 were foreigners, while 363 of the latter gave birth in 2008. In terms of geographical area the largest group of immigrants came from Eastern Europe, followed by sub-Saharan African and Arab countries. The worst outcome of pregnancy was found in African women, who showed the highest incidence of chronic hypertension, pregnancy-induced hypertension and pre-eclampsia and they also developed gestational diabetes more frequently, although a high incidence was also seen for Eastern European and Arab women. Furthermore, African women were found to be HIV-seropositive more frequently, showed a greater tendency to preterm or severely preterm birth, with a significantly lower weight and Apgar at birth compared to all other immigrant women. As a result, African women and infants remained in hospital for a longer period. CONCLUSION: Monitoring, both pre-conceptional and during pregnancy, needs to be intensified, especially among African mothers, in order to reduce the maternal-foetal disadvantage when compared to other women. PMID- 20827246 TI - [Treatment of atrophic and irritative vulvovaginal symptoms with an anhydrous lipogel and its complementary effect with vaginal estrogenic therapy: new evidences]. AB - It is sometimes difficult to treat vulvovaginal itching and dryness, which represent frustrating symptoms for both patients and doctors. In case that the etiological agent is Candida albicans, effective antimycotic therapies are available; however, itching is often caused by aspecific allergic-irritative factors, which are difficult to be defined. In these cases, patients are invited to limit local irritative factors; nevertheless, this advice is not always taken and sometimes it turns out to be insufficient. Besides behavioral suggestions, a therapeutic support would be useful; medical doctors habitually prescribe local symptomatic treatments which, however, do not target numerous causes of irritative vulvovaginal symptomatology, though they are formulated for vulvovaginal application. If there is estrogenic deficit, the best therapeutic approach is based on topical estrogenic therapy, which is sometimes ineffective on vulvar symptoms. Frequently, it is necessary to choose a complementary therapeutic tool for vaginal application in order to alleviate itching, burning, erythema, dryness. The aim of this study was to evaluate the efficacy of an innovative anhydrous lipogel containing vitamin E and boswellic acids. Results of this study, performed on 34-58-year-old patients, confirmed the efficacy of the lipogel on irritative vulvovaginal symptoms. In postmenopausal women, the lipogel is a useful synergistic complement to topical hormonal therapy. PMID- 20827247 TI - [Effects of folic acid supplementation on pregnancy outcomes: a review of randomized clinical trials]. AB - Despite the causal association between defects of the metabolism of the folate (hyperhomocysteinemia) and risk of neural tube defects are both well documented, the association between folate deficiency and other pregnancy pathologies is still not entirely clear. The present article aims to gather the data published about the relationship between serum folate and pregnancy pathologies, distinguishing between the evidences emerged from the observational studies and the results of the clinical trials. We carried out a brief examination of the relationships between folate metabolism and homocysteine. Observational studies have suggested that a good level of folate in pregnancy is associated with higher birthweight, increased placental weight and fewer preterm birth. These results were not entirely consistent with findings from clinical trials. We have identified 12 randomized clinical studies with folate supplementation versus placebo. In the clinical studies where folic acid (FA) could improve pregnancy outcomes, its effect was not statistically significant, except for three studies where FA showed a significant decrease of low birthweight. With regard to preterm birth, pre-eclampsia and abruptio placentae, although in some observational studies AF was found to be associated with a reduction of these adverse outcomes, in currently available controlled clinical trials, FA supplementation had no statistically significant effects. PMID- 20827248 TI - [Evolution and future of contraception]. AB - In order to meet the need for efficacious and safe contraception, contraceptives are in continuous evolution. Among oral contraceptives evolution has brought reduction of ethynylestradiol doses, up to change the estrogenic molecule to natural estradiol. In order to individualize contraception, numerous different progestin molecules have been developed and are being tested. Individualization has also brought at developing new schedules for contraceptive administration, and different routes of administration. Important developments have appeared on parenteral hormonal contraception, such as the intravaginal, subdermal, transdermal or injectable contraception. Intrauterine devices are being developed, becoming smaller, easier to insert, and sometimes capable to locally release progestins. New spermicides, that are capable to protect from sexually transmitted disease, are also being developed. Emergency contraception has evolved in a safer and more acceptable hormonal contraception. Recent introduction of molecules modulating progesterone receptors, seem to bring additional advantages by increasing the efficacy and extending the window of efficacy of emergency contraception. PMID- 20827249 TI - Non-contraceptive benefits of hormonal contraceptives. AB - Besides the contraceptive effect of the various hormonal contraceptives, it is intended to demonstrate the non-contraceptive health benefits for treatment and prevention of bleeding problems, menstruation-related pain and other disorders, such as premenstrual syndrome and signs of androgenization. The effectiveness can be improved by choosing the proper progestogen with antiandrogenic action. Treatment but also prevention can be achieved with hormonal contraceptives in benign proliferative diseases of women, such as ovarian cysts, endometriosis, adenomyosis, endometrial hyperplasia, myoma and benign breast disease. Furthermore, hormonal contraceptives such as estrogen/progestogen combinations reduce pelvic inflammatory disease, rheumatoid arthritis, asthma symptoms and preserve bone density. In addition, a major impact in oncological prevention seems to be possible for ovarian, endometrial and colon cancer and these positive preventive effects seem to persist also after discontinuation of hormonal contraceptives. In addition, practical concepts for hormonal contraceptive selection will be outlined. PMID- 20827250 TI - Contraception and sexuality. AB - Contraception has changed female sexuality. The possibility of sex without pregnancy is taken for granted by most women and facilitates sexual availability. Potential consequences to female sexual response are linked to the various contraceptive methods in use today. This is a comprehensive review article of existing literature that explores the impact of current contraceptive methods upon the female sexual response cycle with potential sexual dysfunction. The definitions and classifications of female sexual response and female sexual dysfunction are also reviewed. Combination estrogen and progesterone contraceptive products decrease testosterone and increase sex hormone binding globulin without consistent impact upon libido. Progesterone only methods can in small numbers decrease libido and cause vaginal dryness and dyspareunia. Bleeding irregularities contribute to vaginal dryness and vulvar irritation. In the postpartum period and during lactation, these changes are exacerbated. Overall, IUD users have no significant effect on libido. Female sterilization generally has a positive impact upon sexuality unless the woman has been ambivalent over the procedure. Barrier and natural family planning methods are neutral. The freedom of sexual activity without pregnancy must be balanced with known side effects, risks and benefits to sexual health. The impact of contraceptive methods upon sexual function is not often discussed with women prior to initiation of a selected method or at subsequent visits. It is important that as clinicians we recognize the impact of contraceptive methods to sexual functioning and counsel our patients appropriately. PMID- 20827251 TI - Social and ethical determinants of human sexuality: 1. The need to reproduce. AB - Aims of this study was to review the many and diverse factors conditioning human sexual behavior; starting with the first and still most important: the need to reproduce and to analyse these factors and how they have changed over time in order to better understand the interplay between the major determinants of human sexuality. For this aim the authors made a literature review of relevant scientific papers and books, including religious websites. At the dawn of humanity, sexuality was focused on reproduction; this, however, did not exclude other important meanings in sexual relationships, since non-conceptive copulations have been a constant aspect of human behavior, becoming an almost unique feature of genus homo. In this respect, the characteristics of a female continuously accessible to her male set the stage for a trend towards monogamy and created the substrate for closed families. Anthropologists have justified conceptive sexuality because sexual activity is costly in terms of energy consumption; for this reason, in the early days, restricting sexual activity made sense for the survival of the species. Traditional ethical considerations and ancient norms by the three major monotheistic religions have favored conceptive sexuality, restricting sexual activity to sanctioned unions and insisting that the major scope of sexuality is procreation. In spite of this, among humans sexuality has always had a wider meaning to the point that for millennia, humans have tried to separate its unitive and procreative meanings. Today much has changed since reproduction can be achieved without intercourse, further separating it from sexual activity. In humans sexuality always possessed multiple meanings, first and foremost reproduction and the creation of a bond between a man and one or several women. PMID- 20827252 TI - Emergency contraception: past, present and future. AB - Women have been using emergency contraception (EC) for decades. Population studies have not shown that increased access to EC decreases abortion rates this is likely because of inconsistent and infrequent use even when it is available. Special populations, such as adolescents, have been shown to be just as good as their adult counterparts in comprehending EC instructions, and its use does not lead to more risky sexual practices or behaviors. There is little evidence on the administration of EC to victims of sexual assault, but what is available reveals more women who are victims of sexual assault should be offered EC as an option. Methods of EC include high doses of ethinyl estradiol; DES; Danzaol; combination ethinyl estradiol with a progestin; progestin alone and copper IUDs. This review describes the history of EC as well as newer medications such as the antiprogestins (gestrinone and uliprisatal acetate) and cyclooxygenase inhibitors(meloxifam). These methods have been added to the armamentarium and may prove to be more effective than current regimens. Finding a product that is highly effective with minimal side effects is a worthy goal, for it presents a woman with her last chance to prevent an unwanted pregnancy. PMID- 20827253 TI - Treatment of endometriosis: a hormonal approach. AB - Endometriosis continues to plague women of reproductive age. It is a chronic disease leading to a decreased quality of life, infertility, and increased societal costs. The gold standard for diagnosis remains visualization and or biopsy of lesions at the time of intraoperative diagnosis, i.e. laparoscopy or laparotomy. The severity of pain does not correlate with the stage of endometriosis, which complicates the treatment process. Hormonal therapies have long been used as a treatment for endometriosis. Therapy is targeted at symptom relief as a cure is lacking. While some regimes use hormonal therapy exclusively, others combine such with surgical excision of lesions. Although hormonal modalities are successful in alleviating or suppressing symptoms, they fail to treat the infertility associated with endometriosis. Therefore, those, desiring to achieve pregnancy should be excluded from hormonal treatment in the short term. Future studies are needed to understand the pathophysiology and allow design of specific, targeted treatment. PMID- 20827254 TI - Comparison of two region of interest definition methods for metabolic response evaluation with [18F]FDG-PET. AB - AIM: In therapy response monitoring by [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), different tumor delineations are used, resulting in different values for change in glucose metabolic rate (DMRglu). We propose a technique to compare metabolic rates in a region of interest (ROI) based on fixed volumes rather than on fixed thresholds. This method involves change in lesion size. METHODS: In 49 patients with colorectal carcinoma (CRC) and 50 patients with non-small cell lung carcinoma (NSCLC) scheduled for chemotherapy, FDG-PET was performed at baseline and during chemotherapy. A ROIfixed thresholds was determined by using a 50% threshold on both baseline and follow-up FDG-PET. A ROIfixed volumes was determined by using a 50% threshold, determined on the series with the largest tumor volume. This ROIfixed volumes is used on consecutive scans. Predictive effects of both methods were investigated by survival analysis for overall and progression free survival. RESULTS: In CRC, only ROIfixed volumes based DMRglu showed significant predictive ability. In NSCLC, both techniques showed significant predictive ability. During multivariate analysis, ROIfixed volumes determined DMRglu was an independent predictor for both overall and progression free survival in NSCLC whereas ROIfixed thresholds determined MRglu was not. After dichotomization at the median DMRglu, median survival ratio was higher in ROIfixed volumes than ROIfixed thresholds for CRC (overall survival: 1.78 vs 1.25, progression free survival: 1.57 vs 1.21) and NSCLC (overall survival: 2.01 vs 2.01, progression free survival: 2.93 vs 2.13). CONCLUSION: ROIfixed volumes based DMRglu shows better correlation with survival than DMRglu determined from a ROIfixed thresholds. PMID- 20827255 TI - Latent Class Factor Analysis of the Functional Independence Measure confirmed four distinct dimensions in patients undergoing neurological rehabilitation. AB - AIM: The FIM instrument is broadly applied in varying rehabilitation services for outcome assessment. Thus, it is important to examine its applicability for services which may differ from the situations and patients for which it was originally developed. The aims of the present study were to examine 1) whether the four FIM dimensions "activities of daily living", "sphincter management", "mobility", and "executive function" can be retrieved by Latent Class Factor Analysis (LCFA); and 2) whether the four dimensions show floor effects in patients with acquired brain injuries undergoing intensive post-acute rehabilitation. METHODS: We analyzed the FIM data of 269 patients with acquired brain injuries undergoing intensive post-acute rehabilitation. To examine the dimensional structure of the FIM instrument we carried out LCFA. Cronbach's alpha was used to measure the internal consistency. We examined the distribution of the dimension scores to identify floor effects. RESULTS: LCFA confirmed the postulated four dimensions. The explained variance of items assigned to the four dimensions ranged from 46% to 89%. Cronbach's alpha coefficients of the four subscales ranged from 0.94 to 0.96. The percentage of patients scoring the minimum possible score in each of the retrieved dimensions ranged from 22.3% to 47.9%. CONCLUSION: When applying the FIM instrument to patients undergoing intensive neurological rehabilitation its dimensionality should be kept in mind. For some patients this outcome measure might not be discriminative enough due to floor effects. PMID- 20827256 TI - Main diagnosis, comorbidity and functional impairment at admission in the rehabilitative wards of Lombardy region. A survey on 6,671 patients. PMID- 20827258 TI - Urinary excretion of twenty peptides forms an early and accurate diagnostic pattern of acute kidney injury. AB - Early and accurate detection of acute kidney injury (AKI) is needed to prevent the progression to chronic kidney disease and to improve outcome. Here we used capillary electrophoresis-mass spectrometry to identify urinary peptides predictive of AKI in a training set of 87 urine samples longitudinally collected from patients in an intensive care unit. Within this patient cohort, 16 developed AKI while 14 maintained normal renal function. The sequence of twenty peptides significantly associated with AKI was identified. They were found to be degradation products of six proteins. These formed a diagnostic pattern. Peptides of albumin, alpha-1-antitrypsin, and beta-2-microglobulin were upregulated but fragments of fibrinogen alpha and collagens 1 alpha(I) and 1 alpha(III) were downregulated in AKI. After cross-validation of the training set, a good diagnostic performance of the marker pattern was found with an area under the ROC curve of 0.91. This was confirmed in a blinded validation set of 20 patients in the intensive care unit and 31 allogeneic hematopoietic stem cell transplantation patients, of which 13 had and 18 had not experienced an episode of AKI. In comparison to more established markers of AKI such as serum cystatin C and urinary kidney injury molecule-1, interleukin-18, and neutrophil gelatinase associated-lipocalin, the proteomic marker pattern was found to be of superior prognostic value, detecting AKI up to 5 days in advance of the rise in serum creatinine. PMID- 20827259 TI - Do meta-analyses in nephrology change the way we treat patients? AB - There has been an exponential increase in the number of nephrological meta analyses published, but their relative contribution to the nephrology literature is unclear and their influence on physician behavior and evidence-based patient care is poorly understood. We studied the nephrology literature, point-of-care resources, guidelines, and a questionnaire survey of the New York Society of Nephrology membership to understand the role and perception of meta-analyses in nephrology. We discuss our results in the context of the strengths and limitations of meta-analyses and their relatively limited, albeit increasing influence on published guidelines and on point-of-care references. The results of our practitioner survey and our review of the nephrology literature suggest an increasing influence at the level of the individual practitioner of meta analyses. This underlines the need to develop a better understanding of the contributions and role of meta-analyses in the literature. PMID- 20827260 TI - Baseline CBF, and BOLD, CBF, and CMRO2 fMRI of visual and vibrotactile stimulations in baboons. AB - Neurovascular coupling associated with visual and vibrotactile stimulations in baboons anesthetized sequentially with isoflurane and ketamine was evaluated using multimodal functional magnetic resonance imaging (fMRI) on a clinical 3 Tesla scanner. Basal cerebral blood flow (CBF), and combined blood-oxygenation level-dependent (BOLD) and CBF fMRI of visual and somatosensory stimulations were measured using pseudo-continuous arterial spin labeling. Changes in stimulus evoked cerebral metabolic rate of oxygen (CMRO(2)) were estimated using calibrated fMRI. Arterial transit time for vessel, gray matter (GM), and white matter (WM) were 250, 570, and 823 ms, respectively. Gray matter and WM CBF, respectively, were 107.8+/-7.9 and 47.8+/-3.8 mL per 100 g per minute under isoflurane, and 108.8+/-10.3 and 48.7+/-4.2 mL per 100 g per minute under ketamine (mean+/-s.e.m., N=8 sessions, five baboons). The GM/WM CBF ratio was not statistically different between the two anesthetics, averaging 2.3+/-0.1. Hypercapnia evoked global BOLD and CBF increases. Blood-oxygenation-level dependent, CBF, and CMRO(2) signal changes by visual and vibrotactile stimulations were 0.19% to 0.22%, 18% to 23%, and 4.9% to 6.7%, respectively. The CBF/CMRO(2) ratio was 2.9 to 4.7. Basal CBF and fMRI responses were not statistically different between the two anesthetics. This study establishes a multimodal fMRI protocol to probe clinically relevant functional, physiological and metabolic information in large nonhuman primates. PMID- 20827261 TI - Decreased cortical serotonin in neonatal rabbits exposed to endotoxin in utero. AB - Maternal intrauterine inflammation is implicated in neurodevelopmental disorders in the offspring. Serotonin is crucial for regulating maturation in the developing brain, and maternal inflammation may result in disruption of the serotonergic system in the perinatal period. Saline or endotoxin was injected intrauterine in pregnant rabbits term. Newborn rabbits underwent positron emission tomography (PET) imaging with alpha[(11)C]methyl-L-tryptophan (AMT) to evaluate tryptophan metabolism in vivo. Decrease in standard uptake value for AMT and decrease in serotonin concentration was noted in the frontal and parietal cortices of endotoxin kits when compared with controls. In addition, a significant decrease in serotonin-immunoreactive fibers and decreased expression of serotonin transporter (5HTT) was measured in the somatosensory cortex. There was a three-fold increase in the number of apoptotic cells in the ventrobasal (VB) thalamus without loss of raphe serotonergic cell bodies in endotoxin kits when compared with controls. Glutamateric VB neurons projecting to somatosensory cortex transiently express 5HTT and store serotonin, regulating development of the somatosensory cortex. Intrauterine inflammation results in alterations in cortical serotonin and disruption of serotonin-regulated thalamocortical development in the newborn brain. This may be a common link in neurodevelopmental disorders resulting in impairment of the somatosensory system, such as cerebral palsy and autism. PMID- 20827262 TI - Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. AB - Understanding regulation of blood-brain barrier (BBB) is crucial to reduce/prevent its disruption during injury. As high brain complexity makes interpretation of in vivo data challenging, BBB studies are frequently performed using simplified in vitro models. However, many models fail to address the three dimensional (3D) cellular interactions that occur in vivo, an important feature that may explain discrepancies in translation of in vitro data to the in vivo situation. We have designed and characterized an innovative 3D model that reproduces morphological and functional characteristics of the BBB in vivo and used it to investigate cellular interactions and contribution of astrocytes and pericytes to BBB development. Our model shows that both astrocytes and pericytes significantly suppress endothelial proliferation. In contrast, differential effects on tubulogenesis were observed with astrocytes reducing the number of tubes formed but increasing diameters and length, whereas pericytes had the opposite effect. Pericytes also induce proper localization of barrier proteins, lumen polarization, and functional activity of ATP-binding cassette (ABC) transporters similar to astrocytes, but the presence of both cells is required to maintain optimal barrier characteristics during hypoxic exposure. This model is simple, dynamic, and convenient to study many aspects of BBB function and represents an exciting new tool to address open questions of BBB regulation. PMID- 20827263 TI - Astrocytes are 'good scouts': being prepared also helps neighboring neurons. AB - Recognition of glycogen as an active participant in the energetics of brain activation is replacing the long-held concept of glycogen as an emergency energy reserve, but the functional roles of glycogen and the cellular utilization of glycogen carbon are unresolved issues. Metabolic modeling by DiNuzzo et al, in this issue predicts that mobilization of glycogen during brain activation provides fuel for activated astrocytes and increases product inhibition of hexokinase thereby reducing astrocytic utilization of blood-borne glucose and increasing glucose availability for activated neurons. Glucose buffering and glucose channeling (not lactate shuttling to neurons) are proposed to be the consequences of glycogenolysis. PMID- 20827264 TI - Glycogenolysis in astrocytes supports blood-borne glucose channeling not glycogen derived lactate shuttling to neurons: evidence from mathematical modeling. AB - In this article, we examined theoretically the role of human cerebral glycogen in buffering the metabolic requirement of a 360-second brain stimulation, expanding our previous modeling study of neurometabolic coupling. We found that glycogen synthesis and degradation affects the relative amount of glucose taken up by neurons versus astrocytes. Under conditions of 175:115 mmol/L (~1.5:1) neuronal versus astrocytic activation-induced Na(+) influx ratio, ~12% of astrocytic glycogen is mobilized. This results in the rapid increase of intracellular glucose-6-phosphate level on stimulation and nearly 40% mean decrease of glucose flow through hexokinase (HK) in astrocytes via product inhibition. The suppression of astrocytic glucose phosphorylation, in turn, favors the channeling of glucose from interstitium to nearby activated neurons, without a critical effect on the concurrent intercellular lactate trafficking. Under conditions of increased neuronal versus astrocytic activation-induced Na(+) influx ratio to 190:65 mmol/L (~3:1), glycogen is not significantly degraded and blood glucose is primarily taken up by neurons. These results support a role for astrocytic glycogen in preserving extracellular glucose for neuronal utilization, rather than providing lactate to neurons as is commonly accepted by the current 'thinking paradigm'. This might be critical in subcellular domains during functional conditions associated with fast energetic demands. PMID- 20827265 TI - Pharmacologic development of male hormonal contraceptive agents. AB - The world population continues to increase dramatically despite the existence of contraceptive technology. The use of male hormonal contraception may help in preventing un intended pregnancies and managing future population growth. Male hormonal contraception relies on the administration of exogenous hormones to suppress spermatogenesis. Clinical trials have tested several regimens using testosterone, alone or in combination with a progestin. These regimens were shown to be >90% effective in preventing conception and were not associated with serious adverse events. PMID- 20827266 TI - Temporal trends in adherence to cardiovascular medications in elderly patients after hospitalization for heart failure. AB - Although the complexity of treatment regimens for patients with heart failure (HF) has increased over time because of the increased availability of efficacious medications, little is known about temporal trends in adherence to treatment regimens in these patients. We assessed trends in adherence to angiotensin-system blockers (ABs), beta-blockers (BBs), and spironolactone (SL) for HF in Medicare beneficiaries enrolled in two statewide pharmacy benefit programs from 1995 to 2004. The proportion of days covered (PDC) (%) was assessed after the first dispensing among users of an AB, BB, or SL. Proportions of full adherence (PDC >80%) did not change over time for ABs (54% in both 1996 and 2003) but increased slightly for BBs (from 47% in 1996 to 57% in 2003) and SL (from 31% in 1996 to 42% in 2003). Black race and dialysis treatment predicted poor adherence to any medications. Adherence to BBs and SL increased modestly over time, but overall nonadherence remained high. PMID- 20827267 TI - Estrogen receptor genotypes, menopausal status, and the effects of tamoxifen on lipid levels: revised and updated results. AB - We previously reported that the ESR1 XbaI genotypes were associated with baseline and tamoxifen-induced serum lipid profiles. The analysis in that study was carried out by PCR followed by restriction-enzyme digestion. After reanalysis using more robust TaqMan assays, the findings related to ~10% of the genotypes for the ESR1 XbaI single-nucleotide polymorphism (SNP) were revised. For the other genotypes (i.e., ESR1 PvuII, ESR2, and CYP2D6), the results were nearly identical to those in the previous study. Upon reanalysis, previously reported associations between the ESR1 Xba1 genotypes and baseline triglyceride and low density lipoprotein (LDL) cholesterol levels were no longer observed. Previously reported associations between the ESR1 XbaI genotypes and tamoxifen-induced changes in levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were also no longer observed. However, the following observations from the original report did not change: (i) the levels of circulating lipids are lower in women taking tamoxifen; (ii) there is an association between the ESR2-02 genotypes and changes in triglyceride levels; and (iii) neither ESR1 PvuII nor CYP2D6 is associated with any changes in serum lipid concentrations in patients receiving treatment with tamoxifen. PMID- 20827268 TI - Elevated levels of asymmetric dimethylarginine in chronic heart failure: a pathophysiologic link between oxygen radical load and impaired vasodilator capacity and the therapeutic effect of allopurinol. AB - Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide dependent vasodilation. In 113 patients with chronic heart failure (CHF) and 26 controls, ADMA level was studied in relation to peripheral blood flow and vasodilator capacity. Further, the effects of allopurinol on concentrations of reactive oxygen species (ROS) and ADMA and peripheral vasodilator capacity were tested in a double-blind design. ADMA level was found to be elevated in CHF patients as compared with controls and increased in parallel with New York Heart Association (NYHA) class and exercise capacity (all P < 0.0001). The level of ADMA predicted resting blood flow (P < 0.05) and postischemic vasodilator capacity (P < 0.001). Sixty eight patients died during the follow-up period. The level of ADMA predicted survival after multivariable adjustment (P = 0.04). Allopurinol reduced uric acid (UA) concentration (P < 0.001) and decreased ROS concentration (allantoin, P < 0.01). Allopurinol lowered ADMA concentration (P = 0.02); postischemic vasodilation as well as endothelium-dependent vasodilation (both P < 0.05) improved. ADMA may be a pathophysiologic factor that is modulated by ROS accumulation and contributes to impaired vascular regulation in CHF. PMID- 20827269 TI - Early warning signals of extinction in deteriorating environments. AB - During the decline to extinction, animal populations may present dynamical phenomena not exhibited by robust populations. Some of these phenomena, such as the scaling of demographic variance, are related to small size whereas others result from density-dependent nonlinearities. Although understanding the causes of population extinction has been a central problem in theoretical biology for decades, the ability to anticipate extinction has remained elusive. Here we argue that the causes of a population's decline are central to the predictability of its extinction. Specifically, environmental degradation may cause a tipping point in population dynamics, corresponding to a bifurcation in the underlying population growth equations, beyond which decline to extinction is almost certain. In such cases, imminent extinction will be signalled by critical slowing down (CSD). We conducted an experiment with replicate laboratory populations of Daphnia magna to test this hypothesis. We show that populations crossing a transcritical bifurcation, experimentally induced by the controlled decline in environmental conditions, show statistical signatures of CSD after the onset of environmental deterioration and before the critical transition. Populations in constant environments did not have these patterns. Four statistical indicators all showed evidence of the approaching bifurcation as early as 110 days (~8 generations) before the transition occurred. Two composite indices improved predictability, and comparative analysis showed that early warning signals based solely on observations in deteriorating environments without reference populations for standardization were hampered by the presence of transient dynamics before the onset of deterioration, pointing to the importance of reliable baseline data before environmental deterioration begins. The universality of bifurcations in models of population dynamics suggests that this phenomenon should be general. PMID- 20827270 TI - A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. AB - Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage associated autoimmune disease-than randomly selected immune response genes (P = 8.85 * 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 * 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D. PMID- 20827271 TI - Gamma oscillatory power is impaired during cognitive control independent of medication status in first-episode schizophrenia. AB - Schizophrenia is characterized by impaired cognitive control associated with prefrontal cortex dysfunction, but the underlying pathophysiological mechanisms remain unknown. Higher cognitive processes are associated with cortical oscillations in the gamma range, which are also impaired in chronic schizophrenia. We tested whether cognitive control-related gamma deficits are observed in first-episode patients, and whether they are associated with antipsychotic medication exposure. Fifty-three first-episode schizophrenia patients (21 without antipsychotic medication treatment) and 29 healthy control subjects underwent electroencephalography (EEG) during performance of a preparatory cognitive control task (preparing to overcome prepotency or POP task). The first-episode schizophrenia patient group was impaired (relative to the control group) on task performance and on delay-period gamma power at each of the three subgroups of frontal electrodes. The unmedicated patient subgroup was similarly impaired compared with controls, and was not different on these measures compared with the medicated patient subgroup. In contrast, delay-period theta power was not impaired in the full patient group nor in the unmedicated patient subgroup. Impaired cognitive control-related gamma cortical oscillatory activity is present at the first psychotic episode in schizophrenia, and is independent of medication status. This suggests that altered local circuit function supporting high-frequency oscillatory activity in prefrontal cortex ensembles may serve as the pathophysiological substrate of cognitive control deficits in schizophrenia. PMID- 20827272 TI - Is slow-onset long-acting monoamine transport blockade to cocaine as methadone is to heroin? Implication for anti-addiction medications. AB - The success of methadone in treating opiate addiction has suggested that long acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48 h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA. PMID- 20827274 TI - Transition to mania during treatment of bipolar depression. AB - Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients. PMID- 20827273 TI - Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. AB - Serotonin (5-hydroxytryptamine, 5-HT) has long been implicated in regulation of mood. Medications that block the neuronal 5-HT transporter (SERT) are used as major pharmacological treatment for mood disorders. Conversely, stimuli that enhance SERT activity might be predicted to diminish synaptic 5-HT availability and increase the risk for 5-HT-related CNS disorders. We have shown that the inflammatory cytokines enhance brain SERT activity in cultured serotonergic cells and nerve terminal preparations in vitro. In this study, we establish that intraperitoneal injection of the cytokine-inducer lipopolysaccharide (LPS) stimulates brain SERT activity, acting at doses below those required to induce overt motor suppression. SERT stimulation by LPS is paralleled by increased immobility in both the tail suspension test (TST) and the forced swim test (FST); antidepressant-sensitive alterations are thought to model aspects of behavioral despair. Both the stimulation of SERT activity and induced immobility are absent when LPS is administered to interleukin-1 receptor (IL-1R)-deficient mice and in the presence of SB203580, an inhibitor of IL-1R-stimulated p38 MAPK. Moreover, the ability of LPS to enhance immobility in TST is lost in SERT knockout mice. These findings reveal an ability of peripheral inflammatory stimuli to enhance brain SERT activity through IL-1R and p38 MAPK pathways in vivo and identify a requirement for SERT expression in immune-system-modulated despair behaviors. Our studies identify IL-1R- and p38 MAPK-dependent regulation of SERT as one of the mechanisms by which environmentally driven immune system activation can trigger despair-like behavior in an animal model, encouraging future analysis of the pathway for risk factors in neuropsychiatric disorders. PMID- 20827275 TI - Influence of HTR2A polymorphisms and parental rearing on personality traits in healthy Japanese subjects. AB - Genetic factors and environmental influences contribute to the determination of human personality traits. This study examined the influence of serotonin receptor 2A polymorphisms and parental rearing on temperament. Subjects included 1245 Japanese volunteers (592 males and 653 females). Three single-nucleotide polymorphisms (SNPs) (rs6311, rs6313 and rs643627) were selected for genotyping. All subjects completed the 125-item Japanese short version of the temperament and character inventory, and 572 completed the Japanese version of the Parental Bonding Instrument. All SNPs were in Hardy-Weinberg equilibrium. A significant association (P=0.0026) was observed between rs643627 and novelty seeking in females. On the other hand, significant effects of maternal overprotection to harm avoidance (HA) were seen for rs6311 (P=0.0005), rs6313 (P=0.0004) and rs643627 (P=0.0003) in males only. In terms of the interaction of genotype and maternal overprotection with HA, interaction was observed in rs6311 (P=0.0290) and rs6313 (P=0.0230) in females only. Our results indicate a relationship between the rs643627 polymorphism and novelty seeking in females. In terms of serotonin receptor 2A gene polymorphisms and maternal overprotection, our findings suggest the existence of a gene-environmental interaction that influences HA. PMID- 20827276 TI - Contemporary retrotransposition of a novel non-coding gene induces exon-skipping in dystrophin mRNA. AB - Non-autonomous retrotransposon-mediated mobilizations of the Alu family are known pathogenic mechanisms of human disease. Here, we report a pathogenic, contemporary, non-autonomous retrotransmobilization of part of a novel non-coding gene into the dystrophin gene. In a Japanese Duchenne muscular dystrophy patient, a 330-bp-long de novo insertion was identified in exon 67 of dystrophin. The insertion induced exon 67-skipping in the dystrophin mRNA, creating a premature stop codon. The sequence of the insertion had certain characteristics of retrotransposons: an antisense polyadenylation signal accompanied by a poly(T) sequence and a target site duplication. The insertion site matched the consensus recognition sequence for the L1 endonuclease, indicating a retrotransposon mediated event, although the inserted sequence did not match any known retrotransposons. The origin of the inserted sequence was mapped to a gene-poor region of chromosome 11. The inserted fragment was expressed in multiple human tissue RNAs, indicating that it is a novel transcript. The full length of the transcript was cloned and showed no meaningful protein coding ability. PMID- 20827277 TI - Matrix metalloproteinase haplotypes associated with coronary artery aneurysm formation in patients with Kawasaki disease. AB - Aneurysms of the vascular wall represent a final common pathway for a number of inflammatory processes, including atherosclerosis and idiopathic vasculitis syndromes. Kawasaki disease (KD) is an acute, self-limited vasculitis in children and the leading cause of acquired coronary artery aneurysms. We sought to identify shared molecular mechanisms of aneurysm formation by genotyping eight polymorphisms in matrix metalloproteinase (MMP)-1, 3, 7, 12 and 13 in the gene cluster on Chr.11q22, whose gene products have been implicated in aneurysm formation or are known to have elastase activity. We genotyped 482 US-UK KD patients (aneurysm+: n=111, aneurysm-: n=371) and tested our findings in an independent cohort of 200 Japanese KD patients (aneurysm+: n=58, aneurysm-: n=142). Analysis of the five MMP genes identified modest trends in allele and genotype frequencies for MMP-3 rs3025058 (-/T) and haplotypes containing MMP-3 rs3025058 (-/T) and MMP-12 rs2276109 (A/G) (nominal P=2 to 4 * 10(-5)) that conferred increased risk of aneurysm formation in US-UK subjects. This finding was validated in Japanese subjects and suggests the importance of this locus in aneurysm formation in children with KD. The region encompassing these risk haplotypes is a prime candidate for resequencing to look for rare genetic variation that may influence aneurysm formation. PMID- 20827278 TI - Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity. AB - Duchenne muscular dystrophy is a fatal, genetic disorder in which dystrophin deficient muscle progressively degenerates, for which dystrophin gene transfer could provide effective treatment. The host immune response to dystrophin, however, is an obstacle to therapeutic gene expression. Understanding the dystrophin-induced host immune response will facilitate the discovery of strategies to prolong expression of recombinant dystrophin in dystrophic muscle. Using whole-body irradiation of the dystrophic mdx mouse before gene transfer, we temporally removed the immune system; a 600 rad dose removed peripheral immune cells, which were restored by self-reconstitution, and a 900 rad dose removed central and peripheral immune cells, which were restored by adoptive transfer of bone marrow from a syngeneic, dystrophin-normal donor. The anti-dystrophin humoral response was delayed and dystrophin expression was partially preserved in irradiated, vector-treated mice. Nonirradiated, vector-treated control mice lost muscle dystrophin expression completely, had an earlier anti-dystrophin humoral response and demonstrated muscle fibers focally surrounded with T cells. We conclude that dystrophin gene transfer induced anti-dystrophin humoral immunity and cell-mediated responses that were significantly diminished and delayed by temporal removal of the host central or peripheral immune cells. Furthermore, manipulation of central immunity altered the pattern of regulatory T cells in muscle. PMID- 20827280 TI - Strict vs. mild blood pressure control in the elderly. PMID- 20827279 TI - From aldosteronism to oxidative stress: the role of excessive intracellular calcium accumulation. AB - Inappropriately (relative to dietary Na(+)) elevated plasma aldosterone concentrations (PAC), or aldosteronism, have been incriminated in both the appearance of the cardiometabolic syndrome (CMS) and its progressive nature. The deleterious dual consequences of elevated PAC and dietary Na(+) have been linked to several components of the CMS, including salt-sensitive hypertension. Moreover, their adverse consequences are considered to be synergistic, culminating in a pro-oxidant phenotype with oxidative injury involving the heart and systemic tissues, including peripheral blood mononuclear cells (PBMC). Our experimental studies in rats receiving aldosterone/salt treatment have identified a common pathogenic event that links aldosteronism to the induction of oxidative stress. Herein, we review these findings and the important role of excessive intracellular Ca(2+) accumulation (EICA), or intracellular Ca(2+) overloading, which occurs in the heart and PBMC, leading to, respectively, cardiomyocyte necrosis with a replacement fibrosis and an immunostimulatory state with consequent coronary vasculopathy. The origin of EICA is based on elevations in plasma parathyroid hormone, which are integral to the genesis of secondary hyperparathyroidism that accompanies aldosteronism and occurs in response to plasma-ionized hypocalcemia and hypomagnesemia whose appearance is the consequence of marked urinary and fecal excretory losses of Ca(2+) and Mg(2+). In addition, we found intracellular Ca(2+) overloading to be intrinsically coupled to a dyshomeostasis of intracellular Zn(2+), which together regulate the redox state of cardiac myocytes and mitochondria via the induction of oxidative stress and generation of antioxidant defenses, respectively. To validate our hypothesis, a series of site-directed, sequential pharmacological and/or nutriceutical interventions targeted along cellular-molecular cascades were carried out to either block downstream events leading to the pro-oxidant phenotype or to enhance antioxidant defenses. In each case, the interventions were found to be cardioprotective. These cumulative salutary responses raise the prospect that pharmacological agents and nutriceuticals capable of influencing extra- and intracellular Ca(2+) and Zn(2+) equilibrium could prevent adverse cardiac remodeling and thereby enhance the management of aldosteronism. PMID- 20827281 TI - A comprehensive analysis of microRNA expression during human keratinocyte differentiation in vitro and in vivo. AB - Here, we report a comprehensive investigation of changes in microRNA (miRNA) expression profiles on human keratinocyte (HK) differentiation in vitro and in vivo. We have monitored expression patterns of 377 miRNAs during calcium-induced differentiation of primary HKs, and have compared these patterns with miRNA expression profiles of epidermal stem cells, transient amplifying cells, and terminally differentiated HKs from human skin. Apart from the previously described miR-203, we found an additional nine miRNAs (miR-23b, miR-95, miR-210, miR-224, miR-26a, miR-200a, miR-27b, miR-328, and miR-376a) that are associated with HK differentiation in vitro and in vivo. In situ hybridization experiments confirmed miR-23b as a marker of HK differentiation in vivo. Additionally, gene ontology analysis and functional validation of predicted miRNA targets using 3' untranslated region-luciferase assays suggest that multiple miRNAs that are upregulated on HK differentiation cooperate to regulate gene expression during skin development. Our results thus provide the basis for further analysis of miRNA functions during epidermal differentiation. PMID- 20827282 TI - The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. AB - Metastases from primary cutaneous squamous cell carcinoma (SCC) account for the majority of the ~10,000 non-melanoma skin cancer deaths in the United States annually. We studied lymphangiogenesis in human SCC because of the potential link to metastasis. SCC samples were stained for lymphatic endothelial vessel marker LYVE-1 and positive cells were counted and compared with cells in normal skin. Gene set enrichment analysis and reverse transcription (RT)-PCR were performed on SCC, on adjacent non-tumor-bearing skin, and on normal skin to determine the differential expression of lymphangiogenesis-associated genes. Laser capture microdissection (LCM) was performed to isolate tumor cells and tumor-associated inflammatory cells for further gene expression analysis. Immunofluorescence was performed to determine the source of vascular endothelial growth factor-C (VEGF C) in the tumor microenvironment. We found increased lymphatic density and reorganized lymphatic endothelial vessels in the dermis immediately adjacent to SCC nests. RT-PCR confirmed the presence of VEGF-C in skin immediately adjacent to SCC. LCM confirmed the increased expression of VEGF-C, the SCC inflammatory infiltrate. The presence of CD163(+)/CD68(+)/VEGFC(+) cells and absence of VEGF-C expression by CD3(+) or CD11C(+) cells suggested that VEGF-C is derived from tumor-associated macrophages. Clarification of mechanisms governing SCC-mediated lymphangiogenesis may identify potential targets for therapeutic intervention against aggressive or inoperable disease. PMID- 20827283 TI - What can current stimulation tell us about the vascular function of endogenous prostacyclin in healthy rat skin in vivo? AB - In endothelial function, prostacyclin (PGI(2)) is as important as nitric oxide (NO); however, no test assesses specifically the vascular function of endogenous PGI(2). We hypothesized that PGI(2) has a dominant role in cathodal current induced vasodilation (CIV) described in human skin. We thus aimed to study, in physiological conditions, the PGI(2) involvement in cathodal CIV in rats in order to use pharmacological blockers that could not be used in humans. CIV was reduced by cyclooxygenase (COX)-1 and PGI(2) synthase (PGIS) and PGI(2) receptor (IP) blockers, but was unchanged by COX-2 and NO synthase (NOS) blockers. The level of 6-ketoPGF(1)(alpha) present in skin biopsies, measured as endogenous PGI(2), was increased by cathodal current stimulation, except under COX-1 and PGIS inhibition. This study provides evidence that cathodal CIV mainly relies on the release of PGI(2) endogenously produced through the COX-1/PGIS pathway, and then acts on IP receptors to relax the cutaneous microvessels in healthy rats. In contrast, neither COX-2 nor NOS is involved in CIV and the endogenous PGI(2) release by current stimulation. This finding shows that cathodal current stimulation could be a valuable method to assess the vascular function of endogenous PGI(2) in healthy skin. PMID- 20827284 TI - Effects of fluvastatin on insulin resistance and cardiac morphology in hypertensive patients. AB - Among hypertensive patients, cardiovascular disease morbidity is common, even in those who are adequately treated. New pharmacological strategies to mitigate the burden of arterial hypertension are needed. This 12-month, randomized, double blind placebo-controlled study investigated the effect of statin (fluvastatin) treatment on ambulatory blood pressure (ABP), exercise blood pressure (EBP), myocardial structure, endothelial function and insulin resistance in 50 hypertensive patients. At baseline, the groups were comparable in terms of demographic characteristics, ABP, EBP, endothelial function and homeostasis model assessment of insulin resistance (HOMA-IR). At the end of the study, there was no difference between groups in terms of resting systolic blood pressure. However, maximum systolic EBP was lower in the treatment group than in the placebo group (175 +/- 18 vs 192 +/- 23 mm Hg, P<0.05), as was left ventricular mass index (LVMI; 82 +/- 15 vs 100 +/- 23, P<0.05), and HOMA-IR index was lower after fluvastatin treatment (2.77 +/- 1.46 vs 3.33 +/- 1.73, P<0.05). Changes in lipid profile were not correlated with blood pressure, endothelial function, LVMI or HOMA-IR data. In hypertensive patients, fluvastatin can improve maximum systolic EBP, myocardial remodelling and insulin resistance, independently of lipid profile variations and endothelial function. PMID- 20827285 TI - The t(6;9) associated DEK/CAN fusion protein targets a population of long-term repopulating hematopoietic stem cells for leukemogenic transformation. AB - The t(6;9)-positive acute myeloid leukemia (AML) is classified as a separate clinical entity because of its early onset and poor prognosis. The hallmark of t(6;9) AML is the expression of the DEK/CAN fusion protein. The leukemogenic potential of DEK/CAN has been called into question, because it was shown to be unable to block the differentiation of hematopoietic progenitors. We found that DEK/CAN initiated leukemia from a small subpopulation within the hematopoietic stem cell (HSC) population expressing a surface marker pattern of long-term (LT) HSC. The propagation of established DEK/CAN-positive leukemia was not restricted to the LT-HSC population, but occurred even from more mature and heterogeneous cell populations. This finding indicates that in DEK/CAN-induced leukemia, there is a difference between 'leukemia-initiating cells' (L-ICs) and 'leukemia maintaining cells' (L-MCs). In contrast to the L-IC cells represented by a very rare subpopulation of LT-HSC, the L-MC seem to be represented by a larger and phenotypically heterogeneous cell population. PMID- 20827286 TI - Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). AB - Patients with multiple myeloma progressing on current therapies have limited treatment options. Pomalidomide (CC4047), an immunomodulatory drug, has significant activity in relapsed myeloma and previous studies suggest activity in lenalidomide refractory disease. To better define its efficacy in this group, we treated a cohort of lenalidomide refractory patients. Pomalidomide was given orally (2 mg) daily, continuously in 28-day cycles along with dexamethasone (40 mg) given weekly. Responses were assessed by the International Myeloma Working Group Criteria. Thirty-four patients were enrolled. The best response was very good partial response in 3 (9%), partial response (PR) in 8 (23%), best responses (MR) in 5 (15%), stable disease in 12 (35%) and progressive disease in 6 (18%), for an overall response rate of 47%. Of the 14 patients that were considered high risk, 8 (57%) had responses including 4 PR and 4 MR. The median time to response was 2 months and response duration was 9.1 months, respectively. The median overall survival was 13.9 months. Toxicity was primarily hematologic, with grade 3 or 4 toxicity seen in 18 patients (53%) consisting of anemia (12%), thrombocytopenia (9%) and neutropenia (26%). The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-refractory myeloma. PMID- 20827287 TI - B-chronic lymphocytic leukemia chemoresistance involves innate and acquired leukemic side population cells. AB - B-cell chronic lymphocytic leukemia (B-CLL) therapy remains unsatisfactory due to repeated resurgences of the chemoresistant disease. In this study, we investigated the basis of this chemoresistance by applying the 'side population' (SP) analysis to blood samples from B-CLL patients. We report the existence of few natural SP cells, which harbors phenotypic and cytogenetic hallmarks of B-CLL in most patients with this disease (n=22). SP cells appeared resistant to conventional B-CLL treatments, such as Fludarabine, Bendamustin or Rituximab. Indeed, treatment with Fludarabine (16/18 cases) or Bendamustin (5/7 cases) resulted in complete elimination of non-SP, whereas cells displaying the SP phenotype were the only surviving. Although some B-CLL SP cells were innately chemoresistant, chemotherapy by Fludarabine selected not only innate SP cells but also induced some acquired SP cells, which arose from non-SP by drug-driven evolution. This SP selection by chemotherapeutic treatments is further supported by the overall increase of the SP percentage in patients who experienced chemotherapy in the preceding year. Functionally, proliferative stimulation of SP cells was able to partially replenish in vitro the non-SP cell compartment of the B-CLL disease. The chemoresistance of B-CLL relies, in our model, on the cellular heterogeneity of B-CLL SP cells and on their regenerating dynamics. PMID- 20827288 TI - The graft-versus-leukemia effect is mainly restricted to NIH-defined chronic graft-versus-host disease after reduced intensity conditioning before allogeneic stem cell transplantation. AB - Incidence on relapse and nonrelapse mortality (NRM) of chronic graft-versus-host disease (GVHD), per National Institutes of Health (NIH) criteria, is not well defined after reduced-intensity conditioning (RIC) regimens. We analyzed the association of chronic GVHD with the risk of relapse and NRM using Cox models in 177 consecutive patients who underwent transplantation for hematological malignancies after RIC. The cumulative incidence of chronic GVHD at 36 months was 74% when using Seattle's criteria compared with 54% with NIH consensus. In Cox model, NRM was significantly higher in patients with late-onset, persistent and recurrent acute GVHD (hazard ratio (HR): 6, 25 and 11; P = 0.014, P<0.0001, P<0.0001, respectively). The cumulative incidence of relapse was significantly decreased in patients with chronic GVHD compared with no GVHD group using either Seattle's or NIH criteria (HR 0.43 and 0.38; P = 0.022 and 0.016, respectively), whereas the presence of late-onset, persistent and recurrent acute GVHD was not associated with a decreased rate of relapse (HR: not significant, 0.70 and 0.71; P = not significant, P = 0.73 and P = 0.54, respectively). Chronic GVHD per NIH consensus definition is associated with the graft-versus-tumor effect, whereas all forms associated with acute features beyond day 100 are associated with NRM. PMID- 20827289 TI - Diatom-associated bacteria are required for aggregation of Thalassiosira weissflogii. AB - Aggregation of algae, mainly diatoms, is an important process in marine systems leading to the settling of particulate organic carbon predominantly in the form of marine snow. Exudation products of phytoplankton form transparent exopolymer particles (TEP), which acts as the glue for particle aggregation. Heterotrophic bacteria interacting with phytoplankton may influence TEP formation and phytoplankton aggregation. This bacterial impact has not been explored in detail. We hypothesized that bacteria attaching to Thalassiosira weissflogii might interact in a yet-to-be determined manner, which could impact TEP formation and aggregate abundance. The role of individual T. weissflogii-attaching and free living new bacterial isolates for TEP production and diatom aggregation was investigated in vitro. T. weissflogii did not aggregate in axenic culture, and striking differences in aggregation dynamics and TEP abundance were observed when diatom cultures were inoculated with either diatom-attaching or free-living bacteria. The data indicated that free-living bacteria might not influence aggregation whereas bacteria attaching to diatom cells may increase aggregate formation. Interestingly, photosynthetically inactivated T. weissflogii cells did not aggregate regardless of the presence of bacteria. Comparison of aggregate formation, TEP production, aggregate sinking velocity and solid hydrated density revealed remarkable differences. Both, photosynthetically active T. weissflogii and specific diatom-attaching bacteria were required for aggregation. It was concluded that interactions between heterotrophic bacteria and diatoms increased aggregate formation and particle sinking and thus may enhance the efficiency of the biological pump. PMID- 20827290 TI - Sulfide induces phosphate release from polyphosphate in cultures of a marine Beggiatoa strain. AB - Sulfur bacteria such as Beggiatoa or Thiomargarita have a particularly high capacity for storage because of their large size. In addition to sulfur and nitrate, these bacteria also store phosphorus in the form of polyphosphate. Thiomargarita namibiensis has been shown to release phosphate from internally stored polyphosphate in pulses creating steep peaks of phosphate in the sediment and thereby inducing the precipitation of phosphorus-rich minerals. Large sulfur bacteria populate sediments at the sites of recent phosphorite formation and are found as fossils in ancient phosphorite deposits. Therefore, it can be assumed that this physiology contributes to the removal of bioavailable phosphorus from the marine system and thus is important for the global phosphorus cycle. We investigated under defined laboratory conditions which parameters stimulate the decomposition of polyphosphate and the release of phosphate in a marine Beggiatoa strain. Initially, we tested phosphate release in response to anoxia and high concentrations of acetate, because acetate is described as the relevant stimulus for phosphate release in activated sludge. To our surprise, the Beggiatoa strain did not release phosphate in response to this treatment. Instead, we could clearly show that increasing sulfide concentrations and anoxia resulted in a decomposition of polyphosphate. This physiological reaction is a yet unknown mode of bacterial polyphosphate usage and provides a new explanation for high phosphate concentrations in sulfidic marine sediments. PMID- 20827291 TI - UniFrac: an effective distance metric for microbial community comparison. PMID- 20827292 TI - Flexible Macroblock Ordering for Context-Aware Ultrasound Video Transmission over Mobile WiMAX. AB - The most recent network technologies are enabling a variety of new applications, thanks to the provision of increased bandwidth and better management of Quality of Service. Nevertheless, telemedical services involving multimedia data are still lagging behind, due to the concern of the end users, that is, clinicians and also patients, about the low quality provided. Indeed, emerging network technologies should be appropriately exploited by designing the transmission strategy focusing on quality provision for end users. Stemming from this principle, we propose here a context-aware transmission strategy for medical video transmission over WiMAX systems. Context, in terms of regions of interest (ROI) in a specific session, is taken into account for the identification of multiple regions of interest, and compression/transmission strategies are tailored to such context information. We present a methodology based on H.264 medical video compression and Flexible Macroblock Ordering (FMO) for ROI identification. Two different unequal error protection methodologies, providing higher protection to the most diagnostically relevant data, are presented. PMID- 20827298 TI - Viral organization of human proteins. AB - Although maps of intracellular interactions are increasingly well characterized, little is known about large-scale maps of host-pathogen protein interactions. The investigation of host-pathogen interactions can reveal features of pathogenesis and provide a foundation for the development of drugs and disease prevention strategies. A compilation of experimentally verified interactions between HIV-1 and human proteins and a set of HIV-dependency factors (HDF) allowed insights into the topology and intricate interplay between viral and host proteins on a large scale. We found that targeted and HDF proteins appear predominantly in rich clubs, groups of human proteins that are strongly intertwined among each other. These assemblies of proteins may serve as an infection gateway, allowing the virus to take control of the human host by reaching protein pathways and diversified cellular functions in a pronounced and focused way. Particular transcription factors and protein kinases facilitate indirect interactions between HDFs and viral proteins. Discerning the entanglement of directly targeted and indirectly interacting proteins may uncover molecular and functional sites that can provide novel perspectives on the progression of HIV infection and highlight new avenues to fight this virus. PMID- 20827299 TI - Dynamics of wind setdown at Suez and the Eastern Nile Delta. AB - BACKGROUND: Wind setdown is the drop in water level caused by wind stress acting on the surface of a body of water for an extended period of time. As the wind blows, water recedes from the upwind shore and exposes terrain that was formerly underwater. Previous researchers have suggested wind setdown as a possible hydrodynamic explanation for Moses crossing the Red Sea, as described in Exodus 14. METHODOLOGY/PRINCIPAL FINDINGS: This study analyzes the hydrodynamic mechanism proposed by earlier studies, focusing on the time needed to reach a steady-state solution. In addition, the authors investigate a site in the eastern Nile delta, where the ancient Pelusiac branch of the Nile once flowed into a coastal lagoon then known as the Lake of Tanis. We conduct a satellite and modeling survey to analyze this location, using geological evidence of the ancient bathymetry and a historical description of a strong wind event in 1882. A suite of model experiments are performed to demonstrate a new hydrodynamic mechanism that can cause an angular body of water to divide under wind stress, and to test the behavior of our study location and reconstructed topography. CONCLUSIONS/SIGNIFICANCE: Under a uniform 28 m/s easterly wind forcing in the reconstructed model basin, the ocean model produces an area of exposed mud flats where the river mouth opens into the lake. This land bridge is 3-4 km long and 5 km wide, and it remains open for 4 hours. Model results indicate that navigation in shallow-water harbors can be significantly curtailed by wind setdown when strong winds blow offshore. PMID- 20827300 TI - Integrin-linked kinase is a functional Mn2+-dependent protein kinase that regulates glycogen synthase kinase-3beta (GSK-3beta) phosphorylation. AB - BACKGROUND: Integrin-linked kinase (ILK) is a highly evolutionarily conserved, multi-domain signaling protein that localizes to focal adhesions, myofilaments and centrosomes where it forms distinct multi-protein complexes to regulate cell adhesion, cell contraction, actin cytoskeletal organization and mitotic spindle assembly. Numerous studies have demonstrated that ILK can regulate the phosphorylation of various protein and peptide substrates in vitro, as well as the phosphorylation of potential substrates and various signaling pathways in cultured cell systems. Nevertheless, the ability of ILK to function as a protein kinase has been questioned because of its atypical kinase domain. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have expressed full-length recombinant ILK, purified it to >94% homogeneity, and characterized its kinase activity. Recombinant ILK readily phosphorylates glycogen synthase kinase-3 (GSK-3) peptide and the 20-kDa regulatory light chains of myosin (LC(20)). Phosphorylation kinetics are similar to those of other active kinases, and mutation of the ATP binding lysine (K220 within subdomain 2) causes marked reduction in enzymatic activity. We show that ILK is a Mn-dependent kinase (the K(m) for MnATP is approximately 150-fold less than that for MgATP). CONCLUSIONS/SIGNIFICANCE: Taken together, our data demonstrate that ILK is a bona fide protein kinase with enzyme kinetic properties similar to other active protein kinases. PMID- 20827301 TI - Oral and enteral resuscitation of burn shock the historical record and implications for mass casualty care. AB - In the aftermath of a mass disaster, standard care methods for treatment of burn injury will often not be available for all victims. A method of fluid resuscitation for burns that has largely been forgotten by contemporary burn experts is enteral resuscitation. We identified 12 studies with over 700 patients treated with enteral resuscitation, defined as drinking or gastric infusion of salt solutions, from the literature. These studies suggest that enteral resuscitation can be an effective treatment for burn shock under conditions in which the standard IV therapy is unavailable or delayed, such as in mass disasters and combat casualties. Enteral resuscitation of burn shock was effective in patients with moderate (10-40% TBSA) and in some patients with more severe injuries. The data suggests that some hypovolemic burn and trauma patients can be treated exclusively with enteral resuscitation, and others might benefit from enteral resuscitation as an initial alternative and a supplement to IV therapy. A complication of enteral resuscitation was vomiting, which occurred less in children and much less when therapy was initiated within the first postburn hour. Enteral resuscitation is contra-indicated when the patient is in "peripheral circulatory collapse". The optimal enteral solution and regimen has not yet been defined, nor has its efficacy been tested against modern IV resuscitation. The oldest studies used glucose-free solutions of buffered isotonic and hypotonic saline. Studies that are more recent show benefit of adding glucose to electrolyte solutions similar to those used in the treatment of cholera. If IV therapy for mass casualty care is delayed due to logistical constraints, enteral resuscitation should be considered. PMID- 20827302 TI - Renal manifestations in scleroderma: evidence for subclinical renal disease as a marker of vasculopathy. AB - Scleroderma is a disease characterized by immune activation, vasculopathy, fibroblast stimulation, and connective tissue fibrosis. End-organ damage occurs due to progressive tissue fibrosis and vasculopathy. Markers of incipient vasculopathy have not been well studied in scleroderma. However, reduced renal functional reserve and proteinuria are common indicators of progressive vasculopathy in diabetic and hypertensive vasculopathy. Recent studies suggest a strong association between renal involvement and outcomes in scleroderma, with a threefold increased risk of mortality from pulmonary hypertension if renal insufficiency is present. We review the types of renal involvement seen in scleroderma and the data to support the use of renal parameters including proteinuria, glomerular filtration rate, and renal vascular dynamics measured with Doppler ultrasound to identify subclinical renal insufficiency. Further studies are warranted to investigate the use of renal parameters as prognostic indicators in scleroderma. PMID- 20827303 TI - Unnecessary workup of asymptomatic neonates in the era of group B streptococcus prophylaxis. AB - Asymptomatic term neonates born to mothers who are Group B Streptococcus (GBS) unknown or GBS positive but "inadequately" treated prior to delivery do not require invasive laboratory evaluation. We conducted a retrospective cohort study of mother/baby dyads born from January 1, 2005 until September 30, 2007 at the Medical College of Georgia. Their current protocol is to obtain a Complete Blood Count with Differential (CBC with D), Blood Culture (BC), and C-reactive protein (CRP) after birth. Mother/baby dyads (n = 242) that met inclusion criteria were reviewed. Of these 242 babies 25 (10%) were started on antibiotics after the initial lab values were known. None of the blood cultures were positive and the CRP's were normal. The 2002 GBS guidelines call for laboratory evaluation of "at risk" neonates, but the workup of these babies is not only costly, it does not provide any advantage over old fashioned clinical observation for the evaluation and treatment of early onset GBS sepsis. PMID- 20827304 TI - The minimally invasive effect of breast approach endoscopic thyroidectomy: an expert's experience. AB - We evaluated the invasiveness of breast approach endoscopic thyroidectomy (BAET) carried out by surgeon very experienced in this procedure. Twenty-four patients who underwent BAET and 19 patients who underwent conventional thyroidectomy were the study population. Postoperative pain was assessed by a visual analog scale (VAS). The values 2, 12, and 24 h after surgery were significantly lower in the BAET group than those in the conventional group. Serum IL-6 and CRP levels were measured by an ELISA preoperatively and at 2, 12, 24 and 48 h after operation. Their values increased significantly after both procedures when compared to preoperative levels with significant differences between the two groups detected at the 24-hour and 48-hour time points. Subjective and objective evidence supported the notion that BAET could become a minimally invasive procedure if the surgeon gained sufficient experience. PMID- 20827305 TI - Are guidelines needed for the diagnosis and management of incipient Alzheimer's disease and mild cognitive impairment? AB - Current research is aiming to push the boundaries of the point at which a diagnosis of Alzheimer Disease (AD) can be made. Clinical syndromes such as Mild Cognitive Impairment (MCI) and various clinical and biological markers of AD may help to identify people in the early stage of AD, before a full dementia syndrome is present. In the first part of this paper, we discuss whether MCI represents incipient AD, and examine some of the methods currently used in research to identify AD patients in the preclinical phase. In the second part, we discuss whether specific guidelines are needed for the diagnosis and management of MCI and incipient AD, and consider the potential impact of this on clinical practice and public health from the perspective of patients, caregivers, and healthcare providers. PMID- 20827306 TI - Coordinated increased expression of Cyclooxygenase2 and nuclear factor kappaB is a steady feature of urinary bladder carcinogenesis. AB - OBJECTIVES: The inescapable relationship between chronic inflammation and carcinogenesis has long been established. Our objective was to investigate COX-2 and NF-kappaB immunohistochemical expression in a large series of normal epithelium and bladder carcinomas. METHODS: Immunohistochemical methodology was performed on formalin-fixed, paraffin-embedded sections from urinary bladder carcinomas of 140 patients (94 males and 46 females with bladder carcinomas). RESULTS: COX-2 expression is increased in the cytoplasm of bladder cells, during loss of cell differentiation (r(s) = 0.61, P-value < .001) and in muscle invasive carcinomas (P-value < .001). A strong positive association between tumor grade and nuclear expression of NFkappaB has been established. A positive correlation between COX-2 and nuclear NFkappaB immunoreactivity was observed. CONCLUSIONS: The possible coordinated upregulation of NFkappaB and COX-2, during bladder carcinogenesis, indicates that agents inhibitors of these two molecules may represent a possible new treatment strategy, by virtue of their role in bladder carcinogenesis. PMID- 20827307 TI - Evaluating children with otitis media for bacteremia or urinary tract infection. AB - Background. It is unclear if clinicians evaluate for concurrent bacteremia or UTI in young patients diagnosed with acute otitis media (AOM). Objectives. To describe how often, and under which circumstances, emergency providers investigate for bacteremia or UTI in 2-36 month olds with AOM. Methods. Cases of AOM were analyzed from the 2001-2004 National Hospital Ambulatory Medical Care Survey (NHAMCS)-Emergency Department dataset. Results. AOM was diagnosed in 17% of the 10,847 recorded visits of 2-36 month olds. Of these visits, laboratory testing included: CBC: 7%, Blood culture: 4%, urinalysis or urine culture: 5%, and any of these tests: 9%. Rates of testing for 2-6 month olds with temperature >= 38.0 (CBC: 13%, blood culture: 9%, urinalysis or urine culture: 7%, any of the tests: 14%) were not significantly different from testing of patients aged 6-12 months, or 12-36 months (all P > .1). Patients with temperature of >=39.0 were more likely to have all tests, with the exception of urine investigation, than patients with temperature between 38.0 and 38.9. Conclusions. 17% of 2-36 month old patients seen in the emergency department are diagnosed with AOM. Investigating for bacteremia or UTI in these patients is not routine, even in febrile infants. PMID- 20827308 TI - LPS-Toll-Like Receptor-Mediated Signaling on Expression of Protein S and C4b Binding Protein in the Liver. AB - Protein S (PS), mainly synthesized in hepatocytes and endothelial cells, plays a critical role as a cofactor of anticoagulant activated protein C (APC). PS activity is regulated by C4b-binding protein (C4BP), structurally composed of seven alpha-chains (C4BPalpha) and a beta-chain (C4BPbeta). In this paper, based primarily on our previous studies, we review the lipopolysaccharide (LPS)-induced signaling which affects expression of PS and C4BP in the liver. Our in vivo studies in rats showed that after LPS injection, plasma PS levels are significantly decreased, whereas plasma C4BP levels first are transiently decreased after 2 to 12 hours and then significantly increased after 24 hours. LPS decreases PS antigen and mRNA levels in both hepatocytes and sinusoidal endothelial cells (SECs), and decreases C4BP antigen and both C4BPalpha and C4BPbeta mRNA levels in hepatocytes. Antirat CD14 and antirat Toll-like receptor (TLR)-4 antibodies inhibited LPS-induced NFkappaB activation in both hepatocytes and SECs. Furthermore, inhibitors of NFkappaB and MEK recovered the LPS-induced decreased expression of PS in both cell types and the LPS-induced decreased expression of C4BP in hepatocytes. These data suggest that the LPS-induced decrease in PS expression in hepatocytes and SECs and LPS-induced decrease in C4BP expression in hepatocytes are mediated by MEK/ERK signaling and NFkappaB activation and that membrane-bound CD14 and TLR-4 are involved in this mechanism. PMID- 20827309 TI - Applying small-scale DNA signatures as an aid in assembling soybean chromosome sequences. AB - Previous work has established a genomic signature based on relative counts of the 16 possible dinucleotides. Until now, it has been generally accepted that the dinucleotide signature is characteristic of a genome and is relatively homogeneous across a genome. However, we found some local regions of the soybean genome with a signature differing widely from that of the rest of the genome. Those regions were mostly centromeric and pericentromeric, and enriched for repetitive sequences. We found that DNA binding energy also presented large-scale patterns across soybean chromosomes. These two patterns were helpful during assembly and quality control of soybean whole genome shotgun scaffold sequences into chromosome pseudomolecules. PMID- 20827310 TI - Comparison of tracheal diameter measured by chest x-ray and by computed tomography. AB - Assessments of tracheal diameter (TD) are important to select proper endotracheal tubes. Previous studies have used X-ray and physical indices to estimate tracheal diameter but these may not reflect the actual TD. We compared TD measured by X ray (TD-XP) and by computer tomography (TD-CT) in 200 patients. Also, we analyzed correlation of TD-CT with physical indices such as age, height, weight, and BMI. TD-XP and TD-CT were significantly correlated (male: n = 55, P = .0146; female: n = 91, P = .001). TD-XP was 0.4 mm wider in male and 1.0 mm wider in female than TD-CT. However, correlation coefficients of TD-XP and TD-CT are very weak (male: r = 0.36; female: r = 0.653). TD-CT did not correlate with age, height, weight, or BMI. Our findings suggest that correlations of TD-XP and TD are statistically significant but not clinically significant. Physical indices are not useful to estimate TD. PMID- 20827312 TI - CSF Biomarkers Profile in CADASIL-A Model of Pure Vascular Dementia: Usefulness in Differential Diagnosis in the Dementia Disorder. AB - Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is considered a model of pure vascular dementia (VD) because it occurs in young adults unlikely to have concomitant age and Alzheimer's Disease-(AD-) related pathology. CSF levels of beta-amyloid 1-42 (Abeta42), total tau protein (t-tau), and phosphorylated tau-protein (p-tau), well accepted biomarkers of AD, were evaluated in 10 CADASIL patients, 22 AD patients, and 17 healthy age-matched subjects. Innotest beta-amyloid 1-42, Innotest hTAU-Ag, and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay were used to determine CSF biomarkers levels. A case-control statistical analysis was carried out. CSF Abeta42 levels were significantly lower in CADASIL patients and considerable overlap with AD whereas t-tau and p-tau levels were normal and significantly different with respect to AD. A significant altered CSF biomarkers profile in a pure VD supports the use of CSF Abeta42, t tau, and p-tau levels in the differential diagnosis of VD and AD. PMID- 20827311 TI - Effects of S100B on Serotonergic Plasticity and Neuroinflammation in the Hippocampus in Down Syndrome and Alzheimer's Disease: Studies in an S100B Overexpressing Mouse Model. AB - S100B promotes development and maturation in the mammalian brain. However, prolonged or extensive exposure can lead to neurodegeneration. Two important functions of S100B in this regard, are its role in the development and plasticity of the serotonergic neurotransmitter system, and its role in the cascade of glial changes associated with neuroinflammation. Both of these processes are therefore accelerated towards degeneration in disease processes wherein S100B is increased, notably, Alzheimer's disease (AD) and Down syndrome (DS). In order to study the role of S100B in this context, we have examined S100B overexpressing transgenic mice. Similar to AD and DS, the transgenic animals show a profound change in serotonin innervation. By 28 weeks of age, there is a significant loss of terminals in the hippocampus. Similarly, the transgenic animals show neuroinflammatory changes analogous with AD and DS. These include decreased numbers of mature, stable astroglial cells, increased numbers of activated microglial cells and increased microglial expression of the cell surface receptor RAGE. Eventually, the S100B transgenic animals show neurodegeneration and the appearance of hyperphosphorylated tau structures, as seen in late stage DS and AD. The role of S100B in these conditions is discussed. PMID- 20827313 TI - Lower extremity ulcers in systemic sclerosis: features and response to therapy. AB - Nondigital lower extremity ulcers are a difficult to treat complication of scleroderma, and a significant cause of morbidity. The purpose of this study was to evaluate the prevalence of nondigital lower extremity ulcers in scleroderma and describe the associations with autoantibodies and genetic prothrombotic states. A cohort of 249 consecutive scleroderma patients seen in the Georgetown University Hosptial Division of Rheumatology was evaluated, 10 of whom had active ulcers, giving a prevalence of 4.0%. Patients with diffuse scleroderma had shorter disease duration at the time of ulcer development (mean 4.05 years +/- 0.05) compared to those with limited disease (mean 22.83 years +/- 5.612, P value .0078). Ulcers were bilateral in 70%. In the 10 patients with ulcers, antiphospholipid antibodies were positive in 50%, and genetic prothrombotic screen was positive in 70% which is higher than expected based on prevalence reports from the general scleroderma population. Of patients with biopsy specimens available (n = 5), fibrin occlusive vasculopathy was seen in 100%, and all of these patients had either positive antiphospholipid antibody screen, or positive genetic prothrombotic profile. We recommend screening scleroderma patients with lower extremity ulcers for the presence of anti-phospholipid antibodies and genetic prothrombotic states. PMID- 20827315 TI - Modulation of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in sepsis. AB - Previous studies demonstrated that hepatic matrix metalloproteinase-9 (MMP-9) activity increased following cecal ligation and puncture (CLP) in rats, indicating liver injury in sepsis. The activity of MMP-9 in degrading extracellular matrix is controlled by activation of proenzymes and inhibition of tissue inhibitor of MMPs (TIMP-1). To further assess the proteolytic cascade imbalance in sepsis, hepatic MMP-9 and TIMP-1 expressions were examined in CLP rats. In this study, sepsis was induced in rats by CLP, and at 10 and 20 h after sepsis induction, liver samples were collected and MMP-2, MMP-9, and TIMP-1 gene and protein expressions were evaluated by real time PCR and Western blot analysis, respectively. Gene expression of MMP-9 was increased by 6.4-fold and 3.0-fold at 10 h and 20 h after CLP as compared to sham group, respectively. Likewise, MMP-9 protein expression was also significantly increased at both time points. In contrast, MMP-2 gene expression was not altered at 10 h and 20 h after CLP as compared to sham controls. Interestingly, TIMP-1 gene expression was elevated to 89-fold and 46-fold from sham levels at 10 h and 20 h after CLP, respectively. Similarly, TIMP-1 protein levels were also significantly increased at both time points. In addition, MMP-9/TIMP-1 protein ratio was lower at both 10 h and 20 h after CLP compared to sham rats. Results demonstrated an imbalance between MMP and TIMP, with a more evident role for MMP-9 than MMP-2, and high value of TIMP-1 was particularly evident in CLP rats. Our results indicate that MMP-9 and TIMP-1 expressions are increased and they may serve as useful markers to predict the outcome of sepsis. PMID- 20827316 TI - Ability of the ankaferd blood stopper(r) to prevent parenchymal bleeding in an experimental hepatic trauma model. AB - Hepatic parenchymal bleeding (HPB) is a major problem following both trauma and elective hepatic procedures. The present study investigated the effect of the Ankaferd Blood Stopper(r) (ABS) on HPB. METHOD(S): A total of 20 rats were used. After creating a laceration model in the left lateral hepatic lobe, the area was compressed for 3 minutes with the ABS in the rats in group 1 (n=10) and with 0.9% NaCl-soaked gauze in the rats in group 2 (n=10). RESULTS: The mean change in haematocrit levels between baseline and the 24 hour values in group 1 was lower than group 2 (p=0.045). The mean perioperative bleeding in group 1 was lower than group 2 (p=0.003). The histopa-thologic evaluation revealed that there were no differences between the groups with respect to areas of necrosis (p=0.107) or inflammation (p=0.135). CONCLUSION: Although the ABS does not stop HPB completely, it ensures a statistically significant reduction in HPB. PMID- 20827314 TI - Toll-like receptors in the pathogenesis of alcoholic liver disease. AB - In the multifactorial pathophysiology of alcoholic liver disease (ALD), inflammatory cascade activation plays a central role. Recent studies demonstrated that Toll-like Receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD. In this paper, we discuss the importance of gut-derived endotoxin and its recognition by TLR4. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of reactive oxygen radicals is evaluated. The contribution of TLR signaling to induction of liver fibrosis and hepatocellular cancer is reviewed in the context of alcohol-induced liver disease. PMID- 20827318 TI - Prevalence of ultrasound-diagnosed non-alcoholic fatty liver disease in a hospital cohort and its association with anthropometric, biochemical and sonographic characteristics. AB - Non-alcoholic fatty liver disease (NAFLD) is considered as the most common liver disease in Western countries with still rising prevalence due to a lifestyle favoring the development of the metabolic syndrome. AIM: To investigate the prevalence of ultrasound-diagnosed NAFLD in patients with referral for sonographic examination of the abdomen, and to determine risk factors. METHODS: After exclusion of patients with known liver disease or risk factors for secondary NAFLD, a total of 155 arbitrarily selected patients (mean age 53.6+/ 17.4 years; 52.6% male) from the interdisciplinary ultrasound department of a German University Hospital were included in this prospective study. Each patient underwent a standardized ultrasound, anthropometric and biochemical examination. RESULTS: The prevalence of ultrasound-diagnosed NAFLD was 40.0%. NAFLD-patients had significantly higher body mass index (BMI) and waist-to-hip ratio, higher rates of reported hypertension and diabetes mellitus, and lower HDL cholesterol serum levels. Furthermore, NAFLD-patients revealed significantly higher serum ALT levels (23.2+/-22.1 U/l vs. 15.0+/-8.2 U/l; p=0.001), lower AST/ALT ratio (1.76+/ 0.79 vs. 2.11+/-0.94; p=0.019), and notably, decreased flow in the portal vein (22.9+/-6.3 cm/s vs. 26.7+/-10.5 cm/s; p=0.011). Multivariate analysis revealed BMI (odds ratio (OR): 14.05; 95% Confidence interval (CI): 3.3-59.8), AST/ALT ratio (OR: 0.39; CI: 0.18-0.82), and HDL-C (OR: 4.33; CI: 1.6-11.9) as independent risk factors. CONCLUSIONS: Ultrasound-diagnosed NAFLD is frequent in patients with referral for ultrasound examination of the abdomen, and our findings further support that NAFLD is the hepatic manifestation of the metabolic syndrome with obesity being the most important risk factor. PMID- 20827319 TI - MicroRNA-21 is involved in ionizing radiation-promoted liver carcinogenesis. AB - It has been known for decades that ionizing radiation (IR) promotes carcinogenesis and high-linear energy transfer (LET) IR has a higher risk than low-LET IR for carcinogenesis; however, the mechanism remains unclear. MicroRNAs (miRNAs) have a critical effect on carcinogenesis through post-transcriptional modification. In this study, our purpose is to explore whether miRNAs are involved in IR-(especially high-LET IR) promoted liver carcinogenesis. We showed here that among several hundred miRNAs, miR-21 was the only one that increased 6 folds in high-LET IR-promoted mouse liver tumors when compared with that in the non-irradiated liver tissues. We also showed that miR-21 was up-regulated in human or mouse hepatocytes after exposure to IR, as well as in liver tissues derived from whole body irradiated mice. The increased level of miR-21 was more significant in high-LET irradiated cells or liver tissues. After the non irradiated, low-LET or high-LET irradiated human hepatocytes were over-expressed with miR-21, these cells became tumorigenesis in nude mice. The tumors derived from high-LET-irradiated-cells were largest, and accompanied by more significant changes in the miR-21-targets: PTEN and RECK. In addition, we showed that IR induced up-regulation of miR-21 depended on the up-regulation/activation of AP-1 (at an earlier time, within 2 h) and the ErbB/Stat3 pathway (at a later time, more than 2 h), which was also IR dose dependent. Taken together, we conclude that IR-induced up-regulation of miR-21 plays an important role in IR (especially high-LET IR)-promoted liver carcinogenesis. PMID- 20827317 TI - Drug-eluting stents. AB - Coronary artery disease (CAD) is currently a leading cause of death worldwide. Drug-eluting stents (DESs) have been dominant for the treatment of CAD in the interventional cardiology world owing to their efficacy in significantly reducing restenosis. However, late stage stent thrombosis has become a major concern. Stent platform, drug delivery vehicle and type of drug are three parts of DES and each part affects the performance of the DES. Aiming to provide a clue for the design of future DES, this review focuses on the development of the three major components of DES and their roles in restenosis and thrombosis. PMID- 20827320 TI - A cellular model to mimic exhaled cigarette smokeinduced lung microvascular endothelial cell injury and death. AB - Tobacco smoke exhaled from smokers is a key component of secondhand smoke, contributing to lung alveolar wall destruction seen in chronic lung diseases. Although mainstream and sidestream tobacco smoke are cyto-toxic to lung cells, it is unclear whether exhaled smoke induces lung cell injury or even death. We sought to establish an in vitro model to examine the effects of exhaled smoke on lung cells. Phosphate-buffered saline-conditioned cigarette smoke (CCS) derived from a blow-by system was used to mimic exhaled tobacco smoke exposure. Exposure of medium to CCS leads to dose-dependent increases in nicotine/cotinine levels. Scanning spectrophotometric analysis of the CCS-exposed medium reveals an absorption peak at 290 nm wavelength. The OD values at 290 nm are correlated with nicotine levels in the exposed medium, indicating that a simple measurement of OD at 290 nm can be used to monitor CCS exposure. Tobacco smoke contacts the microvascular endothelium located at lung alveoli, before it enters the blood stream. Hence, human lung microvascular endothelial cells (hMVEC) were exposed to CCS and assessed for cell injury and death. Exposure of hMVEC to CCS equivalent to burning 12-16 cigarettes leads to increased LDH release from the cells into the medium. This suggests that CCS can induce lung cell injury. CCS at a low level increases cell growth, whereas the high level of CCS decreases cell viability. In addition, CCS exposure induces cell detachment and morphological changes. Our results demonstrate that exposure of buffer-conditioned mainstream cigarette smoke leads to increased nicotine/cotinine levels and cell injury/death, which may contribute to the pathophysiology of passive smoking associated lung diseases. PMID- 20827322 TI - Dutasteride prevents the growth response to testosterone in benign and androgen sensitive malignant prostate cells. AB - We show that the dual 5-alpha reductase enzyme inhibitor dutasteride prevents enhanced growth of both benign and malignant prostate cell lines, incubated with physiologic to supraphysiologic doses of testosterone. Using androgen-sensitive benign BPH-1 cells, LNCaP cancer cells, their derivative C4-2 cells, or Dunning rat cancer cells, we subjected 30,000 cells/well to concomitant treatment with 10(-9), 10(-8), or 10(-7) M testosterone in the presence of low (0.25 MUM) or high (1.0 MUM) doses of dutasteride. Both low- and high-dose dutasteride abrogated testosterone-stimulated growth of all 4 cell lines. If the in vitro data mimic conditions in men undergoing testosterone replacement, concomitant dutasteride use might make testosterone safe for men with benign prostatic hypertrophy, latent prostate cancer and perhaps even aggressive prostate cancer. Testosterone might also be used to prevent the rare anti-androgen side effects of dutasteride when used for benign prostatic hypertrophy and baldness. Further clinical investigation is indicated. PMID- 20827323 TI - En attendant Godot. PMID- 20827321 TI - Role of the CX3CL1-CX3CR1 axis in chronic inflammatory lung diseases. AB - Persistent inflammation is often present in patients with lung diseases such as chronic obstructive pulmonary diseases (COPD) and pulmonary hypertension. Circulatory leukocyte migration through the lung vascular endothelium contributes to the structural destruction and remodeling seen in these chronic lung diseases. An inflammatory chemokine CX3CL1/fractalkine is associated with inflammatory lung diseases. Membrane-anchored CX3CL1 serves as an adhesion molecule to capture subsets of mononuclear leukocytes that express the sole receptor, CX3CR1. The extracellular chemokine domain of CX3CL1 can be cleaved/shed by a disintegrin and metalloproteinase domain (ADAM) from stimulus-exposed cells. Soluble CX3CL1 chemoattracts and activates CX3CR1+ leukocytes such as CD8+, CD4+, and gammadelta T lymphocytes, natural killer cells, dendritic cells, and monocytes/macrophages. CX3CR1+ leukocyte attachment to and migration through the lung vascular endothelium lead to mononuclear cell accumulation in the lung vessel walls and parenchyma. Infiltrated CX3CR1+ immune cells can release mediators to induce injury, stimulate proliferation, and/or chemoattract inflammatory cells. This contributes to structural destruction and remodeling in the development of inflammatory lung diseases. Limited clinical success in treating chronic pulmonary diseases-associated lung functional decline indicates the urgency and significance of understanding upstream signaling that triggers inflammation. This article reviews the advances in the CX3CL1-CX3CR1 axis-mediated modulation of mononuclear leukocyte adhesion and migration in inflammatory lung diseases such as COPD and pulmonary hypertension. Better understanding of the constant flow of circulating leukocytes into the lung vessel wall and parenchyma will help set a stage for the development of novel therapeutic approaches to treat or even cure chronic lung diseases including COPD and pulmonary hypertension. PMID- 20827325 TI - Antioxidant profile of whole saliva after scaling and root planing in periodontal disease. AB - PURPOSE: This study compared the total antioxidant status (TAS) and superoxide dismutase (SOD) activity in the saliva of periodontally compromised patients before and after scaling and root planing (SRP) to assess their diagnostic utility. METHODS: Severe chronic periodontitis patient (test group) and subjects with no attachment loss, sites showing a 3 mm or more probing depth and a sulcus bleeding index < 10% (control group) were enrolled in this study. Saliva sampling and clinical examination were performed at one week, one month and 3 months after SRP. The TAS and SOD activity in each patient's saliva was measured for the comparative analysis between the groups. RESULTS: In the test group, the TAS decreased directly after SRP. With time, it increased slightly and was relatively unchanged compared to the baseline. In the control group, the TAS also decreased immediately after SRP but increased gradually with time until 3 months. The SOD activity in the test and control subjects decreased immediately after SRP until 1 month. At 3 months, the SOD activity had increased. Both groups had a similar profile of SOD activity. However, the SOD activity of the control group was significantly higher than that of the test group at each point in time (P < 0.05). CONCLUSIONS: There was a significant difference in the total salivary antioxidant level between the periodontitis and healthy or gingivitis (control) group during the experiment period. The total antioxidant level in the saliva was higher in the patients with severe chronic periodontitis than the healthy or gingivitis control before SRP. The SOD activity of the periodontitis patients was lower than the control at each time point. These findings conclusively reveal the possible use of saliva as a diagnostic tool for periodontal health. PMID- 20827324 TI - Vaccines against periodontitis: a forward-looking review. AB - Periodontal disease, as a polymicrobial disease, is globally endemic as well as being a global epidemic. It is the leading cause for tooth loss in the adult population and has been positively related to life-threatening systemic diseases such as atherosclerosis and diabetes. As a result, it is clear that more sophisticated therapeutic modalities need to be developed, which may include vaccines. Up to now, however, no periodontal vaccine trial has been successful in satisfying all the requirements; to prevent the colonization of a multiple pathogenic biofilm in the subgingival area, to elicit a high level of effector molecules such as immunoglobulin sufficient to opsonize and phagocytose the invading organisms, to suppress the induced alveolar bone loss, or to stimulate helper T-cell polarization that exerts cytokine functions optimal for protection against bacteria and tissue destruction. This article reviews all the vaccine trials so as to construct a more sophisticated strategy which may be relevant in the future. As an innovative strategy to circumvent these barriers, vaccine trials to stimulate antigen-specific T-cells polarized toward helper T-cells with a regulatory phenotype (Tregs, CD4+, CD25+, FoxP3+) have also been introduced. Targeting not only a single pathogen, but polymicrobial organisms, and targeting not only periodontal disease, but also periodontal disease-triggered systemic disease could be a feasible goal. PMID- 20827326 TI - Evaluating intra- and inter-examiner reproducibility in histometric measurement: one-wall intrabony periodontal defects in beagle dogs. AB - PURPOSE: Accurate and exact measurement is an important factor for generating meaningful results in any properly designed study. If all the participating examiners are able to yield similar results, it will be possible to evaluate the objective results of the study more easily and quickly. The purpose of this study was to evaluate the intra- and inter-examiner reproducibility of histometric measurements in the intrabony periodontal defect model. METHODS: One wall intrabony defects were surgically created at the distal aspect of the second and the medial aspect of the fourth mandibular premolars in the right and left jaw quadrants in twenty beagle dogs and the defect sites received the following beta tri calcium phosphate, growth differentiation factor-0, growth differentiation factor-100 and sham surgery. Histometric analysis was performed after 8 weeks. Histometric parameters were recorded and repeated at three months interval by three examiners. Intra- and inter-examiner reproducibility was assessed. RESULTS: Most parameters of all the groups showed high intra- and inter-examiner reproducibility. Parameters including defect height, bone regeneration height, cementum regeneration height, and formation of junctional epithelium yielded inter-examiner correlation >= 0.9. The intra-examiner reproducibility showed a high result, over 0.9. CONCLUSIONS: Histometric evaluation of the one-wall intra alveolar periodontal defect model showed high reproducibility not only for a single given examiner but also among the three examiners. PMID- 20827327 TI - Spontaneous healing capacity of rabbit cranial defects of various sizes. AB - PURPOSE: This study evaluated the spontaneous healing capacity of surgically produced cranial defects in rabbits with different healing periods in order to determine the critical size defect (CSD) of the rabbit cranium. METHODS: Thirty two New Zealand white rabbits were used in this study. Defects of three sizes (6, 8, and 11 mm) were created in each of 16 randomly selected rabbits, and 15-mm defects were created individually in another 16 rabbits. The defects were analyzed using radiography, histologic analysis, and histometric analysis after the animal was sacrificed at 2, 4, 8, or 12 weeks postoperatively. Four samples were analyzed for each size of defect and each healing period. RESULTS: The radiographic findings indicated that defect filling gradually increased over time and that smaller defects were covered with a greater amount of radiopaque substance. Bony islands were observed at 8 weeks at the center of the defect in both histologic sections and radiographs. Histometrical values show that it was impossible to determine the precise CSD of the rabbit cranium. However, the innate healing capacity that originates from the defect margin was found to be constant regardless of the defect size. CONCLUSIONS: The results obtained for the spontaneous healing capacity of rabbit cranial defects over time and the underlying factors may provide useful guidelines for the development of a rabbit cranial model for in vivo investigations of new bone materials. PMID- 20827328 TI - Esthetic evaluation of maxillary single-tooth implants in the esthetic zone. AB - PURPOSE: The aim of this study is to assess the influence exerted by the observer's dental specialization and compare patients' opinion with observers' opinion of the esthetics of maxillary single-tooth implants in the esthetic zone. METHODS: Forty-one adult patients, who were treated with a single implant in the esthetic zone, were enrolled in this study. Eight observers (2 periodontists, 2 prosthodontists, 2 orthodontists and 2 senior dental students) applied the pink esthetic score (PES)/white esthetic score (WES) to 41 implant-supported single restorations twice with an interval of 4 weeks. We used a visual analog scale (VAS) to assess the patient's satisfaction with the treatment outcome from an esthetic point of view. RESULTS: In the PES/WES, very good and moderate intraobserver agreements were noted between the first and second rating. The mean total PES/WES was 11.19 +/- 3.59. The mean PES was 5.17 +/- 2.29 and mean WES was 6.02 +/- 1.96. In the total PES/WES, the difference between the groups was not significant. However, in the WES, the difference between the groups was significant and prosthodontists were found to have assigned poorer ratings than the other groups. Periodontists gave higher ratings than prosthodontists and senior dental students. Orthodontists were clearly more critical than the other observers. The statistical analysis revealed statistically significant correlation between patients' esthetic perception and dentists' perception of the anterior tooth. However, the correlation between the total PES/WES and the VAS score for the first premolar was not statistically significant. CONCLUSIONS: The PES/WES is an objective tool in rating the esthetics of implant supported single crowns and adjacent soft tissues. Orthodontists were the most critical observers, while periodontists were more generous than other observers. The statistical analysis revealed a statistically significant correlation between patients' esthetic perception and dentists' perception of the anterior tooth. PMID- 20827329 TI - A simple approach to preserve keratinized mucosa around implants using a pre fabricated implant-retained stent: a report of two cases. AB - PURPOSE: There is no consensus regarding the relationship between the width of keratinized mucosa and the health of peri-implant tissues, but clinicians prefer to provide enough keratinized mucosa around dental implants for long-term implant maintenance. An apically positioned flap during second stage implant surgery is the chosen method of widening the keratinized zone in simple procedures. However, the routine suture techniques used with this method tend to apply tension over the provisional abutments and decrease pre-existing keratinized mucosa. To overcome this shortcoming, a pre-fabricated implant-retained stent was designed to apply vertical pressure on the labial flap and stabilize it in a bucco-apical direction to create a wide keratinized mucous zone. METHODS: During second stage implant surgery, an apically displaced, partial thickness flap with a lingualized incision was retracted. A pre-fabricated stent was clipped over the abutments after connecting to the provisional abutment. Vertical pressure was applied to displace the labial flap. No suture was required and the stent was removed after 10 days. RESULTS: A clinically relevant amount of keratinized mucosa was achieved around the dental implants. Buccally displaced keratinized mucosa was firmly attached to the underlying periosteum. A slight shrinkage of the keratinized zone was noted after the healing period in one patient, but no discomfort during oral hygiene was reported. Clinically healthy gingiva with enough keratinized mucosa was achieved in both patients. CONCLUSIONS: The proposed technique is a simple and time-effective technique for preserving and providing keratinized tissue around dental implants. PMID- 20827330 TI - Esthetic treatment of gingival melanin hyperpigmentation with a Nd:YAG laser and high speed rotary instrument: comparative case report. AB - PURPOSE: The purpose of this study was to evaluate the clinical effectiveness of and patient's satisfaction with treatment of gingival melanin hyperpigmentation with a Nd:YAG laser and a high speed rotary instrument. METHODS: Three patients with melanin hyperpigmentation in the anterior parts of the gingiva were chosen for this case study. Clinical photographs were taken at the preoperative state and three patients were treated under local anesthesia. In the maxilla, the gingival deepithelization was conducted with a high speed diamond bur, whereas, in the mandible with a Nd:YAG laser. Clinical photographs were taken immediately after the procedures and at the 1st, 2nd, and 4th week to evaluate clinical color changes. A week after the procedure, the patients filled out a questionnaire about any pain or discomfort. At the 4th week after the procedure, the patients filled out questionnaires about esthetic aspects of the results of treatment. RESULTS: In all cases, both anterior gingival areas were depigmented with satisfaction and the patients did not complain of severe pain or discomfort. At the 1st week of healing, the gingiva showed moderate to fast epithelization. Two weeks after the procedure, clinically, the gingiva showed almost complete healing. Four weeks after the procedure, there was significant improvement in gingival melanin hyperpigmentation. CONCLUSIONS: The Nd:YAG laser and the high speed rotary instruments seem to be effective for the esthetic treatment of gingival melanin hyperpigmentation. PMID- 20827331 TI - Erratum: figure legend correction. AB - [This corrects the article on p. 105 in vol. 40, PMID: 20607054.]. PMID- 20827332 TI - Erratum: Author's Name Correction. AB - [This corrects the article on p. 144 in vol. 40, PMID: 20607060.]. PMID- 20827333 TI - The efficacy of shikonin on cartilage protection in a mouse model of rheumatoid arthritis. AB - The potential therapeutic action of shikonin in an experimental model of rheumatoid arthritis (RA) was investigated. As a RA animal model, DBA/1J mice were immunized two times with type II collagen. After the second collagen immunization, mice were orally administered shikonin (2 mg/kg) once a day for 35 days, and the incidence, clinical score, bone mineral density (BMD), bone mineral content (BMC) and joint histopathology were evaluated. BMD in the proximal regions of the tibia largely increased in the shikonin treatment group compared with the control group. We also examined the effect of shikonin on inflammatory cytokines and cartilage protection. Shikonin treatment significantly reduced the incidence and severity of collagen-induced arthritis (CIA), markedly abrogating joint swelling and cartilage destruction. Shikonin also significantly inhibited the production of matrix metalloproteinase (MMP)-1 and up-regulated tissue inhibitors of metalloproteinase (TIMP)-1 in mice with CIA. In conclusion, shikonin exerted therapeutic effects through regulation of MMP/TIMP; these results suggest that shikonin is an outstanding candidate as a cartilage protective medicine for RA. PMID- 20827334 TI - Proteomic analysis of differentially expressed proteins in bovine endometrium with endometritis. AB - Endometritis is one of the primary reasons for reproductive failure. In order to investigate endometritis-associated marker proteins, proteomic analysis was performed on bovine endometrium with endometritis. In bovine endometritis, desmin, alpha-actin-2, heat-shock protein (HSP) 27, peroxiredoxin-6, luteinizing hormone receptor isoform 1, collectin-43 precursor, deoxyribonuclease-I (DNase I), and MHC class I heavy chain (MHC-Ih) were up-regulated. In contrast, transferrin, interleukin-2 precursor, hemoglobin beta subunit, and potassium channel tetramerisation domain-containing 11 (KCTD11) were down-regulated in comparison to normal endometrium. The proteomic results were validated by semiquantitative-PCR and immunoblot analysis. The mRNA levels of desmin, transferrin, alpha-actin-2, HSP27, KCTD11, and MHC-Ih were up-regulated by over 1.5-fold, and showed a pattern similar to their proteomic profiles. Desmin and alpha-actin-2 protein showed positive correlations between proteomic analysis and immunoblot analysis. These results suggest that desmin and alpha-actin-2 may play important roles in endometritis-related function, and could be useful markers for the diagnosis of bovine endometritis. PMID- 20827335 TI - Chronic Administration of Monosodium Glutamate under Chronic Variable Stress Impaired Hypothalamic-Pituitary-Adrenal Axis Function in Rats. AB - The hypothalamic-pituitary-adrenal (HPA) axis is the primary endocrine system to respond to stress. The HPA axis may be affected by increased level of corticotrophin-releasing factors under chronic stress and by chronic administration of monosodium glutamate (MSG). The purpose of this study was to investigate whether chronic MSG administration aggravates chronic variable stress (CVS)-induced behavioral and hormonal changes. Twenty-four adult male Sprague Dawley rats, weighing 200~220 g, were divided into 4 groups as follows: water administration (CON), MSG (3 g/kg) administration (MSG), CVS, and CVS with MSG (3 g/kg) administration (CVS+MSG). In addition, for the purpose of comparing the effect on plasma corticosterone levels between chronic stress and daily care or acute stress, 2 groups were added at the end of the experiment; the 2 new groups were as follows: naive mice (n=7) and mice exposed to restraint stress for 2 h just before decapitation (A-Str, n=7). In an open field test performed after the experiment, the CVS+MSG group significant decrease in activity. The increase in relative adrenal weights in the CVS and CVS+MSG group was significantly greater than those in the CON and/or MSG groups. In spite of the increase in the relative adrenal weight, there was a significant decrease in the plasma corticosterone levels in the CVS+MSG group as compared to all other groups, except the naive group. These results suggest that impaired HPA axis function as well as the decrease in the behavioral activity in adult rats can be induced by chronic MSG administration under CVS rather than CVS alone. PMID- 20827336 TI - Changes in endothelin receptor type B and neuronal nitric oxide synthase in puromycin aminonucleoside-induced nephrotic syndrome. AB - The collecting duct endothelin (ET) system, which involves ET-1 and its two receptors, may play a role in the regulation of renal sodium in association with the nitric oxide synthase (NOS) system. We determined whether sodium retention is associated with changes in the endothelin and NOS systems at different stages (i.e., a sodium retaining stage and a compensatory stage) of nephrotic syndromes. On day 7 after puromycin aminonucleoside (PAN) injection, urinary sodium excretion was decreased, ascites had developed, and there was a positive sodium balance. ET-1 mRNA expression was increased in the inner medulla of the kidney, whereas protein expression of ET receptor type B (ET(B)R) was unchanged. The expression of neuronal NOS (nNOS) was decreased in the inner medulla. On day 14, urinary sodium excretion was unchanged compared with controls. The expression of ET(B)R increased, while nNOS expression in the inner medulla was comparable to controls. These findings suggest that decreased nNOS plays a role in the development of sodium retention in the nephrotic syndrome. Recovery of nNOS and increased renal ET(B)R synthesis may promote sodium excretion in later stages of the nephrotic syndrome (on day 14). PMID- 20827337 TI - Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice. AB - Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has been reported that APP BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has been reported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP. These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576 mice compared to age-matched wild-type mice. In addition, APP BP1 knockdown by siRNA treatment reduced cullin-1 neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells. Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in neuronal cells, contributes to the pathogenesis of Alzheimer's disease. PMID- 20827338 TI - Toll-like Receptor3-mediated Induction of Chemokines in Salivary Epithelial Cells. AB - Toll-like receptors (TLRs) functionally expressed in salivary epithelial cells, but their roles remain elusive. Among TLRs family, TLR3 is activated by dsRNA, a byproduct of viral infection. The aim of this study was to investigate the role of TLR3 in the inflammatory immune responses using HSG cells. Reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR and ELISA were performed to identify expression of TLRs and TLR3-mediated chemokine inductions. The chemotaxis assay of activated T lymphocytes was also performed. Treatment of HSG cells with polyinosinic: polycytidylic acid (poly(I:C)) significantly increased interferon-gamma-inducible protein 10 (IP-10), interferoninducible T cell alpha chemoattractant (I-TAC), and regulated on activation, normal T-cells expressed and secreted (RANTES) gene expressions in a concentration-dependent manner. Anti-TLR3 antibody blocked the increases of IP-10 and I-TAC genes. Poly(I:C)-induced increases of IP-10 and I-TAC were also confirmed at protein levels from cell lysates, but their release into extracellular medium was detected only in IP-10. We found that the culture media from HSG cells stimulated with poly(I:C) significantly increases T lymphocyte migration. Our results suggest that TLR3 plays an important role in chemokine induction, particularly IP 10, in salivary epithelial cells. PMID- 20827339 TI - Inhibitory effects of olmesartan on catecholamine secretion from the perfused rat adrenal medulla. AB - The present sutdy aimed to determine whether olmesartan, an angiotensin II (Ang II) type 1 (AT(1)) receptor blocker, can influence the CA release from the isolated perfused model of the rat adrenal medulla. Olmesartan (5~50 uM) perfused into an adrenal vein for 90 min produced dose- and time-dependent inhibition of the CA secretory responses evoked by ACh (5.32 mM), high K(+) (56 mM, a direct membrane-depolarizer), DMPP (100 uM) and McN-A-343 (100 uM). Olmesartan did not affect basal CA secretion. Also, in adrenal glands loaded with olmesartan (15 uM), the CA secretory responses evoked by Bay-K-8644 (10 uM, an activator of voltage-dependent L-type Ca(2+) channels), cyclopiazonic acid (10 uM, an inhibitor of cytoplasmic Ca(2+) -ATPase), veratridine (100 uM, an activator of voltage-dependent Na(+) channels), and Ang II (100 nM) were markedly inhibited. However, at high concentrations (150~300 uM), olmesartan rather enhanced the ACh evoked CA secretion. Taken together, these results show that olmesartan at low concentrations inhibits the CA secretion evoked by cholinergic stimulation (both nicotininc and muscarinic receptors) as well as by direct membrane depolarization from the rat adrenal medulla, but at high concentrations it rather potentiates the ACh-evoked CA secretion. It seems that olmesartan has a dual action, acting as both agonist and antagonist at nicotinic receptors of the isolated perfused rat adrenal medulla, which might be dependent on the concentration. It is also thought that this inhibitory effect of olmesartan may be mediated by blocking the influx of both Na(+) and Ca(2+) into the rat adrenomedullary chromaffin cells as well as by inhibiting the Ca(2+) release from the cytoplasmic calcium store, which is thought to be relevant to the AT(1) receptor blockade, in addition to its enhancement on the CA secreton. PMID- 20827340 TI - Effects of resistance training on the inflammatory response. AB - Resistance training (RT) is associated with reduced risk of low grade inflammation related diseases, such as cardiovascular disease and type 2 diabetes. The majority of the data studying cytokines and exercise comes from endurance exercise. In contrast, evidence establishing a relationship between RT and inflammation is more limited. This review focuses on the cytokine responses both following an acute bout, and after chronic RT. In addition, the effect of RT on low grade systemic inflammation such as individuals at risk for type 2 diabetes is reviewed. Cytokines are secreted proteins that influence the survival, proliferation, and differentiation of immune cells and other organ systems. Cytokines function as intracellular signals and almost all cells in the body either secrete them or have cytokine receptors. Thus, understanding cytokine role in a specific physiological situation such as a bout of RT can be exceedingly complex. The overall effect of long term RT appears to ameliorate inflammation, but the specific effects on the inflammatory cytokine, tumor necrosis factor alpha are not clear, requiring further research. Furthermore, it is critical to differentiate between chronically and acute Interleukin-6 levels and its sources. The intensity of the RT and the characteristics of the training protocol may exert singular cytokine responses and as a result different adaptations to exercise. More research is needed in the area of RT in healthy populations, specifically sorting out gender and age RT acute responses. More importantly, studies are needed in obese individuals who are at high risk of developing low grade systemic inflammatory related diseases. Assuring adherence to the RT program is essential to get the benefits after overcoming the first acute RT responses. Hence RT could be an effective way to prevent, and delay low grade systemic inflammatory related diseases. PMID- 20827341 TI - Anti-stress effects of ginseng via down-regulation of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) gene expression in immobilization-stressed rats and PC12 cells. AB - Catecholamines are among the first molecules that displayed a kind of response to prolonged or repeated stress. It is well established that long-term stress leads to the induction of catecholamine biosynthetic enzymes such as tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) in adrenal medulla. The aim of the present study was to evaluate the effects of ginseng on TH and DBH mRNA expression. Repeated (2 h daily, 14 days) immobilization stress resulted in a significant increase of TH and DBH mRNA levels in rat adrenal medulla. However, ginseng treatment reversed the stress-induced increase of TH and DBH mRNA expression in the immobilization-stressed rats. Nicotine as a ligand of the nicotinic acetylcholine receptor (nAChR) in adrenal medulla stimulates catecholamine secretion and activates TH and DBH gene expression. Nicotine treatment increased mRNA levels of TH and DBH by 3.3- and 3.1-fold in PC12 cells. The ginseng total saponin exhibited a significant reversal in the nicotine induced increase of TH and DBH mRNA expression, decreasing the mRNA levels of TH and DBH by 57.2% and 48.9%, respectively in PC12 cells. In conclusion, immobilization stress induced catecholamine biosynthetic enzymes gene expression, while ginseng appeared to restore homeostasis via suppression of TH and DBH gene expression. In part, the regulatory activity in the TH and DBH gene expression of ginseng may account for the anti-stress action produced by ginseng. PMID- 20827342 TI - Effect of retinoic acid and delta-like 1 homologue (DLK1) on differentiation in neuroblastoma. AB - The principal objective of this study was to evaluate the chemopreventive and therapeutic effects of a combination of all-trans-retinoic acid (RA) and knockdown of delta-like 1 homologue (Drosophila) (DLK1) on neuroblastoma, the most common malignant disease in children. As unfavorable neuroblastoma is poorly differentiated, neuroblastoma cell was induced differentiation by RA or DLK1 knockdown. Neuroblastoma cells showed elongated neurite growth, a hallmark of neuronal differentiation at various doses of RA, as well as by DLK1 knockdown. In order to determine whether or not a combination of RA and DLK1 knockdown exerts a greater chemotherapeutic effect on neuroblastoma, cells were incubated at 10 nM RA after being transfected with SiRNA-DLK1. Neuronal differentiation was increased more by a combination of RA and DLK1 knockdown than by single treatment. Additionally, in order to assess the signal pathway of neuroblastoma differentiation induced by RA and DLK1 knockdown, treatment with the specific MEK/ERK inhibitors, U0126 and PD 98059, was applied to differentiated neuroblastoma cells. Differentiation induced by RA and DLK1 knockdown increased ERK phosphorylation. The MEK/ERK inhibitor U0126 completely inhibited neuronal differentiation induced by both RA and DLK1 knockdown, whereas PD98059 partially blocked neuronal differentiation. After the withdrawal of inhibitors, cellular differentiation was fully recovered. This study is, to the best of our knowledge, the first to demonstrate that the specific inhibitors of the MEK/ERK pathway, U0126 and PD98059, exert differential effects on the ERK phosphorylation induced by RA or DLK1 knockdown. Based on the observations of this study, it can be concluded that a combination of RA and DLK1 knockdown increases neuronal differentiation for the control of the malignant growth of human neuroblastomas, and also that both MEK1 and MEK2 are required for the differentiation induced by RA and DLK1 knockdown. PMID- 20827343 TI - Coffee intake can promote activity of antioxidant enzymes with increasing MDA level and decreasing HDL-cholesterol in physically trained rats. AB - This study investigated the effect of coffee intake and exercise on the antioxidative activity and plasma cholesterol profile of physically trained rats while they were exercising. Forty eight rats were under either the control diet with water (C) or control diet with coffee (CF) and at the same time they were given physical training for 4 weeks. In terms of physical training, the rats were exercised on a treadmill for 30 minutes everyday. At the end of 4 weeks, animals in each dietary group were subdivided into 3 groups: before-exercise (BE); during exercise (DE); after-exercise (AE). Animals in the DE group were exercised on a treadmill for one hour, immediately before being sacrificed. Animals in the AE group were allowed to take a rest for one hour after exercise. TG levels were significantly high in coffee intake group than in control group. Also TG level of AE group was significantly higher than that of BE group. Exercise and coffee exercise interaction effects were significant in total cholesterol (P = 0.0004, 0.0170). The AE of coffee intake group showed highest total cholesterol levels. HDL-cholesterol was significantly lower in coffee intake group than in control group. Coffee, exercise, and coffee-exercise interaction effects were significant in SOD (P = 0.0001, 0.0001, and 0.0001). The AE and BE of coffee intake group showed higher SOD levels than the other four groups. Catalase activities were significantly higher in coffee intake group than control group. No significant main effect was found in GSH/GSSG. Coffee, exercise, and coffee-exercise interaction effects were significant in MDA levels (P = 0.0464, 0.0016, and 0.0353). The DE and AE of coffee intake group and the DE of control group showed higher MDA levels than the BE of control group. Therefore, coffee intake can promote activities of antioxidant enzyme but it also increases MDA and decreases HDL-cholesterol in physically trained rats. PMID- 20827344 TI - Effects of Elsholtzia splendens and Cirsium japonicum on premenstrual syndrome. AB - Premenstrual syndrome is a common chronic disorder in most women of reproductive age. The main symptoms are depression, anxiety, tension, feeling out of control, and mastalgia. In premenstrual syndrome, the effects of aromatic edible Elsholtzia splendens and Cirsium japonicum were investigated for over 3 months in 30 women participants in their twenties. In the Elsholtzia splendens capsule treated group, scores of depression and anxiety were significantly lower than those in the Cirsium japonicum capsule treated group. Moreover, instability of the premenstrual assessment form was significantly decreased in the Elsholtzia splendens capsule treated group. Our results suggest that Elsholtzia splendens could be an effective plant material in relieving symptoms of premenstrual syndrome. PMID- 20827345 TI - Eating habits, obesity related behaviors, and effects of Danhak exercise in elderly Koreans. AB - The aims of this study were to evaluate obesity-related dietary behaviors and to determine long-term exercise effects on obesity and blood lipid profiles in elderly Korean subjects. A total of 120 subjects, aged 60-75 yr, were recruited, and obesity-related dietary behaviors were determined. An exercise intervention was conducted with 35 qualified elderly females for 6 months, and body composition and blood lipids were measured 6 times at 4 week intervals. At baseline, mean BMI (kg/m(2)) was 24.8 for males and 23.1 for females. The females had better eating habits than the males and were more concerned with reading nutrition labels on food products (P < 0.001); they also preferred convenience foods less than the male subjects (P < 0.05). Obese individuals were more likely than overweight or normal weight individuals to misperceive their weight (P < 0.001). Those with a high BMI responded feeling more depressed (P < 0.01), lacking self-confidence (P < 0.01), and feeling isolated (P < 0.01), as well as having more difficulty doing outdoor activities (P < 0.01). After exercise, body fat (%) and WHR were significantly reduced (P < 0.05), while body weight and BMI were also decreased without statistical significance. Total cholesterol and blood HDL were significantly improved (207.1 mg/dl vs. 182.6 mg/dl, HDL: 45.6 mg/dl vs. 50.6 mg/dl, P < 0.05). Other benefits obtained from exercise were improvements in self-confidence (26.4%), movement (22.6%), stress-relief (18.9%), and depression (13.2%). In conclusion, elderly females had better eating habits and were more concerned with nutrition information and healthy diets compared to elderly males. However, misperceptions of weight and obesity-related stress tended to be very high in females who were overweight and obese, which can be a barrier to maintain normal weight. Long-term Danhak practice, a traditional Korean exercise, was effective at reducing body fat (%) and abdominal obesity, and improved lipid profiles, self-confidence, and stress. PMID- 20827346 TI - Intakes of vegetables and related nutrients such as vitamin B complex, potassium, and calcium, are negatively correlated with risk of stroke in Korea. AB - Consumption of vegetables and fruits is associated with a reduced risk of stroke, but it is unclear whether their protective effects are due to antioxidant vitamins or folate and metabolically related B vitamins. The purpose of the study was to test the hypothesis that intake of fruits and vegetables, which are major sources of antioxidant and vitamin B complex vitamins, reduces the risk of stroke. Cases consisted of patients diagnosed with first event of stroke (n = 69). Controls (n = 69) were age-, sex-, and body mass index-matched to cases. Multivariable-adjusted regression analysis showed that subjects who ate four to six servings of vegetable per day had a 32% reduction in the risk of stroke, and those with more than six servings per day had a reduction of 69% after adjusting for age, sex, BMI, and family history of stroke. Intakes of total fat, plant fat, calcium, potassium, vitamin B(1), vitamin B(2), vitamin B(6), niacin, and folate were significantly and negatively associated with the risk of stroke. Although the trend was not significant, stroke risk was reduced in the second quartile (1.21-2.66 servings per week) of fish intake. However, intake of fruits (average daily intake of 1.0 serving) and antioxidant vitamins such as carotene, vitamin C, and vitamin E was not associated with the risk of stroke. In conclusion, our observational study suggests that intake of fat and vegetables, rich sources of vitamin B complex, calcium, and potassium may protect against stroke. PMID- 20827347 TI - Birth weight was negatively correlated with plasma ghrelin, insulin resistance, and coenzyme Q10 levels in overweight children. AB - The purpose of this study was to investigate the relationship between birth weight and appetite related hormones, insulin resistance, and antioxidant status in overweight children aged 9-10 years. Thirty-four healthy overweight children (18 boys, 16 girls) were evaluated with respect to anthropometric measurement, lipid profiles, leptin, ghrelin, glucose, insulin, C-peptide, lipid soluble vitamins, and antioxidant enzyme activities. I found that birth weight was negatively correlated with insulin resistance parameters, ghrelin, and coenzyme Q10 levels. There was a significant positive correlation between present BMI and leptin level, while a negative correlation was noted between the BMI and alpha tocopherol and lycopene levels. When total subjects were classified into three groups by tertiles of birth weight, the lowest tertile of birth weight (LTB) group showed higher levels of fasting glucose, HOMA-IR, and ghrelin level than the highest tertile of birth weight (HTB) groups. On the other hand, HTB group showed an increased oxidative stress (decreased coenzyme Q10 level and catalase activity) compared to the LTB group. In conclusion, plasma ghrelin level might play an important role in accelerated growth in overweight children with LTB. Increased insulin resistance is present in overweight children with LTB, while decreased coenzyme Q10 and catalase activity in overweight children with HTB. These results suggest that birth weight might be an important factor for determination of treatment for obesity related complications in childhood obesity. PMID- 20827348 TI - Dietary intake based on physical activity level in Korean elementary school students. AB - Prevalence of childhood obesity is increasing significantly worldwide due to energy imbalance perhaps stemming from undesirable dietary behavior and physical activity level. The objective of the study was to examine the effects of physical activity level on nutritional status in elementary school students. The subjects were comprised of 287 elementary school students between 4th and 6th grades in Seoul, Korea. The level of physical activity was scored with a modified Godin leisure-time exercise questionnaire and was categorized as active, moderately active, and sedentary. Dietary intakes were obtained using a 24-hour food recall method. An analysis of variance (ANOVA) was conducted to test for global significant differences of nutrient intakes by physical activity level. Boys were more active than girls. Daily intakes of energy in moderately active boys were significantly higher than in the sedentary group, but intakes of calcium and iron in moderately active boys were lower than active boys. For girls, physical activity level did not affect nutrient density at all. Intakes of calcium, vitamin C, and folate for both boys and girls were below 50% of recommended intake. Physical activity did not affect nutrient density and our participants were exposed to nutritional imbalance. Therefore, the results suggest that nutrition education regarding balanced diet and optimum physical activity is required for children's health and growth. PMID- 20827349 TI - Comparison of nutrient intake, life style variables, and pregnancy outcomes by the depression degree of pregnant women. AB - The aim of this study was to analyse effects that the degree of depression have on the life style variables, nutrient intake, iron indices and pregnancy outcome. Subjects were 114 pregnant women who were receiving prenatal care at a hospital in Seoul. We collected data for general characteristics and lifestyle variables from general survey instrument and for depression score from the questionnaire on depression. Dietary intakes of subjects were estimated by 24 hour dietary recall method. Also we analysed iron indices and pregnancy outcomes. We classified subjects by 10 point, which was the average depression score, into two groups [Low depression score group (LS) : High depression score group (HS)]. As to the intakes of total calcium, plant-calcium, plant-iron, potassium, total folate and dietary folate, LS group was far higher than HS group (P < 0.05, P < 0.05, P < 0.01, P < 0.001, P < 0.05, and P < 0.01, respectively). As to pre-pregnancy alcohol drinking, LS group had 41.9% in non-drinker, which was far higher than 28% in HS group in non-drinker (P < 0.05). As for drinking coffee during pre pregnancy, pregnant women who don't drink coffee in LS group took 43.6%, which was higher than 38% in HS group (P < 0.01). Regarding delivery type, the cesarean section in LS group (18%) was significantly lower than that in HS group (45%) (P < 0.01). Bivariate analysis showed that birth weight was significantly associated with the gestational age (P < 0.01). The pregnant women with higher depression score tended to have undesirable life habit, which might affect negative pregnancy outcomes. A better understanding of how depression and intake of nutrients work together to modulate behavior will be benefit nutritional research. PMID- 20827350 TI - Consumer behaviors towards ready-to-eat foods based on food-related lifestyles in Korea. AB - The purpose of this study was to examine consumers' behaviors toward ready-to-eat foods and to develop ready-to-eat food market segmentation in Korea. The food related lifestyle and purchase behaviors of ready-to-eat foods were evaluated using 410 ready-to-eat food consumers in the Republic of Korea. Four factors were extracted by exploratory factor analysis (health-orientation, taste-orientation, convenience-orientation, and tradition-orientation) to explain the ready-to eat food consumers' food-related lifestyles. The results of cluster analysis indicated that "tradition seekers" and "convenience seekers" should be regarded as the target segments. Chi-square tests and t-tests of the subdivided groups showed there were significant differences across marital status, education level, family type, eating-out expenditure, place of purchase, and reason for purchase. In conclusion, the tradition seekers consumed more ready-to-eat foods from discount marts or specialty stores and ate them between meals more often than the convenience seekers. In contrast, the convenience seekers purchased more ready-to eat foods at convenience stores and ate them as meals more often than the tradition seekers. These findings suggest that ready-to-eat food market segmentation based on food-related lifestyles can be applied to develop proper marketing strategies. PMID- 20827351 TI - Impact of nutritional status on birth weight of neonates in Zahedan City, Iran. AB - The objective of this study was to measure anthropometric and haemoglobin level and nutrient intake of expecting women in the third trimester of pregnancy and to relate the birth weight of neonates as outcome of pregnancy. A cross sectional study was performed in Zahedan City. Two hospitals situated in the city were selected based on their approval and cooperation. Five hundred healthy pregnant women in the age group 16-40 years were selected for this study. Findings showed that the mean height, weight, fundal height, and haemoglobin of pregnant women were 156.4 cm, 62.6 kg, 34.2 cm, and 11.1g/dl respectively. Nutrient intake was computed based on 24 hour recall method. The results showed that, the mean intake of energy was 1802 Kcal/day. The intake of protein, calcium, iron, zinc and magnesium were 70.7 g, 544.0 mg, 16.1 mg, 10.6 mg and 266.0 mg respectively. Percentage adequacy of nutrient intakes with reference to RDA recommendation showed 95% and 80% of subjects had sufficient RDA intakes, while energy, calcium, iron and zinc intake considered as insufficient. The mean birth weight of neonates was 3.0 kg and 13% of neonates showed low birth weight. Maternal height, weight, fundal height and haemoglobin level were significantly correlated with birth weight of neonates. Energy, protein and calcium intakes in the third trimester were significantly correlated with birth weight of neonates. Using the binary logistic regression analysis fundal height, haemoglobin level and energy intake of pregnant women were considered as predictor factors of birth weight of neonates. PMID- 20827353 TI - Sample size calculation in clinical trials: part 13 of a series on evaluation of scientific publications. AB - BACKGROUND: In this article, we discuss the purpose of sample size calculation in clinical trials, the need for it, and the methods by which it is accomplished. Study samples that are either too small or too large are unacceptable, for clinical, methodological, and ethical reasons. The physicians participating in clinical trials should be directly involved in sample size planning, because their expertise and knowledge of the literature are indispensable. METHODS: We explain the process of sample size calculation on the basis of articles retrieved by a selective search of the international literature, as well as our own experience. RESULTS: We present a fictitious clinical trial in which two antihypertensive agents are to be compared to each other with a t-test and then show how the appropriate size of the study sample should be calculated. Next, we describe the general principles of sample size calculation that apply when any kind of statistical test is to be used. We give further illustrative examples and explain what types of expert medical knowledge and assumptions are needed to calculate the appropriate sample size for each. These generally depend on the particular statistical test that is to be performed. CONCLUSION: In any clinical trial, the sample size has to be planned on a justifiable, rational basis. The purpose of sample size calculation is to determine the optimal number of participants (patients) to be included in the trial. Sample size calculation requires the collaboration of experienced biostatisticians and physician researchers: expert medical knowledge is an essential part of it. PMID- 20827352 TI - Potentially inappropriate medications in the elderly: the PRISCUS list. AB - BACKGROUND: Certain drugs are classified as potentially inappropriate medications (PIM) for the elderly because they carry an increased risk of adverse drug events in this patient group. PIM lists from other countries are of limited usefulness in Germany because different drugs are on the market in each country and prescribing practices vary as well. Thus, a list of potentially inappropriate medications for the elderly was developed specifically for use in Germany. METHODS: A preliminary PIM list suitable for the German market was created on the basis of a selective literature search and a qualitative analysis of published international PIM lists. The final German PIM list was developed by means of a comprehensive, structured expert survey in two rounds (a so-called Delphi process). RESULTS: 83 drugs in a total of 18 drug classes were rated as potentially inappropriate for elderly patients. For 46 drugs, the experts came to no clear decision after the second Delphi round. For cases in which the administration of a PIM is clinically necessary, the final PRISCUS list contains recommendations for clinical practice, e.g. monitoring of laboratory values and dose adaptation. Therapeutic alternatives are also listed. CONCLUSION: Potentially inappropriate medications carry the risk of causing adverse drug events in the elderly. A drawback of using a Delphi process to generate a PIM list, as was done for the new German list, is that little scientific evidence is currently available for the evaluation of active substances, potential therapeutic alternatives, and indicated monitoring procedures. Thus, the validity and practicability of the PRISCUS list remain to be demonstrated (and the same holds for PIM lists already published in other countries). It should be used as a component of an overall concept for geriatric pharmacotherapy in which polypharmacy and interacting medications are avoided, and doses are regularly re evaluated. PMID- 20827354 TI - Correspondence (letter to the editor): Active support. PMID- 20827355 TI - Correspondence (letter to the editor): Ordering errors were identified. PMID- 20827356 TI - Correspondence (letter to the editor): Experiences with checklists. PMID- 20827357 TI - Correspondence (letter to the editor): Transparency was created. PMID- 20827358 TI - Correspondence (letter to the editor): Cooperation of all participating groups. PMID- 20827360 TI - The Treatment of Patients With Hepatic Encephalopathy: Review of the Latest Data from EASL 2010. PMID- 20827361 TI - The Treatment of Patients With Irritable Bowel Syndrome: Review of the Latest Data From the 2010 DDW Meeting. PMID- 20827363 TI - Using imaging studies to differentiate among benign liver tumors. PMID- 20827362 TI - Update on Dual Delayed-Release PPI Formulations. PMID- 20827365 TI - Gastro-hep news. PMID- 20827364 TI - Colorectal cancer prevention with colonoscopy: recent research and debate. PMID- 20827366 TI - Thiopurines in IBD: What Is Their Mechanism of Action? PMID- 20827367 TI - Random versus targeted biopsies for colorectal cancer surveillance in inflammatory bowel disease. AB - For many years, cancer surveillance colonoscopy in ulcerative colitis patients has involved obtaining at least 30 biopsies of flat and abnormal-appearing mucosa. With the advent of better imaging techniques, biopsies can be better targeted to abnormal-appearing mucosa, thereby increasing the sensitivity of testing. Use of chromoendoscopy, narrow-band imaging, autofluorescence, or confocal endomicroscopy to target biopsies is likely to improve detection of dysplasia and identification of patients at high risk for developing cancer. PMID- 20827368 TI - Acute liver failure: a management challenge for the practicing gastroenterologist. AB - Although comprising a minority of the transplant population, acute liver failure (ALF) patients represent some of the most challenging cases in terms of the level and complexity of care required. An ALF patient requires much more than a single skilled intensivist, gastroenterologist, or surgeon. Successful care of the ALF patient begins with early diagnosis and triage to the appropriate level of care where a multitude of specialties are required to work together to maximize the chance of recovery and/or extend the window of opportunity for transplant. PMID- 20827369 TI - Isolated gastrocnemius myositis related to Crohn's disease. PMID- 20827370 TI - Review. PMID- 20827371 TI - Kaposi sarcoma involving the gastrointestinal tract. PMID- 20827372 TI - Review. PMID- 20827373 TI - M protein and hyaluronic acid capsule are essential for in vivo selection of covRS mutations characteristic of invasive serotype M1T1 group A Streptococcus. AB - The initiation of hyperinvasive disease in group A Streptococcus (GAS) serotype M1T1 occurs by mutation within the covRS two-component regulon (named covRS for control of virulence regulatory sensor kinase), which promotes resistance to neutrophil-mediated killing through the upregulation of bacteriophage-encoded Sda1 DNase. To determine whether other virulence factors contribute to this phase switching phenomenon, we studied a panel of 10 isogenic GAS serotype M1T1 virulence gene knockout mutants. While loss of several individual virulence factors did not prevent GAS covRS switching in vivo, we found that M1 protein and hyaluronic acid capsule are indispensable for the switching phenotype, a phenomenon previously attributed uniquely to the Sda1 DNase. We demonstrate that like M1 protein and Sda1, capsule expression enhances survival of GAS serotype M1T1 within neutrophil extracellular traps. Furthermore, capsule shares with M1 protein a role in GAS resistance to human cathelicidin antimicrobial peptide LL 37. We conclude that a quorum of GAS serotype M1T1 virulence genes with cooperative roles in resistance to neutrophil extracellular killing is essential for the switch to a hyperinvasive phenotype in vivo. PMID- 20827374 TI - Analogous telesensing pathways regulate mating and virulence in two opportunistic human pathogens. AB - Telesensing, or probing of the environment by the release of chemical messengers, plays a central role in the sexual programs of microbial organisms. Sex pheromones secreted by mating cells are sensed by potential partner cells and mediate cell-to-cell contact and the subsequent exchange of genetic material. Although the mechanisms used by bacterial and fungal species to promote genetic exchange are distinct, recent studies have uncovered surprising parallels between pheromone signaling in these species. In addition, it is now apparent that pheromone signaling not only controls sexual reproduction and genetic exchange but can also activate expression of potential virulence factors in diverse opportunistic pathogens. PMID- 20827375 TI - The catecholaminergic nerve plexus of Holothuroidea. AB - Catecholamines have been extensively reported to be present in most animal groups, including members of Echinodermata. In this study, we investigated the presence and distribution of catecholaminergic nerves in two members of the Holothuroidea, Holothuria glaberrima (Selenka, 1867) (Aspidochirotida, Holothuroidea) and Holothuria mexicana (Ludwig, 1875) (Aspidochirotida, Holothuroidea), by using induced fluorescence for catecholamines on tissue sections and immunohistochemistry with an antibody that recognizes tyrosine hydroxylase. The presence of a catecholaminergic nerve plexus similar in distribution and extension to those previously reported in other members of Echinodermata was observed. This plexus, composed of cells and fibers, is found in the ectoneural component of the echinoderm nervous system and is continuous with the circumoral nerve ring and the radial nerves, tentacular nerves, and esophageal plexus. In addition, fluorescent nerves in the tube feet are continuous with the catecholaminergic components of the radial nerve cords. This is the first comprehensive report on the presence and distribution of catecholamines in the nervous system of Holothuroidea. The continuity and distribution of the catecholaminergic plexus strengthen the notion that the catecholaminergic cells are interneurons, since these do not form part of the known sensory or motor circuits and the fluorescence is confined to organized nervous tissue. PMID- 20827376 TI - A Trabecular Bone Explant Model of Osteocyte-Osteoblast Co-Culture for Bone Mechanobiology. AB - The osteocyte network is recognized as the major mechanical sensor in the bone remodeling process, and osteocyte-osteoblast communication acts as an important mediator in the coordination of bone formation and turnover. In this study, we developed a novel 3D trabecular bone explant co-culture model that allows live osteocytes situated in their native extracellular matrix environment to be interconnected with seeded osteoblasts on the bone surface. Using a low-level medium perfusion system, the viability of in situ osteocytes in bone explants was maintained for up to 4 weeks, and functional gap junction intercellular communication (GJIC) was successfully established between osteocytes and seeded primary osteoblasts. Using this novel co-culture model, the effects of dynamic deformational loading, GJIC, and prostaglandin E(2) (PGE(2)) release on functional bone adaptation were further investigated. The results showed that dynamical deformational loading can significantly increase the PGE(2) release by bone cells, bone formation, and the apparent elastic modulus of bone explants. However, the inhibition of gap junctions or the PGE(2) pathway dramatically attenuated the effects of mechanical loading. This 3D trabecular bone explant co culture model has great potential to fill in the critical gap in knowledge regarding the role of osteocytes as a mechano-sensor and how osteocytes transmit signals to regulate osteoblasts function and skeletal integrity as reflected in its mechanical properties. PMID- 20827377 TI - Does Nanoparticle Activity Depend upon Size and Crystal Phase? AB - A method to investigate the dependence of the physicochemical properties of nanoparticles (e.g. size, surface area and crystal phase) on their oxidant generating capacity is proposed and demonstrated for TiO(2) nanoparticles. Gas phase synthesis methods that allow for strict control of size and crystal phase were used to prepare TiO(2) nanoparticles. The reactive oxygen species (ROS) generating capacity of these particles was then measured. The size dependent ROS activity was established using TiO(2) nanoparticles of 9 different sizes (4 - 195 nm) but the same crystal phase. For a fixed total surface area, an S-shaped curve for ROS generation per unit surface area was observed as a function of particle size. The highest ROS activity per unit area was observed for 30 nm particles, and observed to be constant above 30 nm. There was a decrease in activity per unit area as size decreased from 30 nm to 10 nm; and again constant for particles smaller than 10 nm. The correlation between crystal phase and oxidant capacity was established using TiO(2) nanoparticles of 11 different crystal phase combinations but similar size. The ability of different crystal phases of TiO(2) nanoparticles to generate ROS was highest for amorphous, followed by anatase, and then anatase/rutile mixtures, and lowest for rutile samples. Based on evaluation of the entire dataset, important dose metrics for ROS generation are established. Their implications of these ROS studies on biological and toxicological studies using nanomaterials are discussed. PMID- 20827378 TI - Group theory and biomolecular conformation: I. Mathematical and computational models. AB - Biological macromolecules, and the complexes that they form, can be described in a variety of ways ranging from quantum mechanical and atomic chemical models, to coarser grained models of secondary structure and domains, to continuum models. At each of these levels, group theory can be used to describe both geometric symmetries and conformational motion. In this survey, a detailed account is provided of how group theory has been applied across computational structural biology to analyze the conformational shape and motion of macromolecules and complexes. PMID- 20827379 TI - A management dilemma: infectious keratitis associated with soft contact lens use and dubious treatment compliance. AB - Purpose. To present a case of infectious keratitis caused by the microorganism Serratia marcescens in a contact lens user and further to confer on the most advantageous management of comparable situations. Case. After altering the routine that she used for contact lens disinfection, a 24-year-old patient presented with pain and conjunctival redness in both eyes. Slit-lamp examination revealed two infiltrates in the inferior part of the cornea in the right eye and five smaller infiltrates in the superior half of the left cornea. Appropriate treatment, after hospitalization, improved the symptoms while culture of the contact lens material revealed Serratia marcescens as the responsible infectious factor. Conclusion. Enhancing the availability of information with respect to contact lens users and customized analysis regarding treatment for a particular complication could be beneficial in order to reduce the frequency of admission to the eye clinic due to infectious keratitis. In addition, rapid laboratory testing of the infected materials should be a priority for selection of the optimal treatment regimen. PMID- 20827380 TI - Fatal basilar thrombosis possibly related to minor cervical trauma: a case report. AB - Background. Basilar thrombosis is a potentially fatal event, whose traumatic etiology has been repeatedly stated. Methods. We performed the autopsy and the microscopic examination of the brain stem structures from an individual, whose sudden death raised logical suspicions regarding the causative factor. Results. The brain was swollen and clearly hyperemic; a massive basilar thrombus with complete occlusion of the median segment of the basilar artery was macroscopically seen. The brainstem showed an infarcted zone in the pons, with secondary hemorrhagic changes, mainly in the form of multiple petechial hemorrhages. Pontine arteries showed extensive alterations, mainly in the form of severed endothelium, which suggested a thrombotic-traumatic mechanism as the main etiological factor. Conclusions. Minor injuries, such as slight whiplashes, abrupt neck movements, neck trauma related to the slowing down of the vehicles, and critical neck positioning, can all of them explain a thrombotic event in the basilar artery, leading to a fatal occurrence. Other risk factors may obviously concur, but their importance seems unclear. PMID- 20827381 TI - Physician-controlled wire-guided cannulation of the minor papilla. AB - Background. Minor papilla (MiP) cannulation is frequently performed using specialized small-caliber accessories. Outcomes data for MiP cannulation with standard-sized accessories are lacking. Methods. This is a case series describing MiP cannulation outcomes in consecutive patients treated by two endoscopists between July 2005 and November 2008 at two tertiary referral centers. MiP cannulation was attempted using a 4.4 Fr tip sphincterotome loaded with a 0.035("), 260 cm hydrophilic-tip guidewire, using a wire-guided technique under physician control. Results. 25 patients were identified (14 women, mean age 45). Procedure indications included recurrent acute pancreatitis in 16 patients (64%) and chronic pancreatitis in 2 (8%), among other indications. MiP cannulation was successful in 24 patients (96%). Sphincterotomy followed by pancreatic stent placement was performed in 21 patients (84%). Mild post-ERCP pancreatitis occurred in 3 patients (12%). Conclusion. Physician-controlled wire-guided MiP cannulation using a 4.4 Fr sphincterotome and 0.035(") guidewire is an effective and safe technique. PMID- 20827382 TI - Objectively measured physical activity is negatively associated with plasma adiponectin levels in minority female youth. AB - Objective. To evaluate the relationship between adiponectin and physical activity (PA) in minority female youth. Methods. Plasma adiponectin was measured in 39 females (mean age 9.2 +/- 0.9 years; 30 Latina, 9 African-American; 56% overweight). PA was assessed by accelerometry. Mean minutes per day spent in daily PA (DPA) (>=3 metabolic equivalents (METs)), moderate PA (MPA)(4-7 METs), vigorous PA (VPA)(>=7 METs), and moderate-to-vigorous PA (MVPA)(>=4 METs) were calculated. The association between adiponectin and PA, controlling for age, fat weight, lean weight, and insulin sensitivity (SI) was analyzed using linear regression. Results. Adiponectin correlated with fat weight (r = -0.43, P < .01) and SI (r = 0.52, P < .01). Minutes spent in DPA (beta = -0.40, P = .02), MPA (beta = -0.36, P = .04), or MVPA (beta = -0.37, P = .03) were predictors of adiponectin in the adjusted model. Conclusions. Higher PA levels were related to lower adiponectin levels. Potential mechanisms include upregulation of adiponectin receptors or an increase in high-molecular weight adiponectin with increasing PA. PMID- 20827383 TI - AICD Overexpression in Neuro 2A Cells Regulates Expression of PTCH1 and TRPC5. AB - Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a transmembrane protein of undetermined function. APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro and in vivo studies have implicated the role of AICD in cell signaling and transcriptional regulation of Gsk3beta, KAI1, BACE1, EGFR, and other proteins. In this study, by overexpressing AICD in mouse neuroblastoma cell lines, we have demonstrated the alteration in the expressions of two proteins, patched homolog 1 (PTCH1), a receptor for sonic hedgehog signaling, and transient receptor potential cation channel subfamily C member 5 (TRPC5), a component of receptor activated nonselective calcium permeant cation channel. Our results indicate the possibility of regulation by AICD in developmental processes as well as in the maintenance of calcium homeostasis at the transcription level. PMID- 20827384 TI - Capillaroscopy as an Outcome Measure for Clinical Trials on the Peripheral Vasculopathy in SSc-Is It Useful? AB - Peripheral microvascular impairment in systemic sclerosis (SSc) may be easily detected and scored in a safe noninvasive way by nailfold videocapillaroscopy (NVC). The paper highlights clinical conditions related to SSc in which NVC may represent an outcome measure of therapeutical interventions, by elaborating on their already assessed relationship with the NVC patterns and eventually scores. The 3 important biological/clinical conditions are: the positivity for SSc specific serum autoantibodies, the presence of SSc skin digital ulcers (DUs) and of pulmonary arterial hypertension (PAH) SSc associated. In conclusion, to the question if capillaroscopy (NVC) may represent in SSc an outcome measure for clinical trials on the peripheral vasculopathy, based on the growing evidence and our detailed studies, the answer is positive. Recent therapeutic trials in SSc are confirming this role, and the experience is growing rapidly. PMID- 20827385 TI - Issues of recruitment and rationale for conducting clinical trials on mutans streptococci suppression in mothers. AB - The aims of this study are (1) to describe issues related to recruitment of mothers participating in a clinical trial of transmission of mutans streptococci (MS) from mother to child in Bauru, Brazil and (2) to perform cross-cultural and temporal comparisons of levels of infection of the MS in mothers of Bauru. A total of 1422 mothers were visited at their domiciles. Cutoff levels for the MS were established at >=10(5) CFU/mL saliva. The main reason for a mother not enrolling was not being highly infected by the MS, yet 76% of mothers presented with levels >=10(5) CFU/mL saliva. Recent studies in industrialized countries showed a negative coefficient for linear tests indicating significant decline overtime in the levels of MS in mothers. Intercountry comparisons for mothers' salivary levels of the MS with the Bauru study as the reference revealed significant differences with studies conducted in the last two decades. PMID- 20827386 TI - Emergent Properties of EWS/FLI Regulation via GGAA Microsatellites in Ewing's Sarcoma. AB - ETS proteins are a family of transcription factors that play important roles in the development of cancer. The Ewing's sarcoma EWS/ETS fusion oncoproteins control a number of cancer-relevant phenotypes in that disease. We recently demonstrated that EWS/FLI, the most common EWS/ETS fusion in Ewing's sarcoma, regulates a portion of its target genes, including the critical target NR0B1, via GGAA-containing microsatellites in their promoters. Given the unusual nature of microsatellites as EWS/FLI response elements, we sought to elucidate the mechanism of EWS/FLI activity at these sites. We found that the ability to bind GGAA microsatellites is shared by multiple ETS family members from distinct phylogenetic subfamilies. Importantly, however, only EWS/ETS-containing fusions are capable of mediating transcriptional activation via these elements, highlighting a neomorphic function of the Ewing's sarcoma fusion proteins. Additional analysis revealed that the GGAA microsatellite binds EWS/FLI with an affinity that is 2 to 3 orders of magnitude lower than previously identified high affinity consensus/redundant binding sites. The stoichiometry of this interaction is 2 protein molecules for each DNA molecule, suggesting that EWS/FLI binds these elements as a homodimer. The isolated FLI ETS domain bound microsatellite sequences in a nearly identical fashion to full-length EWS/FLI, thus indicating that residues required for homodimeric binding are localized to the ETS domain. These data suggest a new paradigm for an ETS family member binding to DNA at cancer-relevant genetic loci and highlight emergent properties of EWS/FLI that are required for the development of Ewing's sarcoma. PMID- 20827387 TI - Job Displacement and Social Participation over the Lifecourse: Findings for a Cohort of Joiners. AB - We examine the effects of job displacement, an involuntary event associated with socioeconomic and psychological decline, on social participation. Using more than 45 years of panel data from the Wisconsin Longitudinal Study, we find that job displacement is associated with significant, long-term lower probabilities of subsequent involvement with various forms of social participation for workers displaced during their prime earnings years; displacement is not associated with lower probabilities of involvement for workers displaced in the years approaching retirement. We also find that post-displacement socioeconomic and psychological decline explain very little of the negative effect of job displacement on social participation, and that a single displacement event, rather than a series of multiple displacement events, is most strongly associated with lower probabilities of social involvement. PMID- 20827388 TI - Analyzing Direct Effects in Randomized Trials with Secondary Interventions: An Application to HIV Prevention Trials. AB - The Methods for Improving Reproductive Health in Africa (MIRA) trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing HIV infection among susceptible women. 5,045 women were randomly assigned to either the active treatment arm or not. Additionally, all subjects in both arms received intensive condom counselling and provision, the "gold standard" HIV prevention barrier method. There was much lower reported condom use in the intervention arm than in the control arm, making it difficult to answer important public health questions based solely on the intention-to treat analysis. We adapt an analysis technique from causal inference to estimate the "direct effects" of assignment to the diaphragm arm, adjusting for condom use in an appropriate sense. Issues raised in the MIRA trial apply to other trials of HIV prevention methods, some of which are currently being conducted or designed. PMID- 20827389 TI - Study of Proton Coupled Electron Transfer in a Biomimetic Dimanganese Water Oxidation Catalyst with Terminal Water Ligands. AB - The oxomanganese complex [H(2)O(terpy)Mn(III)(MU-O)(2)Mn(IV)(terpy)H(2)O](3+) (1, terpy = 2,2':6-2"-terpyridine) is a biomimetic model of the oxygen evolving complex of photosystem II with terminal water ligands. When bound to TiO(2) surfaces, 1 is activated by primary oxidants (e.g., Ce(4+)(aq), or oxone in acetate buffers) to catalyze the oxidation of water yielding O(2) evolution [G. Li et al. Energy Environ. Sci. 2, 230-238 (2009)]. The activation is thought to involve oxidation of the inorganic core [Mn(III)(MU-O)(2)Mn(IV)](3+) to generate the [Mn(IV)(MU-O)(2)Mn(IV)](4+) state 1(ox) first and then the highly reactive Mn oxyl species Mn(IV)O(*) through proton coupled electron transfer (PCET). Here, we investigate the step 1 -> 1(ox) as compared to the analogous conversion in an oxomanganese complex without terminal water ligands, the [(bpy)(2) Mn (III) (MU O)(2) Mn (IV) (bpy)(2)](3+) complex (2, bpy = 2,2'-bipyridyl). We characterize the oxidation in terms of free energy calculations of redox potentials and pKa's as directly compared to cyclic voltammogram measurements. We find that the pKa's of terminal water ligands depend strongly on the oxidation states of the Mn centers, changing by ~13 pH units (i.e., from 14 to 1) during the III, IV->IV, IV transition. Furthermore, we find that the oxidation potential of 1 is strongly dependent on pH (in contrast to the pH-independent redox potential of 2) as well as by coordination of Lewis base moieties (e.g., carboxylate groups) that competitively bind to Mn by exchange with terminal water ligands. The reported analysis of ligand binding free energies, pKa's and redox potentials indicates that the III, IV->IV, IV oxidation of 1 in the presence of acetate (AcO(-)) involves the following PCET: [H(2)O(terpy)Mn(III)(MU-O)(2)Mn(IV)(terpy)AcO](2+) > [HO(terpy)Mn(IV)(MU-O)(2)Mn(IV)(terpy)AcO](2+) + H(+) + e(-). PMID- 20827390 TI - Abstinence Social Support: The Impact of Children in Oxford House. AB - The present study compared the characteristics of individuals living with (42 men, 52 women) and without children (561 men, 241 women) residing in an communal iving recovery program called Oxford Houses.. Results indicated that men living with children and women living without children had more general social support, compared to men living without children and women living with children. Additionally, women and residents of adult-only houses reported having more drug users in their social networks. However, men and women living with and without children reported similar levels of social support for abstinence. It is suggested that that men in recovery who take care of their children are in situations more advantageous to sustained recovery and have more resources compared to recovering women with children. Women in substance abuse recovery and taking care of children may require additional resources and assistance compared to men. PMID- 20827391 TI - Ferroportin and erythroid cells: an update. AB - In recent years there have been major advances in our knowledge of the regulation of iron metabolism that have had implications for understanding the pathophysiology of some human disorders like beta-thalassemia and other iron overload diseases. However, little is known about the relationship among ineffective erythropoiesis, the role of iron-regulatory genes, and tissue iron distribution in beta-thalassemia. The principal aim of this paper is an update about the role of Ferroportin during human normal and pathological erythroid differentiation. Particular attention will be given to beta-thalassemia and other diseases with iron overload. Recent discoveries indicate that there is a potential for therapeutic intervention in beta-thalassemia by means of manipulating iron metabolism. PMID- 20827392 TI - Iron overload in diabetic retinopathy: a cause or a consequence of impaired mechanisms? AB - Iron is an essential ion for life, playing a central role in many metabolic processes. The most important property of free iron is its capacity to be reversibly oxidized and reduced, but at same time this make it highly pro-oxidant molecule. In this regard, iron is able to generate powerful reactive oxygen species (ROS). For this reason, careful control on iron availability is central to the maintenance of normal cell function in the retina. In the diabetic eye there is an impairment of iron homeostasis, thus leading to iron overload. The mechanisms involved in this process include: (1) Destruction of heme molecules induced by hyperglycemia (2) Intraretinal and vitreal hemorrhages (3) Overexpression of the renin-angiotensin system. The main consequences of iron overload are the following: (1) Retinal neurodegeneration due to the increase of oxidative stress (2) Increase of AGE-RAGE binding (3) Defective phagocytosis of retinal pigment epithelium, which generates the accumulation of autoantigens and the synthesis of proinflammatory cytokines. Further studies addressed to explore not only the role of iron in the pathogenesis of diabetic retinopathy, but also to design novel therapeutic strategies based on the regulation of iron homeostasis are needed. PMID- 20827393 TI - Synthetic biology guides biofuel production. AB - The advancement of microbial processes for the production of renewable liquid fuels has increased with concerns about the current fuel economy. The development of advanced biofuels in particular has risen to address some of the shortcomings of ethanol. These advanced fuels have chemical properties similar to petroleum based liquid fuels, thus removing the need for engine modification or infrastructure redesign. While the productivity and titers of each of these processes remains to be improved, progress in synthetic biology has provided tools to guide the engineering of these processes through present and future challenges. PMID- 20827395 TI - It Started Over Coffee: The Aboriginal Community Youth Resilience Network (ACYRN) in Mi'kmaq And Maliseet Communities of Atlantic Canada. PMID- 20827394 TI - Gene therapy to the kidney using viral vectors. AB - Many pediatric diseases have reached a therapeutic plateau using currently available surgical and pharmacological approaches. Gene therapy has emerged as an exciting new technology to manipulate cells in the mammalian system, and in some cases, this method has achieved amazing therapeutic benefits. Compared to other organs, such as the brain, liver and lung, methods to genetically modify renal cells have received relatively little attention. The current review will discuss the challenges and important developments regarding gene therapy to the kidney, and relate the recent successes and failures to the future potential of gene therapy as a treatment modality in the context of pediatric disease. PMID- 20827396 TI - Inflammatory Myofibroblastic Bladder Tumor in a Patient with Von Recklinghausen's Syndrome. AB - Myofibroblastic tumor, also known as inflammatory pseudotumor or pseudosarcoma, is a benign tumor with mesenchymal origin. Bladder location is very uncommon. We report the case of a 58-year-old man with a history of von Recklinghausen's disease who complained for painless macroscopic hematuria 5 months after suprapubic prostatectomy. The radiograph evaluation revealed a bladder tumor, and the pathologic examination following a transurethral resection showed inflammatory myofibroblastic tumor of the bladder. The patient finally underwent a radical cystectomy due to the uncertain pathogenesis of inflammatory myofibroblastic tumor as well as the rarity of cases published on bladder tumors in Von Recklinghausen's patients. PMID- 20827397 TI - Catalpol increases brain angiogenesis and up-regulates VEGF and EPO in the rat after permanent middle cerebral artery occlusion. AB - To investigate the role and mechanism of catalpol in brain angiogenesis in a rat model of stroke, the effect of catalpol (5 mg/kg; i.p) or vehicle administered 24 hours after permanent middle cerebral artery occlusion (pMCAO) on behavior, angiogenesis, ultra-structural integrity of brain capillary endothelial cells, and expression of EPO and VEGF were assessed. Repeated treatments with Catalpol reduced neurological deficits and significantly improved angiogenesis, while significantly increasing brain levels of EPO and VEGF without worsening BBB edema. These results suggested that catalpol might contribute to infarcted-brain angiogenesis and ameliorate the edema of brain capillary endothelial cells (BCECs) by upregulating VEGF and EPO coordinately. PMID- 20827398 TI - Expression of peptidylarginine deiminase type 4 in ovarian tumors. AB - Peptidylarginine deiminase type 4 (PADI4) converts arginine residues into citrulline. The current study focused on the expression of PADI4 in various subtypes of ovary cancers, and this study investigated the effects of estrogen on PADI4 expression in SKOV-3 cells that originated from ovary tumors. We utilized immunohistochemistry, real-time PCR and western blotting to analyze the expression of PADI4 in the tumor tissues and in the cell line that were cultured with estrodial-17beta. PADI4 was detected in serious cystadenocarcinoma (n=39, positivity=100%), clear cell cancer (n=7, positivity= 100%), mucinous cystadenocarcinoma (n=6, positivity=100%), dysgerminoma (n=6, positivity=100%), squamous cell tumor (n=6, positivity=100%), sibnet-ring cell carcinoma (n=6, positivity=100%), endodermal sinus tumor (n=6, positivity=100%), germ cell tumors (n=6, positivity=100%) and immature teratoma (n=6, positivity=100%). However, PADI4 was either not detected or detected at low levels in granulosa cell tumor (n=6), malignant thecoma (n=6), ovarian cystadenoma (n=5) and normal ovarian tissue (n=11). For serious cystadenocarcinoma, all of the samples with high PADI4 expression belonged to the T1 and T2 stages of pTMN, whereas all of the samples that exhibited weak or moderate PADI4 expression belonged to the T3 and T4 stages. PADI4 was evenly distributed in the cytoplasm of tumor cells of serious cystadenocarcinoma that were classified as being grade II and III by histopathological scoring. However, PADI4 showed granular cellular distribution in the tumor tissues that were isolated from grade I cystadenocarcinoma. In addition, the PADI4 level was positively related with the ages of the patients that presented with serious adenocarcinoma (p=0.029). Real-time PCR and western blot analyses confirmed that PADI4 was expressed at higher levels in ovarian adenocarcinoma (n=8) compared to ovarian cystadenoma (n=5) (p< 0.05). The study also detected an increased level of PADI4 in SKOV-3 cells that were incubated with estrodial-17beta in the range of 10(-12) to 10(-4)M. The results suggest an important role for PADI4 in the tumorigenesis of ovary cancers that are under the regulation of estrogen. PMID- 20827400 TI - Smaller cardiac cell size and reduced extra-cellular collagen might be beneficial for hearts of Ames dwarf mice. AB - PURPOSE: To test the hypothesis that cardiac morphologic differences between Ames dwarf and wild-type littermates might correlate with the increased longevity observed in the Ames dwarf mice. METHODS: Hearts removed from young adult (5-7 mo) and old (24-28 mo) Ames dwarf and wild-type littermates underwent histological and morphometric analysis. Measurements of cell size, nuclear size, and collagen content were made using computerized color deconvolution and particle analysis methodology. RESULTS: In the young mice at six months of age, mean cardiomyocyte area was 46% less in Ames dwarf than in wild-type mice (p<0.0001). Cardiomyocyte size increased with age by about 52% in the wild-type mice and 44% in the Ames dwarf mice (p<0.001). There was no difference in nuclear size of the cardiomyocytes between the young adult wild-type and Ames dwarf mice. There was an age-associated increase in the cardiomyocyte nuclear size by approximately 50% in both the Ames and wild-type mice (p<0.001). The older Ames dwarf mice had slightly larger cardiomyocyte nuclei compared to wild-type (2%, p<0.05). The collagen content of the hearts in young adult Ames dwarf mice was estimated to be 57% less compared to wild-type littermates (p<0.05). Although collagen content of both Ames dwarf and wild-type mouse hearts increased with age, there was no significant difference at 24 months. CONCLUSIONS: In wild-type and Ames dwarf mice, nuclear size, cardiomyocyte size, and collagen content increased with advancing age. While cardiomyocyte size was much reduced in young and old Ames dwarf mice compared with wild-type, collagen content was reduced only in the young adult mice. Taken together, these findings suggest that Ames dwarf mice may receive some longevity benefit from the reduced cardiomyocyte cell size and a period of reduced collagen content in the heart during adulthood. PMID- 20827399 TI - Skeletal muscle stem cells from animals I. Basic cell biology. AB - Skeletal muscle stem cells from food-producing animals are of interest to agricultural life scientists seeking to develop a better understanding of the molecular regulation of lean tissue (skeletal muscle protein hypertrophy) and intramuscular fat (marbling) development. Enhanced understanding of muscle stem cell biology and function is essential for developing technologies and strategies to augment the metabolic efficiency and muscle hypertrophy of growing animals potentially leading to greater efficiency and reduced environmental impacts of animal production, while concomitantly improving product uniformity and consumer acceptance and enjoyment of muscle foods. PMID- 20827402 TI - How do we approach intrinsic motivation computationally. PMID- 20827401 TI - Identification and molecular characterization of a new member of the peritrophic membrane proteins from the meadow moth, loxostege sticticalis. AB - The peritrophic membrane (PM) plays an important role in protecting insects. The PM proteins are important to determinate the formation and function of the PM. A new PM protein, named Lsti99, was identified from the PM of Loxostege sticticalis larvae by cDNA library screening. The full cDNA of Lsti99 is 1392 bp in length, contains an open reading frame (ORF) of 1245 bp that encodes a preprotein of 415 amino acid residues with a 17-amino acid signal peptide. The sequence of Lsti99 showed no homology to other known PM proteins. The recombinant Lsti99 was successfully expressed in insect cells (Sf9) using recombinant baculoviruses and was used to isolate the antibodies to Lsti99 from the polyclonal antiserum. Lsti99 was expressed mainly in the PM, but weaker bands could be detected in the head and integument as well. The Lsti99 protein could be separated from the PM complex by chitinase in vitro, but M2R did not show effect in vitro confirming the chitin-binding activity of Lsti99. The biochemical and physiological functions of Lsti99 in L. sticticalis require further investigation. PMID- 20827403 TI - The Digital Bee Brain: Integrating and Managing Neurons in a Common 3D Reference System. AB - The honeybee standard brain (HSB) serves as an interactive tool for relating morphologies of bee brain neurons and provides a reference system for functional and bibliographical properties (http://www.neurobiologie.fu-berlin.de/beebrain/). The ultimate goal is to document not only the morphological network properties of neurons collected from separate brains, but also to establish a graphical user interface for a neuron-related data base. Here, we review the current methods and protocols used to incorporate neuronal reconstructions into the HSB. Our registration protocol consists of two separate steps applied to imaging data from two-channel confocal microscopy scans: (1) The reconstruction of the neuron, facilitated by an automatic extraction of the neuron's skeleton based on threshold segmentation, and (2) the semi-automatic 3D segmentation of the neuropils and their registration with the HSB. The integration of neurons in the HSB is performed by applying the transformation computed in step (2) to the reconstructed neurons of step (1). The most critical issue of this protocol in terms of user interaction time - the segmentation process - is drastically improved by the use of a model-based segmentation process. Furthermore, the underlying statistical shape models (SSM) allow the visualization and analysis of characteristic variations in large sets of bee brain data. The anatomy of neural networks composed of multiple neurons that are registered into the HSB are visualized by depicting the 3D reconstructions together with semantic information with the objective to integrate data from multiple sources (electrophysiology, imaging, immunocytochemistry, molecular biology). Ultimately, this will allow the user to specify cell types and retrieve their morphologies along with physiological characterizations. PMID- 20827406 TI - Seroepidemiology of a second epidemic of hepatitis E in a population that had recorded first epidemic 30 years before and has been under surveillance since then. AB - PURPOSE: Large-scale waterborne epidemics of hepatitis E occur in developing countries. It is not known why these epidemics occur repeatedly and selectively in adult population? METHODS: We studied seroepidemiology of an outbreak of hepatitis E in one of 15 villages that had recorded first epidemic of hepatitis E 30 years back. Another village not affected by the second epidemic was taken as a control. Overall, 1,216 sera were collected (638 from the epidemic village and 578 from the control village) for serological markers of both hepatitis A virus (HAV) and hepatitis E virus (HEV). RESULTS: The seroprevalence of anti-HEV in this population following the first epidemic in 1978 was 29.4%. Antibodies were detected in only 47% of the 45 patients affected by icteric HEV infection 14 years after the first epidemic. At 30-year follow-up, the seroprevalence of anti HEV was only 4.5% (26/578). In the village affected by second epidemic, 138 (21.6%) subjects had serological evidence of recent HEV infection. The attack rate was 23.6% (78/330) in children (<=14 years) and 19.4% (60/308) in adults (P = 0.21). The attack rate of anicteric HEV infection was 21.8% (72/330) in children and 14.6% (45/308) in adults (P = 0.02). CONCLUSIONS: Following hepatitis E epidemics, there is a gradual loss of antibodies in the community over the decades and poor exposure to HEV infection in the cohort of population born during the interepidemic period. The next epidemic occurs when antibody levels fall to critically low levels and there is associated gross fecal contamination of water resources. During epidemic, persons of all age groups are exposed to infection, with predominant anicteric disease in children. PMID- 20827407 TI - Effect of surveillance for hepatocellular carcinoma on tumor staging and treatment decisions in Egyptian patients. AB - PURPOSE: Egyptian hepatocellular carcinoma (HCC) patients present at advanced stages. We aimed to study the influence of surveillance versus non-surveillance on HCC staging and the potential therapeutic options. METHODS: A retrospective study to evaluate the effect of surveillance on early detection of HCC among cirrhotic patients from 2003 to 2008. Patients examined every 6 months using ultrasound and alpha-fetoprotein (alpha-FP) (group A) and those diagnosed with those that present for the first time symptomatically or incidentally (group B). Groups were compared for alpha-FP level, tumour characteristics, severity of liver disease; tumour staging was evaluated by Okuda, CLIP and BCLC staging systems, in addition to the potential therapeutic options. RESULTS: Group A comprised 122 HCC cases and group B 473. Surveillance improved HCC detection: at the stage of single nodule in 62.3% in group A versus 52.2% in group B, (P = 0.046) and reduced the percentage of HCC with portal vein thrombosis in 16.4 versus 33.8%, (P = 0.000) and the percentage of alpha-FP >400 ng/ml in 19.5 versus 32.6%, (P = 0.006) in groups A and B, respectively. Surveillance doubled the detection of HCC at early stage of BCLC (25.4 vs. 11.9% P = 0.000) and doubled the patients' chance for loco-regional ablation (12.3 vs. 5.9%, P = 0.015) and liver transplantation (10.7 vs. 3.2%, P = 0.001) in groups A and B, respectively. CONCLUSION: HCC surveillance increases early detection of HCC and doubled the chances for curative options. Implementation of both HCC surveillance and cadaveric liver transplantation programs should be recommended in Egypt. PMID- 20827405 TI - Autoimmune hepatitis: new paradigms in the pathogenesis, diagnosis, and management. AB - Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating gamma-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4(+) and CD8(+) T cells are involved together with effector responses mediated by NK cells, gammadelta T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis. PMID- 20827408 TI - Longitudinal assessment of prognostic factors for patients with hepatorenal syndrome in a tertiary center. AB - INTRODUCTION: Hepatorenal syndrome (HRS) is one of the serious complications in patients with advanced cirrhosis and ascites. In tertiary centers, most patients were classified as having type 1 HRS for their rapid progressive diseases. However, no significant predictors have been assessed previously for patients with type 1 HRS. In addition to the initial model of end-stage liver disease (MELD) scores and biochemistry parameters, we want to further investigate the prognostic importance of changes in MELD scores and biochemistry parameters over time for patients with type 1 HRS. MATERIALS AND METHODS: Data from type 1 HRS patients were incorporated, including their demographic, clinical progression, all recording biochemical parameters, therapeutic methods, and outcomes. RESULTS: A total of 103 patients were included in our study. According to the definition of the International Ascites Club, 67 patients (or 65%) had type 1 HRS whereas 36 (or 35%) had type 2 HRS. According to the multivariate COX proportional hazards regression model, either initial biochemistry parameters or MELD scores were not significantly associated with prognosis. By time-dependent proportional hazards model, each point elevated in creatinine (CRE) and total bilirubin (TBI) levels during the admission increased mortality risk by 29 and 4%, respectively. Increasing albumin level during the admission showed its protective value. Changes in MELD score simple during the admission, which were calculated by CRE and TBI [3.8 * log (bilirubin (mg/dl)] + 9.6 * log [Creatinine (mg/dl) + 6.43], were significant predictor for patients with type 1 HRS. CONCLUSION: In patients with type 1 HRS, changes in TBI, CRE, and albumin level during the admission were associated with prognosis. Changes in MELD score simple is superior to initial and changes in MELD scores to predict prognosis in patients with type 1 HRS. PMID- 20827409 TI - Clinical profile of hepatitis B virus chronic infection in patients of Brazilian liver reference units. AB - PURPOSE: To assess data about chronic forms of hepatitis B virus (HBV) infection in Brazilian reference units, the Brazilian Society of Hepatology (SBH) performed a survey, with its associates spread throughout the country. METHODS: SBH members were contacted by electronic mail. They were asked for data from their liver units regarding chronically infected HBV patients between January 2005 and September 2007. All subjects with HBV surface antigenemia lasting more than 6 months were eligible. Patients who died after January 2005 were also included. RESULTS: Data from 24 units of 17 cities (12 Brazilian states) were obtained. These corresponded to 3,913 patients. Mean age was 39 years, ranging from 1 to 84 years. The northern region had the lowest mean age (35 years) and the southern region the highest (43 years). Most of the sampled people were white; 1,448 of 3,614 patients had chronic hepatitis B. Most of them were HBeAg negative (1.4:1). There were 1,695 (46.9%) inactive carriers of 3,614 HBV-infected patients and other 69 (1.9%) were considered as having immune-tolerant status. Hepatitis D coinfection was common among the Amazonian sample (n = 369). CONCLUSIONS: This large sample study shows important tendencies of chronic hepatitis B infection in Brazilian reference units, such as HBeAg-negative chronic hepatitis B cases overwhelming wild-type strains infected cases. Besides, hepatitis D occurs only among the Amazonian patients. PMID- 20827404 TI - Asian Pacific Association for the Study of the Liver consensus recommendations on hepatocellular carcinoma. AB - INTRODUCTION: The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the management of hepatocellular carcinoma (HCC) in December 2008 to develop consensus recommendations. METHODS: The working party consisted of expert hepatologist, hepatobiliary surgeon, radiologist, and oncologist from Asian-Pacific region, who were requested to make drafts prior to the consensus meeting held at Bali, Indonesia on 4 December 2008. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively, according to the Oxford system of evidence-based approach for developing the consensus statements. RESULTS: Participants of the consensus meeting assessed the quality of cited studies and assigned grades to the recommendation statements. Finalized recommendations were presented at the fourth APASL single topic conference on viral-related HCC at Bali, Indonesia and approved by the participants of the conference. PMID- 20827410 TI - A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection. AB - PURPOSE: Hepatitis B viral markers may be useful for predicting outcomes such as liver-related deaths or development of hepatocellular carcinoma. We determined the frequency of these markers in different clinical stages of chronic hepatitis B infection. METHODS: We compared baseline hepatitis B viral markers in 317 patients who were enrolled in a prospective study and identified the frequency of these tests in immune-tolerant (IT) patients, in inactive carriers, and in patients with either hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis or cirrhosis. RESULTS: IT patients were youngest (median age 27 years) and HBeAg-negative patients with cirrhosis were oldest (median age 58 years) (p = 0.03 to <0.0001). The male to female ratio was similar both in IT patients and in inactive carriers, but there was a male preponderance both in patients with chronic hepatitis and in patients with cirrhosis (p < 0.0001). The A1896 precore mutants were most prevalent in inactive carriers (36.4%) and HBeAg negative patients with chronic hepatitis (38.8%; p < 0.0001), and the T1762/A1764 basal core promoter mutants were most often detected in HBeAg-negative patients with cirrhosis (65.1%; p = 0.02). Genotype A was detected only in 5.3% of IT patients, and genotype B was least often detected in both HBeAg-Positive patients with chronic hepatitis and cirrhosis (p = 0.03). The hepatitis B viral DNA levels were lowest in inactive carriers (2.69 log(10) IU/mL) and highest in IT patients (6.80 log(10) IU/mL; p = 0.02 to <0.0001). At follow-up, HBeAg-positive and HBeAg negative patients with cirrhosis accounted for 57 of 64 (89.1%) liver-related deaths (p < 0.0001). CONCLUSION: Differences in baseline hepatitis B viral markers were detected in patients in various clinical stages of hepatitis B virus infection. HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for the majority of the liver-related fatalities. PMID- 20827411 TI - Risk factors, genotype 6 prevalence, and clinical characteristics of chronic hepatitis C in Southeast Asian Americans. AB - PURPOSE: Although infection with hepatitis C virus (HCV) affects 32 million individuals from Southeast Asia, little is known about the mode of HCV acquisition and the epidemiology of chronic hepatitis C (CHC) in these individuals. Our goal was to examine risk factors for HCV acquisition, prevalence, and clinical characteristics of HCV genotype 6 compared with genotypes 1 and 2/3 in Southeast Asian (SEA) patients. METHODS: We performed a cross-sectional study of 308 consecutive SEA Americans with CHC evaluated by five gastroenterologists from January 2000 to December 2008 at two community clinics in northern California via medical record review, using a case report form. RESULTS: A significant proportion of patients (41%) could not recall any specific risk factors for HCV acquisition. The most commonly reported risk factor in patients who reported at least one risk factor was history of surgeries (34%), followed by blood transfusion (25%) and acupuncture (13%). Among patients with core sequence testing for HCV genotype (n = 181), the most common HCV genotypes were genotype 1 (42%) and genotype 6 (41%), followed by genotype 2/3 (17%). There were no major differences in the clinical and virological characteristics between the different genotype groups (1 vs. 2/3 vs. 6). CONCLUSION: HCV genotype 6 is as common as genotype 1 in SEAs. Commonly known risk factors for HCV acquisition were not readily identifiable in a large proportion of SEA Americans (41%) and may not be useful in identifying at-risk individuals for HCV screening in this population. PMID- 20827412 TI - Acute hepatitis B despite a previous high titer of anti-HBs. AB - INTRODUCTION: Loss of HBsAg and development of surface and core antibodies represent clinical cure. However, recent evidence suggests that hepatitis B virus (HBV) persists in a latent state even in those with mounted protective antibodies. After significant immunosuppression, anti-HBs may decrease and HBsAg may reappear (reverse seroconversion). Reverse seroconversion of HBV has been observed in association with hematopoietic stem cell transplantation, renal transplantation, intensive chemotherapy, human immunodeficiency infection, or rituximab usage. CASE REPORT: We present here a case study of a patient with a previous high titer of anti-HBs who later developed HBV reactivation following intensive chemotherapy for leukemia. CONCLUSION: We conclude that in immunosuppressed patients with a history of HBV infection may carry a risk for reverse seroconversion and monitoring anti-HBs levels may help recognising this risk. PMID- 20827413 TI - Intravenous N-acetylcysteine in dengue-associated acute liver failure. PMID- 20827414 TI - N-Acetylcysteine in non-acetaminophen-induced acute liver failure. PMID- 20827415 TI - Erratum to: Seroepidemiology of a second epidemic of hepatitis E in a population that had recorded first epidemic 30 years before and has been under surveillance since then. AB - [This corrects the article DOI: 10.1007/s12072-009-9159-5.]. PMID- 20827416 TI - TLR-mediated preterm birth in response to pathogenic agents. AB - The incidence of preterm birth in developed countries has risen in the past decades. Underlying causes for this enigmatic pregnancy complication are numerous, yet infectious agents that induce dysregulation of immunity at the maternal-fetal interface pose one of the most probable causes of preterm birth. This paper highlights two factors regarding maternal infections that trigger unscheduled inflammatory sequences that are deleterious to the maternal-fetal balance necessary to maintain pregnancy. Firstly, we discuss the role of Toll like receptors (TLRs) as sentinels of uterine immunity in the context of response to pathogens. We highlight the idea that particular TLR activations lead to differential immune cascades that induce preterm birth. Secondly, two alternative routes of pathogenic entry may prove to be critical for inducing preterm birth via a cytokine storm or a secondary and currently unknown cell-mediated mechanism of uterine inflammation. This paper summarizes pathways that underlie activation of adverse and diverse immune responses to foreign agents that may result in preterm birth. PMID- 20827417 TI - Ameloblastic fibro-odontoma: a diagnostic challenge. AB - An 11-year-old girl presented to our department to have a second opinion regarding a lesion involving her left mandible. She had previously undergone several radiographic exams including panoramic, helical, and cone-beam computed tomography. Radiographic examinations revealed a well-defined radiolucent region, which contained an irregular radiopaque mass of 3 cm in diameter, localized to the left angle of the mandible. Our presumptive diagnosis was complex odontoma. Excisional biopsy was performed, and microscopic features showed strands and islands of odontogenic epithelium showing peripheral palisading and loosely arranged central cells, identical to stellate reticulum, embedded in a myxoid cell-rich stroma resembling the dental papilla. Dentin and enamel were also presented. The diagnosis was ameloblastic fibro-odontoma, which is a rare mixed odontogenic tumor, derived from epithelial and ectomesenchymal elements that form the dental tissues. PMID- 20827418 TI - Construction and characterization of a bacterial artificial chromosome library for the A-genome of cotton (G. arboreum L.). AB - A bacterial artificial chromosome (BAC) library for the A-genome of cotton has been constructed from the leaves of G. arboreum L cv. Jianglinzhongmian. It is used as elite A-genome germplasm resources in the present cotton breeding program and has been used to build a genetic reference map of cotton. The BAC library consists of 123,648 clones stored in 322 384-well plates. Statistical analysis of a set of 103 randomly selected BAC clones indicated that each clone has an average insert length of 100.2 kb per plasmid, with a range of 30 to 190 kb. Theoretically, this represents 7.2 haploid genome equivalents based on an A genome size of 1697 Mb. The BAC library has been arranged in column pools and superpools allowing screening with various PCR-based markers. In the future, the A-genome cotton BAC library will serve as both a giant gene resource and a valuable tool for map-based gene isolation, physical mapping and comparative genome analysis. PMID- 20827420 TI - Effects of Dexmedetomidine-Fentanyl Infusion on Blood Pressure and Heart Rate during Cardiac Surgery in Children. AB - Background. The purpose of this study was to access the effects of dexmedetomidine-fentanyl infusion on blood pressure (BP) and heart rate (HR) before surgical stimulation, on their changes to skin incision, and on isoflurane requirement during cardiac surgery in children. Methods. This study had a prospective, randomized, and open-label design. Thirty-two children aged 1 month to 10 years undergoing surgery for repair congenital heart disease (CHD) with CPB were randomly allocated into two groups: group MDZ received midazolam 0.2 mg.kg( 1).h(-1) and group DEX received dexmedetomidine 1 MUg.kg(-1).h(-1) during the first hour followed by half of these rates of infusions thereafter. Both group received fentanyl 10 MUg.kg(-1), midazolam 0.2 mg.kg(-1) and vecuronium 0.2 mg.kg(-1) for induction. These same doses of fentanyl and vecuronium were infused during the first hour then reduced to half. The infusions started after induction and maintained until the end of surgery. Isoflurane was given briefly to control hyperdynamic response to skin incision and sternotomy. Results. In both groups, systolic blood pressure (sBP) and heart rate (HR) decreased significantly after one hour of infusion of the anesthetic solutions, but there were significantly less increase in diastolic blood pressure, sBP, and HR, and less patients required isoflurane supplementation to skin incision in the patients of the DEX group. Discussion. Dexmedetomidine infusion without a bolus appears to be an effective adjunct to fentanyl anesthesia in control of hemodynamic responses to surgery for repair of CHD in children. PMID- 20827419 TI - Therapeutic strategies for SLE involving cytokines: mechanism-oriented therapies especially IFN-gamma targeting gene therapy. AB - Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)-gamma and also IFNalpha/beta are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)-gamma- and IFN-alpha/beta-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN-gamma and IFN-gamma-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN-alpha/beta and tumor necrosis factor (TNF)-alpha together with regulatory T(Treg) cells are briefly introduced. Clinical application will be discussed. PMID- 20827421 TI - S100B Protein, A Damage-Associated Molecular Pattern Protein in the Brain and Heart, and Beyond. AB - S100B belongs to a multigenic family of Ca(2+)-binding proteins of the EF-hand type and is expressed in high abundance in the brain. S100B interacts with target proteins within cells thereby altering their functions once secreted/released with the multiligand receptor RAGE. As an intracellular regulator, S100B affects protein phosphorylation, energy metabolism, the dynamics of cytoskeleton constituents (and hence, of cell shape and migration), Ca(2+) homeostasis, and cell proliferation and differentiation. As an extracellular signal, at low, physiological concentrations, S100B protects neurons against apoptosis, stimulates neurite outgrowth and astrocyte proliferation, and negatively regulates astrocytic and microglial responses to neurotoxic agents, while at high doses S100B causes neuronal death and exhibits properties of a damage-associated molecular pattern protein. S100B also exerts effects outside the brain; as an intracellular regulator, S100B inhibits the postinfarction hypertrophic response in cardiomyocytes, while as an extracellular signal, (high) S100B causes cardiomyocyte death, activates endothelial cells, and stimulates vascular smooth muscle cell proliferation. PMID- 20827423 TI - Angiogenin-mediated rRNA transcription in cancer and neurodegeneration. AB - Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Accumulating evidence indicates that the angiogenic activity of ANG is related to its ability in regulating ribosomal RNA (rRNA) transcription. ANG is translocated to the nucleus of growth-stimulated endothelial cells where it accumulates in the nucleolus, binds to the promoter region of ribosomal DNA (rDNA), and stimulates rRNA transcription. This normally well-controlled process of nuclear translocation of ANG is hijacked by cancer cells that constitutively uptake ANG and translocate it into the nucleus so that rRNA is constantly transcribed to meet a higher metabolic requirement of this cells. Nuclear translocation of ANG therefore controls the rate of rRNA transcription and has been shown to be a molecular target for cancer drug development. Recently, ANG has also been shown to play a role in motor neuron physiology. Loss-of-function mutations in the coding region of ANG gene have been found in patients with amyotrophic lateral sclerosis (ALS). A deficiency in ANG function may result in insufficient rRNA transcription in motor neurons that require robust ribosome biogenesis due to the demand of long axonal transport. Haploinsufficiency of ANG has thus been implicated in ALS pathogenesis, and ANG has been shown to promote motor neuron survival both in vitro and in vivo. Promotion of ANG expression or activity has been recognized as a therapeutic opportunity for ALS treatment. PMID- 20827422 TI - The Calcium-Dependent Interaction of S100B with Its Protein Targets. AB - S100B is a calcium signaling protein that is a member of the S100 protein family. An important feature of S100B and most other S100 proteins (S100s) is that they often bind Ca(2+) ions relatively weakly in the absence of a protein target; upon binding their target proteins, Ca(2+)-binding then increases by as much as from 200- to 400-fold. This manuscript reviews the structural basis and physiological significance of increased Ca(2+)-binding affinity in the presence of protein targets. New information regarding redundancy among family members and the structural domains that mediate the interaction of S100B, and other S100s, with their targets is also presented. It is the diversity among individual S100s, the protein targets that they interact with, and the Ca(2+) dependency of these protein-protein interactions that allow S100s to transduce changes in [Ca(2+)](intracellular) levels into spatially and temporally unique biological responses. PMID- 20827424 TI - The Role of B-RAF Mutations in Melanoma and the Induction of EMT via Dysregulation of the NF-kappaB/Snail/RKIP/PTEN Circuit. AB - Melanoma is a highly metastatic cancer, and there are no current therapeutic modalities to treat this deadly malignant disease once it has metastasized. Melanoma cancers exhibit B-RAF mutations in up to 70% of cases. B-RAF mutations are responsible, in large part, for the constitutive hyperactivation of survival/antiapoptotic pathways such as the MAPK, NF-kappaB, and PI3K/AKT. These hyperactivated pathways regulate the expression of genes targeting the initiation of the metastatic cascade, namely, the epithelial to mesenchymal transition (EMT). EMT is the result of the expression of mesenchymal gene products such as fibronectin, vimentin, and metalloproteinases and the invasion and inhibition of E-cadherin. The above pathways cross-talk and regulate each other's activities and functions. For instance, the NF-kappaB pathway directly regulates EMT through the transcription of gene products involved in EMT and indirectly through the transcriptional up-regulation of the metastasis inducer Snail. Snail, in turn, suppresses the expression of the metastasis suppressor gene product Raf kinase inhibitor protein RKIP (inhibits the MAPK and the NF-kappaB pathways) as well as PTEN (inhibits the PI3K/AKT pathway). The role of B-RAF mutations in melanoma and their direct role in the induction of EMT are not clear. This review discusses the hypothesis that B-RAF mutations are involved in the dysregulation of the NF kappaB/Snail/RKIP/PTEN circuit and in both the induction of EMT and metastasis. The therapeutic implications of the dysregulation of the above circuit by B-RAF mutations are such that they offer novel targets for therapeutic interventions in the treatment of EMT and metastasis. PMID- 20827425 TI - Immobilization Using Dental Material Casts Facilitates Accurate Serial and Multimodality Small Animal Imaging. AB - Custom disposable patient immobilization systems that conform to the patient's body contours are commonly used to facilitate accurate repeated patient setup for imaging and treatment in radiation therapy. However, in small-animal imaging, immobilization is often overlooked or done in a way that is not conducive to reproducible positioning. This has a negative impact on the potential for accurate analysis of serial or multimodality imaging. We present the use of vinyl polysiloxane dental impression material for immobilization of mice for imaging. Four different materials were examined to identify any potential artifacts using magnetic resonance techniques. A water phantom placed inside the cast was used at 4.7 T with magnetic resonance imaging and showed no effect at the center of the image when compared with images without the cast. A negligible effect was seen near the ends of the coil. Each material had no detectable signal using electron paramagnetic resonance imaging at 9 mT. The use of dental material also greatly enhances the use of fiducial markers that can be embedded in the mold. Therefore, image registration is simplified as the immobilization of the animal and fiducials together helps in translating from one image coordinate system to another. PMID- 20827426 TI - Do plant sterol concentrations correlate with coronary artery disease in type 1 diabetes? A report from the Pittsburgh Epidemiology of Diabetes Complications Study. AB - BACKGROUND: It has been suggested that plant sterol absorption is increased in type 1 diabetes mellitus (T1DM) and that this may relate to the increased cardiovascular risk seen in T1DM. The cardiovascular benefit of lowering low density lipoprotein-cholesterol with statin medication has also been shown to be influenced by plant sterol absorption. METHODS: The relationship between sterol concentrations, coronary artery disease (CAD), and the use of statin medications in T1DM was compared between participants with CAD (Minnesota codes 1.1, 1.2, 1.3, 4.1-4.3, 5.1-5.3, and 7.1; n = 82), from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, and those without (n = 213). Serum sterol concentrations reflecting cholesterol absorption (beta-sitosterol and campesterol) and synthesis (desmosterol and lathosterol) were assayed and analyzed by gas chromatography and were expressed as a ratio of total cholesterol (*10(3)). RESULTS: No differences were observed in markers of cholesterol absorption between individuals with and without CAD. In patients with CAD, significantly lower levels were observed for both sterol markers reflecting cholesterol synthesis compared with individuals without CAD [desmosterol: 0.34 vs 0.42, respectively (P = 0.003); lathosterol 0.47 vs 0.54, respectively (P = 0.019)]. Further stratification by statin medication use revealed significantly lower levels of synthesis-reflecting sterols in individuals taking statin medication, particularly those with CAD. CONCLUSIONS: Although previous reports suggest that higher levels of cholesterol absorption in T1DM potentially increase cardiovascular risk in this population, the present data suggest no differences in cholesterol absorption between T1DM individuals with and without CAD. PMID- 20827427 TI - Carotid Intima-media thickness in childhood and adolescent obesity relations to abdominal obesity, high triglyceride level and insulin resistance. AB - AIM: To investigate risk factors which impact on common carotid artery intima media thickness (IMT). METHODS: A total of 86 obese children and adolescents and 22 healthy children and adolescents with normal weight were enrolled. Moreover, 23 of 86 obese children and adolescents were diagnosed with metabolic syndrome (MetS). The clinical, biochemical data and the IMT of the common carotid artery were measured in all subjects. RESULTS: Obese and obese with MetS subjects demonstrated a significantly (p < 0.01) thicker intima media (0.69mm, 0.66mm) as compared to the control group (0.38mm), but there was no significant difference of IMT between obese and MetS group. IMT was correlated to body weight, body mass index, waist circumference, waist to hip ratio, systolic blood pressure, diastolic blood pressure, fasting insulin, homoeostasis model assessment-insulin resistance, triglyceride, high-density lipoprotein- cholesterol, low-density lipoprotein-cholesterol, alanine aminotransferase, aspartate aminotransferase and fatty liver. Waist circumference, waist to hip ratio, triglyceride and homoeostasis model assessment-insulin resistance were independent determinants of mean IMT level. CONCLUSION: Obesity especially abdominal obesity, high TG and insulin resistance may be the main risk predictors of increased IMT. PMID- 20827428 TI - Pathogenic mechanisms shared between psoriasis and cardiovascular disease. AB - Psoriasis is associated with an increased risk of cardiovascular disease, a hallmark of which is atherosclerosis. The objective of this study was to review the pertinent literature and highlight pathogenic mechanisms shared between psoriasis and atherosclerosis in an effort to advocate early therapeutic or preventive measures. We conducted a review of the current literature available from several biomedical search databases focusing on the developmental processes common between psoriasis and atherosclerosis. Our results revealed that the pathogenic mechanisms shared between the two diseases converged onto "inflammation" phenomenon. Within the lymph nodes, antigen-presenting cells activate naive T-cells to increase expression of LFA-1 following which activated T-cells migrate to blood vessel and adhere to endothelium. Extravasation occurs mediated by LFA-1 and ICAM-1 (or CD2 and LFA-3) and activated T-cells interact with dendritic cells (and macrophages and keratinocytes in psoriasis or smooth muscle cells in atherosclerosis). These cells further secrete chemokines and cytokines that contribute to the inflammatory environment, resulting in the formation of psoriatic plaque or atherosclerotic plaque. Additionally, some studies indicated clinical improvement in psoriasis condition with treatment of associated hyperlipidemia. In conclusion, therapeutic or preventive strategies that both reduce hyperlipidemia and suppress inflammation provide potentially useful approaches in the management of both diseases. PMID- 20827429 TI - 1, 25-dihydroxyvitamin D3 decreases adriamycin-induced podocyte apoptosis and loss. AB - BACKGROUND: Selective proteinuria is frequently observed in glomerular diseases characterized by podocyte injury. Although, 1,25-dihydroxyvitamin D3 [1,25(OH)(2)D(3)] has potential therapeutic effects on chronic kidney diseases through decreasing podocyte loss, the mechanism underlying the beneficial effects of 1,25(OH)(2)D(3) on podocytes remains still unknown. The present study tested the hypothesis that 1,25(OH)(2)D(3) directly reduced podocyte apoptosis and loss. METHODS: Sprague-Dawley (SD) rats were randomly assigned into three groups: Adriamycin (ADR) group (n=15), ADR+1,25-(OH)(2)D(3) group (n=16), and control group (n=16). Rats in ADR+1,25-(OH)(2)D(3) group were treated with 1,25(OH)(2)D(3) for 8 weeks. The number of podocytes and foot process width (FPW) were detected by transmission electron microscopy. The number of apoptotic podocytes per glomerulus and that of apoptotic nuclei and caspase-3 activity in cultured podocytes were determined by TUNEL staining. The average number of podocytes per glomerulus was quantified by immunohistochemistry. Expressions of p Smad2/3, p-Smad1/5/8, Fas, Fas-Associated protein with Death Domain (FADD), Bax, and Bcl-2 proteins were examined by Western blot assay. RESULTS: Compared with control group, proteinuria, FPW, apoptotic podocytes, caspase-3 activity, the protein expressions of p-Smad2/3, Fas, FADD, and Bax were significantly increased, podocyte density, p-Smad1/5/8 and Bcl-2 expression were decreased in ADR group. 1,25(OH)(2)D(3) significantly reduced proteinuria, FPW, caspase-3 activity, expressions of p-Smad2/3, Fas, FADD, and Bax and apoptosis of podocytes, but increased serum albumin, number of viable podocytes , p-Smad1/5/8 and Bcl-2 expression in ADR treated rats. CONCLUSION: ADR-induced podocyte apoptosis was associated with the imbalance of p-Smad2/3, p-Smad1/5/8 the activity of caspase-3 and aberrant expressions of, Fas, FADD, Bax and Bcl-2. The beneficial effects of 1,25(OH)(2)D(3 )on podocytes may be attributable to inhibit podocyte apoptosis and the amelioration of podocytopenia. PMID- 20827430 TI - Genetic polymorphism of p53, but not GSTP1, is association with susceptibility to esophageal cancer risk - a meta-analysis. AB - A number of studies have evaluated two functional polymorphisms on p53 Arg72Pro and GSTP1 Ile105Val, in relation to esophageal cancer susceptibility. However, the results remain conflicting rather than conclusive. This meta-analysis on 2919 cases and 4074 controls for p53 Arg72Pro and 1885 cases and 2194 controls for GSTP1 Ile105Val from 13 published case-control studies showed that no significant general main effects for GSTP1 Ile105Val on esophageal cancer risk. However, we found that the p53 Arg72Pro was associated with an increased risk of esophageal cancer ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.20, 95%CI=1.06-1.36) without any between-study heterogeneity. In the stratified analysis by ethnicity, we found that the increased esophageal cancer risk associated with p53 Arg72Pro polymorphism was more evident in Asian group ((Pro/Arg +Pro/Pro) versus Arg/Arg: OR=1.35, 95%CI=1.14-1.60, P=0.09 for heterogeneity test), although we still failed to find any significant association between GSTP1 Ile105Val polymorphism and esophageal cancer risk in different ethnicity. These results suggest that p53 Arg72Pro polymorphism, but not GSTP1 Ile105Val, may contribute to esophageal cancer development, especially in Asian. Additional well-designed large studies were required for the validation of this association. PMID- 20827431 TI - Clinical strategy for the management of solid pseudopapillary tumor of the pancreas: aggressive or less? AB - OBJECTIVE: To further delineate the clinicopathological and radiological features of solid pseudopapillary tumor (SPT) of the pancreas and summarize the surgical therapy strategy for this tumor. METHODS: A retrospective review of 18 pathologically confirmed cases of SPT was performed and the clinical and pathological features, radiological findings and surgical interventions were analyzed. RESULTS: The patients included 17 females and 1 male with a median age of 23 years. The median diameter of the lesions was 8.0 cm. Abdominal pain was the predominant complaint (8/18). The rest of the patients were asymptomatic and presented with a pancreatic mass detected incidentally. Radiological study revealed a well-demarcated mass which was composed of a solid-cystic portion. On post-contrast CT, the solid portions could be enhanced whereas the cystic parts remained unenhanced. With the preoperative diagnosis of SPT in 11 patients and pancreatic cyst, benign or malignant pancreatic tumor in the rest, pancreatic tumor resection was successfully completed. Surgical exploration findings, pathological characteristics and good prognosis of the patients with SPT, indicated its low-grade malignant potential. CONCLUSION: In combination with clinical findings, radiological features of SPT may help to make the correct diagnosis and differentiation from other pancreatic neoplasms. Once diagnosed, given the excellent prognosis and low-grade malignancy, less aggressive surgical resection of the primary lesion is proposed. PMID- 20827432 TI - Bilateral Pneumothorax and Subcutaneous Emphysema following Endoscopic Retrograde Cholangiopancreatography: A Rare Complication. AB - Endoscopic Retrograde Cholangiopancreatography (ERCP) is a widely used diagnostic and therapeutic modality in the management of biliary and pancreatic disease. Some of the complications of the procedure, although rare, may carry significant morbidity and mortality risks. We describe the case of a 68-year-old female who underwent elective ERCP for ductal stone clearance. Immediately postprocedure, the patient developed subcutaneous emphysema and bilateral pneumothoraces. Further imaging revealed the presence of free intra-abdominal air. The patient made a very quick recovery after bilateral chest drain insertion and no further intervention was required. We propose that pneumothorax, pneumomediastinum, and subcutaneous emphysema during ERCP, in the absence of duodenal perforation may be explained by leakage of air from a site of low resistance such as the sphincterotomy site, or as a result of copious Valsalva manoeuvres performed by a patient tolerating the procedure poorly. PMID- 20827433 TI - Pseudoxanthoma elasticum papillary dermal elastolysis: a case report. AB - PXE-PDE is a rare clinicopathological entity with few cases reported. It affects more often elderly women and is characterized by asymptomatic bilateral and symmetrical yellowish papules localized predominantly on the neck and supraclavicular regions. It is clinically similar to Pseudoxanthoma Elasticum. The authors report a case of a 64-year-old woman presenting asymptomatic, yellowish, non-follicular papules, affecting the occipital and the posterior region of the neck for 1 year. The patient denied pruritic or inflammatory changes, marked solar exposition or trauma on the affected areas. Routine laboratory studies: thoracic x-ray and ophthalmologic examination were normal. The histopathologic examination of a biopsy of one of the cutaneous lesions showed an absence of elastic fibers in the papillary dermis.The diagnosis of Pseudoxanthoma Elasticum-like Papillary Dermal Elastolysis (PXE-PDE) was made. Of great importance is the differential diagnosis with Pseudoxanthoma elasticum (PXE), but we have also to consider other elastolytic disorders: mid-dermal elastolysis (MDE), linear focal elastosis (LFE) and white fibrous papulosis of the neck (WFPN). Until know, there is no effective treatment for this pathology. PMID- 20827434 TI - New directions in cariology research. PMID- 20827435 TI - Dynamic metabolic flux analysis demonstrated on cultures where the limiting substrate is changed from carbon to nitrogen and vice versa. AB - The main requirement for metabolic flux analysis (MFA) is that the cells are in a pseudo-steady state, that there is no accumulation or depletion of intracellular metabolites. In the past, the applications of MFA were limited to the analysis of continuous cultures. This contribution introduces the concept of dynamic MFA and extends MFA so that it is applicable to transient cultures. Time series of concentration measurements are transformed into flux values. This transformation involves differentiation, which typically increases the noisiness of the data. Therefore, a noise-reducing step is needed. In this work, polynomial smoothing was used. As a test case, dynamic MFA is applied on Escherichia coli cultivations shifting from carbon limitation to nitrogen limitation and vice versa. After switching the limiting substrate from N to C, a lag phase was observed accompanied with an increase in maintenance energy requirement. This lag phase did not occur in the C- to N-limitation case. PMID- 20827436 TI - 48XXYY Syndrome in an Adult with Type 2 Diabetes Mellitus, Unilateral Renal Aplasia, and Pigmentary Retinitis. AB - A 45-year-old male was referred for diabetes mellitus. Clinical examination found a family history of multiple precocious deaths, strong consanguinity, personal history of seizures during childhood, small testicles, small penis, sparse body hair, long arms and legs, dysmorphic features, mental retardation, dysarthria, tremor, and mild gait ataxia. Investigations found pigmentary retinitis, metabolic syndrome, unilateral renal aplasia, and hypergonadotropic hypogonadism, and ruled out mitochondrial cytopathy and leucodystrophy. Karyotype study showed a 48XXYY chromosomal type. Renal aplasia and pigmentary retinitis have not been described in 48XXYY patients. They may be related to the chromosomal sex aneuploidy, or caused by other genetic aberrations in light of the high consanguinity rate in the patient's family. PMID- 20827437 TI - Rapid Solid-State Photopolymerization of Cyclic Acetal-Containing Acrylates. AB - A cyclic acetal-functionalized urethane acrylate monomer is synthesized here and polymerized in a crystalline state without the polymerization kinetics being deleteriously affected by the solid state. Depending on the processing conditions, the cyclic acetal urethane acrylate monomer exists in either a metastable liquid state or a crystalline state at ambient conditions. Due to mobility restrictions, extremely poor polymerization kinetics and functional group conversions are typically achieved in solid state polymerizations. However, the solid-state photopolymerization of a cyclic acetal urethane acrylate results in nearly identical polymerization rates and ultimately higher conversion in the crystalline state than in the liquid state under otherwise identical conditions. We conclude that the crystallization process occurs in such a manner as to template the acrylic double bonds in a structure that facilitates rapid, minimally activated propagation. PMID- 20827438 TI - Axenfeld-Rieger Syndrome Associated with Congenital Glaucoma and Cytochrome P4501B1 Gene Mutations. AB - Developmental anomalies of the ocular anterior chamber angle may lead to an incomplete development of the structures that form the conventional aqueous outflow pathway. Thus, disorders that present with such dysfunction tend to be associated with glaucoma. Among them, Axenfeld-Rieger (ARS) malformation is a rare clinical entity with an estimated prevalence of one in every 200,000 individuals. The changes in eye morphogenesis in ARS are highly penetrant and are associated with 50% risk of development of glaucoma. Mutations in the cytochrome P4501B1 (CYP1B1) gene have been reported to be associated with primary congenital glaucoma and other forms of glaucoma and mutations in pituitary homeobox 2 (PITX2) gene have been identified in ARS in various studies. This case was negative for PITX2 mutations and compound heterozygote for CYP1B1 mutations. Clinical manifestations of this patient include bilateral elevated intraocular pressure (>40 mmHg) with increased corneal diameter (>14 mm) and corneal opacity. Patient also had iridocorneal adhesions, anteriorly displaced Schwalbe line, anterior insertion of iris, broad nasal bridge and protruding umbilicus. This is the first study from north India reporting CYP1B1 mutations in Axenfeld-Rieger syndrome with bilateral buphthalmos and early onset glaucoma. Result of this study supports the role of CYP1B1 as a causative gene in ASD disorders and its role in oculogenesis. PMID- 20827439 TI - Latent Class Analysis Variable Selection. AB - We propose a method for selecting variables in latent class analysis, which is the most common model-based clustering method for discrete data. The method assesses a variable's usefulness for clustering by comparing two models, given the clustering variables already selected. In one model the variable contributes information about cluster allocation beyond that contained in the already selected variables, and in the other model it does not. A headlong search algorithm is used to explore the model space and select clustering variables. In simulated datasets we found that the method selected the correct clustering variables, and also led to improvements in classification performance and in accuracy of the choice of the number of classes. In two real datasets, our method discovered the same group structure with fewer variables. In a dataset from the International HapMap Project consisting of 639 single nucleotide polymorphisms (SNPs) from 210 members of different groups, our method discovered the same group structure with a much smaller number of SNPs. PMID- 20827440 TI - Acquired Long QT Syndrome and Torsade de Pointes Associated with HIV Infection. AB - Here, we report the case of an HIV infected patient that was treated for pneumonia with a macrolid antibiotic. The patient experienced a prolongation of the already pathologic QTc interval resulting in repeated torsades de pointes necessitating CPR and implantation of an AICD. This case exemplifies that torsades de pointes due to acquired long QT syndrome is a serious and potentially fatal complication in HIV-positive patients. PMID- 20827441 TI - Synthesis of Conjugated Polymers Containing cis-Phenylenevinylenes by Titanium Mediated Reductions. AB - The utility of Sato's titanium-mediated reduction of alkynes towards the synthesis of all cis-poly(phenylenevinylene)s (PPVs) is demonstrated by the syn selective reduction of a variety of model diynes as well as a tetrayne. This technique was then applied to the reduction of a poly(phenyleneethynylene) (PPE) to provide the corresponding all-cis PPV polymer. PMID- 20827442 TI - Neural systems integration. AB - A need is identified to build models of the central nervous system that are semi complete, applied within multiple contexts to multiple tasks, using methodologies that span multiple levels of abstraction. The issues and constraints in building such models are discussed with respect to completeness, validation, cost, scalability and robustness. An approach currently being explored is described that is suited to the creation of large heterogenous models by small independently collaborating research groups. It is based on a network model interface, a software wrapper that abstracts the interaction between a generic component and a generic framework. PMID- 20827443 TI - Syndrome of inappropriate secretion of antidiuretic hormone cholestasis and pericardial effusion due to brucellosis infection: a case report. AB - Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is an extremely rare complication of infectious diseases. A rare case of brucellosis complicated by syndrome of inappropriate secretion of antidiuretic hormone (SIADH) cholestasis and pericardial involvement is reported. A 27-year-old woman was admitted for fever, abdominal pain, and scleral icterus. Her medical history revealed no recent use of diuretic agents. In addition to cholestasis and elevated liver enzymes, euvolemic hyponatremia, hypouricemia, low plasma osmolality, and high urinary osmolality were also detected. Surrenal and thyroid tests were also within normal range. Echocardiography revealed minimal pericardial effusion with normal cardiac functions. The final diagnosis was SIADH due to Brucellosis. Hyponatremia, cholestasis, and pericardial disease were resolved with effective antibrucellar treatment with streptomycine and doxycycline. After completing treatment of brucellosis, there was not any more evidence of cholestasis and pericardial fluid. PMID- 20827444 TI - TRANSLATING BIOLOGY: TEXT MINING TOOLS THAT WORK. PMID- 20827445 TI - Expression of the PAX8/PPARgamma Fusion Protein Is Associated with Decreased Neovascularization In Vivo: Impact on Tumorigenesis and Disease Prognosis. AB - The PAX8/PPARgamma fusion protein (PPFP) occurs in 36% of human follicular thyroid carcinoma (FTC) and is associated with favorable prognosis. To elucidate the function of PPFP in FTC, we analyzed the consequences of PPFP expression in immortalized thyrocytes in vitro and in vivo via xenograft tumorigenesis. While PPFP-expressing cells exhibited oncogenic hallmarks, including increased growth and decreased apoptosis, in vitro, xenograft tumors were initiated but not sustained in vivo. PPFP xenograft tumors exhibited reduced CD31 staining and VEGF expression, suggesting that PPFP modulates neovascularization. Microarray analysis demonstrated increased expression of tissue inhibitor of metalloproteinase (TIMP-3), an inhibitor of angiogenesis, in PPFP cells and tumors, a finding confirmed by quantitative PCR and immunohistochemistry. Immunohistochemical staining of archival human thyroid tumors demonstrates a significant decrease in CD31 staining in all adenomas and carcinomas containing the PAX8/PPARgamma rearrangement. Decreased angiogenesis in PPFP-containing tumors is directly correlated with our observations in the xenograft model and provides evidence for the first time that PPFP may impact FTC tumorigenesis by modulating angiogenesis in vivo. PMID- 20827446 TI - Combined methotrexate and coenzyme Q10 therapy in adjuvant-induced arthritis evaluated using parameters of inflammation and oxidative stress. AB - Rheumatoid arthritis is a common severe joint disease that affects all age groups, it is thus of great importance to develop new strategies for its treatment. The aim of the present study was to examine the combined effect of coenzyme Q10 (CoQ10) and methotrexate (MTX) on the progression of adjuvant induced arthritis in rats. Adjuvant arthritis (AA) was induced by a single intradermal injection of heat-inactivated Mycobacterium butyricum in incomplete Freund's adjuvant. The experiments included healthy animals, arthritic animals not treated, arthritic animals treated with CoQ10, with methotrexate, and with a combination of CoQ10 and methotrexate. The two latter groups received a daily oral dose of 20 mg/kg b.w. of CoQ10, either alone or with methotrexate in an oral dose of 0.3 mg/kg b.w. twice a week. We found that CoQ10 potentiated both the antiarthritic (decrease of hind paw volume) and the antioxidant effect of methotrexate on the level of oxidation of proteins (suppression of protein carbonyl level in plasma) as well as lipoperoxidation (suppression of levels of HNE-adducts and MDA-adducts to plasma proteins). The same effect was observed for plasmatic levels of CoQ9 and IL-1alpha, and partially also for gamma glutamyltransferase activity assessed in joints and spleen. Moreover, the combination therapy improved the functionality of peripheral blood neutrophils in AA, with a balancing effect on the immunosuppression caused by MTX monotherapy. In summary, combined administration of CoQ10 and methotrexate suppressed arthritic progression in rats more effectively than did MTX alone. This finding may help improve treatment of rheumatoid arthritis. PMID- 20827447 TI - Cytokines of the Th1 and Th2 type in sera of rheumatoid arthritis patients; correlations with anti-Hsp40 immune response and diagnostic markers. AB - Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease which affects approximately 1% of the population worldwide. Recent research on the role of heat shock proteins (Hsps) in RA development indicates that they may have pro- or anti-inflammatory effect, most probably via modulating cytokine secretion. We investigated type Th1 (INFgamma, TNFalpha, IL-2) and type Th2 (IL-10, IL-6, IL-4) cytokine levels in sera of RA patients and healthy controls, using flow cytometric bead array assay, and searched for correlations between the cytokine levels and serum antibodies against bacterial (DnaJ) and human (Hdj1, Hdj2 and Hdj3) Hsp40 proteins, as well as clinical and laboratory parameters. The levels of all cytokines studied were significantly increased in RA patients; the highest increase relative to healthy controls (7-fold) was observed for IL-6 and its levels correlated positively with the antibodies directed to DnaJ and to the C terminal domain of Hdj2, and with diagnostic parameters (DAS 28, Steinbrocker RTG criteria, ARA/7, ESR, TEN, SW and GH). INFgamma levels correlated negatively with DAS 28, ESR, TEN and SW. No correlations were found for TNFalpha, IL-2 or IL-4. Our results support the hypothesis of Hsp40 involvement in RA as well as indicate that IL-6 serum level is a good marker of the RA activity. PMID- 20827448 TI - Pain and mobility improvement and MDA plasma levels in degenerative osteoarthritis, low back pain, and rheumatoid arthritis after infrared A irradiation. AB - Infrared (IR)-A irradiation can be useful in back and musculoskeletal pain therapy. In this study joint and vertebral column pain and mobility were measured during two weeks of IR-A irradiation treatment of patients suffering from degenerative osteoarthritis of hip and knee, low back pain, or rheumatoid arthritis. Additionally, before and after IR-A treatment MDA serum levels were measured to check if MDA variations accompany changes in pain intensity and mobility. Two-hundred and seven patients were divided into verum groups getting IR-irradiation, placebo groups getting visible, but not IR irradiation, and groups getting no irradiation. In osteoarthritis significant pain reduction according to Visual Analogue Scale and mobility improvements occurred in the verum group. Even though beneficial mean value changes occurred in the placebo group, the improvements in the placebo and No Irradiation groups were without statistical significance. In low back pain, pain and mobility improvements (by 35 40%) in the verum group were found, too. A delayed (2nd week) mobility improvement in rheumatoid arthritis was seen. However, pain relief was seen immediately. In patients suffering from low back pain or rheumatoid arthritis, the pain and mobility improvements were accompanied by significant changes of MDA serum levels. However, MDA appears not a sensitive biofactor for changes of the pain intensity in degenerative osteoarthritis. Nevertheless, unaffected or lowered MDA levels during intensive IR-A therapy argue against previous reports on free radical formation upon infrared. In conclusion, rapid beneficial effects of IR-A towards musculoskeletal pain and joint mobility loss were demonstrated. PMID- 20827449 TI - Critical behavior of repulsively interacting particles adsorbed on disordered triangular lattices. AB - A simple model for amorphous solids, consisting of a triangular lattice with a fraction of attenuated bonds randomly distributed (which simulate the presence of defects in the surface), is used here to find out, by using grand canonical Monte Carlo simulations, how the adsorption thermodynamics of repulsively interacting monomers is modified with respect to the same process in the regular lattice. The degree of disorder of the surface is tunable by selecting the values of (1) the fraction of attenuated bonds rho (0 <=rho<= 1) and (2) the attenuation factor r (0 <=r<= 1), where r is defined as the ratio between the value of the lateral interaction associated to an attenuated bond and that corresponding to a regular bond. Adsorption isotherm and differential heat of adsorption calculations have been carried out showing and interpreting the effects of the disorder. A rich variety of behavior has been observed for different values of rho and r, varying between two limit cases: bond-diluted lattices (r = 0 and rho? 0) and regular lattices (r = 1 and any value of rho). In addition, the critical behavior of the system was studied, showing that the order-disorder phase transition observed for the regular lattice survives, though with modifications, above a critical curve (rho-r-temperature). PMID- 20827450 TI - [Death due to (no) airway. Adverse events by out-of-hospital airway management?]. AB - Securing the airway is a rarely performed procedure in the out-of-hospital setting. In recent years evidence has been accumulated indicating that out-of hospital airway management is more challenging as compared to elective situations even for experienced health care providers. Furthermore, several authors have questioned the benefit of out-of-hospital tracheal intubation. This review argues the problems regarding out-of-hospital airway management studies and discusses potential solutions which may improve out-of-hospital health care. PMID- 20827452 TI - [Elective use of extracorporeal lung assist: prevention of an airway disaster]. AB - The use of extracorporeal membrane oxygenation (ECMO) was established in Germany 25 years ago in specialized centers as an approach for patients suffering from severe life-threatening lung failure. Apart from such indications the inclusion of ECMO as a planned intervention for safety purposes in the postoperative weaning from mechanical ventilation in a 22-year-old woman is described. Following a complex tracheal reconstruction due to oesophageal-tracheal fistula formation, conventional weaning procedures would have been accompanied by a very high risk as extubation failure might have caused an airway disaster. After elective use of veno-venous ECMO the young patient was extubated without risk and lung function was stabilized safely. Extracorporeal lung assist can be indicated apart from rescue management in elective situations for prevention of an airway catastrophe after careful calculation of the harm/benefit ratio. PMID- 20827451 TI - [Paracetamol for perioperative analgesia. Old substance - new insights]. AB - Since paracetamol was first synthesized in 1878 it has become one of the most popular and widely used drugs for the first-line treatment of fever and pain. The reasons for this popularity are a wide variety of formulations, an assumed positive safety record and the wide availability as an over-the-counter drug. However, recently several studies questioned the positive risk-benefit ratio of paracetamol for postoperative pain by observing several possible adverse effects and limitations. The aim of the present review is to give an update of the recent literature on the efficacy of paracetamol for postoperative pain and on the value of the clinical relevance of different adverse effects of paracetamol. Finally, based on the current findings the authors try to assess the role of paracetamol for the treatment of postoperative pain. PMID- 20827453 TI - [Anaesthesia in patients with maple syrup urine disease. Case report and perioperative anaesthetic management]. AB - Maple syrup urine disease is a rare autosomal-recessive metabolic disorder caused by a deficit of oxidative decarboxylation of branched-chain amino acids. First symptoms appear in the neonatal period. Without treatment the disease is characterized by rapid progression of neurological symptoms. During stressful situations, such as infection or surgery, patients may experience severe ketoacidosis, rapid neurological deterioration and hypoglycemia. The perioperative management of a 26-year-old man with maple syrup urine disease is described, a review of the disease is given and anaesthesia-related implications are discussed. PMID- 20827454 TI - [Hepatocellular carcinoma and cholangiocarcinoma]. AB - Hepatocellular carcinoma and cholangiocarcinoma are relatively rare tumors of the gastrointestinal tract in western Europe but their incidence has been increased in recent years. Newly diagnosed intrahepatic lesions or intrahepatic cholestasis require extensive laboratory tests and imaging studies in order to confirm the diagnosis of hepatocellular carcinoma, intrahepatic or extrahepatic cholangiocarcinoma. The treatment options range from liver resection or liver transplantation to conservative measures (in cases of non-resectable lesions). This review article aims to provide an overview on the diagnostic options and the subsequent treatment. PMID- 20827455 TI - [Clinical presentation and etiology of ichthyoses. Overview of the new nomenclature and classification]. AB - Ichthyoses comprise a heterogeneous group of Mendelian disorders of cornification (MEDOC) affecting the entire skin and characterized by hyperkeratosis and/or scaling. The genetic basis of almost all ichthyosis forms has been elucidated. In 2009, the worldwide first Ichthyosis Consensus Classification was approved. Its nosology is based on the clinical presentation and reflects recent pathogenic aspects. It distinguishes basically between non-syndromic and syndromic ichthyoses. The term ARCI/autosomal recessive congenital ichthyosis represents the umbrella for harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. Ichthyoses due to keratin mutations are referred to as KPI/keratinopathic ichthyosis and include epidermolytic ichthyosis (EI) and superficial epidermolytic ichthyosis (SEI). In Germany the Network for Ichthyoses and Related Keratinization Disorders (NIRK) and the patient organization Selbsthilfe Ichthyose e.V. provide contact points for diagnostic and therapeutic questions. PMID- 20827456 TI - The Rad50 genes of diploid and polyploid wheat species. Analysis of homologue and homoeologue expression and interactions with Mre11. AB - The MRN complex plays a central role in the DNA repair pathways of eukaryotic cells and takes part in many other processes, including cell cycle checkpoint signalling, meiosis, DNA replication and telomere maintenance. This complex is formed by the interaction of the products of the Mre11, Rad50 and Nbs1 genes. This paper reports the molecular characterization, expression and interactions of the Rad50 gene in several wheat species with different levels of ploidy. The homoeologous Rad50 wheat genes were found to show a high level of conservation. Most of the RAD50 domains and motifs previously described in other species were also present in wheat RAD50; these proteins are therefore likely to have similar functions. Interactions between the RAD50 wheat proteins and their MRE11 counterparts in the MRN complex were observed. The level of expression of Rad50 in each of the species examined was determined and compared with those previously reported for the Mre11 genes. In some cases similar levels of expression were seen, as expected. The expression of the RAD50 homoeologous genes was assessed in two polyploid wheat species using quantitative PCR. In both cases, an overexpression of the Rad50B gene was detected. Although the results indicate the maintenance of function of these species' three homoeologous Rad50 genes, the biased expression of Rad50B might indicate ongoing silencing of one or both other homoeologues in polyploid wheat. To assess the consequences of such silencing on the formation of the MRN complex, the interactions between individual homoeologues of Rad50 and their genomic counterpart Mre11 genes were examined. The results indicate the inexistence of genomic specificity in the interactions between these genes. This would guarantee the formation of an MRN complex in wheat. PMID- 20827457 TI - Development of DNA markers associated with beer foam stability for barley breeding. AB - Traits conferring brewing quality are important objectives in malting barley breeding. Beer foam stability is one of the more difficult traits to evaluate due to the requirement for a relatively large amount of grain to be malted and then the experimental costs for subsequent brewing trials. Consequently, foam stability tends to be evaluated with only advanced lines in the final stages of the breeding process. To simplify the evaluation and selection for this trait, efficient DNA makers were developed in this study. Previous studies have suggested that the level of both of the foam-associated proteins Z4 and Z7 were possible factors that influenced beer foam stability. To confirm the relationship between levels of these proteins in beer and foam stability, 24 beer samples prepared from malt made from 10 barley cultivars, were examined. Regression analyses suggested that beer proteins Z4 and Z7 could be positive and negative markers for beer foam stability, respectively. To develop DNA markers associated with contents of proteins Z4 and Z7 in barley grain, nucleotide sequence polymorphisms in barley cultivars in the upstream region of the translation initiation codon, where the promoter region might be located were compared. As a result, 5 and 23 nucleotide sequence polymorphisms were detected in protein Z4 and protein Z7, respectively. By using these polymorphisms, cleaved amplified polymorphic sequence (CAPS) markers were developed. The CAPS markers for proteins Z4 and Z7 were applied to classify the barley grain content of 23 barley cultivars into two protein Z4 (pZ4-H and pZ4-L) and three protein Z7 (the pZ7-H, pZ7-L and pZ7-L2) haplotypes, respectively. Barley cultivars with pZ4-H showed significantly higher levels of protein Z4 in grain, and those with pZ7-L and pZ7 L2 showed significantly lower levels of protein Z7 in grain. Beer foam stability in the cultivars with pZ4-H and pZ7-L was significantly higher than that with pZ4 L and pZ7-H, respectively. Our results indicate that these CAPS markers provide an efficient selection tool for beer foam stability in barley breeding programs. PMID- 20827458 TI - Mapping of epistatic quantitative trait loci in four-way crosses. AB - Four-way crosses (4WC) involving four different inbred lines often appear in plant and animal commercial breeding programs. Direct mapping of quantitative trait loci (QTL) in these commercial populations is both economical and practical. However, the existing statistical methods for mapping QTL in a 4WC population are built on the single-QTL genetic model. This simple genetic model fails to take into account QTL interactions, which play an important role in the genetic architecture of complex traits. In this paper, therefore, we attempted to develop a statistical method to detect epistatic QTL in 4WC population. Conditional probabilities of QTL genotypes, computed by the multi-point single locus method, were used to sample the genotypes of all putative QTL in the entire genome. The sampled genotypes were used to construct the design matrix for QTL effects. All QTL effects, including main and epistatic effects, were simultaneously estimated by the penalized maximum likelihood method. The proposed method was confirmed by a series of Monte Carlo simulation studies and real data analysis of cotton. The new method will provide novel tools for the genetic dissection of complex traits, construction of QTL networks, and analysis of heterosis. PMID- 20827459 TI - Affective, anxiety, and substance-related disorders in patients undergoing herniated disc surgery. AB - PURPOSE: At present only a small number of studies have investigated psychiatric comorbidity in disc surgery patients. Objectives of this study are (1) to examine the prevalence rate of comorbid affective, anxiety, and substance-related disorders in nucleotomy patients in comparison to the German general population and (2) to investigate associations between psychiatric comorbidity and socio demographic and illness-related characteristics. METHODS: The study refers to 349 consecutive disc surgery patients (response rate 87%) between the age of 18 and 55 years. The final study sample consists of 239 lumbar and 66 cervical nucleotomy patients. Face-to-face interviews were conducted approximately 3.45 days (SD 3.170) after disc surgery, during hospital stay. Psychiatric comorbidity was assessed by means of the Composite International Diagnostic Interview (CIDI DIA-X). The corresponding data of the German general population were derived from the German National Health Interview and Examination Survey (GHS). RESULTS: 12 Month prevalence rates of any affective, anxiety or substance-related disorders range between 33.7% in cervical and 23.5% in lumbar disc surgery patients. Four week prevalence rates of any affective, anxiety or substance disorder vary between 13.2% in cervical and 14.0% in lumbar nucleotomy patients. Disc surgery patients suffer more often from affective disorders and illicit substance abuse than the general population. Significant associations were found between psychiatric comorbidity and gender, as well as pain intensity. CONCLUSIONS: Disc surgery patients show a higher risk to suffer from mental disorders than the general population. The assessment of psychiatric distress and the assistance by mental health professionals should be considered during hospital and rehabilitation treatment. PMID- 20827460 TI - Post-operative opiate requirements after hip arthroscopy. AB - PURPOSE: Although hip arthroscopy continues to evolve in its use and its popularity grows, little attention has been paid to the anaesthetic and analgesic management of patients undergoing this procedure. We aimed to report on our initial experience of the anaesthetic and analgesic requirements of a consecutive series of patients undergoing hip arthroscopy. METHODS: We reviewed the surgical and anaesthetic records of the initial, consecutive 85 patients undergoing hip arthroscopy for any reason at our hospital. Basic demographics, intra-operative findings, operative procedures, analgesic requirements in the form of opiate requirement and post-operative pain scores were reviewed. RESULTS: The mean intra operative morphine dose was 7.1 mg (S.D. 3.2 mg). Thirty-nine patients (46%) required I.V. morphine at in the recovery room post-arthroscopy (mean 1.8 mg; S.D. 2.6 mg). Regression analysis showed that lower intra-operative opiate dose resulted in higher maximum VAS pain scores (P = 0.03) and rescue intravenous opiate (P < 0.001) requirement post-surgery. CONCLUSIONS: Adequate intra operative morphine use can minimize post-operative pain and subsequent need for rescue analgesia. PMID- 20827461 TI - Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine. AB - RATIONALE: Drug-associated cues and stress increase craving and lead to greater risk of relapse in abstinent drug users. Animal models of reinstatement of drug seeking have been utilized to study the neural circuitry by which either drug associated cues or stress exposure elicit drug seeking. Recent evidence has shown a strong enhancing effect of yohimbine stress on subsequent cue-elicited reinstatement; however, there has been no examination of the neural substrates of this interactive effect. OBJECTIVES: The current study examined whether inactivation of the bed nucleus of the stria terminalis (BNST), an area previously implicated in stress activation of drug seeking, would affect reinstatement of cocaine seeking caused by conditioned cues, yohimbine stress, or the combination of these factors. METHODS: Male rats experienced daily IV cocaine self-administration, followed by extinction of lever responding in the absence of cocaine-paired cues. Reinstatement of responding was measured during presentation of cocaine-paired cues, following pretreatment with the pharmacological stressor, yohimbine (2.5 mg/kg, IP), or the combination of cues and yohimbine. RESULTS: All three conditions led to reinstatement of cocaine seeking, with the highest responding seen after the combination of cues and yohimbine. Reversible inactivation of the BNST using the gamma-aminobutyric acid receptor agonists, baclofen + muscimol, significantly reduced all three forms of reinstatement. CONCLUSION: These results demonstrate a role for the BNST in cocaine seeking elicited by cocaine-paired cues, and suggest the BNST as a key mediator for the interaction of stress and cues for the reinstatement of cocaine seeking. PMID- 20827462 TI - Intrahippocampal LSD accelerates learning and desensitizes the 5-HT(2A) receptor in the rabbit, Romano et al. AB - RATIONALE: Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT(2A) receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (+/-)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT(2A)-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning. OBJECTIVE: This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy dimethyltryptamine elicit the 5-HT(2A)-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning. MATERIALS AND METHODS: LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT(2A) receptor as measured by a decrease in DOI-elicited head bobs. RESULTS: Acute parenteral or intrahippocampal LSD elicited a 5-HT(2A) but not a 5-HT(2C)-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls. CONCLUSIONS: LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD). PMID- 20827463 TI - Clozapine and other competitive antagonists reactivate risperidone-inactivated h5 HT7 receptors: radioligand binding and functional evidence for GPCR homodimer protomer interactions. AB - RATIONALE: The h5-HT(7) receptor is subject to inactivation by risperidone and 9 OH-risperidone, apparently through a pseudo-irreversible complex formed between these drugs and the receptor. Although risperidone and 9-OH-risperidone ("inactivating antagonists") completely inactivate the receptor, only 50% of the receptors form a pseudo-irreversible complex with these drugs. OBJECTIVES: This study aims to more fully determine the mechanism(s) responsible for the novel effects of risperidone and 9-OH-risperidone and to determine if the inactivation can be reversed (reactivation). METHODS: The ability of non-inactivating drugs (competitive antagonists) to dissociate wash-resistant [(3)H]risperidone binding from h5-HT(7) receptors was investigated. Also, the ability of non-inactivating drugs to reactivate inactivated h5-HT(7) receptors was investigated, using cAMP accumulation as a functional endpoint. RESULTS: The competitive (non inactivating) antagonists clozapine and mesulergine released the wash-resistant [(3)H]risperidone binding to the h5-HT(7) receptor. The competitive antagonists clozapine, SB269970, mianserin, cyproheptadine, mesulergine, and ICI169369 reactivated the risperidone-inactivated h5-HT(7) receptors in a concentration dependent manner. The potencies for reactivation closely match the affinities of these drugs for the h5-HT(7) receptor (r(2) = 0.95), indicating that the reactivating antagonists are binding to and producing their effects through the orthosteric binding site of the h5-HT(7) receptor. Bioluminescence resonance energy transfer analyses indicate that the h5-HT(7) receptor forms homodimers. CONCLUSIONS: The ability of the non-inactivating drugs to bind h5-HT(7) orthosteric sites and reverse the wash-resistant effects of risperidone or 9-OH risperidone, also bound to h5-HT(7) orthosteric sites, is evidence for protomer protomer interactions between h5-HT(7) homodimers. This is the first demonstration of a non-mutated G-protein-coupled receptor homodimer engaging in protomer-protomer interactions in an intact cell preparation. PMID- 20827465 TI - Ratiometric fluorescence-based dissolved carbon dioxide sensor for use in environmental monitoring applications. AB - The focus of this work is on the development and characterisation of a fluorescence-based ratiometric sol-gel-derived dissolved carbon dioxide (dCO(2)) sensor for use in environmental monitoring applications. Fluorescence-based dCO(2) sensors are attractive as they facilitate the development of portable and low-cost systems that can be easily deployed outside the laboratory environment. The sensor developed for this work exploits a pH fluorescent dye 1-hydroxypyrene 3,6,8-trisulfonic acid, ion-paired with cetyltrimethylammonium bromide (HPTS-IP), which has been entrapped in a hybrid sol-gel-based matrix derived from n propyltriethoxysilane along with the liphophilic organic base. The sensor spot deposited on a cover slip has been interrogated with a robust, ratiometric optical probe that combines effective fluorescence excitation and detection and thus facilitates the production of a highly sensitive sensor system using low cost optoelectronic components. The probe design involves the use of dual-LED excitation in order to facilitate ratiometric operation and uses a silicon PIN photodiode. HPTS-IP exhibits two pH-dependent changes in excitation bands, which allows for dual excitation ratiometric detection as an indirect measure of the dCO(2). Such measurements are insensitive to changes in dye concentration, leaching and photobleaching of the fluorophore and instrument fluctuations unlike unreferenced fluorescence intensity measurements. The performance of the sensor system is characterised by a high degree of repeatability, reversibility and stability. Calculated limit of detection for the sensor was 35 ppb. The sensor probe was used to monitor dCO(2) levels in a laboratory-based aquatic habitat, and the expected diurnal pattern was clearly visible. The influence of temperature, biofouling and photobleaching on sensor performance has been also investigated. PMID- 20827464 TI - Heparin-immobilized microspheres for the capture of cytokines. AB - The preparation and characterization of heparin-immobilized microspheres which were used to bind acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), monocyte chemoattractant protein 1 (MCP-1/CCL2), and regulation upon activation normal T cell express sequence (RANTES/CCL5) is described. These beads were used as trapping agents in microdialysis sampling experiments in a separate study. Both free heparin and a synthesized heparin albumin conjugate were immobilized onto microspheres and compared for their effectiveness. The heparin-albumin conjugate microspheres exhibited significant nonspecific adsorption which appeared to be due to the albumin content. The prepared heparin-immobilized microspheres were stable for 3 months at 4 degrees C. A bead-based flow cytometric assay was developed to study the binding capacity and specificity of the heparin-immobilized microspheres to cytokines. These heparin-immobilized microspheres exhibited broad dynamic ranges for binding to the four cytokines (aFGF, 1.0-1,000 ng/mL; VEGF, 0.5-1,000 ng/mL; CCL2, 1.95 1,000 ng/mL; CCL5, 1.95-500 ng/mL). Fast binding kinetics of the cytokines to the heparin-immobilized beads suggests that these beads may be useful as affinity agents in microfluidic flow systems. PMID- 20827466 TI - The preparation of certified calibration solutions for azaspiracid-1, -2, and -3, potent marine biotoxins found in shellfish. AB - The production and certification of a series of azaspiracid (AZA) calibration solution reference materials is described. Azaspiracids were isolated from contaminated mussels, purified by preparative liquid chromatography and dried under vacuum to the anhydrous form. The purity was assessed by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. The final concentration of each AZA in a CD(3)OH stock solution was determined by quantitative NMR spectroscopy. This solution was then diluted very accurately in degassed, high purity methanol to a concentration of 1.47 +/- 0.08 MUmol/L for CRM-AZA1, 1.52 +/- 0.05 MUmol/L for CRM-AZA2, and 1.37 +/- 0.13 MUmol/L for CRM AZA3. Aliquots were dispensed into argon-filled glass ampoules, which were immediately flame-sealed. The calibration solutions are suitable for method development, method validation, calibration of liquid chromatography or mass spectrometry instrumentation and quality control of shellfish monitoring programs. PMID- 20827467 TI - An efficient approach for the isolation, identification and evaluation of antimicrobial plant components on an analytical scale, demonstrated by the example of Radix imperatoriae. AB - Using Radix imperatoriae (the root of masterwort) as an example, we describe an efficient approach for the isolation, identification and evaluation of bioactive plant components on an analytical scale. The extraction of Radix imperatoriae with ethyl acetate was enhanced by the application of ultrasound oscillations. This rhizome extract was applied to three pathogenic bacteria (Bacillus cereus, Escherichia coli, and Staphylococcus aureus) to determine its antimicrobial activity. Disk diffusion was utilized to determine susceptibility. The extract components were separated using a series of chromatography approaches (semi preparative RP-HPLC, or RP-HPLC on an analytical scale), followed by testing. All fractions were analyzed by LC-UV-ESI-MS and 600 MHz microcoil (1)H NMR spectroscopy. Among other findings, in the fraction with the highest antibacterial activity we were able to identify oxypeucedanin and oxypeucedanin hydrate. Subsequent analysis revealed that only oxypeucedanin hydrate had antibacterial activity, whereas oxypeucedanin itself was inactive at the concentrations applied. Furthermore, oxypeucedanin hydrate appears to be largely, or exclusively, a by-product of sample preparation, since it is either not synthesized by the plant as a second metabolite or is produced by it in only very small quantities. PMID- 20827468 TI - Comparison of separation performance of laser-ablated and wet-etched microfluidic devices. AB - Laser ablation of glass allows for production of microfluidic devices without the need for hydrofluoric acid and photolithography. The goal of this study was to compare the separation performance of microfluidic devices produced using a low cost laser ablation system and conventional wet etching. During laser ablation, cracking of the glass substrate was prevented by heating the glass to 300 degrees C. A range of laser energy densities was found to produce channel depths ranging from 4 to 35 MUm and channel widths from 118 to 162 MUm. The electroosmotic flow velocity was lower in laser-ablated devices, 0.110+/-0.005 cm s(-1), as compared to wet-etched microfluidic chips, 0.126+/-0.003 cm s(-1). Separations of both small and large molecules performed on both wet- and laser ablated devices were compared by examining limits of detection, theoretical plate count, and peak asymmetry. Laser-induced fluorescence detection limits were 10 pM fluorescein for both types of devices. Laser-ablated and wet-etched microfluidic chips had reproducible migration times with <= 2.8% relative standard deviation and peak asymmetries ranged from 1.0 to 1.8. Numbers of theoretical plates were between 2.8- and 6.2-fold higher on the wet-etched devices compared to laser ablated devices. Nevertheless, resolution between small and large analytes was accomplished, which indicates that laser ablation may find an application in pedagogical studies of electrophoresis or microfluidic devices, or in settings where hydrofluoric acid cannot be used. PMID- 20827469 TI - Solution to the whipped egg white challenge. PMID- 20827470 TI - Profiling of hydroxycinnamic acid amides in Arabidopsis thaliana pollen by tandem mass spectrometry. AB - Phenylpropanoid polyamine conjugates are widespread in plant species. Their presence has been established in seeds, flower buds, and pollen grains. A biosynthetic pathway proposed for hydroxycinnamoyl spermidine conjugates has been suggested for the model plant Arabidopsis thaliana with a central acyl transfer reaction performed by a BAHD-like hydroxycinnamoyl transferase. A detailed liquid chromatography (LC)-electrospray ionization-mass spectrometry- and tandem-mass spectrometry (MS/MS)-based survey of wild-type and spermidine hydroxycinnamoyl transferase (SHT) mutants identified more than 30 different bis- and tris substituted spermidine conjugates, five of which were glycosylated, in the methanol-soluble fraction of the pollen exine. On the basis of characterized fragmentation patterns, a high-throughput LC-MS/MS method for highly sensitive HCAA relative quantification (targeted profiling) was developed. Only minor qualitative and quantitative differences in the pattern of bis-acyl spermidine conjugates in the SHT mutant compared to wild-type plants provide strong evidence for the presence of multiple BAHD-like acyl transferases and suggest a much more complex array of enzymatic steps in the biosynthesis of these conjugates than previously anticipated. PMID- 20827471 TI - Diagnostic errors in pediatric radiology. AB - BACKGROUND: Little information is known about the frequency, types and causes of diagnostic errors in imaging children. OBJECTIVE: Our goals were to describe the patterns and potential etiologies of diagnostic error in our subspecialty. MATERIALS AND METHODS: We reviewed 265 cases with clinically significant diagnostic errors identified during a 10-year period. Errors were defined as a diagnosis that was delayed, wrong or missed; they were classified as perceptual, cognitive, system-related or unavoidable; and they were evaluated by imaging modality and level of training of the physician involved. RESULTS: We identified 484 specific errors in the 265 cases reviewed (mean:1.8 errors/case). Most discrepancies involved staff (45.5%). Two hundred fifty-eight individual cognitive errors were identified in 151 cases (mean = 1.7 errors/case). Of these, 83 cases (55%) had additional perceptual or system-related errors. One hundred sixty-five perceptual errors were identified in 165 cases. Of these, 68 cases (41%) also had cognitive or system-related errors. Fifty-four system-related errors were identified in 46 cases (mean = 1.2 errors/case) of which all were multi-factorial. Seven cases were unavoidable. CONCLUSION: Our study defines a taxonomy of diagnostic errors in a large academic pediatric radiology practice and suggests that most are multi-factorial in etiology. Further study is needed to define effective strategies for improvement. PMID- 20827472 TI - Radiological-pathological correlation of pleomorphic liposarcoma of the anterior mediastinum in a 17-year-old girl. AB - Liposarcoma is a soft-tissue sarcoma typically seen in adults. It is extremely rare in children. It most often occurs in the extremities or in the retroperitoneum. We present a very rare case of an anterior mediastinal liposarcoma of the pleomorphic subtype in a 17-year-old girl, along with radiological and pathological correlation. The location, patient age and histological subtype are exceedingly uncommon for this tumor. PMID- 20827473 TI - The first derivative of a function of circular dichroism spectra: biophysical study of human telomeric G-quadruplex. AB - Depending on conditions and base modifications, telomeric repeats can form many topological structures; parallel, antiparallel and hybrid forms. The influence of salts and some specific ligands on conformational changes has already been established. In this study, we analyze the human telomeric repeats 5' GGG(TTAGGG)(3)-3' because this sequence forms topologically different structures under various conditions which have been well described by many authors. CD results are compared with electrophoretic and UV absorption spectroscopy results obtained under corresponding conditions in the presence of different ratios of sodium and potassium ions and polyethylene glycol (PEG). We confirmed that the most stable G-quadruplexes could only form under crowding conditions with PEG-200 and K(+) ion, but the molecularity is increased. Other monovalent ions without the presence of K(+) are unable to form the parallel quadruplex conformer and no change of stoichiometry is observed, even when PEG-200 is present. The first derivative of a function applied to CD spectra seems to be a powerful tool for spectra evaluation of any G-quadruplex, and could be more unambiguous than a direct analysis of original spectra. PMID- 20827474 TI - Development and validation of a real-time quantitative PCR assay for rapid identification of Bacillus anthracis in environmental samples. AB - A real-time polymerase chain reaction (PCR) assay was developed for rapid identification of Bacillus anthracis in environmental samples. These samples often harbor Bacillus cereus bacteria closely related to B. anthracis, which may hinder its specific identification by resulting in false positive signals. The assay consists of two duplex real-time PCR: the first PCR allows amplification of a sequence specific of the B. cereus group (B. anthracis, B. cereus, Bacillus thuringiensis, Bacillus weihenstephanensis, Bacillus pseudomycoides, and Bacillus mycoides) within the phosphoenolpyruvate/sugar phosphotransferase system I gene and a B. anthracis specific single nucleotide polymorphism within the adenylosuccinate synthetase gene. The second real-time PCR assay targets the lethal factor gene from virulence plasmid pXO1 and the capsule synthesis gene from virulence plasmid pXO2. Specificity of the assay is enhanced by the use of minor groove binding probes and/or locked nucleic acids probes. The assay was validated on 304 bacterial strains including 37 B. anthracis, 67 B. cereus group, 54 strains of non-cereus group Bacillus, and 146 Gram-positive and Gram-negative bacteria strains. The assay was performed on various environmental samples spiked with B. anthracis or B. cereus spores. The assay allowed an accurate identification of B. anthracis in environmental samples. This study provides a rapid and reliable method for improving rapid identification of B. anthracis in field operational conditions. PMID- 20827475 TI - Differential pathologic variables and outcomes across the spectrum of adenocarcinoma of the esophagogastric junction. AB - BACKGROUND: Adenocarcinoma of the esophagogastric junction (AEG) as described by Siewert et al. is classified as one entity in the latest (7th Edition) American Joint Cancer Committee/International Union Against Cancer (AJCC/UICC) manual, compared with the previous mix of esophageal and gastric staging systems. The origin of AEG tumors, esophageal or gastric, and their biology remain controversial, particularly for AEG type II (cardia) tumors. METHODS: We adapted a large prospective database (n = 520: 180 type I, 182 type II, 158 type III) to compare AEG tumors under the new TNM system Pathological variables associated with prognosis were compared (pT, pN, stage, differentiation, R status, lymphovascular invasion, perineural involvement, number of positive nodes, percent of positive nodes, and tumor length), as well as overall survival. RESULTS: Compared with AEG type I tumors, type II and type III tumors had significantly (p < 0.05) more advanced pN stages, greater number and percentage of positive nodes, poorer differentiation, more radial margin involvement, and more perineural invasion. In AEG type I, 14/180 patients (8%) had >6 involved nodes (pN3), compared with 16 and 30% of patients classified type II and III, respectively. Median survival was significantly (p = 0.03) improved for type I patients (38 months) compared with those with tumors classified as type II (28 months) and type III (24 months). In multivariate analysis node positivity and pN staging but not AEG site had an impact on survival. CONCLUSIONS: In this series AEG type I is associated with more favorable pathologic features and improved outcomes compared with AEG type II and III. This may reflect earlier diagnosis, but an alternative possibility, that type I may be a unique paradigm with more favorable biology, requires further study. PMID- 20827476 TI - Epidemiology and pathogenesis of incident pain-related disability in malignant hematology: an Italian survey. PMID- 20827477 TI - Epidural leukemic involvement and intracranial hemorrhage as initial manifestations in a newly diagnosed chronic myeloid leukemia patient. PMID- 20827478 TI - Comparative biology of pheromonal communication in vertebrates. Editorial. PMID- 20827479 TI - Serotonergic cerebral cells control activity of cilia in the foregut of the pteropod mollusk Clione limacina. AB - Bilaterally symmetrical pair of serotonergic cells, named C1 in Clione, has been described in the cerebral ganglia of all gastropod species. Here we describe a new role of C1 cells in gastropod mollusks: control of activity of ciliated epithelium in the foregut. Detailed morphological investigation of C1 neurons in the pteropod mollusk Clione limacina revealed that these cells among other destinations send their neurites into foregut where they produce intense arborization with large varicosities along the processes. Intracellular stimulation of a single C1 induced pronounced activation (often followed by inhibition) of cilia lining the foregut. This activation was substantially reduced by serotonin antagonist mianserin. Bath application of serotonin also induced transient increase in ciliary transport rate, followed by inhibition of ciliary activity up to its full cessation in some areas of isolated foregut. These data suggest that C1 in Clione may use serotonin to influence cilia in the foregut. Taking into account high homology of serotonergic cerebral cells across studied species we can speculate that these cells may be involved in the neural control of cilia in the foregut in other gastropod mollusks. PMID- 20827480 TI - Acoustic-induced motion of the bushcricket (Mecopoda elongata, Tettigoniidae) tympanum. AB - Bushcrickets have a tonotopically organised hearing organ, the so-called crista acustica, in the tibia of the forelegs. This organ responds to a frequency range of about 5-80 kHz and lies behind the anterior tympanum on top of a trachea branch. We analyzed the sound-induced vibration pattern of the anterior tympanum, using a Laser-Doppler-Vibrometer Scanning microscope system, in order to identify frequency-dependent amplitude and phase of displacement. The vibration pattern evoked by a frequency sweep (4-79 kHz) showed an amplitude maximum which would correspond to the resonance frequency of an open tube system. At higher frequencies of about 30 kHz a difference in the amplitude and phase response between the distal and the proximal part of the tympanum was detected. The inner plate of the tympanum starts to wobble at this frequency. This higher mode in the motion pattern is not explained by purely acoustic characteristics of the tracheal space below the tympanum but may depend on the mechanical impedance of the tympanum plate. In accordance with a previous hypothesis, the tympanum moves over the whole tested frequency range in the dorso-ventral direction like a hinged flap with the largest displacement in its ventral part and no higher modes of vibration. PMID- 20827481 TI - A pair of motion-sensitive neurons in the locust encode approaches of a looming object. AB - Neurons in the locust visual system encode approaches of looming stimuli and are implicated in production of escape behaviours. The lobula giant movement detector (LGMD) and its postsynaptic partner, the descending contralateral movement detector (DCMD) compute characteristics of expanding edges across the locust eye during a loom and DCMD synapses onto motor elements associated with behaviour. We identified another descending interneuron within the locust ventral nerve cord. We named this neuron the late DCMD (LDCMD) as it responds later during an approach, with the firing rate peaking at about the time of collision. LDCMD produced lower amplitude, broader action potentials that were associated with an afterhyperpolarization, whereas DCMD action potentials showed a brief afterhyperpolarization often followed by an afterdepolarization. Within the mesothoracic ganglion, the primary LDCMD axon located adjacent to the DCMD axon, was thinner and lacked collateral projections to the lateral region of the neuropil. When compared with DCMD, LDCMD fired with fewer spikes during a loom and showed weaker habituation to repeated approaches. Coincidence of LDCMD and DCMD firing increased during object approach. Our findings indicate the presence of an additional motion-sensitive descending neuron in the locust that encodes temporally distinct properties of an approaching object. PMID- 20827482 TI - Near-infrared camera for intraventricular neuroendoscopic procedures: in vitro comparison of the efficiency of near-infrared camera and visual light camera during bleeding. AB - PURPOSE: Bleeding is the most important problem in neuroendoscopic procedures. The visibility of the bleeding point for a long period of time is very crucial for the surgeon to stop the bleeding. In this study, the performances of a near infrared camera (NIRC) and a visible light camera (VLC), which is widely used today, were compared in terms of the visibility duration of the bleeding point. METHODS: A bleeding point was generated in vitro, and it was monitored with VLC and NIRC (sensitive to 850-nm infrared light), which were connected to two identical telescope systems. This trial was repeated for 40 times using different telescope systems (Clarus neurochannel endoscopy and Storz Hopkins). The images were merged and analyzed digitally. RESULTS: Statistically, sharper brightness difference levels between bleeding point and background are achieved by NIRC than VLC. Analyses revealed that the bleeding point could be observed for a longer time with NIRC, when compared to VLC. CONCLUSION: NIRCs may provide very significant advantages against bleedings encountered during intraventricular operations. PMID- 20827483 TI - Effect of a neonatal low-protein diet on the morphology of myotubes in culture and the expression of key proteins that regulate myogenesis in young and adult rats. AB - AIM: To investigate the effects of a neonatal low-protein diet on the morphology of myotubes in culture and the expression of key proteins that regulate myogenesis in young and adult rats. METHODS: Male Wistar rats (n = 18) were suckled by mothers fed diets containing 17% protein (controls, C) or 8% protein (undernourished, UN). All rats were fed a normal protein diet after weaning. Muscles were removed from the legs of 42-, 60- and 90-day-old rats. Muscle cells were cultured to assess cell number, morphology and the expression of major proteins involved in myogenesis (Pax7, cadherins, beta1 integrin, IL-4Ralpha and myogenin) by western blotting. IL-4 levels in culture supernatants were measured by ELISA. RESULTS: Offspring from mothers fed a low-protein diet showed a lower body weight gain. Cell number and myotube expansion were reduced in cultured muscle cells from UN, but the expression of myogenic marker proteins was unaltered. CONCLUSIONS: Dietary restriction during lactation had no impact on the synthesis of myogenic marker proteins, and myocyte differentiation occurred normally in the muscles of offspring aged 42, 60 or 90 days. Nevertheless, the number and morphology of the myotubes are altered. PMID- 20827484 TI - Replication-compromised cells require the mitotic checkpoint to prevent tetraploidization. AB - Replication stress often induces chromosome instability. In this study, we explore which factors in replication-compromised cells promote abnormal chromosome ploidy. We expressed mutant forms of either polymerase alpha (Polalpha) or polymerase delta (Poldelta) in normal human fibroblasts to compromise DNA replication. Cells expressing the mutant Polalpha-protein failed to sustain mitotic arrest and, when propagated progressively, down-regulated Mad2 and BubR1 and accumulated 4N-DNA from the 2N-DNA cells. Significantly, a population of these cells became tetraploids. The Polalpha mutant expressing cells also exhibited elevated cellular senescence markers, suggesting as a mechanism to limit proliferation of the tetraploids. Expression of the Poldelta mutant also caused cells to accumulate 4N-DNA. In contrast to the Polalpha mutant expressing cells, the Poldelta mutant expressing cells expressed sufficient levels of Mad2, BubR1, and cyclin B1 to sustain mitotic arrest, and these cells had normal chromosome ploidy. Together, these results suggest that replication compromised cells depend on the mitotic checkpoint to prevent mitotic slippage that could result in tetraploidization. PMID- 20827485 TI - The new Powerplex(r) ESX17 and ESI17 kits in paternity and maternity analyses involving people from Africa--including allele frequencies for three African populations. AB - Paternity and maternity investigations in immigration procedures are frequently done in Germany. Since mostly only one parent and one or more children are investigated, the occurrence of possible mutational events has to be interpreted with great care and the analysis of as many STRs as possible is recommended. The new Powerplex(r) ESX17 and Powerplex(r) ESI17 kits from Promega comprising both eleven established STRs and additionally the loci D1S1656, D2S441, D10S1248, D12S391, and D22S1045 (in different order) are potential tools in such paternity or maternity analyses, but only few allele frequency data for the five new loci exist. Here, we provide allele frequencies for the five additional STRs from three different populations from Africa. In addition, we present two maternity cases and one paternity case in which a clear inclusion or exclusion of the alleged parent could only be achieved by the additional application of the new Powerplex(r) ESX17 kit. PMID- 20827486 TI - Macular edema and visual outcome following cataract surgery in patients with diabetic retinopathy and controls. AB - BACKGROUND: Cystoid macular edema (CME) is a well-known complication after cataract surgery, and diabetic retinopathy is reported to be an important risk factor for impaired visual recovery. In this prospective study, we compared visual outcome 6 months after surgery in eyes with moderate retinopathy and no previous ME with a control group, and observed the incidence of ME seen on fluorescein angiography (FA) and optical coherence tomography (OCT). METHODS: Thirty-four patients with type-2 diabetes and 35 controls were enrolled. Best corrected visual acuity (VA) letters ETDRS was measured pre-op, at day 7, week 6 and month 6. FA performed pre-op and at week 6 was divided into three leakage patterns. OCT performed pre-op, at week 6 and month 6 was qualitatively divided into three types. Macular thickness was measured in three circular fields (central subfield, inner and outer circle) from the macular maps. RESULTS: There was no statistically significant difference in VA before surgery, at day 7 or at 6 months, but at 6 weeks there was a significant difference with lower VA in the diabetic group. Six percent of control and 12% of diabetic eyes developed a clinical CME defined as a loss of >5 letters between day 7 and week 6. Incidence of FA leakage was 23% in control and 76% in diabetic eyes. At 6 weeks, 20% of control and 44% of the diabetic eyes had qualitative changes on OCT. A statistically significant increase in thickness was observed for all three macular areas in both groups, part of it remaining at 6 months. There were, however, no differences in central macular thickness between the groups at any visit. Retinal thickening had poor correlation with VA. CONCLUSION: The final visual outcome in eyes with mild to moderate retinopathy, without previous ME, is as good as in normal eyes, but an increased frequency of macular changes may protract recovery of full vision. Changes on OCT or FA are often seen without any obvious effect on VA. OCT is as good as FA at detecting a clinical CME, and is the technique recommended for follow-up before FA is considered. PMID- 20827487 TI - Cysteines in the loop between IS5 and the pore helix of Ca(V)3.1 are essential for channel gating. AB - The role of six cysteines of Ca(V)3.1 in channel gating was investigated. C241, C271, C282, C298, C313, and C323, located in the extracellular loop between segment IS5 and the pore helix, were each mutated to alanine; the resultant channels were expressed and studied by patch clamping in HEK293 cells. C298A and C313A conducted calcium currents, while the other mutants were not functional. C298A and C313A as well as double mutation C298/313A significantly reduced the amplitude of the calcium currents, shifted the activation curve in the depolarizing direction and slowed down channel inactivation. Redox agents dithiothreitol (DTT) and 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) shifted the current activation curve of wild-type channels in the hyperpolarizing direction. Activation curve for all mutated channels was shifted in hyperpolarizing direction by DTT while DTNB caused a depolarizing shift. Our study reveals that the cysteines we studied have an essential role in Ca(V)3.1 gating. We hypothesize that cysteines in the large extracellular loop of Ca(V)3.1 form bridges within the loop and/or neighboring channel segments that are essential for channel gating. PMID- 20827488 TI - Measurements of cancer extent in a conservatively treated prostate cancer biopsy cohort. AB - The optimal method for measuring cancer extent in prostate biopsy specimens is unknown. Seven hundred forty-four patients diagnosed between 1990 and 1996 with prostate cancer and managed conservatively were identified. The clinical end point was death from prostate cancer. The extent of cancer was measured in terms of number of cancer cores (NCC), percentage of cores with cancer (PCC), total length of cancer (LCC) and percentage length of cancer in the cores (PLC). These were correlated with prostate cancer mortality, in univariate and multivariate analysis including Gleason score and prostate-specific antigen (PSA). All extent of cancer variables were significant predictors of prostate cancer death on univariate analysis: NCC, hazard ration (HR) = 1.15, 95% confidence interval (CI) = 1.04-1.28, P = 0.011; PPC, HR = 1.01, 95% CI = 1.01-1.02, P < 0.0001; LCC, HR = 1.02, 95% CI = 1.01-1.03, P = 0.002; PLC, HR = 1.01, 95% CI = 1.01-1.02, P = 0.0001. In multivariate analysis including Gleason score and baseline PSA, PCC and PLC were both independently significant P = 0.004 and P = 0.012, respectively, and added further information to that provided by PSA and Gleason score, whereas NNC and LCC were no longer significant (P = 0.5 and P = 0.3 respectively). In a final model, including both extent of cancer variables, PCC was the stronger, adding more value than PLC (chi2 (1df) = 7.8, P = 0.005, chi2 (1df) = 0.5, P = 0.48 respectively). Measurements of disease burden in needle biopsy specimens are significant predictors of prostate-cancer-related death. The percentage of positive cores appeared the strongest predictor and was stronger than percentage length of cancer in the cores. PMID- 20827489 TI - Immunohistochemical analysis of pyloric gland adenomas using a series of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53. AB - A pyloric gland adenoma (PGA) of the stomach was first described in a book chapter in 1976 by Kurt Elster and has been rarely reported in the literature. We expanded the current immunohistochemical data of these adenomas in a detailed series to further analyse the immunhistochemical status of PGA. From 60 patients with PGA with and without adenocarcinomas of the gastrointestinal tract, an immunhistochemical panel of Mucin 2, Mucin 5AC, Mucin 6, CD10, Ki67 and p53 was used to define the expression of these markers. All PGA were positive for Mucin 6 (deep mucoid glands), which they express over the whole lesion up to the surface. Mucin 5AC expression varies from case to case. A transition from gastric to intestinal differentiation can be observed focally as depicted by Mucin 2 and CD10 in 65% of the cases. The gastric corpus mucosa of elderly patients with either Helicobacter pylori gastritis or autoimmune gastritis is highly affected. Almost 47% of all PGA already underwent malignant transformation into adenocarcinoma. Significant immunohistochemical differences could be detected between PGA with and without adenocarcinoma regarding ki67 and p53. The diagnosis of PGA can be confirmed immunohistochemically by staining against apomucin 6 and apomucin 5AC. Focal intestinal differentiation supports the hypothesis that gastric adenocarcinomas can initially develop from carcinomas of the gastric type and transform into intestinal type later on. The high frequency of malignant transformation of PGA underlines its high potential for invasive malignancy. PMID- 20827490 TI - Tortoise tick Hyalomma aegyptium as long term carrier of Q fever agent Coxiella burnetii--evidence from experimental infection. AB - The experimental study investigated the ability of tortoise tick Hyalomma aegyptium to play a role in forming and maintaining natural foci of Q fever. We tested the competence of H. aegyptium larvae to acquire Coxiella burnetii infection from mammals, serve as a C. burnetii vector between mammalian hosts, and be a long-term carrier of C. burnetii, including interstadial transmission. H. aegyptium larvae were allowed to feed on guinea pigs experimentally infected with C. burnetii. Engorged larvae molted to nymphs, some of which were preserved in 96% ethanol and later examined by polymerase chain reaction (PCR) using C. burnetii-specific primers (CBCOS, CBCOE). Prevalence of C. burnetii among these nymphs was 5.6% (n=235). Remaining nymphs then fed on other, C. burnetii-negative guinea pigs; and according to results of both, micro-agglutination reaction, and ELISA, they successfully transmitted C. burnetii to those new hosts. Detached engorged nymphs molted to adults, which were kept alive long term and then placed in 96% ethanol 383 days post-infection. Thereafter, they were examined by PCR in the same manner as were the nymphs. Prevalence of C. burnetii among adult H. aegyptium was 28.9% (n=90). According to our results, tortoise-specific ticks have indisputable potential in the epidemiology of Q fever natural foci. PMID- 20827491 TI - Theileria parva genetic diversity and haemoparasite prevalence in cattle and wildlife in and around Lake Mburo National Park in Uganda. AB - Wildlife, especially Cape buffalo (Syncerus caffer), are thought to act as a reservoir for many of the important tick-borne pathogens of cattle. In this study, we have determined the prevalence of the most significant tick-borne haemoparasites in wildlife (buffalo, impala, eland and bushbuck) as well as in cattle grazing inside and neighbouring Lake Mburo National Park (LMNP) in Uganda. A high percentage of buffalo were carriers of Theileria parva, Theileria mutans, Theileria velifera, Theileria buffeli and Theileria sp. (buffalo) as well as Anaplasma marginale and Anaplasma centrale. The majority of impala sampled were carriers of A. centrale, and all were carriers of an unidentified Babesia/Theileria species. The eland and bushbuck sampled were all carriers of Theileria taurotragi and Theileria buffeli, and the majority were carriers of T. mutans. The bushbuck sampled were also carriers for Erhlichia bovis. There were some differences in the prevalence of haemoparasites between the calves sampled inside and neighbouring LMNP. In order to address the question of whether there is evidence for interbreeding between buffalo-associated and cattle-associated T. parva populations, multi-locus genotypes (MLGs) of T. parva (based on micro satellite markers) from buffalo and from calves grazing inside and outside LMNP were compared, and the results revealed that buffalo and cattle gene pools were distinct, showing no evidence for transmission of buffalo-derived T. parva genotypes to the cattle population. PMID- 20827492 TI - Variation in decomposition rates in the fynbos biome, South Africa: the role of plant species and plant stoichiometry. AB - Previous studies in the fynbos biome of the Western Cape, South Africa, have suggested that biological decomposition rates in the fynbos vegetation type, on poor soils, may be so low that fire is the main factor contributing to litter breakdown and nutrient release. However, the fynbos biome also comprises vegetation types on more fertile soils, such as the renosterveld. The latter is defined by the shrub Elytropappus rhinocerotis, while the shrub Galenia africana may become dominant in overgrazed areas. We examined decomposition of litter of these two species and the geophyte Watsonia borbonica in patches of renosterveld in an agricultural landscape. In particular, we sought to understand how plant species identity affects litter decomposition rates, especially through variation in litter stoichiometry. Decomposition (organic matter mass loss) varied greatly among the species, and was related to litter N and P content. G. africana, with highest nutrient content, lost 65% of its original mass after 180 days, while E. rhinocerotis had lost ca. 30%, and the very nutrient poor W. borbonica <10%. Litter placed under G. africana decomposed slightly faster than when placed under E. rhinocerotis. Over the course of the experiment, G. africana and E. rhinocerotis lost N and P, while W. borbonica showed strong accumulation of these elements. Decomposition rates of G. africana and E. rhinocerotis were substantially higher than those previously reported from fynbos vegetation, and variation among the species investigated was considerable. Our results suggest that fire may not always be the main factor contributing to litter breakdown and nutrient release in the fynbos biome. Thus, biological decomposition has likely been underestimated and, along with small-scale variation in ecosystem processes, would repay further study. PMID- 20827493 TI - Enhanced cell fusion activity in porcine epidemic diarrhea virus adapted to suckling mice. AB - Porcine epidemic diarrhea virus (PEDV) is the major causative agent of fatal diarrhea in piglets. To study the pathogenic features of PEDV using a mouse model, PEDV with virulence in mice is required. In pursuit of this, we adapted a tissue-culture-passed PEDV MK strain to suckling mouse brains. PEDV obtained after ten passages through the brains (MK-p10) had increased virulence for mice, and its fusion activity in cultured cells exceeded that of the original strain. However, the replication kinetics of MK and MK-p10 did not differ from each other in the brain and in cultured cells. The spike (S) protein of MK-p10 had four amino acid substitutions relative to the original strain. One of these (an H-to-R substitution at residue 1,381) was first detected in PEDV isolated after eight passages, and both this virus (MK-p8) and MK-p10 showed enhanced syncytium formation relative to the original MK strain and viruses isolated after two, four, and six passages, suggesting the possibility that the H-to-R mutation was responsible for this activity. This mutation could be also involved in the increased virulence of PEDV observed for MK-p10. PMID- 20827494 TI - Role of nitric oxide in tolerance of plants to abiotic stress. AB - Nitric oxide (NO) has now gained significant place in plant science, mainly due to its properties (free radical, small size, no charge, short-lived, and highly diffusible across biological membranes) and multifunctional roles in plant growth, development, and regulation of remarkable spectrum of plant cellular mechanisms. In the last few years, the role of NO in tolerance of plants to abiotic stress has established much consideration. As it is evident from the present review, recent progress on NO potentiality in tolerance of plants to environmental stresses has been impressive. These investigations suggest that NO, itself, possesses antioxidant properties and might act as a signal in activating ROS-scavenging enzyme activities under abiotic stress. NO plays an important role in resistance to salt, drought, temperature (high and low), UV-B, and heavy metal stress. Rapidly increasing evidences indicate that NO is essentially involve in several physiological processes; however, there has been much disagreement regarding the mechanism(s) by which NO reduces abiotic stress. PMID- 20827495 TI - Regulation of taurine homeostasis by protein kinase CK2 in mouse fibroblasts. AB - Increased expression of the ubiquitous serine/threonine protein kinase CK2 has been associated with increased proliferative capacity and increased resistance towards apoptosis. Taurine is the primary organic osmolyte involved in cell volume control in mammalian cells, and shift in cell volume is a critical step in cell proliferation, differentiation and induction of apoptosis. In the present study, we use mouse NIH3T3 fibroblasts and Ehrlich Lettre ascites tumour cells with different CK2 expression levels. Taurine uptake via the Na(+) dependent transporter TauT and taurine release are increased and reduced, respectively, following pharmacological CK2 inhibition. The effect of CK2 inhibition on TauT involves modulation of transport kinetics, whereas the effect on the taurine release pathway involves reduction in the open-probability of the efflux pathway. Stimulation of PLA(2) activity, exposure to exogenous reactive oxygen species as well as inhibition of protein tyrosine phosphotases (PTP) potentiate the swelling induced taurine loss. Inhibition of PI3K and PTEN reduces and potentiates swelling-induced taurine release, respectively. Inhibition of CK2 has no effect on PLA(2) activity and ROS production by NADPH oxidase, whereas it lifts the effect of PTEN and PTP inhibition. It is suggested that CK2 regulates the taurine release downstream to known swelling-induced signal transducers including PLA(2), NADPH oxidase and PI3K. PMID- 20827496 TI - Analysis of characteristics of paratyphoid A in 157 Chinese inpatients between 1998 and 2009. AB - The objectives of this study were to understand the epidemic rules, clinical characteristics, and drug resistance of paratyphoid A by analyzing 157 cases in the Wenzhou area of China during a 12-year period. The subjects included in the present study were patients with paratyphoid A who were admitted to the First Affiliated Hospital of Wenzhou Medical College (Wenzhou, ZJ, China) between 1998 and 2009. The disease mainly occurred in persons aged 20 to 50 years. The peak incidence was between 2001 and 2003 (n = 85). Paratyphoid A was more likely to occur in winter and spring in this area. In many cases (33.8%), the condition was complicated by underlying diseases. The length of hospital stay was relatively long, averaging 17.68 days. The white blood cell (WBC) count was 2-8 * 10(9)/L in 88.5% of cases. Eosinophils disappeared in 51.7% of cases. The erythrocyte sedimentation rate (ESR) was not significant and lower than 60 mm/h in 88.5% of cases. Alanine aminotransferase (ALT) was <=3-fold greater than the normal value in 84.3% of cases. The Widal test was positive in only 7.7% of our cases. The sensitivity of many antibiotics was over 90%. Paratyphoid A in the Wenzhou area has unique epidemic rules, clinical characteristics, and drug resistance. The results of our retrospective analysis are instructive for the early diagnosis and rational treatment of paratyphoid A. PMID- 20827497 TI - Treatment with peginterferon versus interferon in Chinese patients with chronic hepatitis C. AB - Higher sustained virological response (SVR) rates after treating with peginterferon than after treating with interferon have been obtained in some randomized clinical trials (RCTs) in Chinese patients with chronic hepatitis C (CHC). However, the numbers of patients included in these clinical trials were too small to draw a clear conclusion. Therefore, a new meta-analysis including a large number of patients was needed to compare peginterferon with interferon in the treatment of Chinese CHC patients. A search of Medline, the China National Knowledge Infrastructure, the Wanfang Database, and the China Biomedical Database for relevant articles published between 1966 and 2009 was performed. RCTs comparing the use of peginterferon and interferon for the treatment of Chinese patients with CHC were assessed. Of the 236 studies screened, 18 RCTs including 1,148 patients (659 treated with peginterferon therapy and 489 treated with interferon therapy) were analyzed. The total SVR rates obtained in patients treated with peginterferon were significantly higher than those obtained in patients treated with interferon (64% vs. 40%; relative risk, 1.56; 95% confidence interval: 1.28-1.91; p < 0.01), but the difference between the peginterferon alpha-2b and interferon alpha-2b treatments was not significant. Withdrawal rates were similar between patients treated with peginterferon and interferon. Chinese patients with CHC have a greater likelihood of achieving an SVR with peginterferon alpha-2a. PMID- 20827498 TI - Vestibular pneumolabyrinth: why assessment with temporal bone computed tomography utilizing dynamic focal spot mode is important for the diagnosis. AB - We present an interesting and relatively uncommon case of vestibular pneumolabyrinth in a young child post-trauma. His initial clinical exam and imaging studies of the head and cervical spine were negative. He subsequently developed nystagmus and a dedicated temporal bone study demonstrated a subtle fracture and vestibular pneumolabyrinth. Temporal bone fractures can be difficult to appreciate, and therefore, associated findings of fluid in the middle ear, stapes dislocation, or vestibular pneumolabyrinth must be carefully evaluated. Temporal bone computed tomography is a high resolution study, utilizing dynamic focal spot mode which leads to increased sampling and resolution, thereby reducing aliasing artifacts but a longer scan time and increased radiation dose. CT head and cervical spine normally obtained without using this technique leads to aliasing artifacts where even the normal endolymph in the inner ear structures appear hypodense mimicking pneumolabyrinth, thereby obscuring true pneumolabyrinth. It is important to be aware of this finding and technique related artifact, if a temporal bone injury is suspected, to ensure an earlier diagnosis and optimum management. PMID- 20827499 TI - Clinical remission of Henoch-Schonlein purpura nephritis after a monotherapeutic tonsillectomy. AB - We herein describe an adult male patient who presented with tonsillitis, purpura, hematuria, and proteinuria. The serological analyses revealed elevated serum antistreptolysin, and the throat culture yielded Lancefield group A beta hemolytic streptococci. A renal biopsy revealed mild mesangial proliferation associated with granular mesangial depositions of IgA and C3, consistent with Henoch-Schonlein purpura nephritis (HSPN). Initially, the patient was treated with dipyridamole, which was followed by limited improvements in the proteinuria and hematuria. Nine months later, the tonsillitis relapsed due to GAS infection and deteriorated urinary abnormalities were noticed, which finally disappeared after monotherapeutic tonsillectomy. Although the impact of tonsillectomy on the treatment of HSPN remains to be characterized, our observations suggest that tonsillectomy in the present patient played a pivotal role in facilitating the recovery of the renal injuries. Because the arbitrary application of a tonsillectomy appears to be accompanied by ethical concerns, the evaluation of the clinical benefits of this procedure should be addressed more directly in the future. PMID- 20827500 TI - A hybrid bioregulatory model of angiogenesis during bone fracture healing. AB - Bone fracture healing is a complex process in which angiogenesis or the development of a blood vessel network plays a crucial role. In this paper, a mathematical model is presented that simulates the biological aspects of fracture healing including the formation of individual blood vessels. The model consists of partial differential equations, several of which describe the evolution in density of the most important cell types, growth factors, tissues and nutrients. The other equations determine the growth of blood vessels as a result of the movement of leading endothelial (tip) cells. Branching and anastomoses are accounted for in the model. The model is applied to a normal fracture healing case and subjected to a sensitivity analysis. The spatiotemporal evolution of soft tissues and bone, as well as the development of a blood vessel network are corroborated by comparison with experimental data. Moreover, this study shows that the proposed mathematical framework can be a useful tool in the research of impaired healing and the design of treatment strategies. PMID- 20827501 TI - Mesenchymal stem cells display hepato-protective activity in lymphoma bearing xenografts. AB - A disseminated model of non-Hodgkin's lymphoma with prevalent liver metastasis was generated by intraperitoneal (i.p.) injection of EBV(+) B lymphoblastoid SKW6.4 in nude-SCID mice. The survival of SKW6.4 xenografts (median survival = 27 days) was significantly improved when hyaluronan scaffolds embedded with mesenchimal stem cells (MSC) were implanted in the abdominal area 4 days after SKW6.4 injection (median survival = 39.5 days). Mice implanted with MSC showed a significant improvement of hepatic functionality in lymphoma xenografts, as demonstrated by measurement of serum ALT/AST levels. Co-culture of MSC with lymphoma cells enhanced the release of hepatocyte growth factor (HGF) by MSC. These data suggest that hyaluronan-embedded MSC exert anti-lymphoma activity by ameliorating hepatic functionality. PMID- 20827502 TI - Candidate electrophysiological endophenotypes of hyper-reactivity to change in autism. AB - Although resistance to change is a main feature of autism, the brain processes underlying this aspect of the disorder remain poorly understood. The aims of this study were to examine neural basis of auditory change-detection in children with autism spectrum disorders (ASD; N = 27) through electrophysiological patterns (MMN, P3a) and to test whether these are quantitatively related to intolerance of change (using the BSE-R scale). ASD displayed significantly shorter MMN latency and larger P3a than controls, indicating a greater tendency to switch attention to deviant events. These electrophysiological abnormalities were significantly more marked in children who displayed greater difficulties in tolerating change. The atypical neurophysiological mechanism of change perception identified might thus be associated with one of the hallmark behavioural manifestations of autism. PMID- 20827503 TI - Factors associated with antenatal care utilization among rural women in Lao People's Democratic Republic. AB - This study aims at exploring factors related to the antenatal care (ANC) utilization in rural areas of Lao PDR. A quantitative, cross-sectional interview study was conducted in the Khammouane and Champasack provinces. The study population comprised all currently pregnant women 15-45 years of age with a gestational period beyond 32 weeks plus all women who had given birth during the last 12 months. With the informed consent of all eligible women, 460 respondents were included in the study and interviewed using a structured questionnaire. Multiple logistic regression analysis was applied to determine factors significantly related to ANC use. Fifty-one percent of the respondents had at least one ANC visit. Among the users, 63% had visited ANC three times or more but only 28% attended during the first trimester. After adjusting for other factors, using a 95% Confidence Interval (CI), statistically significant associations were found between ANC use and the following factors: women whose husbands were salaried employees (OR=2.66, CI=1.45-4.88); women younger than 18 years old at first pregnancy (OR 0.56, CI=0.28-0.97); women perceiving ANC as somewhat useful (OR=2.88, CI=1.26-6.61) or very useful (OR=7.45, CI=3.59-15.46). Awareness of the usefulness of ANC was related to more frequent use and could be one focus of community intervention to increase utilization. PMID- 20827504 TI - Physical activity, body size and composition, and risk of ovarian cancer. AB - OBJECTIVES: We examined the association between risk of ovarian cancer and physical activity and anthropometry (body mass index, height, waist, fat, and fat free mass) in the Melbourne Collaborative Cohort Study. METHODS: This prospective cohort study included 18,700 women aged 26-76 years old at recruitment between 1990 and 1994. Participants were interviewed about their physical activity, including frequency and intensity. Body measurements were taken directly; fat mass and fat-free mass were calculated from bioelectrical impedance analysis. During an average of 10.2 years of follow-up, 113 ovarian cancers were ascertained. Cox regression was used to estimate hazard ratios. RESULTS: After adjusting for potential confounders, compared with no physical activity, the hazard ratios for levels of total physical activity were 1.56 (95% CI: 0.81, 3.00) for low level, 1.92 (1.07, 3.45) for medium level, and 2.21 (1.16, 4.24) for high level (test for trend, p = 0.01). The hazard ratio for ovarian cancer in relation to BMI was 1.22 (95% CI: 1.00, 1.48; p-trend, 0.06) per 5 kg/m(2) increment, and for fat mass, 1.23 (95% CI: 1.01, 1.49; p-trend, 0.04) per 10 kg increment. CONCLUSIONS: This study found some evidence for a possible relationship between higher levels of physical activity and body size and increased ovarian cancer risk. PMID- 20827505 TI - Dicer is a key player in oocyte maturation. AB - OBJECTIVE: Apply Dicer siRNA to study functions of Dicer and miRNA during oogenesis. MATERIALS AND METHODS: Mouse oocytes were injected with Dicer siRNA and negative control siRNA and then matured in vitro. After IVM, oocytes were examined for maturation rates, spindle and chromosomal organization, and various gene expressions. RESULTS: Dicer siRNA significantly reduced maturation rates, increased abnormal spindle and chromosomal organization, and reduced the transcripts of Dicer miRNAs, spindle formation proteins (plk1 and AURKA) and spindle check points (Bub1, Bublb). Depletion of bulb16 markedly prohibited the first polar body extrusion and increased the incidence of misaligned chromosomes and abnormal meiotic spindle assembly. CONCLUSION: Dicer siRNA triggered a cascade reduction for gene expressions starting from Dicer to miRNAs than to spindle assembly proteins and checkpoints which led to abnormal spindle and chromosomal organization. Thus, Dicer and miRNA appeared to play an important role during oogenesis and were essential for meiotic completion. PMID- 20827506 TI - A study on the phytoaccumulation of waste elements in wetland plants of a Ramsar site in India. AB - Some wetland plant species are adapted to growing in the areas of higher metal concentrations. Use of such vegetation in remediation of soil and water contaminated with heavy metals is a promising cost-effective alternative to the more established treatment methods. Throughout the year, composite industrial effluents bringing various kinds of heavy metals contaminate our study site, the East Calcutta Wetlands, a Ramsar site at the eastern fringe of Kolkata city (formerly Calcutta), India. In the present study, possible measures for remediation of contaminated soil and water (with elements namely, Ca, Cr, Cu, Pb, Zn, Mn, and Fe) of the ecosystem had been investigated. Ten common regional wetland plant species were selected to study their efficiency and diversity in metal uptake and accumulation. Results showed that Bermuda grass (Cynodon dactylon) had the highest total Cr concentration (6,601 +/- 33 mg kg( -1) dw). The extent of accumulation of various elements in ten common wetland plants of the study sites was: Pb (4.4-57 mg kg( -1) dw), Cu (6.2-39 mg kg( -1) dw), Zn (59 364 mg kg( -1) dw), Mn (87-376 mg kg( -1) dw), Fe (188-8,625 mg kg( -1) dw), Ca (969-3,756 mg kg( -1) dw), and Cr (27-660 mg kg( -1) dw) indicating an uptake gradient of elements by plants as Ca>Fe>Mn>Cr>Zn>Cu>Pb. The present study indicates the importance of identification and efficiency of metal uptake and accumulation capabilities by plants in relation to their applications in remediation of a contaminated East Calcutta Wetland ecosystem. PMID- 20827507 TI - Libraries of 2beta-(N-substituted piperazino)-5alpha-androstane-3alpha, 17beta diols: chemical synthesis and cytotoxic effects on human leukemia HL-60 cells and on normal lymphocytes. AB - Libraries of steroid derivatives with two levels of molecular diversity were prepared to optimize the antiproliferative activity on leukemia HL-60 cells by first varying the amino acid (AA) at R(1) (libraries A, B, C, and D: with 45, 45, 20, and 20 members, respectively) and, subsequently, the capping group at R(2) (library E: 168 members). The screening of these aminosteroids revealed interesting structure-activity relationships. In library A, the compounds bearing a tetrahydroisoquinolone residue as the first element of diversity showed potent cytotoxicity, principally when isovaleric or cyclohexyl acetic acid was used as a capping group (>40% of cell growth inhibition at 1 MUM). In library B, the phenylalanine (Phe) derivatives bearing a cyano group induced a higher growth inhibition than the other Phe derivatives. The screening of library C indicated the increase of hydrophobicity of proline (Pro) seems to preserve the cytotoxic effect achieved by the lead compound. However, the synthesis of structural Pro variants (library D) clearly shows weaker activities when compared to L-Pro building blocks. Finally, by incorporating some of the most active AA of libraries A-D in library E, we observed that the amide coupling functionality gave stronger cytotoxic activity compared to the corresponding sulfonamides or benzylamines. Six of the most active amide derivatives (E-37P, E-41P, E-42P, E 46P, E-48F, and E-12T) were selected and IC(50) determined on HL-60 cells as well as on normal human lymphocytes. Among this series of new anticancer agents, good to high selectivity indices (SI = IC(50) (lymphocytes)/IC(50) (HL-60 cells) = 5 - 55) were obtained. PMID- 20827508 TI - Abnormalities of serum potassium concentration in dialysis-associated hyperglycemia and their correction with insulin: review of published reports. AB - The main difference between dialysis-associated hyperglycemia (DH) and diabetic ketoacidosis (DKA) or nonketotic hyperglycemia (NKH) occurring in patients with preserved renal function is the absence of osmotic diuresis in DH, which eliminates the need for large fluid and solute (including potassium) replacement. We analyzed published reports of serum potassium (K(+)) abnormalities and their treatment in DH. Hyperkalemia was often present at presentation of DH with higher frequency and severity than in hyperglycemic syndromes in patients with preserved renal function. The frequency and severity of hyperkalemia were higher in DH episodes with DKA than those with NKH in both hemodialysis and peritoneal dialysis. For DKA, the frequency and severity of hyperkalemia were similar in hemodialysis and peritoneal dialysis. For NKH, hyperkalemia was more severe and frequent in hemodialysis than in peritoneal dialysis. Insulin infusion corrected the hyperkalemia of DH in most cases. Additional measures for the management of hyperkalemia or modest potassium infusions for hypokalemia were needed in a few DH episodes. The predictors of the decrease in serum K(+) during treatment of DH with insulin included the starting serum K(+) level, the decreases in serum values of glucose concentration and tonicity, and the increase in serum total carbon dioxide level. DH represents a risk factor for hyperkalemia. Insulin infusion is the only treatment for hyperkalemia usually required. PMID- 20827509 TI - A multilevel Lab on chip platform for DNA analysis. AB - Lab-on-chips (LOCs) are critical systems that have been introduced to speed up and reduce the cost of traditional, laborious and extensive analyses in biological and biomedical fields. These ambitious and challenging issues ask for multi-disciplinary competences that range from engineering to biology. Starting from the aim to integrate microarray technology and microfluidic devices, a complex multilevel analysis platform has been designed, fabricated and tested (All rights reserved-IT Patent number TO2009A000915). This LOC successfully manages to interface microfluidic channels with standard DNA microarray glass slides, in order to implement a complete biological protocol. Typical Micro Electro Mechanical Systems (MEMS) materials and process technologies were employed. A silicon/glass microfluidic chip and a Polydimethylsiloxane (PDMS) reaction chamber were fabricated and interfaced with a standard microarray glass slide. In order to have a high disposable system all micro-elements were passive and an external apparatus provided fluidic driving and thermal control. The major microfluidic and handling problems were investigated and innovative solutions were found. Finally, an entirely automated DNA hybridization protocol was successfully tested with a significant reduction in analysis time and reagent consumption with respect to a conventional protocol. PMID- 20827510 TI - Prevention of bone resorption by intake of phytoestrogens in postmenopausal women: a meta-analysis. AB - Phytoestrogens as selective estrogen receptor modulators like compounds may consider as a therapeutic option in osteoporosis. In this regard, the effect of phytoestrogens on bone biomarkers was examined in several trials which their results are controversial. We aimed this meta-analysis to evaluate the net effect of phytoestrogens on bone markers. A thorough search was conducted from 2000 to 2010 in English articles. All randomized clinical trials were reviewed, and finally, 11 eligible randomized clinical trials were selected for meta-analysis. Totally 1,252 postmenopausal women were enrolled in the study by considering the changes of pyridinoline (Pyd), desoxypyridinoline (Dpyd), bone alkaline phosphatase, and osteocalcin concentrations in urine and serum after phytoestrogens consumption. The urine Pyd and Dpyd levels decreased significantly in phytoestrogens consumers. Effect size and effect size for weighted mean difference of urine Pyd levels showed -1.229171 (95% confidence interval (CI) = 1.927639 to -0.530703) and -9.780623 (95% CI = -14.240401 to -5.320845), respectively, a significant results in comparison to control group and significant results for Dpyd -0.520132 (95% CI = -0.871988 to -0.168275) and 0.818582 (95% CI = -1.247758 to -0.389407), respectively. Meta-analysis indicates that phytoestrogens intake can prevent bone resorption, but its benefits on bone formation are not significant. This favorable effect was observed in low doses and in at least 3 weeks of phytoestrogens intake. PMID- 20827511 TI - On a class of deterministic population models with stochastic foundation. AB - Generalising a site-based stochastic model due to Royama, Sole et al. and Sumpter et al., we investigate competition in a single species with discrete, non overlapping generations. We show that the deterministic limit of the dynamics depends on a few easily interpretable parameters only. Further, we discuss qualitative properties and limit sets of the corresponding difference equations, and we relate these to modes of competition. Moreover, a detailed analysis of stochastic effects in some relevant scenarios indicates that the behaviour of the stochastic model is very sensitive to further details of the model. PMID- 20827512 TI - On the number of binary characters needed to recover a phylogeny using maximum parsimony. AB - We give an explicit construction to solve a conjecture of Mike Steel and David Penny that any phylogeny involving N taxa can be recovered unambiguously using on the order of log N binary characters and the method of maximum parsimony. Biologically, this means that homoplasy need not be a deterrent to parsimony methods. Some patterns of homoplasy are phylogenetically informative and can exponentially reduce the amount of data needed to resolve a phylogeny. PMID- 20827513 TI - Saturated fat and health: recent advances in research. PMID- 20827514 TI - Pathologic femur fractures after limb-sparing treatment of soft-tissue sarcomas. AB - INTRODUCTION: Local control for sarcomas of the long bones includes limb sparing surgery and radiotherapy. While effective, there are potential complications. METHODS: Patients treated for a soft tissue sarcoma of the thigh with limb sparing surgery and radiation therapy between 1986 and 2000 at the University of Minnesota Masonic Cancer Center (n=89) were identified. Demographic, tumor, and treatment characteristics were abstracted from the medical record. Univariate analysis was conducted to identify significant risk factors for fracture. RESULTS: Survivors (58% male), median age of 50 (7-88) years, reported 8 (9%) fractures at a median of 7.3 (0.8-21.9) years from diagnosis after a median of 6300 (2000-7020) cGy of radiation. All fractures occurred within the previous radiation field, after no trauma. Three of the 8 (37.5%) had delayed union, 2 (25%) nonunion healing. Significant risk factors included periosteal stripping (p=0.006), anterior compartment location (p=0.022), and having 100% of the femoral circumference irradiated (p=0.018). Taking into account time to fracture using Kaplan Meier and log rank tests, these same predictors were identified. Older age, female sex, use of chemotherapy, and timing of radiation were not predictive of femoral fracture. CONCLUSION: Anterior tumor location, periosteal stripping, and radiation to 100% of the femur circumference are associated with femoral fracture. These patients require long-term monitoring and may warrant prophylactic intramedullary pinning or other protective measures. IMPLICATIONS FOR CANCER SURVIVORS: Survivors of soft tissue sarcomas of the femur may be at risk for the development of femur fractures and warrant close observation. PMID- 20827515 TI - Spectroscopic and molecular modeling studies on the interaction between a fluorine-containing triazole derivative and human serum albumin. AB - The interaction between 4-(4-fluorobenzylideneamino)-5-propyl-4H-1,2,4-triazole-3 thiol (FBTZ) and human serum albumin (HSA) under simulative physiological conditions was investigated by fluorescence, UV-vis absorption and circular dichroism (CD) spectroscopy as well as molecular modeling method. Fluorescence spectroscopic data showed that the fluorescence quenching of HSA was a result of the formation of FBTZ-HSA complex. According to the modified Stern-Volmer equation, the effective quenching constants (K (a)) of FBTZ to HSA were obtained at three different temperatures. The enthalpy change (DeltaH) and entropy change (DeltaS) were calculated on the basis of van't Hoff equation, and the results showed that hydrogen-bonding and van der Waals forces were the dominant intermolecular forces to stabilize the complex. Site marker competitive replacement experiments demonstrated that the binding of FBTZ to HSA primarily took place in sub-domain IIA (Sudlow's site I). The binding distance (r) between FBTZ and the tryptophan residue of HSA was estimated according to the theory of fluorescence resonance energy transfer. The conformational investigation showed that the presence of FBTZ induced some changes of secondary structure of HSA. Molecular modeling study further confirmed the binding mode obtained by experimental study. PMID- 20827516 TI - From Vaquez to Dameshek through JAK...2 much for polycythemia vera to be feared? PMID- 20827517 TI - Have the renin-angiotensin-aldosterone system perturbations in cardiovascular disease been exhausted? AB - The renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure control and volume homeostasis. Inappropriate activation of the RAAS has been implicated in the pathogenesis of hypertension and related cardiovascular disease. Several classes of agents that block RAAS signaling have been shown to be effective antihypertensives and to have cardioprotective and renoprotective properties. Because blockade of the RAAS is incomplete with any of the currently available monotherapies, combinations of these agents have been tested and shown to provide additional clinical benefit in patients with hypertension and various forms of cardiovascular and renal disease. PMID- 20827518 TI - Intentions to quit smoking: causal attribution, perceived illness severity, and event-related fear during an acute health event. AB - BACKGROUND: Experiencing a serious consequence related to one's health behavior may motivate behavior change. PURPOSE: This study sought to examine how causal attribution, perceived illness severity, and fear secondary to an acute health event relate to intentions to quit smoking. METHODS: Using a cross-sectional survey design, adult emergency department patients who smoked provided demographic data and ratings of nicotine dependence, causal attribution, perceived illness severity, event-related fear, and intentions to quit smoking. RESULTS: A linear regression analysis was used to examine the relations between the independent variables and quit intentions. We enrolled 186 participants. After adjusting for nicotine dependence, smoking-related causal attribution and event-related fear were associated with intentions to quit (beta = 0.26, p < 0.01 and beta = 0.21, p < 0.01, respectively). Perceived illness severity was correlated with event-related fear (r = 0.46, p < 0.001) but was not associated with intentions to quit (beta = -0.08, p = 0.32). CONCLUSION: While causal attribution and event-related fear were modestly associated with quit intentions, perceived illness severity was not. Longitudinal studies are needed to better explicate the relation between these variables and behavior change milestones. PMID- 20827519 TI - Gender differences in functional limitations in adults living with type 2 diabetes: biobehavioral and psychosocial mediators. AB - BACKGROUND: Differences in functional limitations between adults with and without diabetes are more evident in women than they are in men. PURPOSE: This study aims to investigate if there are gender differences in biological, behavioral, and psychosocial variables, and how these gender-related variables explain the gender functional limitations relationship in adults with type 2 diabetes. METHODS: We drew data on 1,619 adults with type 2 diabetes from the Health and Retirement Study and its diabetes-specific mail survey. The fit of a series of mediation models to the data was assessed by structural equation modeling. RESULTS: Although women had better diet and blood glucose self-monitoring behaviors than did men, they reported less favorable body mass index, glycosylated hemoglobin (HbA1c) value, blood pressure, early complications, exercise behaviors, perceived control, self-efficacy, coping, depressive symptoms, and family support than did men. Psychosocial factors made an indirect contribution in the gender-functional limitations relationship by way of their strong association with biological and behavioral factors, two factors that directly and completely mediated the gender functional limitations relationship. CONCLUSIONS: Interventions promoting psychosocial well-being and empowering perceived diabetes control, coping, and self-efficacy in women with type 2 diabetes may help improve biological and behavioral determinants, and further, their long-term functional health. PMID- 20827520 TI - Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. AB - Traveling through several time zones results in a constellation of symptoms known as jet lag. These include reduced alertness, daytime fatigue, loss of appetite, reduced cognitive skills, and disruption of the sleep/wake cycle. In susceptible air travel passengers, jet lag may exacerbate affective illness and result in psychiatric morbidity. Dysregulation of circadian rhythms and melatonin secretion represent the common underlying factor in jet lag and other circadian disorders. Recent studies have established the effectiveness of strategically timed administration of melatonin and appropriate timed exposure to environmental schedules including light in counteracting the dysregulation (chronobiologic actions). With the introduction of melatonergic agonists such as ramelteon and tasimelteon, which have both a stronger affinity for MT1 and MT2 melatonin receptors and a longer half-life, new therapeutic options now exist for treating the sleep disturbances associated with jet lag. The melatonin analogs are unique inasmuch as they can also enhance daytime alertness. The recently introduced melatonergic antidepressant agomelatine, which has established its supremacy over other antidepressants in having a significant chronobiologic activity, represents a good choice for treating depressive symptoms that are associated with jet lag. PMID- 20827522 TI - Hydrogen-bonded synthetic mimics of protein secondary structure as disruptors of protein-protein interactions. AB - Small molecules which can mimic the key structural facets of protein secondary structure, in particular the alpha-helix, beta-strand, and beta-sheet, have been shown to be potent disruptors of protein-protein interactions. Researchers have recently taken the organizational imitation of protein secondary structure to a new level by using intramolecular hydrogen bonds as stabilizing forces in these small molecule mimetics. The inclusion of these interactions invokes a conformational bias of the system, allowing for greater control of the appearance, and thus often function, of these molecules by design. PMID- 20827523 TI - A rapid, quantitative assay for direct detection of microRNAs and other small RNAs using splinted ligation. AB - This protocol describes a method that uses splinted ligation for in-solution, direct labeling of small RNAs from total RNA. The liquid phase hybridization method makes it possible to achieve sensitive, specific, and quantitative detection while eliminating a number of time-consuming and labor-intensive steps required for the standard Northern blot assay. The assay uses a small RNA specific bridge oligonucleotide to form base pairs with the small RNA and a 5' end radiolabeled ligation oligonucleotide. The captured small RNA is internally labeled by ligation. Detection of the labeled small RNAs is performed by denaturing gel electrophoresis and autoradiography or phosphorimaging. This protocol has been successfully used to study expression of various classes of biological small RNAs from nanogram to microgram amounts of total RNA without an amplification step and is significantly more simple and more sensitive than Northern blotting or ribonuclease protection assays. Once the oligonucleotides have been synthesized and total RNA has been extracted, the procedure can be completed in 6 h. PMID- 20827524 TI - Normalization of microRNA quantitative RT-PCR data in reduced scale experimental designs. AB - Proper normalization of quantitative RT-PCR (qRT-PCR) data is a crucial component of gene -expression analysis. Although arbitrarily selected housekeeping genes have been used to normalize many published mRNA RT-PCR datasets, there is a growing awareness that such normalizers should be first validated empirically. The use of stable reference genes is particularly needed for qRT-PCR of microRNA (miRNA), which represent a novel class of biological regulators whose aberrant expression is associated with a range of disorders. Changes in miRNA levels can be modest, and yet have profound cellular consequences. As a result, precise measurements of miRNA expression are critically important. This chapter describes a detailed workflow for the selection of endogenous normalizers using the NormFinder algorithm, -resulting in more accurate miRNA expression profiling results. This approach is particularly well suited to smaller scale miRNA qRT-PCR experimental designs. PMID- 20827525 TI - MicroRNA detection in bone marrow cells by LNA-FISH. AB - The protocol reported in this chapter describes a method for the detection and spatial localisation of microRNAs (miRNAs) in cryopreserved primary leukaemic suspension cells using digoxigenin (DIG)-labelled, Locked Nucleic Acid (LNA) modified probes, and fluorescence in situ hybridisation (FISH). The LNA probe hybridisation yields highly accurate signals able to discriminate between single nucleotide differences and hence between closely related miRNA family members. DIG-labelled LNA probes for mature miRNAs are detected using an anti-DIG fluorescein isothiocyanate (FITC) conjugated antibody and the fluorescent signals visualised with a confocal microscope, which permits the spatial localisation of the miRNAs. Using LNA-FISH, we visualised the spatial localisation of two mature miRNAs, miR-127 and miR-154, in primary acute myeloid leukaemia (AML) suspension cells, and thus, we confirmed their expression in a specific leukaemic subtype as measured by real-time PCR. PMID- 20827526 TI - Measuring microRNA expression in size-limited FACS-sorted and microdissected samples. AB - MicroRNAs (miRNAs) are small noncoding RNAs of an average length of 22 nucleotides, which repress translation of a large number of target mRNAs. The particular importance of this group of small RNAs arises from the ever growing evidence that they control many biological processes, such as differentiation, proliferation, and apoptosis and that deregulation of individual miRNAs frequently results in cancer. The expression of miRNAs is spatially and temporarily fine-tuned and expression levels can reach more than 50,000 copies of one miRNA within a single cell. It is well documented that the comparison of miRNA signatures of normal and diseased tissues results in a small number of differentially expressed miRNAs, which are consequently of high diagnostic value. However, measuring miRNA expression can easily produce false-positive results, due to the high sequence similarity of the miRNAs within families and because biologically inactive pre-miRNAs as well as contaminating bystander cells may falsify the signal. The application of a quantitative PCR-based method is described here to specifically and reliably detect miRNA expression levels from as little as 50 cells. Pure cell populations were either derived from fluorescence-activated cell sorting (FACS) or laser capture microdissection (LCM). Importantly, a combination of quantitative PCR and LCM can also be applied to measure miRNA expression of cells obtained from formalin-fixed, paraffin embedded (FFPE) tissues, thereby giving experimental access to archives with large numbers of routinely collected normal and diseased tissue samples. PMID- 20827527 TI - MicroRNA cloning from cells of the immune system. AB - MicroRNAs have emerged as - important posttranscriptional regulators of gene expression. Small RNA cloning is a powerful method to identify new microRNAs (miRNAs) and to profile miRNA expression. In addition, it reveals end heterogeneity that may be important in miRNA function. Here, we describe a protocol that is optimized to clone small RNAs from limited amounts of starting material. This is often the case for studying miRNAs in a highly purified population of immune cells or other primary cell types with limited numbers. The small RNAs cloned with this protocol will have a 5'-PO(4) and 3'-OH group, typical features of miRNAs, so majority of the cloned small RNAs will be miRNAs. PMID- 20827528 TI - High-throughput profiling in the hematopoietic system. AB - The expression profile of microRNAs significantly varies in physiological and pathological conditions. Increasing evidence from the literature shows that abnormalities of the miRNome (defined as the full spectrum of miRNAs expressed in a genome) occur in almost all human diseases and have important pathogenetic, prognostic, and therapeutic implications. The study of the aberrancies of the miRNome has become possible by developing high-throughput profiling techniques that allow the simultaneous detection of differences in miRNA expression between normal and pathologic tissues or simply tissues at different stages of differentiation. These techniques provide the basis for further investigations focused on the miRNAs, which are most frequently and widely differentially expressed under the different investigated conditions. PMID- 20827529 TI - Construction of small RNA cDNA libraries for deep sequencing. AB - Since the phenomenon of small RNA-mediated gene silencing was first described over 15 years ago (Lee et al. Cell 75:843-854, 1993; Wightman et al. Cell 75:855 862, 1993), it has become evident that a variety of endogenous small RNAs play an important role in establishing and maintaining cell lineages. MicroRNAs (miRNAs), in particular, have been shown to exert regulatory control over the development and function of the many specialized cells that comprise the mammalian immune system (Baltimore et al. Nat Immunol 9:839-845, 2008; Kanellopoulous and Monticelli Semin Cancer Biol 18:79-88, 2008; Xiao and Rajewsky Cell 136:26-36, 2009). The advent of next generation sequencers provides an important tool for profiling the small RNA transcriptome of many diverse cell types. Compared to traditional Sanger sequencing, next generation sequencing machines can process millions of sequence reads in parallel, generating megabases of data within just a few days. The generation of small RNA libraries for sequencing is relatively straightforward and involves the ligation of platform-specific adapter sequences to small RNAs, followed by reverse transcription of the ligated species and PCR amplification. While other hybridization-based techniques are available for profiling well-characterized small RNAs, high-throughput sequencing remains the most powerful method for discovering novel small RNAs and posttranscriptional editing. PMID- 20827530 TI - MicroRNA-profiling in formalin-fixed paraffin-embedded specimens. AB - The discovery of small regulatory RNA molecules during the last few years has changed our understanding of many biological and pathological processes. The most prominent and best analyzed class of these small regulatory noncoding RNAs is comprised by the microRNAs. The analysis of microRNA expression patterns is now widely used in biology and pathology employing a range of methodologies. However, many precious human tissue samples are only available as formalin-fixed paraffin embedded (FFPE) specimen. In this chapter, the extraction of RNA from FFPE samples and the subsequent microRNA profiling utilizing fluorescence-labeled bead technology from Luminex Inc. is described. PMID- 20827531 TI - Expression of miRNAs in lymphocytes: a review. AB - In this chapter, we provide a review on the functions of the most important miRNAs in lymphocytes. Most of them are involved in lymphopoiesis, immune response, and lymphoid malignancies, highlighting the importance of miRNAs in these cells. PMID- 20827532 TI - Mouse models for miRNA expression: the ROSA26 locus. AB - In 1991, Soriano and coworkers isolated the ROSA26 locus in a gene-trap mutagenesis screening performed in mouse embryonic stem (ES) cells. The ubiquitous expression of ROSA26 in embryonic and adult tissues, together with the high frequency of gene-targeting events observed at this locus in murine ES cells has led to the establishment in the past 10 years of over 130 knock-in lines expressing successfully from the ROSA26 locus a variety of transgenes including reporters, site-specific recombinases and, recently, noncoding RNAs. Different strategies can be employed to drive transgene expression from the ROSA26 locus. This chapter provides an overview of the current methodologies used to generate ROSA26 knock-in lines and describes different approaches that exploit the ROSA26 gene to control expression of transgenes, including miRNAs, in a temporal, cell type, and stage-specific fashion. PMID- 20827533 TI - Regulation of monocytopoiesis by microRNAs. AB - MicroRNAs (miRNAs or miRs) are approximately 22 nt single-stranded noncoding RNAs that control gene expression in eukaryotes. miRNAs play an essential role in all basic cellular processes including cell development, proliferation, differentiation, and apoptosis. Importantly, miRNAs regulate hematopoietic progenitor cells differentiation toward the different hematopoietic lineages. This occurs through the regulation of key factors involved in hematopoiesis (e.g., transcription factors, growth factor receptors). We, hereby, describe how to investigate the role of miRNAs in monocytopoiesis. PMID- 20827534 TI - MicroRNA activity in B lymphocytes. AB - Gene expression regulation by miRNAs has been reported to control key aspects of B cell differentiation and function (Chen et al., Science 303:83-86, 2004; Xiao et al., Cell 131:146-159, 2007; O'Carroll et al., Genes Dev. 21:1999-2004, 2007; Koralov et al. Cell 132:860-874, 2008; Rodriguez et al., Science 316:608-611, 2007; Costinean et al., Proc Natl Acad Sci USA 103:7024-7029, 2006; Thai et al., Science 316:604-608, 2007; Vigorito et al., Immunity 27:847-859, 2007; Dorsett et al., Immunity 28:630-638, 2008; Teng et al., Immunity 28:621-629, 2008; de Yebenes et al., J Exp Med 205:2199-2206, 2008; He et al., Nature 435:828-833, 2005; Ventura et al. Cell 132:875-886, 2008; Xiao et al., Nat Immunol 9:405-414, 2008). In this chapter, we describe the methodology used to perform a functional screening of a miRNA library to identify miRNAs relevant for mature B cell function in primary mouse B cells. These procedures include the construction of a miRNA library and the expression of individual miRNA clones in spleen B cells, as well as the description of functional assays used to determine the impact of miRNA expression on several aspects of B cell function, such as proliferation, apoptosis, and class switch recombination. PMID- 20827535 TI - Isolation and characterization of microRNAs of human mature erythrocytes. AB - Human mature erythrocytes are terminally differentiated cells that have lost their nuclei and organelles during development. Even though mature erythrocytes lack ribosomal and other large-sized RNAs, they still retain small-sized RNAs. We have recently shown that there are abundant and diverse species of microRNAs in mature erythrocytes through the use of several different techniques, including northern blot, miRNA microarray, and real-time PCR. Furthermore, fractionation and genomic analysis has revealed that erythrocyte microRNA expression is different from that of reticulocytes or leukocytes and that mature erythrocytes contribute the majority of microRNA expression in whole blood. Therefore, global analysis of microRNA expression in circulating erythrocytes has the potential to provide mechanistic insights into erythrocyte biology and erythrocyte-related disorders. Here, we have provided the detailed methods for isolating and characterizing the microRNAs from human mature erythrocytes to enable such researches into human diseases involving erythrocytes. PMID- 20827536 TI - Stable overexpression of miRNAs in bone marrow-derived murine mast cells using lentiviral expression vectors. AB - MicroRNAs (miRNAs) constitute a class of molecules regulating gene expression in many different cell types, including cells of the mammalian immune system. Indeed, changes in miRNA expression patterns have been implicated in various physiological and pathological processes. Mast cells (MCs) are hematopoietic cells that originate in the bone marrow and migrate into the tissues, where they mature and reside. They have an important immunoregulatory and effector role in IgE-associated allergic disorders, as well as in certain innate and adaptive immune responses. An effective way to explore the functions of miRNAs in murine MCs includes the modification of miRNA expression in primary bone marrow-derived mast cells (BMMCs), followed by the analysis of the phenotypic consequences of such perturbation. In this chapter, we describe how to differentiate BMMCs and transduce them with lentiviruses. As an example, we expressed miR-221 and miR 222, which showed stable expression in BMMCs and acted as post-transcriptional regulators of c-Kit expression. PMID- 20827537 TI - Monitoring microRNA activity and validating microRNA targets by reporter-based approaches. AB - An essential requirement for discovering microRNAs that may be relevant to an immune cell's function is to identify the microRNAs that are active in the cell and the genes they target. As several chapters in this volume describe, there are a number of technologies available for profiling microRNA expression, including oligonucleotide array-based approaches, real-time PCR, and, now, deep-sequencing. A complementary approach to expression profiling is the use of a microRNA reporter vector for assaying microRNA activity. In their simplest form, these vectors are comprised of a reporter gene tethered to tandem repeats of a sequence that is complementary to a specific microRNA. This technology enables the activity of a microRNA to be detected, and at single-cell resolution, and provides a means to help identify microRNAs that may have a role in cell function. This is particularly relevant for studying microRNAs in the highly heterogeneous cellular network of the immune system. Reporter vectors have also proved useful for validating microRNA target sites and 3' untranslated regions (UTR) that are under microRNA control. This chapter describes how to construct, produce, and use a reporter vector for assaying microRNA activity, and for validating a microRNA target. PMID- 20827538 TI - Lentivirus-mediated antagomir expression. AB - MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation via hybridisation to mRNAs. miRNA function can be inhibited by the so-called "antagomirs" - anti-sense RNA oligonucleotides complementary to individual miRNAs. Since, in principle, any miRNA can be silenced, antagomirs provide a powerful tool to investigate the function of particular miRNAs. However, conventional methods to deliver antagomirs into cells (e.g. transfection) have been shown to only transiently interfere with endogenous miRNA expression and/or function. In this section, we describe a lentivirus-based system for stable antagomir expression to generate longterm loss-of-function phenotypes for individual miRNAs. Moreover, the described strategy is also suitable for studying the function of individual miRNAs encoded within polycistronic clusters.This chapter provides a collection of protocols to antagonize miRNA function by lentiviral antagomir expression, which can be achieved in a wide range of target cells. PMID- 20827539 TI - Solution structure of miRNA:mRNA complex. AB - The use of contemporary nuclear magnetic resonance (NMR) methods in the studies of model systems between microRNA (miRNA) and messenger RNA (mRNA) is reviewed. We describe our studies on structural features of 33-nt RNA model construct between let-7 miRNA and lin-41 mRNA at the second binding site. let-7 miRNA inhibits translation of lin-41 gene through formation of two complexes with the target sequence within 3' untranslated region of lin-41 mRNA in Caenorhabditis elegans. The base pairing, asymmetric internal loops, and adenine bulge in both the complementary sites are important for regulation of gene expression. NMR study on the uniformly (13)C- and (15)N-labeled RNA construct has shown that RNA molecule folds into a stable structure consisting of two stem regions separated by a well-defined asymmetric internal loop. Solution-state NMR can make important contribution toward deeper understanding of assembly, folding, and structural features of miRNA:mRNA complexes. PMID- 20827540 TI - MiRNA editing. AB - RNA editing by A-to-I modification is a widespread mechanism in complex organisms that leads to the posttranscriptional alteration of protein coding as well as noncoding sequences. MiRNA transcripts have been recognized as a major target for RNA editing enzymes, and single-nucleotide changes through editing can impact the biogenesis of mature miRNAs, as well as the target specificity of the regulatory RNA. Bona fide A-to-I RNA editing events are validated experimentally through parallel analysis of genomic DNA and transcribed sequences of miRNA genes isolated from the same specimen through gene-specific amplification and sequencing of endogenous transcripts. PMID- 20827541 TI - Computational prediction of microRNA targets. AB - One critical step in miRNA functional studies is to identify the gene targets that are directly regulated by miRNAs. In this chapter, we describe a computational algorithm and an online database, miRDB, for miRNA target prediction. In miRDB, flexible Web search interface has been developed for the retrieval of target prediction results generated by the newly developed computational algorithm. In addition, a wiki editing interface has been established to allow anyone with Internet access to make contributions on miRNA functional annotation. All data stored in miRDB are freely accessible at http://www.mirdb.org. PMID- 20827542 TI - Large-scale integration of MicroRNA and gene expression data for identification of enriched microRNA-mRNA associations in biological systems. AB - The discovery of microRNAs (miRNAs) revealed a hidden layer of gene regulation that is able to integrate multiple genes into biologically meaningful networks. A number of computational prediction programs have been developed to identify putative miRNA targets. Collectively, the miRNAs that have been discovered so far have the potential to target over 60% of genes in our genome. A minimum of six consecutive nucleotides in the 5'-seed (nucleotides 2-8) in the miRNA must bind through complimentary base pairing to the 3'-untranslated (3'-UTRs) of target genes. Given the small sequence match required, a given miRNA has the potential to target hundreds of genes and a given mRNA can have 0-50 miRNA binding sites. The low-throughput nature of the query design (gene by gene or miRNA by miRNA) and a fairly high rate of false positives and negatives uncovered by the limited number of functional studies remain as the major limitations. Programs that integrate genome-wide gene and miRNA expression data determined by microarray and/or next-generation sequencing (NGS) technologies with the publicly available target prediction algorithms are extremely valuable on two fronts. First, they allow the investigator to fully capitalize on all the data generated to reveal new genes and pathways underlying the biological process under study. Second, these programs allow the investigator to lift a small network of genes they are currently following into a larger network through the integrative properties of miRNAs. In this chapter, we discuss the latest methodologies for determining genome-wide miRNA and gene expression changes and three programs (Sigterms, CORNA, and MMIA) that allow the investigator to generate short lists of enriched miRNA:target mRNA candidates for large-scale miRNA:target mRNA validation. These efforts are essential for determining false positive and negative rates of existing algorithms and refining our knowledge on the rules of miRNA-mRNA relationships. PMID- 20827543 TI - Identification and validation of the cellular targets of virus-encoded microRNAs. AB - Since the identification of the first virus-encoded microRNA (miRNA) in Epstein Barr virus (EBV)-infected B cells in 2004, viral miRNAs have been found in different groups of herpesviruses. Viral miRNAs play an important role in regulating both viral and cellular gene expression. Identification and characterization of the cellular targets of viral miRNAs will not only advance our understanding of virus-cell interaction but might also reveal new strategies for the developments of antivirals. Our demonstration of the targeting of p53 upregulated modulator of apoptosis (PUMA) by an EBV-encoded viral miRNA provides one mechanism by which a viral miRNA facilitates viral replication by promoting cell survival. Using EBV miRNAs as an example, in this chapter, we detail the experimental procedures that can be used to identify and validate cellular targets of viral miRNAs. PMID- 20827544 TI - [Operative versus conservative treatment of non-displaced fractures of the scaphoid bone. Results of a controlled multicenter cohort study]. AB - PURPOSE: Within a prospective, multicenter cohort study we investigated whether operative treatment of scaphoid bone fractures leads to earlier return to previous activity levels. METHODS: Only isolated, acute, complete, stable and non displaced fractures of the mid-third of the scaphoid bone were included. A total of 94 patients with the same number of fractures were recruited. In the operative group, fractures were fixed with a cannulated screw and had postoperative splint immobilization for a maximum of 1 week. In the conservative group a short arm cast was applied until fracture union was achieved. Both groups were followed for 6 months. RESULTS: By 15 weeks patients receiving surgical treatment had returned significantly earlier to their full time work and home activities and achieved significantly better results for functional status, pain, and overall satisfaction. However, after screw fixation, complication rates concerning union and secondary operative management were higher. CONCLUSION: Operative treatment primarily facilitates earlier return to previous activity levels, as well as better functional status, less pain and higher patient satisfaction, but conservative treatment seems to be safer and associated with a lower complication rate. PMID- 20827545 TI - [Applications of free lateral arm flap for hand and forearm defect reconstruction]. AB - BACKGROUND: The purpose of this retrospective study was to verify the advantages and disadvantages of the free lateral arm flap for defect reconstruction of the forearm and hand. PATIENTS AND METHODS: The data of 21 patients who underwent defect coverage of the forearm and hand with the free lateral arm flap between 2002 and 2010 were analyzed. The mean patient age was 48 years (range 17-78 years). The results concerning defect origin, flap size, pedicle length, operative time, revision of the anastomosis or other complications, donor site morbidity and length of hospital stay were evaluated. RESULTS: In 6 cases the defect was on the forearm and in 15 on the hand. The majority of defects were infections or chronic wounds. The overage flap width ranged from 3 to 8 cm and the length from 5 to 20 cm. Revision of the anastomosis was only necessary in one case and flap survival rate was 100%. In all patients primary closure of the donor site was possible without complications during the healing procedure. CONCLUSION: The results underline the good reliability of the free lateral arm flap with a satisfactory aesthetic appearance excellent tissue quality and frequent primary donor site closure. PMID- 20827546 TI - [Platelet-rich plasma combined with autologous cancellous bone : An alternative therapy for persistent non-union?]. AB - BACKGROUND: In addition to a stabile osteosynthesis autologous cancellous bone graft remains an essential therapy option in persistent non-union. Despite this therapy regimen persistent non-union can occasionally occur. The aim of this study was to evaluate the treatment of persistent non-union with a combination of platelet-rich plasma (PRP) and autologous cancellous bone. MATERIAL AND METHODS: In this prospective study 17 patients with persistent non-union of long bones were treated by a combination of PRP and autologous iliac crest bone. Inclusion criteria were a minimum of one previously failed cancellous bone transplantation and an atrophic non-union persisting for 6-14 months (mean 9 months). The patients were examined clinically and radiologically at intervals of 3, 6 and 9 months postoperatively. RESULTS: After an average time of 17 months (range 15-23 months) the patients were treated by a combination of PRP and autologous cancellous bone. In all cases the non-union was successfully treated and osseous bridging was found radiologically after an average of 5 months (range 4-7 months) without any complications. CONCLUSION: The combination of PRP and autologous cancellous bone appears to be a safe and effective method for treatment of persistent non-union. The use of PRP does not result in substantial additional costs. Allergies and graft versus host reactions are not expected because of the autologous origin. PMID- 20827547 TI - Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. AB - In this study, 250 women with osteoporosis were randomized to 12 months with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly, then crossed over to the other treatment. The primary endpoint, treatment adherence at 12 months, was 76.6% for alendronate and 87.3% for denosumab. INTRODUCTION: The purpose of this study is to evaluate treatment adherence with subcutaneous denosumab 60 mg every 6 months or oral alendronate 70 mg once weekly. METHODS: In this multicenter, randomized, open-label, 2-year, crossover study, 250 postmenopausal women with low bone mineral density received denosumab or alendronate for 12 months, then the other treatment for 12 months. The alendronate bottle had a medication event monitoring system cap to monitor administration dates. Definitions were as follows: compliance, receiving both denosumab doses 6 (+/- 1) months apart or 80-100% of alendronate doses; persistence, receiving both denosumab doses and completing the month 12 visit within the visit window or >= 2 alendronate doses in the final month; adherence, achieving both compliance and persistence. This report includes data from the first 12 months. RESULTS: The primary study endpoint, adherence in the first 12 months, was 76.6% (95/124) for alendronate and 87.3% (110/126) for denosumab. Risk ratios for denosumab compared with alendronate at 12 months were 0.58 (p = 0.043) for non-adherence, 0.48 (p = 0.014) for non-compliance, and 0.54 (p = 0.049) for non-persistence. Subject ratings for treatment necessity, preference, and satisfaction were significantly greater for denosumab and ratings for treatment bother were significantly greater for alendronate. Adverse events were reported by 64.1% of alendronate-treated subjects and 72.0% of denosumab-treated subjects (p = 0.403). The most common adverse events were arthralgia, back pain, pain in extremity, cough, and headache (each in <10% of subjects in each group). CONCLUSIONS: Significantly greater treatment adherence was observed for subcutaneous administration of denosumab every 6 months than for oral alendronate once weekly. PMID- 20827548 TI - Variability in the measured response of bone to teriparatide. AB - Apparent failures of bone mineral density (BMD) response to teriparatide at spine or hip occur even in a high compliance context (15% spine and 55% hip). Apparent non-responders nevertheless show good biomarker response, suggesting that apparent BMD non-response is due to measurement imprecision. Calcium intake may be an important determinant of hip response. INTRODUCTION: Individuals vary in response to bone active agents, but that variability is poorly quantified and its basis is not well understood. The study included 203 postmenopausal women with moderately severe osteoporosis, all treated with teriparatide, calcium, and vitamin D. The study was performed at the Creighton University Medical Center, a single site. METHODS: This is a prospective study of change in bone mineral density and resorption biomarkers over a 12-month treatment period. BMD response at spine and total hip was quantified by computing slopes for each participant's values, and biomarker change by the difference in values across the 12-month study period. RESULTS: Of the total number of participants, 85.2% exhibited a significant spine BMD response, while only 44.8% had a significant change at the hip. However, mean biomarker response was marginally larger for the BMD non responders at either site than for the responders, indicating biological, if not measurable densitometric, activity of teriparatide in essentially all participants. CONCLUSIONS: Occasional apparent failures of BMD response in patients receiving teriparatide are probably not due to failure of response at the level of the bone remodeling apparatus, but instead reflect a combination of measurement imprecision and variable bone remodeling balance. The reason for the latter remains unclear. PMID- 20827549 TI - Bone size and density measurements in prepubertal children with Turner syndrome prior to growth hormone therapy. AB - Using computed tomography (CT), we found the decreases in bone size of vertebrae and femur, cortical bone area (CBA) of femur and bone density (BD) of vertebrae in prepubertal female with Turner syndrome (TS) compared to those of controls. INTRODUCTION: Bone mineral density results from previous studies utilizing single photon absorptiometry (SPA) or dual-energy X-ray absorptiometry (DXA) in children with TS are controversial. The present study used CT to assess the differences in cancellous and cortical bone size and BD between prepubertal TS patients prior to growth hormone therapy and historical age and ethnicity-matched female controls. METHODS: Anthropometrics and CT bone measurements including cross-sectional area (CSA) and BD of lumbar vertebrae and femur and CBA of femur in prepubertal TS females were reviewed and compared with those in controls. RESULTS: Twenty-two prepubertal TS patients had delayed bone age, were shorter and lighter than controls (Ps < 0.001). After adjusting for weight, height and skeletal age, vertebral BD and CBA of the femur were lower in patients than in controls (P < 0.001 and P = 0.021, respectively). However, after additional adjusting for puberty, results were not different from controls. While a positive correlation between vertebral BD and age was noted in controls (r = 0.367, P = 0.092), a significant negative correlation was noted in patients (r = -0.615, P = 0.002). CONCLUSIONS: While the decrease in vertebrae and femur sizes of patients with TS appeared to be secondary to their small body size, the decreased BD of vertebrae and CBA of femur were likely secondary to estrogen deficiency. PMID- 20827550 TI - Population pharmacokinetics of CPT-11 (irinotecan) in gastric cancer patients with peritoneal seeding after its intraperitoneal administration. AB - PURPOSE: It is well known that CPT-11 (irinotecan) is biotransformed to its active metabolite, SN-38, by carboxylesterase in the liver and other tissues. However, little is known about its pharmacokinetics (PK) when administered intraperitoneally. The aim of our study was to develop a population pharmacokinetic model for CPT-11 and SN-38 following the intraperitoneal (IP) administration of CPT-11. METHODS: Pharmacokinetic data obtained from 16 gastric adenocarcinoma patients with peritoneal seeding were used. Administered doses ranged from 50 to 250 mg/m(2). To measure CPT-11 and SN-38 levels, we collected samples of peritoneal fluid, plasma and urine 0, 0.5, 1.5, 2, 3.5, 8, 12, 25.5, 49 and 56 h after IP infusion. Several multicompartmental pharmacokinetic models were tested for CPT-11 and SN-38 in the sampled peritoneal fluid, plasma and urine. NONMEM ver. 6 was used throughout the model-building process. RESULTS: Peak concentrations were achieved earlier for peritoneal SN-38 than for plasma SN 38. The apparent metabolic clearance of peritoneal and plasma CPT-11 to peritoneal and plasma SN-38 accounted for 0.2 and 7.3% of the total clearance of peritoneal and plasma CPT-11, respectively. The typical values of steady-state volume of distribution (Vss) (46.6 L/m(2)), inter-compartment clearance (6.70 L/h/m(2)) and clearance (16.0 L/h/m(2)) for plasma CPT-11 were estimated in a two compartment PK model. CONCLUSIONS: Our results demonstrate that a small fraction of intraperitoneally administered CPT-11 was metabolized in situ to active SN-38 and that the Vss of plasma CPT-11 following IP administration in our patient cohort was lower than that estimated in previous reports following the intravenous administration of CPT-11. PMID- 20827551 TI - The flare phenomenon: still learning after 35 years. PMID- 20827552 TI - Alfacalcidol improves muscle power, muscle function and balance in elderly patients with reduced bone mass. AB - We investigated the effect of daily therapy with 1 mcg alfacalcidol (Doss((r)) TEVA/AWD-pharma) on muscle power, muscle function, balance performance and fear of falls in an open, multi-centered, uncontrolled, prospective study on a cohort of patients with reduced bone mass. Among the 2,097 participants, 87.1% were post menopausal women and 12.9% were men. Mean age was 74.8 years and mean body mass index (BMI) 26.3 kg/m2. A total of 75.3% of the study population had osteoporosis, 81% a diagnosis of "increased risk of falls" and 70.1% had a creatinine clearance (CrCl) of <65 ml/min. Participants underwent muscle function and muscle power tests at onset and after 3 and 6 months: the timed up and go test (TUG) and the chair rising test (CRT). At baseline and after 6 months, participants performed the tandem gait test (TGT) and filled out a questionnaire evaluating fear of falling. Successful performance in the muscle tests is associated with a significantly lower risk of falls and non-vertebral fractures in elderly patients (successful test performance: TUG <= 10 s (sec), CRT <= 10 s, TGT >= 8 steps). A significant improvement in the performance of the two muscle tests was proved already after 3 months of treatment with alfacalcidol and further increased by the end of the therapeutic intervention. There were significant increases in the number of participants able to successfully perform the tests: 24.6% at baseline and 46.3% at the end of trial for the TUG (P < 0.0001) and 21.7% at baseline and 44.2% at the end for the CRT test (P = 0.0001). The mean time used for the TUG was decreased by 3.0 s from the average onset value of 17.0 s and by 3.1 s from the initial average 16.5 s for the CRT. The percentage of participants able to perform the balance test (TGT) increased from 36.0% at onset to 58.6% at the end of the trial (P < 0.0001). An increased fear of falling was reduced by the end of the study in 74.4% of the patients. Throughout the study, there were 26 adverse drug reactions in 11 out of 2,097 patients (incidence 0.52%). No serious adverse drug reactions and no cases of hypercalcemia were documented. We conclude that treatment with alfacalcidol is safe, increases muscle power, muscle function and balance and reduces fear of falls. The significant improvement in the three muscle and balance tests and fear of falls may have a preventative effect on falls and fractures. We suggest that the quantitative risk tests used in this study could be reliable surrogate parameters for the risk of falls and fractures in elderly patients. PMID- 20827553 TI - The real additional value of FDG-PET in detecting the occult primary tumour in patients with cervical lymph node metastases of unknown primary tumour. PMID- 20827555 TI - Pleuropericarditis in a patient with inflammatory bowel disease: a case presentation and review of the literature. AB - Inflammatory bowel disease (IBD) can affect the lung parenchyma and airways. Rarely it involves the pleural space and pericardium, causing inflammatory exudative pleural and/or pericardial effusions. In this report, we describe a 76 year-old patient with recurrent sterile exudative pleuropericarditis that gradually responded to treatment with steroids, and we review the relevant literature. Thoracic serositis in patients with IBD can cause pleuritis, pericarditis, pleuropericarditis, or myopericarditis. This is a relatively rare presentation of the uncommon and probably underreported and underrecognized pulmonary extraintestinal manifestations of IBD. Pleuropericardial inflammatory disease and effusion can be directly related to IBD, its complications, associated infections, or the medications used to treat it. Serositis directly related to IBD is a diagnosis of exclusion. It is important to evaluate the pleural effusion and rule out other etiologies before making this diagnosis. Pleural or pericardial biopsies are rarely necessary, and probably show nonspecific acute and chronic inflammatory changes. Although the specific pathophysiology of pleuropericardial disease in patients with IBD remains unclear, the response to systemic steroids is usually adequate. PMID- 20827554 TI - Update of prognostic and predictive biomarkers in oropharyngeal squamous cell carcinoma: a review. AB - Oropharyngeal squamous cell carcinomas (OSCC) constitute about 5% of all cancers in the western world and the incidence and mortality rates of this tumor have shown little improvement over the last 30 years. Molecular targeted therapy, a promising strategy for the treatment of OSCC and other cancers, requires the understanding of specific molecular events of carcinogenesis and the different pathological, partly interrelated pathways. Extended knowledge of the prognostic or predictive value of molecular biomarkers in oropharyngeal cancer is necessary to allow a better characterization and classification of the tumor, improve the appraisal of clinical outcome and help to specify individual multimodal therapy with increased efficiency. This work affords an updated summary regarding recent data about tissue biomarkers in patients with OSCC, based on the six essential hallmarks of cancer described by Hanahan and Weinberg (Cell 100(1):57-70, 2000) providing the characterization of a malignant cell. PMID- 20827556 TI - Tau and 14-3-3 of genetic and sporadic Creutzfeldt-Jakob disease patients in Israel. AB - One of the largest clusters of genetic Creutzfeldt-Jakob disease (gCJD) is found among Jews of Libyan origin in Israel and is linked to the E200K mutation in PRNP (gCJDE200K). The aim of this study was to compare the levels of cerebrospinal fluid (CSF) biomarkers, Tau and 14-3-3 proteins, between gCJDE200K patients, sporadic CJD (sCJD) patients and non-CJD controls in Israel between the years 1996-2006. The levels of Tau and 14-3-3 proteins in CSF were measured by ELISA and immunoblotting, respectively. CSF Tau levels were similar in gCJDE200K and sCJD, both were significantly higher than in controls [1,107 +/- 470 pg/ml [33/46 (72%)] of the cases >1,000 pg/ml, 1,280 +/- 580 pg/ml [25/30 (83.3%)], and 354 +/ 338 pg/ml [17/243 (6.9%)], respectively, p < 0.001]. 14-3-3 was detected in CSF of 41/53 (77%) of each gCJDE200K and sCJD patients tested, but only in 70/417 (16.8%) of controls (p < 0.001). An inverse correlation was found between disease duration and Tau levels in both gCJDE200K and sCJD (r = -0.464 and r = -0.284). No difference was found in Tau or 14-3-3 between the various codon 129 genotypes. We conclude that CSF biomarkers, Tau and 14-3-3, may be used in the diagnosis in both patients' populations, presenting a similar sensitivity yet Tau assay having higher specificity. PMID- 20827557 TI - Neonatal sepsis following maternal amnionitis by Edwardsiella tarda: a case report and a review of the literature. AB - Edwardsiella tarda, a gram-negative bacterium, is a rare pathogen in the neonatal period. We present a term newborn that developed E. tarda septicemia following maternal amnionitis. The severe neurological outcome in this case, as well as in all other reported cases, highlights the need for meticulous neurological evaluation in neonates presenting with E. tarda septicemia even in the absence of bona fide meningitis. PMID- 20827558 TI - Perinatal outcome of illicit substance use in pregnancy--comparative and contemporary socio-clinical profile in the UK. AB - The aim of the study was to determine the contemporary socio-clinical profile and perinatal outcome of illicit substance use in pregnancy in a large UK city and compare with published literature. Cases were identified retrospectively from the 'cause for concern' referrals over 5 years (2003-2007). Data was collected on mother-infant pair from medical notes and laboratory records. Chi-square and Mann Whitney U tests were used where appropriate for statistical analysis. One hundred sixty-eight women were identified as using illicit substance in pregnancy. Smoking (97.4%), unemployment (85.4%) and single status (42.3%) were frequent. Besides controlled use of methadone, heroin, cannabis and benzodiazepines were the most commonly used drugs. Hepatitis C prevalence was high (29.9%) despite low antenatal screening rates (57.7%). Neonatal morbidity was related to prematurity (22.9%), small for dates (28.6%) and neonatal abstinence syndrome (NAS; 58.9%). By day 5 of life, 95.1% of the babies developing NAS and 96.1% of those requiring pharmacological treatment were symptomatic. Of the infants developing NAS, 31.7% required pharmacological treatment. A total of 82.5% babies went home with their mother, and 21.2% were placed on the Child Protection Register. Only 14.3% were breast feeding at discharge. Illicit substance use in pregnancy continues to be associated with significant maternal and neonatal morbidity, and the socio clinical profile in this decade appears unchanged in the UK. Hepatitis C prevalence is high, and detection should be improved through targeted antenatal screening. Where facility in the community is unavailable, 5 days of hospital stay is sufficient to safely identify babies at risk of developing NAS. Most babies were discharged home with their mother. PMID- 20827559 TI - Critical incidents in paediatric critical care: who is at risk? AB - We evaluated the characteristics of children for whom critical incidents (CIs) were reported by performing prospective collection of patient data and retrospective review of reported CIs in a multidisciplinary neonatal-paediatric intensive care unit of a tertiary care university children's hospital. A period of 1 year was analysed (January to December 2007; 1,251 admissions). CIs comprised adverse events (actual patient injury), as well as near-misses. The report form of critical incidents was web-based and reporting was voluntary, anonymous and non-punitive. The severity of all CIs was divided into minor, moderate and major. Patients with and without CIs were compared regarding the following characteristics: Paediatric Index of Mortality (PIM2), duration of mechanical ventilation, length of stay in the intensive care, admission mode (surgery, cardiopulmonary bypass, cardiac/non-cardiac unit), age and sex. There were 360 CI reports (83 per 1,000 patient days; 13% major, 26% moderate, 61% minor severity). Of these, 310 CIs could be assigned to 198 specific patients. In the univariate analysis, patient-related risk factors for CIs were higher PIM2 score (p < 0.0001), increased length of stay (p < 0.0001), mechanical ventilation (p < 0.0001), increased ventilator days (p < 0.0001), male gender (p = 0.022) and young age (p < 0.0001). Using a logistic regression model, mechanical ventilation (p < 0.0001), male gender (p = 0.034) and length of stay (p < 0.0001) continued to be associated with the occurrence of CIs. Conclusion CIs often occur in paediatric intensive care. Among the patient-related factors, male gender, mechanical ventilation, and length of stay are independently associated with CIs. Already known at admission to intensive care are male gender and, usually, requirement for mechanical ventilation. Improved knowledge of the risk factors for CIs could help to minimize their frequency and thus improve quality of care. PMID- 20827560 TI - Analysis of the cost-effectiveness of remifentanil-based general anesthesia: a survey of clinical economics under the Japanese health care system. AB - PURPOSE: Remifentanil has been available in Japan for 3 years. The use of this new opioid is considered a useful adjuvant to general anesthesia. Knowing the exact cost-effectiveness of remifentanil should lead to improved anesthetic outcomes with a reasonable cost. METHODS: This single-blinded, prospective, randomized study compared the cost of remifentanil-based general anesthesia combined with isoflurane, sevoflurane, or propofol with fentanyl-based conventional techniques in 210 women who underwent breast surgeries. RESULTS: Remifentanil-based general anesthesia was no more expensive than fentanyl-based conventional anesthesia. Postoperative nausea and vomiting was significantly less frequent after remifentanil-based than fentanyl-based anesthesia. CONCLUSION: This study shows that remifentanil-based general anesthesia is no more expensive than conventional fentanyl-based anesthesia under the Japanese health care system because of the small difference in price between remifentanil and fentanyl. PMID- 20827561 TI - Scrotal involvement in an adult with Henoch-Schonlein purpura. AB - Henoch-Schonlein purpura is a systemic vasculitis of unknown etiology usually affecting the pediatric age group and characterized by the clinical triad of non thrombocytopenic palpable purpura, abdominal pain, and arthritis. There also may be varying degrees of renal involvement. The findings of scrotal involvement are not as well recognized. We describe a case of acute scrotal swelling as part of a 37-year-old male's presentation of Henoch-Schonlein purpura, a presentation that has not been reported in this age group. PMID- 20827562 TI - A case of acute and severe thrombocytopenia due to readministration of rifampicin. AB - A 49-year-old-woman was diagnosed with tuberculosis of the left humerus. She had received treatment, including rifampicin, for tuberculosis 17 years previously. Treatment was begun with isoniazid, rifampicin, ethambutol, and pyrazinamide, but these were discontinued because of mild neutropenia and thrombocytopenia 2 weeks posttreatment. Rifampicin and ethambutol were readministered after a 4-day interruption; however, generalized purpura appeared several hours later. By the next day, her platelet count was reduced from 160 * 10(3) to 3 * 10(3)/MUl. The patient improved rapidly after platelet transfusion and steroid treatment. Readministration of drugs other than rifampicin did not induce thrombocytopenia; therefore, thrombocytopenia was likely due to rifampicin. PMID- 20827563 TI - Characteristic findings of pediatric inpatients with pandemic (H1N1) 2009 virus infection among severe and nonsevere illnesses. AB - We analyzed the clinical features of inpatients at a Japanese pediatric department who were infected with pandemic (H1N1) 2009 virus. Study participants included 46 children hospitalized from July 2009 to January 2010. Infection with the virus was confirmed using real-time reverse transcriptase polymerase chain reaction (RT-PCR). The epidemic month was October 2009; 34 patients were boys, and median age was 7 years. Pandemic influenza-associated respiratory diseases included pneumonia (n = 42), bronchitis (n = 3), and pharyngitis (n = 1). The median time from onset to admission was 3 days. Children were divided into those with severe (n = 32) versus nonsevere illnesses (n = 14) according to Japanese guidelines. Significant features in the severe group were younger age, previous asthmatic attack, exacerbation of asthma, decreased oxygen saturation, elevated white blood cell/neutrophil counts and serum lactate dehydrogenase, and longer times from admission to being afebrile and discharged. Both groups showed lymphopenia at admission. Additional infection with Streptococcus pneumoniae was frequent in the severe group. Whereas 44 patients received antiviral therapy (median times from onset to initiation 2 days), 32 received antibiotics (median duration 7 days). All children recovered, with a median hospital stay of 8 days. Our observations suggest that history of asthma and preschool age might be risk factors for severe illness. Prompt initiation of antiviral and antibiotic treatments should be considered to prevent development of severe illness. PMID- 20827564 TI - Predictive values of clinical parameters for severe Japanese spotted fever. AB - Japanese spotted fever (JSF) is severe and can progress to disseminated intravascular coagulation (DIC) with a poor prognosis. We considered whether patient factors are related to serious complications. Between August 1999 and March 2009, all patients with JSF and retrievable clinical data (age, gender, length of hospital stay, medication, comorbidities), vital signs (blood pressure, heart rate, temperature), and laboratory test results [blood cell count, liver function, renal function, electrolytes, blood sugar, C-reactive protein (CRP), CRP normalization period, and aspartate aminotransferase normalization period] from the Integrated Intelligent Management System (IIMS) database, were retrospectively analyzed by logistic regression. There were 51 JSF patients (24 men, 27 women) with a mean age of 63.0 years. Six patients (11.8%) had DIC, but there were no in-hospital deaths. The time between fever onset and initiation of medication was approximately 5 days, but this delay was not associated with disease severity. We identified values correlating with disease severity (p < 0.1) by univariate analysis and then applied logistic regression. We found renal dysfunction [serum creatinine (Cr) >= 1.5 mg/dl] at the time of initial presentation to be predictive of DIC. Cr was also predictive of a prolonged disease course. In patients with JSF, renal function must be carefully monitored when determining clinical management. PMID- 20827565 TI - Automatic detection of the existence of subarachnoid hemorrhage from clinical CT images. AB - Subarachnoid hemorrhage (SAH) is a medical emergency which can lead to death or severe disability. Misinterpretation of computed tomography (CT) in patients with SAH is a common problem. How to improve the accuracy of diagnosis is a great challenge to both the clinical physicians and medical researchers. In this paper we proposed a method for the automatic detection of SAH on clinical non-contrast head CT scans. The novelty includes approximation of the subarachnoid space in head CT using an atlas based registration, and exploration of support vector machine to the detection of SAH. The study included 60 patients with SAH and 69 normal controls from clinical hospitals. Thirty patients with SAH and 30 normal controls were used for training, while the rest were used for testing to achieve a testing sensitivity of 100% and specificity of 89.7%. The proposed algorithm might be a potential tool to screen the existence of SAH. PMID- 20827566 TI - Associating clinical archetypes through UMLS Metathesaurus term clusters. AB - Clinical archetypes are modular definitions of clinical data, expressed using standard or open constraint-based data models as the CEN EN13606 and openEHR. There is an increasing archetype specification activity that raises the need for techniques to associate archetypes to support better management and user navigation in archetype repositories. This paper reports on a computational technique to generate tentative archetype associations by mapping them through term clusters obtained from the UMLS Metathesaurus. The terms are used to build a bipartite graph model and graph connectivity measures can be used for deriving associations. PMID- 20827567 TI - 3D matrix pattern based Support Vector Machines for identifying pulmonary cancer in CT scanned images. AB - A novel algorithm of Three Dimension matrix (3D matrix) pattern based Minimum Within-Class Scatter Support Vector Machines (MCSVMs(3Dmatrix)) is presented. Combining Minimum Within-Class Scatter Support Vector Machines (MCSVMs) and higher-order tensor technology, decision functions of MCSVMs(3Dmatrix) are calculated along with three orthogonal directions in the 3D space. And then the final decision is made by Majority Vote Method. In previous reports, each CT image is solely processed and the relation among successive CT scanned images is neglected. The case results in defective judgment at whiles. The proposed method solves the problem effectively and improves the accuracy of classification to a certain extent. PMID- 20827568 TI - Critical factors influencing hospitals' adoption of HL7 version 2 standards: an empirical investigation. AB - Industry predictions focus on future e-hospitals that will integrate all stakeholders into a seamless network, allowing data to be shared. The Health Level Seven (HL7) is a standard for the interchange of data within the healthcare industry. It simplifies communication interfaces and allows the interoperability among heterogeneous applications. Although the benefits of adopting HL7 are well known, only a few hospitals in Taiwan have actually adopted it. What are the reasons behind the hospitals' lack of intention to adopt HL7? Most prior studies on HL7 have focused on technical issues and general overlooked the managerial side. This has caused a lack of understanding of factors influencing hospitals' decision on HL7 adoption. In fact, main reasons behind a hospital's decision on whether to adopt an innovative technology are more often related to organizational than purely technical issues. Hence, we pay our attention to these organizational considerations over HL7 adoption. Based on the Innovation Diffusion Theory, we proposed a research model to explore the critical factors influencing Taiwan hospitals' adoption intention of HL7. 472 questionnaires were distributed to all accredited hospitals in Taiwan and 122 were returned. The valid response rate was 25.21% (119). Factor analysis, logistic regression and Pearson Chi-square test were conducted to verify the research model. The results showed that environmental pressure, top management attitude towards HL7, staff's technology capability, system integrity, and hospital's scale were critical factors influencing hospitals' intention on whether to adopt HL7. The research findings provided the government, the healthcare industry, the hospital administrators and the academia with practical and theoretical references. These factors should be considered in planning promotion plan to encourage hospital adoption of HL7. This study also opens up a new research direction as well as a new viewpoint, and consequentially improves the completeness of related researches in the medical informatics discipline. PMID- 20827569 TI - A mobile Nursing Information System based on human-computer interaction design for improving quality of nursing. AB - A conventional Nursing Information System (NIS), which supports the role of nurse in some areas, is typically deployed as an immobile system. However, the traditional information system can't response to patients' conditions in real time, causing delays on the availability of this information. With the advances of information technology, mobile devices are increasingly being used to extend the human mind's limited capacity to recall and process large numbers of relevant variables and to support information management, general administration, and clinical practice. Unfortunately, there have been few studies about the combination of a well-designed small-screen interface with a personal digital assistant (PDA) in clinical nursing. Some researchers found that user interface design is an important factor in determining the usability and potential use of a mobile system. Therefore, this study proposed a systematic approach to the development of a mobile nursing information system (MNIS) based on Mobile Human Computer Interaction (M-HCI) for use in clinical nursing. The system combines principles of small-screen interface design with user-specified requirements. In addition, the iconic functions were designed with metaphor concept that will help users learn the system more quickly with less working-memory. An experiment involving learnability testing, thinking aloud and a questionnaire investigation was conducted for evaluating the effect of MNIS on PDA. The results show that the proposed MNIS is good on learning and higher satisfaction on symbol investigation, terminology and system information. PMID- 20827570 TI - PKI security in large-scale healthcare networks. AB - During the past few years a lot of PKI (Public Key Infrastructures) infrastructures have been proposed for healthcare networks in order to ensure secure communication services and exchange of data among healthcare professionals. However, there is a plethora of challenges in these healthcare PKI infrastructures. Especially, there are a lot of challenges for PKI infrastructures deployed over large-scale healthcare networks. In this paper, we propose a PKI infrastructure to ensure security in a large-scale Internet-based healthcare network connecting a wide spectrum of healthcare units geographically distributed within a wide region. Furthermore, the proposed PKI infrastructure facilitates the trust issues that arise in a large-scale healthcare network including multi-domain PKI infrastructures. PMID- 20827571 TI - A basic study on application of voice recognition input to an electronic nursing record system -evaluation of the function as an input interface-. AB - As computerization in the nursing field has been recently progressing, an electronic nursing record system is gradually introduced in the medical institution in Japan. Although it is expected for the electronic nursing record system to reduce the load of nursing work, the conventional keyboard operation is used for information input of the present electronic nursing record system and it has some problems concerning the input time and the operationability for common nurses who are unfamiliar with the computer operation. In the present study, we conducted a basic study on application of voice recognition input to an electronic nursing record system. The voice input is recently introduced to an electronic medical record system in a few clinics. However, so far the entered information cannot be processed because the information of the medical record must be entered as a free sentence. Therefore, we contrived a template for an electronic nursing record system and introduced it to the system for simple information entry and easy processing of the entered information in this study. Furthermore, an input experiment for evaluation of the voice input with the template was carried out by voluntary subjects for evaluation of the function as an input interface of an electronic nursing record system. The results of the experiment revealed that the input time by the voice input is obviously fast compared with that by the keyboard input and operationability of the voice input was superior to the keyboard input although all subjects had inexperience of the voice input. As a result, it was suggested our method, the voice input using the template made by us, might be useful for an input interface of an electronic nursing record system. PMID- 20827572 TI - A single spiking neuron that can represent interval timing: analysis, plasticity and multi-stability. AB - The ability to represent interval timing is crucial for many common behaviors, such as knowing whether to stop when the light turns from green to yellow. Neural representations of interval timing have been reported in the rat primary visual cortex and we have previously presented a computational framework describing how they can be learned by a network of neurons. Recent experimental and theoretical results in entorhinal cortex have shown that single neurons can exhibit persistent activity, previously thought to be generated by a network of neurons. Motivated by these single neuron results, we propose a single spiking neuron model that can learn to compute and represent interval timing. We show that a simple model, reduced analytically to a single dynamical equation, captures the average behavior of the complete high dimensional spiking model very well. Variants of this model can be used to produce bi-stable or multi-stable persistent activity. We also propose a plasticity rule by which this model can learn to represent different intervals and different levels of persistent activity. PMID- 20827573 TI - HIV/AIDS stigma and refusal of HIV testing among pregnant women in rural Kenya: results from the MAMAS Study. AB - HIV/AIDS stigma is a common thread in the narratives of pregnant women affected by HIV/AIDS globally and may be associated with refusal of HIV testing. We conducted a cross-sectional study of women attending antenatal clinics in Kenya (N = 1525). Women completed an interview with measures of HIV/AIDS stigma and subsequently information on their acceptance of HIV testing was obtained from medical records. Associations of stigma measures with HIV testing refusal were examined using multivariate logistic regression. Rates of anticipated HIV/AIDS stigma were high-32% anticipated break-up of their relationship, and 45% anticipated losing their friends. Women who anticipated male partner stigma were more than twice as likely to refuse HIV testing, after adjusting for other individual-level predictors (OR = 2.10, 95% CI: 1.15-3.85). This study demonstrated quantitatively that anticipations of HIV/AIDS stigma can be barriers to acceptance of HIV testing by pregnant women and highlights the need to develop interventions that address pregnant women's fears of HIV/AIDS stigma and violence from male partners. PMID- 20827574 TI - Pseudonocardia sichuanensis sp. nov., a novel endophytic actinomycete isolated from the root of Jatropha curcas L. AB - A novel isolate, designated strain KLBMP 1115(T) was isolated from the surface sterilized root of oil-seed plant Jatropha curcas L. collected from Sichuan Province, south-west China. Characterization of the isolate was based on a polyphasic approach. 16S rRNA gene sequence analysis indicated that strain KLBMP 1115(T) belongs to the phylogenetic cluster of the genus Pseudonocardia and was most closely related to Pseudonocardia adelaidensis EUM 221(T) (98.9%) and Pseudonocardia zijingensis DSM 44774(T) (98.6%), whereas the DNA-DNA relatedness values between strain KLBMP 1115(T) and the two type strains were 47.3 and 39.7%, respectively. Levels of lower similarities to the type strains of other recognized Pseudonocardia species ranged from 94.4 to 98.4%. The diagnostic diamino acid in the cell-wall peptidoglycan was meso-diaminopimelic acid. The predominant respiratory quinone was MK-8(H(4)). The major fatty acids of strain KLBMP 1115(T) was iso-C(16:0). The chemotaxonomic properties of strain KLBMP 1115(T) were consistent with those shared by members of the genus Pseudonocardia. On the basis of the phenotypic features and the DNA-DNA hybridization data, strain KLBMP 1115(T) represents a novel species of the genus Pseudonocardia, for which the name Pseudonocardia sichuanensis sp. nov. is proposed. The type strain is KLBMP 1115(T) (=KCTC 19781(T) = CCTCC AA 2010002(T)). PMID- 20827575 TI - Targeted therapies on the horizon for malignant glioma. PMID- 20827576 TI - Potential benefit of resection for stage IV gastric cancer: a national survey. AB - INTRODUCTION: Controversy exists as to whether patients with stage IV gastric cancer should undergo surgical resection. We examined the association of gastrectomy with survival in this population. METHODS: Stage IV gastric cancer diagnoses were identified using the SEER database (1988-2005). Analyses examined three subgroups divided on the basis of whether cancer-directed surgery was recommended and performed. Univariate analyses included chi-square and Kaplan Meier survival analyses. Cox proportional hazards modeling was performed to assess independent determinants of survival. RESULTS: Of 66,751 identified gastric cancer patients, 23,830 had stage IV disease. Resected patients had a significant survival advantage; survival outcomes of patients who had been recommended for, but had not undergone, surgery were identical to that of patients who had not been recommended (3 months vs. 9 months for resected, p < 0.0001). Furthermore, resection status was the most significant independent predictor of increased risk of death (hazard ratios 2.0 for non-cancer-directed surgery groups). CONCLUSIONS: Patients with stage IV gastric cancer who undergo resection, a highly selected population, have significantly greater survival than unresected patients, including those who were recommended for, but did not receive, resection. Stage IV gastric cancer patients who are reasonable operative candidates should be offered resection. PMID- 20827577 TI - TNF-alpha induces vectorial secretion of IL-8 in Caco-2 cells. AB - INTRODUCTION: Intestinal epithelial cells represent an important component of innate immunity, with sophisticated responses to inflammatory stimuli. The manner in which intestinal epithelial cell polarity affects responses to inflammatory stimuli is largely unknown. We hypothesized that polarized intestinal epithelial cells exhibit a bidirectional inflammatory response dependent upon the location of the stimulus. METHODS: Caco-2 cells were grown on semi-permeable inserts in a dual-compartment culture system and treated with tumor necrosis factor-alpha (TNF alpha; 100 ng/ml) or serum-free media in the apical or basolateral chamber. Interleukin-8 (IL-8) production in each chamber was measured by enzyme-linked immunosorbent assay. To determine receptor specificity, anti-TNF receptor antibodies were added to the apical or basolateral chamber. RESULTS: Basolateral stimulation with TNF-alpha resulted in increased apical and basolateral IL-8 production. Apical TNF-alpha stimulation resulted in increased apical, but not basolateral IL-8 production. Receptor blockade suggested TNF receptor 1 involvement on both apical and basolateral membranes, while TNF receptor 2 was only active on the apical membrane. CONCLUSION: Polarized intestinal epithelial cells respond to TNF-alpha stimulation with focused, directional secretion of the proinflammatory cytokine IL-8. These findings are important because they suggest that intestinal epithelial cells are capable of organizing their response to inflammatory signals and producing inflammatory mediators in a bidirectional, vectorial fashion. PMID- 20827578 TI - Whether drainage should be used after surgery for breast cancer? A systematic review of randomized controlled trials. AB - A systematic review of randomized controlled trials (RCTs) was conducted to evaluate whether patients benefit from the suction drainage after axillary lymph node dissection (ALND) in breast cancer surgery. RCTs of drainage versus no drainage after ALND in women with breast cancer were retrieved from PubMed, EMBASE, Cochrane Library and Chinese Biomedical database. Two authors independently assessed the quality of included trials and extracted data. Odds ratio (OR) for dichotomous outcomes and mean difference (MD) for continuous outcomes were presented with 95% confidence intervals (CI). A total of 1115 titles were indentified from the databases; 1109 obvious irrelevant studies were excluded by examining the titles, abstracts, full texts because of duplicates, no RCT, different modality of drainage, drain for lymphedema, application of fibrin sealant and so on. And then, only 6 RCTs to compare drainage with no drainage after ALND in breast cancer surgery were included in the systematic review and a total of 585 patients were included in the pathological diagnosis of breast cancer in women before surgery, management by ALND with or without addition surgical procedures. The study demonstrated that insertion of a drain in the axilla after breast cancer surgery resulted in a statistically significant reduction in the rate of seroma (OR = 0.36, 95% CI, 0.16 to 0.81, P = 0.01), the volume of aspiration (MD = -100.10, 95% CI, -174.36 to -25.85, P = 0.008), or the frequency of seroma aspiration (MD = -1.03, 95% CI, -1.35 to -0.71, P < 0.00001), but prolonged the length of hospital stay (MD = 1.52, 95% CI, 0.36 to 2.68, P = 0.01). There was no statistically significant difference in the incidence of wound infection (OR = 0.67, 95% CI, 0.34 to 1.32, P = 0.25) between drainage group and no drainage group. Based on the current evidence, insertion of a drain in the axilla following ALND in breast cancer surgery effectively decreased seroma formation, volume of aspiration as well as the frequency of seroma aspiration without increasing the incidence of wound infection, but extending their stay in hospital. PMID- 20827579 TI - Clear cell odontogenic carcinoma: report of 6 cases and review of the literature. AB - Clear cell odontogenic carcinoma (CCOC) is a rare malignant tumor. To date, only 67 cases were described in the English literature and complete understanding of the behavior of CCOC was based on limited case reports. In this article, we reported 6 additional cases and reviewed the relevant literature. Our cases included 4 men and 2 women with an average age of 52.8 years. The tumors were all in the mandible and presented as poorly marginated radiolucencies. Patients were treated with resection. All cases consisted of islands and sheets of clear cells that were separated by fibrous septa. Immunohistochemically, the tumor cells were positive for pan-cytokeratins, CK14, CK19, and epithelial membrane antigen, but negative for S-100 protein, smooth muscle actin, desmin, human melanoma antigen, CD3, CD45, and glial fibrillary acidic protein. A series of literature review disclosed the tumor has a female preponderance (44 female vs. 23 male, 1.9:1). The mean age was 54.5 years and the predominant site was the mandible (51, 76.1%). Forty-seven (70.1%) patients were initially treated with surgical resection, 15 (22.4%) patients underwent curettage or enucleation, and 1 patient was treated with chemotherapy. Nine patients had a neck dissection in addition to a surgical resection. Seven (9.6%) patients received postoperative radiotherapy. The recurrence rate after resection was lower than conservative therapy (29 vs. 86.7%). Nine patients died of the tumor. CCOC is a potentially aggressive lesion and owing to a high recurrent rate of conservative measure; therefore, radical surgical treatment is recommended and long-term follow-up is necessary. PMID- 20827581 TI - The University of California-Davis methodology for deriving aquatic life pesticide water quality criteria. PMID- 20827582 TI - An overview of the computational analyses and discovery of transcription factor binding sites. AB - Here we provide a pragmatic, high-level overview of the computational approaches and tools for the discovery of transcription factor binding sites. Unraveling transcription regulatory networks and their malfunctions such as cancer became feasible due to recent stellar progress in experimental techniques and computational analyses. While predictions of isolated sites still pose notorious challenges, cis-regulatory modules (clusters) of binding sites can now be identified with high accuracy. Further support comes from conserved DNA segments, co-regulation, transposable elements, nucleosomes, and three-dimensional chromosomal structures. We introduce computational tools for the analysis and interpretation of chromatin immunoprecipitation, next-generation sequencing, SELEX, and protein-binding microarray results. Because immunoprecipitation produces overly large DNA segments and well over half of the sequencing reads from constitute background noise, methods are presented for background correction, sequence read mapping, peak calling, false discovery rate estimation, and co-localization analyses. To discover short binding site motifs from extensive immunoprecipitation segments, we recommend algorithms and software based on expectation maximization and Gibbs sampling. Data integration using several databases further improves performance. Binding sites can be visualized in genomic and chromatin context using genome browsers. Binding site information, integrated with co-expression in large compendia of gene expression experiments, allows us to reveal complex transcriptional regulatory networks. PMID- 20827583 TI - Components and mechanisms of regulation of gene expression. AB - The control of gene expression is a biological process essential to all organisms. This is accomplished through the interaction of regulatory proteins with specific DNA motifs in the control regions of the genes that they regulate. Upon binding to DNA, and through specific protein-protein interactions, these regulatory proteins convey signals to the basal transcriptional machinery, containing the respective RNA polymerases, resulting in particular rates of gene expression. In eukaryotes, in addition and complementary to the binding of regulatory proteins to DNA, chromatin structure plays a role in modulating gene expression. Small RNAs are emerging as key components in this process. This chapter provides an introduction to some of the basic players participating in these processes, the transcription factors and co-regulators, the cis-regulatory elements that often function as transcription factor docking sites, and the emerging role of small RNAs in the regulation of gene expression. PMID- 20827584 TI - Regulatory regions in DNA: promoters, enhancers, silencers, and insulators. AB - One of the mechanisms through which protein levels in the cell are controlled is through transcriptional regulation. Certain regions, called cis-regulatory elements, on the DNA are footprints for the trans-acting proteins involved in transcription, either for the positioning of the basic transcriptional machinery or for the regulation - in simple terms turn on or turn off - thereof. The basic transcriptional machinery is DNA-dependent RNA polymerase (RNAP) which synthesizes various types of RNA and core promoters on the DNA are used to position the RNAP. Other nearby regions will regulate the transcription: in prokaryotic organisms operators are involved; in eukaryotic organisms, proximal promoter regions, enhancers, silencers, and insulators are present. This chapter will describe the various DNA regions involved in transcription and transcriptional regulation. PMID- 20827585 TI - Three-dimensional structures of DNA-bound transcriptional regulators. AB - Our understanding of the detailed mechanisms of specific promoter/enhancer DNA binding site recognition by transcriptional regulatory factors is primarily based on three-dimensional structural studies using the methods of X-ray crystallography and NMR. Vast amount of accumulated experimental data have revealed the basic principles of protein-DNA complex formation paving the way for better modeling and prediction of DNA-binding properties of transcription factors. In this review, our intent is to provide a general overview of the three dimensional structures of DNA-bound transcriptional regulators starting from the basic principles of specific DNA recognition and ending with high-order multiprotein-DNA complexes. PMID- 20827586 TI - Identification of promoter regions and regulatory sites. AB - Promoter sequences are the main regulatory elements of gene expression. Their recognition by computer algorithms is fundamental for understanding gene expression patterns, cell specificity and development. This chapter describes the advanced approaches to identify promoters in animal, plant and bacterial sequences. Also, we discuss an approach to identify statistically significant regulatory motifs in genomic sequences. PMID- 20827587 TI - Motif discovery using expectation maximization and Gibbs' sampling. AB - Expectation maximization and Gibbs' sampling are two statistical approaches used to identify transcription factor binding sites and the motif that represents them. Both take as input unaligned sequences and search for a statistically significant alignment of putative binding sites. Expectation maximization is deterministic so that starting with the same initial parameters will always converge to the same solution, making it wise to start it multiple times from different initial parameters. Gibbs' sampling is stochastic so that it may arrive at different solutions from the same initial parameters. In both cases multiple runs are advised because comparisons of the solutions after each run can indicate whether a global, optimum solution is likely to have been achieved. PMID- 20827588 TI - Probabilistic approaches to transcription factor binding site prediction. AB - Many different computer programs for the prediction of transcription factor binding sites have been developed over the last decades. These programs differ from each other by pursuing different objectives and by taking into account different sources of information. For methods based on statistical approaches, these programs differ at an elementary level from each other by the statistical models used for individual binding sites and flanking sequences and by the learning principles employed for estimating the model parameters. According to our experience, both the models and the learning principles should be chosen with great care, depending on the specific task at hand, but many existing programs do not allow the user to choose them freely. Hence, we developed Jstacs, an object oriented Java framework for sequence analysis, which allows the user to combine different statistical models and different learning principles in a modular manner with little effort. In this chapter we explain how Jstacs can be used for the recognition of transcription factor binding sites. PMID- 20827589 TI - The Motif Tool Assessment Platform (MTAP) for sequence-based transcription factor binding site prediction tools. AB - Predicting transcription factor binding sites (TFBS) from sequence is one of the most challenging problems in computational biology. The development of (semi )automated computer-assisted prediction methods is needed to find TFBS over an entire genome, which is a first step in reconstructing mechanisms that control gene activity. Bioinformatics journals continue to publish diverse methods for predicting TFBS on a monthly basis. To help practitioners in deciding which method to use to predict for a particular TFBS, we provide a platform to assess the quality and applicability of the available methods. Assessment tools allow researchers to determine how methods can be expected to perform on specific organisms or on specific transcription factor families. This chapter introduces the TFBS detection problem and reviews current strategies for evaluating algorithm effectiveness. In this chapter, a novel and robust assessment tool, the Motif Tool Assessment Platform (MTAP), is introduced and discussed. PMID- 20827590 TI - Computational analysis of ChIP-seq data. AB - Chromatin immunoprecipitation followed by massively parallel sequencing (ChIP seq) is a new technology to map protein-DNA interactions in a genome. The genome wide transcription factor binding site and chromatin modification data produced by ChIP-seq provide invaluable information for studying gene regulation. This chapter reviews basic characteristics of ChIP-seq data and introduces a computational procedure to identify protein-DNA interactions from ChIP-seq experiments. PMID- 20827591 TI - Probabilistic peak calling and controlling false discovery rate estimations in transcription factor binding site mapping from ChIP-seq. AB - Localizing the binding sites of regulatory proteins is becoming increasingly feasible and accurate. This is due to dramatic progress not only in chromatin immunoprecipitation combined by next-generation sequencing (ChIP-seq) but also in advanced statistical analyses. A fundamental issue, however, is the alarming number of false positive predictions. This problem can be remedied by improved peak calling methods of twin peaks, one at each strand of the DNA, kernel density estimators, and false discovery rate estimations based on control libraries. Predictions are filtered by de novo motif discovery in the peak environments. These methods have been implemented in, among others, Valouev et al.'s Quantitative Enrichment of Sequence Tags (QuEST) software tool. We demonstrate the prediction of the human growth-associated binding protein (GABPalpha) based on ChIP-seq observations. PMID- 20827592 TI - Sequence analysis of chromatin immunoprecipitation data for transcription factors. AB - Chromatin immunoprecipitation (ChIP) experiments allow the location of transcription factors to be determined across the genome. Subsequent analysis of the sequences of the identified regions allows binding to be localized at a higher resolution than can be achieved by current high-throughput experiments without sequence analysis and may provide important insight into the regulatory programs enacted by the protein of interest. In this chapter we review the tools, workflow, and common pitfalls of such analyses and recommend strategies for effective motif discovery from these data. PMID- 20827593 TI - Inferring protein-DNA interaction parameters from SELEX experiments. AB - Systematic Evolution of Ligands by EXponential enrichment (SELEX) is an experimental procedure that allows extraction, from an initially random pool of oligonucleotides, of the oligomers with a high binding affinity for a given molecular target. The highest affinity binding sequences isolated through SELEX can have numerous research, diagnostic, and therapeutic applications. Recently, important new modifications of the SELEX protocol have been proposed. In particular, a suitably modified SELEX experiment, together with an appropriate computational procedure, allows inference of protein-DNA interaction parameters with up to now unprecedented accuracy. Such inference is possible even when there is no a priori information on transcription factor binding specificity, which allows accurate predictions of binding sites for any transcription factor of interest. In this chapter we discuss how to accurately determine protein-DNA interaction parameters from SELEX experiments. The chapter addresses experimental and computational procedure needed to generate and analyze appropriate data. PMID- 20827594 TI - Kernel-based identification of regulatory modules. AB - The challenge of identifying cis-regulatory modules (CRMs) is an important milestone for the ultimate goal of understanding transcriptional regulation in eukaryotic cells. It has been approached, among others, by motif-finding algorithms that identify overrepresented motifs in regulatory sequences. These methods succeed in finding single, well-conserved motifs, but fail to identify combinations of degenerate binding sites, like the ones often found in CRMs. We have developed a method that combines the abilities of existing motif finding with the discriminative power of a machine learning technique to model the regulation of genes (Schultheiss et al. (2009) Bioinformatics 25, 2126-2133). Our software is called KIRMES: , which stands for kernel-based identification of regulatory modules in eukaryotic sequences. Starting from a set of genes thought to be co-regulated, KIRMES: can identify the key CRMs responsible for this behavior and can be used to determine for any other gene not included on that list if it is also regulated by the same mechanism. Such gene sets can be derived from microarrays, chromatin immunoprecipitation experiments combined with next generation sequencing or promoter/whole genome microarrays. The use of an established machine learning method makes the approach fast to use and robust with respect to noise. By providing easily understood visualizations for the results returned, they become interpretable and serve as a starting point for further analysis. Even for complex regulatory relationships, KIRMES: can be a helpful tool in directing the design of biological experiments. PMID- 20827595 TI - Identification of transcription factor binding sites derived from transposable element sequences using ChIP-seq. AB - Transposable elements (TEs) form a substantial fraction of the non-coding DNA of many eukaryotic genomes. There are numerous examples of TEs being exapted for regulatory function by the host, many of which were identified through their high conservation. However, given that TEs are often the youngest part of a genome and typically exhibit a high turnover, conservation-based methods will fail to identify lineage- or species-specific exaptations. ChIP-seq has become a very popular and effective method for identifying in vivo DNA-protein interactions, such as those seen at transcription factor binding sites (TFBS), and has been used to show that there are a large number of TE-derived TFBS. Many of these TE derived TFBS show poor conservation and would go unnoticed using conservation screens. Here, we describe a simple pipeline method for using data generated through ChIP-seq to identify TE-derived TFBS. PMID- 20827596 TI - Target gene identification via nuclear receptor binding site prediction. AB - In spite of numerous advances in recent years, the complete list of direct target genes for nuclear receptors remains elusive. The integrated application of new computational and experimental methods reviewed in this chapter provides insight into the complex network of regulatory pathways mediated by nuclear receptors which is expected to improve the understanding of the physiology and the pathology of metabolism, development, homeostasis, and other fundamental processes. PMID- 20827597 TI - Computing chromosome conformation. AB - The "Chromosome Conformation Capture" (3C) and 3C-related technologies are used to measure physical contacts between DNA segments at high resolution in vivo. 3C studies indicate that genomes are likely organized into dynamic networks of physical contacts between genes and regulatory DNA elements. These interactions are mediated by proteins and are important for the regulation of genes. For these reasons, mapping physical connectivity networks with 3C-related approaches will be essential to fully understand how genes are regulated. The 3C-Carbon Copy (5C) technology can be used to measure chromatin contacts genome-scale within (cis) or between (trans) chromosomes. Although unquestionably powerful, this approach can be challenging to implement without proper understanding and application of publicly available bioinformatics tools. This chapter explains how 5C studies are performed and describes stepwise how to use currently available bioinformatics tools for experimental design, data analysis, and interpretation. PMID- 20827598 TI - Large-scale identification and analysis of C-proteins. AB - The restriction-modification system is a toxin-antitoxin mechanism of bacterial cells to resist phage attacks. High efficiency comes at a price of high maintenance costs: (1) a host cell dies whenever it loses restriction modification genes and (2) whenever a plasmid with restriction-modification genes enters a naive cell, modification enzyme (methylase) has to be expressed prior to the synthesis of the restriction enzyme (restrictase) or the cell dies. These phenomena imply a sophisticated regulatory mechanism. During the evolution several such mechanisms were developed, of which one relies on a special C(control)-protein, a short autoregulatory protein containing an HTH-domain. Given the extreme diversity among restriction-modification systems, one could expect that C-proteins had evolved into several groups that might differ in autoregulatory binding sites architecture. However, only a few C-proteins (and the corresponding binding sites) were known before this study. Bioinformatics studies applied to C-proteins and their binding sites were limited to groups of well-known C-proteins and lacked systematic analysis. In this work, the authors use bioinformatics techniques to discover 201 C-protein genes with predicted autoregulatory binding sites. The systematic analysis of the predicted sites allowed for the discovery of 10 structural classes of binding sites. PMID- 20827599 TI - Evolution of cis-regulatory sequences in Drosophila. AB - Cross-species comparison is an emerging paradigm for identifying cis-regulatory sequences and understanding their function and evolution. In this chapter, we review probabilistic models of evolution of transcription factor binding sites, which provide the theoretical basis for a number of new bioinformatics tools for comparative sequence analysis. We illustrate how important functional and evolutionary insights on binding site gain and loss can be acquired through sequence comparison. This includes the observation that binding site turnover follows a molecular clock and that its rate correlates with the strength of binding sites and the presence of other sites in the neighborhood. We also comment on emerging trends that go beyond individual binding sites to a more holistic study of regulatory evolution. We point out common technical challenges, such as reliable sequence alignment and binding site prediction, when doing comparative regulatory sequence analysis and note some potential solutions thereof. PMID- 20827600 TI - Regulating the regulators: modulators of transcription factor activity. AB - Gene transcription is largely regulated by DNA-binding transcription factors (TFs). However, the TF activity itself is modulated via, among other things, post translational modifications (PTMs) by specific modification enzymes in response to cellular stimuli. TF-PTMs thus serve as "molecular switchboards" that map upstream signaling events to the downstream transcriptional events. An important long-term goal is to obtain a genome-wide map of "regulatory triplets" consisting of a TF, target gene, and a modulator gene that specifically modulates the regulation of the target gene by the TF. A variety of genome-wide data sets can be exploited by computational methods to obtain a rough map of regulatory triplets, which can guide directed experiments. However, a prerequisite to developing such computational tools is a systematic catalog of known instances of regulatory triplets. We first describe PTM-Switchboard, a recent database that stores triplets of genes such that the ability of one gene (the TF) to regulate a target gene is dependent on one or more PTMs catalyzed by a third gene, the modifying enzyme. We also review current computational approaches to infer regulatory triplets from genome-wide data sets and conclude with a discussion of potential future research. PTM-Switchboard is accessible at http://cagr.pcbi.upenn.edu/PTMswitchboard / PMID- 20827601 TI - Annotating the regulatory genome. AB - Determining the timing and molecular repertoire responsible for gene expression is fundamental to understanding a gene's function. Heritable differences in this character are increasingly regarded as explanatory for complex and common traits. For many known trait-predisposing genes, studies have sought to elucidate the associated logic behind gene regulation. However, there exist many challenges in deciphering these mechanisms. Among them, it is recognized that we have limited understanding of regulatory complexity, the current models of gene regulation have low specificity and any gene's regulatory logic is dependent on biological context. Addressing these limitations and defining the regulatory genome is an ongoing challenge for molecular biology. We discuss current efforts to define and annotate the regulatory genome by focusing on curation and text-mining activities. We further highlight the type of information and curation process for describing regulatory elements within the ORegAnno database ( www.oreganno.org ) and how the general standards for such information are changing. PMID- 20827602 TI - Computational identification of plant transcription factors and the construction of the PlantTFDB database. AB - Transcription factors (TFs) play an important role in gene regulation. Computational identification and annotation of TFs at genome scale are the first step toward understanding the mechanism of gene expression and regulation. We started to construct the database of Arabidopsis TFs in 2005 and developed a pipeline for systematic identification of plant TFs from genomic and transcript sequences. In the following years, we built a database of plant TFs (PlantTFDB, http://planttfdb.cbi.pku.edu.cn ) which contains putative TFs identified from 22 species including five model organisms and 17 economically important plants with available EST sequences. To provide comprehensive information for the putative TFs, we made extensive annotation at both the family and gene levels. A brief introduction and key references were presented for each family. Functional domain information and cross-references to various well-known public databases were available for each identified TF. In addition, we predicted putative orthologs of the TFs in other species. PlantTFDB has a simple interface to allow users to make text queries, or BLAST searches, and to download TF sequences for local analysis. We hope that PlantTFDB could provide the user community with a useful resource for studying the function and evolution of transcription factors. PMID- 20827603 TI - Practical computational methods for regulatory genomics: a cisGRN-Lexicon and cisGRN-browser for gene regulatory networks. AB - The CYRENE Project focuses on the study of cis-regulatory genomics and gene regulatory networks (GRN) and has three components: a cisGRN-Lexicon, a cisGRN Browser, and the Virtual Sea Urchin software system. The project has been done in collaboration with Eric Davidson and is deeply inspired by his experimental work in genomic regulatory systems and gene regulatory networks. The current CYRENE cisGRN-Lexicon contains the regulatory architecture of 200 transcription factors encoding genes and 100 other regulatory genes in eight species: human, mouse, fruit fly, sea urchin, nematode, rat, chicken, and zebrafish, with higher priority on the first five species. The only regulatory genes included in the cisGRN-Lexicon (CYRENE genes) are those whose regulatory architecture is validated by what we call the Davidson Criterion: they contain functionally authenticated sites by site-specific mutagenesis, conducted in vivo, and followed by gene transfer and functional test. This is recognized as the most stringent experimental validation criterion to date for such a genomic regulatory architecture. The CYRENE cisGRN-Browser is a full genome browser tailored for cis regulatory annotation and investigation. It began as a branch of the Celera Genome Browser (available as open source at http://sourceforge.net/projects/celeragb /) and has been transformed to a genome browser fully devoted to regulatory genomics. Its access paradigm for genomic data is zoom-to-the-DNA-base in real time. A more recent component of the CYRENE project is the Virtual Sea Urchin system (VSU), an interactive visualization tool that provides a four-dimensional (spatial and temporal) map of the gene regulatory networks of the sea urchin embryo. PMID- 20827604 TI - Reconstructing transcriptional regulatory networks using three-way mutual information and Bayesian networks. AB - Probabilistic methods such as mutual information and Bayesian networks have become a major category of tools for the reconstruction of regulatory relationships from quantitative biological data. In this chapter, we describe the theoretic framework and the implementation for learning gene regulatory networks using high-order mutual information via the MI3 method (Luo et al. (2008) BMC Bioinformatics 9, 467; Luo (2008) Gene regulatory network reconstruction and pathway inference from high throughput gene expression data. PhD thesis). We also cover the closely related Bayesian network method in detail. PMID- 20827605 TI - Computational methods for analyzing dynamic regulatory networks. AB - Regulatory and other networks in the cell change in a highly dynamic way over time and in response to internal and external stimuli. While several different types of high-throughput experimental procedures are available to study systems in the cell, most only measure static properties of such networks. Information derived from sequence data is inherently static, and most interaction data sets are measured in a static way as well. In this chapter we discuss one of the few abundant sources for temporal information, time series expression data. We provide an overview of the methods suggested for clustering this type of data to identify functionally related genes. We also discuss methods for inferring causality and interactions using lagged correlations and regression analysis. Finally, we present methods for combining time series expression data with static data to reconstruct dynamic regulatory networks. We point to software tools implementing the methods discussed in this chapter. As more temporal measurements become available, the importance of analyzing such data and of combining it with other types of data will greatly increase. PMID- 20827606 TI - [A possible determination of the damage in the transverse spinal paralysis on the basis of certain disorders of the nervous system. 1910]. PMID- 20827607 TI - Cardiac responses to orthostatic stress deteriorate in Parkinson disease patients who begin to fall. AB - BACKGROUND AND PURPOSE: It is not clear how cardiovascular autonomic nervous system dysfunction can affect falls in Parkinson disease (PD) patients. The aim of the study was to evaluate cardiovascular autonomic responses to orthostatic stress and occurrence of falls in PD patients over a period of 1-2 years. MATERIAL AND METHODS: In 53 patients, who either experienced at least one fall during 12 months preceding the study onset (fallers) or did not fall (non fallers), we monitored RR intervals (RRI), heart rate (HR) and systolic (SBP) and diastolic (DBP) blood pressure, and calculated the coefficient of variation of RRI (RRI-CoV) and the ratio of low to high frequency spectral powers of RRI oscillations (LF/HF) at rest and upon tilting at study entry and after at least 12 months. Based on the number of falls at study closure, we identified three subgroups: non-fallers, chronic fallers, and new fallers. RESULTS: At study entry, RR-CoV, SBP, or DBP did not differ between fallers and non-fallers, while LF/HF ratios were lower in fallers than non-fallers at rest and upon tilting. After the follow-up period, HR and RRI-CoV responses to head-up tilt were reduced in new fallers as compared to study entry, whereas these variables remained unchanged during the study in non-fallers and chronic fallers. Prevalence of orthostatic hypotension did not differ between subgroups of patients. CONCLUSIONS: Cardiac responses to orthostatic stress deteriorate in PD patients who begin to fall. Orthostatic blood pressure responses remain unchanged over time and are not associated with falls in PD. PMID- 20827608 TI - Association between the -1562 C/T MMP-9 polymorphism and cerebrovascular disease in a Polish population. AB - BACKGROUND AND PURPOSE: Matrix metalloproteinase 9 (MMP-9) is an endopeptidase degrading extracellular matrix. There is growing evidence that changes in extracellular matrix play an important role in vascular pathology, especially in cardiovascular and cerebrovascular disease. Previous studies have demonstrated that MMP-9 activity is controlled by --1562 C/T polymorphism. Genotypes with T allele (CT, TT) have higher enzymatic activity. Thus, this polymorphism could be responsible for the higher risk for cerebrovascular disease and death. The aim of this study was to assess the significance of MMP-9 polymorphism as a risk factor for cerebrovascular disease in a Polish population. MATERIAL AND METHODS: A total of 775 consecutive patients with a diagnosis of cerebrovascular disease (ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage) admitted to the Stroke Unit, Jagiellonian University, Krakow, Poland between 2000 and 2004 were studied and compared with 766 matched controls. The polymorphism was studied by polymerase chain reaction (PCR) and restricted enzyme digestion. RESULTS: Among 418 patients with ischaemic stroke of various aetiologies and among 146 patients with primary intracerebral haemorrhage and 211 patients with subarachnoid haemorrhage due to ruptured intracranial aneurysm, statistical analysis did not show a significant difference between occurrence of CC, CT, TT genotypes or C and T alleles in patients with stroke of various aetiology compared with controls. CONCLUSIONS: We found no association between the -1562 C/T MMP-9 polymorphism and ischaemic stroke, subarachnoid haemorrhage or spontaneous intracerebral haemorrhage in the studied Polish population. PMID- 20827609 TI - Quality of life and social support in patients with multiple sclerosis. AB - BACKGROUND AND PURPOSE: The aim of the study was to evaluate quality of life (QoL) in multiple sclerosis (MS) patients and to assess the relationship between QoL and social support taking into account key clinical factors and other sociodemographic variables. MATERIAL AND METHODS: Two hundred and ten MS patients (150 women and 60 men) aged between 21 and 59 years were evaluated; the MS group was compared with 108 healthy controls. QoL (MSQOL-54), disease severity (Expanded Disability Status State, EDSS), social support (Social Provisions Scale, SPS), mood (Beck Depression Inventory, BDI) and basic clinical and demographic data were assessed. RESULTS: Disease severity was mild (EDSS < 4) in 85% of patients, and depressive symptoms (BDI > 13) were present in 41% of patients. Mean physical health composite of MSQOL-54 was 53.6 +/- 20.7 and mean mental health composite was 60.0 +/- 19.8. MS patients scored significantly lower than healthy subjects. Mean SPS was 78.2 +/- 10.9 (range, 6-96) which indicated high social support. In bivariate analysis, social support correlated significantly with the majority of MSQOL domains; in multivariate analysis, however, this relationship was not significant. Emotional well-being was the main predictor of QoL, in both physical and mental domains. CONCLUSIONS: MS influences QoL but to a greater extent in the physical than the psychological domain. The role of social support in QoL is generally positive but its protective function may be weakened when interacting with other factors. Depression is the main predictor of QoL when adjusted for other factors. Thus, treatment of mood disturbances might significantly improve QoL in MS patients. PMID- 20827610 TI - Neuroform stent-assisted coil embolization: a new treatment strategy for complex intracranial aneurysms. Results of medium length follow-up. AB - BACKGROUND AND PURPOSE: We present detailed results of using Neuroform stent assisted coil embolization to treat complex cerebral aneurysms over a three-year period. MATERIAL AND METHODS: Only patients who underwent Neuroform stent assisted coil embolization were included in this study. We assessed patients' history, aneurysm morphology, indications for stenting, and technical details of the procedures, as well as complications and the midterm follow-up data. RESULTS: This study included 26 patients with 39 aneurysms. A total of 32 of 39 aneurysms were treated by Neuroform stent-assisted embolization (SAC), whereas 3 aneurysms were stented without coiling, 2 aneurysms coiled without stenting and 2 aneurysms surgically clipped. The indications for use of stent included broad-neck aneurysms (n = 28), giant or large aneurysms (n = 6), and fusiform aneurysms (n = 5). Of the 32 aneurysms treated with Neuroform SAC, we achieved complete (100%) and near complete (> 95%) occlusion in 27 aneurysms, and partial (< 95%) occlusion in 5 aneurysms. Follow-up angiographic data available in 22 of 32 aneurysms treated with Neuroform SAC (68.7%) demonstrated recanalization in 3 aneurysms (13.6%), and stable occlusion in 19 aneurysms (86.4%). There was no delayed progressive embolization or in-stent stenosis. CONCLUSIONS: Direct and midterm follow-up results confirmed that Neuroform stent-assisted coil embolization was a safe and effective technique in the treatment of complex cerebral aneurysms. Although clinically significant complications were uncommon and the evaluation at midterm follow-up is encouraging, further studies need to assess the long-term stability and durability of the stent. PMID- 20827611 TI - Posterior microlaminoforaminotomy for cervical disc herniation. AB - BACKGROUND AND PURPOSE: Posterior microlaminoforaminotomy is a surgical treatment option for lateral cervical disc herniation. This approach avoids injury of vital structures lying in front of the cervical spine and preserves mobility of the treated spinal segment. The authors present the outcome of 20 patients operated on using this method. MATERIAL AND METHODS: Retrospective analysis was performed on 20 consecutive patients operated on in the years 2005-2009. Posterior microlaminoforaminotomy was used in patients with unilateral cervical radiculopathy resulting from lateral disc herniation. Osteophytes coexisted in 12 cases. The presenting symptoms were: radicular pain (20 patients), paraesthesias (19), neck pain (17), dermatomal sensory loss (11) and motor deficit (9 patients). All operations were performed at a single level (C5/C6 in 8 cases, C6/C7 in 10 cases, C7/Th1 in 2 cases). RESULTS: The herniated disc was removed in 19 cases; nerve root decompression was performed in 1 patient. Osteophytes were additionally excised in 4 cases. Significant relief of radicular pain was achieved in all cases early after surgery. Transient improvement with unsatisfactory late outcome was observed in 1 patient. Satisfactory late outcome (according to Odom's criteria) was obtained in 95% (18/19) of patients. Complete or marked improvement of radicular pain was observed in 95% (18/19), neck pain in 94% (16/17), sensory loss in 82% (9/11) and motor deficit in 78% (7/9). There was no case of spinal instability or secondary operation due to recurrence with a mean follow-up period of 22 months. CONCLUSIONS: Posterior microlaminoforaminotomy is safe and effective. Coexistence of osteophytes does not limit use of this technique. The risk of herniation recurrence and spinal instability is very low. The minimal invasiveness of this method allows faster return to normal life activities. PMID- 20827613 TI - [Levodopa intestinal infusion therapy in Parkinson's disease]. AB - Medical treatment of advanced Parkinson disease complicated with fluctuations and dyskinesias remains difficult or in some patients totally ineffective. Recently, new methods were introduced to manage those problems: deep brain stimulation, subcutaneous apomorphine infusion and the Duodopa system for intrajejunal continuous delivery of gel containing levo-dopa/carbidopa (through percutaneous gastrostomy). This last method was proven to be very effective in reducing the fluctuations of levodopa plasma levels and furthermore in reducing the off periods and dyskinesias. The Duodopa system is used in patients with contraindications to deep brain stimulation or apomorphine infusions. According to recently published studies, it may also be more effective in reducing motor complications than other methods. The authors present the current knowledge on the Duodopa system, its effectiveness (also in relationship to other methods, specially deep brain stimulation and apomorphine) and possible complications (mostly due to gastric tube failures) along with the indications and contraindications. PMID- 20827612 TI - [Continuous dopaminergic stimulation - clinical experience]. AB - Both disease progression and pulsatile stimulation of dopaminergic receptors are responsible for development of fluctuations and dyskinesia in about 50% of patients with Parkinson disease (PD) after 4-6 years of therapy with levodopa. In order to prevent motor complications, the ideal therapy should secure continuous dopaminergic stimulation (CDS). The concept of CDS is supported by the results of both experimental and clinical studies. Several treatment options are available to achieve CDS. Dopamine agonists have a longer half-life than levodopa and the development of dyskinesia is delayed when they are used as monotherapy in early PD. Continuous delivery of agonists can be improved with prolonged-release oral preparations, a transdermal delivery system or continuous subcutaneous infusion. Continuous enteral infusion of levodopa is another way to achieve CDS and it is very effective in reducing motor complications in advanced PD. PMID- 20827614 TI - Prevalence of spasticity following stroke and its impact on quality of life with emphasis on disability in activities of daily living. Systematic review. AB - Spasticity is characterized by a velocity-dependent increase in muscle tone related to disturbed sensory-motor control of muscle tone following upper motor neuron damage. Spasticity and its clinical implications are still poorly described. There is no consensus concerning the number of patients developing spasticity or the relationship between spasticity and motor disabilities after stroke. Surprisingly, only a few studies have addressed the prevalence of spasticity following stroke. The present paper aims to review recent studies on prevalence of spasticity, its risk factors and on quality of life with emphasis on disability in activities of daily living and to relate collected data to situation in Poland. PMID- 20827615 TI - [Red ear syndrome - a case report]. AB - The red ear syndrome was first described by Lance in 1994. Since the initial description, approximately 60 cases have been presented in the literature. The syndrome is characterized by attacks of unilateral ear discomfort or burning during which the ear becomes red. An association with upper cervical spine disorders, primary headaches and trigeminal and glossopharyngeal neuralgia was reported. Some cases were idiopathic. We report a new case of red ear syndrome that responded to greater auricular nerve blockade. The literature on the entity is reviewed and a unifying pathophysiological hypothesis of this syndrome is suggested. PMID- 20827616 TI - Primary osteolytic intraosseous meningioma of the frontal bone. AB - Almost 1-2% of meningiomas are lesions described as ectopic or extradural meningiomas. Primary intraosseous meningiomas are a rare form of intra-bone tumours that account for approximately 67% of extradural meningiomas. A 41-year old male patient presented with a headache and a bulge at the right frontal region. Cranial computed tomography displayed a hyperostotic lesion. Magnetic resonance imaging showed enhancement of the bone lesion after injection of gadolinium. A burr hole was drilled at the thickest section of the lesion, and pathological examination of the bone dust extracted from this site was performed. The pathological study indicated the presence of a meningioma. Right frontal craniectomy was performed and the hyperostotic bone was resected. No invasion was observed at the dura. A calvarial defect was reconstructed during the same session with methyl methacrylate cranioplasty. PMID- 20827617 TI - Spindle cell lipoma of the orbit: a case report of an unusual orbital pathology. AB - Spindle cell lipoma is a rare and distinct variant of soft tissue tumour characterised by spindle cells in which the fat content may be scarce or absent. Most spindle cell lipomas arise as a subcutaneous mass of the neck, shoulders or back. Rarely, they can also be found in unusual sites, such as the oral cavity, larynx, bronchus, breast, and extremities. Localisation of spindle cell lipoma in the orbit has been described in a few cases. We report here on a case of an orbital mass surgically excised in an adult male and discuss the differential diagnosis with other soft tissue tumours with a lipomatous component, such as lipomatous haemangiopericytoma, a rare variant of haemangiopericytoma. PMID- 20827619 TI - Imaging of the elbow. Preface. PMID- 20827620 TI - Normal anatomy and anatomical variants of the elbow. AB - This article provides a brief review of the normal osseous, ligamentous, muscular, and neurovascular imaging anatomy of the elbow. Special attention is paid to the normal structures that may simulate pathology, as well as anatomical variants that may lead to pathology. This review will help clarify distinctions between normal anatomy and abnormal anatomy, as well as elucidate pathological consequences of a seemingly normal structure. PMID- 20827621 TI - Imaging acute trauma of the elbow. AB - Elbow injuries, both acute and chronic, continue to rise as both the young and elderly increase their participation in athletic activities. The role of imaging is to provide supportive data as to the cause of the patient's symptoms and to guide treatment options for the referring physician. Understanding the anatomy and biomechanics of this sophisticated joint, various injury patterns, and the implication of injury to the static and dynamic stabilizers will result in improvement in diagnostic accuracy. Each of these topics are discussed to provide a foundation and overview of key concepts necessary to understand common elbow injuries. PMID- 20827622 TI - Throwing elbow in adults. AB - Biomechanics are central in understanding the pathophysiology and magnetic resonance (MR) imaging of overhead throwing athlete injuries. Repetitive excessive valgus forces at the elbow result in characteristic injuries due to medial joint distraction, lateral joint compression, and rotatory forces at the olecranon. MR imaging is useful for assessment of the throwing elbow in adults. PMID- 20827623 TI - Pediatric throwing injuries of the elbow. AB - Throwing injuries of the elbow in the pediatric population are common. These can occur as lateral compression osteochondral injuries such as osteochondritis dissecans or medial tension overload such as so-called Little League elbow. Extension overload injuries may present in teens as stress injuries of the olecranon process. We review the imaging findings of each of these common injuries, with an emphasis on their magnetic resonance imaging appearance. PMID- 20827624 TI - Imaging of the elbow: muscle and tendon injuries. AB - Elbow injuries can be divided into lateral, medial, anterior, and posterior compartments. Each compartment has specific anatomical landmarks and muscle tendon units that are injured in a specific location and pattern related to the mechanism of injury. Magnetic resonance imaging provides superior soft tissue visualization and assessment of these injuries. Muscle and tendon injuries that occur in each of the four compartments vary in accordance to their population and associated activities. These injuries range from tendinopathy to complete tears that may be a result of repetitive microtrauma, an acute traumatic event, or a combination of the two. Common pathomechanisms of these injuries are discussed including basic treatment options. The treatment options also vary in accordance to the compartment involved and the severity of the injury. The treatment options range from conservative measures such as observation with activity modification to operative measures including debridement and repair. PMID- 20827625 TI - Nerve entrapment and compression syndromes of the elbow. AB - Nerve compression and entrapment syndromes are classic examples of the integrated role of radiologists and clinicians in achieving difficult but accurate diagnoses. The pathology of nerves can only be understood after evaluating the normal architecture and imaging characteristics of nerves. Understanding the correlation of the pathophysiology of nerve compromise with electromyographic findings and imaging findings allows for greater comprehension of a difficult topic. Particularly in the elbow, there are multiple potential areas of nerve entrapment and compression that can be evaluated perhaps best with magnetic resonance imaging. PMID- 20827626 TI - Musculoskeletal ultrasound: elbow imaging and procedures. AB - Elbow injuries, both acute and chronic sports-related cases, have increased over the last decade. With one in every four members of a household participating in sports, both clinics and radiology departments are seeing more patients with elbow pain. High-resolution ultrasound is well suited for evaluating the elbow. Ultrasound is growing in popularity and fast becoming another modality that the radiologist can use to help diagnose elbow pathology. With advancing transducer technology and accessibility, ultrasound offers focused and real-time high resolution imaging of tendons, ligaments, and nerve structures. Its advantages include the use of safe nonionizing radiation, accessibility, and cost effectiveness. Another unique advantage is its ability for dynamic assessment of tendon and ligament structures such as in cases of partial tears of the medial ulnar collateral ligament or ulnar nerve dislocation. It is also easy to assess the contralateral side as a control. Ultrasound is also useful in therapeutic guided injections for its multiplanar capability and clear visualization of major vessels and nerves. We discuss the unique application of ultrasound in evaluating common elbow pathology and in advanced ultrasound-guided treatments such as dextrose prolotherapy and platelet-rich plasma. PMID- 20827633 TI - [Pneumology - a major specialty of internal medicine]. PMID- 20827634 TI - ["The year of the lung" - the centennial year of the German Society for Pneumology (DGP)]. PMID- 20827635 TI - [Disease numbers in pneumology - a projection to 2060]. AB - BACKGROUND: The demographic change leads to a change in the age-composition of the population. We have calculated a status quo projection of the absolute numbers for five diagnoses of the lung (COPD, CAP, lung cancer, bronchial asthma and tuberculosis) for Germany up to 2060. MATERIAL AND METHODS: Based on the 12 (th) coordinated population prediction of the Federal Statistics Office, we transferred age- and sex-specific incidence and prevalence rates, respectively, to the expected population. All described developments are based solely on demographic changes. RESULTS: The absolute numbers of bronchial asthma and tuberculosis will experience a minor decrease. We expect at first increasing and later decreasing case numbers for COPD and lung cancer. A major increase of the case numbers for CAP will be probable. By reason of a decreasing population, the rates (burden of disease for the population) will increase considerably. DISCUSSION: The demographic change is mainly caused by increasing life expectancy, constantly low birth rates, and the entry of the baby-boom generation into the age of higher disease risks. A discussion about prioritisation of health care is needed because of the rising burdens for the health system, including diseases of the lung. PMID- 20827636 TI - [Asthma - historical development, current status and perspectives]. AB - Asthma is not a new disease. It is one of the most common chronic disorders affecting approximately 4-5 % of adults and more than 10 % of children in Germany. This turns asthma into one of the most prevalent chronic disorders. Over the last century ideas about its pathogenesis have changed many times. While around one hundred years ago asthma was often considered a neurotic disease, changes in airway smooth muscle, mast cell accumulation and activation or specific mediators such as platelet-activating factor have since been incriminated in its pathogenesis. Eosinophils, cytokines and T-lymphocytes were favourites some time later. Nowadays, - and this is unlikely to be the end of the story - asthma is considered as a complex disorder of the adaptive immune system. Therapeutic approaches have changed dramatically, too. While until about 30 years ago asthma was still considered a Smooth muscle disorder, recurrent attacks of asthma which required frequent, mostly nocturnal interventions, status asthmaticus, or the necessity of mechanical, invasive ventilation have markedly decreased. In view of the asthma epidemic in recent years, this development suggests that current treatments are at least partially effective. In spite of this patients with asthma are often only moderately well controlled with considerable morbidity from the disease as well as its treatment. Thus, despite recent advances in diagnosis and treatment, asthma is still not a trivial disease and future attempts at improving the care of those affected are warranted. The developments of the past 100 years as well as a careful look into the future are presented in this review. PMID- 20827637 TI - [COPD - a historical review, current management and research perspectives]. AB - The term COPD which comprises chronic obstructive bronchitis and emphysema, was first defined in 1964. Key milestones to the understanding of the etiopathology of COPD were the discovery of the association between tobacco consumption and the development of chronic bronchitis as well as the discovery of the role of a protease-antiprotease imbalance leading to emphysema. The assessment of functional impairement of patients with COPD was established in the 1960s and the quantification and localisation was predominantly explored in the 1980s. The management of COPD comprises preventative measures (e.g. smoking cessation, vaccination against influenza, reduction of occupation hazards), medical therapies (bronchodilators, corticosteroids), non-pharmacological therapies (exercise training, patient education, physiotherapy) as well as surgical options. The prevention and efficiency management of exacerbations are of particular importance. Optimal management of COPD has to take impact of the disease on other organs into account. The future of COPD-related research lies in the development of international and national networks to facilitate the analysis of genetic factors on the pathology of COPD. PMID- 20827638 TI - [Lung cancer - historical development, current status, future prospects]. AB - One hundred years ago lung cancer was a rare disease. In the meantime, as a result of the sharp increase of tobacco smoking, in Germany and worldwide it is the most common cause of cancer death. Since lung cancer is largely asymptomatic in its early stages, the diagnosis is usually first made in the advanced stages IIIB or IV. The development of diagnostic imaging and minimally invasive procedures as well as the refinement of the staging classification allow a better allocation to the tumor stages. The surgical mortality has declined significantly since the 1950s, yet the 5-year survival rates are low. For locally advanced, unresectable non-small cell lung carcinoma a moderate improvement of the prognosis could be achieved by newer methods of radiotherapy and the combination of radiotherapy with chemotherapy. As a result of chemotherapy in patients with non-small cell lung cancer a moderate life extension has been reached, while the new agents are better tolerated and allow for an improved quality of life. The survival of small cell lung cancer has been significantly prolonged by chemotherapy since the 1970s, however, little progress was made in the last 15 - 20 years. The most important and effective preventive measure against lung cancer is to avoid tobacco smoke. Screening tests using annual chest X-ray images and sputum cytology have shown no improvement in overall mortality compared with the control groups in extensive studies. Whether or not an improvement of prognosis is possible by a screening using low-dose CT is being tested by the ongoing studies. For patients with lung cancer more effective agents and therapies are still needed. PMID- 20827639 TI - [Pneumonia -- historical development, current status, future prospects]. AB - Pneumonia is one of the oldest and best known diseases in mankind. Morbidity and mortality of this disease are remarkable. This has not been changed with the development of modern antibiotic therapy. On the contrary new challenges have arisen, more elderly and comorbid patients are involved and an increase in antibiotic resistance has appeared. An improvement in diagnosis and the introduction of risk stratification approaches has led to a standardisation in therapy. Vaccination strategies for special pathogens like S. PNEUMONIAE have reduced the burden of disease. For decades research was focused on the development of new antibiotics. The failure of this strategy has directed more attention to the host-pathogen interaction. Modulation of innate immunity is one of the key issues to overcome the future challenges in this field. PMID- 20827640 TI - [Tuberculosis - historical development, current status, future prospects]. AB - Tuberculosis is one of the leading causes, if not the leading cause of death in human history. Worldwide TB still belongs to the ten most frequent causes of death and represents one of the most urgent public health problems globally. In Germany as in almost all industrialised countries, the incidence and mortality has been continuously declining but globally the situation is worsening dramatically due to HIV coinfection and the increase of polyresistant TB strains. Only rapid and internationally concerted action with the cooperation of the affected countries and combined with intensified research efforts into new diagnostics, therapeutics, and vaccines will be able to prevent a development that will no longer be manageable even with 21st century technology. PMID- 20827641 TI - [Interstitial lung diseases - historical development, current status, future prospects]. AB - Sarcoidosis and lung fibrosis were first described by histopathology in the 19th century. Since then a large number of different forms of diffuse parenchymal lung diseases has been identified. Although all these diseases manifest in the lung interstitium, there is a wide range of predominanthy inflammatory to purely fibrotic disease processes. Accordingly, anti-inflammatory treatment is successful in the former, whereas for the latter an effective medical therapy is lacking. Gene technology has recently led to results which have fundamentally changed our understanding of the pathophysiology of fibrosing lung disease. Early and differential diagnosis has much improved with the help of high-resolution computed tomography. Recent clinical trials in patients with idiopathic pulmonary fibrosis have shown at least some effectiveness for the antioxidant treatment approach using high-dosed N-acetylcysteine as well as for the use of pirfenidone. Importantly, these studies have proven that well-designed treatment trials are feasible in this patient population. This has kindled the hope that, based on a better understanding of the pathophysiology, new targeted therapies will prove to be successful in the future. PMID- 20827642 TI - [Pulmonary hypertension - historical development, current therapy and perspectives]. AB - This article provides a brief overview on the history of pulmonary hypertension, starting with the first descriptions of the accompanying pulmonary vascular lesions by Ernst von Romberg and Victor Eisenmenger at the end of the 19th century. Many of the histopathological changes in the pulmonary vasculature found in the various forms of pulmonary hypertension had already been described in the first half of the 20th century. However, only through the pioneering work by Forssmann and Cournand during the middle of the 20th century was it finally possible to catheterise the right ventricle and the pulmonary arteries. After this it became feasible to study the clinical spectrum of the various forms of pulmonary hypertension as well as the effects of therapeutic interventions. Early treatment attempts with vasodilators, however, were not successful. Intravenous prostacyclin, used to treat some forms of pulmonary hypertension since 1980, became the first effective treatment. Since that time, our understanding of the pathogenesis of pulmonary hypertension has increased substantially, as has the number of effective therapies, at least for some forms of pulmonary hypertension. Many aspects of the disease, however, remain poorly understood and a cure is still not achievable for the majority of the affected patients. PMID- 20827643 TI - [Sleep-related breathing disorders - historical development, current status, future prospects]. AB - Sleep-related breathing disorders are common adult illnesses in Western countries and classified as either dominant obstructive sleep apnoea or dominant central sleep apnoea. Cheyne-Stokes Respiration is part of the spectrum of CSA. The earliest descriptions of patients who presumably suffered from sleep apnoea were made in the 19th century. The term ''Pickwickian'' in connection with sleepy patients was introduced in 1889. The first electrophysiological sleep recordings of Pickwickian patients and the understanding of the syndrome as disordered breathing in sleep, were made during the late 1950s and 1960s at the universities of Heidelberg and Freiburg in Germany. The term sleep apnoea syndrome was introduced by Guilleminault from Stanford. The introduction of continuous positive airway pressure (CPAP) therapy by C. E. Sullivan and co-workers gave an enormous impetus to the field of sleep-disordered breathing. Its recognition as a public health problem was facilitated by the Wisconsin study, investigating the prevalence of sleep apnoea in the middle-aged general population. Nowadays obstructive sleep apnoea (OSA) is recognised as an independent risk factor for a wide range of clinical conditions, such as atherosclerosis, hypertension, heart failure, arrhythmias, stroke, diabetes, and depression. This article focuses on issues related to OSA and CSA/CSR, their pathogenesis, interaction with other comorbidities including cardiovascular diseases. Future research will focus on treatment effects on cardiovascular and metabolic outcomes in sleep apnoea and on the pathophysiological mechanisms responsible for the inflammatory state and cardiovascular morbidity in the syndrome. Other potential areas of research include biochemical markers, new diagnostic and therapeutic modalities. PMID- 20827644 TI - [Acute respiratory insufficiency due to severe lung injury - ARDS and ALI]. AB - As a consequence of the novel therapeutic option of mechanical ventilation in early intensive care medicine, the acute respiratory distress syndrome (ARDS) was defined as a disease entity of its own representing the most severe form of acute lung injury (ALI). Since its first description four decades ago, our knowledge about the aetiology, physiology, histology and epidemiology of this lethal pulmonary complication of severe acute diseases such as pneumonia or sepsis has been increasing steadily. The initial major therapeutic advances were due to improvements in intensive care medical procedures and monitoring. The large ARDS Network clinical trial on the magnitude of tidal volume impressively demonstrated the feasibility of targeted clinical trials in patients with ARDS that provide robust evidence in this field. This clinical trial, as well as following large scale trials in ARDS patients, led to significant changes of ventilation therapy and therapeutic strategies that improve the outcome of this disease entity. Advances in the standardisation of care for ARDS patients involving innovative therapeutic procedures such as extracorporeal gas exchange systems will lead to a further improvement in ARDS management and outcome. Modern pulmonary medicine can play a pivotal role in this process and can contribute its rich experiences in all areas of the respiratory system. PMID- 20827645 TI - [Protracted respiratory insufficiency - epidemiology and network on respiratory weaning after prolonged ventilation]. AB - The prevalence of difficult or prolonged weaning from the ventilator is increasing due to a growing number of multi-morbid, elderly and pulmonary deficient patients being mechanically ventilated. Intensive care units (ICU) tend to refer difficult to wean patients to specialised weaning facilities. A survey of 38 centres - performed in 2006 - included a total number of 2718 patients with difficult or prolonged weaning. Almost three quarters of the patients were transferred to a weaning centre from an external ICU. The weaning success rate was 66.3 %. After weaning in 31.9 % of the patients, home mechanical ventilation was started. The overall hospital mortality rate was 20.8 %. Recently the task force "WeanNet" - a network of weaning units - was founded under the auspices of the German Thoracic Society. The main aim of WeanNet is to improve cooperation among the weaning centres and the quality of patient management. Important tools of WeanNet are (i) the register of weaning patients and (ii) accreditation of the weaning centres. To develop the register an intensive cooperation between the task force and the Institute for Lung Research (ILF) was necessary. The finished register is now logistically run by ILF. In less than 1 year after the official start, already 70 weaning units with ca. 3000 patients are registered. In future "WeanNet", in particular in terms of the register and the accreditation, will stand for the quality of weaning centres in Germany. PMID- 20827646 TI - [Chronic respiratory failure: the role of home mechanical ventilation]. AB - While negative pressure ventilation using cuirass respirators or iron-lung machines was prevailing in the first part of the 20th century, the polio epidemic in Copenhagen 1952 marks the turning point at which positive pressure ventilation following tracheotomy was started. Furthermore, following the introduction of facial masks and starting 1985 in Germany non-invasive positive pressure ventilation has meanwhile been developed as a routine procedure for the long-term treatment of patients with chronic ventilatory failure today. The current article provides an overview of these developments and also outlines the role of two particular national societies: "Deutsche Gesellschaft fur Pneumologie und Beatmungsmedizin (DGP) e. V." (German Medical Association of Pneumology and Ventilatory Support) and "Deutsche Interdisziplinare Gesellschaft fur aubetaerklinische Beatmung (DIGAB) e. V." (German Interdisciplinary Society for Home Mechanical Ventilation). PMID- 20827647 TI - [Chronic respiratory insufficiency: the role of lung transplantation]. AB - Lung transplantation has been established as an appropriate ultimate treatment strategy in end-stage lung disease, when all conventional therapeutic options have been exhausted. Acute and potentially reversible lung diseases (ARDS, pneumonia) and malignancy (broncho-alveolar carcinoma) are not established indications. Retrospective analyses on the natural course of the disease and new medical treatment options have led to fewer transplantations in recipients with emphysema and idiopathic pulmonary hypertension. In end-stage cystic fibrosis and patients with idiopathic pulmonary fibrosis, alternative treatment options are currently not available and lung transplantation is indicated. The available guidelines for candidate selection should be followed. Internationally, there is a trend towards a benefit-orientated allocation of organs. Recommendations for candidate selection, surgical innovations and, especially, the improved long-term follow-up have led to improved results in the last two decades. Long-term results are, however, still unsatisfactory in comparison to liver and kidney transplantations. The main obstacles to long-term survival and causes of death are chronic allograft dysfunction (bronchiolitis obliterans syndrome, BOS) and infections. In the future, the pathogenesis and treatment options for these two entities should be clarified. A further essential task is to increase the donor pool in the future because the current waiting list mortality is approximately 20 %. PMID- 20827648 TI - [The interdisciplinary S3 guidelines dementia: advances in neurology and psychiatry]. PMID- 20827649 TI - [Comment on the S3 Guidelines Dementia by the DGPPN and the DGN from the neurological point of view]. AB - The German Society for Psychiatry, Psychotherapy, and Nervous Diseases (DGPPN) and the German Society for Neurology (DGN) have appointed an expert panel to develop guidelines for the diagnosis of and therapy for dementias and to reach a consensus on these guidelines with other relevant societies. These guidelines have now been broadly consented. They assess the present evidence according to transparent standards and give a number of recommendations that are outlined in the present communication. The guidelines lack recommendations for the organisation of medical and social services and for adequate settings of care. These are key elements of national practice guidelines, the development of which is of key importance in view of the socioeconomic consequences of dementias. The financing of national practice guidelines cannot be the responsibility of scientific societies. PMID- 20827650 TI - [Comment on the S3 guidelines Dementia by the DGPPN and the DGN from the psychiatric point of view]. AB - The S 3 guidelines Dementia from the DGPPN and DGN represent recommendations that fulfil the highest methodological requirements and are based on a consensus process involving all professional societies, associations and organisations that participate in the management of patients with dementia. From the psychiatric point of view, in particular, the broad representation of the diagnostic processes, the inclusion of modern liquor diagnostics, the comprehensive presentation of psychosocial interventions and the detailed description of psychiatric and behavioural symptoms are unique features. The guidelines provide the foundation for substantial improvement in the management of patients with dementia in Germany. PMID- 20827651 TI - [Dementia in morbus Parkinson: reasonable diagnostics and rational therapy]. AB - Cognitive decline is a common disorder in idiopathic Parkinson's syndrome, the risk for the development of a dementia is four- to six-fold higher for Parkinsonian patients. The cognitive profile in Parkinson's disease dementia (PDD) differs from that of Alzheimer-type dementias. The affected cognitive functions include attention, executive functions, visual-spatial functions and recall. The main differential diagnosis for PDD is the Lewy body dementia (LBD), which can be differentiated through the temporal development of motor and cognitive symptoms. Cognitive symptoms in Parkinsonian syndromes have a relevant negative impact on quality of life, on the burden for the care-givers, on the prognosis of the disease and on the possible referral to a nursing home. Dementias in Parkinsonian syndromes (PDD and LBD) need a confirmatory diagnosis at an early stage in order to initiate further therapeutic steps with, e. g., acetylcholine esterase inhibitors or, perspectively, neuropsychological training methods. PMID- 20827652 TI - [Neuropsychological therapy in dementia patients: what is reasonable?]. AB - The aging of the population leads to increasing incidence rates of dementia. Besides pharmacotherapy, non-pharmacological interventions are becoming more and more recognised. Although the data can be regarded as insufficient, many studies indicate that neuropsychological therapy can lead to an improvement of cognitive and non-cognitive symptoms in patients with dementia and mild cognitive impairment, or even decelerate the course of decline. Regulating guidelines of the local health insurance companies do not yet include this type of intervention. However, they are recommended in the recently published German guidelines for the diagnosis and treatment of dementia. Scientific efforts for the evaluation of specific training programmes can be expected; implementation of the results into clinical practice is desirable. PMID- 20827653 TI - [Moyamoya disease - a rare vasculopathy in Europeans]. PMID- 20827654 TI - Muscle coordination while pulling up during cycling. AB - The aim of this study was to determine the influence of the pull up action on the pedalling mechanics and muscle coordination during cycling. 9 elite cyclists pedalled at 320 watts with their preferred technique and while pulling up. The pull up action increased significantly the pedalling effectiveness during the upstroke and around the bottom dead centre. This was associated with a significant enhancement of the biceps femoris activity (48%), an earlier onset of activation of the tibialis anterior, i. e., 211 +/- 83 degrees vs. 259 +/- 22 degrees (crank angle) and a delayed offset of activation of the gastrocnemius lateralis, i. e., 244 +/- 19 degrees vs. 216 +/- 39 degrees . Consequently, co activities between tibialis anterior and gastrocnemius lateralis muscles over 55 +/- 65 degrees (crank angle range), as well as between the biceps femoris and the tibialis anterior over 48 +/- 57 degrees were generated. These higher co activities were necessary to stiffen the ankle joint and to power the pedal during the upstroke. Thus changes in muscle coordination improved the pedalling effectiveness during the upstroke phase but would probably lead to impairment of the oxygen consumption. Therefore, training the pull up action could be of interest to optimize this muscle coordination associated with better pedalling effectiveness by additionally relieving hip or knee extensors during the downstroke. PMID- 20827655 TI - Ergometer rowing with and without slides. AB - A rowing ergometer can be placed on a slide to imitate 'on-water' rowing. The present study examines I) possible differences in biomechanical and physiological variables of ergometer rowing with and without slides and II) potential consequences on training load during exercise. 7 elite oars-women rowed in a randomized order in a slide or stationary ergometer at 3 predefined submaximal and at maximal intensity. Oxygen uptake was measured and biomechanical variables of the rowing were calculated based upon handle force (force transducer) and velocity/length (potentiometer) of the stroke. Stroke frequency was higher (% difference between conditions) at each intensity level (1-11.4%, p<0.05) during slide compared to stationary rowing. Furthermore, at the 2 highest intensities a lower mean force (4.7-9.0%, p<0.05) and max force (3.2-10.6%, p<0.05) were observed on the slide ergometer. During maximal rowing no difference was seen in heart rate, mean oxygen uptake and R-value while maximal oxygen deficit was higher (30.8%, p<0.05) during slide rowing. In conclusion the biomechanical load is lower on a slide than on a stationary ergometer. However, as a training tool the slide ergometer seems just as demanding with regard to aerobic energy sources, and for anaerobic sources possibly even higher, compared with the stationary ergometer. PMID- 20827656 TI - HELLP syndrome with and without eclampsia. AB - We assessed pregnancy outcomes for patients with HELLP syndrome (hemolysis; elevated liver enzymes; low platelet count) with and without concurrent eclampsia. We performed a retrospective investigation of data spanning three decades of patients with class 1 or 2 HELLP syndrome with concurrent eclampsia (HELLP + E) and patients with HELLP syndrome without eclampsia. Data were analyzed by appropriate tests for continuous or categorical outcomes with differences considered significant if P < 0.05. During 1981 to 1996 and 2000 to 2006, there were 693 patients with class 1 or 2 HELLP syndrome; altogether, 70 patients had HELLP + E. The only demographic difference was greater nulliparity in HELLP + E patients. Otherwise, inconsistent and clinically insignificant differences were observed between groups. Despite the relatively large size of the study groups, we were unable to detect a significant worsening of maternal or perinatal outcome in HELLP + E patients compared with HELLP patients. In our experience, eclampsia does not appear to contribute a significant adverse impact upon the course or outcome of HELLP syndrome pregnancies. PMID- 20827657 TI - Conventional direct laryngoscopy versus videolaryngoscopy with the GlideScope(r): a neonatal manikin study with inexperienced intubators. AB - We hypothesized that because the view of the glottis is better with videolaryngoscopes, successful intubation in neonates would be accomplished in a shorter time with the GlideScope ((r)) (Verathon, Inc., Bothell, WA) videolaryngoscope (GVL). Forty-five students of the University of Athens, inexperienced in both techniques, participated in the study (21 medical students and 24 nursing students, crossover randomized study). Following a brief educational session, each participant practiced and attempted intubation on a neonatal manikin using conventional laryngoscope and GVL, as many times as required to secure the airway. The time required to successful intubation and the number of attempts with each device were recorded. No significant difference was observed between the number of attempts required for successful intubation with either laryngoscope. The time required for the first successful intubation with the conventional laryngoscope was significantly shorter compared with that required with the GVL ( P = 0.0013). There was no difference regarding the time required for the successful intubation between medical and nursing students, using the conventional laryngoscope or the GVL. The number of attempts to successful intubation with either device did not differ. The time required for intubation with the GVL was longer, and this is probably due to a design flaw. PMID- 20827658 TI - Massive obstetric hemorrhage in a Jehovah's Witness: intraoperative strategies and high-dose erythropoietin use. AB - A massive obstetric hemorrhage resulting in an extremely low hematocrit (5.9%) required innovative intraoperative and postoperative management. We used a combination of rapid intraoperative volume replacement, aortic compression, chemical coma, high-dose erythropoietin, and enteral iron replacement to elevate the hematocrit in a patient refusing blood transfusions. PMID- 20827659 TI - Induction of pancreatic phenotypes in central nervous system derived pluripotential progenitor cells. AB - Fetal rat brain stem cells (RSCs) have been induced to express pituitary properties when exposed to pituitary cells (U et al., 2002). In this study, we explored whether these RSCs could also be influenced to acquire properties characteristic of the pancreas. To this end, RSCs in culture were exposed to media conditioned by rat islet tumor cells and media containing Exendin-4 and nicotinamide since both have been shown to induce pancreatic phenotypes in embryonic stem cells. Lastly, an expression construct for pdx-1 was introduced into RSCs. The expression of pancreatic markers was analyzed using RT-PRC and immunocytochemistry. When RSCs were exposed to rat islet tumor cell conditioned media and media containing Exendin-4 and nicotinamide, the expression of pdx-1, insulin and somatostatin were observed. They also acquired a spherical shape typical of pancreatic cells in culture. Under these varied conditions, transcriptional factors essential to pancreatic development such as pdx-1 and Isl 1 were induced. The critical role of pdx-1 in stimulating certain endocrine pancreatic properties in RSCs was further confirmed upon the introduction of an expression construct for pdx-1 which markedly induced insulin and somatostatin. Taken together, these findings suggests that fetal brain stem cells are pluripotent and can be reprogrammed to acquire pancreatic properties through pathways which involved the transcription factor Pdx1. PMID- 20827660 TI - Demographic factors and the presence of comorbidities do not promote early detection of Cushing's disease and acromegaly. AB - OBJECTIVE: The aim of the study was to analyze the time-to-diagnosis interval in patients with Cushing's disease (CD) and acromegaly (AC), to assess factors that promote early disease detection and to investigate the medical fields diagnosing the pathologies. METHODS: 33 CD and 52 AC patients operated over 10 years received a self-designed disease-related questionnaire. Data about symptoms and their duration prior to diagnosis, education level, age, gender and place of residence (i. e. rural vs. urban, size of the city) were collected. RESULTS: The mean time-to-diagnosis interval was 6.0 years in CD and 5.8 years in AC patients. The vast majority of 67% of all investigated patients was diagnosed after they changed their primary health care provider or during a hospital stay owing to comorbidities caused by their underlying disease. Only 33% of all cases were diagnosed by their primary physician. In both groups neither gender, age, place of residence, education level, typical comorbidities (e. g. hypertension or diabetes) nor distinctive symptoms and bodily changes of the underlying disease (e. g. prognathism, acral enlargement, weight gain, buffalo hump) were significant factors promoting early detection. CONCLUSIONS: Apparently, patient related factors do not affect the time-to-diagnosis interval, but rather the change of the primary health care provider. Knowledge of the disease among physicians is prerequisite to early detection. Due to the deleterious sequelae of delayed diagnosis, information programmes in the medical community are of paramount importance. Institution of screening programmes should be evaluated. PMID- 20827661 TI - Serum resistin concentrations are higher in human obesity but independent from insulin resistance. AB - Although obesity may be linked to resistin, the role of resistin in humans is still controversial. Conflicting results of the associations between resistin and BMI and measures of insulin resistance were reported. In view of the yet unexplained role of resistin in human obesity, the aim of this study was to examine correlations between serum resistin concentrations and the degree of human obesity and insulin sensitivity. For this purpose, we investigated 2 homogenous groups of obese and non obese humans, in whom the presence of obesity was the solely differentiating factor. The WHO definition of obesity was used. Study group consisted of 136 obese subjects (75 women and 61 men) and 48 non obese controls (31 women, 17 men) aged 48.0 +/- 10.1, and 48.8 +/- 13.4 yrs, respectively. RESULTS: Obese subjects showed higher resistin concentrations than non obese controls (24.89 +/- 9.73 ng/mL, median 26.61 vs. 15.34 +/- 4.68 ng/mL, median 14.76, P < 0.0001). Resistin concentrations correlated with BMI in the whole cohort (r = 0.4296, P < 0.0001), but not in obese and non-obese subjects separately (r = 0.1418, P = 0.0997; r = 0.2712, P = 0.0623, respectively). Moreover, serum resistin was not influenced by insulin resistance in either group examined. CONCLUSION: Although concentrations of resistin differ between obese and non-obese humans, no relationship between resistin concentration and insulin resistance has been found. Correlations between resistin and BMI are present only in a mixed population but disappear in non obese and obese subjects when analyzed separately. PMID- 20827662 TI - Stanniocalcin 1 induction by thyroid hormone depends on thyroid hormone receptor beta and phosphatidylinositol 3-kinase activation. AB - CONTEXT: Thyroid hormone (TH) mediated changes in gene expression were thought to be primarily initiated by the nuclear TH receptor (TR) binding to a thyroid hormone response element in the promoter of target genes. A recently described extranuclear mechanism of TH action consists of the association of TH-liganded TRbeta with phosphatidylinositol 3-kinase (PI3K) in the cytosol and subsequent activation of the PI3K pathway. OBJECTIVE: The aim of this study was to examine the effect of TH, TRbeta and PI3K on stanniocalcin 1 (STC1) expression in human cells. DESIGN: We treated human skin fibroblasts with triiodothyronine (T3) in the absence or presence of the PI3K inhibitor LY294002, a dominant negative PI3K subunit, Deltap85alpha, and the protein synthesis inhibitor cycloheximide (CHX). The role of the TRbeta was studied in cells from patients with resistance to thyroid hormone (RTH). STC-1 mRNA expression was measured by real-time PCR. RESULTS: We found an induction of STC1 by T3 in normal cells, but less in cells from subjects with RTH (2.7 +/- 0.2 vs. 1.6 +/- 0.04, P < 0.01). The effect of T3 was completely abrogated by blocking PI3K with LY294002 (3.9 +/- 0.5 vs. 0.85 +/- 0.5; P < 0.05) and greatly reduced after transfection of a dominant negative PI3K subunit, demonstrating dependency on the PI3K pathway. CONCLUSION: These results establish STC1 as a TH target gene in humans. Furthermore, we show that STC1 induction by TH depends on both TRbeta and PI3K activation. PMID- 20827663 TI - Diet dependence of diabetes in the New Zealand Obese (NZO) mouse: total fat, but not fat quality or sucrose accelerates and aggravates diabetes. AB - BACKGROUND: Obesity and diabetes in mice can be modified by dietary variables. Here we systematically analysed the effect of the sucrose and fat content and of the fat quality in New Zealand Obese mice, a mouse model of the metabolic syndrome. RESULTS: Male NZO mice fed a semi-purified diet with sucrose exhibited an identical weight gain and diabetes incidence as controls without sucrose. In contrast, mice on a chow diet gained weight more slowly and developed diabetes approximately 10 weeks later than those on the semi-purified diet (energy density 3.05 vs. 3.85 kcal/g; fibre content 12.9 vs. 4.7%). In a second experimental series, neither the fat content (10 vs. 40% of the total energy) nor the quality of the fat (lard, safflower oil, or fish oil) of semi-purified diets modified weight gain. However, diabetes started approximately 2 weeks earlier and appeared more severe (blood glucose 30 vs. 20 mmol/l at week 13) in the high-fat diet group (energy density 4.58 kcal/g; fibre content 5.7%). CONCLUSIONS: Obesity in NZO mice develops independent of the dietary sucrose or fat content, and of the fat quality. However, the dietary fat content accelerates the onset of diabetes without enhancing adiposity. In contrast, chow diet exerts an anti adipogenic/anti-diabetogenic effect that appears to be due to its lower caloric density and/or its higher fibre content. PMID- 20827664 TI - Impaired glucose tolerance in obese white children and adolescents: three to five year follow-up in untreated patients. AB - OBJECTIVE: Impaired glucose tolerance (IGT) is a predictor of type 2 diabetes in adults. However, the converting rate from IGT to diabetes is largely unknown in obese children. METHODS: We analyzed all 128 obese white European children diagnosed with IGT at our institution in the years 2003-2006 (mean age 13.5 +/- 2.1 years, 53% female, mean BMI 31.7 +/- 6.1 kg/m2) 3.0-5.6 years (mean 3.9 +/- 0.6 years) later with an oral glucose tolerance test (oGTT). RESULTS: At follow up, 20 (16%) children remained in the IGT status, 96 (75%) children converted to normal glucose metabolism, 3 (2%) children developed type 2 diabetes, and 9 (7%) children were lost to follow-up. Comparing the children according to their outcome concerning glucose metabolism at follow-up demonstrated that 2 h glucose levels in oGTT at baseline were significantly (p<0.001) higher in the children remaining IGT and highest in children developing diabetes, while the children did not differ in respect of age, gender, BMI, blood pressure, fasting glucose levels at baseline, or length of follow-up period. Apart from children developing diabetes, who increased their body weight, all the other children did not change their BMI, blood pressure, or fasting glucose levels significantly at follow-up. CONCLUSIONS: Obese white children with IGT will likely convert to normal glucose metabolism in the next 3-5 years. Risk factors for developing type 2 diabetes in follow-up were higher 2 h glucose levels in oGTT at baseline and weight gain. PMID- 20827665 TI - Rapid response to sorafenib in metastatic medullary thyroid carcinoma. AB - OBJECTIVE: To investigate the efficacy of sorafenib in progressive metastatic Medullary Thyroid Carcinoma (MTC), for which there is currently no effective treatment. DESIGN: Off-label observational study. METHODS: Sorafenib 400 mg twice daily was evaluated. The primary endpoint was the objective Response Evaluation Criteria in Solid Tumours (RECIST) score assessed on day 28 and every 12 weeks thereafter. Additional endpoints were time to response, duration of tumour response, tumour-related symptoms, and changes in tumour markers, calcitonin, and CEA measured initially, at 2 weeks, and then every 4 weeks. Therapy duration was 2 weeks, and 3-12 months. RESULTS: The 5 patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. 2 patients showed a partial response with tumour regression of -46% and -36% after 6 and 9 months, respectively, and 2 patients exhibited tumour regression of -14% and -29%, respectively (stable disease). Ultrasound documented regression of -37% within 2 weeks occurred in 1 patient. Calcitonin decreased within 2 weeks in all patients by -69, -90, -75, -96, and -39%, respectively. 1 patient died because of progressive ascites from acute renal and hepatocellular failure. 2 patients developed grade 3 hand-foot syndrome within the first month, so that sorafenib was interrupted or reduced; other side effects were rash, fatigue, and hair loss. 3 patients remain on sorafenib, 2 at a reduced dosage (600 mg/d). CONCLUSION: These data suggest a possible role for sorafenib in the treatment of progressive metastatic MTC. PMID- 20827666 TI - [Alloplastic cancellous bone replacement and fibrin glue in hand surgery]. AB - INTRODUCTION: Alloplastic replacement of cancellous bone is being increasingly used in the clinical setting. The use in hand surgery, however, is only sparsely documented. MATERIALS AND METHODS: We report about the use of micro- and macroporous biphasic calicium phosphate granulate (Tricos ((r))) in combination with fibrin sealant (Tissucol ((r))) in six patients undergoing surgery of the hand involving cancellous bone deficits. The indications ranged from carpal stabilisation to DIP athrodesis. Follow-up time was up to 15 months. RESULTS: Because cancellous bone harvesting could be avoided, morbidity and the extent of surgery could be reduced in all patients. Healing was uneventful and the clinical course as documented by X-ray controls, toleration of physiotherapeutic exercises and stability was analogous to that of conventional surgery involving cancellous bone grafting. CONCLUSION: These first results indicate that alloplastic replacement of spongiosa grafts, especially by micro- and macroporous biphasic calcium phosphate granulate can possibly be successfully used in surgery of the hand. The extent of bony remodelling still needs to be determined by further examination. PMID- 20827667 TI - Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. AB - We consider random effects meta-analysis where the outcome variable is the occurrence of some event of interest. The data structures handled are where one has one or more groups in each study, and in each group either the number of subjects with and without the event, or the number of events and the total duration of follow-up is available. Traditionally, the meta-analysis follows the summary measures approach based on the estimates of the outcome measure(s) and the corresponding standard error(s). This approach assumes an approximate normal within-study likelihood and treats the standard errors as known. This approach has several potential disadvantages, such as not accounting for the standard errors being estimated, not accounting for correlation between the estimate and the standard error, the use of an (arbitrary) continuity correction in case of zero events, and the normal approximation being bad in studies with few events. We show that these problems can be overcome in most cases occurring in practice by replacing the approximate normal within-study likelihood by the appropriate exact likelihood. This leads to a generalized linear mixed model that can be fitted in standard statistical software. For instance, in the case of odds ratio meta-analysis, one can use the non-central hypergeometric distribution likelihood leading to mixed-effects conditional logistic regression. For incidence rate ratio meta-analysis, it leads to random effects logistic regression with an offset variable. We also present bivariate and multivariate extensions. We present a number of examples, especially with rare events, among which an example of network meta-analysis. PMID- 20827668 TI - First-trimester serum PAPP-A and fbeta-hCG concentrations and other maternal characteristics to establish logistic regression-based predictive rules for adverse pregnancy outcome. AB - OBJECTIVE: To determine the clinical relevance of maternal characteristics and first-trimester serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and free beta human chorionic gonadotrophin (fbeta-hCG) in predicting placenta-related complications, miscarriage and preterm delivery. DESIGN, SETTING AND POPULATION: A historical cohort study of data of the National Institute for Public Health and the Environment of first-trimester screening tests performed between July 2002 and May 2006 was done. Data from 28 566 (64.1%) tests were eligible for analysis. METHODS: By logistic regression, predictive rules were made based on PAPP-A and fbeta-hCG concentrations, maternal smoking, maternal weight and age, low birth weight, stillbirth and hypertensive disorders, miscarriage and preterm birth. Predictive values were analysed with the area under the curve (AUC) of receiver operating curves (ROC). RESULTS: Predictive for placenta-related complications were low PAPP-A, low fbeta-hCG, smoking and weight (AUC 54%). For miscarriage low PAPP-A, low fbeta-hCG and maternal age (MA) were predictive (AUC 78%) and for preterm delivery low PAPP-A, smoking, MA and maternal weight (AUC 55%). CONCLUSION: Only the predictive model for miscarriage had a clinically relevant predictive value of 28%. Results together do not justify closer surveillance of chromosomally normal pregnancies with PAPP-A or fbeta-hCG levels below the fifth percentile. PMID- 20827669 TI - Mechanical stability in a human radius fracture treated with a novel tissue engineered bone substitute: a non-invasive, longitudinal assessment using high resolution pQCT in combination with finite element analysis. AB - The clinical gold standard in orthopaedics for treating fractures with large bone defects is still the use of autologous, cancellous bone autografts. While this material provides a strong healing response, the use of autografts is often associated with additional morbidity. Therefore, there is a demand for off-the shelf biomaterials that perform similar to autografts. Biomechanical assessment of such a biomaterial in vivo has so far been limited. Recently, the development of high-resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure bone structure in humans in great detail. Finite element analysis (FEA) has been used to accurately estimate bone mechanical function from three-dimensional CT images. The aim of this study was therefore to determine the feasibility of these two methods in combination, to quantify bone healing in a clinical case with a fracture at the distal radius which was treated with a new bone graft substitute. Validation was sought through a conceptional ovine model. The bones were scanned using HR-pQCT and subsequently biomechanically tested. FEA derived stiffness was validated relative to the experimental data. The developed processing methods were then adapted and applied to in vivo follow-up data of the patient. Our analyses indicated an 18% increase of bone stiffness within 2 months. To our knowledge, this was the first time that microstructural finite element analyses have been performed on bone-implant constructs in a clinical setting. From this clinical case study, we conclude that HR-pQCT-based micro finite element analyses show high potential to quantify bone healing in patients. PMID- 20827670 TI - Fetal ocular measurements by MRI. AB - OBJECTIVE: To present fetal magnetic resonance imaging (MRI) ocular measurement ranges by gestational age (GA) in normal and growth-restricted fetuses. METHODS: A total of 298 pregnant women from the 18th to the 39th week of gestation were imaged using MRI. Ocular measurements including binocular distance (BOD), interocular distance (IOD), transverse ocular diameter (OD) and anterior posterior (AP) OD were measured. The curve estimation analyses for linear, logarithmic and quadratic models were performed. The ocular measurements of the fetuses with intrauterine growth restriction (IUGR) were compared with that of the normal fetuses. RESULTS: The fetal eye resembles an ellipsoid with significantly longer OD and shorter AP (t = - 22.07, p < 0.001). The quadratic model was the best model in predicting growth of the fetal BOD, IOD, OD and AP. The ocular measurements of the fetuses with IUGR were significantly different from that of the normal fetuses (BOD: t = 3.58, p < 0.001; IOD: t = 5.73, p < 0.001; OD: t = 3.52, p < 0.001; AP: t = 2.19, p < 0.05). CONCLUSION: Fetal ocular growth can be readily assessed by fetal MRI. Using the normative data provided in this study, fetal ocular anomalies may be detected. Ocular size is frequently reduced in the condition of IUGR, with potential pathologic impact on postnatal vision. PMID- 20827671 TI - High-pressure chemical deposition for void-free filling of extreme aspect ratio templates. PMID- 20827672 TI - Diving-surfacing cycle within a stimulus-responsive smart device towards developing functionally cooperating systems. PMID- 20827673 TI - Nanoscopic patterned materials with tunable dimensions via atomic layer deposition on block copolymers. PMID- 20827675 TI - c9t11-Conjugated linoleic acid-rich oil fails to attenuate wasting in colon-26 tumor-induced late-stage cancer cachexia in male CD2F1 mice. AB - SCOPE: Cancer cachexia is characterized by muscle and adipose tissue wasting caused partly by chronic, systemic inflammation. Conjugated linoleic acids (CLAs) are a group of fatty acids with various properties including anti-inflammatory cis9, trans11 (c9t11)-CLA and lipid-mobilizing trans10, cis12 (t10c12)-CLA. The purpose of this study was to test whether dietary supplementation of a c9t11-CLA rich oil (6:1 c9t11:t10c12) could attenuate wasting of muscle and adipose tissue in colon-26 adenocarcinoma-induced cachexia in mice. METHODS AND RESULTS: Loss of body weight, muscle and adipose tissue mass caused by tumors were not rescued by supplementation with the c9t11-CLA-rich oil. In quadriceps muscle, c9t11-CLA-rich oil exacerbated tumor-induced gene expression of inflammatory markers tumor necrosis factor-alpha, IL-6 receptor and the E3 ligase MuRF-1 involved in muscle proteolysis. In epididymal adipose tissue, tumor-driven delipidation and atrophy was aggravated by the c9,t11-CLA-rich oil, demonstrated by further reduced adipocyte size and lower adiponectin expression. However, expression of inflammatory cytokines and macrophage markers were not altered by tumors, or CLA supplementation. CONCLUSION: These data suggest that addition of c9t11-CLA-rich oil (0.6% c9t11, 0.1% t10c12) in diet did not ameliorate wasting in mice with cancer cachexia. Instead, it increased expression of inflammatory markers in the muscle and increased adipose delipidation. PMID- 20827674 TI - Murine model of chronic L. (Viannia) panamensis infection: role of IL-13 in disease. AB - Leishmania (Viannia) organisms are the most prevalent etiologic agents of human cutaneous leishmaniasis in the Americas. Nevertheless, our knowledge of the immunological mechanisms exploited by L. (Viannia) organisms remains limited and the mechanisms underlying disease are not well understood. Here, we report the development of a BALB/c mouse model of L. (V.) panamensis infection that is able to reproduce chronic disease, with persistent infection and clinically evident lesions for over 1 year. The immune response of the mouse resembles that found for L. (V.) panamensis-infected patients with chronic and recurrent lesions, presenting a mixed Th1/Th2 response with the presence of TNF-alpha, IFN-gamma, IL 10 and IL-13. Using immunodeficient mice, the critical role for IL-13 and/or IL 4Ralpha in determining susceptibility to chronic infection was evident. With the induction of healing in the immunodeficient mice, increases in IFN-gamma and IL 17 were found, concomitant with parasite control and elimination. Specifically, increases in CD4(+) (but not CD8(+)) T cells producing IFN-gamma were observed. These results suggest that IL-13 represents an important target for disease control of L. (V.) panamensis infection. This murine model should be useful to further understand the pathology associated with chronic disease and to develop methods for the treatment and prevention of leishmaniasis caused by L. (Viannia) parasites. PMID- 20827676 TI - Coffee, broccoli and spices are strong inducers of electrophile response element dependent transcription in vitro and in vivo - studies in electrophile response element transgenic mice. AB - SCOPE: Cytoprotective gene products, e.g. phase II - and antioxidant enzymes, are important in cellular redox homeostasis. A common feature of these genes is binding sites for transcription factor nuclear factor erythroid-2-related factor 2 (Nrf2), named electrophile response elements (EpREs) within their promoters. METHODS AND RESULTS: To identify dietary bioactive compounds and foods with Nrf2/EpRE inducing properties in an intact organism, we utilized transgenic mice encoding luciferase under control of EpRE from the thioredoxin promoter. We found that 18 of 31 phytochemicals and 10 of 14 dietary plant extracts induced EpRE activity in liver HepG2 cells. Surprisingly, some dietary plant extracts showed profound inducing capability as compared to pure compounds indicating combinatorial effects of compounds found in whole foods. Furthermore, intraperitoneal injections of carnosol, curcumin and tert benzohydroquinine induced EpRE-dependent promoter activity in transgenic mice. In further experiments with curcumin, we found highly induced EpRE activity in intestine, liver, kidney and spleen. Finally, a combination extract made of coffee, thyme, broccoli, rosemary, turmeric and red onion fed orally, induced EpRE mediated luciferase in lung and adipose tissue. CONCLUSION: These results show that plant based foods contain compounds that can be absorbed and induce the antioxidant defence in a living organism in an organ-specific manner. PMID- 20827677 TI - Signalling mechanisms regulating axonal branching in vivo. AB - Identification of the molecular mechanisms underlying axonal branching in vivo has begun in several neuronal systems, notably the projections formed by dorsal root ganglion (DRG) neurons or retinal ganglion cells (RGC). cGMP signalling is essential for sensory axon bifurcation at the spinal cord, whereas brain-derived neurotrophic factor (BDNF) and ephrinA signalling establish position-dependent branching of RGC axons. In the latter system, the degradation of specific signalling components, via the ubiquitin-proteasome system, may provide an additional mechanism involved in axon branching of RGC. The process of arborisation is essential for neurons to innervate multiple targets and to build topographic maps. The various forms of branching found in different types of neurons are regulated by distinct signalling pathways activated by multiple extracellular cues in addition to axonal guidance factors. These signalling cascades, together with transcriptional programs, most likely interact and trigger the polymerisation or depolymerisation of the actin and tubulin cytoskeleton to regulate branching. PMID- 20827678 TI - Uniaxial cyclic tensile stretch inhibits osteogenic and odontogenic differentiation of human dental pulp stem cells. AB - As the most important organs of occlusion, teeth are subjected to a variety of mechanical stresses. These stresses are transmitted into the dental pulp tissue and affect the dental pulp stem cells. In this study, human dental pulp stem cells were isolated from human impacted third molars and their multilineage differentiation abilities were tested. Human dental pulp stem cells were then exposed to cyclic tensile stretch. The results showed that the cyclic tensile stretch inhibited the expression of osteogenic marker genes and proteins such as BMP-2, OCN and ALP. Simultaneously, odontogenic marker genes and proteins such as DSPP, DSP and BSP were also inhibited by the mechanical stress. It was concluded that cyclic tensile stretch inhibits the osteogenic and odontogenic differentiation of dental pulp stem cells. PMID- 20827679 TI - Construction of cuprous oxide electrodes composed of 2D single-crystalline dendritic nanosheets. AB - An unusual anisotropic growth of Cu(2)O is stabilized via the electrochemical synthesis of Cu(2)O in the presence of Ag(+) ions, which results in the formation of Cu(2)O electrodes composed of 2D sheetlike crystals containing complex dendritic patterns. It is quite unusual for Cu(2)O to form a 2D morphology since it has a 3D isotropic cubic crystal structure where the a, b, and c axes are equivalent. Each Cu(2)O sheet is single-crystalline in nature and is grown parallel to the {110} plane, which is rarely observed in Cu(2)O crystal shapes. A various set of experiments are performed to understand the role of Ag(+) ions on the 2D growth of Cu(2)O. The results show that Ag(+) ions are deposited as silver islands on already growing Cu(2)O crystals and serve as nucleation sites for the new growth of Cu(2)O crystals. As a result, the growth direction of the newly forming Cu(2)O crystals is governed by the diffusion layer structure created by the pre-existing Cu(2)O crystals, which results in the formation of 2D dendritic patterns. The thin 2D crystal morphology can significantly increase the surface to-volume ratio of Cu(2)O crystals, which is beneficial for enhancing various electrochemical and photoelectrochemical properties of the electrodes. The photoelectrochemical properties of the Cu(2)O electrodes composed of 2D dendritic crystals are investigated and compared to those of 3D dendritic crystals. This study provides a unique and effective route to maximize the {110} area per unit volume of Cu(2)O, which will be beneficial for any catalytic/sensing abilities that can be anisotropically enhanced by the {110} planes of Cu(2)O. PMID- 20827680 TI - Understanding the photothermal conversion efficiency of gold nanocrystals. AB - Plasmon-based photothermal therapy is one of the most intriguing applications of noble metal nanostructures. The photothermal conversion efficiency is an essential parameter in practically realizing this application. The effects of the plasmon resonance wavelength, particle volume, shell coating, and assembly on the photothermal conversion efficiencies of Au nanocrystals are systematically studied by directly measuring the temperature of Au nanocrystal solutions with a thermocouple and analyzed on the basis of energy balance. The temperature of Au nanocrystal solutions reaches the maximum at ~75 degrees C when the plasmon resonance wavelength of Au nanocrystals is equal to the illumination laser wavelength. For Au nanocrystals with similar shapes, the larger the nanocrystal, the smaller the photothermal conversion efficiency becomes. The photothermal conversion can also be controlled by shell coating and assembly through the change in the plasmon resonance energy of Au nanocrystals. Moreover, coating Au nanocrystals with semiconductor materials that have band gap energies smaller than the illumination laser energy can improve the photothermal conversion efficiency owing to the presence of an additional light absorption channel. PMID- 20827681 TI - Aligned conjugated polymers standing upright. PMID- 20827682 TI - Two-photon microscopy of healthy, infarcted and stem-cell treated regenerating heart. AB - Two-photon excitation autofluorescence (produced in myocytes) and second-harmonic generation (produced mainly by collagen) allow label-free visualization of these two important components of myocardium. Because of their different emission wavelengths, these two signals can be separated spectrally. Here, we examine two photon microscopy images of healthy, infarcted and stem-cell treated rat hearts. We find that in infarcted heart, regions distant from the site of infarct are similar to healthy tissue in composition (mostly myocytes, very little collagen) and organization (densely packed myocytes), but infarct regions are characterized by sparse myocytes and high collagen content indicative of scar tissue formation. Stem cell treated hearts, in contrast, show regions of intertwined myocytes and collagen throughout the infarct, suggesting reduced tissue damage. Finally, these results offer interesting insights into our ongoing polarized light studies of cardiac tissue anisotropy, and reveal that both tissue composition and tissue micro-organization are reflected in polarization-measured linear retardance values. PMID- 20827683 TI - Solution-processed highly efficient blue phosphorescent polymer light-emitting diodes enabled by a new electron transport material. PMID- 20827684 TI - Nanostructured hybrid solar cells: dependence of the open circuit voltage on the interfacial composition. PMID- 20827685 TI - An easily synthesized blue polymer for high-performance polymer solar cells. PMID- 20827686 TI - Thin film field-effect phototransistors from bandgap-tunable, solution-processed, few-layer reduced graphene oxide films. PMID- 20827687 TI - Analysis of charge photogeneration as a key determinant of photocurrent density in polymer: fullerene solar cells. PMID- 20827688 TI - Tunable photonic polyelectrolyte colorimetric sensing for anions, cations and zwitterions. PMID- 20827689 TI - Spectroscopic implications of the electron donor-acceptor effect in the photoactive yellow protein chromophore. AB - The importance of the donor-acceptor push-pull system in the photoabsorption of the trans p-coumaric acid, the cofactor within the photoactive yellow protein and other xanthopsins, has been investigated. We recorded gas-phase absorption spectra and performed high-level quantum chemical calculations of three chromophore models, namely, the deprotonated trans ortho-, meta- and para-methyl coumarates. The ortho and para isomers, which have the electron-donating phenoxy oxygen and the electron-withdrawing acyl group in conjugation, present absorptions in the high-energy region of the visible spectrum, that is, in the interval of wavelengths in which the photoactivity of the xanthopsins is observed. On the other hand, the meta isomer, in which the conjugation between the phenoxy and acyl groups is disrupted, exhibits a significantly shifted maximum and presents no absorption in the region from blue to ultraviolet A. It is found that the push-pull system in the trans p-coumaric acid is critical for the wavelength and the intensity of its photoabsorption. Absorption spectra were also measured in methanol and showed an appreciable hypsochromic effect. Linear response calculations within the formalism of the approximate coupled cluster singles and doubles CC2 model and time-dependent DFT using the functional CAM B3LYP provided insights into the relevant processes of excitation and aided to the interpretation of the experimental results. There is good agreement between theory and experiment in the description of the gas-phase absorption spectra of the considered chromophore models. Differential density plots were used to predict the effect of hydrogen-bonded amino acids to the trans p-coumaric acid on the protein tuning of this chromophore. PMID- 20827690 TI - Conversion of methane to methanol: nickel, palladium, and platinum (d9) cations as catalysts for the oxidation of methane by ozone at room temperature. AB - The room-temperature chemical kinetics has been measured for the catalytic activity of Group 10 atomic cations in the oxidation of methane to methanol by ozone. Ni(+) is observed to be the most efficient catalyst. The complete catalytic cycle with Ni(+) is interpreted with a computed potential energy landscape and, in principle, has an infinite turnover number for the oxidation of methane, without poisoning side reactions. The somewhat lower catalytic activity of Pd(+) is reported for the first time and also explored with DFT calculations. Pt(+) is seen to be ineffective as a catalyst because of the observed failure of PtO(+) to convert methane to methanol. PMID- 20827691 TI - Pentiptycene-derived light-driven molecular brakes: substituent effects of the brake component. AB - Five pentiptycene-derived stilbene systems (1 R; R = H, OM, NO, Pr, and Bu) have been prepared and investigated as light-driven molecular brakes that have different-sized brake components (1 H<1 OM<1 NO<1 Pr<1 Bu). At room temperature (298 K), rotation of the pentiptycene rotor is fast (k(rot)=10(8)-10(9) s(-1)) with little interaction with the brake component in the trans form ((E)-1 R), which corresponds to the brake-off state. When the brake is turned on by photoisomerization to the cis form ((Z)-1 R), the pentiptycene rotation can be arrested on the NMR spectroscopic timescale at temperatures that depend on the brake component. In the cases of (Z)-1 NO, (Z)-1 Pr, and (Z)-1 Bu, the rotation is nearly blocked (k(rot)=2-6 s(-1)) at 298 K. It is also demonstrated that the rotation is slower in [D(6)]DMSO than in CD(2)Cl(2). A linear relationship between the free energies of the rotational barrier and the steric parameter A values is present only for (Z)-1 H, (Z)-1 OM, and (Z)-1 NO, and it levels off on going from (Z)-1 NO to (Z)-1 Pr and (Z)-1 Bu. DFT calculations provide insights into the substituent effects in the rotational ground and transition states. The molar reversibility of the E-Z photoswitching is up to 46%, and both the E and Z isomers are stable under the irradiation conditions. PMID- 20827692 TI - New and facile approach for the synthesis of (E)-alpha,beta-unsaturated esters and ketones. PMID- 20827693 TI - Ligand effects on the surface composition of Rh-containing ionic liquid solutions used in hydroformylation catalysis. PMID- 20827694 TI - Recycling functional colloids and nanoparticles. AB - The stability and separation of colloids and nanoparticles has been addressed in numerous studies. Most of the work reported to date requires high cost, energy intensive approaches such as ultracentrifugation and solvent evaporation to recover the particles. At this point of time, when green science is beginning to make a real impact, it is vital to achieve efficient and effective separation and recovery of colloids to provide environmental and economic benefits. This article explores recent advances in strategies for recycling and reusing functional nanomaterials, which indicate new directions in lean engineering of high-value nanoparticles, such as Au and Pd. PMID- 20827695 TI - The spermine-bisaryl conjugate as a potent inducer of B- to Z-DNA transition. AB - DNA containing alternating purine and pyrimidine repeats has the potential to adopt the Z-DNA structure, one of the well-studied structures besides A- and B DNA. Despite a number of molecular models that have been proposed to explain the mechanism for B->Z transition, there is continued discussion on the mechanism and physiological role of this transition. In this study, we have found that the bis(2-naphthyl)-maleimide-spermine conjugate (3c) exhibits a remarkable ability to cause the B->Z transition of d(CGCGCG)(2) at low salt concentrations. Using isothermal titration calorimetry (ITC) we show that the B->Z transition induced by 3c is both enthalpically and entropically favorable. The ligand might effect the dehydration of B-DNA, which leads to the B->Z transition. Interestingly, an intermediate CD between the B and Z forms was observed in the pH-dependent transition in the presence of the ligand. The unique structure and characteristics of the ligand designed in this investigation will be useful for the study of Z-DNA. PMID- 20827696 TI - Recent strategies for the synthesis of pyridine derivatives. AB - Recent advances in pyridine synthesis are described. Modification of traditional condensation strategies continues to be a recurrent theme in contemporary literature. Advancements in transition-metal-catalyzed cyclization and cross coupling procedures offer new routes to functionalized pyridine derivatives. These recently developed methodologies are a valuable addition to azaheterocycle synthesis. PMID- 20827697 TI - Quasi-one-dimensional electronic systems formed from boron dipyrromethene (BODIPY) dyes. AB - Synthetic strategies have been devised that allow the rational design and isolation of highly coloured boron dipyrromethene (BODIPY) dyes that absorb across much of the visible region. Each dye has an aryl polycycle (usually pyrene or perylene) connected to the central BODIPY core through a conjugated tether at the 3,5-positions. Both mono- and difunctionalised derivatives are accessible, in certain cases containing both pyrene and perylene residues. For all new compounds, the photophysical properties have been recorded in solution at ambient temperature and in a glassy matrix at 77 K. The presence of the aryl polycycle(s) affects the absorption and emission maxima of the BODIPY nucleus, thereby confirming that these units are coupled electronically. Indeed, the band maxima and oscillator strengths depend on the conjugation length of the entire molecule, whereas there is no sign of fluorescence from the polycycle. As a consequence, the radiative rate constant tends to increase with each added appendage. The nature of the linkage (styryl, ethenyl, or ethynyl) also exerts an effect on the photophysical properties and, in particular, the absorption spectrum is perturbed in the region of the aryl polycycle. The perylene-containing BODIPY derivatives absorb over a wide spectral range and emit in the far-red region in almost quantitative yield. A notable exception to this generic behaviour is provided by the anthracenyl derivative, which exhibits charge-transfer absorption and emission spectra in weakly polar media at ambient temperature. Regular BODIPY like behaviour is restored in a glassy matrix at 77 K. Overall, these new dyes represent an important addition to the range of strongly absorbing and emitting reagents that could be used as solar concentrators. PMID- 20827698 TI - Calix[6]arene-based cascade complexes of organic ion triplets stable in a protic solvent. AB - Herein we report a D(3h)-symmetric tail-to-tail bis-calix[6]arene 3 featuring two divergent cavities triply connected by ureido linkages. This calix[6]tube was synthesized by a domino Staudinger/aza-Wittig reaction followed by a macrocyclization reaction. This process also afforded a C(2h)-symmetric isomer that represents a rare example of a self-threaded rotaxane based on calix[6]arene subunits. The binding properties of 3 have been evaluated by NMR studies. Thus, bis-calix[6]arene 3 is able to bind simultaneously two neutral ureido guests through an induced-fit process. The guests are located in the cavities and are recognized through multiple hydrogen-bonding interactions with the ureido bridges. Host 3 can also simultaneously bind multiple ions and is especially efficient for the complexation of organic ion triplets. The anion is recognized through hydrogen-bonding interactions at the ureido binding site and is thus located between the two ammonium ions accommodated in the cavities. The resulting [1+1+2] quaternary complexes represent rare examples of cascade complexes with organic cations. These complexes are unique: 1) They are stable even in a markedly protic solvent, 2) the recognition of the ion triplets proceeds in a cooperative way through an induced-fit process and with a high selectivity, linear cations and doubly charged anions being particularly well recognized, 3) the ions are bound as contact ion triplets thanks to the closeness of the three binding sites, 4) the cationic guests can be exchanged and thus mixed [1+1+1+1] complexes can be obtained, 5) the ureido linkers wrapped around the anion adopt a helical shape and the resulting chirality is sensed by the cations. In other words, bis-calix[6]arene 3 presents a selective inner tunnel in which multiple guests such as organic ion triplets can be aligned in a cooperative way through induced-fit processes. PMID- 20827699 TI - The versatile coordination modes of monophosphine-o-carborane in the formation of iridium and rhodium complexes: synthesis, reactivity, and characterization. AB - Monophosphine-o-carborane has four competitive coordination modes when it coordinates to metal centers. To explore the structural transitions driven by these competitive coordination modes, a series of monophosphine-o-carborane Ir,Rh complexes were synthesized and characterized. [Cp*M(Cl)(2){1-(PPh(2))-1,2 C(2)B(10)H(11)}] (M=Ir (1a), Rh (1b); Cp*=eta(5)-C(5)Me(5)), [Cp*Ir(H){7-(PPh(2)) 7,8-C(2)B(9)H(11)}] (2a), and [1-(PPh(2))-3-(eta(5)-Cp*)-3,1,2-MC(2)B(9)H(10)] (M=Ir (3a), Rh (3b)) can be all prepared directly by the reaction of 1-(PPh(2)) 1,2-C(2)B(10)H(11) with dimeric complexes [(Cp*MCl(2))(2)] (M=Ir, Rh) under different conditions. Compound 3b was treated with AgOTf (OTf=CF(3)SO(3) (-)) to afford the tetranuclear metallacarborane [Ag(2)(thf)(2)(OTf)(2){1-(PPh(2))-3 (eta(5)-Cp*)-3,1,2-RhC(2)B(9)H(10)}(2)] (4b). The arylphosphine group in 3a and 3b was functionalized by elemental sulfur (1 equiv) in the presence of Et(3)N to afford [1-{(S)PPh(2)}-3-(eta(5)-Cp*)-3,1,2-MC(2)B(9)H(10)] (M=Ir (5a), Rh (5b)). Additionally, the 1-(PPh(2))-1,2-C(2)B(10)H(11) ligand was functionalized by elemental sulfur (2 equiv) and then treated with [(Cp*IrCl(2))(2)], thus resulting in two 16-electron complexes [Cp*Ir(7-{(S)PPh(2)}-8-S-7,8 C(2)B(9)H(9))] (6a) and [Cp*Ir(7-{(S)PPh(2)}-8-S-9-OCH(3)-7,8-C(2)B(9)H(9))] (7a). Compound 6a further reacted with nBuPPh(2), thereby leading to 18-electron complex [Cp*Ir(nBuPPh(2))(7-{(S)PPh(2)}-8-S-7,8-C(2)B(9)H(10))] (8a). The influences of other factors on structural transitions or the formation of targeted compounds, including reaction temperature and solvent, were also explored. PMID- 20827700 TI - Hydrogen-atom abstraction from methane by stoichiometric vanadium-silicon heteronuclear oxide cluster cations. AB - Vanadium-silicon heteronuclear oxide cluster cations were prepared by laser ablation of a V/Si mixed sample in an O(2) background. Reactions of the heteronuclear oxide cations with methane in a fast-flow reactor were studied with a time-of-flight (TOF) mass spectrometer to detect the cluster distribution before and after the reactions. Hydrogen abstraction reactions were identified over stoichiometric cluster cations [(V(2)O(5))(n)(SiO(2))(m)](+) (n=1, m=1-4; n=2, m=1), and the estimated first-order rate constants for the reactions were close to that of the homonuclear oxide cluster V(4)O(10) (+) with methane. Density functional calculations were performed to study the structural, bonding, electronic, and reactivity properties of these stoichiometric oxide clusters. Terminal-oxygen-centered radicals (O(t)*) were found in all of the stable isomers. These O(t)* radicals are active sites of the clusters in reaction with CH(4). The O(t)* radicals in [V(2)O(5)(SiO(2))(1-4)](+) clusters are bonded with Si rather than V atoms. All the hydrogen abstraction reactions are favorable both thermodynamically and kinetically. This work reveals the unique properties of metal/nonmetal heteronuclear oxide clusters, and may provide new insights into CH(4) activation on silica-supported vanadium oxide catalysts. PMID- 20827701 TI - Experimental and theoretical investigations on the magnetic-field-induced variation of surface energy of Co3O4 crystal faces. PMID- 20827702 TI - Asymmetric Diels-Alder and inverse-electron-demand hetero-Diels-Alder reactions of beta,gamma-unsaturated alpha-ketoesters with cyclopentadiene catalyzed by N,N' dioxide copper(II) complex. AB - Highly enantioselective Diels-Alder (DA) and inverse-electron-demand hetero-Diels Alder (HDA) reactions of beta,gamma-unsaturated alpha-ketoesters with cyclopentadiene catalyzed by chiral N,N'-dioxide-Cu(OTf)(2) (Tf=triflate) complexes have been developed. Quantitative conversion of beta,gamma-unsaturated alpha-ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) were observed for a broad range of substrates. Both aromatic and aliphatic beta,gamma-unsaturated alpha-ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94%) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65%) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1 1.5 mol%). A strong positive nonlinear effect was observed. PMID- 20827703 TI - A gram-scale batch and flow total synthesis of perhydrohistrionicotoxin. AB - The total synthesis of the spiropiperidine alkaloid (-)-perhydrohistrionicotoxin (perhydro-HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)-(-)-6 Pentyltetrahydro-pyran-2-one 8 underwent nucleophilic ring opening to afford the alcohol 10, which was elaborated to the nitrone 13. Protection of the nitrone as the 1,3-adduct of styrene and side-chain extension to the unsaturated nitrile afforded a precursor 17, which underwent dipolar cycloreversion and 1,3-dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro-HTX 2. The principal steps to the spirocycle 18 have successfully been transferred into flow mode by using different types of microreactors and in a telescoped fashion, allowing for a more rapid access to the histrionicotoxins and their analogues by continuous processing. PMID- 20827704 TI - Sulfur ylide promoted synthesis of N-protected aziridines: a combined experimental and computational approach. AB - A range of N-protected aziridines [N-Tosyl (N-Ts), N-2 trimethylsilylethanesulfonamide (N-SES), N-tert-butoxycarbonylamido (N-Boc), and N-o-nitrobenzenesulfonamide (oNs)] were prepared in moderate to good yield and with high enantiomeric excess of both isomers starting from N-protected imines, using a sulfonium salt derived from Eliel's oxathiane. The diastereoselectivities of the reactions are influenced by the imine N-protecting group, the imine substituent, and the sulfide structure. An unusual cis selectivity was observed in the formation of N-tosyl-2-phenyl-3-tert-butylaziridine and N-o trimethylsilylethanesulfonamide-2-phenyl-3-tert-butylaziridine, which was explained by using computational models. The analysis suggests that betaine formation in the case of N-tosyl-tert-butylaldimine aziridination using oxathiane benzyl sulfonium ylide 1' is reversible and that the selectivity is determined at the rotation step, which is unusual for semistabilized ylide aziridination. We have shown herein that the steric bulk of an imine substituent, in combination with a sterically demanding sulfonium ylide, can also affect the reversibility of the reaction. This is the first example of this sort involving aziridinations using semistabilized ylides. PMID- 20827705 TI - Prediction of EPR spectra of liquid crystals with doped spin probes from fully atomistic molecular dynamics simulations: exploring molecular order and dynamics at the phase transition. AB - Liquid crystals spin their secrets: Electron paramagnetic resonance (EPR) spectra are predicted directly and completely from fully atomistic molecular dynamics (MD) simulations of 4-cyano-4-n-pentylbiphenyl (5CB) nematic liquid crystals with a doped nitroxide spin probe (depicted in yellow; red curve = simulated and blue curve = measured EPR spectrum). PMID- 20827706 TI - Tetrathiafulvalene-amido-2-pyridine-N-oxide as efficient charge-transfer antenna ligand for the sensitization of Yb(III) luminescence in a series of lanthanide paramagnetic coordination complexes. AB - The tetrathiafulvalene-amido-2-pyridine-N-oxide (L) ligand has been employed to coordinate 4f elements. The architecture of the complexes mainly depends on the ionic radii of the lanthanides. Thus, the reaction of L in the same experimental protocol leads to three different molecular structure series. Binuclear [Ln(2)(hfac)(5)(O(2)CPhCl)(L)(3)].2 H(2)O (hfac(-)=1,1,1,5,5,5 hexafluoroacetylacetonate anion, O(2)CPhCl(-)=3-chlorobenzoate anion) and mononuclear [Ln(hfac)(3)(L)(2)] complexes were obtained by using rare-earth ions with either large (Ln(III)=Pr, Gd) or small (Ln(III)=Y, Yb) ionic radius, respectively, whereas the use of Tb(III) that possesses an intermediate ionic radius led to the formation of a binuclear complex of formula [Tb(2)(hfac)(4)(O(2)CPhCl)(2)(L)(2)]. Antiferromagnetic interactions have been observed in the three dinuclear compounds by using an extended empirical method. Photophysical properties of the coordination complexes have been studied by solid state absorption spectroscopy, whereas time-dependent density functional theory (TD-DFT) calculations have been carried out on the diamagnetic Y(III) derivative to build a molecular orbital diagram and to reproduce the absorption spectrum. For the [Yb(hfac)(3)(L)(2)] complex, the excitation at 19,600 cm(-1) of the HOMO >LUMO+1/LUMO+2 charge-transfer transition induces both line-shape emissions in the near-IR spectral range assigned to the (2)F(5/2)->(2)F(7/2) (9860 cm(-1)) ytterbium-centered transition and a residual charge-transfer emission around 13,150 cm(-1). An efficient antenna effect that proceeds through energy transfer from the singlet excited state of the tetrathiafulvalene-amido-2-pyridine-N-oxide chromophore is evidence of the Yb(III) sensitization. PMID- 20827707 TI - Post-synthetic reversible incorporation of organic linkers into porous metal organic frameworks through single-crystal-to-single-crystal transformations and modification of gas-sorption properties. AB - The porous metal-organic framework (MOF) {[Zn(2)(TCPBDA)(H(2)O)(2)]?30 DMF?6 H(2)O}(n) (SNU-30; DMF = N,N-dimethylformamide) has been prepared by the solvothermal reaction of N,N,N',N'-tetrakis(4-carboxyphenyl)biphenyl-4,4'-diamine (H(4)TCPBDA) and Zn(NO(3))(2)?6 H(2)O in DMF/tBuOH. The post-synthetic modification of SNU-30 by the insertion of 3,6-di(4-pyridyl)-1,2,4,5-tetrazine (bpta) affords single-crystalline {[Zn(2)(TCPBDA)(bpta)]?23 DMF?4 H(2)O}(n) (SNU 31 SC), in which channels are divided by the bpta linkers. Interestingly, unlike its pristine form, the bridging bpta ligand in the MOF is bent due to steric constraints. SNU-31 can be also prepared through a one-pot solvothermal synthesis from Zn(II), TCPBDA(4-), and bpta. The bpta linker can be liberated from this MOF by immersion in N,N-diethylformamide (DEF) to afford the single-crystalline SNU 30 SC, which is structurally similar to SNU-30. This phenomenon of reversible insertion and removal of the bridging ligand while preserving the single crystallinity is unprecedented in MOFs. Desolvated solid SNU-30' adsorbs N(2), O(2), H(2), CO(2), and CH(4) gases, whereas desolvated SNU-31' exhibits selective adsorption of CO(2) over N(2), O(2), H(2), and CH(4), thus demonstrating that the gas adsorption properties of MOF can be modified by post-synthetic insertion/removal of a bridging ligand. PMID- 20827708 TI - Assembly of carbon-SnO2 core-sheath composite nanofibers for superior lithium storage. AB - Protective coating: Carbon-SnO(2) core-sheath composite nanofibers are synthesized through the creative combination of electrospinning and electrodeposition processes (see figure). They display excellent electrochemical performance when directly used as binder-free anodes for rechargeable lithium ion batteries. PMID- 20827709 TI - Gold-catalyzed annulations of 1-(2,3-butadienyl)-1H-indole derivatives. PMID- 20827710 TI - Photosensitive surfactants with various hydrophobic tail lengths for the photocontrol of genomic DNA conformation with improved efficiency. AB - We report the synthesis and characterisation of photosensitive cationic surfactants with various hydrophobic tail lengths. These molecules, called AzoCx, are used as photosensitive nucleic acid binders (pNABs) and are applied to the photocontrol of DNA conformation. All these molecules induce DNA compaction in a photodependent way, originating in the photodependent polarity of their hydrophobic tails. We show that increasing hydrophobicity strongly enhances the compaction efficiencies of these molecules, but reduces the possibility of reversible photocontrol of a DNA conformation. Optimal performance was achieved with AzoC5, which allowed reversible control of DNA conformation with light at a concentration seven times smaller than previously reported. PMID- 20827711 TI - Proteomics and Down syndrome screening: a validation study. AB - OBJECTIVE: In a previous discovery study, we identified seven potential screening markers for Down syndrome (DS). Here, we report on an extended study to validate the discriminative potential of these markers. METHODS: Concentrations of the seven analytes were measured using bead-based multiplexed immunoassays in maternal serum from 27 DS pregnancies and 27 matched controls. Control samples were matched to the cases by gestational age (exact day), maternal weight ( +/- 5 kg), and maternal age ( +/- 1 year) and by closest sample date. Prediction values were obtained for current screening markers [pregnancy-associated plasma protein A (PAPP-A), free beta human chorionic gonadotrophin (fbeta-hCG) and nuchal translucency (NT)] and seven markers identified before based on concentration fold ratios between DS and controls. Models were fitted based on data of the discovery study or this study and also tested on both datasets. RESULTS: A significantly higher fold ratio was only found for epidermal growth factor (EGF) (-1.96; p = 0.006). In the prediction model for the current dataset, EGF improved the detection rate (DR) of DS by 5.7% [at a fixed 5% false-positive rate (FPR)] when added to the currently used screening markers. CONCLUSIONS: Validation of previously identified biomarkers only confirmed EGF for further consideration as a DS screening marker. This underlines the importance of validating biomarkers; in this study, limiting the range of plausible biomarkers to only one suitable biomarker. PMID- 20827712 TI - Engineering calcium deposits on polycaprolactone scaffolds for intravascular applications using primary human osteoblasts. AB - Total atherosclerotic occlusions often include significant calcium deposits. Current animal models do not mimic the pathology of gradual occlusion of arteries and lack cell-mediated calcium. The primary goal of this project was to establish an animal model incorporating these features into chronic total occlusions, using biodegradable scaffolds. As the first step, this study sought to determine the optimal dosage of TGF-beta1 on polycaprolactone (PCL) scaffolds cultured with primary human osteoblasts (HOBs) to effectively induce in vitro calcification. HOBs were cultured in TGF-beta1 and dexamethsaone (Dex)-supplemented medium in well plates. Calcium in the cultures was visualized using alizarin red. The highest calcification was observed in groups with both TGF-beta1 (0.02 ng/ml) and Dex (10(-10) M) in the medium. Next, HOBs were cultured on PCL scaffolds with different loadings of TGF-beta1: 0 (control), 5, 10, 50 and 100 ng. These cultures were performed with or without Dex (10(-10) M) in the medium. DNA content, ALP activity and the amount and distribution of calcium were examined at 7, 14, 21 and 28 days. TGF-beta1 appeared to have an inhibitory effect on scaffold calcification when grown in Dex-supplemented medium. When cultured without Dex, the lower amount of TGF-beta1 loading (5 ng) showed the most calcification, high DNA synthesis and high ALP activity on scaffolds. This study demonstrates the potential of implanting a PCL-HOB construct in an animal artery to establish a model of atherosclerotic occlusion with calcification. PMID- 20827713 TI - Effect of nanotubes and apatite on growth factor release from PLLA scaffolds. AB - There is an evident clinical need for artificial bone restorative materials. In this respect, novel composites based on poly(L-lactic acid) (PLLA) have been described. The bone response of such polymer-based composites is usually improved by the addition of bone morphogenetic protein-2 (BMP-2). However, released BMP-2 is cleared almost immediately from the site of implantation by diffusion, whereas a prolonged retention of BMP-2 onto the scaffold has been suggested to be more favourable. Besides the ability to improve the mechanical strength and osteoconductivity of polymeric scaffolds, both carbon nanotubes (CNTs) and microhydroxyapatite (uHA) have been described to facilitate such retention of BMP 2 when incorporated into a composite scaffold. Therefore, in the current study, radiolabelled BMP-2 was loaded onto plain PLLA and composite PLLA-CNT-uHA scaffolds. Subsequently, the scaffolds were implanted subcutaneously for 5 weeks in rats and BMP-2 release was measured. Release started with an initial phase of quick release, followed by a gradual release of BMP-2. Both scaffold types comprised the same in vivo release properties for BMP-2. The bioactivity of the BMP-2 remained unaltered. It can be concluded that incorporated CNTs and uHA did not affect BMP-2 release from composite scaffold materials. PMID- 20827714 TI - Sample size and power calculations for correlations between bivariate longitudinal data. AB - The analysis of a baseline predictor with a longitudinally measured outcome is well established and sample size calculations are reasonably well understood. Analysis of bivariate longitudinally measured outcomes is gaining in popularity and methods to address design issues are required. The focus in a random effects model for bivariate longitudinal outcomes is on the correlations that arise between the random effects and between the bivariate residuals. In the bivariate random effects model, we estimate the asymptotic variances of the correlations and we propose power calculations for testing and estimating the correlations. We compare asymptotic variance estimates to variance estimates obtained from simulation studies and compare our proposed power calculations for correlations on bivariate longitudinal data to power calculations for correlations on cross sectional data. PMID- 20827715 TI - Synthesis of a 2-selenothymidine phosphoramidite and its incorporation into oligodeoxyribonucleotides. AB - The detailed synthetic protocol for a 2-selenothymidine phosphoramidite and its use in preparing Se-derivatized oligonucleotides are described here. The Se modified phosphoramidite synthesis was achieved by activating a 2-thiothymidine derivative, followed by introduction of selenium functionality. The coupling reaction yield of the 2-selenothymidine phosphoramidite during solid-phase synthesis is high (>95%), and the oligonucleotides containing the 2 selenothymidine derivatization are stable. PMID- 20827716 TI - Synthesis of glycerol nucleic acid (GNA) phosphoramidite monomers and oligonucleotide polymers. AB - This unit describes a straightforward method for preparing glycerol nucleic acid (GNA) phosphoramidite monomers and oligonucleotide polymers using standard cyanoethyl phosphoramidite chemistry. GNA is an unnatural nucleic acid analog composed of an acyclic three-carbon sugar-phosphate backbone that contains one stereogenic center per repeating unit. GNA has attracted significant attention as a nucleic acid derivative due to its unique ability to form stable Watson-Crick anti-parallel duplex structures with thermal and thermodynamic stabilities rivaling those of natural DNA and RNA. The chemical simplicity of this nucleic acid structure provides access to enantiomerically pure forms of right- and left handed helical structures that can be used as unnatural building blocks in DNA nanotechnology. PMID- 20827717 TI - Synthesis of peptide-oligonucleotide conjugates using a heterobifunctional crosslinker. AB - Peptide-oligonucleotide conjugates (POCs) are molecular chimeras composed of a nucleic acid moiety covalently attached to a polypeptide moiety. POCs have been used in numerous applications from therapeutics to nanotechnology, and most recently as combinatorial agents in the assembly of bivalent protein affinity reagents. This unit describes the synthesis and purification of POC molecules using the heterobifunctional crosslinking reagent succinimidyl-4-(N maleimidomethyl)cyclohexane-1-carboxylate (SMCC), which enables amine-modified oligonucleotides to become covalently linked to cysteine-modified polypeptides. This solution-based protocol consists of a two-step synthesis followed by a single purification step. PMID- 20827718 TI - Impact of antibody aggregation on a flowthrough anion-exchange membrane process. AB - The impact of typical anion-exchange flowthrough conditions on the IgG mass loading of an anion-exchange membrane scale-down unit (Mustang Q coin) was investigated. High performance size-exclusion chromatography and multiangle laser light scattering results suggested the presence of a small fraction of IgG aggregates with average radius >100 nm under anion-exchange flowthrough conditions. The small filtration area presented by the 0.35 mL membrane volume Mustang Q coin limited the membrane throughput due to fouling from the aggregates at higher antibody loading. Data in this report indicated that a 0.2 MUm hybrid polyethersulfone and polyvinylidene fluoride membrane in-line prefilter with a minimum filtration area of 20 sq cm alleviated the Mustang Q coin fouling. The combined cake filtration and intermediate blocking model was proposed as the most likely membrane pore blocking mechanism. Increasing the filtration area in the in line prefilter resulted in higher IgG mass throughput. Thus, using an appropriately sized in-line prefilter could provide more robust antibody throughput performance on scale-down membrane anion-exchange units. PMID- 20827719 TI - Liver X receptor alpha and farnesoid X receptor are major transcriptional regulators of OATP1B1. AB - Organic anion transporting polypeptide 1B1 (OATP1B1) is a liver-enriched transporter involved in the hepatocellular uptake of many endogenous molecules and several structurally divergent drugs in clinical use. Although OATP1B1 coding region polymorphisms are known to make an impact on substrate drug disposition in humans, little is known regarding the mechanisms underlying the transcriptional regulation of this transporter. In this study, we note that messenger RNA (mRNA) expression of OATP1B1 in a large human liver bank exhibited marked interindividual variability that was not associated with coding region polymorphisms. Accordingly, we hypothesized that such variability in expression is reflective of nuclear receptor-mediated transcriptional regulation of this transporter. We tested prototypical ligands for the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) alpha, and farnesoid X receptor (FXR) in a human hepatoma-derived cell line and noted induction of OATP1B1 mRNA when the cells were treated with LXRalpha or FXR ligands. To confirm a direct role for LXRalpha and FXR to OATP1B1 expression, we performed detailed promoter analysis and cell-based reporter gene assays resulting in the identification of two functional FXR response elements and one LXRalpha response element. The direct interaction between nuclear receptors with the identified response elements was assessed using chromatin immunoprecipitation assays. Using isolated primary human hepatocytes, we show that LXRalpha or FXR agonists, but not PXR or CAR agonists, are capable of OATP1B1 induction. CONCLUSION: We note that OATP1B1 transcriptional regulation is under dual nuclear receptor control through the oxysterol sensing LXRalpha and the bile acid sensor FXR. Accordingly, the interplay between OATP1B1 and nuclear receptors may play an important and heretofore unrecognized role during cholestasis, drug-induced liver injury, and OATP1B1 induction-related drug interactions. PMID- 20827720 TI - Adenosine triphosphate release and purinergic (P2) receptor-mediated secretion in small and large mouse cholangiocytes. AB - Adenosine triphosphate (ATP) is released from cholangiocytes into bile and is a potent secretogogue by increasing intracellular Ca2(+) and stimulating fluid and electrolyte secretion via binding purinergic (P2) receptors on the apical membrane. Although morphological differences exist between small and large cholangiocytes (lining small and large bile ducts, respectively), the role of P2 signaling has not been previously evaluated along the intrahepatic biliary epithelium. The aim of these studies therefore was to characterize ATP release and P2-signaling pathways in small (MSC) and large (MLC) mouse cholangiocytes. The findings reveal that both MSCs and MLCs express P2 receptors, including P2X4 and P2Y2. Exposure to extracellular nucleotides (ATP, uridine triphosphate, or 2',3'-O-[4-benzoyl-benzoyl]-ATP) caused a rapid increase in intracellular Ca2(+) concentration and in transepithelial secretion (I(sc)) in both cell types, which was inhibited by the Cl(-) channel blockers 5-nitro-2-(-3-phenylpropylamino) benzoic acid (NPPB) or niflumic acid. In response to mechanical stimulation (flow/shear or cell swelling secondary to hypotonic exposure), both MSCs and MLCs exhibited a significant increase in the rate of exocytosis, which was paralleled by an increase in ATP release. Mechanosensitive ATP release was two-fold greater in MSCs compared to MLCs. ATP release was significantly inhibited by disruption of vesicular trafficking by monensin in both cell types. CONCLUSION: These findings suggest the existence of a P2 signaling axis along intrahepatic biliary ducts with the "upstream" MSCs releasing ATP, which can serve as a paracrine signaling molecule to "downstream" MLCs stimulating Ca2(+)-dependent secretion. Additionally, in MSCs, which do not express the cystic fibrosis transmembrane conductance regulator, Ca2(+)-activated Cl(-) efflux in response to extracellular nucleotides represents the first secretory pathway clearly identified in these cholangiocytes derived from the small intrahepatic ducts. PMID- 20827721 TI - Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease. PMID- 20827722 TI - MicroRNA-125b suppressesed human liver cancer cell proliferation and metastasis by directly targeting oncogene LIN28B2. AB - MicroRNAs (miRNAs) are small, noncoding RNAs that can act as oncogenes or tumor suppressors in human cancer. Our previous study showed that miR-125b was a prognostic indicator for patients with hepatocellular carcinoma (HCC), but its functions and exact mechanisms in hepatic carcinogenesis are still unknown. Here we demonstrate that miR-125b suppressed HCC cell growth in vitro and in vivo. Moreover, miR-125b increased p21Cip1/Waf1 expression and arrested cell cycle at G1 to S transition. In addition, miR-125b inhibited HCC cell migration and invasion. Further studies revealed that LIN28B was a downstream target of miR 125b in HCC cells as miR-125b bound directly to the 3' untranslated region of LIN28B, thus reducing both the messenger RNA and protein levels of LIN28B. Silencing of LIN28B recapitulated the effects of miR-125b overexpression, whereas enforced expression of LIN28B reversed the suppressive effects of miR-125b. CONCLUSION: These findings indicate that miR-125b exerts tumor-suppressive effects in hepatic carcinogenesis through the suppression of oncogene LIN28B expression and suggest a therapeutic application of miR-125b in HCC. PMID- 20827724 TI - Students as resurrectionists--A multimodal humanities project in anatomy putting ethics and professionalism in historical context. AB - Because medical students have many different learning styles, the authors, medical students at Mayo Clinic, College of Medicine researched the history of anatomical specimen procurement, reviewing topic-related film, academic literature, and novels, to write, direct, and perform a dramatization based on Robert Louis Stevenson's The Body-Snatcher. Into this performance, they incorporated dance, painting, instrumental and vocal performance, and creative writing. In preparation for the performance, each actor researched an aspect of the history of anatomy. These micro-research projects were presented in a lecture before the play. Not intended to be a research study, this descriptive article discusses how student research and ethics discussions became a theatrical production. This addition to classroom and laboratory learning addresses the deep emotional response experienced by some students and provides an avenue to understand and express these feelings. This enhanced multimodal approach to"holistic learning" could be applied to any topic in the medical school curriculum, thoroughly adding to the didactics with history, humanities, and team dynamics. PMID- 20827723 TI - Determining macromolecular assembly structures by molecular docking and fitting into an electron density map. AB - Structural models of macromolecular assemblies are instrumental for gaining a mechanistic understanding of cellular processes. Determining these structures is a major challenge for experimental techniques, such as X-ray crystallography, NMR spectroscopy and electron microscopy (EM). Thus, computational modeling techniques, including molecular docking, are required. The development of most molecular docking methods has so far been focused on modeling of binary complexes. We have recently introduced the MultiFit method for modeling the structure of a multisubunit complex by simultaneously optimizing the fit of the model into an EM density map of the entire complex and the shape complementarity between interacting subunits. Here, we report algorithmic advances of the MultiFit method that result in an efficient and accurate assembly of the input subunits into their density map. The successful predictions and the increasing number of complexes being characterized by EM suggests that the CAPRI challenge could be extended to include docking-based modeling of macromolecular assemblies guided by EM. PMID- 20827725 TI - Building virtual models by postprocessing radiology images: A guide for anatomy faculty. AB - Radiology and radiologists are recognized as increasingly valuable resources for the teaching and learning of anatomy. State-of-the-art radiology department workstations with industry-standard software applications can provide exquisite demonstrations of anatomy, pathology, and more recently, physiology. Similar advances in personal computers and increasingly available software can allow anatomy departments and their students to build their own three-dimensional virtual models. Appropriate selection of a data-set, followed by processing and presentation are the key steps in creating virtual models. The construction, presentation, clinical application, and educational potential of postprocessed imaging techniques including multiplanar reformats, minimum intensity projections, segmentation, volume-rendering, surface-rendering, fly-throughs, virtual endoscopy, angiography, and cine-loops are reviewed using examples created with only a personal computer and freeware software. Although only static images are presented in this article, further material is available online within the electronic version of this article. Through the use of basic and advanced image reconstruction and also paying attention to optimized presentation and integration, anatomy courses can be strengthened with appropriate radiological material. There are several key advantages for the anatomy department, which is equipped with the ability to produce virtual models using radiology images: (1) Opportunities to present anatomy using state-of-the-art technology as an adjunct to current practices, (2) a means to forge an improved relationship with the local radiology department, and (3) the ability to create material locally, which is integrated with the local curriculum avoiding the problem of information overload when using the internet or other commercially available resources. PMID- 20827726 TI - Several methods to assess improvement in risk prediction models: extension to survival analysis. AB - Risk prediction models have been widely applied for the prediction of long-term incidence of disease. Several parameters have been identified and estimators developed to quantify the predictive ability of models and to compare new models with traditional models. These estimators have not generally accounted for censoring in the survival data normally available for fitting the models. This paper remedies that problem. The primary parameters considered are net reclassification improvement (NRI) and integrated discrimination improvement (IDI). We have previously similarly considered a primary measure of concordance, area under the ROC curve (AUC), also called the c-statistic. We also include here consideration of population attributable risk (PAR) and ratio of predicted risk in the top quintile of risk to that in the bottom quintile. We evaluated estimators of these various parameters both with simulation studies and also as applied to a prospective study of coronary heart disease (CHD). Our simulation studies showed that in general our estimators had little bias, and less bias and smaller variances than the traditional estimators. We have applied our methods to assessing improvement in risk prediction for each traditional CHD risk factor compared to a model without that factor. These traditional risk factors are considered valuable, yet when adding any of them to a risk prediction model that has omitted the one factor, the improvement is generally small for any of the parameters. This experience should prepare us to not expect large values of the risk prediction improvement evaluation parameters for any new risk factor to be discovered. PMID- 20827727 TI - The analysis of case cohort design in the presence of competing risks with application to estimate the risk of delayed cardiac toxicity among Hodgkin lymphoma survivors. AB - The case-cohort design is an economical solution to studying the association between an exposure and a rare disease. When the disease of interest has a delayed occurrence, then other types of event may preclude observation of the disease of interest giving rise to a competing risk situation. In this paper, we introduce a modification of the pseudolikelihood proposed by Prentice (Biometrika 1986; 73:1-11) for the analysis of case-cohort design, to accommodate the existence of competing risks. The modification is based on the Fine and Gray (J. Amer. Statist. Assoc. 1999; 94:496-509) approach to enable the modeling of the hazard of subdistribution. We show through simulations that the estimate that maximizes this modified pseudolikelihood is almost unbiased. The predictive probabilities based on the model are close to the theoretical probabilities. The variance for the estimates can be calculated using the jackknife approach. An application of this method on the analysis of late cardiac morbidity among Hodgkin Lymphoma survivors is presented. PMID- 20827728 TI - Evidence for retrochiasmatic tissue loss in Leber's hereditary optic neuropathy. AB - Patients with Leber's hereditary optic neuropathy (LHON) have loss of central vision with severe damage of small-caliber fibers of the papillomacular bundle and optic nerve atrophy. The aim of this study was to define the presence and topographical distribution of brain grey matter (GM) and white matter (WM) injury in LHON patients using voxel-based morphometry (VBM). The correlation of such changes with neuro-ophthalmologic findings and measurements of peripapillary retinal nerve fiber layer (RNFL) thickness by optical coherence tomography (OCT) was also assessed. Dual-echo and fast-field echo scans were acquired from 12 LHON patients and 12 matched controls. VBM analysis was performed using SPM5 and an ANCOVA model. A complete neuro-ophthalmologic examination, including standardized automated Humphrey perimetry as well as average and temporal peripapillary RNFL thickness measurements were obtained in all the patients. Compared with controls, average peripapillary RNFL thickness was significantly decreased in LHON patients. LHON patients also had significant reduced GM volume in the bilateral primary visual cortex, and reduced WM volume in the optic chiasm, optic tract, and several areas located in the optic radiations (OR), bilaterally. Visual cortex and OR atrophy were significantly correlated with average and temporal peripapillary RNFL thickness (P < 0.001; r values ranging from 0.76 to 0.89). Brain damage in patients with LHON is not limited to the anterior visual pathways, but extends posteriorly to the OR and the primary visual cortex. Such a damage to the posterior parts of the visual pathways may be due either to trans synaptic degeneration secondary to neuroaxonal damage in the retina and optic nerve or to local mitochondrial dysfunction. PMID- 20827729 TI - SPE isolation of low-molecular oxygen compounds from essential oils. AB - Analytical procedures of complex mixtures frequently involve their initial pre fractionation to make the analysis easier or possible. Recently, SPE is frequently applied for this purpose. This article discusses the possibility of essential oil's fractionation using SPE with octadecyl modified silica. The presented results show that developed SPE with C-18 sorbent allows for easy and total isolation (100% recovery) of low-molecular oxygen compounds from the remaining compounds, for which the recovery exceeds 95%. The obtained recoveries are satisfactory for preliminary separation of essential oils for analytical and preparative purposes. PMID- 20827730 TI - High-throughput quantification of selenium in individual serum proteins from a healthy human population using HPLC on-line with isotope dilution inductively coupled plasma-MS. AB - In this study, a method, based on dual column affinity chromatography hyphenated to isotope dilution inductively coupled plasma-quadrupole MS, was developed for selenium determination in selenoprotein P, glutathione peroxidase, and selenoalbumin in human serum samples from a group of healthy volunteers (n=399). Method improvement was achieved using methanol-enhanced isotope dilution which resulted in improved sensitivity and removal of isobaric interferences. Although no human serum reference materials are currently certified for their selenium species levels, method development was conducted using human serum reference material BCR 637 and 639 as their Se species content has been reported in the previous studies, and thus comparisons were possible. The mean selenium concentrations determined for the 399 healthy volunteer serum samples were 23 +/- 10 ng Se mL(-1) for glutathione peroxidase, 49 +/- 15 ng Se mL(-1) for selenoprotein P and 11 +/- 4 ng Se mL(-1) for selenoalbumin. These values are found to be in close agreement with published values for a limited number of healthy volunteer samples, and to establish baseline Se levels in serum proteins for an apparently healthy group of individuals, thus allowing for subsequent comparisons with respective values determined for groups of individuals with selenium related health issues, as well as assist in the discovery of potential selenium biomarkers. Also, the relationship between Se serum protein levels and some anthropometric characteristics of the volunteer population were investigated. Additionally, further development of the analytical method used in this study was achieved by adding a size exclusion chromatography column after the two affinity columns via a switching valve. This allowed for the separation of small selenium-containing molecules from glutathione peroxidase and thus enhanced the overall confidence in its identification. PMID- 20827731 TI - Integrated data management and validation platform for phosphorylated tandem mass spectrometry data. AB - MS/MS is a widely used method for proteome-wide analysis of protein expression and PTMs. The thousands of MS/MS spectra produced from a single experiment pose a major challenge for downstream analysis. Standard programs, such as MASCOT, provide peptide assignments for many of the spectra, including identification of PTM sites, but these results are plagued by false-positive identifications. In phosphoproteomic experiments, only a single peptide assignment is typically available to support identification of each phosphorylation site, and hence minimizing false positives is critical. Thus, tedious manual validation is often required to increase confidence in the spectral assignments. We have developed phoMSVal, an open-source platform for managing MS/MS data and automatically validating identified phosphopeptides. We tested five classification algorithms with 17 extracted features to separate correct peptide assignments from incorrect ones using over 2600 manually curated spectra. The naive Bayes algorithm was among the best classifiers with an AUC value of 97% and PPV of 97% for phosphotyrosine data. This classifier required only three features to achieve a 76% decrease in false positives as compared with MASCOT while retaining 97% of true positives. This algorithm was able to classify an independent phosphoserine/threonine data set with AUC value of 93% and PPV of 91%, demonstrating the applicability of this method for all types of phospho-MS/MS data. PhoMSVal is available at http://csbi.ltdk.helsinki.fi/phomsval. PMID- 20827732 TI - Evaluation of changes in serum protein profiles during neoadjuvant chemotherapy in HER2-positive breast cancer using an LC-MALDI-TOF/MS procedure. AB - Comparison of protein profiles of sera acquired before and after preoperative chemotherapy for breast cancer may reveal tumor markers that could be used to monitor tumor response. In this study, we analyzed pre- and post-chemotherapy protein profiles of sera from 39 HER2-postive breast cancer patients (n=78 samples) who received 6 months of preoperative chemotherapy using LC-MALDI-TOF/MS technology. We detected qualitative and quantitative differences in pair-wise comparison of pre- and post chemotherapy samples that were different in patients who achieved pathological complete response (pCR, n=21) compared with those with residual disease (n=18). We identified 2329 and 3152 peaks as differentially expressed in the pre-chemotherapy samples of the responders and non-responders. Comparison of matching pre- and post-chemotherapy samples identified 34 (32 decreased, two increased) and 304 peaks (157 decreased, 147 increased) that significantly changed (p<0.01, false discovery rate <= 20%) after treatment in responders and non-responders, respectively. The top 11 most significantly altered peptide peaks with the greatest change in intensity were positively identified. These corresponded to eight proteins including alpha-2-macroglobulin, complement 3, hemopexin, and serum amyloid P in the responder group and chains C and A of apolipoprotein A-I, hemopexin precursor, complement C, and amyloid P component in the non-responding groups. All proteins decreased after therapy, except chain C apolipoprotein A and hemopexin precursor that increased. These results suggest that changes in serum protein levels occur in response to chemotherapy and these changes partly appear different in patients who are highly sensitive to chemotherapy compared with those with lesser response. PMID- 20827733 TI - Elucidation of the avian nucleolar proteome by quantitative proteomics using SILAC and changes in cells infected with the coronavirus infectious bronchitis virus. AB - The nucleolus is a dynamic subnuclear compartment involved in ribosome subunit biogenesis, regulation of cell stress and modulation of cellular growth and the cell cycle, among other functions. The nucleolus is composed of complex protein/protein and protein/RNA interactions. It is a target of virus infection with many viral proteins being shown to localize to the nucleolus during infection. Perturbations to the structure of the nucleolus and its proteome have been predicted to play a role in both cellular and infectious disease. Stable isotope labeling with amino acids in cell culture coupled to LC-MS/MS with bioinformatic analysis using Ingenuity Pathway Analysis was used to investigate whether the nucleolar proteome altered in virus-infected cells. In this study, the avian nucleolar proteome was defined in the absence and presence of virus, in this case the positive strand RNA virus, avian coronavirus infectious bronchitis virus. Data sets, potential protein changes and the functional consequences of virus infection were validated using independent assays. These demonstrated that specific rather than generic changes occurred in the nucleolar proteome in infectious bronchitis virus-infected cells. PMID- 20827734 TI - Changes in the proteome and phosphoproteome expression in the bryozoan Bugula neritina larvae in response to the antifouling agent butenolide. AB - Larval attachment and metamorphosis, commonly referred to as larval settlement, of marine sessile invertebrates can be triggered or blocked by chemical cues and affected by changes in overall protein expression pattern and phosphorylation dynamics. This study focuses on the effects of butenolide, an effective larval settlement inhibitor, on larval settlement at the proteome level in the bryozoan Bugula neritina. Liquid-phase IEF sample prefractionation combined with 2-DE and MALDI-TOF MS was used to identify the differentially expressed proteins. Substantial changes occurred both in protein abundance and in phosphorylation status during larval settlement and when settling larvae were challenged with butenolide. The proteins that responded to treatment were identified as structural proteins, molecular chaperones, mitochondrial peptidases and calcium binding proteins. Compared with our earlier results, both genistein and butenolide inhibited larval settlement of B. neritina primarily by changes in protein abundance and the phosphorylation status of proteins but have different protein targets in the same species. Clearly, to design potent antifouling compounds and to understand the mode of action of compounds, more studies on the effects of different compounds on proteome and phosphoproteome of different larval species are required. PMID- 20827735 TI - A method to prevent cross contamination during 2-DE by beta-amyloid peptides. AB - A method for the efficient decontamination of aluminium oxide ceramic 2-DE focusing trays from beta-amyloid peptides (Abeta) is reported. As these contaminations were resistant to the standard cleaning procedures, additional harsh cleaning steps were necessary for their efficient removal. Our observations suggest that specific surface properties affect the degree of adsorption of the Abeta-peptides. "Surface catalysed amyloid aggregation" in the aluminium oxide ceramic trays is proposed as a possible underlying mechanism for the occurrence of proteinase K-resistant forms of Abeta. PMID- 20827737 TI - Electrochemically controlled deconjugation and delivery of single quantum dots into the nucleus of living cells. PMID- 20827738 TI - At the nanoscale: nanohemostat, a new class of hemostatic agent. AB - Three basic categories of hemostats are widely used in surgery today: chemical agents, thermal devices, and mechanical methods that use pressure or ligature to slow bleeding. Each has its benefits and limitations. However, nanotechnology is rapidly ushering in new medical technologies. This review focuses on the 'nanohemostat', a new class of hemostatic agent that stops bleeding in less than 15 seconds by using (RADA)4, referred to as nanohemostat-1 (NHS-1), a synthetic biological material that self-assembles at the nanoscale when applied to a wound, and compares it to the characteristics of the 'ideal hemostat'. PMID- 20827740 TI - Amplifications and applications of Pennebaker's analogic to digital model in health promotion, prevention, and psychotherapy. AB - This article expands on James Pennebaker's original model in expressive writing, going from an Analogically unclear and unspecified experiential mass (A) to a Digital specification in words (D). Amplifications of this model are found in philosophy, psychodynamic theory and in Salience learning theory. Applications of this model involve expressive writing, going from ambiguous experiences (A) to using the Dictionary (D), and responding to Sentences with strong psychological impact (S). The undefined and ill-defined analogical mass is constituted by traumas in Pennebaker's work and hurt feelings in L'Abate's and Vangelisti's works. Implications of these approaches for the practice of health promotion, prevention and psychotherapy are discussed. PMID- 20827739 TI - Biominerals--hierarchical nanocomposites: the example of bone. AB - Many organisms incorporate inorganic solids in their tissues to enhance their functional, primarily mechanical, properties. These mineralized tissues, also called biominerals, are unique organo-mineral nanocomposites, organized at several hierarchical levels, from nano- to macroscale. Unlike man-made composite materials, which often are simple physical blends of their components, the organic and inorganic phases in biominerals interface at the molecular level. Although these tissues are made of relatively weak components under ambient conditions, their hierarchical structural organization and intimate interactions between different elements lead to superior mechanical properties. Understanding basic principles of formation, structure, and functional properties of these tissues might lead to novel bioinspired strategies for material design and better treatments for diseases of the mineralized tissues. This review focuses on general principles of structural organization, formation, and functional properties of biominerals on the example the bone tissues. PMID- 20827741 TI - Group cognitive behaviour therapy for adults with Asperger syndrome and anxiety or mood disorder: a case series. AB - Individuals with Asperger syndrome are at increased risk for mental health problems compared with the general population, especially with regard to mood and anxiety disorders. Generic mental health services are often ill-equipped to offer psychotherapeutic treatments to this population, and specialized supports are difficult to find. This case series used a manualized cognitive behaviour therapy group programme (Mind Over Mood) with three adults diagnosed with Asperger syndrome, who were each unable to access psychotherapy through mainstream mental health services. This review highlights the benefits of a cognitive behaviour therapy (CBT) group approach for adults with Asperger syndrome and suggests some potential modifications to traditional CBT provision. PMID- 20827742 TI - When R & R is not rest & recovery but revise & resubmit. PMID- 20827743 TI - Continuous rhodium-catalyzed hydroformylation of 1-octene with polyhedral oligomeric silsesquioxanes (POSS) enlarged triphenylphosphine. PMID- 20827744 TI - Morphology-preserving conversion of a 3D bioorganic template into a nanocrystalline multicomponent oxide compound. PMID- 20827745 TI - Interfacial systems chemistry: out of the vacuum--through the liquid--into the cell. PMID- 20827746 TI - Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors. PMID- 20827747 TI - Functional control of transplantable human ESC-derived neurons via optogenetic targeting. AB - Current methods to examine and regulate the functional integration and plasticity of human ESC (hESC)-derived neurons are cumbersome and technically challenging. Here, we engineered hESCs and their derivatives to express the light-gated channelrhodopsin-2 (ChR2) protein to overcome these deficiencies. Optogenetic targeting of hESC-derived neurons with ChR2 linked to the mCherry fluorophore allowed reliable cell tracking as well as light-induced spiking at physiological frequencies. Optically induced excitatory and inhibitory postsynaptic currents could be elicited in either ChR2(+) or ChR2(-) neurons in vitro and in acute brain slices taken from transplanted severe combined immunodeficient (SCID) mice. Furthermore, we created a clonal hESC line that expresses ChR2-mCherry under the control of the synapsin-1 promoter. On neuronal differentiation, ChR2-mCherry expression was restricted to neurons and was stably expressed for at least 6 months, providing more predictable light-induced currents than transient infections. This pluripotent cell line will allow both in vitro and in vivo analysis of functional development as well as the integration capacity of neuronal populations for cell-replacement strategies. PMID- 20827748 TI - The Wnt/beta-catenin signaling pathway tips the balance between apoptosis and reprograming of cell fusion hybrids. AB - Cell-cell fusion contributes to cell differentiation and developmental processes. We have previously showed that activation of Wnt/beta-catenin enhances somatic cell reprograming after polyethylene glycol (PEG)-mediated fusion. Here, we show that neural stem cells and ESCs can fuse spontaneously in cocultures, although with very low efficiency (about 2%), as the hybrids undergo apoptosis. In contrast, when Wnt/beta-catenin signaling is activated in ESCs and leads to accumulation of low amounts of beta-catenin in the nucleus, activated ESCs can reprogram somatic cells with very high efficiency after spontaneous fusion. Furthermore, we also show that different levels of beta-catenin accumulation in the ESC nuclei can modulate cell proliferation, although in our experimental setting, cell proliferation does not modulate the reprograming efficiency per se. Overall, the present study provides evidence that spontaneous fusion occurs, while the survival of the reprogramed clones is strictly dependent on induction of a Wnt-mediated reprograming pathway. PMID- 20827749 TI - Expression and proliferation-promoting role of Diversin in the neuronally committed precursor cells migrating in the adult mouse brain. AB - The subventricular zone (SVZ) is the largest neurogenic region in the adult rodent brain. In the adult SVZ, unlike in the embryonic brain, neuronally committed precursor cells (neuroblasts) maintain their proliferative activity while migrating toward the olfactory bulb (OB), suggesting that they are inhibited from exiting the cell cycle. Little is known about the mechanisms underlying the unique ability of adult neuroblasts to proliferate during migration. Here, we studied the expression and function of Diversin, a component of the Wnt signaling pathways. In the neonatal and adult mouse brain, Diversin expression was observed in neuroblasts and mature neurons in the SVZ and hippocampus. Retrovirus-mediated overexpression of Diversin promoted the proliferation of neuroblasts and increased the number of neuroblasts that reached the OB. Conversely, the knockdown of Diversin decreased the proliferation of neuroblasts. Our results indicate that Diversin plays an important role in the proliferation of neuroblasts in the SVZ of the adult brain. PMID- 20827751 TI - Podocyte-specific VEGF down-regulation and pathophysiological development. AB - It is well-known that vascular endothelial growth factor (VEGF) plays a key role in development and pathology, but its function in normal adult tissues is rarely understood. Increased use of anti-angiogenic therapies targeting VEGF in human pathologies have shown more and more adverse effects. In this report, a conditional expression model (Tet-On system) was used to down-regulate podocyte VEGF in adult mice, which resulted in many kidney problems, characterized by glomerular morphological changes, proteinuria, reduced water consumption and urination, increased urine electro-conductivity, as well as high susceptibility to BSA stress. Our findings indicated that podocyte-specific VEGF down-regulation resulted in poor kidney performance and led mice to be more susceptible to further kidney damages. PMID- 20827750 TI - Interaction of hypoxia-inducible factor-1alpha and Notch signaling regulates medulloblastoma precursor proliferation and fate. AB - Medulloblastoma (MDB) is the most common brain malignancy of childhood. It is currently thought that MDB arises from aberrantly functioning stem cells in the cerebellum that fail to maintain proper control of self-renewal. Additionally, it has been reported that MDB cells display higher endogenous Notch signaling activation, known to promote the survival and proliferation of neoplastic neural stem cells and to inhibit their differentiation. Although interaction between hypoxia-inducible factor-1alpha (HIF-1alpha) and Notch signaling is required to maintain normal neural precursors in an undifferentiated state, an interaction has not been identified in MDB. Here, we investigate whether hypoxia, through HIF 1alpha stabilization, modulates Notch1 signaling in primary MDB-derived cells. Our results indicate that MDB-derived precursor cells require hypoxic conditions for in vitro expansion, whereas acute exposure to 20% oxygen induces tumor cell differentiation and death through inhibition of Notch signaling. Importantly, stimulating Notch1 activation with its ligand Dll4 under hypoxic conditions leads to expansion of MDB-derived CD133(+) and nestin(+) precursors, suggesting a regulatory effect on stem cells. In contrast, MDB cells undergo neuronal differentiation when treated with gamma-secretase inhibitor, which prevents Notch activation. These results suggest that hypoxia, by maintaining Notch1 in its active form, preserves MDB stem cell viability and expansion. PMID- 20827752 TI - Clinical images: Solitary extranodal malignant lymphoma of the forearm in rheumatoid arthritis. PMID- 20827753 TI - Cancer pain assessment and care: some strides have been made but more are needed, experts say. PMID- 20827754 TI - Disparities found in pain care. PMID- 20827755 TI - Breast disease increases with adolescent drinking. PMID- 20827756 TI - New technologies may reduce breast biopsies. PMID- 20827757 TI - Predicted 30-year protection after vaccination with an aluminum-free virosomal hepatitis A vaccine. AB - Few studies have examined the duration of protection following vaccination against hepatitis A virus (HAV) with currently licensed HAV vaccines. This study explored the long-term immunogenicity in individuals vaccinated with the virosomal hepatitis A virus, Epaxal. Adult volunteers (N = 130) previously enrolled into four different studies between 1992 and 1994 and who had completed a 0/12-month immunization regimen (primary and booster dose) were asked to participate in this follow-up study. Yearly anti-HAV titers up to 6 years following booster vaccination, and then once 9-11 years after booster were measured using two assays, Enzygnost and AxSYM HAVAB 2.0. Based on the Enzygnost assay, the seroprotection rate 9-11 years after booster was 100%, with a geometric mean concentration (GMC) of anti-HAV antibodies of 526 mIU/ml. Females had markedly higher GMCs than males (741 mIU/ml vs. 332 mIU/ml). Using an anti HAV cut-off titer of >or=10 mIU/ml, a linear mixed mathematical model predicted a median duration of protection of 52.1 years. A duration of protection >or= 35.7 years was predicted for 95% of subjects. A more stringent cut-off of >or=20 mIU/ml shortened the median predicted duration of protection to 45.0 years. In conclusion, a two-dose Epaxal vaccination regimen confers in healthy adults a real-time protection of at least 9-11 years; this protection is predicted to last at least 30 years in over 95% of individuals. Further studies are necessary to assess the real duration of seroprotection and whether an additional booster is necessary later. PMID- 20827758 TI - Decline in hepatitis B infection observed after 11 years of regional vaccination among Danish drug users. AB - The aims of this study were to determine the current prevalence of viral hepatitis and HIV among drug users, and to compare this prevalence with previous findings in the same geographical region. Cross-sectional surveys of drug users attending treatment centers on the island of Funen with approximately 500,000 inhabitants were administered in 1996 and 2007. The 2007 prevalence estimates were: anti-HBc 50.2%, HBsAg 0.9%, anti-HCV 66.8%, HCV-RNA 40%, and anti-HIV 1.1%. The corresponding 1996 prevalence values were: anti-HBc 70% (P < 0.0001), HBsAg 9.8% (P < 0.0001), anti-HCV 82.8% (P < 0.0001), HCV-RNA 56.3% (P = 0.002), and anti-HIV 1% (P = 1). The 2007 prevalence of viral hepatitis decreased due to the increasing proportion of non-injectors. Among injectors, the prevalence remained unchanged except for a significant decrease in HBsAg. The 2007 prevalence of ongoing HBV infection among infected (HBsAg/anti-HBc proportion) was the lowest that to our knowledge has been reported among drug-users. Vaccination coverage among susceptible persons tested in 2007 was 24%, compared to 0.7% in 1996. Therefore, despite an unchanged prevalence of anti-HBc among injecting drug users, a highly significant drop in HBsAg prevalence was seen during the last decade. This observation may be linked causally to an increase in hepatitis B vaccination of the susceptible population. Our findings suggest that even incomplete vaccination, without persistent protective anti-HBs levels, may induce an immune memory sufficient to prevent chronic infection upon transmission. PMID- 20827759 TI - Relationship between the hepatitis C viral load and the serum interferon concentration during the first week of peginterferon-alpha-2b-ribavirin combination therapy. AB - In chronic hepatitis C virus (HCV) infections, the current standard of care (combination therapy with pegylated alpha interferon (PEG-IFNalpha) and ribavirin) is only effective in around 50% of cases. The aim of the present study was to analyze the relationship between the HCV load and the PEG-IFN concentration during the first week of treatment. Fifteen treatment-naive patients with chronic hepatitis C infection (genotypes 1, 2, 3, and 4) underwent PEG-IFNalpha-2b/ribavirin combination therapy. Blood samples were collected before the first injection (T(0)) and then at different time points until the next injection a week later. The PEG-IFN concentration and the HCV load were assayed. The serum interferon concentration peaked 2 days after the first injection (mean value for the study population; T(max) = 40.9 hr; C(max) = 490 pg/ml) and a trough in viral load was seen at day 3. The PEG-IFNalpha-2b concentration decreased from day 2 to day 7, enabling a viral rebound in all patients. The change in viral load between day 0 and day 3 differed significantly according to whether the patients were responders at week 12 (Deltalog d(0)/d(3) = 2.729 +/- 1.419 log(10) IU/ml) or not (Deltalog d(0)/d(3) = 1.102 +/- 0.472 log(10) IU/ml). Our results emphasize the potential clinical importance of achieving viral decay immediately after initiation of interferon-ribavirin combination therapy. J. Med. Virol. 82:1640-1646, 2010. 2010 Wiley-Liss, Inc. PMID- 20827760 TI - Hepatitis C virus genotype 3 and the risk of severe liver disease in a large population of drug users in France. AB - Although risk factors for cirrhosis in chronic hepatitis C virus (HCV) infection have been identified, the role of HCV-genotype 3 remains controversial, and limited data are available in drug users. The aim of the study was to assess risk factors for severe liver disease (cirrhosis/hepatocellular carcinoma) in HCV infected drug users between 2001 and 2007 in France. Patients who reported drug use and who had been referred for HCV infection to hepatology centers from a national surveillance system were identified. The severity of liver disease was assessed clinically and histologically (Metavir score). Factors associated with severe liver disease were analyzed after estimating missing values by multiple imputation (MI). Of the 4,065 drug users naive to anti-HCV treatment who were referred to the 26 participating centers, 8.0% had severe liver disease, 25.7% were infected with HCV-genotype 3. Factors associated independently with an increased risk of severe liver disease were HCV-genotype 3 (adjusted odds ratio, multiple imputation (aOR(MI)) = 1.6, [95% confidence interval, 95% CI: 1.2-2.1]), HIV infection (aOR(MI) = 1.8, [1.2-2.8]), male sex (aOR(MI) = 2.0, [1.4-2.8]), age over 40 years (aOR(MI) = 2.1, [1.6-2.9]), history of excessive alcohol consumption (aOR(MI) = 2.8, [2.1-3.7]), and duration of infection >=18 years (aOR(MI) = 2.9, [2.0-4.3]). This analysis shows that HCV-genotype 3 is associated with severe liver disease in drug users, independently of age, sex, duration of infection, alcohol consumption, and co-infection with HIV. These results are in favor of earlier treatment for drug users infected with HCV- genotype 3 and confirm the need for concomitant care for excessive alcohol consumption. PMID- 20827761 TI - A peptide mimotope of hepatitis C virus E2 protein is immunogenic in mice and block human anti-HCV sera. AB - Conformational B-cell epitopes on the HCV E2 protein recognized by human antibodies were characterized by the use of a peptide mimotope named K1. K1 was identified by two HCV anti-E2 monoclonal antibodies (mAbs) following selection and purification of phage clones containing a 15-mer random peptide insert. Murine antisera to the mimotope K1 recognized the E2 protein. Five of eight human sera from patients who had cleared HCV recognized the K1 mimotope. Binding to E2 in four individuals with the capacity to block E2-CD81 interaction was inhibited by the mimotope K1. The results demonstrate that anti-E2 antibodies in sera from patients who have cleared HCV infection are directed against a conformational B cell epitope on E2 that can be mimicked with linear synthetic peptides. These findings could have implications for vaccine design by employing linear mimotopes to direct B-cell responses against those specific E2 epitopes that may correlate with immunity. PMID- 20827762 TI - Low prevalence of hepatitis E infection among pregnant women in Madrid, Spain. AB - Hepatitis E virus, a cause of sporadic hepatitis in developed countries is present in Spain. The aims of this study were to determine whether the prevalence of IgG anti-hepatitis E virus antibodies has increased in recent years in Spain and the prevalence in a study population at risk of developing the disease following the infection. Serum samples from 1,040 women in the first trimester of pregnancy were studied. The prevalence rate of 3.6% has not increased significantly since 1999 in spite of the large number of immigrants from endemic regions. IgM anti-HEV antibodies were detected in 0.67% of the patients suggesting that although subclinical infection exists the prevalence is very low. The reasons for the differences in the morbidity of HEV in pregnant women in different geographical areas remain unclear. Good hygienic measures and public health conditions are important factors for ensuring low prevalence of hepatitis E in Spain. PMID- 20827763 TI - Review part 2: Human herpesvirus-6 in central nervous system diseases. PMID- 20827764 TI - IgG subclasses and DNA detection of HHV-6 and HHV-7 in healthy individuals. AB - Human herpesvirus 6 (HHV-6) and 7 (HHV-7) are common opportunistic agents in immunocompromised hosts, although infection with HHV-6 and HHV-7 can also be observed in immunocompetent hosts. Despite similar biology and epidemiology, this study evaluated differences in the IgG subclass distribution associated with HHV 6 and HHV-7 in seropositive, healthy persons. The identified subclasses were also compared with the detection of HHV-6 and HHV-7 DNA. For these assays, sera, plasma, and saliva samples were obtained from 40 healthy blood donors in Argentina who were seropositive for both HHV-6 and HHV-7. HHV-6 and HHV-7 DNA were detected in saliva and plasma samples using nested PCR, and specific IgG subclasses were determined using immunofluorescent assays of sera samples. HHV-7 DNA was detected in 90% of all plasma samples and in 100% of saliva samples. In contrast, HHV-6 DNA was not detected in any of the plasma samples, and it was detected in only 6 of 40 saliva samples. Determination of IgG subclass distributions showed that HHV-6 was restricted to IgG1, whereas HHV-7 IgG subclasses included two groups, one restricted only to IgG1 and the other to IgG1 and IgG3. These results demonstrate the differences between HHV-6 and HHV-7 DNA range detection in saliva and plasma samples, as well as the IgG subclass patterns for each virus type, in healthy persons in Argentina. PMID- 20827765 TI - Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. AB - Multiple previous studies have sought evidence for ongoing, active infection with, or reactivation of, Herpesviruses in patients with chronic fatigue syndrome (CFS), with conflicting results. This study aimed to clarify this by studying 20 patients enrolled in a well-characterized model of the onset and evolution of CFS, the prospective cohort of the Dubbo Infection Outcomes Study (DIOS). The patients selected for examination included five CFS patients with primary Epstein Barr virus (EBV) infection; five CFS patients with acute viral infection not caused by EBV; and 10 matched controls with prompt resolution of primary EBV infection. Serum samples from three timepoints were assayed using a comprehensive range of serological assays for EBV, HHV-6, and CMV. Viral genomes were assessed using quantitative PCR assays. All patients were seropositive for HHV-6, and 10 were seropositive for CMV at infection baseline (five patients and five controls). Low titer CMV IgM antibodies were found at infection baseline in two of these cases and three control patients. HHV-6 IgG antibody titers were highest at infection baseline but did not differ between the CFS cases and the control patients. There were increases in EBV IgG VCA p18, EBNA-1 IgG, and EA IgG titers over time, but these did not differ between CFS cases and control patients. EBV and HHV6 DNA levels were at control levels in a minority of samples, and CMV was undetectable in all samples. These data do not support the hypothesis of ongoing or reactivated EBV, HHV-6, or CMV infection in the pathogenesis of CFS. PMID- 20827766 TI - Molecular detection of adeno-associated virus in cases of spontaneous and intentional human abortion. AB - Pregnancy failure is a common event and often of unknown cause. Some viruses are thought to cause abortions including the adeno-associated viruses (AAV), viruses which are regarded as being without any definitive association to any human disease. This study investigated AAV infection in 81 human abortions, both spontaneous and intentional that occurred up to the 23rd week of gestation. Nucleic acid of AAV-2, 3, and 5 types from 118 decidual and chorionic tissues, collected from the patients in this study, was amplified by nested-PCR. In situ hybridization (ISH) was developed with a digoxigenin-labeled AAV probe in paraffin embedded tissues from the AAV positive cases. AAV was observed in 28.4% (23/81) of the cases, of which, 78.3% (18/23) were in the decidua and 21.7% (5/23) in the extravillous trophoblast, the chorionic plate, or chorionic villi fragments. AAV-2, the only type detected, occurred in 32.3% (22/68) and in 7.7% (1/13) of the spontaneous and intentional abortions, respectively. ISH revealed AAV in the decidua, chorionic tissue or chorionic plate and extravillous trophoblast. The detection of only AAV-2 type indicates that it is the most frequent in the population studied and/or shows tissue tropism. The presence of AAV in decidual or trophoblastic cells in cases of abortion, as observed by ISH, implies that the virus could jeopardize the pregnancy. The significant predominance in spontaneous cases suggests possibly a causal association between AAV and abortion. PMID- 20827767 TI - Low frequency of cytomegalovirus infection during exacerbations of inflammatory bowel diseases. AB - Although numerous reports have described inflammatory bowel diseases (IBDs) complicated with cytomegalovirus (CMV) infection, the virus participation as an exacerbating factor remains unclear. The aim of this study was thus to clarify the clinical significance of CMV infection complicating exacerbation and to correlate CMV detection with various characteristics in IBD patients. Sixty-seven colonic biopsies obtained from 53 patients admitted for IBD exacerbation were retrospectively analyzed by real-time PCR assay. The CMV genome was detected in seven (10.4%) colonic biopsies related to seven patients (three ulcerative colitis and four Crohn's diseases). Among the patients with IBD studied, patients with evidence of CMV infection were older (P = 0.047), were more likely male gender (relative risk [RR] 4.48; 95% confidence interval [CI] 0.94-21.36), received corticosteroids (RR 3.2; CI 0.79-13.02) or azathioprine (RR 3.17; CI 0.80-12.57) treatments, presented more extended lesions (RR for rectum-sigmoid left colon 3.75 (0.0-69.37) and for pancolitis 2.45 (0.36-16.23)), and had a more severe disease (RR 3.3; CI 0.87-12.48) than those without CMV infection. Viral loads measured in the colonic mucosa of infected patient ranged from 5 to 236961 genome copies by microgram of total extracted DNA. No relationship was observed between the severity of the disease and the viral load level. Furthermore, CMV disappeared in five infected IBD patients in remission without antiviral agents. In conclusion, these results showed infrequent CMV detection in colonic biopsies of IBD patients during exacerbation leaving open the question of the relationship between CMV reactivation and the onset or the severity of IBD exacerbation. PMID- 20827768 TI - Anchored pan dengue RT-PCR and fast sanger sequencing for detection of dengue RNA in human serum. AB - A large number of human infections are caused by different dengue virus strains, mainly in the tropical and subtropical parts of the world, but also outside the endemic regions. RT-PCR methods are used widely for detection of dengue virus RNA in acute-phase serum samples; however, new sequence variation can inhibit these methods. An assay was developed integrating an anchored Pan Dengue RT-PCR with a new Fast Sanger sequencing protocol. For broad detection and identification of dengue virus RNA, including new strains of all serotypes, the conserved 3' genome end was targeted for highly specific cDNA synthesis. A combination of degenerated primers was used for second strand synthesis, followed by tag primed amplification. The mixture of generated amplicons was identified directly by the Fast Sanger sequencing from the anchored 3' genome end. Evaluating the assay on human serum RNA spiked with viral RNA representing the four dengue serotypes demonstrated a detection limit of 44-124 copies viral RNA per reaction for a two step format of the anchored Pan Dengue RT-PCR and 100-500 copies for a one-step protocol, respectively. The different serotypes were clearly identified from the generated sequences. Further, the 5-hr procedure was evaluated and compared to standard real-time RT-PCR protocols on acute-phase serum samples from patients with confirmed dengue infections. This assay demonstrates a strategy for virus detection, which combines nucleic acid amplification adapted for dengue virus RNA with direct and rapid sequencing. It provides a tolerance for new sequence variation and the strategy should be applicable for other RNA viruses. PMID- 20827769 TI - Expression of Epstein-Barr virus-encoded LMP1 and hTERT extends the life span and immortalizes primary cultures of nasopharyngeal epithelial cells. AB - Cell immortalization is regarded as an early and pre-requisite step in tumor development. Defining the specific genetic events involved in cell immortalization may provide insights into the early events of carcinogenesis. Nasopharyngeal carcinoma is common among the Southern Chinese population. Epstein Barr virus (EBV) infection is associated closely with nasopharyngeal carcinoma. The involvement of LMP1 (an EBV-encoded oncogene) has been implicated in the pathogenesis of nasopharyngeal carcinoma. In this study, LMP1 expression, in combination with ectopic expression of hTERT (catalytic unit of human telomerase), was shown to extend the life span of primary cultures of nasopharyngeal epithelial cells and facilitate the immortalization of one of the cell lines (NP446). This is the first report on the successful immortalization of nasopharyngeal epithelial cells involving LMP1. The events associated with the immortalization of nasopharyngeal epithelial cells by LMP1/hTERT were characterized. Expression of c-Myc, Bmi-1, and Id-1 were upregulated at an early stage of immortalization. At a later stage of immortalization, downregulation of p21 and p16 expression were observed. Upregulation of EGFR expression and activation of MAPK signaling pathway were observed in LMP1/hTERT-immortalized nasopharyngeal epithelial cells. The LMP1/hTERT-immortalized NP446 cells were non tumorigenic in immunosuppressed nude mice and retained anchorage-dependent growth, suggesting that additional events are required for tumorigenic transformation. The ability of the EBV-encoded LMP1, in the presence of hTERT expression, to extend the life span and immortalize primary cultures of nasopharyngeal epithelial cells supports the involvement of EBV infection and its viral products in the early stage of pathogenesis of nasopharyngeal carcinoma. PMID- 20827770 TI - Prevalence and genotype distribution of cervical human papillomavirus infection in Macao. AB - Population-specific epidemiological data on human papillomavirus (HPV) infection are essential for formulating strategies to prevent cervical cancer. The age specific prevalence of HPV infection was determined among 1,600 women enrolled for cervical screening in Macao. A U-shaped age-specific prevalence curve with a first peak (prevalence rate, 10%) at 20-25 years and a second peak (13%) at 51-55 years was observed. Co-infections with multiple types were detected in 32.5% of HPV-positive subjects and without significant variation among different age groups (P = 0.318). The majority (84.6%) of the positive samples harbored high- or probable high-risk HPV types, and these types also exhibited a similar U shaped age-specific prevalence curve. In contrast, low and unknown-risk HPV types remained at a low prevalence (1.5-2.5%) throughout the age groups between 20 and 50 years, and with a small peak (4.5%) at 51-55 years. HPV 52 was the most common type found in 26.8% of positive samples, followed by HPV 16 (15.5%), HPV 68 (11.4%), HPV 18 and HPV 58 (8.9% each), HPV 54 (8.1%), HPV 53 (7.3%), HPV 39 (6.5%), HPV 33 and HPV 66 (5.7% each). In conclusion, because of the early peak of infection, vaccination and educational campaigns in Macao should start early and target at teenagers. The presence of a second peak containing mainly high risk HPV types in older women indicates the need to evaluate the cover of the cervical screening programme for older women. Further study to determine the contribution of HPV 52 in high-grade cervical neoplasia and invasive cancers in Macao is warranted. PMID- 20827771 TI - EBNA1 sequences in Argentinean pediatric acute and latent Epstein-Barr virus infection reflect circulation of novel South American variants. AB - Epstein-Barr virus (EBV) is related to the development of lymphomas and is also the etiological agent for infectious mononucleosis (IM). Sequence variation of the EBNA1 gene, consistently expressed in all EBV-positive cells, has been widely studied. Based on the amino acid at codon 487 five major EBNA1 variants have been described, two closely related prototypic variants (P-ala and P-thr) and three variant sequences (V-leu, V-val, and V-pro). Sub-variants were then further classified based on mutations other than the originally described. While several studies proposed associations with tumors and/or anatomical compartments, others argued in favor of a geographical distribution of these variants. In the present study, EBNA1 variants in 11 pediatric patients with IM and 19 pediatric EBV lymphomas from Argentina were compared as representatives of benign and malignant infection in children, respectively. A 3-month follow-up study of EBNA1 variants in peripheral blood cells and in oral secretions of patients with IM was performed. A new V-ala variant which includes five V-ala sub-variants and three new V-leu sub-variants was described. These data favor the geographical association hypothesis since no evidence for a preferential compartment distribution of EBNA1 variants and sub-variants was found. This is the first study to characterize EBNA1 variants in pediatric patients with infection mononucleosis worldwide. PMID- 20827772 TI - Prevalence of human papillomavirus genotypes in northern Taiwanese women. AB - The prevalence of Human Papillomavirus (HPV) in the general population of northern Taiwan is described. A total of 343 consecutive cervical swabs from women visiting the medical center for routine gynecologic care were included. Cervical cell cytology was examined by the Papanicolaou (Pap) test, and a PCR based hybridization gene chip analysis was used to identify HPV genotypes. The HPV prevalence in the overall population was 32.4%. When divided into two groups according to cytology, 20.9% of women with normal cytology were HPV positive while 75.3% of women with abnormal cytology were HPV positive. Among positive samples, 68.5% were single type infections while 31.5% harbored multiple HPV types. A total of 32 types of HPV were identified; the leading five were HPV16 (5.8%), HPV58 (5.3%), HPV53 (4.1%), HPV52 (3.8%), and HPV18 (2.3%). Our results constitute baseline data and may provide important implications for future prophylactic programs. The relatively high prevalence of HPV 58, 53, and 52 among northern Taiwanese women has important implications for vaccine development. PMID- 20827773 TI - Long-term serological follow-up of blood donors with an HTLV-indeterminate western blot: antibody profile of seroconverters and individuals with false reactions. AB - The high proportion of indeterminate results of the screening test for human T lymphotropic virus (HTLV) infection has been a challenge worldwide. In this study, 60 persons with seroindeterminate results for HTLV were followed until their serological status was defined. At least two independent serological tests (EIA and WB) from sequential samples were performed at an average interval of 4.4 years, totaling 141 serum samples tested. Seroconversion occurred in 12 individuals (reactive by EIA, positive by WB and PCR), and 48 were classified as false reactions (non-reactive EIA and negative PCR, but indeterminate WB). The seroconverter group had epidemiological features similar to those seen in HTLV-1 carriers, and the average time of follow-up for seroconversion was 4 years. In the group with false reactions, the most frequent indeterminate WB pattern in the samples was the presence of p24 alone. This pattern was absent in the seroconverter group, suggesting that p24 alone is an indicator of false reactivity. In contrast, the presence of p19 and p24 seems to be an indicator of true reactivity, since this pattern was frequent (66.7%) among the seroconverters and much less common (10.4% of the first samples) among the individuals with false reactions (P = 0.0001). Thus, HTLV infection may be suspected when reactivity to p19 and p24 is observed. Individuals with an indeterminate WB pattern should be followed-up and retested. The improvement of the HTLV algorithm screening of blood donors has been necessary to reduce inconclusive results and to avoid unnecessary follow-up to define the status of infection. PMID- 20827774 TI - Intranasal administration of adjuvant-combined vaccine protects monkeys from challenge with the highly pathogenic influenza A H5N1 virus. AB - The effectiveness in cynomolgus macaques of intranasal administration of an influenza A H5N1 pre-pandemic vaccine combined with synthetic double-stranded RNA (polyI/polyC12U) as an adjuvant was examined. The monkeys were immunized with the adjuvant-combined vaccine on weeks 0, 3, and 5, and challenged with the homologous virus 2 weeks after the third immunization. After the second immunization, the immunization induced vaccine-specific salivary IgA and serum IgG antibodies, as detected by ELISA. The serum IgG antibodies present 2 weeks after the third immunization not only had high neutralizing activity against the homologous virus, they also neutralized significantly heterologous influenza A H5N1 viruses. The vaccinated animals were protected completely from the challenge infection with the homologous virus. These results suggest that intranasal immunization with the Double stranded RNA-combined influenza A H5N1 vaccine induce mucosal IgA and serum IgG antibodies which could protect humans from homologous influenza A H5N1 viruses which have a pandemic potential. PMID- 20827775 TI - Use of a multiplex PCR/RT-PCR approach to assess the viral causes of influenza like illnesses in Cambodia during three consecutive dry seasons. AB - Acute respiratory infections are a major cause of mortality and morbidity worldwide. Using multiplex PCR/RT-PCR methods for the detection of 18 respiratory viruses, the circulation of those viruses during 3 consecutive dry seasons in Cambodia was described. Among 234 patients who presented with influenza-like illness, 35.5% were positive for at least one virus. Rhinoviruses (43.4%), parainfluenza (31.3%) viruses and coronaviruses (21.7%) were the most frequently detected viruses. Influenza A virus, parainfluenza virus 4 and SARS-coronavirus were not detected during the study period. Ninety apparently healthy individuals were included as controls and 10% of these samples tested positive for one or more respiratory viruses. No significant differences were observed in frequency and in virus copy numbers for rhinovirus detection between symptomatic and asymptomatic groups. This study raises questions about the significance of the detection of some respiratory viruses, especially using highly sensitive methods, given their presence in apparently healthy individuals. The link between the presence of the virus and the origin of the illness is therefore unclear. PMID- 20827776 TI - Comparison of laboratory diagnostic methods for measles infection and identification of measles virus genotypes in Hong Kong. AB - The sensitivities of IgM detection, virus isolation, and RT-PCR for the diagnosis of measles infection were assessed using samples collected from confirmed measles cases from 2006 to 2009. The optimal timing of specimen collection and the preferred specimen type(s) for these tests were also determined. IgM detection showed highest sensitivity when serum samples were collected >or=5 days after rash onset. Virus isolation gave the highest sensitivity when samples were collected =1 Z or >=1 S allele. CONCLUSION: Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between alpha(1) AT deficiency and susceptibility to WG. PMID- 20827782 TI - Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study. AB - OBJECTIVE: Reports of therapy-related adverse events suggest an elevated rate of malignancy in patients with juvenile idiopathic arthritis (JIA) treated with biologic therapies. However, the scarcity of data on the underlying risk of malignancy in JIA hampers interpretation of these signals. Therefore, the aim of this study was to determine the risk of cancer in patients with JIA as compared with that in the general population. METHODS: Through linkage with a national database, the Swedish Patient Register (comprising inpatient discharges in 1969 2007 and specialist outpatient visits in 2001-2007 in Sweden), a national JIA cohort (n = 9,027) was identified, and each JIA case was matched with 5 general population comparators. Using data from the Swedish Cancer, Census, Death, and Biologics Registers, the occurrence of cancer, vital status, and start of a biologic therapy were identified. The relative risk (RR) of first occurrence of a primary cancer in patients who had not been treated with biologics (biologics naive patients with JIA) was estimated using Poisson regression, stratified a priori by year of earliest identification of JIA (before 1987 versus 1987 and thereafter). In sensitivity analyses, the data were followed up to 1999, when biologics first became available. RESULTS: In this biologics-naive JIA cohort, 60 malignancies were observed during 131,144 person-years of followup, compared with 266 cancers observed during 661,758 person-years in the general population comparator (0.46 cases/1,000 person-years versus 0.40 cases/1,000 person-years; RR 1.1, 95% confidence interval [95% CI] 0.9-1.5). Patients with JIA identified before 1987 were not at increased risk of cancer, whereas JIA identified in 1987 and thereafter was significantly associated with incident lymphoproliferative malignancies (RR 4.2, 95% CI 1.7-10.7) and cancers overall (RR 2.3, 95% CI 1.2 4.4). Sensitivity analyses did not reveal any ready explanation for this heterogeneity. CONCLUSION: Although absolute risks were low, an elevated risk of malignancy was observed among biologics-naive patients in whom the diagnosis of JIA was made in the past 20 years, which may have implications for the interpretation of cancer signals in patients with JIA treated with newer therapies. PMID- 20827783 TI - Alcohol consumption and markers of inflammation in women with preclinical rheumatoid arthritis. AB - OBJECTIVE: To examine the association between alcohol consumption and markers of inflammation in preclinical rheumatoid arthritis (RA). METHODS: We studied 174 incident RA cases with stored blood collected 1-16 years prior to RA symptoms (preclinical RA), from the Nurses' Health Study. Alcohol intake was measured using a detailed food frequency questionnaire administered every 4 years, prior to blood collection. Plasma was tested for biomarkers of inflammation, including high-sensitivity C-reactive protein (hsCRP), anti-cyclic citrullinated peptide (anti-CCP) antibodies, interleukin-6 (IL-6), and soluble tumor necrosis factor receptor II (sTNFRII). Generalized additive models were used to identify structure in the relationship between each biomarker and cumulative average alcohol intake. Then general linear models were used for multivariable adjusted analyses with appropriate polynomial terms of alcohol consumption. RESULTS: After controlling for age at blood collection, smoking, parity and duration of breastfeeding, menopausal status, oral contraceptive use, body mass index, and the time between blood collection and RA onset, we found that the daily alcohol consumption showed a U-shaped association with IL-6 levels in RA patients, prior to symptoms. We also found an inverse relationship between alcohol intake and sTNFRII levels, but no associations with hsCRP or anti-CCP levels. CONCLUSION: These results demonstrate an association between alcohol consumption and markers of inflammation, including IL-6 and sTNFRII, in RA patients, prior to the occurrence of symptoms. PMID- 20827784 TI - Two sibs with Bardet-Biedl syndrome due to mutations in BBS12: no clues for modulation by a third mutation in BBS10. PMID- 20827785 TI - The hidden benefits of sex: evidence for MHC-associated mate choice in primate societies. AB - Major histocompatibility complex (MHC)-associated mate choice is thought to give offspring a fitness advantage through disease resistance. Primates offer a unique opportunity to understand MHC-associated mate choice within our own zoological order, while their social diversity provides an exceptional setting to examine the genetic determinants and consequences of mate choice in animal societies. Although mate choice is constrained by social context, increasing evidence shows that MHC-dependent mate choice occurs across the order in a variety of socio sexual systems and favours mates with dissimilar, diverse or specific genotypes non-exclusively. Recent research has also identified phenotypic indicators of MHC quality. Moreover, novel findings rehabilitate the importance of olfactory cues in signalling MHC genes and influencing primate mating decisions. These findings underline the importance to females of selecting a sexual partner of high genetic quality, as well as the generality of the role of MHC genes in sexual selection. PMID- 20827786 TI - HIF-1alpha inhibition ameliorates an allergic airway disease via VEGF suppression in bronchial epithelium. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a critical role in immune and inflammatory responses. One of the HIF-1alpha target genes is vascular endothelial growth factor (VEGF), which is a potent stimulator of inflammation, airway remodeling, and physiologic dysregulation in allergic airway diseases. Using OVA-treated mice and murine tracheal epithelial cells, the signaling networks involved in HIF-1alpha activation and the role of HIF-1alpha in the pathogenesis of allergic airway disease were investigated. Transfection of airway epithelial cells with HIF-1alpha siRNA suppressed VEGF expression. In addition, the increased levels of HIF-1alpha and VEGF in lung tissues after OVA inhalation were substantially decreased by an HIF-1alpha inhibitor, 2-methoxyestradiol. Our data also show that the increased numbers of inflammatory cells, increased airway hyperresponsiveness, levels of IL-4, IL-5, IL-13, and vascular permeability in the lungs after OVA inhalation were significantly reduced by 2-methoxyestradiol or a VEGF inhibitor, CBO-P11. Moreover, we found that inhibition of the PI3K p110delta isoform (PI3K-delta) or HIF-1alpha reduced OVA-induced HIF-1alpha activation in airway epithelial cells. These findings indicate that HIF-1alpha inhibition may attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular leakage mediated by VEGF, and that PI3K-delta signaling may be involved in the allergen-induced HIF-1alpha activation. PMID- 20827787 TI - From furan to molecular stairs: syntheses, structural properties, and theoretical investigations of oligocyclic oligoacetals. AB - The synthesis of oligocyclic oligoacetals using five-membered rings as repetitive unit is described. Furan was used as the starting material, which is converted by a three-step procedure consisting of twofold cyclopropanation, reduction, and oxidative ring enlargement into a tricyclic bis(enol ether). A repetition of this synthetic procedure leads to the formation of extended oligoacetal systems. Insights into the structures were gained by X-ray crystallographic investigations and revealed helical arrangements of the subunits in the solid-state. DFT (B3LYP) calculations have been carried out to elucidate the transition state of the ring enlargement and the flexibility of the annelated oligocyclic systems. Strain energies and topologies of potential cyclically condensed oligoacetals are predicted. PMID- 20827788 TI - Hexazirconium- and hexahafnium-containing tungstoarsenates(III) and their oxidation catalysis properties. PMID- 20827789 TI - Dialkylaluminium-, -gallium-, and -indium-based poly-Lewis acids with a 1,8 diethynylanthracene backbone. AB - Potential host systems based on a rigid 1,8-diethynylanthracendiyl backbone were synthesised by treatment of 1,8-diethynylanthracene with the Group 13 trialkyls AlMe(3), GaMe(3), InMe(3), AlEt(3) and GaEt(3). The resulting products were characterised by IR and multinuclear NMR spectroscopy, elemental analyses and determination of their crystal structures by X-ray diffraction. The compounds are dimeric in the solid state and comprise two M(2)C(2) heterocycles. Depending on the steric demand of the alkyl substituents at the metal atom, different types of binding modes were observed, which can be classified to lie between the ideals of side-on coordination with almost linear primary M-C=C units and the 3c-2e coordination with symmetrically bridging alkynyl units in M-C-M bonds. As a solution in THF the dimers are broken into monomers and some are found to undergo ligand scrambling reactions. PMID- 20827790 TI - A novel competitive class of alpha-glucosidase inhibitors: (E)-1-phenyl-3-(4 styrylphenyl)urea derivatives. AB - Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo- and regiocontrolled. Here, we show that readily accessible achiral (E)-1-phenyl-3-(4-strylphenyl)ureas are potent competitive alpha-glucosidase inhibitors. A systematic synthesis study shows that the 1 phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC(50)=8.4 MUM, K(i)=3.2 MUM), manifested a simple slow-binding inhibition profile for alpha-glucosidase with the kinetic parameters k(3)=0.005256 MUM(-1) min(-1), k(4)=0.003024 min(-1), and K(i)(app) =0.5753 MUM. PMID- 20827791 TI - Multimerization of cRGD peptides by click chemistry: synthetic strategies, chemical limitations, and influence on biological properties. AB - Integrin alpha(nu)beta(3) is overexpressed on endothelial cells of growing vessels as well as on several tumor types, and so integrin-binding radiolabeled cyclic RGD pentapeptides have attracted increasing interest for in vivo imaging of alpha(nu)beta(3) integrin expression by positron emission tomography (PET). Of the cRGD derivatives available for imaging applications, systems comprising multiple cRGD moieties have recently been shown to exhibit highly favorable properties in relation to monomers. To assess the synthetic limits of the cRGD multimerization approach and thus the maximum multimer size achievable by using different efficient conjugation reactions, we prepared a variety of multimers that were further investigated in vitro with regard to their avidities to integrin alpha(nu)beta(3.) The synthesized peptide multimers containing increasing numbers of cRGD moieties on PAMAM dendrimer scaffolds were prepared by different click chemistry coupling strategies. A cRGD hexadecimer was the largest construct that could be synthesized under optimized reaction conditions, thus identifying the current synthetic limitations for cRGD multimerization. The obtained multimeric systems were conjugated to a new DOTA-based chelator developed for the derivatization of sterically demanding structures and successfully labeled with (68)Ga for a potential in vivo application. The evaluated multimers showed very high avidities-increasing with the number of cRGD moieties-in in vitro studies on immobilized alpha(nu)beta(3) integrin and U87MG cells, of up to 131- and 124-fold, respectively, relative to the underivatized monomer. PMID- 20827792 TI - An engineered DNA-binding protein self-assembles metallic nanostructures. PMID- 20827793 TI - A novel fungal flavin-dependent halogenase for natural product biosynthesis. PMID- 20827794 TI - Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: a pooled subpopulation analysis. AB - OBJECTIVES: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy. METHODS: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score <=10 at endpoint. RESULTS: Four hundred and nine older patients (placebo, n = 198; aripiprazole, n = 211) and 679 younger patients (placebo, n = 341; aripiprazole, n = 338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p < 0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p < 0.001) and younger (26.9% vs. 16.4%; p < 0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. CONCLUSIONS: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication. PMID- 20827795 TI - Robotic-assisted laparoscopic abdominoperineal resection for anal cancer: feasibility and technical considerations. AB - BACKGROUND: Robotic-assisted laparoscopic surgery is an emerging technology that may prove advantageous for complex colorectal procedures involving the irradiated pelvis, such as abdominoperineal resection for recurrent anal cancer. The authors' initial experience is presented, with assessment of feasibility, safety, and oncologic principles. METHODS: Over a 6 month period, five abdominoperineal resections were performed using the da Vinci(r) robot for recurrent anal cancer in patients initially treated with definitive chemoradiation therapy. Demographics, intraoperative parameters, pathology, and outcomes were assessed. RESULTS: Five patients underwent surgery with a mean age of 58.8 years and body mass index of 24.9 kg m(-2) . The interval between chemoradiation and salvage APR was 14.2 +/- 10.0 months. Operative time was 204 +/- 39.1 min with robotic docking time 12.2 +/- 2.8 min and console time 93.0 +/- 24.9 min. The mean estimated blood loss was 150 cc and there were no intraoperative complications. The mean hospital length of stay was 5.4 days. Pathology analysis revealed that all surgical margins were adequate. There was one postoperative complication consisting of a seroma. CONCLUSION: Robotic-assisted laparoscopic surgery for anal cancer was found to be a safe and feasible procedure. It facilitated enhanced visualization and dissection through deep irradiated pelvic structures. PMID- 20827796 TI - German health reform compromise under attack. PMID- 20827797 TI - Supplementary comment on "Neuropsychological improvement in patients with cervical spondylotic myelopathy after posterior decompression surgery". PMID- 20827798 TI - The objective and subjective sides of malocclusions--more justification for orthodontics? PMID- 20827799 TI - The call of the human proteome. AB - A Human Proteome Project has been proposed. To ensure that such a project will have a transformative impact on biology, its scope should be determined by wide and open discussion. PMID- 20827800 TI - Molecular engineering: Unnatural design. AB - Researchers designed an enzyme to carry out the Diels-Alder reaction, an activity not found in nature. PMID- 20827801 TI - Single molecule: Single molecules meet systems biology. AB - Application of single-molecule methods to assay genome-wide mRNA and protein levels in single bacteria provides a systems-level view of their relationship. PMID- 20827802 TI - Systems biology: Learning from history. AB - The strength of selection that acts on a growing population of cells and the presence of a stochastic switching mechanism may be inferred from lineage data. PMID- 20827803 TI - Microbiology: When bacteria experience a tremor. AB - A trackable multiplex recombineering method in Escherichia coli allows for the identification of genes that affect a selectable trait. PMID- 20827804 TI - Chemical biology: Rapid allosteric activation. AB - Engineered kinases remain off in cells until turned on by small molecules. PMID- 20827805 TI - Biophysics: Melting trapped DNA. AB - Single DNA molecules stretched in a nanochannel display melting patterns characteristic of their sequence. PMID- 20827806 TI - High frequency of MCM6 lactose intolerance genotype in Polynesian people. PMID- 20827807 TI - Abstracts of the ISCO Congress 2010, Dresden, Germany, 17-19 March, 2010. PMID- 20827808 TI - The psychological impact of motor vehicle accidents on emergency service workers. AB - Emergency service workers continuously face situations where they are in charge of the lives of others, and this can be a risk factor for their mental health. This study aims to determine the psychological impact of exposure to current death and physical injury events in the context of motor vehicle accidents among emergency personnel and which variables better predict posttraumatic stress disorder. Participants were National Institute of Medical Emergency workers (nurses and medical doctors; n= 59) in the north of Portugal. They filled out a trauma exposure and posttraumatic stress disorder scale (PTSD), a scale that assesses distress (General Health Questionnaire 12), a peritraumatic dissociation scale (Peritraumatic Dissociative Experiences Questionnaire) and a coping scale (Ways of Coping Questionnaire). Participants reported high exposure to events evaluated as traumatic, but low prevalence of PTSD. When the relation between exposure, time in emergency, sex, distress symptoms, peritraumatic dissociation, and PTSD symptoms was examined, peritraumatic dissociation and distress were the only predictors of PTSD symptoms, but beyond their contribution direct coping explains PTSD variance. In conclusion, taking into account the contribution of distress and peritraumatic dissociation to predict psychopathological symptoms, and the contribution of coping to lower PTSD scores, education and training should help the professionals deal with these reactions and improve coping, and organizations should support professionals in the most disturbing situations. PMID- 20827809 TI - Retraction: Neoplastic meningitis. PMID- 20827810 TI - Electroconvulsive therapy substantially reduces symptom severity and social disability associated with multiple chemical sensitivity: a case report. AB - BACKGROUND: Multiple chemical sensitivity (MCS) is a chronic nonallergic, multisymptom disorder triggered by common environmental chemicals in concentrations considered nontoxic for most individuals. The condition may lead to loss of occupation and social isolation, and no effective treatment has been reported. Electroconvulsive therapy (ECT) is a safe and effective treatment of severe depression and medical conditions such as chronic pain disorders. CASE REPORT: We report a case of a 45-year-old man with a 5-year history of MCS who had to quit his job to live a solitary life without his wife and children because of the condition. The patient had no history of psychiatric illness and no signs of clinical depression at treatment start. Over a 3-week period, he underwent a course of 8 ECTs, giving a remarkable effect on symptom severity and social functional level. After a partial symptom relapse, maintenance treatment was started with 1 ECT every second week. No memory impairment or other complications of ECT were reported at the 4-month follow-up. CONCLUSIONS: In this case, a substantial, positive effect on symptom severity and social disability related to MCS was obtained by an initial ECT course and maintenance treatment. Electroconvulsive therapy should be considered an option in severe and socially disabling MCS, but more studies are needed to evaluate if ECT can be recommended as a treatment in MCS. PMID- 20827811 TI - [Assessment of brain neural pathways in diffuse axonal injuries using diffusion tensor magnetic resonance tomography]. AB - BACKGROUND: Aim of this study was to assess the role of diffusion-tensor magnetic resonance imaging (DT-MRI) in diagnosis and prognosis in severe diffuse axonal injury (DAI). MATERIALS AND METHODS: The studies using 1.5 Tesla MR tomograph were performed on 2nd-17th days after injury in 22 patients with DAI and in 8 healthy volunteers. All patients were comatose in acute period (GCS 4-8), 11 had hemiparesis and in 4 had tetraparesis. Outcomes were evaluated after 6 months using GOS. Indices of diffusion coefficient (DCI) and fraction anisotropy (FA) were assessed bilaterally: in genu and splenium of corpus callosum, posterior limb of internal capsule (PLIC), cerebral peduncles, at the level of pons (along corticospinal tracts (CST). RESULTS: Significant decrease of FA (p < 0.05) along CST bilaterally was found in 7 patients without movement disorders comparing to analogous indices in the control group. Also statistically significant decrease of FA at the level of PLIC and cerebral peduncles was observed on the contralateral side in patients with hemiparesis (p < 0.01). In patients with tetraparesis FA was significantly decreased along CST bilaterally (p < 0.00001). Indices of FA in corpus callosum and along pyramidal tracts significantly correlated with outcomes in patients examined on 10th-17th day after injury (p < 0.01). In the whole group of patients mean indices of FA and DCI in the splenium of corpus callosum were significantly decreased (p < 0.01 and p < 0.05, respectively). 3D reconstruction of CST allowed to discover asymmetry of CST in 3 of 9 patients with hemiparesis on 1st-9th day after injury and in all 6 patients examined on 10th-17th day. CONCLUSION: Indices of FA reflect the degree of integrity of white matter pathways with significant accuracy. Application of DT MRI allows to reveal quantitative and qualitative alterations in white matter tracts and to assess their clinical and prognostic value in DAI. PMID- 20827812 TI - [Planning of surgical approach to intracerebral tumors of the hemispheres using fMRI, neuronavigation, and electrophysiological monitoring]. AB - The paper discusses pre- and intraoperative application of different guiding techniques (frameless neuronavigation, fMRI, electrophysiological monitoring). We performed comparative analysis of different combinations of these methods. 74 patients with intracerebral tumors involving eloquent areas (sensorimotor cortex in 56 and speech zones in 18) were operated. In 9 cases 'awake surgery' was applied. We found that frameless navigation combined with brain mapping allows to optimize planning of surgical approach and to decrease postoperative neurological deficit. Also in certain cases 'awake craniotomy' can be replaced by fMRI and neuronavigation. PMID- 20827813 TI - [A rare case of intraventricular recurrence of melanoma metastasis treated by endoscope-assisted surgery]. AB - In the paper we describe a rare case of intraventricular recurrence of melanoma metastasis treated by endoscope-assisted surgery. Total resection was performed using microsurgical approach with endoscopic assistance. Full regression of neurological deficit, physical rehabilitation and recurrence-free 6-month follow up was achieved in this case. PMID- 20827814 TI - [Local injuries and necroses of cerebral tissue after radiation therapy and stereotactic radiosurgery of intracranial mass lesions]. PMID- 20827815 TI - Uganda steps up efforts to boost male circumcision. PMID- 20827816 TI - Asthma and the value of contradictions. PMID- 20827817 TI - Retraction: Recurrent chiasmatic-hypothalamic glioma treated with oral etoposide. PMID- 20827826 TI - The "magical" language of Mantra. AB - This paper aims to illuminate the phenomenon of mantras and to critique the category of magic through an examination of mantra as magical language. Mantras have often been referred to as "magic formulas" or "spells," yet one searches the scholarly literature in vain for a worthy explanation of precisely why mantra should or should not be considered magical. This essay addresses this lack, (a) explaining how mantra's conflict with modern Western understandings of language has led scholars to conceive of mantra as magic and (b) showing just what is at stake in such characterizations. This examination of mantra will demonstrate how "magic" and related terms have consistently been used not so much to describe as to marginalize and de-authorize that to which they refer. While the issue is partly about flawed terms and categories, the question of mantra as magic ultimately leads to an unsettling confrontation with the limits of our own modern rationalist perspective. PMID- 20827827 TI - Fatherhood, childism, and the creation of society. AB - This essay argues for a new religious ethical approach to fatherhood centered on children and their expanding capabilities for participation in society. Under the notion of "childism"-in analogy to feminism, womanism, humanism, and the like-it takes the perspective of the experiences and concerns of childhood as such. In contrast with a soft patriarchal argument for fatherhood that dominates much religious discourse today, it argues for a larger and more hopeful vision of fatherhood as directed toward the human social good. This requires, methodologically, a richer hermeneutical circle between religion and the social sciences. Substantively, it calls for Christian and other religious ethicists to re-imagine fatherhood as an integrated public-private responsibility that aims to cultivate children's fully human social creativity as images of their Creator. PMID- 20827828 TI - Sex and the City (of God): is sex forfeited or fulfilled in Augustine's resurrection of body? AB - Reading Augustine's hypothetical description of resurrection bodies through Freud and his critics' construction of "sexuality," I suggest that Augustine's mature writings on the resurrection include some-thing like post-Freudian ideas of sexuality, even though the concept itself was not part of Augustine's conceptual universe. Historicizing "sexuality" frees the concept for revision so that sexuality can be thought of as embedded in social assumptions and arrangements rather than individual, as part rather than essence of the self, and as gendered rather than universal. Collecting and composing hints and clues scattered in Augustine's sermons and treatises, I sketch a post-Augustinian proposal for an ideal sexuality that is not incompatible with, but extends, elaborates, and refines Augustine's description of resurrection bodies. PMID- 20827829 TI - Let's cross that body when we get to it: gender and ethnicity in rabbinic literature. AB - This article explores rabbinic constructions of gender and ethnicity by reading two apparently disparate biblical characters together: Mordechai and Zipporah. Zipporah and Mordechai transgress gender boundaries both in the biblical text and subsequent rabbinic traditions. In the book of Exodus (4:25), Zipporah circumcises her son, and in rabbinic literature (Gen. Rab. 30:8) Mordechai nurses Esther-his adopted daughter. Yet in rabbinic literature, a father is obligated to circumcise his son, and a mother is obligated to nurse a child. I examine rabbinic traditions concerned not only with these gender transgressions but also with Mordechai and Zipporah's ethnic ambiguities in order to ask what might these traditions teach us about the fluidity and/or fixedness of gender and ethnicity in rabbinic literature. Finally, I explore the ways in which their gender and ethnicity are connected. In other words, I ask what are some of the "interarticulations" of gender and ethnicity played out in rabbinic literature, specifically in the textual traditions surrounding Mordechai and Zipporah. PMID- 20827830 TI - Teresa Urrea: Mexican mystic, healer, and apocalyptic revolutionary. AB - This article is a study of the mystical and apocalyptic dimensions of Teresa Urrea. As explained in this article, Urrea's mystical experiences and visions are unique for their connection with a propheticapocalyptic and political worldview. This apocalyptic dimension is more than a communication of a hidden message or spiritual world; it also includes a reading of history that is catastrophic and discontinuous. The crisis and terror of history are given expression in Urrea's mystical and apocalyptic pronouncements. In particular, the chaotic and oppressive circumstances of Mexican society during the dictatorship of Porfirio Diaz was confronted and denounced in Urrea's mystical and apocalyptic ministry. This apocalyptic healer castigated those culpable or even complicit with the injustices affecting the indigenous communities of Mexico during the late nineteenth century. In the case of Urrea, the transformation and healing of Church and society was an important aspect of her spiritual, healing powers. Because Urrea possessed neither arms nor the weapon of the pen, her sole weapon became her mystical experiences and the insight and healing powers that flowed from them. People of Mexico-especially indigenous groups-began to flock to her hoping that she would bring God's presence to the troubled and chaotic circumstances of their lives. Her compassion and tenderness for the afflicted as well as the apocalyptic expectations that she stirred up among the indigenous groups of Northern Mexico were enough to get this mystical-political Mexican mestiza exiled from her homeland. PMID- 20827831 TI - "Ararat" and collective memories of the Armenian Genocide. AB - Atom Egoyan's Ararat (2002) has been misread and inappropriately critiqued as a failed cinematic representation of the Armenian genocide. The author of this article argues that the film is instead an ambitious meditation on the question of how to represent genocide in general, and the Armenian genocide specifically. He traces a number of themes in Ararat, including the political stakes involved in genocide commemoration, the reasons for and costs of denial, the difficulty and urgency of constructing a past when only ruins remain, the problematic nature of cinematic treatments of genocide, the intensely personal ways in which collective memory helps to shape individual and family identities, and the complexities of determining which versions of the past are reliable. Further, the author discusses the possible consequences of the film's clearly unintended suggestion that, ultimately, there are no solid criteria for choosing between competing versions of the past. PMID- 20827832 TI - "Cattle car complexes": a correspondence with historical captivity and post Holocaust witnesses. AB - This article explores critical complexes relating to the construction of historical captivity in deportation train journeys by examining fictional and testimonial accounts of that experience. Using Thane Rosenbaum's short story "Cattle Car Complex," the author shows that fiction is a prism through which to view victims' experiences of deportation-experiences that tend to be overlooked in interpretive literature about the Holocaust. Historians have examined deportations above all as a perpetrator narrative, utilizing contemporaneous documents and sources. Their treatment neglects the numerous testimonies about the debilitating effects of deportation travel, as well as the evocation of that traumatic transit in post-Holocaust texts and contexts such as fiction, film, art, and museological and commemorative practice. The author argues that sensory witness is a compelling paradigm that can reveal the silences and elisions in representations of historical captivity. PMID- 20827833 TI - The "Russian" prisoners of war in Nazi-ruled Ukraine as victims of genocidal massacre. AB - Ukrainian and Russian primary sources enable us to integrate the civilian Soviet population into the story of the Wehrmacht's treatment of Soviet POWs during World War II. This article reveals a little-known phenomenon: the myriad attempts of bystanders-usually thwarted-to save the lives of the prisoners. Most importantly, it seems likely that in Ukraine prisoners' mass mortality could have been avoided. However, German policy makers and prison guards' desire to eliminate most Soviet POWs, based on the view that these were "Russians" and thus irreversibly "Bolshevized" or simply superfluous, resulted in a "genocidal massacre" that lasted until at least the end of 1942. PMID- 20827834 TI - Exploding cities: housing the masses in Paris, Chicago, and Mexico City, 1850 2000. AB - In The Mystery of Capitalism , the darling of neoliberalism, Hernando de Soto posits that secure property titles explain "why capitalism triumphs in the West and fails everywhere else." While social scientists have taken him to task for an oversimplification of the causes and remedies of poverty, historians have contributed little to this important policy debate. Applying comparative methods across time and space, such a retrospective analysis exposes serious flaws in de Soto's thesis. Case studies of Paris, Chicago, and Mexico City covering successive, fifty-year periods support his contention that property law was the single most important factor in determining the fate of rural migrants trying to find a place to live in these exploding cities. But in each case, residential property played a far more complex role in creating the social and physical geography of the city than its simple exchange value. This article illuminates some of these alternative economic uses and embedded cultural meanings of identities of place. It also shows how urban growth machines create capital value in property for some by creating environmental injustice of substandard conditions of everyday life for others. PMID- 20827835 TI - "To serve the community best": reconsidering Black politics in the struggle to save Homer G. Phillips Hospital in St. Louis, 1976-1984. AB - The move to consolidate, and eventually to close, Homer G. Phillips Hospital sparked a major uprising in St. Louis, Missouri, during the years 1976 through 1984. This article explores the struggle in St. Louis's black community to keep open, and later to reopen, Homer G. Phillips Hospital from a vantage point that demonstrates the diversity of opinion surrounding the struggle. For many black St. Louis residents, the physical space of Homer G. Phillips Hospital was a metaphor for identity, a manifestation of citizenship rights, and a means of delineating a territory of shared histories, understandings, and values. For others, it was a relic of segregation and racism. In seeking to understand the diversity of public reaction, this article addresses class antagonism, examines the varied and divergent motivations for eliminating or maintaining services at the hospital, and reconsiders the discourse of "black politics." It is a decisive illustration of how the national twin crises of deindustrialization and privatization affected a heterogeneous black community. PMID- 20827836 TI - "The Superorganic," or Kroeber's hidden agenda. AB - Kroeber's "The Superorganic" (1917) stands as the first extreme statement of cultural holism. Some have compared it to Durkheim, the majority to Boas; some have denied any evolutionary message, others read in it a theory of "emergent evolution" arising from his transcendental holism. What was it, exactly? When understood as part of a trilogy comprising two other articles (one from 1915, the other from 1919), it emerged that his extreme brand of cultural holism was a necessary tool to carry out a relatively hidden evolutionary agenda. This led me to rethink his evolutionism, to deny that he was a cultural determinist, to understand this part of his anthropology in terms of "epistemological obstacles" (Bachelard 1938), and show that it reemerges in Appadurai's understanding of globalization (1996). PMID- 20827837 TI - "We all go a little mad sometimes": Alfred Hitchcock, American psychoanalysis, and the construction of the Cold War psychopath. AB - This article explores the image of the psychopath in Alfred Hitchcock's 1960 film Psycho. The famed director's portrayal of a psychologically damaged young man connected with a much larger discussion over political and sexual deviance in the early Cold War, a discussion that cantered on the image of the psychopath as the dominant threat to national security and that played upon normative assumptions about adolescent development and mother-son relations. PMID- 20827838 TI - Something black in the American Psyche: formal innovation and Freudian imagery in the comics of Winsor McCay and Robert Crumb. AB - Winsor McCay's Little Nemo in Slumberland anticipates Robert Crumb's work. McCay's innocent dreamscapes seem antithetical to the sexually explicit work of anti-capitalist Crumb, but Nemo looks forward to Crumb in subject and form. Nemo's presentation of class, gender, and race, and its pre-Freudian sensibility are ironic counterpoints to Crumb's political, Freudian comix. PMID- 20827839 TI - Coping versus grieving in a "death-accepting" society: AIDS-bereaved women living with HIV in Indonesia. AB - The aim of this study was to understand how AIDS-bereaved women in Indonesia cope in a society where death is believed to be fated. Data analyses were conducted based on the women's interview transcripts and journal entries. Each of the women experienced at least three traumatic life events. The most challenging experience was learning that they have contracted a disease they regarded as associated with prostitution. Given the short lapse of time between their husbands' deaths and learning about their seropositivity, biographical disruption appeared to have acted as an 'analgesic', while concerns to protect their children seemed to have triggered biographical reinforcement. This phenomenon may have brought about a positive bereavement outcome. Specific counselling programmes for women affected by HIV/AIDS are needed, but emphasis should first be placed on improving their wellbeing and their perception of stigma. PMID- 20827840 TI - Together and apart: twin beds, domestic hygiene and modern marriage, 1890-1945. AB - This article examines the advent of twin beds as a common sleeping arrangement for English couples. Through an analysis of a range of sources from the late nineteenth to mid twentieth centuries - marketing materials, advertisements, domestic, decorative and marital advice books and novels and films - it argues that while twin beds were initially recommended by proponents of the domestic sanitation movement as part of a raft of hygiene measures, by the 1920s they had become a fashionable item of bedroom furniture for modern couples in "companionate" marriages. It was in this context that Marie Stopes, in her popular marital advice books, railed against them as an "invention of the devil", symptomatic of the evils of modernity, and endangering the happiness of the modern married couple. The article concludes that, despite these changing contexts of consumption, the significance of the history of twin beds needs to be understood through the intersecting discourses of domesticity, health and sexuality. PMID- 20827841 TI - Colonial bones: the 2006 burial of Savorgnan de Brazza in the Congo. AB - The Franco-Congolese agreement to enshrine the corpse of Pierre Savorgnan de Brazza in a grand memorial tomb in Brazzaville (2006) has been decried by many observers as neo-colonial farce. This article interprets France's agenda to propose a "suave reconquest" of its former colonies, and Sassou Nguesso's forceful mobilization of national and regional support. Beyond the immediate political significance of the episode, however, the article proposes new ideas on the ways in which modern states, North and South, depend on "tournaments of value" that assign polarized worth to persons, and often back up international deals with transactions in sanctified human remains. The tactic, forged in part during the colonial era, illuminates important aspects of today's global imaginaries of domination. Brazza's bones work, in France and Africa, as a carnal fetish that, borrowing form various philosophies of power, merges Western and African beliefs in the body politic. PMID- 20827842 TI - Spirits and social reconstruction after mass violence: rethinking transitional justice. AB - A vibrant debate in the field of transitional justice concerns the relative ability of global, national, and local mechanisms to promote justice after violent conflict. Discussion largely focuses on more formal mechanisms of justice (courts, tribunals, or truth commissions), implying that state institutions and the law are solely responsible for shaping the process of social healing. This article suggests that scholars should take seriously more informal, socio cultural processes outside the purview of the state, particularly for how they promote social reconstruction at the micro level. Examining the phenomena of spirit possession and ritual cleansing in northern Uganda, I illustrate how such efforts are expressions of injustice and reflect ordinary people's attempts to seek moral renewal and social repair. This approach is particularly illustrative in cases where 'intimate enemies' exist - that is, settings where ordinary people who engaged in violence against one another must live together again. PMID- 20827843 TI - Out to eat: the emergence and evolution of the restaurant in nineteenth-century New York City. AB - Unheard of in the eighteenth century, restaurants became an integral part of New York City's public culture in the antebellum period. This article examines the emergence and development of New York's restaurant sector in the nineteenth century, focusing on three aspects in particular: the close ties between urbanization and the rise of New York's restaurants, the role restaurants played in enforcing the city's class structure and gender mores, and the role of restaurants in shaping the public culture of the growing metropolis. PMID- 20827844 TI - All connected? Geographies of race, death, wealth, votes and births. AB - In January 2010 we learnt that within London the best-off 10th of the population each had recourse to 273 times the wealth of the worse-off 10th of that population (Hills et al. 2010, An anatomy of economic inequality in the UK Report of the National Equality Panel, Government Equalities Office, London). It is hard to find any city in an affluent country that is more unequal. This wealth gap did not include the assets of the UK super-rich, who mostly live in or near London. In April 2010 the Sunday Times newspaper reported the wealth of the richest 1000 people in the UK had risen by an average of L77 million each in just one year, to now stand at L335.5 billion. Today in the UK we are again as unequal as we were around 1918. For 60 years we became more equal, but for the last 30 years, more unequal. Looking at inequality trends it is very hard, initially, to notice when the party of government changed. However, closer inspection of the time series suggests there were key times when the trends changed direction, when the future was much less like the past and when how people voted and acted appeared to matter more than at other times. With all three main parties offering what may appear to be very similar solutions to the issue of reducing inequality it seems unlikely that voting in 2010 will make much of a difference. However, today inequalities are now at unsustainable extremes. Action has been taken such that some inequalities, especially in education, have begun to shrink. The last two times that the direction of trends in inequalities changed, in the 1920s and 1970s, there were several general elections held within a relatively short time period. Inequality is expensive. The UK is not as well-off as it once was. It could be time for a change again. Which way will we go? PMID- 20827845 TI - The exclusion of (failed) asylum seekers from housing and home: towards an oppositional discourse. AB - "Housing" - the practical provision of a roof over one's head - is experienced by users as "home" - broadly described as housing plus the experiential elements of dwelling. Conversely, being without housing, commonly described as "homelessness", is experienced not only as an absence of shelter but in the philosophical sense of "ontological homelessness" and alienation from the conditions for well-being. For asylum seekers, these experiences are deliberately and explicitly excluded from official law and policy discourses. This article demonstrates how law and policy is propelled by an "official discourse" based on the denial of housing and the avoidance of "home" attachments, which effectively keeps the asylum seeker in a state of ontological homelessness and alienation. We reflect on this exclusion and consider how a new "oppositional discourse" of housing and home - taking these considerations into account - might impact on the balancing exercise inherent to laws and policies concerning asylum seekers. PMID- 20827846 TI - "Weak-Center" Gentrification and the Contradictions of Containment: deconcentrating poverty in downtown Los Angeles. AB - This case study of recent efforts to deconcentrate poverty within the Skid Row area of Los Angeles examines processes of "weak-center" gentrification as it applies to a "service dependent ghetto," thus filling two key gaps in prior scholarship. We document the collaboration between the government, business and development interests, and certain non-profit agencies in this process and identify two key mechanisms of poverty deconcentration: housing/service displacement and the criminalization of low income residents. Following Harvey, we argue that these efforts are driven by pressures to find a "spatial fix" for capital accumulation through Downtown redevelopment. This process has been hotly contested, however, illustrating the strength of counter-pressures to gentrification/poverty deconcentration within "weak-center" urban areas. PMID- 20827847 TI - The Evolving Law of Disputed Relocation: constructing inner-city renewal practices in Shanghai, 1990-2005. AB - The forceful pursuit of inner-city renewal in Shanghai since the early 1990s has to a great extent achieved spatial modernization, but at the same time it has given rise to increasing conflicts over residential relocation. Using law as a prism through which to examine the dialectic relationship between renewal practices and disputed relocation, this article argues that the series of unprecedented enactments in law that have taken place during this period have both paved the way for real estate market expansion and been a significant source of relocation disputes in Shanghai. Rather than viewing law as simply given and determinate, the article traces the regulatory regime's codification of property practices as a means of actively responding to the requirements of the real estate market. Under large-scale renewal practices, residents' legal rights of "return settlement" (huiban) in inner-city areas were largely denied in the early 1990s, before being effectively abolished by the adoption of monetary compensation for displacement in the 2000s. The evolving law on property practices has greatly shaped the process of disputed relocation while simultaneously posing a potential challenge to China's use of law for market oriented development. PMID- 20827848 TI - Building an image of Villages-in-the-City: a clarification of China's distinct urban spaces. AB - Villages-in-the-city (chengzhongcun) as distinct urban spaces in Chinese cities have attracted a lot of scholarly attention, and the term has been variously interpreted. The term "urban village" was initially borrowed and applied to describe this urban phenomenon. While the term in a Western context refers to a planned neighbourhood that features good urban planning and design, the question posed in this essay is: are villages-in-the-city the Chinese equivalent of urban villages? Furthermore, within China, villages-in-the-city are always regarded as migrant enclaves, no different from Zhejiang village or Xinjiang village in Beijing. Are they the same kind of settlement? A primary aim of this essay is to reassert the differences between villages-in-the-city and urban villages that have developed in the United Kingdom. A secondary objective is to explore the variations between villages-in-the-city and Zhejiang village. Through investigating the variations between these urban morphologies, this study attempts to fill gaps in the current literature and hence clarify the misconceptions and confusion about Chinese villages-in-the-city. PMID- 20827849 TI - Introduction: Greening the countryside? Changing frameworks of EU agricultural policy. AB - In response to wide-ranging criticism of agricultural policy, especially within Western industrialized countries, new frameworks of justification are emerging and new hybrid policy fields have been established to tackle some of the 'externalities' of agricultural support. However, institutional frameworks are proving slower to change, partly because this would require coordinated action across different levels of governance. Nevertheless, previously marginalized environmental concerns have successfully gained entrance to agricultural policy networks, while the intersection of trade liberalization and rural diversification have undermined the dominance of the productivist mindset in government. This gives rise to a plurality of policy actors and actions which defy the conventional categories of analysis of agricultural policy, calling for changing frameworks on the polity of agriculture too. PMID- 20827850 TI - "Every family become a school of abominable impurity": incest and theology in the Early Republic. AB - Using the controversy surrounding marriage with a deceased wife's sister that occupied Presbyterian and Congregationalist theologians of the early Republic, this essay explores the eroticization of the sentimental family and the contours and crises of the incest prohibition in the wake of the Revolution. The essay begins by tracing the history of ecclesiastical trials of incestuous marriage in the Presbyterian church, arguing that the failure of the synods and General Assembly to offer definitive judgments of such marriages suggests a tension in the force of a transcendent incest prohibition. Two cases from the late 1820s, in particular, gained national attention in both the theological and secular press, and force the Presbyterian church to explore the legitimacy of their incest prohibition, and exploration that lead, ultimately, to a constriction of the incest prohibition as written in the Westminster confession of Faith. I then turn to the conjunction of kinship, sexuality, and sentiment that animates the texts comprising the controversy and argue that, in an effort to defend an expansive interpretation of the Levitical incest prohibitions these theologians were among the earliest writers to argue that sentimental, affectionate relations between family members were inherently erotic. In this sense, the family becomes the primary site for the deployment of sexuality. Such a concern about the incestuous nature of family relations, in turn, forced theologians to consider the problem of incest in the postlapsarian origins of society. PMID- 20827851 TI - Federal policy and the rise in disability enrollment: evidence for the Veterans Affairs' Disability Compensation Program. AB - The U.S. Department of Veterans Affairs compensates 13 percent of the nation's military veterans for service-related disabilities through the Disability Compensation (DC) program. In 2001, a legislative change made it easier for Vietnam veterans to receive benefits for diabetes associated with military service. In this paper, we investigate this policy's effect on DC enrollment and expenditures as well as the behavioral response of potential beneficiaries. Our findings demonstrate that the policy increased DC enrollment by 6 percentage points among Vietnam veterans and that an additional 1.7 percent experienced an increase in their DC benefits, which increased annual program expenditures by $2.85 billion in 2007. Using individual-level data from the Veterans Supplement to the Current Population Survey, we find that the induced increase in DC enrollment had little average impact on the labor supply or health status of Vietnam veterans but did reduce labor supply among their spouses. PMID- 20827852 TI - Militarized humanitarianism meets carceral feminism: the politics of sex, rights, and freedom in contemporary antitrafficking campaigns. AB - Over the past decade, abolitionist feminist and evangelical Christian activists have directed increasing attention toward the "traffic in women" as a dangerous manifestation of global gender inequalities. Despite renowned disagreements around the politics of sex and gender, these groups have come together to advocate for harsher penalties against traffickers, prostitutes' customers, and nations deemed to be taking insufficient steps to stem the flow of trafficked women. In this essay, I argue that what has served to unite this coalition of "strange bedfellows" is not simply an underlying commitment to conservative ideals of sexuality, as previous commentators have offered, but an equally significant commitment to carceral paradigms of justice and to militarized humanitarianism as the preeminent mode of engagement by the state. I draw upon my ongoing ethnographic research with feminist and evangelical antitrafficking movement leaders to argue that the alliance that has been so efficacious in framing contemporary antitrafficking politics is the product of two historically unique and intersecting trends: a rightward shift on the part of many mainstream feminists and other secular liberals away from a redistributive model of justice and toward a politics of incarceration, coincident with a leftward sweep on the part of many younger evangelicals toward a globally oriented social justice theology. In the final section of this essay, I consider the resilience of these trends given a newly installed and more progressive Obama administration, positing that they are likely to continue even as the terrain of militarized humanitarian action shifts in accordance with new sets of geopolitical interests. PMID- 20827853 TI - Working through mass incarceration: gender and the politics of prison labor from east to west. AB - This article explores the politics and practices of labor in two penal institutions for women: a maximum security facility for women in Hungary and a community-based facility for women in California. Diverging from other accounts of imprisonment that tend to operate at either the individual or macroeconomic level, this article analyzes the concrete institutional relations of prison and complicates the assumption that they simply reflect the logic of the prison industrial complex. Based on years of ethnographic work in two very different penal systems, I describe variation in how prisons institute labor within and across institutions and cultures: the Hungarian facility positioned wage labor as a right and an obligation that formed the basis of women's social relationships and ties to others, while the U.S. prison excluded wage labor from women's lives so they could get on with the work of self-improvement and personal healing. From the comparison, I reveal how prisons can both draw on and subvert broader social meanings assigned to women's work, making it difficult to view prison labor as wholly exploitative or abusive. I also argue that refusing to allow female inmates to engage in wage labor can be a more profound form of punishment than requiring it of them. By juxtaposing the discourses and practices of work in two very different penal contexts, this article offers a critical reflection on the political economy of prison labor from the ground up. PMID- 20827854 TI - Aid effectiveness and women's empowerment: practices of governance in the funding of international development. AB - Although the empowerment of women is a prominent goal in international development, feminist development professionals, activists, and scholars remain deeply dissatisfied with the limited extent to which women's empowerment is actually achieved. Their experiences and analyses raise questions about the connections and disjunctions between discourse, institutional practices, and everyday life. A major effort to reform development aid guided by the Paris Declaration on Aid Effectiveness raises new questions about the place of gender in development practice. Drawing on recently conducted research on women and development in Kyrgyzstan and using a range of institutional texts, we interrogate how development professionals and activists engage with the aid effectiveness discourse. Our analytic approach, institutional ethnography, shares with work on governmentality an empirical focus on practices undertaken by diversely situated people and how these practices constitute a particular field of action. Institutional ethnography directs analytic attention to the operation of texts as local and translocal coordinators of people's everyday activities. The product of this coordinated work is what we call, in this case, the development institution. For those concerned about women and development, we see the usefulness of making visible how global governance is accomplished in both enactments of and resistance to institutional practices, but in ways that do not necessarily benefit women. PMID- 20827855 TI - On difference and capital: gender and the globalization of production. AB - This article is both a review of, and an intervention in, the literature on gender and the globalization of production. Via a discussion of six key texts analyzing export-oriented manufacturing, ranging from Maria Mies's Lace Makers of Narsapur to Melissa Wright's Disposable Women and Other Myths of Global Capitalism, I show that, over time, the focus has shifted from an emphasis on the feminization of manufacturing as a defining feature of globalization to an appreciation of the diverse and contingent ways in which gender matters for offshore production. While this recent scholarship highlights variability in gendered labor regimes at the global-local nexus, I argue that it is also critically important to ask what is similar about the many locations on the global assembly line that have been studied. Specifically, we must look to how gender, as a set of context-specific meanings and practices, works within the macrostructure of the global economy and its systemic logic of capital accumulation. In other words, while capitalism does not determine the concrete modalities of gender that exist in a given locale, it is essential for explaining the gendered dimension of transnational production as a patterned regularity of contemporary globalization. PMID- 20827856 TI - Doing psychology, doing inequality: rethinking the role of psychology in creating and maintaining social inequality. AB - The relationship between psychological disciplines and inequality has been a subject of great scholarly interest in the last several decades. Most works on the subject analyze macro features of psychological disciplines (mainly their evaluative tools, theoretical assumptions, and disciplinary power) and criticize them as biased against minorities. This paper re-examines the relationship between psychology and inequality from a micro, face-to-face standpoint. Drawing on close observations of 33 placement committees in which professionals from various psychological fields (psychology, social work, school counseling, etc.) discuss children's eligibility for special education services, it portrays the actual doing of psychology as an inconsistent and malleable endeavor. In contrast to the macro-oriented research on the relationship between psychology and inequality, it shows that in actual face-to-face interactions, professionals use different types of folk concerns that often exchange formal evaluative criteria, theoretical assumptions or professional authority in final placement decisions. By revealing the different folk considerations professionals use to sort and analyze working- versus middle-class parents, this project adds an essential layer to scholarly understanding of the relationship between psychological practice and inequality. PMID- 20827857 TI - Gender and the transmission of civic engagement: assessing the influences on youth civic activity. AB - The study of civic activity has become a central focus for many social scientists over the past decade, generating considerable research and debate. Previous studies have largely overlooked the role of youth socialization into civic life, most notably in the settings of home and school. Further, differences along gender lines in civic capacity have not been given sufficient attention in past studies. This study adds to the literature by examining the potential pathways in the development of youth civic activity and potential, utilizing both gender neutral and gender-specific structural equation modeling of data from the 1996 National Household Education Survey. Results indicate that involvement by parents in their child's schooling plays a crucial, mediating role in the relationship between adult and youth civic activity. Gender differences are minimal; thus adult school involvement is crucial for transmitting civic culture from parents to both female and male youth. PMID- 20827858 TI - Environmental risks and environmental justice, or how titanic risks are not so titanic after all. AB - Some of the best-known social scientific theories of risks are those that have been elaborated by Anthony Giddens and Ulrich Beck. Although their arguments differ greatly, they agree in seeing the technologically induced risks of today's "Risk Society" as global - so pervasive that they transcend all socioeconomic as well as geopolitical and national boundaries. Most empirical work, however, provides greater support for a theoretical tradition exemplified by Short and Erikson. In this paper, we argue that many of the technological mega-risks described by Giddens and Beck as "transcending" social boundaries are better described as "Titanic risks," referring not so much to their colossal impact as to the fact that - as was the case for the majority of the victims on the Titanic - actual risks are related to victims' socioeconomic as well as sociogeographic locations. Previous research has shown this to be the case with high-risk technologies, such as nuclear energy and weaponry, and also with localized ones, such as toxic waste disposal. This article illustrates that the same is true even for the most genuinely "global" risks of all, namely those associated with global climate disruption. PMID- 20827859 TI - Hurricane Katrina and mental health: a research note on Mississippi Gulf Coast residents. AB - Katrina was the most devastating and deadliest hurricane in recent U.S. history. The storm was particularly destructive for residents of the Mississippi Gulf Coast where sustained winds of 135 mph and a storm surge of 32 feet literally obliterated the built and modified environments. Limited research exists on the chronic (32 months) mental health impacts of survivors in this geographical area. Random-digit dialing telephone surveys were administered in Harrison and Hancock counties (Mississippi) in April and May 2008 and data were collected on a number of mental health outcomes. The results of the calculation of Oridinary Least Squares (OLS) regression models revealed that females, African Americans, and less-educated residents manifested the most severe mental health impacts. Most important, consistent findings for depression and Katrina-related psychological stress indicate that residents who were separated from family members, had maximum residential damage, and suffered severe financial problems remained significantly impacted 32 months after Katrina's landfall. A secondary stressor, in the form of having applications to the Mississippi State Grant Program denied or not processed also predicted personal depression. The implications of these findings are discussed. PMID- 20827861 TI - Seymour Benzer's life. PMID- 20827863 TI - Cavernous malformations. PMID- 20827864 TI - Abnormal 1 hour glucose challenge test followed by a normal 3 hour glucose tolerance test: does it identify adverse pregnancy outcome? AB - OBJECTIVE: To determine if pregnancies with an abnormal glucose challenge test (GCT) but a normal (GTT) are at increased risk for fetal macrosomia or an adverse pregnancy outcome. STUDY DESIGN: This prospective observational study matched women with an abnormal glucose challenge test and a normal GTT with the next patient with a normal GCT. RESULTS: Over 12 months, 107 women with abnormal GCT were matched with 107 women with normal GCT. Women with an abnormal GCT were older (27.3 vs. 24.7, p = 0.001) and less likely to be African-American (OR = 2.2, 95% CI 1.06-4.49) but no more likely to have an adverse pregnancy outcome. ROC curves could not differentiate between macrosomic vs non-macrosomic newborns using GCT values. CONCLUSION: Women with an abnormal GCT but a normal GTT are more likely to be older, less likely to be African-American, but no more likely to have an adverse pregnancy outcome or a macrosomic fetus. PMID- 20827865 TI - Screening for vitamin D deficiency in the elderly. AB - The importance of vitamin D to normal physiologic function is well established. With deficiency becoming increasingly frequent, the potential for preventing and treating diseases through vitamin D supplementation is gaining in appreciation. Deficiency is particularly common in the geriatric population based on both behavioral and biologic factors, and has been associated with increased risk of musculoskeletal, neuropsychiatric, cardiovascular, endocrine and oncologic disease. Although some experts recommend empiric supplementation for all elderly persons, a strategy of routine screening and documented adequacy of replacement in deficient patients appears superior. PMID- 20827866 TI - Uncommon but not rare. PMID- 20827867 TI - Have a good night. PMID- 20827868 TI - Start to finish. PMID- 20827869 TI - Canine behavior. PMID- 20827870 TI - Recurrent, transformed non-Hodgkin's lymphoma presenting as chiasmal syndrome with hyperprolactinemia and hypopituitarism. AB - A 69-year-old white female with past medical history of follicular cell lymphoma presented to her local physician with new neurological findings. She was subsequently diagnosed with a pituitary lesion comprised of diffuse large B cell lymphoma. Non-Hodgkin's lymphoma (NHL) affecting the pituitary uncommonly appears as metastatic disease from a concurrent systemic lymphoma. This case represents the first case of recurrent, transformed NHL as chiasmal syndrome with hyperprolactinemia and hypopituitarism in the American medical literature. PMID- 20827871 TI - Be careful what we ask for, we might get it. PMID- 20827872 TI - Dignity. PMID- 20827873 TI - Will politicians ever change? PMID- 20827874 TI - Eavesdropping. PMID- 20827875 TI - Prevalence and trends in obesity among Mississippi public school students, 2005 2009. AB - The purpose of this research was to determine the prevalence of overweight and obesity in Mississippi children and youth in grades K-12, and to assess any changes in the prevalence during 2005, 2007, and 2009. Body Mass Index was calculated using measured height and weight data for 3,703 public school students, and the prevalence of overweight and obesity was estimated. Additional analysis compared prevalence estimates by gender, race, and grade for the 2009 data, and comparisons were made between the 2005, 2007, and 2009 data. In 2009, the prevalence of obesity for all students in grades K-12 was 23.9%, as compared to 23.5% in 2007 and 25.5% in 2005. However, no statistically significant differences were found over the three time periods. The disparity between races appears to be increasing over time with the prevalence remaining level for Nonwhite students while dropping each year for White students. PMID- 20827876 TI - Cardiovascular disease in rheumatoid arthritis: disease and treatment interactions and their implications on treatment decisions. AB - Cardiovascular disease is highly prevalent in rheumatoid arthritis patients, contributing to significant morbidity and mortality. Few randomized trials are available to guide risk assessment and intervention in these complex patients. This paper discusses traditional atherosclerotic and rheumatoid-related risk factors for cardiovascular disease in these patients, reviews the effect of treatment of cardiovascular risk factors on rheumatoid arthritis activity, and describes the effect of rheumatoid arthritis treatment on risk factors for cardiovascular disease. The authors reviewed the existing literature by cross referencing topics such as cardiovascular disease, rheumatoid arthritis, various risk factors for cardiovascular disease and their treatments, and treatments for rheumatoid arthritis, using Medline and PubMed, reviewing references from 1983 2009. Traditional and rheumatoid-related risk factors (including active inflammation/disease activity and some medications) contribute to this high prevalence of cardiovascular disease in rheumatoid arthritis. Evidence supports aggressive therapy for traditional cardiovascular risk factors, reducing rheumatoid activity, and limiting pro-atherosclerotic medications. PMID- 20827877 TI - Pseudo seizures vs pseudo zebra. PMID- 20827878 TI - Pigs have already flown. PMID- 20827879 TI - There is a tide in the affairs of men. PMID- 20827880 TI - The great myth. PMID- 20827881 TI - Pancreas cancer in Mississippi: present challenges and future directions. AB - Pancreatic cancer remains a deadly disease. Currently, the only hope for cure is surgical resection at an early stage of the disease. However, there is evidence that many individuals do not receive this treatment, perhaps because of health care disparities. Mississippi, because of its socioeconomic composition, has been the focus of concern for health care disparities. In order to determine whether such disparities exist in Mississippi for pancreatic cancer, a retrospective analysis was done from 2000 2006 of case diagnosis, treatment, and mortality from this disease. The Mississippi Cancer Registry, the American College of Surgeons (ACS) National Cancer Data Base (NCDB), and the National Cancer Institute (NCI) Surveillance Epidemiology and End Results (SEER) program were surveyed. Outcomes at all 12 ACS Commission on Cancer (CoC) accredited hospitals within the state were compared to the NCDB nationwide (n=1331 hospitals). In 2006 Mississippi had the highest death rate from pancreas cancer in the nation (12.7/100,000). Age adjusted incidence by county ranged to a high of 26.91/100,000. Fifty-one percent of patients who died from pancreatic cancer in the state were treated at ACS CoC hospitals. The fate of the other 49% is not known. Of the patients tracked at CoC hospitals, there was essentially no significant difference with respect to age distribution, stage at diagnosis, or first treatment modalities when compared to NCDB nationwide CoC data. There were fewer patients surviving two years with locally advanced disease compared to national figures. Of concern was the large number of patients whose treatment for pancreatic cancer is unknown. It is incumbent on health care providers in the state to develop a system of care for pancreatic cancer that is accessible, inclusive, and comprehensive. PMID- 20827882 TI - Perplexing pyretic polyarthritis. PMID- 20827883 TI - Let's change the whole damn system and start over, but we have to wait until Tuesday. PMID- 20827884 TI - But will it take? PMID- 20827885 TI - "Celebrate. Remember. Fight back."--Thoughts on the American Cancer Society Relay for Life. PMID- 20827886 TI - Report card on tobacco use in Mississippi, 2009. AB - Mississippians are failing in their health status particularly as it relates to tobacco use. According to the Behavioral Risk Factor Surveillance System, 2008, 22.7% of Mississippi adults are current smokers compared to 18.4% of U.S. adults. This gives Mississippi a ranking of seventh among the states and the District of Columbia. Considering that smoking is the leading cause of preventable death, change must occur in our state. Resources necessary to combat the problem of tobacco use in Mississippi are available, but it is important that tobacco users are aware of their availability and how to access those resources. Physicians can positively impact the tobacco use statistics by counseling their tobacco dependent patients on the need for cessation and what counseling and pharmacotherapy resources are available to help the patient break his or her addiction. PMID- 20827887 TI - I think it just stopped raining. PMID- 20827888 TI - MSMA House of Delegates votes to make AMA members1ip optional. PMID- 20827889 TI - To agree to disagree is only professional. PMID- 20827890 TI - The death of unification. PMID- 20827891 TI - In the beginning: a Canadian ethnographic study on sources and definitions of spiritual reflection used by health care professionals who are not chaplains. AB - This qualitative study presents a literature review, methodology, findings and discussion from a sample of 20 health care professional around their experiences of sources and definitions of spiritual reflection. The sample includes nursing, social work, occupational therapy, medicine, physiotherapy, music therapy, psychology and recreational therapy. Major sources are music, poetry, stories and sacred texts. Definitions are meaning making and encountering the divine along with personal reflection on values and assumptions. Limitations of the research and recommendations for education, practice and future research are also presented. PMID- 20827892 TI - Feeling whole: the meaning of being consoled narrated by very old people. AB - Interviews with 13 people, over 85 years, with high scored Self-transcendence, were analyzed using a phenomenological hermeneutic method. The meaning of being consoled was interpreted to Feeling whole, an immediate experience of: being carried and embraced by God (Feeling connected to God), supported by the loving care and affection from others (Feeling connected to fellow beings and the world), being relaxed, peaceful and full of joy and experiencing hope (Being connected to self). PMID- 20827893 TI - Practicing discernment: pastoral care in crisis situations. AB - This article correlates a particular experience of providing pastoral care for a person in a crisis situation with a particular understanding of the practice of pastoral care. Through engaging in correlative practical theology, it highlights the need for practicing discernment when providing pastoral care for persons utilizing narratives to work through crisis situations. PMID- 20827894 TI - The taboo of politics in pastoral counseling. AB - The political realities of society are present in counseling in subtle and overt ways. In this article, I argue that the client's (and counselor's) political experiences, beliefs, and commitments can be and, in many cases, should be explored. The idea of the political self or subjectivity and its identifying features and sources are described. I posit that political subjectivity forms through the processes of internalization, identification, and idealization. In identifying several reasons for the taboo of political discourse in pastoral counseling, I suggest a number of ways pastoral counselors may manage the political self in the counseling relationship. The three goals for exploring a client's political subjectivity for the client are: (1) to have a deeper and broader understanding of one's political beliefs, values, and commitments; (2) develop a more empathic understanding of the beliefs and experiences of Others; and (3) be able to take responsibility for the harm that results from one's political commitments. PMID- 20827895 TI - The voice of silence in pastoral conversation. PMID- 20827896 TI - Of mothers & daughters & twilight. PMID- 20827897 TI - CPE student's sermon to the president. PMID- 20827898 TI - Seven days. PMID- 20827899 TI - A case presentation becomes a morning meditation. PMID- 20827900 TI - You're just like me! PMID- 20827901 TI - Living in a world of red caped men. PMID- 20827902 TI - 2:39 AM Gloria. PMID- 20827903 TI - Mirror images. PMID- 20827904 TI - [Congenital anomalies of the vitreous body]. PMID- 20827905 TI - [Neuroprotection in glaucoma]. AB - The present paper is a revue of the basic terms related to the neuroprotection, an up-to-date on the pathophysiology of glaucoma. There are emphasized some of the main directions of evolution in the antiglaucomatous and neuroprotective treatment. PMID- 20827906 TI - [Normal tension glaucoma]. AB - Normal Tension Glaucoma is known to be a special form of glaucoma which is still a matter of dispute in its etymologic, diagnostic, therapeutic aspects and in its terminology. The diagnosis of normal tension glaucoma is by elimination of other disorders by pachymetry, tonometric curve, neurologic examination and sometimes MRI. What remains may be a locus minoris of general pathology. PMID- 20827907 TI - [Macular oedema]. AB - Macular edema is a well-known endpoint of ocular diseases, but the pathogenic impact of extra and intracellular fluid accumulation still remains uncertain. While most author favor an extracellular fluid accumulation as the main causative factor, there are indication that Muller cells swelling may also contribute to edema development. PMID- 20827908 TI - Indices for the detection of keratoconus. AB - Identification of keratoconus has become a step of primary importance in the preoperative evaluation for the refractive surgery. In order to decrease the secondary ectasia after refractive surgery the preoperative screening of keratoconus is very important. Corneal topography, the most useful tool in the diagnosis of keratoconus, offer us the possibility of an early diagnosis of KC by a lot of mathematical indices calculate to determine the disease with a higher specificity and sensitivity. Although useful, these indices may be difficult to understand and use. PMID- 20827909 TI - [Monotherapy with lipid structural derivatives in glaucoma]. AB - Lipid structural derivatives (latanoprost, travoprost and bimatoprost) are ocular hypotensive agents that significantly lower ocular tension with more than 30% from baseline by once-daily dosing.Ocular tension reduction from baseline is statistically significantly greater for bimatoprost than for latanoprost at all time points measured. Compared with travoprost, ocular tension decrease was statistically greater with bimatoprost at 8AM and 12PM. This trend was also seen at 4PM and 8PM, even though the difference was not statistically significant at the former time point and borderline at the latter time point. The findings for latanoprost and travoprost indicate that these two agents are comparable in their ability to reduce ocular pressure with no statistically significant difference seen at any time point measured. There does not exist any evidence, excepting conjunctival hyperemia which has been lesser with latanoprost compared to both the bimatoprost and travoprost, that any of these 3 medications significantly differs with respect to their adverse effects. PMID- 20827910 TI - [Immunological aspects in glaucoma]. AB - Glaucoma is one of the most frequent causes of vision loss and blindness. The increased intraocular pressure does not explain glaucoma in all patients but can be considered as a risk factor of the disease. It seems that systemic immunity of the eye through up-and-down immunological regulation of autoantibodies against ocular antigens make their impact felt on glaucoma patients too. The cells from retinal ganglion and aqueous humor itself can be the aperture selection of ocular immune response involved in glaucoma pathogenesis. Among its multiple functions, the immune system confers a protective action on retinal neurons. It is very important the immune maintenance in glaucoma, which involves on the other side the activity of immunoprotection and neuroprotection factors. PMID- 20827911 TI - [Posterior vitrectomy--ground principles]. AB - In this paper, we present the principles of posterior vitrectomy and describe the devices used for this type of surgery. PMID- 20827912 TI - [About entropy in ophthalmology]. AB - Entropy is one of the most controversial ideas ever described. Clausius, who discovered this natural propriety in 1865, used this notion in order to define the conversion of energy. Out of a thermodynamic point of view, health is seen as a minimum of entropy and illness as a maximum. PMID- 20827913 TI - [Avastin treatment in intraocular tumors]. AB - Bevacizumab is used in the treatment of cancer where it inhibits tumor growth by blocking the formation of new blood vessels (blocking angiogenesis). The purpose of this paper is to evaluate the short-term safety and effectiveness of Avastin injected into the eyeball in cases with intraocular tumors following-up the subjective and objective postoperative results. PMID- 20827914 TI - [Toxoplasmic central chorioretinitis]. AB - Toxoplasma gondii is the most frequent cause of chorioretinitis in immunocompetent patients. This paper highlights the case of a 15 years old girl, an immunocompetent patient, with an active chorioretinal focus in the LE and a chorioretinal scar in the RE. Serologically, the IgG antiToxoplasma titre is increased, but the IgM antibodies are negative. It is the bilateral character of the lesions and the serology found that make this case special. PMID- 20827915 TI - [Corneal ulcer with hypopion in a patient with perforant keratoplasty]. AB - After corneal transplantation, the patients' problems are far from being definitively resolved. The transplant pathology requires an attentive follow-up, as there is always a danger of corneal graft failure. We present here the case of young patient who had a corneal transplantation after an eye injury and who has developed a corneal ulcer on the grafted cornea, with subsequent risk of graft failure and consequent loss of the eye. PMID- 20827916 TI - [Idiopatic parafoveolar telangiectasia associated with pseudoviteliform lesion, basal laminar drusen and optic nerve head drusen]. AB - BACKGROUND: We present a case with bilateral optic disc drusen, associated in one eye with idiopathic parafoveal telangiectasis (Group 1B), basal laminar drusen, and foveal pseudovitelliform lesion. PATIENT: A 45-years old female patient, which complained about a deterioration of vision at the right eye, was ophthalmologically examined. RESULTS: The examination revealed a bilateral optic disc drusen, and on the right eye a macular haemorrhage. An examination after 2 months revealed a good vision, the resorption of the macular haemorrhage, idiopathic parafoveal telangiectasis, basal laminal drusen, and a foveal pseudovitelliform lesion. CONCLUSIONS: The association is of importance because of the rarity of the haemorrhagic complication in the idiopathic parafoveal telangiectasis (Group IB), the possibility of a pathogenic correlation, and the difficulty of differential diagnosis with the optic disc drusen complicated with retinal haemorrhages. This association was not found in the literature we consulted. PMID- 20827917 TI - [Carotid-cavernous fistulas of low-flow type: color Doppler imaging of retrobulbar vessels findings]. AB - BACKGROUND: Carotid-cavernous fistulas (CCF) of low-flow type are the results of development of communication between small arteries and veins of cavernous sinus. PURPOSE: To assess the role of CDI of retrobulbar vessels in the study of two patients with CCF of low-flow type. METHODS: We have used a sonographer with 9MHz linear probe. RESULTS: . The initial diagnosis was suspected clinically: both patients presented unilateral chemosis and orbital bruit. It was sustained by CDI of retrobulbar vessels: reversed flow in the superior ophthalmic vein, with a venous arterialisation and confirmed with complete selective digital substraction angiography, which is essential for a correct diagnosis(early opacification of veins draining cavernous sinus, etc). CONCLUSIONS: CDI of retrobulbar vessels is a repetitive non-invasive technique, which is used for monitoring carotid cavernous fistulas of low-flow type, because they are sometimes a self-limiting pathology (spontaneous venous thrombosis). PMID- 20827918 TI - [Current therapeutic approach to diabetic macular edema refractory to laser coagulation]. AB - The paper presents the evolution of a diabetic patient with CSME resistant to laser treatment. The intravitreal injection of Triamcinolone Acetonid represented a very efficient therapeutic solution the visual accuity improving for a period of 7-9 months. PMID- 20827919 TI - [Panretinal photocoagulation with or without focal photocoagulation--the effect on central retinal thickness]. AB - PURPOSE: To assess the effect of panretinal photocoagulation (with or without focal macular photocoagulation) on central retinal thickness measured by OCT METHOD: Prospective, interventional, non-comparative case series. Panretinal photocoagulation (PRP) was performed in 3 sessions in 28 eyes with proliferative diabetic retinopathy In 9 eyes who had also initial macular edema we have associated focal macular laser treament concomitant with the first PRP session. Macular thickness was assessed by optical coherence tomography at baseline and after 4 and 10 weeks. RESULTS: Baseline mean central retinal thickness was 252 +/ 95 microm. It was modified to 260 +/- 105 microm at 4 weeks, then to 232 +/- 49 microm at 10 weeks. There was no statistical significance of these variations. In 2 eyes (7, 14%) we have noticed an increase of more than 100 microm in central retinal thickness. In the subgroup of 9 eyes with associated initial macular edema, combined PRP-focal treatment resulted in the decrease of central retinal thickness from 306 +/- 123 microm to 236 +/- 49 microm at 10 weeks. CONCLUSIONS: Panretinal photocoagulation can be associated with a significant increase of central retinal thickness in a small percentage of eyes. The PRP-focal macular laser combination is effective in eyes who present with proliferative diabetic retinopathy and macular edema. PMID- 20827920 TI - [The role of iridectomy in glaucoma surgery]. AB - PURPOSE: analysis of the influence of peripheral iridectomy on the efficiency and safety of trabeculectomy and phacotrabeculectomy in patients with open-angle glaucoma. METHODS: interventional, prospective, randomized and comparative study with two groups: 44 eyes with trabeculectomy (group 1) and 24 eyes with phacotrabeculectomy (group 2). Each of the two groups was divided into two main subgroups (with and without iridectomy), compared with each other in terms of efficacy and safety of surgical procedure. RESULTS: Iridectomy was performed on 22 eyes in group 1 (subgroup 1A) and on 12 eyes in group 2 (subgroup 2A), the remaining cases in each group forming subgroups without peripheral iridectomy (subgroup 1B, 2B respectively). Statistical analysis reveals that iridectomy does not seem to influence the efficiency of filtration procedure, regardless of the postoperative moment of analysis (early or final). In all four subgroups at 1 year was a significant decreasing of intraocular pressure, with a low rate of complications. CONCLUSIONS: A proper selection of open-angle glaucoma cases allows the abandonment of peripheral iridectomy in trabeculectomy and phacotrabeculectomy. PMID- 20827921 TI - [Treatment with bevacizumab in exudative age-related macular degeneration]. AB - OBJECTIVES: evaluation of the treatment with bevacizumab for advanced exudative AMD. MATERIAL AND METHOD: prospective study on 163 patients (December 2006 February 2009). All patients received a series of 3 intravitreal injections with bevacizumab (1.25 mg/0.05 ml) at 6 weeks intervals followed by surveillance and continuation or restart of therapy based on clinical criteria and central macular thickness (CMT). The series was subdivided in three groups based on initial VA (VA < or = 0, 1; VA = 0, 1-0, 3; VA > or = 0,3). RESULTS: Final VA increased or remained constant in 88% of patients. VA increased in all three groups: from 0.029 to 0.069 in the first group; from 0.152 to 0.245 in the second group; and from 0.409 to 0.612 in the third group. In all three groups the increase in VA achieved statistical significance (p < 0.001). The whole series manifested an anatomical improvement (final mean CMT of 243.3 microm, as compared to initial mean CMT of 345.3 microm). CONCLUSION: intravitreal treatment with bevacizumab is efficient but should be followed by aggressive follow-up and rapid resume of the treatment if recurrence is diagnosed. PMID- 20827922 TI - [Dynamic nuclear magnetic resonance in strabismus]. AB - PURPOSE: To demonstrate that dynamic MRI is a useful tool in complex strabismus patients. SUBJECTS AND METHODS: 16 patients were referred to us with suspicion of slipped or '"lost" medial rectus (MR), 15 after strabismus surgery. 1 case with lost MR after trauma. One patient had "A" pattern exotropia with over depression in adduction. 8 underwent dynamic MRI examination. RESULTS: The dynamic MRI showed the precise muscle location and the contractility of the muscle. All patients underwent surgery, according to deviation and ocular motility changes. All slipped muscles were found and re-attached to the globe. In the "A" pattern exotropia MRI showed superior displacement of the LR pulleys. The inferior rectus did not demonstrate contractility and a transfer procedure was made. CONCLUSIONS: MRI is an index of functional muscle contractility and precise muscle location. It should be considered in complex cases of strabismus as an important argument in choosing the surgical technique. PMID- 20827923 TI - [Methods for trabeculectomy improvement]. AB - Although the literature provides approximate guidance on the treatment of glaucoma, it remains a complex puzzle with multiple pieces whose importance to the ultimate success varies widely from a person to another. In 1969 trabeculectomy signified a major step in glaucoma surgery becoming the first protected filtering procedure. Performed timely, not as a last therapy resort, trabeculectomy provides a maximum intraocular pressure reduction with a low rate of complications. Moorfield Safer Surgery System combines a number of beneficial chances to the classic trabeculectomy, changes leading to increased efficiency and safety of surgical procedure. PMID- 20827924 TI - Cowboy medicine or good clinical judgment? Testing minimalism. PMID- 20827925 TI - The games our children play. PMID- 20827926 TI - The Warren Alpert Medical School of Brown University Class of 2010. PMID- 20827927 TI - A new home for Alpert Medical School. PMID- 20827928 TI - Development of student academies at Alpert Medical School. PMID- 20827929 TI - Effectiveness of a medical student-organized community vision screening initiative. PMID- 20827930 TI - Karlis Adamsons: a brief gedenkschrift for a brief tenure at Providence lying-in hospital, 1975-1979. PMID- 20827931 TI - A palette of palliative terms. PMID- 20827932 TI - Clostridium difficile in a nursing home patient. PMID- 20827933 TI - HIV in the older adult. PMID- 20827934 TI - Blood levels in refugee children in Rhode Island. PMID- 20827935 TI - Access to oral health care: no simple solution. PMID- 20827936 TI - Important issues in employment agreements. PMID- 20827937 TI - My office manager is out of control. PMID- 20827938 TI - When speaking to patients, say what you mean! PMID- 20827939 TI - Ten 'untruths' your staff will tell you. PMID- 20827940 TI - Dental plans face growing pressures for change. PMID- 20827941 TI - Michigan dentistry and the great recession: where we're at now. PMID- 20827942 TI - Dental management of patients taking antiplatelet medications. AB - Antiplatelet medications are drugs that decrease platelet aggregation and inhibit thrombus (clot) formation. They are widely used in primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease. The most common antiplatelet medications are the cyclo-oxygenase inhibitors (aspirin) and the adenosine disphosphate (ADP) receptor inhibitors clopidogrel (Plavix) and ticlopidine (Ticlid). The dental management of patients taking these drugs is reviewed here. PMID- 20827943 TI - Why 'a united voice for oral health'? PMID- 20827945 TI - The not-so-public health field. PMID- 20827944 TI - A united voice for oral health. Final report and recommendations from the Michigan Access to Oral Health Care Work Group. August 2010. PMID- 20827946 TI - Lead poisoning from Burmese medicines. PMID- 20827947 TI - Public health's head cheerleader. PMID- 20827948 TI - What's in a number? PMID- 20827949 TI - Public servants. PMID- 20827950 TI - Peer grouping must be fair to physicians. PMID- 20827951 TI - Going public. PMID- 20827952 TI - Federal reform bill is a start. PMID- 20827953 TI - Moving forward in Minnesota. PMID- 20827954 TI - Minnesota 10 by 10. Reducing morbidity and mortality in people with serious mental illnesses. AB - Persons with schizophrenia, schizoaffective disorder, and bipolar affective disorder in Minnesota are dying much younger than their age- and sex-matched cohorts. A new initiative, MN 10 By 10, is designed to engage key constituencies in addressing modifiable risk factors in order to lengthen these individuals' lives. PMID- 20827955 TI - Blood lead screening among newly arrived refugees in Minnesota. AB - During the last 10 years, the prevalence rate of elevated blood lead levels (EBLLs) in the general population in the United States has decreased, while the rate of EBLLs among refugee children in this country has remained high. Because of this, national guidelines recommend both an initial and a repeat screening of refugee children. To explore blood lead screening among refugee children in Minnesota, we examined data on 1,256 children who arrived in Minnesota between 2004 and 2007. Our objectives were to describe the characteristics of refugee children who are screened for blood lead; identify the characteristics of refugee children with an EBLL following screening; and describe the characteristics of refugee children who received a repeat blood lead test. Our results showed that approximately 6% of refugee children in Minnesota had an EBLL and fewer than half of all refugee children in the sample received a repeat test. For that reason, primary care providers should be periodically reminded of the importance of repeat lead screening for refugee children. PMID- 20827956 TI - Giving health a place at the table. Two years of progress on Minnesota's obesity plan. AB - Minnesota's rising number of obese and overweight residents prompted the Minnesota Department of Health in 2008 to create a plan to reduce obesity and its associated health consequences. The plan attacks the problem from both an individual and a public health perspective. This article describes Minnesota's obesity plan and reports on progress that has been made to date. PMID- 20827957 TI - Tuberculosis at the University of Minnesota Medical Center, 2000 to 2006. A brief report. AB - For millions of people around the world, tuberculosis (TB) is a cause of significant morbidity and mortality. It continues to affect the well-being of Minnesotans as well. This article reviews one Minnesota hospital's experience withTB. Through retrospective reviews of charts at the University of Minnesota Medical Center, we found that patients who tested positive for TB were more likely to be foreign-born than U.S.-born, that foreign-born patients who tested positive for TB were younger than those who tested positive and were born in the United States, and that foreign-born patients were more likely to have extrapulmonary disease than pulmonary TB. PMID- 20827958 TI - [Optical parameters of Er3+ in Er3+ : YVO4]. AB - In the present paper the authors firstly measured the absorption spectra of Er3+ in the sample Er3+ : YVO4 (0.5%), then calculated the intensity parameters are calculated by using the Judd-Ofelt theory. After that the authors dealed with some predicted spectroscopic parameters, such as the oscillator strength, spontaneous radiative transition rate, branching ratio and integrated emission cross section. And Er : YVO4 crystal application value has been analyzed with the optical parameters. Especially there are large oscillator strengths and large integrated emission cross sections in the transitions of 4 I1/2 --> 4 I15/2, 2 H11/2 --> 4I15/2, 4S3/2 --> 4 I15/2, and 4F9/2 --> 4 I15/2. So, they are more worth of attention. Moreover, by comparing the Er-doped yttrium vanadate crystal and other Er-doped crystal optical properties, the authors can see the advantages of YVO4 as laser crystal. Finally, the authors discussed the splitting of the energy levels of Er3+ in the crystal YVO4 based on the group theory. PMID- 20827959 TI - [Improvement in the calculation of anti-Stokes energy transfer between rare earth ions. 1. Experiment and theoretical basis]. AB - A photonic phenomenon of fluorescence intensity reverse between red and green fluorescence was studied theoretically and experimentally in the present article. It was found by experiment that Er(0.5) Yb(9.5) : FOV oxyfluoride vitroceramics exhibits strong fluorescence intensity reverse phenomenon. The range of the intensity reverse of Er(0.5) Yb(9.5) : FOV was measured to be 877. Moreover, all basic spectroscopic parameters were calculated. The theoretical basis of numerical calculation for dynamics processes of all levels was established. PMID- 20827960 TI - [LIF spectroscopic study of OH radical]. AB - Hydroxyl radical molecular beam was generated by DC pulsed high voltage discharge. The rotational resolution excitation fluorescence spectra of the OH A 2sigma+ -X 2pi (1, 0) band were observed by using second harmonious output of a nanosecond dye laser (around 282 nm). The rotational temperature of the (1, 0) band was determined to be (30 +/- 1) K based on the analysis of the intensity distribution of the OH spectra. Moreover, the fluorescence decay curves of the (1, 1) band and the (0, 0) band and were obtained and the fluorescence lifetimes of A 2sigma+ (v' = 1) state and the X 2pi (v" = 0) state were fitted to be (637 +/- 16) and (675 +/- 13) ns, respectively. PMID- 20827961 TI - [Third harmonic enhancement and spectral analysis within plasma channel based on pump-probe effect]. AB - The experiment realized third harmonic enhancement by using non-collinear dual plasma channels based on pump-probe effect. The coupling action between pump and probe beams can improve saturation effect within filament and overcome the limitation of harmonic enhancement due to intensity clamping. By non-collinearly focusing two ultrafast pulses in air which have respectively a single pulse energy of 4.4 and 10.2 mJ, both with duration of 60 fs and central wavelength of 810 nm, dual filaments as well as weak third harmonics can be generated. When strong beam is ahead of weak one, the former induces a plasma channel in advance which can modulate later weak beam and make obvious harmonic increase produced by probe beam. It was found that oscillation variation of spectral bandwidth in the region of harmonic energy increased significantly. When two beams intersect in a small angle of 27.3 mrad about 15 mm before geometric focus and the probe beam lags behind about 55 fs, the energy increase rate nearly reaches 70, and the corresponding spectral bandwidth is approximately 5 nm. PMID- 20827962 TI - [Identification and classification of textiles based on terahertz time domain spectroscopy]. AB - A method to discriminate textiles was proposed based on terahertz time-domain spectroscopy (THz-TDS) and clustering analysis, and some typical cotton textiles were investigated to prove its feasibility. Their time domain waveforms were measured using THz-TDS system and then their absorption spectra were obtained. Principal component analysis (PCA) was applied to extract features of the data, and then Mahalanobis distance discriminant method was employed to classify these materials. The results show that this method can classify these five textiles accurately. It indicates that the method to classify textiles is feasible which combines PCA and Mahalanobis distance discriminant method based on their THz absorption spectra. The proposed method has a potential for identifying textiles of similar composition. PMID- 20827963 TI - [Influence of the active layer thickness on the performance of bulk heterojunction solar cell]. AB - Bulk heterojunction polymer solar cells based on the blend of MEH-PPV (poly[2 methoxy-5-(2'-ethylhexyloxy)-1,4-phenylenevinylene]) and PCBM (1-(3 mehyloxycarbonyl)propyl-phenyl[6,6]C61) were fabricated. The thickness of the active layer was controlled by changing the concentration of MEH-PPV : PCBM (1 : 4 in weight ratio) solution and spin speeds. Investigation of the effects of active layer thicknesses on the performance of the photovoltaic devices indicates that, when the spin-coated speeds are lower than 4,000 r x min(-1) (round per minute), the open-circuit voltage (V(oc)) remains almost unchanged at approximately 0.8 V, whereas the short-circuit density (J(sc)) monotonically increases and the fill factor (FF) decreases slightly. The spin speeds that are higher than 5,000 r x min(-1) rpm result in the V(oc) and J(sc) both reduced. The V(oc) decreases from 0. 78 V at the spin-speed of 5,000 r x min(-1) to 0.67 V at 8,000 r x min(-1), and the J(sc) even decreases from 3.96 mA x cm(-2) at 5 000 r min(-1) to 1.76 mA x cm(-2) at 8,000 r x min(-1). J(sc) depends on the mutual impact of light absorption and carrier transport, while a contradicting effect from the two aspects is caused by varying the thickness of the active layer. The thicker the active layer, the more the excitons induced by light absorption. However, the build-in electric field becomes weaker and the pathway becomes longer for transporting the opposite charge carriers derived from exiciton separation to their corresponding electrodes at the same time, which makes the probability of charges collection by respective electrodes lower. With respect to the reduced V(oc), it may be attributed to the increased proportion of exciton dissociation at the interfaces of MEH-PPV and PCBM with the relevant electrodes. PMID- 20827964 TI - [Investigation on the electron density of a micro-plasma jet operated at atmospheric pressure]. AB - In the present paper, a micro-hollow cathode discharge setup was used to generate micro-plasma jet in flowing mixture of Ar and N2 at atmospheric pressure. The characteristics of the micro-plasma jet were investigated by means of optical method and electrical one. It has been found that breakdown occurs in the gas between the two electrodes when the input power of electric source is increased to a certain value. Plasma appears along the gas flow direction when the mixed gas flows from the aperture of the micro-hollow cathode, and the length of plasma reaches 4 mm. The discharge current is quasi-continuous, and the duration of discharge pulse is about 0.1 micros. Electron density was studied by using Einstein equation and Stark broadening of spectral lines from the emission spectrum respectively. It was found that the results of electron density calculated by the two methods are consistent with the order of 10(15) x cm(-3). It was also found that the electron density is almost independent of power. A qualitative explanation to the phenomenon is given based on the gas discharge theory. PMID- 20827965 TI - [Determination of brix and POL in sugar cane juice by using near infrared spectroscopy coupled with BP-ANN]. AB - The models of quantitative analysis of brix and pol in sugar cane juice were established by using near infrared spectroscopy (NIR) coupled with the back propagation-artificial neural network method (BP-ANN). The spectra of cane juice samples were obtained by the way of 2 mm optical length transmission and using the NIR spectrometer of 1,000-1,800 nm wavelength. Firstly, the data of original spectra were pretreated by Savitzky-Golay derivative and mean-centering. Secondly, the wavelength range of model was optimized by using correlation coefficient method coupled with the characteristic absorbance of the spectrum. Finally, the principal components, obtained by PLS dimension-reducing, were inputed into BP-ANN. The calibration models were established by calibration set and validated by prediction set. The results showed that the related coefficients (R2) of prediction for brix and pol were 0.982 and 0.979, respectively; and the standard errors of prediction (SEP) for brix and pol were 0.159 and 0.137, respectively. BP-ANN was more accurate in the prediction of brix and pol compared with the partial least square method (PLS). The method can be applied to fast and accurate determination of brix and pol in sugar cane juice. PMID- 20827966 TI - [Investigation on the difference in HCHO metabolic mechanism between Arabidopsis and tobacco using FTIR]. AB - In the present study, the model plants, arabidopsis and tobacco, were chosen for FTIR analysis to investigate the spectrum characters and the changes in their chemical component contents in the time course of HCHO treatment, providing clues to explain the difference in HCHO metabolic mechanism between the two plants. The FTIR data showed that all the chemical components of arabidopsis and tobacco varied under HCHO stress conditions. An interested peak near 1,376 cm(-1) which was assigned as the absorption of methyl group of cellulose was specially existed in the spectrum of arabidopsis. This peak showed a mild decrease compared with other peaks at the beginning (at 1 day) of HCHO stress. This indicated that the major part of HCHO metabolic flux was introduced towards its oxidation pathway to form HCOOH and CO2 subsequently and only small amount of HCHO entered the other pathways. The CO2 was assimilated in Calvin cycle to form sugars which might be used to synthesis of cellulose later. At 7 day of HCHO treatment, the height of the peak decreased whereas the height of the other peaks still increased. This might suggest that the gene expression of some enzymes in the HCHO oxidation pathway was inhibited under HCHO stress conditions and the inhibition might not happen to the gene expression of the enzymes in other pathways. In the case of tobacco, the contents of all chemical components showed the same variation on the FTIR spectrum in the time course of HCHO treatment, which indicated that there was no much difference in HCHO metabolism flux in each pathway. At 4 day of HCHO treatment, the decrease in the height of all peaks is the result of the poor ability of HCHO metabolism of tobacco, which also demonstrated the lower HCHO tolerance of tobacco compared with arabidopsis. PMID- 20827967 TI - [Edaphic FTIR finger print and the area choice of Chinese herb culture]. AB - In order to search for the difference of the soil of Chinese herb growth, and provide useful information for the area choice of Chinese herb culture, 53 soil samples were detected by FTIR. The results showed that all the samples have 8 peaks at 3,621, 3,425, 1,642, 1,435, 1,029, 878, 760 and 690 cm(-1), respectively, but the relative intensity is different. In addition, the peaks at 1,796, 2,982 and 2,874 cm(-1) show difference too. This can be used to distinguish soil in different area. The study also showed that soil in Tianshui and Dingxi of Gansu province are similar to that in Shanxi province. CONCLUSIONS: FTIR finger print of soil can provide useful information for the area choice of Chinese herb culture and transplantation and can be used in the study of soil. PMID- 20827968 TI - [Study on the identification of radix scutellariae and extract using Fourier transform infrared spectroscopy and two-dimensional IR correlation spectroscopy]. AB - 2D-IR correlation spectroscopy was used to do the research on crude and prepared drug of radix scutellariae and the extracts of them. The results show that the holistic shape of peaks among them are similar in the FTIR spectra. In second derivative spectra, the two absorption peaks: 1,745 and 1,411 cm(-1) of processed products move to the bigger wavenumber direction, while 1,357 cm(-1) of processed products moves to the smaller wavenumber direction; There are conspicuous differences in Two-dimensional infrared correlation spectroscopy among them: Four characteristic peaks are shown between 1,300 and 1,800 cm(-1). The intensity of peak at 1,575 cm(-1) is the strongest. There are three main districts about the autopeaks of sliced scutellariae. Wine-fried scutellariae has two auto-peak districts, in which all the auto-peaks are positively correlated. The FTIR spectra of total glycoside extract of different samples present characteristic peaks at 1,615, 1,585, 1,450 cm(-1) (vibration of phenyl framework) and 1,658 cm( 1) (=C-O ) respectively, therefore, the authors speculated that their mutual component is the compound of phenolic glycoside. The two-dimensional infrared correlation spectra present five automatic peaks (vibration of phenyl framework) in 800-1,800 cm(-1) (1,366, 1,420, 1,508, 1,585, 1,669 cm(-1)). So the authors can conclude that a lot of information can be provided by macro-fingerprint technology of infrared spectroscopy which can evaluate overall quality of radix scutellariae accurately and be used to study the characteristics of relevance of crude and prepared scutellariae. PMID- 20827969 TI - [Study on the conversion of acrylic C=C double bonds during dark reaction after UV curing using infrared spectroscopy]. AB - Infrared spectroscopy was used to determine 1,648-1,589 cm(-1) characteristic absorption peak area so as to study the conversation of acrylic C=C double bonds after UV curing. The effects of phototinitiators, active diluents and UV curing resins on the conversion of C=C double bonds were also investigated. The results showed that 40%-85% of C=C double bonds were conversed during dark reaction after 45 s UV curing. Dark reaction will be changed gently after 1.75 h, but 95% conversion of C=C double bonds needed more than 24 h. The rates of polymerization and conversation were affected by photoinitiators, the concentration of photoinitiator, oxygen inhibition, and C=C functional groups of active diluents. The rate of polymerization was affected by the C=C functional groups and types of UV curing resins, but conversation was not. PMID- 20827970 TI - [Study of regeneration based on SERS labelled immunoassay]. AB - Labelled immunoassay by surface enhanced Raman scattering (SERS) has great research and application value. It combines SERS which has the high sensitivity and high selectivity with specific adsorption in immunology. The present paper mainly studies the regeneration about SERS labelled immunoassay, striving to develop the recycling value of it. The authors used glycine-HCl eluent for the sandwich structure including solid matrix antibody, antigen and labelled immuno gold colloids, then the authors had got expected result. The complex of antibody and antigen would be separated by changing the pH scale. It could elute the most antigen and the labelled immuno-gold colloids. Also the authors could assemble it again and distinguish the characteristic SERS spectrum of the reporter molecules. Under this condition, we researched the stability and reusing of this technology. The authors found that it has better stability and it retained activity after 10 recycles of applications. PMID- 20827971 TI - [Study on the treatment turquoise using Raman spectroscopy]. AB - Due to a variety of the enhancement and treatment turquoises discovered in gem markets, the identification of turquoise is becoming more and more difficult. By using laser Raman spectroscopy analysis, the characteristics of Raman spectra of the pressed and filled turquoises were studied. The results show that laser Raman spectroscopy is an effective technique to identify the enhancement and treatment turquoises and the natural ones, moreover, it's a non-destructive testing method. The Raman spectra of the enhancement and treatment turquoises are resulted mainly from the vibrational mode and frequency of water, hydroxyl units, PO4 tetrahedron and CH2 units. Besides, they have the characteristic Raman spectra peaks at 2,937, 2,883 and 1,451 cm(-1) which are attributed to the stretching vibration and the bending vibration of CH2, respectively. These characteristic Raman vibration bands, it will help to distinguish the natural turquoises and the treatment ones. The study provides a new train of thought on the rapid, accurate, and non-destructive identification of turquoise. PMID- 20827972 TI - [Effect of technological parameters of sputtering on the microstructure of silicon film investigated by Raman analysis]. AB - In order to facilitate optical polishing of silicon carbide space telescope, in the present paper, silicon film, which has similar coefficient of thermal expansion with silicon carbide, was fabricated on SiC substrate by radio frequency magnetron sputtering. The effect of substrate temperature, radio frequency power, and substrate bias voltage was investigated by Raman scattering. The results indicate that at lower substrate temperature, the crystalline volume fraction of Si films increases with the increase in deposition temperature. Exceeding a certain temperature, the crystalline volume fraction decreases with further increasing deposition temperature; the increase in substrate bias voltage is bad for forming crystalline structure; the effect of radio power on microstructure of silicon film is comparatively complicated. As the rf power increases, the cluster size and crystallite volume fraction decrease, and both of them increase with further increasing the rf power. But when the rf power is too high, the crystallite volume fraction of the silicon film will decrease slightly. PMID- 20827973 TI - [Raman spectra quantitative analysis on materials with strong fluorescence background]. AB - Aiming at the difficulty of Raman spectra quantitative analysis on materials with strong fluorescence background, together with baseline correction, a new normalization method was performed for concentration quantitative analysis of two kinds of solutions which exhibit strong fluorescence background, the methanol solutions with different concentrations and the mixed solutions of ethanol and methanol with different ratios of concentration. Meanwhile, the data fluctuation caused by collecting spectra data at different space-time was investigated by using statistical method of randomized blocks analysis of variance to evaluate the data fluctuation among different sample groups, and the function of our method proposed in this paper to eliminate this data fluctuation was discussed. Experimental results demonstrate that our proposed method can not only obtain satisfied accuracy for Raman spectra quantitative analysis on methanol with strong fluorescence background, with the mean relative error being 4.7%, but also effectively eliminate the data fluctuation among different sample groups, and the relative standard deviation of them was only 4.2%, indicating that it is possible to carry out simple, quick and precise quantitative determination of sample content for the materials with strong fluorescence background. PMID- 20827974 TI - [Study on the vibrational spectra of 3,5-dimethoxybenzyl alcohol]. AB - 3,5-dimethoxybenzyl alcohol (L1 OH) is a kind of important pharmaceutical intermediate and it is also the starting material of a family of dendrimer LnOH (integer n means the layers of "branch"). A number of articles reported the structure and properties of the L1 OH. However, its molecular vibrational spectra have not been reported up to date. Study of vibrational spectra on L1 OH at the molecular level can provide new information, which is significant for the in depth study of related molecules of drug and the dendrimer. Recent studies indicated a morphology effect on the light-harvesting functions of dendritic macromolecules. In the present report, the Raman and FTIR spectra of 3,5 dimethoxybenzyl alcohol were measured experimentally. And the density functional theory (DFT) method (B3LYP/6-311G(d,p)) were used to calculate the equilibrium geometry and vibration frequencies of L1 OH. The results showed that the calculated frequencies agree well with the experimental ones. Potential energy distribution of each frequency was worked out by normal mode analysis. Thereafter the authors got a detail assignment of the vibrational frequencies for L1 OH for the first time. Also, the results showed that the DFT is really a useful method in the study of molecular vibrational spectra. PMID- 20827975 TI - [Comparative study on UV fluorescence characteristics of Su liquor]. AB - In the present paper, the authors studied Guoyuan and Yanghe which are the most representative types of Su liquor. The authors got the three-dimensional fluorescence spectra of the liquor and analyzed their unique characteristics. Guyuan has obvious characteristics of the fluorescence in the 280-400 nm excitation wavelength range, including a major peak of fluorescence. Yanghe contains five clear fluorescence peaks in the 200-450 nm range of excitation wavelength. The two series of liquor have clear fluorescent characteristics in the 310-350 nm range of excitation wavelength, The range includes some organic compounds which play a decisive role in taste and flavor of Su liquor. The result of research provides a scientific basis for improving the mixing process of Su liquor and enhancing the quality of liquor. PMID- 20827976 TI - [Measurement of chlorophyll content in wheat leaves using hyperspectral scanning]. AB - The objective of the present research was to evaluate the potential of hyperspectral scanning as a way for nondestructive measurement of chlorophyll content in wheat leaves, which can indicates the plant healthy status. One hundred twenty samples were randomly picked from Xiao Tangshan farm. Ninety samples were used as calibration set and others were used for verification set. After capturing hyperspectral image in the range of 400-1,000 nm, the chlorophyll contents of samples were measured immediately. Four different mathematical treatments were used in spectra processing in the wavelength range of 491-887 nm: multiplicative scatter correction (MSC), first derivative correction, and second derivative correction. Statistical models were developed using partial least square regression (PLSR), and stepwise multiple linear regression (SMLR) analysis technique. The results showed that the best calibration model was obtained by PLSR analysis, after processing spectra with MSC and second derivate, with a relatively higher coefficient of determination of calibration (0.82) and validation (0.79) respectively, a relatively lower RMSEC value (0.69), and a small difference between RMSEC (0.69) and RMSEP (0.71). The results indicate that it is feasible to use hyperspectral scanning technique for nondestructive measurement of chlorophyll content in wheat leaves. PMID- 20827977 TI - [Study of spatially resolved hyperspectral scattering images for assessing beef quality characteristics]. AB - Hyperspectral scattering techniques were used to predict beef pH, tenderness (i. e. WBSF: Warner-Bratzler Shear Force) and color parameters. Thirty-three fresh strip loin cuts were collected from 2-day postmortem carcass. After capturing scattering images and measuring pH values, the samples were vacuum packaged and aged to seventh day, then their color parameters (L*, a*, b*) and WBSF were measured as references. The optical scattering profiles were extracted from the hyperspectral images and fitted to the Lorentzian distribution (LD) function with three parameters. LD parameters, such as the peak height, full scattering width at half maximum (FWHM) and the scattering asymptotic were calculated at individual wavelength. Stepwise regression was used to determine optimal combinations of wavelengths for each of parameters. The optimal combinations were then used to establish multi-linear regression (MLR) models to predict the beef attributes. The full cross validation method was used to examine the performance of models. The models were able to predict beef WBSF with R(CV) = 0.86, and with the SE(CV) (the standard error of cross validation) of 11.7 N, 91% classification accuracy could be obtained. Two-day pH values with R(CV) = 0.86, SE(CV) = 0.07 and color parameters (L*, a*, b*) with R(CV) of 0.92, 0.90 and 0.88, with the SE(CV) of 0.90, 1.34 and 0.41 were obtained respectively. This research provided available technique for the development of multispectral system, which could be implemented online to determine beef steaks color and tenderness. PMID- 20827978 TI - [Winter wheat growth spatial variation study based on temporal airborne high spectrum images]. AB - Precision agriculture technology is defined as an information-and technology based agriculture management system to identify, analyze and manage crop spatial and temporal variation within fields for optimum profitability, sustainability and protection of the environment. In the present study, push-broom hyperspectral image sensor (PHI) image was used to investigate the spatial variance of winter wheat growth. The variable-rate fertilization contrast experiment was carried out on the National Experimental Station for Precision Agriculture of China during 2001-2002. Three airborne PHI images were acquired during the wheat growth season of 2002. Then contrast analysis about the wheat growth spatial variation was applied to the variable-rate fertilization area and uniformity fertilization area. The results showed that the spectral reflectance standard deviation increased significantly in red edge and short infrared wave band for all images. The wheat milky stage spectral reflectance has the maximum standard deviation in short infrared wave band, then the wheat jointing stage and wheat filling stage. Then six spectrum parameters that sensitive to wheat growth variation were defined and analyzed. The results indicate that parameters spatial variation coefficient for variable-rate experiment area was higher than that of contrast area in jointing stage. However, it decreased after the variable-rate fertilization application. The parameters spatial variation coefficient for variable-rate area was lower than that of contrast area in filling and milking stages. In addition, the yield spatial variation coefficient for variable-rate area was lower than that of contrast area. However, the yield mean value for variable-rate area was lower than that of contrast area. The study showed that the crop growth spatial variance information can be acquired through airborne remote sensing images timely and exactly. Remote sensing technology has provided powerful analytical tools for precision agriculture variable-rate management. PMID- 20827979 TI - [Tree species discrimination based on leaf-level hyperspectral characteristic analysis]. AB - The emergence of hyperspectral remote sensing technology will provide chance for solving problems of identifying forest tree species precisely. For discrimination of tree species with hyperspectral remote sensing technology, extraction and selection of the spectral characteristics is a very important process. Compared with multispectral data, hyperspectral data have the characteristics of more bands, larger amount of data and larger redundancy degree. The method of derivative reflectance was used to deal with the original spectral data, analyze and compare curves of the original spectrum, the first derivative reflectance and second derivative reflectance of the different tree species, and the bands with bigger difference were selected to identify the different tree species. Then the Euclidean distance method was used to test the selective bands identifying different tree species, and the results showed that the selective bands could identify different tree species effectively. The bands for identifying different tree species were most near-infrared bands, and the bands with maximum difference derived from the three methods are 1,657-1,666, 1,868-1,877 and 1,868-1,877 nm respectively. PMID- 20827980 TI - [Research on crop-weed discrimination using a field imaging spectrometer]. AB - Discrimination of weeds from crop is the first and important step for variable herbicides application and precise physical weed control. Using a new field imaging spectrometer developed by our group, hyperspectral images in the wavelength range 380-870 nm were taken in the wild for the investigation of crop weed discrimination. After normalizing the data to reduce or eliminate the influence of varying illuminance, stepwise forward variable selection was employed to select the proper band sets and fisher linear discriminant analysis (LDA) was performed to discriminate crop and weeds. For the case of considering each species as a different class, classification accuracy reached 85% with eight selected bands while for the case of considering overall weed species as a class, classification accuracy was higher than 91% with seven selected bands. In order to develop a low-cost device and system in future, all combinations of two and three bands were evaluated to find the best combinations. The result showed that the best three bands can achieve a performance of 89% comparable to the performance achieved by five bands selected using stepwise selection. The authors also found that "red edge" could afford abundant information in the discrimination of weed and crop. PMID- 20827981 TI - [Application of ANFIS in in-situ measured hyperspectral data for vegetation chlorophyll content estimation]. AB - Hyperspectral reflectance and green degree of Platanus orientalis L. and Populus tomentosa Carr. leaves were measured by the ASD portable spectrometer and the portable chlorophyll meter SPAD-502, respectively. The chlorophyll concentration retrieval models based on 10 common vegetation indexes were established, and the ANN-BP model which used wave bands with larger correlation coefficient as input variables was established for chlorophyll content estimation. Finally, the ANFIS model was established to inverse vegetation chlorophyll content using hyperspectral data. The results showed that normalized difference vegetation index can inverse chlorophyll content better than other vegetation index, and the determination coefficients R2 of models of Platanus orientalis L. and Populus tomentosa Carr. were 0.795 7 and 0.754 6, respectively. The determination coefficients R2 between the predicted and the measured chlorophyll content based on ANN-BP models of Platanus orientalis L. and Populus tomentosa Carr. were 0.935 2 and 0.917 1, respectively. ANFIS model which is a good method to be applied to hyperspectral data for estimation of vegetation chlorophyll concentration can greatly improve vegetation chlorophyll concentration estimation accuracy, and the determination coefficients R2 between the predicted and the measured chlorophyll content of Platanus orientalis L. and Populus tomentosa Carr. were 0.935 2 and 0.917 1, respectively. PMID- 20827982 TI - [An improved physical model to correct topographic effects in remotely sensed imagery]. AB - Topographic correction for remotely sensed imagery is an important preprocessing step in order to improve the retrieval accuracy of land surface spectral reflectance in mountainous area. Various kinds of topographic correction models have been proposed in the literature. Each model has its advantages and limitations. In consideration of the limitations of the topographic correction models in the literature, an improved Shepherd topographic correction model is proposed in this paper. Diffuse irradiance is an essential factor in the physically based topographic correction model. While in the Shepherd model (originally proposed by Shepherd et al. in 2003), accuracy of the method to compute the diffuse irradiance is relatively low; therefore, the accuracy of the land surface spectral reflectance retrieved with the Shepherd model is impacted. In order to improve the accuracy of diffuse irradiance, hence the accuracy of land surface spectral reflectance, a different method (named the Perez model), is used to obtain the diffuse irradiance with higher accuracy in the improved Shepherd model. Landsat 5 Thematic Mapper (TM) imagery acquired on July 12th 2006, over the mountainous areas in the north of Beijing city, was employed to retrieve land surface spectral reflectance with the improved Shepherd topographic correction model and 6S (Second Simulation of the Satellite Signal in the Solar Spectrum) atmospheric radiative transfer model. Correction results were tested with three different methods. Testing result shows that the improved Shepherd topographic correction model can achieve a good correction result and is better than Shepherd and C topographic correction model. What is more, this improved model is physically based and can be applied to all kinds of optical satellite imagery. PMID- 20827983 TI - [Evaluation of sensor spectral parameters for the simulation accuracy of the vegetation spectrum]. AB - Hyperspectral imaging (HSI) has become one of the most promising and emerging techniques in remote sensing. Due to hundreds of co-registered bands used in HSI system, hyperspectral imagery may provide more spectral information than multi band images. Unfortunately, original hyperspectral images are more expensive and difficult to achieve than multi-band ones. However, an abundance of spectral information has to be acquired by part of special research for the purpose of ground monitoring, which original HSI systems can easily provide. Then a solution, called hyperspectral satellite data simulation, is proposed for studies in satellite data simulation. It is also one of the most important studies to simulate satellite remote sensing data. In the method, the model with low computational complexity can simulate hyperspectral data quickly, which is based on the priori spectral knowledge of the ground objects. But the accuracy of the simulation data depends on spectral parameters of the sensor. In the present paper, the authors experiment with EO-1/ALI bands in VIS/NIR wavelengths. Then the relationship between the spectral parameters, including the number of bands, bandwidth and the peak wavelength, and the simulation accuracy of the vegetation spectrum are analyzed from their variation principles. According to the results, spectral parameters can determine the effective spectral feature of the vegetation, and impact simulation model directly. Optimal parameters are also summarized for spectral reconstruction in the paper. The experiment results are beneficial to enhancing spectral simulation precision. The conclusions can help evaluate the performance of multispectral sensors and perfect spectroscope and filter design. PMID- 20827984 TI - [Progress in research on land cover products of MODIS]. AB - Remote sensing technology has been rapidly developed in recent decades, and has been widely used in ecology and environment field. MODIS is a new data source, and in its many products, land cover product is an important product, and it has often been used in global and regional models. In the present review, the procedure of producing land cover product is clearly discussed, and the feature of the classification based network or decision tree is introduced. The paper emphasized the importance of direction information in classification, detailed introduction of change vector analysis methods and land cover change detection based artificial nerve network, analyzed global 17 land cover types defined by IGBP, and compared with other 3 classification systems. PMID- 20827985 TI - [The spectrum characteristics of an invasion plant: Eupatorium adenophorum Spreng]. AB - Eupatorium adenophorum Spreng. (EAS) is a toxic invasion plant and has caused significant economic and environmental impacts in China. The EAS has the characteristics of widely distributing and quickly spreading. The traditional detecting and supervising methods become invalid when applied for managing the spatial distribution of EAS. Based on the analyzing results of the spectrum features of EAS, the present paper tried to structure the identifying models by remote sensing. The main objective of this paper is to develop an available method for detecting and mapping the spatial distribution of EAS. The study shows that the spectrum of EAS has two reflecting peaks and one absorbing trough. The corresponding wavelengths of those peaks are 560, 730 and 674 nm, respectively. The absorption characteristics of EAS at 647 nm are that the absorbing depth is 0.504 3-1.910 3, the absorbing width is 13.778 9-17.251 8 nm and the area at the left absorption band is greater than the right, and the corresponding area ratio of left to right is 1.771 9-2.444 1. The white flowers of EAS make the reflectance higher at visible bands, and the first-order derivatives of EAS spectral show a wave peak at 420 nm. Compared with the spectral feature of other representative materials, the absorbing characteristics at 647 nm, such as absorption width and absorption depth, and the peak at 420 nm of derivatives spectral are special features of EAS spectral, which can be used as remotely sensed parameters for detecting and mapping the EAS at florescence. PMID- 20827986 TI - [Study on the synthesis of Pd/Au nanostructure and spectral characteristics of particle size composition and spins]. AB - The present paper describes the synthesis of nanostructure Pd/Au core/shell and study of electric catalysis, control of particle size composition and spins. Oil bathing thermal decomposition was adopted to prepare the core/shell Pd/Au bimetallic alloy nanoparticles. The PVP and ethylene glycol were used as surfactant and stabilizing agent. Based on the solution concentration, size, and surface adsorption energy and control of the phase, the uniform homogeneous Pd/Au nanostructure was obtained. The experiments measured the HAADF and HRTEM to test the shape of nanostructure and EDS particle distribution. The products were characterized by TEM/XRD and XPS. The results show that Pd/Au nanoparticles have the structure of truncated octahedron different from Au/Pd core/shell. The Pd/Au nanoparticles have the properties of activity, wear, electric catalysis and stability. PMID- 20827987 TI - [Spectral properties of 2-(2'-hydroxyphenyl) benzimidazole]. AB - 2-(2'-hydroxyphenyl) benzimidazole (HBI) is one kind of organic molecule with excited-state proton transfer (ESPT) effect. The absorption spectra of HBI were observed in toluene, the mixture of toluene and ethanol, and ethanol, respectively. It was found that the absorption spectra in the three solvents are similar. The fluorescence of HBI was observed under the excitation of 317 nm light. Only one fluorescence band with a peak wavelength of 470 nm was observed in the toluene. There appeared two fluorescence bands in the mixed solvents and ethanol, of which the peak wavelength was 370 and 450 nm, respectively. Based on the ESPT theory, the fluorescence band with a peak at 370 nm is attributed to the emission from enol form of HBI molecule, while the band with a peak at 470 nm is attributed to the emission from tautomer form (i. e. keto form) via ESPT process. Because of the strong polarity of ethanol, the intermolecular H-bond can be formed between the HBI molecules and the ethanol and HBI molecules tend to exist in the solvated form. When HBI molecules in solvated form were excited, the zwitterionic form of HBI was formed via ESPT and returned to the ground state accompanied with fluorescence emission, so the fluorescence band with a peak at 450 nm is attributed to the zwitterionic emission of HBI. When the HBI in the three kinds of solvents was excited by the picosecond laser pulse at 532 nm, the two-photon induced fluorescence was not observed in the nonpolar solvents but observed in the polar solvents, which indicate that two-photon effect occurred in solvated form. PMID- 20827988 TI - [Spectrometric investigation of the antioxidant activity of a novel synthetic selenadiazole derivative SPO against DPPH and ABTS free radicals]. AB - The antioxidant activity of a novel synthetic selenadiazole derivative SPO against DPPH and ABTS free radicals was evaluated using spectrometric methods. The results show that the detection wavelength and stable time for DPPH system were 515 nm and 30 min respectively, while those for ABTS system were 734 nm and 6 min, respectively. SPO could effectively and rapidly inhibited the formation of ABTS and DPPH free radicals in a dose- and time-dependent manner, indicating the potent antioxidant activity of SPO under both hydrophilic and hydrophobic conditions. In the optimized systems, the IC50 values of SPO were 85.2 micromol x L(-1) (DPPH assay) and 36.5 micromol x L(-1) (ABTS assay), respectively, which were comparable with the standard antioxidant Trolox, and significantly better than the positive controls BHA and BHT. Taken together, our results suggest the potential applications of selenadiazole derivatives as antioxidative agents. PMID- 20827989 TI - [Study on synthesis and fluorescence characterization of europium and terbium complexes of 1-(5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl) ethanone]. AB - Six solid complexes(TbL3 x 2H2O, TbL2 (phen) x H2O, TbL2 (TPPO), EuL3 x 2H2O, EuL2 (phen) x 2H2O and EuL2 (TPPO) x 2H2O) have been synthesized based on the pyrazole ligand(HL)(phen = 1,10-phenanthroline, TPPO = Tri-phenylphosphine oxide, HL=1-(5-(2-hydroxyphenyl)-3-methyl-4,5-dihydropyrazol-1-yl) ethanone). These complexes were characterized by elemental analysis, IR spectra, and fluorescence spectra. The IR spectra indicated that all complexes exhibited the characteristic peaks of asymmetric stretching vibration v (C=O) and symmetric stretching vibration v (C=N) peaks. The C=O stretching band at 1,644 cm(-1) of HL molecule shifted to lower band in the complexes. The O-H band at 3,072 of the HL ligand is also shifted to lower band. All these shifts indicated that carbonyl group, O-H and C=N take part in coordinating with the rare-earth ion in the form of bridging tridentate. The excitation and emission spectra of the six complexes were determined at room temperature and the results show that EuL2 (Phen) x 2H2O and TbL2 (Phen) X 2H2O display the strongest relative fluorescence intensity with the excited bands at 310 and 320 nm, respectively. Meanwhile, the emission intensities of Eu3+ and Tb3+ complexes were greatly sensitized by phen. PMID- 20827990 TI - [Preparation and spectrum properties of cellulose nanoparticles]. AB - Manipulating cellulose molecules in nanosize range to create excellent nano materials is the frontier of cellulose science. Cellulose nanoparticles, a kind of renewable biomaterial, have become the research focus home and aboard. It is of great importance to develop a simple, green, low energy-consuming, rapid and efficient method to prepare cellulose nanoparticles. In the present paper, cellulose nanoparticles (CNP) which enjoy good dispersity and nanosize were prepared by alkaline hydrolysis in a simple and feasible way, with microcrystalline cellulose (MCC) as the raw material. Moreover, the size and morphology, crystal structure and spectrum properties of the cellulose nanoparticles were analyzed by means of transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared spectrometry (FTIR). TEM images demonstrate that the prepared samples are in quasi-sphere shapes with good dispersity and with size about 20-40 nm. The SEM images of the samples show that the purified cellulose nanoparticles can be obtained after dialysis treatment to remove salt particles. The XRD results show that the microcrystalline cellulose and cellulose nanoparticles almost have the same diffraction peaks in cellulose I crystal form. Because of the damage of amorphous region of MCC by alkaline hydrolysis, the crystallinity of produced samples increases by up to 79.71%. The grain size was calculated with Scherrer's formula, and the average size is about 3-6 nm. Furthermore, the FTIR spectra suggest that the characteristic peaks on the graphs of cellulose nanoparticles have no significant change compared to natural cellulose, which indicates that the sample remains as the basic chemical groups of cellulose. The results show that preparing cellulose nanoparticles (CNP) by alkaline hydrolysis enjoys the ease to operate and can produce high yield, and therefore the study offers a new approach to obtaining cellulose nanoparticles with nanosize and good dispersion. PMID- 20827991 TI - [Spectral characteristics variations of chromophoric dissolved organic matter during growth of filamentous green macroalgae]. AB - As an important component of dissolved organic matter (DOM), chromophoric dissolved organic matter (CDOM) plays a central role in the global biogeochemical carbon cycle. Macroalgae are essential producers in aquatic ecosystems. They can release a considerable part of photosynthetic products as CDOM. So changes in optical properties of CDOM are studied on filamentous green macroalgae Chadophorasle found in tidal flats of a brackish Lake Beihu in natural field condition by using spectrometry. Humic-like fluorescence peaks and protein-like fluorescence peaks detected by fluorescence excitation-emission matrix spectrum (EEMS) change little in control experiment but increase dramatically in incubation experiment. Applying parallel factor analysis (PARAFAC) together with fluorescence excitation-emission matrix can get four components of CDOM (C1, C2, C3 and C4) which are relative to humic-like fluorescence peak A(C), M and protein like fluorescence peak B, T respectively. In incubation experiment four components increase by 211.5%, 255.8%, 75.3% and 129.3% respectively while in control experiment components have little changes except C1 decreasing by 34.3%. Absorption coefficient alpha (355) increases by 92.9% and has positive significant correlation (P < 0.01) with the four components in incubation experiment while alpha (355) decreases by 59.8% and only has correlation (P < 0.05) with C1 in control experiment. As the parameters representing CDOM molecular weight and composition, M and S values in incubation experiment are smaller than in control experiment, which illustrate that aromatic and macromolecular CDOM is produced in growth of Chadophorasle. All results indicate that growth of Chadophorasle can change the content and composition of CDOM. PMID- 20827992 TI - [Observation of and research on intravital microcirculation use of orthogonal polarization multi-spectral technique]. AB - A small, simple intravital microcirculation multi-spectral imaging system was constructed. Orthogonal polarization spectral (OPS) imaging and liquid crystal tunable filter (LCTF) were used for intravital microcirculation multi-spectral imaging. LCTF has excellent imaging quality and low-power loss, without moving parts and image shift. It can provide continuously, rapid and random-access selection of any wavelength in the visible to near-infrared range. An ear of nude mouse was adopted as experiment specimen. The multi-spectral images of ear microvessel of the nude mouse were acquired by this imaging system in two ways (detection polarization angle 90 degrees and 0 degrees). Compared with detection polarization angle 0 degrees way the images acquired by orthogonal polarization spectral imaging way(detection polarization angle 90 degrees) had better contrast and more details. It is concluded that the experiment has proved that the orthogonal polarization multi-spectral technique can enhance the effect of observation of intravital microcirculation. PMID- 20827993 TI - [Research on improving sensitivity of the characteristic spectrum in micro-gas monitor]. AB - In order to realize the indoor micro noxious gas real-time monitor, and enhance measuring accuracy based on the characteristic spectrum examination method, a characteristic wavelengths filtration window was designed, in which the container is full with the highly concentrated testing gas. The container with the highly concentrated testing gas was used as the filtration window, the standard air as the reference window, the air chamber sufficient testing gas for testing density. The experiment demonstrated that using the WQF-520-FTIR infrared spectroscope to obtain the infrared absorption spectrum of dipropyl sebacate, there were mainly four characteristic wavelength lines: 3.385 26, 3.417.64, 5.797 11, and 8.561 65 microm, and the corresponding extinction was 1.520 0, 1.542 1, 2.431 8 and 1.352 6 respectively. The smallest content examined was 50 ppb, but using the characteristic wavelengths filtration window, the method could realize the 10(-4) nm magnitude alignment. The sensitivity was enhanced nearly 10 times, and the characteristic wavelengths filtration window method has the merits of high sensitivity, no discontinuity, real-time examination, and so on. PMID- 20827994 TI - [Study on panchromatic band broadening of new high-resolution satellite sensor]. AB - For developing a remote sensor, the selection of operating waveband is one of the most important factors for detecting and identifying target. In the present paper, the changes of atmospheric effects and imagery quality are simulated due to the increase in the response wave range of optical remote sensor from 0.50 0.85 mm to 0.45-0.90 mm by using MODTRAN4. The experimental results show that there is a slight increase of the adverse factors, including atmospheric transmittance, path radiance, and adjacency effect, after the working waveband has been widened. The disadvantages compared with the improvement in incident radiance, target-background contrast and image quality are negligible. In summary, the scheme of 0.45-0.90 mm is superior to 0.50-0.85 mm and it has been more widely used in the on-orbit operation high-resolution satellite sensor. PMID- 20827995 TI - [A new type of nano-porous gold membrane for surface plasmon resonance biosensor]. AB - Nano-porous gold membrane was fabricated by chemical etching method in the present work. The structures and the unique optical properties of the membrane were studied by scanning electron microscope and spectrometer. We creatively used the nano-porous gold membrane as the sensing layer for surface plasmon resonance biosensor. The results showed that, compared to the traditional evaporated gold film, the nano-porous gold membrane has a unique effect of localized surface plasmon resonance. The sensitivity of detecting the biological agents was obviously increased by the surface plasmon resonance biosensor assembling the nano-porous gold membrane. The fabrication method of the nano-porous gold membrane is simple and low-cost, so it absolutely can replace the use of traditional evaporated gold film. PMID- 20827996 TI - [Reflectance of sea ice in Liaodong Bay]. AB - In the present study, the relationships between sea ice albedo and the bidirectional reflectance distribution in Liaodong Bay were investigated. The results indicate that: (1) sea ice albedo alpha(lambda) is closely related to the components of sea ice, the higher the particulate concentration in sea ice surface is, the lower the sea ice albedo alpha(lambda) is. On the contrary, the higher the bubble concentration in sea ice is, the higher sea ice albedo alpha(lambda) is. (2) Sea ice albedo alpha(lambda) is similar to the bidirectional reflectance factor R(f) when the probe locates at nadir. The R(f) would increase with the increase in detector zenith theta, and the correlation between R(f) and the detector azimuth would gradually increase. When the theta is located at solar zenith 63 degrees, the R(f) would reach the maximum, and the strongest correlation is also shown between the R(f) and the detector azimuth. (3) Different types of sea ice would have the different anisotropic reflectance factors. PMID- 20827997 TI - [The measurement and numerical study of numerical aperture of photonic crystal fiber]. AB - The numerical aperture is an important parameter of optical fiber, and the fiber with high numerical aperture can be well used in fiber laser and laser-induced fluorescence system. The numerical aperture of the photonic crystal fiber is different from that of traditional step optical fiber, which is closely related to the wavelength. In the present paper, a spectrometer was used to measure the numerical aperture of photonic crystal fiber, and a lot of refractive index photonic crystal fibers were measured and simulated to investigate the impact of wavelength, the diameter of air-hole and the pitch on numerical aperture. According to the measured numerical aperture, the parameters of fiber related with wavelength can be better studied, including nonlinearity coefficient, macro bending loss, effective mode area, cut-off wavelength and so on, and satisfactory results were achieved. PMID- 20827998 TI - [Study on nano- and microcrystallites in the urines of calcium oxalate stone formers]. AB - The crystallites in urine are related closely with the formation of urolithiasis. In the present paper the composition, morphology and Zeta potential of crystallites of twenty calcium oxalate stone formers were comparatively studied using X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, nanoparticle size analyzer, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results showed that calcium oxalate calculi usually coexisted with a little of uric acid, calcium phosphate, and magnesium ammonium phosphate. By contrast, the compositions of urine crystallites of the patients with calcium oxalate calculi were mainly uric acid, phosphate, calcium oxalate and so on. Most of them had sharp angularity with a particle size distribution ranging from tens of nanometers to tens of microns; and obvious aggregation was observed. The negative value of Zeta potential of urine crystallites in the twenty stone formers (average value -5.92 mV) was less than that in the twenty normal subjects (-12.9 mV). However, there was no obvious difference in the urine pH between stone formers (average pH 6.03) and normal subjects (average pH 5.92). The study on the relationship between urine crystallites and urinary calculi components will be helpful for finding out the causes of urolithiasis and providing an important basis for the scientific prevention methods and reasonable treatments in clinic. PMID- 20827999 TI - [Preliminary characterization of clay minerals from four typical soils of Northeast China]. AB - The black soil, albic soil, brown soil and cinnamon soil in Northeast China were selected as research objects, and their mineral characteristics were evaluated with Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction spectroscopy (XRD), and scanning electron microscopy(SEM). The results showed that the mineral atlas of test soils were of montmorillonite type. Quartz was the main component of clay minerals in the four soils. Montmorillonite and high mountain stone had higher amounts in black soil and albic soil, and mica and high mountain stone were more in brown soil and cinnamon soil. Generally, the surface of mineral particles in black soil, brown soil and cinnamon soil seems to be of laminarization with significant un-uniformity, and compared with black soil, brown soil and cinnamon soil had more smooth surface. In contrast, the mineral particles in albic soil had distinct profile and smooth surface with some interstice. It was indicated that the components and characteristics of soil clay minerals could be analyzed by soil spectroscopy, and the related information to be obtained could be accurate and available. PMID- 20828000 TI - [Fabrication and analysis of red-green resonant complementary optically variable sub-wavelength microstructures]. AB - Principles of design and production of dual-layer sub-wavelength grating microstructures are analyzed thoroughly. Novel methods for designing and fabricating such structures, with the characteristics of using rectangular grating index profiles when designed and using holographic interference lithography and coating processes when produced, are proposed. Microstructures fabricated by use of this method, will have the same resonant and optically variable properties with pre-designed structures, even improving its color qualities of lights reflected. A sub-wavelength security microstructure with the unique performances of red-green resonant complementary optically variability in color was designed and manufactured successfully and its resonant optically variable spectrum and color changing characteristics were verified theoretically and experimentally. Study results indicate that sinusoidal grating microstructures manufactured have the same resonant and optically variable characteristics, such as the resonant spectrum, color, spectral peak and peak splits, etc. with the pre-designed structures. A rectangular index profile grating is not the necessary requirement to produce resonance behaviors and the grating regions can have any profile such as the holographic type as long as its diffraction characteristics and equivalent waveguide representation are the same with the designed rectangular grating microstructures. The methods proposed are feasible in practice, lowering the making complexity and with potential of low cost mass production commercially by use of the current holographic manufacture equipments. PMID- 20828001 TI - [Study on thermal decompositon properties of hexafluoropropane clean gaseous fire extinguishing agent]. AB - The thermal decomposition properties of hexafluoropropane clean gaseous fire extinguishing agent were studied in tubular reactor from 500 to 750 degrees C and the decomposed gas was characterized by gas chromatography(GC), Fourier transform infrared spectroscopy (FTIR) and gas chromatography-mass spectrometry (GC-MS). Hydrogen fluoride was detected after the decomposed gas was analyzed by pH testing, while pentafluoropropylene was found by GC-MS. The results showed that hydrogen fluoride eliminated from hexafluoropropane was the main reaction, while pentafluoropropylene was the primary product during hexafluoropropane decomposition under high temperature. GC and FTIR results indicated that the reaction temperatures had significant effects on the thermal decomposition of hexafluoropropane. Haxafluropropane was steady at 500 degrees C, whereas started to decompose weakly at 600 degrees C. The degree of the thermal decomposition of hexafluoropropane was enhanced with the temperature increase. And hexafluoropropane underwent intense decompositon at 750 degrees C. FTIR can be used as a new method to study extinguishing mechanism of fluorine-containing fire extinguishing agent online. PMID- 20828002 TI - [Effect of reduction by sodium borohydride on the structural characteristics of brown-rotted lignin]. AB - The FTIR, UV-Visible, 1H NMR and GPC were used to study structural changes of brown-rotted lignin after sodium borohydride reduction. FTIR spectra showed that, after reduction, the band at 1,677 cm(-1) attributed to the conjugated carbonyl groups disappeared, and the band intensity at 1,715 cm(-1) attributed to the nonconjugated carbonyl groups decreased. On the other hand, the band at 1,509 and 1,603 cm(-1) attributed to aromatic skeletal vibration remained almost unchanged. UV spectra showed the decreased absorptions at 288 nm and 300-400 nm after reduction. 1H NMR spectra showed that, after reduction, the number of aromatic methoxyl and aromatic hydroxyls decreased, the number of aliphatic hydroxyls and the proton number attributed to many linkage structures connecting the phenylpropane units increased. GPC results showed that the molecular weight of reduced brown-rotted lignin increased and the molecular distribution got wider, as a consequence of the large molecular weight molecules generated during the reduction reaction. Our results suggest that the conjugated carbonyl groups can be totally reduced to the hydroxyl groups, but only some nonconjugated carbonyl groups can be reduced to the hydroxyl groups. The chemical structure of the brown rotted lignin changed, but the benzyl ring kept stable. The condensation reaction took place during the sodium borohydride reduction process. PMID- 20828003 TI - [Study on the early detection of Sclerotinia of Brassica napus based on combinational-stimulated bands]. AB - The combinational-stimulated bands were used to develop linear and nonlinear calibrations for the early detection of sclerotinia of oilseed rape (Brassica napus L.). Eighty healthy and 100 Sclerotinia leaf samples were scanned, and different preprocessing methods combined with successive projections algorithm (SPA) were applied to develop partial least squares (PLS) discriminant models, multiple linear regression (MLR) and least squares-support vector machine (LS SVM) models. The results indicated that the optimal full-spectrum PLS model was achieved by direct orthogonal signal correction (DOSC), then De-trending and Raw spectra with correct recognition ratio of 100%, 95.7% and 95.7%, respectively. When using combinational-stimulated bands, the optimal linear models were SPA-MLR (DOSC) and SPA-PLS (DOSC) with correct recognition ratio of 100%. All SPA-LSSVM models using DOSC, De-trending and Raw spectra achieved perfect results with recognition of 100%. The overall results demonstrated that it was feasible to use combinational-stimulated bands for the early detection of Sclerotinia of oilseed rape, and DOSC-SPA was a powerful way for informative wavelength selection. This method supplied a new approach to the early detection and portable monitoring instrument of sclerotinia. PMID- 20828004 TI - [Using canopy hyperspectral ratio index to retrieve relative water content of wheat under yellow rust stress]. AB - The aim of this paper is to estimate canopy relative water contents (RWC) of winter wheat under yellow rust stress by using hyperspectral remote sensing. The canopy reflectance of winter wheat that infected different severity yellow rust was collected and the disease index (DI) of the wheat was investigated respectively in the fields, whereafter the wheat was sampled corresponding to the canopy reflectance measurements and the RWC of the whole wheat were measured in the Laboratory. The research showed that the canopy spectra reflectance gradually decreased in the near-infrared (NIR) region (900-1,300 nm) with RWC reduction, however, canopy spectra reflectance gradually increased in the short-wave infrared (SWIR) region (1,300-2,500 nm), and there was just higher minus correlation between RWC and DI. Smoothing the canopy spectra, the ratio indices were built by using the sensitive bands for water in NIR and SWIR, and then the estimation RWC linear models were built by using ratio indices as variables, and the model inversion precision and stability were analyzed and compared for estimation RWC. The result indicated that the inversion precision and the stability of the model with ratio index R1,300/R1,200 as variable excel other models, the linear model's RMSE is 3.43, and the relative error is 4.78%. So, this study results not only can provide assistant information for diagnosing wheat disease but also can supply theories and methods for inversion vegetation RWC by using hyperspectral images in the future. PMID- 20828005 TI - [Visible-light responding BiVO4/TiO2 nanocomposite photocatalyst]. AB - The two kinds of new nanocomposites BiVO4/TiO2 nanowires were synthesized by hydrothermal process. Their crystal structure, morphology and photocatalytic activities for degradation of methylene blue solution were characterized using various measurement techniques. The XRD results indicate that they are made up of monoclinic BiVO4 and anatase TiO2 phases. The SEM, TEM and HRTEM images show that the two samples include BiVO4 nanoparticles supported onto TiO2 nanowires. The UV Vis absorption spectra reveal that the absorption edges of the samples exhibit red-shift in comparison with that of the pure TiO2 nanowires. The measurement results for the visible-light photodegradation of methylene blue show that the nanocomposite sample prepared from the layered titanate nanowires with Bi3+ has the highest photocatalytic activity. PMID- 20828006 TI - [Detection of metal residue in aqueous solutions by electrolyte cathode atmospheric glow discharge emission spectroscopy]. AB - Toxic metal elements in waters and wastewaters contaminate the environment and greatly threaten the health of human beings, therefore developing a rapid monitor for metal residues in aqueous solutions is urgently required. In the present work, a new homemade apparatus of electrolyte cathode atmospheric glow discharge emission spectroscopy was developed and described. It can detect and discriminate many kinds of trace mental elements by atomic emission spectrum from atmospheric pressure liquid cathode glow discharge. In order to estimate the analytical performance of the present atmospheric pressure electrolyte cathode glow discharge emission spectroscopy system, the detection limit values for Na, Li, Cu, Pb and Mn were obtained based on 3sigma of the background signal, and the current limits of detection were 0.008, 0.005, 1.1, 2.06 and 1.95 mg L(-1), respectively. It demonstrates that the atmospheric pressure electrolyte cathode glow discharge emission spectroscopy has a promising application in real time measurements of metal residues in aqueous solutions. PMID- 20828007 TI - [Optical emission spectroscopy for the characteristic parameters measurement of argon microhollow cathode discharge]. AB - In order to measure the basic plasma parameters, well understand the mechanism of microhollow cathode discharge (MHCD), the rotational structures of the N2 first positive bands (B3 pi(g)A3+u) were analyzed with traces of nitrogen added in argon for the measurement of the gas temperature, and the Stark broadening of Hbeta lines was analyzed for the determination of the electron density. The experimental results show that the gas temperature increases with the increasing pressure and the current and can reach 700 K in the stable glow region. The electron density is in the order of 10(14)-10(15) cm(-3). The magnitude and the changing relations can provide substantial experimental data and technical support for the wide application of MHCD. PMID- 20828008 TI - [Analysis of the mineral element contents of axenic and natural Dunaliella salina]. AB - The contents of eleven mineral elements, including Mg, Fe, K, Ca, Na, Mn, Zn, Cu, Ni, Cd and Cr contents of axenic and natural Dunaliella salina and their culture supernatants in the different period of exponential phase were determined with flame atomic absorption spectrophotometer(AAS). The results show as follows: (1) The contents of Mg, Fe, K, Ca, and Na are between 1 and 10 mg x g(-1). The contents of Zn, Cu, Mn, and Ni are between 0.1 and 1 mg x g(-1). There are little Cd and Cr in the microalgae. (2) The changes in the content of mineral elements of axenic and natural Dunaliella salina during different phases are almost the same. The contents of Mg, Fe, K, Ca, Na, Mn and Cu decreased along with the growth of the microalgae, especially the content of Ca. The contents of Mg, Fe, K, Ca and Na in the culture supernatants keep stable in the culture process and have no distinct difference among axenic and natural Dunaliella salina. But the contents of Cu and Mn in the culture supernatants increased greatly in the middle and end of exponential phase. (3) The contents of Mg, K, Cu, and Ni show no significant differences in axenic and natural microalgae. The contents of Fe, Ca, Na and Zn in the natural microalgae decreased greatly in the middle of exponential phase and were less than in axenic one, but increased at the end of exponential phase and were higher than in axenic one. These results provide reference for further to applying the resource of Dunaliella salina and studying the relationship of microalgae and associated bacteria in the culture. PMID- 20828009 TI - [The molecular composition and spectral properties of polysaccharide isolated from pu-erh tea and its material]. AB - Pu-erh tea, a kind of well-known tea from the ancient time, is originally produced in the Yunnan Lanchan River basin through a special solid state fermentation by fungi. It uses sun-dried green tea as its starting materials. To investigate the variation of composition and spectral properties of polysaccharide during solid state fermentation of pu-erh tea by using Saccharomyces cerevisiae as preponderant starter and using sun-dried green tea as materials in the present study. The results showed that the content of water soluble polysaccharide was increased, and the activity of hydrolase such as cellulase, pectinase and glucomylase were also enhanced. The content of neutral sugar increased with the ferment time increasing and the M(w) of raw polysaccharide showed significant difference during fermentation. The main polysaccharide TPS2 and TPS1 were isolated and purified from pu-erh tea and its materials by DEAE-52 and Sephadex G-150 column chromatography. TPS2 contains the higher content of uronic acid, but TPS1 contains the higher contents of neutral sugar and protein. Monosaccharide analysis by GC-MS revealed that TPS1 and TPS2 were composed of arabinose, galactose, glucose, rhamnose, xylose and mannose with molar ratios of 24.2 : 23.6 : 5.9 : 3.2 : 1.8 : 1.1 and 19.3 : 26.9 : 3.2 : 2.7 : 1.3 : 5.5, respectively. The average molecular weight of TPS1 and TPS2 was 1.68 x 10(4) and 1.21 x 10(4) Daltons, respectively. UV scanning spectrum showed that TPS1 and TPS2 had no characteristic absorption between 200 and 400 nm wavelength, it suggested that they contain trace protein. IR spectrum of TPS1 and TPS2 demonstrated that pyranoid rings were contained in them. As shown in the image of atomic force microscope, the molecular appearance of TPS1 and TPS2 resembled islands and apparently consisted of conglomerations. The height of conglomerations of TPS2 was about 40 nm and the length or width was 0.5-0.8 microm, while the height of conglomerations of TPS1 was about 4nm and the length or width was 0.2-0.4 microm. TPS2 shows sheet conglomerations with rough surface, but TPS1 shows squama conglomerations with smooth surface in the image of scanning electron micrograph. The experimental data suggested that the variation of composition and spectral properties of polysaccharide isolated from pu-erh tea and its materials owed to the action of microorganism and humid and thermal action for long time process. PMID- 20828010 TI - [Determination of inorganic elements in chicken muscle by sealed microwave digestion ICP-AES]. AB - The contents of inorganic elements including K, Ca, Na, Mg, P, S, Fe, Cu, Mn, Zn, Mo, and Co from the chicken muscle were determined by ICP-AES using sealed microwave digestion. The sample of the chicken muscle was digested with HNO3-H2O2 system. The relative standard deviation was less than 5% for all the elements, and the recovery was 92.5%-110% by adding standard recovery experiment. This method was simple, sensitive and precise and can perform simultaneous multi elements determination compared with conventional method of the chicken muscle determination, which could satisfy the sample examination request and provide scientific rationale for determining inorganic elements of chicken meat. PMID- 20828011 TI - [Determination of trace elements in tobaccos by microwave digestion/ICP-MS method]. AB - 2 mL 50% HNO3 and 1 mL 47% H2O2 were chosen for tobaccos digestion, and the acidity of final digestion solution was confined to about 2%. Standard solutions were diluted with 2% HNO3. The digestion solutions were determined by ICP-MS directly after adding internal standard elements Ge and Rh. In stead of using concentrated acid, this method not only can leave out the process of drying or dilution and extended the life of relevant components of the instrument, but also eliminate the errors of the inconsistency between digestion solutions and standard solutions could be eliminated. The contents of 30 trace elements, the results of eight representatives of which were provided, in tobaccos from seven areas were determined. The detection limits of measured elements were from 0.006 to 1.133 ng x mL(-1). The relative standard deviations were from 0.90% to 5.66%. The recovery rates of two elements (Cu, Y) were from 93% to 102%. The results showed that this method proposed could be applied to multielement simultaneous determination of tobaccos, and there is a deep relationship between the contents of the trace elements and the production place and classification of tobaccos. PMID- 20828012 TI - [Determination of five trace elements (Pb, Cd, Se, As and Hg) in human whole blood by temperature-controllable wet digestion and ICP-MS technique]. AB - A method for the determination of five trace elements, including Pb, Cd, Se, As and Hg concentrations in human whole blood by HNO3-H2O2 digestion under temperature-controllable condition and ICP-MS was described. Under the optimum experimental conditions and instrumental operation parameters, the limit of detection for the five elements were 2-40 ng x L(-1). The system had a good stability with RSDs of the determination of value repeated 3 times less than 3%. The accuracy of the method was evaluated by the results of determination of the Chinese national standard references GBW(E)09034-09036 and GBW09101b, and the analytical results well agreed with the certified values. Using this method, the concentration of the five elements in whole blood of 34 habitants from mercury mining area in western Human province was studied. The result showed that the blood Se and blood As level was at security scope, however, blood Pb, Cd and Hg level was too high and beyond the safety thresholds which should be concerned about. The analytical method mentioned above can be used for determination of trace elements in human blood to achieve a convenient and rapid operation and accurate result. PMID- 20828013 TI - [Analysis and comparison of trace elements of herba euphorbiae humifusae in different periods by microwave digestion-atomic absorption spectroscopy]. AB - Herba euphorbiae humifusae is the dried whole plant of Euphorbia humi fusa Willd. that belongs to euphorbiaceae. In the present paper, the microwave digestion procedure was used to digest herba euphorbiae humifusae collected in different periods, and then flame atomic absorption spectrometry (FAAS) was used to determine the contents of eight kinds of trace elements of herba euphorbiae humifusae in different periods, and the change in the contents of trace elements at different times was studied and analysed. The results showed that of all the trace elements of herba euphorbiae humifusae in different periods, element Fe was the highest in June, element K was in August at the highest level, element Mn reached the highest content in September, elements Na and Ca were dividedly at the highest content in October and November, and in December the highest content elements were Zn, Cu and Mg. In one word, the change of Na and Ca was jumping, while the change of Cu and Zn was comparatively mild. The results provide scientific basis for the time of collection of herba euphorbiae humifusae. PMID- 20828014 TI - [Determination of trace mercury in wastewater by a flow injection analysis composed of immobilized ionic liquid enrichment and colorimetric detection]. AB - Amberlite XAD-7 resin was modified by room temperature ionic liquid (1-hexyl-3 methylimidazolium hexafluorophosphate, [C6 mim]PF6) coating through a maceration method, gaining a new sort of hydrophobic adsorbent for the solid phase extraction mini-column. Trace inorganic mercury in wastewater samples was preconcentrated and determined by flow injection online mini-column sampling coupled with spectrophotometric determination. In acid medium, dithizone was employed as chelator with cetyltrimethylammonium bromide (CTMAB) to form a red neutral mercury-dithizone complex, which could be extracted quantificationally by solid phase extraction technique on the mini-column. Under the optimized conditions, the linearity and the detection limit of the proposed method were found to be 0.35 to 50.0 microg x L(-1) Hg2+ and 0.067 microg x L(-1) Hg2+, respectively. The enrichment factor of 25 times could be achieved with a 50 mL sampling volume and the developed procedure was successfully applied for the determination of mercury in the certified reference material (GSBZ50016-90) and the spiked dock wastewater samples with the recovery of 99%-103%. PMID- 20828015 TI - [X-ray fluorescence spectrum analysis of chemical element for spider and silkworm silk and its applications]. AB - Elemental compositions in spider and silkworm silks were determined by X-ray fluorescence (XRF) spectrum to probe the silk-forming mechanisms and an elemental basis for spider silk with excellent characteristics. XRF analysis demonstrates that in the silkworm silk, the elemental content is 47.10% for C, 29.92% for O and 16. 52% for N, including metal elemental contents: 0.166 2% for Ca, 0.104 0% for Mg and 0.039 5% for K, while Na, Zn, Ni, Fe and Cr show less micro quantity. Due to relative high quantity for Ca and Mg, they both play an important role in the silk-forming mechanism by silkworm. In the spider silk, the determined main nonmetal elemental contents are 44.09% for C, 26.64% for O and 22.34% for N. The high content of nitrogen may be an elemental basis for spider silk with excellent characteristic. The main metal elemental contents are 0.268 0% for Na, 0.081 4% for K and 0.011 6% for Mg, while Ca, Zn, Ni, Cu and Cr possess less micro quantity in the spider silk. Because of relative high quantity for Na and K, they both play an important role in the silk-forming mechanism by spider. The elemental compositions investigated by using mathematic statistic method are quite in agreement with those demonstrated by using XRF spectrum, which validates the experimentally determined elemental compositions in the spider and silkworm silks. PMID- 20828016 TI - [Technology and provenance of proto-porcelain of Yingguo graveyard in Henna province]. AB - Protoporcelain is a kind of multi-epoch and multi-culture-area ceramic hangover with iterative appearance, and it is the important interim of the development from pottery to porcelain. Therefore, its origin, development and prevalence problems, which relate directly to China development mode and Shang Zhou culture visage, are the important discussion of archaeology, ceramic technic history and chemistry history, and have important learning value. XRF and XRD technique were used to determine several shreds excavated from Yingguo graveyard site in Henan province. The result shows that some samples have abnormity phosphor, hinting that some plant or wood ash was ever used as raw material. From the rate of Ca/Al and P/Al and comparative analysis, we discovered that proto-porcelain of Yingguo site has different chemical character compared to south production. PMID- 20828017 TI - [Calculation of dislocation destiny using X-ray diffraction for 4H-SiC homoepitaxial layers]. AB - A theoretical and experimental study on calculating dislocation destiny for 4H SiC homoepitaxial layers has been carried out. There is some difficulty in measuring dislocation density if it is more than 10(6) * cm(-2). In the paper, a theoretical analysis is made about the effects of dislocation density on the results of X-ray diffraction, and the relationship of dislocation density and FWHM spread is obtained. Then the X-ray diffraction curves of 4H-SiC in omego2theta with two different crystal faces are presented from which the density of dislocation is calculated. According to the result, the cause of dislocation origin is analyzed and the methods of decreasing dislocation density are proposed. PMID- 20828018 TI - [A multi-phase flow detector system based on gamma-ray]. AB - In the present paper, a gamma-ray based on-line detection system was designed for multi-phase flow measurement, where the complicated fluid property of multi-phase flow can be studied by using the principle of ray transmission. The system is made up of three parts, i. e., the sensing unit, the signal conditioning & processing unit and the computer imaging unit. The sensing unit consists of five 241 Am sources with principal energy of 59.5 keV and five sets of CdZnTe semiconductor detectors by using the Geant 4 simulating software toolkits. The sources and detectors are mounted equally at the cross section of pipeline to detect different phase medium simultaneously. This function of the system guarantees the real-time performance of the on-line detecting. In order to improve the accuracy of the probe, a low noise probe circuit was designed, including a low noise charge-sensitive preamplifier, a low noise amplifier, filter circuit and an eliminated zero-poles circuit. Some of the emitted gamma ray photons from the radiation sources are detected by the sensing element, where the photo energy is transferred into electrical energy by using CdZnTe semiconductor detectors. The output of the sensing element is sent to the signal conditioning & processing unit, which is amplified and filtered to be a level discriminated signal. Finally, the output of the signal conditioning & processing unit is sent to the computer imaging unit, in which the 2D images are reconstructed by using a certain reconstruction algorithm. Under the normal temperature, the system performs the test of energy spectrum and then it has better energy resolution about 4.38% for 241 Am 59.5 keV. The result reveals that our system has higher probe accuracy. Using experimental data, the images are reconstructed with Filter back projection (FBP) reconstruction algorithm. Images of high quality are achieved. PMID- 20828019 TI - [Study on the in-depth composition of beads formed by fuse breaking of electric wire at different oxygen concentrations by Auger electron spectroscopy]. AB - The ambience has a critical effect on the characteristic of bead formed by fuse breaking of the electric copper wire in fire. In order to study the influence of oxygen concentration in surroundings on the characteristic of bead formed by fuse breaking, firstly, the oxygen concentration of typical things such as wood, paper, foam, rubber and plastic etc when they were burning was measured. The extreme conditions of oxygen concentration of typical things were ascertained when they were burning. Accordingly the oxygen concentration of simulated environment (100% N2, 10% O2 + 90% N2, and 20% O2 + 80% N2) was determined. Secondly, the in-depth composition of beads formed by fuse breaking of the electric copper wire in different circumstances was studied by AES. The relationship is almost linearity between the average oxygen concentration and the ambient oxygen concentration. Consequently, from the measured oxygen concentration, the authors can deduce the ambient oxygen concentration and the fire cause. PMID- 20828020 TI - [Lidar observations of atmospheric aerosol optical properties over Yinchuan area]. AB - A compact Mie scattering lidar system has been developed to measure the optical properties and temporal-spatial distribution of atmospheric aerosol particles and some continuous experiments were carried out over Yinchuan area (38 degrees 29'N, 106 degrees 06'E) from 1 to 10 April in 2009 for the first time. The laser located at wavelength of 532 nm was selected as the light source and the Fernald method was used to retrieve the extinction coefficient. The aerosol extinction coefficient profiles and temporal-spatial variation properties of aerosol relative density were obtained and analyzed within the whole day at one hour interval, and also an obvious sand-dust-weather process over Yinchuan area was observed and analyzed. The observation results show that the compact Mie scattering lidar is capable of measuring efficiently the optical properties and temporal-spatial distribution of aerosol particles, and the measurement result is useful for studying the variation tendency of atmospheric aerosol and sand weather of Yinchuan area. PMID- 20828021 TI - [Mass spectrometry assay for denitrifying enzyme activity measurement]. AB - Nitrification inhibitors exert inhibition function in soil nitrification process (NH4(+)-N to NO3(-)-N) and are widely applied in order to improve N fertilizer use efficiency. Before the new nitrification inhibitor is used, its effects on denitrification process must be investigated and denitrifying enzyme activity (DEA) is an effective indicator to show this process. In the present paper, a mass spectrometery (MS) method was taken to measure the denitrifying enzyme activity in the new nitrification inhibitor 3, 4-dimethylpyrazole phosphate (DMPP) incubation system. The results showed that the method measured the concentration of N2O in the incubation system accurately and the concentration measured by MS had marked correlation with that measured by gas chromatogram (GC) (MS(N2O) = -0.45 + 1.03GC(N2O, R2 = 0.995). At the same time, enrichment of 15 N2O and 15 N2 was measured to discriminate the nitrate reductase and N2O reductase. Differed with traditional method, the enzymatic inhibitor-acetylene was not appended. The results showed that DMPP had no influence on the denitrifying enzyme activity and indicated that the denitrification process was not influenced by DMPP. PMID- 20828022 TI - [Genomics, self-medication, Bophal, citizenship: why should such a mixed bag matter for the nursing profession? ]. AB - The main themes presented in this issue of AIR (the perspective of a specific role of nurses in the area of clinical genetics-genomics, the expected benefits of a self-medication practice as expression of self-determination and consciousness; the dissociation between the "evidence" of the victims of the Bophal tragic accident and the verdict which denies them "habeas corpus") are the occasion for reflecting on their apparent heterogeneity, to find common threads that could be shaped in a research agenda for the nursing profession. A supplementary provocation is proposed in a book on epidemiology and citizenship, which is the last of the themes discussed in the Editorial. PMID- 20828023 TI - [Genomics in medicine: challenges and perspectives for the nursing care]. AB - INTRODUCTION: The acknowledgment of the genetic component in the majority of pathologies, not only hereditary or oncological, and of the individual biological responses to therapies and in infectious diseases, is now granted. AIMS: The current developments of the genomic fuel new expectations on the modification of medical approach to prevention, diagnosis and therapy of main pathologies, through diagnostic genetic tests, predictive tests and new drugs, towards a "personalized medicine". RESULTS: However, the introduction of the desired benefits to medicine and care derived from this knowledge requires the awareness of health operators of the ethical, social and economical implications of genetics and the estimated risks and opportunities of the genetic information. Nurses should update their knowledge and acquire new competencies in genetics, to be able to answer the new questions that the patients place, especially when affected by genetic diseases. This article offers an update on the practical implications of the genomic knowledge on genetic testing, pharmacogenomics, genetic therapy, determination of the genetic risk and on the role of the genetic nurse. PMID- 20828024 TI - [Adverse drug reactions in emergency department]. AB - INTRODUCTION: Adverse drug reactions (ADR) are among the reasons of admission to Emergency departmens (ED), specifically in elderly people. AIM AND METHOD: To analyze the literature to report the main information on ADR in emergency departments and to describe the most common treatments. RESULTS: The number of patients admitted to ED for an ADR ranges from 0.6 to 3.6%. The most commonly agreed on and aspecific treatments performed are forced diuresis, urine acidification, bowel irrigation and haemodialysis. CONCLUSIONS: The number and characteristics of ADR may be a useful guide for health care professionals in EDs. PMID- 20828025 TI - [Urinary tract infections catheter associated]. AB - Catheter associated urinary tract infections are unfortunately common, both in hospitals and nursing homes. Physiopathology and the most effective prevention techniques are presented and discussed according to the most recent literature and guidelines. PMID- 20828026 TI - [The Bhopal tragedy 25 (10+15) years after]. AB - Almost 25 years have passed after the world's worst industrial accident: methylisocyanate gas leaked from a pesticide plant owned by the US company, Union Carbide (UC), into a densely populated area of Bhopal, in central India killing than 10000 people, and making hundreds of thousands disabled. After the recent and very mild sentence against Union Carbide against 7 administrator of UC (2 years of jail and a fine of little more than 2000 euros), a contribution published 10 years after the tragedy, that documented the efforts done and problems encountered in assessing responsibilities and setting up networks able to permanently document deaths, disabilities and suffering of people involved. PMID- 20828027 TI - [A conceptual and operational framework for an epidemiology of citizenship]. AB - "Epidemiology of citizenship" is the challenge of a multidisciplinary group of clinicians, epidemiologists, social workers that, with this book, try to approach problems implementing a cross-fertilization of methods, approach, languages and interventions across the different disciplines. The introduction of the book is proposed where its background and philosophy are presented and discussed. PMID- 20828028 TI - The next step: framing the progress. PMID- 20828029 TI - Rural health: the startling statistics. PMID- 20828030 TI - Rural America: look beyond the images. PMID- 20828031 TI - Rural renaissance or death throes? Ultimately, rural advocates are key. PMID- 20828032 TI - The rural route to health care. Where mission, neighbor intersect. PMID- 20828033 TI - Rural health reform needs its own Rx. Much left out of the bill. PMID- 20828034 TI - Critical access hospitals: Catholic social teaching in action. PMID- 20828035 TI - Small rural hospitals help keep cost of system's health care in check. PMID- 20828036 TI - How to grow a rural IT network. Steps along the way. PMID- 20828037 TI - Nurturing work and family life in rocky rural soil. PMID- 20828038 TI - When there's no place to turn. Mental health services are a critical rural need. PMID- 20828039 TI - Health care ethics and rural life. Stigma, privacy, boundary conflicts raise concerns. PMID- 20828040 TI - Making a difference close to home: a rural executive knows her turf. PMID- 20828041 TI - The little hospital that could: Lakewood helps power a region. PMID- 20828042 TI - On the road again: Every year thousands of Kentuckians depend on Saint Joseph Hospital for mobile health care. PMID- 20828043 TI - Women's center brings urban services to rural areas. PMID- 20828044 TI - Trauma network comes to Kentucky: CHP leader a driving force. PMID- 20828045 TI - Catholic health care. The ministry's future in a turbulent world. PMID- 20828046 TI - Saint Alphonsus trains to remain. PMID- 20828047 TI - The work ahead. Bring Catholic social teaching back into health reform. PMID- 20828048 TI - We call for your thoughts. The catholic mission of long-term care. PMID- 20828049 TI - Sailing into the future. Nautical theme helps set hospital's course. PMID- 20828050 TI - Shine on. New lighting control technologies increase efficiencies and lower costs. PMID- 20828051 TI - Renovate or replace? Advice on making the billion-dollar decision. PMID- 20828052 TI - Furniture factors. Hospital demand drives product attributes. PMID- 20828053 TI - Shock proof. Complying with lockout/tagout regulations. PMID- 20828054 TI - Clean seating. Selecting and maintaining hospital upholstery. PMID- 20828055 TI - [Itching papules and pustules . Here the domestic animal had to be treated, too]. PMID- 20828056 TI - [Germany's Novartis Chief proposes "More competition through decentralized contracts"]. PMID- 20828057 TI - [Swollen muscles, penis atrophy, gynecomastia ... doping-sin]. PMID- 20828058 TI - [From erysipelas to paronychia: emergency skin infections]. PMID- 20828059 TI - [Nightly hypoxia influences the metabolism. Which is why good sleep is so important for diabetics]. PMID- 20828060 TI - [Type-2 diabetics need individualized diet advice. No evidence for culinary sadism]. PMID- 20828061 TI - [Venous diseases]. PMID- 20828063 TI - [Why patients see their doctor]. PMID- 20828062 TI - [Patient righ-sided heart decompensation. However, the reason was not the heart]. PMID- 20828064 TI - [Paleness and fatigue]. PMID- 20828065 TI - [Incidental finding: increased cholesterol level]. PMID- 20828066 TI - [Hair loss in women]. PMID- 20828067 TI - [External otitis and otitis media: diagnostics and treatment]. PMID- 20828068 TI - [IGOST guideline for pharmacotherapy of low back pain]. PMID- 20828069 TI - [Blood pressure variability--a neglected risk factor]. PMID- 20828070 TI - [The transdermal 7-day buprenorphine patch--an effective and safe treatment option, if tramadol or tilidate/naloxone is insufficient. Results of a non interventional study]. PMID- 20828071 TI - Enhancing objectivity in pastoral education: use of standardized patients in video simulation. AB - Measurement of student learning outcomes in clinical pastoral education has historically been assessed through student self-report instruments and subjective evaluation by CPE supervisors. Valid quantitative measurement is limited. This study utilizes standardized patients and a behavioral interview checklist to measure the impact of an initial summer unit of CPE training. Results demonstrate measurable change in student interview style behavior suggesting that simulation utilizing standardized patients is a valid objective measure of students' behavioral communication styles. PMID- 20828072 TI - Exploring the meaning and role of spirituality for women survivors of intimate partner abuse. AB - Literature on trauma, coping and spirituality has introduced new questions about protective factors in the healing process for intimate partner abuse survivors (IPA). This qualitative study explores the relationship between spirituality and IPA with three focus groups of twenty-two women IPA survivors residing in a shelter. A content analysis revealed central themes that explicate the meaning and role spirituality plays for participants. Viewed as a salient dimension, spirituality provides strength, influences outcomes and assists in the regulation of behavioral responses in a positive manner in terms of participants' traumatic IPA victimization. Practice implications are discussed. PMID- 20828073 TI - 2009 Spiritual Care Collaborative survey results on continuing education. AB - Continuing education for chaplains, pastoral counselors and clinical pastoral educators is important for maintaining and advancing professional competency. Pastoral professionals who visited the Spiritual Care Collaborative (SCC) website to register for a conference were asked to complete a questionnaire on continuing education. Results of the survey show that continuing education, both in-person and through electronic means, were clearly ranked as the most important activities the SCC partner organizations could provide in the future. Additionally, continuing education preferences vary depending upon constituent groups. These findings have implications for the design of future educational programs. PMID- 20828074 TI - Defining and advocating for spiritual care in the hospital. AB - A definition of spiritual care and attention to the scientific literature can strengthen the advocacy efforts of hospital funded chaplaincy programs. Adapting Pargament's work, spiritual care is defined here as giving professional attention to the subjective spiritual and religious worlds of patients, worlds comprised of perceptions, assumptions, feelings, and beliefs concerning the relationship of the sacred to their illness, hospitalization, and recovery or possible death. Results from the scientific literature are then presented in response to four advocacy related questions: 1) How do hospital decision makers and chaplains perceive the experience of hospitalization, 2) Does a need for spiritual care exists; is it relevant, 3) Who can best provide spiritual care, and 4) Are chaplain visits helpful? This definition and advocacy material can be useful when decision makers review the funding of spiritual care. PMID- 20828075 TI - The impact of pastors' spiritual practices on burnout. AB - This qualitative study addressed two research questions (a) what spiritual practices contribute to pastors' emotional and spiritual well-being?, and (b) what factors contribute to pastoral burnout? Based on an inductive analysis of eight pastoral interviews, the study revealed that these spiritual leaders engage in specific spiritual disciplines that contribute to their sense of well-being. The implications of this study prompt further research into the relationship between leaders' spiritual practices and burnout. PMID- 20828076 TI - "Posthumous disillusionment" as a type of complicated grief. AB - This article develops a theoretical concept that delineates the experience of disillusionment toward a deceased loved-one during the grieving process. Through clinical anecdote, film and autobiography, possible therapeutic initiatives are identified which may provide pastoral and clinical approaches to assist those whose grief is complicated by distressing and unexpected revelations requiring a reevaluation of their relationship with the loved-one who has died. PMID- 20828077 TI - A modern voice: contemporary psalms of grief and lament. PMID- 20828078 TI - Sitting next to Jesus on Sunday. PMID- 20828079 TI - My night with Ray the cabdriver. PMID- 20828080 TI - Blessings in disguise. PMID- 20828081 TI - Weep with those who weep: a CPE resident's reflection. PMID- 20828082 TI - One last dance. PMID- 20828083 TI - Living in a time of disasters. PMID- 20828084 TI - Preparing for disaster deployment: suggestions for the disaster responder. AB - The purpose of this article is to help disaster relief workers to adequately prepare for responding to a disaster. It is intended to be a practical guide based on the author's many experiences in providing relief work throughout the world. This article addresses physical and mental health, personal safety, comfort and communication needs. PMID- 20828085 TI - Disaster non-preparedness: the orange bag denial. AB - If denial exists anywhere, it exists here. The seemingly unconscious process of refusing those implements of survival that might be needed during a disaster scenario because acceptance also means acceptance of the likelihood of a disaster occurring, is the focus here. Disasters do and will occur. Refusal of the implements of survival denies that reality. Acceptance confirms it. Perhaps acknowledgement of this process will impact the individual's frame of reference or psychological structuring, and thereby affect observed behavior (Sherif& Sherif 1956). PMID- 20828086 TI - On-scene crisis intervention: psychological guidelines and communication strategies for first responders. AB - Effective emergency mental health intervention for victims of crime, natural disaster or terrorism begins the moment the first responders arrive. This article describes a range of on-scene crisis intervention options, including verbal communication, body language, behavioral strategies, and interpersonal style. The correct intervention in the first few moments and hours of a crisis can profoundly influence the recovery course of victims and survivors of catastrophic events. PMID- 20828087 TI - The use of psychological first aid (PFA) training among nurses to enhance population resiliency. AB - Disaster mental health research has found that psychological casualties from a given disaster can be expected to far outnumber physical casualties. Amidst a shortage of mental health professionals and against the backdrop of natural disasters, continued terrorism, and pandemic influenza, there is a striking need to expand and operationalize available human resources to enhance the psychological resiliency of those affected. Through the utilization of psychological first aid (PFA) as an early crisis intervention tool, and by virtue of their occupation and experience, nurses are particularly well-suited to assume a leadership role in expanding the disaster mental health presence beyond the existing cadre of mental health clinicians. Here, we characterize the importance of integrating PFA in the context of other nursing functions, to augment mental health surge capacity in disaster settings. PMID- 20828088 TI - Training community therapists to deliver cognitive behavioral therapy in the aftermath of disaster. AB - In this paper we examine the effectiveness of disseminating Cognitive Behavioral Therapy for Postdisaster Distress (CBT-PD) to community therapists in Baton Rouge, Louisiana following Hurricane Katrina. One hundred four therapists attended a two-day training in CBT-PD with on-going case consultation. Pre- and post-training, therapists rated eight core cognitive behavioral therapy elements on their importance, how well they understood how to deliver the element, and how confident they were in their ability to deliver the element. Post-training they completed a CBT-PD knowledge questionnaire and session fidelity forms. Seventy seven clients completed satisfaction questionnaires and reported on how often they utilized the skills taught in CBT-PD. Therapists showed significant improvements in their ratings of the importance of various elements of cognitive behavioral therapy, their knowledge and understanding of those elements, and their confidence that they could use them effectively. Immediately following the training 90% of therapists demonstrated excellent retention of CBT-PD. Self report measures from both therapists and clients indicated that critical session elements were delivered. This work suggests that CBT-PD can be applied in a real world setting and that community therapists can be trained in relatively short time spans with on-going support. This finding is especially important in the disaster field given that communities are likely to find themselves in emergency situations in which a number of non-expert trauma therapists will need to deliver trauma services. PMID- 20828089 TI - Treatment of PTSD in Rwandan child genocide survivors using thought field therapy. AB - Thought Field Therapy (TFT), which utilizes the self-tapping of specific acupuncture points while recalling a traumatic event or cue, was applied with 50 orphaned adolescents who had been suffering with symptoms of PTSD since the Rwandan genocide 12 years earlier. Following a single TFT session, scores on a PTSD checklist completed by caretakers and on a self-rated PTSD checklist had significantly decreased (p < .0001 on both measures). The number of participants exceeding the PTSD cutoffs decreased from 100% to 6% on the caregiver ratings and from 72% to 18% on the self-ratings. The findings were corroborated by informal interviews with the adolescents and the caregivers, which indicated dramatic reductions of PTSD symptoms such as flashbacks, nightmares, bedwetting, depression, isolation, difficulty concentrating, jumpiness, and aggression. Following the study, the use of TFT on a self-applied and peer-utilized basis became part of the culture at the orphanage, and on one-year follow-up the initial improvements had been maintained as shown on both checklists. PMID- 20828090 TI - A time for renewal: a lessons-learned review on the role of CISM in caring for missionaries after the Rwandan genocide. AB - In 1994 more than 800,000 people were killed in the Rwandan genocide. Seventh Day Adventist missionaries were forced to evacuate the country under conditions of extraordinary stress and personal threat. Their Church was faced with the necessity of rapidly developing a spectrum of support services to assist the distressed missionaries and their family members in the immediate aftermath of the catastrophe. Individual missionaries, and sometimes their entire family units, had witnessed horrific atrocities perpetrated against members of their congregations and the general public. In some situations of their own church members actively participated in the murders. Church leaders combined their efforts with the resources of the International Critical Incident Stress Foundation to provide immediate, multifaceted support services to the missionaries and their families. This article briefly describes the breadth and depth of the specific Critical Incident Stress Management (CISM) program that was developed and provided to Rwandan Seventh Day Adventist missionaries in April of 1994. The results of a brief post-support evaluation survey are presented. PMID- 20828091 TI - Post-action staff support for the Concerns of Police Survivors Organization (COPS). AB - This concept article presents an overview of a post-action staff support (PASS) session that has been effective in meeting many of the emotional needs of a large, diverse group of volunteers who serve as support personnel for grieving family members, significant others, and co-workers at the annual National Police Survivors Conference in the Washington, DC area. This particular approach to the PASS process is not a fixed, rigid approach. Instead, it is adaptable and flexible and it can be altered as necessary to suit specific populations with special needs. The key elements of the two-hour PASS session have evolved over many years to the current form presented in this article. PMID- 20828092 TI - Urban high school students can successfully screen for high blood pressure in their community. PMID- 20828093 TI - Increasing prevalence of high blood pressure in lean rural populations in sub saharan Africa: is high salt consumption a contributing factor? PMID- 20828094 TI - Elevated risk of type 2 diabetes and metabolic syndrome among Asians and south Asians: results from the 2004 New York City HANES. AB - OBJECTIVE: Although numerous studies have identified an elevated risk of diabetes or impaired fasting glucose among Asians, there are limited data examining variability in risk among Asian subpopulations. We estimated prevalence of diabetes (DM), metabolic syndrome (MS) and impaired fasting glucose (IFG), by race/ethnicity and by Asian subgroup. DESIGN, SETTINGS AND PARTICIPANTS: This study was conducted using the fasting subsample of the 2004 New York City Health and Nutrition Examination Survey (NYC HANES; n = 1,324), a local version of the NHANES. Using country of origin information, we constructed South Asian and other Asian categories. MAIN OUTCOME MEASURES: DM, MS and IFG. RESULTS: Age standardized prevalence estimates of DM, MS and IFG were 10.8%, 13.3% and 21.4% among Whites, 16.1%, 12.0% and 32.4% among all Asians, and 35.4%, 17.7% and 15.9% among foreign-born South Asians, respectively. After adjusting for potential confounders, Asians had significantly higher odds of prevalent IFG (Adjusted odds ratio [AOR]:2.64; 95% confidence interval [CI]: 1.60-4.38) and MS (AOR:2.09; 95%CI: 1.19-3.68), compared to Whites. South Asians were more likely to have DM (AOR:4.88; 95%CI: 1.52-15.66) and MS (AOR:5.59; 95%CI: 1.69-18.50) compared to Whites, while other Asians were at increased prevalence of IFG (AOR:2.89; 95%CI: 1.65-5.07). CONCLUSION: Our findings suggest that the observed White/Asian disparity in DM risk may be primarily attributable to elevated risk among South Asians. PMID- 20828095 TI - Sex and age differences in the association of obesity and smoking with hypertension and type 2 diabetes in Southern California American Indians, 2002 2006. AB - OBJECTIVE: Assess age and sex differences in the association of obesity and smoking with diabetes and hypertension and report the prevalence of these cardiovascular disease (CVD) risk factors in Southern California American Indian/Alaska Native (AlAN) adults. DESIGN: Cross-sectional study. SETTING: Visit data from 2002-2006 were extracted from one Southern California AlAN health clinic system. PARTICIPANTS: 10,351 AIAN adults visiting the health clinic system. MAIN OUTCOME MEASURES: Odds ratios were examined to assess the association of obesity and smoking with diabetes and hypertension and prevalence rates for obesity, smoking, diabetes, and hypertension were reported. RESULTS: Obesity (women: 53%, men: 55%), smoking (women: 16%, men: 18%), diabetes (women: 14%, men: 16%), and hypertension (women: 32%, men: 37%) were very prevalent. For women aged -35 years, increasing obesity was significantly associated with diabetes. For men aged -25 years, morbid obesity and smoking were significantly associated with diabetes for many age groups. Increasing overweight/obesity and smoking were associated with hypertension among adults aged 18-65 years. CONCLUSIONS: Southern California AIANs had higher obesity, diabetes, and hypertension prevalence than the general Southern California population, and higher obesity prevalence compared to other AIANs. Highly prevalent risk factors create a great burden, as CVD is the leading cause of death among AIAN adults. AIANs are diverse and need interventions tailored to cultural customs and health problems most prevalent in each tribal community. PMID- 20828096 TI - Associations between mental health and diabetes: findings from the South Carolina Medicaid managed care program in 2006-2008. AB - OBJECTIVES: To assess differences in services associated with mental health status and prescriptions among Medicaid patients diagnosed with diabetes mellitus. DESIGN: Secondary data analyses of South Carolina (SC) Medicaid enrollees. PARTICIPANTS: SC Medicaid enrollees with a diagnosis of diabetes mellitus (N = 555) continuously enrolled in either managed care (MC) or fee for service (FFS) programs between 2006 and 2008. MAIN OUTCOME MEASURES: Health Plan Employer Data and Information Set (HEDIS)-based diabetes management service outcomes including: 1) whether the recipient received a nephrology exam; 2) the number of eye exams received; 3) the number of low-density lipoprotein cholesterol services received; and 4) the number of Hemoglobin A1c blood tests conducted. Outcomes were fitted to regression models adjusting for sex, race, health program provider type (MC or FFS), rurality, poverty indexes, clinical risk group status, whether there was a female head of household, and indicators for classes of prescription pharmaceuticals (antipsychotics, antidepressants, and anticonvulsants). RESULTS: There are significant differences in the incidence of diabetes management service-use between enrollees in management plans and between recipients of classes of pharmaceuticals and mental health status. Enrollees in FFS have fewer claims associated with diabetes management services compared to counterparts in MC. CONCLUSIONS: Our early findings demonstrate the importance of efforts to collect HEDIS measures data and their potential as a resource for assessing quality of care. More importantly, this study illustrates the association between mental health status and associated pharmaceutical prescriptions. PMID- 20828097 TI - Racial and ethnic differences in weight management behavior by weight perception status. AB - OBJECTIVE: To examine racial/ethnic differences in the relationship between weight perception and weight management behaviors among overweight and obese adults. PARTICIPANTS: The study examined a nationally representative sample of 11,319 non-Hispanic White, non-Hispanic Black and Mexican American overweight and obese adults aged > or = 20 years from the 1999-2006 National Health and Nutrition Examination Survey. DESIGN: Body mass index (BMI, defined as weight in kilograms divided by height in meters squared) was used to categorize overweight (25 < or = BMI < 30) and obesity (BMI > or = 30). Measured height and weight were used to calculate BMI. Subjects reported self-perception of weight status (correct perception and misperception) and weight management behaviors over the previous 12 months (trying to lose weight, trying not to gain weight, and having a desired weight goal). Weight perception stratified logistic regression was used to model odds of weight management behavior by race/ethnicity. RESULTS: Among overweight and obese non-Hispanic White, non-Hispanic Black, and Mexican American adults, correct weight perception was positively associated with weight management behavior. In multiple logistic regression models, overweight non Hispanic Blacks with a weight misperception were less likely to have tried to lose weight (adjusted odds ratio [aOR] = .7; 95% confidence interval [Cl] = .5,1.0) or to have tried not to gain weight (aOR = .7; 95% CI = .5,1.0) compared to overweight non-Hispanic Whites with a weight misperception. Among the obese with a misperception, non-Hispanic Blacks were less likely to desire to weigh less compared to non-Hispanic Whites (aOR = .5; 95% CI = .3,.9). CONCLUSIONS: Weight perception was associated with weight management behaviors, and this relationship varied by race/ethnicity. Weight perception may need to be addressed among overweight and obese individuals to increase appropriate weight management behaviors, particularly among minority communities. PMID- 20828098 TI - Urbanicity affects blood pressure and heart rate reactivity to a speech stressor in Cameroon. AB - OBJECTIVE: To examine the interactive influence of urbanicity on cardiovascular reactivity to speech stressors among 103 urban and 93 rural Cameroonians. METHOD: Heart rate, systolic, and diastolic blood pressure (HR, SBP, and DBP) changes from baseline were assessed during a speech preparation period, speech stressor task, and post-speech recovery period. RESULTS: After adjusting for income, age, BMI, and sex, urban subjects showed greater diastolic reactivity to the pre speech and speech conditions than to recovery. Urban subjects also showed greater reactivity to the speech stressor than to other conditions. Urban subjects showed greater HR reactivity to the speech stressor. Rural subjects showed greater diastolic reactivity to the pre-speech and speech stressor and less recovery. CONCLUSION: Urbanicity affects blood pressure and heart rate differently for urban and rural Cameroonians. It also affects recovery from stressors. More exploration into the influence of urbanization on hypertension risk factors in developing countries is warranted. PMID- 20828099 TI - Determinants of carotid atherosclerosis in the general Mongolian population. AB - OBJECTIVE: Atherosclerotic risk factors contribute to carotid atherosclerosis. Carotid intima-media thickness (IMT), as assessed using a non-invasive high resolution ultrasound, can predict cardiovascular disease (CVD). Whereas the control of CVD is crucial for the Mongolian people, the studies on carotid atherosclerosis are lacking. The present population-based survey was a cross sectional investigation of the determinants of carotid IMT in the general Mongolian population. METHODS: A total of 344 Mongolian volunteers, aged 18 to 69 years, without CVD and on no medication, were recruited from a health screening setting. The current smoking habits, body mass index, mean blood pressure (MBP), blood total cholesterol (TC), glucose, insulin and carotid IMT (maximum level) were measured. RESULTS: Mongolian males had a significantly higher prevalence of current smoking and a higher level of IMT than females (average = .58 mm in males vs .46 in females). Both a single and multiple regression analysis adjusted for all the measures revealed that IMT was significantly and positively correlated with age, male sex, MBP, TC and glucose among all of the participants. IMT was significantly and positively correlated with age, followed by MBP, TC and glucose among males, while among females, IMT was significantly and positively correlated with age, followed by MBP and TC. CONCLUSIONS: Age was the strongest determinant of carotid atherosclerosis, and the increases in blood pressure and cholesterol levels were also important measures in both sexes as well as glucose levels in males in particular, thus suggesting a preventive strategy for CVD in the general Mongolian population. PMID- 20828100 TI - Racial and ethnic differences in preterm delivery among low-risk women. AB - BACKGROUND: Preterm delivery is the leading cause of infant mortality in the United States. The risk of preterm delivery and the prevalence of factors associated with preterm delivery differ by racial and ethnic groups. OBJECTIVE: To examine racial and ethnic differences in preterm delivery among women without the common risk factors for preterm delivery. METHODS: We used data from the Pregnancy Risk Assessment Monitoring System (PRAMS) for singleton births occurring in selected US states between 1988 and 2002. PRAMS is a cross-sectional study of state residents who delivered a live birth within the state. We defined risk status using maternal age, education, marital status at delivery, parity, interpregnancy interval, tobacco or alcohol use, source and amount of income, and pre-pregnancy body mass index. RESULTS: Only 9.6% (18,815) of women were low risk. Between 2.4% (Native Americans) and 12.4% (Asian-Pacific Islanders) were low risk. Low-risk women were 29.0% (95% CI: 23.0%, 34.0%) less likely to deliver preterm than non-low-risk women. Among low-risk women, African American women had more preterm births than White women (PR: 1.3, 95% CI: 1.0, 1.6), but only among multiparous women whose most recent prior birth was neither low birth weight nor preterm. CONCLUSIONS: Traditional risk factors explain about half of the excess prevalence of preterm births among African Americans and explain all of the excess among other racial and ethnic groups. The remaining excess among African American appears to be due to risk factors among multiparous women that occur between pregnancies. PMID- 20828101 TI - Healthy aging in neighborhoods of diversity across the life span (HANDLS): overcoming barriers to implementing a longitudinal, epidemiologic, urban study of health, race, and socioeconomic status. AB - OBJECTIVE: Examine the influences of race, socioeconomic status, sex, and age on barriers to participation in a study of cross-sectional differences and longitudinal changes in health-related outcomes. METHODS: We designed a multidisciplinary, community-based, prospective longitudinal epidemiologic study among socioeconomically diverse African Americans and Whites. We recruited 3722 participants from Baltimore, Md. with a mean age of 47.7 (range 30-64) years, 45% males; 2200 African Americans (59%) and 1522 whites (41%); 41% reported household incomes below the 125% poverty delimiter. RESULTS: There were no significant age differences associated with sex or race. Participants below the 125% poverty delimiter were slightly younger than those above the delimiter. Age, race, and sex, but not poverty status, were associated with the likelihood of a physical examination. Older participants, women, and Whites were more likely to complete their examinations. Among those who completed their examinations, there were no age differences associated with sex and poverty status, but African Americans were negligibly younger than Whites. CONCLUSIONS: Although some literature suggests that minorities and low-income people are less willing to participate in clinical research, these baseline data suggest that African Americans individuals and individuals from households with incomes below 125% of the poverty level are at least as willing to participate in observational clinical studies as Whites and higher income individuals of similar age and sex. PMID- 20828102 TI - Randomized trial using hair stylists as lay health advisors to increase donation in African Americans. AB - OBJECTIVE: To test the efficacy of using hair stylists as lay health advisors to increase organ donation among African American clients. DESIGN: This study was a randomized, controlled intervention trial where we randomized 52 salons (2,789 clients) to receive a 4 session, stylist-delivered health education program (comparison) or a four session brief motivational intervention that encouraged organ donation (intervention). Intervention stylists received a four-hour training in organ donation education and counseling. Organ donation was measured by self-report questionnaire at 4-month posttest as well as by verified enrollment in the Michigan Organ Donor Registry. SETTING: Hair salons in Michigan urban areas. PARTICIPANTS: Blacks (n = 2,449), non-Blacks (n = 261) in Michigan. MAIN OUTCOME MEASURES: Self-reported donation status, registration in Michigan Organ Donor Registry. RESULTS: At posttest, rates of self-reported positive donation status were 19.8% in the intervention group and 16.0% in the comparison group. In multivariate analyses, intervention participants were 1.7 times (95% Cl = 0.98-2.8) more likely than comparison participants to report positive donation status at posttest. Based on verified organ registry data, enrollment rates were 4.8% and 2%, respectively for the intervention and comparison groups. In multivariate analyses, intervention group members were 4.4 (95% CI = 1.3-15.3) more likely to submit an enrollment card than comparison participants. CONCLUSION: Clients of hair stylists trained to provide brief motivational intervention for organ donation were approximately twice as likely to enroll in the donor registry as comparison clients. Use of lay health advisors appears to be a promising approach to increase donation among African Americans. PMID- 20828103 TI - Trust in physicians and blood pressure control in blacks and whites being treated for hypertension in the REGARDS study. AB - OBJECTIVES: Among persons treated for hypertension, Blacks are more likely to have uncontrolled blood pressure compared to Whites. Few studies have focused on trust in physicians as a potential contributor to this disparity in blood pressure (BP) control. The primary objective of this study was to assess the relationship between trust in physicians and blood pressure control among Blacks and Whites being treated for hypertension. DESIGN: Cross-sectional analysis of baseline data collected from the REasons for Geographic And Racial Differences in Stroke cohort, a US national, population-based cohort study. Participants were recruited by telephone from 2003-2007, completed a telephone survey, and had BP measured during an in-home visit. PARTICIPANTS: 2843 Black and White adults aged > 45 years with treated hypertension. MAIN OUTCOME MEASURES: Uncontrolled blood pressure was defined as systolic blood pressure > 140 mm Hg or diastolic blood pressure > 90 mm Hg. For participants with diabetes, renal disease, or self reported previous myocardial infarction, uncontrolled blood pressure was defined as systolic blood pressure > 130 mm Hg or diastolic blood pressure > 80 mm Hg. RESULTS: Trust in physicians was not associated with uncontrolled blood pressure in either unadjusted (odd ratio [OR] 1.07; 95% confidence interval [CI) 0.92, 1.25) or adjusted analyses (OR 0.97; 0.83, 1.14). Both Black race (OR 1.58; 1.36, 1.84) and imperfect medication adherence (OR 1.56; 1.31,1.86) were associated with higher odds of uncontrolled blood pressure. CONCLUSIONS: Trust in physicians was not related to blood pressure control among Blacks and Whites with treated hypertension in this sample. The racial disparity in blood pressure control was not completely explained by trust in physicians or medication adherence, and a better understanding of the mechanisms leading to this disparity is needed. PMID- 20828104 TI - Racial disparities in access to health care and preventive services between Asian Americans/Pacific Islanders and Non-Hispanic Whites. AB - OBJECTIVE: Large-scale comparison and comprehensive estimate on the access to health care and preventive services between Asian Americans/Pacific Islanders (AAPIs) and Non-Hispanic Whites (NHWs) has not been available. This study examines the racial disparities in access to health care and preventive services between AAPIs and NHWs in the USA. METHODS: Cross-sectional study of access to health care and preventive services among AAPIs compared to NHWs, using data from Behavioral Risk Factor Surveillance System 2005 to 2007 among 908,154 respondents aged > or = 18 years. RESULTS: The percentages of AAPIs (aged > or = 18 years) who reported having a personal healthcare provider, a Pap test (women aged > or =18), a fecal occult blood test (aged > or = 50) a sigmoidoscopy/colonoscopy (aged > or = 50), a PSA test (men aged > or = 40), blood cholesterol checked (aged > or =18 yrs), and pneumococcal vaccination (aged > or = 65 yrs) were 76.7%, 83.1%, 27.5%, 47.5%, 35.5%, 74.2%, and 51.2%, respectively. Compared to NHWs, AAPIs were significantly less likely to have a personal health care provider (adjusted odds ratio: 0.69 [95% confidence interval: 0.63-0.75]), a Pap test (0.18 [0.13-0.28]), a fecal occult blood test (0.50 [0.39-0.631), a sigmoidoscopy/colonoscopy (0.64 [0.50-0.81]), a PSA test (0.35 [0.26-0.47]), blood cholesterol checked (0.71 [0.64-0.80]), and pneumococcal vaccination (0.52 [0.42-0.65]). CONCLUSION: This study suggests that disparities exist between AAPIs and NHWs in 1 of 4 selected health care access indicators and 6 of 8 selected preventive services. PMID- 20828105 TI - Race and preterm birth--the case for epigenetic inquiry. AB - Preterm birth and infant mortality disproportionately affect African American families compared to White families. More than 18% of African American infants are born preterm (< 37 weeks' gestation) compared to just less than 12% of White infants. Consequently, African American infants are twice as likely to die in their first year of life as White infants. Differences in socioeconomic status, prenatal care usage, and behavioral characteristics fail to explain the disparity in preterm birth between African Americans and Whites. Epidemiologic data support a life-course conceptual model for African American women's pregnancy disadvantage. Life-course factors influence pregnancy outcomes through two proposed mechanisms: early-life (fetal) programming of reproductive potential and cumulative wear and tear (weathering). The biologic mechanisms behind this theory are poorly understood. In this commentary, we argue that epigenetic inquiry represents the next frontier in investigating the mechanisms underlying racial disparities in birth outcome. We propose this with the hope that these discoveries will lead to opportunities for interventions and ultimate improvements in birth outcomes. PMID- 20828106 TI - Type 2 diabetes epidemic in First Nations people of Canada. AB - Diabetes is a chronic condition that results in the body's inability to either produce or respond to insulin. Abnormal insulin production and sensitivity lead to improper blood glucose levels and energy storage required for homeostatic organ maintenance. Over 151 million people worldwide, including 7% of the US and 5% of Canadian populations have been diagnosed with diabetes, and the prevalence varies greatly by race and ethnicity. However, since the end of World War II, the people with the greatest risk include First Nations people, including Canada's aboriginal, Inuit and Native Indian populations with up to a 5-fold greater prevalence than the general population. Prevalence can vary from 8% to 48% among the sexes and tribes. Understanding the prevalence and causes of this epidemic is immediately needed as diabetes precedes various other endocrine and cardiovascular diseases. Here we review the current understanding of diabetes risk in Canada's First Nations people in the hope to bring greater awareness among healthcare professionals and implementation of measures to prevent spread of this disease. PMID- 20828107 TI - Disparities and social inequities: is the health of African American women still in peril? AB - An amalgam of health concerns differentially affects the behavioral, psychological, and physical well-being of African American women. These disparities are both the result of, and contributors to, marked differences in the perception, interpretation and treatment of various psychological disorders and chronic medical conditions. Data show that African American women are diagnosed with more chronic and debilitating illnesses than found in the general population, and are often misdiagnosed with a myriad of psychiatric and medical disorders. Despite these findings, ambiguity remains about the contextual factors that affect the physical and mental well-being of African American women. The focus of this review was not to describe all psychological or medical conditions with deleterious outcomes among African American women, but rather collectively address identified mental and physical health issues prevailing among African American women. This approach addresses the urgent need to better understand the health needs of African American women in the United States, and demonstrates how advancing our knowledge of this marginalized group may lead to sustaining mental and physical health-related dialogue, while advancing policy. PMID- 20828108 TI - For the patient. Racial and ethnic differences in preterm delivery among very low risk women. PMID- 20828109 TI - For the patient. Study recruitment efforts successful for low-income populations. PMID- 20828110 TI - Newly identified genes influence insulin and glucose regulation. PMID- 20828111 TI - Exploring the binding site of C-terminal hsp90 inhibitors. AB - The 90 kDa heat shock protein (Hsp90) is a prominent target for anticancer drug discovery. While its N-terminal domain has been widely exploited, several lines of evidence are emerging in favor of targeting its C-terminal domain to conceive innovative drugs based on perturbation of the dimer interface. Here, we describe the application of several computational approaches useful to predict the location of the C-terminal binding site. PMID- 20828112 TI - Surfactin activity depends on the membrane dipole potential. AB - The effect of dipole modifying agents phloretin and RH 421 on the membrane conductance induced by surfactin, a lipopeptide antibiotic from Bacillus subtilis, was studied. Surfactin added on both sides of a bilayer formed from diphytanoylphosphocholine in 1 M KCl (pH 6.5) leads to the formation of voltage independent channels of different conductance levels. The conductance of different states of SA channels varies from tens of picosiemens for small pores up to tens of nanosiemens for large ones. Small channels demonstrate pronounced cationic selectivity, whereas large ones practically lose their K(+)/Cl(-) selectivity, most probably because of their large effective radii. The addition of phloretin to the bilayer bathing solution, the agent known to decrease the membrane dipole potential, results in a decrease in the surfactin-induced membrane conductance. At the same time, increasing the membrane dipole potential because of the introduction of RH 421 leads to a rise in the steady-state conductance. Increasing dipole potential is accompanied by increases in both the number of open channels and their conductance. The observed changes in the channel-forming activity of surfactin might be caused by varying the partition coefficient of lipopeptide between the lipid and aqueous phases. PMID- 20828113 TI - (2)H,(15)N-substituted nitroxides as sensitive probes for electron paramagnetic resonance imaging. AB - Electron paramagnetic resonance imaging (EPRI) using nitroxides is an emergent imaging method for studying in vivo physiology, including O(2) distribution in various tissues. Such imaging capabilities would allow O(2) mapping in tumors and in different brain regions following hypoxia or drug abuse. We have recently demonstrated that the anion of 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl (2) can be entrapped in brain tissue to quantitate O(2) concentration in vivo. To increase the sensitivity of O(2) measurement by EPR imaging, we synthesized 3 carboxy-2,2,5,5-tetra((2)H(3))methyl-1-(3,4,4-(2)H(3),1-(15)N)pyrrolidinyloxyl (7). EPR spectroscopic measurements demonstrate that this fully isotopically substituted nitroxide markedly improves signal-to-noise ratio and, therefore, the sensitivity of EPR imaging. The new isotopically substituted nitroxide shows increased sensitivity to changes in O(2) concentration, which will enable more accurate O(2) measurement in tissues using EPRI. PMID- 20828114 TI - Structural characterization of gel-derived calcium silicate systems. AB - The main aim of this study is to synthesize calcium silicate ceramics that exhibit suitable properties to be used for biomedical applications. In the present work, attention was paid to the understanding of processing-structure relationships. A particular effort was made to clarify the identification of Ca-O Si bonds by means of spectroscopy. The calcium silicate systems were prepared via a sol-gel route, varying the chemical compositions, the catalyst concentration, and the temperature and time of aging and heat treatment. The processes and the phases evolved during the sol-gel procedure were determined. The bond systems were investigated by Fourier transform infrared (FTIR) and (29)Si magic angle spinning nuclear magnetic resonance (MAS NMR) spectroscopy and the aggregate structures by scanning electron microscopy (SEM), small-angle neutron scattering (SANS), small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS), and X-ray diffraction (XRD) measurements. PMID- 20828115 TI - Preparation of furan and thiophene-derived fulvene dialdehydes: synthesis and structural characterization of a 22-oxa-21-carbaporphyrin and a related palladium(II) organometallic complex. AB - A series of fulvene monoaldehydes were prepared by reacting furan or thiophene carbaldehydes with an indene-derived enamine in the presence of di-n-butylboron triflate, but considerable difficulties were encountered in the preparation of fulvene dialdehydes needed for the synthesis of novel porphyrin analogues. These problems were overcome by reacting protected iodofulvenes with magnesium ate complexes at low temperatures, followed by addition of DMF and hydrolysis. The thiophene-containing fulvene gave good yields of the dialdehyde at -78 degrees C or -100 degrees C, but the furan system gave a major byproduct formally derived from valeraldehyde under the higher temperature conditions. This compound was fully characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. However, this side reaction could be completely avoided at -100 degrees C, and the required furan-containing fulvene dialdehyde was isolated in 46% yield. The furan-derived dialdehyde reacted with a dipyrrylmethane in the presence of trifluoroacetic acid to give the 22-oxa-21-carbaporphyrin 19 in excellent yields (73-79%). However, the thiophene-containing fulvene dialdehyde failed to give any of the anticipated macrocyclic product. An unstable acyclic intermediate was isolated and partially characterized, but this species could not be induced to cyclize. Steric factors may play a role, but X-ray crystallography confirmed that the fulvene dialdehyde precursor does have the correct geometry to facilitate the formation of the porphyrinoid macrocycle. The new oxacarbaporphyrin was fully characterized and could easily be converted into the corresponding mono- and dicationic species. The second protonation involves addition onto the internal indene carbon and proton NMR spectroscopy for the sample in HCl-TFA demonstrates that it retains strongly diatropic characteristics. The free base oxacarbaporphyrin reacted with Pd(OAc)(2) in DMF to give the corresponding palladium(II) organometallic derivative 27. The proton NMR spectrum for this complex also shows the retention of a strong, albeit slightly reduced, diatropic ring current. The free base oxacarbaporphyrin and the palladium derivative were both structurally characterized by X-ray crystallography. The bond lengths for 19 and 27 were consistent with the presence of significant 18pi-electron delocalization pathways. PMID- 20828116 TI - DFT study of cycloparaphenylenes and heteroatom-substituted nanohoops. AB - Nanohoops are macrocycles formed of aromatic rings linked in a 1,4' fashion. Cycloparaphenylenes 1 and nitrogen analogues formed from the building blocks pyridinyl (2), pyrazinyl (3), pyridazinyl (4), and pyrimidinyl (5) are examined at B3LYP/6-31G(d). The nanohoops contain 3-24 repeat units. The strain energy of the nanohoops exponentially decreases with the number of building blocks n, and this strain strongly correlates with the bend angle at the ipso carbons. Nitrogen substitution reduces the o,o' steric interactions between neighboring rings. Nanohoops 3 and 5 have ribbon-like structure with dihedral angles between neighboring rings near zero. Nanohoops 5 are the least strained and, with their ribbon structure, are suggested as synthetic targets for possible interesting bulk properties and structures. PMID- 20828117 TI - Interaction of ketocyanine dye with a Co2+ ion: an electronic spectroscopic study. AB - The interaction of a ketocyanine dye with a cobalt(II) ion has been studied in solution by monitoring the electronic absorption and emission spectral characteristics of the dye. A new absorption band at a longer wavelength appears in solutions containing cobalt(II) ions. An isosbestic point is observed for systems containing a fixed dye concentration and varying Co(2+) ion concentration, pointing to the formation of a complex. The stoichiometry of the complex has been found to be 1:1. Equilibrium constant has been determined from the observed data. The nature of interaction between the dye (S(0) state) and the Co(II) ion is mostly electrostatic. Spectroscopic results have been supported by DFT/TDDFT calculation. The fluorescence band is characterized by a small blue shift. In the concentration range of 10(-3)-10(-4) M of the Co(II) ion, a quenching of the dye fluorescence is noticed. The Stern-Volmer plot points to the operation of both static and dynamic mechanisms of quenching. For a micromolar concentration of the Co(II) ion, however, an enhancement of fluorescence intensity with a slight blue shift has been observed, which has been explained in terms of formation of a different type of complex in the S(1) state at this concentration level. The value of lifetime increases at the micromolar level of concentration of the Co(II) ion, where the intensity increases and then remains practically unchanged as more salt is added to the system. Values of the decay constant for the different photophysical processes have been calculated. Complexation in the S(1) state is characterized by a slower decay of the excited dye by a nonradiative path. PMID- 20828118 TI - NMR study of the tautomeric behavior of N-(alpha-aminoalkyl)tetrazoles. AB - N-(alpha-Aminoalkyl)tetrazoles exist in solution as equilibrium mixtures of N1 and N2 tautomers. The position of equilibrium depends significantly on the polarity of the solvent and the substituents in the tetrazole ring. Interconversion between individual tautomers is shown to proceed via tight ion pair intermediates in which intramolecular recombination is faster than the intermolecular crossover since the latter probably requires solvent separation of ion-pair intermediates. PMID- 20828119 TI - Room-temperature synthesis of nickel borides via decomposition of NaBH(4) promoted by nickel bromide. AB - We report the formation of nickel borides, at room temperature and pressure, from the decomposition of NaBH(4) promoted by the addition of nickel bromide at different concentrations in a dispersing organic medium, tetrahydrofuran and pentane. The nickel borides, formed as amorphous powders, were analyzed, and the structure information served as input for modeling a periodic lattice structure with the same composition. Experimentally, the nickel boride phases were predominantly composed of a boron-rich phase with composition NiB(3). Combining FT-IR, X-ray diffraction analyses, and theoretical structure determination, we suggest for it a monoclinic structure, with symmetry group P2(1)/c, lattice parameters a =3.038 A, b = 8.220 A, c = 5.212 A, alpha = beta = 90.00 degrees and gamma = 87.57 degrees . The enthalpies of formation of the nickel boride phases, as well as the lattice stability, were calculated using density functional theory and density functional perturbation theory methods. PMID- 20828120 TI - Efficient synthetic approach to potent antiproliferative agent hippuristanol via Hg(II)-catalyzed spiroketalization. AB - The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif. PMID- 20828121 TI - Electrochemical quartz crystal microbalance (EQCM) studies of ions and solvents insertion into highly porous activated carbons. AB - Electrochemical quartz crystal microbalance (EQCM) technique provides a direct assessment to the behavior of electroadsorbed ions and solvent molecules confined in micropores of activated carbon electrodes in contact with practically important aprotic electrolyte solutions. The estimated value of the solvation number equal to 3 is evident for a partial desolvation of Li(+) cations when adsorbed in carbon micropores. PMID- 20828122 TI - Robust light emission from cyclic alkylaminoluciferin substrates for firefly luciferase. AB - Firefly luciferase utilizes the chemical energy of ATP and oxygen to convert its substrate, D-luciferin, into an excited-state oxyluciferin molecule. Relaxation of this molecule to the ground state is responsible for the yellow-green light emission. Synthetic cyclic alkylaminoluciferins that allow robust red-shifted light emission with the modified luciferase Ultra-Glo are described. Overall light emission is higher than that of acyclic alkylaminoluciferins, aminoluciferin, and the native substrate D-luciferin. PMID- 20828123 TI - Mixed low-dimensional nanomaterial: 2D ultranarrow MoS2 inorganic nanoribbons encapsulated in quasi-1D carbon nanotubes. AB - Quasi-one-dimensional nanotubes and two-dimensional nanoribbons are two fundamental forms of nanostructures, and integrating them into a novel mixed low dimensional nanomaterial is fascinating and challenging. We have synthesized a stable mixed low-dimensional nanomaterial consisting of MoS(2) inorganic nanoribbons encapsulated in carbon nanotubes (which we call nanoburritos). This route can be extended to the synthesis of nanoburritos composed of other ultranarrow transition-metal chalcogenide nanoribbons and carbon nanotubes. The widths of previously synthesized MoS(2) ribbons are greater than 50 nm, while the encapsulated MoS(2) nanoribbons have uniform widths down to 1-4 nm and layer numbers down to 1-3, depending on the nanotube diameter. The edges of the MoS(2) nanoribbons have been identified as zigzag-shaped using both high-resolution transmission electron microscopy and density functional theory calculations. PMID- 20828124 TI - Oxygen reduction catalyzed by a fluorinated tetraphenylporphyrin free base at liquid/liquid interfaces. AB - The diprotonated form of a fluorinated free base porphyrin, namely 5-(p aminophenyl)-10,15,20-tris(pentafluorophenyl)porphyrin (H(2)FAP), can catalyze the reduction of oxygen by a weak electron donor, namely ferrocene (Fc). At a water/1,2-dichloroethane interface, the interfacial formation of H(4)FAP(2+) is observed by UV-vis spectroscopy and ion-transfer voltammetry, due to the double protonation of H(2)FAP at the imino nitrogen atoms in the tetrapyrrole ring. H(4)FAP(2+) is shown to bind oxygen, and the complex in the organic phase can easily be reduced by Fc to produce hydrogen peroxide as studied by two-phase reactions with the Galvani potential difference between the two phases being controlled by the partition of a common ion. Spectrophotometric measurements performed in 1,2-dichloroethane solutions clearly evidence that reduction of oxygen by Fc catalyzed by H(4)FAP(2+) only occurs in the presence of the tetrakis(pentafluorophenyl)borate (TB(-)) counteranion in the organic phase. Finally, ab initio computations support the catalytic activation of H(4)FAP(2+) on oxygen. PMID- 20828125 TI - Affinity purification of multifunctional polymer nanoparticles. AB - We report that multifunctional polymer nanoparticles approximately the size of a large protein can be "purified", on the basis of peptide affinity just as antibodies, using an affinity chromatography strategy. The selection process takes advantage of the thermoresponsiveness of the nanoparticles allowing "catch and release" of the target peptide by adjusting the temperature. Purified particles show much stronger affinity (K(dapp) ~ nM) and a narrower affinity distribution than the average of particles before purification (K(dapp) > MUM) at room temperature but can release the peptide just by changing the temperature. We anticipate this affinity selection will be general and become an integral step for the preparation of "plastic antibodies" with near-homogeneous and tailored affinity for target biomacromolecules. PMID- 20828126 TI - Polymerin and lignimerin, as humic acid-like sorbents from vegetable waste, for the potential remediation of waters contaminated with heavy metals, herbicides, or polycyclic aromatic hydrocarbons. AB - Polymerin is a humic acid-like polymer, which we previously recovered for the first time from olive oil mill waste waters (OMWW) only, and chemically and physicochemically characterized. We also previously investigated its versatile sorption capacity for toxic inorganic and organic compounds. Therefore, a review is presented on the removal, from simulated polluted waters, of cationic heavy metals [Cu(II), Zn, Cr(III)] and anionic ones [Cr(VI)) and As(V)] by sorption on this natural organic sorbent in comparison with its synthetic derivatives, K polymerin, a ferrihydrite-polymerin complex and with ferrihydrite. An overview is also performed of the removal of ionic herbicides (2,4-D, paraquat, MCPA, simazine, and cyhalofop) by sorption on polymerin, ferrihydrite, and their complex and of the removal of phenanthrene, as a representative of polycyclic aromatic hydrocarbons, by sorption on this sorbent and its complexes with micro- or nanoparticles of aluminum oxide, pointing out the employment of all these sorbents in biobed systems, which might allow the remediation of water and protection of surface and groundwater. In addition, a short review is also given on the removal of Cu(II) and Zn from simulated contaminated waters, by sorption on the humic acid-like organic fraction, named lignimerin, which we previously isolated for the first time, in collaboration with a Chilean group, from cellulose mill Kraft waste waters (KCMWW) only. More specifically, the production methods and the characterization of the two natural sorbents (polymerin and lignimerin) and their derivatives (K-polymerin ferrihydrite-polymerin, polymerin microAl(2)O(3) and -nanoAl(2)O(3), and H-lignimerin, respectively) as well as their sorption data and mechanism are reviewed. Published and original results obtained by the cyclic sorption on all of the considered sorbents for the removal of the above-mentioned toxic compounds from simulated waste waters are also reported. Moreover, sorption capacity and mechanism of the considered compounds on polymerins and lignimerins are evaluated in comparison with other known natural sorbents, especially of humic acid nature and other organic matter. Some of their technical aspects and relative costs are also considered. Finally, the possible large-scale application of the considered sorption systems for water remediation is briefly discussed. PMID- 20828127 TI - Asparagine decarboxylation by lipid oxidation products in model systems. AB - The decarboxylation of asparagine in the presence of alkanals, alkenals, and alkadienals, among other lipid derivatives, was studied in an attempt to understand the reaction pathways by which some lipid oxidation products are able to convert asparagine into acrylamide. Asparagine was converted into 3 aminopropionamide in the presence of lipid derivatives as a function of reaction conditions (pH, water content, time, and temperature), as well as the type and amount of lipid compound involved. Alkadienals (and analogous ketodienes) were the most reactive lipids followed by hydroperoxides and alkenals. Saturated carbonyls and polyunsaturated fatty acids, or other polyunsaturated derivatives, also exhibited some reactivity. On the other hand, saturated lipids or monounsaturated alcohols did not degrade asparagine. A mechanism for the decarboxylation of asparagine in the presence of alkadienals based on the deuteration results obtained when asparagine/2,4-decadienal model systems were heated in the presence of deuterated water was proposed. The activation energy (E(a)) of asparagine decarboxylation by 2,4-decadienal was 81.0 kJ/mol, which is higher than that found for the conversion of 3-aminopropionamide into acrylamide in the presence of 2,4-decadienal. This result points to the decarboxylation step as the key step in the conversion of asparagine into acrylamide in the presence of alkadienals. Therefore, any inhibiting strategy for suppressing the formation of acrylamide by alkadienals should be mainly directed to the inhibition of this step. PMID- 20828128 TI - Surface plasmon resonance biosensor based fragment screening using acetylcholine binding protein identifies ligand efficiency hot spots (LE hot spots) by deconstruction of nicotinic acetylcholine receptor alpha7 ligands. AB - The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of alpha7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen. PMID- 20828129 TI - A reduced beta-diketiminato-ligated Ni3H4 unit catalyzing H/D exchange. AB - An investigation concerning the stepwise reduction of the beta-diketiminato nickel(II) hydride dimer [LNi(MU-H)(2)NiL], 1 (L = [HC(CMeNC(6)H(3)(iPr)(2))(2)]( )), has been carried out. While the reaction with one equivalent of potassium graphite, KC(8), led to the mixed valent Ni(I)/Ni(II) complex K[LNi(MU-H)(2)NiL], 3, treatment of 1 with two equivalents of KC(8) surprisingly yielded in the trinuclear complex K(2)[LNi(MU-H)(2)Ni(MU-H)(2)NiL], 4, in good yields. The Ni(3)H(4) core contains one Ni(II) and two Ni(I) centers, which are antiferromagnetically coupled so that a singlet ground state results. 4 represents the first structurally characterized molecular compound with three nickel atoms bridged by hydride ligands, and it shows a very interesting chemical behavior: Single-electron oxidation yields in the Ni(II)(2)Ni(I) compound K[LNi(MU-H)(2)Ni(MU-H)(2)NiL], 5, and treatment with CO leads to the elimination of H(2) with formation of the carbonyl complex K(2)[LNi(CO)](2), 6. Beyond that, it could be shown that 4 undergoes H/D exchange with deuterated solvents and the deuteride-compound 4-D(4) reacts with H(2) to give back 4. The crystal structures of the novel compounds 3-6 have been determined, and their electronic structures have been investigated by EPR and NMR spectroscopy, magnetic measurements, and DFT calculations. PMID- 20828130 TI - Analysis of intact and dissected fungal polyketide synthase-nonribosomal peptide synthetase in vitro and in Saccharomyces cerevisiae. AB - The widely found fungal iterative PKS-NRPS hybrid megasynthetases are highly programmed biosynthetic machines involved in the synthesis of 3-acyltetramic acids and related natural products. In vitro analysis of iterative PKS-NRPS has been hampered by the difficulties associated with obtaining pure and functional forms of these large enzymes (>400 kDa). We successfully expressed Aspergillus nidulans aspyridone synthetase (ApdA) from an engineered Saccharomyces cerevisiae strain. The complete functions of ApdA and its enoylreductase partner ApdC are reconstituted in vitro and in S. cerevisiae with the production of preaspyridone 7. The programming rules of both the PKS and NRPS modules were then examined in vitro. The key interaction between the PKS and the NRPS was dissected and reconstituted in trans by using stand-alone modules. Analogs of 7 were synthesized through heterologous combinations of PKS and NRPS modules from different sources. Our results represent one of the largest, multidomain enzyme reconstituted to date and offer new opportunities for engineered biosynthesis of fungal natural products. PMID- 20828131 TI - Atomic-resolution three-dimensional structure of HET-s(218-289) amyloid fibrils by solid-state NMR spectroscopy. AB - We present a strategy to solve the high-resolution structure of amyloid fibrils by solid-state NMR and use it to determine the atomic-resolution structure of the prion domain of the fungal prion HET-s in its amyloid form. On the basis of 134 unambiguous distance restraints, we recently showed that HET-s(218-289) in its fibrillar state forms a left-handed beta-solenoid, and an atomic-resolution NMR structure of the triangular core was determined from unambiguous restraints only. In this paper, we go considerably further and present a comprehensive protocol using six differently labeled samples, a collection of optimized solid-state NMR experiments, and adapted structure calculation protocols. The high-resolution structure obtained includes the less ordered but biologically important C terminal part and improves the overall accuracy by including a large number of ambiguous distance restraints. PMID- 20828132 TI - Site-Selective modification of vitamin D analogue (Deltanoid) through a resin based version of organoselenium 2,3-sigmatropic rearrangement. AB - A site-selective modification of a vitamin D analogue (Deltanoid) through a two step 2,3-sigmatropic rearrangement of organoselenium resin to prepare the key intermediate of calcipotriol has been developed. The polystyrene-supported selenium resins used here not only facilitate separation of product but also assist the crucial 2,3-sigmatropic rearrangement to introduce an important functional group (1alpha-hydroxyl) with high stereo- and regioselectivity. PMID- 20828133 TI - Dynamic regulation of fibrinogen: integrin alphaIIbbeta3 binding. AB - This study demonstrates that two orthogonal events regulate integrin alphaIIbbeta3's interactions with fibrinogen, its primary physiological ligand: (1) conformational changes at the alphaIIb-beta3 interface and (2) flexibility in the carboxy terminus of fibrinogen's gamma-module. The first postulate was tested by capturing alphaIIbbeta3 on a biosensor and measuring binding by surface plasmon resonance. Binding of fibrinogen to eptifibatide-primed alphaIIbbeta3 was characterized by a k(on) of ~2 * 10(4) L mol(-1) s(-1) and a k(off) of ~8 * 10( 5) s(-1) at 37 degrees C. In contrast, even at 150 nM fibrinogen, no binding was detected with resting alphaIIbbeta3. Eptifibatide competitively inhibited fibrinogen's interactions with primed alphaIIbbeta3 (K(i) ~0.4 nM), while a synthetic gamma-module peptide (HHLGGAKQAGDV) was only weakly inhibitory (K(i) > 10 MUM). The second postulate was tested by measuring alphaIIbbeta3's interactions with recombinant fibrinogen, both normal (rFgn) and a deletion mutant lacking the gamma-chain AGDV sites (rFgn gammaDelta408-411). Normal rFgn bound rapidly, tightly, and specifically to primed alphaIIbbeta3; no interaction was detected with rFgn gammaDelta408-411. Equilibrium and transition-state thermodynamic data indicated that binding of fibrinogen to primed alphaIIbbeta3, while enthalpy-favorable, must overcome an entropy-dominated activation energy barrier. The hypothesis that fibrinogen binding is enthalpy-driven fits with structural data showing that its gamma-C peptide and eptifibatide exhibit comparable electrostatic contacts with alphaIIbbeta3's ectodomain. The concept that fibrinogen's alphaIIbbeta3 targeting sequence is intrinsically disordered may explain the entropy penalty that limits its binding rate. In the hemostatic milieu, platelet-platelet interactions may be localized to vascular injury sites because integrins must be activated before they can bind their most abundant ligand. PMID- 20828136 TI - Theory for inverse pulsing of the shutter grid in ion mobility spectrometry. AB - The fundamental transport theory for ion mobility spectrometry is modified to include effects of space charge. The new theory is then applied to describing the performance of "inverse ion mobility spectrometry" recently reported in Tabrizchi, M.; Jazan, E. Anal. Chem. 2010, 82, 746-750 using a discharge ionization source. The improved separation capabilities arise from space charge repulsion of the greater number of ions that are introduced into the drift tube by the technique. A larger effective diffusion coefficient and additional displacement velocities for the leading and trailing edges of the ion mobility peak account for the results. Performance is compared to conventional linear ion mobility spectrometry, with and without a radioactive source for ionization. PMID- 20828134 TI - Key dynamics of conserved asparagine in a cryptochrome/photolyase family protein by fourier transform infrared spectroscopy. AB - Cryptochromes (Crys) and photolyases (Phrs) are flavoproteins that contain an identical cofactor (flavin adenine dinucleotide, FAD) within the same protein architecture but whose physiological functions are entirely different. In this study, we investigated light-induced conformational changes of a cyanobacterium Cry/Phr-like protein (SCry-DASH) with UV-visible and Fourier transform infrared (FTIR) spectroscopy. We developed a system for measuring light-induced difference spectra under the concentrated conditions. In the presence of a reducing agent, SCry-DASH showed photoreduction to the reduced form, and we identified a signal unique for an anionic form in the process. Difference FTIR spectra enabled us to assign characteristic FTIR bands to the respective redox forms of FAD. An asparagine residue, which anchors the FAD embedded within the protein, is conserved not only in the cyanobacterial protein but also in Phrs and other Crys, including the mammalian clock-related Crys. By characterizing an asparagine-to cysteine (N392C) mutant of SCry-DASH, which mimics an insect specific Cry, we identified structural changes of the carbonyl group of this conserved asparagine upon light irradiation. We also found that the N392C mutant is stabilized in the anionic form. We did not observe a signal from protonated carboxylic acid residues during the reduction process, suggesting that the carboxylic acid moiety would not be directly involved as a proton donor to FAD in the system. These results are in contrast to plant specific Crys represented by Arabidopsis thaliana Cry1 that carry Asp at the position. We discuss potential roles for this conserved asparagine position and functional diversity in the Cry/Phr frame. PMID- 20828137 TI - Whole blood assay for elastase, chymotrypsin, matrix metalloproteinase-2, and matrix metalloproteinase-9 activity. AB - The ability to measure protease activity in the blood is important for the development of future diagnostics and for biomedical research. Presently, protease assays require sample preparation, making them time-consuming, costly, less accurate, and unsuitable for point-of-care (POC) diagnostics. Recently, we demonstrated a unique method for measuring clinically relevant levels of trypsin activity in only a few microliters of whole blood. This assay utilizes a charge changing fluorescent peptide substrate that produces a positively charged fluorescent product fragment upon cleavage by the target protease. Using a simple electrophoretic format, the fragments could be rapidly separated, concentrated, and detected directly from a whole blood sample. We now report on the development of new protease substrates for the measurement of elastase, chymotrypsin, matrix metalloproteinase (MMP)-2, and MMP-9 activity in whole blood. In these studies, detection limits ranging from 1 to 40 pg in 6 MUL of 1* phosphate-buffered saline (PBS) (0.2-6 ng/mL) were achieved after a only 1 h reaction of enzyme and substrate. In subsequent experiments measuring spiked protease in whole blood (with endogenous protease present), detection limits ranging from 100 to 200 ng/mL were achieved after a 1 h reaction. Thus, these new substrates demonstrate broad applicability toward clinically relevant detection of important disease relevant proteases. PMID- 20828138 TI - Isopropylamino and isobutylamino groups as recognition sites for carbohydrates: acyclic receptors with enhanced binding affinity toward beta-galactosides. AB - Binding motifs observed in the crystal structures of protein-carbohydrate complexes, in particular the participation of the isopropyl/isobutyl side chain of valine/leucine in the formation of van der Waals contacts, have inspired the design of new artificial carbohydrate receptors. The new compounds, containing a trisubstituted triethylbenzene core, were expected to recognize sugar molecules through a combination of NH...O and OH...N hydrogen bonds, CH...pi interactions, and numerous van der Waals contacts. (1)H NMR spectroscopic titrations in competitive and noncompetitive media, as well as binding studies in two-phase systems, such as dissolution of solid carbohydrates in apolar media and phase transfer of sugars from aqueous into organic solvents, revealed effective recognition of neutral carbohydrates and beta- vs alpha-anomer binding preferences in the recognition of glycosides as well as significantly increased binding affinity of the receptors toward beta-galactoside in comparison with the previously described receptors. PMID- 20828139 TI - Toward the macrocidins: macrocyclization via Williamson etherification of a phenolate. AB - The synthesis of macrocyclic 3-acyltetramic acids which are immediate precursors of the fungal herbicide macrocidin A (1) is reported. The crucial closure of the macrocycle was achieved in excellent yield by an unprecedented Williamson etherification of an omega-bromo phenolate generated in situ by a Pd-mediated O deallylation. PMID- 20828140 TI - Basic modeling approach to optimize elemental imaging by laser ablation ICPMS. AB - The quality of element image maps generated by laser ablation (LA) ICPMS rastering depends on the measurement conditions (laser fluence, repetition rate, beam diameter, scanning speed, flow rate, and acquisition time). Optimizing these conditions is often a matter of trial and error since the quality criteria for elemental imaging (sensitivity, spatial resolution, noise, and analysis time) are intricately linked. A simple mathematical model, and ensuing software, was developed to simulate the LA-ICPMS output upon virtual rastering of a digital image of a cross-section of a sample. Even though the LA-ICPMS map is not directly correlated with elemental imaging, element distributions are often related to visual features in the sample, allowing optimization of the LA-ICPMS settings for the desired quality criteria (samples without any visual features can not be optimized in this way). The virtual LA-ICPMS rastering software assumes that the ablation cell and tube interface act as a continuous stirred tank reactor (i.e., exponential washout) and a plug flow reactor (i.e., zero dispersion), respectively, using an inert gas for transport of the aerosol particles. The software also incorporates a random noise generator which simulates the experimentally deduced signal-to-noise ratios as a function of the anticipated concentration and LA-ICPMS settings. The software was successfully validated and demonstrated by comparing the software output of selected patterns created in the emulsion of a black-and-white negative film with the experimental rastering output performed by measurement of (107)Ag in the emulsion. PMID- 20828141 TI - Does the mass spectrometer define the marker? A comparison of global metabolite profiling data generated simultaneously via UPLC-MS on two different mass spectrometers. AB - By coupling a single UPLC separation to two different types of mass spectrometer an unbiased comparison of the metabolite profiles produced by each instrument for a set of rat urine samples was obtained. The flow from the UPLC column was split equally and both streams of eluent were simultaneously directed to the inlets of the two mass spectrometers. Mass spectrometry on the eluent was undertaken using a triple quadrupole linear ion trap and a hybrid quadrupole time-of-flight mass spectrometer using both positive and negative ESI. Data from both mass spectrometers were subjected to multivariate statistical analysis, after applying the same data extraction software, and showed the same general pattern of correlation between the samples using both unsupervised and supervised methods of statistical analysis. Based on orthogonal partial least-squares discriminant analysis models a number of ions were recognized as "responsible" for the separation of the animal groups. From the peaks detected, and denoted as significant by the statistical analysis a number of ions were found to be unique to one data set or the other, a result which may have consequences for biomarker discovery and interlaboratory comparisons. The software package used for data analysis also had an effect on the outcome of the statistical analysis. PMID- 20828142 TI - Kinetic and theoretical study of the hydrodechlorination of CH(4-x)Cl(x) (x = 1 4) compounds on palladium. AB - The reaction kinetics of hydrodechlorination (HDCl) for a series of CH(4-x)Cl(x) (x = 1-4) compounds were measured on a Pd/carbon catalyst. The rate of HDCl correlated with the C-Cl bond energy, suggesting scission of this bond in the molecularly adsorbed molecule is rate-determining. The measured reaction kinetics of the CH(4-x)Cl(x) compounds support a previously proposed Langmuir-Hinshelwood type reaction mechanism. Kinetic and isotope exchange experiments demonstrated the following: gas phase H2 and HCl are in equilibrium with surface H and Cl; adsorbed Cl is the most abundant surface intermediate; and irreversible scission of the first C-Cl bond is rate-determining. The overall hydrodechlorination reaction rate can be written as kK(R-Cl)[R-Cl]/(1 + K(HCl)[HCl]/K(H2)(1/2)[H2](1/2)). The activation energy of the rate-determining step was related linearly to the dissociation energy of the first C-Cl bond broken in a Bronsted-Evans-Polanyi relationship. This behavior is in agreement with a previous study of CF(3)CF(3-x)Cl(x) compounds. During the reaction of CH3Cl, CH2Cl2, and CHCl3 with deuterium, H-D exchange occurred in only 2%, 6%, and 9% of products, respectively. The increasing H-D exchange with Cl content suggests the steps which determine selectivity in these multipath, parallel reactions. The density functional theory (DFT)-calculated activation energies for the dissociation of the first C-Cl bond in the family of chlorinated methane compounds are in good agreement with the values extracted from kinetic modeling, suggesting that parameters estimated from DFT calculations may be used to estimate the reactivity of a particular chlorinated compound within a family of chlorocarbons. PMID- 20828143 TI - Global fit analysis of glucose binding curves reveals a minimal model for kinetic cooperativity in human glucokinase. AB - Human pancreatic glucokinase is a monomeric enzyme that displays kinetic cooperativity, a feature that facilitates enzyme-mediated regulation of blood glucose levels in the body. Two theoretical models have been proposed to describe the non-Michaelis-Menten behavior of human glucokinase. The mnemonic mechanism postulates the existence of one thermodynamically favored enzyme conformation in the absence of glucose, whereas the ligand-induced slow transition model (LIST) requires a preexisting equilibrium between two enzyme species that interconvert with a rate constant slower than turnover. To investigate whether either of these mechanisms is sufficient to describe glucokinase cooperativity, a transient-state kinetic analysis of glucose binding to the enzyme was undertaken. A complex, time dependent change in enzyme intrinsic fluorescence was observed upon exposure to glucose, which is best described by an analytical solution comprised of the sum of four exponential terms. Transient-state glucose binding experiments conducted in the presence of increasing glycerol concentrations demonstrate that three of the observed rate constants decrease with increasing viscosity. Global fit analyses of experimental glucose binding curves are consistent with a kinetic model that is an extension of the LIST mechanism with a total of four glucose bound binary complexes. The kinetic model presented herein suggests that glucokinase samples multiple conformations in the absence of ligand and that this conformational heterogeneity persists even after the enzyme associates with glucose. PMID- 20828144 TI - Orientation and morphological evolution of catalyst nanoparticles during carbon nanotube growth. AB - We examined the structure, morphology, and orientation of catalyst nanoparticles used for seeding and growing multiwall carbon nanotubes (MWCNTs) by plasma enhanced chemical vapor deposition in CH4/H2 gas mixtures. Iron catalyst nanocrystals are converted to Fe3C in CH4/H2 plasmas and the MWCNTs grow from Fe3C nanocrystals. Initially faceted and equiaxed catalyst nanocrystals are distorted and elongated significantly once a tubular CNT structure is formed around the catalyst particles. Eventually, catalysts deform into elongated tear drop shapes. Once this morphology forms, CNT structures produced are straight and have uniform diameters. Surprisingly, the Fe3C nanocrystals located inside the base of well-graphitized nanotubes do not exhibit a preferred orientation relative to the nanotube axis. Catalyst nanocrystals in a variety of orientations relative to the nanotube axis still produce well-graphitized nanotubes with similar diameters and structures. PMID- 20828145 TI - An in silico design for a DNA nanomechanical switch. AB - We have calculated how the charge transfer properties of DNA change in response to the application of an external stretching force. Since charge transfer occurs through the DNA pi-stack, any disruption to this stacking causes dramatic changes in the transport properties of the biomolecule, as our calculations demonstrate. We therefore propose that the mechanical response of DNA to an applied stretching force might be used in the design of a nanomechanical switch. PMID- 20828146 TI - An asymmetrically surface-modified graphene film electrochemical actuator. AB - It is critically important to develop actuator systems for diverse needs ranging from robots and sensors to memory chips. The advancement of mechanical actuators depends on the development of new materials and rational structure design. In this study, we have developed a novel graphene electrochemical actuator based on a rationally designed monolithic graphene film with asymmetrically modified surfaces. Hexane and O(2) plasma treatment were applied to the opposite sides of graphene film to induce the asymmetrical surface properties and hence asymmetrical electrochemical responses, responsible for actuation behaviors. The newly designed graphene actuator demonstrated here opens a new way for actuator fabrication and shows the potential of graphene film for applications in various electromechanical systems. PMID- 20828147 TI - The conformation and the aggregation kinetics of alpha-synuclein depend on the proline residues in its C-terminal region. AB - The neuronal protein alpha-synuclein (alpha-syn) plays a central role in Parkinson's disease (PD). The pathological features of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies. The C-terminal domain of alpha-syn is characterized by the presence of 15 acidic amino acids and all five proline residues of the protein (P108, P117, P120, P128, and P138). The aggregation of this natively unfolded protein is accelerated in vitro by FK506 binding proteins (FKBPs) showing peptidyl-prolyl cis-trans isomerase activity. These proteins catalyze the cis-trans conformational change of the X-Pro peptide bond, often a rate-limiting step in protein folding. The acceleration of the folding of alpha-syn by FKBPs may accelerate disease-associated aggregation. To further elucidate the role of the proline residues in the conformation and aggregation of alpha-syn, we constructed several mutants of alpha-syn in which one or more proline residues are mutated to alanine via site-directed mutagenesis. For this purpose, we produced and purified His-WT alpha-syn, a recombinant alpha-syn with a polyhistidine tag (six His residues) and a linker, and a number of Pro-to-Ala mutants. The aggregation kinetics of these mutants and His-WT alpha-syn were studied by turbidity, thioflavin T fluorescence, and CD measurements. We can conclude that mutation of the proline residues to alanine accelerates the aggregation kinetics of alpha-syn while all proline mutants formed fibrils similar to His-WT alpha-syn, as visualized via transmission electron microscopy. We also demonstrate that the accelerating effect of hFKBP12 is abolished via removal of the proline residues from the C-terminus. Finally, we show that the mutant of His alpha-syn with all five proline residues mutated to alanine is more structured (more alpha-helix) than His-WT alpha-syn, indicating the role of the Pro residues as potential helix breakers in the inhibitory conformation of the C-terminus. PMID- 20828148 TI - Distance measurements within a concatamer of the plasma membrane Cl-/HCO3- exchanger, AE1. AB - AE1, which exists in the erythrocyte plasma membrane as a noncovalent dimer, facilitates transmembrane Cl-/HCO3- exchange. Here a concatamer of AE1 (two AE1 monomers fused via a two-residue linker to form an intramolecular dimer) was designed to facilitate fluorescence resonance energy transfer (FRET) studies. The concatameric protein (AE1.AE1) was expressed at the plasma membrane at levels similar to that of wild-type AE1 and had Cl-/HCO3- exchange activity indistinguishable from that of wild-type AE1. Nondenaturing gel electrophoresis revealed that AE1.AE1 does not associate into higher-order oligomers when expressed in HEK293 cells and Xenopus laevis oocytes. The cysteine-less concatamer (AE1.AE1-C-) enabled introduction of unique cysteine residues into the whole intramolecular dimer. AE1(Q434C).AE1(Q434C)-C-, with a single cysteine residue in each AE1 subunit, was labeled with the donor Alexa Fluor 488 C(5) maleimide (AF) and the acceptor tetramethylrhodamine methanethiosulfonate (TMR MTS). Energy transfer efficiency revealed that the distance between these residues in the AE1 dimer is 49 +/- 5 A. The 72% FRET efficiency observed between AE1(Q434C).AE1-C- labeled with AF and the lipid bilayer labeled with 1,1' didodecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate indicates that Q434 is less than 33 A from the lipid bilayer. We thus provide two distance constraints for the position of Q434, which is located in extracellular loop 1, connecting the first two transmembrane segments of AE1. PMID- 20828149 TI - Direct observation of transient Ostwald crystallization ordering from racemic serine solutions. AB - The Ostwald rule of stages describes the conjectured transitioning through metastable polymorphic crystal structures during crystallization. Direct observation of the Ostwald rule of stages using was performed using solutions of simple amino acids by second-order nonlinear optical imaging of chiral crystals (SONICC). SONICC, which is based on second-harmonic generation (SHG) imaging, enabled detection of homochiral microcrystals that survived only a few seconds before being converted to the more stable SHG-inactive polymorphic forms. PMID- 20828150 TI - Protein isolation from gutted herring (Clupea harengus) using pH-shift processes. AB - Herring ( Clupea harengus ) and other pelagic fish species are mainly used for fish meal and oil production and not for human consumption. In this study, acid pH-shift processing and alkaline pH-shift processing were used to isolate proteins from whole gutted herring with the aim to investigate the potential use of herring proteins as a food ingredient. The acid and alkaline processes gave rise to similar protein yields, 59.3 and 57.3%. The protein isolates from both processes had a significantly (p < 0.05) whiter color and higher protein and lower lipid contents than the starting material. The removal of ash was >80% for both processes, with a trend (p = 0.07) toward higher removal during the alkaline process. Also, Ca and Mg removal was significantly (p < 0.05) higher during the alkaline process. The isolated proteins from the acid process contained myosin degradation products and had a lower salt solubility than proteins from the alkaline process. Both protein isolates had an amino acid profile meeting the recommendations for adults according to FAO/WHO/UNU and could produce a surimi gel of medium strength. The results show that pH-shift processing could be a valuable method for the production of functional food proteins from gutted herring. PMID- 20828151 TI - Development of a phenol-enriched olive oil with phenolic compounds from olive cake. AB - The recent information regarding the healthy properties of virgin olive oil phenols and the interest in increasing the value of byproducts from the oil extraction processs support the standardized development of phenol-enriched olive oil. Accordingly, the aim of this research work was to evaluate strategies for the development of a virgin olive oil enriched with phenolic compounds obtained from olive cake to increase phenolic ingestion without the drawback of a higher calorie intake. For this proposal, different combinations of phenolic extracts were evaluated at a range of concentrations to obtain the best prototype of enriched olive oil. To study the functionality of the phenol enrichments, the total phenolic content and the oxidative stability were determined by the Folin Ciocalteu and Rancimat tests, respectively. In addition, the phenolic composition and antioxidant capacity (ORAC assay) of the oils were studied. Finally, the stability and potential bioaccesibility of the phenolic fraction of the enriched oils were tested by an in vitro gastrointestinal digestion model. Results of the study showed different strategies to select the best prototype of enriched olive oil, taking into consideration not only their phenolic content but also other important factors such as the feasibility of implementing the preparation process in the food industry. PMID- 20828152 TI - Preparation of a whole-cell biocatalyst of Aspergillus niger lipase and its practical properties. AB - Aspergillus niger lipase (ANL), a widely used hydrolase, was displayed for the first time on the surface of Saccharomyces cerevisiae using a-agglutinin as an anchor protein. Localization of ANL on the cell surface was confirmed by immunofluorescence microscopy. The displayed ANL was confirmed to be active toward tributyrin and p-nitrophenyl caprylate (pNPC). The hydrolytic activity toward pNPC reached 43.8 U/g of dry cell weight after induction by galactose for 72 h. The ANL-displaying cells were characterized for their use as whole-cell biocatalysts. The optimum temperature was 45 degrees C, and the pH was 7.0. The cells had good thermostability, retaining almost 80% of the full activity after incubation at 60 degrees C for 1 h, and >80% of the full activity at 50 degrees C for 6 h. The displayed lipase showed a preference for medium-chain fatty acid p nitrophenyl esters. Therefore, the produced whole-cell catalyst is likely to have a wide range of applications. PMID- 20828153 TI - Chemical profile, rumen degradation kinetics, and energy value of four hull-less barley cultivars: comparison of the zero-amylose waxy, waxy, high-amylose, and normal starch cultivars. AB - The objective of this study was to compare three new Canadian hull-less barley cultivars with altered starch characteristics (zero-amylose waxy, CDC Fibar; waxy, CDC Rattan; and high-amylose, HB08302) with conventional normal starch hull less barley (HB) cultivar (CDC McGwire) in terms of ruminant feed value. The study revealed that altered starch HB cultivars possessed several desirable feed characteristics, distinct from conventional normal starch HB, although they were similar in some respects: (1) basic chemical and carbohydrate subfraction profiles varied; (2) starch degradation kinetics showed altered starch HB containing higher soluble starch, rumen undegraded starch, lower degradable starch, and slower degradation rate; (3) all altered starch HB cultivars had similar soluble and degradable starch, different from that of conventional normal starch HB; (4) two waxy HB cultivars were lower, whereas the high-amylose cultivar was similar in effective degradability of the starch as compared to conventional normal starch HB; (5) zero-amylose waxy HB had the greater effective degradability of protein among HB cultivars; and (6) amylopectin in HB had a positive relationship with protein supply (increasing amylopectin was correlated with increased effective degradability of protein). Overall, these results demonstrate that the alteration of starch structure in granule affects not only starch fermentation and utilization but also protein value in hull-less barley. In summary, the HB cultivars with modified starch might be a better feed grain for ruminants than the normal starch HB. PMID- 20828154 TI - Elliptical structure of phospholipid bilayer nanodiscs encapsulated by scaffold proteins: casting the roles of the lipids and the protein. AB - Phospholipid bilayers host and support the function of membrane proteins and may be stabilized in disc-like nanostructures, allowing for unprecedented solution studies of the assembly, structure, and function of membrane proteins (Bayburt et al. Nano Lett. 2002, 2, 853-856). Based on small-angle neutron scattering in combination with variable-temperature studies of synchrotron small-angle X-ray scattering on nanodiscs in solution, we show that the fundamental nanodisc unit, consisting of a lipid bilayer surrounded by amphiphilic scaffold proteins, possesses intrinsically an elliptical shape. The temperature dependence of the curvature of the nanodiscs prepared with two different phospholipid types (DLPC and POPC) shows that it is the scaffold protein that determines the overall elliptical shape and that the nanodiscs become more circular with increasing temperature. Our data also show that the hydrophobic bilayer thickness is, to a large extent, dictated by the scaffolding protein and adjusted to minimize the hydrophobic mismatch between protein and phospholipid. Our conclusions result from a new comprehensive and molecular-based model of the nanodisc structure and the use of this to analyze the experimental scattering profile from nanodiscs. The model paves the way for future detailed structural studies of functional membrane proteins encapsulated in nanodiscs. PMID- 20828155 TI - Influence of fertilizer practices on S-containing metabolites in garlic (Allium sativum L.) under field conditions. AB - Cysteine sulfoxides (e.g., alliin) are the characteristic sulfur-containing secondary compounds in garlic, which account for taste and pharmaceutical quality. It was the aim of the present study to investigate the influence of sulfur and nitrogen supply under field conditions on the alliin content and cysteine and glutathione as possible precursors. Sulfur and nitrogen were applied in four different rates, and five samplings were conducted. Sulfur fertilization significantly increased the cysteine, glutathione, and alliin contents of leaves and bulbs, while nitrogen fertilization had no significant influence. Cysteine increased by a factor of 1.3-1.5 in leaves and 1.0-2.0 in bulbs. Glutathione increased significantly in bulbs by a factor of 0.9-1.6 but only at main growth and not at maturity. The alliin concentration in bulbs increased with S fertilization significantly at all harvesting dates and at maturity from 5.1 to 11.2 mg g(-1) of dry weight. High sulfur application in combination with low nitrogen fertilization increased the alliin concentration in garlic significantly during main growth until the beginning of ripening. At the last harvest, 15 kg ha(-1) S resulted in high-quality garlic suitable for consumption and use in plant protection or pharmaceutical industries. PMID- 20828156 TI - Geographical and climatic dependencies of green tea (Camellia sinensis) metabolites: a (1)H NMR-based metabolomics study. AB - The effects of climatic conditions on green tea metabolites in three different growing areas of Jeju Island, South Korea, were investigated through global metabolite profiling by (1)H nuclear magnetic resonance (NMR) spectroscopy. Pattern recognition methods, such as principal component analysis (PCA) and orthogonal projection on latent structure-discriminant analysis (OPLS-DA), revealed clear discriminations of green teas from the three different growing areas. Variations of theanine, isoleucine, leucine, valine, alanine, threonine, glutamine, quinic acid, glucose, epicatechin (EC), epigallocatechin (EGC), epigallocatechin-3-gallate (EGCG), and caffeine levels were responsible for the discriminations. Green teas grown in an area with high temperature, long sun exposure time, and high rainfall had higher levels of theanine but lower levels of isoleucine, leucine, valine, alanine, EC, EGC, EGCG, and caffeine than those grown in areas with relatively low temperature, short sun exposure time, and low rainfall. These results indicate that high temperature, long sun exposure, and high preciptation stimulate theanine synthesis in green tea during the spring season. This study highlights how metabolomics coupled with multivariate statistical analysis can illuminate the metabolic characteristics of green tea associated with climatic variables, thereby allowing for the assessment of quality strategy in green tea production. PMID- 20828157 TI - Formation and inhibition of cholesterol oxidation products in tea-leaf eggs during marinating. AB - The objectives of this study were to develop a GC-MS method for determination of cholesterol oxidation products (COPs) in tea-leaf eggs and study the formation and inhibition of COPs as affected by heating time and various ingredients in marinated juice. The various COPs in egg and juice samples were extracted by a solvent system of chloroform/methanol (2:1, v/v), followed by purification using a silica cartridge and GC-MS for subsequent separation and quantitation, with high recovery ranges from 85.9 to 98.3% and from 83.1-100.1% being obtained for egg and juice, respectively. 5alpha-Cholestane was shown to be an appropriate internal standard for quantitation. A total of five COPs, including 7-keto, 5,6 beta-EP, 7alpha-OH, 7beta-OH, and triol, were formed in tea-leaf eggs during marinating, but not in marinated juice. A peak level of total COPs (2272.2 ng/g) was generated in tea-leaf eggs after 24 h of heating, but reduced to 1068.2 ng/g in 48 h. Both the total phenolic and flavonoid compounds in tea-leaf eggs showed a time-dependent increase during marinating and so did the pH and browning index in tea-leaf eggs and juice. The incorporation of soy sauce or black tea leaf into juice was effective in inhibiting COPs formation in tea-leaf eggs, with the latter being more pronounced than the former. The formation of Maillard reaction products during marinating as well as the presence of total phenolic and total flavonoid in black tea leaf was mainly responsible for COPs reduction in tea-leaf eggs. PMID- 20828158 TI - Expanding the diversity of allosteric bcr-abl inhibitors. AB - Inhibition of Bcr-Abl kinase activity by imatinib for the treatment of chronic myeloid leukemia (CML) currently serves as the paradigm for targeting dominant oncogenes with small molecules. We recently reported the discovery of GNF-2 (1) and GNF-5 (2) as selective non-ATP competitive inhibitors of cellular Bcr-Abl kinase activity that target the myristate binding site. Here, we used cell-based structure-activity relationships to guide the optimization and diversification of ligands that are capable of binding to the myristate binding site and rationalize the findings based upon an Abl-compound 1 cocrystal. We elucidate the structure activity relationships required to obtain potent antiproliferative activity against Bcr-Abl transformed cells and report the discovery of new compounds (5g, 5h, 6a, 14d, and 21j-I) that display improved potency or pharmacological properties. This work demonstrates that a variety of structures can effectively target the Bcr-Abl myristate binding site and provides new leads for developing drugs that can target this binding site. PMID- 20828159 TI - Crystallographic characterization of 12-helical secondary structure in beta peptides containing side chain groups. AB - Helices are the most extensively studied secondary structures formed by beta peptide foldamers. Among the five known beta-peptide helices, the 12-helix is particularly interesting because the internal hydrogen bond orientation and macrodipole are analogous to those of alpha-peptide helices (alpha-helix and 3(10)-helix). The beta-peptide 12-helix is defined by i, i+3 C?O...H-N backbone hydrogen bonds and promoted by beta-residues with a five-membered ring constraint. The 12-helical scaffold has been used to generate beta-peptides with specific biological functions, for which diverse side chains must be properly placed along the backbone and, upon folding, properly arranged in space. Only two crystal structures of 12-helical beta-peptides have previously been reported, both for homooligomers of trans-2-aminocyclopentanecarboxylic acid (ACPC). Here we report five additional crystal structures of 12-helical beta-peptides, all containing residues that bear side chains. Four of the crystallized beta-peptides include trans-4,4-dimethyl-2-aminocyclopentanecarboxylic acid (dm-ACPC) residues, and the fifth contains a beta(3)-hPhe residue. These five beta-peptides adopt fully folded 12-helical conformations in the solid state. The new crystal structures, along with previously reported data, allow a detailed characterization of the 12-helical conformation; average backbone torsion angles of beta-residues and helical parameters are derived. These structural parameters are found to be similar to those for i, i+3 C?O...H-N hydrogen-bonded helices formed by other peptide backbones generated from alpha- and/or beta-amino acids. The similarity between the conformational behavior of dm-ACPC and ACPC is consistent with previous NMR-based conclusions that 4,4-disubstituted ACPC derivatives are compatible with 12-helical folding. In addition, our data show how a beta(3)-residue is accommodated in the 12-helix, thus enhancing understanding of the diverse conformational behavior of this flexible class of beta-amino acids. PMID- 20828160 TI - NmerA of Tn501 mercuric ion reductase: structural modulation of the pKa values of the metal binding cysteine thiols. AB - To avoid nonspecific and/or undesirable binding and reactivity of metal ions with cellular components, organisms have evolved metal-specific systems for trafficking proteins. Although systems differ, those handling soft metal ions such as Hg(2+), Cu(+), Zn(2+), etc., all utilize heavy metal-associated (HMA) proteins and domains of ~70 amino acids with a conserved GMXCXXC motif in a betaalphabetabetaalphabeta structural fold. While the conserved cysteines define a common metal binding site in these proteins, other structural features must be utilized to create metal ion, protein partner, and contextual specificities. This paper presents initial structure-function studies of the N-terminal HMA domain (NmerA) of Tn501 mercuric ion reductase (MerA) aimed at identifying structural features critical to its role in facilitating efficient transfer of Hg(2+) to the MerA catalytic core for reductive detoxification. First, NMR solution structures of reduced and Hg(2+)-bound forms of NmerA are presented that allow definition and comparison of the structure of the metal binding loop in the two states. Structural differences between the two forms are compared with differences observed in three HMA domains with different metal ion and functional contexts. Second, analyses of the UV absorbance properties of wild-type, Cys11Ala, and Cys14Ala forms of NmerA are presented that provide assignments of the pK(a) values for the two cysteine thiols of the metal binding motif. Third, results from 13C NMR studies with wild-type and Y62F NmerA labeled with [beta 13C]cysteine are presented that define a role for Tyr62 in modulating the pK(a) values of the cysteine thiols. PMID- 20828162 TI - Novel cytosolic allergens of Aspergillus fumigatus identified from germinating conidia. AB - Aspergillus fumigatus is the common cause of allergic broncho-pulmonary aspergillosis (ABPA) and most of the allergens have been described from its secreted fraction. In the present investigation, germinating conidial cytosolic proteins of A. fumigatus were extracted from a 16 h culture. The proteome from this fraction was developed, and immuno-blots were generated using pooled ABPA patients' sera. Well separated Immunoglobulin-E (IgE) and Immunoglobulin-G (IgG) reactive spots were picked from corresponding 2DE gels and subjected to mass spectrometric analysis. As a result, 66 immuno-reactive proteins were identified from two geographically different strains (190/96 and DAYA) of A. fumigatus. Only 3 out of 66 proteins reacted with IgG, and the remaining 63 proteins were found to be IgE reactive. These 63 IgE-reactive cytosolic proteins from germinating conidia included 2 already known (Asp f12 and Asp f22) and 4 predicted allergens (Hsp88, Hsp70, malate dehydrogenase, and alcohol dehydrogenase) based on their homology with other known fungal allergens. In view of this, the panel of presently identified IgE-reactive novel proteins holds the potential of providing a basis for the wider diagnostic application in assay for allergic aspergillosis. We could demonstrate that recombinantly expressed proteins from this panel showed consistent reactivity with IgE of individual sera of ABPA patients. The recombinantly expressed proteins may also be useful in desensitization therapy of allergic disorders including ABPA. PMID- 20828161 TI - Mapping tissue-specific expression of extracellular proteins using systematic glycoproteomic analysis of different mouse tissues. AB - Due to their easy accessibility, proteins outside of the plasma membrane represent an ideal but untapped resource for potential drug targets or disease biomarkers. They constitute the major biochemical class of current therapeutic targets and clinical biomarkers. Recent advances in proteomic technologies have fueled interest in analysis of extracellular proteins such as membrane proteins, cell surface proteins, and secreted proteins. However, unlike the gene expression analyses from a variety of tissues and cells using genomic technologies, quantitative proteomic analysis of proteins from various biological sources is challenging due to the high complexity of different proteomes and the lack of robust and consistent methods for analyses of different tissue sources, especially for specific enrichment of extracellular proteins. Since most extracellular proteins are modified by oligosaccharides, the population of glycoproteins therefore represents the majority of extracellular proteomes. Here, we quantitatively analyzed glycoproteins and determined the expression patterns of extracellular proteins from 12 mouse tissues using solid-phase extraction of N linked glycopeptides and liquid chromatography-tandem mass spectrometry. We identified peptides enclosing 1231 possible N-linked glycosites from 826 unique proteins. We further determined the expression pattern of formerly N-linked glycopeptides and identified extracellular glycoproteins specifically expressed in each tissue. Furthermore, the tissue specificities of the overexpressed glycoproteins in a mouse skin tumor model were determined by comparing them to the quantitative protein expression from the different tissues. These skin tumor specific extracellular proteins might serve as potential candidates for cell surface drug targets or disease-specific protein markers. PMID- 20828163 TI - Immuno-reactive molecules identified from the secreted proteome of Aspergillus fumigatus. AB - The secreted proteomes of a three week old culture of an Indian (190/96) and a German (DAYA) Aspergillus fumigatus isolate were investigated for reactivity with IgG and/or IgE antibodies derived from pooled allergic broncho-pulmonary aspergillosis (ABPA) patients' sera. Two dimensional Western blotting followed by mass spectrometric analysis of the reactive protein spots revealed 35 proteins from the two A. fumigatus strains. There were seven known A. fumigatus allergens among them (Asp f1-4, Asp f9, Asp f10, and Asp f13/15), whereas three proteins displaying significant sequence similarity to known fungal allergens have been assigned as predicted allergens (Dipeptidyl-peptidase-V precursor, Nuclear transport factor 2, and Malate dehydrogenase, NAD-dependent). Eight IgG and IgE reactive proteins were common in both strains; however, 12 proteins specifically reacted in 190/96 and 15 in DAYA. Further testing with sera of 5 individual ABPA patients demonstrated that 12 out of 20 immunoreactive proteins of 190/96 strain of A. fumigatus had consistent reactivity with IgE. Seven of these proteins reacted with IgG also. The 25 of 35 identified proteins are novel with respect to immuno-reactivity with ABPA patients' sera and could form a panel of molecules to improve the currently existing less-sensitive diagnostic methods. Through expressing recombinantly, these proteins may also serve as a tool in desensibilization strategies. PMID- 20828164 TI - Hepatic alpha-tocopherol transfer protein: ligand-induced protection from proteasomal degradation. AB - There are eight naturally occurring forms of the dietary antioxidant vitamin E. Of these, only alpha-tocopherol is retained at high levels in vertebrate plasma and tissues. This selectivity is achieved in part by the action of the hepatic alpha-tocopherol transfer protein (TTP), which facilitates the selective incorporation of dietary alpha-tocopherol into circulating lipoproteins. We examined the effects of vitamin E on TTP expression in cultured hepatocytes. Treatment with vitamin E precipitated a time- and dose-dependent increase in the steady-state levels of TTP. This stabilization was caused by alpha-tocopherol induced attenuation of the ubiquitination of TTP and its subsequent degradation by the proteasome. In vitro, vitamin E protected TTP from proteolytic degradation by trypsin, suggesting ligand-induced changes in protein conformation. Cell fractionation studies showed that TTP is distributed between the cytosolic and membranous organelle fraction, and that tocopherol induced the translocation of some TTP from the cytosol to the organelle fraction. Furthermore, vitamin E markedly attenuated the degradation of organelle-bound TTP. These findings suggest that vitamin E imparts a distinct conformation on TTP that is associated with localization to a specific cellular compartment, where the protein is less susceptible to proteasomal degradation. PMID- 20828165 TI - Supermolecular-chromophore-sensitized near-infrared-to-visible photon upconversion. AB - Selective near-IR (NIR) excitation (780 nm) of the conjugated supermolecule ruthenium(II) [15-(4'-ethynyl-(2,2';6',2''-terpyridinyl))-bis[(5,5',-10,20 di(2',6'-bis(3,3-dimethylbutoxy)phenyl)porphinato)zinc(II)]ethyne][4'-pyrrolidin 1-yl-2,2';6',2''-terpyridine] bis(hexafluorophosphate) (Pyr(1)RuPZn(2)) in solutions containing N,N-bis(ethylpropyl)perylene-3,4,9,10-tetracarboxylicdiimide (PDI) or tetracene gives rise to a substantial anti-Stokes energy gain (PDI, 0.70 eV; tetracene, 0.86 eV). Experimental data clearly demonstrate that this upconverted fluorescence signal is produced via Pyr(1)RuPZn(2)-sensitized triplet triplet annihilation (TTA) photochemistry. The TTA process was confirmed by the quadratic dependence of the integrated (1)PDI* emission centered at 541 nm derived from 780 nm laser excitation. The T(1)->T(n) excited state absorption decay of Pyr(1)RuPZn(2), monitored at 900 nm as a function of PDI concentration, revealed Stern-Volmer and bimolecular quenching constants of 10 048 M(-1) and 5.9 * 10(8) M(-1) s(-1), respectively, for the PDI triplet sensitization process. The T(1)->T(n) PDI extinction coefficient at 560 nm (epsilon(T) = 6.6 * 10(4) M(-1) cm(-1)) was determined through the triplet energy transfer method utilizing anthracene as the donor chromophore. (3)PDI* transient triplet absorption dynamics observed as a function of 485 nm incident nanosecond pump laser fluence demonstrate a bimolecular (3)PDI*-(3)PDI* TTA rate constant (k(TT) = 1.0 +/- 0.2 * 10(9) M(-1) s(-1)). The maximum quantum yield of the supermolecule-sensitized PDI upconverted emission (Phi(UC) = 0.0075 +/- 0.0002) was determined relative to [Os(phen)(3)][PF(6)](2) at an incident laser power of 22 mW at 780 nm. This study successfully demonstrates NIR-to-visible photon upconversion and achieves a new record anti-Stokes shift of 0.86 eV for sensitized TTA, using the supermolecular Pyr(1)RuPZn(2)sensitizer. The stability of the Pyr(1)RuPZn(2)/PDI chromophore combination is readily apparent as continuous irradiation at 780 nm produces 541 nm centered fluorescence with no significant decrease in intensity measured over time domains exceeding several hours. The molecular components of these NIR-to vis upconverting compositions illustrate that substantial anti-Stokes energy gains via a TTA process can be effortlessly realized. PMID- 20828166 TI - Visual indicator for surfactant abundance in MS-based membrane and general proteomics applications. AB - The existence of surfactants in proteomics samples can severely reduce enzymatic digestion efficiency, liquid chromatography (LC) separation efficiency, column lifetime, and mass spectrometry (MS) sensitivity. Although various techniques are able to remove surfactants, surfactants may occasionally be retained in samples due to variations in sample preparation method or personal skill. Evaluation of surfactant residue in a sample, however, usually requires an additional instrument and is time-consuming. In this study, a simple and rapid visual indicator for surfactant abundance (VISA) was developed. With the detection of a visible surfactant pellet in the solution, this assay was able to detect surfactant residue in aqueous solutions within 5 min. Without the need of additional equipment such as a mass spectrometer, every user can perform a quick test on their bench before sending the sample to the MS facility. The detection limit for the commonly used surfactants, Triton X-114 and SDS, was about 0.0005% and 0.0002%, respectively. The VISA was successfully applied to evaluate the efficiency of removal of surfactants in Triton X-114 extracted membrane proteins using tube-gel. With the combination of Triton X-114 extraction and tube-gel protocol, a study of spermatozoa membrane proteome identified about 252 proteins of which about 67.5% were classified as membrane proteins. The coexistence of protein and surfactant did not affect the VISA sensitivity, suggesting that this indicator is suitable for proteomics applications. The VISA also has potential for the detection of other surfactants and can be applied to other surfactant removing protocols. PMID- 20828167 TI - Capillary-force-induced formation of luminescent polystyrene/(rare-earth-doped nanoparticle) hybrid hollow spheres. AB - This paper presents a "one-pot" procedure to synthesize polystyrene/(rare-earth doped nanoparticles) (PS/REDNPs) hybrid hollow spheres via the in situ diffusion of organic core into inorganic shell under strong capillary force. In this approach, when carboxyl-capped PS colloids were deposited by different REDNPs in aqueous medium, such as LaF3:Eu3+, LaF3:Ce3+-Tb3+, and YVO4:Dy3+, PS/REDNPs inorganic-organic hybrid hollow spheres could be directly obtained via the in situ diffusion of core PS chains into the voids between rare-earth-doped nanoparticles through the strong capillary force. Not only is the synthetic procedure versatile and very simple, but also the obtained hybrid hollow spheres are hydrophilic and luminescent and could be directly used in chemical and biological fields. PMID- 20828169 TI - Use of the curtius rearrangement of acryloyl azides in the synthesis of 3,5 disubstituted pyridines: mechanistic studies. AB - A series of disubstituted pyridine derivatives was synthesized from the corresponding acryloyl azides by acetic acid-promoted cycloaddition. This represents a novel and convenient synthetic approach to the symmetric 3,5 disubstituted pyridines. The nature of the substituent on the double bond and the utilized solvent were found to be crucial to the yield of pyridines. The reactivity of the acid-promoted cycloaddition increases with the presence of aryl groups, such as phenyl and pyridinyl. We also explored the comprehensive mechanism by the acid-promoted cycloaddition of (13)C-labeled cinnamoyl azide. The symmetric 3,5-disubstituted pyridines were synthesized from acryloyl azides by acetic acid-promoted trimolecular condensation. PMID- 20828170 TI - Transmembrane helix I and periplasmic loop 1 of Escherichia coli ProP are involved in osmosensing and osmoprotectant transport. AB - Osmoregulatory transporters stimulate bacterial growth by mediating osmoprotectant uptake in response to increasing osmotic pressure. The ProP protein of Escherichia coli transports proline and other osmoprotectants. Like LacY, ProP is a member of the major facilitator superfamily and a H(+)-solute symporter. ProP is regulated by osmotic pressure via a membrane potential dependent mechanism. A homology model predicts that ionizable and polar residues, highly conserved among ProP homologues, cluster deep within the N-terminal helix bundle of ProP. Chemical labeling of introduced cysteine (Cys) residues supported the homology model by confirming the predicted positions of transmembrane helix I (TMI) and periplasmic loop 1. Replacements of residues in the putative polar cluster impaired or altered ProP function, suggesting that they are important for osmosensing and may interact with the transport substrates. Asn34, Glu37, Phe41, Tyr44, and Ala48 line the most polar face of TMI; Tyr44 is on the periplasmic side of the putative polar cluster, and Ala59 is in periplasmic loop 1. The N ethylmaleimide reactivities of Cys introduced at positions 41, 44, 48, and 59 increased with osmotic pressure, whereas the reactivities of those at cytoplasm proximal positions 34 and 37 did not. Replacements of polar cluster residues that blocked transport also affected the NEM reactivity of Cys44 and its osmolality dependence. This report and previous work suggest that conformational changes associated with osmosensing may shift the equilibria between outward- and inward facing transport pathway intermediates. PMID- 20828171 TI - Nonsolvent annealing polymer films with ionic liquids. AB - Neutron reflectometry has been used to determine the interface structure and swelling of thin polymer films, when annealed in contact with a series of 1-alkyl 3-methylimidazolium ionic liquids (ILs). By choosing immiscible polymer/IL combinations, we have established that thin polymer films can be annealed for several hours in contact with ILs at temperatures well above the glass transition temperature and that this nonsolvent annealing environment can be exploited to direct self-assembly in polymer films. The ingress of IL into polymer films was quantified in terms of the swelling up to 10%. The polymer/IL interfacial width generally also increased from 0.9 nm up to ~3 nm, but there was remarkably little correlation between interfacial width and swelling. For one combination of polymer and IL (deuterated PMMA and Bmim-BF(4)) the interfacial width decreased slightly with increasing temperature, consistent with LCST behavior for this system. All of the ILs tested had a profound influence the distribution of carboxy-end-functionalized deuterated polystyrene, "dPS-COOH", in blended films with polystyrene homopolymers. The ILs promoted dPS-COOH adsorption at the film/IL interface and the simultaneous rapid desorption at the film silicon-oxide interface. The rate of desorption was found to correlate with the swelling behavior of the polymer with respect to the IL anion species: PF(6)(-) < Br(-) < Cl(-) < BF(4)(-), suggesting that the polymer films are plasticized by the IL as it penetrates the film. PMID- 20828172 TI - Synthesis of fluorescent dye-tagged nanomachines for single-molecule fluorescence spectroscopy. AB - In an effort to elucidate the mechanism of movement of nanovehicles on nonconducting surfaces, the synthesis and optical properties of five fluorescently tagged nanocars are reported. The nanocars were specifically designed for studies by single-molecule fluorescence spectroscopy and bear a tetramethylrhodamine isothiocyanate fluorescent tag for excitation at 532 nm. The molecules were designed such that the arrangement of their molecular axles and p carborane wheels relative to the chassis would be conducive to the control of directionality in the motion of these nanovehicles. PMID- 20828173 TI - Large-scale comparison of four binding site detection algorithms. AB - A large-scale evaluation and comparison of four cavity detection algorithms was carried out. The algorithms SiteFinder, fpocket, PocketFinder, and SiteMap were evaluated on a protein test set containing 5416 protein-ligand complexes and 9900 apo forms, corresponding to a subset of the set used earlier for benchmarking the PocketFinder algorithm. For the holo structures, all four algorithms correctly identified a similar amount of pockets (around 95%). SiteFinder, using optimized parameters, SiteMap, and fpocket showed similar pocket ranking performance, which was defined by ranking the correct binding site on rank 1 of the predictions or within the first 5 ranks of the predictions. On the apo structures, PocketFinder especially and also SiteFinder (optimized parameters) performed best, identifying 96% and 84% of all binding sites, respectively. The fpocket program predicts binding sites most accurately among the algorithms evaluated here. SiteFinder needed an average calculation time of 1.6 s compared with 2 min for SiteMap and around 2 s for fpocket. PMID- 20828174 TI - Interplay of processing, morphological order, and charge-carrier mobility in polythiophene thin films deposited by different methods: comparison of spin-cast, drop-cast, and inkjet-printed films. AB - The dependence of morphology and polymer-chain orientation of regioregular poly(3 hexylthiophene) (rrP3HT) thin films on processing conditions have been widely studied. However, their possible variation across the film thickness direction remains largely unknown. We report here a marked difference in the optical dielectric (n,k) spectra between the top and bottom interfaces of spin-cast (sc) rrP3HT films deposited from chlorobenzene solutions. These spectra were obtained from reflection variable-angle spectroscopic ellipsometry using a self-consistent graded optical model with self-imposed Kramers-Kronig consistency. The top interface shows a red-shifted absorption that is characteristic of better order than at the bottom, across a wide range of film thicknesses. This disparity diminishes in drop-cast (dc) and multipass inkjet-printed (ijp) films, and disappears in amorphous films such as those of polystyrene and of a green emitting phenyl-substituted poly(p-phenylenevinylene). The (n,k) spectra also reveal that crystallinity increases across sc < dc < ijp films. This is supported by cross section scanning electron microscopy of the cleaved edges and measurement of the microroughness of both the film interfaces. Furthermore, optical anisotropy decreases across sc > dc > ijp films. Finally, near-edge X-ray absorption fine structure spectroscopy also shows the frontier chains in ijp and dc films are more isotropically oriented than those in sc films. These results suggest that semicrystalline conjugated polymer films can be produced far from equilibrium. This explains the marked variation in their (opto)electronic properties between the top and bottom surfaces that has sometimes been found depending on the film deposition method. In particular, an unusually pronounced crystallization is induced by ijp. We label this marked ijp-induced crystallization the "ijp morphology", which appears to be general, as it is found also in single-inkjet-droplet films. It appears also to be responsible for the lower field-effect mobility measured for ijp films deposited on a variety of linear and circular electrode arrays. This however can fortuitously be reversed by annealing in solvent vapor. As all films were deposited in the low Peclet number regime, we can rule out surface skin formation. We attribute the extensive crystallization to the non-uniform drying of picoliter droplets, further promoted by repeated film swelling-deswelling cycles in multipass-ijp films. PMID- 20828175 TI - Axial-selective H/D exchange of glycine-derived 1H-benzo[e][1,4]diazepin-2(3H) ones: kinetic and computational studies of enantiomerization. AB - Glycine-derived 1H-benzo[e][1,4]diazepin-2(3H)-ones (BZDs) 5d-g featuring C9- and N1- substitution exhibit enantiomerization barriers too high to be measured by (1)H NMR coalescence experiments. To address this problem, we found that room temperature H/D exchange of these compounds is remarkably selective, affording only the axial-d(1) isotopomers. (1)H NMR spectroscopy was then employed to measure the rate of conformational inversion of these d(1)-compounds at elevated temperatures. These studies reveal the highest enantiomerization barriers (up to 28 kcal/mol) ever determined for a BZD. Density functional theory calculations match the experimental enantiomerization barriers within 1.2 kcal/mol. PMID- 20828176 TI - Size-dependent transition to high-symmetry chiral structures in AgCu, AgCo, AgNi, and AuNi nanoalloys. AB - A class of nanomaterials possessing the highest degree of chiral symmetry, the chiral icosahedral symmetry, is found by a combination of global optimization searches and first-principle calculations. These nanomaterials are core-shell nanoalloys with a Cu, Ni, or Co core and a chiral Ag or Au shell of monatomic thickness. The chiral shell is obtained by a transformation of an anti-Mackay icosahedral shell by a concerted rotation of triangular atomic islands which breaks all mirror symmetries. This transformation becomes energetically favorable as the cluster size increases. Other chiral nanoalloys, belonging to a different structural family of C(5) group symmetry, are found in the size range between 100 and 200 atoms. High-symmetry chiral nanoalloys associate strong energetic stability with potential for applications in optics, catalysis, and magnetism. PMID- 20828177 TI - Structural and vibrational properties of diglyme and longer glymes. AB - The conformational states of diglyme in both the solid and liquid states have been determined by an integrated use of both IR and Raman spectroscopy together with ab initio/density functional theory (DFT) calculations. Using knowledge from diglyme also made possible the study of the conformational state of longer glymes, including a quantitative study of the D-LAM mode. We hereby unambiguously can assign the (tgt)(n) conformational state to all glymes and PEO in the solid state. PMID- 20828179 TI - Systematic theoretical study of the zero-field splitting in coordination complexes of Mn(III). Density functional theory versus multireference wave function approaches. AB - This paper presents a detailed evaluation of the performance of density functional theory (DFT) as well as complete active space self-consistent field (CASSCF)-based methods (CASSCF and second-order N-electron valence state perturbation theory, NEVPT2) to predict the zero-field splitting (zfs) parameters for a series of coordination complexes containing the Mn(III) ion. The physical origin of the experimentally determined zfs's was investigated by studying the different contributions to these parameters. To this end, a series of mononuclear Mn(III) complexes was chosen for which the structures have been resolved by X-ray diffraction and the zfs parameters have been accurately determined by high-field EPR spectroscopy. In a second step, small models have been constructed to allow for a systematic assessment of the factors that dominate the variations in the observed zfs parameters and to establish magnetostructural correlations. Among the tested functionals, the best predictions have been obtained with B3LYP, followed by the nonhybrid BP86 functional, which in turn is more successful than the meta-hybrid GGA functional TPSSh. For the estimation of the spin-orbit coupling (SOC) part of the zfs, it was found that the coupled perturbed SOC approach CP is more successful than the Pederson-Khanna method. Concerning the spin-spin interaction (SS), the restricted open-shell Kohn-Sham (ROKS) approach led to a slightly better agreement with the experiment than the unrestricted KS (UKS) approach. The ab initio state-averaged CASSCF (SA-CASSCF) method with a minimal active space and the most recent implementation that treats the SOC and SS contributions on an equal footing provides the best predictions for the zfs. The analysis demonstrates that the major contribution to the axial zfs parameter (D) originates from the SOC interaction but that the SS part is far from being negligible (between 10 and 20% of D). Importantly, the various excited triplet ligand field states account for roughly half of the value of D, contrary to popular ligand field models. Despite covering dynamic correlation contributions to the transition energies, NEVPT2 does not lead to large improvements in the results as the excitation energies of the Mn(III) d-d transitions are already fairly accurate at the SA-CASSCF level. For a given type of coordination sphere (e.g., elongated or compressed octahedron), the magnetic anisotropy of the Mn(III) ion, D, does not appear to be highly sensitive to the nature of the ligands, while the E/D ratio is notably affected by all octahedral distortions. Furthermore, the introduction of different halides into the coordination sphere of Mn(III) only leads to small effects on D. Nevertheless, it appears that oxygen based ligands afford larger D values than nitrogen-based ligands. PMID- 20828178 TI - Multiresponse strategies to modulate burst degradation and release from nanoparticles. AB - Logic gate nanoparticles, where two chemical transformations take place one after the other, were successfully formulated from a newly synthesized random co polymer. This polymer, poly([2,2'-(propane-2,2-diylbis(oxy))bis(ethane-2,1-diyl) diacrylate ]-co-[hexane-1,6-diyl diacrylate]-4,4' trimethylene dipiperidine), (poly-beta-aminoester ketal-2) contains two pH responsive moieties within its backbone. As nanoparticles they function akin to an AND logic gate. The beta aminoester backbone moiety provides a pH triggered solubility switch, only when this switch is "ON" does the ketal moiety also turn "ON" to undergo rapid acid catalyzed hydrolysis. These AND logic gate polymeric nanoparticles were prepared using an oil in water emulsion method. Their degradation in the pH range of 7.4-5 was monitored by dynamic light scattering and showed excellent stability at pH 7.4 and rapid degradation at pH 5. Our results indicate that the prepared logic gate nanoparticles may prove valuable in delivering therapeutics and diagnostics to cells and diseased tissue. PMID- 20828180 TI - Designed synthesis of multi-electrochromic systems bearing diaryl ketone and isophthalates. AB - New multi-electrochromic systems have been developed through the combination of a diaryl ketyl radical system with isophthalate-based electrochromic materials. The location of the isophthalate group in compounds is very critical to obtaining different colors in the multi-electrochromism. PMID- 20828181 TI - Investigating the threshold of aromaticity and antiaromaticity by variation of nuclear charge. AB - Aromatic benzene and nonaromatic borazine can be modeled as the end-points of a continuous process evolving through intermediate systems with fractional nuclear charges. Current-density maps show a smooth, linear progression in which the global diatropic pi ring current weakens as localized diatropic lone-pair currents grow with the increase in charge difference. In contrast, the progression from antiaromatic (planarized) cyclooctatetraene to nonaromatic borazocine shows an initially persistent paratropic ring current with a sharper transition to the localized diatropic system. The different behaviors of aromatic and antiaromatic systems stem from the different orbital origins of diatropic and paratropic ring current, and both can be rationalized in terms of arguments based on pi distortivity and electronegativity. PMID- 20828182 TI - Enzymatic parallel kinetic resolution of mixtures of D/L 2'-deoxy and ribonucleosides: an approach for the isolation of beta-L-nucleosides. AB - We have developed a lipase-catalyzed parallel kinetic resolution of mixtures of beta-D/L-nucleosides. The opposite selectivity during acylation exhibited by Pseudomonas cepacia lipase (PSL-C) with beta-D- and beta-L-nucleosides furnished acylated compounds that have different R(f) values. As a consequence, isolation of both products was achieved by simple column chromatography. Computer modeling of the transition-state analogues during acylation of beta-D- and beta-L-2' deoxycytidine with PSL-C was carried out to explain the high selectivity. PSL-C favored the 3'-O-levulination of the beta-D enantiomer, whereas the 5'-OH group was acylated in 2'-deoxy-beta-L-cytidine. In both cases, the cytosine base was placed in the alternate hydrophobic pocket of PSL's substrate-binding site, where it can form extra hydrogen bonds (in addition to the five essential catalytically relevant hydrogen bonds) that stabilize these intermediates catalyzing the selective acylation of beta-D/L-nucleosides. PMID- 20828183 TI - Solution-phase extraction of ultrathin inner shells from double-wall carbon nanotubes. AB - We present an efficient method to extract inner shells of double-wall carbon nanotubes (DWCNTs) in liquid phase. The extraction of inner from outer shells is achieved by cutting the DWCNTs with vigorous sonication in water containing surfactants. The extracted shells are perfectly isolated single-wall carbon nanotubes (SWCNTs) and can be separated using density gradient ultracentrifugation. Statistical analysis using high-resolution transmission electron microscopy reveals that the enrichment of SWCNTs with narrow diameter (0.62-1.0 nm) up to 100% is achieved from highly pure DWCNTs. Furthermore, the (5,4) SWCNTs, which have the diameter of 0.62 nm, are concentrated. Our findings provide a novel way to obtain very narrow, highly isolated SWCNTs with ultraclean surface that have not been obtained in conventional synthesis methods. PMID- 20828184 TI - Characterization of Acetylcholinesterase Inhibitory Constituents from Annona glabra Assisted by HPLC Microfractionation. AB - The active fraction of the EtOH extract of the stem of Annona glabra against acetylcholinesterase (AChE) was analyzed by combining HPLC microfractionation with a bioassay. The analytical-scale sample was fractionated by HPLC-DAD into 96 well microplates, which, after evaporation, were assayed against AChE. The active subfractions were scaled up by separation over semipreparative HPLC to give 20 compounds. Four of these, (7S,14S)-(-)-N-methyl-10-O-demethylxylopinine salt (3), S-(-)-7,8-didehydro-10-O-demethylxylopininium salt (10), S-(-)-7,8 didehydrocorydalminium salt (11), and 5-O-methylmarcanine D (17), were assigned as new natural products. In addition, compounds 10 and 11 represent the first natural occurrence of 7,8-didehydroprotoberberines. Compound 3, pseudocolumbamine (12), palmatine (15), and pseudopalmatine (16) showed anti-AChE IC50 values of 8.4, 5.0, 0.4, and 1.8 MUM, respectively. PMID- 20828185 TI - From graphene to metal oxide nanolamellas: a phenomenon of morphology transmission. AB - Single-layer-graphene and few-layer-graphene structures have been predicted to have high specific surface area. Recent research has focused largely on utilizing the intriguing morphology of graphene as building blocks or substrates, keeping the structure undisturbed. Relatively little attention has been paid to explore the framework substitution of graphene. Here, we report a procedure for morphology transmission from graphene to metal oxide nanolamellas by in situ replacement with the framework of graphene. Our approach involves using graphene sheets as the starting reagent, thereby transmitting the morphology of layered structure from graphene to as-prepared metal oxides. The heteroconfiguration of as-prepared MnO(2) could play a role in preventing microstructure degradation in the electrochemical cycling process, bestowing MnO(2) nanolamellas an excellent electrochemical stability as a supercapacitor electrode. It is worth mentioning that this methodology is readily adaptable to fabricating MnO(2), Co(3)O(4), and Cr(2)O(3) nanowires from single-walled carbon nanotubes and Co(3)O(4) and Cr(2)O(3) nanolamellas from graphene sheets. PMID- 20828186 TI - Ni(0)-catalyzed 1,4-selective diboration of conjugated dienes. AB - A catalytic stereoselective 1,4-diboration of conjugated dienes with B(2)(pin)(2) was accomplished with Ni(cod)(2) and PCy(3) as the catalyst. This reaction broadens the substrate scope of current methods for catalytic diene diboration by including internal and sterically hindered dienes, and it proceeds efficiently at low catalyst loadings. The intermediate allylboronate was oxidized to the stereodefined allylic 1,4-diol. PMID- 20828187 TI - Engineering of linear molecular nanostructures by a hydrogen-bond-mediated modular and flexible host-guest assembly. AB - The formation of a desired nanostructure with concomitant patterns and functions is of utmost importance in the field of surface molecular engineering and nanotechnology. We here present a flexible host-guest assembly, which steers the formation of linear molecular nanostructures on surfaces by a hydrogen-bond mediated assembly process. A linear monodendron molecular template with periodic hydrogen-bond binding sites is shown to accommodate a variety of molecules with pyridylethynyl terminals. The unit cell parameters in the transverse direction of the linear pattern can be tuned from 3.4 to 7.3 nm in response to the packing of the guest molecules with different sizes, shapes, and aggregation number. The introduction of hydrogen-bonding partners into the host template and into guest molecules is responsible for the steering of the linear pattern of guest molecules. The modular approach could greatly facilitate the ordering of guest molecules with desired functional moieties. PMID- 20828188 TI - Copper-catalyzed synthesis of alpha-amino imides from tertiary amines: Ugi-type three-component assemblies involving direct functionalization of sp3 C-Hs adjacent to nitrogen atoms. AB - alpha-Amino imides can be accessed straightforwardly from tertiary amines through copper-catalyzed three-component reactions involving the direct functionalization of sp(3) C-Hs adjacent to nitrogen atoms. This reaction has demonstrated a tolerance to a wide range of functionalizations and can be performed under very mild conditions. A plausible mechanism has been proposed in which an Ugi-type cascade assembly has been included. PMID- 20828189 TI - A new [3]rotaxane molecular machine based on a dibenzylammonium ion and a triazolium station. AB - A novel two-station [3]rotaxane molecular machine based on triptycene-derived macrotricyclic host was conveniently synthesized by the click reaction and methylation of the subsequent 1,2,3-tiazole group. The shuttle process of the [3]rotaxane molecular machine can be reversibly achieved by acid-base control. PMID- 20828190 TI - Metomyl degradation by electro-Fenton and electro-Fenton-like processes: a kinetics study of the effect of the nature and concentration of some transition metal ions as catalyst. AB - The oxidative degradation of insecticide metomyl as active ingredient and of its commercial formulation Lanate 20 L by an electro-Fenton process using a carbon felt cathode and iron ions as catalyst was compared with different transition metal ions such as, cobalt, silver, and copper as catalyst to produce hydroxyl radicals. The effect of catalyst nature and concentration on the degradation kinetics and COD removal was investigated and optimized. For all metal ions under study as catalyst, there is an optimal concentration value for degradation kinetics and solution COD removal efficiency. Fe(III) was confirmed to be the most efficient catalyst among the metals ions tested. The metomyl oxidative degradation was found to obey apparent first-order reaction kinetics, and the absolute rate constant of the oxidation between metomyl and hydroxyl radicals at pH 3.0 was obtained by competitive kinetics method, being 5.42 * 10(9) L mol(-1) s(-1). PMID- 20828191 TI - Novel reduction-responsive cross-linked polyethylenimine derivatives by click chemistry for nonviral gene delivery. AB - Novel reducible disulfide-containing cross-linked polyethylenimines (PEI-SS-CLs) were synthesized via click chemistry and evaluated as nonviral gene delivery vectors. First, about four azide pendant groups were introduced into a low molecular-weight (LMW) PEI (1.8 kDa) to get an azide-terminated PEI. Then, click reaction between a disulfide-containing dialkyne cross-linker and the azide functionalized LMW PEI resulted in a high-molecular-weight disulfide-containing cross-linked PEI composed of LMW constitute via a reducible cross-linker. The synthesized polymers were characterized by (1)H NMR, FTIR, and size-exclusion chromatography (SEC). It was shown that the obtained disulfide-containing cross linked PEIs were able to condense plasmid DNA into positively charged nanoparticles. The degradation of the disulfide cross-linked polymers PEI-SS-CLs induced by DTT was confirmed by a gel retardation assay and SEC analysis. In vitro experiments revealed that the reducible PEI-SS-CLs were less cytotoxic and more effective in gene transfection (in both the presence and absence of serum) than the control nondegradable 25-kDa PEI. This study demonstrates that a reducibly degradable cationic polymer composed of LMW PEI cross-linked via a disulfide-containing linker possesses both higher gene transfection efficiency and lower cytotoxicity than PEI (25 kDa). These polymers are therefore attractive candidates for further in vivo evaluations. PMID- 20828193 TI - Recent changes in particulate air pollution over China observed from space and the ground: effectiveness of emission control. AB - The Chinese government has moved aggressively since 2005 to reduce emissions of a number of pollutants including primary particulate matter (PM) and sulfur dioxide (SO(2)), efforts inadvertently aided since late 2008 by economic recession. Satellite observations of aerosol optical depth (AOD) and column nitrogen dioxide (NO(2)) provide independent indicators of emission trends, clearly reflecting the sharp onset of the recession in the fall of 2008 and rebound of the economy in the latter half of 2009. Comparison of AOD with ground-based observations of PM over a longer period indicate that emission-control policies have not been successful in reducing concentrations of aerosol pollutants at smaller size range over industrialized regions of China. The lack of success is attributed to the increasing importance of anthropogenic secondary aerosols formed from precursor species including nitrogen oxides (NO(x)), non-methane volatile organic compounds (NMVOC), and ammonia (NH(3)). PMID- 20828194 TI - Catalyst-free one-pot four component synthesis of polysubstituted imidazoles in neutral ionic liquid 1-butyl-3-methylimidazolium bromide. AB - A catalyst-free one-pot four component methodology for the synthesis of 1,2,4,5 substituted imidazoles under conventional heating and microwave irradiation using 1-butyl-3-methylimidazolium bromide, [Bmim]Br, as a neutral reaction media is described. A broad range of structurally diverse aldehydes (aromatic aldehydes bearing electron withdrawing and/or electron releasing groups as well as heteroaromatic aldehydes) and primary amines (aromatic and aliphatic) were applied successfully, and corresponding products were obtained in good to excellent yields without any byproduct. PMID- 20828195 TI - Cytotoxic and apoptotic effects of the oxidized derivatives of stigmasterol in the U937 human monocytic cell line. AB - Dietary exposure to phytosterols has increased in recent years due to the incorporation of these compounds into cholesterol-lowering products. Previous studies have investigated the cytotoxic effects of the oxidized derivatives of beta-sitosterol and determined that phytosterol oxidation products (POP) have a similar but less potent toxicity compared to their cholesterol equivalents. In the present study, the cytotoxicity of the oxidized derivatives of stigmasterol were investigated in the U937 cell line. The stigmasta-5,22-diene-3beta,7beta diol (7beta-OH), 5,6-epoxystigmasta-22,23-diol (epoxydiol), 5,6,22,23 diepoxystigmastane (diepoxide), and (22R,23R)-stigmast-5-ene-3beta,22,23-triol (22R,23R-triol) derivatives were identified as the most cytotoxic, and the mode of cell death was identified as apoptosis in cells incubated with 7beta-OH, epoxydiol, and diepoxide stigmasterol. The antioxidants alpha-tocopherol, gamma tocopherol, and beta-carotene did not protect against apoptosis induced by 7beta OH and diepoxide stigmasterol; however, alpha-tocopherol was found to protect against epoxydiol-induced apoptosis. The cellular antioxidant, glutathione, was depleted and the apoptotic protein, Bcl-2, was down-regulated by the stigmasterol oxides identified as apoptotic. PMID- 20828196 TI - Composition and fatty acid distribution of bovine milk phospholipids from processed milk products. AB - The aim of this work was to assess the accuracy of different extraction methods of phospholipids and to measure the effect that processing has on phospholipid composition. Four methods of extracting phospholipids from buttermilk powder were compared to optimize recovery of sphingomyelin. Using the optimal method, the phospholipid profile of four dairy products (raw milk, raw cream, homogenized and pasteurized milk, and buttermilk powder) was determined. A total lipid extraction by the Folch method followed by a solid-phase extraction using the Bitman method was the most efficient technique to recover milk sphingomyelin. Milk processing (churning, centrifuging, homogenization, spray-drying) affected the profile of milk phospholipids, leading to a loss of sphingomyelin and phosphatidylcholine after centrifugation for cream separation. A corresponding decrease in the saturation content of the raw cream phospholipids and a loss of phosphatidylethanolamine after spray-drying to produce buttermilk powder were also observed. PMID- 20828197 TI - Benzothiazinones: prodrugs that covalently modify the decaprenylphosphoryl-beta-D ribose 2'-epimerase DprE1 of Mycobacterium tuberculosis. AB - Benzothiazinones (BTZs) form a new class of potent antimycobacterial agents. Although the target of BTZs has been identified as decaprenylphosphoryl-beta-D ribose 2'-epimerase (DprE1), their detailed mechanism of action remains obscure. Here we demonstrate that BTZs are activated in the bacterium by reduction of an essential nitro group to a nitroso derivative, which then specifically reacts with a cysteine residue in the active site of DprE1. PMID- 20828199 TI - Endochin optimization: structure-activity and structure-property relationship studies of 3-substituted 2-methyl-4(1H)-quinolones with antimalarial activity. AB - Since the 1940s endochin and analogues thereof were known to be causal prophylactic and potent erythrocytic stage agents in avian models. Preliminary screening in a current in vitro assay identified several 4(1H)-quinolones with nanomolar EC(50) against erythrocytic stages of multidrug resistant W2 and TM90 C2B isolates of Plasmodium falciparum. Follow-up structure-activity relationship (SAR) studies on 4(1H)-quinolone analogues identified several key features for biological activity. Nevertheless, structure-property relationship (SPR) studies conducted in parallel revealed that 4(1H)-quinolone analogues are limited by poor solubilities and rapid microsomal degradations. To improve the overall efficacy, multiple 4(1H)-quinolone series with varying substituents on the benzenoid quinolone ring and/or the 3-position were synthesized and tested for in vitro antimalarial activity. Several structurally diverse 6-chloro-2-methyl-7-methoxy 4(1H)-quinolones with EC(50) in the low nanomolar range against the clinically relevant isolates W2 and TM90-C2B were identified with improved physicochemical properties while maintaining little to no cross-resistance with atovaquone. PMID- 20828200 TI - Label-free impedimetric sensor for a ribonucleic acid oligomer specific to hepatitis C virus at a self-assembled monolayer-covered electrode. AB - A ribonucleic acid (RNA) sensor based on hybridization of its peptide nucleic acid (PNA) molecule with a target RNA oligomer of the internal ribosome entry site sequence specific to the hepatitis C virus (HCV) and the electrochemical impedance detection is described. This RNA is one of the most conservative molecules of the whole HCV RNA genome. The ammonium ion terminated PNA molecule was immobilized via its host-guest interactions with the diaza crown ring of 3 thiophene-acetamide-diaza-18-crown-6 synthesized by a simple two-step method, which forms a well-defined self-assembled monolayer (SAM) on gold. Hybridization events of the probe PNA with the target RNA were monitored by measuring charge transfer resistances for the Fe(CN)(6)(3-/4-) redox probe using Fourier transform electrochemical impedance spectroscopy. The ratio of the resistances of the SAM covered electrode measured before and after hybridization increased linearly with log[RNA] in the rat liver lysate with a detection limit of about 23 pM. PMID- 20828201 TI - Black carbon inclusive multichemical modeling of PBDE and PCB biomagnification and -transformation in estuarine food webs. AB - Bioavailability and bioaccumulation of polybrominated diphenylethers (PBDEs) are affected by adsorption on black carbon (BC) and metabolism in biota, respectively. Recent studies have addressed these two processes separately, illustrating their importance in assessing contaminant dynamics. In order to properly examine biomagnification of polychlorinated biphenyls (PCBs) and PBDEs in an estuarine food-web, here we set up a black carbon inclusive multichemical model. A dual domain sorption model, which accounted for sorption to organic matter (OM) and black carbon (BC), was used to estimate aqueous phase concentrations from the measured chemical concentrations in suspended solids. We adapted a previously published multichemical model that tracks the movement of a parent compound and its metabolites in each organism and within its food web. First, the model was calibrated for seven PCB congeners assuming negligible metabolism. Subsequently, PBDE biomagnification was modeled, including biotransformation and bioformation of PBDE congeners, keeping the other model parameters the same. The integrated model was capable of predicting trophic magnification factors (TMF) within error limits. PBDE metabolic half-lives ranged 21-415 days and agreed to literature data. The results showed importance of including BC as an adsorbing phase, and biotransformation and bioformation of PBDEs for a proper assessment of their dynamics in aquatic systems. PMID- 20828202 TI - Inhalation exposure to fluorotelomer alcohols yield perfluorocarboxylates in human blood? AB - Levels of perfluorinated carboxylates (PFCAs) in different environmental and biological compartments have been known for some time, but the routes of exposure still remain unclear. The opinions are divergent whether the exposure to general populations occurs mainly indirect through precursor compounds or direct via PFCAs. Previous results showed elevated blood levels of PFCAs in ski wax technicians compared to a general population. The objective of this follow-up study was to determine concentrations of PFCAs, perfluorosulfonates (PFSAs), and fluorotelomer alcohols (FTOHs), precursor compounds that are known to degrade to PFCAs, in air collected in the breathing zone of ski wax technicians during work. We collected air samples by using ISOLUTE ENV+ cartridges connected to portable air pumps with an air flow of 2.0 L min(-1). PFCAs C5-C11 and PFSAs C4, C6, C8, and C10 were analyzed using LC-MS/MS and FTOHs 6:2, 8:2, and 10:2 with GC-MS/MS. The results show daily inhalation exposure of 8:2 FTOH in MUg/m(3) air which is up to 800 times higher than levels of PFOA with individual levels ranging between 830-255000 ng/m(3) air. This suggests internal exposure of PFOA through biotransformation of 8:2 FTOH to PFOA and PFNA in humans. PMID- 20828203 TI - Solid-supported synthesis and click conjugation of 4'-C-alkyne functionalized oligodeoxyribonucleotides. AB - 4'-C-[N,N-Di(4-pentyn-1-yl)aminomethyl]thymidine and 4'-C-[N-methyl-N-(4-pentyn-1 yl)aminomethyl]thymidine 3'-(2-cyanoethyl-N,N-diisopropyl)phosphoramidites (1, 2) were synthesized, and one or two such monomers were incorporated into a 15-mer oligodeoxyribonucleotide. After chain assembly, azido-functionalized ligands, including appropriate derivatives of 1,4-phenylenedimethaneamine, mannose, paromamine, and neomycin, were conjugated to the alkynyl groups by the click chemistry on a solid support. The influence of the 4'-modifications on the melting temperature with DNA and 2'-O-methyl RNA targets was studied. Oligonucleotides containing one to four mannose ligands in the central part of the chain (up to two 4'-C-[N,N-di(4-pentyn-1-yl)aminomethyl]thymidine units) form equally stable duplexes with complementary 2'-OMe RNA as the corresponding unmodified DNA sequence. At high salt content, the mannose conjugation is even stabilizing. On using a DNA target, a modest destabilization occurs. All the amino group bearing conjugates stabilized the duplexes, the DNA.DNA duplexes more than the DNA.2'-O-methyl RNA duplexes. PMID- 20828204 TI - Evidence for widespread dechlorination of polychlorinated biphenyls in groundwater, landfills, and wastewater collection systems. AB - One of the few pathways for environmental transformation of polychlorinated biphenyls (PCBs) is microbial dechlorination under anaerobic conditions, which is reported to occur in contaminated sediments of rivers, lakes and harbors. The goal of this work was to determine whether PCB dechlorination occurs in built waste treatment environments. We analyzed a large database on PCB congener concentrations in effluents and some influents of facilities in the Delaware River Basin. Positive matrix factorization was used to identify the sources of PCBs and to look for evidence of dechlorination. Seven factors were resolved from the data set of 89 congeners in 645 samples. Two of the resolved factors represented dechlorination signals. One of these was dominated by PCBs 4 and 19 and represents an advanced stage of dechlorination of Aroclors to di- and trichlorinated congeners. This dechlorination signal was most prevalent in effluents from sites with contaminated groundwater and from wastewater treatment plants (WWTPs) that serve combined sewers or treat landfill leachate. The other dechlorination signal appeared to represent an intermediate stage of dechlorination, because it was dominated by two coeluting groups of tetrachlorinated congeners: PCBs 44 + 47 + 65 and 45 + 51. This partial dechlorination signal was most prevalent in the 40 WWTPs with separate (sanitary) sewer systems, where it often comprised more than 20% of the PCBs in the effluents. Both dechlorination signals were present in WWTP influents, but were not observed in stormwater runoff, suggesting that dechlorination occurs in sewers. This work represents the first convincing evidence of PCB dechlorination occurring outside of contaminated aquatic sediments or anaerobic digesters. The results suggest that PCBs are dechlorinated by anaerobic bacteria in sewers, landfills, and contaminated groundwater. These two dechlorination signals comprise about 19% of the total loads of PCBs to the Delaware River from the sampled dischargers. PMID- 20828205 TI - Label-free detection of lectins on carbohydrate-modified boron-doped diamond surfaces. AB - This paper describes the label-free detection of carbohydrate-lectin interactions. The sensor consists of a boron-doped diamond (BDD) electrode terminated with alkynyl surface groups, which have been functionalized via the CuACC (copper(I)-catalyzed azide-alkyne cycloaddition) "click" reaction with carbohydrate analogues bearing an azido-terminating arm. In this work, electrochemical impedance spectroscopy (EIS) was used as an effective technique to probe the specific interactions of the surface-bound carbohydrates with their complementary lectin partners, and the response was found to be dependent on the relative density of sugar units immobilized on the BDD surface. A BDD interface with 60% surface-bound mannose showed a detection limit of ~5 +/- 0.5 nM for Lens culinaris lectin, with an affinity constant of K(A) = (2.63 +/- 0.5) * 10(6) M( 1). PMID- 20828206 TI - Kinetics of UV-H2O2 advanced oxidation in the presence of alcohols: the role of carbon centered radicals. AB - UV photolysis of aqueous hydrogen peroxide samples was carried out in the presence of methanol, ethanol, or t-butanol. The concentrations of H(2)O(2), dissolved O(2), and the alcohols were monitored as a function of time, and a quantitative chemical kinetics model for the photolysis of the solutions is presented. The observed kinetics consisted of an initial rapid consumption of dissolved oxygen followed by a significant acceleration in the photodecomposition of hydrogen peroxide. The acceleration phase was identified to originate from the fast feedback reaction between hydrogen peroxide and the carbon centered radicals resulting from hydrogen atom abstraction from the primary alcohols. In tertiary butanol solutions the radical species formed are more stable and do not react directly with H(2)O(2). As a consequence no significant acceleration of H(2)O(2) photolysis was observed in the presence of t-butanol. PMID- 20828207 TI - Femtosecond study of the deuteron-transfer dynamics of naphtol salts in water. AB - We study the rate and mechanism of deuteron transfer from the photoacids 1 naphtol-4-sulfonate (1-NPS) and 2-naphtol-3,7-disulphonate (2-NPS) to acetate base in aqueous (D(2)O) solution. The photoacids are activated by excitation with 100 fs laser pulses at 267 nm. The electronic absorption and stimulated emission spectra of the photoacid and the conjugate photobase and the vibrational absorption spectra of the hydrated deuteron and the acetate base are probed with broad-band delayed 100 fs pulses at visible and mid-infrared wavelengths, respectively. A significant fraction of the deuteron transfer events are observed to occur on a timescale of <1 ps within hydrogen-bonded contact photoacid-acetate complexes. For 1-NPS, this fraction is much higher than for 2-NPS. At later delay times, the reaction is dominated by deuteron transfer through short-living water wires of different lengths that connect the photoacid and the acetate base. PMID- 20828209 TI - New insights into the influence of heavy metals on phenanthrene sorption in soils. AB - Soil contamination by combinations of heavy metals and organic contaminants has become an increasingly important environmental issue. Effects of heavy metal cations (Cu(2+), Ni(2+), and Pb(2+)) on phenanthrene sorption were systematically investigated using two soils with contrasting physicochemical properties. Spectral and microscopic analyses provide direct evidence for the modification of composition and conformation of dissolved organic carbon (DOC) and hydrophobicity of the interfaces in the presence of metal cations. Parts of rubbery organic carbon (including flexible DOC and humic acids) became condensed on solid surfaces in the presence of heavy metals as evidenced by an increase in the glass transition temperature of the soils. These modifications led to a significant increase in the capacity and nonlinearity of phenanthrene sorption in the soils. As the added metal cations aged for 70 days, the soil solution gradually recovered its original physicochemical properties, and the facilitating effects of the heavy metals on phenanthrene sorption were significantly attenuated. This work highlights the important implications of DOC properties and aging processes of metals in the sorption of hydrophobic organic compounds (HOCs) such as phenanthrene in soils and provides compelling evidence for the facilitating effects of heavy metals on HOC sorption in soils. PMID- 20828210 TI - Thermodynamic and kinetic stability of DSPE-PEG(2000) micelles in the presence of bovine serum albumin. AB - This work investigated the stability of DSPE-PEG(2000) micelles in the presence of bovine serum albumin (BSA). DSPE-PEG(2000) was found to exist in equilibrium among monomeric, micellar, and BSA-bound states, and this equilibrium shifted toward the BSA-bound state when the temperature increased from 20 to 37 degrees C. The micellar state is thermodynamically unstable at both temperatures when the concentration of BSA approaches that of DSPE-PEG(2000), and micelle breakup occurs with a first-order time constant of 130 +/- 9 min at 20 degrees C and 7.8 +/- 1.6 min at 37 degrees C. Thus, previous targeting experiments that demonstrate synergistic effects in multiply functionalized DSPE-PEG(2000) micelles are likely due to targeting that occurs on a timescale faster than that of micelle breakup. Micelle breakup was limited by diffusion at 20 degrees C whereas at 37 degrees C monomer desorption from the micelle was the rate limiting step. These findings give clear guidance concerning the lifetimes of micelles that may be used as diagnostic and therapeutic nanoparticles. PMID- 20828211 TI - Aggregation properties of a novel class of amphiphilic cationic polyelectrolytes containing gemini surfactant segments. AB - A novel class of amphiphilic cationic polyelectrolytes, poly(A-co-G)s, comprising of gemini type surfactant segment 1,3-bis(N,N-dimethyl-N-dodecylammonium)-2 propylacrylate dibromide (G) and acryloyloxyethyl trimethyl ammonium chloride (A), were synthesized. Their aggregation properties were investigated by employing fluorescence spectroscopy, dynamic light scattering, transmission electron microscopy, and zeta-potential measurements. For comparison, a series of polyelectrolytes containing a traditional single alkyl chain surfactant unit (acryloyloxyethyl-N,N-dimethyl-N-dodecylammonium bromide (D)), poly(A-co-D)s, were also synthesized and investigated. It was found that the critical aggregation concentration (cac) of poly(A-co-G)s is much lower than that of poly(A-co-D)s. The huge interpolymer aggregates (with a hydrodynamic radius of >450 nm) occur in poly(A-co-G)s aqueous solution, and the size of aggregates increases with the increase of the molar content of the gemini-type surfmer segment and the concentration of the copolymer. The size of aggregates in poly(A co-D)s aqueous solution is much smaller than poly(A-co-G)s, which also increases with the increase of the molar content of the single alkyl chain surfmer segment and the concentration of the copolymer. The results of aggregation number and charge density of aggregate in poly(A-co-G)s and poly(A-co-D)s indicate that the copolymers have a strong tendency toward interpolymer aggregation and the aggregates in poly(A-co-G)s are much more compact than those of poly(A-co-D)s. These results are interpreted in terms of the synergistic effects of double hydrophobic chains on the gemini surfactant unit. PMID- 20828212 TI - Kinking-induced structural evolution of metal oxide nanowires into single crystalline nanorings. AB - We report an innovative method to fabricate single-crystalline nanorings based on the conventional vapor-liquid-solid (VLS) mechanism. The controllable formation of kinks in functional oxide nanowires (NWs) can be employed to fold the VLS grown NWs into closed ring-shaped nanostructures. Successful syntheses of single crystalline In2O3 and Zn2GeO4 nanorings were demonstrated. The present work provides an efficient method for nanoring fabrication based on NWs. The functional metal oxide nanomaterials with unique ring-shaped structures are expected to find interesting applications such as wave-guiding and photonic circuits. PMID- 20828213 TI - Osmium(III) complexes with POP pincer ligands: preparation from commercially available OsCl(3).3H(2)O and their X-ray structures. AB - Complexes OsCl(3){dbf(P(i)Pr(2))(2)} [1; dbf(P(i)Pr(2))(2) = 4,6 bis(diisopropylphosphino)dibenzofuran], OsCl(3){xant(P(i)Pr(2))(2)} [2; xant(P(i)Pr(2))(2) = 9,9-dimethyl-4,5-bis(diisopropylphosphino)xanthene], and OsCl(3){xant(PPh(2))(2)} [3; xant(PPh(2))(2) = 9,9-dimethyl-4,5 bis(diphenylphosphino)xanthene] have been obtained in high yield by the reaction of the corresponding diphosphine with OsCl(3).3H(2)O. The ruthenium(III) counterparts RuCl(3){dbf(P(i)Pr(2))(2)} (4), RuCl(3){xant(P(i)Pr(2))(2)} (5), and RuCl(3){xant(PPh(2))(2)} (6) are similarly obtained from RuCl(3).3H(2)O in moderate yields. The X-ray structures of dbf(P(i)Pr(2))(2) and complexes 1-3 are also reported. PMID- 20828214 TI - Electrochemical behavior of single-walled carbon nanotube supercapacitors under compressive stress. AB - The effect of compressive stress on the electrochemical behavior of flexible supercapacitors assembled with single-walled carbon nanotube (SWNT) film electrodes and 1 M aqueous electrolytes with different anions and cations were thoroughly investigated. The under-pressed capacitive and resistive features of the supercapacitors were studied by means of cyclic voltammetry measurements and electrochemical impedance analysis. The results demonstrated that the specific capacitance increased first and saturated in corresponding decreases of the series resistance, the charge-transfer resistance, and the Warburg diffusion resistance under an increased pressure from 0 to 1723.96 kPa. Wettability as well as ion-size effect of different aqueous electrolytes played important roles to determine the pressure dependence behavior of the suerpcapacitors under an applied pressure. An improved high-frequency capacitive response with 1172 Hz knee frequency, which is significantly higher compared to reported values, was observed under the compressive pressure of 1723.96 kPa, indicating an improving and excellent high-power capability of the supercapacitors under the pressure. The experimental results and the thorough analysis described in this work not only provide fundamental insight of pressure effects on supercapacitors but also give an important guideline for future design of next generation flexible/stretchable supercapacitors for industrial and consumer applications. PMID- 20828215 TI - A novel secondary DNA binding site in human topoisomerase I unravelled by using a 2D DNA origami platform. AB - The biologically and clinically important nuclear enzyme human topoisomerase I relaxes both positively and negatively supercoiled DNA and binds consequently DNA with supercoils of positive or negative sign with a strong preference over relaxed DNA. One scheme to explain this preference relies on the existence of a secondary DNA binding site in the enzyme facilitating binding to DNA nodes characteristic for plectonemic DNA. Here we demonstrate the ability of human topoisomerase I to induce formation of DNA synapses at protein containing nodes or filaments using atomic force microscopy imaging. By means of a two-dimensional (2D) DNA origami platform, we monitor the interactions between a single human topoisomerase I covalently bound to one DNA fragment and a second DNA fragment protruding from the DNA origami. This novel single molecule origami-based detection scheme provides direct evidence for the existence of a secondary DNA interaction site in human topoisomerase I and lends further credence to the theory of two distinct DNA interaction sites in human topoisomerase I, possibly facilitating binding to DNA nodes characteristic for plectonemic supercoils. PMID- 20828216 TI - Comprehensive lipidomics analysis of bioactive lipids in complex regulatory networks. AB - In the present work we describe the development of an analytical technique for simultaneous profiling of over 100 biochemically related lipid mediators in biological samples. A multistep procedure was implemented to extract eicosanoids and other bioactive lipids from the biological matrix, chromatographically separate them using fast reversed-phase liquid chromatography, tentatively identify new candidate eicosanoids through a matching process of retention times, isotope distribution patterns, and high-resolution orbitrap MS/MS fragmentation patterns, and subsequently quantify tentative candidates by means of analytical reference standards. Key new aspects of this profiling technique included the classification of bioactive lipids into 12 groups according to their calculated exact masses and the development of optimized liquid chromatographic conditions for these groups to achieve sufficient separation of the numerous isobaric and isomeric species, many of which exhibited virtually identical collision-induced dissociation behavior. Importantly, no analytical standards were required at this screening stage of the assay, and tentative identifications were achieved by matching results to selected reference species from each of the groups. The analytical figures of merit for the orbitrap assay such as linear dynamic range, limit of detection, limit of quantitation, and precision demonstrated that the performance of the assay was very similar to that of a quadrupole linear ion trap assay, which was used for validation purposes. The method allowed us to examine eicosanoid profiles within the signaling cascade in chronic lymphocytic leukemia (CLL) cells under basal conditions and following arachidonic acid stimulation. The preliminary screening based on high-resolution tandem mass spectrometry data along with isotope pattern and retention time matching revealed the presence of 15 bioactive lipids, belonging to a range of prostaglandin, leukotriene, and hydroxy and epoxy fatty acid lipid mediators produced by CLL cells. PMID- 20828218 TI - Effects of molecular sieving and electrostatic enhancement in the adsorption of organic compounds on the zeolitic imidazolate framework ZIF-8. AB - In this work, the adsorption behavior of a range of organic vapors and gases on the zeolitic imidazolate framework, ZIF-8, is investigated using an inverse gas chromatography (IGC) methodology at the zero-coverage limit and elevated temperatures. The measured thermodynamic values and surface energies for the adsorption of n-alkanes on ZIF-8 are found to be reduced from those previously reported for IRMOF-1. This reduction is most likely an effect of the predominately organic accessible surface of ZIF-8 and the resulting weaker interactions in comparison to IRMOF-1. The pore aperture size of ZIF-8, which is significantly reduced from that of IRMOF-1, is seen to introduce molecular sieving effects for branched alkanes, aromatics, and heavily halogenated compounds. Deformation polarizabilities of the adsorbates were used to calculate the specific adsorption free energy, and it is determined that the specific effects account for around 1-5 kJ/mol, or between 10% and 70% of the total free energy of adsorption for the sorbates studied (at 250 degrees C). The importance of electrostatic forces was seen in the significantly enhanced adsorption of propylene and ethylene in comparison to their respective alkanes and in the direct correlation shown between the specific components of the free energy of adsorption and the adsorbate's dipole moment. PMID- 20828217 TI - Investigating neoplastic progression of ulcerative colitis with label-free comparative proteomics. AB - Patients with extensive ulcerative colitis (UC) have an increased risk of colorectal cancer. Although UC patients generally undergo lifelong colonoscopic surveillance to detect dysplasia or cancer in the colon, detection of cancer in this manner is expensive and invasive. An objective biomarker of dysplasia would vastly improve the clinical management of cancer risk in UC patients. In the current study, accurate mass and time methods with ion intensity-based label-free proteomics are applied to profile individual rectal and colon samples from UC patients with dysplasia or cancer (UC progressors) compared to rectal samples from patients that are dysplasia/cancer free (UC nonprogressors) to identify a set of proteins in the rectum mucosa that differentiate the two groups. In addition to the identification of proteins in UC dysplastic colon tissue, we for the first time identified differentially expressed proteins in nondysplastic rectal tissue from UC progressors. This provides a candidate pool of biomarkers for dysplasia/cancer that could be detected in a random nondysplastic rectal biopsy. Mitochondrial proteins, cytoskeletal proteins, RAS superfamily, proteins relating to apoptosis and metabolism were important protein clusters differentially expressed in the nondysplastic and dysplastic tissues of UC progressors, suggesting their importance in the early stages of UC neoplastic progression. Among the differentially expressed proteins, immunohistochemistry analysis confirmed that TRAP1 displayed increased IHC staining in UC progressors, in both dysplastic and nondysplastic tissue, and CPS1 showed a statistically significant difference in IHC staining between the nonprogressor and progressor groups. Furthermore, rectal CPS1 staining could be used to predict dysplasia or cancer in the colon with 87% sensitivity and 45% specificity, demonstrating the feasibility of using surrogate biomarkers in rectal biopsies to predict dysplasia and/or cancer in the colon. PMID- 20828219 TI - A multi-university study of which factors medical students consider when deciding to attend a rural clinical school in Australia. AB - INTRODUCTION: As in many developed nations, there is a shortage in the rural medical workforce in Australia. Research indicates that a strong relationship exists between rural educational exposure and an increased interest in pursuing a rural career or selecting a rural internship. Accordingly, in 2000 the Australian Commonwealth Government established the Rural Clinical Schools (RCS) program. Under this program, 25% of parent medical schools' Commonwealth Supported Place (CSP) medical students must spend at least 1 year of their clinical medical education in a rural setting. Research indicates that positive experiences are of vital importance in determining future rural practice. Arguably, if students are conscripted to a RCS, they may view their overall experience negatively. Thus, the development and sustainability of an adequate future rural medical workforce depends on medical schools understanding and fostering the factors that encourage voluntary student recruitment to the RCSs. The aim of the present study was to determine which factors Australian medical students consider in their decision to attend RCSs. METHODS: This study employed survey research. The questionnaire, which used a 6 point Likert scale, addressed factors influencing students' decision to attend an RCS, including whether these factors were viewed as positive or negative. Open-ended questions provided students with an opportunity to make comments about their decision-making. The setting was the RCSs of six participating Australian universities. The participants were medical students enrolled at one of six Australian universities in 2006 (n=166) who had completed their RCS term; 125 students responded (75% response rate). RESULTS: At least three-quarters of the respondents considered the following when deciding whether to attend an RCS: patient access, academic reputation, their friends, the availability of subsidized accommodation provided by the clinical school, extra curricular activities, social opportunities and transport costs. The majority of students considered the following as positive considerations: 'patient access', 'academic reputation', and 'subsidized accommodation'. However, for other students these same factors were negative considerations. CONCLUSION: Students consider both clinical and non-clinical factors in their decision to attend an RCS. The primary positive factor in the present study was patient access with 97% students (n=119) considering this to be important, and 84% students (n=81) stating that this was a positive factor in their decision-making. The other major factors, friends and academic reputation, appear equally considered. However, they differed in the degree to which they were regarded as a positive or negative consideration. Identifying and promoting positive factors is essential if the future rural medical workforce is to be enhanced. This study supports the importance of RCSs not being over-crowded and, thus, maintaining patient access, and also the importance of institutions having sufficient resources to support an excellent academic reputation. Interestingly, and perhaps somewhat contrary to expectations, students of metropolitan origin appear to be increasingly attracted to RCSs. Although numerous studies show that rural origin is a strong predictor of rural medical workforce membership, urban students who attend an RCS and have a positive experience may also be open to future rural practice. PMID- 20828220 TI - Rurality of communities and incidence of stroke: a confounding effect of weather conditions? AB - INTRODUCTION: An urban-rural gap in stroke incidence or mortality has been reported. However, whether the effect of rurality on stroke is independent of the distribution of conventional individual-level risk factors and other community level risk factors is inconclusive. METHODS: A cohort study was conducted involving 4849 men and 7529 women residing in 12 communities throughout Japan. Baseline data were obtained between April 1992 and July 1995. Follow up was conducted annually to capture first-ever-in-life stroke events. During that period, geographic, demographic and weather information was obtained for each community. Multi-level logistic regression analysis was conducted to evaluate the association between stroke incidence and each geographic/demographic factor adjusted for meteorological parameters (temperature and rainfall), in addition to individual-level risk factors (age, body mass index, smoking, total cholesterol, hypertension, and diabetes). RESULTS: Throughout an average of 10.7 years' follow up, 229 men and 221 women with stroke events were identified. In women, low population (odds ratio [OR] per 1000 persons 0.97; 95% confidence interval 0.94 1.00), low population density (OR per 1/km2 0.85; 0.74-0.97) and high altitude (OR per 100 m 1.18; 1.09-1.28) increased the risk of stroke independently of individual-level risk factors; however, significance was absent for all three associations when further adjusted for weather parameters. Conversely, the association between each meteorological parameter and stroke in women was significant, even after adjustment for each of the three geographic/demographic factors. Similar results were obtained for cerebral infarction. CONCLUSION: The association between living in rural communities and stroke may be caused by the confounding effect of weather conditions in the communities studied. PMID- 20828221 TI - Antiproteinuric effect of cilnidipine in hypertensive Japanese treated with renin angiotensin-system inhibitors - a multicenter, open, randomized trial using 24 hour urine collection. AB - Sustained proteinuria is an important risk factor for not only renal but also cardiovascular morbidity and mortality. Although inhibitors of the renin angiotensin system (RAS) have been shown to reduce proteinuria. Monotherapy with those drugs is often insufficient for optimal blood pressure (BP)-lowering and therefore, combined therapy is needed. Recent reports suggested that cilnidipine, a dual L-/N-type calcium channel blocker, has renoprotective effect by dilating both efferent and afferent arterioles. In this study, a multicenter, open, randomized trial was designed to compare the antiproteinuric effect between cilnidipine and amlodipine when coupled with RAS inhibitors in hypertensive patients with significant proteinuria. Proteinuria was evaluated by 24-h home urine collection for all patients. A total of 35 proteinuric (>0.1 g/day) patients with uncontrolled BP (>135/85 mmHg) were randomized to receive either cilnidipine (n = 18) or amlodipine (n = 17) after a 6-month treatment with RAS inhibitors and were followed for 48 weeks. At baseline, the cilnidipine group was older and had lower body mass index (BMI) compared to the amlodipine group. After 32 weeks of treatment, diastolic blood pressure (DBP) was slightly, but significantly reduced, in the cilnidipine group, although systolic blood pressure (SBP) and mean BP did not differ. The urinary protein did not differ at baseline (cilnidipine group 0.48 g/day, amlodipine group 0.52 g/day); however, it significantly decreased in the cilnidipine group (0.22 g/day) compared to the amlodipine group (0.50 g/day) after 48 weeks of treatment. Our findings suggest that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients even undergoing treatment with RAS inhibitors. PMID- 20828222 TI - Effect of endurance exercise training on oxidative stress in spontaneously hypertensive rats (SHR) after emergence of hypertension. AB - The purpose of this study is to elucidate the effect of wheel training on oxidative stress maker levels in spontaneous hypertensive rats (SHR). 4 hydroxynonenal and 3-nitrotyrosine levels in the aorta of SHRs were allowed to run for 10 weeks from the age of 15 weeks were measured and compared with those of nonexercised SHRs. The 4-hydroxynonenal and 3-nitrotyrosine levels in the exercised group were significantly lower than those in the nonexercised group. The exercised group showed a significant increase of manganese-containing superoxide dismutase. Endurance exercise showed a possible suppressing effect on the arteriosclerosis development by reducing oxidative stress, even after emergence of hypertension. PMID- 20828223 TI - The bedtime administration ameliorates blood pressure variability and reduces urinary albumin excretion in amlodipine-olmesartan combination therapy. AB - Chronotherapy has the potential to improve blood pressure (BP) variability and to decrease stroke and cardiovascular events. The present study examined the efficacy and safety of the bedtime administration in amlodipine-olmesartan combination therapy, as compared with the morning administration. The present study was an open-label, randomized crossover study of the effects of the morning vs. bedtime administration of amlodipine-olmesartan combination. The subject was 31 essential hypertensive patients. Morning BP surge (MBPS) and nocturnal BP pattern were analyzed from ambulatory BP data. Glucose and lipid profiles and cardiovascular-renal data were also collected. The bedtime administration reduced MBPS significantly (24.2 +/- 13.5 mmHg vs. 32.3 +/- 14.2 mmHg, p < 0.001) with no excessive nocturnal BP fall. In nondipper, the bedtime administration significantly improved nocturnal BP. On the other hand, it did not reduce nocturnal BP in dipper. Urinary albumin/creatinine ratio was lower in the bedtime administration than in the morning administration (42.5 +/- 59.9 mg/g vs. 75.3 +/ 26.4 mg/g, p = 0.044). In amlodipine-olmesartan combination therapy, the bedtime administration reduced better MBPS with correcting nocturnal BP fall and improved urinary albumin excretion. The bedtime dosing of amlodipine and olmesartan seems more apt than the morning dose to obtain the therapeutic goal. PMID- 20828224 TI - Cupping for hypertension: a systematic review. AB - The objective of this review is to assess the clinical evidence for or against cupping as a treatment for hypertension. We searched the literature using 15 databases from their inception to 30 June 2009, without language restrictions. We included all clinical trials (CTs) of cupping to treat hypertension in human patients. Risk of bias was assessed using the Cochrane criteria. Two CTs met all inclusion criteria. One RCT (randomized CT) assessed the effectiveness of dry cupping on changes in cerebral vascular function compared with drug therapy. Their results suggested significant effect in favor of cupping on vascular compliance and degree of vascular filling. One uncontrolled observational study (UOS) tested wet cupping for acute hypertension and found that a one-time treatment reduced blood pressure. In conclusion, the evidence is not significantly convincing to suggest cupping is effective for treating hypertension. Further research is required to investigate whether it generates any specific effects for that condition. PMID- 20828225 TI - New agents and approaches to the treatment of B-cell non-Hodgkin lymphoma. AB - IMPORTANCE OF THE FIELD: B-cell non-Hodgkin lymphoma (NHL) is a significant public health problem as the most common hematologic malignancy in many areas of the world. Current treatments are generally effective, but only a minority of this large group of patients can be cured. AREAS COVERED IN THIS REVIEW: Progress in clinical development of novel, targeted agents and newer cytotoxic agents has led to improved, more durable responses in all major subtypes of NHL. This article covers novel therapeutic agents, which are investigational or registered recently for NHL and/or other cancers. Subtypes of B-cell NHL are addressed separately including relevant papers over the past 20 years. WHAT THE READER WILL GAIN: This review provides a better understanding of studies that have formed the basis for current treatment approaches for B-cell NHL. Also, areas of unmet need are covered. Novel agents are described along with their mechanisms of action, as well as how they might advance the treatment of B-cell NHL. TAKE HOME MESSAGE: This review highlights advancements and the current state of knowledge by presenting clinical trial results as well as preclinical data and advances in prognostic and predictive factors that will pave the way to further progress in NHL. PMID- 20828226 TI - Emerging drugs in endometrial cancers. AB - IMPORTANCE OF THE FIELD: Endometrial cancer remains the most common gynecologic malignancy. The treatment of endometrial cancer is rapidly evolving. AREAS COVERED IN THIS REVIEW: In this article, we aim to review current and future treatment options in the medical treatment of endometrial cancers. WHAT THE READER WILL GAIN: The cornerstone of curative therapy for patients with endometrial cancer is surgical treatment. Cytotoxic chemotherapy is the mainstay of therapy for metastatic and advanced endometrial cancer. The most active chemotherapy agents are anthracyclines, platinum compounds and taxanes. Combination chemotherapy has produced higher response rates than single agent therapy. Cisplatin and doxorubicin combination chemotherapy has served as the control arm in many trials. Three-drug combination regimen has shown the highest response rate but with increased toxicity. Despite the lack of published data supporting the superiority of the paclitaxel plus carboplatin combination over doxorubicin and cisplatin, many centers prefer this regimen as a standard of care. Hormonal therapy should be considered in patients with low grade tumors and in those with a poor performance status. Recent advances in the understanding of the molecular biology of endometrial cancer have led to development of targeted therapies. Among these the more promising ones are mTOR inhibitors and antiangiogenic agents. TAKE HOME MESSAGE: Clinical trials are planned to further explore how to best incorporate novel agents into the current treatment algorithm with the aim to improve outcome for women with endometrial adenocarcinomas. PMID- 20828227 TI - Erythropoietin molecules to treat acute ischemic stroke: a translational dilemma! AB - IMPORTANCE OF THE FIELD: Since the realization that erythropoietin (EPO) molecules have 'neuroprotective' properties, they have been investigated as treatments for acute ischemic stroke (AIS), but not systematically. The results of the 2009 clinical trial showed that EPO was ineffective as a stroke treatment, and moreover, increased mortality when combined with tissue plasminogen activator. Currently, CEPO, an EPO analog, is entering into a safety, tolerability and pharmacokinetic clinical trial for the treatment of AIS. AREAS COVERED IN THIS REVIEW: This review covers translational and clinical studies carried out over the period 1998 - 2010. WHAT THE READER WILL GAIN: The primary aim of this article is to review the information available regarding the pharmacological and biological characteristics of EPO molecules. Second, based upon the translational research with EPO molecules in preclinical stroke models, a recommendation is made regarding the continued development of EPO molecules as an option to treat AIS. TAKE HOME MESSAGE: EPO, CEPO and helix B peptide EPO analogs have significant neuroprotective activity is preclinical stroke models. However, given the detrimental effect of EPO in a recent clinical trial, preclinical safety studies of EPO molecules in embolic stroke models that parallel acute ischemic stroke in humans are warrented. PMID- 20828228 TI - Social communication skills group treatment: a feasibility study for persons with traumatic brain injury and comorbid conditions. AB - OBJECTIVES: To evaluate the feasibility of improving impaired social communication skills in persons with traumatic brain injury (TBI) and concomitant neurological or psychiatric conditions, using an intervention with evidence of efficacy in a TBI cohort without such complications. RESEARCH DESIGN: Cohort study with pre-post intervention and follow-up assessments. METHODS: Thirty individuals with TBI >= 1 year post-injury and identified social communication problems participated in a group intervention to improve social communication skills. INTERVENTIONS: Group Interactive Structured Treatment (GIST) for Social Competence; 13 week, 1.5 hour manualized intervention. OUTCOME MEASURES: Profile of Pragmatic Impairment in Communication (PPIC); Social Communication Skills Questionnaire-Adapted (SCSQ-A); LaTrobe Communication Questionnaire (LCQ); Goal Attainment Scale (GAS), Awareness Questionnaire (AQ), Satisfaction with Life Scale (SWLS); Participation Assessment with Recombined Tools (PART). MAIN OUTCOMES AND RESULTS: Participants made statistically significant gains on the SCSQ-A, GAS and SWLS post-treatment and at 6 months follow-up, using self and other ratings. Gains on the PPIC did not reach statistical significance but trended toward improvement. Treatment effects were not noted in analyses of the AQ or the PART. The LCQ showed statistically significant gains post-treatment and at follow-up. CONCLUSIONS: Participants showed improvement on subjective social communication skills measures post-treatment and at follow-up, demonstrating potential efficacy of the intervention in a broader population of persons with TBI, worthy of further investigation. PMID- 20828229 TI - Evaluating the methodological quality of sports neuropsychology concussion research: a systematic review. AB - PRIMARY OBJECTIVE: Sports-related concussion is a frequently-occurring, serious neurological event that can produce a spectrum of potentially debilitating primary and secondary problems. Many investigators-particularly neuropsychologists-have focused their efforts on identifying cognitive changes that accompany such injuries. As such, the present review evaluated the methodological quality of neuropsychological sports-related concussion research using a comprehensive, systematic method. RESEARCH DESIGN: Of 349 studies initially selected by search criteria, a total of 43 studies were evaluated using a Cochrane-style review format. RESEARCH METHODS: Studies were assigned a Level of Evidence using the Centre for Evidence-based Medicine (CEMB) framework. Relevant information related to the methods of each study were extracted and rated for methodological quality using a standardized form-based evaluation tool. RESULTS: The review revealed heterogeneity among the studies in terms of research design, as well as a number of methodological weaknesses and inconsistencies. CONCLUSION: Despite the proliferation of neuropsychological research on sports related concussion over the past decade, the methodological quality of studies appears to be highly variable, with many lacking proper scientific rigour. Future research in this area needs to be carefully controlled, repeatable and generalizable, which will contribute to developing practical, evidence-based guidelines for concussion management. PMID- 20828230 TI - The truth effect in relation to neuropsychological functioning in traumatic brain injury. AB - OBJECTIVES: Individuals with traumatic brain injury may have difficulty accepting other viewpoints, but there is not yet a clinical test to measure the readiness with which one accepts new information as true. This study examined the truth effect-the tendency to rate previously seen material as being 'more true' than newly presented material-to explore whether individual differences in the truth effect can be quantified and related to memory or other neuropsychological variables, including brain injury severity. METHODS: Seventy-four individuals being seen for neuropsychological assessment were asked to classify 15 semantic statements as biographical, scientific or historical and were later asked to rate 10 of the previously viewed statements and 10 new statements as either true or false. RESULTS: A truth effect was clearly present in two groups which had gained familiarity with opposite sets of statements. As well, individuals with better immediate verbal memories rated more of the previously seen statements as true. CONCLUSIONS: A verbal encoding factor appears to underlie the truth effect and may explain the difficulties that some TBI patients have in accepting newly presented information as true. PMID- 20828231 TI - Anterior pituitary dysfunction in moderate-to-severe chronic traumatic brain injury patients and the influence on functional outcome. AB - OBJECTIVE: The objective of this study is to determine the prevalence of anterior pituitary dysfunction in moderate-to-severe chronic traumatic brain injury (TBI) patients. The investigation of a relationship between pituitary hormonal status and body mass index (BMI) in TBI patients by observing changes in BMI was conducted as well as an assessment of whether there is a difference in functional outcome related to anterior pituitary dysfunction in TBI patients. METHODS: Forty five TBI patients and 30 normal controls underwent a series of standard endocrine tests for anterior pituitary hormone function. It was studied whether changes in BMI correlated with anterior pituitary hormone levels. This study also compared changes in mini-mental state examination (K-MMSE) and functional independence measure (FIM) scores between patients in the hormone-sufficient and -deficient groups. RESULTS: Anterior pituitary dysfunction was found in 31.1% of TBI patients. Changes in BMI statistically correlated with IGF-1 and basal cortisol levels. A meaningful difference was found between the hormone-sufficient and deficient groups in light of the K-MMSE and FIM score gains. CONCLUSIONS: These findings strongly suggest that patients who suffer head trauma should be routinely tested for anterior pituitary hormone deficiency. PMID- 20828232 TI - Noninvasive evaluation of splanchnic tissue oxygenation using near-infrared spectroscopy in preterm neonates. AB - BACKGROUND: Diagnosis of necrotizing enterocolitis (NEC) in preterm neonates is challenging. We hypothesized that regional splanchnic oxygen saturation (rsSO2) measured by near-infrared spectroscopy (NIRS) is a biomarker for mesenteric perfusion. OBJECTIVE: To evaluate feasibility and safety of continuous rsSO2 monitoring in preterm infants in the first 14 days of life. METHODS: Preterm neonates <=30 weeks' gestation had a NIRS sensor placed in the left paraumbilical region within 48 h of birth. rsSO2 was recorded every 30 s. Clinical data including pulse oximetry (SaO2) were recorded. Fractional tissue oxygen extraction (FTOE) was computed as follows: (SaO2 - rsSO2) * 100/SaO2. RESULTS: Of 21 infants enrolled, 2 were excluded because of skin breakdown and missing data. Daily mean rsSO2 values decreased over the first 9 days (p < 0.0001) followed by an increase from day 10 (D10) to D14 (p = 0.0061). rsSO(2) was lower and FTOE was higher in infants with feeding intolerance compared to those without feeding intolerance (p = 0.0043). rsSO2 accounted for >=99.5% of the variance in FTOE. Two neonates with NEC had persistently low rsSO2 with loss of variability preceded or followed by very high rsSO2. CONCLUSIONS: We have reported feasibility, safety and ranges for rsSO2 for a small number of preterm infants in the first 2 weeks of life. PMID- 20828233 TI - Neurally adjusted ventilatory assist: a new approach to mechanically ventilated infants. AB - Neurally adjusted ventilator assist (NAVA) is a new mode of partial ventilatory support, in which neural inspiratory activity is monitored through the continuous esophageal recording of the electrical activity of the diaphragm. Assistance is triggered and cycled off in according to this signal and is delivered in proportion to its intensity. NAVA can improve patient-ventilator synchrony while maintaining spontaneous breathing. Small preliminary studies have shown that NAVA can be successfully used also in term and preterm infants, being safe and well tolerated. However, much additional work is still needed before NAVA can be recommended in the everyday practice of the neonatologist. PMID- 20828234 TI - Evaluation of fetal heart rate variation during amniocentesis: correlation with fetal karyotype. AB - OBJECTIVE: We monitored the fetal heart rate (FHR) during amniocentesis in fetuses at 16-18 weeks of gestation and investigated whether an abnormal FHR is associated with chromosomal abnormalities. METHODS: This prospective study involves 807 women at 16-18 weeks of gestation who underwent genetic amniocentesis. The FHR, expressed as beats for minute, is recorded before (FHR1), immediately after (FHR2) and 60 min after (FHR3) the invasive procedure. Structural malformations detected by ultrasound and multiple pregnancy are excluded from the study. RESULTS: Chromosomal abnormalities have been diagnosed in 27 fetuses. A mean FHR decrease after amniocentesis has been observed in normal and in abnormal fetuses. The mean variation during amniocentesis is significant in both groups (P < 0.01). The comparison between the mean FHR of the two groups shows no differences in FHR1 and FHR2 (P > 0.05) but a significant difference in FHR3 (P < 0.05). CONCLUSION: The FHR decreases after amniocentesis; the decrease is larger in chromosomally abnormal fetuses than in normal fetuses. This difference in heart rate reaction to amniocentesis might be due to cardiac defects or developmental delay associated with the abnormal karyotype. PMID- 20828235 TI - Prenatal and postnatal neurological evaluation of a fetus and newborn from pregnancy complicated with IUGR and fetal hypoxemia. AB - In this case report, we present prenatal and postnatal neurological evaluation of a fetus and newborn from pregnancy complicated with intrauterine growth restriction, fetal hypoxemia, and preterm labor. Despite unfavorable intrauterine conditions, this premature infant showed normal early neurological development that was verified not only by postnatal tests but also with a new prenatal neurological screening test. PMID- 20828236 TI - Proposed management for reduced fetal movements: five years' experience in one medical center. AB - OBJECTIVE: To assess the management of reduced fetal movements (RFM) based on repeated fetal movement counts, nonstress test (NST), and ultrasound examination. METHODS: This is a retrospective cohort study carried out in a single tertiary maternity hospital. A total of 2393 women with singleton pregnancies at >28 weeks' were referred to obstetric triage with chief complaint of RFM. Persistent movement counts of <5/h and abnormal results of NST or ultrasound mandated an admission for further evaluation. Women with transient RFM and normal ultrasound and NST were discharged. We compared the outcome between these two groups. Maternal and perinatal parameters were compared between women who were admitted and those who were discharged home after evaluation. RESULTS: A total of 2393 women were referred to obstetric triage with chief complaint of RFM, of whom 753 (31.5%) were admitted for further evaluation. Their demographic and obstetrical parameters were similar to those of the nonadmitted women, as were the fetal demise rates. NICU admission and cesarean section rates and low Apgar scores were significantly higher among admitted patients. CONCLUSION: RFM has a clinical significance as a predictor of adverse perinatal outcome. Our study suggests that repeated fetal movement counts, NST, and ultrasonography may identify women at risk for adverse perinatal outcome. PMID- 20828237 TI - Postnatal management of congenital bilateral renal hypodysplasia. AB - Renal hypodysplasia (RHD) is a congenital disorder, characterized by an abnormally developed kidney. Mutations in genes such as PAX2, HNF1-beta, TCF2, EYA1, that encode factors critical in early renal development, are being found. RHD is the leading cause of chronic renal failure in childhood, with or without associated urologic abnormalities such as vesicoureteric reflux and urinary tract obstruction. Antenatal detection has improved understanding of this disorder, resulting in enhanced outcomes through earlier intervention, including peritoneal dialysis. Management requires a multidisciplinary team approach that commences prior to the birth of the child. PMID- 20828238 TI - Unusual high rate of asymptomatic maternal parvovirus B19 infection associated with severe fetal outcome. AB - OBJECTIVE: To study the role of asymptomatic maternal parvo B19 infection in severe fetal outcome in Province of Vojvodina. METHODS: One hundred seventy-six pregnant women (13-25 weeks of gestation) were divided in two groups - patients with symptoms of imminent spontaneous abortion and poor pregnancy outcome and patients with normal course of pregnancy. Double serum samples were analyzed to quantify IgM and IgG to parvovirus B19. RESULTS: Among pregnant women with symptoms of spontaneous abortion, we found significantly higher percentage of acute parvovirus B19 infection. CONCLUSIONS: Asymptomatic parvo B19 infection is associated with poor fetal outcome much more than we presumed previously. PMID- 20828239 TI - Placental abruption: critical analysis of risk factors and perinatal outcomes. AB - OBJECTIVE: To investigate risk factors and pregnancy outcome of patients with placental abruption. METHODS: A population-based study comparing all pregnancies of women with and without placental abruption was conducted. Stratified analysis using multiple logistic regression models was performed to control for confounders. RESULTS: During the study period there were 185,476 deliveries, of which 0.7% (1365) occurred in patients with placental abruption. The incidence of placental abruption increased between the years 1998 to 2006 from 0.6 to 0.8%. Placental abruption was more common at earlier gestational age. The following conditions were significantly associated with placental abruption, using a multivariable analysis with backward elimination: hypertensive disorders, prior cesarean section, maternal age, and gestational age. Placental abruption was significantly associated with adverse perinatal outcomes such as Apgar scores < 7 at 1 and 5 min and perinatal mortality. Patients with placental abruption were more likely to have cesarean deliveries, as well as cesarean hysterectomy.Using another multivariate analysis, with perinatal mortality as the outcome variable, controlling for gestational age, hypertensive disorders, etc., placental abruption was noted as an independent risk factor for perinatal mortality. CONCLUSIONS: Placental abruption is an independent risk factor for perinatal mortality. Since the incidence of placental abruption has increased during the last decade, risk factors should be carefully evaluated in an attempt to improve surveillance and outcome. PMID- 20828240 TI - Newborns from in vitro fertilization conceived pregnancies. AB - Infertility, defined as 'unsuccessful conception after 1 year of unprotected intercourse', is an increasing problem in many countries. Demographic data in Serbia continue to show negative trend of depopulation. One-third of married couples in Serbia are childless and half of them cannot have offspring due to health problems. Analysis of morbidity and mortality of premature newborns IVT (in vitro fertilization) conceived and treated in two Department of Intensive Care, in Novi Sad and Belgrade, Serbia during 2 years. Significant number of IVF conceived newborns are treated at NICUs. Prematurity, low birth weight, perinatal asphyxia, systemic infection, as well as proper initial stabilization, especially prevention and early treatment of systemic hypotension are important factors contributing to morbidity of these patients. PMID- 20828241 TI - Efficacy of intrapartum chemoprophylaxis less than 4 hours duration. AB - OBJECTIVE: Current guidelines for prevention of group B streptococcus (GBS) early onset infection recommend to administer antibiotic during labor at least 4 h prior to delivery (adequate prophylaxis). We aimed to determine if neonatal GBS colonization may be significantly decreased in case of inadequate (<4 h) duration of ampicillin prophylaxis. METHODS: In prospective, cohort study, 167 infants born to 167 GBS culture-positive mothers without additional risk factors were enrolled. Cultures were collected both, at 10-24 h after birth (admission) and at discharge. RESULTS: Among 137 infants born to mothers who received inadequate prophylaxis, 5 (3.6%, C.I. = 0.5-6.8) were colonized (>=1 sites) at admission, at discharge, or both, at admission and discharge. Eighty-two women received prophylaxis <2 h before delivery and two infants (2.4%) were colonized at discharge. Eighteen (60.0%, C.I. = 42.5-77.5) of 30 infants who were not exposed to prophylaxis were colonized at admission or both, at admission and discharge. Colonization was significantly more frequent among infants born to untreated mothers with respect to infants born to women who received inadequate prophylaxis (either <2 or <4 h). CONCLUSIONS: In this selected group, inadequate prophylaxis significantly interrupted vertical colonization. This effect was evident even if prophylaxis started <2 h before delivery. PMID- 20828242 TI - The relationship between meiotic spindle imaging and outcome of intracytoplasmic sperm injection: a retrospective study. AB - Meiotic spindle analysis with a non-invasive technique, the PolScope, is used to protect the meiotic spindle from damage during microinjection. To evaluate the predictive feature of PolScope, we have designed a retrospective study to analyse the correlation between the meiotic spindle visualisation with regard to spindle location and outcomes of assisted reproductive technologies (ART), including patient age, previous cycles, the number of the collected oocytes, fertilisation rates (FR), pronuclear scoring (PNS) and embryo scoring of the days from two to five. All of the data belonging to 1496 oocytes from 190 patients were statistically analysed. We found that the oocytes having PolScope visualised spindle have higher FR, and also observed that when the spindle located at 0 degrees -30 degrees according to the first polar body, gave the highest FR. PNS gave higher scores in the spindle visualised group, but spindle angle did not affect PNS outcomes. Although a correlation was found between spindle visualisation and developed embryo qualities, particularly at day 2 and 3, spindle angles did not affect embryo quality. We conclude that PolScope microscopy has an efficiency to estimate FR, and cleavage stage embryo development. PMID- 20828243 TI - Heat shock protein 10 regulated apoptosis of mouse ovarian granulosa cells. AB - OBJECTIVES: To study the roles of heat shock proteins10 (HSP10) in the regulation of mouse ovarian granulose cell (GC) apoptosis, and to further define the possible roles of HSP10 in the development of polycystic ovary syndrome (PCOS). METHODS: Mouse HSP10 small interfering RNA (siRNA) and recombinant adenoviruses overexpressing HSP10 were constructed and subsequently transfected into cultured mouse ovarian GCs. After an infection period of 48 h, the expression levels of the HSP10 gene in mouse GCs were confirmed by Western blot. The GCs were also assessed for apoptosis using flow cytometry and the TUNEL assay. Apoptosis of GCs overexpressing HSP10 was assessed by flow cytometry after cisplatin treatment. RESULTS: Compared with control group, the expression of HSP10 was decreased in mouse GCs infected with AdCMV-siRNA/HSP10, whereas mouse GCs infected with AdCMV HSP10 showed increased HSP10 expression p < 0.05. Knock-down of HSP10 in mouse GCs significantly increased apoptosis (p < 0.05), whereas overexpression of HSP10 significantly suppressed apoptosis induced by cisplatin (p < 0.05). CONCLUSION: In the present primary study, we have successfully employed recombinant adenovirus technologies to modulate HSP10 gene expression in mouse GCs, and examined the effects on apoptosis. Our experiments have demonstrated that knock down of HSP10 induces apoptosis of mouse ovarian GCs, whereas overexpression of HSP10 suppresses apoptosis. These findings suggested that HSP10 may play a role in the regulation of apoptosis of mouse ovarian GCs. PMID- 20828244 TI - International web survey shows high prevalence of symptomatic testosterone deficiency in men. AB - INTRODUCTION: Though the clinical significance of testosterone deficiency is becoming increasingly apparent, its prevalence in the general population remains unrecognised. A large web-based survey was undertaken over 3 years to study the scale of this missed diagnosis. METHODS: An online questionnaire giving the symptoms characterising testosterone deficiency syndrome (Aging Male Symptoms-AMS scale) was set up on three web sites, together with questions about possible contributory factors. RESULTS: Of over 10,000 men, mainly from the UK and USA, who responded, 80% had moderate or severe scores likely to benefit from testosterone replacement therapy (TRT). The average age was 52, but with many in their 40s when the diagnosis of 'late onset hypogonadism' is not generally considered. Other possible contributory factors to the high testosterone deficiency scores reported were obesity (29%), alcohol (17.3%), testicular problems such as mumps orchitis (11.4%), prostate problems (5.6%), urinary infection (5.2%) and diabetes 5.7%. CONCLUSIONS: In this self-selected large international sample of men, there was a very high prevalence of scores which if clinically relevant would warrant a therapeutic trial of testosterone treatment. This study suggests that there are large numbers of men in the community whose testosterone deficiency is neither being diagnosed nor treated. PMID- 20828245 TI - Relationship among lifestyles, aging and psychological wellbeing using the General Health Questionnaire 12-items in Japanese working men. AB - INTRODUCTION. The relationship among lifestyle, aging and psychological wellbeing was evaluated in Japanese working men. METHODS. Self-administered questionnaire on six lifestyle factors and the General Health Questionnaire 12-item version (GHQ12) were administered to 3306 male workers. Health practice index (HPI) was calculated as a desirable lifestyle score by summing up each binary lifestyle score (0, 1), ranging from 0 to 6. To check validity of the study outcome, the authors repeated twice with 1 year interval. HPI was categorised into three groups by the score of 0-2, 3-4 and 5-6. RESULTS. The number of subjects categorised by HPI was 532, 1967 and 807, respectively. The mean value of GHQ12 significantly decreased as the HPI increased by adjusting age. Multiple regression analysis was conducted to predict GHQ12 by six lifestyle scores, and age, sleep, night snacking and exercise were significantly related to GHQ12. Multiple logistic regression analysis was conducted and age in 50s, two-shift work, sleep, night snacking and exercise were significantly associated with GHQ12. CONCLUSION. Although cause-effect relationship cannot make clear, some of desirable health practices and aging were closely related to psychological wellbeing judged by GHQ12. PMID- 20828246 TI - Clinical assessment and validation of an Arabic Aging Male Symptoms questionnaire in patients with androgen deficiency. AB - AIM: To develop and to validate an Arabic Aging Male Symptoms (AMS) tool and to clinically assess patients with hypogonadism after hormonal treatment. METHODS: The tool was translated into Arabic and tested on 15 Saudi men. During a period of 9 months all males presented to the andrology clinic of the main University Hospital, King Saud University, Saudi Arabia with signs and symptoms of hypogonadism, were included in the study. Arabic AMS scale was applied in the base line visit, then 12 weeks after treatment. Testosterone was monitored before treatment, 4 weeks and after 12 weeks. RESULTS: Ninety-two subjects were included, Cronbach's alpha of 0.91 showed a very good internal consistency of the Arabic AMS questionnaire. The corresponding alpha for the subscales were 0.83, 0.84 and 0.73. There was a significant improvement in the mean level of TT after hormonal therapy (HT), this was reflected on the mean differences of improvement in the total Arabic AMS scores and subscales scores after HT, ranged from 31 to 35%. CONCLUSION: The present study revealed a significant association between testosterone levels and AMS tool manifested by a its good ability to measure the effect of treatment on quality of life for patients with hypogonadism. PMID- 20828247 TI - Lower urinary tract symptoms and erectile dysfunction associated with depression among Japanese patients with late-onset hypogonadism symptoms. AB - The aim of this study was to investigate the relation between lower urinary tract symptoms (LUTS), erectile dysfunction (ED) and depression in Japanese patients with late-onset hypogonadism (LOH) symptoms. The study comprised 87 Japanese patients with LOH symptoms (>27 points on the Aging Males Symptoms Scale). Thirty four patients were diagnosed as having depression and the remaining 53 patients were diagnosed as not having depression by the Mini International Neuropsychiatric Interview. We compared the International Index of Erectile Function (IIEF) 5, International Prostate Symptom Score (IPSS), IPSS quality-of life (QOL) index, King's Health Questionnaire (KHQ), endocrinological data, and free uroflow study between depression and non-depression patients and performed multiple logistic regression analysis. IIEF5 scores of depression patients were significantly lower than those of non-depression patients. In KHQ, only the category of general health perceptions was significantly higher in depression patients than non-depression patients. However, IPSS, QOL index, and endocrinological and uroflowmetric data showed no significant difference between the groups. Multiple logistic regression analysis revealed moderate and severe ED to be risk factors for depression. However, LUTS are not related to depression. Moderate and severe ED is correlated with depression, whereas LUTS are not related to depression in Japanese LOH patients. PMID- 20828248 TI - The effect of circulating estradiol concentrations on gonadotropin secretion in young and old castrated male-to-female transsexuals. AB - CONTEXT: In aging men, circulating testosterone (T) declines which is associated with an increase in the levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) , albeit insufficient to maintain T at its original level. It has been speculated that a higher sensitivity of the hypothalamus and/or pituitary for the feedback effect of circulating sex hormones in older men is responsible. OBJECTIVE: To compare the effect of experimentally varied plasma levels of estradiol on the LH and FSH secretion in young and old castrated male to-female transsexuals, in almost absence of T. DESIGN, SUBJECTS, AND INTERVENTIONS: In 10 healthy, young (mean age 37.6 +/- 6.2 years) and 11 healthy, old (mean age 68.1 +/- 7.0) male-to-female transsexuals after gonadectomy plasma estradiol levels were experimentally varied with estradiol patches (the first week 100 MUg/day patches, the second week 50 MUg/day, the third week 25 MUg/day and the fourth week no patch was applied) and plasma levels of LH and FSH were monitored after every week. RESULTS: Mean plasma bioavailable estradiol (E2) levels in the two groups ranged between 13.6 and 104 pmol/l. LH and FSH were inversely related to peripheral estradiol levels, were lower in the old group at all time points reaching statistical significance in the last week of the study when no patch was applied and estradiol levels were extremely low. CONCLUSIONS: The results of this study do not support the hypothesis of an age related increasing sensitivity of the hypothalamo-pituitary compartment for the negative feedback of E2, but suggest a deficient feed-forward drive in older male-to female transsexuals. PMID- 20828250 TI - Literature Review. PMID- 20828254 TI - Health education media in the world's developing countries. PMID- 20828249 TI - Specific cross-reaction of anti-dsDNA antibody with platelet integrin GPIIIa49 66. AB - Anti-platelet autoantibodies are frequently found in systemic lupus erythematosus (SLE) patients and contribute to the development of SLE-associated immunologic thrombocytopenia (SLE-ITP). Although the correlation of anti-dsDNA autoantibody with platelet-associated antibody has been reported, the potential mechanism underlying such a correlation is incompletely understood. We have reported that anti-platelet integrin GPIIIa49-66 (CAPESIEFPVSEARVLED) autoantibodies play a major role in the development of HIV-1-related thrombocytopenia (HIV-1-ITP). The strong negative charge of GPIIIa49-66 prompts us to investigate whether GPIIIa49 66 can be an epitope mimicking dsDNA. We report here that anti-GPIIIa49-66 antibodies are found in three out of nine SLE-ITP patients. Double-stranded (ds) DNA competitively inhibited the binding of purified patient anti-dsDNA antibodies to GPIIIa49-66 peptide. Both polyclonal and monoclonal anti-GPIIIa49-66 antibodies are able to cross-react with dsDNA. Consistent with previous reports, the DNA binding activities of anti-GPIIIa49-66 antibodies are mainly dependent on the positively charged amino acid in the heavy-chain complementarity-determining region 3 (HCDR3). The HCDR3 of human SLE anti-dsDNA monoclonal antibody (mAb) 412.67 demonstrates a similar positively charged amino acid chain orientation compared with that of anti-GPIIIa49-66 mAb A11, and it cross-reacts with GPIIIa49 66 peptide. Purified anti-GPIIIa49-66 antibodies from SLE-ITP patients are able to induce platelet fragmentation in vitro and to induce thrombocytopenia in vivo. Thus, our data suggest that specific epitope cross-reaction between GPIIIa49-66 and dsDNA could be a mechanism involved in the development of SLE-associated thrombocytopenia. PMID- 20828255 TI - Visual reinforcement audiometry: an Adobe Flash based approach. AB - Visual Reinforcement Audiometry (VRA) is a key behavioural test for young children. It is central to the diagnosis of hearing-impaired infants (1) . Habituation to the visual reinforcement can give misleading results. Medical Illustration ABM University Health Board has designed a collection of Flash animations to overcome this. PMID- 20828258 TI - The fundamentals of video production. PMID- 20828259 TI - Google scholar and e-journals. PMID- 20828260 TI - Chief Scientific Officers' Conference, London, 24-25 November 2009. Report. PMID- 20828263 TI - Uniforms: an emotive subject? PMID- 20828264 TI - Just in time: surviving decades of change at Yale. PMID- 20828266 TI - Nonresponders to clopidogrel: pharmacokinetics and interactions involved. AB - IMPORTANCE OF THE FIELD: The use of clopidogrel and aspirin has become standard therapy in patients with acute coronary syndromes and stent implantation. However, concern arises because about 25% of subjects are nonresponders to clopidogrel. This nonresponsiveness is associated with a threefold increase in adverse outcomes. Clopidogrel resistance is multifactorial, but genetic polymorphisms in clopidogrel's metabolic activation (e.g., cytochrome P450 2C19) and drug-drug interactions at this level (e.g., between proton pump inhibitors (PPIs) and clopidogrel) are both associated with decreased clopidogrel efficacy. Despite all PPIs being potent inhibitors of CYP2C19, evidence about their clinical impact is controversial. AREAS COVERED IN THIS REVIEW: Pharmacogenomic and pharmacokinetic aspects of clopidogrel nonresponsiveness were considered in detail. WHAT THE READER WILL GAIN: The reader will gain an exhaustive review of the current state of the controversial issues regarding genetic polymorphisms and drug-drug interactions affecting clopidogrel efficacy. TAKE HOME MESSAGE: It is important to consider clopidogrel resistance in some patients and establish strategies to handle this problem (e.g., genotyping, platelet aggregability tests, new antiplatelet drugs). The combined use of PPIs and clopidogrel is at present regulated by the FDA and EMEA; however, the risk/benefit balance should be made for each patient individually. PMID- 20828267 TI - Ketamine for the treatment of chronic non-cancer pain. AB - IMPORTANCE OF THE FIELD: Worldwide the number of patients affected by chronic pain is growing and conventional treatment is often insufficient. Recently the importance of the N-methyl-d-aspartate receptor (NMDAR) in the mechanisms and maintenance of chronic pain was established. Ketamine (introduced in the 1960s as an anesthetic) is the most studied NMDAR antagonist in the treatment of various chronic pain syndromes. AREAS COVERED IN THIS REVIEW: The pharmacology, safety and toxicology of ketamine are discussed. Further, electronic databases were scanned for prospective, randomized controlled trials that assessed ketamine's analgesic effect in patients with chronic pain. The focus of this review is on trials published after 2008 that applied long-term intravenous infusions. WHAT THE READER WILL GAIN: While most studies on intravenous ketamine show acute analgesic effects, three recent trials on long-term ketamine treatment (days to weeks) demonstrate the effectiveness of ketamine in causing long-term (months) relief of chronic pain. Despite these positive results, further studies are needed on safety/toxicity issues. Other administration modes are less effective in causing long-term pain relief. TAKE HOME MESSAGE: There is now evidence form a limited number of studies that pain relief lasting for months is observed after long-term intravenous ketamine infusion, suggesting a modulatory effect of ketamine in the process of chronic pain, possibly via blockade of upregulated NMDAR. PMID- 20828268 TI - Almotriptan for the acute treatment of adolescent migraine. AB - IMPORTANCE OF THE FIELD: Migraine is a common problem affecting 10 - 20% of adolescents. Its treatment has three fundamental components: bio-behavioral interventions, preventive measures, and acute drug therapy. In June 2009, the US FDA approved almotriptan, a 5-HT1B/1D receptor agonist, for the acute treatment of migraine in adolescents aged 12-17 years--the first 'triptan' to be approved for adolescents. AREAS COVERED IN THIS REVIEW: This review will provide an overview of migraine in adolescents focusing on epidemiology, pathophysiology, classification and a review of treatment options with attention on the evidence from the past 5 years surrounding almotriptan. WHAT THE READER WILL GAIN: Given its recent FDA approval, it is important to for clinicians and pharmacists to become familiar with the clinical spectrum of migraine in teenagers and with recent evidence on this newly approved agent, almotriptan. TAKE HOME MESSAGE: Almotriptan is a safe, effective, and approved agent for the acute treatment of migraine headache in adolescents. PMID- 20828269 TI - Three-dimensional assessment of early surgical outcome in repaired unilateral cleft lip and palate: Part 2. Lip changes. AB - OBJECTIVE: To evaluate three-dimensional lip morphology, following primary reconstruction in children with unilateral cleft lip and palate relative to contemporaneous noncleft data. DESIGN: Prospective, cross-sectional, controlled study. SETTING: Glasgow Dental Hospital and School, University of Glasgow, U.K. PATIENTS AND PARTICIPANTS: Two groups of 3-year-old children (21 with unilateral cleft lip and palate and 96 controls) with facial images taken using a three dimensional vision-based capture technique. METHODS: Three-dimensional images of the face were reflected so the cleft was on the left side to create a homogeneous group for statistical analysis. Three-dimensional coordinates of anthropometric landmarks were extracted from facial images. Three-dimensional, generalized Procrustes superimposition was implemented and a set of linear measurements were used to compare cleft and control subjects for right and left sides, adjusting for sex differences. RESULTS: Crista philtri on both the cleft and noncleft sides were displaced laterally and posteriorly; there was also a statistically significant increase in philtrum width. No significant differences between cleft and control regarding the cutaneous height of the upper lip. The lip in the cleft patients was flatter than in the noncleft individuals, with less prominence of labialis superioris. CONCLUSIONS: Stereophotogrammetry allows detection of residual dysmorphology following cleft repair. There was significant increase of the philtrum width. The lip appeared flatter and more posterior displaced in unilateral cleft lip and palate patients compared with controls. PMID- 20828270 TI - Simultaneous premaxillary repositioning and cheiloplasty in adult patients with unrepaired bilateral cleft lip and palate. AB - Primary cheiloplasty in adult patients with unrepaired complete bilateral cleft lip and palate is quite challenging due to severe premaxillary anterior projection. To get the best repair results, the author carried out repositioning of the premaxilla and repair of the lip deformity in a single stage. Positive results for the primary lip repair and appropriate repositioning of the premaxilla were achieved. No avascular necrosis of the premaxilla was observed. Repositioning of the premaxilla and repair of the lip deformity in a single operation appears to be a reliable method for treating adult patients with previously unrepaired or poorly repaired bilateral cleft lip and palate. PMID- 20828271 TI - Cleft lip/palate: incidence of prenatal diagnosis in Glasgow, Scotland, and comparison with other centers in the United Kingdom. AB - OBJECTIVES: To determine the proportion of children with cleft lip and/or cleft palate diagnosed prenatally between 1999 and 2008 in those referred for treatment to the Royal Hospital for Sick Children in Glasgow, Scotland (RHSC); and to compare the percentage prenatally diagnosed in 2008 versus other cleft treatment centers in the U.K. METHOD: A retrospective study was performed using medical records of the 459 cleft patients born and referred to RHSC between 1999 and 2008. Comparable data for year 2008 were requested from other U.K. units. RESULTS: For the period studied, the percentage of all clefts diagnosed prenatally was 15%. This rose to 28% when only the cases of cleft lip with or without cleft palate (CL +/- P) were considered. An increase was seen in prenatal detection of CL +/- P from 11% in 1999 to 50% in 2008 (p = .011). Two of the six U.K. units that responded had a significantly higher percentage of CL +/- P cases diagnosed prenatally compared with RHSC in 2008 (p < .05). CONCLUSIONS: The percentage of CL +/- P cases diagnosed prenatally in this study is consistent with the literature and increased between 1999 and 2008. Routine ultrasound anomaly scanning is shown to significantly improve detection rates compared with scanning of high-risk pregnancies only. Cases of CL +/- P where the alveolus or the palate is involved have significantly higher detection rates than those involving only the lip. PMID- 20828272 TI - Reproductive patterns among Danish women with oral clefts. AB - OBJECTIVE: The aim of this study was to compare reproduction patterns among Danish women born with isolated oral clefts versus the Danish background population. DESIGN AND SETTING: A nationwide population-based historic cohort study based on three registers: The Danish Facial Cleft Register, The Danish Civil Registration System, and the Fertility of Women and Couples Dataset. PARTICIPANTS: Through linkages of the registers, the number of children and the exact age at childbirth of all Danish women born with an oral cleft from 1950 through 1988 (N = 1931) were obtained. These data were compared with similar data for the entire Danish female background population (N = 1,184,390). RESULTS AND CONCLUSIONS: This study suggests that childlessness is higher among women born with an oral cleft (55%) than among women in the Danish background population (44%). Excluding women without children, women born with oral cleft had an average of 1.98 children per woman. This did not differ significantly from the background population (2.02 children/woman). Furthermore, the present study found that Danish women born with oral clefts on average were older (27.3 years of age) than the background population (24.7 years of age) when they had their first child (difference = 2.6 years, confidence interval = 2.41 to 2.80). CONCLUSION: Danish women born with an oral cleft more often are childless or have their first child later, but if they have children, they tend to have as many children as other Danish women. Social, psychological, and biological reasons might be responsible for the reduced fertility. PMID- 20828273 TI - A case report of a patient with cleft palate carrying the risk of tetraplegia. AB - Spondyloepiphyseal dysplasia congenita (SEDC) is an inherited disorder of bone growth that results in short-trunk dwarfism, skeletal abnormalities, disorders in vision and hearing, atlanto-axial instability, and cleft palate. This important anomaly of the cervical vertebrae carries the risk of tetraplegia during cleft palate operations. In this case report, we discuss a case of spondyloepiphyseal dysplasia congenita, the perioperative and postoperative measures, and the risk of tetraplegia. PMID- 20828274 TI - Can we explain the higher prevalence of autoimmune disease in women? PMID- 20828275 TI - Atypical mycobacteria: showerheads, anti-TNF therapy and Crohn's disease. PMID- 20828276 TI - Targeting eosinophils in asthma: current and future state of cytokine- and chemokine-directed monoclonal therapy. PMID- 20828278 TI - Markus Maeurer on the LifeGene project. AB - This year will see the full-scale roll-out of the LifeGene study. Coordinated by the Karolinska Institutet (Stockholm, Sweden), the project looks set to be one of the largest health studies performed in the world, aiming to enroll 500,000 Swedes in order to determine the relationship between disease and environmental, lifestyle and hereditary factors. International experts from a broad spectrum of scientific fields will collaborate on this project, including Mark Maeurer, Chair of the infections working group in LifeGene (www.lifegene.se). Maeurer leads the additional study on influenza-like illnesses, which is currently being run within the LifeGene project. Maeurer studied medicine in Germany, Switzerland and the USA. He is board-certified in medical microbiology, has served as Assistant Professor of Surgery at the University of Pittsburgh Medical School (PA, USA) in the Department of Surgical Oncology and Immunotherapy, as Professor of Medical Microbiology at the University of Mainz, Germany, and is now Professor of Clinical Immunology at the Microbiology and Tumor Cell Biology Center at the Karolinska Institutet. Maeurer has conducted experiments with nonhuman primate models to study TB vaccine take, with the aim to profile markers of immune protection. His general interests are in the field of immune reconstitution and memory immune responses, with a particular focus on gauging protective T-cell responses and antibody immune signatures using high-content peptide microarrays. He has published more than 100 original articles, ten book chapters and serves as a reviewer for a number of international scientific journals. PMID- 20828279 TI - RAPID and FAST4WARD trials: certolizumab pegol for rheumatoid arthritis. AB - In the last decade, biological therapies have dramatically changed the treatment for rheumatoid arthritis (RA) in such a way that remission is currently an achievable goal. The armamentarium of therapeutic options for RA has recently been enriched with another approved anti-TNF-alpha agent, certolizumab pegol (CZP). This article reviews the trials conducted with CZP in RA, the Rheumatoid Arthritis PreventIon of structural Damage (RAPID 1 and 2) and the EFficAcy and Safety of cerTolizumab pegol - 4 Weekly dosAge in RheumatoiD arthritis (FAST4WARD). These trials have demonstrated that this new biological agent significantly improves the clinical signs and symptoms of RA, inhibits progression of structural damage, and improves physical function and quality of life in patients with active RA who have failed treatment with methotrexate. The safety profile of CZP is acceptable and similar to that of other anti-TNF-alpha agents. PMID- 20828280 TI - Golimumab: a new anti-TNF-alpha agent for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone. Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides. Disease-modifying anti rheumatic drugs and biologic therapies including anti-TNF agents are used in their treatment. The TNF antagonists have shown rapid and sustained therapeutic responses. However, a substantial number of patients fail to respond to anti-TNF agents or experience side effects. Golimumab is a human monoclonal antibody to TNF-alpha requiring less frequent administration compared with current anti-TNF products. Various trials have shown promising results in terms of efficacy and safety in methotrexate-naive and -resistant patients with RA as well as in patients previously treated with other anti-TNF agents. The efficacy of golimumab has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis. PMID- 20828281 TI - Tocilizumab: molecular intervention therapy in children with systemic juvenile idiopathic arthritis. AB - Systemic juvenile idiopathic arthritis (JIA) is a subtype of chronic childhood arthritis of unknown etiology, manifested by long-lasting systemic inflammation and complicated by joint destruction, functional disability and growth impairment. Macrophage activation syndrome is the most devastating complication, which is associated with serious morbidity. IL-6 has been hypothesized to be a pathogenic factor of this disease. The anti-IL-6 receptor monoclonal antibody, tocilizumab, was developed, and we investigated the safety and efficacy of tocilizumab in children with this disorder. The Phase II trial revealed that high grade fever abruptly subsided and that inflammatory markers were also normalized. The dose of tocilizumab for systemic JIA was revealed to be 8 mg/kg at 2-week intervals. The Phase III trial, a placebo-controlled, double-blind study, indicated that patients in the tocilizumab group had sustained clinical measures of effectiveness and wellbeing, whereas most of those in the placebo group needed rescue treatment. The most common adverse events were symptoms of mild infections and transient increases of alanine aminotransferase. Serious adverse events were anaphylactoid reaction and gastrointestinal hemorrhage. Clinical and laboratory improvement in fever, sickness behavior, C-reactive protein gene expression and chronic inflammatory anemia in children with systemic JIA treated with tocilizumab indicated the possible roles played by IL-6 in this inflammatory disease. Thus, tocilizumab is generally safe and well tolerated. It might be a suitable treatment in the control of this disorder, which has so far been difficult to manage. PMID- 20828283 TI - Review of the 1st annual world congress of immunodiseases and therapeutics. AB - BIT's 1st Annual World Congress of Immunodiseases and Therapeutics was held in Beijing, China, on 15-17 May 2010. The meeting provided a venue for a wide spectrum of researchers in the basic sciences and clinical areas to present and share their data and ideas. The pervading theme of the meeting dealt with the concept that immune mechanisms underlie most, if not all, medical diseases and therefore the future of medical therapeutics necessitates a greater understanding and corrective manipulation of dysfunctional metabolic and immune pathways. The meeting was well run, educational and enjoyable. PMID- 20828282 TI - Duloxetine for the treatment of fibromyalgia. AB - This article presents a brief review of the physiologic abnormalities seen in fibromyalgia, current theories of widespread pain, and treatment options, including emerging therapeutics, with a focus on the use of duloxetine to manage fibromyalgia symptoms. Major clinical trials that examine the efficacy and effectiveness of duloxetine to date are reviewed, and safety issues are discussed. PMID- 20828284 TI - EAACI 2010: cutting-edge research in allergic diseases and their underlying mechanisms. AB - The European Academy of Allergy and Clinical Immunology (EAACI) congress is considered to be one of the most important annual meetings in the allergy field. This year, the EAACI 2010 took place in London, UK, during 5-9 June, and focused on 'cutting-edge research in allergic diseases and their underlying mechanisms'. PMID- 20828285 TI - Therapeutic implications of advances in our understanding of transitional B-cell development in humans. AB - B-cell development is characterized by the progressive maturation of hematopoietic stem cells through several stages to ultimately give rise to the mature B-cell pool that has been selected for reactivity against non-self antigens. Thus, the mature pool of naive B cells is capable of elicting high affinity responses following natural infection with pathogens or vaccination and provides the host with protective long-lived humoral immunity. However, perturbations during the processes of B-cell development and differentiation can give rise to a diverse array of immunological diseases including autoimmunity, immunodeficiency and malignancy. While we have a very rich understanding of the processes underlying B-cell development in mice, our knowledge of the corresponding events occurring in human B cells is substantially less robust. Here, we overview the latest findings relating to human B cells in health and disease with a particular emphasis on the transitional stage of B-cell development. PMID- 20828286 TI - Current understanding of Kounis syndrome. AB - Inflammatory mediators, adhesion molecules of neutrophils and monocytes, have been shown to be increased in the plasma of patients presenting with acute coronary syndromes. Anaphylaxis is a systemic, immediate hypersensitivity reaction caused by rapid IgE-mediated release of mediators from mast cells and basophils. Kounis syndrome is the coincidental occurrence of these two distinct conditions accompanied by clinical and laboratory findings of angina pectoris caused by inflammatory mediators released during an allergic insult. Allergic angina can progress to acute myocardial infarction, which is termed 'allergic myocardial infarction'. There are several causes reported to be capable of inducing Kounis syndrome. These include a number of conditions, several drugs, foods and insect stings, among others. In this article, the clinical aspects, diagnosis, pathogenesis, incidence and epidemiology, related conditions and therapeutic management of this important syndrome are discussed. PMID- 20828287 TI - Immunological aspects of nonimmediate reactions to beta-lactam antibiotics. AB - beta-lactam antibiotics are the agents most frequently implied in immune drug adverse reactions. These can be classified as immediate or nonimmediate according to the time interval between the last drug administration and their onset. Mechanisms of immediate IgE-mediated reactions are widely studied and are therefore better understood. Nonimmediate reactions include a broad number of clinical entities like mild maculopapular exanthemas, the most common, and other less frequent but more severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute exanthematic pustulosis or cytopenias. These nonimmediate reactions are mainly mediated by T cells but the precise underlying mechanisms are not well elucidated. This fact complicates the allergological evaluation of patients with this type of reaction and available tests have demonstrated poor sensitivity and specificity. PMID- 20828288 TI - At the crossroad between immunity and metabolism: focus on leptin. AB - White adipose tissue is currently considered to be an active endocrine organ that secretes a plethora of factors named adipokines, most of them proinflammatory in nature, which probably contribute to low-level systemic inflammation; a state that is often present in metabolic syndrome-associated chronic pathologies such as obesity and atherosclerosis. Leptin is historically and indisputably one of the most important adipokines secreted by fat cells, with a variety of physiological roles related to the control of metabolism, energy homeostasis and inflammatory response. One of these functions is the connection between nutritional status and immune competence. Indeed, leptin has been shown to modulate both the innate and adaptive immune responses in both normal and pathological conditions. It has been shown that conditions characterized by low leptin levels are associated with increased susceptibility to infection. Conversely, immune-mediated disorders, such as autoimmune diseases, are associated with increased secretion of leptin and the production of proinflammatory pathogenic cytokines. Thus, leptin can easily be considered a frank mediator of the inflammatory/immune response. PMID- 20828289 TI - Innate antimicrobial immunity in inflammatory bowel diseases. AB - Inflammatory bowel diseases are characterized by chronic intestinal inflammation at different sites. Data from animal models as well as human patients including gene-association studies suggest that different components of the innate barrier function are primarily defective. These recent advances support the evolving hypothesis that intestinal bacteria induce inflammation predominantly as a result of a weakened innate mucosal barrier in genetically predisposed individuals. This article discusses our current understanding of the primary events of disease. Together, these findings should result in new therapeutic avenues aimed at restoring antimicrobial barrier function to prevent a bacterial-triggered inflammatory response. PMID- 20828291 TI - Adipose-derived stromal cell autologous transplantation ameliorates pulmonary arterial hypertension induced by shunt flow in rat models. AB - Hyperkinetic pulmonary arterial hypertension (PAH) severely influences the success of operation for congenital heart disease and deteriorates the prognosis of disease. Adipose-derived stromal cell (ADSC) is a good alternative multipotent stem cell for regeneration medicine. PAH rat models were established by arteriovenous shunt and ADSCs were isolated, cultured, and labeled in vitro. Twelve weeks after shunt operation, rats received an injection of 5 * 10(7) ADSCs. Two weeks after transplantation, hemodynamic abnormality induced by the shunt flow and the hypertrophy of right ventricle were reversed, which was confirmed by invasive measurement and echocardiography examination. The PAH rats receiving cell transplantation demonstrated decreased remodeling of small arteries in the lung; immunohistochemistry analysis showed augmented expression of hepatocyte growth factor (HGF) and increased number of pulmonary small arteries. Western blot and real-time reverse transcriptase-polymerase chain reaction indicated that the protein and mRNA levels of HGF and endothelial nitric oxide synthase increased, respectively, in the lung after cell transplantation. Our results suggested that ADSC transplantation can ameliorate PAH induced by shunt flow by enhancing the expression of HGF and subsequently promoting angiogenesis in the injured lung tissue. PMID- 20828292 TI - Simulated microgravity maintains the undifferentiated state and enhances the neural repair potential of bone marrow stromal cells. AB - Recently, regenerative medicine with bone marrow stromal cells (BMSCs) has gained significant attention for the treatment of central nervous system diseases. Here, we investigated the activity of BMSCs under simulated microgravity conditions. Mouse BMSCs (mBMSCs) were isolated from C57BL/6 mice and harvested in 1G condition. Subjects were divided into 4 groups: cultured under simulated microgravity and 1G condition in growth medium and neural differentiation medium. After 7 days of culture, the mBMSCs were used for morphological analysis, reverse transcription (RT)-polymerase chain reaction, immunostaining analysis, and grafting. Neural-induced mBMSCs cultured under 1G conditions exhibited neural differentiation, whereas those cultured under simulated microgravity did not. Moreover, under simulated microgravity conditions, mBMSCs could be cultured in an undifferentiated state. Next, we intravenously injected cells into a mouse model of cerebral contusion. Graft mBMSCs cultured under simulated microgravity exhibited greater survival in the damaged region, and the motor function of the grafted mice improved significantly. mBMSCs cultured under simulated microgravity expressed CXCR4 on their cell membrane. Our study indicates that culturing cells under simulated microgravity enhances their survival rate by maintaining an undifferentiated state of cells, making this a potentially attractive method for culturing donor cells to be used in grafting. PMID- 20828293 TI - Reliability and validity of a computer-mediated, single-word intelligibility test: preliminary findings for children with repaired cleft lip and palate. AB - OBJECTIVE: To determine the reliability and validity of a computer-mediated, 50 word intelligibility test designed to be a global measure of severity of speech disability in children with repaired cleft lip and palate. DESIGN: A prospective between-group design was used with convenience sampling of patients from a university craniofacial center. PARTICIPANTS: A total of 38 children between the ages of 4 and 9 years participated. Of these, 22 had repaired cleft lip and palate; whereas, 16 had no clefts. Twenty adults served as listeners. MAIN OUTCOME MEASURE(S): Speech intelligibility scores were calculated for repeated administrations of a single-word test based upon the number of correct orthographically transcribed words by four groups of five listeners per child. Measures of parallel forms, interlistener, and intralistener reliabilities were estimated; measures of construct validity were also determined. RESULTS: All measures of reliability were adequate. Parallel forms reliability of the test based upon mean scores from five listeners per child was high (r = .97). Thirty seven of 38 children had differences between forms of 11 percentage points or less. Construct validity of the test was shown by (1) significantly lower speech intelligibility scores for children with cleft lip and palate than controls and (2) a moderately high correlation (r = .79) between intelligibility scores and percent consonants correct for all children. CONCLUSIONS: A computerized, single word intelligibility test was described that appears to be a reliable and valid measure of global speech deficits in children with cleft lip and palate. Additional development of the test may further facilitate standardized assessment of children with cleft lip and palate. PMID- 20828294 TI - Introduction to series on mesenchymal stromal (stem) cells-MSCs. PMID- 20828296 TI - Changes in brain FDG metabolism induced by acupuncture in healthy volunteers. PMID- 20828297 TI - Could vertebroplasty and kyphoplasty be regarded as evidence-based treatment of osteoporotic vertebral fractures? PMID- 20828299 TI - CEST and PARACEST MR contrast agents. AB - In this review we describe the status of development for a new class of magnetic resonance (MR) contrast agents, based on chemical exchange saturation transfer (CEST). The mathematics and physics relevant to the description of the CEST effect in MR are presented in an appendix published in the online version only. We discuss the issues arising when translating in vitro results obtained with CEST agents to using these MR agents in in vivo model studies and in humans. Examples are given on how these agents are imaged in vivo. We summarize the status of development of these CEST agents, and speculate about the next steps that may be taken towards the demonstration of CEST MR imaging in clinical applications. PMID- 20828300 TI - Safety and patient comfort with iodixanol: a postmarketing surveillance study in 9515 patients undergoing diagnostic CT examinations. AB - BACKGROUND: Iodinated radiographic contrast media are considered safe diagnostic drugs with a low incidence of adverse drug reactions. PURPOSE: To determine prospectively the incidence and nature of immediate and delayed adverse drug reactions occurring after administration of iodixanol for contrast-enhanced computed tomography (CT) in routine practice in nonselected patients, and to assess patient comfort (pain and sensations of heat or coldness). MATERIAL AND METHODS: Patient characteristics (including demographics, risk factors, indication for CT, and status of the vein used to administer iodixanol) and aspects of iodixanol administration (including dose and volume) were documented on a standardized case report form. Patients were asked to report immediate (during the visit) or delayed (occurring up to 7 days after administration of iodixanol) adverse reactions; those deemed related or possibly related to iodixanol were documented on a standardized adverse drug reaction form. Discomfort was rated by patients on a scale of 0-10 for pain, heat, and coldness; individual scores were combined into a composite score (0-30). RESULTS: Evaluable documentation was provided for 9515 patients in 77 centers across Germany. Adverse drug reactions were reported in 70 patients (0.74%), including hypersensitivity reactions in 55 patients. Thirty patients experienced immediate reactions and 40 experienced delayed reactions. Serious adverse drug reactions were evident in five patients (0.05%). Patients with allergic diathesis appeared to be at increased risk of immediate and delayed adverse drug reactions. Discomfort was generally mild, with 72% of patients reporting a composite score of 0-3. CONCLUSION: In the outpatient setting, where it is often difficult to properly assess patients for specific risk factors, it was reassuring that iodixanol demonstrated an excellent safety profile in over 9500 patients undergoing diagnostic CT examinations. There were no unexpected serious adverse drug reactions, and patient discomfort during administration was mild or absent in most patients. PMID- 20828301 TI - Spinal subdural haematoma concurrent with cranial subdural haematoma: Report of two cases and review of literature. AB - Subdural haematomas co-existing in the cranium and spine are considered extremely rare. We report 2 cases demonstrating the condition described here with a review of literature. One of these 2 patients was the first case in which the spinal lesion was found before the cranial lesion. A 66-year-old man without trauma presented with paraparesis accompanied by severe leg pain. The patient was diagnosed as having spinal subdural haematoma extending from L1 to S1 vertebral levels with magnetic resonance images (MRI). Two days after admission, the patient developed disorientation and abnormal behavior; therefore, computed tomography (CT) of brain was performed, and chronic cranial subdural haematoma was observed. A 60-year-old man who developed headache showing gradually progressive was diagnosed as having cranial subdural haematoma on CT. Three days after admission, he became insomnolent due to severe low back pain radiating to ankle. On MRI, subdural haematoma was found extending from L3/4 to S2 vertebral levels. Only brain surgery was performed for all cases by the neurosurgeons. Paraparesis and severe leg pain, which were derived from spinal lesions, showed recovery approximately 2 weeks after onset and spinal subdural haematoma was completely resolved on MRI obtained 2 or 5 months after onset, respectively. There is a possibility that the incidence of spinal subdural haematoma concurrent with cranial subdural haematoma could be underestimated because the doctor had not obtained CT or MRI of the brain. Doctors should aware of such a condition and check patients with spinal subdural haematoma for neurological signs derived from brain lesions. Spontaneous resolution of spinal subdural haematoma was observed; therefore, surgery for this condition should be indicated only for patients with moderate or severe paraparesis or paraparesis deteriorated. PMID- 20828302 TI - Load modulation of BOLD response and connectivity predicts working memory performance in younger and older adults. AB - Individual differences in working memory (WM) performance have rarely been related to individual differences in the functional responsivity of the WM brain network. By neglecting person-to-person variation, comparisons of network activity between younger and older adults using functional imaging techniques often confound differences in activity with age trends in WM performance. Using functional magnetic resonance imaging, we investigated the relations among WM performance, neural activity in the WM network, and adult age using a parametric letter n-back task in 30 younger adults (21-31 years) and 30 older adults (60-71 years). Individual differences in the WM network's responsivity to increasing task difficulty were related to WM performance, with a more responsive BOLD signal predicting greater WM proficiency. Furthermore, individuals with higher WM performance showed greater change in connectivity between left dorsolateral prefrontal cortex and left premotor cortex across load. We conclude that a more responsive WM network contributes to higher WM performance, regardless of adult age. Our results support the notion that individual differences in WM performance are important to consider when studying the WM network, particularly in age comparative studies. PMID- 20828303 TI - Low bone mineral density with tenofovir: does statistically significant mean clinically significant? PMID- 20828304 TI - Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. AB - BACKGROUND: Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. METHODS: In this European, multicenter, open-label, 96-week study, antiretroviral naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. RESULTS: A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, -1.9%; tenofovir emtricitabine group, -3.6%; P < .001) and lumbar spine (abacavir-lamivudine group, -1.6%; tenofovir-emtricitabine group, -2.4%; P = .036). BMD loss of >or=6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of >or=6% in the hip; 15% vs 5% had a loss of >or=6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofovir-emtricitabine group, +11.92 mg/L; P < .001). CONCLUSIONS: This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine. PMID- 20828305 TI - Bioavailability of iron from cereal products enriched with dried shittake mushrooms (Lentinula edodes) as determined by iron regeneration efficacy method in female rats. AB - Lentinula edodes shiitake mushrooms are rich sources of iron, which in addition to their relatively high nutritive value are also characterized by high contents of biologically active components. However, recommendation of products prepared on the basis of dried shiitake mushrooms and introduced to the diet as sources of iron requires a precise determination of bioavailability of this element. The purpose of this study was to assess the bioavailability of iron from cereal products with the addition of dried shiitake mushrooms using the iron regeneration efficacy method in Fe-deficient female rats. Feeding products with 10% and 20% addition of dried shiitake to female rats with a previously evoked Fe deficiency resulted in a gradual repletion of lowered Fe indices, including an increase in blood hemoglobin concentration and serum and liver Fe levels to values comparable to those of the control group. Bioavailability of iron from cereal products enriched with dried shiitake mushrooms is comparable to that of Fe(II) gluconate. PMID- 20828306 TI - Topical and systemic anti-inflammatory effects of Echinodorus macrophyllus (Kunth) Micheli (Alismataceae). AB - Echinodorus macrophyllus leaf has been used in Brazilian folk medicine to treat inflammatory conditions and kidney dysfunctions. The present study evaluated the effects of leaf ethanolic extract from E. macrophyllus (EEEm) in acute and subchronic models of inflammation. The EEEm was found to cause significant and potent inhibition of carrageenan- and dextran-induced paw edema in rats and marked decreases in the exudate volume and leukocyte migration in rats with carrageenan-induced pleurisy, the vascular permeability increase induced by intraperitoneal acetic acid, and the croton oil-induced topical ear edema in mice. On the other hand, the EEEm was not active in the test model of cotton pellet-induced granuloma in rats. Phytochemical analysis with E. macrophyllus leaves revealed the presence of triterpenoids, steroids, flavones, flavonols, and xanthones. Two flavonoids were isolated from the ethyl acetate fraction and identified as isovitexin and vitexin. Our results support the traditional use of E. macrophyllus leaves in the treatment of acute inflammatory conditions. PMID- 20828307 TI - Investigation of the wound healing activity of Carapa guianensis L. (Meliaceae) bark extract in rats using excision, incision, and dead space wound models. AB - The objective of our study is to investigate the wound healing activity of the bark extract of Carapa guianensis in rats using three different wound models. The animals were randomly divided into two groups of six each in all the models. Test group animals were treated topically with the bark extract (200 mg/kg of body weight), and the controls were treated with petroleum jelly in the excision wound model. In the incision and dead space wound models the test group animals were treated with the extract of C. guianensis (200 mg/kg/day) orally by mixing in drinking water, and the control group animals were maintained with plain drinking water. Healing was assessed by the rate of wound contraction, period of epithelialization, skin breaking strength, granulation tissue weight, and hydoxyproline content. Antimicrobial activities of the extract against the microorganisms were also assessed. On day 15 extract-treated animals exhibited 99% reduction in the wound area compared to controls (93%). The extract-treated wounds were found to epithelialize faster than controls (P < .02). The skin breaking strength was significantly higher in extract-treated animals compared to controls (P < .001). The weight and hydroxyproline content of granulation tissue were significantly increased compared to controls. These observations support the use of C. guianensis is in the management of wound healing. PMID- 20828308 TI - Uncaria rhynchophylla inhibits the production of nitric oxide and interleukin 1beta through blocking nuclear factor kappaB, Akt, and mitogen-activated protein kinase activation in macrophages. AB - The stems with hook of Uncaria rhynchophylla have been used in traditional medicine as an antipyretic, antihypertensive, and anticonvulsant in China and Korea. In this study, we investigated the mechanism responsible for anti inflammatory effects of U. rhynchophylla in RAW 264.7 macrophages. The aqueous extract of U. rhynchophylla inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) and interleukin (IL)-1beta secretion as well as inducible NO synthase (iNOS) expression, without affecting cell viability. Furthermore, U. rhynchophylla suppressed LPS-induced nuclear factor kappaB (NF-kappaB) activation, phosphorylation, and degradation of inhibitory protein IkappaB (IkappaB)-alpha, phosphorylation of Akt, extracellular signal-regulated kinase 1/2, p38 kinase, and c-Jun N-terminal kinase. These results suggest that U. rhynchophylla has the inhibitory effects on LPS-induced NO and IL-1beta production in macrophages through blockade in the phosphorylation of Akt and mitogen-activated protein kinases, following IkappaB-alpha degradation and NF kappaB activation. PMID- 20828309 TI - Protective effect of Cratoxylum formosum extract against acid/alcohol-induced gastric mucosal damage in rats. AB - Cratoxylum formosum is an edible plant that is commonly consumed among the people in Northeast Thailand. This study aimed to investigate the gastroprotective effect of the ethanolic extract of C. formosum leaves (C. formosum ethanolic extract [CFE]). Gastric ulceration was induced in Wistar male rats by oral administration of acid/alcohol. Oral dosing with CFE at 250 and 500 mg/kg of body weight after the acid/alcohol induction significantly decreased the number of bleeding spots, area of bleeding, ulcer score, and ulcer index. Pretreatment with 500 mg/kg CFE significantly prevented the gastric damage. Histological studies of the acid/alcohol-induced animals indicated the gastric inflammation with lesion depth through the mucosal layer. Whereas the gastric lesion of the CFE-treated animals at both 250 and 500 mg/kg doses was decreased to be one-fourth of the mucosal layers, pretreatment with 500 mg/kg CFE prior to acid/alcohol induction completely protected against the mucosal damage. Biochemical analysis of gastric mucosa revealed a significant decrease of malondialdehyde in the CFE-treated group in a dose-response manner. These findings suggest that the gastroprotective activity of CFE could be mediated possibly through its antioxidant effect. PMID- 20828310 TI - Dietary conjugated linoleic acid increases endurance capacity of mice during treadmill exercise. AB - This study was designed to evaluate the effect of dietary conjugated linoleic acid (CLA) on endurance exercise and availability of metabolic substrates in mice. Four-week-old male BALB/c mice were randomized to a control group (normal diet) and a CLA group (normal diet + 1% CLA). Each animal group received its respective diet for 10 weeks and was subjected to forced running on a treadmill system to estimate their maximum endurance capacity at the end of the experiment. All mice were immediately sacrificed after prolonged exercise, and the major metabolic substrates were measured in serum and liver. The body weights of mice in the CLA group were lower than those of the control group after the 10 weeks. The maximum running time in CLA-fed mice was significantly longer, by 26%, compared to that of the control mice. Dietary CLA decreased the serum concentrations of triglycerides, nonesterified fatty acids, and urea nitrogen and significantly reduced the consumption of liver glycogen. The present study demonstrated that dietary CLA enhances the endurance capacity of mice by increasing fat utilization and reducing the consumption of stored liver glycogen as substrates for energy metabolism. PMID- 20828311 TI - Platelet anti-aggregation activities of compounds from Cinnamomum cassia. AB - Cinnamomum cassia is a well-known traditional medicine for improvement of blood circulation. An extract of this plant showed both platelet anti-aggregation and blood anti-coagulation effects in preliminary testing. Among the 13 compounds obtained from this plant, eugenol (2), amygdalactone (4), cinnamic alcohol (5), 2 hydroxycinnamaldehyde (7), 2-methoxycinnamaldehyde (8), and coniferaldehyde (9) showed 1.5-73-fold greater inhibitory effects than acetylsalicylic acid (ASA) on arachidonic acid (AA)-induced aggregation (50% inhibitory concentration [IC50] = 3.8, 5.16, 31.2, 40.0, 16.9, and 0.82 MUM, respectively, vs. 60.3 MUM) and 6.3 730-fold stronger effect than ASA on U46619 (a thromboxane A2 mimic)-induced aggregation (IC50 = 3.51, 33.9, 31.0, 51.3, 14.6, and 0.44 MUM, respectively, vs. 321 MUM). The other compounds, coumarin (3), cinnamaldehyde (6), cinnamic acid (10), icariside DC (11), and dihydrocinnacasside (12), also inhibited (2.5 to four times greater than ASA) U46619-induced aggregation. In addition, compounds 2, 4, 5, 6, 7, 8, and 9 were 1.3-87 times more effective than ASA against epinephrine-induced aggregation (IC50 = 1.86, 1.10, 37.7, 25.0, 16.8, 15.3, and 0.57 MUM, respectively, vs. 50.0 MUM). However, the 13 compounds were only very mildly effective against blood coagulation, if at all. In conclusion, compounds 2, 4, 8, and 9 showed stronger inhibitory potencies than others on AA-, U46619-, and epinephrine-induced platelet aggregation. Eugenol (2) and coniferaldehyde (9) were the two of the most active anti-platelet constituents of C. cassia. PMID- 20828312 TI - Phenolic-containing organic extracts of mulberry (Morus alba L.) leaves inhibit HepG2 hepatoma cells through G2/M phase arrest, induction of apoptosis, and inhibition of topoisomerase IIalpha activity. AB - The entire plant of Morus alba L. (Family Moraceae), or mulberry, possesses medical benefits, including anticancer properties. In this study, we investigated the effect of mulberry leaf extracts on the human hepatoma HepG2 cell line, which is related to hepatocellular carcinoma. Mulberry leaf extracts were prepared using four solvents, each with different polarities: 100% methanol (MeOH), 50% aqueous MeOH, 1-butanol (BuOH), and hot water (W). The phenolic profile, total polyphenol content, antioxidant capacity, and effect on human hepatoma HepG2 cells of the leaf extracts were analyzed by examining cytotoxicity, cell cycle progression, apoptosis, expression of topoisomerase IIalpha, and proteins involved in cell cycle progression. High-performance liquid chromatography-mass spectrometry analysis revealed that 100% MeOH, 50% MeOH, and BuOH extracts contained rutin, isoquercetin, and various derivatives of kaempferol and quercetin glycosides as their major constituents; the W extract contained primarily chlorogenic acid and caffeoylquinic acid derivatives. Total phenolic content based on rutin equivalents was 17.1%, 9.6%, 8.3%, and 6.5% of dry 100% MeOH, 50% MeOH, BuOH, and W extracts, respectively. 2,2-Diphenyl-1-picrylhydrazyl radical scavenging activities were 70.0%, 45.8%, 41.0%, and 33.6%, and 50% inhibitory concentration values were 33.1, 79.4, 35.6, and 204.2 MUg/mL for HepG2 cell proliferation inhibition for 100% MeOH, 50% MeOH, BuOH, and W extracts, respectively. MeOH extracts caused cell cycle G2/M arrest and induced the caspase cascade and apoptosis, but the W extract had very little effect on cell cycle progression. MeOH extracts reduced the level of topoisomerase IIalpha but increased the level of p27(Kip1), with no significant effect on p21(Cip1/waf1). Therefore, we concluded that phenolic-containing organic extracts of mulberry leaves inhibit the growth of HepG2 hepatoma cells through coordinated actions of inducing cell cycle arrest in the G2/M phase (with p27(Kip1) protein expression), inhibiting topoisomerase IIalpha activity, and inducing cell apoptosis by activation of caspases. PMID- 20828313 TI - Pharmacological basis for the medicinal use of black pepper and piperine in gastrointestinal disorders. AB - Dried fruits of Piper nigrum (black pepper) are commonly used in gastrointestinal disorders. The aim of this study was to rationalize the medicinal use of pepper and its principal alkaloid, piperine, in constipation and diarrhea using in vitro and in vivo assays. When tested in isolated guinea pig ileum, the crude extract of pepper (Pn.Cr) (1-10 mg/mL) and piperine (3-300 MUM) caused a concentration dependent and atropine-sensitive stimulant effect. In rabbit jejunum, Pn.Cr (0.01 3.0 mg/mL) and piperine (30-1,000 MUM) relaxed spontaneous contractions, similar to loperamide and nifedipine. The relaxant effect of Pn.Cr and piperine was partially inhibited in the presence of naloxone (1 MUM) similar to that of loperamide, suggesting the naloxone-sensitive effect in addition to the Ca(2+) channel blocking (CCB)-like activity, which was evident by its relaxant effect on K+ (80 mM)-induced contractions. The CCB activity was confirmed when pretreatment of the tissue with Pn.Cr (0.03-0.3 mg/mL) or piperine (10-100 MUM) caused a rightward shift in the concentration-response curves of Ca(2+), similar to loperamide and nifedipine. In mice, Pn.Cr and piperine exhibited a partially atropine-sensitive laxative effect at lower doses, whereas at higher doses it caused antisecretory and antidiarrheal activities that were partially inhibited in mice pretreated with naloxone (1.5 mg/kg), similar to loperamide. This study illustrates the presence of spasmodic (cholinergic) and antispasmodic (opioid agonist and Ca(2+) antagonist) effects, thus providing the possible explanation for the medicinal use of pepper and piperine in gastrointestinal motility disorders. PMID- 20828314 TI - Tetrahydropalmatine inhibits pro-inflammatory mediators in lipopolysaccharide stimulated THP-1 cells. AB - For centuries, Corydalis Rhizoma has been used in Korean traditional medicine. Tetrahydropalmatine is an alkaloid compound and a prominent anti-inflammatory agent found in plants, including Corydalis yanhusuo. However, the therapeutic mechanisms of tetrahydropalmatine are still not well understood. To provide insight into the biological effects of tetrahydropalmatine, we examined its influence on lipopolysaccharide (LPS)-induced interleukin (IL)-8 production in the human monocytic cell line THP-1. In the present study, IL-8 production was measured using enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and mitogen-activated protein kinase (MAPK) activation, as determined by western blot analysis. Tetrahydropalmatine inhibited LPS-induced IL-8 production in a dose-dependent manner. Furthermore, tetrahydropalmatine inhibited extracellular signal-regulated kinase and p38 MAPK phosphorylation, which suggests that tetrahydropalmatine inhibits IL-8 secretion by blocking MAPK phosphorylation. Taken together, these findings may help elucidate the mechanism by which tetrahydropalmatine modulates THP-1 cell activation under inflammatory conditions. PMID- 20828315 TI - Genoprotective effects of the green tea-derived polyphenol/epicatechin gallate in C6 astroglial cells. AB - In vitro and in vivo studies have recently reported significant chemopreventive effects of green tea-derived polyphenols in different diseases. However, it remains unclear how such effects could be triggered. In order to elucidate the effects of epicatechin gallate (ECG) in C6 cells, both by itself and against H2O2 induced genotoxicity, measurements of DNA strand breaks and chromosome loss were performed. DNA damage was measured by comet and micronucleus assays. The present study shows for the first time how ECG, the major green tea-derived polyphenol, is able to exert dose-dependent genoprotective effects in an H2O2-induced toxicity model of C6 astroglial cells. We demonstrate that doses of ECG in a range from 0.1 to 1 MUM were able to completely prevent H2O2-induced genotoxicity in vitro. In contrast, considerably higher concentrations of ECG (10 MUM) were able to reverse previous positive effects in a dose- and time-dependent manner. The same results were confirmed by both comet (F(3,9) = 336,148; P < .001) and micronucleus (F(3,9) = 23,228; P < .001) methods. Together, our data show ECG as a dose-dependent genoprotective compound in C6 astroglial cells. This indicates that small doses of polyphenols included in our diet could have beneficial effects on neural cells, contributing to prevention of oxidative stress associated brain pathologies. In addition, our data highlight the importance of strictly modulating doses and/or consumption of antioxidant-fortified foods or additional supplements containing such beneficial molecules. PMID- 20828316 TI - Chemical composition and antibacterial activities of Illicium verum against antibiotic-resistant pathogens. AB - In recent years, human pathogenic microorganisms have developed multiple drug resistance and caused serious nosocomial infections. In this study, we identified four new antimicrobial compounds from the Chinese herbal medicine Illicium verum and assessed their antibacterial efficacies. The supercritical CO2 and ethanol extracts of Illicium verum showed substantial antibacterial activity against 67 clinical drug-resistant isolates, including 27 Acinetobacter baumannii, 20 Pseudomonas aeruginosa, and 20 methicillin-resistant Staphylococcus aureus. The diethyl ether (EE) fraction obtained from partition extraction and supercritical CO2 extracts revealed an antibacterial activity with a minimum inhibitory concentration value of 0.15-0.70 mg/mL and 0.11 mg/mL, respectively. The EE fraction of I. verum showed synergetic effects with some commercial antibiotics. The antimicrobial mechanism was investigated with killing curves and scanning electron microscopy observation. The chemical components of the extracts were analyzed by spectrophotometry; (E)-anethole, anisyl acetone, anisyl alcohol, and anisyl aldehyde exhibited antibacterial activity against different clinical isolates. These extracts from I. verum can be further developed into antibiotic medicines due to their proven antibacterial activity. PMID- 20828317 TI - 3-(allyltrisulfanyl)-2-aminopropanoic acid, a novel nonvolatile water-soluble antimicrobial sulfur compound in heated garlic. AB - A nonvolatile and slightly water-soluble antimicrobial sulfur compound newly isolated from heated garlic extract was characterized. The compound was generated most when heated at 120 degrees C for 30 minutes and completely disappeared after 90 minutes of heating. It has a molecular mass of 225 daltons with an elemental ratio of C6H11N1O2S3, and the interpretation of 1H- and 13C-nuclear magnetic resonance and Fourier transform-infrared data showed that the compound was CH2=CH CH2-S-S-S-CH2-CH(NH2)COOH, 3-(allyltrisulfanyl)-2-aminopropanoic acid, a derivative of cysteine, presumably derived from alliin (S-allyl-L-cysteine sulfoxide). This novel compound has comparatively potent anti-yeast activity and rather weak antibacterial activity, similar to other antimicrobial compounds in garlic. PMID- 20828318 TI - Antioxidant properties of Urtica pilulifera root, seed, flower, and leaf extract. AB - This study was conducted to evaluate the antioxidative properties of hydroalcoholic (80%) extracts from different parts of Urtica pilulifera L. (Family Urticaceae), including leaf (UPL), flower (UPF), seed (UPS), and root (UPR). Antioxidative activity of the extracts was measured using the ferric thiocyanate method, thiobarbituric acid method, reductive potential, metal chelating, free radical, superoxide anion radical, and hydrogen peroxide scavenging activity. In addition, the results were compared with antioxidants such as tert-butylated hydroxyanisole (BHA), tert-butylated hydroxytoluene (BHT), and alpha-tocopherol. Total antioxidant activities of UPS, UPF, UPL, UPR, BHA, BHT, and alpha-tocopherol were 88.79%, 85.13%, 86.72%, 78.46%, 81.31%, 76.12%, and 46.28%, respectively. Like the antioxidant activity, the reducing power and the superoxide anion radical and free radical scavenging activities of UPL, UPF, UPS, and UPR are concentration dependent. A correlation between higher antioxidant activity and the amount of total phenolics was found in the extracts. PMID- 20828319 TI - Butterbur (Petasites japonicus Max.) extract improves lipid profiles and antioxidant activities in monosodium L-glutamate-challenged mice. AB - We investigated the effect of the butanol fraction from the methanol extract of butterbur (Petasites japonicus Max.) (BMP) on the plasma lipid profiles and oxidative damage of liver in mice challenged with monosodium l-glutamate (MSG). ICR mice (6-8 weeks old, male) were fed BMP (0.1% or 0.3%) for 1 week, and on day 7, MSG (4 mg/g) was administered intraperitoneally to the mice. Administration of MSG resulted in a significant decrease of antioxidant biomarkers such as total glutathione level and antioxidant enzyme activities such as glutathione reductase (GR), glutathione peroxidase (GPx), glutathione S-transferase (GST), and quinone reductase (NQO1), whereas the thiobarbituric acid-reactive substances (TBARS) value was increased in liver tissue. However, BMP supplementation markedly enhanced the hepatic antioxidant enzyme activities, including GPx, GR, GST, and NQO1, whereas it lowered TBARS, compared to the MSG-treated group. Moreover, BMP supplementation decreased total cholesterol, atherogenic index, and low-density lipoprotein-cholesterol, compared to the MSG-treated group. Based on these results, it was proposed that BMP improve the plasma lipid profiles and decrease the oxidative stress by up-regulating the hepatic antioxidant enzymes in mice challenged with MSG. PMID- 20828320 TI - Effect of accessions of Colocasia esculenta-based diets on the hepatic and renal functional indices of weanling Wistar rats. AB - The liver and kidney functional indices of weanling albino rats (Rattus norvegicus) maintained on different accessions (offspring of a variety planted/collected at a specific location and time but differing in certain morphological characteristics) of cooked Colocasia esculenta (cocoyam)-based diets (UFCe1-UFCe7) for 28 days were investigated. All the accessions of C. esculenta-based diets did not significantly (P > .05) alter the serum levels of albumin, globulin, inorganic phosphorus, calcium, magnesium, and uric acid of the animals.The total protein and total bilirubin levels decreased only in the UFCe3- and UFCe4-fed animals, respectively. Whereas UFCe1 and UFCe2 significantly decreased the conjugated bilirubin levels, UFCe3 and UFCe6 increased it. While all the accessions of C. esculenta-based diet decreased the serum alkaline phosphatase activity, gamma-glutamyl transferase activity was increased. UFCe1 and UFCe5 increased the serum alanine aminotransferase activity, whereas UFCe4 decreased the activity of the enzyme. Again, UFCe3 and UFCe1 increased the serum creatinine and aspartate aminotransferase activity of the animals. Furthermore, the computed blood urea nitrogen:creatinine ratio was higher in animals maintained on UFCe1-, UFCe3-, UFCe4-, and UFCe5-based diets. Whereas UFCe6 and UFCe7 increased the level of sodium in the serum of the animals, UFCe4 and UFCe5 decreased the chloride level. The serum urea level was decreased by UFCe1, UFCe3, UFCe4, and UFCe5, whereas the potassium level increased in the UFCe4-, UFCe6-, and UFCe7-fed animals. Overall, the results revealed that all the accessions of C. esculenta produced selective effects on the hepatic and renal functional indices of the weanling rats. The highest alterations were produced by UFCe4, whereas the least was from UFCe2. These alterations may have consequential effects on the normal functioning of the liver and kidney of the animals. UFCe2 exhibited the least toxicity risk among the accessions of C. esculenta growing in the KwaZulu-Natal Province of South Africa. PMID- 20828321 TI - The proximate, mineral, and toxicant compositions of four possible food security crops from southeastern Nigeria. AB - The proximate, nutritional, and antinutritional compositions of the raw, cooked, and roasted samples of four Nigerian indigenous seeds-Sphenostylis stenocarpa, Pentaclethra macrophylla, Mucuna flagellipes, and Citrullus colocynthis-were evaluated. Also estimated were zinc and divalent cation bioavailability of the seeds using millimolar ratios/kg dry weight of [calcium]/[phytate], [phytate]/[zinc], [calcium][phytate]/[Zn], and [phytate]/[total phosphorus]. The results obtained revealed that the seeds of P. macrophylla and C. colocynthis had high protein and lipid levels. All the seeds were also found to have high energy value and low moisture content. Mineral analysis showed the presence of Na, K, Ca, and Mg in appreciable quantities and Zn, I, Fe, and Se in minute quantities. Antinutritional analyses indicated the presence of traces of tannin, oxalate, phytate, saponin, and cyanide in the samples. The various processing techniques had significant (P <= .05) effects on the measured parameters. The calculated [Ca][phytate]/[Zn] molar ratios revealed that these seeds had values above the critical level of 0.5 mL/kg, thus indicating reduced bioavailability of zinc. In view of the high nutrient contents, low antinutritional contents after processing, and their superabundance, these seeds could be cheap nutrient sources. The implications of these findings with regards to food security are enormous. PMID- 20828322 TI - Antimicrobial activity of the extracts and fractions of hexanic fruits of Campomanesia species (Myrtaceae). AB - The antimicrobial activity of the hexanic extracts and fractions of fruits of Campomanesia pubescens pubescens (D.C) O. Berg and Campomanesia adamantium (Cambess.) O. Berg were assayed against six microorganisms. The hexanic extracts of C. pubescens and C. adamantium fruits were also investigated in their composition by gas chromatography-mass spectrometry and high-performance liquid chromatography with diode array detection. The results of this study showed the presence of 34 volatile compounds and flavonoids in the hexanic extract of C. pubescens and 33 volatile compounds and flavonoids in the hexanic extract of C. adamantium. PMID- 20828323 TI - The antioxidant properties of ethanol extracts and their solvent-partitioned fractions from various green seaweeds. AB - The antioxidant activities of the ethanol (EtOH) extracts from the green seaweeds Enteromorpha compressa, Capsosiphon fulvescens, Chaetomorpha moniligera, and Ulva pertusa, as well as their solvent-partitioned fractions, were investigated, and their antioxidant activities were correlated with total phenolic and flavonoid contents. The EtOH extracts and their solvent-partitioned fractions showed 2,2 diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl (OH*) radical scavenging activities with strong reducing ability. The most effective antioxidant properties were observed from the EtOH extracts of E. compressa and C. fulvescens. Among the solvent-partitioned fractions obtained with n-hexane, chloroform (CF), and ethyl acetate, the CF fractions from E. compressa and C. fulvescens exhibited higher radical scavenging activities and stronger reducing ability than other fractions. The OH* radical scavenging capacity and reducing power of these fractions were comparable to those of a positive control, alpha-tocopherol, at concentrations of 0.06-1.0 mg/mL. Total phenolic contents showed little correlation (r2=0.22-0.42) with the antioxidant properties; however, significant correlation (r2 =0.73-0.96) was observed with flavonoid contents, implying that the flavonoid constituents contribute substantially to the antioxidant properties of the extracts. The overall results suggested that the green seaweeds (E. compressa and C. fulvescens), especially their CF fractions, could be good sources of natural antioxidants and of highly beneficial ingredients for healthcare products, such as nutraceuticals, supplements, and cosmeceuticals. PMID- 20828324 TI - In vitro real-time interactions of cranberry constituents with immobilized fructosyltransferase. AB - Cranberry has been proposed as an anti-biofilm agent that does not kill bacteria, but rather prevents the pathogen from survival in the host. This can be achieved by inhibiting the function of virulent factors essential for the pathogen to persist in a host environment. The oral bacterial enzyme fructosyltransferase (FTF) plays an important role in the pathogenesis of dental diseases. The real time interaction of cranberry nondialyzable material (NDM) with immobilized FTF was investigated using the surface plasmon resonance (SPR) technique. To determine its binding efficiency, NDM at concentrations between 0 MUg/mL and 200 MUg/mL was applied onto the immobilized FTF. The effect of NDM or other polyphenols, myricetin, and epicatechin on FTF enzymatic activity was evaluated by applying the above compounds and sucrose onto immobilized FTF. Salivary amylase was applied with NDM onto immobilized FTF to explore the effect on NDM FTF interaction. Our results show that NDM firmly attaches to immobilized FTF in a dose-dependent manner, whereas the presence of salivary amylase reduced this binding interaction. Using nonlinear regression we calculated that the affinity constant of NDM applied alone (106 M-1) was fivefold higher than NDM in the presence of amylase (0.2 x 106 M-1). At 200 MUg/mL, NDM, introduced together with sucrose, inhibited the activity of immobilized FTF by 63% within minutes, in comparison with the control (sucrose alone). The effect of NDM was sustained even after it was washed off the immobilized FTF. Myricetin also strongly inhibited FTF activity, whereas epicatechin was less effective. The real-time SPR observation suggests that one of the anti-biofilm modes of action of NDM is an immediate and irreversible inhibitory effect on the activity of immobilized FTF, which is due to a strong binding affinity to the immobilized enzyme. PMID- 20828325 TI - Effects of chitooligosaccharide lactate salt on activity of acetaldehyde dehydrogenase. AB - Chitooligosaccharides (COS), a kind of oligosaccharide made from chitin or chitosan, have been used a popular remedy for hangovers. In this study we investigated the in vitro effect of COS lactate salt on ethanol-induced cytotoxicity and the in vivo effect of short-term COS lactate salt feeding on ethanol-induced hangover. Pretreatment of HepG2 cells with COS lactate salt significantly reduced ethanol-induced cytotoxicity and suppressed generation of reactive oxygen species. In addition, COS lactate salt dose-dependently increased acetaldehyde dehydrogenase (ALDH) activity in vitro and reversed the ALDH inhibition induced by daidzin. Furthermore, oral administration of COS lactate salt (200 mg/kg) for 5 days significantly decreased the blood levels of alcohol and acetaldehyde in ethanol-treated mice. It was also demonstrated that hepatic mitochondrial ALDH activity was significantly increased in COS lactate salt treated mice. Taken together, these findings indicate that COS lactate salt may have efficacy for the management of alcoholic hangovers. PMID- 20828326 TI - EMDR in paediatrics and rehabilitation: an effective tool for reduction of stress reactions? PMID- 20828327 TI - The effect of seizure disorder on symptom presentation in atypically developing children and children with autism spectrum disorders based on the BDI-2. AB - PURPOSE: Autism Spectrum Disorders (ASD) and seizures are highly comorbid conditions. However, little research has been done to examine this relationship. The purpose of the current study was to examine the effect that seizure disorder has on symptom presentation in children with autism spectrum disorders as compared to atypically developing children. METHOD: The Battelle Developmental Inventory, Second Edition (BDI-2) was used as a measure of impairment across adaptive, personal-social, communication, motor and cognitive skills. RESULTS: A MANOVA indicated significant main effects between diagnostic group and seizure status, without a significant interaction. Follow-up univariate tests were conducted. CONCLUSIONS: Overall, results indicated that children with ASD were more impaired than atypically developing children. In addition, children with seizures tended to be more impaired than children without seizures. PMID- 20828328 TI - Age differences in brain injury characteristics. AB - PURPOSE: Traumatic brain injury (TBI) is an important cause of morbidity and mortality in children. Despite the high incidence of head injury among children, the mortality rate is low. There is a lack of studies that describe children's age-specific symptoms in relation to outcome. The purpose is to investigate if other described symptoms could be used as a predictor of intracranial injury in children. METHODS: Retrospective review of data from all children who during 1 year were admitted due to a brain injury. RESULTS: During 1 year 724 children visited the ED due to a brain injury. A significant difference was found between age groups and other documented initial symptoms, but no single symptoms could be used as a predictor for intracranial injury. CONCLUSION: Unconsciousness as a predictor for brain injury should be used with caution in children. Significant differences were found in other documented symptoms between age groups. PMID- 20828329 TI - Self-concept development and measurement in children with mild intellectual disabilities. AB - OBJECTIVE: Using a multi-trait-multi-method technique, self-concept was analysed as a function of chronological age in children with mild intellectual disabilities. Also, relations between reading achievement and self-concept were measured. METHODS: Participants were assessed on the Woodcock Reading Mastery Test-Revised, the Pictorial Scale of Perceived Competence and Social Acceptance and the Self-Description Questionnaire I--Individual Administration. RESULTS: A median split was run to divide participants into younger and older groups; older participants evidenced coefficients that revealed more multidimensionality, stability and discriminant validity. Also, a significant canonical correlation was found between the Harter Pictorial Scale at Time 1 and WRMT-R at Time 2, chi(2)(8) = 17.99, r = 0.62, p = 0.02. CONCLUSION: As a whole, these results suggest that children with intellectual disabilities evince self-concept development similar to what would be expected in typically-developing children. PMID- 20828330 TI - Interfacing a haptic robotic system with complex virtual environments to treat impaired upper extremity motor function in children with cerebral palsy. AB - OBJECTIVE: To investigate the ability of the New Jersey Institute of Technology Robot Assisted Virtual Rehabilitation (NJIT-RAVR) system training to elicit changes in upper extremity (UE) function in children with hemiplegia secondary to cerebral palsy. METHODS: Nine children (mean age 9 years, three males) participated in three pilots. Subjects trained 1 hour, 3 days a week for 3 weeks. Two groups performed this protocol as their only intervention. The third group also performed 5-6 hours of constraint-induced movement therapy. RESULTS: All subjects participated in a short programme of nine, 60-minute training sessions without adverse effects. As a group, subjects demonstrated statistically significant improvements in Melbourne Assessment of Unilateral Upper Limb Function Test, a composite of three timed UE tasks and several measurements of reaching kinematics. Several subjects demonstrated clinically significant improvements in active shoulder abduction and flexion as well as forearm supination. CONCLUSION: Three small pilots of NJIT-RAVR training demonstrated measurable benefit with no complications, warranting further examination. PMID- 20828331 TI - Traumatic brain injury in children between 7-12 years of age. AB - OBJECTIVE: The purpose of this study was to describe the amount of traumatic brain injuries among children in the western part of Sweden. METHODS: Based on a randomized controlled study, a retrospective analysis was conducted of data for children of 257 children 7-12 years of age. The journals were collected from 1997 2000. RESULTS: The results showed that the most common causes were play and sports and that the accidents occurred in the school environment in the afternoon, whilst the least amount of accidents took place in the home. Nearly half of all the children were admitted to the hospital. Most accidents occurred in March and the least number of accidents occurred during the summer months. CONCLUSION: Prevention strategies are needed, especially for play and sport activities in recreation centres and playgrounds. These places are a high risk in causing a TBI for children after a day at school. PMID- 20828332 TI - Professional development improves staff's implementation of rehabilitation programmes for children with severe-to-profound intellectual disability. AB - OBJECTIVE: To evaluate the effectiveness of supervisory feedback and self management on the acquisition and generalization of correct implementation of rehabilitation training programmes implemented by direct care staff. DESIGN: A non-concurrent multiple baseline design across three trainer-trainee dyads was used. METHODS: Three staff members were trained in how to implement one-to-one teaching programmes with four children with profound-to-severe intellectual disability. Staff received feedback and were taught to self-manage their (in)correct trainer behaviour. RESULTS: Supervisory feedback and self-management increased the mean percentage correct entry behaviour and reinforcement during training. Trainer's use of entry behaviour and reinforcement generalized across settings and trainees. As levels of response prompting for three trainers were already high during baseline, no firm statements could be made concerning its acquisition and generalization. CONCLUSION: Staff can improve the accuracy of training as a result of feedback and/or self-management procedures in the rehabilitation of children with severe disabilities. PMID- 20828333 TI - 'Just like you': a disability awareness programme for children that enhanced knowledge, attitudes and acceptance: pilot study findings. AB - PURPOSE: Participation of people with disabilities is influenced by environmental and contextual factors. Disability awareness programmes aim to increase knowledge and acceptance of disability. This study evaluated a disability awareness programme for students aged 9-11 in Australia. METHOD: Pre-post questionnaires and focus groups evaluated the programme. The intervention took a cognitive behavioural approach including a person with a disability co-presenting. Students (n = 147) participated in two sessions of discussions, written activities, demonstrations and disability simulation activities. RESULTS: Significant improvements (p < 0.001) in knowledge, attitudes and acceptance of disability were evident immediately following the intervention. Focus group analyses further demonstrated these findings. CONCLUSIONS: A brief disability awareness programme for children improved knowledge, attitudes and acceptance of disability in the short-term. Further research is required to identify the potential impact of such programmes on inclusion and social participation of people with disabilities both inside and outside of the school setting. PMID- 20828334 TI - Community integration interventions for youth with acquired brain injuries: a review. AB - OBJECTIVE: To identify and summarize published literature that examined the effectiveness of social and community integration interventions for children and adolescents with ABI in order to provide recommendations regarding future research on this topic. METHODS: A literature review was conducted to identify studies that focused on social and community integration interventions for youth with ABI. Further manual searching of relevant journals with a paediatric rehabilitation focus was also carried out. RESULTS: Currently, limited research has been published evaluating such interventions. The lack of research may stem largely from issues relating to how to measure community integration. Recommendations regarding intervention settings and structure are discussed. CONCLUSION: Additional studies investigating social and community integration interventions are necessary, including those with measures tailored specifically to community integration, larger samples, as are better controls and recruitment of youth with varying severities of brain injuries. PMID- 20828335 TI - Albinterferon-alpha 2b: a new treatment option for hepatitis C. AB - IMPORTANCE OF THE FIELD: HCV infection affects 180 million people worldwide. Standard therapy combines weekly injections of pegIFN and daily ribavirin (RBV). Albinterferon (albIFN)-alpha2b is the most advanced in the development of an IFN based compound. AREAS COVERED IN THIS REVIEW: The rationale for albIFN-alpha2b is to combine IFN-alpha antiviral activity with prolonged presence of human serum albumin in human blood. Initial experimental studies on albIFN-alpha2b were published in 2002. This review provides results of preclinical and subsequent clinical trials. Results of two Phase III clinical trials were presented in 2009 and will be published shortly. WHAT THE READER WILL GAIN: This review discusses the current status of knowledge on the efficacy and safety of albIFN-alpha2b. Phase III clinical trials demonstrated comparable efficacy of albIFN-alpha2b given every 2 weeks to weekly pegIFN-alpha2a, both in combination with RBV. However, the most promising seems to be every 4 weeks dosage. TAKE HOME MESSAGE: Treatment with albIFN-alpha2b combined with RBV can provide comparable efficacy with the current standard of care medication with a reduced number of injections. Lower frequency of some adverse events and improved quality of life can be expected in patients receiving albIFN-alpha2b every 4 weeks. PMID- 20828337 TI - Neuroactive steroids induce changes in fetal sheep behavior during normoxic and asphyxic states. AB - Allopregnanolone and related steroids are potent gamma-aminobutyric acid receptor A receptor agonistic allosteric modulators that suppress central nervous system (CNS) activity; in some species, these neurosteroids regulate normal CNS activity before birth. The aims of this study were to determine the effect of suppressing allopregnanolone production on behavioral responses to transient asphyxia in late gestation fetal sheep using the 5alpha-reductase (R)-2 inhibitor, finasteride. Specificity of the effects of finasteride was assessed by co-infusion of alfaxalone, a synthetic analog of allopregnanolone. Fetal catheters and electrodes for measurement of the electrocorticogram (ECoG) and nuchal electromyogram were implanted at 125 days of gestation, and an inflatable occluder was placed to allow umbilical cord occlusion (UCO). At approximately 130 days of gestation, fetuses received carotid arterial infusion of vehicle (2 hydroxypropyl-beta-cyclodextrin; 40% w/vol), finasteride (40 mg/kg/h), alfaxalone (5 mg/kg/h), or finasteride + alfaxalone. A further three groups of fetuses were subjected to 5 min UCO at 30 min after the start of each infusion regime. Finasteride treatment alone increased the incidence of arousal-like activity; this was reduced by co-infusion of alfaxalone. After UCO, finasteride treatment caused a prolongation of sub-low voltage (LV) ECoG activity and increase in aberrant ECoG spike activity when compared to vehicle-treated UCO fetuses. After UCO, alfaxalone treatment reduced the incidence of sub-LV, reduced the number of aberrant EEG spikes, and restored ECoG activity to the pattern observed after UCO in vehicle-treated fetuses. These results confirm that neurosteroids significantly modulate normal CNS activity in the late gestation fetus, modify, and limit the effects of asphyxia on the brain. PMID- 20828336 TI - The vasopressin Avpr1b receptor: molecular and pharmacological studies. AB - The distribution, pharmacology and function of the arginine vasopressin (Avp) 1b receptor subtype (Avpr1b) has proved more challenging to investigate compared to other members of the Avp receptor family. Avp is increasingly recognised as an important modulator of the hypothalamic-pituitary-adrenal (HPA) axis, an action mediated by the Avpr1b present on anterior pituitary corticotrophs. The Avpr1b is also expressed in some peripheral tissues including pancreas and adrenal, and in the hippocampus (HIP), paraventricular nucleus and olfactory bulb of the rodent brain where its function is unknown. The central distribution of Avpr1bs is far more restricted than that of the Avpr1a, the main Avp receptor subtype found in the brain. Whether Avpr1b expression in rodent tissues is dependent on differences in the length of microsatellite dinucleotide repeats present in the 5' promoter region of the Avpr1b gene remains to be determined. One difficulty of functional studies on the Avpr1b, especially its involvement in the HPA axis response to stress, which prompted the generation of Avpr1b knockout (KO) mouse models, was the shortage of commercially available Avpr1b ligands, particularly antagonists. Research on mice lacking functional Avpr1bs has highlighted behavioural deficits in social memory and aggression. The Avpr1b KO also appears to be an excellent model to study the contribution of the Avpr1b in the HPA axis response to acute and perhaps some chronic (repeated) stressors where corticotrophin-releasing hormone and other genes involved in the HPA axis response to stress do not appear to compensate for the loss of the Avpr1b. PMID- 20828338 TI - Health risk assessment of exposure to selected volatile organic compounds emitted from an integrated iron and steel plant. AB - Workplace air samples from sintering, cokemaking, and hot and cold forming processes in the integrated iron and steel industry were analyzed to determine their volatile organic compound (VOC) concentration. Sixteen VOC species including three paraffins (cyclohexane, n-hexane, methylcyclohexane), five chlorinated VOC species (trichloroethylene, 1,1,1-trichloroethane, tetrachloroethylene, chlorobenzene, 1,4-dichlorobenzene), and eight aromatics (benzene, ethylbenzene, styrene, toluene, m,p-xylene, o-xylene, 1,2,4 trimethylbenzene, 1,3,5-trimethylbenzene) were selected to measure their noncancer risk for workers. Concentrations of toluene, xylene, 1,2,4 trimethylbenzene, 1,3,5-trimethylbenzene, dichlorobenzene, and trichloroethylene were high in all four processes. Carbon tetrachloride and tetrachloroethylene concentrations were high in the hot and cold forming processes. The noncancer risk followed the increasing order: cokemaking > sintering > hot forming > cold forming. 1,2,4-trimethylbenzene and 1,3,5-trimethylbenzene contributed 44% to 65% and 13% to 20% of noncancer risk, respectively, for the four processes. Benzene accounted for a high portion of the noncancer risk in cokemaking. The hazard index (HI: 17-108) of the average VOC concentrations suggests that health risks can be reduced by improving workplace air quality and protecting workers. PMID- 20828339 TI - Comparison of life quality of pregnant adolescents with that of pregnant adults in Turkey. AB - OBJECTIVES: This study aimed to determine the quality of life of pregnant adolescents aged < 20 years and pregnant adults aged between 20-29 years, to evaluate the effects of gestational periods on the quality of life, and to compare the quality of life scores of pregnant adolescents and adults. METHODS: This study was performed in Turkey in 2007. Totally, 147 pregnant adolescents aged < 20 years and 156 pregnant adults aged between 20 and 29 years were included. A questionnaire on socio-demographic and obstetric characteristics was administered by face-to-face interviewing method, and Short Form-36 scale was applied. RESULTS: The mean quality of life scores ranged between 44.2 and 56.1 points for the adolescents and between 44.6 and 59.9 points for the adults. All quality of life scores, except bodily pain, were lower for adolescents than for adults. It was determined that the quality of life scores in pregnancy were generally lower in the first trimester, significantly increased in the second trimester, and decreased to the lowest level in the third trimester. CONCLUSIONS: Quality of life scores of the pregnant adolescents were significantly lower than the pregnant adults. Physical care, support, and education programs may be beneficial to increase the quality of life levels in pregnancy. PMID- 20828340 TI - Device therapy in the elderly heart failure patient: what is the evidence? PMID- 20828341 TI - Everolimus-eluting stents: insights from the SPIRIT IV and COMPARE trials. PMID- 20828343 TI - Clopidogrel in acute coronary syndrome: implications of recent study findings. AB - The platelet ADP receptor antagonist clopidogrel is recommended for the treatment of patients with acute coronary syndrome and/or percutaneous coronary intervention. Patients who received a coronary stent in particular should be protected by sufficient antiplatelet therapy to prevent stent thrombosis. Clopidogrel is a prodrug and has to undergo extensive metabolization before the active metabolite can irreversibly bind to platelets. This makes clopidogrel treatment susceptible to genetic and drug interactions. Recent study findings suggest that initial treatment with a higher dose of clopidogrel may be superior to the currently approved dose. It is not clear whether this approach will be sufficient to entirely overcome clopidogrel hyporesponsiveness, which worsens outcomes in up to one-third of patients. Newer antiplatelet agents are emerging but clopidogrel remains the best established treatment option, with more than 120,000 patients treated in randomized trials and 12 years of clinical postmarketing experience. PMID- 20828344 TI - Heart failure in 2010. AB - The Heart Failure Congress 2010 in Berlin presented the latest trials and trends in the medical and mechanical therapy of heart failure in the presence of impaired or preserved left ventricular ejection fraction. It covered all aspects of heart failure from epidemiology through basic and translational science to prevention. The congress highlighted new drugs, novel biomarkers, updated trials, the role of imaging in risk stratification and the importance of telecare in the reduction of heart failure readmission. PMID- 20828345 TI - Pleiotropic effects of statins in atherosclerotic disease. AB - Statins have an established role in the treatment of hypercholesterolemia and the prophylactic treatment of patients with atherosclerotic disease, and have been found to prevent secondary cardiovascular events and thereby reduce morbidity and mortality. Nevertheless, the pathophysiologic effect of statins on inflammatory responses and local atherosclerotic plaque morphology in humans remains a matter of debate. In particular the question is unanswered whether statin-induced alterations in plaque composition can be ascribed to LDL lowering or an anti inflammatory pleiotropic effect. We will discuss the results of a recent study by Puato et al. concerning the effect of two different atorvastatin dosages and a nonstatin lipid-lowering drug on atherosclerotic plaque morphology. PMID- 20828346 TI - Percutaneous coronary intervention for small-vessel coronary disease: highlight on the everolimus-eluting stent. AB - Smaller coronary arteries are less able to accommodate late loss after percutaneous coronary interventions than larger arteries. The first-generation drug-eluting stents have been shown to have better control of neo-intimal hyperplasia and lower late lumen loss compared with bare-metal stents. However, the reported rates of binary restenosis are still unsatisfactory and small target vessel interventions remain challenging. Recently, a study using a subset of the SPIRIT III trial has demonstrated that the everolimus-eluting stent lowered late lumen loss, rates of binary restenosis and target lesion revascularization compared with the paclitaxel-eluting stent. In this article, we review previous studies evaluating small-vessel interventions and focus on the everolimus-eluting stent in this clinical entity. PMID- 20828347 TI - Percutaneous left ventricular assist devices for high-risk percutaneous coronary intervention. AB - Although coronary artery bypass grafting remains an important therapeutic option for patients with complex coronary artery disease, percutaneous coronary intervention strategies have become an established alternative. Nevertheless, treatment options for surgery-ineligible patients with complex coronary artery disease used to be limited, especially in patients with a reduced left ventricular function. Those patients are at high risk of profound hypotension and mortality, which may be adequately prevented by prophylactic placement of a percutaneous mechanical assist device. Although many devices have been developed and randomized evidence is still pending, the Impella LP2.5 device (Abiomed Impella CardioSystems GmbH, Aachen, Germany) seems to be promising as it is easily applicable, carries a low complication rate and provides adequate circulatory support. PMID- 20828348 TI - Device therapy for the management of cardiac tachyarrhythmias. AB - Implantation of devices that can terminate cardiac arrhythmias has increased rapidly over recent years. This article looks at the evidence base for using such devices in the primary and secondary prevention of sudden arrhythmic death, discusses who should have a device and examines the issues surrounding implantation. Recent advances in technology and the future direction of therapy are also reviewed. PMID- 20828349 TI - Drug-implantable cardioverter-defibrillator interactions. AB - Antiarrhythmic drugs are commonly used synergistically with implantable cardioverter defibrillators in the management of ventricular and supraventricular arrhythmias. However, these drugs may directly or indirectly interact with device function. In addition, expanding indications for implantable cardioverter defibrillators, particularly in patients with multiple comorbidities, further increases the potential for drug-device interactions. These potential drug-device interactions are summarized in this article. PMID- 20828350 TI - Diagnosis and treatment of subclavian artery occlusive disease. AB - Atherosclerosis of the brachiocephalic vessels is uncommon in comparison to the prevalence of disease in the extracranial carotid arteries. Prior to 1980, occlusive disease of this vascular bed had been treated primarily with surgical intervention, which carried a significant rate of morbidity and mortality. In the last 30 years, however, minimally invasive endovascular techniques have become an important tool in the management of symptomatic patients. Angioplasty and stenting have been reported as a viable therapeutic option, producing good technical success and durability. Here, we examine the natural history of subclavian artery occlusive disease, along with the diagnostic evaluation and various treatment modalities currently available, with special attention paid to the evolution of the role of endovascular management. PMID- 20828351 TI - Stents and statins: history, clinical outcomes and mechanisms. AB - The 1980s witnessed the inception of both stents and 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitors (statins). While they evolved separately, it was soon realized that they each offered a unique and powerful mechanism for targeting the major offender in cardiovascular disease, namely atherosclerosis. Coincidentally, the first statin was approved by the US FDA in 1987, the same year that the coronary stent was conceived. Since that time, stents and statins have revolutionized the field of cardiovascular medicine and their paths have been intertwined. Several pivotal randomized clinical trials have established statins as an effective therapy for improving clinical outcomes after percutaneous coronary intervention (PCI) among patients presenting with stable coronary artery disease and acute coronary syndromes. In addition, chronic statin therapy and acute loading of statins prior to PCI has consistently been shown to limit periprocedural myocardial necrosis. The mechanism for improved clinical outcomes with statins has clearly been associated with statin-induced reductions in LDL. In addition, statins may also exert 'pleiotropic' effects, independent of LDL lowering, that might counteract the inflammatory and prothrombotic mileu created with PCI. This article provides a brief historical perspective of the evolution of the use of statins and stents in patients with coronary artery disease, an evaluation of the available clinical data supporting the use of statins in patients undergoing PCI across a wide spectrum of clinical scenarios, and a discussion of the potential mechanisms of the benefit of statins in these patients. PMID- 20828352 TI - Activated platelets and atherosclerosis. AB - Several studies suggest an important role for platelets in atherogenesis, not only as mediators of thrombus formation, but also as inducers of inflammation. Several lines of evidence indicate that platelets are potent inflammatory cells that induce inflammatory responses in adjacent cells such as leukocytes and endothelial cells. Platelets may also themselves respond to inflammatory mediators produced by these neighboring cells. These platelet-mediated inflammatory pathways contribute to atherogenesis in both the early and late stage of the process. The bidirectional interaction between platelets and other cells may also be involved in the nonresolving inflammation characterizing atherosclerosis. In patients with atherosclerotic disorders, platelet-mediated inflammation appears to be operating in spite of the wide use of platelet inhibiting drugs. This underscores the need for new therapeutic tools that more specifically target the pathways in platelet-mediated inflammation. PMID- 20828353 TI - Atherosclerotic vascular damage and rheumatoid arthritis: a complex but intriguing link. AB - Rheumatoid arthritis is a chronic inflammatory disease characterized by a reduced life expectancy mainly due to cardiovascular disease. In long-standing disease, it has been widely demonstrated that both traditional cardiovascular risk and disease-related factors, including chronic inflammation and immune-mediated mechanisms, play a key role in accelerating atherosclerotic damage of the arterial wall. The short- and long-term effects of immunosuppressive treatment on cardiovascular disease outcome is, however, uncertain and a multidisciplinary approach appears to represent the best management of cardiovascular risk in these patients. PMID- 20828354 TI - Management of atherosclerotic renal artery stenosis. AB - The management of atherosclerotic renal artery stenosis is controversial. Although it may appear intuitive that restoring normal blood flow to the kidney(s) is the treatment of choice, there are no data showing an obvious advantage of interventional therapy compared with medical therapy. In this article, we discuss the most recent advances in the treatment of atherosclerotic renal artery stenosis with a focus on randomized studies comparing medical treatment with angioplasty/stenting, particularly in patients with underlying renal dysfunction. The available data are still of limited quality but provide support against indiscriminate use of interventions, as these treatments appear no better than best medical treatment that focuses on blood pressure control, use of blockers of the renin-angiotensin system, and aggressive cardiovascular risk management. PMID- 20828355 TI - Atherosclerosis regression and high-density lipoproteins. AB - Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics. PMID- 20828356 TI - Noninvasive imaging techniques of constrictive pericarditis. AB - Constrictive pericarditis (CP) is the result of scarring and loss of elasticity of the pericardial sac, resulting in external impedance of cardiac filling. It can occur after virtually any pericardial disease process. Patients typically present with signs and symptoms of right heart failure and/or low cardiac output. An important pathophysiological hallmark of CP is exaggerated ventricular interdependence and impaired diastolic filling. Echocardiography is the initial imaging modality for diagnosis of CP. Unfortunately, no echocardiographic sign or combination of signs is pathognomonic for CP. CT scan and cardiac MRI are other imaging techniques that can provide incremental diagnostic information. CT scan can easily detect pericardial thickening and calcification, while cardiac MRI provides a comprehensive evaluation of the pericardium, myocardium and cardiac physiology. Occasionally, a multimodality approach needs to be considered for the conclusive diagnosis of CP. PMID- 20828358 TI - Relationship between birth size and coronary heart disease in China. AB - BACKGROUND: Clinical epidemiological studies suggested a link between fetal growth conditions and later coronary heart disease (CHD) in adult life. However, no such studies have been conducted in a Chinese population. OBJECTIVES: We investigated the association between various birth characteristics and CHD occurrence in a Chinese cohort. DESIGN: Retrospective cohort study. SETTING: Peking Union Medical College Hospital, Beijing, China. PARTICIPANTS: A total of 2,033 subjects who were born at Peking Union Medical College Hospital between 1921 and 1954. MEASUREMENTS: Neonatal birth-weight, placental weight, length from crown to heel, head circumference, and biparietal and occipitofrontal diameters were routinely recorded at the time of birth. All participants were followed up between May 2002 and April 2004 for the occurrence of CHD. RESULTS: CHD was identified in 135 patients. The occurrence of CHD was inversely related to birth sizes, such as birth-weight, head circumference, placental weight (P < 0.05), but was not significantly related to birth length or ponderal index (birth weight/birth length(3)). After multivariable logistic regression, the ratio of birth-weight to birth length was an independent predictor of CHD along with two other variables: obesity and age. LIMITATIONS: This was a single-center retrospective study. CONCLUSIONS: In China low birth size or birth disproportion, which is suggestive of fetal growth retardation, has an effect on CHD occurrence during adulthood. This suggests that environmental factors operate in both the prenatal and postnatal periods with regard to the development of CHD. PMID- 20828359 TI - The ACTION study: methodology of a trial to evaluate safety and efficacy of a higher dose rivastigmine transdermal patch in severe Alzheimer's disease. AB - BACKGROUND: Two sizes of rivastigmine patch (5 cm(2) and 10 cm(2)) are currently approved in the US and Europe, while a 20 cm(2) rivastigmine patch has also been tested. A 15 cm(2) rivastigmine patch may provide an optimal balance between efficacy and safety. Earlier studies have demonstrated the efficacy of rivastigmine in severe Alzheimer's disease (AD), and supported the use of a higher dose patch in AD. OBJECTIVE: The ACTION (ACTivities of daily living and cognitION) trial (Study CENA713DUS44) is designed to evaluate the efficacy and safety of low-dose versus high-dose rivastigmine transdermal patch in patients with severe AD. METHODS: ACTION is a prospective, randomized, parallel-group, double-blind, multicenter study of patients (aged >=50 years) with severe AD and a Mini-Mental State Examination score of 3-12. Novartis began recruitment in July 2009 and is conducting the trial in the United States. Patients are randomized to receive either a 5 cm(2) (4.5 mg/24 h) or a 15 cm(2) rivastigmine patch (13.3 mg/24 h) for 24 weeks. Patients receiving the 15 cm(2) patch will be up-titrated over 8 weeks, via 5 and 10 cm(2) patches. The primary efficacy outcomes include activities of daily living (ADLs), assessed with the Alzheimer's Disease Cooperative Study - Activities of Daily Living - Severe Impairment Version (ADCS ADL-SIV), and cognition, assessed with the Severe Impairment Battery (SIB). Secondary outcomes include behavior (Neuropsychiatric Inventory), global functioning (Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change), response rates, and safety. CONCLUSIONS: The ACTION trial examines the efficacy and tolerability of a 15 cm(2) rivastigmine patch over a 24-week period in patients with severe AD. This is a novel trial in the development of rivastigmine, as it uses a design that does not include a placebo arm, is recruiting patients with severe AD, and includes an ADL measure as a co-primary efficacy variable. CLINICAL REGISTRATION NUMBER: CENA713D US44. PMID- 20828360 TI - Cost-effectiveness of statin therapy for vascular event prevention in adults with elevated C-reactive protein: implications of JUPITER. AB - OBJECTIVES: High-sensitivity C-reactive protein (hs-CRP) has been explored for use in predicting cardiovascular risk. The recent Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study found that statin therapy reduced cardiovascular events in those with low-density lipoprotein (LDL) cholesterol levels below current treatment thresholds (<=130 mg/dL, 3.4 = mmol/L), but with elevated hs-CRP levels (>=2.0 mg/L). This study examines the cost-effectiveness of statin treatment for individuals with elevated hs-CRP but normal LDL cholesterol. METHODS: A Markov decision-analytic model was conducted from the U.S. societal perspective. Data from JUPITER were used to estimate rates of myocardial infarction, angina and stroke. Statin costs were based on generic simvastatin 80 mg, equipotent to the rosuvastatin 20 mg dose used in JUPITER. Primary prevention was the focus and secondary prevention was not modeled explicitly. Quality-adjusted life-years (QALYs) were calculated using nationally representative preference-based utility weights. One-way sensitivity analyses and multivariate probabilistic sensitivity analysis were used to explore uncertainty in model parameters as well as estimate the likelihood of cost-effectiveness when all event rates, costs and utilities were drawn randomly from distributions reflecting uncertainty. RESULTS: Statin therapy cost $10,889/QALY for vascular event prevention in this population. Results were sensitive to the cost of statin treatment. Based on 10,000 simulations, statin therapy was cost-effective in 99.5% of simulations, using a willingness-to-pay threshold of $20,000/QALY, and 100% of simulations using a threshold of $50,000/QALY. CONCLUSIONS: Treatment with statins in patients with elevated hs-CRP but normal cholesterol appears to be cost-effective. Limitations of this study include the assumption that an equipotent dose of simvastatin resulted in the same risk reduction as rosuvastatin. Further, post-event states simulated the average experience of a patient. Continued statin use, subsequent events and/or heart failure were not explicitly modeled. PMID- 20828361 TI - Healthcare resource utilization, adherence and persistence with antipsychotic therapy among schizophrenia patients with vs. without pre-existing metabolic syndrome. AB - OBJECTIVE: To assess the association between pre-existing metabolic syndrome and health outcomes among veterans with schizophrenia. METHODS: The Veterans Integrated Service Network 16 data (VISN16) for 10/2002 - 08/2005 were used to identify patients (n = 593) with schizophrenia (ICD-9 codes: 250.xx) who were switched to a new antipsychotic agent in response to metabolic monitoring as part of a VISN 16 metabolic monitoring program. Two groups (patients with pre-existing metabolic syndrome [MetSyn+] and without [MetSyn-]) were compared on resource utilization, antipsychotic adherence (medication possession ratio: MPR) and persistence (time to all-cause discontinuation of the switched antipsychotic) over 1 year. RESULTS: About one-third of the patients who have undergone metabolic monitoring before the medication switch (35.2%) had metabolic syndrome. The two groups did not significantly differ on healthcare resource utilization, MPR, or time to all-cause medication discontinuation. Adherence and persistence levels were relatively poor for both groups (mean MPR = 0.33 for MetSyn+; MPR = 0.38 for MetSyn-). The median time to all-cause medication discontinuation was 50 days for both groups. CONCLUSIONS: In this retrospective study of patients with schizophrenia, the presence of pre-existing metabolic syndrome did not appear to impact patients' healthcare resource utilization or their adherence and persistence with antipsychotic medication. PMID- 20828362 TI - Nutritional composition of commonly consumed composite dishes in Trinidad. AB - PRIMARY OBJECTIVE: To calculate the nutritional composition of commonly consumed composite dishes in Trinidad in order to analyze dietary intakes obtained using a quantitative food frequency questionnaire developed specifically for the Trinidadian population. METHODS AND PROCEDURES: Multiple weighed versions of each dish were collected from 53 participants throughout Trinidad. Nutritional composition was calculated using NutriBase Clinical Nutrition Manager. MAIN OUTCOMES AND RESULTS: A total of 359 recipes were collected for 89 composite dishes: 19 vegetable, 15 starches, 21 meat/meat alternatives, eight seafood, 10 sweets, five beverages, 11 snacks/miscellaneous items. For each dish, the average nutritional composition (energy and 32 macronutrients/micronutrients) was calculated per 100 g. CONCLUSIONS: The calculated nutritional composition data of 89 commonly consumed dishes in Trinidad can now be used to assess dietary intakes and determine dietary risk factors for chronic disease. PMID- 20828363 TI - Lactic acid is of low predictive value for the diagnosis of bacterial infection in ventricular cerebrospinal fluid samples containing residual blood. AB - BACKGROUND: Lactic acid concentrations (LA) are an established marker of bacterial infection in cerebrospinal fluid (CSF). However, use of LA for the detection of infection in CSF with residual blood has not been fully evaluated. METHODS: Analysis of LA and total protein, cell count and bacterial culture were performed in 90 lumbar and ventricular CSF samples contaminated with blood. RESULTS: Bacterial culture was positive in six CSF samples. The diagnostic value of the cell count was significantly higher than that of LA for the prediction of a positive culture, even if all culture positive and all likely infected samples were included in the analysis. There was no significant difference in LA concentrations between positive or likely positive ventricular CSF samples and all negative, ventricular samples. CONCLUSIONS: Although LA concentrations in CSF are evidently a predictor of bacterial infection, its diagnostic value for the detection of bacterial infection in ventricular CSF with residual blood is limited. PMID- 20828364 TI - Determination of biological variation of alpha-fetoprotein and choriogonadotropin (beta chain) in disease-free patients with testicular cancer. AB - BACKGROUND: Knowledge of biological variation (BV) is important for determining analytical goals and for establishing the magnitude of change between two consecutive measurements which indicate change in a patients' health status. The aim of this work is to determine the BV for total choriogonadotropin (beta chain) (beta-hCG) and alpha-fetoprotein (AFP) in patients diagnosed with testicular cancer but with no evidence of recurrence of disease. METHODS: We estimated BV from a mean of five consecutive measurements in 28 patients diagnosed with testicular cancer, 3 months after tumor resection or 4 months after complete treatment with chemotherapy. The mean sampling interval was 3 months. RESULTS: The mean concentrations of alpha-fetoprotein and choriogonadotropin (beta chain) were 3.9 MUg/L and 0.79 IU/L, respectively. Between-run analytical variation was 7.1% at 4.1 MUg/L for alpha-fetoprotein, and 19% at 0.65 IU/L for choriogonadotropin (beta chain). BV obtained for alpha-fetoprotein and choriogonadotropin (beta chain) was 12.4% and 16.7%, respectively, and the reference change value (RCV) for one-tail showed 38.2% and 60.7% for alpha fetoprotein and choriogonadotropin (beta chain), respectively. CONCLUSIONS: The estimation of BV allows us to calculate analytical goals and RCVs, necessary tools for the correct interpretation of serial measurements in the follow-up of patients. PMID- 20828365 TI - Qualitative detection of the Marburg I alloenzyme of factor VII-activating protease by an immunoassay and its comparison to PCR testing. AB - BACKGROUND: The Marburg I (MRI) single nucleotide polymorphism (SNP) of the factor VII-activating protease (FSAP) gene has been associated with thrombophilia, thromboembolism, atherosclerosis, and the incidence and progression of carotid stenosis. At present, MRI SNP testing is mainly performed using costly nucleic acid analysis. The ratio between FSAP activity and antigen concentrations in citrated plasma has been used to assess the FSAP genotype. METHODS: This article describes the development of a prototype ELISA for the detection of the MRI FSAP alloenzyme, and its correlation to FSAP genotypes to assess whether a positive MRI FSAP ELISA result may be used as a surrogate marker for the presence of the MRI SNP. RESULTS: ELISA results were correlated with FSAP genotypes from 523 blood donors measured using PCR. Diagnostic sensitivity and specificity of the assay for determination of the genotype were 100% (95% confidence interval [CI]: 93.36-100) and 99.79% (95% CI: 98.80-99.96), respectively. Maximum run-to-run, within-run, and total coefficients of variation were 7.8%, 7.9%, and 9.9%, respectively. No cross-reactivities with homologues of the MRI FSAP alloenzyme were observed. Test performance was not affected by typical interfering compounds. CONCLUSIONS: The data demonstrate that an immunoassay applying antibodies specific to the MRI FSAP alloenzyme can provide sufficiently accurate detection of the MRI SNP. This will significantly simplify MRI FSAP testing, particularly in large cohorts. PMID- 20828366 TI - Quantification of coagulation factor XIII activity by a thio-NADH based assay using factor XIII immuno-depleted plasma as a diluent for calibration. AB - BACKGROUND: Accurate determination of factor XIII (FXIII) activity is crucial for replacement therapy. FXIII activity is typically determined using a coupled enzymatic reaction that measures nicotinamide adenine dinucleotide hydride (NADH) consumption at 340 nm. METHODS: Here, we describe the development of a prototype for a novel FXIII activity assay for detection at 405 nm by replacing NADH with thio-NADH, and the application of FXIII immuno-depleted plasma as a diluent for calibration. RESULTS: Performance data show up to two-fold lower susceptibility of the prototype assay to interferences from hemolyzed, icteric, and lipemic samples when compared to a NADH assay format. In addition, the use of FXIII immuno-depleted plasma as diluent for calibration improved recovery almost two fold in the lower measurement range. The novel prototype assay correlates well with a conventional assay (r=0.98, y=0.99.x+2.17% FXIII, n=173). CONCLUSIONS: The described prototype assay has the potential to (a) increase trueness of measurement of low levels of FXIII, (b) improve robustness due to reduction from interferences, and (c) can be used on a broad range of coagulation instruments due to its detection at 405 nm. PMID- 20828367 TI - Hypoxic trophoblast-derived sFlt-1 may contribute to endothelial dysfunction: implication for the mechanism of trophoblast-endothelial dysfunction in preeclampsia. AB - The maternal systemic disorder of widespread endothelial dysfunction is a primary focus in understanding the development of preeclampsia. sFlt-1 (soluble fms-like tyrosine kinase receptor 1), an endogenous inhibitor of VEGF (vascular endothelial growth factor), may play important roles in endothelial dysfunction. The present study aimed to determine whether hypoxic trophoblast-derived sFlt-1 could lead to endothelial dysfunction by establishing a cocultured model of anoxic TEV-1s (human first-trimester extravillous trophoblasts) and HUVECs (human umbilical vein endothelial cells). The results showed that the hypoxic treatment significantly promoted sFlt-1 mRNA and protein expression in TEV-1s in a time dependent manner compared with the effect in HUVECs. When HUVECs were cocultured with anoxic TEV-1s, the endothelial function, which was characterized by NO (nitric oxide) synthesis and monolayer barrier function of HUVECs, were notably decreased, accompanied by increasing sFlt-1 and decreasing VEGF in cell conditioned medium. Moreover, the observed endothelial dysfunction described above was consistent with the dysfunction observed in VEGF siRNA-treated cultures. The findings presented herein imply that chronically hypoxic trophoblasts may release sufficient sFlt-1 to cause endothelial dysfunction by depriving cells of VEGF activity. PMID- 20828368 TI - MicroRNA-488 suppresses cell migration through modulation of the focal adhesion activity during chondrogenic differentiation of chick limb mesenchymal cells. AB - miRNAs (microRNAs) have proven to play essential roles in diverse biological processes including early development, cell proliferation and cell death, and cell differentiation. However, there is only limited amount of information about their potential role in chondrogenesis. In the present study, we investigated the role of miRNA-488 in the cellular condensation, which is essential initiation for chondrogenic differentiation. We found that miRNA-488 expression is up-regulated at the precondensation stage and then down-regulated at the postcondensation stage. Blockade of miRNA-488 via the use of PNA (peanut agglutinin)-based ASOs (antisense oligonucleotides) decreased the protein level of integrins beta1 and phosphorylated FAK (focal adhesion kinase) and resulted in the suppression of cell motility and migration. Moreover, in parallel with theses observation, treatment of anti-miRNA-488 oligonucleotides up-regulated the level of MMP (matrix metalloprotease)-2 activity, and co-treatment with GM6001, an MMP inhibitor, induced recovery of cellular condensation inhibited by blockade of miRNA-488. Collectively, our results suggest that miRNA-488 is one of regulator in cell to ECM (extracellular matrix) interaction through modulation of focal adhesion activity by MMP-2 during chondrogenesis of limb mesenchymal cells. PMID- 20828369 TI - Effect of actin cytoskeleton disruption on electric pulse-induced apoptosis and electroporation in tumour cells. AB - Electric pulses are known to affect the outer membrane and intracellular structures of tumour cells. By applying electrical pulses of 450 ns duration with electric field intensity of 8 kV/cm to HepG2 cells for 30 s, electric pulse induced changes in the integrity of the plasma membrane, apoptosis, viability and mitochondrial transmembrane potential were investigated. Results demonstrated that electric pulses induced cell apoptosis and necrosis accompanied with the decrease of mitochondrial transmembrane potential and the formation of pores in the membrane. The role of cytoskeleton in cellular response to electric pulses was investigated. We found that the apoptotic and necrosis percentages of cells in response to electric pulses decreased after cytoskeletal disruption. The electroporation of cell was not affected by cytoskeletal disruption. The results suggest that the disruption of actin skeleton is positive in protecting cells from killing by electric pulses, and the skeleton is not involved in the electroporation directly. PMID- 20828370 TI - Metallothionein in human immunomagnetically selected CD34(+) haematopoietic progenitor cells. AB - Human umbilical CD34(+) immature haematopoietic cells were rapidly and efficiently obtained from light density MNC (mononuclear cells) by MACS (magnetic cell sorting). An ex vivo expanded population of CD34(+) was cultured in serum free medium supplemented with cytokines FL (flt3 ligand), SCF (stem cell factor) and TPO (thrombopoietin) in order to obtain a sufficient number of CD34(+) cells. CD34(+) cells expanded from cord blood for 7 days were demonstrated to increase in the absolute number of CD34(+) cells by 5.12 +/- 2.47-fold (mean +/- S.D., n = 3). Flow cytometric analysis demonstrated that the percentage of CD34 antigen expression after expansion of the culture was 97.81 +/- 1.07%, whereas it was 69.39 +/- 10.37% in none-expanded CD34(+) cells (mean +/- S.D., n = 3), thus defining a system that allowed extensive amplification accompanied by no maturation. MTs (metallothioneins), low molecular weight, cysteine-rich metal binding proteins, exhibit various functions, including metal detoxification and homoeostasis. We here examined the expression pattern of functional members of the MT gene family in immature CD34(+) cells and compared it with more mature CD34(-) cells in order to strengthen the proposed function of MT in differentiation. Cells were cultured in RPMI 1640 medium, with or without different zinc supplements for 24 h. Relative quantitative expression of MT isogenes in the mature CD34(-) cells was higher than in the immature CD34(+) cells. IHC (immunohistochemical staining) revealed an increased MT protein biosynthesis in CD34(-) cells, greater than in CD34(+) cells. Therefore, the role of MT in differentiation of human haematopoietic progenitor cells from human cord blood is reported for the first time. PMID- 20828371 TI - Baroreflex sensitivity is higher during acute psychological stress in healthy subjects under beta-adrenergic blockade. AB - Acute psychological stress challenges the cardiovascular system with an increase in BP (blood pressure), HR (heart rate) and reduced BRS (baroreflex sensitivity). beta-adrenergic blockade enhances BRS during rest, but its effect on BRS during acute psychological stress is unknown. This study tested the hypothesis that BRS is higher during acute psychological stress in healthy subjects under beta adrenergic blockade. Twenty healthy novice male bungee jumpers were randomized and studied with (PROP, n=10) or without (CTRL, n=10) propranolol. BP and HR responses and BRS [cross-correlation time-domain (BRSTD) and cross-spectral frequency-domain (BRSFD) analysis] were evaluated from 30 min prior up to 2 h after the jump. HR, cardiac output and pulse pressure were lower in the PROP group throughout the study. Prior to the bungee jump, BRS was higher in the PROP group compared with the CTRL group [BRSTD: 28 (24-42) compared with 17 (16-28) ms.mmHg-1, P<0.05; BRSFD: 27 (20-34) compared with 14 (9-19) ms.mmHg-1, P<0.05; values are medians (interquartile range)]. BP declined after the jump in both groups, and post-jump BRS did not differ between the groups. In conclusion, during acute psychological stress, BRS is higher in healthy subjects treated with non-selective beta-adrenergic blockade with significantly lower HR but comparable BP. PMID- 20828372 TI - Circadian clock genes, ovarian development and diapause. AB - Insects, like most organisms, have an internal circadian clock that oscillates with a daily rhythmicity, and a timing mechanism that mediates seasonal events, including diapause. In research published in BMC Biology, Ikeno et al. show that downregulation of the circadian clock genes period and cycle affects expression of ovarian diapause in the insect Riptortus pedestris. They interpret these important results as support for Erwin Bunning's (1936) hypothesis that the circadian clock constitutes the basis of photoperiodism. However, their observations could also be the result of pleiotropic effects of the individual clock genes.See research article http://www.biomedcentral.com/1741-7007/8/116. PMID- 20828373 TI - Oestrogen shuts the door on SOX9. AB - Oestrogen exerts a robust yet imperfectly understood effect on sexual development in vertebrate embryos. New work by Pask and colleagues in BMC Biology indicates that it may interfere with male development by preventing nuclear localization of SOX9, a master regulator of the testis differentiation pathway. See research article http://www.biomedcentral.com/1741-7007/8/113. PMID- 20828374 TI - Variation of cataract surgery costs in four different graded providers of China. AB - BACKGROUND: China has the largest population of cataract patients in the world. However, the cataract surgery rate per million remains low in China. We carried out a survey on costs of cataract surgery from four different graded providers in China and analyzed differences in cost among these clinics. METHODS: 1,189 patients were recruited for the study in four eye clinics, located in two provinces, Guangdong province in southern China and Hubei province in central China. The average cost of each cataract surgery episode was calculated including cost of intraocular lens, cost of drugs and facility cost. We also collected information on reimbursement and disposable annual income of local residents. RESULTS: Mean total cost per cataract intervention of four different providers varied considerably, ranging from US$ 1,293 in Union Hospital to US$ 536 in Jingshan County Hospital. In all providers, except for Jingshan County Hospital, the cost exceeded annual disposable income of local rural residents. As to the proportion of patients with reimbursement, the figure for Union Hospital was only 36%, while for other three clinics it was more than 60%. There was a significant difference between mean reimbursement ratios, with the highest ratio in Zhongshan Ophthalmic Center being 71%. CONCLUSIONS: Significant differences in costs of cataract surgery were found among the 4 different graded providers. A part of the cost was borne by patients. Proportion of patients with reimbursement and mean reimbursement ratios were higher in economically developed regions than in economically developing regions. Much more financial support should be directed into the rural New Cooperative Medical Scheme to raise the reimbursement ratio in rural China. PMID- 20828375 TI - Bed bug deterrence. AB - A recent study in BMC Biology has determined that the immature stage of the bed bug (the nymph) signals its reproductive status to adult males using pheromones and thus avoids the trauma associated with copulation in this species. The success of this nymphal strategy of deterrence is instructive. Against the background of increasing problems with bed bugs, this research raises the question whether pheromones might be used to control them. See research article http://www.biomedcentral.com/1741-7007/8/121. PMID- 20828376 TI - Suppression subtractive hybridization identifies an autotransporter adhesin gene of E. coli IMT5155 specifically associated with avian pathogenic Escherichia coli (APEC). AB - BACKGROUND: Extraintestinal pathogenic E. coli (ExPEC) represent a phylogenetically diverse group of bacteria which are implicated in a large range of infections in humans and animals. Although subgroups of different ExPEC pathotypes, including uropathogenic, newborn meningitis causing, and avian pathogenic E. coli (APEC) share a number of virulence features, there still might be factors specifically contributing to the pathogenesis of a certain subset of strains or a distinct pathotype. Thus, we made use of suppression subtractive hybridization and compared APEC strain IMT5155 (O2:K1:H5; sequence type complex 95) with human uropathogenic E. coli strain CFT073 (O6:K2:H5; sequence type complex 73) to identify factors which may complete the currently existing model of APEC pathogenicity and further elucidate the position of this avian pathotype within the whole ExPEC group. RESULTS: Twenty-eight different genomic loci were identified, which are present in IMT5155 but not in CFT073. One of these loci contained a gene encoding a putative autotransporter adhesin. The open reading frame of the gene spans a 3,498 bp region leading to a putative 124-kDa adhesive protein. A specific antibody was raised against this protein and expression of the adhesin was shown under laboratory conditions. Adherence and adherence inhibition assays demonstrated a role for the corresponding protein in adhesion to DF-1 chicken fibroblasts. Sequence analyses revealed that the flanking regions of the chromosomally located gene contained sequences of mobile genetic elements, indicating a probable spread among different strains by horizontal gene transfer. In accordance with this hypothesis, the adhesin was found to be present not only in different phylogenetic groups of extraintestinal pathogenic but also of commensal E. coli strains, yielding a significant association with strains of avian origin. CONCLUSIONS: We identified a chromosomally located autotransporter gene in a highly virulent APEC strain which confers increased adherence of a non fimbriated E. coli K-12 strain to a chicken fibroblast cell line. Even though flanked by mobile genetic elements and three different genetic regions upstream of the gene, most probably indicating horizontal gene transfer events, the adhesin gene was significantly linked with strains of avian origin. Due to the nucleotide sequence similarity of 98% to a recently published adhesin-related gene, located on plasmid pAPEC-O1-ColBM, the name aatA (APEC autotransporter adhesin A) was adopted from that study.Our data substantiate that AatA might not only be of relevance in APEC pathogenicity but also in facilitating their reservoir life style in the chicken intestine, which might pave the way for future intestinal preventive strategies. PMID- 20828377 TI - Comparison of ELF, FibroTest and FibroScan for the non-invasive assessment of liver fibrosis. AB - BACKGROUND: FibroTest (FT) is the most frequently used serum fibrosis marker and consists of an algorithm of five fibrosis markers (alfa2-macroglobulin, apolipoproteinA1, haptoglobin, GGT, bilirubin). The Enhanced Liver Fibrosis (ELF) test consists of an algorithm of three fibrosis markers (hyaluronic acid, amino terminal propeptide-of-type-III-collagen, tissue-inhibitor of matrix metaloproteinase-1). While a systematic review has shown comparable results for both individual markers, there has been no direct comparison of both markers. METHODS: In the present study, the ELF-test was analyzed retrospectively in patients with chronic liver disease, who received a liver biopsy, transient elastography (TE) and the FibroTest using histology as the reference method. Histology was classified according to METAVIR and the Ludwig's classification (F0 F4) for patients with chronic hepatitis C and B virus (HCV, HBV) infection and primary biliary cirrhosis (PBC), respectively. RESULTS: Seventy-four patients were analysed: 36 with HCV, 10 with HBV, and 28 with PBC. The accuracy (AUROC) for the diagnosis of significant fibrosis (F>=2) for ELF and FibroTest was 0.78 (95%CI:0.67-0.89) and 0.69 (95%-CI:0.57-0.82), respectively (difference not statistically significant, n.s.). The AUROC for the diagnosis of liver cirrhosis was 0.92 (95%CI:0.83-1,00), and 0.91 (95%CI:0.83-0.99), respectively (n.s.). For 66 patients with reliable TE measurements the AUROC for the diagnosis of significant fibrosis (cirrhosis) for TE, ELF and FT were 0.80 (0.94), 0.76 (0.92), and 0.67 (0.91), respectively (n.s.). CONCLUSION: FibroTest and ELF can be performed with comparable diagnostic accuracy for the non-invasive staging of liver fibrosis. Serum tests are informative in a higher proportion of patients than transient elastography. PMID- 20828378 TI - Host gene expression profiling in influenza A virus-infected lung epithelial (A549) cells: a comparative analysis between highly pathogenic and modified H5N1 viruses. AB - BACKGROUND: To understand the molecular mechanism of host responses to highly pathogenic avian influenza virus infection and to get an insight into the means through which virus overcomes host defense mechanism, we studied global gene expression response of human lung carcinoma cells (A549) at early and late stages of infection with highly pathogenic avian Influenza A (H5N1) virus and compared it with a reverse genetics modified recombinant A (H5N1) vaccine virus using microarray platform. RESULTS: The response was studied at time points 4, 8, 16 and 24 hours post infection (hpi). Gene ontology analysis revealed that the genes affected by both the viruses were qualitatively similar but quantitatively different. Significant differences were observed in the expression of genes involved in apoptosis and immune responses, specifically at 16 hpi. CONCLUSION: We conclude that subtle differences in the ability to induce specific host responses like apoptotic mechanism and immune responses make the highly pathogenic viruses more virulent. PMID- 20828379 TI - 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. AB - BACKGROUND: 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin antibiotic, specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone that maintains the structural and functional integrity of various protein clients involved in cellular signaling. In this study, we have investigated the effect of 17-AAG on the regulation of Hsp90-dependent signaling pathways directly implicated in cell cycle progression, survival and motility of human urinary bladder cancer cell lines. METHODS: We have used MTT-based assays, FACS analysis, Western blotting, semi-quantitative RT-PCR, immunocytochemistry and scratch-wound assay in RT4, RT112 and T24 human urinary bladder cancer cell lines. RESULTS: We have demonstrated that, upon 17-AAG treatment, bladder cancer cells are arrested in the G1 phase of the cell cycle and eventually undergo apoptotic cell death in a dose-dependent manner. Furthermore, 17-AAG administration was shown to induce a pronounced downregulation of multiple Hsp90 protein clients and other downstream effectors, such as IGF-IR, Akt, IKK-alpha, IKK-beta, FOXO1, ERK1/2 and c-Met, resulting in sequestration-mediated inactivation of NF-kappaB, reduced cell proliferation and decline of cell motility. CONCLUSIONS: In total, we have clearly evinced a dose-dependent and cell type-specific effect of 17-AAG on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of multiple Hsp90 clients and subsequent disruption of signaling integrity. PMID- 20828380 TI - A modified surgical approach to women with obstetric anal sphincter tears by separate suturing of external and internal anal sphincter. A modified approach to obstetric anal sphincter injury. AB - BACKGROUND: Long-term results after obstetric anal sphincter injury (OASI) are poor. We aimed to improve the long-term outcome after OASI by lessening symptoms of anal incontinence. METHODS: In a prospective study at Malmo University Hospital, twenty-six women with at least grade 3B OASI were classified and sutured in a systematic way, including separate suturing of the internal and external sphincter muscles with monofilament absorbable sutures. The principal outcome assessed by answers given to six questions, was a difference in anal incontinence score, between the study group and two control groups (women with prior OASI [n = 180] and primiparous women delivered vaginally without a diagnose of OASI [n = 100]). RESULTS: An anal incontinence score of zero (i.e., no symptoms) was found in 74% of the study group, 47% of the OASI control group, and 66% of the vaginal control group (p = 0.02 and 0.5, as compared to the study group). CONCLUSIONS: A modified suturing technique was followed by significant improved one-year symptoms of anal incontinence as compared to historical cases. PMID- 20828381 TI - Nymphs of the common bed bug (Cimex lectularius) produce anti-aphrodisiac defence against conspecific males. AB - BACKGROUND: Abdominal wounding by traumatic insemination and the lack of a long distance attraction pheromone set the scene for unusual sexual signalling systems. Male bed bugs (Cimex lectularius) mount any large, newly fed individual in an attempt to mate. Last instar nymphs overlap in size with mature females, which make them a potential target for interested males. However, nymphs lack the female's specific mating adaptations and may be severely injured by the abdominal wounding. We, therefore, hypothesized that nymphs emit chemical deterrents that act as an honest status signal, which prevents nymph sexual harassment and indirectly reduces energy costs for males. RESULTS: Behavioural mating assays showed that males mount nymphs significantly shorter time compared to females, although initial mounting preference was the same. In support of our hypothesis, nymphs experienced the same percentage of mating with sperm transfer as females if they were unable to emit (E)-2-hexenal, (E)-2-octenal 4-oxo-(E)-2-hexenal and 4-oxo-(E)-2-octenal, from their dorsal abdominal glands. We report that the aldehydes and 4-oxo-(E)-2-hexenal are detected by olfactory receptor neurons housed in smooth and grooved peg sensilla, respectively, on the adult antennae, at biologically relevant concentrations. Behavioural experiments showed that application of 4-oxo-(E)-2-hexenal or the two aldehydes at a nymph-emitted ratio, to a male/female pair during mounting initiation, decreased mating frequency to a rate comparable to that of a male/nymph pair. CONCLUSIONS: By combining behavioural and sensory studies, we show that the nymph-specific alarm pheromone plays an important role in intra-specific communication in the common bed bug. Alarm pheromones are commonly looked upon as a system in predator/prey communication, but here we show that alarm pheromones may be used as multipurpose signals such as decreasing the risk of nymphal mating by males. PMID- 20828382 TI - Mutant alleles of FAD2-1A and FAD2-1B combine to produce soybeans with the high oleic acid seed oil trait. AB - BACKGROUND: The alteration of fatty acid profiles in soybean [Glycine max (L.) Merr.] to improve soybean oil quality is an important and evolving theme in soybean research to meet nutritional needs and industrial criteria in the modern market. Soybean oil with elevated oleic acid is desirable because this monounsaturated fatty acid improves the nutrition and oxidative stability of the oil. Commodity soybean oil typically contains 20% oleic acid and the target for high oleic acid soybean oil is approximately 80% of the oil; previous conventional plant breeding research to raise the oleic acid level to just 50-60% of the oil was hindered by the genetic complexity and environmental instability of the trait. The objective of this work was to create the high oleic acid trait in soybeans by identifying and combining mutations in two delta-twelve fatty acid desaturase genes, FAD2-1A and FAD2-1B. RESULTS: Three polymorphisms found in the FAD2-1B alleles of two soybean lines resulted in missense mutations. For each of the two soybean lines, there was one unique amino acid change within a highly conserved region of the protein. The mutant FAD2-1B alleles were associated with an increase in oleic acid levels, although the FAD2-1B mutant alleles alone were not capable of producing a high oleic acid phenotype. When existing FAD2-1A mutations were combined with the novel mutant FAD2-1B alleles, a high oleic acid phenotype was recovered only for those lines which were homozygous for both of the mutant alleles. CONCLUSIONS: We were able to produce conventional soybean lines with 80% oleic acid in the oil in two different ways, each requiring the contribution of only two genes. The high oleic acid soybean germplasm developed contained a desirable fatty acid profile, and it was stable in two production environments. The presumed causative sequence polymorphisms in the FAD2-1B alleles were developed into highly efficient molecular markers for tracking the mutant alleles. The resources described here for the creation of high oleic acid soybeans provide a framework to efficiently develop soybean varieties to meet changing market demands. PMID- 20828383 TI - Transcriptional profile of maize roots under acid soil growth. AB - BACKGROUND: Aluminum (Al) toxicity is one of the most important yield-limiting factors of many crops worldwide. The primary symptom of Al toxicity syndrome is the inhibition of root growth leading to poor water and nutrient absorption. Al tolerance has been extensively studied using hydroponic experiments. However, unlike soil conditions, this method does not address all of the components that are necessary for proper root growth and development. In the present study, we grew two maize genotypes with contrasting tolerance to Al in soil containing toxic levels of Al and then compared their transcriptomic responses. RESULTS: When grown in acid soil containing toxic levels of Al, the Al-sensitive genotype (S1587-17) showed greater root growth inhibition, more Al accumulation and more callose deposition in root tips than did the tolerant genotype (Cat100-6). Transcriptome profiling showed a higher number of genes differentially expressed in S1587-17 grown in acid soil, probably due to secondary effects of Al toxicity. Genes involved in the biosynthesis of organic acids, which are frequently associated with an Al tolerance response, were not differentially regulated in both genotypes after acid soil exposure. However, genes related to the biosynthesis of auxin, ethylene and lignin were up-regulated in the Al-sensitive genotype, indicating that these pathways might be associated with root growth inhibition. By comparing the two maize lines, we were able to discover genes up regulated only in the Al-tolerant line that also presented higher absolute levels than those observed in the Al-sensitive line. These genes encoded a lipase hydrolase, a retinol dehydrogenase, a glycine-rich protein, a member of the WRKY transcriptional family and two unknown proteins. CONCLUSIONS: This work provides the first characterization of the physiological and transcriptional responses of maize roots when grown in acid soil containing toxic levels of Al. The transcriptome profiles highlighted several pathways that are related to Al toxicity and tolerance during growth in acid soil. We found several genes that were not found in previous studies using hydroponic experiments, increasing our understanding of plant responses to acid soil. The use of two germplasms with markedly different Al tolerances allowed the identification of genes that are a valuable tool for assessing the mechanisms of Al tolerance in maize in acid soil. PMID- 20828384 TI - Promising outcomes of a national programme for the prevention of Mother-to-Child HIV transmission in Addis Ababa: a retrospective study. AB - BACKGROUND: Prevention of Mother-to-Child HIV Transmission (PMTCT) is still the most effective intervention in combating new HIV infections. In 2008, revised national PMTCT guidelines that incorporated new policies on HIV counselling and testing, antiretroviral prophylaxis regimen and infant HIV diagnosis came into effect in Ethiopia. In the present study we have examined trends in PMTCT service utilization and assessed the rate of MTCT in relation to policy changes in the national PMTCT programme. METHODS: Reports from February 2004 to August 2009 were reviewed in 10 sub-cities in Addis Ababa, Ethiopia. The data was collected from May to October 2009. RESULTS: The proportion of women who received HIV counselling and testing among new antenatal care attendees increased from 50.7% (95% CI 50.2-51.2) in 2007 to 84.5% (95% CI 84.1-84.9) in 2009 following the shift to routine opt-out testing. Nevertheless, in 2009 only 53.7% of the positive women and 40.7% of their infants received antiretroviral prophylaxis. The HIV prevalence among antenatal attendees decreased significantly from 10.5% in 2004 to 4.6% in 2009 in parallel to the increased number of women being tested. The HIV positive women were over 18 times (RR 18.5, p < 0.0001) more likely to be referred for treatment, care and support in 2009 than in 2004. The proportion of partners tested for HIV decreased by 14% in 2009 compared to 2004, although the absolute number was increasing year by year. Only 10.6% (95% CI 9.9 11.2) of the HIV positive women completed their follow up to infant HIV testing. The cumulative probability of HIV infection among babies on single dose nevirapine regimen who were tested at >=18 months was 15.0% (95% CI 9.8-22.1) in 2007, whereas it was 8.2% (95% CI 5.55-11.97) among babies on Zidovudine regimen who were tested at >=45 days in 2009. CONCLUSION: The paper demonstrates trends in PMTCT service utilization in relation to changing policy. There is marked improvement in HIV counselling and testing service utilization, especially after the policy shift to routine opt-out testing. However, despite policy changes, the ARV prophylaxis uptake, the loss to follow up and the partner testing have remained unchanged across the years. This should be a matter of immediate concern and a topic for further research. PMID- 20828385 TI - Cytostatic and anti-angiogenic effects of temsirolimus in refractory mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare and aggressive type of B-cell non-Hodgkin's lymphoma. Patients become progressively refractory to conventional chemotherapy, and their prognosis is poor. However, a 38% remission rate has been recently reported in refractory MCL treated with temsirolimus, a mTOR inhibitor.Here we had the opportunity to study a case of refractory MCL who had tumor regression two months after temsirolimus treatment, and a progression-free survival of 10 months. In this case, lymph node biopsies were performed before and six months after temsirolimus therapy. Comparison of the two biopsies showed that temsirolimus inhibited tumor cell proliferation through cell cycle arrest, but did not induce any change in the number of apoptotic tumor cells. Apart from this cytostatic effect, temsirolimus had an antiangiogenic effect with decrease of tumor microvessel density and of VEGF expression. Moreover, numerous patchy, well limited fibrotic areas, compatible with post-necrotic tissue repair, were found after 6-month temsirolimus therapy. Thus, temsirolimus reduced tumor burden through associated cytostatic and anti-angiogenic effects.This dual effect of temsirolimus on tumor tissue could contribute to its recently reported efficiency in refractory MCL resistant to conventional chemotherapy. PMID- 20828386 TI - Cytoplasmic- and extracellular-proteome analysis of Diplodia seriata: a phytopathogenic fungus involved in grapevine decline. AB - BACKGROUND: The phytopathogenic fungus Diplodia seriata, whose genome remains unsequenced, produces severe infections in fruit trees (fruit blight) and grapevines. In this crop is recognized as one of the most prominent pathogens involved in grapevine trunk disease (or grapevine decline). This pathology can result in the death of adult plants and therefore it produces severe economical losses all around the world. To date no genes or proteins have been characterized in D. seriata that are involved in the pathogenicity process. In an effort to help identify potential gene products associated with pathogenicity and to gain a better understanding of the biology of D. seriata, we initiated a proteome-level study of the fungal mycelia and secretome. RESULTS: Intracellular and secreted proteins from D. seriata collected from liquid cultures were separated using two dimensional gel electrophoresis. About 550 cytoplasmic proteins were reproducibly present in 3 independent extractions, being 53 identified by peptide mass fingerprinting and tandem mass spectrometry. The secretome analysis showed 75 secreted proteins reproducibly present in 3 biological replicates, being 16 identified. Several of the proteins had been previously identified as virulence factors in other fungal strains, although their contribution to pathogenicity in D. seriata remained to be analyzed. When D. seriata was grown in a medium supplemented with carboxymethylcellulose, 3 proteins were up-regulated and 30 down-regulated. Within the up-regulated proteins, two were identified as alcohol dehydrogenase and mitochondrial peroxyrredoxin-1, suggesting that they could play a significant role in the pathogenicity process. As for the 30 down-regulated proteins, 9 were identified being several of them involved in carbohydrate metabolism. CONCLUSIONS: This study is the first report on proteomics on D. seriata. The proteomic data obtained will be important to understand the pathogenicity process. In fact, several of the identified proteins have been reported as pathogenicity factors in other phytopathogenic fungi. Moreover, this proteomic analysis supposes a useful basis for deepening into D. seriata knowledge and will contribute to the development of the molecular biology of this fungal strain as it has been demonstrated by cloning the gene Prx1 encoding mitochondrial peroxiredoxin-1 of D. seriata (the first gene to be cloned in this microorganism; data not shown). PMID- 20828388 TI - Watch out for malaria: still a leading cause of child death worldwide. AB - BACKGROUND: Due to the efforts in malaria control promoted by the World Health Organization (WHO), the reported malaria burden is being reduced throughout the world. Nevertheless, malaria remains a leading cause of child death worldwide. AIMS: Purpose of the paper is to summarize the main historical steps in fighting malaria, from the first descriptions to the last ones. RESULTS: A case of probable autochthonous malaria has been recently described in Italy, raising concern over the possibility of resurgence of malaria in countries previously interested by this disease. Moreover, both the constant threat of the parasite and vector mosquito developing resistance to medicines and insecticides, and the on-going climate change make the challenge of eradicating malaria really difficult. Therefore, malaria is still an actual disease, requiring adequate programs of surveillance, stronger health systems in poor countries, and efforts in order to develop new and effective tools in malaria control. WHO has definitely demonstrated the effects of "social determinants" on health. So, eradication strategies cannot be based only on a scientific background, because culture, politics, power, resources and wars have a profound impact on health and disease. These elements should be introduced in all the programs of malaria control. CONCLUSIONS: Malaria is still an actual disease with great public health implications, and the approaches for control and prevention should have the appropriate social and political context in addition to the science involved in order to save lives of children at risk. PMID- 20828387 TI - Synergism in hyperhomocysteinemia and diabetes: role of PPAR gamma and tempol. AB - BACKGROUND: Hyperhomocysteinemia (HHcy) and hyperglycemia cause diabetic cardiomyopathy by inducing oxidative stress and attenuating peroxisome proliferator- activated receptor (PPAR) gamma. However, their synergistic contribution is not clear. METHODS: Diabetic Akita (Ins2+/-) and hyperhomocysteinemic cystathionine beta synthase mutant (CBS+/-) were used for M mode echocardiography at the age of four and twenty four weeks. The cardiac rings from WT, Akita and hybrid (Ins2+/-/CBS+/-) of Akita and CBS+/- were treated with different doses of acetylcholine (an endothelial dependent vasodilator). High performance liquid chromatography (HPLC) was performed for determining plasma homocysteine (Hcy) level in the above groups. Akita was treated with ciglitazone (CZ) - a PPAR gamma agonist and tempol-an anti-oxidant, separately and their effects on cardiac remodeling were assessed. RESULTS: At twenty four week, Akita mice were hyperglycemic and HHcy. They have increased end diastolic diameter (EDD). In their heart PPAR gamma, tissue inhibitor of metalloproteinase-4 (TIMP 4) and anti-oxidant thioredoxin were attenuated whereas matrix metalloproteinase (MMP)-9, TIMP-3 and NADPH oxidase 4 (NOX4) were induced. Interestingly, they showed synergism between HHcy and hyperglycemia for endothelial-myocyte (E-M) uncoupling. Additionally, treatment with CZ alleviated MMP-9 activity and fibrosis, and improved EDD. On the other hand, treatment with tempol reversed cardiac remodeling in part by restoring the expressions of TIMP-3,-4, thioredoxin and MMP-9. CONCLUSIONS: Endogenous homocysteine exacerbates diabetic cardiomyopathy by attenuating PPAR gamma and inducing E-M uncoupling leading to diastolic dysfunction. PPAR gamma agonist and tempol mitigates oxidative stress and ameliorates diastolic dysfunction in diabetes. PMID- 20828389 TI - The Delta4-desaturation pathway for DHA biosynthesis is operative in the human species: differences between normal controls and children with the Zellweger syndrome. AB - BACKGROUND: Docosahexaenoic acid (DHA, 22:6omega3) is a fundamental component of cell membranes, especially in the brain and retina. In the experimental animal, DHA deficiency leads to suboptimal neurological performance and visual deficiencies. Children with the Zellweger syndrome (ZS) have a profound DHA deficiency and symptoms that can be attributed to their extremely low DHA levels. These children seem to have a metabolic defect in DHA biosynthesis, which has never been totally elucidated. Treatment with DHA ethyl ester greatly improves these patients, but if we could normalize their endogenous DHA production we could get additional benefits. We examined whether DHA biosynthesis by Delta4 desaturation could be enhanced in the human species by transfecting the enzyme, and if this could normalize the DHA levels in cells from ZS patients. RESULTS: We showed that the Delta4-desaturase gene (Fad4) from Thraustochytrium sp, which can be expressed by heterologous transfection in other plant and yeast cells, can also be transfected into human lymphocytes, and that it expresses the enzyme (FAD4, Delta4-desaturase) by producing DHA from direct Delta4-desaturation of 22:5omega3. We also found that the other substrate for Delta4-desaturase, 22:4omega6, was parallely desaturated to 22:5omega6. CONCLUSIONS: The present "in vitro" study demonstrates that Delta4-desaturase can be transfected into human cells and synthesize DHA (as well as 22:5omega6, DPA) from 22:5omega3 and 22:4omega6, respectively, by putative Delta4-desaturation. Even if this pathway may not be the physiological route for DHA biosynthesis "in vivo", the present study opens new perspectives for the treatment of patients within the ZS spectrum. PMID- 20828390 TI - Comparison of multimarker logistic regression models, with application to a genomewide scan of schizophrenia. AB - BACKGROUND: Genome-wide association studies (GWAS) are a widely used study design for detecting genetic causes of complex diseases. Current studies provide good coverage of common causal SNPs, but not rare ones. A popular method to detect rare causal variants is haplotype testing. A disadvantage of this approach is that many parameters are estimated simultaneously, which can mean a loss of power and slower fitting to large datasets.Haplotype testing effectively tests both the allele frequencies and the linkage disequilibrium (LD) structure of the data. LD has previously been shown to be mostly attributable to LD between adjacent SNPs. We propose a generalised linear model (GLM) which models the effects of each SNP in a region as well as the statistical interactions between adjacent pairs. This is compared to two other commonly used multimarker GLMs: one with a main-effect parameter for each SNP; one with a parameter for each haplotype. RESULTS: We show the haplotype model has higher power for rare untyped causal SNPs, the main effects model has higher power for common untyped causal SNPs, and the proposed model generally has power in between the two others. We show that the relative power of the three methods is dependent on the number of marker haplotypes the causal allele is present on, which depends on the age of the mutation. Except in the case of a common causal variant in high LD with markers, all three multimarker models are superior in power to single-SNP tests.Including the adjacent statistical interactions results in lower inflation in test statistics when a realistic level of population stratification is present in a dataset.Using the multimarker models, we analyse data from the Molecular Genetics of Schizophrenia study. The multimarker models find potential associations that are not found by single-SNP tests. However, multimarker models also require stricter control of data quality since biases can have a larger inflationary effect on multimarker test statistics than on single-SNP test statistics. CONCLUSIONS: Analysing a GWAS with multimarker models can yield candidate regions which may contain rare untyped causal variants. This is useful for increasing prior odds of association in future whole-genome sequence analyses. PMID- 20828391 TI - The psychological burden of an initially unexplained illness: patients with sternocostoclavicular hyperostosis before and after delayed diagnosis. AB - BACKGROUND: Sternocostoclavicular hyperostosis (SCCH) is a rare, debilitating, chronic inflammatory disorder of the anterior chest wall due to a chronic sterile osteomyelitis of unknown origin. SCCH is largely underdiagnosed and often misdiagnosed. In individual cases it can remain unrecognized for years. The purpose of this study is twofold. Firstly, to evaluate the psychological condition of SCCH patients, both in the sometimes quite extended pre-diagnostic period between first manifestations and confirmed diagnosis of the disease, and in the current situation. Secondly, to investigate the relationships between the pre-diagnostic and the current psychological conditions of confirmed SCCH patients. METHODS: Structured interviews were held with 52 confirmed SCCH patients. Questionnaires were included to assess posttraumatic stress symptoms, social support, aspects of pain, illness perceptions, self-reported health status, and quality of life. RESULTS: SCCH patients reported stronger posttraumatic stress symptoms, more unfavorable illness perceptions, lower health status, and poorer quality of life than healthy individuals and patients with other diseases or traumatic experiences. Psychological distress in the pre diagnostic period was associated with unfavorable conditions in the current situation. CONCLUSION: SCCH is an illness with serious psychological consequences. Psychological monitoring of patients with unexplained complaints is recommended as long as a diagnosis has not been reached. PMID- 20828393 TI - Activating Transcription Factor 3 regulates in part the enhanced tumour cell cytotoxicity of the histone deacetylase inhibitor M344 and cisplatin in combination. AB - BACKGROUND: Activating Transcription Factor (ATF) 3 is a key regulator of the cellular integrated stress response whose expression has also been correlated with pro-apoptotic activities in tumour cell models. Combination treatments with chemotherapeutic drugs, such as cisplatin, and histone deacetylase (HDAC) inhibitors have been demonstrated to enhance tumour cell cytotoxicity. We recently demonstrated a role for ATF3 in regulating cisplatin-induced apoptosis and others have shown that HDAC inhibition can also induce cellular stress. In this study, we evaluated the role of ATF3 in regulating the co-operative cytotoxicity of cisplatin in combination with an HDAC inhibitor. RESULTS: The HDAC inhibitor M344 induced ATF3 expression at the protein and mRNA level in a panel of human derived cancer cell lines as determined by Western blot and quantitative RT-PCR analyses. Combination treatment with M344 and cisplatin lead to increased induction of ATF3 compared with cisplatin alone. Utilizing the MTT cell viability assay, M344 treatments also enhanced the cytotoxic effects of cisplatin in these cancer cell lines. The mechanism of ATF3 induction by M344 was found to be independent of MAPKinase pathways and dependent on ATF4, a known regulator of ATF3 expression. ATF4 heterozygote (+/-) and knock out (-/-) mouse embryonic fibroblast (MEF) as well as chromatin immunoprecipitation (ChIP) assays were utilized in determining the mechanistic induction of ATF3 by M344. We also demonstrated that ATF3 regulates the enhanced cytotoxicity of M344 in combination with cisplatin as evidenced by attenuation of cytotoxicity in shRNAs targeting ATF3 expressing cells. CONCLUSION: This study identifies the pro-apoptotic factor, ATF3 as a novel target of M344, as well as a mediator of the co-operative effects of cisplatin and M344 induced tumour cell cytotoxicity. PMID- 20828392 TI - The genome of Geobacter bemidjiensis, exemplar for the subsurface clade of Geobacter species that predominate in Fe(III)-reducing subsurface environments. AB - BACKGROUND: Geobacter species in a phylogenetic cluster known as subsurface clade 1 are often the predominant microorganisms in subsurface environments in which Fe(III) reduction is the primary electron-accepting process. Geobacter bemidjiensis, a member of this clade, was isolated from hydrocarbon-contaminated subsurface sediments in Bemidji, Minnesota, and is closely related to Geobacter species found to be abundant at other subsurface sites. This study examines whether there are significant differences in the metabolism and physiology of G. bemidjiensis compared to non-subsurface Geobacter species. RESULTS: Annotation of the genome sequence of G. bemidjiensis indicates several differences in metabolism compared to previously sequenced non-subsurface Geobacteraceae, which will be useful for in silico metabolic modeling of subsurface bioremediation processes involving Geobacter species. Pathways can now be predicted for the use of various carbon sources such as propionate by G. bemidjiensis. Additional metabolic capabilities such as carbon dioxide fixation and growth on glucose were predicted from the genome annotation. The presence of different dicarboxylic acid transporters and two oxaloacetate decarboxylases in G. bemidjiensis may explain its ability to grow by disproportionation of fumarate. Although benzoate is the only aromatic compound that G. bemidjiensis is known or predicted to utilize as an electron donor and carbon source, the genome suggests that this species may be able to detoxify other aromatic pollutants without degrading them. Furthermore, G. bemidjiensis is auxotrophic for 4-aminobenzoate, which makes it the first Geobacter species identified as having a vitamin requirement. Several features of the genome indicated that G. bemidjiensis has enhanced abilities to respire, detoxify and avoid oxygen. CONCLUSION: Overall, the genome sequence of G. bemidjiensis offers surprising insights into the metabolism and physiology of Geobacteraceae in subsurface environments, compared to non-subsurface Geobacter species, such as the ability to disproportionate fumarate, more efficient oxidation of propionate, enhanced responses to oxygen stress, and dependence on the environment for a vitamin requirement. Therefore, an understanding of the activity of Geobacter species in the subsurface is more likely to benefit from studies of subsurface isolates such as G. bemidjiensis than from the non subsurface model species studied so far. PMID- 20828394 TI - Internet and game behaviour at a secondary school and a newly developed health promotion programme: a prospective study. AB - BACKGROUND: This study investigated the Internet and game use of secondary school children, the compulsiveness of their use and the relationship with other health behaviours. It also evaluated the preliminary results of a recently developed school health promotion programme, implemented at a secondary school in the Netherlands in January 2008. This programme is one of the first to combine seven health behaviours in one educational programme and is a pilot project for a case control study. METHODS: A total of 475 secondary school children completed an extensive questionnaire before and a year after starting the programme. Of these children, 367 were in first, second and third grade; the grades in which the lessons about internet and game behaviour were implemented. Questionnaires contained questions about personal information, Internet and game use (Compulsive Internet Use Scale), and other health behaviours (alcohol use, physical activity, psychosocial wellbeing and body mass index). RESULTS: Heavy Internet use was significantly associated with psychosocial problems, and heavy game use was significantly associated with psychosocial problems and less physical activity. No relationship was found with alcohol use or body mass index. The time spent on Internet (hours/day) and the number of pathological Internet users increased during the study. The number of game users decreased but heavy game use increased. CONCLUSION: The association between heavy Internet use and psychosocial problems and between game use and psychosocial problems and less physical activity emphasizes the need to target different health behaviours in one health education programme. A case-control study is needed to further assess the programme-induced changes in Internet and game behaviour of school children. PMID- 20828395 TI - Chest compressions before defibrillation for out-of-hospital cardiac arrest: a meta-analysis of randomized controlled clinical trials. AB - BACKGROUND: Current 2005 guidelines for advanced cardiac life support strongly recommend immediate defibrillation for out-of-hospital cardiac arrest. However, findings from experimental and clinical studies have indicated a potential advantage of pretreatment with chest compression-only cardiopulmonary resuscitation (CPR) prior to defibrillation in improving outcomes. The aim of this meta-analysis is to evaluate the beneficial effect of chest compression first versus defibrillation-first on survival in patients with out-of-hospital cardiac arrest. METHODS: Main outcome measures were survival to hospital discharge (primary endpoint), return of spontaneous circulation (ROSC), neurologic outcome and long-term survival. Randomized, controlled clinical trials that were published between January 1, 1950, and June 19, 2010, were identified by a computerized search using SCOPUS, MEDLINE, BIOS, EMBASE, the Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts database, and Web of Science and supplemented by conference proceedings. Random effects models were used to calculate pooled odds ratios (ORs). A subgroup analysis was conducted to explore the effects of response interval greater than 5 min on outcomes. RESULTS: A total of four trials enrolling 1503 subjects were integrated into this analysis. No difference was found between chest compression first versus defibrillation-first in the rate of return of spontaneous circulation (OR 1.01 [0.82-1.26]; P = 0.979), survival to hospital discharge (OR 1.10 [0.70-1.70]; P = 0.686) or favorable neurologic outcomes (OR 1.02 [0.31 3.38]; P = 0.979). For 1-year survival, however, the OR point estimates favored chest compression first (OR 1.38 [0.95-2.02]; P = 0.092) but the 95% CI crossed 1.0, suggesting insufficient estimate precision. Similarly, for cases with prolonged response times (> 5 min) point estimates pointed toward superiority of chest compression first (OR 1.45 [0.66-3.20]; P = 0.353), but the 95% CI again crossed 1.0. CONCLUSIONS: Current evidence does not support the notion that chest compression first prior to defibrillation improves the outcome of patients in out of-hospital cardiac arrest. It appears that both treatments are equivalent. However, subgroup analyses indicate that chest compression first may be beneficial for cardiac arrests with a prolonged response time. PMID- 20828396 TI - Natural selection retains overrepresented out-of-frame stop codons against frameshift peptides in prokaryotes. AB - BACKGROUND: Out-of-frame stop codons (OSCs) occur naturally in coding sequences of all organisms, providing a mechanism of early termination of translation in incorrect reading frame so that the metabolic cost associated with frameshift events can be reduced. Given such a functional significance, we expect statistically overrepresented OSCs in coding sequences as a result of a widespread selection. Accordingly, we examined available prokaryotic genomes to look for evidence of this selection. RESULTS: The complete genome sequences of 990 prokaryotes were obtained from NCBI GenBank. We found that low G+C content coding sequences contain significantly more OSCs and G+C content at specific codon positions were the principal determinants of OSC usage bias in the different reading frames. To investigate if there is overrepresentation of OSCs, we modeled the trinucleotide and hexanucleotide biases of the coding sequences using Markov models, and calculated the expected OSC frequencies for each organism using a Monte Carlo approach. More than 93% of 342 phylogenetically representative prokaryotic genomes contain excess OSCs. Interestingly the degree of OSC overrepresentation correlates positively with G+C content, which may represent a compensatory mechanism for the negative correlation of OSC frequency with G+C content. We extended the analysis using additional compositional bias models and showed that lower-order bias like codon usage and dipeptide bias could not explain the OSC overrepresentation. The degree of OSC overrepresentation was found to correlate negatively with the optimal growth temperature of the organism after correcting for the G+C% and AT skew of the coding sequence. CONCLUSIONS: The present study uses approaches with statistical rigor to show that OSC overrepresentation is a widespread phenomenon among prokaryotes. Our results support the hypothesis that OSCs carry functional significance and have been selected in the course of genome evolution to act against unintended frameshift occurrences. Some results also hint that OSC overrepresentation being a compensatory mechanism to make up for the decrease in OSCs in high G+C organisms, thus revealing the interplay between two different determinants of OSC frequency. PMID- 20828397 TI - Modulation of polymorphonuclear neutrophil functions by astrocytes. AB - BACKGROUND: Neuroinflammation is a complex process involving cells from the immune system and the central nerve system (CNS). Polymorphonuclear neutrophils (PMN) are the most abundant class of white blood cells, and typically the first type of leukocyte recruited to sites of inflammation. In the CNS, astrocytes are the most abundant glial cell population and participate in the local innate immune response triggered by a variety of insults. In the present study, we investigated the impacts of astrocytes on PMN function. METHODS: Primary astrocyte cultures were derived from postnatal C57BL/6 mice and primary neutrophils were isolated from 8 to 12 weeks old C57BL/6 mice. PMNs respiratory burst was analyzed by H2DCFDA assay. For phagocytosis assay, neutrophils were incubated with FITC-labeled E. coli and the phagocytosis of E coli was determined by flow cytometer. PMNs degranulation was determined by myeloperoxidase assay. Cytokine expression was determined by real-time PCR. To determine the involvement of different signaling pathway, protein lysates were prepared and western blots were conducted to assess the activation of Akt, Erk1/2, and p38. RESULTS: Using ex vivo neutrophils and primary astrocyte cultures, our study demonstrated that astrocytes differentially regulate neutrophil functions, depending upon whether the interactions between the two cell types are direct or indirect. Upon direct cell-cell contact, astrocytes attenuate neutrophil apoptosis, respiratory bust, and degranulation, while enhancing neutrophil phagocytic capability and pro inflammatory cytokine expression. Through indirect interaction with neutrophils, astrocytes attenuate apoptosis and enhance necrosis in neutrophils, augment neutrophil phagocytosis and respiratory burst, and inhibit neutrophil degranulation. In addition, astrocytes could augment Akt, Erk1/2, and p38 activation in neutrophils. CONCLUSIONS: Astrocytes differentially regulate neutrophil functions through direct or indirect interactions between the two cell types. The diversified actions of astrocytes on neutrophils might provide protection against potential microbial infections given compromised blood-brain barrier integrity under certain neuropathological conditions. The complex actions of astrocytes on neutrophils could provide further insight to harness the inflammatory response to promote CNS repair. PMID- 20828398 TI - Silencing of RhoA and RhoC expression by RNA interference suppresses human colorectal carcinoma growth in vivo. AB - BACKGROUND: RhoA and RhoC have been proved to be over-expressed in many solid cancers, including colorectal cancer. The reduction of RhoA and RhoC expression by RNA interference (RNAi) resulted growth inhibition of cancer cells. The present study was to evaluate the effect of silencing of RhoA and RhoC expression by RNAi on growth of human colorectal carcinoma (CRC) in tumor-bearing nude mice in vivo. METHODS: To establish HCT116 cell transplantable model, the nude mice were subcutaneously inoculated with 1.0 * 10(7) HCT116 cells and kept growing till the tumor xenografts reached 5-7 mm in diameter. Then the mice were randomly assigned to three groups(seven mice in each group): (1) normal saline(NS) group, (2)replication-defective recombinant adenovirus carrying the negative control shRNA (Ad-HK) group and (3)replication-defective recombinant adenovirus carrying the 4-tandem linked RhoA and RhoC shRNAs (Ad-RhoA-RhoC) group. Ad-HK (4 * 10(8) pfu, 30 ul/mouse), Ad-RhoA-RhoC (4 * 10(8) pfu, 30 ul/mouse) or PBS (30 ul/mouse) was injected intratumorally four times once every other day. The weight and volumes of tumor xenografts were recorded. The levels of RhoA and RhoC mRNA transcripts and proteins in tumor xenografts were detected by reverse quantitative transcription polymerase chain reaction (QRT-PCR) and immunohistochemical staining respectively. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay was used to detect the death of cells. RESULTS: The xenografts in mice could be seen at 5th day from the implantation of HCT116 cells and all had reached 5-7 mm in size at 9th day. After injection intratumorally, the growth speed of tumor xenografts in Ad-RhoA-RhoC group was significantly delayed compared with those in NS and Ad-HK group(P < 0.05). The results of QRT-PCR showed that mRNA levels of RhoA and RhoC reduced more in Ad-RhoA-RhoC group than those in NS and Ad-HK group. The relative RhoA and RhoC mRNA transcripts were decreased to 48% and 43% respectively (P < 0.05). Immunohistochemical analyses of tumor xenograft sections also revealed the decreased RhoA and RhoC expression in Ad-RhoA-RhoC group. TUNEL assay also showed higher death of tumor xenograft tissue cells in Ad-RhoA-RhoC group. CONCLUSION: Recombinant adenovirus mediated RhoA and RhoC shRNA in tandem linked expression may inhibit the growth of human colorectal tumor xenografts in vivo. These results indicate that RhoA and RhoC might be potential targets for gene therapy in colorectal cancer. PMID- 20828399 TI - Hypoxic regulation of cytoglobin and neuroglobin expression in human normal and tumor tissues. AB - BACKGROUND: Cytoglobin (Cygb) and neuroglobin (Ngb) are recently identified globin molecules that are expressed in vertebrate tissues. Upregulation of Cygb and Ngb under hypoxic and/or ischemic conditions in vitro and in vivo increases cell survival, suggesting possible protective roles through prevention of oxidative damage. We have previously shown that Ngb is expressed in human glioblastoma multiforme (GBM) cell lines, and that expression of its transcript and protein can be significantly increased after exposure to physiologically relevant levels of hypoxia. In this study, we extended this work to determine whether Cygb is also expressed in GBM cells, and whether its expression is enhanced under hypoxic conditions. We also compared Cygb and Ngb expression in human primary tumor specimens, including brain tumors, as well as in human normal tissues. Immunoreactivity of carbonic anhydrase IX (CA IX), a hypoxia-inducible metalloenzyme that catalyzes the hydration of CO2 to bicarbonate, was used as an endogenous marker of hypoxia. RESULTS: Cygb transcript and protein were expressed in human GBM cells, and this expression was significantly increased in most cells following 48 h incubation under hypoxia. We also showed that Cygb and Ngb are expressed in both normal tissues and human primary cancers, including GBM. Among normal tissues, Cygb and Ngb expression was restricted to distinct cell types and was especially prominent in ductal cells. Additionally, certain normal organs (e.g. stomach fundus, small bowel) showed distinct regional co-localization of Ngb, Cygb and CA IX. In most tumors, Ngb immunoreactivity was significantly greater than that of Cygb. In keeping with previous in vitro results, tumor regions that were positively stained for CA IX were also positive for Ngb and Cygb, suggesting that hypoxic upregulation of Ngb and Cygb also occurs in vivo. CONCLUSIONS: Our finding of hypoxic up-regulation of Cygb/Ngb in GBM cell lines and human tumor tissues suggests that these globin molecules may be part of the repertoire of defense mechanisms that allow cancer cells to survive in hypoxic microenvironments. PMID- 20828400 TI - Development of a neural network model for predicting glucose levels in a surgical critical care setting. AB - Development of neural network models for the prediction of glucose levels in critically ill patients through the application of continuous glucose monitoring may provide enhanced patient outcomes. Here we demonstrate the utilization of a predictive model in real-time bedside monitoring. Such modeling may provide intelligent/directed therapy recommendations, guidance, and ultimately automation, in the near future as a means of providing optimal patient safety and care in the provision of insulin drips to prevent hyperglycemia and hypoglycemia. PMID- 20828401 TI - Anterior knee pain in younger adults as a precursor to subsequent patellofemoral osteoarthritis: a systematic review. AB - BACKGROUND: Patellofemoral osteoarthritis (PFOA) is a common form of knee OA in middle and older age, but its relation to PF disorders and symptoms earlier in life is unclear. Our aim was to conduct a systematic review to investigate the strength of evidence for an association between anterior knee pain (AKP) in younger adults and subsequent PFOA. METHODS: The search strategy included electronic databases (Pubmed, EMBASE, AMED, CINAHL, Cochrane, PEDro, SportDiscus: inception to December 2009), reference lists of potentially eligible studies and selected reviews. Full text articles in any language, - identified via English titles and abstracts, were included if they were retrospective or prospective in design and contained quantitative data regarding structural changes indicative of PFOA, incident to original idiopathic AKP. Eligibility criteria were applied to titles, abstracts and full-texts by two independent reviewers. Data extraction included study location, design, date, sampling procedure, sample characteristics, AKP/PFOA definitions, follow-up duration and rate, and main findings. Foreign language articles were translated into English prior to examination. RESULTS: Seven articles satisfied eligibility (5 English, 2 German). Only one case-control study directly investigated a link between PFOA and prior AKP, providing level 3b evidence in favour of an association (OR 4.4; 95%CI 1.8, 10.6). Rough estimates of the annual risk of PFOA from the remaining six small, uncontrolled, observational studies (mean follow-up range: 5.7 to 23 years) ranged from 0% to 3.4%. This was not the primary aim of these studies, and limitations in design and methodology mean this data should be interpreted with caution. CONCLUSIONS: There is a paucity of high-quality evidence reporting a link between AKP and PFOA. Further, well-designed cohort studies may be able to fill this evidence gap. PMID- 20828403 TI - Pathological complete response after neoadjuvant chemotherapy with trastuzumab containing regimen in gastric cancer: a case report. AB - We report a 49-year-old Chinese male with locally advanced gastric adenocarcinoma achieving pathological complete response after neoadjuvant chemotherapy with trastuzumab-containing regimen. He underwent esophagogastroduodenoscopy in September 2009, which revealed a 2-cm gastric ulcer on the lesser curvature proximal to angularis. Biopsy of gastric ulcer showed moderately differentiated adenocarcinoma with overexpression of human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and fluorescence in situ hybridization. Further workups with endoscopic ultrasound, computed tomography and positron emission tomography staged his cancer as T3N1M0. He received 3 cycles of neoadjuvant chemotherapy consisting of trastuzumab, oxaliplatin, docetaxel and capecitabine without severe toxicities except grade 2 diarrhea near the completion of cycle 3 requiring discontinuation of capecitabine. Afterwards, he received total gastrectomy with extended D2 lymph node dissections showing pathological complete response. He went on to receive 3 more cycles of chemotherapy postoperatively. The role of trastuzumab as a part of perioperative therapy in gastric cancer overexpressing HER2 is worth further investigation. PMID- 20828402 TI - The role of the JAK2-STAT3 pathway in pro-inflammatory responses of EMF stimulated N9 microglial cells. AB - BACKGROUND: In several neuropathological conditions, microglia can become overactivated and cause neurotoxicity by initiating neuronal damage in response to pro-inflammatory stimuli. Our previous studies have shown that exposure to electromagnetic fields (EMF) activates cultured microglia to produce tumor necrosis factor (TNF)-alpha and nitric oxide (NO) through signal transduction involving the activator of transcription STAT3. Here, we investigated the role of STAT3 signaling in EMF-induced microglial activation and pro-inflammatory responses in more detail than the previous study. METHODS: N9 microglial cells were treated with EMF exposure or a sham treatment, with or without pretreatment with an inhibitor (Pyridone 6, P6) of the Janus family of tyrosine kinases (JAK). The activation state of microglia was assessed via immunoreaction using the microglial marker CD11b. Levels of inducible nitric oxide synthase (iNOS), TNF alpha and NO were measured using real-time reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and the nitrate reductase method. Activation of JAKs and STAT3 proteins was evaluated by western blotting for specific tyrosine phosphorylation. The ability of STAT3 to bind to DNA was detected with an electrophoresis mobility shift assay (EMSA). RESULTS: EMF was found to significantly induce phosphorylation of JAK2 and STAT3, and DNA binding ability of STAT3 in N9 microglia. In addition, EMF dramatically increased the expression of CD11b, TNF-alpha and iNOS, and the production of NO. P6 strongly suppressed the phosphorylation of JAK2 and STAT3 and diminished STAT3 activity in EMF-stimulated microglia. Interestingly, expression of CD11b as well as gene expression and production of TNF-alpha and iNOS were suppressed by P6 at 12 h, but not at 3 h, after EMF exposure. CONCLUSIONS: EMF exposure directly triggers initial activation of microglia and produces a significant pro inflammatory response. Our findings confirm that the JAK2-STAT3 pathway may not mediate this initial microglial activation but does promote pro-inflammatory responses in EMF-stimulated microglial cells. Thus, the JAK2-STAT3 pathway might be a therapeutic target for reducing pro-inflammatory responses in EMF-activated microglia. PMID- 20828404 TI - Convergence between Wnt-beta-catenin and EGFR signaling in cancer. AB - Wnt and EGFR signaling play key roles in embryonic development and cell proliferation. It is well documented that dysregulation of these two pathways often leads to tumorigenesis with poor prognosis. However, the possible crosstalk between the two pathways in cancer development is largely unknown. Although some reports show that EGFR might antagonize Wnt signaling during development in Drosophila, an increasing body of evidence indicates that Wnt and EGFR signaling crosstalk and transactivate one another in development and cancer. This review summarizes recent studies on the crosstalk between Wnt and EGFR signaling in cancers and points out several possible convergence points. Wnt ligands can activate EGFR signaling through their 7-transmembrane domain receptor Frizzled while EGFR can activate beta-catenin via receptor tyrosine kinase-PI3K/Akt pathway; EGFR has been shown to form a complex with beta-catenin and increase the invasion and metastasis of cancer cells. NKD2, a Wnt antagonist by interacting with Dishevelled, also escorts TGFalpha-containing exocytic vesicles to the basolateral membrane of polarized epithelial cells. Down-regulation of NKD2 causes Wnt activation and TGFalpha misdelivery, suggesting its functions in cell homeostasis and prevention of tumorigenesis. PMID- 20828405 TI - Spatio-temporal regulation of Wnt and retinoic acid signaling by tbx16/spadetail during zebrafish mesoderm differentiation. AB - BACKGROUND: A complex network of signaling pathways and transcription factors regulates vertebrate mesoderm development. Zebrafish mutants provide a powerful tool for examining the roles of individual genes in such a network. spadetail (spt) is a mutant with a lesion in tbx16, a T-box transcription factor involved in mesoderm development; the mutant phenotype includes disrupted primitive red blood cell formation as well as disrupted somitogenesis. Despite much recent progress, the downstream targets of tbx16 remain incompletely understood. The current study was carried out to test whether any of the five major signaling pathways are regulated by tbx16 during two specific stages of mesoderm development: primitive red blood cell formation in the intermediate mesoderm and somite formation in the tail paraxial mesoderm. This test was performed using Gene Set Enrichment Analysis, which identifies coordinated changes in expression among a priori sets of genes associated with biological features or processes. RESULTS: Our Gene Set Enrichment Analysis results identify Wnt and retinoic acid signaling as likely downstream targets of tbx16 in the developing zebrafish intermediate mesoderm, the site of primitive red blood cell formation. In addition, such results identify retinoic acid signaling as a downstream target of tbx16 in the developing zebrafish posterior somites. Finally, using candidate gene identification and in situ hybridization, we provide expression domain information for 25 additional genes downstream of tbx16 that are outside of both pathways; 23 were previously unknown downstream targets of tbx16, and seven had previously uncharacterized expression in zebrafish. CONCLUSIONS: Our results suggest that (1) tbx16 regulates Wnt signaling in the developing zebrafish intermediate mesoderm, the site of primitive red blood cell formation, and (2) tbx16 regulates retinoic acid signaling at two distinct embryonic locations and developmental stages, which may imply ongoing spatio-temporal regulation throughout mesoderm development. PMID- 20828407 TI - Next generation tools for genomic data generation, distribution, and visualization. AB - BACKGROUND: With the rapidly falling cost and availability of high throughput sequencing and microarray technologies, the bottleneck for effectively using genomic analysis in the laboratory and clinic is shifting to one of effectively managing, analyzing, and sharing genomic data. RESULTS: Here we present three open-source, platform independent, software tools for generating, analyzing, distributing, and visualizing genomic data. These include a next generation sequencing/microarray LIMS and analysis project center (GNomEx); an application for annotating and programmatically distributing genomic data using the community vetted DAS/2 data exchange protocol (GenoPub); and a standalone Java Swing application (GWrap) that makes cutting edge command line analysis tools available to those who prefer graphical user interfaces. Both GNomEx and GenoPub use the rich client Flex/Flash web browser interface to interact with Java classes and a relational database on a remote server. Both employ a public-private user-group security model enabling controlled distribution of patient and unpublished data alongside public resources. As such, they function as genomic data repositories that can be accessed manually or programmatically through DAS/2-enabled client applications such as the Integrated Genome Browser. CONCLUSIONS: These tools have gained wide use in our core facilities, research laboratories and clinics and are freely available for non-profit use. See http://sourceforge.net/projects/gnomex/, http://sourceforge.net/projects/genoviz/, and http://sourceforge.net/projects/useq. PMID- 20828406 TI - Prognostic significance and therapeutic implications of centromere protein F expression in human nasopharyngeal carcinoma. AB - BACKGROUND: Our recent cDNA microarray data showed that centromere protein F (CENP-F) is significantly upregulated in primary cultured nasopharyngeal carcinoma (NPC) tumor cells compared with normal nasopharyngeal epithelial cells. The goal of this study was to further investigate the levels of CENP-F expression in NPC cell lines and tissues to clarify the clinical significance of CENP-F expression in NPC as well as the potential therapeutic implications of CENP-F expression. METHODS: Real-time RT-PCR and western blotting were used to examine CENP-F expression levels in normal primary nasopharyngeal epithelial cells (NPEC), immortalized nasopharyngeal epithelial cells and NPC cell lines. Levels of CENP-F mRNA were determined by real-time RT-PCR in 23 freshly frozen nasopharyngeal biopsy tissues, and CENP-F protein levels were detected by immunohistochemistry in paraffin sections of 202 archival NPC tissues. Statistical analyses were applied to test for prognostic associations. The cytotoxicities of CENP-F potential target chemicals, zoledronic acid (ZOL) and FTI-277 alone, or in combination with cisplatin, in NPC cells were determined by the MTT assay. RESULTS: The levels of CENP-F mRNA and protein were higher in NPC cell lines than in normal and immortalized NPECs. CENP-F mRNA level was upregulated in nasopharyngeal carcinoma biopsy tissues compared with noncancerous tissues. By immunohistochemical analysis, CENP-F was highly expressed in 98 (48.5%) of 202 NPC tissues. Statistical analysis showed that high expression of CENP-F was positively correlated with T classification (P < 0.001), clinical stage (P < 0.001), skull-base invasion (P < 0.001) and distant metastasis (P = 0.012) inversely correlated with the overall survival time in NPC patients. Multivariate analysis showed that CENP-F expression was an independent prognostic indicator for the survival of the patient. Moreover, we found that ZOL or FTI-277 could significantly enhance the chemotherapeutic sensitivity of NPC cell lines (HONE1 and 6-10B) with high CENP-F expression to cisplatin, although ZOL or FTI 277 alone only exhibited a minor inhibitory effect to NPC cells. CONCLUSION: Our data suggest that CENP-F protein is a valuable marker of NPC progression, and CENP-F expression is associated with poor overall survival of patients. In addition, our data indicate a potential benefit of combining ZOL or FTI-277 with cisplatin in NPC suggesting that CENP-F expression may have therapeutic implications. PMID- 20828408 TI - African-American inflammatory bowel disease in a Southern U.S. health center. AB - BACKGROUND: Inflammatory Bowel Diseases (IBD) remain significant health problems in the US and worldwide. IBD is most often associated with eastern European ancestry, and is less frequently reported in other populations of African origin e.g. African Americans ('AAs'). Whether AAs represent an important population with IBD in the US remains unclear since few studies have investigated IBD in communities with a majority representation of AA patients. The Louisiana State University Health Sciences Center in Shreveport (LSUHSC-S) is a tertiary care medical center, with a patient base composed of 58% AA and 39% Caucasian (W), ideal for evaluating racial (AA vs. W) as well and gender (M vs. F) influences on IBD. METHODS: In this retrospective study, we evaluated 951 visits to LSUHSC-S for IBD (between 2000 to 2008) using non-identified patient information based on ICD-9 medical record coding (Crohn's disease 'CD'-555.0- 555.9 and ulcerative colitis 'UC'-556.0-556.9). RESULTS: Overall, there were more cases of CD seen than UC. UC and CD affected similar ratios of AA and Caucasian males (M) and females (F) with a rank order of WF > WM > AAF > AAM. Interestingly, in CD, we found that annual visits per person was the highest in AA M (10.7 +/- 1.7); significantly higher (* -p < 0.05) than in WM (6.3 +/- 1.0). Further, in CD, the female to male (F: M) ratio in AA was significantly higher (*- p < 0.05) (1.9 +/- 0.2) than in Caucasians (F:M = 1.3 +/- 0.1) suggesting a female dominance in AACD; no differences were seen in UC F: M ratios. CONCLUSION: Although Caucasians still represent the greatest fraction of IBD (~64%), AAs with IBD made up >1/3 (36.4%) of annual IBD cases from 2000-2008 at LSUHSC-S. Further studies on genetic and environments risks for IBD risk in AAs are needed to understand differences in presentation and progression in AAs and other 'non-traditional' populations. PMID- 20828409 TI - Borrelia burgdorferi stimulation of chemokine secretion by cells of monocyte lineage in patients with Lyme arthritis. AB - INTRODUCTION: Joint fluid in patients with Lyme arthritis often contains high levels of CCL4 and CCL2, which are chemoattractants for monocytes and some T cells, and CXCL9 and CXCL10, which are chemoattractants for CD4+ and CD8+ T effector cells. These chemokines are produced primarily by cells of monocyte lineage in TH1-type immune responses. Our goal was to begin to learn how infection with Borrelia burgdorferi leads to the secretion of these chemokines, using patient cell samples. We hypothesized that B. burgdorferi stimulates chemokine secretion from monocytes/macrophages in multiple ways, thereby linking innate and adaptive immune responses. METHODS: Peripheral blood mononuclear cells (PBMC) from 24 Lyme arthritis patients were stimulated with B. burgdorferi, interferon (IFN)-gamma, or both, and the levels of CCL4, CCL2, CXCL9 and CXCL10 were measured in culture supernatants. CD14+ monocytes/macrophages from PBMC and synovial fluid mononuclear cells (SFMC) were stimulated in the same way, using available samples. CXCR3, the receptor for CXCL9 and CXCL10, and CCR5, the receptor for CCL4, were assessed on T cells from PBMC and SFMC. RESULTS: In patients with Lyme arthritis, B. burgdorferi but not IFN-gamma induced PBMC to secrete CCL4 and CCL2, and B. burgdorferi and IFN-gamma each stimulated the production of CXCL9 and CXCL10. However, with the CD14+ cell fraction, B. burgdorferi alone stimulated the secretion of CCL4; B. burgdorferi and IFN-gamma together induced CCL2 secretion, and IFN-gamma alone stimulated the secretion of CXCL9 and CXCL10. The percentage of T cells expressing CXCR3 or CCR5 was significantly greater in SFMC than PBMC, confirming that TH1 effector cells were recruited to inflamed joints. However, when stimulated with B. burgdorferi or IFN gamma, SFMC and PBMC responded similarly. CONCLUSIONS: B. burgdorferi stimulates PBMC or CD14+ monocytes/macrophages directly to secrete CCL4, but spirochetal stimulation of other intermediate cells, which are present in PBMC, is required to induce CD14+ cells to secrete CCL2, CXCL9 and CXCL10. We conclude that B. burgdorferi stimulates monocytes/macrophages directly and indirectly to guide innate and adaptive immune responses in patients with Lyme arthritis. PMID- 20828410 TI - Similarity of recombinant human perlecan domain 1 by alternative expression systems bioactive heterogenous recombinant human perlecan D1. AB - BACKGROUND: Heparan sulfate glycosaminoglycans are diverse components of certain proteoglycans and are known to interact with growth factors as a co-receptor necessary to induce signalling and growth factor activity. In this report we characterize heterogeneously glycosylated recombinant human perlecan domain 1 (HSPG2 abbreviated as rhPln.D1) synthesized in either HEK 293 cells or HUVECs by transient gene delivery using either adenoviral or expression plasmid technology. RESULTS: By SDS-PAGE analysis following anion exchange chromatography, the recombinant proteoglycans appeared to possess glycosaminoglycan chains ranging, in total, from 6 kDa to >90 kDa per recombinant. Immunoblot analysis of enzyme digested high Mr rhPln.D1 demonstrated that the rhPln.D1 was synthesized as either a chondroitin sulfate or heparan sulfate proteoglycan, in an approximately 2:1 ratio, with negligible hybrids. Secondary structure analysis suggested helices and sheets in both recombinant species. rhPln.D1 demonstrated binding to rhFGF-2 with an apparent kD of 2 +/- 0.2 nM with almost complete susceptibility to digestion by heparinase III in ligand blot analysis but not to chondroitinase digestion. Additionally, we demonstrate HS-mediated binding of both rhPln.D1 species to several other GFs. Finally, we corroborate the augmentation of FGF mediated cell activation by rhPln.D1 and demonstrate mitogenic signalling through the FGFR1c receptor. CONCLUSIONS: With importance especially to the emerging field of DNA-based therapeutics, we have shown here that proteoglycan synthesis, in different cell lines where GAG profiles typically differ, can be directed by recombinant technology to produce populations of bioactive recombinants with highly similar GAG profiles. PMID- 20828411 TI - Distribution and quantitative changes in amounts of aquaporin 1, 5 and 9 in the pig uterus during the estrous cycle and early pregnancy. AB - BACKGROUND: Aquaporins (AQPs) are a family of membrane channel proteins that facilitate bulk water transport. To date, 11 isoforms of AQPs have been reported to be expressed in the female and male reproductive systems. The purpose of our study was to determine the localization and quantitative changes in the expression of AQP1, 5 and 9 within the pig uterus during different stages of the estrous cycle and early pregnancy. METHODS: Immunoperoxidase and semi quantitative immunoblotting techniques were used to examine the distribution and changes in amounts of AQP1, AQP5 and AQP9 in uteral cells of pigs at the early (Days 2-4), middle (10-12), late (14-16) stage of the luteal phase and late (18 20) stage of the follicular phase of the estrous cycle as well as on Days 14-16 and 30-32 of gestation (the onset and the end of implantation process). RESULTS: The results demonstrated that AQP1, 5, and 9 were clearly detected in all studied stages of the estrous cycle and pregnancy. AQP1 was localized within uterine blood vessels. In cyclic gilts, endometrial and myometrial expression of AQP1 protein did not change significantly but increased during gestation. AQP5 was localized in smooth muscle cells and uterine epithelial cells. Endometrial expression of AQP5 protein did not change significantly between Days 2-4 and 10 12 of the estrous cycle but increased on Days 14-16 and 18-20 as well as during early pregnancy. Myometrial expression of AQP5 did not differ significantly during the estrous cycle but increased in the pregnancy. The anti-AQP9 antibody labeled uterine epithelial cells of uterus. Endometrial expression of AQP9 did not change significantly between Days 2-4 and 10-12 of the estrous cycle but increased on Days 14-16 and 18-20 as well as during early pregnancy. CONCLUSIONS: The results suggest that a functional and distinctive collaboration exists among diverse AQPs in water handling during the different uterine phases in the estrous cycle and early pregnancy. PMID- 20828412 TI - Observed hand cleanliness and other measures of handwashing behavior in rural Bangladesh. AB - BACKGROUND: We analyzed data from the baseline assessment of a large intervention project to describe typical handwashing practices in rural Bangladesh, and compare measures of hand cleanliness with household characteristics. METHODS: We randomly selected 100 villages from 36 districts in rural Bangladesh. Field workers identified 17 eligible households per village using systematic sampling. Field workers conducted 5-hour structured observations in 1000 households, and a cross-sectional assessment in 1692 households that included spot checks, an evaluation of hand cleanliness and a request that residents demonstrate their usual handwashing practices after defecation. RESULTS: Although 47% of caregivers reported and 51% demonstrated washing both hands with soap after defecation, in structured observation, only 33% of caregivers and 14% of all persons observed washed both hands with soap after defecation. Less than 1% used soap and water for handwashing before eating and/or feeding a child. More commonly people washed their hands only with water, 23% after defecation and 5% before eating. Spot checks during the cross sectional survey classified 930 caregivers (55%) and 453 children (28%) as having clean appearing hands. In multivariate analysis economic status and water available at handwashing locations were significantly associated with hand cleanliness among both caregivers and children. CONCLUSIONS: A minority of rural Bangladeshi residents washed both hands with soap at key handwashing times, though rinsing hands with only water was more common. To realize the health benefits of handwashing, efforts to improve handwashing in these communities should target adding soap to current hand rinsing practices. PMID- 20828413 TI - Multivariate Hawkes process models of the occurrence of regulatory elements. AB - BACKGROUND: A central question in molecular biology is how transcriptional regulatory elements (TREs) act in combination. Recent high-throughput data provide us with the location of multiple regulatory regions for multiple regulators, and thus with the possibility of analyzing the multivariate distribution of the occurrences of these TREs along the genome. RESULTS: We present a model of TRE occurrences known as the Hawkes process. We illustrate the use of this model by analyzing two different publically available data sets. We are able to model, in detail, how the occurrence of one TRE is affected by the occurrences of others, and we can test a range of natural hypotheses about the dependencies among the TRE occurrences. In contrast to earlier efforts, pre processing steps such as clustering or binning are not needed, and we thus retain information about the dependencies among the TREs that is otherwise lost. For each of the two data sets we provide two results: first, a qualitative description of the dependencies among the occurrences of the TREs, and second, quantitative results on the favored or avoided distances between the different TREs. CONCLUSIONS: The Hawkes process is a novel way of modeling the joint occurrences of multiple TREs along the genome that is capable of providing new insights into dependencies among elements involved in transcriptional regulation. The method is available as an R package from http://www.math.ku.dk/~richard/ppstat/. PMID- 20828414 TI - Lifestyle and perceived health in subjects with chronic bronchitis or emphysema: a cross-sectional study. AB - BACKGROUND: The study aim was to compare lifestyle behaviors, body mass index (BMI) and perceived health in subjects with and without chronic bronchitis or emphysema, and to explore if these comparisons differed between demographic subgroups. METHODS: A stratified two-stage sample of the population of Serbia was used; 14.522 adults aged >= 20 years were interviewed. RESULTS: Compared with controls, respondents with chronic bronchitis or emphysema reported a 23% increased likelihood of eating fresh vegetables every day (CI 1.02-1.48), 58% increased likelihood of currently smoking (CI 1.32-1.88) and more likely to perceive their health as very bad or bad (OR 4.67, CI 3.64-5.98). After stratification for sex, education, and type of settlement, smoking was significantly associated with chronic bronchitis or emphysema in all subgroups except males. The increased likelihood of very bad or bad perceived health in respondents with chronic bronchitis or emphysema was significant in all subgroups, and was highest for respondents <= 65 years of age (adjusted OR 6.51; CI 4.87-8.72) and lowest for respondents > 65 years of age (adjusted OR 3.25; CI 2.12-4.97). CONCLUSION: Efforts to enhance perceived health and healthy lifestyle behaviors in subjects with chronic bronchitis or emphysema are necessary. Special attention should be paid to smoking cessation in almost all demographic subgroups. PMID- 20828415 TI - Utilization of base deficit and reliability of base deficit as a surrogate for serum lactate in the peri-operative setting. AB - BACKGROUND: Base deficit (BD) is commonly used in the operating room (OR) as an endpoint of resuscitation. BD is used as a surrogate marker for the accumulation of lactic acid(Lac). However, the BD can be affected by large amounts of saline. METHODS: We conducted a survey of anesthesiologists regarding the use of BD. We also studied the reliability of BD to determine the presence of hyperlactatemia (HL). Patients undergoing general anesthesia were eligible for enrollment if they were receiving an arterial line as part of their routine care. If an arterial blood gas was drawn by the operative team as part of the routine care, the remainder of the unused blood was also used to measure Lac. RESULTS: SURVEY: 73 staff anesthesiologists were surveyed. Over 70% of respondents used BD as an endpoint of resuscitation.Base Deficit Study: 35 patients were enrolled resulting in 88 arterial blood gases with corresponding Lac. Mean age was 61.4 +/- 14.3 years, 43% were male. Mean pH was 7.39 +/- 0.05, the mean bicarbonate was 23.0 +/ 2.3 meq/L, the mean BD 1.34 +/- 2.3, and the mean Lac was 1.58 +/- 0.71 mmol/L. Mean ASA risk score was 3.16 +/- 0.71. ROC area under the curve for base deficit to detect HL was 0.58. CONCLUSION: BD can often mislead the clinician as to the actual Lac. Lac can now be measured in the OR in real time. Therefore, if clinicians in the operative setting want to know the Lac, it should be measured directly. PMID- 20828416 TI - The hope and the promise of the UN Resolution on non-communicable diseases. PMID- 20828417 TI - Estimation of the cost of treatment by chemotherapy for early breast cancer in Morocco. AB - BACKGROUND: Breast cancer is the first cancer in women both in incidence and mortality. The treatment of breast cancer benefited from the progress of chemotherapy and targeted therapies, but there was a parallel increase in treatment costs. Despite a relatively high incidence of many sites of cancer, so far, there is no national register for this disease in Morocco.The main goal of this paper is to estimate the total cost of chemotherapy in the early stages of breast cancer due to its frequency and the chances of patients being cured. This study provides health decision-makers with a first estimate of costs and the opportunity to achieve the optimal use of available data to estimate the needs of antimitotics and trastuzumab in Morocco. METHOD: We start by evaluating the individual cost according to the therapeutic sub-groups, namely:1. Patients needing chemotherapy with only anthracycline-based therapy.2. Patients needing chemotherapy with both anthracycline and taxane but without trastuzumab.3. Patients needing trastuzumab in addition to chemotherapy.For each sub-group, the protocol of treatment is described, and the individual costs per unit, and for the whole cycle, are evaluated.Then we estimate the number of women suffering from breast cancer on the basis of two data bases available in Morocco.Finally, we calculate the total annual cost of treatment of breast cancer in Morocco. RESULTS: The total cost of breast cancer in Morocco is given in Moroccan dirhams (MAD), the US dollar at the current exchange rate (MAD 10 = USD 1.30) and in international dollars or purchasing power parity (MAD 10 = PPP 1.95).The cost of a therapy with trastuzumab is 8.4 times the cost of a sequential chemotherapy combining anthracycline and taxane, and nearly 60 times the cost of chemotherapy based on anthracycline alone.Globally, between USD 13.3 million and USD 28.6 million need to be devoted every year by the Moroccan health authorities to treat women with localized breast cancer in keeping with international recommendations. DISCUSSION: According to our estimation methods, the complete cost of adjuvant chemotherapy including trastuzumab will range from 1.3 to 2.4% of the global budget of the Moroccan Health Department (MAD 9.8 billion or USD 1.274 billion). Unfortunately, only one-third of the Moroccan population has healthcare insurance whereas for each patient the treatment with chemotherapy alone costs 1.15 times the annual minimum income (MAD 23,710 or USD 3,082), and treatment requiring both chemotherapy and trastuzumab costs 9.76 times the annual minimum income. For the tumour over expressing HER2Neu, we need to treat 25 women in order to save (cure) one woman: the calculated cost for one life saved is USD 663,000. The question is, is it cost-effective for an emerging country? CONCLUSION: In this paper we aimed at evaluating the total cost of chemotherapy in the early stages of breast cancer in order to provide health decision-makers with a first estimation and a good opportunity for the optimal use of available data for the needs of antimitotics and trastuzumab in Morocco. Different protocols were considered and the individual cost of the whole treatment was given according to therapies using anthracycline alone, sequential chemotherapy combining anthracycline and taxane, and sequential chemotherapy with trastuzumab. According to our estimations, Moroccan health authorities need to devote between USD 13.3 million and USD 28.6 million every year in order to treat women suffering from localized breast cancer in ways consistent with international recommended standards. PMID- 20828418 TI - Prediction of quantitative phenotypes based on genetic networks: a case study in yeast sporulation. AB - BACKGROUND: An exciting application of genetic network is to predict phenotypic consequences for environmental cues or genetic perturbations. However, de novo prediction for quantitative phenotypes based on network topology is always a challenging task. RESULTS: Using yeast sporulation as a model system, we have assembled a genetic network from literature and exploited Boolean network to predict sporulation efficiency change upon deleting individual genes. We observe that predictions based on the curated network correlate well with the experimentally measured values. In addition, computational analysis reveals the robustness and hysteresis of the yeast sporulation network and uncovers several patterns of sporulation efficiency change caused by double gene deletion. These discoveries may guide future investigation of underlying mechanisms. We have also shown that a hybridized genetic network reconstructed from both temporal microarray data and literature is able to achieve a satisfactory prediction accuracy of the same quantitative phenotypes. CONCLUSIONS: This case study illustrates the value of predicting quantitative phenotypes based on genetic network and provides a generic approach. PMID- 20828419 TI - Prozone effect of serum IgE levels in a case of plasma cell leukemia. AB - We describe a case of multiple myeloma (MM) and secondary plasma cell leukemia (PCL) secreting IgE-kappa immunoglobulin. To our knowledge, only 2 cases of IgE producing secondary PCL have been reported in the medical literature. In our patient, the only tumor marker available for monitoring the therapeutic response to chemotherapy and allogeneic stem cell transplantation was the quantitative M component at serum protein electrophoresis (SPEP), because serum free light chains were in the normal range, Bence-Jones proteinuria was absent, and quantitative serum IgE levels provided inaccurate and erratic results, due to the prozone effect. This is a laboratory phenomenon that occurs when antigen excess interferes with antibody-based methods requiring immune complex formation for detection. It is important to recognize the presence of a prozone effect, because it can produce falsely normal results, and therefore it could lead clinicians to incorrect assessment of the response to therapy. PMID- 20828420 TI - Indications and recommended approach for surgical intervention of metastatic disease to the gallbladder. AB - Metastatic disease to the gallbladder is unusual. The most common malignancy metastatic to the gallbladder is melanoma, followed by renal cell carcinoma (RCC) and breast cancer. Due to the unusual nature of the disease, there are no trials available for review. Thus, the management for these patients has been based on institutional experience and review of case series. The indications for surgical intervention for melanoma are metastatic disease discrete to the gallbladder and biliary symptoms, which are uncommon for melanoma, but might occur due to cystic duct obstruction culminating in cholecystitis. Laparoscopic cholecystectomy without a lymphadenectomy is emerging as the preferred approach for this metastatic deposit. The vast majority of patients with metastases to the gallbladder from RCC carry a good prognosis and a laparoscopic cholecystectomy should be considered. Patients with metastases to the gallbladder from the breast classically present with biliary symptoms and commonly undergo a laparoscopic cholecystectomy, which invariably demonstrates a deposit in the gallbladder from lobular breast cancer. In the present report, we review the indications for surgical intervention from various malignancies metastatic to the gallbladder and the current consensus for the laparoscopic approach from the diverse metastatic deposits to the gallbladder. PMID- 20828421 TI - The population genomics of begomoviruses: global scale population structure and gene flow. AB - BACKGROUND: The rapidly growing availability of diverse full genome sequences from across the world is increasing the feasibility of studying the large-scale population processes that underly observable pattern of virus diversity. In particular, characterizing the genetic structure of virus populations could potentially reveal much about how factors such as geographical distributions, host ranges and gene flow between populations combine to produce the discontinuous patterns of genetic diversity that we perceive as distinct virus species. Among the richest and most diverse full genome datasets that are available is that for the dicotyledonous plant infecting genus, Begomovirus, in the Family Geminiviridae. The begomoviruses all share the same whitefly vector, are highly recombinogenic and are distributed throughout tropical and subtropical regions where they seriously threaten the food security of the world's poorest people. RESULTS: We focus here on using a model-based population genetic approach to identify the genetically distinct sub-populations within the global begomovirus meta-population. We demonstrate the existence of at least seven major sub-populations that can further be sub-divided into as many as thirty four significantly differentiated and genetically cohesive minor sub-populations. Using the population structure framework revealed in the present study, we further explored the extent of gene flow and recombination between genetic populations. CONCLUSIONS: Although geographical barriers are apparently the most significant underlying cause of the seven major population sub-divisions, within the framework of these sub-divisions, we explore patterns of gene flow to reveal that both host range differences and genetic barriers to recombination have probably been major contributors to the minor population sub-divisions that we have identified. We believe that the global Begomovirus population structure revealed here could facilitate population genetics studies into how central parameters of population genetics namely selection, recombination, mutation, gene flow, and genetic drift shape the global begomovirus diversity. PMID- 20828422 TI - Patient-cooperative control increases active participation of individuals with SCI during robot-aided gait training. AB - BACKGROUND: Manual body weight supported treadmill training and robot-aided treadmill training are frequently used techniques for the gait rehabilitation of individuals after stroke and spinal cord injury. Current evidence suggests that robot-aided gait training may be improved by making robotic behavior more patient cooperative. In this study, we have investigated the immediate effects of patient cooperative versus non-cooperative robot-aided gait training on individuals with incomplete spinal cord injury (iSCI). METHODS: Eleven patients with iSCI participated in a single training session with the gait rehabilitation robot Lokomat. The patients were exposed to four different training modes in random order: During both non-cooperative position control and compliant impedance control, fixed timing of movements was provided. During two variants of the patient-cooperative path control approach, free timing of movements was enabled and the robot provided only spatial guidance. The two variants of the path control approach differed in the amount of additional support, which was either individually adjusted or exaggerated. Joint angles and torques of the robot as well as muscle activity and heart rate of the patients were recorded. Kinematic variability, interaction torques, heart rate and muscle activity were compared between the different conditions. RESULTS: Patients showed more spatial and temporal kinematic variability, reduced interaction torques, a higher increase of heart rate and more muscle activity in the patient-cooperative path control mode with individually adjusted support than in the non-cooperative position control mode. In the compliant impedance control mode, spatial kinematic variability was increased and interaction torques were reduced, but temporal kinematic variability, heart rate and muscle activity were not significantly higher than in the position control mode. CONCLUSIONS: Patient-cooperative robot-aided gait training with free timing of movements made individuals with iSCI participate more actively and with larger kinematic variability than non-cooperative, position-controlled robot-aided gait training. PMID- 20828423 TI - Heterogeneity in ventilation during positive end-expiratory pressure. PMID- 20828424 TI - A prophylactic vaccine for breast cancer? AB - Cancer vaccines are the Holy Grail for patients and clinicians alike. The possibility that we can be vaccinated against common cancers is very appealing and the socioeconomic consequences are significant. A recent paper from Vincent Tuohy's group, published in the journal Nature Medicine, suggests a new approach for the development of a prophylactic vaccine for breast cancer. Their strategy was to induce mammary gland failure in mice by immunisation with an antibody specific to a milk protein that resulted in autoimmunity during lactation. This also showed some efficacy as a therapeutic vaccine. Can we look forward to the elimination of breast cancer? PMID- 20828425 TI - Microcirculation in cardiogenic shock: from scientific bystander to therapy target. AB - Despite diagnostic and therapeutic improvements, mortality rates in patients with cardiogenic shock remain relatively high. Several studies showed that cardiogenic shock is associated with alterations in the microvascular circulation. These alterations may be reversed by extracorporeal support devices. A study by Munsterman and colleagues adds to the body of evidence showing that in patients deemed ready for discontinuing intra-aortic balloon pump (IABP) support, microcirculatory flow in small vessels increases after ceasing IABP therapy. This study not only highlights the need for optimal timing of weaning from IABP support but also supports recent findings that global hemodynamics do not necessarily result in changes of microvascular perfusion. All modalities of modern treatment in cardiogenic shock need to be evaluated for their effect on the microcirculation. Microcirculatory evaluations should be part of randomized controlled trial protocols. More effort is needed to improve outcomes and understand the microcirculation as a therapy target and not as a silent bystander. PMID- 20828426 TI - From genotype to EEG endophenotype: a route for post-genomic understanding of complex psychiatric disease? AB - Twin and family studies have shown the importance of biological variation in psychiatric disorders. Heritability estimates vary from 50% to 80% for cognitive disorders, such as schizophrenia, attention deficit hyperactivity disorder and autism, and from 40% to 65% for affective disorders, such as major depression, anxiety disorders and substance abuse. Pinpointing the actual genetic variants responsible for this heritability has proven difficult, even in the recent wave of genome-wide association studies. Brain endophenotypes derived from electroencephalography (EEG) have been proposed as a way to support gene-finding efforts. A variety of EEG and event-related-potential endophenotypes are linked to psychiatric disorders, and twin studies have shown a striking genetic contribution to these endophenotypes. However, the clear need for very large sample sizes strongly limits the usefulness of EEG endophenotypes in gene-finding studies. They require extended laboratory recordings with sophisticated and expensive equipment that are not amenable to epidemiology-scaled samples. Instead, EEG endophenotypes are far more promising as tools to make sense of candidate genetic variants that derive from association studies; existing clinical data from patients or questionnaire-based assessment of psychiatric symptoms in the population at large are better suited for the association studies themselves. EEG endophenotypes can help us understand where in the brain, in which stage and during what type of information processing these genetic variants have a role. Such testing can be done in the more modest samples that are feasible for EEG research. With increased understanding of how genes affect the brain, combinations of genetic risk scores and brain endophenotypes may become part of the future classification of psychiatric disorders. PMID- 20828427 TI - Copy number variation in Parkinson's disease. AB - A central theme of human genetic studies is to understand genomic variation and how this underlies the inherited basis of disease. Genomic variation can provide increased biological understanding of disease processes, which is necessary to develop future treatments. Recent technological advances have highlighted the role of copy number variants in normal and pathological phenotypic expression. These applications have been used in studies of Parkinson's disease, a common, late-onset, progressive neurodegenerative disorder. At present the main therapeutic approach is administration of symptom-alleviating drugs, which neither reverses the disease process nor halts its progression. However, the generation of in vivo model systems and development of novel disease intervention strategies for Parkinson's disease have come from research on monogenic forms of the disorder, including those caused by copy number variants. Here, we review the role of copy number variants and the mechanistic insights they have provided on the pathogenesis of Parkinson's disease. PMID- 20828428 TI - Biomarkers for late-onset neonatal sepsis. AB - The diagnosis of healthcare-associated infections is problematic because of the overlap between clinical signs associated with 'normal' physiological disturbances and those of bacteremia or fungemia. Earlier diagnosis of sepsis in critically ill infants would enable timely administration of antibiotics and discontinuation of treatment in infants with a low probability of sepsis. A recent study by Ng et al. identified two novel biomarkers for late-onset neonatal sepsis: the des-arginine variant of serum amyloid A and apolipoprotein C-II. These markers may be of value in the identification of neonates with bacteremia or fungemia. PMID- 20828431 TI - Teaching, learning, and using spectroscopy with commercial, off-the-shelf technology. AB - The astonishing propagation of sophisticated electronics across the globe has attracted the attention of many for developing disease diagnoses, water purity measurements, and security applications using cellular telephones and the complementary metal oxide semiconductor (CMOS) cameras with which many are equipped. This Focal Point article builds on the theme of using technology already in the hands of students/consumers to teach spectrophotometry and, by extension, to suggest how one might inexpensively develop an instrumental analysis curriculum at extraordinarily low cost. A grating spectrophotometer using a white light-emitting diode (LED) light source, plastic sample cuvette, holographic transmission grating, and any camera that produces JPG files as output is described. Optical characteristics are explained and a sample working curve provided. The raw data for that curve are available as Supplementary Material on-line. The behavior of the "Cell Phone Spectrometer" is inadequate for routine analysis but outstanding for teaching the workings of optical instrumentation components and systems. PMID- 20828432 TI - Label-free screening of drug-protein interactions by time-resolved Fourier transform infrared spectroscopic assays exemplified by Ras interactions. AB - Time-resolved Fourier transform infrared (FT-IR) spectroscopy can reveal molecular details of protein interactions. Analysis of difference spectra selects the absorptions of respective protein groups involved in an interaction against the background of the whole sample. By comparison of the same difference spectrum with and without a small molecule, one can determine whether the small molecule interferes with the protein or not. Usually a marker band of a specific residue of the protein is monitored. Here, we show three different time-resolved FT-IR assays detecting interactions of potential small molecules for molecular therapy with the GTPase Ras as an example for small GTPase binding proteins. Ras regulates signal transduction processes through a switching mechanism, cycling between an active "on" GTP-bound form and an inactive "off" GDP-bound state. Molecular defects in Ras can impair the ability of Ras and the Ras-RasGAP complex to hydrolyze GTP, contributing to uncontrolled cell growth and cancer. Oncogenic mutated Ras is found in about 30% of all cancer cells. We show in vitro assays, indicating (I) the shift of Ras into its "off" conformation, which inhibits the Ras pathway; (II) down-regulation of Ras signaling by changes in the Ras-Raf effector interaction; and (III) down-regulation of Ras signaling pathway by catalyzing GTP hydrolysis. Since almost all molecules have characteristic marker bands in the infrared, time-resolved FT-IR spectroscopy can be used label-free. No artificial nucleotides that could influence the interaction are needed. Both, sample preparation and evaluation can be automated in order to allow for high throughput screening. PMID- 20828434 TI - Fluorescent and ultraviolet-visible spectroscopy studies on the antioxidation and DNA binding properties of binuclear Tb(III) complexes. AB - Tb(III) complexes were prepared from Tb(NO(3))(3).6H(2)O and four Schiff-base ligands derived from 8-hydroxyquinoline-2-carboxaldehyde with aroylhydrazines. X ray crystal and other structural analyses indicate that Tb(III) and every ligand can form a binuclear Tb(III) complex with 1:1 metal-to-ligand stoichiometry and nine-coordination at the Tb(III) center. Viscosity titration experiments and fluorescent and ultraviolet-visible (UV-Vis) spectroscopy results indicate that all the Tb(III) complexes can bind to Calf thymus DNA through intercalation with the binding constants at the order of magnitude of 10(6)-10(7) M(-1), and they may be used as potential anticancer drugs, but complexes containing active phenolic hydroxy groups may have stronger antitumor activities. Antioxidation results indicate that all the Tb(III) complexes have strong abilities of scavenging hydroxyl radicals and superoxide radicals, but complexes containing active phenolic hydroxy groups show stronger scavenging effects on hydroxyl radicals and complexes containing N-heteroaromatic substituent show stronger scavenging effects on superoxide radicals. However, Tb(III) emission with these systems is not observed, for these ligands rather are quenchers and unable to sensitize this metal ion. PMID- 20828435 TI - The unique molecular behavior of water at the chloroform-water interface. AB - The molecular bonding and orientation of water at the chloroform-water interface has been examined in this study using vibrational sum-frequency spectroscopy (VSFS). The results provide a key puzzle piece towards our understanding of the systematic changes in the interfacial bonding and orientation of water that occur with variations in the polarity of the organic phase, especially when compared with previous studies of different liquid-liquid interfacial systems. In these VSFS studies the OH spectral responses of interfacial water molecules are used to characterize the interactions between water and the organic phase. The spectral analysis, aided by isotopic dilution studies, shows that the moderate polarity of the chloroform phase results in a mixed interfacial region with stronger organic water bonding and fewer bonding interactions between adjacent water molecules than was previously found for studies of non-polar organic liquid-water interfaces. Even with the more mixed interfacial region and stronger organic water interactions, interfacial water retains a significant amount of orientational ordering. These results are compared with recent predictions from molecular dynamics simulations about how molecules behave at the chloroform-water interface. PMID- 20828433 TI - Simultaneous optical spectroscopic measurement of hemoglobin and myoglobin saturations and cytochrome aa3 oxidation in vivo. AB - A method to simultaneously measure oxygenation in vascular, intracellular, and mitochondrial spaces from optical spectra acquired from muscle has been developed. In order to validate the method, optical spectra in the visible and near-infrared regions (600-850 nm) were acquired from solutions of myoglobin, hemoglobin, and cytochrome oxidase that included Intralipid as a light scatterer. Spectra were also acquired from the rabbit forelimb. Three partial least squares (PLS) analyses were performed on second-derivative spectra, each separately calibrated to myoglobin oxygen saturation, hemoglobin oxygen saturation, or cytochrome aa3 oxidation. The three variables were measured from in vitro and in vivo spectra that contained all three chromophores. In the in vitro studies, measured values of myoglobin saturation, hemoglobin saturation, and cytochrome aa3 oxidation had standard errors of 5.9%, 7.4%, and 12.2%, respectively, with little cross-talk between the in vitro measurements. In the progression from normal oxygenation to ischemia in the rabbit forelimb, hemoglobin desaturated first, followed by myoglobin, while cytochrome aa3 reduction occurred last. The ability to simultaneously measure oxygenations in the vascular, intracellular, and mitochondrial compartments will be valuable in physiological studies of muscle metabolism and in clinical studies when oxygen supply or utilization are compromised. PMID- 20828436 TI - Comparison of the use of volume fractions with other measures of concentration for quantitative spectroscopic calibration using the classical least squares method. AB - Since the commercial development of modern near-infrared spectroscopy in the 1970s, analysts have almost invariably used units of weight percent as the measure of analyte concentration, due largely to the historical precedent from other analytical methods, including other spectroscopic techniques. The application of the CLS algorithm to a set of binary and ternary liquid mixtures reveals that the spectroscopic measurement sees the sample differently; that the measured absorbance spectrum is in fact sensitive to the volume fraction of the various components of the mixture. Because there is not a one-to-one relationship between volume fraction and other measures of analyte concentration, nor is the relationship linear, this has important implications for the application of both the CLS algorithm and the various other, more conventional, calibration algorithms that are commonly used. PMID- 20828437 TI - Optimal choice of baseline correction for multivariate calibration of spectra. AB - Baselines are often chosen by visual inspection of their effect on selected spectra. A more objective procedure for choosing baseline correction algorithms and their parameter values for use in statistical analysis is presented. When the goal of the baseline correction is spectra with a pleasing appearance, visual inspection can be a satisfactory approach. If the spectra are to be used in a statistical analysis, objectivity and reproducibility are essential for good prediction. Variations in baselines from dataset to dataset means we have no guarantee that the best-performing algorithm from one analysis will be the best when applied to a new dataset. This paper focuses on choosing baseline correction algorithms and optimizing their parameter values based on the performance of the quality measure from the given analysis. Results presented in this paper illustrate the potential benefits of the optimization and points out some of the possible pitfalls of baseline correction. PMID- 20828438 TI - What is the origin of positional fluctuation of spectral features: true frequency shift or relative intensity changes of two overlapped bands? AB - We investigated what is really meant by so-called positional or frequency fluctuation of spectral features. To show the difference between the true frequency shift of a single band and apparent peak maximum shift caused by relative intensity changes of overlapped adjacent bands, we analyzed infrared (IR) spectra of the OH stretching band of ethylene glycol during the heating process and the C=O stretching band of acetone in a mixed solvent CHCl(3)/CCl(4) with varying solvent compositions. These spectra are well-known examples of so called "band shift" phenomena often interpreted as the manifestation of gradual changes in the IR frequency associated with a specific chemical bond under the influence of molecular interactions. Analyses of IR spectra showed that the apparent positional shifts of peak maxima in these systems are actually due to relative contribution changes of two overlapped bands, instead of the gradual frequency shift of a single band induced by the change in the strength of molecular interactions. To further clarify our interpretation of "peak maximum shifts", we also analyzed simulated spectral datasets, comparing the true band frequency shift and change in the relative contributions of overlapped bands. It was found that principal component analysis (PCA) is a surprisingly sensitive tool to distinguish the two possible mechanisms of peak maximum shift. The new insight revealed by this study should help the interpretation of molecular interactions probed by vibrational spectroscopy. PMID- 20828439 TI - Applications of microstructured silicon wafers as internal reflection elements in attenuated total reflection Fourier transform infrared spectroscopy. AB - A novel internal reflection element (IRE) for attenuated total reflection Fourier transform infrared (ATR-FT-IR) spectral acquisition is introduced and applied for several surface-sensitive measurements. It is based on microstructured double side-polished (100) silicon wafers with v-shaped grooves of {111} facets on their backside. These facets of the so-called "microstructured single-reflection elements" (mSRE) are formed by a crystal-oriented anisotropic wet etching process within a conventional wafer structuring process. They are used to couple infrared radiation into and out of the IRE. In contrast to the application of the commonly used silicon multiple-reflection elements (MRE), the new elements provide single reflection ATR measurements at the opposite wafer side by using simple reflection accessories without any special collimation. Due to the short light path, the spectral range covers the entire mid-infrared region with a high optical throughput, including the range of silicon lattice vibrations from 300 to 1500 cm(-1). In addition to typical ATR applications, i.e., the measurement of bulk liquids and soft materials, the new reflection elements can be effectively used and customer-specifically designed for in situ and ex situ investigations of aqueous solutions, thin films, and monolayers on Si. Examples presented in this article are in situ etching of native as well as thermal SiO(2) and characterization of polydimethylsiloxane (PDMS) films on Si under various measuring conditions. PMID- 20828440 TI - Dielectric properties of water in butter and water-AOT-heptane systems measured using terahertz time-domain spectroscopy. AB - We investigate the dielectric properties of water confined in nanometer-sized inverse micelles in mixtures of water, AOT, and heptane. We show that the dielectric properties of the confined water are dependent on the water pool size and different from those of bulk water. We also discuss the dielectric properties of different vegetable oils, lard, and butter, and use these properties to deduce the dielectric properties of water in butter, which are shown to deviate significantly from the dielectric properties of bulk water. PMID- 20828441 TI - Transient vibrational echo versus transient absorption spectroscopy: a direct experimental and theoretical comparison. AB - Transient dispersed vibrational echo (DVE) spectroscopy is a practical alternative to transient-absorption spectroscopy because it affords increased sensitivity as well as greater signal-to-noise ratio without the need to detect a reference spectrum. However, as a third-order nonlinear probe, the extraction of kinetic information from transient-DVE is somewhat cumbersome compared to transient absorption. This article provides a direct experimental and theoretical comparison between transient-absorption and transient-DVE measurements and presents a framework for analyzing kinetic measurements while exploring the implications of making some simplifying assumptions in the data analysis. The equations for computing the signal-to-noise ratios under different experimental conditions are derived and used in the analysis of the experimental data. The results, obtained under the same experimental conditions, show that for a relatively strong terminal carbonyl stretching mode, signal-to-noise ratios in transient-DVE spectroscopy are approximately 2.5 times greater than transient absorption. The experimental results along with the theoretical models indicate that transient-DVE could become an attractive alternative to transient-absorption spectroscopy for measuring the kinetics of light-induced processes. PMID- 20828442 TI - Fast elemental screening of soil and sediment profiles using small-spot energy dispersive X-ray fluorescence: application to mining sediments geochemistry. AB - Elemental analysis of different sediment cores originating from the Cartagena-La Union mining district in Spain was carried out by means of a programmable small spot energy-dispersive X-ray fluorescence (EDXRF) spectrometer to study the distribution of heavy metals along soil profiles. Cores were obtained from upstream sediments of a mining creek, from the lowland sedimentation plain, and from a mining landfill dump (tailings pile). A programmable two-dimensional (2D) stage and a focal spot resolution of 600 MUm allow us to obtain complete core mapping. Geochemical results were verified using a more powerful wavelength dispersion X-ray fluorescence (WDXRF) technique. The data obtained was processed in order to study the statistical correlations within the elemental compositions. The results obtained allow us to observe the differential in-depth distribution of heavy metals among the sampled zones. Dump site cores exhibit a homogeneous distribution of heavy metals, whereas the alluvial plain core shows accumulation of heavy metals in the upper part. This approach can be useful for the fast screening of heavy metals in depositional environments around mining sites. PMID- 20828443 TI - Characterization of fungal-degraded lime wood by X-ray diffraction and cross polarization magic-angle-spinning 13C-nuclear magnetic resonance spectroscopy. AB - X-ray diffraction, scanning electron microscopy (SEM), and solid-state cross polarization magic-angle-spinning (CP/MAS) (13)C-NMR spectroscopy were applied to determine changes over time in the morphology and crystallinity of lime wood (Tilia cordata Miller) generated by the soft-rot fungi. Wood samples were inoculated with Trichoderma viride Pers for various durations up to 84 days. Structural and morphological modifications were assessed by comparing the structural features of decayed lime wood samples with references. Significant morphology changes such as defibration or small cavities were clearly observed on the SEM micrographs of lime wood samples exposed to fungi. Following the deconvolution process of the diffraction patterns, the degree of crystallinity, apparent lateral crystallite size, the proportion of crystallite interior chains, and the cellulose fraction have been determined. It was found that all crystallographic data vary with the duration of exposure to fungi. The degree of crystallinity and cellulose fraction tend to decrease, whereas the apparent lateral crystallite size and the proportion of crystallite interior chains increase with prolonged biodegradation processes. The most relevant signals in CP/MAS (13)C-NMR spectra were assigned according to literature data. The differences observed were discussed in terms of lignin and cellulose composition: by fixing the lignin reference signal intensity, the cellulose and hemicelluloses moieties showed a relative decrease compared to the lignin signals in decayed wood. PMID- 20828444 TI - Use of spectra in the visible and near-mid-ultraviolet range with principal component analysis and partial least squares processing for monitoring of suspended solids in municipal wastewater treatment plants. AB - The present work assesses the possibility of using spectrophotometry in the near mid-ultraviolet and visible wavelength ranges (282-790 nm) for the direct monitoring of treatment performance in municipal wastewater treatment plants (WWTPs). Principal component analysis (PCA) was used to analyze spectral data from samples collected along three WWTP process lines with different primary and secondary treatment units. The clustering observed in PCA score plots was mainly attributed to the suspended solids fraction present in the wastewater and highlighted differences in solids quality between plants and along the treatment lines. Thus, satisfactory partial least squares (PLS) calibration models to estimate total suspended solids (TSS) values from the acquired spectra could only be established per plant. The PLS models were established using 1-2 factors, with root mean error of cross-validation and coefficient of determination values in the 50-86 mg TSS L(-1) and 82-95% ranges, respectively. PMID- 20828445 TI - A neutron resonance capture analysis experimental station at the ISIS spallation source. AB - Neutron resonance capture analysis (NRCA) is a nuclear technique that is used to determine the elemental composition of materials and artifacts (e.g., bronze objects) of archaeological interest. NRCA experiments are mostly performed at the GELINA facility in Belgium, a pulsed neutron source operating with an electron linear accelerator. Very intense fluxes of epithermal neutrons are also provided by spallation neutron sources, such as the ISIS spallation neutron source in the United Kingdom. In the present study, the suitability of the Italian Neutron Experimental Station (INES) beam line for NRCA measurements is assessed using a compact (n, gamma) resonance detector made of a Yttrium-Aluminum-Perovskite (YAP) scintillation crystal coupled with a silicon photomultiplier (SiPM) readout. The measurements provided a qualitative recognition of the composition of the standard sample, a lower limit for the sensitivity for NRCA for almost-in-traces elements, and an estimation of the relative isotopic concentration in the sample. PMID- 20828449 TI - Paediatric emergency care in resource-constrained health services is usually neglected: time for change. AB - Emergency care has been neglected in many resource-constrained countries and yet 50% of paediatric admissions die in the 1st 24 hours of admission. Carers may know how to manage clinical problems but there might not be a system in place to provide timely and appropriate care. This article reviews the needs--staffing, materials and physical layout--of a receiving hospital unit and describes how to set up a system of patient flow and care that prioritises and provides timely care, so that when a patient arrives in hospital the system does not fail them. PMID- 20828450 TI - Neonatal brucellosis: rare and preventable. PMID- 20828451 TI - A review of the incidence and prevalence, types and aetiology of childhood cerebral palsy in resource-poor settings. AB - BACKGROUND: With 80% of children with disabilities living in resource-poor settings, it is likely that there is a high prevalence of cerebral palsy (CP) and neurological impairment in these settings. The prevalence and incidence rates of disability, in particular of children with CP in resource-poor settings, are difficult to access and clarify. AIM: To review the recent literature relating to the prevalence, incidence, type and aetiology of cerebral palsy in low-income settings. METHODS: A systematic search of studies published between 1990 and 2009 was performed using PubMed, Cinahl on Ovid, the Cochrane database, SCOPUS and information from international disability organisations. All studies with information about neurodisability, CP or disability in resource-poor settings were included. Titles and/or abstracts of all studies were reviewed and full texts of relevant studies were obtained. RESULTS: Disparities in methodology, age range, classification systems and populations made studies difficult to compare. Population-based studies provided rates of childhood disability of 31-160/1000. When using limited age ranges of 2-9 years with the Ten Question Questionnaire, rates were 82-160/1000 for children disability and 19-61/1000 for neurological impairment. Rates of CP in population-based settings in China and India gave figures of 2-2.8/1000 births, similar to western settings. Hospital-based studies of CP showed increased rates of spastic quadriplegia rather than diplegia or hemiplegia and possibly increased rates of meningitis, jaundice and asphyxia and lower rates of low birthweight and prematurity in CP populations. These studies were small and not case-controlled or population-based. CONCLUSIONS: Rates of CP and neurological impairment are difficult to obtain in resource-poor settings. Methods of identifying children with CP and causal factors and the effects of disability need to be better classified in order to improve management and help shape preventive measures. PMID- 20828452 TI - The external Ballard examination does not accurately assess the gestational age of infants born at home in a rural community of The Gambia. AB - BACKGROUND: Accurate assessment of gestational age at birth is critical to the identification of neonates at high risk. In resource-poor settings, postnatal techniques are commonly used but may be difficult to apply and have not been well validated against ultrasound in community studies. The aim of this study was to evaluate postnatal assessment of gestational age in rural Africa using the external criteria of the Ballard examination against 1st/early 2nd-trimester ultrasound and date of last menstrual period. METHOD: In a sample of women from Kiang West, The Gambia (n=80), the precision of gestational age estimates using the external Ballard examination was compared with those derived from 1st and early 2nd-trimester ultrasound examination and date of last menstrual period. RESULTS: The incidence of preterm delivery was low at 2.5%. The external Ballard examination tended to underestimate gestational age by a mean (SD) of 15.6 (10.9) days compared with that derived from ultrasound and to underestimate by 15.4 (23.1) days compared with that derived from date of last menstrual period. The differences between the methods varied with gestation. CONCLUSION: In this rural, community-born population of infants, postnatal assessment of gestational age by external Ballard examination performed poorly compared with ultrasound and last menstrual period. No reliable gestational age could be derived from its estimate and it failed to detect a significant proportion of high-risk infants. The development of an accurate but simple method of postnatally assessing gestational age specifically for use by health workers in rural Africa is required. PMID- 20828453 TI - Delayed puberty: experience of a tertiary care centre in India. AB - BACKGROUND: Pubertal delay can be a manifestation of a wide variety of diseases, the proportions of which may vary between developing and industrialised countries. OBJECTIVE: A retrospective study was undertaken to investigate the aetiology of delayed puberty in northern India. SUBJECTS AND METHODS: Follow-up records of patients with delayed puberty presenting to the endocrine clinic between 2003 and 2007 were analysed. RESULTS: Forty-two patients (19 boys, 23 girls, age range 14-27 y) of 46 who initially presented had complete evaluation. The main causes of pubertal delay were chronic systemic illnesses (16), e.g. malnutrition, anaemia and chronic infections, hormone deficiencies (11), hypergonadotrophic hypogonadism (7) and constitutional delay (6). While the majority of girls (11/23) were found to have underlying systemic disorders, endocrinopathies (6/19) were the major causes of pubertal delay in boys. CONCLUSION: Chronic systemic illnesses are the major cause of pubertal delay in developing countries. Social awareness and education leading to early detection and treatment can prevent pubertal delay in a large proportion of cases. PMID- 20828454 TI - Increased level of hepatocyte growth factor in children with dengue virus infection. AB - BACKGROUND: Evidence of hepatocellular damage is common in dengue-infected individuals. Hepatocyte growth factor (HGF), a key cytokine responsible for liver regeneration, may play a prognostic role in dengue virus infection. AIM: To determine the relationship between serum HGF level and disease severity in patients with dengue virus infection. METHODS: Serum samples from 27 children [17 dengue fever (DF), ten dengue haemorrhagic fever (DHF)] with serologically confirmed dengue virus infection during the febrile, toxic stages and at follow up were analysed for HGF. Serum samples obtained from nine healthy children served as the control group. RESULTS: In dengue-infected patients, serum HGF was significantly higher at the febrile and toxic stages than at follow-up (p<0.05). In comparison with DF, patients with DHF had a greater level of HGF at the febrile stage (p<0.05). A cut-off HGF level of 1220 pg/mL obtained during the febrile stage showed a sensitivity of 90% and a specificity of 53% for predicting clinical progression to DHF (area under the ROC curve 0.75). CONCLUSION: Serum HGF level at the early stage of dengue virus infection is elevated and may be a useful predictor for clinical progression to DHF. PMID- 20828455 TI - Umbilical separation time delayed by alcohol application. AB - AIMS: To compare the effects on time of umbilical cord separation of cleaning with 95% alcohol and natural drying in a high-humidity subtropical country. METHODS: One hundred and fifty neonates were randomly assigned to two groups, 75 in each. For the control group, umbilical cleansing with 95% alcohol was performed after daily bathing; natural drying without a topical regimen was used for the trial group. RESULTS: Complete information was obtained for 71 neonates in the control group and 71 in the trial group. At 1 month after delivery, no enrolled neonate had developed omphalitis or skin infection. Cord separation time was significantly reduced for the natural-drying group compared with the alcohol cleansing group (p=0.014). In both groups, separation time was longer for newborns delivered by caesarean section than for those delivered vaginally (p=0.001). Nine mothers in the trial group and five in the control group complained of discharge from the umbilicus. Separation time was not influenced by gender, gestational age, birthweight or length, gravidity, meconium staining, maternal age or presence of discharge. CONCLUSIONS: Cleaning with 95% alcohol did not reduce umbilical cord separation time. This traditional method is not necessary for routine cord management, even in a subtropical country. PMID- 20828456 TI - Brucella myocarditis in a 3-month-old: probable transplacental transmission. AB - A 3-month-old girl presented with myocarditis owing to brucellosis. Her mother had been diagnosed with brucellosis at 28 weeks gestation but did not receive treatment until after delivery. The infant had intrauterine retardation and had gained little weight since birth. It is considered likely that the brucellosis was transmitted transplacentally. PMID- 20828457 TI - Congenital brucellosis: case report. AB - A 6-hour-old infant was admitted with severe respiratory distress and hepatosplenomegaly. Her mother had arthralgia for 4 weeks in the 7/8th month of pregnancy and the infant was born at 31 weeks. Brucella spp was detected in blood culture and serology in mother and infant, supporting the diagnosis of brucellosis with presumed transplacental transmission. PMID- 20828459 TI - Ileal perforation in a child with abdominal tuberculosis. AB - A 6-year-old boy presented with a 1-month history of fever followed by abdominal distension, constipation and bilious vomiting for 2 days. The clinical impression was of intestinal obstruction. At exploratory laparotomy, there was an ileal perforation secondary to tuberculosis. There are many case reports of tubercular ileal perforation in adults but in children it is very rare. PMID- 20828458 TI - Bacteraemia with pleural effusions complicating typhoid fever caused by high level ciprofloxacin-resistant Salmonella enterica serotype Typhi. AB - An unusual case of bacteraemia with bilateral pleural effusion caused by Salmonella enterica serotype Typhi in a 10-year-old previously healthy girl is reported. The organism was isolated from pleural fluid aspirate and from blood, and exhibited high-level ciprofloxacin resistance (MIC 16 MUg/ml) associated with triple mutations in the QRDRs of the gyrA and parC genes leading to the amino acid changes Ser83->Phe and Asp87->Asn in gyrA and Ser80->Ile in parC. The patient was successfully treated with parenteral ceftriaxone and intercostal chest tube drainage. The case is notable because of the important issue of antimicrobial resistance in S. Typhi and the therapeutic dilemma faced by clinicians regarding the empirical use of ciprofloxacin and newer fluoroquinolones. PMID- 20828460 TI - Fulminant enterovirus 71 infection: case report. AB - A previously healthy 3-year-old boy presented with high-grade fever, dyspnoea, alteration of consciousness, tachycardia and shock. A few erythematous macules and papules were seen on his palms and soles. Echocardiogram showed poor left ventricular contraction. Cardiac enzymes and pro-B-type natriuretic peptide were elevated. Milrinone, low-dose dopamine and intravenous immunoglobulin were administered. The patient recovered after 5 days without cardiac or neurological sequelae. The serological results showed a four-fold rise of enterovirus 71. In children with severe EV71 infection, early recognition of cardiopulmonary involvement and aggressive treatment are crucial to successful management. PMID- 20828461 TI - Pulmonary haemosiderosis in a 13-year-old girl with coeliac disease after 3 months on a gluten-free diet: case report and review of the literature. AB - A 13-year-old girl with controlled coeliac disease who had been on a gluten-free diet for the past 3 months was admitted with respiratory distress and hypoxia for the past week. Chest radiograph and CT scan showed bilateral widespread alveolar shadowing suggestive of a hypersensitive pneumonitis. There was a dramatic radiological and clinical response to oral corticosteroids. Bronchial lavage was suggestive of recurrent aspiration and histology of a transbronchial biopsy showed pulmonary haemosiderosis. We conclude that pulmonary haemosiderosis may occur in children with coeliac disease who are on a gluten-free diet. PMID- 20828462 TI - Coeliac disease presenting as acute pancreatitis in a 3-year-old. AB - A 3-year-old boy presented with a history of intermittent abdominal pain and vomiting from the age of 1 year. Raised serum amylase and lipase levels supported a diagnosis of acute pancreatitis. Subsequent investigation confirmed coeliac disease. This is the youngest patient to be reported with this combination. PMID- 20828463 TI - Giant intramuscular calcifying aponeurotic fibroma of gluteus maximus: case report. AB - Calcifying aponeurotic fibroma (CAF) is a rare soft tissue tumour which occurs mainly in children and adolescents. It usually involves the distal portion of the extremities, i.e. the hands and feet. A 2-year-old child with a large CAF is presented. The case was unusual in view of its large size (10 * 7 * 5 cm), dense calcification in such a young child, and because it was situated in the substance of gluteus maximus muscle. There has been no recurrence at 3-year follow-up. PMID- 20828464 TI - Qualitative map of Salmonella contamination on young chicken carcasses. AB - Salmonella contamination of poultry is a global public health problem. The objective of this study was to map the distribution of Salmonella on the young chicken carcass, to improve poultry inspection and food safety. Young chickens (n = 70) in the Cornish game hen class were obtained at retail over a 3-year period. Carcasses were aseptically sectioned into 12 parts, and then Salmonella was isolated from whole-part incubations by conventional culture methods. Isolates were characterized for serotype and antibiotic resistance, and by pulsed-field gel electrophoresis (PFGE). Salmonella incidence was 21.5% (181 of 840) for parts and 57.1% (40 of 70) for carcasses. The number of contaminated parts per carcass ranged from 0 to 12, with a mean of 4.5 among contaminated carcasses. Chi-square analysis indicated that Salmonella incidence differed (P < 0.05) among parts, with rib back (38.6%) and sacral back (34.3%) being the most contaminated. Among the 40 contaminated carcasses, there were 37 different patterns of contamination among parts. Of the 33 carcasses with more than one contaminated part, 12.1% contained two serotypes, 33.3% contained two or more antibiotic resistance profiles, and 100% contained two or more PFGE patterns. The most common serotype was Typhimurium (94.5%), and most (97.2%) isolates were resistant to multiple antibiotics. These results indicated a diverse pattern of Salmonella contamination among carcasses and that multiple subtypes of Salmonella were often present on contaminated carcasses. Thus, whole-carcass incubation succeeded by characterization of multiple isolates per carcass is needed to properly assess and manage this risk to public health. PMID- 20828465 TI - Effect of temperature and time of storage on protein stability and anti salmonella activity of egg white. AB - Hen egg white contains numerous molecules of interest for human health, including antimicrobial proteins. Little information is available concerning changes in the antimicrobial activity of egg white during storage; therefore, we analyzed the potential of egg white to inhibit growth of Salmonella enterica serovar Enteritidis following storage at 4, 20, or 37 degrees C for 30 days prior to inoculation. Egg white displayed higher anti-Salmonella activity after a few days of storage at 20 and 37 degrees C. The rate of increase in activity was more rapid and pronounced at the higher temperature. However, egg white stored at 20 degrees C retained higher antimicrobial activity than that of egg white stored at 4 or 37 degrees C, when the entire storage period is taken in consideration. In contrast, storage of egg at 37 degrees C for more than 14 days reduced the bacteriostatic potential of egg white. Statistical analyses revealed a correlation between pH and the antimicrobial activity of egg white. Moreover, diminished antimicrobial activity was associated with degradation of ovalbumin and ovotransferrin, as assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry. However, the fluctuation in anti Salmonella activity of egg white could not be related to any variation of trypsin like, chymotrypsin-like, or gelatinolytic activities that potentially account for degradation of antimicrobial egg white proteins. PMID- 20828466 TI - Occurrence and antimicrobial resistance profiles of Salmonella species in retail meat products. AB - In the present study, a total of 225 retail meat products (poultry meat, ground beef, and beef samples) were tested for the prevalence of Salmonella. Of these, 50 (22.2%) were positive for Salmonella. Overall, the pathogen was detected in 22 (29.3%) samples of poultry meat (n = 75), 16 (21.3%) samples of ground beef (n = 75), and 12 (16%) samples of beef (n = 75). The most common isolate was Salmonella enterica serovar Typhimurium (9.8%), followed by S. bongori species (8.9%) and S. enterica subsp. diarizonae (3.5%). The Salmonella strains isolated were also examined for antimicrobial resistance patterns and production of beta lactamase enzyme. The resistance levels of the isolates against 14 different antimicrobial agents were tested by the disk diffusion method. None of the strains exhibited resistance to cefotaxime, ciprofloxacin, norfloxacin, or levofloxacin. However, the highest resistance rates in the meat isolates were 64% each for ampicillin and cephazolin and 56% for amoxicillin-clavulanic acid. A total of 62% of the 50 Salmonella strains were multiresistant to three or more antimicrobial agents. The exhibited multiple resistance to four or more antimicrobial drugs was 32%. Furthermore, none of the isolates had beta-lactamase enzyme activity. PMID- 20828467 TI - Development of a multiplex real-time PCR assay with internal amplification control for the detection of Shigella species and enteroinvasive Escherichia coli. AB - Shigella species, particularly S. sonnei and S. flexneri, remain some of the leading bacterial etiological agents of gastrointestinal diseases in the United States and globally. The isolation and detection of these foodborne pathogens are critical for preventing the spread of disease and facilitating epidemiological investigations aimed at determining the source of a Shigella infection outbreak. A multiplex real-time PCR-based assay was developed that targets all four species of Shigella plus enteroinvasive Escherichia coli. The assay incorporates primers directed to the ipaH genes located on both the virulence plasmid and chromosome, the plasmid-encoded virulence gene mxiC, a mutated mxiC gene (mxiC::kan) that differentiates wild-type strains from a laboratory control strain, and an internal amplification control. More than 50 isolates of all four Shigella species were tested for inclusivity and specificity of the multiplex PCR assay, and more than 30 non-Shigella isolates were tested for exclusivity of the assay. The sensitivity of the assay was 1 to 3 CFU and 5 to 50 fg of target (total) DNA for the ipaH, mxiC, and mxiC::kan gene targets. The assay performed equally well and with no measurable inhibition in the Shigella target reactions when rinsates of several high-risk produce commodities (parsley, cilantro, alfalfa sprouts, and lettuce) were added to the reactions. This multiplex PCR assay is sensitive and specific and has the added dimension of discriminating all Shigella species from the positive control strain so that in any sample analysis other strains can be excluded as a source of contamination. PMID- 20828468 TI - Development and validation of a predictive model for foodborne pathogens in ready to-eat pork as a function of temperature and a mixture of potassium lactate and sodium diacetate. AB - We developed and validated secondary models that can predict growth parameters of Salmonella Typhimurium and Staphylococcus aureus in cooked-pressed ready-to-eat (RTE) pork as a function of concentrations (0 to 3%) of a commercial potassium lactate and sodium diacetate mixture (PL+SDA) and temperature (10 to 30 degrees C). The primary growth data were fitted to a Gompertz equation to determine the lag time (LT) and growth rate (GR). At 10 degrees C, the growth of Salmonella Typhimurium and S. aureus in cooked-pressed RTE pork containing 2% and 3% PL+SDA was completely inhibited. The effects of temperature and concentration of PL+SDA on the growth kinetics of Salmonella Typhimurium and S. aureus in cooked-pressed RTE pork were modeled by response surface analysis using polynomial models of the natural logarithm transformation of both LT and GR. Model performance was also evaluated by use of the prediction bias (B(f)) and accuracy (A(f)) factors, median relative error, and mean absolute relative error, as well as the acceptable prediction zone method. The results showed that LT and GR models of Salmonella Typhimurium and S. aureus in cooked-pressed RTE pork are acceptable models. Thus, both the LT and GR growth models developed herein can be used for the development of tertiary models for Salmonella Typhimurium and S. aureus in cooked-pressed RTE pork in the matrix of conditions described in the present study. PMID- 20828469 TI - Thermal inactivation of heat-shocked Escherichia coli O157:H7, Salmonella, and Listeria monocytogenes in dairy compost. AB - Thermal resistance of heat-shocked Escherichia coli O157:H7, Salmonella, and Listeria monocytogenes was compared with that of non-heat-shocked (control) strains in finished dairy compost. A three-strain mixture of each pathogen was heat shocked at 47.5 degrees C for 1 h and inoculated into the compost at a final concentration of 10(7) CFU/g. The inoculated compost was placed inside an environmental chamber set at 50, 55, or 60 degrees C with humidity at ca. 70%. The heat-shocked E. coli O157:H7, Salmonella, and L. monocytogenes survived better (P < 0.05) at 50 degrees C, with reductions of 2.7, 3.2, and 3.9 log CFU/g within 4 h compared with reductions of 3.6, 4.5, and 5.1 log CFU/g, respectively, in control cultures. The heat-shocked cultures of E. coli O157:H7, Salmonella, and L. monocytogenes had 1.2-, 1.9-, and 2.3-log reductions, respectively, within 1 h at 55 degrees C, whereas the corresponding control cultures had 4-, 5.6-, and 4.8-log reductions, respectively. At 60 degrees C, a rapid population reduction was observed during the come-up time of 14 min in control cultures of E. coli O157:H7, Salmonella, and L. monocytogenes with 4.9-, 4.8-, and 2.3-log reductions, respectively, compared with 2.6-, 2.4-, 1.7-log reductions, respectively, in heat-shocked cultures. L. monocytogenes survival curves for all three temperatures had extensive tailing. The double Weibull distribution model was a good fit for the survival curves of pathogens, with differences in the shape parameter of heat-shocked and control cultures. Our results suggest that the heat-shocked pathogens may have extended survival at lethal temperatures attained during the composting process. PMID- 20828470 TI - Incidence and persistence of Listeria monocytogenes in the catfish processing environment and fresh fillets. AB - Incidence of Listeria spp. in whole raw catfish, catfish fillets, and processing environments from two catfish processing facilities was determined in August 2008 and August 2009. Thirty-nine (18.4%) of 212 samples collected in August 2008 were positive for Listeria monocytogenes. Prevalences of Listeria species L. innocua and L. seeligeri-L. welshimeri-L. ivanovii were 11.3 and 23.6%, respectively. Of 209 samples collected in August 2009, 12.4% were positive for L. monocytogenes, 11% for L. innocua, and 19.6% for L. seeligeri-L. welshimeri-L. ivanovii. No Listeria grayi was detected in any of the samples. L. monocytogenes was not found in catfish skins and intestines, but was detected in catfish fillets, on food contact surfaces, and on non-food contact surfaces with frequencies of 45.0, 12.0, and 11.1%, respectively. In August 2008 isolates, serotypes 1/2b (62.2%) and 3b (15.6%) were frequently isolated, whereas the majority of the August 2009 isolates (92.3%) were serotype 1/2b. Genotyping analyses revealed that some genotypes of L. monocytogenes isolates were detected in one facility even after a year, but no persistence of L. monocytogenes was observed in the other facility. In addition, some L. monocytogenes isolates from fresh fillets showed genotypes that were either identical, or more than 90% similar, to those of L. monocytogenes isolates from food contact surfaces in the processing lines. The results of this study suggest that processing environment rather than whole raw catfish is an important source of L. monocytogenes contamination in the catfish fillets. These results should assist the catfish industry to develop better control and prevention strategies for L. monocytogenes. PMID- 20828471 TI - Evaluation of various methods for recovering human norovirus and murine norovirus from vegetables and ham. AB - We evaluated and optimized each step in an analytical method for detecting norovirus from various foods. We characterized the buffers needed for eluting norovirus from foods such as ham and lettuce. Two different concentration methods, polyethylene glycol (PEG) precipitation and hollow fiber ultrafiltration (HUF), were compared using both murine norovirus (MNV) and human norovirus (HuNoV). For PEG precipitation, an elution buffer containing 3% beef extract (pH 7.1) was more suitable than 0.05 M glycine plus 0.14 M NaCl (pH 7.5), and the recovery efficiency increased with increasing molecular weight of PEG. To determine the optimal buffer for concentrating norovirus by HUF, glycine buffers with different pH values and ionic strengths were examined as elution buffers. Overall, HUF was more efficient for norovirus recovery than was PEG precipitation. Because there was a significant positive correlation between MNV and HuNoV results, MNV could be a useful surrogate for detecting HuNoV in foods. PMID- 20828472 TI - Iodine concentration in milk sampled from Canadian farms. AB - A study was conducted to determine the iodine concentration in milk and the relationship between that concentration and milking and feeding management practices. Milk samples were collected from the bulk tanks of 501 farms in all provinces of Canada. With a view to obtaining further information about farm management, a questionnaire was completed at each of the selected farms. Total iodine concentration (organic and inorganic) in the milk was determined using inductively coupled plasma mass spectrometry. The farms were grouped for each of the variables and, based on significant differences in iodine concentrations, 15 variables were selected for further analysis. A general linear model was fitted, with milk iodine as the response variable to main and two-way interaction effects. The mean iodine concentration in Canadian milk was 304 +/- 8.4 MUg/kg, with concentrations ranging from 54 to 1,902 MUg/kg. Analysis of the questionnaire data suggested that component feeding was associated with lower iodine levels in milk than the levels obtained with total mixed rations. Neither the use of mineral supplementation nor the form of supplementation affected iodine levels in milk. Washing and dipping the teats before milking affected iodine in milk. The method of application of the teat sanitizers appears to be important, given that spray applications (inline or hand spraying) were associated with higher levels than those observed with the dip-cup procedure. In conclusion, Canadian milk iodine concentration varies considerably and appears to be influenced by feeding and milking practices. PMID- 20828473 TI - Depletion of veterinary drugs used in aquaculture after administration in feed to gilthead seabream (Sparus aurata). AB - This study was conducted to evaluate the depletion of residues of the antibiotics flumequine, oxytetracycline, sulfadiazine, trimethoprim, and oxolinic acid after in-feed administration to gilthead seabream. Fish were treated with the target antibiotics at doses of 30 mg/kg of body weight per day for 10 days at two seawater temperatures. Fish in each of five tanks were fed with a different medicated feed. After in-feed administration, five fish were randomly selected at different times, and antibiotic presence was analyzed in a mixture of muscle and skin. Antibiotic concentrations were determined through a validated analytical method based on liquid chromatography separation and mass spectrometry detection. Two trials were carried out with fish at different temperatures (14.0 and 19.5 degrees C). Depletion of antibiotics occurred more rapidly at the higher temperature. Elimination rates for all antibiotics assayed were high, which indicates that the withdrawal period for these antibiotics could be reduced. The results suggest that in gilthead seabream maintained at these two temperatures no detectable concentrations of the antibiotics used in this study will remain in edible tissues 35 days after treatment. For flumequine and oxolinic acid, the elimination time is shorter (4 and 20 days, respectively). PMID- 20828474 TI - Allergen sanitation in the food industry: a systematic industrial scale approach to reduce hazelnut cross-contamination of cookies. AB - Recently, we investigated the impact of shared equipment on cross-contamination of cookies at a pilot plant scale. Based on those findings, this study investigated the extent and subsequent sanitation of hazelnut cross-contamination (HNCC) of cookies at the industrial scale. Similarly, a product change from cookies with hazelnut ingredient to cookies without hazelnut was performed on standard equipment. HNCC in the hazelnut-free follow-up product was quantified by enzyme-linked immunosorbent assay for each production device and the applied cleaning procedure. All experiments were repeated in duplicate. The highest HNCC was found in concordance with previous studies after mere mechanical scraping: more than 1,000 mg of hazelnut protein per kg was quantified in the follow-up product after processing by a cookie machine. Additional cleaning with hot water decreased the HNCC irrespective of the processing device to levels at or below 1 mg of hazelnut protein per kg. Furthermore, raw materials for cookie production were monitored over a period of 24 months for unwanted preloads of hazelnut and peanut: hazelnut was quantified in 16% of the investigated raw materials as being between 0.26 and 90 mg/kg. Further critical control points at the industrial scale, where cross-contamination might occur, were identified but did not display noteworthy sources of cross-contamination. In conclusion, the quantitative monitoring of the cleaning efficiency at the industrial scale confirmed the procedure of manual scraping plus wet cleaning as a qualified sanitation procedure to effectively reduce the hazelnut protein cross-contamination down to a level at which severe hazelnut-related allergic reactions are unlikely to occur. PMID- 20828475 TI - Prevalence of pathogenic Yersinia enterocolitica strains on liver surfaces of pigs and their antimicrobial susceptibility. AB - A study to determine the occurrence of pathogenic Yersinia enterocolitica on surfaces of slaughtered pig livers and the antimicrobial resistant pattern of the isolates was carried out in a slaughterhouse in Lower Saxony, Germany. During the slaughtering process, 1,500 surfaces of pig livers from 50 fattening herds were swabbed in order to isolate and characterize Y. enterocolitica isolates by serotyping, detecting the virulence plasmid coding the yopT gene, and resistance testing. Of the livers tested, 4.7% were positive for Y. enterocolitica O:3, which was the only identified serotype. The virulence gene yopT was found in 90.0% of these isolates. Antimicrobial susceptibility was tested by the broth dilution method, and the MICs were determined for 13 antimicrobials. All isolates were resistant to ampicillin and sulfamethoxazole but were susceptible to ciprofloxacin, nalidixic acid, gentamicin, ceftiofur, tetracycline, kanamycin, cefotaxime, and chlorphenicol. Up to now, resistance to florfenicol has always been described in combination with resistance to chloramphenicol. In the present study, 15.3% of the isolates were resistant to florfenicol, while no chloramphenicol-resistant strains could be identified. Multiresistance to three or more antimicrobials was detected in 22 strains (27.3%). Nevertheless, third generation cephalosporines or fluoroquinolones, which were recommended for extraintestinal Y. enterocolitica infection in humans, were not affected. PMID- 20828476 TI - Occurrence and antibiotic resistance of coliform bacteria and antimicrobial residues in pasteurized cow's milk from Brazil. AB - In this study we examined the hygienic and sanitary quality of pasteurized cow's milk in the state of Parana, Brazil, by determining the presence of coliforms and occurrence of antimicrobial residues. A total of 260 milk samples were collected from commercial establishments in different regions of the state. Coliform populations were estimated by the multiple-tube test, and antimicrobial residues were detected by enzyme-linked immunosorbent assay. Overall, 105 samples (40.4%) were unsuitable for consumption according to Brazilian legal standards. Among the coliforms, Escherichia coli and Klebsiella pneumoniae were respectively identified in 77.05 and 36.07% of the samples. The highest rates of resistance to antimicrobial agents were observed for ampicillin (19.2%), cephalothin (18.9%), and tetracycline (17.1%). Antimicrobial residues were detected in 80 samples (30.8%). Forty-eight samples (18.5%) were positive for tetracycline, 29 (17.4%) for neomycin, 9 (3.5%) for beta-lactams, 6 (2.3%) for gentamicin, 4 (1.5%) for chloramphenicol, and 1 (0.4%) for streptomycin-dihydrostreptomycin. The results demonstrate a high prevalence of coliforms and also a high occurrence of antimicrobial residues in pasteurized cow's milk from Parana, Brazil. PMID- 20828477 TI - Prevalence of Listeria monocytogenes in retailed meat in the Tokyo metropolitan area. AB - This study was conducted to determine the prevalence of Listeria monocytogenes in retailed meats, comprising beef, chicken, and pork, in the Tokyo metropolitan area. A total of 379 samples of retailed meat were collected from 1998 to 2003, most of which were obtained by simultaneously purchasing the three classes of meat from a shop and then making another simultaneous purchase of meat from the same shop a few weeks later. The prevalence of L. monocytogenes was 28.0%, and the serotypes isolated were mainly 1/2a, 1/2b, 1/2c, and 4b. Comparison of the prevalence of each serotype among the classes of meat showed a predominant distribution of serotypes 1/2a, 1/2b, and 4b in chicken, while serotype 1/2c was dominant in pork. A total of nine cases considered to be due to persistence and/or cross-contamination were found. Most of the strains involved in persistence and/or cross-contamination were of serotypes 1/2c or 4b. These results suggest that contamination in retailed meat in Japan is at almost the same level as in other countries and that chicken has the highest potential as a source of contamination and infection. In addition, we suggest that the ecological niche of serotype 1/2c is distinct from those of 1/2a, 1/2b, and 4b, which may explain why human hosts have less opportunity to be exposed to serotype 1/2c and why there is a lower rate of isolation of this serotype from cases of human listeriosis. PMID- 20828478 TI - Survival of Bacillus anthracis spores in fruit juices and wine. AB - Foods have been identified as a potential target for bioterrorism due to their essential nature and global distribution. Foods produced in bulk have the potential to have large batches of product intentionally contaminated, which could affect hundreds or thousands of individuals. Bacillus anthracis spores are one potential bioterrorism agent that may survive pasteurization and remain viable throughout the shelf life of fruit juices and cause disease if consumed. This project examined B. anthracis spore survival in orange, apple, and grape juices, as well as wine. Samples of beverages were inoculated with spores of two nonpathogenic B. anthracis strains at approximately 10(6) CFU/ml, and the spore count was determined periodically during storage for 30 days at 4 degrees C. After this time, the counts of survival spores never declined more than 1 log CFU/ml in any of the beverage types. These results indicate that spores can survive, with little to no loss in viability, for at least a month in fruit juices and wine. PMID- 20828479 TI - Real-time PCR assay for the detection of pufferfish products. AB - An assay was developed for the rapid detection of products containing tissues from potentially toxic pufferfish (family Tetraodontidae), as part of the U.S. Food and Drug Administration Center for Veterinary Medicine and Center for Food Safety and Applied Nutrition's charter to protect human health. In this study, we developed a TaqMan assay derived from DNA barcode data (650 bp starting at the 5' end of the mitochondrial cytochrome c oxidase I gene) for the specific detection of pufferfish. The method requires only 1 h of total run time, a significant improvement over current methods, which can require 24 to 96 h for completion. The probes were tested against 105 species of fish and were able to detect 20 species of pufferfish; no cross-reactivity was shown with 85 species of nonpufferfish, including 20 related species from the same order (Tetraodontiformes). These results demonstrate that this assay is suitable for the rapid and specific detection of pufferfish and that it could be a useful regulatory tool to protect human health. PMID- 20828480 TI - Detection and quantification of biogenic amines in fermented food products sold in Botswana. AB - The incidence and concentrations associated with four important biogenic amines in leading commercial fermented beverages consumed in Botswana were determined using high-performance liquid chromatography. In 87 sorghum brew and 84 sour milk (madila, amasi) samples tested, putrescine was the most prevalent biogenic amine (63 and 61%, respectively), while histamine was the least prevalent (24 and 8%, respectively). Cadaverine was the most frequently detected biogenic amine in 79 of the commercial sour maize beverage (mageu/mahewu) samples tested (found in 70% of the samples), while tyramine was the least detected (occurring in 3% of the samples). In sorghum brew and sour milk, tyramine was found to be the most concentrated (mean concentration of 2.08 mg/100 ml and 3.2 mg/100 ml, respectively), and histamine was found to be the least concentrated (mean concentration of 0.94 mg/100 ml and 0.31 mg/100 ml, respectively). Overall, the biogenic amine concentrations of all three fermented products were within acceptable limits. However, one sorghum brew sample had a histamine content of 5.8 mg/ 100 ml, which was above the 5.0 mg/100 g allowable limit suggested by the U.S. Food and Drug Administration. PMID- 20828481 TI - Melamine milk powder and infant formula sold in East Africa. AB - This is the first study proving the existence of melamine in milk powder and infant formula exported to the African market. A total of 49 milk powder batches were collected in Dar-es-Salaam (Tanzania, East Africa), the center of international trade in East Africa, which serves as a commercial bottleneck and shipment hub for sub-Saharan, Central, and East Africa. Two categories of samples were collected between October and December 2008, immediately after the melamine contamination of Chinese products became public: (i) market brands of all international companies supplying the East African market and (ii) illegally sold products from informal channels. Melamine concentration was determined with the AgraQuant Melamine Sensitive Assay. Despite the national import prohibition of Chinese milk products and unlabeled milk powder in Tanzania, 11% (22 of 200) of inspected microretailers sold milk powder on the local black market. Manufacturers could be identified for only 55% (27) of the 49 investigated batches. Six percent (3 of 49) of all samples and 11% (3 of 27) of all international brand name products tested revealed melamine concentrations up to 5.5 mg/kg of milk powder. This amount represents about twice the tolerable daily intake as suggested by the U.S Food and Drug Administration. Based on our study, we can assume that the number of affected children in Africa is substantial. PMID- 20828482 TI - Analysis of toxic metals in seafood sold in New York state by inductively coupled plasma mass spectrometry and direct combustion analysis. AB - Concentrations of 12 metals (As, Be, Cd, Cr, Pb, Mo, Ni, Tl, Th, U, V, Hg) were determined in samples of fish and lobster obtained from various stores and markets in New York State. The seafood samples were chosen based on their popularity as a food source and the potential of the species to contain high levels of mercury based on past research results. A total of 177 fish and lobster samples were initially analyzed using combustion for Hg. The samples were then reanalyzed for several elements using microwave digestion followed by inductively coupled plasma mass spectrometry. The detection limits were as follows: 20 ng/g for Th, U, and Hg; 100 ng/g for Be, Cd, V, and As; and 300 ng/g for Cr, Mo, Tl, Pb, and Ni. Twenty-two samples had mercury concentrations greater than the 1,000 ng/g limit set by the Commission of the European Communities. The highest Cd concentration (511 ng/g) was found in a lobster. This level is greater than the 500 ng/g limit set by the Commission of the European Communities. All levels of As, Cd, Cr, Pb, and Ni were below the U.S. Food and Drug Administration action levels for these metals in crustaceans and shellfish. The highest average mercury level (1,190 ng/g) was found in swordfish. The highest average arsenic level (13,400 ng/g) was found in monkfish. Inductively coupled plasma mass spectrometry with microwave digestion was demonstrated to be a very effective technique for analyzing fish and lobster for Hg and other toxic metals. PMID- 20828483 TI - Non-O157 Shiga toxin-producing Escherichia coli in foods. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) strains have been linked to outbreaks and sporadic cases of illness worldwide. Illnesses linked to STEC serotypes other than O157:H7 appear to be on the rise in the United States and worldwide, indicating that some of these organisms may be emerging pathogens. As more laboratories are testing for these organisms in clinical samples, more cases are uncovered. Some cases of non-O157 STEC illness appear to be as severe as cases associated with O157, although in general cases attributed to non-O157 are less severe. There is much variation in virulence potential within STEC serotypes, and many may not be pathogenic. Of more than 400 serotypes isolated, fewer than 10 serotypes cause the majority of STEC-related human illnesses. Various virulence factors are involved in non-O157 STEC pathogenicity; the combined presence of both eae and stx genes has been associated with enhanced virulence. A scientific definition of a pathogenic STEC has not yet been accepted. Several laboratories have attempted to develop detection and identification methods, and although substantial progress has been made, a practical method of STEC detection has yet to be validated. Worldwide, foods associated with non-O157 STEC illness include sausage, ice cream, milk, and lettuce, among others. Results from several studies suggest that control measures for O157 may be effective for non-O157 STEC. More research is needed to uncover unique characteristics and resistances of non-O157 STEC strains if they exist. The public health significance of non-O157 STEC and the implications for industry practices and regulatory actions are discussed. PMID- 20828484 TI - Review of antimicrobial and antioxidative activities of chitosans in food. AB - Interest in chitosan, a biodegradable, nontoxic, non-antigenic, and biocompatible biopolymer isolated from shellfish, arises from the fact that chitosans are reported to exhibit numerous health-related beneficial effects, including strong antimicrobial and antioxidative activities in foods. The extraordinary interest in the chemistry and application in agriculture, horticulture, environmental science, industry, microbiology, and medicine is attested by about 17,000 citations on this subject in the Scopus database. A special need exists to develop a better understanding of the role of chitosans in ameliorating foodborne illness. To contribute to this effort, this overview surveys and interprets our present knowledge of the chemistry and antimicrobial activities of chitosan in solution, as powders, and in edible films and coating against foodborne pathogens, spoilage bacteria, and pathogenic viruses and fungi in several food categories. These include produce, fruit juices, eggs and dairy, cereal, meat, and seafood products. Also covered are antimicrobial activities of chemically modified and nanochitosans, therapeutic properties, and possible mechanisms of the antimicrobial, antioxidative, and metal chelating effects. Further research is suggested in each of these categories. The widely scattered data on the multifaceted aspects of chitosan microbiology, summarized in the text and in 10 tables and 8 representative figures, suggest that low-molecular-weight chitosans at a pH below 6.0 presents optimal conditions for achieving desirable antimicrobial and antioxidative-preservative effects in liquid and solid foods. We are very hopeful that the described findings will be a valuable record and resource for further progress to improve microbial food safety and food quality. PMID- 20828485 TI - Outbreaks where food workers have been implicated in the spread of foodborne disease. Part 8. Gloves as barriers to prevent contamination of food by workers. AB - The role played by food workers and other individuals in the contamination of food has been identified as an important contributing factor leading to foodborne outbreaks. To prevent direct bare hand contact with food and food surfaces, many jurisdictions have made glove use compulsory for food production and preparation. When properly used, gloves can substantially reduce opportunities for food contamination. However, gloves have limitations and may become a source of contamination if they are punctured or improperly used. Experiments conducted in clinical and dental settings have revealed pinhole leaks in gloves. Although such loss of glove integrity can lead to contamination of foods and surfaces, in the food industry improper use of gloves is more likely than leakage to lead to food contamination and outbreaks. Wearing jewelry (e.g., rings) and artificial nails is discouraged because these items can puncture gloves and allow accumulation of microbial populations under them. Occlusion of the skin during long-term glove use in food operations creates the warm, moist conditions necessary for microbial proliferation and can increase pathogen transfer onto foods through leaks or exposed skin or during glove removal. The most important issue is that glove use can create a false sense of security, resulting in more high-risk behaviors that can lead to cross-contamination when employees are not adequately trained. PMID- 20828486 TI - The use of tacit knowledge in occupational safety and health management systems. AB - A systematic approach to occupational safety and health (OSH) management and concepts of knowledge management (KM) have developed independently since the 1990s. Most KM models assume a division of knowledge into explicit and tacit. The role of tacit knowledge is stressed as necessary for higher performance in an enterprise. This article reviews literature on KM applications in OSH. Next, 10 sections of an OSH management system (OSH MS) are identified, in which creating and transferring tacit knowledge contributes significantly to prevention of occupational injuries and diseases. The roles of tacit knowledge in OSH MS are contrasted with those of explicit knowledge, but a lack of a model that would describe this process holistically is pointed out. Finally, examples of methods and tools supporting the use of KM in OSH MS are presented and topics of future research aimed at enhancing KM applications in OSH MS are proposed. PMID- 20828487 TI - Psychosocial and ergonomic factors, and their relation to musculoskeletal complaints in the Swedish workforce. AB - A random sample of 1 000 subjects (20-65 years old) from the national population of Sweden received a questionnaire; 70% (n=695) replied, of whom 532 were occupationally active. Female gender, working with neck and/or body bent forward, arms above shoulders, and precision work tasks were predictors of musculoskeletal symptoms. Neck, shoulder, and upper back symptoms were more common in a strained situation at work (high demands, low control) (adjusted odds ratios [adjOR] 2.76, 2.80, and 2.26, respectively). Among females, neck and shoulder symptoms were more common in an iso-strain situation (high demands, low control and low social support) (adjOR 4.43 and 3.69, respectively), and low back symptoms were more common at low social support combined with a passive work situation (adjOR 3.35). No associations were found between iso-strain model and symptoms among males. In conclusion, iso-strain work situation was associated with neck symptoms among females, even when controlling for ergonomic factors. PMID- 20828488 TI - Preferred handrail height for spiral stairs--a fitting trial study. AB - Stairways are, in general, a thoroughly studied subject, but there is almost no scientific data available about spiral stairs. They are, however, widely used in homes, industrial sites and public buildings. The purpose of this study was to determine preferred handrail heights for a spiral stairway. The most preferred handrail height for descent was 105 cm. On the other hand, 95% of the participants regarded handrail heights between 95 and 100 cm satisfactory for descending. Participants' anthropometric data was combined with the handrail height preference to develop a draft of a model to predict preferred handrail height for other user populations. PMID- 20828489 TI - The influence of occupational and non-occupational factors on the prevalence of musculoskeletal complaints in users of portable computers. AB - INTRODUCTION: Portable computers are becoming an increasingly common main work tool; however, they are not properly adapted to the workstation. Musculoskeletal complaints are a very frequent complaint reported by workers who use computers in their work. AIM. The aim of the study was to assess the prevalence and intensity of pain in the musculoskeletal system in workers who regularly use a portable computer in their work and to determine the influence of working conditions and duration of work with a portable computer. MATERIAL AND METHODS: The study covered 300 workers. Musculoskeletal complaints were assessed with the Nordic musculoskeletal questionnaire complemented with a visual analogue scale. Working conditions was assessed with a questionnaire developed as part of the study. RESULTS AND CONCLUSIONS: The most prevalent faults in the organization of workstations were lack of a computer desk with an adjustable keyboard tray/drawer, no adjustment of chair armrests and no possibility to use an additional keyboard. The most frequent complaints among computer operators were headaches, low-back pain and neck pain. The use of an additional keyboard reduced the intensity of shoulder pain. PMID- 20828490 TI - An ergonomics study of a semiconductors factory in an IDC for improvement in occupational health and safety. AB - The study aimed to conduct an ergonomic intervention on a conventional line (CL) in a semiconductor factory in Malaysia, an industrially developing country (IDC), to improve workers' occupational health and safety (OHS). Low-cost and simple (LCS) ergonomics methods were used (suitable for IDCs), e.g., subjective assessment, direct observation, use of archival data and assessment of noise. It was found that workers were facing noise irritation, neck and back pains and headache in the various processes in the CL. LCS ergonomic interventions to rectify the problems included installing noise insulating covers, providing earplugs, installing elevated platforms, slanting visual display terminals and installing extra exhaust fans. The interventions cost less than 3 000 USD but they significantly improved workers' OHS, which directly correlated with an improvement in working conditions and job satisfaction. The findings are useful in solving OHS problems in electronics industries in IDCs as they share similar manufacturing processes, problems and limitations. PMID- 20828491 TI - Electromagnetic action of heavy-current equipment operating with power frequency. AB - The paper presents an analysis of the effect of magnetic fields of power frequency generated by heavy-current electric equipment on the environment. The results of computation and measurements of the magnetic field in the vicinity of power busducts are included. Possible hazards are considered that result from the effects of the magnetic field on workers present in the vicinity of busducts as well as secondary hazards caused by the degrading effect of the magnetic field on ferromagnetic structural materials (in reinforced concrete structures). Attention is given to an ergonomic aspect of interaction of the magnetic field with cathode ray tube computer monitors (annoying oscillation of the image). PMID- 20828492 TI - Sitting comfort of ergonomic office chairs--developed versus intuitive evaluation. AB - The sitting comfort of office chairs with different ergonomic layouts (inferior, superior) was examined. Fifty participants were randomly assigned to a 2*5 factorial experimental design with 2 different conditions of ergonomic chair layout (inferior or superior) and 5 different conditions of instruction to explore the chair. Four conditions were created to differentiate between various levels of perceptual awareness and processing of chair-related information (guided exploration and developed evaluation). In a 5th condition, participants remained uninstructed (free exploration and intuitive exploration). Under guided exploration, the participants' perception of sitting comfort was in line with objective differences in the chair layout. Different conditions of guided exploration, however, did not influence the evaluations. Under free exploration, the participants' perceptions did not match the ergonomic chair layout. In contrast to participants under guided exploration, they even rated the ergonomically inferior office chair more favourably than the ergonomically superior chair. PMID- 20828493 TI - Work environment and production development in Swedish manufacturing industry. AB - Swedish manufacturing industry has previous held a leading position regarding the development of attractive industrial work environments, but increasing market competition has changed the possibilities to maintain the position. The purpose of this literature study is therefore to describe and analyze how Swedish manufacturing industry manages work environment and production development in the new millennium. The description and analysis is based on recently reported Swedish research and development. The gathered picture of how production systems generally are developed in Sweden strongly contrasts against the idealized theoretical and legal view of how production systems should be developed. Even if some of the researchers' and authorities' ambitions and demands may seem unrealistically high today, there still is a very large potential for improving the processes and tools for designing production systems and work environment. PMID- 20828494 TI - A review of technology of personal heating garments. AB - Modern technology makes garments smart, which can help a wearer to manage in specific situations by improving the functionality of the garments. The personal heating garment (PHG) widens the operating temperature range of the garment and improves its protection against the cold. This paper describes several kinds of PHGs worldwide; their advantages and disadvantages are also addressed. Some challenges and suggestions are finally addressed with regard to the development of PHGs. PMID- 20828495 TI - Osteosarcoma of the inferior turbinate. PMID- 20828496 TI - 30-year Delayed presentation of hyoid strangulation fracture. PMID- 20828497 TI - Bilateral otosclerosis in a child with esophageal atresia, protruding ears, hyperopia, clinodactyly, and broad thumbs: a unique clinical presentation. PMID- 20828498 TI - Postoperative facial paralysis on the side contralateral to head and neck surgery. PMID- 20828499 TI - Adenoid cystic carcinoma of the pterygopalatine fossa presenting as facial pain. PMID- 20828501 TI - Synchronous Thyroid/parathyroid Carcinomas. PMID- 20828500 TI - Laryngeal epithelial-myoepithelial carcinoma treated with partial laryngectomy. PMID- 20828502 TI - Oncocytic lipoadenoma of the parotid gland with sebaceous differentiation in a 73 year-old male. PMID- 20828503 TI - Mycobacterium Avium-intracellulare Sinusitis. PMID- 20828504 TI - Clearing up clear cell tumours of the head and neck: differentiation of hyalinizing and odontogenic varieties. PMID- 20828505 TI - Undifferentiated high-grade pleomorphic sarcoma of the face. PMID- 20828506 TI - Squamous cell carcinoma arising in a proliferating pilar (trichilemmal) cyst with nodal and distant metastases. PMID- 20828507 TI - Tonsillar hairy polyp. PMID- 20828508 TI - Canadian position statement on bilateral cochlear implantation. PMID- 20828509 TI - Asymmetric sudden sensorineural hearing loss: is all this testing necessary? AB - OBJECTIVE: A number of factors have been identified that contribute to the presentation of asymmetric sudden sensorineural hearing loss (ASSNHL). Routinely, patients presenting with ASSNHL undergo a battery of serologic testing and imaging in an attempt to determine a cause. The objective of this study was to assess the utility of this diagnostic evaluation in elucidating a cause of an ASSNHL and to assess the average cost associated with this battery of testing. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care facility. SUBJECTS AND METHODS: Charts from patients presenting to the otolaryngology clinic of a tertiary care facility between December 1, 2002, and November 30, 2007, with ASSNHL confirmed by audiometric evaluation were reviewed. Diagnostic tests included in the workup of ASSNHL and test results were recorded. The percentage of positive tests was determined and compared to national data. Cost analysis of the diagnostic battery was performed. RESULTS: The battery of testing performed for sudden sensorineural hearing loss included antineutrophil antibody, cholesterol, creatinine, anti-DNA antibody, erythrocyte sedimentation rate, blood glucose, Lyme titer, rheumatoid factor, rapid plasmin reagent, triiodothyronine, thyroid-stimulating hormone, and magnetic resonance imaging with gadolinium. The average cost associated with the full diagnostic evaluation is greater than $2000. The diagnostic impact of these tests is extremely low. CONCLUSIONS: The utility of the comprehensive ASSNHL evaluation should be reconsidered. The choice of diagnostic evaluation should be directed by patient risk factors and exposures. PMID- 20828510 TI - Frequency tuning in the tone burst-evoked myogenic potentials in extraocular muscles in normal human subjects. AB - OBJECTIVE: In this cross-sectional study, we investigated the frequency tuning properties of sound-evoked vestibular myogenic potentials in extraocular muscles (OVEMPs) in normal human subjects. METHODS: Acoustic tone bursts (130 dB pSPL, 10 ms plateau, 1 ms rise/fall) with nine frequencies from 125 to 4000 Hz were presented monoaurally to 12 normal subjects while they sat upright and maintained centre gaze. Using surface electrodes, the OVEMPs were recorded at four locations surrounding the contralateral eye (superior, inferior, nasal, and temporal) and were referenced to an electrode placed at the nape of the neck over C7. To measure the amplitudes of the OVEMP, signals from the electrodes were amplified and sampled at 10 kHz and were averaged over 250 repetitions. RESULTS: We found that the OVEMPs recorded at the four sites exhibited similar well-defined frequency tuning with peak amplitude at ~ 1000 Hz. CONCLUSION: Although several studies have examined the frequency tuning of the vestibular evoked myogenic potential measured from the sternocleidomastoid muscles (SVEMP), the reported results are quite variable as regards frequency, which produces peak amplitude. The well-defined OVEMP frequency tuning provides an alternative to the SVEMP for assessing vestibular function via acoustic stimulation. Further studies are needed to identify the extent to which each of the five vestibular end-organs is activated by sound and their contribution to the sound-evoked vestibular myogenic potentials. PMID- 20828511 TI - Hearing impairment and depressive symptoms in an older chinese population. AB - OBJECTIVE: To investigate the association of objectively measured hearing loss and depression in an older Chinese population. DESIGN: Cross-sectional study. SETTING: Screening service provided to the elderly as part of a charity program in collaboration with a local group of medical and audiologic professionals. METHODS: A cross-sectional study was conducted on community-dwelling people aged 60 years or above using pure-tone audiometry in a soundproof environment together with a validated Cantonese version of the Geriatric Depression Scale. The association of hearing loss and depression, together with a number of predisposing factors, was examined with multivariate analysis. The effect of hearing aid use was investigated in some subjects. MAIN OUTCOME MEASURES: The effect of both self-reported hearing impairment and objectively measured hearing loss on depressive symptoms, together with a number of predisposing factors, was examined with multivariate analysis. RESULTS: Excluding those suffering from dementia, 914 people were included. Logistic regression showed that the main predicting factors of depression were poor self-perceived health, measured hearing loss, and female gender. Measured hearing loss gave an odds ratio of 1.649 (95% CI 1.048-2.595). The association of self-reported hearing loss with depression was shown in univariate analysis but not in multivariate analysis. Hearing aid use showed a tendency toward reducing depressive symptom scores. CONCLUSIONS: There is an independent association between depression and measured hearing loss in older Chinese but not between depression and self-reported hearing loss. Self-reported hearing impairment should not replace audiometry in estimating risks of hearing impairment. The use of hearing aids could improve the general well-being of our older population. PMID- 20828512 TI - Predicting hearing thresholds and occupational hearing loss with multiple frequency auditory steady-state responses. AB - OBJECTIVE: An objective investigation is needed to verify the existence and severity of hearing impairments resulting from work-related, noise-induced hearing loss in arbitration of medicolegal aspects. We investigated the accuracy of multiple-frequency auditory steady-state responses (Mf-ASSRs) between subjects with sensorineural hearing loss (SNHL) with and without occupational noise exposure. DESIGN: Cross-sectional study. SETTING: Tertiary referral medical centre. METHODS: Pure-tone audiometry and Mf-ASSRs were recorded in 88 subjects (34 patients had occupational noise-induced hearing loss [NIHL], 36 patients had SNHL without noise exposure, and 18 volunteers were normal controls). MAIN OUTCOME MEASURES: Inter- and intragroup comparisons were made. A predicting equation was derived using multiple linear regression analysis. RESULTS: ASSRs and pure-tone thresholds (PTTs) showed a strong correlation for all subjects (r = .77 ~ .94). The relationship is demonstrated by the equationThe differences between the ASSR and PTT were significantly higher for the NIHL group than for the subjects with non-noise-induced SNHL (p < .001). CONCLUSIONS: Mf-ASSR is a promising tool for objectively evaluating hearing thresholds. Predictive value may be lower in subjects with occupational hearing loss. Regardless of carrier frequencies, the severity of hearing loss affects the steady-state response. Moreover, the ASSR may assist in detecting noise-induced injury of the auditory pathway. A multiple linear regression equation to accurately predict thresholds was shown that takes into consideration all effect factors. PMID- 20828513 TI - Expression of aquaporin-1 in nasopharyngeal cancer tissues. AB - OBJECTIVE: To investigate the expression of aquaporin-1 (AQP1) in nasopharyngeal tumour and nontumour tissues. METHOD: Thirty nasopharyngeal biopsy samples were collected and examined with both immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction (RT-PCR) to detect the expression level of AQP1 in tissues. RESULTS: Immunohistochemistry data suggested that AQP1 was expressed in both nasopharyngeal tumour and normal tissues, but tumour tissues were stained a lot stronger than nontumour tissues. RT-PCR analysis further confirmed the overexpression of AQP1 in tumour tissues; migrated tumour tissue had even higher expression. CONCLUSION: The expression level of aquaporin-1 in nasopharyngeal cancer tissue could be involved in tumour migration. PMID- 20828514 TI - Transfusion as a predictor of recurrence and survival in head and neck cancer surgery patients. AB - OBJECTIVE: There is mixed evidence regarding the association of perioperative blood transfusion to disease recurrence and mortality in head and neck cancer patients. Moreover, few investigations have examined the effects of leukocyte depleted (leukodepleted) red cell transfusion. The presented study was undertaken to ascertain whether perioperative transfusion of leukodepleted blood is associated with recurrence and survival in head and neck cancer surgery patients. METHODS: The records of all patients having undergone head and neck surgery for malignant disease between October 1996 and October 2002 were reviewed. Hospital, blood bank, and cancer registry database records were reviewed and data were recorded onto a standardized computer spreadsheet. The primary outcome variable was the number of perioperatively transfused units of allogeneic leukodepleted blood. Multivariate analysis and Cox regression methods were employed. RESULTS: Five hundred twenty patients met the criteria for inclusion in the study. Recurrence and mortality rates were significantly different between transfusion and no-transfusion groups, in favour of the no-transfusion group. In addition to age, T stage, and N stage, multivariate analysis revealed leukodepleted blood transfusion to be an independent predictor of both recurrence (odds ratio 1.6) and survival (hazard ratio 1.5). CONCLUSION: Perioperative transfusion of leukodepleted blood is associated with higher recurrence rates and decreased survival in head and neck cancer surgery. PMID- 20828515 TI - Survey of current functional outcomes assessment practices in patients with head and neck cancer: initial project of the head and neck research network. AB - BACKGROUND: Functional outcomes assessment has become increasingly important in informing treatment decisions in the area of head and neck cancer. However, consistency of assessment methods across studies has been lacking. For the literature to inform clinical decision making, consensus regarding outcomes measurements is necessary. OBJECTIVE: The Head and Neck Research Network (HNRN) was founded in January 2008 to become a conduit for high-quality research in the area of functional outcomes in patients with head and neck defects. The present study surveyed experts in functional outcomes assessment to determine what are considered the most important tools for assessing speech and swallowing and what background patient characteristics are important to capture. DESIGN, PARTICIPANTS, AND MEASURES: Respondents to the online survey included 54 participants with a background in speech-language pathology, with the majority of respondents from the United States, Canada, and the United Kingdom. RESULTS AND CONCLUSIONS: The results from the survey indicated that clinicians consider both subjective and objective measures as important to use when assessing function. More advanced technical tools were often rated as less important; however, it also was noted that clinicians were most often not able to access these tools or were unfamiliar with them. PMID- 20828516 TI - Systematic review of cases reporting blood extravasation-related complications after thyroid fine-needle biopsy. AB - OBJECTIVE: Thyroid fine-needle biopsy (FNB) is the procedure of choice in the preoperative management of thyroid nodules because of its accuracy and cost effectiveness. Minor hematomas are the most common complications, but their morbidity is usually negligible. On the other hand, massive hematomas seem to be rare, but life-threatening, if the performer is unaware or careless and the patient is not adequately informed. In this review, we tried to summarize all reported blood extravasation-related post-FNB complications (hemorrhage, hematomas, and secondary hemangiomas) and provide useful hints to avoid them. DESIGN: Systematic review of the literature. SETTING: Second Medical Clinic of Aristotle University of Thessaloniki in Greece. METHODS: Computerized advanced search for primary evidence was performed in the PubMed (Public/Publisher MEDLINE) electronic database. The search was not limited by publication time or English language. RESULTS: The reported incidence of blood extravasation-related complications during or after FNB ranges between 1.9 and 6.4% in different studies. This variability is possibly due to definition or record biases. Intranodular hemorrhage within the cystic part of complex nodules following fluid aspiration seems to be even more frequent. Seven cases of post-FNB life threatening massive hematomas resulting in airway obstruction were found as well as four described cases with secondary hemangioma attributed to FNB. CONCLUSIONS: Despite the potential risk of post-FNB hemorrhage, hematomas, or secondary hemangiomas, the overall usefulness and safety of FNB are not questionable, considering the large number of FNBs performed worldwide everyday. PMID- 20828517 TI - Immunohistochemical localization of glutathione s-transferase isoenzymes (gsta, Gstp, Gstm4, And Gstt1) and tumour marker p53 in matched tissue from normal larynx and laryngeal carcinoma: correlations with prognostic factors. AB - OBJECTIVE: The immunohistochemical staining characteristics of glutathione S transferase (GST) alpha (GSTA), pi (GSTP), mu (GSTM4), and theta (GSTT1) and P53 were investigated in laryngeal squamous cell carcinoma (LSCC) cases and normal laryngeal tissue from 46 patients. The relationships between expression of the GST isoenzymes and some clinicopathologic features were also examined. PATIENTS AND METHODS: For immunohistochemical studies, tissues from 46 patients with LSCC at the Dr. Lutfi Kirdar Kartal Education and Research Hospital were used. The relationship between expression of the GST isoenzymes and P53 in normal and tumour tissue was analyzed using the Wilcoxon signed rank test. The correlation between GST isoenzymes and P53 and clinicopathologic data was also examined using the Spearman rank test. RESULTS: When the normal and tumour tissues of these cases were compared according to their staining intensity and percentage of positive staining, GSTA expression in normal cells was significantly higher than in tumour cells, and GSTP and P53 expression was higher in tumour cells (p < .05). GSTM and GSTT1 expression was higher in normal cells; however, the statistical significance was low (p > .05). There was no correlation between P53 and GST expression in patients with LSCC. When the immunohistochemical results of GST isoenzymes and P53 were correlated with the clinical parameters, GSTA expression was increased in poorly differentiated laryngeal tumour, but GSTM4 and GSTT1 expression was decreased (p < .05). CONCLUSION: According to these results, GST-A, -P, and T1 and P53 were important in the diagnosis of LSCC. PMID- 20828518 TI - Location of parathyroid adenomas: 7-year experience. AB - OBJECTIVE: To determine the most common location of parathyroid adenomas. METHODS: Data from 147 patients who underwent parathyroidectomy for primary hyperparathyroidism in Montreal at a McGill University teaching hospital between January 2001 and January 2008 were reviewed retrospectively. Patients with histopathologic confirmation of parathyroid hyperplasia were excluded from the study (n = 26). The 121 patients with confirmed adenomas were grouped according to the locations of the tumour into right superior, right inferior, left superior, left inferior, and ectopic. RESULTS: The left inferior parathyroid glands were the most common site of adenomas. This was the case for 50 patients (41.32% [mean 0.41; 95% CI 0.324-0.506]). The right inferior parathyroid glands were the site in 40 patients (33.06% [mean 0.33; 95% CI 0.248-0.422]). The remainder of the adenomas were distributed as follows: the left superior in 19 patients (15.7% [mean 0.157; 95% CI 0.097-0.234]), the right superior in 10 patients (8.26% [mean 0.0826; 95% CI 0.040-0.147]), and the ectopic in 2 patients (1.65% [mean 0.0165; 95% CI 0.002-0.058]). CONCLUSIONS: In this study, the most common site of adenoma was the left inferior parathyroid gland. This information provides parathyroid surgeons with a starting point when imaging fails to localize the site of the adenoma, which allows for the possibility of minimally invasive surgery especially if used in conjunction with intraoperative parathyroid hormone. PMID- 20828519 TI - Cancer prevalence and education by cancer site: logistic regression analysis. AB - BACKGROUND: Previously, using the American National Health Interview Survey (NHIS) and a logistic regression analysis, we found that upper aerodigestive tract (UADT) cancer is correlated with low socioeconomic status (SES). The objective of this study was to determine if this correlation between low SES and cancer prevalence exists for other cancers. METHODS: We again used the NHIS and employed education level as our main measure of SES. We controlled for potentially confounding factors, including smoking status and alcohol consumption. RESULTS: We found that only two cancer subsites shared the pattern of increased prevalence with low education level and decreased prevalence with high education level: UADT cancer and cervical cancer. CONCLUSIONS: UADT cancer and cervical cancer were the only two cancers identified that had a link between prevalence and lower education level. This raises the possibility that an associated risk factor for the two cancers is causing the relationship between lower education level and prevalence. PMID- 20828520 TI - Free tissue transfer flap reconstruction of parotidectomy defects: outcomes analysis and the utility of three-dimensional laser surface scans. AB - BACKGROUND: Tumours of the parotid gland are generally managed surgically without reconstruction. The usual long-term outcomes of these techniques are facial scars, asymmetry, and permanent contour deficits. These cosmetic deformities can significantly affect patients' self-image and negatively impact their quality of life. Free tissue transfers have been used increasingly over the past years to improve patients' cosmetic and satisfaction outcomes. OBJECTIVE: The purpose of this study was to evaluate the cosmetic and symmetry outcomes of patients undergoing free flap reconstruction after parotid surgery. METHODS: The study was approved by the ethics review board at the University of Alberta. All patients undergoing total parotid surgery were offered a free flap tissue transfer reconstructive procedure. Seven consecutive patients undergoing the reconstruction option were included in the study. The control group was composed of seven patients who had undergone total parotid surgery without reconstruction. Data regarding demographics, surgical procedure, pathology, and postoperative complications were collected. Facial symmetry was evaluated with questionnaires and laser surface scanning. RESULTS: There were no statistically significant differences between the two groups with regard to age, sex, timing of surgery, or pathology. The reconstructed patients tended to perceive a better symmetry when compared to the nonreconstructed patients (p = .0014). The reconstructed patients had all experienced a slight volume increase on the operative side compared to the contralateral side, with a mean difference of 4.99% increase in volume. Conversely, the nonreconstructed patients all experienced a notable volume deficit on the operative side compared to the nonoperative side-an average 12.15% volume loss was seen postoperatively. This difference was statistically significant (p <= .0001). CONCLUSIONS: Free tissue transfer reconstruction is an effective means of reconstructing postparotidectomy defects in patients for whom facial volume asymmetry is a concern. PMID- 20828521 TI - Clinical utility of colour flow Doppler ultrasonography in planning anterolateral thigh flap harvest. AB - BACKGROUND: The anatomic variability of cutaneous perforators contributes to the technical challenges of anterolateral thigh (ALT) free flap harvest. The objective of this study was to assess the accuracy and clinical utility of preoperative colour flow Doppler (CFD) ultrasonography in evaluating planned ALT flap donor sites. METHODS: A prospective study of the infrainguinal vasculature (profunda femoris and lateral circumflex femoral arteries) in 16 consecutive patients scheduled for ALT free flap transfer for reconstruction of head and neck surgical defects was undertaken. All patients underwent CFD ultrasonography. The location of perforators and the thigh thickness determined by CFD ultrasonography were correlated with the actual intraoperative findings using a scatter plot and paired t-test. RESULTS: Two patients were diagnosed with bilateral silent infrainguinal claudication, which precluded safe use of the ALT donor site. In two other patients, the planned ALT donor site ipsilateral to the defect was not used because of silent infrainguinal claudication diagnosed by CFD ultrasonography. In the 14 patients who underwent ALT flap harvest, CFD ultrasonography identified 48 perforators, which coincided with 43 actual perforators found intraoperatively. CFD ultrasonography demonstrated a statistically significant correlation with the actual perforator locations (Spearman coefficient .76; p = .55). Although CFD ultrasonography tended to underestimate flap thickness, there was a statistically significant correlation (Spearman coefficient .94; p <= .0001) with the actual flap thickness. CONCLUSION: CFD ultrasonography has clinical utility in facilitating decision making and planning ALT flap harvest. PMID- 20828522 TI - The scapular free flap: when versatility is needed in head and neck reconstruction. AB - OBJECTIVE: To review the experience with scapular free tissue transfer at the University of Western Ontario and to describe the various applications of both the fasciocutaneous and osteocutaneous versions. DESIGN: Retrospective review. SETTING: Tertiary care centre. METHODS: A retrospective review was conducted of patients who underwent a scapular free flap reconstruction between 1997 and 2007. Osteocutaneous and fasciocutaneous flaps were included. Demographic data including gender and age were collected. Defect analysis and complications were also reviewed. MAIN OUTCOME MEASURES: Defect analysis, flap-related complications, and non-flap-related complications. RESULTS: Sixty procedures, including 31 osteocutaneous and 29 fasciocutaneous flaps, were performed. Most fasciocutaneous flaps were used for large lateral skull base and facial defects (70%). The skin paddle dimensions ranged from 4 * 3 to 15 * 10 cm. All osteocutaneous flaps were used for mandibular reconstruction. The length of the bony defect ranged between 4 and 12 cm. Eleven patients required osteotomies. In most cases, the facial or external carotid arteries and internal jugular or facial veins were selected as recipient vessels. A vein graft was required in four cases. The total flap failure rate was 5%. Seven patients who had osteocutaneous flaps suffered medical complications, including one mortality. CONCLUSIONS: Scapular free flaps are reliable options. Fasciocutaneous applications are suitable for defects requiring facial contouring or complex skull base defects. Osteocutaneous flaps are acceptable options for patients with comorbidities requiring bony reconstructions. The flap complication rates were acceptable even in medically higher-risk patients. PMID- 20828523 TI - Maxillary bone grafts for the repair of traumatic orbital floor defects. AB - PURPOSE: To present maxillary bone (MB) grafts as a viable option for repair of traumatic orbital floor (TOF) defects by comparing their use to titanium mesh (TM) looking at TOF defect size, operative time, and complication rate. METHODS: The senior author's surgical technique is described. Patients undergoing TOF repair using MB versus TM were assessed retrospectively, focusing on TOF defect size, operative time, and follow-up results. RESULTS: One hundred ninety-six patients with 212 TOF defects presented to a single surgeon between 2004 and 2008. One hundred sixty-five patients (178 TOF defects) were repaired with MB and 31 patients (34 TOF defects) with TM. The MB and TM groups were similar with respect to age, gender, time to repair, and other associated facial fractures. TOF defect size was similar between the two groups (MB: mean 1.7 cm2, range 0.32 2.82 cm2; TM: mean 1.9 cm2, range 0.5-2.83 cm2). Follow-up was slightly longer in the TM group; however, many patients were lost to follow-up. There were no donor site complications in the MB group and no significant difference in postoperative complications in the MB group versus the TM group (11% vs 24%). The operative time in patients with TOF defects was slightly longer in the MB group versus the TM group (35 min vs 27 minutes, p = .02). CONCLUSIONS: This series is the largest published series to date. MB was used successfully to repair TOF defects, with no increased risk of complications and only a slightly longer operative time compared to TM. MB offers an autogenous bone graft source that is technically easy to harvest and in the same surgical field, obviating many of the complications associated with alloplastic materials and traditional bone graft choices. MB grafts should be considered a viable option when choosing material to repair TOF defects. PMID- 20828524 TI - Use of complementary and alternative medical therapies for chronic rhinosinusitis: a canadian perspective. AB - BACKGROUND: Many Canadians use complementary and alternative medicines (CAMs) to treat their chronic diseases. The objective of this study was to report patients' use of CAM for chronic rhinosinusitis (CRS) and to determine factors predictive of CAM use. METHOD: A cross-sectional survey was conducted. Self-report questionnaires were administered to patients with CRS using strict inclusion and exclusion criteria. The questionnaire included demographic information, questions pertaining to disease severity, and CAM use for CRS treatment. Statistical analysis was used to compare gender, age range, symptom duration, pharmacotherapy use, and surgical frequency among CAM users and nonusers. A binomial logistic regression model was developed to predict CAM use. Secondary outcome measures included factors predictive of CAM use, type of CAM used, and reasons for using CAM. RESULTS: Data were obtained from 288 patients. Forty-five respondents (15.6%) had used CAM as a treatment for their CRS. CAM users were more likely to be females and more likely to have used each class of pharmacotherapy. On logistic regression, female gender and use of nasal corticosteroids were predictive of CAM use. CONCLUSION: The use of CAM as treatment of CRS is common. Females and those who have used the various classes of pharmacotherapy are more likely to use CAM. Both female gender and nasal corticosteroid use are predictive of CAM use. Physicians should routinely inquire about CAM use from their patients with CRS. PMID- 20828525 TI - Use of duraseal in repair of cerebrospinal fluid leaks. AB - OBJECTIVE: The purpose of our article is to review the use of the DuraSeal Sealant System (Confluent Surgical Inc., Waltham, MA) in the repair of complex cerebrospinal fluid (CSF) leaks in endoscopic skull-base surgery. DESIGN: Retrospective chart review. SETTING: London Health Sciences Centre. METHODS: A database of endoscopic skull-base cases between 2007 and 2009 that involved CSF leakage repaired with DuraSeal was created. Demographic data and operative reports were collected and analyzed qualitatively. MAIN OUTCOME MEASURES: Recurrence of CSF leak after repair. RESULTS: Five cases were identified that met study criteria. In four of the five cases, the repair was successful. There were no complications related to DuraSeal use. Comparison to a subset of patients using Tisseel Fibrin Sealant (Baxter, Toronto, ON) for repair did not show a significant difference in failure rate (chi2 = 0.029, p = .858). CONCLUSIONS: There are a variety of techniques described to repair CSF rhinorrhea, with various studies demonstrating the advantages of using tissue glues in CSF leak repairs. We used DuraSeal in five patients to enhance graft strength and form a watertight seal. The system was effective in the majority of patients. Our study is the first to report on endoscopic endonasal repair of CSF leaks using DuraSeal. PMID- 20828526 TI - Role of interferon-gamma-producing t cells in the pathogenesis of chronic rhinosinusitis with nasal polyps associated with staphylococcal superantigen. AB - OBJECTIVES: The major aims of this study were to characterize the varieties of T cell infiltrates in tissue collected from patients with chronic rhinosinusitis with nasal polyps (CRSwNP), analyze the cytokine profiles of these infiltrating T cells, and determine whether infiltrating T lymphocytes are specific for superantigens (SAGs). METHODS: Anterior ethmoid sinus mucosa and polyp tissue were collected from 23 patients with CRSwNP, and control anterior ethmoid sinus mucosa were obtained from 20 patients without CRS. Infiltrating cells were isolated from tissue samples and analyzed using flow cytometry, enzyme-linked immunosorbent assay, reverse transcriptase-polymerase chain reaction, and in vitro T-lymphocyte stimulation with Staphylococcus aureus. RESULTS: The mean total numbers and proportions of CD3+, CD4+, and CD8+ T cells were significantly higher in the mucosa and polyp tissue of patients with CRSwNP than in the control group. Most infiltrating T cells in patients with CRSwNP were activated CD45RO+ memory T cells. Furthermore, interferon-gamma (IFN-gamma) expression was significantly higher than interleukin (IL)-10 and IL-4 expression in infiltrating T cells isolated from both the mucosa and the polyp tissue. IFN-gamma also showed significantly greater increases in expression compared to IL-4 and IL-10 when isolated T cells were stimulated with SAGs in vitro. CONCLUSION: IFN-gamma producing T cells could play an important role in CRSwNP when sinonasal chronic inflammation is induced by SAGs. PMID- 20828527 TI - Respiratory complications from nasal packing: systematic review. AB - OBJECTIVE: Patients with posterior nasal packing are thought to be at high risk for the development of respiratory complications. Controversy exists regarding the evidence in that regard; consequently, the level of vital sign monitoring required for these patients is unclear. The objective of this article is to systematically review the literature describing respiratory complications from nasal packing. METHODS: Literature published before July 2009 on Medline and Embase was eligible for inclusion. Original research and review articles whose major topic was nasal packing for epistaxis were included. Nonhuman studies and studies not published in English were excluded. Studies were evaluated for quality using a modified Downs and Black scale. Data regarding respiratory complications of nasal packing were extracted and summarized. RESULTS: Of the 262 studies retrieved, 14 met inclusion criteria (7 case series, 3 cohort studies, and 4 reviews). Six studies discussed pulmonary mechanics, three discussed sleep apnea, two reviews described complications of nasal packing, and three articles focused on the treatment of posterior epistaxis. There was a lack of high-quality literature describing adverse respiratory events following posterior packing. CONCLUSION: The literature regarding development of respiratory complications from posterior packing is mostly based on expert opinion or case series. There is some suggestion that sleep apnea may develop after placement posterior nasal packing, but the severity appears to be mild. Evidence is lacking to support the contention that all patients with posterior packing are at risk for developing adverse respiratory events or require admission to a monitored setting. PMID- 20828528 TI - Computerized voice therapy in hypofunctional dysphonia. AB - OBJECTIVE: The aim of this study was to analyze the efficiency and applicability of the Kay CSL 4500 system with the Sona-Speech II software model 3650 (Kay Pentax, Lincoln Park, NJ) in the voice therapy of patients affected by hypofunctional dysphonia. DESIGN: The study evaluated the effect of visual biofeedback, obtained with the Sona-Speech II software, on dysphonia associated with hypofunction dysphonia. SETTING: The study was conducted with 40 male adults affected by hypofunctional dysphonia in the Otolaryngology Department of the University of Genoa (Italy) between April 2008 and April 2009. METHODS: Before, at the end of, and 3 months after voice therapy, all subjects underwent an otolaryngology visit, videostroboscopy, and voice analysis through the Multi Dimensional Voice Program (Kay Elemetrics, Lincoln Park, NJ) as an evaluation of nasal resonance and the Voice Handicap Index (VHI). Each cycle of rehabilitation was characterized by 30 daily consecutive sessions, each for 25 minutes. During each session, the patient was asked to perform specific computer exercises. MAIN OUTCOME MEASURES: The following acoustic parameters were estimated: average of fundamental frequency, percentage of jitter, shimmer, noise to harmonics ratio, voice turbulence index, soft phonation index, degree of voicelessness, degree of voice breaks, and peak amplitude variation. RESULTS: Our data showed significant (p < .05) improvements in acoustic and other parameters in the patients submitted to voice therapy. CONCLUSIONS: Our preliminary results suggest the applicability and efficiency of the Kay CSL 4500 system in association with the Sona-Speech II software model 3650 in a voice therapy program. PMID- 20828529 TI - Current practices in the management of adductor spasmodic dysphonia. AB - INTRODUCTION: Adductor spasmodic dysphonia (ADSD) is a focal dystonia treated most commonly by chemodenervation of the thyroarytenoid (TA) muscles with botulinum toxin. Currently, there are no consensus guidelines regarding this treatment and the management of ADSD. The objective of this study was to assess current practice patterns among physicians who treat ADSD. METHODS: A cross sectional survey study was conducted regarding treatment choices and specific technical aspects of injection technique and botulinum toxin use. The study population consisted of laryngologists from the Canadian Society of Otolaryngology-Head and Neck Surgery and laryngologists obtained from the American Laryngological Association member database and the American Academy of Otolaryngology-Head and Neck Surgery Neurolaryngology Study Group. RESULTS: An overall response rate of 13% was achieved, with a high absolute number of physicians who manage ADSD responding (n = 37). Most respondents treat ADSD by injecting botulinum toxin type A (Botox) through the cricothyroid membrane submucosally at a mode starting dose of 2.5 units per TA muscle using electromyographic guidance with or without fibre-optic laryngoscopy every 3 to 4 months, with the frequency of reinjection being based on patient symptomatology. There is much variability with regard to starting injection dose, alternate treatments for ADSD, unilateral versus bilateral injections, and guidance technique. Most physicians (36 of 37) share one vial among more than one patient, and some (7 of 37) freeze a reconstituted vial that has remaining toxin for reuse at a later time. CONCLUSIONS: There is considerable variability in treatment practices for the management of ADSD. Further study is warranted to define an optimal therapeutic paradigm. PMID- 20828530 TI - Favorably orienting recombinant proteins to develop amperometric biosensors to diagnose Chagas' disease. AB - Clinical immunoassays often display suitable sensitivity but some lack of specificity or vice versa. As a trade-off between specificity improvement and sensitivity loss, biosensors were designed to perform indirect immunoassays with amperometric detection using tailor-made chimeric receptors to react with the analyte, specific anti-Trypanosoma cruzi immunoglobulin G (IgG). Recombinant chimeras were designed to favor their oriented covalent attachment. This allows the chimeras to properly expose their epitopes, to efficiently capture the analyte, and to withstand severe chemical treatment to reuse the biosensors. By further binding the secondary antibody, horseradish peroxidase-labeled anti-human IgG, in the presence of the soluble mediator and the enzyme substrate, a current that increased with the analyte concentration was measured. Biosensors using the chimeric constructions showed 100% specificity with samples that had revealed false-positive results when using other bioreceptors. A protein bearing a poly Lys chain and thioredoxin as directing elements displayed the highest signal-to noise ratio (P<0.05). The limit of detection was 62 ng ml-1, which is eight times lower than that obtained with a currently used commercial Chagas enzyme-linked immunosorbent assay (ELISA) kit. Reusability of the biosensor was assessed. The signal was approximately 80% of the original one after performing 10 consecutive determinations. PMID- 20828531 TI - Zinc(II)-cyclen polyacrylamide gel electrophoresis for detection of mutations in short Ade/Thy-rich DNA fragments. AB - We describe an improved gel-based method with an additive Zn(2+)-cyclen complex (cyclen, 1,4,7,10-tetraazacyclododecane), Zn(2+)-cyclen-PAGE, for mutation detection in DNA fragments by PCR that contain more than 65% Ade/Thy bases and fewer than 100base pairs (bp). Existing techniques have a problem in analyzing such short Ade/Thy-rich fragments because the duplexes are disrupted and are not detectable due to binding of Zn(2+)-cyclen to Thy bases. In this strategy using a PCR primer with a Gua/Cyt-lined sequence attached at its 5'-end, we successfully detected a mutation in an 86-bp Ade/Thy-rich region of the BRCA1 gene from formalin-fixed paraffin-embedded breast cancer-tissue sections. PMID- 20828532 TI - Solubilized elastin substrate for continuous fluorimetric assay of kinetics of elastases. AB - Elastolysis is central to progression of emphysema and aortic aneurysms. Characterization of steady-state enzyme kinetics of elastolysis is fettered by the insolubility of mature elastin and the polydispersity of solubilized elastin. We prepared a fluor-tagged, 100-kDa fraction (fEln-100) from commercial alpha elastin. It is soluble, less heterogeneous in mass, cross-linked like mature elastin, and likely to retain the capacity of alpha-elastin to self-assemble. fEln-100 has introduced the ability to compare quantitatively the apparent k(cat) and K(m) of elastases. For example, metalloelastase (MMP-12) displays higher apparent affinity for fEln-100, while MMP-2 displays faster catalytic turnover. PMID- 20828533 TI - A reliable method to concentrate circulating DNA. AB - Concentration of circulating DNA probes is required to increase the amount of DNA involved in subsequent study (by polymerase chain reaction, sequencing, and microarray). This work was dedicated to the comparison of five different methods used for concentration of DNA circulating in blood. Precipitation of circulating DNA with acetone in the presence of triethylamine provides minimal DNA loss, high reproducibility, and at least three times higher DNA yield in comparison with the standard ethanol protocol. PMID- 20828534 TI - Tube gel isotachophoresis: a method for quantitative isolation of nucleic acids from diluted solutions. AB - The technique of isotachophoresis is intended for separation of molecules having different electrophoretic mobilities in a nonhomogeneous electric field. Since the mobility of nucleic acids in water solutions is uniform and does not depend on their size (because of a uniform distribution of negatively charged phosphate groups along the molecule), isotachophoresis will concentrate rather than separate them in the mobile borderline zone between the rapid (Cl(-)) and the slow (beta-alanine(-)) anions. This idea served as the basis for elaboration of a novel method for isolation of nucleic acids from diluted solutions. Advantages of the method include quantitative yield (regardless of molecule size), high degree of concentration, and the ability to visually monitor the process. The method may find applications in nucleic acid isolation from highly degraded forensic and clinical samples, from bodily fluids in particular, and thereby promote development of this important direction of diagnostics. PMID- 20828535 TI - Kinetic analysis of the interaction between poly(amidoamine) dendrimers and model lipid membranes. AB - We used fluorescence spectroscopy and surface tensiometry to study the interaction between low-generation (G1 and G4) poly(amidoamine) (PAMAM) dendrimers, potential vehicles for intracellular drug delivery, and model lipid bilayers. Membrane association of fluorescently labeled dendrimers, measured by fluorescence anisotropy, increased with increasing size of the dendrimer and with increasing negative charge density in the membrane, indicating the electrostatic nature of the interaction. When the membrane was doped with pyrene-labeled phosphatidyl glycerol (pyrene-PG), pyrene excimer fluorescence demonstrated a dendrimer-induced selective aggregation of negatively charged lipids when the membrane was in the liquid crystalline state. A nonlinear Stern-Volmer quenching of dendrimer fluorescence with cobalt bromide suggested a dendrimer-induced aggregation of lipid vesicles, which increased with the dendrimer's generation number. Surface tensiometry measurements showed that dendrimers penetrated into the lipid monolayer only at subphysiologic surface pressures (<30mN/m). We conclude that the low-generation PAMAM dendrimers associate with lipid membranes predominantly electrostatically, without significantly compromising the bilayer integrity. They bind stronger to membranes with higher fluidity and lower surface pressure, which are characteristic of rapidly dividing cells. PMID- 20828536 TI - Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. AB - CD26/DPP-4 is abundantly expressed on capillary of inflamed lesion as well as effector T cells. Recently, CD26/dipeptidyl peptidase 4 (DPP-4) inhibition has been used as a novel oral therapeutic approach for patients with type 2 diabetes. While accumulating data indicate that vascular inflammation is a key feature of both micro- and macro-vascular complications in diabetes, the direct role of CD26/DPP-4 in endothelial biology is to be elucidated. We herein showed that proinflammatory cytokines such as tumor necrosis factor or interleukin-1 reduce expression of CD26 on microvascular endothelial cells, and that genetical or pharmacological inhibition of CD26/DPP-4 enhances endothelial growth both in vitro and in vivo. With DPP-4 inhibitors being used widely in the treatment of type 2 diabetes, our data strongly suggest that DPP-4 inhibition plays a pivotal role in endothelial growth and may have a potential role in the recovery of local circulation following diabetic vascular complications. PMID- 20828537 TI - Lifespan extension in Caenorhabditis elegans by DMSO is dependent on sir-2.1 and daf-16. AB - Dimethyl sulfoxide (DMSO) is an important solvent that is widely used in industry and medical studies, as well as in the study of aging, in which it is used as a negative control for lifespan assays; however, our data showed that 0.5% and 2% DMSO extended the lifespan of Caenorhabditis elegans by 24.4% and 23.0% (the first trial), respectively. Treatment with 0.5% DMSO did not affect the progeny number or the lifespan of C. elegans under thermal stress. Using real time reverse transcription-polymerase chain reaction (RT-PCR), we found that the expression levels of hsp-16.2, hsp-70, lys-7, old-1, and sod-5 were enhanced by 2.5, 2.9, 1.3, 2.3, and 4.5-fold, respectively, after treatment with 0.5% DMSO. This suggests that these genes downstream of DAF-16 might function in the lifespan extension properties of DMSO. Using the transgenic strain lys-7::GFP, we found that treatment with 0.5% DMSO also caused expression levels of lys-7 increased by 1.5-fold. Genetic analysis using mutants of aging-related genes showed that lifespan extension in C. elegans by DMSO was dependent on sir-2.1 and daf-16 but not eat-2 or hsf-1. In summary, we report the function and the putative mechanism of DMSO in lifespan extension of C. elegans. This study draws attention to using DMSO as a solvent when conducting aging studies. PMID- 20828538 TI - Cellular impedance measurement as a new tool for poxvirus titration, antibody neutralization testing and evaluation of antiviral substances. AB - Impedance-based biosensing known as real-time cell electronic sensing (RT-CES) belongs to an emerging technology for analyzing the status of cells in vitro. In the present study protocols were developed for an RT-CES-based system (xCELLigenceTM, Roche Applied Science, ACEA Biosciences Inc.) to supplement conventional techniques in pox virology. First, proliferation of cells susceptible to orthopoxviruses was monitored. For virus titration cells were infected with vaccinia virus and cell status, represented by the dimensionless impedance-based cell index (CI), was monitored. A virus-dose dependent decrease in electrical impedance could be shown. Calculation of calibration curves at a suitable CI covering a dynamic range of 4 log enabled the quantification of virus titers in unknown samples. Similarly, antiviral effects could be determined as shown for anti-poxviral agents ST-246 and Cidofovir. Published values for the in vitro concentration that inhibited virus replication by 50% (IC50) could be confirmed while cytotoxicity in effective concentrations was excluded in long term incubation experiments. Finally, an RT-CES-based virus neutralization test was established. Various poxvirus-specific antibodies were examined for their neutralizing activity and a calculation mode for the neutralizing antibody titer was introduced. In summary, the presented RT-CES-based methods outmatch end-point assays by observing the cell population throughout the entire experiment while workload and time to result are reduced. PMID- 20828539 TI - Mechanism of cis-prenyltransferase reaction probed by substrate analogues. AB - Undecaprenyl pyrophosphate synthase (UPPS) is a cis-type prenyltransferases which catalyzes condensation reactions of farnesyl diphosphate (FPP) with eight isopentenyl pyrophosphate (IPP) units to generate C(55) product. In this study, we used two analogues of FPP, 2-fluoro-FPP and [1,1-(2)H(2)]FPP, to probe the reaction mechanism of Escherichia coli UPPS. The reaction rate of 2-fluoro-FPP with IPP under single-turnover condition is similar to that of FPP, consistent with the mechanism without forming a farnesyl carbocation intermediate. Moreover, the deuterium secondary KIE of 0.985+/-0.022 measured for UPPS reaction using [1,1-(2)H(2)]FPP supports the associative transition state. Unlike the sequential mechanism used by trans-prenyltransferases, our data demonstrate E. coli UPPS utilizes the concerted mechanism. PMID- 20828540 TI - Hereditary tyrosinemia type 1 metabolites impair DNA excision repair pathways. AB - Hereditary tyrosinemia type 1 is an autosomal recessive metabolic disorder, which is caused by a defective fumarylacetoacetate hydrolase enzyme, and consequently metabolites such as succinylacetone and p-hydroxyphenylpyruvate accumulate. We used a modified comet assay to determine the effect of these metabolites on base- and nucleotide excision repair pathways. Our results indicate that the metabolites affected the repair mechanisms differently, since the metabolites had a bigger detrimental effect on BER than on NER. PMID- 20828541 TI - Astaxanthin upregulates heme oxygenase-1 expression through ERK1/2 pathway and its protective effect against beta-amyloid-induced cytotoxicity in SH-SY5Y cells. AB - Astaxanthin (ATX), the most abundant flavonoids in propolis, has been proven to exert neuroprotective property against glutamate-induced neurotoxicity and ischemia-reperfusion-induced apoptosis. Previous study have revealed that ATX can rescue PC12 cells from Abeta(25-35)-induced apoptotic death. However, the mechanisms by which ATX mediates its therapeutic effects in vitro are unclear. In the present study, we explored the underlying mechanisms involved in the protective effects of ATX on the Abeta(25-35)-induced cytotoxicity in SH-SY5Y cells. Pre-treatment with ATX for 4h significantly reduced the Abeta(25-35) induced viability loss, apoptotic rate and attenuated Abeta-mediated ROS production. In addition, ATX inhibited Abeta(25-35)-induced lowered membrane potential, decreased Bcl-2/Bax ratio. We also demonstrated that ATX could prevent the activation of p38MAPK kinase pathways induced by Abeta. Moreover, we for the first time have revealed the ATX increased antioxidant enzyme heme oxygenase-1 (HO-1) expression in concentration-dependent and time-dependent manners, which were correlated with its protective effect against Abeta(25-35)-induced injury. Because the inhibitor of HO-1 activity, ZnPP reversed the protective effect of ATX against Abeta(25-35)-induced cell death. We also demonstrated that the specific ERK inhibitor, PD98059, concentration-dependently blocked on ATX-induced HO-1 expression, and meanwhile PD98059 reversed the protective effect of ATX against Abeta25-35-induced cell death. Taken together, these findings suggest that astaxanthin can induce HO-1 expression through activation of ERK signal pathways, thereby protecting the SH-SY5Y cells from Abeta(25-35)-induced oxidative cell death. PMID- 20828543 TI - Deletion of adenosine A1 or A(2A) receptors reduces L-3,4-dihydroxyphenylalanine induced dyskinesia in a model of Parkinson's disease. AB - Adenosine A(2A) receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson's disease (PD). Clinical trials of A(2A) antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A1 receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A1 and/or A(2A) receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A1, A(2A) and double A1-A(2A) knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A1 and A(2A) receptors) or saline were treated daily for 18-21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A1 and A(2A) KOs, but not in A1-A(2A) KOs and caffeine pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6 hydroxydopamine lesioning. Our findings raise the possibility that A1 or A(2A) receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear. PMID- 20828542 TI - Age- and hormone-regulation of opioid peptides and synaptic proteins in the rat dorsal hippocampal formation. AB - Circulating estrogen levels and hippocampal-dependent cognitive functions decline with aging. Moreover, the responses of hippocampal synaptic structure to estrogens differ between aged and young rats. We recently reported that estrogens increase levels of post-synaptic proteins, including PSD-95, and opioid peptides leu-enkephalin and dynorphin in the hippocampus of young animals. However, the influence of ovarian hormones on synaptic protein and opioid peptide levels in the aging hippocampus is understudied. Here, young (3- to 5-month-old), middle aged (9- to 12-month-old), and aged (about 22-month-old) female rats were ovariectomized and then, 4 weeks later, subcutaneously implanted with a silastic capsule containing vehicle or 17beta-estradiol. After 48 h, rats were subcutaneously injected with progesterone or vehicle and sacrificed 1 day later. Coronal sections through the dorsal hippocampus were processed for quantitative peroxidase immunohistochemistry of leu-enkephalin, dynorphin, synaptophysin, and PSD-95. With age, females showed opposing changes in leu-enkephalin and dynorphin levels in the mossy fiber pathway, particularly within the hilus, and regionally specific changes in synaptic protein levels. 17beta-estradiol, with or without progesterone, altered leu-enkephalin levels in the dentate gyrus and synaptophysin levels in the CA1 of young but not middle-aged or aged females. Additionally, 17beta-estradiol decreased synaptophysin levels in the CA3 of middle-aged females. Our results support and extend previous findings indicating 17beta-estradiol modulation of hippocampal opioid peptides and synaptic proteins while demonstrating regional and age-specific effects. Moreover, they lend credence to the "window of opportunity" hypothesis during which hormone replacement can modulate hippocampal structure and circuitry to improve cognitive outcomes. PMID- 20828544 TI - Chronic brain tissue remodeling after stroke in rat: a 1-year multiparametric magnetic resonance imaging study. AB - Rats subjected to 2h of transient middle cerebral artery occlusion were studied temporally over 1 year by magnetic resonance imaging (MRI) and behavioral testing. Multiparameter MRI measures of T(2), T(1), T(1) in the presence of off resonance saturation of the bound proton signal (T(1sat)), apparent diffusion coefficient (ADC) and susceptibility-weighted imaging (SWI) were obtained at 1 day, 1, 2, 3 and 4 weeks, and 3, 6, 9 and 12 months post-ischemia. Regions of interest included: ischemic core (damaged both at 1 day and later); new lesion (normal at 1 day, but damaged later); and recovery (damaged at 1 day, but normal later) areas. Hematoxylin and eosin, Prussian blue and ED-1, a monoclonal antibody murine macrophage marker, stainings were performed for histological assessment. Core area T(2) and ADC values increased until ~6 months, and T(1) and T(1sat) until ~12 months. New lesion area MRI parameter values increased until ~6 months (T(2), T(1) and ADC), or ~1 year (T(1sat)). Lesion area was largest at 1day (mean+/-SD: 37.0+/-13.7mm(2)) and smallest at 1 year (18.1+/-10.5mm(2)). Recovery area was largest at 3 weeks (8.9+/-3.8mm(2)) and smallest at 1year (6.4+/-3.3mm(2)). The ipsilateral/contralateral ventricle area ratio was 0.7+/ 0.2 at 1 day and increased significantly at 1 year (2.4+/-0.7). Iron-laden macrophages, histologically confirmed at 1 year, were detected in the lesion borders by SWI at 3, 6, 9 and 12 months. Our data indicate that MRI detectable changes of ischemia-damaged brain tissue continue for at least 1 year post ischemia. PMID- 20828545 TI - Down-regulation of Nogo receptor promotes functional recovery by enhancing axonal connectivity after experimental stroke in rats. AB - The inability of axons in central nervous system (CNS) to regenerate after injury is related partly to multiple endogenous axon growth inhibitors including Nogo receptor (NgR). This study tested the hypothesis that silencing NgR expression by adenovirus-mediated RNA interference (RNAi) (AD-NgR) may permit axonal connectivity after focal cerebral ischemia in rats. Male Sprague-Dawley rats (250 280g, n=97) were assigned into seven groups: sham, MCAO (24h and 2 weeks), MCAO plus AD-NgR (24h and 2 weeks), and MCAO plus AD-HK (control oligonucleotides) (24h and 2 weeks). After cerebral ischemia, NgR mRNA and protein in the cortex and hippocampus were significantly increased at 24h and 2 weeks. However, in AD NgR treated rats, NgR mRNA and protein were reduced by 40-60% in the cortex and hippocampus at both time points as compared to controls. Although there was no significant difference in the infarct volume between the two groups, the number of midline-crossing fibers projecting to the contralateral red nucleus and corticostriatal fibers in the dorsolateral striatum were increased in AD-NgR injected rats, accompanied by improved behavioral outcomes. Taken together, these results suggest that NgR knockdown may promote CNS axonal regeneration and functional recovery after ischemic cerebral injury. PMID- 20828546 TI - Prediction on liver fibrosis using different APRI thresholds when patient age is a categorical marker in patients with chronic hepatitis B. AB - BACKGROUND: Patient age as a predictive variable plays an important role in some indices and models. It was hypothesized that patient age might be a categorical marker. METHODS: We collected the data of 623 CHB patients with liver biopsies. Two-hundred fifty-two patients could provide the duration of HBsAg-positive. RESULTS: The positive correlation between duration of HBsAg-positive and patient age was statistically significant (r = 0.487, P < 0.001). When the cutoff value of patient age was 33.5 y, the best accuracy for liver fibrosis could be obtained. If we could use APRI threshold value of 0.11 for patients with age <= 35 and 0.18 for those > 35 y, we could correctly identify 110 CHB patients with insignificant fibrosis which were free of liver biopsy. For all CHB patients based on the APRI threshold of 0.11, 75 patients could be safely predicted as insignificant fibrosis. CONCLUSIONS: Many more CHB patients with insignificant fibrosis could be free of liver biopsy when we used different APRI threshold values based on patient age, especially in patients with > 35 y. The study indicated that more attention should be paid to the influence of patient age on fibrosis. PMID- 20828547 TI - Robust CYP2D6 genotype assay including copy number variation using multiplex single-base extension for Asian populations. AB - BACKGROUND: We developed a CYP2D6 genotyping method that includes copy number variation (CNV) and recently known functional haplotypes using multiplex single base extension (SBE). METHODS: Twelve CYP2D6 alleles (*1, *2, *5, *10, *14, *18, *21, *41, *49, *52, *60, and a duplication of CYP2D6) were genotyped using 2 PCR reactions followed by multiplex SBE with 10 primers and singleplex SBE with 1 primer. The result from 758 Korean samples was validated by comparison with the results of direct sequencing or other genotyping methods. We also genotyped 89 Chinese and 122 Vietnamese subjects to determine the presence of recently identified functional alleles. RESULTS: All 12 CYP2D6 alleles, including gene deletion and duplication, were obviously discriminated. The concordance rate was 100% between our method and other methods. Our method also covered over 98% of the CYP2D6 genotypes in Japanese and Chinese subjects based on reported data. In addition to published genotypes, *14, *21, *41, *49, and *52 were found in about 5% in Chinese and Vietnamese. CONCLUSIONS: The CYP2D6 genotyping method may be clinically applicable for Asian populations. The method can be improved easily to cover other ethnic groups by utilizing additional haplotype tagging SNPs. PMID- 20828548 TI - Multiple non-psychiatric effects of phenothiazines: a review. AB - The phenothiazine group of drugs has long been known as antipsychotic drugs and previously it was extensively used for the treatment of anxiety. Several pieces of evidence have shown that they interfere with a variety of cellular processes and in vitro can interact with biomolecules like DNA, proteins etc. Recent reports have also revealed some new properties like antimicrobial, antiprionic, anticancerous activities of certain members of the phenothiazine group. Appropriate clinical application of phenothiazines can be developed in the future after gaining a comprehensive knowledge about their function. Information relating to the toxic and beneficial effects of these drugs has been discussed in this review. PMID- 20828549 TI - Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain. AB - Mu-opioids (i.e. morphine, oxycodone, hydrocodone) are considered to be the primary drugs for treatment of moderate to severe acute, chronic and cancer pain. Despite their analgesic effectiveness they have several clinically significant side-effects (cognitive, motor, respiratory, cardiovascular, gastrointestinal). They also have a limited spectrum of action, being more effective for nociceptive than neuropathic pain. In an effort to identify other opioid analgesics with greater effectiveness in mixed pain states and with a better side-effect profile compared to the classical mu-opioid agonist, morphine, a relatively little-known morphine derivative, morphine-6-O-sulfate, was characterized using a range of well-established rodent pain models. The present data demonstrated that morphine 6-O-sulfate was efficacious after several routes of administration, including neuroaxial (intrathecal), parenteral (intraperitoneal) and oral in the rat. It showed potent, dose-related, analgesic activities against acute nociceptive pain (the tail flick test), neuropathic pain (chronic constriction nerve injury hyperalgesia and allodynia) and inflammatory pain (formalin test). It had a good separation based on dose (at least 10-fold) between side-effects (incoordination, hypolocomotion, inhibition of gastrointestinal motility) and analgesia in all models of pain tested. In addition, morphine-6-O-sulfate had a more favorable potency ratio for delay of gastrointestinal transit and analgesia when compared to morphine. These preclinical findings suggest that morphine-6-O-sulfate is a potential candidate for development as a novel opioid for management of nociceptive, neuropathic and mixed pain states. PMID- 20828550 TI - Berberine ameliorates TNBS-induced colitis by inhibiting lipid peroxidation, enterobacterial growth and NF-kappaB activation. AB - Berberine, which is a major constituent of the rhizome of Coptidis japonica (CJ), inhibits IL-8 production in colonic epithelial cells and improves 2,4,6 trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice. In our preliminary studies, berberine inhibited lipid peroxidation in liposomes prepared from l alpha-phosphatidylcholine as well as TLR-4-linked NF-kappaB activation in HEK cells. Therefore, to clarify its anticolitic mechanism, we examined the inhibitory effects of berberine in TNBS-induced colitic C3H/HeN and C3H/HeJ mice. Its oral administration inhibited macroscopic score, body weight gain, colon shortening, myeloperoxidase activity, and lipid peroxidation in the colons of TNBS-treated C3H/HeN and C3H/HeJ mice. Berberine inhibited colonic expression of iNOS, COX-2, IL-1beta, IL-6, and TNF-alpha, but increased IL-10 expression in the colons of TNBS-treated C3H/HeN and C3H/HeJ mice. Berberine also inhibited NF kappaB activation in TNBS-treated C3H/HeN and C3H/HeJ mice, and inhibited TLR-4 expression in C3H/HeN, but not C3H/HeJ, mice. Treating C3H/HeN and C3H/HeJ mice with berberine significantly reduced the number of Enterobacteriaceae induced by TNBS, but restored the number of Bifidobacteria reduced by TNBS. Furthermore, berberine potently inhibited LPS-induced inflammation in peritoneal macrophages mainly via NF-kappaB and weakly via MAPKs. Based on these findings, berberine may improve colitis by inhibiting lipid peroxidation, enterobacterial growth and NF kappaB activation. PMID- 20828551 TI - Dissecting how receptor tyrosine kinases modulate G protein-coupled receptor function. AB - Receptor tyrosine kinases and G protein-coupled receptors modulate physiological processes and are also involved in the pathogenesis of some diseases. These receptors have intense bidirectional crosstalks leading to interactions in their signaling pathways and also modulation of the receptors themselves. In some cases, the receptor tyrosine kinases phosphorylate G protein-coupled receptors whereas in others phosphoinositide 3-kinase, protein kinase B and protein kinase C are key elements in these crosstalks. Two paracrine/ autocrine processes also participate, i.e., epidermal growth factor transactivation and sphingosine 1 phosphate generation and signaling. G proteins seem to mediate actions of receptor tyrosine kinases, but how this takes place is far from completely understood; some models are presented. Recent data indicate that the mitogen activated protein kinase cascade also mediate crosstalks. In the present perspective these processes are outlined using information from receptors that have been intensively studied, and important gaps in our knowledge are indicated. PMID- 20828552 TI - BAY 41-2272 inhibits the development of chronic hypoxic pulmonary hypertension in rats. AB - The present study investigated whether BAY 41-2272(5-cyclopropyl-2-[1-(2-fluoro benzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-pyrimidin-4-ylamine), a novel pyrazolopyridine that activates guanylyl cyclase and sensitizes the enzyme towards nitric oxide (NO), inhibits the development of pulmonary hypertension. BAY 41-2272 (1 or 10 mg/kg/day) was administered intraperitoneally, and sildenafil (25 mg/kg/day), an inhibitor phosphodiesterase type 5, was given in the drinking water to rats kept under chronic hypobaric hypoxia for two weeks. Right ventricular systolic pressure and hypertrophy, degree of muscularization and relaxation of pulmonary arteries were measured, and immunoblotting was performed. Chronic hypoxia increased right ventricular systolic pressure and expression of soluble guanylyl cyclase and phosphorylated vasodilator-stimulated phosphoprotein (VASP-P(ser239)). BAY 41-2272 prevented hypoxia-induced increase in right ventricular systolic pressure and right ventricular hypertrophy to the same extent as sildenafil. Only sildenafil significantly decreased hypoxia induced muscularization of pulmonary arteries. Expressed relative to soluble guanylyl cyclase expression, VASP-P(ser239) was increased in lungs from rats treated with BAY 41-2272. Acutely BAY 41-2272 caused pulmonary as well as systemic vasodilatation. In the chronic setting systemic blood pressure was not different to baseline at trough after intraperitoneally administered BAY 41-2272. BAY 41-2272 vasorelaxation in isolated pulmonary resistance arteries was inhibited by an inhibitor of guanylyl cyclase, ODQ (1H-[1,2,4] oxadiazolo[4,3 a]quinoxaline-1-one), and of Na(+)-K(+)-ATPase, ouabain. In conclusion, in an adult rat model of chronic hypoxic pulmonary hypertension, BAY 41-2272 to a similar degree as sildenafil prevents pulmonary hypertension. Thus, BAY 41-2272 may provide a novel therapeutic compound for treating chronic hypoxic pulmonary hypertension. PMID- 20828553 TI - The role of caveolin1 and sprouty1 in genistein's regulation of vascular smooth muscle cell and endothelial cell proliferation. AB - Genistein prevents atherosclerosis by exerting protective effects on blood vessels. The aim of this study is to investigate the role of caveolin1 and sprouty1 in the regulation of proliferation of vascular smooth muscle cell (VSMC) and endothelial cell by genistein. Using thiazolyl blue tetrazolium bromide(MTT) and [3H]-TdR assay, we found genistein inhibited angiotensin II-induced proliferation in primary cultured VSMC while it stimulated proliferation of quiescent endothelial cells. The effects were attenuated by caveolin1 or sprouty1 siRNA. Western blot analysis indicated that genistein attenuated the phosphorylation of extracellular regulated kinase1/2(ERK1/2) in angiotensin II induced proliferated VSMC but stimulated the phosphorylation of ERK1/2 in quiescent endothelial cell. Double staining immunofluorescence identified caveolin1 and sprouty1 coexpressed in the cytoplasm of both VSMC and endothelial cell. Genistein increased the expression of caveolin1, p-caveolin1 and sprouty1 in VSMC, while it had opposite effects in quiescent endothelial cell. Co immunoprecipitation suggested that genistein exerted its effects through interaction of caveolin1 and sprouty1. Our results demonstrate that the inhibition of angiotensin II-induced proliferation of VSMC and stimulation of quiescent endothelial cell by genistein are regulated by caveolin1 and sprouty1, which are implemented through Ras/MAPK pathway. PMID- 20828554 TI - S-adenosylmethionine decreases the peak blood alcohol levels 3 h after an acute bolus of ethanol by inducing alcohol metabolizing enzymes in the liver. AB - INTRODUCTION: An alcohol bolus causes the blood alcohol level (BAL) to peak at 1 2 h post ingestion. The ethanol elimination rate is regulated by alcohol metabolizing enzymes, primarily alcohol dehydrogenase (ADH1), acetaldehyde dehydrogenase (ALDH), and cytochrome P450 (CYP2E1). Recently, S adenosylmethionine (SAMe) was found to reduce acute BALs 3 h after an alcohol bolus. The question, then, was: what is the mechanism involved in this reduction of BAL by feeding SAMe? To answer this question, we investigated the changes in ethanol metabolizing enzymes and the epigenetic changes that regulate the expression of these enzymes during acute binge drinking and chronic drinking. METHODS: Rats were fed a bolus of ethanol with or without SAMe, and were sacrificed at 3 h or 12 h after the bolus. RESULTS: RT-PCR and Western blot analyses showed that SAMe significantly induced ADH1 levels in the 3 h liver samples. However, SAMe did not affect the changes in ADH1 protein levels 12 h post bolus. Since SAMe is a methyl donor, it was postulated that the ADH1 gene expression up regulation at 3 h was due to a histone modification induced by methylation from methyl transferases. Dimethylated histone 3 lysine 4 (H3K4me2), a modification responsible for gene expression activation, was found to be significantly increased by SAMe at 3 h post bolus. CONCLUSION: These results correlated with the low BAL found at 3 h post bolus, and support the concept that SAMe increased the gene expression to increase the elimination rate of ethanol in binge drinking by increasing H3K4me2. PMID- 20828555 TI - Endothelial nitric oxide gene polymorphisms, nitric oxide production and coronary artery disease risk in a South Indian population. AB - Nitric oxide (NO) synthesized by vascular endothelial cells, is a vasodilator agent produced from endothelial NO synthase (eNOS). It has been reported that decreased bioavailability of NO plays an important role in the development and progression of atherosclerosis. Electrocardiographically proven 100 patients with acute myocardial infarction and 100 age and sex matched healthy individuals with normal coronary arteries were included for the study. The genotypes of a 27-bp insertion/deletion in intron 4 (eNOS 4b/4a) and G894T polymorphism in exon 7, were determined by PCR analysis based on the banding pattern on gel electrophoresis. The genotype frequencies were calculated following the Hardy Weinberg law. Serum NO level was also estimated by the Griess method. NO levels in AMI patients were higher than those of the healthy subjects (median [interquartile range], (14.36[12.42-15.78]) MUM compared with 11.28[10.32-11.89]) MUM; p<0.001; Mann-Whitney rank sum test, U=285. Mutant "T" allele frequency of the eNOS-G894T polymorphism was found to be comparatively higher (0.29) in AMI patients than among the controls (0.17). The calculated Odds ratio showed that the occurrence of mutant allele "T" was 1.6 fold as frequent in cases than controls [OR=1.6 (95%CI 0.898 to 2.833)]. To conclude, in the present study, (i) NO levels were found to be increased in patients than in controls, (ii) the homozygous mutant (TT) genotype confers genetic susceptibility to coronary artery disease (iii) both the eNOS 4a/b and G894T polymorphisms were not associated with serum NO levels in a South Indian Tamil population. PMID- 20828556 TI - Neutrophil elastase and proteinase 3 trafficking routes in myelomonocytic cells. AB - Neutrophil elastase (NE) and proteinase 3 (PR3) differ in intracellular localization, which may reflect different trafficking mechanisms of the precursor forms when synthesized at immature stages of neutrophils. To shed further light on these mechanisms, we compared the trafficking of precursor NE (proNE) and precursor PR3 (proPR3). Like proNE [1], proPR3 interacted with CD63 upon heterologous co-expression in COS cells but endogenous interaction was not detected although cell surface proNE/proPR3/CD63 were co-endocytosed in myelomonocytic cells. Cell surface proNE/proPR3 turned over more rapidly than cell surface CD63 consistent with processing/degradation of the pro-proteases but recycling of CD63. Colocalization of proNE/proPR3/CD63 with clathrin and Rab 7 suggested trafficking through coated vesicles and late endosomes. Partial caveolar trafficking of proNE/CD63 but not proPR3 was suggested by colocalization with caveolin-1. Blocking the C-terminus of proNE/proPR3 by creating a fusion with FK506 binding protein inhibited endosomal re-uptake of proNE but not proPR3 indicating "pro(C)"-peptide-dependent structural/conformational requirements for proNE but not for proPR3 endocytosis. The NE aminoacid residue Y199 of a proposed NE sorting motif that interacts with AP-3 [2] was not required for proNE processing, sorting or endocytosis in rat basophilic leukemia (RBL) cells expressing heterologous Y199-deleted proNE; this suggests operation of another AP 3-link for proNE targeting. Our results show intracellular multi-step trafficking to be different between proNE and proPR3 consistent with their differential subcellular NE/PR3 localization in neutrophils. PMID- 20828557 TI - Suppression of renal fibrosis by galectin-1 in high glucose-treated renal epithelial cells. AB - Diabetic nephropathy is the most common cause of chronic kidney disease. We investigated the ability of intracellular galectin-1 (Gal-1), a prototype of endogenous lectin, to prevent renal fibrosis by regulating cell signaling under a high glucose (HG) condition. We demonstrated that overexpression of Gal-1 reduces type I collagen (COL1) expression and transcription in human renal epithelial cells under HG conditions and transforming growth factor-beta1 (TGF-beta1) stimulation. Matrix metalloproteinase 1 (MMP1) is stimulated by Gal-1. HG conditions and TGF-beta1 treatment augment expression and nuclear translocation of Gal-1. In contrast, targeted inhibition of Gal-1 expression reduces COL1 expression and increases MMP1 expression. The Smad3 signaling pathway is inhibited, whereas two mitogen-activated protein kinase (MAPK) pathways, p38 and extracellular signal-regulated kinase (ERK), are activated by Gal-1, indicating that Gal-1 regulates these signaling pathways in COL1 production. Using specific inhibitors of Smad3, ERK, and p38 MAPK, we showed that ERK MAPK activated by Gal 1 plays an inhibitory role in COL1 transcription and that activation of the p38 MAPK pathway by Gal-1 plays a negative role in MMP1 production. Taken together, two MAPK pathways are stimulated by increasing levels of Gal-1 in the HG condition, leading to suppression of COL1 expression and increase of MMP1 expression. PMID- 20828558 TI - Identification of cardiomyocyte nuclei and assessment of ploidy for the analysis of cell turnover. AB - Assays to quantify myocardial renewal rely on the accurate identification of cardiomyocyte nuclei. We previously 14C birth dated human cardiomyocytes based on the nuclear localization of cTroponins T and I. A recent report by Kajstura et al. suggested that cTroponin I is only localized to the nucleus in a senescent subpopulation of cardiomyocytes, implying that 14C birth dating of cTroponin T and I positive cell populations underestimates cardiomyocyte renewal in humans. We show here that the isolation of cell nuclei from the heart by flow cytometry with antibodies against cardiac Troponins T and I, as well as pericentriolar material 1 (PCM-1), allows for isolation of close to all cardiomyocyte nuclei, based on ploidy and marker expression. We also present a reassessment of cardiomyocyte ploidy, which has important implications for the analysis of cell turnover, and iododeoxyuridine (IdU) incorporation data. These data provide the foundation for reliable analysis of cardiomyocyte turnover in humans. PMID- 20828559 TI - Genetic regulation of skeletal muscle development. AB - During development, skeletal muscles are established in a highly organized manner, which persists throughout life. Molecular and genetic experiments over the last decades have identified many developmental control genes critical for skeletal muscle formation. Developmental studies have shown that skeletal muscles of the body, limb and head have distinct embryonic and cellular origin, and the genetic regulation at work in these domains and during adult myogenesis are starting to be identified. In this review we will summarize the current knowledge on the regulatory circuits that lead to the establishment of skeletal muscle in these different anatomical regions. PMID- 20828560 TI - Pre-clustered TCR complexes. AB - The T-cell antigen receptor (TCR) is a multisubunit transmembrane complex that mediates the antigen-specific activation of T cells. Using a variety of techniques, several research groups have shown that TCRs are at least partially pre-clustered before antigen binding. These new findings are contradictory to the "classical" view, according to which TCRs are randomly distributed on the cell surface and only associate upon antigen binding. In this review we try to answer the following questions: What are the experimental evidences for the existence of pre-clustered TCRs? How can the TCR pre-clusters be activated upon antigen binding? Which functional consequences for T-cell activation arise from the pre clustering of TCRs. PMID- 20828561 TI - Cytoskeletal cross-talk in the control of T cell antigen receptor signaling. AB - T cell antigen receptor signaling is triggered and controlled in specialized cellular interfaces formed between T cells and antigen-presenting cells named immunological synapses. Both microtubules and actin cytoskeleton rearrange at the immunological synapse in response to T cell receptor triggering, ensuring in turn the accuracy of intracellular signaling. Recent reports show that the cross-talk between the cortical actin cytoskeleton and microtubule networks is key for structuring the immunological synapse and for controlling T cell receptor signaling. Immunological synapse architecture and the interaction between the signaling machinery and various cytoskeletal elements are therefore crucial for the fine-tuning of T cell signaling. PMID- 20828562 TI - Negative regulation of immunoreceptor signaling by protein adapters: Shc proteins join the club. AB - Protein adapters couple surface receptors to multiple intracellular signaling modules by acting as scaffolds for the assembly of multimolecular complexes responsible for the coordination and amplification of signals. Through the spatiotemporally controlled recruitment of mediators with opposite activities (e.g. protein tyrosine kinases and phosphatases), adapters are implicated not only in signal initiation and propagation, but also in feedback loops for signal extinction. Moreover, adaptors specialized in preventing or dampening signaling have been more recently discovered. Here we shall present of brief overview of the principal adaptors which act as negative regulators of TCR and BCR signaling, with a focus of the mechanisms underlying this function. We shall then discuss our recent findings implicating p66Shc and Rai, two members of the Shc family of cytosolic protein adapters, in the negative control of antigen receptor signaling, and their role as gatekeepers of autoimmunity and leukemia. PMID- 20828563 TI - What precedes the initial tyrosine phosphorylation of the high affinity IgE receptor in antigen-activated mast cell? AB - An interaction of multivalent antigen with its IgE bound to the high-affinity IgE receptor (FcepsilonRI) on the surface of mast cells or basophils initiates a series of signaling events leading to degranulation and release of inflammatory mediators. Earlier studies showed that the first biochemically defined step in this signaling cascade is tyrosine phosphorylation of the FcepsilonRI beta subunit by Src family kinase Lyn. However, the processes affecting this step remained elusive. In this review we critically evaluate three current models (transphosphorylation, lipid raft, and our preferential protein tyrosine kinase protein tyrosine phosphatase interplay model) substantiating three different mechanisms of FcepsilonRI phosphorylation. PMID- 20828564 TI - Long range dynamic effects of point-mutations trap a response regulator in an active conformation. AB - When a point-mutation in a protein elicits a functional change, it is most common to assign this change to local structural perturbations. Here we show that point mutations, distant from an essential highly dynamic kinase recognition loop in the response regulator Spo0F, lock this loop in an active conformation. This 'conformational trapping' results in functionally hyperactive Spo0F. Consequently, point-mutations are seen to affect functionally critical motions both close to and far from the mutational site. PMID- 20828565 TI - An aminopeptidase from Streptomyces sp. KK565 degrades beta amyloid monomers, oligomers and fibrils. AB - The accumulation of beta amyloid (Abeta) has been a primary target for Alzheimer disease therapeutic strategies. Previously, we discovered an activity from Streptomyces sp. KK565 growth media that inhibits Abeta aggregation. The active component was an aminopeptidase and named Streptomyces sp. KK565 aminopeptidase (SKAP). SKAP cleaved N-terminal amino-acids of Abeta(1-42) monomer, inhibited formation of fibrils and protected Abeta(1-42)-induced neurotoxicity. Over expression of a human homolog of SKAP, glutamate carboxypeptidase II (hGCPII) in Abeta-oversynthesizing cells dramatically reduced the Abeta levels. These findings suggest a possible role of M28 family peptidases in preventing Abeta deposits in mammalian brain. PMID- 20828566 TI - Interplay between the cpSRP pathway components, the substrate LHCP and the translocase Alb3: an in vivo and in vitro study. AB - The chloroplast signal recognition particle (cpSRP) and its receptor, cpFtsY, posttranslationally target the nuclear-encoded light-harvesting chlorophyll binding proteins (LHCPs) to the translocase Alb3 in the thylakoid membrane. In this study, we analyzed the interplay between the cpSRP pathway components, the substrate protein LHCP and the translocase Alb3 by using in vivo and in vitro techniques. We propose that cpSRP43 is crucial for the binding of LHCP-loaded cpSRP and cpFtsY to Alb3. In addition, our data suggest that a direct interaction between Alb3 and LHCP contributes to the formation of this complex. PMID- 20828567 TI - RNA editing competence of trans-factor MEF1 is modulated by ecotype-specific differences but requires the DYW domain. AB - RNA editing in plant mitochondria posttranscriptionally changes multiple cytidines to uridines. The RNA editing trans-factor MEF1 was identified via ecotype-specific editing polymorphisms in Arabidopsis thaliana. Complementation assays reveal that none of the three amino acid changes between Columbia (Col) and C24 individually alters RNA editing. Only one combination of these polymorphisms lowers editing at two of the three target sites, suggesting additive effects of the involved SNPs. Functional importance of the C-terminal DYW domain was analysed with DYW-truncated and extended constructs. These do not recover RNA editing in protoplasts and regain only low levels in stable transformants. In MEF1, the DYW domain is thus required for full competence in RNA editing and its C-terminus has to be accessible. PMID- 20828568 TI - MEGF10 functions as a receptor for the uptake of amyloid-beta. AB - MEGF10 is predominantly expressed in the brain and known to function as a phagocytic receptor. Here, we provide evidence that MEGF10 is involved in the uptake of amyloid-beta peptide (Abeta42) in the brain. Overexpression of MEGF10 dramatically increased Abeta42 uptake in Hela cells. Knockdown of endogenous MEGF10 expression significantly decreased Abeta42 uptake in N2A neuroblastoma cells. MEGF10-mediated Abeta uptake is mostly dependent on lipid raft endocytosis pathway. Furthermore, site-directed mutagenesis revealed that the conserved cytoplasmic NPxY and YxxO motifs are crucial for MEGF10-mediated uptake of Abeta42 peptide. Thus, the identification of the MEGF10 as a functional receptor that mediates the uptake of amyloid-beta peptide will help elucidate the molecular mechanisms of amlyoid-beta clearance in Alzheimer's disease. PMID- 20828569 TI - Multiple pathways leading from the T-cell antigen receptor to the actin cytoskeleton network. AB - Dynamic rearrangements of the actin cytoskeleton, following T-cell antigen receptor (TCR) engagement, provide the structural matrix and flexibility to enable intracellular signal transduction, cellular and subcellular remodeling, and driving effector functions. Recently developed cutting-edge imaging technologies have facilitated the study of TCR signaling and its role in actin dependent processes. In this review, we describe how TCR signaling cascades induce the activation of actin regulatory proteins and the formation of actin networks, and how actin dynamics is important for T-cell homeostasis, activation, migration, and other effector functions. PMID- 20828570 TI - Paired NK cell receptors controlling NK cytotoxicity. AB - Human natural killer (NK) cells possess an arsenal of receptors programmed to regulate the NK cell functions, once encountering a target cell. In general, the activating receptors mediate cytotoxicity when engaged by their tumor specific, stress induced, virally encoded, or rarely, self ligands. Whereas, the inhibitory receptors bind self molecules, mostly MHC class I, presented on all normal and healthy nucleated cells. However, NK cells also possess numerous, highly homologous, pairs of receptors that sometimes even share the same ligands but display divergent functions. In this review we describe the NK cell repertoire of paired receptors and discuss questions regarding their function and mode of action. We focus primarily on the three PVR-binding receptors; the co-stimulatory DNAM1 and CD96 and the inhibitory TIGIT. PMID- 20828571 TI - CD46 signaling in T cells: linking pathogens with polarity. AB - CD46 is a cell surface protein that regulates complement activity and is utilized as a receptor by numerous viral and bacterial pathogens that infect humans. CD46 is not just an entry site for pathogens, but can affect various cellular activities in response to pathogen binding that can have profound consequences for the host response to infection. The study of CD46 signaling in T cells has emerged as an exciting area of research that is shedding new light on how pathogens might manipulate the host immune response. This review will focus on our current understanding of CD46 signaling in T cell polarity and how this might influence disease outcome. PMID- 20828572 TI - Importin beta3 mediates the nuclear import of human ribosomal protein L7 through its interaction with the multifaceted basic clusters of L7. AB - We show that importin beta3 is essential for the nuclear import of L7. The import is mediated via the multifaceted basic amino acid clusters present in the NH(2) region of L7, and is RanGTP-dependent. Using a (EGFP)(3) reporter system and a FRAP assay, the role the individual clusters play as a functional NLS has been characterized, and each cluster was found to exhibit a different rate of real time nuclear uptake. We assume that having such a multiple NLS may provide L7 with preferential nuclear uptake. PMID- 20828573 TI - Fas activation in adipocytes impairs insulin-stimulated glucose uptake by reducing Akt. AB - Fas (CD95) belongs to the superfamily of the tumor necrosis factor (TNF) receptors. Besides its key role in apoptosis, Fas contributes to non-apoptotic pathways such as cell proliferation and inflammation. In 3T3-L1 adipocytes, activation of Fas by Fas ligand decreased insulin-stimulated glucose uptake, without affecting cell viability. This decrease in glucose uptake was accompanied by reduced protein expression and diminished phosphorylation of Akt. Similarly, insulin-stimulated glucose incorporation and protein levels of Akt were increased in isolated adipocytes from Fas deficient mice when compared to wild-type mice. In conclusion, Fas activation in adipocytes decreases Akt expression and thereby impairs insulin sensitivity. PMID- 20828574 TI - Patterns of testicular activity in captive and wild Canada lynx (Lynx canadensis). AB - Canada lynx are listed as a threatened species in the contiguous US. Understanding the reproductive characteristics (i.e., mating system, behavior, physiology) of a species is useful for ensuring effective in situ and ex situ management plans. The goal of this study was to describe patterns of androgen expression in both captive and wild male Canada lynx using fecal hormone metabolite analysis. Among captive lynx, juvenile and castrated males had lower concentrations of fecal androgens (fA) than intact males, thereby demonstrating that the assay detects biologically meaningful differences in testicular activity. We found that captive males in general had much higher fA levels than wild males. All males showed strong seasonal variation in fA concentrations, with significantly higher levels being expressed during the breeding season (February and March) than during the non-breeding season. Among captive males, variation in seasonal fA levels did not correlate with latitude. Finally, males housed with intact cage-mates (either male or female) had significantly higher fA levels than males housed alone or with a neutered cage-mate. PMID- 20828575 TI - Coincident parasite and CD8 T cell sequestration is required for development of experimental cerebral malaria. AB - Cerebral malaria (CM) is a fatal complication of Plasmodium falciparum infection. Using a well defined murine model, we observed the effect on disease outcome of temporarily reducing parasite burden by anti-malarial drug treatment. The anti malarial treatment regime chosen decreased parasitaemia but did not cure the mice, allowing recrudescence of parasites. These mice were protected against CM, despite their parasitaemia having increased, following treatment cessation, to levels surpassing that associated with CM in mice not treated with the drug. The protection was associated with reduced levels of cytokines, chemokines, CD8(+) T cells and parasites in the brain. The results suggest that the development of the immunopathological response that causes CM depends on a continuous stimulus provided by parasitised red blood cells, either circulating or sequestered in small vessels. PMID- 20828577 TI - The impact of maturation delay of mosquitoes on the transmission of West Nile virus. AB - We formulate and analyze a delay differential equation model for the transmission of West Nile virus between vector mosquitoes and avian hosts that incorporates maturation delay for mosquitoes. The maturation time from eggs to adult mosquitoes is sensitive to weather conditions, in particular the temperature, and the model allows us to investigate the impact of this maturation time on transmission dynamics of the virus among mosquitoes and birds. Numerical results of the model show that a combination of the maturation time and the vertical transmission of the virus in mosquitoes has substantial influence on the abundance and number of infection peaks of the infectious mosquitoes. PMID- 20828576 TI - Population genetic structure and history of a generalist parasite infecting multiple sympatric host species. AB - Host specificity is predicted to shape patterns of parasite gene flow between host species; specialist parasites should have low gene flow between host species, while generalists are predicted to have high gene flow between species. However, even for generalist parasites external forces, including ecological differences between host species may sometimes intervene to limit gene flow and create genetic structure. To investigate the potential for cryptic parasite genetic structure to arise under such circumstances, we examined the population genetic structure and history of the generalist nematode, Trichostrongylus axei, infecting six sympatric wild ungulate species in North America. Using genotypes for 186 T. axei larvae at two mitochondrial genes, cox1 and nad4, we found that T. axei was completely panmictic across host species, with 0% of genetic variation structured between host species and 97% within individual hosts. In addition, T. axei showed no evidence of recent genetic bottlenecks, had high nucleotide diversities (above 2%), and an effective population size estimated to be in the tens of millions. Our result that T. axei maintains high rates of gene flow between multiple sympatric host species adds to a growing body of information on trichostrongylid population genetic structure in different ecological contexts. Furthermore, the high rates of gene flow, coupled with high levels of genetic diversity and large effective population size which we observed in T. axei, point to a potentially broad capacity for rapid evolutionary change in this parasite. PMID- 20828578 TI - The autonomic stress-induced hyperthermia response is not enhanced by several anxiogenic drugs. AB - While anxiety models are often based on locomotor activity responses, the stress induced hyperthermia (SIH) paradigm uses the autonomic stress response by measuring body temperature. The effects of putative anxiogenic compounds in the SIH paradigm are inconclusive in mice and have not been examined in rats. Furthermore, it has been suggested that drug-induced effects on body temperature could be dependent on locomotor activity levels. Therefore, the effects of three anxiogenic substances, yohimbine (an alpha(2) receptor antagonist), mCPP (a 5HT(2C) receptor agonist) and FG-7142 (a GABA(A) receptor inverse agonist acting at the benzodiazepine site) on the stress-induced body temperature and locomotor activity response were studied in rats using novel cage stress. All anxiogenic compounds resulted in hypothermia. In contrast, FG-7142 and yohimbine increased locomotor activity levels, whereas mCPP reduced locomotor activity levels. The lack of an increased body temperature response of anxiogenic compounds indicates that the anxiogenic capacity of a drug does not necessarily yield increased autonomic stress responsivity. Moreover, the present study shows that a drug induced decreased body temperature can be accompanied by increased locomotor activity, suggesting that both parameters represent independent parameters of the stress response. PMID- 20828579 TI - Satiety and eating patterns in two species of constricting snakes. AB - Satiety has been studied extensively in mammals, birds and fish but very little information exists on reptiles. Here we investigate time-dependent satiation in two species of constricting snakes, ball pythons (Python regius) and yellow anacondas (Eunectes notaeus). Satiation was shown to depend on both fasting time and prey size. In the ball pythons fed with mice of a relative prey mass RPM (mass of the prey/mass of the snake*100) of 15%, we observed a satiety response that developed between 6 and 12h after feeding, but after 24h pythons regained their appetite. With an RPM of 10% the pythons kept eating throughout the experiment. The anacondas showed a non-significant tendency for satiety to develop between 6 and 12h after ingesting a prey of 20% RPM. Unlike pythons, anacondas remained satiated after 24h. Handling time (from strike until prey swallowed) increased with RPM. We also found a significant decrease in handling time between the first and the second prey and a positive correlation between handling time and the mass of the snake. PMID- 20828580 TI - Teach to reach: the effects of active vs. passive reaching experiences on action and perception. AB - Reaching is an important and early emerging motor skill that allows infants to interact with the physical and social world. However, few studies have considered how reaching experiences shape infants' own motor development and their perception of actions performed by others. In the current study, two groups of infants received daily parent guided play sessions over a 2-weeks training period. Using "Sticky Mittens", one group was enabled to independently pick up objects whereas the other group only passively observed their parent's actions on objects. Following training, infants' manual and visual exploration of objects, agents, and actions in a live and a televised context were assessed. Our results showed that only infants who experienced independent object apprehension advanced in their reaching behavior, and showed changes in their visual exploration of agents and objects in a live setting. Passive observation was not sufficient to change infants' behavior. To our surprise, the effects of the training did not seem to generalize to a televised observation context. Together, our results suggest that early motor training can jump-start infants' transition into reaching and inform their perception of others' actions. PMID- 20828581 TI - Signal detection theory, uncertainty, and Poisson-like population codes. AB - The juxtaposition of established signal detection theory models of perception and more recent claims about the encoding of uncertainty in perception is a rich source of confusion. Are the latter simply a rehash of the former? Here, we make an attempt to distinguish precisely between optimal and probabilistic computation. In optimal computation, the observer minimizes the expected cost under a posterior probability distribution. In probabilistic computation, the observer uses higher moments of the likelihood function of the stimulus on a trial-by-trial basis. Computation can be optimal without being probabilistic, and vice versa. Most signal detection theory models describe optimal computation. Behavioral data only provide evidence for a neural representation of uncertainty if they are best described by a model of probabilistic computation. We argue that single-neuron activity sometimes suffices for optimal computation, but never for probabilistic computation. A population code is needed instead. Not every population code is equally suitable, because nuisance parameters have to be marginalized out. This problem is solved by Poisson-like, but not by Gaussian variability. Finally, we build a dictionary between signal detection theory quantities and Poisson-like population quantities. PMID- 20828582 TI - Single high dose treatment with methotrexate causes long-lasting cognitive dysfunction in laboratory rodents. AB - Clinical studies have suggested that cognitive impairment due to chemotherapy persists long after treatment cessation. While animal studies have similarly found impairments in cognition due to chemotherapy, these studies are limited as they only assess the acute or extremely short-term effects of chemotherapy on cognition (e.g. within 1month of treatment). Male hooded Wistar rats (N=22) received either a high dose of methotrexate (MTX: 250mg/kg i.p.) or physiological saline. Cognitive performance was evaluated acutely at 2weeks, and up to 8months post injection using the Morris water maze, Novel object recognition task, and an instrumental go/no-go task to assess discrimination learning. MTX-treated rats displayed impaired novel object recognition compared to controls at 11, 95, and 255days after treatment. MTX rats were able to learn the hidden spatial location of a platform 22days after treatment. When tested again after a 95-day retention interval, MTX rats showed impaired spatial memory compared to controls, but were subsequently able to re-learn the task. Finally, MTX-treated rats showed considerable difficulty learning to inhibit their behaviour in an instrumental discrimination task. These results show that chemotherapy produces persistent but subtle cognitive deficits in laboratory rodents that vary with time post treatment. PMID- 20828583 TI - Participation in health check-ups and mortality using propensity score matched cohort analyses. AB - OBJECTIVE: All Japanese aged >=40 years are eligible for free annual health check ups including blood pressure and cholesterol measurements. It is well known that health check-up screenees are more likely to have healthy lifestyles and better health conditions than non-screenees. Therefore, controlling these factors is required to investigate whether screenees have a lower mortality risk than non screenees independent of their lifestyles or health conditions. METHODS: We followed 48,775 Japanese National Health Insurance beneficiaries aged 40-79 years since 1994 for 11 years. We used Cox proportional hazard models adjusted for possible confounding factors. We also performed propensity for use of the health check-up matched cohort analyses. RESULTS: Compared to non-screenees, multiple adjusted hazard ratios (95% confidence intervals) for all-cause and cardiovascular disease mortality among screenees were 0.74 (0.62-0.88) and 0.65 (0.44-0.95) for men and 0.69 (0.52-0.91) and 0.61 (0.36-1.04) for women, respectively. These relations were also observed when we used propensity matched cohort analyses. CONCLUSION: This is the first study to show that mortality rates are lower among screenees than non-screenees in Japanese health check-ups when propensity matched cohort analyses were used for adjusting confounding factors. Further prospective studies, including randomized controlled trials, are required to confirm whether screening lowers mortality. PMID- 20828584 TI - Motivational interviewing for smoking cessation in college students: a group randomized controlled trial. AB - OBJECTIVE: To examine the efficacy of four individually-delivered Motivational Interviewing counseling sessions for smoking cessation versus a matched intensity comparison condition. METHOD: From 2006-2009, students attending college in the Midwest smoking at least 1 of 30 days were recruited regardless of their interest in quitting. 30 fraternities and sororities were randomized, resulting in 452 participants. RESULTS: No significant differences were found for 30-day cessation between treatment and comparison at end of treatment (31.4% vs 28%, OR=1.20, 95% CI 0.72,1.99) or at follow-up (20.4% vs 24.6%, OR=0.78, 95% CI 0.50,1.22). Predictors of cessation at follow-up, regardless of condition, included more sessions attended (OR 1.2, 95% CI 1.1,1.8) and more cigarettes smoked in 30 days at baseline (OR 4.7, 95% CI 2.5,8.9). The odds of making at least one quit attempt were significantly greater for those in the smoking group at end of treatment (OR 1.75, 95% CI 1.11,2.74) and follow-up (OR 1.66, 95% CI 1.11,2.47). Modeling showed reduction in days smoked for both groups. At end of treatment, more frequent smokers in the treatment condition had greater reductions in days smoked. CONCLUSION: Motivational Interviewing for smoking cessation is effective for increasing cessation attempts and reducing days smoked in the short run. PMID- 20828585 TI - Contribution of gene-modified mice and rats to our understanding of the cardiovascular pharmacology of serotonin. AB - This review focuses on new insights provided by gene-modified animals into the cardiovascular pharmacology of serotonin. During their development, mice mutant for tryptophan hydroxylase 1 and lacking peripheral serotonin, or mutant for 5 HT(2B) receptors, display cardiac defects and dilated cardiomyopathy. The 5-HT(4) receptor is important for the maturation of cardiac conduction. In fact, transgenic approaches have revealed that adult cardiac status is strongly influenced by maternal serotonin. Serotonin has long been known to be a vasoconstrictor in adult physiology. Analysis of animals knocked-out for the serotonin transporter suggested a role in blood pressure control and revealed an effect of 5-HT(2B) receptor antagonists in hypertension. In the lung vasculature, mice lacking the 5-HT(2B) receptor gene that are exposed to chronic hypoxia are resistant to pulmonary hypertension, while 5-HT(1B) receptor and serotonin transporter mutant animals show partial resistance. In platelets, mutant mice revealed that serotonin transporter regulates not only the mechanisms by which serotonin is packaged and secreted but also platelet aggregation. Studies looking at adult cardiac remodeling showed that mice lacking the 5-HT(2B) receptor gene were protected from cardiac hypertrophy. Their fibroblasts were unable to secrete cytokines. Crossing these animals with mice overexpressing the receptor in cardiomyocytes revealed the contribution of cardiac fibroblasts and 5-HT(2B) receptors to cardiac hypertrophy. In mice lacking the monoamine oxidase-A gene, the role of serotonin degradation in cardiac hypertrophy was confirmed. Works with gene-modified animals has contributed strongly to the re-evaluation of the influence of serotonin on cardiovascular regulation, though several unknowns remain to be investigated. PMID- 20828586 TI - In vivo quantification of protein-protein interactions in Saccharomyces cerevisiae using bimolecular fluorescence complementation assay. AB - Most of the biological processes are carried out and regulated by dynamic networks of protein-protein interactions. In this study, we demonstrate the feasibility of the bimolecular fluorescence complementation (BiFC) assay for in vivo quantitative analysis of protein-protein interactions in Saccharomyces cerevisiae. We show that the BiFC assay can be used to quantify not only the amount but also the cell-to-cell variation of protein-protein interactions in S. cerevisiae. In addition, we show that protein sumoylation and condition-specific protein-protein interactions can be quantitatively analyzed by using the BiFC assay. Taken together, our results validate that the BiFC assay is a very effective method for quantitative analysis of protein-protein interactions in living yeast cells and has a great potential as a versatile tool for the study of protein function. PMID- 20828587 TI - Human gamma-band activity and behavior. AB - Human gamma-band activity (GBA) has been related to a variety of functions ranging from perception and attention to memory and consciousness. Indeed fast spectral activity derived during numerous experimental paradigms has been interpreted as providing support for the functional importance of these signals. The present review provides an overview of findings demonstrating direct or indirect associations between GBA and behavioral measures of task performance or perceptual experience in humans. While the majority of papers have focused on perception and awareness, relationships between GBA and behavior have also been observed during insightful problem solving, short- or long-term memory, and motor tasks. In these studies, GBA was reported to predict behavioral measures such as correct response rates or reaction times both in healthy subjects and patients with neuropsychiatric disorders. The review demonstrates that there is increasingly strong evidence for a close association between GBA during both perceptual and cognitive tasks and behavioral outcome measures. With this in mind, the investigation of GBA might help elucidate the mechanisms underlying deficient functioning in patients with neuropsychiatric disorders. PMID- 20828588 TI - Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. AB - Mesenchymal stem cells (MSCs) possess a set of several fairly unique properties which make them ideally suited both for cellular therapies/regenerative medicine, and as vehicles for gene and drug delivery. These include: 1) relative ease of isolation; 2) the ability to differentiate into a wide variety of seemingly functional cell types of both mesenchymal and non-mesenchymal origin; 3) the ability to be extensively expanded in culture without a loss of differentiative capacity; 4) they are not only hypoimmunogenic, but they produce immunosuppression upon transplantation; 5) their pronounced anti-inflammatory properties; and 6) their ability to home to damaged tissues, tumors, and metastases following in vivo administration. In this review, we summarize the latest research in the use of mesenchymal stem cells in regenerative medicine, as immunomodulatory/anti-inflammatory agents, and as vehicles for transferring both therapeutic genes in genetic disease and genes designed to destroy malignant cells. PMID- 20828589 TI - Mesangial pathology in glomerular disease: targets for therapeutic intervention. AB - The glomerulus is the filtration unit of the kidney. Disruption of glomerular function may be caused by primary glomerular pathology or secondary to systemic diseases. The mesangial, endothelial and epithelial cells of the glomerulus are involved in most pathologic processes. Animal models provide an understanding of the molecular basis of glomerular disease. These studies show that mesangial cells are critical players in the initiation and progression of disease. Therefore, modulation of mesangial cell responses offers a novel therapeutic approach. The complex architecture of the kidney, specifically the renal glomerulus, makes targeted drug delivery especially challenging. Targeted delivery of therapeutic agents reduces dose of administration and minimises unwanted side effects caused by toxicity to other tissues. The currently available modalities demonstrating the feasibility of mesangial cell targeting are discussed. PMID- 20828590 TI - Targeting podocyte-associated diseases. AB - Injury to the podocytes is the initiating cause of many renal diseases, leading to proteinuria with possible progression to end-stage renal disease. Podocytes are highly specialized cells, with an important role in maintaining the glomerular filtration barrier and producing growth factors for both mesangial cells and endothelial cells. With their foot processes they cover the glomerular basement membrane, and form slit diaphragms with neighboring podocytes. Human podocytopathies include focal and segmental glomerulosclerosis, minimal change disease, membranous nephropathy, collapsing glomerulopathy and diabetic nephropathy. Research in the last two decades has demonstrated great progress in understanding the molecular mechanisms leading to podocytopathies. These include single gene defects in slit diaphragm proteins, but also discovery of apoptotic, enzymatic and other pathways involved in podocyte injury. With this progress, a great number of animal models is now available to study either specific podocytopathies, e.g. in mouse models with single gene mutations, or more general podocyte injury patterns, such as the lipopolysaccharide or protamine sulfate model of foot process effacement. In this review, the morphology of the glomerulus will be discussed, with a focus on the podocyte, its interactions with surrounding cells, and the highly differentiated slit diaphragm separating the apical from the basal membrane. We also provide an overview of human podocytopathies and animal models to study these diseases. In the last part we discuss targeted therapies addressing pathways and proteins affected in podocyte injury. PMID- 20828591 TI - Proteomic approaches for qualitative and quantitative characterisation of food allergens. AB - Food allergy is an IgE-mediated hypersensitive reaction estimated to affect up to 4% of infants and adults in developed countries. Proteins termed allergens are mostly responsible for food allergic reactions, consisting of mild to severe systemic reactions. Proteomics include multi-dimensional separation and protein identification by mass spectrometry, followed by data analysis by bioinformatic tools. Proteomics have increasingly been used in the allergy field to (i) identify the genetic and phenotypic variability of allergens in crops, (ii) obtain well-characterised allergens as reported within the EC-funded Integrated Project EuroPrevall, (iii) detect and quantify allergens, either in their native form or in forms resulting from food processing, in complex foods such as bread, cookies, etc., as considered by the EC-funded MoniQA project. These approaches are helping to improve food allergy diagnosis, therapy, and allergenic risk assessment. In the future, the development of more cost effective and sensitive technologies will further enhance the value of proteomics to the allergy field allowing routine use of this approach. We review the applications of proteomics in the field of food allergy. PMID- 20828592 TI - In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression. AB - Recently, the inflammatory and neurodegenerative (I&ND) hypothesis of depression was formulated (Maes et al., 2009), i.e. the neurodegeneration and reduced neurogenesis that characterize depression are caused by inflammation, cell mediated immune activation and their long-term sequels. The aim of this paper is to review the body of evidence that external stressors may induce (neuro)inflammation, neurodegeneration and reduced neurogenesis; and that antidepressive treatments may impact on these pathways. The chronic mild stress (CMS) and learned helplessness (LH) models show that depression-like behaviors are accompanied by peripheral and central inflammation, neuronal cell damage, decreased neurogenesis and apoptosis in the hippocampus. External stress-induced depression-like behaviors are associated with a) increased interleukin-(IL)1beta, tumor necrosis factor-alpha, IL-6, nuclear factor kappaB, cyclooxygenase-2, expression of Toll-like receptors and lipid peroxidation; b) antineurogenic effects and reduced brain-derived neurotrophic factor (BDNF) levels; and c) apoptosis with reduced levels of Bcl-2 and BAG1 (Bcl-2 associated athanogene 1), and increased levels of caspase-3. Stress-induced inflammation, e.g. increased IL 1beta, but not reduced neurogenesis, is sufficient to cause depression. Antidepressants a) reduce peripheral and central inflammatory pathways by decreasing IL-1beta, TNFalpha and IL-6 levels; b) stimulate neuronal differentiation, synaptic plasticity, axonal growth and regeneration through stimulatory effects on the expression of different neurotrophic factors, e.g. trkB, the receptor for brain-derived neurotrophic factor; and c) attenuate apoptotic pathways by activating Bcl-2 and Bcl-xl proteins, and suppressing caspase-3. It is concluded that external stressors may provoke depression-like behaviors through activation of inflammatory, oxidative, apoptotic and antineurogenic mechanisms. The clinical efficacity of antidepressants may be ascribed to their ability to reverse these different pathways. PMID- 20828593 TI - Psychopharmacology: a house divided. AB - BACKGROUND: Psychopharmacology and psychiatry during the past 50 years have focused on the specificity model in which it is assumed that psychiatric disorders are specific entities which should respond to drugs with specific mechanisms of action. However, the validity of this model has been challenged by the approval of multiple drugs for the same disorder, as well as the approval of single agents for a variety of disorders which have little in common. As an example of this unacknowledged paradigm shift, I will examine the foundation for using antipsychotics in the treatment of depression. METHODS: An extensive literature search of studies investigating various mechanisms of actions of antipsychotics and antidepressants with the goal of identifying neurochemical processes common to both. RESULTS: The neurochemical differences in these classes of drugs appear to be profound, although several processes are common in both, including some degree of neuroprotection and changes in the epigenome. Whether these common features have any effect on clinical outcome remains in doubt. CONCLUSIONS: While psychopharmacology and psychiatry remain largely committed to the specificity model, it appears that clinicians are prescribing on a dimensional model wherein symptoms are being treated with a variety of drugs, regardless of the diagnosis. PMID- 20828594 TI - The role of Wnt signaling and its interaction with diverse mechanisms of cellular apoptosis in the pathophysiology of bipolar disorder. AB - The neurobiology of Bipolar Disorder (BD) is not completely understood, although abnormalities in neuroplasticity and control of apoptosis have been considered as central events in its pathophysiology. The molecules of the Wnt family comprise a class of proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation with their actions largely exerted by modulating gene transcription. The Wnt signaling pathway has interface with some mediators with a well documented action in neuroplasticity and regulation of cell surviving. In addition, mood stabilizers such as lithium and valproate may have their neuroprotective properties in part mediated by the Wnt pathway. This article is an overview of how the Wnt signaling cascade might be involved in the pathogenesis of BD and also in details of intracellular events related to this pathway. Further studies of Wnt signaling may lead to a better comprehension of the neuroprotective actions of mood stabilizers and contribute to improving the therapeutics of BD. PMID- 20828595 TI - Effects of discontinuation of long-term biperiden use on cognitive function and quality of life in schizophrenia. AB - BACKGROUND: The high use of long-term antiparkinsonian anticholinergic drugs with antipsychotics has been identified as an important issue in the treatment of schizophrenia in Japan. The aim of this study was to evaluate the effects of gradual discontinuation of biperiden, an anticholinergic drug, on cognitive function and quality of life (QOL) in schizophrenia. METHODS: Thirty-four schizophrenic patients who had received a second-generation antipsychotic (SGA) with concomitant biperiden for at least 3 months were enrolled. Before and 4 weeks after discontinuation of biperiden, the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J) and the Schizophrenia Quality of Life Scale (SQLS-J) were administered. Clinical evaluation also included the Positive and Negative Syndrome Scale (PANSS). To compare the practice effect on BACS-J, 10 chronic patients with schizophrenia were assessed without tapering biperiden. RESULTS: Biperiden was discontinued safely in most patients, and no emergent extrapyramidal symptoms were observed. Significant improvements were shown in attention, processing speed, and composite score, as measured by the BACS-J without practice effect. In addition, the psychosocial condition score on the SQLS-J and the general psychopathology score on the PANSS significantly improved after biperiden discontinuation. CONCLUSION: Discontinuation of long term biperiden use may be warranted in patients with schizophrenia treated with SGAs, as it may improve cognitive function, subjective QOL, and psychiatric symptoms with no significant adverse effects. PMID- 20828596 TI - Significance of NMDA receptor-related glutamatergic amino acid levels in peripheral blood of patients with schizophrenia. AB - Hypo-function of N-methyl d-aspartate (NMDA) receptors is strongly involved in the brain pathophysiology of schizophrenia. Several excitatory amino acids, such as endogenous glutamate, glycine, serine and alanine, which are involved in glutamate neurotransmission via NMDA receptors, were studied to further understand the pathophysiology of schizophrenia and to find a biological marker for this disease, particularly in peripheral blood. In this literature review, we connect several earlier clinical studies and several studies of excitatory amino acid levels in peripheral blood in a historical context. Finally, we join these results and our previous studies, the Juntendo University Schizophrenia Projects (JUSP), which investigated plasma glutamatergic amino acid levels in detail, and considered whether these amino acid levels may be diagnostic, therapeutic, or symptomatic biological markers. This review concludes that peripheral blood levels of endogenous glycine and alanine could be a symptomatic marker in schizophrenia, while peripheral blood levels of exogenous glycine and alanine in augmentation therapies could be therapeutic markers. Noteworthy peripheral blood levels of endogenous d-serine could reflect its brain levels, and may prove to be a useful diagnostic and therapeutic marker in schizophrenia. In addition, measurements of new endogenous molecules, such as glutathione, are promising. Finally, for future therapies with glutamatergic agents still being examined in animal studies, the results of these biological marker studies may lay the foundation for the development of next-generation antipsychotics. PMID- 20828597 TI - Saponins from the roots of Platycodon grandiflorum stimulate osteoblast differentiation via p38 MAPK- and ERK-dependent RUNX2 activation. AB - Changkil (CK), the aqueous extract of the roots of Platycodon grandiflorum, has been used as a traditional oriental medicine for the treatment of chronic adult diseases. Although a saponin fraction derived from CK (CKS) has been suggested to have a variety of functional effects, its effect on bone is unknown. In the present study, the effects of CKS on osteoblast differentiation and function were determined by analyzing the activity of alkaline phosphatase (ALP), an osteoblast marker, and the regulation of RUNX2, a master gene of osteoblast differentiation, in a mesenchymal stem cell line. CKS upregulated ALP activity and the expression of osteogenic marker genes in C2C12 cells. In addition, CKS increased the expression and transcriptional activity of RUNX2. To determine which signaling pathways are involved in the osteogenic effects of CKS, we tested the effect of inhibitors of kinases known to regulate RUNX2. CKS-induced enhancement of RUNX2 and ALP was inhibited by treatment with a p38 inhibitor (SB203580) and an ERK inhibitor (U0126). These findings suggest that CKS stimulates osteoblast differentiation by activation of RUNX2 via mechanisms related to the p38 MAPK and ERK signaling pathways. The regulation of RUNX2 activation by CKS may be an important therapeutic target for osteoporosis. PMID- 20828598 TI - Intrinsic apoptosis and NF-kappaB signaling are potential molecular targets for chemoprevention by black tea polyphenols in HepG2 cells in vitro and in a rat hepatocarcinogenesis model in vivo. AB - Antiproliferative and apoptosis inducing effects of black tea polyphenols (Polyphenon-B) on HepG2 cells in vitro and in a rat hepatocarcinogenesis model in vivo were investigated. Viability of HepG2 cells was evaluated by the MTT assay, and apoptosis by AO-EB and DAPI staining, cell cycle analysis, and annexin V-PI assay. For the in vivo study, male Sprague-Dawley rats treated with dimethylaminoazobenzene (DAB) (0.06%) were used. The expression of Bcl-2 and NF kappaB family members were analyzed by immunoblotting. Administration of Polyphenon-B induced dose-dependent inhibition of growth of HepG2 cells and reduced tumor incidence in DAB administered animals. HepG2 cells also exhibited morphological features characteristic of apoptotic cell death. In addition, administration of Polyphenon-B increased the expression of Bax, tBid, Smac/Diablo, cytochrome C, Apaf-1, caspases, and IkappaB with PARP cleavage, and decreased the expression of Bcl-2, Bcl-xL, pBad, NF-kappaB, p-IkappaB-alpha, IKKbeta and Ub in both HepG2 cells and in DAB-treated animals. These results provide evidence that Polyphenon-B effectively inhibits proliferation and induces apoptosis both in vitro and in vivo by inhibiting NF-kappaB, and inducing intrinsic apoptosis by modulating the expression of a network of interrelated molecules eventually culminating in caspase-mediated cell death. PMID- 20828599 TI - Diazinon-induced oxidative stress and renal dysfunction in rats. AB - Diazinon (O,O-diethyl-O-[2-isopropyl-6-methyl-4-pyrimidinyl] phosphoro thioate), an organo-phosphate insecticide, has been used worldwide in agriculture and domestic for several years, which has led to a variety of negative effects in non target species including humans. However, its nephrotoxic effects and mechanism of action has not been fully elucidated so far. Therefore, the present study was aimed at evaluating the nephrotoxic effects of diazinon and its mechanism of action with special reference to its possible ROS generating potential in rats. Treatment of rats with diazinon significantly enhances renal lipid peroxidation which is accompanied by a decrease in the activities of renal antioxidant enzymes (e.g. catalase, glutathione peroxidise, glutathione reductase, glucose-6 phosphate dehydrogenase, glutathione S-transferase) and depletion in the level of glutathione reduced. In contrast, the activities of renal gamma-glutamyl transpeptidase and quinone reductase were increased. Parallel to these changes, diazinon treatment enhances renal damage as evidenced by sharp increase in blood urea nitrogen and serum creatinine. Additionally, the impairment of renal function corresponds histopathologically. In summary, our results indicate that diazinon treatment eventuates in decreased renal glutathione reduced, a fall in the activities of antioxidant enzymes including the enzymes involved in glutathione metabolism and excessive production of oxidants with concomitant renal damage, all of which are involved in the cascade of events leading to diazinon-mediated renal oxidative stress and toxicity. We concluded that in diazinon exposure, depletion of antioxidant enzymes is accompanied by induction of oxidative stress that might be beneficial in monitoring diazinon toxicity. PMID- 20828600 TI - Composition, antimicrobial activity and in vitro cytotoxicity of essential oil from Cinnamomum zeylanicum Blume (Lauraceae). AB - The essential oil from the bark of Cinnamomum zeylanicum Blume was analyzed by GC MS and bioassays were carried out. Nine constituents representing 99.24% of the oil were identified by GC-MS. The major compounds in the oil were (E) cinnamaldehyde (68.95%), benzaldehyde (9.94%) and (E)-cinnamyl acetate (7.44%). The antimicrobial activity of the oil was investigated in order to evaluate its efficacy against 21 bacteria and 4 Candida species, using disc diffusion and minimum inhibitory concentration methods. The essential oil showed strong antimicrobial activity against all microorganisms tested. The cytotoxic and apoptotic effects of the essential oil on ras active (5RP7) and normal (F2408) fibroblasts were examined by MTT assay and acridine orange/ethidium bromide staining, respectively. The cytotoxicity of the oil was quite strong with IC(50) values less than 20 MUg/mL for both cell lines. 5RP7 cells were affected stronger than normal cells. Morphological observation of apoptotic cells indicated the induction of apoptosis at the high level of the oil, especially in 5RP7 cells. The present study showed the potential antimicrobial and anticarcinogenic properties of the essential oil of cinnamon bark, indicating the possibilities of its potential use in the formula of natural remedies for the topical treatment of infections and neoplasms. PMID- 20828601 TI - Mesolimbic dopaminergic activity responding to acute stress is blunted in adolescent rats that experienced neonatal maternal separation. AB - Neonatal maternal separation (MS), stressful experience early in life, leads to the development of depression-like behaviors in the offspring later in life. This study was conducted to define the neural basis of depression-like behaviors observed in our MS model. Sprague-Dawley pups were separated from dam for 3 h daily during the first 2 weeks of birth (MS) or left undisturbed (NH). All pups were sacrificed on postnatal day 41 with/without 1 h of restraint stress. Restraint stress significantly increased c-Fos expression in the nucleus accumbens (NAcb) of NH pups, but not in MS. In NH pups, restraint stress increased dopamine levels not only in the NAcb but also in the midbrain dopamine neurons; however, these increases were not observed in MS. Gene expression of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) was increased by acute restraint in NH pups, but not in MS pups. The raphe serotonin level was lower in MS than in NH, and not significantly changed by acute restraint neither in NH nor in MS. Results reveal that experience of neonatal MS may lead to a long term suppression in the mesolimbic dopamine system of the offspring later in life, in which an epigenetic control may be implicated, such as suppressed gene expression of TH in the midbrain. We conclude that a decreased activity of the mesolimbic dopamine system may play a role in the pathophysiology of depression like behaviors by neonatal MS, in addition to a decreased serotonin level in the raphe nucleus. PMID- 20828602 TI - Protective effect of berberine on antioxidant enzymes and positive transcription elongation factor b expression in diabetic rat liver. AB - The protective effect of berberine against antioxidant, antilipid peroxidation in serum and liver tissue, and positive transcription elongation factor b (P-TEFb) expression in liver tissue of type 2 diabetic rats was investigated. Overnight fasted rats were intraperitoneally injected 35 mg/kg streptozotocin. Diabetic rats were admitted after 2 weeks and given a high-carbohydrate/high-fat diet to induce hyperlipidemias. From week 16, diabetic rats were treated with 75, 150, 300 mg/kg berberine, 100mg/kg fenofibrate or 4 mg/kg rosiglitazone for another 16 weeks. P-TEFb (composed of cyclin-dependent kinase 9 and cyclin T1) mRNA and protein expression in liver tissue were detected by real time PCR and immunohistochemistry, respectively. Berberine significantly up-regulated the declined cyclin-dependent kinase 9, cyclin T1 mRNA and protein expression in diabetic rat liver. Berberine obviously decreased malondialdehyde level and increased catalase, superoxide dismutase, glutathione peroxidase, and glutathione activities in liver tissue and serum of diabetic rats. These results suggest that the effects of berberine on up-regulation of P-TEFb expression, antioxidant and antilipid peroxidation may be related to its protective potential on diabetes. PMID- 20828603 TI - For the special issue: aging studies in Drosophila melanogaster. PMID- 20828604 TI - Physiologically based biokinetic model of bioactivation and detoxification of the alkenylbenzene methyleugenol in rat. AB - The present study defines a physiologically based biokinetic (PBBK) model for the alkenylbenzene methyleugenol in rat based on in vitro metabolic parameters determined using relevant tissue fractions, in silico derived partition coefficients, and physiological parameters derived from the literature. The model was based on the model previously developed for the related alkenylbenzene estragole and consists of eight compartments including liver, lung, and kidney as metabolizing compartments, and separate compartments for fat, arterial blood, venous blood, richly perfused and slowly perfused tissues. Evaluation of the model was performed by comparing the PBBK predicted concentration of methyleugenol in the venous compartment to methyleugenol plasma levels reported in the literature, by comparing the PBBK predicted dose-dependent percentage of formation of 2-hydroxy-4,5-dimethoxyallylbenzene, 3-hydroxy-4 methoxyallylbenzene, and 1'-hydroxymethyleugenol glucuronide to the corresponding percentage of metabolites excreted in urine reported in the literature, which were demonstrated to be in the same order of magnitude. With the model obtained the relative extent of bioactivation and detoxification of methyleugenol at different oral doses was examined. At low doses, formation of 3-(3,4 dimethoxyphenyl)-2-propen-1-ol and methyleugenol-2',3'-oxide leading to detoxification appear to be the major metabolic pathways, occurring in the liver. At high doses, the model reveals a relative increase in the formation of the proximate carcinogenic metabolite 1'-hydroxymethyleugenol, occurring in the liver. This relative increase in formation of 1'-hydroxymethyleugenol leads to a relative increase in formation of 1'-hydroxymethyleugenol glucuronide, 1' oxomethyleugenol, and 1'-sulfooxymethyleugenol the latter being the ultimate carcinogenic metabolite of methyleugenol. These results indicate that the relative importance of different metabolic pathways of methyleugenol may vary in a dose-dependent way, leading to a relative increase in bioactiviation of methyleugenol at higher doses. PMID- 20828605 TI - Assessment of a dry extract from milk thistle (Silybum marianum) for interference with human liver cytochrome-P450 activities. AB - The effect of a standardised dry extract from Silybum marianum (HEPAR-PASC(r)) on the enzyme kinetics of cytochrome-P450 isoenzymes (CYP) was investigated with primary human hepatocytes and human liver microsomes in order to assess the potential for drug-drug interactions. A cytotoxic effect on hepatocytes was observed at concentrations at and above 50 MUg/ml. The EC(50) value was calculated to be 72.0 MUg/ml. Therefore, the chosen test concentrations for CYP induction on human hepatocytes were 50, 10, and 1.5 MUg/ml, which allowed for interpretation of the clinical significance of the data with a range of 50-1-fold c(max) at maximal recommended doses. No induction was observed at the lowest concentration of 1.5 MUg/ml, which is close to c(max). The extract did not induce CYP 3A4 at any of the tested concentrations. A low or marginal induction of 1A2, 2B6, and 2E1 at the maximum concentration of 50 MUg/ml was observed. CYP inhibition on human microsomes was tested at concentrations of 150, 15, and 1.5 MUg/ml. No or minor CYP inhibition was observed for all CYPs tested at the lowest concentration of 1.5 MUg/ml, i.e. CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. At concentrations of 15 and 150 MUg/ml the extract significantly inhibited CYP 2B6, 2C8, 2C9, 2C19, 2E1, and 3A4. In these cases, K(i) values were determined. All K(i) values exceeded c(max) by at least a factor of 10-fold. According to FDA regulations 1>c(max)/K(i)>0.1 indicates, that drug-drug interactions are possible for CYPs 2C8, and 2C9, but not likely, and are remote for CYPs 2C19, 2D6, and 3A4. PMID- 20828606 TI - Transcriptome profiling of early developing cotton fiber by deep-sequencing reveals significantly differential expression of genes in a fuzzless/lintless mutant. AB - Cotton fiber as a single-celled trichome is a biological model system for studying cell differentiation and elongation. However, the complexity of its gene expression and regulatory mechanism allows only marginal progress. Here, we report the high-throughput tag-sequencing (Tag-seq) analysis using Solexa Genome Analyzer platform on transcriptome of -2 to 1 (fiber initiation, stage I) and 2-8 (fiber elongation, stage II) days post anthesis (DPA) cotton (Gossypium hirsutum) ovules (wild type: WT; Xuzhou 142 and its mutant: fuzzless/lintless or flM, in the same background). To this end, we sequenced 3.5-3.8 million tags representing 0.7-1.0 million unique transcripts for each library (WT1, WT2, M1, and M2). After removal of low quality tags, we obtained a total of 2,973,104, 3,139,306, 2,943,654, and 3,392,103 clean sequences that corresponded to 357,852, 280,787, 372,952, and 382,503 distinct tags for WT1, WT2, M1, and M2, respectively. All clean tags were aligned to the publicly available cotton transcript database (TIGR, http://www.tigr.org). About 15% of the distinct tags were uniquely mapped to the reference genes, and 31.4% of existing genes were matched by tags. The tag mapping to the database sequences generated 23,854, 24,442, 23,497, and 19,957 annotated genes for WT1, WT2, M1, and M2 libraries, respectively. Analyses of differentially expressed genes revealed the substantial changes in gene type and abundance between the wild type and mutant libraries. Among the 20 most differentially expressed genes in WT1/M1 and WT2/M2 libraries were cellulose synthase, phosphatase, and dehydrogenase, all of which are involved in the fiber cell development. Overall, the deep-sequencing analyses demonstrate the high degree of transcriptional complexity in early developing fibers and represent a major improvement over the microarrays for analyzing transcriptional changes on a large scale. PMID- 20828607 TI - S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NF-kappaB pathway in rats. AB - Neuroinflammation exacerbates hyperphosphorylated tau and amyloid-beta (Abeta) generation by generating a plethora of inflammatory mediators and neurotoxic compounds in a transgenic model of Alzheimer's disease (AD), and it was reported that hydrogen sulfide (H2S) attenuates lipopolysaccharide (LPS)-induced neuroinflammation both in vitro and in vivo. In the present study, the protective effects of S-propargyl-cysteine (SPRC) on spatial learning and memory impairment induced by LPS were examined in vivo, and the possible mechanisms were explored. The data showed that SPRC administration by intraperitoneal (i.p.) injection may attenuate cognitive impairment induced by bilateral intracerebroventricular (b.i.c.v.) injection of 5 MUg of LPS in rats. Subsequently, SPRC prevented a decrease of H2S levels in rat hippocampus subjected to LPS. Furthermore, SPRC afforded beneficial actions in inhibitions tumor necrosis factor (TNF)-alpha, TNF alpha receptor 1 (TNFR1) and Abeta generation, as well as IkappaB-alpha degradation and phospho-transcription factors of the nuclear factor kappaB p65 (p NF-kappaB p65) activation induced by LPS. These findings suggested that SPRC, a novel H2S-modulated agent, might be a potential agent for the treatment of neuroinflammation-related diseases, such as AD. PMID- 20828608 TI - Insulin and resveratrol act synergistically, preventing cardiac dysfunction in diabetes, but the advantage of resveratrol in diabetics with acute heart attack is antagonized by insulin. AB - Resveratrol (RSV), a natural phenolic compound, has been found to display cardiovascular protective and insulin-sensitizing properties. In this study, the effects of RSV and its combination with insulin on mortality, hemodynamics, insulin signaling, and nitrosative stress were compared in streptozotocin (STZ) induced diabetic rats with or without acute myocardial ischemia/reperfusion (I/R) injury. Under normoxic conditions, cardiac systolic and diastolic functions and insulin-mediated Akt/GLUT4 (glucose transporter 4) activation were impaired in STZ-diabetic rats. The combination of RSV and insulin significantly prevented the above diabetes-associated abnormalities. Notwithstanding that, the diabetic state rendered the animals more susceptible to myocardial I/R injury, and the mortality rate and inducible nitric oxide synthase (iNOS)/nitrotyrosine protein expression and superoxide anion production were also further increased in I/R-injured diabetic hearts. In contrast, RSV treatment alone resulted in a lower mortality rate (from 62.5 to 18%) and better cardiac systolic function than its combination with insulin. RSV also inhibited iNOS/nitrotyrosine protein overexpression and superoxide anion overproduction in I/R-injured diabetic myocardium. Hyperglycemia, impairment of insulin signaling, overexpression of iNOS/nitrotyrosine, and superoxide anion overproduction were markedly rescued by the combination treatment, which did not show an improvement in mortality rate (30%) or cardiac performance over RSV treatment alone. These results indicate that insulin and RSV synergistically prevented cardiac dysfunction in diabetes and this may be in parallel with activation of the insulin-mediated Akt/GLUT4 signaling pathway. Although activation of the protective signal (Akt/GLUT4) and suppression of the adverse markers (iNOS, nitrotyrosine, and superoxide anion) were simultaneously observed in insulin and RSV combination treatment, insulin counteracted the advantage of RSV in diabetics with acute heart attack. PMID- 20828609 TI - In vivo evaluation of novel nitroxyl radicals with reduction stability. AB - Nitroxyl radicals (nitroxide) have great potential advantages as spin probes, antioxidants, contrast agents, and radiation-protecting agents. However, they are readily reduced by reductants in cells and lose their paramagnetic nature. Recently, tetraethyl-substituted nitroxyl radicals have been reported to have high stability toward reduction by ascorbic acid (AsA). We report the general considerations of tetraethyl nitroxyl radicals for in vivo application. The reason for the low reactivity to AsA reduction was the positive value of Gibbs energy between the tetraethyl nitroxyl radical and AsA. Further, these compounds had an inhibitory effect on lipid peroxidation despite having AsA resistance. They had low antiproliferative effects in HepG2 cells and HUVECs and did not have a lowering effect on blood pressure in animals. Further, after intravenous injection, the ESR signal intensities of tetraethyl-substituted piperidine nitroxyl radicals were very stable in mice over 20 min. These results suggest that tetraethyl-substituted nitroxyl radicals have stability against bioreduction with reductants such as AsA and confer onto them features as antioxidants and paramagnetic tracers/contrast agents. Hence, they will be useful in identifying the foci of oxidative stress in vivo using redox-based imaging approaches. PMID- 20828610 TI - Neutrophil-derived ROS contribute to oxidative DNA damage induction by quartz particles. AB - The carcinogenicity of respirable quartz is considered to be driven by reactive oxygen species (ROS) generation in association with chronic inflammation. The contribution of phagocyte-derived ROS to inflammation, oxidative stress, and DNA damage responses was investigated in the lungs of C57BL/6J wild-type and p47(phox /-) mice, 24h after pharyngeal aspiration of DQ12 quartz (100 mg/kg bw). Bone marrow-derived neutrophils from wild-type and p47(phox-/-) mice were used for parallel in vitro investigations in coculture with A549 human alveolar epithelial cells. Quartz induced a marked neutrophil influx in both wild-type and p47(phox-/ ) mouse lungs. Significant increases in mRNA expression of the oxidative stress markers HO-1 and gamma-GCS were observed only in quartz-treated wild-type animals. Oxidative DNA damage in lung tissue was not affected by quartz exposure and did not differ between p47(phox-/-) and WT mice. Differences in mRNA expression of the DNA repair genes OGG1, APE-1, DNA Polbeta, and XRCC1 were also absent. Quartz treatment of cocultures containing wild-type neutrophils, but not p47(phox-/-) neutrophils, caused increased oxidative DNA damage in epithelial cells. Our study demonstrates that neutrophil-derived ROS significantly contribute to pulmonary oxidative stress responses after acute quartz exposure, yet their role in the associated induction of oxidative DNA damage could be shown only in vitro. PMID- 20828611 TI - Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model. AB - The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q(10), the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4 phenylpyridinium (MPP(+)), an active metabolite of the neurotoxin 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q(10). MPP(+) treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q(10). MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q(10) significantly inhibited both MPP(+)- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD. PMID- 20828612 TI - Loss of GPx2 increases apoptosis, mitosis, and GPx1 expression in the intestine of mice. AB - Localization of glutathione peroxidase 2 (GPx2), the gastrointestinal form of GPx's, in the intestinal crypt epithelium points to a specific but so-far unknown function of this particular GPx. Therefore, the consequences of a GPx2 knockout were tested in mice fed a selenium-restricted, Se-adequate, or Se-supplemented diet. An unexpected increase in total GPx activity was found throughout the intestine in selenium-fed GPx2 knockout (KO) animals. Immunohistochemistry revealed a strong increase in GPx1 in the colon and ileum, especially in crypt bases where typically GPx2 is localized. GPx1 mRNA was not enhanced in GPx2 KO, indicating that up-regulation most probably occurs at the translational level. Loss of GPx2 was accompanied by an increase in apoptotic cells at colonic crypt bases, an area essential for the self-renewal of the intestinal epithelium, particularly under selenium restriction. Additionally, mitotic cells increased in the middle parts of the crypts, indicating an extension of the proliferative area. These findings corroborate a role for GPx2 in regulating mucosal homeostasis. In GPx2 KO mice, an increase in GPx1 can only partially compensate for GPx2, even under selenium supplementation, indicating that GPx2 is the major antiapoptotic GPx in the colon. These data explain why spontaneous ileocolitis becomes manifested only if both Gpx2 and Gpx1 are deleted. PMID- 20828613 TI - Matrix remodeling as stem cell recruitment event: a novel in vitro model for homing of human bone marrow stromal cells to the site of injury shows crucial role of extracellular collagen matrix. AB - The goal of the present study was to devise an in vitro model suitable for investigations of the homing of mesenchymal stem cells to sites of injury. Such a model was designed on the basis of a "transwell" assay, with an insert seeded with human bone marrow stromal cells and a well with a desired cell type. To mimic physiological environment and to simulate "injury", cells in a well were maintained not only on tissue culture plastic but also on collagens I and IV, major matrix components in musculoskeletal and adipose tissues respectively, and subjected to a severe thermal stress. The results obtained showed a massive translocation of bone marrow stromal cells through the inserts' membrane toward the "injury" site. Unexpectedly, it emerged that collagen matrix is essential in producing such a migration. The results obtained suggest that upon injury cells secrete a substance which interacts with collagen matrix to produce a homing agent. The substance in question appears to be a protease and its interaction with the collagen matrix appears to be a digestion of the latter into fragments shown to be chemotactic. Both AEBSF, an inhibitor of serine proteases, and leupeptin, an inhibitor of cysteine proteases as well as of trypsin-like serine proteases, but not the broad spectrum MMP inhibitor marimastat, significantly inhibit the observed homing effect and this inhibition is not due to cytotoxicity. Moreover, immunoprecipitation of HTRA1, a trypsin-like serine protease known to be secreted by cells differentiating into all three major mesenchymal lineages and by stressed cells in general and shown to degrade a number of matrix proteins including collagen, significantly diminished the homing effect. The data suggest that this protease is a major contributor to the observed chemotaxis of bone marrow stromal cells. The present study indicates that collagen fragments can mediate the migration of bone marrow stromal cells. The results also suggest that, at least in musculoskeletal and in adipose tissues, matrix remodeling occurrences, usually closely associated with tissue remodeling, should also be regarded as potential stem cells recruitment events. PMID- 20828614 TI - D-amino acid oxidase knockdown in the mouse cerebellum reduces NR2A mRNA. AB - Virus mediated RNA-interference (RNAi) is a powerful approach to study genes in vivo. Here we report a method using lentivirus-delivered RNAi to knockdown the glial enzyme, D-amino acid oxidase (DAO), in the mouse cerebellum. After initial characterisation in vitro, we achieved a 40-50% reduction of DAO mRNA in the cerebellum 7 and 28 days after a single injection of lentivirus encoding a DAO specific, short-hairpin RNA. Injections also decreased DAO immunoreactivity ( 33%). The major substrate for DAO is D-serine, an N-methyl-D-aspartate receptor (NMDAR) co-agonist. Thus, we also measured whether DAO knockdown impacted on d serine, or expression of NMDAR subunits, and found that DAO RNAi led to increased cerebellar D-serine levels (+77%), and decreased NMDAR subunit NR2A mRNA (-22%), but did not affect NR1 or NR2C mRNAs. These data demonstrate the utility of lentiviruses to deliver RNAi to glial cells within the cerebellum, and confirm the role of DAO in D-serine metabolism. They also provide a tool to investigate DAO, an enzyme currently of considerable interest in the pathophysiology and therapy of schizophrenia. PMID- 20828615 TI - Anti-viral opportunities during transcriptional activation of latent HIV in the host chromatin. AB - Human immunodeficiency virus (HIV) when integrated into a host chromosome exists in a transcriptionally inactive but replication-competent state. Such latent infection represents a major challenge to HIV eradication efforts because a permanent virus reservoir resided in the infected cell is able to spike the viral load on immune suppression or during interruption of highly active anti retroviral therapy. Understanding the molecular mechanisms that control HIV proviral latency and its reactivation could provide new perspectives on host factors as therapeutic targets for abolishing cellular reservoirs of dormant HIV. Although the control of HIV latency is multifactorial, chromatin structure and the chromatin-associated transcriptional machinery are known to be important factors. For instance, transcription initiation of the HIV provirus involves a complex molecular interplay between chromatin-associated proteins and the virus encoded trans-activator, Tat. The first part of this review discusses our current understanding of the elements involved in HIV transcriptional activation and viral mRNA elongation, mainly post-translational modifications of HIV Tat and its interactions with host chromatin-modifying enzymes and chromatin-remodeling complexes. The second part highlights new experimental therapeutic approaches aimed at administrating activators of HIV gene expression to reduce or eliminate the pool of latently HIV-infected cells. PMID- 20828616 TI - Production of congopain, the major cysteine protease of Trypanosoma (Nannomonas) congolense, in Pichia pastoris reveals unexpected dimerisation at physiological pH. AB - African animal trypanosomosis (nagana) is arguably the most important parasitic disease affecting livestock in sub-Saharan Africa. Since none of the existing control measures are entirely satisfactory, vaccine development is being actively pursued. However, due to antigenic variation, the quest for a conventional vaccine has proven elusive. As a result, we have sought an alternative 'anti disease vaccine approach', based on congopain, a cysteine protease of Trypanosoma congolense, which was shown to have pathogenic effects in vivo. Congopain was initially expressed as a recombinant protein in bacterial and baculovirus expression systems, but both the folding and yield obtained proved inadequate. Hence alternative expression systems were investigated, amongst which Pichia pastoris proved to be the most suitable. We report here the expression of full length, and C-terminal domain-truncated congopain in the methylotrophic yeast P. pastoris. Differences in yield were observed between full length and truncated proteins, the full length producing 2-4 mg of protein per litre of culture, while the truncated form produced 20-30 mg/l. The protease was produced as a proenzyme, but underwent spontaneous activation when acidified (pH <5). To investigate whether this activation was due to autolysis, we produced an inactive mutant (active site Cys->Ala) by site-directed mutagenesis. The mutant form was produced at a much higher rate, up to 100mg/l culture, as a proenzyme. It did not undergo spontaneous cleavage of the propeptide when subjected to acidic pH suggesting an autocatalytic process of activation for congopain. These recombinant proteins displayed a very unusual feature for cathepsin L-like proteinases, i.e. complete dimerisation at pH >6, and by reversibly monomerising at acidic pH <5. This attribute is of utmost importance in the context of an anti-disease vaccine, given that the epitopes recognised by the sera of trypanosome-infected trypanotolerant cattle appear dimer-specific. PMID- 20828617 TI - Recombinant human sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) is expressed at high yield as an active homotetramer in baculovirus infected insect cells. AB - The sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDHS) isoform is a promising contraceptive target because it is specific to male germ cells, essential for sperm motility and male fertility, and well suited to pharmacological inhibition. However, GAPDHS is difficult to isolate from native sources and recombinant expression frequently results in high production of insoluble enzyme. We chose to use the Bac-to-Bac baculovirus-insect cell system to express a His-tagged form of human GAPDHS (Hu his-GAPDHS) lacking the proline rich N-terminal sequence. This recombinant Hu his-GAPDHS was successfully produced in Spodoptera frugiperda 9 (Sf9) cells by infection with recombinant virus as a soluble, enzymatically active form in high yield, >35 mg/L culture. Biochemical characterization of the purified enzyme by mass spectrometry and size exclusion chromatography confirmed the presence of the tetrameric form. Further characterization by peptide ion matching mass spectrometry and Edman sequencing showed that unlike the mixed tetramer forms produced in bacterial expression systems, human his-GAPDHS expressed in baculovirus-infected insect cells is homotetrameric. The ability to express and purify active human GAPDHS as homotetramers in high amounts will greatly aid in drug discovery efforts targeting this enzyme for discovery of novel contraceptives and three compounds were identified as inhibitors of Hu his-GAPDHS from a pilot screen of 1120 FDA approved compounds. PMID- 20828618 TI - High level expression, purification and activation of human dipeptidyl peptidase I from mammalian cells. AB - Dipeptidyl peptidase I (DPPI) plays a crucial role in maturation of many regulatory peptides and has been suggested as a pharmaceutical target in several inflammatory diseases. It is also a useful processing enzyme for the generation of authentic protein products by catalyzing the removal of N-terminal fusion peptides. We used a robust transient transfection system in human embryonic kidney 293 cells to exploit expression and activation of DPPI from chicken, rat and man for the development of an industrial production process. The expression of human and rat DPPI was significantly higher in the human HEK293 cell line than that obtained with avian DPPI. A CHO K1SV stable cell line was selected as the optimal stable host system for production of human DPPI yielding expression levels higher than 1.5 g/L. The secreted pro-DPPI underwent auto-maturation during defined buffer conditions during the purification steps. Active human DPPI was purified with a three-step purification strategy employing: Butyl Sepharose 4 Fast Flow, Sephadex G-25 Medium and Q Sepharose Fast Flow chromatography. The final yield of active enzyme was approximately 1 g/L cell culture. The enzyme exhibited exopeptidase activity against both a dipeptide-p-nitroanilide substrate and N-terminally extended MEAE-hGH (Met-Glu-Ala-Glu-human growth hormone). In conclusion, an efficient production process for recombinant human DPPI has been developed including a highly efficient and stable CHO cell system and an efficient purification procedure, which is simple and easy to scale for industrial purposes. The present data facilitates not only industrial applications of DPPI as a processing enzyme, but also provides active enzyme useful in the identification of small molecule inhibitors. PMID- 20828619 TI - Expression, purification and functional analysis of an odorant binding protein AaegOBP22 from Aedes aegypti. AB - Mosquitoes that act as disease vectors rely upon olfactory cues for host-seeking, mating, blood feeding and oviposition. To reduce the risk of infection in humans, one of the approaches focuses on mosquitoes' semiochemical system in the effort to disrupt undesirable host-insect interaction. Odorant binding proteins (OBPs) play a key role in mosquitoes' semiochemical system. Here, we report the successful expression, purification of an odorant binding protein AaegOBP22 from Aedes aegypti in heterologous system. Protein purification methods were set up by Strep-Tactin affinity binding and size-exclusion chromatography. Analysis by SDS PAGE and mass spectrum revealed the protein's purity and molecular weight. Circular dichroism spectra showed the AaegOBP22 secondary structure had a pH dependent conformational change. The protein functions of AaegOBP22 were tested by fluorescent probe 1-NPN binding assays and ligands competitive binding assays. The results show AaegOBP22 proteins have characteristics of selective binding with various ligands. PMID- 20828620 TI - The structure of a COPII tubule. AB - Nearly a third of all eukaryotic proteins are transported from the ER to the Golgi apparatus through the secretory pathway using COPII coated vesicles. Evidence suggests that this transport occurs via 500-900 A vesicles that bud from the ER membrane. It has been shown that procollagen molecules utilize the COPII proteins for transport, but it is unclear how the COPII coat can accommodate these ~3000 A long molecules. We now present a cryogenic electron tomographic reconstruction of a Sec13/31 tubule that is approximately 3300 A long containing a hollow cylindrical interior that is 300 A in diameter, dimensions that are consistent with those that are required to encapsulate a procollagen molecule wrapped in a membrane and accessory COPII components. This structure suggests a novel mechanism that the COPII coat may employ to transport elongated cargo. PMID- 20828621 TI - The elusive pi-helix. AB - Central to protein architecture is the local arrangement or secondary structure of the polypeptide backbone. Thirty to forty percent of protein domains are alpha helices with 3.6 residues per turn. pi-Helices, in which the peptide chain is more loosely coiled (4.4 residues per turn), have also been proposed. However, such structures necessitate an energetically unfavorable ~1A central helical hole. We show that rather than being composed of idealized pi-helices, helical regions formed from putative pi-helices actually consist of a series of concatenated wide turns with unique elliptical configurations. These structures have a larger helical radius akin to that of a pi-helix, but without the loss of favorable cross-core van der Waals interactions. This not only obviates the helical void, but also endows proteins with important functionalities, including metal ion coordination, enhanced flexibility and specific enzyme-substrate binding interactions. PMID- 20828622 TI - Bound pool fractions complement diffusion measures to describe white matter micro and macrostructure. AB - Diffusion imaging and bound pool fraction (BPF) mapping are two quantitative magnetic resonance imaging techniques that measure microstructural features of the white matter of the brain. Diffusion imaging provides a quantitative measure of the diffusivity of water in tissue. BPF mapping is a quantitative magnetization transfer (qMT) technique that estimates the proportion of exchanging protons bound to macromolecules, such as those found in myelin, and is thus a more direct measure of myelin content than diffusion. In this work, we combined BPF estimates of macromolecular content with measurements of diffusivity within human white matter tracts. Within the white matter, the correlation between BPFs and diffusivity measures such as fractional anisotropy and radial diffusivity was modest, suggesting that diffusion tensor imaging and bound pool fractions are complementary techniques. We found that several major tracts have high BPF, suggesting a higher density of myelin in these tracts. We interpret these results in the context of a quantitative tissue model. PMID- 20828623 TI - Improved fMRI calibration: precisely controlled hyperoxic versus hypercapnic stimuli. AB - The calibration of functional magnetic resonance imaging (fMRI) for the estimation of neuronal activation-induced changes in cerebral metabolic rate of oxygen (CMRO(2)) has been achieved through hypercapnic-induced iso-metabolic increases in cerebral blood flow (CBF). Hypercapnia (HC) has been traditionally implemented through alterations in the fixed inspired fractional concentrations of carbon dioxide (F(I)CO(2)) without otherwise controlling end-tidal partial pressures of carbon dioxide (P(ET)CO(2)) or oxygen (P(ET)O(2)). There are several shortcomings to the use of this manual HC method that may be improved by using precise targeting of P(ET)CO(2) while maintaining iso-oxia. Similarly, precise control of blood gases can be used to induce isocapnic hyperoxia (HO) to reduce venous deoxyhaemoglobin (dHb) and thus increase BOLD signals, without appreciably altering CMRO(2) or CBF. The aim of our study was to use precise end-tidal targeting to compare the calibration of BOLD signals under an isocapnic hyperoxic protocol (HOP) (rises in P(ET)O(2) to 140, 240 and 340 mm Hg from baseline) to that of an iso-oxic hypercapnic protocol (HCP) (rises in P(ET)CO(2) of 3, 5, 7 and 9 mm Hg from baseline). Nine healthy volunteers were imaged at 3T while monitoring end-tidal gas concentrations and simultaneously measuring BOLD and CBF signals, via arterial spin labeling (ASL), during graded HCP and HOP, alternating with normocapnic states in a blocked experimental design. The variability of the calibration constant obtained under HOP (M(HOP)) was 0.3-0.5 that of the HCP one (M(HCP)). In addition, M-variances with precise gas targeting (M(HCP) and M(HOP)) were less than those reported in studies using traditional F(I)CO(2) and F(I)O(2) methods (M(HC) and M(HO), respectively). We conclude that precise controlled gas delivery markedly improves BOLD-calibration for fMRI studies of oxygen metabolism with both the HCP and the more precise HOP-alternative. PMID- 20828624 TI - Educational neuroscience: Developmental mechanisms: towards a conceptual framework. PMID- 20828625 TI - Anatomical connectivity mapping: a new tool to assess brain disconnection in Alzheimer's disease. AB - Previous studies suggest that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors. PMID- 20828626 TI - Evaluation of effective connectivity of motor areas during motor imagery and execution using conditional Granger causality. AB - The effective connectivity networks among overlapped core regions recruited by motor execution (ME) and motor imagery (MI) were explored by means of conditional Granger causality and graph-theoretic method, based on functional magnetic resonance imaging (fMRI) data. Our results demonstrated more circuits of effective connectivity among the selected seed regions during right-hand performance than during left-hand performance, implying the influences of brain asymmetry of right-handedness on effective connectivity networks. The increased causal connections were found during ME than during MI, suggesting that the ME network may have some additional connections compared to MI networks to execute the overt physical movement. Furthermore, the In-Out degrees of information flow suggested left dorsal premotor cortex (PMd), inferior parietal lobule (IPL) and superior parietal lobule (SPL) as causal sources in ME/MI tasks, highlighting the dominant function of left PMd, IPL and SPL. These findings depicted the causal connectivity of motor related core regions in fronto-parietal circuit and might indicate the conversion of causal networks between ME and MI. PMID- 20828627 TI - Chloroplast phylogeny and phylogeography of Stellera chamaejasme on the Qinghai Tibet Plateau and in adjacent regions. AB - Historic events such as the uplift of Qinghai-Tibet Plateau (Q-T Plateau) and climatic oscillations in the Quaternary period greatly affected the evolution and modern distribution of Sino-Tibetan flora. Stellera chamaejasme, a perennial herb with flower color polymorphism that is distributed from the mountainous southeastern Q-T Plateau (Hengduan Mountains, H-D Mountains) to the vast platform of the Q-T Plateau and the adjacent plain of northern China, provides an excellent model to explore the effects of historic events on the origination and variation of species. In this study, we conducted a phylogenetic and phylogeographical study using three chloroplast sequences (trnT-L, trnL-F and rpL16) in 26 populations of S. chamaejasme and 12 outgroups from the Thymeleaceae. Phylogenetic analysis and molecular clock estimation revealed that the monophyletic origin of S. chamaejasme occurred ca. 6.5892 Ma, which is consistent with the radical environment changes caused by the rapid uplift of the Q-T Plateau ca. 7 Ma. Intra-specific differentiation of S. chamaejasme is estimated to have occurred after ca. 2.1 Ma. Twelve haplotypes were revealed from combined trnL-F and rpL16 sequences. High genetic diversity (h(T)=0.834) and population differentiation (N(ST)=0.997 and G(ST)=0.982) imply restricted gene flow among populations and significant geographical or environmental isolation. All populations from the vast plain of northern China were dominated by one haplotype (H1), and the same haplotype was fixed in most populations from the high elevation platform of the western and northern Q-T Plateau. In contrast, the majority of the haplotypes were found in the relatively narrow area of the H-D Mountains, in the southeastern distribution of S. chamaejasme. The contrasting haplotype distribution patterns suggested that the H-D Mountains were either a refugium for S. chamaejasme during the Quaternary climatic oscillations or a diversification center of this species. The present wide distribution of this species on the Q-T Plateau platform and in northern China is likely to have resulted from a rapid post-glacial population expansion from the southeastern refugium involving founder effects, facilitated by the adjacent geographic range with a similar grassland habitat. PMID- 20828628 TI - Cardiorespiratory arrest in a healthy volunteer after a single oral dose of 80 mg of the beta-blocker propranolol. PMID- 20828629 TI - Angiotensin modulates long-term memory expression but not long-term memory storage in the crab Chasmagnathus. AB - Memory reconsolidation is a dynamic process in which a previously consolidated memory becomes labile following reactivation by a reminder. In a previous study in the crab Chasmagnathus memory model, we showed that a water-shortage episode, via angiotensin modulation during reconsolidation, could reveal a memory that otherwise remains unexpressed: weakly trained animals cannot reveal long-term memory (LTM) except when an episode of noticeable ethological meaning, water deprivation, is contingent upon reconsolidation. However, these results are at variance with two of our previous interpretations: weak training protocols do not build LTM and angiotensin II modulates the strength of the information storing process. A parsimonious hypothesis is that in Chasmagnathus angiotensins regulate LTM expression, but not LTM storage. Here, we tested three predictions of this hypothesis. First, the well-known retrograde amnesic effect of the angiotensin II antagonist saralasin is not due to interference on memory storage, but to modulation of memory expression. Second, the recovery of the LTM memory expression of the apparently amnesic retrograde effect produced by saralasin, through the water-shortage episode contingent upon reconsolidation, must be reconsolidation specific. Consequently, summation-like effects and retrieval deficits cannot explain these results because of the parametric conditions of reconsolidation. Third, weak training protocols build an unexpressed LTM that requires mRNA transcription and translation, a diagnostic characteristic of LTM. Results show that angiotensin modulates LTM expression but not LTM memory storage in the crab Chasmagnathus. The results lead us to suggest that, in Chasmagnathus, LTM expression - the process of gaining appreciable control over behavior of the reactivated trace in the retrieval session - may be considered a distinct attribute of its long-term storage. This strategy, a positive modulation during reconsolidation, is proposed to distinguish between memories that can be reactivated, labilized and are not expressed, and memories that are not stored long term, obliterated or altered in other retrieval mechanisms. PMID- 20828630 TI - Estradiol and ERbeta agonists enhance recognition memory, and DPN, an ERbeta agonist, alters brain monoamines. AB - Effects of estradiol benzoate (EB), ERalpha-selective agonist, propyl pyrazole triol (PPT) and ERbeta-selective agonists, diarylpropionitrile (DPN) and Compound 19 (C-19) on memory were investigated in OVX rats using object recognition (OR) and placement (OP) memory tasks. Treatments were acute (behavior 4h later) or sub chronic (daily injections for 2 days with behavior 48 h later). Objects were explored in sample trials (T1), and discrimination between sample (old) and new object/location in recognition trials (T2) was examined after 2-4h inter-trial delays. Subjects treated sub chronically with EB, DPN, and C-19, but not PPT, discriminated between old and new objects and objects in old and new locations, suggesting that, at these doses and duration of treatments, estrogenic interactions with ERbeta contribute to enhancements in recognition memory. Acute injections of DPN, but not PPT, immediately after T1, also enhanced discrimination for both tasks (C19 was not investigated). Effects of EB, DPN and PPT on anxiety and locomotion, measured on elevated plus maze and open field, did not appear to account for the mnemonic enhancements. Monoamines and metabolites were measured following DPN treatment in subjects that did not receive behavioral testing. DPN was associated with alterations in monoamines in several brain areas: indexed by the metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), or the MHPG/norepinephrine (NE) ratio, NE activity was increased by 60-130% in the prefrontal cortex (PFC) and ventral hippocampus, and NE activity was decreased by 40-80% in the v. diagonal bands and CA1. Levels of the dopamine (DA) metabolite, homovanillic acid (HVA), increased 100% in the PFC and decreased by 50% in the dentate gyrus following DPN treatment. The metabolite of serotonin, 5 hydroxyindole acetic acid (5-HIAA), was increased in the PFC and CA3, by approximately 20%. No monoaminergic changes were noted in striatum or medial septum. Results suggest that ERbeta mediates sub chronic and acute effects of estrogens on recognition memory and that memory enhancements by DPN may occur, in part, through alterations in monoaminergic containing systems primarily in PFC and hippocampus. PMID- 20828631 TI - Influence of environmental variables and reproduction on the gonadal fatty acid profile of tropical scallop Nodipecten nodosus. AB - We examined the influence of the reproductive cycle and environmental variables on the gonadal fatty acid profile in the tropical scallop Nodipecten nodosus. Individuals from a natural population in north-eastern Venezuela (Caribbean Sea) were sampled monthly during one year. The gonadosomatic index (GSI) and a visual assessment of gonadic status are also reported. The environmental conditions characterized by chlorophyll a, temperature and seston concentration were measured in parallel. The highest reproductive activity, with a GSI of 13-18%, was observed from November 2003 to April 2004, and a decrease in GSI, taken as an indication of three spawning periods, was recorded in October, January and May June. The GSI was 5-8% outside these intervals. A similar trend was observed in maturity stage frequency. Statistical analysis (MDS-ANOSIM) established two different periods; one dominated by upwelling (January to July) and the other characteristic of non-upwelling conditions (August to December). The fatty acids 16:0, 22:6n-3, 20:5n-3 and 16:1n-7 were responsible for the differences between two periods and explained 50% of the observed variance. Accordingly, during the upwelling period, fatty acids such as 22:6n-3 were positively correlated with temperature, organic seston and bivalves in the spent sexual stage and inversely related to the GSI. Furthermore, individuals in the ripe sexual stage were positively related to 20:5n-3 and 18:3n-3, whereas chlorophyll a was directly related to 18:1n-7 and 16:1n-7. In the non-upwelling period, a significant and positive correlation was obtained between fatty acids such as 20:5n-3 and 22:6n-3 and the GSI and the bivalves in the ripe sexual stage, whereas these acids were inversely correlated with the spent sexual stage. In addition, chlorophyll a was positively related to 18:1n-9 and 18:2n-6. Changes in the gonadal fatty acid profile of N. nodosus were influenced by the environmental variables (exogenous factors) during the upwelling and non-upwelling periods and by reproductions (endogenous factors). PMID- 20828632 TI - Gene pathways and subnetworks distinguish between major glioma subtypes and elucidate potential underlying biology. AB - Molecular diagnostic tools are increasingly being used in an attempt to classify primary human brain tumors more accurately. While methods that are based on the analysis of individual gene expression prove to be useful for diagnostic purposes, they are devoid of biological significance since tumorgenesis is a concerted deregulation of multiple pathways rather than single genes. In a proof of concept, we utilize two large clinical data sets and show that the elucidation of enriched pathways and small differentially expressed sub-networks of protein interactions allow a reliable classification of glioblastomas and oligodendrogliomas. Applying a feature selection method, we observe that an optimized subset of pathways and subnetworks significantly improves the prediction accuracy. By determining the enrichment of altered genes in pathways and subnetworks we show that optimized subsets of genes rarely seem to be a target of genomic alteration. Our results suggest that groups of genes play a decisive role for the phenotype of the underlying tumor samples that can be utilized to reliably distinguish tumor types. In the absence of enrichment of genes that are genomically altered we assume that genetic changes largely exert an indirect rather than direct regulatory influence on a number of tumor-defining regulatory networks. PMID- 20828633 TI - Spontaneous type 1 electrocardiographic pattern is associated with cardiovascular magnetic resonance imaging changes in Brugada syndrome. AB - BACKGROUND: Patients with Brugada syndrome (BrS) and a spontaneous type 1 ECG are considered to be at greater increased risk for sudden cardiac death than are patients with an abnormal ECG only after administration of sodium channel blockers and therefore represent a more severe phenotype. Thus, it can be hypothesized that in the presence of a more severe electrical phenotype, structural and functional changes are more likely expected because electrical changes can play a causal role in producing structural changes. OBJECTIVE: The purpose of this study was to investigate whether the different ECG manifestations in patients with BrS are associated with structural changes detected by cardiovascular magnetic resonance imaging. METHODS: Cardiovascular magnetic resonance imaging was performed on 69 consecutive patients with proven BrS and 30 healthy controls. Twenty-six patients had a spontaneous diagnostic type 1 BrS ECG; the remainder had a type 1 response to ajmaline provocation. Left and right ventricular volumes and dimensions were assessed and compared with respect to ECG pattern. RESULTS: The right ventricular outflow tract area was significantly enlarged in patients with a spontaneous type 1 ECG compared to patients with a nondiagnostic resting ECG or controls (11 cm(2), 9 cm(2), and 9 cm(2), respectively, P < .05). Patients with a spontaneous type 1 BrS ECG revealed significantly lower left ventricular ejection fraction than did patients with a nondiagnostic resting ECG and controls (56 +/- 5 vs 59 +/- 5 vs 60 +/- 4, respectively, P < .05) and significantly lower right ventricular ejection fraction (54 +/- 5 vs 59 +/- 5, P = .001) as well as end-systolic volumes compared to controls (34 +/- 9 mL/m(2) vs 28 +/- 79 mL/m(2), P = .02). CONCLUSION: Patients with a spontaneous type 1 BrS ECG reveal significantly functional and morphological alterations in both the left and right ventricles compared to patients with basal nondiagnostic ECG or controls. PMID- 20828634 TI - Research to Encourage Exercise for Fibromyalgia (REEF): use of motivational interviewing design and method. AB - Fibromyalgia (FM), defined as the presence of both chronic widespread pain and the finding of 11/18 tender points on examination, is an illness associated with major personal and societal burden. Supervised aerobic exercise is an important treatment modality to improve patient symptoms. Unfortunately, adherence to an exercise regimen after a structured supervised program is disappointingly low. Since FM is a chronic illness, studies are needed to test strategies that would enhance exercise adherence in these individuals. Individuals who are able to adhere to exercise almost always maintain the symptomatic benefits of exercise. The objective of this paper was to describe the protocol of the Research to Encourage Exercise for Fibromyalgia (REEF). REEF is a randomized attention controlled trial that seeks to test the efficacy of 6 sessions of telephone delivered motivational interviewing (MI) that targets exercise adherence to improve FM-relevant clinical outcomes (i.e., physical function and pain severity). The trial has recently completed enrolling 216 subjects, and randomization has resulted in well-balanced groups. Details on the study design, MI program, and treatment fidelity are provided in the paper. Outcome assessments at week 12, week 24 and week 36 will test the immediate, intermediate and long term effects of exercise-based MI on adherence (as measured by the Community Health Activities Model Program for Seniors/CHAMPS and accelerometer) and clinical outcomes. When completed, REEF will determine whether exercise-based MI could be utilized as a management strategy to sustain the clinical benefits of exercise for FM. PMID- 20828635 TI - A randomized trial of genetic and environmental risk assessment (GERA) for colorectal cancer risk in primary care: trial design and baseline findings. AB - PURPOSE: This paper describes an ongoing randomized controlled trial designed to assess the impact of genetic and environmental risk assessment (GERA) on colorectal cancer (CRC) screening. METHODS: The trial includes asymptomatic patients who are 50-79years and are not up-to-date with CRC screening guidelines. Patients who responded to a baseline telephone survey are randomized to a GERA or Control group. GERA group participants meet with a nurse, decide whether to have a GERA blood test (a combination of genetic polymorphism and folate), and, if tested, receive GERA feedback. Follow-up telephone surveys are conducted at 1 and 6months. A chart audit is performed at 6months. RESULTS: Of 2,223 eligible patients, 562 (25%) have enrolled. Patients who enrolled in the study were significantly younger than those who did not (p<0.001). Participants tended to be 50-59years (64%), female (58%), white (52%), married (51%), and have more than a high school education (67%). At baseline, most participants had some knowledge of CRC screening and GERA, viewed CRC screening favorably, and reported that they had decided to do screening. Almost half had worries and concerns about CRC. CONCLUSIONS: One in four eligible primary care patients enrolled in the study. Age was negatively associated with enrollment. Prospective analyses using data for all participants will provide more definitive information on GERA uptake and the impact of GERA feedback. PMID- 20828636 TI - A web-based medical safety reporting system for a large multicenter clinical trial: the ALIAS experience. AB - An electronic safety reporting (ESR) module was developed and integrated into a home-grown web-based clinical trial management system (CTMS) to enhance the efficiency, completeness and consistency of reporting and reviewing serious adverse events, monitoring safety, and submitting safety reports to regulatory authorities for a large multicenter clinical trial. The architecture of this integrated module provided many advantages. First, the ESR module was developed based on a comprehensive procedure which incorporated both computer logic processing steps and human intervention steps in order to deal with the complex and unexpected situations where pre-programmed computer logic may fail. Second, safety and efficacy data were managed within the same relational database. Relevant data captured on efficacy case report forms, such as demographics, medical history, lab data and concomitant medications, were directly retrievable for MedWatch report composition without requiring redundant data entry. Finally, the ESR module shared the same generic user interfaces and data processing functions with other modules in the CTMS. These generic components include data editing, data retrieving, data reporting, dictionary-based automatic and interactive coding, event-driven and calendar-driven automatic email notifications, and user privilege management. This integrated ESR module was implemented in the Albumin in Acute Stroke (ALIAS) Trial-Part 1. A total of 397 serious adverse event reports were processed and 33 FDA MedWatch reports, 28 initial reports, and 5 follow-up reports were submitted to FDA and Health Canada using this system. Experiences and lessons learned from the development and implementation of this system are presented in this paper. PMID- 20828637 TI - Template-based modeling of a psychrophilic lipase: conformational changes, novel structural features and its application in predicting the enantioselectivity of lipase catalyzed transesterification of secondary alcohols. AB - In order to fully explore the structure-function relationship of a Proteus lipase (LipK107) that was screened from the soil in our previous study, we have modeled the three-dimensional (3-D) structures of the enzyme in its active and inactive conformations on the basis of crystal structures of Burkholderia glumae and Pseudomonas aeruginosa lipases in the present study. Both homology models suggested that LipK107 possessed a catalytic triad (Ser79-Asp232-H254), an oxyanion hole (Leu13 and Gln80) which was used to stabilize the reaction tetrahedral intermediates, and a lid substructure that controlled the access of the substrate to the active site. The existence of the lid was further verified by carrying out the interfacial activation experiment. The conformational change of LipK107 which was caused by lid opening action was predicted by superimposing the two theoretical models for the first time. Finally, both 3-D structures were used to predict the enantioselectivity of LipK107 when the enzyme was used to catalyze the resolution of racemic 1-phenylethanol. Lid-open model of LipK107 identified the R-enantiomer as the preferred enantiomer, while lid-closed mode showed that the S-enantiomer was more favored. However, only the lid-open conformational model could led to predictions that agreed with the following the experimental result of real biocatalysis reaction of 1-phenylethanol. PMID- 20828638 TI - Long-term toughness of photopolymerizable (meth)acrylate networks in aqueous environments. AB - Photopolymerizable (meth)acrylate networks are potentially advantageous biomaterials due to their ability to be formed in situ, their fast synthesis rates and their tailorable material properties. The objective of this study was to evaluate how immersion time in phosphate-buffered saline (PBS) affects the toughness of photopolymerizable methyl acrylate (MA)-co-methyl methacrylate-co poly(ethylene glycol) dimethacrylate networks containing various concentrations of MA. Stress-strain behavior was determined by performing tensile strain to failure testing after soaking in PBS for different periods (1 day up to 9 months). In tandem, differential scanning calorimetry and PBS content measurements were undertaken at each time point in order to determine whether time-dependent changes in toughness were related to changes in T(g) or PBS absorption. The effect of immersion time on network toughness was shown to be dependent upon composition in a manner related to the viscoelastic state of the polymer upon initial immersion in PBS. The results demonstrate that tough acrylate-based materials may not maintain their toughness after several months in PBS. In addition, decreasing the PBS content by changing the network hydrophobicity resulted in better toughness maintenance after 9 months. The results provide a possible means to toughen various amorphous acrylate-based implant materials that are being explored for load-bearing biomedical applications, beyond the systems considered in this work. PMID- 20828640 TI - Neutrophils: Cinderella of innate immune system. AB - Neutrophils are the first line of innate immune defense against infectious diseases. However, since their discovery by Elie Metchnikoff, they have always been considered tissue-destructive cells responsible for inflammatory tissue damage occurring during acute infections. Now, extensive research in the field of neutrophil cell biology and their role skewing the immune response in various infections or inflammatory disorders revealed their importance in the regulation of immune response. Along with releasing various antimicrobial molecules, neutrophils also release neutrophil extracellular traps (NETs) for the containment of infection and inflammation. Activated neutrophils provide signals for the activation and maturation of macrophages as well as dendritic cells. Neutrophils are also involved in the regulation of T-cell immune response against various pathogens and tumor antigens. Thus, the present review is intended to highlight the emerging role of neutrophils in the regulation of both innate and adaptive immunity during acute infectious or inflammatory conditions. PMID- 20828639 TI - Osteopontin is required for unloading-induced osteoclast recruitment and modulation of RANKL expression during tooth drift-associated bone remodeling, but not for super-eruption. AB - Unloading of teeth results in extensive alveolar bone remodeling, causing teeth to move in both vertical ("super-eruption") and horizontal direction ("drift"). In order to decipher the molecular mechanisms of unloading-induced bone remodeling during tooth movement, we focused on the role of osteopontin (OPN) in the un-opposed molar model, comparing wild-type (WT) and OPN-null mice. Our data indicated that OPN was not required for the continuous eruption of un-opposed teeth while OPN was necessary for the drift of teeth. OPN expression and osteoclast counts were greatly increased on alveolar bone surfaces facing the direction of the drift in WT mice, while osteoclast counts were diminished in OPN /- mice. RANKL expression in the distal periodontal ligament of WT molars increased significantly by day 6 following unloading, while overall levels of RANKL expression were decreased in both WT and OPN-null mice. In vitro treatment of MC3T3 cells, WT BMCs and OPN-/- BMCs with recombinant OPN resulted in significantly increased RANKL expression in all three cell types. The PI3K and MEK/ERK pathway inhibitors Ly294002 and U0126 reduced RANKL expression levels in vitro. Treatment of BMCs and MC3T3 with OPN also resulted in increased ERK phosphorylation and reduced OPG levels. Together, our studies suggest that increased OPN expression during unloading-induced drifting of teeth enhances localized RANKL expression and osteoclast activity on drift-direction alveolar bone surfaces via extracellular matrix signaling pathways. PMID- 20828641 TI - Curcumin has bright prospects for the treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS). It is associated with a variety of pathophysiological features, including breakdown of the blood-brain barrier (BBB), autoimmune attack, injury of axons and myelin sheaths. Th17 cells are considered as a key immunological player for the pathophysiological process of MS. Neuroprotective approaches work best prior to the initiation of damage, suggesting that some safe and effective prophylaxis would be highly desirable. Curcumin, a dietary spice from turmeric, has outstanding anti-inflammation and neuroprotective effects. Herein, we review key features of curcumin involved biology, pharmacology, and medicinal chemistry and discuss its potential relevance to pathophysiological progress of MS. PMID- 20828642 TI - Immunomodulatory and therapeutic activity of curcumin. AB - Inflammation is a disease of vigorous uncontrolled activated immune responses. Overwhelming reports have suggested that the modulation of immune responses by curcumin plays a dominant role in the treatment of inflammation and metabolic diseases. Observations from both in-vitro and in-vivo studies have provided strong evidence towards the therapeutic potential of curcumin. These studies have also identified a plethora of biological targets and intricate mechanisms of action that characterize curcumin as a potent 'drug' for numerous ailments. During inflammation the functional influence of lymphocytes and the related cross talk can be modulated by curcumin to achieve the desired immune status against diseases. This review describes the regulation of immune responses by curcumin and effectiveness of curcumin in treatment of diseases of diverse nature. PMID- 20828643 TI - Coronary artery proliferation and steal phenomenon in Takayasu's disease with occlusion of supra-aortal branches demonstrated by 320-slice computed tomography. PMID- 20828644 TI - Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. AB - The addition of clopidogrel to aspirin treatment reduces ischemic events in a wide range of patients with cardiovascular disease. However, recurrent ischemic event occurrence during dual antiplatelet therapy, including stent thrombosis, remains a major concern. Platelet function measurements during clopidogrel treatment demonstrated a variable and overall modest level of P2Y(12) inhibition. High on-treatment platelet reactivity to adenosine diphosphate (ADP) was observed in selected patients. Multiple studies have now demonstrated a clear association between high on-treatment platelet reactivity to ADP measured by multiple methods and adverse clinical event occurrence. However, the routine measurement of platelet reactivity has not been widely implemented and recommended in the guidelines. Reasons for the latter include: 1) a lack of consensus on the optimal method to quantify high on-treatment platelet reactivity and the cutoff value associated with clinical risk; and 2) limited data to support that alteration of therapy based on platelet function measurements actually improves outcomes. This review provides a consensus opinion on the definition of high on-treatment platelet reactivity to ADP based on various methods reported in the literature and proposes how this measurement may be used in the future care of patients. PMID- 20828645 TI - The anti-ischemic mechanism of action of ranolazine in stable ischemic heart disease. AB - OBJECTIVES: The purpose of this explanatory analysis was to investigate the relationship between ST-segment depression and the rate-pressure product (RPP) during exercise to determine whether ranolazine's mechanism of action was related to a reduction in myocardial oxygen demand or preservation of myocardial oxygen supply. BACKGROUND: In patients with stable ischemic heart disease, ranolazine increases exercise duration and reduces maximal ST-segment depression while exerting minimal effects on heart rate and blood pressure, although its mechanism of action during exercise has not been investigated. METHODS: Patients with stable ischemic heart disease (n = 191) were randomly allocated to a 4-period, double-blind, balanced Latin square crossover study to receive placebo, and ranolazine 500, 1,000, and 1,500 mg twice daily (bid) for 1 week each. Exercise treadmill tests were performed at baseline and at the end of each treatment period. The RPP and ST-segment depression were assessed before starting exercise, at each stage of exercise, and at maximal exercise. RESULTS: Compared with placebo, ranolazine produced a dose-dependent reduction in ST-segment depression that became more marked as exercise-induced ischemia became more pronounced, associated with clinically minor decreases in heart rate and blood pressure. At 12-min exercise, the amount of ST-segment depression compared with placebo and controlled for RPP was reduced by 22.3% on ranolazine 500 mg bid (p = 0.137), by 35.4% on 1,000 mg bid (p = 0.005), and by 45.8% on 1,500 mg bid (p < 0.001). CONCLUSIONS: The progressive magnitude of ischemia reduction on ranolazine was proportionally more substantial than the minor reductions in heart rate or RPP, suggesting that ranolazine's beneficial mechanism of action is most likely primarily due to an improvement in regional coronary blood flow in areas of myocardial ischemia. PMID- 20828646 TI - Ranolazine and its anti-ischemic effects: revisiting an old mechanistic paradigm anew? PMID- 20828647 TI - Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events. AB - OBJECTIVES: This study sought to assess whether oxidation-specific biomarkers are associated with an increased risk of coronary artery disease (CAD) events. BACKGROUND: The relationship of a panel of oxidative biomarkers and lipoprotein(a) [Lp(a)] to CAD risk is not fully determined. METHODS: A prospective case-control study nested in the EPIC (European Prospective Investigation of Cancer)-Norfolk cohort of 45- to 79-year-old apparently healthy men and women followed for approximately 6 years was designed. Cases consisted of participants in whom fatal or nonfatal CAD developed, matched by sex, age, and enrollment time with controls without CAD. Baseline levels of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were measured in 763 cases and 1,397 controls. Their relationship to secretory phospholipase A(2) type IIA mass and activity, myeloperoxidase mass, and lipoprotein-associated phospholipase A(2) activity and association with CAD events were determined. RESULTS: After adjusting for age, smoking, diabetes, low- and high-density lipoprotein cholesterol, and systolic blood pressure, the highest tertiles of oxidized phospholipids on apolipoprotein B-100 particles and Lp(a) were associated with a significantly higher risk of CAD events (odds ratios: 1.67 and 1.64, respectively; p < 0.001) compared with the lowest tertiles. The odds ratio of CAD events associated with the highest tertiles of oxidized phospholipids on apolipoprotein B-100 particles or Lp(a) was significantly potentiated (approximately doubled) by the highest tertiles of secretory phospholipase A(2) activity and mass but less so for myeloperoxidase and lipoprotein-associated phospholipase A(2) activity. The odds ratios for fatal CAD were higher than for the combined end point. After taking into account the Framingham Risk Score, c index values progressively increased when oxidative biomarkers were added to the model. CONCLUSIONS: This EPIC-Norfolk study links pathophysiologically related oxidation-specific biomarkers and Lp(a) with CAD events. Oxidation-specific biomarkers provide cumulative predictive value when added to traditional cardiovascular risk factors. PMID- 20828648 TI - Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. AB - OBJECTIVES: The purpose of this study was to determine the benefit and risk associated with antiplatelet therapy in the chronic kidney disease (CKD) population. BACKGROUND: Cardiovascular and possibly bleeding risks are elevated in patients with CKD. The balance of benefit and harm associated with antiplatelet therapy remains uncertain. METHODS: The HOT (Hypertension Optimal Treatment) study randomly assigned participants with diastolic hypertension to aspirin (75 mg) or placebo. Study treatment effects were calculated using univariate proportional hazards regression models stratified by baseline estimated glomerular filtration rate (eGFR) with trends tested by adding interaction terms. End points included major cardiovascular events, total mortality, and major bleeding. RESULTS: The study included 18,597 participants treated for 3.8 years. Baseline eGFR was < 60 ml/min/1.73 m(2) in 3,619 participants. Major cardiovascular events were reduced by 9% (95% confidence interval [CI]: -9% to 24%), 15% (95% CI: -17% to 39%), and 66% (95% CI: 33% to 83%) for patients with baseline eGFR of >= 60, 45 to 59, and < 45 ml/min/1.73 m(2), respectively (p trend = 0.03). Total mortality was reduced by 0% (95% CI: 20% to 17%), 11% (95% CI: -31% to 40%), and 49% (95% CI: 6% to 73%), respectively (p trend = 0.04). Major bleeding events were nonsignificantly greater with lower eGFR (hazard ratio [HR]: 1.52 [95% CI: 1.11 to 2.08], HR: 1.70 [95% CI: 0.74 to 3.88], and HR: 2.81 [95% CI: 0.92 to 8.84], respectively; p trend = 0.30). Among every 1,000 persons with eGFR < 45 ml/min/1.73 m(2) treated for 3.8 years, 76 major cardiovascular events and 54 all-cause deaths will be prevented while 27 excess major bleeds will occur. CONCLUSIONS: Aspirin therapy produces greater absolute reduction in major cardiovascular events and mortality in hypertensive patients with CKD than with normal kidney function. An increased risk of major bleeding appears to be outweighed by the substantial benefits. PMID- 20828649 TI - Aspirin and the prevention of cardiovascular disease in chronic kidney disease: time to move forward? PMID- 20828650 TI - The value of defibrillator electrograms for recognition of clinical ventricular tachycardias and for pace mapping of post-infarction ventricular tachycardia. AB - OBJECTIVES: The purpose of this study was to assess the value of implantable cardioverter-defibrillator (ICD) electrograms (EGMs) in identifying clinically documented ventricular tachycardias (VTs). BACKGROUND: Twelve-lead electrocardiograms (ECG) of spontaneous VT often are not available in patients referred for catheter ablation of post-infarction VT. Many of these patients have ICDs, and the ability of ICD EGMs to identify a specific configuration of VT has not been described. METHODS: In 21 consecutive patients referred for catheter ablation of post-infarction VT, 124 VTs (mean cycle length: 393 +/- 103 ms) were induced, and ICD EGMs were recorded during VT. Clinical VT had been documented with 12-lead ECGs in 15 of 21 patients. The 12-lead ECGs of the clinical VTs were compared with 64 different inducible VTs (mean cycle length: 390 +/- 91 ms) to assess how well the ICD EGMs differentiated the clinical VTs from the other induced VTs. The exit site of 62 VTs (mean cycle length: 408 +/- 112 ms) was identified by pace mapping (10 to 12 of 12 matching leads). The spatial resolution of pace mapping to identify a VT exit site was determined for both the 12-lead ECGs and the ICD EGMs using a customized MATLAB program (version 7.5, The MathWorks, Inc., Natick, Massachusetts). RESULTS: Analysis of stored EGMs by comparison of receiver-operating characteristic curve cutoff values accurately distinguished the clinical VTs from 98% of the other inducible VTs. The mean spatial resolution of a 12-lead ECG pace map for the VT exit site was 2.9 +/- 4.0 cm(2) (range 0 to 17.5 cm(2)) compared with 8.9 +/- 9.0 cm(2) (range 0 to 35 cm(2)) for ICD EGM pace maps. The spatial resolution of pace mapping varied greatly between patients and between VTs. The spatial resolution of ICD EGMs was < 1.0 cm(2) for >= 1 of the target VTs in 12 of 21 patients and 19 of 62 VTs. By visual inspection of the ICD EGMs, 96% of the clinical VTs were accurately differentiated from previously undocumented VTs. CONCLUSIONS: Stored ICD EGMs usually are an accurate surrogate for 12-lead ECGs for differentiating clinical VTs from other VTs. Pace mapping based on ICD EGMs has variable resolution but may be useful for identifying a VT exit site. PMID- 20828651 TI - Is it the same or a different ventricular tachycardia?: an additional use for defibrillator electrograms. PMID- 20828652 TI - Assessment of coronary artery disease using magnetic resonance coronary angiography: a national multicenter trial. AB - OBJECTIVES: This national multicenter study determined the diagnostic performance of 1.5-T whole-heart coronary magnetic resonance angiography (MRA) in patients with suspected coronary artery disease (CAD). BACKGROUND: Whole-heart coronary MRA using steady-state free precession allows noninvasive detection of CAD without the administration of contrast medium. However, the accuracy of this approach has not been determined in a multicenter trial. METHODS: Using a 1.5-T magnetic resonance imaging unit, free-breathing steady-state free precession whole-heart coronary MRA images were acquired for 138 patients with suspected CAD at 7 hospitals. The accuracy of MRA for detecting a >= 50% reduction in diameter was determined using X-ray coronary angiography as the reference method. RESULTS: Acquisition of whole-heart coronary MRA images was performed in 127 (92%) of 138 patients with an average imaging time of 9.5 +/- 3.5 min. The areas under the receiver-operator characteristic curve from MRA images according to vessel- and patient-based analyses were 0.91 (95% confidence interval [CI]: 0.87 to 0.95) and 0.87 (95% CI: 0.81 to 0.93), respectively. The sensitivity, specificity, positive and negative predictive values, and accuracy of MRA according to a patient-based analysis were 88% (49 of 56, 95% CI: 75% to 94%), 72% (51 of 71, 95% CI: 60% to 82%), 71% (49 of 69, 95% CI: 59% to 81%), 88% (51 of 58, 95% CI: 76% to 95%), and 79% (100 of 127, 95% CI: 72% to 86%), respectively. CONCLUSIONS: Non-contrast enhanced whole-heart coronary MRA at 1.5-T can noninvasively detect significant CAD with high sensitivity and moderate specificity. A negative predictive value of 88% indicates that whole-heart coronary MRA can rule out CAD. PMID- 20828653 TI - Magnetic resonance coronary angiography: the condemned live longer. PMID- 20828654 TI - Effects of Reiki on autonomic activity early after acute coronary syndrome. PMID- 20828655 TI - Caveat emptor: the coronary calcium warranty. PMID- 20828657 TI - Timing of intervention in patients undergoing invasive management for acute coronary syndromes. PMID- 20828659 TI - Effect of ionic environment on the transport of cesium ion in alkali chloride solutions from radio tracer studies. AB - The rate of transport (diffusion) of cesium ion in aqueous solutions of all the alkali metal chlorides together with cesium iodide and cesium fluoride (generalized name MX) at 25 degrees C temperature has been measured by the radioactive tracer technique using (134)Cs as tracer, over the 0.04.0 M. These diffusion data along with other transport data in the literature are used to calculate the velocity correlation coefficients (VCC) for Cs-M, Cs-H(2)O and Cs-X, which actually represent the ensemble average time integrals of the velocity correlation functions of the referred pair of species. The concentration dependence of VCC gives a quantitative estimate of the influence of environment and its dynamics on the transport of cation cesium in a highly correlated system like aqueous solutions of 1-1 electrolytes. PMID- 20828660 TI - Evaluation of trace element levels in muscles, liver and gonad of fish species from Sao Francisco River of the Parana Brazilian state by using SR-TXRF technique. AB - This study is focused on the analysis of an accumulation of inorganic elements in muscles, liver and gonad of seven fish species from Sao Francisco River located in the Parana state of Brazil. Concentrations of the elements were determined using the SR-TXRF technique. In the muscles of fish species, negative length dependent relationships were observed for chromium and zinc ion absorption. The obtained results showed that accumulated Cr ions values are above the limits defined in the Brazilian legislative norm on food. PMID- 20828661 TI - Real-time immunohistochemistry analysis of embedded tissue. AB - We present a novel analysis of membrane-protein expression in tissue sections based on semi-automatic real-time measurement using LigandTracer((r)) technology. A commercial antiHER2 antibody developed for immunohistochemistry used in this setup was revealed to have sub-optimal interaction with tissue when analyzed as recommended for immunohistochemistry. We therefore think that real-time measurement of tissue, offering direct and quantitative membrane-protein interaction analysis, can lead to improved reproducibility and eliminate the subjective operator dependences that classical immunohistochemsitry suffers from. PMID- 20828662 TI - Response to review of Cancer Survivor's Guide. PMID- 20828663 TI - The challenges of being 'off to college'. PMID- 20828665 TI - Effect of low-carbohydrate claims on consumer perceptions about food products' healthfulness and helpfulness for weight management. AB - OBJECTIVE: Evaluate effect of low-carbohydrate claims on consumer perceptions about food products' healthfulness and helpfulness for weight management. DESIGN: Experiment in which participants were randomly assigned 1 of 12 front-of-package claim conditions on bread or a frozen dinner. Seven of the 12 conditions also included Nutrition Facts (NF) information. SETTING: Internet. PARTICIPANTS: 4,320 members of a national on-line consumer panel. INTERVENTION: Exposure to images of a food package. MAIN OUTCOME MEASURES: Ratings on Likert scales about perceived healthfulness, helpfulness for weight management, and caloric content. ANALYSIS: Mean ratings by outcome measure, condition, and product were calculated. Ratings were also used as the dependent measure in analysis of variance models. RESULTS: Participants who saw front-of-package-only conditions rated products bearing low carbohydrate claims as more helpful for weight management and lower in calories than the same products without a claim. Those who saw the bread with low carbohydrate claims also rated it as more healthful than those who saw no claim. When the NF label was available and products had the same nutrition profile, participants rated products with low-carbohydrate claims the same as those with no claim. CONCLUSIONS AND IMPLICATIONS: Consumers who do not use the NF panel may interpret low-carbohydrate claims to have meaning beyond the scope of the claim itself. PMID- 20828666 TI - Food security in older australians from different cultural backgrounds. AB - OBJECTIVE: To investigate the experiences and barriers to food security of community-dwelling older people. DESIGN: Quantitative questionnaire and 5 focus group discussions using purposive sampling. SETTING: Shire of Melton, Victoria, Australia. PARTICIPANTS: Thirty-seven people (13 male and 24 female), between 58 and 85 years of age, from Anglo-Celtic (15), Macedonian (6), Serbian (8), and Maltese (8) backgrounds. PHENOMENA OF INTEREST: Food security perceptions and barriers. ANALYSES: Quantitative data were analyzed using descriptive statistics and chi-square. The focus group data (transcripts) were subjected to a systematic thematic analysis to identify major themes and subthemes. RESULTS: Cost and financial considerations, health and physical capacity, transport, intrapersonal factors, and lack of availability of preferred food all emerged as potential barriers to participants accessing nutritious food of their choice. CONCLUSIONS AND IMPLICATIONS: Overall, the quantitative and qualitative data indicated that the changing circumstances that accompany growing older influenced this group's ability to independently shop for, prepare, and eat affordable and nutritious food. Nutrition educators, in conjunction with local government service providers, have the opportunity to play a key role in building upon existing safety nets and innovative initiatives to ensure older people have access to adequate and appropriate food of their choice. PMID- 20828667 TI - Job satisfaction and retention of community nutrition educators: the importance of perceived value of the program, consultative supervision, and work relationships. AB - OBJECTIVE: To investigate how paraprofessional Community Nutrition Educators' (CNEs') perceptions of work context relate to job satisfaction and intention to leave the position. DESIGN: Cross-sectional statewide survey of program personnel. SETTING: Expanded Food and Nutrition Education Program (EFNEP) sites (n = 32) serving low- income families in New York. PARTICIPANTS: CNEs delivering EFNEP (n = 115). MAIN OUTCOME MEASURES: CNE job satisfaction and intention to leave. ANALYSIS: Multivariate regression analysis predicting work attitudes from perceived work context, CNE personality traits, and characteristics of CNEs, supervisors, and programs. RESULTS: Despite low satisfaction with pay, overall job satisfaction was high and intention to leave was low. Satisfaction was positively related to CNEs' perceptions of program value, work relationships, and having a voice in relevant decisions (adjusted R(2) = 0.60). Intention to leave was negatively related to perceptions of program value and supervision and satisfaction with pay (adjusted R(2) = 0.36), but the latter relationship was found only among more educated CNEs. CONCLUSIONS AND IMPLICATIONS: CNEs' satisfaction and intention to leave were strongly associated with perceptions of program value, work relationships, and consultative management. Intrinsically motivating work, often viewed as the domain of professionals, is critical for the morale and retention of paraprofessional nutrition educators. PMID- 20828668 TI - An evaluation of the validity and reliability of a food behavior checklist modified for children. AB - OBJECTIVE: The objective of this study was to report the construct validity and internal consistency reliability of the Food Behavior Checklist modified for children (FBC-MC), with low-income, Youth Expanded Food and Nutrition Education Program (EFNEP)-eligible children. METHODS: Using a cross-sectional research design, construct validity was assessed using confirmatory factor analysis (weighted least squares method), and internal consistency reliability for 3 subscales was assessed using Cronbach alpha. RESULTS: Ninety-seven children from low-income families completed the FBC-MC. Indicator tests suggest adequate model fit (comparative fit index = 0.962; root mean square error of approximation = 0.064) and item factor loadings were significant for all subscales (P < .05). The instrument appeared to have adequate reliability for 1 subscale (fruit and vegetable consumption, alpha = 0.67), but not for the other 2 (milk consumption, alpha = 0.43; healthful eating behaviors, alpha = 0.56). CONCLUSIONS AND IMPLICATIONS: The FBC-MC may be a suitable instrument for evaluating dietary behaviors among Youth EFNEP-eligible children; however, more work is needed to establish internal reliability and criterion validity. PMID- 20828669 TI - A "Healthy Pizza Kitchen" nutrition education program at a Children's Health Museum. PMID- 20828670 TI - Teaching students to cook: an easily incorporated assignment in an academic nutrition course. PMID- 20828671 TI - The Simon effect in cognitive electrophysiology: A short review. AB - In the Simon task, stimuli are presented laterally and typically a non-spatial stimulus dimension demands a lateralized choice response. Responses are faster when the task-irrelevant stimulus location and the response location correspond than when they do not correspond. The present paper explores the impact of the Simon task on cognitive electrophysiological research as well as the insights gained from event-related brain potentials (ERPs) in the attempt to uncover the hidden mechanisms underlying the Simon effect. PMID- 20828672 TI - Sensitivity of the lane change test as a measure of in-vehicle system demand. AB - The Lane Change Test (LCT) is one of the growing number of methods developed to quantify driving performance degradation brought about by the use of in-vehicle devices. Beyond its validity and reliability, for such a test to be of practical use, it must also be sensitive to the varied demands of individual tasks. The current study evaluated the ability of several recent LCT lateral control and event detection parameters to discriminate between visual-manual and cognitive surrogate In-Vehicle Information System tasks with different levels of demand. Twenty-seven participants (mean age 24.4 years) completed a PC version of the LCT while performing visual search and math problem solving tasks. A number of the lateral control metrics were found to be sensitive to task differences, but the event detection metrics were less able to discriminate between tasks. The mean deviation and lane excursion measures were able to distinguish between the visual and cognitive tasks, but were less sensitive to the different levels of task demand. The other LCT metrics examined were less sensitive to task differences. A major factor influencing the sensitivity of at least some of the LCT metrics could be the type of lane change instructions given to participants. The provision of clear and explicit lane change instructions and further refinement of its metrics will be essential for increasing the utility of the LCT as an evaluation tool. PMID- 20828673 TI - Clinical, pathological and genetic evaluations of Chinese patients with autosomal dominant hypophosphatasia. AB - OBJECTIVES: Hypophosphatasia (HPP) is an inherited disorder characterised by defective bone and tooth mineralisation and deficient serum and bone alkaline phosphatase activity, and it results from mutations in alkaline phosphatase (ALPL) encoding tissue-nonspecific alkaline phosphatase (TNAP). The objective of the present work was to explore the correlations between genotype and phenotype in a Chinese family affected by autosomal-dominant HPP. DESIGN: We examined all individuals of a HPP family by clinical and radiographic examinations as well as laboratory assays. Furthermore, a prematurely exfoliated tooth was observed histopathologically. Based on the clinical and pathological manifestations, the causative gene ALPL was selected for further analysis and screened for mutations. RESULTS: The proband presented the characteristic clinical features of childhood HPP such as rachitic skeletal changes, early loss of primary teeth, and short root anomalies of the permanent teeth. Histopathological evaluation of a tooth revealed a "shell" structure, severe mineralisation defects of dentin, and an absence of cementum. The patient's mother and grandfather were clinically diagnosed with adult HPP. The family showed autosomal-dominant moderate hypophosphatasia. DNA sequencing and analysis revealed a novel missense mutation (c.251A>T) in exon4 of ALPL. This mutation (p.E84V) is located in the secondary structure of TNAP's homodimer interface, and it was predicted to have a dominant negative effect. CONCLUSION: Our findings suggest the missense transversion (c.251A>T, p.E84V) should be responsible for the HPP phenotype in this Chinese family. PMID- 20828674 TI - What is the relationship between the recognition of emotions and core beliefs: Associations between the recognition of emotions in facial expressions and the maladaptive schemas in depressed patients. AB - BACKGROUND: Depressed patients are both characterized by social reality distorting maladaptive schemas and facial expression recognition impairments. The aim of the present study was to identify specific associations among symptom severity of depression, early maladaptive schemas and recognition patterns of facially expressed emotions. METHODS: The subjects were inpatients, diagnosed with depression. We used 2 virtual humans for presenting the basic emotions to assess emotion recognition. The Symptom Check List 90 (SCL-90) was used as a self report measure of psychiatric symptoms and the Beck Depression Inventory (BDI) was applied to assess symptoms of depression. The Young Schema Questionnaire Long Form (YSQ-L) was used to assess the presence of early maladaptive schemas. RESULTS: The recognition rate for happiness showed significant associations with both the BDI and the depression subscale of the SCL-90. After performing the second order factor analysis of the YSQ-L, we found statistically significant associations between the recognition indices of specific emotions and the main factors of the YSQ-L. CONCLUSIONS: In this study we found correlations between maladaptive schemas and emotion recognition impairments. While both domains likely contribute to the symptoms of depression, we believe that the results will help us to better understand the social cognitive deficits of depressed patients at the schema level and at the emotion recognition level. PMID- 20828675 TI - Lichtheim's golden shot. AB - Lichtheim belongs to the ranks of most famous aphasiologists, in particular because of a diagram often referred to as 'Lichtheim's House'. His single paper on aphasia has drawn the attention of the aphasiological community for many years and may be considered a golden shot. But it became, to Lichtheim's own disappointment, famous for its schema rather than for the theoretical proposals formulated in that paper regarding various aphasia syndromes. In this paper, a translation is presented on the part of Lichtheim's memoirs, dealing with his views on his work on aphasia. I also discuss his insertion of the conceptual center in the model and Wernicke's response to that. Finally, I argue that it is surprising that Lichtheim's contribution has had such a lasting impact. PMID- 20828677 TI - Facts and hypotheses relevant for contrasting animal and plant life semantics. A comment on Gainotti (2010). PMID- 20828676 TI - Etiology and neuropsychology of comorbidity between RD and ADHD: the case for multiple-deficit models. AB - INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) and reading disability (RD) are complex childhood disorders that frequently co-occur, but the etiology of this comorbidity remains unknown. METHOD: Participants were 457 twin pairs from the Colorado Learning Disabilities Research Center (CLDRC) twin study, an ongoing study of the etiology of RD, ADHD, and related disorders. Phenotypic analyses compared groups with and without RD and ADHD on composite measures of six cognitive domains. Twin analyses were then used to test the etiology of the relations between the disorders and any cognitive weaknesses. RESULTS: Phenotypic analyses supported the hypothesis that both RD and ADHD arise from multiple cognitive deficits rather than a single primary cognitive deficit. RD was associated independently with weaknesses on measures of phoneme awareness, verbal reasoning, and working memory, whereas ADHD was independently associated with a heritable weakness in inhibitory control. RD and ADHD share a common cognitive deficit in processing speed, and twin analyses indicated that this shared weakness is primarily due to common genetic influences that increase susceptibility to both disorders. CONCLUSIONS: Individual differences in processing speed are influenced by genes that also increase risk for RD, ADHD, and their comorbidity. These results suggest that processing speed measures may be useful for future molecular genetic studies of the etiology of comorbidity between RD and ADHD. PMID- 20828678 TI - Gestalt perception and the decline of global precedence in older subjects. AB - Our visual world is hierarchically organized. Hierarchical processing is frequently investigated using Navon figures (large letters made up of smaller ones). In young adults, many studies reported faster reaction times (RT) to target letters presented at the global level [i.e., global precedence (GP)]. Furthermore, an age-related decline of this GP has been reported. We tested whether deficits in perceptual grouping via Gestalt laws (Gestalt principles of Proximity and Continuity) might contribute to this decline. In a directed attention task with valid and invalid cues, 20 young (mean age 22) and 20 older (mean age 57) male subjects had to indicate whether a target letter appeared at the global or local level of a Navon figure. The number of local letters forming the global figure was modulated in 5 steps. As expected, during valid trials, young adults showed a GP that linearly increased with increasing numbers of local letters (i.e., GP enhancement). This suggests that GP is related to perceptual grouping via Gestalt laws. By contrast, the group of older subjects demonstrated no precedence effect in RT and a non-significant trend toward GP in error rates (ER). No GP enhancement with an increasing number of local elements was observed. Exploratory analysis revealed that individual insensitivity to the modulation of matrix density, as revealed by a lack of global RT acceleration, was restricted to subjects that showed an overall local precedence (LP). Because older subjects tended to more frequently display an insensitivity to matrix modulation and an LP, we conclude that deficient Gestalt detection as indicated by non-enhanced global RT might contribute to the RT-related decline of GP with age. PMID- 20828679 TI - Male advantage in sound localization at cocktail parties. AB - Sex differences exist in the structural organization of the human brain and are related to cognitive abilities. Females usually outperform men in verbal fluency, verbal memory, perceptual speed, numerical calculation, and fine motor skills, whereas males are superior in visuospatial abilities, throwing accuracy, and mathematical reasoning. Here we demonstrated a male advantage in spatial abilities for the auditory modality. We employed a sound localization task based on the so-called "cocktail party situation", requiring extraction of auditory information of a specific sound source when multiple competing sound sources were present. The results indicated better performance of males than females for localizing target sounds in a multi-source sound environment. This finding suggests a sex difference in the attentional mechanisms extracting spatial information of one acoustic event of interest from an auditory scene composed of multiple sound sources. It seems that the known male superiority in spatial abilities may be supramodal, rather than a specificity of the visual modality. PMID- 20828680 TI - [Spanish clinical research in heart failure and its contribution to the European congress of internal medicine (1997-2009)]. PMID- 20828681 TI - [Adverse drug events in internal medicine]. PMID- 20828682 TI - [Adaptation of the new medical degree to the European Space for Higher Education. What has been the contribution of Bologna?]. AB - In the last three years, the development of a profound reorganization of university teachings has made it possible to comply with the commitments of the Declaration of Bologna and to adapt all teaching to the new structure of the degree program that will be introduced in October 2010. Along these lines (Order ECI/332/2008), the requirements that must be fulfilled by the university degrees to be able to practice the medical profession have been established. In the new study plans, acquisition of skills by the students is given priority and emphasis is placed on the learning methods of these skills, and on the procedures to evaluate their acquisition. The European Credit Transfer System (ACTS), (between 25 and 30h), is the measurement unit that reflects the learning results. Furthermore, acquisition of clinical skills is promoted through the obligatory performance of pre-professional practices, in form of a period of independent clinical rotation and with a final evaluation of the skills, in health care centers, hospitals, and other care centers. In the upcoming years, it will be verified if this curriculum modernization of the study plans improves the professional practice of the new physicians. PMID- 20828683 TI - Ovarian stimulation and the risk of aneuploid conceptions. AB - OBJECTIVE: To examine the rate of aneuploidy in missed abortions in patients who conceived after FSH ovarian stimulation compared with women who conceived in a natural cycle. DESIGN: Retrospective cohort. SETTING: Academic reproductive endocrinology and infertility center. PATIENT(S): Women with karyotyping of products of conception (POC) from a missed abortion from January 1999 through August 2007. The rate of aneuploidy was compared between patients with a history of infertility who conceived naturally and patients with a history of infertility who conceived with FSH treatment. INTERVENTION(S): Ovarian stimulation with FSH, intrauterine insemination, and in vitro fertilization; genetic testing of POC after dilation and curettage. MAIN OUTCOME MEASURE(S): Embryonic karyotype. RESULT(S): A total of 229 pregnancies met inclusion criteria, and of these, 64% had an abnormal karyotype. The rate of aneuploidy was 63% in the study group and 70% in the control group. This difference was not statistically significant. CONCLUSION(S): The incidence of embryonic aneuploidy was not higher in pregnancies conceived with FSH stimulation compared with spontaneous conceptions in infertility patients. This suggests that exogenous FSH exposure does not increase the risk of aneuploidy. PMID- 20828684 TI - Effects of metformin on the reproductive system of androgenized female rats. AB - Metformin improved the glucose rate and the homeostasis model assessment-insulin resistance (HOMA-IR) index and caused partial reversion of ovaries and uterine morphology in female rats androgenized with testosterone. PMID- 20828685 TI - Gulf Coast oil disaster: impact on human reproduction. AB - The catastrophic British Petroleum oil spill in the Gulf of Mexico has reached the shores of the United States, along with unpredictable effects on the health of local communities. The potential impact of the disaster on female and male reproduction will be discussed in this report, to provide greater clinician awareness about the potential consequences of this calamity and to call for more research on this subject. PMID- 20828686 TI - Effect of bilateral oophorectomy on wound healing of the rabbit vagina. AB - We aimed to assess the effect of bilateral oophorectomy on vaginal wound healing in three groups of New Zealand White rabbits (24 rabbits each). Group 1 underwent bilateral oophorectomy, group 2 underwent a sham surgery, and group 3 served as control. Standardized vaginal tissue specimens were harvested and assessed for wound and scar surface area and tensiometric analysis before wounding, and sequentially thereafter, showing that vaginal wound closure, scar contraction, and recovery of biomechanical properties are significantly slower in oophorectomized rabbits. PMID- 20828687 TI - Autotransplantation of cryopreserved ovarian tissue in 12 women with chemotherapy induced premature ovarian failure: the Danish experience. AB - OBJECTIVE: To describe a cohort of 12 Danish women who received autotransplantation of frozen-thawed cryopreserved ovarian tissue because of premature ovarian failure after cancer treatment. DESIGN: Retrospective study. SETTING: University hospitals. PATIENT(S): Twelve women with autotransplanted frozen-thawed ovarian tissue. INTERVENTION(S): Monitoring of hormonal parameters and results of 56 IVF cycles in 10 women. MAIN OUTCOME MEASURE(S): Levels of gonadotropins and sex steroids, functional life span of the grafts, and results of IVF. RESULT(S): All 12 women regained ovarian function between 8 and 26 weeks (mean 19 weeks) after transplantation. Ten women underwent a total of 56 IVF cycles, 76 follicles developed, 49 oocytes were aspirated, 18 were fertilized, and 16 embryos were transferred resulting in six pregnancies: two biochemical, one clinical that miscarried in week 7, and two ongoing resulting in the delivery of two healthy infants born at term to two women. One of these women subsequently conceived spontaneously and delivered another healthy infant. The life span of the transplanted tissue has been between 6 months and still functioning after 54 months. CONCLUSION(S): Autotransplantation consistently leads to recovery of ovarian function after treatment-induced ovarian failure. Four women became pregnant, after IVF or spontaneously, resulting in the delivery of three healthy infants. PMID- 20828688 TI - Vitrification versus slow freezing of oocytes: effects on morphologic appearance, meiotic spindle configuration, and DNA damage. AB - To assess possible effects on subcellular organization after cryopreservation, we compared vitrified and slowly frozen oocytes in terms of their post-warm/thaw morphology, meiotic spindle configuration, and DNA integrity. DNA integrity of cryopreserved oocytes was not altered after the procedures, but vitrification was more effective than slow cooling, as shown by higher survival rate and spindle assessment despite a higher misalignment between meiotic spindle and polar body. PMID- 20828689 TI - Comminuted fractures of the proximal ulna--Preliminary results with an anatomically preshaped locking compression plate (LCP) system. AB - INTRODUCTION: The purpose of this investigation was to review the preliminary results and patients outcome following treatment with an anatomically preshaped LCP in patients with comminuted fractures of the proximal ulna. We hypothesized that this fixation system provides equal or superior results in fracture care when compared with other available plating devices, but results in better patient's comfort due to its low-profile design. PATIENTS AND METHODS: Between 2007 and 2009, 15 patients with comminuted fractures of the proximal ulna including three posterior Monteggia fractures were managed with the preshaped LCP olecranon plate. The patients were invited for clinical examination at a mean duration of 16 months, retrospectively. Validated patient-oriented assessment scores involving the Mayo Elbow Performance Index (MEPI) and the shortened Disability of the Arm, Shoulder and Hand (Quick-DASH) score, postoperative range of motion, objective muscle-strengths testing and patient's satisfaction were evaluated. All patients had follow-up radiographs. RESULTS: Fourteen patients were available for evaluation. The mean arc of elbow motion was 129 degrees . The mean MEPI was 97 with good results in two patients and excellent results in 12 patients. The mean Quick-DASH was 13. Thirteen of fourteen patients documented satisfaction with their elbow outcome. There was one patient with symptomatic hardware and one patient complained about deficit of motion. In four patients the hardware was removed including two patients with elective removal. Fourteen fractures healed with ulnohumeral congruity after a mean time to union of 11 weeks. One fracture non-union occurred without mechanical failure or loss of reduction. CONCLUSION: Anatomically preshaped LCP olecranon plating is an effective fixation method for comminuted fractures of the proximal ulna allowing reliable stability for early elbow motion. The functional results are comparable with formerly described plating systems. A low rate of symptomatic hardware removal suggests better patient's compatibility. PMID- 20828690 TI - Acetabular both-column fractures: essentials of operative management. AB - Acetabular both-column fractures are challenging articular injuries. They usually require operative treatment. We report on fundamental elements of pathoanatomy and radiology that are reviewed as far as they may influence treatment planning and surgical intervention. Surgical strategy, choice of the most suitable approach, reduction manoeuvres and fixation techniques are presented, together with some tips and tricks that are worth knowing in the surgical reconstruction of these difficult fractures. PMID- 20828691 TI - Treatment of posttraumatic sternal non-union with a locked sternum-osteosynthesis plate (TiFix). AB - Only a minority of sternal fractures require osteosynthesis. Unstable non-union of the sternum is a very disabling condition which often requires treatment. The method most often used is tension-wiring. Due to loosening of the tensile strength or wire cut-out, this method often fails. We report the results of locked plate osteosynthesis of sternal non-union and displaced fractures. Over a five-year period, 12 patients have been treated using this method in a multicentre trial. Mean age at trauma was 32.8 years, the implant used in all cases was an 8-hole titanium plate, the fixation of the screws is based on the principles of angular stable fixation.In all cases the index procedure was possible, in all cases there was bony healing at follow-up examination.Multidirectional locked plating offers a reliable method for the successful treatment of sternal nonunion and displaced fractures. PMID- 20828692 TI - Surgical treatment of pathologic fractures of humerus. AB - This study evaluates different operative treatment options for patients with metastatic fractures of the humerus focusing on surgical procedures, complications, function, and survival rate. From January 2003 to January 2008, 87 pathological fractures of the humerus in 85 cancer patients were surgically treated in our institutions. Histotypes were breast (n=21), lung (n=14), prostate (n=5), bladder (n=4), kidney (n=13), thyroid (n=7), larynx (n=1), lymphoma (n=5), myeloma (n=8), colon-rectum (n=1), melanoma (n=1), testicle (n=1), hepatocellular carcinoma (n=1) and unknown tumours (n=3). Lesions of the proximal epiphysis were treated with resection and endoprosthetic replacement (n=30). The remaining 57 fractures were stabilized with antegrade unreamed intra-medullary locked nailing without (9 cases) or with resection and use of cement (48 cases). The function of the upper limb was assessed using the Musculo-Skeletal Tumor Society (MSTS) rating scale and survival rate was retrospectively analysed. The mean survival time of patients after surgery was 8.3 months. Complications of endoprosthetic replacement recorded included disease relapse (n=3), soft tissue infection (n=2) and palsy of musculocutaneous nerve (n=1) whereas, for intra-medullary locked nailing there were three cases of soft tissue infection and one case of radial nerve palsy. The mean MSTS score at follow-up was 73% for endoprosthesis and 79.2% for locked intra-medullary nailing. Endoprosthetic replacement of the proximal humerus provides a good function of the upper limb, a low risk of local relapse with a low complication rate at follow-up. Unreamed nailing provides immediate stability and pain relief, minimum morbidity and early return of function. PMID- 20828693 TI - The evolving management of venous bullet emboli: a case series and literature review. AB - Bullet emboli are an infrequent and unique complication of penetrating trauma. Complications of venous and arterial bullet emboli can be devastating and commonly include limb-threatening ischaemia,pulmonary embolism, cardiac valvular incompetence, and cerebrovascular accidents. Bullets from penetrating wounds can gain access to the venous circulation and embolise to nearly every large vascular bed. Venous emboli are often occult phenomenon and may remain unrecognised until migration leads to vascular injury or flow obstruction with resultant oedema. The majority of arterial emboli present early with end-organ or limb ischaemia. We describe four separate cases involving venous bullet embolism and the subsequent management of each case. Review of the literature focusing on the reported management of these injuries, comparison of techniques of management, as well as the evolving role of endovascular techniques in the management of bullet emboli is provided. PMID- 20828694 TI - Role stress and personal resources in nursing: a cross-sectional study of burnout and engagement. AB - BACKGROUND: The experience of role stress has been linked to burnout as an important job stressor, but the impact of this stressor in the context of engagement (characterized by vigor, dedication, and absorption) has not yet been sufficiently studied among nurses. Personal resources also appear to influence the process of burnout and engagement. OBJECTIVES: This study examines the influence of role stress and personal resources (optimism, hardy personality and emotional competence) in nursing on burnout and engagement dimensions. DESIGN AND RESULTS: Cross-sectional data from 508 nurses from general hospitals in Madrid (Spain) showed that both role stress and personal resources were related to burnout and engagement dimensions, although role stress was more closely related to nursing burnout, whereas personal resources were more closely related to nursing engagement. In addition, optimism as a personal resource, showed a moderator effect on exhaustion and the three dimensions of engagement. CONCLUSIONS: The study provides additional support about role stress as an important predictor of burnout and engagement in nursing, even after controlling for personal resources and socio-demographic variables. PMID- 20828695 TI - Plasma apolipoprotein M responses to statin and fibrate administration in type 2 diabetes mellitus. AB - PURPOSE: Plasma apolipoprotein M (apoM) is potentially anti-atherogenic, and has been found to be associated positively with plasma total, LDL and HDL cholesterol in humans. ApoM may, therefore, be intricately related to cholesterol metabolism. Here, we determined whether plasma apoM is affected by statin or fibrate administration in patients with diabetes mellitus. METHODS: Fourteen type 2 diabetic patients participated in a placebo-controlled crossover study which included three 8-week treatment periods with simvastatin (40 mg daily), bezafibrate (400 mg daily), and their combination. RESULTS: ApoM was decreased by 7% in response to simvastatin (P<0.05 from baseline and placebo), and remained unchanged during bezafibrate and combined simvastatin+bezafibrate administration. Plasma apoM concentrations correlated positively with apoB-containing lipoprotein measures at baseline and during placebo (P<0.02 to P<0.001), but these relationships were lost during all lipid lowering treatment periods. CONCLUSIONS: This study suggests that, even though plasma apoM is lowered by statins, apoM metabolism is to a considerable extent independent of statin- and fibrate affected pathways involved in cholesterol homeostasis. PMID- 20828697 TI - The influence of proximal stem geometry and surface finish on the fixation of a double-tapered cemented femoral stem. AB - In this study, the in vitro fixation of four otherwise identical double-tapered stem-types, varying only in surface finish (polished or matte) and proximal stem geometry (with or without flanges) were compared under two conditions. First, four specimens of each stem type were tested with initially bonded stem-cement interfaces, representing early post-operative conditions. Then, simulating conditions a few weeks to months later, stems were implanted in unused synthetic femurs, with a thin layer coating the stem to prevent stem-cement adhesion. Per cycle motions were measured at both cement interfaces throughout loading. Overall, surface finish had the smallest relative effect on fixation compared to flanges. Flanges increased axial fixation by 22 MUm per-cycle, regardless of surface finish (P=0.01). Further, all stems moved under dynamic load at the stem cement interface during the first few cycles of loading, even without a thin film. The results indicate that flanges have a greater effect on fixation than surface finish, and therefore adverse findings about matte surfaces should not necessarily apply to all double-tapered stems. Specifically, dorsal flanges enhance the stability of a tapered cemented femoral stem, regardless of surface finish. PMID- 20828696 TI - Update of the Portuguese Familial Hypercholesterolaemia Study. AB - The main aim of the Portuguese Familial Hypercholesterolaemia Study is to identify the genetic cause of hypercholesterolaemia in individuals with a clinical diagnosis of Familial Hypercholesterolaemia (FH). A total of 1340 blood samples were collected from 482 index patients and 858 relatives with the collaboration of clinicians from several hospitals all over the country. The genetic diagnosis of FH in this study is based on the analyses of three genes: LDLR, APOB and PCSK9. In the last 10 years, the Portuguese FH Study identified a genetic defect in a total of 171 index patients, corresponding to an overall of 48% of the total received cases with clinical diagnosis of FH. Although the Simon Broome FH register criteria have been adapted to our study, 59 patients that did not fulfil all criteria were included in the study and a mutation causing disease was identified in 8 of these patients. In the LDLR gene were found 80 different mutations in 165 unrelated index patients: 159 heterozygous, 3 compounds heterozygous and 3 true homozygous. The APOB p.Arg3527Gln and the PCSK9 p.Asp374His mutation were not found in any of our patients since our last report, but a novel mutation in the APOB gene, predicted to cause a single amino acid substitution p.Tyr3560Cys, was found in one patient. The cascade screening in relatives of these 171 index patients allowed the identification and genetic characterization of a total of 404 FH patients in Portugal. PMID- 20828698 TI - Emotional influences on locomotor behavior. AB - Emotional responses to appetitive and aversive stimuli motivate approach and avoidance behaviors essential for survival. The purpose of the current study was to determine the impact of specific emotional stimuli on forward, approach oriented locomotion. Steady state walking was assessed while participants walked toward pictures varying in emotional content (erotic, happy people, attack, mutilation, contamination, and neutral). Step length and step velocity were calculated for the first two steps following picture onset. Exposure to the mutilation and contamination pictures shortened the lengths of step one and step two compared to the erotic pictures. Additionally, step velocity was greater during exposure to the erotic pictures compared to (1) the contamination and mutilation pictures for step one and (2) all other picture categories for step two. These findings suggest that locomotion is facilitated when walking toward approach-oriented emotional stimuli but compromised when walking toward aversive emotional stimuli. The data extend our understanding of fundamental interactions among motivational orientations, emotional reactions, and resultant actions. Theoretical and practical implications are discussed. PMID- 20828699 TI - Changes in contractile properties of muscles receiving repeat injections of botulinum toxin (Botox). AB - Botulinum toxin type A (BTX-A) is a frequently used therapeutic tool to denervate muscles in the treatment of neuromuscular disorders. Although considered safe by the US Food and Drug Administration, BTX-A can produce adverse effects in target and non-target muscles. With an increased use of BTX-A for neuromuscular disorders, the effects of repeat injections of BTX-A on strength, muscle mass and structure need to be known. Therefore, the purpose of this study was to investigate the changes in strength, muscle mass and contractile material in New Zealand White (NZW) rabbits. Twenty NZW rabbits were divided into 4 groups: control and 1, 3 and 6 months of unilateral, repeat injections of BTX-A into the quadriceps femoris. Outcome measures included knee extensor torque, muscle mass and the percentage of contractile material in the quadriceps muscles of the target and non-injected contralateral hindlimbs. Strength in the injected muscles was reduced by 88%, 89% and 95% in the 1, 3 and 6 months BTX-A injected hindlimbs compared to controls. Muscle mass was reduced by 50%, 42% and 31% for the vastus lateralis (VL), rectus femoris (RF) and vastus medialis (VM), respectively, at 1 month, by 68%, 51% and 50% at 3 months and by 76%, 44% and 13% at 6 months. The percentage of contractile material was reduced for the 3 and 6 months animals to 80-64%, respectively, and was replaced primarily by fat. Similar, but less pronounced results were also observed for the quadriceps muscles of the contralateral hindlimbs, suggesting that repeat BTX-A injections cause muscle atrophy and loss of contractile tissue in target muscles and also in non-target muscles that are far removed from the injection site. PMID- 20828700 TI - Non-enzymatic posttranslational modifications of bovine serum albumin by oxo compounds investigated by high-performance liquid chromatography-mass spectrometry and capillary zone electrophoresis-mass spectrometry. AB - Non-enzymatic posttranslational modifications of bovine serum albumin (BSA) by various oxo-compounds (glucose, ribose, glyoxal and glutardialdehyde) have been investigated using high-performance liquid chromatography (HPLC) and capillary zone electrophoresis (CZE). Both of these methods used mass spectrometric (MS) detection. Three enzymes (trypsin, pepsin, proteinase K) were used to digest glycated BSA. The extent of modification depended on the selected oxo-compound. Reactivity increased progressively from glucose to glutardialdehyde (glucose12-months-old patients for crying, pain, cough, and vomiting. RESULTS: A total of 70 of 225 tracings were discarded. Of 2172 symptoms, 1136 (52%) were reflux-associated (45% acid reflux [AR], 51% weakly AR, 3% alkaline reflux). The strongest reflux-symptom association was found for vomiting. Cough-reflux association was higher in infants than in older children. In older patients, symptom-reflux association was more with AR. Symptoms were associated with proximal reflux in 70% of patients. The symptom index and symptom association probability (SAP) were positive (>50% for symptom index and >95% for SAP) for all refluxes in 83% and 46% of patients and for AR in 49% and 47% of patients, respectively. In 1- to 6-month-old infants, symptom index and SAP were higher for weakly AR than for AR. For crying, SAP was independent of AR or weakly AR. For cough, SAP was positive in one-third of patients, predominantly with AR in 6- to 12-month-old infants and with weakly AR in the other infants. CONCLUSION: Multiple intraluminal esophageal impedance recording with pH-monitoring doubles the probability of documenting an association between symptoms and reflux compared with pH monitoring. In young infants, symptoms are more frequently associated with weakly AR than with AR. PMID- 20828712 TI - Prospective study of spinal anomalies in children with infantile hemangiomas of the lumbosacral skin. AB - OBJECTIVE: To prospectively evaluate a cohort of patients with infantile hemangioma in the midline lumbosacral region for spinal anomalies to determine the positive predictive value of infantile hemangioma for occult spinal anomalies and to make evidence-based recommendations for screening. STUDY DESIGN: A multicenter prospective cohort study was performed at 9 Hemangioma Investigator Group sites. RESULTS: Intraspinal abnormalities were detected in 21 of 41 study participants with a lumbosacral infantile hemangioma who underwent a magnetic resonance imaging evaluation. The relative risk for all patients with lumbosacral infantile hemangiomas for spinal anomalies was 640 (95% confidence interval [CI], 404-954), and the positive predictive value of infantile hemangioma for spinal dysraphism was 51.2%. Ulceration of the hemangioma was associated with a higher risk of having spinal anomalies. The presence of additional cutaneous anomalies also was associated with a higher likelihood of finding spinal anomalies; however, 35% of the infants with isolated lumbosacral infantile hemangiomas had spinal anomalies, with a relative risk of 438 (95% CI, 188-846). The sensitivity for ultrasound scanning to detect spinal anomalies in this high-risk group was poor at 50% (95% CI, 18.7%-81.3%), with a specificity rate of 77.8% (95% CI, 40% 97.2%). CONCLUSIONS: Infants and children with midline lumbosacral infantile hemangiomas are at increased risk for spinal anomalies. Screening magnetic resonance imaging is recommended for children with these lesions. PMID- 20828713 TI - Docosahexaenoic acid is essential to development of critical functions in infants. PMID- 20828714 TI - Efficacy of a new hypotonic oral rehydration solution containing zinc and prebiotics in the treatment of childhood acute diarrhea: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of a hypotonic oral rehydration solution (ORS) containing zinc and prebiotics for treatment of acute diarrhea in children. STUDY DESIGN: We conducted a single-blind, prospective, controlled trial including children (age range, 3-36 months) with acute diarrhea randomly assigned to standard hypotonic ORS (group 1) or to new hypotonic ORS containing zinc and prebiotics (group 2). The main outcome was the rate of resolution of diarrhea at 72 hours. RESULTS: A total of 60 children in group 1 (34 male; mean age, 18.58 months; 95% CI, 15.5-21.6) and 59 in group 2 (36 male; mean age, 19.26 months; 95% CI, 15.9-22.6) completed the study protocol. The rate of diarrhea resolution at 72 hours was higher in group 2 (50% versus 72.9%, P = .010). Total ORS intake in the first 24 hours was higher in group 2 (50 mL/kg; 95% CI, 41-59 versus 22 mL/kg; 95% CI, 17-29; P < .001). The mean number of missed working days by the parents of children in group 2 was lower (0.39; 95% CI, 0.08-0.70 versus 1.45; 95% CI 1.02-1.88; P < .001). Fewer patients in group 2 needed adjunctive drugs for the treatment of diarrhea 6/59 versus 19/60, P = .004. No adverse events were observed in either of the two groups. CONCLUSION: The addition of zinc and prebiotics to ORS limits diarrhea duration in children. PMID- 20828715 TI - Non-high-density lipoprotein cholesterol concentration is associated with the metabolic syndrome among US youth aged 12-19 years. AB - OBJECTIVE: To test the hypothesis that the concentration of non-high-density lipoprotein cholesterol (non-HDL-C) is associated with the metabolic syndrome (MetS) in youth. STUDY DESIGN: Data on children and adolescents aged 12-19 years (n = 2734) from the cross-sectional National Health and Nutrition Examination Survey 1999-2004 were analyzed. RESULTS: Depending on the definition of MetS used, the mean non-HDL-C concentration among youth with MetS ranged from 144.2 to 155.8 mg/dL, compared with 108.8-109.1 mg/dL in those without MetS (all P < .001). The MetS prevalence ranged from 6.9% to 11.7% in youth with a non-HDL-C concentration of 120-144 mg/dL and from 21.5% to 23.4% in those with a concentration >= 145 mg/dL-both significantly higher than the prevalence of 1.9% 3.4% in youth with a concentration <120 mg/dL (all P < .001). After adjustment for potential confounders, youth with a non-HDL-C concentration >= 120 mg/dL or >= 145 mg/dL were about 3 or 4 times more likely to have MetS compared with those with a non-HDL-C <120 mg/dL or <145 mg/dL (all P < .001). CONCLUSIONS: Fasting non-HDL-C concentration was strongly associated with MetS in US youth. Our results support the use of non-HDL-C thresholds of 120 mg/dL and 145 mg/dL to indicate borderline and high MetS risk, respectively. PMID- 20828716 TI - Neonatal morbidity in moderately preterm infants: a Swedish national population based study. AB - OBJECTIVE: To determine the gestational age (GA)-specific risks for neonatal morbidity and use of interventions in infants born at 30 to 34 completed gestational weeks. STUDY DESIGN: A population-based Swedish study including 6674 infants born during 2004-2008. Risks for neonatal morbidity and use of interventions were investigated with respect to GA and birth weight standard deviation scores. RESULTS: Acute lung disorder was diagnosed in 28%, hypoglycemia in 16%, bacterial infection in 15% and hyperbilirubinemia in 59% of the infants. Thirty-eight percent had received antenatal steroid therapy, 43% nasal continuous positive airway pressure, 5.5% required mechanical ventilation, 5.2% were treated with surfactant, and 30% with antibiotic therapy. Neonatal morbidity rates increased with decreasing GA, with odds ratios for different outcomes ranging from 2.1 to 23 at 30 weeks compared with 34 weeks of GA. Low birth weight standard deviation scores was more common at lower GA and was associated with increased morbidity rates. CONCLUSIONS: Despite general advances in perinatal care, moderately preterm infants still have substantially increased risks for neonatal morbidity. Whereas the neonatal morbidity rate was similar to results of previous reports, management of respiratory problems differed markedly from other studies. PMID- 20828717 TI - Predictors of non-diagnostic ultrasound scanning in children with suspected appendicitis. AB - OBJECTIVE: To determine predictors of diagnostically inaccurate ultrasound scanning for suspected appendicitis. STUDY DESIGN: Prospective emergency department cohort study of 263 previously healthy children 4 to 17 years of age undergoing ultrasound scanning. Ultrasound scanning results were interpreted as positive, negative, or equivocal for appendicitis and classified as diagnostically accurate and inaccurate. The main outcome measure was association between inaccurate ultrasound scanning and age, sex, body mass index percentiles, pain duration, white blood cell count, Faces Pain Score-Revised, clinical probability of appendicitis, and ultrasound scanning operator. RESULTS: Of the 263 patients, 95 ultrasound scanning examinations were read as positive, 76 as negative, and 92 were equivocal. A total of 162 (61.6%) ultrasound scanning examinations were accurate (TP86, TN76), and 101 (38.4%) ultrasound scanning examinations were inaccurate (FP88, FN13). Children with body mass index percentiles >= 85 and clinical probability of appendicitis <= 50% had 58.1% probability of inaccurate ultrasound scanning examination (odds ratio, 2.48; 95% confidence interval, 1.48-2.78). In lean children, diagnostic accuracy of the screening ultrasound scanning examination with second ultrasound scanning or clinical reassessment was 93% versus 83% in the obese children (95% confidence interval of the difference, 1-19%). CONCLUSION: Screening ultrasound scanning for pediatric appendicitis has suboptimal accuracy, particularly in obese children with a low likelihood of appendicitis who should not routinely undergo ultrasound scanning. However, when followed by a second ultrasound scanning or a clinical reassessment, it offers high diagnostic accuracy in lean children. PMID- 20828718 TI - Biochemical studies in Normal Pressure Hydrocephalus (NPH) patients: change in CSF levels of amyloid precursor protein (APP), amyloid-beta (Abeta) peptide and phospho-tau. AB - Normal Pressure Hydrocephalus (NPH) is one of the causes of dementia of the elderly characterized by impaired mental function, gait difficulties and urinary incontinence. Previously, it was proposed that some of the NPH patients may develop Alzheimer's disease (AD) like pathology. Aim of this study was to compare levels of different CSF biomarkers, including total secreted beta-amyloid precursor protein (sAPP), sAPP-alpha form (sAPPalpha), amyloid-beta (Abeta) peptide, total-tau protein and hyperphosphorylated-tau protein in subjects from NPH and Non-NPH Control (NNC). CSF was collected from 23 NPH patients and 13 Non NPH controls by lumber puncture. Western blot analysis was performed to measure levels of sAPP-total. ELISA was used separately to determine levels of sAPPalpha, Abeta peptide, total-tau and phospho-tau proteins. We found a significant decrease in levels of total secreted APP, sAPPalpha and Abeta (1-42) in the CSF sample of NPH patients vs. NNC. We did not observe any change in levels of total tau or phospho-tau in NPH vs. NNC subjects. Notably, phospho-tau level was significantly increased in the NPH patients, who were suffering from the disease for more than one year, vs. NNC. Among five biomarkers studied, decreased sAPP, sAPPalpha and Abeta (1-42) levels in CSF can be molecular markers to distinguish NPH cases from NNC. Disease severity can also be assessed by increased levels of CSF phospho-tau protein and the ratio of phospho-tau to Abeta (1-42), which might be a useful tool for predicting conversion of NPH individuals to other neurodegenerative disorders including Alzheimer's disease (AD). PMID- 20828720 TI - Antitumor activity of polyuridylic acid in human soft tissue and bone sarcomas. AB - BACKGROUND: The immunomodulatory properties of polyuridylic acid (PolyU) make it a promising agent in cancer immunotherapy. However, there is limited information on its direct effects on tumor cells. MATERIALS AND METHODS: TLR8 mRNA and protein expression in soft tissue sarcoma (STS) and bone sarcoma (BS) cell lines were determined by PCR and flow cytometry, respectively. Apoptosis and proliferation assays were performed using annexin V staining and BrdU incorporation assays, respectively. A relative cell enumeration was evaluated with WST-1 reagent. Expression levels of apoptotic proteins were evaluated by Western blotting. RESULTS: We demonstrate that PolyU treatment resulted in a significant decrease in STS and BS cell count by inducing apoptosis and inhibition of cell proliferation. All cell lines examined expressed TLR8 and the effect of PolyU was partially mediated through TLR8. Several apoptotic proteins including caspases were activated or increased in STS cells after treatment with PolyU. Administration PolyU resulted in significant growth inhibition of STS without any observable adverse effects in mouse xenograft tumor models. CONCLUSIONS: These results elucidate the effect of PolyU in STS and BS cells and demonstrate that PolyU may be a potential therapeutic agent for STS and BS. PMID- 20828721 TI - Filtration leukocytapheresis therapy ameliorates lipopolysaccharide-induced systemic inflammation in a rat model. AB - BACKGROUND: Systemic inflammation, which is associated with various conditions such as sepsis, pneumonia, and trauma, can lead to multiple organ dysfunction syndrome. Systemic inflammation can be life-threatening and is often associated with conditions seen in the intensive care unit. Leukocytes exert a proinflammatory effect and damage various tissues during systemic inflammation. The purpose of this study was to determine whether leukocytapheresis therapy can prevent lipopolysaccharide (LPS)-induced systemic inflammation in a rat model. MATERIALS AND METHODS: Male Wistar rats weighing 250 to 300 g were used for all experiments. Rats received an LPS injection, followed 6 h later by filtration leukocytapheresis or mock treatment for 30 min under sevoflurane anesthesia. Systemic inflammation was induced in rats by intravenous LPS injection (7.5 mg/kg) followed by filtration leukocytapheresis. Following blood filtration, we evaluated lung and liver histology, serum cytokine levels, and survival rate of rats for each treatment group. RESULTS: Histologic examination revealed markedly reduced inflammatory injury in lung and liver tissue harvested from rats 24 h after leukocytapheresis therapy compared with mock treatment. LPS-induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 secretion was also inhibited by leukocytapheresis therapy. Moreover, survival was significantly increased in rats treated with high-efficiency leukocytapheresis compared to mock-treated rats (P<0.05). CONCLUSIONS: Taken as a whole, our findings indicate that filtration leukocytapheresis therapy protects against LPS-induced systemic inflammation. Therefore, leukocytapheresis shows potential as a new therapy for various systemic inflammatory diseases. PMID- 20828719 TI - Optimizing stem cell function for the treatment of ischemic heart disease. AB - BACKGROUND: Stem cell-based therapies for myocardial ischemia have demonstrated promising early clinical results, but their benefits have been limited in duration due to impaired donor cell engraftment and function. Several strategies have emerged for enhancing stem cell function prior to their therapeutic use particularly with regard to stem cell homing, paracrine function, and survival. This review discusses current understandings of stem cell-mediated cardioprotection as well as methods of enhancing post-transplantation stem cell function and survival through hypoxic preconditioning, genetic manipulation, and pharmacologic pretreatment. MATERIALS AND METHODS: A literature search was performed using the MEDLINE and PubMed databases using the keywords "stem cell therapy," "myocardial ischemia," "hypoxic preconditioning," "paracrine function," and "stem cell pretreatment." Studies published in English since January 1990 were selected. In addition, studies were identified from references cited in publications found using the search terms. RESULTS: All included studies utilized animal studies and/or in vitro techniques. Stem cell modifications generally targeted stem cell homing (SDF-1, CXCR4), paracrine function (VEGF, angiogenin, Ang-1, HGF, IL-18 binding protein, TNFR1/2), or survival (Akt, Bcl-2, Hsp20, HO 1, FGF-2). However, individual modifications commonly exhibited pleiotropic effects involving some or all of these general categories. CONCLUSION: These strategies for optimizing stem cell-mediated cardioprotection present unique potential sets of advantages and disadvantages for clinical application. Additional questions remain including those that are most efficacious in terms of magnitude and duration of benefit as well as whether combinations may yield greater benefits in both the preclinical and clinical settings. PMID- 20828722 TI - Nasogastric placement of sump tube through the leak for the treatment of esophagogastric anastomotic leak after esophagectomy for esophageal carcinoma. AB - OBJECTIVE: We seek to retrospectively analyze the nasogastric placement of sump tube through the leak for the treatment of intra-thoracic esophagastric anastomotic leak after esophagectomy for esophageal carcinoma. MATERIALS AND METHODS: Esophagectomy with intrathoracic esophagogastric anastomotic procedures were performed in 2954 patients who suffered from esophageal carcinoma in our hospital between May 2004 and July 2008. Anastomotic leak had developed in 38 patients, of whom four patients were treated by reoperations. Stent insertion, the traditional "three-tube method" and the nasogastric placement of sump tube through the leak were applied in two, seven, and 25 patients, respectively. RESULTS: The presence of anastomotic leak was proven by radiographic contrast examinations in 38 patients (1.3%). Among them, four received reoperations and recovered. Two patients were treated with the placement of self-expanding metallic coated stents and both died 10 and 13 d after placement due to uncontrollable hematemesis. Seven and 25 patients were managed by the traditional "three-tube method" and the nasogastric placement of sump tube through the leak, respectively. The mean time interval of the leak treatment was 42 d in the traditional "three-tube method" group and 31.2 d in the nasogastric placement of sump tube through the leak group, and the relatively average hospital mortality rates were 14.3% and 12%, respectively. CONCLUSION: The nasogastric placement of sump tube through the leak appears to be an effective, technically feasible, and minimally invasive option for the treatment of intrathoracic esophagogastric anastomotic leak. PMID- 20828723 TI - Glucose balance of porcine liver allograft is an important predictor of outcome. AB - BACKGROUND: The role of glucose metabolism in predicting postoperative liver graft function after transplantation is unclear. We investigated the relation between intraoperative glucose balance of the liver allograft and the postoperative graft function and survival in a porcine partial liver transplant model. MATERIALS AND METHODS: Experiments follow Guiding Principles in the Care and Use of Animals. Fourteen female pigs received liver allografts of 17%-39% recipient liver volume. Recipients were classified into two groups based on positive glucose balance: the mean intraoperative blood glucose of the graft outflow was greater than the blood glucose of inflow, negative glucose balance: the mean blood glucose of graft outflow was less than blood glucose of inflow. Perioperative data and survival were studied. RESULTS: In the positive group (n=9) intraoperative hepatic artery flow was significantly higher (P=0.028), and oxygen consumption was lower (P=0.018) than the negative group (n=5). Postoperatively, maximal serum aspartate aminotransferase (AST) (P=0.028), alanine aminotransferase (ALT) (P=0.028), and total bilirubin (P=0.027) of the positive group were significantly lower than the negative group. In survival analysis, the positive group had significantly better survival rate than the negative group (P=0.034). Using Periodic acid-Schiff staining, glycogen content of the allograft in the positive group at 10 min post-reperfusion was significantly decreased in comparison with the baseline value in the normal liver (P=0.005), however not statistically different in the negative group (P=0.175). CONCLUSION: Intraoperative glucose balance can be used as an early predictor of the graft function following transplantation of partial liver allografts. PMID- 20828724 TI - Nottingham grades of lobular carcinoma lack the prognostic implications they bear for ductal carcinoma. AB - BACKGROUND: Invasive lobular cancer (L) differs clinically and morphologically from invasive ductal cancer (D); differences notwithstanding, Nottingham grades are provided in both. This study compared 22,719 lobular carcinomas with 201,517 ductal carcinomas, dividing them into the grades: well differentiated (W), moderately differentiated (M), poorly differentiated (P), and ungraded to see if differences between comparable grades of lobular and ductal cancer were uniform, consistent with the notion the grading system provides similar information for both cancer subtypes. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to limn relationships among grades, as respects proportions of patients with T3 tumors and nodal metastases, as well as cancer specific survival. Taken into account were age, estrogen and progesterone receptor status, and the administration of radiotherapy. RESULTS: More lobular than ductal carcinomas were T3; grades were not homogenous, with the incidence rate ratio (IRR) comparing lobular and ductal carcinomas being 8.2 for well differentiated, 4.1 for moderately differentiated, and 2.48 for poorly differentiated. With respect to nodal metastases, the 1.16 W L:W D IRR (P < 0.05) was not explicable by chance, but both the 0.97 M L:M D IRR (P > 0.05) and the 0.96 P L:P D IRR (P > 0.05) could have been due to chance. As respects survival, neither the 1.4 P L:P D time ratio (TR) (P < 0.05) nor the 1.23 M L:M D TR (P < 0.05) could have been explained by chance; the 1.05 W L: W D (P > 0.05) might have been due to chance. CONCLUSION: Grades of lobular carcinoma imply different meanings than do grades of ductal carcinoma. Studies of breast cancer should not assume commonality with respect to grade. PMID- 20828725 TI - Detection of microvasculature in rat hind limb using synchrotron radiation. AB - BACKGROUND: New X-ray microangiography and third-generation synchrotron radiation based micro-computed tomography have opened new perspectives for microvascular imaging of extremity. Here we aimed to visualize deep-level microvascular structure in rat hind limb by microangiographic technique, and compare images with those by conventional method. MATERIALS AND METHODS: A total of 10 Sprague Dawley rats were used for in vivo and ex vivo study (five rats/group). Microangiography in vivo and ex vivo was performed and images were compared with those by conventional method. Synchrotron radiation-based micro-computed tomography (SRMUCT) was also performed to reveal three-dimensional (3D) morphology of the blood vessel in rat hind limb. RESULTS: By microangiographic technique, blood vessels in the rat limb could be clearly depicted with the minimum visualized blood vessel about 9 MUm in diameter, and higher angiographic scores were achieved than those by conventional X-ray. In addition, the vascular network could be defined and analyzed at the micrometer scale from the 3D renderings of limb vessel as shown by SRMUCT. CONCLUSIONS: Synchrotron radiation based microangiography and SRMUCT thus provided a practical and effective means to observe the microvasculature of limbs, which might be useful in assessment of angiogenesis in lower limbs. PMID- 20828726 TI - Description of web-enhanced virtual character simulation system to standardize patient hand-offs. AB - INTRODUCTION: The 80-h work week has increased discontinuity of patient care resulting in reports of increased medication errors and preventable adverse events. Graduate medical programs are addressing these shortcomings in a number of ways. METHODS: We have developed a computer simulation platform called the Virtual People Factory (VPF), which allows us to capture and simulate the dialogue between a real user and a virtual character. We have converted the system to reflect a physician in the process of "checking-out" a patient to a covering physician. The responses are tracked and matched to educator-defined information termed "discoveries." Our proof of concept represented a typical post operative patient with tachycardia. The system is web enabled. RESULTS: So far, 26 resident users at two institutions have completed the module. The critical discovery of tachycardia was identified by 62% of users. Residents spend 85% of the time asking intraoperative, postoperative, and past medical history questions. The system improves over time such that there is a near-doubling of questions that yield appropriate answers between users 13 and 22. Users who identified the virtual patient's underlying tachycardia expressed more concern and were more likely to order further testing for the patient in a post-module questionnaire (P = 0.13 and 0.08, respectively, NS). CONCLUSIONS: The VPF system can capture unique details about the hand-off interchange. The system improves with sequential users such that better matching of questions and answers occurs within the initial 25 users allowing rapid development of new modules. A catalog of hand-off modules could be easily developed. Wide-scale web-based deployment was uncomplicated. Identification of the critical findings appropriately translated to user concern for the patient though our series was too small to reach significance. Performance metrics based on the identification of critical discoveries could be used to assess readiness of the user to carry off a successful hand-off. PMID- 20828727 TI - Effects of mechanical stretch on interstitial cells of Cajal in guinea pig bladder. AB - OBJECTIVES: C-kit positive interstitial cells of Cajal (ICCs) play an important role in the regulation of the smooth muscle motility. In this study, we investigated the mechanical sensitivity of ICCs in guinea pig bladder and their possible relationship with detrusor overactivity (DO). METHODS: Stretch load was performed in vivo in DO models produced by 4 wk of partial bladder outlet obstruction (PBOO). Number and morphology of ICCs were examined using a specific ICC marker, c-kit, immunochemistry staining. The spontaneous and stretch-induced calcium transients (SICT) of ICCs were investigated in cells cultured onto flexible silicone membranes preloaded with the Ca(2+) indicator fluo-4AM in vitro. RESULTS: C-kit positive ICCs were mainly located along and between bladder smooth muscle bundles. ICCs in DO bladders displayed more lateral branching with mutual connections. The number of c-kit positive bladder ICCs was increased in the DO group compared with the control group (n = 50, P < 0.05). Cultured ICCs from DO bladders showed spontaneous calcium waves with higher frequency and lower amplitude than those from control bladders (n = 15, P < 0.05). Significant SICT were detected in cultured bladder ICCs. SICT generated in ICCs from DO were more likely to transfer to adjacent smooth muscle cells through cell membrane connection than ICCs from control bladders. CONCLUSIONS: Long-term overload tension following PBOO caused changes in morphology, quantity and spontaneous calcium transients of ICCs in guinea pig bladder. Mechanical sensitivity and interaction with SMC of ICCs may contribute to the mechanosensitive conductances in bladder regulation, and may play a role in the pathogenesis of DO. PMID- 20828728 TI - A physical touch to detect abdominal compartment syndrome. PMID- 20828729 TI - Mechanical simulators versus patient actors: addressing the content validity question. PMID- 20828730 TI - CXCR4 as a predictive marker for locally advanced breast cancer post-neoadjuvant therapy. AB - BACKGROUND: CXCR4 is a G-protein coupled receptor that has been linked with metastasis in several cancers, including breast cancer. We recently demonstrated that high CXCR4 levels in primary tumors of patients with breast cancer had a prognostic significance. We hypothesize that patients whose tumors had a low CXCR4 overexpression level following neoadjuvant chemotherapy will have a lower recurrence rate than those whose tumors remained high. METHODS: Seventeen locally advanced breast cancer (LABC) patients were accrued, and tumor specimens were obtained before and after neoadjuvant therapy. CXCR4 levels were quantified by Western blots against 1 MUg of protein from HeLa cells. The primary end-point was cancer recurrence. Statistical tests utilized include Kaplan-Meier survival analysis and log-rank test. A P value <= 0.05 was considered significant. RESULTS: We previously defined low CXCR4 overexpression as <=6-fold elevation and high overexpression as >6-fold elevation over HeLa cells. Of 17 LABC tumors evaluated, 10 (59%) remained in the low group, 5 (29%) reduced from high to low overexpression, and 2 (12%) maintained a high overexpression after neoadjuvant therapy. With a median follow-up of 28 mo, patients whose tumors maintained a high CXCR4 overexpression level after neoadjuvant therapy had a significantly higher rate of cancer recurrence (P = 0.0068). CONCLUSIONS: CXCR4 was a predictive molecular marker of response to neoadjuvant chemotherapy for patients with LABC. Patients whose tumors had a persistently high CXCR4 overexpression level after neoadjuvant therapy are at a significant risk for recurrence, and therefore, should be targeted for more intensive and/or novel therapy. PMID- 20828731 TI - Gait variability patterns are altered in healthy young individuals during the acute reperfusion phase of ischemia-reperfusion. AB - BACKGROUND: The role of ischemia reperfusion contributing to functional impairment in lower extremity peripheral arterial disease (PAD) patients has not previously been elucidated. The evaluation of gait variability patterns has proven useful in many pathologic populations. Therefore, the purpose of this study is to isolate and determine the specific effect of the acute reperfusion phase of ischemia-reperfusion on gait variability in young individuals with no vascular disease. MATERIALS AND METHODS: Thirty healthy young individuals walked on a treadmill during baseline and the acute reperfusion phase of ischemia reperfusion conditions while lower extremity joint kinematics were captured. Stride to stride variability was assessed using the largest Lyapunov exponent, approximate entropy, standard deviation, and coefficient of variation. Differences in gait variability between conditions were assessed using dependent t-tests. RESULTS: The largest Lyapunov exponent values and approximate entropy values were significantly higher in the acute reperfusion phase of ischemia reperfusion condition for the ankle, knee, and the hip. Coefficient of variation was significantly higher at the hip and standard deviation was higher at the knee and the hip during the acute reperfusion phase of ischemia-reperfusion condition. CONCLUSIONS: The acute reperfusion phase of the ischemia-reperfusion cycle alters gait variability patterns at the ankle, knee, and the hip in healthy young individuals. Our findings indicate increased noise and irregularity of gait variability patterns post-ischemia. In young healthy individuals who do not have neuromuscular impairments, significant gait alterations are present during walking after a period of interruption of blood flow. PMID- 20828732 TI - Intensive fluid therapy combined with epinephrine improves orthotopic small bowel transplantation in mice. AB - BACKGROUND: Mouse model of orthotopic small bowel transplantation (SBT) has great advantages in the researches of post-transplant immunology and physiology, whereas it is infrequently utilized because of low survival rate. To improve this model, we modified the techniques and the perioperative treatments. MATERIALS AND METHODS: Syngeneic orthotopic SBT was performed in C57 mice. Two groups were established in accordance with the perioperative treatments: control group (only intensive fluid therapy was administered); epinephrine group (intensive fluid therapy and epinephrine were applied jointly). Only fluid enteral nutrition was allowed after surgery in all recipients. Survival and the change of body weight were observed for 2 wk after transplantation. The ischemia/reperfusion (I/R) injury of the grafts was assessed by histopathology on postoperative day (POD) 1 and 7. RESULTS: The overall success rate was 76.5% (26/34). In control group and epinephrine group, the success rate was 66.7% (12/18) and 87.5% (14/16), respectively. No complications of thrombosis and bowel obstruction were found. The body weight changed in the same way in both groups. No differences of I/R injury were observed between two groups. CONCLUSIONS: Precise perioperative treatments, especially intensive fluid therapy combined with epinephrine application, improve the mouse model of orthotopic SBT to achieve satisfying success rate. PMID- 20828733 TI - Correlation of Nrf2, HO-1, and MRP3 in gallbladder cancer and their relationships to clinicopathologic features and survival. AB - BACKGROUND: Gallbladder cancer (GC) is considered a relatively rare malignancy with extensively poor prognosis. To guide clinicians in selecting treatment options for GC patients, reliable markers predictive of poor clinical outcome are desirable. This study analyzed the correlation of NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and multidrug resistance-related protein 3 (MRP3) in GC and their relationships to clinicopathologic features and survival. MATERIAL AND METHODS: We immunohistochemically investigated 59 specimens of gallbladder adenocarcinoma tissues using Nrf2, HO-1, and MRP3 antibodies. RESULTS: There were significant correlations between the high level of Nrf2, HO-1, and MRP3 expression and the tumor differentiation, Nevin staging, and metastasis. Significant positive correlations were found between the expression status of Nrf2 and that of HO-1 and MRP3 (r = 0.38, P = 0.008 and r = 0.59, P < 0.001, respectively). High Nrf2 expression was significantly associated with shorter overall survival times in univariate analysis (log-rank test, P < 0.001), being also identified as an independent prognostic factor in multivariate analysis (P = 0.035). CONCLUSIONS: Nrf2, HO-1, and MRP3 were associated with certain clinicopathologic parameters in GC. Evaluation of Nrf2 expression may be an important factor in identifying a poor prognostic group of GC. PMID- 20828734 TI - Hispanic ethnicity and unintentional injury mortality in the elderly. AB - BACKGROUND: Unintentional injury is a leading cause of preventable mortality in elderly populations and is most often related to accidental falls and motor vehicle accidents. Hispanic ethnicity has been previously associated with decreased risk of accidental fall death as well as improved outcomes in other health states, the "Hispanic paradox." A timely analysis of national data with consideration for multiple injury types and age could provide insight into this epidemiologic phenomenon and help guide the use of prevention efforts. MATERIALS AND METHODS: Search of the Center for Disease Control's WISQARS database was performed to identify the number of fatalities in the U.S. between 2003 and 2006 by age group, gender, Hispanic ethnicity, and injury type. Total U.S. population and group populations for the years examined were obtained from the U.S. Census Bureau's American Community Survey for each year. Mortality was calculated as fatalities over the total group population for the years examined. RESULTS: Independent of gender and age group, elderly Hispanics were at decreased risk of death from accidental fall or as an occupant in a motor vehicle accident, but increased risk of pedestrian fatality compared with white-NH. CONCLUSIONS: The reduced fall and occupant mortality seen in elderly Hispanic populations may come at the cost of increased pedestrian-related mortality. This is consistent with and likely reflects differences in culture, socioeconomic status, and geographic distribution for the U.S. Hispanic population. Effective targeting of injury prevention programs, especially community based, should consider the role of Hispanic ethnicity and its impact on lifestyle. PMID- 20828735 TI - Components of geriatric assessments predict thoracic surgery outcomes. AB - BACKGROUND: No tool currently exists to rapidly allow surgeons to objectively quantify surgical risk in geriatric patients. The goal of our prospective study was to determine if individual questions extracted from validated screens for common geriatric syndromes would have predictive value for surgical risk in geriatric patients with thoracic neoplasms. METHODS: Patients >= 70 y old were recruited to participate in a prospective, IRB-approved study involving the preoperative administration of validated screening tests. Patients were given the geriatric depression scale (GDS), nutrition screening initiative nutritional health checklist (NSI NHC), mini mental status exam (MMSE), brief fatigue inventory (BFI), and assessed for activities of daily living (ADLs) and instrumental activities of daily living (IADLs). All patients enrolled in this study were scheduled for thoracic surgery. RESULTS: Patients who responded to having a dependency in the IADL "shopping" were more likely to have major complications and to be discharged to a non-home location than those without a dependency (P = 0.011, 0.003). Patients who answered "yes" to questions 1, 9, and 10 of the NSI NHC had a longer mean length of stay compared with patients who answered "no" (P = 0.039, 0.010, 0.031). Answering "yes" to GDS question 2 correlated with the incidence of major complications (r = 0.270 P = 0.037). Answering "yes" to GDS question 12 increased the likelihood of being discharged to a non-home location postoperatively (odds ratio = 11.64, 95% CI, 0.68-202.86, P = 0.047). CONCLUSIONS: Our data indicate that an abbreviated, rapid presurgical assessment can be developed for estimating operative risk, length of stay, and discharge destination in geriatric patients with thoracic malignancies using individual questions from previously validated screening tools. PMID- 20828736 TI - Mast cell degranulation is essential for anastomotic healing in well perfused and poorly perfused rat colon. AB - BACKGROUND: Mast cell degranulation is an important step in early wound healing in the skin however the role of the mast cell in anastomotic healing is less clear. The aim of this study was to investigate the importance of mast cell degranulation in anastomotic healing and to assess whether a promoter of mast cell degranulation could increase anastomotic healing in poorly perfused bowel. METHODS: Fifty Wistar rats were divided into five groups: control, normally perfused bowel with mast cell stabilisation, normally perfused bowel with mast cell degranulation, hypoperfused bowel, and hypoperfused bowel with mast cell degranulation. A colo-colonic anastomosis was formed in each animal. Four d later, following sacrifice, the strength of the anastomosis was assessed in each animal. RESULTS: Mast cell stabilisation reduced anastomotic healing in normally perfused bowel (P < 0.001). Hypoperfused bowel resulted in reduced anastomotic strength (P < 0.001) however the addition of a mast cell degranulating agent increased healing in hypoperfused bowel to levels comparable with control. CONCLUSIONS: Mast cell degranulation is essential for early anastomotic healing. Healing is reduced in hypoperfused bowel but the administration of a mast cell degranulation agent can compensate for the adverse effects of a poor blood supply on anastomotic healing. PMID- 20828737 TI - Role of the mTOR pathway in LPS-activated monocytes: influence of hypertonic saline. AB - BACKGROUND: As heightened protein synthesis is the hallmark of many inflammatory syndromes, we hypothesize that the mammalian target of rapamycin (mTOR) pathway, which control the cap-dependent translation initiation phase, was activated by lipopolysaccharide (LPS). In addition, we studied the effect of hypertonic saline solution (HTS) on the mTOR cascade in peripheral blood mononuclear cells (PBMCs). MATERIALS AND METHODS: PBMCs were isolated from healthy volunteers and treated with LPS. Cells were pretreated with phosphatidylinositol 3-kinase (PI3K) and mTOR inhibitors, or with HTS. Supernatants were harvested 20 h following LPS treatment, and interleukin-10 (IL-10), interleukin-6 (IL-6) and tumor necrosis alpha (TNFalpha) were analyzed by ELISA. Immunoblot experiments were performed for components of the PI3K/Akt/mTOR pathway at various time points. RNA was extracted after 90 min for real-time RT-PCR quantification. RESULTS: The mTOR pathway is activated in PBMCs within 1 h of LPS stimulation. Pretreatment with rapamycin, a specific inhibitor of mTOR, resulted in a significant decrease of IL 10 and IL-6 translation and expression but did not affect the LPS-induced TNFalpha production. Both the mTOR pathway and the LPS-induced IL-6 production were down-regulated by HTS pretreatment. CONCLUSIONS: The PI3k/Akt/mTOR cascade modulates LPS-induced cytokines production differentially. IL-10 and IL-6 expression are both up-regulated by activation of the mTOR pathway in response to LPS in PBMCs, while TNFalpha is not controlled by the mTOR cascade. Meanwhile, pretreatment of PBMCs with a HTS solution suppresses mTOR activity as well as LPS induced IL-6, suggesting a more central role for mTOR as a regulator of the immuno-inflammatory response. PMID- 20828738 TI - Exosomes derived from immature bone marrow dendritic cells induce tolerogenicity of intestinal transplantation in rats. AB - BACKGROUND: Dendritic cells (DCs) secrete exosomes bearing major histocompatibility complex I and II (MHC I /II) and co-stimulatory molecules, and play a critical role in immune regulation. Because immature DCs can induce T-cell tolerance in vitro and in vivo, we explored the possibility of using exosomes derived from immature DCs (imDex) for the induction of intestinal transplant tolerance in rats. MATERIALS AND METHODS: ImDex were purified from F344 rat bone marrow immature DCs. The tolerizing capacities of imDex were analyzed in vitro and in vivo using a F344-to-Wistar intestinal transplantation model. RESULTS: In the context of a moderate level of MHC class II and a low co-stimulatory level expression, imDex significantly suppressed the alloreactive T-cell response with an increase in IL-10 in vitro. In vivo injection of the lower dose (20 MUg) of donor (but not recipient) imDex can significantly prolong the survival of intestinal allografts. This effect was accompanied by a decrease in the anti donor cellular response, with a significant increase in IL-10. The CD4+CD25+T cells percentage and FOXP3mRNA expression in splenic T-cells were also significantly increased in imDex treatment recipients at five days after transplantation. CONCLUSIONS: The results suggest that imDex can prolong the intestinal allograft survival and may be a potential strategy to facilitate induction of transplant tolerance. PMID- 20828739 TI - Predicting the prognosis of hepatocellular carcinoma using gene expression. AB - BACKGROUND: Many risk factors affect survival after liver resection for hepatocellular carcinoma (HCC), but these lack specificity for the prognosis. Studies of gene expression profiles successfully predicted the survival of HCC. To date, few studies have focused on HBV-associated HCC. Therefore, we investigated the genes involved in tumor prognosis in patients with HBV associated HCC. MATERIALS AND METHODS: We analyzed clinical data and microarray test results in 51 patients who underwent liver resection for HBV-associated HCC between August 1998 and December 2002. We used Kaplan-Meier plots to analyze survival rates and some well-known clinical staging systems. In addition, we performed microarray survival analysis using Cox univariate regression. Then, we devised a scoring system that adds the survival-associated gene expression signature to one or two independent clinical risk factors for survival. RESULTS: The mean follow-up period was 61.4 mo. Thirty-six patients had recurrence during this period, and 22 died. The 5-y survival rate was 58.0%. Multivariate analysis showed that tumor size was an independent risk factor for survival. We identified 194 spots on the microarray in survival analysis. These genes were clustered into two groups and showed a statistically significant difference in the survival rates. In the clinical analysis, the CLIP and Okuda staging systems showed statistically significant relationships. When we added the survival-associated gene expression signature to tumor size, our new method showed a more statistically significant relationship between stage and survival. CONCLUSIONS: We propose that adding the results of microarray survival analysis to the staging system predicts survival more precisely. PMID- 20828740 TI - Intraoperative detection of thyroid carcinoma by fourier transform infrared spectrometry. AB - BACKGROUND: Fourier transform infrared (FTIR) spectroscopy is a powerful tool for distinguishing cancerous tissue from normal one. Our aim in this study was to establish tissue discriminant analysis for thyroid malignancy and benign samples intraoperatively using FTIR spectroscopy. METHODS: Seventeen papillary thyroid cancer and 43 nodular goiter tissues were obtained and underwent FTIR spectroscopy scanning intraoperatively. Nine peak positions were identified and assigned. Peak position values and wave intensity ratios were measured in every single spectrum. Data of malignant and benign groups were compared and equations of canonical discriminant analysis were established. RESULTS: Peak positions of P1640, P1240, P1550, and peak intensity ratios of I3375/I1460, I1640/I1460, I1400/I1460, I1550/I1080, I1080/I1460, and I1640/I1550 of thyroid papillary carcinoma group are significantly different from nodular goiter group. The sensitivity, specificity, and accuracy rate of the discriminants are 83.3%, 95.2%, and 91.67%, respectively. CONCLUSION: FTIR spectroscopy technique in combination with canonical discriminant analysis method can achieve fast and accurate discrimination for malignant and benign thyroid nodules during operation. PMID- 20828741 TI - Ovine smoke/burn ARDS model: a new ventilator-controlled smoke delivery system. AB - BACKGROUND: Our current ovine smoke/burn acute respiratory distress syndrome (ARDS) model utilizes a manual bee smoker. This smoke delivery system lacks standardization and reproducibility, with 20% of sheep failing to meet ARDS criteria. Time to reach ARDS criteria and survival time are also variable. The mild volutrauma (15 mL/kg) applied after smoke/burn injury may also fail to induce ARDS within 24 h. We hypothesized that these inconsistencies were associated with the bee smoker and the mild volutrauma. In the current study, we addressed these problems to improve the consistency of the smoke/burn ARDS model. METHODS: Adult female sheep (n = 10) were given a 40% total body surface area third degree cutaneous burn and 48 breaths (4 * 12) of cotton smoke under general anesthesia. A modified ventilator was then used to deliver a precise and consistent smoke volume (tidal volume) to the sheep. Additional barotrauma was induced by pressure control ventilation (40 cm H(2)0). When ARDS criteria (PaO(2)/FiO(2) < 200) were met, the ARDS Network low tidal volume ventilation protocol (6-8 mL/kg ideal body weight) was used. RESULTS: Carboxyhemoglobin levels were 81.4% +/- 5.6% immediately following smoke injury. All sheep met ARDS criteria within 24 h (12.5 +/- 4.9 h). Mean survival time post-injury was 62.1 +/ 26.4 h. White blood cells and granulocytes were significantly elevated at 24 h post-smoke/burn injury. Lung tissue at necropsy was consistent with ARDS. CONCLUSIONS: The refinements made to the original ovine smoke/burn ARDS model produce a more reliable time to ARDS onset, injury severity, and time of death. PMID- 20828742 TI - Validating the Injury Severity Score (ISS) in different populations: ISS predicts mortality better among Hispanics and females. AB - INTRODUCTION: The Injury Severity Score (ISS) is the most commonly used measure of injury severity. The score has been shown to have excellent predictive capability for trauma mortality and has been validated in multiple data sets. However, the score has never been tested to see if its discriminatory ability is affected by differences in race and gender. OBJECTIVE: This study is aimed at validating the ISS in men and women and in three different race/ethnic groups using a nationwide database. METHODS: Retrospective analysis of patients age 18 64 y in the National Trauma Data Bank 7.0 with blunt trauma was performed. ISS was categorized as mild (<9,) moderate (9-15), severe (16-25), and profound (>25). Logistic regression was done to measure the relative odds of mortality associated with a change in ISS categories. The discriminatory ability was compared using the receiver operating characteristics curves (ROC). A P value testing the equality of the ROC curves was calculated. Age stratified analyses were also conducted. RESULTS: A total of 872,102 patients had complete data for the analysis on ethnicity, while 763,549 patients were included in the gender analysis. The overall mortality rate was 3.7%. ROC in Whites was 0.8617, in Blacks 0.8586, and in Hispanics 0.8869. Hispanics have a statistically significant higher ROC (P value < 0.001). Similar results were observed within each age category. ROC curves were also significantly higher in females than in males. CONCLUSION: The ISS possesses excellent discriminatory ability in all populations as indicated by the high ROCs. PMID- 20828743 TI - Diazoxide suppresses hepatic ischemia/reperfusion injury after mouse liver transplantation by a BCL-2-dependent mechanism. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is responsible for primary liver dysfunction and failure after transplantation. The mitochondrial pathway appears to be involved in liver ischemia-reperfusion injury. Mitochondrial ATP-sensitive K (mitoK(ATP)) channels play a central role in protecting the heart from injury in ischemic preconditioning. The selective mitoK(ATP) channel agonist diazoxide potently reduced mitochondrial injury by preventing cytochrome c loss from the intermembrane space. Therefore, this study sought to determine whether diazoxide can attenuate ischemia-reperfusion injury induced by orthotopic liver transplantation (OLT) in mice. Furthermore, it was found that up-regulation of the Bcl-2 gene is a mechanism of diazoxide cytoprotection. MATERIALS AND METHODS: Donors were treated with diazoxide, Bcl-2 siRNA, or diazoxide + Bcl-2 siRNA and vehicle 10 min or 24 h before liver harvesting. Liver grafts were then orthotopically transplanted into their corresponding recipients. RESULTS: Liver injury, as judged by transaminase level and histologic examination, was significantly lower in the diazoxide group compared with vehicle controls. The percentage of apoptotic cells and the amount of cytochrome c in the cytosol 6 h after transplant were also markedly reduced in diazoxide-treated grafts compared with vehicle-treated controls. Diazoxide notably up-regulated expression of Bcl 2, while siRNA knockdown of Bcl-2 abolished the cytoprotective effects of diazoxide. CONCLUSIONS: Diazoxide attenuated graft injury after mouse liver transplantation. One mechanism of diazoxide protection involves the induction of Bcl-2, an anti-apoptotic protein. Diazoxide might be useful clinically in hepatic surgery and transplantation. PMID- 20828744 TI - Validating quantitative obesity measurements in colorectal cancer patients. AB - BACKGROUND: Over 70,000,000 American adults are overweight, and obesity accounts for $147 billion annually in medical expenses. Since measuring obesity by body mass index (BMI) fails to account for fat distribution and quantity, recent work has explored quantitative measures of visceral fat area (VFA) and subcutaneous fat area (SFA) obtained from CT imaging. However, use of CT to quantify adipose tissue has not been evaluated in colorectal cancer (CRC) patients and the optimal anatomic location for measuring VFA and SFA has yet to be determined. We measured VFA and SFA at three different anatomic locations to determine which location was optimal in CRC patients. METHODS: A database of patients undergoing CRC surgery from 2002 to 2009 was reviewed to identify patients with preoperative CT imaging. Quantitative measurements of both VFA and SFA were calculated at the level of L4 L5, L2-L3, and mid-waist. RESULTS: A total of 244 colorectal cancer patients had preoperative imaging available and 99% were men. VFA and SFA quantified by CT at the levels of L2-L3, L4-L5, and mid-waist were all significant independent predictors for medical complications of obesity including diabetes (HR 1.04 1.06) and hypertension (HR 1.04-1.09) on multivariate analysis. The location used for imaging did not affect predictive power. Additionally, waist circumference was also a significant independent predictor of diabetes (HR 1.56) and hypertension (HR 1.70). CONCLUSIONS: Quantitative measures of obesity from CT imaging in CRC patients correlated significantly with medical conditions known to be associated with obesity. This indicates that direct measurement of adiposity is valid in colorectal cancer patients. PMID- 20828745 TI - The humoral response after laparoscopic versus open colorectal surgery: a meta analysis. AB - BACKGROUND: The local and systemic humoral response after colorectal surgery is thought to affect postoperative recovery. It is commonly claimed that laparoscopic surgery elicits a diminished inflammatory response than equivalent open surgery. Despite these claims, the evidence is conflicting. Therefore, we aimed to systematically review the results from randomized controlled clinical trials comparing the humoral response associated with laparoscopic versus open colorectal surgery. MATERIALS AND METHODS: A high-sensitivity search was conducted independently by two of the authors with no language restriction. Studies were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), Cochrane Library, Medline (January 1966 to January 2009), PubMed (1950 to January 2009), and Embase (1947 to January 2009). Relevant meeting abstracts and reference lists were manually searched. Data analysis was performed using Review Manager ver. 5.0. RESULTS: Thirteen randomized controlled trials were included. Meta-analysis demonstrated a significantly higher serum IL-6 on d 1 after open colorectal resection for neoplasia (n = 97) compared with laparoscopic resection (n = 76, P = 0.0008) without significant heterogeneity. Data for plasma IL-6 were heterogeneous, with no apparent difference between groups. No other significant differences were identified, and there were not enough data on local peritoneal humoral factors to allow meta-analysis. CONCLUSION: Open colorectal resection for neoplasia is associated with higher postoperative serum levels of IL-6 on d 1 than equivalent laparoscopic surgery. The aetiology and clinical significance of this finding is uncertain, and further studies are required to elucidate any differences in the local humoral response which may be more clinically relevant in surgery for this indication. PMID- 20828746 TI - Continuous-flow cardiac assistance: effects on aortic valve function in a mock loop. AB - BACKGROUND: As the use of left ventricular assist devices (LVADs) to treat end stage heart failure has become more widespread, leaflet fusion--with resul-tant aortic regurgitation--has been observed more frequently. To quantitatively assess the effects of nonpulsatile flow on aortic valve function, we tested a continuous flow LVAD in a mock circulatory system (MCS) with an interposed valve. MATERIALS AND METHODS: To mimic the hemodynamic characteristics of LVAD patients, we utilized an MCS in which a Jarvik 2000 LVAD was positioned at the base of a servomotor-operated piston pump (left ventricular chamber). We operated the LVAD at 8000 to 12,000 rpm, changing the speed in 1000-rpm increments. At each speed, we first varied the outflow resistance at a constant stroke volume, then varied the stroke volume at a constant outflow resistance. We measured the left ventricular pressure, aortic pressure, pump flow, and total flow, and used these values to compute the change, if any, in the aortic duty cycle (aortic valve open time) and transvalvular aortic pressure loads. RESULTS: Validation of the MCS was demonstrated by the simulation of physiologic pressure and flow waveforms. At increasing LVAD speeds, the mean aortic pressure load steadily increased, while the aortic duty cycle steadily decreased. Changes were consistent for each MCS experimental setting, despite variations in stroke volume and outflow resistance. CONCLUSIONS: Increased LVAD flow results in an impaired aortic valve-open time due to a pressure overload above the aortic valve. Such an overload may initiate structural changes, causing aortic leaflet fusion and/or regurgitation. PMID- 20828747 TI - Leupeptin preserves cardiac nitric oxide synthase 3 during reperfusion following long-term cardioplegia. AB - The objective of this study was to investigate how long-term cardioplegia/reperfusion affects cardiac nitric oxide synthase 3 (NOS3). To this aim, rat hearts were mounted in a perfusion apparatus and equilibrated with a modified Krebs-Henseleit solution (KH). The hearts were then arrested by soaking them in cold St. Thomas Hospital II solution (STH) for 5, 7, and 15 h. Reperfusion was performed by low-flow cold STH delivering for 1 h followed by 15 min aerobic normothermic KH perfusion. Cardioplegia preserved the amount of NOS3 irrespective of the duration of the cardiac arrest. NOS3 content was also unaffected by reperfusion following 5 and 7 h of cardioplegia. On the contrary, reperfusion performed after 15 h of cardioplegia caused a marked reduction in the amount of NOS3 protein, in both endothelial and cardiac muscle cells, and NOS activity. The involvement of intracellular proteolysis as a cause of reduction in NOS3 cardiac level was then investigated by delivering 0.1 mmol/L of either calpain I and II inhibitors or 0.05 mmol/L leupeptin during heart reperfusion. Only the treatment with leupeptin preserved NOS3, indicating that lysosomal proteases rather then cytoplasmic calpains were mainly responsible for the cleavage of this enzyme. The observed decrease in GSH/GSSG ratio and activation of JNK in the reperfused heart suggested that proteolysis could be triggered by reactive oxygen species. PMID- 20828748 TI - Endothelial microparticles induce inflammation in acute lung injury. AB - BACKGROUND: Previously, we have shown that endothelial microparticles (EMPs) injected into mice induce acute lung injury (ALI) [1]. In this study, we hypothesize that EMPs induce ALI by initiating cytokine release in the lung, leading to recruitment and activation of neutrophils. MATERIALS AND METHODS: C57BL/6J male mice (8-10 wk old) were intravenously injected with EMPs (200,000/mL), LPS (2 mg/kg), or both. Bronchoalveolar lavage (BAL) and serum levels of IL-1beta and TNF-alpha were analyzed by enzyme-linked immunoassay (ELISA). Morphometric analysis was performed on H and E stained lung sections. Myeloperoxidase (MPO) levels were determined via an enzymatic assay and immunofluorescence of stained sections. RESULTS: EMPs led to significantly increased pulmonary and systemic IL-1beta and TNF-alpha levels, which correlated with increased neutrophil recruitment to the lung. MPO levels in the lungs were increased significantly following injection of EMPs or LPS, compared to PBS. In mice treated with EMPs and LPS either simultaneously or successively, the cytokine and MPO levels were significantly increased over that of either treatment alone. CONCLUSION: EMPs contribute to lung injury through the initiation of a cytokine cascade that increases recruitment of neutrophils and subsequent release of MPO. Furthermore, treatment of mice with both EMPs and LPS induced greater lung injury than either treatment alone, suggesting that EMPs prime the lung for increased injury by other pathogens. Therapies aimed at reducing or blocking EMPs may be a useful strategy for attenuating lung injury. PMID- 20828749 TI - The stage dependent changes in NK cell activity and the expression of activating and inhibitory NK cell receptors in melanoma patients. AB - BACKGROUND: As NK cell antitumor activity is regulated by the balance between numerous activating and inhibitory receptors the aim of this study was to analyze the changes in these receptors expression as well as the differences in their association with NK cell activity in melanoma patients in different clinical stages. MATERIALS AND METHODS: Forty-three melanoma patients in the three different clinical stages and 17 healthy controls were analyzed for NK cell activity by the standard (51)Cr radioactive assay, as well as for the percentage and absolute number of CD3-CD56+ NK cells and their subsets and the expression of degranulation marker CD107a, activating NKG2D and CD161, and inhibitory KIR, CD158a, and CD158b receptors on CD3-CD56+ NK cells by flow cytometry. IFN-gamma and TNF-alpha PBL production were evaluated by enzyme-linked immunosorbent assay (ELISA). RESULTS: We show that contrary to nonmetastatic, metastatic melanoma patients have significantly impaired NK cell activity, lower CD107a expression, as well as decreased production of IFN-gamma and TNF-alpha. Furthermore, these melanoma patients have a significant decrease in the expression of activating NKG2D receptor, which positively correlates with NK cytotoxicity, and a significant increase in the expression of inhibitory CD158b on CD3-CD56+ NK cells compared with healthy controls. CONCLUSIONS: In this study, we show that metastatic melanoma patients have significant changes in NK cell activity and the expression of activating as well as inhibitory NK cell receptors. These results indicate that only in this patient group, the blocking of inhibitory or enhancing of activating NK cell receptor expression may promote NK cell-mediated cytolysis. PMID- 20828750 TI - The role of HMGB1 and HSP72 in ischemia and reperfusion injury. PMID- 20828751 TI - Teaching technical skills to medical students during a surgery clerkship: results of a small group curriculum. AB - BACKGROUND: Opportunities for medical students to learn and perform technical skills during their clinical years have decreased. Alternative means to provide instruction are increasingly important. METHODS: Third-year students were assigned to three weekly small group tutorial sessions during their surgery clerkship. One hour sessions covered the following: suturing/knot tying, tubes (Foley catheter/NG tube), and lines (i.v. placement/arterial puncture). Students used a self-reported checklist to report their experience performing these procedures in the hospital after being exposed to them in the skills sessions. These data were compared with results prior to the implementation of the skills curriculum. Results were compared by Fisher's exact test. RESULTS: Seventy-seven students had evaluable checklists during the control period, and 69 were evaluable during the study period. Participations in four specific skills were compared: Foley catheter placement, nasogastric tube insertion/removal, i.v. placement, and arterial stick. In all four skills, students were more likely to have performed the task after having been introduced to it in the skills sessions. For both Foley catheter placement (96% versus 90%; P = 0.05) and NG tube insertion/removal (70% versus 53%; P = 0.06) there was a trend toward a higher incidence of participation, although statistical significance was not met. However, for both IV placement (64% versus 18%; P = 0.0001) and arterial puncture (48% versus 18%; P = 0.0002) there were significant increases in participation between the study periods. CONCLUSIONS: These results suggest that a small group technical skills curriculum facilitates learning of specific technical skills and appears to increase participation in all of the skills taught and assessed. This may be one strategy to introduce students to technical skills during the surgery clerkship and improve participation of these skills in the hospital setting. PMID- 20828752 TI - Gender differences among recidivist trauma patients. AB - BACKGROUND: Gender differences among trauma recidivist patients are not well understood. We hypothesized that males are more likely to be repeatedly involved in the trauma system and have a shorter time to recurrence between repeat episodes of injury compared with females. MATERIALS AND METHODS: A retrospective analysis of trauma patients treated at an urban university-based trauma center was performed. Variables including gender, race, insurance status, age, mechanism of injury, outcomes, and injury secondary to domestic violence were compared. Differences were compared using chi(2) tests and log-rank (Mantel-Cox) Kaplan Meier cumulative event curves. RESULTS: We identified 689 trauma recidivist patients (4.0% of all trauma visits) over a 10-y period. Compared to single-visit patients, recidivist patients were more likely to be male (87% versus 73%), uninsured (78% versus 66%), and have injuries secondary to assaults (54% versus 37%) (P < 0.05). Time from the first to second trauma visit was shorter for females compared with males (23 +/- 2.5 versus 30 +/- 1.2 mo, P < 0.02). Additionally, female recidivists were more likely to be involved in blunt trauma than were male recidivists (69% versus 43%, P < 0.001). Furthermore, domestic violence was identified in a higher proportion of female recidivist patients than female single-visit patients (3.5% versus 1.6%, P < 0.0003). CONCLUSIONS: Contrary to our hypothesis, female recidivist trauma patients have a much shorter time to recurrence for a second traumatic injury than do males. Female recidivists have a high likelihood of assault-associated injuries and domestic violence. Trauma centers should screen for domestic violence among trauma patients to aid in preventing further repeat episodes of injury. PMID- 20828753 TI - Monitoring fibrosis of the pancreatic remnant after a pancreaticoduodenectomy with dynamic MRI: are the results independent of the adopted reconstructive technique? PMID- 20828754 TI - A "solution" to the application of an effective physical barrier for the prevention of intra-abdominal adhesions. PMID- 20828755 TI - An innovative intramedullary nail for stabilizing mouse femoral defects. PMID- 20828756 TI - A surgical perspective on the role of cryopreserved allografts. PMID- 20828757 TI - Perioperative blood transfusions promote pancreas cancer progression. AB - Complex abdominal procedures to extirpate malignancies are often associated with blood transfusion. In particular, perioperative transfusion rates for pancreaticoduodenectomy can be as high as 75%. In the early 1970s it was shown that blood transfusions likely had immunomodulating effects as renal allografts were found to have longer survival in patients who received multiple transfusions. Subsequently, it has been suggested that blood transfusions may promote cancer progression. Many retrospective series have supported this hypothesis, and recent studies examining long-term survival in patients undergoing "Whipple" procedures suggests that transfusion is a negative prognostic factor. Despite these studies, the claim that transfusion is a simple surrogate for patient health, tumor size, location, and biology are difficult to refute. The use of syngeneic murine models has allowed many confounding variables to be controlled, and suggest that transfusion does indeed promote pancreas cancer progression. Based on these findings, as well as the continued need for blood transfusion, alternate strategies in transfusion management are warranted. PMID- 20828758 TI - Hypoxemic versus normoxemic reperfusion in a large animal model of severe ischemia-reperfusion injury. AB - BACKGROUND: Prior studies have suggested a significant benefit of using deliberate hypoxemia to reperfuse ischemic tissue beds, primarily by reducing free radical injury. We sought to examine the effects of a hypoxemic reperfusion strategy in a large animal model of severe truncal ischemia. MATERIALS AND METHODS: Adult swine were subjected to 30 min of supraceliac aortic occlusion and randomized to two groups: normoxemia group (n = 9), with resuscitation at a pO2 >100 mmHg or hypoxemia group (n = 10), with initial resuscitation at a pO2 of 30 50. The two groups were compared using physiologic parameters, fluid and pressor requirements, inflammatory and oxidative markers, and histologic analysis of end organ injury. RESULTS: All animals developed significant hemodynamic instability immediately upon reperfusion. Average mean arterial pressure at baseline rose significantly after 30 min of cross-clamp (76.8 versus 166.3 mmHg, P < 0.001). Upon reperfusion, all animals required epinephrine and fluids to maintain mean arterial pressure (MAP) greater than 60 mmHg. After stabilization, the two groups were similar in terms of central and pulmonary hemodynamics. The hypoxemic group required more mean total epinephrine (18.35 mg versus 5.28 mg, P < 0.01) with no significant difference in total fluid volume (hypoxemic 9111 ml versus 8420 mL, P = 0.730). The hypoxemic group demonstrated a more severe metabolic acidosis at all time intervals after reperfusion (pH 7.02 versus 7.16 and lactate 17 versus 13, both P < 0.01). There was no difference in malondialdehyde concentration between the two groups, but the hypoxemic group had a higher antioxidant reductive capacity at all intervals after 30 min of reperfusion (0.23 versus 0.27 uM, P = 0.03). While there was significant end-organ damage on pathologic examination of all liver and kidney specimens (mean severity of injury 1.59 and 1.76, respectively, on a scale of 1-3), there was no significant difference between the two groups. CONCLUSIONS: A hypoxemic reperfusion strategy in this large animal model failed to demonstrate any significant clinical benefit. Although there was chemical evidence of improved antioxidant capacity with hypoxemia, it was associated with more instability, metabolic and physiologic derangements, and no evidence of end-organ protection. PMID- 20828759 TI - Improving cell-based treatment for ischemic tissue. PMID- 20828760 TI - Early graft function defined by area under the curve serum creatinine 7 days post transplant in a series of live donor kidney transplantation. AB - BACKGROUND: There is a degree of variability in early graft function that is often not highlighted in live kidney donor transplantation. We used the calculation of area under the curve of serum creatinine (AUC Cr) in the first 7 d post-transplant to assess early graft function and examine the influence on longer term outcome. METHODS: A total of 188 live donor renal transplants performed between 1998 and 2007 were analyzed. AUC Cr was calculated over the first 7 d post-transplant and 12 mo serum creatinine levels recorded. Donor and recipient demographics were recorded, and univariable and multivariable analyses were used to determine influencing factors. The sensitivity and specificity of AUC Cr for the detection of reduced serum creatinine at 12 mo (cut-off 130 MUmol/L) were assessed by the receiver operating characteristic (ROC) curve. RESULTS: There was a significant variation in levels of AUC Cr over the first 7 d post-transplant (range, 692-5765 MUmol/L.d). The ROC curve had a relatively low predictive value for the AUC Cr calculation (AUC=0.735). However, multivariable analysis showed that higher levels of AUC Cr were associated with higher serum creatinine levels at 12 mo (slope 0.012; P=0.0005). The need for dialysis, lower kidney weight, and higher recipient weight were significant independent predictors of a higher serum creatinine at 12 mo. CONCLUSION: The calculation of AUC serum creatinine 7 d post-transplant highlighted the significant variation in early graft function following live donor transplantation and was associated with creatinine levels at 12 mo. This calculation may be used as a simple prognostic marker to highlight poorer graft outcome. PMID- 20828761 TI - Burn scar assessment: a systematic review of different scar scales. AB - BACKGROUND: Scars can be devastating and disfiguring, because they are clearly visible, stigmatizing, and permanent reminders of the initial accident or surgical event. Yet, there is still no consensus about the optimal scale or tool to assess the characteristics and evolution. Our aim was to evaluate the clinical importance of scar scales specifically developed for burn scars. MATERIALS AND METHODS: The systematic literature search involved PubMed and the Web of Science (including Science Citation Index). RESULTS: The search resulted in 29 articles (including seven reviews) dealing with a new, modified, or validated scale. Scar scales assess several characteristics, of which color, pliability, and thickness were considered the most important. Physical limitation, pain, and pruritus are often more disturbing than the appearance of the scar, and are therefore also introduced in scar evaluation, as well as the interference with daily life activities (e.g., psychologic impact). CONCLUSION: In contrast to the more objective scar assessment tools, scar scales usually cover more aspects of the scars and are less time-consuming in clinical practice. However, no strong conclusions can be made about their efficacy and validity. In addition to digital photography, scar scales are a valuable instrument in the clinical evaluation and follow-up of scars. PMID- 20828762 TI - Prevention of early vascular graft infection using regional antibiotic release. AB - BACKGROUND: Infections after prosthetic replacement of the aorta remain a serious and life-threatening complication. The only appropriate treatment is the surgical removal of the infected prosthesis. Accordingly, there is a need for new procedures to prevent the infection of vascular prostheses. This in vitro experiment investigated the effect of the pretreatment of vascular prostheses with antibiotics (daptomycin or baneocin) and the effect of antibiotics combined with fibrin sealant as possible prophylaxis of perioperative graft infection. METHODS: Untreated prostheses served as controls. Pretreated prostheses of double woven velour vascular grafts were contaminated with Staphylococcus epidermidis, and colony-forming units were counted each day (CFU/mL). RESULTS: The period of sterility differed significantly as a function of the pretreatment. Uncoated prostheses were immediately non-sterile and exhibited 2.63 +/- 0.61 * 10(5) CFU/mL. Baneocin pretreatment resulted in sterility for 1.7 +/- 0.6 (95% confidence interval (CI) 1.0-2.4) d before we detected 2.14 +/- 0.57 * 10(5) CFU/mL on the prostheses. Pretreatment with daptomycin yielded 2.9 +/- 0.4 (CI 2.6-3.2) and fibrin sealant/baneocin compound yielded 3.1 +/- 0.3 (CI 2.9-3.3) d of sterility, after which 1.81 +/- 0.86 * 10(5) CFU/mL and 1.04 +/- 0.77 * 10(5) CFU/mL were recorded. Finally, pretreatment with fibrin sealant/daptomycin led to sterility for 7.1 +/- 0.3 (CI 6.9-7.3) d, after which 0.77 +/- 0.60 * 10(5) CFU/mL were observed on the prostheses. CONCLUSIONS: The risk of vascular graft infection is reduced by pretreating the prostheses with antibiotics. The antibiotic/fibrin compound exhibited an effect of delayed antibiotic release. Vascular prostheses should therefore be pretreated with antibiotic solution to reduce bacterial adhesion. This procedure might be an effective prophylaxis for perioperative vascular graft infection and provides suitable protection for the prosthetic material. PMID- 20828763 TI - The plasma fraction of stored erythrocytes augments pancreatic cancer metastasis in male versus female mice. AB - BACKGROUND: Males with pancreatic cancer have decreased survival compared with females. Interestingly, perioperative blood transfusions have been shown to reduce survival in patients with pancreatic adenocarcinoma. Recent evidence incriminates blood transfusions from female donors as a causative factor in acute lung injury. We therefore hypothesize that male mice with pancreatic cancer will have greater tumor progression than female mice in response to transfusion. METHODS: Mice previously inoculated with pancreatic cancer cells received an intravenous injection of acellular plasma collected from single donor erythrocytes from either male or female donors. Control mice received an equal volume of intravenous saline. Necropsy to determine metastasis was performed in female mice at 4 wk status post-transfusion. The male group necessitated sacrifice at 3 wk post-transfusion due to clinical deterioration. RESULTS: Male mice developed more metastatic events than female mice, and this was accentuated when receiving blood from female donors. Male mice experienced weight loss within 2 wk of tail vein injection, and three mice in the male transfused groups died secondary to malignancy. Female mice did not manifest substantial weight loss, and did not die in the study time period. CONCLUSION: Male mice, compared with female, had significantly more metastatic events following transfusion of plasma from stored erythrocytes in an immunocompetent murine model of pancreatic adenocarcinoma. Moreover, the adverse effect of transfusion was augmented with female donor blood. These data are consistent with clinical outcomes from centers of excellence in treating pancreatic cancer and warrant further investigation. PMID- 20828764 TI - Aceruloplasminemia in a Japanese woman with a novel mutation of CP gene: clinical presentations and analysis of genetic and molecular pathogenesis. AB - We report a Japanese woman diagnosed as aceruloplasminemia showing characteristic symptoms. Mutational analysis of CP gene revealed a novel homozygous mutation in exon 18, resulting in prematurely truncated W1017X protein. In vitro study showed that W1017X mutant ceruloplasmin was deficient in endoplasmic reticulum to Golgi trafficking and was not secreted to medium. It has been reported that the presence of both the G (FLI/LI) GP domain and the 881th cysteine residue was sufficient for secretion. Thus, our report on this novel mutant indicates the previously unreported importance of carboxy-terminus residues in the secretion pathway. PMID- 20828765 TI - Dementia, stroke and migraine--some common pathological mechanisms. AB - Dementia, stroke and migraine are very common neurological disorders affecting a large percentage of the population, and leading to a high degree of disability. Often, adequate therapy is not available. Although the symptoms, the progression and the outcome differ in these disorders, to some extent they may share some common pathophysiological mechanisms. The genetic background, an energy deficit, and excitotoxicity, vascular and thrombotic properties can influence all three disorders, resulting in a neuronal dysfunction, increased cellular vulnerability, neurodegeneration and ultimately cell death. All these cellular events occur in dementias and stroke, moreover recent studies suggest that, besides a dysfunction, neuronal damage may be an issue in migraine too. One of the most central events in the multiple mechanisms involved in the pathogenesis of these disorders is a metabolic disturbance of certain brain cells. As mitochondria provide the cells with energy, realization of the importance of these organelles in the aetiopathogenesis of several disorders has emerged in recent years. This review surveys the most important features of the pathogenesis of dementia, stroke and migraine from the aspect of mitochondrial malfunction highlighting some of the considerable connections between these neurological disorders. PMID- 20828766 TI - The role of MEFV gene mutations in Multiple Sclerosis susceptibility. PMID- 20828767 TI - Cardiac catheterization within 24 hours of valve surgery is significantly associated with acute renal failure. AB - OBJECTIVE: Acute renal failure after valve surgery carries significant morbidity and mortality. Preoperative cardiac catheterization is the standard of care. For convenience, catheterization just before surgery is simplest for patients. However, it is not known if this timing of radiocontrast administration significantly affects renal function. We hypothesized that preoperative cardiac catheterization within 24 hours of valve surgery is associated with the development of acute renal failure. METHODS: A retrospective case-control study was performed of all patients undergoing valve surgery between 2003 and 2008 at the University of Virginia. Patients with preoperative renal dysfunction were excluded. Patients with postoperative acute renal failure were matched to those without acute renal failure according to age, gender, year of surgery, New York Heart Association functional class, elective status, concomitant coronary artery bypass grafting, and type of valve procedure. A logistic regression model examined the effects of perioperative risk factors on the development of acute renal failure. RESULTS: Of 1287 patients undergoing valve surgery, 61 with acute renal failure were matched to 136 without acute renal failure. Cardiac catheterization within 24 hours of surgery was significantly greater in patients with acute renal failure (31.2% vs 8.8%, P = .013). The risk of acute renal failure was more than 5 times higher for patients undergoing catheterization within 24 hours of surgery (odds ratio, 5.3; P = .004). The number of postoperative vasopressors was significantly associated with acute renal failure (odds ratio, 1.7; P = .007). CONCLUSIONS: Although catheterization is often performed for patient convenience, catheterization within 24 hours of valve surgery is significantly associated with the development of acute renal failure. Current practices should be adjusted to ensure that more than 24 hours have passed from the time of cardiac catheterization to valve surgery in elective settings. PMID- 20828770 TI - Long-term results of the Heller-Dor operation with intraoperative manometry for the treatment of esophageal achalasia. AB - OBJECTIVE: Quality of outcome of the Heller-Dor operation is sometimes different between studies, likely because of technical reasons. We analyze the details of myotomy and fundoplication in relation to the results achieved over a 30-year single center's experience. METHODS: From 1979-2008, a long esophagogastric myotomy and a partial anterior fundoplication to protect the surface of the myotomy was routinely performed with intraoperative manometry in 202 patients (97 men; median age, 55.5 years; interquartile range, 43.7-71 years) through a laparotomy and in 60 patients (24 men; median age, 46 years; interquartile range, 36.2-63 years) through a laparoscopy. The follow-up consisted of periodical interview, endoscopy, and barium swallow, and a semiquantitative scale was used to grade results. RESULTS: Mortality was 1 of 202 in the laparotomy group and 0 of 60 in the laparoscopy group. Median follow-up was 96 months (interquartile range, 48-190.5 months) in the laparotomy group and 48 months (interquartile range, 27-69.5 months) in the laparoscopy group. At intraoperative manometry, complete abolition of the high-pressure zone was obtained in 100%. The Dor related high-pressure zone length and mean pressure were 4.5 +/- 0.4 cm and 13.3 +/- 2.2 mm Hg in the laparotomy group and 4.5 +/- 0.5 cm and 13.2 +/- 2.2 mm Hg in the laparoscopy group (P = .75). In the laparotomy group poor results (19/201 [9.5%]) were secondary to esophagitis in 15 (7.5%) of 201 patients (in 2 patients after 184 and 252 months, respectively) and to recurrent dysphagia in 4 (2%) of 201 patients, all with end-stage sigmoid achalasia. In the laparoscopy group 2 (3.3%) of 60 had esophagitis. CONCLUSIONS: A long esophagogastric myotomy protected by means of Dor fundoplication cures or substantially reduces dysphagia in the great majority of patients affected by esophageal achalasia and effectively controls postoperative esophagitis. Intraoperative manometry is likely the key factor for achieving the reported results. PMID- 20828771 TI - Clytostoma callistegioides (Bignoniaceae) wax extract with activity on aphid settling. AB - A bioassay-guided fractionation of leaf extracts from Clytostoma callistegioides (Cham.) Bureau ex Griseb. (Bignoniaceae) led to isolation of a natural mixture of four fatty acids with anti-insect activity against aphids. The compounds were identified by GC-MS as palmitic, stearic, linoleic and linolenic acids and quantified as their methyl esters. The anti-aphid activity of the natural mixture was traced to linolenic and linoleic acids, as shown by the settling inhibition activity of synthetic samples. Interestingly, the saturated acids (palmitic and stearic) tested alone stimulated settling on one of the tested aphids (Myzus persicae), but not on the other tested species (Rhopalosiphum padi). Although ubiquitous, none of these free acids have been previously reported in this Bignoniaceae species. The leaf surface chemistry, which is likely involved in modulating aphid settling behavior, was further investigated for the occurrence of lipophilic substances by histochemical staining. Short, stalked glandular trichomes, previously undescribed for this species, stained with osmium tetroxide and Sudan III, suggesting that the secretion of the defensive acids is related to these surface trichomes. PMID- 20828772 TI - Seroepidemiology of hepatitis A and hepatitis E viruses in Aden, Yemen. AB - The burden of hepatitis A (HAV) and hepatitis E (HEV) infection is unknown in Aden, Yemen. This survey describes the prevalence of antibodies against HAV and HEV among individuals attending primary health care facilities in Aden, Yemen. Five hundred and thirty eight participants, stratified by age and district population size, were enrolled and screened for anti-HAV and 356 for anti-HEV antibodies. The age-standardized seroprevalence of antibodies was 86.6% (95% CI 83.7-89.5) for anti-HAV and 10.7% (95% CI 7.5-13.9) for anti-HEV. The prevalence of anti-HAV and anti-HEV ranged from 53% and 0% in infants to 100% and 15.3% in participants >18 years old, respectively (P<0.001). Viral hepatitis remains a major public health problem in Aden with trends of hyperendemicity for both infections. Priority should be given to improve water quality, sanitation coverage, and food hygiene and increase public health awareness concerning the risk of contracting infection. PMID- 20828773 TI - The ultrastructure of the Sertoli cell of the vervet monkey, Chlorocebus aethiops. AB - The ultrastructure of the Sertoli cell of the vervet monkey was studied using both scanning and transmission electron microscopic techniques. SEM micrographs revealed perforated sleeve-like processes which encased mature elongated spermatids which are ready for spermiation. TEM micrographs showed a large Sertoli cell nucleus characterized by many lobes (4-5) and consisting of a homogenous nucleoplasm and a distinctive nucleolus. The nucleus occupies a significant portion of the basal region of the cell. The distribution of chromatin clearly shows high activity of these cells. Lipid droplets and free ribosomes are also found scattered throughout the cytoplasm. Well-developed Golgi apparatus is found in the basal region of the cell. There is phagocytic activity in the Sertoli cells as revealed by the presence of numerous phagosomes. Numerous mitochondria with well-developed tubular cristae are found on the basal side of the nucleus, whereas few mitochondria are located on the apical side of the nucleus. Distinct desmosomes are located between cells. A well-developed smooth endoplasmic reticulum and granular endoplasmic reticulum are frequently found in the cytoplasm of the Sertoli cells. The results of this investigation showed that Sertoli cells of the vervet monkey are almost similar to those of humans and show many similarities with other mammalian species. PMID- 20828774 TI - Calpains expression during Xenopus laevis development. AB - Calpains are cytoplasmic proteases activated by calcium, implicated in cell differentiation and apoptosis. The best characterized enzymes are calpains 1-3. The aim of this work was to localize calpains 1-3 during the development of Xenopus laevis in order to clarify the function of these three proteases. For the first time, we detected the localization of the three proteases at the protein level between one-cell stage and adult age. Their expression was weak at early stages, then increased at tadpole stage and decreased through metamorphosis and adult life. The calpain's expression was maximal during the period characterized by the appearance of organs and modelling process. These observations suggest that calpains play a crucial role during development. PMID- 20828775 TI - Interactions between p27 and p88 replicase proteins of Red clover necrotic mosaic virus play an essential role in viral RNA replication and suppression of RNA silencing via the 480-kDa viral replicase complex assembly. AB - Red clover necrotic mosaic virus (RCNMV), a positive-sense RNA virus with a bipartite genome, encodes p27 and p88 replicase proteins that are required for viral RNA replication and suppression of RNA silencing. In this study, we identified domains in p27 and p88 responsible for their protein-protein interactions using in vitro pull-down assays with the purified recombinant proteins. Coimmunoprecipitation analysis in combination with blue-native polyacrylamide gel electrophoresis using mutated p27 proteins showed that both p27-p27 and p27-p88 interactions are essential for the formation of the 480-kDa complex, which has RCNMV-specific RNA-dependent RNA polymerase activity. Furthermore, we found a good correlation between the accumulated levels of the 480-kDa complex and replication levels and the suppression of RNA silencing activity. Our results indicate that interactions between RCNMV replicase proteins play an essential role in viral RNA replication and in suppressing RNA silencing via the 480-kDa replicase complex assembly. PMID- 20828776 TI - An adenoviral vector expressing human adenovirus 5 and 3 fiber proteins for targeting heterogeneous cell populations. AB - Human adenovirus serotype 5 (HAdV-5) attaches to its primary receptor, the coxsackie and adenovirus receptor (CAR) as the first step of infection. However, CAR expression decreases as tumors progress, thereby diminishing the utility of HAdV-5-based vectors for cancer therapy. In contrast, many aggressive tumor cells highly express CD46, a cellular receptor for HAdV-3. We hypothesized that a mosaic HAdV vector, containing two kinds of fiber proteins, would provide extensive transduction in a heterogeneous population of tumor cells with varying expression levels of HAdV receptors. We therefore generated a fiber-mosaic HAdV vector displaying both a chimeric HAdV-3 fiber and the HAdV-5 fiber protein. We verified the structural integrity of purified viral particles and confirmed that the fiber-mosaic HAdV vector has expanded tropism. We conclude that the use of fiber-mosaic HAdV vectors is a promising approach for transducing a heterogeneous cell population with different expression levels of adenovirus receptors. PMID- 20828777 TI - Requirement of UAP56, URH49, RBM15, and OTT3 in the expression of Kaposi sarcoma associated herpesvirus ORF57. AB - Transport of mRNA from the nucleus to the cytoplasm is mediated by cellular RNA export factors. In this report, we examined how RNA export factors UAP56 and URH49, and RNA export cofactors RBM15 and OTT3, function in modulating KSHV ORF57 expression. We found that knockdown of each factor by RNAi led to decreased ORF57 expression. Specifically, reduced expression of either UAP56 or RBM15 led to nuclear export deficiency of ORF57 RNA. In the context of the KSHV genome, the near absence of UAP56 or RBM15 reduced the expression of both ORF57 and ORF59 (an RNA target of ORF57), but not ORF50. Collectively, our data indicate that the expression of KSHV ORF57 is regulated by cellular RNA export factors and cofactors at the posttranscriptional level. PMID- 20828778 TI - Formation of immature and mature genomic RNA dimers in wild-type and protease inactive HIV-1: differential roles of the Gag polyprotein, nucleocapsid proteins NCp15, NCp9, NCp7, and the dimerization initiation site. AB - Formation of immature genomic RNA (gRNA) dimers is exquisitely nucleocapsid (NC) dependent in protease-inactive (PR-in) HIV-1. This establishes that Pr55gag/Pr160gag-pol has NC-dependent chaperone activity within intact HIV-1. Mutations in the proximal zinc finger and the linker of the NC sequence of Pr55gag/Pr160gag-pol abolish gRNA dimerization in PR-in HIV-1. In wild type, where the NC of Pr55gag is processed into progressively smaller proteins termed NCp15 (NCp7-p1-p6), NCp9 (NCp7-p1) and NCp7, formation of immature dimers is much swifter than in PR-in HIV-1. NCp7 and NCp15 direct this rapid accumulation. NCp9 is sluggish in this process, but it stimulates the transition from immature to mature gRNA dimer as well as NCp7 and much better than NCp15. The amino-terminus, proximal zinc finger, linker, and distal zinc finger of NCp7 contribute to this maturation event in intact HIV-1. The DIS is a dimerization initiation site for all immature gRNA dimers, irrespective of their mechanism of formation. PMID- 20828779 TI - Fouling of microfiltration membranes by organic polymer coagulants and flocculants: controlling factors and mechanisms. AB - Organic polymers are commonly used as coagulants or flocculants in pretreatment for microfiltration (MF). These high molecular weight compounds are potential membrane foulants when carried over to the MF filters. This study examined fouling of three MF membranes of different materials by three commonly used water treatment polymers: poly(diallyldimethylammonium) chloride (pDADMAC), polyacrylamide (PAM), and poly(acrylic acid-co-acrylamide (PACA) with a wide range of molecular weights. The effects of polymer molecular characteristics, membrane surface properties, solution condition and polymer concentration on membrane fouling were investigated. Results showed severe fouling of microfiltration membranes at very low polymer concentrations, suggesting that residual polymers carried over from the coagulation/flocculation basin can contribute significantly to membrane fouling. The interactions between polymers and membranes depended strongly on the molecular size and charge of the polymer. High molecular weight, positively charged polymers caused the greatest fouling. Blockage of membrane pore openings was identified as the main fouling mechanism with no detectable internal fouling in spite of the small molecular size of the polymers relative to the membrane pore size. Solution conditions (e.g., pH and calcium concentration) that led to larger polymer molecular or aggregate sizes resulted in greater fouling. PMID- 20828780 TI - Kinetic assessment and modeling of an ozonation step for full-scale municipal wastewater treatment: micropollutant oxidation, by-product formation and disinfection. AB - The kinetics of oxidation and disinfection processes during ozonation in a full scale reactor treating secondary wastewater effluent were investigated for seven ozone doses ranging from 0.21 to 1.24 g O(3) g(-1) dissolved organic carbon (DOC). Substances reacting fast with ozone, such as diclofenac or carbamazepine (k(P, O3) > 10(4) M(-1) s(-1)), were eliminated within the gas bubble column, except for the lowest ozone dose of 0.21 g O(3) g(-1) DOC. For this low dose, this could be attributed to short-circuiting within the reactor. Substances with lower ozone reactivity (k(P, O3) < 10(4) M(-1) s(-1)) were only fully eliminated for higher ozone doses. The predictions of micropollutant oxidation based on coupling reactor hydraulics with ozone chemistry and reaction kinetics were up to a factor of 2.5 higher than full-scale measurements. Monte Carlo simulations showed that the observed differences were higher than model uncertainties. The overestimation of micropollutant oxidation was attributed to a protection of micropollutants from ozone attack by the interaction with aquatic colloids. Laboratory-scale batch experiments using wastewater from the same full-scale treatment plant could predict the oxidation of slowly-reacting micropollutants on the full-scale level within a factor of 1.5. The Rct value, the experimentally determined ratio of the concentrations of hydroxyl radicals and ozone, was identified as a major contribution to this difference. An increase in the formation of bromate, a potential human carcinogen, was observed with increasing ozone doses. The final concentration for the highest ozone dose of 1.24 g O(3) g( 1) DOC was 7.5 MUg L(-1), which is below the drinking water standard of 10 MUg L( 1). N-Nitrosodimethylamine (NDMA) formation of up to 15 ng L(-1) was observed in the first compartment of the reactor, followed by a slight elimination during sand filtration. Assimilable organic carbon (AOC) increased up to 740 MUg AOC L( 1), with no clear trend when correlated to the ozone dose, and decreased by up to 50% during post-sand filtration. The disinfection capacity of the ozone reactor was assessed to be 1-4.5 log units in terms of total cell counts (TCC) and 0.5 to 2.5 log units for Escherichia coli (E. coli). Regrowth of up to 2.5 log units during sand filtration was observed for TCC while no regrowth occurred for E. coli. E. coli inactivation could not be accurately predicted by the model approach, most likely due to shielding of E. coli by flocs. PMID- 20828781 TI - Long term laboratory column experiments to simulate bank filtration: factors controlling removal of sulfamethoxazole. AB - Microbial removal of the poorly degradable antibiotic sulfamethoxazole (SMX) from surface water was investigated in laboratory columns to identify critical factors for SMX removal during bank filtration, such as the substrate concentration, redox conditions and the availability of biodegradable DOC. About 60% of SMX at a start concentration of 0.25 MUg/L in surface water were removed within 14 d of column passage under aerobic conditions while no removal occurred under anoxic conditions. The adaptation time was very long and was not completed after 2 years of operation. Adaptation was faster and SMX degradation was improved at an elevated concentration of SMX (4.5 MUg/L) with 90% removal in 3.5 d under aerobic conditions. SMX removal was less effective under anoxic conditions (27% in 14 d) but increased again under anaerobic conditions (51% in 14 d). According to the half-lives for SMX determined from the column data (1-9 d aerobic, 49 d anoxic and 16 d anaerobic) it is essential to provide several weeks up to months of travel time in bank filtration to allow for the degradation of SMX, and likely, also for other poorly degradable compounds. Thus, the occurrence of SMX in groundwater samples does not indicate persistency of SMX but reflects insufficient residence time or unfavorable respective redox conditions. Adaptation times of years may also be required for new bank filtration sites to develop their full removal potential towards trace pollutants. Long operation time, a comparable concentration level and similar redox conditions as in the field appear to be essential to obtain realistic results with laboratory column experiments that can be transferred to real bank filtration sites. PMID- 20828782 TI - Formation and removal of genotoxic activity during UV/H(2)O(2)-GAC treatment of drinking water. AB - The objective of this study was to determine the genotoxic activity of water after UV/H(2)O(2) oxidation and GAC filtration. Pre-treated surface water from three locations was treated with UV/H(2)O(2) with medium pressure (MP) lamps and passed through granulated activated carbon (GAC). Samples taken before and after each treatment step were extracted and concentrated by solid phase extraction (SPE) and analyzed for genotoxicity using the Comet assay with HepG2 cells and the Ames II assay. The Comet assay showed no genotoxic response in any of the samples. In the Ames II, no genotoxic response was obtained with the TAMix (a mix of six strains), but the TA98 strain showed an increase in genotoxic activity after MP-UV/H(2)O(2) for all three locations. GAC post treatment effectively reduced the activities to control levels at two of the three locations and to below the level of the pre-treated water at one site. The results indicate that UV/H(2)O(2) treatment may lead to the formation of genotoxic by-products, which can be removed by subsequent GAC filtration. PMID- 20828783 TI - Changes in the Daphnia magna midgut upon ingestion of copper oxide nanoparticles: a transmission electron microscopy study. AB - This work is a follow-up of our previous paper (Heinlaan et al., 2008. Chemosphere 71, 1308-1316) where we showed about 50-fold higher acute toxicity of CuO nanoparticles (NPs) compared to bulk CuO to water flea Daphnia magna. In the current work transmission electron microscopy (TEM) was used to determine potential time-dependent changes in D. magna midgut epithelium ultrastructure upon exposure to CuO NPs compared to bulk CuO at their 48 h EC(50) levels: 4.0 and 175 mg CuO/L, respectively. Special attention was on potential internalization of CuO NPs by midgut epithelial cells. Ingestion of both CuO formulations by daphnids was evident already after 10 min of exposure. In the midgut lumen CuO NPs were dispersed whereas bulk CuO was clumped. By the 48th hour of exposure to CuO NPs (but not to equitoxic concentrations of bulk CuO) the following ultrastructural changes in midgut epithelium of daphnids were observed: protrusion of epithelial cells into the midgut lumen, presence of CuO NPs in circular structures analogous to membrane vesicles from holocrine secretion in the midgut lumen. Implicit internalization of CuO NPs via D. magna midgut epithelial cells was not evident however CuO NPs were no longer contained within the peritrophic membrane but located between the midgut epithelium microvilli. Interestingly, upon exposure to CuO NPs bacterial colonization of the midgut occurred. Ultrastructural changes in the midgut of D. magna upon exposure to CuO NPs but not to bulk CuO refer to its nanosize-related adverse effects. Time dependent solubilisation of CuO NPs and bulk CuO in the test medium was quantified by recombinant Cu-sensor bacteria: by the 48th hour of exposure to bulk CuO, the concentration of solubilised copper ions was 0.05 +/- 0.01 mg Cu/L that was comparable to the acute EC(50) value of Cu-ions to D. magna (48 h CuSO(4) EC(50) = 0.07 +/- 0.01 mg Cu/L). However, in case of CuO NPs, the solubilised Cu-ions 0.01 +/- 0.001 mg Cu/L, explained only part of the toxicity. PMID- 20828784 TI - Environmental toxicology and risk assessment of pharmaceuticals from hospital wastewater. AB - In this paper, we evaluated the ecotoxicological potential of the 100 pharmaceuticals expected to occur in highest quantities in the wastewater of a general hospital and a psychiatric center in Switzerland. We related the toxicity data to predicted concentrations in different wastewater streams to assess the overall risk potential for different scenarios, including conventional biological pretreatment in the hospital and urine source separation. The concentrations in wastewater were estimated with pharmaceutical usage information provided by the hospitals and literature data on human excretion into feces and urine. Environmental concentrations in the effluents of the exposure scenarios were predicted by estimating dilution in sewers and with literature data on elimination during wastewater treatment. Effect assessment was performed using quantitative structure-activity relationships because experimental ecotoxicity data were only available for less than 20% of the 100 pharmaceuticals with expected highest loads. As many pharmaceuticals are acids or bases, a correction for the speciation was implemented in the toxicity prediction model. The lists of Top-100 pharmaceuticals were distinctly different between the two hospital types with only 37 pharmaceuticals overlapping in both datasets. 31 Pharmaceuticals in the general hospital and 42 pharmaceuticals in the psychiatric center had a risk quotient above 0.01 and thus contributed to the mixture risk quotient. However, together they constituted only 14% (hospital) and 30% (psychiatry) of the load of pharmaceuticals. Hence, medical consumption data alone are insufficient predictors of environmental risk. The risk quotients were dominated by amiodarone, ritonavir, clotrimazole, and diclofenac. Only diclofenac is well researched in ecotoxicology, while amiodarone, ritonavir, and clotrimazole have no or very limited experimental fate or toxicity data available. The presented computational analysis thus helps setting priorities for further testing. Separate treatment of hospital wastewater would reduce the pharmaceutical load of wastewater treatment plants, and the risk from the newly identified priority pharmaceuticals. However, because high-risk pharmaceuticals are excreted mainly with feces, urine source separation is not a viable option for reducing the risk potential from hospital wastewater, while a sorption step could be beneficial. PMID- 20828785 TI - Global sensitivity analysis in wastewater treatment plant model applications: prioritizing sources of uncertainty. AB - This study demonstrates the usefulness of global sensitivity analysis in wastewater treatment plant (WWTP) design to prioritize sources of uncertainty and quantify their impact on performance criteria. The study, which is performed with the Benchmark Simulation Model no. 1 plant design, complements a previous paper on input uncertainty characterisation and propagation (Sin et al., 2009). A sampling-based sensitivity analysis is conducted to compute standardized regression coefficients. It was found that this method is able to decompose satisfactorily the variance of plant performance criteria (with R(2) > 0.9) for effluent concentrations, sludge production and energy demand. This high extent of linearity means that the plant performance criteria can be described as linear functions of the model inputs under the defined plant conditions. In effect, the system of coupled ordinary differential equations can be replaced by multivariate linear models, which can be used as surrogate models. The importance ranking based on the sensitivity measures demonstrates that the most influential factors involve ash content and influent inert particulate COD among others, largely responsible for the uncertainty in predicting sludge production and effluent ammonium concentration. While these results were in agreement with process knowledge, the added value is that the global sensitivity methods can quantify the contribution of the variance of significant parameters, e.g., ash content explains 70% of the variance in sludge production. Further the importance of formulating appropriate sensitivity analysis scenarios that match the purpose of the model application needs to be highlighted. Overall, the global sensitivity analysis proved a powerful tool for explaining and quantifying uncertainties as well as providing insight into devising useful ways for reducing uncertainties in the plant performance. This information can help engineers design robust WWTP plants. PMID- 20828786 TI - Stratigraphic context and taxonomic assessment of the large cercopithecoid (Primates, Mammalia) from the late Early Pleistocene palaeoanthropological site of Buia (Eritrea). PMID- 20828787 TI - Two hominin incisor teeth from the middle Pleistocene site of Boxgrove, Sussex, England. AB - In 1995-1996 two isolated hominin lower incisors were found at the middle Pleistocene site of Boxgrove in England, with Lower Palaeolithic archaeology. Boxgrove 2 is a permanent lower right central incisor and Boxgrove 3 a permanent lower left lateral incisor. They were found separately, but close to one another and appear to belong to the same individual. The Boxgrove 1 tibia discovered in 1993 came from a different stratigraphic context and is thus believed to represent a different individual. This paper describes the morphology of the incisors, which is similar to other middle Pleistocene hominin specimens and, as with the tibia, suggests that they could be assigned to Homo heidelbergensis (recognising that the taxonomic status of this species is still a matter of debate). The incisors show substantial attrition associated with secondary dentine deposition in the pulp chamber and clearly represent an adult. They also show extensive patterns of non-masticatory scratches on the labial surfaces of both crown and root, including some marks which may have been made postmortem. The roots were exposed in life on their labial sides by a large dehiscence, extending almost to the root apex. This is demonstrated by deposits of calculus, polishing, and scratching on the exposed surfaces. The dehiscence may have been caused by repeated trauma to the gingivae or remodelling of the tooth-supporting tissues in response to large forces applied to the front of the dentition. PMID- 20828788 TI - Diastereomer-specific bioaccumulation of hexabromocyclododecane (HBCD) in a coastal food web, Western Norway. AB - The present study reports diastereomer-specific accumulation of HBCD from a point source in five marine species representing a typical food web in a Norwegian coastal area. Samples of mussels, polychaetes, crabs and seabird eggs were analyzed for the diastereomers alpha-, beta- and gamma-HBCD, as well as lipid content and stable isotopes of nitrogen ((15)N/(14)N) to estimate trophic level. Accumulated HBCD did not correlate well with lipid content for most of the species, thus wet-weight based concentrations were included in an assessment of biomagnification. In contrast to beta- and gamma-HBCD, the alpha-diastereomer increased significantly with trophic level, resulting in magnification factors >1 in this coastal marine ecosystem. Data for poikilotherms did not show the same positive correlation between the alpha-diastereomer and trophic position as homeotherms. The apparent biomagnification of the alpha-HBCD could be due to bioisomerization or diastereomer-specific elimination that differed between poikilotherms and homeotherms. PMID- 20828789 TI - Burden of disease attributed to anthropogenic air pollution in the United Arab Emirates: estimates based on observed air quality data. AB - This study quantifies the national burden of disease attributed to particulate matter (PM) and ozone (O(3)) in ambient air in the United Arab Emirates (UAE), a rapidly growing nation in which economic development and climatic conditions pose important challenges for air quality management. Estimates of population exposure to these air pollutants are based on observed air quality data from fixed-site monitoring stations. We divide the UAE into small grid cells and use spatial statistical methods to estimate the ambient pollutant concentrations in each cell based on the observed data. Premature deaths attributed to PM and O(3) are computed for each grid cell and then aggregated across grid cells and over a year to estimate the total number of excess deaths attributable to ambient air pollution. Our best estimate is that approximately 545 (95% CI: 132-1224) excess deaths in the UAE in the year 2007 are attributable to PM in ambient air. These excess deaths represent approximately 7% (95% CI: 2-17%) of the total deaths that year. We attribute approximately 62 premature deaths (95% CI: 17-127) to ground level O(3) for the year 2007. Uncertainty in the natural background level of PM, due to the frequent dust storms occurring in the region, has significant impacts on the attributed mortality estimates. Despite the uncertainties associated with the integrated assessment framework, we conclude that anthropogenic ambient air pollution, in particular PM, causes a considerable public health impact in the UAE in terms of premature deaths. We discuss important uncertainties and scientific hypotheses to be investigated in future work that might help reduce the uncertainties in the burden of disease estimates. PMID- 20828790 TI - Efficacy and safety of naproxcinod in patients with osteoarthritis of the knee: a 53-week prospective randomized multicenter study. AB - OBJECTIVE: Comparison of naproxcinod (375 and 750 mg), placebo (up to 13 weeks), and naproxen 500 mg (all bid) for treatment of osteoarthritis (OA) signs and symptoms. METHODS: A 53-week, randomized, double-blind, parallel-group study. One thousand twenty patients with primary knee OA were randomized to naproxcinod 750 mg, naproxcinod 375 mg, naproxen 500 mg, or placebo (all bid). Coprimary efficacy endpoints were Western Ontario and McMaster Universities Osteoarthritis Index (WOMACTM) pain and function subscales and patient overall rating of disease status. An analysis of covariance model tested superiority for both naproxcinod doses over placebo at week 13, and noninferiority of naproxcinod 750 mg bid versus naproxen at weeks 13 and 26. RESULTS: Least-square mean changes from baseline were greater for both naproxcinod doses compared with placebo at week 13 for WOMAC pain (-31.3 [standard error 1.67], -28.1 [1.64], and -20.4 [1.62] mm with naproxcinod 750 mg bid [P < 0.0001], 375 mg bid [P = 0.0008], and placebo, respectively), WOMAC function (-27.8 [1.60], -23.8 [1.58], and -14.9 [1.56] mm, respectively, P < 0.0001), and patient overall rating of disease status (1.00 [0.061], 0.81 [0.060], and 0.49 [0.059], respectively, P < 0.0001). Naproxcinod 750 mg bid was noninferior to naproxen at weeks 13 and 26. Naproxcinod was well tolerated, with no notable differences in orthostatic blood pressure response between treatments. CONCLUSION: Naproxcinod 750 mg bid and 375 mg bid demonstrated superior efficacy over placebo for treatment of OA and were well tolerated over 1 year. Naproxcinod 750 mg bid was noninferior to naproxen 500 mg bid. PMID- 20828791 TI - The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis. AB - OBJECTIVE: To evaluate the efficacy of available bisphosphonate therapies regarding the prevention of vertebral, hip, and nonvertebral-nonhip fractures in postmenopausal women with osteoporosis. METHODS: Eight randomized placebo controlled trials investigating the effects of zoledronic acid (1 study), alendronate (3), ibandronate (1), risedronate (2), and etidronate (1) in terms of fractures with a follow-up of 3 years (or 2 years if used for registration purposes) were identified with a systematic literature search. The endpoints of interest were morphometric vertebral fractures, hip fractures, and nonvertebral nonhip fractures. Results of all trials were analyzed simultaneously with a Bayesian network meta-analysis by which the relative treatment effect of 1 intervention to another can be obtained in the absence of head-to-head evidence. Given the estimated treatment effects and their uncertainty, the Bayesian approach allowed for calculations of the probability of which bisphosphonate is best in terms of overall fracture reductions by weighting the impact of each by type of fracture on costs, quality of life, and incidence. RESULTS: There is a 79% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all bisphophonates compared. Zoledronic acid showed a relative risk (RR) of 0.30 (95% Credible Interval 0.23-0.37) relative to placebo, an RR of 0.55 (0.41-0.76) relative to alendronate, an RR of 0.50 (0.36-0.70) relative to risedronate, and an RR of 0.58 (0.37-0.92) relative to ibandronate. Regarding hip fractures, there is a 47% probability that zoledronic acid shows the greatest risk reduction, followed by alendronate (36%) and risedronate (11%). RRs of zoledronic acid relative to placebo, alendronate, and risedronate were 0.58 (0.41 0.82), 0.95 (0.54-1.68), and 0.73 (0.37-1.44), respectively. Risedronate showed the greatest reduction in nonvertebral-nonhip fractures, followed by zoledronic acid. The RR of zoledronic acid relative to risedronate was 1.28 (0.87-1.90). Overall, there was a 94% probability that zoledronic acid showed the greatest reduction in any fracture. Weighting the impact of the different type of fractures by incidence, cost, or quality of life showed similar results. CONCLUSION: Of the available bisphosphonates for osteoporosis, zoledronic acid has the highest probability of offering the best overall fracture protection. PMID- 20828792 TI - The familial Mediterranean fever gene as a modifier of periodic fever, aphthous stomatitis, pharyngitis, and adenopathy syndrome. AB - OBJECTIVE: Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) syndrome is a sporadic disease, characterized by periodic attacks of inflammation. Mutations in the MEFV, the gene associated with familial Mediterranean fever (FMF), may lead to subclinical inflammation in asymptomatic carriers and modify the phenotype of some inflammatory diseases. We aimed at investigating the effect of MEFV gene mutations on disease phenotype in PFAPA. PATIENTS AND METHODS: The cohort of this ongoing prospective study consisted of 124 children with PFAPA syndrome, followed in a single referral center, who were tested for MEFV mutations. Demographic data, clinical characteristics, and disease course of 65 PFAPA patients with and 59 without MEFV mutations (M+ and M , respectively) were compared. RESULTS: PFAPA attacks in carriers of MEFV mutations were shorter compared with patients without mutations (3.8 +/- 1.7 versus 4.8 +/- 1.9 days, P < 0.01). The difference was more pronounced in those carrying the M694V mutation. In M+ patients, the rates of patients with regularity of their attacks (49.2%) and oral aphthae (24.6%) were lower, compared with M- patients (74.5% and 43.9%, respectively, P < 0.05 for each of the 2 comparisons). M+ patients needed a lower corticosteroid (beclomethasone) dose to abort the attacks (0.16 +/- 0.07mg/kg versus 0.19 +/- 0.08, P = 0.028). No differences were observed in all other clinical and laboratory parameters, over a follow-up period of 4.3 years. CONCLUSION: In PFAPA, MEFV is a modifier gene associated with an attenuated disease severity. PMID- 20828793 TI - Health care utilization in patients with gout. AB - OBJECTIVE: To study health care utilization patterns in patients with gout. METHODS: In a gout population from primary care and rheumatology clinics in 3 U.S. metropolitan cities, we collected data on gout-related utilization (primary care, rheumatology, urgent care, emergency room, and other) in the past year. We evaluated the association of comorbidities, age, gender, gout characteristics (time since last gout attack and tophi), and gout severity ratings (mean of serum uric acid, patient-rated, and physician-rated gout severity) and with emergency/urgent care and primary care utilization using regression and correlation analyses. RESULTS: Of the 296 patients who reported visiting at least 1 type of health practitioner for gout in the past year, the percentage of patients utilizing the service at least once and annual utilization rates among utilizers were as follows: primary care physician, 60%, 3.0 +/- 3.4; nurse practitioner/physician assistant, 26%, 2.7 +/- 2.5; rheumatologist, 51%, 3.7 +/- 5.7; urgent care, 23%, 2.1 +/- 2.2; emergency room, 20%, 2.0 +/- 1.7; and hospitalization, 7%, 2.1 +/- 1.4. Higher overall gout severity was associated with greater use of each resource type and with overall gout-related utilization. Nonemergency/nonurgent care utilization (primary care physician, nurse practitioner, physician's assistant, and rheumatologist for gout) was the strongest predictor of gout-related emergency/urgent care utilization. Patients with more comorbidities had greater gout-related primary care utilization. CONCLUSIONS: Overall gout severity was associated with all types of gout-related utilization. This may help to screen high utilizers for targeted behavioral and therapeutic interventions. Having a higher number of comorbid conditions was a risk factor for higher gout-related primary care utilization. PMID- 20828794 TI - Lack of effect of chronic kidney disease on clopidogrel response with high loading and maintenance doses of clopidogrel after Acute Coronary Syndrome. PMID- 20828795 TI - Roles of Src-like adaptor protein 2 (SLAP-2) in GPVI-mediated platelet activation SLAP-2 and GPVI signaling. AB - BACKGROUND: Glycoprotein VI (GPVI) /Fc receptor gamma (FcRgamma)-chain complex is one of the collagen receptors in platelets and responsible for the majority of the intracellular signaling events through a similar pathway to immune receptors. Src-like adaptor protein 2 (SLAP-2) is a recently characterized adaptor protein predominantly expressed in hematopoietic cells. In T cells, SLAP-2 was reported to associate with several tyrosine phosphorylated proteins, and function as a negative regulator of signaling downstream of T cell antigen receptor by virtue of its interaction with the ubiquitin ligase c-Cbl. But the data regarding the presence and role of SLAP-2 proteins in platelets is limited. OBJECTIVES: We describe the characterization of SLAP-2 in human platelets. METHODS: Human platelets were analyzed by Western blot analysis, immunoprecipitation, and pull down assay, etc. RESULTS: Immunoprecipitation revealed the presence of two forms of SLAP-2 with approximately 28 kD and 25 kD, and following stimulation of GPVI, the additional form with approximately 32 kD apppeared. We have found that upon GPVI activation, SLAP-2 translocated from the Triton X-100-soluble fraction to the Triton X-100-insoluble cytoskeleton fraction, with concomitant association with Syk, c-Cbl, and LAT. CONCLUSIONS: SLAP-2 appears to play a role in regulating signaling pathways by bringing important signaling molecules such as c Cbl and Syk into proximity of cytoskeletal substrates. In platelets, SLAP-2 may have function as a negative regulator of GPVI-mediated signaling by interacting with c-Cbl, being similar to that reported in T cells. PMID- 20828796 TI - The 'carry-over' effects of patient self-testing: positive effects on usual care management by an anticoagulation management service. AB - INTRODUCTION: Patient self-testing (PST) of the international normalised ratio (INR) has a positive effect on anticoagulation control. This study investigated whether the benefits of PST (other than increased frequency of testing, e.g. patient education, empowerment, compliance etc.) could be 'carried-over' into usual care management after a period of home-testing has ceased. MATERIAL AND METHODS: Patients that completed a six month period of PST (as part of a randomised controlled trial) but returned to clinic management when the trial ended were included in the study. The primary outcome variable was the difference in anticoagulation control (measured using the time in therapeutic range) between the two periods. A group of patients who were managed solely by the anticoagulation clinic served as the control. RESULTS: There was no significant difference in median time in therapeutic range (TTR) between the 52 patients during clinic management post-PST and the six month period of PST (75% vs 75.3%; p=0.061). Patients tested more frequently while home-testing compared with the subsequent six month period of clinic management (once every 5.6+/-0.7days compared with once every 23.2+/-7.4days; p=0.000). Patients with previous experience of PST performed significantly better than the control group of patients (n=107) that were managed solely by the anticoagulation clinic (75% vs 59.7%; p=0.009) despite less frequent monitoring of the INR (every 23.2+/-7.4days vs. 17.4+/-6.7days; p=0.000). CONCLUSIONS: The improvements in anticoagulation control observed during a period of PST can be sustained when patients cease home testing and revert back to usual care management. PMID- 20828797 TI - A series of natural flavonoids as thrombin inhibitors: structure-activity relationships. AB - A series of natural flavonoids has been evaluated as potential inhibitors of thrombin using the optimized method of thrombin time. Myricetin and quercetin have shown to be the best thrombin inhibitors tested. In order to investigate the thrombin recognition of the most active and selective compounds, a molecular modeling study has been performed using available Protein Data Bank (PDB) structures as receptor models for docking experiments. Structure-activity relationships of flavonoids (SARs) on thrombin would facilitate the design of chemical compounds with higher potency to serve as potential thrombin inhibitors, and provide information for the exploitation and utilization of flavonoids as thrombin inhibitors for thrombotic disease treatment. PMID- 20828798 TI - The irreversibility of platelet aggregation is regulated by myosin IIA, but is not compromised in MYH9-related disease. PMID- 20828799 TI - The role of thrombin-activatable fibrinolysis inhibitor in diabetic wound healing. AB - INTRODUCTION: One of the major complications in patients with diabetes mellitus is impaired wound healing. The fibrinolytic system is involved in parts of the wound healing process and deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI) results in delayed wound closure. Moreover, levels of TAFI are affected by diabetes mellitus. The aim of this study was to elucidate the effect of hyperglycaemia on TAFI and to determine the effect of deficiency of TAFI on wound healing under hyperglycaemic conditions. MATERIALS AND METHODS: Hyperglycaemia was induced with streptozotocin (STZ) and used as a model for diabetes mellitus. TAFI plasma levels and TAFI gene expression in the liver were determined. Incisional and excisional wound healing were studied in non-treated and STZ-treated wild-type and TAFI-deficient mice. Wound closure was scored daily as open or closed. RESULTS: Mice treated with STZ showed hyperglycaemia, and TAFI plasma levels and TAFI gene expression were increased in diabetic mice. TAFI deficient mice and diabetic wild-type and diabetic TAFI-deficient mice showed delayed wound healing of incisional wounds. No differences were observed between diabetic and non-diabetic TAFI-deficient mice and between diabetic wild-type and diabetic TAFI-deficient mice. CONCLUSIONS: This study illustrated that TAFI was affected by hyperglycaemia and confirmed that TAFI is involved in wound healing. No additional effect was observed under hyperglycaemic conditions, indicating that deficiency of TAFI did not have an additive or synergistic effect in diabetic wound healing. Further research has to elucidate if TAFI and hyperglycemia affect wound healing via similar mechanisms. PMID- 20828800 TI - Effect of the photoperiod and administration of melatonin on folliculostellate cells of the pituitary pars distalis of adult male viscacha (Lagostomus maximus maximus). AB - Numerous reports have shown the effect of photoperiod and melatonin administration on the different hormone secreting cell types in the pituitary pars distalis. The viscacha (Lagostomus maximus maximus) is a rodent with photoperiod-dependent seasonal reproduction. The aim of this study was to examine the effect of photoperiod seasonal variations and melatonin administration on the folliculostellate cells in pituitary pars distalis of viscacha. Immunohistochemistry and image analysis were used to measure the percentage of S 100-positive area (total, cellular and colloidal) and the number of folliculostellate cells. The S-100 protein was immunolocalized at intracellular (folliculostellate cells) and extracellular (follicular colloid) levels. The morphometric parameters analyzed exhibited seasonal variations with highest values in the summer (long photoperiod) and lowest values in the winter (short photoperiod). The administration of melatonin caused a significant decrease of immunostaining. Results suggest that the natural photoperiod might be the most important environmental signal causing the decrease in folliculostellate cells immunostaining observed in the winter. These findings agree with seasonal changes previously reported in endocrine cells and suggest that folliculostellate cells may be involved in the paracrine regulation of the secretory activity of pituitary pars distalis through S-100 protein production. PMID- 20828801 TI - Analysis of early complications of robotic-assisted radical cystectomy using a standardized reporting system. AB - OBJECTIVE: To analyze the early complications of robotic-assisted laparoscopic radical cystectomy (RARC) with extracorporeal ileal conduit or orthotopic (Studer) bladder reconstruction using the Clavien Classification, the management of these complications, and possible preventive measures. MATERIALS AND METHODS: Detailed data on all patients undergoing RARC were recorded prospectively on an encrypted database, including intraoperative or postoperative complications within 90 days of surgery. Outcome data during follow-up of up to 4 years was also collected prospectively. RESULTS: A total of 50 patients (M:F 44:6) underwent RARC and extracorporeal ileal conduit urinary diversion (n = 45) or orthotopic bladder reconstruction (n = 5) between 2004 and 2008. The overall perioperative complication rate was 17 of 50 (34%), including 3 (6%) Clavien I, 9 (18%) Clavien II, and 5 (10%) Clavien III. Final histology showed 9 (18%) patients had no residual disease pT0, 7 (14%) pTa, 11 (22%) pT1, 9 (18%) pT2, 11 (22%) pT3, and 3 (6%) pT4. CONCLUSION: Radical cystectomy remains a complex and morbid procedure with significant complication rate regardless of surgical approach. Using the Clavien reporting system, we identified early complications in 34% of patients, of which five required a significant intervention. Use of this standardized reporting system has allowed us to stratify complications after RARC, allowing easy comparison to other techniques and targeting further reductions in the future. PMID- 20828802 TI - Comparison of laparoscopic radical nephrectomy and open radical nephrectomy for pathologic stage T1 and T2 renal cell carcinoma with clear cell histologic features: a multi-institutional study. AB - OBJECTIVES: To assess the oncologic efficacy of laparoscopic radical nephrectomy (LRN) compared with open radical nephrectomy (ORN) in patients with clear cell renal cell carcinoma (RCC). METHODS: We analyzed the data from 2561 patients who had undergone radical nephrectomy for RCC at 26 institutions in Korea from June 1998 to December 2007. The clinical data of 631 patients with clear cell RCC in the LRN group were compared with the clinical data of 924 patients in the ORN group. The patients with Stage pT3 or greater and those with lymph node or distant metastases were excluded to avoid a selection bias. To evaluate the technical adequacy and oncologic outcome, we compared the perioperative parameters and 5-year overall and disease-free survival rates. RESULTS: The operative time was significantly longer in the LRN group than in the ORN group (219 +/- 77 vs 182 +/- 62 minutes, P < .001), but the estimated blood loss and complication rate were significantly lower in the LRN group than in the ORN group (P < .001 and P < .001, respectively). On univariate analysis, the LRN group had 5-year overall (93.5% vs 89.8%, P = .120) and recurrence-free (94.0% vs 92.8%, P = .082) survival rates equivalent to those of the ORN group. Even after adjusting for age, sex, T stage, tumor grade, and body mass index in a Cox proportional hazards model, statistically significant differences between the 2 groups were not found for the 5-year overall (hazard ratio 1.523, P = .157) and recurrence free (hazard ratio 0.917, P = .773) survival rates. CONCLUSIONS: Our large multi institutional data have shown that LRN provides survival outcomes equivalent to those of ORN in patients with Stage pT1-T2 clear cell RCC. PMID- 20828803 TI - Dose escalation and pharmacokinetic study of AEZS-108 (AN-152), an LHRH agonist linked to doxorubicin, in women with LHRH receptor-positive tumors. AB - OBJECTIVES: Receptors for luteinizing hormone-releasing hormone (LHRH) can be utilized for targeted chemotherapy of cytotoxic LHRH analogs. The compound AEZS 108 (previously AN-152) consists of [D-Lys6]LHRH linked to doxorubicin. The objectives of this first study in humans with AESZ-108 were to determine the maximum tolerated dose and to characterize the dose-limiting toxicity, pharmacokinetics, preliminary efficacy, and hormonal effects. METHODS: The study included 17 women with histologically confirmed epithelial cancer of the ovary, endometrium, or breast that was metastatic or unresectable and for which standard curative or palliative measures could not be used or were no longer effective or tolerated. In each patient, immunohistochemistry of primary tumor or metastatic lesion confirmed that the tumors expressed LHRH receptors. RESULTS: One patient each received intravenous doses of 10, 20, 40, or 80 mg/m2 of AEZS-108, six received 160 mg/m2 and seven 267 mg/m2 at 3 week intervals. Dose-limiting leukopenia and neutropenia were observed at the highest dose. A total of 6 patients, 3 patients each in both upper dose groups, showed responses to AEZS 108. The half-life of AESZ-108 was estimated to be about 2h. CONCLUSIONS: The maximum tolerated dose of AESZ-108 in the absence of supportive medication is 267 mg/m2 and this dose is recommended as starting dose for therapeutic Phase II studies. PMID- 20828804 TI - Surface roughness and EDS characterization of a Y-TZP dental ceramic treated with the CoJetTM Sand. AB - OBJECTIVES: (1) To determine the surface roughness and material loss of a Y-TZP ceramic before and after tribochemical grit blasting and (2) to characterize the changes in elemental surface composition and the phase transformations after tribochemical treatment. METHODS: Machined bar shaped specimens (Zeno, Wieland) were subdivided into three groups. After grit blasting for 10, 20 and 30s respectively, half of the specimens of each group were ultrasonically cleaned in ethanol for 10min. The other half was rinsed with a water spray. Surface roughness was measured using an electro-mechanical profilometer. The elemental composition of the samples was obtained by energy dispersive X-ray spectroscopy (EDS). X-ray diffraction (XRD) was used for phase transformations determination. RESULTS: The median Ra increased significantly from 0.24 to 0.32-0.38MUm after grit blasting. Augmentations were also noted for R(max), R(v) and R(p). The highest roughness parameters were, obtained for water sprayed specimens and samples abraded for 30s. Loss of material ranged between 1 and 3MUm for 30s grit blasting. Tetragonal and cubic phases were identified in 'as machined' specimens. Grit blasting resulted in domain switching and lattice deformations. The elemental composition comprised Si and Al. The duration of grit blasting did not significantly, influence the atomic percentages of Si or Al. Significantly lower values for both Si and Al were noted, after ultrasonic cleaning. SIGNIFICANCE: Grit blasting with CoJetTM Sand resulted in an increase of surface roughness, a removal of maximum 3MUm of material and coated the surface with submicron silica and alumina particles. PMID- 20828805 TI - Non-destructive three-dimensional evaluation of pores at different welded joints and their effects on joints strength. AB - OBJECTIVES: The purpose of this study was to measure the porosity in different laser welded cast alloys non-destructively using X-ray micro-focus computerized tomography (micro-CT) and to evaluate the effect of porosity on the tensile strength of the welded joints. MATERIALS AND METHODS: The welding procedure was conducted in rectangular cast metals, CoCr, Ti and platinum added gold alloy (AuPt). The metal plates were butted CoCr to CoCr (CoCr/CoCr) or Ti to Ti (Ti/Ti) for welding of similar metals and Ti to AuPt (Ti/AuPt) for welding of dissimilar metals. Specimens were welded under several laser-welding conditions; with groove (normal), without groove (no groove), spatter, crack, or no overlapped welding (no overlap) (n=5). Porosity in the welded area was evaluated using a micro-CT. Tensile strength of the welded specimens was measured at a crosshead speed of 1mm/min. Multiple comparisons of the group means were performed using ANOVA and Fisher's multiple comparisons test (alpha=.05). The relationship between the porosity and the tensile strength was investigated with a regression analysis. RESULTS: Three-dimensional images of Ti/AuPt could not be obtained due to metal artifacts and the tensile specimens of Ti/AuPt were debonded prior to the tensile test. All other welded specimens had porosity in the welded area and the porosities ranged from 0.01% to 0.17%. The fractures of most of the CoCr/CoCr and Ti/Ti specimens occurred in the parent metals. Joint strength had no relationship with the porosity in the welded area (R(2)=0.148 for CoCr/CoCr, R(2)=0.088 for Ti/Ti, respectively). SIGNIFICANCE: The small amount of porosity caused by the laser-welding procedures did not affect the joint strength. The joint strength of Ti/AuPt was too weak to be used clinically. PMID- 20828806 TI - Effects of organic enrichment on nematode assemblages in a microcosm experiment. AB - Marine nematodes from subtidal tropical sediments of Cienfuegos Bay were subjected to organic enrichment in a microcosm experiment for 32 days. Nematode abundance and diversity decreased, and the taxonomic and trophic structure was altered. The results suggested that the nematodes were not food limited in the microcosms or in their natural environment. Chemical stressors such as ammonia and hydrogen sulfide derived from reduced conditions in sediments may be important factors affecting the assemblages. Hypoxic conditions occurred in all experimental units, as well as in the field, suggesting a nematode assemblage adapted to naturally enriched sediments. However, tolerant species showed a grade of sensitivity to reduced conditions. In agreement with the model by Pearson and Rosenberg (1978), we predict that further organic enrichment in sediments from Cienfuegos Bay may cause a phase shift into a strongly depleted benthic fauna and reduced conditions in water and sediments. PMID- 20828807 TI - Flow-manipulated, crosslinked collagen gels for use as corneal equivalents. AB - Our aim was to construct a mechanically stable and optically transparent collagen gel from an acidified atelocollagen solution which is suitable for use as a corneal stromal equivalent. Light transmission and mechanical testing were conducted on variously crosslinked constructs at different pH levels. Ultrastructural analysis was performed to assess directionality of the molecular arrangement produced by flow manipulation, as well as the amount of collagen fibrillogenesis which resulted from different pH and/or crosslinking conditions. Clinical and histological integration of the gels with living tissue was examined following implantation into rabbit corneal intra-stromal pockets. Transmission electron microscopy revealed the importance of the fine control of pH levels during gel formation and indicated that the stage at which collagen fibrillogenesis is halted within the constructs was critically dependent on the pH of the collagen solution. Transparency testing disclosed that high levels of collagen fibrillogenesis, as well as high levels of crosslinker concentration, detrimentally affected the transparency of the construct. As a result, a dual titration was required to achieve good light transmission through the gels. It was also evident that the amount of crosslinking required to gelate the collagen solution was reduced as the level of fibrillogenesis progressed. Thus, it was necessary to establish a balance between the solution pH and crosslinker concentration. Implantation of the collagen constructs into partial depth intra stromal pockets in rabbits was followed up for 6 months, and demonstrated favourable biocompatibility. This showed that gels which had lower levels of both fibrillogenesis and crosslinking were degraded more readily by the host tissue. The collagen gels described here are mass-production friendly, and have promise as potential functional stromal equivalents for use in stromal grafting, or in constructing full thickness artificial corneas. PMID- 20828808 TI - A high throughput micro-array system of polymer surfaces for the manipulation of primary pancreatic islet cells. AB - We developed a high throughput micro-arrayed polymer system for the study of polymer surfaces for islet cell culture. A micro-arrayed library with 496 different polymers was synthesized and used to examine attachment and insulin expression of islet cells. While most polymers were not supportive, several related polymers were identified as suitable ("hit's"). The "hit" arrays composed of "hit" polymers with 36 replicates were fabricated to confirm their capacities to support the attachment of islet cells, and these capacities were further validated in large surfaces. Notably, the attachment of islet cells on these synthetic polymeric films has been found to be as supportive as 804G supernatant coated tissue culture polystyrene dishes, one of the most extensively used substrates for the islet cell attachment. Interestingly, the polymeric surfaces optimal for a different cell type, hES derived cells, were distinct, highlighting the utility of these approaches for identifying cell type specific surfaces. PMID- 20828809 TI - The relationship between collagen scaffold cross-linking agents and neutrophils in the foreign body reaction. AB - In order to get more insight into the role of neutrophils on the micro environment and consequently on macrophages in the foreign body reaction in mice, we investigated the fate of the two differently cross-linked dermal sheep collagen disks (glutaraldehyde = GDSC, hexamethylenediisocyanate = HDSC) in mice implanted in one anatomical location, namely subcutaneously. In GDSC massive infiltration of neutrophils is seen at day 2 and day 21, whereas in HDSC only minor infiltration is seen at day 2. The presence of neutrophils coincided with high levels of IFN-gamma, a cytokine that activates macrophages. Major differences were seen in degradation rate of the two disks: GDSC was almost completely degraded after 28 days, whereas HDSC remained intact. Degradation of GDSC occurred through collagenolytic activity and phagocytosis by macrophages. Phagocytosis was observed at day 2 and day 21. IL-13 was only observed in HDSC, and this resulted in the presence of giant cells in HDSC. These giant cells produced IL-10, that promoted TIMP-1 expression and that inhibits collagenolytic and phagocytic activity. We conclude that the function of macrophages in mice is largely influenced by differences in micro-environment induced by GDSC and HDSC and that the presence/absence of neutrophils play a major role in the shaping of this micro-environment. PMID- 20828810 TI - Therapeutic effects of a reducible poly (oligo-D-arginine) carrier with the heme oxygenase-1 gene in the treatment of hypoxic-ischemic brain injury. AB - Non-viral carriers for gene therapy have been developed to minimize carrier cytotoxicity and to enhance transfection efficiency. Previously, we synthesized a 9-arginine-based reducible high molecular weight peptide for gene delivery. For the reducible poly(oligo-D-arginines) (rPOA), 9-arginine oligopeptides are connected by internal disulfide linkages to produce a high molecular weight peptide. In this study, rPOA was evaluated as a carrier of the heme oxygenase-1 (HO-1) gene for the treatment of ischemia/reperfusion (I/R) -induced brain stroke. An in vitro transfection assay showed that rPOA had higher transfection efficiency and lower toxicity than polyethylenimine (PEI). For in vivo evaluation, I/R rat models were produced by middle cerebral artery occlusion (MCAO). rPOA/HO-1 expression plasmid (pHO-1) polyplexes were injected into the brain at 1 h before MCAO, and HO-1 expression levels in the brain were then measured by ELISA. The results indicated that rPOA/pHO-1 polyplexes had higher transfection efficiencies than PEI/pHO-1 polyplexes. The rPOA/pHO-1 polyplexes significantly reduced infarct volumes. In addition, tumor necrosis factor-alpha (TNF-alpha) was reduced in the rPOA/pHO-1 polyplex injection group, suggesting that HO-1 had an anti-inflammatory effect, while the PEI/pHO-1 polyplex did not show this effect. These results suggest that rPOA is a potential non-viral vector for HO-1 gene therapy to protect brain cells from I/R-related neuronal injury including stroke. PMID- 20828811 TI - Multifunctional SPIO/DOX-loaded wormlike polymer vesicles for cancer therapy and MR imaging. AB - Stable and tumor-targeting multifunctional wormlike polymer vesicles simultaneously loaded with superparamagnetic iron oxide (SPIO) nanoparticles (NPs) as magnetic resonance imaging (MRI) contrast agent and anticancer drug doxorubicin (DOX) were developed for targeted cancer therapy and ultrasensitive MR imaging. These multifunctional wormlike polymer vesicles were formed by heterobifunctional amphiphilic triblock copolymers R (R = methoxy or folate (FA)) PEG(114)-PLA(x)-PEG(46)-acrylate using a double emulsion method. The long PEG segments bearing methoxy/folate groups (CH(3)O/FA-PEG(114)) were mostly segregated to the outer hydrophilic PEG layers of the wormlike vesicles thereby providing active tumor-targeting ability, while the short PEG segments bearing acrylate groups (PEG(46)-acrylate) were mostly segregated onto the inner hydrophilic PEG layers of the wormlike vesicles thereby allowing the inner PEG layers to be crosslinked via free radical polymerization for enhanced in vivo stability. The hydrophobic anticancer drug, DOX, was loaded into the hydrophobic membrane of the wormlike vesicles. Meanwhile, a cluster of hydrophilic SPIO NPs was encapsulated into the aqueous cores of the stable wormlike vesicles with crosslinked inner PEG layers for ultrasensitive MRI detection. Cellular uptake of the FA-conjugated wormlike vesicles facilitated by the folate receptor-mediated endocytosis process was higher than that of the FA-free vesicles thereby leading to high cytotoxicity against the HeLa human cervical tumor cell line. Moreover, the SPIO/DOX-loaded wormlike vesicles with crosslinked inner PEG layers demonstrated a much higher r(2) relaxivity value than Feridex, a commercially available T(2) agent, which can be attributed to the high SPIO NPs loading level as well as the SPIO clustering effect. These unique stable and tumor-targeting multifunctional SPIO/DOX-loaded wormlike polymer vesicles would make targeted cancer theranostics possible thereby paving the road for personalized medicine. PMID- 20828812 TI - Co-administration of protein drugs with gold nanoparticles to enable percutaneous delivery. AB - An interesting nanoscale interfacial phenomenon mediated by gold nanoparticles (Au-NPs) was found, in that co-administration with Au-NPs enables percutaneous delivery of protein drugs. The Au-NPs with a mean size of 5 nm were revealed to be skin permeable, presumably due to the nano-bio interaction with skin lipids and the consequent induction of transient and reversible openings on the stratum corneum. Importantly, when simultaneously applied with Au-NPs, the protein drugs were also granted the ability to penetrate the skin barrier and migrate into the deep layers. This indicated that co-administration with the skin-permeable Au-NPs could mediate proteins across the skin barrier. Such co-delivery effect highlights a simple yet effective method for overcoming the skin barrier for percutaneous protein drug delivery. Employing this method, a non-invasive vaccine delivery strategy was developed, and by topically co-administrating antigens with Au-NPs, robust immune responses were elicited in the tested animals. The results provide the promise for achieving a needleless and self-administrable transcutaneous vaccination. PMID- 20828813 TI - Impact of maternal and neonatal iron status on placental transferrin receptor expression in pregnant adolescents. AB - OBJECTIVE: To elucidate the role of maternal and neonatal iron status on placental transferrin receptor (TfR) expression. STUDY DESIGN AND OUTCOMES: Ninety-two healthy pregnant adolescents (ages 14-18 years) were followed across pregnancy. Maternal iron status (hemoglobin, hematocrit, serum ferritin, TfR, and total body iron) was assessed in mid-gestation (21-25 wks) and at delivery in the mother and neonate. Placental TfR protein expression was assessed by western blot in placental tissue collected at delivery. RESULTS: Placental TfR expression was inversely associated with maternal iron status at mid-gestation (hemoglobin p = 0.046, R(2) = 0.1 and hematocrit p = 0.005, R(2) = 0.24) and at delivery (serum ferritin p = 0.02, R(2) = 0.08 and total body iron p = 0.02, R(2) = 0.07). Mothers with depleted body iron stores had significantly greater placental expression of TfR than mothers with body iron stores greater than zero (p = 0.003). Neonatal iron stores were also inversely associated with the expression of placental TfR (p = 0.04, R(2) = 0.06). Neonates with serum ferritin values <= 34 MUg/L had significantly greater protein expression of placental TfR compared to neonates with cord serum ferritin values >34 MUg/L (p = 0.01). CONCLUSIONS: Expression of placental TfR is associated with both maternal and neonatal iron demands. Increased expression of placental TfR may be an important compensatory mechanism in response to iron deficiency in otherwise healthy pregnant women. PMID- 20828815 TI - MicroRNA microarrays on archive bone marrow core biopsies of leukemias--method validation. AB - Due to availability of bone marrow core biopsies (CB) in many pathology laboratories, we evaluated the quality and the biological information of the miRNA profiling using 9 acute lymphoblastic leukemia (ALL) and 9 chronic myeloid leukemia (CML) matched CB and bone marrow aspirates (BA). Technical replicates showed reproducible results across platforms and clustered together in hierarchical clustering analysis; and matched samples showed similar biological content having common differentially expressed miRNAs against the same control samples. We showed, that CBs, which have underwent decalcification in addition to formalin-fixation, are suitable for miRNA profiling. PMID- 20828814 TI - Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells. AB - Myeloma is characterized by the overproduction and secretion of monoclonal protein. Inhibitors of the isoprenoid biosynthetic pathway (IBP) have pleiotropic effects in myeloma cells. To investigate whether IBP inhibition interferes with monoclonal protein secretion, human myeloma cells were treated with specific inhibitors of the IBP or prenyltransferases. These studies demonstrate that agents that inhibit Rab geranylgeranylation disrupt light chain trafficking, lead to accumulation of light chain in the endoplasmic reticulum, activate the unfolded protein response pathway and induce apoptosis. These studies provide a novel mechanism of action for IBP inhibitors and suggest that further exploration of Rab-targeted agents in myeloma is warranted. PMID- 20828816 TI - Dynamics of telomere's length and telomerase activity in Philadelphia chromosome negative myeloproliferative neoplasms. AB - Telomere exhaustion and increased telomerase activity are associated with the acquisition of aggressive molecular events in a variety of haematological malignancies. In Philadelphia chromosome negative myeloproliferative neoplasms (Ph(neg)MPN's), telomere dynamics during clonal evolution of these diseases have not yet been fully elucidated. Herein we demonstrated that telomere shortening is a global phenomenon in Ph(neg)MPN's, irrespective of disease phenotype, treatment administration and JAK2V617F mutational status but the presence of additional cytogenetic abnormalities further affects them. Consistent with the above finding, TA was upregulated in CD34+ haemopoietic progenitors from almost all Ph(neg)MPN subgroups compared to healthy donors. Moreover, TL below the cut-off value of 27% could predict disease progression in Ph(neg)MPN patients (PFS at 5 years 39% vs 81%). Thus, TL emerges as a new prognostic marker in Ph(neg)MPN, reflecting probably the genetic instability of highly proliferating MPN clones. PMID- 20828817 TI - Different prognostic factors for survival in acute and lymphomatous adult T-cell leukemia/lymphoma. AB - INTRODUCTION: Adult T-cell leukemia/lymphoma (ATLL) is a clinically aggressive and heterogeneous entity; hence it is likely that different variants of ATLL have different prognostic factors. METHODS: 95 patients with ATLL seen at our institution between 1987 and 2008 were included. Clinical data were compared, according to ATLL variant, using the Mann-Whitney and the Chi-square tests for continuous and categorical variables, respectively. Kaplan-Meier estimates compared using the log-rank test and Cox proportional-hazard test were used for the univariate and multivariate analysis, respectively. RESULTS: Median age was 61 years with male-to-female ratio of 1.07:1. Patients with acute ATLL were more likely to present with bone marrow, liver and spleen involvement, higher beta2 microglobulin and lower albumin levels. Poor performance status, high IPI score, presence of B symptoms, high LDH and low albumin levels were associated with a worse survival in lymphomatous ATLL. High LDH, high beta2-microglobulin and high PIT score were associated with worse survival in acute ATLL. In the multivariate analysis, low albumin level and presence of B symptoms were independent factors for worse survival in lymphomatous ATLL, and high beta2-microglobulin level was independent factor for worse survival in acute ATLL. CONCLUSIONS: Aggressive ATLL variants have a distinct, almost mutually exclusive profile of prognostic factors. PMID- 20828818 TI - Aberrant methylation of the RIZ1 gene in myelodysplastic syndrome and acute myeloid leukemia. AB - We performed methylation specific PCR analysis on the RIZ1 promoter in MDS and AML. Methylation was detected in 17 of 34 MDS (50%) and 22 of 72 AML (31%) (p=0.053). Methylation was detected in eleven of 17 secondary AML from MDS (65%), and eleven of 55 de novo AML (20%) (p=0.0005). Bisulfite sequence revealed methylation at many CpG sites in the promoter. Decreased RIZ1 expression was accompanied by methylation in six of nine samples examined, while it was also observed in seven of 13 without methylation. Treatment of AML cells, that have RIZ1 methylation, with 5-Aza-dC, induced growth suppression with RIZ1 restoration. Our results suggest that the RIZ1 gene is inactivated in MDS and AML in part by methylation, whereas another mechanism should be involved in others. PMID- 20828819 TI - Giemsa versus acridine orange staining in the fish micronucleus assay and validation for use in water quality monitoring. AB - This study concerns a comparative analysis of the acridine orange and Giemsa staining procedures for the fish erythrocyte micronucleus assay. The goal was to optimize the assay in the context of field water monitoring. Fish (Carassius carassius) were exposed to a reference genotoxic agent, cyclophosphamide monohydrate 5 mg l(-1) for 2, 4, and 6 days before testing. Slides from each individual were scored using the two procedures. The results show that the assay was more sensitive when acridine orange was used. When slides were Giemsa stained, the presence of ambiguous artefacts, leading to false positives and increasing random variance, reduced the contrast between exposed and control samples. Acridine Orange staining was then applied in the context of water quality monitoring. Fish were exposed for 4 days to water sampled in two hydrological contexts: basal flow and spring flood. The results show that exposure to spring flood water in an agricultural stream can induce mutagenicity. PMID- 20828820 TI - Study of the air quality in industrial areas of Santa Cruz de Tenerife (Spain) by active biomonitoring with Pseudoscleropodium purum. AB - A biomonitoring technique with terrestrial moss transplants (50 sampling sites in a regular grid) was used in an area of the city of Santa Cruz de Tenerife, close to an oil refinery and to an area of dense road traffic for a period of 2 months. The concentration of metals and metalloids (As, Cd, Hg, Ni, Pb and V) and 16 polycyclic aromatic hydrocarbons (PAHs) were determined. The density distribution was represented, the enrichment factors calculated and multifactorial analysis applied. In addition, contamination maps were elaborated on the basis of the bioconcentration obtained, and after confirming the existence of spatial structure, the response surfaces were represented. The results showed very high levels of contamination by Ni and V in the study area, with similar dispersal patterns observed for both. The concentrations of Cd, Hg, Pb and PAHs were lower. Active biomonitoring with terrestrial mosses was found to be a suitable technique for implementing inexpensive environmental monitoring programmes in urban and industrialized areas. PMID- 20828821 TI - Detection of photosynthetic herbicides: algal growth inhibition test vs. electrochemical photosystem II biosensor. AB - We compared a novel PSII-biosensor assay with a standard algal growth inhibition test for detection of photosynthetic herbicides--diuron, atrazine and isoproturon in liquid samples. To evaluate the convenience and sensitivity, values of the parameters EC50 and LOD and the duration of assays were compared. The biosensor assay was made with an electrochemical biosensor toxicity analyser with immobilised Photosystem II (PSII) complex. Using the PSII-biosensor assay, higher sensitivity (LOD) to herbicides (10(-8)-10(-9)M) was achieved as compared to standard algal growth inhibition tests (about 10(-7)M). The results of both assays showed a good correlation as concerns their EC50 values while the interval of detectable concentrations is about twice wider for PSII-biosensor. A proposed measurement protocol includes the reference standard of phytotoxicity (RSP). The main advantage of the PSII-biosensor assay is that it can be completed in about 1h and is by 1-2 orders more sensitive than standard algal growth inhibition test, which takes 72 h. PMID- 20828822 TI - The influence of gastrointestinal parasitism on fecal elimination of doramectin, in lambs. AB - A study was done to investigate the effect of parasitism on patterns of doramectin (DRM) fecal elimination in lambs. Fourteen Suffolk Down parasitized lambs (26.9 +/- 1.5 kg body weight: bw) were purposely selected for the study. Seven pairs of lambs were allocated into two experimental groups. Group I (non parasitized) was pre-treated with 3 repeated administrations of 5mg/kg bw of fenbendazole to maintain a non-parasitized condition. In Group II (parasitized), the lambs did not receive any anthelmintic treatment. After 85 d of the pre treatment period, both groups were treated with a subcutaneous injection of 200 MUg/kg bw of DRM. Fecal samples were collected at different times between -85 d before and 60 d after the DRM treatment, for both parasitological and chromatographic analysis. Samples were analyzed by high-performance liquid chromatography (HPLC) with fluorescence detection. Data of DRM concentrations were expressed as wet weight. A non-linear pharmacokinetic analysis was performed and results were compared using the Mann Whitney test. Fecal maximum concentrations (C(max)) of DRM were 1.37 +/- 0.19 MUg/g (parasitized group) and 0.86 +/- 0.15 MUg/g (non-parasitized group) observed at the time of the maximum concentration (T(max)) of 2.1 +/- 0.4 and 3.1 +/- 0.3d, respectively. Differences in C(max) values were significant (P<0.05). The accumulated elimination of DRM in feces, expressed as the percentage of DRM total dose, was 67.1% in the parasitized group, whereas in the non-parasitized group it was 56.5%. Our results showed that gastrointestinal parasitic diseases can modify the patterns of DRM fecal elimination, when the drug is administered by subcutaneous route in lambs. PMID- 20828823 TI - Body burden of POPs of Hong Kong residents, based on human milk, maternal and cord serum. AB - This study is one of the very few investigating the body burdens of persistent organic pollutants in residents of Hong Kong. Twenty-nine human milk samples and 21 human blood (and cord blood) samples collected from 2005 were analyzed for PAHs, OCPs and PCBs levels. Higher levels of PAHs, DDTs and PCBs were detected in human milk samples when compared to maternal serum and cord serum (PAHs: milk: 1981 ng g-1 fat, maternal serum: 1461, cord serum: 1158; DDTs: 3099, 1934, 1556; PCBs: 49, 41, 40). Among the 16 PAHs, naphthalene (human milk: 786 ng g-1 fat, maternal serum: 331, cord serum: 348), phenanthrene (361, 144, 193), pyrene (187, 154, 98) and fluoranthene (158, 128, 89) were the major PAHs detected in three human tissues. p,p'-DDE and p,p'-DDT were the only metabolites of DDT detected in the three types of human tissues. High detection rate of the p,p'-DDE and p,p' DDT (> 90%) were noted in the three types of human samples. On the contrary, low detection frequency of PCBs in human milk (10.7%), maternal serum (1.7%) and cord serum (0.8%) were observed. The correlation coefficients of the PAHs, DDTs and PCBs levels in the three types of human tissues together with fish consumption, maternal age and tissue fat were analyzed. The following significant correlations were observed: Sigma DDTs and p,p'-DDE in human milk with consumption of freshwater and marine fish, and maternal age; Sigma PCBs in human milk with marine fish consumption, and maternal age; Sigma PAHs in human milk with maternal age, respectively. The estimated daily intakes of DDTs by infants indicated that 7 out of 29 of the human milk samples exceeded 20 ng g-1 day-1, the tolerable daily intake (TDI) proposed by the Health Canada Guideline in terms of DDTs levels. The high intake of DDTs by infants may be of concern as infants are more susceptible to the adverse effects imposed by various environmental contaminants. Human milk is a reliable and comparatively non-invasive tool for monitoring body loading of POPs, which also allows health risk assessment of residual chemicals on our next generation. PMID- 20828824 TI - T cells expressing two different T cell receptors form a heterogeneous population containing autoreactive clones. AB - During T cell development both alleles of the T cell receptor (TCR) alpha locus are rearranged. As a result, a sizeable proportion of T cells can express two distinct TCRs, but the functional significance of this phenomenon remains controversial. Studies on transgenic mice with two TCRs have focused on the risk of immunopathology that such cells may pose, while some have suggested that most dual-specific T cells are nonfunctional or even protective. We tracked the fate and TCR repertoire of single- and dual-specific T cells within a normal polyclonal population undergoing lymphopenia-induced proliferation, a setting which has been shown to cause immunopathology and autoimmunity. After the expansion the repertoire of dual-specific T cells had become highly biased, with both prominent clonal expansions and the complete disappearance of other clones. Our results suggest that the normal repertoire of dual-specific T cells contains both nonfunctional cells and a small, 5% fraction of clones which display a much higher than average affinity to antigens normally tolerated as harmless. This heterogeneity may also help in reconciling some of the earlier, conflicting results. PMID- 20828825 TI - Epigenetic mechanisms involved in the induction of the mu opioid receptor gene in Jurkat T cells in response to interleukin-4. AB - Various immunomodulatory effects of opioids are mediated by mu opioid receptors. While in resting T lymphocytes their expression is repressed, mu opioid receptors are induced by interleukin-4 via the transcription factor STAT6. Here we investigated mechanisms underlying this induction in human Jurkat T cells. Although interleukin-4 induced a rapid activation of STAT6 by phosphorylation within few minutes, chromatin-immune-precipitation analysis revealed that the binding of STAT6 to its regulatory DNA element on the mu opioid receptor promoter occurs later than 2h after interleukin-4-stimulation. Detectable amounts of the mu opioid receptor mRNA were observed later than 3h after stimulation. Preceding the binding of STAT6, several epigenetic mechanisms were observed that are known to modify the chromatin architecture of a gene. Thus, we detected by chromatin immune-precipitation analysis transient association of the mu opioid receptor gene promoter with trimethylated histone H3 at lysine 4, phosphorylated (serine 10) plus acetylated (lysine 14) histone H3, and acetylated histone H4 at lysine 16. In addition, binding of the methyl-cytosine-guanine dinucleotide-binding protein MeCP2 to the mu opioid receptor promoter decreased during the interleukin 4 treatment of Jurkat cells. Furthermore, we detected a transient association of the mu opioid receptor promoter with Brg-1, which is a protein contained in ATP dependent chromatin remodeling complexes and known to facilitate transcriptional activation of a gene. Together, these data suggest that epigenetic modifications of the chromatin of the mu opioid receptor gene are involved in the transcriptional activation of the gene in response to interleukin-4 in T cells. PMID- 20828827 TI - Myeloid cell death associated with Toll-like receptor 7/8-mediated inflammatory response. Implication of ASK1, HIF-1 alpha, IL-1 beta and TNF-alpha. AB - Programmed cell death or apoptosis is an important part of the host innate immune defence, especially against ssRNA viruses (influenza virus, HIV-1, ebola virus, hepatitis C virus and many others). Viral ssRNA is recognised by endosomal Toll like receptors 7 and 8 (TLR7/8) which induce further stages of immune defence against these pathogens. Some of the immune cells die because of inflammatory stress allowing for the selection of those cells which are resistant to stress induced apoptosis and which are used in further stages of the host immune response. On the other hand, apoptosis could be used as an instrument to suppress the function of activated inflammatory cells. However, the mechanisms underlying death of the inflammatory cells associated with stress induced by ligands of TLR7/8 remain unclear. In this study we have found that programmed death of human myeloid cells from different cell lines associated with ligand-induced TLR7/8 mediated inflammatory stress depends on activation of apoptosis signal-regulating kinase 1 (ASK1). This enzyme is, however, not required for the production of pro inflammatory cytokines - TNF-alpha and IL-1beta. We have found that released IL 1beta and TNF-alpha are involved in apoptosis of myeloid cells associated with TLR7/8-mediated inflammatory stress. The pro-apoptotic effect of released TNF alpha in this case is much lower compared to that of IL-1beta. PMID- 20828826 TI - Mutagenesis dependent upon the combination of activation-induced deaminase expression and a double-strand break. AB - We explored DNA metabolic events potentially relevant to somatic hypermutation (SHM) of immunoglobulin genes using a yeast model system. Double-strand break (DSB) formation has been discussed as a possible component of the SHM process during immunoglobulin gene maturation. Yet, possible mechanisms linking DSB formation with mutagenesis have not been well understood. In the present study, a linkage between mutagenesis in a reporter gene and a double-strand break at a distal site was examined as a function of activation-induced deaminase (AID) expression. Induction of the DSB was found to be associated with mutagenesis in a genomic marker gene located 7 kb upstream of the break site: mutagenesis was strongest with the combination of AID expression and DSB induction. The mutation spectrum of this DSB and AID-mediated mutagenesis was characteristic of replicative bypass of uracil in one strand and was dependent on expression of DNA polymerase delta (Poldelta). These results in a yeast model system illustrate that the combination of DSB induction and AID expression could be associated with mutagenesis observed in SHM. Implications of these findings for SHM of immunoglobulin genes in human B cells are discussed. PMID- 20828828 TI - Syk and Lyn mediate distinct Syk phosphorylation events in FcERI-signal transduction: implications for regulation of IgE-mediated degranulation. AB - Spleen tyrosine kinase (Syk) is a key regulatory factor in the IgE-mediated allergic signal transduction pathway in mast cells and basophils. Syk is phosphorylated on a number of tyrosines following the binding of IgE/allergen complexes to FcERI receptors leading to initiation of inflammatory signaling via downstream enzymes and scaffolding proteins. We examined the kinases responsible for the phosphorylation of key Syk tyrosines in rat RBL-2H3 basophilic cells and bone marrow-derived mast cells (BMMCs). The phosphorylation of Syk tyrosine 346 was completely blocked by the novel Src family kinase inhibitor BIRA766, suggesting this tyrosine is a pure substrate for Src family kinases. This was supported by the findings that kinase-dead (KD) Syk was efficiently phosphorylated on this tyrosine and that a specific Syk inhibitor BAY61-3606 was without effect. The phosphorylation of other Syk tyrosines 317, 342, 519 and 520 was reduced by Syk and Src family inhibitors, suggesting a role for auto- and trans-phosphorylation. Lyn was the predominant Src family kinase expressed and activated in RBL-2H3 cells, meanwhile Lyn knockdown with a specific siRNA interfered with the phosphorylation of all Syk tyrosines and the Syk substrates SLP-76 and LAT. Pharmacological inhibition of Syk completely blocked the degranulation of RBL-2H3 and BMMCs. However, Lyn knockdown sensitized RBL-2H3 cells to FcERI-induced degranulation. We showed that whilst interference with Lyn expression disrupts FcERI proximal signaling via Syk and its direct substrates including SLP-76 and LAT, distal activation of downstream proteins including Erk is enhanced. This study identifies the responsible kinases for the phosphorylation of key Syk tyrosines and the propagation of FcERI receptor mediated signal transduction in allergic responses. PMID- 20828829 TI - Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. AB - OBJECTIVE: To assess the safety and efficacy of the iStent trabecular micro bypass stent (Glaukos Corporation, Laguna Hills, CA) in combination with cataract surgery in subjects with mild to moderate open-angle glaucoma. DESIGN: Prospective, randomized, open-label, controlled, multicenter clinical trial. PARTICIPANTS: A total of 240 eyes with mild to moderate open-angle glaucoma with intraocular pressure (IOP) <=24 mmHg controlled on 1 to 3 medications were randomized to undergo cataract surgery with iStent implantation (treatment group) or cataract surgery only (control). Fifty additional subjects were enrolled to undergo cataract surgery with iStent implantation under protocol expansion. Data in this report are based on the first 240 eyes enrolled. INTERVENTION: Implantation of the iStent trabecular micro-bypass stent in conjunction with cataract surgery or cataract surgery only. MAIN OUTCOME MEASURES: The primary efficacy measure was unmedicated IOP <=21 mmHg at 1 year. A secondary measure was unmedicated IOP reduction >=20% at 1 year. Safety measures included best corrected visual acuity (BCVA), slit-lamp observations, complications, and adverse events. RESULTS: The study met the primary outcome, with 72% of treatment eyes versus 50% of control eyes achieving the criterion (P<0.001). At 1 year, IOP in both treatment groups was statistically significantly lower from baseline values. Sixty-six percent of treatment eyes versus 48% of control eyes achieved >=20% IOP reduction without medication (P = 0.003). The overall incidence of adverse events was similar between groups with no unanticipated adverse device effects. CONCLUSIONS: Pressure reduction on fewer medications was clinically and statistically significantly better 1 year after stent plus cataract surgery versus cataract surgery alone, with an overall safety profile similar to that of cataract surgery alone. PMID- 20828830 TI - Decomposing the association of completed suicide with air pollution, weather, and unemployment data at different time scales. AB - BACKGROUND: Research has implicated environmental risk factors, such as meteorological variables, in suicide. However, studies have not investigated air pollution, known to induce acute medical conditions and increase mortality, in suicide. This study comprehensively assesses the temporal relationship between suicide and air pollution, weather, and unemployment variables in Taipei City from January 1 1991 to December 31 2008. METHODS: This research used the empirical mode decomposition (EMD) method to de-trend the suicide data into a set of intrinsic oscillations, called intrinsic mode functions (IMFs). Multiple linear regression analysis with forward stepwise method was used to identify significant predictors of suicide from a pool of air pollution, weather, and unemployment data, and to quantify the temporal association between decomposed suicide IMFs with these predictors at different time scales. RESULTS: Findings of this study predicted a classic seasonal pattern of increased suicide occurring in early summer by increased air particulates and decreased barometric pressure, in which the latter was in accordance with increased temperature during the corresponding time. Gaseous air pollutants, such as sulfur dioxide and ozone, were found to increase the risk of suicide at longer time scales. Decreased sunshine duration and sunspot activity predicted the increased suicide. After controlling for the unemployment factor, environmental risks predicted 33.7% of variance in the suicide data. CONCLUSIONS: Using EMD analysis, this study found time-scale dependent associations between suicide and air pollution, weather and unemployment data. Contributing environmental risks may vary in different geographic regions and in different populations. PMID- 20828831 TI - The functional Val158Met polymorphism in catechol-O-methyltransferase (COMT) is associated with depression and motivation in men from a Swedish population-based study. AB - BACKGROUND: Environmental risk factors together with genetic vulnerability create a complex background to develop depression. METHODS: We investigated the associations between COMT Val(158)Met and depression in a Swedish population based sample of 405 depressed individuals (major depression diagnosis, dysthymia or mixed anxiety depression defined according to DSM-IV) and 2,151 healthy controls. We also analyzed interaction between this genetic variation and some environmental risk factors for depression and the link between this polymorphism and the low motivational level and negative mood state found in depressed individuals. RESULTS: Depressed individuals displayed a higher frequency of the Met/Met and Met/Val genotypes compared to controls (OR=1.49, CI(95%)=1.11-2.00, P=0.009). The association was found among men only (OR=2.26, CI(95%)=1.26-4.05, p=0.008). Regression analysis including some potential risk factors for depression, did further indicate that Met/Met and Met/Val were associated with depression in men (P=0.005). There was also an interaction between genotype and family childhood problems (RERI=0.876, CI(95%)=0.090-1.662 and AP=0.426, CI(95%)=0.030-0.821). Further, depressed men homozygous for the Val-allele, had a higher motivational level than depressed men with a Met-variant (P=0.02). LIMITATIONS: The sample size of depressed individuals per group when stratifying cases according to gender and genotypes is considered a limitation. CONCLUSIONS: The Met-variants of COMT Val(158)Met are risk variants for depression and low motivational level in depressed Swedish men, but not women. Individuals with this risk variant in combination with a problematic childhood, have an even higher risk to develop depression. PMID- 20828832 TI - Association between daily environmental temperature and suicide mortality in Korea (2001-2005). AB - Little attention has been paid to whether temperature is associated with suicide and to whether suicide seasonality appears in Asian countries as shown in Western countries, even though suicide rates in Korea have increased steadily. The goal of the present study was to examine the association between daily temperature and daily suicide rate in Korea, taking gender, age, and education level into account. Data were analyzed using a generalized additive model, adjusting for confounding factors such as sunshine, relative humidity, holidays, and long-term trends. Suicide rates were higher in spring and summer than other seasons. We observed a 1.4% increase (95% confidence interval=1.0-1.7%) in suicide with each 1 degrees C-increase in daily mean temperature. The suicide risks related to the temperature for males, elderly people, and those with less education were higher than for females, younger people, and those with more education, respectively. These findings have confirmed that temperature is associated with suicide in Korea and further our understanding of more susceptible groups, the effects of gender, age, and education level. Therefore, temperature, one of the meteorological factors, is an important risk factor on suicide. PMID- 20828833 TI - Molecular cloning and expression analysis of feline alpha1-microglobulin. AB - Full-length cDNA that encodes feline alpha1-microglobulin (Fealpha1m)-bikunin was obtained from a feline liver and cloned using an oligo-capping method. The Fealpha1m-bikunin cDNA was found to contain 1284 nucleotides, and Fealpha1m was found to include an open reading frame encoding a polypeptide of 201 amino acids. The deduced amino acid sequence of Fealpha1m showed varying amino acid identity when compared with the published sequences of the related alpha1-m of other species, ranging from 71.1 to 82.1%. Fealpha1m mRNA expression was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR analysis in the cerebrum, cerebellum, lung, heart, liver, spleen, pancreas, kidney, adrenal gland, and testicle. The highest Fealpha1m mRNA level was found in the liver. PMID- 20828834 TI - In vitro identification and verification of inflammatory biomarkers in swine. AB - Currently there are no non-steroidal anti-inflammatory drugs (NSAIDs) approved for the control of inflammation in swine due to a lack of validated animal models and suitable biomarkers to assess drug efficacy. This study investigates the differential expression of genes altered in response to Escherichia coli lipopolysaccharide (LPS) induced inflammation which may serve as indicators of NSAID efficacy. Unstimulated whole blood from swine was mixed with tissue culture media, stimulated with LPS, and RNA extracted at the following time points 0h, 1h, 3h, 24h and 48h. Total RNA was extracted and analyzed using a commercial swine DNA microarray. The DNA microarray was utilized as a screen to determine potential biomarkers, focusing on the genes that exhibited the greatest degree of differential expression. A master list of 57 genes was formed based on the differential expression as a result of the stimulation. Following analysis, 12 genes whose expressions were significantly altered (8 up- and 4 down-regulated) were chosen for verification via quantitative RT-PCR (qRT-PCR). The qRT-PCR analysis confirmed the differential expression of 11 of the 12 genes chosen via the microarray analyses. Specifically, traditional genes such as SAA, G-CSF, and IL-10 were up-regulated, while CD4 was down-regulated; all of the genes were altered by 24h or 48h post-stimulation. We demonstrate here that expression of these 11 genes is altered as a direct result of LPS stimulation and consequently inflammation. PMID- 20828835 TI - Fas ligand acts as a counter-receptor in Schwann cells and induces the secretion of bioactive nerve growth factor. AB - Fas ligand (FasL) is best known for its role in apoptosis. Membrane-bound FasL can signal in FasL-bearing cells, a process known as reverse signalling. The biological and functional consequences of FasL reverse signalling in Schwann cells were studied. FasL engagement induced the secretion of soluble mediator(s) that stimulated neurite growth in PC12 cells, NGF secretion, and NGF mRNA levels. ERK1/2 and Src phosphorylation was rapidly increased and inhibition of their activation affected NGF synthesis and release. FasL can therefore act as a signal transducing molecule in Schwann cells, leading to the secretion of NGF, and may contribute to peripheral nerve regeneration. PMID- 20828836 TI - Is discordance in TEOAE and AABR outcomes predictable in newborns? AB - OBJECTIVE: To determine the perinatal predictors of discordant screening outcomes based on a two-stage screening protocol with transient-evoked otoacoustic emissions (TEOAE) and automated auditory brainstem response (AABR). METHODS: A cross-sectional study of infants tested with TEOAE and AABR under a hospital based universal newborn hearing screening program in Lagos, Nigeria. Maternal and infant factors associated with discordant TEOAE and AABR outcomes were determined with multivariable logistic regression analyses adjusting for potential confounding factors. RESULTS: Of the 4718 infants enrolled under the program 1745 (36.9%) completed both TEOAE and AABR. Of this group, 1060 (60.7%) passed both TEOAE and AABR ("true-negatives"); 92 (5.3%) failed both TEOAE and AABR ("true positive"); 571 (32.7%) failed TEOAE but passed AABR ("false-positives") while 22 (1.3%) passed TEOAE but failed AABR ("false-negatives"). Infants with false positives were likely to be admitted into well-baby nursery (p=0.001), belong to mothers who attended antenatal care (p=0.010) or who delivered vaginally (p<0.001) compared to infants with true-negatives while infants with true positives were also more likely to be delivered vaginally (p=0.002) or admitted into well-baby nursery (p=0.035) compared to infants with false-negatives. Infants with true-positives were significantly more likely to be delivered vaginally (p<0.001) and have severe hyperbilirubinemia (p=0.045) compared with infants with true-negatives. No association was observed between false-negatives and true-negatives. Antenatal care status, mode of delivery and nursery type were useful predictors of discordant outcomes among all infants undergoing screening (c-statistic=0.73). CONCLUSIONS: Given the available screening technologies, discordant TEOAE and AABR may be inevitable for some categories of hearing loss among apparently healthy newborns whose mothers received prenatal care. The potential limitations of perinatal morbidities as basis of targeted screening for such cases therefore merit further consideration. PMID- 20828837 TI - International consensus on Vibrant Soundbridge(r) implantation in children and adolescents. AB - OBJECTIVE: Active middle ear implants augment hearing in patients with sensorineural, conductive, and mixed hearing losses with great success. However, the application of active middle ear implants has been restricted to compromised ears in adults only. Recently, active middle ear implants have been successfully implanted in patients younger than 18 years of age with all types of hearing losses. The Vibrant Soundbridge (VSB) active middle ear implant has been implanted in more than 60 children and adolescents worldwide by the end of 2008. In October 2008, experts from the field with experience in this population met to discuss VSB implantation in patients below the age of 18. METHODS: A consensus meeting was organized including a presentation session of cases from worldwide centers and a discussion session in which implantation, precautions, and alternative means of hearing augmentation were discussed. At the end of the meeting, a consensus statement was written by the participating experts. The present consensus paper describes the outcomes and medical/surgical complications: the outcomes are favourable in terms of hearing thresholds, speech intelligibility in quiet and in noise, with a low incidence of intra- and postoperative complications. CONCLUSIONS: Taken together, the VSB offers another viable treatment for children and adolescents with compromised hearing. However, other treatment options should also be taken into consideration. The advantages and disadvantages of all possible treatment options should be weighed against each other in the light of each individual case to provide the best solution; counseling should include a.o. surgical issues and MRI compatibility. PMID- 20828838 TI - Assessment of adenoid size: A comparison of lateral radiographic measurements, radiologist assessment, and nasal endoscopy. AB - OBJECTIVES: Correlate adenoid size as determined by lateral neck radiographs and intra-operative mirror exam. Determine if a radiologist's assessment of the lateral neck X-ray correlates with adenoid size. Assess the correlation of endoscopic findings to the degree of adenoid hypertrophy seen on intra-operative mirror exam. To perform a cost analysis of radiographic and endoscopic evaluations of the adenoids. STUDY DESIGN: Retrospective study. METHODS: Patients who underwent adenoidectomy were reviewed. The adenoid size as determined by the adenoid-to-nasopharyngeal (A/N) ratio, radiology report, and flexible nasal endoscopy were compared to the adenoid size as determined by intra-operative mirror nasopharyngeal exam. Compensation rates for each modality were compared. RESULTS: Sixty-one children had pre-operative airway radiography. Ninety-nine patients underwent flexible nasopharyngoscopy. When the A/N ratio was compared to the intra-operative mirror exam, the Pearson Correlation coefficient was 0.64 (p<0.0001). The radiology reading was compared to intra-operative mirror exam and the Spearman Correlation coefficient was 0.29 (p=0.0258). When endoscopic nasopharyngoscopy was compared to intra-operative mirror exam, the Pearson Correlation coefficient was 0.62 (p<0.0001). The cost of nasal endoscopy was $654. Lateral airway radiography plus radiology interpretation cost $605. CONCLUSION: Children who undergo lateral radiographs to assess adenoid size are younger than those who undergo awake flexible endoscopic nasopharyngoscopy. Both the A/N ratio and endoscopic nasopharyngoscopy correlate well with the findings of the intra-operative mirror exam. The radiologist interpretations that do not utilize the A/N ratio measurement do not correlate well with intra-operative mirror exam findings. Both modalities are comparable in cost. PMID- 20828839 TI - Endoscopic endonasal transsphenoidal surgery for sellar tumors in children. AB - OBJECTIVE: Endoscopic endonasal transsphenoidal surgery (EETS) is still rarely used in pediatric subjects compared with adults. Reports on EETS in children appeared only recently in the literature, usually regarding small series. The aim of the study is to assess the actual role and the limits of EETS in children with sellar tumors by reporting a two-centers experience. METHODS: Twenty-seven children (mean age: 12.2 years) were operated on during the last decade. Seventeen patients harbored a sellar mass, 7 a suprasellar tumor, and 3 a clival mass. Laboratory investigations revealed hypopituitarism in 6 children and hormone hypersecretion in 9. All the operations were carried out by a team including both ENT surgeon and neurosurgeon using a dedicated 18-cm long rigid endoscope (2.7 mm and 4 mm diameter) through the direct paraseptal or the transethmoidal or the transpterygoid route. RESULTS: Overall, 29 operations were performed. Gross total tumor resection was obtained in 22 children (81.5%) while a subtotal and a partial removal in 2 (7.5%) and 3 cases (11%), respectively. Pituitary adenoma was the most common histotype (12 cases), followed by craniopharyngioma (5) and Rathke's cleft cyst (4). No surgical mortality or neurological morbidity or late nasal complications were observed. Postoperative CSF fistula occurred in 3 patients. All children are alive at current follow-up (average: 8.6 years). Preoperative hypopituitarism disappeared or improved in 4 cases and was stable in the remaining 2 (no new hormone deficits appeared). CONCLUSION: EETS is a safe and effective surgical option also in children. As for adults, it allows to manage most of the tumor lesions of the sellar region with stable long-term results. PMID- 20828840 TI - Adenotonsillar hypertrophy: Does it correlate with obstructive symptoms in children? AB - OBJECTIVE: The goal of this study is to determine the correlation of clinical symptoms of UAO (upper airway obstruction) with radiographic evaluation of adenoidal obstruction and tonsil size in children with adenotonsillar hypertrophy and to evaluate the usefulness of lateral neck radiography. STUDY DESIGN: Prospective study. SETTING: Haydarpasa Numune Research and Education Hospital, Istanbul, Turkey. SUBJECTS AND METHODS: This study analyses 95 children with one or more of the symptoms of UAO. Clinical symptoms were assessed by a standardized questionnaire evaluating the severity of symptoms. All patients underwent otolaryngologic examination and their tonsil sizes were graded. 74 of 95 patients underwent digital lateral soft tissue radiographs. Assessment of nasopharyngeal obstruction in radiographs was done according to four different methods. RESULTS: We did not find statistically siginificant correlation between symptom scores and radiologic measurements according to Johanneson (r=0.072, p=0.544, p>0.05) and Crepeau (r=0.034, p=0.773, p>0.05). The correlations between OSA score and Cohen and Konak's method and AN ratio were weak and not statistically siginificant (p=0.133, r=0.176; p=0.290, r=0.125 respectively; p>0.05). But, we found a statistically siginificant correlation between the tonsil grade and symptom scores (r=0.216, p=0.036, p<0.05). CONCLUSION: Our results have demonstrated that radiologic measurements of the nasopharyngeal obstruction do not correlate with clinical symptoms of UAO, but clinical assessment of tonsil size does. PMID- 20828841 TI - In vivo biodistribution and efficacy of peptide mediated delivery. AB - To transverse the plasma membrane and gain access to the cellular interior is one of the major obstacles for many novel pharmaceutical molecules. Since the late 1990s, cell-penetrating peptides (CPPs) have been utilized as transport vectors for a broad spectrum of 'biological cargoes', ranging from inert gold particles to multifaceted macromolecules such as proteins and plasmids. Numerous studies have shown that CPPs are efficient carriers for bioactive cargoes in vitro. However, even though CPPs are versatile transport vectors, this does not guarantee they can be developed into useful pharmaceutical molecules. Nevertheless, recent progress in the field has shown CPPs to be effective for in vivo delivery with retained biological activity of a wide variety of bioactive cargoes into virtually any mammalian tissue. This review will focus on recent developments and applications for CPP delivery and distribution in vivo. PMID- 20828842 TI - Serial monitoring of reverse left-atrial remodeling after pulmonary vein isolation in patients with atrial fibrillation: a magnetic resonance imaging study. AB - PURPOSE: To prospectively determine the impact of sinus rhythm restoration on left-atrial (LA) volumes and function assessed by cardiac magnetic resonance (CMR) imaging within the first year after pulmonary vein isolation (PVI). METHODS: Forty-one patients (28 men; age: 57 +/- 10 years) with paroxysmal or non paroxysmal atrial fibrillation were studied serially using CMR at baseline and at 1-, 3-, 6- and 12-month intervals following PVI. LA diastolic and systolic volumes were determined by cine imaging with full gapless LA coverage applying Simpson's rule. Successful PVI was defined by a persisting sinus rhythm during the 12-month follow-up after a 3-month blanking period; patients with a relapse of atrial fibrillation after the blanking period were censored (4 patients at 6 month follow-up and additional 6 patients at 12-month follow-up). RESULTS: In all patients, LA diastolic and systolic volumes decreased significantly and progressively during the 12-month follow-up (p<0.001 and p=0.001, respectively). At baseline patients with successful PVI demonstrated a significantly smaller LA diastolic volume compared to patients with relapsed atrial fibrillation (p=0.009). During the 3-month blanking period, patients with successful PVI showed a significant decrease of LA diastolic and systolic volumes (p=0.026 and p=0.006, respectively) and a significant increase of LA ejection fraction (p=0.028); patients with subsequent relapse of atrial fibrillation, however, exhibited no significant change of LA diastolic and systolic volumes or LA ejection fraction. CONCLUSION: Restoration of sinus rhythm led to a significant and progressive decrease of left-atrial diastolic and systolic volumes during one year following pulmonary vein isolation. PMID- 20828843 TI - Adjusted indirect comparison meta-analysis of prasugrel versus ticagrelor for patients with acute coronary syndromes. AB - BACKGROUND: Clopidogrel is beneficial after ACS. Recent data suggest the superiority of prasugrel or ticagrelor compared with clopidogrel. However, there is no comparison of prasugrel vs. ticagrelor. We performed an adjusted indirect meta-analysis comparing prasugrel vs. ticagrelor for acute coronary syndromes (ACSs). METHODS: Randomized trials were searched in PubMed. The primary end-point was the composite of death, myocardial infarction (MI) or stroke. Odds ratios (OR) were computed (95% confidence intervals). RESULTS: Three trial (32,893) patients were included. Overall, either prasugrel or ticagrelor appeared significantly superior to clopidogrel for the 12-month risk of death, MI or stroke (OR=0.83 [0.77-0.89], p<0.001), death (OR=0.83 [0.74-0.93], p=0.001), MI (OR=0.79 [0.73-0.86], p<0.001), and stent thrombosis (OR=0.61 [0.51-0.74], p<0.001), without any significant difference in stroke or major bleeding (both p>0.05), despite more frequent drug discontinuation (OR=1.12 [1.05-1.19], p<0.001). Head-to-head comparison of prasugrel vs. ticagrelor showed no significant differences in overall death, MI, stroke, or their composite (all p>0.05). Prasugrel was associated with a significantly lower risk of stent thrombosis (OR=0.64 [0.43-0.93], p=0.020). Ticagrelor was associated with a significantly lower risk of any major bleeding (OR=1.43 [1.10-1.85], p=0.007), and major bleeding associated with bypass grafting (OR=4.30 [1.73-10.6], p=0.002). However, the more clinically relevant risk of major bleeding not related to bypass surgery was similar with either prasugrel or ticagrelor (OR=1.06 [0.77-1.45], p=0.34). CONCLUSIONS: Prasugrel and ticagrelor are superior to clopidogrel for ACS. Head-to-head comparison suggests similar efficacy and safety of prasugrel and ticagrelor, but prasugrel appears more protective from stent thrombosis, while causing more bleedings. PMID- 20828844 TI - The economic and poverty impacts of animal diseases in developing countries: new roles, new demands for economics and epidemiology. AB - Animal disease outbreaks pose significant threats to livestock sectors throughout the world, both from the standpoint of the economic impacts of the disease itself and the measures taken to mitigate the risk of disease introduction. These impacts are multidimensional and not always well understood, complicating effective policy response. In the developing world, livestock diseases have broader, more nuanced effects on markets, poverty, and livelihoods, given the diversity of uses of livestock and complexity of livestock value chains. In both settings, disease control strategies, particularly those informed by ex ante modeling platforms, often fail to recognize the constraints inherent among farmers, veterinary services, and other value chain actors. In short, context matters. Correspondingly, an important gap in the animal health economics literature is the explicit incorporation of behavior and incentives in impact analyses that highlight the interactions of disease with its socio-economic and institutional setting. In this paper, we examine new approaches and frameworks for the analysis of economic and poverty impacts of animal diseases. We propose greater utilization of "bottom-up" analyses, highlighting the strengths and weaknesses of value chain and information economics approaches in impact analyses and stressing the importance of improved integration between the epidemiology of disease and its relationships with economic behavior. PMID- 20828845 TI - Molecular epidemiology of human cases of tuberculosis by Mycobacterium bovis in Mexico. AB - The purpose of this study was to evaluate the role of Mycobacterium bovis in human cases of tuberculosis (TB) in an endemic area of the disease in cattle. Sputum, urine and other tissue samples were obtained from: (1) TB-symptomatic patients, (2) dairy farm workers and (3) abattoir workers. Samples of macroscopic lesions suspicious of TB were also obtained from cattle at slaughter in the same geographic area. A total of 562 human samples were collected: 255 from symptomatic patients, 218 from farm workers and 93 from abattoir workers. Samples were analysed by the bacillus acido-alcohol resitant (BAAR) and polymerase chain reaction (PCR) tests and cultured in Stonebrink and Lowenstein-Jensen. Spoligotyping was performed in all isolates obtained by culture and the DNA obtained by PCR. From the total number of human cases, 34 (6%) showed M. bovis spoligotype; eight spoligotypes from cattle showed an identical pattern to three spoligotypes from humans; a different set of spoligotypes from cattle (n = 8) had only one spacer difference to a set of spoligotypes from humans (n = 2). These results provide further evidence that infected cattle represent a risk to public health and support previous reports about the role of M. bovis in Mexican patients. There is no doubt that genotyping M. bovis isolates collected from cattle may have a substantial impact on our understanding of the epidemiology of TB. PMID- 20828846 TI - Selection stories: understanding movement across health plans. AB - This study assesses the factors influencing the movement of people across health plans. We distinguish three types of cost-related transitions: adverse selection, the movement of the less healthy to more generous plans; adverse retention, the tendency for people to stay where they are when they get sick; and aging in place, enrollees' inertia in plan choice, leading plans with older enrollees to increase in relative cost over time. Using data from the Group Insurance Commission in Massachusetts, we show that adverse selection and aging in place are both quantitatively important. Either can materially impact equilibrium enrollments, especially when premiums to enrollees reflect these costs. PMID- 20828847 TI - Clinical application of FTIR imaging: new reasons for hope. AB - In the 1990s, Fourier transform infrared (FTIR) imaging arrived as an analytical tool for the biological sciences. However, major limitations have appeared with respect to modern techniques of clinical imaging; slow acquisition of data, diffraction limitations, inability to image living biosystems, and weak sensitivity of detectors. Recent technological developments have demonstrated that FTIR imaging can be used to image living biosamples at the surface of specific crystals, lateral resolution can reach 100 nm without diffraction limits, and real-time imaging is accessible. These analytical improvements, in conjunction with industrial efforts in providing a new generation of high photon flux IR sources and more sensitive detectors, will give FTIR imaging a 'second chance' to be introduced into the clinic. PMID- 20828848 TI - Fermentative behavior of Saccharomyces strains during microvinification of raspberry juice (Rubus idaeus L.). AB - Sixteen different strains of Saccharomyces cerevisiae and Saccharomyces bayanus were evaluated in the production of raspberry fruit wine. Raspberry juice sugar concentrations were adjusted to 16 degrees Brix with a sucrose solution, and batch fermentations were performed at 22 degrees C. Various kinetic parameters, such as the conversion factors of the substrates into ethanol (Y(p/s)), biomass (Y(x/s)), glycerol (Y(g/s)) and acetic acid (Y(ac/s)), the volumetric productivity of ethanol (Q(p)), the biomass productivity (P(x)), and the fermentation efficiency (E(f)) were calculated. Volatile compounds (alcohols, ethyl esters, acetates of higher alcohols and volatile fatty acids) were determined by gas chromatography (GC-FID). The highest values for the E(f), Y(p/s), Y(g/s), and Y(x/s) parameters were obtained when strains commonly used in the fuel ethanol industry (S. cerevisiae PE-2, BG, SA, CAT-1, and VR-1) were used to ferment raspberry juice. S. cerevisiae strain UFLA FW 15, isolated from fruit, displayed similar results. Twenty-one volatile compounds were identified in raspberry wines. The highest concentrations of total volatile compounds were found in wines produced with S. cerevisiae strains UFLA FW 15 (87,435 MUg/L), CAT 1 (80,317.01 MUg/L), VR-1 (67,573.99 MUg/L) and S. bayanus CBS 1505 (71,660.32 MUg/L). The highest concentrations of ethyl esters were 454.33 MUg/L, 440.33 MUg/L and 438 MUg/L for S. cerevisiae strains UFLA FW 15, VR-1 and BG, respectively. Similar to concentrations of ethyl esters, the highest concentrations of acetates (1927.67 MUg/L) and higher alcohols (83,996.33 MUg/L) were produced in raspberry wine from S. cerevisiae UFLA FW 15. The maximum concentration of volatile fatty acids was found in raspberry wine produced by S. cerevisiae strain VR-1. We conclude that S. cerevisiae strain UFLA FW 15 fermented raspberry juice and produced a fruit wine with low concentrations of acids and high concentrations of acetates, higher alcohols and ethyl esters. PMID- 20828849 TI - Sex-differences in adiponectin levels and body fat distribution: longitudinal observations in Afro-Jamaicans. AB - We longitudinally explored the relationship of body size and adiponectin levels in 393 community-dwelling Afro-Jamaicans. Adiponectin levels were greater in women, increased with age and declined with abdominal adiposity. Multivariate regression analyses suggest that subcutaneous fat in women may contribute significantly to the variance in their adiponectin levels. PMID- 20828850 TI - Foot ulceration in a secondary care diabetic clinic population: a 4-year prospective study. AB - Diabetes guidelines recommend that feet are stratified into low-risk, increased risk and high-risk. We examined prospective foot ulceration in our secondary care diabetes clinic. At 4-year follow-up, foot ulceration was present in 1/586 (0.17%) in the low-risk, 10/305 (3.3%) in those at increased-risk and 28/236 (11.9%) in the high-risk group. PMID- 20828851 TI - Knowledge, attitudes and practices of persons with type 2 diabetes in a rural community: phase I of the community-based Diabetes Self-Management Education (DSME) Program in San Juan, Batangas, Philippines. AB - AIMS: 1. To determine the knowledge, attitudes, and practices of persons with type 2 diabetes in the rural community of San Juan, Batangas, Philippines. 2. To determine the association between patient factors such as age, sex, duration of diabetes, and type of diabetes on knowledge, attitudes, and practices regarding diabetes. METHODS: Cross-sectional analytic study done among persons with type 2 diabetes in the rural community. Participants were selected using stratified cluster sampling. Data were collected using two main methods: use of investigator administered questionnaires and focus group discussions (FGDs). RESULTS: 156 diabetic residents were included. The overall mean percentage score on knowledge was 43%. Less than half of the respondents strongly believed in the need for patient autonomy (38%). 35 respondents were included in the FGDs. Only 4 out of 35 diabetic respondents owned a glucose meter while only 16 out of the 35 consult their doctors on a regular basis. CONCLUSIONS: The study comprises Phase I of the proposed 5-year community-based DSME Program in the Philippines. It highlights the importance of evaluating knowledge, attitudes and practices as crucial means to understand observed behaviors and guide behavioral change. PMID- 20828852 TI - Liver-specific Ldb1 deletion results in enhanced liver cancer development. AB - BACKGROUND & AIMS: LIM-domain-binding (Ldb) proteins have been demonstrated to be essential not only to key embryonic developmental processes but also to carcinogenesis. We have previously demonstrated Ldb1 to be of high biological and developmental relevance, as a targeted deletion of the Ldb1 gene in mice results in an embryonic lethal and pleiotropic phenotype. METHODS: We have now established a liver-specific Ldb1 knock out to investigate the role of Ldb1 in carcinogenesis, in particular in hepatocellular carcinoma (HCC) development, in vivo. RESULTS: These mice demonstrated a significantly enhanced growth of liver cancer by means of tumor size and number, advocating for an essential role of Ldb1 in HCC development. In addition, proliferation and resistance against apoptosis were increased. In order to identify the functional disturbances due to a lack of Ldb1, we performed a 15k mouse gene microarray expression analysis. We found the Myc oncogene to be regulated in the microarray analysis and were able to further confirm this regulation by demonstrating an over-expression of its downstream target Cyclin D1. Furthermore, we were able to demonstrate a down regulation of the tumor suppressor p21. Finally, the liver stem cell marker EpCAM was also identified to be over expressed in Ldb1(-/-) knock out mice. CONCLUSIONS: We have established a significant role of Ldb1 in cancer development. Furthermore, we provided evidence for a myc/cyclin D1, p21, and EpCAM-dependent signalling to be key downstream regulators of this novel concept in HCC development. PMID- 20828853 TI - Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin. AB - BACKGROUND & AIMS: The beneficial effects of rosiglitazone on non-alcoholic fatty liver disease (NAFLD) have been reported. Rosiglitazone treatment stimulates the production of adiponectin, an insulin-sensitizing adipokine with hepatoprotective functions. The present study aims to investigate the hepatic actions of rosiglitazone in mice without adiponectin. METHODS: NAFLD was induced in wild type and adiponectin knockout (AKO) mice by high-fat diet feeding. After rosiglitazone treatment, mice were subjected to evaluations on systemic insulin sensitivity, lipid profiles, hepatic steatosis, and inflammation, as well as the expression and activity of key molecules involved in energy metabolism and mitochondrial functions. RESULTS: Rosiglitazone treatment prevented hepatic inflammation and reduced the expression of pro-inflammatory cytokines in livers of wild type mice. In contrast, in livers of AKO mice, the same treatment induced severe hepatomegaly and microvesicular hepatosteatosis, and caused abnormal accumulation of fatty acyl CoA, glycogen, and their intermediate metabolites. Compared to wild type littermates, the anti-inflammatory and the mitochondria stimulatory activity of rosiglitazone were largely attenuated in AKO mice. Replenishment with either adiponectin or uncoupling protein 2 (UCP2) significantly reduced fatty acyl CoA accumulation and increased mitochondrial activities in livers of rosiglitazone-treated AKO mice. In addition, adiponectin, but not UCP2, promoted the activation of glycogen synthase kinase 3beta (GSK3beta), a key molecule involved in regulating glycogen homeostasis. CONCLUSIONS: Rosiglitazone elicits its protective functions against NAFLD largely through the induction of adiponectin, which prevents mitochondria stresses by promoting GSK3beta activation and UCP2 upregulation, two pathways coordinating the glucose and lipid metabolism in liver. PMID- 20828854 TI - Access to care and medicines, burden of health care expenditures, and risk protection: results from the World Health Survey. AB - OBJECTIVES: We assessed the contribution of health insurance and a functioning public sector to access to care and medicines and household economic burden. METHODS: We used descriptive and logistic regression analyses on 2002/3 World Health Survey data in 70 countries. RESULTS: Across countries, 286,803 households and 276,362 respondents contributed data. More than 90% of households had access to acute care. However, less than half of respondents with a chronic condition reported access. In 51 low and middle income countries (LMIC), health care expenditures accounted for 13-32% of total 4-week household expenditures. One in four poor households in low income countries incurred potentially catastrophic health care expenses and more than 40% used savings, borrowed money, or sold assets to pay for care. Between 41% and 56% of households in LMIC spent 100% of health care expenditures on medicines. Health insurance and a functioning public sector were both associated with better access to care and lower risk of economic burden. CONCLUSION: To improve access, policy makers should improve public sector provision of care, increase health insurance coverage, and expand medicines benefit policies in health insurance systems. PMID- 20828855 TI - A review of global mechanisms for tracking official development assistance for health in countries affected by armed conflict. AB - BACKGROUND: Poverty is highly concentrated in countries affected by armed conflict which are the furthest from reaching the Millennium Development Goals. Tracking aid patterns for health is crucial for improving the effectiveness of external aid to countries affected by armed conflict which tend to depend heavily upon external assistance and also have particularly acute health needs. OBJECTIVES: This study systematically assesses the reliability of global aid databases which are commonly used for tracking aid to countries affected by armed conflict. It offers analyses of two main databases - the Creditor Reporting System (CRS) and the Financial Tracking System (FTS) by reviewing the strengths and weaknesses of these data sources. METHODS: A literature review was conducted to assess the existing evidence on aid tracking generally, and aid databases more broadly. Interviews were also conducted with experts involved in health resource tracking, donor agencies, and NGOs. RESULTS: Despite limitations, the CRS and FTS are appropriate for tracking aid for conflict-affected countries as they are comprehensive and allow analysis of different aid activities, countries, years, and donors. CONCLUSIONS: The study offers recommendations on how CRS and FTS might be enhanced to try and improve the accountability and effectiveness of aid to countries affected by armed conflict. PMID- 20828856 TI - Illusions of scientific legitimacy: misrepresented science in the direct-to consumer genetic-testing marketplace. AB - Marketers of genetic tests often openly or implicitly misrepresent the utility of genetic information. Scientists who are well aware of the current limitations to the utility of such tests are best placed to publicly counter misrepresentations of the science. PMID- 20828857 TI - Novel recovery mechanism for the restoration of image contents in teleconsultation sessions. AB - In teleconsultation sessions, a critical dependency exists between the image contents and the type and sequential order of the image processing commands used by the various participants. Accordingly, for re-entrant/late users, a significant challenge exists in restoring the image contents of the teleconsultation session in such a way that all the participants maintain a consistent view of the medical images. In this paper, this problem is resolved using a novel recovery mechanism comprising two major components, namely an enhanced content-recording scheme designated as three-level indexing hierarchy (TIH) and a prioritized recovery policy. TIH maintains a record of all the commands which affect the appearance of each of medical images such that when a restoration process is required, these image-affect commands can be rapidly identified and transmitted to the user. As a result, a significant reduction can be gained in both the command identification/transmission time and the image restoration time compared to traditional recovery schemes, which restore the contents by re-executing all of the commands invoked during the course of the session. The prioritized recovery policy further reduces the time required for re entrant/late users to catch up with the on-going session by utilizing the cross linkage design within the TIH architecture to restore the foreground image (i.e. the image under current discussion) before the background images are restored (i.e. the remaining images in the session). To resolve the problem which arises when a background image is selected as the new foreground image before the restoration process is completed, the prioritized recovery policy maintains a set of resuming pointers for each re-entrant/late user to facilitate the process of suspending the current restoration process and switching to the restoration of the new foreground image. The evaluation results confirm that the TIH architecture and prioritized recovery policy yield a significant reduction in the recovery-latency delay compared to that required by traditional message-logging restoration systems. PMID- 20828858 TI - Online analysis of in vitro resistance to antimalarial drugs through nonlinear regression. AB - Malaria remains one of the leading causes of morbidity and mortality worldwide which is partly due to the emergence of the parasite resistance to antimalarial drugs. In vitro testing of drugs allows an early detection of resistance. The common parameter used for the monitoring of resistance is the concentration that inhibits 50% of the parasite's activity (IC(50)). Various methods of calculation are already used but none of them consider new available tools nor display the precision of IC(50) estimation. We proposed an approach based on the inhibitory sigmoid E(max) model, which is often used in pharmacology, with estimation of IC(50) through nonlinear regression using a standard function of the R software. To facilitate the usage of that tool we have developed an online version available on the website ICEstimator (ICEstimator website http://www.antimalarial icestimator.net/, 2009) [1]. This website is used by various teams in the world and the user can do the analysis without knowing R using the GUI. This article describes version 2.1 of this website and shows illustration on five different real examples. PMID- 20828859 TI - Surgical resection of liver non-small cell lung cancer metastasis: a dual weapon? AB - Liver resection for metastases from a colorectal cancer is well established and it is considered the treatment of choice. However, for patients with liver metastases from other carcinomas, the value of resection is incompletely defined and still debated. We report two cases of partial hepatectomies for liver metastases from non-small cell lung cancer leading to different outcomes. A review of the literature suggests that although early reports of similar procedures were not favorable, hepatic resection became a safe procedure, which can sometimes offer a long-term survival and should be considered in selected cases. PMID- 20828860 TI - Single-agent gefitinib with concurrent radiotherapy for locally advanced non small cell lung cancer harboring mutations of the epidermal growth factor receptor. AB - INTRODUCTION: A feasibility study was performed to examine the safety and toxicity profile of daily gefitinib (250 mg) administration with concurrent definitive thoracic radiation therapy (TRT) in patients with unresectable non small cell lung cancer (NSCLC) of stage III. METHODS: Patients received a 14-day induction therapy with gefitinib at 250 mg daily. TRT was initiated on day 15 in 2-Gy fractions administered five times weekly to a total dose of 60 Gy. The primary end point of the study was the rate of treatment completion. Mutation status of the epidermal growth factor receptor gene (EGFR) was evaluated for patients with available tumor specimens. RESULTS: Nine eligible patients enrolled in the study received induction gefitinib monotherapy. Two patients were unable to begin TRT because of the development of progressive disease during the first 2 weeks of the protocol. Three of the remaining seven patients treated with gefitinib and concurrent TRT were unable to complete the planned treatment (two because of pulmonary toxicity and one because of progressive disease), and the study was therefore closed according to the protocol definition. Tumor samples were available for eight patients. EGFR mutations (deletion in exon 19) were detected in two patients, both of whom achieved a partial response and exhibited an overall survival of >5 years. CONCLUSIONS: Our results do not support further trials of gefitinib and TRT for unselected NSCLC patients. This therapeutic strategy may hold promise, however, for locally advanced NSCLC in patients with sensitizing EGFR mutations. PMID- 20828861 TI - Treatment outcomes of patients with adenoid cystic carcinoma of the airway. AB - BACKGROUND: Adenoid cystic carcinoma (ACC) of the airway is a slowly growing tumor and airway narrowing is one of the main causes of death. The purposes of this study were to investigate treatment outcomes, prognostic factors, and the indications and outcomes of bronchoscopic interventions in patients with ACC of the airway. METHODS: We retrospectively analyzed the clinical characteristics, treatment modalities, and clinical outcomes of patients with histologically proven ACC of the airway treated between January 1995 and June 2009 at Samsung Medical Center. RESULTS: A total of 30 patients were included in the study. Sixteen patients were male and the median age was 45 years. Multiple treatment modalities were required for the patients; 17 for surgery, 13 for definitive radiation therapy, 10 for adjuvant radiation therapy, and 1 for adjuvant chemotherapy. Bronchoscopic interventions were required to improve airway narrowing in 20 patients. After bronchoscopic intervention, 19 patients (95%) showed immediate improvement of airway narrowing and suffered no serious complications. The 5- and 10-year overall survival (OS) rates in these patients were 84% and 70%, respectively. The prognostic factors associated with OS were tumor size, tumor location, clinical T stage, surgery as an initial treatment, and bronchoscopic intervention. CONCLUSIONS: ACC of the airway had a good long term prognosis but bronchoscopic interventions were frequently required during the course of the disease due to the development of airway narrowing. Bronchoscopic interventions may be considered as a bridge therapy before surgery or radiation therapy and as a palliative therapy for airway narrowing. PMID- 20828862 TI - Amrubicin at a lower-dose with routine prophylactic use of granulocyte-colony stimulating factor for relapsed small-cell lung cancer. AB - BACKGROUND: Recent reports have suggested the efficacy of amrubicin (AMR) for relapsed small-cell lung cancer (SCLC). However, doses of AMR in these reports were 40 mg/m(2) or 45 mg/m(2), and severe and frequent myelosuppression were observed. Such side effects are occasionally intolerable, as serious myelosuppression may induce fatal infections. To overcome this clinical problem, we investigated whether 35 mg/m(2) of AMR administration with routine prophylactic use of granulocyte-colony stimulating factor (G-CSF) can reduce myelosuppression, while maintaining efficacy. METHODS: Between July 2003 and November 2008, 30 relapsed SCLC patients receiving 35 mg/m(2)/day of AMR were evaluated. Amrubicin was administered on days 1-3 every 3 or 4 weeks. Routine prophylactic use of G-CSF was performed beginning on day 8 and continuing for at least 5 consecutive days or until neutrophils recovered to the normal level. RESULTS: The median number of treatment cycles was four (range 1-9). No complete responses and 13 partial responses were observed, with response rates of: overall 43% (95% confidence interval [CI]: 26-63%); sensitive cases 33% (95% CI: 10-65%); and refractory cases 50% (95% CI: 26-74%) (p=0.4651). The disease control rate (partial response and stable disease) was 80% (95% CI: 61-92%). The progression free survival times were: overall 4.2 months (95% CI: 3.2-5.2 months); sensitive cases 4.7 months (95% CI: 2.6-5.4 months); and refractory cases 3.5 months (95% CI: 2.6-5.2 months) (p=0.7124). The median OS times were: overall 9.6 months (95% CI: 7.2-12.5 months); sensitive cases 8.4 months (95% CI: 4.6-13.4 months); and refractory cases 11.0 months (95% CI: 6.5-12.6 months) (p=0.9315). The 1-year survival rate was 33%. Regarding grade 3/4 hematological toxicities: leukopenia (47%); neutropenia (50%); anemia (30%); and thrombocytopenia (33%) were observed. Febrile neutropenia occurred in three patients (10%). Transfusions of red blood cells and platelets were performed for eight (27%) and one (3%) patients, respectively. Treatment-related deaths and grade 3/4 non-hematological toxicities were not observed at all. CONCLUSIONS: Considering both safety and efficacy, AMR at a dose of 35 mg/m(2) with routine prophylactic use of G-CSF may be more desirable for the treatment of relapsed SCLC in clinical practice. PMID- 20828863 TI - Individuals and populations: the role of long-term, individual-based studies of animals in ecology and evolutionary biology. AB - Many important questions in ecology and evolutionary biology can only be answered with data that extend over several decades and answering a substantial proportion of questions requires records of the life histories of recognisable individuals. We identify six advantages that long-term, individual based studies afford in ecology and evolution: (i) analysis of age structure; (ii) linkage between life history stages; (iii) quantification of social structure; (iv) derivation of lifetime fitness measures; (v) replication of estimates of selection; (vi) linkage between generations, and we review their impact on studies in six key areas of evolution and ecology. Our review emphasises the unusual opportunities and productivity of long-term, individual-based studies and documents the important role that they play in research on ecology and evolutionary biology as well as the difficulties they face. PMID- 20828864 TI - Land-use controls on sources and fate of nitrate in shallow groundwater of an agricultural area revealed by multiple environmental tracers. AB - Sources and transformation processes of nitrate in groundwater from shallow aquifers were investigated in an agricultural area in the mid-western part of South Korea using a multi-tracer approach including delta2H and delta18O values of water, delta15N and delta18O values of nitrate, Cl/Br ratios and chlorofluorocarbons (CFCs). The study area was comprised of four land-use types with natural areas at higher altitudes, upland areas with fruit orchards, paddy fields and residential areas at lower elevations. The isotopic composition of water was suitable for distinguishing groundwater that had infiltrated in the higher elevation natural areas with lower delta2H and delta18O values from groundwater underneath paddy fields that was characterized by elevated delta2H and delta18O values due to evaporation. delta18O-H2O values and Cl- concentrations indicated that groundwater and contaminant sources were derived from three land-use types: natural areas, residential areas and paddy fields. Groundwater age determination based on CFCs showed that nitrate contamination of groundwater is primarily controlled by historic nitrogen loadings at least in areas with higher nitrate contamination. Nitrate sources were identified using the stable isotope composition of nitrate and Cl/Br ratios. Higher delta15N-NO3- values and Cl/Br ratios of 300 to 800 in residential areas indicated that waste water and septic effluents were major nitrate sources whereas lower delta15N-NO3- values and Cl/Br ratios of 100 to 700 in upland areas suggested that synthetic fertilizers constituted a major source of nitrate contamination of aquifers. With only few exceptions in the natural area, contributions of atmospheric nitrate were insignificant due to the resetting of delta18O-NO3- values via immobilization and re-mineralization of nitrate in the soil zone. In groundwater underneath paddy fields, 30% of samples had delta18O-NO3- values at least 20/00 higher than expected for nitrate formed by chemolithoautotrophic nitrification; these samples were also characterized by low DO and NO3-N concentrations and elevated Cl and Mn concentrations indicating anthropogenic contamination and denitrification in the aquifer. These conditions were observed primarily in aquifers on floodplains. Statistical comparison between land-use groups revealed that Cl/Br ratios were more diagnostic for the impact of different land-use types on groundwater quality than stable isotope compositions of nitrate. This indicates that the former is an additional efficient tracer for the effect of land use on groundwater quality in agricultural areas. We conclude that the combination of groundwater age dating together with the use of chemical and isotopic parameters is a highly effective but yet underutilized approach for elucidating the sources and the fate of nitrate in aquifers in Asia. PMID- 20828865 TI - Host defense peptides and their antimicrobial-immunomodulatory duality. AB - Host defence peptides (HDPs) are short cationic molecules produced by the immune systems of most multicellular organisms and play a central role as effector molecules of innate immunity. Host defence peptides have a wide range of biological activities from direct killing of invading pathogens to modulation of immunity and other biological responses of the host. HDPs have important functions in multiple, clinically relevant disease processes and their imbalanced expression is associated with pathology in different organ systems and cell types. Furthermore, HDPs are now evaluated as model molecules for the development of novel natural antibiotics and immunoregulatory compounds. This review provides an overview of HDPs focused on their antimicrobial-immunomodulatory duality. PMID- 20828866 TI - Differential expression of toll-like receptor signaling cascades in LPS-tolerant human peripheral blood mononuclear cells. AB - Pre-exposure to low doses of LPS induces resistance to a lethal challenge, a phenomenon known as endotoxin tolerance. In this study, tolerance was induced in human PBMC by culturing cells with 1 ng/mL LPS for 48 h. Cells were subsequently challenged with 100 ng/mL LPS for 2, 6 and 24 h, and the expression of 84 genes encoding proteins involved in the TLR signaling pathway was evaluated at each time point by PCR array. LPS pretreatment did not modulate the expression of TLR4 and CD14 on the surface of monocytes. A gene was defined as tolerized when LPS pretreatment reversed the effect of LPS challenge on the expression of the gene or as non-tolerized when LPS pretreatment did not reverse the effects of LPS challenge. We observed impaired signal transduction through the NF-kappaB, JNK, ERK and TRIF pathways, whereas expression of p38 pathway-related genes was preserved in LPS-tolerant cells. These results show a distinct regulation of the TLR pathway cascades during tolerance; this may account for the differential gene expression of some inflammatory mediators, such as up-regulation of IL-10 and COX2 as well as down-regulation of TNF-alpha and IL-12. Depending on the effect of LPS-induced gene up-regulation or down-regulation, tolerance, as a reversion of such LPS effects, may result in repression or induction of gene expression. PMID- 20828867 TI - Quercetin regulates oxidized LDL induced inflammatory changes in human PBMCs by modulating the TLR-NF-kappaB signaling pathway. AB - Toll-like receptors (TLRs) have been shown to play a pivotal role in both innate and adaptive immune responses. TLR family is the essential recognition and signaling component of mammalian host defense. Both genetic and biochemical data support a common signaling pathway that finally leads to the activation of NF kappaB and induction of the cytokines and co-stimulatory molecules required for the activation of the adaptive immune response. The present study was designed to examine the involvement of TLR2 and TLR4 in the oxidized LDL induced inflammation in human PBMCs and the effect of flavonoid quercetin on TLR-NF-kappaB signaling mechanism. LDL was isolated from human plasma and oxidation of LDL was done by incubating with 10 MUM CuSO4 overnight at 37 degrees C. The isolated human PBMCs in culture were used as the model system. 50 MUg/ml ox-LDL treatment significantly up regulated TLR2 and TLR4 expression in isol human PBMCs after 24 h of culture and this was down regulated by quercetin at 25 MUM concentration. ox LDL caused a significant activation of NF-kappaB as evidenced by the detection of enhanced p65 subunit in nuclear extracts. Supplementation of quercetin significantly modulates the NF-kappaB p65 nuclear translocation. The cytokine IL 6 production was significantly increased in ox-LDL treated group and was decreased by quercetin treatment. Quercetin mediated reduction of TLR2 and TLR4 expression and the inhibition of nuclear translocation of NF-kappaB p65 in turn decreased the inflammatory enzymes like 5-LOX and COX and also decreased the mRNA expression of inducible enzymes like COX-2 and iNOS. Quercetin inhibited the ox LDL induced TLR2 and TLR4 expression at mRNA level and modulated the TLR-NF kappaB signaling pathway thereby inhibited the cytokine production and down regulated the activity of inflammatory enzymes thus have protective effect against the ox-LDL induced inflammation in PBMCs. PMID- 20828868 TI - Ectopic expression of TrPI, a Taihangia rupestris (Rosaceae) PI ortholog, causes modifications of vegetative architecture in Arabidopsis. AB - In eudicotyledonous model plants, the B-function genes encode a pair of partner MADS-domain proteins, APETALA3 (AP3) and PISTILLATA (PI) in Arabidopsis and DEFICIENS (DEF) and GLOBOSA (GLO) in Antirrhinum. These proteins, which must form heterodimers to function, are required to specify petal and stamen identity during flower development. Here, we report cloning and characterization of TrPI (Taihangia rupestris PISTILLATA), a PI/GLO-like gene from the core eudicot species Taihangia rupestris (Rosaceae). DNA gel blot analysis showed that TrPI is a single copy gene in the T. rupestris genome. Quantitative RT-PCR and in situ hybridization analyses revealed that TrPI is transcribed in both the vegetative and reproductive organs at different levels. Ectopic expression of TrPI in Arabidopsis caused severe modifications in vegetative plant architecture, including rosette leaves and cauline leaves arranged in a non-spiral phyllotaxy, and a flattened primary inflorescence stem that produced two or three offshoots at the base, middle or top. Moreover, we show that the TrPI gene is capable of rescuing pi-1 mutant phenotypes. Yeast two-hybrid assays showed that TrPI forms homodimers. Taken together, these results show that TrPI might function in regulating plant architecture in addition to its function as a floral organ identity gene in T. rupestris, suggesting that the TrPI protein has biochemical features that distinguish it from the well-studied orthologs, PI and GLO. PMID- 20828869 TI - The cellular redox state as a modulator in cadmium and copper responses in Arabidopsis thaliana seedlings. AB - The cellular redox state is an important determinant of metal phytotoxicity. In this study we investigated the influence of cadmium (Cd) and copper (Cu) stress on the cellular redox balance in relation to oxidative signalling and damage in Arabidopsis thaliana. Both metals were easily taken up by the roots, but the translocation to the aboveground parts was restricted to Cd stress. In the roots, Cu directly induced an oxidative burst, whereas enzymatic ROS (reactive oxygen species) production via NADPH oxidases seems important in oxidative stress caused by Cd. Furthermore, in the roots, the glutathione metabolism plays a crucial role in controlling the gene regulation of the antioxidative defence mechanism under Cd stress. Metal-specific alterations were also noticed with regard to the microRNA regulation of CuZnSOD gene expression in both roots and leaves. The appearance of lipid peroxidation is dual: it can be an indication of oxidative damage as well as an indication of oxidative signalling as lipoxygenases are induced after metal exposure and are initial enzymes in oxylipin biosynthesis. In conclusion, the metal-induced cellular redox imbalance is strongly dependent on the chemical properties of the metal and the plant organ considered. The stress intensity determines its involvement in downstream responses in relation to oxidative damage or signalling. PMID- 20828870 TI - Functional characterization of a sucrose:fructan 6-fructosyltransferase of the cold-resistant grass Bromus pictus by heterelogous expression in Pichia pastoris and Nicotiana tabacum and its involvement in freezing tolerance. AB - We have previously reported the molecular characterization of a putative sucrose:fructan 6-fructosyltransferase (6-SFT) of Bromus pictus, a graminean species from Patagonia, tolerant to cold and drought. Here, this enzyme was functionally characterized by heterologous expression in Pichia pastoris and Nicotiana tabacum. Recombinant P. pastoris Bp6-SFT showed comparable characteristics to barley 6-SFT and an evident fructosyltransferase activity synthesizing bifurcose from sucrose and 1-kestotriose. Transgenic tobacco plants expressing Bp6-SFT, showed fructosyltransferase activity and fructan accumulation in leaves. Bp6-SFT plants exposed to freezing conditions showed a significantly lower electrolyte leakage in leaves compared to control plants, indicating less membrane damage. Concomitantly these transgenic plants resumed growth more rapidly than control ones. These results indicate that Bp6-SFT transgenic tobacco plants that accumulate fructan showed enhanced freezing tolerance compared to control plants. PMID- 20828871 TI - Xyloglucan endotransglucosylase and cell wall extensibility. AB - Transgenic tomato hypocotyls with altered levels of an XTH gene were used to study how XET activity could affect the hypocotyl growth and cell wall extensibility. Transgenic hypocotyls showed significant over-expression (line 13) or co-suppression (line 33) of the SlXTH1 in comparison with the wild type, with these results being correlated with the results on specific soluble XET activity, suggesting that SlXTH1 translates mainly for a soluble XET isoenzyme. A relationship between XET activity and cell wall extensibility was found, and the highest total extensibility was located in the apical hypocotyl segment of the over-expressing SlXTH1 line, where the XET-specific activity and hypocotyl growth were also highest compared with the wild line. Also, in the co-suppression SlXTH1 line, total extensibility values were lower than in the wild type line. The study of linkages between cell wall polysaccharides by FTIR showed that hypocotyls over expressing SlXTH1 and having a higher XET-specific activity, were grouped away from the wild line, indicating that the linkages between pectins and between cellulose and xyloglucans might differ. These results suggested that the action of the increased XET activity in the transgenic line could be responsible for the cell wall structural changes, and therefore, alter the cell wall extensibility. On the other hand, results on xyloglucan oligosaccharides composition of the xyloglucan by MALDI TOF-MS showed no differences between lines, indicating that the xyloglucan structure was not affected by the XET action. These results provide evidences that XTHs from group I are involved mainly in the restructuring of the cell wall during growth and development, but they are not the limiting factor for plant growth. PMID- 20828872 TI - Ectopic ferredoxin I protein promotes root hair growth through induction of reactive oxygen species in Arabidopsis thaliana. AB - Ferredoxin I (Fd-1) is a protein existing in green tissues as an electron carrier for photosynthesis. Reactive oxygen species (ROS) are generated from an over accumulation of electrons in photosynthetic electron chains. In previous studies, plant ferredoxin-like protein (PFLP) transgenic plants could be made resistant to virulent pathogens, by inducing the generation of ROS. The generation of ROS is closely associated with root hair development, increasing with the elongation of root hairs. We propose that an ectopic expression of pflp may alter root hair development through the enhanced generation of ROS. In this report, Arabidopsis transformed with pflp was generated to determine the potential role of PFLP in root development. Transgenic Arabidopsis exhibited longer root hairs with a significant increase in endogenous H(2)O(2) compared with wild type. The growth of transgenic lines in root hairs was inhibited when treated with NADPH oxidase inhibitor. Results suggest that an over-expression of pflp had enhanced the accumulation of H(2)O(2) in the roots and further promoted the growth of root hairs. Transcriptional activities of root hair development-related and redox regulated genes were mediated through increased levels of ROS, to alter the growth of transgenic lines in root hairs. In summary, we propose that an ectopic expression of pflp promotes root hair growth, resulting from an enhancement of ROS production. PMID- 20828873 TI - Transcriptome analysis reveals novel genes involved in nonhost response to bacterial infection in tobacco. AB - Plants are continuously exposed to pathogen challenge. The most common defense response to pathogenic microorganisms is the nonhost response, which is usually accompanied by transcriptional changes. In order to identify genes involved in nonhost resistance, we evaluated the tobacco transcriptome profile after infection with Xanthomonas axonopodis pv. citri (Xac), a nonhost phytopathogenic bacterium. cDNA-amplified fragment length polymorphism was used to identify differentially expressed transcripts in tobacco leaves infected with Xac at 2, 8 and 24h post-inoculation. From a total of 2087 transcript-derived fragments (TDFs) screened (approximately 20% of the tobacco transcriptome), 316 TDFs showed differential expression. Based on sequence similarities, 82 differential TDFs were identified and assigned to different functional categories: 56 displayed homology to genes with known functions, 12 to proteins with unknown functions and 14 did not have a match. Real-time PCR was carried out with selected transcripts to confirm the expression pattern obtained. The results reveal novel genes associated with nonhost resistance in plant-pathogen interaction in tobacco. These novel genes could be included in future strategies of molecular breeding for nonhost disease resistance. PMID- 20828874 TI - Emergency physician ultrasonography for evaluating patients at risk for ectopic pregnancy: a meta-analysis. AB - STUDY OBJECTIVE: Ectopic pregnancy is a common concern in emergency departments (EDs) and remains the leading cause of first-trimester mortality. Pelvic ultrasonography by emergency physicians has been investigated as a diagnostic test for ectopic pregnancy. We present a meta-analysis of the use of emergency physician ultrasonography in the evaluation of patients at risk of ectopic pregnancy. METHODS: A structured search was performed of both MEDLINE and EMBASE. Inclusion criteria were that (1) the study reported original research on ED patients at risk for ectopic pregnancy; (2) an emergency physician performed and interpreted the initial pelvic ultrasonography; and (3) follow-up was conducted on all patients. Sensitivity was defined as the proportion of patients with ectopic pregnancy for which ED ultrasonography demonstrated no intrauterine pregnancy. A random-effects model was used to obtain summary test characteristics. RESULTS: The initial search showed 576 publications, abstract review yielded 60 with potential relevance, and 10 studies were included. There was a total of 2,057 patients, of whom 152 (7.5%) had ectopic pregnancy. The pooled sensitivity estimate was 99.3% (95% confidence interval [CI] 96.6% to 100%), negative predictive value was 99.96% (95% CI 99.6% to 100%), and negative likelihood ratio was 0.08 (95% CI 0.025 to 0.25), all without significant heterogeneity. CONCLUSION: The results of this meta-analysis suggest that in a wide variety of clinical settings, the use of bedside ultrasonography performed by emergency physicians as a diagnostic test for ectopic pregnancy provides excellent sensitivity and negative predictive value. Visualization of an intrauterine pregnancy by an emergency physician is generally sufficient to rule out ectopic pregnancy. PMID- 20828875 TI - ECG criteria of the San Francisco Syncope Rule. PMID- 20828876 TI - Zero on the NIHSS does not equal the absence of stroke. AB - STUDY OBJECTIVE: The National Institutes of Health Stroke Scale (NIHSS) measures deficits caused by a stroke, but not all stroke signs are captured on the NIHSS. We determine the symptoms and stroke localization of patients with brain infarction and an NIHSS score of 0. METHODS: We studied all patients who presented with acute neurologic symptoms to our stroke center from 2004 to 2008 and had persistent symptoms at the evaluation in the emergency department, an NIHSS score of 0, and an infarct on diffusion-weighted imaging. We characterized the symptoms, signs, lesion location, demographics, and stroke causes. RESULTS: Twenty patients met inclusion criteria. Symptoms frequently experienced were headache, vertigo, and nausea. The posterior circulation was commonly infarcted in this group. Truncal ataxia was the most common neurologic sign. CONCLUSION: Ischemic stroke may cause symptoms that are associated with no deficits on the NIHSS score. PMID- 20828877 TI - A comparison of the effects of etomidate and midazolam on hospital length of stay in patients with suspected sepsis: a prospective, randomized study. AB - STUDY OBJECTIVE: Etomidate, a widely used induction agent for rapid sequence intubation in the emergency department (ED), causes measurable adrenal suppression after a single bolus dose. The clinical significance of this adrenal suppression in patients with sepsis remains controversial. We seek to determine the difference in hospital length of stay between patients with suspected sepsis who receive either etomidate or midazolam during intubation in our ED. METHODS: We performed a prospective, double-blind, randomized study of patients with suspected sepsis who were intubated in our ED during an 18-month period. Eligible patients who were critically ill and were suspected of having sepsis were randomized to receive either etomidate or midazolam before intubation. RESULTS: A total of 122 patients were enrolled; 59 received midazolam and 63 received etomidate. Two patients in the etomidate group were lost to follow-up. Patient baseline characteristics were similar between groups. There were no significant differences in median hospital length of stay (9.5 versus 7.3 days), ICU length of stay (4.2 versus 3.1 days), or ventilator days (2.8 versus 2.1) between patients who received midazolam and those who received etomidate, respectively. Inhospital mortality was 21 of 59 (36%; 95% confidence interval 24% to 49%) for patients who received midazolam and 26 of 61 (43%; 95% confidence interval 30% to 56%) for patients who received etomidate. For patients who survived to hospital discharge, the median length of stay was 11.3 days in the midazolam group versus 11.8 days in the etomidate group; for patients who died, the median length of stay was 2.9 days in the midazolam group versus 3.3 days in the etomidate group. CONCLUSION: Patients with suspected sepsis and who received a single bolus dose of etomidate for rapid sequence intubation showed no significant increase in hospital length of stay compared with patients who received a single bolus dose of midazolam. PMID- 20828878 TI - Appraisal of family and community medicine. PMID- 20828879 TI - [Large population data bases for primary care research: "We have the advantage"]. PMID- 20828880 TI - [Positive sentinel node risk in relation to oestrogen receptors in breast cancer in premenopausal and postmenopausal women]. AB - OBJECTIVE: The influence of the relationship between pre- and post-menopausal stage of patients with breast cancer (BC) and the risk of sentinel lymph node (SLN) metastasis as well as the influence of oestrogen receptor (ER) status within each one of these groups were analyzed. METHODS: A BC database with 1,388 patients was analysed. Three age groups were studied: A, elderly postmenopausal, 200 patients, >= 70 years old; B, younger postmenopausal, 89 patients, 55-69 years old; C, premenopausal, 85 patients, <55 years old. In each group 2 subgroups were analyzed: positive ER and negative ER tumours. Data analysed: SLN positive patients, non-sentinel node (NSN)-positive patients, non-surgical detections (NSD) and non disease-free (NDF) patients after a follow-up of 52 months. STATISTICAL ANALYSIS: chi-squared test, significance: P <= 0.05. RESULTS: SLN metastasis was significantly (P<0.025) more common in premenopausal than in postmenopausal patients, and within those, mainly in negative ER tumours. Positive-NSN increases slightly in premenopausal patients (exclusively in negative ER tumours). NDF patients are similar in the 3 groups and in all of them it is much more frequent in negative ER tumours. CONCLUSION: SLN metastasis varies significantly according to hormonal state and not according to age, being more frequent in premenopausal patients and mainly in ER negative tumours. PMID- 20828881 TI - [Is it possible to reduce the delay in diagnosing HIV infection?]. PMID- 20828882 TI - Synthesis and screening of some novel fused thiophene and thienopyrimidine derivatives for anti-avian influenza virus (H5N1) activity. AB - Several derivatives containing dihydronaphtho, naphtho[2,1-b]thiophene and thieno[2,3-d]pyrimidine ring systems were prepared starting from 2-amino-4,5 dihydronaphtho[2,1-b]thiophene-1-carbonitrile (1). Structure characterization of the thioxo derivative 7 was also performed and its reaction with some chloro and bromoalkyl reagents was studied. Moreover, the prepared products were tested for antiviral activity against H5N1 virus [A/chicken/Egypt/1/2006 (H5N1)] by determination of both EC50 and LD50 and confirmed by plaque reduction assay on MDCK cells. Compounds 5, 7 and 8 showed the highest effect compared with the other tested compounds. PMID- 20828883 TI - Synthesis and vasodilation activity of some novel bis(3-pyridinecarbonitrile) derivatives. AB - A variety of bis(2-alkoxy-6-aryl-3-pyridinecarbonitriles) 4a-m were prepared via reaction of bis(2-propen-1-ones) 3a-g with malononitrile in the appropriate alcohol in the presence of KOH. The reaction was assumed to take place via Michael addition followed by cyclization due to the alkoxide nucleophilic attack at one of the nitrile groups. This assumption was substantiated by the reaction of ylidenemalononitrile 5 with the corresponding acetophenone 2 in the appropriate alcohol in the presence of KOH. The starting bis(2-propen-1-ones) 3e and f were prepared stereoselectively as E,E'-geometric isomer via condensation of bisbenzaldehyde 1 with substituted acetophenones 2e and f in ethanolic KOH solution. Vasodilating activity screening of the synthesized compounds 4a-g and 4i-m utilizing isolated rat's thoracic aorta pre-contracted by norepinephrine hydrochloride exhibited that many of the tested compounds reveal considerable vasodilating properties, especially 4e and f which reveal remarkable activities. PMID- 20828884 TI - Influence of methoxy groups on the antiproliferative effects of [Fe(III)(salophene-OMe)Cl] complexes. AB - We synthesized methoxy-substituted iron(III)-salophene complexes ([Fe(III)(OMe salophene)Cl] with salophene = N,N'-bis(salicylidene)-1,2-phenylenediamine) and analyzed their biological activity in MCF-7 and MDA-MB-231 breast cancer as well as in HT-29 colon carcinoma cells. The results obtained in a time-dependent chemosensitivity test clearly demonstrated the correlation between the cytotoxicity of the complexes and the position of methoxy substituents in the salicylidene moieties: 3-OCH(3) (4) < 5-OCH(3) (8) < H (2) < 4-OCH(3) (6) = 6 OCH(3) (10). Compounds 6 and 10 caused cytocidal effects already at a concentration of 0.5 MUM. Both lead compound 2 and complex 8 showed similar time response curves, however, with a 5-fold lower activity compared to 6 and 10, respectively. Referring to [Fe(III)(salophene)Cl] (2), methoxy substitution was accompanied with the loss of tumor cell selectivity. Moreover, the free ligands (1, 3, 5, 7, and 9) were inactive. PMID- 20828885 TI - Synthesis of new pyrrolo[2,3-d]pyrimidine derivatives as antibacterial and antifungal agents. AB - A series of new pyrrole derivatives, pyrrolo[2,3-d]pyrimidine derivatives, pyrrolotriazolopyrimidines and pyrrolotetrazolopyrimidines were synthesized. The evaluation of their antimicrobial activities against Staphylococcus aureus, Escherichia coli, and Candida albicans were carried out. Pyrrolo[2,3 d]pyrimidines 3a-d, 7a,e, 11d exhibited excellent activity against C. albicans with MIC 0.31-0.62 mg/mL. These compounds displayed better antifungal activity than that of standard drug (fluconazole with MIC 1.5 mg/mL). Furthermore, pyrrolo[2,3-d]pyrimidines 3b,c, 7e exhibited the best activity against S. aureus with MIC 0.31 mg/mL, compared with the standard drug (ampicillin with MIC 0.62 mg/mL). The rest of the compounds were found to be inactive against bacteria and fungi. PMID- 20828886 TI - Synthesis and antitubercular activities of substituted benzoic acid N' (substituted benzylidene/furan-2-ylmethylene)-N-(pyridine-3-carbonyl)-hydrazides. AB - A series of benzoic acid hydrazones and its nicotinyl derivatives (1-10) were prepared and evaluated for their antitubercular activity towards a strain of Mycobacterium tuberculosis (MTB). The structures of newly synthesized compounds were confirmed by infrared (IR) and 1H-nuclear magnetic resonance (NMR) spectral data and elemental analysis. The in vitro antitubercular activity of synthesized compounds against MTB was carried out in Middlebrook 7H11agar medium supplemented with OADC by agar dilution method. The antitubercular activity results indicated that nicotinic acid N-(3,5-dinitro-benzoyl)-N'-(4-methoxy-benzylidene)-hydrazide (1) is the most potent among the synthesized compounds with MIC of 3.5*10(-3) MUM. PMID- 20828887 TI - Synthesis and biological evaluation of novel 10-benzyl-substituted 4,5-dichloro 10H-anthracen-9-ones as inhibitors of keratinocyte hyperproliferation. AB - A series of 10-substituted 4,5-dichloro-10H-anthracen-9-ones were synthesized in the search for novel agents against keratinocyte hyperproliferation. The antiproliferative activity of these novel anthrones was evaluated using the human keratinocyte line HaCaT as the primary test system. Structure-activity relationships with respect to the nature and position of the substituents at the benzyl moiety were studied, with a 3-hydroxy-4-methoxy-substitution pattern being the most potent (IC(50) = 0.7 MUM) and comparable to the potency of the antipsoriatic anthralin. In contrast to anthralin, inhibition of keratinocyte hyperproliferation was not mediated by damage to the keratinocyte membrane, as the activity of lactate dehydrogenase released from the cytoplasm was in the control range. These findings may be rationalized as a benefit of the ineffectiveness of the novel anthrones to interact with the free radical 2,2 diphenyl-1-picrylhydrazyl. PMID- 20828888 TI - Synthesis and biological evaluation of some 1,3,4-oxadiazole derivatives. AB - The acid hydrazides (2) derived from ibuprofen and 4-methylthiophenyl acetic acids have been subjected to cyclization with carbon disulphide under basic conditions to yield 1,3,4-oxadiazol-2-thiones (3) which on aminomethylation with formaldehyde and secondary amines afforded a series of Mannich bases (4 and 5). Purity of the compounds has been confirmed by TLC. Structures of these compounds were established on the basis of elemental analyses and spectral studies. The newly synthesized compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antimicrobial activities. PMID- 20828889 TI - Synthesis, antioxidant activities and urease inhibition of some new 1,2,4 triazole and 1,3,4-thiadiazole derivatives. AB - New series of 4,5-disubstituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (8a-j) and 2,5-disubstituted-1,3,4-thiadiazoles (9a-h) were synthesized by dehydrative cyclization of hydrazinecarbothioamide derivatives (7a-k) by refluxing in 4N aqueous sodium hydroxide and by overnight stirring with polyphosphoric acid, respectively. The structures of the newly synthesized compounds were characterized by IR, (1)H NMR, (13)C NMR, elemental analysis and mass spectroscopic studies and the synthesized compounds were screened for their antioxidant and urease inhibition activities. N-(2,4-Dimethylphenyl)-5-(4 nitrophenyl)-1,3,4-thiadiazol-2-amine (9h) showed excellent antioxidant activity more than the standard drug whereas 4-(2,4-dimethylphenyl)-5-(3-nitrophenyl)-2,4 dihydro-3H-1,2,4-triazole-3-thione (8d) and 4-(2,3-dimethylphenyl)-5-phenyl-2,4 dihydro-3H-1,2,4-triazole-3-thione (8e) exhibited potent urease inhibitory activities. PMID- 20828890 TI - Studies on quinones. Part 46. Synthesis and in vitro antitumor evaluation of aminopyrimidoisoquinolinequinones. AB - In the search of structure-activity relationship studies and to explore the antitumor effect associated with the pyrimidoisoquinolinequinone scaffold, several diversily substituted 8-aminopyrimido[4,5-c]isoquinolinequinones were regioselectively synthesized. Variation in the structure of the nitrogen substituent bonded to the 8-position of the pyrimidoisoquinolinequinone system led to a set of alkylamino-, phenylamino- and alkyphenylamino derivatives. The cytotoxic activity of the aminoquinone derivatives was evaluated in vitro using the MTT colorimetric method against one normal cell line (MRC-5 lung fibroblasts) and four human cancer cell lines (AGS human gastric adenocarcinoma; SK-MES-1 human lung cancer cells, and J82 human bladder carcinoma; HL-60 human leukemia) in 72-h drug exposure assays. Among the series, five compounds exhibited interesting antitumor activity against AGS human gastric adenocarcinoma and human lung cancer cells. The SAR studies revealed that both the nature of the nitrogen substituent into the quinone ring and the methyl group at the 6-position play key roles in the antitumor activity. PMID- 20828891 TI - [Cyclopentadienyl]metalcarbonyl complexes of acetylsalicylic acid as neo anticancer agents. AB - [(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of the nonsteroidal anti-inflammatory drug aspirin((r)) (ASS), demonstrated high cytotoxic potential against various tumor cells. The [acetylene]Co(2)(CO)(6) cluster strongly increased the biological effects compared to aspirin((r)). In this study we evaluated the use of [cyclopentadienyl]metalcarbonyl as cytotoxic moiety with a broader series of metals: molybdenum, manganese, cobalt and rhodium. All compounds were tested for cytotoxicity against breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines. Their COX-1 and COX-2 inhibitory effects were evaluated at isolated isoenzymes. Additionally, the influence on the level of the major COX metabolite prostaglandin E(2) (PGE(2)) was quantified in MDA-MB-231 breast cancer cells. Whereas the pure ligands or ASS did not show any cytotoxic effect, all metal complexes inhibited the tumor cell growth. The inhibitory effects at COX-1 and COX-2 enzymes were low. Only the Prop-Cp-ASS-Rh complex (10 MUM) caused an important inhibition of COX-1 by 60% and COX-2 by 30%. ASS showed at the same concentration only a marginal repression of COX-1 activity (30%) and no effect on COX-2. PMID- 20828892 TI - [Dupuytren's contracture: percutaneous needle aponeurotomy is an alternative to surgery]. AB - Dupuytren's contracture is a retractile fibrosis of the superficial palmar aponeurosis of the hand, resulting in a progressive and fixed flexion of the fingers that may result in severe limitation of hand function. It affects several millions of people in Europe and North America. Risk factors are genetic and sometimes related to mellitus diabetes. There is no spontaneous remission. Until recently, surgery was the only treatment, but now needle aponeurotomy emerges as a therapeutic alternative. It should be performed as first line treatment by a trained practitioner. Short and long-term results of needle aponeurotomy appear identical to those of surgery, with milder complications. It is indicated in palmar, palmo-digital, as well as in strictly digital forms of the disorder. The "table-test" is used to assess the loss of extension of the digit and to select the indication to needle aponeurotomy. A medico-surgical consensus should define the optimum treatment strategy in this affection. PMID- 20828893 TI - [Bullous lesions]. PMID- 20828894 TI - Mandibular fractures that have healed are not weakened permanently: series of nine patients who sustained mandibular fractures at different sites on two separate occasions. AB - Some patients are concerned that after satisfactory healing of a mandibular fracture the jaw will be weaker than it was before the injury, and will break readily at the same site after relatively minor injury. We aimed to find out if these concerns have any basis, and report the pattern of fracture in a series of nine patients who had sustained fractures of the jaw on two separate occasions. All fractures were at different sites from the original ones, and in only one case was the fracture adjacent to plates that had been placed previously. Once a mandibular fracture has healed, the bone at the fracture site is not obviously weaker from a clinical perspective than it was before the injury. PMID- 20828895 TI - Bacterial contamination of autogenous bone collected by rongeur compared with that collected by bone filter during implant surgery. AB - The aim was to compare the degree of microbial contamination of autogenous bone collected by a bone filter with that of autogenous bone harvested by a rongeur during implant surgery. Thirty healthy patients had dental implants inserted. A strict aspiration protocol was used during the operation to collect particulate bone with minimal risk of contamination by oral flora. A fragment of bone (mainly from the tuberosity) was also harvested with a rongeur. Samples from both groups were sent to the laboratory for the microbes to be counted. All samples yielded viable micro-organisms. There was no significant difference between the number of aerobes in the bone filter and those in the bone fragment group (p=0.9). However, there were significantly more anaerobes in the bone filter group than in the bone fragment group. There were significantly more micro-organisms (both aerobes and anaerobes) in the bone filter group than the bone fragment group (p=0.0001). Even with the use of a stringent aspiration protocol the degree of bacterial contamination was significantly higher in collected bone debris than in bone harvested by rongeur during implant surgery. PMID- 20828896 TI - Surgical navigation in cranio-maxillofacial surgery: an evaluation on a child with a cranio-facio-orbital tumour. AB - Surgical navigation, though well-established, is often associated with extra effort for both patient and surgeon, and with additional exposure to radiation as a result of the necessary extra imaging. Osteoblastoma is a benign bone tumour, malignant transformation of which is rare but possible, and so resection is indicated. The orbit with surrounding structures is a challenging region for accurate three-dimensional reconstruction. A virtual plan based on the patient's mirrored anatomy realised by intraoperative navigation can assist in achieving perfect results. An 8-year-old boy presented with a huge osteoblastoma of the frontal and temporal skull. The tumour had extracranial and intracranial parts, and reached into the orbital roof and the sphenoid and ethmoid bones. The ethmoid sinus was involved, the eye was displaced, and he had functional problems. Virtual planning and navigation were prepared without the need for any additional imaging. The tumour was resected through a coronal approach, and immediately reconstructed with an autologous calvarial split graft, designed and positioned under navigation with a preoperative plan that was based on the mirrored healthy side. Surgical navigation based on a virtual plan can achieve symmetrical results, particularly when dealing with complex three-dimensional anatomy. Navigation does not necessarily mean additional procedures or imaging. We think that virtual planning and navigation are useful for selected cases. PMID- 20828897 TI - Intraoperative impaction of total knee replacements: an explicit finite-element analysis of principal stresses in ceramic vs. cobalt-chromium femoral components. AB - BACKGROUND: In connection with technological advances in the manufacturing of medical ceramics, a newly developed ceramic femoral component was introduced in total knee arthroplasty. We generated an explicit finite-element-model to calculate the stresses developed under the highly dynamic intraoperative impaction with regard to cobalt-chromium and ceramic implant material as well as application of a silicone cover in order to reduce stress. METHODS: The impaction was calculated with the hammer hitting the backside of the impactor at previously measured initial velocities. Subsequently the impactor, consisting of a steel handhold and a polyoxymethylene head, hit the femoral component. Instead of modelling femoral bone, the implant was mounted on four spring elements with spring constants previously determined in an experimental impaction model. The maximum principal stresses in the implants were evaluated at 8000 increments during the first 4 ms of impact. FINDINGS: The ceramic implant showed principal stresses 10% to 48% higher than the cobalt chromium femoral component. The simulation of a 5mm thick silicone layer between the impactor and the femoral component showed a strong decrease of vibration resulting in a reduction of 54% to 68% of the maximum stress amounts. The calculated amounts of principal stress were beneath the ultimate bending strengths of each material. INTERPRETATION: Based on the results, intraoperative fracture of femoral components in total knee replacement may not be caused solely by impaction, but also by contributing geometrical factors such as inadequate preparation of the distal femur. In order to minimize the influence of impaction related stress peaks we recommend limiting the velocity as well as the weight of the impaction hammer when inserting femoral components. The silicone cover seems to deliver a strong decrease of implant stress and should be considered in surgery technique in the future. PMID- 20828898 TI - Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma. AB - The treatment of patients with relapsed and refractory Hodgkin lymphoma (HL), especially those who relapse after autologous stem cell transplantation, remains challenging. Patients with HL whose disease relapses after stem cell transplantation are rarely cured with current treatment modalities, and have a median survival of less than 3 years. Since no new drugs have been approved by the FDA for HL in more than three decades, there is a clear unmet medical need for drug development for this patient population. New treatment strategies that are based on targeting oncogenic signaling pathways are currently explored. This review will focus on emerging new treatment modalities that are currently under investigation for patients with relapsed classical HL. PMID- 20828899 TI - Nitrogen deposition and its ecological impact in China: an overview. AB - Nitrogen (N) deposition is an important component in the global N cycle that has induced large impacts on the health and services of terrestrial and aquatic ecosystems worldwide. Anthropogenic reactive N (N(r)) emissions to the atmosphere have increased dramatically in China due to rapid agricultural, industrial and urban development. Therefore increasing N deposition in China and its ecological impacts are of great concern since the 1980s. This paper synthesizes the data from various published papers to assess the status of the anthropogenic N(r) emissions and N deposition as well as their impacts on different ecosystems, including empirical critical loads for different ecosystems. Research challenges and policy implications on atmospheric N pollution and deposition are also discussed. China urgently needs to establish national networks for N deposition monitoring and cross-site N addition experiments in grasslands, forests and aquatic ecosystems. Critical loads and modeling tools will be further used in N(r) regulation. PMID- 20828900 TI - The pH-dependent adsorption of tributyltin to charcoals and soot. AB - Widespread use of tributyltin (TBT) poses a serious environmental problem. Adsorption by black carbon (BC) may strongly affect its behavior. The adsorption of TBT to well characterized soot and two charcoals with specific surface area in the range of 62-111m(2)g(-1) have been investigated with main focus on pH effects. The charcoals but not soot possess acidic functional groups. TBT adsorption reaches maximum at pH 6-7 for charcoals, and at pH>6 for soot. Soot has between 1.5 and 15 times higher adsorption density (0.09-1.77MUmolm(-2)) than charcoals, but charcoals show up to 17 times higher sorption affinities than soot. TBT adsorption is successfully described by a new pH-dependent dual Langmuir model considering electrostatic and hydrophobic adsorption, and pH effects on TBT speciation and BC surface charge. It is inferred that strong sorption of the TBTOH species to BC may affect TBT toxicity. PMID- 20828901 TI - Assessment of pollution in road runoff using a Bufo viridis biological assay. AB - Road runoff is a major source of environmental pollution, significantly threatening nearby aquatic habitats. Chemical analyses indicate high pollutant concentrations in the road's "first flush", but bioassays are more advantageous for addressing the cumulative effects of the numerous pollutants within the runoff. We used Bufo viridis embryos and larvae to assess the toxicity of road runoff from two major highways in Israel. We show, for the first time, that exposure to midseason runoff not only has an adverse effect on growth and development rates of B. viridis larvae but can also lead to increased rates of morphological deformations. Seasonal first flushes, despite having higher metal concentrations, did not adversely affect the toad larvae, apparently due to a counter effect of organic matter that potentially served as a supplementary energy resource. Road runoff can be a major cause for a qualitative decrease in the quality of aquatic habitats threatening amphibians in Israel. PMID- 20828902 TI - 2,6-Dichlorobenzamide (BAM) herbicide mineralisation by Aminobacter sp. MSH1 during starvation depends on a subpopulation of intact cells maintaining vital membrane functions. AB - Mineralisation capability was studied in the 2,6-dichlorobenzamide (BAM) degrading Aminobacter sp. MSH1 under growth-arrested conditions. Cells were starved in mineral salts (MS) solution or groundwater before (14)C-labelled BAM (0.1mM) was added. Cell physiology was monitored with a panel of vitality stains combined with flow cytometry to differentiate intact, depolarised and dead cells. Cells starved for up to 3 weeks in MS solution showed immediate growth-linked mineralisation after BAM amendment while a lag-phase was seen after 8 weeks of starvation. In contrast, cells amended with BAM in natural groundwater showed BAM mineralisation but no growth. The cell-specific mineralisation rate was always comparable (10(-16)molCintact cell(-1)day(-1)) independent of media, growth, or starvation period after BAM amendment; lower rates were only observed as BAM concentration decreased. MSH1 seems useful for bioremediation and should be optimised to maintain an intact cell subpopulation as this seems to be the key parameter for successful mineralisation. PMID- 20828903 TI - Toxicity of tire wear particle leachate to the marine macroalga, Ulva lactuca. AB - Tire wear particles filed from the treads of end-of-life vehicle tires have been added to sea water to examine the release of Zn and the toxicity of the resulting leachate and dilutions thereof to the marine macroalga, Ulva lactuca. Zinc release appeared to be diffusion-controlled, with a conditional rate constant of 5.4 MUg[L(h)(1/2)](-1), and about 1.6% of total Zn was released after 120 h incubation. Exposure to increasing concentrations of leachate resulted in a non linear reduction in the efficiency of photochemical energy conversion of U. lactuca and, with the exception of the undiluted leachate, increasing accumulation of Zn. Phototoxicity was significantly lower on exposure to equivalent concentrations of Zn added as Zn(NO(3))(2), suggesting that organic components of leachate are largely responsible for the overall toxicity to the alga. Given the ubiquity and abundance of TWP in urban coastal sediments, the generation, biogeochemistry and toxicity of tire leachate in the marine setting merit further attention. PMID- 20828904 TI - Integration of biological responses from a suite of bioassays for the Venice Lagoon (Italy) through sediment toxicity index - part A: development and comparison of two methodological approaches. AB - Marine and coastal quality assessment, based on test batteries involving a wide array of endpoints, organisms and test matrices, needs for setting up toxicity indices that integrate multiple toxicological measures for decision-making processes and that classify the continuous toxicity response into discrete categories according to the European Water Framework Directive. Two toxicity indices were developed for the lagoon environment such as the Venice Lagoon. Stepwise procedure included: the construction of a database that identified test matrix pairs (indicators); the selection of a minimum number of ecotoxicological indicators, called toxicological core metrics (CMs-tox) on the basis of specific criteria; the development of toxicity scores for each CM-tox; the integration of the CMs-tox into two indices, the Toxicity Effect Index (TEI), based on the transformation of Toxic Unit (TU) data that were integrated as logarithmic sum, and the Weighted Average Toxicity Index (WATI), starting from toxicity classes integrated as weighted mean. Results from the indices are compared; advantages and drawbacks of both approaches are discussed. PMID- 20828905 TI - Prioritizing research for trace pollutants and emerging contaminants in the freshwater environment. AB - Organic chemicals have been detected at trace concentrations in the freshwater environment for decades. Though the term trace pollutant indicates low concentrations normally in the nanogram or microgram per liter range, many of these pollutants can exceed an acceptable daily intake (ADI) for humans. Trace pollutants referred to as emerging contaminants (ECs) have recently been detected in the freshwater environment and may have adverse human health effects. Analytical techniques continue to improve; therefore, the number and frequency of detections of ECs are increasing. It is difficult for regulators to restrict use of pollutants that are a human health hazard; scientists to improve treatment techniques for higher priority pollutants; and the public to modify consumption patterns due to the vast number of ECs and the breadth of literature on the occurrence, use, and toxicity. Hence, this paper examines literature containing occurrence and toxicity data for three broad classes of trace pollutants and ECs (industrials, pesticides, and pharmaceuticals and personal care products (PPCPs)), and assesses the relevance of 71 individual compounds. The evaluation indicates that widely used industrials (BPF) and PPCPs (AHTN, HHCB, ibuprofen, and estriol) occur frequently in samples from the freshwater environment but toxicity data were not available; thus, it is important to establish their ADI. Other widely used industrials (BDE-47, BDE-99) and pesticides (benomyl, carbendazim, aldrin, endrin, ethion, malathion, biphenthrin, and cypermethrin) have established ADI values but occurrence in the freshwater environment was not well documented. The highest priority pollutants for regulation and treatment should include industrials (PFOA, PFOS and DEHP), pesticides (diazinon, methoxychlor, and dieldrin), and PPCPs (EE2, carbamazepine, betaE2, DEET, triclosan, acetaminophen, and E1) because they occur frequently in the freshwater environment and pose a human health hazard at environmental concentrations. PMID- 20828906 TI - A physiologic-based approach to the evaluation of a patient with hypokalemia. AB - Hypokalemia is a common electrolyte disorder. Transient causes of hypokalemia are due to cell shift, whereas sustained hypokalemia is caused by either inadequate intake or excessive potassium loss. Evaluation of the intake, distribution, and excretion of potassium should include the following: (1) a careful history, including use of drugs, medications, and the presence of vomiting or diarrhea; (2) physical examination, including orthostatic changes in blood pressure and heart rate; and (3) measurement of urine and plasma electrolytes. Urinary potassium wasting is caused by pathophysiologic conditions that couple increased distal sodium delivery with increased plasma aldosterone levels or aldosterone like effects. If urinary potassium loss is identified, the next step is to determine whether the loss is caused by a primary increase in distal delivery of sodium or a primary increase in mineralocorticoid level. A primary increase in distal delivery should be associated with volume depletion, whereas a primary increase in mineralocorticoid level generally is associated with volume expansion and hypertension. In patients with a primary increase in mineralocorticoid activity, it is useful to measure plasma renin activity and plasma aldosterone levels. Complications of hypokalemia include muscle weakness, rhabdomyolysis, cardiac arrhythmias, impaired urinary concentrating ability, and glucose intolerance. PMID- 20828907 TI - The changing role of agriculture in tobacco control policymaking: a South Carolina case study. AB - To document the behavior of tobacco manufacturers' agricultural third-party allies in South Carolina from the 1970s through 2009, we analyzed news reports, public documents and internal tobacco industry documents and conducted interviews with knowledgeable individuals. We found that agriculture-based interest groups (the Farm Bureau), elected state agency heads (Commissioners of Agriculture) and tobacco-area legislators acted as an iron triangle containing strong third-party allies of tobacco manufacturers from the 1970s through the 1990 s. The Farm Bureau and Commissioners of Agriculture reacted to national-level changes in the tobacco leaf market structure by shifting towards a neutral position on tobacco control, while some tobacco-area legislators remained manufacturer allies (Sullivan, Barnes, & Glantz, 2009). This shift was reinforced by public health outreach and successes, which were in turn facilitated by the lack of opposition from agricultural groups. We conclude that public health advocates in tobacco growing states should use the pragmatic shift of agricultural groups' position to challenge remaining third-party manufacturer alliances and agriculture-based opposition to tobacco control policies. PMID- 20828908 TI - Configuring users of cholesterol lowering foods: a review of biomedical discourse. AB - This paper explores how users of foods containing phytosterols are 'configured' within biomedical research and writing on these substances. A growing range of such foods have been launched and marketed on the basis that they actively lower cholesterol. They are among the most prominent examples of a set of foods designated as 'functional foods'. The paper is based on an analysis of biomedical journal articles which address the use of phytosterols as a cholesterol lowering agent in humans. These include both original research papers and commentaries such as review articles, letters, editorials, news items and professional guidelines. My analysis suggests that users are constituted variously as autonomous, self-motivated consumers, patients and publics needing advice, people resistant to pill use, and practitioners looking for something to offer their patients. I characterise the imagined uses of the products as healthy/holistic, lazy/busy/contemporary, and incompetent use. These varying portrayals of users and their use of these food products entail different ways of understanding health identities and different allocations of responsibilities between the technology, user and health care professionals. I conclude that, while experts and regulators may attempt to configure 'correct' uses of these products, relatively little is known about the rationales and practices of actual users. PMID- 20828909 TI - Mandibular body lengthening by distraction osteogenesis for correction of skeletal class II problems with an impacted premolar. PMID- 20828910 TI - The accuracy of virtual surgical planning in free fibula mandibular reconstruction: comparison of planned and final results. AB - PURPOSE: The concept of virtual surgery uses surgical simulation rather than relying exclusively on intraoperative manual approximation of facial reconstruction. The purpose of this study was to evaluate the degree to which surgical outcomes in free fibula mandibular reconstructions planned with virtual surgery and carried out with prefabricated surgical plate templates and cutting guides correlated to the virtual surgical plan in a series of 11 patients. MATERIALS AND METHODS: This retrospective study evaluated 11 consecutive patients (6 males and 5 females) with an average age of 50.73 years (range, 23-72 years) who required mandibular reconstruction for aggressive benign or malignant disease with a free fibula osseomyocutaneous flap at Emory University Hospital (Atlanta, GA) between January 1, 2009 and December 31, 2009. In each case, a high resolution helical computed tomography (CT) scan of the maxillofacial region and mandible was obtained prior to surgery. The CT data was sent on a CD to a modeling company (Medical Modeling Inc, Golden, CO). The scans were then converted into 3-dimensional models of the maxillofacial skeleton utilizing both automatic and manual segmentation techniques in the SurgiCase CMF software (Materialise NV, Leuven, Belgium). A virtual surgery planning session was held via a Web meeting between the surgeons and the modeling company, at which the resection planes of the mandible, positioning of the plate, and fibula lengths/osteotomy angles were established. The surgery was then carried out using prefabricated cutting guides and manual bending of a reconstruction plate using a prefabricated plate template. A postoperative CT scan of each patient was obtained within the first 7 postoperative days on the same scanner. Three dimensional computer models of the final reconstruction were obtained for comparison with the preoperative virtual plan. To make the desired comparisons, the 3-dimensional objects representing the postoperative surgical outcome were superimposed onto the preoperative virtual plan using manual alignment techniques. These objects were then compared by 1-to-1 magnification for measurements of fibular bone volume, location of mandibular osteotomies, location of fibular osteotomies, plate contour, plate position on fibula, and plate position on mandible. Comparison was made between the virtual and final plates with regard to contour and position through superimposition overlays of the 3 dimensional models that are registered in the same coordinate system. RESULTS: A total of 19 mandibular osteotomies were carried out. The mean distance of the actual mandibular osteotomy when compared to the virtual mandibular osteotomy was 2.00 +/- 1.12 mm. The mean volume determined by the software program of the 11 virtual fibulas was 13,669.45 +/- 3,874.15 mm(3) (range, 9,568 to 22,860 mm(3)), and the mean volume of the 11 actual postoperative fibulas was 12,361.09 +/- 4,161.80 mm(3) (range, 7,142 to 22,294 mm(3)). The mean percentage volumes of the actual postoperative fibula compared to the planned fibula were 90.93 +/- 18.03%. A total of 22 fibular segments were involved in the study created by 44 separate fibula osteotomies. The mean distance of the actual fibula osteotomy when compared to the virtual fibula osteotomy was 1.30 +/- 0.59 mm. The mean percentage overlap of the actual plate to the virtual plate was 58.73% +/- 8.96%. CONCLUSIONS: Virtual surgical planning appears to have a positive impact on the reconstruction of major mandibular defects through the provision of accuracy difficult to achieve through manual placement of the graft, even in the hands of experienced surgeons. Although a reasonably high level of accuracy was achieved in the mandibular and fibula osteotomies through use of the surgical cutting guides, the limited ability to correctly contour the plate by hand to replicate the plate template is reflected in our findings. PMID- 20828911 TI - Hyperplasia of the mandibular condyle: clinical, histopathologic, and treatment considerations in a series of 36 patients. AB - PURPOSE: Mandibular condylar hyperplasia (CH) is a rare entity that causes overdevelopment of the mandible, creating functional and esthetic problems. The aim of this article was to describe demographic and clinical characteristics of CH, analyze histopathologic features and their association with scintigraphic and clinical findings, and evaluate esthetic and functional results after treatment by high condylectomy during the active phase. MATERIALS AND METHODS: This retrospective study included 36 patients whose condyles were removed because of excessive unilateral growth resulting in facial asymmetry and occlusal disturbance. Of the 36 patients, 13 had had symptoms related to the temporomandibular joint, such as pain or clicking. In all the cases, high condylectomy was performed, and surgical specimens were sent for histologic examination and divided into 4 histologic types as described by Slootweg and Muller. Statistical analysis was performed by use of R software (version 2.10.1; R Foundation for Statistical Computing, Vienna, Austria) and SPSS software for Windows (version 15.0; SPSS, Chicago, IL) to evaluate our results. A chi(2) test was carried out to assess the possible association between gender and involved side. The association of histologic appearance with clinical symptoms was estimated by use of the Fisher exact test. An analysis of variance test was performed to evaluate a possible association between patient age and histologic type according to the Slootweg and Muller classification and between histologic type and uptake on bone single photon emission computed tomography (SPECT). RESULTS: We could not find a relationship between histologic type and uptake of the affected condyle on bone SPECT or between age and histologic type. However, our statistical analysis revealed an association between histologic appearance and the presence of joint symptoms (P = .0049). Clinically, occlusion and facial symmetry improved in all patients postoperatively, and no recurrence was noted in any patient. Six patients required secondary surgery. CONCLUSION: We could not find any significant association between age and histologic type or between bone SPECT and histologic type. However, a significant association between histologic type and temporomandibular joint symptoms was observed. High condylectomy combined with orthodontics achieved optimal esthetic and functional results and constituted the unique and definitive treatment in 30 of 36 patients. PMID- 20828912 TI - [Letter to the editor of Annales de chirurgie plastique esthetique]. PMID- 20828913 TI - Hypokalemia during the cooling phase of therapeutic hypothermia and its impact on arrhythmogenesis. AB - BACKGROUND: Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurological outcome in patients resuscitated from out-of hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) as the presenting rhythm. This approach entails the management of physiological variables which fall outside the realm of conventional critical cardiac care. Management of serum potassium fluxes remains pivotal in the avoidance of lethal ventricular arrhythmia. METHODS: We retrospectively analyzed potassium variability with TH and performed correlative analysis of QT intervals and the incidence of ventricular arrhythmia. RESULTS: We enrolled 94 sequential patients with OHCA, and serum potassium was followed intensively. The average initial potassium value was 3.9+/-0.7 mmol l(-1) and decreased to a nadir of 3.2+/-0.7 mmol l(-1) at 10 h after initiation of cooling (p<0.001). Eleven patients developed sustained polymorphic ventricular tachycardia (PVT) with eight of these occurring during the cooling phase. The corrected QT interval prolonged in relation to the development of hypothermia (p<0.001). Hypokalemia was significantly associated with the development of PVT (p=0.002), with this arrhythmia being most likely to develop in patients with serum potassium values of less than 2.5 mmol l(-1) (p=0.002). Rebound hyperkalemia did not reach concerning levels (maximum 4.26+/-0.8 mmol l(-1) at 40 h) and was not associated with the occurrence of ventricular arrhythmia. Furthermore, repletion of serum potassium did not correlate with the development of ventricular arrhythmia. CONCLUSIONS: Therapeutic hypothermia is associated with a significant decline in serum potassium during cooling. Hypothermic core temperatures do not appear to protect against ventricular arrhythmia in the context of severe hypokalemia and cautious supplementation to maintain potassium at 3.0 mmol l(-1) appears to be both safe and effective. PMID- 20828914 TI - Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. AB - AIM: The aim of this investigation was to estimate and contrast the global incidence and outcome of out-of-hospital cardiac arrest (OHCA) to provide a better understanding of the variability in risk and survival of OHCA. METHODS: We conducted a review of published English-language articles about incidence of OHCA, available through MEDLINE and EmBase. For studies including adult patients and both adult and paediatric patients, we used Utstein data reporting guidelines to calculate, summarize and compare incidences per 100,000 person-years of attended OHCAs, treated OHCAs, treated OHCAs with a cardiac cause, treated OHCA with ventricular fibrillation (VF), and survival-to-hospital discharge rates following OHCA. RESULTS: Sixty-seven studies from Europe, North America, Asia or Australia met inclusion criteria. The weighted incidence estimate was significantly higher in studies including adults than in those including adults and paediatrics for treated OHCAs (62.3 vs 34.7; P<0.001); and for treated OHCAs with a cardiac cause (54.6 vs 40.8; P=0.004). Neither survival to discharge rates nor VF survival to discharge rates differed statistically significant among studies. The incidence of treated OHCAs was higher in North America (54.6) than in Europe (35.0), Asia (28.3), and Australia (44.0) (P<0.001). In Asia, the percentage of VF and survival to discharge rates were lower (11% and 2%, respectively) than those in Europe (35% and 9%, respectively), North America (28% and 6%, respectively), or Australia (40% and 11%, respectively) (P<0.001, P<0.001). CONCLUSIONS: OHCA incidence and outcome varies greatly around the globe. A better understanding of the variability is fundamental to improving OHCA prevention and resuscitation. PMID- 20828915 TI - Non-syndromic malformations of the central nervous system in twin pregnancies: diagnostic and other clinical features of importance. AB - OBJECTIVE: The incidence of central nervous system malformations is higher among twins. Our aim was to summarize information about these malformations in twin pregnancies. STUDY DESIGN: Based on a sample originating from the biggest genetic centre in Hungary between January 1990 and December 2008, we examined the data of 42 twin pregnancies associated with non-syndromic malformations of the central nervous system. RESULTS: The involvement of monozygotic fetuses and dizygotic ones of the same gender was found to be 62.5%. Usually only one of the fetuses was affected (57.1%), while the other one was healthy. The male-to-female ratio was 0.75. Identical and fraternal twins were found in 68.4% and 31.6% of the cases, respectively. In the pregnancies of our study the malformation was diagnosed before the 24th gestational week in 90% of the cases. Polyhydramnios (54.8%) was the most commonly associated non-central nervous system malformation. CONCLUSION: Our findings suggest that, in addition to placentation and gestational age, the position of the affected fetus with relation to the uterine orifice is of great importance in determining whether selective abortion is an option in deciding about the outcome of pregnancies affected by craniospinal malformation. PMID- 20828916 TI - A resilience-based approach for comparing expert preferences across two large scale coastal management programs. AB - This report proposes a method for assessing resilience-building components in coastal social-ecological systems. Using the proposed model, the preferences of experts in Masan Bay (South Korea) and Puget Sound (USA) are compared. A total of 30 management objectives were determined and used to build a hierarchic tree designed using the principles of the Analytic Hierarchy Process (AHP). Surveys were performed with 35 Puget Sound experts using face-to-face interviews and with 28 Masan Bay experts by mail. The results demonstrate that the legal objective, which enables legislation, was the highest preferred component in both regions. The knowledge translation variable was also given a high preference score in both regions. An analysis of variance (ANOVA) showed that the Puget Sound experts significantly favored attention to education, habitat restoration and species protection objectives in comparison to the Masan Bay experts. The Masan Bay experts placed greater emphasis on legislation and the type of institutional design than did the Puget Sound experts. Using cluster analysis, four distinct groups of respondents were independently identified in Puget Sound and three groups were identified in Masan Bay. One unique subgroup in the Puget Sound experts group, which was characterized by its high preferences for habitat restoration and species protection, was not observed in Masan Bay. Demographic variables (length of career and role in coastal issue) failed to account for the differences in groupings and preferences in either region, except for the variable 'favoring information source' in the Puget Sound group. This finding implies that the demographic information was not related to differences in group opinions in both regions. The analysis framework presented here was effective in identifying expert preferences regarding the overall structure and emphasis in coastal management programs. Thus, this framework can be applied towards coastal policy development. PMID- 20828917 TI - Habitat evaluation of wild Amur tiger (Panthera tigris altaica) and conservation priority setting in north-eastern China. AB - The Amur Tiger (Panthera tigris altaica) is one of the world's most endangered species. Recently, habitat fragmentation, food scarcity and human hunting have drastically reduced the population size and distribution areas of Amur tigers in the wild, leaving them on the verge of extinction. Presently, they are only found in the north-eastern part of China. In this study, we developed a reference framework using methods and technologies of analytic hierarchy process (AHP), remote sensing (RS), geographic information system (GIS), GAP analysis and Natural Break (Jenks) classification to evaluate the habitat and to set the conservation priorities for Amur tigers in eastern areas of Heilongjiang and Jilin Provinces of northeast China. We proposed a Habitat Suitability Index (HSI) incorporating 7 factors covering natural conditions and human disturbance. Based on the HSI values, the suitability was classified into five levels from the most to not suitable. Finally, according to results of GAP analysis, we identified six conservation priorities and designed a conservation landscape incorporating four new nature reserves, enlarging two existing ones, and creating four linkages for Amur tigers in northeast China. The case study showed that the core habitats (the most suitable and highly suitable habitats) identified for Amur tigers covered 35,547 km(2), accounting for approximately 26.71% of the total study area (1,33,093 km(2)). However, existing nature reserves protected only (7124 km(2) or) 20.04% of the identified core habitats. Thus, enlargement of current reserves is necessary and urgent for the tiger's conservation and restoration. Moreover, the establishment of wildlife corridors linking core habitats will provide an efficient reserve network for tiger conservation to maintain the evolutionary potential of Amur tigers facing environmental changes. PMID- 20828918 TI - Laparoendoscopic single-site and natural orifice transluminal endoscopic surgery in urology: a critical analysis of the literature. AB - CONTEXT: Natural orifice transluminal endoscopic surgery (NOTES) and laparoendoscopic single-site surgery (LESS) have been developed to benefit patients by enabling surgeons to perform scarless surgery. OBJECTIVE: To summarize and critically analyze the available evidence on the current status and future perspectives of LESS and NOTES in urology. EVIDENCE ACQUISITION: A comprehensive electronic literature search was conducted in June 2010 using the Medline database to identify all publications relating to NOTES and LESS in urology. EVIDENCE SYNTHESIS: In urology, NOTES has been completed experimentally via transgastric, transvaginal, transcolonic, and transvesical routes. Initial clinical experience has shown that NOTES urologic surgery using currently available instruments is indeed possible. Nevertheless, because of the immaturity of the instrumentation, early cases have demanded high technical virtuosity. LESS can safely and effectively be performed in a variety of urologic settings. As clinical experience increases, expanding indications are expected to be documented and the efficacy of the procedure to improve. So far, the quality of evidence of all available studies remains low, mostly being small case series or case-control studies from selected centers. Thus, the only objective benefit of LESS remains the improved cosmetic outcome. Prospective, randomized studies are largely awaited to determine which LESS procedures will be established and which are unlikely to stand the test of time. Technology advances hold promise to minimize the challenging technical nature of scarless surgery. In this respect, robotics is likely to drive a major paradigm shift in the development of LESS and NOTES. CONCLUSIONS: NOTES is still an investigational approach in urology. LESS has proven to be immediately applicable in the clinical field, being safe and feasible in the hands of experienced laparoscopic surgeons. Development of instrumentation and application of robotic technology are expected to define the actual role of these techniques in minimally invasive urologic surgery. PMID- 20828919 TI - Integrating surgery with targeted therapies for renal cell carcinoma: current evidence and ongoing trials. AB - CONTEXT: Surgical intervention is the primary treatment for early-stage renal cell carcinoma (RCC), but alone it has limited benefit in patients with metastatic disease. The advent of targeted agents for RCC has improved the outcome in these patients, and there is increasing interest in exploring the efficacy and safety of these agents in combination with surgery in both early and advanced disease. OBJECTIVE: This article reviews approved and emerging targeted therapies for RCC and outlines the rationale and implications for combining these therapies with surgery. EVIDENCE ACQUISITION: A search of the literature, trial registries, and meeting proceedings was performed, and reports on surgery, receptor tyrosine kinase inhibitors, vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and cytokine adjuvant therapy relating to RCC were critically reviewed. EVIDENCE SYNTHESIS: Nephrectomy has been shown to improve overall survival in patients with metastatic RCC (mRCC) treated with interferon alpha. Combining targeted therapy with surgery has the potential to improve efficacy and tolerability relative to cytokine therapy and prospective studies are underway. In the localized setting, there is some evidence of tumor downsizing with neoadjuvant targeted therapy. The tolerability and safety of targeted agents used perioperatively must be considered, particularly in the adjuvant setting where chronic therapy is required to prevent recurrence or metastasis. Novel agents with greater specificity and improved safety profiles are under development and have the potential to enhance efficacy and minimize the risk of complications. CONCLUSIONS: For patients with mRCC, randomized controlled trials are ongoing to define the role and sequence of nephrectomy in combination with targeted therapy. Until data are available, nephrectomy remains part of the mRCC treatment algorithm for patients with good performance status and a resectable tumor. Targeted therapy to downsize large primary tumors in nonmetastatic disease is investigational, but the rate of surgically relevant down-staging and tumor shrinkage seen with the current generation of agents is limited. In patients with high-risk nonmetastatic disease, adjuvant therapy must be administered only in the context of the ongoing clinical trials since there are no data showing efficacy in this setting. PMID- 20828920 TI - Laparoscopic nephroureterectomy: is it always as good as open nephroureterectomy? PMID- 20828921 TI - New advances of sentinel node detection in penile carcinoma with clinical implications and a perspective on possible further research. PMID- 20828922 TI - Midline intracranial hyperdense epidermoid tumor radiologically masquerading a neurenteric cyst. PMID- 20828923 TI - Pathological considerations in the treatment of Parkinson's disease: more than just a wiring diagram. AB - Parkinson's disease (PD) represents a common but challenging condition in which an increasing number of therapeutic options have evolved over the course of the last 50 years. The introduction of dopaminergic therapies has dramatically improved outcomes but life expectancies remain significantly curtailed. Currently, all available treatment options are directed towards the amelioration of symptoms. However, it is hoped that a greater understanding of the distinctive pathology underlying PD might offer some novel therapeutic approaches. The identification of degeneration within the nigrostriatal tract as the most prominent pathological process in PD has led to the development of a number of therapies. However, despite initially good symptomatic control it has become clear that the longer-term use of these medications is associated with a number of debilitating motor complications. The management of these drug-related issues has necessitated a further tier of therapeutic options based largely on a greater understanding of the basal ganglia circuitry involved. Indeed, surgical interventions targeting these neural circuits have provided increased control of motor symptoms in patients with advanced disease, however, such techniques still fail to slow or reverse the disease. To this end, a number of novel approaches focussed on restoration or repair of the diseased brain have received increasing attention. Nevertheless, there are multiple symptoms that are unresponsive to any of these therapies, highlighting the involvement of other neurotransmitter systems and the complexities of the disease beyond the basal ganglia circuitry. An appreciation of the ongoing neurodegenerative processes at the core of PD and the burden of disease associated with them, emphasises the need for increased research into more effective and comprehensive treatment methodologies. PMID- 20828924 TI - Benzotriazole removal from water by Zn-Al-O binary metal oxide adsorbent: behavior, kinetics and mechanism. AB - In this study, a novel Zn-Al-O binary metal oxide adsorbent was prepared and used to remove the emerging polar contaminant benzotriazole from water. The adsorption behavior, kinetics and mechanism were systemically studied. Results showed that benzotriazole was rapidly and effectively adsorbed by the adsorbent. Instantaneous adsorption was observed under each studied condition, and the adsorption reached equilibrium within 30 min. High initial benzotriazole concentration enhanced the adsorption. The amount of absorbed benzotriazole increased with increasing adsorbent dosage, but decreased with increasing ionic strength. Solution pH had little effect on benzotriazole adsorption. The adsorption isotherm was consistent with S-type. Langmuir isotherm model fitted the equilibrium data better than Freundlich, Dubinin-Radushkevich and Temkin isotherm models. The maximum monolayer adsorptive capacity of benzotriazole with and without electrolytes was 7.30 mg g(-1) and 9.51 mg g(-1), respectively. Elovich and pseudo-second-order models were most suitable for describing the adsorption kinetics. Interactions between the surface sites of the adsorbent and benzotriazole may be a combination of electrostatic interaction, ion exchange and hydrogen bond. PMID- 20828925 TI - Experimental studies on removal of microcystin-LR by peat. AB - Cyanotoxins have caused worldwide concerns for their eclectic occurrence and toxic effects, which led to an intensive search of cost-effective techniques for their removal from contaminated waters. A range of biomaterials was tested for their efficacy to adsorb a potent cyanotoxin, microcystin-LR (MCLR). Among these sorbents, peat showed the maximum efficacy to sequester MCLR. The BET (Brunauer Emmett-Teller) surface area of peat was found to be 12.134 m(2)/g. The pH of the reaction media played a significant role in removal of MCLR; maximum adsorption occurred at pH 3. Kinetic studies showed that the adsorption of MCLR onto peat was a rapid process. The adsorption capacity (Q(max)) from the Langmuir model was found to be 255.7 MUg/g at pH 3. Among various desorption media studied, strong alkali (2N NaOH) showed highest desorption (94%). PMID- 20828926 TI - Kinetics of styrene biodegradation in synthetic wastewaters using an industrial activated sludge. AB - Kinetics of styrene biodegradation in synthetic wastewaters, containing either styrene or styrene together with ethanol, by an industrial activated sludge obtained from the wastewater treatment unit of a petrochemical complex was studied. The kinetic data could be fitted using the Haldane kinetic model. This model was previously used to predict kinetic data for biodegradation of styrene by pure or mixed microbial cultures isolated from biofilters, but the values of the model parameters reported in these studies was substantially different from that obtained for the industrial activated sludge. The presence of ethanol did not affect the kinetics of styrene biodegradation by the industrial activated sludge; however, it increased the rates of styrene biodegradation due to the resulting higher microbial growth rates. Styrene concentration was found to affect the specific growth rate in a manner similar to its effect on the styrene degradation rate. No lag phase was observed in styrene biodegradation by industrial activated sludge for styrene concentrations up to 100mg/L. Lag phase was observed for municipal activated sludge even at 50mg/L styrene concentration but the rate of styrene biodegradation after the lag phase was similar to that achieved by the industrial activated sludge. PMID- 20828927 TI - Electrochemical hydride generation atomic fluorescence spectrometry for detection of tin in canned foods using polyaniline-modified lead cathode. AB - An electrochemical hydride generation system with polyaniline-modified lead cathode was developed for tin determination by coupling with atomic fluorescence spectrometry. The tin fluorescence signal intensity was improved evidently as the polyaniline membrane could facilitate the transformation process from atomic tin to the SnH(4) and prevent the aggradation of Sn atom on Pb electrode surface. The effects of experimental parameters and interferences have been studied. The limit of detection (LOD) was 1.5 ng mL(-1) (3sigma) and the relative standard deviation (RSD) was 3.3% for 11 consecutive measurements of 50 ng mL(-1) Sn(IV) standard solution. PMID- 20828928 TI - Characterization of a bacterial strain capable of degrading DDT congeners and its use in bioremediation of contaminated soil. AB - A bacterial strain DDT-6 (D6) capable of utilizing dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane (DDD), and dichlorodiphenyldichloroethylene (DDE) (DDTs) as its sole carbon and energy source was isolated and identified as Sphingobacterium sp. The degradation of DDTs by strain D6 in mineral salt medium and in field soil was investigated. The half-lives of the degradation of DDTs increased with increasing concentration ranging from 1 to 50 mg L(-1). Favorable degradation conditions for DDTs by strain D6 were found to be pH 7.0 and 30 degrees C. The degradation of DDTs by strain D6 was found to be statistically significantly enhanced (p <= 0.05) by the addition of glucose. Based on the metabolites detected, a pathway was proposed for DDT degradation in which it undergoes dechlorination, hydrogenation, dioxygenation, decarboxylation, hydroxylation, and phenyl ring-cleavage reactions to complete the mineralization process. The addition of strain D6 into the contaminated soils was found to statistically significantly enhance (p <= 0.05) the degradation of DDTs. The results indicate that the isolate D6 can be used successfully for the removal or detoxification of residues of DDTs in contaminated soil. PMID- 20828929 TI - Effect of manure compost on the herbicide prometryne bioavailability to wheat plants. AB - Soil amendment with manure compost may influence environmental behaviors and bioavailability of toxic organic chemicals (e.g. pesticide and polycyclic aromatic hydrocarbons). Dynamic parameters like adsorption, kinetics, mobility and degradation of pesticides have been intensively investigated. However, the current methods to evaluate the ultimate real bioavailability of pesticides to crops using physiochemical or biological approaches are limited. In this study, we developed a set of comprehensive and cost-effective parameters relevant to crop response to prometryne (s-triazine herbicide) to assess the accumulation and genotoxicity of the pesticide. Wheat plants exposed to 8 mg kg(-1) prometryne for 10 d showed stunt growth, reduced chlorophyll content and damaged membrane lipid. Concomitant treatment with 5% pig manure compost (PMC) alleviated the toxic effect on the plant. Prometryne in soils was readily accumulated by wheat. However, such an accumulation was significantly inhibited by PMC application. Because excessively accumulated prometryne triggered oxidative damage to plants, the biochemical responses of several antioxidant enzymes along with their molecular expressions were determined. In most cases, the activities and transcriptional expression of the enzymes were activated upon the exposure to prometryne but the process was prevented by PMC application. The set of biological parameters tested in this study were very sensitive and cost effective, and therefore can be used to evaluate the degree of pesticide contamination to plants and other organisms. PMID- 20828930 TI - Photocatalytic degradation of methylene blue by TiO2-Cu thin films: theoretical and experimental study. AB - In this work the effect of doping concentration and depth profile of Cu atoms on the photocatalytic and surface properties of TiO(2) films were studied. TiO(2) films of about 200 nm thickness were deposited on glass substrates on which a thin Cu layer (5 nm) was deposited. The films were annealed during 1s to 100 degrees C and 400 degrees C, followed by chemical etching of the Cu film. The grazing incidence X-ray fluorescence measurements showed a thermal induced migration of Cu atoms to depths between 7 and 31 nm. The X-ray photoelectron spectroscopy analysis detected the presence of TiO(2), Cu(2)O and Cu(0) phases and an increasing Cu content with the annealing temperature. The change of the surface properties was monitored by the increasing red-shift and absorption of the ultraviolet-visible spectra. Contact angle measurements revealed the formation of a highly hydrophilic surface for the film having a medium Cu concentration. For this sample photocatalytic assays, performed by methylene blue discoloration, show the highest activity. The proposed mechanism of the catalytic effect, taking place on Ti/Cu sites, is supported by results obtained by theoretical calculations. PMID- 20828931 TI - Towards the development of an embryotoxicity bioassay with terrestrial snails: screening approach for cadmium and pesticides. AB - Currently no bioassays are available to assess the embryotoxicity of chemicals with terrestrial soil invertebrates. We therefore presented a new method for embryotoxicity testing with snail eggs: a relevant biological material that incubates in soil and that can be exposed to contaminants from leachates and soil solution. The effects of aqueous solutions of two herbicide formulations, Reglone((r)) (active ingredient (a.i.), diquat) and Roundup((r)) or its a.i., glyphosate, of a surfactant (Agral((r)) 90, a.i., nonylphenol polyethoxylates) and of cadmium (Cd) were studied. Endpoints were the hatching success and observations of embryo abnormalities after exposure. Roundup((r)) was found to be more toxic than its a.i. alone (EC50(a.i.)=18 mg/l and about 1300 mg/l, respectively). Reglone((r)) (EC50(a.i.)=0.72 mg/l) and Agral((r)) (EC50(a.i.) ~ 50 mg/l) were also tested together, revealing that Reglone((r)) accounted for more than 99% of the mixture's toxicity. An antagonistic interaction between the two substances was found. For Cd (EC50=3.9 mg/l), a significant transfer from exposure medium to eggs was emphasized, particularly affecting the albumen. Abnormalities of embryogenesis in non-hatched embryos depended on the substance and the concentration considered. PMID- 20828932 TI - Effect of humic acids on the adsorption of paraquat by goethite. AB - The adsorption of the herbicide paraquat (PQ(2+)) on goethite and on the binary system humic acid-goethite has been studied in batch experiments by performing adsorption isotherms under different conditions of pH, supporting electrolyte concentration and temperature. The results were completed with capillary electrophoresis (CE) in order to measure the binding isotherm between PQ(2+) and humic acid (HA) molecules in solution. PQ(2+) adsorption is negligible on the bare goethite surface but important on the HA-goethite adsorbent. In this last case, the adsorption increases by increasing pH and decreasing electrolyte concentration. There are no significant effects of temperature on the adsorption. The adsorption takes place by direct binding of PQ(2+) to adsorbed HA molecules leading to the formation of surface species of the type goethite-HA-PQ(2+). The results are consistent with a mechanism where PQ(2+) binds negatively charged groups of HA (carboxylates and phenolates) forming ionic pairs or outer-sphere complexes. Since goethite in nature usually contains adsorbed HA molecules, it may act as a good adsorbent for cationic herbicides. This will not only benefit the deactivation of the herbicides but also reduce their leaching and transport through groundwater. PMID- 20828933 TI - Distribution and sources of organochlorine pesticides (OCPs) in sediments from upper reach of Huaihe River, East China. AB - Residues of hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) and their environmental risks in surface sediments collected from upper reach of Huaihe River, East China, are investigated in this paper. Based on dry weight (dw), the concentrations of SigmaHCH (alpha-, beta-, gamma- and delta-HCH) and SigmaDDT (p,p'-DDT, o,p'-DDT, p,p'-DDE, p,p'-DDD) in sediments ranged from 1.95 to 11.05 ng g(-1) dw (mean 4.53 ng g(-1)dw) and 4.07 to 23.89 ng g(-1)dw (average 11.07 ng g(-1)dw), respectively. Compared with some published guideline values of organochlorine pesticides (OCPs) in sediments, the concentrations of HCHs were at safe levels while the residues of DDTs would pose adverse biological effects in this studied area. The distribution of OCPs in sediments indicated that the input of tributaries was important factor for Huaihe River. Levels of DDTs in the sediments were influenced by total organic carbon contents of sediments. The present study suggested that historical usage of lindane and technical DDT was the main reason for OCP residues in the sediments from both rivers and lakes. Furthermore, the composition of DDTs reflected fresh inputs of dicofol mixture in this region. PMID- 20828934 TI - Possible contribution of vascular innervation to somatic sensory function. PMID- 20828936 TI - Attraction response of adult Rhipicephalus appendiculatus and Rhipicephalus pulchellus (Acari: Ixodidae) ticks to extracts from Calpurnia aurea (Fabaceae). AB - Experiments were carried out to investigate the response of two tick species Rhipicephalus pulchellus Gerstaker, 1873 and Rhipicephalus appendiculatus Neumann, 1901 to three different extracts (acetone, aqueous and oil) of the dried leaves of Calpurnia aurea (Aiton) Benth in both an inverted glass tube and a dual choice T-olfactometer. The oil extract at 50 and 100mg/ml attracted 46.7% and 65.9% of R. appendiculatus, respectively, in the inverted glass tube assay, which was comparable to 47.8% of the attraction-aggregation-attachment pheromone (AAAP) used as positive control. At a dose of 100mg/ml the oil extract attracted 52.4% of R. pulchellus in the T-olfactometer bioassay. The relative attraction of both tick species to plant extract was also tested in semi-field plot experiments using a trap baited with different concentrations of emulsifiable extract of C. aurea. A dose of 100mg/ml attracted 52.2% of R. pulchellus and 44.4% of R. appendiculatus from a distance of 1m while 14.4% of R. pulchellus and 12.2% of R. appendiculatus were attracted from 5m distance at the same dose. Addition of CO(2) to the plant extract-baited-trap at the dose of 100mg/ml increased the range of attraction of adult R. pulchellus (44.4% from 5m distance) and up to 33.3% of adult R. appendiculatus tick from a distance of 4m. The results of this study suggest that extracts from C. aurea can potentially be used as baits in a trap for the control of ticks in the field. PMID- 20828937 TI - The neurophysics of psychiatric diagnosis: clinical brain profiling. AB - As early as the end of the 19th century Ernest Bruck declared that the brain is a physical entity and should be studied using the science of mathematics and physics. The brain is an extremely intricate physical entity and we have only recently begun to develop the conceptual tools to decipher this complexity. We can begin to comprehend many of the mental functions and dysfunctions by using insights about brain organization as a developing physical entity of connectivity structures. A comprehensive theoretical framework for the re-conceptualization of mental disorders as real brain-disorders, called "Clinical brain profiling" can be generated to make testable predictions about the etiopathology of psychiatric disorders. If validated, this framework has groundbreaking relevance for psychiatry, not only by providing an etiological diagnostic system, in itself revolutionary, but in its potential to develop effective curative interventions. According to the proposed brain profiling all mental disturbances can be defined in a 3 dimensional space of brain disturbances (1) neural-complexity organization, (2) to neural resilience optimization dynamics and (3) to connectivity constructs for context and internal representations. Neural complexity relates to the ability of the brain to balance connectivity dynamics, neural resilience relates to brain plasticity and changeability for optimizing overall brain dynamics and contextual configurations shape the internal representations of outer world that pattern out reaction and personality styles. Each of these organizational brain functions is predicted to involve a relatively specific neuronal circuitry system in the brain. The circuitry of the nigra striautum-cortex, are a component of the connectivity balance stabilizers and regulators, a type of neural complexity pacemaker. Thus a patient that rates high on phenomenology related to functional psychosis indicating a disturbance to connectivity balance will have disturbances that will show up in appropriate signal processing imaging of the nigra-striautum-cortex circuitry. The circuitry of thalamus-amygdala-cortex and related pathways are relevant for neuronal matching and constraint frustration. In this respect the patients scoring high on mood and anxiety disorders are predicted to suffer from perturbation shown on appropriate imaging involving the thalamus-amygdala-cortex circuitries. The hippocampus is related to the formation of internal configurations thus those patients rating highest on parameters related to personality organization and maturation will show alterations in the hippocampal organization and activation indicating deficient organizations of internal configurations. PMID- 20828938 TI - [Fecal carriage of third-generation cephalosporins-resistant Enterobacteriaceae in asymptomatic young adults: evolution between 1999 and 2009]. AB - OBJECTIVES: The aim of this work was to evaluate the fecal carriage of third generation cephalosporins resistant Enterobacteriaceae in nonhospitalized asymptomatic young adults. METHODS: A total of 517 normal fecal samples were spread onto plates agar containing cefotaxime. Isolated strains were identified and studied with agar disk diffusion antibiogram, minimal inhibition concentration in liquid medium and phenotypic and molecular study. Data were compared with a previous study realised in the same conditions in 1999. RESULTS: In 2009, the prevalence of cefotaxime resistant enterobacteria was 4.2%. Of these 22 Enterobacteriaceae, 11 harboured overexpressed cephalosporinase and 11 produced extended-spectrum-betalactamase (ESBL). Among ESBL, six E. coli produced CTX-M from group 1 (n=6), group 2 (n=1), group 9 (n=2), one E. coli produced SHV 12 and one Klebsiella pneumoniae produced CTX-M from group 1. All ESBL were multiresistant. In 1999, all the CTX resistant isolates recovered produced a cephalosporinase and no ESBL was found. CONCLUSIONS: This study highlights the increasing prevalence of fecal carriage of ESBL-producing enterobacteria in asymptomatic young patients in the community (0% in 1999 versus 2.1% in 2009; P<0.001). E. Coli with CTX-M from group 1 was the most frequent ESBL identified, while fecal carriage of Enterobacteteriaceae overproducing cephalosporinase was similar (2.1%). PMID- 20828939 TI - Rapid detection of multidrug resistant Gram-negative bacilli by Cica-Beta-Test strips. AB - AIM OF THE STUDY: This study aimed to evaluate the sensitivity and specificity of a new system (Cica-Beta-Test, Kanto Chemical, Japan) for rapid detection of AmpC derepressed, extended-spectrum beta-lactamases (ESbetaL) and metallo-beta lactamases (MbetaL). METHODS: Two hundred Multi-Drug Resistant (MDR)-Gram negative bacilli were studied: 170 Enterobacteriaceae and 30 Gram-negative non fermentative bacteria. One hundred and eighteen strains produced an ESbetaL, seven MbetaL and 75 derepressed cephalosporinases. One drop of substrate was dispensed onto the filter pad of the Cica-Beta-Test strip. The bacterial colonies were spread on the filter pad of strip. The reading was performed after 2 to 15 min: turning chromogenic indicated the positive test. Three tests were used: Cica Beta I for detection of MDR bacteria; Cica-Beta MbetaL for detection of MbetaL producing bacteria and Cica-Beta CVA, which distinguish ESbetaL and AmpC derepressed producers. Results were compared with molecular assays. RESULTS: Cica Beta-Test I has detected 194 MDR (sensitivity 97%), Cica-Beta-Test MbetaL has shown the presence of six MbetaL tested (sensitivity 85.7%). Five strains were non-MbetaL false positive (specificity 97.3%). Cica-Beta-Test CVA allowed the differentiation of ESbetaL-producing strains (109/115) and AmpC-derepressed strains (56/67) (sensitivity 94.8%, specificity 83.8%). CONCLUSIONS: Because of their epidemic nature, the MDR strains are screened and require strict hygienic measures patients. The simultaneous use of three strips can quickly determine the presence of MDR including ESbetaL and MbetaL. Rapid screening of MDR avoids transmission and limits the use of broad-spectrum antibiotics. PMID- 20828940 TI - [Molecular diagnosis of respiratory enterovirus infections: Use of PCR and molecular identification for a best approach of the main circulating strains during 2008]. AB - The PCR assays are currently used in diagnosis of enterovirus (EV) meningitis. Nevertheless, the use of molecular diagnosis of EV should be investigated in respiratory tract infections (RTI). OBJECTIVES: To perform enterovirus molecular diagnostic tools, PCR and genotyping, in nasal samples for diagnostic and epidemiologic purposes. METHODS: During 2008, 3612 nasal specimen (NS) were studied by IFD and MRC5 culture. Next, we realised successively viral isolation on HuH7 culture (for NS negative by IFD assay) and a duplex PCR enterovirus rhinovirus for the 816 HuH7 positive supernatants. Furthermore, 327 NS collected from neonates were systematically tested by a real-time RT-PCR. This assay was used in routine for EV diagnosis setting in cerebrospinal fluid. Enterovirus genotyping was then performed for the 68 positive supernatants. RESULTS: Thirty five NS (0.97%) were positive for EV by culture (MRC5). A combination of both PCR assays, PEVRV and PEV, allowed an additional identification of 41 EV, eight EV-RV and 12 RV, increasing the number of positive to 96 NS (2.6%). Among the neonates, 32 NS (11.3%) were positive for EV by PEV. Of the 98 NS tested by the two PCR assays (PEV and PEVRV), 27 were positive and we detected 10 EV, five EV-RV and 12 RV. From January to December 2008, the circulation of EV showed the usual peak in June-July when a small outbreak of aseptic meningitis occurred and an additional autumnal peak corresponding to respiratory tract infections. Five main serotypes were isolated: 19 EV68 (29.7%), 12 CB3 (18.7%), nine E3 (14,1%), six CA9 (9.4%) and six CB1 (9.4%); the 19 EV68 were isolated in October-November and 17/19 (89.5%) of positive patients were hospitalised for severe respiratory diseases. CONCLUSION: The use of molecular screening techniques (PCR assays and genotyping) on nasal samples collected from patients with respiratory infections allowed a prospective, effective and precise identification of circulating strains. PMID- 20828941 TI - [Implementation of vanA and vanB genes by PCR technique research interest in system (Xpert vanA/vanB CepheidR) closed in a laboratory of microbiology in managing an outbreak to Enterococcus faecium resistant glycopeptide (EfRG)]. AB - SUBJECT: The closed system PCR for the rapid detection of vanA and vanB genes (Xpert vanA/vanB Cepheid((r))) was evaluated in our laboratory, to improve the rapidity of the response and thus the management of patients and isolation measures during two GRE outbreaks. METHOD: From March to December2009, 565 samples were analysed by PCR associated to bacterial culture initially for all samples for 2months (n = 75), and thereafter for PCR-positive samples only. RESULTS: In this study, sensitivity and negative predictive values of the PCR were 100%. Specificity was evaluated in the presence and absence of outbreak: 69.3 and 76.8% respectively. The variability of false positive rates between units were lower in nonepidemic than during epidemic phase. The global false positive rate was 23.9%. CONCLUSION: This easy-to-use technology provides rapid results... four samples are tested in 1h versus 72h for culture. Despite its reagent cost, it represents an important hospital diagnostic tool: improvement of the management of cohorting areas and patient transfer between units, adaptation of isolation measures and treatments. However, culture remains necessary to confirm any positive result obtained by PCR and for epidemiological surveillance. PMID- 20828942 TI - Mortality among cocaine users: a systematic review of cohort studies. AB - AIMS: To conduct a systematic review of mortality among cohort studies of cocaine users. METHODS: Three electronic databases were searched (EMBASE, Medline and PsychINFO); other online databases were searched using online libraries and repositories of reports and literature in the drug and alcohol field, with requested contributions from trained librarians and experts. Searches and extraction were undertaken using protocols and cross-checking of decisions by two authors. Additional data were requested from study investigators where studies did not report relevant data. RESULTS: 1911 articles and 2 reports were identified from searches, with data from another four studies located from review articles. Seven cohorts of "problem" or dependent cocaine users reported data that permitted mortality rates to be estimated. Crude mortality rates ranged from 0.53 (95% CI: 0.10-1.58) to 6.16 (95% CI: 5.21-7.11) per 100 PY. Standardised mortality ratios (SMRs) reported in four studies suggested that mortality was four to eight times higher among cocaine users than age and sex peers in the general population. CONCLUSIONS: There are limited data on the extent of elevated mortality among problematic or dependent cocaine users and it is unclear how generalisable the results of these studies may be to other populations of problematic cocaine users. Greater attention to both the method of recruitment, and the characteristics of cocaine users, would enhance our understanding of the mortality risks of problematic cocaine use. PMID- 20828943 TI - Randomized, double blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. AB - This study examined the dose-related efficacy of disulfiram for treating cocaine dependence in methadone-stabilized cocaine dependent participants. DESIGN: One hundred and sixty-one cocaine- and opioid-dependent volunteers were entered into a 14-week, double blind, randomized, placebo-controlled clinical trial at two sites. METHODS: Participants were stabilized on methadone during weeks 1-2 and received disulfiram at 0, 62.5, 125 or 250 mg/day during weeks 3-14. All participants also received weekly cognitive behavioral therapy. Thrice-weekly urine samples and weekly self-reported drug use assessments were obtained. RESULTS: Baseline subject characteristics, retention and drug use did not differ across groups. Outcome analyses were performed on those who participated beyond week 2. Opioid-positive urine samples and self-reported opioid use did not differ by treatment group. The prevalence of alcohol use was low prior to and during the trial and did not differ by treatment group. Cocaine-positive urines increased over time in the 62.5 and 125 mg disulfiram groups and decreased over time in the 250 mg disulfiram and placebo groups (p < 0.0001). Self-reported cocaine use increased in the 125 mg disulfiram group relative to the other three treatment groups (p = 0.04). CONCLUSIONS: Disulfiram may be contraindicated for cocaine dependence at doses <250 mg/day. Whether disulfiram at higher doses is efficacious in reducing cocaine use in dually cocaine and opioid dependent individuals needs to be determined. PMID- 20828944 TI - Longitudinal predictors of addictions treatment utilization in treatment-naive adults with alcohol use disorders. AB - BACKGROUND: Despite the substantial prevalence of alcohol use disorders (AUDs), prior research indicates that most people with AUDs never utilize either formal or informal treatment services. Several prior studies have examined the characteristics of individuals with AUDs who receive treatment; however, limited longitudinal data are available on the predictors of receiving AUD services in treatment-naive individuals with AUDs. METHODS: This study utilized data from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) to identify adults in Wave 1 who met criteria for an AUD within the last 12 months and reported no prior lifetime alcohol treatment (N = 2760). These individuals were surveyed again at Wave 2, approximately 3-4 years later (N = 2170). This study examined the Wave 1 demographic and psychiatric conditions that were associated with receipt of AUD treatment services between Waves 1 and 2. RESULTS: In multivariable analyses, use of AUD treatment services between Waves 1 and 2 was significantly more likely among those who were male, non-Caucasian, younger, had lower income, and who had health insurance. Additionally, those who met criteria for a baseline drug use disorder, anxiety disorder or a personality disorder were more likely to receive AUD treatment. CONCLUSIONS: Treatment was more often utilized in those who had more severe baseline psychopathology and in those with fewer economic resources. These findings highlight the need to broaden the types of care available to individuals with AUDs to increase the appeal of AUD services. PMID- 20828945 TI - Efficacy of an inactivated, recombinant bovine herpesvirus type 5 (BoHV-5) vaccine. AB - Bovine herpesvirus type 5 (BoHV-5) is the causative agent of bovine herpetic encephalitis. In countries where BoHV-5 is prevalent, attempts to vaccinate cattle to prevent clinical signs from BoHV-5-induced disease have relied essentially on vaccination with BoHV-1 vaccines. However, such practice has been shown not to confer full protection to BoHV-5 challenge. In the present study, an inactivated, oil adjuvanted vaccine prepared with a recombinant BoHV-5 from which the genes coding for glycoprotein I (gI), glycoprotein E (gE) and membrane protein US9 were deleted (BoHV-5 gI/gE/US9(-)), was evaluated in cattle in a vaccination/challenge experiment. The vaccine was prepared from a virus suspension containing a pre-inactivation antigenic mass equivalent to 10(7.69) TCID(50)/dose. Three mL of the inactivated vaccine were administered subcutaneously to eight calves serologically negative for BoHV-5 (vaccinated group). Four other calves were mock-vaccinated with an equivalent preparation without viral antigens (control group). Both groups were boostered 28 days later. Neither clinical signs of disease nor adverse effects were observed during or after vaccination. A specific serological response, revealed by the development of neutralizing antibodies, was detected in all vaccinated animals after the first dose of vaccine, whereas control animals remained seronegative. Calves were subsequently challenged on day 77 post-vaccination (pv) with 10(9.25) TCID(50) of the wild-type BoHV-5 (parental strain EVI 88/95). After challenge, vaccinated cattle displayed mild signs of respiratory disease, whereas the control group developed respiratory disease and severe encephalitis, which led to culling of 2/4 calves. Searches for viral DNA in the central nervous system (CNS) of vaccinated calves indicated that wild-type BoHV-5 did not replicate, whereas in CNS tissues of calves on the control group, viral DNA was widely distributed. BoHV-5 shedding in nasal secretions was significantly lower in vaccinated calves than in the control group on days 2, 3, 4 and 6 post-challenge (pc). In addition, the duration of virus shedding was significantly shorter in the vaccinated (7 days) than in controls (12 days). Attempts to reactivate latent infection by administration of dexamethasone at 147 days pv led to recrudescence of mild signs of respiratory disease in both vaccinated and control groups. Infectious virus shedding in nasal secretions was detected at reactivation and was significantly lower in vaccinated cattle than in controls on days 11-13 post-reactivation (pr). It is concluded that the inactivated vaccine prepared with the BoHV-5 gI/gE/US9( ) recombinant was capable of conferring protection to encephalitis when vaccinated cattle were challenged with a large infectious dose of the parental wild type BoHV-5. However, it did not avoid the establishment of latency nor impeded dexamethasone-induced reactivation of the virus, despite a significant reduction in virus shedding after challenge and at reactivation on vaccinated calves. PMID- 20828946 TI - Identification of bacteria associated with feline chronic gingivostomatitis using culture-dependent and culture-independent methods. AB - Feline chronic gingivostomatitis (FCGS) is a chronic inflammatory disease of the oral cavity that causes severe pain and distress. There are currently no specific treatment methods available and little is known regarding its aetiology, although bacteria are thought to play a major role. The purpose of this study was to identify the oral bacterial flora in normal and diseased cats. Oral swabs were obtained from the palatoglossal folds of eight cats (three normal and five FCGS) and were subjected to microbiological culture. Pasteurella pneumotropica and Pasteurella multocida subsp. multocida were the most prevalent species identified by culture methods in the normal and FCGS samples, respectively. Bacteria were also identified using culture-independent methods (bacterial 16S rRNA gene sequencing). For the normal samples, 158 clones were analysed and 85 clones were sequenced. Capnocytophaga canimorsus (10.8% of clones analysed) was the predominant species. Uncultured species accounted for 8.2% of clones analysed, and 43.7% of clones analysed represented potentially novel species. For the FCGS samples, 253 clones were analysed and 91 clones were sequenced. The predominant species was P. multocida subsp. multocida (51.8% of clones analysed). Uncultured species accounted for 8.7% of clones analysed, and 4.7% of clones analysed represented potentially novel species. It is concluded that the oral flora in cats with FCGS appears to be less diverse than that found in normal cats. However, P. multocida subsp. multocida is found to be significantly more prevalent in FCGS than in normal cats and consequently may be of aetiological significance in this disease. PMID- 20828947 TI - Influence of sperm concentration on the motility, morphology, membrane and DNA integrity along with oxidative stress parameters of ram sperm during liquid storage. AB - The aim of this study was to determine the influences of two different concentrations in terms of motility, morphology, membrane integrity (viability and HOST response: HE-test; modified hypoosmotic swelling test (HOST) associated with supravital eosin staining test), DNA integrity (COMET assay) and oxidative stress parameters (MDA, malondialdehyde; AOA, total antioxidant activity; GSH, reduced glutathione; NOx, nitric oxide) of liquid stored ram sperm for 5 days. Two different concentrations suitable for laparoscopic and cervical inseminations were employed. A total of 5 Pirlak rams (Daglic * Kivircik, local breed) with satisfactory breeding potential were selected. Semen samples were collected by artificial vagina. Ejaculates were extended to 25 and 100 million sperm per ml with Tris-based egg-yolk (T) extender at room temperature and stored at 4 degrees C. The concentration significantly had effects on motility, morphology, membrane and DNA integrity along with oxidative stress parameters (P<0.05). Overall changes in the motility, morphology, membrane and DNA integrity along with oxidative stress parameters of ram sperm diluted with T in the 100 * 10(6)ml(-1) concentration and preserved at 4 degrees C for a short term was found to be better preservation than that of diluted with T in the 25 * 10(6)ml(-1) concentration. Significant concentration * days of storage interactions were found for all parameters except the NOx. Further studies are required to elucidate the oxidative stress changes on sperm quality parameters in different concentrations during the liquid storage of ram semen. PMID- 20828948 TI - Women's voices in the menopause: results from an international survey on vaginal atrophy. AB - OBJECTIVES: To consider issues relating to vaginal atrophy via an international survey. METHODS: Using a structured questionnaire, interviews were performed on 4246 women aged 55-65 years living in Sweden, Finland, the United Kingdom, the United States and Canada. RESULTS: Overall, 98% of survey respondents were postmenopausal. Thirty-nine percent of the postmenopausal women had experienced vaginal atrophy, with the prevalence varying between countries, from 34% in Canada to 43% in Finland and the United States. Attitudes towards symptoms also varied between countries. Symptoms were described as moderate or severe by less than half of women from Finland and Sweden, compared with nearly two-thirds of women from the United States. However, vaginal atrophy was deemed to impact on quality of life by a higher proportion of women in Finland and Sweden (>=60%) than in the United Kingdom, the United States and Canada (<=50%). Overall, 77% of respondents believed women were uncomfortable discussing vaginal atrophy and 42% did not know that local treatment was available. The proportions of women unaware of the availability of local treatment were higher in the United States, the United Kingdom and Canada (51%, 50% and 48%, respectively), and very low in Finland (10%). Whilst 63% of women who had experienced vaginal atrophy had never been prescribed treatment for the condition, 67% of those who had been treated reported positive effects. CONCLUSION: The survey results illustrate differing needs of menopausal women in different countries. Country-specific approaches may be required to improve the uptake of treatment for vaginal atrophy. PMID- 20828949 TI - Pelvic floor exercise for urinary incontinence: a systematic literature review. AB - Urinary incontinence is a common problem among adults and conservative management is recommended as the first-line treatment. Physical therapies, particularly pelvic floor muscle exercise, are the mainstay of such conservative management. The purpose of this review is to summarise current literature and describe trends in the use of pelvic floor muscle exercise in the management of urinary incontinence in women. Our review confirms that pelvic floor muscle exercise is particularly beneficial in the treatment of urinary stress incontinence in females. Studies have shown up to 70% improvement in symptoms of stress incontinence following appropriately performed pelvic floor exercise. This improvement is evident across all age groups. There is evidence that women perform better with exercise regimes supervised by specialist physiotherapists or continence nurses, as opposed to unsupervised or leaflet-based care. There is evidence for the widespread recommendation that pelvic floor muscle exercise helps women with all types of urinary incontinence. However, the treatment is most beneficial in women with stress urinary incontinence alone, and who participate in a supervised pelvic floor muscle training programme for at least three months. PMID- 20828950 TI - Analysis of pubic hair as an alternative specimen to scalp hair: a contamination issue. AB - Pubic hair is often analyzed as an alternative to scalp hair to prove previous drug use. However, urine is a potential source of external contamination. In the present study, the concentrations of methamphetamine (MA) and amphetamine (AP) in both scalp and pubic hair from illegal MA users were compared. Furthermore, in order to investigate the external contamination of pubic hair by urine, MA and AP absorbed into pubic hair that had been contaminated with authentic urine from a MA user were measured using a previously validated method. The effect of shampoo wash on the contaminated pubic hair was also examined. However, no correlation was found in the MA and AP concentrations between scalp and pubic hair from illegal MA users. As the number of contamination events by authentic urine increased, the concentrations of MA and AP in pubic hair increased. Both MA and AP were detected in the first methanol washes of the contaminated hair samples but were not detected in the second methanol washes. As the number of shampoo washes of the contaminated pubic hair increased, the concentrations of MA and AP gradually decreased. Even though pubic hair can be used as an alternative to scalp hair to prove previous drug use, it should be avoided when estimating drug use history. It should be also noted that higher quantitative results in pubic hair do not necessarily represent heavier drug use. PMID- 20828951 TI - Reliability of ion mobility spectrometry for qualitative analysis of complex, multicomponent illicit drug samples. AB - Ion mobility spectrometry (IMS) has been used for trace analysis of illicit drugs, but it can also provide reliable qualitative analysis of bulk forensic drug items, despite the complexity of these samples. The drug/drug and drug/excipient combinations representing over 80% of the samples reported by state and federal forensic laboratories over the past 7 years were compiled from reports of the National Forensic Laboratory Information System (NFLIS). From this set of materials, IMS detection windows were set for eight controlled substances, including methamphetamine, 3,4-methylenedioxymethamphetamine hydrochloride (MDMA), cocaine, heroin, fentanyl, hydrocodone, oxycodone, and alprazolam. The reduced mobilities of the eight controlled substances were measured over an extended period of time to determine variability with respect to the size of the detection windows. Uncertainties in reduced mobilities smaller than 0.001 cm(2)V( 1)s(-1) were obtained, and detection windows were set to between +/-0.003 and +/ 0.005 cm(2)V(-1)s(-1). Reduced mobilities are instrument and operating condition dependent, and must be determined for each instrument. Peak overlaps are observed in the drug/drug combinations, but at least one controlled substance can be detected in each mixture. Excipient concentrations must be quite high (>75 wt%) in binary mixtures to interfere with the detection of the controlled substance. IMS can be used to identify many of the excipients, and can detect multiple (for these samples, as many as 4) substances in complex samples. Over-the-counter (OTC) tablet medications for cold, flu, and allergy relief can be distinguished from tablets containing controlled substances. Bulk materials, including tablets, are sampled simply by using a fine probe to restrict the amount of material transferred to the IMS substrate. IMS represents a distinct advantage over color tests for field analysis of illicit drugs, except in the case of cannabis/THC samples. PMID- 20828952 TI - Pharmacogenetics and forensic toxicology. AB - Large inter-individual variability in drug response and toxicity, as well as in drug concentrations after application of the same dosage, can be of genetic, physiological, pathophysiological, or environmental origin. Absorption, distribution and metabolism of a drug and interactions with its target often are determined by genetic differences. Pharmacokinetic and pharmacodynamic variations can appear at the level of drug metabolizing enzymes (e.g., the cytochrome P450 system), drug transporters, drug targets or other biomarker genes. Pharmacogenetics or toxicogenetics can therefore be relevant in forensic toxicology. This review presents relevant aspects together with some examples from daily routines. PMID- 20828953 TI - Identification of 1-methylaminoanthraquinone on Australian polymeric bank notes. AB - This paper describes the examination and analysis of 1-methylaminoanthraquinone dye staining on Australian polymeric bank notes. PMID- 20828954 TI - [Detection and quantification of human papillomavirus genital infections: virological, epidemiological, and clinical applications]. AB - Human papillomaviruses (HPV) are the main risk factor for cervical cancer. By introducing its DNA into the genome of infected human cells, the virus expresses two oncoproteins (E6 and E7) that induce inactivation of tumour suppressors and telomerase. HPV infection is extremely common. But most of women will clear the infection over an 8-10-month period without developing any cervical lesion. In fact, it is the persistence of infection that truly exposes to the risk of cervical cancer. HPV testing, used for primary screening, has better sensitivity but lower specificity than cervical cytology. A secondary use of cytology would compensate the loss of HPV testing specificity. Thus, cervical cytology would be performed only in HPV positive women and colposcopy finally performed only in women with abnormal cytology. The characteristics of such screening would allow to increase interscreening intervals and therefore to reduce additional costs. The quantification of HPV viral load could be a way to differentiate significant infections from others. Despite proven significant association between high HPV viral load and the risk of CIN 2-3 and cervical cancer, crude variations within disease grades currently limit the clinical utility of viral load measurement. More than a just measure of HPV viral load, its evolution over time is what would really be of clinical relevance. PMID- 20828955 TI - Acute colonic pseudo-obstruction. PMID- 20828956 TI - A functional MRI study of language networks in left medial temporal lobe epilepsy. AB - PURPOSE: The purpose of this study was to investigate the abnormality of language networks in left medial temporal lobe epilepsy (MTLE) using fMRI. MATERIALS AND METHODS: Eight patients with left MTLE and 15 healthy subjects were evaluated. An auditory semantic judgment (AJ) paradigm was used. The fMRI data were collected on a 3T MR system and analyzed by AFNI (analysis of functional neuroimages) to generate the activation map. RESULTS: Behavioral data showed that the reaction time of the left MTLE patients was significantly longer than that of controls on the AJ task (t=-3.396, P<0.05). The left MTLE patients also exhibited diffusively decreased activation in the AJ task. Right hemisphere dominance of Broca's and Wernicke's areas was demonstrated in left MTLE patients. CONCLUSIONS: Long-term activation of spikes in left MTLE patients results in language impairment, which is associated with an abnormality of the brain neural network. PMID- 20828957 TI - Late sarcoma development after curettage and bone grafting of benign bone tumors. AB - BACKGROUND AND AIM: Rarely sarcomas develop in previous benign lesions, after a long term disease free interval. We report the experience on these rare cases observed at a single Institution. PATIENTS AND METHODS: 12 cases curetted and grafted, without radiotherapy developed sarcomas, between 1970 and 2005, 6.5-28 years from curettage (median 18, average 19). Age ranged from 13 to 55 years (median 30, average 32) at first diagnosis; tumors were located in the extremities (9 GCT, benign fibrous histiocytoma, ABC, and solitary bone cyst). Radiographic and clinic documentation, for the benign and malignant lesions, were available. Histology was available for 7 benign and all malignant lesions. RESULTS: To fill cavities, autogenous bone was used in 4 cases, allograft in 2, allograft and tricalcium-phosphate/hydroxyapatite in 1, autogenous/allograft in 1, heterogenous in 1. For 3 cases the origin was not reported. Secondary sarcomas, all high grade, were 8 osteosarcoma, 3 malignant fibrous histiocytoma, and 1 fibrosarcoma. CONCLUSIONS: Recurrences with progression from benign tumors are possible, but the very long intervals here reported suggest a different cancerogenesis for these sarcomas. This condition is extremely rare accounting for only 0.26% of all malignant bone sarcomas treated in the years 1970-2005 and represents only 8.76% of all secondary bone sarcomas treated in the same years. This incidence is the same as that of sarcomas arising on fibrous dysplasia, and is lower than those arising on bone infarcts or on Paget's disease. This possible event must be considered during follow-up of benign lesions. PMID- 20828958 TI - Frequency and significance of pulmonary nodules on thin-section CT in patients with extrapulmonary malignant neoplasms. AB - PURPOSE: To determine the frequency and significance of pulmonary nodules detected on thin-section CT in patients with extrapulmonary malignant neoplasms. MATERIALS AND METHODS: The institutional review board approved this study. This study retrospectively evaluated 308 patients with extrapulmonary carcinomas or sarcomas and had undergone thin-section chest CT (2mm slice thickness) for staging. Three radiologists identified non-calcified nodules and evaluated the size, the growth and the distance from the nearest pleural surface. The characteristics of the nodules were defined based on the results of either a diagnostic biopsy or nodule growth. RESULTS: One or more non-calcified pulmonary nodules were detected in 75% of the patients (233/308). One hundred and thirty seven of these patients had nodules that met the criteria of either benign or malignant nodules. Nodules smaller than 10mm were more likely to be benign, whereas those 10mm or greater were more likely to be malignant (22/26, 85%; P<.0001). Most nodules less than 10mm from the pleura were benign (91%), whereas approximately half of the nodules 10mm or more away from the pleura were malignant (20/43, 47%; P<.0001). Patients with melanoma, sarcoma, or testicular carcinoma were more likely to have malignant nodules. A multivariable analysis demonstrated the nodule size (P<.0001) and distance from the pleura were predictive of malignancy. CONCLUSION: The nodule detection rate on thin-section CT in patients with extrapulmonary malignancy is high. Most of the nodules smaller than 10mm or less than 10mm from the pleura are benign. PMID- 20828959 TI - BLADE acquisition method improves T2-weighted MR images of the female pelvis compared with a standard fast spin-echo sequence. AB - PURPOSE: To investigate feasibility of the periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER or BLADE) T2-weighted imaging (T2WI) of the female pelvis by comparing it with standard fast spin-echo T2WI (STD-T2WI). MATERIALS AND METHODS: Sagittal STD-T2WI and BLADE-T2WI of the female pelvis were performed with (36 patients) or without (15 patients) administration of butylscopolamine on a 1.5 T MR unit. Two radiologists independently rated depiction of the uterus, ovary, intestines, bladder, gynecological lesions, overall quality, and artifacts using a four-point scale. Results were compared between STD-T2WI vs. BLADE-T2WI either with (B+) or without (B-) administration of butylscopolamine, BLADE-T2WI (B-) vs. BLADE-T2WI (B+), and STD-T2WI (B+) vs. BLADE-T2WI (B-). RESULTS: When butylscopolamine was administrated, depiction of the uterus, ovary, intestines, gynecological lesions, and overall image quality was rated higher and artifacts were rated fewer for BLADE-T2WI with significance compared with STD-T2WI. When the drug was not administrated, significant difference was observed in depiction of the lesion, overall quality, and artifacts. Depiction of the uterus, gynecological lesion, and overall quality was rated significantly higher and artifacts were fewer in BLADE-T2WI (B+) than in BLADE-T2WI (B-). CONCLUSION: BLADE method was feasible for female pelvic MRI, with best image quality in BLADE-T2WI (B+). PMID- 20828961 TI - Vascular tumors of bone: imaging findings. AB - PURPOSE: To identify radiological features of malignant vascular tumors of bone, which can be used to avoid erroneously diagnosing metastases based on radiological multifocality, and histological epitheloid phenotype. MATERIALS AND METHODS: From the databases of the Bologna & Netherlands Committee on Bone Tumors, 63 patients with a histological diagnosis of malignant vascular tumor of bone were retrieved. Epidemiological and imaging characteristics were recorded on a case record form. RESULTS: In 63 patients, 185 lesions were detected by radiographs (61 patients) and/or CT (30 patients) and/or MRI (19 patients). Multifocality was observed in 25 patients (40%), in these patients most lesions were located in the femur. Typically lesions were well-defined, osteolytic, had a geographically pattern of destruction and were also located in the femur. Most lesions showed cortical destruction (118 lesions). No periosteal reaction was seen in most cases (121 lesions). In 13 of 39 patients (33%) tumor extension was more advanced and/or (additional) lesions (29 lesions; 17%) were visible on MRI and CT. In 20 cases (51%) cortex destruction was better shown on CT or MRI. In six patients (15%) periosteal reaction was only seen on MRI or CT and not on radiographs. In 16 (41%) cases soft tissue extension was only seen on MRI or CT, and not on radiographs. Extensive reactive changes on T2-weighted images were seen in 11 patients (58%). CONCLUSION: When single, or regional multifocal osteolytic, well-marginated lesions with cortical destruction are seen, in the femur, and with marked reactive soft tissue changes on MRI, a diagnosis of malignant vascular tumor should trigger the use of additional immunohistochemistry to confirm the vascular nature of the tumor. CLINICAL RELEVANCE STATEMENT: Because of epithelioid phenotype at histology, radiological signs are key in entertaining a diagnosis of malignant vascular tumor of bone which should trigger the use of appropriate immunohistochemical stainings. PMID- 20828962 TI - Ribosomal protein profiling by matrix-assisted laser desorption/ionization time of-flight mass spectrometry for phylogenety-based subspecies resolution of Bifidobacterium longum. AB - The taxonomic positions of the subspecies of Bifidobacterium longum (B. longum subsp. longum, subsp. infantis, and subsp. suis) have been controversial. A current proposal is that the former two species "B. infantis" and "B. suis" be unified with B. longum and all three reclassified as three subspecies. To test this proposal, ribosomal protein profiling as observed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was applied to the classification of 17 strains of B. longum, including three subspecies. Among 41 different kinds of ribosomal proteins selected as biomarkers whose masses were calculated from their amino acid sequences, 31-41 ribosomal proteins were observed in sample strains with the same masses as the references. The high matching rate indicates high conservation of ribosomal proteins within the sample strains, and therefore strongly supports the unification of the former species. However, the masses of some ribosomal proteins varied within species. The phylogenetic tree constructed from the profiles of ribosomal proteins matched the references, showing a clear cluster of the subsp. longum and the subsp. infantis strains. This result supports the proposal to reclassify B. longum into subsp. longum and subsp. infantis. The subsp. suis strains formed an individual sub cluster within the infantis cluster. However, their ribosomal proteins have both characters of longum and infantis types. This result suggests that the taxonomic position of the subsp. suis should be reconsidered. PMID- 20828963 TI - Static headspace gas chromatographic method for the determination of low and high boiling residual solvents in Betamethasone valerate. AB - Currently, there are no analytical methods available in the literature that can simultaneously separate and quantitate residual levels of acetone, methylene chloride, n-butyl ether and dimethylsulfoxide in Betamethasone valerate active pharmaceutical ingredient (API). This paper describes the development and validation of a simple, efficient, accurate and robust static headspace gas chromatography method for the determination of high and low boiling residual solvents, namely acetone, methylene chloride, n-butyl ether and dimethylsulfoxide, in Betamethasone valerate API. This method has been demonstrated to be accurate, linear, precise, reproducible, specific and robust for its intended purpose. Quantitation limits (QL) for acetone, methylene chloride and n-butyl ether are 20 ppm (20 MUg/g of API) and 50 ppm (50 MUg/g of API) for dimethylsulfoxide. Several other APIs (Loratadine and a few other corticosteroid compounds) were analyzed using the conditions of this method to evaluate and assess the versatility of this method for the purpose of residual solvents analysis for a wide range of APIs. The results of this evaluation strongly indicates that this method can be readily used (as-is or with minor modifications) to determine both low and high boiling residual solvents present in a wide range of APIs. PMID- 20828964 TI - Pharmacokinetics, tissue distribution and excretion of porcine fibrinogen after intraperitoneal injection of a porcine-derived fibrin glue to rats. AB - The aim of the present study was to characterize the preclinical pharmacokinetics, tissue distribution and excretion profiles of porcine fibrinogen in rats after intraperitoneal injection of a porcine-derived fibrin glue. A sensitive and rapid isotope-labeled assay method was developed and validated for quantitative analysis in biological analysis. Porcine fibrinogen, the major composition of the fibrin glue, was radioiodinated with Na(125)I using the Iodo-Gen method. Following the purification and identification of (125)I porcine fibrinogen, the fibrin glue containing (125)I-porcine fibrinogen was intraperitoneally administered to rats at three single dosages (100, 200, 400mg/kg of porcine fibrinogen). The results showed that the (125)I-labeled assay method was suitable for the quantification of porcine fibrinogen in plasma samples, tissue samples and excreta samples with satisfactory linear (r(2)>0.998), precision (<13%), accuracy (95.9-104.2%) and recovery (>85%). After three single administrations, plasma concentration profiles showed a slow absorption phase with the mean t(max) of 1.83-5.67 h and a slow elimination proceeding with the terminal elimination half-life (T(1/2)) of 84.5-96.3h. Porcine fibrinogen was widely distributed to most of the tissues examined after a single intraperitoneal administration at 200mg/kg to rats. The radioactive porcine fibrinogen showed substantial disposition in liver, kidneys, stomach and intestine. Approximately 79.3% and 17.2% of administered radioactivity were recovered in urine and feces within 528 h post-dosing, which indicated the major elimination route was urinary excretion. PMID- 20828965 TI - Screening of immunomodulatory components in Yu-ping-feng-san using splenocyte binding and HPLC. AB - Yu-ping-feng-san (YPFS) is a widely used immunomodulatory herbal medication used in traditional Chinese medicine, but the active molecules remain obscure. To screen for bioactive components we combined splenocyte binding with high performance liquid chromatography (SB-HPLC). After enrichment by splenocyte binding, two YPFS components (C1 and C2) were analyzed by HPLC. Compound C2 was identified as linoleic acid (LA) based on UV absorption and mass spectrometry. Silica gel chromatography was used to purify compound C1 from Radix Saposhnikoviae, a major constituent of YPFS. This allowed identification of the molecule as panaxynol (PAN) based on EI-MS and NMR spectrometry. Bioassay in vitro demonstrated that PAN significantly inhibited splenocyte proliferation induced by concanavalin A (ConA) in a concentration-dependent manner, whereas LA had no significant effect on splenocyte proliferation. In vivo, PAN was found to attenuate allergic contact dermatitis in a mouse model of delayed-type hypersensitivity (DTH), a pharmacological activity not previously reported for this molecule. It is suggested that PAN contributes to the anti-DTH effects of YPFS. SB-HPLC provides a rapid and efficient method for the identification of potential immunomodulatory components in traditional Chinese medicines. PMID- 20828966 TI - Generic systems for the enantioseparation of basic drugs in NACE using single isomer anionic CDs. AB - The enantioseparation of 10 basic drugs was evaluated in NACE systems using heptakis(2-O-methyl-3-O-acetyl-6-O-sulfo)-beta-CD (HMAS-beta-CD). For this purpose, a D-optimal design with 21 experimental points was applied. Four antifungal agents (econazole, isoconazole, miconazole, sulconazole), three local anesthetics (bupivacaine, mepivacaine and prilocaine), two sympathomimetics (salbutamol and terbutaline) and one beta-blocker (carvedilol) were selected as basic model analytes. The influence on the enantiomeric resolution of anionic CD and BGE anion concentrations as well as the BGE anion nature was investigated. For all studied analytes, the enantiomeric resolution was shown to be significantly influenced by the CD concentration. Based on the observed results, a generic NACE system was recommended, namely 20mM HMAS-beta-CD and 10mM ammonium camphor SO(3)(-) in methanol acidified with 0.75 M formic acid. Moreover, this NACE system was compared to previous conditions with heptakis(2,3-di-O-methyl-6-O sulfo)-beta-CD (HDMS-beta-CD) or heptakis(2,3-di-O-acetyl-6-O-sulfo)-beta-CD (HDAS-beta-CD). Finally, two generic systems using either HDAS-beta-CD or HMAS beta-CD were proposed and evaluated for the enantioseparation of ketamine and norketamine after incubation of ketamine in phenobarbital-induced male rat liver microsomes systems. PMID- 20828967 TI - Ultrasound-assisted dispersive liquid-liquid microextraction for determination of fluoroquinolones in pharmaceutical wastewater. AB - A simple and rapid ultrasound-assisted dispersive liquid-liquid microextraction (UA-DLLME) coupled with liquid chromatography-ultraviolet detection (LC-UV) was developed for the determination of four fluoroquinolones (ofloxacin, norfloxacin, enrofloxacin, and lomefloxacin) in pharmaceutical wastewater samples. Various parameters affecting the extraction efficiency including type and volume of extraction and dispersive solvents, sample pH, and extraction time were investigated. Good linear relationships were obtained for all analytes in a range of 0.01-2.0 MUg/ml with LODs ranged from 0.14 to 0.81 MUg/l. Average recoveries at three spiking levels were over the range of 82.7-110.9% with RSD less than 5.2% (n=3). Under the optimized conditions the enrichment factors for the four fluoroquinolones were ranged from 32 to 134 folds. The presented method was applied for the determination of four fluoroquinolones in pharmaceutical wastewater samples. PMID- 20828968 TI - The identification of rimonabant polymorphs, sibutramine and analogues of both in counterfeit Acomplia bought on the internet. AB - Acomplia was ordered over the internet resulting in the delivery of counterfeit Acomplia and imitation products. The tablets were analyzed for the presence of rimonabant. Using LC-DAD-MSn the presence of effective quantities of rimonabant was confirmed in samples A-D. Samples A and D also contained traces of the rimonabant analogue NIDA-41020. Furthermore, NIR spectroscopy on the tablets indicated the presence of an unapproved rimonabant polymorph in samples C and D which was confirmed by Raman spectroscopy and X-ray diffraction (XRD). In sample E a low dose of sibutramine was found as well traces of N-desmethylsibutramine and bis-N-desmethylsibutramine. Rimonabant was withdrawn from the market because of serious adverse events and lack of efficacy. The availability of poor quality products with rimonabant, impurities and unapproved polymorphs is worrying. Suspect weight-loss medicines should be screened for the presence of novel analogues. PMID- 20828969 TI - Determination of propofol UDP-glucuronosyltransferase (UGT) activities in hepatic microsomes from different species by UFLC-ESI-MS. AB - Propofol O-glucuronidation has been used as probe reaction to phenotype UGT1A9 activity in human liver, thus a sensitive and specific method for determination of propofol O-glucuronide (PG) is urgently desirable. In the current study, a new LC-ESI-MS method for determination of PG in hepatic microsomes from human (HLM), monkey (CyLM), dog (DLM), minipig (PLM), rat (RLM) and mouse (MLM) was developed and validated using 4-methylumbelliferyl-beta-d-glucuronide as an internal standard (IS). PG and IS was separated by a Shim-pack XR-ODS column (100 mm * 2.0mm, 2.2 MUm, Shimadzu) under gradient conditions with the mobile phase of acetonitrile and water containing 0.2% acetic acid (v/v). The mass spectrometric detection was performed under selected ion monitoring (SIM) for PG at m/z 353 and IS at m/z 351. The assay exhibited linearity over the range 0.05-30 MUM for PG with the correlation coefficient of 0.9995. The intra- and inter-day precision was less than 7.2%, with accuracy in the range 93.8-107.5%. The developed method was successfully used for characterizing interspecies and human individual differences in the O-glucuronidation activity towards propofol, as well as investigating inhibitory effects of androsterone and phenylbutazone on propofol O glucuronidation in HLM. PMID- 20828970 TI - A liquid chromatography-tandem mass spectrometry method for the quantification of PAC-1 in rat plasma. AB - A sensitive and specific liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) method was developed and validated for the determination of PAC-1 in rat plasma. After extraction with ethyl acetate, the chromatographic separation was carried out on an ACQUITY UPLCTM BEH C(18) column, with acetonitrile and water (39:61 (v/v) both containing 0.1% formic acid) as mobile phase at a flow rate of 0.20 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring (MRM) mode via electrospray ionization (ESI) source. The calibration curve was linear over the range of 10-1500 ng/mL (r>0.99). The LOQ was evaluated to be 0.3 ng/mL. The method described herein is sensitive, selective and faster than other existing method, and was successfully applied to the pharmacokinetic study and gender difference investigation of PAC-1 after oral administration in rats. PMID- 20828971 TI - A new bioassay for the immunocytokine L19-IL2 for simultaneous analysis of both functional moieties. AB - Currently, cancer directed new biological entities (NBEs) in the pharmaceutical R&D pipelines are derived from monoclonal antibodies in various formats, such as immunocytokines. Generally, immunocytokines are bi-functional molecules that consist of a specific targeting antibody-based portion and a linked cytokine. To confirm the quality of the drug product both moieties have to be characterized using appropriate techniques. Until now, the binding capacity of antibodies is usually examined by ligand binding assays whereas the biological activity of the linked cytokine is determined by cell-based potency assays. However, the simultaneous analysis of both functional moieties in a single assay format has not been described so far. In this paper we present a newly designed bioassay format for the anti-cancer immunocytokine L19-IL2, comprising of the human vascular targeting single-chain Fv L19 and human interleukin 2 (IL2). This new potency assay allows simultaneous analysis of both moieties, thus specific L19 binding capacity and the ability of IL2 to induce the proliferation of the detector cytotoxic T-cell line CTLL-2. Assay development was performed with special focus on application of different fitting models for the sigmoid dose response curves to evaluate the influence of model optimization on the validity of assay results. For assay validation generally accepted characteristics were determined. Assay specificity was shown by testing L19-IL2 related compounds. All other validation parameters were derived from 25 batch runs using five nominal L19-IL2 concentrations, covering a range from 60% to 140% of the standard's potency. Accuracy ranged from -3.4% to -6.9% relative error (%RE). Interbatch precision ranged from 6.1% to 10.6% coefficient of variation (%CV). For assay linearity a coefficient of determination (R(2)) of 0.9992 was found. Assay robustness was shown with L19-IL2 samples after three freeze-thaw cycles and also with different cell passages of the used cytotoxic T-cell line. Based on the data, we conclude that this assay is valid for potency estimation of the immunocytokine L19-IL2. Moreover, this format represents a major improvement compared to other approaches which only allow potency evaluation of both functional moieties in separate assays. In general the underlying assay principle described seems suitable for potency determination of other immunocytokines. PMID- 20828972 TI - Rhabdomyolysis-induced acute renal failure associated with 2009 influenza A (H1N1) virus infection in a child with Crigler-Najjar syndrome. PMID- 20828973 TI - Elevated troponin T levels in massive pulmonary embolism without an abnormal D dimer level. PMID- 20828974 TI - Electroencephalography during out-of-hospital cardiopulmonary resuscitation. AB - BACKGROUND: At the present time there is no parameter that can estimate the quality of cerebral perfusion and possible success of cerebral resuscitation during advanced cardiac life support (ACLS) efforts. In recent years, various attempts have been made to use electroencephalography (EEG)-based cerebral neuromonitoring to assess the effectiveness of cardiopulmonary resuscitation (CPR). OBJECTIVES: The Cerebral State Monitor M3 (Danmeter A/S, Odense, Denmark) is a portable, single-channel EEG monitor that provides the user with different EEG-based parameters and the raw waveform EEG to measure cerebral activity. CASE REPORT: We report two cases of out-of-hospital CPR with single-channel EEG monitoring conducted parallel to ACLS with external chest compressions. We demonstrate an artifact in waveform EEG recordings that is caused by the external chest compressions, and that leads to a miscalculation of the Burst Suppression Ratio and Cerebral State Index. CONCLUSION: These cases suggest that digitally processed EEG-monitoring is not a useful tool during CPR. PMID- 20828975 TI - Patient satisfaction in the emergency department and the use of business cards by physicians. AB - BACKGROUND: Emergency departments (EDs) across the country become increasingly crowded. Methods to improve patient satisfaction are becoming increasingly important. OBJECTIVE: To determine if the use of business cards by emergency physicians improves patient satisfaction. METHODS: A prospective, convenience sample of ED patients were surveyed in a tertiary care, suburban teaching hospital. Inclusion criteria were limited to an understanding of written and spoken English. Excluded patients included those with altered mental status or too ill to complete a survey. Patients were assigned to receive a business card on alternate days in the ED from the treating physician(s) during their patient introductions. The business cards listed the physician's name and position (resident or attending physician) and the institution name and phone number. Before hospital admission or discharge, a research assistant asked patients to complete a questionnaire regarding their ED visit to determine patient satisfaction. RESULTS: Three hundred-twenty patients were approached to complete the questionnaire and 259 patients (81%) completed it. Patient demographics were similar in both the business card and non-business-card groups. There were no statistically significant differences for patient responses to any of the study questions whether or not they received a business card during the physician introduction. CONCLUSION: The use of business cards during physician introduction in the ED does not improve patient satisfaction. PMID- 20828976 TI - Challenges in primary care relationships: seeing it from both sides. AB - OBJECTIVE: This qualitative study explored perspectives of primary care providers and patients in challenging relationships. METHODS: In 2007, we conducted semi structured interviews with providers recruited from 12 clinics affiliated with a U.S. academic center. Providers identified patients with whom they had ongoing "challenging relationships," and we interviewed the first consenting patient for each provider. We compared numeric ratings of relationship quality statistically. Using an editing analysis style, >=2 investigators coded transcripts to identify themes. RESULTS: Seventeen dyads participated. Providers averaged 14 years in practice. Most were Caucasian (88%) and female (59%). The mean patient age was 49 years, 59% were Caucasian, and 71% female. Relationships averaged 4.6 years. On a 1-10 scale, patients' ratings of the relationship quality (median 9) significantly exceeded providers' ratings (median 5, p=0.002). Three major themes emerged: patients view relationships more positively than providers, the challenges of guarding emotions, and trust matters in challenging relationships. CONCLUSION: Patients felt more positively about these relationships than providers perceived. Both sought ways to achieve mutual trust, despite barriers arising from guarded emotions. PRACTICE IMPLICATIONS: Providers in challenging relationships should consider exploring their patients' views, as they may feel reassured that patients appreciate their efforts and have trust in them. PMID- 20828977 TI - FDG-PET probe-guided surgery for recurrent retroperitoneal testicular tumor recurrences. AB - AIM: Tumor marker based recurrences of previously treated testicular cancer are generally detected with CT scan. They sometimes cannot be visualized with conventional morphologic imaging. FDG-PET has the ability to detect these recurrences. PET probe-guided surgery, may facilitate the extent of surgery and optimize the surgical resection. METHODS: Three patients with resectable 2nd or 3rd recurrent testicular cancer based on elevated tumor markers after previous various chemotherapy schedules and resections of residual retroperitoneal tumor masses were included in this study. A diagnostic FDG-PET was performed and a hotspot in previously operated area of the retroperitoneal space in all three patients was visualized. PET probe-guided surgery was performed using a high energy gamma probe 3 h post-injection of 500 MBq FDG. RESULTS: All patients showed extended adhesions and scar tissue in the retroperitoneal area due to the previous surgeries. Pre-operative PET/CT scan showed a good correlation with intra-operative PET probe-guided detection of recurrent lesions. There was a high target to background ratio (TGB) of 5:1 during the procedure. In one patient, a 2 cm large lesion, which did not show on pre-operative FDG-PET scan, was detected with the PET probe. Histopathologic tissue evaluation demonstrated recurrent vital tumor in all PET probe positive lesions. CONCLUSIONS: PET probe-guided surgery seems to be a promising tool to localize FDG-PET positive lesion in recurrent testicular cancer in hardly accessible surgical locations. PET probe guided surgery might be a useful technique in surgical oncology for recurrent testicular cancer and has the potential to be applied in surgery of other malignant diseases. PMID- 20828978 TI - Transposed right colon segment for vaginal reconstruction after pelvic exenteration. AB - Vaginal reconstruction following pelvic exenteration surgery for malignant disease is an important step in the physical and psychological rehabilitation of such patients. Planning of such procedures must include a strategy for reconstruction of the vagina and the oncological surgical team must be aware of the surgical techniques available in order to optimally plan and execute such procedures. We described a procedure which involves supralevator exenteration of the pelvis along with primary colorectal anastomosis. A transposed right colon segment is used to reconstruct the vagina and an omental flap is interpositioned between the reconstructed vagina and the colorectal anastomosis. The procedure is described in the text and in a didactic video. PMID- 20828979 TI - Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic response. AB - PURPOSE: To assess the safety and efficacy of a new neoadjuvant chemoradiation (CRT) docetaxel-based regimen in patients with resectable adenocarcinoma of the pancreatic head or body. PATIENTS AND METHODS: 34 patients with histologically confirmed resectable pancreatic adenocarcinoma were included in this prospective two-center phase II study. Radiotherapy was delivered at the dose of 45 Gy in 25 fractions of 1.8 Gy per fractions, 5 days/week, over 5 weeks. Docetaxel was administered as a 1-h intravenous (IV) infusion repeated every week during 5 weeks. The dose was 30 mg/m(2)/week. All patients were restaged after completion of CRT. RESULTS: Tumor progression was documented in 11 patients (32%), stable disease was documented in 20 patients (59%), and partial remission was documented in 3 patients (9%). 23 patients still with local disease at restaging underwent explorative laparotomy. Of this, 17 patients (50%) had a curative pancreaticoduodenectomy with lymphadenectomy. Morbidity and mortality rates were 29% and 0%, respectively. Three patients (17%) had complete histological responses and 5 patients had minimal residual disease. All resected patients (n = 17) underwent R0 resection. The median and five-year survival times for the resected patients were 32 months and 41%, respectively. Among the resected patients, ten (59%) died as a result of recurrent pancreatic cancer without local tumor bed recurrence. CONCLUSIONS: Neoadjuvant docetaxel-based chemoradiation is well-tolerated. Resected patients had a prolonged survival time. Further studies are needed to confirm our findings and determine the role of such a neoadjuvant approach. PMID- 20828980 TI - Imaging patterns of atypical renal cell carcinoma recurrence: a pictorial review. PMID- 20828981 TI - Caregiver perspectives on discussions about the use of intensive treatments in cystic fibrosis. AB - CONTEXT: Intensive treatments intended to sustain life are often used for patients with advanced cystic fibrosis (CF). There are no guidelines for selecting patients whose survival and quality of life may be enhanced by such treatments or for communication with patients and caregivers about possible treatment outcomes. OBJECTIVES: We aimed to describe caregivers' perspectives on decision making for the use of intensive treatments for patients with advanced CF lung disease. METHODS: We conducted semi-structured interviews with 36 caregivers of 36 patients who died of CF about treatment preference discussions and solicited recommendations for improving discussions. RESULTS: Twenty (56%) patients received intensive treatments during the last week of life. Twenty-two (61%) caregivers reported ever having discussed intensive treatment preferences with a physician, and 17 (77%) of these discussions were initiated during an acute illness. Only 14 (39%) of all patients participated. Caregivers expressed less certainty about consistency of treatments with patient preferences when patients did not participate. Twenty-nine (81%) caregivers endorsed first discussing treatment preferences during a period of medical stability. CONCLUSIONS: Discussions about preferences for the use of intensive treatments for patients with CF often take place during episodes of acute illness and may be delayed until patients themselves are too ill to participate. Bereaved caregivers suggest first addressing intensive treatment preferences during a stable period so that patient preferences are understood and unwanted treatments are minimized. PMID- 20828982 TI - Aggressive end-of-life care significantly influenced propensity for hospice enrollment within the last three days of life for Taiwanese cancer decedents. AB - CONTEXT: Late hospice enrollment exacts a substantial toll from patients, families, hospices, and society. The relationship between the propensity for late hospice enrollment and aggressive health services received at the end of life (EOL) has been underinvestigated. OBJECTIVES: To identify determinants of hospice enrollment within the last three days of life. METHODS: Retrospective population based cohort study using administrative data for 31,529 Taiwanese cancer decedents who used hospice care in their last year of life. RESULTS: Rates of hospice enrollment within the last three days of life (16.80%-18.73%) remained constant over 2001-2006. After adjustment for patient demographics and disease characteristics, physician specialty, availability of health care resources at the hospital and regional levels, and historical trends, late hospice enrollment was more likely if Taiwanese cancer patients received chemotherapy, had multiple emergency room visits or hospital admissions, and used the intensive care unit in their last month of life (adjusted odds ratio [95% confidence interval] (AOR [95% CI]): 1.61 [1.44-1.80], 1.40 [1.29-1.52], 1.78 [1.51-2.09], and 1.45 [1.19-1.76], respectively). Late hospice enrollment was less likely for patients with hospital stays>14 days or who received cardiopulmonary resuscitation in their last month of life (AOR [95% CI]: 0.51 [0.45-0.58] and 0.41 [0.25-0.65], respectively). CONCLUSION: Aggressive EOL care played a more significant role than patient, physician, or hospital characteristics in determining the propensity of Taiwanese cancer patients to be enrolled in hospice care within their last three days of life. Clinical and health policies should aim to avoid aggressive care when it will not benefit patients but may preclude timely hospice enrollment. PMID- 20828983 TI - The role of meta-cognition and parenting in adolescent worry. AB - In the meta-cognitive model of worry, positive, and negative beliefs about worry interact to make worry problematic. These beliefs have been found to be associated with anxiety in adolescents, but it is unknown whether they are associated with worry. Furthermore, it may be via cognitive mechanisms such as these, or directly through behavior, that parents influence their child's worry. The current study aimed to explore whether adolescent meta-cognition and parenting behaviors and meta-cognitions were associated with adolescent worry. Results indicated that meta-cognitions were specifically associated with worry in adolescents, but there was little evidence that parenting was. Parental worry on the other hand was associated with both parent and child reported parenting. It is concluded that the meta-cognitive model of worry may be relevant in adolescents, but that further research is required to explore how parents influence adolescent worry. PMID- 20828984 TI - Achieving certainty about the structure of intolerance of uncertainty in a treatment-seeking sample with anxiety and depression. AB - Evidence is accumulating that intolerance of uncertainty (IU) may be a transdiagnostic maintaining factor across the anxiety disorders and depression. However, psychometric studies of the most commonly used measure of IU have typically used undergraduate students, and the factor structure has been highly inconsistent. Previous studies have also tended to focus on one diagnostic subgroup or related symptom, thereby limiting transdiagnostic comparisons. The first aim of this study was to test the latent structure of a commonly used measure of IU in a treatment-seeking sample with anxiety and depression (n=463). The second aim was to examine psychometric properties of the best fitting solution, including internal reliability, convergent validity, and discriminant validity. Confirmatory factor analysis was used to compare the goodness of fit of five models previously found with undergraduate and community samples. A two factor solution, comprising of prospective anxiety and inhibitory anxiety, was the best fitting model. The total scale and subscales demonstrated excellent internal reliability. Convergent validity was demonstrated by the scales correlating with symptoms associated with five anxiety disorders and depression, as well as neuroticism, distress and disability. IU explained unique variance in all symptom measures, even after controlling for neuroticism and other symptom measures. Evidence of discriminant validity was also found for each IU subscale. Findings support reliability and validity of the two-factor solution, and are consistent with IU being a transdiagnostic maintaining factor. PMID- 20828985 TI - The characteristics of AD/HD symptoms, self-esteem, and aggression among serious juvenile offenders in Japan. AB - Eighty-three inmates of a correctional facility, who committed serious offences, participated in this study. They were all male and aged 14-17 years, with a mean age of 15.5 (SD=1.21) years. Eighty-six age- and sex-matched controls were enrolled. Some psychological questionnaires such as on self-esteem and aggression were conducted in both groups. The aims of the present study were as follows: first, to clarify the characteristics of the subjects, such as IQ, psychological traits, and AD/HD symptoms; second, to examine how the subjects' self-esteem and aggression changed and/or improved on admission and at the time of parole (during the correctional educational period). For the results of paired t-tests, the self esteem of subjects changed little. Therefore, our findings suggest that the improvement of antisocial behavior and transition of self-esteem are not directly linked with each other. Most inmates of the correctional facility showed a borderline IQ, markedly low self-esteem, unstable aggression, and serious AD/HD symptoms. In addition, the low self-esteem of subjects was not consistently elevated during the correctional education period. Moreover, their aggression was strongly correlated with AD/HD symptoms, both on admission and at the time of parole. PMID- 20828986 TI - The research on the status, rehabilitation, education, vocational development, social integration and support services related to intellectual disability in China. AB - Intellectual disability (ID) is a prevalent form of non-progressive cognitive impairment. The objectives of this articles are: to analyze the changes of ID in China, including its definition, prevalence, rehabilitation, education, vocational development, social life and support services; to review and to compare the issues of intellectual disability in China with the international literatures and research studies and to provide useful updated information and reference data for scholars and researchers who study intellectual disability. Analyzed the data obtained from two national sample surveys on disability with respect to intellectual disability in China. The estimated prevalence of individuals with intellectual disabilities in China was 7.50/00 in 2006 nationally which was lower than the previous results obtained in the 1987 national survey. The fourth level of ID showed a downward trend, while the proportion among the population aged 60 and over with ID tended to increase. The 2006 national survey indicated that the prevalence of ID in rural areas was higher than that in urban areas. This finding was consistent with the national survey conducted in 1987. As indicated by the 2006 national survey, 29.4% cases had no known causes for the ID, the proportion tended to decrease as compared with the first survey. However, when compared to the 1987 report, the proportion of senile dementia among older people as indicated by the 2006 report was higher than before. During the past years, the prevention of ID and the quality of life of individuals with ID have improved due to the enactment and implementation of a series of national laws and regulations, however, there is more that needs to be done in the areas of education, vocational development, social integration and support services for individuals with ID in order to improve the quality of life of individuals with ID in China. The findings of this study are consistent with the research findings presented in the international literatures. ID is the conditions that deserve further study and deserve the attention of policy makers and rehabilitation professionals in China. Furthermore, with the ageing of population in China and its impact to the social security system, the in-depth study of ID and its implications has become more pertinent in China in the future. PMID- 20828987 TI - The psychometric properties of the Socio-Moral Reflection Measure--Short Form and the Moral Theme Inventory for men with and without intellectual disabilities. AB - Drawing conclusions from the literature regarding the moral development of people with intellectual disabilities (IDs) is difficult because of the use of unstandardised and idiosyncratic measures. In order to address this short-coming, a moral reasoning production measure (the Socio-Moral Reflection Measure--Short Form; SRM-SF) and a recognition measure (the Moral Theme Inventory; MTI) were presented to men with and without IDs who had no known history of engaging in illegal behaviour. The instruments were completed on two occasions, separated by a two-week interval, in order to investigate their basic psychometric properties. The results indicated that there was a strong relationship between the MTI and the SRM-SF, suggesting that the MTI has convergent validity. The internal consistency of the MTI and the SRM-SF ranged from moderate to substantial for both men with and without IDs. However, the test-retest reliability of the MTI was poor for men with IDs, while it was good for men without IDs. The test-retest reliability of the SRM-SF was good for both men with and without IDs. Comparison of the moral reasoning abilities of men with and without IDs suggested that many of the differences between the two groups could be accounted for by general intellectual functioning. The exception was overall score on the SRM-SF and moral reasoning in relation to the law, where men with IDs scored at stage 2(1), when intelligence was controlled. The results were interpreted by suggesting that the relationship between moral reasoning and illegal behaviour may take an inverted U curve shape, moderated by intelligence. PMID- 20828988 TI - Mobilizing the stiff hand: combining theory and evidence to improve clinical outcomes. AB - The purpose of this narrative review is to provide a clinically reasonable guide to intervention choices, by combining a sound understanding of theory with available research evidence. The pathology of contracture formation is presented within the context of tissue repair. The soft tissue response to stress is explained and the optimal "dose" of treatment is discussed. The evidence behind the use of exercise, joint mobilization, continuous passive motion, casting motion to mobilize stiffness, and mobilizing splinting is examined. Recommendations regarding treatment implementation and future research needs are highlighted. The importance of mobilizing splinting and exercise as treatment modalities in the management of joint contracture is demonstrated. LEVEL OF EVIDENCE: 5. PMID- 20828989 TI - Comparison of the stability of bioabsorbable and titanium osteosynthesis materials for rigid internal fixation in orthognathic surgery. A prospective randomized controlled study in 101 patients with 192 osteotomies. AB - The purpose of this study was to evaluate the stability of rigid internal fixation in orthognathic surgery with either bioabsorbable or titanium osteosynthesis. Orthognathic surgery was performed on 101 patients. Bilateral sagittal ramus osteotomy was performed on 55 patients using bioabsorbable osteosynthesis in 26 and titanium osteosynthesis in 29 patients. Le Fort I osteotomy was performed on 28 patients with bioabsorbable and titanium osteosynthesis in 17 and 11 patients, respectively. Bimaxillary osteotomies were performed on 18 patients (8 were fixated with bioabsorbable and 10 with titanium osteosynthesis). Poly-70L/30DL-lactide copolymer (PLDLA) consisting of 70% L lactide and 30% DL-lactide was used as the bioabsorbable osteosynthesis material. These plates and screws were compared with corresponding titanium materials. Statistically a clear relapse tendency was seen in skeletal measurements in all patient groups but without clinical importance. Radiological follow-up time was at least 18.3 months and clinical follow-up time at least 6.3 years. The materials used did not cause any adverse reaction except in three cases, one in the bioabsorbable group and two in the titanium group where fistula in connection with the osteosynthesis material was noted resulting in removal of the materials. PMID- 20828990 TI - Epileptogenic ion channel mutations: from bedside to bench and, hopefully, back again. AB - Mutations of genes coding for ion channels cause several genetically determined human epileptic syndromes. The identification of a gene variant linked to a particular disease gives important information, but it is usually necessary to perform functional studies in order to completely disclose the pathogenic mechanisms. The functional consequences of epileptogenic mutations have been studied both in vitro and in vivo with several experimental systems, studies that have provided significant knowledge on the pathogenic mechanisms that leads to inherited human epilepsies, and possibly also on the pathogenic mechanisms of non genetic human epilepsies due to "acquired channelopathies". However, several open issues remain and difficulties in the interpretation of the experimental data have arisen that limit translational applications. We will highlight the value and the limits of different approaches to the study of epileptogenic channelopathies, focussing on the importance of the experimental systems in the assessment of the functional effects of the mutations and on the possible applications of the obtained results to the clinical practice. PMID- 20828991 TI - Cognitive and symptomatic predictors of functional disability in schizophrenia. AB - BACKGROUND: Neurocognition and negative symptoms play a major role in predicting functional outcomes in patients with schizophrenia. Few studies have assessed the relationship between functional outcomes and the MATRICS consensus cognition battery (MCCB), which will be central to future clinical trials of cognitive enhancing agents. AIMS: To assess the role of individual MCCB domains on functional outcomes. METHOD: 185 stable outpatients with schizophrenia were enrolled and assessed with the MCCB, Social Adjustment Scale-II (SAS-II) and Multidimensional Scale for Independent Functioning (MSIF), along with BPRS and SANS. RESULTS: We found significant relationships between MCCB neurocognitive domain scores, negative symptoms and aspects of functional outcome in schizophrenia. Specifically, we found that work/education functioning is predicted by working memory performance and negative symptoms; residential status (independent living) is predicted by verbal memory scores; and social functioning is predicted by social cognition, attention and negative symptoms. We also found that negative symptom severity was not related to residential status, even though it demonstrated the predicted associations to work and social functioning. CONCLUSION: To our knowledge, this is the first study to assess cognition and functional outcomes using MCCB, SAS II and MSIF. Our results extend prior work and help provide more data on the relationships between cognition, symptoms and functional outcome using "real world" measures. PMID- 20828992 TI - Off-label prescription of tigecycline: clinical and microbiological characteristics and outcomes. PMID- 20828993 TI - Prescribing practices in psychiatric hospitals in Eastern Europe. AB - BACKGROUND: There has been no evidence about the prescribing practices in psychiatric care in Eastern Europe. AIMS: To examine the patterns of psychotropic prescribing in five countries of Eastern Europe. METHOD: We conducted a one-day census of psychiatric treatments used in eight psychiatric hospitals in Albania, Croatia, Macedonia, Serbia and Romania. We examined clinical records and medication charts of 1304 patients. RESULTS: The use of polypharmacy was frequent across all diagnostic groups. Only 6.8% of patients were on monotherapy. The mean number of prescribed drugs was 2.8 (SD 0.97) with 26.5% receiving two drugs, 42.1% receiving three drugs and 22.1% being prescribed four or more psychotropic drugs. Typical antipsychotics were prescribed to 63% and atypical antipsychotics to 40% of patients with psychosis. Older generations of antidepressants were prescribed to 29% of patients with depression. Anxiolitic drugs were prescribed to 20.4% and benzodiazepines to 68.5% of patients. One third of patients received an anticholinergic drug on a regular basis. CONCLUSIONS: Older generation antipsychotics and antidepressants were used more frequently than in the countries of Western Europe. Psychotropic polypharmacy is a common practice. There is a need for adopting more evidence-based practice in psychiatric care in these countries. PMID- 20828994 TI - Terpene microemulsions for transdermal curcumin delivery: effects of terpenes and cosurfactants. AB - Microemulsion systems composed of terpenes, polysorbate 80, cosurfactants, and water were investigated as transdermal delivery vehicles for curcumin. Pseudoternary phase diagrams of three terpenes (limonene, 1,8-cineole, and alpha terpineol) at a constant surfactant/cosurfactant ratio (1:1) were constructed to illustrate their phase behaviors. Limonene combined with cosurfactants like ethanol, isopropanol, and propylene glycol were employed as microemulsion ingredients to study their potential for transdermal curcumin delivery. The transdermal delivery efficacy and skin retention of curcumin were evaluated using neonate pig skin mounted on a Franz diffusion cell. The curcumin permeation rates in the limonene microemulsion studied were 30- and 44-fold higher than those of 1,8-cineole and alpha-terpineol microemulsions, respectively. Significant effects on the skin permeation rates were observed from microemulsions containing different limonene/water contents. Histological examination of treated skin was performed to investigate the change of skin morphologies. Characteristics such as droplet size, conductivity, interfacial tension, and viscosity were analyzed to understand the physicochemical properties of the transdermal microemulsions. In conclusion, microemulsions loaded with curcumin were successfully optimized for transdermal delivery after screening various terpenes, cosurfactants, and limonene/water ratios. These results indicate that the limonene microemulsion system is a promising tool for the percutaneous delivery of curcumin. PMID- 20828995 TI - Self-association behavior of amitriptyline hydrochloride as a function of temperature and additive (inorganic salts and ureas) concentration. AB - The critical micelle concentration (cmc) of an amphiphilic drug amitriptyline hydrochloride (AMT) was determined in the presence of varying amounts of inorganic salts (NaF, NaCl, NaBr, LiCl, KCl), urea and thiourea over the temperature range 293-308 K by conductometric and dye solubilization (ambient) techniques. The cmc values showed an inverted U-shaped behavior with temperature. In the presence of salts the cmc decreased which is explained on the basis of the nature and ion size. Urea and thiourea, at low concentrations (0.2mM urea and 0.1mM thiourea), decreased the cmc, whereas, at high concentrations, increase was observed with both the additives. Relevant thermodynamic parameters were also evaluated and discussed. PMID- 20828996 TI - The influence of chitosan valence on the complexation and transfection of DNA: the weaker the DNA-chitosan binding the higher the transfection efficiency. AB - The DNA-chitosan polyplexes have attracted for some years now the attention of physical-chemists and biologists for their potential use in gene therapy, however, the correlation between the physicochemical properties of these polyplexes with their transfection efficiency remains still unclear. In a recent paper we demonstrated by means of DLS that the DNA-chitosan complexation is favored at acidic conditions considering that fewer amounts of chitosan were required to compact the DNA. As a second study, in the present work we analyze the influence of chitosan valence on the complexation and transfection of DNA. Three chitosans of different molecular weights (three different valences) are characterized as gene carriers at 25 degrees C and pH 5 over a wide range of chitosan-Nitrogen to DNA-Phosphate molar ratios, N/P, by means of conductometry, electrophoretic mobility, isothermal titration calorimetry (ITC), transmission electron microscopy (TEM), atomic force microscopy (AFM), and beta-galactosidase and luciferase expression assays. PMID- 20828997 TI - Solubilization of fullerene C60 in micellar solutions of different solubilizers. AB - Fullerene (C(60)), the third carbon allotrope, is a classical engineered material with the potential application in biomedicine. However, extremely high hydrophobicity of fullerene hampers its direct biomedical evaluation and application. In this work, we investigated the solubilization of fullerene using 9 different solubility enhancers: Tween 20, Tween 60, Tween 80, Triton X-100, PVP, polyoxyethylene (10) lauryl ether, n-dodecyl trimethylammonium chloride, myristyl trimethylammonium bromide and sodium dodecyl sulphate and evaluated its antioxidant activity in biorelevant media. The presence of C(60) entrapped in surfactant micelles was confirmed by UV/VIS spectrometry. The efficacy of each modifier was evaluated by chemometric analysis using experimental data for investigating the relationship between solubilization and particle size distribution. Hierarchical clustering and principal component analysis was applied and showed that non-ionic surfactants provide better solubilization efficacy (>85%). A correlation was established (r=0.975) between the degree of solubilization and the surfactant structure. This correlation may be used for prediction of C(60) solubilization with non-tested solubility modifiers. Since the main potential biomedical applications of fullerene are based on its free radical quenching ability, we tested the antioxidant potential of fullerene micellar solutions. Lipid peroxidation tests showed that the micellar solutions of fullerene with Triton and polyoxyethylene lauryl ether kept high radical scavenging activity, comparable to that of aqueous suspension of fullerene and BHT. The results of this work provide a platform for further solubilization and testing of pristine fullerene and its hydrophobic derivatives in a biological benign environment. PMID- 20828998 TI - Synthesis and characterization of COLL-PVA/HA hybrid materials with stratified morphology. AB - This work presents the synthesis of two hybrid materials: collagen (COLL) polyvinyl alcohol (PVA) (1:2 wt) and collagen-polyvinyl alcohol/hydroxyapatite (HA) (1:2:3 wt). Starting from the above compositions, different kinds of composites were obtained based on the drying methods: controlled drying at 30 degrees C and freeze drying. The materials were analysed by X-ray diffraction (XRD), Fourier transform infrared microscopy (FTIR) and scanning electron microscopy (SEM) as well as by measuring the density, porosity and absorption of xylene for each sample by Arthur method. Based on the SEM images, the freeze drying and the controlled drying could be clearly concluded to lead to porous and dense COLL-PVA/HA hybrid materials, respectively. Such materials have exhibited a stratified morphology, the distance between sheets increasing with the increase of the organic components content. Based on the literature data, the obtained COLL-PVA/HA composite materials are valuable bone grafts materials and drug delivery systems. PMID- 20828999 TI - Biosynthesis of gold nanoparticles utilizing marine sponge Acanthella elongata (Dendy, 1905). AB - The growing trend of exploring bacteria, fungi, actinomycetes and plant materials for the biosynthesis of nanoparticles is considered as eco friendly and a green technological approach. In this backdrop the present study reports the synthesis of gold (Au) nanoparticles from gold precursor using the extract derived from the marine sponge, Acanthella elongata (Dendy, 1905) belonging to the primitive phylum Porifera. Water-soluble organics present in the marine sponge extract were mainly responsible for the reduction of gold ions to nano-sized Au particles. The sponge extract added to 10-3 M HAuCl4 aqueous solution at 45 degrees C changed to pinkish ruby red color solution and confirm the bioreduction within 4 h with continuous stirring. UV-visible spectrum of the aqueous medium containing gold nanoparticles showed a peak around 526 nm. High-resolution transmission electron micrographs (HR-TEM) confirmed the monodispersed and spherical shaped with the size ranges from 7 to 20 nm, however a maximum number of particles were in 15 nm diameter. Through Fourier transform infrared spectroscopy (FT-IR) analysis, the reducing agent in the marine sponge extract was identified which is attributed for the biosynthesis of gold colloids. The XRD analysis respects the Bragg's law and confirmed the crystalline nature of the gold nanoparticles. PMID- 20829000 TI - Excess fibrinogen adsorption to monolayers of mixed lipids. AB - Adsorption of fibrinogen to the monolayers of mixed lipids, dipalmitoyl phosphatidyl choline (DPPC) and eicosylamine (EA) was measured at a surface pressure of 20 mN/m by an in situ surface plasmon resonance technique. Pressure area isotherms of DPPC+EA mixtures on water and buffer subphases indicated good lipid miscibility and some contraction of the monolayers at intermediate and higher surface pressures. Surface electric potential of the DPPC+EA monolayers showed excess values for intermediate DPPC:EA ratios. Fibrinogen adsorption and its adsorption rates from a dilute solution (0.03 mg/ml) were proportional to the fraction of EA in the monolayer indicating that protein binding was primarily driven by electrostatic interactions between positive EA charges in the monolayer and a net negative protein charge. At a higher protein concentration (0.06 mg/ml) both the fibrinogen adsorbed amount and its maximum adsorption rate showed excess values relative to the pure EA for 1:1, 2:1 and 3:1 DPPC+EA monolayers. This excess adsorption could be explained, in part, by the contraction of the monolayers with intermediate DPPC:EA ratios which resulted in an excess surface electric potential. PMID- 20829001 TI - [Current events in fetal magnetic resonance]. AB - The challenge of fetal imaging is crucial in France because of the law allowing termination of pregnancy (TOP) until the end of pregnancy. Fetal MRI is an imaging tool always used after ultrasonography (US). Its indications are pertinent only in relation with a prenatal center. Fetal MRI raises parental anxiety to take into account before and during the examination. To date, cerebral indications are predominant. Fetal brain maturation can be followed with MRI (gyration and myelination) but the optimal moment of a fetal MRI depends on the suspected pathology: the analysis of gyration is possible only by 28 WG, as before this time, the brain surface is smooth; in contrast, the posterior fossa demonstrates a definitive morphology since 20 WG. The ventriculomegaly is the most frequent call sign and includes various entities. MRI can disclose associated abnormalities (heterotopia, gyration, white matter, median line), which can suggest diagnosis and pronosis. A cystic pouch of the posterior fossa must lead to a careful analysis of cerebellum and brainstem to approach the diagnosis. Extracerebral indications become progressively larger and fetal MRI is a useful complementary tool after US to study tumors, particularly cervicothoracic masses. MRI can help to assess the level of bowel obstruction but multiple stenosis and post-stenotic bowel is difficult to evaluate. Fetal MRI can help to evaluate bilateral important pyelocalicial dilatation. PMID- 20829002 TI - Molecular and morphological evidence for a sister group relationship of the classes Armophorea and Litostomatea (Ciliophora, Intramacronucleata, Lamellicorticata infraphyl. nov.), with an account on basal litostomateans. AB - Based solely on the localization of the cytostome, Cavalier-Smith (2004) divided the ciliate subphylum Intramacronucleata into three infraphyla: the Spirotrichia, including Armophorea and Spirotrichea; the Rhabdophora, containing exclusively Litostomatea; and the Ventrata, comprising the remaining six intramacronucleate classes. This scheme is supported largely by 18S rRNA phylogenetic analyses presented here, except for the placement of the Armophorea. We argue that this group does not belong to the Spirotrichia but forms a lineage together with the Litostomatea because the molecular sister relationship of the Armophorea and Litostomatea is supported by two morphological and morphogenetic synapomorphies: (i) plate-like arranged postciliary microtubule ribbons, forming a layer right of and between the ciliary rows and (ii) a telokinetal stomatogenesis. Thus, we unite them into a new infraphylum, Lamellicorticata, which replaces Cavalier Smith's Rhabdophora. Further, our phylogenetic analyses consistently classify the most complex haptorian genus Dileptus basal to all other litostomateans, though morphological investigations suggest dileptids to be highly derived and possibly originating from a spathidiid ancestor. These discrepancies between molecular and morphological classifications have not as yet been investigated in detail. Thus, we propose an evolutionary scenario, explaining both the sister relationship of the Armophorea and Litostomatea, as well as the basal position of the morphologically complex dileptids. PMID- 20829003 TI - Laryngeal cancer treatment and survival differences across regional cancer centres in Ontario, Canada. AB - AIMS: We conducted a population-based study of practice patterns and outcome across the regional cancer centres providing care to patients with laryngeal cancer in the Province of Ontario, Canada. MATERIALS AND METHODS: : This was a retrospective cohort study of 1547 patients with cancers of the glottic or supraglottic larynx diagnosed between 1982 and 1995. Data were collected via chart review, including: patient and disease characteristics, treatment, waiting times and treatment volumes. Vital status was obtained from the Ontario Cancer Registry. Variations across the nine regional cancer centres are described and their effect on outcome explored. All analyses were stratified by stage I and II separately from stage III and IV. RESULTS: Treatments differed across centres (P<0.0001); for instance, in the stage I and II group, use of a daily dose of >2.54Gy varied from 0 to 87.6% and in the stage III and IV group, total laryngectomy rates varied from a low of 6% to a high of 53%. The percentage of patients waiting more than 6 weeks from diagnosis to first treatment varied from 17 to 49% (P<0.0001). Multivariate analysis revealed cause-specific survival differences that were not explained by control for case mix, treatment or waiting times. Differences ranged from an 82% risk reduction in one centre compared with the reference (stage I and II group, P=0.008) to a 153% increase in risk (stage III and IV group, P=0.02). Centre case volumes were not associated with cause specific survival. CONCLUSIONS: This study quantifies the degree of variation that can occur in the treatment and outcome of people with cancer. We cannot properly assess whether care delivery is of high quality until we have a better understanding of the factors that drive such variations. PMID- 20829004 TI - Radiofrequency ablation in the treatment of breast cancer liver metastases. AB - Minimally invasive, image-guided thermal ablation is gaining acceptance for the treatment of solid tumour deposits and its use is increasing. This overview discusses one method of thermal ablation in one palliative setting; the local control of breast cancer liver metastases (BCLM) using radiofrequency ablation. Breast cancer is common and over half of all women diagnosed with metastatic disease develop BCLM. The mainstay of therapy remains chemotherapy and supportive care, which may prolong survival to a median of 18-24 months. Despite breast cancer being considered a systemic disease, surgical series of metastectomy for BCLM have shown a survival advantage. Despite this, surgery for BCLM is rarely practiced due to the associated morbidity for a relatively meagre survival benefit. Similarly, radiofrequency ablation has been used for local control of BCLM; the reported series show a median survival of between 30 and 60 months, with no treatment-related deaths and only three serious treatment-related adverse events in 164 patients reported. Despite this, scepticism remains over the efficacy of BCLM ablation due to the heterogeneity of patient inclusion and selective nature of reporting. Randomised trials are needed to formulate robust evidence-based recommendations and direct the necessary allocation of health care resources. Whether or not local ablative treatment of BCLM conveys a survival advantage is an important consideration. However, in this non-curative setting, it is essential that other outcome measures are carefully evaluated in conjunction with survival, including symptoms (local and constitutional), quality of life and psychological morbidity. To these ends, a randomised, multicentre trial to assess best medical therapy alone versus best medical therapy plus radiofrequency ablation in patients presenting with newly diagnosed BCLM with or without the presence of stable extra-hepatic disease will shortly be underway. PMID- 20829005 TI - The surgical palliation of advanced head and neck cancer using photodynamic therapy. AB - End-stage head and neck cancer is a difficult disease to manage. The only curative treatment option remains surgery, but this is frequently not feasible. Often, however, significant palliation can be achieved with minimally invasive surgically directed treatments, such as photodynamic therapy. To avoid the morbidity of treating non-cancer areas, photodynamic therapy can now be very accurately directed by radiological imaging along pre-planned grids to document and optimise laser-guided photo-activation of the chemo-sensitiser. Rapid local tumour control often results, enabling the patient to benefit from both a higher quality and length of life. PMID- 20829006 TI - Correlation of currently used radiobiological parameters with local control and acute and late mucosal toxicity in randomised studies of altered fractionation for locally advanced head and neck cancer. AB - AIMS: There has been a resurgence in interest in radiobiological modelling in head and neck cancer. The aim of this study was to determine if currently used parameters accurately predict both tumour and toxicity outcomes. MATERIALS AND METHODS: Trials were identified from a recent meta-analysis of altered fractionation. The tumour biologically effective dose (tBED; alpha/beta=10Gy, t(k) [onset time of accelerated repopulation]=22 days, t(p) [average doubling time during accelerated repopulation]=3 days, alpha=0.3Gy(-1)), acute mucosal biologically effective dose (amBED; alpha/beta=10Gy, t(k)=7 days, t(p)=2.5 days, alpha=0.3Gy(-1)) and late mucosal biologically effective dose (lmBED; alpha/beta=3Gy) were calculated for each arm of each trial. The correlation between the absolute percentage difference in BED between treatment arms and the observed percentage difference in local control, acute grade 3 mucositis and late grade 3 mucosal reaction was then assessed. RESULTS: A strong correlation was observed between the percentage difference in tBED and the percentage difference in local control (P=0.006). A trend towards a correlation was seen between the percentage difference in amBED and the percentage difference in acute grade 3 mucositis (P=0.06). A significant correlation was observed between the percentage difference in lmBED and the percentage difference in grade 3 late mucosal toxicity (P=0.02). However, a 15% decrease in lmBED between control and experimental arms of the study was necessary for any sparing of late mucosal toxicity to be observed. CONCLUSIONS: Currently used parameters for tumour accurately predict outcomes in randomised trials of altered fractionation. Although the relationship may be more complex for late mucosal reaction, the presence of a correlation is noteworthy given the infrequent reporting or occurrence of this toxicity. In the future, radiobiological modelling with the addition of volumetric parameters will be highly relevant, given attempts to dose escalate with intensity-modulated radiotherapy in poor risk patients and de escalate in patients with an excellent prognosis. PMID- 20829007 TI - Effects of feeding urea and copper sulphate in different combinations on live body weight, carcass weight, percent weight to body weight of different organs and histopathological tissue changes in broilers. AB - The study was carried out on a total of 100 broiler chicks divided into six equal groups at day 7 of age. Birds were fed copper sulphate and urea in different combinations for up to 37 days and then the birds of all the groups were fed plan feed for one week. The general signs were an increased water intake, ruffled feathering, watery droppings along with salivation in treatment groups. These signs were mild in groups fed low level of urea, while were severe in fed higher levels of these compounds together. Mild to moderate gross changes were observed in the birds of group B, C and D, while more pronounced changes were seen in birds of group E and F. In the latter groups, the liver was pale to yellowish and fragile. Kidneys were enlarged, swollen, congested and sometimes hemorrhagic. Histologically, mild cytoplasmic vacuolation and condensation/pyknosis or disappearance of the nucleus in the cells of the liver and kidney were the salient changes observed in the treatment groups, those were severe in birds fed higher levels of the two compounds. Changes in lungs were congestion and edema. Changes in the bursa of Fabricius were mild cytoplasmic vacuolation, cell depletion and chromatolysis. The live and carcass weights were lower in broilers fed higher levels of both copper and urea than the control group. The weights of kidney and heart were higher in birds fed higher levels of both of the compounds than the control group. It can be concluded from the present study that urea above 2% and copper sulphate above 1 gm in combination cause tissue damage, especially the liver and kidneys. PMID- 20829008 TI - Protective effect of a cysteine prodrug and antioxidant, L-2-oxothiazolidine-4 carboxylate, against ethanol-induced gastric lesions in rats. AB - Earlier studies have suggested an important role of glutathione (GSH) in cytoprotection against free radicals induced oxidative damage. This study reports gastroprotective effects of a cysteine precursor, L-2-oxothiazolidine-4 carboxylate (OTC), in experimental models of gastric secretion and ulceration. Acid secretion studies (volume and acidity) were undertaken in pylorus-ligated rats whereas the gastric lesions were induced by ethanol. Different groups of animals were treated with OTC (0, 100, 200 and 400 mg/kg). The levels of gastric wall mucus, nonprotein sulfhydryls (NP-SH) and myeloperoxidase (MPO) were measured in the glandular stomach of rats following ethanol-induced gastric lesions. Both medium and high doses of OTC significantly reduced the volume and acidity of gastric secretion in pylorus-ligated rats. Pretreatment with OTC significantly and dose-dependently attenuated the formation of ethanol-induced gastric lesion. OTC significantly protected the gastric mucosa against ethanol induced depletion of gastric wall mucus, NP-SH and MPO. The gastroprotective effects of OTC may be attributed to its ability to inhibit neutrophils activity and replenish GSH demand. PMID- 20829009 TI - Antioxidant and hepatoprotective activity appraisal of four selected Fumaria species and their total phenol and flavonoid quantities. AB - Fumaria species (Fumariaceae) have been recorded to be used traditionally against liver-related disorders in many countries including Turkey. Oxidative stress is also known to be strongly associated with hepatic problems. Consequently, in the current study, the ethanol extracts of four Fumaria species; F. cilicica Hausskn., F. densiflora DC., F. kralikii Jordan and F. parviflora Lam. growing in Turkey were initially screened for their in vitro antioxidant activities by three methods; 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging test, Fe(+2) ferrozine test system for metal chelating test and ferric-ion reducing antioxidant power (FRAP) at 250, 500 and 1000 MUg/ml concentrations. Then, each of the ethanol extracts was fractionated into petroleum ether, chloroform, ethyl acetate and methanol fractions and their antioxidant activities were estimated by DPPH radical scavenging and xanthine oxidase inhibition tests at 1000 MUg/ml. In both tests, the chloroform and ethyl acetate fractions of F. cilicica were found to be the most active and were further investigated in in vivo hepatoprotective activity experiment against toxicity induced by CCl(4). Total phenol and flavonoid quantities of the ethanol extracts were determined spectrophotometrically using Folin-Ciocalteau's and AlCl(3) reagents, respectively. Our data revealed that the chloroform and ethyl acetate fractions of F. cilicica did not have hepatoprotective effect and the ethanol extracts exerted low antioxidant activity. Although protective effect of some Fumaria species in hepatic diseases was shown in several previous studies, this record seems to be not pertinent for F. cilicica. PMID- 20829010 TI - Nitrite pickling salt as an alternative to formaldehyde for embalming in veterinary anatomy--A study based on histo- and microbiological analyses. AB - Formaldehyde, the traditional embalming agent has negative health effects. Nitrite pickling salt has been reported to be a good and inexpensive alternative when supplemented with antioxidants, but the antioxidants caused yellowish colouration of cadavers, and damaged corrosion-resistant steel tables and stone floors. Here, nitrite pickling salt was supplemented with ethanol and Pluriol((r)) and tested for effectiveness as an embalming agent of twenty dog cadavers: 10 with open, and 10 with closed abdominal cavity. The texture of the tissue was monitored intermittently for 12 months throughout the course of an anatomical dissection class. Histological and microbiological analysis of samples from muscles, lungs, duodenum and colon were performed. Dogs with an open abdomen remained suitable for dissection purposes during the entire course. The abdominal organs of the closed cadavers lost their natural features, without histological signs of autolysis. Enterococcus spp., Staphylococcus spp., Micrococcus spp., Bacillus spp. and Clostridium perfringens were recorded after 24 weeks. The open cadavers underwent additional maintenance via renewed treatment with ethanol and Pluriol((r)) after each dissection. After 30 weeks, C. perfringens was massively reduced in the colon of the open cadavers. The tested solution successfully embalms open bodies, carries no health risks and is environmentally friendly and cost effective. PMID- 20829011 TI - B-cell tolerance: mechanisms and implications. AB - Advances in our knowledge of the spectrum of B-cell activities combined with the remarkable clinical efficacy of B-cell inhibitors in autoimmunity and transplantation settings serve to re-emphasise the importance of tolerance to self and foreign antigens in the B-cell repertoire. In particular, new information is emerging about the molecular mechanisms involved in B-cell tolerance induction and identification of B-cell selective defects that contribute to the pathogenesis of autoimmune/inflammatory diseases. PMID- 20829012 TI - Developmental plasticity of Foxp3+ regulatory T cells. AB - Foxp3(+) regulatory T (Treg) cells constitute a distinct lineage of T lymphocytes committed to suppressive functions, thereby ensuring the robustness of self tolerance and immune homeostasis in a changing environment. Recent studies have challenged this notion by suggesting that they retain developmental plasticity to convert to Foxp3(-) helper T (Th) cells in response to environmental perturbations such as inflammation and lymphopenia. However, this issue of Treg cell plasticity remains controversial because unequivocal evidence for lineage reprogramming is lacking. Instead, available evidence supports an alternative view of plasticity based on pre-existing heterogeneity of Foxp3(+) T cells. Recent studies of Foxp3 gene regulation have provided a framework to dissect the molecular mechanisms underlying Treg cell lineage commitment and plasticity. PMID- 20829013 TI - Infectious tolerance: therapeutic potential. AB - Infectious tolerance describes an in vivo process in which tolerance is passed on from one population of lymphocytes to another. In this way, short-term therapy aimed at generating infectious tolerance has the potential to achieve long term, self-perpetuating immune homeostasis in a clinical setting. In recent years, a number of differing strategies have successfully achieved tolerance in vivo. These include harnessing regulatory T cells and tolerogenic antigen presenting cells, promoting tolerogenic interactions or inhibiting activation of effector cells. Many of these are just beginning to face the harsh realities of the therapeutics industry. PMID- 20829014 TI - Lower sensitivity of nasal polyp fibroblasts to glucocorticoid anti-proliferative effects. AB - BACKGROUND: Treatment with glucocorticoids (GCs) is the cornerstone of nasal polyp (NP) therapy, but some patients respond poorly to them. Fibroblasts are involved in both inflammation and remodelling of NP. We aimed to evaluate whether NP fibroblasts are less sensitive to GCs' anti-proliferative and anti inflammatory effects, compared to nasal mucosa (NM) fibroblasts. METHODS: Fibroblasts were obtained from NP (n = 8) from asthmatic patients undergoing endoscopic surgery and NM (n = 8) from patients undergoing nasal corrective surgery. Fibroblasts were stimulated with DMEM at 0.5% or 5% FBS, or TGF-beta (5 ng/ml), with or without dexamethasone (10(-11) to 10(-5)M) for different times. Cell proliferation, collagen mRNA expression and IL-6 and IL-8 release were measured. RESULTS: After 3-days, dexamethasone dose-dependently inhibited proliferation of NM (p < 0.001) but not that of NP fibroblasts. Dexamethasone (10(-6)M) reduced by 25% the proliferation of NM fibroblasts. Dexamethasone also inhibited proliferation of NM (p < 0.01) but not that of NP fibroblasts at 5 days. TGF-beta induced collagen-1alpha1, -1alpha2, and -3alpha1 mRNA levels in both NM and NP fibroblasts (p < 0.05), and dexamethasone did not alter TGF-beta induced collagen mRNA levels in either fibroblast type at 24 h. Dexamethasone dose-dependently decreased (p < 0.05) FBS-induced IL-6 and IL-8 release in both NM and NP fibroblasts at 4 h, although at 10(-8)M, dexamethasone inhibited cytokine production in NM (p < 0.05) but not in NP fibroblasts. CONCLUSIONS: This impaired sensitivity of nasal polyp fibroblasts to in vitro glucocorticoid effects concurs in part with the poor clinical response that these nasal polyp patients show to glucocorticoid treatment. PMID- 20829015 TI - Meiosis: making a break for it. AB - The perpetuation of most eukaryotic species requires differentiation of pluripotent progenitors into egg and sperm and subsequent fusion of these gametes to form a new zygote. Meiosis is a distinguishing feature of gamete formation as it leads to the twofold reduction in chromosome number thereby maintaining ploidy across generations. This process increases offspring diversity through the random segregation of chromosomes and the exchange of genetic material between homologous parental chromosomes, known as meiotic crossover recombination. These exchanges require the establishment of unique and dynamic chromatin configurations that facilitate cohesion, homolog pairing, synapsis, double strand break formation and repair. The precise orchestration of these events is critical for gamete survival as demonstrated by the majority of human aneuploidies that can be traced to defects in the first meiotic division (Hassold T, Hall H, Hunt P: The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 2007, 16 Spec No. 2:R203-R208.). This review will focus on recent advances in our understanding of key meiotic events and how coordination of these events is occurring. PMID- 20829016 TI - The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. AB - Due to the use of intra-vital imaging techniques and assays for cell migration into 3D matrices there has recently been much interest in different modes of tumour cell migration. Individually moving tumour cells can move either in an elongated-protrusive manner or in rounded, so-called 'amoeboid' modes. This review summarises ongoing efforts to delineate the cell signalling pathways that underlie these different forms of movement. PMID- 20829017 TI - Co-disposal of electronic waste with municipal solid waste in bioreactor landfills. AB - Three pilot scale lysimeters were adopted to evaluate the stability pattern and leaching potential of heavy metals from MSW landfills under the E-waste co disposed condition. One lysimeter served as control and solely filled with MSW, whereas the other two lysimeters were provided with 10% and 25% of E-waste scraps (% by weight), respectively. The reactors were monitored over a period of 280 days at ambient settings with continuous leachate recirculation. Stabilization pattern of carbon appears to be more than 50% in all the three lysimeters with irrespective of their operating conditions. Iron and zinc concentrations were high in leachate during bioreactor landfill operation and correlating with the TCLP leachability test results. In contrast, Pb concentration was around <0.6 mg/L, but which showed maximum leaching potential under TCLP test conditions. But, no heavy metal accumulation was found with leachate recirculation practices in lysimeters. Mobility of the metal content from the E-waste was found to be amplified with the long term disposal or stabilization within landfills. The results showed that the TCLP test cannot be completely reliable tool for measuring long-term leachability of toxic substances under landfill condition; rather landfill lysimeter studies are necessary to get the real scenario. PMID- 20829018 TI - A dual surface plasmon resonance assay for the determination of ribonuclease H activity. AB - There is a demand for efficient tools for the monitoring of RNase H activity. We report on a new assay which allows for simultaneous (1) real-time monitoring of RNase H activity and (2) detection of cleavage reaction products. The dual assay is implemented using a multichannel surface plasmon resonance (SPR) biosensor with two independently functionalized sensing areas in a single fluidic path. In the first sensing area the RNA cleavage by RNase H is monitored, while the products of the cleavage reaction are captured in the second sensing area with specific DNA probes. The assay was optimized with respect to AON concentration and temperature. A significant improvement was obtained with special chimeric probes, which contain RNA substrate for RNase H and a longer deoxyribonucleotide tail, which enhances the SPR signal. It has been shown that RNase H stabilizes the RNA:DNA hybrid duplex before the cleavage. The potential of the assay is demonstrated in the study in which the ability of natural and modified oligonucleotides to activate RNase H is examined. PMID- 20829019 TI - Direct electrochemistry and electrocatalysis of novel single-walled carbon nanotubes-hemoglobin composite microbelts--towards the development of sensitive and mediator-free biosensor. AB - Single-walled carbon nanotubes (SWNTs) and hemoglobin (Hb) were co-electrospun to generate SWNTs-Hb microbelts, a novel composite material combining the advantages of excellent electron transfer property of SWNTs, electrocatalytic capability of redox Hb proteins, and highly porous structure of microbelts. FT-IR spectra confirmed that Hb in the microbelts kept its native conformational structure and Raman spectra demonstrated the successful incorporation of SWNTs in the microbelts. The direct electrochemistry of SWNTs-Hb composite microbelts was investigated and its application for electrocatalytic reductions and sensitive detections of three compounds, trichloroacetic acid (TCA), nitrite, and hydrogen peroxide (H2O2) was also conducted. The SWNTs-Hb composite microbelts based amperometric biosensor showed fast responses to the analytes with excellent detection limits of 2.41 MUM for TCA, 0.30 MUM for nitrite, and 0.22 MUM for H2O2 (S/N=3), and superior apparent Michaelis-Menten constants of 0.24, 0.491 and 0.070 mM for TCA, nitrite and H2O2, respectively. Its application for spiked tap water was also demonstrated. The comparison of the SWNTs-Hb composite microbelts modified electrode with other reported electrodes in the literature indicates that the incorporation of SWNTs into Hb microbelts can significantly enhance the direct electrochemistry of Hb and the SWNTs-Hb microbelts based biosensor has great potential application in the mediator-free detection of various analytes. PMID- 20829020 TI - Electrochemical determination of guanine and adenine by CdS microspheres modified electrode and evaluation of damage to DNA purine bases by UV radiation. AB - Sensitive electrochemical sensor based on a composite of novel pearl-like CdS microspheres and chitosan (CdS-CHIT/GCE) was constructed and characterized using cyclic voltammetry. Single-stranded (ssDNA) and double-stranded (dsDNA) deoxyribonuleic acid were electrochemically adsorbed onto CdS-CHIT/GCE and a significant difference in electrochemical impedance spectra of the ssDNA/CdS CHIT/GCE and dsDNA/CdS-CHIT/GCE electrodes was found. Electrocatalytic properties of CdS allowed to use the CdS-CHIT/GCE successfully for the trace determination of simple guanine and adenine with nanomolar detection limits by differential pulse voltammetry (DPV). Moreover, damage to the DNA purine bases, guanine and adenine, liberated in previously hydrolyzed calf thymus dsDNA, caused by UV-B, UV C, and visible light was evaluated. While only minor changes in anodic DPV response of guanine and adenine could be seen after 60 min exposition to UV-B and visible light, total degradation of DNA bases was observed after 20 min exposure to UV-C. A great potential of the CdS microspheres used as the interface at the nucleic acid based biosensors was demonstrated. PMID- 20829021 TI - Design of a fluorescent DNA IMPLICATION logic gate and detection of Ag+ and cysteine with triphenylmethane dye/G-quadruplex complexes. AB - This paper describes the construction of a DNA IMPLICATION logic gate based on triphenylmethane (TPM) dye/G-quadruplex complexes, using Ag+ and cysteine (Cys) as the two inputs, and fluorescence intensity of the TPM dye as the output signal. Free triphenylmethane (TPM) dyes emit inherently low fluorescence signal, the formation of TPM dye/G-quadruplex complexes yielded greatly enhanced fluorescence signals from the dye, and the output signal of the gate was 1. The addition of Cys had no effect on the fluorescence signal, again yielding an output of 1. However, the addition of Ag+ instead of Cys greatly disrupted the G quadruplex structure, causing a decrease in the fluorescence of the dye, and yielding an output signal of 0. The addition of Cys into the Ag+-quenched fluorescence system led to the release of Ag+ from G-quadruplex-forming DNAs, resulting in the reformation of G-quadruplex structures and the recovery of TMP dye fluorescence, the output signal of 1 was obtained again. Compared with previously published DNA logic gates, the gate operation described here was rapid and reversible, with a reliable, nondestructive readout and excellent digital behavior. In addition, the modulation of TPM dye/G-quadruplex complex fluorescence by Ag+ and Cys could be used to develop a simple, fast, label-free and highly specific homogenous sensing methods for Ag+ and Cys. PMID- 20829022 TI - Magnetic molecularly imprinted nanoparticles for recognition of lysozyme. AB - Molecular imprinting is an attractive technique for preparing mimics of natural, biological receptors. Nevertheless, the imprinting of macromolecule remains a challenge due to their bulkiness and sensitivity to denaturation. In this work, we presented a method for preparing multifunctional lysozyme-imprinted nanoparticles (magnetic susceptibility, molecular recognition and environmental response). The magnetic susceptibility was imparted through the successful encapsulation of Fe3O4 nanoparticles. Selective lysozyme recognition depended on molecularly imprinted film. Moreover, it was also a hydrophilic stimuli responsive polymer, which could undergo a reversible change of imprinted cavity in response to a small change in the environmental conditions. Thus, magnetic molecularly imprinted nanoparticles had high adsorption capacity (0.11 mg mg( 1)), controlled selectivity and direct magnetic separation (22.1 emicro g(-1)) in crude samples. After preconcentration and purification with magnetic MIPs nanoparticles, a sensitive chemiluminescence method was developed for determination of lysozyme in human serum samples. The results indicated that the spiked recoveries were changed from 92.5 to 113.7%, and the RSD was lower than 11.8%. PMID- 20829023 TI - Electrochemical detection of foodborne pathogen Aeromonas hydrophila by DNA hybridization biosensor. AB - The paper describes an electrochemical DNA biosensor used for the detection of Aeromonas hydrophila. This opportunistic pathogen is recognized as an emerging foodborne hazard and is associated with a variety of virulence factors including production of cytotoxic enterotoxin aerolysin. The genosensor recognition layer was prepared using mixed self-assembled monolayer (SAM) consisting of thiolated single-stranded DNA probe (ssDNA) and diluent molecules--mercaptoalcohol: mercaptoethanol (MCE) or mercaptohexanol (MCH) or mercaptononanol (MCN). The voltammetric examination of double-layer capacitance of biosensor recognition interface supported by chronocoulometric quantitation of DNA present on the electrode surface showed that mixed ssDNA and MCH monolayer revealed the lowest defectiveness. Its double-layer capacitance equaled 4.0 MUF cm(-2) and ssDNA probe surface coverage reached 8.5*10(11) molecules cm(-2) of gold electrode surface. Chronocoulometric quantitation of DNA and square wave voltammetry (SWV) measurements of electroactive indicator, methylene blue (MB) were performed to investigate the influence of hybridization reaction time, concentration of target DNA fragments, and presence of non-complementary DNA on the electrochemical response of genosensor recognition interface. The biosensor enabled distinction between the DNA samples isolated from A. hydrophila (present at the concentration of 2.5 MUg cm(-3)) and other microbial DNA. PMID- 20829024 TI - Ultrasensitive mycotoxin detection by STING sensors. AB - Signal transduction by ion nano-gating (STING) technology is a label-free biosensor capable of identifying DNA and proteins. Based on a functionalized quartz nanopipette, the STING sensor includes specific recognition elements for analyte discrimination based on size, shape and charge density. A key feature of this technology is that it does not require any nanofabrication facility; each nanopipette can be easily, reproducibly, and inexpensively fabricated and tailored at the bench, thus reducing the cost and the turnaround time. Here, we show that STING sensors are capable of the ultrasensitive detection of HT-2 toxin with a detection limit of 100 fg/ml and compare the STING capabilities with respect to conventional sandwich assay techniques. PMID- 20829025 TI - An advanced investigation on a new algal sensor determining Pb(II) ions from aqueous media. AB - It has been well documented that heavy metal accumulation in environment is harmful for living organisms at even trace levels. A new voltammetric algal sensor based on Phormidium sp. modification for Pb(II) determination from aqueous solutions was developed, and selectivity of the biomass to Pb(II) was investigated comprehensively. Many important experimental parameters were performed by using electrochemical techniques, including cyclic voltammetry and differential pulse stripping voltammetry. The preconcentrated ions at open circuit were reduced by scanning the potential from -1.5 to 1.5 V and current values obtained were related to the concentration of Pb(II) in the solutions. The best peak values belonging to Pb(II) were achieved at pH 8.0 with 0.05 M Tris-HCl solution. Preconcentration time was selected as 10 min, and the sensor was found in a linear range from 5.0*10(-8) M to 2.0*10(-5) M Pb(II) (0.01-4.0 mg L(-1)) with a detection limit of 2.5*10(-8) M. Other analytical properties of the developed microbial biosensor were also investigated. According to the Fourier transform infrared attenuated total reflectance (FTIR-ATR) analyses, the possible functional groups involved in Pb(II) accumulation in the Phormidium sp. were defined as carboxyl, sulphoxide and alcoholic groups. A simple chemical modification by formaldehyde both enhanced Pb(II) determination and content of functional groups involving Pb(II) binding. The proposed usage form of Phormidium sp. does not need complicated immobilization procedures and expensive preliminary preparations. PMID- 20829026 TI - Development of a gold nano-particle-based fluorescent molecular beacon for detection of cystic fibrosis associated mutation. AB - Cystic fibrosis is one of the most common genetically inherited diseases in Northern Europe, consisting of an inherited defect of chloride transport in the epithelium. Of the several mutations related to CF, the DeltaF508 mutation occurs in ca. 70% of the cases. In this work the use of a gold nano-particle supported fluorescence molecular beacon was investigated as an optical sensing platform for the detection of the DeltaF508 cystic fibrosis associated mutation. Different parameters such as molecular beacon design, Au nano-particle size, molecular beacon-nano-particle conjugation protocol, molecular beacon loading as well as experimental conditions were evaluated. A 31-base long molecular beacon, containing a 15-base recognition sequence specific for the mutant target, was linked via a thiol modified poly thymine linker (10 bases long) to a 13 nm gold nano-particle and was exposed to mutant and wild type targets, and a clear differentiation was achieved at target concentrations as low as 1 nM. PMID- 20829027 TI - A novel colorimetric aptasensor using gold nanoparticle for a highly sensitive and specific detection of oxytetracycline. AB - We have successfully developed a novel colorimetric aptasensor using gold nanoparticles for highly sensitive and specific detection of oxytetracycline (OTC), one of the most common antibacterial agents. A highly specific ssDNA aptamer that bind to OTC with high affinity was employed to discriminate other tetracyclines (TCs), such as doxycycline (DOX) and tetracycline (TET). Aggregation of AuNPs was specifically induced by desorption of the OTC binding aptamers (OBAs) from the surface of gold nanoparticles as a result of the aptamer target interaction, leading to the color change from red to purple. The detection limit of OTC was enhanced up to 25 nM, which is 20-fold lower than the limit USA EPA regulated, with two orders of magnitudes in its linear dynamic range by successful optimization on the amount of the aptamers, AuNPs, and salts. This colorimetric aptasensor is advantageous over the other conventional methods in terms of its simple signal generation and detection with the naked eye, which can be realized in on-site detection of antibacterial agents. PMID- 20829028 TI - Microfluidic approaches for systems and synthetic biology. AB - Microfluidic systems miniaturise biological experimentation leading to reduced sample volume, analysis time and cost. Recent innovations have allowed the application of -omics approaches on the microfluidic scale. It is now possible to perform 1.5 million PCR reactions simultaneously, obtain transcriptomic data from as little as 150 cells (as few as 2 transcripts per gene of interest) and perform mass-spectrometric analyses online. For synthetic biology, unit operations have been developed that allow de novo construction of synthetic systems from oligonucleotide synthesis through to high-throughput, high efficiency electroporation of single cells or encapsulation into abiotic chassis enabling the processing of thousands of synthetic organisms per hour. Future directions include a push towards integrating more processes into a single device and replacing off-chip analyses where possible. PMID- 20829029 TI - Quantitative understanding of cell signaling: the importance of membrane organization. AB - Systems biology modeling of signal transduction pathways traditionally employs ordinary differential equations, deterministic models based on the assumptions of spatial homogeneity. However, this can be a poor approximation for certain aspects of signal transduction, especially its initial steps: the cell membrane exhibits significant spatial organization, with diffusion rates approximately two orders of magnitude slower than those in the cytosol. Thus, to unravel the complexities of signaling pathways, quantitative models must consider spatial organization as an important feature of cell signaling. Furthermore, spatial separation limits the number of molecules that can physically interact, requiring stochastic simulation methods that account for individual molecules. Herein, we discuss the need for mathematical models and experiments that appreciate the importance of spatial organization in the membrane. PMID- 20829030 TI - Tissue, cell and pathway engineering. PMID- 20829031 TI - Altered states: how gene expression is changed during differentiation. PMID- 20829032 TI - Neurobiology of vocal communication: mechanisms for sensorimotor integration and vocal patterning. AB - This review will focus on recent developments in the sensorimotor integration of vocal communication. Two broad themes are emphasized: the evolution of vocal production and perception, and the role of social context. Advances include: a proposal for the emergence of vocal patterning during vertebrate evolution, the role of sensory mechanisms such as categorical perception in decoding communication signals, contributions of sensorimotor integration phenomena including mirror neurons and vocal learning, and mechanisms of hormone-dependent plasticity in both auditory and vocal systems. Transcriptional networks activated in humans but not in chimps by the FoxP2 gene suggest molecular mechanisms underlying vocal gestures and the emergence of human language. PMID- 20829033 TI - Shedding new light on the role of the basal ganglia-superior colliculus pathway in eye movements. AB - A large body of work spanning 25+ years provides compelling evidence for the involvement of the basal ganglia-superior colliculus pathway in the initiation of rapid, orienting movements of the eyes, called saccades. The role of this pathway in saccade control is similar to the role of the basal ganglia-thalamic pathway in the control of skeletal movement: a transient cessation in tonic inhibition supplied by the basal ganglia to motor structures releases movements via the direct pathway whereas a transient increase in inhibition by the basal ganglia to motor structures prevents movements via the indirect pathway. In parallel with recent advances in the study and treatment of patients with basal ganglia disease and in animal experiments in the skeletal motor system, the results of studies exploring the role of the basal ganglia-superior colliculus pathway in saccades highlight the need for a revisiting of our understanding of the role of this pathway in saccades. The discovery of many different response profiles of neurons in the substantia nigra pars reticulata of the basal ganglia and in the superior colliculus, coupled with advances in experimental and statistical techniques including sophisticated behavioral procedures and multiple neuron recording and analysis, point toward a role for the basal ganglia-superior colliculus pathway in cognitive events intervening between vision and action, such as memory, target selection and saccade choice and valuation. PMID- 20829034 TI - The future of innovation and training in surgical oncology. AB - This article addresses the current paradigms of surgical oncology training and the directions in which the training process may evolve over the course of the next decade. In doing so, the potential influences upon this evolution are discussed along with potential barriers associated with each of these factors. In particular, the topics include issues of specialty training with regard to new technologies and procedures, involvement of the surgeon as part of the multi disciplinary team of oncologists, and the very real issue of burnout and career satisfaction associated with the profession of surgical oncology. Changes to the training of tomorrow's cancer surgeons will need to involve each one of these factors in a comprehensive and efficient manner, in order to ensure the continued strength and growth of the field. PMID- 20829035 TI - Separation of lignocellulosic materials by combined processes of pre-hydrolysis and ethanol extraction. AB - In this paper, we proposed a new modification for an ethanol-based pulping process, which would consist of the pre-hydrolysis (pre-extraction) of wood chips for removing hemicelluloses; the ethanol extraction of pre-hydrolyzed wood chips for removing lignin; and the post purification of cellulose, leading to the production of pure cellulose. We also experimentally evaluated the separation of hemicelluloses from the pre-hydrolysis liquor (PHL) obtained from a pulp mill. To remove lignin from the PHL, it was acidified to a pH of 2, which resulted in 47% lignin precipitation. The lignin separation from the acidified PHL was further improved via adding polyethylene oxide and poly aluminum chloride or adding ethyl acetate. To recover the hemicelluloses from the acidified PHL, ethanol was added to the acidified PHL with a volumetric ratio of 4 to 1. The isolated lignin and hemicelluloses were characterized by a Fourier transform infrared spectroscopy (FTIR) and a gas permeation chromatography (GPC). PMID- 20829036 TI - Effect of additives on fiber yield improvement for kraft pulping of kadam (Anthocephalus chinensis). AB - Projected decline in future wood resources has prompted researchers to try various additives in existing pulping processes for fiber yield improvement. Many studies have been conducted in the past aimed at improving kraft pulp yield with the use of additives in the cooking liquor. In this study, the effects of anthraquinone (AQ) and 2-methylanthraquinone (MAQ) on the pulp yield of kadam (Anthocephalus chinensis) were investigated. Three different active alkali doses (14%, 16% and 19% as NaOH) along with 0.1% of AQ or MAQ on chips were used to obtain various levels of delignification of the hardwood. Addition of AQ or MAQ to kraft pulping, increased fiber yield (0.5-2.7% on chips) and improved delignification selectivity (lignin vs. carbohydrate removal). Increases in pulp yield due to AQ or MAQ were more significant at lower doses of active alkalis. The viscosities and the physical strength properties of the pulps with kappa numbers 16-19 were comparable to kraft although there was a minor decrease in tensile strength for the kraft/MAQ pulp. PMID- 20829037 TI - Immobilization of chloroperoxidase onto highly hydrophilic polyethylene chains via bio-conjugation: catalytic properties and stabilities. AB - Chloroperoxidase (CPO) was covalently immobilized on poly(hydroxypropyl methacrylate-co-polyethyleneglycole-methacrylate) membranes, which were characterized, by swelling test, FT-IR spectroscopy, scanning electron microscopy, and contact angle measurement. The Km and Vmax values for free and immobilized CPO were found to be 34.6 and 47.2 MUM, and 287.5 and 245.2 U/mg protein, respectively. The optimum pH for both the free and immobilized enzyme was observed at 3.0. The immobilized enzyme showed wide pH and temperature profiles. Most importantly, the increased thermal, storage and operational stability of immobilized CPO should depend on the creation of a comfortable strong hydrophilic microenvironment on the designed support to the host enzyme molecule. PMID- 20829038 TI - Exploration of piperidine-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Phenyl derivatives with broad potency against resistant mutant viruses. AB - Further investigation of the recently reported piperidine-4-yl-aminopyrimidine class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out. Thus, preparation of a series of N-phenyl piperidine analogs resulted in the identification of 3-carboxamides as a particularly active series. Analogs such as 28 and 40 are very potent versus wild-type HIV-1 and a broad range of NNRTI-resistant mutant viruses. Synthesis, structure-activity relationship (SAR), clearance data, and crystallographic evidence for the binding motif are discussed. PMID- 20829039 TI - Synthesis and in vivo evaluation of Tc-99m-labeled cyclic CisoDGRC peptide conjugates for targeting alphavbeta3 integrin expression. AB - Two alpha(v)beta(3) integrin-binding peptide conjugates containing the cyclic CisoDGRC motif, a linker, and a chelator to enable Tc-99m labeling via the fac [(99m)Tc(CO)(3)]+ core were synthesized. In vivo biodistribution studies in U87MG tumor-bear nude mice at 1h post-injection revealed a profound effect of the linker on the clearance of the radiotracer from the blood stream. In vivo blocking studies demonstrated the selective binding to the tumors expressing alpha(v)beta(3)-integrin and other tissues. The HPLC analysis of urine samples collected upon necropsy showed no degradation indicating their metabolic stability. These results suggest that cyclic CisoDGRC motif could be exploited as a new alpha(v)beta(3)-targeting vector by an appropriate selection of a linker between the peptide and the payload to obtain optimum pharmacokinetic properties. PMID- 20829040 TI - A novel arylethynyltriazole acyclonucleoside inhibits proliferation of drug resistant pancreatic cancer cells. AB - Novel arylethynyltriazole acyclonucleosides were synthesized and assessed for their anticancer activity on drug-resistant pancreatic cancer MiaPaCa-2 cells. One lead compound was found to have much more potent apoptosis-related antiproliferative effects than gemcitabine, the current first-line treatment for pancreatic cancer. Further investigations showed that this active compound did not inhibit DNA synthesis, which means that it does not resemble gemcitabine and may involve a different mechanism of action. PMID- 20829041 TI - Isoflavone derivatives inhibit NF-kappaB-dependent transcriptional activity. AB - The transcription factor NF-kappaB regulates diverse biological activities, such as inflammatory responses, cell proliferation, and cell survival. Isoflavones are known to have anti-inflammatory and anti-tumor activities, due, in part, to inhibition of NF-kappaB activity. However, the structural moiety of isoflavones responsible for the inhibition of NF-kappaB is not clearly understood. In this work, structure-activity relationships of isoflavone derivatives were examined with regard to NF-kappaB inhibition, using CoMFA and CoMSIA. The results show that substituents at the C-7 and C-4' positions are crucial for the inhibition of TNFalpha-induced transcriptional activity of NF-kappaB. PMID- 20829042 TI - Intrinsic electrophilicity of the 4-methylsulfonyl-2-pyridone scaffold in glucokinase activators: role of glutathione-S-transferases and in vivo quantitation of a glutathione conjugate in rats. AB - Previous studies on the in vitro metabolism of 4-alkylsulfonyl-2-pyridone-based glucokinase activators revealed a facile, non-enzymatic displacement of the 4 alkylsulfonyl group by glutathione. In the present studies, a role for glutathione-S-transferases (GST) as catalysts in the desulfonylation reaction was demonstrated using a combination of human liver microsomes, human liver cytosol and human GSTs. The identification of a glutathione conjugate in circulation following intravenous administration of a candidate 4-methylsulfonyl-2-pyridone to rats confirmed the relevance of the in vitro findings. PMID- 20829043 TI - Willingness of breast cancer survivors to participate in a randomized controlled trial of digital mammography with or without MRI as breast cancer surveillance: a feasibility study. AB - Breast MRI is often used for surveillance of breast cancer (BC) survivors despite the lack of evidence in this population. We surveyed younger BC survivors to evaluate their willingness to participate in a randomized controlled trial (RCT) of annual digital mammography with or without MRI. Median age of the 348 participants was 51 years; 45% had undergone diagnostic MRI. 22% continued to have surveillance MRI. 58% agreed to consider participating in the proposed RCT; 16% remained neutral. An RCT of MRI surveillance for BC survivors =4 OTPD. RESULTS: There were 1,776 actual donors out of 2,760 eligible deaths (conversion rate 64%). Hispanics demonstrated a significantly lower conversion rate than Caucasians (64% vs 77%, p < 0.001), but a considerably higher rate than African Americans (50%) and Asians (51%, p < 0.05 for both). There were no significant changes in conversion rates over time in any race. Age was a negative predictor (odds ratio [OR] 0.95), and trauma mechanism (OR 2.1) and standard criteria donor status (OR 2.5) were positive independent predictors of >=4 OTPD. Race did not affect OTPD (all groups, p > 0.05). CONCLUSIONS: Conversion rates among all ethnic minorities were significantly lower than the rates observed in Caucasians. However, when controlling for other factors, race was not a significant risk factor for the number of organs transplanted per donor. The Collaborative has not had an identifiable effect on race conversion rates during the 5 years since its implementation. Further intervention is necessary to improve the conversion rate in ethnic minorities in Southern California. PMID- 20829077 TI - Prevention of parastomal herniation with biologic/composite prosthetic mesh: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Parastomal herniation is a frequent complication of stoma formation and can be difficult to repair satisfactorily, making it a recognized cause of significant morbidity. A systematic review with meta-analysis of randomized clinical trials was performed to determine the benefits and risks of mesh reinforcement versus conventional stoma formation in preventing parastomal herniation. STUDY DESIGN: Trials were identified from The Cochrane Library trials register, Medline, Embase, Science Citation Index Expanded, and reference lists. The primary outcome was the incidence of parastomal herniation. The secondary outcomes were the incidence of parastomal herniation requiring surgical repair, postoperative morbidity, and mortality. Meta-analysis was performed using a random-effects model. The risk ratio (RR) was estimated with 95% confidence intervals (CI) based on an intention-to-treat analysis. RESULTS: Three trials with 129 patients were included. Composite or biologic mesh was used in either the preperitoneal or sublay position. Mesh reinforcement was associated with a reduction in parastomal herniation versus conventional stoma formation (RR 0.23, 95%CI 0.06 to 0.81; p = 0.02), and a reduction in the percentage of parastomal hernias requiring surgical treatment (RR 0.13, 95%CI 0.02 to 1.02; p = 0.05). There was no difference between groups in stoma-related morbidity (2 of 58, 3.4% in the mesh group versus 2 of 57, 3.5% in the conventional group; p = 0.97), nor was there any mortality related to the placement of mesh. CONCLUSIONS: Composite or biologic mesh reinforcement of stomas in the preperitoneal/sublay position is associated with a reduced incidence of parastomal herniation with no excess morbidity. Mesh reinforcement also demonstrates a trend toward a decreased incidence of parastomal herniation requiring surgical repair. PMID- 20829078 TI - Large-scale investigation into dumping syndrome after gastrectomy for gastric cancer. AB - BACKGROUND: The aim of this study was to investigate early and late dumping syndromes in a large number of patients after gastrectomy for gastric cancer. STUDY DESIGN: Responses to questions on a visual analogue scale survey completed by 1,153 gastrectomy patients were analyzed for associations between clinical factors and occurrence of dumping syndrome. Types of gastrectomy included distal gastrectomy with Billroth I or with Roux-Y reconstruction, pylorus preserving gastrectomy, proximal gastrectomy, and total gastrectomy. RESULTS: Based on the visual analogue scale rating of symptomatic discomfort, patients were categorized into 1 of 2 groups: symptom-free or symptomatic. Incidences of early or late dumping syndrome in all patients were 67.6% and 38.4%, respectively. Patients in whom early dumping syndrome developed were significantly more likely to experience late dumping syndrome than those in whom it did not develop (p < 0.001). According to multivariate analyses, factors that decreased the risk for developing early dumping syndrome were reduced weight loss (p < 0.01), old age (p < 0.01), pylorus preserving gastrectomy (p < 0.01), distal gastrectomy with Roux Y reconstruction (p < 0.01), and distal gastrectomy with Billroth I (p = 0.019). In addition, factors that decreased the risk of developing late dumping syndrome were reduced weight loss (p = 0.03), being male (p < 0.01), pylorus preserving gastrectomy (p < 0.01), and distal gastrectomy with Roux-Y reconstruction (p < 0.01). No other clinical factors (lymph node dissection, vagal nerve preservation, and postoperative period) showed a substantial association with the occurrence of dumping syndrome in multivariate analyses. CONCLUSIONS: Substantially more patients suffered from early dumping syndrome than late dumping syndrome after gastrectomy. Two clinical factors, surgical procedures and amount of body weight loss, associated significantly with the occurrence of both early and late dumping syndrome. PMID- 20829079 TI - The relationship between case volume, care quality, and outcomes of complex cancer surgery. AB - BACKGROUND: How case volume and quality of care relate to each other and to results of complex cancer surgery is not well-understood. STUDY DESIGN: Observational cohort of 14,170 patients 18 years or older who underwent pneumonectomy, esophagectomy, pancreatectomy, or pelvic surgery for cancer between October 1, 2003 and September 1, 2005 at a US hospital participating in a large benchmarking database. Case volumes were estimated within our dataset. Quality was measured by determining whether ideal patients did not receive appropriate perioperative medications (such as antibiotics to prevent surgical site infections), both as individual "missed"measures and as overall number missed. We used hierarchical models to estimate effects of volume and quality on 30-day readmission, in-hospital mortality, length of stay, and costs. RESULTS: After adjustment, we noted no consistent associations between higher hospital or surgeon volume and mortality, readmission, length of stay, or costs. Adherence to individual measures was not consistently associated with improvement in readmission, mortality, or other outcomes. For example, continuing antimicrobials past 24 hours was associated with longer length of stay (21.5% higher, 95% CI, 19.5-23.6%) and higher costs (17% higher, 95% CI, 16-19%). In contrast, overall adherence, although not associated with differences in mortality or readmission, was consistently associated with longer length of stay (7.4% longer with 1 missed measure and 16.4% longer with >=2) and higher costs (5% higher with 1 missed measure, and 11% higher with >=2). CONCLUSIONS: Although hospital and surgeon volume were not associated with outcomes, lower overall adherence to quality measures is associated with higher costs, but not improved outcomes. This finding might provide a rationale for improving care systems by maximizing care consistency, even if outcomes are not affected. PMID- 20829080 TI - Epilepsy with occipital features in children: factors predicting seizure outcome and neuroimaging abnormalities. AB - PURPOSE: The objective of this retrospective study was to identify clinical and EEG features in children with occipital epilepsy that predict MR imaging abnormalities and seizure outcome. METHODS: Patients with clinical and/or EEG features indicating occipital lobe involvement were identified from the epilepsy database at a tertiary children's hospital. The clinical and EEG features were analyzed to identify the most important predictors of abnormal MR imaging and seizure outcome. RESULTS: Sixty-six patients were identified: 21 had symptomatic epilepsy with abnormal MR imaging; 12 patients had probable symptomatic epilepsy based on an abnormal neurological exam; 33 patients had normal neurological development, normal neurological examination and normal neuroimaging. Twenty-two of these 33 patients satisfied criteria for idiopathic occipital syndromes: Panayiotopoulos syndrome (9 patients), Gastaut type idiopathic childhood occipital epilepsy (12 patients) and idiopathic photosensitive occipital epilepsy (1 patient). Eleven patients could not be classified. Early age of seizure onset and an abnormal neurological examination were significant predictors of abnormal MR imaging. None of the variables examined were strong predictors of seizure outcome. CONCLUSION: Early age of seizure onset and an abnormal neurological examination are the best predictors of abnormal MR imaging in children with epilepsy with occipital features. PMID- 20829081 TI - 3D gait analysis in patients with hereditary spastic paraparesis and spastic diplegia: a kinematic, kinetic and EMG comparison. AB - The predominant clinical feature of patients with Hereditary Spastic Paraparesis (HSP) is gait disturbance owing to spasticity and weakness of the lower limbs; the spasticity in early-onset disease (infancy or childhood) often cannot be distinguished from mild form of spastic diplegia (SD). The aim of this study was to quantify the gait strategy in HSP and SD children, focusing on the differences between groups as concerns functional limitation during gait. 9 HSP and 16 SD children were evaluated using Gait Analysis; kinematic and kinetic parameters and EMG pattern during walking were identified and calculated to compare the two gait strategies. The results revealed that these two pathologies are characterised by different gait strategies. In particular we found that knee joint, in terms of kinematics and kinetics, and rectus femoris pattern represent discriminatory aspects in order to compare and differentiate gait patterns of HSP and SD children. The findings strongly support the issue that HSP and SD patients need individualised therapeutical program, either neurosurgical or pharmacological treatment, based on the quantification of gait deficiencies and in order to address the peculiarity of their motor limitations and to prevent the onset of compensatory strategies. PMID- 20829082 TI - Prevention of oxaliplatin-induced mechanical allodynia and neurodegeneration by neurotropin in the rat model. AB - Oxaliplatin is a key drug for colorectal cancer, but it causes acute peripheral neuropathy (triggered by cold) and chronic neuropathy (sensory and motor neuropathy) in patients. Neurotropin, a non-protein extract from the inflamed rabbit skin inoculated with vaccinia virus, has been used to treat various chronic pains. In the present study, we investigated the effect of neurotropin on the oxaliplatin-induced neuropathy in rats. Repeated administration of oxaliplatin caused cold hyperalgesia from Day 5 to Day 29 and mechanical allodynia from Day 15 to Day 47. Repeated administration of neurotropin relieved the oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and inhibited the oxaliplatin-induced axonal degeneration in rat sciatic nerve. Neurotropin also inhibited the oxaliplatin-induced neurite degeneration in cultured pheochromocytoma 12 (PC12) and rat dorsal root ganglion (DRG) cells. On the other hand, neurotropin did not affect the oxaliplatin-induced cell injury in rat DRG cells. These results suggest that repeated administration of neurotropin relieves the oxaliplatin-induced mechanical allodynia by inhibiting the axonal degeneration and it is useful for the treatment of oxaliplatin-induced neuropathy clinically. PMID- 20829083 TI - Characterisation of sensory abnormalities observed in an animal model of multiple sclerosis: a behavioural and pharmacological study. AB - Multiple sclerosis is a chronic inflammatory demyelinating disease, associated, in 50-80% of patients, with persistent pain. While the type of pain that affects these patients is being more documented, the mechanisms underlying this pathology are still poorly understood and animal models of such chronic pain associated with MS are required. The aim of our study was to characterize the sensory abnormalities and in particular the clinical signs linked to persistent pain in two models of Experimental Autoimmune Encephalomyelitis (EAE) in the rat. This behavioural characterization tested several sensory modalities such as mechanical and thermal (heat/cold) hyperalgesia or allodynia and explored some of these modalities on two different extremities: the hindpaws and the tail. Our study showed that while one of the model produced more robust motor impairment, animals of both models suffer from mechanical hyperalgesia and thermal allodynia to cold, both at the level of the tail and the hindpaws. While the time-course changes of some of these modalities are shifted in the time between the two models, they represent good models of the sensory abnormalities experienced by MS patients. The second part of our study aimed at characterizing from a pharmacological point of view the most robust model ("EAE+Cyclosporine") and showed that Gabapentin, Duloxetine and Tramadol partially relieved some of the clinical signs. Our results suggest that the model "EAE+Cyclosporine" in the rat is a good model of chronic sensory abnormalities observed in MS patients both from a behavioural and pharmacological point of view. PMID- 20829084 TI - Simultaneous structure and dynamics of a membrane protein using REDCRAFT: membrane-bound form of Pf1 coat protein. AB - A strategy for simultaneous study of the structure and internal dynamics of a membrane protein is described using the REDCRAFT algorithm. The membrane-bound form of the Pf1 major coat protein (mbPf1) was used as an example. First, synthetic data is utilized to validate the simultaneous study of structure and dynamics with REDCRAFT using dihedral restraints and backbone N-H RDCs from two different alignments. Subsequently, the validated analysis is applied to experimental data and confirms that REDCRAFT produces meaningful structures from sparse RDC data. Furthermore, simulated data from a two-state jump motion is used to illustrate the necessity for simultaneous consideration of structure and dynamics. Disregarding internal dynamics during the course of structure determination is shown to produce an average-state that is not related to the two intermediate states. During the analysis of RDC data from the dynamic model, REDCRAFT appropriately identifies the region separating the static and dynamic domains of the protein. Finally, analysis of experimental data strongly suggests the existence of internal motion between the amphipathic and the transmembrane helices of the membrane-bound form of the protein. The ability to perform fragmented structure determination of each domain without a priori assumption of the order tensors allows an independent determination of the order tensors, which yields a more comprehensive description of protein structure and dynamics and is particularly relevant to the study of membrane proteins. PMID- 20829085 TI - Signs of left heart volume overload in severely anaemic cats. AB - Anaemia induces haemodynamic compensatory mechanisms resulting in volume overload and increased left heart dimensions in humans and dogs. The aims of this retrospective study were to investigate the effects of anaemia on echocardiographic left heart dimensions, vertebral heart size (VHS) and radiographic evidence of congestive heart failure (CHF) in cats. Fifteen cats fulfilled the inclusion criteria and were classified as mildly anaemic (haematocrit (Hct)>18-24%) or severely anaemic (Hct<=18%). Eight out of eight severely anaemic cats had left atrial enlargement compared with 1/6 mildly anaemic cats (P<0.005) and severely anaemic cats also had a larger median left ventricular end-diastolic diameter (1.80cm versus 1.27cm, respectively; P<0.05). No difference was found between the groups in VHS or frequency of radiographic signs of CHF. Despite the small sample size, these preliminary findings suggest that severely anaemic cats are more likely to have enlarged left heart dimensions than mildly anaemic cats. PMID- 20829086 TI - [Importance of an interruption-free environment for the safety of the patient while preparing and administering medications]. PMID- 20829087 TI - [Prevalence of overweight and obesity in adults in an urban health area]. AB - OBJECTIVE: To estimate prevalence of overweight and obesity in adults and to identify those individuals at high cardiovascular risk (subjects with type 2 diabetes or hypertension) in whom a nurse intervention might be beneficial in terms of life-style changes and reduction in body weight. METHOD: A cross sectional study on 2270 adults (18-80 years-old) from an urban Primary Health Care Centre. Medical history, social and demographic data, physical examination and blood tests were collected. RESULTS: The mean body mass index was 26.9+/ 5.1kg/m(2) and was found to be higher in men. Thirty-eight percent of subjects were overweight and 22% were obese. Although the prevalence of obesity was identical in both sexes, women had higher prevalences of type ii and iii obesity than men, but overweight was more frequent in men. Among those older than fifty years-old, 84% were overweight or obese. One-hundred and fifty-six (7%) subjects had type 2 diabetes and 707 (31%) had hypertension, and 111 (5%) subjects with both diabetes and hypertension. BMI was higher (P<0.001) in patients who suffered from, hypertension (29.7+/-5.2), diabetes (28.5+/-4.6), and diabetes and hypertension (31.4+/-5.3), than in those who did not suffer from these diseases (25.4+/-4.3). CONCLUSIONS: Obesity and overweight is highly prevalent in the population studied and is higher in patients with diabetes and hypertension. PMID- 20829088 TI - Effect of ultrasonic pretreatment on chlorine dioxide disinfection efficiency. AB - Ultrasound (US) and chlorine dioxide (ClO(2)) were combined sequentially in an aim to improve wastewater disinfection. Results demonstrated that the combined effect of US and ClO(2) on Escherichia coli (E. coli) and total coliform (TC) inactivation in raw wastewater was synergistic involving high removal of bacteria from the solution. A sequential combination of US (150 or 300 W/L) and ClO(2) (2 mg/L) provided about 3.2-3.5 log reduction in the number E. coli and TC in raw wastewater, while the sum of log reductions by the individual treatments were 1.4 1.9. However, the measured inactivation rate with the combination of ultrasound and ClO(2) in synthetic wastewater or secondary effluent was the same as the sum of the log inactivations with individual treatments. The enhancement attained by combined US and ClO(2) disinfection methods was attributed to the presence of high concentration of particles in raw wastewater and their break up under shock sound waves. PMID- 20829089 TI - Identifiable range of osseointegration of dental implants through resonance frequency analysis. AB - This paper aims to determine the identifiable stiffness range of interfacial tissue of dental implants by means of resonance frequency analysis. Two structural models of the Implant-Tissue-Bone system are built and the lowest two resonance frequencies of these two models are analyzed by Finite Element Method in the software Abaqus. The effects of four key parameters, i.e. the geometry, boundary constrain, material property of the bone and the interfacial tissue, to the resonance frequencies are examined in great detail. An intensive parametric study is conducted to reveal quantitative relationships between the resonance frequencies and these parameters. It is found that when the Young's modulus of the interfacial tissue is less than 15MPa, the resonance frequencies are dominantly affected by the interfacial tissue but not the other three parameters. This finding is extremely important to imply that the lowest two resonance frequencies of the Implant-Tissue-Bone system can be accurately determining the osseointegration of dental implants without worrying about all the other factors, as long as the Young's modulus of the interfacial tissue is in the range of 1 15MPa. However, beyond this range the measured resonance frequencies are affected by all these parameters, and need to be properly interpreted. PMID- 20829090 TI - Mechanical behaviour of DNA molecules--elasticity and migration. AB - A novel multi-scale simulation method developed to describe mesoscale phenomena occurring in biofluidic devices is presented. The approach combines the macro scale modelling of the carrier fluid and the micro-scale description of the transported macromolecules or compounds. Application of the approach is demonstrated through mesoscale simulations of DNA molecules. The investigated phenomena include elastic relaxation of dsDNA molecules and migration of ssDNA molecules in a microchannel flow. The results of the first study demonstrate that the elastic behaviour of the DNA molecules can be captured sucessfully. The second study proves that the migration of ssDNA in pressure-driven microchannel flows can be explained by the hydrodynamic interaction with the carrier liquid. PMID- 20829091 TI - Gastrointestinal dysfunction in Parkinson's disease. AB - In recent years, an increasingly detailed picture of gastrointestinal dysfunction in the setting of Parkinson's disease has emerged. Abnormalities of function may occur at virtually all levels of the gastrointestinal tract. Weight loss, dental deterioration, salivary excess, dysphagia, gastroparesis, decreased bowel movement frequency, and anorectal dysfunction all may occur. The pathophysiologic basis for this dysfunction entails both central and enteric nervous system involvement. PMID- 20829092 TI - Dopamine agonists and Othello's syndrome. AB - BACKGROUND: Othello's syndrome (OS) is a delusion of infidelity. We describe seven cases of OS in Parkinson's disease (iPD) patients using dopamine agonists. METHODS: We searched the Mayo Clinic Medical Records System to identify all patients with OS. Clinical data abstracted include sex, age of onset of iPD, age of onset of OS, medications, effect of discontinuing the dopamine agonist, neuroimaging, and comorbidities. RESULTS: Seven non-demented iPD patients with dopamine agonist implementation time locked to the development and resolution of OS are reported. The average age of iPD onset was 46.6 years (Standard deviation: 5.0 years), and OS onset was 53.7 years (7.1 years). All seven patients had significant marital conflict as a result of the delusions. CONCLUSIONS: OS can be associated with dopamine agonist use and can lead to serious consequences. Dopamine agonist cessation eliminates the delusion of infidelity and should be the first treatment option. PMID- 20829093 TI - Tests of dorsolateral frontal function correlate with objective tests of postural stability in early to moderate stage Parkinson's disease. AB - A substantial number of individuals with Parkinson's disease who display impaired postural stability experience accelerated cognitive decline and an increased prevalence of dementia. To date, studies suggest that this relationship, believed to be due to involvement of nondopaminergic circuitry, occurs later in the disease process. Research has yet to adequately investigate this cognitive posturomotor relationship especially when examining earlier disease states. To gain greater understanding of the relationship between postural stability and cognitive function/dysfunction we evaluated a more stringent, objective measure of postural stability (center of pressure displacement), and also more specific measures of cognition in twenty-two patients with early to moderate stage Parkinson's disease. The magnitude of the center of pressure displacement in this cohort was negatively correlated with performance on tests known to activate dorsolateral frontal regions. Additionally, the postural stability item of the UPDRS exhibited poor correlation with the more objective measure of center of pressure displacement and all specific measures of cognition. These results may serve as rationale for a more thorough evaluation of postural stability and cognition especially in individuals with mild Parkinson's disease. Greater understanding of the relationship between motor and cognitive processes in Parkinson's disease will be critical for understanding the disease process and its potential therapeutic possibilities. PMID- 20829094 TI - Common and not so common symbiotic entry. AB - Great advances have been made in our understanding of the host plant's common symbiosis functions, which in legumes mediate intracellular accommodation of both nitrogen-fixing bacteria and arbuscular mycorrhiza (AM) fungi. However, it has become apparent that additional plant genes are required specifically for bacterial entry inside the host root. In this opinion article, we consider Lotus japonicus nap1 and pir1 symbiotic mutants within the context of other deleterious mutations that impair an intracellular accommodation of bacteria but have no impact on the colonization of roots by AM fungi. We highlight a clear delineation of early signaling events during bacterial versus AM symbioses while suggesting a more intricate origin of the plant's ability for intracellular accommodation of bacteria. PMID- 20829095 TI - Dopamine and adaptive memory. AB - Memory is essential to adaptive behavior because it allows past experience to guide choices. Emerging findings indicate that the neurotransmitter dopamine, which signals motivationally important events, also modulates the hippocampus, a crucial brain system for long-term memory. Here we review recent evidence that highlights multiple mechanisms whereby dopamine biases memory towards events that are of motivational significance. These effects take place over a variety of timescales, permitting both expectations and outcomes to influence memory. Thus, dopamine ensures that memories are relevant and accessible for future adaptive behavior, a concept we refer to as 'adaptive memory'. Understanding adaptive memory at biological and psychological levels helps to resolve a fundamental challenge in memory research: explaining what is remembered, and why. PMID- 20829096 TI - Simple finger prick fresh blood technique for use on the ocular surface. PMID- 20829097 TI - Combinatorial protein recognition as an alternative approach to antibody mimetics. AB - Current approaches to medical diagnostics and drug design are largely based on the ability of monoclonal antibodies or synthetic molecules to bind proteins with high affinity and selectivity. In recent years, however, an alternative approach to protein recognition has emerged, in which proteins are identified using non specific receptor arrays that are inspired by the olfactory neural system. An ultimate challenge for such systems is realizing a single, high-throughput analytical device that can effectively diagnose a range of medicinally relevant proteins. Such devices might overcome the difficulties associated with designing potent synthetic receptors for proteins and hence, could open up new possibilities in medical diagnostics, pathogen detection, and proteomics. Here we summarize recent developments in this area and also highlight its limitations and the challenges that this exciting interdisciplinary field faces. In particular, the goal of this review is to underscore the basic parameters required for obtaining combinatorial sensors for proteins and more importantly, to elucidate the rational methodologies that can be applied for systematically improving these promising analytical devices. PMID- 20829098 TI - Upconverting luminescent nanoparticles for use in bioconjugation and bioimaging. AB - Upconverting luminescent nanoparticles (UCNPs) display the unique property of emitting visible light following photoexcitation with near-infrared laser light. This results in features such as virtually zero autofluorescence of (biological) matter and easy separation of the emission peaks from stray light. Other features include rather narrow emission bands, very high chemical stability, the lack of bleaching, and the absence of blinking effects. This article reviews the work performed in the past few years with UCNPs in terms of surface modifications, bioconjugation, and optical (cellular) imaging. PMID- 20829099 TI - Conformational diversity and computational enzyme design. AB - The application of computational protein design methods to the design of enzyme active sites offers potential routes to new catalysts and new reaction specificities. Computational design methods have typically treated the protein backbone as a rigid structure for the sake of computational tractability. However, this fixed-backbone approximation introduces its own special challenges for enzyme design and it contrasts with an emerging picture of natural enzymes as dynamic ensembles with multiple conformations and motions throughout a reaction cycle. This review considers the impact of conformational variation and dynamics on computational enzyme design and it highlights new approaches to addressing protein conformational diversity in enzyme design including recent advances in multi-state design, backbone flexibility, and computational library design. PMID- 20829100 TI - FTIR and Raman spectra and optimized geometry of 2,3,6-tri-fluorobenzoic acid dimer: a DFT and SQMFF study. AB - Raman and FTIR spectra of the 2,3,6-tri-fluorobenzoic acid molecule have been recorded in the regions 50-4000cm-1 and 400-4000cm-1, respectively. Vibrational frequencies have been calculated by employing DFT method in dimeric form in optimum state. SQM force field has also been used to calculate potential energy distributions in order to make conspicuous vibrational assignments. Raman activities calculated by DFT method have been converted to the corresponding Raman intensities using Raman scattering theory. Optimized bond lengths and angles of the title molecule have been interpreted and compared with the earlier reported experimental values for benzoic acid and some mono and di-fluorinated benzoic acids. Some of the vibrational frequencies of the title molecule are effected upon profusely with the fluorine substitutions in comparison to benzoic acid and these differences have been interpreted. The strong doubly hydrogen bonded interface of the dimerized system is well demonstrated by the red shift in OH stretching frequency concomitant with the elongation of bond length. PMID- 20829101 TI - Simple and sensitive method for the quantification of total bilirubin in human serum using 3-methyl-2-benzothiazolinone hydrazone hydrochloride as a chromogenic probe. AB - We here describe a new spectrophotometric method for measuring total bilirubin in serum. The method is based on the cleavage of bilirubin giving formaldehyde which further reacts with diazotized 3-methyl-2-benzothiazolinone hydrazone hydrochloride giving blue colored solution with maximum absorbance at 630 nm. Sensitivity of the developed method was compared with Jendrassik-Grof assay procedure and its applicability has been tested with human serum samples. Good correlation was attained between both methods giving slope of 0.994, intercept 0.015, and R(2)=0.997. Beers law obeyed in the range of 0.068-17.2 MUM with good linearity, absorbance y=0.044 C(bil)+0.003. Relative standard deviation was 0.006872, within day precision ranged 0.3-1.2% and day-to-day precision ranged 1 6%. Recovery of the method varied from 97 to 102%. The proposed method has higher sensitivity with less interference. The obtained product was extracted and was spectrally characterized for structural confirmation with FT-IR, 1H NMR. PMID- 20829102 TI - Computerized physician order entry of injectable antineoplastic drugs: an epidemiologic study of prescribing medication errors. AB - PURPOSE: In the context of CPOE of standardized antineoplastic drugs, the objectives of the present study were to determine the incidence of prescribing medication errors (PME) and to analyse PME related to antineoplastic treatment in university teaching hospitals. METHODS: All consecutive prescribing medication orders over 1 year were analysed prospectively. Potential clinical impact was quoted according to the Hatoum scale and risk factors identified with a logistic regression model. RESULTS: A total of 14,854 prescriptions were analysed. The PME incidence was estimated at 1.5% [1.3-1.7], i.e. 15 errors per 1000 prescribing medication orders, with a significant or very significant potential clinical impact in 62.9% of cases. Potentially death-threatening events were avoided in 3.7% of cases. Overall, PME incidence related to significant, very significant or vital potential clinical impact was estimated to be 1.0% [0.8-1.2], i.e. 10 errors per 1000 prescribing medication orders. The most common type of error was related to antineoplastic drug dosage (61.0%): inadequate adaptation (43.1%), not taking alarms into account (16.1%), incorrect weight (0.9%), incorrect unit (0.9%). More than 20% of PME are medication errors directly linked to the prescribing medication order (choice of antineoplastic treatment, double prescribing medication order, forgotten or not validated by a resident or senior physician). Occasional users of the CPOE system and resident physicians were identified as main PME risk factors. CONCLUSION: An epidemiologic survey of PME in the context of the use of a partial CPOE has allowed to determine the incidence and epidemiology of PME as well as the potential clinical impact they represent. Two risk factors have emerged that can be considered from an organization and software points of view. Better pharmacist's analysis of prescribing medication order within the CPOE system could possibly minimize duplication of antineoplasic drugs and the vital clinical impact associated with overdosage. PMID- 20829103 TI - Diagnosis of viral gastroenteritis by simultaneous detection of Adenovirus group F, Astrovirus, Rotavirus group A, Norovirus genogroups I and II, and Sapovirus in two internally controlled multiplex real-time PCR assays. AB - BACKGROUND: Norovirus, Rotavirus group A, Astrovirus, Sapovirus and Adenovirus serotypes 40 and 41, are common causes of gastroenteritis. Conventional diagnosis of these causative agents is based on antigen detection and electron microscopy. OBJECTIVE: To improve the diagnostic possibilities for viral gastroenteritis, two internally controlled multiplex real-time PCRs have been developed. STUDY DESIGN: Individual real-time PCRs were developed and optimized for the specific detection of Norovirus genogroup I, Norovirus genogroup II, Rotavirus group A, Astrovirus, Adenovirus group F and Sapovirus. Subsequently, the PCRs were combined to two multiplex PCR reactions. The multiplex assays were clinically evaluated using 239 fecal samples submitted to our laboratory over a 1-year period for the routine detection of Rotavirus and/or Adenovirus antigens using the Vikia((r)) Rota/Adeno test (bioMerieux, Boxtel, The Netherlands). RESULTS: In general, the multiplex real-time PCR assays showed comparable sensitivity and specificity to the individual assays. A retrospective clinical evaluation showed increased pathogen detection in samples from 14% using conventional methods to 45% using PCR. Subsequently, the assay was implemented as a routine diagnostic tool. From September 2007 up to December 2009, 486 positive results were obtained in 1570 samples (31%) analyzed. Norovirus genogroup II was found the most frequently (61.1%), followed by Adenovirus (9.9%), Rotavirus (9.3%), Astrovirus (6.0%), Norovirus genogroup I (3.3%) and Sapovirus (0.4%). CONCLUSIONS: Two internally controlled multiplex real-time PCR assays for the simultaneous detection of Astrovirus, Adenovirus group F, Rotavirus, Norovirus genogroups I and II and Sapovirus have shown significant improvement in the diagnosis of viral gastroenteritis. PMID- 20829104 TI - A 14-year-old girl with a vesicle on her finger and lymphadenitis. PMID- 20829105 TI - Absence of xenotropic murine leukaemia virus-related virus in Danish patients with multiple sclerosis. PMID- 20829106 TI - Long-term continuous adaptation of Escherichia coli to high succinate stress and transcriptome analysis of the tolerant strain. AB - To understand the responses of Escherichia coli to high succinate stress and to determine the roles of upregulated genes in high succinate tolerance, a continuous culture of wild-type E. coli W3110 was performed for 268 days in a gradually increasing concentration of succinate. Growth of the final adapted strain, designated DST160, proceeded growth rate of 0.20 h(-1) without a lag phase in medium containing 0.592 M succinate, while the wild-type strain showed 0.02 h(-1) in 38 h. The growth rates of DST160 in media containing either 0.61 M NaCl, 0.61 M KCl, or at pH 4.5 were 25% higher, 18% lower, and 57% higher than those of wild-type, respectively, implying DST160 acquired salt tolerance and pH shock tolerance as well as succinate tolerance. DNA microarray and real-time PCR results indicated that genes controlling active transport and biosynthesis of osmoprotectants were upregulated in DST160 compared to W3110. When ygjE, encoding a putative tartrate/succinate antiporter, and betA, encoding betaine biosynthesis, were expressed in a wild-type E. coli as represent genes for active transport and osmoprotectant synthesis, respectively, greater growth rates were achieved under 0.592 M succinate stress conditions (seven times higher due to ygjE expression and six times higher due to betA expression) than wild-type. The potential to design a metabolic engineering for microbial succinate production is suggested based on the transcriptional regulation of the long-term adapted DST160. PMID- 20829107 TI - Green-colored plastids in the dinoflagellate genus Lepidodinium are of core chlorophyte origin. AB - Most photosynthetic dinoflagellates possess plastids containing chlorophyllsa+c,but species belonging to the genus Lepidodiniumare unique in bearing non-canonical plastids containing chlorophyllsa+b. According to the pioneering works on pigment composition data, it has been proposed that Lepidodiniumplastids were derived from a prasinophyte species, though this hypothesis was not supported by a recent phylogenetic analysis based on an alignment comprised of eight plastid proteins (Takishita et al. 2008, Gene 410: 26-26). This "8-protein" analysis however was insufficient to clarify the origin of Lepidodiniumplastids for two major reasons: First, the alignment lacked sufficient evolutionary information to resolve the precise origin of Lepidodiniumplastids. Second, the taxa considered did not well represent the diversity of Chlorophyta. Particularly, prasinophytes were poorly sampled in the alignment. In this study, we sequenced plastid-encoded genes from L. chlorophorum, one pedinophyte species, one ulvophyte species, and six prasinophyte species. The 85 sequences newly determined in this study and recent progress in plastid genome sequencing enabled us to prepare an alignment comprised of 11 plastid proteins from green algal taxa that appropriately cover the diversity of Chlorophyta. All the analyses of the 11-protein data set robustly grouped L. chlorophorumwith members of the "core chlorophytes." Thus, we here propose that Lepidodiniumplastids are of core chlorophyte origin. PMID- 20829108 TI - IL-8 released from human lung epithelial cells induced by cystic fibrosis pathogens Burkholderia cepacia complex affects the growth and intracellular survival of bacteria. AB - Burkholderia cepacia complex (Bcc) is a group of Gram-negative pulmonary pathogens associated with life-threatening infections in patients with cystic fibrosis (CF). The airway epithelium plays a crucial role in the initiation and modulation of inflammatory responses to these pathogens. Interleukin (IL)-8 released from epithelial cells is a potent chemoattractant for neutrophils. The aims of this study were to compare the IL-8 response to Bcc infection in different epithelial cell types and to investigate the impact of IL-8 on Bcc growth and intracellular survival. To compare epithelial cell IL-8 responses, 4 human epithelial cell lines were used in the study; A549 cells, an alveolar epithelial cell line, Calu-3 cells, a sub-bronchial epithelial cell line, 16HBE14o- cells, and CFBE41o- cells, which are CFTR-positive and CFTR-negative bronchial epithelial cell lines, respectively. Two B. multivorans and 2 B. cenocepacia strains all induced a significant IL-8 response by 12 h and further increased in all cell lines at 24 h. Furthermore, the levels of IL-8 from Calu-3 and A549 cells were approximately 3 times that of 16HBE14o- or CFBE41o- cells. In 2 of the cell lines examined (16HBE14o- and CFBE41o-), B. cenocepacia LMG 16656 (J2315), an epidemic strain, induced greater levels of IL-8 (P<0.01) compared to other Bcc strains tested. The CFTR-positive and -negative cell lines secreted similar levels of IL-8 indicating a CFTR-independent induction of IL-8. However, the CFTR-negative cells did secrete constitutive levels of IL-8 greater than that of CFTR-positive cells. An investigation of the effect of IL-8 on Bcc extracellular and intracellular growth found that at low concentrations (<10 ng/ml) of recombinant human (rh) IL-8, the growth of B. cenocepacia LMG 16656 and B. multivorans LMG 13010 was enhanced, whereas at higher concentrations (10 ng/ml), growth of both strains was significantly reduced. Growth of both non-CF Bcc strains remained unchanged in the presence of rhIL-8. In contrast to extracellular growth, higher concentrations (10ng/ml) of rhIL-8 enhance the intracellular growth and survival of both LMG 16656 and LMG 13010 in 16HBE14o- and CFBE41o- cell lines. Although LMG 13010 uptake by epithelial cells was higher than LMG 16656 (P<0.01), the intracellular growth of LMG 16656 is greater than LMG 13010 (P<0.05). These studies demonstrated that the type of epithelial cells encountered by Bcc strains determines the extent of the IL-8 responses triggered and that this cytokine in addition to its well-established proinflammatory properties can enhance both the extracellular and intracellular growth of Bcc strains. PMID- 20829109 TI - The effect of assisted jumping on vertical jump height in high-performance volleyball players. AB - Assisted jumping may be useful in training higher concentric movement speed in jumping, thereby potentially increasing the jumping abilities of athletes. The purpose of this study was to evaluate the effects of assisted jump training on counter-movement vertical jump (CMVJ) and spike jump (SPJ) ability in a group of elite male volleyball players. Seven junior national team volleyball players (18.0+/-1.0 yrs, 200.4+/-6.7 cm, and 84.0+/-7.2 kg) participated in this within subjects cross-over counter-balanced training study. Assisted training involved 3 sessions per week of CMVJ training with 10 kg of assistance, applied through use of a bungee system, whilst normal jump training involved equated volume of unassisted counter-movement vertical jumps. Training periods were 5 weeks duration, with a 3-week wash-out separating them. Prior to and at the conclusion of each training period jump testing for CMVJ and SPJ height was conducted. Assisted jump training resulted in gains of 2.7+/-0.7 cm (p<0.01, ES=0.21) and 4.6+/-2.6 cm (p<0.01, ES=0.32) for the CMVJ and SPJ respectively, whilst normal jump training did not result in significant gains for either CMVJ or SPJ (p=0.09 and p=0.51 respectively). The changes associated with normal jump training and assisted jump training revealed significant differences in both CMVJ and SPJ (p=<0.03) in favour of the assisted jump condition, with large effect (CMVJ, ES=1.22; SPJ, ES=1.31). Assisted jumping may promote the leg extensor musculature to undergo a more rapid rate of shortening, and chronic exposure appears to improve jumping ability. PMID- 20829110 TI - Molecular biology and functional genomics of liver X receptors (LXR) in relationship to metabolic diseases. AB - The metabolic syndrome constitutes a group of metabolic conditions that increase the risk of developing diseases, including cardiovascular disease (CVD) and type 2 diabetes (T2D). LXRalpha/beta are regulators of lipogenesis, cholesterol/glucose homoeostasis and inflammatory pathways, processes that are intertwined with development of the metabolic syndrome. The employment of LXRs as pharmaceutical targets for treatment of various aspects of the metabolic syndrome has been promptly investigated but serious side effects, like hepatic steatosis, have hampered this process. Novel treatment regimes now focus on development of isoform-specific or tissue-specific LXR agonist/antagonist compounds to circumvent effects on lipid biosynthesis. Other strategies to explore the beneficial aspects of LXR activation include targeting co-factors or pathways that are modifying LXR activity. PMID- 20829111 TI - Multidirectional interplay between nuclear receptors and microRNAs. AB - Nuclear receptors (NRs) form one of the largest superfamilies of transcription factors in metazoans. MicroRNAs (miRNAs) are small non-coding RNAs that bind the 3' untranslated region (3'UTR) of target mRNAs to reduce their stability and/or translation. miRNAs can directly regulate the protein output of target NR mRNAs, and, conversely, the expression of miRNAs can be modulated by NRs at the transcriptional level. At least one NR also regulates the posttranscriptional maturation of miRNAs by interacting with miRNA processing factors via NR co regulators. Moreover, miRNAs regulate NR signaling by targeting the mRNAs of NR co-regulators and target genes. This complex set of interactions also leads to an extensive network of feedback and feedforward regulatory loops. PMID- 20829112 TI - Stromal cell-derived factor 1alpha and CXCR4: newly defined requirements for efficient thymic beta-selection. AB - The progressive maturation of T cells is accompanied by their migration through the thymus, with each selection stage occurring in distinct microenvironments. Many specialized receptor-ligand pairs have been defined that drive T cell differentiation, but our understanding of the complex relationship between T cells and the thymic stroma is incomplete. Recent reports have identified a role for the chemokine stromal cell-derived factor 1alpha and its receptor CXC chemokine receptor 4 in beta-selection. This review explores these findings in detail. PMID- 20829113 TI - CD56 negative NK cells: origin, function, and role in chronic viral disease. AB - Natural killer (NK) cells serve as a first line of defense against acute viral infections. Immunogenetic association data suggest that NK cells also influence the course of chronic viral infections, such as infections with HIV-1 and hepatitis C virus (HCV). Chronic stages of these infections have a negative impact on NK cell function and promote the appearance of phenotypically and functionally abnormal NK cells. In this paper, we summarize available data on CD56(neg) NK cells, an aberrant NK cell subset found in small numbers in healthy individuals and at elevated levels in individuals chronically infected with HIV-1 and HCV. We discuss current knowledge of CD56(neg) NK cells, with a particular emphasis on their accumulation during chronic infection and the possible consequences of this for the host. PMID- 20829114 TI - How do facilitators of practice development gain the expertise required to support vital transformation of practice and workplace cultures? AB - BACKGROUND: Skilled facilitation is at the heart of transformational practice development, and facilitators carry the hopes and expectations of those eager to see the promises of practice development come to fruition. AIM: The aim of this paper is to present a framework that assists facilitators to understand their progress in relation to the development of specific expertise, identify their ongoing needs and make the most of all opportunities for development. CONCLUSION: We argue that insight into several stages of development, and finding appropriate forms of challenge and support, are likely to enhance the experiences of facilitators, their rate of development and the level of expertise achieved. PMID- 20829115 TI - Challenging the shock of reality through digital storytelling. AB - The transition from student to qualified nurse is widely acknowledged to entail a difficult period of adjustment, involving significant personal and professional challenges. Kramer [1974. Reality Shock--Why Nurses Leave Nursing. Mosby, St. Louis] originally described this as a "reality shock" due to the dissonance experienced between the expectations of the newly qualified nurse and the actuality of clinical practice. This experience continues to be echoed throughout the literature exploring factors influencing the quality of compassionate care, post-qualification support strategies, and attrition rates. Despite this, the phenomenon of a reality shock appears to have been accepted as an inevitable aspect of professional socialisation. This paper aims to report on an educational development which attempted to challenge these negative experiences and outcomes. The Division of Nursing at the University of Nottingham worked alongside the Patient Voices Programme (www.patientvoices.org.uk) to create reflective digital stories of newly qualified nurses. In their own words and using personal photos, the newly qualified nurses relate stories about an event that they have found particularly challenging during the transition from student to nurse. The stories were intended to provide opportunities for future students to learn and educationalists to reconsider the curriculum to facilitate preparation for the world of clinical practice. A learning environment was developed and piloted that utilises the digital stories to encourage student nurses to reflect upon the challenges of this transition by engaging with the storytellers, empathising with their experience and considering ways they might respond in similar situations. Evaluation of this educational forum suggests that the digital stories offer the audience a unique opportunity to walk in the shoes of the storyteller. As a consequence, an altered story might be told through encouraging newly qualified nurses to develop their core strengths and, in doing so, maintain their capacity to care. PMID- 20829116 TI - The experiences of children's nursing students: learning urethral catheterisation. AB - BACKGROUND: This study aimed to explore the factors which influence student nurses' ability to urethrally catheterize children in their care. This aimed to inform current pre-registration clinical skill training and education. METHODOLOGY: A mixed method study using focus groups and written questionnaires. RESULTS: The students identified that being able to competently carry out urethral catheterisation was influenced by a lack of exposure to the clinical skill and a need for specific paediatric focused training. Evaluation of current catheterisation training highlighted that, even after training, only a small proportion of the student nurses (24%, n=12) felt confident to catheterize children in practice. CONCLUSION: Student nurses infrequently witnessed paediatric urethral catheterisation in clinical placements which impacted on their ability to consolidate their learning and build competency in this clinical skill. Limited exposure to some clinical skills in practice, may mean that student nurses' education should focus on skills they are more likely to witness in order to optimise their learning opportunities. PMID- 20829117 TI - The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis. AB - The dissemination of Mycobacterium tuberculosis from the primary focus of infection is central to the pathogenesis of tuberculosis. Trafficking of bacteria to the regional lymph nodes is essential to the development of a protective T cell mediated immune response, but bacteria trafficked within the bloodstream can lead to extra-pulmonary dissemination and some of the most devastating clinical consequences of tuberculosis. Yet how M. tuberculosis leaves the lungs is poorly understood. Here, we review the potential pathways and molecular mechanisms behind the dissemination of M. tuberculosis and consider the consequences to both host and bacteria. To disseminate M. tuberculosis must breach the alveolar epithelium and various bacterial factors have been implicated in this process. Heparin binding haemagglutinin adhesin (HBHA) enables M. tuberculosis to bind to sulphated glycoconjugates on epithelial cells; disruption of its synthesis severely impairs the ability of bacteria to disseminate from the lungs to the spleen. Two products of the M. tuberculosis RD1 gene locus, early secretory antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP-10), have been linked to cell lysis and may enable bacteria to invade and spread within the alveolar epithelium. Recent studies in embryonic zebrafish indicate ESAT-6 may also stimulate the trafficking of infected macrophages within granulomas, thereby promoting the early dissemination of bacteria. These findings challenge conventional notions of the protective role of granulomas in mycobacterial infection and indicate M. tuberculosis has evolved specific mechanisms which utilise granulomas as foci of macrophage recruitment, infection, and subsequent bacterial dissemination. Further understanding of the pathways, mechanisms and consequences of M. tuberculosis dissemination could have a major impact in designing novel vaccines and therapeutic strategies. PMID- 20829118 TI - Timing of posterior urethral valve diagnosis and its impact on clinical outcome. AB - OBJECTIVE: Our goals were to assess long-term outcome for patients with posterior urethral valves (PUV) and determine the impact of the timing of diagnosis. PATIENTS AND METHODS: We reviewed the hospital records for patients with PUV treated in 1994-2008. Only those patients diagnosed, treated surgically, and followed clinically at our center were included. RESULTS: There were 52 patients with PUV. Thirty-nine were diagnosed by 1 year of age (early diagnosis cohort), while 13 were diagnosed after 1 year (late diagnosis cohort). Mean follow up after valve operation was 7.2 years (range 15 months-14 years). Chronic renal failure rates were not statistically different between the early and late diagnosis groups after surgical intervention: 48% (14/29) vs 25% (3/12), P = 0.30. Among the early diagnosis cases, 10% (3/29) eventually required renal transplant, while no child in the late diagnosis group has developed end-stage renal disease to date (P = 0.55). CONCLUSIONS: Gestational age at diagnosis is an important predictor of postnatal renal outcome. Our results suggest that diagnosis after 1 year of age is associated with a lower risk of developing renal insufficiency on long-term follow up. PMID- 20829119 TI - Postictal headache. AB - Postictal headache (PIH) is defined by the International Classification of Headache Disorders as "headache with features of tension-type headache or, in a patient with migraine, of migraine headache, which develops within 3 hours following a partial or generalized seizure and resolves within 72 hours after the seizure." PIHs are prevalent, moderate to severe in intensity, last many hours, and frequently have characteristics of migraine. Young adults with a history of interictal headaches are at increased risk of developing PIH. Young age at onset and long duration of epilepsy, drug-resistant seizures, generalized tonic-clonic seizures, and possibly an occipital epileptic focus are additional risk factors. Although PIH is estimated to have a significant impact on the quality of life of people with epilepsy, it is frequently undertreated. Simple analgesics may prove beneficial. Epilepsy and headache share common pathophysiological mechanisms, as suggested by clinical and investigational findings, although the exact processes underlying these conditions are still largely unknown. PMID- 20829121 TI - Myogenic activity in autoregulation during low frequency oscillations. AB - Lower body negative pressure (LBNP) was applied in eight human subjects to trigger low frequency oscillations in order to study the nature of functional coupling between the hemodynamic and autonomic nervous systems, with particular focus on how the myogenic response fits within this coupling. To this end muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were measured at baseline and during LBNP and were then examined in both the time and frequency domains. At the height of low frequency oscillations (~0.1Hz) there was a strong coupling between all the five indices, marked by perfect alignment of their oscillatory frequencies. Results in the time domain show that a fall in MAP is followed by a fall in TPR at 1.58s SD 0.69), a rise in heart rate at 2.64s (SD 0.98), a rise in cardiac output at 3.72s (SD 0.60), a peak in MSNA at 5.71s (SD 1.27) and, finally, a rise in TPR at 7.13s (SD 1.02). A possible interpretation of the latter is that a drop in MAP first triggers a drop in TPR via a myogenic response before the expected rise in TPR via a rise in MSNA. In other words, following a drop in arterial pressure, myogenic response controls vessel diameter before this control is taken over by MSNA. These findings provide a possible resolution of a longstanding conceptual argument against attributing a significant role for the myogenic response in blood flow autoregulation. PMID- 20829122 TI - Development of high performance liquid chromatography/electrospray ionization mass spectrometry for assay of ginkgolic acid (15:1) in rat plasma and its application to pharmacokinetics study. AB - A highly sensitive HPLC-ESI-MS method has been developed and validated for the quantification of ginkgolic acid (15:1) in a small quantity of rat plasma (50MUL) using its homologous compound ginkgolic acid (17:1) as an internal standard. GA (15:1) and GA (17:1) were extracted from biological matrix by direct protein precipitation with 5-fold volume of methanol and separated on an Elite hypersil BDS C(18) column (2.1*100mm, 3MUm), eluted with acetonitrile:water (92:8, v/v, containing 0.3% glacial acetic acid). Linear range was 8-1000ng/mL with the square regression coefficient (r(2)) of 0.996. The lowest concentration (8ng/mL) in the calibration curve was estimated as LLOQ with both deviation of accuracy and RSD of precision <20% (n=6). The intra- and inter-day precision ranged from 3.6% to 9.9%, and the intra- and inter-day accuracy was between 89.9% and 101.3%. This method was successfully applied to study pharmacokinetics of GA (15:1) in rats after oral administration at a dose of 10mg/kg. GA (15:1) pharmacokinetic parameters C(max), T(max), t(1/2), AUC(0-12h) are 1552.9+/-241.0ng/mL, 0.9+/ 0.7h, 5.5+/-2.6h, 3356.0+/-795.3ngh/mL, respectively. PMID- 20829123 TI - Prediction and interpretation of the antioxidant capacity of green tea from dissimilar chromatographic fingerprints. AB - Previously, multivariate calibration techniques have been successfully applied to model and predict the antioxidant activity of green tea from its chromatographic fingerprint. Since the selectivity differences between dissimilar chromatographic systems have already been valuably used in several applications, in this paper it is studied whether combining the complementary information contained in two dissimilar fingerprints can improve the predictive capacity of the multivariate calibration model. The simplest way of combining the data is concatenating both fingerprints for each sample. The resulting matrix can then be subjected to Orthogonal Projections to Latent Structures (O-PLS). Unfortunately, this approach resulted in a more complex model with a prediction error of about the average of the errors obtained with the individual fingerprints. Secondly, only the peaks with high loading and low orthogonal loading from both chromatograms were included in the O-PLS model. This resulted in a reduced complexity, but not in better predictions, probably due to a lack of complementarity of the information concerning the antioxidant capacity. Finally, the concatenated fingerprints were subjected to stepwise multiple linear regression (MLR) in order to build a model based on the variables most correlated with the antioxidant capacity. The obtained prediction error was lower than those of both previous approaches, but still higher than the error of the model based on a single analysis. This is probably again caused by a lack of complementarity in the variables. Nevertheless, it was advantageous to develop fingerprints on dissimilar system, because it enables to choose the most suited chromatographic profile to build a multivariate calibration model for the considered purpose. In contrast to what was expected, the study showed that the most simple (so the worst separated) fingerprints resulted in the best predictions. On the other hand, a more complex fingerprint in which more compounds are separated is still important to improve the interpretability of the model. PMID- 20829124 TI - High-yield expression and purification of the Hsp90-associated p23, FKBP52, HOP and SGTalpha proteins. AB - Hsp90 is a ubiquitous molecular chaperone that plays a key role in the malignant development of hormone-dependent pathologies such as cancer. An important role for Hsp90 is to facilitate the stable binding of steroid hormones to their respective receptors enabling the ligand-based signal to be carried to the nucleus and ultimately resulting in the up-regulation of gene expression. Along with Hsp90, this dynamic and transient process also involves the recruitment of additional proteins and co-chaperones that add further stability to the mature receptor-chaperone complex. In the work presented here, we describe four new protocols for the bacterial over-expression and column chromatographic purification of the human p23, FKBP52, HOP and SGTalpha proteins. Each of these proteins plays a distinct role in the steroid hormone receptor regulatory cycle. Affinity, ion-exchange and size-exclusion techniques were used to produce target yields greater than 50mg/L of cultured media, with each purified sample reaching near absolute sample homogeneity. These results reveal a reliable system for the production of p23, FKBP52, HOP and SGTalpha substrate proteins for use in the investigation of the Hsp90-associated protein interactions of the steroid hormone receptor cycle. PMID- 20829125 TI - Development and validation of a liquid chromatography/mass spectrometry method for pharmacokinetic studies of OZ78, a fasciocidal drug candidate. AB - Fascioliasis is a zoonotic disease of considerable public health and great veterinary significance and new drugs are needed. OZ78 is a promising fasciocidal drug candidate. In order to support the development of OZ78, including pharmacokinetic (PK) studies an accurate, precise, and selective liquid chromatography/mass spectrometry (LC/MS) method for OZ78 was developed for sheep plasma and validated in accordance with the US Food and Drug Administration Guidance on Bioanalytical Method Validation. Protein precipitation was used for sample clean up. Separation was performed through a Phenomenex C8(2) analytical column (50.0mm*2.0mm, 5MUm) with a mobile phase of acetonitrile (buffer B) and 5mM ammonium formate (buffer A) at a flow-rate of 0.3mL/min and a gradient from 20% to 95% acetonitrile. The mass spectrometer was operated under selected ion monitoring, and orifice voltage set to -4.1kV and ion spray temperature to 400 degrees C. Nitrogen was used as a nebulizer, curtain, and collision gas. OZ78 was monitored at 321.4m/z (deprotonated parent compound, M-). The validated linear dynamic range was between 156.25ng/mL and 5MUg/mL and the achieved correlation coefficient (r(2)) was greater than 0.99. The validation results demonstrated that the developed LC/MS method is precise, accurate, and selective for the determination of OZ78 in sheep plasma. The method was successfully applied to the evaluation of the PK profile of OZ78 in sheep. PMID- 20829126 TI - UPLC-QTOF/MS-based screening and identification of the constituents and their metabolites in rat plasma and urine after oral administration of Glechoma longituba extract. AB - Glechoma longituba is a widely used traditional Chinese medicine (TCM) in treating various diseases; however, the in vivo integrated metabolism of its multiple bioactive components remains unknown. In this paper, ultra-performance liquid chromatography (UPLC) coupled to quadrupole time-of-flight (QTOF) and the MetaboLynxTM software combined with mass defect filtering (MDF) together provide unique high throughput capabilities for drug metabolism study, with excellent MS mass accuracy and enhanced MS(E) data acquisition. This rapid automated analysis method was successfully applied for screening and identification of the constituents absorbed and metabolized studies of G. longituba extract after oral administration to rats. The results showed that 21 parent components of G. longituba extract were absorbed into the blood circulation of the rats and a total of 80 metabolites of 9 parent compounds were tentatively detected in vivo by their MS spectra obtained at low or high collision energy scan with the comparison of the authentic standards and literature data. The developed method was simple and reliable, revealing that it could be used to rapid screen and identify the structures of active components responsible for pharmacological effects of G. longituba and to better clarify its action mechanism. This work suggests that the integrative metabolism approach makes a useful template for drug metabolism research of TCM. PMID- 20829127 TI - Determination of lipoic acid in human plasma by HPLC-ECD using liquid-liquid and solid-phase extraction: Method development, validation and optimization of experimental parameters. AB - A rapid, inexpensive, sensitive and specific HPLC-ECD method for the determination of lipoic acid in human plasma was developed and validated over the linearity range of 0.001-10MUg/ml using naproxen sodium as an internal standard (IS). Extraction of lipoic acid and IS from plasma (250MUl) was carried out with a simple one step liquid-liquid extraction using dichloromethane. Similarly solid phase extraction was carried out using dichloromethane as extraction solvent. The separated organic layer was dried under the stream of nitrogen at 40 degrees C and the residue was reconstituted with the mobile phase. Complete separation of both lipoic acid and IS at 30 degrees C on Discovery HS C18 RP column (250mm*4.6mm, 5MUm) was achieved in 6min using 0.05M phosphate buffer (pH 2.5 adjusted with phosphoric acid):acetonitrile (50:50, v/v) as a mobile phase pumped at the rate of 1.5ml/min using electrochemical detector in DC mode at the detector potential of 1.0V. The limit of detection and limit of quantification of lipoic acid were 200pg/ml and 1ng/ml, respectively. While on column limit of detection and limit of quantification of lipoic acid were 10 and 50pg/ml, respectively. The absolute recoveries of lipoic acid with liquid-liquid and solid phase extraction were 98.43, 95.65, 101.45, and 97.36, 102.73, 100.17% at 0.5, 1 and 5MUg/ml levels, respectively. Coefficient of variations for both intra-day and inter-day were between 0.28 and 4.97%. The method is validated and will be quite suitable for the analysis of lipoic acid in the plasma of human volunteers as well as patients with diabetes and cardiovascular diseases. PMID- 20829128 TI - Chromatographic analysis of acetohexamide binding to glycated human serum albumin. AB - Acetohexamide is a drug used to treat type II diabetes and is tightly bound to the protein human serum albumin (HSA) in the circulation. It has been proposed that the binding of some drugs with HSA can be affected by the non-enzymatic glycation of this protein. This study used high-performance affinity chromatography to examine the changes in acetohexamide-HSA binding that take place as the glycation of HSA is increased. It was found in frontal analysis experiments that the binding of acetohexamide to glycated HSA could be described by a two-site model involving both strong and weak affinity interactions. The average association equilibrium constant (K(a)) for the high affinity interactions was in the range of 1.2-2.0*10(5)M(-1) and increased in moving from normal HSA to HSA with glycation levels that might be found in advanced diabetes. It was found through competition studies that acetohexamide was binding at both Sudlow sites I and II on the glycated HSA. The K(a) for acetohexamide at Sudlow site I increased by 40% in going from normal HSA to minimally glycated HSA but then decreased back to near-normal values in going to more highly glycated HSA. At Sudlow site II, the K(a) for acetohexamide first decreased by about 40% and then increased in going from normal HSA to minimally glycated HSA and more highly glycated HSA. This information demonstrates the importance of conducting both frontal analysis and site-specific binding studies in examining the effects of glycation on the interactions of a drug with HSA. PMID- 20829129 TI - A combined A431 cell membrane chromatography and online high performance liquid chromatography/mass spectrometry method for screening compounds from total alkaloid of Radix Caulophylli acting on the human EGFR. AB - We have developed an online analytical method that combines A431 cell membrane chromatography (A431/CMC) with high performance liquid chromatography and mass spectrometry (LC/MS) for identifying active components from Radix Caulophylli acting on human EGFR. Retention fractions on A431/CMC model were captured onto an enrichment column and the components were directly analyzed by combining a 10 port column switcher with an LC/MS system for separation and preliminary identification. Using Sorafenib tosylate as a positive control, taspine and caulophine from Radix Caulophylli were identified as the active molecules which could act on the EGFR. This A431/CMC-online-LC/MS method can be applied for screening active components acting on EGFR from traditional Chinese medicines exemplified by Radix Caulophylli and will be of great utility in drug discovery using natural medicinal herbs as a source of novel compounds. PMID- 20829130 TI - Liquid chromatography-tandem mass spectrometric assay for pravastatin and two isomeric metabolites in mouse plasma and tissue homogenates. AB - A bioanalytical assay for pravastatin and two isomeric metabolites, 3'alpha isopravastatin and 6'-epipravastatin, was developed and validated. Mouse plasma and tissue homogenates from liver, kidney, brain and heart were pre-treated using protein precipitation with acetonitrile containing deuterated internal standards of the analytes. The extract was diluted with water and injected into the chromatographic system. This system consisted of a polar embedded octadecyl silica column using isocratic elution with formic acid in a water-acetonitrile mixture. The eluate was transferred to an electrospray interface using negative ionization and the analytes were detected and quantified with the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was successfully validated in a 3.4-7100ng/ml concentration range for pravastatin, 1.3-2200ng/ml for 3'alpha-isopravastatin and 0.5-215ng/ml for 6'-epipravastatin using only plasma for calibration. For plasma samples, subjected to full validation, within and between day precisions were 1-7% (9-18% at the LLQ level) and accuracies were between 91% and 103%. For tissue homogenates, subjected to partial validation, within and between day precisions were 2-12% (6-19% at the LLQ level) and accuracies were between 87% and 113% (81 and 113% at the LLQ level). Drug and metabolites were shown to be chemically stable under most relevant analytical conditions. Finally, the assay was successfully applied for a pilot study in mice. After intravenous administration of the drug, all isomeric compounds were found in plasma; however, in liver and kidney homogenate only the parent drug showed levels exceeding the LLQ. PMID- 20829131 TI - Simultaneous determination of 8-hydroxy-2'-deoxyguanosine and 5-methyl-2' deoxycytidine in DNA sample by high performance liquid chromatography/positive electrospray ionization tandem mass spectrometry. AB - 8-Hydroxy-2'-deoxyguanosine (8-OHdG) and 5-methyl-2'-deoxycytidine (5-mdC) are utilized as useful biomarkers not only for early diagnosis but also for the detection and assessment of high-risk individuals. In the present study, a sensitive and specific method was developed for simultaneous determination of 8 OHdG and 5-mdC in DNA by high performance liquid chromatography/positive electrospray ionization tandem mass spectrometry. The limits of quantification for 8-OHdG and 5-mdC were 80 and 40pg/ml, respectively. The calibration curves of 8-OHdG and 5-mdC were linear over the concentration range of 0.02-100ng/ml and the correlation coefficients were higher than 0.9990. The intra-day and inter-day relative standard derivative values were in the range of 0.70-7.47% for 8-OHdG and 1.07-7.06% for 5-mdC, respectively. The recoveries were 93.4-108.5% for 8 OHdG and 87.4-104.9% for 5-mdC, respectively. This method was validated by determination of the background levels of 8-OHdG and 5-mdC in calf thymus DNA, and satisfactory results were obtained. PMID- 20829132 TI - Application of one-step liquid chromatography-electrospray tandem MS/MS and collision-induced dissociation to quantification of ezetimibe and identification of its glucuronated metabolite in human serum: A pharmacokinetic study. AB - A new one-step liquid chromatography-electrospray tandem MS/MS method is described to quantify ezetimibe (EZM) a novel lipid lowering drug in human serum. Also using collision-induced dissociation (CID) of the analyte, identification and chromatographic separation of its major metabolite, ezetimibe glucuronide (EZM-G) is achieved in this study. A thawed serum aliquot of 100MUL was deproteinated by addition of 500MUL methanol containing omeprazole as internal standard (I.S.). Separation of the drug, its metabolite and the I.S. were achieved using acetonitrile-water (70:30, v/v) as mobile phase at flow rate of 0.5mL/min on a MZ PerfectSil target C18 column. Multiple reaction monitoring (MRM) mode of precursor-product ion transition (408.7->272.0 for EZM and 345 >194.5 for the I.S.) was applied for detection and quantification of the drug while, EZM-G was chromatographically separated and identified using CID. The analytical method was linear over the concentration range of 1-32ng/mL of EZM in human serum with a limit of quantification of 1ng/mL. The coefficient variation values of both inter- and intra-day analysis were less than 8% whereas the percentage error was less than 3.7. The validated method was applied in a randomized cross-over bioequivalence study of two different EZM preparations in 24 healthy volunteers. PMID- 20829133 TI - A case of fulminant progressing dermatomyositis panarteritis nodosa (DMPAN). PMID- 20829134 TI - Trauma management within UK plastic surgery units. PMID- 20829135 TI - The use of the anterolateral thigh flap for microsurgical reconstruction of distal extremities after oncosurgical resection of soft-tissue sarcomas. AB - Prior to the advent of a multidisciplinary approach to the treatment of soft tissue sarcomas, surgical treatment consisted of extremity amputation. Advances in treatment modalities such as radiotherapy allowed more limited resections with similar survival rates. As local control is the primary objective in the management of these neoplasms, distally located tumours pose a particular reconstructive challenge. Limb preservation is now possible due to the availability of microsurgical techniques. A retrospective analysis was conducted assessing the suitability of the free anterolateral thigh (ALT) flap for distal extremity reconstruction after wide local excision of sarcomas. Nine patients were included in the study with a median follow-up period of 36 months. In all patients, tumours were located at or distal to the elbow and knee, respectively. All flaps survived. In one patient, the ALT donor site was addressed with a split thickness skin graft after wound dehiscence was observed postoperatively after initial primary closure. The free ALT perforator flap is an ideal flap for the reconstruction of distal-extremity defects after sarcoma resection as it allows coverage of large skin defects with minimal donor-site morbidity. Its thinness addresses the shallow defects typically encountered in the distal extremity and thus avoids the bulkiness encountered after reconstruction with musculocutaneous flaps. PMID- 20829136 TI - Star flap with a dermal platform for nipple reconstruction. PMID- 20829137 TI - Invisalign((r)) treatment of patients with craniomandibular disorders. AB - The temporomandibular joint is one of the most complex joint systems in the human body. Craniomandibular disorders (CMD) are a common condition in which symptoms and signs may vary within a single individual and from one person to another. As anatomic and functional aspects of the craniomandibular system (CMS) and the upper cervical spine are closely interconnected, CMD need a close interdisciplinary approach combining orthopedics, manual medicine, orthodontics and dentistry. Splints as a therapeutic treatment instrument in CMD patients are widely accepted. The association of splint therapy and the Invisalign((r)) system not only provides comfortable and almost invisible treatment but also constitutes a powerful instrument for the orthodontic treatment of the CMD patient. To this end, precise knowledge of the temporomandibular joint, temporomandibular disorders and treatment using removable and fixed splints is indispensable. PMID- 20829139 TI - [Sclerodermic renal crisis: case report]. AB - Sclerodermic renal crisis is defined as a severe arterial hypertension or rapidly progressive glomerulonephritis in a sclerodermic patient, associated with anuria due to no other cause but systemic sclerodermia. It constitutes a rare and dangerous complication. The renal prognosis can be effectively improved by converting enzyme inhibitors, allowing a better arterial hypertension control. However, the associated mortality remains high, a follow up must be instaured in order to prevent the apparition of renal lesions in all sclerodermic patients. We report a case of rapidly progressive renal failure with hypertension in a patient with no previous problems, which preceded the development of scleroderma diffuse cutaneous form. The biopsy showed a microangiopathy in the context of scleroderma renal crisis. The evolution was marked by the presence of chronic renal insufficiency which necessitated the dialysing start. PMID- 20829140 TI - [Interest of mycophenolate mofetil in children with membranous lupus nephritis]. AB - The management of lupus nephritis remains a clinical problem in children as in adults. Corticosteroids, cyclophosphamide and azathioprine have been used with satisfactory response, but the most important problems are their potential toxicities. Therefore, we evaluate the use of mycophenolate mofetil (MMF) as a new agent for treatment of lupus nephritis in children. Five children with biopsy proven proliferative glomerulonephritis with active lesions received MMF, combined with corticosteroids during the induction phase and alone during the maintenance phase. We retrospectively studied the efficacy and safety of this therapeutic regimen. All patients had proteinuria and renal failure. Four patients from five presented nephrotic syndrome. During the induction phase, three patients achieved complete remission of their nephrotic syndrome with normalization of renal function. One patient achieved partial remission and kept moderate renal failure. One patient died at 50 days by severe sepsis secondary to leucopenia. During the maintenance phase, three patients had complete remission. One patient was kept proteinuria with a creatinine clearance of 55 mL/min/1,73 m2. The growth of these patients is not affected. In childhood lupus proliferative glomerulonephritis, MMF was well tolerated, and most of the patients achieved remission and improvement of their renal functions. PMID- 20829141 TI - [Cytomegalovirus effects in solid organ transplantation and the role of antiviral prophylaxis]. AB - Cytomegalovirus (CMV) belongs to beta-Herpesviridae family. Morbidity related to this infectious agent remains a serious concern in the context of immunosuppression. Occurence of CMV infection within the first 3 months post renal transplantation without any antiviral prophylaxis is about 70% of patients. Direct and indirect effects of CMV infection in the setting of organ transplantation are described in this review. A 3 to 6 months course of prophylaxis with valganciclovir is advised concerning high-risk transplant recipients (D+/R-) but recommendation regarding intermediate-risk transplant recipients (CMV-seropositive patients) is still unclear. Recent studies highlight a benefit of long time prophylaxis (until 6 months) in terms of CMV disease occurence among D+/R- patients. News assays that measures IFNgamma responses to a variety of CMV epitopes (Quantiferon((r)) and Elispot IFNgamma) are developped to predict CMV disease onset after discontinuation of antiviral prophylaxis. These assays could contribute to adapt prophylaxis to each recipient. PMID- 20829142 TI - Transplanted nonviable human hepatocytes produce appreciable serum albumin levels in mice. AB - In animal models of liver cell therapy serum human albumin levels are universally measured as a marker for the engraftment and function of transplanted human hepatocytes, or hepatocyte-like cells derived from human stem cells. However, even the most efficient cell transplantation protocols encounter a significant amount of graft cell death. If albumin released from dying cells could be detected for prolonged periods of time in the serum of the recipient, it may misleadingly suggest engraftment and function of the transplanted cells. While a half-life of approximately 20 days of human albumin in humans is established, the duration of its detectability in mice is unknown. Here we show that human albumin is readily detectable in the serum of mice injected with nonviable human hepatocytes. Human albumin levels peak 24h after injection of hepatocyte debris, and remain detectable at significant levels for at least 8 days. Our finding suggests that long-term, or in situ, analyses are needed to prove functional engraftment of human primary or stem cell-derived hepatocytes. PMID- 20829143 TI - Distal femoral varus osteotomy outcome: Is associated femoropatellar osteoarthritis consequential? AB - INTRODUCTION: Distal femoral varus osteotomy (FVO) can be indicated for young active patients who have lateral unicompartmental osteoarthritis in a valgus knee originating in the femur. However, its indication remains controversial when associated patellofemoral osteoarthrosis is present. HYPOTHESIS: Associated patellofemoral osteoarthrosis influences the results of osteotomy in cases of lateral tibiofemoral osteoarthrosis. METHODS: Twenty patients (22 knees) underwent opening wedge FVO for lateral tibiofemoral osteoarthrosis of a valgus knee. The osteoarthrosis was lateral and unicompartmental in 11 cases, associated with patellofemoral osteoarthrosis in nine cases, and global in two cases. The osteotomy site was fixed with a 95 degrees blade plate in all cases. At a mean follow-up of 54 months, all the patients were evaluated using the International Knee Society (IKS) score. RESULTS: Eighteen knees had good or excellent results (80%), two had fair results (9.5%), and two had poor results (9.5%). One female patient underwent total knee replacement revision at 8 years and three others are awaiting total knee replacement. The mean preoperative IKS score increased from 49.28 (range, 14-70) to 74.23 (range, 41-92) at the last follow-up. The mean preoperative functional score increased from 50.68 (range, 30-80) to 72.85 (range, 40-90) at the last follow-up (p=0.001). The 8-year survival rate was 91% (confidence interval, 69-100%). We noted improvement in patellofemoral syndrome and recentering of the patella in seven cases out of nine with severe patellofemoral osteoarthrosis. CONCLUSION: Distal femoral varus osteotomy, with lateral opening wedge and fixation can be a good alternative to treatment of lateral tibiofemoral osteoarthritis associated with a valgus knee originating in the femur. The association of patellofemoral osteoarthritis does not affect the functional results. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 20829144 TI - Intrathecal baclofen in cerebral palsy. A retrospective study of 25 wheelchair assisted adults. AB - OBJECTIVE: To study the efficacy and safety of intrathecal baclofen therapy (ITB) in wheelchair-dependent adults with cerebral palsy. PATIENTS AND METHODS: A retrospective analysis and clinical examination of 25 wheelchair-assisted adults with cerebral palsy receiving ITB initiated between 1999 and 2009 in three different cities in western France. RESULTS: ITB improves spasticity and facilitates wheelchair comfort and nursing care. The therapy has an effect on motor disorders and pain. Eighty percent of the ITB patients were satisfied. Dissatisfaction was related to complications or adverse events and not lack of efficacy. Complications occurred in 32% of the patients and transient interruption of the treatment or surgical removal of the ITB pump was necessary in 16% of cases. DISCUSSION AND CONCLUSION: Wider use of ITB in this indication is likely and should lead to a better understanding of the drug's pharmacological effects on motor disorders and pain. Use of the Goal Attainment Assessment Scale or Caregiver Questionnaire can help us. PMID- 20829145 TI - No association between educational level and pancreatic cancer incidence in the European Prospective Investigation into Cancer and Nutrition. AB - INTRODUCTION: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive. AIM: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. METHODS: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region. RESULTS: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII=1.14, 95% CI 0.80-1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII(<= 60 years)=0.85, 95% CI 0.44-1.64, adjusted RII(>60 years)=1.18, 95% CI 0.73-1.90), gender (adjusted RII(male)=1.20, 95% CI 0.68 2.10, adjusted RII(female)=0.96, 95% CI 0.56-1.62) or geographical region (adjusted RII(Northern Europe)=1.14, 95% CI 0.81-1.61, adjusted RII(Middle Europe)=1.72, 95% CI 0.93-3.19, adjusted RII(Southern Europe)=0.75, 95% CI 0.32 1.80). CONCLUSION: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort. PMID- 20829146 TI - How to optimize the economic viability of thyroid surgery in a French public hospital? AB - STUDY OBJECTIVE: Physicians in France have been asked to change their day-to-day medical practice to reduce overall costs. We examine ways to achieve this goal in thyroid surgery. MATERIAL AND METHODS: We defined and implemented a clinical pathway to optimize the economic viability of thyroid surgery by increasing revenues and lowering expenses. An increase in revenue was achieved by decreasing patient length of stay (LOS) through the use of a fast-track rehabilitation protocol. Expenses were decreased by performing all pre-operative work-up in the out-patient setting and by decreasing costs in the operating room. RESULTS: For 292 consecutive patients who underwent thyroidectomy, the average LOS has been decreased over time to a mean of 2.03 days in 2008; 96% of patients were discharged on the first postoperative day. These results were primarily achieved by using a fast-track rehabilitation clinical pathway, and no increase in postoperative morbidity was noted. Operating time was decreased by 20% through the use of a second surgical assistant and hemostatic scissors but this improvement did not translate into better daily utilization of the operating room. CONCLUSION: The economic profitability of thyroid surgery is improved when mean LOS is reduced to 2 days through a fast-track protocol. Decreasing the duration of hospitalization was more effective than decreasing operative duration in controlling overall costs. PMID- 20829147 TI - Right aortic arch and its variants. AB - A number of congenital anomalies of the aortic arch complex can occur, ranging from asymptomatic normal variations in arch vessel branch pattern to symptomatic vascular rings, stenoses, and arch interruptions with a frequency ranging from 0.5% to 3.0%. A right aortic arch is present in 0.1% of the population and can occur in isolation or be associated with congenital heart disease. Patients may present at any age with signs and symptoms of airway or esophageal compression, heart failure, or abnormal chest imaging studies. This pictorial essay will show the computed tomography and appearances of congenital variations of the right aortic arch and use Edwards' hypothetical embryonic double aortic arch model to explain the cause of some of these variants. PMID- 20829148 TI - Attention deficit/hyperactivity disorder: a focused overview for children's environmental health researchers. AB - OBJECTIVES: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed childhood neurobehavioral disorder. Much research has been done to identify genetic, environmental, and social risk factors for ADHD; however, we are still far from fully understanding its etiology. In this review we provide an overview of diagnostic criteria for ADHD and what is known about its biological basis. We also review the neuropsychological functions that are affected in ADHD. The goal is to familiarize the reader with the behavioral deficits that are hallmarks of ADHD and to facilitate comparisons with neurobehavioral deficits associated with environmental chemical exposures. DATA SOURCES: Relevant literature on ADHD is reviewed, focusing in particular on meta analyses conducted between 2004 and the present that evaluated associations between measures of neuropsychological function and ADHD in children. Meta analyses were obtained through searches of the PubMed electronic database using the terms "ADHD," "meta-analysis," "attention," "executive," and "neuropsychological functions." Although meta-analyses are emphasized, nonquantitative reviews are included for particular neuropsychological functions where no meta-analyses were available. DATA SYNTHESIS: The meta-analyses indicate that vigilance (sustained attention), response inhibition, and working memory are impaired in children diagnosed with ADHD. Similar but somewhat less consistent meta-analytic findings have been reported for impairments in alertness, cognitive flexibility, and planning. Additionally, the literature suggests deficits in temporal information processing and altered responses to reinforcement in children diagnosed with ADHD. Findings from brain imagining and neurochemistry studies support the behavioral findings. CONCLUSIONS: Behavioral, neuroanatomical, and neurochemical data indicate substantial differences in attention and executive functions between children diagnosed with ADHD and non ADHD controls. Comparisons of the neurobehavioral deficits associated with ADHD and those associated with exposures to environmental chemicals may help to identify possible environmental risk factors for ADHD and/or reveal common underlying biological mechanisms. PMID- 20829150 TI - Can flap design influence the incidence of alveolar osteitis following removal of impacted mandibular third molars? AB - This study sought to evaluate the influence of flap design (that is, modified triangular flap or buccal envelope flap) on alveolar osteitis (AO) and on healing following the surgical removal of an impacted mandibular third molar. A double blind split-mouth clinical trial examined 17 patients who were candidates for extraction of a bilaterally impacted mandibular third molar with the same difficulty index; a modified triangular flap was placed on one side and a buccal envelope flap (control) was placed on the other side. AO and healing were assessed at three and seven days after surgery. Data were analyzed with the McNemar and Wilcoxon signed-rank tests. The modified triangular flap decreased the incidence of AO and expedited healing at seven days postsurgery. In addition, statistically significant differences were observed in terms of both AO and postoperative healing. PMID- 20829151 TI - Efficacy of composites filled with nanoparticles in permanent molars: Six-month results. AB - This study sought to evaluate the clinical performance of composites filled with nanoparticles six months after placement in the occlusal surface of molars with Class I cavities. This study involved 41 patients, each of whom had three molars affected by primary caries or the need to replace restorations. All restorations were performed in accordance with the manufacturer's recommendations and evaluated in accordance with USPHS modified criteria. Based on the results of the present study, composites reinforced with nanoparticles can be used in posterior teeth, although their performance was not superior to that of the microhybrid composite. Long-term re-evaluations are necessary for a more detailed analysis of these composites. PMID- 20829149 TI - Lead and PCBs as risk factors for attention deficit/hyperactivity disorder. AB - OBJECTIVES: Attention deficit/hyperactivity disorder (ADHD) is the most frequently diagnosed neurobehavioral disorder of childhood, yet its etiology is not well understood. In this review we present evidence that environmental chemicals, particularly polychlorinated biphenyls (PCBs) and lead, are associated with deficits in many neurobehavioral functions that are also impaired in ADHD. DATA SOURCES: Human and animal studies of developmental PCB or lead exposures that assessed specific functional domains shown to be impaired in ADHD children were identified via searches of PubMed using "lead" or "PCB exposure" in combination with key words, including "attention," "working memory," "response inhibition," "executive function," "cognitive function," "behavior," and "ADHD." DATA SYNTHESIS: Children and laboratory animals exposed to lead or PCBs show deficits in many aspects of attention and executive function that have been shown to be impaired in children diagnosed with ADHD, including tests of working memory, response inhibition, vigilance, and alertness. Studies conducted to date suggest that lead may reduce both attention and response inhibition, whereas PCBs may impair response inhibition to a greater degree than attention. Low-level lead exposure has been associated with a clinical diagnosis of ADHD in several recent studies. Similar studies of PCBs have not been conducted. CONCLUSIONS: We speculate that exposures to environmental contaminants, including lead and PCBs, may increase the prevalence of ADHD. PMID- 20829152 TI - Exfoliative cytology of the oral mucosa: comparison of two collection methods. AB - This study compared the sampling efficacy of a cytobrush and metal spatula for exfoliative cytology of the oral mucosa. Thirty students with no detectable oral alterations upon clinical examination were submitted to exfoliative cytology of the lateral border of the tongue, using a metal spatula on the left side and a cytobrush on the right side. The smears were stained using the Papanicolaou technique and evaluated for cellularity, cell type, cell distribution, homogeneity, and cellular distortion, as well as the presence of mucus, inflammatory infiltrate, and hemorrhage. A statistical test (Z-test) with a 95% confidence interval (CI) showed a significant difference between the metal spatula and cytobrush in terms of cellularity (p = 0.02) and homogeneity (p = 0.01). No difference between the two methods was observed regarding cell type (p = 0.4, Z-test) or cell distribution for the 95% confidence interval (p = 0.2, Fisher's test). Cell distortion and the presence of mucus were observed in five cases that used the metal spatula and in two cases that used the cytobrush. No hemorrhage or inflammatory infiltrate was detected in any of the slides. Based on the results of this study, the cytobrush produced qualitatively better smears in terms of cellularity and homogeneity compared to the metal spatula. PMID- 20829153 TI - Biologic width and crown lengthening: case reports and review. AB - The biologic width includes both the connective tissue attachment and the junctional epithelium and has a mean dimension of approximately 2 mm. Invading the biologic width with a restoration can result in localized crestal bone loss, gingival recession, localized gingival hyperplasia, or a combination of these three. When restoring teeth that have subgingival caries or fractures below the gingival attachment, a clinical crown-lengthening procedure is needed to establish the biologic width. This article presents three case reports that utilized crown-lengthening procedures. PMID- 20829154 TI - Assessment of color fidelity of several composite resins compared to their Vita Classical shade registration. AB - This study compared the color fidelity of different composite resins with their registration in the Vita Classical Shade Guide. Using a prefabricated Teflon mold, 120 specimens were divided into four groups (n = 30), according to the resin tested. Three subgroups (n = 10) were prepared for each resin group; these subgroups tested enamel shade, dentin shade, and enamel and dentin shade. Three measurements were performed to verify whether the tooth shade matched that of the Vita Classical Shade Guide. The color was evaluated and the shade variations were calculated. The data were submitted to a three-way ANOVA test (time, color match, and composite type), followed by Tukey's test. It was concluded that all composite resins showed color differences in relation to the Vita Classical Shade Guide. PMID- 20829155 TI - Controlling reduction in the preparation of porcelain laminate veneers. AB - For a clinician to deliver porcelain veneers with optimum esthetics, tooth preparation should be considered during the planning phase. Precise preparation requires depth-cutting burs and reduction indices as essential tools. A well designed preparation will allow the laboratory technician to create ideal tooth contours with lifelike esthetics. PMID- 20829156 TI - The use of ultraviolet LED illumination for composite resin removal: an in vitro study. AB - It may be difficult to recognize composite resin restorations that are correctly shade-matched and well-placed by visual and tactile inspection alone--which can make the replacement of an existing resin restoration challenging. Many composite resins fluoresce under UV light, which can help dentists to detect resin material. This article explores a technique that utilizes a UV LED to cause composite resin to fluoresce. A UV/visible light spectrofluorometer was used to measure fluorescence excitation and emission maxima of 14 composite resin brands. Control samples of dentin and enamel were measured in a similar manner. Subsequently, each brand of composite resin was placed in extracted teeth and relative fluorescence was assessed. The composite resins were then removed and each tooth was inspected using UV light to detect remaining resin. Results from this study indicated that the optimal excitation wavelength was 385-395 nm, while 460 nm was determined to be the mean emission maxima. This study revealed three types of resin: highly fluorescent, moderately fluorescent, and weakly fluorescent. In each instance, the UV light revealed the presence of resin after all resin was believed to have been removed. Based on the results of this study, the use of UV illumination can be a useful technique for determining if composite resin has been removed completely. PMID- 20829157 TI - Comparison of the single cone and cold lateral compaction techniques in sealing 0.04 taper root canal preparations. AB - This study compared the coronal sealing ability of three different combinations of obturation materials and techniques after root canals were prepared with 0.04 taper nickel titanium (NiTi) rotary instruments. This study utilized three experimental groups: Group 1 was obturated with 0.02 taper gutta-percha cones and AH 26 sealer cement, using the cold lateral compaction technique; Group 2 was obturated with 0.02 taper Resilon cones and Epiphany sealer, using the cold lateral compaction technique; and Group 3 was obturated with 0.04 taper Resilon cones and Epiphany sealer, using the single cone technique. Coronal microleakage was evaluated using dye penetration methodology. Microleakage results showed that the single cone Resilon obturation technique showed significantly more linear dye penetration than Resilon or gutta-percha subjected to cold lateral compaction. There was no significant difference between gutta-percha and Resilon when the cold lateral compaction technique was used. The results of this study suggest that the single cone Resilon obturation technique is inferior to cold lateral compaction of Resilon or gutta-percha. PMID- 20829159 TI - The top 50 prescription medications dispensed in pharmacies in 2008. PMID- 20829160 TI - To refer or not refer? PMID- 20829161 TI - Treatment planning implant dentistry: an overview for the general dentist. AB - Successful implant surgery and prosthetics involve a multi-step treatment planning sequence. This article outlines five steps designed to help clinicians create a comprehensive treatment plan for implants that combines the surgical and prosthetic aspects of an implant case. PMID- 20829162 TI - Serial extraction protocol for partial arches in implant dentistry: principles and clinical methodology. AB - Serial extraction protocol (SEP) is a clinical technique that facilitates using natural tooth abutments to support a fixed interim resin prosthesis, while inserting a sufficient number of implants to retain a definitive fixed prosthesis. A Class 1 protocol allows all necessary implants to be placed during one surgical appointment, while a Class 2 protocol requires two or more rounds of implant installation to achieve sufficient support for a definitive fixed prosthesis. The SEP methodology can be used to restore full and partially edentulous dentitions. This article addresses rehabilitation of partial arches using an SEP protocol. PMID- 20829163 TI - Comprehensive implant restoration and the shortened dental arch. AB - The restoration of edentulous space or hopeless teeth with implant-supported restorations can involve extensive time, effort, and financial commitment. This article presents a case of a debilitated dentition that was restored by using the shortened dental arch (SDA) concept in a comprehensive implant restoration. An SDA design was used to replace removable partial dentures with multiple nonsplinted implant-supported crowns extending to the premolars. The results showed an immediate and dramatic improvement in comfort, function, and esthetics while allowing the patient to practice normal oral hygiene. PMID- 20829164 TI - Metal bases for implant overdentures. AB - Reinforcement of implant overdenture bases with chromium alloys offers a number of advantages that offset the initial greater cost. These bases offer increased strength, the ability to detect thermal changes, and the option for use when space is at a minimum. Both acrylic resin and chromium alloy have long (approximately 80 years), successful histories as accepted dental materials. Low heat (nickel) or high-heat (cobalt) chromium alloys can be used with equal success. PMID- 20829165 TI - Immediate loading of implants and fixed complete dentures: a simplified prosthetic procedure. AB - The immediate placement of fixed prostheses after the surgical phase is a challenge for prosthodontists using the All-on-four method. This article describes a simplified technique for constructing a conventional complete denture ahead of the surgery date and adapting it to the implants by using a laboratory reline procedure. This technique accommodates the immediate placement of the fixed prosthesis after surgery without compromising the quality of the prosthesis, requiring only a simple dental laboratory procedure. PMID- 20829166 TI - Socket repair utilizing collagen membrane and mineralized allograft in the esthetic zone: a case report. AB - As the number of patients seeking implants increases, so do the esthetic challenges. Adequate bone is necessary to place an implant with an esthetically pleasing outcome. Failing teeth that require implant replacement often have bony deficiencies, and several surgical techniques have been advocated for maintaining bone volume at the time of extraction. This case report utilized a predictable conservative technique for treating a facial bony defect prior to implant surgery. Atraumatic flapless tooth extraction and the placement of a resorbable collagen membrane and mineralized allograft allowed for adequate regeneration of the alveolar socket prior to implant placement. The dentition was later restored with a zirconia abutment and crown. Socket repair utilizing this technique was a clinically acceptable method for obtaining an esthetic implant restoration. PMID- 20829167 TI - Solutions to complications of implant therapy. AB - Restorative dentists face challenges when implant dentistry is performed without a surgical template. Manufactured component parts (particularly screws, gold cylinders, and the implant bodies themselves) can also cause problems during these procedures. These problems will occur regardless of the mode of retention used for the prosthesis, since the same metals are involved and nearly all implant restorations have a screw somewhere. Managing these complications is essential to avoid treatment failures. PMID- 20829168 TI - The differences between providing oral health care to HIV-infected children and HIV-infected adults: a general dentist's guide. AB - People with HIV and AIDS are living much longer today, thanks to a better understanding of the disease process and the development of effective antiviral drugs and multidrug therapies. Consequently, HIV is now considered a chronic disease, one that affects nearly 40 million people worldwide. Highly active anti retroviral therapy (HAART), first instituted in 1996, has led to a dramatic reduction in the number of perinatally infected children; however, in 2004, there were still 640,000 children under the age of 15 living with HIV worldwide.1 This population of patients faces more mature health issues compared to most children their age. For example, rampant dental decay is common among children with HIV and requires advanced treatment planning that needs to be closely coordinated with members of the medical team. Maintaining good oral health in combination with medication compliance leads to sustained overall health in HIV-infected children; however, many of the medications these children take have severe adverse effects on their oral health. Furthermore, these medications may interfere with other medications that are prescribed or administered in connection with oral health care. Lastly, the systemic and oral manifestations of HIV and AIDS are different for children than they are for adults; as a result, the prognosis and treatment options for these manifestations vary, depending on the patient's age. This article will address factors that affect the oral health of HIV-infected children and adults, as well as common oral manifestations of HIV and AIDS. Key differences in treatment planning for HIV-infected children and HIV infected adults will be outlined. PMID- 20829169 TI - A review of neuropathic pain conditions affecting teeth. AB - Occasionally, dentists must face the complex challenge of diagnosing and treating pain of a neuropathic origin in the orofacial region, since persistent and chronic pain is more common in the head and neck region than in any other part of the body. This article reviews various neuropathic pain conditions that affect orofacial structures (including teeth) and are of clinical significance to dental and endodontic practice. PMID- 20829170 TI - Diagnosis, equilibration, and restoration of an orthodontic failure. AB - This case report illustrates how an interdisciplinary team diagnosis led to occlusal correction of a significant postorthodontic malocclusion. The patient had received complete orthodontics twice previously, from different orthodontists. She could not close without pain or chew comfortably and was concerned about progressive gingival recession. A comprehensive clinical examination, occlusal analysis with diagnostic casts verified in centric relation, bite splint therapy, and full-mouth equilibration were completed prior to limited restorative dentistry. The patient has been comfortable with a stable occlusion for three years. PMID- 20829171 TI - Ventral tongue nodule. Mucus extravasation phenomenon. PMID- 20829172 TI - Deeply seated tongue nodules. Multiple endocrine neoplasia, type 2B. PMID- 20829173 TI - Safeguarding your continuing education. PMID- 20829174 TI - NICU procedures are getting sweeter: development of a sucrose protocol for neonatal procedural pain. AB - Neonates in the neonatal intensive care nursery experience multiple, painful, tissue-damaging procedures daily. Pain among neonates is often underestimated and untreated, producing untoward consequences. A literature review established strong evidence supporting the use of sucrose as an analgesic for minor procedural pain among neonates. A review of unit practices and nurses' experiential evidence initiated the production of a standardized protocol in our unit at the University of Washington Medical Center NICU in Seattle.Nursing practices surrounding sucrose use differed widely in dose, timing, and patient application. We carefully evaluated evidence documenting the effectiveness as well as the safety of sucrose administration and wrote a protocol and practice standards for our primarily premature patient population. This article describes the development and execution of a standardized, nurse-implemented, sucrose protocol to reduce procedural pain. PMID- 20829175 TI - Nonimmune hydrops fetalis part I: etiology and pathophysiology. AB - Nonimmune hydrops fetalis (NIHF) is a condition in which excess fluid has accumulated in the fetal interstitial spaces as a result of one or more nonimmune factors. A plethora of maternal, placental, and fetal disease processes have been associated with NIHF. Knowledge of the various etiologies of NIHF and how the disease process affects fluid homeostasis is important for planning patient care and counseling families of patients diagnosed with nonimmune hydrops fetalis. This article discusses the mechanisms governing fluid distribution in the extracellular spaces, examines the various etiologies associated with NIHF, and describes the pathogenesis of NIHF for each etiologic category. PMID- 20829176 TI - A fatal case of neonatal adenovirus infection. AB - Adenovirus can produce severe disease and even death in the immunocompromised neonate. Symptoms of adenovirus infection are similar to those seen with bacterial infections in neonates, making early recognition and diagnosis difficult. Consideration of adenovirus as a causative agent is important to early diagnosis. Currently available culture techniques, particularly the shell vial culture technique, make more rapid identification of adenovirus infection possible. Early identification and treatment are necessary to improve patient outcomes and prevent the spread of infection to other neonates. Available agents for the treatment of adenovirus have had mixed results, yet their use is preferable to nontreatment of critical patients. This article presents the case of a preterm infant who became fatally ill from disseminated adenoviral infection. PMID- 20829177 TI - The experiences of NICU nurses in caring for infants with neonatal abstinence syndrome. AB - PURPOSE: This study explored the experiences of NICU nurses in caring for infants with neonatal abstinence syndrome (NAS). DESIGN: A qualitative research approach was used with open-ended questions employing computer-assisted personal interviews. SAMPLE: Fourteen NICU nurses employed in a regional hospital provided responses. RESULTS: The nurses reflected a personal struggle between a desire to employ their technical and critical nursing skills and the need to provide expected maternal care to NAS infants. Other themes included frustration and burnout, challenges to values about parenting, and increased awareness of drug use in the community and at home. DISCUSSION: The results suggest that nurses underrate the skill required to care for infants with NAS. The level of knowledge, patience, and commitment to these newborns should be reframed to increase job satisfaction, and education should be offered to nurses about women struggling with addictions. PMID- 20829180 TI - Fluconazole to prevent systemic fungal infections in infants: reviewing the evidence. AB - IN NEONATOLOGY, EVIDENCE-BASED practice (EBP) relies on well-designed, adequately powered trials to guide practitioners. Several large randomized controlled trials (RCTs) have been conducted to explore the use of fluconazole for fungal prophylaxis in premature infants. Despite the findings of these studies, practice varies among units. In a recent survey of members of the American Academy of Pediatrics (AAP), 34 percent of clinicians indicated that they have used antifungal prophylaxis and only 11 percent of clinicians indicated that a written protocol was in place in their NICU. Intravenous (IV) fluconazole (66 percent), oral nystatin (59 percent), and IV amphotericin (21 percent) were the three most commonly used agents among the respondents.1. PMID- 20829181 TI - Infant massage in the NICU. Interview by Deb Discenza. PMID- 20829182 TI - The things I know. PMID- 20829183 TI - Review of online evidence-based practice point-of-care information summary providers: response by the publisher of DynaMed. AB - In response to Banzi's et al review of online evidence-based practice point-of care resources published in the Journal of Medical Internet Research, the publisher of DynaMed clarifies his evidence-based methodology. PMID- 20829186 TI - Macrophage migration inhibitory factor elicits an angiogenic phenotype in human ectopic endometrial cells and triggers the production of major angiogenic factors via CD44, CD74, and MAPK signaling pathways. AB - CONTEXT: An active angiogenesis is required for ectopic endometrial tissue growth. Our previous studies led to the identification of macrophage migration inhibitory factor (MIF), which is markedly elevated in active, vascularized, and early-stage endometriotic lesions, as a potent mitogenic factor for endothelial cells. OBJECTIVE: Our objective was to study the mechanisms by which MIF may stimulate angiogenesis in ectopic endometrial implantation sites. DESIGN: Primary cultures of ectopic endometrial cells were exposed to MIF, and the release of major angiogenic factors with targeted disruption of MIF signaling pathways was assessed. PATIENTS: Patients were women found to have endometriosis during laparoscopy. SETTING: The study was conducted at a hospital and reproduction research laboratory. INTERVENTIONS: Biopsies were removed from endometriotic lesions. MAIN OUTCOME MEASURES: Vascular endothelial cell growth factor (VEGF), IL-8, and monocyte chemotactic protein-1 (MCP-1) mRNA and protein levels and expression and small interfering RNA silencing of MIF CD74/CD44 receptor complex and phosphorylation of ERK and p38 MAPKs were evaluated. RESULTS: MIF markedly up regulated VEGF, IL-8, and MCP-1 expression in endometriotic cells. Such an effect was abolished by (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a specific inhibitor of MIF, and significantly down regulated after specific small interfering RNA silencing of CD44 or CD74. MIF treatment strongly activated ERK and p38 MAPKs, and specific inhibitors of both pathways completely blocked basal and MIF-induced VEGF, IL-8, and MCP-1 synthesis. CONCLUSIONS: These results show for the first time that MIF exerts a potent indirect angiogenic effect by interacting with ectopic endometrial cells and inducing the secretion of major angiogenic factors via CD44, CD74, and MAPK signaling pathways and provide evidence for a possible new mechanism underlying endometriosis development and pathophysiology. PMID- 20829185 TI - Insulin resistance in children: consensus, perspective, and future directions. AB - OBJECTIVE: Emerging data indicate that insulin resistance is common among children and adolescents and is related to cardiometabolic risk, therefore requiring consideration early in life. However, there is still confusion on how to define insulin resistance, how to measure it, what its risk factors are, and whether there are effective strategies to prevent and treat it. A consensus conference was organized in order to clarify these points. PARTICIPANTS: The consensus was internationally supported by all the major scientific societies in pediatric endocrinology and 37 participants. EVIDENCE: An independent and systematic search of the literature was conducted to identify key articles relating to insulin resistance in children. CONSENSUS PROCESS: The conference was divided into five themes and working groups: background and definition; methods of measurement and screening; risk factors and consequences; prevention; and treatment. Each group selected key issues, searched the literature, and developed a draft document. During a 3-d meeting, these papers were debated and finalized by each group before presenting them to the full forum for further discussion and agreement. CONCLUSIONS: Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases. PMID- 20829187 TI - Polymerization behavior of Klenow fragment and Taq DNA polymerase in short primer extension reactions. AB - DNA polymerases amplify DNA fragments through primer extension reactions. However, polymerization behavior of short primers in the primer extension process has not been systematically explored. In this study, we examined the minimal primer length required for primer extension, and the effect of primer length, mismatches and other conditions on DNA polymerization using a non-radioactive method. Under the condition we conducted, the shortest primers polymerized by Klenow fragment (KF) and Taq DNA polymerase in our experiments were respectively heptamer and octamer. The extension efficiency was also affected by the up-stream overhanging structure of the primer-template complex. We hypothesized a simple model to interpret these observations based on the polymerase structures. Furthermore, it was found that the longer the primer, the more efficient is the primer extension. These polymerization behavior of short primers lay foundation about DNA polymerization mechanism and development of novel nucleic acid detection assays. PMID- 20829188 TI - Utility of the surface electrocardiogram for confirming right ventricular septal pacing: validation using electroanatomical mapping. AB - AIMS: When targeting the interventricular septum during pacemaker implantation, the lead may inadvertently be positioned on the anterior wall due to imprecise fluoroscopic landmarks. Surface electrocardiogram (ECG) criteria of the paced QRS complex (e.g. negativity in lead I) have been proposed to confirm a septal position, but these criteria have not been properly validated. Our aim was to investigate whether the paced QRS complex may be used to confirm septal lead position. METHODS: Anatomical reconstruction of the right ventricle was performed using a NavX(r) system in 31 patients (70 +/- 11 years, 26 males) to validate pacing sites. Surface 12-lead ECGs were analysed by digital callipers and compared while pacing from a para-Hissian position, from the mid-septum, and from the anterior free wall. RESULTS: Duration of the QRS complex was not significantly shorter when pacing from the mid-septum compared with the other sites. QRS axis was significantly less vertical during mid-septal pacing (18 +/- 51 degrees ) compared with para-Hissian (38 +/- 37 degrees , P = 0.028) and anterior (53 +/- 55 degrees , P = 0.003) pacing, and QRS transition was intermediate (4.8 +/- 1.3 vs. 3.8 +/- 1.3, P < 0.001, and vs. 5.4 +/- 0.9, P = 0.045, respectively), although no cut-offs could reliably distinguish sites. A negative QRS or the presence of a q-wave in lead I tended to be more frequent with anterior than with mid-septal pacing (9/31 vs. 3/31, P = 0.2 and 8/31 vs. 1/31, P = 1.0, respectively). CONCLUSION: No single ECG criterion could reliably distinguish pacing the mid-septum from the anterior wall. In particular, a negative QRS complex in lead I is an inaccurate criterion for validating septal pacing. PMID- 20829189 TI - MEDAFI-Trial (Micro-embolization during ablation of atrial fibrillation): comparison of pulmonary vein isolation using cryoballoon technique vs. radiofrequency energy. AB - AIMS: Cerebral embolism is a possible serious complication during catheter ablation of atrial fibrillation (AF). The purpose of this prospective pilot study was to analyse the incidence and possible impact of cryo ablation on cerebral lesions and possible differences to radiofrequency (RF) ablation during pulmonary vein isolation (PVI). METHODS AND RESULTS: Pulmonary vein isolation was performed in 89 patients, either with the cryoballoon technique (n = 45) or with RF ablation (n = 44). Phenprocoumon was stopped 3 days before intervention and replaced by subcutaneous low-molecular-weight heparin. During the catheter procedure, an infusion of unfractionated heparin was maintained to achieve an activated clotting time (ACT) of > 300 s. Cerebral magnetic resonance imaging scans were performed 1 day before and after PVI, and at 3-month follow-up. Chronic lesions were observed in 11 patients (12.3%) before PVI without statistically significant difference between the two groups. None of the patients had neurological symptoms during or following the procedure. Seven patients (7.9%) developed acute lesions 1 day after PVI, without statistically significant difference between the group treated by cryoenergy (8.9%) and RF ablation (6.8%). Patients with acute lesions were significantly older compared with those without acute cerebral lesions. No additional cerebral lesions during follow-up were observed. CONCLUSION: A considerable portion of patients with AF but without any neurological symptoms had chronic cerebral lesions before PVI. Additional acute lesions could be added after the procedure. Both ablation techniques showed additional cerebral acute lesions with no neurological symptoms after PVI. PMID- 20829190 TI - Relationship between left ventricular stimulation characteristics at implantation and echocardiographic response after 6 months of cardiac resynchronization therapy. AB - AIMS: Although the electrical stimulation of an ischaemic tissue adversely affects the left ventricular (LV) systolic function, the optimal stimulation site in patients with non-ischaemic cardiomyopathy has not been systematically studied. We hypothesized that the local stimulation characteristics at the time of device implantation predict the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: We measured the impedance, sensing, and capture threshold of a bipolar LV lead in 138 patients with non-ischaemic cardiomyopathy undergoing first implantation of CRT device for drug refractory heart failure. All patients underwent echocardiography at baseline and at 6 months post implantation. An absence of favourable response to CRT was defined as <15% decrease in echocardiographic LV end-systolic volume (LVESV) at 6 months. Echocardiographic response to CRT was observed in 70% of patients. The LV lead measurements predicted neither the optimal stimulation site nor the response to CRT. Left ventricular capture threshold (1.50 +/- 1.1 vs. 1.32 +/- 0.8 V) and impedance (725 +/- 287 vs. 720 +/- 261 Omega) were similar between the responders and the non-responders. Independent of baseline LV ejection fraction or ESV, the LV R-wave amplitude at implantation was significantly higher (P = 0.0038) in responders (12.7 +/- 5.2 mV) than in non-responders (9.7 +/- 6.3 mV), with an area under the receiver operating characteristic curve of 0.7. CONCLUSION: Response to CRT, as determined by decrease in LVESV at 6 months, was associated with significantly higher LV R-wave amplitude at the time of device implantation. PMID- 20829191 TI - Chest X-ray mass in a patient with lung cancer! PMID- 20829192 TI - Frontal lobe epilepsy in children and adolescents: a preliminary neuropsychological assessment of executive function. AB - Although research on adults with frontal lobe epilepsy (FLE) has increased in recent years, delays in frontal lobe development preclude the generalization of these findings to children. This study compared children with FLE with typically developing children on cognitive and executive tests. Additionally, the differences between children with early and late seizure onset were explored. Results indicated comparable intelligence among all groups; however, the FLE cohort performed worse than controls on executive tests. The age of seizure onset differentially affected executive performance, such that early FLE onset resulted in greater executive dysfunction. The implications of these findings are discussed. PMID- 20829193 TI - Root-shoot growth responses during interspecific competition quantified using allometric modelling. AB - BACKGROUND AND AIMS: Plant competition studies are restricted by the difficulty of quantifying root systems of competitors. Analyses are usually limited to above ground traits. Here, a new approach to address this issue is reported. METHODS: Root system weights of competing plants can be estimated from: shoot weights of competitors; combined root weights of competitors; and slopes (scaling exponents, alpha) and intercepts (allometric coefficients, beta) of ln-regressions of root weight on shoot weight of isolated plants. If competition induces no change in root : shoot growth, alpha and beta values of competing and isolated plants will be equal. Measured combined root weight of competitors will equal that estimated allometrically from measured shoot weights of each competing plant. Combined root weights can be partitioned directly among competitors. If, as will be more usual, competition changes relative root and shoot growth, the competitors' combined root weight will not equal that estimated allometrically and cannot be partitioned directly. However, if the isolated-plant alpha and beta values are adjusted until the estimated combined root weight of competitors matches the measured combined root weight, the latter can be partitioned among competitors using their new alpha and beta values. The approach is illustrated using two herbaceous species, Dactylis glomerata and Plantago lanceolata. KEY RESULTS: Allometric modelling revealed a large and continuous increase in the root : shoot ratio by Dactylis, but not Plantago, during competition. This was associated with a superior whole-plant dry weight increase in Dactylis, which was ultimately 2.5 fold greater than that of Plantago. Whole-plant growth dominance of Dactylis over Plantago, as deduced from allometric modelling, occurred 14-24 d earlier than suggested by shoot data alone. CONCLUSION: Given reasonable assumptions, allometric modelling can analyse competitive interactions in any species mixture, and overcomes a long-standing problem in studies of competition. PMID- 20829194 TI - Successive silencing of tandem reporter genes in potato (Solanum tuberosum) over 5 years of vegetative propagation. AB - BACKGROUND AND AIMS: Transgenic plants represent an excellent tool for experimental plant biology and are an important component of modern agriculture. Fully understanding the stability of transgene expression is critical in this regard. Most changes in transgene expression occur soon after transformation and thus unwanted lines can be discarded easily; however, transgenes can be silenced long after their integration. METHODS: To study the long-term changes in transgene expression in potato (Solanum tuberosum), the activity of two reporter genes, encoding green fluorescent protein (GFP) and neomycin phosphotransferase (NPTII), was monitored in a set of 17 transgenic lines over 5 years of vegetative propagation in vitro. KEY RESULTS: A decrease in transgene expression was observed mainly in lines with higher initial GFP expression and a greater number of T-DNA insertions. Complete silencing of the reporter genes was observed in four lines (nearly 25 %), all of which successively silenced the two reporter genes, indicating an interconnection between their silencing. The loss of GFP fluorescence always preceded the loss of kanamycin resistance. Treatment with the demethylation drug 5-azacytidine indicated that silencing of the NPTII gene, but probably not of GFP, occurred directly at the transcriptional level. Successive silencing of the two reporter genes was also reproduced in lines with reactivated expression of previously silenced transgenes. CONCLUSIONS: We suggest a hypothetical mechanism involving the successive silencing of the two reporter genes that involves the switch of GFP silencing from the post-transcriptional to transcriptional level and subsequent spreading of methylation to the NPTII gene. PMID- 20829195 TI - A microRNA screen to identify modulators of sensitivity to BCL2 inhibitor ABT-263 (navitoclax). AB - Evasion of apoptosis is a known feature of cancer cells. One mechanism of deregulating the apoptotic pathway is through overexpression of antiapoptotic BCL2 family members. ABT-263 (navitoclax) is a first-in-class BCL2 family inhibitor that restores the ability of cancer cells to undergo apoptosis. However, many cancer cells are resistant to ABT-263 due to high levels of a BCL2 family member, MCL1, which is not targeted by the drug. MCL1 expression is regulated transcriptionally, translationally, and through proteasome-mediated degradation. Recently, MCL1 expression was shown to be affected by microRNAs (miRNA). To identify miRNAs that modulate the sensitivity of cancer cells to ABT 263, we screened a library of 810 human miRNA mimics in HCT-116 cells in the presence of ABT-263. The screen revealed 19 miRNAs that sensitize HCT-116 cells to ABT-263. Fifteen of these miRNAs were also shown to sensitize CHL1 melanoma cells to the same agent. We further evaluated 12 of the strongest sensitizers in these cell lines. We found that these sensitizers induced apoptosis only in the presence of ABT-263. In addition, whereas all 12 of these miRNAs reduced MCL1 protein expression, only 10 of them targeted MCL1 through direct binding to the 3'-untranslated region of the gene, raising the possibility that other resistance regulators of MCL1 expression may be identified using our method. Finally, because sensitizing miRNA expression is lower in tumors compared with normal tissues, our data can facilitate the design of miRNA replacement therapies to increase sensitivity to BCL2 antagonists. PMID- 20829196 TI - I-387, a novel antimitotic indole, displays a potent in vitro and in vivo antitumor activity with less neurotoxicity. AB - (3-(1H-indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel synthetic compound that inhibits tubulin action and exhibits potent antitumor activity in various preclinical models. I-387 inhibited the in vitro growth of several human cancer cell lines with IC50 values in the range of 15 to 39 nmol/L. Nanomolar concentrations of the compound induced apoptosis and caused phosphorylation of the antiapoptotic protein Bcl-2. I-387 induced a strong and concentration-dependent G2-M arrest in PC-3 cells by constitutive activation of Cdc2/cyclin B1 complex and destabilized polymerization of purified tubulin in vitro by binding to the colchicine-binding site. In vivo, I-387 treatment effectively inhibited tumor growth in mice bearing PC-3 tumor xenografts. In vitro studies of nerve growth factor-dependent neurite outgrowth in PC12 pheochromocytoma cells and in vivo studies of mouse behavior showed that I-387 was less neurotoxic than vinblastine and vincristine, tubulin destabilizers with known neurotoxicity. Interestingly, multidrug-resistant cell lines that overexpressed P-glycoprotein (P-gp), multidrug resistance-associated proteins, and breast cancer resistance protein were rendered resistant to docetaxel, vinblastine, SN-38, and doxorubicin, but not to I-387. I-387 dosed at 10 mg/kg was equally effective with 76% tumor growth inhibition in xenograft models using MES-SA uterine sarcoma cells and MES-SA/DX5 cells overexpressing P-gp. In contrast, docetaxel and vinblastine were not effective in MES-SA/DX5 xenograft models. The potent in vitro and in vivo antitumor activity of I-387 suggests that it may represent a new antimitotic agent for management of various malignancies, particularly for patients with drug-resistant cancer. PMID- 20829199 TI - ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis. AB - The amount of NSAID intake could be considered as a clinically relevant outcome measure in ankylosing spondylitis. The information should include at least the following: (1) the type of NSAID; (2) the dose; (3) the number of days taking NSAID during the period of interest. The objectives of this initiative were to propose both an NSAID equivalent score and a way of collecting and analysing this information in longitudinal clinical studies/trials. For the NSAID equivalent scoring system, the recommendations are (1) to refer to a scale in which 0 = no intake, 100 = 150 mg diclofenac, 1000 mg naproxen, 200 mg aceclofenac, 400 mg celecoxib, 600 mg etodolac, 90 mg etoricoxib, 200 mg flurbiprofen, 2400 mg ibuprofen, 150 mg indometacin, 200 mg ketoprofen, 15 mg meloxicam, 400 mg phenylbutazone, 20 mg piroxicam, 20 mg tenoxicam; (2) to present the results as mean daily intake by considering the number of days on which NSAID has been taken during a period of interest. This initiative should facilitate the conduct and analysis of clinical studies/trials. PMID- 20829200 TI - Do knee abnormalities visualised on MRI explain knee pain in knee osteoarthritis? A systematic review. AB - OBJECTIVE: To systematically evaluate the association between MRI findings (cartilage defects, bone marrow lesions (BML), osteophytes, meniscal lesion, effusion/synovitis, ligamentous abnormalities, subchondral cysts and bone attrition) and pain in patients with knee osteoarthritis (OA) in order to establish the relevance of such findings when assessing an individual patient. METHODS: The Medline, Web of Science, Embase and Cumulative Index to Nursing & Allied Health Literature (CINAHL) databases up to March 2010 were searched without language restriction to find publications with data on the association between MRI findings of knee OA (exposure of interest) and knee pain (outcome). The quality of included papers was scored using a predefined criteria set. The levels of evidence were determined qualitatively using best evidence synthesis (based on guidelines on systematic review from the Cochrane Collaboration Back Review Group). Five levels of evidence were used: strong, moderate, limited, conflicting and no evidence. RESULTS: A total of 22 papers were included; 5 had longitudinal and 17 cross-sectional data. In all, 13 reported a single MRI finding and 9 multiple MRI findings. Moderate levels of evidence were found for BML and effusion/synovitis. The OR for BML ranged from 2.0 (no CI was given) to 5.0 (2.4 to 10.5). The OR of having pain when effusion/synovitis was present ranged between 3.2 (1.04 to 5.3) and 10.0 (1.1 to 149). The level of evidences between other MRI findings and pain were limited or conflicting. CONCLUSIONS: Knee pain in OA is associated with BML and effusion/synovitis suggesting that these features may indicate the origin of pain in knee OA. However, due to the moderate level of evidence these features need to be explored further. PMID- 20829201 TI - Methicillin-resistant Staphylococcus aureus CC398 isolates with indistinguishable ApaI restriction patterns in colonized and infected pigs and humans. PMID- 20829202 TI - Comparative dosimetry of radon and thoron. AB - There is a well-known discrepancy between dosimetrically derived dose conversion factor (DCF) and epidemiologically derived DCF for radon. As the latter DCFs, International Commission on Radiological Protection (ICRP) recommends a value of ~6.4 nSv (Bq h m(-3))(-1) and 7.9 nSv (Bq h m(-3))(-1) for radon decay products (RnDP) in dwellings and workplaces, respectively. On the other hand, the dosimetric calculations based on the ICRP-66 respiratory tract model derived a DCF of 13 nSv (Bq h m(-3))(-1) and 17 nSv (Bq h m(-3))(-1) for RnDP in dwellings and workplaces, respectively, and 83 nSv (Bq h m(-3))(-1) for thoron decay products (TnDP) in dwellings. In addition, the DCFs derived from both approaches and UNSCEAR were applied to comparative dosimetry for two thoron-enhanced areas (cave dwellings in China and dwellings at a spa town in Japan), where the equilibrium equivalent concentration of radon and equilibrium equivalent concentration of thoron have been measured. In the case of the spa town dwellings, the dose from TnDP was larger than the dose from RnDP. PMID- 20829203 TI - Electret ion chamber-based passive radon-thoron discriminative monitors. AB - Electret ion chambers (EICs), commercially available under brand name E PERM((r)), are widely used for measuring indoor and outdoor (222)Rn concentrations in air. These are designed to respond only to (222)Rn and not to (220)Rn by restricting diffusional entry area. Such radon EIC (R EIC) monitors are modified by increasing the entry area to allow (220)Rn, in addition to (222)Rn. Such modified units are called RT EIC. When a set of R and RT EICs are collocated, it is possible to discriminate and measure both radon and thoron concentrations, using appropriate calibration factors (CFs) and algorithms. The EICs come in different volumes, providing different sensitivities. The thoron CFs for 58-, 210- and 960-ml volume R and RT pairs are, respectively, 2.8-, 18.7- and 89-V drop per (kBq m(-3) d ), respectively. These provide much wider sensitivities and ranges compared to alpha track-based passive radon-thoron discriminative monitors. PMID- 20829204 TI - Evaluation of 25 y of environmental monitoring data around Madras Atomic Power Station (MAPS), Kalpakkam, India. AB - The Environmental Survey Laboratory at Kalpakkam, India carries out elaborate monitoring programme involving atmospheric, terrestrial and aquatic samples for radioactivity to evaluate the impact of operating two pressurised heavy water reactors. This paper presents the evaluation of 25 y (1983-2008) data. Statistical analysis of the environmental data for different radionuclides showed that the data best fits log-normal distribution. The data analysed showed that fission products such as (137)Cs, (90)Sr and (131)I were due to global fallout only. A ratio of 0.2 was obtained for (90)Sr to (137)Cs in air filter samples, only during Chernobyl accident period. The transfer factor of (137)Cs and (90)Sr for rice was computed to be 0.23 and 0.03 and vegetables 0.25 and 0.10, respectively. Activation products (3)H and (41)Ar are the only radionuclides that are related to MAPS operation. A strong correlation (r = 0.9) was observed between (3)H activity in air and (3)H discharged to the atmosphere. A similar correlation (r = 0.8) was observed in (3)H concentration in seawater and (3)H discharged in the liquid waste. The annual internal dose due to (3)H and annual external dose due to (41)Ar evaluated in the last 25 y show that the members of the public received less than 2 % of the dose limit (1 mSv y(-1)) set by ICRP 72. PMID- 20829205 TI - Effectiveness of protective patient equipment for CT: an anthropomorphic phantom study. AB - Protective patient equipment for CT examinations is not routinely provided. The aim of this study was to determine whether, and if so what, specific protective equipment is beneficial during CT scans. The absorbed organ doses and the effective doses for thorax, abdomen/pelvis and brain CT investigation with and without the use of protective patient equipment have been determined and compared. All measurements were carried out on modern multislice CT scanner using an anthropomorphic phantom and thermoluminescence dosemeters. The measurements show that protective equipment reduces the dose within the scattered beam area. The highest organ dose reduction was found in organs that protrude from the trunk like the testes or the female breasts that can largely be covered by the protective equipment. The most reduction of the effective dose was found in the male abdomen/pelvis examination (0.32 mSv), followed by the brain (0.11 mSv) and the thorax (0.06 mSv). It is concluded that the use of protective equipment can reduce the applied dose to the patient. PMID- 20829206 TI - Solid thoron source preparation in a porous mineral matrix. AB - Thoron and progeny are decay products of (232)Th with a great impact on human health. The release of thoron gas from the mining and milling of thorite, monazite and other major thorium ores has been recognised as a potential radiological health hazard. For precise measurements, calibration is a very important factor. This paper describes a cheap and easy way of producing a stable thoron source made of thorium nitrate packed in a porous clay mineral matrix used as (220)Rn generator. The source should have a small spherical shape and be fired at 600 degrees C; this will lead to a great pore volume, necessary for the thoron gas. High importance should be given to the water uptake. The exhalation power of (220)Rn was measured using a Lucas scintillation cell. Experimental efficiency values obtained ranged between 0.16 and 1.44 %. PMID- 20829207 TI - Identification and resolution of artifacts in the interpretation of imprinted gene expression. AB - Genomic imprinting refers to genes that are epigenetically programmed in the germline to express exclusively or preferentially one allele in a parent-of origin manner. Expression-based genome-wide screening for the identification of imprinted genes has failed to uncover a significant number of new imprinted genes, probably because of the high tissue- and developmental-stage specificity of imprinted gene expression. A very large number of technical and biological artifacts can also lead to the erroneous evidence of imprinted gene expression. In this article, we focus on three common sources of potential confounding effects: (i) random monoallelic expression in monoclonal cell populations, (ii) genetically determined monoallelic expression and (iii) contamination or infiltration of embryonic tissues with maternal material. This last situation specifically applies to genes that occur as maternally expressed in the placenta. Beside the use of reciprocal crosses that are instrumental to confirm the parental specificity of expression, we provide additional methods for the detection and elimination of these situations that can be misinterpreted as cases of imprinted expression. PMID- 20829208 TI - The additive value of three-dimensional derived left atrial volume and carotid imaging in dobutamine stress echocardiography. AB - AIMS: to evaluate whether the three-dimensional (3D) left atrial volume index (LAVI) and/or the presence of carotid plaques (CP) can predict the result of dobutamine stress echocardiography (DSE), thereby aiding interpretation. METHODS AND RESULTS: we studied 130 patients (52 male, mean age 63 +/- 11 years) with normal resting wall motion (WM) undergoing DSE. All patients had the end-systolic 2D and 3D LAVI measured, as well as bilateral carotid scanning. DSE was reported as abnormal in 50 (38.5%) patients. 3D end-systolic LAVI measurements were significantly higher (31.5 +/- 8.2 vs 27.4 +/- 7.4 mL/m(2), P = 0.004) in those with an abnormal DSE. The two groups did not differ significantly on the 2D derived maximum LAVI measurements (36.2 +/- 9.5 vs 34.2 +/- 11.2, P = 0.299) and the presence of plaques in the carotid arteries (89.1 vs. 76.2%, P = 0.100). Receiver operating characteristic curves were created to define cut-offs that could predict the DSE result for the 3D LAVI. A 3D LAVI of >24.5 mL/m(2) had a sensitivity of 80% for predicting an abnormal DSE, whereas a value of >36.0 mL/m(2) had a specificity of 93% for the same cause. Intra-observer (r = 0.997, P < 0.0001) and inter-observer (r = 0.961, P < 0.0001) variability for 3D LAVI measurements was found to be excellent. CONCLUSION: three-dimensional (but not 2D) assessment of LAVI may offer additional information in predicting the result of DSE. Carotid scanning did not offer additional information for the same cause. PMID- 20829209 TI - Transcatheter closure of ruptured sinus of Valsalva aneurysm using the Amplatzer duct occluder: immediate results and mid-term follow-up. AB - AIMS: To assess the immediate and mid-term outcome of transcatheter closure (TCC) using the first-generation Amplatzer duct occluder (ADO) in patients with ruptured sinus of Valsalva aneurysm (SOVA). Ruptured SOVA is a rare cardiac shunt lesion, with scant data about its TCC. METHODS AND RESULTS: Twenty patients (8 females and 12 males) aged 17-52 years (median 27 years) with ruptured SOVA were selected for TCC. Most (13/20) were in symptomatic NYHA class III or IV. Three had previous cardiac surgeries. Associated defects were bicuspid aortic valve in one, trivial pre-existing aortic regurgitation (AR) in five, coarctation of the aorta in one, and secundum atrial septal defect in one. Patients with co-existing ventricular septal defect or significant AR requiring surgery were excluded. Echocardiography revealed ruptured SOVA from right coronary sinus to right atrium (RA) in 4 and right ventricular (RV) outflow in 5, whereas non-coronary sinus ruptured into RA in 10 and RV inflow in 1. At cardiac catheterization, the defect was 4-11 mm (median 9 mm) at its aortic end as measured by online transoesophageal echocardiography or angiography. The Q(p)/Q(s) ratio ranged from 1.5 to 3.2 (mean 2.32 +/- 0.53). In all patients, the defect was closed from the venous side, using ADOs 2-4 mm larger than the aortic end of the defect. The ADO sizes ranged from 8/6 to 16/14 mm (median 13/11 mm). The procedure was successful in 18 out of 20 patients (90%). Of these 18, 13 had a complete closure at discharge. Five had a residual shunt (four small and one moderate with self abating haemolysis). Trivial AR occurred in four. On a median follow-up of 24 months (range 1-60 months), 15 patients were in NYHA class I and 3 in class II. The residual shunt disappeared in three and was small in two; procedure-related AR vanished in two of four. There was no AR progression, recurrence, infective endocarditis, or device embolization. CONCLUSION: In appropriately selected patients with ruptured SOVA, TCC is an attractive alternative to surgery with encouraging short- and mid-term outcomes. PMID- 20829210 TI - Impaired microcirculation predicts poor outcome of patients with acute myocardial infarction complicated by cardiogenic shock. AB - AIMS: we investigated the relationship between sublingual perfused capillary density (PCD) as a measure of tissue perfusion and outcome (i.e. occurrence of organ failure and mortality) in patients with cardiogenic shock from acute myocardial infarction. METHODS AND RESULTS: we performed a prospective study in 68 patients. Using Sidestream Dark Field imaging, PCD was measured after hospital admission (T0, baseline) and 24 h later (T1). We compared patients with baseline PCD <= median to patients with baseline PCD > median. Sequential organ failure assessment (SOFA) scores were calculated at both time points. The Kaplan-Meier 30 day survival analyses were performed and predictors of 30-day mortality were identified. The baseline PCD was a predictor of the change in the SOFA score between T0 and T1 (DeltaSOFA; rho = -0.25, P = 0.04). Organ failure recovered more frequently in patients with PCD > median (>10.3 mm mm(-2); n = 33) than in patients with PCD <= median (n = 35; 52 vs. 29%, P < 0.05). Twenty-two patients (32%) died: 17 patients (49%) with PCD <= median vs. 5 patients (15%) with PCD > median (P = 0.004). After adjustment, the cardiac power index [odds ratio (OR): 0.48, 95% CI: 0.24-0.94) and PCD (OR: 0.65, 95% CI: 0.45-0.92) remained significant predictors of 30-day outcome. Patients with baseline sublingual PCD <= median that improved at T1 had a considerable better prognosis relative to patients who had a persistently low PCD. CONCLUSION: diminished sublingual PCD, at baseline or following treatment, is associated with development of multi-organ failure and is a predictor of poor outcome in patients with acute myocardial infarction complicated by cardiogenic shock. PMID- 20829211 TI - Ionizing radiation risks of cardiac imaging: estimates of the immeasurable. PMID- 20829212 TI - Aiming at a disorder's concept by 3D QCA vs. FFR: a case of advanced ballistics. PMID- 20829213 TI - Prognostic and therapeutic implications of pulmonary hypertension complicating degenerative mitral regurgitation due to flail leaflet: a multicenter long-term international study. AB - AIMS: To determine the frequency, predictors, and outcome implications of pulmonary hypertension (PH) diagnosed by Doppler echocardiography in a large cohort of patients with the homogenous diagnosis of degenerative mitral regurgitation (MR) due to flail leaflets. METHODS AND RESULTS: The Mitral Regurgitation International DAtabase (MIDA) is a registry including patients with MR due to flail leaflets consecutively referred at tertiary centres in Europe and the USA. Between 1987 and 2004, pulmonary artery systolic pressure (PASP) was measured at baseline by Doppler echocardiography in 437 patients (age 67 +/- 11 years; 66% men). Pulmonary hypertension (PASP > 50 mmHg) was observed in 102 patients (23%). Independent predictors of PH were age and left atrial size (P < 0.0001). During a mean follow-up of 4.8 +/- 2.8 years, PH was a strong independent predictor of death [adjusted HR 2.03 (1.30-3.18) P = 0.002], cardiovascular death [CVD; adjusted HR 2.21 (1.30-3.76) P = 0.003], and heart failure [adjusted HR 1.70 (1.10-2.62) P = 0.018]. Mitral valve surgery at any time during follow-up (performed in 325 patients, 75%) was beneficial [adjusted HR for death 0.22 (0.14-0.36) P < 0.001], but PH was associated with the increased risk of postoperative death and CVD (P = 0.01). CONCLUSION: Pulmonary hypertension is a frequent complication of significant MR due to flail leaflet and is associated with major outcome implications, approximately doubling the risk of death and heart failure after diagnosis. Mitral valve surgery performed during follow-up is beneficial but does not completely abolish the adverse effects of PH once it is established and is particularly beneficial in patients without PH. These data support relieving PH secondary to MR due to flail leaflet, but also careful consideration for mitral surgery before PH is established. PMID- 20829214 TI - The effect of melatonin against FK506-induced renal oxidative stress in rats. AB - BACKGROUND: Nephrotoxicity is an important side effect of FK506 and oxidative stress has been considered as one of the possible mechanisms. The present investigation examines the ability of melatonin to protect against FK506-induced renal oxidative stress. METHODS: Thirty rats were divided into 3 groups (n = 10 each group). Group A was the sham group. Group B received 14 days FK506 (5 mg/kg/d, intraperitoneally [i.p.]) and group C received FK506 (5 mg/kg/d, i.p.) together with melatonin (4 mg/kg, i.p.) for 14 days. Kidney tissues were harvested to determine the tissue levels of malondialdehyde (MDA), total nitrite and nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6). RESULTS: In group C, the levels of TNF-alpha, IL-6, and NO were lower than in the group B (P < .01, P < .03, and P < .04, respectively) and although MDA levels were lower than in group B, the differences were not statistically significant (P > .05). CONCLUSION: These results suggest that melatonin has protective effect against FK506-induced renal oxidative stress. PMID- 20829215 TI - Vacuum-assisted healing of a devastating retroperitoneal colonic perforation with a homemade device. PMID- 20829216 TI - What are the elements of safe gastrotomy closure in NOTES? A systematic review. AB - INTRODUCTION: The safe closure of the gastrotomy needs to be established before natural orifice translumenal endoscopic surgery (NOTES) can be extended to routine clinical practice. As yet no optimum closure method has been identified. METHODS: A systematic review of the literature on gastrotomy closure modalities for NOTES up until December 2009 was undertaken. An assessment of each closure modality was determined using specified quantitative and qualitative parameters. RESULTS: There were 46 studies included in this review describing 20 closure techniques. Some robustly designed experimental studies have now been published particularly in relation to the over-the-scope clip system. CONCLUSION: Current evidence is experimental and therefore limited, but there appears to be some clarification in the direction of the innovative process in this area outlining favorable characteristics of an ideal system. Based on the studies examined in this review, a standardized assessment method is summarized for future in vivo studies, necessary prior to phase 1 trials. PMID- 20829217 TI - GABAergic mechanism in the rostral ventrolateral medulla contributes to the hypotension of moxonidine. AB - AIMS: The depressor action of the centrally antihypertensive drug moxonidine has been attributed to activation of I(1)-imidazoline receptor in the rostral ventrolateral medulla (RVLM). The objective of this study was to determine the role of the gamma-aminobutyric acid (GABA) mechanisms in the RVLM in mediating the effect of moxonidine in anaesthetized normotensive rats. METHODS AND RESULTS: The relationship between the effects of microinjection or picoinjection of moxonidine and the functional state of GABA receptors at the level of the RVLM or pre-sympathetic neuron was determined. Microdialysis was performed to detect the effect of moxonidine on the release of GABA in the RVLM. Western blot analysis was carried out to test the effect of chronic intracerebroventricular injection of moxonidine on the protein expression of GABA receptors in the RVLM. Pre treatment with the GABA(A) or GABA(B) receptor antagonist bicuculline (5 pmol) or CGP35348 (200 pmol), respectively, microinjected into the RVLM significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity induced by moxonidine. In 22 moxonidine-sensitive pre-sympathetic neurons in the RVLM, picoinjection of bicuculline (100 fmol/5 nL) significantly attenuated the neuronal inhibition evoked by moxonidine (100 pmol/5 nL). The release of GABA in the RVLM was increased after intravenous moxonidine (50 MUg/kg). Central infusion of moxonidine upregulated the protein expression of both GABA(A) and GABA(B) receptors in the RVLM. CONCLUSION: The current data demonstrate that GABAergic mechanisms in the RVLM are responsible for the hypotension and sympathoinhibition of moxonidine. PMID- 20829218 TI - Epigenetic control of vascular smooth muscle cells in Marfan and non-Marfan thoracic aortic aneurysms. AB - AIMS: Human thoracic aortic aneurysms (TAAs) are characterized by extracellular matrix breakdown associated with progressive smooth muscle cell (SMC) rarefaction. These features are present in all types of TAA: monogenic forms [mainly Marfan syndrome (MFS)], forms associated with bicuspid aortic valve (BAV), and degenerative forms. Initially described in a mouse model of MFS, the transforming growth factor-beta1 (TGF-beta1)/Smad2 signalling pathway is now assumed to play a role in TAA of various aetiologies. However, the relation between the aetiological diversity and the common cell phenotype with respect to TGF-beta signalling remains unexplained. METHODS AND RESULTS: This study was performed on human aortic samples, including TAA [MFS, n = 14; BAV, n = 15; and degenerative, n = 19] and normal aortas (n = 10) from which tissue extracts and human SMCs and fibroblasts were obtained. We show that all types of TAA share a complex dysregulation of Smad2 signalling, independent of TGF-beta1 in TAA derived SMCs (pharmacological study, qPCR). The Smad2 dysregulation is characterized by an SMC-specific, heritable activation and overexpression of Smad2, compared with normal aortas. The cell specificity and heritability of this overexpression strongly suggest the implication of epigenetic control of Smad2 expression. By chromatin immunoprecipitation, we demonstrate that the increases in H3K9/14 acetylation and H3K4 methylation are involved in Smad2 overexpression in TAA, in a cell-specific and transcription start site-specific manner. CONCLUSION: Our results demonstrate the heritability, the cell specificity, and the independence with regard to TGF-beta1 and genetic backgrounds of the Smad2 dysregulation in human thoracic aneurysms and the involvement of epigenetic mechanisms regulating histone marks in this process. PMID- 20829224 TI - Genome scanning of Amazonian Plasmodium falciparum shows subtelomeric instability and clindamycin-resistant parasites. AB - Here, we fully characterize the genomes of 14 Plasmodium falciparum patient isolates taken recently from the Iquitos region using genome scanning, a microarray-based technique that delineates the majority of single-base changes, indels, and copy number variants distinguishing the coding regions of two clones. We show that the parasite population in the Peruvian Amazon bears a limited number of genotypes and low recombination frequencies. Despite the essentially clonal nature of some isolates, we see high frequencies of mutations in subtelomeric highly variable genes and internal var genes, indicating mutations arising during self-mating or mitotic replication. The data also reveal that one or two meioses separate different isolates, showing that P. falciparum clones isolated from different individuals in defined geographical regions could be useful in linkage analyses or quantitative trait locus studies. Through pairwise comparisons of different isolates we discovered point mutations in the apicoplast genome that are close to known mutations that confer clindamycin resistance in other species, but which were hitherto unknown in malaria parasites. Subsequent drug sensitivity testing revealed over 100-fold increase of clindamycin EC(50) in strains harboring one of these mutations. This evidence of clindamycin-resistant parasites in the Amazon suggests that a shift should be made in health policy away from quinine + clindamycin therapy for malaria in pregnant women and infants, and that the development of new lincosamide antibiotics for malaria should be reconsidered. PMID- 20829225 TI - Puromycin-sensitive aminopeptidase protects against aggregation-prone proteins via autophagy. AB - A major function of proteasomes and macroautophagy is to eliminate misfolded potentially toxic proteins. Mammalian proteasomes, however, cannot cleave polyglutamine (polyQ) sequences and seem to release polyQ-rich peptides. Puromycin-sensitive aminopeptidase (PSA) is the only cytosolic enzyme able to digest polyQ sequences. We tested whether PSA can protect against accumulation of polyQ fragments. In cultured cells, Drosophila and mouse muscles, PSA inhibition or knockdown increased aggregate content and toxicity of polyQ-expanded huntingtin exon 1. Conversely, PSA overexpression decreased aggregate content and toxicity. PSA inhibition also increased the levels of polyQ-expanded ataxin-3 as well as mutant alpha-synuclein and superoxide dismutase 1. These protective effects result from an unexpected ability of PSA to enhance macroautophagy. PSA overexpression increased, and PSA knockdown or inhibition reduced microtubule associated protein 1 light chain 3-II (LC3-II) levels and the amount of protein degradation sensitive to inhibitors of lysosomal function and autophagy. Thus, by promoting autophagic protein clearance, PSA helps protect against accumulation of aggregation-prone proteins and proteotoxicity. PMID- 20829226 TI - Effects of cis-regulatory variation differ across regions of the adult human brain. AB - Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cis-regulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated. PMID- 20829227 TI - Mutations in the neuronal beta-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects. AB - Mutations in the TUBB3 gene, encoding beta-tubulin isotype III, were recently shown to be associated with various neurological syndromes which all have in common the ocular motility disorder, congenital fibrosis of the extraocular muscle type 3 (CFEOM3). Surprisingly and in contrast to previously described TUBA1A and TUBB2B phenotypes, no evidence of dysfunctional neuronal migration and cortical organization was reported. In our study, we report the discovery of six novel missense mutations in the TUBB3 gene, including one fetal case and one homozygous variation, in nine patients that all share cortical disorganization, axonal abnormalities associated with pontocerebellar hypoplasia, but with no ocular motility defects, CFEOM3. These new findings demonstrate that the spectrum of TUBB3-related phenotype is broader than previously described and includes malformations of cortical development (MCD) associated with neuronal migration and differentiation defects, axonal guidance and tract organization impairment. Complementary functional studies revealed that the mutated betaIII-tubulin causing the MCD phenotype results in a reduction of heterodimer formation, yet produce correctly formed microtubules (MTs) in mammalian cells. Further to this, we investigated the properties of the MT network in patients' fibroblasts and revealed that MCD mutations can alter the resistance of MTs to depolymerization. Interestingly, this finding contrasts with the increased MT stability observed in the case of CFEOM3-related mutations. These results led us to hypothesize that either MT dynamics or their interactions with various MT-interacting proteins could be differently affected by TUBB3 variations, thus resulting in distinct alteration of downstream processes and therefore explaining the phenotypic diversity of the TUBB3-related spectrum. PMID- 20829228 TI - De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we found disease-associated sequence variants. In addition, we screened for desmin mutations and found a novel desmin-mutation p.N116S in a patient with ARVC and terminal heart failure, which is located in segment 1A of the desmin rod domain. The mutation leads to the aggresome formation in cardiac and skeletal muscle without signs of an overt clinical myopathy. Cardiac aggresomes appear to be prominent, especially in the right ventricle of the heart. Viscosimetry and atomic force microscopy of the desmin wild-type and N116S mutant isolated from recombinant Escherichia coli revealed severe impairment of the filament formation, which was supported by transfections in SW13 cells. Thus, the gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients. PMID- 20829229 TI - Glutaredoxin 2 prevents aggregation of mutant SOD1 in mitochondria and abolishes its toxicity. AB - Vulnerability of motoneurons in amyotrophic lateral sclerosis (ALS) arises from a combination of several mechanisms, including protein misfolding and aggregation, mitochondrial dysfunction and oxidative damage. Protein aggregates are found in motoneurons in models for ALS linked to a mutation in the gene coding for Cu,Zn superoxide dismutase (SOD1) and in ALS patients as well. Aggregation of mutant SOD1 in the cytoplasm and/or into mitochondria has been repeatedly proposed as a main culprit for the degeneration of motoneurons. It is, however, still debated whether SOD1 aggregates represent a cause, a correlate or a consequence of processes leading to cell death. We have exploited the ability of glutaredoxins (Grxs) to reduce mixed disulfides to protein thiols either in the cytoplasm and in the IMS (Grx1) or in the mitochondrial matrix (Grx2) as a tool for restoring a correct redox environment and preventing the aggregation of mutant SOD1. Here we show that the overexpression of Grx1 increases the solubility of mutant SOD1 in the cytosol but does not inhibit mitochondrial damage and apoptosis induced by mutant SOD1 in neuronal cells (SH-SY5Y) or in immortalized motoneurons (NSC-34). Conversely, the overexpression of Grx2 increases the solubility of mutant SOD1 in mitochondria, interferes with mitochondrial fragmentation by modifying the expression pattern of proteins involved in mitochondrial dynamics, preserves mitochondrial function and strongly protects neuronal cells from apoptosis. The toxicity of mutant SOD1, therefore, mostly arises from mitochondrial dysfunction and rescue of mitochondrial damage may represent a promising therapeutic strategy. PMID- 20829231 TI - Invisible victims: same-sex IPV in the National Violence Against Women Survey. AB - With intimate partner violence (IPV) among same-sex couples largely ignored by policy makers and researchers alike, accurately estimating the size of the problem is important in determining whether this minimal response is justified. As such, the present study is a secondary data analysis of the National Violence Against Women Survey and represents the first multiple variable regression analysis of U.S. adult same-sex IPV prevalence using a nationally representative sample (N = 14,182). Logistic regressions indicate that, independent of sex, respondents with a history of same-sex relationships are more likely to experience verbal, controlling, physical, and sexual IPV. Behaviorally "bisexual" respondents experience the highest IPV rates and are most likely to be victimized by an opposite-sex partner. Implications for future IPV research regarding sexual orientation and gender are discussed. PMID- 20829230 TI - A Drosophila model of GSS syndrome suggests defects in active zones are responsible for pathogenesis of GSS syndrome. AB - We have established a Drosophila model of Gerstmann-Straussler-Scheinker (GSS) syndrome by expressing mouse prion protein (PrP) having leucine substitution at residue 101 (MoPrP(P101L)). Flies expressing MoPrP(P101L), but not wild-type MoPrP (MoPrP(3F4)), showed severe defects in climbing ability and early death. Expressed MoPrP(P101L) in Drosophila was differentially glycosylated, localized at the synaptic terminals and mainly present as deposits in adult brains. We found that behavioral defects and early death of MoPrP(P101L) flies were not due to Caspase 3-dependent programmed cell death signaling. In addition, we found that Type 1 glutamatergic synaptic boutons in larval neuromuscular junctions of MoPrP(P101L) flies showed significantly increased numbers of satellite synaptic boutons. Furthermore, the amount of Bruchpilot and Discs large in MoPrP(P101L) flies was significantly reduced. Brains from scrapie-infected mice showed significantly decreased ELKS, an active zone matrix marker compared with those of age-matched control mice. Thus, altered active zone structures at the molecular level may be involved in the pathogenesis of GSS syndrome in Drosophila and scrapie-infected mice. PMID- 20829232 TI - The mediating effect of world assumptions on the relationship between trauma exposure and depression. AB - The association between trauma exposure and mental health-related challenges such as depression are well documented in the research literature. The assumptive world theory was used to explore this relationship in 97 female survivors of intimate partner violence (IPV). Participants completed self-report questionnaires that assessed trauma history, world assumptions, and depression severity. Regression analyses revealed that diminished world assumptions mediate the relationship between trauma exposure and depression severity. As predicted, this relationship held for interpersonal forms of trauma, whereas noninterpersonal forms of trauma were related neither to diminished world assumption nor to depression severity. This suggests that our conceptual system of relating to the world, our core beliefs that comprise our assumptive world, may be challenged in the face of human-induced trauma, increasing our risk for developing adverse psychological outcomes such as depression. PMID- 20829233 TI - Elder mistreatment and emotional symptoms among older adults in a largely rural population: the South Carolina elder mistreatment study. AB - Although two recent major studies provide some insight into the prevalence and correlates of elder mistreatment, the relationship between elder mistreatment and mental health remains unclear. This study begins to address this issue by examining the relationship between elder mistreatment (i.e., a recent history of emotional and physical abuse) and negative emotional symptoms (e.g., anxiety and depression) among 902 older adults aged 60 and above residing in South Carolina. Results demonstrate that emotional, but not physical, abuse is significantly correlated with higher levels of emotional symptoms. This relationship is sustained when controlling for established demographic and social/dependency risk factors. These data suggest that mistreated older adults also suffer from greater emotional symptoms and highlight the need for more research in this area. PMID- 20829234 TI - Strategy, structure, and patient quality outcomes in ambulatory surgery centers (1997-2004). AB - The purpose of this study was to examine potential associations among ambulatory surgery centers' (ASCs) organizational strategy, structure, and quality performance. The authors obtained several large-scale, all-payer claims data sets for the 1997 to 2004 period. The authors operationalized quality performance as unplanned hospitalizations at 30 days after outpatient arthroscopy and colonoscopy procedures. The authors draw on related organizational theory, behavior, and health services research literatures to develop their conceptual framework and hypotheses and fitted fixed and random effects Poisson regression models with the count of unplanned hospitalizations. Consistent with the key hypotheses formulated, the findings suggest that higher levels of specialization and the volume of procedures may be associated with a decrease in unplanned hospitalizations at ASCs. PMID- 20829235 TI - Emergency department use by older adults: a literature review on trends, appropriateness, and consequences of unmet health care needs. AB - Older adults use emergency departments (EDs) more than any other age group and are more prone to subsequent adverse events. This article reviews the literature on ED use by older adults within the context of evaluating their need for emergency care and the extent to which access to primary and supportive care services affect use. While a substantial research literature describes general patterns of ED use, there is much less research on ED use as a function of other health service use. Gaps in the research literature result in a limited understanding of the full scope of the issue and opportunities for practice and policy intervention. PMID- 20829236 TI - Racial and gender disparities in implantable cardioverter-defibrillator placement: are they due to overuse or underuse? AB - Previous studies documented racial and gender disparities in implantable cardioverter-defibrillator (ICD) placement. The authors examined whether racial and gender disparities in ICD placement are due to underutilization or overutilization. Among 1,054 adults hospitalized from 2001 to 2004 with ventricular arrhythmias in a large academic hospital, the study found that 17% of patients had clinical indicators concordant with ICD placement criteria. Among those, Blacks were less likely than Whites to receive an ICD (adjusted odds ratio [OR] = 0.24; 95% CI = 0.08-0.71). Among the 83% who were discordant with ICD placement criteria, Blacks (adjusted OR = 0.30; 95% CI = 0.18-0.52) and Hispanics (adjusted OR = 0.24, 95% CI = 0.10-0.57) were less likely than Whites, and women less likely than men, to receive an ICD (adjusted OR = 0.48; 95% CI = 0.34-0.67). In this cohort, these differences appear related to overutilization among men and Whites who are discordant with ICD placement criteria in addition to underutilization among Blacks concordant with placement criteria. PMID- 20829237 TI - An evaluation of the influence of primary care team functioning on the health of Medicare beneficiaries. AB - In service industries other than health care, unit employees who report a favorable service climate--characterized by commitment to a team concept and intrateam interactions that are supportive, collegial, and collaborative--have high levels of consumer satisfaction and work unit productivity. The authors evaluated whether similar primary care team (PCT) functioning influenced the short-term future health (SF-36) of elderly Medicare beneficiaries (N = 991) in a group model managed care organization (MCO). PCT functioning was assessed by surveys of practitioners and support staff on the MCO's 14 primary care practices and included measures of perceived task delegation, role collaboration, patient orientation, and team ownership. On average, patient physical and emotional health declined over 2 years. Medicare beneficiaries empanelled to relatively high functioning PCTs had significantly better physical and emotional health at 2 years following baseline assessment than those empanelled to relatively low functioning PCTs. PMID- 20829238 TI - Reducing disparities in health care quality: the role of health IT in underresourced settings. AB - Health information technology (health IT) and the Internet have tremendous potential to transform health care. The implications of the adoption of health IT within the context of underresourced health care settings have not been adequately evaluated. For this reason, the Agency for Healthcare Research and Quality sponsored a 2-day invitational expert meeting in October 2009. The theme of the meeting was "Reducing Disparities in Healthcare Quality in Under Resourced Settings Using HIT and Other Quality Improvement Strategies." In preparation for the meeting, five background manuscripts were commissioned, presented, and discussed. Attendees also participated in one of three breakout sessions. Several overarching themes, key recommendations, and research topics emerged across five general categories of (a) the health care delivery setting, (b) research and evaluation methodologies, (c) patients and target populations, (d) technology applications and platforms, and (e) providers and clinicians. This article outlines the process, findings, and key recommendations of this expert workshop. PMID- 20829239 TI - Explaining the increase in family financial pressures from medical bills between 2003 and 2007: do affordability thresholds change over time? AB - This study examines whether affordability thresholds for medical care as defined by families change over time. The results from two nationally representative surveys show that while financial stress from medical bills--defined as the percent with problems paying medical bills--increased between 2003 and 2007, greater out-of-pocket spending accounted for this increase only for higher-income persons with employer-sponsored insurance coverage. Increased spending did not account for an increase in medical bill problems among lower-income persons. Moreover, the increase in medical bill problems among low-income persons occurred at relatively low levels of out-of-pocket spending rather than at higher levels. The results suggest that "affordability thresholds" for medical care as defined by individuals and families are not stable over time, especially for lower-income persons, which has implications for setting affordability standards in health reform. PMID- 20829240 TI - Comparative analysis of hospital costs of open and endovascular thoracic aortic repair. AB - BACKGROUND: Endovascular technologies represent major advancements in treating descending thoracic aortic aneurysms (DTAA). We compared hospital charges of open thoracic aortic replacement (OTAR) with endovascular repair of thoracic aortic aneurysms (TEVAR). METHODS: Retrospective analysis of hospital charges related to repair of DTAA (2000-2009). Charges were inflation adjusted for dollars in 2009. RESULTS: There were 50 OTAR and 50 TEVAR patients. Open thoracic aortic replacement charges were $64 531 (interquartile range [IQR]: 49 000-108 515) versus $61 909 (IQR: 41 307-92 109) for TEVAR(P = .4). A total of 10 patients (10%) died before discharge, with 0 TEVAR deaths (P < .05). For OTAR, supply charges ($9167) accounted for 13% of total charges versus 56% for TEVAR ($40 468), P < .01. Open thoracic aortic replacement length of stay (LOS) was 12 days (6 days intensive care unit [ICU] stay); bed charges comprised 40% of the total charges. Thoracic endovascular aneurysm repair had lower LOS (5days with 2 days ICU stay, P < .001). CONCLUSIONS: Descending thoracic aortic aneurysm repair remains a formidable operation with significant resource utilization. Thoracic endovascular aneurysm repair does not significantly reduce overall hospital charges due to device costs but demonstrates improved mortality, ICU, and total LOS. PMID- 20829241 TI - 64-slice MDCT angiography of upper extremity in assessment of native hemodialysis access. AB - OBJECTIVE: To compare multidetector row computed tomographic (MDCT) angiography with conventional digital subtraction angiography (DSA) in the evaluation of vascular access stenoses in hemodialysis patients. MATERIALS AND METHODS: Twenty one consecutive patients were imaged with MDCT angiography and subsequent DSA. The superficial vein of leg was used as the route for intravenous administration. The vascular stenosis was assessed in not significant (<50% stenosis), moderate stenosis (50%-74% stenosis), severe stenosis (75%-99%), and total occlusion (100%). The accuracy, sensitivity, specificity, positive, and negative predictive values were calculated for significant vascular stenosis using DSA as the standard reference. RESULTS: The sensitivity and specificity of MDCT angiography for the detection of significant hemodialysis vascular access were 100% (95% CI, 89.3%-100%) and 94.8% (95% CI, 89.1%-97.6%), respectively. The positive and negative predictive values were 84.2% (95% CI, 68.1%-93.4%) and 100% (95% CI, 95.8%-100%), respectively. The accuracy of MDCT angiography for detection of significant stenoses was 95.9% (95% CI, 91.4%-97.0%). CONCLUSIONS: MDCT angiography provides excellent correlation in vascular stenosis as compared with DSA in hemodialysis access. Complete assessment of entire vascular segments could be performing with MDCT angiography in planning before endovascular intervention or surgical correction. PMID- 20829242 TI - Spontaneous recanalization of chronic internal carotid artery occlusions: report of 3 cases. AB - Spontaneous recanalization of a chronically occluded internal carotid artery (ICA) is a rare occurrence. The authors report 3 patients who had documented total occlusion of the ICA followed by late spontaneous recanalization with subsequent high-grade stenosis. The patients in this series had occlusions for 11 months, 36 months, and 39 months, respectively. One patient had symptoms ipsilateral to the recanalized vessel, and 2 patients were asymptomatic. Endarterectomy was performed uneventfully in 2 patients and pathologic specimens demonstrated typical atherosclerotic plaque with patent lumens. Our experience demonstrates that although chronic recanalizations of occluded ICAs are rare, this does occur. Pathology demonstrates typical atherosclerotic plaque which appeared to have been recanalized by lysis of thrombus. The natural history of this condition is not well known and indications for intervention are not well established. PMID- 20829243 TI - Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis. PMID- 20829244 TI - Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. AB - BACKGROUND: Bladder dysfunction is a common feature of multiple sclerosis (MS). OBJECTIVE: In this study we aimed to assess the efficacy, tolerability and safety of Sativex((r)) (nabiximols) as an add-on therapy in alleviating bladder symptoms in patients with MS. METHODS: We undertook a 10-week, double-blind, randomized, placebo-controlled, parallel-group trial in 135 randomized subjects with MS and overactive bladder (OAB). RESULTS: The primary endpoint was the reduction in daily number of urinary incontinence episodes from baseline to end of treatment (8 weeks). Other endpoints included incidence of nocturia and urgency, overall bladder condition (OBC), daytime frequency, Incontinence Quality of Life (I-QOL), Patient's Global Impression of Change (PGIC) and volume voided. The primary endpoint showed little difference between Sativex and placebo. Four out of seven secondary endpoints were significantly in favour of Sativex: number of episodes of nocturia (adjusted mean difference -0.28, p = 0.010), OBC (-1.16, p = 0.001), number of voids/day (-0.85, p = 0.001) and PGIC (p = 0.005). Of the other endpoints, number of daytime voids was statistically significantly in favour of Sativex (-0.57, p = 0.044). The improvement in I-QOL was in favour of Sativex but did not reach statistical significance. CONCLUSIONS: Although the primary endpoint did not reach statistical significance, we conclude that Sativex did have some impact on the symptoms of overactive bladder in patients with MS, providing evidence of some improvement in symptoms associated with bladder dysfunction in these subjects. PMID- 20829245 TI - Auditory-motor expertise alters "speech selectivity" in professional musicians and actors. AB - Several perisylvian brain regions show preferential activation for spoken language above and beyond other complex sounds. These "speech-selective" effects might be driven by regions' intrinsic biases for processing the acoustical or informational properties of speech. Alternatively, such speech selectivity might emerge through extensive experience in perceiving and producing speech sounds. This functional magnetic resonance imaging (fMRI) study disambiguated such audiomotor expertise from speech selectivity by comparing activation for listening to speech and music in female professional violinists and actors. Audiomotor expertise effects were identified in several right and left superior temporal regions that responded to speech in all participants and music in violinists more than actresses. Regions associated with the acoustic/information content of speech were identified along the entire length of the superior temporal sulci bilaterally where activation was greater for speech than music in all participants. Finally, an effect of performing arts training was identified in bilateral premotor regions commonly activated by finger and mouth movements as well as in right hemisphere "language regions." These results distinguish the seemingly speech-specific neural responses that can be abolished and even reversed by long-term audiomotor experience. PMID- 20829246 TI - Soil engineering in vivo: harnessing natural biogeochemical systems for sustainable, multi-functional engineering solutions. AB - Carbon sequestration, infrastructure rehabilitation, brownfields clean-up, hazardous waste disposal, water resources protection and global warming-these twenty-first century challenges can neither be solved by the high-energy consumptive practices that hallmark industry today, nor by minor tweaking or optimization of these processes. A more radical, holistic approach is required to develop the sustainable solutions society needs. Most of the above challenges occur within, are supported on, are enabled by or grown from soil. Soil, contrary to conventional civil engineering thought, is a living system host to multiple simultaneous processes. It is proposed herein that 'soil engineering in vivo', wherein the natural capacity of soil as a living ecosystem is used to provide multiple solutions simultaneously, may provide new, innovative, sustainable solutions to some of these great challenges of the twenty-first century. This requires a multi-disciplinary perspective that embraces the science of biology, chemistry and physics and applies this knowledge to provide multi-functional civil and environmental engineering designs for the soil environment. For example, can native soil bacterial species moderate the carbonate cycle in soils to simultaneously solidify liquefiable soil, immobilize reactive heavy metals and sequester carbon-effectively providing civil engineering functionality while clarifying the ground water and removing carbon from the atmosphere? Exploration of these ideas has begun in earnest in recent years. This paper explores the potential, challenges and opportunities of this new field, and highlights one biogeochemical function of soil that has shown promise and is developing rapidly as a new technology. The example is used to propose a generalized approach in which the potential of this new field can be fully realized. PMID- 20829247 TI - A novel approach for correcting mandibular asymmetry with a combination of autologous fat and alloplastic implants. AB - Unilateral mandibular asymmetry has numerous etiologies. In the absence of current dentofacial deformities, this asymmetry, although not functionally debilitating, can still be troubling to the patient. There are several approaches to correcting this asymmetry, mainly focusing on the facial skeleton. However, with unilateral asymmetry, correction of the hard tissue alone often produces a suboptimal result. The overlying soft tissue becomes stretched, producing an angulated appearance dissimilar to the contralateral normal side. The authors present a case report of a patient with mandibular asymmetry who was treated with our novel technique of intentionally undercorrecting the skeletal asymmetry with alloplastic implants while augmenting the overlying soft tissue with autologous fat grafting. PMID- 20829248 TI - Management of the delayed traumatic medial telecanthal deformity. AB - BACKGROUND: The normal shape of the medial canthus is a very important aesthetic and functional determinant of the eyes. Disruption of the medial canthal ligament (through trauma or cancer resection, for example) can lead to medial telecanthal deformities, including shortened palpebra, obtuse-angled medial canthi with infraplacement, increased intercanthal distance, and an absent naso-orbital valley. OBJECTIVES: The authors describe the successful application of microscrew and microplate fixation for medial canthoplasty. METHODS: Thirty-eight patients (38 eyes) with unilateral medial telecanthal deformity were included in this series. For 31 patients, a self-tapping, titanium, low-profile head microscrew was propelled into the solid bone on the posterior aspect of the anterior lacrimal crest at the estimated attachment position of the medial canthal ligament, without a predrilled hole. For the remaining patients, four required placement of a microplate into which the wire could be affixed and three required autologous fascia lata graft injections into the soft tissue because of prior loss. Preoperative and postoperative measurements of each patient's lateral displacement distance were recorded and compared. RESULTS: The patients corrected with microscrews only were divided into three preoperative groups. The patients in group 1 had a displacement distance between 4 mm and 6 mm (seven patients); group 2, between 7 mm and 9 mm (20 patients); and group 3, more than 9 mm (four patients). Postoperative lateral displacement measurements showed that the displacement distance was less than or equal to 2 mm in 27 patients, about 3 mm in one patient, and about 5 mm in the remaining three patients. Of the entire series, the majority (84.2%) of the patients were successfully corrected, with a difference in the canthal distance between their two eyes of less than or equal to 2 mm. For comparison, 60.5% of the patients had a preoperative difference of 7 to 9 mm. CONCLUSIONS: Based on the outcomes obtained in this series of 38 patients, the authors' titanium microscrew and microplate approach is shown to be an excellent choice for correcting medial telecanthal deformity. The technique, when applied in appropriate cases, achieves optimal anatomic outcomes while minimizing facial incisions. PMID- 20829249 TI - Anatomical characteristics of the conchal cartilage with suggested clinical applications in rhinoplasty surgery. AB - BACKGROUND: Numerous cartilage grafts from a number of donor sites have been described, each with a different shape and size. These donor sites include the nasal septum, costal chondral cartilage, and the conchal bowl. Although harvests from the conchal bowl are commonly-employed, the techniques have been minimally described in the literature, particularly as it applies to rhinoplasty. OBJECTIVES: The authors identify differences in the conchal bowl cartilage parameters that could aid in the planning and harvesting of conchal grafts during augmentation rhinoplasty. METHODS: The authors dissected ears from fourteen cadavers (eight females and six males), ranging between 59 and 77 years of age. The conchal bowls were isolated, after which a reference point or was marked at the junction of the helical root and the conchal extension of the helical root. A cartilage grid was mapped out at 3-mm interval divisions with a horizontal limb axis parallel to the helical root extension and a vertical limb axis perpendicular to the latter. Conchal cartilage width, height, and thickness were then measured. Axial tissue slices were harvested and histologic preparations completed with hemotoxylin and eosin (H&E) staining to delineate microscopic characteristics of the cartilage. RESULTS: Maximum conchal bowl width ranged from 1.9 to 2.9 cm and was widest on average over the cymba (2.4 +/- 0.3 cm). Maximum conchal bowl height ranged from 1.7 to 3.1 cm and was greatest on average over the region posterior to the junction of the helical root and conchal bowl (2.4 +/ 0.5 cm). Conchal bowl thickness ranged from 1.9 to 4.4 mm and was observed thickest over both the conchal extension of the helical root (3.5 +/- 0.4 mm) as well as over a distinct region in the inferior-anterior aspect of the cavum (3.7 +/- 0.9 mm). No difference in thickness was observed between the conchal extension of the helical root (3.5 +/- 0.4 mm) and the distinct region in the inferioranterior aspect of the cavum (3.7 +/- 0.9 mm; P > .05). Naturally occurring cartilaginous divisions were appreciated on histologic specimens located at the junction of the cavum and external auditory meatus and at the junction of the helical root and conchal extension of the helical root. CONCLUSIONS: The results, examination, and outline of conchal bowl parameters from cadaver cartilage demonstrated in this article will aid the surgeon in effectively obtaining the appropriate cartilage grafts for placement during rhinoplasty. PMID- 20829250 TI - Primary rhinoplasty. AB - Rhinoplasty is generally considered to be one of the most challenging, complex, and exciting of all the plastic surgery procedures. In this article, the authors discuss key concepts related to patient evaluation and analysis, as well as techniques and maneuvers that reliably lead to favorable long-term results in rhinoplasty. PMID- 20829252 TI - Breast infections with atypical mycobacteria following reduction mammaplasty. AB - Reduction mammaplasty is one of the most common plastic surgery procedures performed in the US, with the goal of correcting symptomatic macromastia. More than 70,000 cases were performed in 2009, with few complications and low infection rates. The authors present two cases of breast infections with Mycobacterium fortuitum and one with Mycobacterium chelonei following bilateral reduction mammaplasty. Infection with these organisms is exceptionally rare following breast surgery in the absence of a prosthetic implant. All of the patients had a delayed presentation following complete wound healing and were refractory to first-line antibiotic therapy. All three required long-term antibiotics in consultation with an infectious disease specialist. The patients all required surgical drainage, and two patients also required formal operative debridement. All three patients eventually went on to complete wound healing. PMID- 20829253 TI - Autogenous fat grafting and breast augmentation: a review of the literature. AB - Since the 1980s, there has been an increased interest in autogenous fat grafting for breast augmentation. However, concerns over graft survival and interference with breast cancer screening have limited its application. Since its introduction, refinements in harvesting and grafting techniques have improved results. The available literature consists primarily of case reports and series. There are no controlled trials, and outcomes thus far have not been measured in a standardized way. The limited data relating to breast cancer screening did not note a significant interference. Concerns have been raised that the placement of mature adipocytes and adipocyte-derived stem cells into the hormonally-active environment of the breast may potentiate breast cancer, but there are no clinical trials that investigate this possibility and a consensus regarding the basic science is still developing. Large multicenter, controlled, prospective trials are necessary to further investigate the many issues relating to the application of autogenous fat grafting for augmentation of the breast. PMID- 20829254 TI - Breast implants: saline or silicone? AB - The United States has seen significant shifts in the breast implant market over the past five decades. From the moratorium on silicone gel breast implants in 1992 to their approval in 2006, there have been many developments in their manufacturing and usage. Meanwhile, saline breast implants have remained somewhat unchanged, still offering a few distinct advantages but none of the technological innovation of the silicone gel models. In this article, the authors review the current state of silicone gel and saline implants, as well as the advantages and disadvantages of each. Much of the current data on complications of gel and saline implants are examined, as well as some practical implications associated with the use of each implant type. PMID- 20829255 TI - Instant identification of redundant tissue in abdominoplasty with a marking grid. AB - BACKGROUND: It is generally believed that continuous or discontinuous undermining of an abdominoplasty flap is necessary for its advancement, but it is also recognized that such undermining may increase the risk of ischemic complications. OBJECTIVE: The author describes a grid-marking system to quickly identify the redundant tissue in abdominoplasty, making the procedure simpler, safer, and more consistent. METHODS: A standardized grid was preoperatively marked on 35 consecutive female abdominoplasty patients to determine the exact pattern and extent of skin resection at the beginning of the procedure. This allowed resection of redundant tissue while confining proximal flap undermining to the minimum amount necessary for diastasis repair and umbilical repositioning. RESULTS: The 35 patients who underwent abdominoplasty with the author's technique were followed from three months to 2.5 years. Of these, 12 underwent simultaneous liposuction. All procedures were performed on an outpatient basis under general anesthesia in an accredited office operating facility. Overall results were excellent, with no flap ischemia or other complications directly related to wound tension or to limited undermining. CONCLUSIONS: A standardized grid system allows identification of redundant abdominoplasty tissue before any incisions are made, which limits undermining to the area over the medial rectus abdominis muscles, the minimum amount necessary for diastasis repair and umbilical repositioning. Simultaneous liposuction can be performed with relative safety, although it is not required for flap advancement. PMID- 20829256 TI - Gluteoplasty: anatomic basis and technique. AB - BACKGROUND: Although the placement of implants for gluteal augmentation is becoming more common, the procedure still faces strong resistance from patients and some surgeons as a result of unsatisfactory outcomes in the past. OBJECTIVE: The authors describe easily-identifiable anatomic reference points that can assist the surgeon in the performance of gluteoplasty, making the procedure simpler and safer. METHODS: Based on a literature review, an anatomic study was performed of dissections of the gluteal region in seven formalinized and fresh cadavers. This study allowed the authors to observe anatomic details and propose bony reference points to guide gluteoplastic surgery. Between July 2006 and February 2009, 105 patients underwent gluteoplasty according to the guidelines resulting from the cadaveric study. RESULTS: All patients were female, ages 22 to 50 years. The surgical procedure, once refined, resulted in a low complication rate. In the final 50 patients in the series, there was only one seroma, one wound infection, and no cases of dehiscence. Bruising on the side of the thigh was encountered in four of the total 105 cases (3.8%). The clinical photos demonstrate the positive aesthetic results of this technique. CONCLUSIONS: When gluteoplasty is performed utilizing a systematic strategy based on bone anatomy references, it can be a predictable procedure with reproducible results and minimal complications. PMID- 20829257 TI - Randomized, blinded split abdomen study evaluating skin shrinkage and skin tightening in laser-assisted liposuction versus liposuction control. AB - BACKGROUND: Laser-assisted liposuction has shown great potential in facilitating fat removal, improving patient recovery time, and decreasing postoperative side effects. Clinical experience has indicated superior skin tightening after laser assisted liposuction than with liposuction alone. OBJECTIVES: The aim of the present study was to obtain quantitative, objective data for comparing tissue shrinkage and skin tightening achieved by laser-assisted liposuction versus liposuction alone. METHODS: Ten female subjects from the author's private practice with unwanted abdominal adiposity and mild to moderate skin laxity were enrolled. On the abdominal skin of each patient, the corners of four rectangular regions (approximately 5 * 5 cm each) were tattooed with India ink and randomly assigned to treatment with laser-assisted liposuction (Smartly MPX laser, Cynosure, Inc., Westford, Massachusetts) or with liposuction alone. The laser system permits individual as well as sequential emission of 1064-nm and 1320-nm wavelengths. Skin shrinkage was quantified by calculating the changes in surface area of the regions. Skin tightening was quantified by changes in the skin stiffness index measured in the treated regions. RESULTS: One month and three months after treatment, the mean skin shrinkage ratios were significantly higher on the laser-treated side than on the suction side. One month after treatment with or without laser, the mean skin stiffness and skin tightening showed no statistically significant difference from baseline. Three months after treatment, the mean skin stiffness and skin tightening were significantly higher on the laser-treated side. CONCLUSIONS: Laser-assisted liposuction has a statistically significant effect on skin shrinkage and tightening of the skin in the abdominal area when compared to liposuction alone. PMID- 20829258 TI - TUNEL assay to characterize acute histopathological injury following treatment with the active and deep FX fractional short-pulse CO2 devices. AB - BACKGROUND: This is a report of the histopathological evaluation of the acute damage profile in human skin following treatment with two novel short-pulsed fractional carbon dioxide resurfacing devices used independently and in combination in vivo. METHODS: The panni of eight abdominoplasty patients were treated with either the Active FX, the Deep FX (Lumenis Ltd., Yokneum, Israel), or a combination of the two (Total FX) prior to the start of the excisional surgical procedure. Multiple combinations of energies, pulse widths, and densities were evaluated for each device. After surgical removal (two to five hours), each pannus was immediately biopsied and samples were processed for histopathological evaluation. RESULTS: The Active FX system resulted in extensive epidermal injury with wide shallow ablation craters that, at higher fluences, extended through the basement membrane of the epidermis into the papillary dermis. The Deep FX fractional treatment caused deep microcolumns of ablation penetrating up to 3 to 4 mm from the epidermal surface into the deep reticular dermis with a variable rim of coagulated collagen surrounding each ablation column. CONCLUSIONS: The in vivo histopathological evaluation of these devices furthers our understanding of the fundamental laser/tissue interaction following treatment with each device independently and in combination. PMID- 20829259 TI - The battle for hearts and minds: who is communicating most effectively with the cosmetic marketplace? AB - BACKGROUND: Cosmetic surgery, historically the purview of plastic surgeons, has in recent years seen an influx of practitioners from other fields of training. Many of these new providers are savvy in marketing and public relations and are beginning to control a surprisingly large amount of cosmetic patient care. OBJECTIVES: The purpose of this study is to measure the amount of traffic being attracted to the Web sites of individual practitioners and organizations vying for cosmetic patients. This study investigates the trends of the past 12 months and identifies changes of special concern to plastic surgeons. METHODS: The Web sites of 1307 cosmetic providers were monitored over a year's time. The Web activity of two million individuals whose computers were loaded with a self reporting software package was recorded and analyzed. The Web sites were analyzed according to the specialty training of the site owner and total unique visits per month were tallied for the most prominent specialties. The dominant Web sites were closely scrutinized and the Web optimization strategies of each were also examined. RESULTS: There is a tremendous amount of Web activity surrounding cosmetic procedures and the amount of traffic on the most popular sites is continuing to grow. Also, a large sum of money is being expended to channel Web traffic, with sums in the thousands of dollars being spent daily by top Web sites. Overall in the past year, the private Web sites of plastic surgeons have increased their reach by 10%, growing from 200,000 to approximately 220,000 unique visitors monthly. Plastic surgery remains the specialty with the largest number of Web visitors per month. However, when combined, the private Web sites of all other providers of aesthetic services have significantly outpaced plastic surgery's growth. The traffic going to non-plastic surgeons has grown by 50% (200,000 visitors per month in September 2008 to 300,000 visitors monthly in September 2009). CONCLUSIONS: For providers of aesthetic services, communication with the public is of utmost importance. The Web has become the single most important information resource for consumers because of easy access. Plastic surgeons are facing significant competition for the attention of potential patients, with increasingly sophisticated Web sites and listing services being set up by independent parties. It is important for plastic surgeons to become familiar with the available Internet tools for communication with potential patients and to aggressively utilize these tools for effective practice building. PMID- 20829260 TI - Commentary. PMID- 20829261 TI - L-brachioplasty: an adaptable technique for moderate to severe excess skin and fat of the arms. AB - The L-brachioplasty is an L-shaped pattern of excision with the long limb from the elbow to the axilla and the short limb extending at right angles through the axilla and along the lateral chest. The width of the excisions through the arm, axilla and chest is based on preoperative assessment through anatomical point locations followed by pinch and gathering maneuvers. The following modifications have improved aesthetics and reduced complications: 1) improved geometric design, 2) anchor fixation of the posterior V-shaped advancement flap to the deltopectoral fascia, 3) excision site liposuction (ESL), and 4) and barbed suture closure. The free hand markings are followed by measuring equal anterior and posterior incision distances. The subcutaneous fat within the excision site is completely suctioned. After the perimeter is incised, the skin resection begins full thickness from the chest and through the axilla and then the skin only through proximal to distal arm skin. An anchor suture advances the posterior triangular flap to the deltopectoral fascia. A long-lasting absorbable barbed suture is passed through as a running horizontal mattress, starting from the center of the wound. A second continuous rapidly absorbing barbed intradermal suture completes the closure. Over the past 30 arms, only one seroma was aspirated on one occasion. There have been no lymphoceles. Appreciable swelling is over within a month. Incision dehiscence was limited to less than one centimeter in five patients. Tip necrosis of the V advancement flap occurred in three arms, leaving small wounds in the axilla to heal secondarily. Minor secondary skin reduction is rare. There were no contractures across the axilla. The women appreciated the reduced hair and axillary hollow. In most cases the skin laxity was corrected and the contour from the arm across the axilla to the lateral chest was excellent. No patient expressed regret over their scar. PMID- 20829262 TI - Ethical issues in aesthetic research. PMID- 20829264 TI - The lateral transhelical approach to otoplasty: a not-so-new concept for separating the helix from the antihelix. PMID- 20829266 TI - Re: "Estimation of the contribution of non-assisted reproductive technology ovulation stimulation fertility treatments to US singleton and multiple births". PMID- 20829267 TI - Invited commentary: Body mass index and suicide--untangling an unlikely association. AB - A now robust series of prospective studies have found body mass index to be inversely associated with risk of completed suicide, dating back approximately 4 decades. In the progression from disturbed mental health to suicidal ideation to attempted suicide and completed suicide, augmented by impulsivity and access to highly lethal means, there are several potential steps at which body mass index has been hypothesized to lower risk. These include improved mood and self-image and reduced impulsivity, but relatively little empirical support for these exists in populations. More evidence exists to suggest that greater body weight reduces the case fatality of poisonings and shifts suicidal acts away from selected highly lethal means, such as hanging. However, in the absence of longitudinal studies with repeated measures of weight, mental health, and suicidal ideation, it remains difficult to exclude the possibility of residual confounding, particularly by psychiatric disorders that could lead to both weight loss and suicidal ideation. PMID- 20829269 TI - Body mass index and attempted suicide: Cohort study of 1,133,019 Swedish men. AB - Associations between body mass index (BMI) and attempted (nonfatal) suicide have recently been reported. However, the few existing studies are relatively small in scale, the majority cross-sectional, and results contradictory. The authors have explored BMI-attempted suicide associations in a large cohort of 1,133,019 Swedish men born between 1950 and 1976, with BMI measured in early adulthood. During a mean follow-up of 23.9 years, a total of 18,277 (1.6%) men had at least 1 hospital admission for attempted suicide. After adjustment for confounding factors, there was a stepwise, linear decrease in attempted suicide with increasing BMI across the full BMI range (per standard deviation increase in BMI, hazard ratio = 0.93, 95% confidence interval: 0.91, 0.94). Analyses excluding men with depression at baseline were essentially identical to those based on the complete cohort. In men free from depression at baseline, controlling for subsequent depression slightly attenuated the raised risk of attempted suicide, particularly in lower weight men. This study suggests that lower weight men have an increased risk of attempted suicide and that associations may extend into the "normal" BMI range. PMID- 20829270 TI - The effects of temperature and use of air conditioning on hospitalizations. AB - Several investigators have documented the effect of temperature on mortality, although fewer have studied its impact on morbidity. In addition, little is known about the effectiveness of mitigation strategies such as use of air conditioners (ACs). The authors investigated the association between temperature and hospital admissions in California from 1999 to 2005. They also determined whether AC ownership and usage, assessed at the zip-code level, mitigated this association. Because of the unique spatial pattern of income and climate in California, confounding of AC effects by other local factors is less likely. The authors included only persons who had a temperature monitor within 25 km of their residential zip code. Using a time-stratified case-crossover approach, the authors observed a significantly increased risk of hospitalization for multiple diseases, including cardiovascular disease, ischemic heart disease, ischemic stroke, respiratory disease, pneumonia, dehydration, heat stroke, diabetes, and acute renal failure, with a 10 degrees F increase in same-day apparent temperature. They also found that ownership and usage of ACs significantly reduced the effects of temperature on these health outcomes, after controlling for potential confounding by family income and other socioeconomic factors. These results demonstrate important effects of temperature on public health and the potential for mitigation. PMID- 20829271 TI - An analysis of children with brucellosis associated with isolated thrombocytopenia. AB - Hematologic abnormalities of mild anemia and leucopenia have been frequently associated with acute brucellosis, but thrombocytopenia are less frequently seen. In the present study, we documented 5 (2.6%) isolated thrombocytopenic patients with the manifestations of brucellosis observed during the course of active infection. Five (2.6%) patients, 4 boys and 1 girl, with ages ranging from 2 to 14 years, had isolated thrombocytopenic at diagnosis. In 5 (2.6%) patients, platelet counts ranged from 39,000 to 120,000/mm(3). Tube agglutination tests for brucellosis were positive for all patients (1/160-1/1280). All patients recovered completely, and their thrombocytopenia returned to normal by 2 to 4 weeks after antibiotic treatment of brucellosis. In our study, we present 5 patients with Brucella-induced thrombocytopenia mimicking idiopathic thrombocytopenic purpura to emphasize the isolated thrombocytopenia and the resolution of thrombocyte counts following treatment of brucellosis. PMID- 20829272 TI - Venous thromboembolism risk and thromboprophylaxis among hospitalized patients: data from the Turkish arm of the ENDORSE study. AB - OBJECTIVES: To evaluate venous thromboembolism (VTE) risk and use of thromboprophylaxis in the acute care hospital setting. METHODS: A total of 1701 patients hospitalized for acute or exacerbated chronic medical illnesses or elective major surgery at 11 different hospitals across Turkey were included in the study. Patients at risk and VTE prophylaxis application were retrospectively identified based on medical charts. RESULTS: According to the American College of Chest Physicians (ACCP) criteria, overall 35.6% (606 of 1701) of the patients were identified to be at VTE risk. Venous thromboembolism-risk was observed in 64.9% of surgical and 23.8% of medical patients, the latter being lower than global Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting (ENDORSE) study results; while prophylaxis was prescribed in 39.0% and 38.5% of them, respectively. Contraindication to anticoagulant prophylaxis was observed in 8.7% of medical and 8.8% of surgical patients. CONCLUSIONS: VTE remains a risk factor among patients hospitalized across Turkey, since identification as well as prophylaxis of patients at VTE risk seems to be neglected. PMID- 20829273 TI - An assessment of surgical thromboprophylaxis in a tertiary care center. AB - BACKGROUND: Venous thromboembolism (VTE) is a frequent surgical complication. The American College of Chest Physicians (ACCP) recommends implementation of pharmacologic thromboprophylaxis according to surgery type and VTE risk factors. We conducted a retrospective cohort study of surgical admissions to determine the rate and predictors of use and appropriate use of thromboprophylaxis as defined by the 2004 ACCP guidelines and to determine the risk of postoperative VTE. METHODS: Using data from an administrative health care database of the Centre Hospitalier Universitaire de Sherbrooke in the province of Quebec, we assembled a cohort of all consecutive surgical admissions in 2006 that met ACCP criteria for pharmacologic thromboprophylaxis and assessed rates of thromboprophylaxis presence and appropriateness. Multiple logistic regression was used to determine characteristics associated with thromboprophylaxis prescription. The incidence of postoperative VTE was assessed at 3 months. RESULTS: Of 2286 surgical admissions that met criteria for pharmacologic thromboprophylaxis, 81% received thromboprophylaxis and, of these, 31% received appropriate thromboprophylaxis as per ACCP guidelines. Male sex, age below 40 years, and short-duration hospitalization were significantly associated with absent and inappropriate thromboprophylaxis. Cancer diagnosis and heart failure within 3 months preceding surgery were protective against inappropriate thromboprophylaxis (OR 0.43, 95% CI [0.33-0.57] and 0.43 [0.26-0.70], respectively). At 3 months following surgery, 27 patients (1.2%) developed VTE. Patients who developed VTE were more likely to have had a previous VTE than patients who did not develop a VTE (P < .0001). CONCLUSIONS: Targeted recommendations, in particular concerning male patients with short duration hospitalization, may improve thromboprophylaxis compliance and appropriateness rates. PMID- 20829274 TI - A qualitative exploration of youth in the "new" China: perspectives on tobacco use from adolescents in southwest China. AB - School-based prevention programs are not common in China and the attempts to modify successful Western prevention programs have largely shown little effect. Distinct cultural and social systems differences could explain why modified programs have been unsuccessful. Smoking behavior is examined from the perspective of Chinese adolescents as part of the development of a large intervention trial. A total of 16 focus groups with 128 participants were conducted in Chengdu in Sichuan province of China. Impressions of adolescent smokers were mixed, most seeing the behavior as common among boys. Smokers were seen as being overwhelmed and stressed. Girls' smoking was mostly seen as universally "bad" and reflecting poorly on a girl's character. However, a small portion of focus group participants suggested that female smoking was fashionable and trendy. With social norms changing rapidly in the "new" China, understanding what the new generation of Chinese youth thinks about smoking is critical in determining how to address and tailor prevention efforts. PMID- 20829275 TI - Predictors of contraceptive use among married youths and their husbands in a rural area of Myanmar. AB - This study aimed to determine the predictors of contraceptive use among married female youths and their husbands using the behavioral theory of the Health Belief Model (HBM). A community-based survey was conducted in a rural area of Myanmar in 2008. A total of 444 respondents (222 couples) were interviewed separately using a pretested, structured questionnaire. Significant predictors of contraceptive use were determined by univariate and multivariate analysis. Wife's HBM perception was a highly significant predictor of contraceptive use in married youths (adjusted odds ratio = 10; 95% confidence interval = 2.7, 37.6). Wives aged 20 to 24 years and having their own income, experience of spousal communication, and shorter distance from home to health center were also significant predictors of contraceptive use. A poor agreement on HBM perception between wife and husband was noted. This study highlights the importance of HBM perceptions, wife's income, spousal communication, and geographic barriers in contraceptive use among married youths in rural Myanmar. PMID- 20829276 TI - Physical activity and its association with cardiovascular risk factors in Vietnam. AB - This study examined physical activity in leisure time and at work as estimated by the Global Physical Activity Questionnaire (GPAQ) and the associations between both total and domain-specific physical activity with cardiovascular risk factors in a population-based Vietnamese sample. Participants (n = 1978) were 25- to 64 year-old adults selected by stratified multistage sampling. Leisure activity contributed to <5% of total moderate and vigorous activity and was not associated with cardiovascular risk factors. Total moderate and vigorous activity was associated with body composition (r = -0.16 to -0.22; P < .001), blood glucose (r = -0.07; P < .05), and total cholesterol (r = -0.17; P < .001) for men and with total cholesterol (r = -0.07; P < .05) for women after adjusting for age. Further adjustment for smoking and alcohol intake made negligible changes. These associations were largely driven by work activity, which accounted for 80% of total activity. PMID- 20829277 TI - Perceived service quality and its influence on behavioral intention in South Korean public dental hospitals. AB - South Korean national university dental hospitals (NUDHs) face unprecedented challenges in maintaining primary function as public hospitals and surviving in intensified competition. The aim of the study was to evaluate the perceived service quality of NUDH patients and its influences on behavior and to gain managerial implications. Perceived service quality, value, satisfaction, and behavioral intention were measured in 438 NUDH patients from 3 NUDHs. With demographic analyses, the authors used structural equation models to test the validity to prove the relationship between dimensions. RESULTS: showed that the dimension of dentist concern directly influenced satisfaction and behavior, and tangibles was the only significant antecedent factor of value that had a significant positive effect on satisfaction. Based on demographic characteristics, highly educated, self-motivated patients who underwent multiple treatments had lower perceptions of value and satisfaction. NUDHs need to maintain their public image and to improve the dimensions of communication and tangibles to gain competitiveness. PMID- 20829278 TI - Patients' experiences and satisfaction with out-of-hours GP home visiting provided by a GP cooperative. AB - BACKGROUND: Within the UK, patients place a fairly high value on the out-of-hours GP home visiting service. Although satisfaction with the range of out-of-hours services has been found to be high, little is known about patients' specific experiences of the home visiting services. OBJECTIVE: To investigate the satisfaction with, and experiences of, patients receiving a GP out-of-hours (OOH) home visit from a GP cooperative. METHODS: A postal questionnaire study sent to all patients receiving a home visit from a single cooperative. The questionnaire asked patients a range of questions about their experiences of the home visiting service that they received and also contained a validated satisfaction measure. RESULTS: The OOH home visiting services largely provide care for an older population, most of whom consider that they are either too ill to travel or have limited mobility. The majority (43%) of home visits are made during the daytime at weekends, with just 25% of visits made during the night-time. If the home visit was not available, 67% of patients stated that they would have phoned for an ambulance or gone directly to hospital. The majority of patients (87%) were satisfied with the overall home visiting service that they received; however, 32% of patients were dissatisfied with the time it took for them to see a doctor or a nurse. CONCLUSIONS: Although the OOH services have received considerable criticism over the past 5 years, this study reveals that patients remain largely satisfied with the service and would have called 999 or gone directly to hospital if there had been no service. PMID- 20829279 TI - How do French GPs consider participating in primary care research: the DRIM study. AB - BACKGROUND: Recruiting GPs is an issue faced by most research teams in primary care. OBJECTIVES: To assess GPs' willingness and expectations with regard to research in French primary care and to identify factors that may increase their participation in research projects. METHODS: Cross-sectional study conducted with a representative sample of 452 GPs from the Rhone-Alpes region in France. RESULTS: Among 284 GPs (63%) who participated, 85 [29.9%, 95% confidence interval (CI) = 26.4-35.3%] were willing to participate in research as investigators and 83 (29.2%, 95% CI: 23.9-34.5%) had already participated in research projects. Multivariate analysis showed that an earlier participation in research projects [odds ratio (OR) = 3.3], a training practice (OR = 2.3), membership in a research network (OR = 2.1) and younger age (OR = 1.9 for 10 years less) were associated with the willingness to participate in future research projects. Whereas 55% of practitioners who already had an experience in research had participated in a therapeutic trial, those willing to participate in the future preferred to participate in descriptive (26%) or etiologic (22%) studies. Preventive, diagnostic and therapeutic procedures and quality of care were the domains, which interested GPs most. The most expected clinical themes concerned cardiovascular, metabolic, musculoskeletal and respiratory problems. CONCLUSIONS: To meet the expectations of French GPs willing to participate in primary care research, it is advisable to diversify studies with respect to their types, domains and themes. Linkage to universities and research networks should also be encouraged. PMID- 20829280 TI - Functional convergence in reduced genomes of bacterial symbionts spanning 200 My of evolution. AB - The main genomic changes in the evolution of host-restricted microbial symbionts are ongoing inactivation and loss of genes combined with rapid sequence evolution and extreme structural stability; these changes reflect high levels of genetic drift due to small population sizes and strict clonality. This genomic erosion includes irreversible loss of genes in many functional categories and can include genes that underlie the nutritional contributions to hosts that are the basis of the symbiotic association. Candidatus Sulcia muelleri is an ancient symbiont of sap-feeding insects and is typically coresident with another bacterial symbiont that varies among host subclades. Previously sequenced Sulcia genomes retain pathways for the same eight essential amino acids, whereas coresident symbionts synthesize the remaining two. Here, we describe a dual symbiotic system consisting of Sulcia and a novel species of Betaproteobacteria, Candidatus Zinderia insecticola, both living in the spittlebug Clastoptera arizonana. This Sulcia has completely lost the pathway for the biosynthesis of tryptophan and, therefore, retains the ability to make only 7 of the 10 essential amino acids. Zinderia has a tiny genome (208 kb) and the most extreme nucleotide base composition (13.5% G + C) reported to date, yet retains the ability to make the remaining three essential amino acids, perfectly complementing capabilities of the coresident Sulcia. Combined with the results from related symbiotic systems with complete genomes, these data demonstrate the critical role that bacterial symbionts play in the host insect's biology and reveal one outcome following the loss of a critical metabolic activity through genome reduction. PMID- 20829281 TI - Correlating gene expression variation with cis-regulatory polymorphism in Saccharomyces cerevisiae. AB - Identifying the nucleotides that cause gene expression variation is a critical step in dissecting the genetic basis of complex traits. Here, we focus on polymorphisms that are predicted to alter transcription factor binding sites (TFBSs) in the yeast, Saccharomyces cerevisiae. We assembled a confident set of transcription factor motifs using recent protein binding microarray and ChIP-chip data and used our collection of motifs to predict a comprehensive set of TFBSs across the S. cerevisiae genome. We used a population genomics analysis to show that our predictions are accurate and significantly improve on our previous annotation. Although predicting gene expression from sequence is thought to be difficult in general, we identified a subset of genes for which changes in predicted TFBSs correlate well with expression divergence between yeast strains. Our analysis thus demonstrates both the accuracy of our new TFBS predictions and the feasibility of using simple models of gene regulation to causally link differences in gene expression to variation at individual nucleotides. PMID- 20829283 TI - Replication of plasmids derived from Shiga toxin-converting bacteriophages in starved Escherichia coli. AB - The pathogenicity of Shiga toxin-producing Escherichia coli (STEC) depends on the expression of stx genes that are located on lambdoid prophages. Effective toxin production occurs only after prophage induction, and one may presume that replication of the phage genome is important for an increase in the dosage of stx genes, positively influencing their expression. We investigated the replication of plasmids derived from Shiga toxin (Stx)-converting bacteriophages in starved E. coli cells, as starvation conditions may be common in the intestine of infected humans. We found that, unlike plasmids derived from bacteriophage lambda, the Shiga toxin phage-derived replicons did not replicate in amino acid starved relA(+) and relA(-) cells (showing the stringent and relaxed responses to starvation, respectively). The presence of the stable fraction of the replication initiator O protein was detected in all tested replicons. However, while ppGpp, the stringent response effector, inhibited the activities of the lambda P(R) promoter and its homologues from Shiga toxin-converting bacteriophages, these promoters, except for lambda P(R), were only weakly stimulated by the DksA protein. We suggest that this less efficient (relative to lambda) positive regulation of transcription responsible for transcriptional activation of the origin contributes to the inhibition of DNA replication initiation of Shiga toxin converting bacteriophages in starved host cells, even in the absence of ppGpp (as in starved relA(-) hosts). Possible clinical implications of these results are discussed. PMID- 20829282 TI - High level of structural polymorphism driven by mobile elements in the Hox genomic region of the Chaetognath Spadella cephaloptera. AB - Little is known about the relationships between genome polymorphism, mobile element dynamics, and population size among animal populations. The chaetognath species Spadella cephaloptera offers a unique perspective to examine this issue because they display a high level of genetic polymorphism at the population level. Here, we have investigated in detail the extent of nucleotide and structural polymorphism in a region harboring Hox1 and several coding genes and presumptive functional elements. Sequencing of several bacterial artificial chromosome inserts representative of this nuclear region uncovered a high level of structural heterogeneity, which is mainly caused by the polymorphic insertion of a diversity of genetic mobile elements. By anchoring this variation through individual genotyping, we demonstrated that sequence diversity could be attributed to the allelic pool of a single population, which was confirmed by detection of extensive recombination within the genomic region studied. The high average level of nucleotide heterozygosity provides clues of selection in both coding and noncoding domains. This pattern stresses how selective processes remarkably cope with intense sequence turnover due to substitutions, mobile element insertions, and recombination to preserve the integrity of functional landscape. These findings suggest that genome polymorphism could provide pivotal information for future functional annotation of genomes. PMID- 20829284 TI - Heterologous expression of the surface-layer-like protein SllB induces the formation of long filaments of Escherichia coli consisting of protein-stabilized outer membrane. AB - Escherichia coli is one of the best studied micro-organisms and is the most widely used host in genetic engineering. The Gram-negative single cells are rod shaped, and filaments are usually not found. Here, we describe the reproducible formation of elongated E. coli cells. During heterologous expression of the silent surface (S)-layer protein gene sllB from Lysinibacillus sphaericus JG-A12 in E. coli BL21(DE3), the cells were arranged as long chains which were surrounded by highly stable sheaths. These filaments had a length of >100 MUm. In the stationary growth phase, microscopic analyses demonstrated the formation of unusually long transparent tube-like structures which were enclosing separate single cells. The tube-like structures were isolated and analysed by SDS-PAGE, infrared-spectroscopy and different microscopic methods in order to identify their unusual composition and structure. The tube-like structures were found to be like outer membranes, containing high levels of proteins and to which the recombinant S-layer proteins were attached. Despite the entire structure being indicative of a disordered cell division, the bacterial cells were highly viable and stable. To our knowledge, this is the first time that the induction of drastic morphological changes in E. coli by the expression of a foreign protein has been reported. PMID- 20829285 TI - 6S RNA regulation of relA alters ppGpp levels in early stationary phase. AB - 6S RNA is a small, non-coding RNA that interacts directly with sigma(70)-RNA polymerase and regulates transcription at many sigma(70)-dependent promoters. Here, we demonstrate that 6S RNA regulates transcription of relA, which encodes a ppGpp synthase. The 6S RNA-dependent regulation of relA expression results in increased ppGpp levels during early stationary phase in cells lacking 6S RNA. These changes in ppGpp levels, although modest, are sufficient to result in altered regulation of transcription from sigma(70)-dependent promoters sensitive to ppGpp, including those promoting expression of genes involved in amino acid biosynthesis and rRNA. These data place 6S RNA as another player in maintaining appropriate gene expression as cells transition into stationary phase. Independent of this ppGpp-mediated 6S RNA-dependent regulation, we also demonstrate that in later stationary phase, 6S RNA continues to downregulate transcription in general, and specifically at a subset of the amino acid promoters, but through a mechanism that is independent of ppGpp and which we hypothesize is through direct regulation. In addition, 6S RNA-dependent regulation of sigma(S) activity is not mediated through observed changes in ppGpp levels. We suggest a role for 6S RNA in modulating transcription of several global regulators directly, including relA, to downregulate expression of key pathways in response to changing environmental conditions. PMID- 20829286 TI - Crystal structure and mutagenesis analysis of chitinase CrChi1 from the nematophagous fungus Clonostachys rosea in complex with the inhibitor caffeine. AB - Chitinases are a group of enzymes capable of hydrolysing the beta-(1,4) glycosidic bonds of chitin, an essential component of the fungal cell wall, the shells of nematode eggs, and arthropod exoskeletons. Chitinases from pathogenic fungi have been shown to be putative virulence factors, and can play important roles in infecting hosts. However, very limited information is available on the structure of chitinases from nematophagous fungi. Here, we present the 1.8 A resolution of the first structure of a Family 18 chitinase from this group of fungi, that of Clonostachys rosea CrChi1, and the 1.6 A resolution of CrChi1 in complex with a potent inhibitor, caffeine. Like other Family 18 chitinases, CrChi1 has the DXDXE motif at the end of strand beta5, with Glu174 as the catalytic residue in the middle of the open end of the (beta/alpha)(8) barrel. Two caffeine molecules were shown to bind to CrChi1 in subsites -1 to +1 in the substrate-binding domain. Moreover, site-directed mutagenesis of the amino acid residues forming hydrogen bonds with caffeine molecules suggests that these residues are important for substrate binding and the hydrolytic process. Our results provide a foundation for elucidating the catalytic mechanism of chitinases from nematophagous fungi and for improving the pathogenicity of nematophagous fungi against agricultural pest hosts. PMID- 20829287 TI - Hetero-oligomeric glutamate dehydrogenase from Thermus thermophilus. AB - An extremely thermophilic bacterium, Thermus thermophilus, possesses two glutamate dehydrogenase (GDH) genes, gdhA and gdhB, putatively forming an operon on the genome. To elucidate the functions of these genes, the gene products were purified and characterized. GdhA showed no GDH activity, while GdhB showed GDH activity for reductive amination 1.3-fold higher than that for oxidative deamination. When GdhA was co-expressed with His-tag-fused GdhB, GdhA was co purified with His-tagged GdhB. Compared with GdhB alone, co-purified GdhA-GdhB had decreased reductive amination activity and increased oxidative deamination activity, resulting in a 3.1-fold preference for oxidative deamination over reductive amination. Addition of hydrophobic amino acids affected the GDH activity of the co-purified GdhA-GdhB hetero-complex. Among the amino acids, leucine had the largest effect on activity: addition of 1 mM leucine elevated the GDH activity of the co-purified GdhA-GdhB by 974 and 245 % for reductive amination and oxidative deamination, respectively, while GdhB alone did not show such marked activation by leucine. Kinetic analysis revealed that the elevation of GDH activity by leucine is attributable to the enhanced turnover number of GDH. In this hetero-oligomeric GDH system, GdhA and GdhB act as regulatory and catalytic subunits, respectively, and GdhA can modulate the activity of GdhB through hetero-complex formation, depending on the availability of hydrophobic amino acids. This study provides the first finding, to our knowledge, of a hetero-oligomeric GDH that can be regulated allosterically. PMID- 20829288 TI - A quadruple-enterotoxin-deficient mutant of Bacillus thuringiensis remains insecticidal. AB - Bacillus thuringiensis is the leading biopesticide used to control insect pests worldwide. Although they have a long record of safe use, under certain conditions commercial strains of B. thuringiensis have the ability to produce numerous putative enterotoxins that have been associated with food poisoning attributed to Bacillus cereus. Therefore, we designed a strategy to delete the genes encoding these toxins. B. thuringiensis strain VBTS 2477 contained genes encoding NHE, CytK-2 and three homologues of haemolysin BL (HBL, HBL(a1) and HBL(a2)). This is the first report, to our knowledge, of a strain of B. cereus or B. thuringiensis containing three sets of hbl operons. The genes encoding HBL(a1) and HBL(a2) were 96-97 % identical to each other and 76-84 % identical to those encoding HBL. The hbl(a2) operon was detected by PCR amplification only after hbl(a1) was deleted. We used sequential gene replacement to replace the wild-type copies of the NHE and three HBL operons with copies that contained internal deletions that span the three genes in each operon. The insecticidal activity of the quadruple enterotoxin-deficient mutant was similar to that of the wild-type strain against larvae of Trichoplusia ni, Spodoptera exigua and Plutella xylostella. This demonstrates that the genes for enterotoxins can be deleted, eliminating the possibility of enterotoxin production without compromising the insecticidal efficacy of a strain of B. thuringiensis. PMID- 20829289 TI - Peroxynitrite stress is exacerbated by flavohaemoglobin-derived oxidative stress in Salmonella Typhimurium and is relieved by nitric oxide. AB - Oxidative and nitrosative stresses including nitric oxide (NO), superoxide (O2-) and peroxynitrite play key roles in determining the outcome of bacterial infections. In order to survive within the host and allow proliferation within immune cells such as macrophages, Salmonella isolates have a number of inducible proteins that are able to detoxify these highly reactive species, notably the anoxically functioning NO reductase NorVW, and the aerobically functioning flavohaemoglobin, Hmp, which catalyses the reaction between oxygen and NO to produce relatively inert nitrate. However, in the absence of NO but in the presence of reducing substrates and oxygen, O2- is generated from Hmp-mediated electron transfer to bound oxygen and may form a variety of further oxidative species. Hence, Hmp expression is under tight negative regulation by the transcription factor NsrR, abolition of which causes an increase in the production of Hmp. In a previous study, this increase in Hmp levels conferred resistance to the nitrosating agent S-nitrosoglutathione but, perhaps surprisingly, the organism became more sensitive to killing by macrophages. Here, we report that an nsrR mutant that constitutively overexpresses Hmp is also hypersensitive to peroxynitrite in vitro. This sensitivity is alleviated by deletion of the hmp gene or pre-incubation of growing bacteria with NO-releasing agents. We hypothesize that Hmp-expressing cells, in the absence of NO, generate reactive oxygen species, the toxicity of which is exacerbated by peroxynitrite in vitro and in macrophages. RT-PCR confirmed that peroxynitrite causes oxidative stress and upregulation of katG and ahpC, whilst hmp and norV expression are affected very little. The katG gene upregulated by peroxynitrite encodes a catalase peroxidase enzyme with well-established roles in detoxifying peroxides. Here, we report that KatG is also able to enhance the breakdown of peroxynitrite, suggesting that the protective role of this enzyme may be wider than previously thought. These data suggest that spatial and temporal fluctuations in the levels of NO and reactive oxygen species will have important consequences for bacterial survival in the macrophage. PMID- 20829290 TI - Intestinal lactobacilli and the DC-SIGN gene for their recognition by dendritic cells play a role in the aetiology of allergic manifestations. AB - Diminished exposure to harmless micro-organisms, such as lactobacilli, has been suggested to play a role in the increased prevalence of allergic disorders in Westernized communities. The development of allergies depends on both environmental factors and genetic variations, including polymorphisms in genes encoding pattern recognition receptors. The present study examines the effects of both colonization with specific Lactobacillus species and genetic variations in DC-SIGN, a pattern recognition receptor on dendritic cells that recognizes lactobacilli, on the development of atopic dermatitis (AD) and sensitization in infancy. Within the KOALA Birth Cohort Study, faecal samples of 681 one-month-old infants were collected and quantitatively screened for five Lactobacillus species: L. casei, L. paracasei, L. rhamnosus, L. acidophilus and L. reuteri. Eleven haplotype-tagging polymorphisms in the DC-SIGN gene were genotyped in these children. Allergic outcomes were a clinical diagnosis of AD and sensitization (specific IgE) at age 2 years. L. rhamnosus (31.5 %), L. paracasei (31.3 %) and L. acidophilus (14.4 %) were frequently detected in the faecal samples of one-month-old infants, whereas L. casei (2.5 %) and L. reuteri (<1 %) were rare. Colonization with L. paracasei decreased the risk of AD significantly (odds ratio 0.57, 95 % confidence interval 0.32-0.99), whereas effects of L. acidophilus were of borderline statistical significance (0.46, 0.20-1.04). Two DC SIGN polymorphisms, rs11465413 and rs8112555, were statistically significantly associated with atopic sensitization. The present study supports the 'old friends' hypothesis suggesting that certain health-beneficial micro-organisms protect us from developing allergies and that these protective effects are species-dependent. Firm conclusions on the potential interaction between lactobacillus colonization and genetic variations in DC-SIGN in association with the development of allergic disorders cannot be drawn, given the limited power of our study. Therefore, incorporation of consecutive faecal sampling in newly started (birth) cohort studies would be a first requisite to further increase our understanding of host-microbial interactions in health and disease. PMID- 20829291 TI - Twenty-eight divergent polysaccharide loci specifying within- and amongst-strain capsule diversity in three strains of Bacteroides fragilis. AB - Comparison of the complete genome sequence of Bacteroides fragilis 638R, originally isolated in the USA, was made with two previously sequenced strains isolated in the UK (NCTC 9343) and Japan (YCH46). The presence of 10 loci containing genes associated with polysaccharide (PS) biosynthesis, each including a putative Wzx flippase and Wzy polymerase, was confirmed in all three strains, despite a lack of cross-reactivity between NCTC 9343 and 638R surface PS-specific antibodies by immunolabelling and microscopy. Genomic comparisons revealed an exceptional level of PS biosynthesis locus diversity. Of the 10 divergent PS associated loci apparent in each strain, none is similar between NCTC 9343 and 638R. YCH46 shares one locus with NCTC 9343, confirmed by mAb labelling, and a second different locus with 638R, making a total of 28 divergent PS biosynthesis loci amongst the three strains. The lack of expression of the phase-variable large capsule (LC) in strain 638R, observed in NCTC 9343, is likely to be due to a point mutation that generates a stop codon within a putative initiating glycosyltransferase, necessary for the expression of the LC in NCTC 9343. Other major sequence differences were observed to arise from different numbers and variety of inserted extra-chromosomal elements, in particular prophages. Extensive horizontal gene transfer has occurred within these strains, despite the presence of a significant number of divergent DNA restriction and modification systems that act to prevent acquisition of foreign DNA. The level of amongst strain diversity in PS biosynthesis loci is unprecedented. PMID- 20829292 TI - Longitudinal investigation of the faecal microbiota of healthy full-term infants using fluorescence in situ hybridization and denaturing gradient gel electrophoresis. AB - From birth onwards, the gastrointestinal (GI) tract of infants progressively acquires a complex range of micro-organisms. It is thought that by 2 years of age the GI microbial population has stabilized. Within the developmental period of the infant GI microbiota, weaning is considered to be most critical, as the infant switches from a milk-based diet (breast and/or formula) to a variety of food components. Longitudinal analysis of the biological succession of the infant GI/faecal microbiota is lacking. In this study, faecal samples were obtained regularly from 14 infants from 1 month to 18 months of age. Seven of the infants (including a set of twins) were exclusively breast-fed and seven were exclusively formula-fed prior to weaning, with 175 and 154 faecal samples, respectively, obtained from each group. Diversity and dynamics of the infant faecal microbiota were analysed by using fluorescence in situ hybridization and denaturing gradient gel electrophoresis. Overall, the data demonstrated large inter- and intra individual differences in the faecal microbiological profiles during the study period. However, the infant faecal microbiota merged with time towards a climax community within and between feeding groups. Data from the twins showed the highest degree of similarity both quantitatively and qualitatively. Inter individual variation was evident within the infant faecal microbiota and its development, even within exclusively formula-fed infants receiving the same diet. These data can be of help to future clinical trials (e.g. targeted weaning products) to organize protocols and obtain a more accurate outline of the changes and dynamics of the infant GI microbiota. PMID- 20829293 TI - Functional and phenotypic characterization of a protein from Lactobacillus acidophilus involved in cell morphology, stress tolerance and adherence to intestinal cells. AB - Structural components of the cell surface have an impact on some of the beneficial attributes of probiotic bacteria. In silico analysis of the L. acidophilus NCFM genome sequence revealed the presence of a putative cell surface protein that was predicted to be a myosin cross-reactive antigen (MCRA). As MCRAs are conserved among many probiotic bacteria, we used the upp-based counterselective gene replacement system, designed recently for use in L. acidophilus, to determine the functional role of this gene (LBA649) in L. acidophilus NCFM. Phenotypic assays were undertaken with the parent strain (NCK1909) and deletion mutant (NCK2015) to assign a function for this gene. The growth of NCK2015 (DeltaLBA649) was reduced in the presence of lactate, acetate, porcine bile and salt. Adhesion of NCK2015 to Caco-2 cells was substantially reduced for both stationary-phase (~45 % reduction) and exponential-phase cells (~50 % reduction). Analysis of NCK2015 by scanning electron microscopy revealed a longer cell morphology after growth in MRS broth compared to NCK1909. These results indicate a role for LBA649 in stress tolerance, cell wall division and adherence to Caco-2 cells. PMID- 20829295 TI - National health spending projections: the estimated impact of reform through 2019. AB - This paper presents updated national health spending projections for 2009-2019 that take into account recent comprehensive health reform legislation and other relevant changes in law and regulations. Relative to our February 2010 projections under prior law, average annual growth in national health spending over the projection period is estimated to be 0.2 percentage point higher than our previous estimate. The health care share of gross domestic product (GDP) is expected to be 0.3 percentage point higher in 2019. Within these net overall impacts are larger differences for trends in spending and spending growth by payer, attributable to reform's many major changes to health care coverage and financing. PMID- 20829294 TI - Muscle performance and physical function are associated with voluntary rate of neuromuscular activation in older adults. AB - BACKGROUND: Muscle power is related to mobility function in older adults, and effective power production requires rapid neuromuscular activation. Accordingly, this study examines the association of neuromuscular activation rate with muscle performance in persons of different age and mobility function. METHODS: Participants were recruited to three experimental groups: middle-aged healthy adults (MH), older healthy adults (OH), and older adults with mobility limitations (OML). OH and OML were primarily differentiated by performance on the Short Physical Performance Battery (SPPB). Muscle performance (acceleration and power) and electromyography (EMG) were recorded during a maximal-effort leg press task at an absolute resistance (260 N) and at a relative resistance (70% of the one-repetition maximum [1 RM]). Neuromuscular activation rate was quantified as pre-movement time (duration between EMG onset and movement onset) and the rate of EMG rise. RESULTS: Pre-movement time, rate of EMG rise, leg press acceleration, and leg press power were lower in OML relative to MH and OH but did not differ between OH and MH, with the exception of power at 70% 1RM. Across all older participants, rate of EMG rise was positively associated with acceleration, power, and the SPPB score. CONCLUSIONS: Slowing of neuromuscular activation rate is associated with compromised dynamic muscle performance, which may contribute to mobility limitations in some older adults. Future research should identify the precise neurophysiological impairments that contribute to declines in neuromuscular activation rate and mobility function with aging. PMID- 20829296 TI - Truancy, alcohol use and alcohol-related problems in secondary school pupils in Norway. AB - This study focuses on a vulnerable group of pupils often missed by mainstream school surveys. It explores alcohol use and alcohol-related problems for a sample of truants of secondary school age, comparing behaviours with a school-based sample from the same geographical area. Analyses are based on a survey among truants (n = 107) and a school survey (n = 3702) undertaken in Bergen, Norway. When compared with mainstream pupils, the truants reported an earlier alcohol debut and a higher frequency of drinking. They reported significantly higher levels of binge drinking (6+ units). Truants were four times more likely to report regular drunkenness and twice as likely to report problems associated with their alcohol consumption. In the truancy sample, boys were more likely to engage in regular and excessive drinking, while girls reported higher levels of problems linked to their drinking. Results suggest that higher levels of truancy were related to more frequent drinking, drunkenness and alcohol-related problems. There are strong indications for early intervention activities directed at truants, and registration of truancy in itself could be a simple and effective way of identifying pupils at risk of a wide range of social and health problems, including high levels of alcohol use. PMID- 20829297 TI - 'These things don't happen in Greece': a qualitative study of Greek young people's attitudes to smoking, secondhand smoke and the smokefree legislation. AB - Greece has the highest smoking prevalence in the European Union, with adolescents having high levels of exposure to secondhand smoke (SHS). In July 2009, national smokefree legislation was implemented in Greece. This study explored Greek young people's attitudes to smoking, SHS and the impending legislation. Semi-structured qualitative interviews were undertaken with 11 groups of 14- to 16-year-old smokers and non-smokers in May and June 2009. Participants described social worlds in which smoking and exposure to SHS were viewed as normal and acceptable. There was little awareness of the health risks of SHS. Smoking was perceived to be both an inherent part of socializing and highly addictive. The 'right' to smoke in public places was thus viewed as greater than that of not being exposed to SHS. There was limited awareness of the impending smokefree legislation. Participants drew on their experience of previous legislation, the perceived rebellious Greek character, and their cynicism about the government in concluding that the legislation would be ineffective. The perceived social norms around smoking and SHS combined with a poor understanding of the health risks and negative attitudes about the impending legislation help to explain the subsequent limited impact of the Greek smokefree legislation. PMID- 20829299 TI - Investigating secondary hyperhidrosis. PMID- 20829298 TI - Objectively measured physical capability levels and mortality: systematic review and meta-analysis. AB - OBJECTIVE: To do a quantitative systematic review, including published and unpublished data, examining the associations between individual objective measures of physical capability (grip strength, walking speed, chair rising, and standing balance times) and mortality in community dwelling populations. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Relevant studies published by May 2009 identified through literature searches using Embase (from 1980) and Medline (from 1950) and manual searching of reference lists; unpublished results were obtained from study investigators. STUDY SELECTION: Eligible observational studies were those done in community dwelling people of any age that examined the association of at least one of the specified measures of physical capability (grip strength, walking speed, chair rises, or standing balance) with mortality. DATA SYNTHESIS: Effect estimates obtained were pooled by using random effects meta-analysis models with heterogeneity between studies investigated. RESULTS: Although heterogeneity was detected, consistent evidence was found of associations between all four measures of physical capability and mortality; those people who performed less well in these tests were found to be at higher risk of all cause mortality. For example, the summary hazard ratio for mortality comparing the weakest with the strongest quarter of grip strength (14 studies, 53 476 participants) was 1.67 (95% confidence interval 1.45 to 1.93) after adjustment for age, sex, and body size (I(2)=84.0%, 95% confidence interval 74% to 90%; P from Q statistic <0.001). The summary hazard ratio for mortality comparing the slowest with the fastest quarter of walking speed (five studies, 14 692 participants) was 2.87 (2.22 to 3.72) (I(2)=25.2%, 0% to 70%; P=0.25) after similar adjustments. Whereas studies of the associations of walking speed, chair rising, and standing balance with mortality have only been done in older populations (average age over 70 years), the association of grip strength with mortality was also found in younger populations (five studies had an average age under 60 years). CONCLUSIONS: Objective measures of physical capability are predictors of all cause mortality in older community dwelling populations. Such measures may therefore provide useful tools for identifying older people at higher risk of death. PMID- 20829302 TI - Cancer survival rates are improving but regional disparities remain across England. PMID- 20829305 TI - The simultaneous repression of CCR and CAD, two enzymes of the lignin biosynthetic pathway, results in sterility and dwarfism in Arabidopsis thaliana. AB - Cinnamoyl CoA reductase (CCR) and cinnamyl alcohol dehydrogenase (CAD) catalyze the last steps of monolignol biosynthesis. In Arabidopsis, one CCR gene (CCR1, At1g15950) and two CAD genes (CAD C At3g19450 and CAD D At4g34230) are involved in this pathway. A triple cad c cad d ccr1 mutant, named ccc, was obtained. This mutant displays a severe dwarf phenotype and male sterility. The lignin content in ccc mature stems is reduced to 50% of the wild-type level. In addition, stem lignin structure is severely affected, as shown by the dramatic enrichment in resistant inter-unit bonds and incorporation into the polymer of monolignol precursors such as coniferaldehyde, sinapaldehyde, and ferulic acid. Male sterility is due to the lack of lignification in the anther endothecium, which causes the failure of anther dehiscence and of pollen release. The ccc hypolignified stems accumulate higher amounts of flavonol glycosides, sinapoyl malate and feruloyl malate, which suggests a redirection of the phenolic pathway. Therefore, the absence of CAD and CCR, key enzymes of the monolignol pathway, has more severe consequences on the phenotype than the individual absence of each of them. Induction of another CCR (CCR2, At1g80820) and another CAD (CAD1, At4g39330) does not compensate the absence of the main CCR and CAD activities. This lack of CCR and CAD activities not only impacts lignification, but also severely affects the development of the plants. These consequences must be carefully considered when trying to reduce the lignin content of plants in order to facilitate the lignocellulose-to-bioethanol conversion process. PMID- 20829306 TI - Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. AB - Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naive patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas. PMID- 20829307 TI - Anti-amnesic and neuroprotective potentials of the mixed muscarinic receptor/sigma 1 (sigma1) ligand ANAVEX2-73, a novel aminotetrahydrofuran derivative. AB - Tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2 73) binds to muscarinic acetylcholine and sigma(1) (sigma(1)) receptors with affinities in the low micromolar range. We characterized its anti-amnesic and neuroprotective potentials in pharmacological and pathological amnesia models. Spatial working memory was evaluated using spontaneous alternation in the Y-maze and non-spatial memory using passive avoidance procedures. ANAVEX2-73 (0.01-3.0 mg/kg i.p.) alleviated the scopolamine- and dizocilpine-induced learning impairments. ANAVEX2-73 (300 ug/kg) also reversed the learning deficits in mice injected with Abeta(25-35) peptide, a non-transgenic Alzheimer's disease model. When the drug was injected simultaneously with Abeta(25-35), 7 days before the tests, it blocked the appearance of learning impairments. This protective activity was confirmed since ANAVEX2-73 blocked the Abeta(25-35)-induced oxidative stress in the hippocampus. This effect was differentially sensitive to the muscarinic receptor antagonist scopolamine or the sigma(1) protein antagonist BD1047, confirming the mixed muscarinic/sigma(1) pharmacological action. Finally, its unique demethyl metabolite, ANAVEX19-144, was also effective and ANAVEX2-73 presented a longer duration of action, effective 12 h before Abeta(25-35), than its related compound ANAVEX1-41. The neuroprotective activity of ANAVEX2-73, its mixed cholinergic/sigma(1) activity, its low active dose range and its long duration of action together reinforce its therapeutic potential in Alzheimer's disease. PMID- 20829308 TI - Effects of antidepressant drug treatment and psychotherapy on striatal and thalamic dopamine D2/3 receptors in major depressive disorder studied with [11C]raclopride PET. AB - Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D(2/3) receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D(2/3) receptor binding was quantified before and after treatment as the binding potential (BP (ND)) using [(11)C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D(2/3) receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [(11)C]raclopride BP (ND) in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored. PMID- 20829309 TI - Factors influencing the health related quality of life in patients with systemic lupus erythematosus: long-term results (2001--2005) of patients in the German Lupus Erythematosus Self-Help Organization (LULA Study). AB - The aim of this longitudinal study was to determine disease-specific and individual factors associated with health-related quality of life (HRQOL) in a cohort of patients with systemic lupus erythematosus (SLE) organized in the German Lupus Erythematosus Self-Help Organization. Three hundred and seventeen patients aged between 11 and 77 years participated annually in five surveys carried out between 2001 and 2005. Regression analyses were carried out for physical and mental HRQOL as dependent variables. Factors influencing HRQOL were the respective HRQOL scores of the previous year, SLE activity as measured by the Systemic Lupus Activity Questionnaire (SLAQ), and impairments in everyday life. Social support indicated by living in marriage or in a marriage-like partnership had a positive influence on both mental and physical HRQOL, whereas individual factors such as education seemed to be of minor importance. PMID- 20829310 TI - Polymorphisms of PXK are associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in Chinese mainland population. AB - Systemic lupus erythematosus (SLE) is a complex immune disease. The genetic variation in the PXK gene was found to associate with SLE in Caucasian populations. However, the association of rs6445975 with SLE has not been extensively studied in a Chinese mainland population. A total of 288 SLE patients and 357 controls were recruited. Unlabeled probe-based high-resolution melting analysis (HRMA) was used in genotyping. HRMA with unlabeled probe successfully distinguished all genotypes. Neither genotype nor allele frequencies of SNP rs6445975 showed statistically significant differences between SLE patients and controls. The association of SNP rs6445975 with the diagnostic criteria of SLE was also examined. No obvious association was observed between rs6445975 and the incidence of clinical symptoms. However, the minor allele (G) of rs6445975 was found to significantly associate with increased abnormalities of anti-Smith (p = 0.004, odds ratio (OR) = 1.95, 95% confidence interval (CI) = 1.22-3.09), anti-Ro (p = 0.015, OR = 1.69, 95% CI = 1.10-2.58), anti-La (p = 0.008, OR = 1.86, 95% CI = 1.17-2.93) and C3C4 (p = 0.007, OR = 1.79, 95% CI = 1.17-2.74). Polymorphisms of rs6445975 in the PXK gene were associated with autoantibody production, but not disease risk, of systemic lupus erythematosus in a Chinese population. PMID- 20829311 TI - The role of socio-economic position in predicting orthodontic treatment outcome at the end of 1 year of active treatment. AB - Socio-economic position (SEP) has not been tested as a predictor of orthodontic treatment outcome. This study aimed to determine whether SEP can predict orthodontic treatment outcome at the end of 1 year of active treatment. A hospital-based, prospective longitudinal design was adopted including 145 consecutively selected 12- to 16-year-old males and females. Patients were followed-up on a monthly basis during their orthodontic treatment with fixed appliances. After 1 year of treatment, orthodontic treatment outcome was assessed as the amount of improvement in occlusion achieved. Logistic regression analysis was used. The response rate was 98.6 per cent and the dropout was 5.6 per cent. Adolescents whose mothers were from a low social class were less likely to achieve a high improvement in occlusion than those whose mothers were from a high social class [odds ratio (OR) = 0.1; 95 per cent confidence interval (CI) = 0.01 0.97; P = 0.047). Adolescents from a low household social class were less likely to achieve a high improvement in occlusion compared with their counterparts from a high household social class (OR = 0.2; 95 per cent CI = 0.07-0.79; P = 0.019). The father's social class, parental education, and employment status were not significantly associated with improvement in occlusion (P > 0.05). The regression model confirmed the significance of maternal and household social class as predictors of orthodontic treatment outcome at the end of 1 year of active treatment. PMID- 20829312 TI - Association between intraoral pressure and molar position and inclination in subjects with facial asymmetry. AB - Although it has been suggested that an imbalance in buccolingual pressure may play a role in dental compensation of the molars and asymmetry in the mandibular dental arch in subjects with facial asymmetry, it is still unclear whether buccolingual pressure is associated with this phenomenon. Thus, the purpose of this study was to test the null hypothesis that there are no differences in cheek and tongue pressure between the shifted and non-shifted sides in 12 (8 females and 4 males, mean age: 24.9 years) subjects with facial asymmetry defined as 4 mm or more deviation of the midline in the mandibular incisors. The resting buccolingual pressure on the bilateral mandibular first molars was measured simultaneously using four miniature pressure sensors. Moreover, a postero anterior (PA) cephalogram was used to determine the buccolingual positions and the inclination of the mandibular first molars. Wilcoxon t-, Kruskal-Wallis H-, and Mann-Whitney U-tests and Spearman correlation coefficient by rank were used for statistical analysis. Significance was set at P < 0.05. Cheek pressure was significantly greater on the shifted than that on the non-shifted side, while tongue pressure on the shifted side was significantly less than that on the non shifted side. On the other hand, tongue/cheek pressure ratio on the shifted side was significantly less than that on the non-shifted side. There were significant differences between the shifted and non-shifted sides in the buccolingual positions and inclination of the mandibular first molars. Regardless of the side, there were significant negative correlations between the buccolingual position of the mandibular first molars and cheek pressure and significant positive correlations between the buccolingual position of the mandibular first molars and tongue/cheek pressure ratio. There were also significant negative correlations between tongue/cheek pressure ratio and inclination of the mandibular first molars on both the shifted and the non-shifted sides. Thus, the present findings reject the null hypothesis. The imbalance in buccolingual pressure in subjects with facial asymmetry appears to be related to dental compensation of the molars and mandibular asymmetry. PMID- 20829313 TI - Keratopathy: white patches, clear dots and grey lines. PMID- 20829314 TI - Macular edema associated with hydrochlorothiazide therapy. PMID- 20829315 TI - Investigation of the potential of polymer therapeutics in corneal re epithelialisation. AB - In this study, the first use of a bioresponsive polymer therapeutic agent in the promotion of corneal re-epithelialisation after injury in an ex vivo whole-eye organ culture model was described. A polymer-protein conjugate consisting of dextrin and recombinant human epidermal growth factor was synthesised and applied as a single dose to a 2 mm ex vivo corneal ulcer, in culture. Enhanced wound healing was observed in response to dextrin-recombinant human epidermal growth factor, when exposed to alpha-amylase, compared with controls. This highlights the potential for polymer therapeutics to provide a platform for bioresponsive drug/protein delivery in the field of ophthalmology. PMID- 20829316 TI - Axial elongation following prolonged near work in myopes and emmetropes. AB - BACKGROUND/AIMS: To investigate the influence of a period of sustained near work upon axial length in groups of emmetropes (EMM) and myopes. METHODS: Forty young adult subjects (20 myopes and 20 emmetropes) were recruited for the study. Myopes were further classified as early onset (EOM), late onset (LOM), stable (SM) or progressing (PM) subgroups. Axial length was measured with the IOLMaster instrument before, immediately after and then again 10 min after a continuous 30 min near task of 5 D accommodation demand. Measures of distance objective refraction were also collected. RESULTS: Significant changes in axial length were observed immediately following the near task. EOM axial length elongated on average by 0.027+/-0.021 mm, LOM by 0.014+/-0.020 mm, EMM by 0.010+/-0.015 mm, PM by 0.031+/-0.022 mm and SM by 0.014+/-0.018 mm. At the conclusion of the 10 min regression period, axial length measures were not significantly different from baseline values. CONCLUSION: Axial elongation was observed following a prolonged near task. Both EOM and PM groups showed increases in axial length that were significantly greater than emmetropes. PMID- 20829317 TI - Incontinentia pigmenti--ophthalmological observation of a series of cases and review of the literature. AB - AIM: The aims of this study were to make an inventory of the disease in Ireland, to acquire better knowledge of the relationship between genetic makeup and phenotypic ocular presentation and, finally, through literature review and personal experience, to establish clear guidelines on best practice in the management of children with this rare condition both in terms of screening and follow-up. METHODS: All patients who attended the dermatology and genetic clinic in Our Lady's Hospital for Sick Children, Crumlin, with incontinentia pigmenti (IP) were contacted and invited to attend the eye clinic for ocular assessment. Children who were already attending the ophthalmic services before commencement of the study had their charts reviewed for assessment. RESULTS: 11 of 19 patients agreed to attend the clinic for ocular assessment. Of these patients, nine had genetic testing. The mean age of the patients at the examination was 8 years (3 months to 29 years). In 10 patients, IP was the result of a spontaneous mutation, whereas the condition was inherited from an affected mother in one patient. Of the 11 patients with IP, 5 have visually significant ocular findings (47%). We describe the case history of four of these children briefly to outline the severity of this condition. CONCLUSION: Our patients had a significant percentage of ocular abnormalities (47%). We have outlined an examination schedule for patients with and without retinal pathology and recommend fluorescein angiography in patients with retinal pathology to fully determine the extent of ischaemia. Like other studies, early treatment with peripheral retinal photocoagulation to reduce the risk of retinal detachment is recommended in this study. PMID- 20829318 TI - Visual acuity outcomes after deep anterior lamellar keratoplasty: a case-control study. AB - AIM: To compare visual outcomes between deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PK). Secondarily to compare refractive outcomes, complications and graft survival between the three cohorts. METHODS: Retrospective case-control study evaluating visual acuity outcomes (VA) following DALK with complete Descemet's baring (DALKa) (modified Anwar big bubble technique -51 eyes), pre-descemetic anterior lamellar keratoplasty (DALKm) (manual technique--52 eyes) and PK (103 eyes) with mean follow-up of 13.6, 19.3 and 18.6 months, respectively. RESULTS: The common indications for surgery were corneal scars (36.4%), keratoconus (28.6%) and corneal dystrophies (13.6%). A best corrected VA of 6/7.5 or better was achieved in 19.4% (PK), 21.6% (DALKm) and 38.5% (DALKa) of cases (p=0.02), and eyes that underwent DALKa had significantly better visual outcomes than PK (p=0.03). Complications following PK were glaucoma (15%), endothelial rejection (12%) and epithelial problems (11%); in the lamellar group, glaucoma (9%), epithelial problems (5%) and Descemet's detachment (3%) were more common. The 2-year estimated probability of graft survival was 90% for PK, 98% for DALKm and 100.0% for DALKa (p=0.35). CONCLUSIONS: Lamellar keratoplasty with complete baring of the Descemet's membrane (DALKa) gave significantly better visual outcomes compared to PK or pre-descemetic ALK and should be the preferred from of corneal replacement in corneal disorders with healthy endothelium. PMID- 20829319 TI - Combined arteriovenous sheathotomy and intraoperative intravitreal triamcinolone acetonide for branch retinal vein occlusion. AB - PURPOSE: To describe the treatment of macular oedema secondary to branch retinal vein occlusion (BRVO) with concomitant pars plana vitrectomy/arteriovenous sheathotomy and intraoperative intravitreal triamcinolone acetonide. METHODS: Retrospective case series. RESULTS: Four eyes of four patients were identified. Patients improved from a mean best-corrected visual acuity of 20/124 at baseline to 20/122 at month 1, 20/83 at month 3, 20/74 at month 6, 20/59 at month 9 and 20/44 at month 12 (p = 0.01). All patients demonstrated improvement in visual acuity and macular oedema on fluorescein angiography and/or optical coherence tomography (OCT). CONCLUSION: For patients with persistent macular oedema due to BRVO refractory to pharmacotherapy and/or laser photocoagulation, concomitant pars plana vitrectomy with arteriovenous sheathotomy and intravitreal triamcinolone may improve best-corrected acuity and reduce macular oedema on fluorescein angiography and OCT. PMID- 20829320 TI - Nitrous oxide cryotherapy for primary periocular basal cell carcinoma: outcome at 5 years follow-up. AB - AIM: To report the outcome at 5-year follow-up of a defined series of patients with primary periocular basal cell carcinoma treated by cryotherapy using a nitrous oxide probe. METHODS: A prospective, non-comparative, interventional case series. One hundred primary periocular basal cell carcinomas were treated with a double freeze-thaw cycle nitrous oxide contact cryotherapy probe. Inclusion criteria were clinically well-defined primary periocular basal cell carcinomas with maximum diameter of 8 mm. The main outcome measure was histologically proven recurrence rate at 5-year follow-up. RESULTS: Kaplan-Meier survival analysis showed a 5-year recurrence rate of 8%. Cox regression analysis revealed no correlation between tumour site, tumour size, cryotherapy freeze time and recurrence (p=0.60, p=0.86 and p=0.71, respectively). Thirty-six per cent of patients were lost to follow-up at 5 years following treatment. CONCLUSION: The results of this series suggest that nitrous oxide probe cryotherapy for primary periocular basal cell carcinomas up to 8 mm diameter has a recurrence rate of ~8%. Cryotherapy has certain advantages over surgical removal of tumours of this size in the periocular region, but careful follow-up is advisable. PMID- 20829321 TI - Comparing rates of retinal nerve fibre layer loss with GDxECC using different methods of visual-field progression. AB - BACKGROUND: This prospective analysis was designed to examine the rate of RNFL loss using scanning laser polarimetry (GDx enhanced corneal compensation (GDxECC)) in progressing versus non-progressing eyes using various methods to define functional progression. METHODS: Glaucoma suspect and glaucomatous eyes with >=3 years of follow-up participating in the Advanced Imaging for Glaucoma Study were enrolled. All eyes underwent standard automated perimetry (SAP) and GDxECC imaging every 6 months. The annual rate of RNFL loss with GDxECC was calculated using linear regression analysis. Functional progression was determined using the Early Manifest Glaucoma Trial (EMGT) criterion, SAP Visual Field Index (VFI) and Progressor software. RESULTS: Fifty-three eyes (30 glaucoma suspect, 23 glaucoma) of 53 patients (mean age 64.5+/-10.7 years, range 42-79) were enrolled. Eighteen eyes (40%) demonstrated SAP progression during the follow up period using the Progressor criterion, 10 eyes (18.9%) using the VFI criterion, and 3 eyes (5.7%) using the EMGT criterion. The annual rate (MUm/year) of mean RNFL loss was significantly greater (p<0.05) in progressing versus non progressing eyes using Progressor (-1.24+/-0.99 vs -0.18+/-0.49), EMGT (-1.95+/ 0.99 vs -0.46+/-0.78) and VFI (-1.11+/-0.64 vs -0.41+/-0.85) criteria. CONCLUSION: Despite differences in the criteria used to judge functional progression, progressing eyes have a significantly greater rate of RNFL loss measured using GDxECC as compared with non-progressing eyes. PMID- 20829322 TI - Cognitive profile of elders in an ophthalmic ambulatory setting. AB - AIMS: To assess the potential association between vision and cognition in an ambulatory older population. METHODS: A sample of 84 adults aged 65 and older seeking non-emergent ophthalmic care. Participants were interviewed with the Mini Mental State Examination (MMSE) during their regular scheduled visit. RESULTS: The average individual was a 78-year-old female, with at least a high school diploma and mildly affected vision (logMAR 0.27). Vision and cognition scores were unrelated (Pearson=-0.09, p=0.41). An MMSE<24 (out of 30) was found in 19% of individuals. A score of 16 in the MMSE(blind) (out of 22) identified 14 (88%) of them. Memory was the most frequently affected component (13 patients, 81%), and recall the most frequently involved item (nine patients, 56%). More individuals (16-26%) with moderate to severe vision impairment (logMAR 0.6 to 1.3) tended to have psychomotor and concentration deficiencies and fewer (14%) memory problems compared with those with normal vision or mild impairment (logMAR -0.3 to 0.5). Language was uniformly affected across levels of vision impairment. CONCLUSIONS: An absent relationship between cognition and vision based on overall scores of standard instruments does not preclude the existence of such association as characterised by more comprehensive measures, and thus greater vision impairment may confer some cognitive ageing in specific abilities. PMID- 20829323 TI - Writing migrants back into NHS history: addressing a 'collective amnesia' and its policy implications. PMID- 20829324 TI - Seventh nerve palsy as a false localizing sign in benign intracranial hypertension. PMID- 20829325 TI - Relationship between smoking reduction and cessation among light smokers. AB - INTRODUCTION: To determine the smoking reduction patterns of light smokers (<= 10 CPD) and whether reduction predicts future cessation. METHODS: Study is a secondary analysis of data that were derived from a 2 * 2 randomized study that assessed the efficacy of nicotine gum (vs. placebo) and counseling (motivational interviewing vs. health education) for smoking cessation among 755 light smokers. Participants were categorized into three groups based on self-reported CPD smoked at time of study enrollment compared with CPD smoked a year prior to enrollment. That is, (a) those who reduced number of cigarettes per day (CPD), (b) those who smoked the same number of CPD, and (c) those who increased their number of CPD. Sociodemographic and smoking characteristics were assessed at enrollment as well as cotinine-verified 7-day smoking abstinence rates at the Week 26 follow-up assessment. A stepwise logistic regression model to predict the probability abstinence at 26-week follow-up was also performed. RESULTS: Compared with a year prior to enrollment, 43.7% of participants reduced, 35.2% smoked the same, and 21.2% increased their CPD. Compared with those who smoked the same or increased their CPD, those who had reduced their CPD were older, more likely to be males, smoked fewer CPD at enrollment, initiated smoking at a younger age, and less likely to be nicotine dependent. Adjusted logistic regression showed that those who had reduced their smoking prior to enrollment were more likely to quit at Week 26 (odds ratio [OR] = 1.77; 95% CI = 1.062-2.957; p = .029). DISCUSSION: Findings suggest that reducing number of CPD smoked prior to enrolling in a clinical trial is a positive predictor of abstinence. Therefore, encouraging smoking reduction prior to attempting cessation may enhance cessation outcomes for light smokers. PMID- 20829326 TI - Cognitive reappraisal and expressive suppression emotion regulation strategies in cigarette smokers. AB - INTRODUCTION: Negative affect is an important psychological factor in the promotion and maintenance of cigarette smoking, though the underlying factors that account for this relationship remain to be determined. One possible mechanism may be smokers' emotion regulation strategies. Preliminary research among adolescents and young adults suggests that greater utilization of expressive suppression versus cognitive reappraisal is associated with higher rates of smoking initiation. There is limited research, however, on the role of emotion regulation strategies in smoking maintenance in adult smokers. METHODS: Data from participants in a laboratory study (N = 121) were used to examine whether utilization of cognitive reappraisal and/or expressive suppression were related to smoking characteristics and subjective (i.e., mood, urge to smoke ratings) and behavioral reactions (i.e., Emotional Stroop Task performance, smoking behavior) to a mood induction procedure. Data were evaluated for the full sample and subsample who endorsed current depressive symptoms (n = 46). RESULTS: Frequent reappraisal was associated with weaker expectancies that smoking alleviates unpleasant feelings, greater positive mood, and fewer depressive symptoms. In contrast, frequent suppression was related to longer smoking history and greater attentional bias to smoking cues on an Emotional Stroop Task. Among the depressed subsample, reappraisal moderated the effect of mood condition on smoking duration, number of cigarette puffs, and carbon monoxide boost. CONCLUSIONS: These results provide preliminary support that emotion regulation strategies may be associated with motivational correlates of smoking as well as actual smoking behavior among depressed smokers. PMID- 20829327 TI - Nicotine gum dependence treated with varenicline--a case report. AB - INTRODUCTION: The buccal absorption of nicotine replacement therapy is a part of the treatment to quit smoking. In some cases, this use could last more than six months. METHODS AND RESULTS: We report the case of a woman, former smoker, who took nicotine gums for over five years and was treated successfully with Varenicline during six months according to the recommended posology. DISCUSSION: Varenicline, a partial alpha 4 beta 2 nicotinic receptor agonist, could be a solution to help former smokers to stop long-term use of nicotine gums or lozenges. Further studies will be necessary to confirm this result. PMID- 20829328 TI - Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. AB - PURPOSE: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood-tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. EXPERIMENTAL DESIGN: Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. RESULTS: Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C-paclitaxel and 14C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (~10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin. CONCLUSIONS: This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. PMID- 20829329 TI - Evaluation of a 30-gene paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide chemotherapy response predictor in a multicenter randomized trial in breast cancer. AB - PURPOSE: We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FACx6 preoperative chemotherapy. We also did an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms. EXPERIMENTAL DESIGN: Two hundred and seventy-three patients were randomly assigned to receive either weekly paclitaxel * 12 followed by FAC * 4 (T/FAC, n = 138), or FAC * 6 (n = 135) neoadjuvant chemotherapy. All patients underwent a pretreatment fine-needle aspiration biopsy of the tumor for gene expression profiling and treatment response prediction. RESULTS: The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (P < 0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% [95% confidence interval (95% CI), 21-56%], the negative predictive value was 88% (95% CI, 77-95%), and the area under the receiver operating characteristic curve (AUC) was 0.711. In the FAC arm, the PPV was 9% (95% CI, 1-29%) and the AUC was 0.584. This suggests that the genomic predictor may have regimen specificity. Its performance was similar to a clinical variable based predictor nomogram. CONCLUSIONS: Gene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next-generation predictive markers will need to be developed separately for different molecular subsets of breast cancers. PMID- 20829330 TI - New strategies in ovarian cancer: uptake and experience of women at high risk of ovarian cancer who are considering risk-reducing salpingo-oophorectomy. AB - Here, we review factors associated with uptake of risk-reducing salpingo oophorectomy by women at increased hereditary risk for ovarian cancer, as well as quality of life issues following surgery. Forty-one research studies identified through PubMed and PsychInfo met inclusion criteria. Older age, having had children, a family history of ovarian cancer, a personal history of breast cancer, prophylactic mastectomy, and BRCA1/2 mutation carrier status increase the likelihood of undergoing surgery. Psychosocial variables predictive of surgery uptake include greater perceived risk of ovarian cancer and cancer-related anxiety. Most women report satisfaction with their decision to undergo surgery and both lower perceived ovarian cancer risk and less cancer-related anxiety as benefits. Hormonal deprivation is the main disadvantage reported, particularly by premenopausal women who are not on hormonal replacement therapy (HRT). The evidence is mixed about satisfaction with the level of information provided prior to surgery, although generally, women report receiving insufficient information about the pros and cons of HRT. These findings indicate that when designing decision aids, demographic, medical history, and psychosocial variables need to be addressed in order to facilitate quality decision making. PMID- 20829331 TI - PF-03732010: a fully human monoclonal antibody against P-cadherin with antitumor and antimetastatic activity. AB - PURPOSE: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models. EXPERIMENTAL DESIGN: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated. RESULTS: PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB 435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3'-[(18)F]fluoro-3' deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane beta-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3'-[(18)F]fluoro-3' deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts. CONCLUSIONS: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials. PMID- 20829332 TI - Simulation training improves diagnostic performance on a real patient with similar clinical findings. AB - BACKGROUND: Training on a cardiopulmonary simulator improves subsequent diagnostic performance on the same simulator. But data are lacking on transfer of learning. The objective of this study was to determine whether training on a cardiorespiratory simulator improves diagnostic performance on a real patient. METHODS: We randomly allocated first-year medical students at the University of Calgary to simulator training in one of three clinical scenarios of acute-onset chest pain: pulmonary embolism with right ventricular strain but no murmur, symptomatic aortic stenosis, or myocardial ischemia causing mitral regurgitation. Simulation sessions ran for 20 min, after which participants had a standardized debriefing session and reviewed the physical findings. Immediately following the training sessions, students assessed the auscultatory findings of a real patient with mitral regurgitation. Our outcome measures were accuracy of identifying abnormal auscultatory findings and diagnosing the underlying cardiac abnormality (mitral regurgitation). RESULTS: Eighty-six students participated in the study. Students trained on mitral regurgitation were more likely to identify and diagnose these findings on a real patient with mitral regurgitation than those who had trained on aortic stenosis or a scenario with no cardiac murmur. The accuracy (SD) of identifying clinical features of mitral regurgitation for these three groups was 74.0 (36.4) vs 56.2 (34.3) vs 36.8 (33.1), respectively (P = .0005), and for diagnosing mitral regurgitation, the accuracy was 68.0 (45.4) vs 51.6 (50.0) vs 29.9 (40.7), respectively (P = .01). CONCLUSIONS: Simulator training on mitral regurgitation increases the likelihood of diagnosing this abnormality on a real patient. PMID- 20829333 TI - Increased expression of growth differentiation factor-15 in systemic sclerosis associated pulmonary arterial hypertension. AB - BACKGROUND: Growth differentiation factor (GDF)-15 is a secreted member of the transforming growth factor-beta cytokine superfamily. GDF-15 levels are elevated in the serum of patients with cardiovascular diseases. We hypothesized that GDF 15 levels would also be increased in the plasma and lung tissue of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). METHODS: GDF-15 levels were measured in plasma in subjects with SSc-PAH (n = 30) and compared with subjects with systemic sclerosis (SSc) without pulmonary arterial hypertension (PAH) (n = 24). Patients with idiopathic PAH (IPAH) (n = 44) and normal individuals (n = 13) served as control subjects. Immunohistochemistry and immunofluorescence assay identified GDF-15 protein in lung tissue from patients with SSc-PAH and IPAH. RESULTS: Patients with SSc-PAH had significantly higher mean circulating levels of GDF-15 in plasma compared with patients with SSc without PAH (422.3 +/- 369.5 pg/mL vs 108.1 +/- 192.8 pg/mL, P = .004). GDF-15 levels correlated positively with estimated right ventricular systolic pressure on echocardiogram and plasma levels of the amino terminal propeptide form of brain natriuretic peptide. There was an inverse correlation between circulating GDF-15 and diffusing capacity of the lung for carbon monoxide (Dlco) and a positive correlation with the FVC to Dlco ratio on pulmonary function test. GDF 15 levels > 125 pg/mL were associated with reduced survival. GDF-15 protein expression was increased in lung tissue from patients with SSc-PAH. CONCLUSIONS: GDF-15 may be a useful biomarker in PAH associated with SSc. Its presence in lung tissue may suggest a role in the pathology of the disease. PMID- 20829334 TI - Prognostic significance of nestin expression in resected non-small cell lung cancer. AB - BACKGROUND: Nestin is a class 6 intermediate filament protein expressed in stem/progenitor cells during CNS development. Nestin expression has been detected in many kinds of tumors and was reported in a recent small-scale study in non small cell lung cancer (NSCLC). We investigated the relationships between nestin expression and clinicopathologic parameters and determined its prognostic significance concerning survival in patients with resected NSCLC. METHODS: Nestin expression in tumor cells was studied immunohistochemically in 171 consecutive patients with NSCLC, and associations with clinicopathologic parameters were evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of nestin expression on survival. RESULTS: Nestin expression was observed in tumor cell samples in 27 of the 171 patients with NSCLC (15.8%). Nestin had only cytoplasmic expression. Clinicopathologically, nestin expression was significantly associated with squamous cell carcinoma (P = .001), poorer differentiation (P = .007), lymph node metastasis (P = .008), intratumoral vascular invasion (P = .003), intratumoral lymphatic invasion (P = .008), pleural invasion (P = .039), and poorer prognosis (P < .001). Multivariable analysis confirmed that nestin expression increased the hazard of death after adjusting for other clinicopathologic factors (hazard ratio, 2.75; 95% CI, 1.39-5.46). CONCLUSIONS: The present study suggests that nestin expression is a prognostic indicator of poorer survival probability for patients with resected NSCLC and may be used as a potential marker for select patients who should receive adjuvant chemotherapy. PMID- 20829335 TI - ICU care associated with symptoms of depression and posttraumatic stress disorder among family members of patients who die in the ICU. AB - BACKGROUND: Psychologic symptoms of posttraumatic stress disorder (PTSD) and depression are relatively common among family members of patients who die in the ICU. The patient-level risk factors for these family symptoms are not well understood but may help to target future interventions. METHODS: We performed a cohort study of family members of patients who died in the ICU or within 30 h of ICU transfer. Outcomes included self-reported symptoms of PTSD and depression. Predictors included patient demographics and elements of palliative care. RESULTS: Two hundred twenty-six patients had chart abstraction and family questionnaire data. Family members of older patients had lower scores for PTSD (P = .026). Family members that were present at the time of death (P = .021) and family members of patients with early family conferences (P = .012) reported higher symptoms of PTSD. When withdrawal of a ventilator was ordered, family members reported lower symptoms of depression (P = .033). There were no other patient characteristics or elements of palliative care associated with family symptoms. CONCLUSIONS: Family members of younger patients and those for whom mechanical ventilation is not withdrawn are at increased risk of psychologic symptoms and may represent an important group for intervention. Increased PTSD symptoms among family members present at the time of death may reflect a closer relationship with the patient or more involvement with the patient's ICU care but also suggests that family should be offered the option of not being present. PMID- 20829336 TI - Hospital-acquired pneumonia after lung resection surgery is associated with characteristic cytokine gene expression. AB - BACKGROUND: Infection in humans has been linked with altered cytokine gene transcription. It is unclear whether this phenomenon is a consequence of an established disease process or precedes the infective process. The primary end point of this study was to determine whether hospital-acquired pneumonia (HAP) was associated with differential gene expression of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-23p19. The secondary end point was to identify whether alteration in gene expression preceded the clinical onset of infection. METHODS: Sixty consecutive patients undergoing elective thoracic surgery were recruited. HAP was diagnosed as per National Nosocomial Infection Surveillance guidelines. Messenger RNA (mRNA) and protein levels were analyzed preoperatively and 24 h and 5 days postoperatively. RESULTS: Forty-one patients had an uncomplicated recovery. Nineteen patients developed HAP. IL-6, IL-10, IL 12p35, IL-23p19, IL-27p28, TNF-alpha, and IFN-gamma mRNA and protein levels of IL 6, IL-23, and IFN-gamma in peripheral blood leukocytes were analyzed before surgery and 24 h and 5 days postsurgery. IL-23p19 mRNA levels were reduced in the pneumonia group (median, 4.19; 10th-90th centile range, 3.90-4.71) compared with the nonpneumonia group (4.50; 3.85-5.32) day 1 postsurgery (P=02). IFN-gamma mRNA levels were reduced in the pneumonia group (2.48; 1.20-3.20) compared with nonpneumonia group (2.81; 2.10-3.26) (P=03) day 5 postsurgery. Results are expressed as log to base 10 copy numbers of cytokine mRNA per 10 million beta actin mRNA copy numbers. All values are given as median and 10th to 90th centile range. CONCLUSIONS: Cytokine gene expression is altered immediately following surgery in patients with postoperative HAP. PMID- 20829337 TI - A call for high-quality advance care planning in outpatients with severe COPD or chronic heart failure. AB - BACKGROUND: Patients with severe COPD or chronic heart failure (CHF) are often confronted with decisions concerning life-sustaining treatments. The aim of this prospective, observational study was to assess life-sustaining treatment preferences, advance care planning, and the quality of end-of-life care communication in Dutch outpatients with clinically stable but severe COPD or CHF. METHODS: The following outcomes were assessed in outpatients with severe COPD (n = 105) or CHF (n = 80): life-sustaining treatment preferences (CPR and mechanical ventilation; Willingness to Accept Life-sustaining Treatment instrument), advance care planning, and quality of end-of-life care communication (Quality of Communication questionnaire). RESULTS: Most patients asserted that in their current health status, they would prefer CPR (COPD, 70.5%; CHF, 62.5%) and/or mechanical ventilation (COPD, 70.5%; CHF, 66.3%). Patients' treatment preferences were influenced by burden of treatment, outcome of treatment, and likelihood of outcome. Advance directives were discussed with the physician specialist by 5.9% of patients with COPD and 3.9% of patients with CHF. Patients rated quality of patient-physician end-of-life care communication as poor. Physicians rarely discussed prognosis, dying, and palliative care. CONCLUSIONS: Despite the fact that patients are able to indicate their preferences regarding life-sustaining treatments, based on burden of treatment, outcome of treatment, and likelihood of outcome, these preferences are rarely discussed with their physician specialist. This study shows a need for advance care planning, taking into account the burden of treatment, outcome of treatment, and likelihood of outcome, in patients with severe COPD or CHF. Finally, the quality of patient-physician end-of-life care communication needs to improve. PMID- 20829338 TI - Nontuberculous mycobacterial infection as a cause of difficult-to-control asthma: a case-control study. AB - BACKGROUND: Symptomatic disease due to nontuberculous mycobacteria (NTM) is known to occur commonly in the presence of structural lung disease, but is not described in association with asthma. METHODS: This was a case-control study nested in a cohort. We identified 22 patients with difficult asthma referred to a tertiary academic referral center and subsequently found to have infection with NTM. We matched each case with two control subjects (next two consecutive patients referred for asthma management). RESULTS: It took on average 2.1 years from the onset of new or worsening symptoms to NTM diagnosis. The most common symptoms were worsening cough (77%), sputum production (40.9%), and frequent exacerbations (31.8%). Mycobacterium avium complex accounted for 63.6% of the infections, Mycobacterium xenopi the balance. Case subjects were older (59.8 +/- 8.9 vs 42.6 +/- 18 years; P < .001) and had more severe airflow obstruction (FEV(1), 57% [40%-74%] vs 89.5% [80%-98%]; P < .001). There was no difference between case and control subjects in the proportion using inhaled corticosteroids (ICS) or the average daily dose at the time of presentation, but case subjects had used ICS for a longer period (17 [6.2-20] vs 4 [0.75-6.0] years; P=.002). Six subjects with NTM were being treated with daily oral steroids, whereas none of the control subjects was. Of the 22 cases, 10 were treated with antibiotics for NTM, seven demonstrating clinical improvement or resolution of the presenting symptoms. CONCLUSIONS: NTM infection can be associated with asthma and should be considered in difficult-to-treat disease, especially in older individuals with more severe airflow obstruction and greater exposure to inhaled or systemic corticosteroids. PMID- 20829339 TI - Effects of exercise on respiratory flow and sputum properties in patients with cystic fibrosis. AB - BACKGROUND: The physiologic mechanisms by which exercise may clear secretions in subjects with cystic fibrosis (CF) are unknown. The purpose of this study was to compare ventilation, respiratory flow, and sputum properties following treadmill and cycle exercise with resting breathing (referred to as "control"). METHODS: In 14 adult subjects with CF, ventilation and respiratory flow were measured during 20 min of resting breathing, treadmill exercise, and cycle exercise in a 3-day crossover study. Treadmill and cycle exercise were performed at the work rate equivalent to 60% of the subject's peak oxygen uptake. Ease of expectoration and sputum properties (solids content and mechanical impedance) were measured before and immediately after the interventions and after 20-min recovery. RESULTS: Ease of expectoration improved following exercise. Ventilation and respiratory flow were significantly higher during treadmill and cycle exercise compared with control. Sputum solids content did not change following treadmill or cycle exercise. There was a significantly greater decrease in sputum mechanical impedance following treadmill exercise compared with control, but no significant decrease in sputum mechanical impedance following cycle exercise compared with control. CONCLUSIONS: The improvement in ease of expectoration following exercise may have been due to the higher ventilation and respiratory flow. The reductions in sputum mechanical impedance with treadmill exercise may have been due to the trunk oscillations associated with walking. TRIAL REGISTRY: Australian and New Zealand Clinical Trials Registry; No. 12605000422628; URL: www.anzctr.org.au. PMID- 20829340 TI - Number of lymph nodes harvested from a mediastinal lymphadenectomy: results of the randomized, prospective American College of Surgeons Oncology Group Z0030 trial. AB - BACKGROUND: Lymph node status is a major determinant of stage and survival in patients with lung cancer; however, little information is available about the expected yield of a mediastinal lymphadenectomy. METHODS: The American College of Surgeons Oncology Group Z0030 prospective, randomized trial of mediastinal lymph node sampling vs complete mediastinal lymphadenectomy during pulmonary resection enrolled 1,111 patients from July 1999 to February 2004. Data from 524 patients who underwent complete mediastinal lymph node dissection were analyzed to determine the number of lymph nodes obtained. RESULTS: The median number of additional lymph nodes harvested from a mediastinal lymphadenectomy following systematic sampling was 18 with a range of one to 72 for right-sided tumors, and 18 with a range of four to 69 for left-sided tumors. The median number of N2 nodes harvested was 11 on the right and 12 on the left. A median of at least six nodes was harvested from at least three stations in 99% of patients, and 90% of patients had at least 10 nodes harvested from three stations. Overall, 21 patients (4%) were found to have occult N2 disease. CONCLUSIONS: Although high variability exists in the actual number of lymph nodes obtained from various nodal stations, complete mediastinal lymphadenectomy removes one or more lymph nodes from all mediastinal stations. Adequate mediastinal lymphadenectomy should include stations 2R, 4R, 7, 8, and 9 for right-sided cancers and stations 4L, 5, 6, 7, 8, and 9 for left-sided cancers. Six or more nodes were resected in 99% of patients in this study. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00003831; URL: clinicaltrials.gov. PMID- 20829341 TI - Does a protective ventilation strategy reduce the risk of pulmonary complications after lung cancer surgery?: a randomized controlled trial. AB - BACKGROUND: Protective ventilation strategy has been shown to reduce ventilator induced lung injury in patients with ARDS. In this study, we questioned whether protective ventilatory settings would attenuate lung impairment during one-lung ventilation (OLV) compared with conventional ventilation in patients undergoing lung resection surgery. METHODS: One hundred patients with American Society of Anesthesiology physical status 1 to 2 who were scheduled for an elective lobectomy were enrolled in the study. During OLV, two different ventilation strategies were compared. The conventional strategy (CV group, n=50) consisted of FIO2 1.0, tidal volume (Vt) 10 mL/kg, zero end-expiratory pressure, and volume controlled ventilation, whereas the protective strategy (PV group, n=50) consisted of FIO2 0.5, Vt 6 mL/kg, positive end-expiratory pressure 5 cm H2O, and pressure-controlled ventilation. The composite primary end point included PaO2/FIO2<300 mm Hg and/or the presence of newly developed lung lesions (lung infiltration and atelectasis) within 72 h of the operation. To monitor safety during OLV, oxygen saturation by pulse oximeter (SpO2), PaCO2, and peak inspiratory pressure (PIP) were repeatedly measured. RESULTS: During OLV, although 58% of the PV group needed elevated FIO2 to maintain an SpO2>95%, PIP was significantly lower than in the CV group, whereas the mean PaCO2 values remained at 35 to 40 mm Hg in both groups. Importantly, in the PV group, the incidence of the primary end point of pulmonary dysfunction was significantly lower than in the CV group (incidence of PaO2/FIO2<300 mm Hg, lung infiltration, or atelectasis: 4% vs 22%, P<.05). CONCLUSION: Compared with the traditional large Vt and volume-controlled ventilation, the application of small Vt and PEEP through pressure-controlled ventilation was associated with a lower incidence of postoperative lung dysfunction and satisfactory gas exchange. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: ACTRN12609000861257; URL: www.anzctr.org.au. PMID- 20829342 TI - Intracellular and extracellular free N-glycans produced by plant cells: occurrence of unusual plant complex-type free N-glycans in extracellular spaces. AB - As a part of the study to reveal the biological significance of de-N glycosylation in plants, we analysed the structural features of free N-glycans (FNGs) accumulated inside cells and secreted to the extracellular space using a rice cell culture system. The structural analysis of FNGs obtained from the intracellular fraction revealed that the high-mannose type N-glycans with one GlcNAc residue (GN1-type) occurred at a concentration of ~10 nmol/g, while the truncated complex type N-glycans with a N, N'-diacetylchitobiosyl unit (GN2-type) occurred at a concentration of ~1 nmol/g. This result suggested that two kinds of glycoenzymes, cytosolic endo-beta-N-acetylglucosaminidase (ENGase) and intracellular acidic peptide:N-glycanse (PNGase), are involved in the production of FNGs in rice cell as well as in other plant cells. On the other hand, in the culture medium, Lewis a epitope-containing complex and high-mannose type FNGs with the N, N'-diacetylchitobiosyl unit were found, suggesting extracellular acidic PNGase to be involved in the release of N-glycans from folded/processed glycoproteins in extracellular space. Furthermore, in the culture medium, we found unusual GN1-FNGs that have a biantennary complex type structure harbouring the Lewis a epitope, suggesting cytosolic ENGase and golgi N-glycan-processing enzymes to be involved in the production of these plant complex type FNGs. PMID- 20829343 TI - Cell proliferation effect of GnRH agonist on pathological lesions of women with endometriosis, adenomyosis and uterine myoma. AB - BACKGROUND: We recently demonstrated the effect of gonadotrophin-releasing hormone agonist (GnRHa) on tissue inflammation, angiogenesis and apoptosis in endometriosis, adenomyosis and uterine myoma. Here, we investigated expression of GnRH receptors (GnRHRs) and effect of GnRHa on the proliferation of cells derived from endometria and pathological lesions of women with these reproductive diseases. METHODS: Biopsy specimens were collected from lesions and corresponding endometria of 35 women with pelvic endometriosis, 45 women with ovarian endometrioma, 35 women with adenomyosis and 56 women with uterine myoma during laparoscopy or laparotomy. The gene and protein expressions of GnRHR in eutopic/ectopic cells and tissues were examined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. The immunoreactivity of GnRHR in tissue was analysed by quantitative-histogram (Q-H) scores. The exogenous effect of GnRHa on cell proliferation was examined by 5-bromo-2 deoxyuridine incorporation assay. The Ki-67-immunoreactive cell proliferation index was analysed in biopsy specimens derived from GnRHa-treated and -non treated women. RESULTS: Types I and II GnRHRs mRNA and proteins were expressed in eutopic endometria and pathological lesions derived from women with endometriosis, adenomyosis and uterine myoma. GnRHR expression was the highest in the menstrual phase when compared with other phases of the menstrual cycle. Higher Q-H scores of GnRHR immunoreaction were found in blood-filled opaque red lesions than in other peritoneal lesions. Exogenous treatment with GnRHa significantly suppressed the proliferation of cells derived from respective endometria and pathological lesions when compared with GnRHa-non-treated cells. CONCLUSIONS: Local tissue expression of GnRHR was detected in endometriosis, adenomyosis and uterine myoma. In addition to a hypo-estrogenic effect, a direct anti-proliferative effect of GnRHa may be involved in the regression of these reproductive diseases with consequent remission of clinical symptoms. PMID- 20829344 TI - Evolution of function of a fused metazoan tRNA synthetase. AB - The origin and evolution of multidomain proteins are driven by diverse processes including fusion/fission, domain shuffling, and alternative splicing. The 20 aminoacyl-tRNA synthetases (AARS) constitute an ancient conserved family of multidomain proteins. The glutamyl-prolyl tRNA synthetase (EPRS) of bilaterian animals is unique among AARSs, containing two functional enzymes catalyzing ligation of glutamate and proline to their cognate transfer RNAs (tRNAs). The ERS and PRS catalytic domains in multiple bilaterian taxa are linked by variable number of helix-turn-helix domains referred to as WHEP-TRS domains. In addition to its canonical aminoacylation activities, human EPRS exhibits a noncanonical function as an inflammation-responsive regulator of translation. Recently, we have shown that the WHEP domains direct this auxiliary function of human EPRS by interacting with an mRNA stem-loop element (interferon-gamma-activated inhibitor of translation [GAIT] element). Here, we show that EPRS is present in the cnidarian Nematostella vectensis, which pushes the origin of the fused protein back to the cnidarian-bilaterian ancestor, 50-75 My before the origin of the Bilateria. Remarkably, the Nematostella EPRS mRNA is alternatively spliced to yield three isoforms with variable number and sequence of WHEP domains and with distinct RNA-binding activities. Whereas one isoform containing a single WHEP domain binds tRNA, a second binds both tRNA and GAIT element RNA. However, the third isoform contains two WHEP domains and like the human ortholog binds specifically to GAIT element RNA. These results suggest that alternative splicing of WHEP domains in the EPRS gene of the cnidarian-bilaterian ancestor gave rise to a novel molecular function of EPRS conserved during metazoan evolution. PMID- 20829345 TI - Transcriptomic evidence that longevity of acquired plastids in the photosynthetic slugs Elysia timida and Plakobranchus ocellatus does not entail lateral transfer of algal nuclear genes. AB - Sacoglossan sea slugs are unique in the animal kingdom in that they sequester and maintain active plastids that they acquire from the siphonaceous algae upon which they feed, making the animals photosynthetic. Although most sacoglossan species digest their freshly ingested plastids within hours, four species from the family Plakobranchidae retain their stolen plastids (kleptoplasts) in a photosynthetically active state on timescales of weeks to months. The molecular basis of plastid maintenance within the cytosol of digestive gland cells in these photosynthetic metazoans is yet unknown but is widely thought to involve gene transfer from the algal food source to the slugs based upon previous investigations of single genes. Indeed, normal plastid development requires hundreds of nuclear-encoded proteins, with protein turnover in photosystem II in particular known to be rapid under various conditions. Moreover, only algal plastids, not the algal nuclei, are sequestered by the animals during feeding. If algal nuclear genes are transferred to the animal either during feeding or in the germ line, and if they are expressed, then they should be readily detectable with deep-sequencing methods. We have sequenced expressed mRNAs from actively photosynthesizing, starved individuals of two photosynthetic sea slug species, Plakobranchus ocellatus Van Hasselt, 1824 and Elysia timida Risso, 1818. We find that nuclear-encoded, algal-derived genes specific to photosynthetic function are expressed neither in P. ocellatus nor in E. timida. Despite their dramatic plastid longevity, these photosynthetic sacoglossan slugs do not express genes acquired from algal nuclei in order to maintain plastid function. PMID- 20829346 TI - Molecular evolution of the endosperm starch synthesis pathway genes in rice (Oryza sativa L.) and its wild ancestor, O. rufipogon L. AB - The evolution of metabolic pathways is a fundamental but poorly understood aspect of evolutionary change. One approach for understanding the complexity of pathway evolution is to examine the molecular evolution of genes that together comprise an integrated metabolic pathway. The rice endosperm starch biosynthetic pathway is one of the most thoroughly characterized metabolic pathways in plants, and starch is a trait that has evolved in response to strong selection during rice domestication. In this study, we have examined six key genes (AGPL2, AGPS2b, SSIIa, SBEIIb, GBSSI, ISA1) in the rice endosperm starch biosynthesis pathway to investigate the evolution of these genes before and after rice domestication. Genome-wide sequence tagged sites data were used as a neutral reference to overcome the problems of detecting selection in species with complex demographic histories such as rice. Five variety groups of Oryza sativa (aus, indica, tropical japonica, temperate japonica, aromatic) and its wild ancestor (O. rufipogon) were sampled. Our results showed evidence of purifying selection at AGPL2 in O. rufipogon and strong evidence of positive selection at GBSSI in temperate japonica and tropical japonica varieties and at GBSSI and SBEIIb in aromatic varieties. All the other genes showed a pattern consistent with neutral evolution in both cultivated rice and its wild ancestor. These results indicate the important role of positive selection in the evolution of starch genes during rice domestication. We discuss the role of SBEIIb and GBSSI in the evolution of starch quality during rice domestication and the power and limitation of detecting selection using genome-wide data as a neutral reference. PMID- 20829347 TI - Endoplasmic reticulum stress-activated C/EBP homologous protein enhances nuclear factor-kappaB signals via repression of peroxisome proliferator-activated receptor gamma. AB - Endoplasmic reticulum (ER) stress is a causative factor of inflammatory bowel diseases. ER stress mediators, including CCAAT enhancer-binding protein (C/EBP) homologous protein (CHOP), are elevated in intestinal epithelia from patients with inflammatory bowel diseases. The present study arose from the question of how chemical ER stress and CHOP protein were associated with nuclear factor kappaB (NF-kappaB)-mediated epithelial inflammatory response. In a human intestinal epithelial cell culture model, chemical ER stresses induced proinflammatory cytokine interleukin-8 (IL-8) expression and the nuclear translocation of CHOP protein. CHOP was positively involved in ER-activated IL-8 production and was negatively associated with expression of peroxisome proliferator-activated receptor gamma (PPARgamma). ER stress-induced IL-8 production was enhanced by NF-kappaB activation that was negatively regulated by PPARgamma. Mechanistically, ER stress-induced CHOP suppressed PPARgamma transcription by sequestering C/EBPbeta and limiting availability of C/EBPbeta binding to the PPARgamma promoter. Due to the CHOP-mediated regulation of PPARgamma action, ER stress can enhance proinflammatory NF-kappaB activation and maintain an increased level of IL-8 production in human intestinal epithelial cells. In contrast, PPARgamma was a counteracting regulator of gut inflammatory response through attenuation of NF-kappaB activation. The collective results support the view that balances between CHOP and PPARgamma are crucial for epithelial homeostasis, and disruption of these balances in mucosal ER stress can etiologically affect the progress of human inflammatory bowel diseases. PMID- 20829348 TI - Cactin targets the MHC class III protein IkappaB-like (IkappaBL) and inhibits NF kappaB and interferon-regulatory factor signaling pathways. AB - Toll-like receptors (TLRs) act as primary sensors of the immune system by recognizing specific microbial motifs and inducing proinflammatory genes that facilitate innate and adaptive immunity. TLRs regulate gene expression by activating transcription factors, such as NF-kappaB and interferon-regulatory factors. Dysregulation of these pathways can lead to inflammatory diseases, and thus they are subject to stringent control by negative regulators of innate immune signaling. Cactin (Cactus interactor) was initially discovered as a novel interactor of Drosophila Cactus, a regulator of Drosophila Toll signaling. We now describe the first functional characterization of the human ortholog of Cactin (hCactin) and show that it acts as a negative regulator of TLRs. Overexpression of hCactin suppresses TLR-induced activation of NF-kappaB and interferon regulatory factor transcription factors and induction of TLR-responsive genes, whereas knockdown of endogenous hCactin augments TLR induction of these responses. hCactin also interacts with IkappaB-like protein and targets other proteins that are encoded by genes in the MHC Class III region of chromosome 6. We demonstrate that hCactin localizes to the nucleus, and this nuclear localization is critical for manifesting its inhibitory effects on TLR signaling. This study thus defines hCactin as a novel negative regulator of TLR signaling and reveals its capacity to target MHC Class III genes at the molecular and functional level. PMID- 20829349 TI - Interleukin-7-induced Stat-5 acts in synergy with Flt-3 signaling to stimulate expansion of hematopoietic progenitor cells. AB - The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt 3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il 7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors. PMID- 20829350 TI - Polymeric immunoglobulin receptor-mediated invasion of Streptococcus pneumoniae into host cells requires a coordinate signaling of SRC family of protein-tyrosine kinases, ERK, and c-Jun N-terminal kinase. AB - Streptococcus pneumoniae are commensals of the human nasopharynx with the capacity to invade mucosal respiratory cells. PspC, a pneumococcal surface protein, interacts with the human polymeric immunoglobulin receptor (pIgR) to promote bacterial adherence to and invasion into epithelial cells. Internalization of pneumococci requires the coordinated action of actin cytoskeleton rearrangements and the retrograde machinery of pIgR. Here, we demonstrate the involvement of Src protein-tyrosine kinases (PTKs), focal adhesion kinase (FAK), extracellular signal-regulated kinase (ERK), and c-Jun N terminal kinase (JNK) but not p38 mitogen-activated protein kinases (MAPK) in pneumococcal invasion via pIgR. Pharmacological inhibitors of PTKs and MAPKs and genetic interference with Src PTK and FAK functions caused a significant reduction of pIgR-mediated pneumococcal invasion but did not influence bacterial adhesion to host cells. Furthermore, pneumococcal ingestion by host cells induces activation of ERK1/2 and JNK. In agreement with activated JNK, its target molecule and DNA-binding protein c-Jun was phosphorylated. We also show that functionally active Src PTK is essential for activation of ERK1/2 upon pneumococcal infections. In conclusion, these data illustrate the importance of a coordinated signaling between Src PTKs, ERK1/2, and JNK during PspC-pIgR-mediated uptake of pneumococci by host epithelial cells. PMID- 20829351 TI - C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity. AB - Toll-like receptor 8 (TLR8), which is expressed primarily in myeloid cells, plays a central role in initiating immune responses to viral single-stranded RNA. Despite the great interest in the field of TLR8 research, very little is known in terms of TLR8 biology and its transcriptional regulation. Here, we describe the isolation of the hTLR8 promoter and the characterization of the molecular mechanisms involved in its regulation. Reporter gene analysis and ChIP assays demonstrated that the hTLR8 regulation of the basal transcription is regulated via three C/EBP cis-acting elements that required C/EBPdelta and C/EBPbeta activity. In addition, we observed that R848 stimulation increases TLR8 transcriptional activity via an enhanced binding of C/EBPdelta, and not C/EBPbeta, to its responsive sites within the TLR8 promoter. Moreover, we showed that IFN-gamma also increased TLR8 transcription activity via the binding of STAT1 transcription factor to IFN-gamma activated sequence elements on the TLR8 promoter and enhanced TLR8 functionality. These results shed new light on the mechanisms involved during TLR8-mediated innate immune response. PMID- 20829352 TI - Differentiation of human T cells alters their repertoire of G protein alpha subunits. AB - Because T cell differentiation leads to an expanded repertoire of chemokine receptors, a subgroup of G protein-coupled receptors, we hypothesized that the repertoire of G proteins might be altered in parallel. We analyzed the abundance of mRNA and/or protein of six G protein alpha-subunits in human CD4(+) and CD8(+) T cell subsets from blood. Although most G protein alpha-subunits were similarly expressed in all subsets, the abundance of Galpha(o), a protein not previously described in hematopoietic cells, was much higher in memory versus naive cells. Consistent with these data, activation of naive CD4(+) T cells in vitro significantly increased the abundance of Galpha(o) in cells stimulated under nonpolarizing or T(H)17 (but not T(H)1 or T(H)2)-polarizing conditions. In functional studies, the use of a chimeric G protein alpha-subunit, Galpha(qo5), demonstrated that chemokine receptors could couple to Galpha(o)-containing G proteins. We also found that Galpha(i1), another alpha-subunit not described previously in leukocytes, was expressed in naive T cells but virtually absent from memory subsets. Corresponding to their patterns of expression, siRNA mediated knockdown of Galpha(o) in memory (but not naive) and Galpha(i1) in naive (but not memory) CD4(+) T cells inhibited chemokine-dependent migration. Moreover, although even in Galpha(o)- and Galpha(i1)-expressing cells mRNAs of these alpha-subunits were much less abundant than Galpha(i2) or Galpha(i3), knockdown of any of these subunits impaired chemokine receptor-mediated migration similarly. Together, our data reveal a change in the repertoire of Galpha(i/o) subunits during T cell differentiation and suggest functional equivalence among Galpha(i/o) subunits irrespective of their relative abundance. PMID- 20829353 TI - Structural basis for the cAMP-dependent gating in the human HCN4 channel. AB - Hyperpolarization-activated cAMP-regulated (HCN) channels play important physiological roles in both cardiovascular and central nervous systems. Among the four HCN isoforms, HCN2 and HCN4 show high expression levels in the human heart, with HCN4 being the major cardiac isoform. The previously published crystal structure of the mouse HCN2 (mHCN2) C-terminal fragment, including the C-linker and the cyclic-nucleotide binding domain (CNBD), has provided many insights into cAMP-dependent gating in HCN channels. However, structures of other mammalian HCN channel isoforms have been lacking. Here we used a combination of approaches including structural biology, biochemistry, and electrophysiology to study cAMP dependent gating in HCN4 channel. First we solved the crystal structure of the C terminal fragment of human HCN4 (hHCN4) channel at 2.4 A. Overall we observed a high similarity between mHCN2 and hHCN4 crystal structures. Functional comparison between two isoforms revealed that compared with mHCN2, the hHCN4 protein exhibited marked different contributions to channel function, such as a ~3-fold reduction in the response to cAMP. Guided by structural differences in the loop region between beta4 and beta5 strands, we identified residues that could partially account for the differences in response to cAMP between mHCN2 and hHCN4 proteins. Moreover, upon cAMP binding, the hHCN4 C-terminal protein exerts a much prolonged effect in channel deactivation that could have significant physiological contributions. PMID- 20829354 TI - Complexin 2 modulates vesicle-associated membrane protein (VAMP) 2-regulated zymogen granule exocytosis in pancreatic acini. AB - Complexins are soluble proteins that regulate the activity of soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes necessary for vesicle fusion. Neuronal specific complexin 1 has inhibitory and stimulatory effects on exocytosis by clamping trans-SNARE complexes in a prefusion state and promoting conformational changes to facilitate membrane fusion following cell stimulation. Complexins are unable to bind to monomeric SNARE proteins but bind with high affinity to ternary SNARE complexes and with lower affinity to target SNARE complexes. Far less is understood about complexin function outside the nervous system. Pancreatic acini express the complexin 2 isoform by RT-PCR and immunoblotting. Immunofluorescence microscopy revealed complexin 2 localized along the apical plasma membrane consistent with a role in secretion. Accordingly, complexin 2 was found to interact with vesicle-associated membrane protein (VAMP) 2, syntaxins 3 and 4, but not with VAMP 8 or syntaxin 2. Introduction of recombinant complexin 2 into permeabilized acini inhibited Ca(2+) stimulated secretion in a concentration-dependent manner with a maximal inhibition of nearly 50%. Mutations of the central alpha-helical domain reduced complexin 2 SNARE binding and concurrently abolished its inhibitory activity. Surprisingly, mutation of arginine 59 to histidine within the central alpha helical domain did not alter SNARE binding and moreover, augmented Ca(2+) stimulated secretion by 130% of control. Consistent with biochemical studies, complexin 2 colocalized with VAMP 2 along the apical plasma membrane following cholecystokinin-8 stimulation. These data demonstrate a functional role for complexin 2 outside the nervous system and indicate that it participates in the Ca(2+)-sensitive regulatory pathway for zymogen granule exocytosis. PMID- 20829355 TI - The aryl hydrocarbon receptor-interacting protein (AIP) is required for dioxin induced hepatotoxicity but not for the induction of the Cyp1a1 and Cyp1a2 genes. AB - The aryl hydrocarbon receptor (AHR) plays an essential role in the toxic response to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), in the adaptive up-regulation of xenobiotic metabolizing enzymes, and in hepatic vascular development. In our model of AHR signaling, the receptor is found in a cytosolic complex with a number of molecular chaperones, including Hsp90, p23, and the aryl hydrocarbon receptor-interacting protein (AIP), also known as ARA9 and XAP2. To understand the role of AIP in adaptive and toxic aspects of AHR signaling, we generated a conditional mouse model where the Aip locus can be deleted in hepatocytes. Using this model, we demonstrate two important roles for the AIP protein in AHR biology. (i) The expression of AIP in hepatocytes is essential to maintain high levels of functional cytosolic AHR protein in the mammalian liver. (ii) Expression of the AIP protein is essential for dioxin induced hepatotoxicity. Interestingly, classical AHR-driven genes show differential dependence on AIP expression. The Cyp1b1 and Ahrr genes require AIP expression for normal up-regulation by dioxin, whereas Cyp1a1 and Cyp1a2 do not. This differential dependence on AIP provides evidence that the mammalian genome contains more than one class of AHR-responsive genes and suggests that a search for AIP-dependent, AHR-responsive genes may guide us to the targets of the dioxin induced hepatotoxicity. PMID- 20829356 TI - Intracellular cysteine 346 is essentially involved in regulating Panx1 channel activity. AB - Pannexins constitute a family of proteins exhibiting predominantly hemichannel activity. Pannexin channels have been suggested to participate in a wide spectrum of biological functions such as propagation of calcium waves, release of IL 1beta, and responses to ischemic conditions. At present, the molecular mechanisms regulating pannexin hemichannel activity are essentially unknown. Because cysteines have been shown to constitute key elements in regulating hemichannel properties of the connexin-type we performed site-directed mutagenesis of intracellular cysteine residues of Panx1. Cysteine to serine exchange (Cys -> Ser) at the C-terminal position amino acid 346 led to a constitutively leaky hemichannel and subsequently to cell death. Increased channel activity was demonstrated by dye uptake and electrophysiological profiling in injected Xenopus laevis oocytes and transfected N2A cells. Mutations of the remaining intracellular cysteines did not result in major changes of Panx1 channel properties. From these data we conclude that the Cys-346 residue is important for proper functioning of the Panx1 channel. PMID- 20829357 TI - Identification of a novel HSP70-binding cochaperone critical to HSP90-mediated activation of small serine/threonine kinase. AB - We previously reported the identification of small serine/threonine kinase (SSTK) that is expressed in postmeiotic germ cells, associates with HSP90, and is indispensable for male fertility. Sperm from SSTK-null mice cannot fertilize eggs in vitro and are incapable of fusing with eggs that lack zona pellucida. Here, using the yeast two-hybrid screen, we have discovered a novel SSTK-interacting protein (SIP) that is expressed exclusively in testis. The gene encoding SIP is restricted to mammals and encodes a 125-amino acid polypeptide with a predicted tetratricopeptide repeat domain. SIP is co-localized with SSTK in the cytoplasm of spermatids as they undergo restructuring and chromatin condensation, but unlike SSTK, is not retained in the mature sperm. SIP binds to SSTK with high affinity (K(d) ~10 nM), and the proteins associate with each other when co expressed in cells. In vitro, SIP inhibited SSTK kinase activity, whereas the presence of SIP in cells resulted in enzymatic activation of SSTK without affecting Akt or MAPK activity. SIP was found to be associated with cellular HSP70, and analyses with purified proteins revealed that SIP directly bound HSP70. Importantly, SSTK recruited SIP onto HSP90, and treatment of cells with the specific HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin, completely abolished SSTK catalytic activity. Hence, these findings demonstrate that HSP90 is essential for functional maturation of the kinase and identify SIP as a cochaperone that is critical to the HSP90-mediated activation of SSTK. PMID- 20829358 TI - Ubiquitin-dependent and ubiquitin-independent control of subunit stoichiometry in the SWI/SNF complex. AB - The mammalian SWI/SNF chromatin remodeling complex is a key player in multiple chromatin transactions. Core subunits of this complex, including the ATPase, Brg 1, and various Brg-1-associated factors (BAFs), work in concert to maintain a functional remodeling complex. This intra-complex regulation is supervised by protein-protein interactions, as stoichiometric levels of BAF proteins are maintained by proteasomal degradation. We show that the mechanism of BAF155 mediated stabilization of BAF57 involves blocking its ubiquitination by preventing interaction with TRIP12, an E3 ubiquitin ligase. Consequently, as opposed to complexed BAF57, whose principal lysines are unavailable for ubiquitination, uncomplexed BAF57 can be freely ubiquitinated and degraded by the proteasome. Additionally, a BAF57 mutant, which contains no lysine residues, was found to retain its ability to be stabilized by interaction with BAF155, suggesting that in addition to the ubiquitin-dependent mechanism of BAF57 degradation, there exists a ubiquitin-independent mechanism that may involve the direct interaction of BAF57 with the proteasome. We propose that this regulatory mechanism exists to ensure functional fidelity of the complex and prevent the accumulation of uncomplexed proteins, which may disrupt the normal activity of the complex. PMID- 20829359 TI - Relevant elements of a maize gamma-zein domain involved in protein body biogenesis. AB - The N-terminal proline-rich domain of gamma-zein (Zera) plays an important role in protein body (PB) formation not only in the original host (maize seeds) but in a broad spectrum of eukaryotic cells. However, the elements within the Zera sequence that are involved in the biogenesis of PBs have not been clearly identified. Here, we focused on amino acid sequence motifs that could be involved in Zera oligomerization, leading to PB-like structures in Nicotiana benthamiana leaves. By using fusions of Zera with fluorescent proteins, we found that the lack of the repeat region (PPPVHL)(8) of Zera resulted in the secretion of the fusion protein but that this repeat by itself did not form PBs. Although the repeat region containing eight units was the most efficient for Zera self assembly, shorter repeats of 4-6 units still formed small multimers. Based on site-directed mutagenesis of Zera cysteine residues and analysis of multimer formation, we conclude that the two N-terminal Cys residues of Zera (Cys(7) and Cys(9)) are critical for oligomerization. Immunoelectron microscopy and confocal studies on PB development over time revealed that early, small, Zera-derived oligomers were sequestered in buds along the rough ER and that the mature size of the PBs could be attained by both cross-linking of preformed multimers and the incorporation of new chains of Zera fusions synthesized by active membrane-bound ribosomes. Based on these results and on the behavior of the Zera structure determined by molecular dynamics simulation studies, we propose a model of Zera induced PB biogenesis. PMID- 20829360 TI - Conserved and novel functions for Arabidopsis thaliana MIA40 in assembly of proteins in mitochondria and peroxisomes. AB - The disulfide relay system of the mitochondrial intermembrane space has been extensively characterized in Saccharomyces cerevisiae. It contains two essential components, Mia40 and Erv1. The genome of Arabidopsis thaliana contains a single gene for each of these components. Although insertional inactivation of Erv1 leads to a lethal phenotype, inactivation of Mia40 results in no detectable deleterious phenotype. A. thaliana Mia40 is targeted to and accumulates in mitochondria and peroxisomes. Inactivation of Mia40 results in an alteration of several proteins in mitochondria, an absence of copper/zinc superoxide dismutase (CSD1), the chaperone for superoxide dismutase (Ccs1) that inserts copper into CSD1, and a decrease in capacity and amount of complex I. In peroxisomes the absence of Mia40 leads to an absence of CSD3 and a decrease in abnormal inflorescence meristem 1 (Aim1), a beta-oxidation pathway enzyme. Inactivation of Mia40 leads to an alteration of the transcriptome of A. thaliana, with genes encoding peroxisomal proteins, redox functions, and biotic stress significantly changing in abundance. Thus, the mechanistic operation of the mitochondrial disulfide relay system is different in A. thaliana compared with other systems, and Mia40 has taken on new roles in peroxisomes and mitochondria. PMID- 20829361 TI - A eukaryotic (insect) tricistronic mRNA encodes three proteins selected by context-dependent scanning. AB - Eukaryotic mRNAs are generally considered monocistronic and encode only one protein. Although dicistronic mRNAs encoding two proteins were found in fungi, plants, and animals, polycistronic mRNAs encoding more than two proteins have remained elusive so far in any eukaryote. Here we demonstrate that a single mRNA from silkworm encodes the precursor of an insect cytokine paralytic peptide (PP) and two new cytokine precursor-like proteins, uENF1 and uENF2. RT-PCR analysis showed that this mRNA is widely conserved in moths. Western blot analyses and reporter assays using its modified mRNAs, created by replacing each one of the three ORFs with the firefly luciferase ORF, showed that all three proteins were translated from this mRNA in cell lines, larval tissues, and cell-free systems. Insertion experiments using the Renilla luciferase ORF or a stem loop ruled out the possible involvement of internal ribosome entry site in the three protein translation. On the other hand, systematic mutation analysis of the translation initiation sequence of the 5'-proximal uENF1 ORF suggested that the context dependent leaky-scanning mechanism is involved in translation of the downstream uENF2 and PP ORFs. In vitro, a synthetic peptide corresponding to the putative mature form of uENF1 stimulated spreading of hemocytes as did the synthetic PP, whereas that of uENF2 antagonized the stimulating activities of PP and the uENF1 peptide, suggesting that the three proteins control cellular immunity interactively. Thus, eukaryotes have a cellular tricistronic mRNA that encodes three functionally related proteins as in an operon. PMID- 20829362 TI - Modification of cysteine 179 of IkappaBalpha kinase by nimbolide leads to down regulation of NF-kappaB-regulated cell survival and proliferative proteins and sensitization of tumor cells to chemotherapeutic agents. AB - Reverse pharmacology, also called the "bedside to bench" approach, that deals with new uses for a well known molecular entity has been used extensively in cancer drug development to identify novel compounds and delineate their mechanisms of action. Here, we show that nimbolide, a triterpenoid isolated from Azadirachta indica, enhanced the apoptosis induced by inflammatory cytokines and chemotherapeutic agents in tumor cells. This limonoid abrogated the expression of proteins associated with cell survival (Bcl-2, Bcl-xL, IAP-1, and IAP-2), proliferation (cyclin D1), invasion (MMP-9), and angiogenesis (VEGF), all regulated by nuclear factor (NF)-kappaB. Nimbolide inhibited the activation of NF kappaB induced by carcinogens and inflammatory stimuli. Constitutively active NF kappaB found in most tumor cells was also inhibited. We found that suppression of NF-kappaB activation by nimbolide was caused by inhibition of IkappaB kinase (IKK), which led to suppression of IkappaBalpha phosphorylation and degradation, nuclear translocation, DNA binding, and gene transcription. Reducing agent reversed the action of the limonoid, suggesting the involvement of a cysteine residue. Replacement of Cys(179) of IKK-beta with alanine abolished the effect of nimbolide, suggesting that Cys(179) plays a critical role in inhibiting the NF kappaB activation. Overall, our results indicate that nimbolide can sensitize tumor cells to chemotherapeutic agents through interaction with IKK, leading to inhibition of NF-kappaB-regulated proteins. PMID- 20829363 TI - Stability and function of mammalian lethal giant larvae-1 oncoprotein are regulated by the scaffolding protein RanBPM. AB - The evolutionarily conserved lethal giant larvae (Lgl) tumor suppressor gene has an essential role in establishing apical-basal cell polarity, cell proliferation, differentiation, and tissue organization. However, the precise molecular mechanism by which the Lgl carries out its function remains obscure. In the current study, we have identified Ran-binding protein M (RanBPM) as a novel binding partner of Mgl-1, a mammalian homolog of Drosophila tumor suppressor protein lethal (2) giant larvae (L(2)gl) by yeast two-hybrid screening. RanBPM seems to act as a scaffolding protein with a modulatory function with respect to Mgl-1. The Mgl-1 and RanBPM association was confirmed by co-immunoprecipitation and GST pull-down experiments. Additionally, expression of RanBPM resulted in inhibition of Mgl-1 degradation, and thereby extended the half-life of Mgl-1. Furthermore, the ability of Mgl-1 activity in cell migration and colony formation assay was enhanced by RanBPM. Taken together, our findings reveal that RanBPM plays a novel role in regulating Mgl-1 stability and contributes to its biological function as a tumor suppressor. PMID- 20829364 TI - Glucosamine treatment-mediated O-GlcNAc modification of paxillin depends on adhesion state of rat insulinoma INS-1 cells. AB - Protein-protein interactions and/or signaling activities at focal adhesions, where integrin-mediated adhesion to extracellular matrix occurs, are critical for the regulation of adhesion-dependent cellular functions. Although the phosphorylation and activities of focal adhesion molecules have been intensively studied, the effects of the O-GlcNAc modification of their Ser/Thr residues on cellular functions have been largely unexplored. We investigated the effects of O GlcNAc modification on actin reorganization and morphology of rat insulinoma INS 1 cells after glucosamine (GlcN) treatment. We found that paxillin, a key adaptor molecule in focal adhesions, could be modified by O-GlcNAc in INS-1 cells treated with GlcN and in pancreatic islets from mice treated with streptozotocin. Ser 84/85 in human paxillin appeared to be modified by O-GlcNAc, which was inversely correlated to Ser-85 phosphorylation (Ser-83 in rat paxillin). Integrin-mediated adhesion signaling inhibited the GlcN treatment-enhanced O-GlcNAc modification of paxillin. Adherent INS-1 cells treated with GlcN showed restricted protrusions, whereas untreated cells showed active protrusions for multiple-elongated morphologies. Upon GlcN treatment, expression of a triple mutation (S83A/S84A/S85A) resulted in no further restriction of protrusions. Together these observations suggest that murine pancreatic beta cells may have restricted actin organization upon GlcN treatment by virtue of the O-GlcNAc modification of paxillin, which can be antagonized by a persistent cell adhesion process. PMID- 20829365 TI - Pma1, a P-type proton ATPase, is a determinant of chronological life span in fission yeast. AB - Chronological life span is defined by how long a cell can survive in a non dividing state. In yeast, it is measured by viability after entry into stationary phase. To date, some factors affecting chronological life span have been identified; however, the molecular details of how these factors regulate chronological life span have not yet been elucidated clearly. Because life span is a complicated phenomenon and is supposedly regulated by many factors, it is necessary to identify new factors affecting chronological life span to understand life span regulation. To this end, we have screened for long-lived mutants and identified Pma1, an essential P-type proton ATPase, as one of the determinants of chronological life span. We show that partial loss of Pma1 activity not only by mutations but also by treatment with the Pma1 inhibitory chemical vanadate resulted in the long-lived phenotype in Schizosaccharomyces pombe. These findings suggest a novel way to manipulate chronological life span by modulating Pma1 as a molecular target. PMID- 20829366 TI - Newborn TSH concentration and its association with cognitive development in healthy boys. AB - OBJECTIVE: An association between thyroid function during pregnancy or infancy and neurodevelopment in children has been demonstrated. We aimed to investigate whether newborn TSH concentrations are related to subsequent neurocognitive development. DESIGN: We conducted a longitudinal study on 178 children from a general population birth cohort in Granada (Spain) born in 2000-2002. METHODS: TSH concentrations were measured in umbilical cord blood, and cognitive functions were assessed at 4 years of age using the McCarthy's scales of children's abilities (MSCA). Organochlorine (OC) compound concentrations and the combined oestrogenicity (total effective xeno-oestrogenic burden (TEXB)) were also determined in the placentae. RESULTS: Mean newborn TSH was 3.55 mU/l (range=0.24 17 mU/l). In multivariate regression analyses, adjusting for maternal and child characteristics, higher newborn TSH concentrations showed a decrease of 3.51 and 3.15 points on the MSCA general cognitive and executive function scores respectively and were associated with a higher risk of scoring below the 20th percentile (P20) on the quantitative score (odds ratio (OR)=2.64). Children with TSH in the upper quartile (4.19-17.0 mU/l) were at higher risk of scoring = 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (>= 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE. PMID- 20829375 TI - A KIR-TLR connection. PMID- 20829376 TI - Sialic acid-IVIg targeting CD22. PMID- 20829377 TI - Improving specificity in HIT testing. PMID- 20829378 TI - Mightier than the sickle cell. PMID- 20829379 TI - Balancing clotting. PMID- 20829381 TI - Clearly defined response criteria evaluating treatment of CLL patients in clinical research trials. PMID- 20829382 TI - MALT lymphoma-derived rheumatoid factors are nonpolyreactive high-affinity antibodies. PMID- 20829384 TI - Repair of left coronary artery ostial isolation caused by aortic valve leaflet. AB - A 13-year-old girl had recurrent syncope episodes and chest oppression during exercise caused by myocardial ischemia that was confirmed by stress myocardial scintigraphy. Echocardiography revealed mild aortic regurgitation (AR). Cineangiography revealed persistent opacification of the left coronary sinus. Freeing of the adherent left coronary cusp from the aortic wall increased antegrade left coronary flow and commissural resuspension restored AR. Postoperative recovery was uneventful and myocardial ischemia did not develop after surgery. Hence, although left coronary artery ostial isolation by aortic valve leaflet is rare, it can be successfully treated by aortic valve repair. PMID- 20829385 TI - Second successful surgical ventricular reconstruction: a cardiac magnetic resonance imaging illustration. AB - This case reports a magnetic resonance imaging (MRI) illustration of a successful ventricular reconstruction of a left ventricle pseudoaneurysm that developed four months after postmyocardial infarction ventricular repair. Thus, preoperative non invasive MRI techniques are valuable diagnostic tools in this setting. Indeed, the present case shows that MRI greatly helped in the management and surgical decision-making. PMID- 20829386 TI - Rupture of Kommerell diverticulum after total arch replacement. AB - A 62-year-old man was brought to the emergency room of our hospital because of chest pain. Computed tomography revealed a right aortic arch and an aberrant left subclavian artery with Kommerell diverticulum and acute aortic dissection (Stanford type A). Total arch replacement was performed emergently through a median full sternotomy. A stomach feeding tube was placed postoperatively for the patient to receive nutrition, and esophageal bleeding was observed postoperatively. The patient died because of the bleeding. Autopsy findings showed a communication between the esophagus and Kommerell diverticulum. Rupture of Kommerell diverticulum and perforation of the esophagus were indicated. PMID- 20829387 TI - Transvalvular intramyocardial bone marrow stem cell transplantation in combination with videoscopic mitral valve repair. AB - In the last years both minimally-invasive therapy approaches as well as intramyocardial cell therapy have entered clinical practice in cardiac surgery. Stem cell therapy has been combined in most cases with coronary artery bypass grafting (CABG) for chronic ischemic heart disease. Here, we report the first case of a patient with ischemic mitral regurgitation treated by videoscopic, transvalvular, intramyocardial bone marrow stem cell injection, while undergoing minimally-invasive mitral valve repair. PMID- 20829388 TI - Diverticulum of the mitral valve, a rare cause of mitral regurgitation. AB - Non-infective mitral valve diverticulum is extremely rare. We present a case of intraoperatively diagnosed mitral valve diverticulum of a 69-year-old man presenting with mitral regurgitation who was successfully treated with mitral valve replacement. PMID- 20829389 TI - How good patient blood management leads to excellent outcomes in Jehovah's witness patients undergoing cardiac surgery. AB - OBJECTIVES: The refusal of blood products makes open-heart surgery in Jehovah's witnesses (JW) an ethical challenge. We demonstrate how patient blood management strategies lead to excellent surgical outcomes. METHODS: From 2003 to 2008, 16 JW underwent cardiac surgery at our institution. Only senior surgeons performed coronary revascularization (n=6), valve (n=6), combined (n=1) and aortic surgery (n=3) of which two patients presented with acute type-A dissection. Off-pump surgery remained the method of choice for patients requiring a bypass procedure (n=5). Preoperative hematocrit (Hk) and hemoglobin (Hb) were 42.8+/-4.7% and 14.5+/-2 g/dl. In three patients with an Hb<12 g/dl, preoperative hematological stimulating treatment was implemented. RESULTS: All patients survived, no major complications occurred and no blood transfusion was administered. The Cell Saver(r) system (transfused volume: 474+/-101 ml) and synthetic plasma substitutes [Ringer's Lactate: 873+/-367 ml and hydroxyethyl starch (HES) 6%: 700+/-388 ml] were used routinely as well as hemostaticas, such as bone wax, and fibrin glue. The decrease of Hk and Hb appeared to be the lowest after off-pump surgery when compared to all other procedures requiring cardiopulmonary bypass (CPB) (25+/-9% vs. 33+/-6%; P=0.01 and 22+/-9% vs. 31+/-6%; P=0.04). Similarly, the decrease of platelets was significantly lower (20+/-12% vs. 43+/-14%; P=0.01). In the follow-up period (52+/-34 months), one patient died due to a non cardiac reason, whereas all others were alive, in good clinical condition and did not have major adverse cardiac events (MACE) or recurrent symptoms requiring re intervention. CONCLUSION: Patient blood management leads to excellent short- and long-term outcomes in JW. Combined efforts in regard to preoperative hematological parameter optimization, effective volume management and meticulous surgical techniques make this possible but raise the cautionary note why this is only possible in JW patients. PMID- 20829390 TI - Research resource: T-antigen transformation of pituitary cells captures three novel cell lines in the Pit-1 lineage. AB - We report the establishment of three distinct pituitary-derived murine cell lines generated by targeted T-antigen-induced transformation. The Pit1/0 line expresses pituitary-specific transcription factor-1 (Pit-1) but lacks expression of GH, prolactin (Prl), or TSH, and the Pit1/Prl line is selectively positive for Pit-1 and Prl. The third line, Pit1/Triple, expresses Pit-1 and all three of the Pit-1 dependent hormones: GH, Prl, and TSHbeta/glycoprotein hormone alpha-subunit. The three corresponding transformation events appear to have captured pituitary cells representing: 1) an initial step in the Pit-1(+) lineage, 2) a cell line that corresponds to the differentiated lactotrope, and 3) a novel tri-hormone intermediate that may represent a pivotal step in Pit-1(+) cell lineage differentiation. The documented dependence of the tri-hormone expression in the Pit-1/Triple line on Pit-1 activity supports its potential role in the pathway of pituitary cell differentiation. The presence of a 123-kb human transgene encompassing the hGH locus (hGH/bacterial artificial chromosome) in two of these lines, Pit1/0 and Pit1/Prl, further expands their potential utility to the analysis of gene activation within the hGH gene cluster. PMID- 20829391 TI - The inositol phosphatase SHIP2 negatively regulates insulin/IGF-I actions implicated in neuroprotection and memory function in mouse brain. AB - Impairment of insulin and IGF-I signaling in the brain is one of the causes of dementia associated with diabetes mellitus and Alzheimer's disease. However, the precise pathological processes are largely unknown. In the present study, we found that SH2-containing inositol 5'-phosphatase 2 (SHIP2), a negative regulator of phosphatidylinositol 3,4,5-trisphosphate-mediated signals, is widely expressed in adult mouse brain. When a dominant-negative mutant of SHIP2 was expressed in cultured neurons, insulin signaling was augmented, indicating physiological significance of endogenous SHIP2 in neurons. Interestingly, SHIP2 mRNA and protein expression levels were significantly increased in the brain of type 2 diabetic db/db mice. To investigate the impact of increased expression of SHIP2 in the brain, we further employed transgenic mice overexpressing SHIP2 and found that increased amounts of SHIP2 induced the disruption of insulin/IGF-I signaling through Akt. Neuroprotective effects of insulin and IGF-I were significantly attenuated in cultured cerebellar granule neurons from SHIP2 transgenic mice. Consistently, terminal deoxynucleotide transferase-mediated dUTP nick end labeling assay demonstrated that the number of apoptosis-positive cells was increased in cerebral cortex of the transgenic mice at an elderly age. Furthermore, SHIP2 transgenic mice exhibited impaired memory performance in the Morris water maze, step-through passive avoidance, and novel-object-recognition tests. Importantly, inhibition of SHIP2 ameliorated the impairment of hippocampal synaptic plasticity and memory formation in db/db mice. These results suggest that SHIP2 is a potent negative regulator of insulin/IGF-I actions in the brain, and excess amounts of SHIP2 may be related, at least in part, to brain dysfunction in insulin resistance with type 2 diabetes. PMID- 20829392 TI - Isoform-specific degradation of PR-B by E6-AP is critical for normal mammary gland development. AB - E6-associated protein (E6-AP), which was originally identified as an ubiquitin protein ligase, also functions as a coactivator of estrogen (ER-alpha) and progesterone (PR) receptors. To investigate the in vivo role of E6-AP in mammary gland development, we generated transgenic mouse lines that either overexpress wild-type (WT) human E6-AP (E6-AP(WT)) or ubiquitin-protein ligase-defective E6 AP (E6-AP(C833S)) in the mammary gland. Here we show that overexpression of E6 AP(WT) results in impaired mammary gland development. In contrast, overexpression of E6-AP(C833S) or loss of E6-AP (E6-AP(KO)) increases lateral branching and alveolus-like protuberances in the mammary gland. We also show that the mammary phenotypes observed in the E6-AP transgenic and knockout mice are due, in large part, to the alteration of PR-B protein levels. We also observed alteration in ER alpha protein level, which might contribute to the observed mammary phenotype by regulating PR expression. Furthermore, E6-AP regulates PR-B protein levels via the ubiquitin-proteasome pathway. Additionally, we also show that E6-AP impairs progesterone-induced Wnt-4 expression by decreasing the steady state level of PR B in both mice and in human breast cancer cells. In conclusion, we present the novel observation that E6-AP controls mammary gland development by regulating PR B protein turnover via the ubiquitin proteasome pathway. For the first time, we show that the E3-ligase activity rather than the coactivation function of E6-AP plays an important role in the mammary gland development, and the ubiquitin dependent PR-B degradation is not required for its transactivation functions. This mechanism appears to regulate normal mammogenesis, and dysregulation of this process may be an important contributor to mammary cancer development and progression. PMID- 20829393 TI - Differential activation of pregnane X receptor and constitutive androstane receptor by buprenorphine in primary human hepatocytes and HepG2 cells. AB - Buprenorphine is a partial MU-opioid receptor agonist used for the treatment of opioid dependence that has several advantages over methadone. The principal route of buprenorphine disposition has been well established; however, little is known regarding the potential for buprenorphine to influence the metabolism and clearance of other drugs by affecting the expression of drug-metabolizing enzymes (DMEs). Here, we investigate the effects of buprenorphine on the activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR), as well as the induction of DMEs, in both HepG2 cells and human primary hepatocytes (HPHs). In HepG2 cells, buprenorphine significantly increased human PXR-mediated CYP2B6 and CYP3A4 reporter activities. CYP2B6 reporter activity was also enhanced by buprenorphine in HepG2 cells cotransfected with a chemical-responsive human CAR variant. Real-time reverse transcription-polymerase chain reaction analysis revealed that buprenorphine strongly induced CYP3A4 expression in both PXR- and CAR-transfected HepG2 cells. However, treatment with the same concentrations of buprenorphine in HPHs resulted in literally no induction of CYP3A4 or CYP2B6 expression. Further studies indicated that buprenorphine could neither translocate human CAR to the nucleus nor activate CYP2B6/CYP3A4 reporter activities in transfected HPHs. Subsequent experiments to determine whether the differential response was due to buprenorphine's metabolic stability revealed a dramatically differential rate of elimination for buprenorphine between HPHs and HepG2 cells. Taken together, these studies indicate that metabolic stability of buprenorphine defines the differential induction of DMEs observed in HepG2 and HPHs, and the results obtained from PXR and CAR reporter assays in immortalized cell line require cautious interpretation. PMID- 20829394 TI - Protein connectivity and protein complexity promotes human gene duplicability in a mutually exclusive manner. AB - It has previously been reported that protein complexity (i.e. number of subunits in a protein complex) is negatively correlated to gene duplicability in yeast as well as in humans. However, unlike in yeast, protein connectivity in a protein protein interaction network has a positive correlation with gene duplicability in human genes. In the present study, we have analyzed 1732 human and 1269 yeast proteins that are present both in a protein-protein interaction network as well as in a protein complex network. In the human case, we observed that both protein connectivity and protein complexity complement each other in a mutually exclusive manner over gene duplicability in a positive direction. Analysis of human haploinsufficient proteins and large protein complexes (complex size >10) shows that when protein connectivity does not have any direct association with gene duplicability, there exists a positive correlation between gene duplicability and protein complexity. The same trend, however, is not found in case of yeast, where both protein connectivity and protein complexity independently guide gene duplicability in the negative direction. We conclude that the higher rate of duplication of human genes may be attributed to organismal complexity either by increasing connectivity in the protein-protein interaction network or by increasing protein complexity. PMID- 20829395 TI - Superantigen gene profiles and presence of exfoliative toxin genes in community acquired meticillin-resistant Staphylococcus aureus isolated from Chinese children. AB - This study aimed to evaluate the distribution of superantigen gene profiles and the presence of exfoliative toxin genes in community-acquired meticillin resistant Staphylococcus aureus (CA-MRSA) isolated from Chinese children, and simultaneously to assess virulence gene profiles and genetic background. Of the CA-MRSA isolates, 88.9 % (88/99) harboured toxin genes, with sek as the most frequent toxin gene (62.6 %), followed by seq (61.6 %), seb (60.6 %) and sea (35.4 %). The eta gene was detected only in one ST398-IVa-spa t034 strain. The sed and etd genes were not found in any of the isolates tested. A total of 38 virulence genotypes were observed, of which the genotype seb-sek-seq (27.3 %, 24/88) comprised the majority, followed by sea-seb-sek-seq (18.2 %, 16/88). The enterotoxin gene cluster including seg-sei-sem-sen-seo-seu predominated at a rate of 15.1 %. The relationship among toxin genotypes, toxin genes encoding profiles of mobile genetic elements and genetic background was analysed. Among 66 clonal complex (CC) 59 isolates, 87.9 % (58/66) were positive for toxin genes, and 75.8 % (50/66) harboured the toxin gene combination seb-sek-seq. Among seb-sek-seq positive CC59 strains, 42.0 % (21/50) also carried the sea gene. CC59 corresponded exclusively to accessory gene regulator 1 (agr-1). The data presented here enhance our current knowledge on the virulence determinants of CA MRSA. PMID- 20829396 TI - Bactericidal effects of non-thermal argon plasma in vitro, in biofilms and in the animal model of infected wounds. AB - Non-thermal (low-temperature) physical plasma is under intensive study as an alternative approach to control superficial wound and skin infections when the effectiveness of chemical agents is weak due to natural pathogen or biofilm resistance. The purpose of this study was to test the individual susceptibility of pathogenic bacteria to non-thermal argon plasma and to measure the effectiveness of plasma treatments against bacteria in biofilms and on wound surfaces. Overall, Gram-negative bacteria were more susceptible to plasma treatment than Gram-positive bacteria. For the Gram-negative bacteria Pseudomonas aeruginosa, Burkholderia cenocepacia and Escherichia coli, there were no survivors among the initial 10(5) c.f.u. after a 5 min plasma treatment. The susceptibility of Gram-positive bacteria was species- and strain-specific. Streptococcus pyogenes was the most resistant with 17 % survival of the initial 10(5) c.f.u. after a 5 min plasma treatment. Staphylococcus aureus had a strain dependent resistance with 0 and 10 % survival from 10(5) c.f.u. of the Sa 78 and ATCC 6538 strains, respectively. Staphylococcus epidermidis and Enterococcus faecium had medium resistance. Non-ionized argon gas was not bactericidal. Biofilms partly protected bacteria, with the efficiency of protection dependent on biofilm thickness. Bacteria in deeper biofilm layers survived better after the plasma treatment. A rat model of a superficial slash wound infected with P. aeruginosa and the plasma-sensitive Staphylococcus aureus strain Sa 78 was used to assess the efficiency of argon plasma treatment. A 10 min treatment significantly reduced bacterial loads on the wound surface. A 5-day course of daily plasma treatments eliminated P. aeruginosa from the plasma-treated animals 2 days earlier than from the control ones. A statistically significant increase in the rate of wound closure was observed in plasma-treated animals after the third day of the course. Wound healing in plasma-treated animals slowed down after the course had been completed. Overall, the results show considerable potential for non-thermal argon plasma in eliminating pathogenic bacteria from biofilms and wound surfaces. PMID- 20829397 TI - Helicobacter pylori dupA and gastric acid secretion are negatively associated with gastric cancer development. AB - Few reports have described the cancer prevalence of peptic ulcer patients with long-term follow-up studies. We have conducted a long-term retrospective cohort study of Japanese peptic ulcer patients and evaluated the risk factors for the occurrence of gastric cancer (GCa). A total of 136 patients diagnosed with peptic ulcers from 1975 to 1983 were enrolled. These 136 cases [102 males and 34 females; 69 gastric ulcer (GU) and 67 duodenal ulcer (DU) patients at the time of enrollment; mean follow-up period of 14.4 years (range 1-30 years)] after being matched with a tumour registry database in Hiroshima prefecture were surveyed for GCa. We investigated Helicobacter pylori duodenal ulcer promoter gene A (dupA) using paraffin-embedded gastric biopsy specimens in 56 cases. Gastric acid secretion and basal acid output (BAO) in 40 cases, and maximal acid output in 68 cases, had been measured at first diagnosis of peptic ulcers. GCa was detected in 24 patients (17 with GU, 7 with DU) during the follow-up. The prevalence of GCa was significantly higher in GU patients than in DU patients (log-rank test P<0.05). dupA-positive H. pylori was detected not only in DU patients (9/20) but also in GU patients (9/36). Gastric acid output was significantly larger in quantity in patients with dupA-positive H. pylori than in those with dupA negative H. pylori (P<0.05). The occurrence of GCa was significantly lower in patients with dupA-positive H. pylori and a high BAO level (log-rank test P<0.05). DUs, higher acid output and dupA-positive H. pylori were negatively associated with GCa. PMID- 20829398 TI - Interleukin-18-mediated enhancement of the protective effect of an infectious laryngotracheitis virus glycoprotein B plasmid DNA vaccine in chickens. AB - The immunogenicity of an infectious laryngotracheitis virus (ILTV) glycoprotein B (gB) plasmid DNA vaccine and the immunoregulatory activity of chicken interleukin 18 (IL-18) were investigated in a challenge model. Two recombinant plasmids, pcDNA3.1/gB (pgB) and pcDNA3.1/IL-18 (pIL-18), containing gB and IL-18 were constructed. Chickens were intramuscularly administered two immunizations 2 weeks apart, and challenged with the virulent CG strain of ILTV 2 weeks later. All animals vaccinated with pgB alone or with a combination of pgB plus pIL-18 developed a specific anti-ILTV ELISA antibody and splenocyte proliferation response. The ratios of CD4(+) to CD8(+) T lymphocytes in chickens immunized with pgB plus pIL-18 were significantly higher than in those immunized with pgB alone. Co-injection of pIL-18 significantly increased the production of gamma interferon and IL-2, indicating that IL-18 enhances the T helper 1-dominant immune response. Challenge experiments showed that the morbidity rate in the pgB group (25 %) was significantly higher than that in the pgB plus pIL-18 group (10 %). The mortality rates in the pgB and pgB plus pIL-18 groups were 10 and 0 %, respectively, and the corresponding protection rates were 60 and 80 %. These results indicate that IL-18 may be an effective adjuvant for an ILTV vaccine. PMID- 20829399 TI - A report of Streptococcus pneumoniae serotype 6D in Europe. AB - Serotype 6D of Streptococcus pneumoniae has been reported in Asia and the Fijian islands among nasopharyngeal carriage isolates. We now report a 6D isolate from a Finnish adult with invasive pneumococcal disease. Interestingly, the Finnish isolate and Asian isolate capsule gene loci are almost identical. PMID- 20829400 TI - Sepsis with prolonged hypotension due to Moraxella osloensis in a non immunocompromised child. AB - We report a case of septicaemia with prolonged, refractory hypotension related to Moraxella osloensis isolated in a non-immunocompromised paediatric patient. PMID- 20829401 TI - Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Guidelines: a European Renal Best Practice (ERBP) commentary statement. AB - Under the auspices of the European Renal Best Practice, a group of European nephrologists, not serving on the Kidney Disease Improving Global Outcomes (KDIGO) working group, but with significant clinical and research interests and expertise in these areas, was invited to examine and critique the Chronic Kidney Disease-Mineral and Bone Disorder KDIGO document published in August 2009. The final form of this paper in Nephrology Dialysis Transplantation, as a commentary, not as a position statement, reflects the fact that we have had no more evidence to review, discuss and debate available to us than was available to the KDIGO working group. However, we have felt that we were able to comment on specific areas where we feel that further clinical guidance would be helpful, thereby going beyond the KDIGO position as reflected in their document. This present paper, we hope, will be of most use to the practising kidney specialist and those allied to the clinical team. PMID- 20829402 TI - A comparison of validity rates between paper-and-pencil and computerized testing with the MMPI-2. AB - Although the use of computerized testing in psychopathology assessment has increased in recent years, limited research has examined the impact of this format in terms of potential differences in test validity rates. The current study explores potential differences in the rates of valid and invalid Minnesota Multiphasic Personality Inventory-2 (MMPI-2) protocols between computerized and paper-and-pencil administrations. Participants were 387 undergraduate students (157 men and 230 women) from a Midwestern university who completed either a computerized version or a paper-and-pencil version of the MMPI-2. Chi-square analyses revealed some important differences between administration modalities by gender. Overall, results indicated that although no differences existed in the computerized version, men were more likely to invalidate the paper-and-pencil version. Furthermore, although less likely overall to produce invalid MMPI-2 results, women were more likely to invalidate the paper-and-pencil version via random responding compared with the computerized version. Limitations and future directions are discussed. PMID- 20829403 TI - Prenatal exposure to alcohol reduces nephron number and raises blood pressure in progeny. AB - Prenatal ethanol exposure is teratogenic, but the effects of ethanol on kidney development and the health of offspring are incompletely understood. Our objective was to investigate the effects of acute ethanol exposure during pregnancy on nephron endowment, mean arterial pressure, and renal function in offspring. We administered ethanol or saline by gavage to pregnant Sprague-Dawley rats on embryonic days 13.5 and 14.5. At 1 month of age, the nephron number was 15% lower and 10% lower in ethanol-exposed males and females, respectively, compared with controls. Mean arterial pressure, measured in conscious animals via indwelling tail-artery catheter, was 10% higher in both ethanol-exposed males and females compared with controls. GFR was 20% higher in ethanol-exposed males but 15% lower in ethanol-exposed females; moreover, males had increased proteinuria compared with controls. Furthermore, embryonic kidneys cultured in the presence of ethanol for 48 hours had 15% fewer ureteric branch points and tips than kidneys cultured in control media. Taken together, these data demonstrate that acute prenatal ethanol exposure reduces the number of nephrons, possibly as a result of inhibited ureteric branching morphogenesis, and that these changes affect adult cardiovascular and renal function. PMID- 20829404 TI - The EP4 receptor for prostaglandin E2 in glomerular disease: a good receptor turned bad? PMID- 20829405 TI - Mechanisms of type I and type II pseudohypoaldosteronism. AB - Pseudohypoaldosteronism (PHA) types I and II are curious genetic disorders that share hyperkalemia as a predominant finding. Together they have become windows to understanding new molecular physiology in the kidney. Autosomal recessive PHAI results from mutations in the epithelial sodium channel (ENaC), whereas autosomal dominant PHAI is characterized by mutations in the mineralocorticoid receptor. PHAII is the result of mutations in a family of serine-threonine kinases called with-no-lysine kinases (WNK)1 and WNK4. WNK4 negatively regulates the NaCl cotransporter (NCC), and PHAII mutations in WNK4 abrogate this affect. WNK4 also regulates the expression or function of renal outer medullary potassium (ROMK) channels, ENaCs, and Cl transporters. WNK1 also regulates NCC and ROMK. Aldosterone inactivates WNK1 and WNK4 activity. Whether angiotensin II can fine tune the actions of aldosterone is still unclear. PMID- 20829406 TI - Quantifying severity of chronic kidney disease as a risk factor for acute kidney injury. PMID- 20829407 TI - HO-1 in control of a self-eating kidney. PMID- 20829408 TI - Combined immunosuppression in high-risk patients with IgA nephropathy? PMID- 20829409 TI - Glomerular epithelial stem cells: the good, the bad, and the ugly. AB - Global glomerulosclerosis with loss of podocytes in humans is typical of end stage renal pathology. Although mature podocytes are highly differentiated and nondividing, converging evidence from experimental and clinical data suggests adult stem cells within Bowman's capsule can rescue some of this loss. Glomerular epithelial stem cells generate podocytes during kidney growth and regenerate podocytes after injury, thus explaining why various glomerular disorders undergo remission occasionally. This regenerative process, however, is often inadequate because of inefficient proliferative responses by glomerular epithelial stem cells with aging or in the setting of focal segmental glomerulosclerosis. Alternatively, an excessive proliferative response by glomerular epithelial stem cells after podocyte injury can generate new lesions such as extracapillary crescentic glomerulonephritis, collapsing glomerulopathy and tip lesions. Better understanding of the mechanisms that regulate growth and differentiation of glomerular epithelial stem cells may provide new clues for prevention and treatment of glomerulosclerosis. PMID- 20829410 TI - How long is the recovery of global aphasia? Twenty-five years of follow-up in a patient with left hemisphere stroke. AB - BACKGROUND: Current knowledge regarding the time course of aphasia recovery is based on observations limited to the first years after stroke. OBJECTIVE: The authors studied long-term outcome (25 years) of language in a patient with global aphasia. METHODS: A 37-year-old man with global aphasia from a large ischemic lesion in the left middle cerebral artery territory was tested 9 times between 3 weeks and 25 years poststroke by means of the Milan Language Examination, Token Test, Raven Test, and apraxia tests. RESULTS: Three main periods of recovery were identified. The first year after stroke was characterized by recovery of verbal comprehension and word repetition. From 1 to 3 years, naming and reading improved. From 3 to 25 years, progressive improvement of previously emerged functions was found, as well as the appearance of spontaneous speech. CONCLUSIONS: This unique long-term follow-up shows that the time span for recovery of language functions in global aphasia after stroke may be much longer than previously documented. PMID- 20829411 TI - Kinematic variables quantifying upper-extremity performance after stroke during reaching and drinking from a glass. AB - BACKGROUND: Three-dimensional kinematic analysis provides quantitative and qualitative assessment of upper-limb motion and is used as an outcome measure to evaluate impaired movement after stroke. The number of kinematic variables used, however, is diverse, and models for upper-extremity motion analysis vary. OBJECTIVE: The authors aim to identify a set of clinically useful and sensitive kinematic variables to quantify upper-extremity motor control during a purposeful daily activity, that is, drinking from a glass. METHODS: For this purpose, 19 participants with chronic stroke and 19 healthy controls reached for a glass of water, took a sip, and placed it back on a table in a standardized way. An optoelectronic system captured 3-dimensional kinematics. Kinematical parameters describing movement time, velocity, strategy and smoothness, interjoint coordination, and compensatory movements were analyzed between groups. RESULTS: The majority of kinematic variables showed significant differences between study groups. The number of movement units, total movement time, and peak angular velocity of elbow discriminated best between healthy participants and those with stroke as well as between those with moderate (Fugl-Meyer scores of 39-57) versus mild (Fugl-Meyer scores of 58-64) arm impairment. In addition, the measures of compensatory trunk and arm movements discriminated between those with moderate and mild stroke impairment. CONCLUSION: Kinematic analysis in this study identified a set of movement variables during a functional task that may serve as an objective assessment of upper-extremity motor performance in persons who can complete a task, such as reaching and drinking, after stroke. PMID- 20829412 TI - Auxiliary sensory cues improve automatic postural responses in individuals with diabetic neuropathy. AB - BACKGROUND: A loss of sensation in the lower limbs, observed in individuals with diabetes as well as elderly individuals, contributes to postural instability, altered gait patterns, increased risk of falling, and decreased quality of life. OBJECTIVE: To determine if somatosensory cues delivered to sensate areas of the lower limbs above the ankle joints enhance the control of posture in individuals with peripheral neuropathy. METHODS: Twelve subjects with sensory neuropathy due to diabetes participated in static and dynamic balance tests with and without auxiliary sensory cues provided to the lower limbs without stabilizing the ankle joints. During the tests the subjects were required to stand on a fixed or moving computer-controlled platform with their eyes open or closed. Equilibrium scores and response latency were obtained. RESULTS: For all tests, equilibrium scores were significantly larger in experiments with auxiliary sensory cues in comparison with conditions without cues (P < .05). Smaller latency scores were recorded in conditions with auxiliary sensory information. The results indicate that auxiliary sensory cues improved automatic postural responses. CONCLUSIONS: The observed enhancement of automatic postural responses has clinical implications that aid in the understanding of postural control in individuals with peripheral neuropathy. Future controlled trials could examine whether devices that provide auxiliary sensory cues can improve balance, mobility, and the performance of daily activities. PMID- 20829413 TI - A novel approach to ambulatory monitoring: investigation into the quantity and control of everyday walking in patients with subacute stroke. AB - BACKGROUND: Promoting whole body activities, such as walking, can help improve recovery after stroke. However, little information exists regarding the characteristics of daily walking in patients enrolled in rehabilitation poststroke. The objectives of this study were to: (1) examine the quantity of walking and duration of individual bouts of walking during an inpatient day, (2) compare standard laboratory symmetry measures with measures of symmetry captured throughout the day, and (3) investigate the association between quantity of walking and indices of stroke severity. METHODS: The study examined ambulatory activity among 16 inpatients with subacute stroke who were bilaterally instrumented with a wireless accelerometer above the ankle for approximately 8 continuous hours. RESULTS: On average, patients demonstrated 47.5 minutes (standard deviation [SD] = 26.6 minutes) of total walking activity and walking bout durations of 54.4 s (SD = 21.5 s). A statistically significant association was found between the number of walking bouts to total walking time (r = .76; P = .006) and laboratory gait speed (r = .51; P = .045) and between laboratory gait speed and balance impairment (r = .60; P = .013). Also, a significant increase in gait asymmetry was observed during day-long measurement compared with the standard laboratory-based assessment (P = .006). CONCLUSIONS: Rather modest amounts of daily walking were found for these ambulatory inpatients, consistent with previous reports about patients after stroke. Bouts of walking were short in duration, and the gait was more asymmetrical, compared with a standard gait assessment. Unobtrusive monitoring of daily walking exposes the characteristics and temporal qualities of poststroke ambulation. PMID- 20829414 TI - Compensational strategies for a merchant after stroke with anosognosia for alexia without agraphia. AB - We report the first case, to our knowledge, of successful return to work of a patient with alexia without agraphia. This case is also interesting as it is the first report of which we are aware of anosognosia for alexia without agraphia: the patient confabulated when asked to read English text, but immediately stated that he could not read Chinese text because he did not know that language. The selective nature of this confabulation would not be inconsistent with anosognosia being one of the brain's responses to absence of afferent information. PMID- 20829415 TI - In vivo visualization of vascular patterns of rotator cuff tears using contrast enhanced ultrasound. AB - BACKGROUND: Hypoxia and decreased blood supply have been proposed as risks for tendon rupture. Visualization of the vascularity of intact and torn rotator cuffs would be useful for improving treatments for rotator cuff tear. PURPOSE: To assess vascularity inside a tendon or an adjacent rotator cuff insertion point in patients differing in age and extent of damage to the tendon. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: Ten volunteers (all men) and 15 patients (10 men, 5 women) consented to participate in the study. Contrast agent for enhanced ultrasound was injected intravenously. Enhanced ultrasound images of the torn cuff and the contralateral shoulder were recorded for 1 minute. Four small regions of interest, the articular and bursal sides of the tendon and the medial and lateral sides of the bursa, were studied in all shoulders. RESULTS: There was a significant decrease in blood flow in the intratendinous region in elderly subjects compared with young subjects, but age had no effect on blood flow in bursal tissue. Blood flow in ruptured rotator cuffs did not differ from that in intact rotator cuffs. The intraclass correlation coefficient for intraobserver reproducibility was 0.82 (95% confidence interval: 0.77-0.86). CONCLUSIONS: The findings of this investigation were the hypovascular pattern in intratendinous tissue compared with the subacromial bursa, the age-related decrease in intratendinous vascularity, and the hypovascular pattern in the tendon, regardless of rupture of the tendon. Clarification of vascular patterns inside or around the torn ends of a rotator cuff will assist in the development of successful treatments for torn rotator cuffs. PMID- 20829416 TI - Cost-effectiveness of anterior cruciate ligament reconstruction: a preliminary comparison of single-bundle and double-bundle techniques. AB - BACKGROUND: There has been growing interest in anatomical reconstruction of the anterior cruciate ligament (ACL), including the use of double-bundle (DB) reconstruction techniques. HYPOTHESIS: The DB technique will not be cost effective when compared with single-bundle (SB) reconstruction. STUDY DESIGN: Economic and decision analysis; Level of evidence, 1. METHODS: A decision analysis model with input values derived from the literature was used to estimate the cost-effectiveness of DB ACL reconstruction compared with SB ACL reconstruction. Effectiveness was based on the revision rate and the postoperative International Knee Documentation Committee (IKDC) score. RESULTS: Sixty-four percent of DB knees result in an IKDC score of A, compared with 54% of SB knees. The incremental cost-effectiveness ratio of a DB reconstruction compared with an SB reconstruction was $6416 per quality adjusted life year in the baseline scenario and $64 371 per quality adjusted life year in the alternate scenario. The model is very sensitive to the proportions of IKDC A outcomes. The model is also sensitive to the utility values assigned to IKDC A and B outcomes and is less sensitive to the marginal cost of a DB reconstruction. CONCLUSION: This preliminary analysis based on published clinical results to date shows DB ACL reconstruction may be cost-effective, despite increased upfront cost. More research is needed to confirm whether there is any difference in the distribution of IKDC outcomes between the 2 techniques. Perhaps more importantly, the lack of any other demonstrated clinical benefit from the DB technique questions the clinical relevance of this difference in IKDC scores. CLINICAL RELEVANCE: Revision data and longer term outcomes after DB reconstruction and more reliable clinical utility data are needed to definitively compare the cost-effectiveness of DB and SB ACL reconstruction. Studies of ACL reconstruction and other sports medicine procedures should report the distribution of outcomes data to facilitate future analyses of clinical effectiveness. PMID- 20829417 TI - Autologous chondrocyte implantation for treatment of focal cartilage defects in patients age 40 years and older: A matched-pair analysis with 2-year follow-up. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) is an accepted surgical treatment in patients with isolated cartilage defects of the knee. Age has been considered as a limiting factor and the technique has not been recommended in patients older than 40 to 50 years. Nevertheless, some more recent studies report satisfying clinical results in middle-aged patients. HYPOTHESIS: Analogous to the microfracture technique, age over 40 years is associated with inferior clinical outcome after ACI. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Thirty-seven patients with an average age of 47.8 years (group 1) were matched with 37 patients with an average age of 31 years (group 2). Both groups underwent ACI for treatment of isolated cartilage defects of the knee. All patients were enrolled prospectively and followed for a period of 24 months using International Knee Documentation Committee (IKDC), Lysholm scale, Cincinnati sports scale, and Tegner activity evaluation instruments. RESULTS: Statistical analysis revealed a significant increase in function after ACI in both groups as early as 6 months after surgery until the end of the study period. There was only a slight tendency for better clinical outcome in younger patients (IKDC at 24 months: group 1, 72.2 +/- 15.8 [standard deviation]; group 2: 76.1 +/- 14.1; P = .261; Lysholm at 24 months: group 1: 80.42 +/- 15.37; group 2: 80.65 +/- 12.01), no statistical significant differences were found between patients of group 1 and group 2 at any of the time points investigated. CONCLUSION: In contrast to other cartilage repair techniques, patients 40 years and older do not have an inferior outcome up to 24 months after ACI for isolated cartilage defects when compared with younger patients. PMID- 20829418 TI - Ulnohumeral chondral and ligamentous overload: biomechanical correlation for posteromedial chondromalacia of the elbow in throwing athletes. AB - BACKGROUND: Previous studies have documented increased posteromedial contact forces with the elbow at lower flexion angles associated with valgus extension overload; however, the authors believe that posteromedial elbow impingement in association with valgus laxity is a complex pathological process that may occur throughout the entire throwing motion in the form of ulnohumeral chondral and ligamentous overload. HYPOTHESIS: Valgus laxity with the elbow at 90 degrees of flexion may lead to chondromalacia secondary to a subtle shift in the contact point between the tip of the olecranon and the distal humeral trochlea. STUDY DESIGN: Controlled laboratory study. METHODS: Six fresh human cadaveric elbows were dissected and subjected to a static valgus load. Pressure-sensitive Fuji film measured the contact pressure, contact area, and shift in contact area across the posteromedial elbow before and after sectioning the anterior bundle of the ulnar collateral ligament. RESULTS: The contact pressure between the tip of the olecranon process and the medial crista of the posterior humeral trochlea significantly increased, from an average of 0.27 +/- 0.06 kg/cm2 to 0.40 +/- 0.08 kg/cm2. The contact area also significantly decreased, from an average of 30.34 +/- 9.17 mm2 to 24.59 +/- 6.44 mm2, and shifted medially on the medial humeral crista, which corresponds to the position of the posteromedial chondral lesions that was observed in throwing athletes in the authors' clinical practice. CONCLUSION: While simulating the early acceleration phase of the throwing motion with the elbow in 90 degrees of flexion, the results illustrate that abnormal contact may occur as a result of valgus laxity through increased contact pressures across the posteromedial elbow between the medial tip of the olecranon and medial crista of the humeral trochlea. In addition, congruency of the ulnohumeral joint changed, as there was a statistically significant medial shift of the olecranon on the posterior humeral trochlea with the elbow at 90 degrees of flexion after sectioning the anterior bundle of the ulnar collateral ligament. CLINICAL RELEVANCE: In the throwing athlete who continues the repetitive, throwing motion despite valgus laxity from ulnar collateral ligament insufficiency, the authors believe that these results provide a plausible mechanism for injury throughout the entire throwing motion secondary to ulnohumeral chondral and ligamentous overload. As throwing athletes may produce a tremendous amount of force and subsequent chondromalacia within the posteromedial aspect of the elbow, the findings of this study illustrate the importance of prompt clinical recognition of ulnar collateral ligament insufficiency. PMID- 20829419 TI - Comparison of cystatin C and creatinine-based glomerular filtration rate formulas with 51Cr-EDTA clearance in patients with cirrhosis. AB - BACKGROUND AND OBJECTIVES: Renal function is an important predictor of survival in cirrhosis and liver transplantation. GFR estimates using serum cystatin C (CysC) are proposed as better predictors of renal function than ones on the basis of serum creatinine (Cr). Our aims were: (1) evaluate correlations between serum CysC and different methods of creatinine measurements; (2) compare CysC and Cr GFR formulas with (51)Cr-EDTA; and (3) evaluate liver-related parameters potentially influencing GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 254 blood samples in 65 patients with cirrhosis correlating CysC with four Cr methods were used; another 74 patients comparing (51)Cr-EDTA GFR to Modification of Diet in Renal Disease and Larsson and Hoek formulas for CysC were also included. Agreement was assessed using Bland-Altman plots and concordance correlation coefficients. Multivariate linear regression analysis was used for GFR predictors. RESULTS: Serum CysC correlated modestly with O'Leary modified Jaffe, compensated kinetic Jaffe, enzymatic creatinine, and standard kinetic Jaffe 0.72/0.71/0.72/0.72 (all P < 0.001). Bland-Altman agreement with (51)Cr-EDTA GFR was poor; the best agreement was Modification of Diet in Renal Disease (concordance 0.61; 95% CI, 0.47 to 0.71); the worst agreement was the Hoek formula (concordance 0.46; 95% CI, 0.27 to 0.61). A new GFR formula including the Child-Pugh score improved the accuracy of Cr GFR formulas compared with (51)Cr EDTA GFR. CONCLUSIONS: Estimated GFR in cirrhosis is not better with CysC formulas compared with creatinine ones: specific formulas may be necessary. PMID- 20829420 TI - Routine preoperative vascular ultrasound improves patency and use of arteriovenous fistulas for hemodialysis: a randomized trial. AB - BACKGROUND AND OBJECTIVES: Arteriovenous fistulas (AVFs) are the preferred vascular access for hemodialysis but have a considerable failure rate. This study investigated whether routine preoperative vascular ultrasound results in better AVF outcome than physical examination. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with end-stage kidney disease referred for permanent access formation were assessed by independent examiners using physical examination and ultrasound. After random allocation, the ultrasound report was disclosed to the surgeon for patients in the ultrasound group but not for the clinical group. End points were AVF failure and survival rates, analyzed by intention to treat and by use for hemodialysis. RESULTS: AVFs were made in 208 of 218 randomized patients. Clinical and ultrasound groups were similar in terms of patient characteristics, allocation to individual surgeons, and proportion of forearm AVFs. The ultrasound group had a significantly lower rate of immediate failure (4% versus 11%, P = 0.028) and, among failed AVFs, less thrombosis (38% versus 67%, P = 0.029). Primary AVF survival at 1 year was not statistically different (ultrasound = 65%, clinical = 56%, P = 0.081). Assisted primary AVF survival at 1 year was significantly better for the ultrasound group (80% versus 65%, P = 0.012). The number of patients requiring preoperative ultrasound to prevent one AVF failure was 12. CONCLUSIONS: Routine preoperative vascular ultrasound in addition to clinical assessment improves AVF outcomes in terms of patency and use for dialysis. National Research Register, United Kingdom, trial number N0046131432. PMID- 20829421 TI - Inflammation, oxidative stress, and insulin resistance in polycystic kidney disease. AB - BACKGROUND AND OBJECTIVES: Most deaths in autosomal dominant polycystic kidney disease (ADPKD) are attributable to cardiovascular disease (CVD). We examined novel CVD biomarkers in different stages of ADPKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We recruited 50 hypertensive subjects with ADPKD with estimated GFR (eGFR) of >60 ml/min per 1.73 m(2); 52 hypertensive subjects with ADPKD with eGFR of 25 to 60 ml/min per 1.73 m(2); 42 normotensive subjects with ADPKD and eGFR of >60 ml/min per 1.73 m(2); and 50 healthy controls. We assayed serum C reactive protein and IL-6 as markers of inflammation; plasma 8-epi-prostaglandin F(2alpha (8-epi-PGF2alpha)) and superoxide dismutase (SOD) as markers of oxidative stress; and homeostasis model assessment (HOMA) as a measure of insulin resistance. RESULTS: The hypertensive ADPKD eGFR of 25 to 60 group had higher levels of C-reactive protein and IL-6 than controls, normotensive ADPKD with eGFR of >60, and hypertensive ADPKD with eGFR of >60. The normotensive ADPKD eGFR >60, hypertensive ADPKD eGFR >60, and hypertensive ADPKD eGFR 25 to 60 groups had higher 8-epi-PGF(2alpha) and lower SOD than controls, with no difference between the ADPKD groups. There was no difference in HOMA levels between any of the groups. Adjustment for age, race, gender, and body mass index did not alter these relationships. CONCLUSIONS: Inflammation and oxidative stress are evident early in ADPKD even with preserved kidney function. Inflammation exhibits a graded relationship with levels of kidney function, whereas oxidative stress demonstrates a threshold effect. These pathways may be therapeutic targets for CVD risk mitigation. PMID- 20829422 TI - The origin of multiple molecular forms in urine of HNL/NGAL. AB - BACKGROUND AND OBJECTIVES: Several molecular forms of human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), a novel biomarker for acute kidney injury (AKI), have been found in urine. The origin of these different forms and the effect of antibody configuration on assay performances were investigated in this report. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The molecular forms of HNL/NGAL from human neutrophils and present in urine obtained from cardiac surgery patients and patients with urinary tract infection (UTI), as well as secreted from HK-2 cells, were studied by Western blotting. The levels of HNL/NGAL in urine were measured by ELISAs. Kidney injury was simulated by incubation of HK-2 cells under stressful conditions. RESULTS: The major molecular form of HNL/NGAL secreted by neutrophils is dimeric, whereas the major form secreted by HK-2 cells is monomeric. This was reflected by a predominance of the monomeric form in urine from patients with AKI and the dimeric form in patients with UTIs. The epitope specificities of the antibody used in the ELISAs had a profound effect on assay performance and paralleled differences of the antibodies to identify the different forms of urine HNL/NGAL. CONCLUSIONS: The monomeric form is the predominant form secreted by tubular epithelial cells, and the dimeric form is the predominant form secreted by neutrophils. The development of molecular form-specific assays for HNL/NGAL may be a means to identify the origin of HNL/NGAL in urine and construct more specific tools for the diagnosis of AKI. PMID- 20829423 TI - Measuring total blood calcium displays a low sensitivity for the diagnosis of hypercalcemia in incident renal transplant recipients. AB - BACKGROUND AND OBJECTIVES: Hypercalcemia is a common complication in renal transplant recipients and has been associated with nephrocalcinosis and poor graft outcome. The performance of total calcium (tCa) in the diagnosis of blood calcium disturbances in renal transplant recipients is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared the ability of total tCa concentration to identify low, normal, or high ionized calcium (iCa) concentration, i.e., the gold standard, in an unselected cohort of 268 renal transplant recipients. All patients were studied 3 and 12 months after successful engraftment. RESULTS: Hypercalcemia, defined as a iCa >1.29 mmol/L, was present in 58.6 and 44.8% of the patients at months 3 and 12, respectively. tCa concentrations >10.3 mg/dl, conversely, were observed in only 13.1% of the patients. Measuring tCa had a low sensitivity (20.3 and 24.2% at months 3 and 12, respectively) for the diagnosis of hypercalcemia. The agreement (kappa coefficient [95% confidence interval]) between tCa concentrations and iCa was poor (month 3: 0.11 [0.05 to 0.17]; month 12: 0.20 [0.11 to 0.30]). The risk for underestimating iCa was increased by a low total bicarbonate concentration. Metabolic acidosis was observed in 48.1 and 37.3% of the patients at months 3 and 12, respectively. CONCLUSIONS: Total calcium greatly underestimates the diagnosis of hypercalcemia in incident renal transplant recipients. This is mainly explained by the high prevalence of metabolic acidosis in these patients. PMID- 20829425 TI - Cell death mechanisms and their implications in toxicology. AB - Necrotic cell death was long regarded as the ultimate consequence of chemical toxicity and was thought to result from simple cell failure because of toxic interference with vital cell functions. Introduction of the novel concept of programmed cell death (PCD), or apoptosis, has changed this view dramatically. This development has been further stimulated by the characterization of several other genetically PCD modalities, such as autophagy and pyroptosis. Like apoptosis, these modes of cell death are governed by complex signaling networks, containing "switches" responsible for cross talk between them. Recruitment or repression of these cell death signaling networks by foreign chemicals can lead to acute as well as chronic toxicity. In many instances, such effects of toxicants are mediated by disruption/modulation of cellular Ca(2+) homeostasis or increased generation of reactive oxygen species in the mitochondria or other intracellular compartments. Caspases, calpains, lysosomal proteases, and endonucleases are the main executioners of cell death, and they often co-operate during the execution stage of apoptosis. Finally, dead or dying cells are recognized and engulfed by phagocytes to prevent inflammation and associated tissue damage. Defective macrophage engulfment and degradation of cell corpses may also result from toxicity and can contribute to both the inflammatory response and dysregulation of tissue homeostasis. Hence, the cell death and phagocytosis regulatory networks offer a multitude of targets for toxic chemicals. PMID- 20829424 TI - Prognostic value of aortic stiffness and calcification for cardiovascular events and mortality in dialysis patients: outcome of the calcification outcome in renal disease (CORD) study. AB - BACKGROUND AND OBJECTIVES: Radiographic calcification and arterial stiffness each individually are predictive of outcome in dialysis patients. However, it is unknown whether combined assessment of these intermediate endpoints also provides additional predictive value. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Scoring of abdominal aortic calcification (AAC) using plain lateral abdominal x ray and measurement of carotid-femoral pulse wave velocity (PWV) were performed in a cohort of 1084 prevalent dialysis patients recruited from 47 European dialysis centers. RESULTS: During a follow-up of 2 years, 234 deaths and 91 nonfatal cardiovascular (CV) events occurred. Compared with the lowest tertile of AAC, the risk of an event was increased by a factor 3.7 in patients with a score of 5 to 15 (middle tertile), and by a factor 8.6 in patients with scores of 16 to 24. Additionally, each 1-m/s increase in PWV was associated with a 15% higher risk. At higher AAC (scores >= 5), the effect of PWV was attenuated because of a negative PWV * AAC interaction (hazard ratio [HR]: 0.895 and 0.865 for middle and upper AAC tertiles). After accounting for age, diabetes, and serum albumin, AAC and PWV remained independent predictors of outcome. CONCLUSIONS: AAC and central arterial stiffness are independent predictors of mortality and nonfatal CV events in dialysis patients. The risk associated with an increased PWV is less pronounced at higher levels of calcification. Assessment of AAC and PWV is feasible in a clinical setting and both may be used for an accurate CV risk estimation in this heterogeneous population. PMID- 20829426 TI - Adding insult to injury: effects of xenobiotic-induced preantral ovotoxicity on ovarian development and oocyte fusibility. AB - Mammalian females are born with a finite number of nonrenewing primordial follicles, the majority of which remain in a quiescent state for many years. Because of their nonrenewing nature, these "resting" oocytes are particularly vulnerable to xenobiotic insult, resulting in premature ovarian senescence and the formation of dysfunctional oocytes. In this study, we characterized the mechanisms of ovotoxicity for three ovotoxic agents, 4-vinylcyclohexene diepoxide (VCD), methoxychlor (MXC), and menadione (MEN), all of which target immature follicles. Microarray analysis of neonatal mouse ovaries exposed to these xenobiotics in vitro revealed a more than twofold significant difference in transcript expression (p < 0.05) for a number of genes associated with apoptotic cell death and primordial follicle activation. Histomorphological and immunohistological analysis supported the microarray data, showing signs of primordial follicle activation and preantral follicle atresia both in vitro and in vivo. Sperm-oocyte fusion assays on oocytes obtained from adult Swiss mice treated neonatally revealed severely reduced sperm-egg binding and fusion in a dose-dependent manner for all the xenobiotic treatments. Additionally, lipid peroxidation analysis on xenobiotic-cultured oocytes indicated a dose-dependent increase in oocyte lipid peroxidation for all three xenobiotics in vitro. Our results reveal a novel mechanism of preantral ovotoxicity involving the homeostatic recruitment of primordial follicles to maintain the pool of developing follicles destroyed by xenobiotic exposure and to our knowledge provide the first documented evidence of short-term, low- and high-dose (VCD 40 80 mg/kg/day, MXC 50-100 mg/kg/day, MEN 7.5-15 mg/kg/day) neonatal exposure to xenobiotics causing long-term reactive oxygen species-induced oocyte dysfunction. PMID- 20829427 TI - Characterization of developmental neurotoxicity of As, Cd, and Pb mixture: synergistic action of metal mixture in glial and neuronal functions. AB - Neurotoxicity of individual metals is well investigated but that of metal mixture (MM), an environmental reality, in the developing brain is relatively obscure. We investigated the combinatorial effect of arsenic (As), cadmium (Cd), and lead (Pb) on rat brain development, spanning in utero to postnatal development. MM was administered by gavage to pregnant and lactating rats, and to postweaning pups till 2 months. The pups exhibited behavioral disturbances characterized by hyperlocomotion, increased grip strength, and learning-memory deficit. Disruption of the blood-brain barrier (BBB) was associated with dose-dependent increase in deposition of the metals in developing brain. Astrocytes were affected by MM treatment as evident from their reduced density, area, perimeter, compactness, and number of processes, and increased apoptosis in cerebral cortex and cerebellum. The metals induced synergistic reduction in glial fibrillary acidic protein (GFAP) expression during brain development; however, postweaning withdrawal of MM partially restored the levels of GFAP in adults. To characterize the toxic mechanism, we treated rat primary astrocytes with MM at concentrations ranging from lethal concentration (LC)(10) to LC(75) of the metals. We observed synergistic downregulation in viability and increase in apoptosis of the astrocytes, which were induced by proximal activation of extra cellular signal regulated kinase (ERK) signaling and downstream activation of Jun N-terminal kinase (JNK) pathway. Furthermore, rise in intracellular calcium ion ([Ca(2+)](i)) and reactive oxygen species generation promoted apoptosis in the astrocytes. Taken together, these observations are the first to show that mixture of As, Cd, and Pb has the capacity to induce synergistic toxicity in astrocytes that may compromise the BBB and may cause behavioral dysfunction in developing rats. PMID- 20829428 TI - Chronic ethanol exposure alters the levels, assembly, and cellular organization of the actin cytoskeleton and microtubules in hippocampal neurons in primary culture. AB - The organization and dynamics of microtubules (MTs) and the actin cytoskeleton are critical for the correct development and functions of neurons, including intracellular traffic and signaling. In vitro ethanol exposure impairs endocytosis, exocytosis, and nucleocytoplasmic traffic in astrocytes and alters endocytosis in cultured neurons. In astrocytes, these effects relate to changes in the organization and/or function of MTs and the actin cytoskeleton. To evaluate this possibility in hippocampal cultured neurons, we analyzed if chronic ethanol exposure affects the levels, assembly, and cellular organization of both cytoskeleton elements and the possible underlying mechanisms of these effects by morphological and biochemical methods. In the experiments described below, we provide the first evidence that chronic alcohol exposure decreases the amount of both filamentous actin and polymerized tubulin in neurons and that the number of MTs in dendrites lowers in treated cells. Alcohol also diminishes the MT associated protein-2 levels, which mainly localizes in the somatodendritic compartment in neurons. Ethanol decreases the levels of total Rac, Cdc42, and RhoA, three small guanosine triphosphatases (GTPases) involved in the organization and dynamics of the actin cytoskeleton and MTs. Yet when alcohol decreases the levels of the active forms (GTP bound) of Rac1 and Cdc42, it does not affect the active form of RhoA. We also investigated the levels of several effector and regulator molecules of these GTPases to find that alcohol induces heterogeneous results. In conclusion, our results show that MT, actin cytoskeleton organization, and Rho GTPase signaling pathways are targets for the toxic effects of ethanol in neurons. PMID- 20829429 TI - An integrative overview on the mechanisms underlying the renal tubular cytotoxicity of gentamicin. AB - Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death. PMID- 20829430 TI - Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. AB - The bile salt export pump (BSEP) is an efflux transporter, driving the elimination of endobiotic and xenobiotic substrates from hepatocytes into the bile. More specifically, it is responsible for the elimination of monovalent, conjugated bile salts, with little or no assistance from other apical transporters. Disruption of BSEP activity through genetic disorders is known to manifest in clinical liver injury such as progressive familial intrahepatic cholestasis type 2. Drug-induced disruption of BSEP is hypothesized to play a role in the development of liver injury for several marketed or withdrawn therapeutics. Unfortunately, preclinical animal models have been poor predictors of the liver injury associated with BSEP interference observed for humans, possibly because of interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation or constitutive expression, as well as other mechanisms. Thus, a BSEP-mediated liver liability may go undetected until the later stages of drug development, such as during clinical trials or even postlicensing. In the absence of a relevant preclinical test system for BSEP-mediated liver injury, the toxicological relevance of available in vitro models to human health rely on the use of benchmark compounds with known clinical outcomes, such as marketed or withdrawn drugs. In this study, membrane vesicles harvested from BSEP-transfected insect cells were used to assess the activity of more than 200 benchmark compounds to thoroughly investigate the relationship between interference with BSEP function and liver injury. The data suggest a relatively strong association between the pharmacological interference with BSEP function and human hepatotoxicity. Although the most accurate translation of risk would incorporate pharmacological potency, pharmacokinetics, clearance mechanisms, tissue distribution, physicochemical properties, indication, and other drug attributes, the additional understanding of a compound's potency for BSEP interference should help to limit or avoid BSEP related liver liabilities in humans that are not often detected by standard preclinical animal models. PMID- 20829431 TI - The human organic anion transporter genes OAT5 and OAT7 are transactivated by hepatocyte nuclear factor-1alpha (HNF-1alpha). AB - Organic anion transporters (OATs) are anion exchangers that transport small hydrophilic anions and diuretics, antibiotics, nonsteroidal anti-inflammatory drugs, antiviral nucleoside analogs, and antitumor drugs across membrane barriers of epithelia of diverse organs. Three OATs are present in human liver: OAT2, OAT5, and OAT7. Given that hepatocyte nuclear factor-1alpha (HNF-1alpha) has previously been shown to regulate the expression of several hepatocellular transporter genes, we investigated whether the liver-specific human OAT genes are also regulated by HNF-1alpha. Short interfering RNAs targeting HNF-1alpha reduced endogenous expression of OAT5 and OAT7, but not OAT2, in human liver-derived Huh7 cells. Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1alpha in HepG2 cells. Two putative HNF-1alpha binding elements in the proximal OAT5 promoter, located at nucleotides -68/-56 and -173/-160, and one element in the OAT7 promoter, located at nucleotides -14/-2 relative to the transcription start site, were shown to bind HNF-1alpha in electromobility shift assays, and these promoter regions also interacted with HNF-1alpha in chromatin immunoprecipitation assays. A correlation between HNF-1alpha and OAT5 (r = 0.134, P < 0.05) or OAT7 (r = 0.461, P < 0.001) mRNA expression levels in surgical liver biopsies from 75 patients further supported an important role of HNF-1alpha in the regulation of OAT gene expression. PMID- 20829432 TI - The high-affinity binding site for tricyclic antidepressants resides in the outer vestibule of the serotonin transporter. AB - The structure of the bacterial leucine transporter from Aquifex aeolicus (LeuT(Aa)) has been used as a model for mammalian Na(+)/Cl(-)-dependent transporters, in particular the serotonin transporter (SERT). The crystal structure of LeuT(Aa) liganded to tricyclic antidepressants predicts simultaneous binding of inhibitor and substrate. This is incompatible with the mutually competitive inhibition of substrates and inhibitors of SERT. We explored the binding modes of tricyclic antidepressants by homology modeling and docking studies. Two approaches were used subsequently to differentiate between three clusters of potential docking poses: 1) a diagnostic SERT(Y95F) mutation, which greatly reduced the affinity for [(3)H]imipramine but did not affect substrate binding; 2) competition binding experiments in the presence and absence of carbamazepine (i.e., a tricyclic imipramine analog with a short side chain that competes with [(3)H]imipramine binding to SERT). Binding of releasers (para chloroamphetamine, methylene-dioxy-methamphetamine/ecstasy) and of carbamazepine were mutually exclusive, but Dixon plots generated in the presence of carbamazepine yielded intersecting lines for serotonin, MPP(+), paroxetine, and ibogaine. These observations are consistent with a model, in which 1) the tricyclic ring is docked into the outer vestibule and the dimethyl-aminopropyl side chain points to the substrate binding site; 2) binding of amphetamines creates a structural change in the inner and outer vestibule that precludes docking of the tricyclic ring; 3) simultaneous binding of ibogaine (which binds to the inward-facing conformation) and of carbamazepine is indicative of a second binding site in the inner vestibule, consistent with the pseudosymmetric fold of monoamine transporters. This may be the second low-affinity binding site for antidepressants. PMID- 20829433 TI - Characterization of a mouse model of hyperglycemia and retinal neovascularization. AB - One of the limitations of research into diabetic retinopathy is the lack of suitable animal models. To study how the two important factors--hyperglycemia and vascular endothelial growth factor--interact in diabetic retinopathy, the Akimba mouse (Ins2AkitaVEGF+/-) was generated by crossing the Akita mouse (Ins2Akita) with the Kimba mouse (VEGF+/+). C57Bl/6 and the parental and Akimba mouse lines were characterized by biometric measurements, histology, immunohistochemistry, and Spectralis Heidelberg retinal angiography and optical coherence tomography. The Akimba line not only retained the characteristics of the parental strains, such as developing hyperglycemia and retinal neovascularization, but developed higher blood glucose levels at a younger age and had worse kidney-body weight ratios than the Akita line. With aging, the Akimba line demonstrated enhanced photoreceptor cell loss, thinning of the retina, and more severe retinal vascular pathology, including more severe capillary nonperfusion, vessel constriction, beading, neovascularization, fibroses, and edema, compared with the Kimba line. The vascular changes were associated with major histocompatibility complex class II+ cellular staining throughout the retina. Together, these observations suggest that hyperglycemia resulted in higher prevalences of edema and exacerbated the vascular endothelial growth factor-driven neovascular and retinal changes in the Akimba line. Thus, the Akimba line could become a useful model for studying the interplay between hyperglycemia and vascular endothelial growth factor and for testing treatment strategies for potentially blinding complications, such as edema. PMID- 20829434 TI - Identification of NURR1 as a mediator of MIF signaling during chronic arthritis: effects on glucocorticoid-induced MKP1. AB - Elucidation of factors regulating glucocorticoid (GC) sensitivity is required for the development of "steroid-sparing" therapies for chronic inflammatory diseases, including rheumatoid arthritis (RA). Accumulating evidence suggests that macrophage migration inhibitory factor (MIF) counterregulates the GC-induction of anti-inflammatory mediators, including mitogen-activated protein kinase phosphatase 1 (MKP1), a critical mitogen-activated protein kinase signaling inhibitor. This observation has yet to be extended to human disease; the molecular mechanisms remain unknown. We investigated NURR1, a GC-responsive transcription factor overexpressed in RA, as a MIF signaling target. We reveal abrogation by recombinant MIF (rMIF) of GC-induced MKP1 expression in RA fibroblast-like synoviocytes (FLS). rMIF enhanced NURR1 expression, artificial NBRE (orphan receptor DNA-binding site) reporter transactivation, and reversed GC inhibition of NURR1. NURR1 expression was reduced during experimental arthritis in MIF-/- synovium, and silencing MIF reduced RA FLS NURR1 mRNA. Consistent with NBRE identification on the MKP1 gene, MKP1 mRNA was reduced in FLS that ectopically express NURR1, and silencing NURR1 enhanced MKP1 mRNA in RA FLS. rMIF enhanced NBRE binding on the MKP1 gene, and the absence of the NBRE prevented NURR1-repressive effects on basal and GC-induced MKP1 transactivation. This study defines NURR1 as a novel MIF target in chronic inflammation and demonstrates a role for NURR1 in regulating the anti-inflammatory mediator, MKP1. We propose a MIF-NURR1 signaling axis as a regulator of the GC sensitivity of MKP1. PMID- 20829435 TI - MicroRNAs as biomarkers in colorectal cancer. AB - Colorectal cancer is a leading cause of cancer-related morbidity and mortality in the Western world. While improved diagnostic surveillance and treatment strategies involving surgery, chemo-, and radiotherapy have all contributed to earlier detection and improved survival, treatment decisions are still made almost exclusively based on the cancer's clinicopathological stage at diagnosis. Therefore, the search for new biomarkers to facilitate early diagnosis and individualized treatment is particularly warranted. MicroRNAs (miRNAs) are short, noncoding RNAs that regulate gene expression through posttranscriptional interactions with mRNA, thereby potentially leading to a vast range of downstream effects that depend on the target proteins affected. The discovery that miRNAs may act as either oncogenes or tumor suppressors has initiated extensive research in the cancer field, leading to the identification of numerous miRNAs implicated in carcinogenesis and tumor progression. MiRNAs are chemically stable and can thus be detected in a broad range of clinical samples, making these molecules particularly attractive as potential biomarkers in cancer. While the knowledge of miRNA involvement in colorectal cancer biology is less extensive than for other cancer types and several targets with potential biological and clinical relevance have been identified, a significant amount of research is still needed. In this review, we explore the literature regarding the relevance of miRNAs in colorectal cancer, focusing in particular on miRNAs as potential diagnostic, prognostic, and predictive biomarkers. PMID- 20829436 TI - Induction of podocyte VEGF164 overexpression at different stages of development causes congenital nephrosis or steroid-resistant nephrotic syndrome. AB - The tight regulation of vascular endothelial growth factor-A (VEGF-A) signaling is required for both the development and maintenance of the glomerular filtration barrier, but the pathogenic role of excessive amounts of VEGF-A detected in multiple renal diseases remains poorly defined. We generated inducible transgenic mice that overexpress podocyte VEGF164 at any chosen stage of development. In this study, we report the phenotypes that result from podocyte VEGF164 excess during organogenesis and after birth. On doxycycline induction, podocin-rtTA:tet O-VEGF164 mice express twofold higher kidney VEGF164 levels than single transgenic mice, localized to podocytes. Podocyte VEGF164 overexpression during organogenesis resulted in albuminuria at birth and was associated with glomerulomegaly, uniform podocyte effacement, very few and wide foot processes joined by occluding junctions, almost complete absence of slit diaphragms, and swollen endothelial cells with few fenestrae as revealed by transmission electron microscopy. Podocyte VEGF164 overexpression after birth caused massive albuminuria in 70% of 2-week-old mice, glomerulomegaly, and minimal changes on light microscopy. Transmission electron microscopy showed podocyte effacement and fusion and morphologically normal endothelial cells. Podocyte VEGF164 overexpression induced nephrin down-regulation without podocyte loss. VEGF164 induced abnormalities were reversible on removal of doxycycline and were unresponsive to methylprednisolone. Collectively, the data suggest that moderate podocyte VEGF164 overexpression during organogenesis results in congenital nephrotic syndrome, whereas VEGF164 overexpression after birth induces a steroid resistant minimal change like-disease in mice. PMID- 20829437 TI - Thymic stromal lymphopoietin contributes to myeloid hyperplasia and increased immunoglobulins, but not epidermal hyperplasia, in RabGEF1-deficient mice. AB - Mice overexpressing the proallergic cytokine thymic stromal lymphopoietin (TSLP) in the skin develop a pathology resembling atopic dermatitis. RabGEF1, a guanine nucleotide exchange factor for Rab5 GTPase, is a negative regulator of IgE dependent mast cell activation, and Rabgef1-/- and TSLP transgenic mice share many similar phenotypic characteristics, including elevated serum IgE levels and severe skin inflammation, with infiltrates of both lymphocytes and eosinophils. We report here that Rabgef1-/- mice also develop splenomegaly, lymphadenopathy, myeloid hyperplasia, and high levels of TSLP. Rabgef1-/-TSLPR-/- mice, which lack TSLP/TSLP receptor (TSLPR) signaling, had levels of blood neutrophils, spleen myeloid cells, and serum IL-4, IgG1, and IgE levels that were significantly reduced compared with those in Rabgef1-/-TSLPR+/+ mice. However, Rabgef1-/-TSLPR /- mice, like Rag1- or eosinophil-deficient Rabgef1-/- mice, developed cutaneous inflammation and epidermal hyperplasia. Therefore, in Rabgef1-/- mice, TSLP/TSLPR interactions are not required for the development of epidermal hyperplasia but contribute to the striking myeloid hyperplasia and overproduction of immunoglobulins observed in these animals. Our study shows that RabGEF1 can negatively regulate TSLP production in vivo and that excessive production of TSLP contributes to many of the phenotypic abnormalities in Rabgef1-/- mice. However, the marked epidermal hyperplasia, cutaneous inflammation, and increased numbers of dermal mast cells associated with RabGEF1 deficiency can develop via a TSLPR independent pathway, as well as in the absence of Rag1 or eosinophils. PMID- 20829438 TI - The implication of aberrant GM-CSF expression in decidual cells in the pathogenesis of preeclampsia. AB - Preeclampsia is characterized by an exaggerated systemic inflammatory state as well as shallow placentation. In the decidual implantation site, preeclampsia is accompanied by an excessive number of both macrophages and dendritic cells as well as their recruiting chemokines, which have been implicated in the impairment of endovascular trophoblast invasion. Granulocyte-macrophage colony-stimulating factor is known to regulate the differentiation of both macrophages and dendritic cells, prompting both in vivo and in vitro evaluation of granulocyte-macrophage colony-stimulating factor expression in human decidua as well as in a mouse model of preeclampsia. This study revealed increased granulocyte-macrophage colony stimulating factor expression levels in preeclamptic decidua. Moreover, both tumor necrosis factor-alpha and interleukin-1 beta, cytokines that are implicated in the genesis of preeclampsia, markedly up-regulated granulocyte-macrophage colony-stimulating factor production in cultured first-trimester human decidual cells. The conditioned media of these cultures promoted the differentiation of both macrophages and dendritic cells from a monocyte precursor. Evaluation of a murine model of preeclampsia revealed that the decidua of affected animals displayed higher levels of immunoreactive granulocyte-macrophage colony stimulating factor as well as increased numbers of both macrophages and dendritic cells when compared to control animals. Because granulocyte-macrophage colony stimulating factor is a potent inducer of differentiation and activation of both macrophages and dendritic cells, these findings suggest that this factor plays a crucial role in the pathogenesis of preeclampsia. PMID- 20829439 TI - Impaired Wnt signaling in embryonal rhabdomyosarcoma cells from p53/c-fos double mutant mice. AB - Rhabdomyosarcoma is a primitive neoplasm with a poorly understood etiology that exhibits features of fetal skeletal muscle. It represents the most frequent malignant soft tissue sarcoma affecting the pediatric population and is often treated very aggressively. Embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma constitute the two major subtypes and exhibit different molecular features. We investigated one potential molecular basis for ERMS by using cells derived from tumors produced in p53(-/-)/c-fos(-/-) mice. This model closely recapitulates the timing, location, molecular markers, and histology seen in human ERMS. A combined chromatin immunoprecipitation/promoter microarray approach was used to identify promoters bound by the c-Jun-containing AP-1 complex in the tumor-derived cells that lacked c-Fos. Identification of the Wnt2 gene and its overexpression in ERMS cells was confirmed in human rhabdomyosarcoma cell lines and prompted further analysis of the Wnt signaling pathway. Contrary to our expectations, the canonical Wnt/beta-catenin signaling pathway was down regulated in ERMS cells compared with normal myoblasts, and activating this pathway promoted myogenic differentiation. Furthermore, the identification of both survivin and sfrp2 through promoter and expression analyses suggested that increased resistance to apoptosis was associated with the inhibition of the Wnt signaling pathway. These results suggest that altered AP-1 activity that leads to the down-regulation of the Wnt pathway may contribute to the inhibition of myogenic differentiation and resistance to apoptosis in ERMS cases. PMID- 20829440 TI - An omega-3 fatty acid-enriched diet prevents skeletal muscle lesions in a hamster model of dystrophy. AB - Currently, despite well-known mutational causes, a universal treatment for neuromuscular disorders is still lacking, and current therapeutic efforts are mainly restricted to symptomatic treatments. In the present study, delta sarcoglycan-null dystrophic hamsters were fed a diet enriched in flaxseed-derived omega3 alpha-linolenic fatty acid from weaning until death. alpha-linolenic fatty acid precluded the dystrophic degeneration of muscle morphology and function. In fact, in dystrophic animals fed flaxseed-derived alpha-linolenic fatty acid, the histological appearance of the muscular tissue was improved, the proliferation of interstitial cells was decreased, and the myogenic differentiation originated new myocytes to repair the injured muscle. In addition, muscle myofibers were larger and cell membrane integrity was preserved, as witnessed by the correct localization of alpha-, beta-, and gamma-sarcoglycans and alpha-dystroglycan. Furthermore, the cytoplasmic accumulation of both beta-catenin and caveolin-3 was abolished in dystrophic hamster muscle fed alpha-linolenic fatty acid versus control animals fed standard diet, while alpha-myosin heavy chain was expressed at nearly physiological levels. These findings, obtained by dietary intervention only, introduce a novel concept that provides evidence that the modulation of the plasmalemma lipid profile could represent an efficacious strategy to ameliorate human muscular dystrophy. PMID- 20829442 TI - ODES: an overlapping dense sub-graph algorithm. AB - SUMMARY: Enumeration of the dense sub-graphs of a graph is of interest in community discovery and membership problems, including dense sub-graphs that overlap each other. Described herein is ODES (Overlapping DEnse Sub-graphs), pthreads parallelized software to extract all overlapping maximal sub-graphs whose densities are greater than or equal to a specified cutoff density of at least 1/2. AVAILABILITY AND IMPLEMENTATION: http://dense.sf.net PMID- 20829441 TI - Absence of high-risk human papillomavirus (HPV) detection in endocervical adenocarcinoma with gastric morphology and phenotype. AB - A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination. PMID- 20829443 TI - SBML2TikZ: supporting the SBML render extension in LaTeX. AB - MOTIVATION: The SBML Render Extension enables coloring and shape information of biochemical models to be stored in the Systems Biology Markup Language (SBML). Rendering of this stored graphical information in a portable and well supported system such as TeX would be useful for researchers preparing documentation and presentations. In addition, since the Render Extension is not yet supported by many applications, it is helpful for such rendering functionality be extended to the more popular CellDesigner annotation as well. RESULTS: SBML2TikZ supports automatic generation of graphics for biochemical models in the popular TeX typesetting system. The library generates a script of TeX macro commands for the vector graphics languages PGF/TikZ that can be compiled into scalable vector graphics described in a model. AVAILABILITY: Source code, documentation and compiled binaries for the SBML2TikZ library can be found at http://www.sbml2tikz.org. In addition, a web application is available at http://www.sys-bio.org/layout PMID- 20829444 TI - The Chemical Translation Service--a web-based tool to improve standardization of metabolomic reports. AB - SUMMARY: Metabolomic publications and databases use different database identifiers or even trivial names which disable queries across databases or between studies. The best way to annotate metabolites is by chemical structures, encoded by the International Chemical Identifier code (InChI) or InChIKey. We have implemented a web-based Chemical Translation Service that performs batch conversions of the most common compound identifiers, including CAS, CHEBI, compound formulas, Human Metabolome Database HMDB, InChI, InChIKey, IUPAC name, KEGG, LipidMaps, PubChem CID+SID, SMILES and chemical synonym names. Batch conversion downloads of 1410 CIDs are performed in 2.5 min. Structures are automatically displayed. IMPLEMENTATION: The software was implemented in Groovy and JAVA, the web frontend was implemented in GRAILS and the database used was PostgreSQL. AVAILABILITY: The source code and an online web interface are freely available. Chemical Translation Service (CTS): http://cts.fiehnlab.ucdavis.edu CONTACT: ofiehn@ucdavis.edu PMID- 20829445 TI - PubDNA Finder: a web database linking full-text articles to sequences of nucleic acids. AB - SUMMARY: PubDNA Finder is an online repository that we have created to link PubMed Central manuscripts to the sequences of nucleic acids appearing in them. It extends the search capabilities provided by PubMed Central by enabling researchers to perform advanced searches involving sequences of nucleic acids. This includes, among other features (i) searching for papers mentioning one or more specific sequences of nucleic acids and (ii) retrieving the genetic sequences appearing in different articles. These additional query capabilities are provided by a searchable index that we created by using the full text of the 176 672 papers available at PubMed Central at the time of writing and the sequences of nucleic acids appearing in them. To automatically extract the genetic sequences occurring in each paper, we used an original method we have developed. The database is updated monthly by automatically connecting to the PubMed Central FTP site to retrieve and index new manuscripts. Users can query the database via the web interface provided. AVAILABILITY: PubDNA Finder can be freely accessed at http://servet.dia.fi.upm.es:8080/pubdnafinder PMID- 20829446 TI - Destiny is now. PMID- 20829447 TI - State the obvious. PMID- 20829448 TI - The Physical Therapy and Society Summit (PASS) Meeting: observations and opportunities. AB - The construct of delivering high-quality and cost-effective health care is in flux, and the profession must strategically plan how to meet the needs of society. In 2006, the House of Delegates of the American Physical Therapy Association passed a motion to convene a summit on "how physical therapists can meet current, evolving, and future societal health care needs." The Physical Therapy and Society Summit (PASS) meeting on February 27-28, 2009, in Leesburg, Virginia, sent a clear message that for physical therapists to be effective and thrive in the health care environment of the future, a paradigm shift is required. During the PASS meeting, participants reframed our traditional focus on the physical therapist and the patient/client (consumer) to one in which physical therapists are an integral part of a collaborative, multidisciplinary health care team with the health care consumer as its focus. The PASS Steering Committee recognized that some of the opportunities that surfaced during the PASS meeting may be disruptive or may not be within the profession's present strategic or tactical plans. Thus, adopting a framework that helps to establish the need for change that is provocative and potentially disruptive to our present care delivery, yet prioritizes opportunities, is a critical and essential step. Each of us in the physical therapy profession must take on post-PASS roles and responsibilities to accomplish the systemic change that is so intimately intertwined with our destiny. This article offers a perspective of the dynamic dialogue and suggestions that emerged from the PASS event, providing further opportunities for discussion and action within our profession. PMID- 20829449 TI - The generating function of CID, ETD, and CID/ETD pairs of tandem mass spectra: applications to database search. AB - Recent emergence of new mass spectrometry techniques (e.g. electron transfer dissociation, ETD) and improved availability of additional proteases (e.g. Lys-N) for protein digestion in high-throughput experiments raised the challenge of designing new algorithms for interpreting the resulting new types of tandem mass (MS/MS) spectra. Traditional MS/MS database search algorithms such as SEQUEST and Mascot were originally designed for collision induced dissociation (CID) of tryptic peptides and are largely based on expert knowledge about fragmentation of tryptic peptides (rather than machine learning techniques) to design CID-specific scoring functions. As a result, the performance of these algorithms is suboptimal for new mass spectrometry technologies or nontryptic peptides. We recently proposed the generating function approach (MS-GF) for CID spectra of tryptic peptides. In this study, we extend MS-GF to automatically derive scoring parameters from a set of annotated MS/MS spectra of any type (e.g. CID, ETD, etc.), and present a new database search tool MS-GFDB based on MS-GF. We show that MS-GFDB outperforms Mascot for ETD spectra or peptides digested with Lys-N. For example, in the case of ETD spectra, the number of tryptic and Lys-N peptides identified by MS-GFDB increased by a factor of 2.7 and 2.6 as compared with Mascot. Moreover, even following a decade of Mascot developments for analyzing CID spectra of tryptic peptides, MS-GFDB (that is not particularly tailored for CID spectra or tryptic peptides) resulted in 28% increase over Mascot in the number of peptide identifications. Finally, we propose a statistical framework for analyzing multiple spectra from the same precursor (e.g. CID/ETD spectral pairs) and assigning p values to peptide-spectrum-spectrum matches. PMID- 20829450 TI - Neutrino spectroscopy can probe the dark matter content in the Sun. AB - After being gravitationally captured, low-mass cold dark-matter particles (mass range from 5 to ~50 * 10(9) electron volts) are thought to drift to the center of the Sun and affect its internal structure. Solar neutrinos provide a way to probe the physical processes occurring in the Sun's core. Solar neutrino spectroscopy, in particular, is expected to measure the neutrino fluxes produced in nuclear reactions in the Sun. Here, we show how the presence of dark-matter particles inside the Sun will produce unique neutrino flux distributions in (7)Be-nu and (8)B-nu, as well as (13)N-nu, (15)O-nu, and (17)F-nu. PMID- 20829451 TI - Cellodextrin transport in yeast for improved biofuel production. AB - Fungal degradation of plant biomass may provide insights for improving cellulosic biofuel production. We show that the model cellulolytic fungus Neurospora crassa relies on a high-affinity cellodextrin transport system for rapid growth on cellulose. Reconstitution of the N. crassa cellodextrin transport system in Saccharomyces cerevisiae promotes efficient growth of this yeast on cellodextrins. In simultaneous saccharification and fermentation experiments, the engineered yeast strains more rapidly convert cellulose to ethanol when compared with yeast lacking this system. PMID- 20829452 TI - Universal dynamical decoupling of a single solid-state spin from a spin bath. AB - Controlling the interaction of a single quantum system with its environment is a fundamental challenge in quantum science and technology. We strongly suppressed the coupling of a single spin in diamond with the surrounding spin bath by using double-axis dynamical decoupling. The coherence was preserved for arbitrary quantum states, as verified by quantum process tomography. The resulting coherence time enhancement followed a general scaling with the number of decoupling pulses. No limit was observed for the decoupling action up to 136 pulses, for which the coherence time was enhanced more than 25 times compared to that obtained with spin echo. These results uncover a new regime for experimental quantum science and allow us to overcome a major hurdle for implementing quantum information protocols. PMID- 20829453 TI - Greater neural pattern similarity across repetitions is associated with better memory. AB - Repeated study improves memory, but the underlying neural mechanisms of this improvement are not well understood. Using functional magnetic resonance imaging and representational similarity analysis of brain activity, we found that, compared with forgotten items, subsequently remembered faces and words showed greater similarity in neural activation across multiple study in many brain regions, including (but not limited to) the regions whose mean activities were correlated with subsequent memory. This result addresses a longstanding debate in the study of memory by showing that successful episodic memory encoding occurs when the same neural representations are more precisely reactivated across study episodes, rather than when patterns of activation are more variable across time. PMID- 20829454 TI - Tau reduction prevents Abeta-induced defects in axonal transport. AB - Amyloid-beta (Abeta) peptides, derived from the amyloid precursor protein, and the microtubule-associated protein tau are key pathogenic factors in Alzheimer's disease (AD). How exactly they impair cognitive functions is unknown. We assessed the effects of Abeta and tau on axonal transport of mitochondria and the neurotrophin receptor TrkA, cargoes that are critical for neuronal function and survival and whose distributions are altered in AD. Abeta oligomers rapidly inhibited axonal transport of these cargoes in wild-type neurons. Lowering tau levels prevented these defects without affecting baseline axonal transport. Thus, Abeta requires tau to impair axonal transport, and tau reduction protects against Abeta-induced axonal transport defects. PMID- 20829455 TI - Overbuilding research capacity. PMID- 20829456 TI - High-energy physics. Higgs or bust? Fermilab weighs adding 3 years to Tevatron run. PMID- 20829457 TI - Planetary science. Phoenix lander revealing a younger, livelier Mars. PMID- 20829459 TI - Biodiversity. Brazil says rate of deforestation in Amazon continues to plunge. PMID- 20829460 TI - Biodiversity. Joint expedition discovers deep-sea biodiversity, new volcanoes. PMID- 20829462 TI - Despite progress, biodiversity declines. PMID- 20829463 TI - Tending the global garden. PMID- 20829464 TI - Saving forests to save biodiversity. PMID- 20829465 TI - Overuse could leave Southwest high and dry. PMID- 20829466 TI - No return from biodiversity loss. PMID- 20829467 TI - Test ban results could be negative. PMID- 20829469 TI - Demography. Remeasuring aging. PMID- 20829470 TI - Cell biology. Septins at the nexus. PMID- 20829471 TI - Plant science. Oscillating roots. PMID- 20829472 TI - Medicine. The blood stem cell Holy Grail? PMID- 20829473 TI - Climate change. Farewell to fossil fuels? PMID- 20829474 TI - Materials science. Shape memory bulk metallic glass composites. PMID- 20829475 TI - Biochemistry. Exciting structures. PMID- 20829476 TI - Biodiversity conservation: challenges beyond 2010. AB - The continued growth of human populations and of per capita consumption have resulted in unsustainable exploitation of Earth's biological diversity, exacerbated by climate change, ocean acidification, and other anthropogenic environmental impacts. We argue that effective conservation of biodiversity is essential for human survival and the maintenance of ecosystem processes. Despite some conservation successes (especially at local scales) and increasing public and government interest in living sustainably, biodiversity continues to decline. Moving beyond 2010, successful conservation approaches need to be reinforced and adequately financed. In addition, however, more radical changes are required that recognize biodiversity as a global public good, that integrate biodiversity conservation into policies and decision frameworks for resource production and consumption, and that focus on wider institutional and societal changes to enable more effective implementation of policy. PMID- 20829477 TI - Oscillating gene expression determines competence for periodic Arabidopsis root branching. AB - Plants and animals produce modular developmental units in a periodic fashion. In plants, lateral roots form as repeating units along the root primary axis; however, the developmental mechanism regulating this process is unknown. We found that cyclic expression pulses of a reporter gene mark the position of future lateral roots by establishing prebranch sites and that prebranch site production and root bending are periodic. Microarray and promoter-luciferase studies revealed two sets of genes oscillating in opposite phases at the root tip. Genetic studies show that some oscillating transcriptional regulators are required for periodicity in one or both developmental processes. This molecular mechanism has characteristics that resemble molecular clock-driven activities in animal species. PMID- 20829478 TI - A transient and low-populated protein-folding intermediate at atomic resolution. AB - Proteins can sample conformational states that are critical for function but are seldom detected directly because of their low occupancies and short lifetimes. In this work, we used chemical shifts and bond-vector orientation constraints obtained from nuclear magnetic resonance relaxation dispersion spectroscopy, in concert with a chemical shift-based method for structure elucidation, to determine an atomic-resolution structure of an "invisible" folding intermediate of a small protein module: the FF domain. The structure reveals non-native elements preventing formation of the native conformation in the carboxyl-terminal part of the protein. This is consistent with the kinetics of folding in which a well-structured intermediate forms rapidly and then rearranges slowly to the native state. The approach introduces a general strategy for structure determination of low-populated and transiently formed protein states. PMID- 20829479 TI - Electromechanical computing at 500 degrees C with silicon carbide. AB - Logic circuits capable of operating at high temperatures can alleviate expensive heat-sinking and thermal-management requirements of modern electronics and are enabling for advanced propulsion systems. Replacing existing complementary metal oxide semiconductor field-effect transistors with silicon carbide (SiC) nanoelectromechanical system (NEMS) switches is a promising approach for low power, high-performance logic operation at temperatures higher than 300 degrees C, beyond the capability of conventional silicon technology. These switches are capable of achieving virtually zero off-state current, microwave operating frequencies, radiation hardness, and nanoscale dimensions. Here, we report a microfabricated electromechanical inverter with SiC complementary NEMS switches capable of operating at 500 degrees C with ultralow leakage current. PMID- 20829480 TI - Coherence resonance in a single-walled carbon nanotube ion channel. AB - Biological ion channels are able to generate coherent and oscillatory signals from intrinsically noisy and stochastic components for ultrasensitive discrimination with the use of stochastic resonance, a concept not yet demonstrated in human-made analogs. We show that a single-walled carbon nanotube demonstrates oscillations in electroosmotic current through its interior at specific ranges of electric field that are the signatures of coherence resonance. Stochastic pore blocking is observed when individual cations partition into the nanotube obstructing an otherwise stable proton current. The observed oscillations occur because of coupling between pore blocking and a proton diffusion limitation at the pore mouth. The result illustrates how simple ionic transport can generate coherent waveforms within an inherently noisy environment and points to new types of nanoreactors, sensors, and nanofluidic channels based on this platform. PMID- 20829481 TI - Ion-mediated electron transfer in a supramolecular donor-acceptor ensemble. AB - Ion binding often mediates electron transfer in biological systems as a cofactor strategy, either as a promoter or as an inhibitor. However, it has rarely, if ever, been exploited for that purpose in synthetic host-guest assemblies. We report here that strong binding of specific anions (chloride, bromide, and methylsulfate but not tetrafluoroborate or hexafluorophosphate) to a tetrathiafulvalene calix[4]pyrrole (TTF-C4P) donor enforces a host conformation that favors electron transfer to a bisimidazolium quinone (BIQ2+) guest acceptor. In contrast, the addition of a tetraethylammonium cation, which binds more effectively than the BIQ2+ guest in the TTF-C4P cavity, leads to back electron transfer, restoring the initial oxidation states of the donor and acceptor pair. The products of these processes were characterized via spectroscopy and x-ray crystallography. PMID- 20829482 TI - Nonthermal current-stimulated desorption of gases from carbon nanotubes. AB - The desorption of gases from carbon nanotubes is usually a slow process that limits the nanotubes' utility as sensors or as memristors. Here, we demonstrate that flow in the nanotube above the Poole-Frenkel conduction threshold can stimulate adsorbates to desorb without heating the sensor substantially. The method is general: alcohols, aromatics, amines, and phosphonates were all found to desorb. We postulate that the process is analogous to electron-stimulated desorption, but with an internally conducted rather than externally applied source of electrons. PMID- 20829483 TI - Future CO2 emissions and climate change from existing energy infrastructure. AB - Slowing climate change requires overcoming inertia in political, technological, and geophysical systems. Of these, only geophysical warming commitment has been quantified. We estimated the commitment to future emissions and warming represented by existing carbon dioxide-emitting devices. We calculated cumulative future emissions of 496 (282 to 701 in lower- and upper-bounding scenarios) gigatonnes of CO2 from combustion of fossil fuels by existing infrastructure between 2010 and 2060, forcing mean warming of 1.3 degrees C (1.1 degrees to 1.4 degrees C) above the pre-industrial era and atmospheric concentrations of CO2 less than 430 parts per million. Because these conditions would likely avoid many key impacts of climate change, we conclude that sources of the most threatening emissions have yet to be built. However, CO2-emitting infrastructure will expand unless extraordinary efforts are undertaken to develop alternatives. PMID- 20829484 TI - Stable isotope measurements of martian atmospheric CO2 at the Phoenix landing site. AB - Carbon dioxide is a primary component of the martian atmosphere and reacts readily with water and silicate rocks. Thus, the stable isotopic composition of CO2 can reveal much about the history of volatiles on the planet. The Mars Phoenix spacecraft measurements of carbon isotopes [referenced to the Vienna Pee Dee belemnite (VPDB)] [delta13C(VPDB) = -2.5 +/- 4.3 per mil (per thousand)] and oxygen isotopes [referenced to the Vienna standard mean ocean water (VSMOW)] (delta18O(VSMOW) = 31.0 +/- 5.7 per thousand), reported here, indicate that CO2 is heavily influenced by modern volcanic degassing and equilibration with liquid water. When combined with data from the martian meteorites, a general model can be constructed that constrains the history of water, volcanism, atmospheric evolution, and weathering on Mars. This suggests that low-temperature water-rock interaction has been dominant throughout martian history, carbonate formation is active and ongoing, and recent volcanic degassing has played a substantial role in the composition of the modern atmosphere. PMID- 20829485 TI - Self-assembly of filopodia-like structures on supported lipid bilayers. AB - Filopodia are finger-like protrusive structures, containing actin bundles. By incubating frog egg extracts with supported lipid bilayers containing phosphatidylinositol 4,5 bisphosphate, we have reconstituted the assembly of filopodia-like structures (FLSs). The actin assembles into parallel bundles, and known filopodial components localize to the tip and shaft. The filopodia tip complexes self-organize--they are not templated by preexisting membrane microdomains. The F-BAR domain protein toca-1 recruits N-WASP, followed by the Arp2/3 complex and actin. Elongation proteins, Diaphanous-related formin, VASP, and fascin are recruited subsequently. Although the Arp2/3 complex is required for FLS initiation, it is not essential for elongation, which involves formins. We propose that filopodia form via clustering of Arp2/3 complex activators, self assembly of filopodial tip complexes on the membrane, and outgrowth of actin bundles. PMID- 20829486 TI - Human SIRT6 promotes DNA end resection through CtIP deacetylation. AB - SIRT6 belongs to the sirtuin family of protein lysine deacetylases, which regulate aging and genome stability. We found that human SIRT6 has a role in promoting DNA end resection, a crucial step in DNA double-strand break (DSB) repair by homologous recombination. SIRT6 depletion impaired the accumulation of replication protein A and single-stranded DNA at DNA damage sites, reduced rates of homologous recombination, and sensitized cells to DSB-inducing agents. We identified the DSB resection protein CtIP [C-terminal binding protein (CtBP) interacting protein] as a SIRT6 interaction partner and showed that SIRT6 dependent CtIP deacetylation promotes resection. A nonacetylatable CtIP mutant alleviated the effect of SIRT6 depletion on resection, thus identifying CtIP as a key substrate by which SIRT6 facilitates DSB processing and homologous recombination. These findings further clarify how SIRT6 promotes genome stability. PMID- 20829487 TI - Hemocyte differentiation mediates innate immune memory in Anopheles gambiae mosquitoes. AB - Mosquito midgut invasion by ookinetes of the malaria parasite Plasmodium disrupts the barriers that normally prevent the gut microbiota from coming in direct contact with epithelial cells. This triggers a long-lived response characterized by increased abundance of granulocytes, a subpopulation of hemocytes that circulates in the insect's hemocoel, and enhanced immunity to bacteria that indirectly reduces survival of Plasmodium parasites upon reinfection. In mosquitoes, differentiation of hemocytes was necessary and sufficient to confer innate immune memory. PMID- 20829488 TI - Sequence- and structure-specific RNA processing by a CRISPR endonuclease. AB - Many bacteria and archaea contain clustered regularly interspaced short palindromic repeats (CRISPRs) that confer resistance to invasive genetic elements. Central to this immune system is the production of CRISPR-derived RNAs (crRNAs) after transcription of the CRISPR locus. Here, we identify the endoribonuclease (Csy4) responsible for CRISPR transcript (pre-crRNA) processing in Pseudomonas aeruginosa. A 1.8 angstrom crystal structure of Csy4 bound to its cognate RNA reveals that Csy4 makes sequence-specific interactions in the major groove of the crRNA repeat stem-loop. Together with electrostatic contacts to the phosphate backbone, these enable Csy4 to bind selectively and cleave pre-crRNAs using phylogenetically conserved serine and histidine residues in the active site. The RNA recognition mechanism identified here explains sequence- and structure-specific processing by a large family of CRISPR-specific endoribonucleases. PMID- 20829489 TI - Prediction of individual brain maturity using fMRI. AB - Group functional connectivity magnetic resonance imaging (fcMRI) studies have documented reliable changes in human functional brain maturity over development. Here we show that support vector machine-based multivariate pattern analysis extracts sufficient information from fcMRI data to make accurate predictions about individuals' brain maturity across development. The use of only 5 minutes of resting-state fcMRI data from 238 scans of typically developing volunteers (ages 7 to 30 years) allowed prediction of individual brain maturity as a functional connectivity maturation index. The resultant functional maturation curve accounted for 55% of the sample variance and followed a nonlinear asymptotic growth curve shape. The greatest relative contribution to predicting individual brain maturity was made by the weakening of short-range functional connections between the adult brain's major functional networks. PMID- 20829491 TI - Exploring challenges in rational enzyme design by simulating the catalysis in artificial kemp eliminase. AB - One of the fundamental challenges in biotechnology and in biochemistry is the ability to design effective enzymes. Doing so would be a convincing manifestation of a full understanding of the origin of enzyme catalysis. Despite an impressive progress, most of the advances on this front have been made by placing the reacting fragments in the proper places, rather than by optimizing the environment preorganization, which is the key factor in enzyme catalysis. Rational improvement of the preorganization would require approaches capable of evaluating reliably the actual catalytic effect. This work takes previously designed kemp eliminases as a benchmark for a computer aided enzyme design, using the empirical valence bond as the main screening tool. The observed absolute catalytic effect and the effect of directed evolution are reproduced and analyzed (assuming that the substrate is in the designed site). It is found that, in the case of kemp eliminases, the transition state charge distribution makes it hard to exploit the active site polarity, even with the ability to quantify the effect of different mutations. Unexpectedly, it is found that the directed evolution mutants lead to the reduction of solvation of the reactant state by water molecules rather that to the more common mode of transition state stabilization used by naturally evolved enzymes. Finally it is pointed out that our difficulties in improving Kemp eliminase are not due to overlooking exotic effect, but to the challenge in designing a preorganized environment that would exploit the small change it charge distribution during the formation of the transition state. PMID- 20829492 TI - Effective shutdown in the expression of celiac disease-related wheat gliadin T cell epitopes by RNA interference. AB - Celiac disease (CD) is an enteropathy triggered by the ingestion of gluten proteins from wheat and similar proteins from barley and rye. The inflammatory reaction is controlled by T cells that recognize gluten peptides in the context of human leukocyte antigen (HLA) DQ2 or HLA-DQ8 molecules. The only available treatment for the disease is a lifelong gluten-exclusion diet. We have used RNAi to down-regulate the expression of gliadins in bread wheat. A set of hairpin constructs were designed and expressed in the endosperm of bread wheat. The expression of gliadins was strongly down-regulated in the transgenic lines. Total gluten protein was extracted from transgenic lines and tested for ability to stimulate four different T-cell clones derived from the intestinal lesion of CD patients and specific for the DQ2-alpha-II, DQ2-gamma-VII, DQ8-alpha-I, and DQ8 gamma-I epitopes. For five of the transgenic lines, there was a 1.5-2 log reduction in the amount of the DQ2-alpha-II and DQ2-gamma-VII epitopes and at least 1 log reduction in the amount of the DQ8-alpha-I and DQ8-gamma-I epitopes. Furthermore, transgenic lines were also tested with two T-cell lines that are reactive with omega-gliadin epitopes. The total gluten extracts were unable to elicit T-cell responses for three of the transgenic wheat lines, and there were reduced responses for six of the transgenic lines. This work shows that the down regulation of gliadins by RNAi can be used to obtain wheat lines with very low levels of toxicity for CD patients. PMID- 20829493 TI - Power loss is greater in old men than young men during fast plantar flexion contractions. AB - It is unclear during human aging whether healthy older adults (>70 yr old) experience greater, lesser, or the same fatigability compared with younger adults. The reported disparate findings may be related to the task-dependent nature of fatigue and the limited number of studies exploring nonisometric contractile function and aging. The purpose here was to determine the effects of fast shortening contractions on the fatigability of the triceps surae in 10 young (~24 yr old) and 10 old (~78 yr old) men using isometric and dynamic measures. Participants performed 50 maximal velocity-dependent plantar flexions at a constant load of 20% maximal voluntary isometric contraction (MVC). Isometric twitch properties and MVCs were tested at baseline and during and following the fatigue task. Voluntary activation was similar between the old and young (~98%) and was unaltered with fatigue. The old had 26% lower (P < 0.01) isometric MVC torque and 18% slower (P < 0.01) maximal shortening velocity than the young. Hence, peak power was 38% lower in the old (P < 0.01). At task termination, MVC torque was maintained in the old (P = 0.15) but decreased by 21% in the young (P < 0.01). Twitch half-relaxation time was lengthened in the old at task termination by 26% (P < 0.01) but unchanged in the young (P = 0.10). Peak power was reduced by 24% and 17% at task termination in the old and young, respectively (P < 0.01). Despite a better maintenance in isometric MVC torque production, the weaker and slower contracting triceps surae of the old was more fatigable than the young during fast dynamic efforts with an unconstrained velocity. PMID- 20829494 TI - Age-related changes in the control of finger force vectors. AB - We explored changes in finger interaction in the process of healthy aging as a window into neural control strategies of natural movements. In particular, we quantified the amount of force produced by noninstructed fingers in different directions, the amount of force produced by the instructed finger orthogonally to the task direction, and the strength of multifinger synergies stabilizing the total force magnitude and direction during accurate force production. Healthy elderly participants performed accurate isometric force production tasks in five directions by individual fingers and by all four fingers acting together. Their data were compared with a dataset obtained in a similar earlier study of young subjects. Finger force vectors were measured using six-component force/torque sensors. Multifinger synergies were quantified using the framework of the uncontrolled manifold hypothesis. The elderly participants produced lower force magnitudes by noninstructed fingers and higher force magnitudes by instructed fingers in nontask directions. They showed strong synergies stabilizing the magnitude and direction of the total force vector. However, the synergy indexes were significantly lower than those observed in the earlier study of young subjects. The results are consistent with an earlier hypothesis of preferential weakening of intrinsic hand muscles with age. We interpret the findings as a shift in motor control from synergic to element-based, which may be causally linked to the documented progressive neuronal death at different levels of the neural axis. PMID- 20829495 TI - Length oscillation mimicking periodic individual deep inspirations during tidal breathing attenuates force recovery and adaptation in airway smooth muscle. AB - Airway smooth muscle (ASM) is able to generate maximal force under static conditions, and this isometric force can be maintained over a large length range due to length adaptation. The increased force at short muscle length could lead to excessive narrowing of the airways. Prolonged exposure of ASM to submaximal stimuli also increases the muscle's ability to generate force in a process called force adaptation. To date, the effects of length and force adaptation have only been demonstrated under static conditions. In the mechanically dynamic environment of the lung, ASM is constantly subjected to periodic stretches by the parenchyma due to tidal breathing and deep inspiration. It is not known whether force recovery due to muscle adaptation to a static environment could occur in a dynamic environment. In this study the effect of length oscillation mimicking tidal breathing and deep inspiration was examined. Force recovery after a length change was attenuated in the presence of length oscillation, except at very short lengths. Force adaptation was abolished by length oscillation. We conclude that in a healthy lung (with intact airway-parenchymal tethering) where airways are not allowed to narrow excessively, large stretches (associated with deep inspiration) may prevent the ability of the muscle to generate maximal force that would occur under static conditions irrespective of changes in mean length; mechanical perturbation on ASM due to tidal breathing and deep inspiration, therefore, is the first line of defense against excessive bronchoconstriction that may result from static length and force adaptation. PMID- 20829496 TI - Onset of airflow limitation in a collapsible tube model: impact of surrounding pressure, longitudinal strain, and wall folding geometry. AB - We studied the impact of wall strain and surrounding pressure on the onset of airflow limitation in a thin-walled "floppy" tube model. A vacuum source generated steady-state (baseline) airflow (0-350 ml/s) through a thin-walled latex tube (length 80 mm, wall thickness 0.23 mm) enclosed within a rigid, sealed, air-filled, cylindrical chamber while upstream minus downstream pressure, chamber pressure (Pc), and lumen geometry [in-line digital camera; segmentation (Amira 5.2.2) and analysis (Rhinoceros 4) software] were monitored. Longitudinal strain (S; 0-62.5%) and Pc (0-20 cmH(2)O) combinations were imposed, and Pc associated with onset of 1) reduced airflow and 2) fully developed airflow limitation recorded. At any strain, increasing Pc resulted in a decrease in airflow. Across all baseline airflow, threshold pressure was 1-7 cmH(2)O for S < 25%, 6-8 cmH(2)O at S = 25% and 37.5%, and 5-7 cmH(2)O at S = 50% and 62.5%. Pc associated with fully developed airflow limitation was 4-6 cmH(2)O for S < 25%, >20 cmH(2)O at S = 25% (i.e., no flow limitation), 18 cmH(2)O at S = 37.5%, and 8 12 cmH(2)O at S = 50% and 62.5%. Lumen area decreased with increasing Pc but was 1) larger at S = 25% and 2) characterized by bifold narrowing at S < 25% and trifold narrowing at S >= 25%. In conclusion, tube function was modulated by Pc vs. S interactions, with S = 25% producing trifold lumen narrowing, maximal patency, and no airflow limitation. Findings may have implications for understanding peripharyngeal tissue pressure and pharyngeal wall strain effects on passive pharyngeal airway function in humans. PMID- 20829497 TI - Melatonin attenuates the vestibulosympathetic but not vestibulocollic reflexes in humans: selective impairment of the utricles. AB - Melatonin has been reported to decrease nerve activity of medial vestibular nuclei in the rat and is associated with attenuated muscle sympathetic nerve activity (MSNA) responses to baroreceptor unloading in humans. The purpose of this study was to determine if melatonin alters the vestibulosympathetic reflex (VSR) and vestibulocollic reflex (VCR) in humans. In study 1, MSNA, arterial blood pressure, and heart rate were measured in 12 healthy subjects (28 +/- 1 yr; 6 men, 6 women) during head-down rotation (HDR) before and 45 min after ingestion of either melatonin (3 mg) or placebo (sucrose). Subjects returned at least 2 days later at the same time of day to repeat the trial after ingesting the opposite treatment (melatonin or placebo). Melatonin significantly attenuated MSNA responses during HDR compared with placebo (burst frequency Delta 4 +/- 1 vs. Delta 7 +/- 1 bursts/min, and total MSNA Delta 51 +/- 20 and Delta 96 +/- 15%, respectively; P < 0.02). In study 2, vestibular evoked myogenic potentials (VEMP) were measured in 10 healthy subjects (26 +/- 1 yr; 4 men and 6 women) before and after ingestion of 3 mg melatonin. Melatonin did not alter the timing of the p13 and n23 peaks (pre-melatonin 13.2 +/- 0.4 and 21.3 +/- 0.6 ms vs. post melatonin 13.5 +/- 0.4 and 21.4 +/- 0.7 ms, respectively) or the p13-n23 interpeak amplitudes [pre-melatonin 22.5 +/- 4.6 arbitrary units (au) and post melatonin 22.7 +/- 4.6 au]. In summary, melatonin attenuates the VSR and supports the concept that melatonin negatively affects orthostatic tolerance. However, melatonin does not alter the VCR in humans suggesting melatonin's effect on the VSR appears to be mediated by the utricles. PMID- 20829498 TI - Transversal stiffness of fibers and desmin content in leg muscles of rats under gravitational unloading of various durations. AB - The aim of this research was the analysis of structural changes in various parts of the sarcolemma and contractile apparatus of muscle fibers by measuring their transversal stiffness by atomic force microscopy under gravitational unloading. Soleus, medial gastrocnemius, and tibialis anterior muscles of Wistar rats were the objects of the study. Gravitational unloading was carried out by antiorthostatic suspension of hindlimbs for 1, 3, 7, and 12 days. It was shown that the transversal stiffness of different parts of the contractile apparatus of soleus muscle fibers decreases during gravitational unloading in the relaxed, calcium-activated, and rigor states, the fibers of the medial gastrocnemius show no changes, whereas the transversal stiffness of tibialis anterior muscle increases. Thus the transversal stiffness of the sarcolemma in the relaxed state is reduced in all muscles, which may be due to the direct action of gravity as an external mechanical factor that can influence the tension on a membrane. The change of sarcolemma stiffness in activated fibers, which is due probably to the transfer of tension from the contractile apparatus, correlates with the dynamics of changes in the content of desmin. PMID- 20829499 TI - HISS, not insulin, causes vasodilation in response to administered insulin. AB - Meal-induced sensitization to the dynamic actions of insulin results from the peripheral actions of a hormone released by the liver (hepatic insulin sensitizing substance or HISS). Absence of meal-induced insulin sensitization results in the pathologies associated with cardiometabolic risk. Using three protocols that have previously demonstrated HISS metabolic action, we tested the hypothesis that HISS accounts for the vasodilation that has been associated with insulin. The dynamic metabolic actions of insulin and HISS were determined using a euglycemic clamp in response to a bolus of 100 mU/kg insulin in pentobarbital anesthetized Sprague-Dawley rats. Hindlimb blood flow was measured with an ultrasound flow probe on the aorta above the bifurcation of the iliac arteries. Fed rats showed tightly coupled metabolic and vascular responses, which were completed by 35 min after insulin administration. Blocking HISS release, with the use of atropine or hepatic surgical denervation, eliminated the HISS-dependent metabolic and vascular responses to insulin administration. Physiological suppression of HISS release occurs with fasting. In 24-h fasted rats, HISS metabolic and vascular actions were absent, and atropine had no effect on either action. Fed rats with liver denervation did not release HISS, but intraportal venous infusion of acetylcholine, to mimic the permissive parasympathetic nerve signal, restored the ability of insulin to cause HISS release and restored both the metabolic and vascular actions. These studies report vascular actions of HISS for the first time and demonstrate that HISS, not insulin action, results in the peripheral vasodilation generally attributed to insulin. PMID- 20829500 TI - Motor unit behavior during submaximal contractions following six weeks of either endurance or strength training. AB - The study investigated changes in motor output and motor unit behavior following 6 wk of either strength or endurance training programs commonly used in conditioning and rehabilitation. Twenty-seven sedentary healthy men (age, 26.1 +/ 3.9 yr; mean +/- SD) were randomly assigned to strength training (ST; n = 9), endurance training (ET; n = 10), or a control group (CT; n = 8). Maximum voluntary contraction (MVC), time to task failure (isometric contraction at 30% MVC), and rate of force development (RFD) of the quadriceps were measured before (week 0), during (week 3), and after a training program of 6 wk. In each experimental session, surface and intramuscular EMG signals were recorded from the vastus medialis obliquus and vastus lateralis muscles during isometric knee extension at 10 and 30% MVC. After 6 wk of training, MVC and RFD increased in the ST group (17.5 +/- 7.5 and 33.3 +/- 15.9%, respectively; P < 0.05), whereas time to task failure was prolonged in the ET group (29.7 +/- 13.4%; P < 0.05). The surface EMG amplitude at 30% MVC force increased with training in both groups, but the training-induced changes in motor unit discharge rates differed between groups. After endurance training, the motor unit discharge rate at 30% MVC decreased from 11.3 +/- 1.3 to 10.1 +/- 1.1 pulses per second (pps; P < 0.05) in the vasti muscles, whereas after strength training it increased from 11.4 +/- 1.2 to 12.7 +/- 1.3 pps (P < 0.05). Finally, motor unit conduction velocity during the contractions at 30% MVC increased for both the ST and ET groups, but only after 6 wk of training (P < 0.05). In conclusion, these strength and endurance training programs elicit opposite adjustments in motor unit discharge rates but similar changes in muscle fiber conduction velocity. PMID- 20829502 TI - Commentaries on Viewpoint: Standards for quantitative assessment of lung structure. Instillation fixation and overinflation of the mouse lung. PMID- 20829501 TI - ATP and the purine type 2 X7 receptor affect sleep. AB - Sleep is dependent upon prior brain activities, e.g., after prolonged wakefulness sleep rebound occurs. These effects are mediated, in part, by humoral sleep regulatory substances such as cytokines. However, the property of wakefulness activity that initiates production and release of such substances and thereby provides a signal for indexing prior waking activity is unknown. We propose that extracellular ATP, released during neuro- and gliotransmission and acting via purine type 2 (P2) receptors, is such a signal. ATP induces cytokine release from glia. Cytokines in turn affect sleep. We show here that a P2 receptor agonist, 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP), increased non-rapid eye movement sleep (NREMS) and electroencephalographic (EEG) delta power while two different P2 receptor antagonists, acting by different inhibitory mechanisms, reduced spontaneous NREMS in rats. Rat P2X7 receptor protein varied in the somatosensory cortex with time of day, and P2X7 mRNA was altered by interleukin-1 treatment, by sleep deprivation, and with time of day in the hypothalamus and somatosensory cortex. Mice lacking functional P2X7 receptors had attenuated NREMS and EEG delta power responses to sleep deprivation but not to interleukin-1 treatment compared with wild-type mice. Data are consistent with the hypothesis that extracellular ATP, released as a consequence of cell activity and acting via P2 receptors to release cytokines and other sleep regulatory substances, provides a mechanism by which the brain could monitor prior activity and translate it into sleep. PMID- 20829504 TI - Deep inspiration and airway physiology: human, canine, porcine, or bovine? PMID- 20829506 TI - Matrix metalloproteinase 2 and 9 dysfunction underlie vascular stiffness in circadian clock mutant mice. AB - OBJECTIVE: To determine if elasticity in blood vessels is compromised in circadian clock-mutant mice (Bmal1-knockout [KO] and Per-triple KO) and if matrix metalloproteinases (MMPs) might confer these changes in compliance. METHODS AND RESULTS: High-resolution ultrasonography in vivo revealed impaired remodeling and increased pulse-wave velocity in the arteries of Bmal1-KO and Per-triple KO mice. In addition, compliance of remodeled arteries and naive pressurized arterioles ex vivo from Bmal1-KO and Per-triple KO mice was reduced, consistent with stiffening of the vascular bed. The observed vascular stiffness was coincident with dysregulation of MMP-2 and MMP-9 in Bmal1-KO mice. Furthermore, inhibition of MMPs improved indexes of pathological remodeling in wild-type mice, but the effect was abolished in Bmal1-KO mice. CONCLUSIONS: Circadian clock dysfunction contributes to hardening of arteries, which may involve impaired control of the extracellular matrix composition. PMID- 20829507 TI - alpha-Lipoic acid prevents neointimal hyperplasia via induction of p38 mitogen activated protein kinase/Nur77-mediated apoptosis of vascular smooth muscle cells and accelerates postinjury reendothelialization. AB - OBJECTIVE: To explore whether alpha-lipoic acid (ALA), a naturally occurring antioxidant, inhibits neointimal hyperplasia by inducing apoptosis of vascular smooth muscle cells and to examine its potential effects on reendothelialization and platelet aggregation. METHODS AND RESULTS: Restenosis and late stent thrombosis, caused by neointimal hyperplasia and delayed reendothelialization, are significant clinical problems of balloon angioplasty and drug-eluting stents. ALA treatment strongly induced apoptosis of vascular smooth muscle cells and enhanced the expression and cytoplasmic localization of Nur77, which triggers intrinsic apoptotic events. Small interfering RNA-mediated downregulation of Nur77 diminished this proapoptotic effect of ALA. Moreover, ALA increased p38 mitogen-activated protein kinase phosphorylation, and inhibition of p38 mitogen activated protein kinase completely blocked ALA-induced vascular smooth muscle cell apoptosis and Nur77 induction and cytoplasmic localization. In balloon injured rat carotid arteries, ALA enhanced Nur77 expression and increased TUNEL positive apoptotic cells in the neointima, leading to inhibition of neointimal hyperplasia. This preventive effect of ALA was significantly reduced by infection of an adenovirus encoding Nur77 small hairpin (sh)RNA. Furthermore, ALA reduced basal apoptosis of human aortic endothelial cells and accelerated reendothelialization after balloon injury. ALA also suppressed arachidonic acid induced platelet aggregation. CONCLUSIONS: ALA could be a promising therapeutic agent to prevent restenosis and late stent thrombosis after angioplasty and drug eluting stent implantation. PMID- 20829508 TI - The relationship between plasma angiopoietin-like protein 4 levels, angiopoietin like protein 4 genotype, and coronary heart disease risk. AB - OBJECTIVE: To investigate the relationship between angiopoietin-like protein 4 (Angptl4) levels, coronary heart disease (CHD) biomarkers, and ANGPTL4 variants. METHODS AND RESULTS: Plasma Angptl4 was quantified in 666 subjects of the Northwick Park Heart Study II using a validated ELISA. Seven ANGPTL4 single nucleotide polymorphisms were genotyped, and CHD biomarkers were assessed in the whole cohort (N=2775). Weighted mean+/-SD plasma Angptl4 levels were 10.0+/-11.0 ng/mL. Plasma Angptl4 concentration correlated positively with age (r=0.15, P<0.001) and body fat mass (r=0.19, P=0.003) but negatively with plasma high density lipoprotein cholesterol (r=-0.13, P=0.01). No correlation with triglycerides (TGs) was observed. T266M was independently associated with plasma Angptl4 levels (P<0.001) but was not associated with TGs or CHD risk in the meta analysis of 5 studies (4061 cases/15 395 controls). E40K showed no independent association with plasma Angptl4 levels. In human embryonic kidney 293 and human hepatoma 7 cells compared with wild type, E40K and T266M showed significantly altered synthesis and secretion, respectively. CONCLUSIONS: Circulating Angptl4 levels may not influence TG levels or CHD risk for the following reasons: (1) Angptl4 levels were not correlated with TGs; (2) T266M, although associated with Angptl4 levels, showed no association with plasma TGs; and (3) TG-lowering E40K did not influence Angptl4 levels. These results provide new insights into the role of Angptl4 in TG metabolism. PMID- 20829509 TI - The ATP-binding cassette transporter BCRP1/ABCG2 plays a pivotal role in cardiac repair after myocardial infarction via modulation of microvascular endothelial cell survival and function. AB - OBJECTIVE: To clarify the impact of breast cancer resistance protein 1 (BCRP1)/ATP-binding cassette transporter subfamily G member 2 (ABCG2) expression on cardiac repair after myocardial infarction (MI). METHODS AND RESULTS: The ATP binding cassette transporter BCRP1/ABCG2 is expressed in various organs, including the heart, and may regulate several tissue defense mechanisms. BCRP1/ABCG2 was mainly expressed in endothelial cells of microvessels in the heart. MI was induced in 8- to 12-week-old wild-type (WT) and Bcrp1/Abcg2 knockout (KO) mice by ligating the left anterior descending artery. At 28 days after MI, the survival rate was significantly lower in KO mice than in WT mice because of cardiac rupture. Echocardiographic, hemodynamic, and histological assessments showed that ventricular remodeling was more deteriorated in KO than in WT mice. Capillary, myofibroblast, and macrophage densities in the peri infarction area at 5 days after MI were significantly reduced in KO compared with WT mice. In vitro experiments demonstrated that inhibition of BCRP1/ABCG2 resulted in accumulation of intracellular protoporphyrin IX and impaired survival of microvascular endothelial cells under oxidative stress. Moreover, BCRP1/ABCG2 inhibition impaired migration and tube formation of endothelial cells. CONCLUSIONS: BCRP1/ABCG2 plays a pivotal role in cardiac repair after MI via modulation of microvascular endothelial cell survival and function. PMID- 20829510 TI - Apolipoprotein CIII induces monocyte chemoattractant protein-1 and interleukin 6 expression via Toll-like receptor 2 pathway in mouse adipocytes. AB - OBJECTIVE: To examine the direct effect of apolipoprotein CIII (apoCIII) on adipokine expressions that are involved in obesity, insulin resistance, or metabolic syndrome. METHODS AND RESULTS: ApoCIII in triglyceride-rich lipoproteins is elevated in patients with obesity, insulin resistance, or metabolic syndrome. Its level is also associated with proinflammatory adipokines. Fully differentiated mouse 3T3L1 adipocytes were incubated with apoCIII. ApoCIII activated nuclear factor kappaB of 3T3L1 adipocytes and induced the expression of monocyte chemoattractant protein (MCP) 1 and interleukin (IL) 6. ApoCIII also activated extracellular signal-regulated kinase and p38. Mitogen-activated protein kinase kinase (MEK)-1 inhibitor PD98059, but not p38 inhibitor SB203580, inhibited apoCIII-induced upregulation of MCP-1 and IL-6. Previously, it was shown that apoCIII activates proinflammatory signals through toll-like receptor (TLR) 2. TLR2-blocking antibody abolished activation of nuclear factor kappaB and extracellular signal-regulated kinase induced by apoCIII and inhibited apoCIII induced upregulation of MCP-1 and IL-6. ApoCIII also reduced adiponectin expression of 3T3L1 adipocytes, which was recovered by TLR2-blocking antibody. ApoCIII induced the expression of MCP-1 and IL-6 in TLR2-overexpressed human embryonic kidney 293 cells but not wild-type human embryonic kidney 293 cells without TLR2. ApoCIII induced the expression of MCP-1 and IL-6 and decreased adiponectin expression in white adipose tissue of wild-type mice but not of TLR2 deficient mice in vivo. CONCLUSIONS: ApoCIII may activate extracellular signal regulated kinase and nuclear factor kB through TLR2 and induce proinflammatory adipokine expression in vitro and in vivo. Thus, apoCIII links dyslipidemia to inflammation in adipocytes, which, in turn, may contribute to atherosclerosis. PMID- 20829511 TI - Variability in timing of spontaneous calcium release in the intact rat heart is determined by the time course of sarcoplasmic reticulum calcium load. AB - BACKGROUND: Abnormalities in intracellular calcium (Ca) cycling during Ca overload can cause triggered activity because spontaneous calcium release (SCR) activates sufficient Ca-sensitive inward currents to induce delayed afterdepolarizations (DADs). However, little is known about the mechanisms relating SCR and triggered activity on the tissue scale. METHODS AND RESULTS: Laser scanning confocal microscopy was used to measure the spatiotemporal properties of SCR within large myocyte populations in intact rat heart. Computer simulations were used to predict how these properties of SCR determine DAD magnitude. We measured the average and standard deviation of the latency distribution of SCR within a large population of myocytes in intact tissue. We found that as external [Ca] is increased, and with faster pacing rates, the average and SD of the latency distribution decreases substantially. This result demonstrates that the timing of SCR occurs with less variability as the sarcoplasmic reticulum (SR) Ca load is increased, causing more sites to release Ca within each cell. We then applied a mathematical model of subcellular Ca cycling to show that a decrease in SCR variability leads to a higher DAD amplitude and is dictated by the rate of SR Ca refilling following an action potential. CONCLUSIONS: Our results demonstrate that the variability of the timing of SCR in a population of cells in tissue decreases with SR load and is dictated by the time course of the SR Ca content. PMID- 20829512 TI - DOCK180 is a Rac activator that regulates cardiovascular development by acting downstream of CXCR4. AB - RATIONALE: During embryogenesis, the CXC chemokine ligand (CXCL)12 acts on endothelial cells to control cardiac development and angiogenesis. Although biological functions of CXCL12 are exerted in part through activation of the small GTPase Rac, the pathway leading from its receptor CXC chemokine receptor (CXCR)4 to Rac activation remains to be determined. OBJECTIVE: DOCK180 (dedicator of cytokinesis), an atypical Rac activator, has been implicated in various cellular functions. Here, we examined the role of DOCK180 in cardiovascular development. METHODS AND RESULTS: DOCK180 associates with ELMO (engulfment and cell motility) through the N-terminal region containing a Src homology 3 domain. We found that targeted deletion of the Src homology 3 domain of DOCK180 in mice leads to embryonic lethality with marked reduction of DOCK180 expression at the protein level. These mutant mice, as well as DOCK180-deficient mice, exhibited multiple cardiovascular abnormalities resembling those seen in CXCR4-deficient mice. In DOCK180 knocked down endothelial cells, CXCL12-induced Rac activation was impaired, resulting in a marked reduction of cell motility. CONCLUSIONS: These results suggest that DOCK180 links CXCR4 signaling to Rac activation to control endothelial cell migration during cardiovascular development. PMID- 20829513 TI - Low rates of acute recanalization with intravenous recombinant tissue plasminogen activator in ischemic stroke: real-world experience and a call for action. AB - BACKGROUND AND PURPOSE: Acute rates of recanalization after intravenous (IV) recombinant tissue plasminogen activator (rt-PA) in proximal vessel occlusion have been estimated sparingly, typically using transcranial Doppler (TCD). We aimed to study acute recanalization rates of IV rt-PA in CT angiogram-proven proximal (internal carotid artery [ICA], M1 middle cerebral artery [MCA], M2-MCA, and basilar artery) occlusions and their effects on outcome. MATERIALS AND METHODS: The CT angiogram database of the Calgary stroke program was reviewed for the period 2002 to 2009. All patients with proximal vessel occlusions receiving IV rt-PA who were assessed for recanalization by TCD or angiogram (for acute endovascular treatment) were included for analysis. Rates of acute recanalization as observed on TCD/first run of angiogram and postendovascular therapy recanalization rates were noted. Modified Rankin Scale score <=2 at 3 months was used as a good outcome. RESULTS: Among 1341 patients in the CT angiogram database, 388 patients with proximal occlusion were identified. Of these, 216 patients had received IV rt-PA; 127 patients underwent further imaging to assess recanalization. Among the patients undergoing TCD (n=46) and cerebral angiogram (n=103), only 27 (21.25%) patients had acute recanalization. By occlusion subtype, the rates of recanalization were: distal ICA (with or without ICA neck occlusion or stenotic disease) 1 of 24 (4.4%); M1-MCA (with or without ICA neck occlusion or stenotic disease) 21 of 65 (32.3%); M2-MCA 4 of 13 (30.8%); and basilar artery 1 of 25 (4%). Onset to rt-PA time was comparable in patients with and without recanalization. Recanalization (P<0.0001; risk ratio, 2.7; 95% confidence interval, 1.5-4.6) was the strongest predictor of outcome (adjusted for age and National Institutes of Health Stroke Scale score). CONCLUSIONS: A low rate of acute recanalization was observed with IV rt-PA in proximal vessel occlusions identified by baseline CT angiogram. Recanalization was the strongest predictor of good outcome. PMID- 20829514 TI - The pattern of leptomeningeal collaterals on CT angiography is a strong predictor of long-term functional outcome in stroke patients with large vessel intracranial occlusion. AB - BACKGROUND AND PURPOSE: The role of noninvasive methods in the evaluation of collateral circulation has yet to be defined. We hypothesized that a favorable pattern of leptomeningeal collaterals, as identified by CT angiography, correlates with improved outcomes. METHODS: Data from a prospective cohort study at 2 university-based hospitals where CT angiography was systematically performed in the acute phase of ischemic stroke were analyzed. Patients with complete occlusion of the intracranial internal carotid artery and/or the middle cerebral artery (M1 or M2 segments) were selected. The leptomeningeal collateral pattern was graded as a 3-category ordinal variable (less, equal, or greater than the unaffected contralateral hemisphere). Univariate and multivariate analyses were performed to define the independent predictors of good outcome at 6 months (modified Rankin Scale score <=2). RESULTS: One hundred ninety-six patients were selected. The mean age was 69+/-17 years and the median National Institute of Health Stroke Scale score was 13 (interquartile range, 6 to 17). In the univariate analysis, age, baseline National Institute of Health Stroke Scale score, prestroke modified Rankin Scale score, Alberta Stroke Programme Early CT score, admission blood glucose, history of hypertension, coronary artery disease, congestive heart failure, atrial fibrillation, site of occlusion, and collateral pattern were predictors of outcome. In the multivariate analysis, age (OR, 0.95; 95% CI, 0.93 to 0.98; P=0.001), baseline National Institute of Health Stroke Scale (OR, 0.75; 0.69 to 0.83; P<0.001), prestroke modified Rankin Scale score (OR, 0.41; 0.22 to 0.76; P=0.01), intravenous recombinant tissue plasminogen activator (OR, 4.92; 1.83 to 13.25; P=0.01), diabetes (OR, 0.31; 0.01 to 0.98; P=0.046), and leptomeningeal collaterals (OR, 1.93; 1.06 to 3.34; P=0.03) were identified as independent predictors of good outcome. CONCLUSIONS: Consistent with angiographic studies, leptomeningeal collaterals on CT angiography are also a reliable marker of good outcome in ischemic stroke. PMID- 20829515 TI - Mexican Americans with atrial fibrillation have more recurrent strokes than do non-Hispanic whites. AB - BACKGROUND AND PURPOSE: Atrial fibrillation is a common cause of stroke with a known preventive treatment. We compared poststroke recurrence and survival in Mexican Americans (MAs) and non-Hispanic whites (NHWs) with atrial fibrillation in a population-based study. METHODS: Using surveillance methods from the Brain Attack Surveillance in Corpus Christi Project, cases of ischemic stroke/transient ischemic attack with atrial fibrillation were prospectively identified from January 2000 to June 2008. Recurrent stroke and all-cause mortality were compared by ethnicity with survival analysis methods. RESULTS: A total of 236 patients were available (88 MAs, 148 NHWs). MAs were younger than NHWs, with no ethnic differences in severity of the first stroke or proportion discharged on warfarin. MAs had a higher risk of stroke recurrence than did NHWs (Kaplan-Meier estimates of survival free of stroke recurrence risk at 28 days and 1 year were 0.99 and 0.85 in MAs and 0.98 and 0.96 in NHWs, respectively; P=0.01, log-rank test), which persisted despite adjustment for age and sex (hazard ratio=2.46; 95% CI, 1.19-5.11). Severity of the recurrent stroke was higher in MAs than in NHWs (P=0.02). There was no ethnic difference in survival after stroke in unadjusted analysis or after adjusting for demographic and clinical factors (hazard ratio=1.03; 95% CI, 0.63-1.67). CONCLUSIONS: MAs with atrial fibrillation have a higher stroke recurrence risk and more severe recurrences than do NHWs but no difference in all-cause mortality. Aggressive stroke prevention measures focused on MAs are warranted. PMID- 20829516 TI - Is thrombolysis safe in the elderly?: analysis of a national database. AB - BACKGROUND AND PURPOSE: Thrombolysis for acute ischemic stroke in the elderly population is seldom administered. METHODS: In this study, we evaluated the risks of thrombolysis, including the mortality and intracerebral hemorrhage (ICH) rates in this population. A cohort of patients was identified from the National Inpatient Sample database for the years 2000-2006. Age was categorized in 2 groups, including those between 18 and 80 years and those >80 years. Multivariate logistic regression analysis was used to assess covariates associated with hospital mortality and ICH. A total of 524 997 patients were admitted for acute ischemic stroke; 143 093 (27.2%) were >80 years. A total of 7950 patients were treated with thrombolysis, of which 1659 (20.9%) were >80 years. Elderly patients received less frequent thrombolysis compared with the younger population (1.05% versus 1.72%). RESULTS: In the whole cohort, the mortality rate was higher in the older population (12.80% versus 8.99%). For those treated with thrombolysis, the mortality rate and risk of ICH were higher among those >80 years (16.9% versus 11.5%; odds ratio: 1.56 [95% CI: 1.35 to 1.82] and 5.73% versus 4.40%; odds ratio: 1.31 [95% CI: 1.03 to 1.67], respectively). Multivariate logistic regression analysis showed that the presence of ICH (odds ratio: 2.24 [95% CI: 1.89 to 2.65]) was associated with higher mortality rates but not the use of thrombolysis (odds ratio: 1.14 [95% CI: 0.98 to 1.33]). CONCLUSIONS: Despite the higher mortality rate in the older population, the use of thrombolysis does not predict death; however, the use of thrombolysis was associated with high risk of ICH. PMID- 20829517 TI - Childhood posterior circulation arterial ischemic stroke. AB - BACKGROUND AND PURPOSE: Limited data exist on childhood posterior circulation arterial ischemic stroke (PCAIS). We describe clinical and radiological features of childhood PCAIS to determine whether there are differences in infarct topography, vascular abnormalities, risk factors, and stroke subtypes when compared to adults. METHODS: Children with radiologically confirmed PCAIS were prospectively identified from August 2002 to February 2008. Infarcts were divided into proximal, middle, and distal posterior circulation segments utilizing an adult topographical classification system. Vascular abnormalities were described in terms of location, severity, and evolution over time. A pediatric modification of the TOAST classification system was used to define stroke subtypes. RESULTS: Twenty seven (37%) of 73 children recruited to our registry had 34 radiologically confirmed PCAIS events. Infarct location was distal (25), middle (2), proximal (1), and multiple segments (6). Fourteen events were associated with single infarcts and 20 were associated with multiple infarcts. Magnetic resonance angiography was abnormal in 16 of 25 children with PCAIS at presentation with stenosis (8) or occlusion (8). Vascular lesions progressed (5), transiently worsened before stabilizing (2), remained stable or improved (8), or normalized (1) over 12 months. Stroke subtypes included nonprogressive steno-occlusive cerebral arteriopathy (9), cardioembolic (4), dissection (3), Moyamoya syndrome (3), other determined (4), probable (1), and undetermined etiology (3). Fifty-two percent of children had recurrent posterior (6) or anterior (8) strokes. CONCLUSIONS: Nonprogressive arteriopathies are the most common cause of childhood PCAIS, usually affecting distal segments. Atherosclerosis-related risk factors do not play an important role in stroke causation. PCAIS is frequently associated with recurrent events. PMID- 20829518 TI - Graphic reanalysis of the two NINDS-tPA trials confirms substantial treatment benefit. AB - BACKGROUND AND PURPOSE: Multiple statistical analyses of the 2 NINDS-tPA trials have confirmed study findings of benefit of fibrinolytic therapy. A recent graphic analysis departed from best practices in the visual display of quantitative information by failing to take into account the skewed functional importance of NIH Stroke Scale raw scores and by scaling change axes at up to 20 times the range achievable by individual patients. METHODS: Using the publicly available datasets of the 2 NINDS-tPA trials, we generated a variety of figures appropriate to the characteristics of acute stroke trial data. RESULTS: A diverse array of figures all visually delineated substantial benefits of fibrinolytic therapy, including: bar charts of normalized gain and loss; stacked bar, bar, and matrix plots of clinically relevant ordinal ranks; a time series stacked line plot of continuous scale disability weights; and line plot, bubble chart, and person icon array graphs of joint outcome table analysis. The achievable change figure showed substantially greater improvement among tPA than placebo patients, median 66.7% (interquartile range, 0 to 92.0) versus 50.0% (interquartile range, 7.1 to 80.0), P=0.003. CONCLUSIONS: On average, under 3 hour patients treated with tPA recovered two-thirds while placebo patients improved only half of the way toward fully normal. Graphical analyses of the 2 NINDS-tPA trials, when performed according to best practices, is a useful means of conveying details about patient response to therapy not fully delineated by summary statistics, and confirms a valuable treatment benefit of under 3 hour fibrinolytic therapy in acute stroke. PMID- 20829519 TI - Comparison of outcomes on continuous ambulatory peritoneal dialysis versus automated peritoneal dialysis: results from a USA database. AB - BACKGROUND AND OBJECTIVE: Automated peritoneal dialysis (APD) is being increasingly used as an alternative to continuous ambulatory peritoneal dialysis (CAPD). However, there has been concern regarding reduced sodium removal leading to hypertension and resulting in a faster decline in residual renal function (RRF). The objective of the present study was to compare patient and technique survival and other relevant parameters between patients treated with APD and patients treated with CAPD. METHODS: Data for incident patients were retrieved from the database of the Renal Research Institute, New York. Treatment modality was defined 90 days after the start of dialysis treatment. In addition to technique and patient survival, RRF, blood pressure, and laboratory parameters were also compared. RESULTS: 179 CAPD and 441 APD patients were studied. Mean as treated survival was 1407 days [95% confidence interval (CI) 1211 - 1601] in CAPD patients and 1616 days (95% CI 1478 - 1764) in APD patients. Adjusted hazard ratio (HR) for mortality was 1.31 in CAPD compared to APD (95% CI 0.76 - 2.25, p = NS). Unadjusted as-treated technique survival was lower in CAPD compared to APD, with HR 2.84 (95% CI 1.65 - 4.88, p = 0.002); adjusted HR was 1.81 (95% CI 0.94 - 3.57, p = 0.08). Peritonitis rate was 0.3 episodes/patient-year for CAPD and APD; exit-site/tunnel infection rate was 0.1 and 0.3 episodes/patient-year for CAPD and APD respectively (p = NS). CONCLUSIONS: Patient survival was not significantly different between APD and CAPD patients, whereas technique survival appeared to be higher in APD patients and could not be explained by differences in infectious complications. No difference in blood pressure control or decline in RRF was observed between the 2 modalities. Based on these results, APD appears to be an acceptable alternative to CAPD, although technique prescription should always follow individual judgment. PMID- 20829520 TI - The exposure of urologists and the treatment for male factor infertility on the Web sites of ART centers in Taiwan. AB - Couples with male factor disorders can have their own biologic offspring nowadays via in vitro fertilization or intracytoplasmic sperm injection technologies. Because infertile couples commonly seek treatment options through public Web sites on the Internet, an appropriate exposure of urologic opinions on male factor infertility is important. It was therefore of interest to survey the extent of urologists' exposure on the official Web sites of the assisted reproductive technology (ART) centers. We surveyed the official Web sites of all 74 qualified ART centers in Taiwan. Web sites of these centers were evaluated for their information on male factor infertility and varicoceles, especially treatment suggestions for varicocele and attitudes toward urologist referral. Among the 74 centers, only 69 had established official Web sites. Forty-eight Web sites (69.6%) provided information regarding infertility, whereas only 42 Web sites (60.9%) mentioned male factor infertility and 23 (33.3%) had descriptions of varicoceles. The quantity and quality of disclosed information varied, 11 (15.9%) sites provided treatment opinions for varicocele, and only 4 (5.8%) supported surgical intervention. Most Web sites of ART centers in Taiwan had content on male factor infertility, but the vast majority did not mention urologist referral or varicocele treatment. Urologists' opinions are relatively less exposed on the Web sites of fertility services. Further efforts should be made by urologists to provide comprehensive information to the public and to reinforce the importance of urologist referral in male factor infertility. PMID- 20829521 TI - Effects of metoclopramide on duodenal motility and flow events, glucose absorption, and incretin hormone release in response to intraduodenal glucose infusion. AB - The contribution of small intestinal motor activity to nutrient absorption is poorly defined. A reduction in duodenal flow events after hyoscine butylbromide, despite no change in pressure waves, was associated with reduced secretion of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and a delay in glucose absorption. The aim of this study was to investigate the effect of metoclopramide on duodenal motility and flow events, incretin hormone secretion, and glucose absorption. Eight healthy volunteers (7 males and 1 female; age 29.8 +/- 4.6 yr; body mass index 24.5 +/- 0.9 kg/m2) were studied two times in randomized order. A combined manometry and impedance catheter was used to measure pressure waves and flow events in the same region of the duodenum simultaneously. Metoclopramide (10 mg) or control was administered intravenously as a bolus, followed by an intraduodenal glucose infusion for 60 min (3 kcal/min) incorporating the 14C labeled glucose analog 3-O-methylglucose (3-OMG). We found that metoclopramide was associated with more duodenal pressure waves and propagated pressure sequences than control (P < 0.05 for both) during intraduodenal glucose infusion. However, the number of duodenal flow events, blood glucose concentration, and plasma 3-[14C]OMG activity did not differ between the two study days. Metoclopramide was associated with increased plasma concentrations of GLP-1 (P < 0.05) and GIP (P = 0.07) but lower plasma insulin concentrations (P < 0.05). We concluded that metoclopramide was associated with increased frequency of duodenal pressure waves but no change in duodenal flow events and glucose absorption. Furthermore, GLP-1 and GIP release increased with metoclopramide, but insulin release paradoxically decreased. PMID- 20829522 TI - Phosphorylated HSP20 modulates the association of thin-filament binding proteins: caldesmon with tropomyosin in colonic smooth muscle. AB - Small heat shock proteins HSP27 and HSP20 have been implicated in regulation of contraction and relaxation in smooth muscle. Activation of PKC-alpha promotes contraction by phosphorylation of HSP27 whereas activation of PKA promotes relaxation by phosphorylation of HSP20 in colonic smooth muscle cells (CSMC). We propose that the balance between the phosphorylation states of HSP27 and HSP20 represents a molecular signaling switch for contraction and relaxation. This molecular signaling switch acts downstream on a molecular mechanical switch [tropomyosin (TM)] regulating thin-filament dynamics. We have examined the role of phosphorylation state(s) of HSP20 on HSP27-mediated thin-filament regulation in CSMC. CSMC were transfected with different HSP20 phosphomutants. These transfections had no effect on the integrity of actin cytoskeleton. Cells transfected with 16D-HSP20 (phosphomimic) exhibited inhibition of acetylcholine (ACh)-induced contraction whereas cells transfected with 16A-HSP20 (nonphosphorylatable) had no effect on ACh-induced contraction. CSMC transfected with 16D-HSP20 cDNA showed significant decreases in 1) phosphorylation of HSP27 (ser78); 2) phosphorylation of PKC-alpha (ser657); 3) phosphorylation of TM and CaD (ser789); 4) ACh-induced phosphorylation of myosin light chain; 5) ACh induced association of TM with HSP27; and 6) ACh-induced dissociation of TM from caldesmon (CaD). We thus propose the crucial physiological relevance of molecular signaling switch (phosphorylation state of HSP27 and HSP20), which dictates 1) the phosphorylation states of TM and CaD and 2) their dissociations from each other. PMID- 20829523 TI - Mechanical strain and TLR4 synergistically induce cell-specific inflammatory gene expression in intestinal smooth muscle cells and peritoneal macrophages. AB - Mechanical trauma of the gut is an unavoidable event in abdominal surgery. Former studies demonstrated that intestinal manipulation induces a strong inflammation within the tunica muscularis. We hypothesized that mechanical strain initiates or aggravates proinflammatory responses in intestinal smooth muscle cells (iSMC) or macrophages. First, an appropriate isolation and culture method for neonatal rat iSMC was established. Purified iSMC and primary peritoneal macrophages (pMacs) were subjected to static or cyclic strain, and gene expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), IL-6, and IL-1beta was analyzed by quantitative PCR. Supernatants from stretched iSMC were transferred to untreated pMacs or contrariwise, and medium transfer-triggered inflammatory gene expression was measured in unstretched cells. Finally, we investigated the synergistic effect of static strain on LPS-induced proinflammatory gene expression. Although cyclic strain failed, static strain significantly induced iNOS, COX-2, and IL-1beta mRNA in iSMC. pMacs showed an increase in all inflammatory genes investigated as well as macrophage inflammatory protein (MIP) 1alpha and MIP-2 mRNA after static strain. Both cell entities liberated unknown mediators in response to stretch that mutually stimulated iNOS gene expression. Finally, mechanostimulation amplified LPS-induced iNOS and IL-1beta gene expression in iSMC as well as COX-2 and IL-6 mRNA in pMacs. In conclusion, static strain initiates proinflammatory gene expression in iSMC and pMacs and triggers a bidirectional paracrine communication between both cultured cell entities via the liberation of unknown mediators. Furthermore, static strain synergistically operates with Toll-like receptor 4 ligation in a cell-specific manner. Hence, this study demonstrates that mechanical strain functions as an immunomodulatory stimulus in abdominal cells. PMID- 20829524 TI - Mechanism of hypoxia-inducible factor 1 alpha-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium. AB - Hypoxia-inducible factor 1 (HIF1) consists of a hypoxia-inducible alpha subunit and a constitutively expressed beta subunit. Reactive oxygen species (ROS) induced by Helicobacter pylori stabilize HIF1alpha in the human gastric epithelium in normoxia. HIF1alpha plays crucial role in carcinogenesis and has been associated with malignant progression of gastric cancer. Several genes contain functional hypoxia-response elements (HREs) in their promoters including Bcl2 family member, Mcl1. Cellular ratios of antiapoptotic oncogenic protein, Mcl1, and tumor suppressor proapoptotic protein, Noxa, determine cell fate by regulating normal cellular growth, cell death and oncogenic processes. The aim of the present study was to examine the mechanism of HIF1alpha induction in the H. pylori-infected gastric epithelium to better understand disease pathogenesis by H. pylori relevant to gastric carcinogenesis. Our data showed that the dose dependent increase in HIF1alpha in H. pylori-infected gastric epithelia is mediated by induction of a ROS-inducible protein, apurinic/apyrimidinic endonuclease 1 (APE1), and an enhanced interaction of APE1 with the transcriptional coactivator p300. Surprisingly, with accumulation of HIF1alpha, further transcriptional activation of mcl1 was not observed. We identified a HIF binding site (HBS) in the hif1alpha promoter and showed that increased HIF1alpha expression, whether H. pylori-induced or hypoxia-mimetic agent, CoCl(2)-induced, resulted in enhanced HIF1alpha binding to its own promoter. This resulted in a transcriptionally inactive hif1alpha promoter since hif1alpha HBS lacks HIF ancillary sequence (HAS) required for HIF1 transcriptional activity. We conclude that enhanced binding of "nonfunctional" HIF1alpha to hif1alpha promoter and limiting availability of p300 in the cell serves as checkpoints for uncontrolled HIF1alpha activity. PMID- 20829525 TI - Re: Predictive value of symptoms for early detection of ovarian cancer. PMID- 20829526 TI - Re: Predictive value of symptoms for early detection of ovarian cancer. PMID- 20829527 TI - Chronic portal vein thrombosis: transcapsular hepatic collateral vessels and communicating ectopic varices. AB - PURPOSE: To assess patients with chronic portal vein thrombosis (PVT) with respect to transcapsular collateral veins, the communication between these veins and ectopic varices, and the cause of PVT. MATERIALS AND METHODS: This study was approved by the institutional review committees, and written informed consent was obtained. From November 2003 to March 2008, 145 consecutive patients with chronic PVT due to a variety of causes were assessed for transcapsular collaterals and ectopic varices with ultrasonography (US). Analysis of contingency tables was performed with the Fisher exact test. RESULTS: Transcapsular collaterals were detected in 15 (10.3%) of 145 patients with chronic PVT. They were restricted to patients with a history of hepatobilary surgery, severe pancreatitis, or abdominal surgery (n = 21) and were not detected in patients with liver cirrhosis, systemic coagulopathy, extrahepatic malignancy, idiopathic PVT, chronic pancreatitis, or infectious or inflammatory diseases (n = 124) (P < .001). Ectopic varices were infrequent in 70 patients with liver cirrhosis (n = 2, 3%) but were common in 14 patients with PVT after hepatobiliary surgery (n = 9, 64%) (P < .001, odds ratio = 21.4). Direct communication between transcapsular collaterals and ectopic varices was visible in all nine patients in this cohort. In eight of these patients, ectopic varices were found to be the bleeding source in gastrointestinal hemorrhage. CONCLUSION: Transcapsular collaterals frequently occur in patients with chronic PVT due to hepatobilary surgery or necrotizing pancreatitis. They are associated with ectopic varices; therefore, awareness of transcapsular collaterals in this patient subgroup will help to localize ectopic varices as potential bleeding source. PMID- 20829529 TI - Differential features of pancreatobiliary- and intestinal-type ampullary carcinomas at MR imaging. AB - PURPOSE: To define the differential imaging features of pancreatobiliary- and intestinal-type ampullary carcinomas at magnetic resonance (MR) imaging and to correlate these features with pathologic findings. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board; informed consent was waived. Fifty patients with surgically confirmed ampullary carcinoma and preoperative MR results were included. Two radiologists, blinded to histologic type of cancer, evaluated imaging findings in consensus. Univariate and multiple logistic regression analysis were performed to define imaging findings that were useful for differentiation of the two types of carcinomas. RESULTS: On the basis of hematoxylin-eosin and immunohistochemical staining, 35 patients were classified as having pancreatobiliary type; and 15 patients, intestinal type. At MR, all of 15 intestinal carcinomas were nodular, whereas 16 (46%) of 35 pancreatobiliary carcinomas were infiltrative. Intestinal carcinomas were isointense (13 [87%] of 15) to hyperintense (two [13%] of 15), whereas 34% (12 of 35) of pancreatobiliary carcinomas manifested as hypointense compared with the duodenum on T2-weighted MR images (P = .034). Intestinal carcinoma commonly manifested with an oval filling defect at the distal end of the bile duct on MR cholangiopancreatographic (MRCP) images (11 [73%] of 15 vs four [11%] of 35 in pancreatobiliary type) (P < .001). At endoscopy, intestinal carcinoma manifested with an extramural protruding mass (n = 15, 100%) with a papillary surface (n = 11, 73%), whereas pancreatobiliary carcinoma manifested with intramural protruding (n = 5, 28%) or ulcerating (n = 1, 6%) gross morphologic features (P = .047) with a nonpapillary surface (n = 17, 94%) (P < .001). Multiple logistic regression analysis showed that an oval filling defect at the distal end of the bile duct was the only independent finding for differentiating intestinal from pancreatobiliary carcinoma (P = .027). CONCLUSION: An oval filling defect at the distal end of the bile duct on MRCP images and an extramural protruding appearance with a papillary surface at endoscopy are likely to suggest intestinal ampullary carcinoma. PMID- 20829530 TI - Anatomic variations in the first extensor compartment of the wrist: accuracy of US. AB - PURPOSE: To evaluate the accuracy of ultrasonography (US) in determining the anatomic variations in the first extensor compartment of the wrist. MATERIALS AND METHODS: Approval from the anatomic donations department was obtained. The first extensor compartment of the wrist of 40 nonembalmed cadaveric forearms (15 male and 25 female; age range at death, 65-100 years) were assessed at US by two observers for the presence or absence of a vertical septum, the presence or absence of an osseous ridge with a double groove in the bony floor, and whether there were single or multiple slips of the abductor pollicis longus and the extensor pollicis brevis tendons. These findings were also evaluated at dissection. RESULTS: The accuracies of US in depicting a septum and an osseous ridge with a double groove were respectively 95% (95% confidence interval [CI]: 83%, 99%) and 100% (95% CI: 91%, 100%). At dissection, a septum was invariably associated with the presence of an osseous ridge. The accuracies of US in depicting multiple tendon slips of the abductor pollicis longus and the extensor pollicis brevis were respectively 80% (95% CI: 64%, 91%) and 97% (95% CI: 86%, 100%). CONCLUSION: US was highly accurate in depicting anatomic variations in the first extensor compartment. US detection of an osseous ridge was an indirect sign of the presence of a septum dividing the first extensor compartment into two subcompartments. PMID- 20829531 TI - Posttransplantation lymphoproliferative disorder in children: manifestations in hematopoietic cell recipients in comparison with liver recipients. AB - PURPOSE: To compare the clinical and imaging features of posttransplantation lymphoproliferative disorder (PTLD) in pediatric patients who underwent hematopoietic cell transplantation with those in pediatric patients who underwent liver transplantation. MATERIALS AND METHODS: This study was approved by the institutional review board, and the requirement to obtain informed consent was waived. The authors retrospectively reviewed the medical records and images of 552 hematopoietic cell transplant recipients and 195 liver transplant recipients. PTLD was histopathologically confirmed in 17 of the patients who underwent hematopoietic cell transplantation and 27 of the patients who underwent liver transplantation. The overall frequency, clinical course, histopathologic type, and imaging findings of PTLD were compared between the two patient groups by using the Fisher exact test. RESULTS: The overall frequency of PTLD was 3% (17 of 552 patients) after hematopoietic cell transplantation (12% [nine of 75 patients] after umbilical cord blood transplantation) and 14% (27 of 194 patients) after liver transplantation. PTLD occurred within 6 months of transplantation in 14 of the 17 hematopoietic cell recipients (82%) and 11 of the 27 liver recipients (41%) (P = .012). Histopathologic examination revealed monomorphic disease in 11 of the 17 hematopoietic cell recipients (65%) and eight of the 27 liver recipients (30%) (P = .031). The abdomen was the most common site of involvement in both groups. Extraabdominal PTLD developed in 12 of the 17 hematopoietic cell recipients (71%) and five of the 27 liver recipients (19%) (P = .002). Although 15 of the 17 patients with hematopoietic cell transplantation-related PTLD (88%) exhibited responses after treatment, the overall mortality rate was 35% (six of 17 patients). All 27 patients with PTLD after liver transplantation improved after treatment and remain alive. CONCLUSION: PTLD after umbilical cord blood transplantation occurred as frequently as liver transplantation-related PTLD. Compared with liver transplantation-related PTLD, PTLD after hematopoietic cell transplantation is characterized by an earlier onset, a higher proportion of malignant monomorphic disease, and a worse outcome. PMID- 20829532 TI - Differentiation of intraductal growing-type cholangiocarcinomas from nodular-type cholangiocarcinomas at biliary MR imaging with MR cholangiography. AB - PURPOSE: To describe the magnetic resonance (MR) findings of intraductal growing (IDG)-type cholangiocarcinoma (CC) and to identify the features that differentiate it from nodular-type CC. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the informed consent requirement. Thirty-nine patients with pathologically proved IDG-type (n = 19) or nodular-type (n = 20) CCs who had undergone preoperative gadolinium-enhanced MR imaging with MR cholangiography were included in this study. Analysis of MR findings included determination of the (a) shape, enhancement degree, and pattern of the tumor; (b) outer caliber of the tumor-bearing segment; and (c) presence of tumor multiplicity, upstream and downstream bile duct dilatation, bile duct wall thickening adjacent to the tumor, and adjacent organ invasion. The significance of these findings was determined with the chi2 test. RESULTS: Significant features in the differentiation of IDG-type CCs from nodular-type CCs included papillary or irregular polypoid shape, lack of constriction of the tumor-bearing segment, hypoenhancement of the tumor to the liver during the equilibrium phase, tumor multiplicity, upstream and downstream bile duct dilatation, and no bile duct wall thickening adjacent to the tumor (P < .05). When at least two of these six imaging features were used in combination, sensitivity and specificity in the diagnosis of IDG-type CCs were 95% and 70%, respectively. CONCLUSION: By using characteristic MR features, one can differentiate IDG-type CC from nodular-type CC with a high degree of accuracy at biliary MR imaging with MR cholangiography. PMID- 20829533 TI - MR imaging depicts oxidative stress induced by methemoglobin. AB - PURPOSE: To correlate the effect of red blood cell hemoglobin on signal generation during magnetic resonance (MR) imaging and local oxidation of low density lipoprotein (LDL). MATERIALS AND METHODS: Informed consent was obtained from all volunteers participating in this study, which was approved by the research ethics board. T1 relaxometry of blood samples from six volunteers was performed. Lipid peroxidation was assayed by using thiobarbituric acid reactive species (TBARS) and fluorescence quenching of cis-parinaric acid. Two-tailed Student t tests were used to detect differences between means. A Pearson correlation coefficient was calculated to determine the linearity of the data. RESULTS: Lipid oxidation was significantly enhanced after addition of blood, according to results of the TBARS assay; greater oxidation occurred with ferric than with ferrous blood. The cis-parinaric acid assay demonstrated increased oxidative stress caused by extracellular as compared with intracellular ferric hemoglobin. MR imaging measures showed a T1 relaxivity that was 10 times higher for ferric than for ferrous forms of hemoglobin. CONCLUSION: Extracellular ferric hemoglobin is significantly more pro-oxidant and has higher T1 relaxivity than its ferrous counterparts. These results support the hypothesis that ferric methemoglobin-generated T1 high signal intensity reflects a pro-oxidant environment that, in the setting of vessel wall disease, might be proatherogenic. PMID- 20829534 TI - Bone metastases from prostate cancer: assessing treatment response by using diffusion-weighted imaging and functional diffusion maps--initial observations. AB - PURPOSE: To prospectively investigate and monitor the response to antiandrogen treatment of bone metastases in patients with prostate cancer by using diffusion weighted (DW) magnetic resonance (MR) imaging with the apparent diffusion coefficient (ADC) and functional diffusion maps (DMs). MATERIALS AND METHODS: This study had institutional review board approval; informed consent was obtained from all patients. Nine treatment-naive men (mean age, 73 years; range, 66-86 years) with 20 pelvic bone metastases were included. Imaging was performed before antiandrogen treatment and at 1, 2, and 3 months afterward. Imaging included a DW MR imaging sequence with five b factors (0-800 sec/mm2). Serum prostate-specific antigen (PSA) levels and mean ADCs of each metastasis were measured over time and analyzed by using the general linear model. Pairwise comparisons (paired-samples t tests) of PSA levels and ADCs before and after therapy were performed with the significance level set at P < .017 (Bonferroni correction). To determine the relationship between serum PSA level and the averaged mean ADCs in each patient, the two parameters were correlated across time. In addition, an analysis with functional DMs was performed to evaluate ADC response to treatment on a per-voxel basis. RESULTS: Serum PSA levels decreased by more than 90% during therapy. The mean ADCs of metastases were increased significantly at 1 (P < .001), 2 (P = .002), and 3 (P = .011) months after therapy compared with pretreatment values. Heterogeneous response was revealed at functional DM analysis. After 1 month of therapy, 47.3% of all analyzed tumor voxels showed significantly increased ADCs, while 46.5% were unchanged and 6.2% exhibited decreased ADCs in comparison to the pretreatment values. At 3 months after therapy, the proportion of voxels showing ADC decrease was higher (13.7%) than that at 1 month. CONCLUSION: DW MR imaging allows monitoring of antiandrogen therapy in bone metastases. PSA level decrease corresponded well with an increase in mean tumor ADC. Heterogeneity of tumor response to therapy was demonstrated by functional DM analysis. PMID- 20829535 TI - Abdominal CT: comparison of adaptive statistical iterative and filtered back projection reconstruction techniques. AB - PURPOSE: To compare image quality and lesion conspicuity on abdominal computed tomographic (CT) images acquired with different x-ray tube current-time products (50-200 mAs) and reconstructed with adaptive statistical iterative reconstruction (ASIR) and filtered back projection (FBP) techniques. MATERIALS AND METHODS: Twenty-two patients (mean age, 60.1 years +/- 7.3 [standard deviation]; age range, 52.8-67.4 years; mean weight, 78.9 kg +/- 18.3; 12 men, 10 women) gave informed consent for this prospective institutional review board-approved and HIPAA-compliant study, which involved the acquisition of four additional image series at multidetector CT. Images were acquired at different tube current-time products (200, 150, 100, and 50 mAs) and encompassed an abdominal lesion over a 10-cm scan length. Images were reconstructed separately with FBP and with three levels of ASIR-FBP blending. Two radiologists reviewed FBP and ASIR images for image quality in a blinded and randomized manner. Volume CT dose index (CTDI(vol)), dose-length product, patient weight, objective noise, and CT numbers were recorded. Data were analyzed by using analysis of variance and the Wilcoxon signed rank test. RESULTS: CTDI(vol) values were 16.8, 12.6, 8.4, and 4.2 mGy for 200, 150, 100, and 50 mAs, respectively (P < .001). Subjective noise was graded as below average at 150 mAs and average at 100 and 50 mAs for ASIR images, as compared with FBP images, on which noise was graded as average at 150 mAs, above average at 100 mAs, and unacceptable at 50 mAs. A substantial blotchy image appearance was noted in four of 22 image series acquired at 4.2 mGy with 70% ASIR. Lesion conspicuity was significantly better at 4.2 mGy on ASIR than on FBP images (observed P < .044), and overall diagnostic confidence changed from unacceptable on FBP to acceptable on ASIR images. CONCLUSION: ASIR lowers noise and improves diagnostic confidence in and conspicuity of subtle abdominal lesions at 8.4 mGy when images are reconstructed with 30% ASIR blending and at 4.2 mGy in patients weighing 90 kg or less when images are reconstructed with 50% or 70% ASIR blending. PMID- 20829536 TI - Automated three-dimensional quantification of noncalcified coronary plaque from coronary CT angiography: comparison with intravascular US. AB - PURPOSE: To determine the accuracy of a previously developed automated algorithm (AUTOPLAQ [APQ]) for rapid volumetric quantification of noncalcified and calcified plaque from coronary computed tomographic (CT) angiography in comparison with intravascular ultrasonography (US). MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant; all patients provided written informed consent. APQ combines derived scan-specific attenuation threshold levels for lumen, plaque, and knowledge-based segmentation of coronary arteries for quantification of plaque components. APQ was validated with retrospective analysis of 22 coronary atherosclerotic plaques in 20 patients imaged with coronary CT angiography and intravascular US within 2 days of each other. Coronary CT angiographic data were acquired by using dual-source CT. For each patient, well-defined plaques without calcifications were selected, and plaque volume was measured with APQ and manual tracing at CT and with intravascular US. Measurements were compared with paired t test, correlation, and Bland-Altman analysis. RESULTS: There was excellent correlation between noncalcified plaque volumes quantified with APQ and intravascular US (r = 0.94, P < .001), with no significant differences (P = .08). Mean plaque volume with intravascular US was 105.9 mm3 +/- 83.5 (standard deviation) and with APQ was 116.6 mm3 +/- 80.1. Mean plaque volume with manual tracing from CT was 100.8 mm3 +/- 81.7 and with APQ was 116.6 mm3 +/- 80.1, with excellent correlation (r = 0.92, P < .001) and no significant differences (P = .23). CONCLUSION: Automated scan-specific threshold level-based quantification of plaque components from coronary CT angiography allows rapid, accurate measurement of noncalcified plaque volumes, compared with intravascular US, and requires a fraction of the time needed for manual analysis. PMID- 20829537 TI - Interventional oncology research in the United States: slowing growth, limited focus, and a low level of funding. AB - PURPOSE: To establish the characteristics of published interventional oncology (IO) research, including the volume, growth, geographic distribution, type of research, and funding patterns, and to determine how IO research compares with overall radiology research. MATERIALS AND METHODS: This retrospective bibliometric analysis of public data was exempt from Institutional Review Board approval. IO articles published between 1996 and 2008 were identified in the National Library of Medicine MEDLINE database. Country of origin, article methodology, study topic, and source of funding were recorded. Growth was analyzed by using linear and nonlinear regression. RESULTS: Total journal articles numbered 3801, including 847 (22.3%) from the United States, 722 (19.0%) from Japan, and 390 (10.3%) from China. World publications grew with a sigmoid (logistic) pattern (predicted maximum of 586.8 articles per year, P < .001). The United States and China also had logistic and slowing growth (maximums of 111.0 and 48.1 articles per year, respectively; both P < .001). Growth was linear in Japan (growth of 3.0 articles per year, P < .001) and exponential and accelerating in Germany, Italy, South Korea, France, and the United Kingdom. The United States produced 187 (36.9%) review articles but only 52 (13.1%) clinical trials. Japan (75, 18.8%) and China (71, 17.8%) both produced more clinical trials than other countries. U.S. IO articles were less likely than general radiology articles to receive funding from government (12.5% vs 23.7%) and nongovernment (15.0% vs 17.0%) sources. Liver cancer articles constituted 2388 (62.8%) of all IO articles. CONCLUSION: IO research is slowing in the United States but growing elsewhere. Japan and China are leaders in clinical trial research. U.S. IO research receives less funding than does overall radiology research. IO research focuses primarily on liver cancer. PMID- 20829538 TI - Diagnostic imaging of colorectal liver metastases with CT, MR imaging, FDG PET, and/or FDG PET/CT: a meta-analysis of prospective studies including patients who have not previously undergone treatment. AB - PURPOSE: To obtain diagnostic performance values of computed tomography (CT), magnetic resonance (MR) imaging, fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and FDG PET/CT in the detection of colorectal liver metastases in patients who have not previously undergone therapy. MATERIALS AND METHODS: A comprehensive search was performed for articles published from January 1990 to January 2010 that fulfilled the following criteria: a prospective study design was used; the study population included at least 10 patients; patients had histopathologically proved colorectal cancer; CT, MR imaging, FDG PET, or FDG PET/CT was performed for the detection of liver metastases; intraoperative findings or those from histopathologic examination or follow-up were used as the reference standard; and data for calculating sensitivity and specificity were included. Study design characteristics, patient characteristics, imaging features, reference tests, and 2 * 2 tables were recorded. RESULTS: Thirty-nine articles (3391 patients) were included. Variation existed in study design characteristics, patient descriptions, imaging features, and reference tests. The sensitivity estimates of CT, MR imaging, and FDG PET on a per-lesion basis were 74.4%, 80.3%, and 81.4%, respectively. On a per-patient basis, the sensitivities of CT, MR imaging, and FDG PET were 83.6%, 88.2%, and 94.1%, respectively. The per-patient sensitivity of CT was lower than that of FDG PET (P = .025). Specificity estimates were comparable. For lesions smaller than 10 mm, the sensitivity estimates for MR imaging were higher than those for CT. No differences were seen for lesions measuring at least 10 mm. The sensitivity of MR imaging increased significantly after January 2004. The use of liver-specific contrast material and multisection CT scanners did not provide improved results. Data about FDG PET/CT were too limited for comparisons with other modalities. CONCLUSION: MR imaging is the preferred first-line modality for evaluating colorectal liver metastases in patients who have not previously undergone therapy. FDG PET can be used as the second-line modality. The role of FDG PET/CT is not yet clear owing to the small number of studies. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100729/-/DC1. PMID- 20829539 TI - Global trends in hybrid imaging. AB - At the 2009 Scientific Assembly and Annual Meeting of the Radiological Society of North America, a special session was devoted to global trends in hybrid imaging. This article expands on the key points of the session, focusing primarily on positron emission tomography/computed tomography. Global trends in hybrid imaging equipment acquisition, usage, and image interpretation practices are reviewed, and emerging requirements for training and clinical privileging are discussed. Also considered are the current benefits of hybrid imaging for patient care and workflow and the potential of hybrid imaging for advancing drug development and personalized medicine. PMID- 20829540 TI - Bronchial collapsibility at forced expiration in healthy volunteers: assessment with multidetector CT. AB - PURPOSE: To assess forced-expiratory bronchial collapsibility in healthy volunteers by using multidetector computed tomography (CT) and to compare the results with the current diagnostic criterion for bronchomalacia. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study. Following informed consent, 51 healthy volunteers with normal pulmonary function and no history of smoking were imaged by using a 64-detector row scanner with spirometric monitoring at total lung capacity and during forced exhalation. The total study population (in whom both main bronchi were imaged) included 25 men and 26 women (mean age, 50 years). Each scan was analyzed at a workstation by a fellowship-trained thoracic radiologist. Cross-sectional area measurements were obtained from end-inspiratory and forced-expiratory CT images for the right main bronchus (RMB), left main bronchus, (LMB), and bronchus intermedius (BI), and the mean percentage of expiratory collapse was calculated for each bronchus. The number of participants who exceeded the current diagnostic threshold level (>50% expiratory reduction in cross-sectional area) for bronchomalacia was calculated. Comparisons of airway dimensions and airway collapse according to bronchial segment and sex were made by using repeated-measures analysis of variance. RESULTS: Mean percentage of expiratory collapse was 66.9% +/- 19.0 (standard deviation) for the RMB and 61.4% +/- 16.7 for the LMB. Thirty-seven (73%) of 51 participants exceeded the diagnostic threshold level for bronchomalacia. Significant differences were observed in mean percentage of expiratory collapse between the RMB (66.9% +/- 19.0) and LMB (61.4% +/- 16.7) (P = .0005). Among a subgroup of 37 participants in whom the BI was also imaged, the mean percentage of expiratory collapse was 61.8% +/- 22.8, and 27 (73%) participants exceeded the diagnostic threshold level for bronchomalacia. CONCLUSION: Healthy volunteers demonstrate a wide range of forced-expiratory bronchial collapse, frequently exceeding the current diagnostic threshold level for bronchomalacia. PMID- 20829541 TI - Zinc transmetallation and gadolinium retention after MR imaging: case report. AB - A patient with chronic zinc poisoning from denture cream retained gadolinium after a magnetic resonance imaging procedure, likely due to transmetallation. During chelation therapy, high levels of gadolinium in excreted urine (up to 89 MUg/d, 29 days after gadolinium administration) were present, indicating that gadolinium had been retained. Almost 21/2 years after gadolinium exposure, a 24 hour urine collection indicated that the gadolinium level remained in the elevated range (0.6 MUg/d). This single case report suggests that patients with elevated zinc exposure may be at increased risk of gadolinium retention. PMID- 20829542 TI - Ordinal scoring of coronary artery calcifications on low-dose CT scans of the chest is predictive of death from cardiovascular disease. AB - PURPOSE: To assess the usefulness of ordinal scoring of the visual assessment of coronary artery calcification (CAC) on low-dose computed tomographic (CT) scans of the chest in the prediction of cardiovascular death. MATERIALS AND METHODS: All participants consented to low-dose CT screening according to an institutional review board-approved protocol. The amount of CAC was assessed on ungated low dose CT scans of the chest obtained between June 2000 and December 2005 in a cohort of 8782 smokers aged 40-85 years. The four main coronary arteries were visually scored, and each participant received a CAC score of 0-12. The date and cause of death was obtained by using the National Death Index. Follow-up time (median, 72.3 months; range, 0.3-91.9 months) was calculated as the time between CT and death, loss to follow-up, or December 31, 2007, whichever came first. Logistic regression analysis was used to determine the risk of mortality according to CAC category adjusted for age, pack-years of cigarette smoking, and sex. The same analysis to determine the hazard ratio for survival from cardiac death was performed by using Cox regression analysis. RESULTS: The rate of cardiovascular deaths increased with an increasing CAC score and was 1.2% (43 of 3573 subjects) for a score of 0, 1.8% (66 of 3569 subjects) for a score of 1-3, 5.0% (51 of 1015 subjects) for a score of 4-6, and 5.3% (33 of 625 subjects) for a score of 7-12. With use of subjects with a CAC score of 0 as the reference group, a CAC score of at least 4 was a significant predictor of cardiovascular death (odds ratio [OR], 4.7; 95% confidence interval: 3.3, 6.8; P < .0001); when adjusted for sex, age, and pack-years of smoking, the CAC score remained significant (OR, 2.1; 95% confidence interval: 1.4, 3.1; P = .0002). CONCLUSION: Visual assessment of CAC on low-dose CT scans provides clinically relevant quantitative information as to cardiovascular death. PMID- 20829543 TI - Differential gene expression in well-healed and poorly healed experimental aneurysms after coil treatment. AB - PURPOSE: To compare gene expression patterns between well-healed and poorly healed aneurysms following coil embolization in a rabbit model. MATERIALS AND METHODS: The Institutional Animal Care and Use Committee approved all procedures before initiation of the study. Elastase-induced, saccular aneurysms were created in rabbits and embolized by using platinum microcoils. Group 1 aneurysms were densely packed (volumetric packing density, >30%) to achieve good healing, whereas group 2 aneurysms were loosely packed (volumetric packing density, <20%), which yields poor healing. At 2 or 4 weeks after implantation, samples were harvested. RNA was isolated separately from the necks and domes of the aneurysms and analyzed by using a microarray containing 294 rabbit genes. Genes with significant differences between groups (P < .05; false discovery rate, <0.1; fold change, >=1.2 and <=0.8) were considered differentially expressed. RESULTS: At 2 weeks, of 294 genes, 22 (7.5%) genes in the neck and 14 (4.8%) genes in the dome were differentially expressed between groups; at 4 weeks, of 294 genes, 25 (8.5%) genes in the neck and 17 (5.8%) genes in the dome were differentially expressed between groups. Genes overexpressed in group 1 as compared with group 2 aneurysms included those encoding proteases, adhesion molecules, and chemoattractant molecules. Conversely, group 2 aneurysms had increased expression of genes encoding structural molecules, including collagens, as compared with expression in group 1 aneurysms. CONCLUSION: Robust healing after coil embolization is associated with substantial biological activity, as evidenced by overexpression of proteases, adhesion molecules, and chemoattractants. However, contrary to prior hypotheses, structural molecules such as collagen were not associated with the healing response in the rabbit model. PMID- 20829544 TI - Monitoring blood-brain barrier status in a rat model of glioma receiving therapy: dual injection of low-molecular-weight and macromolecular MR contrast media. AB - PURPOSE: To evaluate the sequential injection of a low-molecular-weight (gadoterate meglumine [Gd-DOTA], 0.5 kDa) and a macromolecular (P846, 3.5 kDa) contrast media in monitoring the effect of antitumor therapies (antiangiogenic therapy and/or microbeam radiation therapy [MRT]) on healthy brain tissue and implanted tumors. MATERIALS AND METHODS: Animal use was compliant with official French guidelines and was assessed by the local Internal Evaluation Committee for Animal Welfare and Rights. Eighty male rats bearing 9L gliosarcoma were randomized into four groups: untreated, antiangiogenic (sorafenib) therapy, MRT, and both treatments. Magnetic resonance (MR) imaging was performed 1 day before and 1, 5, and 8 days after the start of the treatment. At all time points, vascular integrity to a macromolecular contrast medium (P846) and, 11 minutes 30 seconds later, to low-molecular-weight contrast medium (Gd-DOTA) was evaluated by using a dynamic contrast material-enhanced MR imaging approach. To quantify vessel wall integrity, areas under the signal intensity curves were computed for each contrast medium. Unpaired t tests and one-way analysis of variance were used for statistical analyses. RESULTS: Tumor vessels receiving antiangiogenic therapy became less permeable to the macromolecular contrast medium, but their permeability to the low-molecular-weight contrast medium remained unchanged. Healthy double-irradiated vessels became permeable to the low-molecular-weight contrast medium but not to the macromolecular contrast medium. CONCLUSION: Antiangiogenic therapy and MRT generate different effects on the extravasation of contrast medium in tumoral and healthy tissues. This study indicates that the use of a low-molecular-weight contrast medium and a macromolecular contrast medium provides complementary information and suggests that the use of two contrast media within the same MR imaging session is feasible. PMID- 20829546 TI - Isolated lesser sac infection: an uncommon cause of abdominal pain in CAPD patients. AB - Peritonitis in peritoneal dialysis (PD) patients is characterized by abdominal pain and dialysate leukocytosis. Abdominal abscesses have been reported in PD patients with relapsing peritonitis. We report here 3 cases of lesser sac infection in PD patients who had severe abdominal pain but not generalized or diffuse peritonitis. PMID- 20829547 TI - The anatomy and pathology of the lesser sac: implications for peritoneal dialysis. AB - Pathological conditions involving the lesser sac of the peritoneal cavity in patients on peritoneal dialysis (PD) can pose significant diagnostic and therapeutic challenges. Lack of appreciation of these challenges may delay diagnosis and compromise outcome. A case series by Li and colleagues in this issue of Peritoneal Dialysis International highlights the diagnostic challenges presented by lesser sac infection in PD patients, and in this accompanying commentary we discuss the development and anatomy of the lesser sac, as well as the pathological conditions and investigations relevant to the management of patients on PD. PMID- 20829548 TI - Open surgical insertion of tenckhoff catheters for peritoneal dialysis. PMID- 20829549 TI - The self-locating peritoneal catheter: fifteen years of experience. PMID- 20829550 TI - Should the "trocar and cannula" method be used for peritoneal catheter implantation? PMID- 20829551 TI - Peritoneal dialysis catheter removal by nephrologists: technical aspect from a single center. PMID- 20829553 TI - Sudden increase in "urine" output in a peritoneal dialysis patient. PMID- 20829552 TI - Jejunal mesenteric artery laceration following blind peritoneal catheter insertion using the trocar method. PMID- 20829554 TI - Peritonitis due to Candida rugosa: the first case report. PMID- 20829555 TI - Successful use of CAPD in a patient with von Willebrand disease. PMID- 20829556 TI - Encapsulating peritoneal sclerosis presenting as acute limb ischemia. PMID- 20829557 TI - Concomitant laparoscopic peritoneal dialysis catheter placement and total extraperitoneal hernioplasty: a case report. PMID- 20829558 TI - Retroperitoneal hematoma in a peritoneal dialysis patient on oral anticoagulant treatment. PMID- 20829559 TI - Implantation of 3951 long-term central venous catheters: performances, risk analysis, and patient comfort after ultrasound-guidance introduction. AB - BACKGROUND: Despite evidence demonstrating improved safety with ultrasound-guided placement of central venous catheters (CVC) in comparison with the use of anatomical landmarks, ultrasound guidance is still not routinely used by all physicians when obtaining central venous access. METHODS: We report data pertaining to the placement of long-term CVCs in a 7-year period before and after ultrasound guidance was introduced. We included 3951 procedures (total of 1,642,402 catheter days) in our study: 1584 using the anatomical landmark method (landmark group, January 2000 to May 2003), and 2367 with ultrasound guidance (ultrasound group, June 2003 to May 2007). All procedures were performed by the same team of intensivists. Comparison criteria included procedural data, complications, patient's comfort, and perceptions. Variables were analyzed with Student's t test and chi(2) test. Multivariate analysis was performed according to the Cox proportional hazards regression model. RESULTS: Using ultrasound guidance, we noted a significant reduction in procedure time in both port (mean difference 4.9 +/- 0.4 minutes, confidence interval [CI] 4.1 to 5.7) and tunneled catheter (mean difference 2.4 +/- 0.8 minutes, CI 0.9 to 3.8) placement. The landmark method was associated with an increased risk of overall perioperative complications (4.5, CI 3.6 to 5.6). Among disease entities, acute leukemia patients had a significantly higher risk of CVC-related infections (2.6, CI 2.1 to 3.8). On the basis of questionnaires submitted to patients from both groups, ultrasound guidance was associated with improved patient comfort and satisfaction. CONCLUSIONS: Ultrasound guidance reduces complications and improves patient comfort. Further studies are needed to define whether acute leukemia patients should be considered a separate category with regard to the higher incidence of infections. PMID- 20829560 TI - Autonomic dysreflexia-like syndrome in a T12 paraplegic during thoracic spine surgery. AB - A 19-year-old African American man with a T12 spinal cord lesion underwent a T4 L5 thoracolumbar spinal fusion. Intraoperatively, his arterial blood pressure acutely increased from 110/60 to 260/130 mm Hg without a change in heart rate. The patient did not have pheochromocytoma, carcinoid syndrome, or thyroid storm. This presentation differs from autonomic dysreflexia because the spinal cord lesion was well below T6, hypertension was elicited with somatic stimulation above the lesion, and the response required aggressive pharmacologic management. This presentation is consistent with similar cases that support a central autonomic process. PMID- 20829561 TI - The relationship between inflammatory activation and clinical outcome after infant cardiopulmonary bypass. AB - BACKGROUND: Cardiopulmonary bypass (CPB) induces a systemic inflammatory response. The magnitude and consequences in infants remain unclear. We assessed the relationship between inflammatory state and clinical outcomes in infants undergoing CPB. METHODS: Plasma concentrations of interleukin (IL)-6, IL-8, IL 10, tumor necrosis factor alpha, IL-1beta, and C-reactive protein (CRP) were measured pre-CPB and immediately post-CPB, and at 6, 12, and 24 hours post-CPB in infants <=9 months old. Perioperative clinical data were collected prospectively. RESULTS: Diagnoses of 93 patients included transposition of the great arteries (40), tetralogy of Fallot (28), ventricular septal defect (21), truncus arteriosus (2), and complete atrioventricular canal (2). The median age was 37 days (range = 2 to 264). Pre-CPB IL-6 and CRP were higher in younger infants but were not associated with postoperative inflammatory mediator concentrations or measured clinical outcomes. IL-6 increased post-CPB (median 3.2 pg/mL pre-CPB, 24.2 post-CPB, 95.4 at 6 hours, and 90.3 at 24 hours; all P < 0.001). CRP increased post-CPB, peaking at 24 hours (median 27.5 at 24 hours, 0.3 pre-CPB; P < 0.001). IL-10 and IL-8 increased immediately post-CPB. After adjusting for age and diagnosis, postoperative IL-6 and IL-8 correlated with intensive care unit length of stay and postoperative blood product administration and, for IL-8, 24 hour lactate. CONCLUSIONS: Greater preoperative cytokine and CRP production in younger infants did not correlate with postoperative outcomes; correlation between postoperative inflammatory mediator production and clinical course was statistically significant but clinically modest. We conclude that in infants undergoing low-to-moderate-complexity cardiac surgery in a single high-volume center, the contribution of inflammatory mediator production to postoperative morbidity is relatively limited. PMID- 20829564 TI - Liquid injection atomic layer deposition of silver nanoparticles. AB - Silver nanoparticles are being developed for applications in plasmonics, catalysts and analytical methods, amongst others. Herein, we demonstrate the growth of silver nanoparticles using an atomic layer deposition (ALD) process for the first time. The silver was deposited from pulses of the organometallic precursor (hfac)Ag(1,5-COD) ((hexafluoroacetylacetonato)silver(I)(1,5 cyclooctadiene)) dissolved in a 0.1 M toluene solution. Catalytic oxidative dehydrogenation of the silver was achieved using intermittent pulses of propanol. The effect of substrate temperature on the size and distribution of nanoparticles has been investigated over the temperature range 110-150 degrees C. Transmission electron microscopy reveals that the nanoparticles consist of face centred cubic, facetted silver crystallites. The localized surface plasmon modes of the nanoparticles have been investigated using electron energy loss spectroscopy mapping. The distributions of plasmons within the ALD nanoparticles are comparable to those grown by solution methods. Both dipolar and quadrupolar resonant modes are observed, which is consistent with previous discrete dipole approximation models. Energy loss mapping of a loss feature at 8.1 eV reveals that it correlates with the bulk or volume region of the silver nanoparticles investigated here. PMID- 20829563 TI - Genetic and chemical modulation of spastin-dependent axon outgrowth in zebrafish embryos indicates a role for impaired microtubule dynamics in hereditary spastic paraplegia. AB - Mutations in the SPAST (SPG4) gene, which encodes the microtubule-severing protein spastin, are the most common cause of autosomal dominant hereditary spastic paraplegia (HSP). Following on from previous work in our laboratory showing that spastin is required for axon outgrowth, we report here that the related microtubule-severing protein katanin is also required for axon outgrowth in vivo. Using confocal time-lapse imaging, we have identified requirements for spastin and katanin in maintaining normal axonal microtubule dynamics and growth cone motility in vivo, supporting a model in which microtubule severing is required for concerted growth of neuronal microtubules. Simultaneous knockdown of spastin and katanin caused a more severe phenotype than did individual knockdown of either gene, suggesting that they have different but related functions in supporting axon outgrowth. In addition, the microtubule-destabilising drug nocodazole abolished microtubule dynamics and growth cone motility, and enhanced phenotypic severity in spast-knockdown zebrafish embryos. Thus, disruption of microtubule dynamics might underlie neuronal dysfunction in this model, and this system could be used to identify compounds that modulate microtubule dynamics, some of which might have therapeutic potential in HSP. PMID- 20829565 TI - Quartz-crystal scanning probe microcantilevers with a silicon tip based on direct bonding of silicon and quartz. AB - This paper reports on the design, fabrication and characterization of cantilever shaped quartz-crystal resonators for scanning probe microscopy (SPM) in order to operate under various environments, especially in liquids for biological applications. The cantilevers have functions of self-sensing and self-actuation using piezoelectric effects, and these properties are demonstrated experimentally. Compared to conventional SPM cantilevers, this quartz cantilever is easy to utilize as a SPM based force sensor in liquids because the self actuating properties can lead to no spurious resonant peaks. In addition, the self-sensing properties will enable its use even in an opaque liquid and can simplify the SPM system. In this research, quartz cantilevers are fabricated on silicon using a silicon-quartz direct bonding technique, and the sharp silicon tip is integrated at the end of the cantilever as well. Additionally, the electrical Q-enhancement (active Q-control) was tested. PMID- 20829562 TI - It takes nerves to fight infections: insights on neuro-immune interactions from C. elegans. AB - The innate immune response is evoked as a consequence of interactions between invading foreign infectious agents and host immune cells. A successful innate immune response is pivotal in maintaining the delicate balance between health and disease; an insufficient response results in infection, whereas an excessive response results in prolonged inflammation and tissue damage. Alterations in the state and function of the nervous system influence the immune response. The nervous system regulates innate immune responses through the release of neurotransmitters, neuropeptides and neurohormones. However, many questions related to the molecular and cellular mechanisms involved, the physiological role of the link between the immune and the nervous system, and the biological significance of neuro-immune interactions remain unresolved. The interactions between the nematode Caenorhabditis elegans and its pathogens provide insights into mechanisms of neuroendocrine regulation of immunity and address many outstanding issues related to neuro-immune interactions. PMID- 20829566 TI - High-speed growth of TiO2 nanotube arrays with gradient pore diameter and ultrathin tube wall under high-field anodization. AB - Highly ordered TiO(2) nanotubular arrays have been prepared by two-step anodization under high field. The high anodizing current densities lead to a high speed film growth (0.40-1.00 microm min(-1)), which is nearly 16 times faster than traditional fabrication of TiO(2) at low field. It was found that an annealing process of Ti foil is an effective approach to get a monodisperse and double-pass TiO(2) nanotubular layer with a gradient pore diameter and ultrathin tube wall (nearly 10 nm). A higher anodic voltage and longer anodization time are beneficial to the formation of ultrathin tube walls. This approach is simple and cost-effective in fabricating high-quality ordered TiO(2) nanotubular arrays for practical applications. PMID- 20829567 TI - A tunable carbon nanotube polarizer. AB - The electro-optic response of a carbon nanotube (CNT) cluster has been investigated. The cluster absorbs incident light before stretching. In the presence of an electric field, the cluster starts stretching along the field direction and contracts back to its original stage when the applied voltage is removed. The stretched cluster absorbs and transmits incident light with its electric vector propagating parallel and perpendicular to the long axis of the stretched cluster, respectively. Utilizing this selective light absorption property of a CNT cluster, a tunable polarizer or non-emissive light modulator can be realized. PMID- 20829568 TI - ZnO nanotube-based dye-sensitized solar cell and its application in self-powered devices. AB - High-density vertically aligned ZnO nanotube arrays were fabricated on FTO substrates by a simple and facile chemical etching process from electrodeposited ZnO nanorods. The nanotube formation was rationalized in terms of selective dissolution of the (001) polar face. The morphology of the nanotubes can be readily controlled by electrodeposition parameters for the nanorod precursor. By employing the 5.1 microm-length nanotubes as the photoanode for a dye-sensitized solar cell (DSSC), a full-sun conversion efficiency of 1.18% was achieved. Furthermore, we show that the DSSC unit can serve as a robust power source to drive a humidity sensor, with a potential for self-powered devices. PMID- 20829569 TI - The applications of statistical quantification techniques in nanomechanics and nanoelectronics. AB - Although nanoscience and nanotechnology have been developing for approximately two decades and have achieved numerous breakthroughs, the experimental results from nanomaterials with a higher noise level and poorer repeatability than those from bulk materials still remain as a practical issue, and challenge many techniques of quantification of nanomaterials. This work proposes a physical statistical modeling approach and a global fitting statistical method to use all the available discrete data or quasi-continuous curves to quantify a few targeted physical parameters, which can provide more accurate, efficient and reliable parameter estimates, and give reasonable physical explanations. In the resonance method for measuring the elastic modulus of ZnO nanowires (Zhou et al 2006 Solid State Commun. 139 222-6), our statistical technique gives E = 128.33 GPa instead of the original E = 108 GPa, and unveils a negative bias adjustment f(0). The causes are suggested by the systematic bias in measuring the length of the nanowires. In the electronic measurement of the resistivity of a Mo nanowire (Zach et al 2000 Science 290 2120-3), the proposed new method automatically identified the importance of accounting for the Ohmic contact resistance in the model of the Ohmic behavior in nanoelectronics experiments. The 95% confidence interval of resistivity in the proposed one-step procedure is determined to be 3.57 +/- 0.0274 x 10( - 5) ohm cm, which should be a more reliable and precise estimate. The statistical quantification technique should find wide applications in obtaining better estimations from various systematic errors and biased effects that become more significant at the nanoscale. PMID- 20829570 TI - Piezoelectric touch-sensitive flexible hybrid energy harvesting nanoarchitectures. AB - In this work, we report a flexible hybrid nanoarchitecture that can be utilized as both an energy harvester and a touch sensor on a single platform without any cross-talk problems. Based on the electron transport and piezoelectric properties of a zinc oxide (ZnO) nanostructured thin film, a hybrid cell was designed and the total thickness was below 500 nm on a plastic substrate. Piezoelectric touch signals were demonstrated under independent and simultaneous operations with respect to photo-induced charges. Different levels of piezoelectric output signals from different magnitudes of touching pressures suggest new user interface functions from our hybrid cell. From a signal controller, the decoupled performance of a hybrid cell as an energy harvester and a touch sensor was confirmed. Our hybrid approach does not require additional assembly processes for such multiplex systems of an energy harvester and a touch sensor since we utilize the coupled material properties of ZnO and output signal processing. Furthermore, the hybrid cell can provide a multi-type energy harvester by both solar and mechanical touching energies. PMID- 20829571 TI - The electromechanical response of silicon nanowires to buckling mode transitions. AB - Here we show how the electromechanical properties of silicon nanowires (NWs) are modified when they are subjected to extreme mechanical deformations (buckling and buckling mode transitions), such as those appearing in flexible devices. Flexible devices are prone to frequent dynamic stress variations, especially buckling, while the small size of NWs could give them an advantage as ultra-sensitive electromechanical stress sensors embedded in such devices. We evaluated the NWs post-buckling behavior and the effects of buckling mode transition on their piezoresistive gauge factor (GF). Polycrystalline silicon NWs were embedded in SiO(2) microbridges to facilitate concurrent monitoring of their electrical resistance without problematic interference, while an external stylus performed controlled deformations of the microbridges. At points of instability, the abrupt change in the buckling configuration of the microbridge corresponded to a sharp resistance change in the embedded NWs, without altering the NWs' GF. These results also highlight the importance of strategically positioning the NW in the devices, since electrical monitoring of buckling mode transitions is feasible when the deformations impact a region where the NW is placed. The highly flexible NWs also exhibited unusually large fracture strength, sustaining tensile strains up to 5.6%; this will prove valuable in demanding flexible sensors. PMID- 20829572 TI - The formation of symmetric SiC bi-nanowires with a Y-shaped junction. AB - Transmission electron microscopy was used to investigate the formation mechanism of SiC bi-nanowires (BNW) with a Y-shaped junction. Different from the previously reported growth mechanisms, our study suggests that when two individual nanowires that are growing through the vapor-liquid-solid mechanism meet with a proper angle, they will merge and form a straight and symmetric BNW with its two side branches maintaining their original crystallographic orientations and sharing the same crystallographic growth direction, which can be (110), (112) or (113), depending on the meeting angle between the two initial nanowires. According to our observations, a growth model of SiC BNWs with a Y-shaped junction was proposed. The radii and the microstructure of the BNWs are controlled to a certain extent by the meeting angle and the radii of the two SiC single NWs. PMID- 20829573 TI - Customizable in situ TEM devices fabricated in freestanding membranes by focused ion beam milling. AB - Nano- and microelectromechanical structures for in situ operation in a transmission electron microscope (TEM) were fabricated with a turnaround time of 20 min and a resolution better than 100 nm. The structures are defined by focused ion beam (FIB) milling in 135 nm thin membranes of single crystalline silicon extending over the edge of a pre-fabricated silicon microchip. Four-terminal resistance measurements of FIB-defined nanowires showed at least two orders of magnitude increase in resistivity compared to bulk. We show that the initial high resistance is due to amorphization of silicon, and that current annealing recrystallizes the structure, causing the electrical properties to partly recover to the pristine bulk resistivity. In situ imaging of the annealing process revealed both continuous and abrupt changes in the crystal structure, accompanied by instant changes of the electrical conductivity. The membrane structures provide a simple way to design electron-transparent nanodevices with high local temperature gradients within the field of view of the TEM, allowing detailed studies of surface diffusion processes. We show two examples of heat-induced coarsening of gold on a narrow freestanding bridge, where local temperature gradients are controlled via the electrical current paths. The separation of device processing into a one-time batch-level fabrication of identical, generic membrane templates, and subsequent device-specific customization by FIB milling, provides unparalleled freedom in device layout combined with very short effective fabrication time. This approach significantly speeds up prototyping of nanodevices such as resonators, actuators, sensors and scanning probes with state of-art resolution. PMID- 20829574 TI - On-chip SQUID measurements in the presence of high magnetic fields. AB - We report a low temperature measurement technique and the magnetization data of a quantum molecular spin, by implementing an on-chip SQUID technique. This technique enables SQUID magnetometry in high magnetic fields, up to 7 T. The main challenges and the calibration process are detailed. The measurement protocol is used to observe quantum tunneling jumps of the S = 10 molecular magnet, Mn(12) tBuAc. The effect of a transverse field on the tunneling splitting for this molecular system is addressed as well. PMID- 20829575 TI - Phase stability and photocatalytic activity of Zr-doped anatase synthesized in miniemulsion. AB - A series of mesoporous anatase-type TiO(2) doped with zirconium (0-50 mol% Zr) was synthesized by combining the sol-gel process with the inverse miniemulsion technique. Nanoparticles between 100 and 300 nm were directly prepared from acidic precursor solutions of titanium glycolate (EGMT) and zirconium isopropoxide. The miniemulsion technique is a simple and convenient method to synthesize nanoparticles of homogeneous size because the reactions (here hydrolysis and condensation) take place in the confined space of nanodroplets (several hundreds of nanometres) and therefore in a highly controlled manner. For low doping levels (0-7.1 mol% Zr), Zr(x)Ti(1 - x)O(2) solid solutions were formed where Zr was uniformly dispersed into the anatase framework. For higher amounts of zirconium (Zr >or= 7.1 mol%), the crystallization of zirconium titanate (ZrTiO(4)) occurred at a low temperature of 650 degrees C and it was obtained as a pure material for 47.4 mol% 0.05). Regression analysis showed no significant relationship (p = 0.449) between the outcome (receiving research results) and veterans' responses after controlling for demographics and educational levels. CONCLUSION: Participants believed they would prefer receiving their genetic research results. Veterans are similar to nonveterans in their preferences. Offering genetic research results to participants should be based on well defined and structured plans to enhance interpretation of genetic data. PMID- 20829582 TI - Adrenal and extra-adrenal nonfunctioning composite pheochromocytoma/paraganglioma with immunohistochemical ectopic hormone expression: comparison of two cases. AB - Adrenal composite pheochromocytoma is rare, most of which is functional, and extra-adrenal composite paraganglioma is extremely rare. We describe and compare the clinicopathological and immunohistochemical features of a retroperitoneal extra-adrenal composite paraganglioma and an adrenal composite pheochromocytoma. Both tumors were nonfunctioning and laboratory tests revealed no biochemical abnormalities. Both tumors were composed of typical paraganglioma/pheochromocytoma closely admixed with ganglioneuroma component. In addition to typical immunohistochemical phenotypes characteristic of each component, both tumors showed focal staining of somatostatin, and the adrenal tumor was also regionally positive for insulin and prolactin. Despite this aberrant immunohistochemical expression, relevant clinical symptoms or laboratory abnormalities were absent. These tumors serve to exemplify the extremely rare occurrences of clinically silent, nonfunctioning composite pheochromocytoma or paraganglioma with aberrant expression of hormones. PMID- 20829583 TI - Scientific evidence for the medical use of probiotics. PMID- 20829584 TI - Advances and limitations of evidence-based medicine--impact for probiotics. PMID- 20829585 TI - Probiotics and diarrhea. PMID- 20829586 TI - Probiotics in irritable bowel syndrome. PMID- 20829587 TI - Probiotics and the prevention of necrotizing enterocolitis. PMID- 20829588 TI - Probiotics in the treatment and prevention of atopic dermatitis. PMID- 20829589 TI - Probiotics and obesity. PMID- 20829590 TI - Probiotics and respiratory tract diseases. PMID- 20829591 TI - Probiotics and intestinal diseases. PMID- 20829592 TI - Probiotics in surgical and critically ill patients. PMID- 20829593 TI - Temporary percutaneous gastric electrical stimulation: significant progress in the treatment of drug-refractory vomiting and nausea. PMID- 20829594 TI - Case conferences on integrative medicine - a new tool to improve patient-centred care in medicine. PMID- 20829595 TI - The potential influence of plant polyphenols on the aging process. AB - Cellular senescence is characterized by cellular hypertrophy: cell growth in the absence of cell division. The genes that regulate this process can be activated or inactivated by numerous plant polyphenols such as resveratrol, quercetin, butein, fistein, piceatannol, curcumin. Many of these substances have been shown to lengthen the lifespan of invertebrates. Many of these compounds have other potential beneficial effects on lifespan as antiatherogenic or antineoplastic agents. Challenges to human testing of such substances on lifespan include determination of dosage, low bioavailability, time and resources necessary to conduct tests, and understanding which formulation of substances to use. PMID- 20829596 TI - Protective mechanisms of Moringa oleifera against CCl(4)-induced oxidative stress in precision-cut liver slices. AB - OBJECTIVE: The present study was designed to evaluate the efficacy of Moringa oleifera leaves against carbon tetrachloride (CCl(4))-treated liver slices in vitro. MATERIAL AND METHODS: The study evaluated the antioxidant properties of Moringa oleifera leaves against CCl(4)-induced oxidative damage in liver slices. RESULTS: CCl(4) treatment significantly decreased the activities of antioxidant enzymes such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase and caused decreased glutathione content and increased the thiobarbituric acid-reacting substances (TBARS). Treatment with Moringa oleifera extract increased the activities of antioxidant enzymes and glutathione content and reduced the levels of TBARS significantly. Observed reduction in the level of lipid peroxides showed a decreased tendency of peroxidative damage. DISCUSSION AND CONCLUSION: We conclude that, under these experimental conditions, the leaf extracts effectively suppress CCl(4)-induced oxidative stress. Our findings provide evidence to demonstrate that the possible mechanism of this activity may be due to the strong antioxidant property of the leaves. PMID- 20829597 TI - The effect of warming of the abdomen and of herbal medicine on superior mesenteric artery blood flow - a pilot study. AB - BACKGROUND: In traditional Japanese and Chinese medicine, warming the abdomen with moxibustion or herbal medicines has been used for various diseases. However, the effects of these therapies on hemodynamics have not been clear. We clarify the physiological effects of these therapies on the superior mesenteric artery (SMA) blood flow. PARTICIPANTS AND METHODS: 28 healthy male volunteers were randomly assigned to groups A and B. Group A (n = 14) underwent local thermal stimulation of the paraumbilical region for 20 min at a temperature of 40 degrees C; this simulated the heat and mechanical pressure effects of moxibustion. Group B (n = 14) took the herbal medicine Daikenchuto (TJ-100; 5.0 g) with distilled water. As a control, group C (n = 14) took distilled water alone. Blood flow volume in the SMA was measured by ultrasound from rest to 50 min after the start of each intervention. RESULTS: The SMA blood flow volume increased significantly between 10 to 40 min after the start of thermal stimulation (p < 0.05), and it also increased significantly between 10 to 50 min after administration of TJ-100 (p < 0.01) as compared to the resting volume. However, SMA blood flow volume did not change significantly after administration of water alone. There was no significant difference in SMA blood flow changes between groups A and B. CONCLUSIONS: The results suggest that one of the physiological effects of warming the abdomen according to a traditional concept in thermal stimulation and herbal medicine is an increase of SMA blood flow volume. PMID- 20829598 TI - Personal growth in chronic illness - a biographical case study of living with fibromyalgia. AB - BACKGROUND/AIM: Chronic illness can be distressing for patients. It confronts them with the challenge of having to cope with their life and of having to adjust their self-image. Nevertheless, patients often experience that they go through a process of personal growth. Although there is empirical proof of the potential that coping with severe illness has with regard to personal growth, fairly little is known about the conditions that bring about such a development. Based on a singlecase study of fibromyalgia (FM) from Germany, the paper reveals the potential of a biographical approach for understanding the process of personal growth in chronic illness. METHODS: The case is part of a qualitative study on the occurrence of biographical transformation in severe illnesses. A narrative, biographical interview was conducted with the patient. The analysis takes objective biographical data as well as the subjective experience of the patient into account. RESULTS: Our analysis is confirmed by qualitative studies on the subjective experience of FM. Although these studies report a favorable development with some FM sufferers, they neither investigate its significance for the life of the patient nor the factors that make personal growth possible. We tried to identify biographical resources and personal strategies of the patient that facilitated her inner growth. CONCLUSION: A biographical approach is a way towards understanding individual growth in the face of severe suffering. By including the patients' objective life data as well as their subjective experiences, deeper insights into the process of personal growth can be gained. PMID- 20829599 TI - Novel use of silymarin as delayed therapy for acetaminophen-induced acute hepatic injury. AB - AIM: Recently, we have demonstrated that silymarin has a comparable pharmaceutical activity as Phyllanthus urinaria extract when used to rescue mice from acetaminophen-induced acute liver injury. In the present study, we further compared the therapeutic action of silymarin with N-acetyl cysteine (commonly used in clinical practice for emergency treatments) as a rescuer in mice after administering a lethal dose of acetaminophen for 24 h. METHODS: Acute liver injury was induced in the treatment groups by intraperitoneally administered acetaminophen at a dose of 550 mg/kg body weight on day 1. The control group received an equal volume of physiological saline intraperitoneally. From day 2 to 4, the treatment groups received various doses of silymarin or N-acetyl cysteine orally once daily, while the control group and the acetaminophen group received an equal volume of water orally. The mortality rate was recorded in all groups. On day 5, all mice were sacrificed for examination. RESULTS: Silymarin greatly improved the counteracting effects on mortality rate as compared to N-acetyl cysteine. CONCLUSION: Silymarin should be further considered as an antidote for patients with acetaminopheninduced acute hepatic injury and delayed treatment. PMID- 20829600 TI - Antigenic heterogeneity of the NS3 proteins in hepatitis C virus genotypes 1 and 6. AB - OBJECTIVE: To investigate the effect of sequence variability between different genotypes of hepatitis C virus (HCV) on the antigenic properties of the NS3 proteins, and to evaluate the significance of the proteins in the serological diagnosis. METHODS: The recombinant expression plasmids of pET/NS3-1 and pET/NS3 6 were constructed with the NS3 region fragments from HCV genotypes 1 and 6, respectively. The antigenic reactivity of the recombinant NS3 proteins was determined. The NS3 nucleotide sequences were aligned with 6 HCV full-length strains representing different genotypes. RESULTS: The two recombinant NS3 proteins were generated and enzyme immunoassay tests were developed. The positive rates of anti-NS3 were 61.2 and 58.8% by using the NS3 antigens from HCV genotypes 1 and 6, respectively. This difference had no statistical significance (p > 0.05). However, it was interesting that 16 samples gave a discordant result for different genotype NS3 antigens.The two partial NS3 sequences shared approximately 63.9-79.9% identity with the different genotype strains. CONCLUSION: The primary structure of the HCV NS3 region is highly variable. Thus, sequence variability has a profound effect on the antigenic properties of the NS3 regions, and the antigenic differences should be taken into account for the development of more effective diagnostic tests. PMID- 20829601 TI - Quantitative determination of hepatitis C core antigen in therapy monitoring for chronic hepatitis C. AB - The correlation and kinetics of hepatitis C virus (HCV) RNA and HCV core antigen levels in chronic hepatitis C patients treated with pegylated interferon + ribavirin were evaluated in order to envision a combined use of the two assays in therapy monitoring. HCV core antigen levels by a chemiluminescent immunoassay (Abbott ARCHITECT) and HCV-RNA levels by branched DNA (bDNA) or real-time PCR have been evaluated on plasma specimens from 32 patients treated for chronic hepatitis C. An early virological response (undetectable levels of HCV-RNA 4 weeks after start of treatment) was found in 10/23 subjects (43.5%) followed up for 5 months or more. The response was linked to the HCV genotype (20% in genotype 1B vs. 61.5% in other genotypes; p < 0.05). HCV RNA and HCV antigen showed a good correlation (r = 0.814); HCV antigen was still detectable in 3 samples with undetectable (<615 IU/ml) RNA by bDNA, while no differences in clinical sensitivity were recorded in comparison with real-time PCR. These findings suggest that HCV-RNA and HCV antigen may be used at different time points in order to tailor therapy monitoring to individual needs. PMID- 20829602 TI - hSNF5 is required for human papillomavirus E2-driven transcriptional activation and DNA replication. AB - OBJECTIVE: To determine the participation of the SWI/SNF complex in the transcription and replication of human papillomavirus (HPV) E2 protein. METHOD: We checked the interaction between hSNF5 and HPV E2 through glutathione S transferase (GST) pull-down and coimmunoprecipitation assays. The transcriptional activation of E2 was analyzed by reporter assay and the level of HPV DNA replication was determined by a transient DNA replication assay. RESULTS: We demonstrated that hSNF5 binds to the HPV E2 protein in vivo and in vitro and activates E2-dependent viral transcription. SWI/SNF components enhanced E2 dependent viral transcription. The ATPase activity of BRG-1/hSNF2 was required for efficient E2-dependent transcriptional activation. Transient DNA replication assays showed that hSNF5 and BRG-1 enhance HPV-18 DNA replication in vivo. A dominant negative hSNF5 and a BRG-1 ATPase mutant each repressed E2-dependent viral transcription and E2-driven HPV DNA replication in vivo. The fact that the transcriptional activation function of HPV-18 E2 was defective in the SNF5 knockout strains of the yeast Saccharomyces cerevisiae implies that the SWI/SNF complex is required for the transcriptional activation function of E2. CONCLUSION: These results suggest that the SWI/SNF complex is involved in HPV E2 driven transcription and DNA replication via interaction with E2. PMID- 20829603 TI - Increased neutralizing antibody response after simultaneous immunization with leucogen and the feline leukemia virus transmembrane protein. AB - To develop improved vaccination strategies against feline leukemia virus (FeLV), rats were immunized with the transmembrane envelope protein p15E of FeLV alone or in combination with the commercial vaccine Leucogen(r) comprising the nonglycosylated FeLV surface envelope protein. Binding and neutralizing antibodies were induced in both groups and in the group immunized with Leucogen alone. Higher titers of antibodies neutralizing FeLV were induced by simultaneous immunization with Leucogen and p15E compared to the responses using Leucogen or p15E alone, suggesting that combination vaccines should be used in the future. Epitope mapping of p15E-specific antibodies induced by simultaneous immunization with Leucogen and p15E revealed the same pattern of response as obtained after immunization with p15E alone: one epitope was localized in the membrane-proximal external region (MPER) and the other in the fusion peptide-proximal region, and they are related to the epitopes detected after immunization with p15E of the porcine endogenous retrovirus and the koala retrovirus. The data indicate that these epitopes in the MPER are an effective target for neutralization and that antigens containing them may therefore prove to be a useful component of vaccines against retroviruses, including HIV-1. PMID- 20829604 TI - IL-8 is associated with non-viremic state and IFN-gamma with biochemical activity in HCV-seropositive blood donors. AB - OBJECTIVE: The aim of this study was to explore a possible association between the pattern of serum cytokines with the virological and biochemical status of hepatitis C virus (HCV)-seropositive blood donors. METHODS: 23 non-viremic and 33 viremic HCV-seropositive blood donors based on HCV-RNA tests, and 29 healthy individuals were included. Cytometric bead array assays were performed to detect cytokines. RESULTS: The subjects were classified as low, medium or high cytokine producers based on the tertile distribution. The absence of detectable viremia was associated with high IL-1beta and IL-8 producers. Conversely, elevated levels of IL-6, IL-10 and IL-12 were associated with detectable viremia. An increased frequency of high IL-1beta producers was observed frequently in the non-viremic recombinant immunoblot assay (RIBA)-indeterminate subjects, while the high IL-4, IL-6, IL-8, IL-10 and IL-12 producers were more frequent in the non-viremic RIBA positive subjects. Furthermore, the levels of IL-1beta and IL-8 were higher in viremic subjects with a low level of alanine-aminotransferase (ALT), whereas the level of IFN-gamma was increased among viremic subjects with a high ALT level. CONCLUSION: IL-1beta and IL-8 were more likely to be associated with a non viremic or less severe HCV infection, whereas IL-2 and IFN-gamma levels correlated with a high ALT level. PMID- 20829605 TI - Activation of T-cell-factor-dependent transcription by Kaposi's sarcoma associated herpesvirus replication transactivation activator. AB - OBJECTIVE: To elucidate the cellular function of Kaposi's sarcoma-associated herpesvirus (KSHV) replication transactivation activator (RTA) at the transcriptional level. METHODS: Transcriptional activation of T-cell-factor (TCF) dependent genes by RTA was determined using the luciferase reporter assay. The specific regions of RTA required for the activation of TCF-dependent transcription and association with beta-catenin were established. RESULTS: RTA specifically activated TCF-dependent transcription in a dose-dependent manner, to an extent comparable to the activation achieved by latency-associated nuclear antigen. In contrast, other KSHV viral proteins investigated, such as basic leucine zipper and viral interferon regulatory factor 1, did not affect TCF dependent transcription. The C-terminal region of RTA appeared to be necessary for transcription. However, RTA did not affect the beta-catenin level or the subcellular localization thereof. CONCLUSION: Our results collectively demonstrate that KSHV RTA activates TCF-dependent transcription without involving the beta-catenin pathway. PMID- 20829606 TI - Bacteria and phagocytes: mortal enemies. PMID- 20829607 TI - Inactivation of macrophage Rab7 by Burkholderia cenocepacia. AB - Strains of the Burkholderia cepacia complex can survive within macrophages by arresting the maturation of phagocytic vacuoles. The bacteria preclude fusion of the phagosome with lysosomes by a process that is poorly understood. Using murine macrophages, we investigated the stage at which maturation is arrested and analyzed the underlying mechanism. Vacuoles containing B. cenocepacia strain J2315, an isolate of the transmissible ET12 clone, recruited Rab5 and synthesized phosphatidylinositol-3-phosphate, indicating progression to the early phagosomal stage. Despite the fact that the B. cenocepacia-containing vacuoles rarely fused with lysosomes, they could nevertheless acquire the late phagosomal markers CD63 and Rab7. Fluorescence recovery after photobleaching and use of a probe that detects Rab7-guanosine triphosphate indicated that activation of Rab7 was impaired by B. cenocepacia, accounting at least in part for the inability of the vacuole to merge with lysosomes. The Rab7 defect was not due to excessive cholesterol accumulation and was confined to the infected vacuoles. Jointly, these experiments indicate that B. cenocepacia express virulence factors capable of interfering with Rab7 function and thereby with membrane traffic. PMID- 20829608 TI - agr-Dependent interactions of Staphylococcus aureus USA300 with human polymorphonuclear neutrophils. AB - The emergence of serious infections due to community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) has fueled interest in the contributions of specific staphylococcal virulence factors to clinical disease. To assess the contributions of agr-dependent factors to the fate of organisms in polymorphonuclear neutrophils (PMN), we examined the consequences for organism and host cells of feeding PMN with wild-type CA-MRSA (LAC) or CA-MRSA (LAC agr KO) at different multiplicities of infection (MOIs). Phagocytosed organisms rapidly increased the transcription of RNAIII in a time- and MOI-dependent fashion; extracellular USA300 (LAC) did not increase RNAIII expression despite having the capacity to respond to autoinducing peptide-enriched culture medium. HOCl-mediated damage and intracellular survival were the same in the wild-type and USA300 (LAC agr KO). PMN lysis by ingested USA300 (LAC) was time- and MOI dependent and, at MOIs >1, required alpha-hemolysin (hla) as USA300 (LAC agr KO) and USA300 (LAC hla KO) promoted PMN lysis only at high MOIs. Taken together, these data demonstrate activation of the agr operon in human PMN with the subsequent production of alpha-hemolysin and PMN lysis. The extent to which these events in the phagosomes of human PMN contribute to the increased morbidity and mortality of infections with USA300 (LAC) merits further study. PMID- 20829610 TI - Epidemiology of Cushing's syndrome. AB - Overt Cushing's syndrome is a rare disorder with an annual incidence of 2 3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing's syndrome in certain risk populations such as patients with type 2 diabetes or osteoporosis. The clinical implications of these observations are presently unclear. Surgery remains first line treatment for overt disease and initial cure or remission is obtained in 65-85% of patients with Cushing's disease. Late recurrences, however, occur in up to 20% and the risk does not seem to plateau even after 20 years of follow-up. A 2- to 3-fold increase in mortality is observed in most studies, and this excess mortality seems confined to patients in whom initial cure was not obtained. Cushing's syndrome continues to pose diagnostic and therapeutic challenges and life-long follow-up is mandatory. PMID- 20829609 TI - Nuclease expression by Staphylococcus aureus facilitates escape from neutrophil extracellular traps. AB - Neutrophils are key effectors of the host innate immune response against bacterial infection. Staphylococcus aureus is a preeminent human pathogen, with an ability to produce systemic infections even in previously healthy individuals, thereby reflecting a resistance to effective neutrophil clearance. The recent discovery of neutrophil extracellular traps (NETs) has opened a novel dimension in our understanding of how these specialized leukocytes kill pathogens. NETs consist of a nuclear DNA backbone associated with antimicrobial peptides, histones and proteases that provide a matrix to entrap and kill various microbes. Here, we used targeted mutagenesis to examine a potential role of S. aureus nuclease in NET degradation and virulence in a murine respiratory tract infection model. In vitro assays using fluorescence microscopy showed the isogenic nuclease deficient (nuc-deficient) mutant to be significantly impaired in its ability to degrade NETs compared with the wild-type parent strain USA 300 LAC. Consequently, the nuc-deficient mutant strain was significantly more susceptible to extracellular killing by activated neutrophils. Moreover, S. aureus nuclease production was associated with delayed bacterial clearance in the lung and increased mortality after intranasal infection. In conclusion, this study shows that S. aureus nuclease promotes resistance against NET-mediated antimicrobial activity of neutrophils and contributes to disease pathogenesis in vivo. PMID- 20829611 TI - Genetics of Cushing's syndrome. AB - Cushing's syndrome (CS) is characterized by pathologically elevated free glucocorticoid levels. Endogenous hypercortisolism is usually due to ACTH secreting pituitary corticotropic adenomas and less often due to ectopic ACTH secreting neuroendocrine neoplasms or ACTH-independent adrenal cortisol hypersecretion. CS is a serious chronic disease leading to a several-fold increase in cardiovascular morbidity and mortality. Multiple genetic alterations have been described in the setting of sporadic corticotropinoma formation. Changes in the expression profiles have been demonstrated in growth factors and their receptors, cell-cycle regulators and in various genes related to hormonal gene transcription, synthesis and secretion. Sporadic adrenal adenomas and carcinomas may demonstrate dysfunction in genes such as TP53 among others. Cushing's disease can be an inherited condition also. Multiple endocrine neoplasia type 1 (MEN1) and familial isolated pituitary adenomas (FIPA) together account for 5% of pituitary adenomas. Cushing's disease occurs infrequently in an inherited setting in both of these conditions. To date only 2 cases of Cushing's disease have been described in association with mutations in AIP. One case of Cushing's disease has been reported as part of MEN4, a rare MEN1-like syndrome due to mutation in the CDKN1B gene. Carney complex (CNC) due to PRKAR1A mutations in most cases is associated with CS, mainly as a cause of bilateral adrenal hyperplasia. The cAMP signaling pathway is affected in this setting. In recent times the involvement of genes such as PDE11A, PDE8B and others have expanded the spectrum of the genetic pathophysiology of CS. PMID- 20829612 TI - Role of somatostatin receptors in normal and tumoral pituitary corticotropic cells. AB - Normal and tumoral pituitary corticotropic cells express sst(2) and sst(5), of which sst(5) is the predominantly expressed receptor subtype. Somatostatin (SS) inhibits pituitary adrenocorticotropin hormone (ACTH) secretion in vitro, but the sensitivity to SS is strongly regulated by glucocorticoids. In pathological conditions of a low endogenous cortisol level, i.e. in patients with adrenal insufficiency and in patients with Nelson's syndrome, SS and sst(2)-preferring SS analogs (SSA), such as octreotide, are able to lower circulating ACTH and cortisol levels. On the other hand, sst(2)-preferring SSA seem not effective in lowering ACTH and cortisol levels in patients with untreated Cushing's disease (CD), in which circulating cortisol levels are high. This is likely due to the downregulation of sst(2) receptors by glucocorticoids. sst(5) receptor expression is more resistant to the inhibitory effect of glucocorticoids. In recent years, novel sst subtype-selective and universal SSA have been developed. In particular, SSA with a high sst(5)-binding affinity are potent inhibitors of ACTH secretion by pituitary corticotropic adenoma cells. This knowledge has initiated clinical trials evaluating the efficacy of these novel SSA in patients with CD, with the aim to lower circulating ACTH and cortisol levels by targeting multiple ssts on the corticotropic adenoma cells. In this minireview, the effects of SS in the regulation of normal and tumoral ACTH secretion, the role of sst subtypes involved herein, as well as the potentials of novel SSA in the treatment of patients with recurrent or persisting CD are discussed. PMID- 20829613 TI - Role of dopamine receptors in normal and tumoral pituitary corticotropic cells and adrenal cells. AB - The recent depiction of dopamine receptors (DRs) in tumors that cause Cushing's syndrome (CS) has renewed the debate about the dopamine control on pituitary adrenal axis, and opened interesting new perspectives for medical treatment of CS. The new insights arise from the recent accurate characterization of DR subtypes expression within tumors causing CS, the discovery of new mechanisms, such as the dimerization between DRs and other G-protein coupled receptors (CPCRs), including somatostatin receptors (SSTRs), and the recent availability of new agents targeting these receptor subtypes. Corticotropic adenomas express DR subtype 2 (D(2)R), together with different SSTR subtypes (ssts), in particular sst(5). In vitro, activation of D(2)R inhibits ACTH release in the majority of cultures of corticotropic cells, whereas, in vivo, dopaminergic agents display an inhibitory effect on cortisol levels in a subset of patients with CS. In animal models the receptor profile can be deeply modulated in specific environmental conditions, that may resemble the different clinical phases of CS. The new insights about DRs and receptor-targeting drugs may offer different approaches for medical treatment of CS: combination therapies with different types of compounds, treatment with novel molecules (hybrid compounds) with a wider spectrum of activity, or even pretreatment manipulation of receptor profile. Finally, recent studies showed that D(2)R is also significantly expressed in ectopic ACTH-secreting tumors and in both normal and tumoral adrenal tissues. Dopamine-agonists may decrease cortisol levels in a number of these patients, strengthening the current (re)emerging interest in DRs as possible targets for medical treatment of CS. PMID- 20829614 TI - Role of the PPAR-gamma system in normal and tumoral pituitary corticotropic cells and adrenal cells. AB - PPAR-gamma is a member of the nuclear hormone receptor superfamily of transcription factors, whose thiazolidinedione ligands (TZD) have been recently demonstrated to also possess anticancer properties in addition to their well known insulin-sensitizer and glucose/lipid regulation activity. In this minireview, we summarize the current knowledge on PPAR-gamma in normal and tumoral corticotropic pituitary and adrenal cells. The receptor expression has been shown in ACTH-secreting cells in both normal and adenomal pituitary as well as in normal and tumor adrenal cortex. Preclinical studies conducted both in vitro on tumor cells and in vivo on xenograft tumor models obtained by subcutaneous injection of cancer cells have evidenced the anticancer properties of TZD, in particular rosiglitazone (RGZ) and pioglitazone (PIO). In both pituitary and adrenocortical cancer, RGZ treatment results in inhibition of cell proliferation, through G0/G1 cell-cycle arrest and induction of cell apoptosis, leading to significant inhibition of tumor growth in the xenograft tumor models. In addition, since RGZ can reduce ACTH and corticosterone secretion in mouse corticotropic pituitary tumors, both RGZ and PIO have been used in the treatment of Cushing's disease with variable but generally unsatisfactory results. Discrepancies in the antitumor effects of TZD observed between successful preclinical and unsuccessful clinical studies may be particularly due to differences in treatment duration and doses used. PMID- 20829615 TI - Role of the mTOR pathway in normal and tumoral adrenal cells. AB - The mammalian target of rapamycin (mTOR) is a kinase of the phosphoinositide 3 kinase (PI3Ks)/protein kinase B (PKB or AKT) signaling pathway, which is one of the most important intracellular mediators of the activity of growth factors receptors, including vascular endothelial growth factor (VEGF) and insulin-like growth factors (IGFs). Dysregulation of the mTOR pathway has been found in many human tumors. Therefore, the mTOR pathway is considered as a target for antineoplastic therapy in several malignancies. Presently, the role and functions of mTOR and its signaling pathway in the normal and pathological adrenal gland has not been clarified yet. However, many growth factors and growth factor receptors, which are considered to play a role in the pathogenesis of adrenal tumors, can at least in part exert their effects through the activation of PI3K/AKT/mTOR pathway. Dysregulation of AKT has been reported in adrenocortical carcinomas and adrenomedullary tumors, named pheochromocytomas. Adrenocortical carcinomas and malignant pheochromocytomas are aggressive tumors with poor prognosis and scant treatment options. Therefore, new treatment options are warranted for these malignancies. On the basis of the current knowledge, mTOR could play a role in the pathogenesis of both adrenocortical carcinomas and pheochromocytomas. Moreover, mTOR inhibitors, interfering with the activation of several mitogenic and angiogenic factors, could be considered as a novel treatment opportunity for the management of malignant adrenal tumors. PMID- 20829616 TI - Novel insights in the diagnosis of Cushing's syndrome. AB - Cushing's syndrome (CS) results from sustained pathologic hypercortisolism. Increased identification of cyclical CS and the similarities between the metabolic syndrome and mild CS has resulted in an increased prevalence of CS, necessitating more accurate diagnostic tests to screen and diagnose CS in its earliest stages. Many studies have examined the utility of resistance to steroid feedback by the dexamethasone suppression tests and increases in secretion assessing 24-hour urinary free cortisol; however, the most sensitive indicator is the loss of circadian rhythmicity. Therefore, midnight sleeping cortisol is undoubtedly an extremely sensitive indicator of CS but impractical for screening purposes. In this situation assessment late-night salivary cortisol (NSC) is being increasingly investigated as a simple and convenient outpatient procedure. Salivary cortisol has also been used in stimulation or suppression tests because of the detection of rapid changes in cortisol concentration. This paper discusses the effectiveness of SC as a putative accurate, stress-free, and non-invasive sampling procedure. Some studies have shown no difference between tests while others demonstrated a higher sensitivity of SC, while the combination of tests seems to increase their diagnostic value. However, the different assays used for SC estimation and the variable types of control groups in the published studies render a comparison of studies difficult. In conclusion, NSC measurement is increasingly being used as a first-line test for CS, but we recommend that local centres establish their own normative ranges, and there is still a place for the more traditional tests to confirm the diagnosis. PMID- 20829617 TI - Hypertension in Cushing's syndrome: from pathogenesis to treatment. AB - Hypertension is one of the most distinguishing features of endogenous Cushing's syndrome (CS), as it is present in about 80% of adult patients whereas in children its prevalence is about 47%. Hypertension in CS is significantly correlated with the duration of hypercortisolism and results from the interplay between several pathophysiological mechanisms regulating plasma volume, peripheral vascular resistance and cardiac output, all of which are increased in this state. Glucocorticoids cause hypertension through several mechanisms: their intrinsic mineralocorticoid activity; through activation of the renin-angiotensin system; by enhancement of vasoactive substances, and by causing suppression of the vasodilatory systems. In addition, glucocorticoids may exert some hypertensive effects on cardiovascular regulation through the CNS via both glucocorticoid and mineralocorticoid receptors. Hypertension in CS usually resolves with surgical removal of the tumor, but some patients require pharmacological antihypertensive treatment both pre- and postoperatively. Thiazides and furosemide should be avoided, while adrenergic blockade and calcium channel antagonists are usually ineffective. Mineralocorticoid receptor antagonists, Ang II blockers and ACE inhibitors are good anti-hypertensive options; PPAR-gamma agonists may help in many aspects of the insulin resistance syndrome. The relatively selective glucocorticoid receptor antagonist Mifepristone (RU 486) could reduce blood pressure in patients with CS. Neuromodulatory agents such as the serotonin inhibitors cyproheptadine and ritanserin, valproid acid, dopamine agonists, somatostatin analogs may occasionally be effective, as well as drugs acting directly at the adrenal levels, such as Ketoconazole and aminoglutetimide or even opDDD. Treating hypertension in CS remains a difficult task and a big challenge, in order to decrease the morbidity and mortality associated with the disease. PMID- 20829618 TI - Cardiovascular disease in Cushing's syndrome: heart versus vasculature. AB - Cushing's syndrome (CS) causes metabolic abnormalities that determine an increased cardiovascular risk not only during the active phase of the disease but also for a long time after cure. Cardiovascular complications, such as premature atherosclerosis, coronary artery disease, heart failure, and stroke, in patients with CS cause a mortality rate higher than that observed in a normal population. The increased cardiovascular risk is mainly due to metabolic complications, such as metabolic syndrome, but also to vascular and cardiac alterations such as atherosclerosis and cardiac structural and functional changes. In the clinical management of patients with CS the focus should be on identifying the global cardiovascular risk and the aim should be to control not only hypertension but also other correlated risk factors, such as obesity, glucose intolerance, insulin resistance, dyslipidemia, endothelial dysfunction and the prothrombotic state. Considering that remission from hypercortisolism is often difficult to achieve and that the cardiovascular risk can persist even during disease remission, care and control of all cardiovascular risk factors should be one of the primary goals during the follow-up of these patients. PMID- 20829619 TI - Coagulopathy in Cushing's syndrome. AB - A hypercoagulable state and its consequent increased incidence of thromboembolic complications are reported in patients with Cushing's syndrome (CS). These alterations are related to cortisol excess that induces prothrombotic changes in blood by several and complex mechanisms including increased levels of clotting factors, mainly factor VIII and von Willebrand factor (VWF) and impaired fibrinolytic capacity. However, it has recently been observed that the increase in VWF levels is not a constant feature of CS and that VWF response to glucocorticoids is genetically determined and depends on the presence of particular polymorphisms in the VWF gene promoter. The risk of venous thromboembolism is moreover enhanced in patients with CS by additional endogenous and exogenous risk factors such as obesity, bed rest, surgery and invasive diagnostic procedures like inferior petrosal sinus (IPS) sampling. In line with all these data, patients with active CS should be treated as having a prothrombotic disorder and undergo antithrombotic prophylaxis during IPS sampling. Special care should be taken in the immediate perioperative period in order to avoid thromboembolic events. In the absence of prospective randomized trials, preventive antithrombotic treatment (best with heparin) during IPS sampling and low-dose heparin treatment early after surgery should be suggested. PMID- 20829620 TI - Skeletal diseases in Cushing's syndrome: osteoporosis versus arthropathy. AB - Structural and functional impairment of the skeletal system remains an important cause of morbidity and disability in patients with Cushing's syndrome (CS). Glucocorticoid (GC) excess inhibits bone formation and calcium absorption from the gut, increases bone resorption, and alters the secretion of gonadotropin and growth hormones, cytokines and growth factors influencing bone. Both overt and subtle endogenous hypercortisolism affect bone, leading to vertebral fractures in up to 70% of patients. Fracture risk is related to age at onset, duration and severity of the disease and individual susceptibility to GCs that is genetically determined. Bone mineral density (BMD) measurement at the lumbar spine should be performed as a screening test in all patients with CS due to the preferential loss of trabecular bone induced by GCs. The higher risk of fractures at comparable BMD values with controls suggests that bone quality features, not assessed by routine BMD approaches, are also important and should be addressed when indicated applying specific radiological means. Successful treatment of GC excess is associated with improvement in bone mass which, although delayed and often incomplete, reduces the risk of osteoporotic fractures. Bisphosphonates can induce a more rapid improvement in BMD than cortisol normalization alone and can be used in patients with increased risks for further fractures and/or persistent hypercortisolemia to prevent further bone loss. Anabolic agents have not as yet been systemically used. Avascular necrosis, mainly of the femoral neck, and growth arrest in children are the most common skeletal disorders unrelated to osteoporosis encountered in patients with endogenous hypercortisolism. PMID- 20829621 TI - Neuropsychiatric disorders in Cushing's syndrome. AB - Glucocorticoids are crucial in the initiation and consolidation of the stress response. Patients with active Cushing's syndrome (CS) are exposed to excessive endogenous glucocorticoid levels. In these patients, psychopathology is often being observed. The most common co-morbid disorder is major depression, but to a lesser extent mania and anxiety disorders have also been reported. A severe clinical presentation of CS often also includes depression. Reduction of glucocorticoid synthesis or action, either with metyrapone, ketoconazole, or mifepristone, rather than treatment with antidepressant drugs, is generally successful in relieving depressive symptoms, as well as other disabling symptoms. Following successful surgical treatment of hypercortisolism, both physical and psychiatric signs and symptoms improve substantially. However, it appears that patients do not completely return to their premorbid level of functioning and persistent impairment of quality of life and cognitive function has been reported despite long-term cure. At present, it is not clear whether, and to which extent, psychopathology still affects general well-being after long-term cure of CS. PMID- 20829622 TI - Mortality in Cushing's disease. AB - The causes of premature death in untreated Cushing's syndrome are vascular disease (myocardial infarction/stroke), uncontrolled diabetes mellitus and complications and infections. Long-term mortality outcome studies on pituitary dependent Cushing's disease (CD) are limited to six studies in the English language literature. This paper reviews these studies on CD, other causes of Cushing's syndrome being excluded, because CD represents 80% of patients with the syndrome. The period covered by these studies (1970-1990) is when transsphenoidal surgery was well established as primary treatment for CD. Two studies were exclusively from surgical centres and are likely biased in favour of surgically resectable adenomas, so this needs to be borne in mind when interpreting their results. The criteria for remission of hypercortisolism and persistent disease were variable. The overall number of patients in each report is small, and the number of deaths even smaller by epidemiological standards giving very wide confidence intervals to the standardised mortality ratios (SMR). Moreover, follow up time was relatively short (median 10-12 years) for a disease diagnosed in the patients' late 30s. Notwithstanding the above limitations of retrospective studies, and potential for positive bias, the overall SMR of around 1.5 was not significantly different from the relevant normal population for those patients deemed in remission. However, SMR was significantly worse for those patients with persistent disease. Where it was possible to analyse contributing factors to mortality, the presence of hypertension and diabetes mellitus, in addition to persistence of hypercortisolism, was shown to be significant. It remains possible that an overall SMR in 'cured' patients would be significant given a larger cohort, followed for longer, and with more deaths. What is clearly required is a multicentre prospective cohort study with >30 years' follow-up to answer the question definitively and identify the contributing factors in detail in order to achieve optimum long-term outcome. PMID- 20829623 TI - Pathophysiology of diabetes mellitus in Cushing's syndrome. AB - Cushing's syndrome is commonly complicated with an impairment of glucose metabolism, which is often clinically manifested as diabetes mellitus. The development of diabetes mellitus in Cushing's syndrome is both a direct and indirect consequence of glucocorticoid excess. Indeed, glucocorticoid excess induces a stimulation of gluconeogenesis in the liver as well as an inhibition of insulin sensitivity both in the liver and in the skeletal muscles, which represent the most important sites responsible for glucose metabolism. In particular, glucocorticoid excess stimulates the expression of several key enzymes involved in the process of gluconeogenesis, with a consequent increase of glucose production, and induces an impairment of insulin sensitivity either directly by interfering with the insulin receptor signaling pathway or indirectly, through the stimulation of lipolysis and proteolysis and the consequent increase of fatty acids and amino acids, which contribute to the development of insulin resistance. Moreover, the peculiar distribution of adipose tissue throughout the body, with the predominance of visceral adipose tissue, significantly contributes to the worsening of insulin resistance and the development of a metabolic syndrome, which participates in the occurrence and maintenance of the impairment of glucose tolerance. Finally, glucocorticoid excess is able to impair insulin secretion as well as act at the level of the pancreatic beta cells, where it inhibits different steps of the insulin secretion process. This phenomenon is probably responsible for the passage from an impairment of glucose tolerance to an overt diabetes mellitus in susceptible patients with Cushing's syndrome. PMID- 20829624 TI - Management of diabetes mellitus in Cushing's syndrome. AB - Active Cushing's syndrome is associated with insulin resistance induced by the high and prolonged circulating level of glucocorticoids. In endogenous Cushing's syndrome the overall incidence of diabetes mellitus and insulin resistance is very likely to be under-reported as not all patients are actively investigated with glucose tolerance tests. Whilst it is common clinical experience that management of diabetes mellitus is necessary in patients with Cushing's syndrome there is a dearth of literature-based evidence to support which regimes are the most effective. Therefore, a pragmatic approach is necessary on an individualized patient basis, whereby patients are stratified according to the severity of their impaired glucose homeostasis. The most effective means of control of diabetes mellitus in a patient with active Cushing's syndrome is to lower the levels of circulating cortisol. This may initially be achieved by using adrenal steroidogenesis blockade with drugs including metyrapone, ketaconazole, or, on occasion, mitotane. The rapid action of metyrapone is particularly suitable in this circumstance. Despite this, diabetes-specific therapy is often necessary and metformin and PPAR-gamma agonists may be of use, but in the acute setting insulin therapy is frequently needed. Definitive management directed against source driving Cushing's syndrome is often highly effective at either reducing the severity of diabetes, or allowing its complete resolution. Patients experiencing diabetes mellitus in the context of exogenously administered glucocorticoids may well require insulin therapy for the period that the high levels of steroids are being administered. Despite resolution of Cushing's syndrome after definitive treatment patients may continue to exhibit insulin resistance. This and other cardiovascular risk factors require ongoing and long-term attention. PMID- 20829625 TI - Pathophysiology of dyslipidemia in Cushing's syndrome. AB - Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing's syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing's syndrome. In Cushing's syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing's syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, very-low-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing's syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk. PMID- 20829626 TI - Management of dyslipidemia in Cushing's syndrome. AB - Cardiovascular risk factors such as hypertension, hyperlipidemia and glucose intolerance are highly prevalent in Cushing's syndrome. Lipid abnormalities have been reported in 40-70% of patients, including those with 'subclinical' disease. Surgical cure is associated with significant amelioration of lipid profile in the majority of patients. Treatment of persistent hyperlipidemia should be conducted according to the accepted general principles in use for other medical conditions. Nevertheless, patients requiring medical treatment for persistent hypercortisolism present specific challenges, according to the selected therapeutic agent. For example, treatment with the adrenolytic drug o,p'DDD is associated with a prominent increase in cholesterol levels that necessitates intensive use of lipid lowering agents. The use of ketoconazole, a potent inhibitor of cytochrome P450 3A4 (CYP3A4), may significantly increase plasma concentrations of certain statins (such as simvastatin and atorvastatin) that undergo metabolism by the same pathway, thus increasing the risk of complications and side effects. Therefore, preference should be given to HMG-CoA inhibitors that are metabolized by different pathways, such as pravastatin. In summary, hyperlipidemia should be aggressively treated in patients with Cushing's syndrome in view of the increased cardiovascular morbidity and mortality associated with this disorder. PMID- 20829627 TI - Metabolic syndrome in Cushing's syndrome. AB - Although the concept of metabolic syndrome (MetS) as a disease entity continues to be debated, it provides a means by which patients at risk for diabetes and cardiovascular disease can be identified and categorized with routinely available criteria. Insulin resistance plays a central role in these abnormalities. Risk factors include central obesity, elevated fasting glucose, hypertension, elevated serum triglycerides, and low high-density-lipoprotein cholesterol. Various definitions of MetS have been proposed since 1998. Recently, a joint statement by several major organizations concluded that three abnormal values in a series of five criteria determined whether a person had MetS, and that elevated waist circumference was not an obligatory feature. A single set of cutoff points was proposed, except for waist circumference, which should be defined according to population and ethnic group. Cushing's syndrome (CS) represents an archetype of MetS. High glucocorticoid levels lead to muscle, liver and adipocyte insulin resistance. Almost all patients with CS are obese or overweight, and have abdominal visceral adiposity. Many also have glucose metabolism abnormalities (21 60% and 20-47% of the patients have impaired glucose tolerance and diabetes, respectively), hypertension (more than 70% of the patients), and elevated triglyceride levels (20% of the patients). Almost two thirds of CS patients fulfill at least three criteria for MetS. The elevated incidence of diabetes and premature atherosclerosis (directly related to the length of exposure to hypercortisolism), and the increased mortality (particularly cardiovascular mortality) relative to the general population (2 to 4 times higher) show that the predictive value of MetS is also valid in CS. Effective treatment of hypercortisolism improves each of the five MetS components, but MetS and carotid atherosclerosis persist in most patients, and the cardiovascular risk therefore remains elevated. This calls for aggressive treatment of comorbidities and for very long-term follow-up. PMID- 20829628 TI - Pituitary surgery for Cushing's disease. AB - In this article, the present status of neurosurgical operations for Cushing's disease is briefly reviewed. Transsphenoidal surgery is considered the treatment of choice in most patients with Cushing's disease once the diagnosis has been established. In a considerable proportion of patients, even sophisticated imaging does not directly depict the tiny microadenoma. The search for the tumor is technically difficult, particularly when the sella turcica is small, the dura vascularized and the sphenoid sinus poorly pneumatized. Thus, even in expert hands, microadenomas cannot always be identified intraoperatively. Usually, a selective adenomectomy is attempted, preserving pituitary functions. There is a huge variation of surgical outcomes reported. As an estimate, a remission rate of some 75% can be expected 5 years after surgery. Almost all data available to date derive from microsurgical operations. Unfortunately, even in patients who initially remit, recurrences may occur. Low postoperative serum cortisol levels and a long-lasting adrenocortical insufficiency seem to be factors associated with a favorable long-term outcome. When no distinct microadenoma can be identified intraoperatively, partial or even total hypophysectomy has been suggested. However, the outcome of these procedures is less favorable than with selective resections of distinct adenomas. Less than 10% of pituitary adenomas associated with Cushing's disease are macroadenomas. These also bear a less favorable outcome than microadenomas. Only for selected patients with mainly extrasellar tumor localizations are craniotomies recommended. A close cooperation with the endocrinologist is mandatory for a neurosurgeon operating on patients with Cushing's disease, namely for the pre- and perioperative care and for long term follow-up. PMID- 20829629 TI - Pituitary radiotherapy for Cushing's disease. AB - BACKGROUND: The treatment of choice for Cushing's disease is pituitary surgery. Second-line treatments include repeat pituitary surgery, radiation therapy, medical therapy, and bilateral adrenalectomy. The most used modalities to irradiate patients with Cushing's disease include fractionated radiotherapy and single-dose Gamma Knife. We aim to review the efficacy and safety of radiotherapy in patients with persistent or recurring Cushing's disease. RESULTS: Remission of Cushing's disease after radiotherapy ranges from 42 to 83%. There seems to be no clear difference according to the technique of radiation used. Most patients experience remission of disease within 3 years from treatment, with only few cases reaching normal cortisol secretion after a longer follow-up. Control of tumor growth varies from 93 to 100%. Severe side effects of radiotherapy, such as optic neuropathy and radionecrosis, are uncommon. New-onset hypopituitarism is the most frequent side effect of radiation, occurring in 30-50% of patients treated by fractionated radiotherapy while it has been reported in 11-22% of patients after Gamma Knife. CONCLUSION: Radiotherapy is an effective second-line treatment in patients with Cushing's disease not cured by surgery. Consideration of the advantages and disadvantages of radiotherapy in comparison with other therapeutic options should always be carried out in the single patient before deciding the second-line therapeutic strategy for persisting or recurring Cushing's disease. PMID- 20829630 TI - Medical treatment of Cushing's syndrome: adrenal-blocking drugs and ketaconazole. AB - Cushing's syndrome is associated with serious morbidity and increased mortality. Irrespective of its cause, i.e. a pituitary adenoma, ectopic ACTH production or an adrenal neoplasia, Cushing's syndrome is primarily treated surgically. However, when surgery is unsuccessful or contraindicated, medical therapy is needed to treat hypercortisolism. The spectrum of available drugs includes adrenal-blocking agents, neuromodulatory drugs and glucocorticoid receptor antagonists. Adrenal blocking drugs suppress adrenal cortisol production via inhibition of steroidogenic enzymes. Ketoconazole and metyrapone are most frequently used for this purpose, but chronic treatment with these drugs can be limited by side effects like hepatotoxicity (ketoconazole) and increased androgen and mineralocorticoid production (metyrapone). Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of (severe) hypercortisolism like psychosis. In Cushing's disease, combination therapy with drugs that target the corticotropic adenoma, i.e. the universal somatostatin analogue pasireotide and/or the dopamine agonist cabergoline, and low-dose ketoconazole seems a rational approach to achieve biochemical control. PMID- 20829631 TI - Medical treatment in Cushing's syndrome: dopamine agonists and cabergoline. AB - Dopamine (DA) is a catecholamine with a wide range of functions and whose five subtype receptors are found in different organs where they exert a mainly inhibitory action. Since this action may also appear in a number of secretory tumors in various locations, DA agonists have elicited some interest as a medical treatment for hypercorticism. Non-iatrogenic Cushing's syndromes are due in 70% of the cases to a pituitary adrenocorticotropic hormone (ACTH)-producing adenoma, and, less frequently, to an adrenal adenoma or an ectopic ACTH secretion by a neuroendocrine tumor. First-line treatment in Cushing's syndrome consists of the surgical removal of the secreting tumor. However, surgery may not achieve a complete cure in a number of cases, hence emphasizing the potential benefit of a medical complementary treatment, which could also benefit patients as an alternative approach, either when waiting for, or when the patient is not eligible for surgery. Studies of corticotropic adenomas have shown that 80% of these tumors express D2 receptors. Clinical trials of DA agonists in Cushing's disease have shown an inhibitory effect of these drugs with an inhibition of ACTH secretion and/or a decrease of tumor size. There are only a few cases of documented use of DA agonists in ectopic ACTH secretion, but when the tumor expresses DA receptors, DA agonists may represent a useful complementary treatment. DA receptors are also expressed in normal and tumoral adrenals, suggesting a potential use of DA agonists in Cushing's syndrome secondary to adrenal tumors. However, clinical data regarding this specific situation are very scarce, maybe due to the relatively high rate of surgical cure of adrenal adenomas. In conclusion, DA agonists represent a potential preparatory or complementary treatment for endogenous Cushing's syndrome, especially in Cushing's disease. These compounds may be underused as suggested by the scarce number of publication and case reports in the literature. In the future, association of these drugs with somatostatin analogs may also prove beneficial. PMID- 20829632 TI - Medical treatment of Cushing's disease: somatostatin analogues and pasireotide. AB - Cushing's disease is Cushing's syndrome caused by an adrenocorticotropic hormone secreting pituitary adenoma and, in the absence of adequate treatment, can be fatal. Cushing's disease represents an unmet medical need, with no approved medical therapies. Pasireotide is a novel multi-receptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5). Compared with octreotide, pasireotide has an in vitro binding affinity 40-, 30- and 5-fold higher for sst(5,) sst(1) and sst(3), respectively, and 2-fold lower for sst(2). Adrenocorticotropic hormone-secreting pituitary adenomas predominantly express sst(5), followed by sst(2) and sst(1), suggesting that pasireotide may be effective in the treatment of Cushing's disease. In a 15-day phase II trial of pasireotide 600 MUg s.c. b.i.d. in patients with de novo or persistent/recurrent Cushing's disease, 22 of 29 patients (76%) achieved reduced urinary free cortisol (UFC) levels, 5 of whom (17%) achieved normalized UFC. Patients who achieved normalized UFC had a significantly greater reduction in serum cortisol than those who did not (p = 0.04), and minimum pasireotide plasma concentrations appeared to be higher in responders. Based on these results, a randomized, double-blind phase III study comparing pasireotide 600 MUg b.i.d. and 900 MUg b.i.d. was initiated and is ongoing. This is the largest ever phase III study in patients with Cushing's disease. The primary end point of this study is normalization of UFC after 6 months of treatment. Finally, preliminary results from a study on 17 patients with Cushing's disease suggest that the combined use of pasireotide, cabergoline and low-dose ketoconazole may have additive beneficial effects in the medical treatment of Cushing's disease. PMID- 20829633 TI - Medical treatment of Cushing's syndrome: glucocorticoid receptor antagonists and mifepristone. AB - Mifepristone is the first and only available glucocorticoid receptor antagonist. It was initially mainly considered as a so-called 'contragestive' pill due to its antiprogestin activity. In this review, we summarize the results of mifepristone reported in the literature as a treatment of Cushing's syndrome. Most of the patients were treated due to unsuccessful surgery and/or partially effective anticortisolic drugs. The majority of them presented a rapid decrease of clinical signs of hypercortisolism during the first month of treatment; about half experienced a reduction in their elevated blood pressure, and half of the diabetic patients presented improved blood glucose levels. Mifepristone treatment has 2 main drawbacks: (1) the blockade of glucocorticoid receptors leads to increased ACTH and cortisol levels, making it difficult to adapt the treatment and diagnose adrenal deficiency, and (2) increased cortisol levels can also lead to severe hypokalemia. Follow-up of efficacy should only be clinical (weight, blood pressure, skin lesions) and biological (regular blood potassium sampling). Dose adjustment will be performed based on these parameters. The lack of a large available prospective cohort of patients on mifepristone, and the scarcity of data on its long-term effects, does not allow recommending it as a first-line drug in the treatment of hypercortisolism. However, as mifepristone is a rapidly effective drug, it can play a role in the management of hypercortisolism. The main indication is the partial efficacy or bad tolerance of other well-known anticortisolic drugs, either by replacement (bad tolerance, lack of effectiveness) or addition (multimodal approach) of mifepristone. PMID- 20829634 TI - Delayed onset of cardiac compressions in cardiopulmonary resuscitation of newborn pigs with asphyctic cardiac arrest. AB - BACKGROUND: When 30 s of initial positive pressure ventilation fails to stabilize the heart rate (HR) of newborns in the delivery room, the International Liaison Committee on Resuscitation guidelines recommend initiation of cardiac compressions. However, it may take longer than 30 s to establish effective pulmonary gas exchange. Whether a longer period of initial ventilation to reverse asphyxia would result in less need for cardiac compressions is unknown. OBJECTIVES: Our purpose was to investigate the effect of three different initial ventilation intervals prior to initiation of cardiac compressions on hemodynamic parameters, arterial blood gases, oxygen saturations and markers of inflammation and hypoxic damage in a piglet model of asystole due to asphyxia. METHODS: Noroc piglets were anesthetized and mechanically ventilated. Progressive asphyxia was induced until asystole occurred. Randomization was made to ventilation with 21% O(2) for (1) 30 s (n = 16), (2) 1 min (n = 16), or (3) 1.5 min (n = 8) before initiation of cardiac compressions. Return of spontaneous circulation (ROSC) was defined as HR >=100 min(-1). RESULTS: Piglets initially ventilated for 30 s and 1 and 1.5 min achieved ROSC in a median of 150 (interquartile range 115-180),163 (124-177) and 282 (199-364) s, respectively. p value for group 1 versus group 2 was 0.51 and <0.001 for group 1 versus group 3. There were no differences in temporal changes in oxygen saturations, mean arterial blood pressure, HR, pH, pCO(2), interleukin-1beta or lactate/pyruvate ratios between groups. CONCLUSION: Although an additional 30 s to ensure effective ventilation does not impair the speed or success in achieving ROSC, delaying circulatory support for as long as 1.5 min of initial ventilation may be harmful. PMID- 20829635 TI - No influence of DTNBP1 polymorphisms on the response to aripiprazole. AB - AIMS: The aim of the present study was to investigate possible influences of a panel of markers in the dysbindin gene DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761 and rs2619522) on the clinical outcome and side effects associated to the treatment with aripiprazole in schizophrenic patients. METHODS: Efficacy was assessed at baseline and weeks 1, 2, 4, 6 and 8 using the Clinical Global Impression Severity and Improvement Scales, the Brief Psychiatric Rating Scale and the Schedule for the Assessment of Negative Symptoms. Side effects were evaluated by the Simpson-Angus, Barnes Akathisia and Abnormal Involuntary Movement Scales. Multivariate analysis of covariance was used to test possible influences of single nucleotide polymorphisms on clinical and safety scores. Analysis of haplotypes was also performed. RESULTS: No relevant association between DTNBP1 variants and clinical or safety scores was observed. Additionally, haplotype analysis did not reveal any significant association with clinical and safety scores at any time as well. CONCLUSION: Our data suggest no association between the investigated alleles and genotypes in DTNBP1 and the response to aripiprazole. However, because several limitations characterize the present study, further investigations are required. PMID- 20829636 TI - Computer-assisted sleep classification according to the standard of the American Academy of Sleep Medicine: validation study of the AASM version of the Somnolyzer 24 * 7. AB - BACKGROUND: In 2007, the AASM Manual for the Scoring of Sleep and Associated Events was published by the American Academy of Sleep Medicine (AASM). Concerning the visual classification of sleep stages, these new rules are intended to replace the rules by Rechtschaffen and Kales (R&K). METHODS: We adapted the automatic R&K sleep scoring system Somnolyzer 24 * 7 to comply with the AASM rules and subsequently performed a validation study based on 72 polysomnographies from the Siesta database (56 healthy subjects, 16 patients, 38 females, 34 males, aged 21-86 years). Scorings according to the AASM rules were performed manually by experienced sleep scorers and semi-automatically by the AASM version of the Somnolyzer. Manual scorings and Somnolyzer reviews were performed independently by at least 2 out of 8 experts from 4 sleep centers. RESULTS: In the quality control process, sleep experts corrected 4.8 and 3.7% of the automatically assigned epochs, resulting in a reliability between 2 Somnolyzer-assisted scorings of 99% (Cohen's kappa: 0.99). In contrast, the reliability between the 2 manual scorings was 82% (kappa: 0.76). The agreement between the 2 Somnolyzer assisted and the 2 visual scorings was between 81% (kappa: 0.75) and 82% (kappa: 0.76). CONCLUSION: The AASM version of the Somnolyzer revealed an agreement between semi-automated and human expert scoring comparable to that published for the R&K version with a validity comparable to that of human experts, but with a reliability close to 1, thereby reducing interrater variability as well as scoring time to a minimum. PMID- 20829637 TI - Anti-aging in ophthalmology. PMID- 20829638 TI - The era of antiaging ophthalmology comes of age: antiaging approach for dry eye treatment. AB - Recent advances in the understanding of aging have paved a new way of thinking about intervening with the aging process. There is a global agreement in the scientific community that calorie restriction (CR) can actually extend the life span of various kinds of animals so that this has become a real intervention in aging. In addition to the CR theory, the free radical theory is another important hypothesis, which is believed to be involved in aging. According to this theory, we can manage the aging process by controlling calories or reactive oxygen species. In this paper, these two important aging theories, CR and free radical aging, are reviewed, and it is discussed how to apply these theories to the prevention and treatment of eye diseases. Finally, we share the preliminary results of our animal study on dry eye, and I report my personal experience as a dry eye patient, which has been alleviated by the antiaging approach. PMID- 20829640 TI - The importance of nutrition in the prevention of ocular disease with special reference to cataract. AB - BACKGROUND: The lens is the ocular structure most susceptible to oxidative damage. Antioxidants, micronutrients and phytochemicals have been extensively studied for their possible effects to prevent or delay the progression of various eye diseases. OBJECTIVES: A brief overview of the updated literature on the role of antioxidants and micronutrients in the prevention and treatment of ocular diseases is to be presented with an emphasis on cataract. DATA SOURCES: PubMed search and individual papers from journals. DATA SYNTHESIS: The review discusses linkages of various micronutrients and antioxidants as well as oxidative stress with cataract. Dietary interventions as strategy for prevention of cataract and other ocular disorders are also reviewed. CONCLUSIONS: Consumption of food-based antioxidants like beta-carotene lutein and zeaxanthin seem to be useful for the treatment of macular degeneration and cataracts. Supplements of vitamin A, vitamin C, vitamin E and zinc may prevent advanced age-related macular degeneration only in high-risk individuals. PMID- 20829639 TI - Oxidative damage and the prevention of age-related cataracts. AB - PURPOSE: Cataracts are often considered to be an unavoidable consequence of aging. Oxidative damage is a major cause or consequence of cortical and nuclear cataracts, the most common types of age-related cataracts. METHODS: In this review, we consider the different risk factors, natural history and etiology of each of the 3 major types of age-related cataract, as well as the potential sources of oxidative injury to the lens and the mechanisms that protect against these insults. The evidence linking different oxidative stresses to the different types of cataracts is critically evaluated. RESULTS: We conclude from this analysis that the evidence for a causal role of oxidation is strong for nuclear, but substantially lower for cortical and posterior subcapsular cataracts. The preponderance of evidence suggests that exposure to increased levels of molecular oxygen accelerates the age-related opacification of the lens nucleus, leading to nuclear cataract. Factors in the eye that maintain low oxygen partial pressure around the lens are, therefore, important in protecting the lens from nuclear cataract. CONCLUSIONS: Maintaining or restoring the low oxygen partial pressure around that lens should decrease or prevent nuclear cataracts. PMID- 20829641 TI - Mechanisms of retinal ganglion cell injury in aging and glaucoma. AB - Aging is the greatest risk factor for glaucoma, implying that intrinsic age related changes to retinal ganglion cells, their supporting tissue or both make retinal ganglion cells susceptible to injury. Changes to the ocular vasculature, connective tissue of the optic nerve head and mitochondria, which have been documented with advancing age and shown to be exacerbated in glaucoma, may predispose to glaucomatous injury. When considering such age-related changes, it is difficult to separate pathological change from physiological change, and cause from consequence. The insults that predispose aged retinal ganglion cells to injury are likely to be varied and multiple; therefore, it may be more relevant to identify and treat common mechanisms that predispose to retinal ganglion cell failure and/or death. We suggest that mitochondrial dysfunction, as either a cause or consequence of injury, renders retinal ganglion cells sensitive to degeneration. Therapeutic approaches that target mitochondria and promote energy production may provide a general means of protecting aged retinal ganglion cells from degeneration, regardless of the etiology. PMID- 20829643 TI - Free radicals, antioxidants and eye diseases: evidence from epidemiological studies on cataract and age-related macular degeneration. AB - Cataract and age-related macular degeneration (AMD) are the major causes of vision impairment and blindness worldwide. Both conditions are strongly age related with earlier signs (usually asymptomatic) occurring in middle age and becoming severer and more prevalent with increasing age. The aetiology of these conditions is thought to fit with the 'free radical theory' of ageing which postulates that ageing and age-related diseases result from the accumulation of cellular damage from reactive oxygen species (ROS). Mitochondrial energy production is a major source of endogenous ROS. External sources of ROS include environmental sources especially solar radiation, biomass fuels and tobacco smoking. There is strong evidence from epidemiological studies that smoking is a risk factor for both cataract and AMD. There is moderate evidence for an association with sunlight and cataract but weak evidence for sunlight and AMD. The few studies that have investigated this suggest an adverse effect of biomass fuels on cataract risk. The antioxidant defence system of the lens and retina include antioxidant vitamins C and E and the carotenoids lutein and zinc, and there is mixed evidence on their associations with cataract and AMD from epidemiological studies. Most epidemiological studies have been conducted in well nourished western populations but evidence is now emerging from other populations with different dietary patterns and antioxidant levels. PMID- 20829644 TI - Retinal aging and sirtuins. AB - The process of aging involves the accumulating changes in the microenvironment that lead to cell senescence or apoptosis, and subsequent tissue or organ dysfunction. Multiple extrinsic and intrinsic events that cause DNA instability are associated with aging. Cells containing unstable DNA are biologically vulnerable, and if the DNA damage is too great for the cell to repair, it becomes senescent or dies by apoptosis. Thus, the cell's capacity to repair its DNA determines the progress of aging, at least in part. Here, we focus on the sirtuins, the mammalian homologs of the yeast life-span-extending molecule, Sir2. Among the sirtuin family proteins in mammals, the one most similar to yeast Sir2 is SIRT1, which is involved in multiple pathways, including the repair of DNA double-strand breaks. Although the role of SIRT1 in mammalian longevity is not clear, it is expressed throughout the retina, where it may suppress aging. In fact, a mutant mouse model of retinal degeneration shows an abnormal subcellular localization of SIRT1 protein and accelerated retinal cell apoptosis. Further analyses are required to elucidate the mechanism of DNA damage and repair, including the contributions of the sirtuins, in the aged or diseased retinas, which will help us understand the mechanisms of retinal aging. PMID- 20829645 TI - Antidepressants: clinically relevant drug interactions to be considered. AB - Drug interactions in clinical practice are common and have developed into an increasing challenge for the medical profession. Specifically antidepressant drugs (ADs), which are among the 5 most frequently prescribed drugs, are predestined for adverse drug interactions because of their multiple mechanisms of action and/or their influence on drug-metabolizing cytochrome P450 (CYP) enzymes. Although selective serotonin reuptake inhibitors (SSRIs) and other new-generation ADs have an overall improved safety profile, their potential for drug interactions is to be considered. A review of the current literature has been performed, and selected examples of clinically relevant interactions with ADs have been chosen. With regard to pharmacodynamic interactions, the serotonin syndrome, the risk of bleeding under SSRI therapy, and the corrected Q-T interval prolongation are discussed in this review. The inhibitory effects of new generation ADs on CYP enzymes show great variability and might be relevant for prescription recommendations in elderly patients and in patients with polypharmacy. The CYP-enzyme-inducing effect of St. John's wort, a popular over the-counter herbal drug, may lead to decreased plasma levels of CYP substrates. When comparing prescription data and observed adverse drug events, there is fortunately a safety gap between the number of potential drug-drug interactions and the number of clinically observed side effects due to drug-drug interactions. PMID- 20829642 TI - The importance of mitochondria in age-related and inherited eye disorders. AB - Mitochondria are critical for ocular function as they represent the major source of a cell's supply of energy and play an important role in cell differentiation and survival. Mitochondrial dysfunction can occur as a result of inherited mitochondrial mutations (e.g. Leber's hereditary optic neuropathy and chronic progressive external ophthalmoplegia) or stochastic oxidative damage which leads to cumulative mitochondrial damage and is an important factor in age-related disorders (e.g. age-related macular degeneration, cataract and diabetic retinopathy). Mitochondrial DNA (mtDNA) instability is an important factor in mitochondrial impairment culminating in age-related changes and pathology, and in all regions of the eye mtDNA damage is increased as a consequence of aging and age-related disease. It is now apparent that the mitochondrial genome is a weak link in the defenses of ocular cells since it is susceptible to oxidative damage and it lacks some of the systems that protect the nuclear genome, such as nucleotide excision repair. Accumulation of mitochondrial mutations leads to cellular dysfunction and increased susceptibility to adverse events which contribute to the pathogenesis of numerous sporadic and chronic disorders in the eye. PMID- 20829646 TI - Analgesic and antiallodynic effects of antidepressants after infiltration into the rat. AB - Tricyclic antidepressants (TCA) have potent local anesthetic properties and may produce a long-lasting pain blockade that could be of interest in relieving chronic pain states such as neuropathic pain, but there are only few data comparing their dose-response curves of analgesic activity under the same experimental conditions. This study examines the time course of pain-relieving properties of 7 TCA in heat-induced paw withdrawal after subcutaneous administration. Mixed inhibitors of norepinephrine and serotonin uptake (amitriptyline, nortriptyline, imipramine, desipramine, doxepin) and selective inhibitors of serotonin uptake (fluoxetine and fluvoxamine) were assayed. The TCA with the longest analgesic activity were selected to test its antiallodynic effect in the neuropathic pain model of chronic sciatic nerve constriction injury. Bupivacaine was used as a reference drug in both experiments. A dose versus time of maximal analgesic effect curve was constructed for each drug. The longest analgesic effect was obtained for doxepin and imipramine. Although low doses of amitriptyline showed the same activity than doxepin, higher doses failed to reach the same effect. Selective inhibitors of serotonin showed no action at all doses tested. In the chronic sciatic nerve constriction injury model, doxepin and, to a smaller degree, amitriptyline and imipramine protected from allodynia; bupivacaine was ineffective. The antiallodynic effect always lasted less long than the analgesic effect. These observations provide support for the potential use of TCA as durable analgesics. Doxepin overall showed the most outstanding results in pain relief. PMID- 20829647 TI - Blockade of proteinase-activated receptor-4 inhibits the eosinophil recruitment induced by eotaxin-1 in the pleural cavity of mice. AB - OBJECTIVE AND DESIGN: Although proteinase-activated receptor (PAR)-4 has been implicated in inflammation, its role in regulating eosinophil recruitment in response to chemoattractants has not yet been demonstrated. To investigate the contribution of proteinases and PAR-4 activation to eosinophil migration in response to eotaxin-1 or leukotriene B(4) (LTB(4)), the effects of aprotinin or PAR-4 antagonist trans-cinnamoyl-YPGKF-NH(2) (tcY-NH(2)) on eosinophil migration induced by these chemoattractants were investigated. METHODS: BALB/c mice were pretreated with aprotinin or tcY-NH(2) (30 MUg/mouse) prior to intrapleural injection of LTB(4) or eotaxin-1 and the number of infiltrating eosinophils was determined 48 h later. RESULTS: Aprotinin (1 mg/kg) inhibited eosinophil recruitment induced by eotaxin-1 (p < 0.01), but not that induced by LTB(4). Moreover, tcY-NH(2) treatment inhibited eosinophil recruitment in response to eotaxin-1 (p < 0.01 by ANOVA/Tukey post-test). CONCLUSION: These data suggest that aprotinin-inhibited proteinases participate in eosinophil migration induced by eotaxin-1 and that PAR-4 activation plays an important role in regulating this migration. PMID- 20829648 TI - Cognitive-behavioral self-help treatment for nightmares: a randomized controlled trial. AB - BACKGROUND: Several cognitive-behavioral techniques are effective in reducing nightmare frequency, but the therapeutic factor (e.g. cognitive restructuring, systematic desensitization) remains unclear. The aim of this study was to compare the nightmare treatments imagery rehearsal therapy (IRT), exposure, and recording (keeping a diary)--in a self-help format--with a waiting list. METHODS: Participants were recruited through a Dutch nightmare website. After completion of the baseline questionnaires, 399 participants were randomly assigned to a condition, received a 6-week self-help treatment (or were placed on the waiting list), and filled out the post-treatment measurements 11 weeks after baseline. RESULTS: Compared to the waiting list, IRT and exposure were effective in ameliorating nightmare frequency and distress, subjective sleep quality, anxiety (after imagery rehearsal), and depression (after exposure; Deltad = 0.25-0.56). Compared to recording, IRT reduced nightmare frequency while exposure reduced nightmare distress (Deltad = 0.20-0.30; p < 0.05). The recording condition was more effective compared to the waiting list in ameliorating nightmare frequency, nightmare distress, and subjective sleep quality (Deltad = 0.19-0.28; p < 0.05). IRT had a more rapid reduction on the diary compared to exposure and recording. CONCLUSIONS: IRT and exposure appear equally effective in ameliorating nightmare complaints. Exposure to nightmare imagery may function as the crucial therapeutic factor; however, cognitive restructuring may be a useful addition to increase immediate effects. PMID- 20829649 TI - Patient and clinician perceptions of therapeutic alliance as predictors of improvement in depression. AB - BACKGROUND: Meta-analyses have consistently concluded that a positive therapeutic alliance is associated with better clinical outcomes and progress. To date, however, very few studies have focused on sociodemographic or clinical patient characteristics as moderators of alliance. METHOD: A multicenter longitudinal treatment outcome study was conducted to investigate the associations of patient and clinician perceptions of the therapeutic alliance with improvement in depression, and to investigate whether these associations were influenced by sociodemographic or clinical characteristics of the patient. Clinician-rated Montgomery Asberg Depressive Rating Scale scores and both patient- and therapist rated Helping Alliance Questionnaire (HAQ-I) scores were obtained from 567 outpatients with major depressive disorder who received 6 months of combined psycho- and pharmacotherapy. RESULTS: Multilevel repeated-measures analyses indicated that patient- and therapist-rated HAQ-I scores, 4 weeks after treatment began, positively predicted subsequent clinical change, controlling for the effect of early improvement and a range of patient characteristics. Next to alliance, early improvement, initial depressive symptom severity, a history of psychiatric disorders, and occupational status affected the rate of clinical improvement. Personality pathology comorbidity, marital and occupational status, and the atypical character of the major depressive episode (MDE) moderated the alliance-outcome relationship, depending on the informant (patient or therapist) of therapeutic alliance. CONCLUSIONS: The present findings suggest that therapist and patient ratings of therapeutic alliance predict therapeutic progress, and that this relation may be moderated by client characteristics, including personality pathology comorbidity, marital status, occupational status, and the atypical character of the MDE. PMID- 20829650 TI - The 'Weight' of recurrent depression: a comparison between individuals with recurrent depression and the general population and the influence of antidepressants. PMID- 20829651 TI - A second thought on subtyping major depression. PMID- 20829652 TI - Adverse effects of multiple physical symptoms on the course of depressive and anxiety symptoms in primary care. PMID- 20829653 TI - Major depression in cardiac patients is accurately assessed using the cardiac depression scale. PMID- 20829654 TI - The complaint of oral malodour: psychopathological and personality profiles. PMID- 20829656 TI - Polihexanide for wound treatment--how it began. AB - The essential role of wound antiseptics was discovered in the 18th century. Since then, many different procedures and substances have been developed and used for this indication. In the 1980s, polihexanide was introduced by Prof. Willenegger in Switzerland. Today, consensus recommendations confirm the potential of this substance for wound treatment. Various polihexanide-containing wound care products are available and these are now also gaining in importance throughout Europe and throughout the world. PMID- 20829655 TI - Polihexanide--perspectives on clinical wound antisepsis. PMID- 20829657 TI - Polihexanide: a safe and highly effective biocide. AB - Polihexanide is a broad-spectrum antiseptic with excellent tolerance and a low risk profile. The physicochemical action on the bacterial envelope prevents or impedes the development of resistant bacterial strains. Thus, polihexanide is particularly suitable and useful in the struggle against multidrug-resistant bacteria. The ecological database is still incomplete. There is some evidence that biodegradation requires adsorption to inert surfaces and that only a small number of bacterial species are capable of utilizing polihexanide. PMID- 20829658 TI - Review on the efficacy, safety and clinical applications of polihexanide, a modern wound antiseptic. AB - Infected wounds are still one of the great challenges in medicine. In the last decade, it has become increasingly clear that antimicrobial chemotherapy is limited by the spread of antimicrobial resistance. Fortunately, new, highly effective antiseptic substances with a broad antimicrobial spectrum are available, so local treatment is expected to get increasingly more important in wound therapy. This paper reviews the antiseptic agent polihexanide (polyhexamethylene biguanide, PHMB), one of the most promising substances available today, from a clinical point of view, focusing on efficacy, safety and clinical applications. PMID- 20829659 TI - Efficacy of chlorhexidine, polihexanide and tissue-tolerable plasma against Pseudomonas aeruginosa biofilms grown on polystyrene and silicone materials. AB - BACKGROUND: The formation of biofilms is crucial in the pathogenesis of many acute and subacute microbial infections, including chronic wounds and foreign body-related infections. Topical antimicrobial therapy with chemical antiseptics or physical treatment with tissue-tolerable plasma (TTP) may be promising to control bacterial infection. METHODS: We assessed the efficacy of 0.1% chlorhexidine digluconate (CHX), 0.02 and 0.04% polihexanide (polyhexamethylene biguanide, PHMB) and of TTP against Pseudomonas aeruginosa SG81 biofilm grown in microtitre plates (polystyrene) and on silicone materials in an artificial wound fluid. RESULTS: Overall, PHMB was as effective as CHX in reducing the total amount of biofilm (gentian violet assay) and in reducing the bacterial metabolism in biofilms (XTT assay). TTP also led to a significant reduction in colony forming units. CONCLUSION: The antimicrobial activity of PHMB in biofilms is comparable to that of CHX. TTP could become an interesting physical alternative to chemical antisepsis in the future. PMID- 20829660 TI - Response analysis of stimulating efficacy of polihexanide in an in vitro wound model with respiratory ciliary epithelial cells. AB - In animal wound models, accelerated wound closure has been shown by use of polihexanide applied in antimicrobially effective concentrations. Additionally, an increased ATP production of keratinocytes in vitro induced by polihexanide was demonstrated and interpreted as a stimulatory effect on cell proliferation. Based on these results and the clinical reports on improved wound healing after introduction of polihexanide for preoperative antisepsis in the nasal cavity, polihexanide was tested in a wound model on respiratory ciliary epithelial cells allowing measurement of the healing process after artificial injury. 0.5 MUg/ml polihexanide accelerated wound healing in terms of proliferation and migration significantly after an exposure time of 1 and 96 h. At a concentration of 1 MUg/ml polihexanide, the stimulation of wound healing was significantly increased only after an exposure time of 96 h. This is the first study to demonstrate acceleration of wound healing in a standardized in vitro model using an epithelial cell line. Considering the present results and previous reports on the impact of polihexanide on wound healing, the conclusion is drawn that the positive effect of polihexanide on wound healing is a separate, dose-dependent effect independent of its antiseptic properties. PMID- 20829661 TI - Evaluation of the efficacy and tolerability of a solution containing propyl betaine and polihexanide for wound irrigation. AB - Wound cleansing represents a fundamental step in chronic wound management. Several investigations in recent years have led to a refinement of the wound cleansing protocol in order to obtain a better control of the bacterial burden during wound bed preparation and to avoid further cell and tissue damage. The aim of the present randomized controlled trial was to investigate the effects of a wound cleansing solution containing polihexanide and betaine in venous leg ulcers by means of clinical and instrumental assessment. A portable device was used on the wound bed to assess surface pH, which has been shown to be one of the most useful non-invasive biophysical parameters in order to correlate the level of bacterial burden in different types of chronic wounds. Baseline pH on the wound surface (median range) was initially 8.9, and after 4 weeks of cleansing treatment and moist wound dressing was reduced and stable at 7.0 in the group treated with active cleanser. The pH value was significantly lower (p < 0.05) in this group compared to the control group at the end of the study. The treatment with the solution containing polihexanide and betaine was well tolerated by the patients and was found useful in the absorption of wound odours. PMID- 20829662 TI - Clinical use of polihexanide on acute and chronic wounds for antisepsis and decontamination. AB - Polihexanide is an antimicrobial compound suitable for clinical use in critically colonized or infected acute and chronic wounds. Its beneficial characteristic is attributable particularly to its broad antimicrobial spectrum, good cell and tissue tolerability, ability to bind to the organic matrix, low risk of contact sensitization, and wound healing promoting effect. In addition, no development of microorganism resistance during polihexanide use has been detected to date, nor does this risk appear imminent. The aim of therapy using polihexanide is to reduce the pathogen burden in a critically colonized or infected acute or chronic wound. An increasing number of articles on the subject of wound antisepsis with polihexanide can be found in the medical literature. However, there is still little published information on the practical use of polihexanide-containing wound antiseptics. The purpose of this review article is to describe the handling and the different possibilities of use of polihexanide-containing preparations, including the currently approved indications, contraindications and reservations. The use of polihexanide is not the only therapeutic option in management of wounds; therefore, priority is also given to prior surgical debridement and clarification of the cause of the underlying disease, including appropriate therapy. PMID- 20829663 TI - Does extracranial arterial pathology play a role in late-onset psychiatric disorders? AB - INTRODUCTION: Carotid interventions are commonly performed to reduce the risk of disabling stroke and stroke-related death. Carotid interventions may also have an effect on cognitive functions. Mental disorders in the elderly have been related to structural brain pathology. This review of literature was performed to test the hypothesis that atherosclerotic lesions in the carotid and vertebral arteries may have an impact on the development and treatment of late-onset psychiatric disorders. METHODS: A literature search identified articles focusing on the key issues using the Pubmed and Cochrane databases. RESULTS: Cardiovascular risk factors seem to be increased in patients with late-onset mania, depression, and schizophrenia. Cerebral infarctions, especially right-sided, have repeatedly been associated with various psychiatric disorders. Several case reports suggest that chronic cerebral hypoperfusion may also induce psychiatric disease and that these disorders might disappear after reconstruction. CONCLUSIONS: There seems to be an association between occlusive carotid and vertebral disease and the late-onset of various psychiatric disorders. Both thromboembolic and chronic cerebral hypoperfusion might contribute to its pathophysiology. This group of patients might benefit from an intervention. PMID- 20829664 TI - Impairments in social cognition in early medicated and unmedicated Parkinson disease. AB - BACKGROUND: Theory of mind (ToM) refers to the ability to infer others' mental states, including intentions and feelings, and is considered to be a critical part of social cognition. Earlier studies in individuals with Parkinson disease (PD) have shown ToM deficits in the more advanced stages of the disease. There is currently no evidence of social cognition deficits in patients in the early stages of PD. METHODS: In this study, we compared patients with early PD (n=36) and a control group of healthy subjects (n=36). Patients were assessed with 2 ToM tasks designed to differentially detect subtle deficits in the affective and cognitive aspects of ToM. Patients were also assessed with a complete neuropsychologic battery which included classic executive tests aimed at investigating the relationship between ToM and executive functions. Performance of medicated (n=16) and unmedicated (n=20) patients was also compared. RESULTS: Our results are the first to indicate that ToM is affected in the early stages of PD. As has already been reported in more advanced stages of PD, such deficits seem to be related to the cognitive aspects of this domain. In our study, these deficits were not related with performance on executive functioning, depression, or medication usage. CONCLUSIONS: These results provide evidence for ToM impairments early in the course of PD. Recognition of ToM impairments in early PD is important, as these deficits may impact patients' social interactions and quality of life. PMID- 20829665 TI - The use of profanity during letter fluency tasks in frontotemporal dementia and Alzheimer disease. AB - OBJECTIVE: To assess whether the production of profanity during letter fluency testing distinguishes frontotemporal dementia (FTD) and Alzheimer disease (AD) patients. BACKGROUND: Alterations in language and social behavior typify FTD spectrum disorders. Nonetheless, in can be difficult to distinguish pathologically defined frontotemporal lobar degeneration (FTLD) from AD clinically. Assessing verbal fluency by having patients generate words beginning with specific letters in a given period of time can yield diverse information of diagnostic use. METHOD: Words produced during FAS letter fluency testing were reviewed, and instances of the use of "f*ck," "*ss," and "sh*t" and other words felt to be inappropriate were sought. The frequency of these words was compared between clinically diagnosed FTD and AD patients using chi(2) tests. RESULTS: We found that 6/32 (18.8%) patients with FTD generated the word "f*ck" during the "F" trial as opposed to none of 38 patients with AD (P=0.007). Patients who said "f*ck" had diagnoses of either behavioral variant FTD (3/15), progressive nonfluent aphasia (2/8), or semantic dementia (1/3). CONCLUSIONS: Though the specific neuropathology in these cases is uncertain, generation of "f*ck" during letter fluency testing seems to have use in differentiating FTD from AD. PMID- 20829666 TI - Computerized analysis of speech and language to identify psycholinguistic correlates of frontotemporal lobar degeneration. AB - OBJECTIVE: To evaluate the use of a semiautomated computerized system for measuring speech and language characteristics in patients with frontotemporal lobar degeneration (FTLD). BACKGROUND: FTLD is a heterogeneous disorder comprising at least 3 variants. Computerized assessment of spontaneous verbal descriptions by patients with FTLD offers a detailed and reproducible view of the underlying cognitive deficits. METHODS: Audiorecorded speech samples of 38 patients from 3 participating medical centers were elicited using the Cookie Theft stimulus. Each patient underwent a battery of neuropsychologic tests. The audio was analyzed by the computerized system to measure 15 speech and language variables. Analysis of variance was used to identify characteristics with significant differences in means between FTLD variants. Factor analysis was used to examine the implicit relations between subsets of the variables. RESULTS: Semiautomated measurements of pause-to-word ratio and pronoun-to-noun ratio were able to discriminate between some of the FTLD variants. Principal component analysis of all 14 variables suggested 4 subjectively defined components (length, hesitancy, empty content, grammaticality) corresponding to the phenomenology of FTLD variants. CONCLUSION: Semiautomated language and speech analysis is a promising novel approach to neuropsychologic assessment that offers a valuable contribution to the toolbox of researchers in dementia and other neurodegenerative disorders. PMID- 20829667 TI - Impaired comprehension of nonliteral language in Tourette syndrome. AB - OBJECTIVE: To investigate theory of mind and the understanding of nonliteral language in patients with Tourette syndrome (TS). BACKGROUND: In TS, striatal dysfunction could affect the functioning of the frontal cortex. Changes in frontal functioning could lead to impairments in theory of mind: the understanding of mental states, such as beliefs, emotions, and intentions. Poor understanding of a speaker's mental state may also impair interpretation of their nonliteral remarks. METHOD: In this study, patients with TS and healthy controls completed tasks to assess their understanding of sarcasm, metaphor, indirect requests, and theory of mind. These tasks were the Pragmatic Story Comprehension Task, the Hinting task, and a faux pas task. Inhibitory ability was also assessed through the use of the Hayling task and a black and white Stroop test. RESULTS: Patients with TS exhibited significant impairment on the faux pas task and Pragmatic Story Comprehension Task despite limited evidence of inhibitory impairment. CONCLUSION: TS may be associated with changes in theory of mind. PMID- 20829668 TI - Subjective report of word-finding and memory deficits in normal aging and dementia. AB - OBJECTIVE: Compare subjective reports of both memory and word-finding deficits to clinical diagnosis and objective neuropsychological testing. BACKGROUND: With the increasing number of aging individuals with cognitive impairments, effective screening measures would improve the likelihood of detection. Subjective reports of symptoms are typically obtained in clinical settings, yet the validity of these reports is relatively unknown. METHODS: Clinical screening for dementia was carried out at an Alzheimer disease center. Dichotomous ratings for memory and word-finding/language problems were given by patients and neurologists. These ratings were compared with 13 neuropsychological measures of word finding/language and episodic memory. RESULTS: Ratings of memory by both patients and neurologists correlated well with standard neuropsychological measures of memory. However, both the patients' and physicians' ratings of word finding/language impairments had notably less of a correlation with the relevant neuropsychological measures of word-finding/language. CONCLUSION: Compared with ratings of memory, similar assessments of word-finding/language difficulties were relatively inaccurate, and thus poor predictors of impairment. It is imperative to develop effective screening methods that will help reveal cognitive impairments, as this issue will almost certainly become more pressing given the projected increase in the number of aging individuals and those with dementia. PMID- 20829669 TI - The Computerized Test of Information Processing (CTIP) offers an alternative to the PASAT for assessing cognitive processing speed in individuals with multiple sclerosis. AB - OBJECTIVE: To compare the ability of the Computerized Test of Information Processing (CTIP) to detect impaired cognitive processing speed in patients with multiple sclerosis (MS) with a traditional 3.0 second Paced Auditory Serial Addition Test (PASAT) and the Adjusting-PASAT which allows for calculation of a speed score. BACKGROUND: A primary cognitive deficit in MS is an impaired ability to process information quickly. Unfortunately, relatively few clinical tests effectively measure information processing speed. Of these, the PASAT is generally acknowledged to be the most sensitive, but use of this test is constrained by several factors. METHODS: All tests were administered to 30 adults with relapsing-remitting MS and 30 control participants. RESULTS: A series of analysis of variances revealed MS participants performed significantly worse than controls on the CTIP and the 3.0 second PASAT, whereas no significant difference was observed for the Adjusting-PASAT. CONCLUSIONS: The results suggest the CTIP can detect deficits in the speed at which people with MS process information. Thus, the CTIP offers an alternative means to the 3.0 second PASAT included in the Multiple Sclerosis Functional Composite for assessing such impairment. PMID- 20829670 TI - Five-year survival after Helicobacter pylori eradication in Alzheimer disease patients. AB - BACKGROUND: Alzheimer disease (AD) is a progressive, fatal neurodegenerative condition. OBJECTIVE: We tested the hypothesis that eradication of Helicobacter pylori infection (Hp-I) could improve survival in a Greek cohort of AD patients, in a 5-year follow-up. METHOD: Forty-six patients diagnosed with probable AD were enrolled in the analysis. Study population was classified into 3 groups: patients for whom Hp eradication treatment was successful; those for whom eradication of Hp had failed, they refused, and/or were noncompliant with eradication therapy; and those who were Hp negative at baseline. Cox proportional hazards model was built with all-cause mortality as the dichotomous outcome. RESULTS: During the 5 year follow-up [47.19+/-15.11 mo (range 12 to 60)], overall 21 patients died and 25 patients remained alive. Patients who died were older and exhibited lower mean MMSE score compared with the patients still alive. Successful eradication of Hp-I was associated with a significantly lower mortality risk [HR (95% CI)=0.287 (0.114-0.725), P=0.008]. The results were similar in adjusted and unadjusted models, for age and MMSE at baseline. CONCLUSION: Hp eradication regimen in AD patients is associated with a higher 5-year survival rate. PMID- 20829671 TI - Dementia developing in late-onset and treatment-refractory obsessive-compulsive disorder. AB - BACKGROUND: Although several studies have been conducted in an attempt to characterize the phenotype and underlying pathophysiology of individuals with early-onset obsessive-compulsive disorder (OCD), the literature on patients who develop OCD later in life remains sparse. OBJECTIVE: To describe clinical outcomes in the 7-year follow-up of a patient with late-onset OCD. METHOD: Single case report. RESULTS: A 64-year-old woman exhibiting a 7-year history of treatment-refractory late-onset OCD developed significant cognitive deterioration. We suggest that the association between late-onset treatment refractory OCD and dementia may stem from at least 3 different scenarios. First, dementia may be an inexorable end-point of some forms of malignant, primary, and late-onset obsessional illness. Second, late-onset OCD and dementia may result from a common pathophysiologic basis, such as in fronto-temporal dementia. Finally, the association between both conditions may result by the interaction between vulnerability toward OCD-type symptoms and the nonspecific effects of a neurodegenerative process. In our case, although subclinical OCD was likely to be "unmasked" by cognitive decline and/or bilateral caudate vascular lesions, ensuing cognitive deterioration could be ascribed to development of Alzheimer dementia. CONCLUSION: Our observation suggests that treatment refractoriness in an individual with late-onset OCD may indicate underlining organicity. PMID- 20829674 TI - Fantastic voyage and opportunities of engineered nanomaterials: what are the potential risks of occupational exposures? PMID- 20829677 TI - How low can you go: the impact of a modestly effective HIV vaccine compared with male circumcision. AB - OBJECTIVE: The first evidence of modest effectiveness of an HIV vaccine was demonstrated by the RV144 trial in Thailand in 2009. Although promising, this vaccine has largely been dismissed because it only had 30% efficacy. In contrast, male circumcision is widely supported and has approximately twice the efficacy, but can only be targeted to half of the population. We question the vaccine efficacy required before being considered in prevention strategies. DESIGN: We forecast the expected population-level impact of implementing circumcision among males compared with a 30% effective vaccine among males and females. METHODS: A mathematical transmission model was developed to describe the HIV epidemics in two different settings, Thailand and South Africa, and to forecast the expected impact of circumcision or vaccine interventions. RESULTS: Interventions using a vaccine with 30% efficacy would likely have a greater population benefit than male circumcision because a proportion of males are already circumcised, thus diminishing the potential target population. Both males and females will receive considerable benefit from vaccination (for example, 33% of infections averted for males and 36% for females in South Africa), whereas females will receive only moderate benefit from male circumcision (for example, 47% of infections averted for males and 19% for females in South Africa). In both settings, it would likely take a number of years before the interventions could have a noticeable impact on HIV epidemics. CONCLUSION: A moderately effective vaccine, such as the one demonstrated in the RV144 trial, may have a potential role in public health programs. PMID- 20829679 TI - Solar elastotic material in dermal lymphatics and lymph nodes. AB - The movement of material via passive mechanical transport through lymphatic channels (also known as benign mechanical transport) is a physiologic mechanism invoked to explain the occasional presence of benign heterotopic tissues within lymph nodes. However, historically, the concept of benign mechanical transport has provoked controversy. The proof of this concept is of fundamental importance to the claim that foreign cells or cellular aggregates found within a sentinel lymph node do not necessarily represent clinically relevant metastatic disease. Herein we present the previously undescribed finding of solar elastotic material within the dermal lymphatics, and/or capsules, subcapsular sinuses, and parenchyma of lymph nodes of 9 patients. Eight of the patients were treated and/or staged for cutaneous melanoma; one had Merkel cell carcinoma. Solar elastotic material was found in lymph nodes in association with metastatic melanoma, nodal melanocytic nevi, and in otherwise unremarkable lymph nodes lacking extrinsic cells. These findings support the concept of the mechanical transport of both benign and malignant tissues through lymphatics and document that passively transported material can appear in any compartment of the lymph node; an important concept to give evidence for, as it offers a sound explanation for the presence of some cellular deposits within lymphoid tissue and supports the assertion that some of these deposits are benign. PMID- 20829678 TI - Virologic and immunologic response to HAART, by age and regimen class. AB - OBJECTIVE: To determine the impact of age and initial HAART regimen class on virologic and immunologic response within 24 months after initiation. DESIGN: Pooled analysis of data from 19 prospective cohort studies in the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD). METHODS: Twelve thousand, one hundred and ninety-six antiretroviral-naive adults who initiated HAART between 1998 and 2008 using a boosted protease inhibitor-based regimen or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen were included in our study. Discrete time-to-event models estimated adjusted hazard odds ratios (aHOR) and 95% confidence intervals (CIs) for suppressed viral load (<=500 copies/ml) and, separately, at least 100 cells/MUl increase in CD4 cell count. Truncated, stabilized inverse probability weights accounted for selection biases from discontinuation of initial regimen class. RESULTS: Among 12 196 eligible participants (mean age = 42 years), 50% changed regimen classes after initiation (57 and 48% of whom initiated protease inhibitor and NNRTI-based regimens, respectively). Mean CD4 cell count at initiation was similar by age. Virologic response to treatment was less likely in those initiating using a boosted protease inhibitor [aHOR = 0.77 (0.73, 0.82)], regardless of age. Immunologic response decreased with increasing age [18-<30: ref; 30-<40: aHOR = 0.92 (0.85, 1.00); 40-<50: aHOR = 0.85 (0.78, 0.92); 50-<60: aHOR = 0.82 (0.74, 0.90); >=60: aHOR = 0.74 (0.65, 0.85)], regardless of initial regimen. CONCLUSION: We found no evidence of an interaction between age and initial antiretroviral regimen on virologic or immunologic response to HAART; however, decreased immunologic response with increasing age may have implications for age-specific when-to-start guidelines. PMID- 20829680 TI - Adult-type fibrosarcoma: A reevaluation of 163 putative cases diagnosed at a single institution over a 48-year period. AB - Adult-type fibrosarcoma (FS) was once considered the most common adult sarcoma, but is now considered a diagnosis of exclusion. No recent series has critically reevaluated putative FSs to estimate their true incidence. One hundred ninety five cases diagnosed as adult FS in somatic soft tissue were retrieved from our institutional archives for the period 1960 to 2008. Thirty-two cases with insufficient material were excluded. On the basis the morphology of the final 163 cases, immunohistochemical studies (IHC) was conducted using some combination of: wide-spectrum cytokeratin (CK), EMA, high molecular weight CK, S100, Melan A, HMB 45, CD34, TLE1, CD31, HHV8, smooth muscle actin, desmin, ALK1, CD99, Myo-D1, myogenin, c-kit, INI1, CD21, p63, calretinin, WT1, and TTF1. Fluorescence in situ hybridization analysis for SYT gene rearrangement was done in 6 putative CK negative synovial sarcomas (SS). Revised diagnoses were based on clinical, morphologic, IHC, and molecular findings. The original group of putative FS occurred in 84 males and 79 females (median 52.5 y, range 2 to 99 y), and involved various anatomic sites. Only 26 cases met WHO criteria for FS, including 2 postradiation FS. These occurred in 16 males and 10 females (median 50 y, range 6 to 74 y), and involved the lower extremities (12 cases), head/ neck (5 cases), trunk (4 cases), upper extremities (3 case), and mediastinum/abdomen (2 cases). Clinical follow-up information was available for 24 of 26 (92%) cases, with a median of 5 years follow-up (range <1 to 35 y). Twelve patients (50%) died of locally aggressive and/or metastatic disease (median follow-up 1-year; range <1 to 8 y), 6 patients (25%) were alive without disease (median follow-up 11.5 y; range 2.5 to 35 y), and 6 patients (25%) died of other causes (median follow-up 10 y; range 9 to 18 y) (). Fluorescence in situ hybridization analysis was positive for SYT gene rearrangement in all cases tested. Non-FS (137 cases) were reclassified as: undifferentiated pleomorphic sarcoma (32 cases), SS (21 cases), solitary fibrous tumor (14 cases), myxofibrosarcoma (11 cases), malignant peripheral nerve sheath tumor (8 cases), FS dermatofibrosarcoma protuberans, and desmoplastic melanoma (4 cases each), low-grade fibromyxoid sarcoma, sarcomatoid carcinoma, desmoid-type fibromatosis, rhabdomyosarcoma, myofibroblastic sarcoma, spindle-cell liposarcoma (3 cases each), sclerosing epithelioid FS, fibroma-like epithelioid sarcoma, leiomyosarcoma, cellular fibrous histiocytoma (2 cases each), and others (17 cases). Using modern diagnostic criteria with ancillary IHC and molecular genetics, we have been able to reclassify 84% of putative FS. Exclusive of undifferentiated pleomorphic sarcoma, the distinction of which from FS is subjective, 64% of putative FS were reclassified, most commonly as monophasic SS and solitary fibrous tumor. We conclude that true FS is exceedingly rare, accounting for <1% of approximately 10,000 adult soft tissue sarcomas seen at our institution during this time period, and should be diagnosed with great caution. PMID- 20829681 TI - Dysfibrinogenemia in childhood: two cases of congenital dysfibrinogens. AB - A 2-year-old asymptomatic boy and his relatives were investigated for a suspected fibrinogen mutation after coagulation tests revealed a decreased functional fibrinogen level (family A). Eight-year-old and 1-year-old asymptomatic brothers were investigated for a suspected fibrinogen mutation after coagulation tests revealed a decreased functional fibrinogen level and prolonged thrombin time (family B). To identify whether genetic mutations were responsible for these dysfibrinogens, DNA extracted from the blood was analyzed. Fibrin polymerization and fibrinolysis were measured by a turbidimetric method at 450 nm. DNA analysis was performed by the Sanger method. Mass spectroscopy was performed on a Biflex IV mass spectrometer. DNA sequencing showed the heterozygous point mutation Aalpha Arg16His in the fibrinogen of family A and the heterozygous point mutation Aalpha Arg16Cys in the fibrinogen of family B. Kinetics of fibrinopeptide release, fibrinolysis, and fibrin polymerization were impaired in the carriers of the mutations in both families. Mass spectroscopy showed the presence of mutant fibrinogen chains in circulation. Scanning electron microscopy revealed thicker fibrin fibers, differing significantly from the normal control in both cases. Two cases of asymptomatic dysfibrinogenemias, found by routine coagulation testing, were genetically identified as new cases of fibrinogen variants Aalpha Arg16His and Aalpha Arg16Cys. PMID- 20829682 TI - Long-term prospective study of recurrent venous thromboembolism in a Hispanic population. AB - The aim of this study was to assess the incidence and risk factors for recurrent venous thromboembolism (VTE) in a Hispanic population. We prospectively followed 343 patients after a first episode of objectively proven VTE. We excluded all patients with VTE at unusual sites, older than 70 years old, with neoplasia, liver or renal chronic disease and antiphospholipid syndrome. Predictors for recurrence were evaluated by Cox model. The probability of recurrent VTE was estimated by the method of Kaplan-Meier. The cumulative probability of recurrent VTE was 19.1% in 5 years and 30.0% in 10 years. Male sex [relative risk (RR) 1.7, 95% confidence interval (CI) 1.0-2.8], spontaneous first VTE (RR 2.9, 95% CI 1.7 5.0) and FII G20210A mutation (RR 4.2, 95% CI 1.9-9.4) were independent risk factors for recurrent VTE. The fibrinogen, coagulation factors VIII, IX, X and XI were measured in 200 patients and were not associated to thrombotic recurrence risk. This study indicates that the incidence of recurrent VTE is high in Hispanics and depends on clinical and laboratory findings. In this population, FII G20210A mutation may represent a specific risk factor for recurrence. The inclusion of different ethnic populations in epidemiological studies of VTE as well as new approaches to the management of anticoagulation therapy in Hispanics is warranted. PMID- 20829683 TI - The use of desmopressin in mild hemophilia A. AB - Owing to its ability to raise plasma levels of factor VIII and von Willebrand factor levels, the synthetic vasopressin analogue desmopressin has become the mainstay of treatment for type 1 von Willebrand disease and mild hemophilia A. A long clinical experience with this drug for prevention or treatment of bleedings in these patients has been accumulated over the past 30 years, supporting its hemostatic effectiveness and safety. In this paper, we summarize the current knowledge on the mechanisms of action as well as its biological effects in patients with mild hemophilia A. The results of the most important clinical trials in this setting are also reviewed. PMID- 20829684 TI - Wound infiltration with local anaesthetics in ambulatory surgery. AB - PURPOSE OF REVIEW: Wound infiltration analgesia using local anaesthetics has been used for several decades. Recently, newer techniques to prolong analgesia have developed, including the use of catheters and injection of local anaesthetics or other adjuvants, and local infiltration analgesia using large volumes of local anaesthetics injected into different tissue planes. The aim of this review is to present the current status of wound infiltration analgesia in management of postoperative pain and to highlight the risks of this technique in clinical practice. RECENT FINDINGS: Several studies have shown beneficial effects of local anaesthetics, with or without adjuvant drugs, in the management of postoperative pain. Specifically, the use of local anaesthetics injected via catheters to prolong analgesia reduces postoperative pain, albeit to a limited extent. The use of large volumes of local anaesthetics into tissue planes during surgery is also beneficial in pain management. Single doses of local anaesthetics provide pain relief, but the short duration of effect can be a limiting factor. There is a growing concern about some side-effects associated with the use of local anaesthetics, specifically toxicity when drugs are injected in large doses, chondrotoxicity when bupivacaine is injected intra-articularly in higher concentrations and over a period and finally, infection when using catheters that are retained in situ. SUMMARY: Used correctly and in adequate doses, wound infiltration analgesia can be used in a multimodal analgesic regime without major complications. It offers the benefit of providing analgesia at a low cost when used as a single injection. PMID- 20829685 TI - Resistance exercise and appropriate nutrition to counteract muscle wasting and promote muscle hypertrophy. AB - PURPOSE OF REVIEW: Loss of skeletal muscle mass is a common feature of a number of clinical scenarios including limb casting, bed rest, and various disorders such as HIV-AIDS, sepsis, cancer cachexia, heart failure, and uremia. Commonly, muscle disuse (hypodynamia) is the sole reason, or a large part, of why muscle mass is lost. The reduction in strength, or dynapenia, that accompanies these conditions is also a function of the degree of hypodynamia and is related to muscle loss. RECENT FINDINGS: The major and consistent finding in a number of human-based models of muscle wasting is a decline in the synthesis of new muscle proteins both in the postabsorptive and fed states. Thus, countermeasures are best suited to those that augment muscle protein synthesis and not those that attempt to counteract proteolysis. Our main thesis is that retention of muscle mass in wasting conditions will be achieved to the greatest extent by focussing on increased muscle use with moderate-to-high resistance loads as the primary countermeasure with a secondary countermeasure being to provide adequate nutritional support. Either intervention alone will alleviate some part of hypodynamia-induced muscle mass loss and dynapenia; however, together nutrition and muscular contraction will result in greater mitigation of muscle loss. SUMMARY: Advances in our understanding of hypodynamia-induced muscle loss, a condition common to almost all syndromes of muscle wasting, has led to a focus on reduced basal and feeding-induced elevations in protein synthesis. Countermeasures for wasting should focus on stimulating anabolism rather than alleviating catabolism. PMID- 20829686 TI - Effects of energy balance on postprandial triacylglycerol metabolism. AB - PURPOSE OF REVIEW: To present the effect of negative energy balance on postprandial triacylglycerol concentrations (pTAG), an independent risk factor for the development of cardiovascular disease. RECENT FINDINGS: Aerobic exercise reduces pTAG; however, recent findings confirm that this effect is only evident with an accompanying energy deficit. Moreover, a recent study showed that acute diet-induced energy deficit also reduces pTAG. The extent of energy deficit required to significantly attenuate pTAG depends on the type of given meal, the type of deficit (aerobic/resistance exercise, diet, or combination of diet and exercise), and patients' health status. Apart from the acute effects, prolonged energy deficit leading to moderate weight loss attenuates pTAG, when it is combined with other known hypotriacylglycerolemic agents, such as carbohydrate restriction. SUMMARY: For healthy population, it seems that it is up to patient's preference and ability which type of energy deficit will follow to attenuate pTAG; an energy deficit of approximately 30 kJ/kg of body mass is required; for resistance exercise a smaller deficit is probably sufficient. More studies are needed to investigate dose-response/plateau effects, the effects of energy deficit-energy surplus every other day, and the threshold of energy deficit weight loss in diabetics and other high-risk populations. Finally, investigation of the underlying mechanisms may be clinicall helpful in individualizing the appropriate intervention. PMID- 20829687 TI - Traumatic optic neuropathy: a review of the current literature. AB - PURPOSE OF REVIEW: Traumatic optic neuropathy is common clinical problem for neuro-ophthalmologists, without evidence-based guidelines regarding evaluation and therapy. Although no large natural history or randomized controlled trial has been published, corticosteroid therapy, surgical decompression or observation remains the mainstays of therapy. RECENT FINDINGS: Additional research is ongoing, concerning medications and therapies to enhance visual recovery following trauma; future treatments may concern neuroprotective factors and retinal ganglion cell regeneration. SUMMARY: A randomized control trial would likely provide the best understanding of the disease as well as reliable treatment guide. PMID- 20829688 TI - Future for biological therapy for uveitis. AB - PURPOSE OF REVIEW: To review biological therapies as they pertain to the treatment of inflammatory eye diseases, especially uveitis. RECENT FINDINGS: Biological therapies including antibodies, soluble receptors, and cytokines are being tested increasingly for a variety of ocular inflammations. As a class, tumor necrosis factor inhibitors have arguably been the most widely employed and have emerged as a successful approach to treat Behcet's disease. Alpha interferon has demonstrated efficacy in the treatment of Behcet's disease and other forms of posterior uveitis. Additional cytokines, cell surface markers, adhesion molecules, and accessory molecules are targets of biological therapy, but the relevance of these targets in eye inflammation is sometimes just theoretical. And any disruption of the immune response entails potential risk. SUMMARY: Biological therapies offer tremendous potential in the treatment of ocular inflammation, but their study to date has been limited and both the efficacy and the risk are incompletely known for most of the available interventions. PMID- 20829689 TI - Vogt-Koyanagi-Harada disease: diagnosis and treatments update. AB - PURPOSE OF REVIEW: To review current advances in the diagnosis and therapy of Vogt-Koyanagi-Harada (VKH) disease. RECENT FINDINGS: A new T-cell subset (Th17) may play an important role in the initiation and maintenance of inflammatory disease when stimulated by the interleukin (IL)-23, thus producing IL-17. Recent developments of new imaging techniques, such as high-resolution optical coherence tomography 3 scanner (OCT3), have allowed greater accuracy in VKH disease diagnosis. The OCT3 examinations have shown that cystoid spaces appear in the neurosensory layer (between the inner and outer segments of photoreceptors) and not in the subretinal space. This structural finding was also supported by functional studies with multifocal electroretinography that measured the photoreceptors activity. Antimetabolites (azathioprine, mycophenolate mofetil and methotrexate), T-cell inhibitors (cyclosporine and tacrolimus) and biologic agents, associated with the well known glucocorticosteroids therapy, showed good results in acute and chronic phases of the disease. Intravitreal triamcinolone and bevacizumab were reported to have encouraging results for progressive or stubborn cases of VKH disease. SUMMARY: To uphold visual acuity, an early, fast and accurate diagnosis is necessary, followed by an aggressive and lengthy immunosuppressive treatment. PMID- 20829690 TI - Prenatal genetic screening and diagnosis for pediatricians. AB - PURPOSE OF REVIEW: Prenatal genetic screening and diagnostic testing can identify many disorders that will require specialized newborn care and follow-up. Pediatricians should be aware of recent advances in testing that may have implications for their patients and families. RECENT FINDINGS: Over the last half decade, there have been important changes in the breadth and depth of prenatal screening and diagnostic procedures. Carrier screening for selected genetic disorders is now offered routinely to pregnant women or those contemplating pregnancy. Newly developed strategies for first-trimester screening for fetal chromosome abnormalities have improved the detection rate for these disorders, while maintaining a low screen-positive rate. The American College of Obstetricians and Gynecologists and the American College of Medical Genetics now recommend that invasive prenatal diagnostic testing be made available to all pregnant women, regardless of age or prenatal screening results. And prenatal ultrasound findings of unknown clinical significance require that pediatricians provide appropriate follow-up in the newborn period and beyond. SUMMARY: Prenatal genetic screening and diagnostic tests are changing rapidly, and results of these tests may impact the postnatal evaluation and treatment strategies for pediatric care. PMID- 20829691 TI - Spinal muscular atrophy: a time for screening. AB - PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through carrier detection and prenatal diagnosis becomes extremely important. RECENT FINDINGS: The correlation between the SMA phenotype and the SMN2 copy number and the demonstration that sufficient SMN protein from SMN2 in transgenic mice can ameliorate the disease has made the SMN2 gene an obvious target that is being modulated in current therapeutic trials. Most recent work, utilizing gene therapy, has also shown a rescue of the phenotype in the mouse model. Since SMA children are often asymptomatic at birth, newborn screening is a means which will allow the implementation of the most early intervention to take place, before the irreversible loss of motor neurons. Since there is no effective cure for SMA presently, prevention through the identification of carriers becomes an important alternative and has recently been initiated. SUMMARY: Treatment and prevention of SMA are complementary responses to the scourge presented by SMA. This review first describes the molecular genetics of SMA and then focuses on newborn screening, as a means of ensuring the earliest intervention, and the prevention through population carrier screening. PMID- 20829692 TI - Prevention strategies in child maltreatment. AB - PURPOSE OF REVIEW: Child maltreatment remains a prevalent problem for which notable best practices such as home visitation can be effective; however, most eligible families do not receive these beneficial services. Additionally, there are other promising prevention interventions to effectively address child maltreatment. This review focuses on the recent advances and strategies for child maltreatment prevention. RECENT FINDINGS: Although home visiting does not have a single clearly defined methodology of providing service to children and families, the general supportive framework to improve maternal, child, and family factors makes this intervention the most widely studied and accepted prevention strategy. However, there has been limited effectiveness for most models. The Nurse-Family Partnership (NFP) has provided consistently positive results by targeting families with many risk factors by using highly trained professionals when implementing a research-based intervention. A promising public health approach to parent training (Triple P) may reduce maltreatment and out-of-home placement. Parent-child interaction therapy (PCIT), while a treatment model, is becoming an increasingly important approach to child maltreatment prevention. There may be an opportunity to reduce child maltreatment by enhancing care in the pediatric medical home setting. SUMMARY: Effective child maltreatment prevention efforts exist; however, not all programs provide the same effectiveness, or target the same maltreatment issues. Pediatricians are in a key position to offer support to families in their own practice, as well as to direct families to the appropriate resources available. PMID- 20829693 TI - Current research on cognitive aspects of anxiety disorders. AB - PURPOSE OF REVIEW: Cognitive dysfunction is frequently reported in anxiety disorders. Our aim is to describe recent advances concerning these cognitive aspects. RECENT FINDINGS: Cognitive dysfunction in anxiety disorders can be classified into four domains. The first concerns executive functions, mainly attentional processes. The second concerns memory, including deficits in working, episodic, and autobiographical memory. The third encompasses maladaptive cognitions, or thoughts and beliefs. Finally, a burgeoning area of research (mainly in obsessive-compulsive disorder and posttraumatic stress disorder) concerns metacognitions, or thoughts and beliefs about one's own thoughts and beliefs. All of these dysfunctions may contribute to maintain or aggravate anxiety disorders. When developing and implementing interventions, researchers and clinicians alike must consider these cognitive aspects, and may need to tailor their approaches accordingly. SUMMARY: Advances have clearly been made in the elucidation of the cognitive functioning associated with anxiety disorders. It remains unclear if particular cognitive profiles can help to distinguish anxiety disorders from one another, although emerging evidence suggests this may be the case. Further clarification will add to our understanding of the development and maintenance of these disorders, and may provide targets for future therapy and endophenotypes. PMID- 20829694 TI - Anxiety and depression in the elderly: do we know any more? AB - PURPOSE OF REVIEW: The advent of global population ageing raises understandable concerns about the high-prevalence mental disorders in older people. Accordingly, this review covers recently published scientific articles concerning anxiety and depression. RECENT FINDINGS: There is a paucity of findings on anxiety in older people, although the availability of several new scales suggests increased interest in this topic. The low prevalence of late-life depression in many population surveys does not appear to be due to misattribution of depressive symptoms to physical disorders. Although it is well established that dementia leads to depression, there is now increasing evidence for the proposition that depression leads to cognitive decline and dementia. There is now good evidence also for a bidirectional relationship between obesity and depression. The prognosis of treated late-life depression varies with baseline neuropsychological function and the severity of white matter hyperintensities. SUMMARY: An excellent body of research on depression in older people is now available, although more work on both pharmacological and nonpharmacological treatments is needed. More research is urgently required into anxiety disorders in older people. These are highly prevalent and associated with considerable disease burden. As the literature on depression in older people reaches maturity, there should be greater research and clinical interest in anxiety. PMID- 20829695 TI - Cystic fibrosis: year in review. PMID- 20829696 TI - Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. AB - PURPOSE OF REVIEW: Recent progress in understanding the production, processing, and function of the cystic fibrosis gene product, the cystic fibrosis transmembrane conductance regulator (CFTR), has revealed new therapeutic targets to repair the mutant protein. Classification of CFTR mutations and new treatment strategies to address each will be described here. RECENT FINDINGS: High throughput screening and other drug discovery efforts have identified small molecules that restore activity to mutant CFTR. Compounds such as VX-770 that potentiate CFTR have demonstrated exciting results in recent clinical trials and demonstrate robust effects across several CFTR mutation classes in the laboratory. A number of novel F508del CFTR processing correctors restore protein to the cell surface and improve ion channel function in vitro and are augmented by coadministration of CFTR potentiators. Ongoing discovery efforts that target protein folding, CFTR trafficking, and cell stress have also indicated promising results. Aminoglycosides and the novel small molecule ataluren induce translational readthrough of nonsense mutations in CFTR and other genetic diseases in vitro and in vivo and have shown activity in proof of concept trials, and ataluren is now being studied in confirmatory trials. SUMMARY: An improved understanding of the molecular mechanisms underlying the basic genetic defect in cystic fibrosis have led to new treatment strategies to repair the mutant protein. PMID- 20829697 TI - Acute ventilatory failure complicating obesity hypoventilation: update on a 'critical care syndrome'. AB - PURPOSE OF REVIEW: Obesity can result in serious complications, including obesity hypoventilation syndrome (OHS). OHS patients may present with acute-on-chronic ventilatory failure, necessitating acute care management. The purpose of this review is to discuss the recent literature on acute ventilatory failure in OHS patients. RECENT FINDINGS: Obese persons can develop acute hypercapnic respiratory failure and sleep hypoventilation due to disorders in lung mechanics, ventilatory drive, and neurohormonal and neuromodulators of breathing. Although there are no clearly defined predictors for OHS patients who are likely to develop acute hypercapnic respiratory failure, most such patients are middle-aged (mid-50s), morbidly obese, and have daytime hypercapnia, hypoxemia, and low serum pH values. Immediate ventilatory support, without sleep study confirmation, is necessary in most such patients. Patients with respiratory acidemia (pH <7.30) or altered mental status may require intensive care unit monitoring. Noninvasive application of bilevel positive airway pressure therapy is the recommended initial ventilatory support under close monitoring. Prompt initiation of noninvasive positive pressure ventilation reduces the need for invasive mechanical ventilation and rapidly improves the levels of blood gases. SUMMARY: Obese patients with sleep hypoventilation have an increased risk of acute hypercapnic respiratory failure. Early diagnosis and implementation of noninvasive positive pressure ventilation is recommended for these patients. PMID- 20829698 TI - Technology-limited and patient-derived versus audibility-derived fittings in bone anchored hearing aid users: a validation study. AB - OBJECTIVES: Current approaches to fit bone-anchored hearing aid (Baha) rely heavily on patient feedback of "loudness" and "sound quality." Audiologists are limited to this approach for two reasons: (1) the technology in current models of Baha does not allow for much fine-tuning of frequency response or maximum output on an individual basis and (2) there has not been a valid approach to verify the frequency response or maximum output on an individual basis. The objectives of this study are to (1) describe an alternative approach to fit Baha, an "audibility-derived (AD)" fitting, and (2) test whether outcomes improve with this new fitting compared with the current "patient-derived (PD)" fitting. DESIGN: This study used a repeated measures design where each subject experienced both the AD and PD fittings in random order. Subjects were tested on a variety of outcome measures including output levels of aided speech, hearing in noise test (quiet and in noise), consonant recognition in noise, aided loudness, and subjective percentage of words understood. RESULTS: Electromechanical testing revealed significantly higher aided output with the AD fitting, especially in the high frequencies. Subjects performed significantly better in all outcome measures with the AD fitting approach except when testing aided loudness and subjective perception for which the differences were nonsignificant. When the input levels to the Baha were soft, advantages for the AD fitting were emerging on these tests, but they did not reach significance. CONCLUSIONS: This study presents a more objective, fitting approach for Baha that leads to better outcomes in the laboratory. The next steps will be to test these fittings in the real world and to make the approach generally available to clinicians fitting Bahas. PMID- 20829699 TI - Cross-modal plasticity and speech perception in pre- and postlingually deaf cochlear implant users. AB - OBJECTIVE: A great amount of variability is observed in speech perception outcomes with cochlear implants. The mechanisms behind the observed variability need to be elucidated. One possible mechanism contributing to the observed variability is the development of cross-modal plasticity. This study examines the association between visual/auditory cross-modal plasticity and speech perception with a cochlear implant in individuals with pre- and postlingual onset of severe to profound hearing loss. DESIGN: The N1 visual evoked potential (VEP) in response to peripheral visual motion stimuli was recorded in individuals with pre (N = 10) and postlingual (N = 12) onset of severe to profound hearing loss who use a cochlear implant. The association between the amplitude of the N1 VEP response over the right temporal lobe and sentence and word perception scores obtained with the cochlear implant was examined through linear regression analyses. In addition, the association between the duration of auditory deprivation and the amplitude of the N1 VEP response was examined. RESULTS: As the amplitude of the N1 VEP recorded over the right temporal lobe increased, speech perception scores in individuals with prelingual onset of severe to profound hearing loss decreased. However, a clear association between the amplitude of the N1 VEP over the right temporal lobe and speech perception scores was not observed for individuals with postlingual onset of severe to profound hearing loss. Neither group demonstrated an association between the amplitude of the VEP over the right temporal lobe and the duration of auditory deprivation before cochlear implantation. CONCLUSION: The results suggest that cross-modal plasticity accounts for a significant amount of the variability observed in speech perception performance with a cochlear implant in individuals with prelingual onset of severe to profound hearing loss but not in individuals who acquire severe to profound hearing loss later in life. Furthermore, the results suggest that the influence of cross-modal plasticity on speech perception ability is more greatly influenced by when (pre- or postlingually) a person acquires a severe to profound hearing impairment rather than the duration of auditory deprivation before receipt of a cochlear implant. PMID- 20829700 TI - Antiemetic efficacy of metoclopramide and diphenhydramine added to patient controlled morphine analgesia: a randomised controlled trial. AB - BACKGROUND AND OBJECTIVE: the objective of this study was to assess whether antiemetic drugs metoclopramide and diphenhydramine, administered together as opposed to alone, can have better efficacy in preventing postoperative nausea and vomiting when added to patient-controlled morphine analgesia. PATIENTS AND METHODS: during the period July 2007 to August 2008, 200 women scheduled for abdominal total hysterectomy were randomised to one of four postoperative, patient-controlled analgesia regimens: group 1, morphine 1 mg ml; group 2, morphine 1 mg ml with metoclopramide 0.5 mg ml; group 3, morphine 1 mg ml with diphenhydramine 0.6 mg ml; and group 4, morphine 1 mg ml with metoclopramide 0.5 mg ml and diphenhydramine 0.6 mg ml. Dexamethasone 4 mg was administered to all patients in all groups after anaesthesia induction as a prophylactic antiemetic medication, and prochlorperazine 5 mg was administered by intramuscular injection as necessary as a salvage/rescue therapy. Nausea, vomiting, pruritus, level of sedation, pain and morphine consumption were compared between the four groups. RESULTS: the incidence of nausea was significantly (P < 0.05) lower in group 4 compared to the other groups. In addition, there was a significant (P = 0.006) difference in the incidence of vomiting between groups 1 and 4. Repeated measurement analysis showed that numeric rating scale scores for group 4 were significantly (P < 0.001) lower than those for the other groups. CONCLUSION: results of this study showed that a combination of metoclopramide with diphenhydramine in patients treated with dexamethasone at anaesthesia induction decreased postoperative nausea and vomiting compared to metoclopramide or diphenhydramine in these patients, when added to patient-controlled anaesthesia with morphine. PMID- 20829701 TI - Comparison of TruView EVO2 with Miller laryngoscope in paediatric patients. AB - BACKGROUND: Except for neonates and specific malformations in children, management of the paediatric airway is not a major problem for the anaesthetist. Miller laryngoscope was traditionally used for paediatric intubation. The TruView EVO2 system is a recently introduced device with a unique blade that provides a wide and magnified laryngeal view. OBJECTIVE: To assess the value of the TruView EVO2 laryngoscope with that of Miller laryngoscope in paediatric patients. DESIGN: Prospective analysis. MEASUREMENTS AND RESULTS: Fifty 2-8-year paediatric patients presenting for surgery requiring tracheal intubation were randomly assigned to undergo intubation using a Miller (Group M, n = 25) and TruView EVO2 laryngoscope (Group T, n = 25). Preoperative airway evaluation was performed by using the Mallampati scores. The Intubation Difficulty Scale (IDS), the duration of the tracheal intubation procedure, the rate of successful placement of the endotracheal tube in the trachea, the view of the glottis according to the Cormack and Lehane grading criteria, number of intubation attempts, mean arterial pressure (MAP) and heart rate (HR) before and after intubation, lowest peripheric oxygen saturation during intubation attempts and all complications (minor laseration, dental or other airway trauma) were all recorded. RESULTS: Preoperative Mallampati scores and the IDS scores were similar between the Miller and TruView EVO2 laryngoscope. The average time for laryngoscopy was 6.36 +/- 0.99 s in group M and 13.8 +/- 7.99 s in group T (P < 0.001). The TruView EVO2 laryngoscope improved the Cormack and Lehane glottic view compared with the Miller laryngoscope. The HR change (difference before and after) in group M was significantly lower than that in group T (P < 0.001). However, the MAP change was similar between groups. The lowest peripheric oxygen saturation during intubation attempts was different between groups, 99.4 +/- 0.57% in group M and 97.6 +/- 2.41% in group T (P < 0.001). CONCLUSION: The results suggest that when compared with the Miller laryngoscope, the TruView EVO2 laryngoscope appears to improve the view of the larynx but requires a longer time for tracheal intubation. The IDS scores were similar; thus, the TruView EVO2 laryngoscope can be a good alternative to traditionally used Miller laryngoscope. PMID- 20829702 TI - Mortality and postoperative care after emergency laparotomy. AB - BACKGROUND AND OBJECTIVE: Emergency laparotomy is a common high-risk surgical procedure, but with few outcome data and few data on postoperative care. We aimed to observe mortality within a mixed general surgical population and to explore the potential impact of postoperative care on mortality. METHOD: A prospective observational study of 124 patients undergoing emergency laparotomy. For all patients, overall mortality and 30-day survival were observed; the predicted death rate (PDR) using the P-POSSUM (Portsmouth predictor - Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity) score and the standardised mortality ratio (SMR) were calculated. RESULTS: Twenty-four patients died (19.4%); 21 in the first 30 days (16.9%). Twenty-six patients were over 80 years; 10 died (38%). PDR for all patients was 27.4%. The overall SMR was 0.71. Eighty-seven patients (70.2%) followed a postanaesthesia care unit (PACU) ward pathway (observed mortality 13.6%; mean PDR 15.4%; SMR 0.82). Thirty (24.2%) patients followed an ICU-high dependency unit (HDU)-ward pathway (observed mortality 40.0%; mean PDR 57.2%; SMR 0.69). Six patients (4.8%) followed a PACU HDU-ward pathway (observed mortality 0%, mean PDR 41.8%, SMR 0.0). CONCLUSION: Mortality after emergency laparotomy was high and very high in patients more than 80 years of age. The SMR was higher in the PACU-ward pathway compared to the ICU HDU-ward pathway, suggesting room for improvement in the postoperative period. PMID- 20829703 TI - Assessment of age modulated vascular inflammation in ApoE-/- mice by USPIO enhanced magnetic resonance imaging. AB - OBJECTIVE: Inflammation within atherosclerotic lesions increases the risk for plaque rupture and thrombosis. A functional approach to plaque analysis is the intravenous administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) that enables visualization of macrophages residing in the plaques. In this study, we sought to characterize the age-related inflammatory status associated with atherosclerosis lesion progression in ApoE mice using USPIO enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 24 ApoE mice were divided in 4 groups (N = 6) and were given a high cholesterol diet from 6 weeks of age to the end of the protocol. One group per MR time point was investigated at 10, 16, 24, and 34 weeks of age. Each MR examination was performed on a 4.7 T scanner and consisted of baseline and 48 hours post-USPIO administration imaging sessions. P904, a USPIO contrast agent (Guerbet, Paris, France) with a potential for plaque macrophage targeting, was used.Vessel wall area measurements were performed on high resolution spin echo transverse images. Multi-echo gradient-echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. A one-way analysis of variance was performed to characterize the temporal variation of vessel wall area, susceptibility artifact area, baseline, and post USPIO T2* values. MR measurements were correlated with the histologic findings. RESULTS: A significant increase was found in the aortic wall area from 1.4 +/- 0.2 at 10 weeks to 2.0 +/- 0.3 mm at 34 weeks of age (P < 0.05). Concerning the post-USPIO MRI, signal loss regions, with patterns spanning from focal to the complete disappearance of the vessel wall, were observed on all postcontrast images. A significant increase in the size of the susceptibility artifact was observed from 0.5 +/- 0.2 to 2.4 +/- 1.0 at 24 weeks (P < 0.05) and to 2.0 +/- 0.9 mm at 34 weeks (P < 0.05).The T2* values calculated on the 48 hours post USPIO images were shorter compared with baseline. The decrease was 34% +/- 16% at 10 weeks, 57% +/- 11% at 16 weeks, 57% +/- 16% at 24 weeks, and 48% +/- 13% at 34 weeks.The Pearson's correlation test between measurement of aortic wall area performed on both MR images and histologic analysis showed a statistically significant correlation (r = 0.695 and P < 0.05). A correlation was also obtained between the signal loss area and the macrophages covered area (r = 0.68 and P < 0.05). CONCLUSIONS: This study demonstrated the feasibility of USPIO-enhanced MRI in assessing the inflammatory status related to the temporal progression of the atherosclerosis plaque in ApoE transgenic mice model of atherosclerosis. In our experimental conditions, the vascular inflammation peak, for the ApoE mice feeding high-fat/high-cholesterol diet is measured between 16 and 24 weeks of age. PMID- 20829704 TI - Quantitative analysis of adipose tissue in single transverse slices for estimation of volumes of relevant fat tissue compartments: a study in a large cohort of subjects at risk for type 2 diabetes by MRI with comparison to anthropometric data. AB - OBJECTIVES: Aim of the study was to assess the potential value of cross-sectional adipose tissue evaluation in well defined single transverse slices for estimation of volumes of metabolically important adipose tissue compartments as visceral adipose tissue (VAT), nonvisceral adipose tissue (NVAT), and total body adipose tissue (TAT). In addition, validity of easily accessible anthropometric indices (waist-to-hip-ratio [WHR] and body mass index [BMI]) for prediction of volumes of those adipose tissue compartments were validated and compared. MATERIALS AND METHODS: True volumes of main adipose tissue compartments VAT, TAT, and NVAT were carefully assessed based on whole-body magnetic resonance (MR) examinations in 367 volunteers (227 females, 140 males, age 18-69 years) at increased risk for type 2 diabetes. Volumes of VAT, NVAT, and TAT were compared with cross-sectional areas of adipose tissue in single transverse slices recorded on the level of (1) umbilicus (u), (2) head of humerus (h), (3) head of femur (f), and anthropometric data such as BMI and WHR. Separate analyses were performed in males and females. RESULTS: In both genders, strong correlations were found between TAT and the cross-sectional areas: subcutaneous adipose tissue (u) with r = 0.88 in females and r = 0.92 in males, TAT(h) with r = 0.80 in females and r = 0.82 in males, and TAT(f) with r = 0.90 in females and r = 0.90 in males. VAT assessed by MR single slice evaluation at the umbilical level (VAT(u)) showed a strong correlation with total VAT in both genders (r = 0.93 in females, r = 0.87 in males). Suitable algorithms for predicting VAT in liter from fat planimetry in a slice recorded at the umbilical level were derived: VAT = 0.16 x (VAT(u) x body height) + 0.3 in women and VAT = 0.15 x (VAT(u) x body height) + 1.2 in men. Disregarding the body height, the best equations were as follows: VAT = 0.03 x VAT(u) + 0.3 in women and VAT = 0.02 x VAT(u) + 1.4 in men. In contrast, BMI versus VAT showed a lower correlation in both genders: r = 0.71 in females, r = 0.56 in males, and WHR versus VAT was only weakly correlated in females and in males (r = 0.49 and r = 0.55, respectively). For WHR versus TAT, significant results were only found in males (r = 0.44). CONCLUSIONS: Axial MRI at the umbilical level allowed for a fast and reliable estimation, especially for VAT and TAT in a collective at risk for type 2 diabetes. WHR and BMI were found clearly worse in prediction of VAT volumes compared with single slice evaluation at the umbilical level. PMID- 20829705 TI - Carotid plaques in transient ischemic attack and stroke patients: one-year follow up study by magnetic resonance imaging. AB - OBJECTIVE: To investigate the natural course of carotid plaque progression in transient ischemic attack/stroke patients by using serial multisequence magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty transient ischemic attack/stroke patients with ipsilateral <70% carotid stenosis underwent MRI of the plaque ipsilateral to the symptomatic side at baseline and after 1 year. The MRI protocol consisted of T1-weighted turbo field-echo, time-of-flight, T2 weighted turbo spin-echo (TSE), and pre- and postgadopentetate dimeglumine enhanced T1-weighted TSE images. For each plaque, carotid lumen volume, wall volume, total vessel volume (=carotid lumen volume + wall volume), the presence of a lipid-rich necrotic core (LRNC), fibrous cap (FC) status, and the presence of intraplaque hemorrhage (IPH) were assessed at both time points. RESULTS: Over a 1-year period, mean carotid lumen volume decreased with 4.8% +/- 2.0% (+/ standard error) (P = 0.013). Mean wall volume increased with 11.2% +/- 2.2% (P < 0.001). Total vessel volume did not significantly change (P = 0.147). At baseline, there were 18 plaques with a LRNC, which also had a LRNC at 1-year follow-up. No plaque without a LRNC at baseline developed a LRNC during the follow-up period. All plaques with a LRNC had a thin and/or ruptured FC at both time points. Twelve patients had IPH both at baseline and at follow-up. In one patient, IPH disappeared, whereas in another patient, new IPH appeared at follow up. The presence of IPH and a LRNC with a thin and/or ruptured FC were not significantly associated with plaque progression (P > 0.05). CONCLUSIONS: In symptomatic patients with an ipsilateral carotid plaque causing <70% stenosis, we found evidence for inward plaque remodeling over a 1-year period. Overall, the presence/absence of IPH, a LRNC, and FC status did not change over 1 year. PMID- 20829706 TI - Biopsy targeting gliomas: do functional imaging techniques identify similar target areas? AB - OBJECTIVE: Because of the heterogeneous nature of glioma, biopsies performed should be targeted at the most anaplastic region. Several functional magnetic resonance imaging (MRI) or positron emission tomography (PET) techniques have been proposed for identifying the most anaplastic tumor area. However, it is unclear whether the recommended biopsy targets based on these various functional imaging modalities correspond with each other. Thus, the purpose was to evaluate whether they identify similar target areas. MATERIALS AND METHODS: A total of 61 patients with suspected glioma were assessed within 2.3 +/- 3.5 days by MRI, 18F fluorothymidine-, and 18F-fluorodeoxyglucose-PET. Thirty-five patients underwent gross total resection and 26 were stereotactically biopsied. MRI was performed on a 1.5 Tesla broadband transmit/receive system, using a double-resonant birdcage coil. The MRI protocol comprised of sodium (23Na)-MRI (3D-radial projection imaging), proton spectroscopic imaging (1H-MRSI, point-resolved spectroscopy), arterial spin-labeling (ASL) perfusion MRI, dynamic contrast-enhanced (DCE) MRI, and dynamic-susceptibility-weighted (DSC) perfusion MRI after a single dose each of gadobenate dimeglumine. Also, apparent diffusion coefficient (ADC) maps were processed from diffusion tensor images. Image analysis comprised a detailed semiquantitative region of interest analysis of the different parameter values as well as visual identification of the most conspicuous tumor areas on parameter maps, for example, areas with maximum tumor perfusion, highest metabolite ratios of choline-containing compounds/N-acetyl-aspartate, or lowest ADC values within tumor tissue. Colocalization of these areas was then assessed. RESULTS: Regarding tumor vascularity-related parameters and tumor proliferation-related parameters, the higher the glioma grade the higher were the respective parameters in semiquantitative analysis. ADC values decreased with glioma grade. In the whole study population comprising low- (N = 15) and high-grade gliomas (N = 42), except for 23Na-MRI, there was good (>50%) or perfect (100%) agreement of the tumor areas with highest values on parameter images in the majority of cases (>80%), that is, tumor areas with increased thymidine-uptake and highest choline, both suggestive of increased tumor proliferation, and elevated microcirculation as demonstrated by DSC-, arterial spin-labeling-, and DCE-MRI. 23Na-MRI depicted the highest signal within necrotic tumor areas, but non-necrotic gliomas also showed a perfect agreement in more than 61%. 18F-fluorothymidine-PET, DSC-, and DCE-MRI, diffusion-weighted imaging as well as MR spectroscopic imaging correctly detected no glioma heterogeneity in all 15 histologically proven grade II gliomas but identified suspicious areas in all 3 nonenhancing grade III gliomas. CONCLUSION: Both imaging techniques that depict microcirculation and techniques that visualize proliferation identify similar target areas. PMID- 20829707 TI - Brain iron deposition and sequence characteristics in Parkinsonism: comparison of SWI, T2* maps, T2-weighted-, and FLAIR-SPACE. AB - OBJECTIVES: To compare quantitatively T2- and T2*-based magnetic resonance imaging sequences in patients with symptoms of Parkinson disease and to evaluate the information content of those sequences regarding brain iron concentration. MATERIALS AND METHODS: We imaged 51 patients with symptoms of Parkinson disease on 3-T magnetic resonance imaging with T2-weighted sampling perfection with application optimized contrasts using different flip-angle evolution (SPACE), fluid attenuation inversion recovery (FLAIR)-SPACE, susceptibility-weighted imaging (SWI), and parametric T2* sequence (MapIt). Signal analysis was performed in 22 regions of interest in the brain. RESULTS: Correlations (r2 = 0.82...0.96) with brain iron concentration were excellent. Contrast and tissue separability ratios were best in the T2* maps and FLAIR-SPACE, respectively. Good correlations of contrast were reached between SWI and both T2-weighted SPACE and FLAIR-SPACE. Their relation to quantitative T2* values was reminiscent of a quadratic curve shape. However, separation into gray and white matter revealed a linear positive and negative correlation, respectively. CONCLUSIONS: SWI showed potential in differentiating illnesses characterized by brain iron deposition. Closely similar information was given by T2-weighted SPACE and FLAIR-SPACE, whereas other sequence comparisons revealed dispersion from intersequence agreement. PMID- 20829708 TI - Evaluation of renal hypoxia in diabetic mice by BOLD MRI. AB - OBJECTIVE: Renal hypoxia has been proposed to be a pathophysiologic feature of diabetic kidney disease but it has been difficult to demonstrate in vivo, particularly in mouse models of diabetes. The objective of this work was to examine the sensitivity of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) to assess renal oxygenation in vivo in a mouse model of diabetic kidney disease, the db/db mice. RESEARCH DESIGN AND METHODS: Kidney BOLD MRI studies were performed on a 3.0 T scanner using multiple gradient echo sequence with a custom-designed surface coil to acquire T2*-weighted images. Studies were performed in 10-week-old db/db mice (n = 7) and db/m controls (n = 6). RESULTS: R2* is a measure of the tissue deoxyhemoglobin concentration and higher values of R2* are associated with hypoxia. The db/db mice had higher medullary (43.1 +/- 5.1 s-1 vs. 32.3 +/- 3.7-1 s, P = 0.001) and cortical R2* (31.7 +/- 3.1 s-1 vs. 27.1 +/- 4.1 s-1, P = 0.04) values. Using pimonidazole staining as a marker of kidney hypoxia, in kidney sections from 10-week-old db/db mice neither cortex nor medulla had significant differences as compared with 10-week-old db/m mice (cortex: db/db 2.14 +/- 0.05 vs. db/m 2.02 +/- 0.28, medulla: db/db 2.81 +/- 0.08 vs. db/m 2.6 +/- 0.08). The db/db mice demonstrated further increased cortical and medullary hypoxia when scanned again at 15 weeks of age. CONCLUSIONS: The report shows that renal BOLD MRI is a sensitive method for the in vivo evaluation of renal hypoxia in a mouse model of diabetic kidney disease where progressive renal hypoxia can be documented over time. BOLD MRI may be useful to monitor therapeutic interventions that may improve tissue hypoxia in the diabetic kidney. PMID- 20829709 TI - Cardiac magnetic resonance elastography: toward the diagnosis of abnormal myocardial relaxation. AB - AIM: To assess the potential of cardiac magnetic resonance elastography (MRE) for elasticity-based detection of abnormal left ventricular (LV) relaxation. MATERIALS AND METHODS: Cardiac MRE was performed in 3 groups: young volunteers (n = 11; mean age, 31.7 years), older volunteers (n = 5; mean age, 54.8 years), and a group with relaxation abnormalities (n = 11; mean age, 58 years) identified by transthoracic echocardiography. Cine MR imaging served to measure LV volumes and global LV systolic function. Wave-amplitude-sensitive electrocardiograph-gated steady-state MRE was performed using an extended piston driver attached to the anterior chest wall. Phase contrast shear wave images were acquired in all 3 Cartesian components and combined to generate amplitude maps. This was done using the time-gradient operator for linear high-pass filtering and phase unwrapping followed by temporal Fourier transformation for extracting externally induced 24.13-Hz shear oscillations from intrinsic motion and blood flow. Amplitudes were evaluated in the left ventricle and normalized by wave amplitudes outside the heart, adjacent to the right ventricle. RESULTS: One patient and 1 young volunteer had to be excluded from final analysis because of considerable body movement during the acquisition of the MRE scans. Mean wave amplitudes in the remaining subjects were 0.22 +/- 0.05 mm in young volunteers, 0.23 +/- 0.09 in older volunteers, and 0.14 +/- 0.03 mm in patients. The mean ratio of amplitudes inside the ventricle to the anterior chest wall was 0.62 +/- 0.15 for young volunteers, 0.50 +/- 0.09 for older volunteers, and 0.33 +/- 0.08 for patients. CONCLUSION: MRE identifies significantly reduced LV shear wave amplitudes in patients with mild relaxation abnormality. Thus, cardiac MRE provides a promising modality for an elasticity-based diagnosis of dysfunctional myocardial relaxation. PMID- 20829710 TI - Blood velocity calculated from volumetric dynamic computed tomography angiography. AB - OBJECTIVE: Though functional intravascular parameters such as blood velocity and direction of blood flow are available via imaging modalities such as Doppler ultrasound and phase contrast magnetic resonance imaging, such quantitative information is not yet supported by computed tomography (CT). In this study, we examined a method to calculate intra-arterial blood velocity from contrast enhanced dynamic CT angiography (4D CTA) using the unique advantages of a volumetric 320 detector row scanner. MATERIALS AND METHODS: Contrast boluses were injected into a flow phantom under volumetric 4D CTA examination. Two pipe diameters were tested, each diameter with 4 various flow velocities, creating 8 independent flow conditions. The internal carotid arteries of 5 patients (10 arteries in total) were subjected to a similar dynamic CTA examination and reconstructed with a 1-second temporal resolution through the arterial phase. Intraluminal velocities were calculated using distance between 2 regions of interest placed proximally and distally over the vessel, divided by delay in time to peak of contrast arrival in each region of interest. Results were compared with flow velocities attained by quantitative magnetic resonance angiography in vivo. RESULTS: Phantom experiments demonstrate reasonable agreement between calculated and measured intraluminal velocity (P = 0.05). Similarly, in vivo blood velocity calculations in all internal carotid arteries show agreement with results attained by quantitative magnetic resonance angiography. CONCLUSIONS: Intraluminal blood velocity may be estimated from first-pass contrast bolus profiles acquired via volumetric 4D CTA examinations. PMID- 20829711 TI - Prediction of preadolescent depressive symptoms from child temperament, maternal distress, and gender: results of a prospective, longitudinal study. AB - OBJECTIVE: The delineation of developmental pathways to juvenile depressive symptoms is of major clinical interest because these are known to be predictive for adult mood disorders and for a range of other mental health problems. This study investigates the impact of child temperament and early maternal distress, both of which are known to influence children's emotional development, on preadolescent depression. METHODS: In a prospective, longitudinal at-risk sample (163 boys, 178 girls), we assessed temperament at the age of 3 months and at 2 years, 4.5 years, and 8 years, respectively, and chronic maternal distress during infancy. Hierarchical linear regression analysis was used to investigate the prediction of depressive symptoms at the age of 11 years measured by the Child Depression Inventory. In addition, we controlled for psychosocial and obstetric perinatal risks and gender. RESULTS: Psychosocial risks and self-control temperament made significant independent contributions to preadolescent depression, whereas fearful, difficult temperament and obstetric risks were unrelated to depressive outcome. Interestingly, a clear gender difference emerged with a significant prediction from maternal distress only in girls. CONCLUSIONS: Our data extend previous findings of a concurrent association between regulative temperament and juvenile depression to a predictive view. Furthermore, the results point toward gender-specific pathways to preadolescent depression and support earlier findings indicating that subclinical maternal distress may exert as detrimental effects on child development as clinical depression. PMID- 20829712 TI - Response to angiotensin-converting enzyme inhibition is selectively blunted by high sodium in angiotensin-converting enzyme DD genotype: evidence for gene environment interaction in healthy volunteers. AB - BACKGROUND: Renin-angiotensin-aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype-phenotype relationship, we hypothesize gene-environment interaction between sodium-status, the response to ACEi, and ACE genotype. METHOD: Thirty-five male volunteers (26 +/- 9 years; II n = 6, ID n = 18, DD n = 11) were studied during placebo and ACEi (double blind, enalapril 20 mg/day) on low [7 days 50 mmol Na/day (low salt)] and high [7 days 200 mmol Na/day (high salt)] sodium, with a washout of 6 weeks in-between. After each period mean arterial pressure (MAP) was measured before and during graded infusion of angiotensin II (Ang II). RESULTS: During high salt, ACEi reduced MAP in II and ID, but not in DD [II: 88 (78-94) versus 76 (72-88); ID: 87 (84-91) versus 83 (79 87); both P < 0.05 and DD: 86 (82-96) versus 88 (80-90); ns, P < 0.05 between genotypes]. However, during low salt, ACEi reduced MAP in all genotype groups [II: 83 (78-89) versus 77 (72-83); ID: 88 (84-91) versus 82 (78-86); DD: 84 (80 91) versus 81 (75-85); all P < 0.05]. During high salt + ACEi, the Ang II response was blunted in DD, with an 18% rise in MAP during the highest dose versus 22 and 31% in ID and II (P < 0.05). Low salt annihilated these differences. CONCLUSION: In healthy participants, the MAP response to ACEi is selectively blunted in DD genotype during high salt, accompanied by blunted sensitivity to Ang II. Low salt corrects both abnormalities. Further analysis of this gene-environment interaction in patients may contribute to strategies for improvement of individual treatment efficacy. PMID- 20829713 TI - Antihypertensive efficacy and safety of olmesartan medoxomil and ramipril in elderly patients with mild to moderate essential hypertension: the ESPORT study. AB - OBJECTIVE: To compare the efficacy and safety of the angiotensin II antagonist olmesartan medoxomil (O) and the ACE inhibitor ramipril (R) in elderly patients with essential arterial hypertension. METHODS: After a 2-week placebo wash-out 1102 treated or untreated elderly hypertensive patients aged 65-89 years (office sitting diastolic blood pressure, DBP, 90-109 mmHg and/or office sitting systolic blood pressure, SBP, 140-179 mmHg) were randomized double-blind to 12-week treatment with O 10 mg or R 2.5 mg once-daily. After the first 2 and 6 weeks doses could be doubled in non-normalized [blood pressure (BP) < 140/90 mmHg for nondiabetic and < 130/80 mmHg for diabetic) individuals, up to 40 mg for O and 10 mg for R. Office BPs were assessed at randomization, after 2, 6 and 12 weeks of treatment, whereas 24-h ambulatory BP was recorded at randomization and after 12 weeks. RESULTS: In the intention-to-treat population (542 patients O and 539 R) after 12 weeks of treatment baseline-adjusted office SBP and DBP reductions were greater (P < 0.01) with O [17.8 (95% confidence interval: 16.8/18.9) and 9.2 (8.6/9.8) mmHg] than with R [15.7 (14.7/16.8) and 7.7 (7.1/8.3) mmHg]. BP normalization rate was also greater under O (52.6 vs. 46.0% R, P < 0.05). In the subgroup of patients with valid ambulatory BP recording (318 O and 312 R) the reduction in 24-h average BP was larger (P < 0.05) with O [SBP: 11.0 (12.2/9.9) and DBP: 6.5 (7.2/5.8) mmHg] than with R [9.0 (10.2/7.9) and 5.4 (6.1/4.7) mmHg]. The larger blood pressure reduction obtained with O was particularly evident in the last 6 h from the dosing interval; a better homogeneity of the 24-h BP control with O was confirmed by higher smoothness indices. The proportion of patients with drug-related adverse events was comparable in the two groups (3.6 O vs. 3.6% R), as well as the number of patients discontinuing study drug because of a side effect (14 O vs. 19 R). CONCLUSION: In elderly patients with essential arterial hypertension O provides an effective, prolonged and well tolerated BP control, representing a useful option among first-line drug treatments of hypertension in this age group. PMID- 20829714 TI - Myeloproliferative disorder in Noonan syndrome. AB - Children with Noonan syndrome (NS) are at increased risk of developing juvenile myelomonocytic leukemia (JMML) or a myeloproliferative disorder associated with NS (MPD/NS) resembling JMML in the first weeks of life; whereas JMML is an aggressive disorder requiring hematopoietic stem cell transplantation, MPD/NS may resolve without treatment and cases with spontaneous remission have also been reported. Two cases of NS with hematologic disorders are described. Diagnosis of the syndrome was confirmed by the identification of earlier reported germline missense mutations in the PTPN11 gene. Splenomegaly in 1 patient and leukocytosis, monocytosis and "in vitro" culture assays consistent with JMML in both were the most salient hematologic features. After a 24-month follow-up, these 2 infants continue to improve and JMML has been ruled out. Splenomegaly persists in 1 patient and monocytosis in both, but without signs of malignancy, thereby suggesting abnormal hematopoiesis or MPD/NS, as described in NS. PMID- 20829715 TI - Isolated pulmonary Langerhans cell histiocytosis in a 3-year-old girl with atypical radiologic findings. PMID- 20829716 TI - A pediatric B lineage leukemia with coincident MYC and MLL translocations. AB - Translocations are key oncogenic events, and many rearrangements are characteristic for a specific malignancy. We present here a case of phenotypic precursor-B acute lymphoblastic leukemia (ALL), subsequently found to have both MYC and MLL translocations. Owing to the potential prognostic impact of these translocations, a novel treatment strategy was applied which merged precursor-B ALL, Burkitt-ALL, and "MLL-adapted" rationales. With the advent of expanding diagnostic panels and molecular therapeutic options, use of such adapted therapies for individualized treatment will undoubtedly continue to increase as we move toward pharmacogenomic-based approaches. PMID- 20829717 TI - Metastatic squamous cell carcinoma of the oropharynx in a child with a mutation in the Connexin 26 gene. AB - Pediatric oral squamous cell carcinoma is an extremely rare occurence. In our report, we describe a 6-year-old White female with sensorineural hearing loss found to have a Connexin 26 gene mutation who developed a well-differentiated squamous cell carcinoma of the hard palate with metastatic disease to submandibular lymph nodes and the lungs. This association emphasizes the need to consider Connexin 26 gene mutations in children who develop oral squamous cell carcinoma and to monitor for oral squamous cell carcinoma in children with Connexin 26 gene mutations. PMID- 20829718 TI - The effect of 2 M hydrochloric acid on silicone rubber central venous catheters. AB - BACKGROUND: It has been suggested that the instillation of 2 M hydrochloric acid (HCl) can clear bacterial and fungal colonization in central venous catheters (CVCs). The aim of the study was to determine the physical effect of HCl on the inner surface of silicone rubber Hickman CVCs. METHODS: Five CVCs had 2 M HCl installed and 5 CVCs had saline installed for 30 minutes once a week for 12 weeks. Before instillation and after infusion, a section of each CVC was removed and examined by scanning electron microscopy. The examination was blinded. RESULT: Over 12 weeks no damage was detected in the CVCs. There was no difference between the CVCs flushed with saline compared with those flushed with HCl. CONCLUSIONS: Repetitive instillation of 2 M HCL in CVCs did not cause electron microscopically detectable damage of the silicone rubber CVCs. PMID- 20829719 TI - Intracranial subdural hematoma and pneumocephalus after spinal instrumentation of myelodysplastic scoliosis. AB - To report a case of acute intracranial subdural hematoma, pneumocephalus, and pneumorachis, which occurred because of cerebrospinal fluid (CSF) leak caused by a malpositioned transpedicular screw during spinal surgery for severe myelodysplastic scoliosis accompanied with hydrocephalus. Intracranial hemorrhage may occur as a consequence of dural sac penetration and CSF leakage after various medical procedures at the spinal level. The awareness of this severe complication is especially important during spinal instrumentation procedures in which inadvertent dural sac violation and CSF loss may be overlooked. A case report and literature review are presented here. A 12-year-old girl with a history of myelomeningocele and hydrocephalus underwent instrumentation for severe myelodysplastic scoliosis. Postoperatively, she became aphasic and increasingly somnolent. An urgent computed tomographic scan of the head and spine showed massive intracranial hematoma, pneumocephalus, pneumorachis, and a malpositioned pedicular screw that caused CSF leakage, intracranial hypotension, and bleeding remote from the surgical site. The patient needed neurosurgical cranial decompression and subsequent spinal reoperation with dural tear repair. The final outcome was an uneventful complete recovery. The increasing use of pedicular screws in spinal surgery carries a potential risk of occult dural sac violation with subsequent CSF leakage, intracranial hypotension, and the possibility of intracranial bleeding and pneumocephalus remote from the surgical site. This potentially fatal complication should always be considered after spinal surgery in the presence of early signs of neurological deterioration and necessitates an urgent cranial and spinal imaging to confirm the diagnosis and to make adequate treatment decisions. PMID- 20829720 TI - Percutaneous radiofrequency ablation of lung tumors: evaluation of the literature using evidence-based techniques. AB - PURPOSE: The aim of this study was to evaluate the literature for articles assessing radiofrequency ablation (RFA) for pulmonary malignancy. MATERIALS AND METHODS: The "bottom-up" approach to evidence-based practice was applied by 2 reviewers to the retrieval and appraisal of original research articles published on pulmonary RFA between 2002 and 2009. Primary lung cancer and pulmonary metastases data were analyzed separately. The relationship between the percentage of local recurrence rate and lesion size, patient age, follow-up duration, and time to local recurrence was assessed using Spearman's rank correlation. Discrete time series were used to evaluate time trends. RESULTS: Secondary evidence yielded 1 review of 26 observational studies. Primary evidence yielded 46 studies that seemed suitable for detailed appraisal. A total of 2905 ablations were performed in 1584 patients. Eight studies evaluated primary lung cancers alone, 11 evaluated pulmonary metastases alone, 25 evaluated both, and 2 did not specify the histology. Results revealed trends toward increasing use of conscious sedation over general anesthesia, increasing use of multitined probes, decreasing size of nodule selection, and use of positron emission tomography/computed tomography as the optimal follow-up tool. Mean morbidity was 24.6%. The most prevalent side effects included pneumothorax (28.3%), pleural effusions (14.8%), and pain (14.1%). Procedure-related mortality ranged from 0 to 5.6, with an overall procedure-related mortality rate of 0.21%. There were 282 (12.2%) local recurrences occurring at a mean of 13 months. The mean overall survival rate was 59.4%, and the cancer-specific survival rate was 82.6%. CONCLUSIONS: This evidence-based practice review of pulmonary RFA shows it to be a promising treatment for pulmonary malignancy in carefully selected patient populations. Studies with higher levels of evidence, including case-control, prospective nonrandomized and randomized trials, that compare RFA with alternative contemporary local treatments are urgently needed. PMID- 20829721 TI - Nurse/physician communication through a sensemaking lens: shifting the paradigm to improve patient safety. AB - Physician-nurse communication has been identified as one of the main obstacles to progress in patient safety. Breakdowns in communication between physicians and nurses often result in errors, many of which are preventable. Recent research into nurse/physician communication has borrowed heavily from team literature, tending to study communication as one behavior in a larger cluster of behaviors. The multicluster approach to team research has not provided enough analysis of and attention to communication alone. Research into communication specifically is needed to understand its crucial role in teamwork and safety. A critique of the research literature on nurse/physician communication published since 1992 revealed 3 dominant themes: settings and context, consensus building, and conflict resolution. A fourth implicit theme, the temporal nature of communication, emerged as well. These themes were used to frame a discussion on sensemaking: an iterative process arising from dialogue when 2 or more people share their unique perspectives. As a theoretical model, sensemaking may offer an alternative lens through which to view the phenomenon of nurse/physician communication and advance our understanding of how nurse/physician communication can promote patient safety. Sensemaking may represent a paradigm shift with the potential to affect 2 spheres of influence: clinical practice and health care outcomes. Sensemaking may also hold promise as an intervention because through sensemaking consensus may be built and errors possibly prevented. Engaging in sensemaking may overcome communication barriers without realigning power bases, incorporate contextual influences without drawing attention away from communicators, and inform actions arising from communication. PMID- 20829722 TI - Surgical safety and hospital volume across a wide range of interventions. AB - OBJECTIVES: For certain major operations, inpatient mortality risk is lower in high-volume hospitals than those in low-volume hospitals. Extending the analysis to a broader range of interventions and outcomes is necessary before adopting policies based on minimum volume thresholds. METHODS: Using the United States 2004 Nationwide Inpatient Sample, we assessed the effect of intervention-specific and overall hospital volume on surgical complications, potentially avoidable reoperations, and deaths across 1.4 million interventions in 353 hospitals. Outcome variations across hospitals were analyzed through a 3-level hierarchical logistic regression model (patients, surgical interventions, and hospitals), which took into account interventions on multiple organs, 144 intervention categories, and structural hospital characteristics. Discriminative performance and calibration were good. RESULTS: Hospitals with more experience in a given intervention had similar reoperation rates but lower mortality and complication rates: odds ratio per volume deciles 0.93 and 0.97. However, the benefit was limited to heart surgery and a small number of other operations. Risks were higher for hospitals that performed more interventions overall: odds ratio per 1000 for each event was approximately 1.02. Even after adjustment for specific volume, mortality varied substantially across both high- and low-volume hospitals. CONCLUSION: Although the link between specific volume and certain inpatient outcomes suggests that specialization might help improve surgical safety, the variable magnitude of this link and the heterogeneity of hospital effect do not support the systematic use of volume-based referrals. It may be more efficient to monitor risk-adjusted postoperative outcomes and to investigate facilities with worse than expected outcomes. PMID- 20829723 TI - How does routine disclosure of medical error affect patients' propensity to sue and their assessment of provider quality? Evidence from survey data. AB - BACKGROUND: Although strongly favored by patients and ethically imperative for providers, the disclosure of medical errors to patients remains rare because providers fear that it will trigger lawsuits and jeopardize their reputation. To date little is known how patients might respond to their providers' disclosure of a medical error even when paired with an offer of remediation. RESEARCH DESIGN: A representative sample of Illinois residents was surveyed in 2008 about their knowledge about medical errors, their confidence that their providers would disclose medical errors to them, and their propensity to sue and recommend providers that disclose medical errors and offer to remedy them. We report the response patterns to these questions. As robustness checks, we also estimate the covariate-adjusted distributions and test the associations among these dimensions of medical-error disclosure. RESULTS: Of the 1018 respondents, 27% would sue and 38% would recommend the hospital after medical error disclosure with an accompanying offer of remediation. Compared with the least confident respondents, those who were more confident in their providers' commitment to disclose were not likely to sue but significantly and substantially more likely to recommend their provider. CONCLUSIONS: Patients who are confident in their providers' commitment to disclose medical errors are not more litigious and far more forgiving than patients who have no faith in their providers' commitment to disclose. PMID- 20829724 TI - The science of quality improvement implementation: developing capacity to make a difference. AB - BACKGROUND: Quality improvement (QI) holds promise to improve quality of care; however, organizations often struggle with its implementation. It has been recommended that practitioners, managers, and researchers attempt to increase systematic understanding of the structure, practices, and context of organizations that facilitate or impede the implementation of QI innovations. OBJECTIVES: To critically review the empirical research on QI implementation in health care organizations. RESEARCH DESIGN: A literature review of 107 studies that examined the implementation of QI innovations in health care organizations. Studies were classified into 4 groups based on the types of predictors that were assumed to affect implementation (content of QI innovation, organizational processes, internal context, and external context). RESULTS: Internal context and organizational processes were the most frequently studied categories. External context and organizational process categories exhibited the highest rate of positive effects on QI implementation. CONCLUSIONS: The review revealed several important gaps in the QI implementation literature. Studies often lacked clear conceptual frameworks to guide the research, which may hinder efforts to compare relationships across studies. Studies also tended to adopt designs that were narrowly focused on independent effects of predictors and did not include holistic frameworks to capture interactions among the many factors involved in implementation. Other design limitations included the use of cross-sectional designs, single-source data collection, and potential selection bias among study participants. PMID- 20829725 TI - Comparison of the exposure rate of wrapped hydroxyapatite (Bio-Eye) versus unwrapped porous polyethylene (Medpor) orbital implants in enucleated patients. AB - PURPOSE: To compare the exposure rate of wrapped hydroxyapatite versus unwrapped porous polyethylene orbital implants in enucleated patients. METHODS: Medical records of the patients who underwent primary placement of hydroxyapatite (Bio Eye) or porous polyethylene (Medpor) orbital implants after enucleation between 2002 and 2005 in Farabi Eye Hospital were reviewed, and the occurrence of implant exposure during follow-up visits was recorded. The exclusion criteria were secondary implantation, evisceration, or follow up of less than 1 year unless the exposure had occurred in the year after surgery. In the hydroxyapatite group, the implants were wrapped either in Mersilene mesh (65%) or in donor sclera (35%). Wrapping was not performed for any patient in the porous polyethylene group. RESULTS: A total of 198 cases with hydroxyapatite and 53 cases with porous polyethylene implant were identified. The most common causes of enucleation in both groups were globe trauma and painful blind eye. Rate of exposure was significantly higher [odds ratio (OR) = 7.97, p < 0.001] in patients with porous polyethylene (34.0%) than in those with hydroxyapatite implant (6.1%). This association remained significant after adjustment for potential confounders. Mean time of exposure after surgery was significantly (p < 0.001) longer in patients with porous polyethylene implant. Kaplan-Meier plots depicted a significantly (p < 0.001) higher rate of exposure in patients with porous polyethylene implant during the follow-up time. CONCLUSION: Unwrapped porous polyethylene implants demonstrated a higher rate of exposure, and longer time interval to exposure, compared with wrapped hydroxyapatite implants. PMID- 20829726 TI - Herpes simplex vegetans presenting as an eyelid mass. AB - A 16-year-old girl with congenital T-cell immunodeficiency presented with a 2 month history of an enlarging lower eyelid mass. After complete excision of the mass, the lesion was noted to recur. Histologic and immunohistochemical analysis of the excised mass revealed infection with herpes simplex virus types 1 and 2 with exuberant inflammatory reaction and granulation tissue consistent with the diagnosis of herpes simplex vegetans. Treatment with valacyclovir resulted in complete resolution of the remaining lesions. Herpes simplex vegetans should be included in the clinical and histopathologic differential for rapidly growing cutaneous masses in patients with immunodeficiency. PMID- 20829727 TI - Periorbital Masson's tumor: a case series. AB - Intravascular papillary endothelial hyperplasia (IPEH) or Masson's tumor is an unusual variety of benign vascular tumor. Involvement of periorbital area is uncommon. We report 2 cases of periorbital IPEH and review relevant literature. PMID- 20829728 TI - "Saddle" tailored upper eyelid island myocutaneous flap to repair full-thickness lower eyelid defects after melanoma excision. AB - PURPOSE: To perform an early melanoma diagnosis and to repair the full-thickness lower eyelid defect with an island upper eyelid myocutaneous flap tailored into a new shape. METHODS: Two patients with pigmented lesion involving skin and tarsus of the lower eyelid were reported. Histologic examination, performed after diagnostic punch biopsy, confirmed the diagnosis of in situ melanomas in both cases. A full-thickness excision was done and a single pedicle island myocutaneous flap from the upper eyelid was performed. The flap was designed in a blepharoplastic manner and tunnelized to reach the lower eyelid defect. The flap was tailored into a "saddle" shape, doubled, and folded to restore both the internal and external eyelid walls in a single-stage procedure. RESULTS: Good functional and aesthetic results were obtained with no complications. Interestingly enough, the tissue of the internal layer lost the features of skin epithelium due to metaplasia processes and appeared similar to the conjunctiva. After 3 years, no sign of melanoma recurrence was noted. CONCLUSIONS: Early diagnosis was performed in both reported lower eyelid melanoma cases. For the reconstruction, a modified upper eyelid island myocutaneous flap tailored into a "saddle" shape was used, which had the advantages of being a single-stage procedure and avoiding mucosa grafts. The technique could also be used to repair full-thickness lower eyelid defects from other causes. PMID- 20829730 TI - Using the inferior oblique muscle to augment implant coverage in enucleation surgery. AB - PURPOSE: We present a technique modification for enucleation surgery that may decrease implant exposure or extrusion by using native tissue to reinforce the implant at the most susceptible area, specifically the anterior-most aspect. METHODS: An enucleation procedure is performed, and an implant is placed into the orbit. The horizontal rectus muscles are attached to the implant, and the vertical rectus muscles are attached directly to the horizontal muscles. The inferior oblique muscle is then spread over the anterior implant surface and sutured to the superior rectus and lateral rectus muscles. RESULTS: 15 patients underwent this procedure, with implantation of an SST porous polyethylene implant. The mean follow-up interval was 18 months with a range of 4-33 months. One patient suffered an implant exposure, and one experienced a post-operative orbital hemorrhage. Two patients required blepharoptosis surgery to achieve eyelid symmetry. CONCLUSIONS: This retrospective series demonstrates the potential usefulness of the inferior oblique muscle to augment coverage of the orbital implant. Reinforcement of the anterior surface of the implant with vascularized tissue may improve the integrity and strength of the tissues anterior to the implant, and thereby reduce the likelihood of implant exposure. PMID- 20829731 TI - Three carcinomas in one eyelid. AB - A 90-year-old woman presented with 2 masses on the right lower eyelid. Excisional biopsy revealed 1 lesion to be Merkel cell carcinoma and the other to be invasive squamous cell carcinoma. The patient also had a prior history of basal cell carcinoma in the same eyelid. This case emphasizes the importance of careful pathologic examination of all eyelid lesions regardless of previous history. PMID- 20829732 TI - Ptosis and ophthalmoplegia associated with epidermolysis bullosa simplex-muscular dystrophy. AB - The association of epidermolysis bullosa simplex and muscular dystrophy (EBS-MD) has rarely been discussed in ophthalmology literature. This case report offers a brief summary of epidermolysis bullosa and describes what is known about EBS-MD. The case involves a patient with EBS-MD who presented with ptosis and ophthalmoplegia, suggesting that these may be complications of EBS-MD. PMID- 20829733 TI - Orbital schwannoma with fluid-fluid levels on MRI. AB - A 40-year-old man presented with a progressively growing left orbital mass producing proptosis. Orbital MRI revealed a large bilobed mass that was isointense with respect to the extraocular muscles on T1-weighted images and demonstrated heterogenous contrast enhancement. T2-weighted images revealed a markedly heterogenous internal appearance with fluid-fluid levels. The mass was completely excised in one piece. Histopathologically, the encapsulated tumor consisted mostly of spindle-shaped tumor cells with elongated nuclei forming bundles without obvious mitosis. Richly cellular areas were consistent with the Antoni A pattern, and more hypocellular edematous areas were consistent with the Antoni B pattern. Hemorrhagic and cystic areas were seen within the tumor. The tumor cells stained diffusely positive with S-100 protein. Findings were consistent with the diagnosis of orbital schwannoma. Fluid-fluid levels are usually seen in some vascular and bone tumors and soft tissue lesions. Fluid fluid levels have previously been reported to occur in intracranial but not in orbital schwannomas. This case demonstrates that orbital schwannoma can also display fluid-fluid levels on MRI, which were thought to be due to intralesional hemorrhage in this case. PMID- 20829734 TI - Upper eyelid margin mass excision technique: supraciliary approach. AB - PURPOSE: To evaluate the effectiveness of a supraciliary approach for upper eyelid margin excisional biopsies. METHODS: A retrospective, comparative case series. A 2-year review of medical records of patients who underwent the procedure was performed. Data collected included the dates and type of procedure(s), review of operative and pathology reports, dates of follow up, findings of clinical examination, review of photographs, and postoperative complications. The main outcome measure was to assess both the functional and aesthetic outcomes of the procedure. RESULTS: Six patients with a minimum of 3 month follow-up were included in the study. In each case, eyelid contour and function was preserved, and scarring was nearly unnoticeable. No postoperative complications occurred. CONCLUSIONS: The study demonstrates the effectiveness of this surgical approach and as an alternative to more common techniques. PMID- 20829735 TI - Sutureless lens ring fixation for vitrectomy using cellulose eye drain. PMID- 20829736 TI - Ab interno incision for pediatric vitreoretinal surgery. PMID- 20829737 TI - Immersion B-guided versus contact A-mode biometry for accurate measurement of axial length and intraocular lens power calculation in siliconized eyes. AB - PURPOSE: To compare the accuracy of the immersion B-guided versus the contact A mode biometry in measuring the axial length and intraocular lens power of the siliconized eyes. METHODS: Sixty eyes with silicone cataract were divided into two groups. In Group A, the axial length of 30 eyes was measured by contact A mode biometry. In Group B, the axial length of 30 eyes was measured by immersion B-guided biometry. The postoperative refraction was done after 3 months and was compared with the attempted values. RESULTS: Twenty-five eyes of the B-guided group (83.3%) achieved a refraction deviation of +/- 1 D or less versus 14 (46.6%) in the A-mode group. The mean refractive deviation was less with the B mode (0.15 +/- 0.94) versus contact A-mode (-0.95 +/- 1.157); the difference is statistically significant (P = 0.024, Fisher test). CONCLUSION: B-guided biometry was found to be more accurate than the contact method in measuring axial length and intraocular lens power calculation in siliconized eyes and spared the time and cost needed for a separate B-scan. PMID- 20829738 TI - Evaluation of choroidal endothelial cell proliferation after exposure to varying doses of proton beam radiation. AB - PURPOSE: Focal epiretinal radiation has emerged as a promising tool in the management of choroidal neovascularization associated with age-related macular degeneration. However, the dosages tested are not backed by cell culture studies used in the clinical setting empirically. METHODS: Choroidal endothelial cells (RF6A) were maintained in a log scale and exposed to a single fraction of 2, 4, 8, and 12 cobalt gray-equivalent of proton radiation with an internal control. Cell viability was quantified using Vi-cell XR and neutral red assay at days 5, 9, and 12 after radiation. Mitochondrial viability using WST-1 and reactive oxygen species levels using dihydrorhodamine 123 were measured at similar intervals. RESULTS: By using neutral red assay, on day 12, the percentages of viable cells compared with control were 100.1 +/- 5.7%, 96.7 +/- 23.3%, 27.6 +/- 6.6%, and 19.5 +/- 3% at radiation doses of 2, 4, 8, and 12 cobalt gray equivalent, respectively (P < 0.001). Increase in reactive oxygen species levels correlated with the number of dead cells implicating reactive oxygen species as an intermediary molecule (r = 0.85-0.96). CONCLUSION: Our study shows sensitivity of cultured choroidal endothelial cells to proton beam radiation at doses of 8 and 12 cobalt gray-equivalent in an in vitro model. PMID- 20829739 TI - Faster visual recovery after 23-gauge vitrectomy compared with 20-gauge vitrectomy. AB - PURPOSE: To evaluate whether 23-gauge (23 G) pars plana vitrectomy is associated with earlier visual recovery compared with standard 20-gauge (20 G) pars plana vitrectomy. METHODS: Retrospective chart review of patients who underwent pars plana vitrectomy for various indications was performed. Thirty consecutive eyes in each group of 23-G and 20-G pars plana vitrectomy were analyzed. The mean decimal acuity of each patient was recorded at baseline, Day 1, and Weeks 1 and 6. The visual acuity on postoperative Day 1 and Week 1 was calculated as a proportion of the visual acuity at Week 6. The primary outcome measure was the rate of gain in visual acuity. The secondary outcome measures were intraocular pressure and surgical time. RESULTS: The baseline visual acuity between the two groups was similar. The mean visual acuity on Day 1 (0.05 +/- 0.09 20 G versus 0.16 +/- 0.18 23 G; Snellen equivalent 20/400 versus 20/125; P = 0.004) and Week 1 (0.12 +/- 0.20 20 G versus 0.30 +/- 0.27 23 G; Snellen equivalent 20/160 versus 20/63; P = 0.002) was significantly better in the 23-G pars plana vitrectomy group. There was no significant difference in best-corrected Snellen visual acuity at Week 6 between the 2 groups. Eighty-three percent of the mean final visual acuity was attained by Week 1 in the 23-G group compared with only 43% in the 20-G group. CONCLUSION: Twenty-three gauge pars plana vitrectomy is associated with faster visual recovery compared with 20-G pars plana vitrectomy. PMID- 20829740 TI - Structural and functional characteristics in carriers of X-linked retinitis pigmentosa with a tapetal-like reflex. AB - PURPOSE: The purpose of this study was to identify the functional and structural characteristics in three female obligate carriers of X-linked retinitis pigmentosa from the same family by using spectral domain optical coherence tomography, fundus autofluorescence, and microperimetry. METHODS: Three female obligate carriers with a tapetal-like reflex, 21, 49, and 57 years of age, from a single family of X-linked retinitis pigmentosa that was seen in the ophthalmology department at the University of Illinois at Chicago, were enrolled in the study. All carriers underwent a complete ophthalmic examination. Spectral domain optical coherence tomography measurements, a macular microperimetry examination, and fundus autofluorescence testing were performed. RESULTS: The spectral domain optical coherence tomography examination in all three carriers showed a normal retinal microstructure and thickness. Microperimeter testing showed subnormal retinal sensitivity in the areas of the tapetal-like reflex. Fundus autofluorescence examination showed the presence of speckled areas of enhanced autofluorescence. CONCLUSION: Our study demonstrates that the carriers of X linked retinitis pigmentosa with a tapetal-like reflex can show an enhanced reflectance on infrared images, abnormal autofluorescence properties, elevated retinal thresholds, and a normal retinal morphology within the posterior pole on spectral domain optical coherence tomography testing. PMID- 20829741 TI - Endogenous endophthalmitis associated with intravenous drug abuse: seven-year experience at a tertiary referral center. AB - PURPOSE: Intravenous drug use (IVDU) is a known risk factor for endogenous endophthalmitis. Endogenous fungal endophthalmitis (EFE) is emerging as a common problem among this community. We describe the management and visual outcomes of acute IVDU-associated EFE. METHODS: A prospective consecutive case series of 19 patients presenting with presumed acute IVDU-associated EFE from 2001 to 2007 to the Royal Victorian Eye and Ear Hospital was included. All data were collected in a standardized manner. Outcome measures included visual acuity, microbial profiles, and vitrectomy rate. RESULTS: Nineteen cases of IVDU-associated EFE were identified. Eight of these (42%) were men, and the mean age was 32.7 years (SD +/- 8.0 years). Presenting visual acuity ranged from 6/6 to perception of light, with 58% having a visual acuity of 6/48 or less at presentation. Thirteen (68.4%) were culture positive with all cultures identifying Candida species, and 52.7% underwent vitrectomy. Fifty percent of subjects overall achieved a final visual acuity of 6/18 or better. Men demonstrated improved visual acuity when compared with women (P = 0.04). Age had no effect on final acuity. CONCLUSION: Intravenous drug use is a significant risk factor for developing EFE. Good visual outcomes can be achieved with early treatment, often with intravitreal therapy alone. PMID- 20829742 TI - Melanocytoma of the optic disk in the Korean population. AB - PURPOSE: To report on the clinical features and the natural course of optic disk melanocytoma in the Korean population. METHODS: A retrospective review of medical records was performed on 27 consecutive patients with optic disk melanocytoma. In cases with tumor enlargement, surface area and diameter of tumors were measured from fundus images using computer software. RESULTS: The median age at diagnosis was 46 years with a slight female predominance (63%). The median tumor diameter and height were 3.1 mm and 1.9 mm, respectively. There were no cases with tumor related visual loss for a median follow-up of 2 years. Tumor enlargement was observed in 4 of 21 patients (19%) that had follow-up of 1 year or more with no malignant transformation. The mean change of tumor surface area was 2.4 mm (52% increase), and the mean change of tumor diameter was 1.8 mm over a mean follow-up of 53 months in 4 cases with tumor growth. Only tumor vascularization on fluorescent angiography correlated with tumor growth (Log-rank test; P = 0.049). Kaplan-Meier survival estimated that the tumor growth was 0% at 1 year, 14% at 5 years, and 57% at 8 years. CONCLUSION: Optic disk melanocytoma in the Korean population tends to be superiorly located in the optic disk, and visual prognosis was excellent. Periodic ocular examination is warranted because 57% of patients were estimated to show tumor enlargement by 8 years of follow-up. PMID- 20829743 TI - Lack of autofluorescence in fundus albipunctatus associated with mutations in RDH5. AB - PURPOSE: The purpose of this study was to characterize the phenotype of fundus albipunctatus associated with RDH5 mutations. METHODS: Four unrelated patients (patients 1-4) aged 35, 32, 19, and 8 years were examined with full-field electroretinography, multifocal electroretinography, optical coherence tomography, and fundus autofluorescence photography. Molecular genetic investigations included sequencing of RDH5 and RLBP1. RESULTS: Patients 1 to 3 harbored homozygous mutations (c.881G>C, c.625C>T, and c.382G>A, respectively) and patient 4 harbored the compound heterozygous mutations (c.95delT and c.712G>T) in RDH5. A large variability in retinal dysfunction caused by RDH5 mutations was found but not fully explained by a simple prediction of reduced enzymatic function. All patients showed lack of autofluorescence of the fundus, indicating a reduced supply of 11-cis retinal to the photoreceptors. The lesions corresponding to the white dots did not autofluoresce and were seen on optical coherence tomography as discrete hyperreflective elements in the outer retina extending from the external limiting membrane to Bruch membrane. CONCLUSION: Mutations in RDH5 associated with fundus albipunctatus seem to prevent normal lipofuscin accumulation. A relatively good functional status of 2 of 3 adult patients indicates that interference with 11-cis retinol dehydrogenase function may be a promising strategy for therapeutic intervention in retinal disorders featuring excessive lipofuscin accumulation. PMID- 20829744 TI - B-cell lymphoma line (Raji) viability and surface marker expression minimally affected by 20- and 25-gauge vitrectomy systems analyzed by flow cytometry. AB - PURPOSE: The purpose of this study was to evaluate the effect of 20-gauge (20-G) and 25-gauge (25-G) vitrectomy on cell viability and diagnostic yield (surface marker expression) using flow cytometry and human lymphoma cells in culture. METHODS: Cultured human Burkitt lymphoma cells (Raji B-cell lymphoma line) were allocated into five study groups in Roswell Park Memorial Institute media. By using manual aspiration, cells were then processed by aspiration alone, by 20-G vitrectomy at 600 cuts per minute (cpm) and 1,500 cpm, or by 25-G vitrectomy at both 600 and 1,500 cpm. To assess cell viability and cell surface marker expression, samples underwent standard flow cytometry analysis for suspected lymphoma using 7-amino-actinomycin D and antibodies against CD45, CD19, lambda, and kappa light chains. RESULTS: Twenty-five samples were processed after being divided into four vitrectomy groups and one nonvitrectomy group (control). The mean cell viability was 98.5 for both the nonvitrectomized and vitrectomized specimens. The percentage of cells positive for CD45 or kappa light chain was the same in the nonvitrectomized and vitrectomized groups. In addition, the level of expression of these molecules was not significantly different in all five groups. Similarly, no difference was seen for these markers between 20-G and 25-G vitrectomy at either a cut rate of 600 or 1,500 cpm. The percentage positive for CD19 was significantly lower for the 20-G vitrectomy at 1,500 cpm compared with the 25-G vitrectomy at both 600 and 1,500 cpm. Percentage of CD19 cells was greater for the 25-G vitrectomy at 600 cpm than the nonvitrectomy group. CONCLUSION: Compared with simple aspiration, both 20-G and 25-G vitrectomy seem to have no significant effect on cell viability or diagnostic yield for B-cell lymphoma cells (Raji cell line) in suspension based on flow cytometry. Further studies need to be conducted to study and compare 20-G versus 25-G vitrectomy on lymphoma cells in human vitreous or in an animal model. PMID- 20829745 TI - State-specific trends in fruit and vegetable consumption among adults --- United States, 2000-2009. AB - A diet high in fruits and vegetables can reduce the risk for many leading causes of death and can play an important role in weight management. Healthy People 2010 objectives for fruits and vegetables include targets of increasing to 75% the proportion of persons aged >=2 years who consume two or more servings of fruit daily and to 50% those who consume three or more servings of vegetables daily. To assess states' progress over the past decade in meeting these targets among adults and to provide an update of the 2005 subgroup estimates, CDC analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS). This report describes the results of that analysis, which indicated that, in 2009, an estimated 32.5% of adults consumed fruit two or more times per day and 26.3% consumed vegetables three or more times per day, far short of the national targets. Overall, the proportion of adults who met the fruit target declined slightly, but significantly, from 34.4% in 2000 to 32.5% in 2009; no significant change was observed in meeting the vegetable target. No state met either target, and substantial variability occurred among states. Only one state had statistically significant increases in the percentages of adults meeting each target. These findings underscore the need for interventions at national, state, and community levels, across multiple settings (e.g., worksites, community venues, and restaurants) to improve fruit and vegetable access, availability, and affordability, as a means of increasing individual consumption. PMID- 20829746 TI - Parental attitudes and experiences during school dismissals related to 2009 influenza A (H1N1) --- United States, 2009. AB - During the 2009 influenza A (H1N1) pandemic, child care center and school dismissals (i.e., temporary closures) were common and occurred in the majority of states across the United States. However, little is known about the economic and social problems parents face during such dismissals. To learn more about parents' attitudes and experiences after short-term school dismissals related to H1N1, CDC and the Harvard Opinion Research Program (HORP) conducted a randomized telephone poll of 523 parents from 39 states whose child care center or school had been closed temporarily in response to H1N1. This report summarizes the results of that poll, which found that 90% of parents agreed with the dismissal decision, and 85% believed dismissal effectively reduced influenza transmission. In most cases (58%), dismissal lasted <=3 days. Overall, most parents did not report adverse effects related to dismissals of short duration. Only 3% of respondents said dismissal was a major problem, and 75% reported that it was not a problem. Approximately 20% of parents reported that an adult in the household missed work because of the dismissal, and 19% had a child who missed a free or reduced-cost lunch, but only 2% and <1%, respectively, said these were major problems. The findings in this report underscore that when making a decision to close child care centers or schools, public health officials should consider the acceptability of the resulting disruption to students, families, and communities. PMID- 20829747 TI - Vital signs: current cigarette smoking among adults aged >or=18 years --- United States, 2009. AB - BACKGROUND: Cigarette smoking continues to be the leading cause of preventable morbidity and mortality in the United States, causing approximately 443,000 premature deaths annually. METHODS: The 2009 National Health Interview Survey and the 2009 Behavioral Risk Factor Surveillance System were used to estimate national and state adult smoking prevalence, respectively. Cigarette smokers were defined as adults aged >=18 years who reported having smoked >=100 cigarettes in their lifetime and now smoke every day or some days. RESULTS: In 2009, 20.6% of U.S. adults aged >=18 years were current cigarette smokers. Men (23.5%) were more likely than women (17.9%) to be current smokers. The prevalence of smoking was 31.1% among persons below the federal poverty level. For adults aged >=25 years, the prevalence of smoking was 28.5% among persons with less than a high school diploma, compared with 5.6% among those with a graduate degree. Regional differences were observed, with the West having the lowest prevalence (16.4%) and higher prevalences being observed in the South (21.8%) and Midwest (23.1%). From 2005 to 2009, the proportion of U.S. adults who were current cigarette smokers did not change (20.9% in 2005 and 20.6% in 2009). CONCLUSIONS: Previous declines in smoking prevalence in the United States have stalled during the past 5 years; the burden of cigarette smoking continues to be high, especially in persons living below the federal poverty level and with low educational attainment. Sustained, adequately funded, comprehensive tobacco control programs could reduce adult smoking. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: To further reduce disease and death from cigarette smoking, declines in cigarette smoking among adults must accelerate. The Patient Protection and Affordable Care Act is expected to expand access to evidence-based smoking-cessation services and treatments; this likely will result in additional use of these services and reductions of current smoking and its adverse effects among U.S. adults. Population-based prevention strategies such as tobacco taxes, media campaigns, and smoke-free policies, in concert with clinical cessation interventions, can help adults quit and prevent the uptake of tobacco use, furthering the reduction in the current prevalence of tobacco use in the United States across age groups. PMID- 20829748 TI - Vital signs: nonsmokers' exposure to secondhand smoke --- United States, 1999 2008. AB - BACKGROUND: Secondhand exposure to tobacco smoke causes heart disease and lung cancer in nonsmoking adults and sudden infant death syndrome, acute respiratory infections, middle ear disease, exacerbated asthma, respiratory symptoms, and decreased lung function in children. METHODS: National Health and Nutrition Examination Survey data from 1999-2008 were analyzed to determine the proportion of the nonsmoking population with serum cotinine (the primary nicotine metabolite) levels >=0.05 ng/mL, by age, sex, race/ethnicity, household income level, and to determine whether the household included a person who smoked inside the home. RESULTS: During 2007-2008, approximately 88 million nonsmokers aged >=3 years in the United States were exposed to secondhand smoke. The prevalence of serum cotinine levels >=0.05 ng/mL in the nonsmoking population declined significantly from 52.5% (95% CI = 47.1%-57.9%) during 1999-2000 to 40.1% (95% CI = 35.0%-45.3%) during 2007-2008. The decline was significant for each sex, age, race/ethnicity, and income group studied except non-Hispanic whites. The change was greatest from 1999-2000 to 2001-2002. For every period throughout the study, prevalence was highest among males, non-Hispanic blacks, children (aged 3-11 years) and youths (aged 12-19 years), and those in households below the federal poverty level. CONCLUSIONS: Secondhand smoke exposure has declined in the United States, but 88 million nonsmokers aged >=3 years are still exposed, progress in reducing exposure has slowed, and disparities in exposure persist, with children being among the most exposed. Nearly all nonsmokers who live with someone who smokes inside their home are exposed to secondhand smoke. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: The only way to protect nonsmokers fully is to eliminate smoking in indoor spaces. Continued efforts at smoking cessation and comprehensive statewide laws prohibiting smoking in workplaces and public places are needed to ensure that all nonsmokers are protected from this serious health hazard. Health care providers should educate patients and parents about the dangers of secondhand smoke and follow clinical care guidelines to help smokers quit. PMID- 20829750 TI - Science scorned. PMID- 20829749 TI - Use of World Health Organization and CDC growth charts for children aged 0-59 months in the United States. AB - In April 2006, the World Health Organization (WHO) released new international growth charts for children aged 0-59 months. Similar to the 2000 CDC growth charts, these charts describe weight for age, length (or stature) for age, weight for length (or stature), and body mass index for age. Whereas the WHO charts are growth standards, describing the growth of healthy children in optimal conditions, the CDC charts are a growth reference, describing how certain children grew in a particular place and time. However, in practice, clinicians use growth charts as standards rather than references. In 2006, CDC, the National Institutes of Health, and the American Academy of Pediatrics convened an expert panel to review scientific evidence and discuss the potential use of the new WHO growth charts in clinical settings in the United States. On the basis of input from this expert panel, CDC recommends that clinicians in the United States use the 2006 WHO international growth charts, rather than the CDC growth charts, for children aged <24 months (available at https://www.cdc.gov/growthcharts). The CDC growth charts should continue to be used for the assessment of growth in persons aged 2--19 years. The recommendation to use the 2006 WHO international growth charts for children aged <24 months is based on several considerations, including the recognition that breastfeeding is the recommended standard for infant feeding. In the WHO charts, the healthy breastfed infant is intended to be the standard against which all other infants are compared; 100% of the reference population of infants were breastfed for 12 months and were predominantly breastfed for at least 4 months. When using the WHO growth charts to screen for possible abnormal or unhealthy growth, use of the 2.3rd and 97.7th percentiles (or +/-2 standard deviations) are recommended, rather than the 5th and 95th percentiles. Clinicians should be aware that fewer U.S. children will be identified as underweight using the WHO charts, slower growth among breastfed infants during ages 3-18 months is normal, and gaining weight more rapidly than is indicated on the WHO charts might signal early signs of overweight. PMID- 20829751 TI - A destabilizing force. PMID- 20829758 TI - Journal club. A chronobiologist makes sense of circadian dysfunction in illness. PMID- 20829764 TI - US stem-cell chaos felt abroad. PMID- 20829765 TI - NASA panel weighs asteroid danger. PMID- 20829766 TI - Rare victory in fight against melanoma. PMID- 20829767 TI - Teams battle for neuron prize. PMID- 20829768 TI - Big emitters team up. PMID- 20829769 TI - 'Climate wars' claims disputed. PMID- 20829771 TI - Neuroscience: In their nurture. PMID- 20829772 TI - Geology: A trip to dinosaur time. PMID- 20829773 TI - Urban ecosystems research joins mainstream ecology. PMID- 20829774 TI - Big projects would be shooting in the dark without team effort. PMID- 20829775 TI - A call for action to curb invasive species in South America. PMID- 20829776 TI - Chinese journal finds 31% of submissions plagiarized. PMID- 20829777 TI - Time to automate identification. PMID- 20829781 TI - Evolutionary biology: Communication and speciation. PMID- 20829782 TI - Climate change: A glacial test of timing. PMID- 20829783 TI - Gene targeting: Enter the rat. PMID- 20829785 TI - Systems biology: The cost of feedback control. PMID- 20829786 TI - Nanotechnology: Holes with an edge. PMID- 20829787 TI - Functional roles for noise in genetic circuits. AB - The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or 'noise', in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward. PMID- 20829788 TI - Fundamental limits on the suppression of molecular fluctuations. AB - Negative feedback is common in biological processes and can increase a system's stability to internal and external perturbations. But at the molecular level, control loops always involve signalling steps with finite rates for random births and deaths of individual molecules. Here we show, by developing mathematical tools that merge control and information theory with physical chemistry, that seemingly mild constraints on these rates place severe limits on the ability to suppress molecular fluctuations. Specifically, the minimum standard deviation in abundances decreases with the quartic root of the number of signalling events, making it extremely expensive to increase accuracy. Our results are formulated in terms of experimental observables, and existing data show that cells use brute force when noise suppression is essential; for example, regulatory genes are transcribed tens of thousands of times per cell cycle. The theory challenges conventional beliefs about biochemical accuracy and presents an approach to the rigorous analysis of poorly characterized biological systems. PMID- 20829789 TI - Enhancement of proteasome activity by a small-molecule inhibitor of USP14. AB - Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress. PMID- 20829790 TI - High-resolution tunnelling spectroscopy of a graphene quartet. AB - Electrons in a single sheet of graphene behave quite differently from those in traditional two-dimensional electron systems. Like massless relativistic particles, they have linear dispersion and chiral eigenstates. Furthermore, two sets of electrons centred at different points in reciprocal space ('valleys') have this dispersion, giving rise to valley degeneracy. The symmetry between valleys, together with spin symmetry, leads to a fourfold quartet degeneracy of the Landau levels, observed as peaks in the density of states produced by an applied magnetic field. Recent electron transport measurements have observed the lifting of the fourfold degeneracy in very large applied magnetic fields, separating the quartet into integer and, more recently, fractional levels. The exact nature of the broken-symmetry states that form within the Landau levels and lift these degeneracies is unclear at present and is a topic of intense theoretical debate. Here we study the detailed features of the four quantum states that make up a degenerate graphene Landau level. We use high-resolution scanning tunnelling spectroscopy at temperatures as low as 10 mK in an applied magnetic field to study the top layer of multilayer epitaxial graphene. When the Fermi level lies inside the fourfold Landau manifold, significant electron correlation effects result in an enhanced valley splitting for even filling factors, and an enhanced electron spin splitting for odd filling factors. Most unexpectedly, we observe states with Landau level filling factors of 7/2, 9/2 and 11/2, suggestive of new many-body states in graphene. PMID- 20829791 TI - Glacier retreat in New Zealand during the Younger Dryas stadial. AB - Millennial-scale cold reversals in the high latitudes of both hemispheres interrupted the last transition from full glacial to interglacial climate conditions. The presence of the Younger Dryas stadial (approximately 12.9 to approximately 11.7 kyr ago) is established throughout much of the Northern Hemisphere, but the global timing, nature and extent of the event are not well established. Evidence in mid to low latitudes of the Southern Hemisphere, in particular, has remained perplexing. The debate has in part focused on the behaviour of mountain glaciers in New Zealand, where previous research has found equivocal evidence for the precise timing of increased or reduced ice extent. The interhemispheric behaviour of the climate system during the Younger Dryas thus remains an open question, fundamentally limiting our ability to formulate realistic models of global climate dynamics for this time period. Here we show that New Zealand's glaciers retreated after approximately 13 kyr bp, at the onset of the Younger Dryas, and in general over the subsequent approximately 1.5-kyr period. Our evidence is based on detailed landform mapping, a high-precision (10)Be chronology and reconstruction of former ice extents and snow lines from well-preserved cirque moraines. Our late-glacial glacier chronology matches climatic trends in Antarctica, Southern Ocean behaviour and variations in atmospheric CO(2). The evidence points to a distinct warming of the southern mid latitude atmosphere during the Younger Dryas and a close coupling between New Zealand's cryosphere and southern high-latitude climate. These findings support the hypothesis that extensive winter sea ice and curtailed meridional ocean overturning in the North Atlantic led to a strong interhemispheric thermal gradient during late-glacial times, in turn leading to increased upwelling and CO(2) release from the Southern Ocean, thereby triggering Southern Hemisphere warming during the northern Younger Dryas. PMID- 20829792 TI - 2010 Maule earthquake slip correlates with pre-seismic locking of Andean subduction zone. AB - The magnitude-8.8 Maule (Chile) earthquake of 27 February 2010 ruptured a segment of the Andean subduction zone megathrust that has been suspected to be of high seismic potential. It is the largest earthquake to rupture a mature seismic gap in a subduction zone that has been monitored with a dense space-geodetic network before the event. This provides an image of the pre-seismically locked state of the plate interface of unprecedentedly high resolution, allowing for an assessment of the spatial correlation of interseismic locking with coseismic slip. Pre-seismic locking might be used to anticipate future ruptures in many seismic gaps, given the fundamental assumption that locking and slip are similar. This hypothesis, however, could not be tested without the occurrence of the first gap-filling earthquake. Here we show evidence that the 2010 Maule earthquake slip distribution correlates closely with the patchwork of interseismic locking distribution as derived by inversion of global positioning system (GPS) observations during the previous decade. The earthquake nucleated in a region of high locking gradient and released most of the stresses accumulated in the area since the last major event in 1835. Two regions of high seismic slip (asperities) appeared to be nearly fully locked before the earthquake. Between these asperities, the rupture bridged a zone that was creeping interseismically with consistently low coseismic slip. The rupture stopped in areas that were highly locked before the earthquake but where pre-stress had been significantly reduced by overlapping twentieth-century earthquakes. Our work suggests that coseismic slip heterogeneity at the scale of single asperities should indicate the seismic potential of future great earthquakes, which thus might be anticipated by geodetic observations. PMID- 20829793 TI - A bizarre, humped Carcharodontosauria (Theropoda) from the lower cretaceous of Spain. AB - Carcharodontosaurs were the largest predatory dinosaurs, and their early evolutionary history seems to be more intricate than was previously thought. Until recently, carcharodontosaurs were restricted to a group of large theropods inhabiting the Late Cretaceous Gondwanan land masses, but in the last few years Laurasian evidence has been causing a reevaluation of their initial diversification. Here we describe an almost complete and exquisitely preserved skeleton of a medium-sized (roughly six metres long) theropod from the Lower Cretaceous series (Barremian stage) Konservat-Lagerstatte of Las Hoyas in Cuenca, Spain. Cladistic analysis supports the idea that the new taxon Concavenator corcovatus is a primitive member of Carcharodontosauria, exhibiting two unusual features: elongation of the neurapophyses of two presacral vertebrae forming a pointed, hump-like structure and a series of small bumps on the ulna. We think that these bumps are homologous to quill knobs present on some modern birds; the knobs are related to the insertion area of follicular ligaments that anchor the roots of the flight feathers (remiges) to the arm. We propose that Concavenator has integumentary follicular structures inserted on the ulna, as in modern birds. Because scales do not have follicles, we consider the structures anchored to the Concavenator arms to be non-scale skin appendages homologous to the feathers of modern birds. If this is true, then the phylogenetic bracket for the presence of non-scale skin structures homologous to feathers in theropod dinosaurs would be extended to the Neotetanurae, enlarging the scope for explaining the origin of feathers in theropods. PMID- 20829794 TI - A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. AB - Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine. PMID- 20829795 TI - MEC-17 is an alpha-tubulin acetyltransferase. AB - In most eukaryotic cells, subsets of microtubules are adapted for specific functions by post-translational modifications (PTMs) of tubulin subunits. Acetylation of the epsilon-amino group of K40 on alpha-tubulin is a conserved PTM on the luminal side of microtubules that was discovered in the flagella of Chlamydomonas reinhardtii. Studies on the significance of microtubule acetylation have been limited by the undefined status of the alpha-tubulin acetyltransferase. Here we show that MEC-17, a protein related to the Gcn5 histone acetyltransferases and required for the function of touch receptor neurons in Caenorhabditis elegans, acts as a K40-specific acetyltransferase for alpha tubulin. In vitro, MEC-17 exclusively acetylates K40 of alpha-tubulin. Disruption of the Tetrahymena MEC-17 gene phenocopies the K40R alpha-tubulin mutation and makes microtubules more labile. Depletion of MEC-17 in zebrafish produces phenotypes consistent with neuromuscular defects. In C. elegans, MEC-17 and its paralogue W06B11.1 are redundantly required for acetylation of MEC-12 alpha tubulin, and contribute to the function of touch receptor neurons partly via MEC 12 acetylation and partly via another function, possibly by acetylating another protein. In summary, we identify MEC-17 as an enzyme that acetylates the K40 residue of alpha-tubulin, the only PTM known to occur on the luminal surface of microtubules. PMID- 20829796 TI - HAATI survivors replace canonical telomeres with blocks of generic heterochromatin. AB - The notion that telomeres are essential for chromosome linearity stems from the existence of two chief dangers: inappropriate DNA damage response (DDR) reactions that mistake natural chromosome ends for double-strand DNA breaks (DSBs), and the progressive loss of DNA from chromosomal termini due to the end replication problem. Telomeres avert the former peril by binding sequence-specific end protection factors that control the access of DDR activities. The latter threat is tackled by recruiting telomerase, a reverse transcriptase that uses an integral RNA subunit to template the addition of telomere repeats to chromosome ends. Here we describe an alternative mode of linear chromosome maintenance in which canonical telomeres are superseded by blocks of heterochromatin. We show that in the absence of telomerase, Schizosaccharomyces pombe cells can survive telomere sequence loss by continually amplifying and rearranging heterochromatic sequences. Because the heterochromatin assembly machinery is required for this survival mode, we have termed it 'HAATI' (heterochromatin amplification-mediated and telomerase-independent). HAATI uses the canonical end-protection protein Pot1 (ref. 4) and its interacting partner Ccq1 (ref. 5) to preserve chromosome linearity. The data suggest a model in which Ccq1 is recruited by the amplified heterochromatin and provides an anchor for Pot1, which accomplishes its end protection function in the absence of its cognate DNA-binding sequence. HAATI resembles the chromosome end-maintenance strategy found in Drosophila melanogaster, which lacks specific telomere sequences but nonetheless assembles terminal heterochromatin structures that recruit end-protection factors. These findings reveal a previously unrecognized mode by which cancer cells might escape the requirement for telomerase activation, and offer a tool for studying genomes that sustain unusually high levels of heterochromatinization. PMID- 20829797 TI - Telomeres avoid end detection by severing the checkpoint signal transduction pathway. AB - Telomeres protect the normal ends of chromosomes from being recognized as deleterious DNA double-strand breaks. Recent studies have uncovered an apparent paradox: although DNA repair is prevented, several proteins involved in DNA damage processing and checkpoint responses are recruited to telomeres in every cell cycle and are required for end protection. It is currently not understood how telomeres prevent DNA damage responses from causing permanent cell cycle arrest. Here we show that fission yeast (Schizosaccharomyces pombe) cells lacking Taz1, an orthologue of human TRF1 and TRF2 (ref. 2), recruit DNA repair proteins (Rad22(RAD52) and Rhp51(RAD51), where the superscript indicates the human orthologue) and checkpoint sensors (RPA, Rad9, Rad26(ATRIP) and Cut5/Rad4(TOPBP1)) to telomeres. Despite this, telomeres fail to accumulate the checkpoint mediator Crb2(53BP1) and, consequently, do not activate Chk1-dependent cell cycle arrest. Artificially recruiting Crb2(53BP1) to taz1Delta telomeres results in a full checkpoint response and cell cycle arrest. Stable association of Crb2(53BP1) to DNA double-strand breaks requires two independent histone modifications: H4 dimethylation at lysine 20 (H4K20me2) and H2A carboxy-terminal phosphorylation (gammaH2A). Whereas gammaH2A can be readily detected, telomeres lack H4K20me2, in contrast to internal chromosome locations. Blocking checkpoint signal transduction at telomeres requires Pot1 and Ccq1, and loss of either Pot1 or Ccq1 from telomeres leads to Crb2(53BP1) foci formation, Chk1 activation and cell cycle arrest. Thus, telomeres constitute a chromatin-privileged region of the chromosomes that lack essential epigenetic markers for DNA damage response amplification and cell cycle arrest. Because the protein kinases ATM and ATR must associate with telomeres in each S phase to recruit telomerase, exclusion of Crb2(53BP1) has a critical role in preventing telomeres from triggering cell cycle arrest. PMID- 20829798 TI - Structural basis of Na(+)-independent and cooperative substrate/product antiport in CaiT. AB - Transport of solutes across biological membranes is performed by specialized secondary transport proteins in the lipid bilayer, and is essential for life. Here we report the structures of the sodium-independent carnitine/butyrobetaine antiporter CaiT from Proteus mirabilis (PmCaiT) at 2.3-A and from Escherichia coli (EcCaiT) at 3.5-A resolution. CaiT belongs to the family of betaine/carnitine/choline transporters (BCCT), which are mostly Na(+) or H(+) dependent, whereas EcCaiT is Na(+) and H(+) independent. The three-dimensional architecture of CaiT resembles that of the Na(+)-dependent transporters LeuT and BetP, but in CaiT a methionine sulphur takes the place of the Na(+) ion to coordinate the substrate in the central transport site, accounting for Na(+) independent transport. Both CaiT structures show the fully open, inward-facing conformation, and thus complete the set of functional states that describe the alternating access mechanism. EcCaiT contains two bound butyrobetaine substrate molecules, one in the central transport site, the other in an extracellular binding pocket. In the structure of PmCaiT, a tryptophan side chain occupies the transport site, and access to the extracellular site is blocked. Binding of both substrates to CaiT reconstituted into proteoliposomes is cooperative, with Hill coefficients up to 1.7, indicating that the extracellular site is regulatory. We propose a mechanism whereby the occupied regulatory site increases the binding affinity of the transport site and initiates substrate translocation. PMID- 20829800 TI - Economic impact of the clinical benefits of bariatric surgery in diabetes patients with BMI >=35 kg/m2. AB - The medical costs for a type 2 diabetes patient are two to four times greater than the costs for a patient without diabetes. Bariatric surgery is the most effective weight-loss therapy and has marked therapeutic effects on diabetes. We estimate the economic effect of the clinical benefits of bariatric surgery for diabetes patients with BMI >= 35 kg/m2. Using an administrative claims database of privately insured patients covering 8.5 million lives 1999-2007, we identify obese patients with diabetes, aged 18-65 years, who were treated with bariatric surgery identified using Healthcare Common Procedure Coding System codes. These patients were matched with nonsurgery control patients on demographic factors, comorbidities, and health-care costs. The overall return on investment (RoI) associated with bariatric surgery was calculated using multivariate analysis. Surgery and control patients were compared postindex with respect to diagnostic claims for diabetes, diabetes medication claims, and adjusted diabetes medication and supply costs. Surgery costs were fully recovered after 26 months for laparoscopic surgery. At month 6, 28% of surgery patients had a diabetes diagnosis, compared to 74% of control patients (P < 0.001). Among preindex insulin users, insulin use dropped to 43% by month 3 for surgery patients, vs. 84% for controls (P < 0.001). By month 1, medication and supply costs were significantly lower for surgery patients (P < 0.001). The therapeutic benefits of bariatric surgery on diabetes translate into considerable economic benefits. These data suggest that surgical therapy is clinically more effective and ultimately less expensive than standard therapy for diabetes patients with BMI >= 35 kg/m2. PMID- 20829801 TI - Assessment of atrial electromechanical delay by tissue Doppler echocardiography in obese subjects. AB - Our aim was to evaluate whether atrial electromechanical delay measured by tissue Doppler imaging (TDI), which is an early predictor of atrial fibrillation (AF) development, is prolonged in obese subjects. A total of 40 obese and 40 normal weight subjects with normal coronary angiograms were included in this study. P wave dispersion (PWD) was calculated on the 12-lead electrocardiogram (ECG). Systolic and diastolic left ventricular (LV) functions, inter- and intra-atrial electromechanical delay were measured by TDI and conventional echocardiography. Inter- and intra-atrial electromechanical delay were significantly longer in the obese subjects compared with the controls (44.08 +/- 10.06 vs. 19.35 +/- 5.94 ms and 23.63 +/- 6.41 vs. 5.13 +/- 2.67 ms, P < 0.0001 for both, respectively). PWD was higher in obese subjects (53.40 +/- 5.49 vs. 35.95 +/- 5.93 ms, P < 0.0001). Left atrial (LA) diameter, LA volume index and LV diastolic parameters were significantly different between the groups. Interatrial electromechanical delay was correlated with PWD (r = 0.409, P = 0.009), high-sensitivity C-reactive protein (hsCRP) levels (r = 0.588, P < 0.0001). Interatrial electromechanical delay was positively correlated with LA diameter, LA volume index, and LV diastolic function parameters consisting of mitral early wave (E) deceleration time (DT) and isovolumetric relaxation time (IVRT; r = 0.323, P = 0.042; r = 0.387, P = 0.014; r = 0.339, P = 0.033; r = 0.325, P = 0.041; respectively) and, negatively correlated with mitral early (E) to late (A) wave ratio (E/A) (r = 0.380, P = 0.016) and myocardial early-to-late diastolic wave ratio (E(m)/A(m)) (r = -0.326, P = 0.040). This study showed that atrial electromechanical delay is prolonged in obese subjects. Prolonged atrial electromechanical delay is due to provoked low-grade inflammation as well as LA enlargement and early LV diastolic dysfunction in obese subjects. PMID- 20829802 TI - FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKbeta pathways. AB - Free-fatty acids (FFAs) are well-characterized factor for causing production of inflammatory factors and insulin resistance in adipocytes. Using cultured adipocytes, we demonstrate that FFAs can activate endoplasmic reticulum (ER) stress pathway by examination of ER stress sensor activation and marker gene expression. Chemical chaperone tauroursodeoxycholic acid (TUDCA) can reduce FFA induced adipocyte inflammation and improve insulin signaling whereas overexpression of spliced X-box protein 1 (XBP-1s) only attenuates FFA-induced inflammation. PKR-like eukaryotic initiation factor 2alpha kinase (PERK) is one of the three major ER stress sensor proteins and deficiency of PERK alleviates FFA-induced inflammation and insulin resistance. The key downstream target of FFA induced ER stress is IkappaB kinase beta (IKKbeta), a master kinase for regulating expression of inflammatory genes. Deficiency of PERK attenuates FFA induced activation of IKKbeta and deficiency of IKKbeta alleviates FFA-induced inflammation and insulin resistance. Consistently, overexpression of IKKbeta in 3T3-L1 CAR adipocytes causes inflammation and insulin resistance. In addition, IKKbeta overexpression has profound effect on adipocyte lipid metabolism, including inhibition of lipogenesis and promotion of lipolysis. Furthermore, increased endogenous IKKbeta expression and activation is also observed in isolated primary adipocytes from mice injected with lipids or fed on high-fat diet (HFD) acutely. These results indicate that ER stress pathway is a key mediator for FFA-induced inflammation and insulin resistance in adipocytes with PERK and IKKbeta as the critical signaling components. PMID- 20829803 TI - Parents and vehicle purchases for their children: a surprising source of weight bias. AB - According to current estimates, 68% of the population in United States is considered either overweight or obese. Despite its relative frequency, prejudice and discrimination against overweight and obese Americans is a common occurrence. This study seeks to build on previous findings that overweight individuals are more likely than their skinnier peers to rely on themselves, rather than family, to fund their education. We examined whether this trend continued in car-buying practices. Results suggest that overweight and obese individuals differentially rely on their own sources of income to finance a car, even after controlling for socioeconomic differences. Possible explanations and implications are discussed. PMID- 20829804 TI - Effects of diabetes and obesity on vascular reactivity, inflammatory cytokines, and growth factors. AB - We examined the influences of obesity and diabetes on endothelium-dependent and independent vasodilation, inflammatory cytokines, and growth factors. We included 258 subjects, age 21-80 years in four groups matched for age and gender: 40 healthy nonobese (BMI <30 kg.m(-2)) nondiabetic subjects, 76 nonobese diabetic patients, 37 obese (BMI >30) nondiabetic subjects, and 105 obese (BMI >30) diabetic patients. The flow-mediated dilation (FMD, endothelium-dependent) and nitroglycerin-induced dilation (NID, endothelium-independent) in the brachial artery, the vascular reactivity at the forearm skin and serum growth factors and inflammatory cytokines were measured. FMD was reduced in the nonobese diabetic patients, obese nondiabetic controls, and obese diabetic patients (P < 0.0001). NID was different among all four groups, being highest in the obese nondiabetic subjects and lowest in the obese diabetic patients (P < 0.0001). The resting skin forearm blood flow was reduced in the obese nondiabetic subjects (P < 0.01). Vascular endothelial growth factor (VEGF) was higher in the obese nondiabetic subjects (P < 0.05), tumor necrosis factor-alpha was higher in the obese diabetic patients (P < 0.0001) and C-reactive protein was higher in both the obese nondiabetic and diabetic subjects (P < 0.0001). Soluble intercellular adhesion molecule-1 was elevated in the two diabetic groups and the obese nondiabetic subjects (P < 0.05). We conclude that diabetes and obesity affect equally the endothelial cell function but the smooth muscle cell function is affected only by diabetes. In addition, the above findings may be related to differences that were observed in the growth factors and inflammatory cytokines. PMID- 20829805 TI - ADRB2 haplotype is associated with glucose tolerance and insulin sensitivity in obese postmenopausal women. AB - The beta(2)-adrenergic receptor (ADRB2) mediates obesity, cardiorespiratory fitness, and insulin resistance. We examined the hypothesis that ADRB2 Arg16Gly Gln27Glu haplotype is associated with body composition, glucose tolerance, and insulin sensitivity in obese, postmenopausal women. Obese (>35% body fat), postmenopausal (age 45-75 years) women (n = 123) underwent genotyping, dual energy X-ray absorptiometry, and computed tomography scans, exercise testing (VO(2(max))), 2-h oral glucose tolerance tests (OGTTs), and hyperinsulinemic euglycemic clamps (80 mU/m(2)/min). Analysis of covariance (ANCOVA) tested for differences among haplotypes, with race, % body fat, and VO(2(max)) as covariates. We found that ADRB2 haplotype was independently associated with % body fat, abdominal fat distribution, VO(2(max)), insulin sensitivity (M/DeltaInsulin), and glucose tolerance (ANOVA, P < 0.05 for all). Women homozygous for Gly16-Gln27 haplotype had the highest % body fat (52.7 +/- 1.9%), high abdominal fat, low M/DeltaInsulin (0.49 +/- 0.08 mg/kg/min/pmol/l/10(2)), and impaired glucose tolerance (IGT) during an OGTT (G(120) = 10.2 +/- 0.9 mmol/l). Women homozygous for Gly16-Glu27 haplotype also had low M/DeltaInsulin (0.51 +/- 0.05 mg/kg/min/pmol/l/10(2)) and IGT (G(120) = 8.2 +/- 0.7 mmol/l). Subjects with Arg16-Gln27/Gly16-Gln27 haplotype combination had the highest VO(2(max)) (1.84 +/- 0.07 l/min) and M/DeltaInsulin (0.7 +/- 0.04 mg/kg/min/pmol/l/10(2)), and normal glucose tolerance (G(120) = 6.4 +/- 0.4 mmol/l), despite being obese. These data show associations of the ADRB2 Arg16Gly Gln27Glu haplotype with VO(2(max)) and body composition, and an independent association with glucose metabolism, which persists after controlling for body composition and fitness. This suggests that ADRB2 haplotypes may mediate insulin action, glucose tolerance, and potentially risk for type 2 diabetes mellitus (T2DM) in obese, postmenopausal women. PMID- 20829806 TI - The identity problem. PMID- 20829807 TI - Avastin's commercial march suffers setback. PMID- 20829809 TI - Pfizer explores rare disease path. PMID- 20829814 TI - India's Cipla sets sights on Avastin, Herceptin and Enbrel. PMID- 20829816 TI - Cochrane meta-analysis on alpha-1 antitrypsin prompts furor. PMID- 20829817 TI - Disclosing discoveries. PMID- 20829818 TI - Trends in biotech literature 2009. PMID- 20829819 TI - Oncology's energetic pipeline. PMID- 20829820 TI - The Cartagena Protocol and genetically modified mosquitoes. PMID- 20829821 TI - The FEBS Letters/BioCreative II.5 experiment: making biological information accessible. PMID- 20829822 TI - Biofortified sorghum in Africa: using problem formulation to inform risk assessment. PMID- 20829823 TI - Towards patient-based cancer therapeutics. PMID- 20829824 TI - Global health or global wealth? PMID- 20829825 TI - First-in-human clinical trials with vaccines--what regulators want. PMID- 20829826 TI - Biopharmaceutical benchmarks 2010. PMID- 20829827 TI - Will the patentability of genes survive? PMID- 20829829 TI - A holistic view of GPCR signaling. PMID- 20829830 TI - Pushing the envelope on HIV-1 neutralization. PMID- 20829831 TI - LINCing chromatin remodeling to metastasis. PMID- 20829834 TI - Cleantech: brave new world or coming home? PMID- 20829836 TI - Dental practitioners and ill health retirement: causes, outcomes and re employment. AB - AIM: The aim of this project was, by means of a questionnaire to ill health retirees, to determine the factors which have contributed to the premature retirement of general dental practitioners (GDPs) due to ill health. METHODS: A questionnaire was designed to determine the effects of illness and ill health retirement (IHR) on the lives of those dentists who were affected. This was distributed to 207 dentists who were known to have retired because of ill health but were not suffering from serious, debilitating or life-threatening illnesses. RESULTS: A total of 189 questionnaires were returned. The mean age at retirement of respondents was 51.5 years, with a range of 31 to 62 years. Of the respondents, 90% selected general dental practitioner as their last job title. The most common cause of IHR was musculoskeletal disorders (55%), followed by mental and behavioural disorders (28%). A majority of respondents (90%) considered that their ill health was work related. Sixty-three percent of respondents stated that they were able to keep working until their retirement, 34% of respondents stated that they would have liked to have been offered part time work as an alternative to full retirement, and 27% of dentists reported to have found re-employment since their retirement. In univariate analyses, re employment of dentists after IHR was significantly associated with age, having dependants, cause of IHR, health having improved and wanting to work again. Multiple logistic regression analyses showed that a combination of age, having dependents and cause of IHR was predictive of re-employment status (p = 0.024). CONCLUSION: This study used a database of dentists who were ill health retired and who were not suffering from life threatening illnesses The results confirmed that the majority were able to work up to their retirement and a similar number would have liked to continue working, particularly if part-time work had been possible. It seems likely that many of the ill health retirees could have been retained in the dental workforce with better support or opportunities for more flexible working. PMID- 20829833 TI - The BioPAX community standard for pathway data sharing. AB - Biological Pathway Exchange (BioPAX) is a standard language to represent biological pathways at the molecular and cellular level and to facilitate the exchange of pathway data. The rapid growth of the volume of pathway data has spurred the development of databases and computational tools to aid interpretation; however, use of these data is hampered by the current fragmentation of pathway information across many databases with incompatible formats. BioPAX, which was created through a community process, solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. Using BioPAX, millions of interactions, organized into thousands of pathways, from many organisms are available from a growing number of databases. This large amount of pathway data in a computable form will support visualization, analysis and biological discovery. PMID- 20829837 TI - Dental practitioners and ill health retirement: a qualitative investigation into the causes and effects. AB - INTRODUCTION: Data published in 1999 from the Government Actuary on the National Health Service Pension Scheme (1989-1994) have indicated that the frequency of ill health premature retirement (IHR) was four times more prevalent among dentists at age 42 years compared with doctors.Objective The aim of this project was to determine the factors that contributed to IHR in dental practitioners, and the effects of IHR on their lives. METHOD: Semi-structured interviews were carried out during 2007. A topic list was developed, piloted and used to guide the interviewer. A purposive sampling technique was used to recruit the respondents from an insurance company database. A framework approach to data analysis was utilised. RESULTS: Twenty-three respondents were interviewed, 19 male and 4 female, aged between 39-59 years. Depression, stress and anxiety were reported by respondents to be major causes of their retirement, followed by musculoskeletal disease and premature disability caused by trauma. This is illustrated by the following: '...just went straight into general practice but with some regrets. Practice was so depressing' (GDS/NHS); 'I withdraw, I don't engage ... I found it more and more difficult and one morning... I collapsed in tears at the practice' (GDS/NHS). Dentists reported both negative and positive comments in relation to support received from their health insurance company. CONCLUSIONS: The main causes of IHR were depression, musculoskeletal disease and specific skin conditions. Respondents expressed concern regarding the level of support available to dentists in distress. Respondents to this study found that continuing to work had a positive impact on their health. PMID- 20829839 TI - Quest for truth. PMID- 20829840 TI - Retaining individuality. PMID- 20829841 TI - Dysmorphic disorder. PMID- 20829842 TI - Wholly appropriate. PMID- 20829856 TI - Risk management in clinical practice. Part 5. Ethical considerations for dental enhancement procedures. AB - After the demise of the Industrial Age, we currently live in an 'Information Age' fuelled mainly by the Internet, with an ever-increasing medically and dentally literate population. The media has played its role by reporting scientific advances, as well as securitising medical and dental practices. Reality television such as 'Extreme makeovers' has also raised public awareness of body enhancements, with a greater number of people seeking such procedures. To satiate this growing demand, the dental industry has flourished by introducing novel cosmetic products such as bleaching kits, tooth coloured filling materials and a variety of dental ceramics. In addition, one only has to browse through a dental journal to notice innumerable courses and lectures on techniques for providing cosmetic dentistry. The incessant public interest, combined with unrelenting marketing by companies is gradually shifting the balance of dental care from a healing to an enhancement profession. The purpose of this article is to endeavour to answer questions such as, What is aesthetic or cosmetic dentistry? Why do patients seek cosmetic dentistry? Are enhancement procedures a part of dental practice? What, if any, ethical guidelines and constraints apply to elective enhancement procedures? What is the role of the dentist in providing or encouraging this type of 'therapy'? What treatment modalities are available for aesthetic dental treatment? PMID- 20829861 TI - Summary of: Dental practitioners and ill health retirement: causes, outcomes and re-employment. PMID- 20829862 TI - Summary of: Dental practitioners and ill health retirement: a qualitative investigation into the causes and effects. PMID- 20829863 TI - Evidence summary: what do we know from qualitative research about people's care seeking about oral health? AB - Since August 2009, members of the Primary Care Dentistry Research Forum (http://www.dentistryresearch.org) have taken part in an online vote to identify questions in day-to-day practice that they felt most needed to be answered with conclusive research. The question which receives the most votes each month forms the subject of a critical appraisal of the relevant literature. Each month a new round of voting takes place to decide which further questions will be reviewed. Dental practitioners and dental care professionals are encouraged to take part in the voting and submit their own questions to be included in the vote by joining the website. The paper below details a summary of the findings of the ninth critical appraisal. In conclusion, the critical appraisal showed a wide range of factors that influence care-seeking about oral health. These included both barriers and triggers to care-seeking. Only five papers were found that provided relevant data, and their data collection settings varied widely. Further research into care-seeking about oral health would be useful for both policy makers and practitioners in understanding patients' needs. PMID- 20829864 TI - Introducing care pathway commissioning to primary dental care: the concept. AB - Care pathways are defined as 'a methodology for the mutual decision making and organisation of care for a well-defined group of patients during a well-defined period'. Although most often used in Europe as a tool to improve the quality of care and to aid the continuity of care between disciplines and settings, care pathways also have an application in underpinning the commissioning process. This paper describes the development of a new model of commissioning for general dental practice services based on a need and risk assessment linked to specified care pathways for preventive care. In this system dentists are monitored on adherence to care protocols based on nationally accepted guidelines for preventive care interventions as well as recommended recall intervals for routine dental examinations. A traffic light system to distinguish between patients with different levels of need and risk of disease is being used. PMID- 20829865 TI - Managed clinical networks. AB - Managed clinical networks (MCNs) are self-supporting groups of professionals working together to ensure cross-speciality sharing of patients and expertise. They are a strong mechanism for ensuring that patients receive the care they need in a timely fashion from the most suitable professional in the network area. This short article will explain how they work and how they can work for you. PMID- 20829882 TI - Listening to public concerns about human life extension. The public view of life extension technologies is more nuanced than expected and researchers must engage in discussions if they hope to promote awareness and acceptance. PMID- 20829881 TI - SATB2 augments DeltaNp63alpha in head and neck squamous cell carcinoma. AB - DeltaNp63alpha is a critical pro-survival protein overexpressed in 80% of head and neck squamous cell carcinomas (HNSCCs) where it inhibits TAp73beta transcription of p53-family target genes, which is thought to increase HNSCC resistance to chemotherapy-induced cell death. However, the mechanisms governing DeltaNp63alpha function are largely unknown. In this study, we identify special AT-rich-binding protein 2 (SATB2) as a new DeltaNp63alpha-binding protein that is preferentially expressed in advanced-stage primary HNSCC and show that SATB2 promotes chemoresistance by enhancing DeltaNp63alpha-mediated transrepression by augmenting DeltaNp63alpha engagement to p53-family responsive elements. Furthermore, SATB2 expression positively correlates with HNSCC chemoresistance, and RNA interference-mediated knockdown of endogenous SATB2 re-sensitizes HNSCC cells to chemotherapy- and gamma-irradiation-induced apoptosis, irrespective of p53 status. These findings unveil SATB2 as a pivotal modulator of DeltaNp63alpha that governs HNSCC cell survival. PMID- 20829883 TI - BRG1 helps RNA polymerase II to overcome a nucleosomal barrier during elongation, in vivo. AB - RNA polymerase II (RNAPII) transcribes genes in a chromatin context. We have designed a system to investigate the role of chromatin remodelling during elongation in vivo, which involves inserting a strong nucleosome-positioning sequence between a promoter and a reporter gene. Our data indicate that a nucleosome positioned in the body of a transcription unit impairs RNAPII progression, provokes RNAPII accumulation upstream to the positioned nucleosome and reduces transcription. By using this system, we show that BRG1, the enzymatic motor of the SWI-SNF chromatin-remodelling complex, is recruited to the positioned nucleosome in a transcription elongation-dependent manner and facilitates traversal of the nucleosome by RNAPII. PMID- 20829884 TI - Peroxiredoxin 6 interferes with TRAIL-induced death-inducing signaling complex formation by binding to death effector domain caspase. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent with cancer-selective apoptogenic activity. It evokes the canonical caspase-mediated cell death pathway through death-inducing signaling complex (DISC) formation. We identified that Peroxiredoxin 6 (Prx6) interacts with caspase-10 and caspase-8 via the death effector domain (DED). Prx6 suppresses TRAIL-mediated cell death in human cancer cells, but not that induced by intrinsic apoptosis inducers such as etoposide, staurosporine, or A23187. Among Prx1-6 members, only Prx6 binds to DED caspases and is most effective in suppressing TRAIL or DED caspase-induced cell death. The antiapoptotic activity of Prx6 against TRAIL is not likely associated with its peroxidase activity but is associated with its ability to bind to DED caspases. Increased expression of Prx6 enhances the binding of Prx6 to caspase-10 but reduces TRAIL-induced DISC formation and subsequently caspase activation. Interestingly, Prx6 is highly upregulated in metastatic gastric cancer cells, which are relatively resistant to TRAIL as compared with primary cancer cells. Downregulation of Prx6 sensitizes the metastatic cancer cells to TRAIL-induced cell death. Taken together, these results suggest that Prx6 modulates TRAIL signaling as a negative regulator of caspase-8 and caspase-10 in DISC formation of TRAIL-resistant metastatic cancer cells. PMID- 20829885 TI - The Notch2-Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. AB - Stem cell factor (SCF), the ligand for the c-kit receptor, is essential for the production of red blood cells during development and stress erythropoiesis. SCF promotes erythroblast proliferation and survival, while delaying erythroid differentiation through mechanisms that are largely unknown. In cultures of primary human differentiating erythroblasts, we found that SCF induces an increase in the expression of Notch2, a member of the Notch family implicated in the control of cell growth and differentiation. Functional inhibition of either Notch or its ligand Jagged1 inhibited the effects of SCF on erythroid cell expansion. SCF also induced the expression of Hes-1 and GATA-2, which may contribute to transduce Notch2 signals in response to SCF. Transduction of primary erythroid precursors with a dominant-negative Notch2 mutant inhibited both basal and SCF-mediated erythroblast expansion, and counteracted the effects of SCF on erythroblast differentiation. These findings provide a clue to understand the effects of increased proliferation and delayed differentiation elicited by SCF on the erythroid compartment and indicate Notch2 as a new player in the regulation of red cell differentiation. PMID- 20829887 TI - Pinguecula and contact lenses. AB - PURPOSE: To assess the relationship between age and the incidence and severity (determined by a grading system) of pinguecula in contact lens (CL) wearers, and to compare the grade of pinguecula between CL wearers and non-wearers. METHODS: A total of 600 CL wearers (94 wore hard CLs (HCLs) and 506 wore soft CLs (SCLs)) aged 11-60 years and 579 non-wearers aged 10-60 years were enrolled. The age, gender, medical history, ocular history, and grade of pinguecula at two locations (nasal and temporal) were determined in all subjects. RESULTS: There was an age related increase in the grade of pinguecula among both CL wearers and non wearers. The grade of pinguecula at the temporal conjunctiva was higher in CL wearers than in non-wearers (P=0.01907), whereas it was higher in HCL wearers than SCL wearers at both the nasal and temporal conjunctiva (P<0.00001 and P<0.00001). CONCLUSIONS: This was the first assessment of the severity of pinguecula in a large consecutive series of CL wearers. Our results suggest that the use of CLs is an important risk factor for pinguecula. PMID- 20829888 TI - Preliminary survey of educational support for patients prescribed ocular hypotensive therapy. AB - PURPOSE: to establish the impact of educational support on patients' knowledge of glaucoma and adherence, in preparation for an intervention study. METHODS: structured observation encapsulated the educational support provided during clinical consultations and patient interviews captured the depth of glaucoma knowledge, problems associated with glaucoma therapy, and adherence issues. RESULTS: one hundred and thirty-eight patients completed the study. Education was didactic in nature, limited for many patients and inconsistent across clinics. Patients showed generally poor knowledge of glaucoma with a median score of 6 (range 0-16). A significant association was found between educational support and knowledge for newly prescribed patients (Kendall's tau=0.30, P=0.003), but no association was found for follow-up patients (Kendall's tau=0.11, P=0.174). Only five (6%) patients admitted to a doctor that they did not adhere to their drop regimen, yet 75 (94%) reported at interview that they missed drops. CONCLUSIONS: although important, knowledge alone may not sufficiently improve adherence: a patient-centred approach based on ongoing support according to need may provide a more effective solution for this patient group. PMID- 20829886 TI - Antiviral immune responses in the genital tract: clues for vaccines. AB - Mucosal surfaces are exploited as a portal of entry into hosts by a wide variety of microorganisms. Over the past decade, an advanced understanding of the immune system of the gastrointestinal and the respiratory mucosae has been gained. However, despite the fact that many viruses are transmitted sexually through the genital tract, the immune system of the male and female genital mucosae has received much less attention. Here, I describe and highlight differences in the innate and adaptive immune systems of the genital and intestinal mucosae, and discuss some of the challenges we face in the development of successful vaccines against sexually transmitted viral pathogens. PMID- 20829889 TI - Natural evolution from macular retinoschisis to full-thickness macular hole in highly myopic eyes. AB - PURPOSE: to evaluate the morphological changes that occurred during the development of a full-thickness macular hole (FTMH) from macular retinoschisis (MRS) in highly myopic eyes by optical coherence tomography (OCT). PATIENTS AND METHODS: the clinical characteristics and OCT images of five eyes of five patients with myopic MRS who developed FTMH during the follow-up period were evaluated. RESULTS: the natural evolution from MRS to FTMH was classified into two patterns by OCT findings. In FTMH formation pattern 1, a focal area of the external retinal layer was elevated and followed by the development of a small outer lamellar macular hole (OLMH) and retinal detachment (RD). The OLMH and RD were then enlarged horizontally and elevated vertically until the OLMH was attached to the overlying retinal layer. A FTMH finally developed when the roof of RD opened. In FTMH formation pattern 2, the opening of the roof of MRS or cystoid space caused an inner lamellar macular hole (ILMH). The MRS was then gradually resolved except the residual MRS beneath the ILMH, the ILMH would finally proceed into a FTMH as long as the remained external retinal layer beneath the ILMH continued splitting posteriorly until it reached retinal epithelium pigment. CONCLUSION: our longitudinal study revealed two patterns of FTMH formation in highly myopic eyes with MRS. This finding might be useful in further understanding the pathogenesis of macular hole formation in high myopia. PMID- 20829891 TI - Endoscope with optical sectioning capability. AB - The optical sectioning capability of a fiber-optic scanning microscope with a 9 cm-long gradient-index-rod lens probe has been demonstrated. A transverse resolution of 1.3 um and a longitudinal resolution of 30 um were achieved. The dimensions of the probe allow the device to be used as an endoscope. PMID- 20829892 TI - Multimode analysis of compound parabolic concentrators with flat absorber. AB - We introduce the concept of the reflection mode in the analysis of data generated by ray tracing for the study of the overall optical behavior of compound parabolic concentrators (CPC's) for beam radiation. The light ray paths in two classical CPC cavities with a flat absorber, full and truncated, were simulated by a system of two recurrent series derived for this purpose. The optical behavior of the cavities is summarized by two sets of functions, P(k)(theta(i)) and S(k)(a, theta(i)), each with an infinite number of terms, that depends on the incident angle theta(i) and on the aperture position a traversed by a light ray. These functions satisfy general properties of symmetry, inclusion, and convergence, either in the angular or in the spatial domains of the aperture and absorber. The use of those functions for calculating the angular acceptance, local and average optical efficiency, and flux density distribution is illustrated. Applications to the design of gaps are also discussed. Although this method of analysis is exemplified for the classical CPC's, the properties and applications of these functions are likely to extend to other types of nonimaging concentrators. PMID- 20829890 TI - Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a beta-galactosidase-activatable prodrug seco-analog of duocarmycin SA. AB - Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV 1h68 was used in combination with a beta-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of beta-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a beta-galactosidase activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV 1h68-treated GI-101A-xenografted mice. PMID- 20829893 TI - Surface-plasmon excitation using a polarization-preserving optical fiber and an index-matching fluid optical cell. AB - Existing experimental configurations to excite surface plasmons are reviewed, and a new experimental method for exciting surface plasmons is described. A transverse magnetic polarized wave is guided by a polarization-preserving optical fiber, collimated by a gradient-index lens, and launched into an optical cell filled with index-matching fluid. The wave is reflected off of a rotating mirror and excites a surface plasmon on a dielectric-metal interface by attenuated total reflection. The reflectance and incidence angles are measured simultaneously with a position-sensitive photodiode. The main advantages of this new method, compared with existing methods, are the low equipment costs and the ease with which a variety of surface-plasmon experiments can be performed. PMID- 20829894 TI - 400-ps time resolution with a passively quenched avalanche photodiode. AB - Avalanche photodiodes (APD's) operated in a single-photon-counting Geiger mode are becoming attractive alternatives to photomultiplier tubes for low-light-level detection and signal timing. By paying careful attention to the design and construction of a simple APD passive quenching circuit to reduce stray capacitances, we directly measured a time resolution of 410 ps FWHM for a commercial APD. A more detailed data analysis shows the actual time resolution to be ~ 390 ps FWHM. This is believed to be the most accurate time response for such a simple, inexpensive, and widely available device achieved to date. PMID- 20829895 TI - Diffraction characteristics of surface-relief gratings. AB - We present a theoretical and experimental study on the diffraction characteristics of gratings, with particular attention focused on the effects of polarization. The goal of our study is to develop multifunctional devices for use in a pickup head for optical storage systems. Experiments and numerical calculations are carried out systematically to determine the effects of the grating parameters of depth, period, and duty cycle and also the effects of the incident-wave parameters of incident angle, wavelength, and polarization. It is shown that, theoretically, the diffraction efficiency can reach 100% for both TE and TM polarizations that are incident at the Bragg angle. The simple dispersion characteristics of the Floquet modes are invoked to explain the different diffraction behaviors between the two polarizations. We conclude that a suitably designed grating may split an incident light beam of mixed polarizations into two beams of the opposite polarizations, each propagating in a different direction. Based on the numerical results, simple criteria are suggested for the design of the grating structures for both polarizing and nonpolarizing beam splitters. PMID- 20829896 TI - Laser beam collimation using Talbot interferometry. AB - A modified method of checking laser beam collimation by using Talbot interferometry coupled with a moir6 phenomenon is described. PMID- 20829897 TI - Reconstruction of refractive index fields by using relative fringe data. AB - Tomographic reconstruction techniques used to obtain three-dimensional refractive index fields from interferometric data all assume that the correct fringe number has been assigned. In confined fields or where the imaging beam is smaller than the object field, only relative fringe numbers can be determined from the interferogram because no reference (undisturbed) region is visible. An algorithm that can be applied to iterative reconstruction techniques is described that permits the quantitative reconstruction of three-dimensional fields by using only relative fringe numbers provided that a priori data are supplied. This method is applied to an existing reconstruction technique and is demonstrated by using simulated interferometric data. PMID- 20829898 TI - Measuring humidity with planar polyimide light guides. AB - Planar polyimide light guides can be used for optical detection of humidity. In a phase-matched guide a TE mode and a TM mode of different orders are influenced differently by a humid atmosphere. With crossed polarizers a phase shift induced by the moisture is detectable in the form of an oscillating output signal. For fully cured and thus well-defined and stable fluorinated polyimide light guides a sensitivity curve is presented for the humidity range of 10-75% relative humidity. A special sensitivity is obtained by using a four-layer waveguide arrangement with two layers of polyimide. The shift of the effective mode indices is also measured for each polarization by using a half-integrated interferometer. The results are interpreted in terms of a refractive-index increase that is due to water indiffusion and a swelling process for higher humidities. The measurement in the waveguide interferometer required a moisture-insensitive coating of the reference channel. This was achieved by the use of fluorinated polymers. PMID- 20829900 TI - GEMINI spectrograph optics. AB - In this paper the optical system design of one of the spectrograph instruments to be employed in the General Excitation Mechanisms in Nightglow project is described. The instrument has a high throughput with a numerical aperture equivalent to f/1.7 and covers the spectral range from 255 to 327.5 nm. A 3-deg line in the object space is imaged onto a two-dimensional intensified CCD array with spatial and spectral resolutions at least matching those of the detector. PMID- 20829899 TI - National Institute of Standards and Technology detector-based photometric scale. AB - The Systeme International base unit for photometry, the candela, has been realized by using absolute detectors rather than absolute sources. This change in method permits luminous intensity calibrations of standard lamps with an expanded uncertainty of 0.46%, almost a factor-of-2 improvement. A group of eight reference photometers has been constructed with silicon photodiodes, matched with filters to mimic the Commission Internationale de l'Eclairage spectral luminous efficiency function for photopic vision.The design, characterization, calibration, evaluation, and further application of the photometers are discussed. PMID- 20829901 TI - Focused-beam attenuated total-reflection technique on absorptive film in Kretschmann's configuration. AB - The conventional algorithm for obtaining the p-ray reflectance (R) of a metal in an attenuated total-reflection (ATR) experiment is to normalize the p-ray reflecting power of the metal (I(p)) with its s-ray reflecting power (I(s)). We found that for these ATR experiments in Kretschmann's configuration, two conditions will make I(s) less than I(p). In the first condition the film itself is absorptive; in the second the film is weakly absorptive but has thin thickness. When I(p) < I(p), the conventional algorithm is not applicable anymore; otherwise, the measured reflectance will be greater than one. With a modified focused-beam ATR experiment, we demonstrated that the above hindrance can be overcome by taking the intensity distribution of the incident p ray as the normalizing signal. The reflectance of the bare prism at incident angles greater than the critical angle is also suggested to be taken as a proper normalization factor. PMID- 20829902 TI - Resolution of two problems in the Fourier analysis of thin films. AB - The most common approaches to the application of the Fourier transform method to the synthesis of thin films suffer from two difficulties. The function of reflectance or transmittance to be transformed has been variously approximated, but none of the approximations has been recognized as giving accurate results for all cases. The transformed results for high-reflectance cases have what appear to be distortions in the frequency and in the amplitude scales. These problems and their solutions are the subjects of this paper. It is shown that the reflectance amplitude is the function that should be transformed and that the inclusion of multiple reflections eliminates the distortions in frequency and amplitude. PMID- 20829903 TI - Design of optical coatings for two widely separated spectral regions. AB - A systematic method for the design of antireflection coatings for two widely separated spectral regions has been previously described. This method, based on the buffer layer concept, has been extended to the design of optical coatings with virtually any spectral characteristics in the two regions. To demonstrate the principle, coatings with all possible combinations of the properties of antireflection coatings, neutral filters, reflectors, edge filters and narrow band filters in the visible and in the infrared spectral regions are presented. PMID- 20829904 TI - Technique for measuring the reflectance of irregular, submillimeter-sized samples. AB - Details are given of a technique for measuring the reflectance at near-normal incidence of small, irregular, submillimeter-sized samples from the far IR (40 cm(-1)) to the visible (40000 cm(-1)) between 10 and 300 K by using a modified Michelson interferometer or grating spectrometer. The sample and a reference mirror are mounted on nonreflecting cones. At the focus the size of the beam is larger than either the sample or the reference, so that the entire area of the sample is utilized. The positions are interchanged by a 90 degrees rotation by using preset mechanical stops. The scattering caused by geometrical effects is corrected for by the in situ evaporation of gold or aluminum onto the sample. The effect of diffraction is estimated from Mie theory by assuming the sample and reference to be spheres. For frequencies above ~ 40 cm(-1) and sample diameters of ~ 1 mm with a detector field of view of 30 degrees , the calculations show that the ratio of the backscattered intensities gives a good approximation of the specular reflectance. PMID- 20829905 TI - Comparison of the smoothing and shaping of optics by plasma-assisted chemical etching and ion milling using the surface evolution theory. AB - Plasma-assisted chemical etching (PACE) and ion milling (IM), originally developed for microelectronic fabrication, can now be used to shape or figure and smooth or polish optical and other surfaces with the unique advantage of doing so without mechanical contact. Using a recent theory of the temporal evolution of surfaces that is due to arbitrary additive or subtractive microscopic processes, the author critically compares the predicted and observed smoothing of PACE and IM in this paper to provide insight into their smoothing and other behavior. PACE removes > 10 mm(3)/min and smooths surfaces of considerable roughness (> 10-um rms). It has produced smoothed surfaces to < 1.0-nm rms without generating electronic subsurface damage. The IM removal rate is > 10(3) times slower, is used primarily for making corrections of less than a micrometer, intrinsically generates electronic subsurface damage, and furthermore requires starting with a smooth surface (~ 1.0 nm) to maintain smoothness. Both PACE and IM remove mechanical subsurface damage. In agreement with observation, it is shown theoretically that the central distinction between PACE and IM stems from substantial differences in their intrinsic smoothing. PMID- 20829906 TI - Combined approach to the Hubble Space Telescope wave-front distortion analysis. AB - Stellar images taken by the Hubble Space Telescope at various focus positions have been analyzed to estimate wave-front distortion. Rather than using a single algorithm, we found that better results were obtained by combining the advantages of various algorithms. For the planetary camera, the most accurate algorithms consistently gave a spherical aberration of -0.290-um rms with a maximum deviation of 0.005 um. Evidence was found that the spherical aberration is essentially produced by the primary mirror. The illumination in the telescope pupil plane was reconstructed and evidence was found for a slight camera misalignment. PMID- 20829907 TI - Diffuser speckle model: application to multiple moving diffusers. AB - A simple model for the scattering of coherent light through diffusers has been applied to a moving diffuser despeckler in order to estimate the scattering angles, speckle decorrelation length, and interaction between multiple diffusers. A Gaussian model for the diffuser thickness variations has been used to derive a relation between the scattering cone of a diffuser and its decorrelation properties. This model is equivalent to a randomized array of lenslets. The lenslet's thickness and diameter correspond to the characteristic heights and widths of the diffuser roughness. This model predicts that a decrease in the decorrelation distance for two closely spaced counterrotating diffusers is accompanied by an increase in their scattering cone. Simulation and experimental measurements have been used to verify the predictions of this model. Significant speckle decorrelation has been demonstrated for a nanosecondpulsed laser source by using moderate diffuser rotation speeds. PMID- 20829908 TI - Optimum color filters for CCD digital cameras. AB - A procedure for the definition of optimum spectral transmission curves for any solid-state (especially silicon-based CCD) color camera is presented. The design of the target curves is based on computer simulation of the camera system and on the use of test colors with known spectral reflectances. Color errors are measured in a uniform color space (CIELUV) and by application of the Commission Internationale de l'Eclairage color difference formula. Dielectric filter stacks were designed by simulated thermal annealing, and a stripe filter pattern was fabricated with transmission properties close to the specifications. Optimization of the color transformation minimizes the residual average color error and an average color error of ~1 just noticeable difference should be feasible. This means that color differences on a side-to-side comparison of original and reproduced color are practically imperceptible. In addition, electrical cross talk within the solid-state imager can be compensated by adapting the color matrixing coefficients. The theoretical findings of this work were employed for the design and fabrication of a high-resolution digital CCD color camera with high calorimetric accuracy. PMID- 20829909 TI - Analytical modeling of the interfacial shearing stress in dual-coated optical fiber specimens subjected to tension. AB - A simple analytical model is developed for the evaluation of interfacial shearing stress at the glass fiber surface in dual-coated optical fiber specimens subjected to tension. The analysis has been performed for pull-out testing and in situ evaluation of Young's (shear) modulus of the primary coating material and is aimed at assessment of the effect of the materials properties and the specimen's geometry on the magnitude and distribution of interfacial shearing stress. It is shown that the longitudinal distribution of this stress is nonuniform and that, for the given specimen's length, its maximum value increases with a decrease in the thickness of the primary coating. It is concluded that, while currently used 1-cm-long specimens with approximately 30-um-thick primary coatings are acceptable, shorter specimens (say, 5 mm long) are expected to result in more stable experimental data. The results obtained can be useful for comparing the adhesive strength of the primary coating material in fibers of different lengths and with different coating designs, as well as for the evaluation of Young's (shear) modulus of this material from the measured axial displacement of the glass fiber. PMID- 20829910 TI - Temporal phase-unwrapping algorithm for automated interferogram analysis. AB - A new algorithm is proposed for unwrapping interferometric phase maps. Existing algorithms search the two-dimensional spatial domain for 2pi discontinuities: only one phase map is required, but phase errors can propagate outward from regions of high noise, corrupting the rest of the image. An alternative approach based on one-dimensional unwrapping along the time axis is proposed. It is applicable to an important subclass of interferometry applications, in which a sequence of incremental phase maps can be obtained leading up to the final phase difference map of interest. A particular example is quasi-static deformation analysis. The main advantages are (i) it is inherently simple, (ii) phase errors are constrained within the high-noise regions, and (iii) phase maps containing global discontinuities are unwrapped correctly, provided the positions of the discontinuities remain fixed with time. The possibility of real-time phase unwrapping is also discussed. PMID- 20829911 TI - Iterative processing on a hybrid optical parallel array logic system with a selectable coherent correlator. AB - A new version of an experimental system of an optoelectronic hybrid optical parallel array logic system is constructed. The experimental system is composed of a two-dimensional correlator with selectable holographic filters and parallel electronic circuits. The system can process images consisting of 3 * 3 pixels at a time. Several types of processing are achieved both without and with dynamic selection of the holographic filters. On the experimental system, parallel operations of several logical functions and data transmission are demonstrated. Processing rates of iterative operation without and with filter selection are 278 and 143 frames/s, respectively. PMID- 20829912 TI - Triple and autocorrelation functions from factorial moments measured. AB - This research establishes a clear relation between the autocorrelation (AC) and triple-correlation (TC) functions of a signal and its second- and third-order factorial moments (FM's). Theoretical expressions of the variances corresponding to the AC and TC obtained from the measurement of FM's is developed for low-light level conditions. Experimental values corresponding to direct AC measurements were also compared with those obtained from the FM measurement. The conclusion is that the measurement of FM's may be an alternative to AC and TC measurements. PMID- 20829913 TI - Integrating mode for an optically addressed spatial light modulator. AB - We describe the integrating-mode operation of an optically addressed spatial light modulator that incorporates a ferroelectric liquid-crystal light-modulating layer and an amorphous-silicon photodiode. This mode of operation uses a higher drive frequency and produces a readout response that extends over several driving periods, thereby permitting cw operation. The response characteristics of the device can be adjusted by varying the amplitude and offset of the applied voltage. Spatial resolution of 40 line pairs/mm, response times of 1 ms, and contrast ratios of 30:1 were achieved in this mode. We compare the integrating mode of operation with our standard reset mode of operation, whereby the electrical driving frequency is sufficiently low that the liquid crystal can respond fully to the voltage level during each part of the drive, and the device is reset fully to its off state during the forward-bias part of each electrical bias period. PMID- 20829914 TI - Ultraviolet spectrally responsive holograms in dichromated gelatin. AB - A method for making ultraviolet-responsive holograms in dichromated gelatin by using the 488-nm radiation from an argon laser is presented. We obtain the main shift toward short wavelengths by swelling the gelatin layer in a high-humidity atmosphere before exposure, and we adjust the final reconstruction wavelength (355 nm) by controlled heating of the holograms. These holograms, which exhibit the high performance of dichromated-gelatin holograms, are quite uniform compared with those made with other swelling agents. The swelling effects are discussed, and some procedures for improving efficiency are given. PMID- 20829915 TI - Enhanced optical modulation using azo-dye polymers. AB - The performance of the conventional azo-dye polymer modulation system is compared with that of the recently developed attenuated-total-reflection (ATR) dye-polymer modulation techniques. Experiments based on Fabry-Perot resonance shifting in ATR geometry indicate that the modulation parameters, namely, speed, contrast, and efficiency, are enhanced. Although the dye-polymer response still remains fairly slow, ATR methods provide substantial improvement over the existing system. An all-optic long-range surface-plasmon azo-dye polymer modulation system is also proposed. Computer simulation of the reflectance and the photoinduced resonance shifting suggest that the proposed system can be used effectively for all-optic modulation. Some of the limitations of both systems and a pratical application of the ATR modulation methods are discussed. PMID- 20829916 TI - Acousto-optic supermultispectral imaging. AB - An assumption of supermultispectral imaging is presented. The focal point is to encode an object between spatial and spectral information with a tunable bandpass filter, which is called the spatial-spectral encoder. Theoretical and experimental results have verified that the assumption is correct. A supermultispectral imaging system that uses an acousto-optic tunable filter as the encoder was based on the assumption. Approximately 5 nm of spectral resolution with 10 degrees * 10 degrees of the two-dimensional instant field of view was obtained in the visible range. The most fascinating features may be that the spectral resolution is insensitive to the field of view and effective optical aperture and that the system has no mechanical moving parts. PMID- 20829917 TI - MOSAIC: a space-multiplexing technique for optical processing of large images. AB - A technique for Fourier processing of images larger than the space-bandwidth products of conventional or smart spatial light modulators and two-dimensional detector arrays is described. The technique involves a spatial combination of subimages displayed on individual spatial light modulators to form a phase coherent image, which is subsequently processed with Fourier optical techniques. Because of the technique's similarity with the mosaic technique used in art, the processor used is termed an optical MOSAIC processor. The phase accuracy requirements of this system were studied by computer simulation. It was found that phase errors of less than lambda/8 did not degrade the performance of the system and that the system was relatively insensitive to amplitude nonuniformities. Several schemes for implementing the subimage combination are described. Initial experimental results demonstrating the validity of the mosaic concept are also presented. PMID- 20829918 TI - Two-dimensional image reconstruction from Fourier coefficients computed directly from zero crossings. AB - Two-dimensional image reconstruction using Fourier coefficients that are computed directly from the sampled representation of zero crossings is demonstrated. A two dimensional image of dimensions N(x) * N(y) is interpreted as a set of N(y) independent x-space lines (in gray-scale format) that are arranged uniquely along the y direction. Each line has N(x) elements. Reconstruction is achieved first by computing the entire set of N(y) one-dimensional Fourier transforms from the measured zero crossings using Newton's formula. Each N(y)th line spectra has N(x) Fourier coefficients. The inverse Fourier transform is then applied to each of the line spectra to obtain a set of N(y) reconstructed x-space lines. The reconstructed image is obtained by arranging the reconstructed lines properly along they direction. PMID- 20829919 TI - Optical correlator using very-large-scale integrated circuit/ferroelectric-liquid crystal electrically addressed spatial light modulators. AB - The use of 2-kHz 64 * 64 very-large-scale integrated circuit/ferroelectric-liquid crystal electrically addressed spatial light modulators as the input and filter planes of a VanderLugt-type optical correlator is discussed. Liquid-crystal layer thickness variations that are present in the devices are analyzed, and the effects on correlator performance are investigated through computer simulations. Experimental results from the very-large-scale-integrated/ferroelectric-liquid crystal optical-correlator system are presented and are consistent with the level of performance predicted by the simulations. PMID- 20829920 TI - Preprocessed multiobject joint transform correlator. AB - The performance of a joint transform correlator (JTC) in a multiobject environment is improved by the use of a Roberts operator to preprocess the input joint image. This technique yields significantly better results than the classical JTC, and it also avoids the false alarms and reduces the overall computation overhead required in a binary JTC. PMID- 20829921 TI - Performance analysis of optical shadow-casting correlators. AB - We analyze the performance of two optical shadow-casting image correlators that use two-dimensional source arrays to encode the system point-spread function (PSF). The analysis of a standard shadowcasting correlator suggests that the angular divergence of the source array is a critical parameter in the determination of the maximum space-bandwidth product of the image and of the PSF that can be used with such a system. Further, the energy efficiency of a standard shadow-casting correlator is related inversely to the size of the PSF. We show that the constraints on energy efficiency and on the space-bandwidth product of the PSF can be overcome by beam steering the source elements. A modified shadow casting correlator is proposed that uses phase-only blazed gratings to beam steer the sources. Experimental results generated by a mechanically beam-steered array are presented. PMID- 20829922 TI - Shift-invariant photorefractive joint-transform correlator using Fe:LiNbO(3). crystal plates. AB - We report the results of our experimental investigation on a shift-invariant photorefractive image correlator that uses a thin crystal plate of Fe:LiNbO(3), which operates in the Raman-Nath regime of diffraction. PMID- 20829923 TI - Fast design of circular-harmonic filters using simulated annealing. AB - A new method is presented for determining the proper center of the circular harmonic filter using an analytical expression for circular-harmonic expansion about an arbitrary center and simulated annealing for the automatic search of the maximum. The new method is two orders of magnitude faster than the previous method. PMID- 20829924 TI - Iterative interlacing error diffusion for synthesis of computer-generated holograms. AB - The iterative interlacing error-diffusion technique is a combination of the error diffusion and the modified iterative interlacing techniques for synthesizing computer-generated holograms. The iterative interlacing error-diffusion technique leads to a dramatic improvement in the quality of reconstructed images, provided that the two constant parameters involved in iterations are chosen properly. PMID- 20829925 TI - Complex-valued error diffusion for off-axis computer-generated holograms. AB - Error diffusion has been proven to be a valuable tool in the calculation of computer-generated holograms. Real-valued error diffusion has been used to calculate the transmission functions for real-valued holograms with off-axis reconstructions. We demonstrate the use of a complex-valued error-diffusion algorithm on real-valued hologram data in order to achieve larger flexibility in the shaping of the noise spectrum. PMID- 20829926 TI - Multif requency three-dimensional optical read-only memory disks using metallic island films: preliminary experiments. AB - Basic operation of new multifrequency three-dimensional (3-D) optical read-only memory (ROM) disks has been demonstrated experimentally. Several types of metallic island film exhibiting a selectiveresonance absorption in a visible-near infrared region are used as recording layers on the 3-D disks. The monochromatic light with a suitable wavelength near the resonance wavelength of each layer is used for the readout of information. We demonstrate that bar-code patterns recorded in silver and copper island layers can be read by using transmitted or reflected light. Furthermore, we also show that the 3-D disks with >=3 recording layers can be realized. PMID- 20829927 TI - Heterodyne detection using a diffraction-free beam: background-noise effects. AB - The effect of using a diffraction-free beam in heterodyne detection in the presence of background noise is investigated. The theoretical model developed is then extended to include the effects of tilt and offset. The maximum tolerable background noise is identified for specific values of tilt and offset. PMID- 20829928 TI - Use of biphase-coded pulses for wideband data storage in time-domain optical memories. AB - We demonstrate that temporally long laser pulses with appropriate phase modulation can replace either temporally brief or frequency-chirped pulses in a time-domain optical memory to store and retrieve information. A 1.65-us-long write pulse was biphase modulated according to the 13-bit Barker code for storing multiple bits of optical data into a Pr(3+):YAlO(3) crystal, and the stored information was later recalled faithfully by using a read pulse that was identical to the write pulse. Our results further show that the stored data cannot be retrieved faithfully if mismatched write and read pulses are used. This finding opens up the possibility of designing encrypted optical memories for secure data storage. PMID- 20829929 TI - Parallel processing system for rapid analysis of speckle-photography and particle image-velocimetry data. AB - An automated system has been constructed to process double-exposure speckle photography and particle-image-velocimetry images. A 3 * 3 array of laser beams probes the photograph, forming nine fringe patterns in parallel; these are then analyzed sequentially by digital computer and the use of a two-dimensional Fourier-transform method. Results are presented showing that the random errors in the measured displacements from such a system approach the expected speckle-noise limited performance, with a total analysis time per displacement vector of 160 ms. PMID- 20829930 TI - Nasa patter. PMID- 20829931 TI - Accounting for absorption saturatio effects in pulsed infrared laser-excited photothermal spectroscopy. AB - Equations that relate photothermal lens focal lengths and photothermal deflection angles to saturation absorption coefficients are derived. These equations are derived for two-level absorbers with both homogeneously and inhomogeneously broadened transitions. Initial and time-dependent photothermal lens signals are calculated. Equations describing the zero-time signals are exact to within the simplifying assumptions of the derivation, while the time-dependent signals are approximate. The approximation is performed by the use of a finite series of Gaussian functions to model the temperature change profile distorted by nonlinear absorption. The excitation irradiance-dependent signal behavior for rectangular and exponential excitation pulse time profiles for homogeneously and inhomogeneously broadened transitions are compared. Absorbed energies are used to calculate effective absorbances obtained by the use of conventional and photothermal lensing spectrometry. The conclusions drawn from these comparisons are tha pulsed laser photothermal spectroscopy is sensitive to the excitationlaser's pulse temporal profile and the transition broadening mechanism. PMID- 20829932 TI - Degenerated confocal resonato. AB - The properties of confocal resonators with g(1) = g(2) = 0 and with one mirror confined by an aperture were investigated both theoretically and experimentally. The fundamental mode operation with complete filling of the medium, which ds located near the unconfined mirror, can always be obtained by an appropriate choice of the aperture radius. Numerical calculations based on Fresnel integrals, including the amplification of the gain medium, provide a detailed understanding of the resonator properties, with guidelines for an optimum resonator performance. Diffraction loss, mode structure, beam quality, extraction efficiency, and misalignment sensitivity of these resonators are measured with a pulsed Nd:YAG laser in a single-shot operation. PMID- 20829933 TI - Optical and mechanical properties of single-crystal sapphire optical fibers. AB - Single-crystal sapphire fibers are produced by the laser heated pedestal growth technique. The fibers have attenuation coefficients of less than 2 dB/m at the Er:YAG laser wavelength of 2.94 um and are used to deliver over 600 mJ of Er:YAG laser energy. Mechanical testing of these fibers and the sapphire fibers produced by the edge-defined, film-fed growth technique results in a measured 0.4% strain to failure when testing is done under a 4-point load. Teflon-FEP (perfluorinated ethylene propylene) is applied to sapphire fibers as a cladding. The cladding is extremely effective in preventing leakage of energy from the fibers into absorbing environments that may surround the fiber. PMID- 20829934 TI - 1.06-um absorption caused by stable color centers in flash-lamp-pumped Nd:YAG laser rods. AB - The absorption losses for 1.06-um laser radiation in Nd:YAG laser rods that are due to stable color centers are investigated. Stable color centers are created by a two-photon absorption process caused by theultraviolet part of the Xe flash lamp spectrum. The reverse process of color center annihilation that is due to a one-photon bleaching process is observed. A model explaining these processes is proposed, and rate equations describing the creation and the annihilation of color centers are developed. PMID- 20829935 TI - Simple method for eliminating the warming-up time of an Antares cw mode-locked Nd:YLF laser. AB - Mode locking of a cw Nd:YLF laser is sensitive to cavity-length mismatch. When a cw mode-locked Nd:YLF laser is turned on the power dissipation from the lamps causes a slow change in the cavity length because of heating of mechanical resonator parts. A method is presented to eliminate these warming-up effects. PMID- 20829936 TI - Spatial optical beam steerin with an AlGaAs integrated phased array. AB - A passive spatial light beam deflector based on a channel waveguide phased-array concept is presented. Diffraction gratings patterned by electron-beam lithography couple light into and out of the device. Phasing is achieved electro-optically with indium tin oxide/AlGaAs Shottky junctions. Discrete beam steering is first demonstrated with a 43-element rib waveguide array at an 850-nm wavelength. A sawtooth electrode keeps the device length short and the electrode surface small. Continuous deflection over a +/-7.2 mrad range at a 900-nm wavelength is then reported. A set of seven sawtooth and offset electrodes permits addressing any point within this range. The beam has a width of 1.5 mrad, and the maximum modulation voltage is -8.5 V. PMID- 20829937 TI - Laser to single-mode fiber coupling in the laboratory. AB - All the information necessary to achieve reasonably efficient coupling of semiconductor lasers to single-mode fibers is collected from the literature, derived when necessary, and presented in mainly tabular form. Formulas for determining the laser beam waist radius and the fiber-mode radius are given. Imaging relations connecting these values with the object and the image distances, including thick-lens correction factors, are given for three types of lenses: ball, hemisphere, and graded index. Sources for these lenses are indicated, and a discussion is also given about ways of reducing feedback effects and about the use of wedge-ended fibers. PMID- 20829938 TI - Predicted stresses and strains in fused biconical taper couplers subjected to tension. AB - In fused biconical taper (FBT) couplers, the cores of the fibers are positioned close to each other. In order to bring the cores of the fibers in close proximity, the cladding in the fused midportion of the coupler has to be made thin. At the same time the coupler must be sufficiently strong, both on a short- and a long-time scale, and must be able to withstand appreciable axial deformations. These can be caused by the thermal contraction mismatch of the coupler with its substrate or can be due to a deliberate prestressing of the coupler structure in order to improve its dynamic stability. In this study an easy-to-apply analytical stress model is developed for the evaluation of stresses and strains in FBT couplers from the expected or measured total elongation. In the analysis the nonprismaticity of the coupler structure as well as the nonlinear behavior of the material was considered. The numerical example has been carried out for a coupler that is intended for undersea applications. The results obtained can be used in the stress-strain analyses and physical design of light wave FBT couplers. PMID- 20829939 TI - Minimization of the chromatic dispersion over a broad wavelength range in a single-mode optical fiber. AB - The effective refractive index as a function of vacuum wavelength is approximated by Lagrange interpolation polynomials. The rms value of the chromatic dispersion is then calculated analytically. Itis demonstrated that use of fourth-degree polynomials is far more efficient than the use of second-degree polynomials. The rms value of the chromatic dispersion over the wavelength range (1.25 um, 1.60 um) is calculated and minimized for step-index fibers, triangular index fibers, and alpha-power fibers. The full vector solution of Maxwell's equations is used. The error induced by the approximate refractive-indexmodel is found to be negligible at the point of minimum dispersion. PMID- 20829940 TI - Fabrication of low-loss integrated optical corner mirrors. AB - Waveguides and corner mirrors are fabricated in InGaAsP/lnP. Properly aligned mirrors have a loss of 0.8 dB per reflection. This result is obtained by improved waveguide and mirror quality (surface roughness). Measured additional losses that are due to misalignment agree well with calculated values when a simple transformation method is used. PMID- 20829941 TI - Inversion of lidar signals with the slope method. AB - In homogeneous atmospheres, backscatter and extinction coefficients are commonly determined by the inversion of lidar signals by using the slope method, i.e., from a linear least-squares fit to the logarithm on the range-compensated lidar return. We investigate the accuracy of this method. A quantitative analysis is presented of the influence of white noise and atmospheric extinction on the accuracy of the slope method and on the maximum range of lidar systems. To meet this objective, we simulate lidar signals with extinction coefficients ranging from 10(-3) km(-1) to 10 km(-1) with different signal-to-noise ratios. It is shown that the backscatter coefficient can be determined by using the slope method with an ccuracy of better than ~ 10% if the extinction coefficient is smaller than 1 km(-1) and the signal-to-noise ratio is better than ~ 1000. The accuracy in the calculated extinction coefficient is only better than ~ 10% if the extinction is larger than 1 km(-1) and the signal-to-noise ratio is better than ~2000. If th atmospheric extinction coefficient is smaller than 0.1 km(-1), then it is not possible to invert the extinction from lidar measurements with an accuracy of 10% or better unless the signal-to-noise ratio isunrealistically high. PMID- 20829942 TI - Effect of nonuniform spectral dome transmittance on the accuracy of infrared radiation measurements using shielded pyrradiometers and pyrgeometers. AB - We discuss the problem arising from the nonuniform distribution of spectral transmittance of the instrument's shielding dome. Recently, by using high resolution atmospheric radiation software, itbecame possible to evaluate both the real downward IR spectral flux density and the transmitted spectral flux density of the instrument's dome. By using a simplified model we obtained a theoretical formula that describes the effect of dome transmittance on the instrument's response. By the formula, the effective dome transmittance (average dome transmittance weighted by the spectral flux density) is directly proportional to the calibration constant of the instrument. In order to obtain a quantitative relationship we computed the effective dome transmittance for several domes and model atmospheres. ccording to our results the maximum difference in effective dome transmittance of individual domes is 20% for Eppley-type silicon domes and 10% for polyethylene domes. These relatively large differencesmust be corrected when the domes are replaced. The effective dome transmittance shows strongcorrelation with precipitable water and the total downward IR flux density. The combined effect on thecalibration factor is a maximum 2% for the Eppley domes and 5% for the polyethylene domes. By usingthe linear regression method these types of error can be minimized. PMID- 20829943 TI - Multiangle lidar performance in the presence of horizontal inhomogeneities in atmospheric extinction and scattering. AB - The performance of single-ended multiangle lidar for measurements of atmospheric extinction andbackscattering is analyzed in the presence of shot noise. An algorithm for determining the transmission coefficient in the presence of horizontal inhomogeneities is described. The analysis indicates that real-time measurements of atmospheric properties with the multiangle lidar may be feasible even ininhomogeneous regions. PMID- 20829944 TI - Measurement of the spectral absorption coefficient in the ocean with an isotropic source. AB - Closed-form equations that describe the vector irradiance from an isotropic source embedded in the oceanare rigorously derived from the steady-state radiative transfer equation. The equations are exact for a homogeneous medium and are believed to be an excellent approximation along the vertical axis for a plane parallel ocean. The equations are solved for the absorption coefficient as a function of distance from the source. For clear ocean water, it is shown that vector irradiance measurements alone provide sufficient information for an accurate calculation of the absorption coefficient. Measurements in Pacificwater of the vector irradiance from an isotropic source are presented, and the absorption coefficient is computed. The estimated value of the absorption coefficient from a linear least-squares fit to the data has a standard error of ~ 1%. PMID- 20829945 TI - Fast computational scheme for inverse modelinb of multispectral radiances: application for remote sensing of the ocean. AB - In a variety of remote sensing applications inverse modeling is used to retrieve parameters of ourenvironment from measurements of the radiance spectrum. As the dimensionality of the data increaseswith the number of spectral channels or as models become more complicated, inverse modeling becomes expensive in terms of computing time. We describe a technique to parameterize a given inverse model, which reduces the necessary computing time by orders of magnitude. An example that uses simulated data of SeaWiFS, an advanced ocean color sensor to be launched in 1993, is given, whereby the concentrations of suspended matter, phytoplankton, and gelbstoff (yellow substance) in water are determined. PMID- 20829946 TI - Scattering of a light beam from waves at an air-sea interface. AB - The authors report a new theory that describes the scattering of an upward propagating laser beam from the sea through the air-sea interface in the presence of sea waves. The sea is assumed to be a uniform dielectric and conventional scattering theory is employed by using a modification to the first Born approximation that permits treatment of surface refraction phenomena. Methods of statistical radiometry are also used in a new manner by assuming that the surface scattering function for the sea waves can be treated by a quasi-homogeneous source model to calculate the second-order correlation functions for the partially coherent scattered field. These correlation functions yield a simple expression for the radiant intensity of the scattered field as the convolution of the Fourier transform of the complex degree of spectral coherence for the sea waves with the squared modulus of the angular spectrum of plane waves for the incident laser beam. We believe that this theory is a significant improvement over the models that are usually used for modeling this phenomenon. PMID- 20829947 TI - Temperature and size of single transparent droplets by light scattering in the forward and rainbow regions. AB - A light-scattering anaysis based on Lorenz-Mie theory shows that the size and refractive index of transparent droplets can be determined by measuring the polarized components of the scattered light at two angles in the forward direction. The horizontally polarized cross section C(HH)(33 degrees ) depends exclusively on the droplet diameter, whereas the ratio C(HH)(33 degrees )/C(HH)(60 degrees ) is a sensitive function of the refractive index and hence of the temperature. On this basis, a new optical system for measuring the temperature, size, and velocity of transparent droplets has been developed. This system can make possible the determination of droplet temperature within a few degrees centigrade. In addition, a critical review of the rainbow method to determine droplet temperature is also presented. These techniques have been applied to vaporizing tetradecane droplets (D(0) = 72 um), which are heated up in a tube furnace with a temperature range of 20 degrees -200 degrees C. PMID- 20829948 TI - Scattering by two spheres in contact: comparisons between discrete-dipole approximation and modal analysis. AB - This paper applies two different techniques to the problem of scattering by two spheres in contact: modal analysis, which is an exact method, and the discrete dipole approximation (DDA). Good agreement is obtained, which further demonstrates the utility of the DDA to scattering problems for irregular particles. The choice of the DDA polarizability scheme is discussed in detail. We show that the lattice dispersion relation provides excellent improvement over the Clausius-Mossoti polarizability parameterization. PMID- 20829949 TI - Determination of volume and surface contributionsto the total attenuation in ZnS waveguides. AB - We relate the modal waveguide attenuation of polycrystalline ZnS films to their mode field properties, namely the field amplitudes at the interfaces and the power confinement factor, to show that the totalwaveguide attenuation is caused by a combination of volume and surface effects. Our results show that the surface losses for the TE(0) mode, which are approximately 1.5 dB/cm, are independent of the total attenuation, which varies from 6 to 40 dB/cm. This suggests that the losses of the lower-order modes are dominated by volume effects such as scattering from crystallite boundaries and absorption. PMID- 20829950 TI - Patents. AB - 5,090,400; 5,090,400; 5,108,172; 5,111,343; 5,113,284; 5,116,121; 5,116,126; 5,119,679; 5,120,128; 5,120,130; 5,120,133; 5,120,961; 5,123,730; 5,129,718; 5,129,724; 5,131,747; 5,136,164; 5,137,348; 5,138,159; 5,141,312; 5,142,403; 5,142,418; 5,144,356; 5,144,477. PMID- 20829951 TI - Surface roughness and scattering: papers from the first topical meeting. AB - This is an introduction to the feature on surface roughness and scattering. PMID- 20829953 TI - Specification of surface figure and finish in terms of system performance. AB - We describe methods of predicting the degradation of the performance of a simple imaging system in terms of the statistics of the shape errors of the focusing element and, conversely, of specifying those statistics in terms of requirements on image quality. Results are illustrated for normal-incidence, x-ray mirrors with figure errors plus conventional and/or fractal finish errors. It is emphasized that the imaging properties of a surface with fractal errors are well behaved even though fractal-power spectra diverge at low spatial frequencies. PMID- 20829952 TI - Enhanced backscattering of light from weakly rough, random metal surfaces. AB - The enhanced backscattering of p-polarized light from a small-rms-height, small rms-slope, onedimensional, random metal surface was first predicted on the basis of an infinite-order perturbation calculation that used the techniques of many body theory and the concepts of weak localization theory. We present an elementary calculation of the contribution to the mean differential reflection coefficient from the incoherent component of the scattered light that is based on the first two nonzero terms in the expansion of this function in powers of the surface-profile function. We show that this approach not only accounts for enhanced backscattering but also gives the correct order of magnitude of the effect predicted by infinite-order perturbation theory. PMID- 20829954 TI - Random rough surfaces: numerical study of localized electromagnetic surface modes. AB - We show numerically that surface modes are associated with poles of the scattering operator in the complex plane of wavelengths, which permits one to excite a mode strongly in such a way that the amplitudes of the incident wave and of the waves scattered in the air are negligible. Then the shape of the surface mode clearly appears, and localization effects are well isolated. The influence of Bragg resonances on the location of the poles of the scattering operator in the complex plane was studied. PMID- 20829955 TI - Wavelength and angular dependence of light scattering from beryllium: comparison of theory and experiment. AB - The purpose of this study was (1) to measure angle-resolved scattering (ARS) and the wavelength dependence of scattering from polished and sputtered beryllium, (2) to measure surface-roughness parameters by profilometry, (3) to calculate the power spectral density (PSD) of the surface roughness and use it with ARS theory to compare with ARS measurements, and (4) to investigate a dual-source scattering theory and compare calculations from the theory with measured ARS. The wavelengths considered here were 0.633, 1.06, and 10.6 um, the angle of incidence was 60 degrees , and s and p polarization of the incident and scattered radiation were taken into account both in the theory and in the experiments.Two types of theoretical comparison were attempted. First, two-dimensional PSD functions were calculated from one-dimensional, mechanical-stylus-profile data, and these data were used in first-order roughness ARS theory to compare with ARS measurements. The calculated ARS curves were much too low at some wavelengths and showe incorrect wavelength scaling. Second, a dual-source (surfaceroughness and dielectric inhomogeneity) ARS theory was used. In this model the surface roughness PSD functions calculated from surface-profile data were used, and reasonable values for parameters characterizing the dielectric inhomogeneities were used in an analytic PSD function. This dual-source ARS theory can predict a significantly different angle and wavelength dependence of ARS than that predicted by roughness-only ARS theory. In contrast to ARS predicted by surface roughness alone, it was found that the dual-source theory was able to provide good agreement with measured ARS in angular and wavelength dependence. It is concluded that, for the two beryllium samples studied here, scattering caused by spatial variations in the near-surface dielectric response (variations in reflectance) is a significant and sometimes dominant source of scattering, especially at a 10.6-uim wavelength. PMID- 20829956 TI - Light scatter from polysilicon and aluminum surfaces and comparison with surface roughness statistics by atomic force microscopy. AB - Optical-scatter measurements from polysilicon and aluminum surfaces were performed by using 632.8-nm illumination at 45 deg and 488-nm illumination at 76.8 deg. Scatter was recorded up to 60 deg from the specular beam by using a concentric ring photodetector. The results are compared with surface statistics derived from atomic force microscopy. Quantitative predictions of the scatter were derived from power spectral density curves and angle-resolved-scattering theory. The agreement was fair for polysilicon samples with rms surface roughnesses of ~18 and 42 nm and aluminum with 17-nm rms roughness but poor for other samples. The discrepancy is attributed primarily to internal scatter within the measuring instrument. PMID- 20829957 TI - Regimes of surface roughness measurable with light scattering. AB - In this paper we summarize a number of previous experiments on the measurement of the roughness of metallic surfaces by light scattering. We identify several regimes that permit measurement of different surface parameters and functions, and we establish approximate limits for each regime. Using a straightforward criterion, we calculate that the smooth-surface regime, in which the angular distribution of scattered light is closely related to the power spectral density of the roughness, ranges over 0 < sigma/lambda ? 0.05, where sigma is the rms roughness and lambda is the opitcal wavelength. Above that the surfaceautocorrelation function may be calculated from a Fourier transform of the angular distribution over 0 < sigma/lambda ? 0.14. Then comes the specular regime where the specular beam can still be identified andmeasured over 0 < sigma/lambda ? 0.3. For all these regimes and for rougher surfaces too, the rms width of thescatter distribution is proportional to the rms slope of the surface. PMID- 20829958 TI - Correlation between substrate preparation technique and scatter observed from optical coatings. AB - We present experimental evidence of the dependence of coating scatter on a substrate preparation technique for fused silica substrates. Samples included conventionally polished, superpolished, andfloat-polished substrates. We used scatterometry and total internal reflection microscopy to investigate the effects of substrate preparation on the performance of zirconium oxide thin films. Results indicate that scatter from coatings dominates the scatter signature of the coated optic. They also demonstrate that substrate preparation can affect the level of scatter produced in optical coatings. In addition it is observed that the substrates with the lowest scatter do not necessarily result in the coatings with the lowest scatter. PMID- 20829959 TI - Teflon laps: some new developments and results. AB - The process of superpolishing with Teflon laps has enabled supersmooth [< 0.1 nm rms] and extremely flat (lambda/100) optical surfaces to be produced on a large range of amorphous and crystalline optical materials. Stable surface conditions and the very low wear of a Teflon lap during polishing provide an opportunity to examine the effects of varying different polishing parameters. These include sample-tolap mismatch and the influence of different polishing compounds and fluid chemistry. The results show that when large optical flats are superpolished with Teflon laps, microroughness, subsurface damage, and scattering can be minimized and reliably and consistently predicted for a wide variety of optical materials, while extremely flat surfaces are simultaneously achieved. PMID- 20829960 TI - Correlation of light-scattering measurement and visual ranking of optical surfaces. AB - Visual ranking of optical surfaces with a Nomarski differential interference contrast microscope correlates well with a modified fractallike dimension and the average intensity of their scattered light ield. PMID- 20829961 TI - Ultrasonic measurements of surface roughness. AB - Pulsed ultrasound propagating in water was used at megahertz carrier frequencies (nominally 10-50MHz) to reflect and scatter from rough surfaces in the same way as light. We have considered noncontact ultrasonic techniques as complementary to optical techniques in several ways: (a) for specificapplications such as wet surfaces, (b) for rougher surfaces with average roughness, R(a) >= 0.1 um, and (c) for (simultaneous) profilometry by time-of-flight measurements. Stylus and ultrasonic data are compared. An example of application to the manufacturing environment is for on-line, real-time sensor feedback and process control in the cutting or grinding of metals and ceramics. PMID- 20829962 TI - Interferometric profiler for rough surfaces. AB - Conventional interferometric methods of surface profiling are limited in the magnitude of surface height that can be accurately measured because of phase ambiguity errors on steep local slopes. Other optical methods that have been developed for surface profiling frequency suffer from poor height resolution and low measurement speed for three-dimensional profiles. Contact profilometers such as stylus-based instruments suffer from slow measurement speed, especially when three-dimensional profiles of the surface are required. Stylus tips can also scratch delicate surfaces duringthe course ofthe measurement. A new method of optical, noncontact profiling of rough surfaces is described that utilizes interferometric techniques as well as digital signal-processing algorithms to produce fast, accurate, and repeatable three-dimensional surface profile measurements. PMID- 20829963 TI - Recent developments in profiling optical surfaces. AB - To understand better the fabrication of optical surfaces and to be able to produce smoother, lower-scatter surfaces, we need to extend characterization techniques to shorter and longer surface spatial wavelengths beyond the conventional 1-um to 1-mm region. Scanning probe microscopes are now available for profiling optical surfaces with height and lateral resolutions of a few atomic spacings. In this paper we report on measurements made with a Nanoscope II atomic force microscope on a variety of supersmoothoptical surfaces and compare these results with measurements made with a conventional stylus profiling instrument. Consistent results have been obtained. To cover the long-spatial wavelength region, long-scan profilers can be used to measure surface waviness in the range from a few millimeters to a few centimeters with height sensitivities ~10 times better than conventional interferometers. The characterization of a Nanostep long-scan mechanical profiler is described, and examples of surface profiles taken on selected flat samples are given. PMID- 20829964 TI - Determination of interface roughness by using a spectroscopic total-integrated scatter instrument. AB - A spectroscopic total-integrated-scatter instrument has been constructed. It uses a Coblentz sphere for the collection of the scattered light and a lamp with a monochromator as a light source. It can be used to measure diffuse reflectance as well as transmittance. The instrument has been used to measure diffuse reflectance of thermally and chemical-vapor-deposition oxidized silicon wafers. Comparisons are made with measurements by using a spectrophotometer with an integrating sphere. The data have been interpreted with a parameterized model for light scattering from a double layer, to obtain rms surfaceroughness values for the two interfaces of the oxide film. PMID- 20829965 TI - Light scattering from periodic rough cylindrical surfaces. AB - Light scattering from rough cylindrical surfaces at near-zero grazing angle is investigated by applying Beckmann's scalar scattering model to the surface's tangential planes and superimposing the individual intensities to form the scattering pattern. A solution for sinusoidal surface-roughness profiles is derived and numerical results are obtained to study the influences of surface wavelength and amplitude on the far-field scattering pattern. The spatial and intensity distributions of the fringe (across and along thefringe) are found to be related to the surface wavelength and amplitude, respectively. Scattering intensity-distribution measurements are carried out on turned surfaces, and the results obtained are in agreement with the model's prediction. As a direct application, a technique to estimate the surface broughness of turned surfaces is proposed. This technique offers an absolute measurement in which the roughness amplitude and wavelength of the surface are defined relative to the illumination wavel gth. PMID- 20829967 TI - Talbot effect reinterpreted: comment. AB - In this Technical Note are comments on some misconceptions and omissions present in a recent attempt at reinterpretation of the Talbot effect by P. Latimer and R. F. Crouse [Appl. Opt. 31, 80-89 (1992)]. PMID- 20829966 TI - Highly conducting wire gratings in the resonance region. AB - We present a theoretical approach for calculating the fields diffracted by gratings made of highlyconducting wires that have a rectangular shape. The fields between the wires are represented in terms of modal expansions that satisfy the approximated impedance boundary condition. Our results show thatthis procedure is particularly suited to dealing with gold gratings used in the infrared range, a spectral region where the assumption of a perfect conductor does not hold, and where the rigorous modal method assuming penetrable wires exhibits numerical instabilities linked with the high conductivity of gold. Numerical results are presented, and the theory is used to determine wire parameters by fitting theoretical and experimental data. PMID- 20829968 TI - Talbot effect reinterpreted: reply to comment. AB - This Technical Note is a reply to the comment concerning our paper on the Talbot effect reinterpreted by P. Szwaykowski [Appl. Opt. 32, 3466-3467 (1993)]. PMID- 20829969 TI - Effect of retroreflection on a Fizeau phase-shifting interferometer. AB - Phase errors in a Fizeau phase-shifting interferometer caused by multiple reflected beams from a retroreflective optics, such as a corner cube and a right angle prism, are studied. Single- and double-pass configurations are presented, and their measurement results are compared. An attenuator is not needed in a double-pass configuration because light is reflected by the retroreflective optics twice and the reference surface once and hence the intensities match. It is more accurate to test a corner cube or a right-angle prism in a double-pass configuration than in a single-pass configuration. Simulations and experimental results are presented. PMID- 20829970 TI - Using gradient-index lenses for laser-beam expansion in interferometry. AB - The use of gradient-index lenses, which inherently have fewer surface defects than conventional convex lenses, for laser-beam expansion in interferometry results in improved fringe visibility without loss of light intensity and the need for stringent alignment requirements. PMID- 20829971 TI - Quantum-noise-limited interferometric phase measurements. AB - Two schemes for interferometric optical phase measurement, with sensitivity limited only by quantum noise in the light, are analyzed. Direct detection is applicable to signals at modulation frequencies away from the technical noise of the light, so that quantum noise dominates the measurement. Alternatively signals otherwise obscured by classical optical noise may be recovered with a phase modulation technique that shifts the signals to a quantum-noise-limited region of the photocurrent spectrum. The analysis is tested experimentally by using a polarimetric electric-field sensor. In the direct-detection scheme quantum-noise limited performance produced a phase sensitivity of 0.25 urad. The indirect scheme allowed subkilohertz signals to be extracted from classical noise 67 dB greater with sensitivity approaching the quantum noise limit. PMID- 20829972 TI - Balancing the astigmatic fields when all other aberrations are absent. AB - When all aberrations are absent other than third-order astigmatism and Petzval, it is demonstrated that selection of a flat tangential astigmatic field is optimum if the smallest maximum spot size is desired over the entire field of view. With balanced sagittal and tangential fields the spot size is observed to be smaller than the flat-tangential-field case until the field angle reaches ?? of the full-field angle. Comparisons of the spot sizes and shapes for these cases and the flat-sagittal-field case are made for flat and optimally curved image surfaces. PMID- 20829973 TI - Minimum resolution specification of intraocular lens implantsusing the modulation transfer function. AB - We investigated the use of modulation transfer function (MTF) measurements to provide a standard test of minimum optical quality of intraocular lenses. We used a water cell with plane entrance and exit windows. This geometry is independent of lens material but relatively simple to implement. We investigated the choice of aperture stop, and 3.0 mm was deemed a suitable choice of stop diameter. Minimum acceptable performance must be specified if this technique is to be adopted as a standard method. The MTF of an ideal lens defocused 1/2 wave is suggested as a possible reference. Strehl ratios, although desirable because they can be measured directly without determining MTF's, were found to be unsuitable. These ratios tend to emphasize the high-frequency response, and the observed ratios are typically too low to provide assurance that the low-frequency response is as high as desired. MTF integrals or contrast at spatial frequencies of particular interest were found to be useful benchmarks of acceptable optical quality. PMID- 20829974 TI - System analysis of CCD-based bar code readers. AB - The basic constraints on the working range of CCD-based bar code readers are analyzed. A comprehensive model that allows the calculation of the optimal working range and its corresponding optical system parameters is derived. Experimental results are found to be in good agreement with theoretical calculations. Finally, comparisons between bar code laser scanners and CCD readers are presented. PMID- 20829975 TI - Measurements of linear diattenuation and linear retardance spectra with a rotating sample spectropolarimeter. AB - A technique to measure linear diattenuation and retardance spectra of infrared materials in transmission is described. A sample is rotated between two stationary linear polarizers in the sample compartment of a Fourier transform infrared spectrometer. The intensity modulation that results from the rotation of the sample is Fourier analyzed, and the linear diattenuation and linear retardance of the sample are calculated from the Fourier series coefficients for each wavelength. The advantages of this technique include immunity of the measurement to instrumental polarization, to circular diattenuation, and to circular retardance. The rotating sample polarimeter does not require retarders. Compensation for systematic errors from polarizers with diattenuation less than one is included in the data reduction. This technique is useful for the calibration of retarders and polarizers and hence for the bootstrap calibration of more elaborate polarimeters such as Mueller matrix polarimeters. We present as an example of t technique the caliration spectra 3-14 um of an infrared quasi achromatic retarder whose fast axis orientation oscillates with wavelength. PMID- 20829976 TI - Development and testing of a synchronous-scanning underwater imaging system capable of rapid two-dimensional frame imaging. AB - The design and construction of a synchronous-scanning underwater imaging system capable of rapid two-dimensional scanning are described. The imager employs a 7 W, all-lines, argon-ion laser in onjunction with a galvanometrically driven raster scanner and an image-dissector tube receiver. The imager is capable of directly generating real-time RS-170 video imagery. The results of an in-water test of the imaging system, in which a high-contrast imaging test pattern was imaged, demonstrate operating anges of up to 4 attenuation lengths (AL) when the test was run at real-time frame rates, ranges of 5.1-5.5 AL when the system operated with an eight-frame running average, and ranges of 6.3 AL when a 128 frame running average was used. The system performance was compared with that of several floodlight/silicon-intensified-target TV camera configurations, which produced a maximum imaging range of ~2.6 AL. Also, an imaging configuration that used the raster-scanned beam of the laser as an illumination source for the sil n intensified-target camera was tested. That system had an ultimate range of ~ 4 AL. PMID- 20829977 TI - Refractive indices of water and ice in the 0.65- to 2.5-um spectral range. AB - New accurate values of the imaginary part, k, of the refractive index of water at T = 22 degrees C, supercooled water at T = -8 degrees C and polycrystalline ice at T = -25 degrees C are reported. The k spectrum for water in the spectral region 0.65-2.5 um is found to be in excellent agreement with those of previous studies. The k values for polycrystalline ice in the 1.44-2.50-um region eliminate the large uncertainties existing among previously published conflicting sets of data. The imaginary part of refractive index of supercooled water shows a systematic shift of absorption peaks toward the longer wavelengths compared with that of water at warmer temperatures. PMID- 20829978 TI - Normal-incidence reflectance of W/B(4) C multilayer mirrors in the 34-50-A wavelength region. AB - The measured normal-incidence reflectances of W/B(4)C multilayers mirrors are 2% in the 34-50-A wavelength region and are consistent with interfacial roughness in the range of 3-4 A. PMID- 20829979 TI - Sensitivity analysis of a thin-film optical waveguide biochemical sensor using evanescent field absorption. AB - A multichannel thin-film optical waveguide sensor for determining aqueous biochemical concentration with a high dynamic range of measurement is proposed. The sensitivity dependence of the proposed sensor on interaction length and waveguide thickness is investigated for dye solutions and three different hemoglobin concentration levels of carboxyhemoglobins. The sensitivity is inversely proportional to the waveguide thickness while proportional to the interaction length. As a consequence the variability of the interaction length makes the proposed sensor a flexible tool for concentration measurements. Moreover, an efficient method for determining the absorption coefficient is discussed. PMID- 20829980 TI - Measurement of spectral, directional reflectivities of solids at high temperatures between 9 and um. AB - A new apparatus to measure spectral,=90% have been measured at 10 um, and the threedimensional angular intensity distributions agree with the cosine law that defines a perfect uniform diffusing surface to within ~10%. Careful extrapolation of the 10-um data into the far IR, combined with sample measurements at 90 and 250 um, indicate that reflectivities of > 96% can be achieved for lambda >= 90 um with comparable uniformity of diffusion. These surfaces are intended for use in overmoded resonator cavities excited by continuously tunable, pulsed, far-IR lasers, but they should also find use in other applications where high net reflectivity, uniform diffusion, and ready contrl of the dimensions of the individ scattering elements are important considerations. PMID- 20830143 TI - Design of gradient-index lens systems for laser beam reshaping. AB - Refractive systems using two gradient-index lenses have been designed to convert a collimated Gaussian-profile laser beam into a plane wave with a uniform intensity distribution. The axial gradient-index distribution for two lenses is determined by using the energy conservation condition and the constant optical path-length condition. The design consideration and theoretical analysis are presented along with several applications. PMID- 20830144 TI - Analytic design of hybrid diffractive-refractive achromats. AB - An analytic design of hybrid achromats that combine refractive and diffractive elements is presented. The design procedure does not rely on paraxial approximations and involves two separate stages. In the first stage the chromatic aberrations are corrected for the paraxial rays, and in the second stage the spherical aberrations are corrected by addition of an aspherical phase function to the diffractive element. The residual spherochromatic aberrations of the achromat are evaluated both analytically and numerically, with good agreement between the results. Finally, we illustrate the design procedure by designing a plano-convex achromat for IR radiation with little chromatic dispersion. PMID- 20830145 TI - Curved kinoform lenses for stigmatic imaging of axial objects. AB - We present a generalized approach for determination of the location of full period zones and the surface-relief profile of a spherically curved kinoform lens that provides stigmatic imaging between any two prespecified points on axis. A common framework is provided for the treatment of both converging and diverging kinoform lenses. Some illustrative numerical results demonstrate the convenient amenability of our method in practical applications. PMID- 20830146 TI - Fourier transform refractometry using multichannel detection. AB - A versatile refractometer that utilizes multichannel interferometry is developed. The refractive index of a homogeneous sample placed in one arm of the triangular common-path interferometer is computed from the induced shift in the position of the He-Ne probe wavelength. The interferogram is detected by a 2048-element CCD line sensor and Fourier transformed by using a dedicated 32-bit microprocessor. The resolution and accuracy of refractive-index measurements depend on the angle of incidence that the sample makes with the optical axis of the interferometer. PMID- 20830147 TI - Estimation of the potential of a fluorescence thermometer for Diesel spray studies. AB - One of the most important tools for the development of Diesel engines is the numerical simulation of the combustion processes. One of the key variables for such simulations is the liquid-phase temperature. The potential study of a fluorescence thermometer for Diesel spray investigations is discussed. Nonintrusive measurements of the liquid-phase temperature in a Diesel spray have been carried out for the first time to the author's knowledge. The results are presented as two-dimensional temperature maps. PMID- 20830148 TI - Differential wax-wane focus servo. AB - We describe a differential wax-wane focus servo technique for use in optical data storage. A combination of scalar diffraction modeling and experiment is used to quantify performance. Our results indicate that the differential technique is superior to the single-detector wax-wane technique with respect to gain, linearity, and lock-on range. We present modeling results that show the effects of aberrations and detector misalignment. The differential system was found to be robust. It can also reject many common pattern noise effects such as tracking cross talk, which was reduced from 0.7 um in a single channel to < 0.1 um in the optimized differential channel. PMID- 20830149 TI - Simulation of fan-beam-type optical computed-tomography imaging of strongly scattering and weakly absorbing media. AB - Numerical simulations of the transmission of a light impulse through strongly scattering and weakly absorbing slab media and of fan-beam-type optical computed tomography imaging for cylindrical media are presented. A hybrid calculation scheme of scattering by the Monte Carlo method is employed to obtain the temporal variation of transmittance of the light impulse through the media. A set of projection data is provided by temporally extrapolating the difference in the optical density between the absorbing object and the nonabsorbing reference to the shortest time of flight. For the case of identical scattering between the object and reference, the reconstructed image of the difference in the absorption coefficient has better accuracy and spatial resolution than those images by the time-gating method. PMID- 20830150 TI - Calibration of 254-nm irradiance based on the silicon photodiode self-calibration technique. AB - A method of calibrating the germicidal irradiance (254 nm) based on the silicon photodiode self-calibration technique has been developed. The absolute responsivity of silicon photodiodes at 254 nm was determined by the self calibration technique at 633 nm combined with the relative spectral responsivity measurement in the 220-780-nm region based on a standard thermal detector. By using pure 254-nm radiation, the responsivity at 254 nm was transferred to a working standard detector with a sensitivity of onlyt ~254 nm. The irradiance values measured by this detector are compared with those measured with conventional methods; for one method we used an absolutely calibrated thermal detector; for another method we used a monochromator with a spectral irradiance standard. They agreed to within a 3% difference. PMID- 20830151 TI - Dynamic range enhancement of Fourier transform infrared spectrum measurement using delta sigma modulation. AB - A method for reconstructing a spectrum from a binary interferogram observed with an Fourier transform IR spectrometer is described. With this method an interferogram is quantized with a 1-bit analog-todigitalconverter with a differentiator and an integrator. This method, called delta sigma modulation, features an oversampling of a signal at a rate much higher than the Nyquist sampling rate. We show experimental examples of IR spectra reconstructed by the method, which demonstrate the potential applications of the method to Fourier transform IR analysis. The results imply that the method may exceed the dynamic range over the one attainable with a conventional Fourier transform spectrometer with an analog-to-digital converter of a finite bit number. PMID- 20830152 TI - Method of accurately measuring the spectral line tilt in the Ebert spectrograph. AB - A simple method for accurate spectral-line-tilt measurement in Ebert spectrographs is presented; it utilizes a special diaphragm situated in front of the entrance or behind the exit slit. This diaphragm splits the image of each tilted line into two fringes. The mutual distance is proportional to the exit slit tilt away from its position for which the line tilt is compensated. PMID- 20830153 TI - Rugate filter sidelobe suppression using half-apodization. AB - Rugate filters reflectance spectra were calculated for various index profiles with half-Gaussian modulation; graded-index as well as step-index profiles were used. The results show excellent sidelobe suppression around the stopbands, relatively high optical density, and good flatness in the reflectance band. PMID- 20830154 TI - Circular, variable, broad-bandpass filters with induced transmission at 200-1100 nm. AB - Circular, variable, broad-bandpass filters with induced transmission (CV-IT-BF) at 200-1100 nm are introduced and their advantages are described. Designs are also presented of CV-IT-BF's for regions of 200-400, 400-700, 700-1100 nm, as well as regularities of the matching coefficients of circular, wedge-shaped matching layers and of the physical thickness of metallic circular, wedge-shaped layers, both of which continuously vary linearly with the wavelengths. Finally, parameter analyses of typical designs of the CV-IT-BF are described together with experimental demonstrations and examples of applications. PMID- 20830155 TI - Analytical solutions for zero-phase-shift transparent coatings on metallic reflectors at 10.6 um. AB - The relationships for refractive indices for zero-phase-shift quarter-wave coatings on metallic reflectors are given. Small variations in lambda/4-layer phase thicknesses are also considered. PMID- 20830156 TI - Low-radiation-damage multilayer coatings for the soft-x-ray region. AB - Highly reflecting multilayer coatings used to form resonant cavities for soft-x ray lasers or for other high-intensity applications (free-electron lasers, x-ray projection lithography, etc.) can be destroyed by strong electric fields generated at the multilayer boundaries. Electric-field strengths can be reduced at the boundaries by altering slightly the layer thicknesses of the final or topmost layers. Calculations are presented showing reduced field strengths caused by altering final-layer thicknesses. PMID- 20830157 TI - Long-term stability of a Mo/Si multilayer structure. AB - The normal-incidence reflectance of a Mo/Si multilayer mirror, with peak reflectance near 130 A, was measured over a period of 20 months by using synchrotron radiation. The measured reflectances were unchanged over this period of time, and this indicates that the material layers and interfaces were stable. PMID- 20830158 TI - Tin-polyimide and indium-polyimide thin-film composites as soft x-ray bandpass filters. AB - A tin-polyimide and an indium-polyimide soft x-ray bandpass filter were fabricated with thicknesses of 1400 and 1750 A for the metal and polyimide components, respectively. The transmission of each filter was measured at the Stanford Synchrotron Radiation Laboratory. The transmission of the tin-polyimide filter was found to be ~40% for radiation with wavelengths between 60 and 80 A. The transmission of the indium-polyimide filter was greater than 40% between 70 and 90 A. The indium was ~5% more transmissive than the tin and attained a maximum transmission of ~48% at 76 A. Such filters have potential applications to soft x-ray telescopes that operate in this region. They might also be of interest to investigators who work with x-ray microscopes that image live biological specimens in the 23-44-A water window. PMID- 20830159 TI - System of optical noncontact microtopography. AB - In this paper we describe a method of noncontact optical microtopography based on discrete triangulation. We show that a light beam with an oblique incidence on a surface can be used to assess the distance of the latter to a reference plane if the bright spot produced on the surface is imaged onto an array of detectors that tracks its lateral displacement. The light beam is swept over the surface so that large areas can be scanned. The authors have used their system with success for the topographic inspection of several surfaces, e.g., thin copper and silver films, polyethylene rough films and molds, graphite, machined metallic parts, and fabrics. PMID- 20830160 TI - Control of the tip-surface distance in near-field optical microscopy. AB - An experimental technique that makes use of the intensity of the interference pattern formed by light that propagates directly from the single-mode fiber tip and light that is reflected by the surface under anoblique angle of incidence is developed to control the tip-surface distance in near-field opticalmicroscopy. It is shown that by using another fiber as a detector with a polished edge placed at the surface near the fiber tip one can determine the tip-surface separation with an accuracy better than 15 nm at distances less than 1 um. The technique proposed is used to investigate the influence of the shape of the tip in near-field measurements. PMID- 20830161 TI - Model of a new temperature-compensated optical current sensor using Bi(12)SiO(20). AB - A new optical bulk current sensor is presented with Bi(12)SiO(20) as a sensing crystal. Through the use of a mirror in the setup and the reciprocity of the optical activity of Bi(12)SiO(20), the sensor becomes insensitive to intrinsic linear birefringence and birefringence that is due to the enclosure of the crystal. Therefore the sensor is also insensitive to temperature, which affects the total linear birefringence. By making a computer model of the Bi(12)SiO(20) sensor, it was proved that the output signal of the sensor, which has a sinusoidal response, has a maximum relative error of 0.05%, apart from the variation of the Verdet constant, for a temperature change of approximately 100 degrees C. PMID- 20830162 TI - Holographic spherical gratings: a new family of quasi-stigmatic designs for the Rowland-circle mounting. AB - In the context of aberration-corrected holographic spherical gratings used in the Rowland-circle mounting, we have investigated the off-Rowland recording geometries with stigmatic sources that nullify the defocus and meridional coma at all wavelengths. We introduce the additional requirement that astigmatism vanishes at a given wavelength. Then we demonstrate that a family of solutions exists and has a quasi-zero sagittal coma at the wavelength adopted for the astigmatism correction. This simultaneous reduction of sagittal coma and astigmatism greatly enhances the spectral performances of the Rowland mount. We also point out that a subfamily is found when the derivative of astigmatism is equal to zero at the wavelength of correction; the performances are then extended to a wider spectral range. Finally ray traces and performances of two representative examples of the new family of gratings are presented. PMID- 20830163 TI - Deformed ellipsoidal gratings for far-ultraviolet spectrographs: analytic optimization. AB - Analytic formulas are developed for the semiaxes and for the deformation coefficients of a deformed ellipsoidal grating that minimize aberrations over a given spectral range. These include the Rowland circle mount and quasi-Rowland circle mounts, as required for systems that combine spectra from multiple gratings on a common detector. It is also shown that the necessary condition for a holographic grating to give a better performance over a conventional grating is the use of a convergent beam and a divergent beam for the recording. Examples applicable to the Far-Ultraviolet Spectroscopic Explorer are given. The light path function for a deformed ellipsoidal holographic grating is also presented. PMID- 20830164 TI - On-blaze operation of a Mo/Si multilayer-coated, concave diffraction grating in the 136-142-A wavelength region and near normal incidence. AB - The efficiency and resolving power of a concave, 2400-groove/mm, blazed diffraction grating that had a Mo/Si multilayer coating were determined. The multilayer coating had a peak reflectance of 55% at 140-A near normal incidence. The efficiency of the multilayer grating for wavelengths in the 136-139-A range was 2% near normal incidence. This efficiency was a factor of 150 greater than the efficiency of a sister replica Au-coated grating in the same wavelength region. The resolving power of the multilayercoated grating in the third order of a V viii transition with a first-order wavelength of 140.451 A was 9100. Comparisons with the Au-coated grating indicated that the application of the multilayer coating did not affect the resolving power or the blaze angle. PMID- 20830165 TI - Surface-roughness measurement using Fourier transformation of doubly scattered speckle pattern. AB - The statistical properties of the doubly scattered speckle pattern generated from a rough surface, under a fully developed and static speckle pattern illumination, have been investigated by numerical analysis. The real-time Fourier transformation of the doubly scattered speckle pattern by an optical process enables us to measure the surface roughness in quasi real time. PMID- 20830166 TI - Testing an optical window of a small wedge angle: effect of multiple reflections. AB - Multiple reflections between two surfaces of a window introduce a fixed pattern error in optical measurements. One way to remove these spurious reflections is to use a reasonably large wedge so that the interference fringes formed by the two surfaces are too dense for the detector to resolve. However, this method does not work if the wedge angle is small, e.g., several arcseconds. By tilting both the window and the return mirror properly, it is possible to remove the effect of multiple reflections of a window. Theory and experimental results are presented. PMID- 20830167 TI - Output beam intensity noise induced by fiber perturbations in a fiber-linked laser. AB - The effects of acoustic perturbations on an optical fiber intended to link a laser to an optical cavity have been studied. Acoustic noise above the level of 45 dBre(l ubar) in the frequency band of 500-1500 Hz has a measurable effect on intensity fluctuations at the fiber's output. PMID- 20830168 TI - Fabrication of buried channel waveguides on silicon substrates using spin-on glass. AB - A new process for the deposition of thick (~10-um) films of silica and titania doped silica on silicon substrates is described. Films are built up by repetitive operation of a simple process cycle in which a layer of sol-gel material is deposited by spin coating, then densified by rapid thermal annealing. Stressfree layers are obtained through careful choice of the anneal temperature. Bilayer structures suitable for waveguide fabrication may also be constructed by performing two successive deposition runs using sol-gel precursors with different titania concentrations. These bilayers may be patterned topographically into ridges by using reactive ion etching, and the ridges may be planarized by applying additional layers of sol-gel material to form buried channel waveguides. PMID- 20830169 TI - Effects of finite stylus width in surface contact profilometry. AB - A study of the effects of stylus width in the profilometry of a randomly rough surface is presented. An approximate solution for the path of a flat-tipped stylus on an arbitrary surface is expressed as a nonlinear function of the local surface height and its first two derivatives. This solution is then averaged to find the first two moments of the measured profile when the surface and its derivatives are jointly Gaussian variates. The measured surface variance is found to decrease with increasing stylus size in a manner consistent with computer simulations. PMID- 20830170 TI - Analysis of shearogram reconstruction. AB - The high-pass Fourier filtering technique with an opaque stopper is commonly used for the reconstruction of shearograms. We believe that no analysis of this technique as applied to the shearogram reconstruction has been described. We present here a theoretical analysis of this reconstruction system taking into account the stopper that blocks the low-frequency region in the Fourier transform plane. The results show that the light-intensity distribution after reconstruction is different from that of the original shearogram. High fringe visibility is obtained with high-pass filtering. PMID- 20830171 TI - Loss-reduced photonic liquid-crystal fiber by using photoalignment method. AB - We present a loss-reduced photonic liquid-crystal fiber (PLCF) using the noncontact photoalignment method. The photoexcited and adsorbed azo dye on the capillary surface of a PLCF induces uniform and highly ordered orientation of the liquid crystal (LC). The anchoring force of the photoalignment effect is combined with that generated by surface boundary conditions of the photonic crystal fiber (PCF). Transmission loss resulting from LC scattering can be reduced from -2.8 to -1.3 db/cm within 10 min. This photoinduced alignment yields a permanent boundary for the LC in the PCF that reduces scattering loss and can be further modulated by electrical fields. The electrical tunable effect and fast dynamic response of the photoaligned PLCF are also presented. This low-loss PLCF can be applied conveniently in various PLCF devices. PMID- 20830172 TI - Measurement of signal intensity depth profiles in rat brains with cardiac arrest maintaining primary temperature by wide-field optical coherence tomography. AB - We have already reported that after an injection for euthanasia, the signal intensity of optical coherence tomography (OCT) images are 2.7 times increased before cardiac arrest (CA) using OCT and rat brains without temperature control to show the potential of OCT to monitor tissue viability in brains [Appl. Opt.48, 4354 (2009)APOPAI0003-693510.1364/AO.48.004354]. In this paper, we similarly measured maintaining the primary temperature of rat brains. It was confirmed that when maintaining the primary temperature, the time courses of the ratios of signal intensity (RSIs) were almost the same as those without temperature control. RSIs after CA varied from 1.6 to 4.5 and depended on positions measured in tissues. These results mean that the OCT technique has clinical potential for applications to monitor or diagnose a focal degraded area, such as cerebral infarctions due to focal ischemia in brains. PMID- 20830173 TI - Design and fabrication of a 200 GHz Si-nanowire-based reflective arrayed waveguide grating (de)multiplexer with optimized photonic crystal reflectors. AB - A compact Si-nanowire-based reflective arrayed-waveguide grating (AWG) for dense wavelength-division multiplexing is proposed. At the end of each waveguide in the array, there is an individual photonic crystal (PhC) reflector, which makes the AWG layout design very flexible. All the PhC reflectors are with the same design. With such a design, the total size of the AWG (de)multiplexer is reduced by more than a half. The reflection efficiency of the used PhC reflectors is enhanced by optimizing the taper between the arrayed waveguides and the PhC reflector. A 200 GHz AWG (de)multiplexer is designed and fabricated as an example. The total size is only about 193 MUm * 168 MUm. PMID- 20830174 TI - Wavelength-compensated time-sequential multiplexed color joint transform correlator. AB - We report a wavelength-compensated three-channel (RGB) joint transform correlator (JTC) for color pattern recognition using a ferroelectric liquid-crystal spatial light modulator (SLM) operating in binary pure phase modulation. We apply a previously reported time-multiplexing technique useful in creating wavelength compensated diffraction patterns, based on the synchronization of properly scaled diffraction masks with the input wavelength selection obtained by applying a rotating RGB color-filter wheel to an Ar-Kr laser. The application of this technique to a JTC architecture permits real-time color object detection. In order to achieve a high light efficiency for the correlation process, we combine the design of zero-order joint power spectra in all color channels with the selection of a certain polarization configuration of the SLM, producing a broadband phase-only modulation. Excellent experimental results demonstrating color-object detection are provided. PMID- 20830175 TI - Random angular coding for superresolved imaging. AB - In this paper, we present a new approach capable of working under coherent and incoherent illumination for achieving superresolution by random coding of the object's angular information. By placing two static random masks in optically conjugate planes inside an aperture-limited imaging setup, one may obtain a transmitted image containing spatial resolution higher than the one obtained without the masks. As the most noticeable fact, the superresolution effect is obtained without imposing any restrictions either in the time domain or in the field-of-view domain but rather only in the dynamic range of the camera device. Experimental verifications for the proposed technique with incoherent illumination with a low numerical aperture (NA) lens are presented. PMID- 20830176 TI - Predictive analog-to-digital converter for Fourier-transform spectrometers. AB - This paper proposes the use of predictive analog-to-digital converters (ADC) to handle dynamic range issues in Fourier-transform spectrometers. Several predictive approaches are proposed, and one is implemented experimentally to show that the technique works. A system was implemented with 16 bit (13 bits effective) ADCs and digital-to-analog converters (DACs) operated at 8 bits to provide a comparison basis. Measurements of a blackbody at 900 degrees C performed using the setup show a 13 bit effective performance, limited by the input noise of the data acquisition card. PMID- 20830177 TI - Ultraviolet analysis of donated corneas: a portable prototype. AB - As technology improves human vision, some procedures currently performed may be causing a decrease of the natural UV protection of the cornea. A portable dual beam system prototype was assembled for physicians for clinical studies of these effects on the corneas endowing two types of 300-400 nm evaluations: 1, regularly donated corneas and 2, simulating refractive keratectomy by corneal lamellae removal. The system performs 500 measurements/s, providing +/-0.25% precision for the transmittance. The measurements performed on the prototype are 95% in agreement with Cary 17 and HR4000CG-UV-NIR Ocean Optics spectrophotometers. Preliminary studies on cadaveric corneas demonstrate that, as the stromal layer is reduced (~150 MUm depth), there is significant loss--an average of 7.1%.--of the cornea's natural UV protection. The prototype is being tested in an eye bank for routine evaluation of donor corneas. PMID- 20830178 TI - Cryogenic fluid level sensors multiplexed by frequency-shifted interferometry. AB - We present a liquid level sensing system for cryogenic fluids based on an array of aluminum-coated fiber Bragg gratings written in high-attenuation fibers (HAFs) interrogated by frequency-shifted interferometry (FSI). The sensors are heated up optically through the absorption of light at the core of the HAF sections. The distinct thermal response of sensors in the liquid from that in the gas provides an unambiguous means to detect the liquid level. FSI allows the sensors to have overlapped spectral response, and, therefore, has the potential of accommodating a larger number of sensors in the array. The measurement of liquid nitrogen level using this system was experimentally demonstrated. The successful combination of aluminum-coated HAF Bragg grating sensors and the FSI technique promises a viable solution for liquid level sensor networks at cryogenic temperatures. PMID- 20830179 TI - High sensitivity detection of NO2 employing cavity ringdown spectroscopy and an external cavity continuously tunable quantum cascade laser. AB - A trace gas sensor for the detection of nitrogen dioxide based on cavity ringdown spectroscopy (CRDS) and a continuous wave external cavity tunable quantum cascade laser operating at room temperature has been designed, and its features and performance characteristics are reported. By measuring the ringdown times of the cavity at different concentrations of NO(2), we report a sensitivity of 1.2 ppb for the detection of NO(2) in Zero Air. PMID- 20830180 TI - Omnidirectional-view three-dimensional display system based on cylindrical selective-diffusing screen. AB - We utilized a high-frame-rate projector, a rotating mirror, and a cylindrical selective-diffusing screen to present a novel three-dimensional (3D) omnidirectional-view display system without the need for any special viewing aids. The display principle and image size are analyzed, and the common display zone is proposed. The viewing zone for one observation place is also studied. The experimental results verify this method, and a vivid color 3D scene with occlusion and smooth parallax is also demonstrated with the system. PMID- 20830181 TI - Nanoparticle detection using dual-phase interferometry. AB - The detection and identification of nanoparticles is of growing interest in atmospheric monitoring, medicine, and semiconductor manufacturing. While elastic light scattering with interferometric detection provides good sensitivity to single particles, active optical components prevent scalability of realistic sizes for deployment in the field or clinic. Here, we report on a simple phase sensitive nanoparticle detection scheme with no active optical elements. Two measurements are taken simultaneously, allowing the amplitude and phase to be decoupled. We demonstrate the detection of 25 nm Au particles in liquid in Deltat ~ 1 ms with a signal-to-noise ratio of ~ 37. Such performance makes it possible to detect nanoscale contaminants or larger proteins in real time without the need of artificial labeling. PMID- 20830182 TI - Probabilistic color matching and tracking of human subjects. AB - Pattern discovery algorithms based on the computational mechanics (CM) method have been shown to succinctly describe underlying patterns in data through the reconstruction of minimum probabilistic finite state automata (PFSA). We apply the CM approach toward the tracking of human subjects in real time by matching and tracking the underlying color pattern as observed from a fixed camera. Objects are extracted from a video sequence, and then raster scanned, decomposed with a one-dimensional Haar wavelet transform, and symbolized with the aid of a red-green-blue (RGB) color cube. The clustered causal state algorithm is then used to reconstruct the corresponding PFSA. Tracking is accomplished by generating the minimum PFSA for each subsequent frame, followed by matching the PFSAs to the previous frame. Results show that there is an optimum alphabet size and segmentation of the RGB color cube for efficient tracking. PMID- 20830183 TI - Monte Carlo code for high spatial resolution ocean color simulations. AB - A Monte Carlo code for ocean color simulations has been developed to model in water radiometric fields of downward and upward irradiance (E(d) and E(u)), and upwelling radiance (L(u)) in a two-dimensional domain with a high spatial resolution. The efficiency of the code has been optimized by applying state-of the-art computing solutions, while the accuracy of simulation results has been quantified through benchmark with the widely used Hydrolight code for various values of seawater inherent optical properties and different illumination conditions. Considering a seawater single scattering albedo of 0.9, as well as surface waves of 5 m width and 0.5 m height, the study has shown that the number of photons required to quantify uncertainties induced by wave focusing effects on E(d), E(u), and L(u) data products is of the order of 10(6), 10(9), and 10(10), respectively. On this basis, the effects of sea-surface geometries on radiometric quantities have been investigated for different surface gravity waves. Data products from simulated radiometric profiles have finally been analyzed as a function of the deployment speed and sampling frequency of current free-fall systems in view of providing recommendations to improve measurement protocols. PMID- 20830184 TI - Time-resolved Raman spectroscopy for in situ planetary mineralogy. AB - Planetary mineralogy can be revealed through a variety of remote sensing and in situ investigations that precede any plans for eventual sample return. We briefly review those techniques and focus on the capabilities for on-surface in situ examination of Mars, Venus, the Moon, asteroids, and other bodies. Over the past decade, Raman spectroscopy has continued to develop as a prime candidate for the next generation of in situ planetary instruments, as it provides definitive structural and compositional information of minerals in their natural geological context. Traditional continuous-wave Raman spectroscopy using a green laser suffers from fluorescence interference, which can be large (sometimes saturating the detector), particularly in altered minerals, which are of the greatest geophysical interest. Taking advantage of the fact that fluorescence occurs at a later time than the instantaneous Raman signal, we have developed a time-resolved Raman spectrometer that uses a streak camera and pulsed miniature microchip laser to provide picosecond time resolution. Our ability to observe the complete time evolution of Raman and fluorescence spectra in minerals makes this technique ideal for exploration of diverse planetary environments, some of which are expected to contain strong, if not overwhelming, fluorescence signatures. We discuss performance capability and present time-resolved pulsed Raman spectra collected from several highly fluorescent and Mars-relevant minerals. In particular, we have found that conventional Raman spectra from fine grained clays, sulfates, and phosphates exhibited large fluorescent signatures, but high quality spectra could be obtained using our time-resolved approach. PMID- 20830185 TI - Application of time-division-multiplexed lasers for measurements of gas temperature and CH4 and H2O concentrations at 30 kHz in a high-pressure combustor. AB - Two time-division-multiplexed (TDM) sources based on fiber Bragg gratings were applied to monitor gas temperature, H(2)O mole fraction, and CH(4) mole fraction using line-of-sight absorption spectroscopy in a practical high-pressure gas turbine combustor test article. Collectively, the two sources cycle through 14 wavelengths in the 1329-1667 nm range every 33 MUs. Although it is based on absorption spectroscopy, this sensing technology is fundamentally different from typical diode-laser-based absorption sensors and has many advantages. Specifically, the TDM lasers allow efficient, flexible acquisition of discrete wavelength information over a wide spectral range at very high speeds (typically 30 kHz) and thereby provide a multiplicity of precise data at high speeds. For the present gas turbine application, the TDM source wavelengths were chosen using simulated temperature-difference spectra. This approach is used to select TDM wavelengths that are near the optimum values for precise temperature and species concentration measurements. The application of TDM lasers for other measurements in high-pressure, turbulent reacting flows and for two-dimensional tomographic reconstruction of the temperature and species-concentration fields is also forecast. PMID- 20830186 TI - Optical properties of Nd-doped rare-earth vanadates. AB - Rare-earth orthovanadates are being used as substitutes for traditional solid state laser hosts, such as YAG. While the most common of these is yttrium orthovanadate, other rare-earth vanadates, such as lutetium vanadate and gadolinium vanadate, are being used for their special properties in certain applications. We report new measurements of the refractive indices and thermo optic coefficients of these materials, which will aid in the design of laser cavities and other nonlinear optical elements. PMID- 20830187 TI - Laser direct-write technique for fabricating microlens arrays on soda-lime glass with a Nd:YVO4 laser. AB - A one-step direct-write technique for fabricating spherical microlenses on soda lime glass substrates is described. Using a Q switched Nd:YVO(4) laser combined with a galvanometer system, square and triangular microlens arrays were fabricated. The focal length of microlenses is measured using direct and nondirect methods. Values around 118 and 125 um were obtained for the microlens focal length of square and triangular arrays, respectively. A noncontact profilometer is used for determining the surface roughness of square and triangular arrays. Results are compared with that of glass substrate. PMID- 20830188 TI - Nonlinear chirped-pulse propagation and supercontinuum generation in photonic crystal fibers. AB - Based on the generalized nonlinear Schrodinger equation and waveguiding properties typical of the photonic crystal fiber structure, nonlinear chirped pulse propagation and supercontinua generation in the femtosecond and picosecond regimes are investigated numerically. The simulation results indicate that an input chirp parameter mainly affects the initial stage of spectral broadening caused by the self-phase modulation (SPM) effect. In the femtosecond regime where the SPM effect plays an important role in the process of spectral broadening, an input positive chirp can enhance the supercontinuum bandwidth through a modified pulse compression phase and a decreased propagation distance required by soliton fission. In the picosecond regime, where the SPM effect contributes less to the continuum bandwidth and four-wave mixing process or modulational instability dominates the initial stage of spectral and temporal evolution, the output spectral shape and bandwidths are less sensitive to the input chirp parameters. PMID- 20830189 TI - Computationally efficient signal modeling for vertical scanning interferometry. AB - This paper presents a computationally efficient model to simulate the interference signal of vertical scanning interferometry. Existing models are either oversimplified or computationally intensive. Our model incorporates the geometric and spectral effects on vertical scanning interferometry, but removes the computationally intensive numerical integration process by modeling the light spectrum as a sum of piecewise cosine functions. Compared to direct numerical integration of the generalized model, the computational time (for an interference signal) of the proposed model is 256,800 times faster. To verify the accuracy of the proposed model, we simulate the interference signal of a phosphor-based LED, and verify our result with experimental data and a computationally intensive counterpart. Other than reduced computational time, the elementary form of an interference signal derived in this paper will facilitate future work. PMID- 20830190 TI - Rapid fabrication of an electrically switchable liquid crystal Fresnel zone lens. AB - Based on a nanoimprint technique, a new method is proposed for the rapid fabrication of an electrically switchable liquid crystal Fresnel zone lens (SLCFZL). The flow chart of the proposed fabrication method for a SLCFZL is given and a binary SLCFZL is experimentally demonstrated using the proposed method. The diffraction efficiency of the SLCFZL is continuously tunable through an external electric field, and the driving voltage is relatively low (<15V(rms)). The measured maximal diffraction efficiency reaches ~35% for a linearly polarized light, which is close to the theoretical value of 40.5%. The focusing and imaging properties of the SLCFZL are also experimentally tested. PMID- 20830191 TI - Circular multireflection cell for optical spectroscopy. AB - We constructed a circular multireflection (CMR) cell, allowing multireflection around the center of the cell. This is caused by a skewed adjustment of the entering beam (equivalent to a simple parallel shift/offset), avoiding the center of the cell, thus leading to multiple reflections. The experimental setup with a cell with an inner diameter of 6 cm showed up to 17.5 beam passes on polished aluminum and attained path lengths up to 105 cm, demonstrated by Fourier transform infrared measurements of CO(2) gas between 2283 and 2400 cm(-1). The circular concept, i.e., the centering of the reflections, is useful for absorption spectroscopy on trace gases and aerosols. The optical alignment of the cell can completely be performed from outside the experimental setup, e.g., an aerosol flow reactor or a vacuum system. The variation of the path length is easily possible by adjusting the position of the cell with respect to the entering light beam. PMID- 20830192 TI - Pattern effect reduction in all-optical wavelength conversion using a two electrode semiconductor optical amplifier. AB - A two-electrode semiconductor optical amplifier that has two sections and two separated electrodes is proposed for an all-optical wavelength converter. Pattern effect reduction based on dynamic gain compensation is theoretically investigated using a time-domain model that takes into account the carrier diffusion process between the two sections, and the Q factor of the converted light is calculated to evaluate pattern effects. Simulation results show that the Q factor is greatly improved when the section lengths and the currents are appropriately selected. PMID- 20830193 TI - Enhancement of magneto-optical effects in magnetic nanoparticles near gold dielectric surfaces. AB - We report enhanced magneto-optical Kerr rotation in the layer systems of a magnetic granular film coated by uniform gold and dielectric films. The Kerr rotation spectra measured from 1.2 to 5 eV show a peak at about 2.7 eV, not present in either uncoated magnetic particle films. It was shown that the polar magneto-optical Kerr signal is about five times higher than that obtained for CoFe-MgO granular films in similar conditions. The physical nature of the magneto optical effect enhancement in three layers (magnetic/noble/dielectric films) is related to the excitation of surface plasmons and their fast propagation on the interface of a complex three-layer structure. The Kerr rotation enhancement corresponds to intrinsic electronic transitions in the CoFe nanogranules due to the spectral overlap of these transitions with propagating surface plasmons. PMID- 20830194 TI - Defining the true sensitivity of culture for the diagnosis of melioidosis using Bayesian latent class models. AB - BACKGROUND: Culture remains the diagnostic gold standard for many bacterial infections, and the method against which other tests are often evaluated. Specificity of culture is 100% if the pathogenic organism is not found in healthy subjects, but the sensitivity of culture is more difficult to determine and may be low. Here, we apply Bayesian latent class models (LCMs) to data from patients with a single Gram-negative bacterial infection and define the true sensitivity of culture together with the impact of misclassification by culture on the reported accuracy of alternative diagnostic tests. METHODS/PRINCIPAL FINDINGS: Data from published studies describing the application of five diagnostic tests (culture and four serological tests) to a patient cohort with suspected melioidosis were re-analysed using several Bayesian LCMs. Sensitivities, specificities, and positive and negative predictive values (PPVs and NPVs) were calculated. Of 320 patients with suspected melioidosis, 119 (37%) had culture confirmed melioidosis. Using the final model (Bayesian LCM with conditional dependence between serological tests), the sensitivity of culture was estimated to be 60.2%. Prediction accuracy of the final model was assessed using a classification tool to grade patients according to the likelihood of melioidosis, which indicated that an estimated disease prevalence of 61.6% was credible. Estimates of sensitivities, specificities, PPVs and NPVs of four serological tests were significantly different from previously published values in which culture was used as the gold standard. CONCLUSIONS/SIGNIFICANCE: Culture has low sensitivity and low NPV for the diagnosis of melioidosis and is an imperfect gold standard against which to evaluate alternative tests. Models should be used to support the evaluation of diagnostic tests with an imperfect gold standard. It is likely that the poor sensitivity/specificity of culture is not specific for melioidosis, but rather a generic problem for many bacterial and fungal infections. PMID- 20830195 TI - The etiology of eruption disorders - further evidence of a 'genetic paradigm' AB - The clinical spectrum of tooth eruption disorders includes both syndromic and non syndromic problems ranging from delayed eruption to a complete failure of eruption. A defect in the differential apposition/resorption mechanism in alveolar bone can cause conditions such as tooth ankylosis, primary failure of eruption, failure of eruption due to inadequate arch length and canine impaction. As our knowledge of the molecular events underlying normal tooth eruption has increased, so too has our understanding of clinical eruption disorders. The recent finding that one gene, parathyroid hormone receptor 1 (PTH1R), is causative for familial cases of primary failure of eruption (PFE) suggests that other disturbances in tooth eruption may have a genetic etiology. In this report, we evaluated the current terminology (ankylosis, PFE, secondary retention, etc.) used to describe non-syndromic eruption disorders, in light of this genetic discovery. We observed that some individuals previously diagnosed with ankylosis were subsequently found to have alterations in the PTH1R gene, indicating the initial misdiagnosis of ankylosis and the necessary re-classification of PFE. We further investigated the relationship of the PTH1R gene, using a network pathway analysis, to determine its connectivity to previously identified genes that are critical to normal tooth eruption. We found that PTH1R acts in a pathway with genes such as PTHrP that have been shown to be important in bone remodeling, hence eruption, in a rat model. Thus, recent advances in our understanding of normal and abnormal tooth eruption should allow us in the future to develop a clinical nomenclature system based more on the molecular genetic cause of the eruption failures versus the clinical appearance of the various eruption disorders. PMID- 20830196 TI - Video-assisted thoracoscopic surgery in the treatment of patients with bullous emphysema. AB - PURPOSE: Surgical operation for bullous emphysema is indicated for patients with symptoms related to the compression of giant bullae (usually >30% of hemithorax) or other related complications, such as infection, rupture, or bleeding. Video assisted thoracoscopic surgery (VATS) has been widely applied in the diagnosis and treatment of patients with intrathoracic diseases, including bullous emphysema. MATERIALS AND METHODS: We retrospectively reviewed nine patients with symptomatic or complicated bullous emphysema, who were treated by bullectomy using VATS in the past two years. Eight males and one female were included, with ages ranging from 39 to 82 (median 62) years. Eight (89%) were heavy smokers. Pulmonary function tests were performed preoperatively in only three patients because of their compromised condition on admission. RESULTS: Bullae resection and pleurodesis was performed using VATS in the eight patients. The operating time ranged from 35 to 75 (median 50) minutes. Two patients had minor postoperative complications (one prolonged air leak for more than seven days and one wound infection), which recovered with conservative treatment. The chest tube was successfully removed 5-14 days postoperatively. Either symptomatic relief or improved pulmonary function was noted in these patients postoperatively. One patient complained of intermittent dyspnea during follow-up, but the imaging study was essentially normal. CONCLUSION: Bullectomy for patients with bullous emphysema can be performed safely and effectively using VATS. Additional pleurodesis or suturing reinforcement can prevent the complication of air leak. PMID- 20830197 TI - Substantial decline in sugar-sweetened beverage consumption among California's children and adolescents. AB - INTRODUCTION: Few studies have looked at changes among risk factors that might help explain why childhood obesity prevalence in the US has leveled off in recent years. We present an analysis of the California Health Interview Survey (CHIS) that examines trends in childhood and adolescent obesity as well as trends in sugar-sweetened beverage (SSB) consumption. METHOD: We compared 3 separate cross sectional samples (2003, 2005, and 2007) from biennial CHIS for 3 age groups, age 2-5, age 6-11 and age 12-17. We calculated the prevalence of high SSB consumption (defined as having more than one SSB during the previous day). 2 measures of obesity were used - weight-for-age at or above the 95th percentile on national growth charts for children aged 2-11, and body mass index for age at or above the 95th percentile on national growth charts for adolescents aged 12-17. Logistic regression analysis is used to estimate adjusted odds ratios of high SSB consumption in 2005 and 2007 compared with the baseline year of 2003. RESULTS: From 2003 to 2007, each age group experienced a substantial decline in high SSB consumption (16.4%-5.0% for age 2-5, P < 0.001; 22.5%-9.9% for age 6-11, P < 0.001; 35.7%-25.7% for age 12-17, P < 0.001). Declines in the prevalence of children's obesity were significant among children age 2-5 (P < 0.001) and age 6 11 (P < 0.05) but not among adolescents (P = 0.42). Children and teenagers in 2005 and 2007 were significantly less likely than those surveyed in 2003 to have high SSB consumption after adjusting for gender, age, race/ethnicity, poverty level, and parental education (P < 0.001). CONCLUSION: Policy actions may have impacted the prevalence of SSB consumption in the population. Further research is needed to examine the contribution of declining SSB consumption on the leveling off of obesity trends and the extent to which these declines are attributable to new policies and programs. PMID- 20830198 TI - The Delphi process: a solution for reviewing novel grant applications. AB - INTRODUCTION: Traditional scientific review processes are not well suited for evaluating the merits of research in situations where the available scientific evidence is limited and if review panels have widely divergent opinions. This study tested whether a Delphi process is useful in grant selection. MATERIALS AND METHOD: A Delphi process prioritized novel research proposals in pancreatic cancer. Five reviewers holding similar grants overseas ranked research applications by scientific merit, innovativeness, and level of risk. RESULT: Three rounds of voting evaluated the best 10 applications received. In the first round of the Delphi process, scores ranged from 5.0 to 8.3. After the second round, the cumulative scores of the eight remaining applications ranged from 10 to 12.6. At the end of the third round, the final cumulative scores of the remaining six applications ranged from 13.6 to 18.2. The four highest ranking applications were recommended for funding, with agreement from reviewers. CONCLUSION: A modified Delphi process proved to be an efficient, transparent, and equitable method of reviewing novel grant applications in a specialized field of research, where no local expertise was available. This process may also be useful for other peer review processes, particularly where there is limited access to local experts. PMID- 20830199 TI - Perspectives on use of personal alarms by older fallers. AB - BACKGROUND: Personal alarms are proposed as a reliable mechanism for older people to obtain assistance after falling. However, little is known about how older people feel about owning and using personal alarms. AIM: This paper reports on experiences of independently living older people, who have recently fallen, regarding alarm use and their independence. METHOD: Volunteers older than 65 years who had sustained a fall in the previous six months were sought via community invitations. Semistructured telephone interviews were conducted to gain information about their fall and their perspectives on personal alarm use. Interviews were content-analyzed to identify key concepts and themes. RESULTS: Thirty-one interviews were conducted. Twenty callers owned personal alarms. Four subgroups of older fallers were identified; the first group used personal alarms effectively and were advocates for their benefits, the second group owned an alarm but did not use it effectively, the third group did not own alarms mostly because of cost, although were receptive to an alarm should one be provided, and the fourth group did not have an alarm and would not use it even if it was provided. DISCUSSION: Personal alarms produce positive experiences when used effectively by the right people. The cost of personal alarms prohibits some older fallers from being effective alarm users. However, other elderly fallers remain unwilling to consider alarm use even if one was provided. In view of their cost, personal alarms should be targeted to people who will benefit most. Alternative strategies should be considered when alarms are unlikely to be used appropriately. PMID- 20830200 TI - Anthroposophic therapy for attention deficit hyperactivity: a two-year prospective study in outpatients. AB - BACKGROUND: Anthroposophic treatment for attention deficit hyperactivity disorder (ADHD) includes special artistic and physical therapies and special medications. METHODS: We studied 61 consecutive children starting anthroposophic treatment for ADHD symptoms under routine outpatient conditions. Primary outcome was FBB-HKS (a parents' questionnaire for ADHD core symptoms, 0-3), and secondary outcomes were disease and symptom scores (physicians' and parents' assessment, 0-10) and quality of life (KINDL((r)) total score, 0-100). RESULTS: A total of 67% of patients fulfilled the DSM-IV criteria for ADHD, 15% had an exclusion diagnosis such as pervasive developmental disorders, while 18% did not fulfill ADHD criteria for another reason. Anthroposophic treatment modalities used were eurythmy therapy (in 56% of patients), art therapy (20%), rhythmical massage therapy (8%), and medications (51%). From baseline to six-month follow-up, all outcomes improved significantly; average improvements were FBB-HKS total score 0.30 points (95% confidence interval [CI]: 0.18-0.43; P < 0.001), FBB-HKS inattention 0.36 (95% CI: 0.21-0.50; P < 0.001), FBB-HKS hyperactivity 0.29 (95% CI: 0.14-0.44; P < 0.001), FBB-HKS impulsivity 0.22 (95% CI: 0.03-0.40; P < 0.001), disease score 2.33 (95% CI: 1.84-2.82; P < 0.001), symptom score 1.66 (95% CI: 1.17-2.16; P < 0.001), and KINDL 5.37 (95% CI: 2.27-8.47; P = 0.001). Improvements were similar in patients not using stimulants (90% of patients at months 0-6) and were maintained until last follow-up after 24 months. CONCLUSION: Children with ADHD symptoms receiving anthroposophic treatment had long-term improvement of symptoms and quality of life. PMID- 20830201 TI - Optimal management of carpal tunnel syndrome. AB - In order to improve health care efficiency and effectiveness, treatments should provide disease improvement or resolution at a reasonable cost. The American Academy of Orthopedic Surgeons (AAOS) published a guideline for treatment of carpal tunnel syndrome (CTS) in 2009 based on review of the literature up to April 6, 2007. We have now reviewed the material published since then. Through reviewing evidence-based articles published during this period, this paper examines the current options and trends for treating CTS. We performed a systematic review of the randomized controlled trials, meta-analyses, systematic reviews, and practice guidelines to present the outcomes of current treatments for this disease. Twenty-five studies met our inclusion criteria. Thirteen randomized, controlled trials and 12 systematic reviews, including three Cochrane database systematic reviews, were retrieved. Our review revealed that most of the recent studies support the AAOS guideline. However, the recent literature demonstrates a trend towards recommending early surgery for CTS cases with or without median nerve denervation, although the AAOS guideline recommends early surgical treatment only for cases with denervation. The usefulness of splinting and steroids as initial treatments for improving patients' symptoms are also supported by the recent literature, but these effects are temporary. The evidence level for ultrasound treatment is still low, and further studies are needed to determine the effectiveness of this treatment. Finally, our review revealed a paucity of articles comparing the costs of CTS diagnosis and treatment. With the recent focus on health care reform and rising costs, attention to the direct and indirect costs of health care is important for all conditions. Future well designed studies should include cost analyses to help determine the cost burden of CTS. PMID- 20830202 TI - Metabolomics unravel contrasting effects of biodiversity on the performance of individual plant species. AB - In spite of evidence for positive diversity-productivity relationships increasing plant diversity has highly variable effects on the performance of individual plant species, but the mechanisms behind these differential responses are far from being understood. To gain deeper insights into the physiological responses of individual plant species to increasing plant diversity we performed systematic untargeted metabolite profiling on a number of herbs derived from a grassland biodiversity experiment (Jena Experiment). The Jena Experiment comprises plots of varying species number (1, 2, 4, 8, 16 and 60) and number and composition of functional groups (1 to 4; grasses, legumes, tall herbs, small herbs). In this study the metabolomes of two tall-growing herbs (legume: Medicago x varia; non legume: Knautia arvensis) and three small-growing herbs (legume: Lotus corniculatus; non-legumes: Bellis perennis, Leontodon autumnalis) in plant communities of increasing diversity were analyzed. For metabolite profiling we combined gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF MS) and UPLC coupled to FT-ICR-MS (LC-FT-MS) analyses from the same sample. This resulted in several thousands of detected m/z-features. ANOVA and multivariate statistical analysis revealed 139 significantly changed metabolites (30 by GC-TOF MS and 109 by LC-FT-MS). The small-statured plants L. autumnalis, B. perennis and L. corniculatus showed metabolic response signatures to increasing plant diversity and species richness in contrast to tall-statured plants. Key metabolites indicated C- and N-limitation for the non-leguminous small-statured species B. perennis and L. autumnalis, while the metabolic signature of the small statured legume L. corniculatus indicated facilitation by other legumes. Thus, metabolomic analysis provided evidence for negative effects of resource competition on the investigated small-statured herbs that might mechanistically explain their decreasing performance with increasing plant diversity. In contrast, taller species often becoming dominant in mixed plant communities did not show modified metabolite profiles in response to altered resource availability with increasing plant diversity. Taken together, our study demonstrates that metabolite profiling is a strong diagnostic tool to assess individual metabolic phenotypes in response to plant diversity and ecophysiological adjustment. PMID- 20830203 TI - Incipient resistance of Helicoverpa punctigera to the Cry2Ab Bt toxin in Bollgard II cotton. AB - Combinations of dissimilar insecticidal proteins ("pyramids") within transgenic plants are predicted to delay the evolution of pest resistance for significantly longer than crops expressing a single transgene. Field-evolved resistance to Bacillus thuringiensis (Bt) transgenic crops has been reported for first generation, single-toxin varieties and the Cry1 class of proteins. Our five year data set shows a significant exponential increase in the frequency of alleles conferring Cry2Ab resistance in Australian field populations of Helicoverpa punctigera since the adoption of a second generation, two-toxin Bt cotton expressing this insecticidal protein. Furthermore, the frequency of cry2Ab resistance alleles in populations from cropping areas is 8-fold higher than that found for populations from non-cropping regions. This report of field evolved resistance to a protein in a dual-toxin Bt-crop has precisely fulfilled the intended function of monitoring for resistance; namely, to provide an early warning of increases in frequencies that may lead to potential failures of the transgenic technology. Furthermore, it demonstrates that pyramids are not 'bullet proof' and that rapid evolution to Bt toxins in the Cry2 class is possible. PMID- 20830204 TI - A mouse model of post-arthroplasty Staphylococcus aureus joint infection to evaluate in vivo the efficacy of antimicrobial implant coatings. AB - BACKGROUND: Post-arthroplasty infections represent a devastating complication of total joint replacement surgery, resulting in multiple reoperations, prolonged antibiotic use, extended disability and worse clinical outcomes. As the number of arthroplasties in the U.S. will exceed 3.8 million surgeries per year by 2030, the number of post-arthroplasty infections is projected to increase to over 266,000 infections annually. The treatment of these infections will exhaust healthcare resources and dramatically increase medical costs. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate novel preventative therapeutic strategies against post-arthroplasty infections, a mouse model was developed in which a bioluminescent Staphylococcus aureus strain was inoculated into a knee joint containing an orthopaedic implant and advanced in vivo imaging was used to measure the bacterial burden in real-time. Mice inoculated with 5x10(3) and 5x10(4) CFUs developed increased bacterial counts with marked swelling of the affected leg, consistent with an acute joint infection. In contrast, mice inoculated with 5x10(2) CFUs developed a low-grade infection, resembling a more chronic infection. Ex vivo bacterial counts highly correlated with in vivo bioluminescence signals and EGFP-neutrophil fluorescence of LysEGFP mice was used to measure the infection-induced inflammation. Furthermore, biofilm formation on the implants was visualized at 7 and 14 postoperative days by variable-pressure scanning electron microscopy (VP-SEM). Using this model, a minocycline/rifampin impregnated bioresorbable polymer implant coating was effective in reducing the infection, decreasing inflammation and preventing biofilm formation. CONCLUSIONS/SIGNIFICANCE: Taken together, this mouse model may represent an alternative pre-clinical screening tool to evaluate novel in vivo therapeutic strategies before studies in larger animals and in human subjects. Furthermore, the antibiotic-polymer implant coating evaluated in this study was clinically effective, suggesting the potential for this strategy as a therapeutic intervention to combat post-arthroplasty infections. PMID- 20830205 TI - Stability of the neurotensin receptor NTS1 free in detergent solution and immobilized to affinity resin. AB - BACKGROUND: Purification of recombinant membrane receptors is commonly achieved by use of an affinity tag followed by an additional chromatography step if required. This second step may exploit specific receptor properties such as ligand binding. However, the effects of multiple purification steps on protein yield and integrity are often poorly documented. We have previously reported a robust two-step purification procedure for the recombinant rat neurotensin receptor NTS1 to give milligram quantities of functional receptor protein. First, histidine-tagged receptors are enriched by immobilized metal affinity chromatography using Ni-NTA resin. Second, remaining contaminants in the Ni-NTA column eluate are removed by use of a subsequent neurotensin column yielding pure NTS1. Whilst the neurotensin column eluate contained functional receptor protein, we observed in the neurotensin column flow-through misfolded NTS1. METHODS AND FINDINGS: To investigate the origin of the misfolded receptors, we estimated the amount of functional and misfolded NTS1 at each purification step by radio-ligand binding, densitometry of Coomassie stained SDS-gels, and protein content determination. First, we observed that correctly folded NTS1 suffers damage by exposure to detergent and various buffer compositions as seen by the loss of [(3)H]neurotensin binding over time. Second, exposure to the neurotensin affinity resin generated additional misfolded receptor protein. CONCLUSION: Our data point towards two ways by which misfolded NTS1 may be generated: Damage by exposure to buffer components and by close contact of the receptor to the neurotensin affinity resin. Because NTS1 in detergent solution is stabilized by neurotensin, we speculate that the occurrence of aggregated receptor after contact with the neurotensin resin is the consequence of perturbations in the detergent belt surrounding the NTS1 transmembrane core. Both effects reduce the yield of functional receptor protein. PMID- 20830206 TI - Being attractive brings advantages: the case of parrot species in captivity. AB - BACKGROUND: Parrots are one of the most frequently kept and bred bird orders in captivity. This increases poaching and thus the potential importance of captive populations for rescue programmes managed by zoos and related institutions. Both captive breeding and poaching are selective and may be influenced by the attractiveness of particular species to humans. In this paper, we tested the hypothesis that the size of zoo populations is not only determined by conservation needs, but also by the perceived beauty of individual parrot species assessed by human observers. METHODOLOGY/PRINCIPAL FINDINGS: For the purpose of data collection, we defined four sets of species (40 parrots, 367 parrots, 34 amazons, 17 macaws). Then, we asked 776 human respondents to evaluate parrot pictures of the selected species according to perceived beauty and we analyzed its association with color and morphological characters. Irrespective of the species set, we found a good agreement among the respondents. The preferred species tended to be large, colorful, and long-tailed. CONCLUSIONS/SIGNIFICANCE: We repeatedly confirmed significant, positive association between the perceived beauty and the size of worldwide zoo population. Moreover, the range size and body size appeared to be significant predictors of zoo population size. In contrast, the effects of other explanatory variables, including the IUCN (International Union for Conservation of Nature) listing, appeared insignificant. Our results may suggest that zoos preferentially keep beautiful parrots and pay less attention to conservation needs. PMID- 20830207 TI - Choice of mouse strain influences the outcome in a mouse model of chemical induced asthma. AB - BACKGROUND: The development of occupational asthma is the result of interactions between environmental factors and individual susceptibility. We assessed how our model of chemical-induced asthma is influenced by using different mouse strains. METHODOLOGY/PRINCIPAL FINDINGS: On days 1 and 8, male mice of 7 different strains (BALB/c, BP/2, A/J, C57Bl/6, DBA/2, CBA and AKR) were dermally treated with toluene-2,4-diisocyanate (TDI) (0.3%) or vehicle (acetone/olive oil, AOO, 2:3) on each ear (20 microl). On day 15, they received an oropharyngeal instillation of TDI (0.01%) or AOO (1:4). Airway reactivity to methacholine, total and differential cell counts in bronchoalveolar lavage (BAL) and total serum IgE and IgG(2a) levels were measured. Lymphocyte subpopulations in auricular lymph nodes and in vitro release of cytokines by ConA stimulated lymphocytes were assessed. In TDI-sensitized and challenged mice, airway hyper-reactivity was only observed in BALB/c, BP/2, A/J and AKR mice; airway inflammation was most pronounced in BALB/c mice; numbers of T-helper (CD4(+)), T-activated (CD4(+)CD25(+)), T cytotoxic (CD8(+)) and B- lymphocytes (CD19(+)) were increased in the auricular lymph nodes of BALB/c, BP/2, A/J and CBA mice; elevated concentrations of IL-4, IL-10, IL-13 and IFN-gamma were detected in supernatant of lymphocytes from BALB/c, BP/2, A/J, C57Bl/6 and CBA mice cultured with concanavaline A, along with an increase in total serum IgE. CONCLUSION: The used mouse strain has considerable and variable impacts on different aspects of the asthma phenotype. The human phenotypical characteristics of chemically-induced occupational asthma were best reproduced in Th2-biased mice and in particular in BALB/c mice. PMID- 20830208 TI - The G215R mutation in the Cl-/H+-antiporter ClC-7 found in ADO II osteopetrosis does not abolish function but causes a severe trafficking defect. AB - BACKGROUND: ClC-7 is a ubiquitous transporter which is broadly expressed in mammalian tissues. It is implied in the pathogenesis of lysosomal storage disease and osteopetrosis. Because of its endosomal/lysosomal localization it is still poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: An electrophysiological characterization of rat ClC-7 using solid-supported membrane-based electrophysiology is presented. The measured currents show the characteristics of ClC-7 and confirm its function as a Cl(-)/H(+)-antiporter. We have used rat ClC-7 in CHO cells as a model system to investigate the functionality and cellular localization of the wt transporter and its variant G213R ClC-7 which is the analogue of human G215R ClC-7 responsible for autosomal dominant osteopetrosis type II. Our study shows that rat G213R ClC-7 is functional but has a localization defect in CHO cells which prevents it from being correctly targeted to the lysosomal membrane. The electrophysiological assay is tested as a tool for drug discovery. The assay is validated with a number of drug candidates. It is shown that ClC-7 is inhibited by DIDS, NPPB and NS5818 at micromolar concentrations. CONCLUSIONS/SIGNIFICANCE: It is suggested that the scenario found in the CHO model system also applies to the human transporter and that mislocalization rather than impaired functionality of G215R ClC-7 is the primary cause of the related autosomal dominant osteopetrosis type II. Furthermore, the robust solid-supported membrane-based electrophysiological assay is proposed for rapid screening for potential ClC-7 inhibitors which are discussed for treatment of osteoporosis. PMID- 20830209 TI - A score of the ability of a three-dimensional protein model to retrieve its own sequence as a quantitative measure of its quality and appropriateness. AB - BACKGROUND: Despite the remarkable progress of bioinformatics, how the primary structure of a protein leads to a three-dimensional fold, and in turn determines its function remains an elusive question. Alignments of sequences with known function can be used to identify proteins with the same or similar function with high success. However, identification of function-related and structure-related amino acid positions is only possible after a detailed study of every protein. Folding pattern diversity seems to be much narrower than sequence diversity, and the amino acid sequences of natural proteins have evolved under a selective pressure comprising structural and functional requirements acting in parallel. PRINCIPAL FINDINGS: The approach described in this work begins by generating a large number of amino acid sequences using ROSETTA [Dantas G et al. (2003) J Mol Biol 332:449-460], a program with notable robustness in the assignment of amino acids to a known three-dimensional structure. The resulting sequence-sets showed no conservation of amino acids at active sites, or protein-protein interfaces. Hidden Markov models built from the resulting sequence sets were used to search sequence databases. Surprisingly, the models retrieved from the database sequences belonged to proteins with the same or a very similar function. Given an appropriate cutoff, the rate of false positives was zero. According to our results, this protocol, here referred to as Rd.HMM, detects fine structural details on the folding patterns, that seem to be tightly linked to the fitness of a structural framework for a specific biological function. CONCLUSION: Because the sequence of the native protein used to create the Rd.HMM model was always amongst the top hits, the procedure is a reliable tool to score, very accurately, the quality and appropriateness of computer-modeled 3D-structures, without the need for spectroscopy data. However, Rd.HMM is very sensitive to the conformational features of the models' backbone. PMID- 20830210 TI - Influenza A (H1N1) 2009 antibodies in residents of New South Wales, Australia, after the first pandemic wave in the 2009 southern hemisphere winter. AB - BACKGROUND: The first wave of pandemic influenza A(H1N1)2009 (pH1N1) reached New South Wales (NSW), Australia in May 2009, and led to high rates of influenza related hospital admission of infants and young to middle-aged adults, but no increase in influenza-related or all-cause mortality. METHODOLOGY/PRINCIPAL FINDINGS: To assess the population rate of pH1N1 infection in NSW residents, pH1N1-specific haemagglutination inhibition (HI) antibody prevalence was measured in specimens collected opportunistically before (2007-2008; 474 specimens) and after (August-September 2009; 1247 specimens) the 2009 winter, and before the introduction of the pH1N1 monovalent vaccine. Age- and geographically-weighted population changes in seroprevalence were calculated. HI antibodies against four recent seasonal influenza A viruses were measured to assess cross-reactions. Pre- and post-pandemic pH1N1 seroprevalences were 12.8%, and 28.4%, respectively, with an estimated overall infection rate of 15.6%. pH1N1 antibody prevalence increased significantly - 20.6% overall - in people born since 1944 (26.9% in those born between 1975 and 1997) but not in those born in or before 1944. People born before 1925 had a significantly higher pH1N1 seroprevalence than any other age group, and against any seasonal influenza A virus. Sydney residents had a significantly greater change in prevalence of antibodies against pH1N1 than other NSW residents (19.3% vs 9.6%). CONCLUSIONS/SIGNIFICANCE: Based on increases in the pH1N1 antibody prevalence before and after the first pandemic wave, 16% of NSW residents were infected by pH1N1 in 2009; the highest infection rates (27%) were among adolescents and young adults. Past exposure to the antigenically similar influenza A/H1N1(1918) is the likely basis for a very high prevalence (49%) of prepandemic cross-reacting pH1N1 antibody and sparing from pH1N1 infection among people over 85 years. Unless pre-season vaccine uptake is high, there are likely to be at least moderate rates including some life-threatening cases of pH1N1 infection among young people during subsequent winters. PMID- 20830212 TI - As Go the Feet ... : On the Estimation of Attentional Focus from Stance. AB - The estimation of the direction of visual attention is critical to a large number of interactive systems. This paper investigates the cross-modal relation of the position of one's feet (or standing stance) to the focus of gaze. The intuition is that while one CAN have a range of attentional foci from a particular stance, one may be MORE LIKELY to look in specific directions given an approach vector and stance. We posit that the cross-modal relationship is constrained by biomechanics and personal style. We define a stance vector that models the approach direction before stopping and the pose of a subject's feet. We present a study where the subjects' feet and approach vector are tracked. The subjects read aloud contents of note cards in 4 locations. The order of 'visits' to the cards were randomized. Ten subjects read 40 lines of text each, yielding 400 stance vectors and gaze directions. We divided our data into 4 sets of 300 training and 100 test vectors and trained a neural net to estimate the gaze direction given the stance vector. Our results show that 31% our gaze orientation estimates were within 5 degrees , 51% of our estimates were within 10 degrees , and 60% were within 15 degrees . Given the ability to track foot position, the procedure is minimally invasive. PMID- 20830213 TI - A Novel Model Predictive Control Formulation for Hybrid Systems With Application to Adaptive Behavioral Interventions. AB - This paper presents a novel model predictive control (MPC) formulation for linear hybrid systems. The algorithm relies on a multiple-degree-of-freedom formulation that enables the user to adjust the speed of setpoint tracking, measured disturbance rejection and unmeasured disturbance rejection independently in the closed-loop system. Consequently, controller tuning is more flexible and intuitive than relying on move suppression weights as traditionally used in MPC schemes. The formulation is motivated by the need to achieve robust performance in using the algorithm in emerging applications, for instance, as a decision policy for adaptive, time-varying interventions used in behavioral health. The proposed algorithm is demonstrated on a hypothetical adaptive intervention problem inspired by the Fast Track program, a real-life preventive intervention for improving parental function and reducing conduct disorder in at-risk children. Simulation results in the presence of simultaneous disturbances and significant plant-model mismatch are presented. These demonstrate that a hybrid MPC-based approach for this class of interventions can be tuned for desired performance under demanding conditions that resemble participant variability that is experienced in practice when applying an adaptive intervention to a population. PMID- 20830211 TI - Lazarus1, a DUF300 protein, contributes to programmed cell death associated with Arabidopsis acd11 and the hypersensitive response. AB - BACKGROUND: Programmed cell death (PCD) is a necessary part of the life of multi cellular organisms. A type of plant PCD is the defensive hypersensitive response (HR) elicited via recognition of a pathogen by host resistance (R) proteins. The lethal, recessive accelerated cell death 11 (acd11) mutant exhibits HR-like accelerated cell death, and cell death execution in acd11 shares genetic requirements for HR execution triggered by one subclass of R proteins. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes required for this PCD pathway, we conducted a genetic screen for suppressors of acd11, here called lazarus (laz) mutants. In addition to known suppressors of R protein-mediated HR, we isolated 13 novel complementation groups of dominant and recessive laz mutants. Here we describe laz1, which encodes a protein with a domain of unknown function (DUF300), and demonstrate that LAZ1 contributes to HR PCD conditioned by the Toll/interleukin-1 (TIR)-type R protein RPS4 and by the coiled-coil (CC)-type R protein RPM1. Using a yeast-based topology assay, we also provide evidence that LAZ1 is a six transmembrane protein with structural similarities to the human tumor suppressor TMEM34. Finally, we demonstrate by transient expression of reporter fusions in protoplasts that localization of LAZ1 is distributed between the cytosol, the plasma membrane and FM4-64 stained vesicles. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that LAZ1 functions as a regulator or effector of plant PCD associated with the HR, in addition to its role in acd11-related death. Furthermore, the similar topology of a plant and human DUF300 proteins suggests similar functions in PCD across the eukaryotic kingdoms, although a direct role for TMEM34 in cell death control remains to be established. Finally, the subcellular localization pattern of LAZ1 suggests that it may have transport functions for yet unknown, death-related signaling molecules at the plasma membrane and/or endosomal compartments. In summary, our results validate the utility of the large-scale suppressor screen to identify novel components with functions in plant PCD, which may also have implications for deciphering cell death mechanisms in other organisms. PMID- 20830214 TI - DISYUNTIVAS EN LAS CONCEPCIONES SOBRE AUTONOMIA Y BENEFICENCIA QUE AFECTAN LA TERAPEUTICA DEL INTENTO SUICIDA. AB - El objetivo del trabajo es conocer las disyuntivas entre los principios de beneficencia y autonomia, que se presentan en la relacion medico-paciente, durante la terapeutica del intento de suicidio.La investigacion se realizo en dos hospitales psiquiatricos de la Ciudad de Mexico. La muestra incluyo a tres sujetos con intento de suicidio, mayores de 18 anos, que eran atendidos en consulta externa a causa de una lesion autoinfligida en el ultimo ano, y a tres psiquiatras que trataban a estos pacientes. La informacion se obtuvo previo consentimiento informado en entrevistas individuales. Se llevo a cabo un analisis de discurso argumentado para encontrar los significados que los participantes otorgaron a los principios bioeticos y las posibles disyuntivas entre estos.Las discordancias entre la beneficencia y la autonomia estuvieron relacionadas con el beneficio del tratamiento, el respeto por los valores y las creencias de los pacientes, entre otros. Este trabajo presenta consideraciones eticas relevantes en el escenario clinico, al ofrecer al psiquiatra un analisis bioetico que le permita actuar de acuerdo con la beneficencia y respetando la autonomia del paciente frente a casos de intento de suicidio y, de esta forma procurar una mejor atencion para ellos. PMID- 20830215 TI - Extracting and Representing the Cortical Sulci. PMID- 20830216 TI - Rolling Circle DNA Synthesis: Small Circular Oligonucleotides as Efficient Templates for DNA Polymerases. AB - We report that small, single-stranded circular DNA oligonucleotides 26 to 74 nucleotides (nt) in size can behave as catalytic templates for DNA synthesis by several DNA polymerase enzymes. The DNA products are repeating end-to-end multimeric copies of the synthetic circular DNAs, and range from 1 000 to > 12 000 nucleotides in length. Several aspects of this reaction are unusual: first, the synthesis proceeds efficiently despite the curvature and small size of the circles, some of which have diameters significantly smaller than that of the enzyme itself. Second, the synthesis can proceed hundreds of times around the circle, while rolling replication of larger circular plasmid DNAs requires other proteins for processive synthesis. Finally, the synthesis scheme produces multiple copies of the template without the requirement for either heating or cooling cycles and requires less than stoichiometric amounts of primer, unlike other DNA synthesis methods. We report on the scope of this reaction, and demonstrate that the multimeric products can be cleaved enzymatically to short, sequence-defined oligodeoxynucleotides. This new approach to DNA synthesis may be a practical way to produce useful repeating DNAs, and combined with DNA cleavage strategies, it may represent a useful enzymatic approach to short, sequence defined oligodeoxynucleotides. PMID- 20830217 TI - Non-gastric marginal zone B-cell lymphoma in Korea: clinical features, treatment, and prognostic factors. AB - Marginal zone B-cell lymphoma (MZL) is the second most common subtype of non Hodgkin's lymphoma in Korea (17.3%). Mucosa-associated lymphoid tissue (MALT) can develop in almost any organ as a result of exposure to a persistent stimulus, such as chronic infection or certain autoimmune processes. Under conditions of prolonged lymphoid proliferation, a malignant clone may emerge, which is followed by the development of a MALT lymphoma. Whereas MALT lymphoma of the stomach is the most common and the most extensively studied, we focus on non-gastric MZL studies conducted in Korea that highlight the most recent advances with respect to MZL definition, etiology, clinical characteristics, natural history, treatment approaches, outcomes, and prognostic factors. Moreover, we discuss current organ specific considerations and controversies, and identify areas for future research. PMID- 20830218 TI - The effect of parental transmission of diabetes on the development of gestational diabetes mellitus. PMID- 20830219 TI - The ballooning time in endoscopic papillary balloon dilation for the treatment of bile duct stones. AB - BACKGROUND/AIMS: Endoscopic papillary balloon dilation (EPBD) is a safe and effective method for the treatment of choledocholithiasis, but previous studies have rarely reported the appropriate ballooning time (BT). We prospectively evaluated the safety and efficacy of EPBD according to BT in patients undergoing bile duct stone removal. METHODS: Seventy consecutive patients with bile duct stones were randomly assigned to receive EPBD with either conventional (n = 35, 60 seconds) or short (n = 35, 20 seconds) BT. RESULTS: EPBD alone achieved complete bile duct clearance in 67 patients (long BT, n = 33, 94.3%; short BT, n = 34, 97.1%; p = 0.808). We also found no significant difference in the rate of complete duct clearance, including procedures that used mechanical lithotripsy, between the long and short BT groups (97.1% vs. 100%; p = 0.811). Mild pancreatitis was noted in four (11.4%) patients in the long BT group and two (5.7%) patients in the short BT group, but this incidence was not significantly different. CONCLUSIONS: The study showed that EPBD using both 20-sec and 60-sec BTs is safe and effective for the treatment of bile duct stones. Short and long BTs produced comparable outcomes. PMID- 20830220 TI - Left ventricular dyssynchrony in patients showing diastolic dysfunction without overt symptoms of heart failure. AB - BACKGROUND/AIMS: Few studies have assessed left ventricular (LV) dyssynchrony in cases of diastolic dysfunction that do not include overt symptoms of heart failure. We hypothesized that systolic or diastolic dyssynchrony involves unique features with respect to the degree of diastolic impairment in isolated diastolic dysfunction. METHODS: We examined 105 subjects with no history of overt symptoms of heart failure and a left ventricular ejection fraction > 50% for mechanical dyssynchrony using tissue Doppler imaging. RESULTS: In terms of longitudinal dyssynchrony, four cases showed (6.3%) LV intraventricular systolic dyssynchrony (SDS(LV)), whereas none had LV intraventricular diastolic dyssynchrony (DDS(LV)) or co-existing systolic dyssynchrony. Radial dyssynchrony (RD) was found in six cases (9.4%). After adjusting for age, SDS(LV) and DDS(LV) were found to be significantly related to increases in the E/E' ratio (r = 0.405 and p < 0.001 vs. r = 0.216 and p = 0.045, respectively). RD at the base and apex was also significantly related to increases in E/E' (r = 0.298 and p = 0.002 vs. r = 0.196 and p = 0.045, respectively). CONCLUSIONS: Systolic and diastolic dyssynchrony in subjects with isolated diastolic dysfunction but without overt symptoms of heart failure was not as common as in patients with diastolic heart failure; however, the systolic and diastolic intraventricular time delay increased with increases in the E/E' ratio, an indicator of diastolic dysfunction. PMID- 20830221 TI - Combination of uric acid and NT-ProBNP: a more useful prognostic marker for short term clinical outcomes in patients with acute heart failure. AB - BACKGROUND/AIMS: In patients with heart failure (HF), N-terminal prohormone brain natriuretic peptide (NT-ProBNP) is a standard prognostic indicator. In addition, uric acid (UA) was recently established as a prognostic marker for poor outcome in chronic HF. The aim of this study was to determine the combined role of UA and NT-ProBNP as prognostic markers for short-term outcomes of acute heart failure (AHF). METHODS: The levels of UA and NT-ProBNP were determined in 193 patients (age, 69 +/- 13 years; 76 males) admitted with AHF. Patients were followed for 3 months and evaluated for cardiovascular events, defined as cardiac death and/or readmission for HF. RESULTS: Of the 193 patients, 23 (11.9%) died and 20 (10.4%) were readmitted for HF during the 3-month follow-up period. Based on univariate analysis, possible predictors of short-term cardiovascular events were high levels of UA and NT-ProBNP, low creatinine clearance, no angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and old age. Multivariate Cox hazard analysis showed that UA levels were independently associated with increased incidence of cardiovascular events (hazard ratio, 1.115; 95% confidence interval, 1.006 to 1.235; p = 0.037). Kaplan-Meier survival analysis revealed that patients with UA levels > 8.0 mg/dL and NT-ProBNP levels > 4,210 pg/mL were at highest risk for cardiac events (p = 0.01). CONCLUSIONS: The combination of UA and NT-ProBNP levels appears to be more useful than either marker alone as an independent predictor for short-term outcomes in patients with AHF. PMID- 20830222 TI - Usefulness of peak systolic strain measurement by automated function imaging in the prediction of coronary perfusion in patients with acute myocardial infarction. AB - BACKGROUND/AIMS: The usefulness of global longitudinal peak systolic strain (GLPSS) measurement by automated function imaging (AFI) in the prediction of perfusion status of infarct-related artery (IRA) before percutaneous coronary intervention (PCI) was evaluated. METHODS: Sixty-nine patients with acute myocardial infarction (AMI) who underwent successful primary PCI were divided into two groups; the patients with occlusion of IRA (Group I, 41 patients, 63.0 +/- 14.9 years of age, 31 males) versus the patients with patent IRA (Group II, 28 patients, 63.8 +/- 11.2 years of age, 15 males). GLPSS by AFI and wall-motion score index (WMSI) were analyzed in both groups. RESULTS: GLPSS was significantly decreased in Group I compared with Group II (-11.2 +/- 3.7 vs. -14.1 +/- 4.7%, p = 0.005), but WMSI (1.49 +/- 0.28 vs. 1.35 +/- 0.32, p = 0.062) did not differ between groups. GLPSS of infarct segments was significantly lower (-3.7 +/- 5.4 vs. -11.4 +/- 4.8%, p < 0.001), and WMSI of infarct segments was significantly higher (2.13 +/- 0.57 vs. 1.66 +/- 0.57, p = 0.001) in Group I compared with Group II. By receiver operation curve analysis, the area under the curve to predict IRA occlusion was 0.850 in GLPSS of infarct segments and 0.719 in WMSI of infarct segments. The optimal cut-off value to predict IRA occlusion was -9.4% in GLPSS of infarct segments (sensitivity, 85.4%; specificity, 67.9%) and 1.68 in WMSI of infarct segments (sensitivity, 78.0%; specificity, 60.7%). CONCLUSIONS: The present study suggested that GLPSS measured by AFI is a more sensitive predictor of IRA occlusion than is WMSI before PCI. Routine measurement of GLPSS by AFI can be a very useful tool in risk stratification of AMI. PMID- 20830223 TI - Familial clustering of type 2 diabetes in Korean women with gestational diabetes mellitus. AB - BACKGROUND/AIMS: This study was conducted to examine the relationship between family history of type 2 diabetes (T2DM) and risk of developing gestational diabetes mellitus (GDM) in Korean women. METHODS: We performed a 100-g oral glucose tolerance test in 858 pregnant women who had abnormal glucose tolerance in 50-g oral glucose challenge. In addition, we reviewed the incidence of T2DM in the parents and siblings and analyzed the association between the familial history of T2DM and the risk of GDM. RESULTS: Of the 858 subjects, 427 were normal, and 431 were diagnosed with GDM. Compared with women with no family history of T2DM, women with first degree family history of T2DM displayed higher risk of T2DM (odd ratio: parent only 1.91, sibling only 6.24, any 2.27). CONCLUSIONS: The risk of developing GDM was significantly increased in Korean women with a family history of T2DM in first-degree relatives. PMID- 20830224 TI - The effect of early insulin therapy on pancreatic beta-cell function and long term glycemic control in newly diagnosed type 2 diabetic patients. AB - BACKGROUND/AIMS: Based on the results of well designed clinical studies, intensive insulin therapy has been established to improve glycemic control in newly diagnosed diabetes. However, discrepancies exist between the findings of clinical trials and experiences in general practice. Furthermore, the efficacy of an early insulin therapy (EIT) - commonly used in general practice - on long-term glycemic control has not been established. Therefore, we evaluated the effects of EIT on pancreatic beta-cell function and glycemic control using insulin-based methods widely employed in general practice. METHODS: We performed a retrospective cohort study that initially involved reviewing patients' medical records. Following a thorough review, 61 patients who received either biphasic or prandial EIT at the time of diagnosis were enrolled. We then evaluated changes in beta-cell function and glycemic control during a 48-month follow-up period. RESULTS: Mean HbA1c decreased significantly as a result of EIT from 10.7 +/- 1.8% to 6.2 +/- 1.1% (p < 0.001). On average, 2.6 months was required to achieve an HbA1c value < 7%. EIT significantly improved the insulinogenic index. Glycemic control was well maintained for 48 months. More than 70% of patients were able to maintain glycemic control following lifestyle modifications or treatment with oral antidiabetic drugs. No significant differences were identified between patients receiving biphasic EIT and prandial EIT in terms of glycemic control or pancreatic beta-cell function. CONCLUSIONS: Our results suggest that regardless of the method of delivery, EIT significantly improves beta-cell function and facilitates long-term glycemic control in patients with newly diagnosed type 2 diabetes mellitus. PMID- 20830225 TI - Effect of glutathione administration on serum levels of reactive oxygen metabolites in patients with paraquat intoxication: a pilot study. AB - BACKGROUND/AIMS: Based on preliminary in vitro data from a previous study, we proposed that 50 mg/kg glutathione (GSH) would be adequate for suppressing reactive oxygen species in patients with acute paraquat (PQ) intoxication. METHODS: Serum levels of reactive oxygen metabolites (ROM) were measured before and after the administration of 50 mg/kg GSH to each of five patients with acute PQ intoxication. RESULTS: In one patient, extremely high pretreatment ROM levels began to decrease prior to GSH administration. However, in the remaining four cases, ROM levels did not change significantly prior to GSH administration. ROM levels decreased significantly after GSH administration in all cases. In two cases, ROM levels decreased below that observed in the general population; one of these patients died after a cardiac arrest at 3 hours after PQ ingestion, while the other represented the sole survivor of PQ intoxication observed in this study. In the survivor, ROM levels decreased during the first 8 hours of GSH treatment, and finally dropped below the mean ROM level observed in the general population. CONCLUSIONS: Treatment with 50 mg/kg GSH significantly suppressed serum ROM levels in PQ-intoxicated patients. However, this dose was not sufficient to suppress ROM levels when the PQ concentration was extremely high. PMID- 20830226 TI - Changing donor source pattern for kidney transplantation over 40 years: a single center experience. AB - BACKGROUND/AIMS: Kidney transplantations at our center rely mainly on living donors. The purpose of this study was to suggest future donor supply directions by reviewing changing trends in donor type. METHODS: During the past 40 years, 1,690 kidney transplantations were performed at our center. We divided the follow up period into four decades and the donor population into three groups: living related, living unrelated, and deceased. We analyzed changing trends in donors from each group for each decade. Patients receiving overseas transplantation were also included. RESULTS: The proportion of living related donors decreased from 84% (54/64) in the 1970s to 61% (281/458) in the 2000s. Living unrelated donors showed a sustained proportion of around 20% after 1990. However, among living unrelated donors, the proportion of spouse donors increased from 4.6% (17/369) in the 1980s to 8.5% (39/458) in the 2000s. Transplants from deceased donors were only 3.3% (12/369) in the 1980s. However the proportion of deceased donors increased gradually, reaching 13.2% (105/799) in the 1990s and 19.9% (91/458) after 2000. Overseas transplantations increased after 2000 and reached 20% of all cases treated in our center during the 2000s. Such transplantations peaked in 2006 and decreased markedly thereafter. CONCLUSIONS: The proportion of each donor type has continuously changed, and the changes were associated with changes in the social structure and system. We expect that this study could be an important reference for other countries to estimate future changes of donor type. PMID- 20830227 TI - Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. AB - BACKGROUND/AIMS: The efficacy and safety of pemetrexed, gefitinib, and erlotinib administration in previously treated patients with non-small cell lung cancer (NSCLC) were compared. METHODS: THE STUDY PATIENTS MET THE FOLLOWING CRITERIA: histologically confirmed, previously treated advanced (stage IIIB or IV) or recurrent NSCLC; a measurable lesion; >= 18 years of age; Eastern Cooperative Oncology Group Performance status 0 to 2; and no prior exposure to the three study drugs. Patients received 500 mg/m(2) of pemetrexed intravenously every 3 weeks with vitamin supplementation, gefitinib (250 mg/day per os), or erlotinib (150 mg/day per os). RESULTS: Of 57 patients (pemetrexed, 20; gefitinib, 20; and erlotinib, 17), 55 were evaluated for a response. The numbers of males, smokers, and squamous histology were increased in the pemetrexed group compared to the other groups. The objective response rates were 5.3%, 25.0%, and 12.5% (p = 0.22), and the disease control rates (DCR) were 5.3%, 40.0%, and 50.0%, respectively (p < 0.01). The median progression-free survival (PFS) was 1.7, 3.5, and 4.4 months (p < 0.01) and the median overall survival (OS) was 5.6, 21.8, and 21.5 months (p = 0.04), respectively. In subgroup analyses, patients with non squamous histology, males, and a smoking history had a higher DCR and longer PFS with gefitinib and erlotinib than with pemetrexed. All three chemotherapeutic agents had manageable toxicities. CONCLUSIONS: Both oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) had comparable efficacy and safety. The superior PFS and OS of EGFR TKIs with more favorable baseline clinical characteristics than those of pemetrexed suggest the impact of baseline clinicopathological factors. PMID- 20830228 TI - Modified number of extranodal involved sites as a prognosticator in R-CHOP treated patients with disseminated diffuse large B-cell lymphoma. AB - BACKGROUND/AIMS: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP) has improved survival in patients with diffuse large B-cell lymphoma (DLBCL) and weakened the prognostic power of the international prognostic index (IPI). We evaluated the efficacy of the IPI and revised IPI (R-IPI) in patients with DLBCL who were treated with R-CHOP, focusing on extranodal site number (ENS) because extranodal involvement occurs frequently in Koreans. METHODS: A total of 126 R-CHOP-treated patients with stage III/IV DLBCL were analyzed. We performed a retrospective analysis of the clinicopathologic factors and verified the predictive power of the standard IPI and R-IPI. Various numbers of extranodal sites were analyzed for further stratification, and we set the extranodal site-modified IPI (E-IPI) as the IPI when the number of extranodal sites was stratified as < 3 vs. >= 3. RESULTS: A univariate analysis showed that ENS was associated with complete response (CR, p = 0.04), event-free survival (EFS, p = 0.01), and overall survival (OS, p < 0.001) when the ENS cut-off was set at >= 3. A multivariate analysis revealed that an ENS >= 3 remained associated with EFS (p < 0.01; hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.29 to 5.26) and OS (p < 0.01; HR, 3.52; 95% CI, 1.68 to 7.35). The IPI was effective for determining prognosis in terms of OS (p = 0.04) but not EFS (p = 0.17). The R-IPI was effective in terms of both variables (p = 0.02 and 0.04, respectively), as was the E-IPI (p = 0.01 and 0.001, respectively). CONCLUSIONS: An ENS < 3 vs. >= 3, rather than the original < 2 vs. >= 2, was the most significant prognostic factor for EFS and OS. All three indices were predictive, but only the E-IPI identified the high-risk group of R-CHOP-treated Korean patients with disseminated DLBCL. PMID- 20830229 TI - Airway responsiveness to inhaled aspirin is influenced by airway hyperresponsiveness in asthmatic patients. AB - BACKGROUND/AIMS: Many patients with aspirin-induced asthma have severe methacholine airway hyperresponsiveness (AHR), suggesting a relationship between aspirin and methacholine in airway response. This study was performed to determine whether methacholine AHR affects the response of asthmatics to inhaled aspirin. METHODS: The clinical records of 207 asthmatic patients who underwent inhalation challenges with both aspirin and methacholine were reviewed retrospectively. An oral aspirin challenge was performed in patients with a negative inhalation response. The bronchial reactivity index (BRindex) was calculated from the percent decrease in lung function divided by the last dose of the stimulus. RESULTS: Forty-one (20.9%) and 14 (7.1%) patients showed a positive response to aspirin following an inhalation and oral challenge, respectively. Only 24.3 and 14.3% of the responders had a history of aspirin intolerance, respectively. The methacholine BRindex was significantly higher in the inhalation responders (1.46 +/- 0.02) than in the oral responders (1.36 +/- 0.03, p < 0.01) and in non-responders (n = 141, 1.37 +/- 0.01, p < 0.001). The aspirin BRindex was significantly correlated with the methacholine BRindex (r = 0.270, p < 0.001). Three of four patients who received the oral challenge, despite a positive inhalation test, showed negative responses to the oral challenge. Two of these patients had severe AHR. CONCLUSIONS: A considerable number of asthmatic patients with no history of aspirin intolerance responded to the inhalation aspirin challenge. The airway response to aspirin was significantly correlated with methacholine-AHR, and a false-positive response to aspirin inhalation test seemed to occur primarily in patients with severe AHR. PMID- 20830231 TI - A case of type B dissecting aneurysm involving right sided aorta with Kommerell's diverticulum. AB - A right-sided aortic arch (RAA) is a rare congenital anomaly, and Stanford type B dissection aneurysms involving this anomaly is also uncommon. Surgical approaches to dealing with an RAA are complicated by the unusual anatomical features of the condition. Here we report the case of a 47-year-old male who had a type B dissecting aneurysm involving an RAA with Kommerell's diverticulum. Graft replacement was successfully performed with an uneventful postoperative course. PMID- 20830230 TI - Induction of macrophage migration inhibitory factor in ConA-stimulated rheumatoid arthritis synovial fibroblasts through the P38 map kinase-dependent signaling pathway. AB - BACKGROUND/AIMS: This study was undertaken to identify the intracellular signaling pathway involved in induction of macrophage migration inhibitory factor (MIF) in human rheumatoid arthritis (RA) synovial fibroblasts. METHODS: Human RA synovial fibroblasts were treated with concanavalin A (ConA), various cytokines, and inhibitors of signal transduction molecules. The production of MIF by synovial fibroblasts was measured in culture supernatants by ELISA. The expression of MIF mRNA was determined using reverse transcriptase polymerase chain reaction (RT-PCR) and real-time PCR. Phosphorylation of p38 mitogen activated protein (MAP) kinase in synovial fibroblasts was confirmed using Western blotting. The expression of MIF and p38 MAP kinase in RA synovium was determined using dual immunohistochemistry. RESULTS: The production of MIF by RA synovial fibroblasts increased in a dose-dependent manner after ConA stimulation. MIF was also induced by interferon-gamma, CD40 ligand, interleukin-15, interleukin-1beta, tumor necrosis factor-alpha, and transforming growth factor beta. The production of MIF by RA synovial fibroblasts was significantly reduced after inhibition of p38 MAP kinase. The expression of MIF and p38 MAP kinase was upregulated in the RA synovium compared with the osteoarthritis synovium. CONCLUSIONS: These results suggest that MIF production was induced through a p38 MAP-kinase-dependent pathway in RA synovial fibroblasts. PMID- 20830232 TI - Primary pulmonary biphasic synovial sarcoma confirmed by molecular detection of a SYT-SSX2 fusion gene: report of 1 case. AB - We experienced a case of primary pulmonary biphasic synovial sarcoma, which was confirmed by immunohistochemistry and molecular testing of SYT-SSX2 fusion transcripts. The patient was a 61-year-old man who presented with a well-defined mass in the left upper lung field on chest radiography. Left upper lobectomy with lymph node dissection was performed. Histological and immunophenotypic features were consistent with biphasic synovial sarcoma. Reverse transcriptase polymerase chain reaction, performed using RNA extracted from frozen tumor samples for the detection of SYT-SSX fusion gene, amplified a single 331-bp fragment that was characteristic of the SYT-SSX2 fusion transcripts. We report a case of primary pulmonary biphasic synovial sarcoma, which was confirmed by SYT-SSX2 fusion transcripts, and present a brief review of the literature on Korean cases. PMID- 20830233 TI - High-dose fentanyl patch for cancer pain of a patient with cholangiocarcinoma. AB - We describe here a patient who obtained a good analgesic effect with high-dose fentanyl patches for controlling cancer pain. A 52-year-old man was referred to our hospital because of severe cancer pain that was 7/10 on a numeric rating scale (NRS). He had been diagnosed with locally advanced cholangiocarcinoma 3 months previously. We prescribed weak opioids and an antidepressant, but his pain was not relieved. We introduced strong opioids (transdermal fentanyl patches for the background pain and a short-acting opioid for the breakthrough pain) and his pain was tolerable on 250 ug/hr of fentanyl patches for 3 months. With time, however, his pain intensity became worse and this reached up to 8/10 to 9/10 on the NRS. Percutaneous transhepatic biliary drainage was performed, which did not relieve his pain. We increased gradually the dose of transdermal fentanyl to 1,050 ug/hr (20 patches). At this dose, the patient was mentally alert, with good pain control (NRS 2/10 to 3/10) and no exacerbation of side effects. To the best of our knowledge, we report here on the highest dose of transdermal fentanyl that has been successfully used for treating a patient suffering from visceral cancer pain. PMID- 20830234 TI - A case of systemic lupus erythematosus presenting as malignant hypertension with hypertensive retinopathy. AB - The variability of cardiovascular abnormalities is one of the characteristics of systemic lupus erythematosus (SLE). Among the cardiovascular manifestations, hypertension is reported in 14% to 58.1% of patients in diverse ethnic populations, and remains a clinically important issue due to its close relationship with early mortality in patients with SLE. The development of hypertension in patients with SLE has been associated with advanced lupus-related renal disease and the medications used for the treatment of lupus. Malignant hypertension is a serious complication of hypertension; it rarely occurs in patients with SLE. However, it can occur in patients with other complicated medical conditions such as the antiphospholipid antibody syndrome (APS) or cardiac tamponade. Here, we report the case of a patient with SLE and malignant hypertension with hypertensive retinopathy that initially presented without clinical evidence of APS or hypertensive nephropathy. PMID- 20830235 TI - Skin wound healing modulation by macrophages. AB - Skin wound healing is a multi stage phenomenon that requires the activation, recruitment or activity of numerous cell types as keratinocytes, endothelial cells, fibroblast and inflammatory cells. Among the latter, macrophages appear to be central to this process. They colonize the wound at its very early stage and in addition to their protective immune role seem to organize the activity of other cell types at the following stages of the healing. Their benefit to this process is however controversial, as macrophages are described to promote the speed of healing but may also favour the fibrosis resulting from it in scars. Moreover wound healing defects are associated with abnormalities in the inflammatory phase. In this review, we summarise our knowledge on what are the Wound Associated Macrophages, and how they interact with the other cell types to control the reepithelisation, angiogenesis and the extracellular matrix remodelling. We believe this knowledge may open new avenues for therapeutic intervention on skin wounds. PMID- 20830236 TI - STAT3 upregulates the protein expression and transcriptional activity of beta catenin in breast cancer. AB - The expression of beta-catenin detectable by immunohistochemistry has been reported to be prognostically important in breast cancer. In this study, we investigated the mechanism by which beta-catenin is regulated in breast cancer cells. Our analysis of the gene promoter of beta-catenin revealed multiple putative STAT3 binding sites. In support of the concept that STAT3 is a transcriptional regulator for beta-catenin, results from our chromatin immunoprecipitation studies showed that STAT3 binds to two of the three potential STAT3-binding sites in the gene promoter of beta-catenin (-856 and -938). Using our generated MCF-7 cell clones that carry an inducible STAT3C construct, we found that the expression levels of STAT3C significantly correlated with the transcriptional activity of beta-catenin. Similar observations were made when we subjected two breast cancer cell lines (MCF-7 and BT-474) to STAT3 knock-down or transient gene transfection of STAT3C. Using immunohistochemistry, we found that pSTAT3 and beta-catenin significantly correlated with each other (p=0.003, Fisher's exact test) in a cohort of primary breast tumors (n=129). To conclude, our results support the concept that STAT3 upregulates the protein expression and transcriptional activity of beta-catenin in breast cancer, and these two proteins may cooperate with each other in exerting their oncogenic effects in these tumors. PMID- 20830237 TI - Hereditary diffuse leukoencephalopathy with spheroids: ultrastructural and immunoelectron microscopic studies. AB - Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with myelin loss and axonal swellings (spheroids) leading to progressive cognitive and motor dysfunction. Histopathology of HDLS has been well characterized, but ultrastructural details are lacking. Here we report ultrastructural and immunoelectron microscopic characterization of spheroids and capillary basal lamina in white matter of HDLS brains. Spheroids had thin or discontinuous or no myelin sheaths. They contained various combinations of aggregated neurofilaments (NF), cytoplasmic organelles, dense bodies, and laminated figures. Aggregated filaments labeled with antibodies to phosphorylated NF (pNF), non-pNF and amyloid precursor protein. The gliotic white matter had many reactive astrocytes, and lipid-laden macrophages with membranous and fingerprint-like bodies. The basal laminas (BL) of many capillaries were dilated, and the enlarged space was heavily deposited with banded collagen type I and III. Some BL had focal thickenings and duplications. Fibronectin, not collagen IV, was found associated with banded collagen. The various types of axonal spheroids and changes in capillary basal lamina have not been emphasized previously. It remains to be determined if they are a reactive process or a primary mechanism of white matter degeneration in HDLS. PMID- 20830238 TI - Hepatic steatosis causes induction of the chemokine RANTES in the absence of significant hepatic inflammation. AB - Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to cirrhosis. Hepatocellular lipid accumulation is a hallmark of both nonalcoholic steatosis and steatohepatitis (NASH). The latter develops upon pro-inflammatory cell infiltration and is widely considered as the first relevant pathophysiological step in NAFLD-progression. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. We here aimed to investigate its expression in NAFLD. Incubation of primary human hepatocytes with palmitic acid induced a dose-dependent lipid accumulation, and corresponding dose-dependent RANTES induction in vitro. Furthermore, we observed significantly elevated hepatic RANTES expression in a dietary model of NAFLD, in which mice were fed a high-fat diet for 12 weeks. This diet induced significant hepatic steatosis but only minimal inflammation. In contrast to the liver, RANTES expression was not induced in visceral adipose tissue of the group fed with high fat diet. Finally, RANTES serum levels were elevated in patients with ultrasound diagnosed NAFLD. In conclusion, our data indicate hepatocytes as cellular source of elevated hepatic as well as circulating RANTES levels in response to hepatic steatosis. Noteworthy, upregulation of RANTES in response to lipid accumulation occurs in the absence of relevant inflammation, which further indicates that hepatic steatosis per se has pathophysiological relevance and should not be considered as benign. PMID- 20830239 TI - Skeletal muscle-derived stem cells differentiate into hepatocyte-like cells and aid in liver regeneration. AB - The liver is unique for its ability to regenerate after injury, however, critical injuries or disease cause it to lose this quality. Stem cells have been explored as a possibility to restore the function of seriously damaged livers, based on their self-renewability and multiple differentiation capacity. These experiments examine the ability of muscle derived stem cells (MDSCs) to differentiate into hepatocyte-like cells in vitro and acquire functional liver attributes for repairing damaged livers. In vitro experiments were performed using MDSCs from postnatal mice and mouse hepatocyte cell lines. Our data revealed that MDSCs differentiated into hepatocyte-like cells and expressed liver cell markers, albumin, hepatocyte nuclear factor 4 alpha, and alpha feto-protein, both at the RNA and protein level. Additionally, in vivo studies showed successful engraftment of MDSCs into hepatectomized mouse livers of mice. These results provide evidence suggesting that MDSCs have the capacity to differentiate into liver cell-like cells and may serve as potential candidates to aid in liver regeneration. PMID- 20830240 TI - Persistent hyperinsulinemic hypoglycemia of infancy: constitutive activation of the mTOR pathway with associated exocrine-islet transdifferentiation and therapeutic implications. AB - BACKGROUND: Amino-acids stimulate the mammalian target of rapamycin complex(mTORC)1; mTORC1 integrates amino-acid and energy-sensing pathways in beta cells. Rapamycin inhibits mTORC1. We examined the mTOR pathway and cell cycle data in the exocrine pancreas in diffuse persistent hyperinsulinemic hypoglycemia of infancy (PHHI). DESIGN: Tissues from two diffuse PHHI cases, one pediatric control and from adult pancreatic tissue microarray were analyzed. The case studies are newborns of non-diabetic mothers, one with SUR1 mutation, and the other with a family history of PHHI. Immunostaining for (p)-mTOR(Ser2448), phospholipase(PLD)1, cell cycle analytes ( Ki67, Skp2, p27Kip1), and insulin were performed. Cell cycle analytes were assessed by automated cellular imaging or visual quantification. Multispectral imaging of double immunostaining for insulin/p-mTOR and transmission electron microscopy (TEM) were performed. RESULTS: Hematoxylin-eosin and insulin-staining showed beta-cell hyperplasia in the exocrine pancreas, without mass effect. Overexpression of (p)-mTOR on the plasmalemmal, but not nuclear compartment, consistent with mTORC1, was noted in acinar elements. Residual expression was noted in islets. Double immunostaining revealed occasional exocrine cells co-expressing mTOR and insulin. No such co expressions were seen in the control. TEM showed acinar cells containing zymogen and hormone-secreting granules. No nuclear Skp2 was noted. Obversely, p27Kip1 was expressed. Mitotic index was 1/40 (0.25/10) HPF. CONCLUSION: Morphoproteomic, histopathologic and morphometric findings in this study of diffuse PHHI coincide with existing genomic and signal transduction data in: 1) supporting a role for a constitutively activated and overexpressed mTORC1 pathway in the acinar pancreas in its pathogenesis; 2) reaffirming transdifferentiation of acinar-to-islet cells; 3) raising the possibility of rapamycin as a therapeutic option in PHHI. PMID- 20830241 TI - Anti-angiogenic effects of epigallocatechin-3-gallate in human skin. AB - Epigallocatechin-3-gallate (EGCG) is the main polyphenol component of green tea. This compound exhibits antioxidant, immunomodulatory, photoprotective, anti angiogenic, and anti-inflammatory properties. We conducted a small randomized, double blind, split face trial using a cream containing 2.5% w/w of EGCG. Four healthy volunteers with significant erythema and telangiectasia on the face applied EGCG cream to one side of the face, and vehicle control cream to the other, twice daily for six weeks. After six weeks, biopsies were taken from EGCG and vehicle treated sites. Immunohistochemistry was used to measure VEGF and HIF 1 alpha. HIF-1 alpha expression was decreased in EGCG treated sites, such that 28.4% of the epidermis showed positive staining in vehicle treated vs. 13.8% in EGCG treated sites (p<0.001). A similar decrease in VEGF expression was found (6.7% in EGCG vs. 11.0%in in vehicle-treated skin (p<0.005). EGCG topical treatments influence HIF-1 alpha induction and VEGF expression and may serve as a potential agent in the prevention of telangiectasias. PMID- 20830242 TI - The specific inhibition of HepG2 cells proliferation by apoptosis induced by gabexate mesilate. AB - Many anticancer drugs are developing until now. However, conventional anticancer drugs causes damage to not only cancer cells but also non-cancerous tissues and cells. Therefore, the development of new drugs are anticipated.HepG2 cell proliferation in cell culture was significantly inhibited by gabexate mesilate. In TUNEL method, a significant amount of HepG2 cells cultured with gabexate mesilate showed a decrease in the number of total cells and an increased in the number of positive cells. Further immunohistochemical staining for P-53,ss-DNA and caspase 3 showed samely a decrease in the number of total cells and an increase in the number of positive cells. The staining for bcl2 showed a decrease in the number of total cells and no remarkable change in the number of positive cells. The cell growth inhibition by gabexate mesilate was almost blocked by caspase 3 inhibitor. Therefore, the inhibition itself of HepG2 cell proliferation by gabexate mesilate was mainly due to the apoptosis. This agent causes mainly damage to HepG2 cell by apoptosis but does not cause side effects, differing from the above anticancer drugs, Gabexate mesilate is a useful drug. PMID- 20830243 TI - Isolated trisomy 10 in an infant with acute myeloid leukemia: a case report and review of literature. AB - Trisomy 10 as the sole cytogenetic abnormality in AML is rare, with an incidence rate of < 0.5%. It tends to affect the elderly and is extremely rare in pediatric patients. We describe a case of an 8-month-old Caucasian baby who presented with prominence of left eye and fever without lymphadenopathy or hepatosplenomegaly. Bone survey showed diffuse periosteal reaction in the femur, pelvis, maxillary and orbital bones (with fracture). CBC revealed normal white blood cell count with increased blasts, mild anemia and moderate thrombocytopenia. Bone marrow biopsy showed increased myeloblasts with bilineage dysplasia and 3-4+ reticulin fibrosis. Flow cytometry revealed blasts positive for CD34, CD33, and MPO and negative for CD7, CD13, and HLA-DR. Trisomy 10 was demonstrated by chromosome analysis and fluorescence in-situ hybridization. The patient received induction chemotherapy and achieved complete clinical and hematologic remission at day 28. However, he relapsed after three cycles of chemotherapy. Compared to the two other reported pediatric cases, our patient has some unique features such as much younger age and additional findings such as bilineage dysplasia and bone marrow fibrosis. Both reported cases and our case were classified as AML-M2 indicating that this may be a common subtype in pediatric patients. Bone involvement was present in our patient and one other case and both had similar immunophenotype (CD33+, CD7-). These findings suggest that isolated trisomy 10 may be associated with distinct clinicopathologic features in pediatric AML. Studies on additional patients are needed to establish this association. PMID- 20830244 TI - Array-CGH and quantitative PCR genetic analysis in a case with bilateral hypoplasia of pulmonary arteries and lungs and simultaneous unilateral renal agenesis. AB - We describe the clinical course and have characterised anatomically and genetically a unique case of a newborn with bilateral hypoplasia of pulmonary arteries, consecutive extremely hypoplastic lung tissue and associated unilateral renal agenesis. Intrauterine oxygenation by the placenta seemed to have allowed normotrophic body maturity but immediately after delivery, in the third trimester, progressive hypoxemia developed and the newborn succumbed to acute respiratory failure. Genetic analysis by array-based comparative genomic hybridisation and quantitative PCR revealed duplication of 1p21, which, however, might not be the disease causing aberration. This case might represent an extreme form of previously reported, rare cases with simultaneous dysorganogenesis of lungs and kidneys. PMID- 20830245 TI - Primary lung seminoma in a 76-year-old man: a case report. AB - BACKGROUND: Seminoma is a rare event in old male population. In this report, we present a rare case of primary seminoma in the lung of a 76-years-old man. CASE PRESENTATION: The patient was a 76-year-old man admitted with respiratory tract symptom and hemoptysis. The Chest Routine Scan and CT showed there was a consolidation area in the basal segments at the lower lobe of left lung. Bronchoscope also exhibited a neoplasm in left lung. During left lower lobectomy, we found that adherence occurred widely in left thoracic wall, and the pleural membrane was shrinkage. No chemotherapy or radiotherapy was given. Patient was died at 140 days after the surgery mainly due to the dyscrasia and secondary seminoma in left 7th to 9th ribs. Placental alkaline phosphatase (PLAP) and CD117 were found to be positive with immunohistochemical studies. Along with other evidences, this case was identified as the manifestations of seminoma. CONCLUSION: Although primary seminoma of the lung is rare in old male population, the diagnosis should be taken into serious consideration in order to improve the treatment. And in this case, primary lung seminoma is associated with high degree of malignancy and metastasis. PMID- 20830246 TI - Primary mixed lymphoepithelioma-like carcinoma and intra-hepatic cholangiocarcinoma: a case report and review of literature. AB - Primary lymphoepithelioma-like carcinomas (LELC) of the hepatobiliary tract are quite rare and the majority are associated with the Epstein-Barr virus (EBV). Here we report an unusual case of intrahepatic cholangiocarcinoma (ICC), admixed with LELC in a 63 year-old Filipino woman who presented clinically with right flank and back pain. Histologically, the tumor showed a dense lymphocytic infiltrate, predominantly composed of CD3 (+) T cells, and two components: an undifferentiated carcinoma, morphologically similar to nasopharyngeal carcinoma, and a poorly differentiated ICC intimately admixed. Immunohistochemical studies revealed that both components were immunoreactive for AE1/AE3, cytokeratin 7 and, focally, for monoclonal CEA. Both components were negative for cytokeratin 20 and HePar 1. EBER-1 in situ hybridization was uniformly positive in the tumor cells. The presence of EBV in ICC and LELC suggests that the virus may be linked to the pathogenesis of both components of the tumor. The mechanism of virus-driven neoplastic transformation needs further study. PMID- 20830247 TI - Monoclonal antibody Cam 5.2 targeted mainly CK8, but not CK18--Comment on: "Chromophobe renal cell carcinoma with liposarcomatous dedifferentiation--report of a unique case. Int J Clin Exp Pathol. 2010 May 5; 3 (5):534-40.". PMID- 20830248 TI - Magnetic resonance imaging assessment of arrhythmogenic right ventricular cardiomyopathy/dysplasia in children. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetically determined disease that progresses continuously from conception and throughout life. ARVC/D manifests predominantly in young adulthood. Early identification of the concealed cases in childhood is of utmost importance for the prevention of sudden cardiac death later in life. Magnetic resonance imaging (MRI) is routinely requested in patients with a confirmed or suspected diagnosis of ARVC/D and in family members of the patients with ARVC/D. Although the utility of MRI in the assessment of ARVC/D is well recognized in adults, MRI is a low yield test in children as the anatomical, histological, and functional changes are frequently subtle or not present in the early phase of the disease. MRI findings of ARVC/D include morphologic changes such as right ventricular dilatation, wall thinning, and aneurismal outpouchings, as well as abnormal tissue characteristics such as myocardial fibrosis and fatty infiltration, and functional abnormalities such as global ventricular dysfunction and regional wall motion abnormalities. Among these findings, regional wall motion abnormalities are the most reliable MRI findings both in children and adults, while myocardial fibrosis and fat infiltration are rarely seen in children. Therefore, an MRI protocol should be tailored according to the patient's age and compliance, as well as the presence of other findings, instead of using the protocol that is used for adults. We propose that MRI in children with ARVC/D should focus on the detection of regional wall motion abnormalities and global ventricular function by using a cine imaging sequence and that the sequences for myocardial fat and late gadolinium enhancement of the myocardium are reserved for those who show abnormal findings at cine imaging. Importantly, MRI should be performed and interpreted by experienced examiners to reduce the number of false positive and false negative readings. PMID- 20830249 TI - Hybrid approach for complex thoracic aortic pathology. PMID- 20830250 TI - Pentraxin 3 as a novel marker predicting congestive heart failure in subjects with acute coronary syndrome. AB - BACKGROUND AND OBJECTIVES: Pentraxin 3 (PTX3) was shown to be elevated in the acute phase of acute myocardial infarction (AMI) and to have prognostic significance in AMI patients. The aim of this study was to estimate whether the value of PTX3 could be used as a prognostic biomarker, with the global registry of acute coronary events (GRACE) risk assessment tool, in patients with acute coronary syndrome (ACS). SUBJECTS AND METHODS: Between July 2007 and June 2008, 137 patient subjects (mean age : 61+/-12 years, M : F=108 : 29) with ACS who underwent coronary intervention, but did not have a prior percutaneous coronary intervention (PCI) and/or follow-up coronary angiogram, were enrolled. We estimated the all-cause mortality or death/MI, in-hospital and to 6 months, using the GRACE risk scores and compared these estimates with serum PTX3 concentrations. RESULTS: The serum PTX3 concentration showed a significant increase in ST segment elevation myocardial infarction (STEMI) greater than the unstable angina pectoris (UAP) group (2.4+/-2.1 ng/mL vs. 1.3+/-0.9 ng/mL, p= 0.017, respectively), but did not show a significant difference between non-ST segment elevation myocardial infarction (NSTEMI) and the UAP group (1.9+/-1.4 ng/mL vs. 1.3+/-0.9 ng/mL, p=0.083, respectively). The serum PTX3 concentration was closely related to death/MI in-hospital (r=0.242, p=0.015) and death/MI to 6 months (r=0.224, p=0.023), respectively. The serum PTX3 concentration was not related to all-cause mortality in-hospital (r=0.112, p=0.269) and to 6 months (r=0.132, p=0.191), respectively. Among the parameters determining the GRACE risk scores, the degree of Killip class in congestive heart failure (CHF) was independently associated with the supramedian PTX3 concentration [odds ratio: 2.229 (95% confidence interval: 1.038-4.787), p=0.040]. CONCLUSION: The serum PTX3 level provides important information for the risk stratification of CHF among the parameters determining the GRACE risk scores in subjects with ACS. PMID- 20830251 TI - Prognostic value of initial echocardiographic features in patients with tuberculous pericarditis. AB - BACKGROUND AND OBJECTIVES: Tuberculous (TB) pericarditis is a major cause of constrictive pericarditis requiring pericardiectomy. We sought to determine initial prognostic factors in patients with TB pericarditis. SUBJECTS AND METHODS: We evaluated initial presentation and clinical outcomes (mean follow-up 32+/-27 months) in 60 consecutive patients newly diagnosed with TB pericarditis. RESULTS: Initial presentations were pericardial effusion (PE), effusive constrictive pericarditis, and constrictive pericarditis in 45 (75%), 9 (15%), and 6 (10%) patients, respectively. Of the 54 patients without initial constrictive pericarditis, 32 (59%) showed echogenic materials in PE, including frond-like exudative coating and fibrinous strands. These patients had a longer disease duration before diagnosis, were initially more symptomatic, in a more advanced state, showed more persistent pericardial constrictions (38% vs. 0%, p<0.001) despite anti-TB medications, and tended to require pericardiectomy more often (19% vs. 0%, p=0.07, p<0.05 by Kaplan-Meier). All patients with effusive constrictive pericarditis showed echogenic PE. Of the 60 total patients, 10 (17%) underwent pericardiectomies during follow-up. All of these patients showed initial pericardial constrictions, whereas no patient without initial pericardial constriction underwent pericardiectomy (p<0.001). Seven patients showed transient pericardial constrictions that resolved without pericardiectomy. CONCLUSION: Initial pericardial constriction and echogenic PE are poor prognostic signs for persistent pericardial constriction and pericardiectomy in patients with newly diagnosed TB pericarditis. These results suggest that early diagnosis and prompt anti-TB medication may be critical. PMID- 20830252 TI - Short-term autonomic denervation of the atria using botulinum toxin. AB - BACKGROUND AND OBJECTIVES: Major epicardial fat pads contain cardiac ganglionated plexi (GP) of the autonomic nervous system. Autonomic denervation may improve the success rate of atrial fibrillation (AF) ablation. This study was designed to elucidate the acute effects of blocking the right atrium-pulmonary vein (RA-PV) and left atrium-inferior vena cava (LA-IVC) fat pads on the electrophysiologic characteristics of the atrium and AF inducibility with a botulinum toxin injection. MATERIALS AND METHODS: Eight mongrel dogs were studied. The RA-PV and LA-IVC fat pads were exposed through a median thoracotomy. Botulinum toxin (BT, 50 U to each fat pad, n=6) or normal saline (NS, n=2) was injected in the entire area of two fat pads. The study protocol was applied before injection and repeated at 1, 2, 3, 4, and 5 hours thereafter. The sinus rate, ventricular rate during rapid atrial pacing with a cycle length of 50 ms, and AF inducibility were measured with and without vagal stimulation (VS). Bilateral cervical VS was applied (20 Hz, 0.2 ms, 5.6+/-2.0 V). AF inducibility was evaluated with burst pacing with 200 impulses at a 50-ms cycle length. RESULTS: VS effects on the sinus node and AF inducibility were eliminated a few hours after injection of BT; these changes were not observed after injection of NS. CONCLUSION: Short-term autonomic denervation of the atria was achieved by blocking the major epicardial GP with BT. PMID- 20830253 TI - Dual pulsed-wave Doppler tracing of right ventricular inflow and outflow: single cardiac cycle right ventricular tei index and evaluation of right ventricular function. AB - BACKGROUND AND OBJECTIVES: The reliability and usefulness of the right ventricular (RV) Tei index (RTX) remains controversial because it has not been possible to simultaneously measure RV inflow and outflow. However, dual pulsed wave Doppler (DPD) enables flow velocities to be obtained at different sampling sites simultaneously. In this study we evaluated the feasibility and reliability of RTX values obtained by DPD (RTX(DPD)). SUBJECTS AND METHODS: Forty-one patients who underwent cardiac catheterization and echocardiography for RV volume or pressure overloading conditions were evaluated. Symptom-limited exercise treadmill testing with expired gas analysis was performed and maximal exercise capacity was measured. RESULTS: RTX by conventional flow Doppler (RTX(CFD), 0.262+/-0.164) was similar to RTX(DPD) (0.253+/-0.117, p=NS), whereas RTX by tissue Doppler echocardiography (RTX(TDE), 0.447+/-0.125) was significantly larger than RTX(DPD) (p<0.001). Based on multiple regression analysis, maximal exercise capacity was independently related to RTX(DPD) (beta=-0.60, p<0.001), mid-RV dimension (beta=-0.26, p=0.012), left ventricular ejection fraction (beta=0.22, p=0.023), and early diastolic tricuspid annular velocity (beta=0.21, p=0.048). CONCLUSION: It is feasible and reliable to evaluate RV function using RTX(DPD) values. However, to evaluate the clinical usefulness of RTX(DPD), additional studies are required with a large number of patients and long-term follow-up. PMID- 20830254 TI - Combined open and endovascular repair for aortic arch pathology. AB - BACKGROUND AND OBJECTIVES: We describe our experience with combined open and endovascular repair in patients who have aortic arch pathology. SUBJECTS AND METHODS: This study is a retrospective analysis of 7 patients who underwent combined open and endovascular repair for aortic arch pathology. Medical records and radiographic information were reviewed. RESULTS: A total of 7 consecutive patients (5 men, 71.4%) underwent thoracic stent graft implantation. The mean age was 59.9+/-16.7 years. The indication for endovascular repair was aneurysmal degeneration in 5 patients, and rupture or impending rupture in 2 patients. In all 7 cases, supra-aortic transposition of the great vessels was performed successfully. Stent graft implantation was achieved in all cases. Surgical exposure of the access vessel was necessary in 2 patients. A total of 9 stent grafts were implanted (3 stent grafts in one patient). The Seal thoracic and the Valiant endovascular stent graft were implanted in 6 patients and 1 patient, respectively. There were no post-procedure deaths or neurologic complications. In 2 patients, bleeding and injury of access vessel were noted after the procedure. Postoperative endoleak was noted in 1 patient. One patient died at 10 months after the procedure due to a newly developed ascending aortic dissection. No patients required secondary intervention during the follow-up period. The aortic diameter decreased in 4 patients. In 3 patients, including 1 patient with endoleak, there was no change in aortic diameter. CONCLUSION: Our experience suggests that combined open and endovascular repair for aortic arch pathology is safe and effective, with few complications. PMID- 20830255 TI - A novel technique for retrieval of a drug-eluting stent after catheter break and stent loss. AB - Break of a stent delivery catheter and subsequent stent loss (SL) has been a rare event in the drug-eluting stent (DES) era. We here report a case of successful retrieval of a stent after a break if the delivery catheter and SL from a balloon catheter at a culprit lesion. We finally resolved this situation using a simple balloon technique for both the broken stent catheter inside of the guide catheter and the unexpanded stent in the culprit lesion. Thus balloons are an important weapon in our armamentarium in the cardiac catheterization laboratory for urgent retrieval of a lost stent. Their apt use definitely allowed our patient to avoid undergoing emergency cardiovascular thoracic surgery. PMID- 20830256 TI - Left ventricular metastasis from renal cell carcinoma causing left ventricular outflow tract obstruction. AB - Most cases of cardiac metastasis from renal cell carcinoma (RCC) involve the vena cava or right atrium. Left ventricular metastases from RCC without involving the vena cava or right atrium are extremely rare. Herein we report a case of RCC with left ventricular metastasis causing left ventricular outflow obstruction (LVOT). PMID- 20830257 TI - Successful Percutaneous Renal Artery Angioplasty and Stenting for Acute Oliguric Renal Failure in a Solitary Functioning Kidney Caused by Takayasu's Arteritis. AB - Takayasu's arteritis (TA) is a nonspecific, chronic and stenotic panarteritis which usually involves the aorta and its major branches. Corticosteroid and immunosuppressants are recommended to manage the acute inflammatory phase, but their long term benefits are uncertain. Blood pressure (BP) control during the chronic phase of TA is essential to preserve renal function, which is associated with the patient's long-term prognosis and survival. Revascularization in organ damaging arterial stenosis with percutaneous angioplasty (PTA)/stenting or bypass surgery have been accepted as established treatment options in chronic complicated phase of TA. We present a case of a 31-year-old female patient with a two-day history of sudden onset oliguria and generalized edema whose acute oliguric renal failure was successfully reversed following PTA and stenting in a solitary functioning kidney with critical renal artery stenosis (RAS) caused by TA. PMID- 20830258 TI - Implantable cardioverter-defibrillator lead extraction by conventional traction and counter-traction technique. AB - A 46-year-old man presented to our institution with inappropriate implantable cardioverter-defibrillator (ICD) shock delivery. The ICD (single chamber, dual shock coils) was implanted for sustained monomorphic ventricular tachycardia with unstable hemodynamics and underlying systolic left ventricular dysfunction. ICD interrogation revealed recurrent episodes of ICD shock due to noise sensing and increased impedance of right ventricular (RV)-lead. With the impression of lead fracture, ICD lead extraction was performed. The fractured ICD lead was completely removed by traction of locking stylet and counter-traction of polypropylene dilator sheath. A new lead was inserted and the patient was discharged without complications after 2 days. To our knowledge, this is the first report on ICD lead extraction by conventional traction and counter-traction technique in Korea. PMID- 20830259 TI - The "Five-in-Seven" Guiding Technique to Overcome Proximal Coronary Tortuosity During Primary Percutaneous Coronary Intervention. PMID- 20830260 TI - Neuroimaging studies of chronic pain. AB - The evolution of brain imaging techniques over the last decade has been remarkable. Along with such technical developments, research into chronic pain has made many advances. Given that brain imaging is a non-invasive technique with great spatial resolution, it has played an important role in finding the areas of the brain related to pain perception as well as those related to many chronic pain disorders. Therefore, in the near future, brain imaging techniques are expected to be the key to the discovery of many unknown etiologies of chronic pain disorders and to the subjective diagnoses of such disorders. PMID- 20830261 TI - Effect of perioperative perineural injection of dexamethasone and bupivacaine on a rat spared nerve injury model. AB - BACKGROUND: Neuropathic pain resulting from diverse causes is a chronic condition for which effective treatment is lacking. The goal of this study was to test whether dexamethasone exerts a preemptive analgesic effect with bupivacaine when injected perineurally in the spared nerve injury model. METHODS: Fifty rats were randomly divided into five groups. Group 1 (control) was ligated but received no drugs. Group 2 was perineurally infiltrated (tibial and common peroneal nerves) with 0.4% bupivacaine (0.2 ml) and dexamethasone (0.8 mg) 10 minutes before surgery. Group 3 was infiltrated with 0.4% bupivacaine (0.2 ml) and dexamethasone (0.8 mg) after surgery. Group 4 was infiltrated with normal saline (0.2 ml) and dexamethasone (0.8 mg) 10 minutes before surgery. Group 5 was infiltrated with only 0.4% bupivacaine (0.2 ml) before surgery. Rat paw withdrawal thresholds were measured using the von Frey hair test before surgery as a baseline measurement and on postoperative days 3, 6, 9, 12, 15, 18 and 21. RESULTS: In the group injected preoperatively with dexamethasone and bupivacaine, mechanical allodynia did not develop and mechanical threshold forces were significantly different compared with other groups, especially between postoperative days 3 and 9 (P < 0.05). CONCLUSIONS: In conclusion, preoperative infiltration of both dexamethasone and bupivacaine showed a significantly better analgesic effect than did infiltration of bupivacaine or dexamethasone alone in the spared nerve injury model, especially early on after surgery. PMID- 20830262 TI - Antiallodynic Effect of Thalidomide and Morphine on Rat Spinal Nerve Ligation induced Neuropathic Pain. AB - BACKGROUND: Tumor necrosis factor-alpha and other proinflammatory cytokines are becoming well recognized as key mediators in the pathogenesis of many types of neuropathic pain. Thalidomide has profound immunomodulatory actions in addition to their originally intended pharmacological actions. There has been debate on the analgesic efficacy of opioids in neuropathic pain. The aim of this study was to investigate the effect of thalidomide and morphine on a spinal nerve ligation model in rats. METHODS: Male Sprague-Dawley rats weighing 100-120 g were used. Lumbar (L) 5 and 6 spinal nerve ligations were performed to induce neuropathic pain. For assessment of mechanical allodynia, mechanical stimulus using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of intraperitoneal thalidomide (6.25, 12.5, 25 and 50 mg/kg, respectively) and morphine (3 and 10 mg/kg, respectively) were examined on a withdrawal threshold evoked by spinal nerve ligation. RESULTS: After L5 and 6 spinal nerve ligation, paw withdrawal thresholds on the ipsilateral side were significantly decreased compared with pre-operative baseline and with those in the sham-operated group. Intraperitoneal thalidomide and morphine significantly increased the paw withdrawal threshold compared to controls and produced dose-responsiveness. CONCLUSIONS: Systemic thalidomide and morphine have antiallodynic effect on neuropathic pain induced by spinal nerve ligation in rat. These results suggest that morphine and thalidomide may be alternative therapeutic approaches for neuropathic pain. PMID- 20830263 TI - Antinociceptive Effect of Memantine and Morphine on Vincristine-induced Peripheral Neuropathy in Rats. AB - BACKGROUND: Vincristine-induced peripheral neuropathy is a major dose limiting side effect and thus effective therapeutic strategy is required. In this study, we investigated the antinociceptive effect of memantine and morphine on a vincristine-induced peripheral neuropathy model in rats. METHODS: Male Sprague Dawley rats weighing 220-240 g were used in all experiments. Rats subsequently received daily intraperitoneal injections of either vincristine sulfate (0.1 ml/kg/day) or saline (0.1 ml/kg/day) over 12 days, immediately following behavioral testing. For assessment of mechanical allodynia, mechanical stimuli using von Frey filament was applied to the paw to measure withdrawal threshold. The effects of N-methyl-D-aspartate receptors antagonist (memantine; 2.5, 5, 10 mg/kg intraperitoneal), opioid agonist (morphine; 2.5, 5, 10 mg/kg intraperitoneal) and vehicle (saline) on vicristine-induced neuropathy were evaluated. RESULTS: Mechanical allodynia developed over the course of ten daily injections of vincristine relative to groups receiving saline at the same time. Morphine abolished the reduction in paw withdrawal threshold compared to vehicle and produced dose-responsiveness. Only the highest dose of memantine (10 mg/kg) was able to increase paw withdrawal threshold compared to vehicle. CONCLUSIONS: Systemic morphine and memantine have an antinociceptive effect on the vincristine induced peripheral neuropathy model in rats. These results suggest morphine and memantine may be an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain. PMID- 20830264 TI - Circadian effects on neural blockade of intrathecal hyperbaric bupivacaine. AB - BACKGROUND: Circadian variations in the absorption, distribution, protein binding, elimination and metabolism of drugs account for many of the administration-time-dependent differences in their pharmacokinetics. The aim of this study is to determine whether the time of intrathecal injection influences spinal anesthesia. METHODS: Ninety patients scheduled for orthopedic surgery were randomly assigned to three groups. Each group received spinal anesthesia with 0.5% bupivacaine 10 mg at different times; group AM (8 am to 12:00), group Noon (12:00 to 4:00 pm) and group PM (4:00 pm to 8:00 pm). Sensory and motor blockade were assessed by pinprick and a four-point modified Bromage scale. Time to first postoperative analgesic requirement and side effects such as hypotension, bradycardia, nausea, and shivering were recorded. RESULTS: No significant differences were found among the three groups in peak sensory blockade, duration of motor block to Bromage 1 or side effects, but time to first postoperative analgesic requirement (P = 0.008), and recovery time of S1 sensation to pinprick were significantly prolonged in group Noon compared with the other groups (P = 0.03). CONCLUSIONS: The tine of administration of spinal local anesthetics influences the duration of local anesthesia. PMID- 20830265 TI - Is It Useful and Safe to Maintain the Sitting Position During Only One Minute before Position Change to the Jack-knife Position? AB - BACKGROUND: Conventional spinal saddle block is performed with the patient in a sitting position, keeping the patient sitting for between 3 to 10 min after injection of a drug. This amount of time, however, is long enough to cause prolonged postoperative urinary retention. The trend in this block is to lower the dose of local anesthetics, providing a selective segmental block; however, an optimal dose and method are needed for adequate anesthesia in variable situations. Therefore, in this study, we evaluated the question of whether only 1 min of sitting after drug injection would be sufficient and safe for minor anorectal surgery. METHODS: Two hundred and sixteen patients undergoing minor anorectal surgery under spinal anesthesia remained sitting for 1 min after completion of subarachnoid administration of 1 ml of a 0.5% hyperbaric bupivacaine solution (5 mg). They were then placed in the jack-knife position. After surgery, analgesia levels were assessed using loss of cold sensation in the supine position. The next day, urination and 11-point numeric rating scale (NRS) for postoperative pain were assessed. RESULTS: None of the patients required additional analgesics during surgical manipulation. Postoperative sensory levels were T10 [T8-T12] in patients, and no significant differences were observed between sex (P = 0.857), height (P = 0.065), obesity (P = 0.873), or age (P = 0.138). Urinary retention developed in only 7 patients (3.2%). In this group, NRS was 5.0 +/- 2.4 (P = 0.014). CONCLUSIONS: The one-minute sitting position for spinal saddle block before the jack-knife position is a safe method for use with minor anorectal surgery and can reduce development of postoperative urinary retention. PMID- 20830266 TI - Ultrasound-guided Pulsed Radiofrequency Lesioning of the Phrenic Nerve in a Patient with Intractable Hiccup. AB - Persistent and intractable hiccups (with respective durations of more than 48 hours and 1 month) can result in depression, fatigue, impaired sleep, dehydration, weight loss, malnutrition, and aspiration syndromes. The conventional treatments for hiccups are either non-pharmacological, pharmacological or a nerve block treatment. Pulsed radiofrequency lesioning (PRFL) has been proposed for the modulation of the excited nervous system pathway of pain as a safe and nondestructive treatment method. As placement of the electrode in close proximity to the targeted nerve is very important for the success of PRFL, ultrasound appears to be well suited for this technique. A 74 year-old man suffering from intractable hiccups that had developed after a coronary artery bypass graft and had continued for 7 years was referred to our pain clinic. He had not been treated with conventional methods or medications. We performed PRFL of the phrenic nerve guided by ultrasound and the hiccups disappeared. PMID- 20830267 TI - Air bubbles mimic disc herniation in MRI after cervical epidural block. AB - Magnetic resonance image (MRI) is the most sensitive imaging test of the spine in routine clinical practice. Unlike conventional x-ray examinations and computed tomography scans, high-quality magnetic resonance images can be assured only if patients are able to remain perfectly still. However, some patients find it uncomfortable to remain still because of pain. In that condition, interlaminar cervical epidural injections can reduce pain and allow the procedure. When using air with the "loss of resistance" technique in epidural injections to identify the epidural space, there is the possibility of injected excessive air epidurally to mimic a herniated disc. We describe a case report of epidural air artifact in a cervical MRI after cervical epidural injections. PMID- 20830268 TI - Early diagnosis of fabry disease in a patient with toe tip pain. AB - Fabry disease is an X-linked lysosomal disease caused by deficiency of alpha galactosidase, in which early diagnosis may be missed due to the wide variety of clinical symptoms presenting during disease progression. A 13 year-old boy visited our pain clinic complaining of pricking and burning pain in the toe tips of both feet. Continuous epidural infusion for pain management was performed because of oral analgesics ineffectiveness. The patient underwent alpha galactosidase A (GLA) enzyme analysis based on the clinical impression of Fabry disease from pain with a peripheral neuropathic component and history of anhidrosis. He was diagnosed with Fabry disease after confirming mutation of the GLA gene through a screening test of GLA activity. Enzyme replacement therapy was initiated and pain was tolerated with oral analgesics. PMID- 20830269 TI - Spontaneous retropharyngeal hematoma - a case report -. AB - Spontaneous retropharyngeal hematoma is rare and difficult to diagnosis early. A 23-year-old male spontaneously developed acute onset of neck pain, limitation of neck motion, and mild dysphagia. Magnetic resonance imaging demonstrated blood products in prevertebral space from C2 to C4, suggesting a diagnosis of retropharyngeal hematoma. We report a rare case of spontaneous retropharyngeal hematoma causing neck pain. PMID- 20830270 TI - Severe pain attack associated with neurocardiogenic syncope induced by glossopharyngeal neuralgia: successful treatment with carbamazepine and a permanent pacemaker -a case report-. AB - Glossopharyneal neuralgia (GPN) is generally considered to be a pain disease. However, it can be also be a life-threatening cardiac cause of syncope. Neuralgia in the throat and neck can trigger severe bradycardia up to the point of asystole, which can progress to cardiac syncope with or without seizures. A 65 year-old male patient diagnosed with glossopharyngeal neuralgia complained of severe paroxysmal pain in his right chin and ear followed by bradycardia, aystole and syncope. We report a case successfully treated with a permanent pacemaker and carbamazepine in a patient with GPN who had syncopal attacks preceded by paroxysms of pain. PMID- 20830271 TI - Point-of-care testing in hospitals and primary care. AB - BACKGROUND: Many medical laboratory tests can now be done near the patient (point of-care testing, POCT), ranging from basic blood glucose measurement to complex coagulation testing. Switching from conventional laboratory testing to POCT shortens the time to decision-making about further testing or treatment, as delays are no longer caused by specimen transport and preparation, and the test results are rapidly available at the point of care. Better medical outcomes and lower costs may ensue. METHOD: Selective literature review. RESULTS: The available methods and equipment enable persons not specially trained in laboratory medicine to perform high-quality laboratory testing at the point of care, under certain conditions. Before POCT is introduced in a hospital or outpatient practice, a cost-benefit analysis should be performed, because the introduction is costly and requires a certain amount of organizational work especially for quality management. The potential medical and economic benefits should be assessed individually in each case. CONCLUSION: POCT for certain applications is a useful complement to conventional laboratory testing. The future utilization of POCT will depend not only on technical advances, but also on developments in costs and reimbursement. PMID- 20830272 TI - Dilemma in Jurisdiction. PMID- 20830273 TI - Epigenetics. PMID- 20830274 TI - Influence of the therapeutic environment. PMID- 20830275 TI - Professional ban. PMID- 20830276 TI - Therapies that promote emancipation. PMID- 20830277 TI - Stop the trench wars. PMID- 20830278 TI - Results are easily manipulated. PMID- 20830279 TI - Statistical methods are inadequate. PMID- 20830281 TI - More factors should have been considered. PMID- 20830282 TI - Substantial deficiencies. PMID- 20830284 TI - The post mortem external examination: determination of the cause and manner of death. AB - BACKGROUND: The post mortem external examination is the final service that a physician can render to a patient. Its purpose is not just to establish medical diagnoses, but to provide facts in the service of the judicial process and the public interest. Its main tasks are the definitive ascertainment of death, determination of the cause of death and assessment of the manner of death. METHODS: Selective search and review of relevant literature on cause-of-death statistics, judicial principles, and the performance of the post mortem examination, with emphasis on determination of the cause and manner of death. RESULTS AND DISCUSSION: An important duty of the physician performing the post mortem external examination is to know the patient's history. Thus, in principle, the treating physician is the most suitable person to perform the post mortem examination. In most cases of death (perhaps 60% to 70%), the treating physician will be able to give reliable information on the patient's underlying illnesses and the cause of death, based on the patient's history and circumstances at the time of death. Problems arise when death is unexpected and the post mortem external examination alone does not suffice to establish the cause of death. If the cause of death cannot be determined, this fact should be documented, and the manner of death should likewise be documented as undetermined. The autopsy rate in Germany is less than 5% of all deaths, which is very low. PMID- 20830285 TI - Thyrotroph embryonic factor regulates light-induced transcription of repair genes in zebrafish embryonic cells. AB - Numerous responses are triggered by light in the cell. How the light signal is detected and transduced into a cellular response is still an enigma. Each zebrafish cell has the capacity to directly detect light, making this organism particularly suitable for the study of light dependent transcription. To gain insight into the light signalling mechanism we identified genes that are activated by light exposure at an early embryonic stage, when specialised light sensing organs have not yet formed. We screened over 14,900 genes using micro array GeneChips, and identified 19 light-induced genes that function primarily in light signalling, stress response, and DNA repair. Here we reveal that PAR Response Elements are present in all promoters of the light-induced genes, and demonstrate a pivotal role for the PAR bZip transcription factor Thyrotroph embryonic factor (Tef) in regulating the majority of light-induced genes. We show that tefbeta transcription is directly regulated by light while transcription of tefalpha is under circadian clock control at later stages of development. These data leads us to propose their involvement in light-induced UV tolerance in the zebrafish embryo. PMID- 20830286 TI - Drag-based 'hovering' in ducks: the hydrodynamics and energetic cost of bottom feeding. AB - Diving ducks use their webbed feet to provide the propulsive force that moves them underwater. To hold position near the bottom while feeding, ducks paddle constantly to resist the buoyant force of the body. Using video sequences from two orthogonal cameras we reconstructed the 3-dimensional motion of the feet through water and estimated the forces involved with a quasi-steady blade-element model. We found that during station holding, near the bottom, ducks use drag based propulsion with the webbed area of the foot moving perpendicular to the trajectory of the foot. The body was pitched at 76+/-3.47 degrees below the horizon and the propulsive force was directed 26+/-1.9 degrees ventral to the body so that 98% of the propulsive force in the sagittal plane of the duck worked to oppose buoyancy. The mechanical work done by moving both feet through a paddling cycle was 1.1+/-0.2 J which was equivalent to an energy expenditure of 3.7+/-0.5 W to hold position while feeding at 1.5 m depth. We conclude that in shallow water the high energetic cost of feeding in ducks is due to the need to paddle constantly against buoyancy even after reaching the bottom. The mechanical energy spent on holding position near the bottom, while feeding, is approximately 2 fold higher than previous estimates that were made for similar bottom depths but based on the presumed motion of the body instead of motion of the feet. PMID- 20830287 TI - Is IP-10 an accurate marker for detecting M. tuberculosis-specific response in HIV-infected persons? AB - BACKGROUND: The suboptimal sensitivity of Interferon (IFN)-gamma-based in-vitro assays, especially in immunocompromised individuals, emphasizes the need for alternative markers for diagnosing tuberculosis (TB). The objective of this study was to evaluate whether interferon-inducible protein (IP)-10, monocyte chemotactic protein (MCP)-2 and interleukin (IL)-2 can be useful biomarkers for evaluating a specific response to RD1 antigens associated to active TB disease in HIV-infected individuals. METHODOLOGY/PRINCIPAL FINDINGS: The study was carried out in India, the country with the highest TB burden in the world. Sixty-six HIV infected individuals were prospectively enrolled, 28 with active-pulmonary-TB and 38 without. The whole blood assay based on RD1-selected peptides (experimental test) and QuantiFERON-TB Gold In tube (QFT-IT) was performed. Plasma was harvested at day-1-post-culture and soluble factors were evaluated by ELISA. The results indicate that by detecting IP-10, the sensitivity of the experimental test and QFT-antigen (75% and 85.7% respectively) for active TB was higher compared to the same assays based on IFN-gamma (42.9% and 60.7% respectively) and was not influenced by the ability to respond to the mitogen. By detecting IP-10, the specificity of the experimental test and QFT-antigen (57.9% and 13.2% respectively) for active TB was lower than what was reported for the same assays using IFN-gamma-detection (78.9% and 68.4% respectively). On the other side, in vitro IL-2 and MCP-2 responses were not significantly associated with active TB. CONCLUSIONS: HIV infection does not impair RD1-specific response detected by IP 10, while it significantly decreases IFN-gamma-mediated responses. At the moment it is unclear whether higher detection is related to higher sensitivity or lower specificity of the assay. Further studies in high and low TB endemic countries are needed to elucidate this. PMID- 20830288 TI - Decreased levels of bisecting GlcNAc glycoforms of IgG are associated with human longevity. AB - BACKGROUND: Markers for longevity that reflect the health condition and predict healthy aging are extremely scarce. Such markers are, however, valuable in aging research. It has been shown previously that the N-glycosylation pattern of human immunoglobulin G (IgG) is age-dependent. Here we investigate whether N-linked glycans reflect early features of human longevity. METHODOLOGY/PRINCIPAL FINDINGS: The Leiden Longevity Study (LLS) consists of nonagenarian sibling pairs, their offspring, and partners of the offspring serving as control. IgG subclass specific glycosylation patterns were obtained from 1967 participants in the LLS by MALDI-TOF-MS analysis of tryptic IgG Fc glycopeptides. Several regression strategies were applied to evaluate the association of IgG glycosylation with age, sex, and longevity. The degree of galactosylation of IgG decreased with increasing age. For the galactosylated glycoforms the incidence of bisecting GlcNAc increased as a function of age. Sex-related differences were observed at ages below 60 years. Compared to males, younger females had higher galactosylation, which decreased stronger with increasing age, resulting in similar galactosylation for both sexes from 60 onwards. In younger participants (<60 years of age), but not in the older age group (>60 years), decreased levels of non-galactosylated glycoforms containing a bisecting GlcNAc reflected early features of longevity. CONCLUSIONS/SIGNIFICANCE: We here describe IgG glycoforms associated with calendar age at all ages and the propensity for longevity before middle age. As modulation of IgG effector functions has been described for various IgG glycosylation features, a modulatory effect may be expected for the longevity marker described in this study. PMID- 20830289 TI - Olprinone attenuates the acute inflammatory response and apoptosis after spinal cord trauma in mice. AB - BACKGROUND: Olprinone hydrochloride is a newly developed compound that selectively inhibits PDE type III and is characterized by several properties, including positive inotropic effects, peripheral vasodilatory effects, and a bronchodilator effect. In clinical settings, olprinone is commonly used to treat congestive cardiac failure, due to its inotropic and vasodilating effects. The mechanism of these cardiac effects is attributed to increased cellular concentrations of cAMP. The aim of the present study was to evaluate the pharmacological action of olprinone on the secondary damage in experimental spinal cord injury (SCI) in mice. METHODOLOGY/PRINCIPAL FINDINGS: Traumatic SCI is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should be preventable, no effective treatment options currently exist for patients with SCI. Spinal cord trauma was induced in mice by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of inflammatory mediators, tissue damage, apoptosis, and locomotor disturbance. Olprinone treatment (0.2 mg/kg, i.p.) 1 and 6 h after the SCI significantly reduced: (1) the degree of spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation, (4) pro-inflammatory cytokines, (5) NF kappaB expression, (6) p-ERK1/2 and p38 expression and (7) apoptosis (TUNEL staining, FAS ligand, Bax and Bcl-2 expression). Moreover, olprinone significantly ameliorated the recovery of hind-limb function (evaluated by motor recovery score). CONCLUSIONS/SIGNIFICANCE: Taken together, our results clearly demonstrate that olprinone treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. PMID- 20830290 TI - Default network deactivations are correlated with psychopathic personality traits. AB - BACKGROUND: The posteromedial cortex (PMC) and medial prefrontal cortex (mPFC) are part of a network of brain regions that has been found to exhibit decreased activity during goal-oriented tasks. This network is thought to support a baseline of brain activity, and is commonly referred to as the "default network". Although recent reports suggest that the PMC and mPFC are associated with affective, social, and self-referential processes, the relationship between these default network components and personality traits, especially those pertaining to social context, is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In the current investigation, we assessed the relationship between PMC and mPFC deactivations and psychopathic personality traits using fMRI and a self-report measure. We found that PMC deactivations predicted traits related to egocentricity and mPFC deactivations predicted traits related to decision-making. CONCLUSIONS/SIGNIFICANCE: These results suggest that the PMC and mPFC are associated with processes involving self-relevancy and affective decision-making, consistent with previous reports. More generally, these findings suggest a link between default network activity and personality traits. PMID- 20830291 TI - Pathophysiological mechanisms of severe anaemia in Malawian children. AB - BACKGROUND: Severe anaemia is a major cause of morbidity and mortality in African children. The aetiology is multi-factorial, but interventions have often targeted only one or a few causal factors, with limited success. METHODS AND FINDINGS: We assessed the contribution of different pathophysiological mechanisms (red cell production failure [RCPF], haemolysis and blood loss) to severe anaemia in Malawian children in whom etiological factors have been described previously. More complex associations between etiological factors and the mechanisms were explored using structural equation modelling. In 235 children with severe anaemia (haemoglobin<3.2 mMol/L [5.0 g/dl]) studied, RCPF, haemolysis and blood loss were found in 48.1%, 21.7% and 6.9%, respectively. The RCPF figure increased to 86% when a less stringent definition of RCPF was applied. RCPF was the most common mechanism in each of the major etiological subgroups (39.7-59.7%). Multiple aetiologies were common in children with severe anaemia. In the final model, nutritional and infectious factors, including malaria, were directly or indirectly associated with RCPF, but not with haemolysis. CONCLUSION: RCPF was the most common pathway leading to severe anaemia, from a variety of etiological factors, often found in combination. Unlike haemolysis or blood loss, RCPF is a defect that is likely to persist to a significant degree unless all of its contributing aetiologies are corrected. This provides a further explanation for the limited success of the single factor interventions that have commonly been applied to the prevention or treatment of severe anaemia. Our findings underline the need for a package of measures directed against all of the local aetiologies of this often fatal paediatric syndrome. PMID- 20830292 TI - A whole-genome SNP association study of NCI60 cell line panel indicates a role of Ca2+ signaling in selenium resistance. AB - Epidemiological studies have suggested an association between selenium intake and protection from a variety of cancer. Considering this clinical importance of selenium, we aimed to identify the genes associated with resistance to selenium treatment. We have applied a previous methodology developed by our group, which is based on the genetic and pharmacological data publicly available for the NCI60 cancer cell line panel. In short, we have categorized the NCI60 cell lines as selenium resistant and sensitive based on their growth inhibition (GI50) data. Then, we have utilized the Affymetrix 125K SNP chip data available and carried out a genome-wide case-control association study for the selenium sensitive and resistant NCI60 cell lines. Our results showed statistically significant association of four SNPs in 5q33-34, 10q11.2, 10q22.3 and 14q13.1 with selenium resistance. These SNPs were located in introns of the genes encoding for a kinase scaffolding protein (AKAP6), a membrane protein (SGCD), a channel protein (KCNMA1), and a protein kinase (PRKG1). The knock-down of KCNMA1 by siRNA showed increased sensitivity to selenium in both LNCaP and PC3 cell lines. Furthermore, SNP-SNP interaction (epistasis) analysis indicated the interactions of the SNPs in AKAP6 with SGCD as well as SNPs in AKAP6 with KCNMA1 with each other, assuming additive genetic model. These genes were also all involved in the Ca(2+) signaling, which has a direct role in induction of apoptosis and induction of apoptosis in tumor cells is consistent with the chemopreventive action of selenium. Once our findings are further validated, this knowledge can be translated into clinics where individuals who can benefit from the chemopreventive characteristics of the selenium supplementation will be easily identified using a simple DNA analysis. PMID- 20830293 TI - Direct detection of diverse metabolic changes in virally transformed and tax expressing cells by mass spectrometry. AB - BACKGROUND: Viral transformation of a cell starts at the genetic level, followed by changes in the proteome and the metabolome of the host. There is limited information on the broad metabolic changes in HTLV transformed cells. METHODS AND PRINCIPAL FINDINGS: Here, we report the detection of key changes in metabolites and lipids directly from human T-lymphotropic virus type 1 and type 3 (HTLV1 and HTLV3) transformed, as well as Tax1 and Tax3 expressing cell lines by laser ablation electrospray ionization (LAESI) mass spectrometry (MS). Comparing LAESI MS spectra of non-HTLV1 transformed and HTLV1 transformed cells revealed that glycerophosphocholine (PC) lipid components were dominant in the non-HTLV1 transformed cells, and PC(O-32:1) and PC(O-34:1) plasmalogens were displaced by PC(30:0) and PC(32:0) species in the HTLV1 transformed cells. In HTLV1 transformed cells, choline, phosphocholine, spermine and glutathione, among others, were downregulated, whereas creatine, dopamine, arginine and AMP were present at higher levels. When comparing metabolite levels between HTLV3 and Tax3 transfected 293T cells, there were a number of common changes observed, including decreased choline, phosphocholine, spermine, homovanillic acid, and glycerophosphocholine and increased spermidine and N-acetyl aspartic acid. These results indicate that the lipid metabolism pathway as well as the creatine and polyamine biosynthesis pathways are commonly deregulated after expression of HTLV3 and Tax3, indicating that the noted changes are likely due to Tax3 expression. N-acetyl aspartic acid is a novel metabolite that is upregulated in all cell types and all conditions tested. CONCLUSIONS AND SIGNIFICANCE: We demonstrate the high throughput in situ metabolite profiling of HTLV transformed and Tax expressing cells, which facilitates the identification of virus-induced perturbations in the biochemical processes of the host cells. We found virus type specific (HTLV1 vs. HTLV3), expression-specific (Tax1 vs. Tax3) and cell-type specific (T lymphocytes vs. kidney epithelial cells) changes in the metabolite profiles. The new insight on the affected metabolic pathways can be used to better understand the molecular mechanisms of HTLV induced transformation, which in turn can result in new treatment strategies. PMID- 20830294 TI - Protective role of taurine against arsenic-induced mitochondria-dependent hepatic apoptosis via the inhibition of PKCdelta-JNK pathway. AB - BACKGROUND: Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway. METHODOLOGY/PRINCIPAL FINDINGS: Rats were exposed to NaAsO(2) (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO(2) (10 microM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCdelta and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCdelta is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO(2) exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As induced oxidative stress and apoptosis. CONCLUSIONS/SIGNIFICANCE: Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKCdelta-JNK signalling pathways. Therefore taurine supplementation could provide a new approach for the reduction of hepatic complication due to arsenic poisoning. PMID- 20830295 TI - Reassortant between human-Like H3N2 and avian H5 subtype influenza A viruses in pigs: a potential public health risk. AB - BACKGROUND: Human-like H3N2 influenza viruses have repeatedly been transmitted to domestic pigs in different regions of the world, but it is still uncertain whether any of these variants could become established in pig populations. The fact that different subtypes of influenza viruses have been detected in pigs makes them an ideal candidate for the genesis of a possible reassortant virus with both human and avian origins. However, the determination of whether pigs can act as a "mixing vessel" for a possible future pandemic virus is still pending an answer. This prompted us to gather the epidemiological information and investigate the genetic evolution of swine influenza viruses in Jilin, China. METHODS: Nasopharyngeal swabs were collected from pigs with respiratory illness in Jilin province, China from July 2007 to October 2008. All samples were screened for influenza A viruses. Three H3N2 swine influenza virus isolates were analyzed genetically and phylogenetically. RESULTS: Influenza surveillance of pigs in Jilin province, China revealed that H3N2 influenza viruses were regularly detected from domestic pigs during 2007 to 2008. Phylogenetic analysis revealed that two distinguishable groups of H3N2 influenza viruses were present in pigs: the wholly contemporary human-like H3N2 viruses (represented by the Moscow/10/99 like sublineage) and double-reassortant viruses containing genes from contemporary human H3N2 viruses and avian H5 viruses, both co-circulating in pig populations. CONCLUSIONS: The present study reports for the first time the coexistence of wholly human-like H3N2 viruses and double-reassortant viruses that have emerged in pigs in Jilin, China. It provides updated information on the role of pigs in interspecies transmission and genetic reassortment of influenza viruses. PMID- 20830296 TI - Long-term IGF-I exposure decreases autophagy and cell viability. AB - A reduction in IGF-I signaling has been found to increase lifespan in multiple organisms despite the fact that IGF-I is a trophic factor for many cell types and has been found to have protective effects against multiple forms of damage in acute settings. The increase in longevity seen in response to reduced IGF-I signaling suggests that there may be differences between the acute and chronic impact of IGF-I signaling. We have examined the possibility that long-term stimulation with IGF-I may have a negative impact at the cellular level using quiescent human fibroblasts. We find that fibroblast cells exposed to IGF-I for 14 days have reduced long-term viability as judged by colony forming assays, which is accompanied by an accumulation of senescent cells. In addition we observe an accumulation of cells with depolarized mitochondria and a reduction in autophagy in the long-term IGF-I treated cultures. An examination of mice with reduced IGF-I levels reveals evidence of enhanced autophagy and fibroblast cells derived from these mice have a larger mitochondrial mass relative to controls indicating that changes in mitochondrial turnover occurs in animals with reduced IGF-I. The results indicate that chronic IGF-I stimulation leads to mitochondrial dysfunction and reduced cell viability. PMID- 20830297 TI - Plant-type trehalose synthetic pathway in cryptosporidium and some other apicomplexans. AB - BACKGROUND: The trehalose synthetic pathway is present in bacteria, fungi, plants and invertebrate animals, but is absent in vertebrates. This disaccharide mainly functions as a stress protectant against desiccation, heat, cold and oxidation. Genes involved in trehalose synthesis have been observed in apicomplexan parasites, but little was known about these enzymes. Study on trehalose synthesis in apicomplexans would not only shed new light into the evolution of this pathway, but also provide data for exploring this pathway as novel drug target. METHODOLOGY/PRINCIPAL FINDINGS: We have observed the presence of the trehalose synthetic pathway in Cryptosporidium and other apicomplexans and alveolates. Two key enzymes (trehalose 6-phosphate synthase [T6PS; EC 2.4.1.15] and trehalose phosphatase [TPase; EC 3.1.3.12] are present as Class II bifunctional proteins (T6PS-TPase) in the majority of apicomplexans with the exception of Plasmodium species. The enzyme for synthesizing the precursor (UDP-glucose) is homologous to dual-substrate UDP-galactose/glucose pyrophosphorylases (UGGPases), rather than the "classic" UDP-glucose pyrophosphorylase (UGPase). Phylogenetic recontructions indicate that both T6PS-TPases and UGGPases in apicomplexans and other alveolates are evolutionarily affiliated with stramenopiles and plants. The expression level of T6PS-TPase in C. parvum is highly elevated in the late intracellular developmental stage prior to or during the production of oocysts, implying that trehalose may be important in oocysts as a protectant against environmental stresses. Finally, trehalose has been detected in C. parvum oocysts, thus confirming the trehalose synthetic activity in this parasite. CONCLUSIONS/SIGNIFICANCE: A trehalose synthetic pathway is described in the majority of apicomplexan parasites including Cryptosporidium and the presence of trehalose was confirmed in the C. parvum oocyst. Key enzymes in the pathway (i.e., T6PS-TPase and UGGPase) are plant-type and absent in humans and animals, and may potentially serve as novel drug targets in the apicomplexans. PMID- 20830298 TI - Behavior of a metabolic cycling population at the single cell level as visualized by fluorescent gene expression reporters. AB - BACKGROUND: During continuous growth in specific chemostat cultures, budding yeast undergo robust oscillations in oxygen consumption that are accompanied by highly periodic changes in transcript abundance of a majority of genes, in a phenomenon called the Yeast Metabolic Cycle (YMC). This study uses fluorescent reporters of genes specific to different YMC phases in order to visualize this phenomenon and understand the temporal regulation of gene expression at the level of individual cells within the cycling population. METHODOLOGY: Fluorescent gene expression reporters for different phases of the YMC were constructed and stably integrated into the yeast genome. Subsequently, these reporter-expressing yeast were used to visualize YMC dynamics at the individual cell level in cultures grown in a chemostat or in a microfluidics platform under varying glucose concentrations, using fluorescence microscopy and quantitative Western blots. CONCLUSIONS: The behavior of single cells within a metabolic cycling population was visualized using phase-specific fluorescent reporters. The reporters largely recapitulated genome-specified mRNA expression profiles. A significant fraction of the cell population appeared to exhibit basal expression of the reporters, supporting the hypothesis that there are at least two distinct subpopulations of cells within the cycling population. Although approximately half of the cycling population initiated cell division in each permissive window of the YMC, metabolic synchrony of the population was maintained. Using a microfluidics platform we observed that low glucose concentrations appear to be necessary for metabolic cycling. Lastly, we propose that there is a temporal window in the oxidative growth phase of the YMC where the cycling population segregates into at least two subpopulations, one which will enter the cell cycle and one which does not. PMID- 20830299 TI - Intraspecific diversity regulates fungal productivity and respiration. AB - Individuals and not just species are key components of biodiversity, yet the relationship between intraspecific diversity and ecosystem functioning in microbial systems remains largely untested. This limits our ability to understand and predict the effects of altered genetic diversity in regulating key ecosystem processes and functions. Here, we use a model fungal system to test the hypothesis that intraspecific genotypic richness of Paxillus obscurosporus stimulates biomass and CO(2) efflux, but that this is dependent on nitrogen supply. Using controlled experimental microcosms, we show that populations containing several genotypes (maximum 8) of the fungus had greater productivity and produced significantly more CO(2) than those with fewer genotypes. Moreover, intraspecific diversity had a much stronger effect than a four-fold manipulation of the carbon:nitrogen ratio of the growth medium. The effects of intraspecific diversity were underpinned by strong roles of individuals, but overall intraspecific diversity increased the propensity of populations to over-yield, indicating that both complementarity and selection effects can operate within species. Our data demonstrate the importance of intraspecific diversity over a range of nitrogen concentrations, and the need to consider fine scale phylogenetic information of microbial communities in understanding their contribution to ecosystem processes. PMID- 20830300 TI - Role of Rac1 GTPase in NADPH oxidase activation and cognitive impairment following cerebral ischemia in the rat. AB - BACKGROUND: Recent work by our laboratory and others has implicated NADPH oxidase as having an important role in reactive oxygen species (ROS) generation and neuronal damage following cerebral ischemia, although the mechanisms controlling NADPH oxidase in the brain remain poorly understood. The purpose of the current study was to examine the regulatory and functional role of the Rho GTPase, Rac1 in NADPH oxidase activation, ROS generation and neuronal cell death/cognitive dysfunction following global cerebral ischemia in the male rat. METHODOLOGY/PRINCIPAL FINDINGS: Our studies revealed that NADPH oxidase activity and superoxide (O(2)(-)) production in the hippocampal CA1 region increased rapidly after cerebral ischemia to reach a peak at 3 h post-reperfusion, followed by a fall in levels by 24 h post-reperfusion. Administration of a Rac GTPase inhibitor (NSC23766) 15 min before cerebral ischemia significantly attenuated NADPH oxidase activation and O(2)(-) production at 3 h after stroke as compared to vehicle-treated controls. NSC23766 also attenuated "in situ" O(2)(-) production in the hippocampus after ischemia/reperfusion, as determined by fluorescent oxidized hydroethidine staining. Oxidative stress damage in the hippocampal CA1 after ischemia/reperfusion was also significantly attenuated by NSC23766 treatment, as evidenced by a marked attenuation of immunostaining for the oxidative stress damage markers, 4-HNE, 8-OHdG and H2AX at 24 h in the hippocampal CA1 region following cerebral ischemia. In addition, Morris Water maze testing revealed that Rac GTPase inhibition after ischemic injury significantly improved hippocampal-dependent memory and cognitive spatial abilities at 7-9 d post reperfusion as compared to vehicle-treated animals. CONCLUSIONS/SIGNIFICANCE: The results of the study suggest that Rac1 GTPase has a critical role in mediating ischemia/reperfusion injury-induced NADPH oxidase activation, ROS generation and oxidative stress in the hippocampal CA1 region of the rat, and thus contributes significantly to neuronal degeneration and cognitive dysfunction following cerebral ischemia. PMID- 20830301 TI - Expression profiling of a genetic animal model of depression reveals novel molecular pathways underlying depressive-like behaviours. AB - BACKGROUND: The Flinders model is a validated genetic rat model of depression that exhibits a number of behavioural, neurochemical and pharmacological features consistent with those observed in human depression. PRINCIPAL FINDINGS: In this study we have used genome-wide microarray expression profiling of the hippocampus and prefrontal/frontal cortex of Flinders Depression Sensitive (FSL) and control Flinders Depression Resistant (FRL) lines to understand molecular basis for the differences between the two lines. We profiled two independent cohorts of Flinders animals derived from the same colony six months apart, each cohort statistically powered to allow independent as well as combined analysis. Using this approach, we were able to validate using real-time-PCR a core set of gene expression differences that showed statistical significance in each of the temporally distinct cohorts, representing consistently maintained features of the model. Small but statistically significant increases were confirmed for cholinergic (chrm2, chrna7) and serotonergic receptors (Htr1a, Htr2a) in FSL rats consistent with known neurochemical changes in the model. Much larger gene changes were validated in a number of novel genes as exemplified by TMEM176A, which showed 35-fold enrichment in the cortex and 30-fold enrichment in hippocampus of FRL animals relative to FSL. CONCLUSIONS: These data provide significant insights into the molecular differences underlying the Flinders model, and have potential relevance to broader depression research. PMID- 20830302 TI - Molecular modeling study for interaction between Bacillus subtilis Obg and Nucleotides. AB - The bacterial Obg proteins (Spo0B-associated GTP-binding protein) belong to the subfamily of P-loop GTPase proteins that contain two equally and highly conserved domains, a C-terminal GTP binding domain and an N-terminal glycine-rich domain which is referred as the "Obg fold" and now it is considered as one of the new targets for antibacterial drug. When the Obg protein is associated with GTP, it becomes activated, because conformation of Obg fold changes due to the structural changes of GTPase switch elements in GTP binding site. In order to investigate the effects and structural changes in GTP bound to Obg and GTPase switch elements for activation, four different molecular dynamics (MD) simulations were performed with/without the three different nucleotides (GTP, GDP, and GDP + Pi) using the Bacillus subtilis Obg (BsObg) structure. The protein structures generated from the four different systems were compared using their representative structures. The pattern of C(alpha)-C(alpha) distance plot and angle between the two Obg fold domains of simulated apo form and each system (GTP, GDP, and GDP+Pi) were significantly different in the GTP-bound system from the others. The switch 2 element was significantly changed in GTP-bound system. Also root-mean-square fluctuation (RMSF) analysis revealed that the flexibility of the switch 2 element region was much higher than the others. This was caused by the characteristic binding mode of the nucleotides. When GTP was bound to Obg, its gamma-phosphate oxygen was found to interact with the key residue (D212) of the switch 2 element, on the contrary there was no such interaction found in other systems. Based on the results, we were able to predict the possible binding conformation of the activated form of Obg with L13, which is essential for the assembly with ribosome. PMID- 20830303 TI - Stereoscopic vision in the absence of the lateral occipital cortex. AB - Both dorsal and ventral cortical visual streams contain neurons sensitive to binocular disparities, but the two streams may underlie different aspects of stereoscopic vision. Here we investigate stereopsis in the neurological patient D.F., whose ventral stream, specifically lateral occipital cortex, has been damaged bilaterally, causing profound visual form agnosia. Despite her severe damage to cortical visual areas, we report that DF's stereo vision is strikingly unimpaired. She is better than many control observers at using binocular disparity to judge whether an isolated object appears near or far, and to resolve ambiguous structure-from-motion. DF is, however, poor at using relative disparity between features at different locations across the visual field. This may stem from a difficulty in identifying the surface boundaries where relative disparity is available. We suggest that the ventral processing stream may play a critical role in enabling healthy observers to extract fine depth information from relative disparities within one surface or between surfaces located in different parts of the visual field. PMID- 20830304 TI - Potential role for MATER in cytoplasmic lattice formation in murine oocytes. AB - BACKGROUND: Mater and Padi6 are maternal effect genes that are first expressed during oocyte growth and are required for embryonic development beyond the two cell stage in the mouse. We have recently found that PADI6 localizes to, and is required for the formation of, abundant fibrillar Triton X-100 (Triton) insoluble structures termed the oocyte cytoplasmic lattices (CPLs). Given their similar expression profiles and mutant mouse phenotypes, we have been testing the hypothesis that MATER also plays a role in CPL formation and/or function. METHODOLOGY/FINDINGS: Herein, we show that PADI6 and MATER co-localize throughout the oocyte cytoplasm following Triton extraction, suggesting that MATER co localizes with PADI6 at the CPLs. Additionally, the solubility of PADI6 was dramatically increased in Mater(tm/tm) oocytes following Triton extraction, suggesting that MATER is involved in CPL nucleation. This prediction is supported by transmission electron microscopic analysis of Mater(+/+) and Mater(tm/tm) germinal vesicle stage oocytes which illustrated that volume fraction of CPLs was reduced by 90% in Mater(tm/tm) oocytes compared to Mater(+/+) oocytes. CONCLUSIONS: Taken together, these results suggest that, similar to PADI6, MATER is also required for CPL formation. Given that PADI6 and MATER are essential for female fertility, these results not only strengthen the hypothesis that the lattices play a critical role in mediating events during the oocyte-to-embryo transition but also increase our understanding of the molecular nature of the CPLs. PMID- 20830305 TI - Evidence for a relationship between VEGF and BMI independent of insulin sensitivity by glucose clamp procedure in a homogenous group healthy young men. AB - BACKGROUND: This is the first study to experimentally explore the direct relationship between circulating VEGF levels and body mass index (BMI) as well as to unravel the role of insulin sensitivity in this context under standardized glucose clamp conditions as the methodical gold-standard. In order to control for known influencing factors such as gender, medication, and arterial hypertension, we examined a highly homogeneous group of young male subjects. Moreover, to encompass also subjects beyond the normal BMI range, low weight and obese participants were additionally included and stress hormones as a main regulator of VEGF were assessed. METHODOLOGY/PRINCIPAL FINDINGS: Under euglycemic clamp conditions, VEGF was measured in 15 normal weight (BMI 20-25 kg/m(2)), 15 low weight (BMI<20 kg/m(2)), and 15 obese (BMI>30 kg/m(2)) male subjects aged 18-30 years and the insulin sensitivity index (ISI) was calculated. Since stress axis activation promotes VEGF secretion, concentrations of ACTH, cortisol, and catecholamines were monitored. Despite of comparable ACTH (P = 0.145), cortisol (P = 0.840), and norepinephrine (P = 0.065) levels, VEGF concentrations differed significantly between BMI-groups (P = 0.008) with higher concentrations in obese subjects as compared to normal weight (P = 0.061) and low weight subjects (P = 0.002). Pearson's correlation analysis revealed a positive relationship between BMI and VEGF levels (r = 0.407; P = 0.010) but no correlation of VEGF with ISI (r = 0.224; P = 0.175). CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a positive correlation between concentrations of circulating VEGF levels and BMI in healthy male subjects under highly controlled conditions. This relationship which is apparently disconnected from insulin sensitivity may be part of some pathogenetic mechanisms underlying obesity and type 2 diabetes. PMID- 20830306 TI - Kinin B1 receptor enhances the oxidative stress in a rat model of insulin resistance: outcome in hypertension, allodynia and metabolic complications. AB - BACKGROUND: Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications. METHODS AND FINDINGS: Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(*-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(*-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(*-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10 100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(*-) production induced by the B(1)R agonist was blocked only by apocynin. CONCLUSIONS: Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model. PMID- 20830307 TI - Diffusion model based spectral clustering for protein-protein interaction networks. AB - BACKGROUND: A goal of systems biology is to analyze large-scale molecular networks including gene expressions and protein-protein interactions, revealing the relationships between network structures and their biological functions. Dividing a protein-protein interaction (PPI) network into naturally grouped parts is an essential way to investigate the relationship between topology of networks and their functions. However, clear modular decomposition is often hard due to the heterogeneous or scale-free properties of PPI networks. METHODOLOGY/PRINCIPAL FINDINGS: To address this problem, we propose a diffusion model-based spectral clustering algorithm, which analytically solves the cluster structure of PPI networks as a problem of random walks in the diffusion process in them. To cope with the heterogeneity of the networks, the power factor is introduced to adjust the diffusion matrix by weighting the transition (adjacency) matrix according to a node degree matrix. This algorithm is named adjustable diffusion matrix-based spectral clustering (ADMSC). To demonstrate the feasibility of ADMSC, we apply it to decomposition of a yeast PPI network, identifying biologically significant clusters with approximately equal size. Compared with other established algorithms, ADMSC facilitates clear and fast decomposition of PPI networks. CONCLUSIONS/SIGNIFICANCE: ADMSC is proposed by introducing the power factor that adjusts the diffusion matrix to the heterogeneity of the PPI networks. ADMSC effectively partitions PPI networks into biologically significant clusters with almost equal sizes, while being very fast, robust and appealing simple. PMID- 20830308 TI - Circadian integration of glutamatergic signals by little SAAS in novel suprachiasmatic circuits. AB - BACKGROUND: Neuropeptides are critical integrative elements within the central circadian clock in the suprachiasmatic nucleus (SCN), where they mediate both cell-to-cell synchronization and phase adjustments that cause light entrainment. Forward peptidomics identified little SAAS, derived from the proSAAS prohormone, among novel SCN peptides, but its role in the SCN is poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Little SAAS localization and co-expression with established SCN neuropeptides were evaluated by immunohistochemistry using highly specific antisera and stereological analysis. Functional context was assessed relative to c-FOS induction in light-stimulated animals and on neuronal circadian rhythms in glutamate-stimulated brain slices. We found that little SAAS expressing neurons comprise the third most abundant neuropeptidergic class (16.4%) with unusual functional circuit contexts. Little SAAS is localized within the densely retinorecipient central SCN of both rat and mouse, but not the retinohypothalamic tract (RHT). Some little SAAS colocalizes with vasoactive intestinal polypeptide (VIP) or gastrin-releasing peptide (GRP), known mediators of light signals, but not arginine vasopressin (AVP). Nearly 50% of little SAAS neurons express c-FOS in response to light exposure in early night. Blockade of signals that relay light information, via NMDA receptors or VIP- and GRP-cognate receptors, has no effect on phase delays of circadian rhythms induced by little SAAS. CONCLUSIONS/SIGNIFICANCE: Little SAAS relays signals downstream of light/glutamatergic signaling from eye to SCN, and independent of VIP and GRP action. These findings suggest that little SAAS forms a third SCN neuropeptidergic system, processing light information and activating phase-shifts within novel circuits of the central circadian clock. PMID- 20830309 TI - Behavioural and genetic evidence for C. elegans' ability to detect volatile chemicals associated with explosives. AB - BACKGROUND: Automated standoff detection and classification of explosives based on their characteristic vapours would be highly desirable. Biologically derived odorant receptors have potential as the explosive recognition element in novel biosensors. Caenorhabditis elegans' genome contains over 1,000 uncharacterised candidate chemosensory receptors. It was not known whether any of these respond to volatile chemicals derived from or associated with explosives. METHODOLOGY/PRINCIPAL FINDINGS: We assayed C. elegans for chemotactic responses to chemical vapours of explosives and compounds associated with explosives. C. elegans failed to respond to many of the explosive materials themselves but showed strong chemotaxis with a number of compounds associated with commercial or homemade explosives. Genetic mutant strains were used to identify the likely neuronal location of a putative receptor responding to cyclohexanone, which is a contaminant of some compounded explosives, and to identify the specific transduction pathway involved. Upper limits on the sensitivity of the nematode were calculated. A sensory adaptation protocol was used to estimate the receptive range of the receptor. CONCLUSIONS/SIGNIFICANCE: The results suggest that C. elegans may be a convenient source of highly sensitive, narrowly tuned receptors to detect a range of explosive-associated volatiles. PMID- 20830310 TI - Calcium regulation of EGF-induced ERK5 activation: role of Lad1-MEKK2 interaction. AB - The ERK5 cascade is a MAPK pathway that transmits both mitogenic and stress signals, yet its mechanism of activation is not fully understood. Using intracellular calcium modifiers, we found that ERK5 activation by EGF is inhibited both by the depletion and elevation of intracellular calcium levels. This calcium effect was found to occur upstream of MEKK2, which is the MAP3K of the ERK5 cascade. Co-immunoprecipitation revealed that EGF increases MEKK2 binding to the adaptor protein Lad1, and this interaction was reduced by the intracellular calcium modifiers, indicating that a proper calcium concentration is required for the interactions and transmission of EGF signals to ERK5. In vitro binding assays revealed that the proper calcium concentration is required for a direct binding of MEKK2 to Lad1. The binding of these proteins is not affected by c-Src-mediated phosphorylation on Lad1, but slightly affects the Tyr phosphorylation of MEKK2, suggesting that the interaction with Lad1 is necessary for full Tyr phosphorylation of MEKK2. In addition, we found that changes in calcium levels affect the EGF-induced nuclear translocation of MEKK2 and thereby its effect on the nuclear ERK5 activity. Taken together, these findings suggest that calcium is required for EGF-induced ERK5 activation, and this effect is probably mediated by securing proper interaction of MEKK2 with the upstream adaptor protein Lad1. PMID- 20830312 TI - Helping Children Hospitalized for Rages. PMID- 20830311 TI - Array-based DNA methylation profiling for breast cancer subtype discrimination. AB - BACKGROUND: Abnormal DNA methylation is well established for breast cancer and contributes to its progression by silencing tumor suppressor genes. DNA methylation profiling platforms might provide an alternative approach to expression microarrays for accurate breast tumor subtyping. We sought to determine whether the distinction of the inflammatory breast cancer (IBC) phenotype from the non-IBC phenotype by transcriptomics could be sustained by methylomics. METHODOLOGY/PRINCIPAL FINDINGS: We performed methylation profiling on a cohort of IBC (N = 19) and non-IBC (N = 43) samples using the Illumina Infinium Methylation Assay. These results were correlated with gene expression profiles. Methylation values allowed separation of breast tumor samples into high and low methylation groups. This separation was significantly related to DNMT3B mRNA levels. The high methylation group was enriched for breast tumor samples from patients with distant metastasis and poor prognosis, as predicted by the 70 gene prognostic signature. Furthermore, this tumor group tended to be enriched for IBC samples (54% vs. 24%) and samples with a high genomic grade index (67% vs. 38%). A set of 16 CpG loci (14 genes) correctly classified 97% of samples into the low or high methylation group. Differentially methylated genes appeared to be mainly related to focal adhesion, cytokine-cytokine receptor interactions, Wnt signaling pathway, chemokine signaling pathways and metabolic processes. Comparison of IBC with non-IBC led to the identification of only four differentially methylated genes (TJP3, MOGAT2, NTSR2 and AGT). A significant correlation between methylation values and gene expression was shown for 4,981 of 6,605 (75%) genes. CONCLUSIONS/SIGNIFICANCE: A subset of clinical samples of breast cancer was characterized by high methylation levels, which coincided with increased DNMT3B expression. Furthermore, an association was observed with molecular signatures indicative of poor patient prognosis. The results of the current study also suggest that aberrant DNA methylation is not the main force driving the molecular biology of IBC. PMID- 20830313 TI - Pathways to legal immigration. AB - In this paper we use the New Immigrant Survey Pilot Study (NISP) to describe the amount and kind of experience that immigrants accumulate in the United States before they become permanent resident aliens. The NISP surveyed a representative sample of legal immigrants who acquired residence papers during July and August of 1996, yielding a completed sample of 1,135 adults. Our analysis revealed that roughly two-thirds of these newly arrived immigrants had prior experience in the United States within one of six basic categories: illegal border-crossers, visa abusers, non-resident visitors, non-resident workers, students or exchange visitors, and refugees/asylees. Each of these pathways to legal immigration was associated with a different profile with respect to nationality, social background, and economic status. Using simple earnings regressions we demonstrate how these differences can yield misleading conclusions about the process of immigrant adaptation and assimilation, even if measured effects are reasonably accurate. We suggest that social scientists should change the way they think and ask about immigrants' arrival in the United States. PMID- 20830314 TI - Measurement of human breast tumor cell-secreted shNDPK-B in a murine breast cancer model suggests its role in metastatic progression. AB - Human breast cancers metastasize early in tumorigenesis and distant lesions, though dormant are very likely extant at the time of diagnosis and treatment in the majority of cases. Removal of primary tumors by surgeons as an imperative of the current treatment approach, also removes inhibitory factors secreted by the primary tumor that had maintained the dormancy of the metastases. We have identified a factor secreted by human breast cancer cells that supports the formation of blood vessels and may be a principal early factor supporting the growth and development of metastases in human disease. Here we demonstrate for the first time that this factor, secreted (s) human (h) nucleoside diphosphate kinase type B (shNDPK-B), product of the nm23-h2 gene, can be detected specifically with high sensitivity (50 pg/ml; 2.5 pM) in an ELISA assay of our own design. We further demonstrate that shNDPK-B is released into the circulation in immunocompromized mice carrying the human breast carcinoma cell MDA-MB-231. These data support the hypothesis that shNDPK-B may be responsible for the early events in angiogenesis supporting both primary and metastatic tumor growth and development. PMID- 20830315 TI - Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema. AB - Hereditary angioedema (HAE) is a debilitating, potentially fatal disease characterized by variable and unpredictable acute attacks of swelling affecting the subcutaneous tissue and mucosa. It is an autosomal dominant disorder resulting from a genetic deficiency of functional C1-esterase inhibitor. Available treatments include long-term prophylaxis, short-term prophylaxis and treatment of acute attacks. Ecallantide is a novel, specific and potent inhibitor of plasma kallikrein that was recently approved in the United States for the treatment of acute attacks of HAE in patients aged 16 years and older. In two phase III clinical trials, the subcutaneous administration of 30 mg ecallantide resulted in significantly greater symptom improvement than placebo for acute attacks of HAE. Ecallantide was generally well tolerated throughout the clinical development program. The main safety concern following ecallantide treatment is hypersensitivity reactions, including anaphylaxis. A Risk Evaluation and Management Strategy (REMS) has been implemented to minimize this risk and a long term observational safety study is currently under way to collect more information about hypersensitivity and immunogenicity. Ecallantide represents a novel treatment option for patients with HAE. PMID- 20830316 TI - Everolimus in renal cell carcinoma. AB - Everolimus (also known as RAD-001; Afinitor(r)) is an orally active inhibitor of the intracellular protein kinase mammalian target of rapamycin. The U.S. Food and Drug Administration and the European Medicines Agency recently approved everolimus for the treatment of advanced renal cell carcinoma (RCC) on the basis of the results of a randomized phase III clinical trial. In the trial, 10 mg daily everolimus was effective and well tolerated by patients with advanced RCC, whose disease had progressed while under the treatment with sunitinib and/or sorafenib. Everolimus treatment led to 36% of 6-month progression-free survival (PFS) rate and 31% of 3-month PFS rate. Most of the adverse events were mild to moderate (grade 1-2) in severity. The most frequent grade 3-4 adverse events were stomatitis, fatigue, pneumonitis and infections. Clinical trials on everolimus in combination with sunitinib, sorafenib, imatinib and vatalanib for the treatment of RCC are ongoing. PMID- 20830317 TI - Iloperidone for the treatment of schizophrenia. AB - Iloperidone is a recently approved antipsychotic agent indicated for the acute treatment of schizophrenia in adults. Iloperidone is characterized as a serotonin 5-HT(2A) and dopamine D(2) receptor antagonist, which makes its core mechanism of action similar to other second-generation antipsychotic agents. The affinity (or lack thereof) of iloperidone for other receptors (e.g., histamine, muscarinic, alpha(1)-adrenoceptors, serotonin) results in a unique side effect and perhaps response profile that may make it an additional option for patients who have previously not tolerated or adequately responded to other available agents. Iloperidone has been studied in over 3,200 patients throughout its development. Its efficacy appears to be similar to haloperidol, risperidone and ziprasidone. It appears to be safe with minimal extrapyramidal side effects, weight gain and prolactin elevation. A cautious dosing and titration schedule is recommended at the initiation of therapy due to the potential for orthostatic hypotension and dizziness. Drug interactions through the CYP3A4 and CYP2D6 enzymes, along with the potential for QT prolongation, may influence its use in certain patients. Genetic studies conducted during drug development may facilitate the clinical use of pharmacogenomic tests to aid clinicians in optimizing the risk-benefit ratio of iloperidone. The purpose of this review is to summarize the chemistry, pharmacology and clinical aspects of iloperidone, with the goals of identifying key scientific and clinical issues for its use, as well as assessing the potential utility of iloperidone for the treatment of schizophrenia. PMID- 20830318 TI - Quetiapine fumarate for schizophrenia and bipolar disorder in young patients. AB - During the past decade, there has been a substantial increase in the prescribing of antipsychotics to young patients for a variety of pediatric psychiatric disorders. Quetiapine (Seroquel(r)) received its initial indication from the U.S. Food and Drug Administration for treatment of schizophrenia in 1997, and it received its second indication for the treatment of mania-associated bipolar disorder in 2004. Currently, in young patients, authorized quetiapine indications are schizophrenia in individuals aged 13 or older and manic episodes associated with bipolar I disorder in children 10 to 17 years old. Quetiapine has different pharmacological actions and acts as an antagonist for following receptors: D(2) receptor, serotonin 5-HT(2A) also known as alpha(1)-adrenoceptor, histamine 1 receptor and muscarinic acetylcholine receptor. Several studies have shown its favorable profile of effectiveness and tolerability in young bipolar and schizophrenic patients. However, the current data make it very clear that the risks and benefits of this drug need to be weighed individually for each patient. PMID- 20830319 TI - Sapropterin dihydrochloride: a new drug and a new concept in the management of phenylketonuria. AB - Phenylketonuria (PKU) is characterized by persistent hyperphenylalaninemia, due to mutations in the gene coding for phenylalanine hydroxylase (PAH). If untreated, patients develop profound mental retardation. The principal treatment for PKU is lifelong dietary phenylalanine restriction, requiring the administration of special phenylalanine-free protein supplements. Adhering to the diet is burdensome, and poor compliance and control of blood phenylalanine are common, especially in adolescents and adults. A subset of patients, particularly those with milder forms of PKU, shows a clinically significant reduction in blood phenylalanine when treated with pharmacological doses of tetrahydrobiopterin, the cofactor of PAH. A tablet formulation of sapropterin dihydrochloride is approved for therapeutic use in Europe and the USA. Clinical trials have demonstrated durable reductions in blood phenylalanine, and/or increased dietary phenylalanine tolerance, in some patients with hyperphenylalaninemia due to PKU. Although further data are needed, especially with regard to long-term neuropsychological outcomes or possible use in pregnancy, sapropterin appears to represent a useful addition to the management of PKU. PMID- 20830320 TI - Atherosclerotic plaque regression - the role of statin therapy. AB - Increasing knowledge of the atherosclerotic process, as well as atherosclerotic plaque composition and morphology, has lead to the identification of vulnerable plaques that lead to acute coronary syndromes. There is growing evidence for atherosclerotic plaque regression, which makes an aggressive targeted therapeutic response based on achieving plaques regression necessary in order to reduce the significant mortality and morbidity associated with coronary heart disease. This review will examine the evidence for atherosclerotic plaque regression, the important role of statins and the available imaging techniques used to investigate this condition. We will also discuss future evolving therapies and possible predictors of plaque regression, which may aid the therapeutic process. PMID- 20830321 TI - A report from the 106th International Conference of the American Thoracic Society (May 14-19, 2010 - New Orleans, Louisiana, USA). AB - Flowing oil covered the Gulf like a blanket, but while no attempts so far had been effective at controlling the oil spill, treatments that do work to improve symptoms, prevent disability and offer an improved quality of life were discussed during the meeting on respiratory tract diseases. Within the same context of pollution by human activity, it is interesting to know that retreatment with anacardic acids reduced lung inflammation upon exposure to diesel exhaust particles in experimental animals (Carvalho, A.L.N. et al., A1729), suggesting ways to improve human health. Along with pollution, which in New Orleans during the days of the meeting was largely washed away by the heavy rains, smoking remains a major health threat of specific interest for respiratory tract disease specialists. Although effective, well-tolerated treatments are available for smoking cessation in patients willing to quit, including, as reported during this year's ATS meeting in New Orleans, varenicline (Bolliger, C.T. et al., A2648; Tashkin, D.P. et al., A2858), smoking habits persist across cultures, countries, genders and geographical areas, and relapses are remarkably common even after successful pharmacological treatment (Ponnuswamy, A. et al., A2651). Effective smoking cessation certainly requires more than drugs, as the overall effectiveness has been shown to depend on the subjects' education level (Santos, S.R. et al., A2653), and psychobehavioral/cognitive interventions may help obtain successful outcomes. However, in addition to the already known but repeatedly confirmed negative impact of smoke on respiratory tract health, an interesting observation among this year's discussions was that use of olive oil throughout pregnancy results in a reduced likelihood for wheezing during the first year of life in the offspring (Castro-Rodriguez, J.A. et al., A1865) (an effect probably not dependent on the observed ability of oleanoic acid for preventing experimental acute lung injuries through inflammatory pathway modulation [Santos, R. et al., A2156]), whereas use of antibiotics during pregnancy was associated with an increased likelihood of wheezing in the offspring from the third year of age, peaking in the early school age and waning slowly up to young adulthood (Garcia-Marcos, L. et al., A4144). However, many other therapeutic issues of interest competed with all the attractions in New Orleans for the attention of congress attendees, and are briefly summarized in the following report. PMID- 20830322 TI - From MFC to MXC: chemical and biological cathodes and their potential for microbial bioelectrochemical systems. AB - Microbial fuel cells (MFC) are the archetype microbial bioelectrochemical system (BES), producing electricity from microbially catalyzed anodic oxidation processes. The greatest potential of MFC lies in the use of wastewater as a substrate (fuel), which allows combining waste treatment and energy recovery. Recently, a development has been initiated that expands the scope of these bioelectrochemical systems from power generation to an increasing number of further applications. This development has become possible by the introduction of new cathode catalyst concepts. The corresponding devices, here summarized as MXCs -the X standing for the different types and applications--share one common element: the microbial anode. The cathode, however, has to fulfil rather different tasks and thus differs quite remarkably across these systems. In this critical review we analyze the different cathode tasks and the resulting requirements for the respective cathode and discuss the available catalyst options in the light of their major advantages and weaknesses. These catalyst options comprise inorganic, biomolecular as well microbial catalyst systems. Hereby, special emphasis is put on a comparative analysis of chemical and biological cathodes and their individual potentials and limitations. For this purpose, criteria are defined based on relevant properties (performance, price, longevity, etc.) and are evaluated by means of a multi-factor analysis, based on the individual target reaction and catalyst. This analysis is exemplarily elaborated for the oxygen reduction reaction (typical for MFCs) and for the hydrogen production (in MECs) (91 references). PMID- 20830323 TI - A probabilistic approach for estimating infant exposure to environmental pollutants in human breast milk. AB - Effective risk assessment and management are often hampered by a lack of reliable exposure data. The probabilistic exposure assessment approach takes into account individual variations in exposure, and thus, overly conservative estimates based on worst case scenarios can be avoided. The aim was to provide reliable information on the intake of non-dioxinlike (NDL) and dioxinlike PCBs, PCDDs and PCDFs in breastfed infants and their mothers during 2000-2006. Hence, a probabilistic model was developed to estimate the exposure and compare it with a deterministic exposure assessment approach. The estimated probabilistic mean intake in 1, 3 and 6 months old infants was 44, 31 and 17 pg total-TEQ/kg bw per day, and 418, 294 and 165 ng NDL-PCBs/kg bw per day, respectively. Intakes differed up to 41% between the upper-bound percentiles of the probabilistic approach and the deterministic worst case scenario approach, whereas no difference in mean values was observed between the two approaches. The median cumulative intake increased during 6 months of breastfeeding to 20 ng total-TEQ and 352 MUg NDL-PCBs. There was a significant temporal decrease in infant exposure during 2000-2006 (30%). Less than 4% of the mothers had an intake exceeding the TDI of 2 pg TEQ/kg bw per day (median: 1.2 pg total-TEQ/kg bw). To conclude, by use of a probabilistic approach and biomonitoring data we were able to calculate reliable estimates of infant exposure to environmental pollutants and the daily intakes of the nursing mothers using the same data. PMID- 20830324 TI - Accurate histopathology from low signal-to-noise ratio spectroscopic imaging data. AB - Fourier Transform Infrared (FT-IR) spectroscopic imaging is emerging as an automated alternative to human examination in studying development and disease in tissue. The technology's speed and accuracy, however, are limited by the trade off with signal-to-noise ratio (SNR). Signal processing approaches to reduce noise have been suggested but often involve manual decisions, compromising the automation benefits of using spectroscopic imaging for tissue analysis. In this manuscript, we describe an approach that utilizes the spatial information in the data set to select parameters for noise reduction without human input. Specifically, we expand on the Minimum Noise Fraction (MNF) approach in which data are forward transformed, eigenimages that correspond mostly to signal selected and used in inverse transformation. Our unsupervised eigenimage selection method consists of matching spatial features in eigenimages with a low noise gold standard derived from the data. An order of magnitude reduction in noise is demonstrated using this approach. We apply the approach to automating breast tissue histology, in which accuracy in classification of tissue into different cell types is shown to strongly depend on the SNR of data. A high classification accuracy was recovered with acquired data that was ~10-fold lower SNR. The results imply that a reduction of almost two orders of magnitude in acquisition time is routinely possible for automated tissue classifications by using post-acquisition noise reduction. PMID- 20830325 TI - Competitive surface-enhanced Raman scattering assay for the 1,25-dihydroxy metabolite of vitamin D3. AB - This paper describes the development and preliminary testing of a competitive surface-enhanced Raman scattering (SERS) immunoassay for calcitriol, the 1,25 dihydroxy metabolite (1,25-(OH)(2)-D(3)) of vitamin D(3). Deficiencies in 1,25 (OH)(2)-D have been linked to renal disease, while elevations are linked to hypercalcemia. Thus, there has been a sharp increase in the clinical demand for measurements of this metabolite. The work herein extends the many attributes of SERS-based sandwich immunoassays that have been exploited extensively in the detection of large biolytes (e.g., DNA, proteins, viruses, and microorganisms) into a competitive immunoassay for the low level determination of a small biolyte, 1,25-(OH)(2)-D(3) (M(w) = 416 g mol(-1)). The assay uses surface modified gold nanoparticles as SERS labels, and has a dynamic range of 10-200 pg mL(-1) and a limit of detection of 8.4 +/- 1.8 pg mL(-1). These analytical performance metrics match those of tests for 1,25-(OH)(2)-D(3) that rely on radio or enzyme-labels, while using a much smaller sample volume and eliminating the disposal of radioactive wastes. Moreover, the SERS-based data from pooled-patient sera show strong agreement with that from radioimmunoassays. The merits and potential utility of this new assay are briefly discussed. PMID- 20830326 TI - Distinction of single base mismatches in duplex DNA using methylene blue as optical indicator. AB - A simple and sensitive approach for the recognition of single base mismatches in duplex DNA was developed. The single base mismatched double-strand (ds) DNA and the completely complementary dsDNA can quench the fluorescence of methylene blue to the different values, so the point mutation dsDNA can be identified from the duplex DNA effectively. The fluorescence intensity was decreased with the increasing dsDNA concentration in the range of 10~1000 nM, the detection limit was estimated to be 50 nM (S/N = 3). The contrast experiment showed that this method possesses the universality for the distinction of other single base mismatches in duplex DNA. Moreover, the interaction mechanism between methylene blue and dsDNA was also discussed in detail. The UV-Visible absorption and the fluorescence experiments indicated that the interaction of methylene blue and dsDNA had at least two effective modes: the electrostatic binding and the intercalation binding. When more methylene blue molecules bound onto mismatched dsDNA, the fluorescence intensity of methylene blue would decrease to a lower value than that of completely complementary dsDNA. Therefore, single base mismatched dsDNA can be recognized from duplex DNA effectively. PMID- 20830327 TI - Adenosine-aptamer recognition-induced assembly of gold nanorods and a highly sensitive plasmon resonance coupling assay of adenosine in the brain of model SD rat. AB - In this contribution, we report a molecular recognition between adenosine and its aptamer, which leads to the formation of a four-stranded tetraplex structures (G quartet) of the aptamer. It is found that the formed G-quartet could induce the side-by-side self-assembly of gold nanorods (AuNRs) owing to the electrostatic interaction between the positive charge of cetyltrimethylammonium bromide (CTAB) on the AuNR surface and the negative charge of the formed G-quartet. Furthermore, the side-by-side self-assembly of AuNRs is characterized by the enhancement of plasmon resonance light scattering (PRLS) signals and the blue-shift of the longitudinal plasmon resonance absorption (LPRA) band owing to the plasmon resonance coupling. Then, based on the enhanced PRLS signals, a simple, highly selective and sensitive detection method for adenosine was developed in the range of 4.0-80.0 nM with the limit of determination of 2.0 nM, which is up to now the best sensitive optical detection method to our knowledge. This method has been successfully applied to the detection of adenosine phosphates in the brains of SD rats, which was in good agreement with a high-performance liquid chromatographic (HPLC) method. PMID- 20830328 TI - Separation and identification of oligonucleotides by hydrophilic interaction liquid chromatography (HILIC)-inductively coupled plasma mass spectrometry (ICPMS). AB - A method for the separation and detection of oligonucleotides utilizing hydrophilic interaction liquid chromatography (HILIC) with inductively coupled plasma mass spectrometry (ICPMS) is described. Polythymidylic acids of various lengths (10, 15, 20 and 30 nucleotides) were separated under gradient HILIC conditions. Selective detection of oligonucleotides was possible through monitoring m/z 47, corresponding to (31)P(16)O(+), using ICPMS. Oxygen was used as a reaction gas in the collision/reaction cell to produce PO(+) by reacting with phosphorus in the gas phase, thereby effectively eliminating the interferences for phosphorus normally seen at m/z 31. Limits of detections (LODs) were determined to be 1.69 pmol, 1.21 pmol, 1.0 pmol and 0.55 pmol loaded on column for the 10, 15, 20 and 30 mer, respectively. PMID- 20830329 TI - Discovery of a highly selective turn-on fluorescent probe for Ag+. AB - An ideal fluorescent probe should show the strongest affinity with the relevant target (binding-selectivity) by means of a selective fluorescence change (signal selectivity). [15]aneNO(2)S(2) (1,4-dioxa-7,13-dithia-10-azacyclopentadecane) based probes usually show high binding selectivity for Ag(+) but signal selectivity for Hg(2+), because Ag(+) can quench or silence the fluorescence. To amplify the Ag(+) binding to the greatest extent, a carbonyl group was positioned between 1,8-naphthalimide and [15]aneNO(2)S(2) which played a key role of displaying selective fluorescence enhancements with Ag(+) through increasing the oxidation potential of the fluorophore, blocking Ag(+) from sterically interacting with the naphthalimide fluorophore, and by acting as a sacrificial donor. Probe 2 can detect Ag(+) with a selective fluorescence enhancement (~14 fold) and high affinity (K(a) = 1.64 * 10(5) M(-1)). PMID- 20830330 TI - Interface design and multiplexed analysis with surface plasmon resonance (SPR) spectroscopy and SPR imaging. AB - Ever since the advent of surface plasmon resonance (SPR) and SPR imaging (SPRi) in the early 1990s, their use in biomolecular interaction analysis (BIA) has expanded phenomenally. An important research area in SPR sensor development is the design of novel and effective interfaces that allow for the probing of a variety of chemical and biological interactions in a highly selective and sensitive manner. A well-designed and robust interface is a necessity to obtain both accurate and pertinent biological information. This review covers the recent research efforts in this area with a specific focus towards biointerfaces, new materials for SPR biosensing, and novel array designs for SPR imaging. Perspectives on the challenges ahead and next steps for SPR technology are discussed. PMID- 20830331 TI - Investigation of DNA methylation by direct electrocatalytic oxidation. AB - A rapid, convenient and accurate method for the assessment of DNA methylation status is presented based on the direct electrocatalytic oxidation of DNA bases without any bisulfite conversion, PCR amplification or labeling procedures. PMID- 20830332 TI - A chemical solution approach for superconducting and hard epitaxial NbC film. AB - Epitaxial NbC thin films were grown by a chemical solution technique, polymer assisted deposition. High quality epitaxial NbC film showed a transition temperature of 10 K and a hardness of 19.54 GPa. PMID- 20830333 TI - A novel oxidative cyclisation onto vinyl silanes. AB - A novel osmium-catalysed oxidative cyclisation of 1,2-diols bearing a pendant vinyl silane affords THFs that contain silicon functionality at the ring junction. When the cyclisation occurs onto a vinyl benzyldimethylsilyl group, the resulting silyl group can act as a masked hydroxyl group and undergo a Fleming Tamao type oxidation at a later stage to form the corresponding lactol. The scope of this reaction can also be extended beyond 1,2-diols and applied to the cyclisation of alpha-hydroxy-sulfonamides and alpha-hydroxy-amides. PMID- 20830334 TI - The evolvability of lead peptides from small library screens. AB - Very little is known about the evolvability of lead peptides that are isolated from small library screens. Here we begin to explore this question by comparing the directed evolution of two peptides previously isolated from a small library screen to new ligands generated de novo by in vitro selection. PMID- 20830336 TI - G-quadruplex facilitated turn-off fluorescent chemosensor for selective detection of cupric ion. AB - A simple turn-off fluorescent method was utilized to quantitatively detect Cu(II) which can selectively quench fluorescent dye molecules. Addition of DNA G quadruplex into the solution significantly magnifies the discrimination, lowers the limit of detection and broadens the linear response range. PMID- 20830335 TI - Efficient and chemoselective alkylation of amines/amino acids using alcohols as alkylating reagents under mild conditions. AB - We report a mild and environmentally benign method for the synthesis of tertiary amines using alcohols as the alkylating reagents. Not only secondary amines such as piperazines but also amino acids and amino alcohols can be N-alkylated selectively. For N,O-benzyl protected amino alcohols, both N,O-de-benzylation and N-methylation were achieved in one-pot. PMID- 20830337 TI - Real-time monitoring of cell viability by its nanoscale height change with oxygen as endogenous indicator. AB - A method for real-time evaluation of cell viability was developed by using oxygen as an endogenous indicator in scanning electrochemical microscopy to monitor the nanoscale height change of a single cell in a physiological environment with a novel Pt nanodisk electrode and a newly designed step-approaching strategy. PMID- 20830339 TI - Microwave-assisted Kochetkov amination followed by permanent charge derivatization: a facile strategy for glycomics. AB - We report a simple and rapid microwave-assisted method for the preparation of oligosaccharide-glycosylamines, followed by labelling with tris(2,4,6 trimethoxyphenyl)phosphonium acetic acid N-hydroxysuccinimide ester. The facile strategy introduced a permanent charge at the reducing end of the oligosaccharide. In combination of MALDI-MS, the detection limit for maltoheptaose was as low as 2 fmol MUL(-1). PMID- 20830338 TI - Measuring the stoichiometry of functional PspA complexes in living bacterial cells by single molecule photobleaching. AB - We report a general method based on wide-field fluorescence imaging of single molecule photobleaching and the Chung-Kennedy algorithm to measure the stoichiometry of functional protein complexes in living bacterial cells. PMID- 20830340 TI - Bio-inspired amino acid oxidation by a non-heme iron catalyst modeling the action of 1-aminocyclopropane-1-carboxylic acid oxidase. AB - In this communication we describe the first example of a biomimetic mononuclear iron complex, [Fe(III)(Salen)Cl] (Salen = N,N'-bis(salicylidene) ethylenediaminato), that highly selectively and efficiently catalyzes the oxidation of 1-aminocyclopropane-1-carboxylic acid (ACCH), alpha-aminoisobutyric acid (AIBH), and alanine (ALAH) to ethylene or the corresponding carbonyl compounds, mimicking the action of the non-heme iron enzyme 1-aminocyclopropane-1 carboxylic acid oxidase (ACCO). PMID- 20830341 TI - In situ formation of ligand 2,2'-[(E)-diazene-1,2-diyldicarbonothioyl]diphenol and structural characterization of its binuclear rhodium(V) complex containing RhO2+. AB - The ligand 2,2'-[(E)-diazene-1,2-diyldicarbonothioyl]diphenol has been synthesised in situ by aerial oxidation of o-hydroxythiobenzhydrazide [H(htbh)] in presence of rhodium(III) in DMSO. Each ligand binds two RhO(2)(+) ions through its N and S atoms and the O atom of its deprotonated hydroxy group. Each RhO(2)(+) contains two cis-Rh=O bonds. The sixth coordination site of each rhodium(V) is occupied by the O of DMSO. PMID- 20830342 TI - Fe/Al synergy in Fe(2)O(3) nanoparticles supported on porous aluminosilicate materials: excelling activities in oxidation reactions. AB - A synergetic Fe-Al effect in Fe(2)O(3) nanoparticles supported on mesoporous aluminosilicates compared to pure siliceous silicates has been demonstrated, for the first time, by a remarkably superior catalytic activity of the former in the microwave-assisted selective oxidation of benzyl alcohol to benzaldehyde. This significant finding, that also deeply influences the acidity of the materials (increasing total and particularly Lewis acidity), can have important consequences in the improved efficiency of these systems in related oxidations as well as in acid catalysed processes. PMID- 20830343 TI - Quantitative, label-free and site-specific monitoring of molecular recognition: a multivariate resonance Raman approach. AB - A site-specific and quantitative approach for label-free monitoring of molecular recognition is presented. Specifically, the binding site of an artificial receptor is probed selectively by UVRR spectroscopy. The ligand binding constant can be determined by non-negative matrix factorization. PMID- 20830344 TI - Coarse-grained simulations of stretching entangled DNA using oscillating electric fields. AB - DNA stretching in entangling media with oscillating electric fields is useful in DNA sequencing. We propose that stretching occurs around hairpin loops at the chain ends, caused by interactions with the medium. Brownian dynamics simulations show that this mechanism explains several experimental observations, including a resonance with varying field frequency. PMID- 20830345 TI - Efficient receptor-independent intracellular translocation of aptamers mediated by conjugation to carbon nanotubes. AB - We have covalently grafted aptamers onto carboxylated carbon nanotubes to design a novel vector system that can easily translocate into the cytosol of different cell types independent of receptor-mediated uptake. We propose the use of carbon nanotubes for the efficient intracellular delivery of biologically active aptamers for potential therapeutic applications. PMID- 20830346 TI - Grafted cellulose strands on the surface of silica: effect of environment on reactivity. AB - The design, synthesis and characterization of materials consisting of grafted poly(1 -> 4-beta-glucan) strands on silica is reported. The silanol-rich environment provided in these materials activates the glycosidic bond for hydrolysis under mild conditions. PMID- 20830347 TI - Synthesis of well-defined polymers grafted onto fumed silica by chain exchange reaction and highly pure block copolymers thereby. AB - Radical-induced addition-fragmentation processes were efficiently used for surface modification of fumed silica, and Z-supported solid CTAs could be reused in presence of excess sacrificial thermal initiator. PMID- 20830348 TI - The pattern recognition molecule deleted in malignant brain tumors 1 (DMBT1) and synthetic mimics inhibit liposomal nucleic acid delivery. AB - Liposomal nucleic acid delivery is a preferred option for therapeutic settings. The cellular pattern recognition molecule DMBT1, secreted at high levels in various diseases, and synthetic mimics efficiently inhibit liposomal nucleic acid delivery to human cells. These findings may have relevance for therapeutic nucleic acid delivery strategies. PMID- 20830349 TI - The natural product hybrid of Syringolin A and Glidobactin A synergizes proteasome inhibition potency with subsite selectivity. AB - The preparation of a Syringolin A/Glidobactin A hybrid (SylA-GlbA) consisting of a SylA macrocycle connected to the GlbA side chain and its potent proteasome targeting of all three proteasomal subsites is reported. The influence of the syrbactin macrocycle moiety on subsite selectivity is demonstrated. PMID- 20830350 TI - Perfluoroalkylated amphiphilic MUC1 glycopeptide antigens as tools for cancer immunotherapy. AB - The synthesis of perfluoroalkylated glycopeptide antigens and their specific binding to anti-MUC1 mouse antibodies is reported. PMID- 20830351 TI - DNA-nanoparticle micelles as supramolecular fluorogenic substrates enabling catalytic signal amplification and detection by DNAzyme probes. AB - Catalytic DNA molecules have tremendous potential in propagating detection events via nucleic acid sequence selective signal amplification. However, they suffer from product inhibition limiting their widespread utility. Herein, this limitation is overcome utilizing a novel fluorogenic substrate design consisting of cooperatively assembled DNA-nanoparticle micelles. PMID- 20830352 TI - When chiral product and catalyst are the same: discovery of asymmetric organoautocatalysis. AB - The process of asymmetric organoautocatalysis appears to be a natural extension to asymmetric organocatalysis, and holds implications for models on the origin of biological homochirality. The discovery of asymmetric organoautocatalysis (i.e. the process in which the chiral product of a purely organic reaction acts as an organocatalyst for its own formation under conservation of its absolute configuration) and more recent reports on related systems are discussed in this review. PMID- 20830353 TI - Catalysts by the meter: rapid screening approach of N-heterocyclic carbene ligand based catalysts. AB - Here, we demonstrate a versatile screening platform for NHC ligand based catalysts by coating fused-silica micro capillaries with a bonded 1,3-bismesityl 2-imidazolidinylidene ligand. Such micro capillaries can be efficiently converted into (pre)-catalysts from various organometallic precursors by solid-phase chemistry techniques and can be quantitatively screened using on-column reaction chromatography. PMID- 20830355 TI - Electrochemically erasable hydrogen-bonded thin films. AB - We report a new method to trigger the dissolution of hydrogen-bonded layer-by layer thin films through electrochemical reduction of dissolved oxygen, which raises the local pH. PMID- 20830354 TI - Surface-mediated release of a synthetic small-molecule modulator of bacterial quorum sensing: gradual release enhances activity. AB - We demonstrate an approach to the surface-mediated release of a synthetic N acylated L-homoserine lactone (AHL) modulator of bacterial quorum sensing (QS). AHL released gradually from thin films of poly(lactide-co-glycolide) (PLG) is shown to activate QS in the model symbiont Vibrio fischeri at levels that exceed those promoted by direct solution-based administration. PMID- 20830356 TI - Development of photostable near-infrared cyanine dyes. AB - With the emerging interest in optical in vivo imaging, there is an increasing demand of photostable near-infrared (NIR) dyes. Herein we report the rational design of an amine tricarbocyanine structure with improved photostability (CyNA) and its combinatorial derivatization to render CyNA-414 as a NIR-fluorescent dye with stronger emission intensity and higher photostability than the NIR standard IndoCyanine Green (ICG). PMID- 20830357 TI - Highly efficient photoluminescent graphene oxide with tunable surface properties. AB - A bright blue fluorescent graphene oxide that originates from passivation of surface reactive sites by amide formation and ring-opening amination of epoxide has been prepared. The surface polarity and charges of the fluorescent graphene oxide can synchronously be tuned by varying the used alkylamines. PMID- 20830358 TI - Programmable microfluidic patterning of protein gradients on hydrogels. AB - Computer-controlled hydrodynamic flow focusing was utilized to generate tethered protein gradients of any user-defined shape on the surface of soft synthetic hydrogels. PMID- 20830359 TI - Selective synthesis of dibenzo[a,c]cyclooctatetraenes via palladium-catalyzed [4+4] cyclic homocoupling of borylvinyl iodobenzene derivatives. AB - Dibenzo[a,c]cyclooctatetraenes were selectively generated in good yields from the palladium-catalyzed [4+4] cyclic homocoupling of borylvinyl iodobenzene derivatives, which were prepared via the selective Suzuki-Miyaura cross-coupling of the gem-diboryl reagents with iodo compounds. PMID- 20830360 TI - Rhodamine-sugar based turn-on fluorescent probe for the detection of cysteine and homocysteine in water. AB - A new turn-on fluorescent probe utilizing the "chemosensing ensemble" method is developed to detect thiol-containing amino acids. A complex of Au(+) and a rhodamine hydroxylamine having 2-deoxyribose can selectively detect cysteine and homocysteine in water. PMID- 20830361 TI - Quantum-dot-embedded ionomer-derived films with ordered honeycomb structures via breath figures. AB - A new approach for fabricating a series of multi-functional honeycomb-patterned films was successfully achieved using ionomers via breath figures. PMID- 20830362 TI - Turn-on fluorescence switch involving aggregation and elimination processes for beta-lactamase-tag. AB - The targeted protein of interest is fused with genetically modified beta lactamase enzyme, which reacts with the probe in physiological conditions to break the aggregated interaction between the fluorophore and quencher. This alliance-separation technique is new for protein labeling and is probed in vitro and in live cell imaging studies. PMID- 20830363 TI - Double-decked molecular crescents. AB - Molecules with a defined crescent shape have been generated from the folding or covalent locking of curved structural components connected together via multiple covalent tethers. PMID- 20830364 TI - Synthesis of phosphonamidate peptides by Staudinger reactions of silylated phosphinic acids and esters. AB - The Staudinger reaction of unprotected azido-peptides with silylated phosphinic acids and esters on the solid support offers a straightforward acid-free entry to different phosphonamidate peptide esters or acids under mild conditions in high purity and yield. PMID- 20830365 TI - Carbon nanotube-amorphous FePO4 core-shell nanowires as cathode material for Li ion batteries. AB - Carbon nanotube (CNT)-amorphous FePO(4) core-shell nanowires are synthesized by aqueous solution-based mineralization through sequential adsorption of Fe(3+) and PO(4)(3-) ions onto the CNT surface. The hierarchical nanostructure with FePO(4) shell directly grown on the CNT core exhibits excellent electrochemical properties and performance as a cathode material for Li ion batteries. PMID- 20830366 TI - The first supraicosahedral bis(heteroborane). AB - The first supraicosahedral bis(heteroborane), 1-(4'-Cp-4',1',6'-closo CoC(2)B(10)H(11))-4-Cp-4,1,6-closo-CoC(2)B(10)H(11) has been synthesised as a mixture of racemic and meso diastereoisomers. Analysis of the molecular structures reveals clear evidence of internally crowded molecules. PMID- 20830367 TI - Dramatic micellar rate enhancement of the Cu(2+) catalyzed vinologous Friedel Crafts alkylation in water. AB - A dramatic rate enhancement of the Cu(2+) catalyzed Friedel-Crafts alkylation in water was achieved in the presence of sodium dodecyl sulfate (SDS) micelles. PMID- 20830368 TI - Halocyclization of o-(alkynyl)styrenes. Synthesis of 3-halo-1H-indenes. AB - o-(Alkynyl)styrenes undergo halocarbocyclization processes via a 5-endo-dig ring closure. By this strategy an efficient synthesis of 3-halo-1H-indene derivatives has been developed. PMID- 20830369 TI - Site-specific introduction of gold-carbenoids by intermolecular oxidation of ynamides or ynol ethers. AB - Ynamides and ynol ethers undergo intermolecular gold-catalysed reaction with a nucleophilic oxidant to access metal-carbenoid reactivity patterns. A site specific oxidation/1,2-insertion cascade is used for a general access to functionalised alpha,beta-unsaturated carboxylic acid derivatives and vinylogous carbimates. PMID- 20830370 TI - Noncovalent functionalization of multiwall carbon nanotubes by methylated-beta cyclodextrins modified by a triazole group. AB - Multiwall carbon nanotubes have been efficiently suspended into water thanks to methylated beta-cyclodextrins (CDs) containing a triazole group, itself substituted in the 4-position by hydrophilic moieties. PMID- 20830371 TI - Direct observation of key intermediates by negative-ion electrospray ionisation mass spectrometry in palladium-catalysed cross-coupling. AB - Negative-ion electrospray ionisation mass spectrometry with an anionic phosphine ligand enables detection of key intermediates in the Sonogashira reaction. MS/MS techniques are used to generate a Hammett plot for the key reductive elimination step. PMID- 20830372 TI - High-connected mesoporous metal-organic framework. AB - An indium trimer has been employed to construct a mesoporous metal-organic framework with the highest connectivity, the amine functionalization of which leads to the effective use of central space for the adsorption of small molecules, and then results in the enhancement of adsorption capacity. PMID- 20830373 TI - Group 3-centred dehydrocoupling of Me2NH.BH3. AB - Stoichiometric and catalytic reactions of group 3 (Sc, Y) amides with Me(2)NH.BH(3) result in formation of the corresponding amidoborane derivatives and dehydrogenative coupling of two amine borane fragments under mild conditions. PMID- 20830374 TI - Structural and biochemical basis for the firm chemo- and regioselectivity of the nitro-forming N-oxygenase AurF. AB - Site-directed mutagenesis based on the crystal structure of AurF, a nitro group forming monooxygenase from Streptomyces thioluteus, revealed that AurF variants are capable of selectively transforming guanidyl- and amidinyl-substituted anilines into the corresponding nitro compounds. Our results provide new insights into the biochemical basis of regioselective N-oxygenation. PMID- 20830375 TI - Reactions of dizincocene with sterically demanding bis(iminodi(phenyl)phosphorano)methanes. AB - Reactions of Cp*(2)Zn(2) with sterically demanding bis(iminodi(phenyl)phosphorano)methanes LH (LH = CH(2)(Ph(2)P=NR)(2) (R = Ph L(1)H, SiMe(3)L(2)H, 2,6-i-Pr(2)C(6)H(3) (Dipp) L(3)H) at ambient temperature occurred with elimination of Cp*H and subsequent formation of the homoleptic complex L(1)(2)Zn(2)1 and the heteroleptic complexes LZnZnCp* (L = L(2)2, L(3)3, L(1)4). 3 is the first structurally characterized heteroleptic organozinc complex with the zinc atoms in the formal oxidation state +1. PMID- 20830376 TI - Peptidomimetic inhibitors targeting the CCR5-binding site on the human immunodeficiency virus type-1 gp120 glycoprotein complexed to CD4. AB - A helical tyrosine-sulfated epitope in CCR5 that is recognized by the human immunodeficiency virus type-1 envelope glycoprotein gp120 in its CD4-induced conformation can be mimicked structurally by a cyclic beta-hairpin peptide containing two sulfated tyrosine residues at positions i and i + 2 along one beta strand. PMID- 20830377 TI - A pyridine-bridged bis-benzimidazolylidene pincer nickel(II) complex: synthesis and practical catalytic application towards Suzuki-Miyaura coupling with less activated electrophiles. AB - A novel robust pyridine-bridged bis-benzimidazolylidene nickel pincer complex 3 accessible from inexpensive, commercially available precursors efficiently catalyzes the first practical Suzuki-Miyaura cross-coupling reactions with various less-reactive electrophiles ArX (X = Br, Cl, OTs and OMs) and even tolerates electron-rich, sterically demanding and heterocyclic arenes in the presence of catalytic amounts of PPh(3). PMID- 20830378 TI - On the nature of the B...N interaction and the conformational flexibility of arylboronic azaesters. AB - It is shown that the structural and physicochemical properties of arylboronic azaesters result from the properties of the key B-N bond. This bond is different in arylboronic azaesters from typical single/double/triple B-N bonds present in other boron-nitrogen compounds. By studying a model example, 6-tert-butyl-2 (3',5'-difluorophenyl)-(N-B)-1,3,6,2-dioxazaborocane, it is proved that the molecule adopts the closed form in the solid state with the BN bond length equal to 1.7646(3) A. This represents the longest B-N bond length for an arylboronic ester reported in literature. According to the results of experimental charge density studies and QTAIM analysis, the BN bond/contact shows good separation of the respective atomic basins and significant flexibility. The source function and NBO analyses indicate an evident involvement of the oxygen atoms in the creation of the B-N bonding. According to our DFT calculations the isolated model molecule exists in the open conformer. The constrained energy scans reveal an E(d(B-N)) potential energy surface which depends strongly on the nature of the substituents at the nitrogen and aromatic carbon atoms. It appears that an appropriate substitution can produce either conformer. A dipole moment analysis provides a good insight into the reactivity properties of the compound in solution. The opening of the azaester cage is associated with a breaking of the B-N bond, thus decreasing the magnitude of the dipole moment. The existence of the open conformer is confirmed by multi-temperature NMR studies. When decreasing the temperature of the measurements the (1)H and (11)B NMR spectra show features corresponding to the open form of the model arylboronic azaester. PMID- 20830379 TI - Vibrational solvatochromism and electrochromism of cyanide, thiocyanate, and azide anions in water. AB - Small IR probe molecules have been found to be useful to measure local electric fields in condensed phases and proteins and also to study nucleic acid and protein structure and dynamics by monitoring their vibrational couplings and frequency shifts. However, it is still difficult to accurately describe the vibrational solvatochromic frequency shifts of such IR probes, because the local electric fields produced by surrounding solvent molecules or by protein peptide and side groups are spatially non-uniform and highly inhomogeneous around a probe. We recently developed a distributed interaction site model to describe the vibrational solvatochromism and electrochromism of nitrile-, thiocyanato-, and azido-derivatized compounds and amino acids in solutions. Here, the nitrile or azido stretch is the maker mode. It was found that those interaction sites distributed over the IR probe molecule collectively act as an antenna sensing local electric field distributions around the IR probes. Once the vibrational solvatochromism of a given IR probe is understood, it becomes possible to quantitatively describe their vibrational Stark effects. Carrying out quantum chemistry calculations of cyanide, thiocyanate, and azide anions in water clusters, we extended the distributed site model for ionic IR probes and calculated the vibrational Stark tuning rates for direct comparisons with experimental results. It turns out that the charge transfers from an anionic solute to surrounding water molecules are significant, but their effects on vibrational solvatochromism and electrochromism of pseudohalide ionic IR probes are not. We anticipate that the present computational results will be of use to establish the relationship between vibrational frequency of an ionic IR probe and local electric field in condensed phases and protein matrices. PMID- 20830380 TI - Functional colloidal trimers by quenched electrostatic assembly. AB - It is shown how to assemble three particles into a single "colloidal trimer". The particles may consist of different materials and be different sizes, and they can be assembled in a particular sequence (i.e. 1-2-3 or 2-1-3 or 2-3-1). Several trimer assemblies are demonstrated, including polystyrene-silica-polystyrene, gold-polystyrene-silver, and gold-silicon-silver. The gold-silicon-silver assembly operates as a catalytic motor, moving rapidly by autoelectrophoresis when placed in a hydrogen peroxide solution. The assemblies are made by allowing oppositely-charged particles to aggregate in a diffusion-limited manner for a time, and then quenching the aggregation by the addition of a nanoparticle coating on one of the particles. We call this method "Quenched Electrostatic Assembly", and it serves as a general, scalable method for synthesizing multi component colloidal trimers, including those requiring a certain sequential order, but not requiring particular orientations. In addition, when polymer nanoparticles are used to quench the aggregation, they can be fused above their glass transition temperature to produce assemblies that are mechanically stable. PMID- 20830381 TI - Physical insights of salt transfer through solvent polymeric membranes by means of electrochemical methods. AB - A combined voltammetric study of the joint transfer of the two constituting ions of a water-soluble salt has been carried out using normal-pulse voltammetry, linear-sweep voltammetry and square-wave voltammetry in a system with two liquid liquid polarized interfaces. As a result, we have explained the voltammetric features that allow us to distinguish this uptake from that corresponding to two equally charged ions, in spite of the appearance in both situations of two current peaks with the same sign in both square-wave and linear-sweep voltammograms, and we have found that linear-sweep voltammetry and square-wave voltammetry complement each other excellently.A theoretical comparison with a system of a single polarized interface has also been made, showing that these systems are much less appropriate for characterizing these salt-ion transfers. PMID- 20830382 TI - Alkyl-chain dividing layer at an alcohol/ionic liquid buried interface studied by sum-frequency generation vibrational spectroscopy. AB - We demonstrate for the first time the formation of a non-polar alkyl-chain dividing layer between a room-temperature ionic liquid (RTIL) and an n-alcohol. This newly described non-polar interfacial layer, which should be more hydrophobic than both RTIL and alcohol phases, might find applications in liquid/liquid reaction systems, or serve as a soft nano-functional space. PMID- 20830383 TI - Computational studies of gas phase reactions of carbon chain anions with N and O atoms. AB - Experimental studies of gas phase reactions of carbanions with N and O atoms have been reported previously to understand ion chemistry relevant to the interstellar medium. In all cases reactions of anions with O atoms exhibit larger reaction rate constants compared to the corresponding N atom reactions. In addition, the open-shell carbon chain anions exhibit higher reactivities than the corresponding closed-shell species in N atom reactions, whereas similar reactivities were observed for both open and closed-shell anions in O atom reactions. These trends are investigated by the current theoretical study of the reactions of HC(n)(-)(n = 2, 4, and 6) and C(n)(-) (n = 2, 4-7) with N and O atoms. Our results indicate that spin-forbidden processes are the probable pathways in reactions of closed shell anions HC(n)(-) with N atoms, and spin conversion limits the reaction efficiency. In reactions of open-shell anions C(n)(-) with N atoms, about 50% of the collisions may proceed through spin-allowed barrierless pathways, which results in relatively higher reaction efficiencies than for the closed-shell reactions. For reactions of all anions with O atoms, the spin-allowed barrierless pathways are the only channels, such that all reactions occur with very high efficiencies. This work provides a greater understanding of the influence of spin effects on the reactivities of anion reactions involving N and O atoms that may be important in the interstellar medium. PMID- 20830384 TI - Mass transport effects in CO bulk electrooxidation on Pt nanoparticles supported on vertically aligned carbon nanofilaments. AB - In this work we report on the influence of the catalytic layer architecture on the autocatalytic reaction of CO-bulk oxidation in liquid electrolyte by employing two types of nanomaterials: 2D arrays of Pt particles prepared on the surface of glassy carbon by colloidal lithography and 3D arrays of Pt nanoparticles supported on vertically aligned carbon nanofilaments. Oxidation of dissolved CO is studied experimentally using RDE approach and computationally using finite element method. For the first time, the influence of 3D architecture of the electrode on a complex bistable electrochemical system was investigated. The modelling results are in qualitative agreement with the experiment and explain the influence of nanostructure of the electrodes on such key characteristics of CO electrooxidation as the ignition potential, the width and the shape of the bistability region, and the value of the limiting current. Analysis of the experimental RDE curves suggests spontaneous formation of active and passive reaction zones along the fibre length which is supported by modelling. PMID- 20830385 TI - Mass-spectrometric and computational study of tryptophan radicals (Trp + H) produced by collisional electron transfer to protonated tryptophan in the gas phase. AB - Hydrogen atom adducts to tryptophan were generated for the first time in the gas phase by collisional electron transfer to protonated tryptophan at 7170 eV kinetic energy. The radicals showed fast dissociations by C(alpha)-C(beta) bond cleavage and cross-ring cleavages occurring on the 7.3 MUs time scale. The mechanism of the C(alpha)-C(beta) bond cleavage was explained by ab initio computational analysis of the radical potential energy surface. This showed spontaneous isomerization of the primary tryptophan radical by ammonium hydrogen atom migration to the carboxyl group. The stable intermediate formed by the isomerization can undergo radical-induced scission of the C(alpha)-C(beta) bond in competition with H-atom migrations to the C-2 and C-4 positions of the indole ring. RRKM calculations of unimolecular rate constants on the B3-ROMP2/6 311++G(2d,p) potential energy surface indicated that the C(alpha)-C(beta) bond cleavage was the fastest unimolecular reaction of the radical intermediates within the range of internal energies acquired upon electron transfer. We also report an updated G2(MP2) proton affinity of tryptophan (PA = 946 kJ mol(-1)) and hydrogen atom affinities of the tryptophan indole ring of relevance to electron based peptide dissociations. PMID- 20830386 TI - Microscopic structure of liquid 1-1-1-2-tetrafluoroethane (R134a) from Monte Carlo simulation. AB - 1-1-1-2-tetrafluoroethane (R134a) is one of the most commonly used refrigerants. Its thermophysical properties are important for evaluating the performance of refrigeration cycles. These can be obtained via computer simulation, with an insight into the microscopic structure of the liquid, which is not accessible to experiment. In this paper, vapour-liquid equilibrium properties of R134a and its liquid microscopic structure are investigated using coupled-decoupled configurational-bias Monte Carlo simulation in the Gibbs ensemble, with a recent potential [J. Phys. Chem. B 2009, 113, 178]. We find that the simulations agree well with the experimental data, except at the vicinity of the critical region. Liquid R134a packs like liquid argon, with a coordination number in the first solvation shell of 12 at 260 K. The nearest neighbours prefer to be localized in three different spaces around the central molecule, in such a manner that the dipole moments are in a parallel alignment. Analysis of the pair interaction energy shows clear association of R134a molecules, but no evidence for C-HF type hydrogen bonding is found. The above findings should be of relevance to a broad range of fluoroalkanes. PMID- 20830387 TI - Probing the mechanisms of electron capture dissociation mass spectrometry with nitrated peptides. AB - Previously we have shown that the presence of 3-nitrotyrosine within a peptide sequence severely depletes the peptide backbone fragments typically observed following electron capture dissociation (ECD) mass spectrometry. Instead, ECD of nitrated peptides is characterised by abundant losses of small neutrals (hydroxyl radicals, water and ammonia). Here, we investigate the origin of ammonia loss by comparing the ECD behaviour of lysine- and arginine-containing nitrated peptides, and their N-acetylated counterparts, and nitrated peptides containing no basic amino acid residues. The results reveal that ammonia loss derives from the N terminus of the peptides, however, the key finding of this work is the insight provided into the hierarchy of various proposed ECD mechanisms: the Utah Washington mechanism, the electron predator mechanism and the Oslo mechanism. PMID- 20830388 TI - Computational insights into the nature of increased ionic conductivity in concentrated samarium-doped ceria: a genetic algorithm study. AB - Classical force field simulations and genetic algorithms are used to navigate low energy configurations of samarium-doped ceria (SDC) at a number of concentrations, up to 20% SDC, such that the experimentally observed peak in ionic conductivity is mapped out in its entirety and fresh insight into samarium's role is reported. PMID- 20830389 TI - Radiolysis of water in nanoporous gold. AB - Nanoporous gold was used as a high specific surface material to describe the water radiolysis in the vicinity of metal surfaces. Porous gold monoliths were prepared by electrolytic dissolution of silver in Au-Ag alloys and characterized by small angle neutron scattering. The hydroxyl radical production under gamma irradiation was measured by benzoate scavenging in water confined in 50 nm porous gold or in silica glasses of similar pore size, and in bulk water. Whereas a silica interface induces minimal modifications to the HO radical production with respect to bulk water, HO production near gold is enhanced more than seven times on the short time scale, and almost completely suppressed by reaction with the metal on the long time scale. PMID- 20830390 TI - Polynuclear complexes of macrocyclic oxamide with 5-sulfosalicylate: syntheses, crystal structures and magnetic properties. AB - Hydrothermal reactions of mixed ligands 5-sulfosalicylic acid (H(3)SSAL) and macrocyclic oxamide complex (CuL) with M(ClO(4))(2).6H(2)O (M = Mn, Gd and Cu) afford three new complexes, including [Mn(II)(2)Mn(III)(SSAL)(2)(CuL)(2)(OH)(H(2)O)(3)]n (1), {[Gd(2)(HSSAL)(2)(CuL)(4)(C(2)O(4))(H(2)O)(2)].2H(2)O}(n) (2) and [Cu(2)(HSSAL)(2)(CuL)(4)].2H(2)O (3) (CuL, H(2)L = 2,3-dioxo-5,6,14,15-dibenzo 1,4,8,12-tetraazacyclo-pentadeca-7,13-diene). Complex 1 has very interesting mixed-valence manganese-copper Cu(II)Mn(II)Mn(III)Mn(II)Cu(II) units and consists of a 1D ladderlike chain formed by the linkage of copper(ii) and Mn(3) clusters via the oxamide and SSAL(3-) bridges. The structure of 2 consists of hexanuclear Cu(II)(4)Gd(III)(2) molecules and is arranged in a 1D ladderlike chain formed by the linkage of copper(ii) and gadolinium(iii) via the oxamide, oxalate and HSSAL(2-) bridges. Complex 3 is a hexanuclear Cu(II)(6) molecule including both oxamide and HSSAL(2-) bridges. The results of magnetic determination show pronounced antiferromagnetic interactions in 1 and 3, and ferromagnetic interactions in 2. PMID- 20830391 TI - The building blocks of metallothioneins: heterometallic Zn(2+) and Cd(2+) clusters from first-principles calculations. AB - Electronic structures of Zn(2+) and Cd(2+) thiolate clusters found in metallothioneins (MT) have been obtained using density functional theory. We have found that the inherent asymmetry of cluster architectures gives rise to seven distinct metal sites. Whereas the non-strained bond lengths of such tetrathiolate complexes are found to be 2.60 A and 2.39 A for Cd-S and Zn-S, in the MT clusters four characteristic terminal and bridging bonds are observed with average lengths 2.55 A (Cd-S(t)); 2.35 A (Zn-S(t)); 2.62 A (Cd-S(b)); and 2.42 A (Zn-S(b)). For each stoichiometry of Zn(2+) and Cd(2+), all possible isomers have been characterized and ranked according to relative free energy and metal ion selectivity. The most stable distribution at low Cd(2+) concentration is computed to be Zn(4) + CdZn(2), whereas at 2 : 1 Cd(2+) : Zn(2+) concentration, only heteroclusters are thermodynamically stable, explaining experimental data. The presence of two different clusters in MTs must and can be rationalized already in their intrinsic differences. The results indicate that the asymmetry allows for Zn(2+) transfer to various molecular targets having different thresholds for Zn(2+) binding, while maintaining detoxification sites. PMID- 20830392 TI - Application of the sila-Friedel-Crafts reaction to the synthesis of pi-extended silole derivatives and their properties. AB - The intramolecular sila-Friedel-Crafts reaction was developed as a new method for the construction of a dibenzosilole skeleton. This reaction proceeds under mild conditions to afford the target in relatively good yield, indicating its availability as a versatile synthetic method. This reaction can be applied to the synthesis of pi-extended silole derivatives such as ladder-type silafluorene 8 and spiro-type silabifluorene 9. Furthermore, the synthesis of two-dimensionally extended silole derivatives utilizing the sila-Friedel-Crafts reaction as the multiple intramolecular cyclization was achieved, including the first synthesis of trisilasumanene 18. The X-ray crystallographic analysis of trisilasumanene 18 demonstrated the planarity in the main pi-framework, in contrast to sumanene and its sulfur analogue, trithiasumanene, bearing the bowl-shaped structures. In the UV-vis absorption spectra, the absorption bands of triphenylenosiloles 18 and 19 were slightly red-shifted compared to that of hexabutoxytriphenylene 22. The weak absorption bands were also observed in the longer-wavelength region in 18 and 19, which is derived from sigma*-pi* conjugation of the silole skeletons. In addition, 18 and 19 showed the blue fluorescence in dichloromethane and in the solid state. PMID- 20830393 TI - Photo-reactive Ru(II)-oligonucleotide conjugates: influence of an intercalating ligand on the inter- and intra-strand photo-ligation processes. AB - The damaging efficacy towards OligoDeoxyriboNucleotides (ODNs) of two photoreactive polyazaaromatic ruthenium(II) complexes, Ru(T) and Ru(D), has been evaluated. Both compounds correspond to the known [Ru(TAP)(2)(dppz)](2+) complex, but they are anchored differently to a guanine-containing single strand ODN (probe strand). This has allowed us to investigate the influence of the interactions existing between the tethered complexes and the single or double strand, on the photo-ligation processes. From melting temperature measurements of the duplex formed between these Ru-ODNs and their complementary sequence (target strand), it has been found that Ru(T) anchored via the TAP ligand interacts with the duplex by means of the intercalating dppz ligand (head on geometry), while Ru(D) anchored via the dppz ligand likely adopts a side on geometry without intercalation. Both single stranded Ru conjugates self-inhibit in the absence of their target ODN by forming exclusively a cyclic "seppuku" photo-adduct (intra molecular photoreaction). In contrast, this intra-molecular photo-product is precluded in presence of the target strand, and the Ru-ODN sequence photo crosslinks with the latter (inter-molecular photoreaction). Both intra- and inter molecular processes with both complexes are efficient (80% yields) and lead to stable photo-adducts. Interestingly, detailed studies have revealed that the similar photo-damaging efficacy of crosslinking by Ru(T) and Ru(D) is a consequence of a cascade of events with compensatory effects, originating from the different geometry of interaction of the tethered complexes. Notably, antagonistic effects are present when the complex is intercalated, the guanine oxidation step being highly favoured and the recombination of the quenching products being hindered. PMID- 20830394 TI - Chelated orthoborate ionic liquid as a reactant for the synthesis of a new cobalt borophosphate containing extra-large 16-ring channels. AB - 1-Ethyl-3-methylimidazolium bis(oxalato)borate ([Emim][BOB]), a room-temperature ionic liquid, has been prepared and used for the first time to develop new borate containing material. A new open-framework cobalt borophosphate, (NH(4))(7)Co(4)(H(2)O)[B(2)P(4)O(15)(OH)(2)](2)[H(2)PO(4)][HPO(4)], with peanut shaped extra-large 16-ring channels has been obtained. PMID- 20830395 TI - Facile hydrothermal synthesis and observation of bubbled growth mechanism in nano ribbons aggregated microspherical Covellite blue-phosphor. AB - Well uniform microspheres of phase pure Covellite were synthesized through a simple hydrothermal approach using poly vinyl pyrrolidone (PVP) as surfactant. The micro-spheres were constituted of numerous self-organized knitted nano ribbons of ~ 30 nm thickness. The effect of conc. PVP in the hydrothermal precursor solution on the product morphology was investigated. Based on the out coming product micro-architecture a growth mechanism was proposed which emphasized bubbled nucleation inside the hydrothermal reactor. In a comparative study on linear optical properties, enhancement of luminescent intensity was observed for nano-ribbon clung microspheres rather than that of agglomerates of distorted particles, which may be attributed to better crystallinity as well as reduced surface defects and ionic vacancies for ribbon-like nano-structures. PMID- 20830396 TI - Raman- and infrared-spectroscopic investigations of dilute aqueous phosphoric acid solutions. AB - Phosphoric acid in water and heavy water has been studied by Raman and infrared spectroscopy over a broad concentration range (0.00873-1.560 mol kg(-1)) at 23 degrees C. The vibrational modes of the PO(4) skeleton (C(3v) symmetry) of H(3)PO(4)(aq) and D(3)PO(4)(D(2)O) have been assigned. In addition to the P-O stretching modes a deformation mode has been detected, deltaPO-H(D) at 1250 and 935 cm(-1), respectively. In addition to the modes of the phosphoric acid and heavy phosphoric acid a mode of the dissociation product H(2)PO(4)(-) and D(2)PO(4)(-) has been detected at 1077 cm(-1) and 1084 cm(-1) respectively. H(3)PO(4) and D(3)PO(4) is hydrated in aqueous solution which could be verified by Raman spectroscopy following the nuP[double bond, length as m-dash]O and nu(s)P(OH)(3) mode as a function of temperature. These modes show a pronounced temperature dependence inasmuch as nuP[double bond, length as m-dash]O shifts to higher wavenumbers with temperature increase and nu(s)P(OH)(3) to lower wavenumbers. In the range between 300-600 cm(-1) the deformation modes have been observed. In very dilute H(3)PO(4) solutions however, the dissociation product is the dominant species. The dissociation degree, alpha for H(3)PO(4)(aq) and D(3)PO(4)(D(2)O) as a function of dilution has been measured at 23 degrees C. In these dilute H(3)PO(4)(aq) and D(3)PO(4)(D(2)O) solutions no spectroscopic features for a dimeric species of the formula H(6)P(2)O(8) and D(6)P(2)O(8) could be detected. Quantitative Raman measurements have been carried out to follow the dissociation of H(3)PO(4) and D(3)PO(4) over a very broad concentration range and also as a function of temperature. From the dissociation data, the pK(1) value for H(3)PO(4) has been determined to 2.14(1) and for D(3)PO(4) to 2.42(1) at 23 degrees C. In the temperature interval from 24.5 to 99.7 degrees C the pK(1) values for H(3)PO(4)(aq) have been determined and thermodynamic data have been derived. PMID- 20830397 TI - A tungsten-mediated closed cycle of reactivity for the reduction of CO(2) to CO. AB - The recycling of CO(2) by reduction to CO is an important objective in the context of renewable carbon feedstock chemicals. A tungsten-mediated reduction of CO(2) to CO reported by Mayer and coworkers has been re-examined, and it is shown that a series of four well-defined stoichiometric steps can be executed which form a closed cycle and sum as CO(2) + 2H(+) + 2e(-)-> CO + H(2)O. Energetic parameters of this system are probed by cyclic voltammetry, by calculations of gas-phase reaction enthalpies for each of the four steps, and by calculation of the W[triple bond, length as m-dash]O bond dissociation energy for the tungsten species that results from oxidation addition of CO(2). PMID- 20830398 TI - Photoinduced four- and six-electron reduction of mononuclear ruthenium complexes having NAD+ analogous ligands. AB - The ruthenium complexes [Ru(bpy)(pbn)(2)](PF(6))(2) ([2](2+); bpy = 2,2' bipyridine, pbn = 2-(2-pyridyl)benzo[b]-1,5-naphthyridine) and [Ru(pbn)(3)](PF(6))(2) ([3](2+)) were synthesized. Photoirradiation (lambda > 420 nm) of [2](2+) and [3](2+) in CH(3)CN/triethanolamine (TEOA) brought about proton coupled four- and six-electron reduction of the complexes to produce [Ru(bpy)(pbnH(2))(2)](PF(6))(2) ([2.H(4)](2+); pbnH(2) = 5,10-dihydro-2-(2 pyridyl)benzo[b]-1,5-naphthyridine) and [Ru(pbnH(2))(3)](PF(6))(2) ([3.H(6)](2+)), respectively. The photoexcited [Ru(III)(bpy)(pbn( ))(pbnH(2))](2+) intermediate is quenched by intermolecular electron transfer from TEOA to Ru(III), while intramolecular transfer from pbnH(2) to Ru(III) is negligible. As a result, novel photochemical four- and six-electron reduction of [2](2+) and [3](2+) is achieved through repetition of the two-electron reduction of the Ru-pbn group. The high efficiency photochemical two-, four- and six electron reductions of [Ru(bpy)(2)(pbn)](2+) ([1](2+)), [2](2+) and [3](2+), respectively, by taking advantage of proton coupled two electron reduction of NAD(+) analogous type ligands such as pbn opens a general pathway for multi electron reduction of metal complexes via illumination with visible light. PMID- 20830399 TI - Synthesis, structures and electrochemistry studies of 2Fe2S-Fe(ii)(S-2N)(2) models for H-cluster of [FeFe]-hydrogenase. AB - A series of model complexes [(MU-pdt)Fe(2)(CO)(5)](2)M(sip)(2) (M = Fe, Ni) were synthesized as H-cluster analogues of [FeFe]-hydrogenase. Their electrochemical behaviours were investigated and it is proposed that the bridging metal bis(tris chelate) groups act as electron transfer sites in theses mimics. PMID- 20830400 TI - Synthesis, single-crystal and solution structure analysis and in vitro cytotoxic activity of two novel complexes of ruthenium(II) with in situ formed flavanone based ligands. AB - Synthesis, structure and properties of two new flavanone complexes of Ru(ii) are described. The new complexes form during the reaction of ruthenium(iii) chloride with 3-aminoflavone (3-af) dissolved in an aliphatic alcohol. The formed products depend on the alcohol used and were found to be: cis-dichloridobis(3-imino-2 methoxyflavanone)ruthenium(ii).3H(2)O (1) from a methanolic solution and cis dichloridobis(3-imino-2-ethoxyflavanone)ruthenium(ii).2H(2)O (2) from an ethanolic solution, in which the original ligand 3-af had been converted by dehydrogenative alcoholysis to an entirely new ligand. This paper presents the X ray structure and detailed (1)H-NMR analysis of both new compounds, as well as the study of their antiproliferative activity. The coordination of Ru(ii) is octahedral with [RuCl(2)N(2)O(2)] chromophores, having trans chlorides and common Ru-L distances. Both 1 and 2 are highly cytotoxic towards the cisplatin resistant EJ and L1210 cell lines, and both complexes are as active as cisplatin in the sensitive cell lines. They display the ability to overcome cisplatin resistance in the drug resistant sub-lines EJcisR and L1210R. The present evidence suggests that the mechanism of biological activity may be different for these ruthenium compounds compared to cisplatin. PMID- 20830401 TI - Efficient phenylmercury(II) methylferrocenyldithiocarbamate functionalized dye sensitized solar cells. AB - Two new heterobimetallic phenylmercury(ii) dithiocarbamate complexes incorporating the ferrocenyl moiety (C(5)H(5))Fe(C(5)H(4)) (Fc), namely PhHgS(2)CN(CH(2)Fc)CH(2)C(5)H(4)N, (1) and PhHgS(2)CN(CH(2)Fc)CH(2)C(4)H(3)O, (2) have been prepared and characterized by elemental analysis, UV-Vis, IR, (1)H and (13)C NMR spectroscopies. The crystal structures of 1 and 2 showed a linear core at the Hg(ii) centre of the molecule, bound by the sulfur atom of the dithiocarbamate ligand and carbon atom of the aromatic ring. Weak intermolecular HgS interactions form "head-to-tail" dimers in the cases of 1 and 2. The observed quasi-reversible cyclic voltammograms of the complexes have been corroborated by calculating gross natural electron population and gross natural electron spin population at each atom for the neutral as well its oxidized species obtained at density functional level (DFT) of theory, which suggests that the delocalization of electron spin population can affect the magnitude of DeltaE(p). The electronic absorption bands of both the complexes were assigned with the help of time dependent density functional theory (TD-DFT) calculations. The light harvesting properties of both 1 and 2 in conjunction with our previously reported compound PhHgS(2)CN(CH(2)Fc)CH(2)C(6)H(5) (3) have been reported. PMID- 20830402 TI - Structural and solution studies of phenylbismuth(III) sulfonate complexes and their activity against Helicobacter pylori. AB - Three bis-phenylbismuth sulfonates [Ph(2)Bi(O(3)SR)](infinity) (R = p-tolyl 1, mesityl 2 or S-(+)-10-camphoryl 3) have been synthesised and characterised. Their tendency for ligand redistribution in solution, and activity against the bacterium Helicobacter pylori have been investigated. The structures of 2 and 3 have been authenticated by X-ray diffraction crystallography. They are structurally very similar with polymeric helical chain structures composed of four coordinate Bi atoms which bridge between two sulfonate O atoms with near linear O-Bi-O bond angles. The two phenyl rings are cis to one another and trans to the stereochemically active lone pair. Upon dissolution of the pure compounds 1, 2 and 3, a ligand redistribution reaction occurs in which the mono phenylbismuth bis-sulfonates, the bismuth tris-sulfonates and triphenylbismuth are formed. Two further complexes of general formula [PhBi(O(3)SR)(2)](infinity) (where R = p-tolyl 4, and mesityl 5) were thus obtained and their crystal structures determined. The presence of the single sulfonato ligand in compounds 1, 2 and 3 resulted in a dramatic increase in bacteriocidial activity towards H. pylori (MIC values of >=6.25 MUg mL(-1)) relative to BiPh(3) (>64 MUg mL(-1)) and the sulfonic acids, which were essentially inactive. PMID- 20830403 TI - Preparation and characterisation of divalent hard and soft metal (M = Ca, Co, Cu, Zn, Cd, Hg and Pb) complexes of 1,10-dithia-18-crown-6: structural versatility. AB - A range of divalent metal complexes (1-10) of 1,10-dithia-18-crown-6 (L) were synthesised in benzonitrile and structurally characterised. In particular cases (Cd, Hg and Pb), the anion effect on the resulting structures was investigated. The calcium(ii) complex [Ca(L)(ClO(4))(2)] (1) for L, adopting an 'egg-in-nest' conformation was isolated. The calcium centre is six-coordinate with a distorted trigonal prismatic geometry, being bound to four oxygens of L and two perchlorato ligands. When Co(ClO(4))(2).6H(2)O was employed, the purple complex [Co(L)(H(2)O)(3)](2)(ClO(4))(4) (2a) with a distorted octahedral geometry was obtained as a kinetic product, which then transformed to the solvato-complex [Co(C(6)H(5)CN)(4)(H(2)O)(2)](ClO(4))(2) (2b, yellow) as a thermodynamic product. In contrast to 2a, the reaction with Cu(ClO(4))(2).6H(2)O afforded an anion coordinated complex [Cu(L)(ClO(4))(2)].2C(6)H(5)CN (3). In 3, the copper centre is also six-coordinate, being bound to two oxygens and two sulfurs from L, in which the distorted octahedral geometry is completed by two perchlorato ligands. Reaction of L with Zn(ClO(4))(2).6H(2)O yielded the mononuclear species [Zn(L)(H(2)O)(3)](2)(ClO(4))(4) (4), in which the octahedral geometry of the zinc(ii) is almost same as that of 2a. L reacts with CdX(2) (X = ClO(4) and NO(3)) to yield [Cd(L)(ClO(4))(2)] (5) and [Cd(L)(NO(3))](2)[Cd(NO(3))(4)] (6), respectively. In perchlorato-complex 5, all six donors in L participate in the coordination sphere, in which the eight-coordinated 'tight and bent' conformation is completed by two perchlorate ions, adopting a dicapped trigonal prismatic geometry. Interestingly, the nitrato-complex 6 features three separated units of formula [Cd(L)(NO(3))](2)[Cd(NO(3))(4)]: two macrocyclic complex cation units and one cadmium quadru-nitrato complex anion unit. In the reaction with HgX(2) (X = ClO(4) and NO(3)), L afforded an unusual triple-decker type dinuclear complex [Hg(2)(L)(3)](ClO(4))(4) (7) with 3 : 2 (L : M) stoichiometry and a 1 : 1 complex [Hg(L)(NO(3))(2)].2H(2)O (8) with an eight-coordinate mercury centre, adopting a distorted hexagonal bipyramidal geometry. L reacts with PbX(2) (X = ClO(4) and NO(3)) to yield [Pb(L)(ClO(4))(2)] (9) and [Pb(L)(NO(3))(2)] (10). In 9, the lead(ii) is six-coordinate, being bound to four oxygens, in which the distorted octahedral geometry is completed by two perchlorato ligands. In 10, the lead(ii) coordinates to four oxygens together with two bidentate nitrato-ligands to yield an overall metal coordination geometry of eight, adopting the 'egg-in-nest' conformation again. PMID- 20830404 TI - Optically active bis(beta-diketonate) complexes of titanium. AB - The 2,2'-bis(methylene)biphenyl bridged bis(diketonate) (Tol(2)Bob)Ti(IV) fragment is resolved by reaction of the isopropoxide complex with (R)-1,1'-bi-2 naphthol, which selectively forms (S,Delta)-(Tol(2)Bob)Ti(R-BINOL). The binaphtholate ligand can be cleaved from titanium by careful treatment with trifluoromethanesulfonic acid to give (S,Delta)-(Tol(2)Bob)Ti(OTf)(2), which has a half-life toward racemization of at least 34 h at 51 degrees C. Racemization of the (Tol(2)Bob)Ti(IV) fragment is strongly accelerated under protic conditions, probably due to protonolysis of one of the diketonate ligands. Analogous optically active titanium bis(diketonates) can also be prepared by using an optically active 2,2'-bis(methylene)-1,1'-binaphthyl bridged bis(diketonate) ligand, Tol(2)Bobbinap, prepared from (R)-BINOLH2. Complexation of (R)-Tol(2)BobbinapH(2) with Ti(OiPr)(4) gives only a single diastereomer with the Lambda configuration at titanium. The bis(diketonate)titanium(IV) fragment gives rise to characteristic signals in circular dichroism spectra which can be used to identify the configuration at the metal centre. PMID- 20830405 TI - Germanium(II) hydride mediated reduction of carbon dioxide to formic acid and methanol with ammonia borane as the hydrogen source. AB - LGeOC(O)H (3) (L = CH{(CMe)(2,6-iPr(2)C(6)H(3)N)}(2)), from the straightforward conversion of LGeH (2) with CO(2), reacts with LiH(2)NBH(3) giving 2 and LiOC(O)H (4), while the corresponding reaction of 3 with H(3)NBH(3) after aqueous workup releases 2 and CH(3)OH (5). This opens the possibility to use hydride 2 as a mediator in the reduction of carbon dioxide to formic acid and methanol. PMID- 20830406 TI - New binuclear double-stranded manganese helicates as catalysts for alkene epoxidation. AB - New binuclear double-stranded helicates were formed between manganese(ii) perchlorate and chiral phenyl- and polyphenyl-bridged oligopyridines; they are active catalysts for alkene epoxidation. PMID- 20830407 TI - Highly stable and soluble bis-aqua Gd, Nd, Yb complexes as potential bimodal MRI/NIR imaging agents. AB - A tripodal ligand based on the 8-hydroxyquinolinate binding unit yields a soluble and highly stable bis-hydrated Gd(3+) complex in water (pGd = 19.2(3)) with relaxivity change in the pH range 4.5-7.4 and Nd(3+), Yb(3+) analogues with sizeable NIR emission upon excitation at 370 nm providing a new architecture for the development of bimodal agents. PMID- 20830408 TI - Automatic trace metal monitoring station use for early warning and short term events in polluted rivers: application to streams loaded by mining tailing. AB - An automatic trace metal monitoring station (ATMS) system was implemented to study seasonal and short time changes in selected metal concentrations in two river courses influenced by mine drainage. High frequency monitoring over periods of months revealed daily variations of zinc, iron and copper, and also proved the use of ATMS as an early warning system in such polluted environments. Complementary measurements with ICP-MS (inductively coupled plasma-mass spectrometry), ionic chromatography, and thermodynamic equilibrium calculations also gave some new insights into the geochemical behaviour of the metals in these two rivers. PMID- 20830409 TI - Iridium, platinum and rhodium baseline concentration in lichens from Tierra del Fuego (South Patagonia, Argentina). AB - Lichen samples of Usnea barbata were used as possible biomonitors of the atmospheric background level of iridium (Ir), platinum (Pt) and rhodium (Rh) in the remote region of Tierra del Fuego (South Patagonia, Argentina). Lichens were collected in 2006 at 53 sites covering 7 different areas of the region (24 transplanted lichens of the northern region and 29 native lichen samples of the central-southern region). A microwave acidic digestion procedure was used to mineralize the samples and a sector field inductively coupled plasma mass spectrometry method was developed to quantify the elements. The study of the influence of interferences on analyte signals and a quality control procedure were carried out. The analytical protocol was further applied to evaluate Ir, Pt and Rh bioaccumulation in lichens. The detection limits obtained were 0.010 ng g 1, 0.013 ng g-1 and 0.030 ng g-1 for Ir, Pt and Rh, respectively. Recoveries at different fortification levels were between 96.3% and 106% and precision was 3.3% on average. The metals concentration (as dry weight) spanned the following ranges: Ir, <0.010-1.011 ng g-1; Pt, 0.016-2.734 ng g-1; and Rh, 0.063-1.298 ng g 1. Data on 7 areas were similar suggesting that no specific source, for example traffic or anthropogenic activity, influenced directly the metal concentrations in Tierra del Fuego. Values detected are more likely influenced by the long-range atmospheric transport of these pollutants and, in comparison with densely populated areas in the world, they can represent the baseline for low impacted areas. PMID- 20830410 TI - Specifying information needs for Dutch National Policy evaluation. AB - There is mutual dissatisfaction among policy makers and monitoring specialists about producing what is considered useful information for policy development, implementation and evaluation. Insufficient or inappropriate communication between information users and producers is considered to be a main cause for this water information gap. This paper tests the rugby-ball methodology that has been designed to bridge the gap. The rugby-ball methodology consist of a five step plan that helps policy makers and monitoring specialists to communicate in a proper way and to come to a joint process of defining information needs. The methodology is first tested in a study to assess the information needs for the 4th National Policy Document on Water Management in the Netherlands. From the study it is concluded that the rugby-ball methodology is an important step in bridging the water information gap by better defining what useful information is. The methodology is also improved on the basis of this study by including a structure to support the breakdown of policy objectives into information needs. PMID- 20830411 TI - Target: ligand interactions of the vascular endothelium. Implications for molecular imaging in inflammation. AB - Molecular imaging refers to the non-invasive visualisation of biological processes at the molecular and cellular levels within a living organism, and offers a wide range of potential benefits to both clinical medicine and research into novel therapeutic agents. Inflammation plays an important role in a wide variety of pathological processes and imaging the molecular and cellular machinery that underlies chronic inflammation is attractive and feasible. In this review, we present an overview of molecular imaging of inflammation. We start by characterising molecular and cellular events in early inflammation, identifying current and potential future imaging targets. We focus on the imaging of endothelial cells, which mediate the important first steps in inflammation in any tissue, are readily accessible to imaging probes and which present an approach that can be applied across multiple modalities. We then review the generic requirements for imaging contrast agents and focus on the important considerations in respect of ligands, ligand-target interactions and contrast vehicles. We aim to provide an integrated view of current progress with a focus on promising recent developments in experimental and translational molecular imaging. PMID- 20830412 TI - Low-temperature synthesis of CdSe nanocrystal quantum dots. AB - A method for fabricating colloidal CdSe nanocrystals at low reaction temperatures was developed. The transition from CdSe clusters to continuously-growing nanocrystals was found to be crucial in the formation of high-quality quantum dots with narrow size distribution and efficient, tunable optical properties. PMID- 20830413 TI - The citrate-mediated shape evolution of transforming photomorphic silver nanoparticles. AB - The photoconversion of photomorphic silver nanoparticles from discs to prisms via citrate mediated growth on the twin plane faces of the nanoparticles is demonstrated. This systematic shape evolution from discs to hexagons and then prisms of increasing aspect ratios is a result of the growth process being confined to specific faces of the growing nanoparticles. PMID- 20830414 TI - Multiple quantum NMR of spin-carrying molecules in nanopores: high order corrections to the two-spin/two-quantum Hamiltonian. AB - This paper is devoted to multiple quantum (MQ) NMR spectroscopy in nanopores filled by a gas of spin-carrying molecules (s = 1/2) in a strong external magnetic field. It turns out that the high symmetry of the spin system in nanopores yields a possibility to overcome the problem of the exponential growth of the Hilbert space dimension with an increase in the number of spins and to investigate MQ NMR dynamics in systems consisting of several hundred spins. We investigate the dependence of the MQ coherence intensities on their order (the profile of the MQ coherence intensities) for a spin system governed by the standard MQ NMR Hamiltonian (the nonsecular two-spin/two-quantum Hamiltonian) together with the second order correction of average Hamiltonian theory. It is shown that the profile depends on the value of this correction and varies from an exponential to a logarithmic one. PMID- 20830415 TI - A DFT study on the Pd-mediated decarboxylation process of aryl carboxylic acids. AB - Decarboxylation process in a series of PdL(2)X(eta(2)-OOCAr(R)) complexes 2OS(R) (L = DMSO; X = OOCCF(3)(-); R = H, OMe, NO(2), Me and CN) with substituent R at an ortho, meta or para position were investigated with the aid of density functional theory calculations. Through our study, we found that the OOCCF(3)(-) ligand is not just a spectator ligand but assists the decarboxylation process. The results indicated that electron-donating substituents have greater promotion effect than electron-withdrawing substituents on the decarboxylation process. An ortho substituent in the substrate ligands OOCAr(R)(-) is normally necessary for a successful decarboxylation. The reason behind this has been explained. PMID- 20830416 TI - Synthesis, structure and electrochemistry of isomeric nickel(II) complexes of a [9]ane fused cyclam macrotricycle: evidence for a stable trans-IV and a redox induced rearrangement in a trans-I conformation. AB - The macrotricyclic ligand, 1,11-dithia-4,8,14,18-tetraaza-[5,2,2,5]-eicosane, L3 has been synthesized from cyclam. Both the cis- and the trans- isomers of the Ni(ii) complexes have been prepared and characterized by single crystal X-ray crystallography. In the cis-[Ni(trans-I, syn-L3)](Cl(2)).4H(2)O, the syn-isomer of L3 is present in which the cyclam ring adopts a trans-I stereochemistry. Crystal structure data (Pna2(1), tetragonal, a = 17.450(3), b = 12.188(2), c = 11.897(2) A, V = 2530.2(8) A(3), R(1) = 0.032 and wR(2) = 0.078) indicate that two of the Ni-N distances, Ni-N(4) = 2.164(3) A and Ni-N(2) = 2.179(3) A are longer than Ni-N(1) = 2.100(3) A and Ni-N(3) = 2.101(3) A. The Ni-S distances, 2.4265(11) A and 2.4512(11) A, are similar to lengths observed in many thioether complexes. The cyclic voltammogram for the Ni(2+/3+) redox couple of the cis complex is scan rate dependent. Although quasi-reversible at a scan rate of 1000 mV s(-1), when the scan rate is lowered below 100 mV s(-1) the redox couple shows chemical irreversibility. There is evidence for rearrangement of the inner coordination sphere and adsorption of the oxidized species onto the Pt electrode. However, there is no evidence to suggest that isomerization of the cis- to the trans-complex occurs. Consistent with this electrochemical behavior, a time dependent change in the ESR spectrum for the Ni(iii) species was also observed. A mechanism is proposed where through dissociation of a thioether donor and subsequent substitution of a solvent CH(3)CN, the trans-I conformation changes from a cis-type coordination to a trans-mode. In the trans-[Ni(trans-IV, anti L3)](ClO(4))(2) complex, the anti-form of L3 is present where the cyclam moiety adopts the rare trans-IV stereochemistry. The trans-complex (C(2)/(c), monoclinic, a = 22.382(9), b = 10.118(2), c = 14.300(3) A, V = 2493.3(13) A(3), R(1) = 0.051 and wR(2) = 0.142) is a minor product with all Ni-N distances at 2.124(4) A and Ni-S distances at 2.5321(13) A. The trans-complex shows a reversible cyclic voltammogram for the Ni(2+/3+) couple and an axial ESR spectrum for the Ni(iii) species that is expected for such a symmetrical system. That there are no changes in the ESR spectroscopic features following redox cycles is consistent with the structural rigidity expected in an encapsulated system. PMID- 20830417 TI - Theoretical study of the opsin shift of deprotonated retinal schiff base in the M state of bacteriorhodopsin. AB - The origin of the opsin shift, which deprotonated Schiff base (DPSB) shows in the M state of the bacteriorhodopsin (bR) photocycle, was theoretically investigated for the first time using a combined quantum mechanical and molecular mechanical (QM/MM) method. From the QM(SAC-CI)/MM(AMBER99) results, the chromophore conformational effect was found to be the main factor, whereas the Coulombic interaction with the protein environment gave a non-negligible contribution. The present result revised the conclusion drawn by previous studies and provided a new interpretation of the opsin shift mechanism of DPSB. To test the computational models for taking into account the electronic polarization and charge redistribution effects of the surrounding environment, the size of the QM region was expanded up to 5-7 A from DPSB, which decreased the excitation energies in solution and in protein by 0.08-0.13 eV and 0.21-0.26 eV, respectively. We also found that the rCAM-B3LYP functional significantly improves the B3LYP results when calculating the potential energy curve for the C(6)-C(7) twisting. PMID- 20830418 TI - NIR-enhanced drug release from porous Au/SiO2 nanoparticles. AB - The ability of core/shell SiO(2)/Au nanoparticles (NPs) to heat upon being exposed to near-infrared (NIR) radiation is well known. In this work we have modified the synthesis procedure to obtain a mesoporous SiO(2) core and a porous Au shell that allows drugs to be loaded within the core porous space. The release of a model drug (ibuprofen) upon NIR activation is demonstrated. PMID- 20830419 TI - Progressive release of a palladium-pyridyl complex from a layer-by-layer multilayer and illustrative application to catalytic Suzuki coupling. AB - Quartz slides bearing layers of a palladium azopyridine complex are seen to liberate catalytic amounts of a soluble active palladium species which can be used for Suzuki coupling. PMID- 20830420 TI - One-electron oxidation of DNA: reaction at thymine. AB - The feature article is a review of the reaction of thymine in the one-electron oxidation of duplex DNA. Oxidation of DNA causes chemical reactions that result in remote damage (mutation) to a nucleobase. Normally this reaction occurs at guanine, but in oligonucleotides that lack guanines, or when the DNA contains a thymine-thymine mispair, reaction occurs primarily at thymine notwithstanding its high oxidation potential. Selective substitution of uracil for thymine in TT sequences indicates the operation of a tandem reaction mechanism at adjacent thymines. Analysis of the reaction products suggests that proton-coupled electron transfer generates the 5-thymidyl methyl radical, which is trapped by molecular oxygen to give eventually 5-formyl-2'-deoxyuridine and 5-(hydroxymethyl)-2' deoxyuridine. In a second process, water adds to the 5,6-double bond of the oxidized thymine giving eventually the cis- and trans-diastereomers of 5,6 dihydroxy-5,6-dihydrothymidine. PMID- 20830421 TI - Functionalized polyoxometalates with intrinsic photochromic properties and their association with spiropyran cations. AB - The presence of alkylammonium groups covalently grafted on bisphosphonato ligands induces photochromic properties to ligand-coordinated polyoxomolybdate systems. Such intrinsically photoactive polyanions can be used for the preparation of materials combining photochromic polyoxometalates and functional countercations. PMID- 20830425 TI - Emerging methods for fabricating functional structures by patterning and assembling engineered nanocrystals. AB - Inorganic nanocrystals and nanoparticles have aroused increasing attention in the last years due to their original optoelectronic, thermodynamic, mechanical and catalytic properties, which are extremely attractive for fundamental understanding as well as for their huge potential in applications. The ability to strongly exploit the original potential of such nano-objects and access their properties relies on the ability to bridge the gap between the nanoscopic and mesoscopic scale. Indeed, to integrate nanoparticles in structures, materials and finally devices, their incorporation in processable systems, and their organization in morphologically controlled assembly and/or ordered arrays is crucial. The fabrication of 2/3 D patterned micro- and nanostructure is a promising strategy for integrating the nanoparticles in macroscopic entities in order to properly exploit their unprecedented functionality for biomedical, electronic, catalytic materials and devices. In this paper, different and complementary strategies able to engineer inorganic colloidal nanocrystals due to their organization in original functional materials and structures will be described. PMID- 20830427 TI - Photochemical behavior of (bisphosphane)(eta(2)-tolane)Pt(0) complexes. Part B: An insight from DFT calculations. AB - A series of various (bisphosphane)(eta(2)-tolane)Pt(0) complexes, exhibiting a manifold of substitution patterns of the tolane ligand (5a-g) and different rigid bisphosphanes defining various P-Pt-P bite angles at the Pt center (9a-b) have been theoretically investigated using time-dependent density functional theory (TD-DFT). UV/Vis absorption spectra have been calculated in order to rationalize the photochemistry of the complexes. Metal-ligand charge transfer (MLCT) transitions from the Pt atom to the alkyne are assigned as the photochemical "active" states responsible for promoting the C(aryl)-C(ethynyl) bond activation. The steric, the electronic effects, as well as the P-Pt-P bite angle play an important role in determining the presence/absence of photochemical "active" states of d->pi*(alk) character. Thus, electron-withdrawing substituted series and ortho-substituted complexes are best candidates to achieve C(aryl)-C(ethynyl) bond activation. C-Br bond cleavage is also theoretically rationalized. The observed photochemical C(aryl)-C(ethynyl) bond cleavage is, oppositely to C-Br bond activation, reversible under thermal conditions regaining the appropriate Pt(0) complexes by reductive elimination (see T. Weisheit, D. Escudero, H. Petzold, H. Gorls, L. Gonzalez and W. Weigand, Photochemical behavior of (bisphosphane)(eta(2)-tolane)Pt(0) complexes in solution and in the solid state. Part A: Experimental considerations, Dalton Trans., 2010, 39, DOI: 10.1039/B925562a). In this part, we rationalize and clarify the thermal reductive elimination reactions via mechanistic DFT studies on the ground state. PMID- 20830428 TI - Generation of surface-confined catechol terminated SAMs via electrochemically triggered Michael addition: characterization, electrochemistry and complex with Ni(II) and Cu(II) cations. AB - In this paper, catechol, 1,4-dihydroxybenzene and dopamine are investigated as precursors of electrophiles for Michael addition reaction with the self-assembled monolayer (SAM) of 4-thiouracil (4-TU) via electrochemical triggering. All compounds can undergo Michael addition reaction with 4-TU; however, only catechol can react with 4-TU with high efficiency. The catechol-terminated SAMs, via electrochemically triggered Michael addition reaction, exhibit reversible redox response. In addition, we find that catechol-terminated SAMs can complex with Ni(2+) and Cu(2+) with different electrochemical behaviors. Moreover, the mechanism of complexation of Ni(2+)and Cu(2+) with catechol-terminated SAMs is also demonstrated with electrochemical and spectrometric methods. Based on the different electrochemical behaviors of Cu(2+) and Ni(2+) complex, the catechol terminated SAMs provide a potential platform for metal ions recognition. PMID- 20830429 TI - Microvalve and micropump controlled shuttle flow microfluidic device for rapid DNA hybridization. AB - We present a novel microfluidic device integrated with microvalves and micropumps for rapid DNA hybridization using shuttle flow. The device is composed of 48 hybridization units containing 48 microvalves and 96 micropumps for the automation of shuttle flow. We used four serotypes of Dengue Virus genes (18mer) to demonstrate that the automatic shuttle flow shortened the hybridization time to 90 s, reduced sample consumption to 1 MUL and lowered detection limit to 100 pM (100 amol in a 1 MUL sample). Moreover, we applied this device to realize single base discrimination and analyze 48 samples containing different DNA targets, simultaneously. For kinetic measurements of nucleotide hybridization, on line monitoring of the processes was carried out. This rapid hybridization device has the ability for accommodating the entire hybridization process (i.e., injection, hybridization, washing, detection, signal acquisition) in an automated and high-throughput fashion. PMID- 20830430 TI - Detecting influential observations by cluster analysis and Monte Carlo cross validation. AB - The detection of influential observations is an essential step for building high performance models and has been recognized as an important and challenging task in many industrial and laboratorial applications. A new approach for detecting influential observations is developed based on their effect on partial least squares (PLS) modeling. In this method, we build a large number of PLS models by using Monte Carlo cross-validation (MCCV), and then perform principal component analysis (PCA) on the regression coefficients of these models. Because a model with influential observations is different from the one without influential observation, the series of PLS models cluster into different groups in principal component (PC) spaces, based on the different number of influential observations they contain. The influential observations can be therefore recognized according to the frequency number of each sample in each group. By three examples quantitatively modeling near-infrared (NIR) and Raman spectra, it was shown that the method can detect the influential observations intuitively and veraciously. PMID- 20830431 TI - Mycobacterium tuberculosis tyrosine phosphatase A (PtpA) activity is modulated by S-nitrosylation. AB - M. tuberculosis PtpA and PtpB, the only two phosphotyrosine phosphatases (Ptps) present in this pathogen, play an important role in mycobacteria survival inside macrophages. The aim of the present work was to investigate M. tuberculosis PtpA and PtpB susceptibility to S-nitrosylation, a reversible covalent bond between nitric oxide (NO) and specific cysteine (sulfur) residues in proteins. PtpB was not modified by NO, in contrast, PtpA Cys53 was identified by site directed mutagenesis as the target of S-nitrosylation. PMID- 20830432 TI - Si nanoparticle-decorated Si nanowire networks for Li-ion battery anodes. AB - We designed and fabricated binder-free, 3D porous silicon nanostructures for Li ion battery anodes, where Si nanoparticles electrically contact current collectors via vertically grown silicon nanowires. When compared with a Si nanowire anode, the areal capacity was increased by a factor of 4 without having to use long, high temperature steps under vacuum that vapour-liquid-solid Si nanowire growth entails. PMID- 20830433 TI - A turn-on split-luciferase sensor for the direct detection of poly(ADP-ribose) as a marker for DNA repair and cell death. AB - Designed sensors comprising split-firefly luciferase conjugated to tandem poly(ADP-ribose) binding domains allow for the direct solution phase detection of picogram quantities of PAR and for monitoring temporal changes in poly(ADP ribosyl)ation events in mammalian cells. PMID- 20830434 TI - The change of corrin-amides to carboxylates leads to altered structures of the B12-responding btuB riboswitch. AB - By applying four different acid derivatives of vitamin B(12), we demonstrate that the H-bonding pattern and the electrostatic environment provided by each side chain of the corrin ring are crucial for the correct structural rearrangement of the btuB riboswitch of E. coli. PMID- 20830435 TI - Inherently reactive polyHIPE material from dicyclopentadiene. AB - A simple formulation of a stable high internal phase emulsion of dicyclopentadiene which is cured by using properly selected ring opening metathesis polymerization initiators yields highly porous monolithic materials with paramount mechanical properties and the possibility of easy functionalisation. PMID- 20830436 TI - High intensity focused ultrasound and redox dual responsive polymer micelles. AB - A novel class of HIFU and redox dual responsive polymer with a disulfide bond weak linkage is developed. The novel modality of HIFU and redox triggered release allows for the fine-tuning of the release kinetics of the encapsulants from the micelles in a remote and controlled way. PMID- 20830437 TI - Templated polar order of a guest in a quasiracemic organic host. AB - A quasiracemic mixture of Dianin's compound and its thiol derivative enforces additional anisotropy of the guest-accessible space, thus facilitating a net polar arrangement of guest molecules; guest alignment is rationalized in terms of van der Waals volume considerations. PMID- 20830438 TI - Improved complexation of paraquat derivatives by the formation of crown ether based cryptands. AB - Self-assembly allows the construction of advanced molecular or supramolecular systems from small building blocks. Host-guest recognition, for its self selectivity, environmental responsiveness and convenient application to complex molecular devices, plays a significant role in self-assembled systems. During this process, the association constant between the host and guest is an important standard to identify the properties of the systems. In order to prepare mechanically interlocked structures and large supramolecular systems efficiently from small molecules based on a host-guest recognition motif, it is necessary to increase host-guest association constants. Crown ether-based cryptands have been designed and prepared to improve the binding of paraquat derivatives. This feature article aims to describe the design and syntheses of crown ether-based cryptand hosts for paraquat derivatives and the application of the cryptand/paraquat recognition motif in the fabrication of threaded structures, molecular switches and supramolecular polymers. PMID- 20830439 TI - Identification of complex dynamic modes on prion protein peptides using multifrequency ESR with mesoporous materials. AB - Identifying protein dynamics is essential for studying protein function. However, the time-scale of dynamic modes varies over domains and segments of a protein. Here we describe an approach using multifrequency ESR with mesoporous materials for protein dynamics in confined nanospace that may mimic the crowded nature within a cell where proteins evolve to fold. While multifrequency ESR permits the separation of dynamic motions in different time-scales, we demonstrate its capability to capture dynamics can still be significantly enhanced by the encapsulation of nitroxide-labeled macromolecule into mesopores. Two mutants of a 26-residue prion protein peptide at temperatures from 2 to 27 degrees C are studied. The nanochannel provides the peptide with an ordered environment such that the global tumbling of peptide is slow, and 'frozen' on the ESR timescale. The local dynamic modes of the peptide in nanochannel are, therefore, distinctly reported on the spectra. The spectra of the peptide in beta-hairpin vs.alpha helical forms differ markedly, demonstrating the significant improvement of ESR spectroscopic capability due to our methodology. Such distinctly different spectral patterns between the two secondary structures of the peptide cannot be obtained from ESR studies in viscous aqueous solution. The dynamic modes on the peptide are thus unambiguously identified in our multifrequency experiments at the X- and Q-bands. Additionally, the multifrequency spectra for each mutant and temperature are simultaneously fitted to the rigorous models, e.g. the slowly relaxing-local-structure model, for slow-motion ESR. Marked correlations are revealed and characterized quantitatively for the backbone flexibility between the beta-hairpin and alpha-helical forms of the prion protein peptide. Confirmation of the slow collective dynamic modes extending across the beta hairpin is also provided through the spectral simulations. PMID- 20830440 TI - The photo-induced commensurate modulated structure in site-selective spin crossover complex trans-[Fe(abpt)(2)(NCS)(2)]. AB - The photo-induced superstructure of polymorph C of trans-[Fe(abpt)(2)(NCS)(2)] (abpt = 4-amino-3,5-bis(pyridin-2-yl)-1,2,4-triazole) is discovered as a commensurate modulated structure by single-crystal X-ray diffraction under irradiation. The crystal structure at 25 K before the photo-irradiation composed of two crystallographically independent iron molecules, one of which exhibits high spin (HS) state and the other at low spin (LS) state. Under green laser light (lambda = 532 nm) irradiation, the LS molecule (Fe1) is found to be excited to a metastable HS state and gives rise to a commensurate tripled superstructure along the c axis. In addition, it is confirmed that this modulation persists until the HS -> LS relaxation temperature beyond 52 K. Our structural findings suggest that the structural modulation and the site-selective LS -> HS excitation are highly correlated. PMID- 20830441 TI - Direct asymmetric bromination of aldehydes catalyzed by a binaphthyl-based secondary amine: highly enantio- and diastereoselective one-pot synthesis of bromohydrins. AB - One-pot stereoselective synthesis of bromohydrins as a useful chiral building block was achieved by the reaction of Grignard reagents with optically active alpha-bromoaldehydes, which were in situ generated by direct asymmetric bromination of aldehydes catalyzed by a binaphthyl-based secondary amine (S)-3. PMID- 20830442 TI - Development of 5-silylethynyl-1,3-dioxolan-4-one as a new prochiral template for asymmetric phase-transfer catalysis. AB - Phase-transfer catalyzed asymmetric alkylation and Michael addition of 5 silylalkynyl-1,3-dioxolan-4-one were developed as a novel strategy to provide highly modular tertiary alpha-alkyl-alpha-hydroxy acids bearing an alkyne moiety. PMID- 20830443 TI - Highly efficient chemoenzymatic synthesis of beta1-3-linked galactosides. AB - A novel D-galactosyl-beta1-3-N-acetyl-D-hexosamine phosphorylase cloned from Bifidobacterium infantis (BiGalHexNAcP) was used with a recombinant E. coli K-12 galactokinase (GalK) for efficient one-pot two-enzyme synthesis of T-antigens, galacto-N-biose (Galbeta1-3GalNAc), lacto-N-biose (Galbeta1-3GlcNAc), and their derivatives. PMID- 20830444 TI - The potential of individual based population models to extrapolate effects measured at standardized test conditions to relevant environmental conditions--an example for 3,4-dichloroaniline on Daphnia magna. AB - In current risk assessment ecotoxicological biotests (e.g.Daphnia reproduction test) are used to assess the potential impact of xenobiotics on ecosystems. The effects of chemicals and pesticides on populations of non-target organisms in the field depend not only on the exposure and the toxicity, but also on other factors such as life history characteristics. The effects of 3,4-dichloroaniline (3,4 DCA) measured with standardized test procedures, namely the Daphnia immobilisation test (OECD 202) and Daphnia reproduction test (OECD 211), were extrapolated to the population level using an individual-based Daphnia magna population model (IDamP) integrating only the effects on mortality and reproduction. The application of IDamP to extrapolate the effects on population levels was tested on two different population datasets, differing in the start population as well as in the feeding regime. The simulation results were compared to data derived from population experiments under semi-static and flow-through conditions. The IDamP model with an integrated toxicity module was able to predict the effects of 3,4-DCA on the population level under constant laboratory conditions for both datasets. This modelling approach was used to establish concentration-response relationships for 3,4-DCA on the population level. For this purpose two endpoints, the population capacity and the extinction probability, were calculated for different food levels. It turned out that the concentration-response relationship of the population capacity was less influenced by food supply, whereas for daphnid populations exposed to 3,4-DCA the extinction risk was twice as high with lower (environmental relevant) food supply. For both endpoints the lowest EC(50) was calculated to be 25 and 35 ug l( 1). The calculation of concentration-effect relationships on the population level by using a modelling approach provides a tool to extrapolate from effects derived from lab experiments to effects on the population level and can improve the ecological risk assessment of chemicals and pesticides. PMID- 20830445 TI - Selective and enantioselective analysis of mono- and disaccharides using surface plasmon resonance spectroscopy and imprinted boronic acid-functionalized Au nanoparticle composites. AB - A method was developed for the synthesis of molecularly imprinted Au nanoparticle (NP) composites on electrodes by electrochemical means. The resulting composites include specific recognition sites for mono- or disaccharides. The method is based on the formation of a boronate complex between the respective saccharide and the boronic acid ligands associated with the Au NPs. The electropolymerization of the Au NPs leads, after cleavage of the respective boronate esters, and removal of the saccharide, to specific recognition sites for the association of the imprinted monosaccharides or disaccharides. The binding of the saccharides to the imprinted sites is followed by surface plasmon spectroscopy (SPR). The changes in the refractive index of the Au NP composites upon the binding of the saccharides to the imprinted sites are amplified by the coupling between the localized plasmon associated with the NPs and the surface plasmon wave propagating on the Au surface. This leads to the highly sensitive stereoselective and chiroselective detection of monosaccharides and disaccharides. PMID- 20830446 TI - Minimally invasive application of a radial plate following placement of an ulnar rod in treating antebrachial fractures. Technique and case series. AB - OBJECTIVE: To describe a surgical technique for placement of a minimally invasive radial plate following application of an ulnar rod (MIPR) for treatment of antebrachial fractures. METHODS: Medical records (November 2005-June 2009) were searched to identify dogs with diaphyseal radius and ulna fractures stabilised by MIPR. Data retrieved included signalment, weight, limb affected, cause of injury, open versus closed fracture, number of fragments, implant size, number of screws used and cortices engaged, number of open screw holes, operative time, rod removal, complications and time to radiographic healing. To be included, dogs had to have evidence of radiographic healing during follow-up. RESULTS: Eight dogs with diaphyseal radius and ulna fractures treated with MIPR were included in the case series. All fractures were due to trauma and two fractures were open (grade 1). Rod loosening and osteomyelitis of the ulna occurred in one case which subsequently resolved with rod removal. Healing occurred in all cases with no implant failures. Median time to radiographic union was 10.5 weeks (mean +/- SD = 17 +/- 15 weeks; range 4-52 weeks). CLINICAL RELEVANCE: Use of MIPR constructs on diaphyseal fractures of the radius and ulna is an effective technique for managing these fractures using principles of biological osteosynthesis. An intramedullary rod in the ulna assists with fracture reduction and stabilisation and rod removal is recommended once fracture healing has occurred. PMID- 20830447 TI - Imaging studies of the hindlimbs of pacas (Cuniculus paca) bred in captivity. AB - OBJECTIVE: To evaluate the hindlimbs of pacas bred in captivity using radiographic and computed tomography (CT) studies. ANIMALS: Nine mature pacas (Cuniculus paca) 5.9-8.2 kg in body weight. METHODS: Radiographical aspects of the bones of the hindlimbs were evaluated, and the Norberg angle and inclination angle were measured for each hindlimb. Anteversion angle were measured in CT examination. RESULTS: The bone anatomy of the hindlimb of the paca was similar to that of the guinea pig, apart from two lunulae and a single fabella (lateral) which were observed. The Norberg angle had mean value of 130.56o +/- 3.81 without any significant difference between testers. Inclination angles ranged from 142.44o +/- 4.82 to 145.44o +/- 4.09 by Hauptman's method, and from 144.94o +/- 3.13 to 148.22o +/- 3.25 by Montavon's method, for right and left hindlimbs respectively. Average values for the anteversion angles measured with CT ranged from 28.56o +/- 5.56 to 32.91o +/- 2.62. CLINICAL SIGNIFICANCE: The data may be used in future studies comparing the paca to other rodent species. In addition, the paca could be used as an animal model in orthopaedic research. PMID- 20830448 TI - Deformity secondary to bilateral incomplete ossification of the humeral condyle in a German Shorthaired Pointer dog. A case report with ten-year follow-up. AB - A five-month-old male, German Shorthaired Pointer dog was presented for severe, bilateral, thoracic-limb-lameness, with elbow swelling, pain, and crepitus. Radiography and computed tomography confirmed bilateral incomplete ossification of the humeral condyles (IOHC), with a non-displaced incomplete fracture of the left medial epicondylar crest and condylar deformity, characterised by enlargement of the trochleas with extension of the disto-medial aspect of the bone below the normal elbow joint level, and a deformed proximo-medial aspect of the ulna and radius. Transcondylar lag screws were placed bilaterally in an attempt to prevent fracture. Microscopic examination of biopsies, harvested from both humeral condyles, was supportive of IOHC. Six years after surgery, radiographs showed severe osteoarthritis and it appeared that fusion of the humeral condyles had not occurred. The dog followed an active life style until 10 years after surgery when the elbows showed almost no observable range-of-motion. However, discomfort was evident only after heavy exercise. Incomplete ossification of the humeral condyles may be associated with osteoarthritis, risk for non-union, implant failure, or secondary condylar fracture. This dog maintained good limb function despite these concerns, and despite bilateral humeral condylar deformity as well as development of severe osteoarthritis. This is the first report of a German Shorthaired Pointer dog with IOHC and the first histological description supportive of this condition in a five-month-old dog. PMID- 20830449 TI - Tibial tuberosity transposition-advancement for treatment of medial patellar luxation and concomitant cranial cruciate ligament disease in the dog. Surgical technique, radiographic and clinical outcomes. AB - OBJECTIVE: To report surgical technique, morphometric effects and clinical outcomes for tibial tuberosity transposition-advancement (TTTA), sulcoplasty and para-patellar fascial imbrication for management of concomitant medial patellar luxation (MPL) and cranial cruciate ligament (CCL) disease in 32 dogs. STUDY DESIGN: Case series. METHODS: A previous technique for tibial tuberosity advancement was modified to incorporate lateral and distal tibial tuberosity transposition. Preoperative, immediate, and six to eight week postoperative radiographs were reviewed with morphometry of a range of tibial and stifle anatomic parameters. Findings of sequential clinical examinations to six to 20 months postoperatively were recorded. RESULTS: Thirty-nine stifles were treated by surgery. Medial patellar luxation grade ranged from II to IV/IV. The CCL rupture was complete in 17/39 stifles, and incomplete in 22/39. Complications occurred in 11/39 stifles including MPL recurrence (n=4). Resolution of subjectively-assessed lameness occurred in 29/39 stifles at the six to eight week assessment. Resolution of lameness was eventually documented in 35/39 stifles (4/39 lost to follow-up), and was maintained at the six to 20 month reassessment where available. The TTTA induced relative patella baja in 31/39 stifles. Magnitude of actual tibial tuberosity advancement was lower than that predicted by cage size. CLINICAL SIGNIFICANCE: Tibial tuberosity transposition-advancement is a potential treatment modality for concomitant CCL disease and MPL in the dog, but refinement of planning is required, while biomechanical and kinematic effects remain unknown. PMID- 20830450 TI - Non-steroidal anti-inflammatory drugs inhibit bone healing: a review. AB - The ability of non-steroidal anti-inflammatory drugs (NSAID) to inhibit bone healing has been established in experimental animal models using mice, rats, and rabbits. The mechanism of action is largely unknown but stems from prostaglandin inhibition and is likely multifactorial. In human medicine NSAID are known to prevent heterotopic ossification, however the clinical importance of their effects on bone healing remains controversial. Although a small handful of reports suggest that NSAID suppress bone healing in dogs and horses, there is little published information to direct veterinary practice in domestic species. PMID- 20830451 TI - Relation of the Norberg angle and position of the femoral head centre to the dorsal acetabular edge in evaluation of canine hip dysplasia. AB - Canine hip dysplasia (CHD) is a locomotive-system disease in dogs, which in many countries is the target of screening programs aimed at reducing the prevalence of CHD among descendants of predisposed dog breeds. Despite the efforts to apply genetic testing or ultrasound diagnostics in diagnosing CHD (as is common in human medicine), the main diagnostic process in veterinary medicine is by radiographic examination. The main two parameters which are used in diagnosing HD are the Norberg angle (NA) and the position of femoral head centre to the dorsal acetabular edge (FHC/DAE). We examined the relationship between these two parameters in the process of the determination of CHD degree by evaluating 225 randomly selected radiographs which were made during the period from 1993 to 2008. The aim of our study was to examine the validity of these two parameters in CHD classification as used in three different classification programs. Using Pearson's correlation coefficient, the value of which was 0.85 (p <0.05), we observed a positive correlation. Comparing the three scoring systems for CHD evaluation, we found that the final degree of CHD was similar for 78% to 85% of cases using Fluckiger's scoring system versus a modified scoring system of 5 parameters without FHC/DAE. Results were significant. PMID- 20830452 TI - Comparison of four commercial devices to measure limb circumference in dogs. AB - We evaluated four measurement devices for obtaining circumferential measurements at four locations on the canine hindlimb and forelimb. We hypothesised that these devices would be consistent and precise in the hands of veterinary professionals with varying experience levels. Circumferential measurements were made in five dogs with no history or clinical evidence of orthopaedic disease. Measurements were obtained in triplicate by three observers at mid-thigh, tibial tuberosity, hock and carpus bilaterally. Results indicated a significantly larger measurement at the left mid-thigh region than the right, with no significant differences between limbs noted at other sites. Measurements with a tape measure and a retractable tape measure resulted in significantly smaller values at each site than an ergonomic measuring tape and a circumference measuring tape. Interobserver variation was 3.6 times higher than intraobserver variation. These results illustrate the importance of consistency when obtaining these measurements. Sequential circumference measurements should be made by the same individual using the same device to decrease measurement variability. Devices were equally precise for repeat measurements although the absolute measurement varied by device. PMID- 20830453 TI - Double pelvic osteotomy for the treatment of hip dysplasia in young dogs. AB - The aim of this study was to evaluate the feasibility of the double pelvic osteotomy (DPO) (osteotomy of the ilium and pubis) to treat clinical cases of hip dyplasia in young dogs instead of performing a triple pelvic osteotomy (TPO) (osteotomy of the ilium, pubis, and ischium). Candidates for DPO were 4.5- to nine-month-old dogs with coxofemoral joint subluxation and laxity, indicative of susceptibility to future development of severe hip dysplasia. The angle of reduction (AR) and angle of subluxation (AS) with Ortolani's sign, Norberg angle (NA), percentage of femoral head (PC) covered by the acetabulum, and the pelvic diameters and their relationships were measured clinically and radiographically before and after surgery. The surgical technique was similar to the TPO technique, but excluded ischiatic osteotomy. A DPO was carried out in 53 joints of 34 dogs; AR and AS values immediately postoperatively and at the one- and two month follow-up examinations were significantly lower than the preoperative values (p <0.01). The complications encountered were mainly represented by implant failure (3.5%), partial plate pull-out (9.4%), and incomplete fracture of the ischial table (7.5%). Changes in PC and NA values obtained immediately after surgery and at the first and second follow-up examinations were significantly greater (p <0.01 both) than values obtained before surgery. Sufficient acetabular ventroversion was achieved to counteract joint subluxation and the modifications of AR and AS. The NA and PC direct postoperative values reflected a significant improvement in the dorsal acetabular coverage. CLINICAL RELEVANCE: Restoration of normal joint congruity (PC from 50 to 72%) and maintenance of the pelvic geometry without pelvic narrowing were the most intriguing features of DPO. The complications observed were greatly reduced when using dedicated DPO plates. Based on our experience, the morbidity after unilateral and bilateral DPO was lower than after TPO because elimination of the ischiatic osteotomy allowed for increased stability of the pelvis. The surgical technique of DPO was a little more demanding than TPO because of the difficulty in handling and rotating the acetabular iliac segment, but this difficulty was offset by elimination of ischial osteotomy. PMID- 20830454 TI - The rationale behind novel bone grafting techniques in small animals. AB - Autograft is considered ideal for grafting procedures, providing osteoinductive growth factors, osteogenic cells, and an osteoconductive scaffold. Limitations, however, exist regarding donor site morbidity and graft availability. Although allograft provides an osteoconductive matrix with some osteoinductivity, its availability is limited. To achieve optimal bone graft properties, researchers are developing new materials with the goal of designing synthetics as close to autograft as possible while still facilitating their clinical use. However, the constant evolution of internal fixation stimulates the search for growth factors and cells which could stimulate bone healing. PMID- 20830456 TI - Complications of cementless total hip replacement. A retrospective study of 163 cases. AB - Cementless total hip implants are relatively new to the veterinary market and therefore complication rates and prognostic indicators associated with the procedure have not been thoroughly documented. The objective of this study was to determine the prevalence of complications and identify prognostic indicators of success or failure for the Zurich cementless total hip replacement (THR). Medical records of 163 dogs that underwent Zurich cementless-THR were reviewed; continuous and categorical variables, clinical outcomes and complications were recorded. Complications were separated into intra-operative (IOC), short-term (STC), and long-term (LTC). Bivariate and multivariate statistical analysis was used to compare complications. The clinical significance of this study was to provide surgeons with prognostic indicators of success or failure when evaluating prospective Zurich cementless-THR patients, and to report the complication rate of Zurich cementless-THR. The complication rates of Zurich cementless-THR were then compared to previously-reported complication rates of cemented-THR and other cementless-THR systems. Short-term complications, LTC, and IOC rates of Zurich cementless-THR were found to be 6.75%, 10.4%, and 11.0% respectively. The most common complications were intra-operative femoral fracture, luxation of the implant, and septic loosening of the implant. Increased body weight and prior cemented-THR or femoral head and neck ostectomy of the contra-lateral hip were identified as negative prognostic indicators. The overall complication rate identified was greater than those previously reported for other cementless- and cemented-THR systems. PMID- 20830455 TI - Investigation of the effects of prostaglandin E2 on equine superficial digital flexor tendon fibroblasts in vitro. AB - OBJECTIVES: To evaluate the effects of prostaglandin E2 (PGE2) treatment on the metabolism of equine tendon fibroblasts in vitro to aid in investigating the response of tendon fibroblasts to injury and novel therapeutics. METHODS: Superficial digital flexor tendon fibroblasts isolated via collagenase digestion from six young adult horses were grown in monolayer in four concentrations of PGE2 (0, 10, 50, 100 ng/ml) for 48 hours. Cells and medium were harvested for gene expression (collagen types I and III, cartilage oligomeric matrix protein [COMP], decorin, and matrix metalloproteinase-1, -3, and -13), biochemical analysis (glycosaminoglycan, DNA, and collagen content), and cytological staining. RESULTS: Gene expression for collagen type I was significantly increased at 100 ng/ml PGE2 compared to 10 and 50 ng/ml. There were not any significant differences detected for gene expression of collagen type III, COMP or decorin or for biochemical content and cell morphology. CLINICAL SIGNIFICANCE: Under the conditions investigated, exogenous treatment of equine tendon fibroblasts with PGE2 failed to alter cell metabolism in a manner useful as a model of tendon injury. A model that applies cyclic strain to a three dimensional construct seeded with tendon fibroblasts may prove to be a more useful model and merits further investigation for this purpose. The ability to assess cellular responses in an environment where the cells are supported within the extracellular matrix may prove beneficial. PMID- 20830457 TI - Triple pelvic osteotomy in dogs less than 12 kg in weight. Technical feasibility and short-term radiographic and clinical complications in fourteen hips. AB - Triple pelvic osteotomy (TPO) was used to treat a selected group of young dogs with clinical and radiographic signs of hip dysplasia. Good clinical outcomes have been reported in dogs between 17-85 kg body weight. Hip dysplasia however is also encountered in smaller dogs. If surgery is performed in smaller dogs, femoral head and neck ostectomy is the main treatment method used. We wanted to determine if TPO could also be used in dogs under 12 kg bodyweight. Our study showed that it is technically possible to perform TPO surgery in dogs less than 12 kg of weight (down to 4.6 kg) with a good clinical outcome even in hips with high angles of reduction and subluxation. PMID- 20830458 TI - Mechanical testing of a modified stabilisation method for tibial tuberosity advancement. AB - OBJECTIVES: This in vitro study evaluated three modified techniques of tibial tuberosity advancement (TTA). Loads to failure were calculated for each technique. METHODS: A 9 mm TTA procedure was performed in the tibiae of dogs weighing between 32 and 38 kg. In group 1 (n = 12), the distal part of the tibial crest was left attached to the tibia by the cranial cortex, and a figure-of-eight wire was added for stabilisation. In group 2 (n = 12), the tibial crest was left attached but no additional device was used for stabilisation. In group 3 (n = 12), the tibial crest was completely separated from the tibia and fixed by a figure-of-eight wire so that, in this group, only the wire opposed avulsion of the tibial crest. Unidirectional axial force was applied via the patella to determine the maximal load to failure of the model. RESULTS: There was no significant difference between group 1 and group 2. These two groups both had a significantly stronger construct than that of group 3. CLINICAL SIGNIFICANCE: We described modifications to the TTA procedure without plate fixation that warrant clinical investigation. When the crest is broken during its advancement, the tension sustained by the repair is significantly weaker from a biomechanical point of view and the use of such a repair clinically is not recommended by the authors. PMID- 20830459 TI - Radiographic features of the dorsal condylar sagittal ridge of the third metacarpal and metatarsal bones in young Warmblood stallions. AB - OBJECTIVES: To describe the radiographic appearance of the dorsoproximal aspect of the sagittal ridge of the third metacarpal/metatarsal bone in Warmblood horses. METHODS: The lateromedial radiographic projections of the metacarpo /metatarsophalangeal joints performed on horses as a part of stallion selection were used. The dorsal aspect of the distal third metacarpal/metatarsal bone was divided in two areas. The appearance of the bone surface in area I was classified as normal, irregular, notch, indentation and lucency. For area II, the categories were normal, irregular, depression or lucency and flattening of the sagittal ridge. Other abnormalities at the dorsal aspect were also noted. RESULTS: In area I, 51.5% of the ridges appeared normal, 19.3% were irregular, 8.9% had a notch, 8.1% had a lucency, and 12.2% had an indentation. In 1.2% of the horses a fragment was present, and in 1.7% a fragment was suspected. In area II, 90.6% of the metacarpo-/metatarsophalangeal joints were normal, 6.2% were irregular, 2.9% showed a depression or lucency, and the sagittal ridge in 0.2% was flattened. A fragment was present in 0.3%, and suspected in 0.4%. CLINICAL SIGNIFICANCE: Morphological variation is present at the dorsal aspect of the metacarpo /metatarsophalangeal joint in young Warmblood stallions. These various aspects should be recognised and described in horses presented for prepurchase examination. However, their clinical relevance in the individual horse is unclear and needs further investigation. PMID- 20830460 TI - [Postoperative wound infections. Pathophysiology, risk factors and preventive concepts]. AB - Postoperative wound infections are the third most common type of nosocomial infection in German emergency hospitals after pneumonia and urinary infections. They are associated with increased morbidity and mortality, prolonged hospital stay and increased costs. The most important risk factors include the microbiological state of the skin surrounding the incision, delayed or premature prophylaxis with antibiotics, duration of surgery, emergency surgery, poorly controlled diabetes mellitus, malignant disease, smoking and advanced age. Anesthesiological measures to decrease the incidence of wound infections are maintaining normothermia, strict indications for allogenic blood transfusions and timely prophylaxis with antibiotics. Blood glucose concentrations should be kept in the range of 8.3-10 mmol/l (150-180 mg/dl) as lower values are associated with increased complications. Intraoperative and postoperative hyperoxia with 80% O(2) has not been shown to effectively decrease wound infections. The application of local anesthetics into the surgical wound in clinically relevant doses for postoperative analgesia does not impair wound healing. PMID- 20830461 TI - [Primum nil nocere. Regional anesthesia in neurologic diseases]. PMID- 20830462 TI - [Geriatric rehabilitation. Inpatient, day patient and outpatient]. AB - Geriatric rehabilitation is a cornerstone of every treatment plan in elderly persons in the inpatient, day clinic and outpatient settings. Geriatric patients tend to be more in need of care and to have a loss of domestic independence due to multimorbidities. The goal of geriatric rehabilitation is to preserve and/or restore the disease-related functional deficits in order to guarantee mobility and activities of daily living (ADL) in addition to curative treatment. Structural prerequisites in all geriatric units are the comprehensive geriatric assessment (CGA) and the existence of an interdisciplinary geriatric team. Geriatric rehabilitative treatment is based on functionality (ICF) and is therefore indicated in a wide spectrum of diseases. The demographic shift necessitates an increase in geriatric treatment structures with innovative concepts such as geronto-traumatological interdisciplinary units or geriatric outpatient office groups with a better networking of different care structures. PMID- 20830463 TI - Anticancer efficacy of 5F in NNK-induced lung cancer development of A/J mice and human lung cancer cells. AB - The mechanism responsible for the apoptotic effect induced by ent-11alpha-hydroxy 15-oxo-kaur-16-en-19-oic-acid (5F) is not fully understood and its in vivo effect has not been tested. In this study, the effect and mechanism of 5F was investigated in cigarette smoking carcinogen 4-methylnitrosamino-1-3-pyridyl butanone (NNK)-induced mouse lung tumor model and in cultured lung cancer cells NCI-H23 and CRL-2066. 5F were given to mice after they were treated with NNK for 18 weeks. The effect of 5F on the lung tumor formation was examined, and its side effect was monitored. Cell proliferation and apoptosis were determined through expression of PCNA, Bcl-2, Bax, and TUNEL assay in in vivo animal model. 5F significantly inhibited the NNK-induced lung tumors by inducing apoptosis and suppressing cell proliferation in vivo with minimal side effects. Cell culture experiments showed that 5F translocated Bax into the mitochondria, downregulated Bcl-2, activated caspase-9 and caspase-3, released cytochrome c into the cytosol, and translocated AIF from the mitochondria to the nucleus, which leading to G2-M cell cycle arrest and cell apoptosis. 5F also activated ERK1/2 and the inhibition of ERK1/2 suppressed 5F-mediated changes in apoptotic molecules. In addition to ERK1/2, 5F activated Akt. The inhibition of Akt further facilitated the apoptosis induced, suggesting that Akt activation was anti-apoptotic rather than pro apoptotic. Collectively, 5F is effective against lung cancer in vivo with minimal side effects. It induces apoptosis in lung cancer through the mitochondrial mediated pathway, in which the activation of ERK is critical. PMID- 20830464 TI - A genetic map of Lophopyrum ponticum chromosome 7E, harboring resistance genes to Fusarium head blight and leaf rust. AB - The leaf rust resistance gene Lr19 and Fusarium head blight (FHB) resistance quantitative trait loci (QTL) derived from the wild wheatgrass Lophopyrum ponticum have been located on chromosome 7E. The main objectives of the present study were to develop a genetic map of chromosome 7E and map the two resistance loci using a population of 237 F(7:8) recombinant inbred lines (RILs) derived from a cross between two Thatcher-L. ponticum substitution lines, K11463 (7el(1)(7D)) and K2620 (7el(2)(7D)). 532 G-SSR, E-SSR and STS markers from wheat chromosome group 7 were screened in the parent lines. Of these, 118 markers were polymorphic, with a polymorphism frequency of 22.2%. A genetic map of L. ponticum chromosome 7E was constructed with 64 markers, covering 95.76 cM, with an average genetic distance of 1.47 cM between markers. The major FHB resistance locus, temporarily assigned as FhbLoP, was mapped to the very distal region of the long arm of chromosome 7E within a 3.71 cM interval flanked by Xcfa2240 and Xswes19, which accounts for 30.46% of the phenotypic variance. Lr19 was bracketed by Xwmc273 and XBE404744, with a map distance of 1.54 and 1.43 cM from either side, respectively. The closely linked markers identified in this study will be helpful for marker-assisted introgression of the L. ponticum-derived FhbLoP and Lr19 genes into elite cultivars of wheat, and the development of a genetic map will accelerate the map-based cloning of these two genes. PMID- 20830465 TI - Chromosomal loci associated with endosperm hardness in a malting barley cross. AB - A breeding objective for the malting barley industry is to produce lines with softer, plumper grain containing moderate protein content (9-12%) as they are more likely to imbibe water readily and contain more starch per grain, which in turn produces higher levels of malt extract. In a malting barley mapping population, 'Arapiles' * 'Franklin', the most significant and robust quantitative trait locus (QTL) for endosperm hardness was observed on the short arm of chromosome 1H, across three environments over two growing seasons. This accounted for 22.6% (Horsham 2000), 26.8% (Esperance 2001), and 12.0% (Tarranyurk 2001) of the genetic variance and significantly increased endosperm hardness by 2.06-3.03 SKCS hardness units. Interestingly, Arapiles and Franklin do not vary in Ha locus alleles. Therefore, this region, near the centromere on chromosome 1H, may be of great importance when aiming to manipulate endosperm hardness and malting quality. Interestingly, this region, close to the centromere on chromosome 1H, in our study, aligns with the region of the genome that includes the HvCslF9 and the HvGlb1 genes. Potentially, one or both of these genes could be considered to be candidate genes that influence endosperm hardness in the barley grain. Additional QTLs for endosperm hardness were detected on chromosomes 2H, 3H, 6H and 7H, confirming that the hardness trait in barley is complex and multigenic, similar to many malting quality traits of interest. PMID- 20830466 TI - Regional impact of adipose tissue morphology on the metabolic profile in morbid obesity. AB - AIMS/HYPOTHESIS: The aim of this study was to determine whether the mean size of fat cells in either visceral or subcutaneous adipose tissue has an impact on the metabolic and inflammatory profiles in morbid obesity. METHODS: In 80 morbidly obese women, mean visceral (omental) and subcutaneous fat cell sizes were related to in vivo markers of inflammation, glucose metabolism and lipid metabolism. RESULTS: Visceral, but not subcutaneous, adipocyte size was significantly associated with plasma apolipoprotein B, total cholesterol, LDL-cholesterol and triacylglycerols (p ranging from 0.002 to 0.015, partial r ranging from 0.3 to 0.4). Subcutaneous, but not visceral, adipocyte size was significantly associated with plasma insulin and glucose, insulin-induced glucose disposal and insulin sensitivity (p ranging from 0.002 to 0.005, partial r ranging from -0.34 to 0.35). The associations were independent of age, BMI, body fat mass or body fat distribution. Adipose tissue hyperplasia (i.e. many small adipocytes) in both regions was significantly associated with better glucose, insulin and lipid profiles compared with adipose hypertrophy (i.e. few large adipocytes) in any or both regions (p ranging from <0.0001 to 0.04). Circulating inflammatory markers were not associated with fat cell size or corresponding gene expression in the fat cell regions examined. CONCLUSIONS/INTERPRETATION: In morbidly obese women region-specific variations in mean adipocyte size are associated with metabolic complications but not systemic or adipose inflammation. Large fat cells in the visceral region are linked to dyslipidaemia, whereas large subcutaneous adipocytes are important for glucose and insulin abnormalities. Hyperplasia (many small adipocytes) in both adipose regions may be protective against lipid as well as glucose/insulin abnormalities in obesity. PMID- 20830468 TI - Impact of the deuterium isotope effect on the accuracy of 13C NMR measurements of site-specific isotope ratios at natural abundance in glucose. AB - The application of isotope ratio methods in authenticity and traceability relies on the accuracy and robustness of the methodology employed. An unexpected source of error has now been identified, which can introduce major and variable inaccuracies into the determination of site-specific isotope ratio measurement by quantitative (13)C NMR spectrometry if not correctly controlled. This is the isotope chemical shift effect, which comes into play when hydrogen atoms in the target molecule enter into exchange with deuterated water present at trace levels in the deuterated solvent used as the frequency lock. Even at a level of contamination as low as 0.02%, an error of 50/00 can be introduced, fivefold the required accuracy of 10/00. How to avoid this source of error is discussed. PMID- 20830470 TI - Cleopatra's cocktail challenge. PMID- 20830467 TI - [Slipped capital femoral epiphysis]. AB - Slipped capital femoral epiphysis (SCFE) is a common hip disorder in adolescence and should be diagnosed and treated surgically as soon as possible. The etiology, biomechanical, biochemical and hereditary factors are still under investigation. The classification of SCFE is based on the acuteness, clinical and radiomorphological findings. Avascular necrosis of the epiphysis (AVN) and chondrolysis occur more often in operated than in non-operated patients. Medium and long-term sequelae of SCFE are loss of function and degenerative joint disease due to femoroacetabular impingement (FAI) or consequences from complications such as AVN and chondrolysis. For mild slips the long-term prognosis is better than for moderate or severe slips. Higher grade unstable SCFE may benefit from reduction while in chronic slips corrective osteotomy may be indicated. Traditional osteotomy procedures, such as Imhauser or Southwick intertrochanteric osteotomy are safe procedures but correct the deformity distant from the site of the deformity. The surgical dislocation with modified Dunn osteotomy according to Ganz allows the preparation of an extended retinacular soft tissue flap and offers an extensive subperiosteal exposure of the circumference of the femoral neck before reducing the slipped epiphysis anatomically. In cases of FAI due to mild deformities restoration of the head neck offset via hip arthroscopy or surgical dislocation should be considered before higher grade cartilage damage occurs. PMID- 20830471 TI - Production of antioxidant and antitumor metabolites by submerged cultures of Inonotus obliquus cocultured with Phellinus punctatus. AB - While Inonotus obliquus produces a diverse range of bioactive metabolites in its natural habitats, it accumulates less in its submerged cultures. We show here that coculture of I. obliquus with Phellinus punctatus resulted in less production of mycelial biomass but an increased accumulation of phenolic compounds, melanins, and lanostane-type triterpenoids. Metabolites increased in production by coculture include phelligridin C, phelligridin H, methyl inoscavin A, inoscavin C, inoscavin B, davallialactone, methyl davallialactone, foscoparianol D, 21,24-cyclopentalanosta-3beta,21,25-triol-8-en, lanosta 7,9(11),23-triene-3beta,22,25-triol, and inotodisaccharide and melanins. Metabolites from coculture also showed an increased potential for scavenging free radicals and inhibiting the proliferation of HeLa 229 cells. Davallialactone, methyl davallialactone, and minor phenolic components are the major contributors for scavenging DPPH and hydroxyl radical in monoculture, and phelligridin C, phelligridin H, methyl inoscavin A, inoscavin C, methyl davallialactone, foscoparianol D, and inotodisaccharide are those for scavenging the tested radicals in coculture. Lanostane-type triterpenoids indicated limited roles in scavenging free radicals. Nearly all the detected metabolites correlate positively with inhibiting proliferation of HeLa 229 cells. Thus, coculture of I. obliquus with other fungi seems to be a cost-effective strategy for upregulating biosynthesis of bioactive metabolites. PMID- 20830472 TI - The Bicontact cementless primary total hip arthroplasty: long-term results. AB - We report on a prospective series of 201 primary uncemented total hip arthroplasties with a Bicontact prosthesis at a mean follow-up of 12.9 years. The mean Harris hip score improved from 41 before surgery to 89 at final follow-up. Two femoral stems, one each for infection and fracture, and 12 cups were revised. The mean number of years to revision post-primary surgery was 8.7 years (six months to 16 years). The cumulative survival of the prosthesis was 95.42% for any cause at ten years and 93.57% at 12 years. Survivorship for aseptic loosening of the femoral stem was 100%. In our series, the Bicontact uncemented total hip arthroplasty stem without hydroxyapatite coating showed excellent survival and the cup survival was comparable to other leading series. PMID- 20830473 TI - Histopathology of aseptic necrosis of the femoral head in sickle cell disease. AB - This study compares the histopathology of bone biopsies from patients suffering from sickle cell anaemia (homozygote SS) to heterozygote patients (SA) and homozygotes with aseptic osteonecrosis (AA). The sensitivity to bacterial infection of sickle cell patients raises the question of the aetiology of sepsis in the onset of the necrosis. To our knowledge this study is the first to analyse the histopathology of osteonecrosis of the femoral head, at its early stages, in sickle cell anaemia. At the University Hospital of Pointe-a-Pitre, from 1994 to 2007, 38 bone biopsies were obtained from adult patients with avascular necrosis of the femoral head at the time of a core decompression procedure (SS, SC: 27; AS: 5; AA: 6). The histology of the biopsies confirmed the necrosis; all bacteriological cultures were negative. Patients displaying one S gene (SS, SC, AS) compared to homozygote subjects (AA) showed a significant increase of a nonspecific inflammatory granulomatosis (p = 0.003). No relationship was observed between the radiological stages and the histology whatever the genotype (p = 0.1). Inflammatory histopathology without sepsis or advanced alteration characterises the early stages of sickle cell necrosis. This inflammatory process is absent in idiopathic avascular necrosis. PMID- 20830474 TI - Science-policy interactions in MPA site selection in the Dutch part of the North Sea. AB - At the 7th conference of the parties to the Convention on Biological Diversity (CBD-COP7, Kuala Lumpur, 2004) it was agreed to establish a global network of marine and coastal protected areas by 2012. The defined objectives of this MPA network are based on the ecosystem approach: to protect biodiversity and other ecological values, and to ensure sustainable use. The (inter)national policy guidelines state that the selection of MPAs should be based on scientific information and ecological criteria only. As a signatory to the Convention, the Netherlands is now faced with meeting this obligation, and the process of designating the first Marine Protected Areas (MPAs) in the Dutch part of the North Sea is currently in progress. We focus on the science-policy interactions that are part of this Dutch MPA selection process. By taking a closer look at the contemporary site selection process as well as its historical background, we show that ecological, socio-economic and political considerations cannot always be easily separated. Uncertainty is high and the ultimate selection and delimitation of candidate sites rather seems to be the result of a balancing act between ecological, socio-economic and political interests, in which scientific and policy guiding procedures blend with ad-hoc political decision making, and with expert judgment in cases where data is lacking. As such, this paper presents an example of present-day environmental policy making in action. PMID- 20830475 TI - Alpha multicenter phase II study of pegylated liposomal doxorubicin in combination with irinotecan as second-line treatment of patients with refractory small-cell lung cancer. AB - PURPOSE: To evaluate efficacy and toxicity of a combination of pegylated liposomal doxorubicin and irinotecan in patients with refractory small-cell lung cancer. PATIENTS AND METHODS: Thirty-one patients with early relapse after first line therapy with cisplatin/etoposide were treated with pegylated liposomal doxorubicin 15 mg/m(2) and irinotecan 125 mg/m(2) on days 1 and 15. Treatment was repeated every 28 days. RESULTS: A total of 144 chemotherapy courses were administered. All patients were evaluable for toxicity and twenty-six (84%) for response. Grade 3 neutropenia occurred in two (6.5%) patients and grade 1 thrombocytopenia in one (3.2%). Fatigue was the most frequent grade 3 non hematologic toxicity and was observed in seven patients (23%). Four (12.9; 95% CI: 1.1-24.7%) patients achieved a partial response, and disease stabilization was observed in additional two (6.5%) patients (Tumor Growth Control: 19.4; 95% CI: 5.5-33.3%). The median TTP was 2.03 months, and the median survival time was 3.16 months. CONCLUSIONS: The combination of pegylated doxorubicin and irinotecan is very well tolerated but with modest activity in patients with refractory SCLC. PMID- 20830476 TI - Benchmarks for success in focal therapy of prostate cancer: cure or control? AB - BACKGROUND: The place of focal therapy in prostate cancer management requires further evaluation within randomized comparative clinical trials. METHODS: This review article discusses the place of focal therapy and asks whether it is an alternative to active surveillance or radical therapy. This question therefore is at the heart of whether this proposed paradigm shift should be delivered with the intent of cure or cancer control. RESULTS: For such trials to report on outcomes that have meaningful utility in the clinic, it is necessary to discuss whether focal ablation should be delivered with intent to eradicate all cancer foci ('cure') or ablate all clinically significant lesions with surveillance of all remaining tissue (benign or harboring clinically insignificant cancer). While the former will inevitably mean that fewer men will be appropriate for focal therapy were it to become standard care, it is the safest approach. The latter strategy will open focal therapy to the majority of men with low- to intermediate-risk disease with the potential of offering a treatment strategy that treats important cancer while preserving function with a high degree of probability. CONCLUSION: A pragmatic randomized controlled clinical in which focal therapy is randomized against standard of care may be feasible. The pragmatic nature of such a trial would allow eligibility criteria, localization of cancer to reflect local practice (novel imaging and transrectal biopsy or template prostate mapping), and the focal intervention (ablative modality, intent to ablate all cancer foci or all clinically significant foci) to be kept broad to reflect clinical practice. Further, it would satisfy individual equipoise by allowing either active surveillance or radical therapy in the standard care arm, to be decided on by patient and physician. PMID- 20830477 TI - Severe involvement of pulmonary arteries in Takayasu arteritis: magnetic resonance imaging. PMID- 20830478 TI - Sensory circumventricular organs in health and disease. AB - Circumventricular organs (CVOs) are specialized brain structures located around the third and fourth ventricles. They differ from the rest of the brain parenchyma in that they are highly vascularised areas that lack a blood-brain barrier. These neurohaemal organs are classified as "sensory", when they contain neurons that can receive chemical inputs from the bloodstream. This review focuses on the sensory CVOs to describe their unique structure, and their functional roles in the maintenance of body fluid homeostasis and cardiovascular regulation, and in the generation of central acute immune and febrile responses. In doing so, the main neural connections to visceral regulatory centres such as the hypothalamus, the medulla oblongata and the endocrine hypothalamic-pituitary axis, as well as some of the relevant chemical substances involved, are described. The CVOs are vulnerable to circulating pathogens and can be portals for their entry in the brain. This review highlights recent investigations that show that the CVOs and related structures are involved in pathological conditions such as sepsis, stress, trypanosomiasis, autoimmune encephalitis, systemic amyloidosis and prion infections, while detailed information on their role in other neurodegenerative diseases such as Alzheimer's disease or multiple sclerosis is lacking. It is concluded that studies of the CVOs and related structures may help in the early diagnosis and treatment of such disorders. PMID- 20830479 TI - Cross-cultural adaptation and validation of the Oxford 12-item knee score in Japanese. AB - INTRODUCTION: With the high incidence of knee osteoarthritis (OA) in Japan, there is a strong need not only for surgical therapies, but also for validated outcome measures. For this study, we completed cross-cultural adaptation, testing and validation of the Oxford knee score (OKS) for prospective use in national and international clinical studies involving Japanese patients. MATERIALS AND METHODS: The Japanese version of the OKS was developed according to the standard cross-cultural adaptation guidelines. For validation, the OKS was tested on 54 patients diagnosed with OA, osteonecrosis, ligament or meniscus injury. Reliability was tested using the intraclass correlation coefficient (ICC). Internal consistency or homogeneity was assessed using Cronbach's alpha. The correlation between the Japanese OKS, WOMAC and SF-36 questionnaires was used to assess construct validity. RESULTS: No major difficulties were encountered with the translation and pre-testing stages. For reliability and validity, the Japanese OKS was completed without any missed responses by 53 (98.15%) and 52 (96.30%) patients at the first and second distribution, respectively. The total OKS showed good reliability with an ICC of 0.85. Internal consistency was strong (Cronbach's alpha = 0.90). Strong construct validity (ICC values of 0.51-0.84) was obtained against the WOMAC and SF-36 (physical functioning, role-physical, bodily pain, and social functioning subscales) scores. Notable "ceiling" effects of the OKS were reported for 11 of the 12 questionnaire items. CONCLUSION: The Japanese OKS has proven to be a reliable and valid instrument for the self assessment of knee pain and function in Japanese speaking patients with knee OA and other knee complaints. PMID- 20830480 TI - Morphological evaluation of lateral ventricles of fetuses with ventriculomegaly by three-dimensional ultrasonography and magnetic resonance imaging: correlation with etiology. AB - PURPOSE: To evaluate morphology of lateral ventricles of ventriculomegaly/hydrocephaly fetuses using 3D-sonography by virtual organ computer-aided analysis (VOCAL) technique and magnetic resonance imaging (MRI) and verify morphologic patterns related to etiology. METHODS: Seventeen fetuses presenting with ventricular enlargement (atria > 10 mm) were evaluated. 3D datasets were acquired from a coronal reference plane and post-processed by the rotational imaging using VOCAL 30 degrees . MRI study was analyzed in the three plans in all sequences. Morphologic aspects such as global shape, anterior, posterior and inferior horn characteristics, wall irregularities and deformities were analyzed and related to etiology factor. RESULTS: Twenty-nine percent of the cases were secondary to Arnold-Chiari syndrome and presented with global dilation of the three-horns. Cases related to aqueduct stenosis presented with ependymal rupture and wall irregularities in advanced cases. Corpus callosum agenesis cases presented with small ventricular volumes, thin shape, normal or slightly enlarged anterior and inferior horns with dilation restricted to posterior horn. Cases related to trisomy 18 and cytomegalovirus presented irregular ventricular walls associated with anomalous ventricular shapes, suggesting parenchymal destruction. CONCLUSION: Ventricular morphology evaluation gives important information on etiology of ventricular enlargement, supporting prognosis prediction and decision making process of the affected fetuses and their families. PMID- 20830481 TI - Laparoscopic-assisted vaginal hysterectomy with and without laparoscopic transsection of the uterine artery: an analysis of 1,255 cases. AB - INTRODUCTION: To evaluate the operative outcomes of patients managed by laparoscopic-assisted vaginal hysterectomy (LAVH) with and without laparoscopic transsection of the uterine artery for benign gynaecologic diseases. PATIENTS AND METHODS: A retrospective analysis of 1,255 women from two different centers undergoing hysterectomy between 1998 and 2009 with benign indications is presented. 856 patients were treated by LAVH type I (vaginal transsection of the uterine artery) and 399 patients by LAVH type II (laparoscopic transsection of the uterine artery). Operative outcomes, intraoperative and postoperative complications, as well as laparoconversion rates were the main objectives of the study. RESULTS: Median operative time was similar between LAVH type I and II (136 vs. 126 min, respectively, P = NS). Intraoperative complication rate was not significantly different between the two groups of the study (LAVH type I: 1.5% vs. LAVH type II: 1.26%, respectively, P = NS). The injury of the urinary tract, especially of the bladder, was the most common intraoperative complication for both the groups of the study. Laparoconversion rate was similar in LAVH type I and II (0.5 vs. 0.35%, respectively, P = NS), while postoperative complications were significantly higher in LAVH type I (2.25%) compared to LAVH type II (1.16%), mainly because of postoperative vaginal and intrabdominal haemorrhage in the group of the LAVH type I. CONCLUSION: LAVH with laparoscopic transsection of the uterine artery is an effective and safe technique with less postoperative complication compared to LAVH with vaginal transsection of the uterine vessels. PMID- 20830482 TI - Rudimentary-horn pregnancy: some points to review. PMID- 20830483 TI - Maternal and fetal leptin and ghrelin levels: relationship with fetal growth. AB - PURPOSE: In our study, we investigated the influence of plasma levels ghrelin, leptin and other metabolic hormones (ILGF-1 and ILGF-2) in pregnants in regulating fetal body weight and mode of delivery. METHODS: A total of 36 appropriately healthy pregnants 19-36-year-old were involved in the study. Demographic characteristics, serum ghrelin, leptin, IGF-1 and IGF-2 levels of the pregnants were studied. RESULTS: Plasma ghrelin and leptin levels did not differ significantly among trimesters and delivery, in contrast to IGF-I and IGF-II concentrations were significantly higher in the first half of the pregnancy (P < 0.05). Serum leptin was significantly associated with mode of delivery (r = 0.231; P = 0.008), BMI (r = 0.462; P = 0.004). CONCLUSION: Metabolic factors are associated with fetal growth, but in AGA babies, there were no differences between any parameter and clinical factor. PMID- 20830484 TI - Comparison of techniques for measuring anterior chamber depth: Orbscan imaging, Smith's technique, and van Herick's method. AB - BACKGROUND: Evaluation of anterior chamber depth (ACD) can potentially identify those patients at risk of angle-closure glaucoma. We aimed to: compare van Herick's limbal chamber depth (LCDvh) grades with LCDorb grades calculated from the Orbscan anterior chamber angle values; determine Smith's technique ACD and compare to Orbscan ACD; and calculate a constant for Smith's technique using Orbscan ACD. METHODS: Eighty participants free from eye disease underwent LCDvh grading, Smith's technique ACD, and Orbscan anterior chamber angle and ACD measurement. RESULTS: LCDvh overestimated grades by a mean of 0.25 (coefficient of repeatability [CR] 1.59) compared to LCDorb. Smith's technique (constant 1.40 and 1.31) overestimated ACD by a mean of 0.33 mm (CR 0.82) and 0.12 mm (CR 0.79) respectively, compared to Orbscan. Using linear regression, we determined a constant of 1.22 for Smith's slit-length method. CONCLUSIONS: Smith's technique (constant 1.31) provided an ACD that is closer to that found with Orbscan compared to a constant of 1.40 or LCDvh. Our findings also suggest that Smith's technique would produce values closer to that obtained with Orbscan by using a constant of 1.22. PMID- 20830485 TI - Prevention of infectious complications after laparoscopic appendectomy for complicated acute appendicitis--the role of routine abdominal drainage. AB - PURPOSE: Complicated acute appendicitis is still associated with an increased morbidity. If laparoscopy has been accepted as a valid approach, some questions remain concerning intra-abdominal abscess formation. Routine prophylactic drainage of the abdomen has been proposed. However, this practice remains a matter of debate, poorly validated in the literature. With the present study, we investigated the impact of drainage in laparoscopic appendectomy for complicated appendicitis. METHOD: This is a case match study of consecutive patients operated on by laparoscopy in a single institution. One hundred and thirty patients operated for complicated appendicitis (local peritonitis without perforation, with perforation, or with periappendicular abscess) with prophylactic intraperitoneal drainage were matched one by one to 130 patients operated without drainage. Uncomplicated appendicitis and generalized peritonitis were excluded. Primary endpoint was surgical complications and secondary endpoints were transit recovery time and length of hospital stay. RESULTS: Patients without drain had significantly less overall complications (7.7% vs. 18.5%, p = 0.01). Moreover, the absence of drainage was of significant benefit for transit recovery time (2.5 vs. 3.5 days, p = 0.0068) and length of hospital stay (4.2 vs. 7.3 days, p < 0.0001). CONCLUSION: No benefits were observed for prophylactic drainage of the abdominal cavity during emergency laparoscopic treatment of complicated appendicitis. For this reason, this practice may be abandoned. PMID- 20830486 TI - Growth charts for children with Ellis-van Creveld syndrome. AB - Ellis-van Creveld (EvC) syndrome is a congenital malformation syndrome with marked growth retardation. In this study, specific growth charts for EvC patients were derived to allow better follow-up of growth and earlier detection of growth patterns unusual for EvC. With the use of 235 observations of 101 EvC patients (49 males, 52 females), growth charts for males and females from 0 to 20 years of age were derived. Longitudinal and cross-sectional data were collected from an earlier review of growth data in EvC, a database of EvC patients, and from recent literature. To model the growth charts, the GAMLSS package for the R statistical program was used. Height of EvC patients was compared to healthy children using Dutch growth charts. Data are presented both on a scale for age and on a scale for the square root of age. Compared to healthy Dutch children, mean height standard deviation score values for male and female EvC patients were -3.1 and 3.0, respectively. The present growth charts should be useful in the follow-up of EvC patients. Most importantly, early detection of growth hormone deficiency, known to occur in EvC, will be facilitated. PMID- 20830487 TI - Cell-cell contacts induce STAT3 activity in colon carcinoma cells through an autocrine stimulation loop. AB - PURPOSE: Signal transducer and activator of transcription 3 (STAT3) is persistently activated in colorectal carcinoma (CRC) cells in the tumor context, but inactive in cultivated CRC cell lines. We approached mechanisms leading to STAT3 activation in CRC by mimicking "tumor-like" growth conditions and forcing cell-cell contacts of HT-29 CRC cells in culture. Further aims were to analyze in how far HT-29 cells growing in a tumorous manner spread STAT3 activity by secretion of soluble factors. METHODS: Non-adhesive growth and aggregation of HT 29 cells were achieved by cultivation on non-coated plastic surfaces. STAT3 activity was assessed by Western blot employing a phospho-STAT3-specific antibody as well as by electrophoretic mobility shift assay (EMSA). Expression changes of STAT3 target gene mmp-1 were quantified by real-time RT-PCR, Cytokine/chemokine patterns in conditioned media were characterized by cytokine arrays. RESULTS: Forced aggregation and non-adhesive growth of HT-29 CRC cells resulted in enhanced tyrosine phosphorylation of STAT3 and elevated expression of matrix metalloproteinase MMP-1. Furthermore, an activity was secreted into the medium that evoked STAT3 phosphorylation in adhesively growing HT-29 cells. The degree of activity in the conditioned medium was enhanced when wild-type STAT3 was overexpressed and reduced when a dominant variant of STAT3 was expressed in HT-29 cells. A characteristic panel of chemokines appeared in STAT3-activating conditioned medium. CONCLUSIONS: Changing cultivation conditions of the CRC cell line HT-29 toward detachment and aggregation, thus toward the situation in tumors, induces STAT3 activity and evokes an autocrine STAT3 activation loop. PMID- 20830488 TI - Transposition and target preferences of an active nonautonomous DNA transposon nDart1 and its relatives belonging to the hAT superfamily in rice. AB - The nonautonomous nDart1 element in the hAT superfamily is one of a few active DNA transposons in rice. Its transposition can be induced by crossing with a line containing an active autonomous element, aDart1, and stabilized by segregating aDart1. No somaclonal variation should occur in nDart1-promoted gene tagging because no tissue culture is involved in nDart1 activation. By transposon display analysis, we examined the activities of nDart1-related elements in the selfed progeny of a mutable virescent pyl-v plant containing aDart1. Although various nDart1-related elements are present in the rice genome, only nDart1-3 subgroup elements, nDart1-0 and nDart1-3 in particular, were found to be transposed frequently and integrated into various sites almost all over the genome, and a fraction of the transposed elements were found to be transmitted to the next generation. More than half of the newly integrated elements were identified as nDart1-0. Analysis of the newly inserted sites revealed that the nDart1-3 subgroup elements were predominantly integrated into single-copy regions. More than 60% of the transposed elements were inserted into the genic regions that comprise putative coding regions and their 0.5-kb flanking segments, and approximately two-thirds of them were within the 0.5-kb area in front of the putative initiation codons, i.e., promoter-proximal genic regions. These characteristic features of nDart1-3 subgroup elements seem to be suitable for developing an efficient and somaclonal variation-free gene tagging system for rice functional genomics. PMID- 20830490 TI - Medical cost analysis for antifungal prophylaxis in neutropenic patients with hematological malignancies: a systematic simulation analysis. AB - GOALS OF WORK: We assessed the medical costs of different antifungal agents for prophylaxis of invasive fungal infections in neutropenic patients in Japan with a cost simulation model designed for the study. PATIENTS AND METHODS: We used probabilities of prophylaxis failure, possible cases for empiric therapy, probable proportions of infections caused by fungus species among prophylaxis failure patients, and incidence of adverse events caused by any reason, based on systematic analysis of previously reported randomized trials identified by a computerized search of the PubMed database. Antifungal agents were limited to oral fluconazole, oral itraconazole, micafungin, and liposomal amphotericin B. The range of the expected medical cost was simulated as a sensitivity analysis using 95% of confidence interval of a mean. MAIN RESULTS: Fifteen studies were identified for our analysis. The prophylactic efficacy was comparable between the four agents. The simulated expected cost for invasive fungal infection prophylaxis and treatment of the infection was $1,035.74 when oral itraconazole was used for prophylaxis, $1,552.81 with oral fluconazole, $2,245.96 with micafungin, and $3,028.10 with liposomal amphotericin B. The total cost including treatment cost for adverse events related to each drug was $2,742.14, $3,547.91, $3,034.57, and $3,028.10, respectively. This result was confirmed in a sensitivity analysis in which IFI incidence and therapy duration were tested as parameters. CONCLUSIONS: Our analysis results suggest that oral itraconazole is the most cost-effective prophylactic antifungal agent for invasive fungal infections in neutropenic patients with hematological malignancies, and this result was robust by sensitivity analysis. PMID- 20830491 TI - Quality of lidocaine analgesia with and without midazolam for intravenous regional anesthesia. AB - PURPOSE: Midazolam has analgesic effects mediated by gamma aminobutyric acid-A receptors. This study was designed to evaluate the effect of midazolam on anesthesia and analgesia quality when added to lidocaine for intravenous regional anesthesia (IVRA). METHODS: Forty patients undergoing hand surgery were randomly assigned to two groups to receive IVRA. The control group received 3 mg/kg lidocaine 2% w/v diluted with saline to a total volume of 40 ml, and the midazolam group received an additional 50 MUg/kg midazolam. Sensory and motor block onset and recovery times, tourniquet pain, intraoperative analgesic requirements, sedation, and anesthesia quality were recorded. Postoperative pain and sedation scores, time to first analgesic requirements, analgesic use in the first 24 h, and side effects were noted. RESULTS: Sensory and motor block onset and recovery times did not differ significantly between groups. Tourniquet pain scores were lower at 10, 15, 20, and 30 min (P < 0.0001) in the midazolam group. Three (15%) patients in the midazolam group required fentanyl for tourniquet pain compared with thirteen (65%) patients in the control group (P = 0.02). Patients in both groups received fentanyl once. Midazolam group showed that significantly less patients required diclofenac for postoperative analgesia (P < 0.01) and analgesic-free period during first postoperative 24 h was significantly longer (726.8 +/- 662.8 min vs. 91.0 +/- 35.9 min, P < 0.0001). Postoperative pain scores were lower (P < 0.0001) and sedation scores higher (P < 0.05) for the first 2 h in the midazolam group. CONCLUSION: Addition of midazolam to lidocaine for IVRA improves anesthesia quality and enhances intraoperative and postoperative analgesia without causing side effects. PMID- 20830489 TI - Using proteomics to study sexual reproduction in angiosperms. AB - While a relative latecomer to the postgenomics era of functional biology, the application of mass spectrometry-based proteomic analysis has increased exponentially over the past 10 years. Some of this increase is the result of transition of chemists, physicists, and mathematicians to the study of biology, and some is due to improved methods, increased instrument sensitivity, and better techniques of bioinformatics-based data analysis. Proteomic Biological processes are typically studied in isolation, and seldom are efforts made to coordinate results obtained using structural, biochemical, and molecular-genetic strategies. Mass spectrometry-based proteomic analysis can serve as a platform to bridge these disparate results and to additionally incorporate both temporal and anatomical considerations. Recently, proteomic analyses have transcended their initial purely descriptive applications and are being employed extensively in studies of posttranslational protein modifications, protein interactions, and control of metabolic networks. Herein, we provide a brief introduction to sample preparation, comparison of gel-based versus gel-free methods, and explanation of data analysis emphasizing plant reproductive applications. We critically review the results from the relatively small number of extant proteomics-based analyses of angiosperm reproduction, from flowers to seedlings, and speculate on the utility of this strategy for future developments and directions. PMID- 20830492 TI - The role of prosthesis design on segmental biomechanics: semi-constrained versus unconstrained prostheses and anterior versus posterior centre of rotation. AB - The purpose of this study was to evaluate the influence of different implant designs of total lumbar disc replacements on the segmental biomechanics of the lumbar spine. The unconstrained Charite, the semi-constrained Prodisc and a semi constrained Prototype with more posterior centre of rotation than the Prodisc were tested in vitro using six human, lumbar spines L2-L5. The segmental lordosis was measured on plain radiographs and the range of motion (ROM) for all six degrees of freedom with a previously described spine tester. All prostheses were implanted at level L3-L4. Compared with the intact status all prostheses resulted in a significant increase of segmental lordosis (intact 5.1 degrees ; Charite 10.6 degrees , p = 0.028; Prodisc 9.5 degrees , p = 0.027; Prototype 8.9 degrees , p = 0.028), significant increase of flexion/extension (intact 6.4 degrees , Charite 11.3 degrees , Prodisc 12.2 degrees , Prototype 12.2 degrees ) and axial rotation (intact 1.3 degrees , Charite 5.4 degrees , Prodisc 3.9 degrees , Prototype 4.2 degrees ). Lateral bending increased significantly only for the Charite (intact 7.7 degrees ; Charite 11.6 degrees , p = 0.028; Prodisc 9.6 degrees , Prototype 9.8 degrees ). The segmental lordosis after Prototype implantation was significantly lower compared with Charite (p = 0.024) and Prodisc (p = 0.044). No significant difference could be observed for segmental lordosis between Charite and Prodisc and for ROM between the two semi-constrained prosthesis Prodisc and Prototype. The axial rotation for the unconstrained Charite was significantly higher than for the semi-constrained prosthesis Prodisc and Prototype, flexion/extension and lateral bending did not differ. Summarizing, the unconstrained prosthesis design increased segmental lordosis and showed a tendency towards higher ROM for axial rotation/lateral bending and lower ROM for flexion/extension than a semi-constrained prosthesis. A more anterior centre of rotation in a semi-constrained prosthesis resulted in a higher increase of segmental lordosis after TDR than a semi-constrained prosthesis with more posterior centre of rotation. The location of the centre of rotation in a semi constrained prosthesis did not alter the magnitude of ROM. Despite the different alterations of ROM and segmental lordosis due to implant design, these differences were negligible compared with the overall increase of ROM and segmental lordosis by the implantation of a TDR compared with the physiologic state. PMID- 20830493 TI - Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease. AB - During the last decade, substantia nigra (SN) hyperechogenicity has been established as a valuable supplementary diagnostic marker for Parkinson's disease. As an increasing number of studies indicate that this ultrasound feature may even be evident before motor symptoms of Parkinson's disease occur, longitudinal studies revealing its value as a screening instrument for subjects at risk are awaited with great expectancy. At the same time, other studies have shown that SN hyperechogenicity is not only found in Parkinson's disease but also in other disease entities. Limitations and pitfalls of the method need to be considered to evaluate and compare these studies. Taking these into account, it is important to realize that in some other neurodegenerative diseases as well as in disorders associated with an increased risk for Parkinson's disease hyperechogenicity can be found--usually, however, less prevalent. Interestingly, even in subgroups of patients with non-neurodegenerative disorders, SN hyperechogenicity can be detected. This holds, for example, true for multiple sclerosis patients with a higher rate of disease progression. In this disorder, microglia activation is known to occur, which is also evident in Parkinson's disease. This pathomechanism as well as increased iron content is known to contribute to SN hyperechogenicity. From the studies published so far it can be concluded that, although SN hyperechogenicity is not only found in Parkinson's disease, assessment of the echogenicity of the SN and other ultrasound features is valuable in the differential diagnosis of Parkinsonian syndromes and most probably in subjects at risk. Further elucidation of the cause of the echosignal will not only contribute to the understanding of the pathophysiology of some neurodegenerative diseases but also to an even better implementation in the clinical routine and for scientific studies. PMID- 20830494 TI - Variations on theme: spindle assembly in diverse cells. AB - The mitotic spindle faithfully separates the genetic material, and has been reverently observed for well over a century. Across eukaryotes, while the mechanisms for moving chromosomes seem quite conserved, mechanisms for assembling the spindle often seem distinct. Two major pathways for spindle assembly are known, one based on centrosomes and the other based on chromatin, and these pathways are usually considered to be fundamentally different. We review observations of spindle assembly in animals, fungi, and plants, and argue that microtubule assembly at a particular location, centrosomes, or chromatin, reflects contingent, cell-type specific factors, rather than reflecting a fundamental distinction in the process of spindle building. We hypothesize that the essential process for spindle assembly is the motor-driven organization of microtubules that accumulate in the form of dense bundles at or near the chromosomes. PMID- 20830495 TI - Roles of arabinogalactan proteins in cotyledon formation and cell wall deposition during embryo development of Arabidopsis. AB - Arabinogalactan proteins (AGPs) are a class of highly glycosylated, widely distributed proteins in higher plants. In the previous study, we found that the green fluorescence from JIM13-labeled AGPs was mainly distributed in embryo proper and the basal part of suspensor but gradually disappeared after the torpedo-stage embryos in Arabidopsis. And (beta-D-Glc)(3) Yariv phenylglycoside (betaGlcY), a synthetic reagent that specifically binds to AGPs, could inhibit embryo development. In this study, as a continuous work, we investigated the AGP functions in embryo germination, cotyledon formation, and cell wall deposition in Arabidopsis embryos by using immunofluorescent, immunoenzyme, transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR) techniques. The results showed that 50 MUM betaGlcY caused inhibition of embryo germination, formation of abnormal cotyledon embryos, and disorder of cotyledon vasculature. Compared with the normal embryos in vitro and in vivo, the AGPs and pectin signals were quite weaker in the whole abnormal embryos, whereas the cellulose signal was stronger in the shoot apical meristem (SAM) of abnormal embryo by calcofluor white staining. The FTIR assay demonstrated that the cell wall of abnormal embryos was relatively poorer in pectins and richer in cellulose than those of normal embryos. By TEM observation, the SAM cells of the abnormal embryos had less cytoplasm, more plastid and starch grains, and larger vacuole than that of normal embryos. These results indicated that AGPs may play roles in embryo germination, cotyledon formation, cell wall cellulose and pectin deposition, and cell division potentiality during embryo development of Arabidopsis. PMID- 20830496 TI - Kinetics of amino acid production from bean dregs by hydrolysis in sub-critical water. AB - Amino acids play an important physiological role in all life-forms and can be recovered from bean dregs waste using sub-critical water hydrolysis. This work deals with the hydrolysis kinetics of bean dregs. Kinetics was conducted in a temperature range of 200-240 degrees C using a 300-ml stainless steel batch reactor. Since the reaction kinetics in sub-critical water is very complicated, a simplified kinetic model to describe the hydrolysis of bean dregs is proposed: a single consecutive reaction. The differential equations resulting from the model were fit to experimental data to obtain kinetic rate constants. By means of the Arrhenius plot, the activation energy as well as the pre-exponential factor was determined. A good agreement between the simplified model and the experimental data was obtained. The kinetic parameters provided useful information for understanding the hydrolysis reaction of bean dregs. The experimental results show that the best hydrolysis technology is: reaction temperature 200 degrees C, reaction time 20 min. Under this condition, the total amino acid yield reaches 52.9%. Based on the results, this method could become an efficient method for bean dregs liquefaction, producing valuable amino acid. PMID- 20830497 TI - The effect of the post length and cusp coverage on the cycling and static load of endodontically treated maxillary premolars. AB - In endodontically treated teeth, cuspal coverage plays a fundamental role in reducing the risk of fracture. However, the adhesive techniques with or without fiber post increased the possibilities in restoring root-filled teeth. The aim of this study was to determine the effect of the fiber post and/or post length and/or cuspal coverage on the fracture resistance of endodontically treated maxillary premolars. Seventy intact single-rooted maxillary premolars were selected and divided in seven groups of ten each: "intact teeth" (control), "inlay without fiber post" (G1), "inlay with long fiber post" (G2), "inlay with short fiber post" (G3), "onlay without fiber post" (G4), "onlay with long fiber post" (G5), and "onlay with short fiber post" (G6). Except for intact teeth, all specimens were prepared with a mesio-occluso-distal (MOD) cavity, endodontically treated and restored with or without long or short post, with or without cusp coverage. All specimens were thermal-cycled, exposed to a cyclic loading, and then submitted to the static fracture resistance test. Fracture loads and mode of failure were evaluated. A statistically significant difference in fracture resistance was found between group 1 and the other groups (p < 0.001). chi2 test showed statistically significant differences in the patterns of fractures between the groups (p < 0.001). The highest number of favorable fractures was observed in groups 3 and 4. Similar fracture resistance was detected in maxillary premolars endodontically treated with MOD cavity preparations, restored with either direct resin composite with fiber post or cusp capping. The "short post" direct restoration may be a valid alternative in the restoration of root-filled premolars. PMID- 20830498 TI - Modulation of physical understanding by common marmosets (Callithrix jacchus). AB - The understanding of physical causality in common marmosets was tested using support problems in which a pair of sheets was presented to determine whether subjects would choose the sheet that had a food item on it (i.e., the sheet was supporting the food item). In two experiments, the conditions were manipulated in terms of the length of the sheet, the distance between the sheet and the food item, the presence of a gap separating the two sheets, and the size of the food item. In Experiment 1, the marmosets had difficulty rejecting an irretrievable food item when it was located closer to them than a retrievable item. Although their performance was strongly affected by the size of the irretrievable food item, they quickly learned to reject that alternative. In contrast, no improvement was found when one sheet was divided into two pieces such that the food item could not be retrieved when its near side was pulled. A similar response tendency was observed in Experiment 2, in which the effects of the large food item were examined in three different conditions. Thus, common marmosets were influenced by the perceptual features of the food in solving the support problems, as are other non-human primates. In addition, they consistently failed to appreciate the presence of a gap and, therefore, failed to reject the distracter alternative. However, all animals rapidly learned that the size of the food item was an irrelevant variable, and some showed an elementary conceptual understanding of support. These findings suggest that marmosets' physical understanding may improve with experience. PMID- 20830499 TI - HCV genotype distribution in Flanders and Brussels (Belgium): unravelling the spread of an uncommon HCV genotype 5a cluster. AB - In order to study the hepatitis C virus (HCV) epidemiology in Flanders, Belgium, the HCV genotype of 2,301 patients diagnosed with HCV between 2001 and 2009 was determined. HCV genotyping was conducted using the Versant LiPA 1.0 or Versant LiPA 2.0 assay. To explore the transmission history of a remarkable cluster of the rarely found HCV genotype 5a, face-to-face interviews based on detailed questionnaires and maximum likelihood phylogenetic analysis were performed. HCV genotype 1 was the most prevalent genotype in all provinces, followed by HCV genotype 3 in East Flanders, Antwerp, Flemish Brabant and Limburg. In Brussels, HCV genotype 4 was the second most prevalent genotype. This observation is due to the immigration of patients from the Middle East and Africa. Remarkably, a cluster of HCV genotype 5a was found in West Flanders, where it represents the second most prevalent genotype, accounting for 26.2% of HCV infections. We could not identify one major transmission source explaining the whole HCV genotype 5a epidemic. Instead, several smaller possible transmission chains were identified and confirmed phylogenetically. Overall, the HCV genotype 5a epidemic in West Flanders seems to be mainly associated with blood transfusion and unsafe medical practices. PMID- 20830500 TI - Chemokines in mesenchymal stem cell therapy for bone repair: a novel concept of recruiting mesenchymal stem cells and the possible cell sources. AB - Skeletal injury is one of the most prevalent clinical problems that jeopardize the activities of daily life, especially in our aging society. Mesenchymal stem cells (MSCs) play pivotal roles in regenerating bones after bone injury. MSCs come from the surrounding tissues and/or circulation. Cell sources may be the bone marrow, periosteum, vessel walls, muscle, circulation, and elsewhere, and the migration of MSCs is necessary for bone healing. The mechanism(s) of recruitment and crucial molecules for cell migration are still unclear, but chemokines and their receptors seem to play critical roles. The induction of MSC recruitment from surrounding tissues or from the circulation can be a helpful modality to induce or to support cell-based therapy for bone regeneration. PMID- 20830501 TI - Tracking PACS usage with open source tools. AB - A typical choice faced by Picture Archiving and Communication System (PACS) administrators is deciding how many PACS workstations are needed and where they should be sited. Oftentimes, the social consequences of having too few are severe enough to encourage oversupply and underutilization. This is costly, at best in terms of hardware and electricity, and at worst (depending on the PACS licensing and support model) in capital costs and maintenance fees. The PACS administrator needs tools to asses accurately the use to which her fleet is being subjected, and thus make informed choices before buying more workstations. Lacking a vended solution for this challenge, we developed our own. PMID- 20830502 TI - Vandetanib with docetaxel as second-line treatment for advanced breast cancer: a double-blind, placebo-controlled, randomized Phase II study. AB - PURPOSE: The aim of this Phase II study was to assess the efficacy and safety of vandetanib in combination with docetaxel in patients with pretreated advanced breast cancer. METHODS: The primary study objective was to compare the number of progression events in patients receiving once-daily oral vandetanib (100 mg) in combination with docetaxel (100 mg/m(2) iv every 21 days) versus placebo plus docetaxel. Sixty-four patients were randomized to receive study treatment (n = 35, vandetanib; n = 29, placebo). RESULTS: A slightly greater number of patients had experienced a progression event by the data cut-off in the vandetanib group (24 [69%]) compared with the placebo group (18 [62%]); HR = 1.19, two-sided 80% CI: 0.79-1.81; two-sided P = 0.59), suggesting that the addition of vandetanib to docetaxel did not affect the risk of disease progression compared with placebo plus docetaxel. The safety and tolerability profile of the combination therapy reflected those of both drugs as monotherapy agents. CONCLUSIONS: In patients with advanced breast cancer, vandetanib plus docetaxel was generally well tolerated. Clinical benefit was not different to that observed with placebo plus docetaxel. However, due to the small patient number it was not possible to yield robust results, further research is required to identify predictive factors for patient selection. PMID- 20830503 TI - Minimizing early relapse and maximizing treatment outcomes in hormone-sensitive postmenopausal breast cancer: efficacy review of AI trials. AB - Breast cancer is one of the leading causes of cancer-related deaths in women. Regardless of prognosis, all women with breast cancer are at risk for early recurrence. Nearly 50% of early recurrences occur within 5 years of surgery, and they peak at 2 years after surgery in women treated with adjuvant tamoxifen. Most early recurrences are distant metastases, which strongly correlate with increased mortality. Treatments that mitigate the risk of early distant metastases (DM) are, therefore, likely to improve overall survival in women with early breast cancer (EBC). Aromatase inhibitors (AIs)--anastrozole, letrozole, and exemestane have been investigated as alternatives to tamoxifen for adjuvant treatment of hormone receptor-positive (HR+) EBC in postmenopausal women (PMW). AIs are better at minimizing risk of early relapse compared with tamoxifen. However, it is not clear if preferential use of AIs over tamoxifen will benefit all PMW with HR+ EBC. The ability to subtype HR+ breast cancer on the basis of biomarkers predictive of response to AIs and tamoxifen would likely be key to determining the most beneficial hormonal treatment within patient subpopulations, but this process requires thorough investigation. Until then, adjuvant therapies that provide the greatest reduction in risk of DM should be considered for all PMW with HR+ EBC. This article reviews the clinical trials of AI adjuvant therapies for hormone-sensitive breast cancer, particularly in the context of how they compare with tamoxifen in minimizing the risk of relapse, occurrence of DM, and breast cancer-related deaths. PMID- 20830504 TI - Regulatory T cells and breast cancer: implications for immunopathogenesis. AB - Current understanding of the role of several cancer risk factors is more comprehensive, as reported for a number of sites, including the brain, colon, breasts, and ovaries. Despite such advances, the incidence of breast cancer continues to increase worldwide. Signals from the microenviroment have a profound influence on the maintenance or progression cancers. Although T cells present the most important immunological response in tumor growth in the early stages of cancer, they become suppressive CD4(+) and CD8(+) regulatory T cells (Tregs) after chronic stimulation and interactions with tumor cells, thus promoting rather than inhibiting cancer development and progression. Tregs have an important marker protein which is FoxP3, though it does not necessarily confer a Treg phenotype when expressed in CD4(+) T lymphocytes. High Treg levels have been reported in peripheral blood, lymph nodes, and tumor specimens from patients with different types of cancer. The precise mechanisms by which Tregs suppress immune cell functions remain unclear, and there are reports of both direct inhibition through cell-cell contact and indirect inhibition through the secretion of anti inflammatory mediators such as interleukin. In this review, we present the molecular and immunological aspects of Treg cells in the metastasis of breast cancer. PMID- 20830505 TI - Characterization of the satellite DNA Msat-160 from species of Terricola (Microtus) and Arvicola (Rodentia, Arvicolinae). AB - In the subfamily Arvicolinae (Cricetidae, Rodentia) the satellite DNA Msat-160 has been so far described in only some species from the genus Microtus and in one species from another genus, Chionomys nivalis. Here we cloned and characterized this satellite in two new arvicoline species, Microtus (Terricola) savii and Arvicola amphibius (terrestris). We have also demonstrated, by PCR and FISH, its existence in the genomes of several other species from both genera. These results suggest that Msat-160 already occurred in the common ancestor of the four genera/subgenera of Arvicolinae (Microtus, Chionomys, Arvicola, and Terricola). In Arvicola and Terricola, Msat-160 showed the basic monomer length of 160 bp, although a higher-order repeat (HORs) of 640 bp could have been probably replacing the original monomeric unit in A. a. terrestris. Msat-160 was localized by FISH mostly on the pericentromeric regions of the chromosomes, but the signal intensity and the number of carrier chromosomes varied extremely even between closely related species, resulting in a species-specific pattern of chromosomal distribution of this satellite. Such a variable pattern most likely is a consequence of a rapid amplification and contraction of particular repeats in the pericentromeric regions of chromosomes. In addition, we proposed that the rapid variation of pericentromeric repeats is strictly related to the prolific species radiation and diversification of karyotypes that characterize Arvicolinae lineage. Finally, we performed phylogenetic analysis in this group of related species based on Msat-160 that results to be in agreement with previously reported phylogenies, derived from other molecular markers. PMID- 20830506 TI - Cyp1B1 mRNA expression in correlation to cotinine levels with respect to the Cyp1B1 L432V gene polymorphism. AB - Cytochrome P450 1B1 (CYP1B1) is involved in the activation of a broad spectrum of procarcinogens. An association of the Cyp1B1 Leu432Val polymorphism with cancer as well as an impact on the enzyme activity has been described. To study gene environmental interactions we investigated the quantitative Cyp1B1 mRNA expression in smokers (N = 102) and non-smokers (N = 192) with regards to the Cyp1B1 L432V gene polymorphism. Tobacco smoke exposure was assessed by serum cotinine levels. Genotypes were analysed by melting curve analysis and quantification of Cyp1B1 mRNA by real-time PCR. In comparing Cyp1B1 expression, significant differences between the two homozygote genotypes *1/*1 and *3/*3 (0.105 +/- 0.019; n = 26 vs. 0.051 +/- 0.017; n = 14; P = 0.039) and between the heterozygote genotype *1/*3 and *3/*3 (0.121 +/- 0.029; n = 55 vs. 0.051 +/- 0.017; n = 14; P = 0.039) of smokers were revealed. According to the serum cotinine levels, three subgroups (low; medium; high) were build. The group "high" (0.248 +/- 0.089; n = 32) showed proportionally high Cyp1B1 mRNA expression compared to "medium" (0.101 +/- 0.024; n = 33), "low" (0.086 +/- 0.015; n = 32) and non-smokers (0.084 +/- 0.007; n = 176). This result was reflected in the homozygote *1/*1 and the heterozygote *1/*3 genotypes. In contrast the homozygote *3/*3 genotype was missing the high Cyp1B1 mRNA expression in the cotinine subgroup "high". Our results suggest that genotypes carrying the C-allele (*1/*1 and *1/*3) at Cyp1B1 Leu432Val polymorphism show a higher response to environmental factors, such as tobacco smoke than homozygote *3/*3 genotypes. PMID- 20830507 TI - A systematic review evaluating the methodological aspects of meta-analyses of genetic association studies in cancer research. AB - Meta-analyses and Individual Patient Data (IPD) meta-analyses of genetic association studies are a powerful tool to summarize the scientific evidences, however their application present considerable potential and several pitfalls. We reviewed systematically all published meta-analyses and IPD meta-analyses of genetic association studies in the field of cancer research, searching for relevant studies on the Medline, Embase, and HuGE Reviews Archive databases until January 2009. The association between selected predictors of methodological quality and the year of publication was also evaluated. 144 meta-analyses involving 299 gene-disease associations, and 25 IPD meta-analyses on 83 gene disease were included. Overall quality of the reports showed a substantial improvement over time, as authors have become more inclusive of primary papers published in all languages since 2005 (P-value = 0.087), as well as statistical heterogeneity and publication bias were evaluated more systematically. Only 35.4% of the meta-analyses, however, adopted a comprehensive bibliographic search strategy to identify the primary reports, 63.9% did not specify the language of the included studies, 39.8% did not test for Hardy-Weinberg Equilibrium (HWE), while 62.2 and 75.9% of the meta-analyses and IPD meta-analyses, respectively, did not declare the scientific rationale for the genetic model chosen. Additionally, the HWE assessment showed a substantial decreasing trend over time (P-value = 0.031) while publication bias was more often evaluated when statistical heterogeneity was actually present (P-value = 0.007). Although we showed a general methodological improvement over time, guidelines on conducting and reporting meta-analyses of genetic association studies are needed to enhance their methodological quality. PMID- 20830508 TI - Cardioprotection by ischemic postconditioning is abolished in depressed rats: role of Akt and signal transducer and activator of transcription-3. AB - Ischemic postconditioning (IPC) represents one of the most effective cardioprotective strategies against myocardial ischemia/reperfusion. Depression is commonly present in patients with coronary heart disease. However, whether depression interferes with the cardioprotection of IPC during myocardial ischemia/reperfusion and their underlying mechanisms remain largely unknown. Isolated hearts from chronic mild stress induced-depressed rats and non-depressed rats were subjected to 30 min of regional ischemia followed by 120 min of reperfusion in the presence or absence of IPC (consisting of 6 cycles of 10 s of reperfusion and 10 s of ischemia immediately after the sustained ischemia). Myocardial infarct size, creatine kinase (CK) and cardiac troponin T (cTnT) release, cardiac function and phosphorylated AKT and signal transducer and activator of transcription-3 (STAT-3) were measured. IPC significantly prevented the hearts from myocardial ischemia/reperfusion injury by decreasing infarct size, and CK and cTnT release in coronary effluent, and improving cardiac functional recovery in non-depressed rats. However, these cardioprotective effects of IPC were not observed in depressed rats. In addition, IPC had no effects on the phosphorylation of AKT and STAT-3 at reperfusion in depressed hearts, although it markedly increased the phosphorylation of AKT and STAT-3 at reperfusion in non-depressed hearts. In conclusion, these data indicate that cardioprotection by IPC is abolished during myocardial ischemia/reperfusion in depressed rats, and the underlying mechanisms are probably related to the impaired activation of AKT and STAT-3 at reperfusion. PMID- 20830509 TI - ACE gene polymorphism and serum ACE activity in Iranians type II diabetic patients with macroalbuminuria. AB - There are controversial results related to the contribution of insertion (I)/deletion (D) polymorphism of the angiotensin I-converting enzyme (ACE) in the development of diabetic nephropathy. To assess the distribution of this polymorphism in diabetic patients with and without nephropathy we studied 140 unrelated type 2 diabetic patients from the Kermanshah Province of Iran with ethnic background of Kurds including 68 patients with macroalbuminuria and 72 normoalbuinuric diabetic patients as controls. Genotyping was done by polymerase chain reaction (PCR). The frequency of D allele in nephropathic and normoalbuminuric patients were 69.1 and 58.3%, respectively (P = 0.061). In individuals with DD genotype the risk of macroalbuminuria increased 2.87-fold (P = 0.057). Significant lower level of serum ACE activity was found in the normoalbuminuric (59.76 IU/l) compared to macroalbuminuric (97.43 IU/l) patients. The serum ACE activity was significantly higher in macroalbuminuric patients with ID (105.7 IU/l) and ID + DD (100.7 IU/l) genotypes compared to normoalbuminuric patients with the same genotypes (63.5 and 64.2 IU/l, respectively). Treatment with captopril significantly (P = 0.045) reduced the serum ACE activity in normoalbuminuric patients with DD genotype compared to macroalbuminuric patients with the same genotype (33.6 vs. 73.8 IU/l). However, the greatest benefit effect of losartan therapy on ACE activity was observed only in macroalbuminuric patients with DD genotype compared to that in normoalbuminuric patients (61.0 vs. 109.0 IU/l, P = 0.06). Our study suggests the importance of ethnic origin in the development of diabetic nephropathy and demonstrates different responses to therapy according to genotype and stage of diabetes. PMID- 20830511 TI - Maternal control of child feeding during the weaning period: differences between mothers following a baby-led or standard weaning approach. AB - A controlling maternal feeding style has been shown to have a negative impact on child eating style and weight in children over the age of 12 months. The current study explores maternal feeding style during the period of 6-12 months when infants are introduced to complementary foods. Specifically it examines differences between mothers who choose to follow a traditional weaning approach using spoon feeding and purees to mothers following a baby-led approach where infants are allowed to self feed foods in their solid form. Seven hundred and two mothers with an infant aged 6-12 months provided information regarding weaning approach alongside completing the Child Feeding Questionnaire. Information regarding infant weight and perceived size was also collected. Mothers following a baby-led feeding style reported significantly lower levels of restriction, pressure to eat, monitoring and concern over child weight compared to mothers following a standard weaning response. No association was seen between weaning style and infant weight or perceived size. A baby-led weaning style was associated with a maternal feeding style which is low in control. This could potentially have a positive impact upon later child weight and eating style. However due to the cross sectional nature of the study it cannot be ascertained whether baby-led weaning encourages a feeding style which is low in control to develop or whether mothers who are low in control choose to follow a baby-led weaning style. PMID- 20830510 TI - Endocrine disruptors provoke differential modulatory responses on androgen receptor and pregnane and xenobiotic receptor: potential implications in metabolic disorders. AB - A systematic comparison of the impact of some potential endocrine disruptors (EDs) on modulation of androgen receptor (AR) and pregnane and xenobiotic receptor (PXR) function was conducted in a multi-step analysis. Promoter-reporter based transcription assays were performed in conjunction with receptor dynamic studies in living cells that helped implicating the suspected EDs for their deleterious effects. We demonstrate that most of the selected EDs not only inhibit AR transcriptional activity, but also alter its subcellular dynamics. Conversely, some of these anti-androgenic compounds were potent activator of xeno sensing nuclear receptor, PXR. Interestingly, agonist-activated AR that associates with the mitotic chromatin fails to achieve this association when bound to anti-androgenic EDs. Conclusively, most EDs (except BCH) behaved like pure antagonist for AR while as agonist for PXR. Subsequent experiments with DDT treatment in mice model indicated that in testis AR and its regulated genes PEM and ODC levels are down-regulated, whereas in liver of same mice PEM is up regulated while AR and ODC remain unchanged. On the contrary, PXR and its regulated genes CYP3A11 and MDR1 levels in mice liver were up-regulated while in testis PXR remained unchanged, CYP3A11 up-regulated and MDR1 were down-regulated. Based on a novel "Biopit" concept it is speculated that long-term exposure to endocrine disrupting chemicals may influence the epigenetic profile of target cells via transcription factors thereby making them vulnerable to onset of chemically induced endocrine-related malignancies or metabolic disorders. PMID- 20830512 TI - A network of spiking neurons that can represent interval timing: mean field analysis. AB - Despite the vital importance of our ability to accurately process and encode temporal information, the underlying neural mechanisms are largely unknown. We have previously described a theoretical framework that explains how temporal representations, similar to those reported in the visual cortex, can form in locally recurrent cortical networks as a function of reward modulated synaptic plasticity. This framework allows networks of both linear and spiking neurons to learn the temporal interval between a stimulus and paired reward signal presented during training. Here we use a mean field approach to analyze the dynamics of non linear stochastic spiking neurons in a network trained to encode specific time intervals. This analysis explains how recurrent excitatory feedback allows a network structure to encode temporal representations. PMID- 20830513 TI - Sex, condoms and sexually transmissible infections: a qualitative study of sexual health in young Australian men. AB - Young males have a key role in shaping contraceptive use in a sexual relationship, yet often remain the invisible partner in safe sex promotion. This article describes a conceptual model of STI risk and condom use based on the perceptions and experiences of condom use in a group of young Australian males. An explorative descriptive design was used to conceptualize participants' condom use histories into an organized description of behavior. Forty-two semi structured interviews were conducted with a purposive sample of males aged 15 to 25 years over an 18 month period. A sequential analytical process of data immersion, coding, and category generation was used to identify personal meanings, motivations, and contextual factors associated with condom use and non use. Three primary discourses associated with young males' perceptions of STI risk and responding approach to condom use constructed personal commitment to sexual safety as dynamic, context-dependent, and outcome-driven (pregnancy versus STIs as the primary motivator of condom use). A regretful discourse associated with experiences of, or suspected unwanted outcomes, also emerged through changes in risk appraisals and safe sex intentions and behavior. Interventions to increase condom use should go beyond the traditional focus on risky behavior and disease prevention frameworks by addressing the contextual influences on personal risk appraisals and deliver innovative messages to reduce negative social meanings associated with condom use. PMID- 20830514 TI - Individual responses to chemotherapy-induced oxidative stress. AB - Differences in redox homeostatic control between cancer patients may underlie predisposition to drug resistance and toxicities. To evaluate interindividual differences in redox response among newly diagnosed breast cancer patients undergoing standard chemotherapy, urine samples were collected before (T0), and at 1 (T1) and 24 h (T24) after chemotherapy administration. Oxidative status was assessed by urinary levels of allantoin and four F2-isoprostanes, quantified by LC-MS/MS. In all subjects, biomarker levels increased at T1 and returned to baseline at T24. Analyzing individual responses, two patterns were revealed: 10 subjects showed uniform increases of biomarker levels at T1 ("increase" pattern) and 8 subjects showed mixed (increase/unchanged/decrease) responses for different biomarkers ("mixed" pattern). The increase-pattern group had lower pre-treatment (T0) levels of the biomarkers and showed a sharp increase at T1 (64-141%) with a subsequent decrease at T24. The mixed-pattern group had higher pre-treatment biomarker levels and showed no change in biomarkers either at T1 or at T24. These findings indicate that there may be at least two distinct redox phenotypes with different homeostatic mechanisms balancing oxidative stress in humans. Recognizing redox phenotypes in human populations may lead to more precise assessment of health risks and benefits associated with individual redox make-up, and may also help to identify cancer patients who are especially susceptible to drug resistance and/or drug toxicity. PMID- 20830515 TI - Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo. AB - In breast cancer, there is a correlation between tissue factor (TF) expression, angiogenesis and disease progression. TF stimulates tumour angiogenesis, in part, through up-regulation of vascular endothelial growth factor (VEGF). Therefore, this study aimed to establish whether TF stimulates angiogenesis and tumour progression directly and independent of VEGF up-regulation. Initially, the effects of TF and VEGF were assessed on endothelial cell migration (Boyden chamber) and differentiation (tubule formation on Matrigel). Subsequently, MDA-MB 436 breast cancer cells, which produce high levels of both TF and VEGF (western blot analysis), were established in vivo, following which tumours were treated three times per week for 3 weeks with intra-tumoural injections of either anti VEGF siRNA, anti-TF shRNA, the two treatments combined, or relevant controls. Both VEGF and TF significantly stimulated endothelial cell migration and tubule formation (P < 0.02). Breast cancer xenografts (MDA-MB-436) treated with TF or VEGF-specific agents demonstrated significant inhibition in tumour growth (VEGFsiRNA 61%; final volume: 236.2 +/- 23.2 mm(3) vs TFshRNA 89%; 161.9 +/- 17.4 mm(3) vs combination 93%; 136.3 +/- 9.2 mm(3) vs control 400.4 +/- 32.7 mm(3); P < 0.005). Microvessel density (MVD), a measure of angiogenesis, was also significantly inhibited in all groups (MVD in control = 29 +/- 2.9; TFshRNA = 18 +/- 1.1; VEGFsiRNA = 16.7 +/- 1.5; both = 12 +/- 2.1; P < 0.004), whereas the proliferative index of the tumours was only reduced in the TFshRNA-treated groups (control = 0.51 +/- 0.011; TFshRNA = 0.41 +/- 0.014; VEGFsiRNA = 0.49 +/- 0.013; both = 0.41 +/- 0.004; P < 0.008). These data suggest that TF has a direct effect on primary breast cancer growth and angiogenesis, and that specific inhibition of the TF-signalling pathway has potential for the treatment of primary breast cancer. PMID- 20830516 TI - Changes in the area of inland lakes in arid regions of central Asia during the past 30 years. AB - Inland lakes are major surface water resource in arid regions of Central Asia. The area changes in these lakes have been proved to be the results of regional climate changes and recent human activities. This study aimed at investigating the area variations of the nine major lakes in Central Asia over the last 30 years. Firstly, multi-temporal Landsat imagery in 1975, 1990, 1999, and 2007 were used to delineate lake extents automatically based on Normalized Difference Water Index (NDWI) threshold segmentation, then lake area variations were detailed in three decades and the mechanism of these changes was analyzed with meteorological data and hydrological data. The results indicated that the total surface areas of these nine lakes had decreased from 91,402.06 km(2) to 46,049.23 km(2) during 1975-2007, accounting for 49.62% of their original area of 1975. Tail-end lakes in flat areas had shrunk dramatically as they were induced by both climate changes and human impacts, while alpine lakes remained relatively stable due to the small precipitation variations. With different water usage of river outlets, the variations of open lakes were more flexible than those of other two types. According to comprehensive analyses, different types of inland lakes presented different trends of area changes under the background of global warming effects in Central Asia, which showed that the increased human activities had broken the balance of water cycles in this region. PMID- 20830517 TI - Determination of redox potential of sulfidic groundwater in unconsolidated sediments by long-term continuous in situ potentiometric measurements. AB - This study was undertaken to investigate the redox potential (Eh) of sulfidic groundwater in unconsolidated sediments. The Eh was determined by long-term (several days to several weeks) continuous in situ potentiometric measurements using a platinum (Pt) electrode. The Eh values measured in two monitoring campaigns were -259 and -202 mV, respectively. Chemical analysis of groundwater showed that the redox species in the groundwater were sulfide (S2-) and iron, respectively. The saturation indices calculated from the chemical analysis results indicated that FeS(am) and mainly mackinawite were close to equilibrium in the analyzed waters. Comparison of the measured Eh values with those calculated using different redox couples revealed that the Eh values measured in the first monitoring campaign were nearly equal to those calculated using HS /SO42-, S2-/SO42-, FeS(am)/SO42-, and mackinawite/SO42- redox couples; on the other hand, the Eh values measured in the second monitoring campaign were almost consistent with those measured using the FeS2/SO42- redox couple. The good fit between the measured Eh values and the theoretical calculated Eh values suggests that the sulfur system is related to the Eh value of sulfidic groundwater in unconsolidated sediments. PMID- 20830518 TI - Distribution pattern of plant species diversity in the mountainous region of Ili River Valley, Xinjiang. AB - In this paper, detrended canonical correspondence analysis was performed to analyze the relationships between diversity indices and environmental gradients, generalized additive model was employed to modal the response curves of diversity indices to the elevation, based on data from field investigation in the mountainous region of the Ili River Valley and a survey of 94 sample plots. Two hundred fifty-nine plant species were recorded in the 94 sample plots investigated, up to 235 species all appeared in the herb layer, and the species of woody plants were very limited. The communities with a complicated vertical structure presented higher values of indices. The distribution pattern of plant species diversity on the northern slope was affected by such factors as elevation, slope aspect, slope gradient, total nitrogen, total potassium, soil water content, organic matter, and that on the southern slope was mainly affected by such factors as slope gradient, elevation, available phosphorus, and soil water content. On the northern slope, Patrick index and Shannon-Wiener index of the plant communities presented a bimodality pattern along altitude; Simpson index and Pielou index showed a partially unimodal pattern. On the southern slope all the distribution pattern of species diversity indices showed two peaks, though Patrick index's bimodality pattern was not an obvious one. These altitudinal patterns were formed by the synthetic action of a variety of environmental factors with elevation playing an important role. PMID- 20830519 TI - Domino Michael-O-alkylation: one-pot synthesis of dialkyl 4-oxo-2,3-dihydro-2,3 furandicarboxylates. AB - The KSCN-catalyzed reaction of dialkyl acetylenedicarboxylates with pentane-2,4 dione in acetone, led to dialkyl 2-(1-acetyl-2-oxopropyl)-2-butenedioates in excellent yields. When these reactions were carried out in MEK (butane-2-one), dialkyl 4-oxo-2,3-dihydro-2,3-furandicarboxylates were obtained exclusively. This difference in reactivity is discussed in terms of the possibility of cationic exchange in butane-2-one. PMID- 20830520 TI - Investigation of selected biochemical indicators of Equine Rhabdomyolysis in Arabian horses: pro-inflammatory cytokines and oxidative stress markers. AB - A total of 30 horses were divided into two groups, one served as a control whereas other was rhabdomyolysis diseased horses. After blood collection, the resulted sera were used for estimation of the activities of creatin kinase (CK), aspartate transaminase (AST), lactate dehydrogenase (LDH), lactic acid, triacylglycerol (TAG), glucose, total protein, albumin, globulin, urea, creatinine, Triiodothyronine (T(3)), calcium, sodium, potassium, phosphorus, chloride, vitamin E, interleukin-6 (IL-6) and tumor necrosis-alpha (TNF-alpha). In addition, whole blood was used for determination of selenium, reduced glutathione (G-SH) and prostaglandin F2-alpha (PGF2alpha). The erythrocyte hemolysates were used for the determination of the activities of super oxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), nitric oxide (NO) and malondialdehyde (MDA). The present findings revealed a significant (p <= 0.05) increase in the values of CK, AST, LDH, glucose, lactate, TAG, urea, creatinine, phosphorus, MDA, TNF- alpha, IL6 and PGF2- alpha in diseased horses when compared with the control. Furthermore, the values of calcium, SOD, CAT, TAC, NO and GSH in diseased horses were significantly (p <= 0.05) lower than the control. The other examined parameters were not statistically significant. In conclusion, the examined pro-inflammatory cytokines were useful biomarkers for the diagnosis of Equine rhabdomyolysis (ER) in Arabian horses beside the old examined biomarkers. In the future, efforts should be made to confirm this in other breed. If this could be achieved, it would open up new perspectives in research fields dealing with ER. PMID- 20830521 TI - Comparison and causes of transfer from one dialysis modality to another. AB - AIM: To evaluate the patients transferred from one dialysis modality to another and to compare the patient characteristics on both renal replacement modalities. PATIENTS AND METHOD: The data of dialysis patients, who were followed up between January 2000 and December 2009 in our nephrology department, was evaluated retrospectively. Fifty-seven patients were transferred from HD to PD (Group 1) and 94 patients were transferred from PD to HD (Group 2) were included in this study. We recorded patients' demographic, clinical, and laboratory findings, and the cause of transfer from HD to PD or from PD to HD. RESULTS: The mean age of the patients was 52.1 +/- 14.1 years. Eighty-four of the 151 patients were men and 67 were women. The etiology of end-stage renal failure was diabetes mellitus and hypertension in most of the patients. The causes of transfer from HD to PD were vascular access problems in 37 (64.9%), patient preference in 8 (14.0%), cardiovascular problems in 7 (12.3%), inadequate dialysis in 4 (7.0%) patients, and unknown in 1 (1.8%) patient. On the other hand, the causes of transfer from PD to HD were refractory peritonitis in 61 (64.9%), catheter-related problems in 14 (14.9%), inadequate dialysis in 8 (8.5%), increased intraabdominal pressure related problems in 7 (7.4%), patient preference in 2 (2.1%), and ultrafiltration failure in 2 (2.1%) patients. Alkaline phosphatase and calcium * phosphorus products were significantly higher in Group 1 compared to Group 2. The presence of diabetes mellitus, Kt/V(urea), and 24-h residual urine volume were significantly higher in Group 2 than in Group 1. There was no significant difference in terms of other parameters. CONCLUSION: Vascular access problems were the most frequent cause of transfer from HD to PD. On the other hand, the most frequent cause of transfer from PD to HD was refractory peritonitis. Preservation of residual urine volume was better in PD patients compared to HD patients. PMID- 20830523 TI - Treatment of cobalamin C (cblC) deficiency during pregnancy. AB - OBJECTIVE: To report the successful pregnancy of a woman with methylmalonic acidemia and hyperhomocysteinemia, cblC type [cobalamin C (cblC) deficiency] (MIM 277400). METHOD: Retrospective chart review. RESULTS: A 24-year-old woman presented at 14 weeks gestation with nausea, self-restricted protein diet, and weight loss. She had a past history of asymptomatic methylmalonic acidemia but had been lost to follow-up since the age of 15 years. Biochemical evaluation revealed combined methylmalonic acidemia and hyperhomocysteinemia. Complementation analysis confirmed cblC deficiency. One copy of the most common mutations in the MMACHC gene, c.271dupA, was identified. The women was treated from 15 weeks of gestation with a low protein diet (64 g/day) (1.1 g /kg of weight/day), L-carnitine (1 g per os 3 times daily to 3 g per os 3 times daily in the third trimester), aspirin (salicylic acid) 80 mg per day, folic acid 5 mg per day, and hydroxocobalamin 1 mg intramuscular every week to two times per week in the third trimester. The pregnancy was uneventful and the delivery at term. The newborn was healthy at delivery and at follow-up. CONCLUSION: We report on the successful outcome of pregnancy in a treated woman with cblC disease. The pregnancy was uneventful for both fetus and mother with the delivery of a term healthy boy. There is a need for an international registry on the management and outcomes of pregnancy in women with inborn errors of metabolism. PMID- 20830524 TI - Long-term follow-up results in enzyme replacement therapy for Pompe disease: a case report. AB - Pompe disease (PD) is a metabolic myopathy caused by a deficiency of acid-alpha glucosidase (GAA), a lysosomal enzyme that cleaves glycogen. The classic infantile-onset form is characterised by severe hypotonia and cardiomyopathy. Untreated patients usually die within the first year of life due to cardiorespiratory failure. Several studies involving patients with infantile onset PD have shown that enzyme replacement therapy (ERT) with alglucosidase alfa, recombinant human GAA (rhGAA), significantly prolongs survival, decreases cardiomegaly, and improves cardiac function and conduction abnormalities. However, the efficacy on motor, cognitive and social milestones appears to be more related to the condition of the patient before the start of treatment. To date, the sample of early diagnosed and treated patients is small and the length of follow-up is still limited. We report the results of a long-term follow-up of one patient presenting severe bradycardia and cardiomyopathy at birth, diagnosed in the third day of life and successfully treated by ERT. Serum muscle enzymes at diagnosis were AST 200 U/L, ALT 99 U/L and CPK 731 U/L (n.v. 0-295); the molecular study identified the homozygous missense mutation c.1933 G> A p.Asp645Asn (GAA exon 14). Left Ventricular Mass Index (LVMI) at baseline was 171 g/m(2) (Z-score = 4.3) and decreased to normal values since the 3-month follow up. A muscle biopsy performed at 18 months after the start of therapy, showed only a low degree of muscle involvement. To our knowledge, this is the longest ERT treatment follow-up in a symptomatic neonatal patient with Pompe disease. PMID- 20830525 TI - Fatty acid profile in patients with phenylketonuria and its relationship with bone mineral density. AB - BACKGROUND: Patients with phenylketonuria (PKU) undergo a restrictive vegan-like diet, with almost total absence of n-3 fatty acids, which have been proposed as potential contributors to bone formation in the healthy population. The PKU diet might lead these patients to bone mass loss and, consequently, to the development of osteopenia/osteoporosis. Therefore, we proposed to analyze their plasma fatty acid profile status and its relationship with bone health. METHODS: We recruited 47 PKU patients for this cross-sectional study and divided the cohort into three age groups (6-10 years, 11-18 years, 19-42 years). We measured their plasma fatty acid profile and bone mineral density (BMD) (both at the femoral neck and the lumbar spine). Seventy-seven healthy controls also participated as reference values of plasma fatty acids. RESULTS: Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and total n-3 fatty acids were significantly diminished in PKU patients compared with healthy controls. DHA, EPA, and total n 3 fatty acids were also positively associated with bone mineral density (r = 0.83, p = 0.010; r = 0.57, p = 0.006; r = 0.73, p = 0.040, respectively). There was no association between phenylalanine (Phe), Index of Dietary Control (IDC), calcium, 25-hydroxivitamin D concentrations, daily calcium intake, and BMD. CONCLUSION: Our results suggest a possible influence of essential fatty acids over BMD in PKU patients. The lack of essential n-3 fatty acids intake in the PKU diet might affect bone mineralization. Further clinical trials are needed to confirm the effect of the n-3 essential fatty acids on bone accrual in a cohort of PKU patients. PMID- 20830526 TI - Current issues regarding treatment of mitochondrial fatty acid oxidation disorders. AB - Treatment recommendations in mitochondrial fatty acid oxidation (FAO) defects are diverse. With implementation of newborn screening and identification of asymptomatic patients, it is necessary to define whom to treat and how strictly. We here discuss critical questions that are currently under debate. For some asymptomatic long-chain defects, long-chain fat restriction plays a minor role, and a normal diet may be introduced. For patients presenting only with myopathic symptoms, e.g., during exercise, treatment may be adapted to energy demand. As a consequence, patients with exercise-induced myopathy may be able to return to normal activity when provided with medium-chain triglycerides (MCT) prior to exercise. There is no need to limit participation in sports. Progression of retinopathy in disorders of the mitochondrial trifunctional protein complex is closely associated with hydroxyacylcarnitine accumulation. A strict low-fat diet with MCT supplementation is recommended to slow or prevent progression of chorioretinopathy. Additional docosahexanoic acid does not prevent the decline in retinal function but does promote nonspecific improvement in visual acuity and is recommended. There is no evidence that L-carnitine supplementation is beneficial. Thus, supplementation with L-carnitine in a newborn identified by screening with either a medium-chain or long-chain defect is not supported. With respect to the use of the odd-chain medium-chain triglyceride triheptanoin in myopathic phenotypes, randomized trials are needed to establish whether triheptanoin is more effective than even-chain MCT. With increasing pathophysiological knowledge, new treatment options have been identified and are being clinically evaluated. These include the use of bezafibrates in myopathic long-chain defects. PMID- 20830527 TI - Modulating malignant epithelial tumor cell adhesion, migration and mechanics with nanorod surfaces. AB - The failure of tumor stents used for palliative therapy is due in part to the adhesion of tumor cells to the stent surface. It is therefore desirable to develop approaches to weaken the adhesion of malignant tumor cells to surfaces. We have previously developed SiO2 coated nanorods that resist the adhesion of normal endothelial cells and fibroblasts. The adhesion mechanisms in malignant tumor cells are significantly altered from normal cells; therefore, it is unclear if nanorods can similarly resist tumor cell adhesion. In this study, we show that the morphology of tumor epithelial cells cultured on nanorods is rounded compared to flat surfaces and associated with decreased cellular stiffness and non-muscle myosin II phosphorylation. Tumor cell viability and proliferation was unchanged on nanorods. Adherent cell numbers were significantly decreased while single tumor cell motility was increased on nanorods compared to flat surfaces. Together, these results suggest that nanorods can be used to weaken malignant tumor cell adhesion, and therefore potentially improve tumor stent performance. PMID- 20830528 TI - Aging-related kidney damage is associated with a decrease in klotho expression and an increase in superoxide production. AB - The purpose of this study was to determine changes in klotho, endothelin (ET) receptors, and superoxide production in kidneys of aged rats and whether these changes are exacerbated in aged rats with cognitive impairment. Twenty aged rats (male, 27 months) were divided into an Old Impaired group (n=9) and an Old Intact group (n=11) according to a cognitive function test. A group of 12-month-old rats (n=10) was used as a Young Intact group. Serum creatinine was increased significantly in the Old Impaired group, suggesting impaired renal function. Aged rats showed glomerulosclerosis and tubulointerstitialfibrosis. These pathological changes were markedly aggravated in the old cognitively impaired than in the old cognitively intact animals. Notably, aged rats demonstrated a significant decrease in klotho protein expression in renal cortex and medulla. Protein expression of IL-6, Nox2, ETa receptors and superoxide production were increased whereas mitochondrial SOD (MnSOD) and ETb receptors expression were decreased in kidneys of the aged rats. Interestingly, these changes were more pronounced in the old impaired than in the old intact rats. In conclusion, the aging-related kidney damage was exacerbated in aged rats with cognitive impairment. Klotho, ETB, and MnSOD were downregulated but ETa, IL-6, Nox2, and superoxide production were upregulated in the aging-related kidney damage. These changes were more pronounced in rats with cognitive impairment. PMID- 20830529 TI - Dietary lecithin source affects growth potential and gene expression in Sparus aurata larvae. AB - Soybean lecithin (SBL), used as a phospholipid source in larval fish diets, may compromise growth and survival in marine species, and affect gene expression, due to differences in fatty acid composition relative to marine lecithins (ML). The potential of SBL as a phospholipid source in gilthead seabream microdiets as compared to ML was evaluated. Two stocking densities were tested in order to exacerbate possible dietary effects: 5 and 20 larvae L(-1). Larvae reflected dietary fatty acid profiles: linoleic acid was higher, whereas eicosapentaenoic and arachidonic acids were lower in SBL fed groups than in ML fed larvae. Highest stocking density decreased survival, and led to elevated saturates and lower docosahexaenoic acid levels in polar lipid. Muscle histology observations showed hindered growth potential in SBL fed larvae. Despite similar cortisol levels between treatments, higher glucocorticoid receptor (GR), as well as hormone sensitive lipase (HSL) mRNA levels in SBL fed groups revealed a role for fatty acids in gene regulation. Further analysed genes suggested these effects were independent from the hypothalamus-pituitary-interrenal axis control and the endocannabinoid system. Cyclooxygenase-2 and gluconeogenesis seemed unaffected. For the first time in fish, a link between dietary lecithin nature and HSL gene transcription, perhaps regulated through GR fatty acid-induced activation, is suggested. Enhanced lipolytic activity could partly explain lower growth in marine fish larvae when dietary ML is not provided. PMID- 20830530 TI - The preoperative manometric pattern predicts the outcome of surgical treatment for esophageal achalasia. AB - BACKGROUND: A new manometric classification of esophageal achalasia has recently been proposed that also suggests a correlation with the final outcome of treatment. The aim of this study was to investigate this hypothesis in a large group of achalasia patients undergoing laparoscopic Heller-Dor myotomy. METHODS: We evaluated 246 consecutive achalasia patients who underwent surgery as their first treatment from 2001 to 2009. Patients with sigmoid-shaped esophagus were excluded. Symptoms were scored and barium swallow X-ray, endoscopy, and esophageal manometry were performed before and again at 6 months after surgery. Patients were divided into three groups: (I) no distal esophageal pressurization (contraction wave amplitude <30 mmHg); (II) rapidly propagating compartmentalized pressurization (panesophageal pressurization >30 mmHg); and (III) rapidly propagating pressurization attributable to spastic contractions. Treatment failure was defined as a postoperative symptom score greater than the 10th percentile of the preoperative score (i.e., >7). RESULTS: Type III achalasia coincided with a longer overall lower esophageal sphincter (LES) length, a lower symptom score, and a smaller esophageal diameter. Treatment failure rates differed significantly in the three groups: I = 14.6% (14/96), II = 4.7% (6/127), and III = 30.4% (7/23; p = 0.0007). At univariate analysis, the manometric pattern, a low LES resting pressure, and a high chest pain score were the only factors predicting treatment failure. At multivariate analysis, the manometric pattern and a LES resting pressure <30 mmHg predicted a negative outcome. CONCLUSION: This is the first study by a surgical group to assess the outcome of surgery in 3 manometric achalasia subtypes: patients with panesophageal pressurization have the best outcome after laparoscopic Heller-Dor myotomy. PMID- 20830531 TI - Changes of relative weight and cell cycle, and lesions of bursa of Fabricius induced by dietary excess vanadium in broilers. AB - The purpose of this 42-day study was to investigate the effects of dietary excess vanadium on immune function by determining the morphological changes and cell cycle of bursa of Fabricius, and the serum Ig contents. A total of 420 one-day old avian broilers were divided into six groups and fed on a corn-soybean basal diet as control diet, or the same diet amended to contain 5, 15, 30, 45, and 60 ppm vanadium supplied as ammonium metavanadate. When compared with that of control group, the relative weight of bursa was significantly increased in the 15 ppm group from 14 to 35 days of age and increased in the 5 ppm group at 42 days of age, and significantly decreased in the 60 ppm group from 14 to 42 days of age and decreased in 30 and 45 ppm groups from 35 to 42 days of age. Pathological lesions progressed as the dietary vanadium increased. The gross lesions of bursa showed obvious atrophy with decreased volume and pale color in 45 and 60 ppm groups. Histopathologically, widened cortex and increased number of lymphocytes appeared in 5 and 15 ppm groups, and reduced lymphocytes and connective tissue hyperplasia appeared in 45 and 60 ppm groups. The bursal cells in static phase (G(0)/G(1)) were decreased, and those in the mitotic phase (G(2) + M) and the proliferating index (PI) were increased in 5 and 15 ppm groups. However, bursal cells in the G(0)/G(1) phase were increased, and those in G(2) + M phase, synthesis phase (S) and the PI were decreased in 45 and 60 ppm groups. Also, the serum IgG and IgA contents were increased in 5 and 15 ppm groups, and the serum IgG, IgA, and IgM contents were decreased in 45 and 60 ppm groups. These results suggested that dietary excess vanadium (45 and 60 ppm) could inhibit growth of bursa of Fabricius and impair humoral immunity in chicken. PMID- 20830532 TI - Lymphoma of the breast in a male patient. AB - Primary lymphoma of the breast is very rare especially in a male patient. Treatment alternatives include surgery, chemotherapy, immunotherapy and radiation. It is still controversial which combination is the best. Here, we report a male patient who presented with a left breast mass. The excisional biopsy was applied, and pathological assessment revealed marginal zone lymphoma. Both conventional computed tomography and 18)F-Fluorodeoxyglucose positron emission tomography/computed tomography were used for staging. The clinical stage was IIE for Ann Arbor staging and so local radiation following chemo immunotherapy was planned. Left-sided primary breast lymphoma in a male patient is a very rare entity. Treatment modalities are still controversial. Some authors believe that primary breast lymphomas have poor prognosis, and they must be treated aggressively with combined treatment modalities. Another important point is that 18)F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET)/CT could be used for staging of disease and assessing treatment response in a patient with primary breast marginal zone lymphoma. PMID- 20830533 TI - Approach to the child with coma. AB - Coma and other states of impaired consciousness represent a medical emergency. The potential causes are numerous, and the critical window for diagnosis and effective intervention is often short. The common causes of non-traumatic coma include central nervous system infections, metabolic encephalopathy (hepatic, uremic, diabetic ketoacidosis etc.), intracranial bleed, stroke and status epilepticus. The basic principles of management include 1) Rapid assessment and stabilization, 2) Focussed clinical evaluation to assess depth of coma, localization of lesion in the central nervous system and possible clues to etiology, and 3) Treatment including general and specific measures. Commonly associated problems such as raised intracranial pressure and seizures must be recognized and managed to prevent secondary neurologic injury. PMID- 20830534 TI - The effects of early parenteral amino acids on sick premature infants. AB - OBJECTIVES: To study the effects of early parenteral amino acid administration on body weight, fluid compartments and metabolic parameters during the first week of life in sick premature infants. METHODS: Appropriate for gestational age, sick premature infants were randomized into two groups. Group A infants (n=8, birth weight 1258+/-339 g) were supplemented with amino acids starting within 24 h of birth and advanced to 2.5 g/kg per day by day 3. Group G infants (n=9, birth weight 1182+/-214 g) received amino acids starting on day 4 of life. Energy intake was comparable in the 2 groups. Amino acid concentrations and nitrogen balance studies were performed on day 3 of life. Total body water and extracellular water were measured on day 1 and 8 and change in intracellular volume was calculated. RESULTS: There was no significant difference between the 2 groups in terms of weight, intracellular volume change from day 1 to day 8 of life, despite a significant (P<0.01) difference in protein intake. Plasma ammonia levels were comparable in the 2 groups, but plasma urea levels were significantly higher in group A vs. group G infants (7.2+/-3.4 mmol/L vs. 3.2+/-1.2 mmol/L respectively, P<0.01). Nitrogen balance was positive in all group A infants and negative in group G infants. Nitrogen loss was inversely correlated with energy intake in group G infants (P<0.05). The mean plasma amino acid concentrations in group A infants (compared to those of group G) were within previously reported ranges in older premature infants. CONCLUSIONS: There was no significant effect on body weight and redistribution of body fluid compartments in infants receiving amino acids early during the first week of life. Serum urea concentrations were significantly higher in infants receiving early amino acids. Nitrogen losses in infants who did not receive amino acids were inversely correlated with energy intake during the first 3 days of life. PMID- 20830535 TI - Efficacy of pyridoxine in early-onset idiopathic intractable seizures in children. AB - OBJECTIVE: To identify pyridoxine responsive seizures among children with early onset intractable seizures, and to identify pyridoxine-dependency as a subset in this group. METHODS: Patients with neonatal onset idiopathic, intractable seizures were identified over a 6-month period and subjected to a 'pyridoxine trial', at the Pediatric Neurology Clinic of a tertiary-care teaching hospital in New Delhi, India. This consisted of an intravenous infusion of 100 mg of pyridoxine over 10-min with a simultaneous EEG monitoring. This procedure was carried out in the EEG laboratory with all appropriate precautions (including availability of resuscitation equipment and trained personnel). Continuous EEG monitoring was done throughout the infusion and till 20 min later, to look for correction of EEG abnormalities. All patients were then prescribed oral pyridoxine, 10-15 mg/kg/day divided TDS for 6 weeks, in addition to their current anticonvulsant therapy. Patients were reviewed every 15 days regarding compliance and change in seizure frequency. A reduction in seizure frequency by 50% of the baseline was considered as 'response' (significant change), meriting further continuation of pyridoxine therapy. In patients who remained seizure free on pyridoxine therapy, previous anti-epileptics were gradually tapered one by one. RESULTS: 621 children with active epilepsy were seen at the PNC, of which 48 had early-onset, medical intractable epilepsy, and 21 children (13 males and 8 females), aged between 11 month and 38 month were enrolled. The median age at onset of seizure was 5.1 months. The major seizure type was focal in 3 and generalized in 18 (including infantile spasm in 11). No patient had normalization of EEG during the 'trial'. Two patients (9.5%) had a response during the 2 weeks of oral treatment and oral therapy was continued. No toxicity or side-effects of pyridoxine were observed in these two patients over a follow-up of more than 18 months. CONCLUSIONS: Pyridoxine responsive seizures contribute a significant proportion to early-onset idiopathic intractable epilepsy in childhood. Routine use of pyridoxine in the management of early onset resistant seizures would go a long way in identifying these patients early. PMID- 20830536 TI - Burden, differentials, and causes of child deaths in India. AB - OBJECTIVE: To review the current information on trends, burden, differentials, causes, and timing of under five (U5) child deaths in India. METHODS: We reviewed and analyzed data on child deaths in India from official government sources, reports, surveys, and from the published literature. The secondary analyses were carried out to provide additional insight. RESULTS: An estimated 1.84 million under 5 child deaths, including approx 1.44 million infant and 940,000 neonatal deaths occurred in India during 2007. More than 60% of these Under 5 child deaths occurred in 5 states: Uttar Pradesh (27.0%), Bihar (11.3%), Madhya Pradesh (9.9%), Rajasthan (8.0%) and Andhra Pradesh (5.7%). Approximately 41% of all Under 5 child deaths happen in the first week of life and the risk of deaths during neonatal period was at least 68 times higher than the rest of childhood. The children living in rural areas, in the central Indian states, in the lowest 20% of wealth index have the highest risk of death in India. The mortality rates in under 5, infant, neonates and early neonatal period in India declined by 43.5%, 31.2%, 32.1%, and 21.6%, respectively, between 1990 to 2007. However, the rate of reduction has slowed in last 4 years (2003-2007), with negative trend in the early neonatal mortality rate. Neonatal conditions (33%), pneumonia (22%) and diarrhea (14%) are the leading causes of under 5 deaths in India. Sepsis, pneumonia (30.4%), birth asphyxia (19.5%), and pre-maturity (16.8%) are the 3 commonest causes of neonatal deaths (0-27 days). CONCLUSIONS: The reduction in under 5 child mortality in India during 1990-2007 has been insufficient to attain Millennium Development Goal 4 (MDG4). However, there have been variable declines in early neonatal, neonatal, infant and child mortality. Despite the well known importance of neonatal survival to attain MDG4, our data suggest the early neonatal mortality rate in India may be increasing in the recent years, which is a cause for serious concern. Achievement of MDG4 in India will require further acceleration in the reduction of the under 5 mortality rate, particularly, in the 5 highest burden states: Uttar Pradesh, Bihar, Madhya Pradesh, Rajasthan and Andhra Pradesh. PMID- 20830537 TI - Risk stratification and prediction of cancer of focal thyroid fluorodeoxyglucose uptake during cancer evaluation. AB - BACKGROUND: Focal thyroid incidentaloma by F-18 2-deoxy-2-F18-fluoro-D: -glucose (FDG) positron emission tomography (PET) has been reported 1-4% of cancer patients and normal healthy population, with a risk of cancer ranging 14-50%. The aim of this study was to investigate the prevalence of thyroid incidentaloma in F 18 FDG PET/CT and risk of cancer, usefulness of visual and SUV(max) and SUV(mean) differentiating malignant nodules and to define the predictable variables. PATIENTS AND METHODS: A total 159 patients with focal thyroid FDG incidentaloma during cancer evaluation with non-thyroid cancer were enrolled. After F-18 PET/CT, we analyzed the image visually and obtained semiquantitative indices. RESULT: The incidence of focal FDG thyroid incidentaloma is 1.36% and cancer risk is 23.3%. The incidence of focal thyroid FDG uptake was significantly higher in women (2.88 vs. 0.31%; chi (2) = 136.4, p < 0.0001). Malignant thyroid incidentalomas show statistically significant higher value of SUV(max) (malignant: median 4.53, range 2.1-12.0; benign: median 3.08, range 1.6-35, p = 0.0093). However, SUV(mean) have no statistical differences (malignant: median 2.17, range 1.77-3.19; benign: median 2.05, range 1.15-5.77, p = 0.0541). In ROC analyses, the optimal visual grades were >grade 3, and the optimal semiquantitative indices were 4.46 for SUV(max), 2.03 for SUV(mean). The visual grade was superior to other variables for the differentiation malignant from benign thyroid incidentalomas. The size and visual grade was the potent predictor by logistic regression analysis. CONCLUSION: Focal thyroid FDG incidentalomas in non-thyroid cancer patients during evaluation have a high risk of malignancy. The size and visual grade are potential predictors for malignant thyroid incidentaloma. PMID- 20830538 TI - HIV and bone loss. AB - The use of antiretroviral therapy has significantly reduced the number of deaths due to HIV/AIDS. However, no current therapy can suppress the virus completely, and as the HIV-infected population continues to live longer new complications are emerging from the persistence of the virus and use of antiretroviral therapy. This review summarizes the clinical evidence linking HIV-associated osteoporosis to direct infection and antiretroviral therapy (ART) use. The purported molecular mechanisms involved in bone loss are also reviewed. Additionally, recommendations regarding the pharmacologic management of HIV/ART-related osteoporosis are given. PMID- 20830539 TI - Skin shift and its effect on navigation accuracy in image-guided neurosurgery. AB - Neuronavigation systems have been developed for image-guided neurosurgery to aid in the accurate resection of malignant brain tumors. Therefore, the accuracy of the neuronavigation is important. However, many factors can reduce the navigation accuracy during surgery. Before craniotomy, the patient's head is secured to a head frame with head pins; this fixation may cause displacement of fiducial markers and reduce the accuracy. We term this phenomenon skin shift. In this study, the extent of skin shift and its effect on navigation accuracy were determined by use of both preoperative magnetic resonance imaging (MRI) scans acquired before fixation and intraoperative MRI scans acquired after fixation. We measured the displacement of the fiducial markers by using fusion images obtained by integrating preoperative and intraoperative MRI scans. We also evaluated the navigation accuracy of registration based on preoperative and on intraoperative MRI. The mean (+/- SD) extent of skin shift was 5.34 (+/- 2.65) mm. The navigation accuracy of registration based on preoperative MRI was 4.06 (+/- 2.25) mm, and that of registration based on intraoperative MRI was 2.51 (+/- 1.32) mm. No significant correlation was observed between the extent of skin shift and the distance between the head pins and fiducial markers (p > 0.05). The navigation accuracy of registration based on intraoperative MRI was significantly higher than that of registration based on preoperative MRI (p < 0.001). The results indicated that skin shift was caused by the fixation, and that this shift reduced the navigation accuracy. Intraoperative MRI can correct the effect of skin shift. PMID- 20830540 TI - Quantitative evaluation of expression difference in report assignments between nursing and radiologic technology departments. AB - Our purpose in this study was to investigate the expression differences in report assignments between students in nursing and radiologic technology departments. We have known that faculties could identify differences, such as word usage, through grading their students' assignments. However, there are no reports in the literature dealing with expression differences in vocabulary usage in medical informatics education based on statistical techniques or other quantitative measures. The report assignment asked for students' opinions in the event that they found a rare case of a disease in a hospital after they graduated from professional school. We processed student report data automatically, and we applied the space vector model and TF/IDF (term frequency/inverse document frequency) scoring to 129 report assignments. The similarity-score distributions among the assignments for these two departments were close to normal. We focused on the sets of terms that occurred exclusively in either department. For terms such as "radiation therapy" or "communication skills" that occurred in the radiologic technology department, the TF/IDF score was 8.01. The same score was obtained for terms such as "privacy guidelines" or "consent of patients" that occurred in the nursing department. These results will help faculties to provide a better education based on identified expression differences from students' background knowledge. PMID- 20830541 TI - Countermeasures against physical motion in schoolchildren requiring no sedation during rest and stress myocardial perfusion imaging with technetium-99m tetrofosmin. AB - For children, cardiac nuclear medicine imaging has not been widely used because of problems of physical motion, even in schoolchildren who require no sedation. In this study, rest-stress myocardial perfusion imaging (MPI) with technetium-99m tetrofosmin (Tc-99m TF) was performed with the use of a Vac-Loc cushion, a patient immobilizer commonly used for radiotherapy, for immobilizing school-age patients. The immobilizer attenuated the gamma radiation by 6%. By visual assessment, physical motion-related artifacts were markedly improved in images acquired with the immobilizer, compared to those without. In the assessment of image reproducibility with the immobilizer, taking the reproducibility as 2.5Sigma + 0.7sigma, there were deviations of 4.45, 5.28, and 3.28 mm along the X , Y-, and Z-axes, respectively, demonstrating a high reproducibility and a negligible rest-stress position error. It is suggested that for radiotherapy, the immobilizer could expand the versatility of MPI while allowing only minimal physical motion in children. PMID- 20830543 TI - Ultrasound simulation of internal jugular vein cannulation in pregnant and non pregnant women. AB - BACKGROUND: Pregnancy alters the anatomic landmarks for internal jugular vein (IJV) cannulation. In this study, IJV cannulation was simulated, and success of the technique was evaluated using ultrasound. METHODS: Term pregnant women and non-pregnant female volunteers were recruited. The degree of difficulty in assessing neck anatomy was noted. The optimal insertion points for cannulation were marked on the skin of each subject according to the central landmark and palpatory techniques. The midpoint of a 15-10 MHz linear transducer was placed over each insertion point, and the vertical cursor of the ultrasound, which represented the path of the needle, was placed in the image. The outcome was an IJV puncture, a carotid artery (CA) puncture, or a missed attempt. RESULTS: One hundred and sixty-one women, 99 pregnant and 62 non-pregnant, were studied. The identification of landmarks was more difficult in pregnant women (P = 0.01). The rates of successful IJV punctures, CA punctures, and missed attempts did not differ significantly between pregnant and non-pregnant women. Carotid artery punctures using the central landmark technique in pregnant and non-pregnant subjects were 19% and 10%, respectively. Corresponding figures for the palpatory approach were 6% and 3%, respectively. The degree of IJV overlap of the CA in the palpatory technique was greater in pregnant women (38% vs 18% showed > 75% overlap; P < 0.001), a difference that remained after controlling for body mass index CONCLUSION: The IJV overlies the CA to a greater extent in pregnant patients than in non-pregnant patients. Thus, a landmark approach for IJV cannulation might expose pregnant women to a greater risk of carotid puncture. This trial was registered at www.clinicaltrials.gov (NCT T00464828). PMID- 20830542 TI - Mortality after distal femur fractures in elderly patients. AB - BACKGROUND: Hip fractures in the elderly are associated with high 1-year mortality rates, but whether patients with other lower extremity fractures are exposed to a similar mortality risk is not clear. QUESTIONS/PURPOSES: We evaluated the mortality of elderly patients after distal femur fractures; determined predictors for mortality; analyzed the effect of surgical delay; and compared survivorship of elderly patients with distal femur fractures with subjects in a matched hip fracture group. PATIENTS AND METHODS: We included 92 consecutive patients older than 60 years with low-energy supracondylar femur fractures treated between 1999 and 2009. Patient, fracture, and treatment characteristics were extracted from operative records, charts, and radiographs. Data regarding mortality were obtained from the Social Security Death Index. RESULTS: Age-adjusted Charlson Comorbidity Index and a previous TKA were independent predictors for decreased survival. Congestive heart failure, dementia, renal disease, and history of malignant tumor led to shorter survival times. Patients who underwent surgery more than 4 days versus 48 hours after admission had greater 6-month and 1-year mortality risks. No differences in mortality were found comparing patients with native distal femur fractures with patients in a hip fracture control group. CONCLUSIONS: Periprosthetic fractures and fractures in patients with dementia, heart failure, advanced renal disease, and metastasis lead to reduced survival. The age-adjusted Charlson Comorbidity Index may serve as a useful tool to predict survival after distal femur fractures. Surgical delay greater than 4 days increases the 6-month and 1-year mortality risks. Mortality after native fractures of the distal femur in the geriatric population is high and similar to mortality after hip fractures. LEVEL OF EVIDENCE: Level II, prognostic study. See the guidelines online for a complete description of evidence. PMID- 20830544 TI - Pictures worthy of a thousand words. PMID- 20830545 TI - [Organ transplantation with a living donor : A solution to the organ shortage?]. PMID- 20830546 TI - [Living-donor kidney transplantation]. AB - Due to the existing organ shortage the option of a kidney transplantation (KTx) in patients with end-stage renal disease is not always possible despite the offer of this therapy. So far the required number of KTx could not be adequately achieved by organ donations from deceased persons. To solve this problem living donation KTx programs have already become established in many transplantation centers. In published reports it has been shown that with the living donation program better results could be achieved in terms of graft function and patient survival compared to cadaver donation KTx. Therefore, living donation KTx allows an optimal alternative to expand the organ pool. The aim of our study is to present the long-term results of our living donation KTx program regarding graft function and patient survival. Finally, the risks of living donation KTx will be discussed based on the reported experiences of other centers. PMID- 20830548 TI - [Knowledge acquisition through non-university surgical studies]. PMID- 20830547 TI - [Stem cells from fatty tissue : A new resource for regenerative medicine?]. AB - While stem cells derived from the bone marrow are well-known in clinical medicine, fatty tissue as a source of mesenchymal stem cells is still the subject of recent research. However, adipose-derived stem cells (ASC) are not only harvested less invasively, i.e. via minimally invasive liposuction, but also yield higher numbers of multipotent stem cells.Due to cell-cell interactions and also because of the very favorable secretion profile of growth factors and cytokines ASCs displayed an extraordinary regenerative potential in recent preclinical and clinical applications and achieved a significantly better healing in ischemic muscle, heart, and brain insults and in impaired wound healing. ASCs enhanced regeneration in skeletal tissues such as cartilage or bone. They also revealed immunomodulatory effects and improved the clinical status in immunological diseases.In conclusion ASCs are comparable to bone marrow-derived stem cells concerning possible applications in clinical medicine. PMID- 20830549 TI - [Diabetic foot syndrome]. AB - For patients with a diabetic foot wound the risk for amputation is high. The three main reasons for developing foot ulcers in diabetes are biomechanical factors, neurologic and vascular alterations. According to this the ulcers can be categorized in neuropathic (50%), ischemic (15%) and neuroischemic (35%). Sensomotoric polyneuropathy leads to the loss of perception of pain in the feet and in combination with extrinsic and intrinsic biomechanical factors, chronic wounds evolve (malum perforans). The therapy should take place within an interdisciplinary network and based on guidelines. Besides pressure off-loading debridement of the wound is mandatory. The arterial occlusions in diabetes mainly affect the cruropedal vessels and when ischemia occurs a reconstruction must be attempted. The risk of recurrence is high so that regular follow-up examinations, screening to detect high risk patients and education are necessary. PMID- 20830550 TI - [Hopeful old age. Abstracts of the 2nd Joint Congress of the German Society for Gerontology and Geriatrics and the Swiss Society for Gerontology and the 10th Congress of the German society for Gerontology and Geriatrics. September 15-17, 2010. Berlin, Germany]. PMID- 20830553 TI - Molecular methods to study complex microbial communities. AB - Microbes, which constitute a major fraction of the total biomass, are the main source of biodiversity on our Planet and play an essential role in maintaining global processes, which ultimately regulate the functioning of the Biosphere. Recent emergence of "metagenomics" allows for the analysis of microbial communities without tedious cultivation efforts. Metagenomics approach is analogous to the genomics with the difference that it does not deal with the single genome from a clone or microbe cultured or characterized in laboratory, but rather with that from the entire microbial community present in an environmental sample; it is the community genome. Global understanding by metagenomics depends essentially on the possibility of isolating the entire bulk DNA and identifying the genomes, genes, and proteins more relevant to each of the environmental sample under investigation. Following on this, in this chapter, we provide an analysis of methods available to isolate environmental DNA and to establish metagenomic libraries that can further be used for extensive activity screens. PMID- 20830554 TI - Construction of small-insert and large-insert metagenomic libraries. AB - The vast majority of the Earth's biological diversity is hidden in uncultured and yet uncharacterized microbial genomes. The construction of metagenomic libraries is a cultivation-independent molecular approach to assess this unexplored genetic reservoir. In the last few years, a high number of novel biocatalysts have been identified by function-based or sequence-based screening of metagenomic libraries. Here, we describe detailed protocols for the construction of metagenomic small-insert and large-insert libraries in plasmids and fosmids, respectively, from environmental DNA. PMID- 20830555 TI - Construction and screening of marine metagenomic libraries. AB - Marine microbial communities are highly diverse and have evolved during extended evolutionary processes of physiological adaptations under the influence of a variety of ecological conditions and selection pressures. They harbor an enormous diversity of microbes with still unknown and probably new physiological characteristics. Besides, the surfaces of marine multicellular organisms are typically covered by a consortium of epibiotic bacteria and act as barriers, where diverse interactions between microorganisms and hosts take place. Thus, microbial diversity in the water column of the oceans and the microbial consortia on marine tissues of multicellular organisms are rich sources for isolating novel bioactive compounds and genes. Here we describe the sampling, construction of large-insert metagenomic libraries from marine habitats and exemplarily one function based screen of metagenomic clones. PMID- 20830556 TI - Metagenomic analysis of isotopically enriched DNA. AB - This detailed protocol describes an approach for combining DNA stable-isotope probing-based enrichment, multiple displacement amplification (MDA), and metagenomics. Together, these three methodologies enable selective access to the genomes of uncultivated organisms that actively grow using isotopically labelled carbon and nitrogen sources. Incubations with stable-isotope-labelled substrates enrich isotopically labelled DNA from functionally relevant micro-organisms; this serves as a filter to reduce the complexity of the metagenome. The MDA step generates sufficient DNA from labelled nucleic acid for metagenomic library construction. Subsequently, genome fragments can be subjected to a variety of screens for phylogenetic or functional genes relevant to active community members. The MDA-generated DNA can also serve as template for direct high throughput sequencing to aid reconstruction of metabolic pathways of those active organisms. Recent proof-of-concept studies have demonstrated that this novel combination of molecular methods can offer substantial enhancements to gene detection frequencies and may have great future potential for the discovery of novel genes, enzymes, and metabolic pathways. PMID- 20830557 TI - Wide host-range cloning for functional metagenomics. AB - We describe how wide host-range cloning vectors can lead to more flexible and effective procedures to isolate novel genes by screening metagenomic libraries in a range of bacterial hosts, not just the conventionally used Escherichia coli. We give examples of various wide host-range plasmid, cosmid, and BAC cloning vectors and the types of genes and activities that have been successfully obtained to date. We present a detailed protocol that involves the construction and screening of a metagenomic library comprising fragments of bacterial DNA, obtained from a wastewater treatment plant and cloned in a wide host-range cosmid. We also consider future prospects and how techniques and tools can be improved. PMID- 20830558 TI - Cloning and expression vectors for a Gram-positive host, Streptomyces lividans. AB - The choice of an expression system for the meta-genomic DNA of interest is of vital importance for the detection of any particular gene or gene cluster. Most of the screens to date have used the Gram-negative bacterium Escherichia coli as a host for the meta-genomic gene libraries. However, the use of E. coli introduces a potential host bias since only 40% of the enzymatic activities may be readily recovered by random cloning in E. coli (Gabor et al., Environ Microbiol 6:879-886, 2004). To recover some of the remaining 60%, alternative cloning hosts such as Streptomyces spp. have been used (Lorenz and Eck, Nat Rev Microbiol 3:510-516, 2005). Streptomycetes are high-GC Gram-positive bacteria that belong to the Actinomycetales, and they have been studied extensively in the last 10 years as an alternative expression system (reviewed in Vrancken and Anne, Future Microbiol 4:181-188, 2009). Streptomyces is extremely well suited for the expression of DNA from other actinomycetes and genomes of high GC content (Wang et al., Org Lett 2:2401-2404, 2000). Furthermore, due to its high innate secretion capacity, it can be a superior system than E. coli for the production of many extra-cellular proteins. PMID- 20830559 TI - Heterologous gene expression in the hyperthermophilic archaeon Sulfolobus solfataricus. AB - One of the few available systems for gene expression in (hyper)thermophilic Archaea is the virus-based shuttle vector pMJ05 for Sulfolobus solfataricus. Although it is still not fully developed and there are some difficulties arising from the large size of the vector (>20 kb), it has successfully been used for the production of foreign and own proteins in S. solfataricus. Most often, the development of genetic tools for Archaea is held back by the lack of an efficient transformation system. In the case of pMJ05, this difficulty has been alleviated by using the Sulfolobus virus SSV1 as the vector backbone. The ability of the pMJ05 plasmid to spread in the culture as a virus, the availability of an effective selection marker (pyr) and of tunable promoters (araS and tf55alpha) make this system one of the first choices for heterologous gene expression in (hyper)thermophilic Archaea. PMID- 20830560 TI - Novel tools for the functional expression of metagenomic DNA. AB - The functional expression of environmental genes in a particular host bacterium is hampered by various limitations including inefficient transcription of target genes as well as improper assembly of the corresponding enzymes. Therefore, the identification of novel enzymes from metagenomic libraries by activity-based screening requires efficient expression and screening systems. In the following chapter, we present two novel tools to improve the functional expression of metagenomic genes. (1) Comparative screenings of metagenomic libraries demonstrated that different enzymes were detected when phylogenetically distinct expression host strains were used. Thus, we have developed a strategy, which comprises library construction using a shuttle vector that allows comparative expression and screening of metagenomic DNA in Escherichia coli, Pseudomonas putida, and Bacillus subtilis. (2) Expression studies have revealed that functional expression of environmental genes in heterologous expression hosts is often limited by insufficient promoter recognition. Therefore, a method is described allowing to enhance the expression capacity of E. coli by using the transposon MuExpress. This recombinant transposon is able to insert randomly into environmental DNA fragments thereby facilitating gene expression from its two inducible promoters. PMID- 20830561 TI - Screening of functional promoter from metagenomic DNA for practical use in expression systems. AB - The functional overproduction of proteins is an essential step required for providing enzymes and proteins for practical applications. Accordingly, the expression system used is important, e.g., cis-acting elements including promoters for the expression of recombinant proteins in a broad range of hosts or preferential expression in a specific host. We have introduced a bidirectional promoter trap system (pBGR1) for screening of promoters with up- or/and down regulatory elements from resources of metagenomic DNA. The pBGR1 is equipped with a pair of fluorescent proteins acting as reporters, facing opposite directions without promoters; this is a promising system that can function regardless of the direction of inserted promoters. Subsequently, promoters trapped by pBGR1 can be employed in the construction of new expression vectors for practical applications. PMID- 20830562 TI - Substrate-induced gene expression screening: a method for high-throughput screening of metagenome libraries. AB - The SIGEX (substrate-induced gene expression) method is a novel approach for the screening of gene (genome) libraries. In addition to the commonly used function- and sequence-driven approaches to screening, SIGEX provides a third option; in SIGEX, positives are identified using a reporter gene, and the library is constructed using an "operon-trap" vector. This vector contains the reporter gene immediately downstream of the cloning site for the genomic insert so that the expression of the inserted gene(s) is coupled with that of the reporter gene. This system is especially suitable for screening catabolic genes that are induced in response to metabolically relevant compounds, such as substrates. If expression of the inserted gene(s) is activated in response to the addition of these compounds, then positive clones can be identified based on the reporter signal. The most effective selection is obtained by the use of a FACS (fluorescence-activated cell sorter) in conjunction with a FACS-compatible fluorescent reporter protein, such as GFP (green fluorescent protein). Activity based screening of metagenomic libraries often suffers from low sensitivity and low throughput. In contrast, the high throughput, high sensitivity, and versatility of SIGEX make it a particularly suitable method for screening metagenomic libraries. PMID- 20830563 TI - Screens for active and stereoselective hydrolytic enzymes. AB - A procedure for the high-throughput screening (HTS) of esterases is described. This includes a pretest for discrimination of active and inactive clones using an agar plate overlay assay, the enzyme expression in microtiter plates and the measurement of activity and enantioselectivity (E) of the esterase variants using acetates of secondary alcohols as model substrates. Acetic acid released is converted in an enzyme cascade leading to the stoichiometric formation of NADH, which is quantified in a spectrophotometer. The method allows screening of several thousand mutants per day and has already been successfully applied to identify an esterase mutant with an E > 100 towards an important building block for organic synthesis. This protocol can also be used for lipases and possibly other hydrolases that are expressed in soluble form in conventional Escherichia coli strains. PMID- 20830564 TI - Screening for cellulase-encoding clones in metagenomic libraries. AB - Modern biotechnology has the steady need to continuously identify novel enzymes for use in biotechnological applications. In industrial applications, however, enzymes often have to function under extreme and nonnatural conditions (i.e., in the presence of solvents, high temperature and/or at extreme pH values). Cellulases have many industrial applications from the generation of bioethanol, a realistic long-term energy source, to the finishing of textiles. These industrial processes require cellulolytic activity under a range of pH, temperature, and ionic conditions, and they are usually carried out by mixtures of cellulases. Investigation of the broad diversity of cellulolytic enzymes involved in the natural degradation of cellulose is necessary for optimization of these processes. PMID- 20830565 TI - Screening metagenomic libraries for laccase activities. AB - Laccases are multi-copper oxidoreductases (benzenediol:oxygen oxidoreductases, EC 1.10.3.2) able to oxidise a wide variety of phenolic and non-phenolic compounds. They are useful enzymes for a variety of applications, including bioremediation and craft pulp bio-bleaching as the most significant ones. There is a considerable interest to find new laccases through the exploration of biological diversity. Laccases have been found in plants, insects, and bacteria but predominantly in fungi: these enzymes have been documented in about 60 fungal strains. Microbial diversity constitutes a largely unexplored treasure chest with new laccases with a good potential for basic science and biotechnology. At present, due to our inability to cultivate most microbes, the only means of accessing the resources of the microbial world is to harvest genetic resources ("metagenomes"), which can further on be subjected to extensive screening programs. In this chapter, we provide an overview of screening methods to identify laccase-encoding genes from environmental resources. PMID- 20830566 TI - Screening for N-AHSL-based-signaling interfering enzymes. AB - Quorum sensing (QS)-based signaling is a widespread pathway used by bacteria for the regulation of functions involved in relation to their environment or host. QS relies upon the production, accumulation, and perception of small diffusible molecules by the bacterial population, hence linking high gene expression with high cell population densities. Amongst the different QS signal molecules, an important class of signal molecules is the N-acyl homoserine lactone (N-AHSL) class. In pathogens such as Erwinia or Pseudomonas, N-AHSL-based QS is crucial to overcome the host defenses and ensure a successful infection. Interfering with QS regulation allows the alga Delisea pulchra to avoid surface colonization by bacteria. Thus, interfering in the QS regulation of pathogenic bacteria is a promising antibiotic-free antibacterial therapeutic strategy. To date, two N-AHSL lactonase and one amidohydrolase families of N-ASHL degradation enzymes have been characterized and proven to be efficient in vitro to control N-AHSL-based QS regulated functions in pathogens. PMID- 20830567 TI - Identification of molecular markers to follow up the bioremediation of sites contaminated with chlorinated compounds. AB - The use of microorganisms to clean up xenobiotics from polluted ecosystems (soil and water) represents an ecosustainable and powerful alternative to traditional remediation processes. Recent developments in molecular-biology-based techniques have led to rapid and sensitive strategies for monitoring and identifying bacteria and catabolic genes involved in the degradation of xenobiotics. This chapter provides a description of recently developed molecular-biology-based techniques, such as PCR with degenerate primers set, real-time quantitative PCR (qPCR), reverse transcription PCR (RT-PCR), southern blot hybridization, and long range PCR, used to give a picture of the catabolically relevant microorganisms and of the functional genes present in a polluted system. By using a case study of a groundwater aquifer contaminated with 1,2-dichloroethane (1,2-DCA), we describe the identification of microorganisms potentially involved in the 1,2-DCA dehalorespiration (Dehalobacter sp. and Desulfitobacterium sp.) and a complete new gene cluster encoding for a 1,2-DCA reductive dehalogenase. The application of these techniques to bioremediation can improve our understanding of the inner mechanisms to evaluate the feasibility of a given treatment and provide us with a method to follow up bacteria and catabolic genes involved in the degradation of contaminants during the activities in situ. PMID- 20830568 TI - Methods for the isolation of genes encoding novel PHB cycle enzymes from complex microbial communities. AB - Development of different PHAs as alternatives to petrochemically derived plastics can be facilitated by mining metagenomic libraries for diverse PHA cycle genes that might be useful for synthesis of bioplastics. The specific phenotypes associated with mutations of the PHA synthesis pathway genes in Sinorhizobium meliloti allows for the use of powerful selection and screening tools to identify complementing novel PHA synthesis genes. Identification of novel genes through their function rather than sequence facilitates finding functional proteins that may otherwise have been excluded through sequence-only screening methodology. We present here methods that we have developed for the isolation of clones expressing novel PHA metabolism genes from metagenomic libraries. PMID- 20830569 TI - Metagenomic approaches to identify and isolate bioactive natural products from microbiota of marine sponges. AB - Many marine sponges harbor massive consortia of symbiotic bacteria belonging to diverse phyla. Sponges are also an unusually rich source of biologically active natural products, and evidence is accumulating that these compounds might often be synthesized by the symbionts. Since the study of sponge-associated bacteria is generally hampered by very low cultivation rates, cultivation-independent, metagenomic methods have recently been applied to sponges. These methods allow for the isolation of biosynthetic gene clusters that can ultimately be exploited to develop sustainable natural product sources by heterologous expression. However, general challenges encountered in sponge metagenomic research are the poor quality of the isolated DNA with respect to size and yield, the difficulty to identify genes of interest among numerous homologs, insufficient clone numbers in metagenomic libraries, and time-consuming screening procedures to identify and isolate rare positive clones. Here, we give an overview of methods that address these problems and can be used to streamline isolation of biosynthetic and other genes of interest. PMID- 20830570 TI - Screening for novel antibiotic resistance genes. AB - Knowledge of novel antibiotic resistance genes aids in the understanding of how antibiotics function and how bacteria fight them. This knowledge also allows future generations of an antibiotic or antibiotic group to be altered to allow the greatest efficacy. The method described here is very simple in theory. The bacterial strains are screened for antibiotic resistance. Cultures of the strain are grown, and DNA is extracted. A partial digest of the extraction is cloned into Escherichia coli, and the transformants are plated on selective media. Any colony that grows will possess the antibiotic resistance gene and can be further examined. In actual practice, however, this technique can be complicated. The detailed protocol will need to be optimized for each bacterial strain, vector, and cell line chosen. PMID- 20830571 TI - Novel metal resistance genes from microorganisms: a functional metagenomic approach. AB - Most of the known metal resistance mechanisms are based on studies of cultured microorganisms, and the abundant uncultured fraction could be an important source of genes responsible for uncharacterized resistance mechanisms. A functional metagenomic approach was selected to recover metal resistance genes from the rhizosphere microbial community of an acid-mine drainage (AMD)-adapted plant, Erica andevalensis, from Rio Tinto, Spain. A total of 13 nickel resistant clones were isolated and analyzed, encoding hypothetical or conserved hypothetical proteins of uncertain functions, or well-characterized proteins, but not previously reported to be related to nickel resistance. The resistance clones were classified into two groups according to their nickel accumulation properties: those preventing or those favoring metal accumulation. Two clones encoding putative ABC transporter components and a serine O-acetyltransferase were found as representatives of each group, respectively. PMID- 20830572 TI - Retrieval of full-length functional genes using subtractive hybridization magnetic bead capture. AB - Numerous gene-specific PCR methods have been developed for the cultivation independent discovery of novel genes from complex environmental DNA samples. The recovery of full-length genes is, however, technically challenging. Here, we present an efficient and relatively simple approach that combines magnetic bead capture with subtractive hybridization for the rapid and direct recovery of full length target ORFs. When compared with other PCR-based techniques, a higher degree of specificity is achieved through the use of larger gene fragments during hybridization followed by several high-stringency washes. Together with the recent advances in environmental nucleic acid extraction techniques, this approach should allow for the further exploration of the metagenomic sequence space. PMID- 20830573 TI - Detection and isolation of selected genes of interest from metagenomic libraries by a DNA microarray approach. AB - A DNA microarray-based approach is described for screening metagenomic libraries for the presence of selected genes. The protocol is exemplified for the identification of flavin-binding, blue-light-sensitive biological photoreceptors (BL), based on a homology search in already sequenced, annotated genomes. The microarray carried 149 different 54-mer oligonucleotides, derived from consensus sequences of BL photoreceptors. The array could readily identify targets carrying 4% sequence mismatch, and allowed unambiguous identification of a positive cosmid clone of as little as 10 ng against a background of 25 MUg of cosmid DNA. The protocol allows screening up to 1,200 library clones in concentrations as low as ca. 20 ng, each with a ca. 40 kb insert size readily in a single batch. Calibration and control conditions are outlined. This protocol, when applied to the thermophilic fraction of a soil sample, yielded the identification and functional characterization of a novel, BL-encoding gene that showed a 58% similarity to a known, BL-encoding gene from Kineococcus radiotolerans SRS30216 (similarity values refer to the respective LOV domains). PMID- 20830574 TI - Application of DNA microarray for screening metagenome library clones. AB - Sequence-based screening tools of a metagenome library can expedite metagenome researches considering tremendous metagenome diversities. Several critical disadvantages of activity-based screening of metagenome libraries could be overcome by sequence-based screening approaches. DNA microarray technology widely used for monitoring environmental genes can be employed for screening environmental fosmid and BAC clones harboring target genes due to its high throughput nature. DNAs of fosmid clones are extracted and spotted on a glass slide and fluorescence-labeled probes are hybridized to the microarray. Specific hybridization signals can be obtained only for the fosmid clones that contain the target gene with high sensitivity (10 ng/MUL of fosmid clone DNA) and quantitativeness. PMID- 20830575 TI - MetaGenomeThreader: a software tool for predicting genes in DNA-sequences of metagenome projects. AB - We consider a gene finding method that is specifically designed to work on metagenome sequences. The method can handle short metagenome sequences with in frame stop codons as well as frame shifts. It delivers gene predictions for a set of metagenome sequences, which may be individual reads or a collection of assembled reads sequenced from an environmental sample. The method searches for stretches of DNA that are conserved within the environmental sample. Conserved coding sequences are discriminated from conserved non-coding regions based on their synonymous substitution rate. We describe the program MetaGenomeThreader which implements the method and show its application on a synthetic metagenome. PMID- 20830576 TI - [The disaster of Dresden. German Medical Assembly 2010]. PMID- 20830577 TI - [Unrepaired fracture of the styloid process of the ulna: not a bad treatment result at distal radius fracture]. AB - BACKGROUND: There are well-defined criteria for the treatment of distal radius fractures but the impact of an unrepaired fracture of the styloid process of the ulnar on recovery after operative treatment is uncertain. This study evaluated radiological and functional results after different operative treatment procedures of distal radius fractures in patients with an untreated fracture of the styloid process of the ulna and those without such a fracture. METHODS: Out of 480 patients with operatively treated distal radius fractures 238 were examined at least 1 year after injury. The fracture of the styloid process of the ulna was not repaired. Three groups (patients without a fracture of the styloid process of the ulna, patients with a tip fracture and those with a basal fracture) were evaluated by multivariate analysis (MANOVA) in order to detect influences of the fracture of the styloid process of the ulna on the radiological and functional results. RESULTS: Neither the existence nor the location of the fracture of the styloid process of the ulna had a significant effect on the radiological and functional results (p(function)=0,849, p(radiology)=0,330, p(scores)=0,426, MANOVA). CONCLUSIONS: The repair of a fracture of the styloid process of the ulna is not necessary if reduction and fixation of the distal radius fracture is anatomical and stable. PMID- 20830578 TI - [High pressure injection injuries to the hand]. AB - The severity of high pressure injection injuries to the hand is often underestimated in the initial clinical examination. Therefore, it is critical to obtain information about the course of the accident, the pressure involved and the injected substance. X-ray examination can reveal the injected substance or accompanying air in the tissues and therapy is usually surgical. All compartments should be released and all foreign material should be thoroughly removed. There is often a need for second look surgery. Wound closure should be achieved within 1 week and the decision about amputation should fall within 2 weeks. Hand therapy is essential beginning from the day after trauma and it may be continued for weeks or even months.From 1998 to 2008, 36 patients were treated after high pressure injection injury to the hand, 19 patients were transferred to the replantation centre immediately and 17 secondarily. These 19 injuries resulted in finger amputations and/or pain syndromes in 12 patients (33%) including 2 out of the primary group (10%) and 10 out of the secondary group (59%). It can be concluded that high pressure injuries to the hand should be treated in replantation centres. PMID- 20830579 TI - [First results with a multidirectional fixed angle implant for internal fixation of distal radius fractures]. AB - BACKGROUND: The management of fractures of the distal radius continues to evolve. New operative strategies have recently been developed including the use of fixed angle plates. This study reviews the results of 20 patients with fractures of the distal radius treated with a new multidirectional fixed angle plate. METHOD AND MATERIALS: A total of 20 patients with closed Colles type fractures of the distal radius were treated with Medartis (Aptus 2.5) palmar fixed-angle plates. Surgery was performed under plexus anesthesia using the standard or extended flexor carpi radialis (FCR) approach. Patients were evaluated prospectively with a mean follow up of 26 weeks (range 23-28 weeks). Pain, range of motion, grip strength, DASH score, modified Mayo wrist score and radiographs were obtained. The level of significance was set at 95% and the chi(2) and ANOVA tests in combination with a post hoc Tukey test were used for statistical analysis. RESULTS: The average range of motion (ROM) in extension-flexion was 87 degrees (76% of the contralateral side) and in ulnar-radial deviation 42 degrees (88% of the contralateral side). Pain values (visual analogue scale 0-100) at follow-up were 3 (without stress) and 24 (with stress). Grip strength improved to 84% of the contralateral side, the mean DASH score was 13 points and the modified Mayo wrist score confirmed the excellent results with a mean value of 83+/-27 points. Radiological examination showed a satisfactory result with an ulna variance of 0.9+/-0.4 mm, radio-ulnar inclination of 21+/-5 degrees and palmar inclination of 4+/-6 degrees . CONCLUSIONS: Our data show that treating unstable distal radius fractures with multidirectional palmar fixed-angle plates is reliable and effective and produces good early functional and radiological results. However, long-term results with a larger number of patients and randomized prospective studies comparing this technique with other established procedures are required. PMID- 20830580 TI - [Subarachnoid pleural fistula and subsequent pneumocephalus as complication of vertebral body replacement of the thoracic spine]. AB - A pneumocephalus caused by a subarachnoid pleural fistula following spinal surgery using an anterior approach is a rare complication, especially in vertebral body replacement. We report the case of a 66-year-old male suffering from metastatic prostatic cancer of the thoracic spine who underwent replacement of a vertebral body using a transthoracic approach. A pneumocephalus occurred 4 weeks postoperatively resulting in delirium. PMID- 20830581 TI - Comparison of clinical outcome and urodynamic findings using "Perigee and/or Apogee" versus "Prolift anterior and/or posterior" system devices for the treatment of pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: This study aims to compare clinical outcome using the Perigee/Apogee(r) vs. Prolift(r) devices for the treatment of pelvic organ prolapse (POP). METHODS: One hundred and eight women with POP stages II to IV were scheduled for either Perigee/Apogee(r) (Perigee group; n = 60) or Prolift(r) device (Prolift group; n = 48). Preoperative and postoperative assessments included pelvic examination, urodynamic study, and a personal interview about urinary and sexual symptoms. RESULTS: Despite different follow-up period (20 months for the Perigee group vs. 12 months for Prolift group; P < 0.01), the success rates for two groups were comparable (P > 0.05). Postoperative points Aa and Ba of Prolift group were significantly higher than the other group (P < 0.01). The prevalences of detrusor overactivity and urinary symptoms decreased significantly postoperatively in both groups (P < 0.05). Comparisons of all operative complications revealed no significant differences between the two groups (P > 0.05). CONCLUSIONS: Perigee/Apogee(r) and Prolift(r) devices for POP repair have comparable success rates, mesh-related morbidities, and similar impacts on functional outcome. PMID- 20830582 TI - Rhamnolipid production by pseudomonas aeruginosa GIM 32 using different substrates including molasses distillery wastewater. AB - A rhamnolipid production strain newly isolated from oil-contaminated soil was identified as Pseudomonas aeruginosa GIM32 by its morphology and 16S rDNA sequence analysis. The effect of carbon source and carbon to nitrogen (C/N) ratio on rhamnolipids production was investigated. Palm oil was favorable as a carbon source for rhamnolipid production. The maximum biomass and rhamnolipid concentration were 8.24 g/L and 30.4 g/L, respectively, with an optimization medium containing 50 g/L palm oil and 5 g/L sodium nitrate. Molasses distillery wastewater as an unconventional substrate for rhamnolipid production was investigated. It was found that 2.6 g/L of rhamnolipids was produced; this amount was higher than that of past reports using wastewater as a substrate. In addition, 44% of the chemical oxygen demand of wastewater was removed at the same time under the optimization condition. Eleven kinds of different molecular weight rhamnolipid homologues were identified in the rhamnolipids obtained from molasses distillery wastewater by P. aeruginosa GIM32 by LC-MS analysis. PMID- 20830583 TI - Endpoint fragmentation index: a method for monitoring the evolution of microbial degradation of polysaccharide feedstocks. AB - We describe a simple method for tracking the course of microbial degradation of polysaccharide-rich feedstocks. The method involves determining total polysaccharides present in the feedstock, measured in glucose equivalents, relative to the fractional component of polysaccharides exhibiting 2,3 dinitrosalycylic acid aldehyde activity. The ratio of total polysaccharide to aldehyde activity, defined as the end-point fragmentation (EPF) index, is then calculated and tracked as it shifts as microbial degradation of polysaccharide rich feedstock progresses. While degradation occurs, the EPF index falls. It bottoms out at an asymptotic limit marking the point in time where further degradation of the polysaccharide-rich feedstock has ceased. The EPF index can be used to follow the progressive breakdown of composting polysaccharide-rich waste. It may also have applicability as a means of tracking the turnover of polysaccharides in other complex environments including soil, sediments, wetlands, and peat bogs. PMID- 20830584 TI - The birth of neuro-simulation. PMID- 20830585 TI - Complete mitochondrial genome sequence of the yeast Pichia farinosa and comparative analysis of closely related species. AB - Yeasts of the Pichia genus have been isolated from different natural environments. Phylogenies based on multigene sequence analysis have shown that the genus is polyphyletic. Some species of this genus are member of the CTG group. In order to have a better insight into the relationship among species assigned to the yeast genera Pichia into the CTG group, we first sequenced the mitochondrial genome of the osmotolerant yeast Pichia farinosa. We then compared this genome with mitochondrial genomes of yeasts of the CTG group. The P. farinosa mitochondrial DNA is a circular-mapping genome of 32,065 bp, which contains 43 genes transcribed from both strands. It contains a complete set of tRNAs, the small and the large rRNAs, as well as 14 protein-coding genes. Yeasts of the CTG group contain the same core of mitochondrial genes. Phylogenetic analysis based on mitochondrial sequences clearly shows that the CTG group is divided into two distinct clades: the first one contains diploid Candida species, whereas the second mainly contains haploid Pichia species. Moreover, this analysis provides clear evidence that Pichia farinosa and Pichia sorbitophila, which were known to be unique species, are two distinct species. PMID- 20830586 TI - CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury. AB - Endothelial progenitor cells (EPCs) contribute to the process of reendothelialization and prevent neointimal formation after vascular injury. The present study was designed to investigate whether the cysteine-rich 61 (CYR61, CCN1), an important matricellular component of local vascular microenvironment, has effect on EPCs differentiation and reendothelialization in response to vascular injury in rat. Following balloon injury, CCN1 was rapidly induced and dynamically changed at vascular lesions. Overexpression of CCN1 by adenovirus (Ad CCN1) accelerated reendothelialization and inhibited neointimal formation in the early phase (day 14) after vascular injury (p < 0.05), while no effect was shown on day 21. Ad-CCN1 treatment increased the adhering EPCs on the surface of injured vessels on day 7, and the ratio of GFP- and vWF-positive area to the total luminal length on day 14 was 2.3-fold higher in the Ad-CCN1-EPC transplanted group than in controls. Consistent with these findings, CCN1 stimulated EPC differentiation in vitro and 20 genes were found differentially expressed during CCN1-induced EPC differentiation, including Id1, Vegf-b, Vegf-c, Kdr, Igf-1, Ereg, Tgf, Mdk, Ptn, Timp2, etc. Among them, negative transcriptional regulator Id1 was associated with CCN1 effect on EPC differentiation. Our data suggest that CCN1, from the microenvironment of injured vessels, enhances reendothelialization via a direct action on EPC differentiation, revealing a possible new mechanism underlying the process of vascular repair. PMID- 20830590 TI - The chronology of second and third molar development in Koreans and its application to forensic age estimation. AB - The accuracy of forensic age estimation based on the chronology of second (M2) and third molar (M3) development was investigated using 2,087 orthopantomograms of Korean men and women aged between 3 and 23 years. The developmental stages of M2s and M3s in these subjects were classified using the criteria of Demirjian. Inter-observer reliability and statistical data on each stage of mineralization of M2s and M3s were evaluated. The left-right symmetries of the maturation degrees in the M2s and M3s were observed in both sexes, between which no arch differences were found, but statistically significant sex-specific differences were observed in some stages of M2 and M3 development. In multiple regression analysis, a strong positive relationship was observed between age and mineralization of M2s and M3s. The regression formulas for estimating the age of Koreans were presented based on sex and combination of teeth. These results suggest that the developments of second and third molars can be considered as valuable age indicators in Korean adolescents and young adults. PMID- 20830591 TI - Developing equine mtDNA profiling for forensic application. AB - Horse mtDNA profiling can be useful in forensic work investigating degraded samples, hair shafts or highly dilute samples. Degraded DNA often does not allow sequencing of fragments longer than 200 nucleotides. In this study we therefore search for the most discriminatory sections within the hypervariable horse mtDNA control region. Among a random sample of 39 horses, 32 different sequences were identified in a stretch of 921 nucleotides. The sequences were assigned to the published mtDNA types A-G, and to a newly labelled minor type H. The random match probability within the analysed samples is 3.61%, and the average pairwise sequence difference is 15 nucleotides. In a "sliding window" analysis of 200 nucleotide sections of the mtDNA control region, we find that the known repetitive central motif divides the mtDNA control region into a highly diverse segment and a markedly less discriminatory segment. PMID- 20830592 TI - Arterial elongation ("redundancy") is not a feature of spontaneous cervical artery dissection. AB - The prevalence of elongation of the internal carotid arteries (ICA) is suggested to be significantly higher in patients with spontaneous cervical artery dissection (sCAD) than in other stroke patients. We reassessed this hypothesis in a case-control study by means of an improved semiautomated MR imaging technique. We compared the length of the cervical arteries in patients with and without sCAD. In 40 consecutive patients with MRI proven sCAD, we measured the arterial lengths of both ICA from the cervical bifurcation to the carotid-T, as well as both vertebral arteries (VA) from their origin to the vertebro-basilar junction. The measurements were performed on the basis of high-resolution, three dimensional (3D) MR-angiographies with the use of specialized software calculating the length of the coaxial line of these arteries. These results were compared to the findings of 40 age-matched controls with an ischemic stroke due to other etiologies. The mean arterial lengths in patients with sCAD (left ICA 169.62 mm, right ICA 170.05 mm, left VA 233.56 mm, right VA 224.57 mm) compared to patients without sCAD (left ICA 171.07 mm, right ICA 171.88 mm, left VA 232.54 mm, right VA 222.08 mm) did not differ significantly. In our case-control study, cervical arteries are not elongated in patients with sCAD when compared to age matched stroke patients due to other etiologies. The finding of an arterial elongation is not a distinct clinical marker in patients with suspected sCAD. The macroscopic appearance of the cervical arteries on MR-angiograms does not suggest an underlying elongative or dilatative arteriopathy. PMID- 20830593 TI - Excellent response to acetazolamide in a case of paroxysmal dyskinesias due to GLUT1-deficiency. PMID- 20830594 TI - Role of the pepper cytochrome P450 gene CaCYP450A in defense responses against microbial pathogens. AB - Plant cytochrome P450 enzymes are involved in a wide range of biosynthetic reactions, leading to various fatty acid conjugates, plant hormones, or defensive compounds. Herein, we have identified the pepper cytochrome P450 gene CaCYP450A, which is differentially induced during Xanthomonas campestris pv. vesicatoria (Xcv) infection. CaCYP450A contains a heme-binding motif, PXFXXGXRXCXG, located in the C-terminal region and a hydrophobic membrane anchor region at the N terminal. Knock-down of CaCYP450A by virus-induced gene silencing (VIGS) led to increased susceptibility to Xcv infection in pepper. CaCYP450A-overexpressing Arabidopsis plants exhibited lower pathogen growth and reduced disease symptoms, and they were more resistant to Pseudomonas syringae pv. tomato (Pst) and Hyaloperonospora arabidopsidis than wild-type plants. Overexpression of CaCYP450A also enhanced H(2)O(2) accumulation and cell death. However, CaCYP450A Arabidopsis ortholog CYP94B3 mutants showed enhanced susceptibility to virulent Pst DC3000, but not to avirulent Pst DC3000 avrRpm1 or virulent H. arabidopsidis infection. Taken together, these results suggest that CaCYP450A is required for defense responses to microbial pathogens in plants. The nucleotide sequence data reported here has been deposited in the GenBank database under the accession number HM581974. PMID- 20830596 TI - Dormancy removal in apple embryos by nitric oxide or cyanide involves modifications in ethylene biosynthetic pathway. AB - The connection between classical phytohormone-ethylene and two signaling molecules, nitric oxide (NO) and hydrogen cyanide (HCN), was investigated in dormancy removal and germination "sensu stricto" of apple (Malus domestica Borkh.) embryos. Deep dormancy of apple embryos was removed by short-term (3-6 h) pre-treatment with NO or HCN. NO- or HCN-mediated stimulation of germination was associated with enhanced emission of ethylene by the embryos, coupled with transient increase in ROS concentration in embryos. Ethylene vapors stimulated germination of dormant apple embryos and eliminated morphological anomalies characteristic for young seedlings developed from dormant embryos. Inhibitors of ethylene receptors completely impeded beneficial effect of NO and HCN on embryo germination. NO- and HCN-induced ethylene emission by apple embryo was only slightly reduced by inhibitor of 1-aminocyclopropane-1-carboxylic acid (ACC) oxidase activity during first 4 days of germination. Short-term pre-treatment of the embryos with NO and HCN modified activity of both key enzymes of ethylene biosynthetic pathway: ACC synthase and ACC oxidase. Activity of ACC synthase declined during first 4 days of germination, while activity of ACC oxidase increased markedly at that time. Additional experiments point to non-enzymatic conversion of ACC to ethylene in the presence of ROS (H(2)O(2)). The results indicate that NO and HCN may alleviate dormancy of apple embryos "via" transient accumulation of ROS, leading to enhanced ethylene emission which is required to terminate germination "sensu stricto". Therefore, ethylene seems to be a trigger factor in control of apple embryo dormancy removal and germination. PMID- 20830595 TI - Identification and characterization of dwarf 62, a loss-of-function mutation in DLT/OsGRAS-32 affecting gibberellin metabolism in rice. AB - A dwarf mutant, dwarf 62 (d62), was isolated from rice cultivar 93-11 by mutagenesis with gamma-rays. Under normal growth conditions, the mutant had multiple abnormal phenotypes, such as dwarfism, wide and dark-green leaf blades, reduced tiller numbers, late and asynchronous heading, short roots, partial male sterility, etc. Genetic analysis indicated that the abnormal phenotypes were controlled by the recessive mutation of a single nuclear gene. Using molecular markers, the D62 gene was fine mapped in 131-kb region at the short arm of chromosome 6. Positional cloning of D62 gene revealed that it was the same locus as DLT/OsGRAS-32, which encodes a member of the GRAS family. In previous studies, the DLT/OsGRAS-32 is confirmed to play positive roles in brassinosteroid (BR) signaling. Sequence analysis showed that the d62 carried a 2-bp deletion in ORF region of D62 gene which led to a loss-of-function mutation. The function of D62 gene was confirmed by complementation experiment. RT-PCR analysis and promoter activity analysis showed that the D62 gene expressed in all tested tissues including roots, stems, leaves and panicles of rice plant. The d62 mutant exhibited decreased activity of alpha-amylase in endosperm and reduced content of endogenous GA(1). The expression levels of gibberellin (GA) biosynthetic genes including OsCPS1, OsKS1, OsKO1, OsKAO, OsGA20ox2/SD1 and OsGA2ox3 were significantly increased in d62 mutant. Briefly, these results demonstrated that the D62 (DLT/OsGRAS-32) not only participated in the regulation of BR signaling, but also influenced GA metabolism in rice. PMID- 20830597 TI - Influence of mitochondrial genome rearrangement on cucumber leaf carbon and nitrogen metabolism. AB - The MSC16 cucumber (Cucumis sativus L.) mitochondrial mutant was used to study the effect of mitochondrial dysfunction and disturbed subcellular redox state on leaf day/night carbon and nitrogen metabolism. We have shown that the mitochondrial dysfunction in MSC16 plants had no effect on photosynthetic CO(2) assimilation, but the concentration of soluble carbohydrates and starch was higher in leaves of MSC16 plants. Impaired mitochondrial respiratory chain activity was associated with the perturbation of mitochondrial TCA cycle manifested, e.g., by lowered decarboxylation rate. Mitochondrial dysfunction in MSC16 plants had different influence on leaf cell metabolism under dark or light conditions. In the dark, when the main mitochondrial function is the energy production, the altered activity of TCA cycle in mutated plants was connected with the accumulation of pyruvate and TCA cycle intermediates (citrate and 2-OG). In the light, when TCA activity is needed for synthesis of carbon skeletons required as the acceptors for NH(4) (+) assimilation, the concentration of pyruvate and TCA intermediates was tightly coupled with nitrate metabolism. Enhanced incorporation of ammonium group into amino acids structures in mutated plants has resulted in decreased concentration of organic acids and accumulation of Glu. PMID- 20830598 TI - Liquid barium is not representative of infant formula: characterisation of rheological and material properties. AB - Infants experiencing dysphagia may undergo a videofluoroscopic swallow study (VFSS) to assess radiologically their coordination for sucking, swallowing, and breathing. No studies known to these authors have investigated whether the liquids used during infant radiological procedures are representative of liquids routinely fed to infants (e.g., formula). This study used an Advanced Rheometric Expansion System (ARES) strain-controlled rheometer to compare prethickened antiregurgitation formula, regular (thin) infant formula, and two types of regular infant formula, hand-thickened with a thickening agent and with liquid PolibarTM (barium-impregnated liquid). The viscosity, density, and yield stress of all samples were determined. Heated versus cooled liquids were compared. Results showed a significant difference in all rheological and material property parameters among the barium-impregnated liquids and the thickened and unthickened infant formula. This finding has important implications for the interpretation of the radiological results and subsequent clinical recommendations. PMID- 20830599 TI - Pretreatment prediction of response to peginterferon plus ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis. AB - BACKGROUND: This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C. METHODS: Data from 800 genotype 1b chronic hepatitis C patients with high viral load (>100,000 IU/ml) treated by peg-interferon plus ribavirin at 6 hospitals in Japan were randomly assigned to a model building (n = 506) or an internal validation (n = 294). Data from 524 patients treated at 29 hospitals in Japan were used for an external validation. Factors predictive of SVR were explored using data mining analysis. RESULTS: Age (<50 years), alpha fetoprotein (AFP) (<8 ng/mL), platelet count (>= 120 * 10(9)/l), gamma glutamyltransferase (GGT) (<40 IU/l), and male gender were used to build the decision tree model, which divided patients into 7 subgroups with variable rates of SVR ranging from 22 to 77%. The reproducibility of the model was confirmed by the internal and external validation (r (2) = 0.92 and 0.93, respectively). When reconstructed into 3 groups, the rate of SVR was 75% for the high probability group, 44% for the intermediate probability group and 23% for the low probability group. Poor adherence to drugs lowered the rate of SVR in the low probability group, but not in the high probability group. CONCLUSIONS: A decision tree model that includes age, gender, AFP, platelet counts, and GGT is useful for predicting the probability of response to therapy with peg-interferon plus ribavirin and has the potential to support clinical decisions regarding the selection of patients for therapy. PMID- 20830600 TI - Three genetic grapevine leafroll-associated virus 3 variants identified from South African vineyards show high variability in their 5'UTR. AB - Three genetic variants of grapevine leafroll-associated virus 3 (GLRaV-3) were identified in vineyards of the Western Cape, South Africa. The GLRaV-3 variants were identified by single-strand conformation polymorphism (SSCP) profiles generated from a region amplified in ORF5. ORF5 sequence data confirmed the three genetic variant groups, and a specific SSCP profile was assigned to each variant group. The results of SSCP analysis of this region in ORF5 showed that this method gives a fast and reliable indication of the GLRaV-3 variant status of a plant, which in many instances showed mixed infections. The full genome sequence of one representative of each variant group i.e. isolates 621 (group I), 623 (group II) and PL-20 (group III), was determined by sequencing overlapping cloned fragments of these isolates. The sequences of genomic 5' ends of these isolates were determined by RLM-RACE. Sequence alignment of the 5'UTRs indicated significant sequence and length variation in this region between the three South African variant groups. Alignment of the Hsp70h and CP gene regions of these isolates with those of isolates from elsewhere in the world, followed by phylogenetic analysis, further supported the presence of three variants of GLRaV 3 in South Africa and the presence of two or three additional variant groups elsewhere in the world. PMID- 20830601 TI - Binding of Ca2+ and Zn2+ to factor IX/X-binding protein from venom of Agkistrodon halys Pallas: stabilization of the structure during GdnHCl-induced and thermally induced denaturation. AB - Coagulation factor IX/coagulation factor X binding protein from the venom of Agkistrodon halys Pallas (AHP IX/X-bp) is a unique coagulation factor IX/coagulation factor X binding protein (IX/X-bp). Among all IX/X-bps identified, only AHP IX/X-bp is a Ca(2+)- and Zn(2+)-binding protein. The binding properties of Ca(2+) and Zn(2+) ions binding to apo-AHP IX/X-bp and their effects on the stability of the protein have been investigated by isothermal titration calorimetry, fluorescence spectroscopy, and differential scanning calorimetry. The results show that AHP IX/X-bp has two metal binding sites, one specific for Ca(2+) with lower affinity for Zn(2+) and one specific for Zn(2+) with lower affinity for Ca(2+). The bindings of Ca(2+) and Zn(2+) in the two sites are entropy- and enthalpy-driven. The binding affinity of AHP IX/X-bp for Zn(2+) is 1 order of magnitude higher than for Ca(2+) for either high-affinity binding or low affinity binding, which accounts for the existence of one Zn(2+) in the purified AHP IX/X-bp. Guanidine hydrochloride (GdnHCl)-induced and thermally induced denaturations of Ca(2+)-Ca(2+)-AHP IX/X-bp, Zn(2+)-Zn(2+)-AHP IX/X-bp, and Ca(2+) Zn(2+)-AHP IX/X-bp are all a two-state processes with no detectable intermediate state(s), indicating the Ca(2+)/Zn(2+)-induced tight packing of the protein. Ca(2+) and Zn(2+) increase the structural stability of AHP IX/X-bp against GdnHCl or thermal denaturation to a similar extent. Although Ca(2+) and Zn(2+) have no obvious effect on the secondary structure of AHP IX/X-bp, they induce different rearrangements in local conformation. The Zn(2+)-stabilized specific conformation of AHP IX/X-bp may be helpful to its recognition of the structure of coagulation factor IX. This work suggests that in vitro, Ca(2+) plays a structural rather than an active role in the anticoagulation of AHP IX/X-bp, whereas Zn(2+) plays both structural and active roles in the anticoagulation. In blood, Ca(2+) binds to AHP IX/X-bp and stabilizes its structure, whereas Zn(2+) cannot bind to AHP IX/X-bp owing to the low Zn(2+) concentration. AHP IX/X-bp prolongs the clotting time in vivo through its binding only with coagulation factor X/activated coagulation factor X. PMID- 20830602 TI - Evaluation of biosynthetic pathways for the unique dithiolate ligand of the FeFe hydrogenase H-cluster. PMID- 20830603 TI - Hypofractionated stereotactic radiotherapy for acoustic neuromas: safety and effectiveness over 8 years of experience. AB - BACKGROUND: Little information is available about long-term outcomes of hypofractionated stereotactic radiotherapy (hypo-FSRT) for acoustic neuromas. In this study, the safety and effectiveness of hypo-FSRT for unilateral acoustic neuroma were reviewed over 8 years of experience at our institution. METHODS: Between May 1998 and October 2006, 27 patients were consecutively treated by linear accelerator-based hypo-FSRT. Two patients were excluded from this study because they were lost to follow-up within 12 months. The median follow-up period for the rest was 59 (range 24-133) months. Two types of treatment schedules were adopted. Thirteen patients received 30-39 Gy, given in 10-13 fractions (regimen A), whereas after July 2003, 12 patients received 20-24 Gy, given in 5-6 fractions at the tumor periphery (regimen B). These treatments were scheduled to be delivered in three fractions per week (Monday, Wednesday, Friday). The median planning target volume was 2.0, with 1.7 ml (range 0.7-10.6) in regimen A and 5.2 ml (range 0.9-9.3) in regimen B. In the pretreatment audiogram, seven patients (two in regimen A and five in regimen B) had serviceable hearing (Gardner Robertson Class I-II). RESULTS: Local control rates were 100% with regimen A and 92% with regimen B. Serviceable hearing was preserved in four of five patients in regimen B but no patients in regimen A at the last follow-up. No permanent facial or trigeminal nerve morbidity was observed following treatment, and no salvage surgery was needed. CONCLUSIONS: Hypo-FSRT for acoustic neuromas achieved a high local control rate with minimal facial and trigeminal nerve morbidity. PMID- 20830605 TI - Biodegradation of polyfluorinated biphenyl in bacteria. AB - Fluorinated aromatic compounds are significant environmental pollutants, and microorganisms play important roles in their biodegradation. The effect of fluorine substitution on the transformation of fluorobiphenyl in two bacteria was investigated. Pseudomonas pseudoalcaligenes KF707 and Burkholderia xenovorans LB400 used 2,3,4,5,6-pentafluorobiphenyl and 4,4'-difluorobiphenyl as sole sources of carbon and energy. The catabolism of the fluorinated compounds was examined by gas chromatography-mass spectrometry and fluorine-19 nuclear magnetic resonance spectroscopy (19F NMR), and revealed that the bacteria employed the upper pathway of biphenyl catabolism to degrade these xenobiotics. The novel fluorometabolites 3-pentafluorophenyl-cyclohexa-3,5-diene-1,2-diol and 3 pentafluorophenyl-benzene-1,2-diol were detected in the supernatants of biphenyl grown resting cells incubated with 2,3,4,5,6-pentafluorobiphenyl, most likely as a consequence of the actions of BphA and BphB. 4-Fluorobenzoate was detected in cultures incubated with 4,4'-difluorobiphenyl and 19F NMR analysis of the supernatant from P. pseudoalcaligenes KF707 revealed the presence of additional water-soluble fluorometabolites. PMID- 20830604 TI - A novel bispecific ligand-directed toxin designed to simultaneously target EGFR on human glioblastoma cells and uPAR on tumor neovasculature. AB - A bispecific ligand-directed toxin (BLT), called EGFATFKDEL, consisting of human epidermal growth factor, a fragment of urokinase, and truncated pseudomonas exotoxin (PE38) was assembled in order to target human glioblastoma. Immunogenicity was reduced by mutating seven immunodominant B-cell epitopes on the PE38 molecule to create a new agent, EGFATFKDEL 7mut. In vitro, the drug selectively killed several human glioblastoma cell lines. EGFATFKDEL is our first BLT designed to simultaneously target EGFR on solid tumors and uPAR on the tumor neovasculature. In vitro assays revealed that the agent is effective against glioblastoma cell lines as well as human umbilical vein endothelial cells (HUVEC). Additionally, the bispecific drug displayed enhanced binding to overexpressed epidermal growth factor receptor and urokinase receptor when compared to similar monospecific drugs, EGFKDEL and ATFKDEL. In vivo, an aggressive human glioblastoma cell line was genetically marked with a firefly luciferase reporter gene and administered to the flanks of nude mice. Treatment with intratumoral injections of EGFATFKDEL 7mut eradicated small tumors in over half of the treated mice, which survived with tumor free status at least 100 days post tumor inoculation. ATFKDEL, which primarily targets the tumor neovasculature, prevented tumor growth but did not result in tumor-free mice in most cases. Specificity was shown by treating with an irrelevant BLT control which did not protect mice. Finally, immunization experiments in immunocompetent mice revealed significantly reduced anti-toxin production in EGFATFKDEL 7mut treated groups. Thus, EGFATFKDEL 7mut is an effective drug for glioblastoma therapy in this murine model and warrants further study. PMID- 20830608 TI - Maintenance and expansion of hematopoietic stem/progenitor cells in biomimetic osteoblast niche. AB - In this study, we employed bio-derived bone scaffold and composited with the marrow mesenchymal stem cell induced into osteoblast to replicate a "biomimetic niche." The CD34(+) cells or mononuclear cells (MNC) from umbilical cord blood were cultured for 2-5 weeks in the biomimetic niche (3D system) was compared with conventional two dimensional cultures (2D system) without adding cytokine supplement. After 2 weeks in culture, the CD34(+) cells from umbilical cord blood in the 3D system increased 3.3-4.8 folds when compared with the initial CD34(+) cells. CD34(+)/CD38(-) cells accounted for 82-90% of CD34(+) cells. After 5 weeks, CD34(+)/CD38(-) cells in the 3D system increased when compared with initial (1.3 +/- 0.3 * 10(3) vs. 1.0 +/- 0.5 * 10(4), p < 0.05), but were decreased in the 2D system (1.3 +/- 0.3 * 10(3) vs. 2.5 +/- 0.7 * 10(2), p < 0.05). The CFU progenitors were produced more in the 3D system than in the 2D system (4.6-9.3 folds vs. 1.0-1.5 folds) after 2 weeks in culture, and the colony distribution in the 3D system manifested higher percentage of BFU-E and CFU-GEMM, but in the 2D system was mainly CFU-GM. The LTC-ICs in the 3D system showed 5.2 7.2 folds increase over input at 2 weeks in culture, and maintain the immaturation of hematopoietic progenitor cells (HPCs) over 5 weeks. In conclusion, this new 3D hematopoietic progenitor cell culture system is the first to utilize natural cancellous bone as scaffold with osteoblasts as supporting cells; it is mimicry of natural bone marrow HSC niche. Our primary work has demonstrated it could maintain and expand HSC/HPC in vitro. PMID- 20830606 TI - Creatine prevents the inhibition of energy metabolism and lipid peroxidation in rats subjected to GAA administration. AB - Guanidinoacetate methyltransferase (GAMT) deficiency is an inherited neurometabolic disorder, biochemically characterized by the tissue accumulation of guanidinoacetate (GAA). Affected patients present epilepsy and mental retardation whose etiopathogeny is unclear. Previous reports have shown that GAA alters brain energy metabolism and that creatine, which is depleted in patients with GAMT deficiency, can act as a neuroprotector; as such, in the present study we investigated the effect of creatine administration on some of the altered parameters of energy metabolism (complex II, Na(+),K(+)-ATPase and creatine kinase) and lipid peroxidation caused by intrastriatal administration of GAA in adult rats. Animals were pretreated for 7 days with daily intraperitonial administrations of creatine. Subsequently, these animals were divided into two groups: Group 1 (sham group), rats that suffered surgery and received saline; and group 2 (GAA-treated). Thirty min after GAA or saline, the animals were sacrificed and the striatum dissected out. Results showed that the administration of creatine was able to reverse the activities of complex II, Na(+),K(+)-ATPase and creatine kinase, as well as, the levels of thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation. These findings indicate that the energy metabolism deficit caused by GAA may be prevented by creatine, which probably acts as an antioxidant since it was able to prevent lipid peroxidation. These data may contribute, at least in part, to a better understanding of the mechanisms related to the energy deficit and oxidative stress observed in GAMT deficiency. PMID- 20830609 TI - OmpR controls Yersinia enterocolitica motility by positive regulation of flhDC expression. AB - Flagella and invasin play important roles during the early stages of infection by the enteric pathogen Yersinia enterocolitica. Our previous study demonstrated that OmpR negatively regulates invasin gene expression at the transcriptional level. The present study focused on the role of OmpR in the regulation of flagella expression. Motility assays and microscopic observations revealed that an ompR mutant strain exhibits a non-motile phenotype due to the lack of flagella. An analysis of flhDC::lacZYA chromosomal fusions demonstrated a decrease in flhDC expression in ompR mutant cells, suggesting a role for OmpR in the positive control of flagellar master operon flhDC, which is in contrast to the negative role it plays in Escherichia coli. Moreover, high temperature or osmolarity and low pH decreased flhDC expression and OmpR was not required for the response to these factors. Evidence from an examination of the DNA binding properties of OmpR in vitro indicated that the mechanism by which OmpR regulates flhDC is direct. Electrophoretic mobility shift assays confirmed that OmpR binds specifically to the flhDC promoter region and suggested the presence of more than one OmpR-binding site. In addition, phosphorylation of OmpR by acetyl-P appeared to stimulate the binding abilities of OmpR. Together with the results of our previous studies revealing the negative role of OmpR in the regulation of invasin expression, these findings support a model in which invasion and motility might be reciprocally regulated by OmpR. PMID- 20830610 TI - Multiple limit cycles in a Gause type predator-prey model with Holling type III functional response and Allee effect on prey. AB - This work aims to examine the global behavior of a Gause type predator-prey model considering two aspects: (i) the functional response is Holling type III and, (ii) the prey growth is affected by the Allee effect. We prove the origin of the system is an attractor equilibrium point for all parameter values. It has also been shown that it is the omega-limit of a wide set of trajectories of the system, due to the existence of a separatrix curve determined by the stable manifold of the equilibrium point (m,0), which is associated to the Allee effect on prey. When a weak Allee effect on the prey is assumed, an important result is obtained, involving the existence of two limit cycles surrounding a unique positive equilibrium point: the innermost cycle is unstable and the outermost stable. This property, not yet reported in models considering a sigmoid functional response, is an important aspect for ecologists to acknowledge as regards the kind of tristability shown here: (1) the origin; (2) an interior equilibrium; and (3) a limit cycle of large amplitude. These models have undoubtedly been rather sensitive to disturbances and require careful management in applied conservation and renewable resource contexts. PMID- 20830612 TI - Islet versus pancreas transplantation in type 1 diabetes: competitive or complementary? AB - Whole organ pancreas and pancreatic islet transplantation are currently the only forms of clinically available beta-cell replacement. Both therapeutic options can provide good glycemic control and prevention or stabilization of diabetic complications, but at the price of permanent immunosuppression. Therefore, the indication for transplantation of type 1 diabetes patients must be balanced carefully and should be restricted to a subgroup of patients with extreme lability of metabolic control and frequent hypoglycemia despite optimal medical therapy. PMID- 20830611 TI - Mesenchymal stem cells stimulate endogenous neurogenesis in the subventricular zone of adult mice. AB - Mammalian neurogenesis has been demonstrated in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. However, the low rate and the restricted long term survival of newborn cells limit the restorative ability of this process. Adult bone marrow derived mesenchymal stem cells (MSCs) have been extensively studied due to their wide therapeutic potential. The aim of this study was to determine if MSC transplantation to the normally restrictive SVZ of mice housed in an enriched environment stimulates endogenous neurogenesis. In the presented study 30 C57BL/6 female mice were divided into 3 groups: standard environment injected with phosphate buffered saline (PBS) and enriched environment injected with either PBS or MSCs. Bromodeoxyuridine was injected for 6 days, and 3 weeks later the mice were sacrificed and the brain tissue analyzed immunohistochemically. PBS-treated mice housed in enriched cages showed augmented neurogenesis in the SGZ but not the SVZ. MSC transplantation was associated with increased proliferation and neuronal differentiation of neural progenitors within the SVZ and an increase in the proportion of the newborn neurons out of the total proliferating cells. Histological analysis confirmed the survival of a significant amount of the transplanted cells at least 3 weeks after transplantation, and the presence of brain-derived neurotrophic factor expression. To our knowledge, this is the first study to show that MSCs might interfere with the tight regulation of the SVZ, independent of the induced brain lesion. PMID- 20830613 TI - Giant granulocytic sarcoma of the vagina concurrent with acute myeloid leukemia with t(8;21)(q22;q22) translocation. PMID- 20830614 TI - Intensified consolidation therapy with dose-escalated doxorubicin did not improve the prognosis of adults with acute lymphoblastic leukemia: the JALSG-ALL97 study. AB - We designed a treatment protocol for newly diagnosed adult acute lymphoblastic leukemia (ALL) in the pre-imatinib era, employing intensified consolidation therapy with a total of 330 mg/m2 doxorubicin and adopting slightly modified induction and maintenance regimen of the CALGB 8811 study. Of 404 eligible patients (median age 38 years, range 15-64 years), 298 (74%) achieved complete remission (CR). The 5-year overall survival (OS) rate was 32%, and the 5-year disease-free survival (DFS) rate was 33%. Of 256 Philadelphia chromosome (Ph) negative patients, 208 (81%) achieved CR and the 5-year OS rate was 39%, and 60 of them underwent allogeneic-hematopoietic stem cell transplantation (allo-HSCT) from related or unrelated donors during the first CR, resulting in 63% 5-year OS. Of 116 Ph-positive patients, 65 (56%) achieved CR and the 5-year OS rate was 15%, and 22 of them underwent allo-HSCT from related or unrelated donors during the first CR, resulting in 47% 5-year OS. In Ph-negative patients, multivariate analysis showed that older age, advanced performance status and unfavorable karyotypes were significant poor prognostic factors for OS and higher WBC counts for DFS. The present treatment regimen could not show a better outcome than that of our previous JALSG-ALL93 study for adult ALL. PMID- 20830615 TI - Clinical significance of minimal residual disease in adult acute lymphoblastic leukemia. AB - Monitoring minimal residual disease (MRD) in patients with acute lymphoblastic leukemia (ALL) is a useful way for assessing treatment response and relapse. We studied the value of MRD and showed a correlation with relapse for 34 adult patients with ALL. MRD was evaluated by real-time quantitative polymerase chain reaction (RQ-PCR) with probes derived from fusion chimeric genes (BCR/ABL) (n = 12) or PCR-based detection of clonal immunoglobulin and T cell receptor gene rearrangements (n = 16), or both (n = 6). We analyzed 27 of the 34 patients who could be examined for MRD on day 100 after induction therapy. The overall survival (OS) rate (45.0%) and relapse-free survival (RFS) rate (40.0%) at 2 years in complete remission (CR) patients with MRD level >= 10-3 (n = 12) were significantly lower than those in CR patients with MRD level <10(-3) (n = 15) (OS rate 79.0%, RFS rate 79.4%) (log-rank test, P = 0.017 and 0.0007). We also applied multicolor flow cytometry for comparison with MRD results analyzed by PCR methods. The comparison of results obtained in 27 follow-up samples showed consistency in 17 samples (63.0%) (P = 0.057). MRD analysis on day 100 is important for treatment decision in adult ALL. PMID- 20830618 TI - What does the match mean for the growth and development of family medicine? PMID- 20830616 TI - Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors. AB - It is well known that sonic hedgehog signaling pathway plays a vital role during early embryonic development. It is also responsible for stem cell renewal and development of several cancers like colorectal and breast carcinoma and major brain tumors as medulloblastoma and glioblastoma. The role of sonic hedgehog signaling in the development of neuroblastoma has not been thoroughly investigated. In this study, we attempted to determine the expression of Bmi-1 stem cell marker and of Shh pathway downstream target genes glioma-associated oncogene homolog 1 (GLI1), protein patched homolog 1 (PTCH1), Cyclin D2, plakoglobin (gamma catenin), NK2 homeobox 2 (NKX2.2), paired box gene 6 (PAX6), secreted frizzled-related protein 1 (SFRP1), and hedgehog interacting protein (HHIP) in 11 neuroblastoma cell lines and 41 neuroblastoma samples. Also, inhibition of the pathway was performed genetically by GLI1 knockdown siRNA or chemically by cyclopamine. After inhibition, low transcript expression was detected in downstream target genes like PTCH1, in the cell lines. We further preformed promoter methylation studies of Cyclin D2, PTCH1, HHIP, and SFRP1 genes by melting curve analysis-based methylation assay (MCA-Meth) and methylation specific PCR (MSP). Results revealed no methylation in Cyclin D2 gene promoter in neuroblastoma samples or in cell lines; one cell line (MHH-NB-11) showed PTCH1 methylation; 3/11 (27%) cell lines and 9/41 (22%) neuroblastoma samples showed HHIP methylation; and 3/11 (27%) cell lines and 11/41 (27%) samples showed SFRP1 methylation. Taken together, our results suggest the possibility of two levels of control of the sonic hedgehog signaling pathway: transcriptional and epigenetic, which might offer new therapeutic possibilities to modulate the pathway and try to suppress tumor growth. PMID- 20830619 TI - Entry of US medical school graduates into family medicine residencies: 2009--2010 and 3-year summary. AB - This is the 29th report prepared by the American Academy of Family Physicians (AAFP) on the percentage of each US medical school's graduates entering family medicine residency programs. Approximately 7.5% of the 16,617 graduates of US medical schools between July 2008 and June 2009 were first-year family medicine residents in 2009, compared with 8.2% in 2008 and 8.3% in 2007. Medical school graduates from publicly funded medical schools were more likely to be first-year family medicine residents in October 2009 than were residents from privately funded schools, 8.8% compared with 5.3%. The Mountain and West North Central regions reported the highest percentage of medical school graduates who were first-year residents in family medicine programs in October 2009 at 13.4% and 11.0%, respectively; the New England and Middle Atlantic regions reported the lowest percentages at 7.0% and 4.4%, respectively. Nearly half of the medical school graduates (48.3%) entering a family medicine residency program as first year residents in October 2009 entered a program in the same state where they graduated from medical school. The percentages for each medical school have varied substantially from year to year since the AAFP began reporting this information. This article reports the average percentage for each medical school for the last 3 years. Also reported are the number and percentage of graduates from colleges of osteopathic medicine who entered Accreditation Council for Graduate Medical Education-accredited family medicine residency programs, based on estimates provided by the American Association of Colleges of Osteopathic Medicine. These numbers are retrospective analyses based on numbers reported to the AAFP from medical schools and family medicine residency programs. PMID- 20830620 TI - Results of the 2010 national resident matching program: family medicine. AB - The results of the 2010 National Resident Matching Program (NRMP) reflect a small but promising increased level of student interest in family medicine residency training in the United States. Compared with the 2009 Match, 75 more positions (with 101 more US seniors) were filled in family medicine residency programs through the NRMP in 2010, at the same time that seven more positions were filled in primary care internal medicine (one more US senior), 14 fewer positions were filled in pediatrics-primary care (16 fewer US seniors), and 16 more positions were filled in internal medicine-pediatrics programs (58 more US seniors). Multiple forces including student perspectives of the demands, rewards, and prestige of the specialty; national dialogue about health care reform; turbulence in the economic environment; lifestyle issues; the advice of deans; and the impact of faculty role models continue to influence medical student career choices. Ninety-four more positions (90 more US seniors) were filled in categorical internal medicine. Fifty-seven more positions (29 more US seniors) were filled in categorical pediatrics programs. The 2010 NRMP results suggest that there is a small increase in primary care careers; however, students continue to show an overall preference for subspecialty careers. Despite matching the highest number of US seniors into family medicine residencies since 2004, in 2010 the production of family physicians remains insufficient to meet the current and anticipated need to support the nation's primary care infrastructure. PMID- 20830621 TI - Faculty, resident, and clinic staff's evaluation of the effects of EHR implementation. AB - BACKGROUND AND OBJECTIVES: There have been few reports on the effect of electronic health record (EHR) implementation as seen by those most responsible for using the system in a residency program. Our objective was to investigate how faculty, residents, and both clinical and nonclinical staff view the effects of EHR implementation on a broad range of issues. METHODS: All 72 personnel were surveyed at 8 months (response rate 75%) and 12 months (response rate 57%) following full implementation of the EHR. The survey inquired into subjective perceptions of amount of time spent documenting and occurrence of documentation, effect on patient care, interference with other activities, effect on communication and relationships, coding/billing process, and overall efficiency. RESULTS: Since EHR implementation, faculty and residents perceived documentation as taking 13 minutes per patient. It was seen as interfering with personal and educational time. Perception of all personnel was that the EHR was having a negative effect on patient care. There was no detectable statistically significant change between the 8- and 12-month surveys. CONCLUSION: A perception of the promised improvement in patient care, provider communications, and billing efficiency due to EHR implementation was not realized in this population. PMID- 20830622 TI - Using the communication assessment tool in family medicine residency programs. AB - BACKGROUND AND OBJECTIVES: The Communication Assessment Tool (CAT), developed by Makoul et al assesses patient perceptions of physicians' interpersonal and communication skills. The objective of this study was to gather initial benchmarking data for the use of the CAT in family medicine residency programs. METHODS: Data were collected from patients seeing 127 residents from six family medicine residency programs. A total of 1,931 patients completed the paper and pencil version of the CAT following an appointment with a resident; 1,880 of the CAT forms met the inclusion criteria for analysis. RESULTS: The overall mean percentage of items from which residents were rated as excellent was 69.7%. Significant differences were found in the overall percentage of items rated as excellent based on training year, with PGY-1 (77.0%) residents being rated significantly higher than PGY-2 (69.5%) and PGY-3 (68.1%) residents. There were no significant differences found in the overall percentage of items rated as excellent based on the native language or gender of the residents. CONCLUSIONS: This initial benchmarking data can allow family medicine residency programs to compare the performance of their residents with the performance of residents from other programs. We recommend that the results of the CAT be used as both an evaluative and learning tool. PMID- 20830623 TI - ACGME core competencies: Who knows what and does it matter? PMID- 20830624 TI - Comparison of methods for setting weight loss goals in males. PMID- 20830625 TI - How to build a medical home in your residency program. PMID- 20830626 TI - Teaching palliative care to residents and medical students. PMID- 20830627 TI - The night a student doctor cut the cord. PMID- 20830628 TI - The role of intravenous valproate in convulsive status epilepticus in the future. PMID- 20830630 TI - Speaking of events: the case of C.M. AB - C.M. is an agrammatic patient who on assessment tests shows a disproportionate difficulty when producing verbs compared with nouns. In three experiments, we investigated whether C.M. also has difficulties with nouns referring to events and whether event nouns and verbs show similar patterns of disruption. Experiment 1 suggested that she is sensitive to argument structure complexity and has a greater impairment in the production of event nouns and verbs than object nouns. Experiment 2 revealed that C.M. finds derivationally complex words, such as event nouns, difficult to produce. However, morphological complexity does not completely explain C.M.'s problems with event nouns. In Experiment 3, an assessment of C.M.'s ability to use different aspects of semantic and syntactic knowledge relative to event nouns and verbs showed an almost identical performance with the two types of words. The relevance of the findings with respect to models of word production is considered. PMID- 20830629 TI - Psychometric properties of the Generalized Anxiety Disorder Questionnaire for DSM IV among four racial groups. AB - The Generalized Anxiety Disorder Questionnaire-IV (GAD-Q-IV) is a self-report diagnostic measure of generalized anxiety disorder. Previous studies have established the psychometric properties of the GAD-Q-IV, revealing excellent diagnostic specificity and sensitivity as well as good test-retest reliability and convergent and discriminant validity (Newman et al., 2002). Recent analyses with other measures of anxiety symptoms have revealed differences across racial or national groups. Given that the GAD-Q-IV was tested primarily on Caucasians (78%), the purpose of this study was to demonstrate the psychometric properties of the GAD-Q-IV across four racial groups: African American, Caucasian, Hispanic/Latino, and Asian. A student sample of 585 undergraduate psychology students completed the GAD-Q-IV as well as other measures of anxiety symptoms. A clinical replication sample included 188 participants who completed the GAD-Q-IV as part of a larger psychotherapy study. Results indicated excellent and very similar factor structures in the student sample and similar psychometric properties in both samples across the racial groups. Implications for the use of the GAD-Q-IV across racial groups are discussed. PMID- 20830631 TI - Grammatical category dissociation in multilingual aphasia. AB - Word retrieval deficits for specific grammatical categories, such as verbs versus nouns, occur as a consequence of brain damage. Such deficits are informative about the nature of lexical organization in the human brain. This study examined retrieval of grammatical categories across three languages in a trilingual person with aphasia who spoke Arabic, French, and English. In order to delineate the nature of word production difficulty, comprehension was tested, and a variety of concomitant lexical-semantic variables were analysed. The patient demonstrated a consistent noun-verb dissociation in picture naming and narrative speech, with severely impaired production of verbs across all three languages. The cross linguistically similar noun-verb dissociation, coupled with little evidence of semantic impairment, suggests that (a) the patient has a true "nonsemantic" grammatical category specific deficit, and (b) lexical organization in multilingual speakers shares grammatical class information between languages. The findings of this study contribute to our understanding of the architecture of lexical organization in bilinguals. PMID- 20830632 TI - Is dietary fat "fattening"? A comprehensive research synthesis. AB - The goal of this research synthesis was to separate and articulate questions that had clear meaning, were empirically addressable, and were germane to the broad question "Is fat fattening?" Four such questions addressing the effect of varying the proportion of dietary fat on body weight and body fat were formulated. A comprehensive review of electronic citation databases was conducted to identify studies that addressed each question. The results of the studies addressing each question were tabulated and summarized, and an answer for each question was formulated. The results indicated that whether "fat is fattening" depends on exactly what one means by the question. It is apparent that under conditions of energy deficit, high-fat diets lead to greater weight loss than low-fat diets, but under ad libitum feeding conditions, instructing persons to follow a low-fat diet promotes loss of body weight and body fat. For one question, studies were few but convincing that altering the proportion of energy from fat in daily snacks has no effect on weight, while for another there were not enough studies available to answer the question with confidence. General recommendations to reduce dietary fat to promote weight loss or maintenance in all circumstances may merit reconsideration. PMID- 20830633 TI - Functional microorganisms for functional food quality. AB - Functional microorganisms and health benefits represent a binomial with great potential for fermented functional foods. The health benefits of fermented functional foods are expressed either directly through the interactions of ingested live microorganisms with the host (probiotic effect) or indirectly as the result of the ingestion of microbial metabolites synthesized during fermentation (biogenic effect). Since the importance of high viability for probiotic effect, two major options are currently pursued for improving it--to enhance bacterial stress response and to use alternative products for incorporating probiotics (e.g., ice cream, cheeses, cereals, fruit juices, vegetables, and soy beans). Further, it seems that quorum sensing signal molecules released by probiotics may interact with human epithelial cells from intestine thus modulating several physiological functions. Under optimal processing conditions, functional microorganisms contribute to food functionality through their enzyme portfolio and the release of metabolites. Overproduction of free amino acids and vitamins are two classical examples. Besides, bioactive compounds (e.g., peptides, gamma-amino butyric acid, and conjugated linoleic acid) may be released during food processing above the physiological threshold and they may exert various in vivo health benefits. Functional microorganisms are even more used in novel strategies for decreasing phenomenon of food intolerance (e.g., gluten intolerance) and allergy. By a critical approach, this review will aim at showing the potential of functional microorganisms for the quality of functional foods. PMID- 20830634 TI - Chemistry and biotechnology of carotenoids. AB - Carotenoids are one of the most widespread groups of pigments in nature and more than 600 of these have been identified. Beside provitamin A activity, carotenoids are important as antioxidants and protective agents against various diseases. They are isoprenoids with a long polyene chain containing 3 to 15 conjugated double bonds, which determines their absorption spectrum. Cyclization at one or both ends occurs in hydrocarbon carotene, while xanthophylls are formed by the introduction of oxygen. In addition, modifications involving chain elongation, isomerization, or degradation are also found. The composition of carotenoids in food may vary depending upon production practices, post-harvest handling, processing, and storage. In higher plants they are synthesized in the plastid. Both mevalonate dependent and independent pathway for the formation of isopentenyl diphosphate are known. Isopentenyl diphosphate undergoes a series of addition and condensation reactions to form phytoene, which gets converted to lycopene. Cyclization of lycopene either leads to the formation of beta-carotene and its derivative xanthophylls, beta-cryptoxanthin, zeaxanthin, antheraxanthin, and violaxanthin or alpha-carotene and lutein. Even though most of the carotenoid biosynthetic genes have been cloned and identified, some aspects of carotenoid formation and manipulation in higher plants especially remain poorly understood. In order to enhance the carotenoid content of crop plants to a level that will be required for the prevention of diseases, there is a need for research in both the basic and the applied aspects. PMID- 20830635 TI - New applications and mechanisms of action of saffron and its important ingredients. AB - Saffron (Crocus sativus L.) has been an important subject of interest for research teams in the past two decades because of its various biological properties. Chemical analysis has shown the presence of more than 150 components in saffron stigmas. Here, we review the medicinal and industrial applications of saffron. Then, the new findings from different research groups about its medicinal properties and various cellular and molecular mechanisms of action will be discussed. The methods used for this study included searching Web of Science and Medline for saffron and its constituent's applications. The results show that in recent years saffron's application in a variety of disorders involving neuronal, cardiovascular and other systems, as well as cancer have been investigated. The cellular and molecular mechanisms of its action are also under study. The more powerful components of saffron are carotenoids and monoterpene aldehydes. Structure-function relationship studies show that some properties are related to deglycosylated derivatives, while others belong to more glycosylated ones. Our study concludes that saffron has a wide range of usefulness in medicine, cosmetics, and coloring industries, so it can be used for new drug designs. However, more research about its mechanism of action is needed. PMID- 20830636 TI - Role of ingredients in pasta product quality: a review on recent developments. AB - Pasta is prepared using dough made from any suitable material such as semolina, durum flour, farina flour, corn, rice, wheat, or any combination of these, with water. Also, pasta can be enriched, supplemented, fortified, or remain conventional. In recent years, several ingredients and additives have been developed and are being used to improve the quality of pasta made from aestivum or durum wheat. Here we analyze how the different ingredients play an important role in pasta manufacture by enhancing nutritional parameters, palatability, and overall product quality. PMID- 20830637 TI - Desire, drug use and unsafe sex: a qualitative examination of gay men who attend gay circuit parties. AB - Recently, there has been an increase in research dedicated to the topic of drug/alcohol use and unsafe sex among gay men. Findings of this work suggest that drug/alcohol use is particularly common within gay circuit parties (GCPs). More recently, this work has begun to suggest that further exploration is needed to understand the desires of gay men who use drugs and alcohol and who engage in unsafe sex. Based on the foregoing, an ethnographic study was undertaken with the goal of better understanding the role of desire in the sequence of drugs/alcohol and unsafe sex. This research was guided theoretically by Deleuze and Guattari's work on desire. Using this theoretical orientation, the results revealed that some GCP-goers intentionally use drugs/alcohol to form connections. PMID- 20830638 TI - Neurologic birth injury. Protecting the legal rights of the child. PMID- 20830639 TI - The Pharmacist's duty to warn. Beneficial impact on quality of care, economically sound, and commensurate with federal law. PMID- 20830640 TI - The need for more specific legislation in sexual consent capacity assessments for nursing home residents. PMID- 20830643 TI - Romantic preferences in Brazilian undergraduate students: from the short term to the long term. AB - A number of studies have described different preference patterns typically found for men and women when choosing romantic mates. These vary according to the involvement level expected in the relationship. Despite the number of investigations on the topic, one must be careful not to generalize because most studies use samples composed of North American university undergraduates. This study sought to determine if the preference patterns typically found in other countries also occur among Brazilian undergraduates. The importance of characteristics and modifications in preference patterns under gradually restrictive conditions was also investigated. In general, the results obtained suggest that the preferences found in a number of countries also occur in Brazil. In short-term relationships, men prioritize physical attributes, whereas personal traits gain importance when involvement increases. Women in short-term relationships value physical and personal traits, whereas in the long term, they emphasize personal characteristics and their mate's desire to acquire resources. Resource-related traits were less important than the other traits, and were more important for women than for men. PMID- 20830644 TI - Cognitive and neural components of the phenomenology of agency. AB - A primary aspect of the self is the sense of agency - the sense that one is causing an action. In the spirit of recent reductionistic approaches to other complex, multifaceted phenomena (e.g., working memory; cf. Johnson &Johnson, 2009), we attempt to unravel the sense of agency by investigating its most basic components, without invoking high-level conceptual or 'central executive' processes. After considering the high-level components of agency, we examine the cognitive and neural underpinnings of its low-level components, which include basic consciousness and subjective urges (e.g., the urge to breathe when holding one's breath). Regarding urges, a quantitative review revealed that certain inter representational dynamics (conflicts between action plans, as when holding one's breath) reliably engender fundamental aspects both of the phenomenology of agency and of 'something countering the will of the self'. The neural correlates of such dynamics, for both primordial urges (e.g., air hunger) and urges elicited in laboratory interference tasks, are entertained. In addition, we discuss the implications of this unique perspective for the study of disorders involving agency. PMID- 20830645 TI - Importance of precentral motor regions in human kinesthesia: a single case study. AB - Prompted by our neuroimaging findings in 60 normal people, we examined whether focal damage to the hand section of precentral motor regions impairs hand kinesthesia in a patient, and investigated brain regions related to recovery of kinesthetic function. The damage impaired contralateral kinesthesia. The peri lesional cerebral motor region, together with the ipsilateral intermediate cerebellum, participated in the recovered kinesthetic processing. The study confirmed the importance of precentral motor regions in human kinesthesia, and indicated a contribution of the peri-lesional cerebral region in recovered kinesthesia after precentral damage, which conceptually fits with cases of recovery of motor function. PMID- 20830646 TI - Do brief online planning interventions increase physical activity amongst university students? A randomised controlled trial. AB - Brief planning interventions, usually delivered within paper and pencil questionnaires, have been found to be effective in changing health behaviours. Using a double-blind randomised controlled trial, this study examined the efficacy of two types of planning interventions (action plans and coping plans) in increasing physical activity levels when they are delivered via the internet. Following the completion of self-reported physical activity (primary outcome) and theory of planned behaviour (TPB) measures at baseline, students (N = 1273) were randomised into one of four conditions on the basis of a 2 (received instructions to form action plans or not) * 2 (received instructions to form coping plans or not) factorial design. Physical activity (primary outcome) and TPB measures were completed again at two-month follow-up. An objective measure (attendance at the university's sports facilities) was employed 6 weeks after a follow-up for a duration of 13 weeks (secondary outcome). The interventions did not change self reported physical activity, attendance at campus sports facilities or TPB measures. This might be due to low adherence to the intervention protocol (ranging from 58.8 to 76.7%). The results of this study suggest that the planning interventions under investigation are ineffective in changing behaviour when delivered online to a sample of participants unaware of the allocation to different conditions. Possible moderators of the effectiveness of planning interventions in changing health behaviours are discussed. PMID- 20830647 TI - Narrative and emotion integration in psychotherapy: investigating the relationship between autobiographical memory specificity and expressed emotional arousal in brief emotion-focused and client-centred treatments of depression. AB - Clinically depressed individuals have consistently been shown to demonstrate a bias for overgeneral autobiographical memory (ABM) disclosure, a strategy used to protect against the access of intense, primary emotions that may accompany specific memories. The present study examined how ABM specificity in client narratives was related to expressed emotional arousal in brief emotion-focused and client-centred psychotherapy for depression. Emotion episodes identified in two early-, two middle-, and two late-therapy transcripts drawn from 34 clients from the York I Depression Study were rated for degree of ABM specificity and expressed emotional arousal. A hierarchical linear modelling analysis demonstrated that greater ABM specificity was associated with higher expressed emotional arousal for clients who were no longer depressed at therapy termination. PMID- 20830648 TI - Assessment of depression in multiple sclerosis: development of a "trunk and branch" model. AB - The objective of the present investigation was to improve the detection of depression in multiple sclerosis (MS). It has been hypothesized that the overlap of MS symptomatology and neurovegetative depression symptoms may lead to an over diagnosis of depression in MS. Discerning what is depression and what is more attributable to the disease renders a complicated picture when assessing depression in medically ill people. Given this, "trunk and branch" models have been proposed. In such models "trunk" symptoms are purported to be the symptoms common to the medical condition and less likely reflective of depression. "Branch" items are those symptoms that are independent of the medical condition and likely reflect depression. In the present investigation we compared depressed individuals with MS, non-depressed individuals with MS, and non-depressed controls, to devise a "trunk and branch" model for use with individuals with MS. By identifying which symptoms are typical in MS, which exceed what is typical in MS, and which symptoms are independent of MS, but more often present in depressed individuals with MS, we hoped to present a better understanding of the nature of depression in MS. PMID- 20830649 TI - Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. AB - Cognitive dysfunction is common in multiple sclerosis (MS), yet the magnitude of change on objective neuropsychological (NP) tests that is clinically meaningful is unclear. We endeavored to determine NP markers of the transition from employment to work disability in MS, as indicated by degree of decline on individual tests. Participants were 97 employed MS patients followed over 41.3 +/ 17.6 months with a NP battery covering six domains of cognitive function. Deterioration at follow-up was designated as documented and paid disability benefits (conservative definition) or a reduction in hours/work responsibilities (liberal definition). Using the conservative definition, 28.9% reported deteriorated employment status and for the liberal definition, 45.4%. The Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test, Total Learning (CVLT2-TL) measures distinguished employed and disabled patients at follow-up. Controlling for demographic and MS characteristics, the odds ratio of a deterioration based on a change of 2.0 on the CVLT2-TL was 3.7 (95% CI 1.2-11.4 and SDMT by 4.0 was 4.2 (95% CI 1.2-14.8), accounting for 86.7% of the area under the ROC curve. We conclude that decline on NP testing over time is predictive of deterioration in vocational status, establishing a magnitude of decline on NP tests that is clinically meaningful. PMID- 20830650 TI - Magnetic resonance mammography in small vs. advanced breast lesions - systematic comparison reveals significant impact of lesion size on diagnostic accuracy in 936 histologically verified breast lesions. AB - PURPOSE: This study was conducted to investigate the appearance of breast lesions in MR mammography (MRM) as a function of size and to identify the potential impact on diagnostic accuracy. MATERIALS AND METHODS: 936 histologically verified breast lesions (standardized MRM protocol; consecutive 12-year period at our institution, diameter 5 - 50 mm) were prospectively evaluated in consensus by two radiologists with significant MRM experience. For this purpose previously published descriptors (n = 17) were used. These were summarized as the "basic catalog and extended catalog" of descriptors (BC vs. EC). According to a cut-off of 20 mm, the database was divided into the subgroups "small" (n = 669) and "advanced" (n = 267). The diagnostic accuracy of MRM in these two subgroups was then determined using BC and EC, separately (binary logistic regression analysis; AUC analysis). RESULTS: The majority of descriptors (n = 11) showed a significantly different prevalence in correlation with size (p < 0.05). The diagnostic accuracy of MRM for "advanced" lesions (AUC = 0.969) was significantly higher (p < 0.001). This difference was significantly decreased (p < 0.001), if instead of BC (AUC = 0.865) EC was applied for the assessment of "small" lesions (AUC: 0.908 vs. 0.865). CONCLUSION: The typical appearance of breast lesions in MRM depends on lesion size. This resulted in lower diagnostic accuracy in small lesions compared to advanced findings. This difference was able to be significantly decreased by applying the catalog of extended descriptors. PMID- 20830651 TI - [Toxic lipid rescue therapy effect of local anesthesia in interventional radiology]. PMID- 20830652 TI - [Rasmussen encephalitis]. PMID- 20830653 TI - [Idiopathic hypertrophic pachymeningitis]. PMID- 20830654 TI - Discrimination of u-14 soccer players by level and position. AB - Adolescence is often viewed as a critical period for selection in youth soccer. The present study compared the characteristics of regionally selected and non selected under-14 players (U-14) as a group and by position. Players were classified as local (n=69) and regional (n=45). Weight, height, skinfolds, functional capacities, soccer skills and goal orientation were measured and skeletal age was assessed with the Fels method. Factorial ANOVA was used to test the effect of selection, position and respective interaction terms, while discriminant analysis was used to identify the variables that contributed to selection. Selected players had an advanced maturity status (F=24.97, p<0.01), were heavier (F=30.67, p<0.01) and taller (F=35.07, p<0.01); performed better in explosive power (F=21.25, p<0.01), repeated sprints (F=20.04, p<0.01) and ball control (F=3.69, p<0.05); and were more ego oriented (F=13.29, p<0.01). The 2 competitive groups did not differ in agility, aerobic endurance, dribbling, shooting, passing, and task orientation. Position-related variation was negligible. The percentage of players who were correctly classified in the original groups was slightly lower when the analysis was performed for the total sample (86%) than by position (86-90%). Future research on talent identification and selection should adopt a multidimensional approach including variables related to the physiological, perceptual, cognitive and tactical demands. PMID- 20830655 TI - Measurement of head impacts in youth ice hockey players. AB - Despite growing interest in the biomechanical mechanisms of sports-related concussion, ice hockey and the youth sport population has not been studied extensively. The purpose of this pilot study was: 1) to describe the biomechanical measures of head impacts in youth minor ice hockey players; and, 2) to investigate the influence of player and game characteristics on the number and magnitude of head impacts. Data was collected from 13 players from a single competitive Bantam boy's (ages 13-14 years) AAA ice hockey team using telemetric accelerometers implanted within the players' helmets at 27 ice hockey games. The average linear acceleration, rotational acceleration, Gadd Severity Index and Head Injury Criterion of head impacts were recorded. A significantly higher number of head impacts per player per game were found for wingers when compared to centre and defense player positions (df=355, t=3.087, p=0.00218) and for tournament games when compared to regular season and playoff games (df=355, t=2.641, p=0.086). A significant difference in rotational acceleration according to player position (F2,1812=4.9551, p=0.0071) was found. This study is an initial step towards a greater understanding of head impacts in youth ice hockey. PMID- 20830656 TI - ACTN3 genotype does not influence muscle power. AB - The R577X polymorphism within the ACTN3 gene has been associated with elite athletic performance, strength, power, fat free mass, and adaptations to strength training, though inconsistencies exist in the literature. The specific muscle power phenotypes most influenced by the polymorphism are uncertain. The purpose of this study was to examine the association between ACTN3 R577X genotype and muscle power phenotypes. Recreationally active young men and women (N=57) were selected to complete 2 muscle performance assessments, an isokinetic fatigue protocol at testing speeds of 180 degrees s (-1) and 250 degrees s (-1) and a 30 s Wingate test. Isokinetic torque and Wingate power significantly decreased over the duration of each test, but no differences in the rate of decline were observed among ACTN3 genotype groups. Similarly, no significant genotype differences were observed for isokinetic peak torque, Wingate absolute or relative peak power, or fatigue index. These results indicate that in recreationally active individuals the ACTN3 R577X polymorphism is not associated with muscle performance phenotypes, supporting recent findings that R577X may only be important for predicting performance in elite athletes. Our data also indicate that using this polymorphism for genetic screening in the lay population is scientifically questionable. PMID- 20830657 TI - A pilot study to evaluate knowledge and attitudes of Illinois pediatricians toward newborn screening for sickle cell disease and cystic fibrosis. AB - In Illinois, newborn screening (NBS) for sickle cell disease (SCD) began in 1989 and for cystic fibrosis (CF) in 2008. We measured pediatricians' knowledge and attitudes regarding CF and SCD, the significance of carrier status, and NBS methodologies. Of 730 eligible Illinois pediatricians randomly selected from the American Academy of Pediatrics Web-based directory, 391 (54%) fully or partially completed the survey. Approximately three-fifths were women, two-thirds were Caucasians, and one-quarter had specialty training. Ninety-seven percent (377/390) and 93% (364/391) of respondents have at one point cared for a patient with SCD and CF, respectively, and virtually all support NBS for SCD (389/391, 99.5%) and CF (382/389, 98%). Overall mean knowledge of SCD (81.2%) and CF (84.5%) was high but did not correlate with self-reported familiarity. Questions regarding the interpretation of NBS results were less well understood, with 37% of our respondents unaware that Illinois NBS identifies all infants with sickle cell trait, and 28% unaware that Illinois NBS does NOT identify all infants who are CF carriers. Pediatricians support NBS but need additional education about the meaning of a positive and negative screen with respect to carrier detection to effectively counsel or appropriately refer. PMID- 20830658 TI - 10-year-old girl with severe edema caused by adder bite. AB - We report a case of acute hemorrhagic edema in a 10-year-old girl caused by adder bite. Therapy consisted of analgesics, antihistamines, corticosteroids. Antivenum serum was applied in a single dose due to severe spreading of the edema. The patient recovered almost completely after 10 days of treatment. PMID- 20830659 TI - [Appendicitis in childhood: correlation of clinical data with histopathological findings]. AB - BACKGROUND: Quantifying the histopathological diagnoses of appendectomies in daily routine paidopathology results in a high percentage of appendices without histomorphological sign of acute inflammation. To identify clinical factors significantly associated with the morphological diagnosis, histopathological findings and clinical data--documented in patients' files--were examined. PATIENTS: All 856 children (age: 5 m-15 yrs) whose appendix had been resected within a 7-year-period were--depending on the histopathological diagnoses- allocated to the group "appendix without" resp. "appendix with signs of acute inflammation". METHOD: All files were examined concerning anamnestic data, clinical signs of acute appendicitis and laboratory parameters. The data were analysed by chi(2)-test and Wilcoxon-test concerning differences between the 2 groups with regard to the anamnestic and clinical facts and parameters. Using binary logistic regression, these clinical parameters were analyzed in correlation with the histopathological diagnoses. RESULTS: By consideration of the factors "leucocyte count", "vomiting" and "percussion tenderness" 75% of the children would have been allocated to the accurate postoperative pathomorphological diagnosis. CONCLUSIONS: There was a significant correlation of "leucocyte count", "vomiting" and "percussion tenderness" with histopathology in 75% of the children. As hence 25% were not allocated correctly this combination is no unequivocal combination for prediction or exclusion of an acute appendicitis. Hence, even with these statistically significant parameters a comparably high percentage of falsely-positive appendectomies has to be anticipated. PMID- 20830660 TI - The impact of an inpatient family-oriented rehabilitation program on parent reported psychological symptoms of chronically ill children. AB - OBJECTIVE: To investigate the change of psychological symptoms and quality of life in children and adolescents with congenital heart disease, cancer, or cystic fibrosis after a family-oriented inpatient rehabilitation program. METHODS: 302 participants in the intervention (aged 4-17 years, mean=8.7) were assessed using standard questionnaires at admission to the rehabilitation program, at discharge, and 6 months post discharge. Parent-reported behavioral and emotional symptoms were compared to a healthy control group from the National Health Interview and Examination Survey for Children and Adolescents (n=903). RESULTS: At admission, 27.5% of patients showed abnormal levels on the total difficulties score of the Strengths and Difficulties Questionnaire - parent version (SDQ), while an additional 16.9% had slightly elevated symptoms (relative risk=2.16). Patients' psychological symptoms were negatively correlated with their quality of life (QoL) and with parental QoL. After rehabilitation, the patients' symptoms improved significantly, and the improvement persisted for 6 months in those patients who could be followed. CONCLUSIONS: The rehabilitation program can be considered a promising strategy to improve the patients' psychological adaptation. PMID- 20830661 TI - Intracranial hemorrhage in immune thrombocytopenia (ITP): fatal course in spite of maximum therapy. AB - We report the case of a 2-year-old boy with immune thrombocytopenia (ITP) who developed fatal intracranial hemorrhage (ICH) despite maximum therapy according to the guidelines. Hitherto defined risk factors do not predict severe or atypical courses. PMID- 20830662 TI - Coincidence of immune thrombocytopenia, intracranial hemorrhage and graft-versus host disease in an 11-year-old girl. AB - Primary immune thrombocytopenia (ITP) in children is usually self-limiting and harmless but can, rarely, result in life-threatening complications. The case of an 11-year-old girl with ITP is presented who developed recurrent intracranial hemorrhages followed by cerebral infarctions. The clinical course was complicated by a graft-versus-host disease involving several organs. Treatment was performed according to the current international consensus report of 2010 with glucocorticoids, immunoglobulin G, anti-D-immunoglobulin and additionally embolisation of the splenic artery. The girl survived. Reliable predictors, preventive measures for life-threatening complications in ITP and more information about the effectiveness and side-effects of the recommended treatment are urgently needed. PMID- 20830663 TI - [Angina pectoris without coronary stenosis--current concepts]. AB - This review aims at demonstrating current concepts for the occurrence of angina pectoris (AP) and myocardial ischemia in patients without significant epicardial stenoses based on typical clinical examples. For applying these concepts, it is of utmost importance to clinically distinguish patients with resting AP only from those with exercise-induced symptoms or both. Resting AP may not only be caused by plaque rupture and subsequent coronary thrombosis, but may also be due (especially when repeated attacks occur in the early morning hours) to coronary vasospasm (in the microvasculature as well as in epicardial coronary segments). Similarly, exercise-induced AP and/or a pathological exercise test result may not only be caused by severe coronary stenoses, but may also be due to a reduced coronary perfusion reserve secondary to microvascular dysfunction. Hence, a pathological non-invasive stress-test result should not be necessarily described as "false positive" in case of the absence of any significant stenosis. In principle, proatherogenic cardiovascular risk factors are not only associated with atherosclerotic coronary artery disease (CAD), but also with the occurrence of a coronary vasomotility disorder. Both disease entities are characterised by the occurrence of myocardial ischemia. So far, the exact pathomechanism of respective subforms of coronary vasomotility disorders has not yet been not elucidated in detail. Endothelial dysfunction, abnormalities of the smooth muscle cells in the media as well as genetic predisposition or specific immunological abnormalities are discussed as underlying reasons. Intracoronary provocative testing (such as the acetylcholine-test) may help to diagnose as well as to differentiate the different subforms of coronary vasomotility disorders. PMID- 20830664 TI - HAM-D17 and HAM-D6 sensitivity to change in relation to desvenlafaxine dose and baseline depression severity in major depressive disorder. AB - INTRODUCTION: This retrospective analysis compared sensitivity to change on the 17-item and 6-item Hamilton Rating Scales For Depression (HAM-D (17) and HAM-D (6), respectively) in relation to antidepressant dose and baseline depression severity. METHODS: Data were derived from 6 randomized, double-blind, placebo controlled, 8-week trials of fixed-dose desvenlafaxine (50, 100, 200 or 400 mg/d) for major depressive disorder. HAM-D (17) and HAM-D (6) effect sizes were assessed. RESULTS: HAM-D (17) effect sizes were negative (favoured placebo) for higher desvenlafaxine doses (200-400 mg/d) at week 1, but were positive for all doses after week 2, with no clear dose-response pattern. However, HAM-D (6) effect sizes were positive for all doses at all weeks. Effect sizes were consistently greater for HAM-D (6) vs. HAM-D (17), regardless of time spent under therapy. Effect sizes were greater for HAM-D (6) vs. HAM-D (17) for all desvenlafaxine doses among patients with baseline HAM-D (17) <25, but not among patients with baseline HAM-D (17) >= 25. DISCUSSION: The HAM-D (6) demonstrated greater sensitivity to change and robustness than the HAM-D (17), supporting the greater homogeneity of the HAM-D (6). PMID- 20830665 TI - Serotonin syndrome with severe hyperthermia after ingestion of tranylcypromine combined with serotonin reuptake inhibitors and tyramine-rich food in a case of suicide. PMID- 20830666 TI - [CAPS--cryopyrin-associated periodic syndrome]. PMID- 20830667 TI - Sexual recombination in Colletotrichum lindemuthianum occurs on a fine scale. AB - Glomerella cingulata f. sp phaseoli is the sexual phase of the fungus Colletotrichum lindemuthianum, the causal agent of common bean anthracnose. This fungus is of great concern, because it causes large economic losses in common bean crops. RAPD markers of five populations of G. cingulata f. sp phaseoli from two Brazilian states were analyzed to determine if this population possesses the sexual reproductive potential to generate the genetic variation that is observed in this phytopathogen. We identified 128 polymorphic bands, amplified by 28 random primers. The estimates of genetic similarity in this analysis ranged from 0.43 to 1.00, and the dendrogram generated from analysis of all genotypes displayed five principal groups, coinciding with the five populations. Genetic differentiation was observed between the populations (GST=0.6455); 69% of the overall observed genetic variation was between individual populations and 31% of the variance was within the sub-populations. We identified significant levels of linkage disequilibrium in all populations. However, the values of the disequilibrium ranged from low to moderate, indicating that this pathogen maintains a genetic structure consistent with sexual reproduction. The mean contribution of sexual reproduction was determined by comparison of the amplitudes of genetic similarity of isolates from sexual and asexual phases. These results support the hypothesis that recombination plays an important role in determining the amplitude of variability in this pathogen population and that this determination occurs on a fine scale. PMID- 20830668 TI - Isolation and characterization of microsatellite markers in the armored catfish Hypostomus gymnorhynchus (Loricariidae). AB - We isolated and characterized 10 microsatellite loci in the armored catfish (Hypostomus gymnorhynchus, Loricariidae), using a genomic shotgun library to obtain the repetitive sequences. Twenty-four primers were designed and 14 individuals of H. gymnorhynchus from the Caiapo River, in central Brazil, were genotyped using these primers to analyze the polymorphism at each locus. All loci showed low polymorphism, with a low number of alleles per locus (1 or 2), except locus Hg_E19, which had 11 alleles. Expected heterozygosities for polymorphic loci ranged from 0.182 to 0.901. Combined paternity exclusion probability (0.857) was low and combined genetic identity (0.0026) was high, when we examined parentage. The low degree of polymorphism that we detected may be due to the small sample size and the small microsatellite size, despite the large motif size. PMID- 20830669 TI - Genetic mapping of Theobroma cacao (Malvaceae) seedlings of the Parinari series, carriers of the lethal gene Luteus-Pa. AB - The lethal gene 'Luteus-Pa' is found in cacao genotypes (Theobroma cacao) of the Parinari (Pa) series, from Peru. Seedlings affected by this gene have yellowing leaves and subsequently die. We mapped this gene based on microsatellite markers and RAPDs, in order to elucidate the inheritance of 'Luteus-Pa' and investigate possible lethal mechanisms. DNA samples of genitors were amplified with 87 SSR and 64 RAPD primers. The SSR primers amplified 65 RAPD primers, giving 179 polymorphic bands. After screening with SSR and RAPD markers, we selected 20 SSR primers, two SSR primers with ESTs and 22 RAPD primers that were polymorphic for genitors Pa 30 and Pa 169. Only two of the 22 RAPD primers and three of the 20 SSR primers were informative and polymorphic in the analysis of the bulk samples of progenies. Among these, primer RAPD E11 produced a band linked to the lethal gene (38.5 cM); none of the SSRs were associated with 'Luteus-Pa'. PMID- 20830670 TI - A novel COMP mutation in an Inuit patient with pseudoachondroplasia and severe short stature. AB - Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia, generally identified clinically at two years of age due to decreased linear growth and a waddling gait. Radiographic features include small and irregular epiphyses, with metaphyseal changes of the long bones and characteristic vertebral changes. Mutations in the COMP gene cause PSACH and some cases of multiple epiphyseal dysplasia. Mutations generally cluster in the calmodulin-like repeat regions of the gene. Mutations in exon 13 (encoding the seventh calmodulin like repeat) have been associated with severe short stature (-6 SD) in PSACH. We examined an Inuit boy with PSACH and severe short stature. Height essentially remained at -1 SD on the PSACH growth curve (-7.5 SD on a normal growth curve at 10.5 years). Analysis of COMP in our patient revealed a previously undescribed heterozygous A>T substitution in exon 8, at nucleotide 812. This change in the sequence resulted in replacement of a highly conserved and negatively charged aspartic acid with an uncharged, hydrophobic valine at amino acid position 271. Both unaffected parents were negative for this genetic change. This exon encodes the first calmodulin-like repeat, which has not been previously implicated in severe short stature. We propose that this novel missense substitution is responsible for the phenotype of this patient. PMID- 20830671 TI - Development and characterization of polymorphic microsatellite markers in the gray mullet (Mugil cephalus). AB - Using an (AG)13 enriched genomic library of Mugil cephalus, 12 polymorphic microsatellite loci were isolated and characterized in a test population; the number of alleles ranged from 2 to 11. The observed and expected heterozygosities ranged from 0.2593 to 0.8966 and from 0.3047 to 0.8454, respectively. Two loci deviated from Hardy-Weinberg equilibrium; linkage disequilibrium among the 12 loci was non-significant. These polymorphic microsatellite loci will be useful for genetic diversity analysis and molecule-assisted breeding of the gray mullet. PMID- 20830672 TI - Isolation and characterization of NBS-LRR- resistance gene candidates in turmeric (Curcuma longa cv. surama). AB - Turmeric (Curcuma longa), an important asexually reproducing spice crop of the family Zingiberaceae is highly susceptible to bacterial and fungal pathogens. The identification of resistance gene analogs holds great promise for development of resistant turmeric cultivars. Degenerate primers designed based on known resistance genes (R-genes) were used in combinations to elucidate resistance gene analogs from Curcuma longa cultivar surama. The three primers resulted in amplicons with expected sizes of 450-600 bp. The nucleotide sequence of these amplicons was obtained through sequencing; their predicted amino acid sequences compared to each other and to the amino acid sequences of known R-genes revealed significant sequence similarity. The finding of conserved domains, viz., kinase 1a, kinase-2 and hydrophobic motif, provided evidence that the sequences belong to the NBS-LRR class gene family. The presence of tryptophan as the last residue of kinase-2 motif further qualified them to be in the non-TIR-NBS-LRR subfamily of resistance genes. A cluster analysis based on the neighbor-joining method was carried out using Curcuma NBS analogs together with several resistance gene analogs and known R-genes, which classified them into two distinct subclasses, corresponding to clades N3 and N4 of non-TIR-NBS sequences described in plants. The NBS analogs that we isolated can be used as guidelines to eventually isolate numerous R-genes in turmeric. PMID- 20830673 TI - Composite thin film and electrospun biomaterials for urologic tissue reconstruction. AB - A replacement material for autologous grafts for urinary tract reconstruction would dramatically reduce the complications of surgery for these procedures. However, acellular materials have not proven to work sufficiently well, and cell seeded materials are technically challenging and time consuming to generate. An important function of the urinary tract is to prevent urine leakage into the surrounding tissue--a function usually performed by the urothelium. We hypothesize that by providing an impermeable barrier in the acellular graft material, urine leakage would be minimized, as the urothelium forms in vivo. However, since urothelial cells require access to nutrients from the supporting vasculature, the impermeable barrier must degrade over time. Here we present the development of a novel biomaterial composed of the common degradable polymers, poly(epsilon-caprolactone) and poly(L-lactic acid) and generated by electrospinning directly onto spin-coated thin films. The composite scaffolds with thin films on the luminal surface were compared to their electrospun counterparts and commercially available small intestinal submucosa by surface analysis using scanning electron microscopy and by analysis of permeability to small molecules. In addition, the materials were examined for their ability to support urothelial cell adhesion, proliferation, and multilayered urothelium formation. We provide evidence that these unique composite scaffolds provide significant benefit over commonly used acellular materials in vitro and suggest that they be further examined in vivo. PMID- 20830674 TI - Modeling of uncertainties in biochemical reactions. AB - Mathematical modeling is an indispensable tool for research and development in biotechnology and bioengineering. The formulation of kinetic models of biochemical networks depends on knowledge of the kinetic properties of the enzymes of the individual reactions. However, kinetic data acquired from experimental observations bring along uncertainties due to various experimental conditions and measurement methods. In this contribution, we propose a novel way to model the uncertainty in the enzyme kinetics and to predict quantitatively the responses of metabolic reactions to the changes in enzyme activities under uncertainty. The proposed methodology accounts explicitly for mechanistic properties of enzymes and physico-chemical and thermodynamic constraints, and is based on formalism from systems theory and metabolic control analysis. We achieve this by observing that kinetic responses of metabolic reactions depend: (i) on the distribution of the enzymes among their free form and all reactive states; (ii) on the equilibrium displacements of the overall reaction and that of the individual enzymatic steps; and (iii) on the net fluxes through the enzyme. Relying on this observation, we develop a novel, efficient Monte Carlo sampling procedure to generate all states within a metabolic reaction that satisfy imposed constrains. Thus, we derive the statistics of the expected responses of the metabolic reactions to changes in enzyme levels and activities, in the levels of metabolites, and in the values of the kinetic parameters. We present aspects of the proposed framework through an example of the fundamental three-step reversible enzymatic reaction mechanism. We demonstrate that the equilibrium displacements of the individual enzymatic steps have an important influence on kinetic responses of the enzyme. Furthermore, we derive the conditions that must be satisfied by a reversible three-step enzymatic reaction operating far away from the equilibrium in order to respond to changes in metabolite levels according to the irreversible Michelis-Menten kinetics. The efficient sampling procedure allows easy, scalable, implementation of this methodology to modeling of large-scale biochemical networks. PMID- 20830675 TI - C-terminal lysine processing of human immunoglobulin G2 heavy chain in vivo. AB - Although human IgG heavy chain genes encode a C-terminal lysine, this residue is mostly absent from the endogenous antibodies isolated from serum. Some low but variable level of C-terminal lysine is present on therapeutic antibodies expressed in mammalian cell culture systems. Here, we monitored the C-terminal lysine processing of a recombinant human IgG2 antibody after intravenous injection into human subjects. Peptide mapping of the therapeutic antibody isolated from serum samples by affinity purification was used to quantify the C terminal lysine levels over time in vivo. The C-terminal lysine residue was found to be rapidly lost in vivo with a half life of about an hour (62 min). In vivo C terminal lysine processing could be reproduced in vitro, but at a faster rate, by incubating in human serum. Pretreated serum, under conditions used to inactivate carboxypeptidase U, generated in vitro C-terminal lysine processing rates that more closely matched those in vivo. Endogenous IgG, isolated from human blood, contained very low levels of C-terminal lysine (~0.02%), consistent with the expected circulating half life of antibodies and the calculated C-terminal lysine processing rate. Thus, the low residual IgG2 C-terminal lysine is rapidly processed in vivo and such processing likely occurs on endogenous antibodies in circulation. PMID- 20830677 TI - Reaction engineering analysis of hydrogenotrophic production of acetic acid by Acetobacterium woodii. AB - Great interest has emerged in biological CO2-fixing processes in the context of current climate change discussions. One example for such a process is the hydrogenotrophic production of acetic acid by anaerobic microorganisms. Acetogenic microorganisms make use of carbon dioxide in the presence of hydrogen to produce acetic acid and biomass. In order to establish a process for the hydrogenotrophic production of acetic acid, the formation of acetate by Acetobacterium woodii was studied in a batch-operated stirred-tank bioreactor at different hydrogen partial pressures (pH2) in the gas phase. The volumetric productivity of the batch processes increased with increasing hydrogen partial pressure. A maximum of the volumetric productivity of 7.4 g(acetate) L-1 day-1 was measured at a pH2 of 1,700 mbar. At this pH(2) a final acetate concentration of 44 g L-1 was measured after a process time of 11 days, if the pH was controlled at pH 7.0 (average cell density of 1.1 g L-1 cell dry weight). The maximum cell specific actetate productivity was 6.9 g(acetate) g(cdw)-1 day-1 under hydrogenotrophic conditions. PMID- 20830676 TI - Effects of the antimicrobial tylosin on the microbial community structure of an anaerobic sequencing batch reactor. AB - The effects of the antimicrobial tylosin on a methanogenic microbial community were studied in a glucose-fed laboratory-scale anaerobic sequencing batch reactor (ASBR) exposed to stepwise increases of tylosin (0, 1.67, and 167 mg/L). The microbial community structure was determined using quantitative fluorescence in situ hybridization (FISH) and phylogenetic analyses of bacterial 16S ribosomal RNA (rRNA) gene clone libraries of biomass samples. During the periods without tylosin addition and with an influent tylosin concentration of 1.67 mg/L, 16S rRNA gene sequences related to Syntrophobacter were detected and the relative abundance of Methanosaeta species was high. During the highest tylosin dose of 167 mg/L, 16S rRNA gene sequences related to Syntrophobacter species were not detected and the relative abundance of Methanosaeta decreased considerably. Throughout the experimental period, Propionibacteriaceae and high GC Gram positive bacteria were present, based on 16S rRNA gene sequences and FISH analyses, respectively. The accumulation of propionate and subsequent reactor failure after long-term exposure to tylosin are attributed to the direct inhibition of propionate-oxidizing syntrophic bacteria closely related to Syntrophobacter and the indirect inhibition of Methanosaeta by high propionate concentrations and low pH. PMID- 20830678 TI - Differential regulation by fucoidan of IFN-gamma-induced NO production in glial cells and macrophages. AB - Fucoidan has shown numerous biological actions; however, the molecular bases of these actions have being issued. We examined the effect of fucoidan on NO production induced by IFN-gamma and the molecular mechanisms underlying these effects in two types of cells including glia (C6, BV-2) and macrophages (RAW264.7, peritoneal primary cells). Fucoidan affected IFN-gamma-induced NO and/or iNOS expression both in macrophages and glial cells but in a contrast way. Our data showed that in C6 glioma cells both JAK/STAT and p38 signaling positively regulated IFN-gamma-induced iNOS, which were inhibited by fucoidan. In contrast, in RAW264.7 cells JAK/STAT is a positive regulator whereas p38 is a negative regulator of NO/iNOS production. In RAW264.7 cells, fucoidan enhanced p38 activation and induced TNF-alpha production. We also confirmed the dual regulation of p38 in BV-2 microglia and primary peritoneal macrophages. From these results, we suggest that fucoidan affects not only IFN-gamma-induced NO/iNOS production differently in brain and peritoneal macrophages due to the different roles of p38 but the effects on TNF-alpha production in the two cell types. These novel observations including selective and cell-type specific effects of fucoidan on IFN-gamma-mediated signaling and iNOS expression raise the possibility that it alters the sensitivity of cells to the p38 activation. PMID- 20830679 TI - Plasmid DNA fermentation strain and process-specific effects on vector yield, quality, and transgene expression. AB - Industrial plasmid DNA manufacturing processes are needed to meet the quality, economy, and scale requirements projected for future commercial products. We report development of a modified plasmid fermentation copy number induction profile that increases gene vaccination/therapy vector yields up to 2,600 mg/L. We determined that, in contrast to recombinant protein production, secretion of the metabolic byproduct acetate into the media had only a minor negative effect on plasmid replication. We also investigated the impact of differences in epigenetic dcm methylase-directed cytosine methylation on plasmid production, transgene expression, and immunogenicity. While Escherichia coli plasmid production yield and quality are unaffected, dcm- versions of CMV and CMV-HTLV-I R promoter plasmids had increased transgene expression in human cells. Surprisingly, despite improved expression, dcm- plasmid is less immunogenic. Our results demonstrate that it is critical to lock the plasmid methylation pattern (i.e., production strain) early in product development and that dcm- strains may be superior for gene therapy applications wherein reduced immunogenicity is desirable and for in vitro transient transfection applications such as AAV production where improved expression is beneficial. PMID- 20830680 TI - Small-scale and automatable high-throughput compositional analysis of biomass. AB - Conventional wet chemistry methods to determine biomass composition are labor- and time-intensive and require larger amounts of biomass (300 mg) than is often available. To overcome these limitations and to support a high-throughput pretreatment and hydrolysis (HTPH) screening system, this article reports on the development of a downscaled biomass compositional analysis that is based on conventional wet chemistry techniques but is scaled down by a factor of 100 to use significantly less material. The procedure is performed in readily available high-performance liquid chromatography vials and can be automated to reduce operator input and increase throughput. Comparison of the compositional analyses of three biomasses determined by the downscaled approach to those obtained by conventional methods showed that the downscaled method measured statistically identical carbohydrate compositions as standard procedures and also can provide reasonable estimates of lignin and ash contents. These results demonstrate the validity of the downscaled procedure for measuring biomass composition to enable the calculation of sugar yields and determination of trends in sugar release behavior in HTPH screening studies. PMID- 20830681 TI - Enzymatic synthesis of L-lactic acid from carbon dioxide and ethanol with an inherent cofactor regeneration cycle. AB - Efficient conversion of carbon dioxide is of great interests to today's endeavors in controlling greenhouse gas emission. A multienzyme catalytic system that uses carbon dioxide and ethanol to produce L-lactate was demonstrated in this work, thereby providing a novel reaction route to convert bio-based ethanol to an important building block for synthesis biodegradable polymers. The synthetic route has a unique internal cofactor regeneration cycle, eliminating the need of additional chemical or energy for cofactor regeneration. Lactate was successfully synthesized with 41% of ethanol converted in a batch reaction, while a turnover number of 2.2 day-1 was reached for cofactor regeneration in a reaction with continuous feeding of ethanol. A kinetic model developed based on reaction kinetic parameters determined separately for each reaction step predicted well the reaction rates and yields of the multienzyme reaction system. PMID- 20830682 TI - Scalable expansion of multipotent adult progenitor cells as three-dimensional cell aggregates. AB - Many applications of stem cell technologies require a large quantity of cells for which scalable processes of cell expansion and differentiation are essential. Multipotent adult progenitor cells (MAPCs) are adult stem cells isolated from the bone marrow with extensive self-renewal and broad differentiation capabilities. MAPCs are typically cultured surface adherent (2D) and at low cell density, making the large surface required for cell expansion a hindrance for many applications. This study demonstrates that MAPCs can be cultivated as aggregates in an undifferentiated state for at least 16 days, as levels of a number of transcripts, including Oct4, remained similar, Oct4 protein was unchanged, and differentiation to neural progenitor, endothelial cell and hepatocyte like cells was retained. Cultivation of these aggregates in stirred bioreactor lead to a 70 fold expansion in 6 days with final cell densities of close to 106/mL. Importantly, the MAPC aggregates recovered from stirred bioreactors could be differentiated to hepatocyte-like cells that expressed albumin, alpha-1 antitrypsin (AAT), and tyrosine amino transferase (TAT) transcripts and also secreted albumin and urea. This method of scalable expansion combined with differentiation of MAPCs can potentially be used for generating large numbers of MAPC and MAPC-derived differentiated cells. PMID- 20830683 TI - Conserved microRNAs in Chinese hamster ovary cell lines. AB - MicroRNAs (miRNAs), a class of short (20-24 nt) non-coding RNAs that direct post transcriptional repression of messenger RNAs, increasingly have been shown to play a key role in regulating cellular physiology. We investigated the prevalence of miRNAs in Chinese hamster ovary (CHO) cells by high-throughput sequencing. Six cDNA libraries of small RNAs from four CHO cell lines were constructed and sequenced by Illumina sequencing. Three hundred fifty distinct miRNA and miRNA* sequences were identified through homology with other species, including mouse, rat, and human. While the majority of the identified miRNAs appear to be expressed ubiquitously, many miRNAs were found to have a wide range of expression levels between cell lines. The identification of these miRNAs will facilitate investigations of their contribution to the hyperproductivity trait. PMID- 20830684 TI - Cyclic stretch of alveolar epithelial cells alters cytoskeletal micromechanics. AB - Cytoplasmic transport of large molecules such as plasmid DNA (pDNA) has been shown to increase when cells are subjected to mild levels of cyclic stretch for brief periods. In the case of pDNA, this is in part due to the increased active transport of pDNA along stabilized, acetylated microtubules in the cytoplasm, whose levels are increased in response to stretch. It also has been shown that disruption of the dense actin network leads to increased pDNA and macromolecule diffusion as well. We hypothesize that stretch not only increases active transport of pDNA but also, similar to actin disrupting drugs, decreases cytoplasmic stiffness leading to a less restive pathway for macromolecules to diffuse. To test this we used particle tracking microrheology to measure cytoplasmic mechanics. We conclude that while cyclic stretch transiently decreases cytoplasmic stiffness and increases diffusivity, stretch-independent modulation of the levels of acetylated, stable microtubules has no effect on cytoplasmic stiffness. Furthermore, stretching cells that have maximally acetylated microtubules increases cytoplasmic trafficking of pDNA, without increasing levels of acetylated microtubules. These findings suggest that stretch enhanced gene transfer may occur by two independent mechanisms: increased levels of acetylated microtubules for directed active transport, and reduced cytoplasmic stiffness for increased diffusion. PMID- 20830685 TI - Testosterone promotes an anabolic increase in the rat female prostate (Skene's paraurethral gland) which acquires a male ventral prostate phenotype. AB - The female prostate (Skene's paraurethral gland) in the rat is morphologically similar to the ventral lobe of male adults and has been described in other rodent species and humans. Previous studies on prostate morphogenesis suggest that female Wistar rats (Rattus norvegicus) do not develop this gland due to the absence of testosterone during the embryonic and neonatal periods. On the other hand, studies conducted in our laboratory have shown that some females of this species can present an undeveloped but functional prostate. Recent studies on this gland have caused scientific interest because, besides being active in the processes of synthesis and secretion of prostatic material, it is also targeted by both malignant and benign lesions, mainly during senescence. Thus, this work aims to evaluate the structure of female prostate of adult rats (Rattus norvegicus) under normal conditions and under the effect of testosterone treatment and carry out comparative studies on the ventral prostate of young and adult male rats. Morphological and morphometric stereological analyses and immunocytochemical and ultrastructural studies were conducted. The results have shown that the prostate gland of rats exposed to androgen therapy have experienced intense growth, becoming more active in relation to synthesis and secretion. It may be concluded that the prostate in control adult female rats is morphologically very similar to the prostatic ventral lobe of young male rats. Besides, under androgenic action, the female prostate grows considerably and becomes similar to the prostatic ventral lobe in male adults. PMID- 20830686 TI - Epithelial thickness of the palatal mucosa: a histomorphometric study in Koreans. AB - Subepithelial connective tissue grafting (SCTG) is a frequently used method in the field of periodontal plastic surgery. There are relatively few reports defining epithelial thickness criteria for palatal mucosal SCTG. The aim of this study was to histologically measure the epithelial thickness of the palatal mucosa in a sample of Korean patients, with the goal of minimizing epithelium associated complications after root coverage procedures. A total of 30 Korean patients (12 males and 18 females) were enrolled in this study. To measure epithelial thicknesses, palatal mucosa adjacent to premolars and molars was obtained during procurement of SCTG. The effects of donor site, age and gender on the thickness of the epithelium were assessed and compared by histomorphometric analysis. The mean epithelial thickness of the palatal mucosa in our 30 patients was 430.63 MUm, ranging from 113 to 823 MUm. Epithelial thickness was not associated with donor site or age, but there were significant differences between genders, with males having much thicker palates than females. PMID- 20830687 TI - Structural organization of hepatic portal vein in rat with special reference to musculature, intimal folds, and endothelial cell alignment. AB - Structural organization of hepatic portal vein (HPV) was examined in adult rats by means of light and electron microscopy. Three characteristic features were found in the wall structure of rat HPV. (1) Tunica media consisted of two kinds of smooth muscle. The inner circular smooth muscle (CSM) was composed with one or two layer of smooth muscle cells, and was found in the entire length of the HPV and its tributaries. The outer longitudinal smooth muscle (LSM) was limited to a specific region of HPV; in particular it was well-developed at distal half of HPV. CSM counteracts luminal hydrostatic pressure to prevent circumferential hyperextension of venous wall, whereas LSM is likely to counteract a tractive force produced by gravity and movement of small intestine. (2) Intima of HPV showed a unique feature, intimal folds, which protruded into the lumen and were aligned almost circumferentially. Intimal folds were found only at the same region where the LSM was well-developed. Thus, LSM is presumably involved in the formation of intimal folds. (3) The endothelial cells between intimal folds were circumferentially aligned along the folds, although those in the other regions of HPV were arrayed along the longitudinal axis of HPV or the direction of blood flow as reported in other kinds of blood vessel. This finding implied that the circumferential blood flow locally occurs on the surface of intima between the intimal folds. PMID- 20830688 TI - Signaling pathways in early cardiac development. AB - Cardiomyocyte differentiation is a complex multistep process requiring the proper temporal and spatial integration of multiple signaling pathways. Previous embryological and genetic studies have identified a number of signaling pathways that are critical to mediate the initial formation of the mesoderm and its allocation to the cardiomyocyte lineage. It has become clear that some of these signaling networks work autonomously, in differentiating myocardial cells whereas others work non-autonomously, in neighboring tissues, to regulate cardiac differentiation indirectly. Here, we provide an overview of three signaling networks that mediate cardiomyocyte specification and review recent insights into their specific roles in heart development. In addition, we demonstrate how systems level, 'omic approaches' and other high-throughput techniques such as small molecules screens are beginning to impact our understanding of cardiomyocyte specification and, to identify novel signaling pathways involved in this process. In particular, it now seems clear that at least one chemokine receptor CXCR4 is an important marker for cardiomyocyte progenitors and may play a functional role in their differentiation. Finally, we discuss some gaps in our current understanding of early lineage selection that could be addressed by various types of omic analysis. PMID- 20830689 TI - Neonatal exposure to citalopram selectively alters the expression of the serotonin transporter in the hippocampus: dose-dependent effects. AB - Infants born to mothers taking selective serotonin reuptake inhibitors (SSRIs) late in pregnancy have been reported to exhibit signs of antidepressant withdrawal. Such evidence suggests that these drugs access the fetal brain in utero at biologically significant levels. Recent studies in rodents have revealed that early exposure to antidepressants can lead to long lasting abnormalities in adult behaviors, and result in robust decreases in the expression of a major serotonin synthetic enzyme (tryptophan hydroxylase) along the raphe midline. In the present investigation, we injected rat pups with citalopram (CTM: 5 mg/kg, 10 mg/kg, and 20 mg/kg) from postnatal Days 8-21, and examined serotonin transporter (SERT) labeling in the hippocampus, ventrobasal thalamic complex, and caudate putamen when the subjects reached adulthood. Our data support the idea, that forebrain targets in receipt of innervation from the raphe midline are particularly vulnerable to the effects of CTM. SERT-immunoreactive fiber density was preferentially decreased throughout all sectors of the hippocampal formation, whereas the subcortical structures, each supplied by more lateral and rostral aspects of the raphe complex, respectively, were not significantly affected. Reductions in SERT staining were also found to be dose-dependent. These findings suggest that SSRIs may not only interfere with the establishment of chemically balanced circuits in the neonate but also impose selective impairment on higher cortical function and cognitive processes via more circumscribed (i.e., regionally specific) deficits in 5-HT action. PMID- 20830690 TI - The utility of napsin-A in the identification of primary and metastatic lung adenocarcinoma among cytologically poorly differentiated carcinomas. AB - BACKGROUND: New developments in the treatment of lung cancer have necessitated the further histologic and cytologic subtyping of nonsmall cell lung carcinomas. Thyroid transcription factor-1 (TTF-1) long has served as the predominant marker for demonstrating lung origin. However, it is also expressed in a variety of other tumors, particularly neuroendocrine neoplasms and, to a much lesser degree, squamous cell carcinoma of the lung. Napsin-A, which is expressed in lung tissue, is a relatively new marker for lung adenocarcinoma. In this study, the authors examined the utility of napsin-A compared with TTF-1 in cytologic specimens of primary and metastatic, poorly differentiated lung adenocarcinomas. METHODS: The archives of the Department of Pathology at The Johns Hopkins Hospital were searched for cytologic cases of poorly differentiated lung adenocarcinoma that were histologically confirmed. In total, 75 patients (cases) along with 95 controls were included, each of whom had adequate cell block material for TTF-1 and napsin-A staining. Tissue microarrays of lung adenocarcinoma also were examined. RESULTS: TTF-1 and napsin-A were detected in 61 of 75 cases (81.3%) and in 49 of 75 cases (65.3%), respectively. The sensitivity and specificity of TTF-1 were 81% each; and napsin-A had a greater specificity of 96%, and sensitivity of 65%. Napsin-A was not detected in small cell carcinomas or in other carcinomas of nonlung origin except for renal cell carcinoma. CONCLUSIONS: Although TTF-1 had a higher sensitivity, napsin-A was useful as a surrogate marker when encountering a poorly differentiated lung adenocarcinoma or an unknown primary tumor, particularly in cytologic specimens and difficult cases. The current results indicate that the dual use of both markers may be necessary to improve diagnostic accuracy. PMID- 20830691 TI - Gamma knife radiosurgery for brain metastasis of nonsmall cell lung cancer: is there a difference in outcome between morning and afternoon treatment? AB - BACKGROUND: Circadian cell-cycle progression causes fluctuating radiosensitivity in many tissues, which could affect clinical outcomes. The purpose of this study was to determine whether outcomes of single-session gamma knife radiosurgery (GKRS) for metastatic nonsmall cell lung cancer (NSCLC) differ based on treatment time. METHODS: Fifty-eight patients received GKRS between 10:00 am and 12:30 pm and 39 patients received GKRS between 12:30 pm and 3:00 pm. The mean peripheral dose was 18.6 Gy. The mean tumor size was 7.3 cm3. Magnetic resonance imaging was used to score local control at 3 months. Cause of death (COD) was categorized as central nervous system (CNS)-related or systemic. RESULTS: Demographic and disease characteristics of the 2 groups were similar. Local control at 3 months was achieved in 97% (35/36) of patients who underwent GKRS early in the day versus 67% (8/12) of patients who underwent GKRS later in the day (chi-square, P = .014). Early GKRS was associated with better survival (median 9.5 months) than late GKRS (median 5 months) (Kaplan-Meier log-rank test, P = .025). Factors contributing to better survival in a Cox regression model included early treatment time (P = .004) and recursive partition analysis class (P < .001). Cause of death in the early treatment group was CNS-related in 6% (3/47) of patients versus 24% (8/34) of patients in the late treatment group (chi-square test, P = .026). CONCLUSIONS: GKRS for metastatic NSCLC had better local control, better survival, and a lower rate of CNS-related cause of death when given earlier in the day versus later in the day. These retrospective data should encourage future study in brain radiosurgery and non-CNS stereotactic body radiotherapy series. PMID- 20830694 TI - Clinical images: Calcinosis and capillaries. PMID- 20830695 TI - Trauma-focused cognitive behavioral therapy for children: impact of the trauma narrative and treatment length. AB - BACKGROUND: Child sexual abuse (CSA) is associated with the development of a variety of mental health disorders, and Trauma-Focused Cognitive Behavioral Therapy (TF-CBT) is an established treatment for children who have experienced CSA. However, there are questions about how many TF-CBT sessions should be delivered to achieve clinical efficacy and whether a trauma narrative (TN) component is essential. This study examined the differential effects of TF-CBT with or without the TN component in 8 versus 16 sessions. METHODS: Two hundred and ten children (aged 4-11 years) referred for CSA and posttraumatic stress disorder symptoms were randomly assigned to one of the four treatment conditions: 8 sessions with no TN, 8 sessions with TN, 16 sessions with no TN, and 16 sessions with TN. RESULTS: Mixed-model ANCOVAs demonstrated that significant posttreatment improvements had occurred with respect to 14 outcome measures across all conditions. Significant main and interactive effect differences were found across conditions with respect to specific outcomes. CONCLUSIONS: TF-CBT, regardless of the number of sessions or the inclusion of a TN component, was effective in improving participant symptomatology as well as parenting skills and the children's personal safety skills. The eight session condition that included the TN component seemed to be the most effective and efficient means of ameliorating parents' abuse-specific distress as well as children's abuse-related fear and general anxiety. On the other hand, parents assigned to the 16 session, no narrative condition reported greater increases in effective parenting practices and fewer externalizing child behavioral problems at posttreatment. PMID- 20830697 TI - The potential use of Echinacea in acne: control of Propionibacterium acnes growth and inflammation. AB - Acne is a chronic inflammatory disorder of skin follicles caused by the gram positive bacterium Propionibacterium acnes. The possibility was investigated that a standardized preparation of Echinacea purpurea (Echinaforce(r)), with known antiviral, antiinflammatory and antibacterial properties, might provide a useful alternative treatment in the control of the disease. The herbal extract readily killed a standard laboratory strain of the bacterium and several clinical isolates. In cell culture models of human bronchial epithelial cells and skin fibroblasts, P. acne induced the secretion of substantial amounts of several pro inflammatory cytokines, including IL-6 and IL-8 (CXCL8), as determined by means of cytokine-antibody arrays. However, the E. purpurea completely reversed this effect and brought the cytokine levels back to normal. Thus Echinaforce(r) could provide a safe two-fold benefit to acne individuals by inhibiting proliferation of the organism and reversing the bacterial-induced inflammation. PMID- 20830698 TI - Antioxidant and anticholinesterase constituents from the petroleum ether and chloroform extracts of Iris suaveolens. AB - The aim of this study was to investigate the phytochemical, antioxidant and anticholinesterase activities of Iris suaveolens. After determining total phenolic and flavonoid contents of the petroleum ether, chloroform and methanol extracts prepared from the rhizomes, the antioxidant capacity of the extracts was established using beta-carotene-linoleic acid and CUPRAC methods. The chloroform extract which was rich in phenolic content exhibited the highest inhibition of lipid peroxidation in the beta-carotene-linoleic acid system, and the best cupric reducing antioxidant capacity among the tested extracts. The petroleum ether extract indicated moderate anticholinesterase activity while the chloroform extract revealed significant butyrylcholinesterase inhibitory activity (75.03 +/- 1.29%). Spectroscopic methods were used for the structural elucidation of the compounds (1-13) isolated from the petroleum ether and chloroform extracts. Coniferaldehyde (6), having the highest antioxidant activity in the beta-carotene linoleic acid assay at 25 and 50 ug/mL, demonstrated also the best effect in the CUPRAC method among the tested compounds (1-12). 3-Hydroxyirisquinone (10) showed the best anticholinesterase activity among the tested compounds (1-4, 6-12), and coniferaldehyde exhibited almost the same butyrylcholinesterase inhibitory activity (82.60 +/- 2.33%) as galantamine (86.26 +/- 0.66%). PMID- 20830699 TI - Comparison of the effect of oligonol, a new lychee fruit-derived low molecular form of polyphenol, and epigallocatechin-3-gallate on lipolysis in rat primary adipocytes. AB - Several polyphenols have been shown to be beneficial in preventing the accumulation of body fat in mammals. This paper reports that adding oligonol, a lychee fruit-derived low-molecular form of polyphenol mixture, has a greater effect on lipolysis in primary adipocytes compared with tea (-)-epigallocatechin 3-gallate (EGCG) alone, accompanied by a significant increase in activation of extracellular signalling-related kinase 1/2 (ERK1/2). However, neither phosphorylation of mitogen-activated protein kinase 1/2 (MEK1/2), a molecule upstream of ERK1/2, nor the level of heme oxygenase-1 (HO-1), a molecule downstream of ERK1/2 was significantly changed between oligonol and EGCG, although the addition of oligonol and EGCG significantly increased the levels of phosphorylated MEK1/2 and HO-1 compared with the non-treated control cells. These results suggest that the coordinated direct effect of mixed polyphenol, which comprises oligonol, on ERK1/2 plays a key role in a greater lipolytic response to oligonol than EGCG alone. PMID- 20830696 TI - A review of empirically supported psychological therapies for mood disorders in adults. AB - BACKGROUND: The mood disorders are prevalent and problematic. We review randomized controlled psychotherapy trials to find those that are empirically supported with respect to acute symptom reduction and the prevention of subsequent relapse and recurrence. METHODS: We searched the PsycINFO and PubMed databases and the reference sections of chapters and journal articles to identify appropriate articles. RESULTS: One hundred twenty-five studies were found evaluating treatment efficacy for the various mood disorders. With respect to the treatment of major depressive disorder (MDD), interpersonal psychotherapy (IPT), cognitive behavior therapy (CBT), and behavior therapy (BT) are efficacious and specific and brief dynamic therapy (BDT) and emotion-focused therapy (EFT) are possibly efficacious. CBT is efficacious and specific, mindfulness-based cognitive therapy (MBCT) efficacious, and BDT and EFT possibly efficacious in the prevention of relapse/recurrence following treatment termination and IPT and CBT are each possibly efficacious in the prevention of relapse/recurrence if continued or maintained. IPT is possibly efficacious in the treatment of dysthymic disorder. With respect to bipolar disorder (BD), CBT and family-focused therapy (FFT) are efficacious and interpersonal social rhythm therapy (IPSRT) possibly efficacious as adjuncts to medication in the treatment of depression. Psychoeducation (PE) is efficacious in the prevention of mania/hypomania (and possibly depression) and FFT is efficacious and IPSRT and CBT possibly efficacious in preventing bipolar episodes. CONCLUSIONS: The newer psychological interventions are as efficacious as and more enduring than medications in the treatment of MDD and may enhance the efficacy of medications in the treatment of BD. PMID- 20830700 TI - Acyl glucuronides: the good, the bad and the ugly. AB - Acyl glucuronidation is the major metabolic conjugation reaction of most carboxylic acid drugs in mammals. The physiological consequences of this biotransformation have been investigated incompletely but include effects on drug metabolism, protein binding, distribution and clearance that impact upon pharmacological and toxicological outcomes. In marked contrast, the exceptional but widely disparate chemical reactivity of acyl glucuronides has attracted far greater attention. Specifically, the complex transacylation and glycation reactions with proteins have provoked much inconclusive debate over the safety of drugs metabolised to acyl glucuronides. It has been hypothesised that these covalent modifications could initiate idiosyncratic adverse drug reactions. However, despite a large body of in vitro data on the reactions of acyl glucuronides with protein, evidence for adduct formation from acyl glucuronides in vivo is limited and potentially ambiguous. The causal connection of protein adduction to adverse drug reactions remains uncertain. This review has assessed the intrinsic reactivity, metabolic stability and pharmacokinetic properties of acyl glucuronides in the context of physiological, pharmacological and toxicological perspectives. Although numerous experiments have characterised the reactions of acyl glucuronides with proteins, these might be attenuated substantially in vivo by rapid clearance of the conjugates. Consequently, to delineate a relationship between acyl glucuronide formation and toxicological phenomena, detailed pharmacokinetic analysis of systemic exposure to the acyl glucuronide should be undertaken adjacent to determining protein adduct concentrations in vivo. Further investigation is required to ascertain whether acyl glucuronide clearance is sufficient to prevent covalent modification of endogenous proteins and consequentially a potential immunological response. PMID- 20830701 TI - Freeze substitution followed by low melting point wax embedding preserves histomorphology and allows protein and mRNA localization techniques. AB - Fixation and embedding are major steps in tissue preservation for histological analysis. However, conventional fixatives like aldehyde-based solutions usually mask tissular epitopes preventing their immunolocalization. Alternative fixation methods used to avoid this drawback, such as cryopreservation, alcohol- or zinc salts-based fixatives do not efficiently preserve tissue and cell morphology. Likewise, paraffin and resin embedding, commonly used for thin sectioning, frequently damage epitopes due to the clearing agents and high temperatures needed along the embedding procedure. Alternatives like cryosectioning avoid the embedding steps but yield sections of poorer quality and are not suitable for all kinds of samples. To overcome these handicaps, we have developed a method that preserves histoarchitecture as well as tissue antigenic properties. This method, which we have named CryoWax, involves freeze substitution of the samples in isopentane and methanol, followed by embedding in low melting point polyester wax. CryoWax has proven efficient in obtaining thin sections of embryos and adult tissues from different species, including amphioxus, zebrafish, and mouse. CryoWax sections displayed optimal preservation of tissue morphology and were successfully immunostained for fixation- and temperature-sensitive antigens. Furthermore, CryoWax has been tested for in situ hybridization application, obtaining positive results. PMID- 20830702 TI - Morphological and molecular pathology of CCL4-induced hepatic fibrosis in connexin43-deficient mice. AB - Gap junction channels, formed by connexins (Cx), are involved in the maintenance of tissue homeostasis, cell growth, differentiation, and development. Several studies have shown that Cx43 is involved in the control of wound healing in dermal tissue. However, it remains unknown whether Cx43 plays a role in the control of liver fibrogenesis. Our study investigated the roles of Cx43 heterologous deletion on carbon tetrachloride (CCl(4))-induced hepatic fibrosis in mice. We administered CCl(4) to both Cx43-deficient (Cx43(+/-)) and wild-type mice and examined hepatocellular injury and collagen deposition by histological and ultrastructural analyses. Serum biochemical analysis was performed to quantify liver injury. Hepatocyte proliferation was analyzed immunohistochemically. Protein and messenger RNA (mRNA) expression of liver connexins were evaluated using immunohistochemistry as well as immunoblotting analysis and quantitative real-time PCR. We demonstrated that Cx43(+/-) mice developed excessive liver fibrosis compared with wild-type mice after CCl(4) induced chronic hepatic injury, with thick and irregular collagen fibers. Histopathological evaluation showed that Cx43(+/-) mice present less necroinflammatory lesions in liver parenchyma and consequent reduction of serum aminotransferase activity. Hepatocyte cell proliferation was reduced in Cx43(+/-) mice. There was no difference in Cx32 and Cx26 protein or mRNA expression in fibrotic mice. Protein expression of Cx43 increased in CCl(4)-treated mice, although with aberrant protein location on cytoplasm of perisinusoidal cells. Our results demonstrate that Cx43 plays an important role in the control and regulation of hepatic fibrogenesis. PMID- 20830703 TI - Ionic liquid enables simple and rapid sample preparation of human culturing cells for scanning electron microscope analysis. AB - Ionic liquid is a kind of salt that stays in a molten state even at room temperature. It does not vaporize at all in vacuum and facilitates electrical conductivity to the sample surfaces for observations with a scanning electron microscope (SEM). In this study, we used an ionic liquid in SEM for the first time to observe fixed human culture cells. The condition for the cell culture using wrapping sheets and SEM settings were varied to elucidate the optimized protocol. Compared to samples prepared by the conventional way, the ionic liquid treatment of samples gave SEM images of the cellular ultra structures in more detail, enabling observation of microvilli that made bridges between separated cells. In addition, the ionic liquid treatment is less time consuming as well as less laborious compared with the conventional way that includes dehydration, drying, and conductivity treatments. Totally, we concluded the ionic liquid is a useful reagent for SEM sample preparation. PMID- 20830704 TI - A soft-cache strategy for pathologist's navigation in virtual microscopy. AB - Navigation through large microscopical images demands special characteristics like flexibility to access image data and progressive recovery or relevant information, i.e., several qualities, magnifications, and random accesses to any desired Window of Interest in the Virtual Slide (VS). Nowadays there exist systems that allow such interaction, but with a certain delay, which is dependent on the application. It has been shown that caching or prefetching policies can speed up interaction with these systems. This article presents an optimal soft cache strategy, which improves the navigation times in virtual microscopy. The entire method includes an optimal soft-cache strategy and a dynamical probabilistic model of a pathologist's navigation. This strategy was implemented as a Client-Server application, using the JPEG2000-JPIP standard and evaluated using different navigation patterns, namely, four different pathologists exploring 10 VS, stained with different dyes. The present approach was compared with a conventional soft-cache method and the cache performance improved, in average, in about a 10%. PMID- 20830705 TI - Overexpression of eIF5A-2 is an adverse prognostic marker of survival in stage I non-small cell lung cancer patients. AB - We have previously isolated an oncogene EIF5A2 (eukaryotic initiation factor 5A2) from a frequently amplified region at 3q of a primary ovarian cancer cell line, and demonstrated its impact on prognosis in human ovarian cancer. Amplification of chromosome 3q has also been detected frequently in non-small cell lung cancer (NSCLC), however, abnormalities of EIF5A2 and its clinicopathologic significance in NSCLC haven't been studied. In our study, the methods of immunohistochemistry and fluorescence in situ hybridization were utilized to examine protein expression and amplification of EIF5A2 in 248 surgically resected NSCLCs (learning cohort) and another validation cohort of 120 stage I NSCLC patients. Overexpression and amplification of EIF5A2 was detected informatively in 48.7% and 13.7% of NSCLCs in learning cohort, 33.3% and 6.0% of NSCLCs in validation cohort. Overexpression of eIF5A-2 was found to correlate with gene amplification, increased cell proliferation and advanced T stage. In learning cohort, eIF5A-2 expression was evaluated as a strong prognostic factor on disease-specific survival, but in subgroup analyses, it only retained its stratified significance in stage I set (Hazards ratio = 2.799, p = 0.001). In validation cohort, the impact of eIF5A-2 expression on survival in stage I NSCLC patients was also observed (Hazard ratio = 2.097, p = 0.014). Our findings suggested that overexpression of eIF5A-2 correlates with local invasion of NSCLC, and might serve as an adverse prognostic marker of survival for stage I NSCLC patients. PMID- 20830706 TI - Id3 modulates cellular localization of bHLH Ptf1-p48 protein. AB - Ptf1-p48 is a pancreas-specific bHLH transcriptional protein, which, in the normal adult pancreas, shows a restricted expression in acinar cells where it is predominantly localized in the nucleus and activates the transcription of exocrine-specific genes. Ptf1-p48 partners with two proteins to form the PTF1 active complex: a bHLH E-protein and suppressor of hairless RBP-J. Cytoplasmic mislocalization of Ptf1-p48 has been reported in pancreatic pathologies, suggesting its contribution in the early steps of pancreatic carcinogenesis. The aim of the our work was to elucidate the mechanisms regulating Ptf1-p48 subcellular localization. We hypothesized a role of Id proteins acting in a dominant-negative fashion by heterodimerizing with bHLH proteins. We reproduced Ptf1-p48 cytoplasmic mislocalization in acinar AR4-2J cells and demonstrated that a proliferative signal elicited by gastrin leads to increases in Id3 protein expression and levels of Id3/E47 and Id3/Ptf1-p48 interactions, and a decrease in the level of E47/Ptf1-p48 interaction. By contrast, Id3 silencing reversed the cytoplasmic mislocalization of Ptf1-p48 induced by gastrin. As E47 is responsible for the nuclear import of the PTF1 complex, disruption of this complex via Id3 interactions with both E47 and Ptf1-p48 appears to induce cytoplasmic mislocalization of Ptf1-p48. We then found that Ptf1-p48 is either absent or mislocalized in the cytoplasm and Id3 is overexpressed in human and murine pancreatic preneoplastic lesions. Our data provide novel insight into the regulation of Ptf1-p48 function and provide evidence that Ptf1-p48 cytoplasmic mislocalization and Id3 overexpression are early events in pancreatic cancer progression. PMID- 20830708 TI - Molecularly intercalated nanoflakes: a supramolecular composite for strong energy absorption. PMID- 20830707 TI - Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia: Testing a device as an adjunct to colposcopy. AB - Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer. PMID- 20830709 TI - Crumpled graphene nanosheets as highly effective barrier property enhancers. PMID- 20830710 TI - A metal-oxide interconnection layer for polymer tandem solar cells with an inverted architecture. PMID- 20830711 TI - Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy. AB - New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3* weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors. PMID- 20830712 TI - CXCR4 peptide antagonist inhibits primary breast tumor growth, metastasis and enhances the efficacy of anti-VEGF treatment or docetaxel in a transgenic mouse model. AB - CXCR4 is a chemokine receptor implicated in the homing of cancer cells to target metastatic organs, which overexpress its ligand, stromal cell-derived factor (SDF)-1. To determine the efficacy of targeting CXCR4 on primary tumor growth and metastasis, we used a peptide inhibitor of CXCR4, CTCE-9908, that was administered in a clinically relevant approach using a transgenic breast cancer mouse model. We first performed a dosing experiment of CTCE-9908 in the PyMT mouse model, testing 25, 50 and 100 mg/kg versus the scrambled peptide in groups of 8-16 mice. We then combined CTCE-9908 with docetaxel or DC101 (an anti-VEGFR2 monoclonal antibody). We found that increasing doses of CTCE-9908 alone slowed the rate of tumor growth, with a 45% inhibition of primary tumor growth at 3.5 weeks of treatment with 50 mg/kg of CTCE-9908 (p = 0.005). Expression levels of VEGF were also found to be reduced by 42% with CTCE-9908 (p = 0.01). In combination with docetaxel, CTCE-9908 administration decreased tumor volume by 38% (p = 0.02), an effect that was greater than that observed with docetaxel alone. In combination with DC101, CTCE-9908 also demonstrated an enhanced effect compared to DC101 alone, with a 37% decrease in primary tumor volume (p = 0.01) and a 75% reduction in distant metastasis (p = 0.009). In combination with docetaxel or an anti-angiogenic agent, the anti-tumor and anti-metastatic effects of CTCE-9908 were markedly enhanced, suggesting potentially new effective combinatorial therapeutic strategies in the treatment of breast cancer, which include targeting the SDF-1/CXCR4 ligand/receptor pair. PMID- 20830713 TI - A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. AB - Desmoid-type fibromatoses are neoplasms of fibroblastic origin, occurring sporadically or associated with familial adenomatous polyposis (FAP) coli. By comparing sporadic and FAP-associated desmoid-type fibromatoses, we tried to identify clinical characteristics, which may indicate FAP. Histopathology data of all Dutch patients with desmoid-type fibromatoses diagnosed between 1999 and 2009 were retrieved from PALGA, the nation-wide network and registry of histopathology in the Netherlands. For calculation of incidence rates, person-years from the general matched population were used. Based on polyp counts in pathological records, the cohort was divided into a FAP group and a non-FAP group. Patient- and tumor characteristics were compared between the two groups. A total number of 519 patients older than 10 years with a confirmed diagnosis of desmoid-type fibromatoses were included. Thirty-nine (7.5%) desmoid patients were documented of having FAP. The incidences of sporadic and FAP-related desmoid-type fibromatoses were 3.42 and 2,784 per million person-years, respectively. The majority of FAP patients developed desmoid-type fibromatoses after the diagnosis of FAP. Having FAP was associated with male gender [odds ratio (OR) 2.0, p = 0.034], desmoid diagnosis at an earlier age (mean 36 vs. 42 years, p = 0.031), and desmoid localization intra-abdominally (OR 18.9, p <= 0.001) or in the abdominal wall (OR 4.8, p <= 0.001), compared to extra-abdominal desmoid localization. In conclusion, patients with desmoid-type fibromatoses are at risk of underlying FAP. Especially cases with desmoid localization intra-abdominal or in the abdominal wall, and all patients younger than 60 years, have a substantial increased risk and should be referred for colonoscopy. PMID- 20830714 TI - Batch fabrication of high-performance planar patch-clamp devices in quartz. PMID- 20830715 TI - Rollable transparent glass-fabric reinforced composite substrate for flexible devices. PMID- 20830716 TI - The topographic effect of zinc oxide nanoflowers on osteoblast growth and osseointegration. PMID- 20830717 TI - Self-assembled hybrid structures of DNA block-copolymers and nanoparticles with enhanced DNA binding properties. PMID- 20830718 TI - Nanofibrous bio-inorganic hybrid structures formed through self-assembly and oriented mineralization of genetically engineered phage nanofibers. PMID- 20830719 TI - BCL6 gene rearrangement and protein expression are associated with large cell presentation of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. AB - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is an indolent B-cell lymphoma, which is often localized in the stomach. It is characterized by typical morphology, immunology, cytogenetics and expression profile. The coexistence of a large B-cell lymphoma and a MALT lymphoma in the gastrointestinal tract is defined as a composite lymphoma (ComL) and, as we have previously shown, is almost always the consequence of secondary transformation of MALT lymphoma. Here, we have analyzed a panel of seven MALT lymphomas, seven ComL and thirteen large cell variants of marginal zone B-cell lymphomas (MZBL) using FISH for the detection of rearrangements of IGH, MALT1, BCL6, BCL10 and FOXP1 and immunohistochemistry for Bcl6, Bcl10 and FoxP1. Translocations involving IGH were found in 10/27 lymphomas including two cases with IGH-BCL6 fusion and one with IGH-BCL10 fusion; in 7/10 cases, the translocation partner was not identified. Bcl10 and FoxP1 protein expression was heterogeneous throughout the series. Genetic rearrangements of BCL6 and Bcl6 protein expression were found almost exclusively in the large cell components of the ComL and the large cell extranodal MZBL (p = 0.2093 and p = 0.0261, respectively). These findings suggest Bcl6 as a marker for transformation of MALT lymphoma. PMID- 20830720 TI - MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation. AB - Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) ethyl]-9-[(pyridine-3-ylmethyl)amino]pyrido[2',1':2,3]imida-zo[4,5-c]isoquinolin 5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited tubulin polymerization significantly both in tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified tubulin directly, with the K(D) value of 10.6 MUM. The binding of MT119 in turn caused tubulin conformational changes as evidenced by the quenched tryptophan fluorescence, the reduction of the bis-ANS reactivity and the decreased DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to tubulin at its colchicine site. Consequently, by inhibiting tubulin polymerization, MT119 arrested different tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to vincristine-, adriamycin- or mitoxantrone-resistant cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of colchicine-site-targeted inhibitors against tubulin polymerization, which might be a promising starting point for future cancer therapeutics. PMID- 20830721 TI - An inhibitor of a cell adhesion receptor stimulates cell migration. PMID- 20830722 TI - The DAT ligand [(18)F]PR17.MZ mirrors the in vivo pharmacokinetic profile of [(11)C]cocaine with significantly improved monoamine transporter selectivity. PMID- 20830723 TI - Homogeneous oxidation reactions of propanediols at low temperatures. AB - O2 reacts with propanediols via homogeneous pathways at 400-500 K. 1,2 Propanediol forms CH3CHO, HCHO, and CO2 via oxidative C--C cleavage and acetone via dehydration routes, while symmetrical 1,3-propanediol undergoes dehydration and oxidative dehydrogenation to form, almost exclusively, acrolein (ca. 90 % selectivity). The products formed and their kinetic dependence on reactant concentrations are consistent with radical-mediated pathways initiated by O2 insertion into C--H bonds in a beta position relative to oxygen atoms in diol reactants. Propagation involves beta-scission reactions that form hydroxyl and hydroxyalkyl radicals. Acrolein/O2/H2O mixtures from the homogeneous oxidation of 1,3-propanediol form acrylic acid (with 90 % yield) in tandem reactors containing molybdenum-vanadium oxide catalysts. These data reveal the unique reactivity of diols, compared with triols and alkanols, in homogeneous oxidations, while also providing useful insight into the molecular basis for reactivity in biomass derived oxygenates. PMID- 20830724 TI - Green oxidation of alcohols to carbonyl compounds by heterogeneous photocatalysis. PMID- 20830725 TI - A green and highly selective oxidation of alcohols by fluorous silica gel supported gold nanoparticles in aqueous H2O2 under base-free conditions. PMID- 20830726 TI - An efficient route to nanostructured tungsten oxide films with improved electrochromic properties. AB - An effective chemical route to nanostructured tungsten oxide films derived from a peroxopolytungstic acid (PTA)/thiourea precursor solution is demonstrated. The conventional procedure of preparing the precursor needs more than 24 h for well mixing and refluxing the PTA-based solution, while the thiourea-assisted approach takes less than 1 h to prepare the precursor solution because the excess hydrogen peroxide can be efficiently eliminated by oxidation of thiourea. With the precursor solution, tungsten oxide films are deposited by spin coating followed by high temperature annealing. The film annealed at 400 degrees C possesses a porous nanostructure of nanocrystalline tungsten oxide embedded in an amorphous tungsten oxide matrix, which arises from the gaseous species released through decomposition of thiourea oxides during annealing. The 400 degrees C-annealed, thiourea-assisted tungsten oxide film exhibits electrochromic (EC) properties superior to those of the film prepared without thiourea, including large transmittance modulation and coloration efficiency, fast response time and adequate reliability. When increasing the annealing temperature to 450 degrees C, the thiourea-assisted tungsten oxide film is also porous but well-crystallized and shows inferior EC properties. Electrochemical impedance spectroscopy analysis indicates that, in addition to the porous structure, a fast charge-transport rate within the solid portion of the 400 degrees C-annealed nanostructured film plays a crucial role in enhancing EC performances of the thiourea-assisted tungsten oxide film. PMID- 20830727 TI - Molecular dynamics simulation of the adsorption of oxalic acid on an ice surface. AB - The adsorption properties of oxalic acid molecules on the surface of hexagonal ice are investigated by means of molecular dynamics simulations performed at tropospheric temperatures. Although the oxalic acid-water interaction is strong at low coverage, due to the possible formation of a large number of hydrogen bonds between the adsorbed oxalic acid and the surface water molecules, the results of the simulations at finite coverage show the predominant role played by the oxalic acid-oxalic acid lateral interactions in the adsorption/desorption process. These interactions are even stronger than the water-water or water oxalic acid interactions. With increasing temperature these strong lateral interactions favor the formation of oxalic acid aggregates on the ice surface, with the concomitant departure of water molecules through the ducts in the adsorbed layer created by the aggregation process. These results support conclusions of experimental data on the oxalic acid-ice interactions. Moreover, in comparison to previously obtained results for formic and acetic acid adsorbed on ice, the present study suggests that not only the organic functionality is of importance for atmospheric implications of partially oxidized hydrocarbons (POH) interactions with ice, but also the balance between water-ice, water-POH, and POH POH interactions. PMID- 20830728 TI - Quantum chemical study of the reaction between Ni+ and H2S. AB - The reaction between the Ni(+) cation and H(2)S is studied by considering both the doublet ground state and the lowest-lying quartet state. For the doublet state the reaction is endothermic, whereas it is exothermic for the quartet state. Both CCSD(T)//B3LYP and B3LYP levels of theory, combined with the triple zeta quality TZVP++G(3df,2p), predict that there are three spin crossings along the characterized reaction path. The first one is located after the first transition state, and the second and third ones before and after the second transition state. On the quartet potential energy surface, both transition states are close in energy to the reactants, while on the doublet surface both lie quite higher in energy. The doublet and quartet states of the HNiSH(+) four-membered intermediate lie very close in energy and their corresponding electronic configurations are connected by a single electron flip. This suggests that the SH ligand would not prevent a facile intersystem crossing at this intermediate molecule, in contrast to the larger protection provided by the more electronegative -OH ligand. PMID- 20830729 TI - Thermodynamics and kinetics of the complexation reaction of lead by calix-DANS4. AB - The thermodynamics and kinetics of the complexation reaction between lead ions and the fluorescent sensor Calix-DANS4 are determined to optimize the geometry of the microreactor used for the flow-injection analysis of lead and to tune the working conditions of this microdevice. Under our experimental conditions (pH 3.2, low concentration of Calix-DANS4) the 1:1 Pb(2+)-Calix-DANS4 complex is predominantly formed with a high stability constant (log K(1:1)=6.82) and a slow second-order rate constant (k=9.4*10(4) L mol(-1) s(-1)). Due to this sluggish complexation reaction, the microchannel length must be longer than 130 mm and the flow rate lower than 0.25 mL h(-1) to have an almost complete reaction at the output of the microchannel and a high sensitivity for the heavy metal detection. After determination of the values of the reaction times in our different microdevices, it is possible to simulate the calibration curves for the fluorimetric detection of lead under different conditions. An original method is also presented to determine mixing times in microreactors. PMID- 20830730 TI - Simultaneous optical and electrical recording of single molecule bonding to single channel proteins. PMID- 20830732 TI - Cybernetic models based on lumped elementary modes accurately predict strain specific metabolic function. AB - In a recent article, Song and Ramkrishna (Song and Ramkrishna [2010]. Biotechnol Bioeng 106(2):271-284) proposed a lumped hybrid cybernetic model (L-HCM) towards extracting maximum information about metabolic function from a minimum of data. This approach views the total uptake flux as distributed among lumped elementary modes (L-EMs) so as to maximize a prescribed metabolic objective such as growth or uptake rate. L-EM is computed as a weighted average of EMs where the weights are related to the yields of vital products (i.e., biomass and ATP). In this article, we further enhance the predictive power of L-HCMs through modifications in lumping weights with additional parameters that can be tuned with data viewed to be critical. The resulting model is able to make predictions of diverse metabolic behaviors varying greatly with strain types as evidenced from case studies of anaerobic growth of various Escherichia coli strains. Incorporation of the new lumping formula into L-HCM remarkably improves model predictions with a few critical data, thus presenting L-HCM as a dynamic tool as being not only qualitatively correct but also quantitatively accurate. PMID- 20830731 TI - Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65). AB - BACKGROUND: We have previously shown that two injections of 20 ug alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd((r))) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months' follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months. METHODS: Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, 13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction. RESULTS: Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time. CONCLUSIONS: Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. PMID- 20830733 TI - Taking the next step. PMID- 20830734 TI - Reduction of the Earth's magnetic field inhibits growth rates of model cancer cell lines. AB - Small alterations in static magnetic fields have been shown to affect certain chemical reaction rates ex vivo. In this manuscript, we present data demonstrating that similar small changes in static magnetic fields between individual cell culture incubators results in significantly altered cell cycle rates for multiple cancer-derived cell lines. This change as assessed by cell number is not a result of apoptosis, necrosis, or cell cycle alterations. While the underlying mechanism is unclear, the implications for all cell culture experiments are clear; static magnetic field conditions within incubators must be considered and/or controlled just as one does for temperature, humidity, and carbon dioxide concentration. PMID- 20830735 TI - Identification of p10 as a neurotoxic product generated from the proteolytic cleavage of the neuronal Cdk5 activator. AB - The involvement of cyclin-dependent kinase-5 (Cdk5) and p25, the proteolytic fragment of activator p35, has long been implicated in the development of neuron fibrillary tangles (NFTs), a hallmark of Alzheimer's disease (AD). Findings in this area over the past decade have been highly controversial and inconclusive. Here we report unprecedented detection of endogenous p10, the smaller proteolytic fragment of the Cdk5 activator p35 in treated primary cortical neurons that underwent significant apoptosis, triggered by proteasome inhibitors MG132 and lactacystin, and protein kinase inhibitor staurosporine (STS). p10 appeared exclusively in the detergent-resistant fraction made up of nuclear matrix, membrane-bound organelles, insoluble membrane proteins, and cytoskeletal components. Intriguingly, transient overexpression of p10 in neural cells induced apoptotic morphologies, suggesting that p10 may play an important role in mediating neuronal cell death in neurodegenerative diseases. We demonstrated for the first time that p10-mediated apoptosis occurred via a caspases-independent pathway. Furthermore, as p10 may contain the myristoylation signal for p35 which is responsible for binding p35 to several intracellular components and the membrane, all in all these novel results present that the accumulation of p10 to the detergent-insoluble fraction may be a crucial pathological event to triggering neuronal cell death. PMID- 20830736 TI - Glucose effectiveness and insulin sensitivity measurements derived from the non insulin-assisted minimal model and the clamp techniques are concordant. AB - BACKGROUND: We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin assisted intravenous glucose tolerance test (IVGTT) implemented by SG(MM) and SI(MM); simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SG(CLAMP) and SI(CLAMP)). METHODS: Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SG(CLAMP) was calculated in two ways based on data from study (2) alone (Day 2 SG(CLAMP210-240')) or from data from study day (2) and (3) (Day 2-3 SG(CLAMP330 360')). RESULTS: SG(MM) was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SG(CLAMP) protocols correlated (r = 0.72, p = 0.003), but SG(CLAMP210-240') was significantly (p = 0.001) higher than SG(CLAMP330-360'). Employing the Day 2 and 3 SG(CLAMP) protocol, the whole body SG(CLAMP330-360') was similar to SG(MM) (1.80 +/- 0.82 versus 1.73 +/- 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SG(CLAMP210-240') did not correlate with SG(MM) (r = 0.24). SI(MM) and SI(CLAMP) were similar (0.093 +/- 0.060 versus 0.087 +/- 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). CONCLUSIONS: The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SG(CLAMP), and significant concordance coefficients are observed between SG(MM), and SG(CLAMP330-360'), and SI(MM) and SI(CLAMP). PMID- 20830738 TI - Hip screw migration testing: first results for hip screws and helical blades utilizing a new oscillating test method. AB - Despite continued improvement in the methods and devices used to treat intertrochanteric fractures, there remains an unacceptable amount of failures. The cut-out rate for hip screws has been recorded up to 8.3%. To evaluate the migration of different implants under physiological loads, a multiplanar biomechanical test method for hip screws was developed, the first to incorporate a simulation of the human gait cycle by an oscillating flexion/extension movement of the test device. The new method was used to compare different hip screw and blade designs with respect to their directional migration resistance. The test method generated failure modes that were consistent with those observed clinically. Under cyclic loading, the hip screws migrated predominantly in a cephalad direction. In contrast, the helical blades exhibited a distinct migration in their axial direction. The Gamma3 hip screw design showed a significantly higher migration resistance compared with other screw and helical blade designs. The results demonstrate the ability of hip screws to significantly reduce axial migration and prevent cut-out under simulated walking loads. Further, the new multiplanar test method creates a physiological environment that can be used to optimize designs for intertrochanteric fracture fixation. PMID- 20830737 TI - Role of AMPK throughout meiotic maturation in the mouse oocyte: evidence for promotion of polar body formation and suppression of premature activation. AB - This study was conducted to assess the role of AMPK in regulating meiosis in mouse oocytes from the germinal vesicle stage to metaphase II. Exposure of mouse cumulus cell-enclosed oocytes (CEO) and denuded oocytes (DO) during spontaneous maturation in vitro to AMPK-activating agents resulted in augmentation of the rate and frequency of polar body formation. Inhibitors of AMPK had an opposite, inhibitory effect. In addition, the AMPK inhibitor, compound C (Cmpd C) increased the frequency of oocyte activation. The stimulatory action of the AMPK-activating agent, AICAR, and the inhibitory action of Cmpd C were diminished if exposure was delayed, indicating an early action of AMPK on polar body formation. The frequency of spontaneous and Cmpd C-induced activation in CEO was reduced as the period of hormonal priming was increased, and AMPK stimulation eliminated the activation response. Immunostaining of oocytes with antibody to active AMPK revealed an association of active kinase with chromatin, spindle poles, and midbody during maturation. Immunolocalization of the alpha1 catalytic subunit of AMPK showed an association with condensed chromatin and the meiotic spindle but not in the spindle poles or midbody; alpha2 stained only diffusely throughout the oocyte. These data suggest that AMPK is involved in a regulatory capacity throughout maturation and helps promote the completion of meiosis while suppressing premature activation. PMID- 20830739 TI - Comparison of patellar bone strain in the natural and implanted knee during simulated deep flexion. AB - Instances of anterior knee pain and patellar fracture are significant complications following total knee replacement (TKR). Bone strain measured in the patella can provide an indication of patellar fracture risk and may also be related to anterior knee pain. The objective of this study was to develop subject specific finite element models of the patellofemoral (PF) joint including density mapped material properties to gain insight into the patellar bone strain distribution in the natural and implanted knee. In eight subjects, the volume of bone experiencing strains >0.5% in the implanted condition was ~200% larger, on average, than the natural condition. An inverse relationship with a correlation of -0.74 was established between postoperative bone volume and strain in the implanted specimens, suggesting that patellar geometry may be a useful indicator of postoperative strain. Comparing strains between regions (superior, inferior, medial, and lateral), it was found that although highly strained bone was evenly distributed between medial and lateral regions in the natural case, the implanted specimens demonstrated significantly larger volumes of highly strained bone medially as a result of substantially lower modulus bone in the medial compartment. Understanding distributions of PF strain may aid in preoperative identification of those patients at risk for patellar fracture or anterior knee pain, guidance regarding altered component placement for at-risk patients, and design of components considering the implications of PF load transfer and patellar strain distribution. PMID- 20830740 TI - Expression of homeobox genes in oral squamous cell carcinoma cell lines treated with all-trans retinoic acid. AB - Oral squamous cell carcinoma (OSCC) may arise from potentially malignant oral lesions. All-trans retinoic acid (atRA), which plays a role in cell growth and differentiation, has been studied as a possible chemotherapeutic agent in the prevention of this progression. While the mechanism by which atRA suppresses cell growth has not been completely elucidated, it is known that homeobox genes are atRA targets. To determine if these genes are involved in the atRA-mediated OSCC growth inhibition, PCR array was performed to evaluate the expression of 84 homeobox genes in atRA-sensitive SCC-25 cells compared to atRA-resistant SCC-9 cells following 7 days with atRA treatment. Results showed that the expression of 8 homeobox genes was downregulated and expression of 4 was upregulated in SCC-25 cells but not in SCC-9 cells. Gene expression levels were confirmed for seven of these genes by RT-qPCR. Expression of three genes that showed threefold downregulation was evaluated in SCC-25 cells treated with atRA for 3, 5, and 7 days. Three different patterns of atRA-dependent gene expression were observed. ALX1 showed downregulation only on day 7. DLX3 showed reduced expression on day 3 and further reduced on day 7. TLX1 showed downregulation only on days 5 and 7. Clearly the expression of homeobox genes is modulated by atRA in OSCC cell lines. However, the time course of this modulation suggests that these genes are not direct targets of atRA mediating OSCC growth suppression. Instead they appear to act as downstream effectors of atRA signaling. PMID- 20830741 TI - Low-level laser irradiation enhances BMP-induced osteoblast differentiation by stimulating the BMP/Smad signaling pathway. AB - Low-level laser irradiation (LLLI) has been shown to induce bone formation and osteoblast differentiation both in vivo and in vitro. However, the molecular mechanism by which LLLI stimulates osteoblast differentiation is still unclear. The aim of the present study was to examine whether Ga-Al-As laser irradiation could enhance BMP2-induced alkaline phosphatase (ALP) activity in C2C12 cells. Laser irradiation at 0.5 W for 20 min enhanced BMP2-induced ALP activity. Laser treatment alone did not affect ALP activity. To exclude the effect of pH or temperature changes during irradiation, we shortened the exposure time to 2 min, with various levels of laser power. At 2.5 W, irradiation stimulated BMP2-induced ALP activity but not cell proliferation, whereas 1 or 5 W laser power did not induce any significant effects. Irradiation stimulated BMP2-induced phosphorylation of Smad1/5/8 and BMP2 expression, but had no effect on the expression of inhibitory Smads 6 and 7, BMP4, or insulin-like growth factor 1. Laser irradiation enhanced Smad-induced Id1 reporter activity as well as expression of bone morphogenetic protein (BMP)-induced transcription factors such as Id1, Osterix, and Runx2. Laser irradiation also stimulated BMP-induced expressions of type I collagen, osteonectin, and osteocalcin mRNA, markers of osteoblasts. This enhancement of BMP2-induced ALP activity and Smad phosphorylation by laser irradiation was also observed in primary osteoblasts. These results suggest that LLLI accelerates the differentiation of BMP-induced osteoblasts by stimulating the BMP/Smad signaling pathway. PMID- 20830742 TI - Anti-fibrotic effect of chorionic plate-derived mesenchymal stem cells isolated from human placenta in a rat model of CCl(4)-injured liver: potential application to the treatment of hepatic diseases. AB - Translational studies have explored the therapeutic effects of stem cells, raising hopes for the treatment of numerous diseases. Here, we evaluated the therapeutic effect of chorionic plate-derived mesenchymal stem cells (CP-MSCs) isolated from human placenta and transplanted into rats with carbon tetrachloride (CCl(4))-injured livers. CP-MSCs were analyzed for hepatocyte-specific gene expression, indocyanine green (ICG) uptake, glycogen storage, and urea production following hepatogenic differentiation. PKH26-labeled CP-MSCs were directly transplanted into the livers of rats that had been exposed to CCl(4) (1.6 g/kg, twice per week for 9 weeks). Blood and liver tissue were analyzed at 1, 2, and 3 weeks post-transplantation. The expression of type I collagen (Col I) and matrix metalloproteinases (MMPs) was analyzed in rat T-HSC/Cl-6 hepatic stellate cells co-cultured with CP-MSCs following exposure to TGF-beta. The expression levels of alpha-smooth muscle actin (alpha-SMA) and Col I were lower in transplanted (TP) rats than in non-transplanted (Non-TP) animals (P < 0.05), whereas the expression levels of albumin and MMP-9 were increased. TP rats exhibited significantly higher uptake/excretion of ICG than non-TP rats (P < 0.005). In addition, collagen synthesis in T-HSC/Cl-6 cells exposed to TGF-beta was decreased by co culture with CP-MSCs, which triggered the activation of MMP-2 and MMP-9. These results contribute to our understanding of the potential pathophysiological roles of CP-MSCs, including anti-fibrotic effects in liver disease, and provide a foundation for the development of new cell therapy-based strategies for the treatment of difficult-to-treat liver diseases. PMID- 20830743 TI - Sorting nexin 6 interacts with breast cancer metastasis suppressor-1 and promotes transcriptional repression. AB - Sorting nexin 6 (SNX6), a predominantly cytoplasmic protein involved in intracellular trafficking of membrane receptors, was identified as a TGF-beta family interactor. However, apart from being a component of the Retromer, little is known about SNX6 cellular functions. Pim-1-dependent SNX6 nuclear translocation has been reported suggesting a putative nuclear role for SNX6. Here, we describe a previously non-reported association of SNX6 with breast cancer metastasis suppressor 1 (BRMS1) protein detected by a yeast two-hybrid screening. The interaction can be reconstituted in vitro and further FRET analysis confirmed the novel interaction. Additionally, we identified their coiled-coil domains as the minimal binding motives required for interaction. Since BRMS1 has been shown to repress transcription, we sought the ability of SNX6 to interfere with this nuclear activity. Using a standard gene reporter assay, we observed that SNX6 increases BRMS1-dependent transcriptional repression. Moreover, over-expression of SNX6 was capable of diminishing trans activation in a dose-dependent manner. PMID- 20830744 TI - Identification of new modulators and protein alterations in non-apoptotic programmed cell death. AB - This study describes the first proteomic analysis of paraptosis--a non-apoptotic form of programmed cell death. As with apoptosis, the first description of paraptosis was based on morphological criteria. Since there are no known markers for paraptosis, the purpose of this study was to dissect changes in the proteome profile occurring during paraptosis. Using one- and two-dimensional SDS-PAGE, Western analysis, and mass spectrometry, we show that during paraptosis, alterations occur mainly in cytoskeletal proteins, signal transduction proteins, mitochondrial proteins, and some metabolic proteins. We also report the identification of: (1) a paraptosis inhibitor, phosphatidylethanolamine binding protein (PEBP-1), and (2) a candidate mediator of paraptosis, prohibitin. Identification of specific paraptotic changes will ultimately lead to tools to detect this type of programmed cell death in in vivo systems and allow for its further characterization. PMID- 20830745 TI - PTEN suppression promotes neurite development exclusively in differentiating PC12 cells via PI3-kinase and MAP kinase signaling. AB - As a dual-specificity phosphatase catalyzing the dephosphorylation of phosphatidylinositols and protein substrates, PTEN is critically involved in the nervous system development. However, the regulatory role of PTEN in neurite outgrowth is still controversial, and the downstream signaling events remain elusive. Here, we show that PTEN knockdown promoted the proliferation and survival but not the neurite outgrowth of rat pheochromocytoma PC12 cells when exposed to nerve growth factor (NGF). In contrast, selective PTEN silencing in differentiating PC12 cells that express nestin significantly facilitated neurite elongation. Elevated Akt and Erk1/2 phosphorylation was involved in accelerated NGF-induced neurite development of PC12 cells following PTEN knockdown. Discriminated roles of the lipid phosphatase and protein phosphatase activities of PTEN in neurite development, as well as the detailed molecular profiles affected by these phosphatase activities, were defined by restored expression of a lipid phosphatase-deficient PTEN mutant following endogenous PTEN silencing in PC12 cells. Our study suggests an overall inhibitory effect of PTEN in neurite development reconciled by a probably indispensable role of this phosphatase in the initiation of PC12 cell differentiation. PMID- 20830746 TI - Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: the cellular mechanism. AB - Extensive studies have revealed that berberine, a small molecule derived from Coptidis rhizoma (Huanglian in Chinese) and many other plants, has strong anti tumor properties. To better understand berberine-induced cell death and its underlying mechanisms in cancer, we examined autophagy and apoptosis in the human hepatic carcinoma cell lines HepG2 and MHCC97-L. The results of this study indicate that berberine can induce both autophagy and apoptosis in hepatocellular carcinoma cells. Berberine-induced cell death in human hepatic carcinoma cells was diminished in the presence of the cell death inhibitor 3-methyladenine, or following interference with the essential autophagy gene Atg5. Mechanistic studies showed that berberine may activate mitochondrial apoptosis in HepG2 and MHCC97-L cells by increasing Bax expression, the formation of permeable transition pores, cytochrome C release to cytosol, and subsequent activation of the caspases 3 and 9 execution pathway. Berberine may also induce autophagic cell death in HepG2 and MHCC97-L cells through activation of Beclin-1 and inhibition of the mTOR-signaling pathway by suppressing the activity of Akt and up regulating P38 MAPK signaling. This is the first study to describe the role of Beclin-1 activation and mTOR inhibition in berberine-induced autophagic cell death. These results further demonstrate the potential of berberine as a therapeutic agent in the emerging list of cancer therapies with novel mechanisms. PMID- 20830747 TI - Prohibitin is a cholesterol-sensitive regulator of cell cycle transit. AB - Cholesterol is essential in establishing most functional animal cell membranes; cells cannot grow or proliferate in the absence of sufficient cholesterol. Consequently, almost every cell, tissue, and animal tightly regulates cholesterol homeostasis, including complex mechanisms of synthesis, transport, uptake, and disposition of cholesterol molecules. We hypothesize that cellular recognition of cholesterol insufficiency causes cell cycle arrest in order to avoid a catastrophic failure in membrane synthesis. Here, we demonstrate using unbiased proteomics and standard biochemistry that cholesterol insufficiency causes upregulation of prohibitin, an inhibitor of cell cycle progression, through activation of a cholesterol-responsive promoter element. We also demonstrate that prohibitin protects cells from apoptosis caused by cholesterol insufficiency. This is the first study tying cholesterol homeostasis to a specific cell cycle regulator that inhibits apoptosis. PMID- 20830748 TI - Changes in cell adhesivity and cytoskeleton-related proteins during imatinib induced apoptosis of leukemic JURL-MK1 cells. AB - The fusion protein Bcr-Abl, which is the molecular cause of chronic myelogenous leukemia (CML) interacts in multiple points with signaling pathways regulating the cellular adhesivity and cytoskeleton architecture and dynamics. We explored the effects of imatinib mesylate, an inhibitor of Bcr-Abl protein used in front line CML therapy, on the adhesivity of JURL-MK1 cells to fibronectin and searched for underlying changes in the cell proteome. As imatinib induces apoptosis of JURL-MK1 cells, we used three different caspase inhibitors to discriminate between direct consequences of Bcr-Abl inhibition and secondary changes related to the apoptosis. Imatinib treatment caused a transient increase in JURL-MK1 cell adhesivity to fibronectin, possibly due to the switch off of Bcr-Abl activity. Subsequently, we observed a number of changes including a decrease in cell adhesivity, F-actin decomposition, reduction of integrin beta1, CD44, and paxillin expression levels and a marked increase in cofilin phophorylation at Ser3. These events were generally related to the proceeding apoptosis but they differed in their sensitivity to the individual caspase inhibitors. PMID- 20830749 TI - Flashing light signaling circuit in sponges: endogenous light generation after tissue ablation in Suberites domuncula. AB - The skeleton of siliceous sponges (phylum Porifera: classes Demospongiae and Hexactinellida), composed of tightly interacting spicules that assemble to a genetically fixed scaffold, is formed of bio-silica. This inorganic framework with the quality of quartz glass has been shown to operate as light waveguide in vitro and very likely has a similar function in vivo. Furthermore, the molecular toolkit for endogenous light generation (luciferase) and light/photon harvesting (cryptochrome) has been identified in the demosponge Suberites domuncula. These three components of a light signaling system, spicules-luciferase-cryptochrome, are concentrated in the surface layers (cortex) of the poriferan body. Specimens from which this cortex has been removed/ablated do not emit light. However, with regeneration and reconstitution of the cortex the animals re-gain the capacity to flash light. This newly discovered characteristic of sponges to generate light prompted us to investigate the genetic basis for the endogenous light signaling system. As a potential transcription factor involved in the expression of luciferase and cryptochrome, a SOX-related protein has been identified. In dark adapted animals or in tissue from below the cortex region, the medulla, no gene or protein expression of SOX-related protein, luciferase, and cryptochrome could be detected. However, during the regeneration of the cortex, a stage-specific expression pattern was recorded: SOX-related protein > luciferase > cryptochrome. We conclude that a flashing light signaling circuit exists, which might control the retinoic acid-induced differentiation of stem cells into pulsating and contracting sponge cells, that is, pinacocytes and myocytes. PMID- 20830750 TI - Determination of insoluble soap in agricultural soil and sewage sludge samples by liquid chromatography with ultraviolet detection. AB - We have developed a new analytical procedure for determining insoluble Ca and Mg fatty acid salts (soaps) in agricultural soil and sewage sludge samples. The number of analytical methodologies that focus in the determination of insoluble soap salts in different environmental compartments is very limited. In this work, we propose a methodology that involves a sample clean-up step with petroleum ether to remove soluble salts and a conversion of Ca and Mg insoluble salts into soluble potassium salts using tripotassium ethylenediaminetetraacetate salt and potassium carbonate, followed by the extraction of analytes from the samples using microwave-assisted extraction with methanol. An improved esterification procedure using 2,4-dibromoacetophenone before the liquid chromatography with ultraviolet detection analysis also has been developed. The absence of matrix effect was demonstrated with two fatty acid Ca salts that are not commercial and are never detected in natural samples (C13:0 and C17:0). Therefore, it was possible to evaluate the matrix effect because both standards have similar environmental behavior (adsorption and precipitation) to commercial soaps (C10:0) to C18:0). We also studied the effect of the different variables on the clean-up, the conversion of Ca soap, and the extraction and derivatization procedures. The quantification limits found ranged from 0.4 to 0.8 mg/kg. The proposed method was satisfactorily applied for the development of a study on soap behavior in agricultural soil and sewage sludge samples. PMID- 20830751 TI - Ketone and quinone-substituted polycyclic aromatic hydrocarbons in mussel tissue, sediment, urban dust, and diesel particulate matrices. AB - Polycyclic aromatic hydrocarbons (PAHs) substituted with a ketone or quinone functionality (OPAHs) may be important environmental contaminants. The OPAHs from environmental samples have demonstrated toxicity and may be more harmful than PAHs. Knowledge gaps concerning the occurrence of OPAHs in the total environment arise from analytical difficulties, as well as limited standards and methodologies. An optimized method was developed to quantify five ketone and four quinone OPAHs from matrices ranging from biological tissue to diesel particulates. Five National Institute of Standards and Technology Standard Reference Materials (SRMs) were analyzed. This is the first report of OPAH quantitation in SRM 2977 (mussel tissue), SRM 1944 (New York/New Jersey, USA waterway sediment), SRM 1975 (diesel extract), and SRM 1650b (diesel particulate matter) and among the few to report concentrations from SRM 1649 (urban dust). Furthermore, this is one of the first reports of OPAHs in biological tissue. Sigma9OPAHs were 374 +/- 59 mg/kg (mussel tissue), 5.4 +/- 0.5 mg/kg (sediment), 16.9 +/- 1.6 mg/kg (urban dust), 33.4 +/- 0.4 mg/kg (diesel extract), and 150 +/- 43 mg/kg (diesel particulate matter). In all SRMs, the levels of OPAHs were similar to or exceeded levels of PAHs. Of the OPAHs tested, the most frequently occurring in the environmental matrices were 9-fluorenone, 9,10-anthraquinone, benzofluorenone, and 7,12-benz[a]anthracenequinone. PMID- 20830753 TI - In reference to exostoses of the external auditory canal in white-water kayakers. PMID- 20830754 TI - Block method of human temporal bone removal: a technical modification to permit rapid removal. AB - OBJECTIVES/HYPOTHESIS: To describe a technical modification to the block method (BM) of harvesting human cadaveric temporal bones for otolaryngology resident education and training. STUDY DESIGN: Human cadaveric study. METHODS: Human cadavers previously dissected by medical students in a professional health science program were identified as potential candidate specimens for temporal bone removal. Cadaveric heads were prepared for temporal bone harvesting by excising the calvarium and brain via standard techniques. A reciprocating saw was used to make four bone cuts to harvest two temporal bone specimens. RESULTS: Temporal bone specimens could be harvested using only four bone cuts to release both temporal bones from one human cadaver as opposed to four bone cuts for a single temporal bone per the traditional BM. All temporal bones were inspected and found to have all the anatomical landmarks necessary for resident education and training intact. CONCLUSIONS: The modified BM for temporal bone removal is a rapid, efficient, and reproducible method of harvesting two complete and intact temporal bones per cadaver with fewer bone cuts as compared to the traditional BM. PMID- 20830755 TI - Transoral endonasal-controlled combined adenoidectomy (TECCA). PMID- 20830756 TI - Sealing of small postlaryngectomy pharyngocutaneous fistulas with voice prosthesis. AB - Pharyngocutaneous fistulas (PCFs) following total laryngectomy is a common complication. The standard therapy is conservative management, and if this is not successful, surgical closure. There is a group of patients with limited survival chance who have small PCFs. In these patients who are not candidates for surgery, sealing of the PCF with a voice prosthesis can significantly improve the functionality of these patients allowing them to swallow and phonate. PMID- 20830757 TI - Facial motor nuclei cell loss with intratemporal facial nerve crush injuries in rats. AB - OBJECTIVES/HYPOTHESIS: Injuries of cranial nerves that are distal to but near the motor nucleus might result in retrograde motoneuron cell death. The hypothesis of this article is that an intratemporal crush injury of the facial nerve in rats can cause facial motor nuclei cell death. STUDY DESIGN: Prospective, randomized, controlled animal study. METHODS: Sprague-Dawley rats were randomly divided into four groups: intratemporal sham, intratemporal crush injury, extratemporal crush injury, and extratemporal sham. The intratemporal (n = 9) and extratemporal crush injury (n = 4) groups underwent a 60-second crush of the nerve at the facial nerve tympanic segment or main facial nerve trunk distal to the stylomastoid foramen, respectively. The intratemporal sham group (n = 4) underwent identical exposure to the intratemporal crush without subsequent injury. Both sham groups and the extratemporal crush group were sacrificed at 4 weeks. The intratemporal crush group was subdivided into 4- (n = 4) and 8-week (n = 5) postinjury groups. Brain sections were stained with thionin and facial motor nuclei were counted under magnification. The contralateral uninjured facial motor nucleus was used to compare motor nucleus cell survival. RESULTS: Intratemporal crush injury resulted in increased cell loss at 4 (89.43% +/- 8.57% standard error of mean) and 8 weeks (85.78% +/- 3.15%) after injury compared to sham injury (119.09% +/- 13.35%) (P <.05). No significant change in cell survival was noted between the distal crush (103.29% +/- 6.34%) and sham group (111.71% +/- 3.24%) (P >.05). CONCLUSIONS: A rat intratemporal crush injury resulted in approximately 15% facial motor nuclei cell loss compared to an intratemporal sham injury. An extratemporal crush injury did not lead to any significant facial motor nuclei cell loss. This might have future translational implications in humans with intratemporal facial nerve injuries. PMID- 20830758 TI - Comparison of systemic and otic administration of ofloxacin. AB - OBJECTIVES: To assess the feasibility of delivering ofloxacin across the intact tympanic membrane; to compare middle ear bioavailability of ofloxacin after otic and systemic administrations; to determine distribution of otically delivered ofloxacin to other tissues. STUDY DESIGN: A prospective, controlled animal study. METHODS: Rats underwent surgery wherein the middle ear cavity was opened and filled with saline. An equivalent amount of ofloxacin was delivered intraperitoneally or into the external ear canal. Saline within the middle ear was sampled and completely replaced in 15-minute intervals for 3 hours. Blood was collected twice after the initial application of ofloxacin for high-performance liquid chromatography (HPLC). Animals were sacrificed 3 hours after the initial addition of ofloxacin; the temporal bones were harvested for histological analysis; urine and colon mucosa were collected for HPLC analysis. RESULTS: Both systemic and otic applications led to a comparable accumulation of ofloxacin in the middle ear over the 3-hour period after the initial administration. The pharmacokinetics of ofloxacin penetration into the middle ear was sporadic and subject-dependent. Both methods of administration led to drug accumulation in blood serum, urine, and colonic mucosa. CONCLUSIONS: Topical application of ofloxacin to the intact tympanic membrane allows for drug penetration into the middle ear space. Similar middle ear ofloxacin levels could be achieved with systemic and topic applications, but drug concentrations were inconsistent. The accumulation of ofloxacin in other tissues suggests applications designed to be ototopical may also result in systemic absorption. PMID- 20830759 TI - The effects of decorin and HGF-primed vocal fold fibroblasts in vitro and ex vivo in a porcine model of vocal fold scarring. AB - OBJECTIVES: Vocal fold injury can be irreversible, leading to vocal fold scarring, with permanent functional effects and no optimal treatment. A porcine model of vocal fold scarring was used to test effects of decorin and primed vocal fold fibroblasts in vitro using a cell migration assay and immunoblotting, and by using functional measurements of porcine larynges and excised porcine vocal folds. METHODS: In vitro: primary pig vocal fold fibroblasts (PVFFs) were subjected to cell migration assays (scratch) and treated with decorin 20 MUg/mL, hepatocyte growth factor (HGF) 200 ng/mL, epidermal growth factor (EGF) 1 nM, or transforming growth factor-beta1 10 ng/mL. Cells also underwent decorin dose response testing. Scratch assays were analyzed in MetaMorph(r) Imaging; cell lysates were processed for MMP-8 and type I collagen content. Eleven pigs underwent unilateral vocal fold stripping procedures. At day 3 postoperatively, subjects underwent superficial injection into the affected vocal fold either with decorin 20 MUg/mL or 1 * 10(6) HGF-primed fibroblasts. Larynges were harvested and either used for ex vivo laryngeal testing or for rheological testing. RESULTS: Scratch assay indicated significantly reduced cell migration in PVFFs treated with decorin or HGF. MMP-8 production was increased (P <0.01) and collagen was decreased in cells treated with decorin at increasing doses. Viscoelastic measurements suggested somewhat increased stiffness for decorin treated samples. Ex vivo aerodynamic testing suggested improved vocal efficiency scores in decorin-treated larynges. CONCLUSIONS: Decorin has a noticeable effect on PVFF migration in vitro and appears to increase vocal fold stiffness but either does not change or slightly increases vocal efficiency. PMID- 20830760 TI - Effects of smoking on taste: assessment with contact endoscopy and taste strips. AB - OBJECTIVES: This study aims to compare the taste function between smokers and nonsmokers with clinical testing, subjective ratings, and contact endoscopy of the tongue. STUDY DESIGN: Cross-sectional survey. METHODS: Data were collected from 38 smokers (mean age 37 years; 25 female, 23 male) and 34 nonsmokers (mean age 33.5 years; 18 female, 16 male). The parameters assessed were the number of fungiform papillae per square centimeter in a noncontact way and their morphology (surface, capillary vessels) by contact endoscopy. The morphology of the filiform papillae has also been assessed. In addition, clinical testing of gustatory function was performed by means of taste strips and subjective intensity ratings of natural taste stimuli. RESULTS: No significant difference was found in clinical testing and intensity ratings between the two study groups. A trend toward significance was found in taste strip results for decreased bitter taste in heavy smokers (P = .06). The number and the size of fungiform papillae did not significantly differ between the study groups. No sex-related differences were observed. Smokers exhibited significantly more keratin structures on the fungiform papillae surface, less tortuous capillary vessels, and a significant distortion of their filiform papillae. CONCLUSIONS: Taste function presents significant resistance to smoking, although changes in morphology of fungiform and filiform papillae have been observed especially in heavy smokers. Laryngoscope, 2010. PMID- 20830761 TI - Laser stimulation of single auditory nerve fibers. AB - OBJECTIVES/HYPOTHESIS: One limitation with cochlear implants is the difficulty stimulating spatially discrete spiral ganglion cell groups because of electrode interactions. Multipolar electrodes have improved on this some, but also at the cost of much higher device power consumption. Recently, it has been shown that spatially selective stimulation of the auditory nerve is possible with a mid infrared laser aimed at the spiral ganglion via the round window. However, these neurons must be driven at adequate rates for optical radiation to be useful in cochlear implants. We herein use single-fiber recordings to characterize the responses of auditory neurons to optical radiation. STUDY DESIGN: In vivo study using normal-hearing adult gerbils. METHODS: Two diode lasers were used for stimulation of the auditory nerve. They operated between 1.844 MUm and 1.873 MUm, with pulse durations of 35 MUs to 1,000 MUs, and at repetition rates up to 1,000 pulses per second (pps). The laser outputs were coupled to a 200-MUm-diameter optical fiber placed against the round window membrane and oriented toward the spiral ganglion. The auditory nerve was exposed through a craniotomy, and recordings were taken from single fibers during acoustic and laser stimulation. RESULTS: Action potentials occurred 2.5 ms to 4.0 ms after the laser pulse. The latency jitter was up to 3 ms. Maximum rates of discharge averaged 97 +/- 52.5 action potentials per second. The neurons did not strictly respond to the laser at stimulation rates over 100 pps. CONCLUSIONS: Auditory neurons can be stimulated by a laser beam passing through the round window membrane and driven at rates sufficient for useful auditory information. Optical stimulation and electrical stimulation have different characteristics; which could be selectively exploited in future cochlear implants. PMID- 20830762 TI - Self-reported impact of dysphonia in a primary care population: an epidemiological study. AB - OBJECTIVES/HYPOTHESIS: This study's objectives are to 1) to assess the prevalence of dysphonia in the primary care community, 2) evaluate the severity of dysphonia, 3) explore potential risk factors for dysphonia, 4) examine the treatment of dysphonic patients, and 5) assess treatment-related barriers. The hypotheses are that 1) dysphonia is common in the primary care community, 2) it adversely impacts patients' quality of life (QOL), and 3) patients are underevaluated and experience obstacles with respect to seeking treatment. STUDY DESIGN: Cross-sectional, practice-based study in the primary care population. METHODS: English-speaking patients 18 years of age and older were recruited from a primary care research network. Patients presenting to their primary care practices were given a packet of questionnaires to complete that documented demographic information, risk factors, presence of dysphonia, prior treatment, and reasons for not seeking treatment. The Voice-Related Quality of Life (VRQOL) and Center for Epidemiological Studies-Depression Scale (CES-D) served as quality of-life outcome measures. A priori sample size calculations were performed indicating a sample size of 780. Univariate analyses, descriptive statistics, odds ratios and 95% confidence intervals, and multivariate analyses were performed. RESULTS: A total of 789 patients with a mean age of 49.9 years and range of 18 to 94 years participated. Lifetime prevalence of dysphonia was 29.1%, point prevalence of dysphonia 7.5%, and 4.3% had had dysphonia for >4 weeks. Of those with current dysphonia, only 46% had not missed work. Of those with current dysphonia, 73.3% had had dysphonia more than once. Patients with dysphonia had lower VRQOL scores and higher CES-D scores (t test, P <=.001). Risk factors for dysphonia and impaired VRQOL on multivariate analysis included neurologic disease, dry mouth, family history of dysphonia, college or postgraduate level education, allergies or sinus problems, neck pain, medication for depression/anxiety, more than three upper respiratory infections per year, gastroesophageal reflux at least monthly, and asthma or lung disease. Of the patients who had ever had dysphonia, 22.1% received treatment. Common treatment modalities included antireflux treatment, antiallergy treatment, and antibiotics. Speech-language pathology evaluation was rare. Compared to those not interested in treatment, patients wanting treatment were more likely to have chronic dysphonia >4 weeks (30.6% vs. 8.1%; chi(2), P <=.001), more likely to have dysphonia more than once (85.1% vs. 58.0%; chi(2), P <=.001), and lower VRQOL scores (median 67.5 vs. 97.5; rank sum test, P <.001). Reasons for not seeking treatment included thinking the dysphonia would go away, physicians did not ask about voice problems, and being unaware of treatment options. CONCLUSIONS: At the time one in 13 primary care patients had dysphonia resulting in significant functional impairment with reduced voice-specific QOL and greater depression scores. Risk factors for dysphonia and voice-specific QOL impairment were identified and might be useful for identifying patients at risk for dysphonia. Barriers exist that prevent dysphonic patients from receiving evaluation and treatment. Whether improved methods of dysphonia screening leads to better outcomes and reduced societal impact needs investigation. Laryngoscope, 2010. PMID- 20830763 TI - Morphometric analysis of yak placentomes during gestation. AB - To study the morphological characteristics of placentomes during gestation, thirty-one yaks were used to determine anatomical and histological data of placentomes by morphometric method. The results showed that there were no significant changes in the total number of yak placentomes during gestation, but remarkably fewer placentomes in the non-pregnant horn compared with the pregnant horn. The mean size of placentomes increased significantly from <61 days to 181 210 days and decreased in 211+ days. The development of placentomes in the pregnant horn were obviously different from that of the non-pregnant horn except <61 days, which were longer, wider, and thicker. The volume density of fetal villi increased during gestation, with a concomitant reduction in the volume density of caruncular endometrium. However, there was no significant change in the surface density of fetal villi. The volume density of binucleate cell increased in prophase and then decreased. No apparent changes in the volume densities of maternal and fetal pyknotic cell occurred throughout gestation. There was a significant increase in the average total volume of yak placentomes from 61-90 days to 181-210 days and a significant decrease in 211+ days. The same patterns were showed in the average total volumes of caruncular endometrium and binucleate cell as well as the mean total surface area of fetal villi. However, the mean total volumes of fetal villi, maternal and fetal pyknotic cell increased constantly with increasing gestation time. Three types of placentome shape were identified in yak. The results showed that the maternal-fetal contact area of yak was enlarged by increasing the placentome size as well as the total volume and surface area of placentome component during pregnancy, so placental function could be enhanced further to meet the needs of fetal development. PMID- 20830764 TI - Serrated flippers and directional asymmetry in the appendicular skeleton of the Commerson's dolphin (Cephalorhynchus commersonii). AB - Presence of saw-toothed structures (serrations) on the leading edge of the flippers in the Commerson's dolphin and their relation with directional asymmetry in the appendicular skeleton were investigated in individuals from the Tierra del Fuego population, Argentina. Serrations were more frequent in the left flipper than in the right (P < 0.001) and in males than in females (P < 0.001). Serration length was significantly longer in the left flipper than in the right (P = 0.023), in males than in females (P = 0.004), and in older individuals than young (P < 0.001). The length of the radius (P = 0.028) and the length (P = 0.004), width (P < 0.001) and weight (P = 0.006) of the scapula showed significant directional asymmetry favoring the right side, whereas the length (P < 0.001) and width (P < 0.001) of the second digit favored the left side. The asymmetry appears to be innate in the species but is likely to be enhanced by differential mechanical stress between flippers as a result of lateralized behavior. We propose that the left flipper would be more flexible and preferably used in sensory or tactile activities that involve the serrations, whereas the right flipper would be more responsible for actions requiring a larger muscular exercise, possibly related to the maintenance of stability during swimming. PMID- 20830765 TI - 17beta-estradiol exposure accelerates skeletal development in Xenopus laevis tadpoles. AB - Although it is well established that estrogen regulates skeletal growth and ossification in mammals, the effects of estrogen on skeletal development in amphibians are relatively uncharacterized. This study was conducted to characterize the impact of 17beta-estradiol exposure on skeletal development in Xenopus laevis tadpoles. On day 48 postfertilization, tadpoles were placed in tanks containing 50% Holtfreter's Solution +/-17beta-estradiol at one of four concentrations (10(-11), 10(-10), 10(-9), and 10(-8) M). At 7-11 day intervals until day 91, 7-10 tadpoles per group were killed, fixed, measured, and staged. Specimens were then cleared and double-stained for cartilage and bone, and 34 skeletal elements were analyzed for ossification. Results from the study indicate that both low (10(-11) M) and high (10(-8) M) concentrations of 17beta-estradiol have a significant stimulatory effect on tadpole development. Both the larval stage and ossification index of tadpoles exposed to 10(-11) or 10(-8) M 17beta estradiol were significantly greater than those observed in control animals by day 91 postfertilization. These results are consistent with the hypothesis that endogenous and exogenous estrogen could play a role in the regulation of bone ossification in amphibians. PMID- 20830766 TI - Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol. AB - BACKGROUND: Unresectable colorectal liver metastases have a 1- and 2-year survival of 55% and 33% with current systemic therapies. The authors evaluated response and survival after transarterial chemoembolization. METHODS: Chemoembolization with cisplatin, doxorubicin, mitomycin C, ethiodized oil, and polyvinyl alcohol particles was performed at monthly intervals for 1 to 4 sessions. Cross-sectional imaging and clinical and laboratory evaluation were performed before treatment, 1 month after treatment, and then every 3 months. A second cycle was performed for intrahepatic recurrence. Toxicity was assessed using National Cancer Institute's Common Toxicity Criteria version 3.0. Response was evaluated using Response Evaluation Criteria in Solid Tumors criteria. Progression and survival were estimated with Kaplan-Meier analysis. RESULTS: A total of 245 treatments were performed over 141 cycles on 121 patients. Ninety five of 141 treatment cycles were evaluable for response: 2 (2%) partial response, 39 (41%) stable disease, and 54 (57%) progression. Median time to disease progression (TTP) in the treated liver was 5 months, and median TTP anywhere was 3 months. Median survival was 33 months from diagnosis of the primary colon cancer, 27 months from development of liver metastases, and 9 months from chemoembolization. Survival was significantly better when chemoembolization was performed after first- or second-line systemic therapy (11 12 months) than after third- to fifth-line therapies (6 months) (P = .03). Presence of extrahepatic metastases did not adversely affect survival (P = .48). CONCLUSIONS: Chemoembolization provided local disease control of hepatic metastases after 43% of treatment cycles. Median survival was 27 months overall, and 11 months when initiated for salvage after failure of second-line systemic therapy. PMID- 20830767 TI - Contemporary use of perioperative cisplatin-based chemotherapy in patients with muscle-invasive bladder cancer. AB - BACKGROUND: Level I evidence indicates that neoadjuvant cisplatin-based chemotherapy, in combination with radical cystectomy (RC), is associated with a significant survival advantage for patients with muscle-invasive bladder cancer. Despite this, neoadjuvant chemotherapy is not uniformly used. Our objective was to determine the patterns of utilization of neoadjuvant chemotherapy in patients undergoing RC for muscle invasive bladder cancer in a contemporary cohort in a tertiary care center. METHODS: A retrospective review was performed of patients with bladder cancer who underwent RC between 2003 and 2008 at our institution. Clinical stage, pathologic stage, renal function, and perioperative chemotherapy treatments were tabulated. Primary outcome measures were the type and use of neoadjuvant chemotherapy among eligible patients. Secondary measures were the utilization patterns of adjuvant chemotherapy, renal function, pathologic outcomes, and disease specific and overall survival. Reasons for nonutilization of chemotherapy were also examined. RESULTS: Among 238 patients who underwent RC for bladder cancer, 145 had a preoperative clinical stage >=T2. Only 17% (25 of 145) of these patients received cisplatin-based neoadjuvant chemotherapy. The renal function was adequate (CrCl > 60 ml/min) in 97 (67%) of these patients. Patients who received neoadjuvant chemotherapy had higher p0 rates (29% vs 8%) than patients who did not receive neoadjuvant therapy. Advanced patient age, comorbidities, concerns over toxicity of chemotherapy, and the modest nature of benefit from neoadjuvant chemotherapy may explain why this treatment is not often used. CONCLUSIONS: Despite level I evidence, neoadjuvant cisplatin-based chemotherapies continue to be underutilized in the management of bladder cancer, even at a high-volume tertiary center. A prospective evaluation of management choices, including the patient and physician factors involved in the use of perioperative cisplatin-based chemotherapy in bladder cancer, is indicated. PMID- 20830769 TI - Soft tissue sarcoma presenting with metastatic disease: outcome with primary surgical resection. AB - BACKGROUND: The objective of this study was to assess patient, tumor, and treatment factors that affected overall survival in a group of patients who underwent surgery for soft tissue sarcoma (STS) and presented with American Joint Commission on Cancer stage IV disease. METHODS: A retrospective review was undertaken of a single institution's database from the years 1986 to 2006 in all patients who met the following inclusion criteria: 1) surgical management of the primary tumor was undertaken, and 2) metastatic disease was present at the time of initial presentation. In total, 112 patients were identified who met the inclusion criteria. RESULTS: The 5-year survival rate for the entire group was 17%. In univariate analysis, the variables that were identified as statistically significant for predicting improved overall survival were resection of metastatic disease (P = .003), <4 pulmonary metastases (P = .05), and the presence of lymph node metastases versus pulmonary metastases (P = .0002). In multivariate analysis, only the presence of lymph node metastases versus pulmonary metastases retained statistical significance (P = .05). The 5-year survival rate for patients who had lymph nodes metastases at diagnosis was 59%, whereas it was only 8% for patients who presented with pulmonary metastases. CONCLUSIONS: Patients who presented with metastatic STS had a very poor prognosis despite aggressive surgical management of their primary tumor. The current results indicated that, although patients with isolated lymph node metastases may be cured by surgical resection, patients with pulmonary metastases are unlikely to be cured even with aggressive surgical management and should be treated with palliation of symptoms as the main objective. PMID- 20830768 TI - Phase 2 trial of concurrent 5-fluorouracil, hydroxyurea, cetuximab, and hyperfractionated intensity-modulated radiation therapy for locally advanced head and neck cancer. AB - BACKGROUND: The objective of this phase 2 study was to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated-boost (SIB), intensity-modulated radiation therapy (IMRT) into a well described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. METHOD: Patients with stage IVA and IVB or high-risk stage III squamous cell carcinomas of the head and neck were enrolled on a phase 2 trial. Prior organ-conserving surgery or induction chemotherapy was allowed off protocol. SIB-IMRT was prescribed to low risk volumes (43.2 gray [Gy] to 48 Gy) and intermediate-risk volumes (54-63 Gy). A separate IMRT cone-down plan was targeted to macroscopic disease (72 Gy). The median radiation dose was 72 Gy (range, 60-72 Gy) administered in 1.5 Gy fractions twice daily during Weeks 1, 3, 5, 7 and 9. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg twice daily), and cetuximab (250 mg/m2). RESULTS: From January 2007 through April 2008, 33 patients were enrolled. At a median follow-up of 24 months, the 2-year rates of locoregional control, distant control, disease-free survival, and overall survival were 83%, 79%, 69%, and 86%, respectively. Grade 3 toxicity consisted of mucositis in 33% of patients, radiation dermatitis in 15%of patients, anemia in 18% of patients, leukopenia in 18% of patients, neutropenia in 12% of patients, and thrombocytopenia in 3% of patients. Most patients (64%) were able to tolerate treatment without a feeding tube, and there were no acute or late grade >=4 adverse events. CONCLUSIONS: The current results indicated that concurrent 5-FU, HU, and cetuximab plus SIB-IMRT is a promising and reasonably well tolerated approach to incorporating molecularly targeted therapy into curative therapy for patients with locally advanced head and neck cancer. PMID- 20830770 TI - The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases. AB - BACKGROUND: Inhibitors of the mammalian target of rapamycin (mTOR) are emerging as promising therapies for metastatic renal cell carcinoma (RCC). Because rational treatment strategies require understanding the activation status of the underlying signaling pathway being targeted at the desired stage of disease, the authors examined the activation status of different components of the mTOR pathway in RCC metastases and matched primary tumors. METHODS: The authors immunostained metastatic RCC samples from 132 patients and a subset of 25 matched primary RCCs with antibodies against phosphatidylinositol 3'-kinase, PTEN, phospho-Akt, phospho-mTOR, and p70S6. PTEN genomic status was assessed by fluorescent in situ hybridization. Marker expression was correlated to clinicopathologic variables and to survival. RESULTS: The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion. Only cytoplasmic phospho-mTOR showed independent prognostic significance (P = .029) and fidelity between primary RCCs and their matched metastases (P = .004). CONCLUSIONS: Activation of various components of the mTOR signaling pathway in metastatic RCC lesions across various tumor histologies, nuclear grades, and metastatic sites suggests the potential for vertical blockade of multiple steps of this pathway. Patient selection may be improved by mTOR immunostaining of primary RCC. PMID- 20830772 TI - Isolated extracranial recurrence of anaplastic ependymoma. AB - Anaplastic ependymoma is a malignant glial tumor thought to arise from radial glial cells of the ventricular zone. Because ependymoma is frequently encountered within ventricular spaces, they are prone to leptomeningeal dissemination. Metastatic extracranial ependymoma has been reported, but in the context of progressive intracranial disease. We report on a boy who developed isolated extracranial recurrence of his anaplastic ependymoma, initially at the scalp and later metastases to cervical lymph nodes. The location of tumor recurrence proximate to the surgical site suggested surgical seeding. This case demonstrates an unusual site of recurrence of anaplastic ependymoma and highlights a previously underappreciated surgical complication. PMID- 20830771 TI - Genetic modifiers of HbF and response to hydroxyurea in sickle cell disease. AB - Fetal hemoglobin (HbF) levels are generally inversely proportional to severity of sickle cell disease (SCD) for given sickle phenotypes. Molecular regulation of HbF occurs through complex interactions cis and trans to the beta globin gene locus. Novel insights made through population-based genetic epidemiologic studies of non-anemic populations were replicated in SCD groups, despite large differences in HbF levels. Identification of the lymphoid transcription factor BCL11A as a key suppressor of HbF expression validates approaches using population genetics to study HbF expression. We review these methods and findings, and speculate on applying pharmaco-genetics to optimize hydroxyurea therapy aimed at increasing HbF. PMID- 20830773 TI - Effect of eradication of Helicobacter pylori in children with chronic immune thrombocytopenia: a prospective, controlled, multicenter study. AB - BACKGROUND: The eradication of Helicobacter pylori has been associated with remission of immune thrombocytopenia (ITP) in approximately half of eradicated patients. Data on children are limited to small case series. PROCEDURE: Children from 16 centers in Italy, who were less than 18 years of age and diagnosed with chronic ITP (cITP), were screened for H. pylori infection. Positive patients underwent standard triple therapy with amoxicillin, clarithromycin, and omeprazole. The eradication response was defined as follows: complete response, platelet (PLT) count >= 150 * 10(9) /L; partial response, PLT count of at least 50 * 10(9) /L; no response, PLT count <50 * 10(9) /L. RESULTS: Of 244 screened patients, 50 (20%) had H. pylori infection, 37 of which received eradication therapy and completed follow-up. Eradication was successful in 33/37 patients (89%). PLT recovery was demonstrated in 13/33 patients after eradication (39%), whereas spontaneous remission was observed in 17/166 (10%) H. pylori-negative patients (P < 0.005). Responders more often required second line eradication (9/13), whereas a second cycle was required in 3/20 non-responders (P < 0.005). CONCLUSIONS: Among the large cohort of patients, those who underwent successful H. pylori eradication showed a significantly higher PLT response. Therefore, it may be appropriate to look for H. pylori and eventually eradicate it in children with cITP. PMID- 20830774 TI - 42nd Congress of the International Society of Pediatric Oncology (SIOP) in Boston: a tribute to the two pioneers in pediatric oncology. PMID- 20830775 TI - Thyroid and hepatic function after high-dose 131 I-metaiodobenzylguanidine (131 I MIBG) therapy for neuroblastoma. AB - BACKGROUND: (131) I-Metaiodobenzylguanidine ((131) I-MIBG) provides targeted radiotherapy for children with neuroblastoma, a malignancy of the sympathetic nervous system. Dissociated radioactive iodide may concentrate in the thyroid, and (131) I-MIBG is concentrated in the liver after (131) I-MIBG therapy. The aim of our study was to analyze the effects of (131) I-MIBG therapy on thyroid and liver function. PROCEDURE: Pre- and post-therapy thyroid and liver functions were reviewed in a total of 194 neuroblastoma patients treated with (131) I-MIBG therapy. The cumulative incidence over time was estimated for both thyroid and liver toxicities. The relationship to cumulative dose/kg, number of treatments, time from treatment to follow-up, sex, and patient age was examined. RESULTS: In patients who presented with Grade 0 or 1 thyroid toxicity at baseline, 12 +/- 4% experienced onset of or worsening to Grade 2 hypothyroidism and one patient developed Grade 2 hyperthyroidism by 2 years after (131) I-MIBG therapy. At 2 years post-(131) I-MIBG therapy, 76 +/- 4% patients experienced onset or worsening of hepatic toxicity to any grade, and 23 +/- 5% experienced onset of or worsening to Grade 3 or 4 liver toxicity. Liver toxicity was usually transient asymptomatic transaminase elevation, frequently confounded by disease progression and other therapies. CONCLUSION: The prophylactic regimen of potassium iodide and potassium perchlorate with (131) I-MIBG therapy resulted in a low rate of significant hypothyroidism. Liver abnormalities following (131) I-MIBG therapy were primarily reversible and did not result in late toxicity. (131) I-MIBG therapy is a promising treatment for children with relapsed neuroblastoma with a relatively low rate of symptomatic thyroid or hepatic dysfunction. PMID- 20830776 TI - Childhood cancer trends in a western Canadian province: a population-based 22 year retrospective study. AB - OBJECTIVES: The objective of this study was to describe children and youth <20 years of age diagnosed with malignant cancer in Alberta, Canada over 22 years. We consider both temporal and geographical variations. PROCEDURE: The Alberta Cancer registry was used to extract information on cancer diagnoses during April 1, 1982, and March 31, 2004. Data extracted included gender, age at diagnosis, diagnosis, and geographic information. Population data were also obtained and analyses included descriptive summaries, rates, and cluster detection tests. RESULTS: During 22 fiscal years, 2,758 Alberta children and youth were diagnosed with malignant cancer. The average age of diagnosis was 9.6 years. The most common diagnoses were leukemia (24.8%), central nervous system (16.7%), lymphoma (15.8%), and other epithelial neoplasm and melanoma (11.2%). The number of malignant cases varied over year with crude rates of 13.4 per 100,000 in 1982/1983 to 17.3 per 100,000 in 2003/2004. Variation was also seen over diagnosis sub-group and geographic region. CONCLUSIONS: Although a relatively rare number of children and youth in Alberta were diagnosed with cancer during the study period, there were suggestions that an increase incidence in childhood cancer occurred in later years and some geographic areas have more cases than expected by chance. Further study is required to see if emerging trends continue and explain higher rate areas. PMID- 20830777 TI - Increasing prevalence of nasal and rectal colonization with methicillin-resistant Staphylococcus aureus in children with cancer. AB - BACKGROUND: Infections with methicillin-resistant Staphylococcus aureus (MRSA), in community-settings, especially with strains carrying the Panton-Valentine Leukocidin (PVL) genes, have increased markedly in recent years. Colonization with S. aureus is a risk factor for infection. However, there are few studies that examine colonization and infection with PVL-positive strains of MRSA in cancer patients. PROCEDURE: The epidemiology of colonization and infection with MRSA was studied in children with cancer during two time periods: 2000/2001 and 2006/2007. PVL genes were screened and spa typing performed on the isolates. RESULTS: The prevalence of colonization with MRSA increased from 0.6% in 2000/2001 to 2.9% in 2006/2007 (P = 0.0003). MRSA colonization at admission was associated with infection (P < 0.0001; RR 38.32; 95% CI: 23.36-62.84). The prevalence of infection increased from 0.99% in 2000/2001 to 3.78% in 2006-2007 (P = 0.0002). Of the 32 colonized patients, 18 (56%) had infection. None of the 14 colonized but non-infected patients had dual colonization of nares and rectum, while 8 of the 18 infected patients had colonization of both of these sites (P = 0.004). Ten patients (31%) were colonized with PVL-positive strains. Patients colonized with PVL-positive strains were more likely to be colonized both in the nares and rectum (P = 0.005), and more likely to have infection (P = 0.001). Recurrent MRSA infections were seen in 22% of patients. CONCLUSION: An increasing prevalence of colonization with MRSA was observed in children with cancer at our institution. Colonization with MRSA especially with PVL-positive strains was associated with infection. PMID- 20830778 TI - Height impairment after lower dose cranial irradiation in children with acute lymphoblastic leukemia. AB - PURPOSE: The purpose of this study is to determine whether height measurements are affected by cranial radiation doses of 12-18 Gy. PATIENTS AND METHODS: From 1997 to 2007, 23 children received cranial RT for T-cell or pre-B-cell acute lymphoblastic leukemia (ALL). Dose fractionation schemes included 18 Gy in 9 fractions (n = 8), 18 Gy in 10 fractions (n = 5), 12.6 Gy in 7 fractions (n = 6), and 12 Gy in 8 fractions (n = 4). These patients were matched and compared to a control group of 23 patients who had ALL but no cranial RT. Height z-scores at diagnosis and last follow-up were compared using the paired Student's t-test. Differences in z-scores according to host and treatment parameters were compared using the unpaired Student's t-test. Median follow-up for irradiated patients was 63.5 months while for unirradiated patients was 91 months. RESULTS: The mean z scores at initial diagnosis and last follow-up were 0.14 and -0.48 for patients receiving 12-12.6 Gy (P = 0.016), -0.16 and -0.89 for 18 Gy (P = 0.003), and 0.34 and 0.22 for no RT (P = 0.62). For children receiving RT, the mean difference in z-scores at initial diagnosis and last follow-up was -0.67 while for those not receiving RT, it was -0.10 (P = 0.043). CONCLUSION: Children receiving 12-18 Gy cranial RT for ALL were found to have height impairment compared to those not receiving RT. PMID- 20830779 TI - Long term G-CSF-induced remission of ulcerative colitis-like inflammatory bowel disease in a patient with glycogen storage disease Ib and evaluation of associated neutrophil function. AB - We present a 23-year-old female with Glycogen storage disease Ib (GSD Ib) who was diagnosed with ulcerative colitis-like inflammatory bowel disease (IBD) at 7 years of age. G-CSF therapy reversed the IBD, was required to maintain IBD remission and was well tolerated. Neutrophil functions at time of diagnosis showed impaired chemotaxis but normal superoxide anion production and bactericidal activity. Ulcerative colitis-like IBD may also be seen in GSD Ib and is responsive to G-CSF therapy. Neutrophil dysfunction is variable among patients with GSD Ib. PMID- 20830780 TI - Serum prohepcidin concentrations at birth and 1 month after birth in premature infants. AB - BACKGROUND: Premature newborns are vulnerable to iron imbalance, although the iron homeostasis during the perinatal period remains unclear. To clarify the iron metabolism of premature infants, we measured serum prohepcidin concentrations of preterm infants, and analyzed the association with iron parameters. METHODS: Seventy-one (61 preterm and 10 term) infants were enrolled for the study, that had no underlying diseases including asphyxia, bleedings, infection, and anomalies. Serum concentrations of prohepcidin at birth and 1 month after birth were determined by enzyme-linked immunosorbent assay. RESULTS: Prohepcidin levels at birth but not 1 month postnatal age positively correlated with gestational age (correlation coefficient [CC]:0.334, P = 0.005) and birth weight (CC: 0.367, P = 0.002). The levels at birth of preterm infants (median: 29.93 ng/ml, range: 4.0 110.6) were lower than those of full-term infants, and increased thereafter. On the other hand, the levels in small-for-gestational age infants were not associated with gestational age or birth weight. Prohepcidin levels at birth correlated positively with red cell counts (CC = 0.487, P = 0.025), unsaturated iron binding capacity (CC = 0.755, P = 0.001), total protein (CC = 0.624, P = 0.005), and serum albumin levels (CC = 0.500, P = 0.025), and negatively with serum iron levels (CC = -0.688, P = 0.003), but not ferritin levels. Multivariate analyses indicated that prohepcidin levels at birth were lower in infants with pregnancy-induced hypertension (P = 0.03) or premature rupture of membrane (P = 0.01). CONCLUSIONS: Prohepcidin production was physiologically low at birth of preterm infants according to the gestational age, and the levels might be susceptible to the in utero stress. The postnatal increase might reflect the maturation and/or adaptation of iron homeostasis. PMID- 20830781 TI - Prospective evaluation of legal difficulties and quality of life in adult survivors of childhood cancer. AB - BACKGROUND: Adult survivors of childhood cancer (ASCC), especially those of the central nervous system (CNS), have increased risks of educational and social difficulties. It is therefore hypothesized they are more likely to encounter legal difficulties (LDs), such as workplace discrimination and disability insurance denials, which may negatively affect their quality of life (QoL). PROCEDURE: We developed a survey to collect information on patients' legal needs. QoL was assessed using the Functional Assessment of Cancer Therapy (FACT). RESULTS: We prospectively approached 112 ASCC, 111 (99.1%) of whom completed the survey. The median age of respondents was 7 years at diagnosis and 31 years at survey completion. CNS tumors were the most common malignancy (32.4%). LDs were common overall (40.7%), though more prevalent in patients with CNS versus non-CNS tumors (58.6% vs. 32.3%; P = 0.023). The most prevalent LD was workplace discrimination (58.3%). On multivariate analysis, CNS tumor was the only variable significantly associated with LDs (OR = 4.49, P = 0.041). Individuals with LDs had lower QoL scores compared to those without LDs (79.96 versus 91.83 on the FACT; P = 0.005). On multivariate analysis, individuals with LDs had lower QoL scores (14.95 points lower on the FACT), which is both clinically and statistically significant (P = 0.047). CONCLUSIONS: Legal difficulties are common in adult survivors of childhood cancer, especially those with brain tumors. Furthermore, individuals with legal difficulties have worse quality of life. Research is needed to develop effective and accessible legal resource programs. PMID- 20830782 TI - Beta-barrel models of soluble amyloid beta oligomers and annular protofibrils. AB - Both soluble and membrane-bound prefibrillar assemblies of Abeta (Abeta) peptides have been associated with Alzheimer's disease (AD). The size and nature of these assemblies vary greatly and are affected by many factors. Here, we present models of soluble hexameric assemblies of Abeta42 and suggest how they can lead to larger assemblies and eventually to fibrils. The common element in most of these assemblies is a six-stranded beta-barrel formed by the last third of Abeta42, which is composed of hydrophobic residues and glycines. The hydrophobic core beta barrels of the hexameric models are shielded from water by the N-terminus and central segments. These more hydrophilic segments were modeled to have either predominantly beta or predominantly alpha secondary structure. Molecular dynamics simulations were performed to analyze stabilities of the models. The hexameric models were used as starting points from which larger soluble assemblies of 12 and 36 subunits were modeled. These models were developed to be consistent with numerous experimental results. PMID- 20830783 TI - COX-2-mediated regulation of VEGF-C in association with lymphangiogenesis and lymph node metastasis in lung cancer. AB - The mechanisms underlying the effects of COX-2 on tumor lymphangiogenesis remain largely undefined. Here, the human lung cancer cell lines A549, 95D, Anip973, and AGZY83-a with different metastatic capacities were investigated by immunostaining, western blotting, and real-time RT-PCR. We observed increased expressions of COX-2 and VEGF-C in the three highly metastatic cell lines compared with the less metastatic AGZY83-a cell line. The COX-2-specific inhibitor Celecoxib suppressed VEGF-C expression whereas the main COX-2 metabolite PGE(2) elevated VEGF-C expression in Anip973 and AGZY83-a cells in positive and negative experiments. To determine the functional link to COX-2 more specifically and elucidate the mechanistic pathway, we used a siRNA to knock down the high COX-2 expression in Anip973 cells and transfected a COX-2 cDNA to enhance the low COX-2 expression in AGZY83-a cells, and then treated the cells with EP1/EP4 agonists or antagonists, respectively. The results revealed that the EP1/EP4 agonists significantly increased VEGF-C production in the COX-2-knockdown Anip973 cells. In contrast, the EP1/EP4 antagonists diminished VEGF-C production in the COX-2-overexpressing AGZY83-a cells. Furthermore, animal models provided evidence that Celecoxib decreased VEGF-C expression, lymphangiogenesis, and lymph node metastases in Anip973 cells, whereas PGE(2) treatment increased the same factors in the parental AGZY83-a cells. A positive correlation between COX-2 and VEGF-C was also confirmed in vivo. The present data suggest that COX-2 regulates VEGF-C expression via the PGE(2) pathway, and that EP1/EP4 receptors are involved in PGE(2)-mediated VEGF-C production. Thus, COX-2 may represent a candidate gene for blocking tumor lymphangiogenesis and lymph node metastasis. PMID- 20830784 TI - Risk factors for infection during treatment with peginterferon alfa and ribavirin for chronic hepatitis C. AB - Neutropenia during treatment with peginterferon alfa and ribavirin for chronic hepatitis C virus (HCV) infection is a common cause of dose reductions of peginterferon alfa. These reductions are performed to prevent bacterial and fungal infections, which are common during HCV treatment and can be attributed to neutropenia. The aims of this study were to investigate the occurrence of infections and their relation to neutropenia and to identify potential risk factors for infections during HCV treatment. In this single-center cohort study, 2,876 visits of 321 patients treated with peginterferon alfa and ribavirin were evaluated for neutropenia, infections, dose reductions, and potential risk factors for infection during HCV treatment. The baseline mean absolute neutrophil count (ANC) was 3,420 cells/MUL, and 16 patients had a baseline ANC of <1,500 cells/MUL. During treatment, neutropenia, which was defined as ANC <750 cells/MUL, was observed in 95 patients (29.7%) and ANC <375/MUL was observed in 16 patients (5%). Ninety-six infections were observed in 70 patients (21.8%). Thirteen infections (13.5%) were defined as severe. Infections were not correlated with neutropenia during treatment. Dose reductions did not lead to a decrease in infection rate. Multivariate logistic regression analysis revealed that age >55 years (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.19-3.56, P = 0.01) and baseline hyperglycemia (OR 2.17, 95% CI 1.15-4.10, P = 0.016) were associated with an increased risk of infection during HCV treatment. Cirrhosis and chronic obstructive pulmonary disease were not risk factors for infection. CONCLUSION: Bacterial infections during treatment with peginterferon alfa and ribavirin are not associated with neutropenia. Older patients and patients with poorly controlled diabetes mellitus have a greater risk of developing infections during HCV treatment. PMID- 20830785 TI - Anatomical variation of the nasal septum: Correlation among septal components. AB - The nasal septum consists of multiple components with various developmental origins and is considered a mosaic structure. Few studies have focused on anatomical relationships among the components of the nasal septum, even though they are essential for clinical assessments of morphological abnormalities in the nasal septum. This study was performed to evaluate anatomical correlations among components of the nasal septum using computed tomography (CT) of the paranasal sinus. We studied images from CT scans of 168 paranasal sinuses collected at a secondary referral hospital between July 2008 and February 2009. The area of each component of the nasal septum was measured using median sagittal images of CT scans after three-dimensional reconstruction using computer software. The area of the cartilaginous septum decreased with age, whereas the area of the total nasal septum remained constant. The area of the perpendicular plate of ethmoid increased with age at the expense of the area of the septal cartilage. PMID- 20830786 TI - The incidence and structure of the fabella in a South African cadaver sample. AB - The fabella, a sesamoid bone located in the tendon of the lateral head of the gastrocnemius muscle, was dissected from 102 lower limbs of 51 cadavers of age range 40-95 years (mean, 75.5 +/- 14.5 years). The incidence of this sesamoid was determined as were its dimensions and radiological and histological features. The fabella was present in 23.5% of individuals, and it was bilaterally located in 50% of cases. It had an equal likelihood of occurring in males or females (P = 0.60), and in either right or left lower limb (P = 1.0). The consistency of the fabella was mostly bony (72.2%), a variety predominantly seen in male subjects. The mean diameters were 9.98 +/- 0.9 mm and 8.78 +/- 1.23 mm in males and females, respectively, with a statistically significant difference of P = 0.033. Histologically, bony fabellae had a core of spongy bone surrounded by compact bone, whereas nonbony fabellae were characterized by fibrocartilage. PMID- 20830787 TI - Prediction of sustained response to peginterferon alfa-2b for hepatitis B e antigen-positive chronic hepatitis B using on-treatment hepatitis B surface antigen decline. AB - Serum hepatitis B surface antigen (HBsAg) levels may reflect the immunomodulatory efficacy of pegylated interferon (PEG-IFN). We investigated within a large randomized trial whether quantitative HBsAg levels predict response to PEG-IFN in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Serum HBsAg was measured in samples taken at baseline and weeks 4, 8, 12, 24, 52, and 78 of 221 patients treated with PEG-IFN alfa-2b with or without lamivudine for 52 weeks. HBsAg decline was compared between treatment arms and between responders and nonresponders. Response was defined as HBeAg loss with HBV DNA < 10,000 copies/mL at 26 weeks after treatment (week 78); 43 of 221 (19%) patients achieved a response. One year of PEG-IFN with or without lamivudine resulted in a significant decline in serum HBsAg, which was sustained after treatment (decline 0.9 log IU/mL at week 78, P < 0.001). Patients treated with combination therapy experienced a more pronounced on-treatment decline, but relapsed subsequently. Responders experienced a significantly more pronounced decline in serum HBsAg compared to nonresponders (decline at week 52: 3.3 versus 0.7 log IU/mL, P < 0.001). Patients who achieved no decline at week 12 had a 97% probability of nonresponse through posttreatment follow-up and no chance of HBsAg loss. In a representative subset of 149 patients similar results were found for prediction through long-term (mean 3.0 years) follow-up. CONCLUSION: PEG-IFN induces a significant decline in serum HBsAg in HBeAg-positive patients. Patients who experience no decline from baseline at week 12 have little chance of achieving a sustained response and no chance of HBsAg loss and should be advised to discontinue therapy with PEG-IFN. PMID- 20830788 TI - Anomalous subaortic left brachiocephalic vein in surgical cases and literature review. AB - Anomalous subaortic left brachiocephalic vein (ASLBV) is a rare systemic venous anomaly. We review our experience with patients associated with ASLBV who underwent cardiac surgery at three institutions. From 1989 to 2009, the medical records of surgically treated patients with ASLBV were analyzed; the incidence of ASLBV, clinical characteristics, and associated anatomical findings were assessed. Fifteen patients had ASLBV. All ASLBVs coursed left lateral to the aortic arch, passed under the ascending aorta anterior to the central pulmonary artery, and joined the right brachiocephalic vein. Fourteen patients had congenital heart disease (CHD), and the remaining patient did not have cardiac anomalies. Its incidence was 0.57% (14 of 2,449) in patients with CHD and only 0.02% (1 of 4,805) in patients without CHD. In patients with CHD, 73.3% (11 of 15) of the patients had conotruncal cardiac anomalies such as tetralogy of Fallot, ventricular septal defect with pulmonary atresia, truncus arteriosus, and interruption of the aortic arch. Eight patients had aortic arch anomalies, including right aortic arch and cervical aortic arch. The deletion of chromosomal 22q11.2 was confirmed in two patients, and one patient was diagnosed with DiGeorge syndrome. ASLBV was clinically silent even without any surgical intervention. ASLBV is a very rare anomaly and is highly associated with conotruncal cardiac anomalies and aortic arch anomalies, including right aortic arch and cervical aortic arch. Preoperative diagnosis is important when any surgical interventions are intended, especially, in patients with conotruncal cardiac anomalies. PMID- 20830789 TI - P2Y13 receptor is critical for reverse cholesterol transport. AB - A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote "reverse cholesterol transport" (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y(13) (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y(13) as a target to promote RCT has not been documented. Here, we show that P2Y(13)-deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y(13)-deficient mice. Furthermore, cangrelor, a partial agonist of P2Y(13), stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BI-knockout(liver)) but had no effect in P2Y(13) knockout mice, which indicate that P2Y(13)-mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake. CONCLUSION: These results establish P2Y(13) as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT. PMID- 20830790 TI - Inconsistencies in surface anatomy: The need for an evidence-based reappraisal. AB - Accurate surface anatomy is a key component of safe clinical practice. But how consistent are modern clinical and surface anatomy texts in their reporting of common surface anatomy landmarks? Thirteen popular texts in common use were analyzed in detail: one clinical and anatomical reference text; seven clinical anatomy texts; two surface anatomy texts; and three clinical examination texts. Content relating to surface anatomy was reviewed, summarized, and assessed for consistency. Four main findings emerged: (i) there are numerous inconsistencies in clinically important surface markings (e.g., the femoral artery in the groin, superficial and deep inguinal rings, and accessory nerve in the posterior triangle), including inconsistencies within some texts; (ii) there is a consensus on many surface markings, e.g., the spleen and termination of the spinal cord; (iii) few texts address variation in surface anatomy related to age, sex, body mass, posture, respiration, and ethnicity; and (iv) the three standard clinical examination texts included in this review contain comparatively little surface anatomy. Seven surface anatomy landmarks were redefined within an evidence-based framework: termination of the spinal cord, supracristal plane, base of the appendix, renal length, the deep inguinal ring, the femoral artery in the groin, and the accessory nerve in the posterior triangle of the neck. An evidence-based framework is essential if surface anatomy is to be accurate and clinically relevant. PMID- 20830791 TI - Variations in the course and microanatomical study of the lateral femoral cutaneous nerve and its clinical importance. AB - The lateral femoral cutaneous nerve (LFCN), a branch from the lumbar plexus, may come to the clinician's or surgeon's attention. We studied this nerve to determine its location and its relationship with neighboring structures around the anterior superior iliac spine (ASIS) and the inguinal ligament (IL). Additionally, cross-sectional microanatomy of the LFCN at the IL was studied. The LFCN was dissected in 47 lower limbs from formalin-fixed cadavers. The distances from the ASIS to the point where the LFCN crossed the IL and the lateral border of the sartorius were measured. The distance between the ASIS and the point it pierced the deep fascia was also measured. Twelve nerve specimens at the IL were collected for histological sectioning and were stained with hematoxylin and eosin. On examination of the cross-sectional area, the nonfascicular area was wider than the fascicular area because of an increased amount of thick collagen fibers. This study may be of help to clinicians managing meralgia paresthetica and may also assist in defining a safe area for surgical intervention on the anterolateral aspect of the thigh. PMID- 20830792 TI - Intergender differences in histological architecture of the fascia pelvis parietalis: a cadaveric study. AB - The fascia pelvis parietalis (FPP) or endopelvic fascia is a well-known structure, but few studies described the detailed histological architecture, including the composite fiber directions. We hypothesized a gender-specific fiber architecture corresponding to the functional demand. For the first step to examine this hypothesis, we investigated specimens from 27 adult cadavers (10 males and 17 females) and 11 midterm fetuses (five males and six females) using immunohistochemistry and aldehyde-fuchsin staining. The adult female FPP was a solid, thick monolayered structure that was reinforced by abundant elastic fibers running across the striated muscle fibers, but it contained little or no smooth muscles (SM). In contrast, the male FPP was multilayered with abundant SM. In midterm fetuses, SM originated from the inferior part of the bladder and extended inferiorly along the gender-specific courses. Thus, we found a clear intergender difference in FPP architecture. However, the functional significance remained unknown because the basic architecture was common between nulliparous and multiparous women. Rather than for meeting the likely mechanical demands of pregnancy and vaginal delivery, the intergender difference of the FPP seemed to result from differences in the amount and migration course of bladder-derived SM as well as in hormonal background. PMID- 20830793 TI - Oral and dental abnormalities in Barber-Say syndrome. AB - A previously unreported case of Barber-Say syndrome is described with special attention to dental manifestations. A 7-year-old female with multiple congenital anomalies such mammary gland hypoplasia, hypertrichosis, ectropion, and redundant skin was seen at the School of Dentistry of the University of Sao Paulo. Oral examination revealed macrostomia, broad alveolar ridges, gingival fibromatosis, taurodontism, delayed tooth eruption, and malocclusion. Dental treatment included gingivoplasty and orthodontic treatment. PMID- 20830794 TI - Balanced transmission of a paternal complex chromosomal rearrangement involving chromosomes 2, 3, and 18. PMID- 20830795 TI - Pituitary stalk duplication in ventral-dorsal direction in a patient with pituitary gland adenoma and aqueductal stenosis. PMID- 20830796 TI - Supernumerary semitendinosus muscle: A rare case presentation and its clinical significance. PMID- 20830797 TI - Autistic and psychiatric findings associated with the 3q29 microdeletion syndrome: case report and review. AB - The screening of individuals with mild dysmorphic features and mental retardation using whole genome scanning technologies has resulted in the delineation of several previously unrecognized microdeletion syndromes. Microdeletion of 3q29 has been recently described as one such new syndrome. The clinical phenotype is variable despite an almost identical submicroscopic deletion size in most cases. We report on two individuals that further expand the clinical presentation of this rare disorder and compare the findings with earlier reports to refine the 3q29 microdeletion syndrome phenotype. The propositi are a 10-year-old female and a 15-year-old male, who have in common intellectual disabilities, a history of autism and psychiatric symptoms ranging from bipolar disorder presenting with increasing suicidal ideation to aggressive behavior and general anxiety. Other shared physical findings include asymmetric face, high-nasal bridge, crowded/dysplastic teeth, and tapered fingers. Oligonucleotide array-based chromosomal microarray analysis (CMA) using a genome-wide SNP array identified a de novo subtelomeric microdeletion of chromosome region 3q29 ranging from 1.6 to 2.1 Mb. The region of overlap encompasses 20 RefSeq genes, including FBX045, DLG1, and PAK2. These genes are related to neuronal postsynaptic membrane function and PTEN signaling, suggesting a role for synaptic connectivity dysfunction in the etiology of autism in these children. The novel clinical presentation of our patients expands the clinical spectrum of the 3q29 microdeletion syndrome and provides additional insights into the pathophysiology of autism and psychiatric disorders. PMID- 20830798 TI - Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome. AB - Epilepsy and Mental Retardation Limited to Females (EFMR) [OMIM 300088] was first described in 1971 [Juberg and Hellman, 1971] in 15 related females with early onset grand mal seizures and mental retardation. Although EFMR demonstrates X linked inheritance, it follows an unusual pattern by sparing transmitting males and affecting only heterozygous females. In 2008, mutations within the protocadherin 19 (PCDH19) gene were implicated as causative of EFMR [Dibbens et al. (2008); Nat Genet 40:776-781]. The EFMR phenotype is typically characterized by seizure onset in infancy and mild to severe intellectual impairment. Several individuals with EFMR have also been described as having autistic features. We describe three unrelated female individuals, ranging in age from 3 to 19 years, with de novo novel PCDH19 mutations. All three individuals have seizure onset in infancy and require the use of multiple antiepileptic drugs. They also have varying degrees of intellectual impairment along with the presence of autistic features. Although most individuals with EFMR described to date demonstrate this unusual familial X-linked inheritance, our three unrelated females with de novo mutations highlight the importance of testing PCDH19 in females with early onset epilepsy, intellectual impairment, and autistic features, regardless of family history. PMID- 20830799 TI - Epigenetic profiling of the H19 differentially methylated region and comprehensive whole genome array-based analysis in Silver-Russell syndrome. AB - Silver-Russell syndrome (SRS) is a clinically and genetically heterogeneous congenital disorder characterized by severe growth retardation. Hypomethylation of the differentially methylated region (DMR) of the H19 gene and uniparental disomy of maternal chromosome 7 is present in ~45% of the patients with SRS so more than half of these patients have no known genetic etiology. We combined several molecular technologies including multiplex methylation polymerase chain reaction, methylation-sensitive multiple ligation probe-dependent amplification, and methylation-sensitive high-resolution melting to assess the epigenetic status of 34 patients with SRS. Additionally, we applied a whole genome strategy to detect copy number changes and loss of heterozygosity. Thirteen patients (38.2%) had hypomethylation of the DMR of the H19 gene and none had uniparental disomy of maternal chromosome 7. The whole genome arrays identified five patients (14.7%) with microdeletions on chromosomes 1q23q24.3, 7p15.3, 13q31.3, 14q32.31, and 15q26.2qter, respectively. The overall mutation detection rate was 52.9% by the epigenetic study and the whole genome strategy. Although epimutation may be the major cause of SRS and can be identified by multiplex methylation polymerase chain reaction, the whole genome approach also provides information on the etiology of SRS. If no epimutation is identified in the patients with typical SRS, microdeletions should be suspected. PMID- 20830800 TI - Shells and heart: are human laterality and chirality of snails controlled by the same maternal genes? AB - The body of most animals display left-right asymmetry of internal organs. Alteration of such asymmetry results in severe congenital defects particularly affecting the cardiovascular system. The earliest known genes involved in asymmetry, the Nodal signalling cascade, are expressed asymmetrically during embryonic development. Nodal was discovered in the mouse, but orthologs (also involved in left-right specification) were reported in ascidians, sea-urchins, and snails. Mutations in Nodal-pathway genes cause alteration of several aspects of chirality, but not entirely mirror phenotypes of the body. Other factors upstream of nodal must be involved in the generation of left-right asymmetry. In snails, breeding experiments have demonstrated that chirality is controlled by a nuclear gene with maternal effect. Given the available evidence, we propose that an evolutionarily conserved genetic basis of chirality (the same that controls left-right asymmetry in snails) is a major synapomorphy of the Bilateria. This hypothesis fits with the observation that: (a) the proportion of patients with heterotaxy and a detected mutation in a gene of the Nodal cascade is actually low, and (b) horizontal recurrence of laterality defects is remarkably more frequent than vertical recurrence, and includes a notable number of affected sibs and/or repeated abortions from unaffected mothers. Identification of the maternal gene(s) involved will allow for the identification of homozygous females at risk of having affected children and spontaneous abortions, and would provide a general medical framework for understanding the genetics of most alterations of chirality. PMID- 20830801 TI - A de novo 22q11.22q11.23 interchromosomal tandem duplication in a boy with developmental delay, hyperactivity, and epilepsy. AB - The recent development of high-throughput analysis for genomic copy numbers has enabled to identify microscopic chromosomal duplications that had never been recognized before. Microarray-based comparative genomic hybridization (aCGH) identified a de novo 2.1-Mb microduplication in the 22q11.22q11.23 region surrounded by low copy repeats (LCRs) LCR22E and LCR22H in a 5-year-old boy with developmental delay, hyperactivity, epilepsy, and distinctive facial features, which were within the wide range of the clinical manifestations of the patients with the same duplication pattern. Fiber-fluorescent in situ hybridization (FISH) analysis confirmed that the duplicated segments were aligned in a tandem configuration. Familial single nucleotide polymorphism (SNP) typing determined that the duplication was derived from paternal interchromosomal non-allelic homologous recombination (NAHR) during the first meiotic process of spermatogenesis. Although no patient with the deletions of the distal 22q11.2 has been reported as showing epilepsy, at least five patients including the presenting patient having the duplication between LCR22E and LCR22G showed epilepsy. Thus, the gain of the genomic copy number of this region may have epileptogenesis. PMID- 20830802 TI - Congenital diaphragmatic hernia and a complex heart defect in association with Wolf-Hirschhorn syndrome. PMID- 20830803 TI - Maternal body mass index as a risk factor for craniosynostosis. PMID- 20830804 TI - Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. AB - We recently reported on the deficiency of carbohydrate sulfotransferase 3 (CHST3; chondroitin-6-sulfotransferase) in six subjects diagnosed with recessive Larsen syndrome or humero-spinal dysostosis [Hermanns et al. (2008); Am J Hum Genet 82:1368-1374]. Since then, we have identified 17 additional families with CHST3 mutations and we report here on a series of 24 patients in 23 families. The diagnostic hypothesis prior to molecular analysis had been: Larsen syndrome (15 families), humero-spinal dysostosis (four cases), chondrodysplasia with multiple dislocations (CDMD "Megarbane type"; two cases), Desbuquois syndrome (one case), and spondylo-epiphyseal dysplasia (one case). In spite of the different diagnostic labels, the clinical features in these patients were similar and included dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The most useful radiographic clues were the changes of the lumbar vertebrae. Twenty-four different CHST3 mutations were identified; 16 patients had homozygous mutations. We conclude that CHST3 deficiency presents at birth with congenital dislocations of knees, hips, and elbows, and is often diagnosed initially as Larsen syndrome, humero-spinal dysostosis, or chondrodysplasia with dislocations. The incidence of CHST3 deficiency seems to be higher than assumed so far. The clinical and radiographic pattern (joint dislocations, vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance) is characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations such as filamin B associated dominant Larsen syndrome and Desbuquois syndrome. PMID- 20830805 TI - Mild phenotype in a patient with mosaic del(8p)/inv dup del(8p). AB - We report on a female with a mild phenotype who is mosaic for two cell lines with different structural abnormalities of 8p, both resulting in large genomic imbalances. Molecular cytogenetic and G-banded chromosome analyses demonstrated that one cell line has a large terminal 8p deletion, with a breakpoint in 8p21.2. The other cell line contains a derivative chromosome 8, known as an inv dup del(8p) in the literature. This female has developmental delay, but lacks congenital anomalies that are associated with either 8p abnormality in non-mosaic form. The attenuated phenotype in this individual may be due to compensation of one cell line for imbalances in the other cell line. PMID- 20830806 TI - The release of cytokines by macrophages is not affected by myelin ingestion. AB - Macrophages play an important role in demyelination in multiple sclerosis (MS). Activated macrophages ingest myelin particles, thereby acquiring a foamy appearance. Foamy macrophages in MS lesions were described as being anti inflammatory. Therefore, these cells might play a role in modulating the inflammatory state of an active lesion. Here, we investigated the mechanism by which myelin uptake leads to skewing of macrophages toward an anti-inflammatory phenotype. Macrophages were incubated with myelin, leading to the development of foamy macrophages. Afterwards, the cells were stimulated with the TLR-4 ligand lipopolysaccharide (LPS), and cytokine production was determined. Interestingly, foamy macrophages appeared to have a reduced cytokine secretion and were LPS insensitive only when generated with one of the myelin preparations. The factor responsible for the different outcomes between different myelin batches turned out to be LPS. We demonstrated that LPS contamination induced insensitivity to LPS in foamy macrophages. On the contrary, foamy macrophages generated in the presence of LPS-free myelin were able to secrete cytokines upon activation. To conclude, myelin-laden macrophages were not LPS insensitive, indicating that they had not acquired an anti-inflammatory phenotype. PMID- 20830807 TI - A proteome map of axoglial specializations isolated and purified from human central nervous system. AB - Compact myelin, the paranode, and the juxtaparanode are discrete domains that are formed on myelinated axons. In humans, neurological disorders associated with loss of myelin, including Multiple Sclerosis, often also result in disassembly of the node of Ranvier. Despite the importance of these domains in the proper functioning of the CNS, their molecular composition and assembly mechanism remains largely unknown. We therefore performed a large-scale proteomics MudPIT screen for the identification of proteins in human myelin and axogliasomal fractions. We identified over 1,000 proteins in these fractions. Since even minor perturbations in neuron-glial interactions can uncouple the glial support of axons, the proteome map presented here can be used as a reference library for "myelin health" and disease states, including white matter disorders such as leukodystrophies and multiple sclerosis. PMID- 20830808 TI - Pathological adaptive responses of Schwann cells to endoplasmic reticulum stress in bortezomib-induced peripheral neuropathy. AB - Bortezomib, a proteasome inhibitor, has been considered as a promising anticancer drug in the treatment of recurrent multiple myeloma and some solid tumors. The bortezomib-induced peripheral neuropathy (BIPN) is a prominent cause of dose limiting toxicities after bortezomib treatment. In this study, we found that BIPN in a mouse model is characterized by acute but transient endoplasmic reticulum (ER) damages to Schwann cells. These damaged Schwann cells exhibit abnormal outcomes from healing processes such as the myelination of Remak bundles. A morphometric analysis of polymyelinated Remak bundles revealed that the pathological myelination was not related to the axonal parameters that regulate the normal myelination process during development. In addition, demyelinating macrophages were focally infiltrated within endoneurium of the sciatic nerve. To identify the mechanism underlying these pathologies, we applied a gene microarray analysis to bortezomib-treated primary Schwann cells and verified the changes of several gene expression in bortezomib-treated sciatic nerves. The analysis showed that bortezomib-induced ER stress was accompanied by the activation of several protective molecular chaperones and the down-regulation of myelin gene expression. ER stress inducers such as thapsigargin and bredelfin A also suppressed the mRNA expression of myelin gene P0 at transcriptional levels. In addition, the expression of chemokines such as the macrophage chemoattractants Ccl3 and Cxcl2 was significantly increased in Schwann cells in response to bortezomib and ER stress inducers. Taken together, these observations suggest that the pathological adaptive responses of Schwann cells to bortezomib-induced ER stress may, in part, participate in the development of BIPN. PMID- 20830809 TI - Collagen XXVIII is a distinctive component of the peripheral nervous system nodes of ranvier and surrounds nonmyelinating glial cells. AB - Growing evidence indicates that collagens perform crucial functions during the development and organization of the nervous system. Collagen XXVIII is a recently discovered collagen almost exclusively expressed in the peripheral nervous system (PNS). In this study, we show that this collagen is associated with nonmyelinated regions of the PNS. With the notable exception of type II terminal Schwann cell in the hairy skin, collagen XXVIII surrounds all nonmyelinating glial cells studied. This includes satellite glial cells of the dorsal root ganglia, terminal Schwann cells type I around mechanoceptors in the skin, terminal Schwann cells around proprioceptors in the muscle spindle or at the neuromuscular junction and olfactory ensheathing cells. Collagen XXVIII is also detected at nodes of Ranvier where the myelin sheath of myelinated fibers is interrupted and is thus a distinctive component of the PNS nodal gap. The correlation between the absence of myelin and the presence of collagen XXVIII is confirmed in a mouse model of Charcot-Marie-Tooth characterized by dysmyelinated nerve fibers, in which enhancement of collagen XXVIII labeling is observed. PMID- 20830811 TI - Comparative assessment of empirical and physiological approaches on predicting human clearances. AB - The empirical and physiological predictive approaches to human clearance were evaluated using preclinical in vitro and in vivo data of various datasets to establish a methodology for the prediction of clearance. Among the examined empirical approaches, an allometric scaling method with the rule of exponent (ROE), based on the exponent in simple allometry, provided better prediction. The effect of lipophilicity (clog P) and clearance on the predictivity was investigated using the ROE method. High predictivity was found for a low lipophilic compound with clog P < 0 and for a compound with moderate or high clearance. As a physiological approach, the in vitro-in vivo scaling method using metabolic stability in liver microsomes and hepatocytes was evaluated, and the predictivity taking the plasma protein binding and the nonspecific binding in incubation into consideration was compared with the ROE method. The two methods appeared to show comparable predictivity, although the in vitro-in vivo scaling was conducted under limited conditions like the use of physiological scaling factor and lipophilicity-derived nonspecific binding data. The ROE method could be an alternative predictor of the human clearance of compounds to which a physiological approach cannot be applied, in addition to low lipophilic compounds, with acceptable accuracy. PMID- 20830810 TI - Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. AB - Neuronal activity leads to arteriole dilation and increased blood flow in retinal vessels. This response, termed functional hyperemia, is diminished in the retinas of diabetic patients, possibly contributing to the development of diabetic retinopathy. The mechanism responsible for this loss is unknown. Here we show that light-evoked arteriole dilation was reduced by 58% in a streptozotocin induced rat model of type 1 diabetes. Functional hyperemia is believed to be mediated by glial cells and we found that glial-evoked vasodilation was reduced by 60% in diabetic animals. The diabetic retinas showed neither a decrease in the thickness of the retinal layers nor an increase in neuronal loss, although signs of early glial reactivity and an upregulation of inducible nitric oxide synthase (iNOS) were detected. Inhibition of iNOS restored both light- and glial-evoked dilations to control levels. These findings suggest that high NO levels resulting from iNOS upregulation alters glial control of vessel diameter and may underlie the loss of functional hyperemia observed in diabetic retinopathy. Restoring functional hyperemia by iNOS inhibition may limit the progression of retinopathy in diabetic patients. PMID- 20830812 TI - Gold nanoparticles and quantum dots for bioimaging. AB - Nanoparticles are the latest tool acquired by the science of bioimaging, serving primarily as new contrast agents, sensors, or signal enhancing agents in established and developing imaging techniques. This review focuses on the unique properties of two classes of nanoparticles: gold nanoparticles (GNP) and quantum dots, and how these properties are benefiting cellular and in vivo imaging. We discuss the surface plasmon resonance of GNP and its implications for various imaging techniques of biological relevance. Furthermore, the key properties of quantum dots are reviewed, and their use alone or in combination with traditional fluorescent dyes for biological imaging are described. The underlying principles of these techniques are provided, along with some representative examples. PMID- 20830813 TI - Immunology and liver diseases. Proceedings of the Falk Workshop 2009. Liver and metabolic syndrome. Proceedings of the Falk Symposium 171. October 15-18, 2009. Hannover, Germany. Workshop dedicated to the 80th birthday of Karl-Hermann Meyer zum Bueschenfelde. PMID- 20830814 TI - Thailand Cadmium 2010. Proceedings of an International Conference on Cadmium in Food and Human Health. January 15-17, 2010. Phitsanulok, Thailand. PMID- 20830816 TI - Proceedings of the Third Annual Statistical Assessment of the Modeling of Proteins and Ligands (SAMPL) Challenge and Workshop. June 2009. Montreal, Canada. PMID- 20830815 TI - Seamless care-safe care. The challenges of interoperability and patient safety in health care. Proceedings of the Tenth European Federation Medical Informatics Special Topic Conference. June 2-4, 2010. Reykjavik, Iceland. PMID- 20830817 TI - Proceedings of the 7th International Symposium on Polyelectrolytes. 2008. Coimbra, Portugal. PMID- 20830818 TI - Festschrift to honor Eli Glatstein on his 70th birthday. PMID- 20830819 TI - Deep-brain stimulation for Parkinson's disease. PMID- 20830820 TI - Oral phosphate binders in patients with kidney failure. PMID- 20830821 TI - Specialist practices as medical homes. PMID- 20830822 TI - Specialist practices as medical homes. PMID- 20830823 TI - Images in clinical medicine. Subclavian steal syndrome. PMID- 20830824 TI - Retraction. HIV-specific cytotoxic T lymphocytes traffic to lymph nodes and localize at sites of HIV replication and cell death. PMID- 20830825 TI - Vision screening to detect refractive error. PMID- 20830826 TI - Images in clinical medicine. Serpentine supravenous hyperpigmentation. PMID- 20830827 TI - The renaissance in HIV vaccine development--future directions. PMID- 20830828 TI - Duration of clopidogrel therapy with drug-eluting stents. PMID- 20830829 TI - Duration of clopidogrel therapy with drug-eluting stents. PMID- 20830830 TI - Duration of clopidogrel therapy with drug-eluting stents. PMID- 20830831 TI - Physician cost profiling. PMID- 20830832 TI - Physician cost profiling. PMID- 20830833 TI - Physician cost profiling. PMID- 20830834 TI - Outpatient management of severe COPD. PMID- 20830835 TI - What's keeping us so busy in primary care? PMID- 20830836 TI - Abstracts of the 23rd Annual European Society of Intensive Care Medicine (ESICM) Congress. Barcelona, Spain. October 9-13, 2010. PMID- 20830837 TI - Current awareness in contrast media and molecular imaging. PMID- 20830838 TI - Numbers do count. PMID- 20830839 TI - Misery in Canada ignored. PMID- 20830840 TI - For the patient. Diabetes is the tip of the iceberg. PMID- 20830841 TI - For the patient. Atherosclerosis among the Mongolian population. PMID- 20830842 TI - Special focus issue to honor Professor Neil Kelleher, recipient of the 2009 Biemann Medal. PMID- 20830843 TI - Abstracts of the 65th Annual Owen H. Wangensteen Surgical Forum of the 2010 Clinical Congress of the American College of Surgeons. October 3-7, 2010. Washington, DC, USA. PMID- 20830844 TI - Exposed crystal face controlled synthesis of 3D ZnO superstructures. AB - We report a method for synthesizing exposed crystal face controlled 3D ZnO superstructures under mild conditions (at room temperature or 90 degrees C under 1 atm) without organic additives. The exposed crystal faces of the building blocks of the 3D structures were controlled by varying the reactant concentrations and the reaction temperatures. On the basis of the experimental results, we speculated a possible mechanism for the formation of the four distinct 3D ZnO superstructures (structures I, II, III, and IV) under the different growth conditions. The optical properties of the 3D ZnO superstructures were probed by UV-vis diffuse reflectance spectroscopy. The spectra were shifted depending on the dimensions and sizes of the building blocks of the 3D superstructures. The photocatalytic activities of the 3D superstructures varied according to the exposed crystal faces, which could be controlled by this method (structure I > structure IV > structure III > structure II). PMID- 20830845 TI - Noninvasive cerebral oximetry: is there light at the end of the tunnel? AB - PURPOSE OF REVIEW: There is increasing interest in the application of near infrared spectroscopy (NIRS) as a noninvasive monitor of cerebral oxygenation. This review will briefly describe the principles of NIRS and examine current evidence for its clinical application as a monitor of the adequacy of cerebral oxygenation in adults. RECENT FINDINGS: There has been a recent surge of interest in the clinical application of NIRS following studies that have quantified the benefits of NIRS-guided management of cerebral oxygenation during cardiopulmonary bypass. However, there are limited data to support its widespread application in other clinical scenarios. New NIRS systems are being introduced to the market and technological advancements have improved their accuracy and extended the range of variables measured. SUMMARY: NIRS offers noninvasive monitoring of cerebral oxygenation over multiple regions of interest in a wide range of clinical scenarios. It has many potential advantages over other neuromonitoring techniques, but further technological advances are necessary before it can be introduced more widely into clinical practice. PMID- 20830846 TI - Light sedation protects memory. PMID- 20830847 TI - Evaluating the aging driver. PMID- 20830848 TI - Brighter future for AMD treatment. PMID- 20830849 TI - Are overweight older adults healthier? PMID- 20830850 TI - I've had a couple of drinks every night since I was 30. Now at 70, the same amount of alcohol makes me feel tipsy. What is going on? PMID- 20830851 TI - Global leprosy situation, 2010. PMID- 20830852 TI - Water and sanitation in health emergencies: the role of WHO in the response to the earthquake in Haiti, 12 January 2010. PMID- 20830853 TI - Monthly report on dracunculiasis cases, January-July 2010. PMID- 20830854 TI - Evaluation of elimination of neonatal tetanus in Madagascar, 2009. PMID- 20830855 TI - Performance of acute flaccid paralysis (AFP) surveillance and incidence of poliomyelitis,2010. PMID- 20830858 TI - Future of medicine in the United States is uncertain. PMID- 20830856 TI - [The skills of the specialist in rheumatology: a document of the European Board of Rheumatology]. PMID- 20830857 TI - Does access to compensation have an impact on recovery outcomes after injury? Comment. PMID- 20830859 TI - [Combining psychosomatic medicine and psychotherapy research]. PMID- 20830862 TI - Backyard desperadoes: American attitudes concerning toy guns in the early Cold War era. PMID- 20830861 TI - The candy prophylactic: danger, disease, and children's candy around 1916. PMID- 20830863 TI - A scarlet pansy goes to war: subversion, Schlock, and an early gay classic. PMID- 20830864 TI - An enemy deep: spectacular addiction in Hubert Selby's "Requiem for a Dream". PMID- 20830865 TI - Discipline and punish? Youth gangs' response to "zero-tolerance" policies in Honduras. AB - The response of youth gangs to "zero tolerance" policing in Honduras are examined with respect to territoriality. Focusing on two main gangs, the Mara Salvatrucha and the 18th Street Gang, the ways in which state authority is challenged are assessed from an analysis of body territoriality, the respatialisation of organisational structures across urban neighbourhoods, and the production of new enclosed spaces of gang territoriality. These redefinitions of group territoriality strengthen the emotional bonds and sense of belonging towards the gang, enabling the emergence of a transnational/imagined community. PMID- 20830866 TI - Barriers prevent patients from seeking treatment. PMID- 20830867 TI - The Africanization of poverty: a retrospective on "Make Poverty History". AB - This article explores the ways in which the British campaign coalition Make Poverty History represented Africa throughout 2005. Focusing particularly on the G8 Gleneagles summit, Make Poverty History (MPH) asserted a series of justice claims which had no geographical reference. Nevertheless, as a result of internal tensions within the coalition, and especially as a result of the ways in which MPH interacted with other political agencies as the summit approached, MPH's messages became increasingly interpolated by references to Africa as a result of the emergence of government, media, and celebrity involvement. The result of this was that global poverty increasingly became an African issue. As 2005 became the "Year of Africa," the justice messages that constituted MPH were largely effaced by the more familiar imperial legacy which represents Africa as a place of indigence in need of outside assistance. PMID- 20830868 TI - All-payer claims databases: state initiatives to improve health care transparency. AB - States are facing increasing health care challenges, from variable quality of care to ever-increasing costs. Comprehensive information on disease incidence, treatment costs, and health outcomes is essential for informing and evaluating state health policies, but it is not readily available. To address these information needs, some states are developing all-payer claims databases (APCDs), and these systems are proving to be valuable information sources. As more states implement APCDs, efforts will be made to standardize common data elements that will improve the comparability of data from state to state. The National Association of Health Data Organizations (NAHDO) and the Regional All Payer Healthcare Information Council (RAPHIC) are coordinating a multistate effort to support state APCD initiatives and shape state reporting systems to be capable of supporting a broad range of information needs. This brief is based on this ongoing work with states and reflects current knowledge about states' APCD initiatives. PMID- 20830869 TI - [Transposition of the great arteries with interventricular communication and pulmonary stenosis: what is the best surgical option?]. PMID- 20830870 TI - Perioperative inflammatory response in total knee arthroplasty patients: impact of limb preconditioning. AB - BACKGROUND AND OBJECTIVES: Ischemic preconditioning of tissue that is to undergo procedure-induced underperfusion has been used in a number of surgical settings to reduce the subsequent inflammatory response and its sequelae. The objective of this prospective, randomized study was to evaluate the effect of ischemic preconditioning on the systemic inflammatory response, degree of lung catabolism, and postoperative-pain associated with total knee arthroplasty (TKA). MATERIALS: Thirty-four patients undergoing unilateral TKA under tourniquet ischemia were enrolled with half (n = 17) being randomized to an episode of limb preconditioning before induction of ischemia for surgery. Markers of inflammation (interleukin 6 [IL-6], C-reactive protein,tumor necrosis factor >, and leukocyte count) and elastin catabolism(desmosine) were measured at baseline and various points postoperatively.Pain scores and length of stay were recorded. RESULTS: A significant increase in the levels of IL-6, C-reactive protein,tumor necrosis factor >, and white blood cell count was observed after surgery in both groups. Despite trends toward decrease in the IL-6 level in the preconditioning group, no significant difference between groups was observed for all markers at any given time point. Urine desmosine-creatinine-ratios did not differ between groups, and no significant-changes from baseline were seen postoperatively. However, median pain scores and length of hospital stay were lower in the treatment group. CONCLUSIONS: Preconditioning of the lower extremity in the setting of TKA under regional anesthesia may have limited value in reducing the systemic inflammatory response and level of lung injury. However, preconditioning may be associated with beneficial effects such as reduction in postoperative pain levels, and thus, further investigations are warranted. PMID- 20830871 TI - Ultrasound-guided continuous oblique subcostal transversus abdominis plane blockade: description of anatomy and clinical technique. AB - BACKGROUND: Recently, ultrasound-guided transversus abdominis plane blockade for abdominal wall analgesia has been described, and it involves injection of local anesthetic into the transversus abdominis plane. The posterior approach involves injection of local anesthetic in the lateral abdominal wall between the costal margin and the iliac crest and is suitable for postoperative analgesia after surgery below the umbilicus. The subcostal approach is suitable after abdominal surgery in the periumbilical region. The subcostal block can be modified, and the needle can be introduced along the oblique subcostal line from the xyphoid process toward the anterior part of the iliac crest. OBJECTIVE: The purpose of this brief technical report was to describe in detail the anatomy and the technique of continuous oblique subcostal blockade. The goal of this approach was to produce a wider sensory blockade suitable for analgesia after surgery both superior and inferior to the umbilicus. CONCLUSIONS: A catheter can be placed along the oblique subcostal line in the transversus abdominis plane for continuous infusion of local anesthetic. Multimodal analgesia and intravenous opioid are used in addition because visceral pain is not blocked. Continuous oblique subcostal transversus abdominis plane block is a new technique and requires both a detailed knowledge of sonographic anatomy and technical skill for it to be successful. PMID- 20830872 TI - Ultrasound-guided continuous phrenic nerve block for persistent hiccups. AB - BACKGROUND: Phrenic nerve block can be performed and repeated if necessary for persistent hiccups, when conservative and pharmacological treatment is unsuccessful. We report the first description of an in-plane ultrasound (US) guided phrenic nerve block (PhNB) with a catheter, after US investigation of the bilateral diaphragm, to treat hiccups while avoiding repeated PhNBs. CASE: A 36 year-old man had persistent postoperative hiccups not responding to conservative and pharmacological treatment. Bilateral diaphragmatic US evaluation showed abnormal right-sided movement. A right-sided in-plane US-guided PhNB with catheter was performed. Injection of local anesthetic stopped the hiccups, and a continuous infusion of local anesthetic was started for 24 hrs. After discontinuation of the infusion, the hiccups recurred. Restart of the continuous infusion of the local anesthetic through the catheter was performed, and after discontinuation 24 hrs later, no further hiccups occurred. No adverse effect occurred. CONCLUSIONS: An US-guided in-plane PhNB with catheter is feasible and avoids repeated PhNB when hiccups reoccur. Ultrasound investigation of the bilateral diaphragm should be performed before performing the nerve block. PMID- 20830873 TI - [Importance of pain management to anesthesiologists]. PMID- 20830874 TI - The uncommon thread. PMID- 20830875 TI - Across-the-board salary increases--a reward for mediocrity. PMID- 20830876 TI - The Berlin declaration on oral health and oral health services. PMID- 20830877 TI - Multidisciplinary and esthetic approach to clinical crown lengthening: report of a case. AB - This paper describes the combined efforts of an orthodontist, periodontist, and a restorative dentist to save an unrestorable tooth by clinical crown lengthening. A maxillary lateral incisor, originally treatment planned for extraction, was treated with orthodontic extrusion, circumferential fiberotomy, and metal-ceramic crown restoration. To maximize the esthetic appearance of the tooth during orthodontic treatment, an acrylic resin facing was designed together with the orthodontic appliance used to facilitate vertical extrusion. Clinical crown lengthening may be used as an alternative approach to the treatment of severely broken down anterior teeth. PMID- 20830878 TI - Enamel stripping and the spring aligner appliance--an update. AB - Irregularity of the mandibular incisors in an otherwise good occlusion is quite common in young adult patients. Through use of enamel stripping in the incisor region, it is possible to create sufficient space to align the teeth with a mandibular sectional removable appliance, commonly known as the spring aligner. This article reviews the methods of enamel stripping and describes the author's preferred technique of enamel stripping and the various modifications of the spring aligner appliances that can be prescribed by the general practitioner to correct mandibular anterior crowding. PMID- 20830879 TI - Complete root coverage of denuded root surface using expanded polytetrafluoroethylene membrane in conjunction with tetracycline root conditioning and fibrin-fibronectin glue application: case reports. AB - A new surgical technique can promote complete root coverage in deep and wide recessions. A root isolation procedure with expanded polytetrafluoroethylene membrane is combined with tetracycline treatment of the root surface and fibrin fibronectin glue application. Treatment of two patients resulted in the disappearance of the anatomic defect and an increase in the amount of keratinized gingiva. PMID- 20830880 TI - Root treatment in vivo with a new rotary periodontal instrument: a profilometer study. AB - The purpose of this study was to compare, in vivo, in 30 teeth destined for extraction, the abilities of the Scalex rotary bur system and Gracey curettes to obtain a smooth root surface. The time taken for each treatment was also evaluated. The profilometry results showed no significant differences between instruments with regard to roughness or working time, in single-rooted teeth, multirooted teeth, or in pockets of 5 mm or more. Only for distal longitudinal roughness and in pockets less than 5 mm did the Scalex system perform slightly better. There was some improvement in working time when the distal surfaces were instrumented with Scalex. Both systems demonstrated a similar capacity to render smooth surfaces. PMID- 20830881 TI - Adaptability and microleakage of indirect resin inlays: an in vivo investigation. AB - The purpose of this in vivo study was to evaluate the microleakage of indirect composite resin inlays and to determine the thickness of composite resin luting material. Twenty periodontally involved posterior teeth scheduled for extraction were selected and Class II cavities were prepared. Ten cavities had gingival margins placed in enamel above the cementoenamel junction, and the other 10 were placed in dentin below the cementoenamel junction. Six months after cementation, the teeth were extracted and analyzed. The leakage was higher in inlays with gingival margins in dentin than in inlays with gingival margins in enamel. The cement thickness was between 15 and 40 microm, a clinically acceptable range. PMID- 20830882 TI - Resin restorations: causes of porosities. AB - Porosities in composite resin can be incorporated at many stages of packaging and placement. Porosities can be minimized through vacuum loading of syringes and use of light-curing materials that require minimal handling. Even so, the method of placement of the material can lead to inclusion of submicron bubbles in the resin or formation of structures and pockets that can trap air at the surface. The consequences of material viscosity, method of placement, and cavity design are examined in relation to porosity incorporation. PMID- 20830883 TI - The effect of cuspal coverage on the fracture resistance of teeth restored with indirect composite resin restorations. AB - The effect of cuspal coverage on the in vitro fracture resistance of teeth restored with indirect composite resin inlays was examined. After standardized preparation differing only in cavity width, two groups of teeth were restored with indirect composite resin restorations. Two further groups of teeth were prepared in a similar manner, except that the buccal and palatal cusps were reduced by 2 mm, and cuspal-coverage indirect composite resin restorations placed. In another group, indirect composite resin restorations with only palatal cuspal coverage were placed. One group of intact teeth acted as a control. Forces were applied to the restored teeth by means of a 4-mm steel bar in a Universal testing machine. For each of the preparation designs assessed, the fracture load for onlays was greater than that for equivalent inlays; the onlay fracture strength was equivalent, for some preparation designs, to that of sound teeth. PMID- 20830884 TI - Dispensing, mixing, and delivering alginates: an alternative technique. AB - Although careful mixing of alginate material will reduce the number of airborne particles, some will always be observed directly above the site of spatulation. An alternative method of dispensing, mixing, and delivering alginate impression material is introduced. This technique not only protects dental personnel but also results in a creamier mix and a superior impression. PMID- 20830885 TI - Wear of enamel cusps opposed by posterior composite resin. AB - The use of posterior composite resins has grown considerably over the past 5 years. While most research efforts have been devoted to improving wear resistance, little effort had been made to determine possible wear of the cusp of the opposing tooth. A recently developed in vitro wear system was used to evaluate a series of composite resins for their ability to abrade opposing enamel cusps. When the resins were tested under the same conditions, a considerable range in enamel wear was observed. Representing opposite ends of the scale, the quartz-containing composite resin caused the enamel to wear away ten times more than did the microfilled composite resin. PMID- 20830886 TI - The teachers must learn too. PMID- 20830887 TI - Ignorance beats science and quality: are not preparation techniques the origin of many problems in dental practice? PMID- 20830888 TI - Powder to liquid ratios. PMID- 20830889 TI - Ceramic-fused-to-metal restorations with a new CAD/CAM system. AB - Experience has shown that a cast restoration will rarely have proper occlusal contacts. One possible solution could involve the application of a computerized design and fabrication system for restorations with accurately calculated and computer-milled occlusal surfaces. The Cicero system for the production of ceramic-fused-to-metal restorations makes use of optical scanning, nearly net shaped metal and ceramic sintering, and computer-aided crown fabrication techniques to fabricate restorations with maximal static and dynamic occlusal contact relations. The Cicero system produces crowns, fixed partial dentures, and inlays with different layers, such as metal and dentin and incisal porcelains, for maximal strength and esthetics. Fabrication of a crown for a mandibular first molar is described to demonstrate the computer-based design system. PMID- 20830890 TI - The corrected cast impression: an alternative technique. AB - Although the corrected or altered cast impression technique is widely taught, it seems to be used very little, in part because it requires separate appointments for framework try-in, corrected cast impression, and occlusal registration. This article describes a technique whereby each of these procedures may be accomplished accurately in one appointment. Visible light-cured resin impression trays with integral occlusion rims are fabricated after the framework has been fitted. Standard procedures are used for the corrected cast impression, and interocclusal records are made with the framework with the impression attached. A stable occlusal registration material allows the interocclusal records to be set aside and used to articulate the corrected cast before the impression tray is separated from the cast. Benefits of this technique include significant time savings, improved accuracy, and simplified procedures. PMID- 20830891 TI - Clinical and radiographic evaluation of cermet tunnel restorations on primary molars. AB - Fifty-one restorations of the tunnel type were performed with "cermet" cement on primary molars. The restorations were assessed clinically, radiographically, and by direct examination of the proximal surface 6 months (group I) and 12 months (group II) after placement. The incidence of fractured marginal ridges was found to be 3.8% in group I and 4.2% in group II. All restorations had their occlusal portion intact and were caries-free. Clinically detectable occlusal wear was found in 7.7% of teeth in group I and in 4.2% of teeth in group II. No correlation was found between direct and radiographic assessment of proximal caries. White spots, without carious penetration, were detected on 53.8% of proximal surfaces at 6 months and on 60.0% of proximal surfaces at 12 months. PMID- 20830892 TI - Class II direct composite resin restorations with beta-quartz glass-ceramic inserts. AB - With the increasing demand for esthetic posterior restorations, numerous techniques have been developed. The direct resin restoration has probably been used most extensively in Class II situations. Problems with Class II direct resin restorations include difficulty in developing proximal contact, occlusal wear, and polymerization shrinkage. Beta-quartz glass-ceramic inserts have been developed in an attempt to reduce the incidence of these potential problems. They can be placed in a one-appointment technique, are relatively inexpensive, and can readily be utilized by the clinician adept in placing Class II composite resin restorations. PMID- 20830893 TI - Apexification of wide-open apices in nonvital, immature permanent incisors: a case report. AB - Apexification is the accepted procedure to form an apical stop in nonvital teeth with incomplete root formation. A case is presented in which apexification with calcium hydroxide was performed on two permanent central incisors with immature roots and wide-open apices; treatment concluded with gutta-percha root canal restoration. Spontaneous apical seal had probably been initiated before the calcium hydroxide was inserted, but it was weak and nonhomogenous. PMID- 20830894 TI - An evaluation of two electronic apex locators in a dental student clinic. AB - The purpose of this study was to compare the accuracy and efficiency of two electronic apex locators to those of a conventional technique of determining working length with radiographs. Data were collected from 53 patients with a total of 96 canals treated by dental students. No significant difference was noted in the accuracy of the two apex locators. The readings from these units exactly agreed with the working lengths established by the students and faculty in 34% of the canals and were within 1.0 mm of the length in 80 to 86% of the canals. The data seem to indicate that apex locators have the potential for reducing the number of radiographs required if used before the working length radiographs are taken. Working lengths should be verified radiographically, because electronic apex locators were not accurate in every case. PMID- 20830895 TI - Reticulohistiocytic granuloma of the tongue: a case report. AB - Reticulohistiocytic granuloma is a type of reticulohistiocytosis that is manifested without systemic disturbances. A rare case of reticulohistiocytic granuloma presenting as a solitary nodule on the tongue is reported and discussed. PMID- 20830896 TI - Overcasting to repair a fractured porcelain fixed partial denture. AB - Long-span, permanently cemented, multiunit prostheses that suffer a fracture of one of the porcelain facings present difficult and often embarassing problems to the clinician. Silane coupling repair systems, although quick, simple, and inexpensive, do not ensure a long-lasting result. An alternative technique involving use of a porcelain-fused-to-metal overcasting and composite resin cement is presented. The overcasting is luted to the original metal casting. PMID- 20830897 TI - Protective and maintenance functions of human saliva. AB - The role of human saliva has traditionally been considered to be to aid in digestion. However, saliva's major role is not digestion but the protection and maintenance of the alimentary canal, especially the oral cavity. Loss of salivary flow may be devastating to a patient. Simple tasks such as speaking, chewing, and swallowing may become arduous and uncomfortable. Oral infections and mucosal irritations may drastically affect the patient's systemic and oral well-being. Plaque-mediated diseases and fungal infections may prevail in the absence of saliva. Understanding the functions of saliva and recognizing signs and symptoms of salivary dysfunction will allow increased evaluation and awareness of the salivary-distressed patient. PMID- 20830898 TI - The effect of four bleaching agents on the enamel surface: a scanning electron microscopic study. AB - Many methods of bleaching teeth and their effects on the surrounding tissues and pulp have been reported. The effect of bleaching agents on the enamel surface has received some investigation, but the products selected for the present study have not been included in previous scanning electron microscopic studies. In vitro scanning electron microscopic evaluation revealed that the enamel surface underwent considerable changes after 1 hour of exposure to one of four bleaching agents. These changes increased in direct relation to the length of time that the enamel surface was exposed to the oxygenation (bleaching) agent. PMID- 20830899 TI - Sources, interactions, and ecological impacts of organic contaminants in water, soil, and sediment: an introduction to the special series. AB - Agricultural and urban activities result in the release of a large number of organic compounds that are suspected of impacting human health and ecosystems: herbicides, insecticides, human and veterinary pharmaceuticals, natural and synthetic hormones, personal care products, surfactants, plasticizers, fire retardants, and others. Sorbed reservoirs of these compounds in soil represent a potentially chronic source of water contamination. This article is an introduction to a series of technical papers stemming from a symposium at the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America 2008 Annual Meeting, which was held jointly with The Geological Society of America, The Gulf Coast Association of Geological Scientists, and the Houston Geological Society, under one of the Joint Meeting's overarching themes: Emerging Trace Contaminants in Surface and Ground Water Generated from Waste Water and Solid Waste Application. The symposium emphasized the role of soils as sources, sinks, and reaction catalysts for these contaminants and the occurrence and fate of these contaminants in surface and underground water supplies. Topics covered included novel advances in analytical techniques, transport of infectious agents, occurrence and fate of veterinary pharmaceuticals, characterization of sorption mechanism, biotic and abiotic transformation reactions, the role of soil components, occurrence and fate in wastewater treatment systems, transport of engineered nanoparticles, groundwater contamination resulting from urban runoff, and issues in water reuse. Overviews of the reports, trends, gaps in our knowledge, and topics for further research are presented in this special series of papers. The technical papers in this special series reflect current gains in knowledge and simultaneously underscore how poorly we are able to predict the fate and, hence, the associated risk to ecological and human receptors of these contaminants. PMID- 20830900 TI - Transformation of triclosan and triclocarban in soils and biosolids-applied soils. AB - Triclosan (TCS) and triclocarban (TCC), widely used as antibacterial agents, have been frequently detected in biosolids. Biosolids land application may introduce pharmaceuticals and personal care products (PPCPs) such as TCS and TCC into the environment. Microcosm studies were conducted to investigate TCS and TCC transformation in Marietta fine loam and McLaurin coarse loam. Both compounds were spiked into the soils with and without biosolids amendment under non sterilized and sterilized conditions and incubated aerobically at 30 degrees C for up to 100 d. In both soils, transformation of TCS followed second-order reaction kinetics, with estimated reaction rate constants of (5.27 +/- 0.920) x 10(-1) and (9.13 +/- 1.58) x 10(-2) (mg kg(-1))(-1) d(-1) for Marietta fine loam and McLaurin coarse loam, respectively. Transformation of TCC in both soils was slower than that for TCS. After 100 d, 53 +/- 1% and 71 +/- 2% of the initially added TCC and only 2.8 +/- 0.35% and 6.2 +/- 0.80% of initially added TCS remained in Marietta fine loam and McLaurin coarse loam, respectively. The transformation of both compounds were faster in the Marietta fine loam (pH 7.8; 1.8% organic matter) than in the McLaurin coarse loam (pH 4.7; 0.65% organic matter). Our result suggests that biotic processes are more of a controlling factor affecting TCS transformation, whereas abiotic processes may affect TCC transformation more significantly. Addition of biosolids to the two soils slowed the transformation of both compounds, indicating interactions between both compounds and biosolids may adversely affect their transformation in soils, an important factor that must be included in models predicting environmental fate of biosolids-associated PPCPs. PMID- 20830901 TI - Transport of the pathogenic prion protein through soils. AB - Transmissible spongiform encephalopathies (TSEs) are progressive neurodegenerative diseases and include bovine spongiform encephalopathy of cattle, chronic wasting disease (CWD) of deer and elk, scrapie in sheep and goats, and Creutzfeldt-Jakob disease in humans. An abnormally folded form of the prion protein (designated PrP(TSE)) is typically associated with TSE infectivity and may constitute the major, if not sole, component of the infectious agent. Transmission of CWD and scrapie is mediated in part by an environmental reservoir of infectivity. Soil appears to be a plausible candidate for this reservoir. The transport of TSE agent through soil is expected to influence the accessibility of the pathogen to animals after deposition and must be understood to assess the risks associated with burial of infected carcasses. We report the results of saturated column experiments designed to evaluate PrP(TSE) transport through five soils with relatively high sand or silt contents and low organic carbon content. Protease-treated TSE-infected brain homogenate was used as a model for PrP(TSE) present in decomposing infected tissue. Synthetic rainwater was used as the eluent. All five soils retained PrP(TSE); no detectable PrP(TSE) was eluted over more than 40 pore volumes of flow. Lower bound apparent attachment coefficients were estimated for each soil. Our results suggest that TSE agent released from decomposing tissues to soils with low organic carbon content would remain near the site of initial deposition. In the case of infected carcasses deposited on the land surface, this may result in local sources of infectivity to other animals. PMID- 20830902 TI - Degradation kinetics of testosterone by manure-borne bacteria: influence of temperature, pH, glucose amendments, and dissolved oxygen. AB - Land application of manure may contribute endocrine disrupting compounds (EDCs) such as steroid hormones to the environment. Little attention has been paid to the potential for degradation of steroid hormones by manure-borne bacteria and their degradation kinetics and pathways. In a laboratory study, the potential for biodegradation of testosterone, 17beta-estradiol (E2) and progesterone by swine (Sus scrofa) manure-borne bacteria was examined. In addition, the impact of temperature, pH (6, 7, and 7.5), glucose amendments (0, 3, and 22 mmol L(-1)), and presence of oxygen on testosterone degradation kinetics was determined. Testosterone, 17beta-estradiol and progesterone were biodegraded within 25 h of reaction initiation under aerobic conditions. The degradation of testosterone followed pseudo first-order and zero-order reaction kinetics under aerobic and anaerobic conditions, respectively, in tryptic soy broth (TSB) pre-enriched systems. The half-life (t1/2) for the degradation of testosterone under anaerobic conditions was six times longer than aerobic conditions. Testosterone degradation was found to significantly increase (- 17%) when incubated at 37 degrees C vs. 22 degrees C. The impact of pH (t1/2 ranged from 4.4-4.9 h) and glucose amendments (t1/2 ranged from 4.6-5.1 h) on the testosterone degradation rate were found to be small. Testosterone was transformed to dehydrotestosterone (DHT) (major degradation product), androstenedione (AD), and androstadienedione (ADD) under aerobic conditions as revealed by liquid chromatography-time-of-flight mass spectrometry (LC/TOF-MS). These results indicate that testosterone is rapidly degraded by manure-borne bacteria under a wide range of environmentally relevant conditions. However, the formed degradation products are still of potential concern due to their endocrine disrupting potential. PMID- 20830903 TI - Sources and distribution of organic compounds using passive samplers in Lake Mead national recreation area, Nevada and Arizona, and their implications for potential effects on aquatic biota. AB - The delineation of lateral and vertical gradients of organic contaminants in lakes is hampered by low concentrationsand nondetection of many organic compounds in water. Passive samplers (semipermeable membrane devices [SPMDs] and polar organic chemical integrative samplers [POCIS]) are well suited for assessing gradients because they can detect synthetic organic compounds (SOCs) at pg L(-1) concentrations. Semi-permeable membrane devices and POCIS were deployed in Lake Mead, at two sites in Las Vegas Wash, at four sites across Lake Mead, and in the Colorado River downstream from Hoover Dam. Concentrations of hydrophobic SOCs were highest in Las Vegas Wash downstream from waste water and urban inputs and at 8 m depth in Las Vegas Bay (LVB) where Las Vegas Wash enters Lake Mead. The distribution of hydrophobic SOCs showed a lateral distribution across 10 km of Lake Mead from LVB to Boulder Basin. To assess possible vertical gradient SOCs, SPMDs were deployed at 4-m intervals in 18 m of water in LVB. Fragrances and legacy SOCs were found at the greatest concentrations at the deepest depth. The vertical gradient of SOCs indicated that contaminants were generally confined to within 6 m of the lake bottom during the deployment interval. The high SOC concentrations, warmer water temperatures, and higher total dissolved solids concentrations at depth are indicative of a plume of Las Vegas Wash water moving along the lake bottom. The lateral and vertical distribution of SOCs is discussed in the context of other studies that have shown impaired health of fish exposed to SOCs. PMID- 20830904 TI - Occurrence of herbicides and pharmaceutical and personal care products in surface water and groundwater around Liberty Bay, Puget Sound, Washington. AB - Organic contaminants, such as pharmaceuticals and personal care products (PPCPs), pose a risk to water quality and the health of ecosystems. This study was designed to determine if a coastal community lacking point sources, such as waste water treatment plant effluent, could release PPCPs, herbicides, and plasticizers at detectable levels to their surface water and groundwater. Research was conducted in Liberty Bay, an embayment within Puget Sound, where 70% of the population (-10,000) uses septic systems. Sampling included collection of groundwater and surface water with grab samples and the use of polar organic chemical integrative samplers (POCIS). We analyzed for a broad spectrum of 25 commonly used compounds, including PPCPs, herbicides, and a flame retardant. Twelve contaminants were detected at least once; only N,N-diethyl-meta-toluamide, caffeine, and mecoprop, a herbicide not attributed to septic systems, were detected in more than one grab sample. The use of POCIS was essential because contaminants were present at very low levels (nanograms), which is common for PPCPs in general, but particularly so in such a small community. The use of POCIS allowed the detection of five compounds that were not present in grab samples. Data suggest that the community is contaminating local water with PPCPs; this effect is likely to increase as the population and product usage increase. The results presented here are a first step toward assessing the transport of herbicides and PPCPs into this coastal system. PMID- 20830905 TI - Fate of effluent-borne contaminants beneath septic tank drainfields overlying a Karst aquifer. AB - Groundwater quality effects from septic tanks were investigated in the Woodville Karst Plain, an area that contains numerous sinkholes and a thin veneer of sands and clays overlying the Upper Floridan aquifer (UFA). Concerns have emerged about elevated nitrate concentrations in the UFA, which is the source of water supply in this area of northern Florida. At three sites during dry and wet periods in 2007-2008, water samples were collected from the septic tank, shallow and deep lysimeters, and drainfield and background wells in the UFA and analyzed for multiple chemical indicators including nutrients, nitrate isotopes, organic wastewater compounds (OWCs), pharmaceutical compounds, and microbiological indicators (bacteria and viruses). Median NO3-N concentration in groundwater beneath the septic tank drainfields was 20 mg L(-1) (8.0-26 mg L(-1)). After adjusting for dilution, about 25 to 40% N loss (from denitrification, ammonium sorption, and ammonia volatilization) occurs as septic tank effluent moves through the unsaturated zone to the water table. Nitrogen loading rates to groundwater were highly variable at each site (3.9-12 kg N yr(-1)), as were N and chloride depth profiles in the unsaturated zone. Most OWCs and pharmaceutical compounds were highly attenuated beneath the drainfields; however, five Cs (caffeine, 1,7-dimethylxanthine, phenol, galaxolide, and tris(dichloroisotopropyl)phosphate) and two pharmaceutical compounds (acetaminophen and sulfamethoxazole) were detected in groundwater samples. Indicator bacteria and human enteric viruses were detected in septic tank effluent samples but only intermittently in soil water and groundwater. Contaminant movement to groundwater beneath each septic tank system also was related to water use and differences in lithology at each site. PMID- 20830906 TI - Impact of drought on wastewater contaminants in an urban water supply. AB - The concentrations of selected wastewater contaminants, including conductivity, nitrate, and pharmaceuticals and endocrine disrupting compounds (EDCs), were monitored from 2003 to 2007 in Lake Mead, the raw (untreated) drinking water for southern Nevada. Monitoring was also conducted in two inflows to Lake Mead: the Colorado River and the wastewater-dominated Las Vegas Wash. There was a statistically significant increase in source water conductivity, nitrate, and pharmaceutical and EDC concentrations over this time period, concomitant with a statistically significant decline in the volume of Lake Mead. There was no statistically significant increase in conductivity and nitrate in the Colorado River or the Las Vegas Wash over this period, nor was there an increase in flow of the Las Vegas Wash or Colorado River. Thus, the deterioration of source drinking water quality is due to the decrease in the volume of Lake Mead which has been attributed to drought. This phenomenon may also be a harbinger of how water quality may be adversely affected by climate change as patterns of surface water flow shift and treated wastewater becomes a larger fraction of surface water flow in some areas. PMID- 20830907 TI - Transport of pharmaceuticals in columns of a wastewater-irrigated Mexican clay soil. AB - The irrigation or agricultural land with wastewater is increasingly practiced in many parts of the world as a consequence of growing populations and urbanization. The risks emerging from pharmaceuticals that are contained in wastewater for soils and groundwater have hardly been investigated. We studied leaching and effects of naproxen, ibuprofen, bezafibrate, diclofenac, gemfibrocil, clarithromycin, trimethoprim, clindamycin, erythromycin, and metoprolol in a soil column experiment simulating an irrigation event with 8.6 cm of wastewater containing 20 microg L(-1) or 2000 microg L(-1) of each compound or of erythromycin alone. The leached fraction of applied pharmaceuticals ranged from 0.1 +/- 0.1% (clarithromycin, 2000 microg L(-1)) to 130 +/- 41% (naproxen, 20 microg L(-1)) and tended to increase with decreasing K(d) or K(oc). Naproxen transport was similar to that of the tracer chloride. Ibuprofen was also hardly retarded (R = 1.20 +/- 0.18), but showed a higher degradation rate of 0.02 +/- 0.004 h(-1) (2000 microg L(-1)) than naproxen. The transport of a pulse of 2000 microg L(-1) of bezafibrate could be described with a retardation factor of 1.5 and a degradation rate of 0.033 h(-1). The application of erythromycin alone or of a cocktail of all pharmaceuticals significantly increased soil CO2 emissions by 50% 1 d after the application. There is a considerable risk that pharmaceuticals are leached to groundwater during wastewater irrigation. PMID- 20830908 TI - Selected veterinary pharmaceuticals in agricultural water and soil from land application of animal manure. AB - Veterinary pharmaceuticals are commonly administered to animals for disease control, and added into feeds at subtherapeutic levels to improve feeding efficiency. As a result of these practices, a certain fraction of the pharmaceuticals are excreted into animal manures. Land application of these manures contaminates soils with the veterinary pharmaceuticals, which can subsequently lead to contamination of surface and groundwaters. Information on the occurrence and fate of pharmaceuticals in soil and water is needed to assess the potential for exposure of at-risk populations and the impacts on agricultural ecosystems. In this study, we investigated the occurrence and fate of four commonly used veterinary pharmaceuticals (amprolium, carbadox, monensin, and tylosin) in a farm in Michigan. Amprolium and monensin were frequently detected in nearby surface water, with concentrations ranging from several to hundreds of nanograms per liter, whereas tylosin or carbadox was rarely found. These pharmaceuticals were more frequently detected in surface runoff during nongrowing season (October to April) than during growing season (May to September). Pharmaceuticals resulting from postharvest manure application appeared to be more persistent than those from spring application. High concentrations of pharmaceuticals in soils were generally observed at the sites where the respective concentrations in surface water were also high. For monensin, the ratios of soil-sorbed to aqueous concentrations obtained from field samples were within the order of the distribution coefficients obtained from laboratory studies. These results suggest that soil is a reservoir for veterinary pharmaceuticals that can be disseminated to nearby surface water via desorption from soil, surface runoff, and soil erosion. PMID- 20830909 TI - Biochar and the nitrogen cycle: introduction. AB - Nitrogen (N) is an essential nutrient, and research to date shows that biochar potentially has the ability to manipulate the rates of N cycling in soil systems by influencing nitrification rates and adsorption of ammonia and increasing NH4+ storage by enhancing cation exchange capacity in soils. Its influence on these processes may have further implications in terms of reducing gaseous N losses such as N2O and nitrate leaching. However, further detailed research is required to fully understand the transformation mechanisms and fate of N when associated with biochar treated soils. The three research papers that comprise this special collection of papers on biochar and the nitrogen cycle focus on biochar's diverse ability to influence N cycling processes. These papers show for the first time (i) how microbial nitrification communities and function differ with exposure to biochar, (ii) how the length of time the soil has been in contact with biochar influences N transformation and how this can vary with soil type, and (iii) how composting of organic materials with biochar can reduce N losses and enhance the nutrient status of the composted product. Considerable knowledge gaps still exist in terms of understanding the precise mechanisms through which biochar influences soil N transformations, and how biochar affects both plant and microbial N supply. The general direction that research on biochar should focus on with respect to the N cycle is the effect(s) that biochar has on N transformation in soils, both chemical and biological mechanisms, and the fate of N applied to biochar treated soils. This research needs to be performed at both field plot and microbial scales. PMID- 20830910 TI - Influence of biochars on nitrous oxide emission and nitrogen leaching from two contrasting soils. AB - The influence of biochar on nitrogen (N) transformation processes in soil is not fully understood. This study assessed the influence of four biochars (wood and poultry manure biochars synthesized at 400 degrees C, nonactivated, and at 550 degrees C, activated, abbreviated as: W400, PM400, W550, PM550, respectively) on nitrous oxide (N2O) emission and N leaching from an Alfisol and a Vertisol. Repacked soil columns were subjected to three wetting-drying (W-D) cycles to achieve a range of water-filled pore space (WFPS) over a 5-mo period. During the first two W-D cycles, W400 and W550 had inconsistent effects on N2O emissions and the soils amended with PM400 produced higher N2O emissions relative to the control. The initially greater N2O emission from the PM400 soils was ascribed to its higher labile intrinsic N content than the other biochars. During the third W D cycle, all biochar treatments consistently decreased N2O emissions, cumulatively by 14 to 73% from the Alfisol and by 23 to 52% from the Vertisol, relative to their controls. In the first leaching event, higher nitrate leaching occurred from the PM400-amended soils compared with the other treatments. In the second event, the leaching of ammonium was reduced by 55 to 93% from the W550- and PM550-Alfisol and Vertisol, and by 87 to 94% from the W400- and PM400 Vertisol only (cf. control). We propose that the increased effectiveness of biochars in reducing N2O emissions and ammonium leaching over time was due to increased sorption capacity of biochars through oxidative reactions on the biochar surfaces with ageing. PMID- 20830911 TI - Reducing nitrogen loss during poultry litter composting using biochar. AB - Poultry litter (PL) is a potentially underused fertilizer because it contains appreciable amounts of N, P, K, and micronutrients. However, treatments like composting to reduce potential pathogens, weed seeds, and odor often result in high losses of N through NH3 volatilization. Biochar (BC) has been shown to act as an absorber of NH3 and water-soluble NH4+ and might therefore reduce losses of N during composting of manure. We produced three PL compost mixtures that consisted of PL without added BC (BCO), PL + 5% BC (BC5), and PL + 20% BC (BC20). The BC was produced from pine chips and used without further modifications. Three replicates of each treatment were placed in nine bioreactors to undergo composting for 42 d. The entire composting experiment was repeated three times in a complete-block design. Moisture content, temperature, pH, mass loss, gas (NH3, CO2, H2S) emissions, C, and nutrient contents were measured periodically throughout the experiments. Results showed no difference in PL mass loss with BC addition. Moisture content decreased, pH increased significantly, and peak CO2 and temperatures were significantly higher with BC20 compared with BC0. These results indicate a faster decomposition of PL if amended with BC. Ammonia concentrations in the emissions were lower by up to 64% if PL was mixed with BC (BC20), and total N losses were reduced by up to 52%. Biochar might be an ideal bulking agent for composting N-rich materials. PMID- 20830912 TI - Wildfire and charcoal enhance nitrification and ammonium-oxidizing bacterial abundance in dry montane forest soils. AB - All forest fire events generate some quantity of charcoal, which may persist in soils for hundreds to thousands of years. However, few studies have effectively evaluated the potential for charcoal to influence specific microbial communities or processes. To our knowledge, no studies have specifically addressed the effect of charcoal on ammonia-oxidizing bacteria (AOB) in forest soils. Controlled experiments have shown that charcoal amendment of fire-excluded temperate and boreal coniferous forest soil increases net nitrification, suggesting that charcoal plays a major role in maintaining nitrification for extended periods postfire. In this study, we examined the influence of fire history on gross nitrification, nitrification potential, and the nature and abundance of AOB. Soil cores were collected from sites in the Selway-Bitterroot wilderness area in northern Idaho that had been exposed twice (in 1910, 1934) or three times (1910, 1934, and 1992) in the last 94 yr, allowing us to contrast soils recently exposed to fire to those that experienced no recent fire (control). Charcoal content was determined in the O horizon by hand-separation and in the mineral soil by a chemical digestion procedure. Gross and net nitrification, and potential rates of nitrification were measured in mineral soil. Analysis of the AOB community was conducted using primer sets specific for the ammonia mono-oxygenase gene (amoA) or the 16S rRNA gene of AOB. Denaturing gradient gel electrophoresis was used to analyze the AOB community structure, while AOB abundance was determined by quantitative polymerase chain reaction. Recent (12-yr-old) wildfire resulted in greater charcoal contents and nitrification rates compared with sites without fire for 75 yr, and the more recent fire appeared to have directly influenced AOB abundance and community structure. We predicted and observed greater abundance of AOB in soils recently exposed to fire compared with control soils. Interestingly, sequence data revealed that Clusters 3 and 4, and not Cluster 2, of genus Nitrosospira dominated these forest soils, with a shift toward Cluster 3 in recently burned sites. PMID- 20830913 TI - Laboratory system for dust generation from soils. AB - Farm workers and residential communities adjacent to agricultural fields can be exposed to soil dust generated during field operations at levels that could result in respiratory problems. However, field sampling of agricultural dust faces logistical problems from spatial and temporal differences in soil properties, field operations, and meteorological conditions. To minimize these problems, we designed a dust generator that simulates dust generation during tilling of agricultural fields to provide samples of particulate matter derived from bulk soil and developed optimal operating conditions to assure reproducible results. The dust generator consisted of a rotating chamber, where soil samples were loaded and tumbled, and a settling chamber, where airborne soil dust samples were collected using particle size-selective samplers. The following operating conditions for dust generation were evaluated: initial soil mass, air intake, rotation speed, and sampling time to optimize dust sampling. We compared the laboratory-generated dust from soil samples with field dust that we collected from the same plots during agricultural operations. We determined from X-ray diffraction and energy-dispersive X-ray analyses that the mineralogy and chemical composition of field- and laboratory-generated dust were similar, indicating that the apparatus reasonably simulated field mechanical processes that produce airborne particulate matter from soils. The results suggest that the laboratory dust generator provides reliable samples of soil-derived dust and could be useful for future studies involving airborne particulate material from soils. PMID- 20830914 TI - Cadmium tolerance and accumulation in cultivars of a high-biomass tropical tree (Averrhoa carambola) and its potential for phytoextraction. AB - Averrhoa carambola is a high-biomass tropical tree that has been identified as a Cd accumulator. In the present study, field survey, pot, and hydroponic experiments were conducted to investigate the variation of Cd tolerance and accumulation in cultivars of A. carambola as well as its potential for phytoextraction. In the field survey, it was found that concentrations of Cd in aerial tissues of A. carambola varied greatly among sites and cultivars. The Cd bioconcentration factors (BCFs) and Cd removals by the field-grown A. carambola differed significantly among sites but not among cultivars. Nonetheless, all four carambola cultivars investigated were able to accumulate considerably high concentrations of Cd in their shoots, which indicated that the 4-yr-old carambola stands could remove 0.3 to 51.8% of the total Cd content in the top 20-cm soil layer. When cultured in Cd-spiked soils, the carambola cultivar Hua-Di always showed higher Cd tolerance than the other cultivars; however, this tendency was not confirmed by hydroponic experiment. The Cd BCFs of cultivar Thailand grown in soils with 6 and 12 mg Cd kg(-1) were highest among cultivars, whereas this trend was reversed at 120 mg Cd kg(-1) treatment. Nevertheless, the pot- and hydroponics-grown carambola cultivars generally showed higher capacities to tolerate and accumulate Cd, compared with the control species. The present results indicate that a strong ability to tolerate and accumulate Cd seems to be a trait at the species level in A. carambola, although some degree of variances in both Cd tolerance and accumulation exists among cultivars. PMID- 20830915 TI - Dissipation of sulfamethazine and tetracycline in the root zone of grass and tree species. AB - The detection of veterinary antibiotics (VAs) in drinking water resources resulting from manure disposal operations has raised public health concerns. Previous studies have demonstrated the benefits of using multispecies vegetated buffer strips (VBS) to reduce agrichemical transport from agroecosystems. However, VA fate and subsequent effects of VAs on microbial activities in the root zone ofVBS have not been well documented. A growth chamber study was conducted to investigate dissipation of two commonly administered VAs, sulfamethazine (SMZ) and tetracycline (TC), and the relationship between VA dissipation and soil enzyme activities in the root zone of selected plant species. Switchgrass, eastern gammagrass, orchardgrass, and a hybrid poplar tree were grown in pots containing a Mexico silt loam/sand mixture for 3 mo, followed by plant biomass removal and collection of root zone soil. Radiolabeled (3H) SMZ or TC was applied to the soils and samples were incubated in the dark for 5 wk. Among the plant species studied, hybrid poplar showed enhanced capability for promoting SMZ dissipation. The half-lives of SMZ in soil planted to the poplar tree were significantly reduced by the enhanced enzymatic activity. Comparison of soil enzymatic activities between the antibiotic treatments revealed that fluorescein diacetate hydrolytic and glucosaminidase enzyme activities were significantly lower in TC-treated soils than in SMZ-treated soils. The beta glucosidase activities were similar between the two VA treatments. Correlation analyses showed that the half-life of SMZ in the soil was negatively correlated with enzymatic activity. Enhanced SMZ dissipation in soil planted to hybrid poplar suggests that incorporation of this plant species in VBS may mitigate deleterious effects of SMZ in the environment. PMID- 20830916 TI - Modeling nutrient flows in the food chain of China. AB - Increasing nitrogen (N) and phosphorus (P) inputs have greatly contributed to the increasing food production in China during the last decades, but have also increased N and P losses to the environment. The pathways and magnitude of these losses are not well quantified. Here, we report on N and P use efficiencies and losses at a national scale in 2005, using the model NUFER (NUtrient flows in Food chains, Environment and Resources use). Total amount of "new" N imported to the food chain was 48.8 Tg in 2005. Only 4.4.Tg reached households as food. Average N use efficiencies in crop production, animal production, and the whole food chain were 26, 11, and 9%, respectively. Most of the imported N was lost to the environment, that is, 23 Tg N to atmosphere, as ammonia (57%), nitrous oxide (2%), dinitrogen (33%), and nitrogen oxides (8%), and 20 Tg to waters. The total P input into the food chain was 7.8 Tg. The average P use efficiencies in crop production, animal production, and the whole food chain were 36, 5, and 7%, respectively. This is the first comprehensive overview of N and P balances, losses, and use efficiencies of the food chain in China. It shows that the N and P costs of food are high (for N 11 kg kg(-1), for P 13 kg kg(-1)). Key measures for lowering the N and P costs of food production are (i) increasing crop and animal production, (ii) balanced fertilization, and (iii) improved manure management. PMID- 20830917 TI - Reactivity of nickel in soils: evidence of retention kinetics. AB - The bioavailability and mobility of nickel (Ni) is highly dependent on the mechanisms associated with Ni adsorption-desorption and its kinetics in soils. To examine the characteristics of Ni retention and release, kinetic sorption batch experiments were performed on three soils having different properties, followed by Ni desorption using successive dilutions. Sorption of Ni by all soils was highly nonlinear and strongly kinetic, where the rate of Ni retention was rapid initially and was followed by gradual or somewhat slow retention behavior with increasing reaction time. Desorption of Ni was strongly irreversible and hysteretic in nature, indicating lack of equilibrium retention and/or irreversible or slowly reversible processes. A sequential extraction procedure provided evidence that a significant amount of Ni was irreversibly adsorbed on all soils. A nonlinear multireaction model with equilibrium-kinetic-irreversible reaction sites successfully described the retention (adsorption) and subsequent release of Ni on the different soils. The model was also capable of predicting Ni desorption kinetics based on adsorption data sets only. PMID- 20830918 TI - Release of metals from metal-amended soil treated with a sulfosuccinamate surfactant: effects of surfactant concentration, soil/solution ratio, and pH. AB - Anionic surfactants, mainly sulfosuccinamates, can be found in soils as the result of sludge application, wastewater irrigation, and remediation processes. Relatively high concentrations of surfactants together with multimetals can represent an environmental risk. A study was performed to assess the potential of the anionic surfactant Aerosol 22 (A22) for release of Cd, Cu, Pb, and Zn from a metal-amended soil representative of a Mediterranean area. Metal desorption was performed by batch experiments and release kinetics were assessed. Response surface methodology was applied to determine the influence of A22 concentration and the surfactant/soil ratio, as extraction key factors. An increase in solution/soil ratio to 100 (mL g(-1)) caused higher metal release. Leaching predictions found Pb to have the lowest and Cd the highest hazard. Metal release was highly dependent on pH. When extraction was made at pH less than 7, low or negligible amounts of metals were leached, whereas an increase to pH 7 caused desorption rates of 50 to 55% for Cd, Cu, and Zn but only 35% for Pb. Complexed metal-carboxylic groups from A22 were mainly responsible for its higher extractive capacity, especially of Cd and Cu. PMID- 20830919 TI - Increasing precision of turbidity-based suspended sediment concentration and load estimates. AB - Turbidity is an effective tool for estimating and monitoring suspended sediments in aquatic systems. Turbidity can be measured in situ remotely and at fine temporal scales as a surrogate for suspended sediment concentration (SSC), providing opportunity for a more complete record of SSC than is possible with physical sampling approaches. However, there is variability in turbidity-based SSC estimates and in sediment loadings calculated from those estimates. This study investigated the potential to improve turbidity-based SSC, and by extension the resulting sediment loading estimates, by incorporating hydrologic variables that can be monitored remotely and continuously (typically 15-min intervals) into the SSC estimation procedure. On the Roanoke River in southwestern Virginia, hydrologic stage, turbidity, and other water-quality parameters were monitored with in situ instrumentation; suspended sediments were sampled manually during elevated turbidity events; samples were analyzed for SSC and physical properties including particle-size distribution and organic C content; and rainfall was quantified by geologic source area. The study identified physical properties of the suspended-sediment samples that contribute to SSC estimation variance and hydrologic variables that explained variability of those physical properties. Results indicated that the inclusion of any of the measured physical properties in turbidity-based SSC estimation models reduces unexplained variance. Further, the use of hydrologic variables to represent these physical properties, along with turbidity, resulted in a model, relying solely on data collected remotely and continuously, that estimated SSC with less variance than a conventional turbidity-based univariate model, allowing a more precise estimate of sediment loading, Modeling results are consistent with known mechanisms governing sediment transport in hydrologic systems. PMID- 20830920 TI - Assessment of total maximum daily load implementation strategies for nitrate impairment of the Raccoon River, Iowa. AB - The state of Iowa requires developing total maximum daily loads (TMDLs) for over 400 water bodies that are listed on the 303(d) list of the impaired waters. The Raccoon River watershed, which covers approximately 9400 km2 of prime agriculture land and represents a typical Midwestern corn-belt region in west-central Iowa, was found to have three stream segments impaired by nitrate-N. The Soil and Water Assessment Tool (SWAT) was applied to this watershed to facilitate the development of a TMDL. The modeling framework integrates SWAT with supporting software and databases on topography, land use and management, soil, and weather information. Annual and monthly simulated and measured streamflow and nitrate loads were strongly correlated. The watershed response was evaluated for a suite of watershed management scenarios where land use and management changes were made uniformly across the watershed. A scenario of changing the entire land to row crop resulted in an increased nitrate load of about 12% over the baseline condition at the watershed outlet. Results from the 15 nitrate load reduction strategies were found to reduce nitrate from < 1% to about 85%, with the greatest potential reduction associated with changing the row crops to grassland. This research demonstrated the use of a modeling system to facilitate the analyses of TMDL implementation strategies, including the ability to target the most efficient allocation of alternative practices on a subwatershed basis. PMID- 20830921 TI - Sediment fingerprinting to determine the source of suspended sediment in a southern Piedmont stream. AB - Thousands of stream miles in the southern Piedmont region are impaired because of high levels of suspended sediment. It is unclear if the source is upland erosion from agricultural sources or bank erosion of historic sediment deposited in the flood plains between 1830 and 1930 when cotton farming was extensive. The objective of this study was to determine the source of high stream suspended sediment concentrations in a typical southern Piedmont watershed using sediment fingerprinting techniques. Twenty-one potential tracers were tested for their ability to discriminate between sources, conservative behavior, and lack of redundancy. Tracer concentrations were determined in potential sediment sources (forests, pastures, row crop fields, stream banks, and unpaved roads and construction sites), and suspended sediment samples collected from the stream and analyzed using mixing models. Results indicated that 137Cs and 15N were the best tracers to discriminate potential sediment sources in this watershed. The delta15N values showed distinct signatures in all the potential suspended sediment sources, and delta15N was a unique tracer to differentiate stream bank soil from upland subsurface soils, such as soil from construction sites, unpaved roads, ditches, and field gullies. Mixing models showed that about 60% of the stream suspended sediment originated from eroding stream banks, 23 to 30% from upland subsoil sources (e.g., construction sites and unpaved roads), and about 10 to 15% from pastures. The results may be applicable to other watersheds in the Piedmont depending on the extent of urbanization occurring in these watersheds. Better understanding of the sources of fine sediment has practical implications on the type of sediment control measures to be adopted. Investment of resources in improving water quality should consider the factors causing stream bank erosion and erosion from unpaved roads and construction sites to water quality impairment. PMID- 20830922 TI - A simple metric to predict stream water quality from storm runoff in an urban watershed. AB - The contribution of runoff from various land uses to stream channels in a watershed is often speculated and used to underpin many model predictions. However, these contributions, often based on little or no measurements in the watershed, fail to appropriately consider the influence of the hydrologic location of a particular landscape unit in relation to the stream network. A simple model was developed to predict storm runoff and the phosphorus (P) status of a perennial stream in an urban watershed in New York State using the covariance structure of runoff from different landscape units in the watershed to predict runoff in time. One hundred and twenty-seven storm events were divided into parameterization (n = 85) and forecasting (n = 42) data sets. Runoff, dissolved P (DP), and total P (TP) were measured at nine sites distributed among three land uses (high maintenance, unmaintained, wooded), three positions in the watershed (near the outlet, midwatershed, upper watershed), and in the stream at the watershed outlet. The autocorrelation among runoff and P concentrations from the watershed landscape units (n = 9) and the covariance between measurements from the landscape units and measurements from the stream were calculated and used to predict the stream response. Models, validated using leave-one-out cross validation and a forecasting method, were able to correctly capture temporal trends in streamflow and stream P chemistry (Nash-Sutcliffe efficiencies, 0.49 0.88). The analysis suggests that the covariance structure was consistent for all models, indicating that the physical processes governing runoff and P loss from these landscape units were stationary in time and that landscapes located in hydraulically active areas have a direct hydraulic link to the stream. This methodology provides insight into the impact of various urban landscape units on stream water quantity and quality. PMID- 20830923 TI - Analysis of polycyclic aromatic hydrocarbons and their oxygen-containing derivatives and metabolites in soils. AB - Although polycyclic aromatic hydrocarbons (PAHs) have been extensively studied, the knowledge of their oxygen-containing derivatives and metabolites (OPAHs) in soils is limited. We modified and tested an existing analytical protocol involving pressurized liquid extraction of soil followed by fractionation of target compounds into PAHs and OPAHs on a silica gel column and gas chromatography/ mass spectrometry-based separation and quantification. Polycyclic aromatic hydrocarbons and carbonyl-OPAHs were quantified directly after separation on silica gel columns, and hydroxyl/carboxyl-OPAHs were quantified after silylation with N,O-bis(trimethylsilyl)trifluoroacetamide. Recoveries between 78 and 97% (relative standard deviation [RSD], 5-12%) were obtained for six carbonyl-OPAHs, whereas 1,2-acenaphthenequinone and 1,4-naphthoquinone showed lower recoveries of 34 and 44% (RSD, 19 and 28%, respectively). Five hydroxyl/carboxyl-OPAHs had recoveries between 36 and 70% (RSD, 13-46%), six others had between 2 and 7% (RSD, 8-25%), and nine were lost in sample preparation. Limits of detection ranged from 0.1 to 1.6 ng g(-1) for OPAHs and from 0.01 to 0.56 ng g(-1) for PAHs. The protocol was applied to soils from a former gasworks site, Berlin, an urban soil from Mainz, both in Germany, and a forest soil from near Manaus, Brazil. The sums of 34 PAH concentrations were 107,000, 3505, and 21 ng g(-1); those of seven carbonyl-OPAHs were 15,690, 170, and 7 ng g(-1); and those of 11 hydroxyl/carboxyl-OPAHs 518, 36, and 16 ng g(-1) for Berlin, Mainz, and Manaus soils, respectively. Several OPAHs were present at concentrations higher than or equal to their parent PAHs, demonstrating the importance of OPAH measurement for the assessment of PAH-related environmental risks. PMID- 20830924 TI - Effects of natural organic matter on PCB-activated carbon sorption kinetics: implications for sediment capping applications. AB - In situ capping of polychlorinated biphenyl (PCB)-contaminated sediments with a layer of activated carbon has been proposed, but several questions remain regarding the long-term effectiveness of this remediation strategy. Here, we assess the degree to which kinetic limitations, size exclusion effects, and electrostatic repulsions impaired PCB sorption to activated carbon. Sorption of 11 PCB congeners with activated carbon was studied in fixed bed reactors with organic-free water (OFW) and Suwannee River natural organic matter (SR-NOM), made by reconstituting freeze-dried SR-NOM at a concentration of 10 mg L(-1) as carbon. In the OFW test, no PCBs were detected in the column effluent over the 390-d study, indicating that PCB-activated carbon equilibrium sorption capacities may be achieved before breakthrough even at the relatively high hydraulic loading rate (HLR) of 3.1 m h(-1). However, in the SR-NOM fixed-bed test, partial PCB breakthrough occurred over the entire 320-d test (HLRs of 3.1-, 1.5-, and 0.8 m h(-1)). Simulations from a modified pore and surface diffusion model indicated that external (film diffusion) mass transfer was the dominant rate-limiting step but that internal (pore diffusion) mass transfer limitations were also present. The external mass transfer limitation was likely caused by formation of PCB-NOM complexes that reduced PCB sorption through a combination of (i) increased film diffusion resistance; (ii) size exclusion effects; and (iii) electrostatic repulsive forces between the PCBs and the NOM-coated activated carbon. However, the seepage velocities in the SR-NOM fixed bed test were about 1000 times higher than would be expected in a sediment cap. Therefore, additional studies are needed to assess whether the mass transfer limitations described here would be likely to manifest themselves at the lower seepage velocities observed in practice. PMID- 20830925 TI - Enhanced degradation and soil depth effects on the fate of atrazine and major metabolites in Colorado and Mississippi soils. AB - The aim of this report is to inform modelers of the differences in atrazine fate between s-triazine-adapted and nonadapted soils as a function of depth in the profile and to recommend atrazine and metabolite input values for pesticide process submodules. The objectives of this study were to estimate the atrazine mineralizing bacterial population, cumulative atrazine mineralization, atrazine persistence, and metabolite (desethylatrazine [DEA], deisopropylatrazine [DIA], and hydroxyatrazine [HA]) formation and degradation in Colorado and Mississippi s triazine-adapted and nonadapted soils at three depths (0-5, 5-15, and 15-30 cm). Regardless of depth, the AMBP and cumulative atrazine mineralization was at least 3.8-fold higher in s-triazine-adapted than nonadapted soils. Atrazine half-life (T1/2) values pooled over nonadapted soils and depths approximated historic estimates (T1/2 = 60 d). Atrazine persistence in all depths of s-triazine-adapted soils was at least fourfold lower than that of the nonadapted soil. Atrazine metabolite concentrations were lower in s-triazine-adapted than in nonadapted soil by 35 d after incubation regardless of depth. Results indicate that (i) reasonable fate and transport modeling of atrazine will require identifying if soils are adapted to s-triazine herbicides. For example, our data confirm the 60 d T1/2 for atrazine in nonadapted soils, but a default input value of 6 d for atrazine is required for s-triazine adapted soils. (ii) Literature estimates for DEA, DIA, and HA T1/2 values in nonadapted soils are 52, 36, and 60 d, respectively, whereas our analysis indicates that reasonable T1/2 values for s triazine-adapted soils are 10 d for DEA, 8 d for DIA, and 6 d for HA. (iii) An estimate for the relative distribution of DIA, DEA, and HA produced in nonadapted soils is 18, 72, and 10% of parent, respectively. In s-triazine-adapted soils, the values were 6, 23, and 71% for DIA, DEA, and HA, respectively. The effects of soil adaptation on metabolite distribution need to be confirmed in field experiments. PMID- 20830926 TI - Rapid identification of oil-contaminated soils using visible near-infrared diffuse reflectance spectroscopy. AB - In the United States, petroleum extraction, refinement, and transportation present countless opportunities for spillage mishaps. A method for rapid field appraisal and mapping of petroleum hydrocarbon-contaminated soils for environmental cleanup purposes would be useful. Visible near-infrared (VisNIR, 350-2500 nm) diffuse reflectance spectroscopy (DRS) is a rapid, nondestructive, proximal-sensing technique that has proven adept at quantifying soil properties in situ. The objective of this study was to determine the prediction accuracy of VisNIR DRS in quantifying petroleum hydrocarbons in contaminated soils. Forty-six soil samples (including both contaminated and reference samples) were collected from six different parishes in Louisiana. Each soil sample was scanned using VisNIR DRS at three combinations of moisture content and pretreatment: (i) field moist intact aggregates, (ii) air-dried intact aggregates, (iii) and air-dried ground soil (sieved through a 2-mm sieve). The VisNIR spectra of soil samples were used to predict total petroleum hydrocarbon (TPH) content in the soil using partial least squares (PLS) regression and boosted regression tree (BRT) models. Each model was validated with 30% of the samples that were randomly selected and not used in the calibration model. The field-moist intact scan proved best for predicting TPH content with a validation r2 of 0.64 and relative percent difference (RPD) of 1.70. Because VisNIR DRS was promising for rapidly predicting soil petroleum hydrocarbon content, future research is warranted to evaluate the methodology for identifying petroleum contaminated soils. PMID- 20830927 TI - NASA-modified precipitation products to improve USEPA nonpoint source water quality modeling for the Chesapeake Bay. AB - The USEPA has estimated that over 20,000 water bodies within the United States do not meet water quality standards. One of the regulations in the Clean Water Act of 1972 requires states to monitor the total maximum daily load, or the amount of pollution that can be carried by a water body before it is determined to be "polluted," for any watershed in the United States (Copeland, 2005). In response to this mandate, the USEPA developed Better Assessment Science Integrating Nonpoint Sources (BASINS) as a decision support tool for assessing pollution and to guide the decision-making process for improving water quality. One of the models in BASINS, the Hydrological Simulation Program-Fortran (HSPF), computes continuous streamflow rates and pollutant concentration at each basin outlet. By design, precipitation and other meteorological data from weather stations serve as standard model input. In practice, these stations may be unable to capture the spatial heterogeneity of precipitation events, especially if they are few and far between. An attempt was made to resolve this issue by substituting station data with NASA-modified/NOAA precipitation data. Using these data within HSPF, streamflow was calculated for seven watersheds in the Chesapeake Bay Basin during low flow periods, convective storm periods, and annual flows. In almost every case, the modeling performance of HSPF increased when using the NASA-modified precipitation data, resulting in better streamflow statistics and, potentially, in improved water quality assessment. PMID- 20830928 TI - Nutrients in runoff from a furrow-irrigated field after incorporating inorganic fertilizer or manure. AB - Use of dairy manure to supply crop nutrients is gaining broader acceptance as the cost of fertilizer rises. However, there are concerns regarding manure's effect on water quality. In 2003 and 2004, we measured sediment, NO3-N, NH4-N, K, dissolved reactive P (DRP), and total P (TP) concentrations in runoff from furrow irrigated field plots (6-7 irrigations yr(-1)) cropped to corn (Zea mays L.) in the semiarid climate of southern Idaho. Annual treatments included 13 (Year 1) and 34 Mg ha(-1) (Year 2) stockpiled dairy manure (M); 78 (Year 1) and 195 kg N ha(-1) (Year 2) inorganic N fertilizer (F); or control-no amendment (C). Available N in manure applied each year was similar to amounts applied in fertilizer. Constituent concentrations (mg L(-1)) in runoff ranged widely among all treatments: sediment, 10 to 50,000; NO3-N, 0 to 4.07; NH4-N, 0 to 2.28; K, 3.6 to 46.4; DRP, 0.02 to 14.3; and TP, 0.03 to 41.5. Over both years, fertilizer and manure treatments increased irrigation mean values (averaged across irrigations) for NO3-N runoff concentrations (M = 0.30, F = 0.26, C = 0.21 mg L( 1)) and mass losses (M = 0.50, F = 0.42, C = 0.33 kg ha(-1)) relative to the control. Over both years, the manure treatment also increased mean irrigation runoff concentrations of DRP (M = 0.19, F = 0.09, C = 0.08 mg L(-1)) and K (M = 1.13, F = 0.79, C = 0.62 mg L(-1)) compared with fertilizer and control plots. Average DRP and K runoff mass losses were 2.0 to 2.4 times greater in manure treatments than in control plots. Neither F or M affected season-long cumulative infiltration. Runoff DRP and inorganic-N losses appeared to be influenced more by the timing of the amendment application and environmental conditions than by the quantity of nutrients applied. Nutrient additions to furrow irrigated soils, whether from fertilizer or manure, can potentially increase nutrient losses in irrigation runoff, with the degree of impact depending on the nutrient, amount, and timing of application and whether inorganic fertilizer or manure was applied. PMID- 20830929 TI - Order of functionality loss during photodegradation of aquatic humic substances. AB - The time course photodegradation of the Nordic aquatic fulvic and humic acids and Suwannee River XAD-4 acids subjected to UV irradiation with an unfiltered medium pressure mercury lamp was studied by liquid-state 13C nuclear magnetic resonance. Photodecarboxylation was a significant pathway in all cases. Decreases in ketone, aromatic, and O-alkyl carbons were observed throughout the course of the irradiations, whereas C-alkyl carbons resisted photodegradation. Peaks attributable to the low-molecular-weight photodegradation products bicarbonate, formate, acetate, and succinate grew in intensity with irradiation time. The final products of the irradiations were decarboxylated, hydrophobic, predominantly C-alkyl and O-alkyl materials that were resistant to further photodegradation. The total amount of carbon susceptible to loss appeared to be related mainly to the total concentration of carbonyl and aromatic carbons and partly to the concentration of O-alkyl carbons in the fulvic, humic, and XAD-4 acids. The carbon losses for Nordic fulvic, Nordic Humic, Suwannee fulvic, and Suwannee XAD-4 acids were estimated to be 75, 63, 56, and 17%, respectively. More detailed analyses of the effects of irradiation on the carbonyl functionality in Nordic humic acid and Laurentian soil fulvic acid through reaction with hydroxylamine in conjunction with 15N nuclear magnetic resonance analysis confirmed preferential photodegradation of the quinone/hydroquinone functionality over ketone groups and the loss of ester groups in Laurentian fulvic acid. PMID- 20830930 TI - Predicting water quality in unmonitored watersheds using artificial neural networks. AB - Land use and land cover (LULC) play a central role in fate and transport of water quality (WQ) parameters in watersheds. Developing relationships between LULC and WQ parameters is essential for evaluating the quality of water resources. In this paper, we present an artificial neural network (ANN)-based methodology to predict WQ parameters in watersheds with no prior WQ data. The model relies on LULC percentages, temperature, and stream discharge as inputs. The approach is applied to 18 watersheds in west Georgia, United States, having a LULC gradient and varying in size from 2.96 to 26.59 km2. Out of 18 watersheds, 12 were used for training, 3 for validation, and 3 for testing the ANN model. The WQ parameters tested are total dissolved solids (TDS), total suspended solids (TSS), chlorine (Cl), nitrate (NO3), sulfate (SO4), sodium (Na), potassium (K), total phosphorus (TP), and dissolved organic carbon (DOC). Model performances are evaluated on the basis of a performance rating system whereby performances are categorized as unsatisfactory, satisfactory, good, or very good. Overall, the ANN models developed using the training data performed quite well in the independent test watersheds. Based on the rating system TDS, Cl, NO3, SO4, Na, K, and DOC had a performance of at least "good" in all three test watersheds. The average performance for TSS and TP in the three test watersheds were "good." Overall the model performed better in the pastoral and forested watersheds with an average rating of "very good." The average model performance at the urban watershed was "good." This study showed that if WQ and LULC data are available from multiple watersheds in an area with relatively similar physiographic properties, then one can successfully predict the impact of LULC changes on WQ in any nearby watershed. PMID- 20830931 TI - Estimating catchment vulnerability to diffuse herbicide losses from hydrograph statistics. AB - The prediction of diffuse herbicide losses to surface waters using process-based models is data and time demanding. There is a need for simpler and more efficient catchment screening tools. We developed and tested a new proxy for screening catchments for their vulnerability to diffuse herbicide losses relying on widely available river flow data only. The proxy combines the fast flow index (FFI) (i.e., the long-term average proportion of fast flow to total discharge) and the fast flow volume (FFVs) (i.e., the stormflow component of the hydrograph during the spring flush period). We tested the proxy and the underlying hypotheses by regression analyses of existing high-frequency, multiannual monitoring datasets of atrazine, metolachlor, alachlor, and acetochlor concentrations from six US and European catchments. The percentages of applied amounts of three of the four herbicides lost to surface water were positively correlated with the FFV, and the slope of the correlation was positively correlated with the FFI. Based on the empirical data, we derived quantitative proxies to estimate atrazine and metolachlor losses based on the measured FFI and FFV values. The application to 65 European catchments revealed that many of them had a lower vulnerability than the six test catchments. The observed FFI dependency of the slope seems reasonable because with increasing FFI less rain is needed to trigger fast flow and more herbicide is available in the topsoil. The proposed FFI-FFVs proxy can guide researchers and authorities in selecting monitoring areas, setting monitoring results into context, and prioritizing mitigation strategies according to catchment vulnerability. PMID- 20830932 TI - Fate of two herbicides in zero-tension lysimeters and in field soil. AB - In Germany, zero-tension lysimeters are used as part of the registration requirements in case pesticides pose a potential threat to contaminate the groundwater. However, the water regime and the method of pesticide sampling differ between the lysimeters and the field. We monitored the transport of the two herbicides ethidimuron [1-(5- ethylsulfonyl-1,3,4-thiadiazol-2-yl)-1,3 dimethylurea] (ETD) and methabenzthiazuron [1-benzothiazol-2-yl-1,3-dimethyl urea] (MBT) and their main metabolite, accompanied with bromide as conservative tracer, in zero-tension lysimeters filled with undisturbed soil and in the field. The herbicides were applied as a short pulse to the bare soil surface. Herbicide concentrations were analyzed in the drainage water of the 1.2-m-deep lysimeters and from soil cores taken from the field during six campaigns. Soil coring in the field emphasized matrix flow and allowed us to estimate the field-based dissipation and sorption parameters. Based on mass recovery calculations, the field fate half-life was 870 d for ETD compared with 389 d for its main metabolite. The initially fast field-based dissipation of MBT with a half-life value of approximately 1 mo was followed by a much slower dissipation. The retardation factor was estimated from the concentration profiles by inversely solving the convection-dispersion equation and yielded 18.2 +/- 1.3 for ETD and 36.9 +/- 17.5 for MBT. For the lysimeters, a leaching period of 2 1/2 yr was too short to monitor bulk herbicide mass through the soil matrix. Only 1.7% of the applied EDT and 1.4% of the applied MBT were sampled in the drainage water at 1.2 m depth. Despite contrasting sorption and dissipation properties, both herbicides appeared fast and at the same time in the drainage water, hinting at preferential flow phenomena. Compared with field fate of herbicides measured by soil coring, zero-potential lysimeters emphasize the transport of small amounts of herbicides triggered by preferential flow events. PMID- 20830933 TI - Chemistry and transport of metals from entrenched biosolids at a reclaimed mineral sands mining site. AB - Deep row incorporation of biosolids is an alternative land treatment method whose typically high rates may result in elevated pollutant transport. The objectives of this research were to compare the effects of entrenched biosolids stabilization type and rate on heavy metal chemistry and mobility. Two rates each of Alexandria (Virginia) Sanitation Authority anaerobically digested (213 and 426 dry Mg ha(-1)) and Blue Plains (Washington, DC) lime-stabilized (329 and 657 dry Mg ha(-1)) biosolids were placed in trenches at a mineral sands mine reclamation site in Dinwiddie County, Virginia, in summer 2006. Vertical and lateral transport of heavy metals from the biosolids seams were determined by analyzing leachate collected in zero tension lysimeters below the trenches and suction lysimeters adjacent to the trenches. Silver, Cd, Pb, and Sn did not move vertically or laterally to any significant extent. During the 15-mo period following entrenching, lime-stabilized biosolids produced higher cumulative metal mass transport for Cu (967 g ha(-1)), Ni (171 g ha(-1)), and Zn (1027 g ha(-1)) than did the anaerobically digested biosolids and control. Barium mass loss was similar for both biosolids. All metals moved primarily with particulates. MINTEQA) predicted that > 70% of Cu was bound to fulvic acids, whereas > 80% of Ba was found as Ba2+. As pH decreased with time, free ions of Zn decreased and the metal's association with fulvic acids increased. Largely insignificant transport of metals into the lysimeters demonstrated that biosolids-borne heavy metals posed little risk to groundwater even when entrenched in very coarse textured soil. PMID- 20830934 TI - Maximizing ammonium nitrogen removal from solution using different zeolites. AB - Zeolite minerals are ideal for removing ammonium nitrogen (NH4(+)-N) from animal wastes, leachates, and industrial effluents. The objectives of this study were to compare NH4+ removal and kinetics among several commercially available zeolites under various conditions and determine if calorimetry could provide information regarding kinetics of NH4+ removal. Ammonium sorption onto potassium (K) saturated zeolites was compared using synthetic vs. natural swine effluent and with either traditional batch-shaken system or a "tea bag" approach in which zeolites were contained in a mesh sack and suspended in a solution of swine effluent. Ammonium sorption was measured at four retention times using a flow through system, and the resulting heat response was measured using isothermal calorimetry. Ammonium removal was not significantly different in synthetic vs. natural swine effluent. Ammonium removal was lower in batch-stirred compared to batch-shaken systems, suggesting that diffusion between particles was rate limiting in the former system. Flow-through cells possessing contact times > 100 s displayed greater NH4+ sorption than batch systems, suggesting that maintaining high NH4+ concentration in solution, removal of exchange products, and sufficient reaction time are critical to maximizing NH4+ removal by zeolites. Within 100 s after NH4+ addition, endothermic heat responses indicated that NH4(+)-K+ exchange had peaked; this was followed by significant heat rate reduction for 50 min. This confirmed findings of an initial fast NH4(+)-K+ exchange followed by a slower one and suggests the 100-s period of rapid reaction is an indicator of the minimum flow through retention time required to optimize NH4+ sorption to zeolites used in this study. PMID- 20830935 TI - Pyrolysis-gas chromatography/mass spectrometry identification of distinctive structures providing humic character to organic materials. AB - Flash pyrolysis-gas chromatography/mass spectrometry(Py-GC/MS) was used to study the structural transformations of humic fractions formed as a result of composting processes of diverse organic materials (solid wastes of wineries, solid olive-mill wastes, domestic wastes, ovine manures plus straw, and mixtures of animal manures). Sodium hydroxide-extracted total humic-like extracts (THE; humic plus fulvic acids) from the composted and the initial noncomposted wastes and several reference humic and fulvic acids from soils were analyzed. These results were compared with results from previous studies using 13C-cross polarization magic angle spinning-nuclear magnetic resonance (NMR), UV-visible, and fluorescence emission spectroscopies. Alkylbenzenes and alkylphenols predominate in the pyrograms of the soil humic acids, whereas the fulvic acids showed higher contents of phenolic and polysaccharide-derived compounds. The pyrolysates of THE from the composted samples showed an increase in aromatic and nitrogenated structures and a decrease in polysaccharide-derived compounds. The aromatic contents as determined by Py-GC/MS and 13C-NMR were well correlated in the reference humic substances and THE from composted materials (r = 0.99 and 0.94, respectively; P < 0.01) but not in the case of THE from noncomposted materials, probably due to an aliphatic enhancement in the pyrolysates of these samples and other secondary reactions. The content in alkylbenzenes was consistent with the variations found previously for several UV-visible and fluorescence indexes as a function of the degree of humification, suggesting their involvement in structures that are a characteristic feature of the formation and evolution of humic substances. PMID- 20830936 TI - Manure odor potential and Escherichia coli concentrations in manure slurries of feedlot steers fed 40% corn wet distillers grains. AB - This study evaluated feeding 0 and 40% wet distillers grains with solubles (WDGS) diets to cattle and the effects on feedlot manure collected from soil-based pens and incubated for 28 d. Steers (n = 603; 261 +/- 32 kg) were fed in eight pens (15 x 150 m) of 75 to 77 steers per pen. Two consecutive experiments were conducted with WDGS--one in which the corn source fed with WDGS was high-moisture and one in which WDGS was fed with dry-rolled corn. We compared odorants (volatile fatty acids [VFAs], aromatic compounds, NH3, H2S) and persistence of Escherichia coli in feedlot manure slurries stored from 0 to 28 d. From both experiments, manure collected from cattle fed 40% WDGS had lower (P < 0.05) total VFAs, including acetate, propionate, and butyrate, all of which continued to be lower to 28 d. However, these slurries had greater concentrations (P < 0.05) of branched-chained VFAs (isobutyrate and isovalerate), especially after 14 d of incubations. Similarly, p-cresol and skatole concentrations tended to be greater in slurries originating from 40% WDGS diets and increased with incubation time. Indole was initially greater in the slurries from 40% WDGS diets; however, it was metabolized by microbes during incubation. Manure slurries from the 40% WDGS diets had greater quantities of H2S, NH3, and P (P < 0.05). Levels of E. coli in 0 and 40% WDGS manure slurries were similar when high-moisture corn was used in the diets. However, when dry-rolled corn was used, E. coli persisted longer in 40% WDGS manure slurries in comparison to 0% WDGS. Results here support earlier studies that suggest feeding WDGS increases odor emissions, N loss, E. coli survival, and surface water contamination due to greater potential P runoff. PMID- 20830937 TI - Denitrification: an important pathway for nitrous oxide production in tropical mangrove sediments (Goa, India). AB - Net nitrous oxide production and denitrification activity were measured in two mangrove ecosystems of Goa, India. The relatively pristine site Tuvem was compared to Divar, which is prone to high nutrient input. Stratified sampling at 2-cm intervals within the 0- to 10-cm depth range showed that N2O production at both the locations decreased with depth. Elevated denitrification activity at Divar resulted in maximum production of up to 1.95 nmol N2O-N g(-1) h(-1) at 2 to 4 cm, which was three times higher than at Tuvem. Detailed investigations to understand the major pathway contributing to N2O production performed at Tuvem showed that incomplete denitrification was responsible for up to 43 to 93% of N2O production. Nitrous oxide production rates closely correlated to nitrite concentration (n = 15; r = -0.47; p < 0.05) and denitrifier abundance (r = 0.55; p < 0.05), suggesting that nitrite utilization by microbial activity leads to N2O production. Nitrous oxide production through nitrification was below detection, affirming that denitrification is the major pathway responsible for production of the greenhouse gas. Net N2O production in these mangrove systems are comparatively higher than those reported from other natural estuarine sediments and therefore warrant mitigation measures. PMID- 20830938 TI - Soil phosphorus forms in hydrologically isolated wetlands and surrounding pasture uplands. AB - Newly created and restored wetlands play an important role in sequestering excess nutrients at the landscape scale. In evaluating the long-term efficacy of nutrient management strategies to increase wetland capacity for sequestering P, information is needed on the forms of P found across the upland-wetland transition. To assess this, we studied soils (0-10 cm) from four wetlands within cow-calf pastures north of Lake Okeechobee, FL. Wetlands contained significantly (P < 0.05) greater concentrations of organic matter (219 g C kg(-1)), total P (371 mg P kg(-1)), and metals (Al, Fe) relative to surrounding pasture. When calculated on an aerial basis, wetland surface soils contained significantly greater amounts of total P (236 kg ha(-1)) compared with upland soils (114 kg ha( 1)), which was linked to the concomitant increase in organic matter with increasing hydroperiod. The concentration of P forms, determined by extraction with anion exchange membranes, 1 mol L(-1) HCl, and an alkaline extract (0.25 mol L(-1) NaOH and 50 mmol L(-1) ethylenediaminetetraacetic acid [EDTA]) showed significant differences between uplands and wetlands but did not alter as a proportion of total P. Speciation of NaOH-EDTA extracts by solution 31P nuclear magnetic resonance spectroscopy revealed that organic P was dominated by phosphomonoesters in both wetland and pasture soils but that myo-inositol hexakisphosphate was not detected in any sample. The tight coupling of total C and P in the sandy soils of the region suggests that the successful management of historically isolated wetlands for P sequestration depends on the long-term accumulation and stabilization of soil organic matter. PMID- 20830939 TI - Additional comments on"Synthetic nitrogen fertilizers deplete soil nitrogen: a global dilemma for sustainable cereal production," by R.L. Mulvaney, S.A. Khan, and T.R. Ellsworth in the Journal of Environmental Quality 2009 38:2295-2314. PMID- 20830940 TI - Lost knowledge. PMID- 20830941 TI - Opportunities for engagement: seeing with new eyes. PMID- 20830942 TI - Intra-operative hemodialysis during liver transplantation: an expanded role of the nephrology nurse. AB - Hemodialysis is widely acknowledged as a treatment option to stabilize acute medical conditions where biochemistry management is paramount. One of the most challenging situations is during liver transplantation, when patients with moderate renal dysfunction are likely to become acutely acidotic. For nephrology nurses, this extended role requires increased knowledge, advanced skills, and a high level of communication with unfamiliar team members. With appropriate procedures and a supportive environment, delivering such a service is feasible. PMID- 20830943 TI - Dialysis during liver transplant surgery. PMID- 20830944 TI - Negotiating living with an arteriovenous fistula for hemodialysis. AB - The purpose of this study was to examine how clients with end stage renal disease on hemodialysis negotiate living with an arteriovenous fistula. A fistula is the preferred access for hemodialysis, and clients must continually monitor and protect their fistula. In this qualitative, ethnographic study, data were collected during fieldwork and semistructured interviews. Constructivism and a cultural negotiation model provided frameworks for the study. Fourteen clients were interviewed; interviews lasted 1.5 to 4 hours. Results revealed new insights into informants'perspectives and experiences with a vascular access. The overarching theme was vulnerability, and underlying themes were body awareness, dependency, mistrust, and stigma. The response to vulnerability was to be continually vigilant and assertive to protect the holistic self Stigma of the vascular access was an important issue for informants and evoked the greatest emotional responses. PMID- 20830945 TI - The End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ): testing the psychometric properties in patients receiving in-center hemodialysis. AB - Reported treatment adherence rates of patients with end stage renal disease (ESRD) have been extremely varied due to lack of reliable and valid measurement tools. This study was conducted to develop and test an instrument to measure treatment adherence to hemodialysis (HD) attendance, medications, fluid restrictions, and diet prescription among patients with ESRD. This article describes the methodological approach used to develop and test the psychometric properties (such as reliability and validity) of the 46-item ESRD-Adherence Questionnaire (ESRD-AQ) in a cohort of patients receiving maintenance HD at dialysis centers in Los Angeles County. The ESRD-AQ is the first self-report instrument to address all components of adherence behaviors of patients with ESRD. The findings support that the instrument is reliable and valid and is easy to administer. Future studies are needed in a larger sample to determine whether additional modifications are needed. PMID- 20830946 TI - Postpartum plasma exchange in a woman with suspected thrombotic thrombocytopenic purpura (TTP) vs. hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP): a case study. AB - The occurrence of a hypercoagulable state and decreasing concentration of ADAMTS 13 in late pregnancy and during the postpartum period increases the risk for a woman to develop life-threatening thrombotic thrombocytopenic purpura (TTP). This is also the time of great risk for the more common obstetric complications of preeclampsia; eclampsia; and hemolysis, elevated liver functions tests, low platelets (HELLP) syndrome. These conditions are associated with high maternal and perinatal mortality. Differential diagnosis may be difficult due to the overlapping of clinical and laboratory findings, including thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, and renal insufficiency, making it difficult or impossible to distinguish them from TTP. Management of microangiopathic disorders encountered during pregnancy differ; therefore, an accurate diagnosis is required. Outcomes of TTP without plasma exchange therapy (TPE) are almost uniformly fatal. Early recognition and management of symptoms with prompt and aggressive TPE is essential when TTP is suspected. PMID- 20830947 TI - Renal replacement therapy for children: a family decision. AB - Although Anne had many complex health issues and experienced considerable support from her extended family, she wanted freedom from the restrictions posed by peritoneal dialysis. Her quality of life changed after transplantation, with more opportunities to engage in leisure activities, ability to travel, a less restricted diet, and an improved self-image. She required fewer treatments, surgeries, and hospitalizations. She left behind the role of sick child and took up a role more like a healthy child. During the disease and decision-making process, Anne learned coping mechanisms, allowing her to gain autonomy to make decisions. The case study illustrates both the need to listen to children as well as to care for the entire family. The nursing management of this child and her family was continually changing, and multiple strategies were used to support the family. The nurse came to understand the roles of family members in constant change, the sources of their resources, and foci of tensions. Based on this knowledge, the nurse can act by mobilizing resources, strengthening the confidence of family members, and helping them develop coping mechanisms. In conclusion, care of the ill child must be family-centered. Stresses on the family have an impact on the child and vice versa. The potential to influence the quality of life of both the child and the family is considerable. PMID- 20830948 TI - Circling around in tiredness: perspectives of patients on peritoneal dialysis. AB - The experience of tiredness linked to poor sleep in patients on peritoneal dialysis was explored using the qualitative method phenomenology. Eight women and six men in southeast Sweden were interviewed. The patients' descriptions were characterized by a circular structure "circling around in tiredness." This study illustrates the problems of tiredness and illuminates the need for healthcare professionals to assess the impact of tiredness and highlight the need for strategies to improve the patient's situation. PMID- 20830949 TI - Post-kidney transplant rejection and infection complications. AB - The care of a patient after kidney transplant is multifactorial and complex, often involving other organ systems. The clinical picture can frequently be complicated with symptoms that may be misleading, and hence, challenging to assess. The nephrology nurse caring for the recipient of a transplant should be able to assess the entire clinical situation, rather than focus only on renal function. When caring for recipients of transplants, nephrology nurses need to use their extensive knowledge base and employ critical thinking skills. Although all members of the multidisciplinary team are important for success, the patient remains the focal point of the team. Post-transplant management will be successful when patients actively participate in their care. Patient teaching plays a critical role in this success, and it starts when a transplant is anticipated and continues as long as the grafted kidney is functioning. PMID- 20830950 TI - How do you prevent indented buttonhole sites? PMID- 20830951 TI - Vitamin D in chronic kidney disease--new insights. PMID- 20830952 TI - Domestic violence screening in a military setting: provider screening and attitudes. AB - Domestic violence is an important healthcare problem, and it appears more prevalent in military patient populations although no one has demonstrated the cause behind this phenomenon. The purpose of this observational study was to assess data regarding domestic violence screening from practitioners at one military training center. This study used an anonymous questionnaire for physicians, nurses and nurse midwives, which surveyed current methods, attitudes toward screening, and barriers for such assessment. Fifty-seven surveys were distributed, and 26 were returned for a response rate of 45.6%. Only about a third (38.5%) of the practitioners screened all obstetric patients while the remainder screened selected patients for domestic violence. Even less (19%) screened gynecology patients routinely, whereas 69% reported they screened selected women with chronic or somatic complaints. A history of prior abuse in the respondents led practitioners to try to identify such patients within their practice. Lack of education or training was the most common barrier to universal screening followed by time constraints and frustration about not being able to address adequately the problem when noted. These results emphasized the importance of an educational program to increase domestic violence awareness and routine screening. PMID- 20830953 TI - An interview with Timothy J. Alford, MD. 2010-2011 MSMA president. Interview by Karen A Evers. PMID- 20830954 TI - I wish you hearts that race, minds that dream... PMID- 20830955 TI - Culture and sensitivity: part 1. "Adventures with Juan and Bud". PMID- 20830956 TI - Management of the substernal goiter: a team approach. AB - OBJECTIVES: Review the diagnosis and management of patients with substernal goiter. STUDY DESIGN: Retrospective study of a series of patients treated for substernal goiter. METHODS: Retrospective chart review of patients with substernal goiter (N=16). Records were tabulated for demographics, symptoms, physical and CT findings as well as surgical management and comorbidities. RESULTS: Substernal goiter occurs infrequently. Of the seventeen surgical procedures performed in these sixteen patients, only three required a median sternotomy. All of the patients had multinodular goiter. There were no instances of well differentiated thyroid cancer in this series. Co-morbidities were present in each patient. CONCLUSIONS: Substernal goiters are often quite large at the time of diagnosis as they enlarge slowly. The majority of patients can be managed with a cervical approach. Technological advancements such as the nerve integrity monitor (NIM-2; Medtronic Xomed, Jacksonville, Florida) and Harmonic scalpel as well as team approach to surgery are advantageous for the patient. PMID- 20830957 TI - Now you see it, now you don't. PMID- 20830958 TI - Inaugural address of the 143rd MSMA president. PMID- 20830959 TI - Address of the MSMA president 2009-2010 S. Randy Easterling, MD. PMID- 20830960 TI - Dr. Frothingham named recipient of the A. A. Derrick Physician Quality Award. PMID- 20830961 TI - Parental expectations and outcomes of pediatric cochlear implantation. AB - BACKGROUND: Cochlear implants have been used with increasing frequency over the past twenty years, including very young patients. OBJECTIVE: To determine if parents are satisfied with their children's performance after cochlear implantation. DESIGN: Survey mailed to parents of children receiving cochlear implants. RESULTS: 31 questionnaires were returned out of 69 mailed (45 %). The vast majority of responding parents felt that their children benefited substantially from cochlear implant surgery. CONCLUSION: Cochlear implantation is effective in helping children develop auditory-oral communication skills. Access to auditory/oral communication programs in this state remains an obstacle in postoperative habilitation. PMID- 20830962 TI - Mississippi burnout part II: satisfaction, autonomy and work/family balance. AB - Documented Mississippi physician shortages' make evidence about factors shaping physicians' career choices especially important if Mississippi policymakers are to devise workable strategies to maximize the physician workforce. Work-life interactions influence physicians' choices about how they manage their careers and professional burnout is one documented cause of physicians' decisions to change work hours or to choose early retirement. We find that women and mid career physicians are more likely than men or later career physicians to experience stress and burnout. Additionally, physicians who experience burnout are less likely to report being satisfied with nearly every aspect of their professional life and work-life balance indicating that burnout permeates several dimensions of physicians' lives. The associations in our findings are suggestive; however, to minimize deleterious effects of burnout on the Mississippi physician workforce, future research should examine the causal factors underlying stress and burnout. PMID- 20830963 TI - A hole in one. PMID- 20830964 TI - We need to reform healthcare reform. PMID- 20830965 TI - More than just drainage. PMID- 20830966 TI - ED utilization by Medicaid beneficiaries. PMID- 20830967 TI - Exploring neurogenesis outside the niche: atypical locations of mammalian neural stem/progenitor cells. PMID- 20830968 TI - Stem cells and their niche in the adult olfactory mucosa. AB - It is well known that new neurons are produced in the adult brain, in the hippocampus and in the subventricular zone. The neural progenitors formed in the subventricular zone migrate forward and join in neural circuits as interneurons in the olfactory bulb, the target for axons from the olfactory sensory neurons in the nose. These neurons are also continually replaced during adulthood from a stem cell in a neurogenic niche in the olfactory epithelium. The stem cell responsible can regenerate all the cells of the olfactory epithelium if damaged by trauma or toxins. This stem cell, the horizontal basal cell, is in a niche defined by the extra cellular matrix of the basement membrane as well as the many growth factors expressed by surrounding cells and hormones from nearby vasculature. A multipotent cell has been isolated from the olfactory mucosa that can give rise to cells of endodermal and mesodermal origin as well as the expected neural lineage. Whether this is an additional stem cell or the horizontal basal cell is still an open question. PMID- 20830969 TI - A decade of mammalian retinal stem cell research. AB - Ten years have now passed since the discovery of quiescent neural stem cells within the mammalian retina. Beside the fascinating aspect of stem cell biology in basic science, these cells have also offered hope for the treatment of incurable retinal diseases. The field has thus rapidly evolved, fluctuating between major advances and recurring doubts. In this review, we will retrace the efforts of scientists during this last decade to characterize these cells and to use them in regenerative medicine. We will also highlight advances made in animal models capable of stem cell-mediated retinal regeneration. PMID- 20830970 TI - Neurogenesis in the enteric nervous system. AB - The enteric nervous system (ENS) represents the highly organized intrinsic innervation of the gastrointestinal tract and plays a critical role for all stages of postnatal life. Severe disturbances of ENS function can significantly influence life quality or, in severe cases, can have acute life-threatening effects. Recent in vitro and in vivo studies demonstrated the persistence of neural stem cells in postnatal gut and there seem to be many interesting parallels to the more extensively studied neural stem cells in the brain. Enteric stem cells have been proposed as an appropriate cell source to provide an alternative therapeutic option for a number of neurogastrointestinal diseases, however a better understanding of these cells would be crucial for the translation of cell-based therapies into clinic. This review tries to highlight the recent findings in the field of enteric neurogenesis and additionally gives a brief overview about the development, structure and function of the ENS and about the developmental or age-related disturbances affecting the ENS. PMID- 20830971 TI - Exploring atypical locations of mammalian neural stem cells: the human filum terminale. AB - Neurogenesis is a multifactorial event determined by local environmental cues, inherent cellular program as well as cellular milieu and may not necessarily be restricted to the SVZ and SGZ. NSCs have been isolated from or neurogenesis has been demonstrated in traditionally non neurogenic regions. This more permissive view of neurogenesis, however, is not widely accepted due to concerns regarding the methodologies used. Furthermore, it is compounded by the fact that the basal levels of increased neurogenesis in such regions has not been completely confirmed and thus precludes a paradigm shift. Were this non limited view of neurogenesis to be generally accepted after thorough investigation, it would open new avenues for regenerative medicine and stem cell therapy. PMID- 20830972 TI - The carotid body, a neurogenic niche in the adult peripheral nervous system. AB - We have described a new population of adult neural stem cells residing in the carotid body, a chemoreceptor organ in the peripheral nervous system. These progenitor cells support neurogenesis in vivo in response to physiological stimuli like hypoxemia, and give rise to multipotent neurospheres in culture. Studying the biology of CB stem cells helps to understand the physiological adaptations of the organ, and might shed light on the pathogenesis of CB tumors. Understanding proliferation and differentiation of these cells will enable their use for cell therapy against neurodegenerative diseases. PMID- 20830974 TI - Glial cells in non-germinal territories: insights into their stem/progenitor properties in the intact and injured nervous tissue. AB - In the adult murine central nervous system (CNS), the germinal astroglia residing in the subependymal zone of the lateral ventricles and in the subgranular layer of the hippocampal dentate gyrus behaves as neural stem cells actively undergoing neurogenesis and gliogenesis. Although neurogenesis does not normally occur outside the germinal niches, two types of parenchymal glial cells, namely astrocytes and NG2-expressing cells, display distinct progenitor activities in the intact brain or upon injury. Importantly, in defined experimental conditions both cell types reveal the potential to behave as multipotent stem cells suggesting that the mature CNS parenchyma may retain a latent stem cell potential, normally inhibited in vivo that, if properly evoked, might be exploited in situ for endogenous cell replacement following injury. In this review we scrutinise recent studies focussing on (i) the molecular and functional relationships between precursors in germinal niches and non-germinal areas; (ii) the ability of adult parenchymal glia to undergo lineage transgressions and neurogenesis in the intact brain and upon CNS injury. We also compare evidence for lineage plasticity in astrocytes or NG2+ cells, and discuss possible approaches for the implementation of stem/progenitor cell capabilities in non germinal glial cells. PMID- 20830975 TI - The prospective white matter: an atypical neurogenic niche in the developing cerebellum. AB - Cerebellar GABAergic interneurons comprise heterogeneous phenotypes located at strategic levels of the local networks. Recent findings indicate that they all derive from a common population of multipotent progenitors whose fate choices are determined by instructive information provided by the PWM environment. Here we review about the atypical neurogenic strategy operated within such postnatal niche and we discuss possible instructive mechanisms governing interneuron specification and differentiation. PMID- 20830973 TI - Taste bud regeneration and the search for taste progenitor cells. AB - While the taste periphery has been studied for over a century, we are only beginning to understand how this important sensory system is maintained throughout adult life. With the advent of molecular genetics in rodent models, and the upswing in translational approaches that impact human patients, we expect the field will make significant advances in the near future. PMID- 20830976 TI - Adult neurogenesis without germinal layers: the "atypical" cerebellum of rabbits. AB - Unlike non mammalian vertebrates, adult neurogenesis in mammals is detectable in highly restricted brain sites. Persistent neurogenesis is thought to depend on stem cells residing in neural stem cell niches which are remnants of the embryonic germinal layers. Local progenitors which retain some proliferative capacity have been identified in the mature brain parenchyma, yet they do not support a constitutive, 'actual' neurogenesis, but rather a 'potential' neurogenesis which does not extrinsecate fully and spontaneously in vivo. In contrast with such a view, genesis of neuronal and glial cells from local progenitors does occur in the peripuberal and adult rabbit cerebellum. This process is independent from persisting germinal layers and involves different cell populations. PMID- 20830977 TI - "Arrested development". Immature, but not recently generated, neurons in the adult brain. AB - After the division of neuronal precursors, many of the newly generated cells become immature neurons, which migrate to their final destination in the nervous system, extend neurites and make appropriate connections. For most neurons these events occur in a narrow time window and, once in their definitive location, they immediately start the final stages of their differentiation program, remaining immature only for a short time. The main objective of this review is to present and discuss recent data on a peculiar population of cells in the adult brain, which retain an immature neuronal phenotype for an unusually prolonged time. We review and discuss recent evidence on the temporal and spatial origin of these cells, their distribution in rodents and other mammals, their structure and neurochemical phenotype, and their putative fate and function. The review is mainly focused on the population of immature neurons located in the layer II of certain cortical regions, but we will also describe similar populations found in other regions of the peripheral and central nervous systems. PMID- 20830978 TI - Remodelling the injured CNS through the establishment of atypical ectopic perivascular neural stem cell niches. AB - Compelling evidence exists that somatic neural stem/precursor cell (NPC)-based therapies protect the central nervous system (CNS) from chronic inflammation driven degeneration, such as that occurring in experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS), cerebral ischemic/hemorrhagic stroke and spinal cord injury (SCI). However, while it was first assumed that NPC transplants may act through direct replacement of lost/damaged cells, it has now become clear that they are able to protect the damaged nervous system through a number of 'bystander' mechanisms other than the expected cell replacement. In immune-mediated experimental demyelination--both in rodents and non-human primates--others and we have shown that transplanted NPC possess a constitutive and inducible ability to mediate efficient 'bystander' myelin repair and axonal rescue. This novel mechanism(s), which may improve the success of transplantation procedures, is likely to be exerted by undifferentiated NPCs whose functional characteristics are regulated by both CNS-resident and blood-borne inflammatory cells releasing in situ major stem cell regulators. Here, we discuss some of these alternative 'bystander' mechanisms, while pointing at the formation of the atypical ectopic perivascular niches, as the most challenging example of reciprocal biologically sound cross talk between the inflamed microenvironment(s) and transplanted therapeutic NPCs. PMID- 20830979 TI - Twin delivery: comparison of incidence and foetal outcome in two health institutions in Benin City, Nigeria. AB - BACKGROUND: The incidence of twin delivery in Nigeria may have changed, in view of the worldwide increase in the rates of twinning attributed to increasing maternal age and use of fertility therapies. OBJECTIVE: To determine the current incidence of twin delivery in Benin City and document the foetal outcome in twins. METHODS: A four-year descriptive (cross-sectional) study of twin deliveries in a Nigerian mission hospital was conducted. The foetal outcome in 115 sets of twin was compared with that of 230 singleton controls. RESULTS: The current incidence of twin delivery was 25.3 per 1000 deliveries or one in 40 births, representing a reduction by 24.2%. Sex ratio was 0.98 : 1 in favour of females. Seasonal variation was observed in the incidence of twin delivery with a significantly higher incidence in wet than in dry season (p < 0.001). Twin pregnancies are at a significantly higher risk of adverse foetal outcome such as low birth weight (LBW), preterm delivery, birth asphyxia and Caesarean delivery compared to singleton pregnancies (p < 0.001). CONCLUSIONS: Although the incidence of twin delivery remains high in Benin City, it appears to have dropped. Twin pregnancy is associated with increased risk of adverse foetal outcome. PMID- 20830980 TI - Potential health risks due to telecommunications radiofrequency radiation exposures in Lagos State Nigeria. AB - BACKGROUND: The global system mobile telecommunications system (GSM) which was recently introduced in Nigeria is now being used by over 40 million people in Nigeria. The use of GSM is accompanied with exposure of the users to radiofrequency radiation (RFR), which if significant, may produce health hazards. This is the reason why many relevant national and international organizations recommended exposure limits to RFR and why it is made compulsory for GSM handsets to indicate the maximum power output as a guide to potential consumers. OBJECTIVE: This study was conducted to measure the RFR output power densities (S) from the most commonly used GSM handsets used in Lagos State and compare with the limit recommended for safety assessment. METHODS: Over 1100 most commonly used handsets of different makes and models as well as wireless phones were sampled and studied in all over the local government areas of the State. An RFR meter, Electrosmog from LESSEMF USA was used for the measurements. The handsets were assessed for health risks using the reference value of 9 Wm(-2) as recommended by the International Commission on Non-Ionizing Radiation Protection (ICNIRP). RESULTS: The range of the S-values obtained varied from a minimum of 1.294 0.101 Wm(-2) with Siemens model R228 to a maximum of 16.813 +/- 0.094 Wm(-2) with Samsung model C140*. The results from wireless telephones showed very low S values ranging from a minimum of 0.024 +/- 0.001 Wm(-2) with HUAWEI and ST CDMA 1 to a maximum of 0.093 +/- 0.002 Wm(-2) with HISENSE. CONCLUSION: The results showed that the population in Lagos State may be at risk due to significant RFR exposures resulting principally from the use of GSM. Quite a number of handsets emit power above the ICNIRP recommended value. Measured RFR power close to Radio and Television masts and transmitters are within tolerable limits in most cases, only that the public should not reside or work close to RFR installations. Phone calls with GSM should be restricted to essential ones while youths and children that are more susceptible to RFR hazards should be supervised in their use of GSM. Wireless phones are quite safe. PMID- 20830981 TI - Catalase activity, lipid peroxidation, cholesterol and triglyceride levels in alloxan--induced diabetes mellitus in female and male rats. AB - BACKGROUND: Diabetes mellitus is a disorder of carbohydrate metabolism and is associated with oxidative reactions. OBJECTIVE: The present study is to determine the activities of catalase, lipid peroxidation, glucose, protein, cholesterol and triglyceride concentrations in the liver and kidney in alloxan-induced diabetes in female and male rats. In addition, the study is to ascertain if gender differences affect oxidative stress in diabetes. METHODS: Forty male (165 +/- 8.46 g) and female (162.7 +/- 7.94 g) albino Sprague Dawley rats were used for the study. The rats were injected intraperitoneally with a single dose of 150 mg/body weight of alloxan monohydrate, to induce diabetes-for 14 days. The rats were divided into four groups, consisting of 10 diabetic male, 10 non-diabetic male, 10 diabetic female and 10 non-diabetic female. The rats were fed rat chow and water ad libitum for 14 days and then sacrificed by decapitation. Blood was taken by cardiac puncture, while liver and kidney were quickly excised. The catalase activity, lipid peroxidation, glucose, protein, cholesterol and triglyceride concentrations in the liver and kidney of rats were determined. RESULTS: Bats administered alloxan monohydrate had elevated plasma glucose levels. The body weights of diabetic female and male rats were significantly reduced compared to the non-diabetic rats. The catalase activities in liver and kidney of diabetic male or female rats were significantly lower than in non diabetic rats but the reduction was more pronounced in diabetic female rats. The liver lipid peroxidation, cholesterol and triglyceride levels were significantly higher in the diabetic male or female than in the non-diabetic rats, but with no significant differences in the diabetic female or male rats. CONCLUSION: Data of the study indicate that sex differences do not significantly affect oxidative stress in alloxan-induced diabetes mellitus. PMID- 20830982 TI - Antimalarial prescribing patterns in state hospitals and selected parastatal hospitals in Lagos, Nigeria. AB - BACKGROUND: Malaria is a curable and preventable disease and it is a major public health problem in Nigeria. Chloroquine was the first line drug in its treatment in Nigeria until recently where the Artemisinin based Combination Therapies (ACTs) are being promoted. Inappropriate prescribing, i.e., the failure to prescribe drugs in accordance with guidelines based on scientific evidence to ensure safe, effective, and economic use, is an irrational drug use behavior. Increased benefits from chloroquine or a slowdown of progression to resistance could be achieved by improving prescribing practice, drug quality, and patient compliance. OBJECTIVE: To determine the antimalarial prescribing pattern and to assess rational prescribing of chloroquine by prescribers in government hospitals and parastatals in Lagos State. METHODS: The study was carried out in all the ten government General Hospitals under Lagos State Hospitals Management Board (now Lagos State Health Service Commission), one parastatal hospital and one oil company clinic, using patient prescriptions. One hundred prescriptions each for adults and children for each month for a period of one year (January to December 2000) were systematically sampled. Where there were fewer than 100 prescriptions in a month, all the prescriptions available were sampled for analysis. RESULTS: Average number of drugs per encounter in all the hospitals was 4.259 +/- 0.009. Average number of injections per encounter was 1.215 +/- 0.009. About 48.5% of all the presriptions had at least one injection while 40.9% of the prescriptions had dipyrone injection. Average drug cost per encounter was N 147.40 +/- 0.765. Percentage of encounters with chloroquine was 82.5% followed by sulphadoxine pyrimethamine 14.2%. Percentage of prescriptions with correct dose of chloroquine was 47.5% CONCLUSIONS: Polypharmacy exists in all the hospitals. The average number of drugs per encounter for the majority of the hospitals was above 4. Less than half of the prescriptions had the correct dose of chloroquine. This study can serve as a baseline for intervention on irrational prescribing. PMID- 20830983 TI - Analysis of stillbirths in a Nigerian mission hospital. AB - BACKGROUND: In Nigeria, perinatal mortality remains a major health problem with the balance heavily tilted towards the stillbirth component. Knowledge of the relative importance of the different causes of stillbirth is lacking, even in hospital settings. OBJECTIVE: To determine the stillbirth rate in a Nigerian mission hospital and document its risk factors. METHODS: In this retrospective study, the case records of 131 mothers who had stillbirths were studied and the data obtained analyzed. The relevant hospital delivery registers were also examined. RESULTS: Stillbirth rate was 39.7 per 1000 births with 51.9% and 48.1% being macerated and fresh stillbirths respectively. Antepartum haemorrhage, pre eclampsia/ eclampsia and prolonged/obstructed labour were the three leading risk factors for stillbirth. Low birthweight babies were also at increased risk of foetal death. Majority (61.8%) of mothers whose babies were still-born belonged to low social class. CONCLUSION: Our stillbirth rate remains unacceptably high and strategies to reduce it must focus on antenatal and intrapatum emergency obstetric care and early referrals in hospital setting. PMID- 20830984 TI - Pattern of endodontic treatment in children in a Nigerian tertiary hospital. AB - OBJECTIVES: The aim of this study was to determine the frequency and reasons for endodontic treatment in patients aged 16 years and below seen at the Paedodontic clinic of the Department of Child Dental Health of the Lagos University Teaching Hospital. METHODS: Dental records of patients aged 16 years and below treated for various dental problems at the Paedodontic clinic of the Lagos University Teaching Hospital between January 2006 and December 2007 were reviewed to select cases that received endodontic treatment. The survey was conducted to determine the frequency of endodontic treatment for each tooth in the maxilla and mandible, the reasons for endodontic treatment and type of endodontic treatment performed in each tooth. Data on age, sex, endodontically treated teeth, reasons for endodontic treatment and date of treatment was retrieved from the patients' dental records. RESULTS: A total of 2376 patients were seen during the period of survey, out of which 260 (11%) patients received endodontic treatment of three hundred teeth comprising 194 mandibular teeth and 106 maxillary teeth. The primary lower second molar (26%) was the most frequently endodontically treated tooth followed by the permanent lower first molar (22%). All the primary and permanent molars were endodontically treated due to caries while 62.5% and 60% of permanent and primary central incisors respectively were endodontically treated due to caries. The other infrequent reasons for endodontic treatment were trauma (5.3%) and failed root canal treatment (1.3%). CONCLUSION: The primary lower second molar was the most frequently (26%) treated endodontically and the major reason (93.3%) for endodontic treatment was caries. Only 5.3% of the endodontically treated teeth were due to trauma. PMID- 20830985 TI - Home management of malaria by care givers of under-five children in an urban area in Lagos, Nigeria. AB - BACKGROUND: One of the key interventions proposed under the Roll back malaria initiative is improvement of case management of malaria at the home and community levels to reduce malaria burden. This study was conducted to determine the practice and determinants of Home Management of Malaria (HMM) among care givers of children below 5 years old in an urban community in Lagos State, Nigeria. METHODS: This was a cross-sectional study conducted in 2007. A multi-stage sampling method was used to select the 340 respondents who participated in this study. Data was collected using interviewer administered questionnaires and analysed with Epi-info software. A care giver was included in the study if he/she takes care of a child/children less than 5 years old. RESULTS: The commonest treatment practice by caregivers for their young children with malaria was home treatment with antimalarial drugs [51.5%]. HMM was not significantly determined by care givers' age nor educational level. Most children were treated with chloroquine and only a few [4.2%] of the children were treated with the recommended drug [ACT]. Overall, only 1.24% received adequate treatment. CONCLUSION: Few respondents correctly practice HMM. There is need to educate care givers of young children on the proper management of malaria at home. PMID- 20830986 TI - Cigarette smoking among healthcare professional students of University of Lagos and Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos, Nigeria. AB - BACKGROUND: It is a known fact that health professionals can play a critical role in reducing tobacco use. In fact, it has been shown that even brief and simple advice from health care professionals can substantially increase smoking cessation rates. Students in healthcare professions are future healthcare professionals, identifying and documenting their knowledge, attitudes and practices with regards to tobacco smoking would shed light as to their future effectiveness in providing this much needed public health initiative in their practices. OBJECTIVE: This research was carried out to determine cigarette smoking habit among healthcare professional students of University of Lagos and Nursing students of Lagos University Teaching Hospital. METHODS: The study was a cross-sectional descriptive survey. Data was collected by the use of a structured, self administered questionnaire which was aimed at determining their smoking status and their attitudes. The target population was first and final professional year students representing the two class extremes and attempt was made to survey all the students that fell within this identified target population without randomization. Data was collected between March and June 2007. RESULTS: Out of 814 qualified participants, 433 responded to the questionnaire (53%). Smoking prevalence was highest among dental students (8.48%) while both Physiotherapy and Nursing students had nil prevalence rates. Overall, the current smoking prevalence was 3.93%. There was no statistically significant difference between the smoking habits of first year and final year students (p = 0.99). Based on Fagerstrom nicotine addiction test, only a small proportion of the current smokers can be classified as being maximally addicted (6.0%). CONCLUSIONS: From this study it can be concluded that smoking prevalence is low among healthcare professional students at the University of Lagos and this is a good indication that they would play critical role in reducing tobacco use. It is recommended that a tobacco counselling unit should be set up by the school authority. PMID- 20830987 TI - Patient satisfaction: a survey of dental outpatients at the Lagos University Teaching Hospital, Nigeria. AB - BACKGROUND: Patient satisfaction with dental services has received minimal attention in Nigeria. Quality of service is however, an integral part of any business. The study assessed dental outpatients' satisfaction with oral health care delivery a tertiary institution in Nigeria. The perceptions of the oral health care provider and suggestions that will improve service delivery were also obtained from these consumers. METHODS: A modified Dental Satisfaction Questionnaire (DSQ) was used to assess the patients. An aggregate score was also calculated for each respondent for all variables tested under the five items on dental patient satisfaction. The highest possible score was 76, based on the number of items assessed. The cut off point for satisfaction was set at 38. RESULTS: Three hundred patients participated in the study. The items with the top three scores were dentist-patient relationship (respect/listen), rapport and infection control with mean scores of 3.5, 3.4, and 3.3 respectively. The range for the aggregate score for level of satisfaction was 16-68. High level of satisfaction reported in 159 (53%) of the respondents and low level in 141 (47%). Dissatisfaction was expressed with regards to the infrastructure, electricity/regular supply of water and being treated by unsupervised students in 85.7%, 59.5% and 89% respectively. CONCLUSIONS: The overall high level of satisfaction was related to the communication skills and rapport of staff with the patients. There is an urgent need for improvement on infrastructure and provision of a steady supply of water and electricity. PMID- 20830988 TI - Acute oral toxicity test and phytochemistry of some West African medicinal plants. AB - BACKGROUND: Although there is increased acceptance and utilization of medicinal plants worldwide, many are used indiscriminately without recourse to any safety test. Thus, the need for toxicity tests to determine the safe dose for oral consumption. OBJECTIVE: LD50 and phytochemistry of four medicinal plants of West Africa were investigated. METHODS: Thirty male and non pregnant female Swiss albino mice weighing 20grams each were used for this study. They were divided into the Control (C), Oldenlandia corymbosa L. aqueous leaf-extract treated (OCG), Parquetina nigrescens aqueous leaf extract treated (PNG), Hybanthus enneaspermus aqueous leaf extract treated (HEG), Ficus carica leaf extract treated (FCG) and Sesamum indicum aqueous seeds extract treated group (SIG). Each group except the control was further divided into four sub-groups of six mice each, and were administered orally, graded doses (SI; 1, 2, 4 and 8, PN; 2.5, 5, 10 and 20, OC; 5, 10, 20 and 40, FC; 1, 2, 4 and 8, HE; 4, 8, 16, 32) of the aqueous extract of each plant (g/kg body weight) after 12 hours fasting. RESULTS: The dry aqueous leaf extracts of HE, OC, PN, FC all have dark brown colour and pH ranging from 6.1 to 7.2 while the seed extract of SI has a light brown color with pH of 7.0. Flavonoids, cardiac glycosides, anthocyanosides, saponin, and reducing sugar were present in all extracts, while cyanogenic glycoside was present only in HE. LD50 determination results obtained using Thompson and Finney methods were as follows; OC; 14.14 +/- 0.27 and 10.56 +/- 0.20, PN; 12.60 +/- 0.10 and 13.10 +/- 0.10, HE; 8.14 +/- 0.30 and 8.24 +/- 0.35, FC; 3.36 +/- 0.26 and 4.00 +/- 0.04, SI; 4.00 +/- 0.10 and 3.10 +/- 0.22 respectively (LD50 values are in g/kg body weight. CONCLUSION: The results of this study have provided an oral LD50 from where a safe dose can be chosen for further research into the merits of the consumption of these medicinal plants. PMID- 20830989 TI - Coping with oral pain: lay management strategies adopted by patients prior to presentation. AB - OBJECTIVES: To identify lay measures taken by patients in response to oral pain before seeking professional care and to determine factors leading to demand for professional oral health care. METHODS: A cross-sectional survey of patients aged 16 years and above who presented with oral pain at the oral diagnosis clinics of the Lagos University Teaching Hospital and the Lagos State University Teaching Hospital was carried out. Data was collected by means of questionnaires which sought information on onset and duration of pain, character, aggravating and relieving factors and actions taken by the patients before presentation at the dental clinic. RESULTS: A total of 215 patients participated. More than half of them described their pain as severe to very severe with 106 (49.3%) and 21 (9.8%) reporting sleep disruptions and severe agony respectively. Delay in presentation range from over a month in 56 (26%) patients to years in 85 (39.5%). Responses to pain symptoms included, communication with different persons for advice in 192 (89.3%) and application of at least one lay measure in 183 (85.1%) patients. Duration and persistence of pain was associated significantly with the use of more than one measure. There was no association between gender or age and the use of lay measures. Use of measures with possible adverse effects like petrol and acid was reported in 5 (2.7%) of the respondents. CONCLUSION: Lay strategies in response to oral pain are common in this Nigerian population and appear to be used as an alternative to professional oral health care. PMID- 20830990 TI - Obesity prevalence in adult residents of Ile-Ife, Nigeria. AB - BACKGROUND AND PURPOSE: Few data on obesity exist on Sub-Sahara population in Africa. This study investigated the prevalence of obesity and Body Mass Index (BMI) percentile and quartiles in accordance with sex and age in adult residents of the historic ancient semi-urban community of Ile-Ife, South-West, Nigeria. MATERIALS AND METHODS: 2097 adults aged 21 years and above were recruited into the door-to-door survey through a multi-stage cluster sampling technique. The World Health Organization (WHO) criteria based on BMI was used in the definition of overweight and obesity. Height and weight were measured using standardized procedures. RESULTS: The mean age and BMI of the participants were 44.2 years and 24.2 Kg/m2 respectively. Although age-matched; the females had higher BMI values compared to males (23.8 vs. 24.5 Kg/m2). The overall crude prevalence of overweight (25.0-29.9 Kg/m2) and obesity (>30 Kg/m2) were 20.3% and 12.5% respectively. The rates of overweight (17.9 vs. 22.1 Kg/m2) and obesity (9.7 vs. 14.5 Kg/m2) were both higher in women than men. Obesity increased across age gradient from young to old adults; peaking in the 60-69-year age group. The first to fourth BMI quartiles were = 20.4 Kg/m2, 20.5-24.1 Kg/m2, 24.2-25.2 Kg/m2, = 25.3 Kg/ m2 respectively in the study population. At all ages; more females (32.4%) than males (24.7%) were placed within fourth BMI quartile. The 95th percentile BMI in the study population was 33.4 Kg/m2. CONCLUSION: Overweight and obesity are common in Nigerians, particular among females and elderly. The prevalence estimates of overweight and obesity in Nigerians is comparable with prevalence among Blacks in other populations. PMID- 20830991 TI - Maternal and perinatal mortality in ward A, Ikosi-Isheri LCDA in Lagos State, Nigeria: from "guestimates" to near actuals. AB - BACKGROUND: The problem of authentic statistics on maternal and peri-natal mortality has persisted in Nigeria probably because of inadequate involvement of community members in data management. OBJECTIVE: The objective of this study was to improve the accuracy of information on pregnancy outcome in a ward in Lagos state. METHODS: Residents of Ward A of Ikosi-Isheri Local Council Development Area (LCDA) of Lagos State were educated on the importance of accurate health data. Youths selected based on criteria and community-based health care providers, following refresher training on research methods, assisted with the collection, analysis and presentation of data. RESULTS: The records of churches, mosques, Traditional Birth Attendants, the government owned Primary Health Care (PHC) centre and 7 private health facilities in the ward reported no (0) maternal mortality, but 14 out of 633 live births in the latter died, giving a peri-natal mortality of 22.1 per thousand in one year. However, neither the CDAs, nor LCDA nor the state received regular reports on pregnancy outcome. CONCLUSION: Under reporting or over-estimation of pregnancy outcome can be reduced by involvement of the leaders of Residents Associations and other relevant community members in data management. Data should be collected by smaller units into which a ward is divided and collated at the ward level for transmission to the LGA/LCDA. Feedback to community members will improve awareness about the importance of appropriate antenatal, natal and peri-natal care. Health care providers are also more likely to take prompt action to prevent maternal and peri-natal mortality. PMID- 20830992 TI - Medicare solvency extended...but with many caveats. PMID- 20830993 TI - Nurse staffing. Finding the right number and mix. AB - Dissatisfaction with staffing is the main reason nurses leave hospitals. Hospital acquired conditions are higher in hospitals with lower RN hours per patient day. Finance and nursing need to collaborate to determine appropriate nurse staffing so units are not overstaffed or understaffed. PMID- 20830994 TI - Physician practice and hospital revenue cycle drivers: what's the difference? AB - There are two key differences between hospitals and physician practices in revenue cycle management: unit of work and its value, and per unit cost to collect. Reducing a physician practice's cost to collect requires, first and foremost, the right technology and functionality and the right staff. Three advanced collections techniques-denials management, contract compliance, and fee schedule management and maintenance-should be examined for their potential value in ensuring that an owned practice is paid correctly for every service. PMID- 20830995 TI - Weighing the benefits and the risks of ACOs. PMID- 20830996 TI - The Medicare bundled payment pilot program participation considerations. AB - The Medicare bundled payment pilot program is scheduled to begin in January 2013 and will run for five years. The program holds the promise of increased alignment between hospitals and physicians, presenting opportunities for hospital cost reduction and improvements in quality. Nonetheless, the program carries fixed costs and assumption of risks that hospitals need to evaluate as they deliberate over whether to seek to participate in the program. PMID- 20830997 TI - Blunting the negative impact of healthcare reform. AB - To prepare for reform, organizations should take the following preventive measures: Create an integrated plan to evaluate the changes under health reform and implement actions for long-term financial success. Plan for lower Medicare payments by negotiating with commercial insurance carriers for contract renewals and implementing cost containment measures. Assess the effectiveness of the charge structure. Improve or establish new procedures to identify and report all charity care services provided. PMID- 20830998 TI - HFMA's reform resources. PMID- 20830999 TI - A closer look at self-pay segmentation. AB - Successful scoring approaches for self-pay accounts have three common characteristics: Thoughtful selection of a scoring model and segmentation approach. Deployment of workflows (either segmented or account prioritization) consistent with a hospital's capabilities and the likelihood of collection. Ongoing performance monitoring. PMID- 20831000 TI - Improving the revenue cycle by taking the patient's perspective. AB - UPMC revenue cycle operations analyzed front-end processes to improve them, thereby also improving the patient experience. UPMC focused on scheduling, eligibility/insurance verification, and financial counseling to develop an integrated work flow ensuring data integrity and expediting account resolution. Automating the processes increased efficiency and reduced errors, while improving patient satisfaction. PMID- 20831001 TI - Inside the audit and RAC preparation process at Norton Healthcare. AB - Healthcare providers should look both outside and inside their organizations to prepare for Recovery Audit Contractor (RAC) program challenges. Organizations should have the right team in place to focus on their RAC audit response. Preparation for RAC audits should include mining data to identify potential risk, automating claim filing, educating staff and physicians, and communicating to key stakeholders. PMID- 20831002 TI - Measuring the true return of your hospital's revenue cycle. AB - Actions that hospitals can undertake to improve the yield of revenue cycle initiatives include the following: Adopt patient-centric operations. Centralize financial clearance functions. Use point-of-service collection training and incentive programs. Implement patient self-service technologies, such as registration kiosks and web portals. PMID- 20831003 TI - Is your property tax-exempt status at risk? AB - Healthcare reform includes specific requirements for hospitals and health systems related to property tax exemption. Some states impose their own requirements for hospitals to qualify as a charity. Hospitals should proactively address property tax exemption status. PMID- 20831004 TI - Medical tourism: game-changing innovation or passing fad? AB - Outbound medical tourism presents several concerns for U.S. providers: Potential lost revenue could reach almost $600 billion by 2017. Continuity of care can become an issue if complete medical records are not available to the patient's home physician and communications are not maintained between the domestic physician and the physician who rendered medical care abroad. Potential malpractice liability could place the U.S.-based provider at risk. PMID- 20831005 TI - Mapping out. Strategies for revenue cycle sucess. PMID- 20831006 TI - How CFOs can help compensation committees make better decisions. PMID- 20831007 TI - Turning data into actionable information--and improved outcomes. PMID- 20831008 TI - The endowment model: alive and well. PMID- 20831009 TI - Medicaid payer mix varies widely by state. PMID- 20831010 TI - [The state of the art: tool for improvement in orthopedics]. PMID- 20831011 TI - [Cost-benefit of various treatments for patients with distal radius fracture]. AB - Fractures of the distal third of the radius seriously impair quality of life and have high economic and social costs, and families face the high costs of care in our country. There are only a few studies evaluating the direct medical and non medical costs resulting from distal radius fractures, from the patient perspective. OBJECTIVE: Determine the treatment-related costs and their relation with the benefits provided by the treatment. MATERIAL AND METHODS: A total of 120 patients with distal radius fracture were enrolled; they were divided into two groups based on their treatment, which included a cast and surgery with an angular stability plate, both provided by the hand surgery and microsurgery services; treatment-related costs were analyzed: Bed days, surgery, implant, cast, visit to the doctor, disability days and rehabilitation. RESULTS: 80% were females, mean age was 50 years, the patients' disability cost time was estimated using the 2007 minimum wage for geographic area "A". The mean surgical treatment related expenses amounted to $ 9,850, with a mean cost for disability days of $8,462. In the case of conservative treatment, mean expenses were $1,075, with a mean cost for disability days of $16,004; however, the return to the family economy took longer and involved delayed wrist mobility. PMID- 20831012 TI - [New flexor tendon graft of fingers using the extensor carpus radialis longus. Anatomical and clinical study]. AB - The palmaris longus has long been used as the source of a tendinous graft for the reconstruction of finger flexor tendons with good results. There are other sources of tendons, such as the plantaris, the finger extensors, and the toe extensors and flexors. A recent descripiton includes harvesting a graft from the plantaris with a bone fragment, as a bone-tendon, to allow for a more solid distal fixation using a screw. This report describes an anatomical study of a new source of tendon graft never described before, the extensor carpus radialis longus. Its mean length is 20.5 mm (20-22 mm), its thickness is 5 x 3 mm in most of the reviewed cases. We performed finger mobility and excursion tests after fixing the tendon, with very favorable results. We recommend this tendon as a source of a tendinous graft for the hand, as it is constant, has a proper thickness, does not require preparing another surgical field and can be easily removed. PMID- 20831013 TI - [Spastic hip surgery in children]. AB - BACKGROUND: Spasticity in patients with infantile cerebral palsy may lead to progressive subluxation and/or hip dislocation. MATERIAL AND METHODS: Retrospective, cross-sectional trial of a cohort of patients with infantile cerebral palsy who underwent subtrochanteric osteotomy of the hip at the Shriner's Hospital for children in Mexico City, with a 5-year follow-up. X-ray evaluation was conducted pre- and postoperatively and at the 5-year follow-up using the Settecerri classification. RESULTS: Twenty cases were analyzed; mean age was 8.8 years. They included spastic quadriplegia, spastic diplegia, spastic paraplegia. Good results accounted for 50%, fair 30% and poor 20%. Good results in patients with quadriplegia represented 50%, with diplegia 25%, and with paraplegia 75%. Among patients undergoing single osteotomy, good results were 28%, fair 57%,and poor 14%; among those undergoing osteotomy plus cotyloplasty, good results were 63%, fair 9%, and poor 27%. Results with osteotomy plus soft tissues were good and fair in 50% of patients. DISCUSSION: Spasticity and its effects are always present, regardless of surgery, treatment or no treatment; this is the reason for the recurrence of deformities or articular problems of the hip. The benefit of treatment cannot be denied despite spasticity. CONCLUSIONS: The best results were seen among the youngest patients with spastic diplegia and spastic paraplegia. Osteotomy as a single procedure is insufficient and therefore cotyloplasty is recommended. PMID- 20831014 TI - [Clinical and radiographic correlation after anterior cruciate ligament reconstruction]. AB - The purpose of this work is to correlate the clinical, functional and radiographic results of the anterior cruciate ligament (ACL) reconstruction with the angulation and orientation of the femoral and tibial tunnels. INTRODUCTION: The ACL is one of the most frequently injured articular structures of the knee. The reason for this being that it is the primary limiting structure of anterior tibial translation; its tear causes kinematic alterations and results in long term degenerative and functional changes. Repair can restore the kinematics. MATERIAL AND METHODS: 26 patients, 20-50 years old, post-ACL reconstruction with the semitendinous-gracilis technique. From November 2006 to July 2007. Clinical and functional assessments: Tegner and Lysholm. Radiographic assessment: anteroposterior view with knee extension and lateral view with 30 degrees flexion. Pearson correlations (r) were used in the analysis. RESULTS: 26 patients (100%), 20 males (76.92%), 6 females (23.08%). Mean of 2.4 in the Lysholm scale (fair to good); standard deviation 1.2. Bernard-Lysholm quadrant r = -0.772. Tegner quadrant r = 0.790. CONCLUSIONS: The Lysholm and Tegner scale is associated with the graft quadrant. The situation of the tibial implant in the saggital plane is associated with the Lysholm scale. The correlation of patients with an inadequate placement with respect to the quadrants was associated with good-to-excellent results and fair-to-good results. Two patients had a poor clinical outcome; the orientation of the AP angle and the quadrant were within acceptable parameters, with the exception of the lateral angle-shaft axis. PMID- 20831015 TI - [Clinical association between patellofemoral pain with arthroscopic findings]. AB - The purpose of this study was to associate patellofemoral pain with the findings of arthroscopic procedures. A visual analogue scale was used considering that 1 represented no pain and 10 severe pain, the functional Lysholm scale for function, and the Outerbridge classification to determine the grade of the articular cartilage lesion. MATERIAL AND METHODS: The study population was composed of an heterogeneous group of patients with chondral lesions. This is a retrospective, observational and longitudinal study undertaken for a period of 18 months. Sixty-nine patients had patellofemoral pain, and traumatic knee injuries were excluded. RESULTS: Sixty-eight patients were found to have a chondral lesion, only one patient did not. In the latter only loose body removal was performed. The most frequent procedure was articular lavage, debridement and chondroplasty in 98.5%. Thirty-five patients were found to have knee arthrosis grade IV (50.7%); the broadest functional improvement range occurred in patients with arthrosis grades I and III. DISCUSSION: Patients with mild-to-moderate knee arthrosis grades I to III are the ones with the highest chance of success from the perspective of pain relief and functionality of arthroscopic surgery. PMID- 20831016 TI - [Multimodal treatment of chronic unspecific low back pain]. AB - A prospective longitudinal was conducted using three multimodal treatment regimens that included a different NSAID for each of the regimens (thiaprofenic acid, piroxicam, meloxicam), a steroid (betamethasone) and a muscle relaxant (tetrazepam). 240 patients with a history of chronic low back pain for more than six months were treated; they were divided into three groups of 80 patients assigned to each regimen. RESULTS: Patients treated with thiaprophenic acid and meloxicam improved a total of 6 points, going from an initial mean score of 8 in the VAS at the onset of treatment, to a score of 2 at the end of treatment during a mean of 3 months. Patients treated with piroxicam had a 5-point improvement in the VAS, from a mean score of 7 at the onset of treatment to a mean score of 2 in a mean of 3 months. COMPLICATIONS: The meloxicam group had less epigastric complications, 1.25% compared with 2.91% for the thiaprophenic acid group and 3.75% for piroxicam. CONCLUSION: This combination, which includes an antiinflammatory agent, a steroid and a muscle relaxant, is an appropriate treatment regimen because it includes drugs that act on the antiinflammatory component, the pain component and the emotional component, which are the most common factors mentioned as probable causes of unspecific low back pain. PMID- 20831017 TI - [Minimally-invasive circumferential lumbar arthrodesis. Functionality and complications]. AB - OBJECTIVE: Report the experience of the authors with the treatment of degenerative disc disease using minimally-invasive circumferential arthrodesis and considering the functional results, healing and complications. MATERIAL AND METHODS: Circumferential arthrodesis was performed with an anterior approach using an interbody spacer, and with a posterior approach using translaminar facet screws in 36 patients. All of them had disc degeneration with some type of contraindication for lumbar arthroplasty, with a history of conservative treatment for at least 6 months. They were evaluated before and after surgery with the visual analogue pain scale and the Oswestry scale, as well as a treatment satisfaction scale (0 to 10 points). RESULTS: The pain scale went from 9.1 preoperatively to 23 postoperatively, and the Oswestry disability scale went from 47% to 21%. The satisfaction rate at the two-year follow-up was 9.2. All patients were found to have interbody healing at the 6-month follow-up and there were 2 complications: one vascular injury and one case of transient retrograde ejaculation. CONCLUSION: Circumferential arthrodesis using minimally-invasive methods leads to interbody healing and good functional recovery rates and low complication rates. PMID- 20831018 TI - [Fracture dislocation of the thoracolumbar spine in pregnant patient: diagnostic by image and treatment]. AB - BACKGROUND: Fracture dislocations of the thoracolumbar spine are, to a great extent, associated with neurologic deficit and instability, so a large percentage of them require surgical treatment. Being pregnant does not rule out the possibility of having this type of lesions. There are only a few bibliographic references concerning these cases and medical and treatment ignorance about them is frequent. OBJECTIVE: Present a review of concepts and specifications for the correct and safe imaging diagnosis as well as considerations on the surgical treatment of patients with traumatic thoracolumbar spine lesions who are pregnant. MATERIAL AND METHODS: A bibliographic review will be presented together with a clinical case of the CALRM, a 31-year-old female with a fracture dislocation at T12-L1, ASIA E, who at the time of the lesion was nine weeks pregnant, and was managed with a multidisciplinary approach that included the following services: Obstetrics and Gynecology, Pediatrics, Anesthesiology, Radiology and Imaging, Legal Medicine, Spine Surgery, and the hospital's Ethics Committee. RESULTS: The diagnosis and characteristics of the lesion were assessed properly with standard X-rays and the support of MRI. The patient underwent posterior stabilization with a transpedicular system while she was pregnant, and bone graft harvesting and application with an anterior approach after the pregnancy, without any complications. CONCLUSIONS: The correct understanding of the nature of ionizing radiation allows using an acceptable dose range according to the study performed and the patient's gestational age. Any patient with a fracture dislocation of the thoracolumbar spine who can tolerate the procedure should be stabilized. Moreover, the fetal risks of the surgical and anesthetic procedure may be avoided with an appropriate selection of the technique and the anesthetic agents, as well as with continuous maternal and fetal monitoring. PMID- 20831019 TI - [Beyond musculoskeletal oncologic surgery]. AB - Musculoskeletal tumors may be benign, which have a variable and unpredictable behavior pattern, or malignant, which have to be treated promptly and appropriately, as they are very aggresive. The diagnosis and treatment have changed, as new surgical techniques, biocompatible materials and chemo- and radiotherapy drugs have been added to the therapeutic armamentarium. The current purpose of oncologic orthopedics is to preserve function and its priority is a good quality of life. This paper describes the diagnosis and treatment of these conditions. PMID- 20831020 TI - [Analgesics in orthopedics]. AB - Pain is a symptom associated with alterations of the musculoskeletal system and frequently needs to be treated by the orthopedist. The purpose of this review is to analyze the mechanisms involved in the pain sensation and the various treatments that have been applied in orthopedics to control pain. Since it is known that the analgesic response is not the same in all patients, aspects that affect the pain sensation were assessed, such as the placebo effect, patients sex and genomic factors. The treatment varieties analyzed included drug therapy, considering the drugs, their pharmaceutical presentations and the route of administration most frequently used in orthopedics; and acupuncture, which has proven to be effective in special cases. PMID- 20831021 TI - [Polyethylene. First part]. PMID- 20831022 TI - Effect of erythropoietin on the survival of retinal neurocytes in culture upon serum withdrawal. AB - OBJECTIVES: To clarify whether erythropoietin (EPO) could substitute for the serum component in cultured retinal neurocytes suffering from serum withdrawal. METHODS: The study was performed in the Shanghai Institute of Traumatology and Orthopedics, Shanghai, China between April 2008 and March 2009. A total of 160 postnatal 2-3 day-old Sprague-Dawley rats were used for this study. After the retinal neurocytes were cultured for 48 hours, the culture media was replaced with serum-free media, and the cells were exposed to 1 U/ml, 3 U/ml, and 6 U/ml EPO for another 24 or 48 hours, the cell body diameter was then assessed using a computerized image-analysis system, and the survival and apoptosis rates of those cells were estimated by method of transcription and translation assay and flow cytometry. Immunocytochemistry was used to detect EPO and erythropoietin receptor (EPOR) expression. RESULTS: The retinal neurocytes had obvious EPO/ EPOR expression. The early (p = 0.002) and total (p = 0.049) apoptosis rates of retinal neurocytes cultured with serum withdrawal were significantly higher than that of neurocytes cultured with serum, and the cell viability of neurocytes cultured with serum withdrawal was significantly lower than that of neurocytes cultured with serum (p = 0.047). The EPO had no effect on the cell body diameter of cultured retinal neurocytes. The cell viability and the apoptosis rates of retinal neurocytes were not significantly different from that of simple serum withdrawal culture at any EPO concentration. CONCLUSION: As the addition of EPO immediately after serum withdrawal had no effect in preventing retinal neurocytes apoptosis induced by serum withdrawal, EPO cannot substitute for the serum component. PMID- 20831023 TI - Changes in the numbers and distribution of calretinin in the epileptic rat hippocampus. AB - OBJECTIVES: To examine calretinin (CR)-containingObjectives: To examine cairetinin (CR)-containingnterneuronsthatdegenerate inthe hippocampus in post statusinterneurons that dege nera te in the hippocampusepilepticus (SE) ratsatdifferent time in post status epilepticus (SE) rats at different time points. METHODS: This study was conducted at the Central South University, Xiangya Hospital, Hunan Province, P.R. China between September 2008 and January 2010. Pilocarpine-induced SE was chosen as a model to generate chronic epileptic rats. To determine whether hippocampal neuronal populations are affected by hippocampal seizures, immunohistochemical assays were performed in brain sections obtained from age-matched control (n=50) and epileptic rats (n=170). Nissl stain was used to observe pathological changes of the hippocampus. RESULTS: Our results revealed the most dramatic cell loss to be in the hilar, cornu Ammonis (CA)1, and CA3 areas in the epileptic rats. Quantitative analysis revealed significant differences between control and epileptic rats in the number of CR-positive interneurons. These interneurons were distributed in the hilar, CA1, and CA3 areas and in thedentate gyrus of both control and epileptic rats, but was more numerous in the hippocampus of normal rats. However, a transient increase of CR positive interneurons was observed in the CA1 between 7 and 15 days post SE. The CR interneurons were mostly located in the hilar and CA1 for epileptic rats, and in the hilus for control rats. CONCLUSIONS: Our data suggest that a different proportion of inhibitory interneurons was observed in the epileptic rat hippocampus, as their numbers differ from controls. These results indicate that the inhibitory circuits in the hippocampus may represent a compensatory response with a role to balance the enhanced excitatory input in the region. PMID- 20831024 TI - Prevalence of silent stroke in Kurdistan, Iraq. AB - OBJECTIVES: To measure the prevalence of silent strokes in the Iraqi Kurdish population, and to identify silent stroke risk factors. METHODS: This cross sectional study was carried out in Rizgary Teaching Hospital, Erbil, Iraq from January to June 2009. A sample of 200 patients attending the outpatient clinic was taken. The results of CT and MRI were analyzed, and the proportion of silent infarcts was measured. Patients were interviewed for presence of hypertension, diabetes, ischemic heart disease, alcohol drinking, and smoking. Body mass index and serum lipid levels were calculated. RESULTS: Out of 200 subjects, 19% showed silent infarct(s). Logistic regression analysis showed significant association between hypertension and old age with presence of silent infarcts. The age of affected individuals was significantly higher than the age of the non-affected individuals. CONCLUSIONS: The percentage of silent infarcts among apparently normal individuals in the Kurdish population is around 19%, and physicians must always keep this diagnosis in mind, especially among hypertensive and older aged patients. PMID- 20831025 TI - Evaluation of the effect of donepezil on cerebral blood flow velocity in Alzheimer's disease. AB - OBJECTIVES: To evaluate the effect of Donepezil on cerebral blood flow velocity using non-invasive transcranial Doppler (TCD) sonography. METHODS: This clinical trial was carried out in the Department of Neurology, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran from March 2008 to July 2009, on Alzheimer's disease (AD) patients in 2 groups of case and control, each consisting of 11 patients. The case group who received Donepezil medication was examined by TCD before (baseline), after 4 weeks of oral treatment with 5 mg per day Donepezil, and a further 4 weeks of 10mg per day Donepezil, orally. The control group comprised AD patients who did not receive any medications, and were examined by TCD only once. Peak systolic (PSV), end-diastolic (EDV), and mean flow (MFV) velocities of the posterior cerebral artery (PCA) and the middle cerebral artery (MCA) was assessed by TCD. Also, mini-mental state examination (MMSE) was carried out. RESULTS: There were no significant differences between the case and control groups, in terms of age and gender. In the case group, the mean MMSE score reached 20.2 +/- 2.8 from a baseline value of 15.8 +/- 3.3 after 4 weeks of oral treatment with 5 mg/d Donepezil, and reached 20.6 +/- 3.9 after 4 more weeks at 10 mg/d Donepezil. In the MCA, the difference in PSV and MFV values after 4 weeks of treatment with 10 mg/d Donepezil was statistically significant compared with the baseline values. In PCA, the values of MFV and EDV after 4 weeks of treatment with 10 mg/d Donepezil were statistically significant in comparison with the baseline value. CONCLUSION: Donepezil (10 mg/d) increased cerebral blood flow velocity and MMSE score in our AD patients, but more extensive trials are recommended. PMID- 20831026 TI - Assessment of health-related quality of life, depression, and anxiety in slowly and rapidly progressive neuromuscular disorders. AB - OBJECTIVES: To compare health-related quality of life (HRQoL) and psychosocial features in rapidly progressive neuromuscular disorders (RPNMD) and slowly progressive neuromuscular disorders (SPNMD) in adult ambulatory patients, to determine individual needs in 2 separate progression groups. METHODS: Thirty-nine SPNMD patients and 46 RPNMD patients were recruited. The functional independence measurement (FIM) was employed to evaluate the functional status. For the assessment of depression, anxiety, and HRQoL, patients were requested to fill out a Beck Depression Inventory, State-Trait Anxiety Inventory, and the Nottingham Health Profile (NHP). This study was performed at the Department of Physical Therapy and Rehabilitation, Hacettepe University Faculty of Health Science, Ankara, Turkey between August and December 2009. RESULTS: The FIM total score did not differ between the 2 groups. Only energy was significantly high (worse) among the dimensions of NHP in RPNMD patients. None of the other sub-items differed between the 2 patient groups. The SPNMD patients were more depressed than the RPNMD patients. The mean state and trait anxiety scores were significantly higher in SPNMD patients as well. CONCLUSIONS: Significant depressive or anxious symptomatology is not associated with amyotrophic lateral sclerosis (ALS). The diagnosis of SPNMD should alert physicians in an equivalent promptness to ALS and possible depression or anxiety, and concerns of patients regarding the chronic, though slowly progressive course of the disease. PMID- 20831027 TI - Gene polymorphisms and related risk factors in Mongolian hypertensive stroke patients. AB - OBJECTIVES: To identify susceptible single nucleotide polymorphisms causing prevailing essential hypertension complicating stroke in the Mongolian population. METHODS: This study was carried out at the Beijing Huada Genome Company, Beijing, and the Clinical Testing Center of Inner Mongolia Medical College, Hohhot, P.R. China from March to November 2005, and included 96 patients with hypertension (control group) with an average age of 53 +/- 11 years, and 68 patients with hypertensive stroke with an average age of 60 +/- 10 years. The gene polymorphisms were examined by the polymerase chain reaction-restriction fragment length polymorphism technique and the Sequenom system, and analyzed by multiple regression analysis. RESULTS: Logistic multiple regression analysis revealed significant differences between the groups for age and smoking. Genotypes and allele gene frequencies were not significantly different between the groups. The significant incidence risks were p = 0.011, odds ration (OR) = 3.182 for the ACE DD genotype, p = 0.038, OR = 6.179 for the CYP CT genotype, and p = 0.042, OR = 6.089 for the CYP TT genotype. All the other genotypes did not significantly correlate to hypertension and hypertensive stroke. CONCLUSION: The ACE DD, CYP CT andTT genotypes are candidates for hypertension complicating stroke in the Mongolian population. The risk of disease was lowest among the ACE II and CYP CC genotypes. PMID- 20831028 TI - Malignant cutaneous melanoma associated with cerebral venous sinus thrombosis. AB - Cerebral venous sinus thrombosis (CVST) is an infrequent disease (representing around 1% of all strokes) manifested by clotting of blood in cerebral venous or dural sinuses as well as cortical veins. Herein, we describe an unusual case of malignant melanoma presenting with CVST in whom the diagnosis of CVST was suspected on the basis of clinical findings along with brain CT scan, and finally was confirmed by brain MRI and magnetic resonance venography. Intravenous heparin treatment was started immediately; but unfortunately the patient died one week after hospitalization. We suggest that the hypercoagulable state provoked by malignant melanoma generated the CVST as brain MRI did not indicate any evidence of brain metastasis; therefore, direct invasion of the sinus by the tumor is less likely; on the other hand, we should not omit the possible role of microscopic sinus metastasis. PMID- 20831029 TI - Central nervous system aspergillosis in an immunocompetent patient. AB - A 12-year-old girl was admitted to the Emergency Department with seizures and headache for 2 months. A CT scan and MRI showed a mass in the right frontal lobe with obvious mass effect. Surgery was carried out, and the resultant pathology was found to be aspergillosis. This study reports aspergillosis in an immunocompetent host following recurrent fungal otitis media. Although this condition is rare, it should be considered in patients with a history of fungal infections. PMID- 20831030 TI - Steroid responsive encephalopathy associated with autoimmune thyroiditis presenting with late onset depression. AB - Steroid responsive encephalopathy associated withSteroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), (also known as Hashimoto's encephalopathy) is a rare autoimmune encephalitis associated with high antithyroid antibodies, and presents with a relapsing-remitting or monophasic course, consisting of confusion, seizures, psychosis, dementia, or stroke-like episodes. In this report, a late onset depression was the initial presentation of SREAT in a middle aged patient, something rarely described before, indicating the need to suspect SREAT as a possible etiology for depression in this age group. PMID- 20831031 TI - Pseudotumor cerebri and prolactin secreting pituitary adenoma. Association or coincidence? AB - The occurrence of pseudotumor cerebri (PTC) and hyperprolactinemia related to a prolactinoma are extremely rare, and the link between these pathologies has not been examined adequately in the post-MRI era. We report a patient with a small intrasellar prolactinoma who also developed PTC. Magnetic resonance venography did not show any evidence of compression of the cavernous or any other sinuses. She initially responded to treatment with acetazolamide and cabergoline. However 9 months later, her PTC symptoms recurred despite a normal serum prolactin level and a mild reduction of the pituitary tumor size on MRI. She improved after a lumboperitoneal shunt. We conclude that the findings in our patient do not support an association between PTC and hyperprolactinemia or prolactinoma. However, the case supports the need for clinicians to consider the diagnosis of PTC when patients with small pituitary lesions exhibit raised intracranial pressure features. PMID- 20831032 TI - Stereoscopic virtual reality presurgical planning for cerebrospinal otorrhea. AB - We present a complicated case of spontaneous cerebrospinal otorrhea, which had not been cured despite undergoing 5 surgical interventions in the past. The disability to identify the location of the fistula was the main crux of the past failures. On this occasion, stereoscopic virtual reality presurgical planning was applied to identify the exact location of the fistula and a surgical simulation was performed, and was later confirmed during the actual operation. Interactive manipulation in a stereoscopic virtual environment makes the decision making process easier in the treatment of cerebrospinal otorrhea. PMID- 20831033 TI - Magnetic resonance imaging findings of hypothalamic hamartoma correlated with clinical features. PMID- 20831034 TI - Depression, Parkinson disease, Alzheimer disease. The homocysteine hypothesis. PMID- 20831035 TI - Is mitral early to late wave ratio a predictor for silent cerebral infarction in elderly patients with coronary artery disease. PMID- 20831036 TI - Rhythmic temporal theta bursts of drowsiness: psychomotor variant pattern. PMID- 20831037 TI - Juvenile myoclonic epilepsy. PMID- 20831039 TI - Drug-resistant tuberculosis now at record levels. PMID- 20831038 TI - Afghanistan first in world to use new vaccine against polio. Critical step as global eradication effort faces entrenched challenges. PMID- 20831040 TI - [Percutaneous coronary interventions in patients with acute myocardial infarction after successful thrombolysis]. AB - In 259 patients with acute myocardial infarction admitted to N.V. Sklifosofsky Institute of Urgent Aid in 2003-20007 we compared efficacy of 3 strategies of treatment after successful thrombolytic therapy (TLT): percutaneous coronary intervention (PCI) because of recurrent ischemia within 5 days after thrombolytic therapy (n = 66), PCI in patients with elevated risk of death according to TIMI during 12-24 hours after TLT (n = 26); conservative treatment after TLT (n = 167). Differences at comparison of two invasive strategies were related to the state of infarct-related artery and clinical effect. The use of PCI in patients with elevated risk of death in 12-24 hours after TLT was in all cases associated with timely provision of completed reperfusion, improvement of contractility, prevention of development of left ventricular aneurism. The use of both invasive strategies allowed to lessen rate of complications, and achieve several fold lowering of mortality. The data obtained show that for more objective and timely selection of patients for PCI after effective TLT it is expedient to use quantitative estimation of risk according to TIMI. Such approach allows without waiting for ischemia recurrence to detect patients with elevated risk and critical stenoses being in acute need of combined reperfusion. PMID- 20831041 TI - [Possibilities of correction of rheological properties of the blood and free radical processess in patients with acute myocardial infarction combined with type 2 diabetes mellitus]. AB - Aim of the study was assessment of rheological parameters of the blood and processes of free radical oxidation as well as rate of arrhythmia development in patients with acute myocardial infarction (AMI) and type 2 diabetes mellitus (DM) whose otherwise standard therapy was supplemented with 90% omega-3 polyunsaturated fatty acid (PFA). We examined 63 patients with AMI and concomitant diabetes. 90% omega-3 PFA was given to 16 of these patients. Control group consisted of 22 practically healthy patients. Investigation of blood rheological parameters included measurement of viscosity of whole blood, determination of aggregation and morphofunctional structure of erythrocytes. Free radical processes were assessed by total amount of nitrates and nitrites in blood plasma, concentration of citrulline and malone dialdehyde. In patients with AMI taking its course at the background of type 2 DM compared with control group we observed changes of rheological properties of blood and processes of free radical oxidation which led to lowering of tissue oxygen supply. Standard therapy of AMI in more than 50% of patients did not result in adequate correction of impaired rheological parameters of blood. Addition of 90% omega-3 PFA to standard treatment of AMI was associated with improvement of aggregation and cytoarchitectonics of erythrocytes, lowering of activity of free radical oxidation, and by the end of 2nd week of treatment--with lessening of number of ventricular disturbances of cardiac rhythm. Thus supplementation of standard therapy with preparation 90% omega-3 PFA in patients with AMI and type 2 DM facilitates improvement of rheological properties of blood and processes of free radical oxidation, and prevention of arrhythmia. PMID- 20831042 TI - [Possibilities of if channels inhibitor ivabradine in complex treatment of survivors of myocardial infarction with stable angina]. PMID- 20831043 TI - [Genetic predisposition to development of atrial fibrillation in patients with hypertensive disease]. AB - We studied associations of genes of adrenoreceptor types 1, 2 and 3 (ADRB1, ADRB2, ADRB3), connexin (CX40) and voltage gated potassium channel type 2 (KCNH2) with development of atrial fibrillation (AF) in patients with hypertensive disease. We examined 102 patients with hypertensive disease which in 51 was complicated with AF. The groups were comparable by sex, age, Ketle index, presence of concomitant diseases. We determined alleles and genotypes of polymorphic markers G(-44)A and A71G of CX40 gene, Lys897Thr of KCNH2 gene, Ser49Gly of ADRB1 gene, Trp64Arg of ADRB3 gene with the help of PCR. Left atrial volume turned out to be significantly higher in patients with AF (88.7 +/- 4.13 ml and 65.4 +/- 3.96 ml, respectively, p = 0.001). No associations of genotypes of polymorphic markers Ser49Glu of ADRB1 gene, G(-44)A and A 71G of CX40 gene, Lys897Thr of KCNH2 gene, with emergence of AF in patients with arterial hypertension were revealed. For polymorphic marker Trp64Arg of ADRB3 gene frequency of Trp allele turned out to be significantly higher (OR 2.20, p = 0.0176), while frequency of Arg allele significantly lower (OR 0.43, p = 0.0176) in the group of patients with AF. In patients with AF frequency of Arg/ Arg genotype turned out to be significantly lower (OR 0.24, p = 0.0257). PMID- 20831044 TI - [Effect of atorvastatin on hemorheological parameters in patients with arterial hypertension with dyslipidemia]. AB - We assessed effect of 6-weeks therapy with atorvastatin on parameters of lipid metabolism and some hemorheological characteristics in 27 patients with arterial hypertension (AH) and dyslipoproteinemia (DLP). In addition to general clinical examination we studied hemorheological profile including hematocrit, blood plasma and whole blood viscosity with the method of rotational viscosimetry at various shear rates, deformability of erythrocytes by filtration method, and cytoarchitectonics of erythrocytes. At the background of pronounced lipid lowering effect of atorvastatin we noted obvious improvement of microrheological properties of erythrocytes appearing as significant decrease of rigidity index of erythrocytes and of their aggregation. Basing on these findings we concluded that improvement of fluidity of erythrocytes promoting facilitation of blood flow efficacy in microcirculatory vascular bed can be a supplementary reason for administration of atorvastatin to patients with AH and DLP. PMID- 20831045 TI - [Dynamics of structural-functional parameters of cardiovascular system during use of complex therapy of women with type 2 diabetes mellitus]. AB - Aim of the work was to study dynamics of parameters of cardiovascular system in women during use of various sugar lowering drugs in complex multifactorial therapy of type 2 diabetes mellitus (DM). We included in this 12 months study 182 women older than 55 years with type 2 DM, abdominal obesity and artrerial hypertension (AH). All women received angiotensin converting enzyme inhibitors and statins. As sugar lowering drugs we used metformin (n = 46), metformin with glyclazide (n = 47), monotherapy with insulin (n = 45). Long-term use of metformin in complex multifactorial therapy of women with decompensated type 2 diabetes DM, AH and abdominal obesity provides improvement of carbohydrate and lipid metabolism, lowering of arterial pressure, diminishment of albuminuria, diastolic dysfunction, and stiffness of left ventricular myocardium. The use of combination of metformin with glyclazide MB provides advantages in lowering of insulin resistance, contol glycemia, and lessening of hypertrophy of left ventricular myocardium. PMID- 20831046 TI - [Lipid lowering, antiinflammatory, and vasoprotective effects of fenofibrate in patients with type 2 diabetes mellitus]. AB - Aim of the study was to assess effect of fenofibrate on lipid blood composition, markers of inflammation and the state of vascular wall in patients with type 2 diabetes mellitus (DB2). We randomized 73 patients with DB2 in 2 groups. Patients of group one (n = 34) in addition to hypoglycemic and lipid lowering therapy with statins received fenofibrate (145 mg/day), patients of control group (n = 38) received standard therapy. We assessed effect of selected therapy on lipids, endothelium dependent vasodilatation (EDVD) in a test with reactive hyperemia of brachial artery, intimaAmedia thickness of common carotid arteries, levels of CAreactive protein (CRP) and uric acid, parameters of stiffness of arterial wall. At the end of the study we found in the fenofibrate group significant lowering of mean levels of total cholesterol, low density lipoprotein cholesterol, CRP, uric acid. We also noted more significant elevation of EDVD, improvement of parameters of arterial wall thickness. The use of fenofibrate in a daily dose 145 mg in patients with DB2 at the background of traditional hypoglycemic, antihypertensive, and lipid lowering therapy corrects effectively lipid disturbances and normalizes function of endothelium and parameters of vascular wall stiffness. This substantially decreases risk of vascular complications of DB2. PMID- 20831047 TI - [Anticoagulant action and safety of warfarin dosing based on pharmacogenetic testing: results of the first Russian prospective pilot study]. AB - Aim of the study was to compare numbers of episodes of excess hypocoagulation and bleeding with warfarin dosing based on pharmacogenetic testing and traditional method in patients with high risk of thromboembolic complications. In 76 patients (43 men and 33 women aged 60.3 +/- 12.3 years) warfarin was administered starting with the dose calculated according to the gage algorithm with consideration of results of pharmacogenomic testing (genotyping of CYP2C9 and VKORC1). Control group comprised 78 patients aged 63.4 +/- 9.4 years who had participated in an earlier retrospective study in which they received warfarin according to traditional scheme with starting dose of 5 mg/day. In both groups we analyzed data obtained during 6 months after start of drug administration. Genotyping was carried out by polymerase chain reaction. Episodes of excess hypocoagulation (international normalized ratio above therapeutic range) and bleeding accurred more rarely with the use of pharmacogenetic approach to dosing of warfarin compared with standard method (17.1 vs 56.4%, p = 4.1 x10(-7), and 4 vs 18%, p = 0.009 respectively). PMID- 20831048 TI - [Psychiatric disturbances in patients with acute myocardial infarction and other critical states in conditions of department of reanimation and intensive therapy]. AB - In this review we present in short data of domestic and foreign studies on somatogenic delirium in patients with acute myocardial infarction and with other critical states. The review also contains definitions of basic conceptions, contemporary approaches to diagnosis and management of this complication. PMID- 20831049 TI - [Value of endothelial dysfunction in cardiovascular diseases and methods of its correction with drugs]. AB - Vascular endothelium is not simply a barrier between blood and extra vascular bed but is a source of large number of mediators regulating various functions of the body among which nitrous oxide appears to be one of most important. Endothelial dysfunction (ED) develops in a number of processes: diabetes mellitus, smoking, arterial hypertension, hypercholesterolemia. ED promotes increase of rate development of cardiovascular diseases. One of most well known markers of ED is microalbuminuria (MAU). Drug and nondrug means are used for the treatment of ED. Calcium antagonists and angiotensin converting enzyme inhibitors both separately and as components of combination therapy are able to maximally diminish MAU. PMID- 20831050 TI - [Cardiology news 2009: arterial hypertension, primary and secondary prevention of atherosclerosis, antithrombotic therapy]. PMID- 20831051 TI - [Thienopyridines in the treatment and prevention of cardiovascular diseases. Part V. Combination of clopidogrel and acetylsalicylic acid in the treatment of stable patients with atherothrombotic cardiovascular diseases]. AB - In a series of articles the authors consider clinical pharmacology and experience of clinical application of blockers of platelet P2Y12 receptors, most well known representatives of which ticlopidine and clopidogrel according to chemical structure belong to thienopyridine derivatives. In the fifth communication we consider data of two randomized studies in which efficacy and safety of clopidogrel in combination with acetylsalicylic acid (ASA) has been assessed in comparison with ASA in stable patients with atherothrombotic cardiovascular disease. It has been shown in both studies that in stable patients with atherothrombotic cardiovascular disease long-term therapy with combination of clopidogrel and ASA was no more effective than monotherapy with ASA or clopidogrel but was associated with high risk of hemorrhagic complications. Thus contrary to acute coronary syndromes and percutaneous interventions with stenting combinations of clopidogrel and ASA is not indicated to patients with stable course cardiovascular diseases. PMID- 20831052 TI - [Anticytokine therapy in the treatment of patients with chronic heart failure]. PMID- 20831053 TI - [Atrioventricular nodal reciprocal tachycardia: classification, clinical manifestations, diagnosis, and treatment]. AB - Data on prevalence, mechanisms of arrhythmogenesis and classification of atrioventricular (AV) nodal reciprocal tachycardia are presented. Clinical electrocardiographical and electrophysiological features of typical and atypical forms of AV nodal reciprocal tachycardia are described. Main diagnostic measures are delineated and principles of tactical approach to management of patients with AV nodal reciprocal tachycardia presented. Indications to radiofrequency catheter ablation, and physical characteristics of radiofrequency interventions in the region of registration of AV junction slow part fibers potentials of lower isthmus of the right atrium are discussed. Data of analysis of comparative efficacy of pharmacological and interventional approaches to management of patients with AV nodal reciprocal tachycardia as well as spectrum of possible complications associated with surgery are also presented. PMID- 20831054 TI - [Aortic stenosis of alkaptonuric genesis]. AB - Main approaches to intravital diagnosis of alcaptonuria are described. Attention is focused on damages determining invalidisation of patients. A clinical case is presented which demonstrates success of surgical treatment of aortic stenosis of alkaptonuric genesis. PMID- 20831055 TI - Point/counterpoint. The use of effective dose for medical procedures is inappropriate. PMID- 20831056 TI - Wide field array calibration dependence on the stability of measured dose distributions. AB - PURPOSE: The aim of this work was to simulate the effect of dose distribution changes on detector array calibrations and to explore compensatory methods that are used during calibration measurements. METHODS: The array calibration technique that was investigated is known as wide field (WF) calibration. Using this method, a linear array [y-axis (65 detectors) of the IC PROFILER (Sun Nuclear Corporation, Melbourne, FL)] is calibrated with three measurements (alpha, theta, and lamda); each measurement uses the same radiation field, which is larger than the array. For measurement configuration theta, the array is rotated by 180 degrees from its position in a; for lamda, the array is shifted by one detector from its position in theta. The relative detector sensitivities are then determined through ratios of detector readings at the same field locations (using theta and lamda). This method results in error propagation that is proportional to the number of detectors in the array. During the procedure, the calibration protocol operates under three postulates, which state that (a) the beam shape does not change between measurements; (b) the relative sensitivities of the detectors do not change; and (c) the scatter to the array does not change as the array is moved. The WF calibration's sensitivity to a postulate (a) violation was quantified by applying a sine shaped perturbation (of up to 0.1%) to a, theta, or lamda, and then determining the change relative to a baseline calibration. Postulate (a) violations were minimized by using a continuous beam and mechanized array movement during theta and lamda. A continuously on beam demonstrated more stable beam symmetry as compared to cycling the beam on and off between measurements. Additional side-scatter was also used to satisfy postulate (c). RESULTS: Simulated symmetry perturbations of 0.1% to theta or lamda resulted in calibration errors of up to 2%; alpha was relatively immune to perturbation (<0.1% error). Wide field calibration error on a linear accelerator with similar symmetry variations was +/- 1.6%. Using a continuous beam during theta and lamda with additional side-scatter reduced the calibration error from +/- 1.6% to +/- 0.48%. CONCLUSIONS: This work increased the reproducibility of WF calibrations by limiting the effect of measurement perturbations primarily due to linear accelerator symmetry variations. The same technique would work for any array using WF calibration. PMID- 20831057 TI - Total skin electron therapy (TSET): a reimplementation using radiochromic films and IAEA TRS-398 code of practice. AB - PURPOSE: The aim of this work is to present an updated implementation of total skin electron therapy (TSET) using IAEA TRS-398 code of practice for absolute dosimetry and taking advantage of the use of radiochromic films. The optimization of quality control tests is also included. METHODS: A Varian 2100 C/D linear accelerator equipped with the special procedure HDTSe- (high dose rate total skin electron mode, E=6 MeV) was employed to perform TSET irradiations using the modified Stanford technique. The commissioning was performed following the AAPM report 23 recommendations. In particular, for dual-field beams irradiation, the optimal tilt angle was investigated and the dose distribution in the treatment plane was measured. For a complete six dual-field beams irradiation, the treatment skin dose on the surface of a cylindrical phantom was evaluated by radiochromic films and the B factor which relates the single dual-field skin dose to the six dual-field skin dose was assessed. Since the TRS-398 reference conditions do not meet the requirements of TSET absolute dosimetry, GafChromic EBT films were also employed to check and validate the application of the protocol. Simplified procedures were studied to verify beam constancy in PMMA phantoms without the more difficult setup of total skin irradiation. RESULTS: The optimized geometrical setup for dual-field beams was: Tilt angle = +/- 19 degrees, SSD=353 cm, and the beam degrader (200 x 100 X 1 cm3) placed at 320 cm from the source. As regards to dose homogeneity in the treatment plane, for dual field beams irradiation, the mean relative dose value was 97% +/- 5% (normalizing to 100% at the calibration point level). For six dual-field beams irradiation, the multiplication factor B was 2.63. In addition, beam quality, dose rate, and bremsstrahlung contribution were also suitable for TSET treatments. The TRS-398 code of practice was used for TSET dosimetry, as dose measurements performed by ionization chamber and radiochromic film agreed within 2.5%. Simplified quality control tests and baseline values were presented in order to check flatness, symmetry, and field size with radiochromic films and output and beam quality constancy with ionization chamber. Short-term reproducibility and MU linearity tests were also included. CONCLUSIONS: Commissioning parameters met the requirements of TSET treatments and the matching of AAPM guidelines with the IAEA code of practice was successful. Frequent beam performance controls can be easily performed through the presented quality assurance tests. Radiochromic dosimetry facilitated the TSET commissioning and played a major role to validate the application of TRS-398. PMID- 20831058 TI - Contrast detection in fluid-saturated media with magnetic resonance poroelastography. AB - PURPOSE: Recent interest in the poroelastic behavior of tissues has led to the development of magnetic resonance poroelastography (MRPE) as an alternative to single-phase MR elastographic image reconstruction. In addition to the elastic parameters (i.e., Lame's constants) commonly associated with magnetic resonance elastography (MRE), MRPE enables estimation of the time-harmonic pore-pressure field induced by external mechanical vibration. METHODS: This study presents numerical simulations that demonstrate the sensitivity of the computed displacement and pore-pressure fields to a priori estimates of the experimentally derived model parameters. In addition, experimental data collected in three poroelastic phantoms are used to assess the quantitative accuracy of MR poroelastographic imaging through comparisons with both quasistatic and dynamic mechanical tests. RESULTS: The results indicate hydraulic conductivity to be the dominant parameter influencing the deformation behavior of poroelastic media under conditions applied during MRE. MRPE estimation of the matrix shear modulus was bracketed by the values determined from independent quasistatic and dynamic mechanical measurements as expected, whereas the contrast ratios for embedded inclusions were quantitatively similar (10%-15% difference between the reconstructed images and the mechanical tests). CONCLUSIONS: The findings suggest that the addition of hydraulic conductivity and a viscoelastic solid component as parameters in the reconstruction may be warranted. PMID- 20831059 TI - Noise variance analysis using a flat panel x-ray detector: a method for additive noise assessment with application to breast CT applications. AB - PURPOSE: A simplified linear model approach was proposed to accurately model the response of a flat panel detector used for breast CT (bCT). METHODS: Individual detector pixel mean and variance were measured from bCT projection images acquired both in air and with a polyethylene cylinder, with the detector operating in both fixed low gain and dynamic gain mode. Once the coefficients of the linear model are determined, the fractional additive noise can be used as a quantitative metric to evaluate the system's efficiency in utilizing x-ray photons, including the performance of different gain modes of the detector. RESULTS: Fractional additive noise increases as the object thickness increases or as the radiation dose to the detector decreases. For bCT scan techniques on the UC Davis prototype scanner (80 kVp, 500 views total, 30 frames/s), in the low gain mode, additive noise contributes 21% of the total pixel noise variance for a 10 cm object and 44% for a 17 cm object. With the dynamic gain mode, additive noise only represents approximately 2.6% of the total pixel noise variance for a 10 cm object and 7.3% for a 17 cm object. CONCLUSIONS: The existence of the signal-independent additive noise is the primary cause for a quadratic relationship between bCT noise variance and the inverse of radiation dose at the detector. With the knowledge of the additive noise contribution to experimentally acquired images, system modifications can be made to reduce the impact of additive noise and improve the quantum noise efficiency of the bCT system. PMID- 20831060 TI - Efficient generation of a magnetic field-free line. AB - PURPOSE: Signal encoding in magnetic particle imaging (MPI) is achieved by moving a field-free point (FFP) through the region of interest. One way to increase the sensitivity of the method is to scan the region of interest with a field-free line (FFL) instead of the FFP. Recently, the first feasible FFL coil setup was introduced. The purpose of this article is to improve the efficiency of the FFL coil geometry even further. METHODS: In order to reduce the electrical power loss of the setup, an additional Maxwell coil pair is introduced that is tailored to generate the static part of the FFL field. RESULTS: Using the proposed coil assembly, the electrical power loss for the generation of a rotating FFL is considerably reduced compared to previously known coil setups. Furthermore, the quality of the generated FFL is significantly increased. CONCLUSIONS: The proposed coil assembly is almost as efficient as an equivalent FFP scanner. Furthermore, the assembly cannot only be used for FFL imaging but for FFP imaging as well. Hence, the findings of this article denote an important step toward the first practical implementation of the FFL coil geometry. PMID- 20831061 TI - Direct absorbed dose to water determination based on water calorimetry in scanning proton beam delivery. AB - PURPOSE: The aim of this manuscript is to describe the direct measurement of absolute absorbed dose to water in a scanned proton radiotherapy beam using a water calorimeter primary standard. METHODS: The McGill water calorimeter, which has been validated in photon and electron beams as well as in HDR 192Ir brachytherapy, was used to measure the absorbed dose to water in double scattering and scanning proton irradiations. The measurements were made at the Massachusetts General Hospital proton radiotherapy facility. The correction factors in water calorimetry were numerically calculated and various parameters affecting their magnitude and uncertainty were studied. The absorbed dose to water was compared to that obtained using an Exradin T1 Chamber based on the IAEA TRS-398 protocol. RESULTS: The overall 1-sigma uncertainty on absorbed dose to water amounts to 0.4% and 0.6% in scattered and scanned proton water calorimetry, respectively. This compares to an overall uncertainty of 1.9% for currently accepted IAEA TRS-398 reference absorbed dose measurement protocol. The absorbed dose from water calorimetry agrees with the results from TRS-398 well to within 1 sigma uncertainty. CONCLUSIONS: This work demonstrates that a primary absorbed dose standard based on water calorimetry is feasible in scattered and scanned proton beams. PMID- 20831063 TI - Determination of multislice computed tomography dose index (CTDI) using optically stimulated luminescence technology. AB - PURPOSE: The extensive use of multislice computed tomography (MSCT) and the associated increase in patient dose calls for an accurate dose evaluation technique. Optically stimulated luminescence (OSL) dosimetry provides a potential solution to the arising concerns over patient dose. This study was intended to evaluate the feasibility and accuracy of OSL dosimeter systems in the diagnostic CT x-ray beam energy range. METHODS: MSCT dose profiles were measured by irradiating OSL strips placed inside the extended PMMA head and body phantoms at different scan conditions by varying kVp settings (100, 120, and 140 kVp) and collimated beam widths (5, 10, 20, and 40 mm). All scans in this study were performed using a GE Lightspeed VCT scanner in axial mode. The exposed strips were then read out using a custom-made OSL strip reader and corrected with field specific conversion factors. Based on the corrected OSL dose profile, the CTDI(450-OSL) and CTDI(l00-OSL) were evaluated. CTDI(100-IC) was also obtained using a 100 mm long pencil ionization chamber for accuracy verification. CTDI(100 efficiency) can be further evaluated by calculating the ratio of CTDI(100-OSL) and CTDI(450-OSL), which was compared to results from previous studies as well. RESULTS: The OSL detectors were found to have good sensitivity and dose response over a wide range of diagnostic CT x-ray beam energy viz. the primary beam and the scatter tail section of the dose profile. The differences between CTDI100 values obtained using the OSL strips and those obtained with 100 mm long pencil ionization chamber were < +/- 5% for all scan conditions, indicating good accuracy of the OSL system. It was also found that the CTDI(100-efficiency) did not significantly change as the beam width increased and tube voltage changed. The average CTDI(100-efficiency) at the center of the head and body phantoms were 72.6% and 56.2%, respectively. The corresponding values for the periphery of the head and body phantoms were 85.0% and 81.7%. These results agreed very well with previous results from the literature using other detection techniques or Monte Carlo simulations. CONCLUSIONS: The LED-based OSL system can be an accurate alternative device for CT dose evaluations. CTDI100 measurement with the use of a 100 mm pencil ionization chamber substantially underestimates the CTDIinfinity value even with 5 mm collimated beam width. The established complete set of CTDI(100-efficiency) correction factors for various scan parameters allows for accurately estimating CTDIinfinity with the current use of pencil chamber and dose phantoms. Combined with the simple calibration, it gives this work great potential to be used not only in routine clinical quality assurance checks but also as a promising tool for patient organ dose assessment. PMID- 20831062 TI - Evaluating 99mTc Auger electrons for targeted tumor radiotherapy by computational methods. AB - PURPOSE: Technetium-99m (99mTc) has been widely used as an imaging agent but only recently has been considered for therapeutic applications. This study aims to analyze the potential use of 99mTc Auger electrons for targeted tumor radiotherapy by evaluating the DNA damage and its probability of correct repair and by studying the cellular kinetics, following 99mTc Auger electron irradiation in comparison to iodine-131 (131I) beta minus particles and astatine-211 (211At) alpha particle irradiation. METHODS: Computational models were used to estimate the yield of DNA damage (fast Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision repair algorithm), and cell kinetic effects (virtual cell radiobiology algorithm) after irradiation with the selected particles. RESULTS: The results obtained with the algorithms used suggested that 99mTc CKMMX (all M-shell Coster-Kroning--CK--and super-CK transitions) electrons and Auger MXY (all M-shell Auger transitions) have a therapeutic potential comparable to high linear energy transfer 211At alpha particles and higher than 131I beta minus particles. All the other 99mTc electrons had a therapeutic potential similar to 131I beta minus particles. CONCLUSIONS: 99mTc CKMMX electrons and Auger MXY presented a higher probability to induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful electrons for targeted tumor radiotherapy. PMID- 20831064 TI - The energy dependence of lithium formate and alanine EPR dosimeters for medium energy x rays. AB - PURPOSE: To perform a systematic investigation of the energy dependence of alanine and lilthium formate EPR dosimeters for medium energy x rays. METHODS: Lithium formate and alanine EPR dosimeters were exposed to eight different x-ray beam qualities, with nominal potentials ranging from 50 to 200 kV. Following ionometry based on standards of absorbed dose to water, the dosimeters were given two different doses of approximately 3 and 6 Gy for each radiation quality, with three dosimeters for each dose. A reference series was also irradiated to three different dose levels at a 60Co unit. The dose to water energy response, that is, the dosimeter reading per absorbed dose to water relative to that for 60Co gamma rays, was estimated for each beam quality. In addition, the energy response was calculated by Monte Carlo simulations and compared to the experimental energy response. RESULTS: The experimental energy response estimates ranged from 0.89 to 0.94 and from 0.68 to 0.90 for lithium formate and alanine, respectively. The uncertainties in the experimental energy response estimates were typically 3%. The relative effectiveness, that is, the ratio of the experimental energy response to that following Monte Carlo simulations was, on average, 0.96 and 0.94 for lithium formate and alanine, respectively. CONCLUSIONS: This work shows that lithium formate dosimeters are less dependent on x-ray energy than alanine. Furthermore, as the relative effectiveness for both lithium formate and alanine were systematically less than unity, the yield of radiation-induced radicals is decreased following x-irradiation compared to irradiation with 60Co y-rays. PMID- 20831065 TI - Characterization of masses in digital breast tomosynthesis: comparison of machine learning in projection views and reconstructed slices. AB - PURPOSE: In digital breast tomosynthesis (DBT), quasi-three-dimensional (3D) structural information is reconstructed from a small number of 2D projection view (PV) mammograms acquired over a limited angular range. The authors developed preliminary computer-aided diagnosis (CADx) methods for classification of malignant and benign masses and compared the effectiveness of analyzing lesion characteristics in the reconstructed DBT slices and in the PVs. METHODS: A data set of MLO view DBT of 99 patients containing 107 masses (56 malignant and 51 benign) was collected at the Massachusetts General Hospital with IRB approval. The DBTs were obtained with a GE prototype system which acquired 11 PVs over a 50 degree arc. The authors reconstructed the DBTs at 1 mm slice interval using a simultaneous algebraic reconstruction technique. The region of interest (ROI) containing the mass was marked by a radiologist in the DBT volume and the corresponding ROIs on the PVs were derived based on the imaging geometry. The subsequent processes were fully automated. For classification of masses using the DBT-slice approach, the mass on each slice was segmented by an active contour model initialized with adaptive k-means clustering. A spiculation likelihood map was generated by analysis of the gradient directions around the mass margin and spiculation features were extracted from the map. The rubber band straightening transform (RBST) was applied to a band of pixels around the segmented mass boundary. The RBST image was enhanced by Sobel filtering in the horizontal and vertical directions, from which run-length statistics texture features were extracted. Morphological features including those from the normalized radial length were designed to describe the mass shape. A feature space composed of the spiculation features, texture features, and morphological features extracted from the central slice alone and seven feature spaces obtained by averaging the corresponding features from three to 19 slices centered at the central slice were compared. For classification of masses using the PV approach, a feature extraction process similar to that described above for the DBT approach was performed on the ROIs from the individual PVs. Six feature spaces obtained from the central PV alone and by averaging the corresponding features from three to 11 PVs were formed. In each feature space for either the DBT-slice or the PV approach, a linear discriminant analysis classifier with stepwise feature selection was trained and tested using a two-loop leave-one-case-out resampling procedure. Simplex optimization was used to guide feature selection automatically within the training set in each leave-one-case-out cycle. The performance of the classifiers was evaluated by the area (Az) under the receiver operating characteristic curve. RESULTS: The test Az values from the DBT-slice approach ranged from 0.87 +/- 0.03 to 0.93 +/- 0.02, while those from the PV approach ranged from 0.78 +/- 0.04 to 0.84 +/- 0.04. The highest test Az of 0.93 +/- 0.02 from the nine-DBT-slice feature space was significantly (p = 0.006) better than the highest test Az of 0.84 +/- 0.04 from the nine-PV feature space. CONCLUSION: The features of breast lesions extracted from the DBT slices consistently provided higher classification accuracy than those extracted from the PV images. PMID- 20831066 TI - Evaluation of the peripheral dose in stereotactic radiotherapy and radiosurgery treatments. AB - PURPOSE: The main purpose of this work was to compare peripheral doses absorbed during stereotactic treatment of a brain lesion delivered using different devices. These data were used to estimate the risk of stochastic effects. METHODS: Treatment plans were created for an anthropomorphic phantom and delivered using a LINAC with stereotactic cones and a multileaf collimator, a CyberKnife system (before and after a supplemental shielding was applied), a TomoTherapy system, and a Gamma Knife unit. For each treatment, 5 Gy were prescribed to the target. Measurements were performed with thermoluminescent dosimeters inserted roughly in the position of the thyroid, sternum, upper lung, lower lung, and gonads. RESULTS: Mean doses ranged from of 4.1 (Gamma Knife) to 62.8 mGy (LINAC with cones) in the thyroid, from 2.3 (TomoTherapy) to 30 mGy (preshielding CyberKnife) in the sternum, from 1.7 (TomoTherapy) to 20 mGy (preshielding CyberKnife) in the upper part of the lungs, from 0.98 (Gamma Knife) to 15 mGy (preshielding CyberKnife) in the lower part of the lungs, and between 0.3 (Gamma Knife) and 10 mGy (preshielding CyberKnife) in the gonads. CONCLUSIONS: The peripheral dose absorbed in the sites of interest with a 5 Gy fraction is low. Although the risk of adverse side effects calculated for 20 Gy delivered in 5 Gy fractions is negligible, in the interest of optimum patient radioprotection, further studies are needed to determine the weight of each contributor to the peripheral dose. PMID- 20831067 TI - Dosimetric characterization of the iBEAM evo carbon fiber couch for radiotherapy. AB - PURPOSE: This study characterizes the dosimetric properties of the iBEAM evo carbon fiber couch manufactured by Medical Intelligence and examines the accuracy of the CMS XiO and Nucletron Oncentra Masterplan (OMP) treatment planning systems for calculating beam attenuation due to the presence of the couch. METHODS: To assess the homogeneity of the couch, it was CT scanned at isocentric height and a number of signal intensity profiles were generated and analyzed. To simplify experimental procedures, surface dose and central axis depth dose measurements were performed in a solid water slab phantom using Gafchromic film for 6 and 10 MV photon beams at gantry angles of 0 degree (normal incidence), 30 degrees, and 60 degrees with an inverted iBEAM couch placed on top of the phantom. Attenuation measurements were performed in a cylindrical solid water phantom with an ionization chamber positioned at the isocenter. Measurements were taken for gantry angles from 0 degree to 90 degrees in 10 degrees increments for both 6 and 10 MV photon beams. This setup was replicated in the XiO and OMP treatment planning systems. Dose was calculated using the pencil beam, collapsed cone, convolution, and superposition algorithms. RESULTS: The CT scan of the couch showed that it was uniformly constructed. Surface dose increased by (510 +/-0)% for a 6 MV beam and (600 +/- 20)% for a 10 MV beam passing through the couch at normal incidence. Obliquely incident beams resulted in a higher surface dose compared to normally incident beams for both open fields and fields with the couch present. Depth dose curves showed that the presence of the couch resulted in an increase in dose in the build up region. For 6 and 10 MV beams incident at 60 degrees, nearly all skin sparing was lost. Attenuation measurements derived using the ionization chamber varied from 2.7% (0 degree) to a maximum of 4.6% (50 degrees) for a 6 MV beam and from 1.9% (0 degree) to a maximum of 4.0% (50 degrees) for a 10 MV beam. The pencil beam and convolution algorithms failed to accurately calculate couch attenuation. The collapsed cone and superposition algorithms calculated attenuation within an absolute error of +/- 1.2% for 6 MV and +/- 0.8% for 10 MV for gantry angles from 0 degree to 40 degrees. Some differences in attenuation were observed dependent on how the couch was contoured. CONCLUSIONS: These results demonstrate that the presence of the iBEAM evo carbon fiber couch increases the surface dose and dose in the build up region. The inclusion of the couch in the planning scan is limited by the field of view employed and the couch height at the time of CT scanning. PMID- 20831068 TI - Impact of source-production revision on the dose-rate constant of 131Cs interstitial brachytherapy sources. AB - PURPOSE: Since its introduction in 2004, the model CS-1 Rev.1 131Cs source has been used in many radiation therapy clinics for prostate brachytherapy. In 2006, this source model underwent a Rev.2 production revision. The aim of this work was to investigate the dosimetric influences of the Rev.2 production revision using high-resolution photon spectrometry. METHODS: Three CS-1 Rev.1 and three CS-1 Rev.2 131Cs sources were used in this study. The relative photon energy spectrum emitted by each source in the transverse bisector of the source was measured using a high-resolution germanium detector designed for low-energy photon spectrometry. Based on the measured photon energy spectrum and the radioactivity distribution in the source, the dose-rate constant (lamda) of each source was determined. The effects of the Rev.2 production revision were quantified by comparing the emitted photon energy spectra and the lamda values determined for the sources manufactured before and after the production revision. RESULTS: The relative photon energy spectrum originating from the principal emissions of 131Cs was found to be nearly identical before and after the Rev.2 revision. However, the portion of the spectrum originating from the production of fluorescent x rays in niobium, a trace element present in the source construction materials, was found to differ significantly between the Rev.1 and Rev.2 sources. The peak intensity of the Nb Kalpha and Nb Kbeta fluorescent x rays from the Rev.2 source was approximately 35% of that from the Rev.1 source. Consequently, the nominal lamda value of the Rev.2 source was found to be greater than that determined for the Rev.1 source by approximately 0.7% +/- 0.5%. CONCLUSIONS: A significant reduction (65%) in relative niobium fluorescent x-ray yield was observed in the Rev.2 131Cs sources. The impact of this reduction on the dose-rate constant was found to be small, with a relative difference of less than 1%. This study demonstrates that photon spectrometry can be used as a sensitive and convenient tool for monitoring and for quantifying the dosimetric effects of brachytherapy source-production revisions. Because production revision can change both the geometry and the atomic composition of brachytherapy sources, its dosimetric impact should be carefully monitored and evaluated for each production revision. PMID- 20831069 TI - Evaluation of two-dimensional bolus effect of immobilization/support devices on skin doses: a radiochromic EBT film dosimetry study in phantom. AB - PURPOSE: In this study, the authors have quantified the two-dimensional (2D) perspective of skin dose increase using EBT film dosimetry in phantom in the presence of patient immobilization devices during conventional and IMRT treatments. METHODS: For 6 MV conventional photon field, the authors evaluated and quantified the 2D bolus effect on skin doses for six different common patient immobilization/support devices, including carbon fiber grid with Mylar sheet, Orfit carbon fiber base plate, balsa wood board, Styrofoam, perforated AquaPlast sheet, and alpha-cradle. For 6 and 15 MV IMRT fields, a stack of two film layers positioned above a solid phantom was exposed at the air interface or in the presence of a patient alpha-cradle. All the films were scanned and the pixel values were converted to doses based on an established calibration curve. The authors determined the 2D skin dose distributions, isodose curves, and cross sectional profiles at the surface layers with or without the immobilization/support device. The authors also generated and compared the dose area histograms (DAHs) and dose area products from the 2D skin dose distributions. RESULTS: In contrast with 20% relative dose [(RD) dose relative to dmax on central axis] at 0.0153 cm in the film layer for 6 MV 10 x 10 cm2 open field, the average RDs at the same depth in the film layer were 71%, 69%, 55%, and 57% for Orfit, balsa wood, Styrofoam, and alpha-cradle, respectively. At the same depth, the RDs were 54% under a strut and 26% between neighboring struts of a carbon fiber grid with Mylar sheet, and between 34% and 56% for stretched perforated AquaPlast sheet. In the presence of the alpha-cradle for the 6 MV (15 MV) IMRT fields, the hot spot doses at the effective measurement depths of 0.0153 and 0.0459 cm were 140% and 150%, (83% and 89%), respectively, of the isocenter dose. The enhancement factor was defined as the ratio of a given DAH parameter (minimum dose received in a given area) with and without the support device. For 6 MV conventional 10 x 10 cm2 field, the enhancement factor was the highest (3.4) for the Orfit carbon fiber plate. As for the IMRT field, the enhancement factors varied with the size of the area of interest and were as high as 3.8 (4.3) at the hot spot of 5 cm2 area in the top film layer (0.0153 cm) for 6 MV (15 MV) beams. CONCLUSIONS: Significant 2D bolus effect on skin dose in the presence of patient support and immobilization devices was confirmed and quantified with EBT film dosimetry. Furthermore, the EBT film has potential application for in vivo monitoring of the 2D skin dose distributions during patient treatments. PMID- 20831070 TI - Peak SNR in automated coronary calcium scoring: selecting CT scan parameters and statistically defined scoring thresholds. AB - PURPOSE: Development and verification of peak signal-to-noise ratio (SNR(P)) equations for determining optimum CT scanning and scoring parameters for a new automated coronary calcium scoring program (N-vivo). Experimental evaluation of the new program for scoring small calcium hydroxyapatite (CaHA) microspheres with small voxel CT images. METHODS: Theoretical SNR(P) equations were developed using measures of noise, resolution, contrast, scatter, and x-ray photon energy. A coronary calcium scoring test phantom containing very small CaHA microspheres was scanned simultaneously with a calibration phantom at three kVps, three voxel sizes, and three phantom sizes. Agatston and calibrated mass scores, noise standard deviations, peak noise, and peak signal voxel intensities were measured by the N-vivo method for individual microspheres and in patient CT scans. RESULTS: The SNR(P) equation was predictive of the optimum voxel size, kVp, and phantom size, and allowed automated computation of mass scoring thresholds specific to each patient and CT scan. The smallest microcalcification scored in the full sized phantom with the N-vivo method by calibrated mass score (volume 0.075 mm3, mass 0.17 mg) was approximately four times smaller than that scored with the Agatston method (0.27 mm3, mass 0.63 mg). CONCLUSIONS: The SNR(P) equation can be used to model and optimize calcium scoring and CT scan parameters. The common assumptions that noise is too high in thin slice CT or requires high radiation dose for CAC scoring are shown to be misleading. The N vivo method showed higher detection sensitivity for small microspheres and more consistent mass scores at different beam energies than the conventional Agatston method. Advanced calcium scoring methods with higher sensitivity may allow improved monitoring of plaque changes and provide earlier detection of atherosclerosis. PMID- 20831071 TI - Fast-marching segmentation of three-dimensional intravascular ultrasound images: a pre- and post-intervention study. AB - PURPOSE: Intravascular ultrasound (IVUS) is a vascular imaging technique that is used to study atherosclerosis since it has the ability to show the lumen and the vessel wall. Cross-sectional images of blood vessels are produced and they provide quantitative assessment of the vascular wall, information about the nature of atherosclerotic lesions, as well as the plaque shape and size. Due to the ultrasound speckle, catheter artifacts, or calcification shadows, the automated analysis of large IVUS data sets represents an important challenge. METHODS: A multiple interface 3D fast-marching method is presented for the detection of the lumen and external vessel wall boundaries. The segmentation is based on a combination of region and contour information, namely, the gray level probability density functions of the vessel structures and the intensity gradient. The detection of the lumen boundary is fully automatic. The segmentation method includes an interactive initialization procedure of the external vessel wall border. The segmentation method was applied to 20 in vivo IVUS data sets acquired from femoral arteries. This database contained three subgroups: Pullbacks acquired before balloon angioplasty (n=7), after the intervention (n=7), and at a 1 yr follow-up examination (n=6). Results were compared to validation contours that were manually traced by two experts on more than 1500 individual frames. RESULTS: For all subgroups, no significant difference was found between the area measurements of the segmentation and validation contours for the lumen and external vessel wall. Moreover, high intraclass correlation coefficients (> 0.96) between the area of the manually traced contours and detected boundaries with the fast-marching method were obtained for both vessel layers over the whole database. The segmentation performance was also evaluated with point-to-point contour distances between segmentation results and manually traced contours. A good overall accuracy was obtained with average distances < 0.13 mm and maximum distances < 0.46 mm, indicating a good performance in regions lacking information or containing artifacts. Only small differences of less than a pixel (0.02 mm) were observed between the average distance metrics of each subgroup, which prove the segmentation consistency. CONCLUSIONS: This new IVUS segmentation method provides accurate results that correspond well to the experts' manually traced contours, but requires much less manual interactions and is faster. PMID- 20831072 TI - Kilovoltage cone-beam CT: comparative dose and image quality evaluations in partial and full-angle scan protocols. AB - PURPOSE: To assess imaging dose of partial and full-angle kilovoltage CBCT scan protocols and to evaluate image quality for each protocol. METHODS: The authors obtained the CT dose index (CTDI) of the kilovoltage CBCT protocols in an on board imager by ion chamber (IC) measurements and Monte Carlo (MC) simulations. A total of six new CBCT scan protocols were evaluated: Standard-dose head (100 kVp, 151 mA s, partial-angle), low-dose head (100 kVp, 75 mA s, partial-angle), high quality head (100 kVp, 754 mA s, partial-angle), pelvis (125 kVp, 706 mA s, full angle), pelvis spotlight (125 kVp, 752 mA s, partial-angle), and low-dose thorax (110 kVp, 271 mA s, full-angle). Using the point dose method, various CTDI values were calculated by (1) the conventional weighted CTDI (CTDIw) calculation and (2) Bakalyar's method (CTDIwb). The MC simulations were performed to obtain the CTDIw and CTDIwb, as well as from (3) central slice averaging (CTDI(2D)) and (4) volume averaging (CTDI(3D)) techniques. The CTDI values of the new protocols were compared to those of the old protocols (full-angle CBCT protocols). Image quality of the new protocols was evaluated following the CBCT image quality assurance (QA) protocol [S. Yoo et al., "A quality assurance program for the on-board image, "Med. Phys. 33(11), 4431-4447 (2006)] testing Hounsfield unit (HU) linearity, spatial linearity/resolution, contrast resolution, and HU uniformity. RESULTS: The CTDI, were found as 6.0, 3.2, 29.0, 25.4, 23.8, and 7.7 mGy for the new protocols, respectively. The CTDI, and CTDIwb differed within +3% between IC measurements and MC simulations. Method (2) results were within +/- 12% of method (1). In MC simulations, the CTDIw and CTDIwb were comparable to the CTDI(2D) and CTDI(3D) with the differences ranging from -4.3% to 20.6%. The CTDI(3D) were smallest among all the CTDI values. CTDIw of the new protocols were found as approximately 14 times lower for standard head scan and 1.8 times lower for standard body scan than the old protocols, respectively. In the image quality QA tests, all the protocols except low-dose head and low-dose thorax protocols were within the tolerance in the HU verification test. The HU value for the two protocols was always higher than the nominal value. All the protocols passed the spatial linearity/resolution and HU uniformity tests. In the contrast resolution test, only high-quality head and pelvis scan protocols were within the tolerance. In addition, crescent effect was found in the partial-angle scan protocols. CONCLUSIONS: The authors found that CTDIw of the new CBCT protocols has been significantly reduced compared to the old protocols with acceptable image quality. The CTDIw values in the point dose method were close to the volume averaging method within 9%-21% for all the CBCT scan protocols. The Bakalyar's method produced more accurate dose estimation within 14%. The HU inaccuracy from low-dose head and low-dose thorax protocols can render incorrect dose results in the treatment planning system. When high soft-tissue contrast data are desired, high-quality head or pelvis scan protocol is recommended depending on the imaging area. The point dose method can be applicable to estimate CBCT dose with reasonable accuracy in the clinical environment. PMID- 20831073 TI - Variability in PET quantitation within a multicenter consortium. AB - PURPOSE: The purpose of this study was to evaluate the variability in quantitation of positron emission tomography (PET) data acquired within the context of a multicenter consortium. METHODS: PET quantitation phantoms designed by American Association of Physicists in Medicine/ Society of Nuclear Medicine Task Group 145 were sent to the ten member sites of the Pediatric Brain Tumor Consortium (PBTC), a NIH-funded research consortium investigating the biology and therapies for brain tumors in children. The phantoms were water-filled cylinders (18.6 cm inside height and 20.4 cm inside diameter) based on the standard ACR phantom with four small, "hot" cylinders of varying diameters (8, 12, 16, 25 mm, all with 38 mm height), consisting of an equilibrium mixture of 68Ge/68Ga in an epoxy matrix. At each site, the operator added the appropriate amount of 18F to the water in the background in order to attain a feature-to-background ratio of roughly 4:1. The phantom was imaged and reconstructed as if it were a brain PET scan for the PBTC. An approximately 12 mm circular region of interest (ROI) was placed over each feature and in a central area in the background. The mean and maximum pixel values for each ROI were requested from local sites in units of activity concentration (Bq/ml) and the standard uptake value (SUV) (g/mL) based on bodyweight. The activity concentration was normalized by the decay-corrected known activity concentration for the features, and reported as the absolute recovery coefficient (RC). In addition, central analyses were performed by two observers RESULTS: The ten sites successfully imaged the phantom within 5 months and submitted the quantitative results and the phantom image data to the PBTC Operations and Biostatistics Center. The local site-based and central analyses yielded similar mean values for RC. Local site-based SUV measurements of the hot cylindrical features yielded greater variability than central analysis (COV range of 29.9%-42.8% compared to 7.7%-23.2%). Correcting for miscalculations in the local site reported SUVs substantially reduced the variation to levels similar to the central analysis (COV range of 8.8%-18.4%) and also led to the local sites providing a similar mean of the SUV values to those from the central analysis. In the central analysis, the use of mean SUV in place of maximum SUV for an ROI of fixed size substantially reduced the variation in the SUV values (COV ranges of 7.7%-11.3% vs. 9.3%-23.2%). CONCLUSIONS: Based on this investigation, a SUV variability in the range of 10%-25% due solely to instrument and analysis factors can be expected in the context of a multicenter consortium if a central reading is used and quality assurance and quality control procedures are followed. The overall SUV variability can be expected to be larger than this due to biological and protocol factors. PMID- 20831074 TI - Fast and memory-efficient Monte Carlo-based image reconstruction for whole-body PET. AB - PURPOSE: Several studies have shown the benefit of an accurate system modeling using Monte Carlo techniques. For state-of-the-art whole-body positron emission tomography (PET) scanners, Monte Carlo-based image reconstruction is associated with a significant computational cost to calculate the system matrix as well as a large memory capacity to store it. In this article, the authors present a simulation-reconstruction framework to solve these problems on the Philips Gemini GS PET scanner. METHODS: A fast, realistic system matrix simulation module was developed using egs_pet, which is an efficient PET simulation code based on EGSnrc. The generated system matrix was then used in a rotator-based ordered subset expectation maximization (OS-EM) algorithm, which exploits the rotational symmetry of a cylindrical PET scanner. The system matrix was further compressed by using sparse storage techniques. RESULTS: The system matrix simulation took five days on 50 cores of Xeon 2.66 GHz, resulting in a system matrix of 2.01 GB. The entire system matrix could be stored in the main memory of a standard personal computer. The image quality in terms of contrast-noise trade-offs was considerably improved compared to a standard OS-EM algorithm. The image quality was also compared to the clinical software on the scanner using routine parameter settings. The contrast recovery coefficient of small hot spheres and cold spheres was significantly improved. CONCLUSIONS: The results indicated that the proposed framework could be used for this PET scanner with improved image quality. This method could also be applied to other state-of-the-art whole-body PET scanners and preclinical PET scanners with a similar shape. PMID- 20831075 TI - Automatic image guidance for prostate IMRT using low dose CBCT. AB - PURPOSE: Varian's On-Board Imager is a linac-integrated cone-beam CT (CBCT) system used at the authors' institution to acquire images prior to delivering each fraction of prostate intensity modulated radiotherapy. The images are used to determine a couch shift that realigns the tumor with the position obtained in the planning CT. However, this manual image-guided radiotherapy (IGRT) technique is operator dependent, time consuming, offers limited degrees of freedom, and requires significant imaging dose over the course of treatment. To overcome these problems, the authors propose two fully automatic IGRT techniques that require significantly less imaging dose. METHODS: Dose is reduced by lowering the x-ray tube mA s during CBCT acquisition at the cost of increasing image noise. In "forward" IGRT, the CBCT image is automatically registered to the planning CT to obtain the necessary couch shift. The "reverse" technique offers additional degrees of freedom as it involves nonrigid registration of the planning CT to the CBCT. Both techniques were evaluated using images of an anthropomorphic phantom with simulated motion and by retrospectively analyzing data from ten prostate cancer patients. RESULTS: IGRT error for the phantom data at 100% relative imaging dose was 8.2 +/- 3.7, 3.5 +/- 1.2,, and 2.1 +/- 0.6 mm for setup only, forward, and reverse techniques, respectively. For patient images acquired at 100% relative imaging dose, the errors were 5.4 +/- 1.7, 5.0 +/- 1.6, 5.0 +/- 2.0, and 4.0 +/- 1.6 mm for setup only, manual forward (performed clinically), automatic forward, and reverse IGRT, respectively. Furthermore, imaging dose could be reduced to 20% without a significant loss in image guidance accuracy. CONCLUSIONS: The presented image guidance methods are accurate while requiring only 20% of the standard imaging dose. The combination of low dose, automation, and accuracy enables frequent corrections during treatment, possibly leading to reduced margins and improved treatment outcomes. PMID- 20831076 TI - Evaluation of EBT-2 model GAFCHROMIC film performance in water. AB - PURPOSE: The authors present results of the measurements on the impact of radiochromic film immersion in water. The impact of film piece size, initial optical density, postimmersion waiting time prior to scanning, and the time film was kept in water has been investigated. The authors also investigated the pathways of water penetration into the film during the film immersion in water. METHODS: To study the impact of water immersion on change in optical density, the authors used various sizes of the latest EBT-2 model GAFCHROMICTM film: 2 x 2, 4 x 4, and 8 x 8 in.2. In addition, to test any existing dependence of the film's optical density on water diffusion, the authors used two sets of films: Unexposed (0 Gy) and film pieces exposed to a dose of 3 Gy. Times that film pieces were left in water ranged from 30 min to 24 h, and once the film was permanently removed from water, the authors also studied the impact of the scanning time (deltat) that ranged from 0 (films scanned right after removal from water) to 72 h postimmersion. RESULTS: While the penetration depth can reach as much as 9 mm around the edges of the EBT-2 GAFCHROMIC film, the anticipated dose error due to the change in optical density due to the water immersion appears to be negligible for the short immersions of the order of 30 min. However, as the immersion time increases, the anticipated dose error may reach 22 cGy on a 2 x 2 in.2 piece of film, which corresponds to 7% dose error at 3 Gy of measured dose. CONCLUSIONS: In this work, the authors report on an undoubted impact of radiochromic film immersion in water on the measured change in optical density, which may lead to systematic errors in dose measurements if the film is kept in water for longer periods of time. The magnitude of the impact depends on many parameters: Size of the film piece, initial optical density, postimmersion waiting time prior to scanning (defined by the current radiochromic film dosimetry protocol in. place), and the time film was kept in water. The authors also suggested various approaches in correcting for the change in netOD due to water penetration into the film, but the authors believe that the use of the control film piece would be the most appropriate. PMID- 20831077 TI - Light emission efficiency and imaging performance of Gd2O2S: Eu powder scintillator under x-ray radiography conditions. AB - PURPOSE: To evaluate Gd2O2S:Eu powder phosphor as a radiographic image receptor and to compare it to phosphors often used in radiography. Gd2O2S:Eu is nonhygroscopic, emitting red light with decay time close to that of Gd2O2S:Tb. METHODS: The light intensity emitted per unit of x-ray exposure rate (absolute luminescence efficiency) was measured for laboratory prepared screens with coating thicknesses of 33.1, 46.4, 63.1, 78.3, and 139.8 mg/cm2 and tube voltages ranging from 50 to 140 kVp. Parameters related to image quality such as the modulation transfer function (MTF) and the detective quantum efficiency (DQE) were also experimentally examined. In addition, a previously validated Monte Carlo code was used to estimate intrinsic x-ray absorption and optical properties, as well as the MTF and the Swank factor (I) of the Gd2O2S:Eu scintillators. RESULTS: Gd2O2S:Eu light intensity was found higher than that of single CsI:T1 crystal for tube voltages up to 100 kVp. The MTF and the DQE were found to be comparable with those of Gd2O2S:Tb and CsI:T1 screens. MTF estimated by the Monte Carlo code was found very close to the experimental MTF values. Gd2O2S:Eu showed peak emission in the wavelength range 620-630 nm. Its emission spectrum was excellently matched to various optical detectors (photodiodes, photocathodes, CCDs, and CMOS) employed in flat panel detectors. CONCLUSIONS: Gd2O2S:Eu is an efficient phosphor potentially well suited to radiography and especially to some digital detectors sensitive to red light. PMID- 20831078 TI - Evaluation of MatriXX for IMRT and VMAT dose verifications in peripheral dose regions. AB - PURPOSE: MatriXX is a two-dimensional ion chamber array designed for IMRT/VMAT (RapidArc, IMAT, etc.) dose verifications. Its dosimetric properties have been characterized for megavoltage beams in a number of studies; however, to the best of the authors' knowledge, there is still a lack of an investigation into its performance in the peripheral or low dose regions. In this work, the authors have carried out a systematic study on this issue. METHODS: The authors compare the performance of MatriXX with a cylindrical ion chamber in solid water phantoms in the peripheral dose regions. The comparisons are performed for a number of typical irradiation conditions that involve different gantry and/or MLC motions, field sizes, and distances to the target including static gantry/open fields, static gantry/sweeping MLC gap (mimicking an IMRT delivery), dynamic gantry/oscillating sweeping MLC gap (mimicking a VMAT delivery), as well as clinical IMRT and VMAT plans. RESULTS: MatriXX, when used according to the manufacturer's recommendations, is found to disagree with an ion chamber in peripheral dose regions. This disagreement has been attributed to four types of MatriXX errors, namely, positive bias, over-response to scattered doses, round off error, and angular dependence, all of which contribute to dose inaccuracies in the peripheral regions. The positive bias, which is independent of the dose level, is cumulative when MatriXX operates in the movie mode. The accumulation is proportional to the number of movie frames (snaps) when the sampling time is greater than 500 ms and is proportional to the overall movie time for a sampling time shorter than 500 ms. This behavior suggests multiple sources of the bias. MatriXX is also found to over-respond to peripheral doses by about 2.0% for the regions investigated in this work (3-15 cm from the field edge), where phantom scatter and collimator scatter dominate. Round-off error is determined to be due to insufficient precision in conversion of the raw signals to MatriXX software data for low doses. Angular dependence is defined as the dose response of MatriXX at different gantry angles. Up to 8% difference in detector response has been observed between 0 degree and 180 degrees. Possible sources of these errors are discussed and a correction method is suggested. With corrections, MatriXX shows good agreement with the ion chamber in all cases involving different gantry and/or MLC dynamics, as well as the clinical plans. For both primary and peripheral doses, MatriXX shows dose linearity down to 2 cGy with an accuracy of within 1% of the local dose. CONCLUSIONS: The performance of MatriXX has been systematically evaluated in the peripheral dose regions. Major sources of error associated with MatriXX are identified and a correction method is suggested. This method has been successfully tested using both experimental and clinical plans. In all cases, good agreements between MatriXX and an ion chamber are achieved after corrections. The authors conclude that with proper corrections, MatriXX can be reliably used for peripheral dose measurements within the ranges studied. PMID- 20831079 TI - In vivo quantitative imaging of normal and cancerous breast tissue using broadband diffuse optical tomography. AB - PURPOSE: A NIR tomography system that combines frequency domain (FD) and continuous wave (CW) measurements was used to image normal and malignant breast tissues. METHODS: FD acquisitions were confined to wavelengths less than 850 nm because of detector limitations, whereas light from longer wavelengths (up to 948 nm) was measured in CW mode with CCD-coupled spectrometer detection. The two data sets were combined and processed in a single spectrally constrained reconstruction to map concentrations of hemoglobin, water, and lipid, as well as scattering parameters in the breast. RESULTS: Chromophore concentrations were imaged in the breasts of nine asymptomatic volunteers to evaluate their intrasubject and intersubject variability. Normal subject data showed physiologically expected trends. Images from three cancer patients indicate that the added CW data is critical to recovering the expected increases in water and decreases in lipid content within malignancies. Contrasts of 1.5 to twofold in hemoglobin and water values were found in cancers. CONCLUSIONS: In vivo breast imaging with instrumentation that combines FD and CW NIR data acquisition in a single spectral reconstruction produces more accurate hemoglobin, water, and lipid results relative to FD data alone. PMID- 20831080 TI - Three dimensional intensity modulated brachytherapy (IMBT): dosimetry algorithm and inverse treatment planning. AB - PURPOSE: The feasibility of intensity modulated brachytherapy (IMBT) to improve dose conformity for irregularly shaped targets has been previously investigated by researchers by means of using partially shielded sources. However, partial shielding does not fully explore the potential of IMBT. The goal of this study is to introduce the concept of three dimensional (3D) intensity modulated brachytherapy and solve two fundamental issues regarding the application of 3D IMBT treatment planning: The dose calculation algorithm and the inverse treatment planning method. METHODS: A 3D IMBT treatment planning system prototype was developed using the MATLAB platform. This system consists of three major components: (1) A comprehensive IMBT source calibration method with dosimetric inputs from Monte Carlo (EGSnrc) simulations; (2) a "modified TG-43" (mTG-43) dose calculation formalism for IMBT dosimetry; and (3) a physical constraint based inverse IMBT treatment planning platform utilizing a simulated annealing optimization algorithm. The model S700 Axxent electronic brachytherapy source developed by Xoft, Inc. (Fremont, CA), was simulated in this application. Ten intracavitary accelerated partial breast irradiation (APBI) cases were studied. For each case, an "isotropic plan" with only optimized source dwell time and a fully optimized IMBT plan were generated and compared to the original plan in various dosimetric aspects, such as the plan quality, planning, and delivery time. The issue of the mechanical complexity of the IMBT applicator is not addressed in this study. RESULTS: IMBT approaches showed superior plan quality compared to the original plans and tht isotropic plans to different extents in all studied cases. An extremely difficult case with a small breast and a small distance to the ribs and skin, the IMBT plan minimized the high dose volume V200 by 16.1% and 4.8%, respectively, compared to the original and the isotropic plans. The conformity index for the target was increased by 0.13 and 0.04, respectively. The maximum dose to the skin was reduced by 56 and 28 cGy, respectively, per fraction. Also, the maximum dose to the ribs was reduced by 104 and 96 cGy, respectively, per fraction. The mean dose to the ipsilateral and contralateral breasts and lungs were also slightly reduced by the IMBT plan. The limitations of IMBT are the longer planning and delivery time. The IMBT plan took around 2 h to optimize, while the isotropic plan optimization could reach the global minimum within 5 min. The delivery time for the IMBT plan is typically four to six times longer than the corresponding isotropic plan. CONCLUSIONS: In this study, a dosimetry method for IMBT sources was proposed and an inverse treatment planning system prototype for IMBT was developed. The improvement of plan quality by 3D IMBT was demonstrated using ten APBI case studies. Faster computers and higher output of the source can further reduce plan optimization and delivery time, respectively. PMID- 20831081 TI - An attenuation integral digital imaging technique for the treatment portal verification of conventional and intensity-modulated radiotherapy. AB - PURPOSE: To propose an attenuation integral digital imaging (AIDI) technique for the treatment portal verification of conventional and intensity-modulated radiotherapy (IMRT). METHODS: In AIDI technique, an open in air fluence image Io and a patient fluence image I were acquired under the same exposure. Then after doing the dark field correction for both the Io and I, the AIDI image was simply calculated as log(Io/I), which is the attenuation integral along the ray path from the x-ray source to a detector pixel element. Theoretical analysis for the low contrast detection and the contrast to noise ratio (CNR) of AIDI was presented and compared to those for the fluence imaging. With AIDI, the variation of x-ray fluence and the variation of individual detector pixel's response can be automatically compensated without using the flood field correction. RESULTS: The AIDI image for a contrast detail phantom demonstrated that it can efficiently suppress the background structures such as the couch and generate better visibility for low contrast objects with megavoltage x rays. The AIDI image acquired for a Catphan 500 phantom using a 60 degrees electronic dynamic wedge field also revealed more contrast disks than the fluence imaging did. Finally, AIDI for an IMRT field of a head/neck patient successfully displayed the anatomical structures underneath the treatment portal but not shown in fluence imaging. CONCLUSIONS: For IMRT and high degree wedge beams, direct imaging using them is difficult because their photon fluence is highly nonuniform. But AIDI can be used for the treatment portal verification of these beams. PMID- 20831082 TI - Assessment of ultrasound modulation of near infrared light on the quantification of scattering coefficient. AB - PURPOSE: To assess the effect of ultrasound modulation of near infrared (NIR) light on the quantification of scattering coefficient in tissue-mimicking biological phantoms. METHODS: A unique method to estimate the phase of the modulated NIR light making use of only time averaged intensity measurements using a charge coupled device camera is used in this investigation. These experimental measurements from tissue-mimicking biological phantoms are used to estimate the differential pathlength, in turn leading to estimation of optical scattering coefficient. A Monte-Carlo model based numerical estimation of phase in lieu of ultrasound modulation is performed to verify the experimental results. RESULTS: The results indicate that the ultrasound modulation of NIR light enhances the effective scattering coefficient. The observed effective scattering coefficient enhancement in tissue-mimicking viscoelastic phantoms increases with increasing ultrasound drive voltage. The same trend is noticed as the ultrasound modulation frequency approaches the natural vibration frequency of the phantom material. The contrast enhancement is less for the stiffer (larger storage modulus) tissue, mimicking tumor necrotic core, compared to the normal tissue. CONCLUSIONS: The ultrasound modulation of the insonified region leads to an increase in the effective number of scattering events experienced by NIR light, increasing the measured phase, causing the enhancement in the effective scattering coefficient. The ultrasound modulation of NIR light could provide better estimation of scattering coefficient. The observed local enhancement of the effective scattering coefficient, in the ultrasound focal region, is validated using both experimental measurements and Monte-Carlo simulations. PMID- 20831083 TI - Quantitative microwave-induced thermoacoustic tomography. AB - PURPOSE: Microwave-induced thermoacoustic tomography (MI-TAT) is an imaging modality that exploits dielectric contrast while producing images with high ultrasound resolution. Existing reconstruction algorithms for MI-TAT are qualitative and can image only the distribution of the absorbed microwave energy or power loss density. Here the authors describe a method for quantitative MI-TAT and obtain the distribution of dielectric property which directly correlates with tissue structural and functional information. METHODS: The authors implement the quantitative MI-TAT method based on the finite-element (FE) solution to the Helmholtz equation for electromagnetic field coupled with the thermoacoustic wave equation. Regularization techniques are also used in the FE-based reconstruction algorithm. RESULTS: Simulation results are obtained under various practical scenarios including different noise levels, different contrast levels between the heterogeneity and background region, and multiple targets with various sizes and shapes. CONCLUSIONS: The quantitative MI-TAT method described can provide accurate recovery of conductivity distribution in heterogeneous media and is insensitive to noise effect. PMID- 20831084 TI - A symmetric nonrigid registration method to handle large organ deformations in cervical cancer patients. AB - PURPOSE: Modern radiotherapy requires assessment of patient anatomical changes. By using unidirectional registration methods, the quantified anatomical changes are asymmetric, i.e., depend on the direction of the registration. Moreover, the registration is challenged by the large and complex organ deformations that can occur in, e.g., cervical cancer patients. The aim of this work was to develop, test, and validate a symmetric feature-based nonrigid registration method that can handle organs with large-scale deformations. METHODS: A symmetric version of the unidirectional thin plate spline robust point matching (TPS-RPM) algorithm was developed, implemented, tested, and validated. Tests were performed by using the delineated cervix and uterus and bladder in CT scans of five cervical cancer patients. For each patient, five CT scans with a large variability in organ shape, volume, and deformations were acquired. Both the symmetric and the unidirectional algorithm were employed to calculate the registration geometric accuracy (surface distance and surface coverage errors), the inverse consistency, the residual distances after transforming anatomical landmarks, and the registration time. Additionally, to facilitate the further use of our symmetric method, a large set of input parameters was tested. RESULTS: The developed symmetric algorithm handled successfully the registration of bladders with extreme volume change for which TPS-RPM failed. Compared to the unidirectional algorithm the symmetric algorithm improved, for the registration of organs with large volume change, the inverse consistency by 78% and the surface coverage by 46%. Similarly, for organs with small volume change, the symmetric algorithm improved the inverse consistency by 69% and the surface coverage by 13%. The method allowed for anatomically coherent registration in only 35 s for cervix uterus and 151 s for bladder, while keeping the inverse consistency errors around 1 mm and the surface matching errors below 1 mm. Compared to rigid alignment the symmetric method reduced the residual distances between anatomical landmarks from a range of 5.8 +/- 2-70.1 +/- 20.1 mm to a range of 1.9 +/- 0.2-8.5 +/- 5.2 mm. CONCLUSIONS: The developed symmetric method could be employed to perform fast, accurate, consistent, and anatomically coherent registration of organs with large and complex deformations. Therefore, the method is a useful tool that could support further developments in high precision image guided radiotherapy. PMID- 20831086 TI - Ant colony algorithm implementation in electron and photon Monte Carlo transport: application to the commissioning of radiosurgery photon beams. AB - PURPOSE: In this work, the authors describe an approach which has been developed to drive the application of different variance-reduction techniques to the Monte Carlo simulation of photon and electron transport in clinical accelerators. METHODS: The new approach considers the following techniques: Russian roulette, splitting, a modified version of the directional bremsstrahlung splitting, and the azimuthal particle redistribution. Their application is controlled by an ant colony algorithm based on an importance map. RESULTS: The procedure has been applied to radiosurgery beams. Specifically, the authors have calculated depth dose profiles, off-axis ratios, and output factors, quantities usually considered in the commissioning of these beams. The agreement between Monte Carlo results and the corresponding measurements is within approximately 3%/0.3 mm for the central axis percentage depth dose and the dose profiles. The importance map generated in the calculation can be used to discuss simulation details in the different parts of the geometry in a simple way. The simulation CPU times are comparable to those needed within other approaches common in this field. CONCLUSIONS: The new approach is competitive with those previously used in this kind of problems (PSF generation or source models) and has some practical advantages that make it to be a good tool to simulate the radiation transport in problems where the quantities of interest are difficult to obtain because of low statistics. PMID- 20831085 TI - Multibeam field emission x-ray system with half-scan reconstruction algorithm. AB - PURPOSE: In this article, the authors propose a multibeam field emission x-ray (MBFEX) system along with a half-scan fan-beam reconstruction algorithm. METHODS: The proposed system consists of a linear CNT-based MBFEX source array, a single large area detector that is divided into same number of segments as the number of x-ray beams, a multihole collimator that aligns each beam with a corresponding detector segment, and a sample rotation stage. The collimator is placed between the source and the object to restrict the x-ray radiations through the target object only. In this design, all the x-ray beams are activated simultaneously to provide multiple projection views of the object. The detector is virtually segmented and synchronized with the x-ray exposure and the physiological signals when gating is involved. The transmitted x-ray intensity from each beam is collected by the corresponding segment on the detector. After each exposure, the object is rotated by a step angle until sufficient data set is collected. The half-scan reconstruction formula for MBFEX system is derived from the conventional filtered backprojection algorithm. To demonstrate the advantages of the system and method in reducing motion artifacts, the authors performed simulations with both standard and dynamic Shepp-Logan phantoms. RESULTS: The numerical results indicate that the proposed multibeam system and the associated half-scan algorithm can effectively reduce the scanning time and improve the image quality for a time-varying object. CONCLUSIONS: The MBFEX technique offers an opportunity for the innovation of multisource imaging system. PMID- 20831087 TI - Prostate and seminal vesicle volume based consideration of prostate cancer patients for treatment with 3D-conformal or intensity-modulated radiation therapy. AB - PURPOSE: The purpose of this article was to determine the suitability of the prostate and seminal vesicle volumes as factors to consider patients for treatment with image-guided 3D-conformal radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT), using common dosimetry parameters as comparison tools. METHODS: Dosimetry of 3D and IMRT plans for 48 patients was compared. Volumes of prostate, SV, rectum, and bladder, and prescriptions were the same for both plans. For both 3D and IMRT plans, expansion margins to prostate+SV (CTV) and prostate were 0.5 cm posterior and superior and 1 cm in other dimensions to create PTV and CDPTV, respectively. Six-field 3D plans were prepared retrospectively. For 3D plans, an additional 0.5 cm margin was added to PTV and CDPTV. Prescription for both 3D and IMRT plans was the same: 45 Gy to CTV followed by a 36 Gy boost to prostate. Dosimetry parameters common to 3D and IMRT plans were used for comparison: Mean doses to prostate, CDPTV, SV, rectum, bladder, and femurs; percent volume of rectum and bladder receiving 30 (V30), 50 (V50), and 70 Gy (V70), dose to 30% of rectum and bladder, minimum and maximum point dose to CDPTV, and prescription dose covering 95% of CDPTV (D95). RESULTS: When the data for all patients were combined, mean dose to prostate and CDPTV was higher with 3D than IMRT plans (P < 0.01). Mean D95 to CDPTV was the same for 3D and IMRT plans (P > 0.2). On average, among all cases, the minimum point dose was less for 3D-CRT plans and the maximum point dose was greater for 3D-CRT than for IMRT (P < 0.01). Mean dose to 30%, rectum with 3D and IMRT plans was comparable (P > 0.1). V30 was less (P < 0.01), V50 was the same (P > 0.2), and V70 was more (P < 0.01) for rectum with 3D than IMRT plans. Mean dose to bladder was less with 3D than IMRT plans (P < 0.01). V30 for bladder with 3D plans was less than that of IMRT plans (P < 0.01). V50 and V70 for 3D plans were the same for 3D and IMRT plans (P > 0.2). Mean dose to femurs was more with 3D than IMRT plans (P < 0.01). For a given patient, mean dose and dose to 30% rectum and bladder were less with 3D than IMRT plans for prostate or prostate+SV volumes <65 (38/48) and 85 cm3 (39/48), respectively (P < 0.01). The larger the dose to rectum or bladder with 3D plans, the larger also was the dose to these structures with IMRT (P < 0.001). For both 3D and IMRT plans, dose to rectum and bladder increased with the increase in the volumes of prostate and seminal vesicles (P < 0.02 to 0.001). CONCLUSIONS: Volumes of prostate and seminal vesicles provide a reproducible and consistent basis for considering patients for treatment with image-guided 3D or IMRT plans. Patients with prostate and prostate+SV volumes <65 and 85 cm3, respectively, would be suitable for 3D-CRT. Patients with prostate and prostate+SV volumes >65 and 85 cm3, respectively, might get benefit from IMRT. PMID- 20831088 TI - Computerized comprehensive data analysis of lung imaging database consortium (LIDC). AB - PURPOSE: Lung Image Database Consortium (LIDC) is the largest public CT image database of lung nodules. In this study, the authors present a comprehensive and the most updated analysis of this dynamically growing database under the help of a computerized tool, aiming to assist researchers to optimally use this database for lung cancer related investigations. METHODS: The authors developed a computer scheme to automatically match the nodule outlines marked manually by radiologists on CT images. A large variety of characteristics regarding the annotated nodules in the database including volume, spiculation level, elongation, interobserver variability, as well as the intersection of delineated nodule voxels and overlapping ratio between the same nodules marked by different radiologists are automatically calculated and summarized. The scheme was applied to analyze all 157 examinations with complete annotation data currently available in LIDC dataset. RESULTS: The scheme summarizes the statistical distributions of the abovementioned geometric and diagnosis features. Among the 391 nodules, (1) 365 (93.35%) have principal axis length < or =20 mm; (2) 120, 75, 76, and 120 were marked by one, two, three, and four radiologists, respectively; and (3) 122 (32.48%) have the maximum volume overlapping ratios -80% for the delineations of two radiologists, while 198 (50.64%) have the maximum volume overlapping ratios <60%. The results also showed that 72.89% of the nodules were assessed with malignancy score between 2 and 4, and only 7.93% of these nodules were considered as severely malignant (malignancy > or =4). CONCLUSIONS: This study demonstrates that LIDC contains examinations covering a diverse distribution of nodule characteristics and it can be a useful resource to assess the performance of the nodule detection and/or segmentation schemes. PMID- 20831089 TI - Estimation of microscopic dose enhancement factor around gold nanoparticles by Monte Carlo calculations. AB - PURPOSE: An approach known as gold nanoparticle-aided radiation therapy (GNRT) is a recent development in radiation therapy which seeks to make a tumor more susceptible to radiation damage by modifying its photon interaction properties with an infusion of gold nanoparticles (GNPs). The purpose of this study was to quantify the energy deposition due to secondary electrons from GNPs on a nanometer scale and to calculate the corresponding microscopic dose enhancement factor around GNPs. METHODS: The Monte Carlo code EGSnrc was modified to obtain the spectra of secondary electrons from atoms of gold approximating GNPs and molecules of water under photon irradiation of a tumor loaded with GNPs. Six different photon sources were used: 125I, 103Pd, 169Yb, 192Ir, 50 kVp, and 6 MV x rays. Treating the scored electron spectra as point sources within an infinite medium of water, the event-by-event Monte Carlo code NOREC was used to quantify the radial dose distribution, giving rise to gold/water electron dose point kernels and corresponding microscopic dose enhancement factors. These kernels were applied to a test case based on a scanning electron microscope image of a GNP distribution in tissue, enabling the determination of the microscopic dose enhancement at each dose point. RESULTS: For the lower energy sources 125I, 103Pd, 169Yb, and 50 kVp, the secondary electron fluence within a GNP-loaded tumor was increased by as much as two orders of magnitude, leading to two orders of magnitude increase in electron energy deposition over radial distances up to 10 microm. For the test case considered, the dose was enhanced by factors ranging from 2 to 20 within 5 microm of GNPs, and by 5% as far away as 30 microm. CONCLUSIONS: This study demonstrates a remarkable microscopic dose enhancement due to GNPs and low energy photon sources. By quantifying the microscopic dose enhancement factor for a given photon source as a function of distance from GNPs, it also enables the selection of either a passive or an active tumor targeting strategy using GNPs which will maximize the radiobiological benefit from GNRT. PMID- 20831090 TI - Combined mixed approach algorithm for in-line phase-contrast x-ray imaging. AB - PURPOSE: In the past decade, phase-contrast imaging (PCI) has been applied to study different kinds of tissues and human body parts, with an increased improvement of the image quality with respect to simple absorption radiography. A technique closely related to PCI is phase-retrieval imaging (PRI). Indeed, PCI is an imaging modality thought to enhance the total contrast of the images through the phase shift introduced by the object (human body part); PRI is a mathematical technique to extract the quantitative phase-shift map from PCI. A new phase retrieval algorithm for the in-line phase-contrast x-ray imaging is here proposed. METHODS: The proposed algorithm is based on a mixed transfer-function and transport-of-intensity approach (MA) and it requires, at most, an initial approximate estimate of the average phase shift introduced by the object as prior knowledge. The accuracy in the initial estimate determines the convergence speed of the algorithm. The proposed algorithm retrieves both the object phase and its complex conjugate in a combined MA (CMA). RESULTS: Although slightly less computationally effective with respect to other mixed-approach algorithms, as two phases have to be retrieved, the results obtained by the CMA on simulated data have shown that the obtained reconstructed phase maps are characterized by particularly low normalized mean square errors. The authors have also tested the CMA on noisy experimental phase-contrast data obtained by a suitable weakly absorbing sample consisting of a grid of submillimetric nylon fibers as well as on a strongly absorbing object made of a 0.03 mm thick lead x-ray resolution star pattern. The CMA has shown a good efficiency in recovering phase information, also in presence of noisy data, characterized by peak-to-peak signal-to-noise ratios down to a few dBs, showing the possibility to enhance with phase radiography the signal-to-noise ratio for features in the submillimetric scale with respect to the attenuation-based imaging. CONCLUSIONS: It has been shown that phase-retrieved radiographies can be used both to have quantitative phase information about soft tissues, complementary to the attenuation information, and to enhance the visibility of details inside soft tissues, with higher efficiency with respect to phase radiography. PMID- 20831091 TI - Designing passive MRI-safe implantable conducting leads with electrodes. AB - PURPOSE: The presence of implanted electronic devices with conducting leads and electrodes are contraindicated for magnetic resonance imaging (MRI), denying many patients its potential benefits. The prime concern is MRI's radio frequency (RF) fields, which can cause elevated local specific absorption rates (SARs) and potential heat injury. The purpose of this article is to develop and compare a range of passive implantable "MRI-safe" lead designs. METHODS: Conducting leads incorporating different lengths (3-75 cm), insulation thicknesses (0-105 microm), resistances (100-3000 omega), coiled conductors (inner diameter < or = 1.2 mm), high-impedance (135-2700 omega) RF traps, and single-coiled and triple-coiled coaxial-wound "billabong" leads with reversed coil sections that oppose and reduce the induced current, are investigated both experimentally using local temperature measurements, and by numerical full-wave electromagnetic field analysis of the local SAR, in three different-sized bioanalogous model saline-gel phantoms at 1.5 T MRI and 4 W/kg exposure. RESULTS: In all designs, the maximum computed 1 g average SAR and experimental temperature rise occur at the bare electrodes. Electrode heating increases with lead insulation thickness and peaks for uncoiled leads 25-50 cm long. A reasonable match between computed SAR and the point SAR estimated from thermal sensors obtained by approximating the computation volume to that of the thermal probes. Factors that maximize the impedance of leads with resistive, coiled, RF trap and billabong elements can effectively limit heating below 1-2 degrees, but folded lead configurations can be a concern. The RF trap and billabong designs can both support multiple conductors and electrodes, with billabong prototype leads also heating <1 degrees C when tested for 3 T MRI. CONCLUSIONS: Lead insulation and length strongly affect implanted lead safety to RF exposure during MRI. Lead designs employing impedance and reversed winding sections offer hope for the development of passive, MRI-safe, implantable conducting leads for future human use. PMID- 20831092 TI - A generic geometric calibration method for tomographic imaging systems with flat panel detectors--a detailed implementation guide. AB - PURPOSE: To present a generic geometric calibration method for tomographic imaging systems with flat-panel detectors in a very detailed manner, in the aim to provide a useful tool to the public domain. METHODS: The method is based on a projection matrix which represents a mapping from 3D object coordinate system to 2D projection image plane. The projection matrix can be determined experimentally through the imaging of a phantom of known marker geometry. Accurate implementation was accomplished through direct computation algorithms, including a novel ellipse fitting using singular value decomposition and data normalization. Benefits of the method include: (1) It is capable of being applied to systems of different scan trajectories, source-detector alignments, and detector orientations; (2) projection matrices can be utilized in image reconstructions or in the extraction of explicit geometrical parameters; and (3) the method imposes minimal limits on the design of calibration phantom. C++ programs that calculate projection matrices and extract geometric parameters from them are also provided. For validation, the calibration method was applied to the computer simulation of a cone-beam CT system, as well as to three tomosynthesis prototypes of different source-detector movement patterns: Source and detector rotating synchronizedly; source rotating and detector wobbling; and source rotating and detector staying stationary. RESULTS: Projection matrices were computed on a view by view basis. Geometric parameters extracted from projection matrices were consistent with actual settings. Images were reconstructed by directly using projection matrices, and were compared to virtual Shepp-Logan image for CT simulation and to central projection images of CIRS breast phantoms for tomosynthesis prototypes. They showed no obvious distortion or blurring, indicating the high quality of geometric calibration results. When the computed central ray offsets were perturbed with Gaussian noises of 1 pixel standard deviation, the reconstructed image showed apparent distortion, which further demonstrated the accuracy of the geometric calibration method. CONCLUSIONS: The method is suitable for tomographic imaging systems with flat-panel detectors. PMID- 20831093 TI - ADC response to radiation therapy correlates with induced changes in radiosensitivity. AB - PURPOSE: Magnetic resonance imaging was used to compare the responses of human glioma tumor xenografts to a single fraction of radiation, where a change in radiosensitivity was induced by use of a suture-based ligature. METHODS: Ischemia was induced by use of a suture-based ligature. Six mice were treated with 800 cGy of 200 kVp x rays while the ligature was applied. An additional six mice had the ligature applied for the same length of time but were not irradiated. Quantitative maps of each tumor were produced of water apparent diffusion coefficient (ADC) and transverse relaxation time (T2). Mice were imaged before and at multiple points after treatment. Volumetric, ADC, and T2 responses of the ligated groups were compared to previously measured responses of the same tumor model to the same radiation treatment, as well as those from an untreated control group. RESULTS: Application of the ligature without irradiation did not affect tumor ADC values, but did produce a temporary decrease in tumor T2 values. Average tumor T2 was reduced by 6.2% 24 h after the ligature was applied. Average tumor ADC increased by 9.6% 7 days after irradiation with a ligature applied. This response was significantly less than that observed in the same tumor model when no ligature is present (21.8% at 7 days after irradiation). CONCLUSIONS: These observations indicate that the response of ADC to radiation therapy is not determined entirely by physical dose deposition, but at least in part by radiosensitivity and resultant biological response. PMID- 20831094 TI - The sensitivity of patient specific IMRT QC to systematic MLC leaf bank offset errors. AB - PURPOSE: Patient specific IMRT QC is performed routinely in many clinics as a safeguard against errors and inaccuracies which may be introduced during the complex planning, data transfer, and delivery phases of this type of treatment. The purpose of this work is to evaluate the feasibility of detecting systematic errors in MLC leaf bank position with patient specific checks. METHODS: 9 head and neck (H&N) and 14 prostate IMRT beams were delivered using MLC files containing systematic offsets (+/- 1 mm in two banks, +/- 0.5 mm in two banks, and 1 mm in one bank of leaves). The beams were measured using both MAPCHECK (Sun Nuclear Corp., Melbourne, FL) and the aS1000 electronic portal imaging device (Varian Medical Systems, Palo Alto, CA). Comparisons with calculated fields, without offsets, were made using commonly adopted criteria including absolute dose (AD) difference, relative dose difference, distance to agreement (DTA), and the gamma index. RESULTS: The criteria most sensitive to systematic leaf bank offsets were the 3% AD, 3 mm DTA for MAPCHECK and the gamma index with 2% AD and 2 mm DTA for the EPID. The criterion based on the relative dose measurements was the least sensitive to MLC offsets. More highly modulated fields, i.e., H&N, showed greater changes in the percentage of passing points due to systematic MLC inaccuracy than prostate fields. CONCLUSIONS: None of the techniques or criteria tested is sufficiently sensitive, with the population of IMRT fields, to detect a systematic MLC offset at a clinically significant level on an individual field. Patient specific QC cannot, therefore, substitute for routine QC of the MLC itself. PMID- 20831095 TI - Validation of 3D reconstructions of a mimicked femoral artery with an ultrasound imaging robotic system. AB - PURPOSE: The degree of stenosis is the most important criterion to assess peripheral arterial disease manifested by atherosclerosis mainly in lower limb arteries. Ultrasound (U.S.) imaging offers low-cost, safe, and convenient options to evaluate this disease, but most U.S. freehand approaches cannot optimally locate stenoses and map lower limb arterial geometries. A 3D-U.S. imaging robotic system that can control and standardize image acquisition by scanning typically encountered diseased arterial lower limb segments is presented and validated with phantoms. METHODS: A Z-phantom calibration procedure was used to characterize spatial transformation of the U.S. probe image plane for different clinical image acquisition settings. Moreover, the accuracy of the calibration transform to reconstruct a lower-limb-mimicking vessel geometry was evaluated with a vascular phantom. RESULTS: A 3D calibration precision of 0.47 +/- 0.27 mm was achieved. Reconstruction errors were less than 1.74 +/- 0.08 mm in all 3D vessel representations and the cross-sectional areas of each image section were close to those of gold standard phantom measures. The best reconstruction accuracy (smallest error) was 0.40 +/- 0.03 mm. CONCLUSION: Altogether, these results demonstrate the potential of the robotic scanner to adequately represent lower limb vessels for the clinical evaluation of stenoses. PMID- 20831096 TI - Comment on "On the insensitivity of single field planar dosimetry to IMRT inaccuracies" [Med. phys. 37, 2516-2524 (2010)]. PMID- 20831097 TI - The question of friction. PMID- 20831098 TI - Dr. Ravindra Nanda on orthodontic mechanics. Interview by Robert G Keim. PMID- 20831099 TI - A new method for superimposition of CBCT volumes. PMID- 20831100 TI - Forced eruption of an impacted third molar using a bracket-head miniscrew. PMID- 20831101 TI - Miniscrew-supported transitional tooth replacement: an esthetic alternative. PMID- 20831102 TI - Etching masks for precise indirect bonding. PMID- 20831103 TI - Clinical application of the Essix III Corrector. PMID- 20831104 TI - 'Ideal' nurses need support. PMID- 20831105 TI - Chief nurse to push for profession's place on key NHS board. Interview by Tamsin Snow. PMID- 20831106 TI - Drive to abolish 'politically motivated' NHS targets raises serious clinical issues. PMID- 20831107 TI - Champions of dementia care. Interview by Jenny Knight. AB - Bupa nurses who have had specialised training are making a difference to people with dementia. PMID- 20831108 TI - The power of words. AB - Reading in a group can help patients with mental health conditions to build up their self-belief. PMID- 20831109 TI - A local crisis. AB - Community nurse leaders are experiencing increasing workloads, but are denied the authority to cope with the changes. PMID- 20831110 TI - Any NHS overhaul needs to be tested. PMID- 20831111 TI - Venous thromboprophylaxis: reducing needlestick injury. AB - This article discusses needlestick injuries in relation to the prevention of venous thromboembolism (VTE) in the healthcare setting. The article explores the use of oral anticoagulants for the prevention of VTE. The introduction of oral prophylaxis for VTE following orthopaedic surgery may help to optimise post operative patient outcomes, as well as reduce the number of sharps-related accidents. PMID- 20831112 TI - The role of the nurse specialist in placement education. AB - Changes in health service provision have created a shortage of practice placements for pre-registration nursing students on acute hospital wards. However, high quality practice learning opportunities are essential in pre registration nursing education. An initiative to allocate nursing students to short placements with nurse specialist teams increased student learning opportunities and placement capacity. Student evaluations indicate that students allocated to nurse specialist placements receive effective mentoring and are supported in developing nursing skills and knowledge relevant to the varied and often complex needs of patients. PMID- 20831113 TI - Prevention of deterioration in acutely ill patients in hospital. AB - The shift towards providing critical care in general wards has changed the way acutely ill patients are identified, treated and managed in hospital. This requires the expertise of knowledgeable, informed and capable staff. Effective education and appropriate knowledge and skills are required to aid identification of the deteriorating patient and provide prompt, timely and appropriate intervention to prevent further deterioration and possibly death. This article provides information about a systematic approach that will enable healthcare professionals to intervene to prevent deterioration in acutely ill patients. PMID- 20831114 TI - Wound-related pain management. PMID- 20831115 TI - Staying the course. PMID- 20831116 TI - Sharing valuable skills. PMID- 20831117 TI - Lessons to be learned. PMID- 20831118 TI - 4 strategies for MGMA's future. PMID- 20831119 TI - Diagnosis coding: it's not all about ICD-10-CM. PMID- 20831120 TI - What changes with more nonphysician providers? PMID- 20831121 TI - Data dashboard spurs staff to improve performance. PMID- 20831122 TI - Improve work flow, patient care with document management systems. PMID- 20831123 TI - Hiring the ideal administrator. The 9 essential steps for success in finding, hiring and keeping your next administrator. PMID- 20831124 TI - Managing discord. How to lead a conflict-competent medical practice. AB - No doubt conflicts will arise in your practice. Following some simple guidelines can help you deal with difficult situations and, in some cases, even prevent them. PMID- 20831125 TI - Show me the money. Developing the right compensation structure for your practice. AB - Keep lines of communication open to avoid common pitfalls associated with financial responsibility. PMID- 20831126 TI - Multidisciplinary team streamlines hospital schedules, patient care. AB - Massachusetts General Hospital staff members use data to reassess patient flow, optimize facilities and enhance patient experience. PMID- 20831127 TI - Increased dental trauma in children with attention deficit hyperactivity disorder treated with methylphenidate--a pilot study. AB - The purpose of this pilot study was to investigate the prevalence of trauma to incisor teeth in children with normal overjet and lip competence, treated with methylphenidate (Ritalin) for attention deficit hyperactivity disorder (ADHD). The study group consisted of 24 children (19 boys, 5 girls) aged 5-12 years (mean 8.45 +/- 2.25), diagnosed with ADHD and treated with methylphenidate at a minimal dosage of 10 mg per day. The control group consisted of 22 healthy children (13 boys, 9 girls) aged 5-12 years (mean 9.15 +/- 2.28). The dental examination included incisor relation measurements in the anterior segment (overjet), which was recorded using an orthodontic ruler. Lip competence was clinically determined, and anterior teeth were examined for dental trauma. The prevalence of dental trauma was significantly higher in the study group than in the control group (29.1% vs. 4.5% P = 0.02, t-test one tail). In conclusion, children with ADHD treated with methylphenidate have a high-risk for dental trauma. We believe that preventing dental trauma in this high risk group is possible. Consequently, the pediatrician and all medical staff attending to these children should encourage parents to consult frequently with a pediatric dentist to diagnose dental trauma and provide early treatment when needed. PMID- 20831128 TI - Prenatal counseling for pregnant women: a survey of general dentists. AB - OBJECTIVE: To assess the attitudes, behavior, and demographics of general dentists in the state of Nebraska with regard to overall prenatal oral health counseling for pregnant women. STUDY DESIGN: The survey asked for demographic information, number of years practicing dentistry, and patient base. The survey also asked questions about prenatal oral health counseling for pregnant women. A self-addressed stamped envelope was enclosed for dentists' returned responses. RESULTS: Out of the 800 surveys sent, 371 (46.4%) were returned. Nearly 50% of general dentists in Nebraska who responded to the survey do not provide any prenatal counseling (45.6%) and 5.9% provide prenatal counseling only once a year. There were no correlations between providing prenatal counseling and age of general dentists, gender of general dentists, type of practice, and length of time in practice or additional training completed. When asked why they do not provide prenatal counseling, 19.7% say that it is not a priority for the office and 9.5% do not provide prenatal counseling because they are not reimbursed by a third party payer. CONCLUSIONS: Fifty percent of general practitioners do provide prenatal counseling. The most common reason for not providing prenatal counseling was it is not a priority for the office and the parents are not interested. PMID- 20831129 TI - Impact of infant feeding practices on caries experience of preschool children. AB - AIM: This study investigated the association between breastfeeding, bottle feeding, night feeding, age, and sex of the child on the caries experience. METHOD: Information was collected from the mothers of preschool children. Information included the age of the child, sex of the child, form of breastfeeding (whether exclusive, almost exclusive or mixed), duration of breastfeeding, night feeding habits of the child, and duration and content of bottle feeding. Intraoral examination was done to assess the dmft. The impact of the variables on the caries experience (rampant caries, no caries and the dmft) was then assessed. RESULTS: The duration of breast feeding (p = 0.002), and form of breast feeding (p = 0.03) were significant predictors of the dmft. The dmft was highest in children who were breastfed for longer than 18 months and highest for children who were exclusively breastfed. There is a strong association between rampant caries and duration of breast feeding only (p < 0.001). The risk of having rampant caries increases by 10% (p = 0.012) with every month increase in the duration of breastfeeding. CONCLUSION: The duration of breastfeeding increased the risk for rampant caries in preschool children in Nigeria. The longer the duration, the higher the risk for caries. PMID- 20831130 TI - Spectrophotometric analysis on bleaching efficacy of blood stained demineralized and deproteinized dentin--an in vitro study. AB - BACKGROUND AND OBJECTIVE: The objectives of this in vitro study, is to evaluate the influence of various dentin treatment procedures prior to bleaching namely, demineralization and demineralization in conjunction with deproteinization on the dentin permeability and bleaching efficacy. METHOD: The study used a total of 40 sound premolars, which were sectioned longitudinally, and their color coefficients and absorption spectrum was recorded and used as control values for the later study. These dentin samples were then discolored by blood and their color coefficients and absorption spectrum were calibrated. They were then divided into two Groups with 20 samples each per group. Group A--dentin samples were demineralized prior to bleaching. Group B--dentin samples were deproteinized also in conjunction to demineralization prior to bleaching. The values of color coefficient and absorption spectrum were determined using Spectrophotometer for samples of each group respectively. RESULTS: There were significantly higher color coefficient and absorption spectrum values in the group where dentin was treated with demineralization in conjunction with deproteinization prior to bleaching when compared to the group where dentin was treated by demineralization alone prior to bleaching. CONCLUSION: Demineralization in conjunction with deproteinization has proven to be a good method of increasing dentin permeability for achieving a higher bleaching efficacy. PMID- 20831131 TI - Retentive strength of luting cements for stainless steel crowns: an in vitro study. AB - The present study evaluated and compared the retentive strength of three luting cements. A total of forty five freshly extracted human primary molars were used in this study. The teeth were prepared to receive stainless steel crowns. They were then randomly divided into three groups, of fifteen teeth each, so as to receive the three different luting cements: conventional glass ionomer resin modified glass ionomer and adhesive resin. The teeth were then stored in artificial saliva for twenty four hours. The retentive strength of the crowns was determined by using a specially designed Instron Universal Testing Machine (Model 1011). The data was statistically analyzed using ANOVA to evaluate retentive strength for each cement and Tukey test for pair wise comparison. It was concluded that retentive strength of adhesive resin cement and resin modified glass ionomer cement was significantly higher than that of the conventional glass ionomer cement. PMID- 20831132 TI - Can parents assess dental pain in children with cognitive impairment? AB - It is often said that the "gold standard" for pain assessment in both children and adults is verbal report. This means that the individual is best at describing his or her pain experience. This however does not take into account individuals who lack the ability to communicate their feelings including those with cognitive immaturity such as infants and very young children, people with cognitive impairment and adults with dementia. This is even complicated by the fact that children who experience the most pain are those who are least able to verbally describe it; those with greater physical and cognitive disability. This paper reviews past and current beliefs on the experience and expression of pain in children with cognitive impairment and how parents can be used as useful tools in diagnosing their pain. PMID- 20831133 TI - Formocresol versus calcium hydroxide direct pulp capping of human primary molars: two year follow-up. AB - OBJECTIVES: Clinical and radiographic evaluation of the premedicated direct pulp capping using formocresol (PDC) versus conventional direct pulp capping using calcium hydroxide (CDC) in human carious primary molars. STUDY DESIGN: A total of 120 vital primary molars with pinpoint exposure during caries removal in 84 patients aged 4-5 years were selected. In the PDC group (n = 60), 20% Buckley's formocresol solution, and in the CDC group (n = 60), calcium hydroxide powder were applied to the exposure sites followed by placement of zinc oxide-eugenol base. Teeth were restored with preformed stainless steel crowns. Clinical and radiographic evaluations of the treatment outcomes were performed at regular intervals of 6 and 12 months, respectively, for two years post-operatively. RESULTS: The prevalence of spontaneous pain, sensitivity on percussion, and fistula were significantly higher in the CDC group compared to the PDC group (P < 0.05). The number of teeth exhibiting periapical/furcal radiolucency or external/internal root resorption was also higher in the CDC group (P < 0.05). The clinical success rate of the PDC was 90% compared to the 61.7% of the CDC (P < 0.05). The radiographic success rates of the PDC and CDC groups were 85% and 53.3%, respectively (P < 0.05). CONCLUSION: It seems formocresol premedicated direct pulp capping could safely be used as a substitute for conventional direct pulp capping. PMID- 20831134 TI - In vitro comparison of self versus professionally applied remineralizing materials. AB - OBJECTIVE: To compare the effect of 4 remineralizing materials on the incipient artificial carious lesion and its proximal sound enamel when used with fluoride dentifrice. STUDY DESIGN: Models mimicking proximal contact were made, each of which was placed with an artificial carious specimen in contact with a sound enamel specimen. Each carious specimen was treated with one of four materials: glass ionomer cement (GIC), resin modified glass ionomer cement (RMGIC), 5000 ppm sodium fluoride (F-gel), and casein phosphopeptide amorphous calcium phosphate (CPP-ACP). The GIC and RMGIC specimens were thermocycled. Then all specimens were pH-cycled for 5 days with twice a day soaking in 1,000 ppm NaF dentifrice solution. Specimens were examined by polarized light microscopy and lesion area quantified by image analysis. RESULTS: RMGIC significantly yielded smaller areas of lesion than CPP-ACP and GIC (p < 0.05). F-gel reduced more area of lesion than CPP-ACP significantly (p < 0.05). In the associated contact, RMGIC significantly reduced the area of lesion better than CPP-ACP (p < 0.05). CONCLUSIONS: The most effective remineralizing material in reducing the carious lesion areas was RMGIC followed by F-gel, GIC and CPP-ACR The demineralization inhibitory effects on the associated sound contact enamel followed the same trend. PMID- 20831135 TI - Identification of cultivable microorganisms from primary teeth with necrotic pulps. AB - The objective of this study was to identify cultivable microorganisms from primary teeth with necrotic pulps. This experimental study included 21 patients of both sexes between 4 and 7 years of age with necrotic pulps in primary teeth. Twenty-one maxillary and mandibular molars containing at least 1 necrotic canal, an abscess or sinus tract, one or more radiolucent areas in the furcation or periapical region, teeth having at least two thirds of root length, and carious lesions directly exposed to the oral environment were included. After antisepsis of the oral cavity, anesthesia of the affected tooth, and isolation and disinfection of the operative field, 3 sterile absorbent paper points were sequentially placed for 30 seconds for the collection of samples. The samples were immediately processed in an anaerobic chamber, and all isolated microorganisms were identified. Anaerobic species (anaerobic facultative and moderate anaerobes) were isolated in all root canals; 68.4% of root canal samples studied showed a polymicrobial nature. Most of the isolate consisted of Bifidobacterium Spp2 and Streptococcus intermedius. Other less frequently encountered species were Actinomyces israelii, Bifidobacterium spp 1, Clostridium spp, and Candida albicans. Results indicate the existence of combinations of bacterial species in root canal infections of the primary dentition with necrotic pulps, anaerobic bacteria predominating. PMID- 20831136 TI - Intralingual dermoid cyst in an infant presenting swallowing and sleeping difficulties. AB - Dermoid cysts of the oral cavity are extremely rare. The most common site is the floor of the mouth whereas intralingual location is the most unusual. They may be congenital or acquired and according to their histological appearance they are distinguished in "true" dermoid, epidermoid or teratoid cysts. We present the clinical and radiographic findings of a large congenital intralingual "true" dermoid cyst in a 10-month-old boy. The large size of the lesion and the subsequent enlargement of the tongue caused difficulties in swallowing and sleeping, symptoms which subsided after the surgical treatment. The uncommon location, the large size and the very young age of the patient were the noteworthy parameters. PMID- 20831137 TI - Localized idiopathic internal resorption in the primary dentition. AB - CASE REPORT: We present the clinical and histological findings in a case of a six year old male patient who had unexplained sequential spontaneous abscesses associated with an unusual pattern of resorption, resulting in the loss of his non-carious second primary molars. CONCLUSIONS: Despite a wide differential diagnosis, the case represents unusual clinical and histological features of resorption in multiple primary teeth. PMID- 20831138 TI - Asymmetric crying facies with a couple of primary mandibular central incisor and 22q11 deletion. AB - Facial asymmetry present only on crying has been described as a separate entity and termed asymmetric crying facies. The cause of the facial asymmetry in this disorder is congenital absence or hypoplasia of the depressor anguli oris muscle at the corner of the mouth. This defect is associated at times with major congenital anomalies, most commonly in the cardiovascular system. Chromosome 22q11 microdeletions in cases with ACF have been reported. We report a newborn infant who had ACF associated with a couple of primary mandibular central incisor teeth and chromosome 22q11 microdeletion. This clinical sign in association with ACF has not been previously described. PMID- 20831139 TI - Total antioxidant capacity of saliva in children with HIV. AB - Several recent reports have indicated high levels of reactive oxygen species, causing oxidative stress, in the pathogenesis of HIV infection. Oxidative stress may lead to enhanced HIV replication in infected cells and may also aggravate the immunodeficiency by reduction of cellular immunity and possibly by increased programmed cell death of lymphocytes. Saliva can constitute a first line of defense against free radical mediated oxidative stress. The use of saliva as a diagnostic fluid has become somewhat of a translational research success story. Technologies are now available enabling saliva to be used to diagnose disease and predict disease progression. PURPOSE: The antioxidant capacity of saliva was investigated in 68 children who were divided into two groups. 34 children who were investigated were diagnosed as having HIV infection and the other group consisted of children who reported to the department and served as healthy controls. Total antioxidant capacity of saliva was evaluated by spectrophotometric assay. CONCLUSIONS: The results indicated that the total antioxidant capacity (TAC) of saliva decreased in children with HIV infection. TAC was seen to increase with the age of the children. PMID- 20831140 TI - Klippel-Trenaunay syndrome manifesting as gingival overgrowth and teeth agenesis. AB - OBJECTIVE: Klippel-Trenaunay syndrome (KTS) is characterized by triad of venous varicosity, naevus flammeus, and soft/hard tissue hypertrophy. Manifestations of the syndrome in the head and neck region are rare, but in some cases hemangioma of the lips, tongue, and gums, open bite and cross bite, and early tooth eruption are associated with the disease. STUDY DESIGN: We report a 12-year-old KTS patient with gingival hyperplasia, congenital missing teeth, and increased mucosal vascularization as oral manifestations. RESULTS AND CONCLUSION: All manifestations of the KTS were observed on the same side of the head, except bilateral missing teeth. Histological examination showed several vascular enlargements in enlarged gingiva. It is suggested that oral manifestations of the syndrome are generally related to the severity of the disease, but they do not always present in the same pattern. PMID- 20831141 TI - Relation of salivary risk factors to dental caries in children with cerebral palsy. AB - One of the primary handicapping conditions of childhood is cerebral palsy (CP). Controversy exists about the incidence of dental caries and its associated salivary risk factors in cerebral palsied children. Thus the present study evaluated the correlation between dental caries and certain salivary risk factors in these children. One hundred non-institutionalized children in the age group of 5-12 years having cerebral palsy were selected. The W.H.O. criteria was used for diagnosis and recording of dental caries. Determination of the unstimulated salivary pH, buffering capacity and flow rate of stimulated saliva was carried out. The mean deft and DMFT values were 2.51 and 0.73, respectively. Salivary pH was 6.83, buffering capacity 10.84 and salivary flow rate 1.08ml/per min. A significant correlation was observed only between salivary pH and dental caries in the primary dentition of CP children. PMID- 20831142 TI - Using superimposition of 3-dimensional cone-beam computed tomography images with surface-based registration in growing patients. AB - OBJECTIVE: The purpose of this research was to evaluate a new method of superimposing detailed cone-beam computed tomography (CBCT) images. MATERIALS AND METHODS: This study used 5 different software programs to transform the digital imaging and communication in medicine (DICOM) data from CBCT image into polygon data. The data conversion errors from different software programs were verified by the poly-acetal ball test and the dry skull test. The iterative closest point (ICP) method was used for precise superimposition. To evaluate changes related to growth, three different domains were superimposed in order to investigate appropriate areas for evaluation by the ICP method. RESULTS: The ICP method in the cranial base (excluding the peripheral zone) was indicated as the most reliable surface in this research. There were no measurement errors in converting the image data between software programs. CONCLUSION: The ICP method in the cranial base (excluding the peripheral zone) is one of the most accurate methods for superimposition when the mandibular rotation or displacement has not occurred during growth or treatment. This 3-dimensional (3D) superimposition technique can be used for a valid and reproducible assessment of treatment outcomes for growing subjects. This method is considered to be of clinical value because of the manageability and 3D accuracy of the data comparison with multi planar reconstruction (MPR) images. PMID- 20831143 TI - Evaluation of changes in muscle thickness, bite force and facial asymmetry during early treatment of functional posterior crossbite. AB - OBJECTIVE: To determine morphological and functional effects on masticatory system of early treatment of functional posterior crossbite in young children. STUDY DESIGN: 23 children were divided into two groups: deciduous (DecG, n = 11) and early mixed dentition (MixG, n = 12), which received slow maxillary expansion. Maximal bite force, ultrasonographic masticatory muscle thickness and facial asymmetry were evaluated in three stages: before the start of treatment (s1), after three months of retention (s2), and after three months of observation (s3). The results were analyzed by Mann-Whitney U-test, correlation test, repeated measures ANOVA and backward stepwise multiple regression. RESULTS: Bite force and temporalis thickness increased from s1 to s2 and s3 in both groups (p < 0.05). Body mass index (BMI) increased significantly from s1 to s3 only in the MixG, but the masseter thickness did not differ among the stages. The correlation between the angle of the eye and the angle of the mouth in relation to the mid sagital plane increased from s1 to s3. Masticatory muscle thickness contributed significantly to bite force magnitude in all stages, whereas age and BMl showed no significant contribution to its variation. CONCLUSION: Bite force and temporalis muscle thickness increased significantly in children after early treatment of functional crossbite. PMID- 20831144 TI - Photocurrent generation from porphyrin/fullerene complexes assembled in a tethered lipid bilayer. AB - A modular photocurrent generation system, based on amphiphilic porphyrin and fullerene species assembled in a tethered lipid bilayer matrix, is reported here. The key findings are (1) the amount of photoactive species can be quantitatively controlled in each leaflet of the bilayer and (2) the sequential formation of the bilayer allows a directional organization of these agents on electrodes. Photocurrent generation from seven differently configured photoactive bilayers is studied, which reveals several critical factors in achieving efficient photoinduced electron transfer across lipid membranes. Detailed fluorescence characterization is performed on porphyrin samples either in liposomes or surface tethered bilayers; and the observed fluorescence quenching is correlated with photocurrents generated from the electrode-immobilized lipid films. The potential usefulness of this lipid-based approach is discussed in connection to several existing molecular photovoltaic systems. PMID- 20831145 TI - Heat-driven release of a drug molecule from carbon nanotubes: a molecular dynamics study. AB - Hydrophobicity and the ability to absorb light that penetrates through living tissues make carbon nanotubes (CNTs) promising intracellular drug delivery agents. Following insertion of a drug molecule into a CNT, the latter is delivered into a tissue, is heated by near-infrared radiation, and releases the drug. To assess the feasibility of this scheme, we investigate the rates of energy transfer between CNT, water, and the drug molecule and study the temperature and concentration dependence of the diffusion coefficient of the drug molecule inside CNTs. We use ciprofloxacin (CIP) as a sample drug: direct penetration of CIP through cell membranes is problematic due to its high polarity. The simulations show that a heated CNT rapidly deposits its energy to CIP and water. All estimated time scales for the vibrational energy exchange between CNT, CIP, and water are less than 10 ps at 298 K. As the system temperature grows from 278 to 363 K, the diffusion coefficient of the confined CIP increases 5-7 times, depending on CIP concentration. The diffusion coefficient slightly drops with increasing CIP concentration. This effect is more pronounced at higher temperatures. The simulations support the idea that optical heating of CNTs can assist in releasing encapsulated drugs. PMID- 20831146 TI - The peculiar spectral properties of amino-substituted uracils: a combined theoretical and experimental study. AB - A detailed experimental and computational study of the absorption and fluorescence spectra of 5-aminouracil (5 AU) and 6-aminouracil (6 AU) in aqueous solution is reported. The lowest energy band of the steady-state absorption spectra of 5 AU is considerably red-shifted, noticeably less intense, and broader than its counterpart in uracil (U). On the contrary, the 6 AU lowest energy absorption peak is close in energy to that of U, but it is much narrower and the transition is much more intense. The emission properties of 5 AU, 6 AU, and U are also very different. Both amino-substituted compounds exhibit indeed a much larger Stokes shift as compared to U, and the emission band of 5 AU is much narrower than that of 6 AU. Those features are fully rationalized with the help of PCM/TD-PBE0 calculations in aqueous solution and MS-CASPT2/CASSCF calculations in the gas phase. A stable minimum on the potential energy surface of the lowest energy bright state is found for 5 AU, both in the gas phase and in aqueous solution. For 6 AU a barrierless path leads to the conical intersection with the ground electronic state, but a nonplanar plateau region is predicted in aqueous solution, which is responsible for the very large Stokes shift. Some general considerations on the excited-state dynamics of uracil derivatives are also reported. PMID- 20831147 TI - Ethanol hydrates and solid solution formed by gas condensation: an in situ study by micro-Raman scattering and X-ray diffraction. AB - Thin films of ethanol-water solid mixtures formed by gas co-condensation are investigated in situ by micro-Raman scattering in the 800-1600 and 2800-3800 cm( 1) spectral regions. Information at the molecular level on the structure is derived from accompanying changes observed in band shapes and vibrational mode frequencies. Depending on the ethanol content, the formation of two distinct ethanol hydrates is spectroscopically characterized, and their structures are independently confirmed by X-ray diffraction measurements. The attribution of the different phases is made in comparison with literature data and in relation with the ethanol phase diagram. Raman characteristic spectral features of ethanol extremely diluted in ice and corresponding to a solid solution regime are reported. PMID- 20831148 TI - Solvent-controlled electron transfer in crystal violet lactone. AB - Steady-state and picosecond time-resolved emission experiments are used to examine the excited-state charge transfer reaction of crystal violet lactone (CVL) in aprotic solvents. Solvatochromic analysis using a dielectric continuum model suggests dipole moments of 9-12 D for the initially excited (LE) state and ~24 D for the charge-transfer (CT) state. Intensities of steady-state emission as well as kinetic data provide free energies for the LE -> CT reaction that range from +12 kJ/mol in nonpolar solvents to -10 kJ/mol in highly polar solvents at 25 degrees C. Reaction rates constants, which lie in the range of 10-100 ns(-1) in most solvents, depend on both solvent polarity and solvent friction. In highly polar solvents, rates are correlated to solvation times in a manner that indicates that the reaction is a solvent-controlled electron transfer on an adiabatic potential surface having a modest barrier. PMID- 20831149 TI - Comparing simulated and experimental translation and rotation constants: range of validity for viscosity scaling. AB - Proper simulation of dynamic properties, including molecular diffusion, is an important goal of empirical force fields. However, the widely used TIP3P water model does not reproduce the experimental viscosity of water. Consequently, scaling of simulated diffusion constants of solutes in aqueous solutions is required to effectively compare them with experiment. It is proposed that scaling by the ratio of viscosities of model and real water is appropriate in the regime where the concentration dependence of simulated and experimental solution viscosities is parallel. With this ansatz, viscosity scaling can be carried out for glucose and trehalose up to 20 wt % for simulations carried out with the CHARMM additive carbohydrate force field C35 and TIP3P water; above this value, the concentration dependence of simulated viscosities lags that of experiment, and scaling is not advised. Scaled translational diffusion constants for glucose and the disaccharides trehalose, maltose, and melibiose at low concentration agree nearly quantitatively with experiment, as do NMR (13)C T(1)'s for glucose, trehalose, and maltose; these results support the use of C35 for simulations of sugar transport properties at low concentration. At high concentrations the scaled diffusion constants for glucose and trehalose underestimate and overestimate experiment, respectively. Hydrodynamic bead model calculations indicate a hydration level of approximately 1 water/hydroxyl for glucose. Patterns for the disaccharides are more complicated, though trehalose binds 0.5 to 1 more water than does maltose depending on the analysis. PMID- 20831150 TI - Intrinsically disordered mollusk shell prismatic protein that modulates calcium carbonate crystal growth. AB - The formation of calcite prism architecture in the prismatic layer of the mollusk shell involves the participation of a number of different proteins. One protein family, Asprich, has been identified as a participant in amorphous calcium carbonate stabilization and calcite architecture in the prismatic layer of the mollusk, Atrina rigida . However, the functional role(s) of this protein family are not fully understood due to the fact that insufficient quantities of these proteins are available for experimentation. To overcome this problem, we employed stepwise solid-phase synthesis to recreate one of the 10 members of the Asprich family, the 61 AA single chain protein, Asprich "3". We find that the Asprich "3" protein inhibits the formation of rhombohedral calcite crystals and induces the formation of round calcium carbonate deposits in vitro that contain calcite and amorphous calcium carbonate (ACC). This mineralization behavior does not occur under control conditions, and the formation of ACC and calcite is similar to that reported for the recombinant form of the Asprich "g" protein. Circular dichroism studies reveal that Asprich "3" is an intrinsically disordered protein, predominantly random coil (66%), with 20-30% beta-strand content, a small percentage of beta-turn, and little if any alpha-helical content. This protein is not extrinsically stabilized by Ca(II) ions but can be stabilized by 2,2,2 trifluoroethanol to form a structure consisting of turn-like and random coil characteristics. This finding suggests that Asprich "3" may require other extrinsic interactions (i.e., with mineral or ionic clusters or other macromolecules) to achieve folding. In conclusion, Asprich "3" possesses in vitro functional and structural qualities that are similar to other reported for other Asprich protein sequences. PMID- 20831151 TI - Density functional theory study of the interaction of carbon monoxide with bimetallic Co-Mn clusters. AB - Using spin-polarized density functional calculations, we have studied the interaction of carbon monoxide (CO) with bimetallic Co(n)Mn (n = 1-6) and Co(n)Mn(6-n) (n = 0-6) clusters. Various adsorption sites including atop, hollow, and bridge adsorption patterns and different possible spin states are considered. The CO molecule prefers to adsorb at the Co site rather than at the Mn site. Atop adsorption structure is energetically more favored over the hollow and bridge adsorption ones for the bimetallic clusters with an exception of Co(5)Mn. Large adsorption energy is found at Co(3)Mn, Co(2)Mn(4), and Co(3)Mn(3), associating with the relative stability of the bare Co-Mn clusters and the electrostatic interactions as well as adsorption patterns. The activation of the C-O bond and the red shift of the C-O stretching frequency are sensitive to the adsorption sites and high chemical activity is identified for Co(6), Co(5)Mn, and Mn(6) clusters. More interestingly, the adsorption of CO has different influence on the magnetism of the clusters: the magnetic moment remains unchanged for CoMn and Co(2)Mn, while it is reduced by 2 MU(B) for Co(n)Mn (n = 3-6) and Co(n)Mn(6-n) (n = 0-5) and is enhanced by 2 MU(B) for Mn(6) when a CO molecule is loaded to the cluster. PMID- 20831152 TI - Method for the analysis of oxygen isotopic composition of soil phosphate fractions. AB - The isotopic signature of oxygen in phosphate (delta(18)O(P)) of various soil fractions may shed light on P transformations, including phosphorus (P) recycling by soil microorganisms, uptake by plants and P adsorption, precipitation and release by oxides and minerals, thus increasing our understanding on P cycling and lability in soils. We developed and tested a protocol to extract and purify inorganic phosphate (Pi) from different soil fractions distinguished by binding strength and precipitate it as silver phosphate (Ag(3)PO(4)) for delta(18)O(P) analysis. Soil P is extracted sequentially using water, NaHCO(3), NaOH and HCl and Pi in each solution is purified and precipitated as Ag(3)PO(4). The unique characteristics and possible interferences of the soil solution extracts are addressed. Two agricultural soil samples receiving reclaimed wastewater or fresh water were analyzed, and results indicate that all soil fractions analyzed have been impacted to some degree by biologically enzyme mediated cycling of P in the soil. PMID- 20831153 TI - Biokinetic uptake and efflux of silver nanoparticles in Daphnia magna. AB - Silver nanoparticles (AgNP) are widely used as antibacterial products, and there are increasing concerns for their potential environmental risks in aquatic ecosystems. The biokinetics of AgNP in aquatic organisms has not yet been determined. In the present study, we employed a radiotracer methodology to quantify the biokinetics of AgNP in a freshwater cladoceran Daphnia magna, including the uptake from water, dietary assimilation, and elimination of AgNP. We found that the uptake of AgNP was concentration dependent and governed by two phases. The uptake rate constant (k(u)) was 0.060 L/g/h at low AgNP concentrations (2, 10, and 40 MUg/L), which was 4.3 times lower than that of the Ag free ion. At a higher AgNP concentration (160 and 500 MUg/L), the uptake rate increased disproportionately, likely as a result of direct ingestion of these nanoparticles by the daphnids. When the AgNP were associated with the algal food, their dietary assimilation efficiency (AE) was in the range of 22-45%, which was much higher than the dietary assimilation of Ag quantified under the same food conditions. The efflux rate constants of AgNP in daphnids were also much lower than those of the Ag, again suggesting the difficulty of eliminating AgNP by the daphnids. Water excretion was the main elimination route for both AgNP and Ag, but a higher percentage of AgNP was lost through fecal production. Finally, we used a kinetic equation to compare the importance of aqueous and dietary uptake of AgNP using the quantified kinetic parameters. The biokinetic model showed that more than 70% of AgNP accumulated in the daphnids was through ingestion of algae, highlighting the importance of AgNP transport along the food chain. Our present study showed the unique characteristic of AgNP biokinetics and suggested that more attention should be paid to the dietborne AgNP toxicity in aquatic ecosystems. PMID- 20831154 TI - High efficient photocatalytic degradation of p-nitrophenol on a unique Cu2O/TiO2 p-n heterojunction network catalyst. AB - p-Nitrophenol (PNP) is a difficultly decomposed organic pollutant under solar light in the absence of strong oxidants. This study shows that under artificial solar light PNP can be effectively degraded by a Cu(2)O/TiO(2) p-n junction network which is fabricated by anodizing Cu(0) particles-loaded TiO(2) nanotubes (NTs). The network is composed of p-type Cu(2)O nanowires on the top surface and Cu(2)O nanoparticles on the inner walls of the n-type TiO(2) NT arrays. The Cu(2)O/TiO(2) network shows much higher degradation rate (1.97 MUg/min cm(2)) than the unmodified TiO(2) NTs (0.85 MUg/min cm(2)). The enhanced photocatalytic acitivity can be attributed to the extended absorption in the visible resulting from the Cu(2)O nanowire networks and the effective separation of photogenerated carriers driven by the photoinduced potential difference generated at the Cu(2)O/TiO(2) p-n junction interface. PMID- 20831155 TI - Are compatible solutes compatible with biological treatment of saline wastewater? Batch and continuous studies using submerged anaerobic membrane bioreactors (SAMBRs). AB - This study investigated fundamental mechanisms that anaerobic biomass employ to cope with salinity, and applied these findings to a continuous SAMBR. When anaerobic biomass was exposed to 20 and 40 g NaCl/L for 96 h, the main solute generated de novo by biomass was trehalose. When we separately introduced trehalose, N-acetyl-beta-lysine and potassium into a batch culture a slight decrease in sodium inhibition was observed. In contrast, the addition of 0.1 mM and 1 mM of glycine betaine dramatically improved the adaptation of anaerobic biomass to 35 g NaCl/L, and it continued to enhance the adaptation of biomass to the salt for the next three batch feedings without further addition. No shift in archaeal microbial diversity was found when anaerobic biomass was exposed in batch mode to 35 g NaCl/L for 360 h, and no changes were found when glycine betaine was added. The dominant species identified under these conditions were Methanosarcina mazeii and Methanosaeta sp. The addition of 5 mM glycine betaine to a continuous SAMBR at 12 h hydraulic retention time (HRT), and operation in batch mode for 2 days can significantly enhance saline (35 g NaCl/L) synthetic sewage degradation. In addition, the injection of 1 mM of glycine betaine into a SAMBR for five subsequent days also significantly enhanced dissolved organic carbon (DOC) removal from sewage under these conditions. The main compatible solutes generated by anaerobic biomass after 44 days exposure to 35 g NaCl/L in a SAMBR were N-acetyl-beta-lysine and glycine betaine. Finally, the addition of 1 mM glycine betaine to the medium was beneficial for anaerobic biomass in batch mode at 20 degrees C under saline and non saline conditions. PMID- 20831156 TI - Occupational exposure to airborne perfluorinated compounds during professional ski waxing. AB - The concentration levels of 11 perfluorinated carboxylic (PFCA) and eight sulfonic (PFSA) acids were determined in the serum of 13 professional ski waxers. The same components were also determined in workroom aerosols and in fluoro containing solid ski waxes and ski wax powders. The highest median concentration (50 ng/mL) was detected for perfluorooctanoic acid (PFOA), which is around 25 times higher than the background level. For the first time perfluorotetradecanoic acid (PFTeDA) has been found in human serum. Positive statistically significant associations between years exposed as ski waxer and seven different PFCAs were observed. The serum concentrations of the PFCAs with carbon chain lengths from C(8) to C(11) were reduced by around five to 20% on average during the eight month exposure free interval, whereas the reduction was substantially larger when the carbon chain lengths were smaller than C(8) or larger than C(11). This study links for the first time PFCAs in the ski waxers serum to exposure from the work room aerosols. Not only professional ski waxers but also the significant larger group of amateur skiers and waxers are potentially exposed to these compounds. PMID- 20831157 TI - Secondary structure and solvent accessibility of a calmodulin-binding C-terminal segment of membrane-associated myelin basic protein. AB - Myelin basic protein (MBP), specifically the 18.5 kDa isoform, is a peripheral membrane protein and a major component of mammalian central nervous system myelin. It is an intrinsically disordered and multifunctional protein that binds cytoskeletal and other cytosolic proteins to a membrane surface and thereby acquires ordered structure. These associations are modulated by post translational modifications of MBP, as well as by interactions of MBP with Ca(2+) calmodulin (CaM). Enzymatic deimination of usually six arginine residues to citrulline results in a decrease in the net positive charge of the protein from 19 to <=13. This deiminated form is found in greater amounts in normal children and in adult patients with the demyelinating disease multiple sclerosis. In this paper, we examine the secondary structure of a calmodulin-binding domain, residues A141-L154, when associated with a lipid bilayer in recombinant murine 18.5 kDa forms rmC1 (unmodified) and rmC8 (pseudodeiminated). We demonstrate here by site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy that the Y142-L154 segment in membrane-associated rmC1 forms an amphipathic alpha-helix, with high accessibility to O(2) and low accessibility to NiEDDA. In membrane-associated rmC8, this segment assumed a structure distorted from an alpha-helix. Spin-labeled residues in rmC1 in solution were more immobilized on binding Ca(2+)-CaM than those in rmC8. Furthermore, rmC8 was dissociated more readily from a lipid bilayer by Ca(2+)-CaM than was rmC1. These results confirm both a predicted induced ordering upon membrane association in a specific segment of 18.5 kDa MBP, and that this segment is a CaM-binding site, with both interactions weakened by deimination of residues outside of this segment. The deiminated form would be more susceptible to regulation of its membrane binding functions by Ca(2+)-CaM than the unmodified form. PMID- 20831158 TI - How to catch a membrane protein in action: a review of functional membrane protein immobilization strategies and their applications. PMID- 20831159 TI - Tunability in polyatomic molecule diffusion through tunneling versus pacing. AB - The diffusion temperature of molecular 'walkers', molecules that are capable of moving unidirectionally across a substrate violating its symmetry, can be tuned over a wide range utilizing extension of their aromatic backbone, insertion of a second set of substrate linkers (converting bipedal into quadrupedal species), and substitution on the ring. Density functional theory simulation of the molecular dynamics identifies the motion of the quadrupedal species as pacing (as opposed to trotting or gliding). Knowledge about the diffusion mode allows us to draw conclusions on the relevance of tunneling to the surface diffusion of polyatomic organic molecules. PMID- 20831160 TI - Nature and kinetic analysis of carbon-carbon bond fragmentation reactions of cation radicals derived from SET-oxidation of lignin model compounds. AB - Features of the oxidative cleavage reactions of diastereomers of dimeric lignin model compounds, which are models of the major types of structural units found in the lignin backbone, were examined. Cation radicals of these substances were generated by using SET-sensitized photochemical and Ce(IV) and lignin peroxidase promoted oxidative processes, and the nature and kinetics of their C-C bond cleavage reactions were determined. The results show that significant differences exist between the rates of cation radical C1-C2 bond cleavage reactions of 1,2 diaryl-(beta-1) and 1-aryl-2-aryloxy-(beta-O-4) propan-1,3-diol structural units found in lignins. Specifically, under all conditions C1-C2 bond cleavage reactions of cation radicals of the beta-1 models take place more rapidly than those of the beta-O-4 counterparts. The results of DFT calculations on cation radicals of the model compounds show that the C1-C2 bond dissociation energies of the beta-1 lignin model compounds are significantly lower than those of the beta O-4 models, providing clear evidence for the source of the rate differences. PMID- 20831161 TI - Proteome analysis of pod and seed development in the model legume Lotus japonicus. AB - Legume pods serve important functions during seed development and are themselves sources of food and feed. Compared to seeds, the metabolism and development of pods are not well-defined. The present characterization of pods from the model legume Lotus japonicus, together with the detailed analyses of the pod and seed proteomes in five developmental stages, paves the way for comparative pathway analysis and provides new metabolic information. Proteins were analyzed by two dimensional gel electrophoresis and tandem-mass spectrometry. These analyses lead to the identification of 604 pod proteins and 965 seed proteins, including 263 proteins distinguishing the pod. The complete data set is publicly available at http://www.cbs.dtu.dk/cgi-bin/lotus/db.cgi , where spots in a reference map are linked to experimental data, such as matched peptides, quantification values, and gene accessions. Identified pod proteins represented enzymes from 85 different metabolic pathways, including storage globulins and a late embryogenesis abundant protein. In contrast to seed maturation, pod maturation was associated with decreasing total protein content, especially proteins involved in protein biosynthesis and photosynthesis. Proteins detected only in pods included three enzymes participating in the urea cycle and four in nitrogen and amino group metabolism, highlighting the importance of nitrogen metabolism during pod development. Additionally, five legume seed proteins previously unassigned in the glutamate metabolism pathway were identified. PMID- 20831162 TI - Multistep N2 breathing in the metal-organic framework co(1,4 benzenedipyrazolate). AB - A variety of spectroscopic techniques combined with in situ pressure-controlled X ray diffraction and molecular simulations have been utilized to characterize the five-step phase transition observed upon N(2) adsorption within the high-surface area metal-organic framework Co(BDP) (BDP(2-) = 1,4-benzenedipyrozolate). The computationally assisted structure determinations reveal structural changes involving the orientation of the benzene rings relative to the pyrazolate rings, the dihedral angles for the pyrazolate rings bound at the metal centers, and a change in the metal coordination geometry from square planar to tetrahedral. Variable-temperature magnetic susceptibility measurements and in situ infrared and UV-vis-NIR spectroscopic measurements provide strong corroborating evidence for the observed changes in structure. In addition, the results from in situ microcalorimetry measurements show that an additional heat of 2 kJ/mol is required for each of the first four transitions, while 7 kJ/mol is necessary for the last step involving the transformation of Co(II) from square planar to tetrahedral. Based on the enthalpy, a weak N(2) interaction with the open Co(II) coordination sites is proposed for the first four phases, which is supported by Monte Carlo simulations. PMID- 20831163 TI - Chemiluminogenic properties of 10-methyl-9-(phenoxycarbonyl)acridinium cations in organic environments. AB - The chemiluminogenic (CL) properties of aryl esters of 9-carboxy-10 methylacridinium acid and 9-carboxy-2-methoxy-10-methylacridinium acid (AE), variously substituted in the benzene ring (2-H, 2-CH(3), 2-Cl) were investigated in aliphatic alcohols, acetonitrile, and dimethyl sulfoxide in the presence of hydrogen peroxide and different bases-potassium hydroxide, tetra-n-butylammonium hydroxide, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The dependence of their CL properties (decay rate constants (k(CL)) and relative efficiencies (RE)) on solvent parameters, the nature and concentration of base, as well as H(2)O(2) concentration were investigated. Comparison of the various AE revealed that substituents at the benzene ring strongly influence the reaction kinetics, while 2-OCH(3) substitution of the acridine nucleus is manifested, in general, by a red shift in the emission spectrum and slight increase in CL efficiency. The values of k(CL) depend linearly on polarity and acid-base properties of solvents as well as on concentration of bases (over certain concentration ranges) and demonstrate a nonlinear dependence on H(2)O(2) concentration. RE values depend on solvent polarity and nucleophilicity but are rather weakly dependent on base and oxidant concentrations. The CL properties of the above systems are discussed in the context of their physicochemical features gained from fluorescence spectroscopy, spectrophotometric titration, MS, and HPLC. Electronically excited 10-methyl-9 acridinones are the light-emitting entities in both organic and aqueous environments. It was also found that the tendency for an unwanted side-process, the production of a pseudobase form of AE, to take place was similar in alcoholic and aqueous media, although 2-methoxy ring-substituted derivatives seemed to be less susceptible to this dark-type conversion. On the basis of these results new CL systems are postulated that are more efficient than their aqueous counterparts. PMID- 20831164 TI - Chemoselective attachment of small molecule effector functionality to human adenoviruses facilitates gene delivery to cancer cells. AB - We demonstrate here a novel two-step "click" labeling process in which adenoviral particles are first metabolically labeled during production with unnatural azido sugars. Subsequent chemoselective modification allows access to viruses decorated with a broad array of effector functionality. Adenoviruses modified with folate, a known cancer-targeting motif, demonstrated a marked increase in gene delivery to a murine cancer cell line. PMID- 20831165 TI - Surface enhanced NMR spectroscopy by dynamic nuclear polarization. AB - It is shown that surface NMR spectra can be greatly enhanced using dynamic nuclear polarization. Polarization is transferred from the protons of the solvent to the rare nuclei (here carbon-13 at natural isotopic abundance) at the surface, yielding at least a 50-fold signal enhancement for surface species covalently incorporated into a silica framework. PMID- 20831166 TI - DIBPillar[n]arenes (n = 5, 6): syntheses, X-ray crystal structures, and complexation with n-octyltriethyl ammonium hexafluorophosphate. AB - DIBPillar[n]arenes (n = 5, 6) were synthesized. They showed different host-guest properties with n-octyltriethyl ammonium hexafluorophosphate G due to their different cavity sizes. DIBpillar[5]arene showed no complexation with G, while DIBpillar[6]arene formed a 1:1 complex with G with an association constant of 334 (+/-24) M(-1) in chloroform. In this letter, the first pillar[6]arene crystal structure and the first investigation of the host-guest chemistry of pillar[6]arenes are reported. PMID- 20831167 TI - Alkene hydroboration: hot intermediates that react while they are cooling. AB - Non-TST behavior has recently attracted a great deal of attention. If such behavior is general, then the standard way in which synthetic chemists rationalize and predict reactivity and selectivity would be at least partially invalid. The work in this article was inspired by recent results which highlighted a departure from the predictions of TST for rationalization of the regiochemical outcome of the hydroboration reaction mechanism, suggesting that the isomeric product ratios arise because of nonstatistical dynamical effects (J. Am. Chem. Soc. 2009, 131, 3130-3131). We suggest, based on new calculations using a weak collision RRKM-Master Equation (ME) model, an alternative interpretation of the experimental results which preserves a statistical reaction model. While it is a common assumption that all intermediates and transition states along the reaction path are in thermal equilibrium with solvent, our ME results show that hot intermediates may react while they are undergoing stepwise relaxation through weak collisions, even in solution. To our knowledge, this work represents the first application of master equation methodology to a solution phase thermal reaction in organic chemistry that cannot be otherwise explained using conventional TST. Explicit modeling of solvent and solute dynamics is often prohibitively expensive; however, the master equation offers a computationally tractable model with considerable predictive power that may be utilized to investigate whether stepwise collisional relaxation is prevalent in other polyatomic systems. PMID- 20831168 TI - Latent porosity in potassium dodecafluoro-closo-dodecaborate(2-). Structures and rapid room temperature interconversions of crystalline K2B12F12, K2(H2O)2B12F12, and K2(H2O)4B12F12 in the presence of water vapor. AB - Structures of K(2)(H(2)O)(2)B(12)F(12) and K(2)(H(2)O)(4)B(12)F(12) were determined by X-ray diffraction. They contain [K(MU-H(2)O)(2)K](2+) and [(H(2)O)K(MU-H(2)O)(2)K(H(2)O)](2+) dimers, respectively, which interact with superweak B(12)F(12)(2-) anions via multiple K...F(B) interactions and (O)H...F(B) hydrogen bonds (the dimers in K(2)(H(2)O)(4)B(12)F(12) are also linked by (O)H...O hydrogen bonds). DFT calculations show that both dimers are thermodynamically stabilized by the lattice of anions: the predicted DeltaE values for the gas-phase dimerization of two K(H(2)O)(+) or K(H(2)O)(2)(+) cations into [K(MU-H(2)O)(2)K](2+) or [(H(2)O)K(MU-H(2)O)(2)K(H(2)O)](2+) are +232 and +205 kJ mol(-1), respectively. The calculations also predict that DeltaE for the gas-phase reaction 2 K(+) + 2 H(2)O -> [K(MU-H(2)O)(2)K](2+) is +81.0 kJ mol, whereas DeltaH for the reversible reaction K(2)B(12)F(12 (s)) + 2 H(2)O((g)) -> K(2)(H(2)O)(2)B(12)F(12 (s)) was found to be -111 kJ mol(-1) by differential scanning calorimetry. The K(2)(H(2)O)(0,2,4)B(12)F(12) system is unusual in how rapidly the three crystalline phases (the K(2)B(12)F(12) structure was reported recently) are interconverted, two of them reversibly. Isothermal gravimetric and DSC measurements showed that the reaction K(2)B(12)F(12 (s)) + 2 H(2)O((g)) -> K(2)(H(2)O)(2)B(12)F(12 (s)) was complete in as little as 4 min at 25 degrees C when the sample was exposed to a stream of He or N(2) containing 21 Torr H(2)O((g)). The endothermic reverse reaction required as little as 18 min when K(2)(H(2)O)(2)B(12)F(12) at 25 degrees C was exposed to a stream of dry He. The products of hydration and dehydration were shown to be crystalline K(2)(H(2)O)(2)B(12)F(12) and K(2)B(12)F(12), respectively, by PXRD, and therefore these reactions are reconstructive solid-state reactions (there is also evidence that they may be single-crystal-to-single-crystal transformations when carried out very slowly). The hydration and dehydration reaction times were both particle size dependent and carrier-gas flow rate dependent and continued to decrease up to the maximum carrier-gas flow rate of the TGA instrument that was used, demonstrating that the hydration and dehydration reactions were limited by the rate at which H(2)O((g)) was delivered to or swept away from the microcrystal surfaces. Therefore, the rates of absorption and desorption of H(2)O from unit cells at the surface of the microcrystals, and the rate of diffusion of H(2)O across the moving K(2)(H(2)O)(2)B(12)F(12 (s))/K(2)B(12)F(12 (s)) phase boundary, are even faster than the fastest rates of change in sample mass due to hydration and dehydration that were measured. The exchange of 21 Torr H(2)O((g)) with either D(2)O or H(2)(18)O in microcrystalline K(2)(D(2)O)(2)B(12)F(12) or K(2)(H(2)(18)O)(2)B(12)F(12) at 25 degrees C was also facile and required as little as 45 min to go to completion (H(2)O((g)) replaced both types of isotopically labeled water at the same rate for a given starting sample of K(2)B(12)F(12), demonstrating that water molecules were exchanging, not protons. Significant portions of mass (m) vs time (t) plots for the (1,2)H(2)O((g))/K(2)((2,1)H(2)O)(2)B(12)F(12 (s)) exchange reactions fit the equation m ? e(-kt), with 10(3)k = 1.9 s(-1) for one particle size distribution and 10(3)k = 0.50 s(-1) for another. Finally, K(2)(H(2)O)(2)B(12)F(12) was not transformed into K(2)(H(2)O)(4)B(12)F(12) after prolonged exposure to 21 Torr H(2)O((g)) at 25 degrees C, 37 Torr H(2)O((g)) at 35 degrees C, or 55 Torr H(2)O((g)) at 45 degrees C. PMID- 20831169 TI - Autoprogrammed synthesis of triple-layered Au@Pd@Pt core-shell nanoparticles consisting of a Au@Pd bimetallic core and nanoporous Pt shell. AB - Here we report an autoprogrammed synthesis of unique Au@Pd@Pt triple-layered core shell structured nanoparticles consisting of a Au core, Pd inner layer, and nanoporous Pt outer shell. The proposed synthesis rationally utilizes the temporal separations of the depositions of Au, Pd, and Pt which affords spontaneously step-by-step formation of triple-layered core-shell colloids. The proposed one-step method is unique in its simplicity and is a significant finding for the facile creation of multilayered nanoarchitectures with designed compositions and desired functions. PMID- 20831170 TI - Electric field destabilizes noncovalent protein-DNA complexes. AB - Noncovalent protein-DNA interactions are involved in many vital biological processes. In cells, these interactions may take place in the environment of an electric field which originates from the plasma and organelle membranes and reaches strengths of 1 MV/cm. Moreover, protein-DNA interactions are often studied in vitro using an electric field as strong as 1 kV/cm, for example by electrophoresis. It is widely accepted that an electric field does not affect such interactions. Here we report on the first proof that an electric field of less than 1 kV/cm can destabilize the protein-DNA complexes through increasing the monomolecular rate constant of complex dissociation. PMID- 20831171 TI - Far-field autofluorescence nanoscopy. AB - We demonstrate far-field optical imaging at the nanoscale with unlabeled samples. Subdiffraction resolution images of autofluorescent samples are obtained by depleting the ground state of natural fluorophores by transferring them to a metastable dark state and simultaneously localizing those fluorophores that are transiently returning. Our approach is based on the insight that nanoscopy methods relying on stochastic single-molecule switching require only a single fluorescence on-off cycle to yield an image, a condition fulfilled by various biomolecules. The method is exemplified by recording label-free nanoscopy images of thylakoid membranes of spinach chloroplasts. PMID- 20831172 TI - Use of metallopeptide based mimics demonstrates that the metalloprotein nitrile hydratase requires two oxidized cysteinates for catalytic activity. AB - Nitrile hydratases (NHases) are non-heme Fe(III) or non-corrin Co(III) containing metalloenzymes that possess an N(2)S(3) ligand environment with nitrogen donors derived from amidates and sulfur donors derived from cysteinates. A closely related enzyme is thiocyanate hydrolase (SCNase), which possesses a nearly identical active-site coordination environment as CoNHase. These enzymes are redox inactive and perform hydrolytic reactions; SCNase hydrolyzes thiocyanate anions while NHase converts nitriles into amides. Herein an active CoNHase metallopeptide mimic, [Co(III)NHase-m1] (NHase-m1 = AcNH-CCDLP-CGVYD-PA-COOH), that contains Co(III) in a similar N(2)S(3) coordination environment as CoNHase is reported. [Co(III)NHase-m1] was characterized by electrospray ionization-mass spectrometry (ESI-MS), gel-permeation chromatography (GPC), Co K-edge X-ray absorption spectroscopy (Co-S: 2.21 A; Co-N: 1.93 A), vibrational, and optical spectroscopies. We find that [Co(III)NHase-m1] will perform the catalytic conversion of acrylonitrile into acrylamide with up to 58 turnovers observed after 18 h at 25 degrees C (pH 8.0). FTIR data used in concert with calculated vibrational data (mPWPW91/aug-cc-TZVPP) demonstrates that the active form of [Co(III)NHase-m1] has a ligated SO(2) (nu = 1091 cm(-1)) moiety and a ligated protonated SO(H) (nu = 928 cm(-1)) moiety; when only one oxygenated cysteinate ligand (i.e., a mono-SO(2) coordination motif) or the bis-SO(2) coordination motif are found within [Co(III)NHase-m1] no catalytic activity is observed. Calculations of the thermodynamics of ligand exchange (B3LYP/aug-cc-TZVPP) suggest that the reason for this is that the SO(2)/SO(H) equatorial ligand motif promotes both water dissociation from the Co(III)-center and nitrile coordination to the Co(III)-center. In contrast, the under- or overoxidized motifs will either strongly favor a five coordinate Co(III)-center or strongly favor water binding to the Co(III)-center over nitrile binding. PMID- 20831173 TI - C-H activation of acetonitrile at nickel: ligand flip and conversion of N-bound acetonitrile into a C-bound cyanomethyl ligand. AB - Nickel joins the fairly exclusive list of metals that can activate nitrile C-H bonds. We report the first example of the C-H activation of an acetonitrile ligand on a nickel center. The acetonitrile ligand formally loses a proton and undergoes a sharp flip to give a cyanomethyl ligand that is coordinated to the nickel atom. Structures of an initial N-bound acetonitrile-nickel complex and of a final cyanomethyl-nickel complex are both presented. PMID- 20831174 TI - Enantioenriched synthesis of C1-symmetric BINOLs: iron-catalyzed cross-coupling of 2-naphthols and some mechanistic insight. AB - Highly enantioselective aerobic oxidative cross-coupling of 2-naphthols with broad substrate scope was achieved using an iron(salan) complex as the catalyst. Enantiomeric excesses of the products ranged from 87 to 95%. The scope of the cross-coupling reaction was found to be different from that of the homocoupling reaction under the same reaction conditions. PMID- 20831176 TI - The role of molecular clusters in the filling of carbon nanotubes. AB - We have demonstrated that the ability of fullerenes to form clusters is essential for the filling of single-walled carbon nanotubes in solution. In solutions where C60 exists in the form of discrete solvated molecules (e.g., in CS2) no fullerene encapsulation in nanotubes takes place, as the large molar excess of solvent compared to solute prohibits C60 from entering the nanotubes. However, in solutions containing large clusters of C60 (e.g., in n-hexane) nanotubes become densely filled with fullerene molecules despite the large excess of solvent. The interactions between carbon nanotubes and fullerene clusters provide an efficient transport of C60 into nanotubes that avoids the detrimental effects of the solvent molecules. This new mechanism provides the first rational explanation of experiments involving nanotube filling with guest-molecules in solution. PMID- 20831175 TI - Total synthesis and biological evaluation of tyroscherin. AB - The efficient synthesis and biological evaluation of both the reported and revised structures of tyroscherin have been achieved. Central to our synthesis is a cross metathesis reaction that generated the trans-olefin regioselectively. This synthetic strategy enabled the facile manipulation of tyroscherin stereochemistry, facilitating the generation of all 16 tyroscherin diastereomers and a photoactivatable tyroscherin-based affinity probe for future mode of action studies. PMID- 20831177 TI - Dye-sensitized solar cells. PMID- 20831178 TI - Efficient synthesis of a small molecule, nonpeptide inhibitor of LFA-1. AB - A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph(3)PCl(2)-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg exchange of 9 followed by addition to SO(2) in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with L-alaninamide using K(2)CO(3) as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production of 1 on a metric ton scale. PMID- 20831179 TI - Carbanionic route to electroactive carbon-centered anion and radical oligomers. AB - The synthesis of poly-1,3-bisdiphenylene-2-phenyl allyl (BDPA) radicals via a new anionic oligomerization strategy is reported. The material displays a reversible reduction from the orange-red radical to the blue carbanion in solution. PMID- 20831180 TI - Enantiopure 1,2-bis(tert-butylmethylphosphino)benzene as a highly efficient ligand in rhodium-catalyzed asymmetric hydrogenation. AB - An electron-rich P-stereogenic bisphosphine ligand named "BenzP*" was conveniently prepared from o-dibromobenzene and enantiopure tert butylmethylphosphine-borane. Its rhodium complex exhibited excellent enantioselectivities of up to 99.9% and high catalytic activity of up to 10,000 h(-1) TOF in asymmetric hydrogenations of various functionalized alkenes. PMID- 20831181 TI - Rapid cytosolic delivery of luminescent nanocrystals in live cells with endosome disrupting polymer colloids. AB - Luminescent nanocrystals hold great potential for bioimaging because of their exceptional optical properties, but their use in live cells has been limited. When nanocrystals enter live cells, they are taken up in vesicles. This vesicular sequestration is persistent and precludes nanocrystals from reaching intracellular targets. Here, we describe a unique, cationic core-shell polymer colloid that translocates nanocrystals to the cytosol by disrupting endosomal membranes via a low-pH triggered mechanism. Confocal fluorescence microscopy and flow cytometry indicate that picomolar concentrations of quantum dots are sufficient for cytosolic labeling, with the process occurring within a few hours of incubation. We anticipate a host of advanced applications arising from efficient cytosolic delivery of nanocrystal imaging probes: from single particle tracking experiments to monitoring protein-protein interactions in live cells for extended periods. PMID- 20831182 TI - Responsive plasmonic assemblies of amphiphilic nanocrystals at oil-water interfaces. AB - We report a new class of amphiphilic nanocrystals with mixed polymer brush coatings, which can spontaneously assemble into two-dimensional arrays at oil water interfaces. The plasmon coupling of gold nanoparticles and nanorods in the assembly can be reversibly modulated by conformational changes of the stimuli responsive polymer brushes. Amphiphilic gold nanocrystals (nanoparticles and nanorods) with mixed polymer brushes were synthesized via sequential "grafting to" (ligand exchange) and "grafting from" (surface initiated atom transfer radical polymerization) reactions. The integration of "grafting to" and "grafting from" reactions offers great flexibility for the surface modification of the nanocrystal scaffolds, allowing the combination of polymers with distinctly different properties on well-defined nanocrystals. For nanocrystals with poly(ethylene glycol) and poly(methyl methacrylate) coatings, the collective plasmonic property of the assembly can be tailored by changing solvent quality. In the case of the amphiphilic nanocrystal with poly(ethylene glycol) and poly(2 (diethylamino)ethyl methacrylate), the pH-sensitivity of poly(2 (diethylamino)ethyl methacrylate) provides an additional means to reversibly tune the assembly by varying the pH. All of the components, including nanocrystals, materials for self-assembled monolayers (polymers and biomacromolecules) on nanocrystal surfaces, and monomers suitable for surface-initiated living radical polymerization, in this construct have a wealth of possibilities available, indicating the potential of our strategy for developing hybrid materials with integrated and collective functionalities. PMID- 20831183 TI - Magnetic resonance studies of a redox probe in a reverse sodium bis(2 ethylhexyl)sulfosuccinate/octane/water microemulsion. AB - The location and dynamics of the [Ru(bpy)(3)](2+) complex inside sodium bis(2 ethylhexyl)sulfosuccinate (AOT)/octane/water microemulsions were studied, over a range of droplet sizes, using magnetic resonance spectroscopy, dynamic light scattering, and molecular modeling. The T(1) magnetic resonance relaxation times of water inside the AOT reverse micelles (RMs) were measured in both the presence and the absence of the [Ru(bpy)(3)](2+) complex. Large size droplet RMs (omega(0) > 20) were found to be sensitive to the presence of the [Ru(bpy)(3)](2+) complex, which was detected through a decrease in the T(1) relaxation time of the water inside the RM core, as compared to RMs containing no [Ru(bpy)(3)](2+). However, no difference in T(1) relaxation time was observed for water in small RMs (omega(0) < 20). Two-dimensional (1)H-(1)H NOESY spectroscopy was performed to probe the location of the [Ru(bpy)(3)](2+) complex in both small (omega(0) = 9.2) and large droplets (omega(0) = 34.9). Cross-peaks between protons in the AOT tail groups and bipyridyl ligands were observed, showing that the [Ru(bpy)(3)](2+) complex resided in the RM interface. Finally, molecular modeling simulations were performed to probe the location of the [Ru(bpy)(3)](2+) complex and the structure of the RM. Molecular dynamics simulations confirmed the location of the [Ru(bpy)(3)](2+) complex in the RM interface and detected differences in the surfactant layer and the amount of water penetration into this layer with changing droplet size. PMID- 20831185 TI - Pickering emulsions stabilized by nanoparticles with thermally responsive grafted polymer brushes. AB - A study is presented of emulsification by silica nanoparticles with poly(2 (dimethylamino)ethyl methacrylate) brushes grafted from their surfaces (SiO(2) PDMAEMA) by atom-transfer radical polymerization (ATRP). The grafted nanoparticles were used to stabilize xylene-in-water and cyclohexane-in-water Pickering emulsions. PDMAEMA is a water-soluble weak polyelectrolyte with a pH dependent lower critical solution temperature (LCST). Accordingly, SiO(2)-PDMAEMA nanoparticles were thermally responsive, as shown by the fact that they displayed a critical flocculation temperature (CFT) when heated. ATRP provides a high degree of control over the brush grafting density and degree of polymerization, two of the principal variables examined in this study. The effects of the solvent quality of the "oil" for the PDMAEMA brush were studied in addition to the effects of aqueous pH, ionic strength, and temperature relative to the CFT. The preferred emulsion type was oil in water in all cases. The lowest grafting density particles (0.077 chains/nm(2)) proved to be the most efficient and robust emulsifiers, producing stable emulsions using as little as 0.05 wt % particles in the aqueous phase and successfully emulsifying over a broader range of solution conditions than for the higher grafting density particles (0.36 and 1.27 chain/nm(2)). Both good (xylene) and poor (cyclohexane) solvents could be emulsified, but the poor solvent could be emulsified over a broader range of conditions than the good solvent. Emulsions have been stable for over 13 months, and some have dispersed as much as 83 vol % oil in the emulsion phase. Thermally responsive emulsions were created with the SiO(2)-PDMAEMA particles such that stable emulsions prepared at low temperature were rapidly broken by increasing the temperature above the CFT. PMID- 20831186 TI - New lithium iron pyrophosphate as 3.5 V class cathode material for lithium ion battery. AB - A new pyrophosphate compound Li(2)FeP(2)O(7) was synthesized by a conventional solid-state reaction, and its crystal structure was determined. Its reversible electrode operation at ca. 3.5 V vs Li was identified with the capacity of a one electron theoretical value of 110 mAh g(-1) even for ca. 1 MUm particles without any special efforts such as nanosizing or carbon coating. Li(2)FeP(2)O(7) and its derivatives should provide a new platform for related lithium battery electrode research and could be potential competitors to commercial olivine LiFePO(4), which has been recognized as the most promising positive cathode for a lithium ion battery system for large-scale applications, such as plug-in hybrid electric vehicles. PMID- 20831184 TI - Multiple turnovers of the nicotino-enzyme PdxB require alpha-keto acids as cosubstrates. AB - PdxB catalyzes the second step in the biosynthesis of pyridoxal phosphate by oxidizing 4-phospho-d-erythronate (4PE) to 2-oxo-3-hydroxy-4-phosphobutanoate (OHPB) with concomitant reduction of NAD(+) to NADH. PdxB is a nicotino-enzyme wherein the NAD(H) cofactor remains tightly bound to PdxB. It has been a mystery how PdxB performs multiple turnovers since addition of free NAD(+) does not reoxidize the enzyme-bound NADH following conversion of 4PE to OHPB. We have solved this mystery by demonstrating that a variety of physiologically available alpha-keto acids serve as oxidants of PdxB to sustain multiple turnovers. In a coupled assay using the next two enzymes of the biosynthetic pathway for pyridoxal phosphate (SerC and PdxA), we have found that alpha-ketoglutarate, oxaloacetic acid, and pyruvate are equally good substrates for PdxB (k(cat)/K(m) values ~1 * 10(4) M-1s-1). The kinetic parameters for the substrate 4PE include a k(cat) of 1.4 s-1, a K(m) of 2.9 MUM, and a k(cat)/K(m) of 6.7 * 10(6) M-1s-1. Additionally, we have characterized the stereochemistry of alpha-ketoglutarate reduction by showing that d-2-HGA, but not l-2-HGA, is a competitive inhibitor vs 4PE and a noncompetitive inhibitor vs alpha-ketoglutarate. PMID- 20831187 TI - Catalytic enantioselective alkylative dearomatization-annulation: total synthesis and absolute configuration assignment of hyperibone K. AB - The asymmetric total synthesis of the polyprenylated acylphloroglucinol hyperibone K has been achieved using an enantioselective alkylative dearomatization-annulation process. NMR and computational studies were employed to probe the mode of action of a chiral phase-transfer (ion pair) catalyst. PMID- 20831188 TI - Palladium-catalyzed intermolecular decarboxylative coupling of 2-phenylbenzoic acids with alkynes via C-H and C-C bond activation. AB - A novel protocol for palladium-catalyzed intermolecular formal [4 + 2] annulation of 2-phenylbenzoic acids with alkynes is described. Acridine is shown to be essential for the high reaction efficiency. Phenanthrene derivatives are formed in moderate to good yields without coupling (pseudo)halides or organometallic species. PMID- 20831189 TI - A unifying model for the operation of light-emitting electrochemical cells. AB - The application of doping in semiconductors plays a major role in the high performances achieved to date in inorganic devices. In contrast, doping has yet to make such an impact in organic electronics. One organic device that does make extensive use of doping is the light-emitting electrochemical cell (LEC), where the presence of mobile ions enables dynamic doping, which enhances carrier injection and facilitates relatively large current densities. The mechanism and effects of doping in LECs are, however, still far from being fully understood, as evidenced by the existence of two competing models that seem physically distinct: the electrochemical doping model and the electrodynamic model. Both models are supported by experimental data and numerical modeling. Here, we show that these models are essentially limits of one master model, separated by different rates of carrier injection. For ohmic nonlimited injection, a dynamic p-n junction is formed, which is absent in injection-limited devices. This unification is demonstrated by both numerical calculations and measured surface potentials as well as light emission and doping profiles in operational devices. An analytical analysis yields an upper limit for the ratio of drift and diffusion currents, having major consequences on the maximum current density through this type of device. PMID- 20831190 TI - Therapeutic promises of 2-methoxyestradiol and its drug disposition challenges. AB - 2-Methoxyestradiol (2MeO-E2) is an endogenous metabolite of estrogen which was initially considered to be inactive. During the last few decades it has been shown that 2MeO-E2 is a promising anticancer drug. In vitro experiments have demonstrated that it has several anticancer activities, and potential to alleviate hypertension, glomerulosclerosis, hypercholesterolemia, and other disorders. However, due to its low solubility and extensive glucuronidation, to achieve effective concentrations large doses of 2MeO-E2 would be required. Clinical studies reflected very high inter- and intrapatient variability and oral bioavailability of 1 to 2%. Thus, this review paper highlights the origin of this compound, its therapeutic promises, and possible mechanisms of action. It also discusses the pharmacokinetic properties of 2MeO-E2 as well as current developments to overcome low drug solubility and its extensive first pass metabolism. PMID- 20831191 TI - Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of enantiomerically enriched potassium beta-trifluoroboratoamides with various aryl- and hetaryl chlorides. AB - Enantiomerically enriched potassium beta-trifluoroboratoamides were synthesized as air-stable solids in greater than 95:5 dr using pseudoephedrine as the chiral auxiliary. With these chiral nucleophiles, Suzuki-Miyaura cross-coupling reactions were carried out with various aryl- and hetaryl chlorides in good to excellent yields. Moreover, the diastereoselectivities were preserved throughout the Suzuki-Miyaura cross-coupling reactions. PMID- 20831192 TI - Role of Nrf2 in suppressing LPS-induced inflammation in mouse peritoneal macrophages by polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid. AB - This study is to investigate the role of Nrf2 in suppressing LPS-mediated inflammation in ex vivo macrophages by polyunsaturated fatty acids (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Primary peritoneal macrophages from Nrf2 wild-type (+/+; WT) and Nrf2 knockout (-/-; KO) mice were treated with lipopolysaccharides (LPS) in the presence or absence of DHA or EPA. Quantitative real-time PCR (qPCR) analyses showed that LPS potently induced cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha) in the macrophages collected from Nrf2 (+/+) wild-type mice. DHA and EPA inhibited LPS-induced COX-2, iNOS, IL-1beta, IL-6, or TNF-alpha, but increased hemeoxygenase (HO-1) expression. DHA was found to be more potent than EPA in inhibiting COX-2, iNOS, IL-1beta, IL-6, and TNF-alpha mRNA expression. DHA and EPA were also found to induce HO-1 and Nrf2 mRNA with a different dose-response. LPS induced COX-2, iNOS, IL-1beta, IL-6, and TNF-alpha in the macrophages collected from Nrf2 (-/-) mice as well, however, DHA and EPA suppression of COX 2, iNOS, IL-1beta, IL-6, and TNF-alpha was attenuated as compared to that in Nrf2 (+/+) macrophages. Taken together, using Western blotting, ELISA and qPCR approaches coupled with Nrf2 (-/-) mice, our study clearly shows for the first time that DHA/EPA would induce Nrf2 signaling pathway and that Nrf2 plays a role in DHA/EPA suppression of LPS-induced inflammation. PMID- 20831194 TI - Density functional theory calculations on the mononuclear non-heme iron active site of Hmd hydrogenase: role of the internal ligands in tuning external ligand binding and driving H2 heterolysis. AB - DFT calculations on active-site models of the non-heme Fe site of Hmd hydrogenase are reported. Binding of several biologically relevant ligands (e.g., CN(-), CO, H(-), H(2), and O(2)) to the active site of Hmd was investigated using a method that reproduced the geometric and vibrational properties of the resting site. The results indicate that this neutral ferrous active site has higher affinity toward anionic ligands (e.g., H(-) and CN(-)) than pi-acidic ligands (e.g., CO and O(2)). Natural population analysis and molecular orbital analysis revealed that this is due to extensive delocalization of electron density into the low-lying unoccupied orbitals of the CO, acyl, and pyridinol ligands present in the active site. In addition to normal d-pi back-bonding, metal 3d orbital-mediated charge transfer from occupied ligand orbitals to the unoccupied orbitals of the internal ligands was observed. This charge transfer leads to systematic variations in the experimentally observed C-O stretching frequencies. Protonation of the thiolate ligand present in the active site significantly enhances these anion ligand binding affinities. In fact, the calculated vibrational frequencies indicate that CN(-) binding is possibly associated with protonation of the thiolate ligand. The high affinity for binding of the anionic H(-) ligand (where 81% of the electron density of H(-) is delocalized into the active site) is calculated to play a dominating role in the H-H bond heterolysis step during catalysis. The binding energies of these ligands relative to the substrate, H(2), highlight the importance of a proposed structural reorganization during catalysis. PMID- 20831193 TI - Quantitative structure activity relationship for inhibition of human organic cation/carnitine transporter. AB - Organic cation/carnitine transporter (OCTN2; SLC22A5) is an important transporter for L-carnitine homeostasis, but can be inhibited by drugs, which may cause L carnitine deficiency and possibly other OCTN2-mediated drug-drug interactions. One objective was to develop a quantitative structure-activity relationship (QSAR) of OCTN2 inhibitors, in order to predict and identify other potential OCTN2 inhibitors and infer potential clinical interactions. A second objective was to assess two high renal clearance drugs that interact with OCTN2 in vitro (cetirizine and cephaloridine) for possible OCTN2-mediated drug-drug interactions. Using previously generated in vitro data of 22 drugs, a 3D quantitative pharmacophore model and a Bayesian machine learning model were developed. The four pharmacophore features include two hydrophobic groups, one hydrogen-bond acceptor, and one positive ionizable center. The Bayesian machine learning model was developed using simple interpretable descriptors and function class fingerprints of maximum diameter 6 (FCFP_6). An external test set of 27 molecules, including 15 newly identified OCTN2 inhibitors, and a literature test set of 22 molecules were used to validate both models. The computational models afforded good capability to identify structurally diverse OCTN2 inhibitors, providing a valuable tool to predict new inhibitors efficiently. Inhibition results confirmed our previously observed association between rhabdomyolysis and C(max)/K(i) ratio. The two high renal clearance drugs cetirizine and cephaloridine were found not to be OCTN2 substrates, and their diminished elimination by other drugs is concluded not to be mediated by OCTN2. PMID- 20831195 TI - Enantioselective alpha-benzylation of aldehydes via photoredox organocatalysis. AB - The first enantioselective aldehyde alpha-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a chiral imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst in the presence of household fluorescent light directly affords the desired homobenzylic stereogenicity in good to excellent yield and enantioselectivity. The utility of this methodology has been demonstrated via rapid access to an enantioenriched drug target for angiogenesis suppression. PMID- 20831196 TI - Carbon-carbon bond activation by 1,1-carboboration of internal alkynes. AB - Internal alkynes undergo 1,1-carboboration reactions upon treatment with boranes RB(C(6)F(5))(2) (R = C(6)F(5), CH(3)) to yield trisubstituted alkenylboranes. These products can be used as substrates in Pd-catalyzed cross-coupling reactions. PMID- 20831197 TI - Probing the influence of anomeric effects on the lithium ion affinity in 1,3 diaza systems: a computational study. AB - Lithium ion affinities of methanediamine (MDA), N,N,N',N' tetramethylmethanediamine (TMMDA), 1,3-diazacyclohexane (DAC), trans-3,5 diazabicyclo[4.4.0]decane (trans-3,5-DBD), trans-1,3-diazabicyclo[4.4.0]decane (trans-1,3-DBD), cis-1,3-diazabicyclo[4.4.0]decane (cis-1,3-DBD), 1,5 diazabicyclo[3.3.1]nonane (DBN), trans-decahydro-8a,9a-diazaanthracene (trans DDA), cis-decahydro-8a,9a-diazaanthracene (cis-DDA), 1,3-diazetidine (DAT), 1,3 imidazolidine (IMD), and 1,3-diazepane (DAP) have been studied by using density functional theory (DFT) and correlated ab initio methods. Possible conformers of these compounds were optimized at the B3LYP/6-31+G* level, and relative energies were evaluated at the MP2/6-311+G**//B3LYP/6-31+G* level. The experimental lithium ion affinities for reference molecules (i.e., ammonia and trimethylamine) are well-reproduced at these levels of theory. NBO analysis shows the influence of anomeric effects (n(N) -> sigma*(C-N) hyperconjugative interactions) on the conformational stability of the title compounds; however, the electrostatic and steric contributions included in the NBO Lewis term also affect the stabilities in some cases. The influence of anomeric effect is apparent in cis-DDA, where the nitrogen involved in n(N) -> sigma*(C-N) hyperconjugative interaction (cis-DDA Li2) has a lithium ion affinity 1.7 kcal/mol lower than the nitrogen not involved in n(N) -> sigma*(C-N) hyperconjugative interaction (cis-DDA-Li1). In general, the computed lithium ion affinities were found to be conformationally dependent. The NBO results showed that the lithium ion affinities are also governed by the interplay of n(N) -> sigma*(C-N) hyperconjugative interactions and the steric strain caused upon lithiation. Further, the ring size also influences the lithium ion affinities in the 1,3-diaza monocyclic systems. In some complexes multiple coordination of the lithium ion is possible by inversion of one of the nitrogen atoms. PMID- 20831198 TI - Asymmetric total synthesis of caribenol A. AB - A unified strategy toward the asymmetric total synthesis of carbenol A is reported, featuring intramolecular Diels-Alder (IMDA) and biomimetic oxidation reactions as key steps. PMID- 20831199 TI - Surface modification of polyimide sheets for regenerative medicine applications. AB - In the present work, two strategies were elaborated to surface-functionalize implantable polyimide sheets. In the first methodology, cross-linkable vinyl groups were introduced on the polyimide surface using aminopropylmethacrylamide. In the second approach, a reactive succinimidyl ester was introduced on the surface of PI. Using the former approach, the aim is to apply a vinyl functionalized biopolymer coating. In the latter approach, any amine containing biopolymer can be immobilized. The foils developed were characterized in depth using a variety of characterization techniques including atomic force microscopy, static contact angle measurements, and X-ray photoelectron spectroscopy. The results indicated that both modification strategies were successful. The subcutaneous implantation in mice indicated that both modification strategies resulted in biocompatible materials, inducing only limited cellular infiltration to the surrounding tissue. PMID- 20831200 TI - Syntheses of click PEG-dexamethasone conjugates for the treatment of rheumatoid arthritis. AB - A novel linear multifunctional polyethylene glycol (PEG)-dexamethasone (Dex) conjugate (click PEG-Dex) was synthesized using facile Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a click reaction). Dex was conjugated to the click PEG via an acid-labile hydrazone bond to allow the drug release in a pathophysiological environment. To evaluate click PEG's potential as a versatile drug delivery platform, the click PEG-Dex conjugates were tested in an adjuvant induced arthritis (AA) rat model. In vivo optical imaging data confirmed the arthrotropism of the conjugates in the arthritic rats. A long-term treatment study revealed that a single click PEG-Dex conjugate administration provided sustained (>15 days) amelioration of ankle joint inflammation to the AA rats. Treatment with an equivalent dose of dexamethasone phosphate sodium (free Dex) only provided temporal resolution of the arthritis, which recurred upon treatment withdrawal. Further histological and bone mineral density comparison between the ankle joints from both click PEG-Dex and free Dex treatment groups confirmed the superior anti-inflammatory and disease modifying effects of the novel polymer drug conjugates. PMID- 20831201 TI - Immobilization of biomolecules to plasma polymerized pentafluorophenyl methacrylate. AB - Thin films of plasma polymerized pentafluorophenyl methacrylate (pp-PFM) offer highly reactive ester groups throughout the structure of the film that allow for subsequent reactions with different aminated reagents and biological molecules. The present paper follows on from previous work on the plasma deposition of pentafluorophenyl methacrylate (PFM) for optimum functional group retention (Francesch, L.; Borros, S.; Knoll, W.; Foerch, R. Langmuir 2007, 23, 3927) and reactivity in aqueous solution (Duque, L.; Queralto, N.; Francesch, L.; Bumbu, G. G.; Borros, S.; Berger, R.; Forch, R. Plasma Process. Polym. 2010, accepted for publication) to investigate the binding of a biologically active peptide known to induce cellular adhesion (IKVAV) and of biochemically active proteins such as BSA and fibrinogen. Analyses of the films and of the immobilization of the biomolecules were carried out using infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The attachment of the biomolecules on pulsed plasma polymerized pentafluorophenyl methacrylate was monitored using surface plasmon resonance spectroscopy (SPR). SPR analysis confirmed the presence of immobilized biomolecules on the plasma polymer and was used to determine the mass coverage of the peptide and proteins adsorbed onto the films. The combined analysis of the surfaces suggests the covalent binding of the peptide and proteins to the surface of the pp-PFM. PMID- 20831202 TI - Concise total synthesis of the potent translation and cell migration inhibitor lactimidomycin. AB - An efficient total synthesis of the antiproliferative macrolide and cell migration inhibitor lactimidomycin (3) is reported, which relies on the performance of ring closing alkyne metathesis (RCAM). The strained 12-membered 1,3-enyne 21 as the key intermediate was forged with the aid of [(Ph(3)SiO)(3)Mo=CPh].OEt(2) (27) as the most effective member of a new generation of powerful alkyne metathesis catalysts. 21 was elaborated to the target by a ruthenium catalyzed trans-hydrosilylation/proto-desilylation sequence and a highly diastereoselective Mukaiyama aldol reaction controlled by oxazaborolidinone 29 as strategic operations. PMID- 20831203 TI - ortho-Phenylenes: unusual conjugated oligomers with a surprisingly long effective conjugation length. AB - ortho-Phenylenes represent a fundamental but relatively unexplored class of conjugated molecular architecture. We have developed a robust synthetic approach to monodisperse o-phenylene oligomers which we have demonstrated by synthesizing a homologous series up to the dodecamer. The o-phenylenes exhibit complex conformational behavior but are biased toward a specific 2-fold-symmetric conformation which we believe corresponds to a stacked helix. Surprisingly, the series exhibits long-range delocalization, as measured by bathochromic shifts in UV/vis spectra. Although the overall magnitude of the shifts is modest (but comparable to some other classes of conjugated materials), the effective conjugation length of the series is approximately eight repeat units. The oligomers also exhibit an unusual hypsochromic shift in their fluorescence spectra with increasing length. The origin of these trends is discussed in the context of conformational analysis and DFT calculations of the frontier molecular orbitals for the series. PMID- 20831204 TI - Interaction of atomic and molecular hydrogen with tholin surfaces at low temperatures. AB - We study the interaction of atomic and molecular hydrogen with a surface of tholin, a man-made polymer considered to be an analogue of aerosol particles present in Titan's atmosphere, using thermal programmed desorption at low temperatures below 30 K. The results are fitted and analyzed using a fine-grained rate equation model that describes the diffusion, reaction, and desorption processes. We obtain the energy barriers for diffusion and desorption of atomic and molecular hydrogen. These barriers are found to be in the range of 30-60 meV, indicating that atom/molecule-surface interactions in this temperature range are dominated by weak adsorption forces. The implications of these results for the understanding of the atmospheric chemistry of Titan are discussed. PMID- 20831205 TI - The photophysics of a polar molecule in a nonpolar cryogenic glass--the effects of dimerization on (1-butyl-4-(1H-inden-1-ylidene)-1,4-dihydropyridine (BIDP). AB - The first excited state of BIDP was shown in a previous communication to exhibit an ultrafast decay in fluid nonpolar, nonprotic solutions due to the presence of a S(1)/S(0) conical intersection (CI). In frozen polar and nonpolar glasses a strong fluorescence was observed, rationalized by the hindering of the internal torsion required to reach the geometry of the CI. Complete analysis of the data was hampered by some unusual observations in nonpolar glasses. In this paper we show that they can be explained by assuming dimer formation, with a formation constant of K(eq) = (4 +/- 3) * 10(5) M(-1) at 83 K and DeltaH(dim) = 7 +/- 2 kcal/mol. A complete analysis of the spectra is presented, and fluorescence quantum yields of the monomer and dimer are reported. Efficient self-quenching is found, with a Stern Volmer constant, K(SV) = (1.5 +/- 0.1) * 10(6) M(-1), assigned to static quenching. The dimer absorption spectrum was extracted from the data and is compared to Kasha's exciton model and to quantum chemical (QC) calculations. The basic features of exciton splitting are reproduced by quantum mechanical calculations, but complete quantitative agreement of the QC computations with the experimental results is not attained. The previous analysis of the monomer spectra using the displaced harmonic oscillator model is extended to the more demanding conditions prevailing at cryogenic temperatures. The derived DeltaH(dim) is in good agreement with other dimers formation enthalpies and with the quantum mechanical calculation presented. The new analysis corrects tau(f) in MCHIP to 2.9 * 10(-13) s, somewhat smaller than the value reported in polar solvent in a previous communication, thereby strengthening the assumption that polarity can reduce the efficiency of CI. PMID- 20831206 TI - Development of a troponin I biosensor using a peptide obtained through phage display. AB - A small synthetic peptide with nanomolar affinity for cardiac troponin I (TnI), previously identified from a polyvalent phage displayed library, has been immobilized on a gold surface for TnI detection. The binding affinity of gold immobilized peptides for TnI was studied and compared with that of phage immobilized peptides. Quartz crystal microbalance (QCM), cyclic voltammetry, and electrochemical impedance spectroscopy (EIS) were used to monitor both the immobilization and target binding processes. All three techniques show that the binding is specific for TnI as compared to a streptavidin (SA) control. The response curves obtained at TnI concentrations ranging from 0 to 10 MUg/mL, using both QCM and EIS, were also compared. For the EIS measurements, the sensitivity was 0.30 +/- 0.030 normalized impedance/(MUg/mL) and the limit of detection (LOD) was 0.34 MUg/mL. Using the QCM, a sensitivity of 18 +/- 1 Hz/(MUg/mL) was obtained, corresponding to an LOD of 0.11 MUg/mL. Although the QCM demonstrated a lower LOD as compared to EIS, the latter technique exhibited a larger linear dynamic range than QCM. In a relevant tissue culture milieu, Minimum Essential Media (MEM), the sensitivity of the EIS measurement was greater than that obtained in a phosphate buffer system (PBS). The kinetics of target binding using QCM were analyzed by two independent methods, and the dissociation constants (K(D) = 66 +/- 4 nM and 17 +/- 8 nM) were an order of magnitude higher than that calculated for the polyvalent phage particles (K(D) = 2.5 +/- 0.1 nM). Even though the affinity of the immobilized peptides for TnI was somewhat reduced, overall, these results demonstrate that peptides obtained from the biopanning of phage display libraries can be readily used as sensing probes in biosensor development. PMID- 20831208 TI - Fe(II)-Fe(III)-bearing phases as a mineralogical control on the heterogeneity of arsenic in Southeast Asian groundwater. AB - Although groundwater arsenic constitutes a major hazard to the health of the people of Southeast Asia, the exact mineralogical origin of the arsenic in these fluvial aquifers is still under debate. Fe(III) oxides are the dominant hosts of mobilizable arsenic in the sediments, with the role of secondary Fe(II)-bearing phases like mackinawite, siderite, vivianite, magnetite, and carbonate green rust (fougerite) still unclear. Based on published field data from Chakdaha (India), the importance of the phases for arsenic mobility is evaluated quantitatively using models of growing complexity. Arsenic heterogeneity can be explained by the presence of two contrasted redox zones in the aquifers, with Fe(III) oxides being the dominant sorbent for arsenic in the less reduced zones and Fe(II) sulfides and/or Fe(II) carbonates being the solid-phase hosts for arsenic under more reduced conditions below impermeable soils or close to rivers where sulfate is reduced. A 1D reactive transport model which simulates the transition between the two environments has been developed and compared to field data. The results show that microbial sulfate reduction followed by abiotic and/or biotic reduction of As(III)-bearing iron oxides accounts for the spatial heterogeneity of arsenic in such reduced aquifers. PMID- 20831209 TI - Cyanotoxin mixtures and taste-and-odor compounds in cyanobacterial blooms from the Midwestern United States. AB - The mixtures of toxins and taste-and-odor compounds present during cyanobacterial blooms are not well characterized and of particular concern when evaluating potential human health risks. Cyanobacterial blooms were sampled in twenty-three Midwestern United States lakes and analyzed for community composition, thirteen cyanotoxins by liquid chromatography/mass spectrometry and immunoassay, and two taste-and-odor compounds by gas chromatography/mass spectrometry. Aphanizomenon, Cylindrospermopsis and/or Microcystis were dominant in most (96%) blooms, but community composition was not strongly correlated with toxin and taste-and-odor occurrence. Microcystins occurred in all blooms. Total microcystin concentrations measured by liquid chromatography/mass spectrometry and immunoassay were linearly related (r(s) = 0.76, p < 0.01) and LC/MS/MS concentrations were lower than or similar to ELISA in most (85%) samples. Geosmin (87%), 2-methylisoborneol (39%), anatoxin-a (30%), saxitoxins (17%), cylindrospermopsins (9%), and nodularin-R (9%) also were present in these blooms. Multiple classes of cyanotoxins occurred in 48% of blooms and 95% had multiple microcystin variants. Toxins and taste-and odor compounds frequently co-occurred (91% of blooms), indicating odor may serve as a warning that cyanotoxins likely are present. However, toxins occurred more frequently than taste-and-odor compounds, so odor alone does not provide sufficient warning to ensure human-health protection. PMID- 20831210 TI - High-frequency electron-spin-resonance study of the octanuclear ferric wheel CsFe(8). AB - High-frequency (f = 190 GHz) electron paramagnetic resonance (EPR) at magnetic fields up to 12 T and Q-band (f = 34.1 GHz) EPR were performed on single crystals of the molecular wheel CsFe(8). In this molecule, eight Fe(III) ions, which are coupled by nearest-neighbor antiferromagnetic (AF) Heisenberg exchange interactions, form a nearly perfect ring. The angle-dependent EPR data allow for the accurate determination of the spin Hamiltonian parameters of the lowest spin multiplets with S <= 4. Furthermore, the data can be well reproduced by a dimer model with a uniaxial anisotropy term, with only two free parameters J and D. A fit to the dimer model yields J = -15(2) cm(-1) and D = -0.3940(8) cm(-1). A rhombic anisotropy term is found to be negligibly small, E = 0.000(2) cm(-1). The results are in excellent agreement with previous inelastic neutron scattering and high-field torque measurements. They confirm that the CsFe(8) molecule is an excellent experimental model of an AF Heisenberg ring. These findings are also important within the scope of further investigations on this molecule such as the exploration of recently observed magnetoelastic instabilities. PMID- 20831211 TI - Ambient air pollutant measurement error: characterization and impacts in a time series epidemiologic study in Atlanta. AB - In time-series studies of ambient air pollution and health in large urban areas, measurement errors associated with instrument precision and spatial variability vary widely across pollutants. In this paper, we characterize these errors for selected air pollutants and estimate their impacts on epidemiologic results from an ongoing study of air pollution and emergency department visits in Atlanta. Error was modeled for daily measures of 12 air pollutants using collocated monitor data to characterize instrument precision and data from multiple study area monitors to estimate population-weighted spatial variance. Time-series simulations of instrument and spatial error were generated for each pollutant, added to a reference pollutant time-series, and used in a Poisson generalized linear model of air pollution and cardiovascular emergency department visits. Reductions in risk ratio due to instrument precision error were less than 6%. Error due to spatial variability resulted in average risk ratio reductions of less than 16% for secondary pollutants (O(3), PM(2.5) sulfate, nitrate and ammonium) and between 43% and 68% for primary pollutants (NO(x), NO(2), SO(2), CO, PM(2.5) elemental carbon); pollutants of mixed origin (PM(10), PM(2.5), PM(2.5) organic carbon) had intermediate impacts. Quantifying impacts of measurement error on health effect estimates improves interpretation across ambient pollutants. PMID- 20831212 TI - Comment on "More of EPA's SPARC online calculator--the need for high-quality predictions of chemical properties". PMID- 20831213 TI - Single nanowire electrochemical devices. AB - We report the single nanowire electrode devices designed as a unique platform for in situ probing the intrinsic reason for electrode capacity fading in Li ion based energy storage devices. In this device, a single vanadium oxide nanowire or single Si/a-Si core/shell nanowire was used as working electrode, and electrical transport of the single nanowire was recorded in situ to detect the evolution of the nanowire during charging and discharging. Along with lithium ion intercalation by shallow discharge, the vanadium oxide nanowire conductance was decreased over 2 orders. The conductance change can be restored to previous scale upon lithium ion deintercalation with shallow charge. However, when the nanowire was deeply discharged, the conductance dropped over 5 orders, indicating that permanent structure change happens when too many lithium ions were intercalated into the vanadium oxide layered structures. Different from vanadium oxide, the conductance of a single Si/a-Si core/shell nanowire monotonously decreased along with the electrochemical test, which agrees with Raman mapping of single Si/a-Si nanowire at different charge/discharge states, indicating permanent structure change after lithium ion insertion and extraction. Our present work provides the direct relationship between electrical transport, structure, and electrochemical properties of a single nanowire electrode, which will be a promising and straightforward way for nanoscale battery diagnosis. PMID- 20831214 TI - Soluble P3HT-grafted graphene for efficient bilayer-heterojunction photovoltaic devices. AB - CH(2)OH-terminated regioregular poly(3-hexylthiophene) (P3HT) was chemically grafted onto carboxylic groups of graphene oxide (GO) via esterification reaction. The resultant P3HT-grafted GO sheets (G-P3HT) are soluble in common organic solvents, facilitating the structure/property characterization and the device fabrication by solution processing. The covalent linkage and the strong electronic interaction between the P3HT and graphene moieties in G-P3HT were confirmed by spectroscopic analyses and electrochemical measurements. A bilayer photovoltaic device based on the solution-cast G-P3HT/C(60) heterostructures showed a 200% increase of the power conversion efficiency (eta = 0.61%) with respect to the P3HT/C(60) counterpart under AM 1.5 illumination (100 mW/cm(2)). PMID- 20831216 TI - Perfluorinated compounds in infiltrated river rhine water and infiltrated rainwater in coastal dunes. AB - Different studies have shown that surface waters contain perfluorinated compounds (PFCs) in the low ng/L range. Surface waters are used to produce drinking water and PFCs have been shown to travel through the purification system and form a potential threat to human health. The specific physicochemical properties of PFCs cause them to be persistent and some of them to be bioaccumulative and toxic in the environment. This study investigates the evolvement of PFC concentrations in Rhine water and rainwater during dune water infiltration processes over a transect in the dune area of the western part of The Netherlands. The difference between infiltrated river water and rainwater in terms of PFC composition was investigated. Furthermore, isomer profiles were investigated. The compound perfluorobutanesulfonate (PFBS) was found at the highest concentrations of all PFCs investigated, up to 37 ng/L in infiltrated river water (71 +/- 13% of SigmaPFCs). This is in contrast with the predominant occurrence of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) reported in literature. The concentrations of PFBS found in infiltrated river Rhine water were significantly higher than those in infiltrated rainwater. For perfluorohexanesulfonate (PFHxS) the opposite was found: infiltrated rainwater contained more than infiltrated river water. The concentrations of PFOA, perfluorohexanoic acid (PFHxA), perfluoroheptanoic acid (PFHpA), PFBS, PFOS, and PFHxS in infiltrated river water showed an increasing trend with decreasing age of the water. The relative contribution of the branched PFOA and PFOS isomers to total concentrations of PFOA and PFOS showed a decreasing trend with decreasing age of the water. PMID- 20831217 TI - Insights into enzyme kinetics of chloroethane biodegradation using compound specific stable isotopes. AB - While compound specific isotope analysis (CSIA) has been used extensively to investigate remediation of chlorinated ethenes, to date considerably less information is available on its applicability to chlorinated ethanes. In this study, biodegradation of 1,1,1-trichloroethane (1,1,1-TCA) and 1,1-dichloroethane (1,1-DCA) was carried out by a Dehalobacter-containing mixed culture. Carbon isotope fractionation factors (epsilon) measured during whole cell degradation demonstrated that values for 1,1,1-TCA and 1,1-DCA (-1.80/00 and -10.50/00, respectively) were significantly smaller than values reported for abiotic reductive dechlorination of these same compounds. Similar results were found in experiments degrading these two priority pollutants by cell free extracts (CFE) where values of -0.80/00 and -7.90/00, respectively, were observed. For 1,1,1-TCA in particular, the large kinetic isotope effect expected for cleavage of a C-Cl bond was almost completely masked during biodegradation by both whole cells and CFE. Comparison to previous studies demonstrates that these patterns of isotopic fractionation are not attributable to transport effects across the cell membrane, as had been seen for other compounds such as PCE. In contrast these results reflect significant differences in the kinetics of the enzymes catalyzing chlorinated ethane degradation. PMID- 20831218 TI - Geochip-based functional gene analysis of anodophilic communities in microbial electrolysis cells under different operational modes. AB - A microbial electrolysis cell (MEC) is a bioelectrochemical system that can produce hydrogen from acetate at high hydrogen recoveries, but the composition and structure of the microbial communities in this system have not been extensively studied. We used a high throughput metagenomics technology (GeoChip) to examine the microbial community functional structure in MECs initially operated under different conditions. We found that startup conditions had little or no effect on reactor performance in terms of Coulombic efficiencies (CEs) and COD removals, somewhat greater effects on CO(2) and CH(4) production, and very large effects on hydrogen production. Hydrogen yields were generally higher for reactors that were always operated as MECs than those initially operated as MFCs. Hydrogen yields were nine times larger for MEC reactors with an applied voltage of 0.7 V (64%~80% efficiencies) than 0.3 V (<7-8%), independent of startup conditions. GeoChip analysis revealed that the functional and phylogenetic diversity of MEC microbial communities after 4 months was quite high despite the use of only a single substrate (acetate). MECs with the largest hydrogen yields had the highest microbial diversity. Multivariate analyses showed that communities that developed in the MECs were well separated from those present under startup conditions, indicating reactor operation altered microbial community composition. Community shifts based on a Mantel test were significantly related to CEs and COD removals in these reactors, suggesting that there were significant changes in microbial community composition as a result of conditions that affected MEC performance. Common well-known exoelectrogenic bacteria (e.g., Geobacter, Shewanella, Desulfovibrio, and Anaeromyxobacter) were found in these systems, but their importance in determining reactor functional performance was not supported with a high confidence in our statistical analysis. PMID- 20831219 TI - Elaborate ligand-based modeling reveals new nanomolar heat shock protein 90alpha inhibitors. AB - Heat shock protein (Hsp90alpha) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90alpha inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90alpha inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure activity relationship (QSAR) of optimal predictive potential (r(67)(2)=0.811, F 42.8, r(LOO)(2)=0.748, r(PRESS)(2) (against 16 external test inhibitors) = 0.619). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the Hsp90alpha binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds and our in-house-built drugs and agrochemicals database (DAC). Twenty-five nanomolar and low micromolar Hsp90alpha inhibitors were identified. The most potent were formoterol, amodaquine, primaquine, and midodrine with IC(50) values of 3, 5, 6, and 20 nM, respectively. PMID- 20831222 TI - Polyamine conjugation of curcumin analogues toward the discovery of mitochondria directed neuroprotective agents. AB - Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curcumin-like moiety allowed an efficient intracellular uptake and mitochondria targeting. It also resulted in a significant decrease in the cytotoxicity effects. 2-5 are therefore promising molecules for neuroprotectant lead discovery. PMID- 20831223 TI - Comparison of Rh-OCH3 and Rh-CH2OH bond dissociation energetics from methanol C-H and O-H bond reactions with rhodium(II) porphyrins. AB - Reaction of methanol in toluene with tetramesityl rhodium(II) porphyrin ((TMP)Rh(II*)) produces a (1)H NMR-observable equilibrium with rhodium methoxide ((TMP)Rh-OCH(3)(CH(3)OH)) and rhodium hydride ((TMP)Rh-H) complexes. Equilibrium concentrations for each of these species, obtained from integration of (1)H NMR spectra, were used in determining the equilibrium constant, K(298 K) = [Rh OCH(3)(CH(3)OH)][Rh-H]/[Rh(II*)](2)[CH(3)OH](2) = 3.0(0.3), and free energy change, DeltaG(0)(298 K) = -0.65(0.5) kcal mol(-1), for the reaction. Equilibrium thermodynamic measurements in CD(2)Cl(2) give DeltaG(0)(298 K) = -5.5(0.2) kcal mol(-1) for association of methanol with (TMP)Rh-OCH(3) to form the six coordinate 18-electron complex (TMP)Rh-OCH(3)(CH(3)OH). Equilibrium measurements in conjunction with (TMP)Rh-H and CH(3)O-H bond energetics are used to evaluate the (TMP)Rh-OCH(3) bond dissociation free energy (Rh-OCH(3) BDFE(298 K) = 38 (1.3) kcal mol(-1)), which is 15 kcal mol(-1) smaller than the Rh-H BDFE and approximately equal to the Rh-CH(2)OH BDFE. PMID- 20831224 TI - Inter-residue coupling and equilibrium unfolding of PPII helical peptides. Vibrational spectra enhanced with (13)C isotopic labeling. AB - Unordered proteins, unfolded peptides, and several "random coil" models have been shown to have local conformations similar to that of polyproline II (PPII). Inter residue coupling of selected residues in a series of related peptides having predominantly PPII conformations were measured using IR, VCD, and Raman spectra of selected variants that were doubly C(1)-labeled with (13)C on the amide C?O. The characteristics of the (13)C?O component of the IR, VCD, and Raman amide I' bands and their sensitivity to the local structure of the peptide are compared to predictions based on DFT level calculations for related structures and used to estimate coupling interactions between pairs of C?O groups along the backbone of this helical structure. In the PPII case, the coupling is relatively weak, due to the extended structure, yet by combining IR, Raman, and VCD observations with results of DFT level model calculations, we have determined bounds for experimental interaction constants for this structure. Correlation of properties for PPII structures with those of "random coils" can be done by comparing Pro(n) and Pro-rich sequences with Lys-rich sequences. The experimental band shifts and implied couplings reflect the computed results in both cases. Thermal unfolding of these peptides appears to be multistate, with monotonic spectral changes but little evidence of a cooperative (sigmoidal) transition. For the Lys-rich series, a transition from PPII to alpha-helix structure was induced by TFE addition, and the spectra were fit to an equilibrium model. These spectral changes show a large variation in (13)C?O coupling that occurs with a local conformational change from PPII- to alpha-helical, which is both well-fit by our theoretical results and offers a new site-specific method of assigning local PPII/disordered vs alpha helical (or other) structure. PMID- 20831225 TI - Extension of a classic theory of the low frequency dielectric dispersion of colloidal suspensions to the high frequency domain. AB - The classic Shilov-Dukhin theory of the low frequency dielectric dispersion of colloidal suspensions in binary electrolyte solutions [ Shilov , V. N. ; Dukhin , S. S. , Colloid J. 1970 , 32 , 245. ; Dukhin , S. S. ; Shilov , V. N. Dielectric Phenomena and the Double Layer in Disperse Systems and Polyelectrolytes ; Wiley : New York , 1974 ] was developed for the frequency range corresponding to the concentration polarization phenomenon: up to a few megahertz. While a few extensions to a broad frequency range including the Maxwell-Wagner-O'Konski dispersion exist, they all consist of modifications of the final results of the theory rather than modifications of its hypothesis, extending their validity to high frequencies. In this work we avoid this artificial process by providing a high frequency extension fully from within the theory. PMID- 20831226 TI - Norbadione a: kinetics and thermodynamics of cesium uptake in aqueous and alcoholic media. AB - Norbadione A (NbA) is a mushroom pigment, which is assumed to be involved in (137)Cs accumulation all over Europe during the Chernobyl nuclear accident. NbA bears seven acid-base functional groups, among which are two enolic and two carboxylic acid moieties. This work deals with complex formation of Cs(+) and NbA in ethanol, ethanol/water (9:1) (M1), and water with, when required, the support of two Cs(+) ionophore probes, calix[4]arene-bis(crown-6-ether)dioxycoumarine (A1) and its tetrasuslfonated form (A2). In ethanol, two Cs(+) complexes are formed, with the affinity constants K(1EtOH) = (1.1 +/- 0.25) * 10(5) and K(2EtOH) = (2.1 +/- 0.4) * 10(3). In M1, a single Cs(+) complex occurs when only the enols are deprotonated, whereas a bicomplex is formed when both enols and carboxylic acids are deprotonated: K(1M1) = (1.5 +/- 0.3) * 10(5) and K(2M1) = (4 +/- 2) * 10(3). These data are confirmed by stopped-flow and T-jump kinetics. In ethanol, a fast Cs(+) exchange occurs between NbA and A1: direct rate constant, k(1) = (3.1 +/- 0.1) * 10(7) M(-1) s(-1); reverse rate constant k(-1) = (2.8 +/- 1) * 10(5) M(-1) s(-1); and Cs(+) exchange constant, K(1Exchange) = (9 +/- 4) * 10(-3). In M1, the quenching of A2 fluorescence by NbA is used to determine the kinetics of complex formation with Cs(+): k(2) = (1.8 +/- 0.4) * 10(9) M(-1) s( 1); k(-2) = (1.80 +/- 0.15) * 10(4) s(-1); and K(1M1) = (1.5 +/- 0.5) * 10(5). The affinity of NbA for Cs(+) is probably the result of the particular structure in which the two pulvinic acid arms adopt a conformation that forms two complexation sites composed of the two enolates and/or the two carboxylates. This renders the efficiency in Cs(+) uptake comparable to that of some calixarenes or crown ethers. PMID- 20831227 TI - Brightening and locking a weak and floppy N-H chromophore: the case of pyrrolidine. AB - The N-H stretching signature of the puckering equilibrium between equatorial and axial pyrrolidine is analyzed via FTIR and Raman spectroscopy in supersonic jets as a function of aggregation. Vibrational temperatures along the expansion axis can be extracted from the Raman spectra and allow for a localization of the compression shock waves. While the equatorial conformation is more stable in the ground state monomer, this preference is probably switched in the excited state with one N-H stretching quantum. Furthermore, the dominant dimer involves an axial donor and the trimer and tetramer structures seem to prefer uniform axial conformations. The IR intensity is boosted by up to 3 orders of magnitude upon aggregation, whereas the Raman scattering intensity shows only moderate hydrogen bond effects. B3LYP and MP2 calculations provide a reasonable description of the N-H vibrational dynamics under the influence of self-aggregation. In mixed dimers with pyrrole, pyrrolidine assumes the role of a hydrogen bond acceptor. PMID- 20831228 TI - Scaparvin A, a novel caged cis-clerodane with an unprecedented C-6/C-11 bond, and related diterpenoids from the liverwort Scapania parva. AB - A novel caged cis-clerodane diterpenoid, scaparvin A, possessing an unprecedented C-6/C-11 bond and a ketal ring, as well as four new cis-clerodane derivatives, scaparvins B-E, were isolated from the Chinese liverwort Scapania parva. Their absolute structures were elucidated by analysis of NMR and CD data coupled with electronic circular dichroism (ECD) calculations. It was proposed that an enzymatic intramolecular aldol reaction was the key step in the biogenetic pathway of scaparvin A. PMID- 20831229 TI - Enantioselective total synthesis of spirofungins A and B. AB - The enantioselective total synthesis of spirofungins A (1) and B (2) is reported in 14 steps over the longest linear sequence. Key steps include the use of thiazolidinethione-mediated aldol reactions to assemble the major fragments and installation of the C1-C6 side chain using a cross metathesis reaction. PMID- 20831230 TI - Cytosine-cytosinium dimer behavior in a cocrystal with a decavanadate anion as a function of the temperature. AB - We have performed X-ray diffraction measurements on single crystals of Na(3)[V(10)O(28)](C(4)N(3)OH(5))(3)(C(4)N(3)OH(6))(3).10H(2)O as a function of the temperature. When the sample is cooled, from room temperature to 100 K, we have observed additional peaks well indexed in P1, while the phase at room temperature crystallizes in P1. The molecular structure at 210 K indicates that the center of inversion is located between two cytosinium molecules, formally described with a charge of +0.5. When this crystal is heated to room temperature and the structure in P1 reindexed, some peaks remained unindexed. A protonation deprotonation process gives rise to additional diffraction peaks at temperatures lower than 210 K. The triply bridged hydrogen bonded cytosine-cytosinum dimer is discussed according to the results of the charge density analysis and topological analysis at 210 K. The structure at 100 K has been completely solved based on a comparative study with other compounds containing cytosine-cytosinium dimer. This description could be considered as a reference for such dimer. It could help for discrimination between cytosine and cytosinium molecules, for any new structure containing a cytosine-cytosinium pair, and for which the quality does not allow a precise determination of the hydrogen localization. PMID- 20831231 TI - Solvent-dependent spectral diffusion in a hydrogen bonded "vibrational aggregate". AB - Two-dimensional infrared spectroscopy (2DIR) is used to measure the viscosity dependent spectral diffusion of a model vibrational probe, Mn(2)(CO)(10) (dimanganese decacarbonyl, DMDC), in a series of alcohols with time scales ranging from 2.67 ps in methanol to 5.33 ps in 1-hexanol. Alcohol-alkane solvent mixtures were found to produce indistinguishable linear IR spectra, while still demonstrating viscosity-dependent spectral diffusion. Using a vibrational exciton model to characterize the inhomogeneous energy landscape, several analogies emerge with multichromophoric electronic systems, such as J-aggregates and light harvesting protein complexes. An excitonic, local vibrational mode Hamiltonian parametrized to reproduce the vibrational structure of DMDC serves as a starting point from which site energies (i.e., local carbonyl frequencies) are given Gaussian distributed disorder. The model gives excellent agreement with both the linear IR spectrum and the inhomogeneous widths extracted from 2DIR, indicating the system can be considered to be a "vibrational aggregate." This model naturally leads to exchange narrowing due to disorder-induced exciton localization, producing line widths consistent with our 1D and 2D measurements. Further, the diagonal disorder alone effectively reduces the molecular symmetry, leading to the appearance of Raman bands in the IR spectrum in accord with the measurements. Here, we show that the static inhomogeneity of the excitonic model with disorder successfully captures the essential details of the 1D spectrum while predicting the degree of IR activity of forbidden modes as well as the inhomogeneous widths and relative magnitudes of the transition moments. PMID- 20831232 TI - Extinction times in autocatalytic systems. AB - Systems evolving under the influence of autocatalytic processes have been the subject of much study due to their appearance in a wide variety of contexts. Well known examples range from the simplest autocatalytic chemical reactions, biochemical models of ribozyme or prion replication, right up to the duplication of entire organisms in models of population dynamics. While the deterministic approach frequently taken to model such systems is adequate in the limit of large reactant numbers, the intrinsic fluctuations exert an important influence on the dynamics when the supply of reactants is limited. In particular, when combined with spontaneous degradation of the autocatalytic reactant population, such fluctuations can lead to the extinction of that population. In this paper, we study reversible autocatalytic processes of the form X + Y ? 2X in the limit that there exists a surplus of Y and in the presence of a spontaneous degradation process X -> Z. Through the use of the Poisson representation, we identify an exact analytical expression for the mean extinction time of the X population. We show that the exact result can be neatly approximated by an Arrhenius-like expression involving an effective activation energy separating a quasi-stationary state from the extinct state. PMID- 20831233 TI - A single molecule Kondo switch: multistability of tetracyanoethylene on Cu(111). AB - Single tetracyanoethyelene (TCNE) molecules on Cu(111) are reversibly switched among five states by applying voltage pulses with the tip of a scanning tunneling microscope. A pronounced Kondo resonance in tunneling spectroscopy indicates that one of the states is magnetic. Side bands of the Kondo resonance appear at energies which correspond to inter- and intramolecular vibrational modes. Density functional theory suggests that molecular deformation changes the occupancy in TCNE's molecular orbitals, thus producing the magnetic state. PMID- 20831234 TI - Isomerization and decomposition of a model nerve agent: a computational analysis of the reaction energetics and kinetics of dimethyl ethylphosphonate. AB - The gas-phase isomerization and decomposition reactions of dimethyl ethylphosphonate (DMEP) are investigated using the CBS-QB3 method followed by the calculation of rate constant for all reaction pathways using Rice-Ramsperger Kassel-Marcus (RRKM) theory. Three conformational isomers C1, C2, and C3 are identified for DMEP having stability order C1 (0.00) < C2 (0.11) < C3 (1.87). Each conformer can isomerize via H-transfer reaction and can decompose via CH(3)OH, CH(2), and H(2) elimination at higher temperatures. The conformers C1, C2, and C3 can isomerize to IM1, IM2, and IM3, respectively, via different pathways. Decomposition requires much higher activation energy and therefore higher temperatures than the corresponding isomerization. For instance, the most stable conformer C1 isomerizes to IM1 twice as fast as decomposing to P1 + CH(2) at 1000 K whereas the least stable conformer C3 isomerizes to IM3 10(4) times faster than decomposing to P5 + CH(3)OH. Only one decomposition channel is identified for C1 and two different decomposition channels are identified for C2 as well as for C3. The decompositions of C2 and C3 to P2 + CH(3)OH and P5 + CH(3)OH, respectively, are predicted to be more favorable thermodynamically as well as kinetically over the other decomposition channels within the temperature range 1000-3000 K. For the lack of experimental data, we have calculated the low as well as high-pressure limit rate constants for the decomposition reactions of DMEP. In addition, consistent and reliable enthalpies of formation at 298.15 K (Delta(f)H degrees (298.15)) have been computed for all the species involved in the isomerization and decomposition reaction of DMEP. The results obtained for DMEP for the reaction mechanism and energetics are compared with that for DMHP and DMMP. PMID- 20831235 TI - Scratch-resistant, highly conductive, and high-strength carbon nanotube-based composite yarns. AB - High-strength and conductive carbon nanotube (CNT) yarns are very attractive in many potential applications. However, there is a difficulty when simultaneously enhancing the strength and conductivity of CNT yarns. Adding some polymers into CNT yarns to enhance their strength will decrease their conductivity, while treating them in acid or coating them with metal nanoparticles to enhance their conductivity will reduce their strength. To overcome this difficulty, here we report a method to make high-strength and highly conductive CNT-based composite yarns by using a continuous superaligned CNT (SACNT) yarn as a conductive framework and then inserting polyvinyl alcohol (PVA) into the intertube spaces of the framework through PVA/dimethyl sulphoxide solution to enhance the strength of yarns. The as-produced CNT/PVA composite yarns possess very high tensile strengths up to 2.0 GPa and Young's moduli more than 120 GPa, much higher than those of the CNT/PVA yarns reported. The electric conductivity of as-produced composite yarns is as high as 9.2 * 10(4) S/m, comparable to HNO(3)-treated or Au nanoparticle-coated CNT yarns. These composite yarns are flexible, lightweight, scratch-resistant, very stable in the lab environment, and resistant to extremely humid ambient and as a result can be woven into high-strength and heatable fabrics, showing potential applications in flexible heaters, bullet-proof vests, radiation protection suits, and spacesuits. PMID- 20831236 TI - Multicomponent reaction of imidazo[1,5-a]pyridine carbenes with aldehydes and dimethyl acetylenedicarboxylate or allenoates: a straightforward approach to fully substituted furans. AB - The facile three-component reactions of N,N-substituted imidazo[1,5-a]pyridine carbenes, namely imidazo[1,5-a]pyridin-3-ylidenes, with aldehydes and DMAD or allenoates were disclosed. Both reactions proceeded via tandem nucleophilic addition, [3 + 2]-cycloaddition, and ring transformation to produce different 4 [(2-pyridyl)methyl]aminofuran derivatives generally in moderate yields. This work not only provided the first example of the application of imidazo[1,5-a]pyridin-3 ylidenes in organic synthesis but also developed a straightforward approach to fully substituted furans that are not easily accessible by other methods. PMID- 20831237 TI - Interactions of boranes and carboranes with aromatic systems: CCSD(T) complete basis set calculations and DFT-SAPT analysis of energy components. AB - The noncovalent interactions of heteroboranes with aromatic systems have only recently been acknowledged as a source of stabilization in supramolecular complexes. The physical basis of these interactions has been studied in several model complexes using advanced computational methods. The highly accurate CCSD(T)/complete basis set (CBS) value of the interaction energy for the model diborane...benzene complex in a stacking geometry exhibiting a B(2)H...pi hydrogen bond was calculated to be -4.0 kcal.mol(-1). The DFT-SAPT/CBS approach, which is shown to reproduce the CCSD(T)/CBS data reliably asserted that the major stabilizing component was dispersion, followed by electrostatics. Furthermore, the effect of the benzene heteroatom- and exosubstitutions was studied and found to be small. Next, when aromatic molecules were changed to cyclic aliphatic ones, van der Waals complexes stabilized by the dispersion term only were formed. As the last step, interactions of two larger icosahedral borane cages with benzene were explored. The complex of the monoanionic CB(11)H(12)(-) exhibited two minima: the first stacked above the plane of the benzene ring with a C-H...pi hydrogen bond and the second planar, in which the carborane cage bound to benzene via five B-H...H-C dihydrogen bonds. The DFT-SAPT/CBS calculations revealed that both of these binding motifs were stabilized by dispersion followed by electrostatic terms, with the planar complex being 1.4 kcal.mol(-1) more stable than the stacked one. The dianionic B(12)H(12)(2-) interacted with benzene only in the planar geometry, similarly as smaller anions do. The large stabilization energy of 11.0 kcal.mol(-1) was composed of dominant attractive dispersion and slightly smaller electrostatic and induction terms. In summary, the borane/carborane...aromatic interaction is varied both in the complex geometries and in the stabilizing energy components. The detailed insight derived from high level quantum chemical computations can help us understand such important processes as host-guest complexation or carborane...biomolecule interactions. PMID- 20831238 TI - Interaction of formic acid with nitrogen: stabilization of the higher-energy conformer. AB - Conformational change is an important concept in chemistry and physics. In the present work, we study conformations of formic acid (HCOOH, FA) and report the preparation and identification of the complex of the higher-energy conformer cis FA with N(2) in an argon matrix. The cis-FA...N(2) complex was synthesized by combining annealing and vibrational excitation of the ground-state trans-FA in a FA/N(2)/Ar matrix. The assignment is based on IR spectroscopic measurements and ab initio calculations. The cis-FA...N(2) complex decay in an argon matrix is much slower compared with the cis-FA monomer. In agreement with the experimental observations, the calculations predict a substantial increase in the stabilization barrier for the cis-FA...N(2) complex compared with the uncomplexed cis-FA monomer. A number of solvation effects in an argon matrix are computationally estimated and discussed. The present results on the cis-FA...N(2) complex show that intermolecular interaction can stabilize intrinsically unstable conformers, as previously found for some other cis-FA complexes. PMID- 20831239 TI - Gas-phase basicities around and below water revisited. AB - This work employs Fourier transform ion cyclotron resonance (FT-ICR) and the Gaussian quantum chemistry composite methods W1 and G2 to experimentally and computationally analyze gas-phase basicities (GB) for a series of weak bases in the basicity region around and below water. The study aims to clarify the long standing discrepancy between reported GB values for weak bases obtained via high pressure mass spectrometry (HPMS) and ICR; the ICR scale is observed to be more than 2 times contracted compared to the HPMS scale. The computational results of this work support published HPMS data. This agreement improves with increasing sophistication of the computational method and is excellent at the W1 level. Several equilibria were also re-examined experimentally using FT-ICR. In the experiments with some polyfluorinated weak bases (hexafluoro-2-propanol and nonafluoro-2-methyl-2-propanol), it was found that two protonation processes compete in the gas phase: protonation on oxygen and protonation on fluorine. In these species, protonation on fluorine proceeds faster and is statistically favored over protonation on oxygen but leads to cations that are thermodynamically less stable than oxygen-protonated cations. The process may also lead to the irreversible loss of HF. The rearrangement of fluorine protonated cations to oxygen-protonated cations is very slow and is further suppressed by the process of HF abstraction. These results at least partially explain the discrepancy between published HPMS data and earlier FT-ICR findings and call for the utmost care in using FT-ICR for gas-phase basicity measurements of heavily fluorinated compounds. The narrower dynamic range of ICR necessitates the measurement of several problematic bases and produces some differences between the ICR results in the present work and the published HPMS data; the wider dynamic range allows HPMS to overcome these difficulties in connecting the ladder. PMID- 20831240 TI - Training a scoring function for the alignment of small molecules. AB - A comprehensive data set of aligned ligands with highly similar binding pockets from the Protein Data Bank has been built. Based on this data set, a scoring function for recognizing good alignment poses for small molecules has been developed. This function is based on atoms and hydrogen-bond projected features. The concept is simply that atoms and features of a similar type (hydrogen-bond acceptors/donors and hydrophobic) tend to occupy the same space in a binding pocket and atoms of incompatible types often tend to avoid the same space. Comparison with some recently published results of small molecule alignments shows that the current scoring function can lead to performance better than those of several existing methods. PMID- 20831241 TI - Combined statistical analyses of peptide intensities and peptide occurrences improves identification of significant peptides from MS-based proteomics data. AB - Liquid chromatography-mass spectrometry-based (LC-MS) proteomics uses peak intensities of proteolytic peptides to infer the differential abundance of peptides/proteins. However, substantial run-to-run variability in intensities and observations (presence/absence) of peptides makes data analysis quite challenging. The missing observations in LC-MS proteomics data are difficult to address with traditional imputation-based approaches because the mechanisms by which data are missing are unknown a priori. Data can be missing due to random mechanisms such as experimental error or nonrandom mechanisms such as a true biological effect. We present a statistical approach that uses a test of independence known as a G-test to test the null hypothesis of independence between the number of missing values across experimental groups. We pair the G test results, evaluating independence of missing data (IMD) with an analysis of variance (ANOVA) that uses only means and variances computed from the observed data. Each peptide is therefore represented by two statistical confidence metrics, one for qualitative differential observation and one for quantitative differential intensity. We use three LC-MS data sets to demonstrate the robustness and sensitivity of the IMD-ANOVA approach. PMID- 20831242 TI - Methylamidation for sialoglycomics by MALDI-MS: a facile derivatization strategy for both alpha2,3- and alpha2,6-linked sialic acids. AB - Neutralization of carboxylic acid is an important means to avoid sialic acid dissociation when sialylated glycans are analyzed by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). In this paper, we describe a simple and rapid method to modify the sialic acids of sialylated glycans in the presence of methylamine and (7-azabenzotriazol-1-yloxy) trispyrrolidinophosphonium hexafluorophosphate (PyAOP). After methylamidation, sialylated glycans can be analyzed by MALDI-MS without loss of the sialic acid moiety. The electrospray ionization mass spectrometry (ESI-MS) and MALDI-MS analysis of both 3'- and 6'-sialyllactose derivatives indicated that the quantitative conversion of sialic acids was achieved, regardless of their linkage types. This derivatization strategy was further validated with the N-glycans released from three standard glycoproteins (fetuin, human acid glycoprotein, and bovine acid glycoprotein) containing different types of complex glycans. Most importantly, this derivatization method enabled the successful characterization of N-glycans of sera from different species (human, mouse, and rat) by MALDI-MS. Because of the mild reaction conditions, the modification in sialic acid residues can be retained. This improvement makes it possible to detect sialylated glycans containing O-acetylated sialic acid moieties using MALDI-MS in positive-ion mode. PMID- 20831243 TI - Computational study of molecules with high intrinsic hyperpolarizabilities. AB - In the current manuscript we present the results of a computational study on a series of chromophores with enhanced intrinsic hyperpolarizability. The high hyperpolarizability values of these molecules were previously reported and were achieved by making use of aromatic moieties in order to modulate the aromatic stabilization energy along the conjugated bridge between the donor and the acceptor. Calculations were performed using semiempirical, DFT, and TDDFT methods, and the results reproduce the trend determined experimentally for the first hyperpolarizability values. Several calculation schemes were used, and the best agreement was achieved when long-range Hartree-Fock exchange corrections and solvent effects are included in the DFT calculations. The long-range corrections proved to be especially important for the azobenzene derivatives, which otherwise have their hyperpolarizability overestimated considerably in the DFT calculations. The results are also analyzed within the framework of a two-level model, which correctly reproduces the trend in the hyperpolarizabilities of the molecules under study. PMID- 20831244 TI - Synthesis of 3,3-disubstituted oxindoles by palladium-catalyzed tandem reaction of 2-(alkynyl)aryl isocyanates with benzylic alcohols. AB - A palladium complex sequentially promoted two mechanistically distinct reactions, the first, cyclization of 2-(alkynyl)aryl isocyanates with benzylic alcohols, and the second, [1,3] rearrangement of a benzyl group from oxygen to carbon, furnishing 3,3-disubstituted oxindoles in one pot. PMID- 20831245 TI - Nickel-catalyzed ring-opening three-component coupling of methylenecyclopropane with aldehydes and silanes. AB - A nickel-catalyzed three-component coupling between methylenecyclopropane, aldehydes, and silanes afforded silylated allylic alcohols that possess an alkyl substituent at the 2-position via cleavage of the proximal C-C bond of methylenecyclopropane. PMID- 20831246 TI - Photoisomerizable metallomesogens and soft crystals based on orthopalladated complexes. AB - With the aim of obtaining light-responsive liquid-crystalline palladium complexes, six palladium complexes derived from an orthometalated imine, bearing one or two azocarboxylato bridges, have been synthesized: [Pd(2)(MU SC(10)H(21))(MU-O(2)CAzo)(L(1,2))(2)] (7 and 8), [Pd(2)(MU-SC(10)H(21))(MU O(2)CAzo3C(10))(L(1,2))(2)] (9 and 10), [Pd(MU-O(2)CAzo)L(1)](2) (11), and [Pd(MU O(2)CAzo3C(10))L(1)](2) (12), in which L(1) = p H(21)C(10)OC(6)H(3)CH?NC(6)H(4)OC(10)H(21)-p, L(2) = p H(21)C(10)OC(6)H(3)CH?NC(14)H(29), AzoCO(2)(-) = p-(phenylazo)benzoate, and Azo3C(10)CO(2)(-) = p-(2',3',4'-tris-n-decyloxyphenylazo)benzoate. Three of them (7-9), as well as the precursor Azo3C(10)CO(2)H (3), are thermotropic liquid crystals displaying nematic and smectic A mesophases, while 10-12 have been identified by X-ray diffraction to give rise to "soft" crystal phases. Electronic spectroscopy and (1)H NMR show that all of them undergo a trans-cis isomerization of the azobenzene moiety at lambda = 365 nm. The molecular structure determines the photoresponse in solution, which is faster and more stable when the trisubstituted azocarboxylate is present and the motion of the azo group is not hindered by the orthometalated imine. The photoresponse has also been observed in the condensed phases, which change from the ordered phase to the isotropic liquid upon irradiation, except for compound 10, a soft crystal in which a permanent photoalignment highly sensitive to light polarization is produced. The latter is a behavior with potential applications, rather unusual in low-molecular-weight compounds. PMID- 20831247 TI - Food texture: pleasure and pain. AB - Food texture provides sensory signals to consumers. Most of these signals stimulate responses from consumers, both good and bad, because of the expected pleasure - from creamy puddings and ice cream to crispy crackers and snacks. One critical role that texture plays in the success of products is its indication of the freshness and stability of the food product. The mechanical properties of food texture, such as hardness, cohesiveness, crispness, crunchiness, and denseness, are easy indicators of a product's freshness and wholesomeness. Although texture is often considered to be secondary to flavor in evaluating a product's success and acceptability, texture will tip the scales for the consumer, if the texture does not meet the consumer's expectation. Two case studies demonstrate the different texture properties of foods, how they function to generate consumer likes and dislikes, and how texture is key in determining food staleness versus freshness. PMID- 20831248 TI - Effect of grape seed extract, Cistus ladanifer L., and vegetable oil supplementation on fatty acid composition of abomasal digesta and intramuscular fat of lambs. AB - Thirty-six lambs were used in a 6 week experiment to evaluate the effect of vegetable oil blend supplementation (0 vs 60 g/kg of dry matter (DM)) and two dietary condensed tannin sources, grape seed extract (0 vs 25 g/kg of DM) and Cistus ladanifer L. (0 vs 250 g/kg of DM), on fatty acid (FA) composition of abomasal digesta and intramuscular polar and neutral lipids. Grape seed extract did not affect the FA profile of abomasal digesta or muscle lipid fractions. C. ladanifer had a minor effect in lambs fed diets with no oil but greatly changed the abomasal and muscle FA profiles in oil-supplemented lambs. It decreased 18:0 and increased 18:1 trans-11 in abomasal digesta and increased 18:1 trans-11 and 18:2 cis-9,trans-11 (P = 0.062) in muscle neutral lipids, resulting in an important enrichment of meat 18:2 cis-9,trans-11 when compared to other oil supplemented diets (19.2 vs 41.7 mg/100 g of muscle). PMID- 20831249 TI - Soybean toxin (SBTX), a protein from soybeans that inhibits the life cycle of plant and human pathogenic fungi. AB - Soybean toxin (SBTX) is a 44 kDa glycoprotein that is lethal to mice (LD(50) = 5.6 mg/kg). This study reports the toxicity of SBTX on pathogenic fungi and yeasts and the mechanism of its action. SBTX inhibited spore germination of Aspergillus niger and Penicillium herguei and was toxic to Candida albicans, Candida parapsilosis, Kluyveromyces marxiannus , Pichia membranifaciens, and Saccharomyces cerevisiae. In addition, SBTX hampered the growth of C. albicans and K. marxiannus and inhibited the glucose-stimulated acidification of the incubation medium by S. cerevisiae, suggesting that SBTX interferes with intracellular proton transport to the external medium. Moreover, SBTX caused cell wall disruption, condensation/shrinkage of cytosol, pseudohyphae formation, and P. membranifaciens and C. parapsilosis cell death. SBTX is toxic to fungi at concentrations far below the dose lethal to mice and has potential in the design of new antifungal drugs or in the development of transgenic crops resistant to pathogens. PMID- 20831250 TI - Structure and reactivity of the (1)Au6Pt clusters. AB - In this paper we report the geometries, properties, and reactivity descriptors of 12 structural isomers located on the MP2/SDDALL potential energy surface of the (1)Au(6)Pt binary clusters. A nonplanar, D(3d) symmetry, cyclohexane chairlike structure is predicted to be the global minimum. Binding energies per atom in the range ~44-51 kcal/mol account for very stable clusters. The relative stability of the clusters is directly related to all global and local reactivity descriptors. All structures are predicted to have large electron affinities. The chemical environment of the Pt atom on the structures plays a central role in the resulting relative stabilities and global and local reactivities. Our results show that more peripheral Pt atoms are more likely to be involved in electron accepting processes. PMID- 20831251 TI - Discrimination of the geographical origin of beef by (1)H NMR-based metabolomics. AB - The geographical origin of beef is of increasing interest to consumers and producers due to "mad cow" disease and the implementation of the Free Trade Agreement (FTA). In this study, (1)H NMR spectroscopy coupled with multivariate statistical analyses was used to differentiate the geographical origin of beef samples. Principal component analysis (PCA) and orthogonal projection to latent structure-discriminant analysis (OPLS-DA) showed significant separation between extracts of beef originating from four countries: Australia, Korea, New Zealand, and the United States. The major metabolites responsible for differentiation in OPLS-DA loading plots were succinate and various amino acids including isoleucine, leucine, methionine, tyrosine, and valine. A one-way ANOVA was performed to statistically certify the difference in metabolite levels. The data suggest that NMR-based metabolomics is an efficient method to distinguish fingerprinting difference between raw beef samples, and several metabolites including various amino acids and succinate can be possible biomarkers for discriminating the geographical origin of beef. PMID- 20831252 TI - Structural studies of aliphatic substituted phthalocyanine-lipid multilayers. AB - A Langmuir-Blodgett film of aliphatic substituted phthalocyanines on a C18 silane supporting layer coupled onto a silicon substrate has been investigated using neutron reflectometry. This multilayer structure is seen as a possible candidate for phthalocyanine-lipid biosensor devices. The results show the suitability of the C18 ligands as an anchoring layer for the phthalocyanines. The scattering length density profiles demonstrate the effectiveness of a lipid monolayer in partitioning the composition of phthalocyanine layers from that of the bulk liquid. The effectiveness of this barrier is a critical factor in the efficiency of such devices. PMID- 20831253 TI - Novel functionalized metal-organic framework based on unique hexagonal prismatic clusters. AB - The novel porous 3D metal-organic framework synthesized from fluorenone-2,7 dicarboxylate contains zinc-glycolate-carboxylate layers in which the unique hexagonal prismatic [Zn(6)(OCH(2)CH(2)O)(6)] clusters are connected by planar [Zn(3)(OCH(2)CH(2)O)(COO)(2)] motifs; the pore surface is furnished with carbonyl groups and open metal sites. PMID- 20831254 TI - Bioturbation-driven release of buried PCBs and PBDEs from different depths in contaminated sediments. AB - Bioturbation can remobilize previously buried contaminants, leading to an increased exposure of aquatic biota. The remobilization of buried polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) from three different sediment depth layers (2.0-2.5 cm, 5.0-5.5 cm, and 10.0-10.5 cm) was studied in a laboratory experiment with two benthic macrofauna species, the amphipod Monoporeia affinis and the polychaete Marenzelleria spp. Remobilization of PCBs and PBDEs was significantly higher in the presence of Marenzelleria spp. than in M. affinis treatments and controls (without macrofauna). The highest remobilization occurred from the most shallow layers (2.0-2.5 cm > 5.0-5.5 cm > 10.0-10.5 cm), but contaminants were remobilized due to bioturbation from layers down to at least 10 cm. Congeners with lower hydrophobicity were remobilized to a higher extent than more hydrophobic congeners. The contaminant distribution between the particulate and the dissolved phase in the water column depended on hydrophobicity and burial depth of the contaminant, with congeners from deeper layers displaying an increased distribution to the particulate phase. Release fluxes and sediment-to-water mass transfer coefficients (MTCs) show that bioturbation by the polychaete Marenzelleria spp. can lead to a significant remobilization of buried contaminants from Baltic Sea sediments. PMID- 20831255 TI - Highly flexible and all-solid-state paperlike polymer supercapacitors. AB - In recent years, much effort have been dedicated to achieve thin, lightweight and even flexible energy-storage devices for wearable electronics. Here we demonstrate a novel kind of ultrathin all-solid-state supercapacitor configuration with an extremely simple process using two slightly separated polyaniline-based electrodes well solidified in the H(2)SO(4)-polyvinyl alcohol gel electrolyte. The thickness of the entire device is much comparable to that of a piece of commercial standard A4 print paper. Under its highly flexible (twisting) state, the integrate device shows a high specific capacitance of 350 F/g for the electrode materials, well cycle stability after 1000 cycles and a leakage current of as small as 17.2 MUA. Furthermore, due to its polymer-based component structure, it has a specific capacitance of as high as 31.4 F/g for the entire device, which is more than 6 times that of current high-level commercial supercapacitor products. These highly flexible and all-solid-state paperlike polymer supercapacitors may bring new design opportunities of device configuration for energy-storage devices in the future wearable electronic area. PMID- 20831256 TI - Stereodivergent synthesis of 1,3-syn- and -anti-tetrahydropyrimidinones. AB - An efficient protocol for the stereoselective synthesis of 1,3-syn and -anti tetrahydropyrimidinones (syn- and anti-11a) is reported. The modular procedure is based on a stereodivergent cyclization of readily available urea-type substrates (10a) by intramolecular allylic substitution. The cyclization proceeds with excellent yield (up to 99%) and selectivity (up to dr > 20:1), purely based on substrate control. The product pyrimidines can be readily transformed into the corresponding free syn- and anti-amines. PMID- 20831257 TI - Improving protein pharmacokinetics by engineering erythrocyte affinity. AB - Poor pharmacokinetic profiles are often the underlying reason for the failure of novel protein drugs to reach clinical translation. Current passive half-life improvement methods focus on increasing the apparent hydrodynamic radius of the drug. We sought to develop an active method to increase the circulation half-life of proteins by binding to erythrocytes in blood. Screening a naive phage displayed peptide library against whole mouse erythrocytes yielded a 12 amino acid peptide (ERY1) that binds the erythrocyte surface with high specificity. ERY1-displaying phage bind mouse and rat erythrocytes 95-fold higher than wild type phage and exhibit negligible binding to mouse leukocytes, as determined by flow cytometry. Affinity experiments with soluble peptide revealed the extracellular domain of glycophorin-A as the membrane protein ligand. When expressed as an N-terminal fusion to maltose-binding protein and administered intravenously, the erythrocyte-binding variant exhibits a 3.2- to 6.3-fold increase in circulation half-life, 2.15-fold decrease in clearance, and 1.67-fold increase in bioavailability as compared to the wild-type protein. The peptide fails to induce ERY1-reactive immunoglobulin production, furthering the potential of the concept in therapeutic design, although this sequence does not bind human erythrocytes. We conclude that engineering erythrocyte affinity into proteins effectively increases their circulation half-life, thereby offering a solution to improve pharmacokinetic profiles of the numerous therapeutic protein drugs in clinical development. PMID- 20831258 TI - Highly luminescent poly(methyl methacrylate)-incorporated europium complex supported by a carbazole-based fluorinated beta-diketonate ligand and a 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene oxide co-ligand. AB - A novel efficient antenna complex of Eu(3+) [Eu(CPFHP)(3)(DDXPO)] supported by a highly fluorinated carbazole-substituted beta-diketonate ligand, namely, 1-(9H carbazol-2-yl)-4,4,5,5,5-pentafluoro-3-hydroxypent-2-en-1-one (CPFHP) and the 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene oxide (DDXPO) ancillary ligand, has been synthesized, structurally characterized, and its photoluminescent behavior examined. The single-crystal X-ray diffraction analysis of Eu(CPFHP)(3)(DDXPO) revealed that this complex is mononuclear, and that the central Eu(3+) ion is surrounded by eight oxygen atoms, six of which are provided by the three bidentate beta-diketonate ligands. The remaining two oxygen atoms are furnished by the chelating phosphine oxide ligand. The coordination polyhedron is best described as that of a distorted square antiprism. The photophysical properties of Eu(CPFHP)(3)(DDXPO) benefit from adequate protection of the metal by the ligands with respect to non-radiative deactivation as well as an efficient ligand to-metal energy transfer process which exceeds 66% in chloroform solution with a quantum yield of 47%. As an integral part of this work, the synthesis, characterization, and luminescent properties of poly(methyl methacrylate) (PMMA) polymer films doped with Eu(CPFHP)(3)(DDXPO) are also reported. The luminescent efficiencies of the doped films (photoluminescence quantum yields 79-84%) are dramatically enhanced in comparison with that of the precursor complex. The new luminescent PMMA-doped Eu(CPFHP)(3)(DDXPO) complex therefore shows considerable promise for polymer light-emitting diode and active polymer optical fiber applications. PMID- 20831259 TI - Replacement of an oxo by an imido group in oxotransferase model compounds: influence on the oxygen atom transfer. AB - Treatment of [MoO(N-t-Bu)Cl(2)(dme)] (dme = dimethoxyethane) with 2 equiv of the potassium salts of Schiff base ligands of the type KArNC(CH(3))CHC(CH(3))O afforded oxo imido molybdenum(VI) compounds [MoO(N-t-Bu)L(2)] {1, with Ar = phenyl (L(Ph)), 2 with Ar = 2-tolyl (L(MePh)), 3 with Ar = 2,6-dimethylphenyl (L(Me2Ph)) and 4 with Ar = 2,6-diisopropylphenyl (L(iPr2Ph))}. We have also prepared related bisimido complexes [Mo(N-t-Bu)(2)L(2) (5 with L = L(Ph), 6 with L = L(MePh), and 7 with L = L(Me2Ph)) by treatment of [Mo(N-t-Bu)(2)Cl(2)(dme)] with 2 equiv of the potassium salt of the respective ligand. 1, 3, 5, and 6 were characterized via single crystal X-ray diffraction. The oxo imido complexes exhibit oxygen atom transfer (OAT) reactivity toward trimethyl phosphine. Kinetic data were obtained for 1 and 3 by UV/vis spectroscopy revealing decreased OAT reactivity in comparison to related dioxo complexes with the same Schiff base ligands and decreased reactivity of 1 versus 3. Cyclic voltammetry was used to probe the electronic situation at the molybdenum center showing reversible reduction waves for 3 and [MoO(2)(L(Me2Ph))(2)] at comparable potentials while 1 exhibits a significant lower potential. Density functional theory (DFT) calculations showed a higher electron density on oxygen in the oxo imido complexes. PMID- 20831261 TI - Synthesis of 5-carboxamide-oxazolines with a Passerini-Zhu/Staudinger-Aza-Wittig two-step protocol. PMID- 20831260 TI - Use of recombinant cell-permeable small peptides to modulate glucocorticoid sensitivity of acute lymphoblastic leukemia cells. AB - Glucocorticoid (GC) hormones induce apoptosis in T-cell and pre-B-cell acute lymphoblastic leukemia (ALL) cells. Steroid-mediated apoptosis requires a threshold level of the glucocorticoid receptor (GR) protein, and increasing the intracellular GR levels in ALL cells would augment their hormone sensitivity. A protein transduction domain (PTD) approach was used to accomplish this. We produced an HIV Tat PTD domain fusion protein (Tat-GR(554-777)) that potentially competes for the degradation of GR protein by the ubiquitin-proteasome system and should thus increase its intracellular levels by "stabilizing" the GR. We also designed a fusion peptide for the c-Myb DNA binding domain, Tat-c-Myb DBD, since the biological function of this peptide as a dominant negative inhibitor of the c Myb protein was already known. Purified, bacterially expressed Tat-c-Myb DBD and Tat-GR(554-777) exhibited highly efficient transduction into cultured ALL cell lines including 697 (pre-B-ALL) and CEM-C7 (T-ALL) cells. As expected, the transduced Tat-c-Myb DBD peptide inhibited steroid-mediated stimulation of a GR promoter-luciferase reporter gene. Significantly, transduced Tat-GR(554-777) effectively increased intracellular GR levels in the GC-resistant T-ALL cell line, CEM-C1, and in the pre-B-ALL 697 cell line. Furthermore, transduction of Tat-GR(554-777) rendered GC-resistant CEM-C1 cells sensitive to steroid killing and further sensitized 697 cells to steroid. The use of Tat-fusion peptide transduction may eventually lead to innovative therapeutic modalities to improve the clinical response of patients suffering from T-cell and pre-B-cell acute lymphoblastic leukemia by increasing steroid responsiveness and perhaps converting steroid-resistant leukemia to a hormone-responsive phenotype. PMID- 20831262 TI - Novel isocyanide-based one-pot multicomponent syntheses of tetrahydrobenzo[b][1,4]oxazepine and malonamide derivatives. AB - In this work, a novel one-pot multicomponent reaction of 2-aminophenols, Meldrum's acid, and isocyanides leads to the synthesis of tetrahydrobenzo[b][1,4]oxazepine or malonamide derivatives using 1 or 2 equiv of 2-aminophenols, respectively, in good to excellent yields at ambient temperature. PMID- 20831263 TI - Synthesis of diheterocyclic compounds based on triazolyl methoxy phenylquinazolines via a one-pot four-component-click reaction. AB - A facile and highly efficient method for one-pot four-component synthesis of triazolyl methoxy phenylquinazolines is described. A mixture of aromatic propargylated aldehydes, different azides, 2-aminobenzophenone derivatives, and ammonium acetate were condensed in the presence of catalytic amounts of acidic ionic liquid, 1-methylimidazolium trifluoroacetate, ([Hmim]TFA), and Cu(OAc)(2)/sodium ascorbate to afford the corresponding products in excellent yields. This methodology is highly efficient for structurally diverse azides. PMID- 20831264 TI - Fluorous tagged N-hydroxy phthalimide for the parallel synthesis of O aryloxyamines. AB - The parallel synthesis of O-aryloxyamines remains an unfulfilled need in the field of medicinal chemistry and fragment-based approaches. To fill this gap a solution-phase two-step process based on (1) a copper-catalyzed cross-coupling of aryl boronic acids with a fluorous tagged N-hydroxyphthalimide, and (2) a supported aminolysis was designed and optimized using Taguchi's method. A library of O-aryloxyamines was synthesized in high yields with high purity and diversity. PMID- 20831265 TI - Novel and efficient one-step parallel synthesis of dibenzopyranones via Suzuki Miyaura cross coupling. AB - Microwave-promoted novel and efficient one-step parallel synthesis of dibenzopyranones and heterocyclic analogues from bromo arylcarboxylates and o hydroxyarylboronic acids via Suzuki-Miyaura cross coupling reaction is described. Spontaneous lactonization gave dibenzopyranones and heterocyclic analogues bearing electron-donating and -withdrawing groups on both aromatic rings in good to excellent yields. PMID- 20831266 TI - Quick access to druglike heterocycles: facile silver-catalyzed one-pot multicomponent synthesis of aminoindolizines. AB - A direct and efficient approach to 1-aminoindolizines through three-component one pot reaction of heteroaryl aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF(4) has been developed. Desired products were obtained in moderate to excellent yields. Similar aminoindolizines products were afforded from trimethylsilyl protected alkyne substrates as well. This methodology provides a rapid access to construct a diversity-oriented library of indolizines. PMID- 20831267 TI - Multidisciplinary synthetic approach for rapid combinatorial library synthesis of triaza-fluorenes. AB - A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields. Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis. PMID- 20831269 TI - Biofuel vs bioinvasion: seeding policy priorities. PMID- 20831270 TI - Rapid cellular internalization of multifunctional star polymers prepared by atom transfer radical polymerization. AB - Poly(ethylene glycol) (PEG) star polymers containing GRGDS (Gly-Arg-Gly-Asp-Ser) peptide sequences on the star periphery were synthesized by atom transfer radical polymerization (ATRP) of poly(ethylene glycol) methyl ether methacrylate (PEGMA), GRGDS modified poly(ethylene glycol) acrylate (GRGDS-PEG-Acryl), fluorescein o methacrylate (FMA), and ethylene glycol dimethacrylate (EGDMA) via an "arm-first" method. Star polymers were approximately 20 nm in diameter, as measured by dynamic light scattering and atomic force microscopy. Conjugation of FMA to the stars was confirmed by fluorescence microscopy, and successful attachment of GRGDS segments to the star periphery was confirmed by (1)H NMR spectroscopy. Both fluorescent PEG star polymers with and without peripheral GRGDS peptide segments were cultured with MC3T3-E1.4 cells. These star polymers were biocompatible with >= 90% cell viability after 24 h of incubation. Cellular uptake of PEG star polymers in MC3T3-E1.4 cells was observed by confocal microscopy. Rapid uptake of PEG star polymers with GRGDS peptides (~ 100% of FITC-positive cells in 15 min measured by flow cytometry) was observed, suggesting enhanced delivery potential of these functional star polymers. PMID- 20831271 TI - Bioactive supramolecular hydrogel with controlled dual drug release characteristics. AB - Heparin, a powerful anticoagulant used for the prophylaxis of both surgical and medical thrombosis, was covalently incorporated into a supramolecular hydrogel network. For this attempt, heparin was first conjugated with amino-terminated poly(ethylene glycol) methyl ether by carbodiimide chemistry and then used to interact with alpha-cyclodextrin in aqueous solution. The rheological measurements and X-ray diffraction analyses were used to characterize the hydrogel formation. It was found that the gelation kinetics and hydrogel properties could be modulated by changing the amount of conjugated heparin or alpha-cyclodextrin. By circular dichroism analyses and in vitro release experiments, resultant hydrogel material was found to have a great potential as an injectable matrix for the encapsulation and sustained release of model protein drug (bovine serum albumin). By in vitro release, blood clotting, and hemolysis experiments, such a supramolecular hydrogel was also confirmed to have a controlled release profile for conjugated heparin and shows good anticoagulant and blood-compatible properties. PMID- 20831272 TI - Core-cross-linked micelles synthesized by clicking bifunctional Pt(IV) anticancer drugs to isocyanates. AB - Most low molecular weight platinum-based anticancer drugs have a short circulation time in the bloodstream. One of the potential strategies to improve the targeted delivery of cisplatin and prolong its circulation is via the use of nanocarriers. An improved drug delivery system was developed via reversible addition-fragmentation chain transfer (RAFT) polymerization. In a one-pot reaction, the incorporation of anticancer drug and core cross-linking was simultaneously carried out by using the highly effective reaction of isocyanate groups in the core of the polymeric micelles poly(oligo(ethylene glycol) methyl ether methacrylate)-block-poly(styrene-co-3-isopropenyl-alpha,alpha dimethylbenzyl isocyanate) (POEGMA-block-P(STY-co-TMI)) with amine groups in the prepared platinum(IV) drug. The micelles with platinum(IV) incorporated with a size of 36 nm were very stable in water. In a reductive environment, in this study simulated using ascorbate, the drug was released at a slow rate of 82% in 22 days and at the same time the cross-linked micelle broke down into free block copolymers as evidenced using inductively coupled plasma-mass spectrometer (ICP MS), size exclusion chromatography (SEC), and dynamic light scattering (DLS). The in vitro study also revealed the promising antitumor activity of prepared platinum(IV) drugs encapsulated into the micelle structure. PMID- 20831273 TI - Difference of the crystal structure of cellulose in wood after hydrothermal and aging degradation: a NIR spectroscopy and XRD study. AB - The change of crystalline structure in hydrothermally treated hinoki wood was investigated by means of Fourier-transform near-infrared spectroscopy in combination with a deuterium exchange method and X-ray diffraction. The results were compared with analogous data of dry-exposed archeological wood taken from an old wooden temple. Although the decomposition of the amorphous regions in cellulose and hemicelluloses, which corresponds to an increase of the degree of crystallinity, was observed for both, archeologically and hydrothermally treated wood, the increase of crystallite thickness was confirmed only for hydrothermally treated wood. The increase of the average size of crystallites corresponds well to the measured decrease of the deuteration accessibility of the crystalline regions. As the accessibility of the crystalline regions decreased for both, D(2)O and t-butanol, it is assumed that due to the expansion of the crystalline domains by hydrothermal treatment several elementary fibrils are arranged at distances below 0.3 nm. PMID- 20831274 TI - Polyelectrolyte multilayers fabricated from antifungal beta-peptides: design of surfaces that exhibit antifungal activity against Candida albicans. AB - The fungal pathogen Candida albicans can form biofilms on the surfaces of medical devices that are resistant to drug treatment and provide a reservoir for recurrent infections. The use of fungicidal or fungistatic materials to fabricate or coat the surfaces of medical devices has the potential to reduce or eliminate the incidence of biofilm-associated infections. Here we report on (i) the fabrication of multilayered polyelectrolyte thin films (PEMs) that promote the surface-mediated release of an antifungal beta-peptide and (ii) the ability of these films to inhibit the growth of C. albicans on film-coated surfaces. We incorporated a fluorescently labeled antifungal beta-peptide into the structures of PEMs fabricated from poly-l-glutamic acid (PGA) and poly-l-lysine (PLL) using a layer-by-layer fabrication procedure. These films remained stable when incubated in culture media at 37 degrees C and released beta-peptide gradually into solution for up to 400 h. Surfaces coated with beta-peptide-containing films inhibited the growth of C. albicans , resulting in a 20% reduction of cell viability after 2 h and a 74% decrease in metabolic activity after 7 h when compared to cells incubated on PGA/PLL-coated surfaces without beta-peptide. In addition, beta-peptide-containing films inhibited hyphal elongation by 55%. These results, when combined, demonstrate that it is possible to fabricate beta-peptide containing thin films that inhibit the growth and proliferation of C. albicans and provide the basis of an approach that could be used to inhibit the formation of C. albicans biofilms on film-coated surfaces. The layer-by-layer approach reported here could ultimately be used to coat the surfaces of catheters, surgical instruments, and other devices to inhibit drug-resistant C. albicans biofilm formation in clinical settings. PMID- 20831275 TI - Ultrastructure and mechanical properties of populus wood with reduced lignin content caused by transgenic down-regulation of cinnamate 4-hydroxylase. AB - Several key enzymes in lignin biosynthesis of Populus have been down-regulated by transgenic approaches to investigate their role in wood lignification and to explore their potential for lignin modification. Cinnamate 4-hydroxylase is an enzyme in the early phenylpropanoid pathway that has not yet been functionally analyzed in Populus . This study shows that down-regulation of cinnamate 4 hydroxylase reduced Klason lignin content by 30% with no significant change in syringyl to guaiacyl ratio. The lignin reduction resulted in ultrastructural differences of the wood and a 10% decrease in wood density. Mechanical properties investigated by tensile tests and dynamic mechanical analysis showed a decrease in stiffness, which could be explained by the lower density. The study demonstrates that a large modification in lignin content only has minor influences on tensile properties of wood in its axial direction and highlights the usefulness of wood modified beyond its natural variation by transgene technology in exploring the impact of wood biopolymer composition and ultrastructure on its material properties. PMID- 20831276 TI - Tannin oxidation: intra- versus intermolecular reactions. AB - Grape and apple condensed tannin fractions were autoxidized at high concentrations (5 g/L) in aqueous solutions and analyzed by thiolysis (depolymerization followed by HPLC analysis) and small angle X-ray scattering (SAXS). Structural parameters of native (unoxidized) tannin polymers were derived from SAXS according to the wormlike chain model: the length per monomer is 15 A, the length of the statistical segment 17 A, and the cross section of the macromolecule has a radius within the range 3-4.5 A. The rather short length of the statistical segment is an effect of the different location of interflavanol linkages, which cause a loss of orientational correlation between successive monomers. Oxidation created new bonds that were resistant to thiolysis, and, according to thiolysis, some of these new bonds were intramolecular. However, according to SAXS, oxidation at high tannin concentration caused the weight average degree of polymerization to increase, indicating that intermolecular reactions took place as well, creating larger macromolecules. In the case of the smaller grape seed tannins, these intermolecular reactions took place "end to end" leading to the formation of longer linear macromolecules, at least in the earlier stages of oxidation. In the case of the larger apple tannins, the SAXS patterns were characteristic of larger branched macromolecules. Accordingly, the intermolecular reactions were mainly "end to middle". This is in agreement with the higher probabilities of "end to middle" reactions arising from a higher ratio extension unit/terminal unit in the latter case. PMID- 20831277 TI - Improved therapeutic effect of DOX-PLGA-PEG micelles decorated with bivalent fragment HAb18 F(ab')(2) for hepatocellular carcinoma. AB - Although surgery offers the only hope of cure for hepatocellular carcinoma (HCC), patients with inoperable or metastatic disease have a dismal prognosis. Therefore, there is an urgent need for new and effective treatment strategies. Polymeric micelles composed of drug conjugated to a diblock copolymer have attracted great interest for clinical administration of anticancer drugs. In this work, characteristics and cytotoxicity of doxorubicin-poly(d,l-lactic-co-glycolic acid)-poly(ethylene glycol) (DOX-PLGA-PEG) micelle and its targeted micelle decorated with bivalent fragment HAb18 F(ab')(2) for HCC were studied. These micelles possessed spherical morphology and higher loading efficiency. Cellular uptake and accumulation in tumor tissue of micelles was observed. The accumulation of the targeted micelles depends on dual effects of passive and active targeting. The drug-loading micelles showed cytotoxicity on tumor cells in vitro and in vivo. The targeted micelles resulted in significant improvement in therapeutic response. These results suggest that the novel micelles could be a promising candidate with excellent therapeutic efficacy for targeting the drugs to cancer cells. PMID- 20831278 TI - Biocompatible two-layer tantalum/titania-polymer hybrid coating. AB - Using a two-step procedure, radiopaque and biocompatible coatings were obtained, consisting of a tantalum layer deposited by sputtering technique and of an upper organic-inorganic hybrid layer synthesized via sol-gel. As shown by radiographic images, tantalum confers to plastic substrates good X-ray visibility, adjustable via control of deposition time, but its adhesion to the substrate is poor and manipulation easily damages the metal layer. Polymer-titania hybrid coatings, synthesized using poly-epsilon-caprolactone (PCL) or carboxy-terminated polydimethylsiloxane (PDMS) as organic precursors, were applied on the metal layer as biocompatible protective coatings. Biocompatibility is demonstrated by cytotoxicity tests conducted using vascular wall resident-mesenchymal stem cells (VW-MSCs). Both coatings show very good adhesion to the substrate, showing no sign of detachment upon large substrate deformations. Under such conditions, SEM observations show that the PCL-containing hybrid forms cracks, whereas the PDMS based hybrid does not crack, suggesting possible applications of the latter material as a protective layer of sputtered tantalum radiopaque markers for flexible medical devices. PMID- 20831279 TI - Effect of moisture on electrospun nanofiber composites of poly(vinyl alcohol) and cellulose nanocrystals. AB - The effect of humidity on the morphological and thermomechanical properties of electrospun poly(vinyl alcohol) (PVA) fiber mats reinforced with cellulose nanocrystals (CNs) was investigated. Scanning electron microscopy (SEM) images revealed that the incorporation of CNs improved the morphological stability of the composite fibers even in high humidity environments. Thermal and mechanical properties of the electrospun fiber mats were studied by using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and large deformation tensile tests under controlled humidity and temperatures. The balance between the moisture-induced plasticization and the reinforcing effect of rigid CN particles was critical in determining the thermomechanical behaviors of the electrospun fiber mats. Results indicated that the stabilizing effect of the CNs in the PVA matrix might be compromised by water absorption, disrupting the hydrogen bonding within the structure. The amount of this disruption depended on the surrounding humidity and the CN loading. The reduction in tensile strength of neat PVA fiber mats as they were conditioned from low relative humidity (10% RH) to high relative humidity (70% RH) was found to be about 80%, from 1.5 to 0.4 MPa. When the structure was reinforced with CNs, the reduction in strength was limited to 40%, from 2 to 0.8 MPa over the same range in relative humidity. More importantly, the CN-loaded PVA fiber mats showed a reversible recovery in mechanical strength after cycling the relative humidity. Finally, humidity treatments of the composite PVA fiber mats induced significant enhancement of their strength as a result of the adhesion between the continuous matrix and the CNs. PMID- 20831280 TI - Degradation of chitosans with a family 46 chitosanase from Streptomyces coelicolor A3(2). AB - We have studied the degradation of well-characterized soluble heteropolymeric chitosans by a novel family 46 chitosanase, ScCsn46A from Streptomyces coelicolor A3(2), to obtain insight into the enzyme's mode of action and to determine its potential for production of different chitooligosaccharides. The degradation of both a fully deacetylated chitosan and a 32% acetylated chitosan showed a continuum of oligomeric products and a rapid disappearance of the polymeric fraction, which is diagnostic for a nonprocessive endomode of action. The kinetics of the degradation of the 32% acetylated chitosan demonstrated an initial rapid phase and a slower second phase, in addition to a third and even slower kinetic phase. The first phase reflects the cleavage of the glycosidic linkage between two deacetylated units (D-D), the primary products being fully deacetylated dimers, trimers, and tetramers, as well as longer oligomers with increasing degrees of acetylation. In the subsequent slower kinetic phases, oligomers with a higher degree of acetylated units (A) appear, including oligomers with A's at the reducing or nonreducing end, which indicate that there are no absolute preferences for D in subsites -1 and +1. After maximum degradation of the chitosan, the dimers DA and DD were the dominant products. The degradation of chitosans with varying degrees of acetylation to a maximum degree of scission showed that ScCsn46A could degrade all chitosan substrates extensively, although to decreasing degrees of scission with increasing F(A). The potential use of ScCsn46A to prepare fully deacetylated oligomers and more highly acetylated oligomers from chitosan substrates with varying degrees of acetylation is discussed. PMID- 20831281 TI - Ligand identification in titanium complexes using X-ray valence-to-core emission spectroscopy. AB - The identification of ligands in metalloorganic complexes is crucial for understanding many important biological and chemical systems. Nonresonant Kbeta valence-to-core X-ray emission spectroscopy (XES) has been demonstrated as a ligand identification technique which is complementary to other spectroscopies, such as X-ray absorption. In this study we show the Kbeta valence-to-core XES alongside the Ti K-edge X-ray absorption near edge structure spectra for a series of chemically relevant low-symmetry Ti organometallic complexes. The spectra are modeled using density functional theory calculations. XES spectra are analyzed in terms of the molecular orbitals probed, in order to understand the effects of bond length, bond nature, orbital hybridization, and molecular symmetry on the observed spectral features. PMID- 20831282 TI - Polymeric substrates with tunable elasticity and nanoscopically controlled biomolecule presentation. AB - Despite tremendous progress in recent years, nanopatterning of hydrated polymeric systems such as hydrogels still represents a major challenge. Here, we employ block copolymer nanolithography to arrange gold nanoparticles on a solid template, followed by the transfer of the pattern to a polymeric hydrogel. In the next step, these nanoparticles serve as specific anchor points for active biomolecules. We demonstrate the engineering of poly(ethylene glycol) hydrogel surfaces with respect to elasticity, nanopatterning, and functionalization with biomolecules. For the first time, biomolecule arrangement on the nanometer scale and substrate stiffness can be varied independently from each other. Young's moduli, a measure of the compliance of the substrates, can be tuned over 4 orders of magnitude, including the values for all of the different tissues found in the human body. Structured hydrogels can be used to pattern any histidine-tagged protein as exemplified for his-protein A as an acceptor for immunoglobulin. When cell-adhesion-promoting peptide cRGDfK is selectively coupled to gold nanoparticles, the surfaces provide cues for cell-surface interaction and allow for the study of the modulation of cellular adhesion by the mechanical properties of the environment. Therefore, these substrates represent a unique multipurpose platform for studying receptor/ligand interactions with adhering cells, mechanotransduction, and cell-adhesion-dependent signaling. PMID- 20831283 TI - Localized cell uptake of His-tagged polyplexes immobilized on NTA self-assembled monolayers. AB - A new method to study substrate-mediated gene delivery was developed using a hexahistidine-tagged polymeric gene delivery vehicle (His-tagged polyplex) and nickel nitrilotriacetic acid (Ni-NTA) self-assembled monolayers (SAMs) on gold surfaces. The His-tagged polyplexes showed specific interaction with Ni-NTA surfaces compared to control surfaces, with increasing NTA content in SAM formulations corresponding to increasing amounts of immobilized His-tagged polypexes on the surface. Cells seeded on NTA SAMs demonstrated uptake of His tagged polyplexes in the presence of imidazole and EDTA with low cytotoxicity. Cells seeded on NTA SAMs without imidazole and EDTA showed minimal a amount of His-tagged polyplex uptake. This showed that the release of polyplexes from the surface by imidazole and EDTA was necessary for cell uptake. Thus, this system provides potential spatial specificity for polyplex delivery controlled by location of NTA surfaces and temporal specificity for polyplex delivery controlled by the addition of imidazole and EDTA. PMID- 20831284 TI - Simulation of adhesion forces and energies of peptides on titanium dioxide surfaces. AB - Force field molecular dynamics simulations on a decapeptide in contact with a rutile (100) surface in aqueous solution are reported. The peptide sequence is part of alpha(1)-collagen. Force-distance curves yield discrete peaks to the rupture of charged lysine and glutamate side chains from the surface according to the model of contact points. The rupture forces are 0.2-2.2 nN, and the values strongly depend on the charges of surface hydroxyl groups. Adhesion energies are evaluated from the areas of the rupture peaks. For proton charges of 0.4 and 1, adhesion energies between 40 and 190 kJ/mol were found being comparable to recent ab initio molecular dynamics results. Flips in the torsional angles of the peptide are observed during restrained desorption. The partial charges of hydroxyproline are revised, and the polarization of the C(beta)-C(gamma) bond as well as the ring pucker conformations are taken into account. It is shown that transition from collagen to helix fold is more likely for hydroxyproline than for proline and might be relevant for differences in the properties of POG (proline, hydroxyproline, glycine) and PPG collagen sequences. PMID- 20831285 TI - Pressure perturbation calorimetry of unfolded proteins. AB - We report the application of pressure perturbation calorimetry (PPC) to study unfolded proteins. Using PPC we have measured the temperature dependence of the thermal expansion coefficient, alpha(T), in the unfolded state of apocytochrome C and reduced BPTI. We have shown that alpha(T) is a nonlinear function and decreases with increasing temperature. The decrease is most significant in the low (2-55 degrees C) temperature range. We have also tested an empirical additivity approach to predict alpha(T) of unfolded state from the amino acid sequence using alpha(T) values for individual amino acids. A comparison of the experimental and calculated functions shows a very good agreement, both in absolute values of alpha(T) and in its temperature dependence. Such an agreement suggests the applicability of using empirical calculations to predict alpha(T) of any unfolded protein. PMID- 20831286 TI - Introducing perspectives on comparative effectiveness research. PMID- 20831287 TI - Perspectives on comparative effectiveness research: views from diverse constituencies. PMID- 20831288 TI - Using comparative effectiveness research to inform policy and practice in the UK HHS: past, present and future. AB - Health systems that have fixed budgets and a coherent organizational structure generally have found it valuable to have a dedicated primary research capacity to answer decision-oriented value-for-money questions of particular importance to the system. The UK NHS is one example of such a system. Here, we review the historical evolution of building comparative effectiveness research (CER) capacity in the NHS, describe the current situation, with a focus on how this research is used to inform decisions, and discuss present and emerging challenges. We draw some possible lessons for the US, which is currently considering using CER to inform healthcare policy and practice decisions. PMID- 20831289 TI - International comparison of comparative effectiveness research in five jurisdictions: insights for the US. AB - Spurred by a desire to improve quality of care and to understand the relative value of medical treatments, there has been a recent surge of interest in publicly funded comparative effectiveness research (CER) in the US. As health technology assessment (HTA) shares some of the same goals as CER, and publicly funded HTA has been a feature within other industrialized countries for many years, a review of HTA activities in some of these countries can be a helpful source of information for the US debate. Informed by a literature review, and in two cases augmented by informant interviews, we reviewed the organization of HTA activities in five jurisdictions: Canada, Sweden, Scotland, the Netherlands and Australia. We provide a summary description of the healthcare system in each country as well as a description of the key features of their HTA bodies, with a particular focus on the processes of HTA for listing medications on public formularies. Four of the committees evaluating medications for formulary inclusion are funded by, but remain at arm's length from, the government (Canada, Australia, Sweden and Scotland), while the process is fully embedded within the government in the Netherlands. Each of these jurisdictions has a stated preference for comparative outcomes evidence from randomized controlled trials, but will, under certain circumstances, accept randomized evidence using surrogate markers, other comparators that are not directly relevant or non-randomized evidence. Health technology evaluation committees largely comprise health professionals, with public representatives included in the Canadian, Australian and Scottish committees. Scotland is the only one of the five jurisdictions reviewed to have industry representation on the evaluation committee. We identified seven characteristics that are shared across the jurisdictions reviewed and that potentially serve as insights for development of CER in the US: (i) the process must be responsive to stakeholders' interests, in that the turn around time for assessments must be minimized, transparency must be maximized, the process must be considered fair using universally agreed standards and the process must be modifiable based on stakeholders' requirements; (ii) the assessment of medical technologies other than drugs may present different challenges and is managed separately in other HTA organizations; (iii) because of the link between HTA and reimbursement decisions, completion of the HTA process following regulatory approval can delay market access to new technologies, thus closer integration between regulatory approval and HTA processes is being explored internationally; (iv) there is a direct or indirect link to reimbursement in the jurisdictions explored - without this link the role of CER in the US will remain advisory; (v) each jurisdiction reviewed benefits from a single payer that is informed by the process - given the diverse multipayer environment in the US, CER in the US may usefully focus on generating comparative effectiveness evidence; (vi) a common metric for assessing intended and unintended effects of treatment allows comparison across different technologies; and (vii) one stated focus of CER is on therapeutic benefit among 'high-priority populations', including specific demographic groups (the elderly and children, racial and ethnic minorities) and individuals with disabilities, multiple chronic conditions and specific genomic factors. This will be difficult to achieve because epidemiological evidence of differences in therapeutic benefit among subgroups is detected through effect modification, or more specifically, statistical evidence of effect measure modification, typically on relative measures of effect. Few randomized trials have enough power to detect effect modification and these have been uncommon in the scientific literature. As consideration is given to the development of a publicly funded CER body in the US, much can be learned from the international experience. Nevertheless, there are some distinctive features of the US healthcare system that must be taken into account when assessing the transferability of these insights. PMID- 20831291 TI - Guiding comparative effectiveness research--a US perspective: an interview between Howard Birnbaum (of Analysis Group, Inc., and Guest Co-Editor of this Special Issue) and Jean R. Slutsky (Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality). Interview by Howard Birnbaum. PMID- 20831290 TI - Value-based approaches to healthcare systems and pharmacoeconomics requirements in Asia: South Korea, Taiwan, Thailand and Japan. AB - Asian healthcare systems are very diverse, representing cultures, political systems and economies from more than 30 countries with varying histories. Despite the diversity in the region, there has been enormous growth in health economics and outcomes research since the beginning of the 21st century. Whilst Japan has seen very limited use of health technology assessment (HTA), South Korea, Taiwan and Thailand have had remarkable success in establishing government agencies for HTA, employing HTA concepts from the UK National Institute for Health and Clinical Excellence (NICE). These three countries are driven by the following common factors: (i) a desire to establish universal healthcare insurance coverage in their respective nations; (ii) the need for rational allocation of scarce resources; (iii) a desire for government to provide leadership in HTA; and (iv) availability of HTA professionals and faculties through international networks. The HTA models introduced by these three countries are both similar to and different from those of HTA agencies in Europe, but might work well as examples for other countries in the region. PMID- 20831292 TI - The economics of comparative effectiveness studies: societal and private perspectives and their implications for prioritizing public investments in comparative effectiveness research. AB - Comparative effectiveness research (CER) can provide valuable information for patients, providers and payers. These stakeholders differ in their incentives to invest in CER. To maximize benefits from public investments in CER, it is important to understand the value of CER from the perspectives of these stakeholders and how that affects their incentives to invest in CER. This article provides a conceptual framework for valuing CER, and illustrates the potential benefits of such studies from a number of perspectives using several case studies. We examine cases in which CER provides value by identifying when one treatment is consistently better than others, when different treatments are preferred for different subgroups, and when differences are small enough that decisions can be made based on price. We illustrate these findings using value-of information techniques to assess the value of research, and by examining changes in pharmaceutical prices following publication of a comparative effectiveness study. Our results suggest that CER may have high societal value but limited private return to providers or payers. This suggests the importance of public efforts to promote the production of CER. We also conclude that value-of information tools may help inform policy decisions about how much public funds to invest in CER and how to prioritize the use of available public funds for CER, in particular targeting public CER spending to areas where private incentives are low relative to social benefits. PMID- 20831293 TI - Regulatory benefit-risk assessment and comparative effectiveness research: strangers, bedfellows or strange bedfellows? AB - Over the past 5 years, we have witnessed growing interest in both comparative effectiveness research (CER) and regulatory benefit-risk assessment (BRA). Both deal with benefits and harms, although at different stages of the product lifecycle. There are growing pressures for a more systematic and quantitative approach to regulatory BRA. However, there is also a need for CER - beyond the evidence that can reasonably be generated during pre-launch product development. Important regulatory and policy questions include the following: What would be a level playing field across disease areas and companies? Who should bear the costs of these studies? What role can benefit-risk modelling play? What is the value of research and how is it related to the prevalence of disease? What is the relationship between uncertainty and the value of evidence? We need to recognize the lifecycle nature of evidence generation, moving from the regulatory setting to the real world and affecting potentially hundreds of thousands, or even millions, of patients worldwide. We need to emphasize not only the public goods nature of information embedded in innovations, but also that it is global. Finally, we need to more systematically explore the benefits and costs of gathering further information - the value of research - recognizing that doing this requires a model or methodology, which we have, for systematically appraising our current state of knowledge and what could be gained from further research. All said, it would seem that BRA and CER should be neither strangers nor strange bedfellows, but may need to be coaxed into being bedfellows. PMID- 20831294 TI - Cost-effectiveness analysis in markets with high fixed costs. AB - We consider how to conduct cost-effectiveness analysis when the social cost of a resource differs from the posted price. From the social perspective, the true cost of a medical intervention is the marginal cost of delivering another unit of a treatment, plus the social cost (deadweight loss) of raising the revenue to fund the treatment. We focus on pharmaceutical prices, which have high markups over marginal cost due to the monopoly power granted to pharmaceutical companies when drugs are under patent. We find that the social cost of a branded drug is approximately one-half the market price when the treatment is paid for by a public insurance plan and one-third the market price for mandated coverage by private insurance. We illustrate the importance of correctly accounting for social costs using two examples: coverage for statin drugs and approval for a drug to treat kidney cancer (sorafenib). In each case, we show that the correct social perspective for cost-effectiveness analysis would be more lenient than researcher recommendations. PMID- 20831295 TI - Comparative effectiveness regulations and pharmaceutical innovation. AB - As healthcare reform evolves and takes shape, comparative effectiveness research (CER) appears to be one of the central topics on the national healthcare agenda. Over the past couple of years, comparative effectiveness has been explicitly incorporated in more than ten bills. For example, the passage of the American Recovery and Reinvestment Act of 2009 authorized $US1.1 billion for CER. Comparative effectiveness, when costs are formally considered, offers the hope of efficient resource allocation within US healthcare markets. However, the future operationalization and implementation of comparative effectiveness is uncertain, and there exist potentially negative, and unintended, consequences under certain scenarios. One example, and the focus of this article, is pharmaceutical innovation. Incentives for pharmaceutical R&D could be affected if drug development costs increase as a result of firms having to bear, directly or indirectly, the costs of running larger, randomized, head-to-head comparative effectiveness trials. While this may or may not be the case with current and future comparative effectiveness legislation and its subsequent implementation, the potential consequences for pharmaceutical innovation warrant recognition. This is the purpose of the article. To achieve this goal, we develop several models of clinical trial design, drug development costs and R&D investment. By example, we shed light on the causal links between the models and the ways in which industry R&D investment can be affected. PMID- 20831296 TI - Perspective and desire in comparative effectiveness research: the relative unimportance of mere preferences, the central importance of context. AB - Economists engaged in comparative effectiveness research (CER) commonly adopt particular value judgements that underpin many of their methods. Two of these are the idea of a 'societal perspective' and that the foundation of values in measures of health outcome is individual preferences. This article takes issue with both value judgements and argues instead that the values to be adopted are not ones to be determined a priori or independently of the context of the analysis. Indeed, the first task of analysts is to discover these values by early and ongoing consultation with the commissioners of the CER. The same arguments apply to the practice of cost-effectiveness analysis. PMID- 20831297 TI - Comparative effectiveness research and the psychology of medical practice: the vicissitudes of knowledge implementation. AB - Comparative effectiveness research should provide much-needed information about the benefits and risks of different current treatment options in the community. Taking the perspective of medical care providers, we consider many of the psychological, social and behavioural hurdles to implementation of comparative effectiveness analyses and explain why these obstacles should not be ignored. PMID- 20831298 TI - Comparative effectiveness research and personalized medicine: catalyzing or colliding? AB - Comparative effectiveness research (CER) is generating intense attention as interest grows in finding new and better drug technology assessment processes. The federal government is supporting the expansion of CER through funding made available in the American Recovery and Reinvestment Act of 2009 (ARRA) and by establishing the Patient-Centered Outcomes Research Institute through the Patient Protection and Affordable Care Act of 2010. At the same time, personalized medicine is generating debate about its place in clinical medicine, and so, naturally, how CER can or cannot play a role in personalized medicine is part of these debates. At the heart of the debate around the role of CER in personalized medicine is the nature of personalized medicine and how it fits within contemporary clinical research concepts. We maintain in this article that CER can serve to catalyze personalized medicine, but we recognize that, for this to happen, researchers will need to embrace new data sources and new analytic approaches. We also recognize that drug technology assessment processes will have to undergo necessary adaptations to accommodate CER as configured for personalized medicine, and that clinicians will need to be educated appropriately and provided access to decision-support systems through health information technology to use the information coming from this research. To illustrate our argument, we describe two ongoing CER studies funded and managed in the private sector evaluating personalized medicine interventions that have important clinical and financial implications. One of the studies investigates the clinical and financial effects of pharmacogenomic testing for warfarin as prescribed in conditions of typical practice settings. The other study is also set in community practice settings and compares cardiovascular outcomes of patients receiving clopidogrel who are extensive metabolizer phenotypes for the cytochrome P450 2C19 hepatic isoenzyme with all patients receiving prasugrel. PMID- 20831299 TI - Comparative effectiveness research: the view from a pharmaceutical company. AB - Comparative effectiveness research (CER) represents the next stage in an evolution of research and knowledge development in regard to medical interventions. In this article we describe the challenges currently facing the innovative pharmaceuticals industry and briefly summarize the history of drug development, as context for the current movement to comparative effectiveness. CER should be considered alongside the wider field of health technology assessment (HTA), and we review the status of both CER and HTA internationally and their role in health policy. Limitations as to what can be achieved with HTA and limitations to the availability of evidence of comparative effectiveness at the time of market authorization provide ongoing challenges to all stakeholders. However, embracing CER is regarded as an essential step for the innovative pharmaceutical industry, as companies strive to more clearly demonstrate the effectiveness of their pipeline products with evidence that is compelling to payers and HTA agencies. Examples are given of how these evolving requirements from regulatory and HTA agencies are impacting on drug development efforts and how one company is responding. Finally, there are signs of increasing understanding and alignment across the various partners in drug development, registration and evaluation, and further suggestions are provided for consideration as the field matures and expands. PMID- 20831300 TI - Comparative effectiveness, personalized medicine and innovation: the path forward. PMID- 20831301 TI - Managed care pharmacy sees potential of comparative effectiveness research to improve patient care and lower costs. PMID- 20831302 TI - Comparative effectiveness without head-to-head trials: a method for matching adjusted indirect comparisons applied to psoriasis treatment with adalimumab or etanercept. AB - The absence of head-to-head trials is a common challenge in comparative effectiveness research and health technology assessment. Indirect cross-trial treatment comparisons are possible, but can be biased by cross-trial differences in patient characteristics. Using only published aggregate data, adjustment for such biases may be impossible. Although individual patient data (IPD) would permit adjustment, they are rarely available for all trials. However, many researchers have the opportunity to access IPD for trials of one treatment, a new drug for example, but only aggregate data for trials of comparator treatments. We propose a method that leverages all available data in this setting by adjusting average patient characteristics in trials with IPD to match those reported for trials without IPD. Treatment outcomes, including continuous, categorical and censored time-to-event outcomes, can then be compared across balanced trial populations. The proposed method is illustrated by a comparison of adalimumab and etanercept for the treatment of psoriasis. IPD from trials of adalimumab versus placebo (n = 1025) were re-weighted to match the average baseline characteristics reported for a trial of etanercept versus placebo (n = 330). Re-weighting was based on the estimated propensity of enrolment in the adalimumab versus etanercept trials. Before matching, patients in the adalimumab trials had lower mean age, greater prevalence of psoriatic arthritis, less prior use of systemic treatment or phototherapy, and a smaller mean percentage of body surface area affected than patients in the etanercept trial. After matching, these and all other available baseline characteristics were well balanced across trials. Symptom improvements of >=75% and >=90% (as measured by the Psoriasis Area and Severity Index [PASI] score at week 12) were experienced by an additional 17.2% and 14.8% of adalimumab-treated patients compared with the matched etanercept treated patients (respectively, both p < 0.001). Mean percentage PASI score improvements from baseline were also greater for adalimumab than for etanercept at weeks 4, 8 and 12 (all p < 0.05). Matching adjustment ensured that this indirect comparison was not biased by differences in mean baseline characteristics across trials, supporting the conclusion that adalimumab was associated with significantly greater symptom reduction than etanercept for the treatment of moderate to severe psoriasis. PMID- 20831303 TI - There's a reason they call them dummy variables: a note on the use of structural equation techniques in comparative effectiveness research. AB - Many research designs and statistical methodologies will be used to conduct comparative effectiveness research (CER). In particular, it is almost certainly the case that the demand for real-world evidence will drive increased demand for CER analyses of observational data. Although a great deal of progress has been made in the development and application of statistical methods for the analysis of observational data, the ordinary least squares multiple regression model remains, by far, the most widely applied multivariate analysis tool. This article begins with a brief review of the interpretation of treatment effects captured through the use of dummy variables in multiple regression models. This review makes clear just how limited this typical estimator of treatment effect is. Structural equation and decomposition methods for CER analyses of observational data are then reviewed. Although these methods have not been commonly used for outcomes research, they offer the opportunity to extract significantly more information regarding treatment effects than the standard dummy variable approach. I have attempted to make the point that traditional dummy variable methods in regression models provide an extremely limited estimate of treatment effects. Structural equation models and decomposition methods provide considerably more information about treatment effects - in particular, the ability to identify how outcomes may vary differentially with respect to patient characteristics and other factors for alternative treatment cohorts. Such an understanding is fundamental to deciphering the heterogeneity of treatment response among patient subpopulations. Structural equation and decomposition methods may be further enhanced by incorporating propensity score matching prior to the analysis. On the other hand, researchers should be wary of the potential pitfalls associated with parametric sample selection bias models. Although tests for selection bias and other forms of endogeneity are an excellent research practice, it is entirely possible that attempts to correct for endogeneity may introduce more bias than they remove. Nonparametric methods, such as differences in differences, while making strong assumptions of their own, avoid the need to identify instrumental variables that are correlated with treatment selection but uncorrelated with residuals in the outcome equation. PMID- 20831304 TI - No head-to-head trial? simulate the missing arms. AB - Establishing efficacy relative to placebo is no longer sufficient for payers to agree to cover new interventions. Evidence from comparisons of competing interventions is increasingly important, although head-to-head studies are seldom available to inform decisions. In this article, we describe the simulated treatment comparison (STC) approach to incorporating 'missing arms' into an existing trial. This approach yields a simulated head-to-head trial and can address many of the differences among source trials. It provides inputs for economic models and can inform decision makers until actual trial data are available. A simulation is constructed to replicate an index trial, including enrolment, randomization and follow-up of patients. The simulation is driven by predictive equations derived from the index trial. Separate data for the comparators are used to calibrate the index equations to reflect the alternative interventions. The simulation is used to add the missing arms to the index trial and estimate the results that would have been obtained in a head-to-head trial. The STC can also be used to estimate results in various settings and populations and to explore variations in the trial design. An STC offers a way to derive comparative effectiveness in the absence of direct trial evidence and a platform to test design features that may help in planning future head-to-head studies. PMID- 20831306 TI - Communication: Novel quantum states of electron spins in polycarbenes from ab initio density matrix renormalization group calculations. AB - An investigation into spin structures of poly(m-phenylenecarbene), a prototype of magnetic organic molecules, is presented using the ab initio density matrix renormalization group method. It is revealed by achieving large-scale multireference calculations that the energy differences between high-spin and low spin states (spin-gaps) of polycarbenes decrease with increasing the number of carbene sites. This size-dependency of the spin-gaps strikingly contradicts the predictions with single-reference methods including density functional theory. The wave function analysis shows that the low-spin states are beyond the classical spin picture, namely, much of multireference character, and thus are manifested as strongly correlated quantum states. The size dependence of the spin gaps involves an odd-even oscillation, which cannot be explained by the integer spin Heisenberg model with a single magnetic-coupling constant. PMID- 20831305 TI - Generating evidence for comparative effectiveness research using more pragmatic randomized controlled trials. AB - Comparative effectiveness research (CER), or research design to meet the needs of post-regulatory decision makers, has been brought into the spotlight with the introduction of the American Recovery and Reinvestment Act, which provided $US1.1 billion over 2 years to support CER. In the short run, the majority of this money will be invested in observational studies and building of infrastructure; however, in the long run, we will likely see an increase in the number of randomized controlled trials (RCTs), as this method is arguably the most unbiased approach for establishing causal effect between treatments and health outcomes. RCTs are an integral component of CER for generating credible evidence on the relative value of alternative interventions in order to meet the needs of post regulatory decision makers (patients, physicians, payers and policy makers). Explanatory phase III RCTs are fit for purpose; researchers make use of guidance documents produced by the US FDA to inform the design of these clinical trials. Historically, without explicit FDA guidance, broad patient populations, including women and minorities, often were not considered in trial design. In addition, attempts to minimize cost and maximize efficiency have led to smaller sample sizes, as is clear from the increase in 'creeping phase II-ism'. To demonstrate effectiveness, RCTs must be reflective of how an intervention will be used in the healthcare market. The concept of pragmatic clinical trials has emerged to describe those trials that are designed explicitly with this need in mind. Use of pragmatic trials will be most impactful if post-regulatory decision makers are engaged in the development of recommendations for trial design features, such as indicating outcomes measures and articulating patient populations of interest, which clearly express their evidence needs. PMID- 20831307 TI - Communication: Resolving the vibrational and configurational contributions to thermal expansion in isobaric glass-forming systems. AB - A fundamental understanding of isobaric thermal expansion behavior is critical in all areas of glass science and technology. Current models of glass transition and relaxation behavior implicitly assume that the thermal expansion coefficient of glass-forming systems can be expressed as a sum of vibrational and configurational contributions. However, this assumption is made without rigorous theoretical or experimental justification. Here we present a detailed statistical mechanical analysis resolving the vibrational and configurational contributions to isobaric thermal expansion and show experimental proof of the separability of thermal expansion into vibrational and configurational components for Corning Jade glass. PMID- 20831308 TI - Communication: Photodissociation of N(2)O-frustrated NN bond breaking causes diffuse vibrational structures. AB - The photodissociation of N(2)O is studied by wave packet calculations using a global three-dimensional potential energy surface for the first excited (1)A(') state. It is shown that the weak vibrational structures of the absorption cross section are caused by large-amplitude NN stretch motion, combined with strong excitation of the bend as well as the O-NN stretch. Weakening of the NN bond toward the N+NO channel is the necessary prerequisite. PMID- 20831309 TI - Interface effects in thermal conduction through molecular junctions: Numerical simulations. AB - Thermal conductance in solid-molecule-solid junctions is studied within Langevin type classical molecular dynamics simulations. The solids attached at the two ends, characterized by phonon bands mismatching the molecular vibrational window, are simulated using colored thermal noises with analytic correlation functions. We find that the dissimilarity in the vibrational spectra of the molecule and the interfacing materials crucially controls both the magnitude and the chain-length dependence of the heat current considering both harmonic and anharmonic molecules. By using reservoirs with distinct spectral functions, we also demonstrate that one can optimize the thermal rectifying (diodelike) properties of the junction. PMID- 20831310 TI - A first principles based polarizable O(N) interatomic force field for bulk silica. AB - We present a reformulation of the Tangney-Scandolo interatomic force field for silica [J. Chem. Phys. 117, 8898 (2002)], which removes the requirement to perform an Ewald summation. We use a Yukawa factor to screen electrostatic interactions and a cutoff distance to limit the interatomic potential range to around 10 A. A reparametrization of the potential is carried out, fitting to data from density functional theory calculations. These calculations were performed within the local density approximation since we find that this choice of functional leads to a better match to the experimental structural and elastic properties of quartz and amorphous silica than the generalized gradient approximation approach used to parametrize the original Tangney-Scandolo force field. The resulting O(N) scheme makes it possible to model hundreds of thousands of atoms with modest computational resources, without compromising the force field accuracy. The new potential is validated by calculating structural, elastic, vibrational, and thermodynamic properties of alpha-quartz and amorphous silica. PMID- 20831311 TI - Fast vibrational configuration interaction using generalized curvilinear coordinates and self-consistent basis. AB - In this paper, we couple a numerical kinetic-energy operator approach to the direct-vibrational self-consistent field (VSCF)/vibrational configuration interaction (VCI) method for the calculation of vibrational anharmonic frequencies. By combining this with fast-VSCF, an efficient direct evaluation of the ab initio potential-energy surface (PES), we introduce a general formalism for the computation of vibrational bound states of molecular systems exhibiting large-amplitude motion such as methyl-group torsion. We validate our approach on an analytical two-dimensional model and apply it to the methanol molecule. We show that curvilinear coordinates lead to a significant improvement in the VSCF/VCI description of the torsional frequency in methanol, even for a simple two-mode coupling expansion of the PES. Moreover, we demonstrate that a curvilinear formulation of the fast-VSCF/VCI scheme improves its speed by a factor of two and its accuracy by a factor of 3. PMID- 20831312 TI - Polarization of molecular targets using infrared stimulated Raman adiabatic passage. AB - We suggest that infrared stimulated Raman adiabatic passage, a coherent multiple excitation process, can be used to create a superposition of (2J+1) highly correlated M-state sublevels of a rigid rotor molecule with vibrational level v and rotational level J. This method employs the (v=0,J-2) to (v=2,J) S-branch transition, which is carried out in a counterintuitive manner in which the v=1 to v=2 transition is pumped prior to the v=0 to v=1 transition, causing nearly complete population transfer to the v=2 final level. We use perpendicular and parallel linearly polarized infrared excitation (biaxial excitation). Specifically, the perpendicular polarization connects the v=1 intermediate level to the final vibrational level v=2, and the parallel polarization connects the initial level v=0 to the intermediate level v=1. By this means we break the cylindrical symmetry for an ensemble of vibrationally excited molecules in a rovibrational eigenstate (v=2,J). The angular momentum polarization is determined by the relative phases rather than by the populations of the magnetic M sublevels. For the phase correlated ensemble, the angular momentum polarization can be considered as a purely quantum mechanical effect. Using a fully general density matrix treatment, we illustrate this approach by considering a beam of carbon monoxide (CO) molecules. We find that significant polarization for J=2, 5, and 10 can be achieved with a cw infrared laser source having modest power (~100 mW/mm(2)). We believe that this technique is a general one and may offer an experimentally accessible new platform for different applications, from scattering studies with M-state entangled ensembles of molecules to logic gate operations of a quantum computer. PMID- 20831313 TI - Structure determination in 55-atom Li-Na and Na-K nanoalloys. AB - The structure of 55-atom Li-Na and Na-K nanoalloys is determined through combined empirical potential (EP) and density functional theory (DFT) calculations. The potential energy surface generated by the EP model is extensively sampled by using the basin hopping technique, and a wide diversity of structural motifs is reoptimized at the DFT level. A composition comparison technique is applied at the DFT level in order to make a final refinement of the global minimum structures. For dilute concentrations of one of the alkali atoms, the structure of the pure metal cluster, namely, a perfect Mackay icosahedron, remains stable, with the minority component atoms entering the host cluster as substitutional impurities. At intermediate concentrations, the nanoalloys adopt instead a core shell polyicosahedral (p-Ih) packing, where the element with smaller atomic size and larger cohesive energy segregates to the cluster core. The p-Ih structures show a marked prolate deformation, in agreement with the predictions of jelliumlike models. The electronic preference for a prolate cluster shape, which is frustrated in the 55-atom pure clusters due to the icosahedral geometrical shell closing, is therefore realized only in the 55-atom nanoalloys. An analysis of the electronic densities of states suggests that photoelectron spectroscopy would be a sufficiently sensitive technique to assess the structures of nanoalloys with fixed size and varying compositions. PMID- 20831314 TI - Calculation of ground state rotational populations for kinetic gas homonuclear diatomic molecules including electron-impact excitation and wall collisions. AB - A model has been developed to calculate the ground state rotational populations of homonuclear diatomic molecules in kinetic gases, including the effects of electron-impact excitation, wall collisions, and gas feed rate. The equations are exact within the accuracy of the cross sections used and of the assumed equilibrating effect of wall collisions. It is found that the inflow of feed gas and equilibrating wall collisions can significantly affect the rotational distribution in competition with nonequilibrating electron-impact effects. The resulting steady-state rotational distributions are generally Boltzmann for N>=3, with a rotational temperature between the wall and feed gas temperatures. The N=0,1,2 rotational level populations depend sensitively on the relative rates of electron-impact excitation versus wall collision and gas feed rates. PMID- 20831315 TI - Argon pair potential at basis set and excitation limits. AB - A new ab initio interaction potential for the electronic ground state of argon dimer has been developed. The potential is a sum of contributions corresponding to various levels of the coupled-cluster theory up to the full coupled-cluster method with single, double, triple, and quadruple excitations. All contributions have been calculated in larger basis sets than used in the development of previous Ar(2) potentials, including basis sets optimized by us up to the septuple(sextuple)-zeta level for the frozen-core (all-electron) energy. The diffuse augmentation functions have also been optimized. The effects of the frozen-core approximation and the relativistic effects have been computed at the CCSD(T) level. We show that some basis sets used in literature to compute these corrections may give qualitatively wrong results. Our calculations also show that the effects of high excitations do not necessarily converge significantly faster (in absolute values) in basis set size than the effects of lower excitations, as often assumed in literature. Extrapolations to the complete basis set limits have been used for most terms. Careful examination of the basis set convergence patterns enabled us to determine uncertainties of the ab initio potential. The interaction energy at the near-minimum interatomic distance of 3.75 A amounts to 99.291+/-0.32 cm(-1). The ab initio energies were fitted to an analytic potential which predicts a minimum at 3.762 A with a depth of 99.351 cm(-1). Comparisons with literature potentials indicate that the present one is the most accurate representation of the argon-argon interaction to date. PMID- 20831316 TI - Core-valence double photoionization of the CS(2) molecule. AB - Double photoionization spectra of the CS(2) molecule have been recorded using the TOF-PEPECO technique in combination with synchrotron radiation at the photon energies hnu=220, 230, 240, 243, and 362.7 eV. The spectra were recorded in the S 2p and C 1s inner-shell ionization regions and reflect dicationic states formed out of one inner-shell vacancy and one vacancy in the valence region. MCSCF calculations were performed to model the energies of the dicationic states. The spectra associated with a S 2p vacancy are well structured and have been interpreted in some detail by comparison to conventional S 2p and valence photoelectron spectra. The lowest inner-shell-valence dicationic state is observed at the vertical double ionization energy 188.45 eV and is associated with a (2p(3/2))(-1)(2pi(g))(-1) double vacancy. The spectrum connected to the C 1s vacancy shows a distinct line at 310.8 eV, accompanied by additional broad features at higher double ionization energies. This line is associated with a (C 1s)(-1)(2pi(g))(-1) double vacancy. PMID- 20831317 TI - Primary photodissociation pathways of epichlorohydrin and analysis of the C-C bond fission channels from an O((3)P)+allyl radical intermediate. AB - This study initially characterizes the primary photodissociation processes of epichlorohydrin, c-(H(2)COCH)CH(2)Cl. The three dominant photoproduct channels analyzed are c-(H(2)COCH)CH(2)+Cl, c-(H(2)COCH)+CH(2)Cl, and C(3)H(4)O+HCl. In the second channel, the c-(H(2)COCH) photofission product is a higher energy intermediate on C(2)H(3)O global potential energy surface and has a small isomerization barrier to vinoxy. The resulting highly vibrationally excited vinoxy radicals likely dissociate to give the observed signal at the mass corresponding to ketene, H(2)CCO. The final primary photodissociation pathway HCl+C(3)H(4)O evidences a recoil kinetic energy distribution similar to that of four-center HCl elimination in chlorinated alkenes, so is assigned to production of c-(H(2)COC)=CH(2); the epoxide product is formed with enough vibrational energy to isomerize to acrolein and dissociate. The paper then analyzes the dynamics of the C(3)H(5)O radical produced from C-Cl bond photofission. When the epoxide radical photoproduct undergoes facile ring opening, it is the radical intermediate formed in the O((3)P)+allyl bimolecular reaction when the O atom adds to an end C atom. We focus on the HCO+C(2)H(4) and H(2)CO+C(2)H(3) product channels from this radical intermediate in this report. Analysis of the velocity distribution of the momentum-matched signals from the HCO+C(2)H(4) products at m/e=29 and 28 shows that the dissociation of the radical intermediate imparts a high relative kinetic energy, peaking near 20 kcal/mol, between the products. Similarly, the energy imparted to relative kinetic energy in the H(2)CO+C(2)H(3) product channel of the O((3)P)+allyl radical intermediate also peaks at high recoil kinetic energies, near 18 kcal/mol. The strongly forward-backward peaked angular distributions and the high kinetic energy release result from tangential recoil during the dissociation of highly rotationally excited nascent radicals formed photolytically in this experiment. The data also reveal substantial branching to an HCCH+H(3)CO product channel. We present a detailed statistical prediction for the dissociation of the radical intermediate on the C(3)H(5)O potential energy surface calculated with coupled cluster theory, accounting for the rotational and vibrational energy imparted to the radical intermediate and the resulting competition between the H+acrolein, HCO+C(2)H(4), and H(2)CO+C(2)H(3) product channels. We compare the results of the theoretical prediction with our measured branching ratios. We also report photoionization efficiency (PIE) curves extending from 9.25 to 12.75 eV for the signal from the HCO+C(2)H(4) and H(2)CO+C(2)H(3) product channels. Using the C(2)H(4) bandwidth averaged absolute photoionization cross section at 11.27 eV and our measured relative photoion signals of C(2)H(4) and HCO yields a value of 11.6+1/-3 Mb for the photoionization cross section of HCO at 11.27 eV. This determination puts the PIE curve of HCO measured here on an absolute scale, allowing us to report the absolute photoionization efficiency of HCO over the entire range of photoionization energies. PMID- 20831318 TI - Transition from single-file to Fickian diffusion for binary mixtures in single walled carbon nanotubes. AB - The transition from single-file diffusion to Fickian diffusion in narrow cylindrical pores is investigated for systems of rigid single-walled armchair carbon nanotubes, solvated with binary mixtures of Lennard-Jones fluids (Ar/Ne, Ar/Kr, and Ar/Xe). A range of effects is examined including the mixture concentration, the size ratio of the two components, and the nanotube diameter. The transition from single-file to Fickian diffusion in varying carbon nanotube diameters is analyzed in terms of the Fickian self-diffusivity and the single file mobility of the mixture components. It is found that the single-file to Fickian carbon nanotube transition diameter is a unique property of the individual molecule's diameter and remains unchanged regardless of the mixture composition. In applications of binary mixtures, each component may crossover from single-file to Fickian diffusion in a different carbon nanotube diameter, giving rise to bimodal diffusion in some nanotubes. This transition allows for one species to diffuse in single-file while the other diffuses by a Fickian mechanism, yielding orders of magnitude difference between the self-diffusional rates of the two molecules. This phenomenon might be further extended to alter the diffusional motion of molecules in nanoporous materials. PMID- 20831319 TI - Infrared study of glycolaldehyde isolated in parahydrogen matrix. AB - The infrared spectrum of glycolaldehyde sugar model in solid parahydrogen is reported and interpreted in the light of ab initio anharmonic frequency calculations. The advantages of parahydrogen lead to a simplification of its infrared spectroscopy compared to other conventional matrices. Surprisingly, the sugar molecule is found to display an unexpected large bandwidth compared to the smaller organic molecules studied in parahydrogen so far. Among them, only glycolaldehyde possesses an internal hydrogen-bond. Band broadening in glycolaldehyde is interpreted as originating mainly from the presence of the hydrogen-bond and to a lesser extent from clustering with oH(2) impurities. PMID- 20831320 TI - EXP6 fluids at extreme conditions modeled by two-Yukawa potentials. AB - A two-Yukawa representation of the EXP6 fluids at supercritical temperatures and high pressures has been developed and examined using molecular simulations. A uniquely defined mapping of the repulsive part of the EXP6 potential curve onto the two-Yukawa potential is used. Two ranges of temperatures, one encountered in geochemical applications (T(geo) range) and the other at conditions of detonations (T(det) range), are considered and it is shown that the local structures of both fluids are practically identical. Deviations between the EXP6 and two-Yukawa potential functions at intermediate separations lead to differences in the thermodynamic properties of the two fluids at lower temperatures of the T(geo) range; at higher temperatures and in the high T(det) temperature range both the structural and thermodynamic properties of the EXP6 and two-Yukawa fluids are practically identical. PMID- 20831321 TI - Product gas evolution above planar microstructured model catalysts--a combined scanning mass spectrometry, Monte Carlo, and Computational Fluid Dynamics study. AB - The transport and distribution of reaction products above catalytically active Pt microstructures was studied by spatially resolved scanning mass spectrometry (SMS) in combination with Monte Carlo simulation and fluid dynamics calculations, using the oxidation of CO as test reaction. The spatial gas distribution above the Pt fields was measured via a thin quartz capillary connected to a mass spectrometer. Measurements were performed in two different pressure regimes, being characteristic for ballistic mass transfer and diffusion involving multiple collisions for the motion of CO(2) product molecules between the sample and the capillary tip, and using differently sized and shaped Pt microstructures. The tip height dependent lateral resolution of the SMS measurements as well as contributions from shadowing effects, due to the mass transport limitations between capillary tip and sample surface at close separations, were evaluated and analyzed. The data allow to define measurement and reaction conditions where effects induced by the capillary tip can be neglected ("minimal invasive measurements") and provide a basis for the evaluation of catalyst activities on microstructured model systems, e.g., for catalyst screening or studies of transport effects. PMID- 20831322 TI - Double-quantum two-dimensional electronic spectroscopy of a three-level system: Experiments and simulations. AB - Double-quantum coherence two-dimensional (2Q2D) electronic spectroscopy is utilized to probe the dynamic fluctuations of electronic states in a solvated molecule at approximately twice the energy of the ground state bleach transition. The 2Q2D spectrum gives insight into the energetic position and spectral fluctuations (system-bath interaction) of the probed excited states. Combining it with single-quantum two-dimensional (1Q2D) electronic spectroscopy enables one to determine the strength of the excited state absorption transition and the relative detuning of electronic states, as well as the dynamics of the single quantum coherence. To investigate the correlation of spectral fluctuations in different electronically excited states, we have carried out experiments on a solvated dye (Rhodamine 6G) with 23 fs pulses centered at the maximum of the linear absorption spectrum. The 2Q2D spectrum reveals three peaks of alternating signs with the major negative peak located at higher frequencies along the emission axis compared to the single positive peak. The 1Q2D spectrum, on the other hand, shows a negative peak stemming from excited state absorption at lower frequencies along the emission axis. Analysis of the signal in the homogeneous limit fails to account for this observation as well as the number of peaks in the 2Q2D spectrum. Employing a three-level model in which all time correlations of the third-order response function are accounted for via second-order cumulant expansion gives good agreement with both the 1Q2D and 2Q2D data. Furthermore, the analysis shows that the fluctuations of the probed electronic states are highly correlated, reflecting the modulation by a common nuclear bath and similarities in the nature of the electronic transitions. PMID- 20831323 TI - On the relation between the microscopic structure and the sound velocity anomaly in elemental melts of groups IV, V, and VI. AB - The sound velocity of some liquid elements of groups IV, V, and VI, as reported in the literature, displays anomalous features that set them apart from other liquid metals. In an effort to determine a possible common origin of these anomalies, extensive neutron diffraction measurements of liquid Bi and Sb were carried out over a wide temperature range. The structure factors of liquid Sb and Bi were determined as a function of temperature. The structure of the two molten metals was carefully analyzed with respect to peak locations, widths, and coordination numbers in their respective radial distribution function. The width of the peaks in the radial distribution functions was not found to increase and even decreased within a certain temperature range. This anomalous temperature dependence of the peak widths correlates with the anomalous temperature dependence of the sound velocity. This correlation may be accounted for by increased rigidity of the liquid structure with temperature. A phenomenological correlation between the peak width and the sound velocity is suggested for metallic melts and is found to agree with available data for normal and anomalous elemental liquids in groups IV-VI. PMID- 20831324 TI - On the kinetics of tautomerism in drugs: New application of broadband dielectric spectroscopy. AB - There are a number of chemical compounds that readily convert to other isomers when their crystalline structure is lost (e.g., during melting or dissolution). This phenomenon, commonly known as tautomerism, is a subject of intense research. It is an important problem especially in pharmaceutical industry because various isomers of a drug may have different pharmacological activity. Therefore, it is important to find appropriate experimental technique which enables the determination of the isomerization ability of compounds. In this communication, we demonstrate that broadband dielectric spectroscopy (BDS) method has the potential of detection and monitoring of tautomerism of drugs. To investigate the tautomerism phenomenon we have chosen one of the hypoglycemic agents that belong to the class II of sulfonylurea drugs. Based on density functional theory (DFT) calculations we have analyzed two possible tautomerization pathways of glibenclamide. By using BDS as a tool, we show it can detect the conversion between the isomeric forms through time dependence in the dielectric properties. The activation energy (E(a)) of this process is in good agreement with that obtained from DFT analysis. Finally, we discuss the possible effects of tautomerism on basic pharmaceutical parameters such as biological activity or bioavailability in the case of the glibenclamide drug. PMID- 20831325 TI - Structural aspects in the dielectric properties of pentyl alcohols. AB - At temperatures between 0 and 60 degrees C densities, shear viscosities and dielectric spectra have been measured for isomers 1-pentanol, 2-pentanol, 3 pentanol, isopentylalcohol, and tert-pentanol, as well as for mixtures of these alcohols. The density and shear viscosity data are discussed in terms of deviations from ideal mixing behavior. The dielectric spectra are evaluated to yield the extrapolated static permittivity and the relaxation time of the principal (low-frequency) relaxation term. The former parameter is analyzed in view of dipole orientation correlations, the latter one is discussed in terms of the activation enthalpy controlling the relaxation process. A noticeable result is the effect of isomer structure on both the dipole orientation correlation and the dielectric relaxation. Especially the dielectric parameters of tert-pentanol deviate significantly from the relevant parameters of the other pentanols. Such deviations are considered in the light of models of hydrogen network structure and fluctuations. PMID- 20831326 TI - Molecular chemisorption on open metal sites in Cu(3)(benzenetricarboxylate)(2): A spatially periodic density functional theory study. AB - Chemical interactions of H(2)O, CO, NO, pyridine, C(2)H(2), H(2)S, and NH(3) with open metal sites in the metal-organic framework (MOF) Cu(3)(benzenetricarboxylate)(2) are examined using plane wave periodic density functional theory (DFT). In the case of single molecule adsorption on a Cu dimer, NH(3) and pyridine have the strongest binding, while NO binds weakly. Binding of pairs of molecules on a Cu dimer shows significant interaction energies, that is, the binding energy of the pair of molecules is not a simple summation of the binding energies of each molecule. The effect of molecular adsorption on the magnetic moments of Cu atoms in the MOF is also examined. Using the binding energies from DFT calculations, the effects of the pressure and temperature on the chemisorbed species are investigated. Finally the effect of water adsorption on the elastic behavior of Cu(3)(BTC)(2) is described. PMID- 20831327 TI - Shape of the Q band in the absorption spectra of porphyrin nanotubes: Vibronic coupling or exciton effects? AB - Absorption and linear dichroism spectra of self-assembled tubular aggregates of TPPS(4) porphyrin are studied theoretically with special emphasis on the low energy part of the spectra (the Q band region) where the coupling with intramolecular vibrations is pronounced. The model Hamiltonian includes both the excitonic coupling between four molecular electronic excited states contributing to the porphyrin Q and B bands as well as the intermediate-strength linear exciton-phonon coupling to one effective high-frequency molecular vibrational mode. Good agreement between the calculated and experimental spectra is obtained. The results allow us to identify the nature of the peaks observed in the Q band region of the aggregate's absorption spectrum; we show that the two most prominent peaks within the Q band originate from two different excitonic subbands. It is shown that the coupling between the Q and B bands plays an important role and the vibronic coupling affects the details of the absorption lineshape. PMID- 20831328 TI - Molecular simulations of structures and solvation free energies of passivated gold nanoparticles in supercritical CO(2). AB - The interfacial structures and solvation free energies of gold nanoparticles passivated by self-assembled monolayer (SAM) of fluorinated alkanethiols in supercritical CO(2) (scCO(2)) have been studied by using classical molecular dynamics simulation. A fragment-based free-energy perturbation approach was developed here, in which the solvation free energy of passivated metal nanoparticles was partitioned into the contributions from the inner metal core and the outer SAM. This is a first-time attempt to directly simulate the solvation free energy of nano-objects in supercritical fluids. The simulation result suggests that the nanoparticles can be thermodynamically soluble at lower scCO(2) density but insoluble at higher density. We have demonstrated that this density dependence of solvation free energy can be ascribed to the effect of the surface SAM in scCO(2). The presence of solvent molecules greatly affects the morphology of SAM on nanoparticle. It was observed that increasing the chain length in SAM makes nanoparticles more solvophilic at lower scCO(2) density or more solvophobic at higher density. This solvation thermodynamics behavior has been correlated with the specific solvation structure of scCO(2) around the passivated nanoparticles. PMID- 20831329 TI - Charge effect in S enhanced CO adsorption: A theoretical study of CO on Au, Ag, Cu, and Pd (111) surfaces coadsorbed with S, O, Cl, and Na. AB - The extraordinary sulfur enhanced CO adsorption on Au surface creates curiosity to many scientists in the field, and is expected to have potential applications in catalyst design. In this work, we have investigated the interactions of the coadsorption of CO and various adatoms X (X=Na, S, O, and Cl) on Au and Pd(111) surfaces and made further comparison with CO adsorption on charged Au and Pd surfaces by a first-principles study. We find out that the enhancement of CO adsorption by S on Au originates from S-induced positive polarization of Au surface. The d band of metal atoms in the positively polarized Au surface shifts up toward the Fermi level (E(F)) without remarkable changes of its shape and occupation. In contrast, in the negatively polarized Au(111) surface, achieved by electropositive adatom such as Na adsorption or artificially adding additional electrons to the substrate, d bands shift down relative to E(F), and thus CO adsorption is weakened. Further study of CO coadsorption with X on two other noble metal (Ag and Cu) surfaces manifests that Ag shows the same behavior as Au does, while the situation of Cu is just between that on Au and Pd. It suggests that the extraordinary S-induced enhancement of CO adsorption on Au/Ag, different from other transition metals (TMs), ultimately results from the inertness of d bands buried below E(F). The S-induced charge can introduce a significant d band shift on Au/Ag with respect to E(F) due to their narrow density of states at E(F) and thus strengthens CO adsorption subsequently. PMID- 20831330 TI - Cellular network formation of hydrophobic alkanethiol capped gold nanoparticles on mica surface mediated by water islands. AB - Dendritic and cellular networks of nanoparticles are known to form commonly either by random diffusion-limited aggregation or by solvent evaporation dynamics. Using alkanethiol capped gold nanoparticles deposited on mica imaged under ambient and controlled water vapor conditions by atomic force microscope and in situ scanning electron microscope, respectively, we show a third mechanism in action. The cellular network consisting of open and closed polygons is formed by the nucleation and lateral growth of adsorbed water islands, the contact lines of which push the randomly distributed hydrophobic nanoparticles along the growth directions, eventually leading to the polygonal structure formation as the boundaries of the growing islands meet. Such nanoparticle displacement has been possible due to the weakly adhering nature of the hydrophilic substrate, mica. These results demonstrate an important but hitherto neglected effect of adsorbed water in the structure formation on hydrophilic substrates and provide a facile tool for the fabrication of nanoparticle networks without specific particle or substrate modifications and without a tight control on particle deposition conditions during the solvent evaporation. PMID- 20831331 TI - Charge transfer between the Au(111) surface and adsorbed C(60): Resonant photoemission and new core-hole decay channels. AB - The interaction of C(60) with the Au(111) surface has been investigated using synchrotron radiation-based electron spectroscopy. Resonant photoelectron spectroscopy and autoionization spectroscopy have been used to probe the coupling between the molecule and the substrate. Three distinct high energy spectator Auger features were observed that are only evident for a monolayer of C(60) chemisorbed to the Au(111) surface and not a multilayer or the clean surface itself. Combined with C 1s x-ray absorption and valence band spectra, the data suggest a decay process not previously reported for this system. This is a spectator decay channel involving electrons transferred from the gold substrate to the adsorbed molecule, either in the ground state or during the timescale of the core-hole lifetime. Both possibilities are considered in the interpretation of the results, which support, on balance, a ground state charge transfer. PMID- 20831332 TI - General approach to polymer chains confined by interacting boundaries. AB - Polymer chains, confined to cavities or polymer layers with dimensions less than the chain radius of gyration, appear in many phenomena, such as gel chromatography, rubber elasticity, viscolelasticity of high molar mass polymer melts, the translocation of polymers through nanopores and nanotubes, polymer adsorption, etc. Thus, the description of how the constraints alter polymer thermodynamic properties is a recurrent theoretical problem. A realistic treatment requires the incorporation of impenetrable interacting (attractive or repulsive) boundaries, a process that introduces significant mathematical complications. The standard approach involves developing the generalized diffusion equation description of the interaction of flexible polymers with impenetrable confining surfaces into a discrete eigenfunction expansion, where the solutions are normally truncated at the first mode (the "ground state dominance" approximation). This approximation is mathematically well justified under conditions of strong confinement, i.e., a confinement length scale much smaller than the chain radius of gyration, but becomes unreliable when the polymers are confined to dimensions comparable to their typically nanoscale size. We extend a general approach to describe polymers under conditions of weak to moderate confinement and apply this semianalytic method specifically to determine the thermodynamics and static structure factor for a flexible polymer confined between impenetrable interacting parallel plate boundaries. The method is first illustrated by analyzing chain partitioning between a pore and a large external reservoir, a model system with application to chromatography. Improved agreement is found for the partition coefficients of a polymer chain in the pore geometry. An expression is derived for the structure factor S(k) in a slit geometry to assist in more accurately estimating chain dimensions from scattering measurements for thin polymer films. PMID- 20831333 TI - Correlation of mass fractal dimension and cluster size of silica in styrene butadiene rubber composites. AB - The morphology of the precipitated silica VN3 filled in styrene butadiene rubber was studied as a function of the volume fraction Phi by means of small-angle X ray scattering experiments. The wide q-range of 0.008 nm(-1)2 cans/week for >10 years. MATERIAL AND METHODS: A prospective, open, non-randomized intervention trial was undertaken including baseline oral examination and soft tissue biopsy, minor physical examination, brief cessation advice, NRT recommendations and five prospective follow-up visits within 12 months. Individual cessation counseling was given, together with oral examination in the dental office. Fifty snus users with a minimum consumption of 100 g/week who were actively seeking cessation treatment were recruited through advertising. Self-reported abstaining, including random-sample biochemical verification, and NRT use were evaluated at 6 weeks and 3, 6 and 12 months. RESULTS: At the 3-, 6- and 12-month visits, 58%, 46% and 30% of subjects, respectively were tobacco-abstinent. All nicotine abstinence was randomly controlled during the study except at 12 months, where all subjects claiming abstinence were confirmed biochemically and clinically. CONCLUSION: Smokeless tobacco cessation achieved together with suitable NRT seems a promising way to improve a persistent tobacco-free condition. PMID- 20831358 TI - Combination of high-fluoride toothpaste and no post-brushing water rinsing on enamel demineralization using an in-situ caries model with orthodontic bands. AB - OBJECTIVE: To compare the effects on enamel demineralization and fluoride (F) retention of two different brushing-rinsing regimens. MATERIAL AND METHODS: An in situ caries model with orthodontic bands was used for 8-9 weeks. A total of 20 orthodontic patients participated. They were randomized into two groups: (1) a test group using 5000 ppm F (n = 10) with no post-brushing water rinsing; and (2) a control group using 1450 ppm F (n = 10) with three sessions of post-brushing water rinsing. Orthodontic stainless-steel bands were applied to the two upper first premolars, leaving 2-3 mm of space away from the exposed buccal surface in order to accumulate plaque and provoke initial caries development. The teeth were extracted after 8 and 9 weeks, then analysed using quantitative light-induced fluorescence (QLF). Additionally, oral F retention was compared for the two groups. RESULTS: In comparison to the control group, the test regimen resulted in a non-significant smaller QLF lesion area and a significantly lower average QLF loss of fluorescence (P < 0.05). The highest F retention concentration under the band was found in the test group (P < 0.001). CONCLUSIONS: The combination of using a 5000 ppm F toothpaste and no post-brushing water rinsing had a greater anti-caries potential and resulted in elevated oral F retention compared to a 1450 ppm F toothpaste with three sessions of post-brushing water rinsing. PMID- 20831359 TI - Comparison between 3 infusion methods to measure cerebrospinal fluid outflow conductance. AB - OBJECT: There are several infusion methods available to estimate the outflow conductance (Cout) or outflow resistance (Rout=1/Cout) of the CSF system. It has been stated that for unknown reasons, the bolus infusion method estimates a higher C(out) than steady-state infusion methods. The aim of this study was to compare different infusion methods for estimation of Cout. METHODS: The following 3 different infusion methods were used: the bolus infusion method (Cout bol); the constant flow infusion method, both static (Cout stat) and dynamic (Cout dyn) analyses; and the constant pressure infusion method (Cout cpi). Repeated investigations were performed on an experimental model with well-known characteristics, with and without physiological pressure variations (B-waves, breathing, and so on). All 3 methods were also performed in a randomized order during the same investigation in 20 patients with probable or possible idiopathic normal-pressure hydrocephalus; 6 of these patients had a shunt and 14 did not. RESULTS: Without the presence of physiological pressure variations, the concordance in the experimental model was good between all methods. When they were added, the repeatability was better for the steady-state methods and a significantly higher Cout was found with the bolus method in the region of clinically relevant Cout (p<0.05). The visual fit for the bolus infusion was dependent on subjective assessment by the operator. This experimental finding was confirmed by the clinical results, where significant differences were found in the investigations in patients without shunts between Cout of the visual bolus method and Cout stat, Cout dyn, and Cout cpi (4.58, 4.18, and 6.12 MUl/[second*kPa], respectively). CONCLUSIONS: This study emphasized the necessity for standardization of Cout measurements. An experienced operator could partly compensate for difficulties in correctly estimating the pressure parameters for the bolus infusion method, but for the general user this study suggests a steady state method for estimating Cout. PMID- 20831360 TI - Temporal lobe epilepsy surgery failures: predictors of seizure recurrence, yield of reevaluation, and outcome following reoperation. AB - OBJECT: The authors provide a systematic analysis of electroclinical characteristics in patients with persistent seizures following temporal lobe epilepsy (TLE) surgery and identify ideal candidates for reoperation. METHODS: The authors retrospectively reviewed the records of 68 adult patients (mean follow-up 8.7 years) who underwent a video electroencephalography evaluation and high-resolution imaging after failed TLE surgery performed between 1990 and 2004 at The Cleveland Clinic. Multivariate logistic regression analyses were performed to identify predictors of the yield of a repeat evaluation, location of the recurrence focus, and outcome following reoperation. RESULTS: Although a focus of recurrence was identified in 44 patients, only 15 underwent reoperation, and only 6 of these became seizure free. Localized foci of recurrence were successfully identified in patients with early (within 1 postoperative year) and frequent (>=4 per month) recurrent seizures (yield of 100% if both conditions were fulfilled). Predictors of contiguity of the focus of recurrence to the initial surgical bed were variable depending on the type of the initial surgery: patients with baseline contralateral temporal spiking were 6 times (OR 6.34, p<0.05) more likely to experience seizure recurrence from the contralateral temporal lobe after a "standard" temporal lobectomy, while the need to use subdural electrodes and the timing of recurrence were more significant following limited temporal resections. The focus of recurrence was distant to the original surgical bed when subdural electrodes were used prior to first surgery (OR 28.0, p=0.01) or when seizures recurred early (within <6 postoperative months; OR 12.5, p=0.04). With reoperation, only patients with mesial and basal extension of the temporal resections became seizure free. Interestingly, seizure freedom was achieved with medical therapy alone in 42% of patients with a nonidentifiable recurrence focus as opposed to 4% of those with an unoperated identifiable focus. CONCLUSIONS: The timing and frequency of recurrent seizures following unsuccessful TLE surgery provide useful guidelines for the yield of a surgical reevaluation, and potentially for the mechanisms of surgical failure. PMID- 20831361 TI - Guanfacine extended-release for attention-deficit/hyperactivity disorder (ADHD). AB - IMPORTANCE OF THE FIELD: Guanfacine extended-release (GXR) is a non-stimulant approved in the US for treatment of attention deficit/hyperactivity disorder (ADHD). GXR is a 'first in class' alpha(2A)-adrenoceptor agonist reformulated to optimize efficacy. GXR enters a rapidly growing but crowded ADHD market as an alternative not only to psychostimulants but also to atomoxetine. AREAS COVERED IN THIS REVIEW: Pharmacodynamics, pharmacokinetics, clinical efficacy and safety of GXR are covered based on a literature review (MEDLINE and EMBASE) from 1980 to 2010. Two large pivotal controlled trials are reviewed along with companion safety studies over 24 months. Collateral studies in ADHD children with oppositional symptoms and combination use of GXR in psychostimulant partial responders are featured. WHAT THE READER WILL GAIN: Novel aspects of apparent GXR mechanism of action may complement existing treatments. Study evidence indicates that GXR is a well-tolerated and effective treatment for children and adolescents with ADHD, and appears efficacious to reduce oppositional symptoms in children with these complicating features. The GXR safety database reflects mild and asymptomatic decreases in both blood pressure and heart rate throughout, with most adverse events being somnolence-related and time-limited. TAKE HOME MESSAGE: This review of GXR will allow the reader to determine the place for GXR in the ADHD treatment landscape. PMID- 20831362 TI - Update on lymphocyte specific kinase inhibitors: a patent survey. AB - IMPORTANCE OF THE FIELD: Lck (p56(lck) or lymphocyte specific kinase) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and natural killer (NK) cells. Genetic evidence from knockout mice and human mutations demonstrates that Lck kinase activity is critical for T cell receptor (TCR) mediated signaling, leading to normal T-cell development and activation. Selective inhibition of Lck is expected to offer a new therapy for the treatment of T-cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. AREAS COVERED IN THIS REVIEW: This review covers the patents, patent applications and associated publications for small molecule kinase inhibitors of Lck since 2005 and attempts to place them in context from a structural point of view. WHAT THE READER WILL GAIN: Readers will gain an overview of the structural classes and binding modes of Lck inhibitors, the major players in this area and an insight into the current state of the field. TAKE HOME MESSAGE: The search for a potent and orally active inhibitor of Lck has been an intense area of research for a number of years. Despite tremendous efforts, the identification of a highly selective and potent Lck inhibitor suitable for use as an immunosuppressive agent remains elusive. PMID- 20831363 TI - Bruton's tyrosine kinase as a molecular target in treatment of leukemias and lymphomas as well as inflammatory disorders and autoimmunity. AB - IMPORTANCE OF THE FIELD: Bruton's tyrosine kinase (BTK) has emerged as a new anti apoptotic molecular target for the treatment of B-lineage leukemias and lymphomas. Preclinical and early clinical results indicate that BTK inhibitors may be useful in the treatment of leukemias and lymphomas. BTK inhibitors may also be helpful in prevention and treatment of thromboembolic complications as well as inflammatory disorders. AREAS COVERED IN THIS REVIEW: We provide a comprehensive review of the target diseases for which the use of BTK inhibitors may be helpful as well as the activity profiles of BTK inhibitors. WHAT THE READER WILL GAIN: We review the currently available translational research, biomarker as well as patent literature regarding BTK molecular target and BTK inhibitors. TAKE HOME MESSAGE: BTK inhibitors may provide the foundation for therapeutic innovation against B-lineage leukemias/lymphomas, inflammatory disorders and autoimmunity. PMID- 20831364 TI - Probing the role of point mutations in the cyp51A gene from Aspergillus fumigatus in the model yeast Saccharomyces cerevisiae. AB - Azole-resistant strains of Aspergillus fumigatus have been detected and the underlying molecular mechanisms of resistance characterized. Point mutations in the cyp51A gene have been proved to be related to azole resistance in A. fumigatus clinical strains and with different resistance profiles depending on the amino acid change (G54E, G54V, G54R, G54W, M220V, M220K, M220T, M220I). The aim of this work was to express A. fumigatus cyp51A genes in the yeast Saccharomyces cerevisiae in order to better assess the contribution of each independent amino acid substitution to resistance. A tetracycline regulatable system allowing repression of the endogenous essential ERG11 gene was used. The expression of Aspergillus cyp51A alleles could efficiently restore the absence of ERG11 in S. cerevisiae. In general, S. cerevisiae clones expressing. A. fumigatus cyp51A alleles from azole-resistant isolates showed higher MICs to all azoles tested than those expressing alleles from susceptible isolates. The azole susceptibility profiles obtained in S. cerevisiae upon expression of specific cyp51A alleles recapitulated susceptibility profiles observed from their A. fumigatus origins. In conclusion this work supports the concept that characteristics of specific A. fumigatus cyp51A alleles could be investigated in the heterologous host S. cerevisiae. PMID- 20831365 TI - Intracavitary voriconazole for the treatment of hemoptysis complicating Pseudallescheria angusta pulmonary mycetomas in fibrocystic sarcoidosis. AB - Pulmonary mycetomas often occur in fibrocystic sarcoidosis. When this condition is complicated by hemoptysis, definitive surgery is usually precluded because of poor lung function. Intracavitary antifungal therapy has been described for the treatment of symptomatic pulmonary mycetomas. We report the first use of intracavitary voriconazole in the management of a Pseudallescheria angusta pulmonary mycetoma complicated by hemoptysis in a patient with fibrocystic sarcoidosis and renal transplant. PMID- 20831366 TI - Dual tasking and stuttering: from the laboratory to the clinic. AB - PURPOSE: The aim of the three studies in this article was to develop a way to include dual tasking in speech restructuring treatment for persons who stutter (PWS). It is thought that this may help clients maintain the benefits of treatment in the real world, where attentional resources are frequently diverted away from controlling fluency by the demands of other tasks. METHOD: In Part 1, 17 PWS performed a story-telling task and a computer semantic task simultaneously. Part 2 reports the incorporation of the Part 1 protocol into a handy device for use in a clinical setting (the Dual Task and Stuttering Device, DAS-D). Part 3 is a proof of concept study in which three PWS reported on their experiences of using the device during treatment. RESULTS: In Part 1, stuttering frequency and errors on the computer task both increased under dual task conditions, indicating that the protocol would be appropriate for use in a clinical setting. All three participants in Part 3 reported positively on their experiences using the DAS-D. CONCLUSIONS: Dual tasking during treatment using the DAS-D appears to be a viable clinical procedure. Further research is required to establish effectiveness. PMID- 20831367 TI - Safety of oscillating-rotating powered brushes compared to manual toothbrushes: a systematic review. AB - BACKGROUND: Oscillating-rotating power toothbrushes have been proven clinically efficacious. To our knowledge, a comprehensive review of all clinical and laboratory investigations solely comparing the safety of these toothbrushes to the standard of care (i.e., manual toothbrushes) has not been published. The aim of this systematic review is to examine the literature concerning the relative soft and/or hard tissue safety outcomes with the use of oscillating-rotating toothbrushes compared to manual toothbrushes. METHODS: With the use of electronic databases of the National Library of Medicine (PubMed-MEDLINE), the Cochrane Central Register of Controlled Trials (Cochrane-CENTRAL), and the Excerpta Medical Database (EMBASE), a search of in vivo and in vitro trials through May 2010 was conducted to identify appropriate studies that evaluated the effects of an oscillating-rotating power toothbrush compared to a manual toothbrush with respect to soft and/or hard tissue safety. Eligible trials incorporated a safety evaluation as a primary or secondary outcome parameter (i.e., gingival recession, observed/reported adverse events, and hard tissue effects) or used a surrogate parameter (i.e., stained gingival abrasion and brushing force) to assess safety. Data extraction for the primary- and surrogate-measure safety studies, which included mean values and SDs when available, and a meta-analysis of the gingival recession data were performed. RESULTS: Independent screening of the titles and abstracts of 697 PubMed-MEDLINE, 436 Cochrane-CENTRAL, and 664 EMBASE papers resulted in 35 publications that met the eligibility criteria. The mean change in gingival recession was not significantly different among toothbrush groups in the two selected trials with safety as a primary outcome (weighted mean difference: 0.03). A meta-analysis of the five trials that evaluated safety with a surrogate parameter was not possible; however, there were no significant between-group differences at the study end in any trial. A descriptive analysis of the 24 selected studies assessing safety as a secondary outcome revealed few brushing related adverse events. The heterogeneity in objectives and methodology of the four in vitro trials that met the eligibility criteria precluded generalization of the results. CONCLUSION: A large body of published research in the preceding 2 decades has consistently shown oscillating-rotating toothbrushes to be safe compared to manual toothbrushes, demonstrating that these power toothbrushes do not pose a clinically relevant concern to hard or soft tissues. PMID- 20831368 TI - Locally delivered doxycycline as an adjunct to mechanical debridement at retreatment of periodontal pockets: outcome at furcation sites. AB - BACKGROUND: The goal was to evaluate the clinical outcome of non-surgical retreatment at molar furcation sites by ultrasonic debridement with or without adjunctive application of locally delivered doxycycline, and to explore factors affecting the healing results. METHODS: This study involves 32 patients with chronic periodontitis, who received initial pocket/root debridement by ultrasonic instrumentation, followed by random assignment to retreatment of remaining pathologic sites at 3 months by ultrasonic instrumentation with or without adjunctive local application of an 8.8% doxycycline gel. Clinical examinations of plaque, probing depth (PD), relative attachment level, furcation involvement, and bleeding after furcation probing were performed initially, before retreatment at 3 months (baseline), and 3 and 9 months after retreatment. The primary efficacy variable was reduction in the degree of furcation involvement. A multilevel logistic model was used to evaluate the impact of patient and tooth site related factors on the main outcome variable. RESULTS: The retreatment including locally delivered doxycycline resulted in closure of 50% of degree I furcation sites, compared to 29% for sites treated with mechanical debridement only (P >0.05). Of the degree II furcation sites, 17% in the test and 11% in the control group were reduced in depth (P >0.05). The logistic multilevel model with "furcation improvement" as the dichotomous outcome variable revealed that local application of doxycycline had no statistically significant effect. The odds ratio for ?furcation improvement? was 0.80 (95% confidence interval [CI], 0.65 to 0.99) for 1-mm increase of initial vertical PD, 0.36 (95% CI, 0.17 to 0.80) for initial furcation involvement degree II compared to degree I, and 0.24 (95% CI, 0.08 to 0.72) for smokers compared to non-smokers. CONCLUSION: Improvement in molar furcation involvement after non-surgical periodontal therapy was not enhanced by adjunctive locally applied doxycycline and negatively affected by increased vertical PD and tobacco smoking. PMID- 20831369 TI - Arginine-nitric oxide-polyamine metabolism in periodontal disease. AB - BACKGROUND: Arginine is converted to nitric oxide (NO) via NO synthase and to ornithine via arginase. Ornithine decarboxylase (ODC) catalyzes the conversion of ornithine to polyamines. Arginase can inhibit NO production, and NO can inhibit ODC activity as part of an early inflammatory response. This study examines the arginine-NO-polyamine pathway alteration in saliva and gingival biopsy samples of patients with gingivitis or periodontitis and healthy controls and evaluates the response to periodontal treatment. METHODS: This study includes nine gingivitis patients, 15 chronic periodontitis patients, and 11 healthy age-matched controls. Periodontal clinical measurements, gingival biopsies, and saliva samples were obtained before treatment (BT) and 1 month after periodontal treatment (AT). Arginase and ODC activities and NO levels were determined spectrophotometrically. RESULTS: The BT salivary and gingival NO levels were found to be highest in the gingivitis group, followed by the healthy and the periodontitis groups, respectively. Salivary NO levels significantly increased in the periodontitis group and decreased in the gingivitis group AT (P <0.05). Gingival NO levels decreased significantly in the periodontitis and the gingivitis groups AT (P <0.05). Arginase levels were detected highest in the gingivitis group and lowest in the periodontitis group, both in saliva and gingiva. Only gingival arginase levels significantly increased AT (P <0.05). ODC activity was highest in saliva, and lowest in the gingiva of the periodontitis patients BT. It was found to be significantly higher in the periodontitis group AT (P <0.05). CONCLUSIONS: In this study, regarding arginine-NO-polyamine metabolism, gingival tissue seems to be more informative about periodontal pathogenesis than saliva. At early phase of periodontal inflammation, NO arginase and ODC levels were measured as higher than at an established lesion of periodontitis. PMID- 20831370 TI - Periodontal status and neutrophilic enzyme levels in gingival crevicular fluid during pregnancy and postpartum. AB - BACKGROUND: Pregnancy induces or enhances susceptibility to gingivitis; however, the presence and role of neutrophilic enzymes in pregnancy-related gingivitis are not well known. The present study demonstrates the relationship between neutrophilic enzymes in gingival crevicular fluid (GCF) and periodontal status during pregnancy and postpartum. METHODS: At baseline, 30 periodontally healthy pregnant women (Pr group) and 24 non-pregnant women (N-Pr group) as their controls participated in the study. The Pr group was examined once per each trimester and twice during postpartum and the N-Pr group three times (on successive months). During each visit, GCF samples were collected from all first molars, and clinical measurements (visible plaque index, bleeding on probing [BOP], probing depth [PD], and clinical attachment level) were recorded. The samples were analyzed for matrix metalloproteinase (MMP)-8, polymorphonuclear neutrophil (PMN) elastase, myeloperoxidase (MPO), and tissue inhibitor of matrix metalloproteinase (TIMP)-1. Their levels were compared to the periodontal status at the collection site. RESULTS: In the Pr group, BOP and PD scores significantly increased between the first and second trimester, indicating pregnancy gingivitis. This increased inflammation was not reflected by the enzymes examined in GCF; the amounts of PMN elastase decreased continuously during the follow-up period, and those of MPO and MMP-8 did not increase until delivery, whereas TIMP 1 amounts remained stable throughout the follow-up period. In the N-Pr group, all parameters remained steady. CONCLUSION: Despite an increased susceptibility to gingivitis during mid-pregnancy, the host response does not seem to activate its own degradative enzymes. PMID- 20831371 TI - Stability of contour augmentation and esthetic outcomes of implant-supported single crowns in the esthetic zone: 3-year results of a prospective study with early implant placement postextraction. AB - BACKGROUND: Early implant placement is one of the treatment options after tooth extraction. Implant surgery is performed after a healing period of 4 to 8 weeks and combined with a simultaneous contour augmentation using the guided bone regeneration technique to rebuild stable esthetic facial hard- and soft-tissue contours. METHODS: In this prospective study, 20 patients were treated with an implant-born single crown and followed for 3 years. Clinical, radiologic, and esthetic parameters were recorded to assess treatment outcomes. RESULTS: At the 3 year examination, all 20 implants were successfully integrated, demonstrating ankylotic stability and healthy peri-implant soft tissues as documented by standard clinical parameters. Esthetic outcomes were assessed by the pink esthetic score (PES) and white esthetic score (WES) and confirmed pleasing results overall. WES values were slightly superior to PES values. Periapical radiographs showed minimal crestal bone loss around used bone-level implants with a mean bone loss of 0.18 mm at 3 years. Only two implants revealed bone loss between 0.5 and 1.0 mm. One of these implants had minor mucosal recession <1.0 mm. CONCLUSIONS: This prospective study evaluates the concept of early implant placement and demonstrated successful tissue integration for all 20 implants and stable bone-crest levels around implant-abutment interfaces according to the platform-switching concept. The midterm 3-year follow-up revealed pleasing esthetic outcomes and stable facial soft tissues. The risk of mucosal recession was low, with only one patient showing minor recession of the facial mucosa. These encouraging results need to be confirmed with a 5-year follow-up examination. PMID- 20831372 TI - Survival rate for implants placed in the posterior maxilla with and without sinus augmentation: a comparative cohort study. AB - BACKGROUND: The reduced bone height and proximity of the maxillary sinus are the most common limitations for placement of dental implants in the posterior maxilla. Reconstruction of the atrophic posterior maxilla can be performed with a sinus augmentation procedure. The aim of this cohort study is to compare the survival rate of implants placed in augmented sinus to implants placed in native bone in the posterior maxilla. METHODS: This study was designed as a prospective cohort study and included consecutively treated patients. Patients who required the sinus augmentation (test group) were treated according to the two-stage technique. Patients were scheduled for follow-up evaluation at 3, 6, and 12 months after implant placement and then every 6 months for <= 6 years. RESULTS: One hundred and five patients with 393 implants were enrolled in the study. Two hundred and one implants were placed after preliminary sinus floor grafting in 41 patients. The control group contained 64 patients with 192 implants that were placed in pristine bone of the posterior maxilla. The cumulative implant survival rates were 86.1% and 96.4%, respectively. The difference between the two groups was highly significant (P <0.005). CONCLUSIONS: These findings show that implants placed in augmented sinuses had a lower survival rate compared to implants placed in pristine bone. All the implant failures in the augmented sinuses occurred before the prosthetic rehabilitation. Moreover, it should be considered that most of the failures were observed in few patients, thus suggesting cluster behavior. PMID- 20831373 TI - Knowledge about the association between periodontal diseases and diabetes mellitus: contrasting dentists and physicians. AB - BACKGROUND: There is a strong body of evidence that supports the relationship between periodontal diseases and diabetes mellitus (DM). Many patients are unaware of the effects of diabetes on oral health. Whether health care providers are applying the information about the link between DM and periodontal diseases in their practices depends on the levels of their knowledge of such valuable information. Therefore, the aims of this study are to evaluate the knowledge of dental and medical practitioners concerning the effects of diabetes on periodontal health and to find out if the practitioners are aware of the bidirectional relationship between periodontal diseases and DM. METHODS: This was a cross-sectional survey of randomly selected general practitioners practicing in Kuwait. Participants were asked about specific periodontal complications that they believed patients diagnosed with diabetes were more susceptible to, and their awareness of the bidirectional relationship between diabetes and periodontal diseases was evaluated. RESULTS: A total of 510 general practitioners (232 physicians and 278 dentists) participated in the study. There were no significant differences between the two groups regarding mean ages, sex distributions, and years in practice. Only 50% of all study participants believed that patients with diabetes were more susceptible to tooth loss because of periodontal diseases than were individuals without diabetes. Dentists were significantly more aware of gingival bleeding, tooth mobility, and alveolar bone resorption than were physicians. Factors significantly associated with having knowledge about the effects of diabetes on periodontal health in logistic regression analyses were older age, female sex, and the dental profession. CONCLUSION: The knowledge about the association between periodontal diseases and DM should be increased among dental and medical practitioners to effectively prevent, manage, and control diabetes and periodontal diseases. PMID- 20831374 TI - Elevated plasma homocysteine levels in chronic periodontitis: a hospital-based case-control study. AB - BACKGROUND: Plasma homocysteine (Hcy), a novel risk factor for cardiovascular disease, has been found to be increased in inflammatory diseases, such as rheumatoid arthritis. Our study investigates the association between chronic periodontitis and plasma Hcy. METHODS: This case-control study involves 85 age- and sex-matched subjects with chronic periodontitis and 91 healthy controls. Patients were grouped into moderate and severe periodontitis. Plaque index, calculus component of simplified oral hygiene index, and modified gingival index were recorded. Body mass index, fasting blood sugar, total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very-low density lipoprotein, and plasma Hcy were also assessed. RESULTS: Case and control groups had similar levels of fasting blood sugar, lipid profile, and body mass index. The mean plasma Hcy was found to be 19.22 +/- 8.27 and 10.27 +/- 2.50 MUmol/L for cases and controls, respectively. A significant elevation in plasma Hcy levels was observed in cases (P <0.05). No significant differences were observed in plasma Hcy levels between moderate and severe chronic periodontitis (P = 0.722). CONCLUSIONS: Elevated levels of plasma Hcy were observed in patients with chronic periodontitis. Future research should be directed on the effect of periodontal therapy on plasma Hcy levels. PMID- 20831375 TI - The impact of stroke-related dysarthria on social participation and implications for rehabilitation. AB - INTRODUCTION: Each year an estimated 30,000-45,000 UK individuals experience stroke-related dysarthria (impairment of movements required to produce speech). Many will experience persistent dysarthria long after discharge from stroke services. Although we have some insight into the impact of other communication impairments, we have very limited information on the impact of dysarthria on social participation. PURPOSE: To explore the impact of dysarthria on social participation following stroke. METHODS: We report data from in-depth semi structured interviews with 24 individuals with stroke-related dysarthria. RESULTS: Our findings suggest a complex association between the severity of an individual's dysarthria and the impact on their social participation. Participants' descriptions highlighted their experiences of social participation and isolation. We further suggest that, in some cases, the coping strategies adopted by the participants could be seen to further exacerbate this isolation. These results have important implications for the prioritisation, planning and delivery of therapeutic interventions for people with dysarthria. CONCLUSIONS: The impact of stroke-related dysarthria transcends the physiological impairment to impact upon individuals' social participation, which is key to the process of rehabilitation. The development and evaluation of the effectiveness of an intervention that addresses these impacts is the next challenge for therapists and researchers working in this area. PMID- 20831376 TI - Frequency of consonant articulation errors in dysarthric speech. AB - This paper analyses consonant articulation errors in dysarthric speech produced by seven American-English native speakers with cerebral palsy. Twenty-three consonant phonemes were transcribed with diacritics as necessary in order to represent non-phoneme misarticulations. Error frequencies were examined with respect to six variables: articulatory complexity, place of articulation, and manner of articulation of the target phoneme; and change in articulatory complexity, place, and manner resulting from the misarticulation. Results showed that target phonemes with high articulatory complexity were most often misarticulated, independent of intelligibility, but low-intelligibility speakers reduced the complexity of target consonants more frequently. All speakers tended to misarticulate to the adjacent place of the target place, but this pattern was most prominent for high-intelligibility speakers. Low- and mid-intelligibility speakers produced more manner errors than high-intelligibility speakers. Based on these results, a two-part model of consonant articulation errors is proposed for CP-associated spastic dysarthia. PMID- 20831377 TI - Typical acquisition by atypical children: Initial consonant cluster acquisition by Israeli Hebrew-acquiring children with cochlear implants. AB - This paper studies the developmental stages of word initial consonant clusters (CCs) in the speech of six monolingual Israeli Hebrew (IH) acquiring hearing impaired children using cochlear implant (CI). Focusing on the patterns of cluster reduction, this study compares the CI children with typically-developing hearing children. All the CI children, three boys and three girls with age ranged from 1;5-2;8 years at their first recording session, were with pre-lingual hearing impairment with bilateral sensorineural hearing loss. Productions of word initial CCs were elicited in an isolated-word picture-naming task combined with spontaneously produced words. Data collection started 2-4 months after implantation and continued until the correct production of word initial biconsonantal clusters. Results reveal that both the developmental stages and reduction patterns of word initial CCs of the CI children are very similar to typically-developing IH acquiring children, thus supporting earlier studies which show that children with CIs follow the same stages of acquisition as hearing children. PMID- 20831378 TI - Extensions to the Speech Disorders Classification System (SDCS). AB - This report describes three extensions to a classification system for paediatric speech sound disorders termed the Speech Disorders Classification System (SDCS). Part I describes a classification extension to the SDCS to differentiate motor speech disorders from speech delay and to differentiate among three sub-types of motor speech disorders. Part II describes the Madison Speech Assessment Protocol (MSAP), an ~ 2-hour battery of 25 measures that includes 15 speech tests and tasks. Part III describes the Competence, Precision, and Stability Analytics (CPSA) framework, a current set of ~ 90 perceptual- and acoustic-based indices of speech, prosody, and voice used to quantify and classify sub-types of Speech Sound Disorders (SSD). A companion paper provides reliability estimates for the perceptual and acoustic data reduction methods used in the SDCS. The agreement estimates in the companion paper support the reliability of SDCS methods and illustrate the complementary roles of perceptual and acoustic methods in diagnostic analyses of SSD of unknown origin. Examples of research using the extensions to the SDCS described in the present report include diagnostic findings for a sample of youth with motor speech disorders associated with galactosemia, and a test of the hypothesis of apraxia of speech in a group of children with autism spectrum disorders. All SDCS methods and reference databases running in the PEPPER (Programs to Examine Phonetic and Phonologic Evaluation Records) environment will be disseminated without cost when complete. PMID- 20831379 TI - Perceptual and acoustic reliability estimates for the Speech Disorders Classification System (SDCS). AB - A companion paper describes three extensions to a classification system for paediatric speech sound disorders termed the Speech Disorders Classification System (SDCS). The SDCS uses perceptual and acoustic data reduction methods to obtain information on a speaker's speech, prosody, and voice. The present paper provides reliability estimates for the two perceptual methods (narrow phonetic transcription; prosody-voice coding) and the acoustic analysis methods the SDCS uses to describe and classify a speaker's speech competence, precision, and stability. Speech samples from 10 speakers, five with significant motor speech disorder and five with typical speech, were re-measured to estimate intra-judge and inter-judge agreement for the perceptual and acoustic methods. Each of the speakers completed five speech tasks (total = 50 datasets), ranging in articulatory difficulty for the speakers, with consequences for the difficulty level of data reduction. Point-to-point percentage of agreement findings for the two perceptual methods were as high or higher than reported in literature reviews and from previous studies conducted within the laboratory. Percentage of agreement findings for the acoustics tasks of segmenting phonemes, editing fundamental frequency tracks, and estimating formants ranged from values in the mid 70% to 100%, with most estimates in the mid 80% to mid 90% range. Findings are interpreted as support for the perceptual and acoustic methods used in the SDCS to describe and classify speakers with speech sound disorders. PMID- 20831380 TI - Echolalia or functional repetition in conversation--a case study of an individual with Huntington's disease. AB - PURPOSE: In this case study, we investigated the use of repetition in an individual with a neurogenic communication disorder. METHOD: We present an analysis of interaction in natural conversations between a woman with advanced Huntington's disease (HD), whose speech had been described as sometimes characterised by echolalia, and her personal assistant. The conversational interaction is analysed on a sequential level, and recurrent patterns are explored. RESULTS: Although the ability of the person with HD to interact is affected by chorea, word retrieval problems and reduced comprehension, she takes an active part in conversation. The conversational partner's contributions are often adapted to her communicative ability as they are formulated as questions or suggestions that can be elaborated on or responded to with a simple 'yes' or 'no'. The person with HD often repeats the words of her conversational partner in a way that extends her contributions and shows listenership, and this use of repetition is also frequent in ordinary conversations between non-brain-damaged individuals. CONCLUSIONS: The results show that the conversation partners in this case cooperate in making the conversation proceed and evolve, and that verbal repetition is used in a way that works as a strategy for compensating for the impairment. PMID- 20831383 TI - The membrane protein of severe acute respiratory syndrome coronavirus acts as a dominant immunogen revealed by a clustering region of novel functionally and structurally defined cytotoxic T-lymphocyte epitopes. AB - BACKGROUND: Severe acute respiratory syndrome coronavirus (SARS-CoV), which emerged with highly contagious and life-threatening characteristics in 2002, remains a potential risk for future outbreaks. Membrane (M) and envelope (E) proteins are major structural proteins of the SARS-CoV. The M protein has been determined as a protective antigen in humoral responses. However, its potential roles in stimulating cellular immunity remain elusive. METHODS: In this study, a panel of peptides derived from M and E proteins were tested by in vitro refolding, T2 cell-binding assays, and responses stimulated by cytotoxic T lymphocyte (CTL) epitopes in HLA-A2.1/K(b) transgenic mice and human peripheral blood mononuclear cells (PBMCs). RESULTS: A nonameric epitope Mn2 and a decameric epitope Md3 derived from the M protein were identified and used for the evaluation of M protein-specific immunity. Responses stimulated by M protein specific CTL epitopes have been found in the PBMCs of donors who had recovered from SARS infection. Additionally, the transmembrane domain of the M protein may contain a T cell epitope cluster revealed by the immunogenic and structural analysis of a panel of truncated peptides overlapping with Mn2 and Md3. CONCLUSIONS: The M protein of SARS-CoV holds dominant cellular immunogenicity. This, together with previous reports of a strong humoral response against the M protein, may help to further explain the immunogenicity of SARS and serves as potential targets for SARS-CoV vaccine design. PMID- 20831384 TI - Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. AB - BACKGROUND: Influenza A(H5N1) continues to cause infections and possesses pandemic potential. METHODS: Data sources were primarily clinical records, published case series, and governmental agency reports. Cox proportional hazards regression was used to estimate the effect of treatment on survival, with adjustment using propensity scores (a composite measure of baseline variables predicting use of treatment). RESULTS: In total, 308 cases were identified from 12 countries: 41 from Azerbaijan, Hong Kong SAR, Nigeria, Pakistan, and Turkey (from clinical records); 175 from Egypt and Indonesia (from various sources); and 92 from Bangladesh, Cambodia, China, Thailand, and Vietnam (from various publications). Overall crude survival was 43.5%; 60% of patients who received >=1 dose of oseltamivir alone (OS(+)) survived versus 24% of patients who had no evidence of anti-influenza antiviral treatment (OS(-)) (P <.001). Survival rates of OS(+) groups were significantly higher than those of OS(-) groups; benefit persisted with oseltamivir treatment initiation = 30 kg/m2) and nonobese women; p < 0.05 was considered significant. RESULTS: Of 357 women, 172 (48.2%) were obese, and 185 (51.8%) were not. Among the baseline characteristics, only race was statistically different between the groups. There were more African American women among the obese women (82.5% vs. 70%, p < 0.05). Postoperative complications, including urinary tract injury, were not significantly increased in the obese group. On the contrary, nonobese women had a significantly higher incidence of ileus (13.5% vs. 6.4%, p < 0.05). Although operative time was significantly prolonged for obese women, obesity did not increase the length of hospitalization, transfusion rate, and perioperative hemoglobin change. All these results remained the same even after controlling for race. CONCLUSIONS: Contrary to the general opinion, obesity does not significantly affect the perioperative outcomes for TAH performed for benign gynecological causes. PMID- 20831428 TI - Follow-up care among HIV-infected pregnant women in Mississippi. AB - BACKGROUND: Data from the Centers for Disease Control and Prevention (CDC) indicate that reproductive-age black women in the Southeast are disproportionately affected by the HIV epidemic. There are few data describing HIV infection, pregnancies, and follow-up care in this population. METHODS: A retrospective chart review was performed at the Perinatal HIV Service at the University of Mississippi Medical Center in Jackson, Mississippi, to identify HIV infected women >= 18 years of age with deliveries from 1999 to 2006. Optimal follow-up was defined as at least two follow-up visits with an HIV provider within 1 year of delivery. Univariate and multivariate logistic regression analyses were used to identify factors associated with optimal adherence. RESULTS: We identified 274 women with 297 total deliveries. Median age was 25, and 89% were black. Only 37% of women had two or more visits with an HIV provider in the postpartum year. On univariate analysis, presentation before the third trimester was associated with optimal follow-up (p = 0.04). On multivariate analyses, presentation before the third trimester was the only variable associated with optimal follow-up (odds ratio [OR] 2.1, p = 0.02). CONCLUSIONS: The poor follow-up rates in this growing population highlight the critical need for research and development of targeted interventions to improve rates of retention in care, particularly in women with late trimester presentation. PMID- 20831429 TI - Patient gender differences in the prediction of medical expenditures. AB - AIMS: The prediction of individuals' use of medical services and associated costs is crucial for medical systems. We modeled a risk assessment equation that included patient sociodemographic characteristics and health risk behaviors (obesity, smoking, and alcohol abuse) to strengthen the power of self-reported health status to predict healthcare resource use. We also sought to uncover gender-specific differences in the predictive value of the models. METHODS: Before their first primary care visit, 509 new patients were interviewed. Data collected included sociodemographics, self-reported health status Medical Outcomes Study Short-Form (MOS SF-36), body mass index (BMI), and screening for alcoholism and smoking. Subsequent use of healthcare services for 1 year was determined by reviewing medical and billing records. RESULTS: Generalized linear models and two-part regressions were estimated relating the five types of charges (plus total charges) to self-reported physical health status, controlling for gender, age, education, income, obesity, smoking, alcohol abuse, and mental health status. Lower physical health status was associated with higher charges for primary care (p = 0.0022), specialty care (p = 0.0141), diagnostic services (p < 0.0001), hospitalizations (p = 0.0069), and total charges (p < 0.0001). For female patients, the regression equation predicted 14% of the variation in total medical charges compared with 28% for males. Female patients had higher charges for primary care (p = 0.0019), diagnostic services (p = 0.0005), and total charges (p = 0.0180). CONCLUSIONS: Health status and patient gender were significant predictors of healthcare use and charges. The R2 of total charges was two times higher for men vs. women. This research has policy implications for healthcare organizations in predicting the usage patterns. PMID- 20831430 TI - Differences in editorial board reviewer behavior based on gender. AB - BACKGROUND: Reports indicate that there are gender-based differences in aspects of the peer-review process. METHODS: This is an analysis of editorial board members' reviews of original research submissions based on gender using the web based management program, Editorial Manager, from January 1, 2002, through December 31, 2008. We evaluated recommendations of editorial board members for acceptance/rejection using a four-tier system, agreement with editor's final decision, turnaround time from review request to submission, and editors' grades of reviews on a 5-point scale. We evaluated the performance of editorial board members with advancing tenure, seeking trends in recommendations over time. RESULTS: We included 6062 manuscript reviews representing 5958 manuscripts; 67% were assigned to male editorial board members and 33% to females. There were 38 editorial board members (25 men, 13 women) with tenure duration from 2 to 4.9 years, and 3 editors (2 men, 1 woman) serving 7, 7, and 6 years, respectively. Women were less likely to accept or accept with minor revisions than men (p < 0.003). Median turnaround times were 14 (0-55) days for women and 10 (0-33) days for men (p < 0.001). The editors' grades assigned to women were more often than men's grades in the very good to exceptional category (p < 0.0001). There was no difference based on gender, with approximately 73% decision congruence overall with the editors' final decisions. Men rejected more manuscripts than did women with advancing tenure on the editorial board (p < 0.0001). CONCLUSIONS: There are differences based on gender of editorial board members' recommendations about manuscript triage, turnaround time, and editors' grades assigned. Overall, however, these differences do not affect editors' ultimate decisions about manuscript publication. PMID- 20831432 TI - Family violence exposure and health outcomes among older African American women: do spirituality and social support play protective roles? AB - BACKGROUND: Family violence (FV), spirituality, and social support are salient psychosocial determinants of health. FV is associated with poor health among older African American women. The effect of spirituality and social support levels on the health of older African American women is unknown. METHODS: To assess the role of spirituality and social support as culturally relevant determinants of health status for older African American women independent of FV levels, we used a cross-sectional observational study. Two hundred twelve African American women, aged >= 50, were interviewed in two urban primary care practices. The measures used were (1) Family Violence Against Older Women (FVOW) scale, (2) Physical and Mental Composite Scores of the Short-Form 8(r) scale, (3) Medical Outcomes of Social Support survey (MOSS), and (4) Spiritual Well-Being Scale (SWBS). Spearman correlation coefficients estimated to test associations among lifetime FV exposure, spirituality, social support, and health status outcomes and multivariate regression models were used to examine the independent effect of spirituality and social support on physical and mental health status, controlling for FV and significant demographic variables. RESULTS: Mean participant age was 63.9 years. Higher spirituality levels were significantly associated with better physical health status after adjusting for FV levels and demographic factors (F = 6.17, p = 0.0001). Similarly, higher levels of spirituality and social support both significantly correlated with better mental health status in the multivariate model (F = 13.45, p < 0.0001) that controlled for lifetime FV levels and demographic factors. CONCLUSIONS: Spirituality and social support are two potentially modifiable determinants of health for older African American women. Culturally appropriate mechanisms to enhance social support and spirituality levels need to be explored as potential inteventions to improve the health of those African American women who have been exposed to FV. PMID- 20831431 TI - Factors that may influence the experience of hot flushes by healthy middle-aged women. AB - BACKGROUND: Interest in menopausal symptoms in general and hot flushes (HFs) in particular has grown in recent years. This is mostly due to increased awareness and the vast impact these symptoms have on women's lives. Despite the high prevalence of women who experience HFs, a definitive etiology for HFs is yet to be found. Our objective was to review the current literature dealing with associated factors for experiencing HFs and to provide a synthesized overview on this common and often debilitating condition. METHODS: We systematically searched the English-language literature in the PubMed database using relevant key words and included only those articles that contained information on associated factors for HFs in generally healthy midlife women. RESULTS: Both conflicting scientific results between studies documenting factors that influence HFs and the lack of validated measuring tools make it difficult to truly pinpoint associated factors for HFs. Nonetheless, we identified the following clusters of associated factors: the menopausal stages, sex steroid hormones, other endocrine agents, genetic polymorphisms, race/ethnicity, body mass index (BMI) and obesity, mood disorders, smoking, soy isoflavones and phytoestrogens, alcohol consumption, and physical activity. CONCLUSIONS: No single associated factor was consistently identified as having a major role in experiencing HFs. More resources should be directed to develop a unified study system along with multivariable analyses to get a better understanding of this condition, which often imposes a tremendous social and personal toll on the women who experience it. PMID- 20831434 TI - Pilot study to determine the optimal dose of methylphenidate for an n-of-1 trial for fatigue in patients with cancer. AB - PURPOSE: In advanced cancer, the prevalence of fatigue is high and can be related to treatment or disease. Methylphenidate hydrochloride (MPH) is a central nervous system stimulant that has been used to palliate fatigue. There is no standard dose for MPH when used for this indication; recommended doses range from 5-20 + mg/d. METHOD: To identify a dose to test formally in a subsequent n-of-1 trial of fatigue, we recruited patients with advanced cancer and a fatigue score of 4 or more on a 10-point scale. Following a 3-day baseline assessment, each patient titrated MPH at doses ranging from 5 mg/d to 15 mg twice daily at 3-day intervals. In a daily diary, patients recorded measures of fatigue, depression, toxicity, and symptom control. RESULTS: Ten patients provided consent, 9 completed 8 days and 5 received maximum dose at day 15. Three patients were unwilling to increase the dose to maximum levels as they were satisfied with the response at a lower dose. Across all patients, there was a pattern of rapidly improving fatigue and depression scores to day 9 (5 mg twice daily), with minimal improvement thereafter. CONCLUSION: The results indicate a dose of 5 mg twice daily for the definitive study. There was little correlation between performance status and maximum tolerated dose. No patient withdrew because of toxicity. PMID- 20831435 TI - The intersection of need and opportunity: assessing and capitalizing on opportunities to expand hospital-based palliative care services. AB - BACKGROUND: To develop and grow most effectively, palliative care programs must consider how best to align their mission with that of their institution. To do so, programs must identify their institutional mission and needs, what palliative care can do to address those needs given available resources, and how the palliative care team can measure and document its value. Such an approach encourages the palliative care team to think strategically and to see themselves and their service as a solution to issues and concerns within the institution. It also helps a palliative care team decide which, among many potential opportunities and possible initiatives, is the one most likely to be supported by the institution and have a recognized and significant impact. SUBJECTS AND METHODS: We present five case studies to demonstrate how successful programs identify and address institutional needs to create opportunities for palliative care program growth. These case studies can serve as models for other programs seeking to develop or expand their palliative care services. PMID- 20831436 TI - The impact of neonatologists' religiosity and spirituality on health care delivery for high-risk neonates. AB - BACKGROUND: Ethical decision-making regarding life-sustaining therapies (LST) for high-risk neonates can be challenging for both neonatologists and parents. Parents depend on neonatologists to interpret complex information, identify critical opportunities for decision-making, and present options for care. How neonatologists' belief systems affect care delivery for critically ill newborns is unexplored. OBJECTIVE: To characterize the relationship between neonatologists' religiosity or spirituality and the provision of intensive care services for high-risk newborns. METHODS: Neonatologists practicing at an American Academy of Pediatrics Neonatal-Perinatal Training Program were surveyed about their religious/spiritual beliefs, provision of LST for critically ill neonates, and communication with families. RESULTS: Two hundred ninety-eight neonatologists responded to the survey; 66.4% consider themselves very or moderately spiritual, 40.8% very or moderately religious. In response to a hypothetical prenatal consultation for a fetus at 23 1/7 weeks gestation, 96.3% agreed that the physician has a moral obligation to present all options to parents, including the provision of comfort care. More than 95% had no objection to withholding or withdrawing LST, with religion playing almost no part in these decisions. 38% of participants reported no objection to resuscitating an infant with trisomy 13 or 18; 40% of these neonatologists considered themselves very/moderately religious, 60% slightly/not at all religious. Eighty-nine neonatologists reported that their religious beliefs influence their medical practice. These physicians had similar responses as those not influenced by religion. CONCLUSION: For the majority of neonatologists participating in this study, differences in critical care practice cannot be attributed to personal religious or spiritual views. PMID- 20831437 TI - Breast and cervical cancer screening disparity among Asian American women: does race/ethnicity matter [corrected]? AB - BACKGROUND: Ethnic minorities are frequently considered as one homogeneous group in research, and this trend is particularly true for Asian Americans. This article seeks to uncover the intragroup differences in cancer screening behavior among subgroups of Asian American women by disaggregating them into six subgroups. The subgroups were compared with non-Latina white women to examine differences in breast and cancer screening rates and relevant factors associated with receiving these screenings. METHODS: Three-year merged data from the 2001, 2003, and 2005 California Health Interview Survey (CHIS) were used to investigate the subgroup differences. Samples for the current study were restricted to non Latina white and Asian American women whose age was >= 18 years (n = 58,000) for cervical cancer screening and >= 40 years (n = 43,518) for breast cancer screening at the time of the interview. RESULTS: Results showed marked differences in cancer screening rates among Asian American subgroups and between cancer types. Cervical cancer screening rates were noticeably higher than breast cancer screening rates in all groups. The Korean group consistently showed the lowest rates of both cancer screenings. Japanese ranked the highest (79.5%) in breast cancer screening but the second lowest (79.7%) in cervical cancer screening. Enabling factors, such as having private health insurance and a usual source of care, were found to be the strongest predictors of receiving both breast and cervical cancer screening. Screenings for both types of cancer increased if a woman was married or was born in the United States. CONCLUSIONS: The findings of this study illustrate the heterogeneity that exists among Asian American subgroups in their cancer screening behaviors. Further development of culturally relevant and ethnic-specific cancer prevention strategies and policies that address the subgroup differences within the larger racial/ethnic population are needed. Public health outreach and cancer education should be prioritized to the Asian American women who are more recent arrivals in the United States and have minimal access to healthcare. PMID- 20831438 TI - The association between prenatal depression and obstetric outcome in Taiwan: a prospective study. AB - BACKGROUND AND METHODS: The present follow-up study aims to assess the association between depressive symptomatology during the second or third trimester of pregnancy and obstetric-neonatal outcomes in Taiwan. Follow-up evaluations of delivery and birth records in the immediate postpartum period were carried out on 265 nondepressed, 107 mildly to moderately depressed, and 59 severely depressed women and their newborns in three hospitals in Southern Taiwan. Prenatal depression was identified using the Edinburgh Perinatal Depression Scale (EPDS). The medical records of the participant women and their newborns were reviewed after delivery. RESULTS: Prenatally depressed women reported significantly lower marital satisfaction than nondepressed women. Follow up examination of the women's obstetric birth records revealed that prenatal depression had no statistically significant association with obstetric outcome (type of delivery, use of epidural anesthesia, or instrument-assisted delivery), nor did depression influence the neonatal outcome (incidence of prematurity, birth weight, and Apgar score). CONCLUSIONS: Prenatal depression does not lead to unfavorable obstetric outcomes. However, the finding between marital satisfaction and prenatal depression may have implications in terms of social support. PMID- 20831439 TI - The Contraceptive CHOICE Project: recruiting women at highest risk for unintended pregnancy and sexually transmitted infection. AB - BACKGROUND: Unintended pregnancy disproportionately affects younger, minority, and low-income women. The purpose of this analysis is to describe our recruitment strategies and to determine if targeted efforts to reach women at greatest risk for unintended pregnancy and sexually transmitted infection (STI) were successful. METHODS: The Contraceptive CHOICE Project is a prospective cohort study providing reversible contraception at no cost to 10,000 women aged 14-45 years in the St. Louis area in order to evaluate method satisfaction and continuation and to reduce unintended pregnancies in the region. We describe four strategies for effective outreach and recruitment of high-risk women, including forming strong community partnerships. We analyze the evolution of baseline demographic and behavioral characteristics over the three waves of enrollment of the first 2,500 participants in order to assess whether our outreach efforts were successful. RESULTS: Overall, >60% of participants were aged <=25 years. There was a significant increase in the percentage of minority participants enrolled throughout the first 2,500 subjects (p < 0.001). The number of women who reported trouble paying for basic necessities significantly increased over the three waves (p = 0.025). Throughout the three waves of enrollment, there was a significant increase in the number of women who tested positive for an STI at baseline (p < 0.001). CONCLUSIONS: A multiple method approach with collaboration of key community partners led to successful recruitment of hard to reach populations at high risk for unintended pregnancy and STI. PMID- 20831440 TI - Perceived weight gain as a correlate of physical activity and energy intake among white, black, and Hispanic reproductive-aged women. AB - OBJECTIVE: To estimate the effects of perception of weight gain on women's physical activity and eating behaviors over time. METHODS: A total of 608 women self-reported their experience regarding perceived weight gain and physical activity at baseline and every 6 months thereafter for 36 months. Data about dietary habits were obtained every 12 months. Longitudinal relationships of perceived weight gain with physical activity and total energy intake were assessed using mixed model regression analysis after adjusting for age, race/ethnicity, obesity, and lifestyle variables. Effect of body esteem scores on physical activity and energy intake was also examined. RESULTS: At baseline, of 608 reproductive-aged women, 129 (21.2%) reported perceived weight gain, whereas 479 (78.8%) did not. Perceived weight gain was not associated with changes in physical activity over the period of 36 months (-8.04 min/week, 95% confidence interval [CI] -20.80-4.72 min/week, p = 0.22). A separate mixed model based on annual follow-up data over 36 months showed that those who perceived weight gain were more likely to have higher energy intake over time (112 Kcal/day higher, 95% CI 23-200 Kcal/day, p = 0.01). Body esteem was not associated with changes in physical activity over time (-0.13 min, 95% CI -0.44-0.18 min, p = 0.41) or energy intake over time (< 1 Kcal/day, 95% CI -2-2 Kcal/day, p = 0.82). CONCLUSIONS: Neither perceived weight gain nor body esteem was associated with increased physical activity or decreased total energy intake. Rather, increased energy intake was observed among women who perceived weight gain. Future research should look at additional potential cues to action for behavior changes related to physical activity or energy intake. PMID- 20831441 TI - Does controlled ovarian hyperstimulation in women with a history of endometriosis influence recurrence rate? AB - BACKGROUND: Endometriosis is a common estrogen-dependent disease. The aim of this study was to assess whether controlled ovarian hyperstimulation (COH) for assisted reproductive technology (ART) was associated with an increased incidence in endometriosis recurrence as documented by transvaginal ultrasound (TV-US). METHODS: In a retrospective cohort study of 592 patients submitted to laparoscopy for endometriosis, 177 with infertility-related endometriosis who underwent a periodic ultrasound follow-up after laparoscopy were selected. Women who started ART after laparoscopy (n = 90) were compared with the control group, who did not undergo ART (n = 87). Recurrence of endometriosis was defined as the presence of endometriotic lesions observed through TV-US. RESULTS: During a long-term TV-US follow-up (1-15 years), 40 (22.6%) recurrences were observed. Patients submitted to ART showed a cumulative recurrence rate similar to that of the control group (28.6% and 37.9% respectively, p = 0.471). Recurrent lesions were ovarian cysts (47.5%), ovarian nodules (37.5%), and rectovaginal disease (15%). The stratified analysis based on stages of endometriosis and pelvic pain did not show differences. CONCLUSIONS: Gonadotropin treatments do not seem to affect the natural history of endometriotic lesions. The most important prognostic factors in recurrent disease observed by TV-US seem to be the stage of endometriosis and the presence of pelvic pain at the time of the first laparoscopic treatment. PMID- 20831442 TI - Medicaid and preterm births in Virginia: an analysis of recent outcomes. AB - OBJECTIVES: The study objectives were to evaluate adequacy of prenatal care and risk for preterm birth among Medicaid clients in Virginia and to determine if payment method is associated with the risk of preterm birth. METHODS: Birth certificate data for the Commonwealth of Virginia for 2007 and 2008 were linked with Medicaid claims data. Analysis was limited to singleton births. Three payment methods were evaluated: private insurance, self-pay, and Medicaid. The prevalence of preterm birth for each level of prenatal care defined by the Kotelchuck prenatal care index was assessed for each payment method. Unconditional logistic regression modeling was used to assess the association between payment method and preterm birth risk while controlling for known preterm birth risk factors. RESULTS: Preterm birth prevalences (95% confidence interval [CI]) for the different payment methods were 7.9% (4.79-8.07) for the privately insured, 10.1% (9.57-10.60) for the self-pay group, and 10.2% (9.95-10.45) for Medicaid recipients. Compared with those with private insurance, women on Medicaid had an adjusted odds ratio (OR) for preterm birth (95% CI) of 0.99 (0.94 1.03). Self-pay mothers had a 32% increase in the odds of preterm birth relative to the privately insured. All payment groups show a trend toward significant reduction in preterm birth prevalence as adequacy of prenatal care improved from inadequate to adequate. Medicaid enrollees had a high prevalence of known risk factors, including smoking and illicit drug use and cervical insufficiency. CONCLUSIONS: When known risk factors have been controlled, preterm birth risk for Medicaid enrollees did not differ significantly from the privately insured. PMID- 20831443 TI - Disability associated with pain--a clinical approximation of the mediating effect of belief and attitudes. AB - Our objective was to test the hypothesis that pain beliefs are mediators of disability in a population of workers with chronic pain. A cross-sectional study composed of 115 workers with work-related musculoskeletal disorders (WRMD) whose symptoms appeared 6 months before the beginning of the study was conducted. Outcome measures included questionnaires on pain, pain beliefs, physical disability, and depression. Almost half of the sample (42%) reported moderate pain; the mean disability score was 11.5. Assessment of pain beliefs revealed that only the emotion domain was "more adaptive." Thirty-eight workers presented depressive symptoms (33%), with a mean score of 18. A multiple linear regression analysis identified the best predictors associated with disability in sample. The variables that remained in the model were intensity of pain, domains solicitude, and disability from the survey of pain attitudes, physical disability, and depression. Results showed that pain beliefs are partial mediators of the relation between chronic pain and disability. When depression was added to the model, there was a significant increase in the explanation of disability variance, indicating that this variable is an important factor associated with functional limitation. Disability associated with chronic pain is a multidimensional experience, affected by the interaction of social and psychological factors. PMID- 20831444 TI - Distinct folding pathways of two homologous disulfide proteins: bovine pancreatic trypsin inhibitor and tick anticoagulant peptide. AB - The folding pathways of disulfide proteins vary substantially (Arolas et al., Trends Biochem Sci 31: 292-301, 2006). The diversity is mainly manifested by (a) the extent of heterogeneity of folding intermediates, (b) the extent of presence of native-like intermediates, and (c) the variation of folding kinetics. Even among structurally similar proteins, the difference can be enormous. This is demonstrated in this concise review with two structurally homologous kunitz-type protease inhibitors, bovine pancreatic trypsin inhibitor and tick anticoagulant peptide, as well as a group of cystine knot proteins. The diversity of their folding mechanisms is illustrated with two different folding techniques: (a) the conventional method of disulfide oxidation (oxidative folding), and (b) the novel method of disulfide scrambling (Chang, J Biol Chem 277: 120-126, 2002). This review also highlights the convergence of folding models concluded form the conventional conformational folding and those obtained by oxidative folding. PMID- 20831445 TI - Control of mature protein function by allosteric disulfide bonds. AB - Protein disulfide bonds are the links between the sulfur atoms of two cysteine amino acids. All the known life forms appear to make this bond. Most disulfide bonds perform a structural role by stabilizing the tertiary and quaternary structures. Some perform a functional role and can be characterized as either catalytic or allosteric disulfides. Catalytic disulfides/dithiols transfer electrons between proteins, whereas the allosteric bonds control the function of the protein in which they reside when they undergo redox change. There are currently five clear examples of allosteric disulfide bonds and a number of potential allosteric disulfides at various stages of characterization. The features of these bonds and how they control the activity of the respective proteins are discussed. A common aspect of the allosteric disulfides identified to date is that they all link beta-strands or beta-loops. PMID- 20831446 TI - Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress. AB - Macrophage migration inhibitory factor (MIF) is a multifunctional protein that exhibits an intrinsic thiol protein oxidoreductase activity and proinflammatory activities. In the present study to examine intracellular MIF redox function, exposure of MIF-deficient cardiac fibroblasts to oxidizing conditions resulted in a 2.3-fold increase (p < 0.001) in intracellular ROS that could be significantly reduced by adenoviral-mediated reexpression of recombinant MIF. In an animal model of myocardial injury by ischemia/reperfusion (I/R), MIF-deficient hearts exhibited higher levels of oxidative stress than did wild-type hearts, as measured by significantly higher oxidized glutathione levels (decreased GSH/GSSG ratio), increased protein oxidation, reduced aconitase activity, and increased mitochondrial injury (increased cytochrome c release). The increased myocardial oxidative stress after I/R was reflected by larger infarct size (INF) in MIF deficient hearts versus wild-type (WT) hearts (21 +/- 6% vs. 8 +/- 3% INF/LV; p < 0.05). In vivo hemodynamic measurements showed that left ventricular (LV) contractile function of MIF-deficient hearts subjected to 15-min ischemia failed to recover during reperfusion compared with WT hearts (LV developed pressure and +/- dP/dt; p = 0.02). These data represent the first in vivo evidence in support of a cardioprotective role of MIF in the postischemic heart by reducing oxidative stress. PMID- 20831447 TI - Different isoforms of glutathione peroxidase cause opposing effects during the development of allergic asthma in mice. PMID- 20831448 TI - Relationship between plasma carotenoids, fruit and vegetable intake, and plasma extracellular superoxide dismutase activity in women: different in health and disease? AB - Abstract Exogenous antioxidants may influence endogenous antioxidant enzyme activity. We observed in healthy women (n = 95) that higher plasma alpha carotene, beta-carotene, beta-cryptoxanthin, sum of plasma carotenoids, and fruit and vegetable intake were associated with lower plasma extracellular-superoxide dismutase activity. In women with a history of cardiovascular disease, diabetes, or cancer (n = 62), we observed no associations. Our observation that plasma extracellular-superoxide dismutase activity was inversely associated with plasma carotenoids and fruit and vegetable intake in healthy women, but not in women with a history of cardiovascular disease, diabetes, or cancer, suggests that the associations between exogenous and endogenous antioxidants may differ in health and disease. PMID- 20831449 TI - Mesenchymal stem cells: biological properties and clinical applications. AB - IMPORTANCE OF THE FIELD: In the last decade, knowledge of mesenchymal stem cells (MSCs) has evolved rapidly; their immunomodulatory properties and paracrine interactions with specific cell types in damaged tissues and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases. AREAS COVERED IN THIS REVIEW: We present some relevant methodological issues and biological properties of MSCs, as well as clinical applications of MSC therapies with particular emphasis in the treatment of graft versus host disease (GVHD), complex perianal fistula and refractory metastatic neuroblastoma. Other topical aspects relevant to the application of cellular therapies such as biosafety studies and cellular production of MSCs are also discussed in this review. WHAT THE READER WILL GAIN: The growing optimism regarding MSCs research is based on the promising results obtained in in vitro and in vivo studies. The rapid translational research with MSCs necessitated standardization of methodology and terminology and greater focus on other aspects such as biosafety and cellular production, especially for clinical use of MSCs. TAKE HOME MESSAGE: Much has been learned about the biology and applications of MSCs and much remains to be learned. PMID- 20831450 TI - Maternal calcium supplementation during pregnancy and dental caries of children at 12 years of age: follow-up of a randomized controlled trial. AB - OBJECTIVES: To evaluate if calcium supplementation during pregnancy could have any influence on primary dentition measured as the reduction of dental caries of the child. DESIGN: Individual randomized controlled trial. SETTING: One hospital in Rosario, Argentina. POPULATION: Random sample of 195 12-year-old children from a follow-up study of 614 women who were randomized during pregnancy to calcium supplementation or placebo. METHODS: An independent researcher blinded to the group where the mothers were assigned performed a dental examination of the children. MAIN OUTCOME MEASURES: Proportion of children with at least one decayed, missing or filled teeth (DMFT/dmft) and mean number of decayed, missing or filled surfaces (DMFS/dmfs) per children. RESULTS: Ninety-eight children were assessed in the calcium supplementation group and 97 in the placebo group. 63.3% of the children whose mother took calcium supplementation had at least one DMFT/dmft compared to 86.6% in the placebo group (<0.001). The children whose mother received the intervention had a 27% reduction in the risk of developing at least one DMFT/dmft (RR: 0.73, CI 95%: [0.62; 0.87]). CONCLUSIONS: This study shows a modeling effect of calcium intake during pregnancy on dental caries of the offspring. At around 12 years of age children whose mothers received calcium supplementation when pregnant showed a significant reduction in dental caries. PMID- 20831451 TI - High pulse pressure is associated with increased risk of stroke in Japanese: the JMS Cohort Study. AB - BACKGROUND: The relationship between pulse pressure (PP) and stroke has been described in populations outside Japan. Here, we investigated the relationship between PP and stroke incidence in Japan. METHODS: Study subjects were 11,097 people (4315 men and 6782 women) in 12 rural areas of Japan enrolled in the Jichi Medical School Cohort Study, a population-based prospective study. The subjects were divided into quintiles of PP. Baseline data were obtained by questionnaire and health checkups between April 1992 and July 1995, and the incidence of all strokes and stroke subtypes was monitored. RESULTS: A total of 412 strokes were observed during a mean follow-up period of 10.7 years. After adjusting for age, smoking status, drinking status, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein-cholesterol, body mass index and diabetes mellitus, hazard ratios [HRs] in the second to fifth quintiles of PP for all strokes were 1.06 (95% confidence interval [CI] 0.69-1.64), 1.53 (CI 1.02-2.28), 2.02 (CI 1.38-2.96) and 2.22 (CI 1.53-3.20) compared with the first quintile using Cox's proportional hazard model, respectively. CONCLUSION: Our findings suggest high PP is at an increased risk of stroke. PMID- 20831452 TI - An activity-based intervention for obese and physically inactive children organized in primary care: feasibility and impact on fitness and BMI A one-year follow-up study. AB - OBJECTIVE: To investigate the feasibility and impact on BMI and physical fitness of an intervention for obese and inactive children, based on physical activity and carried out in primary health care. DESIGN: A prospective, longitudinal one year follow-up study. SETTING: The community of Kristiansand, Norway (80 000 inhabitants). INTERVENTION: A 40-week structured intervention based on physical training with some lifestyle advice for the obese child and one parent. Subjects. A total of 62 physically inactive children aged 6-14 years with iso-BMI >= 30 kg/m2. MAIN OUTCOME MEASURES: Body mass index (BMI), maximum oxygen uptake, and physical fitness in tests of running, jumping, throwing, and climbing assessed at baseline and after six and 12 months as well as number of dropouts and predicting factors. RESULTS: A total of 49 out of 62 children completed the first six months and 37 children completed 12 months. Dropout rate was higher when parents reported being physically inactive at baseline or avoided physical participation in the intervention. The children's maximum oxygen uptake increased significantly after 12 months from 27.0 to 32.0 ml/kg/min (means), as did physical fitness (endurance, speed, agility, coordination, balance, strength) and BMI was significantly reduced. CONCLUSION/IMPLICATIONS: This one-year activity-based intervention for obese and inactive children performed in primary health care succeeded by increasing cardiovascular capacity and physical fitness combined with reduced BMI in those who completed. Dropout was substantial and depended on the attendance and compliance with physical activity by the parents. PMID- 20831453 TI - Beta-tubulin III expression in prostate cancer. AB - OBJECTIVE: Beta-tubulin isotype III is a microtubule component associated with resistance to chemotherapy and poor outcome in various cancers. This study aimed to investigate its expression in prostate cancer and its role as a prognostic factor in this setting. MATERIAL AND METHODS: A tissue microarray was constructed of 289 prostate cancers from radical prostatectomy specimens with a median follow up of 48.9 months. Slides were immunostained for beta-tubulin III. The intensity and extent of immunoreactivity and their product [immunoreactivity product (IRP)] were evaluated. RESULTS: Tubulin III was expressed in the cytoplasm of prostate cancer cells but not in benign glands. Only 11.6% of cancers were positive for tubulin III. Among low-grade (Gleason score 5-6) and high-grade (Gleason score 7 10) cancers, 6.0% and 16.6% were positive, respectively (p = 0.006). beta-Tubulin III expression was more often seen in high-stage disease and more often in metastases (62.5%) than in primary lesions (11.6%) (p < 0.001). The intensity, extent and IRP of tubulin III all predicted biochemical recurrence in univariate Cox analysis (p = 0.02, p = 0.048 and p = 0.012, respectively). IRP was an independent predictor of prognosis when adjusted for serum prostate-specific antigen in a multivariate Cox analysis (p = 0.005), but not when the Gleason score was added to the model (p = 0.17). CONCLUSION: beta-Tubulin III predicts biochemical recurrence after radical prostatectomy in a subset of patients. Its practical utility is limited by the low number of cases positive for this biomarker. PMID- 20831455 TI - Effect of ustekinumab on physical function and health-related quality of life in patients with psoriatic arthritis: a randomized, placebo-controlled, phase II trial. AB - OBJECTIVE: To use data from a phase II clinical trial to evaluate the effect of ustekinumab, a human immunoglobulin monoclonal antibody that binds with high affinity to the shared p40 subunit of human interleukins-12 and -23, on physical disability and health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). METHODS: In this multicenter, double-blind, placebo-controlled, crossover study of ustekinumab, patients with active PsA were randomized (1:1 ratio) to receive either ustekinumab at weeks 0, 1, 2, and 3 and placebo at weeks 12 and 16 (n = 76) or placebo at weeks 0, 1, 2, and 3 and ustekinumab at weeks 12 and 16 (n = 70). Physical function was assessed using the disability index from the Health Assessment Questionnaire-Disability Index (HAQ-DI) in all randomized patients. HRQoL was evaluated using the Dermatology Life Quality Index (DLQI) in a subset of patients (84.9%) with at least 3% body surface area (BSA) psoriasis involvement at baseline. RESULTS: At baseline, overall mean HAQ-DI and DLQI scores were 0.9 and 11.5, respectively, indicating impaired physical function and moderate effect on HRQoL. At week 12, ustekinumab patients had significantly more improvement (decrease) in the mean HAQ-DI (-0.31) and DLQI (-8.6) scores versus placebo (-0.04 and -0.8, respectively; p < 0.001 for both comparisons). At week 12, 58.7% (37/63) of ustekinumab-treated patients had a DLQI score of 0 or 1 (no negative effect of disease or treatment on HRQoL) versus 5.5% (3/55) for placebo (p < 0.001). The results also indicated a positive but weak correlation between improvement in physical function and HRQoL, pain, and skin response as well as between improvement in joint and skin responses in patients receiving ustekinumab or placebo. Potential limitations of the study include the short duration of the placebo-controlled period and the relatively small patient population. CONCLUSION: Ustekinumab significantly improved physical function and HRQoL in patients with PsA and psoriasis involving at least 3% BSA. PMID- 20831456 TI - Opioid use and healthcare costs among patients with DPNP initiating duloxetine versus other treatments. AB - OBJECTIVE: To compare opioid utilization and healthcare costs over a 1-year period following the initiation with duloxetine versus other standard of care (SOC) treatments among patients with diabetic peripheral neuropathic pain (DPNP). METHODS: This retrospective cohort study assessed commercially-insured DPNP patients between 18 and 64 years old who initiated duloxetine or other SOC treatments (tricyclic antidepressants, venlafaxine, gabapentin, pregabalin) between 3/1/2005 and 12/31/2005. Initiation was defined as a 90-day period without available study medication. The first dispense date of the study medication was denoted as the index date. Selected patients had no opioid pill coverage during the 90 days prior to initiation. Duloxetine and SOC patients were matched via propensity scoring (1:1 ratio), controlling for demographics, comorbidities, prior healthcare utilization and costs, and prior medication history. Opioid utilization and healthcare costs over the 12-month post-index period were compared between study cohorts. RESULTS: The matched sample included 117 patients in each of the duloxetine and SOC cohorts. Compared with SOC-treated patients, duloxetine-treated patients were less likely to use any opioids (52.1 vs. 84.6%, p < 0.05) over the 12-month post-index period. Duloxetine-treated patients, on average, had two fewer opioid prescriptions dispensed, 27 fewer days on opioids, 121 days greater delay in subsequent opioid use, and 1815 mg lower morphine equivalent dosage than SOC-treated patients (all p < 0.05). Also, duloxetine-treated patients had significantly lower total ($18,623 vs. 30,602, p < 0.05) and outpatient costs ($7371 vs. 15,343, p < 0.05). Due to the use of a retrospective administrative claims database, limitations of this study include the potential for selection bias between study cohorts, and inability to measure unobservable confounding and disease severity and/or duration. CONCLUSIONS: Among commercially-insured DPNP patients, duloxetine-treated patients had delayed and reduced opioid use and lower healthcare costs than SOC-treated patients. PMID- 20831457 TI - Increased integrity of circulating cell-free DNA in plasma of patients with acute leukemia. AB - BACKGROUND: Increased cell-free DNA (cf-DNA) and the integrity of cf-DNA in plasma of patients with cancer has been described. We investigated the clinical utility of cf-DNA in the detection and monitoring of progression of leukemia. METHODS: Plasma samples from 60 patients with acute leukemia were analyzed in comparison to plasma from 30 healthy controls. Plasma DNA was determined by quantitative PCR (qPCR) by amplifying the beta-actin gene (ACTB). The DNA integrity index was calculated as the ratio of qPCR results (ACTB384/106). Paired diagnostic/complete remission (CR)/relapse samples from eight of 60 patients were analyzed, and the minimum residual disease (MRD) situations were monitored. RESULTS: DNA concentrations (median: 8.80 ng/mL, p=0.004) and DNA integrity (median: 0.51, p<0.001) in cancer patients were significantly higher. Receiver operating characteristic (ROC) curve analysis showed that the area under the ROC curve of DNA and DNA integrity were 0.79 and 0.88, respectively. DNA integrity at CR had a distinct reduction and then an increase at relapse. DNA integrity in CR cases was higher than that observed in healthy controls. CONCLUSIONS: Our preliminary data suggest that plasma DNA integrity is increased in acute leukemia and may be a potential biomarker for monitoring MRD. However, more work is needed. PMID- 20831458 TI - Healthcare resource utilization and expenditures of women diagnosed with hypoactive sexual desire disorder. AB - OBJECTIVE: To describe healthcare utilization and costs among commercially insured women with a diagnosis of hypoactive sexual desire disorder (HSDD) in the US and to compare them with an age-matched control cohort. METHODS: The Thomson Reuters MarketScan * Commercial Database was used to identify women aged 18-64 with an ICD-9-CM coded diagnosis of HSDD from 1/1/1998 to 9/30/2006. A control group of women with no diagnosis of any sexual dysfunction was matched 3:1 to cases based on age, health plan, and enrolment period. Healthcare utilization and costs were examined in the year prior to (pre-period) and following (post-period) index. Multivariate analyses were used to determine the adjusted difference in cost between women with and without HSDD in the post-period. RESULTS: In both the pre- and post-periods, women with HSDD had more outpatient office visits, radiology services, prescription medication use, and medical visits (e.g., laboratory and outpatient surgeries) relative to controls. In the 12-month post period, women with HSDD had significantly higher total costs relative to controls ($5,504 +/- 11,132 vs. $4,606 +/- 12,601, p < 0.001). After adjusting for clinical characteristics, women with HSDD had total healthcare expenditures that were 16.8% higher than controls (p < 0.001). LIMITATIONS: There is a potential for selection bias among the women who actually received a diagnosis of HSDD from a clinician. Women who received a diagnosis may be different from women without a diagnosis in ways that cannot be measured in this study. Additionally, it is possible that some women in the control group had HSDD but were undiagnosed. To the extent that the control group included women who did have HSDD, the study estimates of differences between the two groups would be underestimated. CONCLUSIONS: Women diagnosed with HSDD use significantly more healthcare services than women without diagnosed sexual dysfunction. These higher costs are driven by a greater use of outpatient services and prescription medications. PMID- 20831459 TI - Positive experiences and quality of life in Meniere's disorder. AB - The objective of this study was to determine the influence of positive experiences on the quality of life of patients with Meniere's disorder. Its deign comprised a cross-sectional investigation of members of a self-help group, using a questionnaire of positive experiences, an oto-neurological questionnaire, EuroQol, and Meniere's impact rating. The study sample was 542 members of the Finnish Meniere Federation. Results showed that the positive questions explained 21% of the variance of the EuroQol TTO, 31% of the EuroQol VAS measure, and 35% of the Meniere's impact. This compared with 40% of the variance explained by symptomatic complaints. When both the symptoms and positive measures were taken together, there was an increase in the proportion of the variance explained for the VAS (42%) and Meniere's rating (50%), but not for the TTO (42%). A perspective on the disorder was the main positive experience associated with the increased variance explained. Positive experiences have a significant impact on self-rated quality of life. The results suggest that encouraging a positive perspective on the condition, in addition to treating the underlying symptoms, could be useful in rehabilitative management. PMID- 20831460 TI - Stigma: a negative and a positive influence on help-seeking for adults with acquired hearing loss. AB - There are stigmas associated with many chronic health conditions that emerge in adulthood. People who present manifestations of hearing loss are often perceived by others to be cognitively diminished, less able, and socially incompetent. In order to avoid being identified as a member of a stigmatized group, individuals with hearing loss may choose not to seek health services or fail to comply with recommended treatments. The purpose of this study was to better understand how stigma impacted upon the help-seeking activities of adults with an acquired hearing loss. Ten people who had hearing loss, and were members of peer-support groups participated in audio-recorded semi-structured interviews. Verbatim transcripts were analysed using thematic analyses. Analyses revealed that lasting decisions about hearing loss management were made following 'critical junctures', when the negative stress found in the respondent's social and physical environment far outweighed positive energy, or when the positive energy found in the respondent's environment far outweighed the negative stress. The time course development of these processes is described. PMID- 20831461 TI - Comparing health care use and related costs between groups with and without hearing impairment. AB - This study aims to compare the use (and related costs) of different health care resources between groups of normally-hearing and hearing-impaired people. A distinction was made between hearing-related and other health care contacts. Data were collected at the baseline measurement of the national longitudinal study on hearing, and at each month during a subsequent period of six months. Hearing status was determined using an internet speech-in-noise test. The sample comprised 1295 normally-hearing and hearing-impaired subjects, aged 18-65 years. Adjusting for confounders, regression models showed that hearing-impaired respondents had significantly more contacts and higher costs for primary, secondary, and occupational care than normally-hearing respondents during the period under investigation. The differences were due to a larger number of health care contacts for which hearing impairment was the main motive to seek help. After excluding these contacts, the differences in health care use and costs between the groups were not significant. This suggests that besides hearing related contacts, adults with hearing impairment do not make more use of health care resources than adults without hearing difficulties. PMID- 20831462 TI - How well does patient self-report predict asthma medication possession? Implications for medication reconciliation and adherence assessment. AB - BACKGROUND: Self-report is the most commonly used method for collecting information regarding asthma medication possession and adherence in clinical practice. OBJECTIVE: To determine the agreement between self-report and pharmacy claims data for asthma medication possession. METHODS: This is a retrospective study that examined pharmacy claims data 12 months before and after participants completed a structured asthma survey. This study was performed in a sample of health care workers and dependents >17 years old in a large, self-insured Midwestern United States health care center. The main outcome measure was agreement (kappa calculation) between self-report and pharmacy claims data of asthma medication possession. RESULTS: Self-report of asthma medication use agreed moderately with pharmacy claims data for short-acting albuterol (kappa=0.47 +/- 0.03), salmeterol (kappa=0.79 +/- 0.04), and montelukast (kappa=0.69 +/- 0.03) but only slightly for inhaled corticosteroids (kappa=0.18 +/- 0.03) and prednisone (kappa=0.10 +/- 0.03) (n=1050 respondents). Both under self-reporting and over self-reporting were common with inhaled corticosteroids (14.4% and 23.1%, respectively) and varied significantly by specific drug type. CONCLUSIONS: Self-report moderately agrees with asthma medication possession for most adult asthma patients, though the agreement differs considerably between and within asthma medication classes. PMID- 20831463 TI - Examining behavioural susceptibility to obesity among Canadian pre-school children: the role of eating behaviours. AB - OBJECTIVE: No study has examined a comprehensive set of approach and avoidance eating behaviours and their relationship with bodyweight among North American children. The purpose of this study was to test whether a variety of individual eating behaviours differed among weight status groups in a sample of Canadian pre school children. METHODS: The sample included 4 and 5-year-old children (N=1 730), who attended a health center in and around Edmonton, Alberta, for a pre school immunization shot between November 2005 and August 2007. A trained health assistant measured children's height and weight. Centers for Disease Control and Prevention (CDC) cut-off criteria were used to classify the children according to body weight status. Parents completed the Children's Eating Behaviour Questionnaire (CEBQ). A one-way between-groups multivariate analysis of variance was performed to investigate eating behaviour differences by weight status groups while adjusting for sex and neighbourhood socioeconomic status (SES). RESULTS: Significant differences (p<0.01) were found between weight status groups for food responsiveness, emotional over-eating, enjoyment of food, satiety responsiveness, slowness in eating, and food fussiness. No significant differences were found for desire to drink or emotional under-eating. An inspection of mean scores showed graded positive linear patterns by weight for food responsiveness and enjoyment of food and graded negative linear patterns by weight for satiety responsiveness, slowness in eating, and food fussiness. CONCLUSION: Future research should examine whether eating behaviours can be modified to reduce children's risk of becoming overweight or obese. In addition potential determinants of eating behaviours should be explored. PMID- 20831464 TI - Measured immunoglobulin E in allergic bronchopulmonary aspergillosis treated with omalizumab. AB - BACKGROUND: The ability to assess adequate reductions in immunoglobulin E (IgE) in allergic bronchopulmonary aspergillosis (ABPA) has been a concern with regards to omalizumab treatment. OBJECTIVE: To describe the clinical course and serial measured IgE levels in two adult patients with elevated IgE levels, hypersensitivity to Aspergillus fumigatus, and bilateral bronchiectasis who were treated with omalizumab. CLINICAL DESCRIPTIONS: Patient 1 met commonly used criteria for ABPA and had a more than 3-fold increase (from 702 to 2462 IU/ml) in measured IgE 4 months after starting omalizumab. Two years after starting omalizumab, the IgE level decreased to baseline (473 IU/ml) even when corticosteroids were discontinued. Patient 2 had near normalization of elevated IgE levels when treated with corticosteroids but IgE levels subsequently rose again to over 10,000 IU/ml. After reducing the IgE level to 586 IU/ml with higher corticosteroid doses, omalizumab was initiated. Twenty months after starting omalizumab, the measured IgE was 510 IU/ml. Based on published omalizumab treatment-associated total/free IgE ratios, the estimated free IgE levels for both patients after more than a year of omalizumab treatment was less than their pre-omalizumab treatment IgE levels. CONCLUSIONS: These data suggest that omalizumab can be beneficial in treating ABPA and that measured IgE levels can still be useful in this context. Noting the pattern of IgE levels associated with ABPA exacerbations and with corticosteroid treatment may help both with achieving an IgE level appropriate for omalizumab treatment and with the interpretation of measured IgE changes associated with omalizumab treatment. PMID- 20831465 TI - Knowledge, attitude, and self-efficacy in asthma self-management and quality of life. AB - BACKGROUND: Cognitive variables such as knowledge, attitude, and self-efficacy affect asthma patients' abilities to be effective self-managers. OBJECTIVE: The objective of this cross-sectional analysis was to determine what patient and clinical factors were associated with these cognitive variables and to assess the contributions of these cognitive variables to clinical status. METHODS: Primary care asthma patients were interviewed using the three domains of the Knowledge, Attitude, and Self-Efficacy Asthma Questionnaire (KASE), as well as established scales to measure social support, depressive symptoms, and ratings of asthma care. Clinical asthma status was measured with the Asthma Quality of Life Questionnaire (AQLQ). RESULTS: In total, 180 patients were enrolled, with a mean age of 43 years and 84% were women. Knowledge was low, with only 50% of patients answering half or more questions correctly (mean score = 52, possible range 0 100, higher is more knowledge). Attitude toward asthma was generally positive (mean score = 82, possible range 20-100, higher is more positive attitude) and self-efficacy was moderate (mean score = 76, possible range 20-100, higher is more self-efficacy). In separate multivariate analyses, younger age and higher education level were associated with more knowledge (p <= .005); more social support, fewer depressive symptoms, and more favorable prior results of asthma care were associated with more positive attitude (p <= .05); and favorable prior results, more satisfaction with asthma status, not having stress-related triggers, and not having had a recent emergency department visit for asthma were associated with more self-efficacy (p <= .07 for all variables). In additional multivariate analyses, more knowledge (p = .0005), more positive attitude (p = .02), and more self-efficacy (p = .01) were associated with better AQLQ scores. CONCLUSIONS: Different patient and clinical characteristics were associated with cognitive variables pertinent to self-management. These variables, in turn, were independently associated with asthma status. Thus, although fostering improvement in all three variables would be desirable, interventions that improve any of these variables potentially could be beneficial. PMID- 20831466 TI - Bronchial hyperreactivity to methacholine in atopic versus nonatopic asthmatic schoolchildren and preschoolers. AB - BACKGROUND: Atopy and bronchial hyperreactivity are factors related to severe and unremitting asthma of childhood; however, the prevalence of these factors could be different according to age of the child. OBJECTIVE: To determine if methacholine bronchial hyperreactivity (BHR) differs between atopic and nonatopic preschoolers and schoolchildren with mild-moderate asthma. METHODS: Data obtained from 340 children with diagnosis of asthma or recurrent wheezing, matched by atopic conditions (positive or negative skin prick test) and age, and who underwent a methacholine bronchial challenge test (by spirometry in schoolchildren and by transcutaneous oxygen pressure [TcP(O2)] in preschoolers) were reviewed. RESULTS: Among 136 schoolchildren (9.07 +/- 2.5 years), the prevalence of positive BHR was significantly higher among atopics than nonatopics (75% versus 48.5%, p = .001, respectively), even after controlling for gender and nutritional status (adjusted odds ratio [aOR] = 3.2129, 95% confidence interval [CI]: 1.5-6.8; p = .002). In addition, atopic schoolchildren had lower PC(20) and required a lower threshold dose of methacholine to induce a reaction (0.53 versus 0.82 mg/ml, p = .055 and .5 versus 1 mg/ml, p = .02, respectively) than nonatopics. Nevertheless, basal and predicted forced expiratory volume in one second (FEV1) were similar between groups. In contrast, among 204 preschoolers (4.74 +/- 1.1 years), there were no differences in the prevalence of positive BHR between atopics and nonatopics (74.5% versus 72.5%, p = .75, respectively). Furthermore, basal TcP(O2), a higher fall of TcP(O2) and lower threshold doses of methacholine required for induction as measured by TcP(O2) were similar between the atopic and nonatopic preschoolers. CONCLUSIONS: Atopic asthmatic schoolchildren have greater hyperresponsiveness to methacholine than nonatopics (only among those with normal nutritional status). However, atopic and nonatopic asthmatic preschoolers have similar hyperresponsiveness to methacholine. Therefore, factors different from atopy may be responsible for wheeze in younger children. PMID- 20831467 TI - Multicenter study of chronic asthma severity among emergency department patients with acute asthma. AB - OBJECTIVE: The initiation of controller therapy for asthma depends on chronic asthma severity. To facilitate initiation of inhaled corticosteroids (ICSs), the preferred controller therapy, in the emergency department (ED), the objective of the study was to describe chronic asthma severity, as defined by the national asthma guidelines, among children presenting to the ED with acute asthma. METHODS: Investigators at 14 U.S. sites prospectively enrolled consecutive children 2-17 years presenting to the ED with acute asthma. Three factors (daytime symptoms, nighttime symptoms, and medication usage) were used to categorize children into four chronic asthma severity groups: intermittent, mild persistent, moderate persistent or severe persistent. RESULTS: This multistate cohort of 311 children had a mean age of 7.7 years, was 51% Black, and 89% had a primary care provider (PCP). Regarding chronic severity, 18% were intermittent and 82% persistent: 37% mild persistent, 24% moderate persistent, and 20% severe persistent. Chronic severity groups did not differ by demographics or PCP status. Patients with persistent asthma were more likely to report moderate-severe asthma symptoms (58% versus 19%; p < .001), poor asthma control (2% versus 18%; p = .002), and more ED visits (median, 2 versus 1; p < .001) in the past year. The groups did not differ in acute asthma severity, ED treatment, or admission rate. Rate of discharge prescription for ICSs was low, albeit higher among children with persistent asthma (24% versus 4%; p = .003). CONCLUSIONS: The high prevalence of persistent asthma among ED patients exceeds the prevalence reported previously, and supports ED initiation of ICS, as recommended by national guidelines. PMID- 20831468 TI - Adherence and asthma control with mometasone furoate versus fluticasone propionate in adolescents and young adults with mild asthma. AB - INTRODUCTION: Because adherence to asthma controller medication among adolescents and young adults is poor but critical for asthma control, strategies are needed to improve adherence. One strategy is to reduce the number of daily doses necessary to maintain adequate control. Mometasone furoate delivered through a dry powder inhaler (MF-DPI) is an inhaled corticosteroid (ICS) approved for once daily dosing in most patients. Fluticasone propionate (FP) is an ICS approved for twice-daily dosing. A retrospective claims analysis was performed to assess treatment adherence and markers of asthma control in adolescent and young adult patients with mild asthma who began treatment with MF-DPI or FP. METHODS: Data from approximately 37 million patients in an administrative insurance claims database in the United States were analyzed. Patients, 12-25 years, with mild asthma and previous asthma medication use were assigned an index date based on their first prescription fill of MF-DPI or FP between 1 January 2005 and 10 October 2008. Demographics, prescription claims, and health care utilization data were captured in the 365-day period before (preindex) and after (postindex) the index date. Patients from each cohort were propensity score-matched 1:1 based on preindex data. Adherence was measured by prescription fills and percentage of days covered (PDC); asthma control was measured by exacerbations and short-acting beta2-agonist (SABA) canister claims. Bivariate and multivariate generalized linear model (GLM) analyses were conducted to determine differences in outcomes between the cohorts. RESULTS: After matching, 692 patients per group (average age - 16 years) were analyzed. Adherence in the postindex period was significantly higher in the MF-DPI cohort compared with the FP cohort as measured by PDC (23.5% vs. 14.5%; p< .0001) and prescription fills (2.70 vs. 1.91; p< .0001). The mean number of postindex SABA canister claims was significantly lower in the MF-DPI cohort compared with the FP cohort (1.04 vs. 1.40; p< .0001). There was no significant difference in the mean number of postindex exacerbations between the cohorts. CONCLUSION: Adolescent/young adult patients with mild asthma who received MF-DPI had better postindex adherence and fewer SABA canister claims than patients receiving FP. PMID- 20831469 TI - The effects of antisense interleukin-4 gene transferred by recombinant adeno associated virus vector on the airway remodeling in allergic rats. AB - BACKGROUND: Th2-derived cytokines, including interleukin-4 (IL-4), are considered to play an important role in the development of airway remodeling of asthma. OBJECTIVES: Our previous study has demonstrated that a recombinant adeno associated virus containing antisense against IL-4 gene (rAAV-asIL4) vector could significantly suppress the expression of IL-4 protein and airway inflammation in the rat models of allergic asthma. In this study, we applied the rAAV-asIL4 vector to allergic rats to investigate the effects of anti-IL4 therapy on airway remodeling in allergic asthma. METHODS: rAAV-asIL4 was used to infect the ovalbumin (OVA)-sensitized and challenged rats by tail-vein injection. IL-4 protein in bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The number of eosinophils in BALF was counted. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2-positive cells in the peribronchial space were detected by immunohistochemical staining, and collagen deposition beneath the basement membrane was detected by Sirius red stain. The lung tissues were collected for histologic analysis of total bronchial wall area (W(At)) and airway smooth muscle area (W(Am)). RESULTS: rAAV-asIL4 significantly decreased IL 4 protein in BALF of OVA-sensitized and challenged rats. The number of eosinophils in BALF, the TGF-beta1 and TGF-beta2-positive cells in the peribronchial space were also suppressed. Moreover, the rAAV-asIL4 treatment inhibited the area of Sirius red staining in airways and the increase in W(At) and W(Am). CONCLUSION: These results suggest that rAAV-asIL4 may attenuate the airway remodeling process relevant to the inhibition of airway inflammation. This study provides elementary evidence for the potential utility of rAAV-asIL4 as an approach to gene therapy for asthmatic airway remodeling. PMID- 20831470 TI - Relationship of medical home quality with school engagement and after-school participation among children with asthma. AB - OBJECTIVES: To examine the relationship between medical home quality and measures of daily life experiences among children with asthma. METHODS: A nationally representative sample of children from the 2007 National Survey of Children's Health (NSCH), aged 6-17 years (n = 6357), who have asthma was used to assess the relationship of a quality medical home and its features with their daily life experiences. Five medical home features - access, continuity, comprehensiveness, family-centered care, and coordination of care - were examined individually and in total in relation to measures of school engagement (missed school days, parents contacted about problems with the child, repeating a grade since kindergarten) and after-school activity participation (physical activity, sports participation, and community service or volunteer work). RESULTS: Before and after adjustment for personal characteristics, health insurance status, family environment, neighborhood variables, and asthma severity, total medical home score was associated with more days exercised [beta (B) = 0.10, p < .05] and a greater likelihood of having performed community service or volunteer work [odds ratio (OR) = 1.16, CI: 1.02-1.31]. Additionally, the medical home features of access, comprehensiveness, and family-centered care remained favorably associated with three of the six measures of school engagement and after-school activity participation, even after adjustment. CONCLUSION: Medical home quality - particularly the features of access, comprehensiveness, and family-centered care is positively associated with the daily life experiences of children with asthma. Working to enhance these aspects of primary care might be one place to start in improving the management of children's chronic conditions and their quality of life. PMID- 20831471 TI - Putative association of SMAPIL polymorphisms with risk of aspirin intolerance in asthmatics. AB - BACKGROUND: Aspirin-intolerant asthma (AIA), as a clinical syndrome caused by aspirin, is characterized by lung inflammation and reversible bronchoconstriction. Recently, the altered trafficking and diminished airway reactivity have been implicated in allergic airway remodeling. The stromal membrane-associated protein 1-like (SMAP1L) exerts common and distinct functions in vesicle trafficking including endocytosis. The disturbance of pulmonary surfactant synthesis has been elucidated to be associated with asthma experimentally. Moreover, in alveolar type II (ATII) cells that synthesize pulmonary surfactant, alterations of clathrin-dependent endocytosis cause disturbance at the surfactant function, suggesting that SMAP1L, which directly interacts with clathrin, could be associated with asthma and related phenotypes. OBJECTIVE: To verify our hypothesis that SMAP1L could play a role in the development of AIA, this study investigated associations between single nucleotide polymorphisms (SNPs) of the SMAP1L gene and AIA. METHODS: We conducted an association study between 19 SNPs of the SMAP1L gene and AIA in a total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of SMAP1L and AIA were analyzed with sex, smoking status, atopy, and body mass index as covariates. RESULTS: Logistic analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (p = .003, p(corr) = .004, OR = 0.24, 95% CI = 0.09-0.62 for rs2982510 and rs2294752; p = .008, p(corr) = .03, OR = 0.44, 95% CI = 0.24-0.80 for rs446738, in the recessive model). In addition, rs2982510 and rs2294752 were significantly associated with the fall of forced expiratory volume in 1 s (FEV1) by aspirin provocation (p = .001, p(corr) = .04 in the recessive model for both SNPs). CONCLUSIONS: Our findings suggest that SMAP1L might be a susceptible gene to AIA, providing a new strategy for the control of aspirin intolerance. PMID- 20831475 TI - Asthma research and randomized controlled trials: a remarkable phenomenon. AB - BACKGROUND: Time trends in the number of publications of randomized controlled trials (RCTs) in asthma research have never been evaluated. METHODS: A PubMed database scan was made to identify publications in asthma research per year since 1990 until 1 January 2010, using the term 'asthma'. The total number of publications was ascertained, as was the number when restricting the search strategy to RCTs only. RESULTS: The total number of publications in asthma research increased from 2240 per year in 1990 to 5601 per year in 2009. The number of publications of RCTs in asthma research was 198 per year in 1990 and 233 per year in 2009. DISCUSSION: The remarkable phenomenon of an almost unchanged number of publications of RCTs in asthma research per year in the period 1990-2009 may be explained by criticism to RCTs in asthma research. CONCLUSION: Despite an increase in total publications of asthma research, time trends in the number of publications of RCTs in asthma research per year show an almost unchanged number in the period 1990-2009. Evidence-based medicine within the field of asthma still faces many challenges. PMID- 20831476 TI - Biology-guided adaptive radiation therapy - presence or future? PMID- 20831477 TI - Non-invasive imaging of combretastatin activity in two tumor models: Association with invasive estimates. AB - INTRODUCTION: The efficacy of the vascular disrupting agent combretastatin A-4 phosphate (CA4P) depends on several factors including tumor size, nitric oxide level, interstitial fluid pressure, and vascular permeability. These factors vary among tumor types. The aim of this study was to investigate all these factors in two tumor models that respond differently to CA4P. MATERIAL AND METHODS: Mice bearing C3H mammary carcinomas or KHT sarcomas (200 to 800 mm(3)) were intraperitoneally injected with CA4P (100 mg/kg). Tumor size and the effect of a nitric oxide inhibitor nitro-L-arginine (NLA) administered intravenously were evaluated by necrotic fraction histologically assessed at 24 hours. Interstitial fluid pressure (IFP) was measured using the wick-in-needle technique, and vascular characteristics were assessed with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Initial necrotic fraction was about 10% in both tumor models at 200 mm(3), but only increased significantly with tumor size in the C3H mammary carcinoma. In this tumor, CA4P significantly induced further necrosis by about 15% at all sizes, but in the KHT tumor, the induced necrotic fraction depended on tumor size. For both tumor types, NLA with CA4P significantly increased necrotic fraction above that for each drug alone. CA4P significantly decreased IFP in all tumors except in the 800 mm(3) C3H tumor, which had an initially non-significant lower value. Interstitial volume estimated by DCE-MRI increased in all groups, except the 800 mm(3) C3H tumors. DCE-MRI vascular parameters showed different initial characteristics and general significant reductions following CA4P treatment. CONCLUSIONS: Both tumor models showed differences in all factors before treatment, and in their response to CA4P. Perfusion and permeability as estimated by DCE-MRI play a central role in the CA4P response, and interstitial volume and IFP seemed related. These factors may be of clinical value in the planning of CA4P treatments. PMID- 20831478 TI - Preclinical dynamic 18F-FDG PET - tumor characterization and radiotherapy response assessment by kinetic compartment analysis. AB - BACKGROUND: Non-invasive visualization of tumor biological and molecular processes of importance to diagnosis and treatment response is likely to be critical in individualized cancer therapy. Since conventional static (18)F-FDG PET with calculation of the semi-quantitative parameter standardized uptake value (SUV) may be subject to many sources of variability, we here present an approach of quantifying the (18)F-FDG uptake by analytic two-tissue compartment modeling, extracting kinetic tumor parameters from dynamic (18)F-FDG PET. Further, we evaluate the potential of such parameters in radiotherapy response assessment. MATERIAL AND METHODS: Male, athymic mice with prostate carcinoma xenografts were subjected to dynamic PET either untreated (n=8) or 24 h post-irradiation (7.5 Gy single dose, n=8). After 10 h of fasting, intravenous bolus injections of 10-15 MBq (18)F-FDG were administered and a 1 h dynamic PET scan was performed. 4D emission data were reconstructed using OSEM-MAP, before remote post-processing. Individual arterial input functions were extracted from the image series. Subsequently, tumor (18)F-FDG uptake was fitted voxel-by-voxel to a compartment model, producing kinetic parameter maps. RESULTS: The kinetic model separated the (18)F-FDG uptake into free and bound tracer and quantified three parameters; forward tracer diffusion (k(1)), backward tracer diffusion (k(2)), and rate of (18)F-FDG phosphorylation, i.e. the glucose metabolism (k(3)). The fitted kinetic model gave a goodness of fit (r(2)) to the observed data ranging from 0.91 to 0.99, and produced parametrical images of all tumors included in the study. Untreated tumors showed homogeneous intra-group median values of all three parameters (k(1), k(2) and k(3)), whereas the parameters significantly increased in the tumors irradiated 24 h prior to (18)F-FDG PET. CONCLUSIONS: This study demonstrates the feasibility of a two-tissue compartment kinetic analysis of dynamic (18)F-FDG PET images. If validated, extracted parametrical maps might contribute to tumor biological characterization and radiotherapy response assessment. PMID- 20831479 TI - Assessing hypoxia in animal tumor models based on pharmocokinetic analysis of dynamic FAZA PET. AB - Positron emission tomography (PET) allows non-invasive detection and mapping of tumor hypoxia. However, slow tracer kinetics and low resolution, results in limited tumor-to-normal tissue contrast and the risk of missing areas where hypoxic cells are intermixed with necrosis. The shape of tumor time activity curves (TACs), as deduced from dynamic scans, may allow further separation of tumors/tumor sub-volumes that are inseparable based on static scans. This study was designed to define the added value of dynamic scans. MATERIAL AND METHODS: Three squamous cell carcinoma tumor models were grown in mice. Mice were injected with the (18)F-labeled PET hypoxia-tracer fluoroazomycin arabinoside (FAZA) and the immunologically-detectable hypoxia-marker pimonidazole, and PET scanned dynamically for three to six hours. Subsequently, microregional tracer retention (autoradiography) and the distribution of pimonidazole-retaining cells (immunohistology) and necrosis were analyzed in tumor tissue sections. Dynamic PET data were analysed based on a two-compartment model with irreversible tracer binding generating estimates of the putative hypoxia surrogate markers k(3) (tracer trapping rate constant) and K(i) (influx rate constant from plasma into irreversible bound tracer). RESULTS/DISCUSSION: High tumor-to-reference tissue ratios and a strong linear correlation (R~0.7 to 0.95) between density of hypoxic cells and FAZA concentration was observed three hours after tracer administration, suggesting that late time PET images provides an accurate measure of hypoxia against which kinetic model estimates can be validated. Tumor TACs varied widely (ranging from distinctly wash-out to accumulative type) among tumor types although pimonidazole-stainings revealed extensive hypoxia in all models. Kinetic analysis of tumor sub-volumes showed that k(3) correlated poorly with late time FAZA retention regionally in two of the three tumor models. The influx rate constant K(i) displayed far less variability and correlated strongly with late time FAZA retention (hypoxia) in two of three tumor models, whereas a non consistent relationship was observed in the last tumor model. Our study demonstrates the potential usefulness of dynamic PET, but also that a simple two compartment model may be inappropriate in some tumor models. PMID- 20831481 TI - Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer. AB - BACKGROUND: The aim of this pilot study was to assess tumour hypoxia in patients with cervical cancer before, during and after combined radio-chemotherapy and Magnetic Resonance Imaging (MRI) guided brachytherapy (BT) by use of the hypoxia Positron Emission Tomography (PET) tracer (18)F-fluoroazomycin-arabinoside ((18)FAZA ). MATERIAL AND METHODS: Fifteen consecutive patients with locally advanced cervical cancer referred for definitive radiotherapy (RT) were included in an approved clinical protocol. Stage distribution was 3 IB1, 1 IB2, 10 IIB, 1 IIIB, tumour volume was 55 cm(3) (+/- 67, SD). Dynamic and static (18)FAZA -PET scans were performed before, during and after external beam therapy (EBRT) and image guided BT +/- concomitant cisplatin. Dose was prescribed to the individual High Risk Clinical Target Volume (HR CTV) taking into account the dose volume constraints for adjacent organs at risk. RESULTS: Five patients had visually identifiable tumours on (18)FAZA -PET scans performed prior to radio-chemotherapy and four patients before brachytherapy. One of five (18)FAZA PET positive patients had incomplete remission three months after RT, one had regional recurrence. Four of ten (18)FAZA-PET negative patients developed distant metastases. The one patient with incomplete remission received 69 Gy (D90) in the HR CTV, whereas all other patients received mean 99 Gy (+/-12, SD). CONCLUSION: PET imaging with (18)FAZA is feasible in patients with cancer of the uterine cervix. However, its predictive and prognostic value remains to be clarified. This applies in particular for the additional value of (18)FAZA-PET compared to morphologic repetitive MRI within the setting of image guided high dose radiotherapy which may contribute to overcome hypoxia related radioresistance. PMID- 20831480 TI - Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. AB - INTRODUCTION: Polarographic oxygen-sensitive electrodes have demonstrated prognostic significance of hypoxia. However, its routine application is limited. (18)F-FMISO PET scans are a noninvasive approach, able to measure spatial and temporal changes in hypoxia. The aim of this study was to examine the association between measures of hypoxia defined by functional imaging and Eppendorf pO(2) electrodes. MATERIALS AND METHODS: A total of 18 patients were included, nine squamous cell carcinoma of the head and neck and nine soft tissue tumors. The tumor volume was defined by CT, MRI, (18)FDG-PET or by clinical examination. The oxygenation status of the tumors was assessed using (18)F-FMISO PET imaging followed by Eppendorf pO(2) electrode measurements. Data were compared in a 'virtual voxel', resulting in individual histograms from each tumor. RESULTS: The percentages of pO(2) <= 5 mmHg ranged from 9 to 94% (median 43%) for all 18 tumors. For (18)F-FMISO PET the T/M ratio ranged from 0.70 to 2.38 (median 1.13). Analyzing the virtual voxel histograms tumors could be categorized in three groups: Well oxygenated tumors with no hypoxia and concordance between the (18)F FMISO data and the Eppendorf measurements, hypoxic tumors likewise with concordance between the two assays and inconclusive tumors with no concordance between the assays. CONCLUSION: This study analyzed the relationship between (18)F-FMISO PET and Eppendorf pO(2) electrode measurements by use of a virtual voxel model. There was a spectrum of hypoxia among tumors that can be detected by both assays. However no correlation was observed, and in general tumors were more hypoxic based on Eppendorf pO(2) measurements as compared to (18)F-FMISO PET. PMID- 20831482 TI - Strategies of assessing and quantifying radiation treatment metabolic tumor response using F18 FDG Positron Emission Tomography (PET). AB - The use of positron emission tomography (PET) using F18 labeled fluorodeoxyglucose (FDG) for both oncology disease staging and radiation therapy target volume delineation has steadily increased over the last decade, and FDG PET is today readily available in all major medical centers. The goal of anti tumor treatment, including chemotherapy and/or radiation therapy is to diminish a tumor cell population, ideally to the state of total eradication. Reducing the number of viable tumor cells can lead to a reduction in anatomical tumor size, and may also be correlated with decreased FDG uptake. Efforts to assess tumor response to therapy have attempted to describe and quantify changes in glucose utilization, also referred to as metabolic tumor response. In this review, an attempt is made to present and discuss methodologies to assess and quantify tumor metabolic response to radiation therapy or chemoradiation treatment courses. PMID- 20831483 TI - Feasibility of dose painting using volumetric modulated arc optimization and delivery. AB - PURPOSE: Dose painting strategies are limited by optimization algorithms in treatment planning systems and physical constraints of the beam delivery. We investigate dose conformity using the RapidArc optimizer and beam delivery technique. Furthermore, robustness of the plans with respect to positioning uncertainties are evaluated. METHODS: A head & neck cancer patient underwent a [(61)Cu]Cu-ATSM PET/CT-scan. PET-SUVs were converted to prescribed dose with a base dose of 60 Gy, and target mean dose 90 Gy. The voxel-based prescription was converted into 3, 5, 7, 9, and 11 discrete prescription levels. Optimization was performed in Eclipse, varying the following parameters: MLC leaf width (5 mm and 2.5 mm), number of arcs (1 and 2) and collimator rotation (0, 15, 30 and 45 degrees). Dose conformity was evaluated using quality volume histograms (QVHs), and relative volumes receiving within +/-5% of prescribed dose (Q(0.95-1.05)). Deliverability was tested using a Delta4((r)) phantom. Robustness was tested by shifting the isocenter 1 mm and 2 mm in all directions, and recalculating the dose. RESULTS: Good conformity was obtained using MLC leaf width 2.5 mm, two arcs, and collimators 45/315 degrees, with Q(0.95-1.05)=92.8%, 91.6%, 89.7% and 84.6%. Using only one arc or increasing the MLC leaf width had a small deteriorating effect of 2-5%. Small changes in collimator angle gave small changes, but large changes in collimator angle gave a larger decrease in plan conformity; for angles of 15 and 0 degrees (two arcs, 2.5 mm leaf width), Q(0.95 1.05) decreased by up to 15%. Consistency between planned and delivered dose was good, with ~90% of gamma values <1. For 1 mm shift, Q(0.95-1.05) was decreased by 5-15%, while for 2 mm shift, Q(0.95-1.05) was decreased to 55-60%. CONCLUSIONS: Results demonstrate feasibility of planning of prescription doses with multiple levels for dose painting using RapidArc, and plans were deliverable. Robustness to positional error was low. PMID- 20831484 TI - Adaptive radiotherapy based on contrast enhanced cone beam CT imaging. AB - Cone beam CT (CBCT) imaging has become an integral part of radiation therapy, with images typically used for offline or online patient setup corrections based on bony anatomy co-registration. Ideally, the co-registration should be based on tumor localization. However, soft tissue contrast in CBCT images may be limited. In the present work, contrast enhanced CBCT (CECBCT) images were used for tumor visualization and treatment adaptation. Material and methods. A spontaneous canine maxillary tumor was subjected to repeated cone beam CT imaging during fractionated radiotherapy (10 fractions in total). At five of the treatment fractions, CECBCT images, employing an iodinated contrast agent, were acquired, as well as pre-contrast CBCT images. The tumor was clearly visible in post contrast minus pre-contrast subtraction images, and these contrast images were used to delineate gross tumor volumes. IMRT dose plans were subsequently generated. Four different strategies were explored: 1) fully adapted planning based on each CECBCT image series, 2) planning based on images acquired at the first treatment fraction and patient repositioning following bony anatomy co registration, 3) as for 2), but with patient repositioning based on co registering contrast images, and 4) a strategy with no patient repositioning or treatment adaptation. The equivalent uniform dose (EUD) and tumor control probability (TCP) calculations to estimate treatment outcome for each strategy. Results. Similar translation vectors were found when bony anatomy and contrast enhancement co-registration were compared. Strategy 1 gave EUDs closest to the prescription dose and the highest TCP. Strategies 2 and 3 gave EUDs and TCPs close to that of strategy 1, with strategy 3 being slightly better than strategy 2. Even greater benefits from strategies 1 and 3 are expected with increasing tumor movement or deformation during treatment. The non-adaptive strategy 4 was clearly inferior to all three adaptive strategies. Conclusion. CECBCT may prove useful for adaptive radiotherapy. PMID- 20831485 TI - Apparent diffusion coefficients in GEC ESTRO target volumes for image guided adaptive brachytherapy of locally advanced cervical cancer. AB - BACKGROUND AND PURPOSE: T2 weighted MRI is recommended for image guided adaptive brachytherapy (IGABT) in cervical cancer. Diffusion weighted imaging (DWI) and the derived apparent diffusion coefficient (ADC) may add additional biological information on tumour cell density. The purpose of this study was to evaluate the distribution of the ADC within target volumes as recommended by GEC-ESTRO: Gross Tumour Volume at BT (GTV(BT)), High-Risk Clinical Tumour Volume (HR-CTV) and Intermediate-Risk Clinical Target Volume (IR-CTV) and to evaluate the change of diffusion between fractions of IGABT. MATERIAL AND METHODS: Fifteen patients with locally advanced cervical cancer were examined by MRI before their first (BT1) and second (BT2) fraction of IGABT, resulting in a total of 30 MR examinations including both T2 weighted and DWI sequences. The Apparent Diffusion Coefficient (ADC) was calculated by use of three levels of b-values (0, 600, 1000 s/mm(2)). ADC maps were constructed and fused with the GEC ESTRO target contours. The mean ADC value within each target volume was calculated. Furthermore, volumes of low diffusion (ADC(low)) were defined based on an ADC threshold of 1.2 * 10(-3) mm(2)/s, and overlap with target volumes was evaluated. Change of ADC level in target volumes and change of ADC(low) volume from BT1 to BT2 was also evaluated. RESULTS: The mean ADC was significantly lower in GTV(BT) than in HR-CTV (p<0.001) which again was significantly lower than in IR-CTV (p<0.001). There was no significant change of the ADC(low) volume or ADC level within each target structure between BT1 and BT2 (p=0.242). All three GEC-ESTRO volumes contained volumes with low diffusion. The GTV(BT) contained 37.2% volume of low diffusion, HR-CTV 20.3% and IR-CTV 10.8%. CONCLUSION: With DWI we were able to find a significant difference in ADC-values for the three different GEC ESTRO targets. This supports the assumption that the target volumes used for dose prescription in IGABT contain tissues with different characteristics, with the tumour (GTV(BT)) being the volume with the lowest diffusion. No significant changes were found from BT1 to BT2 indicating that changes of ADC level and volumes are stable at the time of BT. Further studies are needed to evaluate the role of DWI in target contouring and dose prescription for IGABT. PMID- 20831486 TI - Methodologies for localizing loco-regional hypopharyngeal carcinoma recurrences in relation to FDG-PET positive and clinical radiation therapy target volumes. AB - BACKGROUND: Focal methods to determine the source of recurrence are presented, tested for reproducibility and compared to volumetric approaches with respect to the number of recurrences ascribed to the FDG-PET positive and high dose volumes. MATERIAL AND METHODS: Six patients treated for hypopharyngeal squamous cell carcinoma were extracted from archives. Inclusion criteria were: FDG-PET/CT for primary radiotherapy planning and clinical complete remission followed by loco regional relapse. CT scan at the time of recurrence was also required. The recurrence volume was delineated in the follow-up scans by a radiologist. Putative points of origin (PO) of the recurrence were determined by two strategies 1) defined by an oncologist or 2) as the center-of-volume (COV) of the recurrence. The most likely recurrence point of origin on the treatment planning scan was also determined. All expert based points of origin were repeated to estimate reproducibility. The recurrence volume and PO were propagated to the treatment planning scan using a rigid transformation. Relations of the PO to target volumes, radiation doses and therapy-points-of-origin were quantified. For the volumetric methods, the overlap of the recurrence volume and target volumes was used to determine the source of the recurrence. RESULTS: All recurrences were located in-field, but the volumetric approaches tended to designate fewer recurrences in the PET positive volume (25% for the 95% threshold, 95% confidence interval (CI):3-65%) than the observer-based methods (50% for the COV and both expert evaluations on the recurrence scan, 95% CI: 16-84%). The reproducibility of the expert POs is better on the recurrence scan than on the therapy scan. CONCLUSION: Volumetric approaches favor large target volumes as the source of the recurrence, thus underestimating the number of recurrences originating in the PET positive volume. Expert based and COV approaches on the recurrence scan are the most reproducible methods to determine the PO. PMID- 20831487 TI - Feasibility and sensitivity study of helical tomotherapy for dose painting plans. AB - Important limitations for dose painting are due to treatment planning and delivery constraints. The purpose of this study was to develop a methodology for creating voxel-based dose painting plans that are deliverable using the clinical TomoTherapy Hi-Art II treatment planning system (TPS). Material and methods. Uptake data from a head and neck patient who underwent a [(61)Cu]Cu-ATSM (hypoxia surrogate) PET/CT scan was retrospectively extracted for planning. Non-uniform voxel-based prescriptions were converted to structured-based prescriptions for compatibility with the Hi-Art II TPS. Optimized plans were generated by varying parameters such as dose level, structure importance, prescription point normalization, DVH volume, min/max dose, and dose penalty. Delivery parameters such as pitch, jaw width and modulation factor were also varied. Isodose distributions, quality volume histograms and planning target volume percentage receiving planned dose within 5% of the prescription (Q(0.95-1.05)) were used to evaluate plan conformity. Results. In general, the conformity of treatment plans to dose prescriptions was found to be adequate for delivery of dose painting plans. The conformity was better as the dose levels increased from three to nine levels (Q(0.95-1.05): 69% to 93%), jaw decreased in width from 5.0cm to 1.05cm (Q(0.95-1.05): 81% to 93%), and modulation factor increased up to 2.0 (Q(0.95 1.05): 36% to 92%). The conformity was invariant to changes in pitch. Plan conformity decreased as the prescription DVH constraint (Q(0.95-1.05): 93% vs. 89%) or the normalization point (Q(0.95-1.05): 93% vs. 90%) deviated from the means. Conclusion. This investigation demonstrated the ability of the Hi-Art II TPS to create voxel-based dose painting plans. Results indicated that agreement in prescription dose and planned dose distributions for all plans were sensitive to physical delivery parameter changes in jaw width and modulation factors, but insensitive to changes in pitch. Tight constraints on target structures also resulted in decreased plan conformity while under a relaxed set of optimization parameters, plan conformity was increased. PMID- 20831488 TI - Imaging of normal lung, liver and parotid gland function for radiotherapy. AB - There is growing clinical evidence that functional imaging is useful for target volume definition and early assessment of tumour response to external beam radiotherapy. A subject that has perhaps received less attention, but is no less promising, is the application of functional imaging to the prediction or measurement of radiation adverse effects in normal tissues. In this manuscript, we review the current published literature describing the use of positron emission tomography (PET), four-dimensional computed tomography (4D-CT), single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) to study normal tissue function in the context of radiotherapy to the lung, liver and head & neck. Published results to date demonstrate that functional imaging can be used to preferentially avoid normal tissues not easily identifiable on solely anatomical images. It is also a potentially very powerful tool for the early detection of radiotherapy-induced normal tissue adverse effects and could provide valuable data for building predictive models of outcome. However, one of the major challenges to building useful predictive models is that, to date, there are very little data available with combined images of normal function, 3D delivered radiation dose and clinical outcomes. Prospective data collection through well-constructed studies which use established morbidity scores is clearly a priority if significant progress is to be made in this area. PMID- 20831489 TI - Variability of textural features in FDG PET images due to different acquisition modes and reconstruction parameters. AB - BACKGROUND: Characterization of textural features (spatial distributions of image intensity levels) has been considered as a tool for automatic tumor segmentation. The purpose of this work is to study the variability of the textural features in PET images due to different acquisition modes and reconstruction parameters. MATERIAL AND METHODS: Twenty patients with solid tumors underwent PET/CT scans on a GE Discovery VCT scanner, 45-60 minutes post-injection of 10 mCi of [(18)F]FDG. Scans were acquired in both 2D and 3D modes. For each acquisition the raw PET data was reconstructed using five different reconstruction parameters. Lesions were segmented on a default image using the threshold of 40% of maximum SUV. Fifty different texture features were calculated inside the tumors. The range of variations of the features were calculated with respect to the average value. RESULTS: Fifty textural features were classified based on the range of variation in three categories: small, intermediate and large variability. Features with small variability (range <= 5%) were entropy-first order, energy, maximal correlation coefficient (second order feature) and low-gray level run emphasis (high-order feature). The features with intermediate variability (10% <= range <= 25%) were entropy-GLCM, sum entropy, high gray level run emphsis, gray level non uniformity, small number emphasis, and entropy-NGL. Forty remaining features presented large variations (range > 30%). CONCLUSION: Textural features such as entropy-first order, energy, maximal correlation coefficient, and low-gray level run emphasis exhibited small variations due to different acquisition modes and reconstruction parameters. Features with low level of variations are better candidates for reproducible tumor segmentation. Even though features such as contrast-NGTD, coarseness, homogeneity, and busyness have been previously used, our data indicated that these features presented large variations, therefore they could not be considered as a good candidates for tumor segmentation. PMID- 20831490 TI - Apparent Diffusion Coefficient (ADC) as a quantitative parameter in diffusion weighted MR imaging in gynecologic cancer: Dependence on b-values used. AB - BACKGROUND: Diffusion weighted imaging (DWI) has gained interest as an imaging modality for assessment of tumor extension and response to cancer treatment. The purpose of this study is to assess the impact of the choice of b-values on the calculation of the Apparent Diffusion Coefficient (ADC) for locally advanced gynecological cancer and to estimate a stable interval of diffusion gradients that allows for best comparison of the ADC between patients and institutions. MATERIAL AND METHODS: Six patients underwent a high resolution single shot EPI based DWI scan with 16 different diffusion gradients on a 3 Tesla Philips Achieva MR-scanner. Data analysis was performed by applying a monoexponential and a biexponential model to the acquired data. The biexponential function models the effect of both perfusion and diffusion. RESULTS AND CONCLUSION: ADC changes of up to 40% were seen with the use of different b-values. Using a lower b-value >= 150 s/mm(2) and an upper b-value >= 700 s/mm(2) limited the variation to less that 10% from the reference ADC value. By eliminating the contribution of perfusion the uncertainty of quantitative ADC values were significantly reduced. PMID- 20831491 TI - Propagation of target and organ at risk contours in radiotherapy of prostate cancer using deformable image registration. AB - BACKGROUND: Successful deformable image registration is an essential component of both dose accumulation and plan adaptation in radiotherapy. The aim of this study was to evaluate the performance of a deformable image registration application for propagation of contours using repeat CT scans of the pelvis, a region where considerable deformations are expected. MATERIAL AND METHODS: The study involved four prostate cancer patients, each with 9-11 repeat CT scans. An oncologist contoured bladder, rectum, clinical target volume of pelvic lymph nodes (CTV-ln) and prostate (CTV-p) in all CT scans. The reference CT was retrospectively registered to the repeat CT scans with both rigid and deformable registration using a recently released commercial clinical software application. Two different diffusion-based 'demons' deformable registration algorithms were applied, differing in the amount of deformations being allowed, with algorithm A being more generous than algorithm B. The evaluation of the propagated structures included both quantitative measures and qualitative scoring. RESULTS: We found the differences between the algorithms to be most evident for bladder and rectum. An increase in mean Dice similarity coefficient relative the rigid registrations of 12% and 13% was obtained with algorithm A for bladder and rectum, compared to 2% with algorithm B. For bladder the mean sensitivity and positive predictive value was 0.92 and 0.87 with algorithm A and 0.82 and 0.83 with algorithm B. Corresponding values for rectum was 0.81 and 0.76 with algorithm A and 0.75 and 0.69 with algorithm B. This translated into 57% and 26% passing the clinical evaluation for bladder and rectum, with algorithm A, compared to 17% and 14% with algorithm B. For CTV-ln and CTV-p both algorithms performed well by all measures, e.g. with 86% of the target structures passing the clinical evaluation. CONCLUSIONS: Deformable image registration improved contour propagation in the pelvis for all organs investigated. Differences in the performance of the algorithms were seen which became more pronounced for the highly deformable organs of bladder and rectum. PMID- 20831492 TI - Prediction of residual metabolic activity after treatment in NSCLC patients. AB - PURPOSE: Metabolic response assessment is often used as a surrogate of local failure and survival. Early identification of patients with residual metabolic activity is essential as this enables selection of patients who could potentially benefit from additional therapy. We report on the development of a pre-treatment prediction model for metabolic response using patient, tumor and treatment factors. METHODS: One hundred and one patients with inoperable NSCLC (stage I IV), treated with 3D conformal radical (chemo)-radiotherapy were retrospectively included in this study. All patients received a pre and post-radiotherapy fluorodeoxyglucose positron emission tomography-computed tomography FDG-PET-CT scan. The electronic medical record system and the medical patient charts were reviewed to obtain demographic, clinical, tumor and treatment data. Primary outcome measure was examined using a metabolic response assessment on a post radiotherapy FDG-PET-CT scan. Radiotherapy was delivered in fractions of 1.8 Gy, twice a day, with a median prescribed dose of 60 Gy. RESULTS: Overall survival was worse in patients with residual metabolic active areas compared with the patients with a complete metabolic response (p=0.0001). In univariate analysis, three variables were significantly associated with residual disease: larger primary gross tumor volume (GTV(primary), p=0.002), higher pre-treatment maximum standardized uptake value (SUV(max), p=0.0005) in the primary tumor and shorter overall treatment time (OTT, p=0.046). A multivariate model including GTV(primary), SUV(max), equivalent radiation dose at 2 Gy corrected for time (EQD(2, T)) and OTT yielded an area under the curve assessed by the leave-one-out cross validation of 0.71 (95% CI, 0.65-0.76). CONCLUSION: Our results confirmed the validity of metabolic response assessment as a surrogate of survival. We developed a multivariate model that is able to identify patients at risk of residual disease. These patients may benefit from an individualized and more adequate therapeutic approach, thereby improving local control and survival. PMID- 20831493 TI - Normal Tissue Complication Probability (NTCP) modeling of late rectal bleeding following external beam radiotherapy for prostate cancer: A Test of the QUANTEC recommended NTCP model. AB - PURPOSE/BACKGROUND: Validating a predictive model for late rectal bleeding following external beam treatment for prostate cancer would enable safer treatments or dose escalation. We tested the normal tissue complication probability (NTCP) model recommended in the recent QUANTEC review (quantitative analysis of normal tissue effects in the clinic). MATERIAL AND METHODS: One hundred and sixty one prostate cancer patients were treated with 3D conformal radiotherapy for prostate cancer at the British Columbia Cancer Agency in a prospective protocol. The total prescription dose for all patients was 74 Gy, delivered in 2 Gy/fraction. 159 3D treatment planning datasets were available for analysis. Rectal dose volume histograms were extracted and fitted to a Lyman Kutcher-Burman NTCP model. RESULTS: Late rectal bleeding (>grade 2) was observed in 12/159 patients (7.5%). Multivariate logistic regression with dose-volume parameters (V50, V60, V70, etc.) was non-significant. Among clinical variables, only age was significant on a Kaplan-Meier log-rank test (p=0.007, with an optimal cut point of 77 years). Best-fit Lyman-Kutcher-Burman model parameters (with 95% confidence intervals) were: n = 0.068 (0.01, +infinity); m =0.14 (0.0, 0.86); and TD50 = 81 (27, 136) Gy. The peak values fall within the 95% QUANTEC confidence intervals. On this dataset, both models had only modest ability to predict complications: the best-fit model had a Spearman's rank correlation coefficient of rs = 0.099 (p = 0.11) and area under the receiver operating characteristic curve (AUC) of 0.62; the QUANTEC model had rs=0.096 (p= 0.11) and a corresponding AUC of 0.61. Although the QUANTEC model consistently predicted higher NTCP values, it could not be rejected according to the chi(2) test (p = 0.44). CONCLUSIONS: Observed complications, and best-fit parameter estimates, were consistent with the QUANTEC-preferred NTCP model. However, predictive power was low, at least partly because the rectal dose distribution characteristics do not vary greatly within this patient cohort. PMID- 20831494 TI - Evaluation of adaptive radiotherapy of bladder cancer by image-based tumour control probability modelling. AB - Clinical implementation of adaptive radiotherapy strategies could benefit from extended tools for plan evaluation and selection. For this purpose we investigated the feasibility of image-based tumour control probability (TCP) modelling using the bladder as example of a tumour site with potential benefit from adaptive strategies. MATERIAL AND METHODS: Two bladder cancer patients that underwent planning CT and daily cone beam CT (CBCT) imaging during the treatment course were included. The bladder was outlined in every image series. Following a previously published procedure, various adaptive planning target volumes (PTVs) were generated from the inter-fractional bladder variation observed during the first four CBCT sessions. Intensity modulated treatment plans delivering 60 Gy to a given PTV were generated. In addition, simultaneous integrated boost (SIB) plans giving a 10 Gy boost to the tumour were created. Using the daily CBCT images and polynomial warping, the dose in each bladder volume element was tracked fraction by fraction. TCP calculations employing the tracked accumulated dose distributions, together with radiosensitivity parameters estimated from published data on local control of bladder cancer were performed. The dependence of TCP on the simulated clonogenic cell distribution was also explored. RESULTS: For a uniform clonogenic cell density in the whole bladder, TCP varied between 53% and 58% for the 60 Gy plans, while it was between 51% and 64% for the SIB plans. The lowest values were found when using the smallest PTVs, as they did not geometrically enclose the clinical target volume in all fractions. When increasing the clonogenic cell density in the tumour relative to that in the remaining bladder, the TCP saturated at approximately 75% for the SIB plans. CONCLUSION: Dose tracking and TCP calculation provided additional information to standard criteria such as geometrical coverage for the selected cases. TCP modelling may be a useful tool in plan evaluation and for selection between multiple plans. PMID- 20831495 TI - Hypofractionation does not increase radiation pneumonitis risk with modern conformal radiation delivery techniques. AB - PURPOSE: To study the interaction between radiation dose distribution and hypofractionated radiotherapy with respect to the risk of radiation pneumonitis (RP) estimated from normal tissue complication probability (NTCP) models. MATERIAL AND METHODS: Eighteen non-small cell lung cancer patients previously treated with helical tomotherapy were selected. For each patient a 3D-conformal plan (3D-CRT) plan was produced in addition to the delivered plan. The standard fractionation schedule was set to 60 Gy in 30 fractions. Iso-efficacy comparisons with hypofractionation were performed by changing the fractionation and the physical prescription dose while keeping the equivalent tumor dose in 2 Gy fractions constant. The risk of developing RP after radiotherapy was estimated using the Mean Equivalent Lung Dose in 2-Gy fractions (MELD(2)) NTCP model with alpha/beta=4 Gy for the residual lung. Overall treatment time was kept constant. RESULTS: The mean risk of clinical RP after standard fractionation was 7.6% for Tomotherapy (range: 2.8-15.9%) and 9.2% for 3D-CRT (range 3.2-20.2%). Changing to 20 fractions, the Tomotherapy plans became slightly less toxic if the tumor alpha/beta ratio, (alpha/beta)(T), was 7 Gy (mean RP risk 7.5%, range 2.8-16%) while the 3D-CRT plans became marginally more toxic (mean RP risk 9.8%, range 3.2 21%). If (alpha/beta)(T) was 13 Gy, the mean estimated risk of RP is 7.9% for Tomotherapy (range: 2.8-17%) and 10% for 3D-CRT (range 3.2-22%). CONCLUSION: Modern highly conformal dose distributions are radiobiologically more forgiving with respect to hypofractionation, even for a normal tissue endpoint where alpha/beta is lower than for the tumor in question. PMID- 20831496 TI - Cardiac toxicity and radiation dose to the heart in definitive treated non-small cell lung cancer. PMID- 20831497 TI - Rectum motion and morbidity prediction: Improving correlation between late morbidity and DVH parameters through use of rectum planning organ at risk volumes. AB - BACKGROUND AND PURPOSE: The rectum is a major dose-limiting organ at risk (OR) in radiotherapy (RT) of prostate cancer. Methods to predict adverse effects in the rectum are therefore important but their precision often limited, not the least by the internal motion of this organ. In this study late rectal morbidity is investigated in relation to the internal motion of the rectum by applying the 'Planning organ at Risk Volume' (PRV) concept. MATERIALS AND METHODS: Late rectal morbidity was analysed in 242 prostate cancer patients treated to 70 Gy with conformal RT to either the prostate, the prostate and seminal vesicles or the whole pelvis (initial 50 Gy only). Late rectal morbidity was classified by the late gastro-intestinal (GI) RTOG toxicity scoring system. Cumulative dose-volume histograms (DVHs) were derived for the rectum OR and six rectum PRVs i.e. the OR expanded with six different margins (narrow/intermediate/wide in anterior direction or in both anterior and posterior direction). The difference in rectum dose-volume parameters between patients with Grade 0-1 vs. Grade 2 or higher morbidity was investigated by logistic regression and permutation tests. RESULTS: Late Grade 2 or higher morbidity was observed in 25 of 242 (10%) patients. The logistic regression analysis and the permutation tests reached significance (p <= 0.05) for only one dose level of the rectum OR (40 Gy). For the PRVs, several dose levels were found to be significant (p-value range: 0.01-0.046), most pronounced for the PRV with narrow margins of 6 mm anterior and 5 mm posterior with five intermediate (38-42 Gy) and ten high (62-71 Gy) dose levels. CONCLUSIONS: The statistical methods applied displayed consistently a small though significant difference in DVH parameters between patients with vs. without Grade 2 or higher late rectal morbidity for intermediate and high dose levels. The difference became most evident when using a PRV with narrow margins. PMID- 20831498 TI - A comparison of three different adaptive strategies in image-guided radiotherapy of bladder cancer. AB - The urinary bladder shows considerable individual variation in shape and position during a course of radiotherapy (RT). In this study we have developed and compared three different adaptive RT (ART) strategies for bladder cancer involving daily cone beam CT (CBCT) imaging and plan selection. MATERIAL AND METHODS: Ten patients treated for bladder cancer had daily CBCTs acquired that were registered online using bony anatomy registration. Seven patients received intensity modulated RT (IMRT) with a simultaneous integrated boost (SIB) technique to the bladder and pelvic lymph nodes. Three patients received treatment to the bladder only. Retrospectively, we compared three ART strategies that were all based on daily selection of the most suitable plan from a library consisting of three IMRT-plans corresponding to a small, medium and large target volume. ART method A utilised population-based margins while methods B and C used the bladder as seen on CBCT-scans from the first week of treatment; method B without delineation of the bladder on CBCT and method C with delineation of the bladder. Total dose distributions were calculated using the planning CT. For each patient, we calculated ratios of the dose volume histograms (DVHs) for the three ART strategies relative to non-adaptive therapy. RESULTS: The inter-patient variation was large for all three ART strategies. The mean ratios of the volumes receiving 57 Gy or more (corresponding to 95% of prescribed dose) for methods A, B and C were 0.66 (SD: 0.11), 0.67 (SD: 0.13) and 0.67 (SD: 0.16) respectively when compared to the non-adaptive plan. CONCLUSION: When using any of the ART strategies, it is possible to reduce significantly the volumes receiving high doses compared to the use of a standard non-adaptive plan. The differences in dose volume parameters between the three methods were small compared with the differences from the standard plan. PMID- 20831499 TI - Daily cone-beam computed tomography used to determine tumour shrinkage and localisation in lung cancer patients. AB - PURPOSE/OBJECTIVE: Daily Cone-beam computed tomography (CBCT) in room imaging is used to determine tumour shrinkage during a full radiotherapy (RT) course. In addition, relative interfractional tumour and lymph node motion is determined for each RT fraction. MATERIAL AND METHODS: From November 2009 to March 2010, 20 consecutive lung cancer patients (14 NSCLC, 6 SCLC) were followed with daily CBCT during RT. The gross tumour volume for lung tumour (GTV-t) was visible in all daily CBCT scans and was delineated at the beginning, at the tenth and the 20th fraction, and at the end of treatment. Whenever visible, the gross tumour volume for lymph nodes (GTV-n) was also delineated. The GTV-t and GTV-n volumes were determined. All patients were setup according to an online bony anatomy match. Retrospectively, matching based on the internal target volume (ITV), the GTV-t or the GTV-n was performed. RESULTS: In eight patients, we observed a significant GTV-t shrinkage (15-40%) from the planning CT until the last CBCT. Only five patients presented a significant shrinkage (21-37%) in the GTV-n. Using the daily CBCT imaging, it was found that the mean value of the difference between a setup using the skin tattoo and an online matching using the ITV was 7.3+/-2.9 mm (3D vector in the direction of ITV). The mean difference between the ITV and bony anatomy matching was 3.0+/-1.3 mm. Finally, the mean distance between the GTV-t and the GTV-N was 2.9+/-1.6 mm. CONCLUSION: One third of all patients with lung cancer undergoing chemo-RT achieved significant tumour shrinkage from planning CT until the end of the radiotherapy. Differences in GTV-t and GTV-n motion was observed and matching using the ITV including both GTV-t and GTV-n is therefore preferable. PMID- 20831500 TI - Clinical evaluation of 3D/3D MRI-CBCT automatching on brain tumors for online patient setup verification - A step towards MRI-based treatment planning. AB - BACKGROUND: Magnetic Resonance Imaging (MRI) is often used in modern day radiotherapy (RT) due to superior soft tissue contrast. However, treatment planning based solely on MRI is restricted due to e.g. the limitations of conducting online patient setup verification using MRI as reference. In this study 3D/3D MRI-Cone Beam CT (CBCT) automatching for online patient setup verification was investigated. MATERIAL AND METHODS: Initially, a multi-modality phantom was constructed and used for a quantitative comparison of CT-CBCT and MRI CBCT automatching. Following the phantom experiment three patients undergoing postoperative radiotherapy for malignant brain tumors received a weekly CBCT. In total 18 scans was matched with both CT and MRI as reference. The CBCT scans were acquired using a Clinac iX 2300 linear accelerator (Varian Medical Systems) with an On-Board Imager (OBI). RESULTS: For the phantom experiment CT-CBCT and MRI CBCT automatching resulted in similar results. A significant difference was observed only in the longitudinal direction where MRI-CBCT resulted in the best match (mean and standard deviations of 1.85+/-2.68 mm for CT and -0.05+/-2.55 mm for MRI). For the clinical experiment the absolute difference in couch shift coordinates acquired from MRI-CBCT and CT-CBCT automatching, were <=2 mm in the vertical direction and <=3 mm in the longitudinal and lateral directions. For yaw rotation differences up to 3.3 degrees were observed. Mean values and standard deviations were 0.8+/-0.6 mm, 1.5+/-1.2 mm and 1.2+/-1.2 mm for the vertical, longitudinal and lateral directions, respectively and 1.95+/-1.12 degrees for the rotation (n=17). CONCLUSION: It is feasible to use MRI as reference when conducting 3D/3D CBCT automatching for online patient setup verification. For both the phantom and clinical experiment MRI-CBCT performed similar to CT-CBCT automatching and significantly better in the longitudinal direction for the phantom experiment. PMID- 20831501 TI - Dynamic MLC tracking of moving targets with a single kV imager for 3D conformal and IMRT treatments. AB - BACKGROUND: Tumor motion during radiotherapy is a major challenge for accurate dose delivery, in particular for hypofractionation and dose painting. The motion may be compensated by dynamic multileaf collimator (DMLC) tracking. Previous work has demonstrated that a single kV imager can accurately localize moving targets for DMLC tracking during rotational delivery, however this method has not been investigated for the static gantry geometry used for conformal and IMRT treatments. In this study we investigate the accuracy of single kV-imager based DMLC tracking for static-gantry delivery. MATERIAL AND METHODS: A 5-field treatment plan with circular field shape and 200 MU per field was delivered in 20 s per field to a moving phantom with an embedded gold marker. Fluoroscopic kV images were acquired at 5 Hz perpendicular to the treatment beam axis during a 120 degrees pre-treatment gantry rotation, during treatment delivery, and during inter-field gantry rotations. The three-dimensional marker position was estimated from the kV images and used for MLC adaptation. Experiments included 12 thoracic/abdominal tumor trajectories and five prostate trajectories selected from databases with 160 and 548 trajectories, respectively. The tracking error was determined as the mismatch between the marker position and the MLC aperture center in portal images. Simulations extended the study to all trajectories in the databases and to treatments with prolonged duration of 60 s per field. RESULTS: In the experiments, the mean root-mean-square (rms) tracking error was 0.9 mm (perpendicular to MLC) and 1.1 mm (parallel to MLC) for thoracic/abdominal tumor trajectories and 0.6 mm (perpendicular) and 0.5 mm (parallel) for prostate trajectories. Simulations of these experiments agreed to within 0.1 mm. Simulations of all trajectories in the databases resulted in mean rms tracking errors of 0.6 mm (perpendicular) and 0.9 mm (parallel) for thorax/abdomen tumors and 0.4 mm (perpendicular) and 0.2 mm (parallel) for prostate for both 20 s and 60 s per field. CONCLUSION: Single kV imager DMLC tracking, which is fully compatible with IMRT, was demonstrated for static fields. The mean tracking error was sub-2 mm for most tumor trajectories with respiratory motions and sub-1 mm for most prostate trajectories. PMID- 20831502 TI - Daily kV cone-beam CT and deformable image registration as a method for studying dosimetric consequences of anatomic changes in adaptive IMRT of head and neck cancer. AB - PURPOSE: Evaluating a method for anatomic changes assessment and actually delivered doses during head and neck (H&N) cancer radiotherapy (RT) utilizing volumetric images from cone-beam CT (CBCT) and a commercially available deformable image registration (DIR) software. MATERIAL AND METHODS: Thirty-three daily acquired CBCT image sets and the planning CT of one H&N cancer patient were retrospectively transferred from a standard treatment planning system (TPS) to the DIR software. The planning CT was deformed to each CBCT and the contours delineated for planning purposes were propagated. Transfer of each deformed planning CT back into the TPS enabled re-calculation of the actual daily delivered dose distribution based on online image-guidance. For both normal tissues and target volumes the deformed contours were visually evaluated and dose volume histogram (DVH) parameters were calculated. RESULTS: The workflow of the method took 45 minutes to estimate delivered dose for each treatment fraction. Propagated deformed contours were acceptable for evaluating changes in anatomy. Based on daily DVH parameters the actual delivered dose could be monitored. CONCLUSION: A proof-of-principle method to quantitatively monitor anatomical changes and delivered dose during the course of fractionated RT for H&N cancer has been demonstrated. This provides a tool for exploring adaptive re-planning strategies. PMID- 20831503 TI - Influence of MLC leaf width on biologically adapted IMRT plans. AB - INTRODUCTION: High resolution beam delivery may be required for optimal biology guided adaptive therapy. In this work, we have studied the influence of multi leaf collimator (MLC) leaf widths on the treatment outcome following adapted IMRT of a hypoxic tumour. MATERIAL AND METHODS: Dynamic contrast enhanced MR images of a dog with a spontaneous tumour in the nasal region were used to create a tentative hypoxia map following a previously published procedure. The hypoxia map was used as a basis for generating compartmental gross tumour volumes, which were utilised as planning structures in biologically adapted IMRT. Three different MLCs were employed in inverse treatment planning, with leaf widths of 2.5 mm, 5 mm and 10 mm. The number of treatment beams and the degree of step-and-shoot beam modulation were varied. By optimising the tumour control probability (TCP) function, optimal compartmental doses were derived and used as target doses in the inverse planning. Resulting IMRT dose distributions and dose volume histograms (DVHs) were exported and analysed, giving estimates of TCP and compartmental equivalent uniform doses (EUDs). The impact of patient setup accuracy was simulated. RESULTS: The MLC with the smallest leaf width (2.5 mm) consistently gave the highest TCPs and compartmental EUDs, assuming no setup error. The difference between this MLC and the 5 mm MLC was rather small, while the MLC with 10 mm leaf width gave considerably lower TCPs. When including random and systematic setup errors, errors larger than 5 mm gave only small differences between the MLC types. For setup errors larger than 7 mm no differences were found between non-uniform and uniform dose distributions. CONCLUSIONS: Biologically adapted radiotherapy may require MLCs with leaf widths smaller than 10 mm. However, for a high probability of cure it is crucial that accurate patient setup is ensured. PMID- 20831504 TI - The role of protons in modern and biologically-guided radiotherapy. AB - With the introduction of new biologically based imaging possibilities, a higher degree of individualisation and adaptation of radiotherapy will be possible. Better knowledge of the biology of the target and its sub-volumes will enable dose prescriptions tailored to the individual patients, tissues and sub-volumes. Repeated imaging during the course of treatment will in addition enable adaptation of the treatment to cope with anatomical, as well as biological changes of the patient and of the target tissues. To translate these bright future perspectives into significant improvements in clinical outcome, advanced tools to tailor the physical dose distributions are needed. The most conformal radiotherapy technique known to mankind and clinically available today is proton therapy; in particular Intensity Modulated Proton Therapy (IMPT) with active spot scanning can not only tailor the dose to the desired target, but also effectively avoid sensitive structures in the proximity of the target to a degree far better than other conformal techniques such as Intensity Modulated Radiotherapy with photons (IMRT). The development of IMPT is now mature enough for clinical introduction on a broad scale. Proton therapy is still more expensive than conventional radiotherapy, but with the present rapid increase in the number of proton facilities worldwide and new initiatives to improve efficiency, the difference in affordability will continue to decrease and in comparison with the benefits, soon diminish even further. Contrary to what is sometimes claimed, the demands for better physical dose distributions and better avoidance of non-target tissue, has never been higher. Prolonged expected survival in many groups of patients emphasises the need to reduce late toxicities. The success of concomitant systemic therapies, with their tendency to cause higher morbidity stresses even further the increased need for subtle dose-sculpting methodologies and tools. There is no contradiction between striving for better physical dose distributions and a more biologically based approach. On the contrary, physical dose distributions are the tools to which achieve a treatment that can meet the biological demands. PMID- 20831505 TI - Heidelberg Ion Therapy Center (HIT): Initial clinical experience in the first 80 patients. AB - The Heidelberg Ion Therapy Center (HIT) started clinical operation in November 2009. In this report we present the first 80 patients treated with proton and carbon ion radiotherapy and describe patient selection, treatment planning and daily treatment for different indications. PATIENTS AND METHODS: Between November 15, 2009 and April 15, 2010, 80 patients were treated at the Heidelberg Ion Therapy Center (HIT) with carbon ion and proton radiotherapy. Main treated indications consisted of skull base chordoma (n = 9) and chondrosarcoma (n = 18), malignant salivary gland tumors (n=29), chordomas of the sacrum (n = 5), low grade glioma (n=3), primary and recurrent malignant astrocytoma and glioblastoma (n=7) and well as osteosarcoma (n = 3). Of these patients, four pediatric patients aged under 18 years were treated. RESULTS: All patients were treated using the intensity-modulated rasterscanning technique. Seventy six patients were treated with carbon ions (95%), and four patients were treated with protons. In all patients x-ray imaging was performed prior to each fraction. Treatment concepts were based on the initial experiences with carbon ion therapy at the Gesellschaft fur Schwerionenforschung (GSI) including carbon-only treatments and carbon-boost treatments with photon-IMRT. The average time per fraction in the treatment room per patient was 29 minutes; for irradiation only, the mean time including all patients was 16 minutes. Position verification was performed prior to every treatment fraction with orthogonal x-ray imaging. CONCLUSION: Particle therapy could be included successfully into the clinical routine at the Department of Radiation Oncology in Heidelberg. Numerous clinical trials will subsequently be initiated to precisely define the role of proton and carbon ion radiotherapy in radiation oncology. PMID- 20831506 TI - A treatment planning study of the potential of geometrical tracking for intensity modulated proton therapy of lung cancer. AB - BACKGROUND: Proton therapy of lung cancer holds the potential for a reduction of the volume of irradiated normal lung tissue. In this work we investigate the robustness of intensity modulated proton therapy (IMPT) plans to motion, and evaluate a geometrical tumour tracking method to compensate for tumour motion. MATERIAL AND METHODS: Seven patients with a nine targets with 4DCT scans were selected. IMPT plans were made on the midventilation phase using a 3-field technique. The plans were transferred and calculated on the remaining nine phases of the 4DCT, and the combined dose distribution was summed using deformable image registration (DIR). An additional set of plans were made in which the proton beam was simply geometrically shifted to the centre of the gross tumour volume (GTV), i.e. simulating tracking of the tumour motion but without on-line adjustment of the proton energies. A possible interplay effect between the dynamics of the spot scanning delivery and the tumour motion has not been considered in this work. RESULTS: Around 97-100% of the GTV was covered by 95% of the prescribed dose (V95) for a tumour displacement of less than about 1 cm with a static beam. For the remaining three of nine targets with a larger motion the tracking method studied provided a marked improvement over static beam; raising the GTV V95 from 95 to 100%, 82 to 98% and 51 to 97%, respectively. CONCLUSION: The possibility of performing DIR and summing the dose on the 4DCT data set was shown to be feasible. The fairly simplistic tracking method suggested here resulted in a marked improvement in GTV coverage for tumours with large intra-fractional motion (>1 cm displacement), indicating that on-line adjustment of the proton energies may be redundant. PMID- 20831507 TI - Neutron fluence in antiproton radiotherapy, measurements and simulations. AB - INTRODUCTION: A significant part of the secondary particle spectrum from antiproton annihilation consists of fast neutrons, which may contribute to a significant dose background found outside the primary beam. MATERIALS AND METHODS: Using a polystyrene phantom as a moderator, we have performed absolute fluence measurements of the thermalized part of the fast neutron spectrum using Lithium-6 and -7 Fluoride TLD pairs. The results were compared with the Monte Carlo particle transport code FLUKA. RESULTS: The experimental results are found to be in good agreement with simulations. The thermal neutron kerma resulting from the measured thermal neutron fluence is insignificant compared to the contribution from fast neutrons. DISCUSSION: The secondary neutron fluences encountered in antiproton therapy are found to be similar to values calculated for pion treatment, however exact modeling under more realistic treatment scenarios is still required to quantitatively compare these treatment modalities. PMID- 20831508 TI - Investigation of the dosimetric impact of a Ni-Ti fiducial marker in carbon ion and proton beams. AB - INTRODUCTION: Fiducial markers based on a removable stent are currently used in image guided radiotherapy. Here it is investigated what the possible dosimetric impact of such a marker could be, if used in proton or carbon ion treatment. MATERIAL AND METHODS: The simulations have been done using the Monte Carlo particle transport code FLUKA with its default hadron therapy settings. A 3 cm long stent is approximated in FLUKA by stacking hollow tori. To simulate realistic clinical conditions a field 5 * 5 cm has been used, delivering a 5 cm wide spread out Bragg peak located 5 cm deep for protons and carbon ions. For protons fields mimicking active and passive beam delivery have been investigated. The stent has been arranged perpendicular, turned 45 degrees, and parallel to the beam axis. RESULTS: The position of the 95% dose level shifts for carbon ions 7 mm in proximal direction for the marker perpendicular to the beam and 8 mm if the stent is turned 45 degree for a 1 * 1 cm dose binning on the centre beam axis. For the case where the stent was parallel to beam direction the 95% dose level shifts 26 mm. For active delivered protons, the shift of the 95% dose level is less. The shift for a perpendicular arranged marker is 6 mm, for 45 degrees turned it is 7 mm. For the case where the stent was oriented parallel to the beam, the observed shift is 21 mm. Dose inhomogeneities caused by straggling effects occur only near the distal edge of the field. CONCLUSIONS: The results of our investigations show that the Ni-Ti marker has a non negligible impact on the dose distributions for the used radiation types. However if the treatment plan rules out narrow angles between symmetry axis of the stent and the beam direction, this may be compensated. PMID- 20831509 TI - Dose calculation in biological samples in a mixed neutron-gamma field at the TRIGA reactor of the University of Mainz. AB - To establish Boron Neutron Capture Therapy (BNCT) for non-resectable liver metastases and for in vitro experiments at the TRIGA Mark II reactor at the University of Mainz, Germany, it is necessary to have a reliable dose monitoring system. The in vitro experiments are used to determine the relative biological effectiveness (RBE) of liver and cancer cells in our mixed neutron and gamma field. We work with alanine detectors in combination with Monte Carlo simulations, where we can measure and characterize the dose. To verify our calculations we perform neutron flux measurements using gold foil activation and pin-diodes. Material and methods. When L-alpha-alanine is irradiated with ionizing radiation, it forms a stable radical which can be detected by electron spin resonance (ESR) spectroscopy. The value of the ESR signal correlates to the amount of absorbed dose. The dose for each pellet is calculated using FLUKA, a multipurpose Monte Carlo transport code. The pin-diode is augmented by a lithium fluoride foil. This foil converts the neutrons into alpha and tritium particles which are products of the (7)Li(n,alpha)(3)H-reaction. These particles are detected by the diode and their amount correlates to the neutron fluence directly. Results and discussion. Gold foil activation and the pin-diode are reliable fluence measurement systems for the TRIGA reactor, Mainz. Alanine dosimetry of the photon field and charged particle field from secondary reactions can in principle be carried out in combination with MC-calculations for mixed radiation fields and the Hansen & Olsen alanine detector response model. With the acquired data about the background dose and charged particle spectrum, and with the acquired information of the neutron flux, we are capable of calculating the dose to the tissue. Conclusion. Monte Carlo simulation of the mixed neutron and gamma field of the TRIGA Mainz is possible in order to characterize the neutron behavior in the thermal column. Currently we also speculate on sensitizing alanine to thermal neutrons by adding boron compounds. PMID- 20831510 TI - Dose- and LET-painting with particle therapy. AB - Tumour hypoxia is one of the limiting factors in obtaining tumour control in radiotherapy. The high-LET region of a beam of heavy charged particles such as carbon ions is located in the distal part of the Bragg peak. A modulated or spread out Bragg peak (SOBP) is a weighted function of several Bragg peaks at various energies, which however results in a dilution of the dose-average LET in the target volume. Here, we investigate the possibility to redistribute the LET by dedicated treatment plan optimisation, in order to maximise LET in the target volume. This may be a strategy to potentially overcome hypoxia along with dose escalation or dose painting. The high-LET region can be shaped in very different ways, while maintaining the distribution of the absorbed dose or biological effective dose. Treatment plans involving only carbon ion beams, show very different LET distributions depending on how the fields are arranged. Alternatively, a LET boost can be applied in multi-modal treatment planning, such as combining carbon ions with protons and/or photons. For such mixed radiation modalities, significant "LET boosts" can be achieved at nearly arbitrary positions within the target volume. Following the general understanding of the relationship between hypoxia, LET and the oxygen enhancement ratio (OER), we conclude, that an additional therapeutic advantage can be achieved by confining the high-LET part of the radiation in hypoxic compartments of the tumour, and applying low-LET radiation to the normoxic tissue. We also anticipate that additional advantages may be achieved by deliberate sparing of normal tissue from high LET regions. Consequently, treatment planning based on simultaneous dose and LET optimisation has a potential to achieve higher tumour control and/or reduced normal tissue control probability (NTCP). PMID- 20831511 TI - Evaluation of setup accuracy for NSCLC patients; studying the impact of different types of cone-beam CT matches based on whole thorax, columna vertebralis, and GTV. AB - PURPOSE: The aim of this study is to evaluate the patient setup accuracy by investigating the impact of different types of CBCT matches, performed with 3 (translations only) or 6 (including rotations) degrees-of-freedom (DOF). The purpose is also to calculate and compare CTV to PTV margins based on the various CBCT matches, setups using 2D kV planar imaging or setups using skin markers only (non-IGRT). MATERIAL AND METHODS: Setup images from 16 NSCLC patients with weekly CBCT and daily 2D kV planar imaging were analyzed retrospectively. The CBCT matches were based on the columna vertebralis (CV), the whole thorax (WT) and the soft tissue (ST) delineated GTV, where the ST match was chosen as reference. Thus the translational and rotational shifts in three dimensions were assessed. Finally, setup margins were calculated using van Herk's margin recipe. RESULTS: For 80% of the investigated 3 DOF/2D kV CV setups, the translational shifts were within [-3, 2] mm for all three directions. Corresponding values for the 6 DOF/non-IGRT CV and the 6 DOF/non-IGRT ST matches were [-5, 8] mm. Furthermore, 80% of all setups were within +/- 2 degrees for pitch-, roll- and yaw-rotations, and none exceeded 5 degrees . The calculated margins for non-IGRT, about 10 mm, were reduced to approximately 4 mm, regardless of using IGRT setup by CBCT or 2D kV imaging on CV. However, if using WT CBCT setup, the margin in LNG direction was slightly larger, approximately 6 mm. CONCLUSION: IGRT for NSCLC is an essential tool for margin reduction, since patient setups based on IGRT leads to approximately half the margin sizes compared to non-IGRT setups. Both CBCT and 2D kV planar imaging yields approximately the same margins for CV/ST matches. The magnitudes of the patient rotations were <5 degrees . PMID- 20831512 TI - Investigation of respiration induced intra- and inter-fractional tumour motion using a standard Cone Beam CT. AB - BACKGROUND: To investigate whether a standard Cone beam CT (CBCT) scan can be used to determined the intra- and inter-fractional tumour motion for lung tumours that have infiltrated the mediastinum. MATERIAL AND METHODS: This study includes 23 patients with non small cell lung cancer (NSCLC). The intra-fractional tumour motion was analysed for each patient on a 4D-CT scan as well as on three 4D-CBCT (fraction 3, 10 and 20). The 4D-CBCT was reconstructed from a standard 3D-CBCT using in-house developed software. The tumour (GTV) was delineated in the first phase of the 4D-CT. Registration of phase one from the 4D-CT and 4D-CBCT was used to copy the GTV to the CBCT scans. Hereafter the motion of the outlined GTV was tracked in the planning 4D-CT and the three 4D-CBCT using Pinnacle((r)) version 8.1w (research version). Additionally, the inter-fractional tumour movement, relative to the bony structure, was obtained from the difference in tumour position between the 3D-CT and the standard 3D-CBCT. RESULTS: It is possible to track a lung tumour with mediastinal infiltration in the 4D-CBCT scan based on a standard 3D-CBCT. The respiration motion in the 4D-CBCT is not significantly different from the result found from the initial 4D-CT. Likewise, no differences in respiration motion was found between fractions 3, 10 and 20. CONCLUSION: This study shows that it is possible to track tumour motion for NSCLC patients with mediastinal infiltration using a standard 3D-CBCT. No change in the intra fractional tumour motion of clinically relevance was observed during the fractionated treatment course. The inter-fractional tumour motion found underlines the importance of using daily IGRT with online match on soft tissue in order to be able to reduce treatment margins. PMID- 20831514 TI - Rural clinical placements in optometry: let's get it right. PMID- 20831515 TI - The patterns of in vitro antimicrobial susceptibility and resistance of bacterial keratitis isolates in Glasgow, United Kingdom. AB - PURPOSE: Trends in antibiotic sensitivity of pathogenic bacteria change with time and the emergence of resistance to commonly used antibiotics is not uncommon. The aim of this study is to identify the antibiotic susceptibility and resistance patterns in a tertiary referral centre that commonly manages corneal infections. METHODS: This is a retrospective review of microbiology reports of corneal scrapes in a tertiary care hospital. RESULTS: There were 205 positive corneal scrapes (32 per cent) in 1995 to 1998 and 147 (28 per cent) in 2004 to 2007. There was increased incidence of Staphylococcus aureus (18 to 21 per cent) (p = 0.16), Moraxella catarrhalis (1.5 to 5 per cent) (p = 0.5), pseudomonas species (6 to 14.5 per cent) (p = 0.25) and non-lactose fermenting coliforms (1.5 to 7 per cent) (p = 0.5). In vitro resistance of gram-positive bacterial isolates to ciprofloxacin was increased from 5 to 7 per cent (p = 0.5). The in vitro susceptibility of gram-positive organisms to dual therapy with cefuroxime and gentamicin were 98 per cent in 1995 to 1998, and 94 per cent in 2004 to 2007 (p = 0.1). Pseudomonas species were 100 per cent susceptible to cefuroxime in the first period but developed 100 per cent resistance in the later period (p = 0.0002). However, the susceptibility of gram negative bacterial isolates to dual therapy with cefuroxime and gentamicin (p = 1) and monotherapy with ciprofloxacin (p = 1) was 100 per cent in both periods. The in vitro resistance to chloramphenicol to gram-positive organisms was reduced to 5 from 12 per cent (p = 0.19) but there was an increase in resistance of gram-negative organisms from 23 to 36 per cent (p = 0.3). CONCLUSION: Despite limitations, this study demonstrates that the fortified antibiotics such as 5% cefuroxime 1.5% gentamicin may be the appropriate choices for most episodes of bacterial keratitis, either as an initial therapy or after identification of in vitro susceptibility of bacterial isolates. PMID- 20831513 TI - Emerging treatment options for type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is rapidly increasing in prevalence and is a major public health problem. It is a progressive disease which commonly requires multiple pharmacotherapy. Current options for treatment may have undesirable side effects (particularly weight gain and hypoglycaemia) and contraindications, and little effect on disease progression. Incretin based therapy is one of several newer therapies to improve glycaemia and is available in two different forms, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Use of these agents results in a 'glucose-dependant' increase in insulin secretion and glucagon suppression resulting in improved glycaemia with low incidence of hypoglycaemia. DPP-4 inhibitors are oral drugs which are weight neutral, while GLP-1 agonists are injected subcutaneously and help promote weight loss while improving glycaemia. GLP-1 agonists have also been shown to increase beta cell mass in rat models. Bariatric surgery is another option for the obese patient with T2DM, with blood glucose normalizing in over half of the patients following surgery. Other therapies in development for the treatment of T2DM include sodium-glucose transporter 2 (SGLT-2) inhibitors, glucagon receptor antagonists, glucokinase activators and sirtuins. In this article, we will review the various existing and emerging treatment options for T2DM. PMID- 20831520 TI - Cytopathology of oral infectious diseases: do we really do our best? PMID- 20831521 TI - Abstracts of the American Academy for Cerebral Palsy and Developmental Medicine 64th Annual Meeting. September 22-25, 2010. Washington, DC, USA. PMID- 20831523 TI - Commentary: translation of laboratory findings to clinic in the treatment of status epilepticus--a mission impossible? PMID- 20831524 TI - Letter: lack of association between MDR1 polymorphisms and pharmacoresistance to anticonvulsive drugs in patients with childhood-onset epilepsy. PMID- 20831525 TI - Letter: HLA B*1502 allele association with oxcarbamazepine-induced skin reactions in epilepsy patient from India. PMID- 20831527 TI - Effects on the visual system might contribute to some of the cognitive deficits of cancer chemotherapy-induced 'chemo-fog'. AB - The diminution in certain aspects of cognitive function that is reported to occur in some patients during or after adjuvant cancer chemotherapy is variously known as 'chemo-fog', 'chemo-brain' or other such term. In addition to reported deficits in attention, concentration and other functions, most, if not all, of the studies report deficits involving visual-spatial function or visual memory. Since the visual system is part of the nervous system, it seems reasonable to ask if it is susceptible to some of the deleterious effects produced by adjuvant chemotherapeutic drugs. We propose here the possibility that some portion of the vision-related aspects of the 'chemo-fog' spectrum of cognitive deficits results from a direct action of the adjuvant drugs on the visual system or from drug/drug or site/site interaction between effects on the visual system and other critical brain regions. PMID- 20831528 TI - Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonates. AB - BACKGROUND AND OBJECTIVES: Neonatal sepsis is frequently associated with pathological activation of the coagulation system, leading to microcirculatory derangement and multiple organ dysfunction syndrome (MODS). The key role in the pathogenesis of sepsis has been attributed to proinflammatory cytokines. These trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. Pentoxifylline (PTX), a methylxanthine derivative that is used in peripheral vascular disease, has the potential to modify inflammatory response. The current work was designed to evaluate the potential protective effects of PTX against sepsis-induced microcirculatory derangement in Egyptian neonates. METHODS: A double-blind placebo-controlled quasi-randomized design was used. Thirty-seven neonates with sepsis were randomly allocated into two groups. Seventeen patients were given PTX (5 mg/kg/h for 6 h; for 6 successive days). Twenty patients received equivalent volume of normal saline and represented the placebo group. Prothrombin time (PT), Activated partial thromboplastin time (APTT), fibrinogen, d-dimer, C-reactive protein (CRP), complete blood count (CBC), also hemodynamic parameters comprising arterial blood pressure, heart rate, capillary refill and urinary output were assessed in both groups before and after treatment. RESULTS: Coagulation parameters in the two groups showed no significant differences. However, a higher incidence of DIC was observed in the placebo group neonates. PTX significantly lowered the percentage of bleeding (P = 0.0128) and less frequent use of FFP was observed in the PTX group (35.53% in PTX group vs. 80% in placebo group, P = 0.003). Incidence of MODS was significantly lower (P = 0.037) and hospital stay duration of survivors was significantly shorter (P = 0.044) in the PTX treated infants. CONCLUSION: Pentoxifylline protects against sepsis-induced microcirculatory derangement in neonates. It significantly lowered the incidence of bleeding and MODS and shortened the length of hospital stay. PMID- 20831529 TI - Drug utilization of oral hypoglycemic agents in a university teaching hospital in India. AB - BACKGROUND: India has witnessed a rapidly exploding epidemic of diabetes in recent years and currently leads the world with the largest number of diabetic subjects in a single country. World Health Organization estimates that in 2000, 31.7 million individuals were affected by diabetes in India and these numbers will rise to 79.4 millions by the year 2030. In view of the above situation, drug utilization review of antidiabetic medicines in Indian healthcare settings has a valid significance to promote rational drug use in diabetics. OBJECTIVE: The present study is aimed to determine the drug utilization patterns in type 2 diabetic patients on oral hypoglycemic agents in the Medicine Outpatient Department (OPD) and Inpatient Department (IPD) of Majeedia Hospital, a teaching hospital of Hamdard University, New Delhi. METHODS: Patients with established type 2 diabetes (n = 218) visiting the OPD and IPD were interviewed using a structured questionnaire during the period January-May 2006. RESULTS: A majority of the type 2 diabetic patients in this setting were treated with multiple antidiabetic drug therapy. The most commonly prescribed antidiabetic drug class was biguanides (metformin) followed by sulphonylureas (glimepiride), thiazolidinediones (pioglitazone), insulin and alpha-glucosidase inhibitors (miglitol). As monotherapy insulin was the most common choice followed by metformin. The most prevalent multiple therapy was a three-drug combination of glimepiride + metformin + pioglitazone. More than half of the type 2 diabetic patients showed poor adherence (compliance) to the prescribed therapy. CONCLUSION: This study strongly highlights the need for patient education or counselling on use of antidiabetic and concomitant drugs, monitoring of blood glucose and glycosylated haemoglobin (HbA1c) levels, diet control, and correction of diabetic complications. Metabolic control was poor and HbA1c monitoring was underutilized. Clinical monitoring of patients' adherence to prescribed treatments is recommended and measures should be taken to improve it. PMID- 20831530 TI - Study of microbial contamination and dosing accuracy of oral dispensers. AB - BACKGROUND AND OBJECTIVE: The optimal administration of liquid medications requires accurate dose delivery. This is particularly important in the treatment of infants and children, as well as elderly people, who are more sensitive to dosage errors. Previous studies revealed significant dosage inaccuracies with measuring spoons. Oral syringes are therefore generally recommended instead. There is no data on the efficacy of standard cleaning techniques, and consequently on the degree of microbial contamination associated with the repeated use of oral syringes. This study aimed to investigate the level and types of microorganisms found in oral dispensers subjected to simulated in-use conditions. In addition, the dosing accuracy of the oral dispensers is compared with that of measuring spoons supplied and designed for use with specific medications. METHODS: Exadoral 5 mL oral dispensers from B. Braun Melsungen AG (Melsungen, Germany) were subjected to simulated in-use conditions and microbial assay. Six different liquid medications representing different substance classes were included. The test lasted 4-15 days with two to four doses withdrawn according to dosage recommendations. Dosing accuracy was assessed using six representative amoxicillin suspensions available on the German market after withdrawing 1.25, 2.5 and 5 mL that correspond to 1/4, 1/2 and full measuring spoons. RESULTS AND DISCUSSION: Low counts of Micrococcus luteus, Micrococcus lylae, Staphylococcus epidermidis, Staphylococcus chromogenes as well as Bacillus species and Candida lusitaniae may contaminate the interior surface of the oral dispenser, but the microbial count was below the accepted limit of microbial counts permissible for drinking water over the whole test period. Hence, oral dispensers may be considered safe, provided that cleaning procedures are followed exactly. Moreover, oral dispensers, although not specifically designed for the tested medication, showed much higher dosing accuracy in comparison with the specifically designed measuring spoons. CONCLUSION: The present study revealed that oral dispensers are accurate measuring devices for the safe administration of liquid medication. Pharmacists and physicians should encourage their patients to use oral dispensers routinely in practice. PMID- 20831531 TI - Quadruple therapy with ecabet sodium, omeprazole, amoxicillin and metronidazole is effective for eradication of Helicobacter pylori after failure of first-line therapy (KDOG0201 Study). AB - BACKGROUND AND OBJECT: An antiulcer agent, ecabet sodium, is active against Helicobacter pylori. The aim of the present study was to clinically examine whether eradication therapy, which includes ecabet sodium, is effective in eradication of H. pylori after failure of first-line therapy. METHODS: Patients with peptic ulcer who failed with first-line triple eradication therapy containing clarithromycin received quadruple therapy with omeprazole (20 mg, twice daily), amoxicillin (750 mg, twice daily), metronidazole (500 mg, twice daily) and ecabet sodium (1000 mg, twice daily) for 14 days. Eradication of H. pylori was judged by 13C-urea breath test 8 weeks later. RESULTS: Fifty-two patients (36 men and 16 women) were included. Their mean age was 51.4 years (range 28-73). One patient dropped out because of diarrhoea. The eradication rate was 98.0% (50/51) according to the per-protocol analysis and 96.2% (50/52) according to the intention-to-treat analysis. Side effects occurred in seven patients, but none were serious. CONCLUSIONS: Quadruple therapy including ecabet sodium is useful as second-line eradication treatment for H. pylori. PMID- 20831532 TI - Towards concordance in healthcare: perspectives of general practitioners, complementary and alternative medicine practitioners and pharmacists in Australia. AB - Partnerships and concordance are desirable concepts for optimal healthcare. The concept of concordance is based on negotiation between equals in a therapeutic relationship, forming a therapeutic alliance between all partners. One field of healthcare in which concordant relationships may be particularly desirable is complementary and alternative medicine (CAM). CAM is increasingly used by consumers worldwide, and provider-patient relationships are important across the spectrum of CAM-to-conventional medicine; thus, it was considered useful to research CAM and concordance in parallel. The objective of this problem-detection study (PDS) was to investigate practitioners' (general practitioners', pharmacists' and CAM practitioners') views on their relationships and reaching concordant partnerships with consumers in the areas of both conventional medicine and CAM. Focus groups and semi-structured interviews guided the development of the PDS instrument. The questionnaire consisted of 36 items corresponding to seven thematic units deduced from the preliminary data. The differences in perceptions between the surveyed groups indicated that achieving concordance relies on mutual respect and communication and understanding of roles, responsibilities and limitations, and differences in opinion may be compromising the formation of partnerships. Potentially problematic issues identified by this research could be addressed by educational interventions and enhancement of communication between all parties involved, as information loses value when not shared, and may be prone to contradiction and confusion. Further research is warranted in order to facilitate positive changes in the health system. PMID- 20831533 TI - Effect of plasma uric acid on pharmacokinetics of cyclosporine A in living related renal transplant recipients and pharmacokinetic study in rats with experimental hyperuricaemia. AB - OBJECTIVES: Renal transplant recipients are thought to have an increased risk of hyperuricaemia (HU); therefore, the effects of plasma uric acid (UA) on the pharmacokinetics (PK) of cyclosporine A (CyA), an immunosuppressant, in renal transplant recipients and experimental animals were investigated. METHODS: An open-label, non-randomized, retrospective study was performed in renal transplant recipients. Data from 76 subjects who received a renal transplantation with CyA medication were included. We compared the PK of CyA of recipients showing a high UA level with the other recipients. In addition, PK studies were performed using hyperuricaemic-model rats (HU rats) prepared by subcutaneous injection of the uricase inhibitor, potassium oxonate and intraperitoneal injection of UA. RESULTS: The area under the blood concentration vs. time curve (AUC) up to 9 h, the blood level at 2 h after dose and peak level in high UA recipients (UA > 7.0 mg/dL) was significantly lower (about 10-16%) than that in the other recipients, although there were no differences in dose, and the trough blood level. On the contrary, there were no differences in PK parameters after intravenous administration of CyA between HU and control rats; however, AUC, peak level and bioavailability in HU rats (2.01 +/- 0.56 MUg h/mL, 0.47 +/- 0.26 MUg/mL and 0.186 +/- 0.05, respectively) after oral administration were significantly lower than in the control animals (6.13 +/- 0.97 MUg h/mL, 0.82 +/- 0.17 MUg/mL and 0.458 +/- 0.07 MUg/mL, respectively). In addition, the absorptions of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in HU rats were significantly less (about 50% and 37%, respectively) than in the controls. CONCLUSIONS: The absorption of CyA was affected by plasma UA in transplant recipients and experimental rats. The contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in HU rats was significant. These results suggest that transplant recipients with high UA may have poor absorption of CyA. PMID- 20831534 TI - Naloxone in the management of hepatic encephalopathy. AB - BACKGROUND/AIM: This study aimed to assess the effectiveness and safety of naloxone in the management of hepatic encephalopathy (HE). METHODS: Cochrane collaboration methodology was used in a meta-analysis of randomized controlled trials of naloxone therapy for HE. RESULTS: Seventeen randomized trials were identified with 15 studies involving 1054 patients meeting criteria for inclusion. Naloxone use was associated with a significant improvement in HE [relative risk (RR) 1.46; 95% confidence interval (CI) 1.27-1.67; P = 0.0005]. This comparison showed statistical heterogeneity (P < 0.10, and chi2 = 44.93). Subgroup analysis indicated naloxone administered parenterally by intermittent or continuous infusions to be effective (RR 1.34; 95% CI 1.17-1.53; P < 0.0001). A significant in trials by infusion route (RR 1.42; 95% CI 1.19-1.69; P < 0.0001) interaction was observed. CONCLUSIONS: Naloxone may improve HE. However, published data are limited. PMID- 20831536 TI - Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. AB - BACKGROUND AND OBJECTIVE: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. METHODS: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography-tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post-dose. RESULTS AND DISCUSSION: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC(0-infinity) and C(max) in group C were significantly higher [83.94 +/- 40.41 vs. 16.39 +/- 5.10 MUg.h/mL (P = 0.000) and 1.50 +/- 0.85 vs. 0.45 +/- 0.18 MUg/mL (P = 0.000)], and the oral clearance was significantly lower [1.17 +/- 0.63 vs. 5.38 +/- 1.86 L/h (P = 0.000)]. The half-life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33.47 +/- 12.39 vs. 19.34 +/- 10.45 h), but the difference was not significant (P = 0.052). The increase in serum glucose level at 11 h after dosing (DeltaC(glu11)) in group C was significantly higher than that of group A (-1.08 +/- 0.42 vs. 0.22 +/- 1.01 mmol/L, P = 0.022). The corresponding insulin levels showed no difference between the two groups. CONCLUSION: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result. PMID- 20831535 TI - Pharmacogenetics of esomeprazole or rabeprazole-based triple therapy in Helicobacter pylori eradication in Hong Kong non-ulcer dyspepsia Chinese subjects. AB - OBJECTIVE: Our study aimed to assess the effectiveness of esomeprazole or rabeprazole in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in Hong Kong non-ulcer dyspepsia (NUD) patients. METHODS: A prospective clinical trial was conducted at the Alice Ho Miu ling Nethersole Hospital outpatient endoscopy center from June 2004 to December 2005. Participants received amoxicillin 1 g, clarithromycin 500 mg, and, esomeprazole 20 mg (EAC) or rabeprazole 20 mg (RAC), all given twice daily for 1 week. The H. pylori status was determined by the [13C] urea breath test at least 4 weeks after completion of the treatment. Mutation status of CYP2C19 in exon 4 and exon 5 associated with the poor metabolizer phenotype was determined. RESULTS: The intention-to-treat eradication rates in patients treated with RAC and EAC were 77% and 84.6% respectively, and per protocol-based eradication rates were 83.7% and 88.9% respectively. The eradication rates did not vary with CYP2C19 phenotype found. For clarithromycin-sensitive strains, the cure rates were statistically significant regardless of CYP2C19 polymorphism (P < 0.0001). CONCLUSION: Triple therapy with either EAC or RAC is effective for Hong Kong Chinese NUD patients with H. pylori infection. Success eradication was related to clarithromycin resistance and not CYP2C19 genotype. PMID- 20831537 TI - Hepatotoxicity of alpha-methyldopa in pregnancy. AB - Alpha-methyldopa is one of the most widely prescribed antihypertensive agents used during pregnancy. Despite its known potential hepatotoxicity, there have been only a few reports describing hepatotoxicity with the use of this drug during pregnancy. We report here a new case of acute hepatitis in a pregnant woman related to the use of alpha-methyldopa, and briefly review the literature on alpha-methyldopa-induced hepatotoxicity in pregnancy. PMID- 20831538 TI - DRESS-syndrome on sulfasalazine and naproxen treatment for juvenile idiopathic arthritis and reactivation of human herpevirus 6 in an 11-year-old Caucasian boy. AB - DRESS-syndrome (Drug Rash with Eosinophilia and Systemic Symptoms) is a severe drug-induced hypersensitivity syndrome characterized by diffuse maculopapular rash, lymphadenopathy, multivisceral involvement, eosinophilia and atypical lymphocytes with a mortality rate of 10-40% (Seminars in Cutaneous Medicine and Surgery, 1, 250). It is described in adults treated with aromatic antiepileptics and less frequently with sulphonamides, and non-steroidal anti-inflammatory drugs (Clinics in Dermatology, 23, 171; Pediatrics, 108, 485). We report on an 11-year old Caucasian boy hospitalized with a skin eruption, lymphadenopathy, acute hepatitis, renal tubular involvement, haematological abnormalities and human herpevirus-6 reactivation, treated with sulfasalazine and naproxen for juvenile idiopathic arthritis (JIA). This is the first report in children with rheumatic disease and highlights the possibility of sulfasalazine and naproxen-induced DRESS-syndrome in children with JIA. PMID- 20831540 TI - What do the suffixes--XR, ER, Chrono, Chronosphere--really mean as it pertains to modified-release antiepileptic drugs? AB - BACKGROUND: Epilepsy is a disease requiring chronic therapy with antiepileptic drugs (AEDs). Many conventional AEDs currently available have either too rapid an absorption or elimination, requiring the patient to take multiple doses per day, which may adversely impact adherence or cause peak-related side-effects. Consequently, some AEDs with immediate-release characteristics have been modified to prolong absorption and/or reduce peak serum concentration, enabling dosage regimen simplification. Modified-release (MR) AED formulations have been labelled with various suffixes or names ('XR, ER, -Chrono, -Chronosphere'), but such labelling may not adequately distinguish those MR AEDs with the most prolonged absorption or unique formulation characteristics. Such suffixes lack precise definition. OBJECTIVE: We identified the formulation characteristics of currently available MR AEDs, attempting to distinguish them by suffix designation. DESIGN/METHODS: Nine MR AED formulations, representing six different AEDs, were characterized, utilizing information from FDA-approved inserts (2001 +) and published literature. RESULTS: The formulation characteristics of commercially available MR AEDs are quite variable and do not appear to correlate with their brand name suffix. CONCLUSIONS: When all MR AEDs are compared, suffix designations do not provide distinguishable information about formulation characteristics. Clarification of MR AED suffix terminology may be warranted. PMID- 20831541 TI - Therapeutic effect of statin on aortic stenosis: a review with meta-analysis. AB - BACKGROUND: Aortic stenosis (AS) is a common progressive disease. Statins have been hypothesized to delay its progression via pleiotropic mechanisms. However, results of clinical trials focusing on statin therapy in AS patients have been controversial. OBJECTIVE: To analyse and summarize the findings in recent statin trials and to discuss the rationale of statin usage in AS populations. METHODS: A comprehensive database search was conducted by two independent reviewers. Controlled trials that compared progression of AS between statin and non-statin therapy published before 31 December 2008 were included. Data were extracted for meta-analysis, to estimate overall effects, if available. Factors that contributed to heterogeneities among the trials were analysed. RESULTS: The meta analysis included nine trials with a total of 2947 patients. Statin therapy displayed an overall statistically significant effect on delaying AS progression. The weighted mean difference (statin vs. control) of annual increase of peak aortic-jet velocity was -0.12 m/s (95% confidence interval -0.22 to -0.03); the increase of mean transaortic pressure gradient was -1.64 mmHg per year (-3.27 to 0.01); Heterogeneity-analysis suggested that the baseline risk factors and characteristics of the patients, the use of different statins, and the time point to initiate statin therapy, may be important considerations when interpreting the result of individual studies. CONCLUSION: Although the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial reported negative results in delaying AS progression in low-risk patients, the potential benefits of statins in those with multiple risk factors and their value in preventing future coronary events call for further investigation of different categories of AS patients. PMID- 20831542 TI - Chronic dialysis-associated anaemia in end-stage renal disease: analysis of management in two French centres. AB - BACKGROUND: Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients. METHODS: Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other. RESULTS: A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs. CONCLUSION: The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary. PMID- 20831543 TI - Withdrawal of pioglitazone in patients with type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVE: The remodelling of the adipose tissue by pioglitazone may be associated with the sustained therapeutic effects. We studied the effects of withdrawal of pioglitazone after 3-month treatment on glucose, lipid and high molecular weight (HMW) adiponectin levels as well as liver function in patients with type 2 diabetes mellitus. METHODS: Forty-nine Japanese patients with type 2 diabetes mellitus were randomly assigned into the withdrawal group after 3-month treatment with pioglitazone (15 or 30 mg daily) and the non-withdrawal group. RESULTS AND DISCUSSION: Three-month treatment with pioglitazone improved glycaemic control, homeostasis model assessment for insulin resistance (HOMA), dyslipidaemia and liver function tests in association with a marked increase in serum HMW adiponectin level. Three months later after the withdrawal of pioglitazone, however, fasting plasma glucose and HOMA increased, whereas serum HMW adiponectin decreased to the pretreatment levels. Dyslipidaemia also returned to the pretreatment level. On the other hand, liver enzymes at 3 months after the withdrawal remained lower after a mild rebound. In addition, the bone formation marker, serum bone-specific alkaline phosphatase, was significantly reduced by pioglitazone treatment in post-menopausal women. CONCLUSIONS: The present study suggests that 3-month treatment with pioglitazone has no sustained beneficial effects except in liver function tests in patients with type 2 diabetes mellitus. PMID- 20831544 TI - Marketing of rural and remote pharmacy practice via the digital medium. AB - AIM: The shortage of community and hospital pharmacists is particularly acute in rural and remote areas of Australia. Pharmacy students, in particular, as those who may be able to alleviate this shortage, need to be made more aware of the challenges and rewards of rural pharmacy practice. A marketing tool was developed to promote rural and remote pharmacy practice as a career option. A DVD was produced from interviews with health professionals working in rural and remote areas of Australia. This DVD will complement current rural practical placements, which have been incorporated into the curriculum of Australian schools of pharmacy. METHODS: Interviews were conducted with healthcare professionals from areas in Tasmania, Northern Queensland and the Northern Territory. Interviewees included pharmacists, graduate pharmacists, pharmacy students, aboriginal health workers and a general practitioner. Each of the interviewees was able to provide personal accounts of experiences in rural and remote healthcare, and roles and opportunities for pharmacists. A final draft of the DVD was shown to University of Tasmania students to assess the impact and quality of the production. RESULTS: A number of common themes arose from interviewing and these were subsequently converted into five key chapters of the DVD - Lifestyle, Belonging, Diversity, Indigenous Health and 'Give it a go'. The final DVD, produced from over 15 h of footage, runs for 35 min. Students reported positive feedback on both the technical quality and the information contained within the DVD; 37% of students who viewed the DVD felt that it increased their awareness of what rural pharmacy has to offer. CONCLUSIONS: The rural pharmacy, 'Enjoy the Lifestyle' DVD can be used to increase awareness of rural and remote pharmacy practice to students and other pharmacists, and complements other pharmacy workforce strategies for rural and remote areas of Australia. It could also be a useful approach for adaptation in other countries. PMID- 20831545 TI - A cost-effectiveness analysis of sunitinib in patients with metastatic renal cell carcinoma intolerant to or experiencing disease progression on immunotherapy: perspective of the Spanish National Health System. AB - AIM: To investigate the cost-effectiveness of sunitinib (50 mg/day, schedule 4/2) vs. best supportive care (BSC) in patients with cytokine-refractory metastatic renal cell carcinoma (mRCC), from the perspective of the Spanish National Health Service. MATERIAL AND METHODS: A Markov model compared the cost-effectiveness (taking into account drugs; medical visits; laboratory tests; X-rays; terminal care; adverse event management) of sunitinib and BSC across three disease states: no progression, survival with progression and death from mRCC or other causes. RESULTS: The monthly incremental cost-effectiveness ratio (ICER) values for sunitinib treatment were ?6073/progression-free survival month, ?25,199/life years and ?34,196/quality-adjusted life years (QALY) gained. In 95% of cases, the ICER/QALY values were below the accepted ?45,000/QALY threshold. Efficacy and cost of sunitinib had the greatest impact on cost-effectiveness. CONCLUSION: Sunitinib has a good cost-effectiveness profile in mRCC. The cost per life year and QALY gained is affordable according to current effectiveness thresholds in developed countries. PMID- 20831546 TI - Pharmacy counselling models: a means to improve drug use. AB - BACKGROUND AND OBJECTIVE: Failure to achieve the intended benefit of medical treatment is recognized as an immense problem. The study objective was to examine the usefulness of counselling models containing key questions to facilitate the identification of drug-related problems (DRPs), and to follow up on both pharmacy practitioner and patient experiences. METHODS: Fifty-one pharmacies in Sweden were recruited, along with matching controls. Patients of six therapeutic groups were selected for the counselling model intervention. DRPs were documented in the Swedish DRP database. A telephone follow-up with the patients and a questionnaire survey with the pharmacy practitioners were conducted. An additional follow-up was made in patients sending a representative to pick up their prescribed medications at the pharmacy. RESULTS AND DISCUSSION: In all, 880 DRPs were documented in patients with 8100 prescriptions (10.9%). The DRP documentation rates in study pharmacies were, in general, superior to the control pharmacy rates. DRPs were identified in 24.8% of the non-steroidal anti-inflammation drug (NSAID) patients using a representative to pick up their medications, compared with 9.2% in patients visiting the pharmacy themselves. Of the patients who took part in the follow-up, 94% said that they received suggestions on problem resolution, and twice as many DRPs were reported resolved vs. unresolved. Most patients and pharmacy practitioners were pleased with the new practice. CONCLUSION: The practice of counselling models appears to be a means to improve drug use. More DRPs were found in patients sending a representative to pick up their medications than in patients visiting the pharmacy themselves. PMID- 20831547 TI - An analysis and comparison of commonly available United Kingdom prescribing resources. AB - BACKGROUND AND OBJECTIVE: Safe prescribing requires accurate and practical information about drugs. Our objective was to measure the utility of current sources of prescribing guidance when used to inform practical prescribing decisions, and to compare current sources of prescribing guidance in the UK with idealized prescribing guidance. METHODS: We developed 25 clinical scenarios. Two independent assessors rated and ranked the performance of five common sources of prescribing guidance in the UK when used to answer the clinical scenarios. A third adjudicator facilitated review of any disparities. An idealized list of contents for prescribing guidance was developed and sent for comments to academics and users of prescribing guidance. Following consultation an operational check was used to assess compliance with the idealized criteria. The main outcome measures were relative utility in answering the clinical scenarios and compliance with the idealized prescribing guidance. RESULTS: Current sources of prescribing guidance used in the UK differ in their utility, when measured using clinical scenarios. The British National Formulary (BNF) and EMIS LV were the best performing sources in terms of both ranking [mean rank 1.24 and 2.20] and rating [%excellent or adequate 100% and 72%]. Current sources differed in the extent to which they fulfilled criteria for ideal prescribing guidance, but the BNF, and EMIS LV to a lesser extent, closely matched the criteria. DISCUSSION: We have demonstrated how clinical scenarios can be used to assess prescribing guidance resources. Producers of prescribing guidance documents should consider our idealized template. Prescribers require high-quality information to support their practice. CONCLUSION: Our test was helpful in distinguishing between prescribing resources. Producers of prescribing guidance should consider the utility of their products to end-users, particularly in those more complex areas where prescribers may need most support. Existing UK prescribing guidance resources differ in their ability to provide assistance to prescribers. PMID- 20831548 TI - Cytochrome P450 CYP2C19 genotypes in Nigerian sickle-cell disease patients and normal controls. AB - BACKGROUND AND OBJECTIVE: Subjects with different CYP2C19 genotypes may metabolize proguanil, a pro-drug used for malaria prophylaxis differently and the frequency of the different alleles may be different in patients with sickle-cell disease (SCD) and normal controls. The objective of this study was to evaluate CYP2C19 *1, *2 and *3 allele and genotype frequencies in Nigerian normal controls and SCD patients, and to further compare variant CYP2C19 frequencies in Nigerians with other African populations. METHODS: Genotyping was carried out with PCR and restriction fragment length polymorphism analysis. RESULTS AND DISCUSSION: CYP2C19 *1 (84.3 vs. 84.9%) or *2 allele frequency (15.7 vs. 15.1%) was not significantly different between patients with SCD and normal subjects. No *3 allele was detected in the cohort. The SCD group exhibited a statistically significantly lower frequency of *1/*1 genotype (69.6%) compared with normal controls (74.4%). Frequency of *2/*2 was significantly lower in SCD (0.9%) compared with normal controls (4.7%). Frequencies of *1/*2 (29.6 vs. 20.9%) were no different in SCD and normal controls. CONCLUSION: Prevalence of CYP2C19 polymorphisms was defined for the first time in Nigerian normal and SCD populations. Nigerian SCD patients exhibited significantly lower CYP2C19 *1/*1 and *2/*2 frequencies than normal controls. No differences were detected in CYP2C19 allele or genotype frequencies in normal subjects between this study and previous reports in other African populations. PMID- 20831549 TI - Metabolic acidosis and generalized seizures secondary to citalopram overdose: a case report. AB - Selective serotonin re-uptake inhibitors (SSRIs) are widely used in the community for treating many forms of mental illnesses. Citalopram, a newer generation SSRI, is commonly prescribed, but despite its low toxicity profile has a potential to cause seizures and dysarrythmias in overdose. Data on citalopram overdose-induced metabolic acidosis are scarce. There have been only three cases of metabolic acidosis reported in the literature due to citalopram overdose in humans and we are reporting the fourth one. We report a case of citalopram overdose with metabolic acidosis and generalized seizure. To our best knowledge, this is the first case reported in Saudi Arabia. PMID- 20831550 TI - The effect of high dose of N-acetylcysteine in lupus nephritis: a case report and literature review. AB - An imbalance of oxidative-antioxidant defence mechanism has been proposed in systemic lupus erythematosus patients. Co-administration of N-acetylcysteine (NAC) which has a strong antioxidant activity may produce a satisfactory therapeutic outcome when added to standard therapy. We report a case of a 46-year old lupus nephritis patient who received 1800 mg of NAC orally. After NAC, this patient showed a higher glutathione level, and a normal level of malondialdehyde, a lipid peroxidation product. In addition, the urinary protein levels, the complete blood counts and physical examination of the affected organs showed improvement. However, a well-controlled trial is needed to confirm the value of high-dose NAC in lupus nephritis patients. PMID- 20831551 TI - High-dose loading with extended release quetiapine. AB - Extended release quetiapine fumarate (quetiapine XR) was initiated at the recommended maximum dose 800 mg and maintained at the same dose in five patients with schizophrenia. Although the loadings of quetiapine XR were well tolerated in four patients in these five cases, one patient with a history of cerebral infarction developed serious side-effects, notably bladder distention and dizziness. This case series indicates that loading with maximum dose quetiapine XR may be tolerable and used safely in most schizophrenia patients with no other concurrent disease such as brain infarction. PMID- 20831552 TI - Methylprednisolone worsening neuropathic pain in non-traumatic thoracic myelopathy. AB - Methylprednisolone (MP) is the only neuroprotective medication currently in widespread use for the treatment of spinal cord injury. Increasingly, published studies challenge its clinical effects in view of its serious side-effects including wound infection, pneumonia, sepsis and steroid myopathy. Most cases with spontaneous spinal epidural haematoma (SSEH) need emergency evacuation, and typically show good neurologic recovery. Some patients with SSEH given preoperative or postoperative MP within hours of the onset of symptoms, and have had good motor recovery, although no mention was made of sensory function. Severe, intractable neuropathic pain has not been reported in patients with SSEH. We present a case of SSEH treated with a high-dose MP 16 h after onset of symptoms. Surgical decompression was performed 1 h after MP treatment. Motor recovery was good; however, intractable neuropathic pain developed 5 weeks postoperatively. We discuss the factors contributing to intractable pain. We speculate that the severe, intractable pain might be due to misuse of large-dose steroids in this case of non-traumatic spinal myelopathy, and not because of the injury per se. PMID- 20831553 TI - Developing countries and the 9th World Congress on Genetics Applied to Livestock Production. PMID- 20831554 TI - Statistical methods in animal breeding and Bach's harpsichord concertos. PMID- 20831555 TI - More than a third of the WCGALP presentations on genomic selection. PMID- 20831556 TI - Leipzig: the dawn of the genomes era. PMID- 20831557 TI - Effective population size of an indigenous Swiss cattle breed estimated from linkage disequilibrium. AB - Effective population size is an important parameter for the assessment of genetic diversity within a livestock population and its development over time. If pedigree information is not available, linkage disequilibrium (LD) analysis might offer an alternative perspective for the estimation of effective population size. In this study, 128 individuals of the Swiss Eringer breed were genotyped using the Illumina BovineSNP50 beadchip. We set bin size at 50 kb for LD analysis, assuming that LD for proximal single nucleotide polymorphism (SNP)-pairs reflects distant breeding history while LD from distal SNP-pairs would reflect near history. Recombination rates varied among different regions of the genome. The use of physical distances as an approximation of genetic distances (e.g. setting 1 Mb = 0.01 Morgan) led to an upward bias in LD-based estimates of effective population size for generations beyond 50, while estimates for recent history were unaffected. Correction for restricted sample size did not substantially affect these results. LD-based actual effective population size was estimated in the range of 87-149, whereas pedigree-based effective population size resulted in 321 individuals. For conservation purposes, requiring knowledge of recent history (<50 generations), approximation assuming constant recombination rate seemed adequate. PMID- 20831558 TI - Use of SNP genotyping to determine pedigree and breed composition of dairy cattle in Kenya. AB - High levels of inbreeding in East African dairy cattle are a potential concern because of use of a limited range of imported germplasm coupled with strong selection, especially by disease, and sparse performance recording. To address this, genetic relationships and breed composition in an admixed population of Kenyan dairy cattle were estimated by means of a 50K SNP scan. Genomic DNA from 3 worldwide Holstein and 20 Kenyan bulls, 71 putative cow-calf pairs, 25 cows from a large ranch and 5 other Kenyan animals were genotyped for 37 238 informative SNPs. Sires were predicted and 89% of putative dam-calf relationships were supported by genotype data. Animals were clustered with the HapMap population using Structure software to assess breed composition. Cows from a large ranch primarily clustered with Holsteins, while animals from smaller farms were generally crosses between Holstein and Guernsey. Coefficients of relatedness were estimated and showed evidence of heavy use of one AI bull. We conclude that little native germplasm exists within the genotyped populations and mostly European ancestry remains. PMID- 20831559 TI - D-loop sequence mitochondrial DNA variability of Sarda goat and other goat breeds and populations reared in the Mediterranean area. AB - To provide useful knowledge on goat breed origin and history, we studied the mitochondrial DNA (mtDNA) of 69 goats from five different breeds, Camosciata delle Alpi, Maltese, Nubian, Saanen and Sarda, and one population, the Tunisian. All goats analysed displayed a moderate haplotype and nucleotide diversity. The highest was in the Sarda - the autochthonous breed reared in Sardinia. On the basis of mtDNA control region sequences, animals showed a high genetic haplotype diversity, 35 haplotypes were each represented by a single sequence and only a few haplotypes were shared among the animals. New haplotypes of goats reared in the Mediterranean area were identified and the majority of Italian goats belonged to haplogroup A. This result confirmed worldwide distribution and diversity of haplogroup A. PMID- 20831560 TI - Application of multiple-trait finite mixture model to test-day records of milk yield and somatic cell score of Canadian Holsteins. AB - Multiple-trait (MT) finite mixture random regression (MIX) model was applied using Bayesian methods to first lactation test-day (TD) milk yield and somatic cell score (SCS) of Canadian Holsteins, allowing for heterogeneity of distributions with respect to days in milk (DIM) in lactation. The assumption was that the associations between patterns of variation in these traits and mastitis would allow revealing the hidden structure in the data distribution because of unknown health status of cows. The MIX model assumed separate means and residual co-variance structures for two components in four intervals of lactation, in addition to fitting the fixed effect of herd-test-day, and fixed and random regressions with Legendre polynomials. Results indicated that the mixture model was superior to standard MT model, as supported by the Bayes factor. Approximately 20% of TD records were classified as originated from cows with a putative, sub-clinical form of mastitis. The proportion of records from mastitic cows was the largest at the beginning of lactation. The MIX model exhibited different distributions of data from healthy and infected cows in different parts of lactation. Records from sick cows were characterized by larger (smaller) means for SCS (milk) and larger variances. Residual, and daily genetic and environmental correlations between milk and SCS were smaller from the MIX model when compared with MT estimates. Heritabilities of both traits differed significantly among records from healthy, sick and MT model estimates. Both models fitted milk records from healthy cows relatively well. The ability of the MT model in handling SCS records, measured by model residuals, was low, but improved substantially, however, where the data were allowed to be separated into two components in the MIX parameterization. Correlations between estimated breeding values (EBV) for sires from both models were very high for cumulative milk yield (>0.99) and slightly lower (0.95 in the interval from 5 to 45 DIM) for daily SCS. EBV for SCS from MT and MIX models were weakly correlated with posterior probability of sub-clinical mastitis on the phenotypic scale. PMID- 20831561 TI - Random regression models to estimate genetic parameters for test-day milk yield in Brazilian Murrah buffaloes. AB - The objective of this work was to estimate covariance functions for additive genetic and permanent environmental effects and, subsequently, to obtain genetic parameters for buffalo's test-day milk production using random regression models on Legendre polynomials (LPs). A total of 17 935 test-day milk yield (TDMY) from 1433 first lactations of Murrah buffaloes, calving from 1985 to 2005 and belonging to 12 herds located in Sao Paulo state, Brazil, were analysed. Contemporary groups (CGs) were defined by herd, year and month of milk test. Residual variances were modelled through variance functions, from second to fourth order and also by a step function with 1, 4, 6, 22 and 42 classes. The model of analyses included the fixed effect of CGs, number of milking, age of cow at calving as a covariable (linear and quadratic) and the mean trend of the population. As random effects were included the additive genetic and permanent environmental effects. The additive genetic and permanent environmental random effects were modelled by LP of days in milk from quadratic to seventh degree polynomial functions. The model with additive genetic and animal permanent environmental effects adjusted by quintic and sixth order LP, respectively, and residual variance modelled through a step function with six classes was the most adequate model to describe the covariance structure of the data. Heritability estimates decreased from 0.44 (first week) to 0.18 (fourth week). Unexpected negative genetic correlation estimates were obtained between TDMY records at first weeks with records from middle to the end of lactation, being the values varied from -0.07 (second with eighth week) to -0.34 (1st with 42nd week). TDMY heritability estimates were moderate in the course of the lactation, suggesting that this trait could be applied as selection criteria in milking buffaloes. PMID- 20831562 TI - Genetic correlations between categorical morphological traits in Nelore cattle by applying Bayesian analysis under a threshold animal model. AB - In this study, Bayesian analysis under a threshold animal model was used to estimate genetic correlations between morphological traits (body structure, finishing precocity and muscling) in Nelore cattle evaluated at weaning and yearling. Visual scores obtained from 7651 Nelore cattle at weaning and from 4155 animals at yearling, belonging to the Brazilian Nelore Program, were used. Genetic parameters for the morphological traits were estimated by two-trait Bayesian analysis under a threshold animal model. The genetic correlations between the morphological traits evaluated at two ages of the animal (weaning and yearling) were positive and high for body structure (0.91), finishing precocity (0.96) and muscling (0.94). These results indicate that the traits are mainly determined by the same set of genes of additive action and that direct selection at weaning will also result in genetic progress for the same traits at yearling. Thus, selection of the best genotypes during only one phase of life of the animal is suggested. However, genetic differences between morphological traits were better detected during the growth phase to yearling. Direct selection for body structure, finishing precocity and muscling at only one age, preferentially at yearling, is recommended as genetic differences between traits can be detected at this age. PMID- 20831563 TI - Estimation of genetic parameters for racing speed at different distances in young and adult Spanish Trotter horses using the random regression model. AB - A total of 71 522 records (from 3154 horses) with the times per kilometre (TPK), recorded in Spanish Trotter horses (individual races) from racing performances held from 1991 to 2007, were available for this study. The TPK values for the different age groups (young and adult horses) and different distances (1600-2700 m) were considered as different traits, and a bi character random regression model (RRM) was applied to estimate the (co)variance components throughout the trajectory of age groups and distances. The following effects were considered as fixed: the combination of hippodrome-date of race (404 levels); sex of the animals (3 levels); type of start (2 levels) and a fixed regression of Legendre polynomials (order 2). Those considered as random effects were the random regression Legendre polynomial (order 1) for animals (9201 animals in the pedigree); the individual environment permanent (3154 animals with data) and the driver (n = 957 levels). The residual variance was considered as heterogeneous with two classes (ages). The heritability estimated by distance ranged from 0.12 to 0.34, with a different trajectory for the two age groups. Within each age group, the genetic correlations between adjacent distances were high (>0.90), but decreased when the differences between them were over 400 metres for both age groups. The genetic correlations for the same distance across the age groups ranged from 0.47 to 0.78. Accordingly, the analysed trait (TPK) can be considered as positive genetic correlated but as different traits along the trajectory of distance and age. Therefore, some re-ranking should be expected in the breeding value of the horses at different characteristics of the racing. The use of RRM is recommended because it allows us to estimate the breeding value along the whole trajectory of race competition. PMID- 20831564 TI - Estimates of genetic parameters for conformation measures and scores in Finnhorse and Standardbred foals. AB - The aim of this study was to estimate genetic parameters for conformation measures and scores in the Finnhorse and the Standardbred foals presented in foal shows. Studied traits included height at withers and at croup, six subjectively evaluated conformation traits and overall grade. Data were from 10-year period (1995-2004) and consisted of 5821 Finnhorse foals (1-3 years old) with 7644 records and 2570 Standardbred foals (1-2 years old) with 2864 records. Variance components were estimated with REML - animal model using VCE4 program. The model included age class, year of judging, sex and region as fixed effects, and additive genetic, permanent environmental and residual as random effects. Estimates of heritability for measured traits were very high in both breeds (0.88 0.90). Estimates of heritability for conformation traits varied from 0.13 to 0.32 in the Finnhorse and from 0.06 to 0.47 in the Standardbred. In both breeds, estimates of heritability were lowest for hooves and movements at walk, and highest for type and body conformation among scored traits. Estimate of heritability for overall grade was in the Finnhorse 0.32 and in the Standardbred 0.34. Genetic correlations between overall grade and different conformation traits were 0.35-0.84 in the Finnhorse and 0.31-0.88 in the Standardbred. Thus, selection based on the overall grade would improve all studied characteristics. PMID- 20831565 TI - Fine mapping and detection of the causative mutation underlying Quantitative Trait Loci. AB - The effect on power and precision of including the causative SNP amongst the investigated markers in Quantitative Trait Loci (QTL) mapping experiments was investigated. Three fine mapping methods were tested to see which was most efficient in finding the causative mutation: combined linkage and linkage disequilibrium mapping (LLD); association mapping (MARK); a combination of LLD and association mapping (LLDMARK). Two simulated data sets were analysed: in one set, the causative SNP was included amongst the markers, while in the other set the causative SNP was masked between markers. Including the causative SNP amongst the markers increased both precision and power in the analyses. For the LLD method the number of correctly positioned QTL increased from 17 for the analysis without the causative SNP to 77 for the analysis including the causative SNP. The likelihood of the data analysis increased from 3.4 to 13.3 likelihood units for the MARK method when the causative SNP was included. When the causative SNP was masked between the analysed markers, the LLD method was most efficient in detecting the correct QTL position, while the MARK method was most efficient when the causative SNP was included as a marker in the analysis. The LLDMARK method, combining association mapping and LLD, assumes a QTL as the null hypothesis (using LLD method) and tests whether the 'putative causative SNP' explains significantly more variance than a QTL in the region. Thus, if the putative causative SNP does not only give an Identical-By-Descent (IBD) signal, but also an Alike-In-State (AIS) signal, LLDMARK gives a positive likelihood ratio. LLDMARK detected less than half as many causative SNPs as the other methods, and also had a relatively high false discovery rate when the QTL effect was large. LLDMARK may however be more robust against spurious associations, because the regional IBD is largely corrected for by fitting a QTL effect in the null hypothesis model. PMID- 20831566 TI - Genetic variation in monoamine oxidase A and analysis of association with behaviour traits in beef cattle. AB - Husbandry of beef cattle requires animals that do not behave aggressively or timidly. The enzyme monoamine oxidase A and the coding gene (MAOA) play an important role in the complex regulation of behaviour. The complete coding region and a part of the non-coding sequence of the bovine MAOA gene have been analysed in 20 German Angus and 20 German Simmental bulls and cows with the aim of detecting genetic variability. These two cattle breeds are known to differ regarding their behaviour during handling. Five single nucleotide polymorphisms (SNPs) were identified, three of which were found in the coding region of the gene (exons III and XV). One of the SNPs located in exon XV (NC_007331.3:g.80340C>T) was found to be a non-synonymous mutation. The minor allele frequency of this resulting amino acid substitution was significantly different between 543 German Angus and 417 German Simmental calves (0.39 and 0.49, respectively). The potential functional impact of this polymorphism has been tested by in silico analysis, as well as by association analysis using behaviour scores of the genotyped calves for three behaviour tests that assessed the animals' temperament during tethering, weighing or social separation. In silico analysis did not deliver consistent results arguing for or against a functional impact of the studied amino acid substitution on the function of the biological protein. No significant association was found between this MAOA polymorphism and the behaviour-related scores analysed in the study. PMID- 20831568 TI - Delayed haemorrhage after laparoscopic partial nephrectomy: frequency and angiographic findings. AB - OBJECTIVES: * To determine the frequency of delayed postoperative haemorrhage requiring selective angioembolization (SAE) after laparoscopic partial nephrectomy (LPN). * To describe the clinical presentation and characterize the angiographic findings encountered in this setting. PATIENTS AND METHODS: * Prospective data from 640 LPNs performed between August 1993 and May 2009 were retrospectively analyzed, from which patients with delayed postoperative haemorrhage (defined as 'gross haematuria >= 7 days postoperatively that persists for more than 24 h') and requiring SAE were identified. * Clinicopathological, preoperative and perioperative factors were reviewed. * Selective catheterization and angiography of the renal artery was performed for persistent gross haematuria and for haemodynamic instability associated with a significant drop in haematocrit level. * Arteries feeding the bleeding site were identified and embolized with endovascular coils. RESULTS: * Patients presented with delayed haemorrhage between 7 and 30 days after surgery. SAE was required in 13 patients (2%) for delayed postoperative bleeding. * Of the 640 LPNs, 68 (10.6%) were performed without hilar occlusion ('off-clamp') of whom one (1.5%) had a delayed haemorrhage, which was successfully embolized. * For patients with and without delayed haemorrhage after LPN, the mean tumour size was 2.7 cm and 3.3 cm (P= 0.31), the mean warm ischaemia time was 28.2 min and 14.3 min (P < 0.001), and the mean estimated blood loss 403.8 mL and 308.2 mL (P= 0.26), respectively. * Percutaneous angiography showed renal artery pseudoaneurysm in 10 patients and arterial contrast extravasation in three patients, two of whom also had an arteriovenous fistula. * Following embolization, creatinine levels remained stable in all patients. CONCLUSIONS: * Clinically significant delayed postoperative bleeding after LPN occurs in a small percentage of patients. * Angiography will accurately make the diagnosis of RAP or AVF and SAE is safe and effective procedure that allows for preservation of renal function. PMID- 20831567 TI - Human embryonic stem cells and metastatic colorectal cancer cells shared the common endogenous human microRNA-26b. AB - The increase in proliferation and the lack of differentiation of cancer cells resemble what occur in the embryonic stem cells during physiological process of embryogenesis. There are also striking similarities in the behaviour between the invasive placental cells and invasive cancer cells. In the present study, microarrays were used to analyse the global expression of microRNAs in a human embryonic stem cell line (i.e. HUES-17) and four colorectal cancer (CRC) cell lines (i.e. LoVo, SW480, HT29 and Caco-2) with different metastatic potentialities. Only the expression of miR-26b was significant decreased in HUES 17s and LoVo cells, compared with other three cell lines (P < 0.01). The quantitative real-time PCR analysis confirmed the results of the microarray analysis. Overexpression of miR-26b expression by miR-26 mimics transfection and led to the significant suppression of the cell growth and the induction of apoptosis in LoVo cells in vitro, and the inhibition of tumour growth in vivo. Moreover, the potential targets of miR-26b was predicted by using bioinformatics, and then the predicted target genes were further validated by comparing gene expression profiles between LoVo and NCM460 cell lines. Four genes (TAF12, PTP4A1, CHFR and ALS2CR2) with intersection were found to be the targets of miR 26b. MetaCore network analysis further showed that the regulatory pathways of miR 26b were significantly associated with the invasiveness and metastasis of CRC cells. These data suggest that miR-26b might serve as a novel prognostic factor and a potential therapeutic target for CRC. PMID- 20831569 TI - Joy for morphology: dermatopathology and art. AB - This work displays the bridging of two fields - namely dermatopathology and art. What is astonishing is that structures one sees through the microscope reveal aesthetic and artistic aspects and sometimes resemble in a startling way the designs of certain artists. Specific examples are illustrated to enhance the joy and appreciation of morphologic images. PMID- 20831570 TI - Development and psychometric testing of the Health Beliefs Related to Cardiovascular Disease Scale: preliminary findings. AB - AIM: This paper is a report of an evaluation of the psychometric properties of the Health Beliefs Related to Cardiovascular Disease Scale designed to measure beliefs related to cardiovascular disease risk and diet and exercise in adults with diabetes. BACKGROUND: Heart attack and stroke are 2-4 times more common among adults with diabetes than those without diabetes. To reduce this risk for patients with diabetes, understanding beliefs about cardiovascular disease risk and risk-reduction strategies is important. METHODS: Item development for the 25 item self-report Likert scale was guided by literature review, expert panel review and focus-group feedback. It consists of four subscales, measuring four constructs of the Health Belief Model: perceived susceptibility and severity of cardiovascular disease and benefits and barriers to diet and exercise. A convenience sample of 178 adults with self-reported type 2 diabetes completed the survey between August 2006 and March 2007; 42 participants completed it again 2-3 weeks later to evaluate test-retest reliability. RESULTS: The instrument has more than one dimension, with the best fit identified using a two-factor model specifying the Benefits and Susceptibility subscale items, rather than the four factor solution as predicted. The Susceptibility and Benefits subscales demonstrated stable factor structure and acceptable reliability (alpha = 0.93 and alpha = 0.82 respectively). The Barriers and Severity items demonstrated unstable factor structure and poor internal consistency (alpha = 0.70 and alpha = 0.61 respectively). CONCLUSION: Only the Susceptibility and Benefits subscale items can be used in their current form. The Barriers and Severity items need further refinement including revised wording with clearer focus and evaluation with a larger, more diverse sample. PMID- 20831571 TI - Effectiveness of music intervention on the quality of life of older people. AB - AIM: This paper is a report of a study of the effect of music on the quality of life of community-dwelling older Chinese people in Hong Kong. BACKGROUND: Older people's quality of life can be improved by preparing for the transition into old age. Listening to music, as a vehicle for feeling, can facilitate the non-verbal expression of emotion, reaching people's inner feelings without being threatening, and it can be a tool for emotional catharsis. METHOD: A randomized controlled trial design was conducted from in 2007 in a community centre in Hong Kong. A total of 66 older people (31 in music group and 35 in control group), aged from 65 to 90 years were randomly assigned to undergo either a 30-minute music intervention or a rest period for 4 weeks; quality of life outcomes were then measured. RESULTS: Quality of life improved weekly in the music group, indicating a cumulative dose effect, and a statistically significantly better quality of life was found over time in each sub-score for those in the music group compared with the controls. However, in the music group, there were no statistically significant improvements of quality of life in each sub-score over the 4 weeks. CONCLUSION: Being engaged in music activities can help a person to connect with their life experiences and with other people, and to be more stimulated. Music is a non-invasive, simple and inexpensive therapeutic method of improving quality of life in community-dwelling elders. PMID- 20831572 TI - Nurse practitioner-led surgical spine consultation clinic. AB - AIM: This study is a report of a study of patient satisfaction with non-surgical nurse practitioner management of pre-selected spinal referrals. BACKGROUND: Nurse practitioners are linked to particular patient populations or specific physicians in a medical setting. In a universal healthcare delivery system, patients are often faced with long and anxiety-provoking waiting times, particularly for sub specialized consultations such as spinal surgery. METHOD: A nurse practitioner led spine consultation ambulatory clinic was implemented at a Canadian neuroscience centre. A prospective patient satisfaction and clinical accuracy study was performed in 2008. All patients assessed by the nurse practitioner completed a post-consultation validated patient satisfaction questionnaire. All patients were reviewed with the surgeon for confirmation of diagnosis and management. RESULTS: A total of 177 pre-selected patients (disc-herniations, spinal stenosis, degenerative disc disease) were assessed by the nurse practitioner. Mean time from referral to nurse practitioner clinic assessment was 12 weeks (range: 9.8-21 weeks) compared with 10-52 weeks if seen in a conventional clinic. Nurse practitioner clinical diagnosis and management plan were in agreement with those of the surgeon (100% and 95% respectively). Patient satisfaction was 97% with the consultation and 94% and with examination thoroughness. Preference for a longer waiting period for direct consultation with the surgeon was 26%. CONCLUSION: Nurse practitioners can play an effective and efficient role in providing care to patients requiring specific disease management in a specialty setting. The nurse practitioner-run clinic offers accurate and earlier assessment, thus facilitating a timelier diagnosis and management plan. PMID- 20831573 TI - Nursing Services Delivery Theory: an open system approach. AB - AIM: This paper is a discussion of the derivation of the Nursing Services Delivery Theory from the application of open system theory to large-scale organizations. BACKGROUND: The underlying mechanisms by which staffing indicators influence outcomes remain under-theorized and unmeasured, resulting in a 'black box' that masks the nature and organization of nursing work. Theory linking nursing work, staffing, work environments, and outcomes in different settings is urgently needed to inform management decisions about the allocation of nurse staffing resources in organizations. DATA SOURCES: A search of CINAHL and Business Source Premier for the years 1980-2008 was conducted using the following terms: theory, models, organization, organizational structure, management, administration, nursing units, and nursing. Seminal works were included. DISCUSSION: The healthcare organization is conceptualized as an open system characterized by energy transformation, a dynamic steady state, negative entropy, event cycles, negative feedback, differentiation, integration and coordination, and equifinality. The Nursing Services Delivery Theory proposes that input, throughput, and output factors interact dynamically to influence the global work demands placed on nursing work groups at the point of care in production subsystems. IMPLICATIONS FOR NURSING: THE Nursing Services Delivery Theory can be applied to varied settings, cultures, and countries and supports the study of multi-level phenomena and cross-level effects. CONCLUSION: The Nursing Services Delivery Theory gives a relational structure for reconciling disparate streams of research related to nursing work, staffing, and work environments. The theory can guide future research and the management of nursing services in large-scale healthcare organizations. PMID- 20831574 TI - Condom negotiation: experiences of sexually active young women. AB - AIM: This paper is a report of a study of sexually active young women's experiences of negotiating condom use both before and after diagnosis of a sexually transmitted infection. BACKGROUND: The male condom is the most efficient method in preventing and reducing the transmission of sexually transmitted infections. However, condom use can be hindered by factors including societal norms and gender roles, which can create difficulties for women in initiating and negotiating condom use in heterosexual partnerships. METHODOLOGY: A feminist narrative approach was used, and ten women's stories were collected via online interviews in 2007. FINDINGS: None of the women initiated or negotiated use of the male condom for various reasons. Some relied on their male partners to initiate condom use, some were unable to practise safer sex due to the abuse and unequal gender dynamics that existed in their sexual relationships, and some thought that condom use was not necessary because of a belief that they were in safe and monogamous relationships. Even following diagnosis of a sexually transmitted infection, some women said that they were not empowered enough to initiate condom use with subsequent sexual partners, resulting in continued high risk sexual behaviour. CONCLUSION: Successful condom promotion relies on the recognition of the gender factors that impede young women's condom negotiation and use. Strategies that overcome gender dynamics and empower women to negotiate condom use have the ability to promote condom use among this group. PMID- 20831575 TI - Joint or clinical chairs in nursing: from cup of plenty to poisoned chalice? AB - AIM: This paper presents a discussion of the current state of joint chair or clinical chair positions in nursing. Background. Joint chair positions in nursing or midwifery have been popular approaches to developing clinical research and to bridging the 'theory-practice gap'. Recent personal observations and commentaries in the literature suggest that the service-academy consensus that underpinned such positions may be crumbling. DATA SOURCES: This paper is based on 13 years' experience of holding a joint chair position, an extensive review of the professional literature (up to and including 2009 sources), and conversations and discussions with many professorial and joint chair colleagues. DISCUSSION: Despite its demonstrated success, the joint chair position may be under threat from competing and unrealistic demands from partner organizations and from changing understandings of the essential role and nature of a professor. The situation may be exacerbated by appointing inexperienced or unsuitable applicants to such key posts. IMPLICATIONS FOR NURSING: The joint chair position was a powerful initiative in nursing and midwifery with real potential. In the current climate, this potential is unlikely to be realized and nursing will be the poorer. CONCLUSION: If joint chair positions are still valued and seen as key roles in developing clinical research and university-service partnerships, then serious consideration needs to be given to the current state of position. I argue for a return to trust and what Onora O'Neill calls 'intelligent accountability' rather than the micromanagement that is so prevalent in both the health and academic industries. PMID- 20831576 TI - An update on minor salivary gland secretions. AB - In this article, the literature on minor salivary gland secretion rates, composition, and function is reviewed. Measurements of the minor salivary gland secretion rates and composition are complicated, and the secretions display large biological variability. Despite this, some characteristics of these secretions have been found repeatedly in independent investigations. Minor gland saliva varies between different oral sites. Buccal saliva flow is higher than labial saliva flow, which in turn is usually higher than the palatal gland secretion rate. It is generally agreed that minor gland saliva is important for the whole saliva composition, and especially for the secretory immunoglobulin A and mucins. The secretion from these glands seems also important for subjective feelings of dry mouth and general wellbeing. Further research is essential for understanding the role of these secretions for oral, as well as for general, health. PMID- 20831577 TI - Survival probability of zirconia-based fixed dental prostheses up to 5 yr: a systematic review of the literature. AB - The purpose of this systematic review was to calculate the 5-yr survival rates of all-ceramic zirconia-based fixed dental prostheses (FDPs) and to analyze technical and biological complications. An electronic literature search of MEDLINE (PubMed) was conducted independently by three reviewers to identify clinical studies from 1999 to 2009 and was completed by a manual search. Keywords and inclusion and exclusion criteria were well-defined. The search revealed 399 titles and led to the final analysis of 18 full-text articles. Nine studies met the inclusion criteria. Extracted data were statistically calculated into 5-yr survival rates and 5-yr complication-free rates by using Poisson regression analysis. In total, 310, 3- to 4-unit FDPs and 20 FDPs with more than 4 units were included. The estimated 5-yr survival rate for all FDPs was 94.29% (95% CI: 58.98-99.32); 19 FDPs were lost as a result of catastrophic failures. The 5-yr complication-free rate regarding technical complications was 76.41% (95% CI: 42.42-91.60) with chipping being the most frequent complication. Regarding biological complications, the 5-yr complication-free rate was 91.72% (95% CI: 59.19-98.53). The survival rates of zirconia-based short-unit FDPs are promising. However, an important improvement of the veneering systems is required, and for FDPs with more units in function, further randomized, controlled clinical trials are necessary. PMID- 20831578 TI - Ameloblastin promotes bone growth by enhancing proliferation of progenitor cells and by stimulating immunoregulators. AB - In this study, we examined the role of the enamel matrix protein, ameloblastin, in bone growth and remodelling, and attempted to identify some of the molecular mechanisms involved in these processes. The effects of recombinant ameloblastin (rAmbn) were tested in vivo in rats, and in vitro in primary human mesenchymal stem cells, osteoblasts, chondrocytes, and osteoclasts. We used a microarray technique to identify genes that were regulated in human osteoblasts and verified our findings using multiplex protein analysis and real-time RT-PCR. Recombinant ameloblastin was found to stimulate bone healing in vivo, and to enhance the proliferation of mesenchymal stem cells and osteoblasts, as well as the differentiation of osteoclast precursor cells in vitro. The most profound effect was on the regulation of genes related to immune responses as well as on the expression of cytokines and markers of bone cell differentiation, indicating that ameloblastin has an effect on mesenchymal cell differentiation. A receptor has not yet been identified, but we found rAmbn to induce, directly and indirectly, signal transducer and activator of transcription (STAT) 1 and 2 and downstream factors in the interferon pathway. PMID- 20831579 TI - Short-term zoledronic acid reduces trabecular bone remodeling in dogs. AB - The effects of zoledronic acid, a bisphosphonate, on the trabecular bone remodeling (TBR) of the mandibular condyle are unknown. The objectives of this study were to quantify and compare TBR in the mandibular condyle and vertebrae of 2- to 3-yr-old dogs and to evaluate the effects of short-term zoledronic acid on TBR. Bone samples from two, age-matched groups of dogs [seven dogs were given no treatment (NT group) and seven dogs were treated with four total infusions of zoledronic acid administered monthly (ZOL group)] were analyzed using histomorphometry. Trabecular bone remodeling and microarchitecture were quantified and analyzed statistically. Physiologic TBR, quantified in the NT group, was significantly higher (more than sixfold) in the vertebrae than in the mandibular condyle. Trabecular bone remodeling in the vertebrae of dogs of the ZOL group was 96% lower than in dogs of the NT group. By contrast, TBR in the mandibular condyle of dogs in the ZOL group was statistically equivalent to that of dogs in the NT group. Our results demonstrate that the physiological TBR in aged dogs is vastly different in the mandibular condyle compared to that in the vertebra. A higher level of physiologic TBR in the vertebra than in the mandibular condyle results in greater reduction of TBR in response to short-term treatment with zoledronic acid. PMID- 20831581 TI - Effects of pH and acid concentration on erosive dissolution of enamel, dentine, and compressed hydroxyapatite. AB - The aims of this study were to determine the effects of pH and acid concentration on the dissolution of enamel, dentine, and compressed hydroxyapatite (HA) in citric acid solutions (15.6 and 52.1 mmol l(-1) ; pH 2.45, 3.2, and 3.9), using a pH-stat system. After an initial adjustment period, the dissolution rates of enamel and HA were constant, while that of dentine decreased with time. The dissolution rate increased as the pH decreased, and this was most marked for enamel. To compare substrates, the rate of mineral dissolution was normalized to the area occupied by mineral at the specimen surface. For a given acid concentration, the normalized dissolution rate of HA was always less than that for either dentine or enamel. The dissolution rate for dentine mineral was similar to that for enamel at pH 2.45 and greater at pH 3.2 and pH 3.9. The concentration of acid significantly affected the enamel dissolution rate at pH 2.45 and pH 3.2, but not at pH 3.9, and did not significantly affect the dissolution rates of dentine or HA at any pH. The variation in response of the dissolution rate to acid concentration/buffer capacity with respect to pH and tissue type might complicate attempts to predict erosive potential from solution composition. PMID- 20831580 TI - Molecular epidemiology and spatial distribution of Selenomonas spp. in subgingival biofilms. AB - The aetiology of periodontal disease has been a field of intensive research in the past decades. Along with a variety of other putative pathogens, different members of the genus Selenomonas have repeatedly been associated with both generalized aggressive periodontitis and chronic periodontitis. For the present study, a specific oligonucleotide probe targeting the majority of all oral Selenomonas spp. was designed. Their prevalence was determined, using dot-blot hybridization, in a total of 742 subgingival samples collected from patients with generalized aggressive (n=62) and chronic periodontitis (n=82), and from periodontitis-resistant subjects (n=19). In addition, fluorescence in situ hybridization (FISH) and electron microscopy were performed to analyze the spatial arrangement of Selenomonas in subgingival biofilms collected from patients with generalized aggressive periodontitis. In the samples from patients, Selenomonas spp. showed a lower prevalence in both diseased groups compared with other putative pathogens, and a relatively high prevalence in the periodontitis resistant group. Consequently, Selenomonas spp. do not seem to be suitable diagnostic marker organisms for periodontal disease. By contrast, FISH and electron microscopic analysis of periodontal carriers revealed that Selenomonas spp. appeared in large numbers in all parts of the collected biofilms and seemed, if present in a site from patients, to make a relevant contribution to their structural organization. PMID- 20831582 TI - Effect of an Er,Cr:YSGG laser on water perfusion in human dentine. AB - Changes in fluid perfusion through tubules may affect the sensitivity of exposed and restored dentine. The rate of perfusion is dependent on the structure and composition of dentine, particularly at the surface. This work analyzed the effect of treatment with an Erbium, Chromium-doped: Yttrium Scandium Gallium Garnet (Er,Cr:YSGG) laser on dentine perfusion. Extracted molars were sectioned above the mid-coronal portion, and below the cemento-enamel junction, to create crown segments. The pulp was extirpated and the dentine treated with the Er,Cr:YSGG laser, a diamond bur or sandpaper. Each specimen was mounted, with the pulp chamber oriented upwards, on a petri-dish cover in order to permit a tube filled with water to be connected to the pulp. Movement of the water meniscus over 24 h provided a measurement of the volume of water that filtered across the dentine. The dishes contained water to provide a moist environment in the relevant specimens, or were left dry to provide dry conditions. Specimens were perfused for 24 h with water pressures ranging from 20 to 60 cm. The results (in MUl mm(-2) d(-1) ) showed a significant difference in the perfusion rate between treatments. The difference between perfusion in wet and dry conditions was highly significant. Laser and bur treatment of dentine significantly affected perfusion, which was higher in the former than in the latter. Therefore, laser-treated dentine may be more sensitive than bur-cut dentine. PMID- 20831583 TI - Crystal growth by restorative filling materials. AB - This study examined the activity and ability of materials to mineralize teeth in gaps, simulating microleakage between the materials and teeth. Three restorative materials (two glass ionomer cements and a compomer) were used in this study. Cured disks of restoratives were placed over flat human tooth surfaces (enamel and dentin), separated by a standardized 20-MUm interfacial space, and stored in water for 24 h or 1 yr. After the water-storage period, the materials were detached from the teeth and the opposing surfaces were examined by scanning electron microscopy (SEM) and electron probe micro analysis (EPMA).Hemispherical shaped precipitations, composed of minute semicircle plate-like crystals, were observed by SEM on the enamel surface after 1 yr of water storage for glass ionomer cement. The amount of crystal growth with the chemical-cured type of glass ionomer cement was greater than with the dual-cured type of glass ionomer cement. However, there was no crystal formation in the compomer. Moreover, no structural changes were observed on dentin surfaces for any material in water after 1 yr. The elements detected in the crystals by EPMA were calcium (Ca), phosphorus (P), and aluminum (Al). The two glass ionomer cements tested have the ability to induce crystals whose composition might be derived from cured glass ionomers. PMID- 20831584 TI - Enzymatic degradation of adhesive-dentin interfaces produced by mild self-etch adhesives. AB - Endogenous matrix metalloproteinases (MMPs) released by adhesive procedures may degrade collagen in the hybrid layer and so compromise the bonding effectiveness of etch-and-rinse adhesives. In this study, endogenous enzymatic degradation was evaluated for several simplified self-etch adhesives. In addition, primers were modified by adding two MMP inhibitors: chlorhexidine, a commonly used disinfectant, but also a non-specific MMP inhibitor; and SB-3CT, a specific inhibitor of MMP-2 and MMP-9. Gelatin zymography of fresh human dentin powder was used to identify the enzymes released by the adhesives. Micro-tensile bond strength (MUTBS) testing was used to assess the mechanical properties of resin dentin interfaces over time. In none of the experimental groups treated with the mild self-etch adhesives was MMP-2 and/or MMP-9 identified. Also, no difference in the MUTBS was measured for the inhibitor-modified and the control inhibitor free adhesives after 6 months of water storage. It is concluded that in contrast to etch-and-rinse adhesives, the involvement of endogenous MMP-2 and MMP-9 in the bond-degradation process is minimal for mild self-etch adhesives. PMID- 20831585 TI - Effects of increased exposure times of simplified etch-and-rinse adhesives on the degradation of resin-dentin bonds and quality of the polymer network. AB - One of the reasons for resin-dentin degradation is poor polymerization of the adhesive layer. This study evaluated the effect of prolonged polymerization times on the immediate and 6-month resin-dentin bond strengths, silver nitrate uptake, and polymer quality of etch-and-rinse adhesives. Thirty extracted teeth were obtained, and a flat dentin surface was exposed on each tooth. Adhesives (Adper Single Bond 2 and One Step Plus) were applied to the dentin surface of these teeth and light-cured for 10, 20, or 40 s at 600 mW cm(-2) . Bonded sticks (0.6 mm(2) ) were tested in tension (0.5 mm min(-1) ) and analyzed, after immersion in 50% silver nitrate, using scanning electron microscopy. The polymer quality of adhesive films was evaluated using thermogravimetric analysis. Statistically higher bond strengths were observed for both adhesives when light-cured for 40 s. Degradation of dentin bonds occurred under all experimental conditions but it was less pronounced for adhesives light-cured for 40 s. Longer exposure times reduced silver nitrate uptake for Adper Single Bond 2. Solvent retention and the amount of residual monomer were statistically lower when both adhesives were light-cured for 40 s. Although longer exposure times than those recommended cannot prevent degradation of the dentin bonds, they can increase bond strength, probably because of the removal of an increased amount of solvent and the presence of a lower amount of residual monomer. PMID- 20831587 TI - Role of preliminary etching for one-step self-etch adhesives. AB - The aim of this study was to analyse the effect of preliminary phosphoric acid etching of enamel and dentine before the application of two, one-step self-etch adhesive systems. The systems were applied onto acid-etched or smear-layer covered enamel and dentine. The treatment groups were as follows: group 1, Adper Easy Bond (3M ESPE) on etched substrate; group 2, Adper Easy Bond (control); group 3, iBond Self-Etch (Heraeus Kulzer) on etched substrate; and group 4, iBond Self-Etch (control). Enamel and dentine bond strengths were calculated using microshear and microtensile bond-strength tests. Additional specimens were prepared to evaluate nanoleakage at the dentine-adhesive interface and were investigated using light microscopy or transmission electron microscopy. Both adhesives demonstrated higher microshear bond strengths when enamel was pre-acid etched with phosphoric acid (Adper Easy Bond 28.7 +/- 4.8 MPa; iBond Self-Etch 19.7 +/- 3.6 MPa) compared with controls (Adper Easy Bond 19.2 +/- 3.3 MPa; iBond Self-Etch 17.5 +/- 2.7 MPa) and increased microtensile bond strength when applied on acid-etched (Adper Easy Bond 35.8 +/- 5.7 MPa; iBond Self-Etch 24.3 +/- 7.9 MPa) vs. smear-layer-covered dentine (Adper Easy Bond 26.9 +/- 6.2 MPa; iBond Self-Etch 17.6 +/- 4.3 MPa). Adper Easy Bond showed lower nanoleakage than iBond Self-Etch, irrespective of preliminary etching. The results of this study support the use of phosphoric acid etching before the application of one-step self-etch adhesive systems. PMID- 20831586 TI - Dentin surface treatment using a non-thermal argon plasma brush for interfacial bonding improvement in composite restoration. AB - The objective of this study was to investigate the treatment effects of non thermal atmospheric gas plasmas on dentin surfaces used for composite restoration. Extracted unerupted human third molars were prepared by removing the crowns and etching the exposed dentin surfaces with 35% phosphoric acid gel. The dentin surfaces were treated using a non-thermal atmospheric argon plasma brush for various periods of time. The molecular changes of the dentin surfaces were analyzed using Fourier transform infrared spectrophotometry/attenuated total reflectance (FTIR/ATR), and an increase in the amount of carbonyl groups was detected on plasma-treated dentin surfaces. Adper Single Bond Plus adhesive and Filtek Z250 dental composite were applied as directed. To evaluate the dentin/composite interfacial bonding, the teeth thus prepared were sectioned into micro-bars and analyzed using tensile testing. Student-Newman-Keuls tests showed that the bonding strength of the composite restoration to peripheral dentin was significantly increased (by 64%) after 30 s of plasma treatment. However, the bonding strength to plasma-treated inner dentin did not show any improvement. It was found that plasma treatment of the peripheral dentin surface for up to 100 s resulted in an increase in the interfacial bonding strength, while prolonged plasma treatment of dentin surfaces (e.g. 5 min) resulted in a decrease in the interfacial bonding strength. PMID- 20831588 TI - Surface free-energy measurements as indicators of the bonding characteristics of single-step self-etching adhesives. AB - This study examined the surface free-energy of dentin treated with the single step self-etching adhesives Bond Force, Clearfil tri-S Bond, and G-Bond Plus. The labial dentin surfaces of bovine mandibular incisors were wet ground with #180-, #600-, and #2,000-grit silicon carbide paper. The adhesives were applied to the ground dentin, and then rinsed with acetone and distilled water. The surface free energies were determined by measuring the contact angles of three test liquids placed on the adhesive-treated dentin. The surface free-energies of the samples treated with the G-Bond Plus and Clearfil tri-S Bond adhesives increased as the surface roughness decreased. No significant differences in the surface free energy were found for the samples treated with the Bond Force adhesive, regardless of the surface roughness. These results indicated that dentin surfaces treated with adhesives did not promote a higher surface-energy state, and that differences in the components of surface energy were apparent for the adhesives tested. PMID- 20831589 TI - High-resolution crystal structures of the flavoprotein NrdI in oxidized and reduced states--an unusual flavodoxin. Structural biology. AB - The small flavoprotein NrdI is an essential component of the class Ib ribonucleotide reductase system in many bacteria. NrdI interacts with the class Ib radical generating protein NrdF. It is suggested to be involved in the rescue of inactivated diferric centres or generation of active dimanganese centres in NrdF. Although NrdI bears a superficial resemblance to flavodoxin, its redox properties have been demonstrated to be strikingly different. In particular, NrdI is capable of two-electron reduction, whereas flavodoxins are exclusively one electron reductants. This has been suggested to depend on a lesser destabilization of the negatively-charged hydroquinone state than in flavodoxins. We have determined the crystal structures of NrdI from Bacillus anthracis, the causative agent of anthrax, in the oxidized and semiquinone forms, at resolutions of 0.96 and 1.4 A, respectively. These structures, coupled with analysis of all curated NrdI sequences, suggest that NrdI defines a new structural family within the flavodoxin superfamily. The conformational behaviour of NrdI in response to FMN reduction is very similar to that of flavodoxins, involving a peptide flip in a loop near the N5 atom of the flavin ring. However, NrdI is much less negatively charged than flavodoxins, which is expected to affect its redox properties significantly. Indeed, sequence analysis shows a remarkable spread in the predicted isoelectric points of NrdIs, from approximately pH 4-10. The implications of these observations for class Ib ribonucleotide reductase function are discussed. PMID- 20831590 TI - Temporal shifts of the Norway lobster (Nephrops norvegicus) gut bacterial communities. AB - The aim of this study was to investigate the gut bacterial communities of Nephrops norvegicus individuals, using a suite of molecular tools consisting of automated ribosomal intergenic spacer analysis, 16S rRNA gene-internal transcribed spacer clone libraries and FISH. The animals were collected from Pagasitikos Gulf, Greece, during different months of the year. The diversity of the gut bacterial communities was found to mostly vary with sampling time, which could be related to temporal variations in food supply. The 16S rRNA gene diversity analysis showed dominance of specific phylotypes for each month studied. February, May, July, August and October samples were rich in sequences related to the gammaproteobacterial genera Pseudoalteromonas, Psychrobacter and Photobacterium. September and December samples were dominated by phylotypes affiliated with uncultured representatives of Mollicutes, which are generally associated with the intestinal tracts of various animals. The presence of Gammaproteobacteria and uncultured Mollicutes in August and September samples, respectively, was further confirmed by FISH. None of the morphometric parameters considered was related to the temporal pattern of dominant bacterial communities. PMID- 20831591 TI - Bacterial communities associated with the wood-feeding gastropod Pectinodonta sp. (Patellogastropoda, Mollusca). AB - Even though their occurrence was reported a long time ago, sunken wood ecosystems at the deep-sea floor have only recently received specific attention. Accumulations of wood fragments in the deep sea create niches for a diverse fauna, but the significance of the wood itself as a food source remains to be evaluated. Pectinodonta sp. is a patellogastropod that exclusively occurs on woody substrates, where individuals excavate deep depressions, and is thus a potential candidate for a wood-eating lifestyle. Several approaches were used on Pectinodonta sampled close to Tongoa island (Vanuatu) to investigate its dietary habits. Host carbon is most likely derived from the wood material based on stable isotopes analyses, and high cellulase activity was measured in the digestive mass. Electron microscopy and FISH revealed the occurrence of two distinct and dense bacterial communities, in the digestive gland and on the gill. Gland associated 16S rRNA gene bacterial phylotypes, confirmed by in situ hybridization, included members of three divisions (Alpha- and Gammaproteobacteria, Bacteroidetes), and were moderately related (90-96% sequence identity) to polymer-degrading and denitrifying bacteria. Gill-associated phylotypes included representatives of the Delta- and Epsilonproteobacteria. The possible involvement of these two bacterial communities in wood utilization by Pectinodonta sp. is discussed. PMID- 20831592 TI - Growth-phase-dependent expression of the operon coding for the glycosylated autotransporter adhesin AIDA-I of pathogenic Escherichia coli. AB - The adhesin involved in diffuse adherence (AIDA-I) is an autotransporter found in pathogenic strains of Escherichia coli causing diarrhea in humans and pigs. The AIDA-I protein is glycosylated by a specific enzyme, the AIDA-associated heptosyltransferase (Aah). The aah gene is immediately upstream of the aidA gene, suggesting that they form an operon. However, the mechanisms of regulation of the aah and aidA genes are unknown. Using a clinical E. coli isolate expressing AIDA I, we identified two putative promoters 149 and 128 nucleotides upstream of aah. Using qRT-PCR, we observed that aah and aidA are transcribed in a growth dependent fashion, mainly at the start of the stationary phase. Western blotting confirmed that protein expression follows the same pattern. Using a fusion to a reporter gene, we observed that the regulation of the isolated aah promoter matched this transcription and expression pattern. Lastly, we found glucose to be a repressor and nutrient starvation to be an inducer. Taken together, our results suggest that, in the strain and the conditions we studied, aah-aidA is transcribed as a bicistronic message from a promoter upstream of aah, with maximal expression under conditions of nutrient limitation such as high cell density. PMID- 20831593 TI - Biogenesis of the cyanobacterial thylakoid membrane system--an update. AB - Current molecular analyses suggest that initial steps of the biogenesis of cyanobacterial photosystems progress in a membrane subfraction representing a biosynthetic center with contact to both plasma and thylakoid membranes. This special membrane fraction is defined by the presence of the photosystem II assembly factor PratA. The proposed model suggests that both biogenesis of protein complexes and insertion of chlorophyll molecules into the photosystems occur in this intermediate membrane system. PMID- 20831594 TI - GC-clamp primer batches yield 16S rRNA gene amplicon pools with variable GC clamps, affecting denaturing gradient gel electrophoresis profiles. AB - Fingerprinting methods such as denaturing gradient gel electrophoresis (DGGE) of 16S rRNA gene pools have become a popular tool for comparisons between microbial communities. The GC-clamp portion of primers for DGGE amplicon preparation provides a key component in resolving fragments of similar size but different sequence. We hypothesized that repeat syntheses of identical 40-base GC-clamp primers lead to different DGGE profiles. Three repeat syntheses of the same GC clamp primer and two different GC-clamp primers directed at the V3-5 region of the 16S rRNA gene were compared. Genomic DNA of two separate soil bacterial communities and three bacterial species was amplified and resolved by DGGE. The DGGE profiles obtained with repeat-synthesized primers differed among each other as much as with alternate primers, for both soil DNA and pure single species. The GC-clamp portion of members of amplicon pools varied among each other, deviating from the design sequence, and was the likely cause for multiple bands derived from a single 16S rRNA gene sequence. We recommend procuring an oligonucleotide batch large enough to conduct an entire project. This should help to avoid any DGGE profile variations due to performance differences between repeat syntheses of GC-clamp oligonucleotide primers. PMID- 20831595 TI - Exploring the response of Escherichia coli O157:H7 EDL933 within Acanthamoeba castellanii by genome-wide transcriptional profiling. AB - Free-living protozoa, such as Acanthamoeba castellanii, are environmental hosts for pathogenic bacteria. Protozoa have been implicated in harboring pathogenic bacteria and enhancing virulence factors and antibiotic resistance. To better understand this relationship with Escherichia coli O157:H7, we characterized its transcriptome within A. castellanii compared with broth-grown organisms using two color microarrays. Statistical analysis indicated that 969 genes were differentially expressed at P<0.018, with a false discovery rate of 1.9% and a fold change cutoff of 1.3 or greater. There were 655 upregulated transcripts that include 40 genes associated with virulence, of which 32 are encoded on O-islands, and include shiga toxin genes (stx1A, stx1B stx2A) and 14 genes involved in Type III secretion system components. Also included are SOS response genes such as lexA and recA, genes involved in or predicted to be involved in antibiotic resistance (rarD, macAB, marABR, mdtK, yojI, yhgN), the quorum-sensing operon lsrACDB, and the efe and feo iron-acquisition systems. There were 314 downregulated transcripts that included 19 transcripts associated with virulence, seven of which are encoded on O-islands. Our results demonstrate that a significant portion of the E. coli O157:H7 genome was differentially expressed as a result of the protozoan intracellular environment. PMID- 20831596 TI - Effect of protease inhibitors on the quantitative and qualitative assessment of oral microorganisms. AB - Protease inhibitor cocktails are routinely added to clinical samples used for proteomic studies to inactivate proteases. As these same samples are often used for microbial studies, we determined whether the addition of protease inhibitors could affect the quantitative or qualitative assessment of microbial profiles. Twenty-two saliva samples were collected and processed immediately with or without the addition of a protease inhibitor cocktail. Conventional cultivation methods were used to evaluate total bacterial growth. Total genomic DNA was isolated and a specific 16S rRNA gene-targeted region was PCR-amplified and separated by denaturing gradient gel electrophoresis. A combination of 1D sodium dodecyl sulfate polyacrylamide gel electrophoresis and LC-MS/MS methods was used to determine the effect of the protease inhibitors on the integrity of salivary proteins and peptides. Interestingly, no significant differences were observed in either the bacterial growth and composition or the integrity of salivary proteins between the two groups. Correlation coefficients between the paired samples for total cultivable microbiota (r(2) =0.847), total mutans streptococci (r(2) =0.898), total oral lactobacilli (r(2) =0.933), and total Streptococcus mutans (r(2) =0.870) also exceeded expected values. The results suggest that the addition of a protease inhibitor cocktail in saliva samples does not impact the growth of oral microbiota or compromise the ability to characterize its composition. PMID- 20831597 TI - Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain. AB - Mammalian glycogen synthase kinase-3 (GSK3) is generated from two genes, GSK3alpha and GSK3beta, while a splice variant of GSK3beta (GSK3beta2), containing a 13 amino acid insert, is enriched in neurons. GSK3alpha and GSK3beta deletions generate distinct phenotypes. Here, we show that phosphorylation of CRMP2, CRMP4, beta-catenin, c-Myc, c-Jun and some residues on tau associated with Alzheimer's disease, is altered in cortical tissue lacking both isoforms of GSK3. This confirms that they are physiological targets for GSK3. However, deletion of each GSK3 isoform produces distinct substrate phosphorylation, indicating that each has a different spectrum of substrates (e.g. phosphorylation of Thr509, Thr514 and Ser518 of CRMP is not detectable in cortex lacking GSK3beta, yet normal in cortex lacking GSK3alpha). Furthermore, the neuron-enriched GSK3beta2 variant phosphorylates phospho-glycogen synthase 2 peptide, CRMP2 (Thr509/514), CRMP4 (Thr509), Inhibitor-2 (Thr72) and tau (Ser396), at a lower rate than GSK3beta1. In contrast phosphorylation of c-Myc and c-Jun is equivalent for each GSK3beta isoform, providing evidence that differential substrate phosphorylation is achieved through alterations in expression and splicing of the GSK3 gene. Finally, each GSK3beta splice variant is phosphorylated to a similar extent at the regulatory sites, Ser9 and Tyr216, and exhibit identical sensitivities to the ATP competitive inhibitor CT99021, suggesting upstream regulation and ATP binding properties of GSK3beta1 and GSK3beta2 are similar. PMID- 20831598 TI - Exogenous protein Hsp70/Hsc70 can penetrate into brain structures and attenuate the severity of chemically-induced seizures. AB - Heat shock protein 70 kDa (Hsp70) possesses a remarkable neuroprotective activity and the results of recent studies demonstrated its efficacy in the attenuation of epileptic seizures. The aim of this study was to explore the effects of a pure Hsp70/Hsc70 preparation delivered to the brain regions involved in generalized seizures induced in rats by intracerebroventricular microinjections of NMDA or systemic injections of pentylenetetrazole. Purified Hsp70/Hsc70 was administered (intracerebroventricular) 2 h before the induction of seizures. Compared to the vehicle-treated control animals, Hsp70/Hsc70-pretreated rats demonstrated reduced severity of NMDA- and pentylenetetrazole-induced seizures. To identify the brain structures potentially implicated in the Hsp70/Hsc70-mediated anticonvulsant effect, we analysed the localization of a fluorescently-labelled chaperone in the brain. Labelled Hsp70/Hsc70 was found in neurons and terminals of the limbic seizure complex of the brain and was co-localized in these regions with NMDA receptors, synaptophysin and the GABA-synthesizing enzyme, L-glutamic acid decarboxylase 67. An immunoprecipitation assay confirmed interactions between Hsp70 and both synaptophysin and L-glutamic acid decarboxylase 67 in brain tissue. We suggest that the anticonvulsant effect of exogenous Hsp70/Hsc70 is not only based on its protective capacity but is also related to its ability to modulate GABA neurotransmission, which in turn contributes to the maintenance of the excitatory-inhibitory balance of the CNS. PMID- 20831599 TI - Search for the acetylcholine and vesamicol binding sites in vesicular acetylcholine transporter: the region around the lumenal end of the transport channel. AB - Vesicular acetylcholine transporter (VAChT; TC 2.A.1.2.13) mediates storage of acetylcholine (ACh) by synaptic vesicles. A three-dimensional homology model of VAChT is available, but the binding sites for ACh and the allosteric inhibitor ( )-trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol) are unknown. In previous work, mutations of invariant W331 in the lumenal beginning of transmembrane helix VIII (TM VIII) of rat VAChT led to as much as ninefold loss in equilibrium affinity for ACh and no loss in affinity for vesamicol. The current work investigates the effects of additional mutations in and around W331 and the nearby lumenal end of the substrate transport channel. Mutants of human VAChT were expressed in the PC12(A123.7) cell line and characterized using radiolabeled ligands and filtration assays for binding and transport. Properties of a new and a repeat mutation in W331 are consistent with the original observations. Of 16 additional mutations in 13 other residues (Y60 in the beginning of lumenal Loop I/II, F231 in the lumenal end of TM V, W315, M316, K317, in the lumenal end of TM VII, M320, A321, W325, A330 in lumenal Loop VII/VIII, A334 in the lumenal beginning of TM VIII, and C388, C391, F392 in the lumenal beginning of TM X), only A334F impairs binding. This mutation decreases ACh and vesamicol equilibrium binding affinities by 14- and 4-fold, respectively. The current results, combined with previous results, demonstrate existence of a spatial cluster of residues close to vesicular lumen that decreases affinity for ACh and/or vesamicol when the cluster is mutated. The cluster is composed of invariant W331, highly conserved A334, and invariant F335 in TM VIII and invariant C391 in TM X. Different models for the locations of the ACh and vesamicol binding sites relative to this cluster are discussed. PMID- 20831600 TI - Correlated changes in NMDA receptor phosphorylation, functional activity, and sedation by chronic ethanol consumption. AB - Alcohol abuse leads to tolerance, dependence, and memory impairments that involve excitatory glutamatergic NMDA synaptic transmission. The NMDA receptor (NMDAR) is known to undergo activity-dependent adaptive functional changes. Since we observed that acute ethanol inhibition of the NMDAR was regulated by protein tyrosine phosphorylation, we investigated the role of protein tyrosine kinases and phosphatases on the NMDAR functions by chronic ethanol treatment. We carried out whole-cell recording, western blotting, and behavioral righting reflex measurements to assess the impact of chronic ethanol treatment on NMDAR function. Our results indicated that these receptors became resistant to the acute ethanol inhibition following chronic ethanol consumption. This resistance occurred without an increase in the NMDAR subunit expression but was associated with decreases in the levels of phospho-Y-1472 NR2B, increases in the levels of STEP33, increases in phospho-p38 mitogen-activated protein kinase (pp38 MAPK), and acquisition of tolerance to the sedative effects of ethanol. These data suggested that altered protein tyrosine phosphorylation of the NMDAR subunits significantly contributes to functional changes of this receptor by chronic ethanol ingestion. Therefore, preservation of the integrity of tyrosine phosphorylation mechanisms of the NMDAR may be important in controlling the progression of alcohol tolerance and dependence. PMID- 20831602 TI - Cutaneous leishmaniasis: advances in disease pathogenesis, diagnostics and therapeutics. AB - Cutaneous leishmaniasis is one of the most common tropical dermatoses worldwide and is of major public health importance. It is caused by numerous Leishmania protozoa species, which are responsible for its clinical diversity. With changes in vector (sandfly) habitat and increased travel among human populations, its incidence is rising, and in nonendemic countries, including the UK, it is increasingly diagnosed in migrants, returned travellers, and military personnel. Diagnostic tests have not always been sufficiently sensitive, and despite a wide range of treatments, poor therapeutic responses and adverse effects are common. In the past decade, there have been notable advances in molecular diagnostics, in the understanding of host immune responses to infection, and in new therapeutic interventions and vaccine development. PMID- 20831603 TI - Oral malignant melanoma: immunopathological analysis of a multiphasic case. PMID- 20831604 TI - Recalcitrant cutaneous sarcoidosis responding to adalimumab but not to etanercept. PMID- 20831605 TI - Does adalimumab cause bullous pemphigoid? PMID- 20831606 TI - A rare case of misplaced turban. Cylindroma. PMID- 20831607 TI - Arcuate plaques of the face and scalp. Atypical necrobiosis lipoidica (ANL) of the face and scalp. PMID- 20831608 TI - Widespread papules in a patient with human immunodeficiency virus. Papular mucinosis (PM) in association with HIV infection. PMID- 20831609 TI - An ulcerated plaque on the breast of a young woman. Extragenital bilharziasis cutanea tarda (Schistosoma mansoni). PMID- 20831610 TI - Pigmented facial plaques. Granuloma faciale (GF). PMID- 20831611 TI - A nodular lesion of the toe. Superficial acral fibromyxoma (SAF). PMID- 20831613 TI - Clinical characteristics of the smooth tubercle bacilli 'Mycobacterium canettii' infection suggest the existence of an environmental reservoir. AB - Over a 3-year follow-up, 30 out of the 318 unique Mycobacterium tuberculosis complex isolates recovered in the Republic of Djibouti had a smooth-type morphology and were Niacine-negative, the characteristics of 'Mycobacterium canettii' strains. Unlike M. tuberculosis, 'M. canettii' grew on nutrient-poor media at 30 degrees C, and possessed characteristic lipids. They were isolated from respiratory and extra-respiratory sites from patients with typical forms of tuberculosis. Most cases resolved with antibiotic therapy but in two human immunodeficiency virus-positive patients 'M. canettii' infection led to septicaemia and death. No cases of human-to-human transmission were observed. The proportion of tuberculosis cases caused by 'M. canettii' was higher among French patients than among Djiboutian patients. Patients with 'M. canettii' were significantly younger than those with tuberculosis caused by other M. tuberculosis complex strains. Smooth tubercle bacilli could be misidentified as non-tuberculous mycobacteria and appear to be limited to the Horn of Africa. Their characteristics are consistent with the existence of non-human sources of infection. PMID- 20831614 TI - Treatment of massive bleeding with prothrombin complex concentrate: argument for. PMID- 20831615 TI - Benefits of histone deacetylase inhibitors for acute brain injury: a systematic review of animal studies. AB - Drugs that inhibit histone deacetylase (HDAC) activities have enormous potential as neuroprotective agents. We performed a systematic review of controlled animal studies that administered known inhibitors of the zinc-dependent HDACs before and/or after acute cerebral injury and assessed anatomic/functional outcomes. Relevant studies were found by searching PubMed, Embase and Web of Science. From more than 100 identified publications, those data meeting specific criteria were analyzed using the Cochrane Review Manager software. A beneficial effect of administering HDAC inhibitors was seen in studies involving cerebral ischemia or non-ischemic models of acute cerebral injury. Specific studies assessed efficacy when drug was administered up to 14 days prior to, and 14 days following, the onset of cerebral injury. This systematic review provides objective evidence of a neuroprotective role for drugs that inhibit HDACs and highlights particular areas that require further experimental investigation. PMID- 20831616 TI - Effect of age on proliferation-regulating factors in human adult neurogenic regions. AB - Neurogenesis, the birth of new neurons, continues throughout adulthood in the human subventricular zone (SVZ) and hippocampus. It is not known how levels of putative proliferation-regulating factors change with age in human adult neurogenic areas. The current project employed ELISAs to investigate changes in levels of putative proliferation-regulating factors in the healthy human SVZ and dentate gyrus throughout the adult lifespan (18-104 years). Levels of brain derived neurotrophic factor, basic fibroblast growth factor and interleukin (IL) 1beta were significantly higher in the hippocampus than in the SVZ and levels of glial-derived neurotrophic factor and transforming growth factor-alpha were significantly higher in the SVZ (p < 0.005), suggesting that factors with predominant influences on neurogenesis differ between the two human adult neurogenic areas. Hippocampal levels of transforming growth factor-beta1 strongly increased with age (n = 9, p < 0.01), whereas hippocampal and SVZ levels of brain derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, glial-derived neurotrophic factor, heparin-binding epidermal growth factor, insulin-like growth factor-1, IL-1beta, IL-6 and transforming growth factor-alpha did not change significantly with age in the SVZ or hippocampus. These findings suggest regulation of the adult neurogenic environment in the human brain may differ over time from that in other species. PMID- 20831617 TI - N-methyl-D-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95. AB - NMDA receptors (NMDARs) mediate excitatory synaptic transmission during repetitive or prolonged glutamate release, playing a critical role in synaptic plasticity or cell death, respectively. Evidence indicates that a major pathway of NMDAR signaling to cell death in cortical and hippocampal neurons requires the scaffolding protein post-synaptic density 95 (PSD-95) and activation of neuronal nitric oxide synthase. However, it is not known if this PSD-95-dependent pathway contributes to excitotoxicity in other brain regions. It is also unclear whether the neuroprotective effects of Tat-NR2B9c, a membrane-permeant peptide that disrupts PSD-95/NMDAR binding, correlate with uncoupling NR2B- and/or NR2A-type NMDARs from PSD-95. In this study, we used cultured hippocampal and striatal neurons to test the potency of Tat-NR2B9c on uncoupling NR2 subunits from PSD-95 and protecting against NMDA-induced excitotoxicity. We found that the concentration of Tat-NR2B9c required to dissociate 50% of PSD-95 was fourfold lower for NR2B than NR2A in cultured hippocampal and striatal neurons, and that this concentration correlated tightly with protection against NMDA-induced toxicity in hippocampal neurons without altering NMDAR current. In contrast, NMDAR signaling to cell death in cultured striatal neurons occurred independently of the NR2B/PSD-95 interaction or neuronal nitric oxide synthase activation. These results will facilitate development of neuronal type-specific protective therapies. PMID- 20831618 TI - Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. AB - To investigate whether proton pump inhibitors (PPIs) negatively affect clinical outcome in patients treated with clopidogrel. Systematic review and meta analysis. Outcomes evaluated were combined major adverse cardiac events (MACE), myocardial infarction (MI), stent thrombosis, death and gastrointestinal bleeding. Studies included were randomized trials or post-hoc analyzes of randomized trials and observational studies reporting adjusted effect estimates. Twenty five studies met the selection criteria and included 159 138 patients. Administration of PPIs together with clopidogrel corresponded to a 29% increased risk of combined major cardiovascular events [risk ratio (RR) = 1.29, 95% confidence intervals (CI) = 1.15-1.45] and a 31% increased risk of MI (RR = 1.31, 95%CI = 1.12-1.53). In contrast, PPI use did not negatively influence the mortality (RR = 1.04, 95%CI = 0.93-1.16), whereas the risk of developing a gastrointestinal bleed under PPI treatment decreased by 50% (RR = 0.50, 95% CI = 0.37-0.69). The presence of significant heterogeneity might indicate that the evidence is biased, confounded or inconsistent. The sensitivity analysis, however, yielded that the direction of the effect remained unchanged irrespective of the publication type, study quality, study size or risk of developing an event. Two studies indicate that PPIs have a negative effect irrespective of clopidogrel exposure. In conclusion, concomitant PPI use might be associated with an increased risk of cardiovascular events but does not influence the risk of death. Prospective randomized trials are required to investigate whether a cause and-effect relationship truly exists and to explore whether different PPIs worsen clinical outcome in clopidogrel treated patients as the PPI-clopidogrel drug-drug interaction does not seem to be a class effect. PMID- 20831619 TI - Factor deficiencies in venom-induced consumption coagulopathy resulting from Australian elapid envenomation: Australian Snakebite Project (ASP-10). AB - BACKGROUND: Limited information exists on the dynamics of hemostasis in patients with venom-induced consumption coagulopathy (VICC) from snake envenomation. OBJECTIVE: The aim of the present study was to investigate specific factor deficiencies and their time course in Australasian elapid envenomation. METHODS: We measured coagulation parameters and factor concentrations in patients recruited to the Australian Snakebite Project, an observational cohort study. There were 112 patients with complete VICC, defined as an international normalized ratio (INR) > 3, and 18 with partial VICC. Serial citrated plasma samples were collected from 0.5 to 60 h post-bite. INR, activated partial thromboplastin time (aPTT), coagulation factors (F)I, II, V, VII, VIII, IX, X, von Willebrand factor antigen (VWF:Ag) and D-dimer concentrations were measured. RESULTS: Complete VICC was characterized by near/total depletion of fibrinogen, FV and FVIII, with an INR and aPTT that exceeded the upper limits of detection, within 2 h of snakebite. Prothrombin levels never fell below 60% of normal, suggesting that the toxins were rapidly eliminated or inactivated and re synthesis of clotting factors occurred irrespective of antivenom. Partial VICC caused limited depletion of fibrinogen and FV, and almost complete consumption of FVIII. Onset of VICC was more rapid with brown snake (Pseudonaja spp.) venom, which contains a group C prothrombin activator toxin, compared with the tiger snake group, which contains a group D prothrombin activator toxin and requires human FVa formation. Resolution of VICC occurred within 24-36 h irrespective of snake type. CONCLUSIONS: These results suggest that Australasian elapid prothrombin activators have a potent but short duration of action. Antivenom is unlikely to be administered in time to prevent VICC. PMID- 20831620 TI - Effectiveness of pharmacist-participated warfarin therapy management: a systematic review and meta-analysis. AB - OBJECTIVE: Although pharmacist-participated warfarin therapy management (PWTM) has been accepted and implemented in various parts of the world, the evidence demonstrating the effects of PWTM compared with usual care on clinical outcomes is lacking. We performed a systematic review and meta-analysis to compare the effects of PWTM with usual care on bleeding and thromboembolic outcomes. METHODS: We searched MEDLINE, SCOPUS, EMBASE, IPA, CINAHL, Cochrane CENTRAL, Thai Index Medicus and Thai Medical Index, and reference lists of studies, without language restriction. Databases were searched from their inception to July 2009. The studies using warfarin as an anticoagulant with sufficient data for compilation of 2 * 2 tables were included. Both randomized controlled trials (RCTs) and non RCTs were considered. Two authors independently reviewed each study, assigned quality scores and extracted data for all outcomes using a standardized form. Pooled effect estimates (risk ratio; RR) were obtained using a random effects model. RESULT: Of 661 articles identified, 24 studies with 728,377 patients were included. In the random-effects meta-analysis of RCTs, the PWTM group had statistically significant effects on the prevention of total bleeding [RR, 0.51; 95% confidence interval (CI), 0.28-0.94]. However, the effects on major bleeding (RR, 0.64; 95% CI, 0.18-2.36), thromboembolic events (RR, 0.79; 95% CI, 0.33 1.93), all-cause mortality (RR, 0.93; 95% CI, 0.41-2.13) and warfarin-related mortality (RR, 0.65; 95% CI, 0.18-2.42) were not significant. CONCLUSION: Pharmacist's participation in the management of warfarin therapy significantly reduces total bleeding, with a non-significant trend towards decreases in other warfarin-related complications. PMID- 20831622 TI - Acute and subacute stent thrombosis after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: incidence, predictors and clinical outcome. AB - BACKGROUND: Early coronary stent thrombosis occurs most frequent after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: To identify the specific predictors of, respectively, acute and subacute stent thrombosis in patients after primary PCI for STEMI. PATIENTS/METHODS: Consecutive STEMI patients with angiographically confirmed early stent thrombosis were enrolled and compared in a 2 : 1 ratio with a matched control group. Clinical outcome was collected up to 1 year. RESULTS: Of 5842 STEMI patients treated with primary PCI, 201 (3.5%) presented with a definite early stent thrombosis. Of these, 97 (1.7%) had acute stent thromboses and 104 (1.8%) had subacute stent thromboses. Postprocedurally discovered dissection, undersizing and smaller stent diameter were the strongest predictors for acute stent thrombosis. No glycoprotein IIb/IIIa therapy and the use of drug eluting stents were also associated with acute stent thrombosis. Lack of clopidogrel therapy in the first 30 days after the index PCI was the strongest predictor for subacute stent thrombosis. Mortality rates at 1-year follow-up were lower for acute stent thrombosis than for subacute stent thrombosis (8.3% vs. 13.2%, P = 0.294). The incidence of definite recurrent stent thrombosis at 1-year follow up was significantly lower after a first definite acute stent thrombosis than after a first definite subacute stent thrombosis (6.4% vs. 19.3%, P = 0.007 at 1 year). CONCLUSIONS: The specific risk factors for, respectively, acute and subacute stent thrombosis after primary PCI vary greatly. Mortality rates are high for both categories of stent thrombosis. However, recurrent stent thrombosis occurs more frequently after subacute stent thrombosis. PMID- 20831623 TI - Standardization of platelet-derived microparticle enumeration by flow cytometry with calibrated beads: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. PMID- 20831624 TI - Chronic kidney disease stages 1-3 increase the risk of venous thrombosis. AB - BACKGROUND: End-stage renal disease has been associated with venous thrombosis (VT). However, the risk of VT in the early stages of chronic kidney disease (CKD) has not yet been investigated. The aim of this study was to investigate whether CKD patients with stage 1-3 disease are at increased risk of VT. METHODS: Eight thousand four hundred and ninety-five subjects were included in a prospective cohort study, in which renal function and albuminuria were assessed, starting in 1997-1998, and were followed for the occurrence of VT until 1 June 2007. CKD patients were staged according to the Kidney Disease Outcomes Quality Initiative guidelines, on the basis of 24-h urine albumin excretion and estimated glomerular filtration rates. Objectively verified symptomatic VT was considered to be the endpoint. RESULTS: Of the 8495 subjects, 243 had CKD stage 1, 856 CKD stage 2, and 491 CKD stage 3. During a median follow-up period of 9.2 years, 128 individuals developed VT. The hazard ratios (HRs) for CKD stages 1, 2 and 3 were, respectively, 2.2 [95% confidence interval (CI) 0.9-5.1], 1.9 (95% CI 1.1-3.1) and 1.6 (95% CI 0.9-2.8) relative to those without CKD after adjustment for age, sex, body mass index, hypertension, diabetes, malignancy, and high-sensitivity C reactive protein. Subjects with CKD stage 3 and albuminuria (>= 30 mg d(-1)) had an adjusted HR of 3.0, and subjects with CKD stage 3 without albuminuria had an adjusted HR of 1.0. CONCLUSIONS: CKD stages 1 and 2, and CKD stage 3 in the presence of albuminuria, are risk factors for VT. The risk of VT is more related to albuminuria than to impaired glomerular filtration rate. PMID- 20831625 TI - Association genetics of traits controlling lignin and cellulose biosynthesis in black cottonwood (Populus trichocarpa, Salicaceae) secondary xylem. AB - * An association genetics approach was used to examine individual genes and alleles at the loci responsible for complex traits controlling lignocellulosic biosynthesis in black cottonwood (Populus trichocarpa). Recent interest in poplars as a source of renewable energy, combined with the vast genomic resources available, has enabled further examination of their genetic diversity. * Forty candidate genes were resequenced in a panel of 15 unrelated individuals to identify single nucleotide polymorphisms (SNPs). Eight hundred and seventy-six SNPs were successfully genotyped in a clonally replicated population (448 clones). The association population (average of 2.4 ramets per clone) was phenotyped using pyrolysis molecular beam mass spectrometry. Both single-marker and haplotype-based association tests were implemented to identify associations for composite traits representing lignin content, syringyl : guaiacyl ratio and C6 sugars. * Twenty-seven highly significant, unique, single-marker associations (false discovery rate Q < 0.10) were identified across 40 candidate genes in three composite traits. Twenty-three significant haplotypes within 11 genes were discovered in two composite traits. * Given the rapid decay of within-gene linkage disequilibrium and the high coverage of amplicons across each gene, it is likely that the numerous polymorphisms identified are in close proximity to the causative SNPs and the haplotype associations reflect information present in the associations between markers. PMID- 20831626 TI - Water transfer through biological membranes. PMID- 20831627 TI - The use and reporting of multiple imputation in medical research - a review. AB - BACKGROUND: Multiple imputation (MI) is an advanced, principled method of dealing with missing data in statistical analyses, a common problem in medical research. This paper sought to document the use of MI in general medical journals and to evaluate the information provided to readers about the application of the procedure in studies. METHODS: Research articles using MI in analyses published in JAMA, New England Journal of Medicine, BMJ and the Lancet were identified using full text searches from the earliest date each journal offered such searches until the end of 2008. Ninety-nine articles were found. Studies were classified according to their design. RESULTS: Multiple imputation was used in 49 RCTs and 50 other types of studies. A third of the articles (n = 33) reported no details of the procedure used. In a third of these (n = 11), it was not possible to infer the approach used from references cited or software used. The nature of the imputation model was rarely reported. MI was frequently used as a secondary analysis (n = 40) either to justify reporting a simpler approach or as a form of sensitivity analysis. CONCLUSIONS: Whilst still relatively uncommon, the use of MI has risen substantially, particularly in trials. MI is rarely adequately reported, leading to doubt about its appropriateness in some cases. This gives rise to uncertainty about conclusions reached and poses a barrier to attempts to replicate analyses. Guidelines for the reporting of MI should be developed. PMID- 20831628 TI - Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias. AB - BACKGROUND AND AIM: Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study. DESIGN: Cross-sectional population based study. SETTING: Kuopio, Eastern Finland. SUBJECTS: A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled. MAIN OUTCOME MEASURES: Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI). RESULTS: We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (beta = -0.15, 0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL C was observed. By contrast, 1,25-D was associated with HDL-C (beta = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI. CONCLUSION: Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease. PMID- 20831629 TI - No survival benefit from early-start dialysis in a population-based, inception cohort study of Swedish patients with chronic kidney disease. AB - OBJECTIVE: To investigate how the timing of dialysis initiation is associated with mortality. DESIGN: Population-based, prospective, observational cohort study. SETTING: Clinical laboratories (n = 69) provided information on all patients in Sweden whose serum creatinine level for the first time and exceeded 3.4 mg dL(-1) (men) or 2.8 mg dL(-1) (women) between 20 May 1996 and 31 May 1998. SUBJECTS: All patients (n = 901), aged 18-74 years, in whom the cause of serum creatinine elevation was chronic kidney disease, were included in the study; participants were interviewed and followed for 5-7 years. MAIN OUTCOME MEASURES: Information on date of death was obtained from a national Swedish population register. Early-start dialysis [estimated glomerular filtration rate from serum creatinine (eGFR) >=7.5 mL min(-1) per 1.73 m(2)] was compared to late start of dialysis (eGFR <7.5 mL min(-1) per 1.73 m(2)), and no dialysis. Relative risk [hazard ratio (HR)] of death was modelled with time-dependent multivariate Cox proportional hazards regression. RESULTS: Mean eGFR was 16.1 mL min(-1) per 1.73 m(2) at inclusion and 7.6 mL min(-1) per 1.73 m(2) at the start of dialysis. Among the 385 patients who started dialysis late, 36% died during follow-up compared to 52% of 323 who started early. The adjusted HR for death was 0.84 [95% confidence interval (CI) 0.64, 1.10] among late versus early starters. The mortality among nondialysed patients increased significantly at eGFR below 7.5 mL min(-1) per 1.73 m(2) (HR 4.65; 95% CI 2.28, 9.49; compared to eGFR 7.5-10 mL min(-1) per 1.73 m(2)). After the start of dialysis, the mortality rate further increased. Compared to nondialysed patients with eGFR <=15 mL min(-1) per 1.73 m(2), adjusted HR was 2.65 (95% CI 1.80, 3.89) for patients receiving dialysis. CONCLUSION: We found no survival benefit from early initiation of dialysis. PMID- 20831630 TI - Physical activity and risk of cognitive decline: a meta-analysis of prospective studies. AB - OBJECTIVE: The relationship between physical activity and cognitive function is intriguing but controversial. We performed a systematic meta-analysis of all the available prospective studies that investigated the association between physical activity and risk of cognitive decline in nondemented subjects. METHODS: We conducted an electronic literature search through MedLine, Embase, Google Scholar, Web of Science, The Cochrane Library and bibliographies of retrieved articles up to January 2010. Studies were included if they analysed prospectively the association between physical activity and cognitive decline in nondemented subjects. RESULTS: After the review process, 15 prospective studies (12 cohorts) were included in the final analysis. These studies included 33,816 nondemented subjects followed for 1-12 years. A total of 3210 patients showed cognitive decline during the follow-up. The cumulative analysis for all the studies under a random-effects model showed that subjects who performed a high level of physical activity were significantly protected (-38%) against cognitive decline during the follow-up (hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.54-0.70; P < 0.00001). Furthermore, even analysis of low-to-moderate level exercise also showed a significant protection (-35%) against cognitive impairment (HR 0.65, 95% CI 0.57-0.75; P < 0.00001). CONCLUSION: This is the first meta-analysis to evaluate the role of physical activity on cognitive decline amongst nondemented subjects. The present results suggest a significant and consistent protection for all levels of physical activity against the occurrence of cognitive decline. PMID- 20831631 TI - Hidradenitis suppurativa/acne inversa: bilocated epithelial hyperplasia with very different sequelae. AB - BACKGROUND: Hidradenitis suppurativa/acne inversa is a chronic, inflammatory, scarring disease in the terminal hair follicle and apocrine gland-bearing areas (skin folds). There is considerable histological evidence that perifolliculitis and follicular hyperkeratosis precede the rupture of the follicle. The timing of the epithelial hyperplasia at the infundibula of inflamed terminal follicles has not yet been clarified. OBJECTIVES: To clarify the early histopathological life of lesions ('chronology') in hidradenitis suppurativa/acne inversa, focusing on the terminal follicle structure and its surrounding tissue (hyperkeratosis, hyperplasia of follicular epithelium, perifolliculitis and rupture). METHODS: In total, 485 operative specimens obtained from 128 patients with diagnosed hidradenitis suppurativa/acne inversa (all surgically treated by wide excision) were examined histologically. Two to five histological preparations (total 485) per operation area (total 196) were prepared by multiple slicing. RESULTS: Hidradenitis suppurativa/acne inversa showed a heterogeneous histological pattern: hyperkeratosis of the terminal follicles (89%), hyperplasia of follicular epithelium (80%), pronounced perifolliculitis (68%) and follicle rupture (24%). Perifolliculitis, follicular hyperkeratosis and hyperplasia occurred prior to the rupture of the follicle. Other histological criteria were: subepidermal cellular inflammatory infiltrate (82%), epidermal psoriasiform hyperplasia (56%), pronounced acute dermal inflammation (28%), pronounced chronic dermal inflammation (49%), and involvement of apocrine glands (52%) and subcutis (31%). CONCLUSIONS: Infundibular hyperkeratosis, hyperplasia of the follicular epithelium and perifolliculitis are major histopathological characteristics of hidradenitis suppurativa/acne inversa. These apparently precede rupture of the follicle. In particular, hyperplasia of the follicular epithelium probably marks the beginning of sinus formation, which usually spreads horizontally. Psoriasiform hyperplasia of the interfollicular epidermis with subepidermal inflammatory infiltrate might be interpreted as an inflammation-driven process basically identical to that which is evident at the terminal follicle. However, it does not lead to harmful and progressive sequelae like those (rupture, sinus tracts) seen at the terminal follicles. PMID- 20831632 TI - Transcriptionally active nuclei are selective in mature multinucleated osteoclasts. AB - Multinucleation is indispensable for the bone-resorbing activity of mature osteoclasts. Although multinucleation is evident in mature osteoclasts and certain other cell types, putative regulatory networks among nuclei remain poorly characterized. To address this issue, transcriptional activity of each nucleus in a multinucleated osteoclast was assessed by detecting the distributions of nuclear proteins by immunocytochemistry and primary transcripts by RNA FISH. Patterns of epigenetic histone markers governing transcription as well as localization of tested nuclear receptor proteins appeared indistinguishable among nuclei in differentiated Raw264 cells and mouse mature osteoclasts. However, RNAPII-Ser5P/2P and NFATc1 proteins were selectively distributed in certain nuclei in the same cell. Similarly, the distributions of primary transcripts for osteoclast-specific genes (Nfatc1, Ctsk and Acp5) as well as a housekeeping gene (beta-tubulin) were limited in certain nuclei within individual cells. By fusing two Raw264 cell lines that stably expressed ZsGreen-NLS and DsRed-NLS proteins, transmission of nuclear proteins across all of the nuclei in a cell could be observed, presumably through the shared cytoplasm. Taken together, we conclude that although nuclear proteins are diffusible among nuclei, only certain nuclei within a multinucleated osteoclast are transcriptionally active. PMID- 20831634 TI - Traumatic dental injuries in an urban adolescent population in Tirana, Albania. AB - AIM: The aim of this study was to gather information about traumatic dental injuries (TDI) in an urban adolescent Albanian population. MATERIAL & METHODS: A cross-sectional survey was carried out to acquire epidemiological data about TDI in the permanent incisors of Albanian adolescents. Participants (n = 2789) were adolescents of both genders, aged 16-18 years, attending public high schools in Tirana. RESULTS: The occurrence of TDI in the incisors ranged from 8.9% of 16 year-olds to 10.5% of 18-year-olds. A greater proportion of boys (12.4%) had TDI compared with girls (7.7). The most commonly reported causes were collisions (27.5%) followed by physical leisure activities and sports (mainly cycling and swimming/diving) (14.1%) and falls (13.4%). Of the adolescents affected by TDI, 32% had unmet treatment need because of no or inadequate treatment. Adolescents living in districts with low socio-economic level had significantly more TDI with unmet treatment need than those living in districts with high socio-economic level. CONCLUSION: The occurrence of TDI among Albanian adolescents was moderate. Adolescents who came from low socio-economic districts had a greater probability of having TDI with unmet treatment need. PMID- 20831635 TI - Does removal of the original pulp tissue before autotransplantation influence ingrowth of new tissue in the pulp chamber? AB - In an attempt to extend the indication area for autotransplantation of vital teeth, two possibilities can be proposed: (i) The enlargement of the apical foramen, with the aim to facilitate revascularization and ingrowth of new tissue. The ingrowth of tissue will eliminate the need for endodontic treatment when mature teeth are transplanted and (ii) the cryopreservation of teeth in case they cannot be transplanted immediately to the receptor site. Teeth with an ideal stage of root formation can be cryopreserved to perform transplantation later. Although pulpcell cultures survive crypreservation in vitro, the pulp tissue cannot survive the cryopreservation procedures when it is kept inside the pulpchamber. Therefore, the pulp tissue has to be removed before cryopreservation. It has been demonstrated that revascularization and ingrowth of new tissue can occur in an empty pulp chamber (1). The aim of this study was to find out if revascularization and ingrowth of new pulp tissue is influenced by removal of the original pulp tissue before autotransplantation. Twenty nine single-rooted teeth from three adult beagle dogs were transplanted after resection of the root tip. One group of teeth (n = 14) had the pulp tissue removed before transplantation. The other group (n = 15) had the original pulp left in situ. The transplanted teeth were histologically analysed 90 days post transplantation. In the group with the tissue left in situ, 12 teeth (80%) showed a pulp chamber totally filled or at least 1/3 to 2/3 filled with viable tissue. In the group with the pulp tissue removed, 11 teeth (79%) had no or little vital tissue in the pulp chamber. The necrotic masses that develop in the original pulp tissue immediately after transplantation are a possible stimulating factor in the repair process of the pulp. As a conclusion, it can be stated that in case of autotransplantation of teeth, it is advisable to leave the pulp tissue in situ to stimulate the revascularization and ingrowth of new tissue after transplantation. PMID- 20831636 TI - An investigation into the association between facial profile and maxillary incisor trauma, a clinical non-radiographic study. AB - OBJECTIVES: To explore the association between maxillary incisor trauma (MIT) and facial skeletal forms (sagittal and vertical), overjet (OJ), lip coverage, and gender. SUBJECTS AND METHODS: Five hundred and two subjects (253 females and 249 males, aged 11-14 years) were examined. Sagittal (Class I, II or III) and vertical skeletal pattern (average, increased or decreased Frankfort-Mandibular Plane Angle (FMPA)) were recorded. Samples were categorized into four groups according to OJ severity: OJ <= 3.5 mm, 3.5 mm < OJ <= 6.0 mm with competent lips, 3.5 mm < OJ <= 6.0 mm with incompetent lips and OJ > 6 mm. Samples were also subdivided into two groups: OJ <= 3.5 mm and OJ > 3.5 mm. Chi-square test was performed to determine any gender differences in trauma experience. Logistic regression was performed to test for any differences in risk of MIT in different groups, and to estimate the predictive value of facial skeletal pattern (sagittal), FMPA, gender, OJ, and lip competence for MIT. RESULTS: Nine percent had incisor trauma (8.4% MIT). Boys had greater odds of receiving MIT than girls (OR = 2.16; 95% CI, 1.11-4.21). Subjects with Class II skeletal patterns had greater odds of MIT than those with Class I skeletal patterns (OR = 3.98; 95% CI, 1.98-8.00). Subjects with decreased FMPA had greater odds of MIT than subjects with average FMPA (OR = 4.55; 95% CI, 2.28-9.06). Lip competence was not associated with MIT (P > 0.05). Subjects with OJ > 3.5 mm had greater odds of MIT than subjects with OJ <= 3.5 mm (OR = 2.83; 95% CI, 1.49-5.37). CONCLUSION: Compared with children with normal OJ (<=3.5 mm), Class I skeletal pattern (Straight profile) and average FMPA, the odds of MIT increased significantly in children with OJ > 3.5 mm (OR = 2.83), Class II skeletal pattern (OR = 3.98) and decreased FMPA (short face profile) (OR = 4.55), respectively. PMID- 20831637 TI - An evaluation of various materials and tooth preparation designs used for reattachment of fractured incisors. AB - BACKGROUND/AIM: The present study was undertaken to evaluate and compare the fracture strength of various restorative materials and designs used in the reattachment of anterior fractured teeth. MATERIALS AND METHOD: Sound human maxillary central incisors were selected for the study. These teeth were fractured using universal testing machine so as to obtain Ellis class II fracture with intact fragment. The fractured fragment was reattached to the tooth using three restorative materials namely, bonding agent, resin luting cement and nano composite, and designs incorporated were simply bonding the fragment to the tooth and other one included a chamfer along the fractured line. The reattached teeth were again fractured and the mean fracture strength values recorded. RESULTS AND CONCLUSION: A combination of nano-composite (best material) and chamfer preparation (best design) gave the highest mean fracture strength values. PMID- 20831638 TI - Association of crown discoloration and pulp status in traumatized primary teeth. AB - The aim of the present study was to determine the association of tooth discoloration in traumatized primary teeth with clinical and radiographic signs of pulp necrosis, and pulp status at the time of endodontic access. Clinical and radiographic data from dental reports of the 47 patient charts of the Trauma Patient Care Program were used totaling 55 teeth that underwent endodontic treatment following the protocol of the Federal University of Santa Catarina (Brazil). The following data were collected: gender, age of child at time of trauma; crown discoloration; abscess and/or fistula; periapical bone rarefaction and/or pathological root resorption; and pulp status at the time of endodontic access. The Chi-square test and logistic regression were used in the statistical analysis. The associations between crown discoloration and gender, age, tooth, type of trauma, clinical alteration, and radiographic alteration were not statistically significant. There was a significant association between crown discoloration and pulp necrosis at the time of endodontic access (chi(2) = 7.672; P < 0.05). Traumatized primary teeth with crown discoloration had a fivefold greater likelihood of exhibiting pulp necrosis than teeth without crown discoloration (95% CI: 1.5-17.1). Thus, a significant association was found between crown discoloration and pulp necrosis in traumatized primary teeth. PMID- 20831639 TI - Traumatic dental injuries and related factors among sixth grade schoolchildren in four Palestinian towns. AB - BACKGROUND: Traumatic dental injuries (TDI) are recognized as an important dental public health issue among children. The West Bank, a part of the Palestinian Authority, is in immediate neighborhood to Israel. There are inadequate epidemiologic data among the Palestinian people, on dental health issues. AIM: To determine the occurrence of TDI to permanent teeth among sixth grade Palestinian schoolchildren living in four large towns of the West Bank and to investigate associations with anatomic and demographic factors. MATERIAL AND METHODS: Eight hundred and four children were sampled and examined in Ramallah, Bethlehem, Hebron and Jericho. Data collection included clinical examinations in schools and questionnaires for demographic and socio-economic background. RESULTS: The prevalence of traumatic dental injuries was 17.7%. Enamel fractures and injuries involving dentine accounted for 41% and 42.5% of all injuries, respectively. The most affected teeth (89%) were upper central incisors. Only 5% of the injured teeth were treated. Results of multiple logistic regression confirmed that TDI were significantly (P < 0.001) more prevalent among boys, children presenting incisal overjet larger than 5 mm, and incompetent lip coverage. CONCLUSIONS: The relative high prevalence and very low levels of treated TDI identified in this study suggested that both prevention and treatment of TDI in the West Bank were inadequate. PMID- 20831640 TI - Dilaceration of maxillary central incisor: a literature review. AB - The main purpose of this review is to present the aetiological factors and the mechanism that cause dilaceration of the maxillary central incisors. In early developmental stages, the permanent tooth germ of the maxillary incisor is situated palatally and superiorly to the apex of the primary incisor and gradually changes direction in a labial direction with its crown coming closer to the resorbing primary root. For reasons of this close relationship between the permanent tooth germ and the apex of the primary incisor, it is believed that an acute trauma to the primary predecessor can cause dilaceration of the long axis of the permanent successor. Clinically, dilaceration can be revealed by palpation high in the labial sulcus or in the hard palate, while its radiographic view is characteristic. The therapeutic approach to the dilacerated maxillary central incisors has to be carefully planned and needs the cooperation of several specialities to attain the final objective. PMID- 20831641 TI - Combined technique with dentin post reinforcement and original fragment reattachment for the esthetic recovery of a fractured anterior tooth: a case report. AB - This case report describes the esthetic and functional recovery of a maxillary central incisor. The treatments used were dentin post (biological post) reinforcement and reattachment of the fragment. From the outcomes achieved, it can be concluded that this technique is promising and is yet another alternative method that can be used for the recovery of fractured anterior teeth. PMID- 20831642 TI - Inappropriate use of meta-analysis in an evidence-based assessment of the clinical guidelines for replanted avulsed teeth. Timing of pulp extirpation, splinting periods and prescription of systemic antibiotics. PMID- 20831643 TI - Land clearing reduces gene flow in the granite outcrop-dwelling lizard, Ctenophorus ornatus. AB - An important question for the conservation of species dwelling in fragmented habitats is whether changes to the intervening landscape create a barrier to gene flow. Here, we make use of the spatial distribution of the granite outcrop dwelling lizard, Ctenophorus ornatus, to compare inferred levels of gene flow between outcrops in a nature reserve with that between outcrops in the adjacent agricultural land. Genetic variation, relatedness and subdivision were compared within groups of individuals from different outcrops similar in size and distance apart at each site. In the agricultural land, we found significantly lower genetic variation within outcrops and greater genetic differentiation between outcrops than in the reserve. Further, the rate at which genetic divergence between outcrops increased over geographical distance was significantly greater in the agricultural land than in the reserve. We also found that individuals were more closely related within outcrops but more distantly related between outcrops in the cleared land. These effects occur over a small spatial scale with an average distance between outcrops of less than five kilometres. Thus, even though land clearing around the outcrops leaves outcrop size unchanged, it restricts gene flow, reducing genetic variation and increasing population structure, with potentially negative consequences for the long-term persistence of the lizards on these outcrops. PMID- 20831644 TI - The maintenance of disparate levels of clonality, genetic diversity and genetic differentiation in disjunct subspecies of the rare Banksia ionthocarpa. AB - The evolutionary potential of plant species that reproduce via predominantly clonal means and the conditions under which clonality is favoured are not well known. Long-term clonal reproduction is expected to result in a number of readily detectable genetic signals not present in populations that reproduce by sexual means. We use a hierarchical sampling strategy to assess genotype probabilities and confirm that two rare sister taxa of Banksia ionthocarpa have contrasting modes of reproduction. Banksia ionthocarpa subsp. chrysophoenix reproduces clonally. Populations had low levels of genotypic diversity and were comprised of large clonal patches consisting of many ramets that covered hundreds of square metres and showed little intermixing. The taxon was genetically depauperate (mean Na = 1.97, mean P = 0.66, mean He = 0.282), had high levels of genetic differentiation between populations (theta = 0.481), and populations exhibited excess heterozygosity and linkage disequilibrium (LD) among loci, suggesting historically high levels of clonality. In contrast, the sister taxon B. ionthocarpa subsp. ionthocarpa, which occurs in an area with more than twice the annual rainfall and less extreme minimum and maximum temperatures, showed no evidence of clonality, high levels of genotypic diversity, greater genetic diversity (mean Na = 3.31, mean P = 0.81, mean He = 0.405), lower levels of genetic differentiation between populations (theta = 0.253) and no evidence of excess heterozygosity or LD among loci. We suggest that the development of clonality in subsp. chrysophoenix is associated with its more marginal environment and enhanced by response to recurrent fires. PMID- 20831645 TI - Nucleotide diversity patterns of local adaptation at drought-related candidate genes in wild tomatoes. AB - We surveyed nucleotide diversity at two candidate genes LeNCED1 and pLC30-15, involved in an ABA (abscisic acid) signalling pathway, in two closely related tomato species Solanum peruvianum and Solanum chilense. Our six population samples (three for each species) cover a range of mesic to very dry habitats. The ABA pathway plays an important role in the plants' response to drought stress. LeNCED1 is an upstream gene involved in ABA biosynthesis, and pLC30-15 is a dehydrin gene positioned downstream in the pathway. The two genes show very different patterns of nucleotide variation. LeNCED1 exhibits very low nucleotide diversity relative to the eight neutral reference loci that were previously surveyed in these populations. This suggests that strong purifying selection has been acting on this gene. In contrast, pLC30-15 exhibits higher levels of nucleotide diversity and, in particular in S. chilense, higher genetic differentiation between populations than the reference loci, which is indicative of local adaptation. In the more drought-tolerant species S. chilense, one population (from Quicacha) shows a significant haplotype structure, which appears to be the result of positive (diversifying) selection. PMID- 20831646 TI - Floret initiation, tissue expansion and carbon availability at the meristem of the sunflower capitulum as affected by water or light deficits. AB - * The co-ordination between floret initiation and meristem expansion, and their relationships with carbon availability, were studied and quantified in sunflower (Helianthus annuus) plants subjected to light or water shortages. * Meristem size, number of floret primordia, primordium size, rate of plant biomass accumulation, leaf area, photosynthetic rate, and soluble sugar content in the capitulum were measured until completion of floret initiation. * Although treatments differentially affected tissue expansion and biomass acquisition, a common relationship between the final number of florets and the rate and duration of meristem expansion was conserved. In the absence of water deficit, changes in relative expansion rate in the meristem paralleled changes in soluble sugar content. Water deficit reduced tissue expansion both in leaves and in the capitulum, and induced the accumulation of soluble sugars in the meristem. Use of these sugars at re-watering was associated with increased meristem growth and higher floret numbers compared with control plants. * Floret initiation and meristem tissue expansion remained strongly co-ordinated under all studied circumstances, and both depended on local carbon availability when water supply was unlimited. Transient water deficits favoured reproductive meristem growth and floret production. Equations accounting for these results constitute a framework for phenotyping the response to drought. PMID- 20831647 TI - A hydraulic explanation for size-specific plant shrinkage: developmental hydraulic sectoriality. AB - * While great attention has been paid to the mechanisms controlling plant growth, much less is known about why and how plants shrink. The modular design of plants may facilitate the independence of modules if the xylem vasculature is hydraulically sectored. We examined the hydraulic connectivity of modules comprising juveniles and adults of the aridland chamaephyte Cryptantha flava (Boraginaceae), motivated by the observation that rosette mortality is spatially aggregated in adults, but not in juveniles. * We explored spatial patterns of leaf wilting after clipping a single lateral root, tracked physiological dyes taken up by a single root, and measured within-plant variation in leaf water potentials after watering a portion of the root system. We then measured xylem anatomical features related to hydraulic connectivity. * Our approaches revealed hydraulic integration in juveniles but hydraulic sectoriality in adults. We attribute such developmental changes to increasing distances between xylem bundles, and larger xylem lumen and heartwood areas as plants age. * We have demonstrated functional sectoriality in a desert chamaephyte, and report the mechanism by which sectoriality occurs, offering a hydraulic explanation for the death of whole plant portions resulting in shrinkage of large plants, and for the high occurrence of this design in deserts. PMID- 20831648 TI - Short-term results of intensive physiotherapy in clubfoot deformity treated with the Ponseti method. AB - PURPOSE: We aimed to determine the efficacy of the physical therapy program as an adjunct to the Ponseti technique in the treatment of idiopathic clubfoot. This study was carried out with the presumption of a difference in results between the study group who were included in the physiotherapy program and the control group who performed home exercises. PATIENTS AND METHOD: Forty affected feet of 29 patients were included in the study. The average ages of the control and study groups were 15.00 +/- 21.33 and 20.30 +/- 15.78 months, respectively. Passive range of motion of dorsiflexion, plantar flexion, inversion, eversion, rear foot varus angle and forefoot adduction angle were measured and the Dimeglio classification system was utilized in order to determine the severity of clubfoot deformity. Reassessments were carried out for the study group at the end of 1 month's therapy and for the control group during the first month follow-up. RESULTS: Comparison of pre- and post-treatment assessment results revealed a difference in terms of recovery, concerning all parameters except passive inversion values in the study group and for all parameters in the control group (P < 0.05). For study and control group comparisons, since deformity severity was higher in the study group an effect size analysis was carried out. The effect size analysis showed that the change in range of motion of dorsiflexion and Dimeglio and decrease of rear foot varus angle was higher in the study group. CONCLUSION: The results of this study imply that an intensive physiotherapy program may enhance the effectiveness of the Ponseti protocol. PMID- 20831649 TI - Reappraisal of MMR vaccines currently used in Korea. AB - BACKGROUND: Although MMR vaccine is widely used in Korea, there are limited studies on the currently used vaccines. We evaluated the immunogenicity and safety of MMR vaccines in Korean children. METHODS: For first and second dose immunization, children aged 12-23 months and 4-6 years were enrolled. All subjects received a single dose of either PriorixTM (Glaxo Smithkline Biologicals, Rixensart, Belgium) or MMRII(r) (Merck & Co., Inc., West Point, PA, USA). Pre- and postvaccine sera were collected from all participants. Antibody levels were determined by ELISA (Enzygnost(r); Dade Behring, Schwalbach, Germany). Safety monitoring included local adverse events for 5 days and systemic adverse events for 42 days following vaccination. RESULTS: One hundred twenty-one subjects were enrolled in the 12-23 months age group and 39 in the 4-6 years age group. The seroconversion rate in the 12-23 months age group was 97.9-100.0% for measles, 85.1-88.9% for mumps and 100.0% for rubella. All children 4-6 years of age previously seronegative showed seroconversion for measles, mumps and rubella. Local adverse events were reported in 8.3-16.1% (12-23 months age) and 27.8-31.6% (4-6 years age), and 40.0-48.2% (12-23 months age) and 42.1-61.1% (4-6 years age) experienced at least more than 1 systemic adverse reaction. No vaccine-related serious adverse events were reported. Among the same age groups, there was no significant difference in adverse events between the two vaccines. CONCLUSION: The MMR vaccines are safe and show good immunogenic responses in children. These data will be invaluable when we introduce diverse vaccines in the following future. PMID- 20831650 TI - Nebulized hypertonic saline and recombinant human DNase in the treatment of pulmonary atelectasis in newborns. AB - OBJECTIVE: The aim of this study was to compare and evaluate the efficacy of nebulized 3% hypertonic saline (HS) and recombinant human DNase (rhDNase) treatment for resolution of persistent atelectasis in newborns. STUDY DESIGN: Forty newborns (38 preterms) who did not respond to conventional treatment were enrolled to receive either nebulized 3% HS solution (n = 20) or rhDNase (n = 20) between September 2007 and March 2008. Clinical parameters, oxygen saturation and radiological response (chest X-ray scoring) were analyzed before and after administration of 3% HS or rhDNase. RESULTS: The patients of the nebulized 3% HS solution group improved better chest X-ray scores parameters than the patients of the rhDNase group: chest X-ray scores were 5.1 +/- 1.9 vs 4.8 +/- 1.7 before treatment and 1.0 +/- 0.8 vs 2.1 +/- 1.4 after treatment (P < 0.001). Resolution time of atelectasis did not differ between the two groups after whole treatment but the percentage of atelectasis resolution after 3 days treatment were 90% (18/20) in the 3% HS group and 70% (14/20) in the rhDNase group. The patients in the 3% HS group improved better also in clinical parameters in comparison to the rhDNase treatment. The difference of oxygen saturation before and after the treatment was 4.6 +/- 0.8 in 3% HS group in comparison to 2.6 +/- 0.1 in the rhDNase group (P < 0.05). All serum sodium levels were normal in two groups before and after the treatment modalities. CONCLUSION: This is the first study on the usefulness of nebulized 3% hypertonic saline solution in treating newborns with pulmonary atelectasis. In addition, 3% HS solution was a more effective therapeutic option on the basis of clinical and radiological improvement compared to rhDNase treatment in newborns with pulmonary atelectasis. PMID- 20831651 TI - Staphylococcal scalded skin syndrome in an extremely low-birth-weight neonate: molecular characterization and rapid detection by multiplex and real-time PCR of methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Staphylococcal scalded skin syndrome (SSSS), caused by methicillin resistant Staphylococcus aureus (MRSA) producing exfoliative toxin (ET), is a life-threatening infection for neonates in neonatal intensive care units (NICUs). SSSS in extremely low-birth-weight (ELBW) neonates is rare. A new class of MRSA (community-acquired MRSA, CA-MRSA) has been emerging in the community. The aim of this study was to characterize MRSA from an ELBW neonate with SSSS, and to develop rapid detection methods for SSSS-associated and emerging pediatric MRSA. METHODS: An ELBW infant in the NICU developed SSSS on day 16 after birth. Isolated MRSA was genetically characterized and compared with CA-MRSA from bullous impetigo (biCA-MRSA), which is positive for the ET and collagen-adhesin (CNA) genes in many cases, and the Panton-Valentine leucocidin (PVL) gene rarely. Specific primers and probes for five virulence genes (for ETA, ETB, ETD, PVL, CNA) were designed for multiplex polymerase chain reaction (PCR) and real-time PCR. RESULTS: MRSA strain H5 from SSSS exhibited the genotype (ST91, spa416[t375], agr3, SCCmecIVa, CoaI), and possessed the ETB and CNA genes, similar to ST91 biCA-MRSA (albeit with a divergence). Multiplex PCR detected the ETB and CNA genes of strain H5, and real-time PCR detected strain H5 at as low as 10(2) CFU/mL. The assays were 100% specific and 100% sensitive, for the five virulence genes. CONCLUSION: ETB-positive ST91 MRSA, which was very similar to ST91 biCA-MRSA, was isolated from an ELBW infant with SSSS. The multiplex and real-time PCR assays specifically or quantitatively detected SSSS-associated and emerging pediatric MRSA. PMID- 20831652 TI - Methylenetetrahydrofolate reductase C677T polymorphism in patients with Henoch Schonlein purpura. AB - AIM: Associations between several vascular diseases such as Kawasaki disease, venous and arterial thromboembolism, cardiovascular disease, diabetic nephropathy, focal segmental glomerulosclerosis and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism have been reported. This is a clinical study designed to investigate the possible effects of MTHFR C677T polymorphism on the development of Henoch-Schonlein purpura (HSP). METHODS: Forty-one patients with HSP (25 male/16 female) with a mean age of 7.8 +/- 2.9 years were included in the study. The control group consisted of 50 healthy children. MTHFR genotypes were determined by polymerase chain reaction and by Hindf I restriction enzyme analysis and subsequent 3% agarose gel electrophoresis techniques. RESULTS: No significant differences were observed in the distribution of MTHFR genotypes or allele frequencies in the HSP cases versus controls. Plasma homocysteine levels and vitamin B(12) levels were almost comparable in the HSP patients and control group without a significant difference. Folic acid levels were within normal limits in the HSP cases and the control group, HSP patients' levels being significantly higher than the control group. No significant relationship was present with the MTHFR genotype and plasma homocysteine, vitamin B(12) and folic acid levels in HSP patients. CONCLUSION: No association with MTHFR gene polymorphism and homocysteine plasma levels could be found in patients with HSP. The results of this study indicate that other mechanisms should be operative in the development of HSP. PMID- 20831653 TI - A low fructose diet in the treatment of pediatric obesity: a pilot study. AB - BACKGROUND: Over the last three decades the prevalence of overweight and obesity has increased dramatically among children and adolescents worldwide. As the results of animal and human studies suggest that a diet rich in fructose may be a risk factor for the development of overweight, the aim of the pilot study was to evaluate if a dietary counseling aimed at a moderate reduction of dietary fructose intake (-50% in comparison to intake at baseline) has a positive effect on the body mass index (BMI) of overweight and obese children. METHODS: Fifteen overweight or obese children aged 5-8 years were included into the 3 month dietary intervention study. At baseline and after 4 and 8 weeks children and their parents were trained to reduce fructose in the children's diet. Anthropometric parameters for calculating BMI and BMI standard deviation scores (BMI-SDS) as well as nutritional intake were assessed at baseline, after the 12 week intervention and after 12 week of follow up. RESULTS: After the 12-week intervention children had significantly reduced their total energy, fructose, sucrose and glucose intake. BMI and BMI-SDS were significantly reduced by 0.68 kg/m(2) and 0.21, respectively, at the end of the intervention. At follow up, the BMI-SDS was significantly lower in comparison to baseline while the BMI was only decreased by trend (P= 0.08). CONCLUSIONS: The results of our pilot study indicate that counseling aimed towards a moderate reduction of dietary fructose and/or general sugar intake may have a positive effect on BMI in overweight and obese children. PMID- 20831654 TI - A rapid assay for simultaneous detection of Spiroplasma eriocheiris and white spot syndrome virus in Procambarus clarkii by multiplex PCR. AB - AIMS: To establish a multiplex PCR method for simultaneous and rapid detection of Spiroplasma eriocheiris and white spot syndrome virus (WSSV) in Procambarus clarkii with recommendations for application to other crustacea. METHODS AND RESULTS: Three primer sets were mixed at a ratio of 1:3:1 to amplify specific fragments of the S. eriocheiris, WSSV, P. clarkii crayfish (control organism) genomes, respectively. S. eriocheiris and WSSV were used to challenge the susceptible crustacea in the experimental groups. Total DNA of the samples was purified and detected by multiplex PCR. The PCR-amplified products produced four groups of results as follows. One fragment of 1195 bp, amplified by the primer set ITS-crayfish/28S-crayfish, served as an internal control, showed no pathogen detection, thus confirming the specificity of our positive tests. Two groups represented by: (i) samples challenged by S. eriocheiris alone, or (ii) challenged by WSSV alone, yielded two fragments each; i.e. those from S. eriocheiris (271 bp) plus the internal control and those from WSSV (530 bp) plus the internal control. Finally, for the fourth group, in cases of double challenged treatments, all three amplified products were detected simultaneously. CONCLUSIONS: Simultaneous and rapid detection of two pathogens in P. clarkii is important to maintain productive and healthy crayfish in aquaculture. The direct detection of S. eriocheiris and WSSV from P. clarkii is practicable with multiplex PCR. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows that the two pathogens are simultaneously and rapidly detected in P. clarkii by multiplex PCR, thus increasing the efficiency of pathogen detection. PMID- 20831655 TI - The characterization of Listeria spp. isolated from food products and the food processing environment. AB - AIM: To enhance the information pertaining to the epidemiology of a collection of 378 Listeria spp. isolates obtained from several food-processing plants in Ireland over a 3-year period (2004-2007). METHODS AND RESULTS: The collection was characterized by pulsed-field gel electrophoresis (PFGE). The most prevalent pulse-type was PFGE profile I (n=14.5%) that consisted mainly of environmental Listeria spp. samples. Serotyping of 145 Listeria monocytogenes isolates was performed. The most common serovar was 1/2a and comprised 57.4% (n=77) of the L. monocytogenes collection. The other serovars were as follows: 4b (14.1%, n=19), 1/2b (9.7%, n=13), 4c (4.4%, n=6) and 1/2c (6.7%, n=9), respectively. Eleven isolates were identified as non-Listeria spp., the remaining ten L. monocytogenes isolates were nontypeable. The antimicrobial susceptibility testing revealed the antibiotic that isolates displayed the most resistance to was gentamicin (5%) followed by sulfamethoxazole-trimethoprim (2%), tetracycline and ciprofloxacin (1.5%). CONCLUSIONS: The subtyping has indicated the diversity of the Listeria spp. The presence of serotype 1/2a, 1/2b and 4b in both raw and cooked ready-to eat food products is a public health concern, as these serotypes are frequently associated with foodborne outbreaks and sporadic cases of human listeriosis. In addition, the emergence of antimicrobial-resistant L. monocytogenes isolates could have serious therapeutic consequences. SIGNIFICANCE AND IMPACT OF STUDY: The molecular subtyping and the further characterization of these isolates may be valuable particularly in the context of a suspected common source outbreak in the future. PMID- 20831656 TI - Individual variation in organ histogenesis as a causative factor in the developmental origins of health and disease: unnoticed congenital anomalies? AB - Morphological studies of congenital anomalies have mainly focused on abnormal shape (i.e. malformation) and thus on disturbed organogenesis. However, in regard to postnatal functions of organs that develop through branching mechanisms, organ size is another important morphological feature. These organs consist of a large number of structural and functional units, such as nephrons in the kidney, and the total number of these units, that is approximately proportional to the organ size, has been shown to vary widely among individuals. Organ-specific cells are differentiated and organized to form structural units and realize organ-specific functions during the histogenetic period (i.e. from mid-gestation to the early postnatal period). The total number of units is attained at the end of histogenesis and determines the total functional capacity, including the functional reserve of the organ, and thus may be related to predispositions to postnatal organ-based diseases, because the functional reserve decreases during the course of life and eventually become short of the minimum requirement of each organ. Therefore, it may be hypothesized that a smaller number of units of organs at the end of histogenesis is one of the predisposing factors for postnatal diseases (i.e. a form of unnoticed but late-manifested congenital anomalies), in this era of extended longevity. However, the mechanisms that control the total number of units in each organ during histogenesis and the possible relationship among the numbers of units in different organs remain unknown. Here, we review our trials based on the above hypothesis in order to (1) mathematically analyze the morphometric data of the different organs in fetuses to elucidate relationship among developing organs, (2) analyze the developing neuro-immuno endocrine network as a series of mechanisms to systemically correlate the histogenesis of multiple organs, and (3) examine the maternal environment, including dietary fat, as a factor to influence histogenesis and thus the predisposition to type 1 diabetes. PMID- 20831657 TI - Signaling pathways of isoproterenol-induced ERK1/2 phosphorylation in primary cultures of astrocytes are concentration-dependent. AB - Stimulation of beta-adrenoceptors activates the canonical adenylate cyclase pathway (via G(s) protein) but can also evoke phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2) ) via G(s)/G(i) switching or beta-arrestin mediated recruitment of Src. In primary cultures of mouse astrocytes, activation of the former of these pathways required micromolar concentrations of the beta(1)/beta(2) -adrenergic agonist isoproterenol, that acted on beta(1) adrenoceptors, whereas the latter was activated already by nanomolar concentrations, acting on beta(2) receptors. Protein kinase A activity was required for G(s)/G(i) switching, which was followed by Ca(2+) release from intracellular stores and G(ialpha)- and metalloproteinase-dependent transactivation of the epidermal growth factor receptor (EGFR; at its Y1173 phophorylation site), via its receptor-tyrosine kinase, beta-arrestin 1/2 recruitment, and MAPK/ERK kinase-dependent ERK(1/2) phosphorylation. ERK(1/2) phosphorylation by Src activation depended on beta-arrestin 2, but not beta arrestin 1, was accompanied by Src/EGFR co-precipitation and phosphorylation of the EGFR at the Src-phosphorylated Y845 site and the Y1045 autophosphorylation site; it was independent of transactivation but dependent on MAPK/ERK kinase activity, suggesting EGFR phosphorylation independently of the receptor-tyrosine kinase or activation of Ras or Raf directly from Src. Most astrocytic consequences of activating either pathway (or both) are unknown, but morphological differentiation and increase in glial fibrillary acidic protein in response to dibutyryl cAMP-mediated increase in cAMP depend on G(s)/G(i) switching and transactivation. PMID- 20831658 TI - Macrophage-colony stimulating factor as an inducer of microglial proliferation in axotomized rat facial nucleus. AB - We analyzed the mechanism of microglial proliferation in rat axotomized facial nucleus (axotFN). In immunoblotting analysis for possible mitogens, we noticed that the amounts of macrophage-colony stimulating factor (M-CSF) increased in the axotFN for 3-7 days after transection. In contrast, the amounts of granulocyte macrophage-CSF and interleukin-3 did not significantly increase. A potential source for M-CSF was immunohistochemically verified to be microglia. Immunoblotting showed that the amounts of receptor for M-CSF (cFms) increased in the axotFN for 3-14 days after injury, and immunohistochemical staining showed that cFms is expressed in microglia. Proliferating cell nuclear antigen as a marker of proliferation was immunohistochemically identified in microglia in axotFN, and the level was found to peak 3 days after transection in immunoblotting. Hypothesizing that up-regulated M-CSF triggers the above phenomena, we investigated the effects of M-CSF on cFms and proliferating cell nuclear antigen levels in primary microglia. The biochemical experiments revealed that M-CSF induces cFms and drives the cell cycle in microglia. The neutralization of M-CSF in microglia derived from axotFN significantly reduced the proliferation. These results demonstrate that up-regulated M-CSF triggers the induction of cFms in microglia and causes the microglia to proliferate in the axotFN. PMID- 20831660 TI - The effect of different exercise-testing protocols on atrial natriuretic peptide. AB - The aim of this study was to examine and to compare alterations in the secretion of atrial natriuretic peptide (ANP) during different exercise-testing protocols in moderately trained men. Fifteen healthy male physical education students were studied (mean age 22.3 +/- 2.5 years, training experience 12.3 +/- 2.5 years, height 1.80 +/- 0.06 m, weight 77.4 +/- 8.2 kg). Participants performed an initial graded maximal exercise testing on a treadmill for the determination of VO(2max) (duration 7.45-9.3 min and VO(2max) 55.05 +/- 3.13 ml kg(-1) min(-1) ) and were examined with active recovery (AR), passive recovery (PR) and continuous running (CR) in random order. Blood samples for plasma ANP concentration were taken at rest (baseline measurement), immediately after the end of exercise as well as after 30 min in passive recovery time (PRT). The plasma ANP concentration was determined by radioimmunoassay (RIA). The results showed that ANP plasma values increased significantly from the rest period to maximal values. In the short-term graded maximal exercise testing the ANP plasma values increased by 56.2% (44.8 +/- 10.4 pg ml(-1) versus 102.3 +/- 31.3 pg ml(-1) , P<0.001) and in the CR testing the ANP levels increased by 29.2% (44.8 +/- 10.4 pg ml(-1) versus 63.3 +/- 19.8 pg ml(-1) , P<0.001) compared to the baseline measurement. Moreover, the values of ANP decreased significantly (range 46.4-51.2%, P<0.001) in PRT after the end of the four different exercise modes. However, no significant difference was evident when ANP values at rest and after AR and PR were compared. It is concluded that the exercise testing protocol may affect the plasma ANP concentrations. Particularly, short-term maximal exercise significantly increases ANP values, while the intermittent exercise form of active and passive recovery decreases ANP concentrations. PMID- 20831659 TI - Ganglioside-mediated aggregation of amyloid beta-proteins (Abeta): comparison between Abeta-(1-42) and Abeta-(1-40). AB - Conversion of the soluble, non-toxic amyloid beta-protein (Abeta) into an aggregated, toxic form rich in beta-sheets is considered a key step in the development of Alzheimer's disease. Accumulating evidence suggests that lipid rafts in membranes play a pivotal role in this process. We have proposed that Abeta-(1-40) specifically bound to a ganglioside cluster forms cytotoxic fibrils via a conformational transition from an alpha-helix-rich structure to a beta sheet-rich one. In the present study, we compared the interaction of Abeta-(1-40) and Abeta-(1-42) with both model and living cell membranes. Abeta-(1-42) exhibited lipid specificity and affinity similar to Abeta-(1-40), though its amyloidogenic activity was more than 10-fold that of Abeta-(1-40). Antibody staining experiments, using the A11 antibody specific to Abeta oligomers, demonstrated that oligomers were not detected during the aggregation process, and cell death was observed only after significant accumulation of the proteins, suggesting that the fibril-induced disruption of cell membranes leads to the cytotoxicity. Furthermore, we succeeded in visualizing fibrils formed on cell membranes using total internal reflection fluorescence microscopy. Abeta-(1-40) formed long fibrils extruding to the aqueous phase, whereas Abeta-(1-42) fibrils appeared to be laterally co-assembled and short. PMID- 20831661 TI - Decision modelling of economic evaluation of intervention programme of breast cancer. AB - OBJECTIVES: Economic appraisal of an intervention is a complex and multivariable problem, with probabilistic issues related not only to clinical outcomes but also to costs and willingness to pay. METHODS: We provide a comprehensive framework for economic appraisal of a health intervention to prevent beast cancer mortality, involving probabilistic model of costs as well as of aspects of the disease process. The economic appraisal can give a range of probabilities of cost effectiveness depending on willingness or ability to pay. RESULTS: We apply the method to the example of polychemotherapy for early breast cancer. Results indicate a 30% probability of cost-effectiveness for a willingness to pay of $ 60,000 per quality-adjusted life-year and around 50% for a threshold of $ 100,000. CONCLUSION: The comprehensive economic appraisal model is a powerful tool for decision making over a range of economic environments. PMID- 20831662 TI - Analytical decision model for sample size and effectiveness projections for use in planning a population-based randomized controlled trial of colorectal cancer screening. AB - RATIONALE, AIMS AND OBJECTIVES: Population-based randomized controlled trials (RCTs) often involve enormous costs and long-term follow-up to evaluate primary end points. Analytical decision-simulated model for sample size and effectiveness projections based on primary and surrogate end points are necessary before planning a population-based RCT. METHOD: Based on the study design similar to two previous RCTs, transition rates were estimated using a five-state natural history model [normal, preclinical detection phase (PCDP) Dukes' A/B, PCDP Dukes' C/D, Clinical Dukes' A/B and Clinical Dukes' C/D]. The Markov cycle tree was assigned transition parameters, variables related to screening and survival rate that simulated results of 10-year follow-up in the absence of screening for a hypothetical cohort aged 45-74 years. The corresponding screened arm was to simulate the results after the introduction of population-based screening for colorectal cancer with fecal occult blood test with stop screen design. RESULTS: The natural course of mean sojourn time for five-state Markov model were estimated as 2.75 years for preclinical Dukes' A/B and 1.38 years for preclinical Dukes' C/D. The expected reductions in mortality and Dukes' C/D were 13% (95% confidence intervals: 7-19%) and 26% (95% confidence intervals: 20-32%), respectively, given a 70% acceptance rate and a 90% colonoscopy referral rate. Sample sizes required were 86,150 and 65,592 subjects for the primary end point and the surrogate end point, respectively, given an incidence rate up to 0.0020 per year. CONCLUSIONS: The sample sizes required for primary and surrogate end points and the projection of effectiveness of fecal occult blood test for colorectal cancer screening were developed. Both are very important to plan a population-based RCT. PMID- 20831663 TI - Kinetic epidemiological model for elucidating sexual difference of hypertension (KCIS no.20). AB - BACKGROUND: Woman have lower rate of hypertension than man but it is still elusive how such gender difference can be explained by kinetic epidemiological curves. OBJECTIVE: The aim of this paper was to develop a multi-state model for delineating the kinetic epidemiology of hypertension according to the Seventh Report of the Joint National Committee (JNC 7) classification criteria by gender, and to derive gender-specific kinetic curves. METHODS: We used data from a population-based screening programme with 42,027 participants to fit a four-state Markov model corresponding to the classification of hypertension from the JNC 7. RESULTS: The young man had higher progression rate but lower regression rate for the movement between normal and pre-hypertension than the young woman. Such gender difference disappeared after 50 years old. The mean sojourn time of pre- and stage 1 hypertension for man and stage 1 for woman was approximately 5 years. However, the corresponding figure for pre-hypertension for woman was 25 years at age 30, 10 years at age 40 and 5 years afterwards. CONCLUSION: Elucidating the kinetic epidemiological curves of hypertension explains higher prevalence rate in young man than woman. These findings fit with the role of sex hormones regulating blood pressure demonstrated in the animal model. PMID- 20831664 TI - Mokken scaling of the Myocardial Infarction Dimensional Assessment Scale (MIDAS). AB - AIMS: The purpose of this study was to examine the hierarchical and cumulative nature of the 35 items of the Myocardial Infarction Dimensional Assessment Scale (MIDAS), a disease-specific health-related quality of life measure. METHOD: Data from 668 participants who completed the MIDAS were analysed using the Mokken Scaling Procedure, which is a computer program that searches polychotomous data for hierarchical and cumulative scales on the basis of a range of diagnostic criteria. RESULTS: Fourteen MIDAS items were retained in a Mokken scale and these items included physical activity, insecurity, emotional reaction and dependency items but excluded items related to diet, medication or side-effects. Item difficulty, in item response theory terms, ran from physical activity items (low difficulty) to insecurity, suggesting that the most severe quality of life effect of myocardial infarction is loneliness and isolation. CONCLUSIONS: Items from the MIDAS form a strong and reliable Mokken scale, which provides new insight into the relationship between items in the MIDAS and the measurement of quality of life after myocardial infarction. PMID- 20831665 TI - Friction and shear highly associated with pressure ulcers of residents in long term care - Classification Tree Analysis (CHAID) of Braden items. AB - AIMS: Among various risk assessment scales for the development of pressure ulcers in long-term care residents that have been published in the last three decades, the Braden scale is among the most tested and applied tools. The sum score of the scale implies that all items are equally important. The aim of this study is to show whether specific items are of greater significance than others and therefore have a higher clinical relevance. DESIGN: Data analysis of six pressure ulcer prevalence studies (2004-2009). METHODS: A total of 17,666 residents (response rate 79.6%) in 234 long-term care facilities participated in 6 annual point prevalence studies that were conducted from 2004 to 2009 throughout Germany. For the classification of the sample regarding pressure ulcers as a dependent variable and the Braden items as predictor variables, Chi-square Automatic Interaction Detector (CHAID) for modelling classification trees has been used. RESULTS: Pressure ulcer prevalence was 5.4% including pressure ulcer grade 1 and 3.4% for pressure ulcer grades 2-4. CHAID analysis for the classification tree provided the item 'friction and shear' as the most important predictor for pressure ulcer prevalence. On the second level, the strongest predictors were 'nutrition' and 'activity' and on the third level they were 'moisture' and 'mobility'. Residents with problems regarding 'friction and shear' and poor nutritional status present with an 18.0 (14.8) pressure ulcer prevalence which is 3-4 times higher than average. CONCLUSION: CHAID analyses have shown that all items of the Braden scale are not equally important. For residents in long-term care facilities in Germany, the existence of 'friction and shear' as a potential and especially as a manifest problem has had the strongest association with pressure ulcer prevalence. PMID- 20831666 TI - Out-of-hours demand in primary care: frequency, mode of contact and reasons for encounter in Switzerland. AB - RATIONALE, AIMS AND OBJECTIVES: To investigate the demand for traditional out-of hours general practitioner (GP) emergency care in Switzerland including GPs' satisfaction and reasons for encounter (RFE). METHOD: During a 2-month period (2009), a questionnaire-based, cross-sectional study was performed in GPs participating in the mandatory out-of-hours service in the city of Zurich, Switzerland. The number and mode of patient contacts were assessed to investigate the demand for GP care in traditional out-of-hours services. GPs and patient characteristics, including RFE according to the International Classification of Primary Care, were noted. Descriptive statistics and non-parametric tests were conducted. RESULTS: Out of the 295 out-of-hours episodes during the study period, 148 (50%) duty periods were documented by a total of 93 GPs (75% men) with a mean (SD) age of 48.0 (6.2) years. The median (interquartile range) number of out-of hours contacts was 5 (3-8) and the demand for home visits was significantly more common compared with practice and telephone consultations. A total of 112 different RFEs were responsible for the 382 documented patient contacts with fever accounting for the most common complaint (13.9%). Although 80% of GPs agreed to be satisfied overall with their profession as primary care provider, 57.6% among them were dissatisfied with the current out-of-hours service. Inappropriate payment and interference with their daily work in practice were most frequently reported. CONCLUSIONS: Our findings indicate that there is still strong patient demand for out-of-hours care with special need for home visits, suggesting that new organizational models such as integrating GPs into emergency care may not be an appropriate approach for all patients. Therefore, the ongoing reorganization of the out-of-hours-service in many health care systems has to be evaluated carefully in order not to miss important patient needs. PMID- 20831667 TI - Causal diagrams and change variables. AB - BACKGROUND: The true change in the value of a variable between two time points is often assumed to be a cause or an effect of interest. To our knowledge, this assumption is based on intuition, rather than on any formal theoretical justification. METHODS: We used causal directed acyclic graphs to explore the causal properties of a change variable, and critically examined competing structures. RESULTS: Based on the proposed causal structure, a change variable (true change) is no more than a derived variable. It does not cause anything and is not of causal interest. CONCLUSIONS: A true change is not a variable in the physical world. Therefore, modelling the change between two time points is justified only in a few situations. PMID- 20831668 TI - The importance of communication in collaborative decision making: facilitating shared mind and the management of uncertainty. AB - RATIONALE: Quality medical decision making requires that clinicians and patients incorporate the best available clinical evidence with the patients' values and preferences to develop a mutually agreed upon treatment plan. The interactive process involved in medical decision making is complex and requires patients and clinicians to use both cognitive and communicative skills to reach a shared understanding of the decision. AIMS AND OBJECTIVES: The purpose of this paper is to present a communication model to help better understand quality medical decision making, and how patient-centered, collaborative communication enhances the decision-making process. METHODS: We present research on shared mind and cognitive and communicative skills to highlight how they can facilitate the management of uncertainty during the interactive process involved in medical decision making. We provide simple examples about how to frame messages to achieve shared mind and foster uncertainty tolerance. CONCLUSIONS: Strategies such as providing clear explanations, checking for understanding, eliciting the patient's values, concerns, needs, finding common ground, reaching consensus on a treatment plan, and establishing a mutually acceptable follow-up plan can facilitate collaborative decision making. Future research should explore ways to implement collaborative decision-making processes in existing health care systems. PMID- 20831669 TI - A 6-month study of the effects of 0.3% triclosan/copolymer dentifrice on dental implants. AB - AIM: Supportive therapy to maintain dental implants is increasingly important. This study examined the effect of a 0.3% triclosan/2% copolymer dentifrice on oral biofilms and gingival inflammation (GI) on dental implants and peri-implant tissues. MATERIALS AND METHODS: One hundred and twenty adults with a dental implant and contra-lateral tooth were enrolled in this 6 month, double-blind, two treatment, parallel group study. Sixty subjects were randomly assigned to a triclosan/copolymer dentifrice test group and 60 subjects to a fluoride dentifrice control group and instructed to brush twice daily for 6 months. At baseline, 3, and 6 months, a calibrated dentist assessed dental plaque, GI and collected supragingival dental plaque for microbiological analysis. RESULTS: Subjects in the triclosan/copolymer group demonstrated significantly lower levels of dental plaque, gingivitis, and bleeding on probing at 3 and 6 months at both the implant and contra-lateral tooth compared with the fluoride group (p<0.05). There were significantly fewer Gram-negative anaerobes in the triclosan/copolymer group (p<0.05) including >90% reductions in Aggregatibacter actinomycetemcomitans, Campylobacter rectus, Eubacterium saburreum, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella melaninogenica, Solobacterium moorei, and Tannerella forsythia. CONCLUSIONS: Twice daily use of a triclosan/copolymer dentifrice may enhance dental implant maintenance by reducing dental plaque and GI. PMID- 20831671 TI - Green banana-supplemented diet in the home management of acute and prolonged diarrhoea in children: a community-based trial in rural Bangladesh. AB - SUMMARY OBJECTIVE: To determine the effectiveness of green banana in the home management of acute (<7 days) or prolonged (>= 7 days) diarrhoea at the community level. METHODS: A cluster randomized field trial was conducted among 2968 Bangladeshi rural children 6-36 months old. Wards (villages) were randomly assigned to either a standard care group or a standard care plus green banana group where mothers were instructed to add cooked green banana to the diets of diarrhoeal children. Through a village-based surveillance system, diarrhoeal morbidity data (severity, duration, compliance) were collected for 14 days. Treatment effects were determined by analysing cumulative probability of cure by testing Cox proportional hazards models and relative risk (RR). RESULTS: The cumulative probability of cure was significantly (P < 0.001) different in children receiving GB for both acute [hazard ratio (HR) = 0.63 (95% CI: 0.56 0.67)] and prolonged diarrhoea [HR = 0.38 (95% CI: 0.26-0.59)]. The recovery rates of children with acute diarrhoea receiving GB (vs. control) were significantly more by day 3: 79.9%vs. 53.3% [(RR) = 0.47, 95% CI: 0.41-0.55], (P < 0.001) and day 7: 96.6%vs. 89.1% (RR = 0.32; 0.22-0.46), (P < 0.001). Children with prolonged diarrhoea receiving green banana had significantly higher recovery rates by day 10: 79.8%vs. 51.9% (RR = 0.42; 0.23-0.73), (P < 0.001) and day 14: 93.6%vs. 67.2% (RR = 0.22; 0.08-0.54), (P < 0.001). CONCLUSION: A green banana supplemented diet hastened recovery of acute and prolonged childhood diarrhoea managed at home in rural Bangladesh. PMID- 20831672 TI - Extensively drug-resistant tuberculosis (XDR-TB) among health care workers in South Africa. AB - SUMMARY OBJECTIVE: To determine the clinical profile and outcomes of health care workers (HCWs) with extensively drug resistant tuberculosis (XDR-TB) in the Eastern and Western Cape Provinces of South Africa. METHOD: Retrospective case record review of 334 patients with XDR-TB reported during the period 1996-2008 from Western and Eastern Cape Province, Cape Town, South Africa. Case records of HCWs with XDR-TB were analysed for clinical and microbiological features, and treatment outcomes. RESULTS: From 334 case records of patients with XDR-TB, 10 HCWs were identified. Eight of ten were HIV-uninfected, and four of 10 had died of XDR-TB despite treatment. All 10 HCWs had received an average of 2.4 courses of TB treatment before being diagnosed as XDR-TB. CONCLUSIONS: In the Eastern and Western Cape provinces of South Africa XDR-TB affects HCWs, is diagnosed rather late, does not appear to be related to HIV status and carries a high mortality. There is an urgent need for the South African government to implement WHO infection control recommendations and make available rapid drug susceptibility testing for HCWs with suspected multidrug-resistant (MDR)/XDR-TB. Further studies to establish the actual risk and sources of infection (nosocomial or community) are required. PMID- 20831673 TI - First record of Ae. albopictus (Skuse 1894), in Central African Republic. AB - SUMMARY METHODS: Mosquito aquatic stages were collected in domestic and peri domestic areas, and epidemic risk indexes (Breteau, Container) were calculated for each prospected location. Adult female mosquitoes were captured by human landing catches, while larvae were sampled by inspecting artificial and natural breeding sites in randomly selected premises. RESULTS: Seventy-eight adults Aedes albopictus were collected in Bangui and Bayanga. Mosquito biting rate and abundance were, respectively, 0.33-1.70 bites/human/hour and 14.6% in Bangui and 0.04-0.16 and 0.4% in Bayanga. Larval sampling revealed a large diversity of water container harbouring the species in Bangui, Bayanga, Nola and Salo including unused containers, old tires, vehicle carcasses, buckets, barrels and stem of bamboo. The epidemic risk indices were erratic according to the location, ranging between 1.5-27.6 for Breteau and 1.3-47.1 for Container. CONCLUSION: This is the first record of Ae. albopictus in two bioclimatic zones of CAR This observation emphasizes the need to further investigate its potential impact on dengue and chikungunya viruses transmission regarding their recent emergencies in Africa (Cote d'Ivoire, Senegal, Mali, Somalia, Gabon, Cape Verde Islands). PMID- 20831674 TI - Change in willingness to pay for normal delivery and caesarean section during pregnancy and after delivery in Kathmandu. AB - SUMMARY OBJECTIVES: To determine the change in willingness to pay (WTP) measured at pregnancy and at postpartum before and after knowing hospital costs among women who gave birth by normal delivery (NL) and caesarean section (CS) and to identify factors affecting the change in WTP. METHODS: A prospective study was conducted from May to August 2009 at Tribhuvan University Teaching Hospital, Kathmandu, Nepal. WTP for total costs was measured by double-bound dichotomous contingent valuation and an open-ended technique. The trend of WTP over time was tested using longitudinal analysis. Associated factors to the positive or negative change in WTP were analysed by logistic regression. RESULTS: Of 438 pregnant women followed up both at pregnancy and postpartum, two-thirds were willing to pay for services at the initial bid of the double-bound method by $60 $85 for NL and $110-$170 for CS. There were no significant differences in the median WTP measured during pregnancy between NL and CS. The WTP of both groups changed significantly over time (P < 0.001). Caesarean section, perception of good care, information provided on delivery costs and discussion with family about cost were significantly associated with changes from pregnancy to the postpartum period. CONCLUSIONS: In low-income countries such as Nepal, where out of-pocket health care expenditures are common, women perceived the health benefit of delivery care in hospital, especially for emergency CS. Their WTP had changed substantially after delivery, and awareness of the associated factors is essential for further policy and planning to improve the services and utilization. PMID- 20831675 TI - Toenail onychomycosis: an important global disease burden. AB - Onychomycosis is a fungal infection of the nail plate or nail bed. It does not usually cure itself and it can trigger more infectious lesions in other parts of the body. The reported prevalence of onychomycosis is increasing in Western countries, presumably due to lifestyle changes and the ageing of the population. Approximately 10% of the general population, 20% of the population aged>60 years, up to 50% of people aged>70 years and up to one-third of diabetic individuals have onychomycosis. Care should be taken for the accurate diagnosis and timely treatment of toenail onychomycosis to prevent complications. Current treatment options have relatively limited therapeutic success, particularly long-term. Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged. PMID- 20831677 TI - Investigation of the prediction accuracy of vancomycin concentrations determined by patient-specific parameters as estimated by Bayesian analysis. AB - BACKGROUND/OBJECTIVE: There have been many studies of therapeutic drug monitoring (TDM) of vancomycin (VCM) based on Bayesian analysis, but there have been no reports of the accuracy of prediction based on Bayesian-estimated patient specific parameters. This study was conducted to compare the accuracy of prediction based on the population pharmacokinetic (PPK) method and Bayesian estimated parameters. METHOD: The subjects were 22 patients who were treated with VCM for MRSA infection and whose blood was sampled twice or more during the administration period. The concentrations between the blood samples were predicted based on the concentrations in the first blood samples based on the PPK method using mean parameters for the Japanese population and Bayesian-estimated patient-specific pharmacokinetic parameters. The mean prediction error (ME), mean absolute error (MAE) and root mean squared error (RMSE) were compared to examine the accuracy of prediction based on Bayesian-estimated patient-specific parameters. RESULTS AND DISCUSSION: The mean measured VCM concentration was 10.43+/-5.19 MUg/mL, whereas the mean concentration predicted based on the PPK method was 8.52+/-4.34 MUg/mL, with an ME of -1.91, MAE of 2.93 and RMSE of 3.21. The mean concentration predicted based on patient-specific parameters was 9.62+/ 4.95 MUg/mL with ME of -0.81, MAE of 1.38 and RMSE of 1.74. The ME and MAE for the concentrations predicted using patient-specific parameters were smaller compared with those predicted using the PPK method (P=0.0471 and 0.0003, respectively), indicating superior prediction with a significant difference between approaches. CONCLUSION: Prediction using Bayesian estimates of patient specific parameters was better than by the PPK method. However, when using patient-specific parameters it is still necessary to fully understand the clinical status of the patient and frequently determine VCM concentrations. PMID- 20831676 TI - Solubilization of vorinostat by cyclodextrins. AB - BACKGROUND: Vorinostat (suberoylanilide hydroxamic acid) is the first histone deacetylase inhibitor approved by US FDA for use in oncology. However, as a hydrophobic acid, its limited aqueous solubility poses a problem for parenteral delivery. Such limited solubility may also affect its oral bioavailability. OBJECTIVE: The aim of this study was to evaluate whether cyclodextrins (CDs), common excipients used in pharmaceutical industry, could increase the aqueous solubility of vorinostat. METHODS: The actual aqueous solubility of vorinostat was investigated by phase-solubility method. Molecular simulation was employed to predict the interaction energy and preferred orientation of vorinostat in CD cavities. RESULTS: Phase-solubility studies indicated that the solubility of vorinostat (7.24*10(-1) mm) was substantially increased when complexed with various CDs, in the following order: randomly methylated-beta-cyclodextrin (RM beta-CD)>hydroxypropyl-beta-cyclodextrin (HP-beta-CD)>alpha cyclodextrin>hydroxypropyl-alpha-cyclodextrin>Hydroxypropyl-gamma cyclodextrin>gamma-cyclodextrin. RM-beta-CD 300 mm increased vorinostat solubility to 70.8 mm, almost two orders of magnitude higher than the baseline solubility. Such findings were in good agreement with the results obtained from molecular simulation. CONCLUSION: CDs, particularly RM-beta-CD and HP-beta-CD, increased vorinostat's solubility. Future studies could be focused on the application of HP-beta-CD in parenteral delivery of vorinostat or using RM-beta CD as an oral absorption enhancer. Molecular simulation appeared to be a useful tool for the selection of appropriate CD as excipient for drug delivery. PMID- 20831678 TI - Quality of medicines stored together in multi-compartment compliance aids. AB - BACKGROUND AND OBJECTIVE: Dispensing medicines into compliance aids is a common practice in pharmacy contrary to manufacturers' advice and studies have shown the appearance of light-sensitive tablets is compromised by such storage; we previously found evidence of reduced bioavailability at elevated temperature and humidity. Our objective was to examine the physicochemical stability of two generic atenolol tablets in different compliance aids and with aspirin co-storage at room temperature and at 40 degrees C/75% relative humidity. METHODS: The physicochemical stability of atenolol tablets was evaluated after 28 days of storage and compared with controls by examining visual appearance, weight, disintegration, dissolution, friability and hardness to accepted standards and using a previously validated HPLC method for chemical assay. RESULTS AND DISCUSSION: The response to storage was brand-dependent and not straightforward. With one make of atenolol (Alpharma), storage in compliance aids even at room temperature impacted on physical stability, reducing tablet hardness, with storage in Dosett exerting a greater impact than storage in Medidos (t-test P<0.001). Co-storage at elevated temperature and humidity also impacted on the appearance of non-coated aspirin tablets (Angette). The chemical stability of atenolol was not affected and we did not find evidence of changes to bioavailability with either make. Certainly data for one atenolol make (CP Pharmaceuticals) co-stored with aspirin (Angette and Nu-Seals) in both compliance aids at room temperature provided evidence of short-term stability. But medicines are dispensed into compliance aids in multi-factorial ways so our study highlights not only the lack of evidence but also a realization that evidence to support real practice may not be accomplished through research. CONCLUSION: Reassuring practitioners of the continued stability of medicines in compliance aids under the countless condition in which they are dispensed in practice may requires a different approach involving medical device regulators and more definitive professional guidance. PMID- 20831679 TI - Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. AB - BACKGROUND AND OBJECTIVE: Ingestion of the medicinal herb kava has been associated with hepatotoxicity. We aimed to compare two different quantitative methods of causality assessment of patients with assumed hepatotoxicity by the herb. METHODS: We assessed causality in 26 patients from Germany and Switzerland, using two structured quantitative analytical methods: the system of Maria and Victorino (MV) and that of the Council for International Organizations of Medical Sciences (CIOMS). In all 26 patients, regulatory ad hoc evaluation had suggested a causal relationship between liver disease and kava use. RESULTS AND DISCUSSION: Assessment with the MV scale resulted in no or low graded causality for kava in the 26 patients with liver disease. Causality was probable (n=1), possible (n=2), unlikely (n=7), and excluded (n=16). Causality for kava was more evident with the CIOMS scale: highly probable (n=1), probable (n=2), possible (n=6), unlikely (n=2) and excluded (n=15). However, the results of both quantitative causality assessments are not supportive for most of the regulatory ad hoc causality assessments of the 26 patients. CONCLUSION: Grades of causality for suspected hepatotoxicity by kava were much lower when evaluated by structured quantitative causality assessment scales than by regulatory ad hoc judgements. The quantitative CIOMS scale is the preferable tool for causality assessment of spontaneous reports of hepatotoxcity involving kava. PMID- 20831680 TI - Effect of pioglitazone and acarbose on endothelial inflammation biomarkers during oral glucose tolerance test in diabetic patients treated with sulphonylureas and metformin. AB - WHAT IS KNOWN: The increased risk of cardiovascular events in diabetic patients has been related to numerous metabolic and haemoreological factors. Some of these factors appear to be particularly evident during the post-prandial phases and to be related to peak plasma glucose level. AIM: To compare the effect of addition of pioglitazone and acarbose to sulphonylureas and metformin therapy on metabolic parameters and on markers of endothelial dysfunction and vascular inflammation in type 2 diabetic patients. MATERIALS AND METHODS: We enrolled 473 caucasian type 2 diabetic patients. All patients underwent measurements of height and body weight, body mass index (BMI), glycated haemoglobin (HbA1c) , fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), post prandial plasma insulin (PPI), homeostasis model assessment (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (Tg), sICAM-1, IL-6, high-sensitivity C reactive protein (hsCRP), sVCAM-1, sE-selectin and tumour necrosis factor (TNF alpha). Assessments were made at start of titration, after 3 months [before a first oral glucose tolerance test (OGTT)], after 6 months and at the study end (before a second OGTT). RESULTS: Two-hundred and seventy four patients completed the study: 138 were randomized to double-blind treatment with pioglitazone and 136 with acarbose. Significant BMI and weight increase were observed after full treatment in the pioglitazone group relative to the acarbose group. A decrease in glycated haemoglobin was observed after the titration period in the pioglitazone group compared to both baseline value and the acarbose group. A decrease in glycated haemoglobin was also obtained after full treatment in the pioglitazone group when compared to the end of titration period and to the acarbose group. Significant decrease in FPG was obtained in the pioglitazone group after full treatment compared to the end of titration period. Post-prandial plasma glucose decrease was observed in acarbose group compared to the baseline value and to the end of titration period. Fasting plasma insulin decreased in the pioglitazone group after both the titration period and the full treatment period compared to both the baseline value and the acarbose group. The HOMA index decreased significantly after the full treatment in pioglitazone group compared to the end of titration period and to the acarbose group. Interleukin-6 and tumour necrosis factor-alpha decreased after full treatment in the pioglitazone group relative to the end of titration period. Significant hsCRP decrease was obtained after the titration period when compared to the baseline value in the pioglitazone group. High-sensitivity C reactive protein decreased in the pioglitazone group after full treatment compared to the end of titration period and to the acarbose group. WHAT IS NEW AND CONCLUSION: Pioglitazone reduces the inflammatory response to a glucose challenge more than acarbose in type 2 diabetic patients, already treated with maximal doses of sulphonylureas and metformin. PMID- 20831681 TI - Saffron in the treatment of patients with mild to moderate Alzheimer's disease: a 16-week, randomized and placebo-controlled trial. AB - WHAT IS KNOWN: Herbal medicines have been used in the treatment of behavioural and psychological symptoms of dementia but with variable response. Crocus sativus (saffron) may inhibit the aggregation and deposition of amyloid beta in the human brain and may therefore be useful in Alzheimer's disease (AD). OBJECTIVE: The goal of this study was to assess the efficacy of saffron in the treatment of mild to moderate AD. METHODS: Forty-six patients with probable AD were screened for a 16-week, double-blind study of parallel groups of patients with mild to moderate AD. The psychometric measures, which included AD assessment scale-cognitive subscale (ADAS-cog), and clinical dementia rating scale-sums of boxes, were performed to monitor the global cognitive and clinical profiles of the patients. Patients were randomly assigned to receive capsule saffron 30 mg/day (15 mg twice per day) (Group A) or capsule placebo (two capsules per day) for a 16-week study. RESULTS: After 16 weeks, saffron produced a significantly better outcome on cognitive function than placebo (ADAS-cog: F=4.12, d.f.=1, P=0.04; CDR: F=4.12, d.f.=1, P=0.04). There were no significant differences in the two groups in terms of observed adverse events. WHAT IS NEW AND CONCLUSION: This double-blind, placebo-controlled study suggests that at least in the short-term, saffron is both safe and effective in mild to moderate AD. Larger confirmatory randomized controlled trials are called for. PMID- 20831682 TI - Comparison of two neonatal indomethacin protocols: efficacy and outcome for patent ductus arteriosus closure. AB - WHAT IS KNOWN: Indomethacin, a non-selective inhibitor of prostaglandin synthesis, is the gold standard treatment for patent ductus arteriosus (PDA). Indomethacin has been shown to permanently close the ductus and when given prophylactically, it reduces the incidence of PDA (1, 2). OBJECTIVE: This study compares PDA closure and surgical ligation rates between patients using two different indomethacin administration protocols. METHODS: This is a retrospective comparison analysis of 72 neonates, who received one of two indomethacin administration protocols. Our previous protocol suggested an initial dose of 0.2 mg/kg followed by two 0.1 mg/kg, with doses infused over 4 h and a 24-h dosing interval. A new potentially more useful protocol using the same mg/kg dose regimen but with doses infused over 30 min and a 12-h dosing interval, was evaluated. Each neonate was allowed three courses of treatment before surgical ligation was performed for persistent PDA. RESULTS: There were no statistically significant differences between the two protocol groups when comparing percentages of neonates with gestational age<=28 weeks, birth weight<=1000 g, male gender or receiving indomethacin for the indication of PDA prophylaxis vs. treatment. There was a trend towards a higher PDA closure rate and subsequently a lower PDA ligation rate in the new protocol when compared with the previous protocol. WHAT IS NEW AND CONCLUSION: In this small population of premature neonates, there was a trend, but no significant difference, towards increasing PDA closure and lower surgical ligation rates in neonates given indomethacin with more frequent dosing and shorter infusion time. A well-powered randomized controlled trial is now needed. PMID- 20831683 TI - Pharmacokinetics and its relation to toxicity of pegylated-liposomal doxorubicin in Chinese patients with breast tumours. AB - OBJECTIVES: Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin encapsulated with polyethylene glycol-coated liposomes, which has prolonged circulation time and unique toxicity profile. This study deals with the pharmacokinetics and its relation to toxicity in Chinese patients with breast tumours. METHODS: Twenty-two Chinese female patients with breast tumours were received two PLD products in single dose of 50 mg/m2 with a randomized, two period and cross-over design. Blood was sampled immediately before and at 15, 30, 60 min, 1.17, 2, 5, 13, 25, 49, 73, 97, 121, 145 and 241 h after the PLD infusion. The plasma level of doxorubicin was determined with LC-MS. RESULTS: The pharmacokinetics of PLD was best described by a one-compartment linear structural model with a long elimination T(1/2) (64 h), a slow clearance (0.025 L/h/m2) and a small volume of distribution (2.310 L/m2). The main toxicities were neutropenia (22/44), nausea (22/44), vomiting (8/44) and pigmentation (4/44). The nausea and neutropenia were positively correlated with AUC while negatively correlated with Cl (P<0.05). CONCLUSIONS: The study confirms the different pharmacokinetic and toxicity profiles of PLD compared with non-liposomal doxorubicin. The pharmacokinetic profiles in Chinese patients with breast tumours is different from those reported for European patients with metastatic breast cancer. The correlation between toxicities, neutropenia grade and nausea and two of the pharmacokinetic parameters, AUC and Cl, may be useful for guiding the dosing of the agent. PMID- 20831684 TI - Case report. Intravenous fentanyl patient-controlled analgesia for perioperative treatment of neuropathic/ischaemic pain in haemodialysis patients: a case series. AB - BACKGROUND AND OBJECTIVE: Use of opioids is common in perioperative haemodialysis patients because they often suffer from intractable ischaemic or neuropathic lower extremity pain. Intravenous (IV) fentanyl, patient-controlled analgesia (PCA) does not appear to have been evaluated in this setting; hence this study. METHODS AND RESULTS: This is a prospective, single-centre study. IV fentanyl PCA was used for pain control in 16 patients with lower extremity, neuropathic/ischaemic pain, scheduled for major lower extremity amputation. IV fentanyl PCA was used before and after amputation in eight patients, before but not after amputation in seven patients, and until death in one terminal cancer patient who chose to forgo surgery. Pain intensity was assessed with the Visual Analogue Scale (VAS) and the McGill Pain Questionnaire. Depth of sedation was assessed on a 4-point scale. Ischaemic pain scores were high before fentanyl PCA started, but decreased significantly and remained low with fentanyl PCA use (P<0.001). Phantom pain scores were low (VAS<=4). Respiratory depression was not a problem in any patient. CONCLUSIONS: Concerns about accumulation of active opioid metabolites make provision of adequate analgesia problematic in haemodialysis patients scheduled for amputation, and emergency surgery. Our data on a small patient population suggest that IV fentanyl PCA is safe and effective for severe pain in haemodialysis patients. PMID- 20831685 TI - Case report. Efficacy of Hoodia for weight loss: is there evidence to support the efficacy claims? AB - Increasing rates of adult obesity and its negative health consequences are likely to become an increasing burden to the Canadian health care system. Consumers are looking for treatment options and often try the natural health products that are heavily promoted as safe, fast and effective. In this case report, MH, a 57-year old overweight female wanted advice regarding whether she should use the natural product Hoodia to help her attain her weight loss goals. A literature search was conducted using Medline, EMBASE, the Cochrane Library, Natural Medicines Comprehensive Database and IPA from inception to March 2009. The internet, files of the authors and bibliographies of articles were searched for additional references. No published, peer-reviewed randomized controlled trials examining efficacy of Hoodia were found. Unpublished data from two small trials reported promising results with no adverse events. However, this leaves many unanswered questions regarding the use of Hoodia for weight loss such as the appropriate dose and duration, short and long term safety and use in patients with concomitant diseases. Literature suggests that some commercial products may not actually contain Hoodia at all. Additionally, Hoodia is not yet listed in the Canadian Licensed Natural Health Products Database meaning products sold in Canada may not meet Canadian regulatory standards. Upon discussing this information, MH decided not to use Hoodia, and other evidence-based recommendations were discussed. PMID- 20831686 TI - Case report. Hyperlipoproteinaemia(a): which is the optimal therapy? A case report. AB - This case report presents the clinical history of a patient with elevated lipoprotein(a) and small size isoform, associated with mixed hyperlipaemia, which was probably familial combined hyperlipaemia. After premature myocardial infarction, the subject was treated with fibrates. Niacin was started after recurrence. One year ago, after another episode of acute coronary syndrome, rosuvastatin was added to niacin. The atherogenicity of this lipid disorder, along with the different options for therapy is discussed. PMID- 20831687 TI - Evidence-based guidelines for the prevention, identification and management of occupational contact dermatitis and urticaria. AB - BACKGROUND: Occupational contact dermatitis is the most frequently reported work related skin disease in many countries. A systematic review was commissioned by the British Occupational Health Research Foundation in response to a House of Lords Science and Technology Committee recommendation. OBJECTIVES: The systematic review aims to improve the prevention, identification and management of occupational contact dermatitis and urticaria by providing evidence-based recommendations. METHODS: The literature was searched systematically using Medline and Embase for English-language articles published up to the end of September 2009. Evidence-based statements and recommendations were graded using the Royal College of General Practitioner's three-star system and the revised Scottish Intercollegiate Guidelines Network grading system. RESULTS: Three thousand one hundred and fifty-five abstracts were identified and screened. From these, 786 full papers were obtained and appraised. One hundred and nineteen of these studies were used to produce 36 graded evidence statements and 10 key recommendations. CONCLUSIONS: This evidence review and its recommendations focus on interventions and outcomes to provide a robust approach to the prevention, identification and occupational management of occupational contact dermatitis and urticaria, based on and using the best available medical evidence. PMID- 20831688 TI - Permanent make-up colorants may cause severe skin reactions. AB - BACKGROUND: In recent years, cosmetic tattoos [permanent make-up (PMU)] on eyelids, eyebrows and lips have become increasingly popular. However, most colorants are manufactured for non-medical purposes, without any established history of safe use in humans. OBJECTIVES: To investigate severe adverse reactions, such as swelling, burning, and the development of papules, of the lips and the surrounding area in 4 patients who had had at least two PMU procedures on their lips. PATIENTS, MATERIALS AND METHODS: Adverse skin reactions were examined with patch and prick testing of the colorants. In addition, skin biopsies were taken in the centre of the prick test for histology. One patient declined prick testing. RESULTS: Beauticians tended to use various PMU products, but all contained Pigment Red 181 (CI 73360). All patients tested showed a clear delayed reaction to Pigment Red 181 or the tattoo ink, or both, after prick testing. Histology indicated an allergic reaction. Each lip lesion slowly abated after several months of topical or systemic therapy with steroids in combination with tacrolimus, but none has yet completely resolved. CONCLUSIONS: In light of the severe and often therapy-resistant skin reactions, we strongly recommend the regulation and control of the substances used in PMU colorants. PMID- 20831689 TI - Contact allergy to diltiazem cream. PMID- 20831690 TI - Allergic contact dermatitis caused by topical diltiazem. PMID- 20831691 TI - Allergic contact dermatitis caused by p-tert-butylphenol formaldehyde resin and colophonium in neoprene thermal sauna shorts. PMID- 20831692 TI - Allergic contact dermatitis caused by durable-press finishes does exist in the USA. PMID- 20831695 TI - Vitamin D in health and disease. AB - BACKGROUND/PURPOSE: Investigations have revealed that vitamin D plays an important role in many areas of health and disease. Questions over whether sun avoidance and sunscreen use will decrease vitamin D levels may concern clinicians when counseling patients at risk for vitamin D insufficiency. A review of the role of vitamin D in health and disease, the impact of photoprotection and skin type on vitamin D levels, and recommendations for adequate vitamin D intake is provided to aid clinicians in counseling patients regarding these issues. RESULTS: Review of the literature indicates that adequate vitamin D intake is associated with decreased risk of falls and bone fractures in the elderly, breast and gastrointestinal cancer risk, cardiovascular disease, and possibly all cause mortality, diabetes, and multiple sclerosis. While skin type does affect vitamin D levels, regular use of sunscreen is not associated with vitamin D insufficiency. CONCLUSIONS: Adequate intake of vitamin D is important for maintenance of good health, and may be achieved through diet and oral supplementation. Intentional or prolonged exposure to ultraviolet light should not be used as a means of obtaining vitamin D. PMID- 20831696 TI - Does topical tacrolimus ointment enhance the efficacy of narrowband ultraviolet B therapy in vitiligo? A left-right comparison study. AB - BACKGROUND: Narrowband ultraviolet B (NB-UVB) therapy has emerged as one of the most favored treatment options in patients with generalized vitiligo. The aim of combining topical agents is to improve the efficacy of NB-UVB in causing repigmentation in vitiligo. AIMS AND OBJECTIVES: The present study aims to study the effect of combining topical tacrolimus to NB-UVB therapy in causing repigmentation in vitiligo lesions. METHODS: This prospective single-blind study was performed on 80 patients of generalized vitiligo above 12 years of age who had symmetrically distributed vitiligo lesions on the face, trunk or limbs. The patients applied topical tacrolimus 0.1% ointment twice daily on selected symmetrically distributed lesions on the left side of the body. No topical agent was applied on the corresponding lesions on the right side. The patients also received whole-body NB-UVB exposure three times every week on non-consecutive days according to a set protocol. Lesions selected for the comparison analysis were photographed serially and assessed by a single-blinded observer for the extent or repigmentation achieved. The extent of repigmentation achieved was calculated on the basis of VASI scoring. The time taken for the initial repigmentation to start, the overall repigmentation achieved as well as any adverse effects were noted down and compared between the selected lesions on the two sides. RESULTS: Seventy-four patients with 234 symmetrical vitiligo lesions were available for comparison analysis at the end of study period. The mean repigmentation achieved on the left-sided study lesions was approximately 71% (VASI score of approximately 4.0) as compared with 60.5% on the symmetrically distributed right-sided lesions (VASI score of 3.4). Moreover, the repigmentation started earlier on the study lesions on left side than on the right-sided ones. No significant adverse events were reported with the combination treatment. CONCLUSIONS: Addition of topical tacrolimus increases the extent of overall repigmentation achieved with NB-UVB therapy in vitiligo and also reduces the cumulative NB-UVB dose needed to achieve a therapeutic benefit in affected patients. PMID- 20831697 TI - Bath psoralen+ultraviolet A photochemotherapy vs. narrow band-ultraviolet B in psoriasis: a comparison of clinical outcome and effect on circulating T-helper and T-suppressor/cytotoxic cells. AB - BACKGROUND: Comparative success rates of bath psoralen+ultraviolet A (PUVA) and narrow band-ultraviolet B (NB-UVB) in psoriasis treatment are variably reported with no previous studies on the possible effect of bath PUVA on circulating CD4+ and CD8+ T cells. OBJECTIVE: We aimed to compare the effect of bath PUVA and NB UVB clinically and on circulating T-helper and T-suppressor/cytotoxic cells in psoriasis. PATIENTS AND METHODS: Thirty-four psoriatic patients divided into a bath PUVA-treated group (18 patients) and a NB-UVB-treated group (16 patients) were compared regarding the disease severity by psoriasis area and severity index (PASI) score and percentage of circulating CD4+ and CD8+ T cells by flow cytometry before and after treatment. RESULTS: After treatment, the bath PUVA group showed a significantly higher reduction of PASI score (85.44%) than the NB UVB group (58.72%). Mean peripheral CD4+ T-cell percentage was significantly lower after [36.8; 95% confidence interval (CI) 33.80, 39.97] compared with before treatment (42.06; 95% CI 38.29, 45.83) (P<0.05) in the bath PUVA group while this difference was insignificant in the NB-UVB group (P>0.05). CONCLUSION: Bath PUVA therapy is superior to NB-UVB in the treatment of moderate and severe psoriasis with mild reversible side effects. Both modalities have a systemic effect decreasing peripheral CD4+ T cells, which is more with bath PUVA. PMID- 20831698 TI - Eltrombopag (75 mg) does not induce photosensitivity: results of a clinical pharmacology trial. AB - BACKGROUND/PURPOSE: Eltrombopag is an oral, small molecule, thrombopoietin receptor agonist approved in the United States for the treatment of chronic immune thrombocytopenic purpura and under investigation for treatment of thrombocytopenia due to other etiologies. In vitro studies identified a phototoxic potential for eltrombopag that was not confirmed in subsequent animal studies at exposures up to 11 times the human clinical exposure. A randomized study in healthy men and women was conducted to more fully characterize the photosensitizing potential of a therapeutic dose of eltrombopag (75 mg q.i.d.). METHODS: In this placebo-controlled, randomized, parallel group study, the photosensitizing potential of eltrombopag was evaluated in 36 healthy subjects with 12 subjects per group treated for 6 days with eltrombopag 75 mg q.i.d., placebo q.i.d., or positive control ciprofloxacin 500 mg b.i.d. (a mild photosensitizer). The primary endpoint was the photosensitizing potential of eltrombopag in comparison with the placebo on day 6 as measured by the phototoxic index (PI) at 24-h postirradiation, delayed erythema, and the change from baseline in minimum erythemal dose (MED) at 24-h postirradiation. The PI and MED were determined at discrete wavelengths in the ultraviolet (UV) and visible light spectrum from 290 to 430 nm. RESULTS: At wavelengths of 295+/-5, 300+/-5, 305+/ 30 nm, and solar simulator whole spectrum (SS WS), there were no notable median differences in delayed PI or change from baseline MED at 24-h postirradiation after administration of eltrombopag 75 mg q.i.d., placebo, or ciprofloxacin 500 mg b.i.d. Mild phototoxicity induced by ciprofloxacin 500 mg b.i.d. was observed at wavelengths of 335+/-30 and 365+/-30 nm within the UVA region. Following administration of ciprofloxacin, the median difference in delayed PI relative to placebo at wavelengths of 335+/-30 and 365+/-30 nm was increased to 0.75 [95% confidence interval (CI), 0.222-2.037] and 1.20 (95% CI, 0.404-1.720), respectively. However, there was no evidence that photosensitivity was increased following administration of eltrombopag 75 mg q.i.d. There were no significant differences between median delayed PI following administration of repeat doses of eltrombopag 75 mg q.i.d. and repeat doses of placebo at wavelengths of 335+/-30 and 365+/-30 nm. Comparing eltrombopag 75 mg q.i.d. with ciprofloxacin 500 mg b.i.d., the median difference in delayed PI for wavelengths of 335+/-30 and 365+/ 30 nm was decreased to -0.94 (95% CI, -2.037 to -0.289) and -1.38 (95% CI, -1.882 to -0.432), respectively. With 6 days of treatment, eltrombopag and placebo did not increase the photosensitivity of the skin, while the positive control ciprofloxacin did increase the photosensitivity of skin, resulting in mild phototoxicity. Administration of eltrombopag for 6 days was well tolerated; no deaths, serious adverse events (AEs), or drug-related AEs leading to discontinuation were observed during the study. There were no meaningful differences in AEs reported between the eltrombopag-treated group and either the placebo or ciprofloxacin-treated group. CONCLUSION: Repeat dosing of eltrombopag 75 mg q.i.d. for 6 days in healthy men and women did not induce photosensitivity at any wavelength tested (UVA, ultraviolet B) in this study. Eltrombopag is well tolerated and does not induce photosensitivity. PMID- 20831699 TI - Cutaneous epidermal growth factor receptor system following ultraviolet irradiation: exploring the role of molecular mechanisms. AB - BACKGROUND/PURPOSE: The epidermal growth factor receptor (EGFR) pathway appears to be essential in many cutaneous disorders. It is well established that ultraviolet (UV) irradiation activates the EGFR in the animal and human skin; however, the molecular mechanisms involved in such activation remain unclear. Our aim is to review and analyse them. METHODS: Computerized search and selection of original papers in the MEDLINE database (PubMed) from 1988 to 2009 were performed. Systematic analysis and breakdown of the information selected were carried out. RESULTS: Full manuscripts were retrieved for 32 citations. It was proven that UV light acts directly and indirectly on EGFR (ErbB1/ErbB2) and on numerous intermediaries of extracellular and intracellular signalling. The most closely observed changes imply concentrations and/or molecular activity of the reactive oxygen species group, hydrogen peroxide, matrix metalloproteinases, p38MAPKinase, p21WAF1, p53, signal transducers and activators of transcription 3 and telomerase. CONCLUSION: Our results help to clarify the working and importance of the UV-EGFR system in the human skin. PMID- 20831700 TI - A case of progressive macular hypomelanosis treated with 1% topical clindamycin lotion and narrow-band ultraviolet B. PMID- 20831701 TI - Proceedings of the 17th EADV, Paris, 2008. Editorial. PMID- 20831702 TI - From bench to bedside--translational research in psoriasis. AB - For many years, psoriasis was firmly believed to be a disease of epidermal keratinocytes, but now is attributed to a combination of genetic and environmental factors that promote a T-cell mediated immune response in the skin. Psoriasis is now understood to be a systemic T-cell mediated autoimmune disease with the innate immune system playing an important role. Progress in understanding the pathogenesis of psoriasis has shown that following a stimulus, dendritic and T cell activation leads to the release of cytokines, chemokines and growth factors that initiate the proliferation and altered differentiation of keratinocytes. These factors subsequently lead to continuous activation of T cells and antigen-presenting cells, particularly dendritic cells, within the psoriatic plaque. This vicious cycle of psoriasis, in which the cytokines interleukin 12 (IL-12) and IL-23 play a pivotal role, is a logical target for biological therapy. PMID- 20831703 TI - Novel biologic therapies in development targeting IL-12/IL-23. AB - Recent research has identified the importance of interleukin 12 (IL)-12 and IL-23 in the immunopathogenesis of psoriasis. The p40 subunit common to IL-12 and IL-23 is an attractive target for selective therapy. Clinical study data are available for two anti-IL-12/23 therapies: ustekinumab (CNTO 1275, approved in 2009 for treatment of plaque psoriasis) and ABT-874. The Phase 3 clinical trials PHOENIX 1 and PHOENIX 2 have shown significant benefit for ustekinumab in moderate-to severe plaque psoriasis, with PASI 75 response rates ranging from 66% at week 12 (after two injections) and rising to 85% at week 24 (after three injections). Withdrawal of treatment led to a gradual return of psoriasis whereas continued therapy every 12 weeks with ustekinumab maintained PASI 75 response. Analysis of safety data demonstrated a safety profile similar to placebo at week 12 and did not reveal any major safety concerns in blocking IL-12 and IL-23 for periods as long as 18 months. Phase 2 data indicate that ABT-874 is also efficacious in the treatment of moderate-to-severe plaque psoriasis across a range of dosing strategies. PMID- 20831704 TI - Comparing biological therapies in psoriasis: implications for clinical practice. AB - Treatment of severe or recalcitrant plaque psoriasis with traditional systemic therapies may be limited by efficacy or safety/tolerability considerations. The latest information on the pathophysiology of psoriasis and its targeted treatment with biological therapy points to an emerging new treatment paradigm: continuous and earlier systemic therapy. However, few comparative trials of systemic treatments for psoriasis have been conducted. The Active Comparator (CNTO 1275/Enbrel) Psoriasis Trial (ACCEPT) is the first head-to-head superiority study comparing two biological agents (ustekinumab and etanercept) in the treatment of plaque psoriasis. The results show that ustekinumab, given as two injections over a 12-week period, achieves significantly superior clinical improvement compared with etanercept 50 mg twice weekly. The level of response was consistent with previously published data for both drugs, and may have important implications for the management of psoriasis. PMID- 20831705 TI - Sustainability should be integral to nutrition and dietetics. PMID- 20831706 TI - Socio-economic drivers of overnutrition in China. AB - BACKGROUND: Overnutrition has emerged as a major problem in China. Measuring the associations of socio-economic variables with energy intake and its fat density is important, particularly at the upper tail 'overnutrition' areas of their distributions. The present study aimed to estimate such associations, with an emphasis on overnutrition areas. METHODS: The study used data on individuals aged 20-45 years from the 2006 China Health and Nutrition Survey (n = 3407). Quantile regression methods were employed to determine associations with key drivers at various parts of the conditional distributions of energy intake and its fat density. RESULTS: Household income was found to have little association with energy intake, and only a poor one with fat density of intake (a 1000 Yuan increase in household income was associated with a 0.1-0.3% point increase in fat density across the distribution). Although women had lower energy intakes than men, their energy intake was more fat dense at 1.5% points on average. Urban residents not only had lower energy intakes than rural residents (a 300 kJ difference at the lower tail, rising to a 600 kJ difference at the upper tail), but also more fat-dense intakes (a 2.7% point difference on average). CONCLUSIONS: The small income relationships estimated indicate that dietary excess may no longer only be a problem of the rich in China. A lower energy intake but higher fat density of intake associated with men compared to women and rural compared to urban residents indicates a need for flexible nutrition policy targeting. PMID- 20831707 TI - Health-related beliefs and consumer knowledge as determinants of fish consumption. AB - BACKGROUND: Despite scientific evidence on the positive effects of seafood consumption on human health, the consumption of fish remains below the recommended intake levels for the majority of Europeans. The present study aimed to explore cultural differences in potential determinants of fish consumption: consumers' knowledge and health-related beliefs, as well as the relationship between those variables, socio-demographics and fish consumption frequency, using data from five European countries. METHODS: A cross-sectional consumer survey was carried out in 2004 with representative household samples from Belgium, the Netherlands, Denmark, Poland and Spain. The sample consisted of 4786 respondents, aged 18-84 years, who were responsible for food purchasing and cooking in the household. RESULTS: European consumers had a very strong belief that eating fish is healthy. Consumers' belief that eating fish is healthy, their interest in healthy eating and objective fish-related nutrition knowledge, positively, but only weakly, influenced fish consumption frequency. Subjective knowledge was found to be a stronger predictor of fish consumption than the previously noted factors. Age and education contributed, both directly and indirectly through knowledge, to explain fish consumption behaviour. However, the path coefficients in the estimated model were relatively low, which indicates that fish consumption frequency was also determined by factors other than health-related beliefs and consumers' knowledge. CONCLUSIONS: The findings of the present study suggest that communication should focus on health-related benefits other than fish consumption alone. Communicating that eating fish is healthy and stressing the health benefits of fish alone, as is still commonly performed (e.g. in generic promotion and other types of public information campaigns) will be insufficient to achieve higher levels of compliance with fish consumption recommendations. PMID- 20831708 TI - Neighbourhood deprivation and the price and availability of fruit and vegetables in Scotland. AB - BACKGROUND: Previous research has suggested that fruits and vegetables are more expensive and less readily available in more deprived communities. However, this evidence is mainly based on small samples drawn from specific communities often located in urban settings and thus is not generalisable to national contexts. The present study explores the influence of neighbourhood deprivation and local retail structure on the price and availability of fruit and vegetables in a sample of areas representing the diversity of urban-rural environments across Scotland, UK. METHODS: A sample of 310 stores located in 10 diverse areas of Scotland was surveyed and data on the price and availability of a basket of 15 fruit and vegetable items were collected. The data were analysed to identify the influence of store type and neighbourhood deprivation on the price and availability of fruits and vegetables. RESULTS: Neighbourhood deprivation and store type did not significantly predict the price of a basket of fruit and vegetables within the sample, although baskets did decrease in price as store size increased. The highest prices were found in the smallest stores located in the most deprived areas. Availability of fruit and vegetables is lower in small shops located within deprived neighbourhoods compared to similar shops in affluent areas. Overall, availability increases with increasing store size. CONCLUSIONS: Availability of fruit and vegetables significantly varies by neighbourhood deprivation in small stores. Policies aimed at promoting sales of fruit and vegetable in these outlets may benefit residents in deprived areas. PMID- 20831709 TI - Alpha-tocopherol concentration in the colostrum of nursing women supplemented with retinyl palmitate and alpha-tocopherol. AB - BACKGROUND: Vitamins A and E are recognisably important in the initial stages of life, and the newborn depends on nutritional adequacy of breast milk to meet their needs. These vitamins share routes of transport to the tissues and antagonistic effects have been observed in animals after supplementation with vitamin A. The present study aimed to determine the effect of maternal supplementation with a megadose of retinyl palmitate in the immediate post-partum on alpha-tocopherol concentration in the colostrum. METHODS: Healthy parturient women at a Brazilian public maternity were recruited for the study and divided into two groups: control (n = 37) and supplemented (n = 36). Blood and colostrum samples were collected up to 16 h post-partum. The supplemented group was administered with a retinyl palmitate capsule and, 24 h after the first collection, the second colostrum sample was obtained in the two groups for analysis of alpha-tocopherol. The cut-off points for deficiency are <1.05 MUmol L(-1) for retinol and <11.6 MUmol L(-1) for alpha-tocopherol. RESULTS: The mean (SD) serum concentration of 1.77 (0.50) MUmol L(-1) for retinol and 30.81 (6.46) MUmol L(-1) for alpha-tocopherol indicates an adequate biochemical status. The supplemented group showed an increase of alpha-tocopherol in the colostrum 24 h after supplementation (P = 0.04), and this finding was not observed in the control group. CONCLUSIONS: Supplementation with a 200,000 IU megadose of vitamin A did not negatively affect alpha-tocopherol levels in colostrum. PMID- 20831710 TI - Dietary calcium, dairy food intake and metabolic abnormalities in HIV-infected individuals. AB - BACKGROUND: Epidemiological data suggest that calcium intake may influence lipid metabolism. It is unknown whether this influence also occurs in individuals with HIV/AIDS. The present study aimed to assess the relationship between dietary calcium, dairy food intake and metabolic parameters in individuals with HIV/AIDS. METHODS: A cross-sectional study was conducted with 100 individuals with HIV/AIDS. Calcium intakes and food group consumption were determined by a food 24 h dietary recall and a food frequency questionnaire, respectively. The level of physical activity was determined with the international physical activity questionnaire and metabolic syndrome (MS) was defined by National Cholesterol Education Program Adult Treatment Panel III (2001). Student's t-test, one-way analysis of variance and chi-square were used to compare the groups. RESULTS: The mean (SD) calcium intake was 559.5 (298.84) mg day(-1) and dairy food consumption was 1.73 (0.78) servings per day. Dietary calcium intake below 700 mg day(-1) had greater waist circumference, body mass index (BMI) but not significant and higher systolic blood pressure (SBP) (P < 0.05) and diastolic blood pressure (DBP) (P = 0.07). Dairy food consumers (>2 servings per day) showed lower BMI (P < 0.01), waist circumference (P = 0.05), SBP and DBP (P < 0.05). There was a significant association between calcium intake, MS and hypertension. The odds ratio for MS was 2.0 [95% confidence interval (CI) = 1.23-3.32] and for hypertension was 2.25 (95% CI = 1.44-4.44). Only 21% of the individuals were categorised in the moderate/intense physical activity level. CONCLUSIONS: The results obtained suggest that a dietary pattern with higher proportion of calcium and fruits/vegetables may protect against abdominal obesity and hypertension in HIV infected individuals. PMID- 20831712 TI - CD23/FcepsilonRII: molecular multi-tasking. AB - CD23 is the low-affinity receptor for immunoglobulin (Ig)E and plays important roles in the regulation of IgE responses. CD23 can be cleaved from cell surfaces to yield a range of soluble CD23 (sCD23) proteins that have pleiotropic cytokine like activities. The regions of CD23 responsible for interaction with many of its known ligands, including IgE, CD21, major histocompatibility complex (MHC) class II and integrins, have been identified and help to explain the structure-function relationships within the CD23 protein. Translational studies of CD23 underline its credibility as a target for therapeutic intervention strategies and illustrate its involvement in mediating therapeutic effects of antibodies directed at other targets. PMID- 20831713 TI - Analysis of immune cells draining from the abdominal cavity as a novel tool to study intestinal transplant immunobiology. AB - During intestinal transplant (ITx) operation, intestinal lymphatics are not reconstituted. Consequently, trafficking immune cells drain freely into the abdominal cavity. Our aim was to evaluate whether leucocytes migrating from a transplanted intestine could be recovered from the abdominal draining fluid collected by a peritoneal drainage system in the early post-ITx period, and to determine potential applications of the assessment of draining cellular populations. The cell composition of the abdominal draining fluid was analysed during the first 11 post-ITx days. Using flow cytometry, immune cells from blood and draining fluid samples obtained the same day showed an almost complete lymphopenia in peripheral blood, whereas CD3(+) CD4(+) CD8(-) , CD3(+) CD4(-) CD8(+) and human leucocyte antigen D-related (HLA-DR)(+) CD19(+) lymphocytes were the main populations in the draining fluid. Non-complicated recipients evolved from a mixed leucocyte pattern including granulocytes, monocytes and lymphocytes to an exclusively lymphocytic pattern along the first post-ITx week. At days 1-2 post-Itx, analysis by short tandem repeats fingerprinting of CD3(+) CD8(+) sorted T cells from draining fluid indicated that 50% of cells were from graft origin, whereas by day 11 post-ITx this proportion decreased to fewer than 1%. Our results show for the first time that the abdominal drainage fluid contains mainly immune cells trafficking from the implanted intestine, providing the opportunity to sample lymphocytes draining from the grafted organ along the post-ITx period. Therefore, this analysis may provide information useful for understanding ITx immunobiology and eventually could also be of interest for clinical management. PMID- 20831714 TI - Bundled payment systems: can they be more successful this time. PMID- 20831715 TI - Cost sharing, family health care burden, and the use of specialty drugs for rheumatoid arthritis. AB - OBJECTIVES: To examine the impact of benefit generosity and household health care financial burden on the demand for specialty drugs in the treatment of rheumatoid arthritis (RA). DATA SOURCES/STUDY SETTING: Enrollment, claims, and benefit design information for 35 large private employers during 2000-2005. STUDY DESIGN: We estimated multivariate models of the effects of benefit generosity and household financial burden on initiation and continuation of biologic therapies. DATA EXTRACTION METHODS: We defined initiation of biologic therapy as first-time use of etanercept, adalimumab, or infliximab, and we constructed an index of plan generosity based on coverage of biologic therapies in each plan. We estimated the household's burden by summing up the annual out-of-pocket (OOP) expenses of other family members. PRINCIPAL FINDINGS: Benefit generosity affected both the likelihood of initiating a biologic and continuing drug therapy, although the effects were stronger for initiation. Initiation of a biologic was lower in households where other family members incurred high OOP expenses. CONCLUSIONS: The use of biologic therapy for RA is sensitive to benefit generosity and household financial burden. The increasing use of coinsurance rates for specialty drugs (as under Medicare Part D) raises concern about adverse health consequences. PMID- 20831716 TI - Use of outpatient care in Veterans Health Administration and Medicare among veterans receiving primary care in community-based and hospital outpatient clinics. AB - OBJECTIVE: To examine differences in use of Veterans Health Administration (VA) and Medicare outpatient services by VA primary care patients. DATA SOURCES/STUDY SETTING: VA administrative and Medicare claims data from 2001 to 2004. STUDY DESIGN: Retrospective cohort study of outpatient service use by 8,964 community based and 6,556 hospital-based VA primary care patients. PRINCIPAL FINDINGS: A significant proportion of VA patients used Medicare-reimbursed primary care (>30 percent) and specialty care (>60 percent), but not mental health care (3-4 percent). Community-based patients had 17 percent fewer VA primary care visits (p<.001), 9 percent more Medicare-reimbursed visits (p<.001), and 6 percent fewer total visits (p<.05) than hospital-based patients. Community-based patients had 22 percent fewer VA specialty care visits (p<.0001) and 21 percent more Medicare reimbursed specialty care visits (p<.0001) than hospital-based patients, but no difference in total visits (p=.80). CONCLUSIONS: Medicare-eligible VA primary care patients followed over 4 consecutive years used significant primary care and specialty care outside of VA. Community-based patients offset decreased VA use with increased service use paid by Medicare, suggesting that increasing access to VA primary care via community clinics may fragment veteran care in unintended ways. Coordination of care between VA and non-VA providers and health care systems is essential to improve the quality and continuity of care. PMID- 20831717 TI - Hydrogen sulphide, a novel gasotransmitter involved in guard cell signalling. AB - Hydrogen sulphide (H(2) S) has been proposed as the third gasotransmitter. In animal cells, H(2) S has been implicated in several physiological processes. H(2) S is endogenously synthesized in both animals and plants by enzymes with l-Cys desulphydrase activity in the conversion of l-Cys to H(2) S, pyruvate and ammonia. The participation of H(2) S in both stomatal movement regulation and abscisic acid (ABA)-dependent induction of stomatal closure was studied in epidermal strips of three plant species (Vicia faba, Arabidopsis thaliana and Impatiens walleriana). The effect of H(2) S on stomatal movement was contrasted with leaf relative water content (RWC) measurements of whole plants subjected to water stress. In this work we report that exogenous H(2) S induces stomatal closure and this effect is impaired by the ATP-binding cassette (ABC) transporter inhibitor glibenclamide; scavenging H(2) S or inhibition of the enzyme responsible for endogenous H(2) S synthesis partially blocks ABA-dependent stomatal closure; and H(2) S treatment increases RWC and protects plants against drought stress. Our results indicate that H(2) S induces stomatal closure and participates in ABA-dependent signalling, possibly through the regulation of ABC transporters in guard cells. PMID- 20831718 TI - Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation. AB - BACKGROUND: Recently, we found that Staphylococcus aureus produces extracellular vesicles (EV) that contain pathogenic proteins. Although S. aureus infection has been linked with atopic dermatitis (AD), the identities of the causative agents from S. aureus are controversial. We evaluated whether S. aureus-derived EV are causally related to the pathogenesis of AD. METHODS: Extracellular vesicles were isolated by the ultracentrifugation of S. aureus culture media. The EV were applied three times per week to tape-stripped mouse skin. Inflammation and immune dysfunction were evaluated 48 h after the final application in hairless mice. Extracellular vesicles-specific IgE levels were measured by ELISA in AD patients and healthy subjects. RESULTS: The in vitro application of S. aureus EV increased the production of pro-inflammatory mediators (IL-6, thymic stromal lymphopoietin, macrophage inflammatory protein-1alpha, and eotaxin) by dermal fibroblasts. The in vivo application of S. aureus EV after tape stripping caused epidermal thickening with infiltration of the dermis by mast cells and eosinophils in mice. These changes were associated with the enhanced cutaneous production of IL-4, IL 5, IFN-gamma, and IL-17. Interestingly, the serum levels of S. aureus EV-specific IgE were significantly increased in AD patients relative to healthy subjects. CONCLUSION: These results indicate that S. aureus EV induce AD-like inflammation in the skin and that S. aureus-derived EV are a novel diagnostic and therapeutic target for the control of AD. PMID- 20831720 TI - Hospital protocols for the inpatient care of older adults: results from a statewide survey. AB - OBJECTIVES: To assess the prevalence of protocols or guidelines for selected domains of inpatient care for older adults; to explore associations between hospital characteristics and adoption of these guidelines or protocols. DESIGN: Telephone- and Web-based questionnaire. SETTING: General acute care hospitals in Pennsylvania. PARTICIPANTS: Chief nursing officers, directors of nursing, other hospital executives. MEASUREMENTS: Questionnaire items assessed the presence of written protocols or guidelines for selected processes of inpatient care; written guidelines, protocols, or pathways for hip fracture care; and inpatient geriatric consultation. RESULTS: Responses were obtained from 103 of 147 hospitals (70%) between June 21, 2009, and October 12, 2009. The prevalence of written protocols for general hospital practices (e.g., dosing of preoperative antibiotics, deep venous thrombosis prophylaxis) ranged from 84 of 98 (86%) to 90 of 97 (93%) respondents. Twenty of 95 (21%) and 16 of 94 (17%) respondents reported guidelines for the assessment of risk factors for delirium and for routine screening for delirium. Sixty-six of 92 respondents (72%) reported the presence of a written protocol, guideline, or pathway for hip fracture, and 61 of 100 respondents (39%) confirmed availability of inpatient geriatric consultation. No systematic differences were found in survey responses between facilities on the basis of geriatric consultation availability, hospital size, or teaching status. CONCLUSION: Hospitals vary in their adoption of protocols and guidelines for the care of older adults. Broad opportunities may exist to improve the quality of inpatient care for older adults through better dissemination and implementation of guidelines and protocols for selected geriatric conditions. PMID- 20831719 TI - How should we use age to ration health care? Lessons from the case of kidney transplantation. AB - Competing visions for health reform in the United States and renewed interest in health technology assessment (HTA) have led to fierce national debates about the appropriateness of rationing. Because of a limited supply of organs, kidney transplantation has always required rationing and overt discussion of the ethics that guide it, but the field of transplantation has also contended recently with internal calls for a new rationing system. The aim of the Life Years from Transplantation (LYFT) proposal is to allocate kidneys to patients who obtain the greatest survival benefit from transplantation, which would lengthen the lives of kidney transplant recipients but restrict the ability of older Americans to obtain a transplant. The debate around the LYFT proposal reveals the ethical and policy challenges of identifying which patients should receive a treatment based on the results of cost-effectiveness and other HTA studies. This article argues that attempts to use HTA for healthcare rationing are likely to disadvantage older patients. Guiding principles to help ensure that resources such as kidneys are justly allocated across the life span are proposed. PMID- 20831721 TI - Urinary and fecal incontinence and quality of life in African Americans. AB - OBJECTIVES: To investigate associations between quality of life (QoL) and incontinence in a population-based African-American sample. DESIGN: Cross sectional survey. SETTING: Metropolitan St. Louis, Missouri. PARTICIPANTS: Eight hundred fifty-three non-institutionalized African Americans aged 52 to 68 in the African American Health study. MEASUREMENTS: Respondents who reported having involuntarily lost urine over the previous month were classified as having urinary incontinence (UI), and respondents who reported having lost control of their bowels or stool over the past year were classified as having fecal incontinence (FI). QoL was measured using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the 11-item Center for Epidemiologic Studies Depression Scale (CES-D). RESULTS: Prevalences of UI and FI were 12.1% (weighted n=102/841) and 5.0% (weighted n=42/841). Participants with UI and those with FI had worse SF-36 scores than their referent groups (physical function -15.5 and 38.1 points, respectively; role physical -13.2 and -26.5 points; bodily pain 15.7 and -24.5 points; general health perceptions -15.5 and -27.6 points; vitality -15.0 and -16.5 points; social functioning -18.4 and -25.6 points; role emotional -13.2 and -22.1 points; mental health -12.2 and -17.5 points; all Ps<.001), adjusting for age, sex, body mass index, and chronic conditions. Proportions with clinically relevant levels of depressive symptoms were also higher in both groups (UI+17.9%; P<.001) and FI (+37.2%; P<.001) than in their referent groups. CONCLUSION: UI and FI were strongly associated with worse health related QoL as well as symptoms of depression in this population-based sample of African Americans. PMID- 20831722 TI - Association between life space and risk of mortality in advanced age. AB - OBJECTIVES: To examine the association between life space, a measure of functional status that describes the range of movement through the environment covered during daily functioning, and the risk of mortality in older community based persons. DESIGN: Two ongoing, prospective observational cohort studies of aging. SETTING: Greater metropolitan Chicago area. PARTICIPANTS: One thousand four hundred forty-five community-based older persons without dementia. MEASUREMENTS: Life space was measured at baseline using a series of questions designed to measure the extent of participants' movement throughout their environment, ranging from the bedroom to out of town. The association between life space and mortality was examined using proportional hazards models adjusted for age, sex, race, and education. RESULTS: Over up to 8 years of follow-up (mean 4.1 years), 329 of 1,445 (22.8%) participants died. In a proportional hazards model adjusted for age, sex, race, and education, a more-constricted life space was associated with a greater risk of death (hazard ratio=1.18, 95% confidence interval=1.09-1.27, P<.001), such that people with life spaces constricted to their immediate home environment (score=3) were approximately 1.6 times as likely to die as those whose life spaces included trips out of town (score=0). This association persisted after the addition of terms for several potential confounders, including physical activity, performance-based physical function, disability, depressive symptoms, social networks, body mass index, and number of chronic medical conditions. CONCLUSION: Constricted life space is associated with greater risk of death in older community-based persons. PMID- 20831723 TI - Trail-walking exercise and fall risk factors in community-dwelling older adults: preliminary results of a randomized controlled trial. AB - OBJECTIVES: To evaluate the effects of a trail-walking exercise (TWE) program on the rate of falls in community-dwelling older adults. DESIGN: Pilot randomized controlled trial (RCT). SETTING: This trial was conducted in Japan and involved community-dwelling older adults as participants. PARTICIPANTS: Sixty participants randomized into a TWE group (n=30) and a walking (W) group (n=30). INTERVENTION: Exercise class combined with multicomponent trail walking program, versus exercise class combined with simple indoor walking program. MEASUREMENT: Measurement was based on the difference in fall rates between the TWE and W groups. RESULTS: Six months after the intervention, the incidence rate ratio (IRR) of falls for the TWE group compared with the W group was 0.20 (95% confidence interval (CI)=0.04-0.91); 12 months after the intervention, the IRR of falls for the TWE group compared with the W group was 0.45 (95% CI=0.16-1.77). CONCLUSION: The results of this pilot RCT suggest that the TWE program was more effective in improving locomotion and cognitive performance under trail-walking task conditions than walking. In addition, participants who took part in the TWE demonstrated a decrease in the incidence rate of falls 6 months after trial completion. Further confirmation is needed, but this preliminary result may promote a new understanding of accidental falls in older adults. PMID- 20831724 TI - The modified total body rotation test: a rapid, reliable assessment of physical function in older adults. AB - OBJECTIVES: To describe a quick, modified measure of total body rotation with performance rankings for elderly persons and to highlight the importance of total body rotational ability for overall physical performance. DESIGN: Scores were collected during the same testing session and were compared with other measures using a Pearson correlation. SETTING: Community-based senior centers. PARTICIPANTS: One hundred forty-five participants aged 79.6+/-7.2 were recruited using flyers distributed at health fairs, senior centers, and lifelong learning programs. MEASUREMENTS: The modified total body rotation test (MTBR), the back scratch test, the modified sit-and-reach test, the 30-second chair-stand test, the Short Physical Performance Battery, and the short version of the Continuous Scale Physical Functional Performance Test. RESULTS: The MBTR significantly correlated to all standard measures of physical performance. Norms are reported for all participants, and reliability analyses were conducted using data from 18 participants. Data were divided into quintiles to create cutoffs for physical performance rankings that can be used when reporting results to the general public. CONCLUSION: Many evaluations measure isolated components of physical performance, but few examine whole body movements that allow all components necessary for independence and function to work in harmony as needed considering the task and the individual's movement strategy. The current study offers the MTBR as a quick, easy, and cost-effective evaluation method to quantify the degree of impairment or injury and the rate of improvement with treatment or training. PMID- 20831725 TI - Foot pain, plantar pressures, and falls in older people: a prospective study. AB - OBJECTIVES: To determine whether foot pain and plantar pressure are associated with falls in community-dwelling older adults. DESIGN: Community-based cohort study with 12-month prospective falls follow-up. SETTING: Sydney and Illawarra statistical regions of New South Wales, Australia. PARTICIPANTS: Randomly recruited, community-dwelling adults (158 men and 154 women) aged 60 and older. MEASUREMENTS: Manchester Foot Pain and Disability Index to establish baseline foot pain and dynamic plantar pressures. Participants were then classified as fallers (n=107) or nonfallers (n=196) based on their falls incidence over the following 12 months. RESULTS: Fallers had a significantly higher prevalence of foot pain than nonfallers (57.9% vs 42.1%; chi-square=4.0; P=.04). Fallers also generated a significantly higher peak pressure and pressure-time integral under the foot than non-fallers. In addition, individuals with foot pain had a significantly higher peak pressure and pressure-time integral under the foot than those without foot pain. CONCLUSION: High plantar pressures generated during gait may contribute to foot pain and risk of falls. Providing interventions to older people with foot pain and high plantar pressures may play a role in reducing their falls risk. PMID- 20831726 TI - Indoor and outdoor falls in older adults are different: the maintenance of balance, independent living, intellect, and Zest in the Elderly of Boston Study. AB - OBJECTIVES: To identify risk factors for indoor and outdoor falls. DESIGN: Prospective cohort study. SETTING: The MOBILIZE Boston Study, a study of falls etiology in community-dwelling older individuals. PARTICIPANTS: Seven hundred sixty-five women and men, mainly aged 70 and older, from randomly sampled households in the Boston, Massachusetts, area. MEASUREMENTS: Baseline data were collected by questionnaire and comprehensive clinic examination. During follow up, participants recorded falls on daily calendars. The location and circumstances of each fall were asked during telephone interviews. RESULTS: Five hundred ninety-eight indoor and 524 outdoor falls were reported over a median follow-up of 21.7 months. Risk factors for indoor falls included older age, being female, and various indicators of poor health. Risk factors for outdoor falls included younger age, being male, and being relatively physically active and healthy. For instance, the age- and sex-adjusted rate ratio for having much difficulty or inability to perform activities of daily living relative to no difficulty was 2.57 (95% confidence interval (CI) = 1.69-3.90) for indoor falls but 0.27 (95% CI = 0.13-0.56) for outdoor falls. The rate ratio for gait speed of less than 0.68 m/s relative to a speed of greater than 1.33 m/s was 1.48 (95% CI = 0.81-2.68) for indoor falls but 0.27 (95% CI = 0.15-0.50) for outdoor falls. CONCLUSION: Risk factors for indoor and outdoor falls differ. Combining these falls, as is done in many studies, masks important information. Prevention recommendations for noninstitutionalized older people would probably be more effective if targeted differently for frail, inactive older people at high risk for indoor falls and relatively active, healthy people at high risk for outdoor falls. PMID- 20831727 TI - The optimum follow-up period for assessing mortality outcomes in injured older adults. AB - OBJECTIVES: To compare mortality rates of hospitalized injured aged 67 and older across commonly used follow-up periods (e.g., in-hospital, 30-day, 1-year) and to determine the postinjury time after which mortality rates stabilize. DESIGN: Retrospective analysis of Medicare claims. SETTING: Oregon and Washington Medicare patients. PARTICIPANTS: Patients admitted to 171 Oregon and Washington facilities during 2001/02 with injuries identified according to International Classification of Diseases, Ninth Revision, code and followed for 1 year. MEASUREMENTS: The primary outcome was in-hospital mortality and mortality at 30, 60, 90, 180, and 365 days. Kaplan-Meier survival curves and daily postadmission mortality rates were also evaluated. The rate of change (slope) of the survival curves and daily mortality rates were analyzed to select the point after which mortality rates were no longer decreasing. RESULTS: There were 32,135 injured older adults hospitalized over the 2-year period, with a median age of 82 (interquartile range 77-88). Cumulative in-hospital mortality and at 30, 60, 90, 180, and 365 days was 4.1%, 9.7%, 13.6%, 16.1%, 21.3%, and 28.4%, respectively. Mortality rates stabilized by 6 months after injury, with 89% of the change occurring within 60 days. Although serious injuries, medical comorbidities, and preinjury nursing facility residence were all associated with higher mortality, they did not affect the pattern of mortality after injury. CONCLUSION: In hospital mortality is much lower than postdischarge mortality in injured older adults, with a substantial portion of persons dying shortly after discharge from the hospital. Mortality appears to stabilize by 6 months after injury, although 60-day postadmission follow-up captures most of the excess daily mortality rate. PMID- 20831728 TI - Habitat contrasts reveal a shift in the trophic position of ant assemblages. AB - 1. Trophic structure within a guild can be influenced by factors such as resource availability and competition. While ants occupy a wide range of positions in food webs, and ant community composition changes with habitat, it is not well understood if ant genera tend to maintain their position in the trophic structure, or if trophic position varies across habitats. 2. We used ratios of stable isotopes of carbon and nitrogen to test for differences in the trophic structure and position of assemblages of ants among habitat types. We tested for differences between assemblages in replicate sites of the land use categories: (i) pastures with old large trees; (ii) recently revegetated pastures with small young trees; and (iii) remnant woodlands. Known insect herbivores and predatory spiders provided baselines for herbivorous and predaceous arthropods. Soil samples were used to correct for the base level of isotopic enrichment at each site. 3. We found no significant interactions between land use and ant genus for isotope enrichment, indicating that trophic structure is conserved across land use categories. The fixed relative positions of genera in the trophic structure might be re-enforced by competition or some other factor. However, the entire ant assemblage had significantly lower delta(15) N values in revegetated sites, suggesting that ants feed lower down in the food chain i.e. they are more 'herbivorous' in revegetated sites. This may be a result of the high availability of plant sugars, honeydew and herbivorous arthropod prey. 4. Surprisingly, ants in remnants and pastures with trees displayed similar isotopic compositions. Interactions within ant assemblages are thus likely to be resilient to changes in land use, but ant diets in early successional habitats may reflect the simplicity of communities, which may have comparatively lower rates of saprophagy and predation. PMID- 20831729 TI - Bird community specialization, bird conservation and disturbance: the role of wildfires. AB - 1. Although niche theory predicts that disturbance should favour generalist species, the community-level implications of this pattern have been sparsely analysed. Here, we test the hypothesis that disturbance favours generalist species within communities, analysing effects of wildfires in bird communities in a Mediterranean climate area as a case study. 2. We use bird occurrence data in more than 500 1 * 1 km squares forming a gradient running from forest to completely burnt areas. The level of specialization of bird communities was estimated by means of three complementary species specialization indices, calculated for different landscape gradients and averaged at the community level (i.e. 1 * 1 km squares), and mean species rarity. 3. We also calculated mean habitat preferences along landscape gradients, as well as an index of conservation value and total species richness. 4. Different estimators of bird community specialization varied in contrasting fashion along the wildfire disturbance gradient, and thus we conclude that it is not justified to expect unique community responses to the sharp variations in habitat characteristics brought by wildfire disturbances. 5. Burnt areas tended to have rarer and urban avoider bird species, whereas unburnt forests tended to have larger proportions of forest specialist species. 6. The mean conservation value of communities clearly increased towards the burnt extreme of the wildfire disturbance gradient, while this had a negligible effect on species richness. 7. Wildfires seem to play an important role for the maintenance of open-habitat, urban-avoider bird populations in Mediterranean landscapes and also to benefit a set of bird species of unfavourable European conservation status. 8. In this context, it cannot be unambiguously concluded that fire disturbance, even in a context in which fires are greatly favoured by human-related activities, leads to more functionally simplified communities dominated by generalist species. PMID- 20831730 TI - Contrasting patterns of individual specialization and trophic coupling in two marine apex predators. AB - 1. Apex predators are often assumed to be dietary generalists and, by feeding on prey from multiple basal nutrient sources, serve to couple discrete food webs. But there is increasing evidence that individual level dietary specialization may be common in many species, and this has not been investigated for many marine apex predators. 2. Because of their position at or near the top of many marine food webs, and the possibility that they can affect populations of their prey and induce trophic cascades, it is important to understand patterns of dietary specialization in shark populations. 3. Stable isotope values from body tissues with different turnover rates were used to quantify patterns of individual specialization in two species of 'generalist' sharks (bull sharks, Carcharhinus leucas, and tiger sharks, Galeocerdo cuvier). 4. Despite wide population-level isotopic niche breadths in both species, isotopic values of individual tiger sharks varied across tissues with different turnover rates. The population niche breadth was explained mostly by variation within individuals suggesting tiger sharks are true generalists. In contrast, isotope values of individual bull sharks were stable through time and their wide population level niche breadth was explained by variation among specialist individuals. 5. Relative resource abundance and spatial variation in food-predation risk tradeoffs may explain the differences in patterns of specialization between shark species. 6. The differences in individual dietary specialization between tiger sharks and bull sharks results in different functional roles in coupling or compartmentalizing distinct food webs. 7. Individual specialization may be an important feature of trophic dynamics of highly mobile marine top predators and should be explicitly considered in studies of marine food webs and the ecological role of top predators. PMID- 20831731 TI - The danger of applying the breeder's equation in observational studies of natural populations. AB - The breeder's equation, which predicts evolutionary change when a phenotypic covariance exists between a heritable trait and fitness, has provided a key conceptual framework for studies of adaptive microevolution in nature. However, its application requires strong assumptions to be made about the causation of fitness variation. In its univariate form, the breeder's equation assumes that the trait of interest is not correlated with other traits having causal effects on fitness. In its multivariate form, the validity of predicted change rests on the assumption that all such correlated traits have been measured and incorporated into the analysis. Here, we (i) highlight why these assumptions are likely to be seriously violated in studies of natural, rather than artificial, selection and (ii) advocate wider use of the Robertson-Price identity as a more robust, and less assumption-laden, alternative to the breeder's equation for applications in evolutionary ecology. PMID- 20831732 TI - Male and female secondary sexual traits show different patterns of quantitative genetic and environmental variation in the horned beetle Onthophagus sagittarius. AB - The expression of secondary sexual traits in females has often been attributed to a correlated response to selection on male traits. In rare cases, females have secondary sexual traits that are not homologous structures to secondary sexual traits in males and are thus less likely to have evolved in females because of correlated selection. In this study, we used the dung beetle Onthophagus sagittarius, a species with sex-specific horns, to examine the environmental and quantitative genetic control of horn expression in males and females. Offspring subjected to different brood mass manipulations (dung addition/removal) were found to differ significantly in body size. Brood mass manipulation also had a significant effect on the length of male horns; however, female horn length was found to be relatively impervious to the treatment, showing stronger patterns of additive genetic variance than males. We found no correlations between horn expression in males and females. We therefore conclude that the horns of O. sagittarius females are unlikely to result from genetic correlations between males and females. Rather, our data suggest that they may be under independent genetic control. PMID- 20831733 TI - Selection for thermostability can lead to the emergence of mutational robustness in an RNA virus. AB - Mutational robustness has important evolutionary implications, yet the mechanisms leading to its emergence remain poorly understood. One possibility is selection acting on a correlated trait, as for instance thermostability (plastogenetic congruence). Here, we examine the correlation between mutational robustness and thermostability in experimental populations of the RNA bacteriophage Qbeta. Thermostable viruses evolved after only six serial passages in the presence of heat shocks, and genome sequencing suggested that thermostability can be conferred by several alternative mutations. To test whether thermostable viruses have increased mutational robustness, we performed additional passages in the presence of nitrous acid. Whereas in control lines this treatment produced the expected reduction in growth rate caused by the accumulation of deleterious mutations, thermostable viruses showed no such reduction, indicating that they are more resistant to mutagenesis. Our results suggest that selection for thermostability can lead to the emergence of mutational robustness driven by plastogenetic congruence. As temperature is a widespread selective pressure in nature, the mechanism described here may be relevant to the evolution of mutational robustness. PMID- 20831734 TI - Should we measure routinely oxidised and atherogenic dense low-density lipoproteins in subjects with type 2 diabetes? AB - Beyond low-density lipoprotein (LDL)-cholesterol concentrations, in recent years, several clinical studies have shown that both oxidised and small, dense LDL have a strong predictive role for the presence of vascular atherosclerosis. These two lipid parameters seem to have a synergistic impact on cardiovascular risk, with a greater importance in patients at higher-risk, such as those with type-2 diabetes. Increased levels of oxidised and small, dense LDL levels are a feature of diabetic dyslipidaemia, and small, dense LDL have been shown to be a good predictor of future cardiovascular events, at both univariate and multivariate analyses. On the other hand, although the association of oxidised LDL with surrogate markers of atherosclerosis is consistent, the correlation with hard clinical end points seems to be smaller. Yet, measurement of these two lipid parameters has not been widely used in daily practice because of the limited availability of clinical data and methodological problems: lack of availability of easy, cheap and reproducible essays for measurement of oxidised and, particularly, small, dense LDL has reduced their assessment in large clinical end points trials. However, on the basis of available data, the therapeutic modulation of small, dense LDL is significantly associated with reduced cardiovascular risk, even after adjustment for confounding factors. In conclusion, the routine measurement of oxidised and small, dense LDL in patients with type-2 diabetes cannot be recommended in daily clinical practice so far; yet, their measurement is strongly encouraged to better understand their role on the cardiovascular risk of patients with type-2 diabetes. PMID- 20831735 TI - How a broken tooth saved a life. PMID- 20831736 TI - Oral health status of older adults in Kentucky: results from the Kentucky Elder Oral Health Survey. AB - The purpose of the Kentucky Elder Oral Health Survey (KEOHS) was to assess the oral health status of Kentuckians 65 and older. The KEOHS consisted of a self administered questionnaire and a clinical examination. Recruitment occurred from May 2002 through March 2005 of persons aged 65 and older (n = 1,386) whose functional ability was classified by residential setting. Independent elders living in their own homes were designated as "well-elders," those who lived in skilled nursing facilities and who were functionally dependent were designated as "nursing home elders," and those older adults who were considered frail were designated as "homebound elders." Significant associations were found between the functional ability of the elders and demographic characteristics. While elders who were homebound reported the highest rate of barriers to care, dental insurance, affordability, and transportation were consistently reported as barriers for all groups of elders. This study has established the baseline oral health status of older adults in Kentucky and the data show differences that exist for various community living situations. PMID- 20831738 TI - Does information about patients who are intellectually disabled translate into better cooperation during dental visits? AB - The objective of this study was to investigate whether having background information about a patient with an intellectual disability (ID) would have a positive effect on the level of cooperation during a first dental visit. Study participants were 57 consecutive dental patients (mean age = 24.3 years, range: 4 to 69) with ID, who received a first oral examination at a center for special dental care. They were randomly assigned to a condition in which the dentist either received information about the patient prior to a dental visit (n = 29) or not (n = 28). Patients were assessed on the level of displayed cooperation, using a behavior-rating scale. Patients with less-severe levels of ID displayed better cooperation. No significant difference was found between the cooperation scores of both groups. The results suggest that the availability of comprehensive information concerning patients who are intellectually disabled prior to a dental appointment does not enhance cooperative behavior. PMID- 20831737 TI - Recruitment of rural and cognitively impaired older adults for dental research. AB - The recruitment of community-dwelling older adults, particularly those with cognitive impairment and those residing in rural areas, has been consistently challenging for researchers, especially in the dental field. This study reports on recruitment experiences from an ongoing study investigating the association between oral health and cognitive status in later life. Multiple recruitment strategies, including educational presentations and traveling to participants' homes, were used to enroll rural elderly participants with various levels of cognitive function. In general, multipronged, proactive recruitment strategies were more effective than traditional, passive methods in reaching participants with varying degrees of cognitive impairment. The outcome of this study suggests that successful recruitment of such populations involves gaining the support of staff at relevant community organizations, informing community members (including older adults and their family members) of the project and the importance of oral health, and making data collection sites accessible for older adults. PMID- 20831739 TI - Caries prevalence in patients with cerebral palsy and the burden of caring for them. AB - The aim of this study was to investigate the correlation between caries prevalence in individuals with cerebral palsy (CPG) and the burden on their caregivers (CGCP) compared to nondisabled individuals (CG) and their caregivers (CGCG). In a cross-sectional assessment, 65 subjects with cerebral palsy were evaluated for their caries prevalence. The CGCP answered the Caregiver Burden Scale (CBS) questionnaire. Using the same methodology, 58 CG were evaluated and CGCG replied to the questionnaire. The CGCP had statistically significant higher scores on general strain, isolation, disappointment, environment, and total scores using the CBS questionnaire. The CPG had significantly higher values using the Decayed, Missed and Filled (DMF) index than the CG. Values for the CBS domains in general strain and disappointment and DMF index were found to have a statistically significant correlation. Taking care of an individual with CP is a potential source of continual burden for caregivers, and there is a positive correlation between caries prevalence in individuals with CP and the burden on their caregivers. PMID- 20831740 TI - Oral health condition and treatment needs of Special Olympics athletes in Nigeria. AB - Special Olympics (SO) athletes in many parts of the world were reported to have poor oral health and high unmet treatment needs. This study was carried out to determine the oral health condition and treatment needs of SO athletes in Nigeria and to suggest ways of improving access to oral healthcare. Consenting athletes who participated in SO events in Nigeria from 2007 to 2008 received oral examination and evaluation by trained volunteers, using standardized Special Smiles screening forms and procedures designed for the event. A total of 1,286 athletes aged 3 to 71 years, 480 (37.3%) females and 806 (62.7%) males, participated in the screening. The majority (86.1%) cleaned their mouths once daily, 12.2% complained of pain, 21.1% had untreated decay, 6.6% had dental injury, 48.1% had gingival signs suggestive of periodontal disease, 15.8% required urgent treatment, and 43.7% required non-urgent treatment. We found that the oral health of SO athletes in this study was poorer than that of the general population in Nigeria. PMID- 20831741 TI - Axenfeld-Rieger syndrome (ARS): A review and case report. AB - Axenfeld-Rieger syndrome (ARS) is a rare, autosomal dominant condition characterized by ocular, craniofacial, dental, and periumbilical abnormalities. Relatively little information exists on this syndrome within the dental literature despite the fact that midface hypoplasia and maxillary hypodontia are classical presenting features of this syndrome. This is a case report of a 7-year old Caucasian female with ARS who presented with significant ocular and dental anomalies. She was also found to have osteopenia. Her dental condition is described, her immediate treatment is shown, and her long-term treatment needs are discussed. PMID- 20831742 TI - A systematic review of duloxetine and venlafaxine in major depression, including unpublished data. AB - OBJECTIVE: To determine the short-term antidepressant efficacy and tolerability of duloxetine and venlafaxine vs. each other, placebo, selective serotonin reuptake inhibitors (SSRIs), and tri- and tetracyclic antidepressants (TCAs) in adults with major depression. METHOD: Meta-analysis of randomised controlled trials identified through bibliographical databases and other sources, including unpublished manufacturer reports. RESULTS: Fifty-four studies including venlafaxine arms (n = 12,816), 14 including duloxetine arms (n = 4,528), and two direct comparisons (n = 836) were analysed. Twenty-three studies were previously unpublished. In the meta-analysis, both duloxetine and venlafaxine showed superior efficacy (higher remission and response rates) and inferior tolerability (higher discontinuation rates due to adverse events) to placebo. Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs (OR = 1.20, 95% CI 1.07-1.35 and 1.38, 95% CI 1.15-1.66, respectively), and no differences in efficacy and tolerability to TCAs. Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine (OR = 1.53, 95% CI 1.10-2.13 and OR 1.79, 95% CI 1.16-2.78, respectively). CONCLUSION: Rather than being a first-line option, venlafaxine appears to be a valid alternative in patients who do not tolerate or respond to SSRIs or TCAs. Duloxetine does not seem to be indicated as a first-line treatment. PMID- 20831743 TI - Limited expression of heparan sulphate proteoglycans associated with Abeta deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease. AB - AIMS: Alzheimer's disease (AD) is characterized by deposition of the amyloid beta (Abeta) peptide in brain parenchyma and vasculature. Several proteins co-deposit with Abeta, including heparan sulphate proteoglycans (HSPG). HSPG have been suggested to contribute to Abeta aggregation and deposition, and may influence plaque formation and persistence by stimulating Abeta fibrillization and by protecting Abeta against degradation. Mouse models for AD, expressing the human amyloid precursor protein (APP), produce Abeta deposits similar to humans. These models may be used to study disease pathology and to develop new therapeutic interventions. We aimed to investigate whether co-deposition of HSPG in AD brains can be replicated in the APPswe/PS1dE9 mouse model for AD and if a temporal association of HSPG with Abeta exists. METHODS: We studied the co-deposition of several HSPG and of the glycosaminoglycan side chains of HSPG in the APPswe/PS1dE9 model at different ages by immunohistochemistry. RESULTS: We found that, although APPswe/PS1dE9 mice did develop severe Abeta pathology with age, co deposition of HS glycosaminoglycan chains and the various HSPG (agrin, perlecan and glypican-1) was scarce (<10-30% of the Abeta deposits were stained). CONCLUSIONS: Our data suggest that the molecular composition of Abeta deposits in the APPswe/PS1dE9 mouse, with respect to the several HSPG investigated in this study, does not accurately reflect the human situation. The near absence of HSPG in Abeta deposits in this transgenic mouse model may, in turn, hinder the translation of preclinical intervention studies from mice to men. PMID- 20831744 TI - Human brain weight is correlated with expression of the 'housekeeping genes' beta 2-microglobulin (beta2M) and TATA-binding protein (TBP). AB - AIMS: Many variables affect mRNA measurements in post mortem human brain tissue. Brain weight has not hitherto been considered to be such a factor. This study examined whether there is any relationship between brain weight and mRNA abundance. METHODS: We investigated quantitative real-time RT-PCR data for five 'housekeeping genes' using the 104 adult brains of the Stanley Microarray Consortium series. Eleven data sets were analysed, from cerebellum, hippocampus, and anterior cingulate cortex. We used a specified sequence of correlations, partial correlations and multiple regression analyses. RESULTS: Brain weight correlated with the 'raw' (i.e. non-normalized) data for two mRNAs, beta2 microglobulin and TATA-binding protein, measured in cerebellum and hippocampus, respectively. In hippocampus, the geometric mean of three housekeeping gene transcripts also correlated with brain weight. The correlations were significant after adjusting for age, sex and other confounders, and the effect of brain weight was confirmed using multiple regression. No correlations with brain weight were seen in the anterior cingulate cortex, nor for the other mRNAs examined. CONCLUSIONS: The findings were not anticipated; they need replication in another brain series, and a more systematic survey is indicated. In the interim, we suggest that quantitative gene expression studies in human brain should inspect for a potential influence of brain weight, especially as the affected transcripts are commonly used as reference genes for normalization purposes in studies of neurological and psychiatric disorders. The relationship of brain weight with beta2-microglobulin mRNA may reflect the roles of major histocompatibility complex class I genes in synapse formation and plasticity. PMID- 20831745 TI - CpG island hypermethylation of the neurofibromatosis type 2 (NF2) gene is rare in sporadic vestibular schwannomas. AB - AIMS: Loss of both wild-type copies of the neurofibromatosis type 2 (NF2) gene is found in both sporadic and neurofibromatosis type 2-associated vestibular schwannomas (VS). Previous studies have identified a subset of VS with no loss or mutation of NF2. We hypothesized that methylation of NF2 resulting in gene silencing may play a role in such tumours. METHODS: Forty sporadic VS were analysed by array comparative genomic hybridization using 1 Mb whole genome and chromosome 22 tile path arrays. The NF2 genes were sequenced and methylation of NF2 examined by pyrosequencing. RESULTS: Monosomy 22 was the only recurrent change found. Twelve tumours had NF2 mutations. Eight tumours had complete loss of wild-type NF2, four had one mutated and one wild-type allele, 11 had only one wild-type allele and 17 showed no abnormalities. Methylation analysis showed low level methylation in four tumours at a limited number of CpGs. No high-level methylation was found. CONCLUSIONS: This study shows that a significant proportion of sporadic VS (>40%) have unmethylated wild-type NF2 genes. This indicates that other mechanisms, yet to be identified, are operative in the oncogenesis of these VSs. PMID- 20831746 TI - Interferon (IFN) beta treatment induces major histocompatibility complex (MHC) class I expression in the spinal cord and enhances axonal growth and motor function recovery following sciatic nerve crush in mice. AB - AIMS: Major histocompatibility complex (MHC) class I expression by neurones and glia constitutes an important pathway that regulates synaptic plasticity. The upregulation of MHC class I after treatment with interferon beta (IFN beta) accelerates the response to injury. Therefore the present work studied the regenerative outcome after peripheral nerve lesion and treatment with IFN beta, aiming at increasing MHC class I upregulation in the spinal cord. METHODS: C57BL/6J mice were subjected to unilateral sciatic nerve crush and treatment with IFN beta. The lumbar spinal cords were processed for immunohistochemistry, in situ hybridization, Western blotting and RT-PCR, while the sciatic nerves were submitted for immunohistochemistry, morphometry and counting of regenerated axons. Motor function recovery was monitored using the walking track test. RESULTS: Increased MHC class I expression in the motor nucleus of IFN beta treated animals was detected. In the peripheral nerve, IFN beta-treated animals showed increased S100, GAP-43 and p75NTR labelling coupled with a significantly greater number of regenerated axons. No significant differences were found in neurofilament or laminin labelling. The morphological findings, indicating improvements in the regenerative process after IFN treatment were in line with the motor behaviour test applied to the animals during the recovery process. CONCLUSIONS: The present data reinforce the role of MHC class I upregulation in the response to injury, and suggest that IFN treatment may be beneficial to motor recovery after axotomy. PMID- 20831748 TI - Particle puzzle pieces. PMID- 20831747 TI - Evolutionary evidence of the effect of rare variants on disease etiology. AB - The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs. PMID- 20831754 TI - A 10-year retrospective analysis of marginal bone-level changes around implants in periodontally healthy and periodontally compromised tobacco smokers. AB - AIM: to compare the 10-year marginal bone loss rates around implants supporting single-unit crowns in tobacco smokers with and without a history of treated periodontitis. MATERIALS AND METHODS: in this retrospective controlled study, 40 tobacco smokers were divided into four groups of 10 patients each. Two groups of periodontally compromised (PC) patients and two groups of periodontally healthy (PH) patients were established. PC patients had been treated for their periodontal conditions before implant placement. All patients were enrolled in a regular, individually tailored maintenance care program. For the rehabilitation of PC and PH patients, two different types of implants were used (Nobel Biocare AB; Straumann Dental Implant System). The radiographic bone loss rate was calculated by subtracting the bone levels at the time of crown delivery from the bone levels at the 10-year follow-up. RESULTS: the mean age, mean full-mouth plaque score and full-mouth bleeding score and implant location were similar for the four groups. Implant survival rates ranged between 70% and 100%, without statistically significant differences between the four groups (P>0.05). Implants placed in PC patients yielded statistically significantly higher marginal bone loss rates compared with those in PH patients (P<0.05), independent of the implant system used. CONCLUSION: after 10 years, implants placed in tobacco smokers with a history of treated periodontitis and enrolled in a supportive therapy program yielded lower survival rates and higher marginal bone loss rates compared with those of implants placed in PH smokers. These outcomes were independent of the implant system installed or the healing modality applied. PMID- 20831750 TI - Sodium channel SCN1A and epilepsy: mutations and mechanisms. AB - Mutations in a number of genes encoding voltage-gated sodium channels cause a variety of epilepsy syndromes in humans, including genetic (generalized) epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS, severe myoclonic epilepsy of infancy). Most of these mutations are in the SCN1A gene, and all are dominantly inherited. Most of the mutations that cause DS result in loss of function, whereas all of the known mutations that cause GEFS+ are missense, presumably altering channel activity. Family members with the same GEFS+ mutation often display a wide range of seizure types and severities, and at least part of this variability likely results from variation in other genes. Many different biophysical effects of SCN1A-GEFS+ mutations have been observed in heterologous expression systems, consistent with both gain and loss of channel activity. However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCN1A mutations. PMID- 20831755 TI - Resolution of surgically created three-wall intrabony defects in implants using three different biomaterials: an in vivo study. AB - OBJECTIVES: To histomorphometrically analyze bone formation on amorphous calcium phosphate (ACP), micro-macroporous biphasic calcium phosphate (MBCP), and freeze dried bone allograft (FDBA) in three-wall defects adjacent to structured surface with calcium phosphate nanocoating implants in dogs. MATERIALS AND METHODS: Five male mixed-breed dogs were used in this study. The premolars and molars were extracted on both sides of the mandible. Eight weeks after extraction, four implants were submerged on each side of the mandible. Three-wall intrabony defects (5 * 3 * 3 mm) were surgically created adjacent to the implants before installation. No grafts were placed in the control group. At the experimental sites, each intrabony defect was grafted with either ACP, MBCP, or FDBA. The dogs were sacrificed after 12 weeks, and histological and histomorphometrical analyses of the implant sites were performed. RESULTS: All of the three experimental groups exhibited defect resolution and osseointegration that showed a statistically significant difference compared with the control group in terms of remaining defect depth and bone-to-implant contact (BIC). However, there were no statistical significances among the three experimental groups. MBCP had the highest BIC (63.57 +/- 21.57%), followed by ACP and FDBA. The control group showed the least bone area and the greatest remaining defect depth. CONCLUSION: Grafts with the synthetic biomaterials ACP and MBCP showed bone regeneration that was similar to FDBA in surgically created three-wall intrabony defects adjacent to implants. Within the limitations of this study, it can be concluded that ACP and MBCP synthetic biomaterials are as effective as FDBA at osteoconduction. PMID- 20831751 TI - Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice. AB - PURPOSE: KCNJ10 encodes subunits of inward rectifying potassium (Kir) channel Kir4.1 found predominantly in glial cells within the brain. Genetic inactivation of these channels in glia impairs extracellular K(+) and glutamate clearance and produces a seizure phenotype. In both mice and humans, polymorphisms and mutations in the KCNJ10 gene have been associated with seizure susceptibility. The purpose of the present study was to determine whether there are differences in Kir channel activity and potassium- and glutamate-buffering capabilities between astrocytes from seizure resistant C57BL/6 (B6) and seizure susceptible DBA/2 (D2) mice that are consistent with an altered K(+) channel activity as a result of genetic polymorphism of KCNJ10. METHODS: Using cultured astrocytes and hippocampal brain slices together with whole-cell patch-clamp, we determined the electrophysiologic properties, particularly K(+) conductances, of B6 and D2 mouse astrocytes. Using a colorimetric assay, we determined glutamate clearance capacity by B6 and D2 astrocytes. RESULTS: Barium-sensitive Kir currents elicited from B6 astrocytes are substantially larger than those elicited from D2 astrocytes. In addition, potassium and glutamate buffering by D2 cortical astrocytes is impaired, relative to buffering by B6 astrocytes. DISCUSSION: In summary, the activity of Kir4.1 channels differs between seizure-susceptible D2 and seizure-resistant B6 mice. Reduced activity of Kir4.1 channels in astrocytes of D2 mice is associated with deficits in potassium and glutamate buffering. These deficits may, in part, explain the relatively low seizure threshold of D2 mice. PMID- 20831756 TI - Influence of abutment material on the fracture strength and failure modes of abutment-fixture assemblies when loaded in a bio-faithful simulation. AB - OBJECTIVES: The aim of the present study was to evaluate differences in the ultimate fracture resistance of titanium and zirconia abutments. MATERIAL AND METHODS: Twenty titanium fixtures were embedded in 20 resin mandible section simulators to mimic osseointegrated implants in the premolar area. The embedded implants were then randomly divided into two groups. Afterwards, specimens in group A (n=10) were connected to titanium abutments (TiDesignTM 3.5/4.0, 5.5, 1.5 mm), while specimens in group B (n=10) were connected to zirconia abutments (ZirDesign TM 3.5/4.0, 5.5, 1.5 mm). Both groups were loaded to failure in a dynamometric testing machine. Fractured samples were then analyzed by scanning electron microscopy (SEM). RESULTS: Group A showed a significantly higher fracture strength than that observed in group B. Group A failures were observed at the screw that connects the abutment with the implant while the abutment connection hexagons were plastically bent by the applied load. Group B failures were a result of abutment fractures. SEM analysis showed that in group A the screw failure was driven by crack nucleation, coalescence and propagation, while in group B, the SEM analysis of failed surfaces showed the conchoidal fracture profile characteristic of brittle materials. CONCLUSIONS: The strength of both tested systems is adequate to resist physiologic chewing forces in the premolar area. Conversely, the titanium and zirconia failure modes evaluated here occurred at unphysiological loads. In addition, because the abutments were tested without crowns, the presented data have limited direct transfer to the clinical situation. PMID- 20831757 TI - Peripheral quantitative computer tomographic, histomorphometric, and removal torque analyses of two different non-coated implants in a rabbit model. AB - OBJECTIVE: The objectives of this study were (1) to investigate the bone-tissue response to zirconia and titanium implants at the implant-to-bone interface and at the periosteal level and (2) to quantitatively measure the mineral density of the peri-implant bone using peripheral quantitative computer tomography (pQCT). MATERIAL AND METHODS: Ten 3.5 mm * 6.6 mm screw-shaped threaded implants fabricated from titanium and zirconia were inserted into the mid-tibial diaphysis of five male New Zealand white rabbits. Calcein green was administered at 4 weeks post-implantation. The animals were sacrificed after 6 weeks and implants were retrieved and analyzed in terms of bone-to-implant contact (BIC), bone area (BA), mineralized surface (MS) percentage, inter-thread calcein labels, removal torque (RT) values, as well as pQCT measurements. FINDINGS: No statistically significant differences were detected between the zirconia and titanium implants in terms of BIC, RT, and pQCT. However, statistically significant higher BA and MS levels were found in the titanium group, while the higher amount of calcein labels occupying the threads were found in the zirconium group. Significant differences were also found in the quantity and the composition of bone at the bone-implant interfacial area vs. the region 1.5 mm away from the bone-implant interface, irrespective of the implant type. CONCLUSION: Zirconia implants demonstrated a lower bone remodeling activity in the periosteal region. The bone at the bone implant interface shows a significantly lower cortical bone density, a higher trabecular density, and trabecular mineral content. Finally, zirconia and titanium implants showed similar bone-implant responses in terms of BIC and RT. PMID- 20831758 TI - Maxillary sinus floor elevation with bovine bone mineral combined with either autogenous bone or autogenous stem cells: a prospective randomized clinical trial. AB - AIM: To assess whether differences occur in bone formation after maxillary sinus floor elevation surgery with bovine bone mineral (BioOss((r))) mixed with autogenous bone or autogenous stem cells. The primary endpoint was the percentage of new bone three months after the elevation procedure. MATERIAL AND METHODS: In a randomized, controlled split-mouth design, in 12 consecutive patients (age 60.8 +/- 5.9 years, range 48-69 years) needing reconstruction of their atrophic maxilla, a bilateral sinus floor augmentation procedure was performed. Randomly, on one side the augmentation procedure was performed with bovine bone mineral (BioOss((r))) seeded with mononuclear stem cells harvested from the posterior iliac crest (test group) while BioOss((r)) mixed with autogenous bone (harvested from the retromolar area) was applied on the contra-lateral side (control group). On 14.8 +/- 0.7 weeks after the sinus floor elevation, biopsies from the reconstructed areas were taken at the spots where subsequently the endosseous implants were placed. The biopsies were histomorphometrically analyzed. RESULTS: Significantly more bone formation was observed in the test group (17.7 +/- 7.3%) when compared with the control group (12.0%+/- 6.6; P=0.026). In both the test and control group, all implants could be placed with primary stability. In one patient, not all biopsies contained BioOss((r)). This patient was excluded from analysis. CONCLUSION: Mesenchymal stem cells seeded on BioOss((r)) particles can induce the formation of a sufficient volume of new bone to enable the reliable placement of implants within a time frame comparable with that of applying either solely autogenous bone or a mixture of autogenous bone and BioOss((r)). This technique could be an alternative to using autografts. PMID- 20831759 TI - Ridge dimensions of the edentulous posterior maxilla: a retrospective analysis of a cohort of 127 patients using computerized tomography data. AB - OBJECTIVES: to evaluate the edentulous ridge dimensions of maxillary posterior sextants with a tridimensional radiographic technique. The influence of the presence/absence of teeth adjacent to the edentulous site on the dimensions of the edentulous ridge was also evaluated. MATERIAL AND METHODS: computerized tomography (CT) scans of 127 patients (65 males and 62 females; mean age: 55.2 +/ 10.1 years) with at least one missing tooth in the maxillary posterior sextants were analyzed. On CT cross sections, bone height (BH), bone width (BW) at 1, 3, and 7 mm from the most coronal point of the alveolar crest (BW(1 mm) , BW(3 mm) , and BW(7 mm) , respectively) and the relative vertical ridge position (rVRP) were assessed at the first premolar, second premolar, first molar and second molar edentulous sites. RESULTS: the results of the study indicate that (i) the maxillary sinus was radiographically evident in about 50% of first premolar sites and 90-100% of second premolar and molar sites; (ii) BH showed a significant decrease from first premolar to molar sites; (iii) BW(1 mm) was higher at second molar site compared with the first and second premolar sites, BW(3 mm) and BW(7 mm) were higher at each molar site compared with each premolar site; (iv) the proportion of sites with BH >= 8mm and BWI mm >= 6mm was 28.3%, 18.4%, 8.0% and 18.2% [corrected] at first premolar, second premolar, first molar and second molar sites, respectively. The absence of teeth adjacent to the edentulous site negatively affected rVRP, but not BH and BW. CONCLUSIONS: The results of the study indicate that at premolar and molar sites, [corrected] the dimensions of the alveolar crest may call for bone augmentation procedures for proper implant placement in a substantial amount of edentulous patients. When both mesial and distal tooth adjacent to the edentulous site are absent, the placement of implants of adequate dimensions may be more challenging due to a more apical position of the alveolar ridge compared with sites where both adjacent teeth are present. PMID- 20831760 TI - Couple and Family Therapy theory and practice: innovations in 2010. PMID- 20831761 TI - How queer!--the development of gender identity and sexual orientation in LGBTQ headed families. AB - This paper focuses on the impact of heteronormativity on research and clinical theory, utilizing the case of a lesbian couple with a young gender dysphoric child as a backdrop to discuss the contextual unfolding of gender development within a lesbian parented family. The extant research on LGBTQ-headed families has minimized the complexity of children's developing gender identity and sexual orientation living in queer families, and has been guided by heteronormative assumptions that presume a less optimal outcome if the children of LGBTQ parents are gay or transgender themselves. This article challenges family therapists to recognize the enormous societal pressure on LGBTQ parents to produce heterosexual, gender-normative children, and the expectations on their children, especially those questioning their own sex or gender identities. PMID- 20831762 TI - What is queer about sex?: expanding sexual frames in theory and practice. AB - Psychotherapists often believe if couples improve their communication and emotional dynamics, good sex follows. In practice we often find otherwise and have many questions about how to proceed to work with sexuality issues more directly. This paper presents the many challenges working with sex including the following: the fluidity and multidimensionality of sex and gender, the incongruities and paradoxes in sexual behavior, thoughts, attractions, feelings, and sensations, and the powerful feelings, impasses, surprises, and confusion therapists often experience doing the work. In essence, what is queer about sex? Using the couple as client, expansive ways of thinking and working with sexuality are presented including the development of inclusive models of sex, gender, and sexual response, as well as new approaches to standard sex therapy techniques such as sexual history-taking, redefining sex, and sensate focus. Techniques are presented with an emphasis on the therapist's use of self as sexual change agent including integrating multiple theoretical perspectives (psychodynamic, systemic, and cognitive-behavioral), co-creating a safe treatment frame, and how to intervene within the cognitive, affective, behavioral, somatic, and discursive realms. PMID- 20831763 TI - Changing constructions of machismo for Latino men in therapy: "the devil never sleeps". AB - This paper presents current narratives about masculinity that question simplistic negative stereotypes of machismo for Latino heterosexual men. Various models of masculinity within Latino cultures are described using evidence from ethnographic studies, research data, and clinical observation. Therapeutic advantages of including positive cultural masculine traits such as respect and dignity are illustrated with an extensive case study. The case highlights contradictions in the coexistence of constructions of masculinity and traces progressive stages for transforming these constructions. In this strength-based approach, attention is directed to elements of cultural memory that reclaim a strong relational ethic present in the indigenous cultures. "Within the culture" definitions of masculinity contribute alternative constructions toward a more empowering cultural narrative for Latino men than the usual negative stereotypes. PMID- 20831764 TI - Spiritual diversity: multifaith perspectives in family therapy. AB - This paper addresses the growing diversity and complexity of spirituality in society and within families. This requires a broadly inclusive, multifaith approach in clinical training and practice. Increasingly, individuals, couples, and families seek, combine, and reshape spiritual beliefs and practices--within and among faiths and outside organized religion--to fit their lives and relationships. With rising faith conversion and interfaith marriages, the paper examines challenges in multifaith families, particularly with marriage, childrearing, and the death of a loved one. Clinical guidelines, cautions, and case examples are offered to explore the role and significance of spiritual beliefs and practices in couple and family relationships; to identify spiritual sources of distress and relational conflict; and to draw potential spiritual resources for healing, well-being, and resilience, fitting client values and preferences. PMID- 20831765 TI - Positioning oneself within an epistemology: refining our thinking about integrative approaches. AB - Integrative approaches seem to be paramount in the current climate of family therapy and other psychotherapies. However, integration between and among theories and practices can only occur within a specific epistemology. This article makes a distinction between three different epistemologies: individualizing, systems, and poststructural. It then makes the argument that one can integrate theories within epistemologies and one can adopt practices and some theoretical concepts across theories and across epistemologies, but that it is impossible to integrate theories across epistemologies. It further states that although social constructionism has influenced much of contemporary psychological thinking, because of the divergence between a structural and a poststructural approach, constructionism looks different depending upon one's epistemological stance. Examples of integration within epistemologies and of what looks like integration across epistemologies (but is not) further illustrate these important distinctions. The conclusions reached here are crucial to our philosophical considerations, our pedagogical assumptions, and implications for both research and a reflexive clinical practice. PMID- 20831766 TI - A socio-emotional approach to couple therapy: linking social context and couple interaction. AB - This paper introduces Socio-Emotional Relationship Therapy (SERT), an approach designed to intervene in socio-cultural processes that limit couples' ability to develop mutually supportive relationships, especially within heterosexual relationships. SERT integrates recent advances in neurobiology and the social context of emotion with social constructionist assumptions regarding the fluid and contextual nature of gender, culture, personal identities, and relationship patterns. It advances social constructionist practice through in-session experiential work focused on 4 conditions foundational to mutual support--mutual influence, shared vulnerability, shared relationship responsibility, and mutual attunement. In contrast to couple therapy models that mask power issues, therapist neutrality is not considered possible or desirable. Instead, therapists position themselves to counteract social inequalities. The paper illustrates how empathic engagement of a socio-culturally attuned therapist sets the stage for new socio-cultural experience as it is embodied neurologically and physically in the relationship and discusses therapy as societal intervention. PMID- 20831767 TI - Teaching and learning with therapists who work with street children and their families. AB - Providing training for people working with some of the most marginalized families in Guatemala and Peru meant establishing credibility as a facilitator; entering organizations as a learner; cocreating training agendas; and working in a format that paralleled a strength-based, resilience focus in therapy. Strategies used for different phases of the work are detailed: multiple ways to gather information, shadowing staff, delivering topics on demand, and creating learning environments with a focus on families as teachers. Key processes included moving in and out of the role of facilitator and participant, entering into the trainings from different vantage points within the organizations, and designing activities with an eye to how they would impact work relationships of staff and clients. PMID- 20831768 TI - Location of self: opening the door to dialogue on intersectionality in the therapy process. AB - This article describes the evolution and current practice of a model of location of self, a process in which the therapist self-discloses her or his social locations and invites a conversation about how the intersection of the identities held by the therapist and family may be beneficial and/or limiting. It invites thoughtfulness and dialogue in recognizing and addressing explicit and implicit ways that experience, with its associated privilege or subjugation in the world, can operate in the therapy room. It signifies that the therapist is open to exploring how these issues influence clients' lives outside of therapy as well. The conceptual foundations for location of self, along with its clinical development, are discussed, including the social justice perspective in which it is firmly embedded. Clinical benefits and challenges in its use are also noted. PMID- 20831769 TI - Families as navigators and negotiators: facilitating culturally and contextually specific expressions of resilience. AB - A social ecological model of resilience is used to show that resilience is dependent on a family's ability to both access available resources that sustain individual and collective well-being, as well as participate effectively in the social discourse that defines which resources are culturally and contextually meaningful. In this paper both clinical evidence and a review of the research inform an integrated social ecological model of practice that is focused on advocating for the mental health resources necessary to nurture resilience, including the individual and family processes of coconstruction of meaning. Family therapists can help marginalized families living in challenging contexts develop skills as both navigators who access resources, as well as negotiators who are able to convince therapists and other service providers of what are culturally and contextually meaningful sources of support. A case study of an African-Canadian youth and his family will be presented. The implications of this approach to assessing therapeutic outcomes will also be discussed. PMID- 20831770 TI - Stage IV marginal zone B-cell lymphoma--prognostic factors and the role of rituximab: Consortium for Improving Survival of Lymphoma (CISL) study. AB - Stage IV marginal zone B-cell lymphomas (MZL) are detected in more than 25% of lymphoma patients. In this study, we conducted retrospective analyses of specific cases of stage IV MZL in order to assess their clinical features, as well as the treatments and prognoses of these cases. A total of 94 patients with histological diagnosis of stage IV-MZL from 17 different institutions in Korea were included. Multiple-mucosa-associated lymphoid tissue (MALT)-organs-involved MZL (M-MZL) was detected in 34 patients (36.2%). Bone-marrow-involved stage IV MZL (BM-MZL) was detected in 33 patients (35.1%). Median time to progression (TTP) was 2.4years (95% CI, 1.9-2.9). Five- and 10-year overall survival rates were 84.5% and 79.8%, respectively. Patients with lymph node involvement in stage IV MZL appeared to have worse prognoses in TTP (P=0.015). Thirty-one patients were treated with a regimen including rituximab (CTx-R[+]), and 31 with a regimen that did not include rituximab (CTx-R[-]). The CTx-R(+) group showed better responses than the CTx-R(-) group (83.9%versus 54.8%, P=0.026). However, no differences in TTP duration were detected (P=0.113). Stage IV MZL tend to follow an indolent disease course. Therefore, lymph node involvement is a more valuable prognostic factor for TTP. Rituximab appears to contribute to better responses, but not in cases of TTP. PMID- 20831771 TI - Natural course of idiopathic oligozoospermia: comparison of mild, moderate and severe forms. AB - OBJECTIVES: To investigate the natural courses of mild, moderate and severe idiopathic oligozoospermia, and which factors or semen variables were of utmost importance in predicting the courses. METHODS: A total of 208 men (age 29 47years) who were diagnosed with mild, moderate and severe idiopathic oligozoospermia in a 9-year-period between January 2000 and December 2008 were followed up for more than 6months. RESULTS: Overall, 16 (24.6%) of 65 patients with severe oligozoospermia developed azoospermia, whereas two (3.1%) patients with moderate oligozoospermia developed azoospermia and none of the patients with mild oligozoospermia developed azoospermia. Initial follicle stimulating hormone level and testicular volume between the subgroups were significantly different (P=0.0071 and 0.0039, respectively). The subgroup of patients who became azoospermic (n=18) showed statistically significant differences in terms of body mass index and the level of prolactin (PRL) from the subgroup that maintained the initial lingering sperm count (n=190; P=0.0086 and 0.0154, respectively). As the vitality of semen variables increased 1%, the risk of progression to azoospermia diminished by 0.892-fold, according to Cox's proportional hazards model analysis. A receiver operating characteristic curve analysis showed that the area under the curve was 0.755 and the sperm concentration value with the highest sensitivity and specificity was the reference value of 3-5 million/mL, with a sensitivity of 0.746 and specificity of 0.711 (P=0.01). CONCLUSIONS: Patients with severe oligozoospermia should be warned of the possibility of becoming azoospermic and hence sperm freezing should be encouraged as early as possible. PMID- 20831772 TI - Ruptured internal carotid artery dorsal wall aneurysm; its clinical features and treatment. PMID- 20831773 TI - EFNS guidelines for the diagnosis and management of Alzheimer's disease. AB - BACKGROUND AND OBJECTIVES: In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non-Alzheimer dementias are not included in this guideline. METHODS: The task force working group reviewed evidence from original research articles, meta-analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS: The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline. CONCLUSION: A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non-evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD. PMID- 20831774 TI - Ruptured symptomatic internal carotid artery dorsal wall aneurysm with rapid configurational change. Clinical experience and management outcome: an original article. AB - BACKGROUND: Aneurysms located at non-branching sites, protruding from the dorsal wall of the supraclinoid internal carotid artery (ICA) with rapid configurational changes, were retrospectively reviewed in effort to identify and characterize these high-risk aneurysms. METHODS: A total of 447 patients with 491 intracranial aneurysms were treated from March 2005 to August 2008, and of these, eight patients had ICA dorsal wall aneurysms. Four of them suffered subarachnoid hemorrhage (SAH), and all had aneurysms undergoing rapid configuration changes during the treatment course. Digital subtraction cerebral angiography (DSA) performed soon after the SAH events. Data analyzed were patient age, sex, Hunt and Kosnik grade, time interval from first DSA to second DSA, aneurysm treatment, and modified Rankin scale score after treatment for 3 months. Success or failure of therapeutic management was examined among the patients. RESULTS: Digital subtraction cerebral angiography showed only lesions with small bulges in the dorsal walls of the ICAs. However, the patients underwent DSA again for re bleeding or for post-treatment follow-up, confirming the SAH source. ICA dorsal wall aneurysms with rapid growth and configurational changes were found on subsequent DSA studies. CONCLUSIONS: Among the four patients, ICA dorsal wall aneurysms underwent rapid growth with configurational change from a blister type to a saccular type despite different management. ICA trapping including the lesion segment can be considered as the first treatment option if the balloon occlusion test (BOT) is successful. If a BOT is not tolerated by the patient, extracranial-intracranial bypass revascularization surgery with endovascular ICA occlusion is another treatment option. PMID- 20831775 TI - Isolation of biologically active nanomaterial (inclusion bodies) from bacterial cells. AB - BACKGROUND: In recent years bacterial inclusion bodies (IBs) were recognised as highly pure deposits of active proteins inside bacterial cells. Such active nanoparticles are very interesting for further downstream protein isolation, as well as for many other applications in nanomedicine, cosmetic, chemical and pharmaceutical industry.To prepare large quantities of a high quality product, the whole bioprocess has to be optimised. This includes not only the cultivation of the bacterial culture, but also the isolation step itself, which can be of critical importance for the production process.To determine the most appropriate method for the isolation of biologically active nanoparticles, three methods for bacterial cell disruption were analyzed. RESULTS: In this study, enzymatic lysis and two mechanical methods, high-pressure homogenization and sonication, were compared.During enzymatic lysis the enzyme lysozyme was found to attach to the surface of IBs, and it could not be removed by simple washing. As this represents an additional impurity in the engineered nanoparticles, we concluded that enzymatic lysis is not the most suitable method for IBs isolation.During sonication proteins are released (lost) from the surface of IBs and thus the surface of IBs appears more porous when compared to the other two methods. We also found that the acoustic output power needed to isolate the IBs from bacterial cells actually damages proteins structures, thereby causing a reduction in biological activity.High-pressure homogenization also caused some damage to IBs, however the protein loss from the IBs was negligible. Furthermore, homogenization had no side-effects on protein biological activity. CONCLUSIONS: The study shows that among the three methods tested, homogenization is the most appropriate method for the isolation of active nanoparticles from bacterial cells. PMID- 20831777 TI - 'Palliative care': a contradiction in terms? A qualitative study of cancer patients with a Turkish or Moroccan background, their relatives and care providers. AB - BACKGROUND: Palliative cancer care aims to improve quality of life and ultimately quality of dying, while prolonging life is not an objective anymore when death nears. The question is, however, whether these perspectives on palliative care are congruent with the perspectives of immigrant families with a Turkish or Moroccan background. METHODS: A qualitative design was used as we were looking for the personal views of 'very ill' cancer patients with a Turkish or Moroccan background, their family members and their Dutch care providers. We interviewed 83 people, involved in 33 cases to obtain information about their views, values and norms on 'good care'. RESULTS: The main concerns about 'good care' expressed by Turkish and Moroccan families were: maximum treatment and curative care until the end of their lives, never having hope taken away, devoted care by their families, avoiding shameful situations, dying with a clear mind and being buried in their own country. Their views conflict, to some extent, with the dominant principles in palliative care, for example, the emphasis on quality of life and advanced care planning, which includes discussing diagnosis and prognosis with the patient. CONCLUSIONS: Patients and their families with a Turkish or Moroccan background often have different ideas about 'good care' than their Dutch care providers. As many of them are aiming at cure until the end of life, they find 'good palliative care' a contradiction in terms. PMID- 20831776 TI - The Belgian MIRA (MabThera In Rheumatoid Arthritis) registry: clues for the optimization of rituximab treatment strategies. AB - INTRODUCTION: This study describes the results of the Belgian 'MabThera In Rheumatoid Arthritis (MIRA)' registry: effectiveness, safety and evaluation of the current retreatment practice on the background of the Belgian reimbursement criteria for rituximab. METHODS: All Belgian rheumatologists had the possibility to participate in the study. Patients entered the registry in November 2006 and the entry is still open. RESULTS: By mid-September 2009, 401 patients had entered the registry with a mean follow-up time of 70 weeks. Overall, DAS28-ESR decreased from 6.0 at baseline to 4.2 at week 16. Further decrease of disease activity was observed at the end of year 1 and year 2 with mean DAS28-ESR of 4.0 and 3.7 at these respective time points. More than 80% of patients showed a EULAR response at week 16. Patients could be retreated if they had DAS scores of > 3.2 at least 6 months after the previous course. Second and third courses were given in 224 and 104 patients, respectively. At month 6 after the second course, significantly lower DAS28-ESR values were observed compared to the first course. This was especially the case for patients who were retreated before they showed an obvious flare (DAS increase > 1.2). CONCLUSIONS: This study describes the follow-up of a daily clinical practice cohort of 401 RA patients with long-standing refractory disease treated with rituximab. Relatively high DAS28 values at the start of each retreatment, compared to values 6 months after each treatment course, were noted. Moreover, further decrease of DAS28 scores after the second course was significantly more pronounced in those patients who didn't show an obvious flare. These two elements suggest that treatment of RA patients with rituximab could be optimized by earlier retreatment. PMID- 20831778 TI - Microemboli-monitoring during the acute phase of ischemic stroke: is it worth the time? AB - BACKGROUND: The prevalence of microembolic signals (MES) during the acute phase of ischemic stroke and its influence on outcome is not well studied. The aim of our study was to determine the prevalence of MES, the different factors that are associated with the presence of MES and the association between MES and outcomes in stroke patients investigated within 6 hours after the onset of ischemic stroke. METHODS: We included unselected ischemic stroke patients who underwent microemboli-monitoring within six hours after stroke onset. Microemboli monitoring of both middle cerebral arteries (MCA) was done for a period of 1 hour using 2-MHz probes applied over the trans-temporal window. Prevalence of MES, predictors for the presence of MES and the association between MES and various outcome factors were analyzed. RESULTS: Forty patients were included. The mean age of the patients was 70 years. The prevalence of either ipsilateral or contralateral MES were 25% (n = 10). The predictors for the presence of MES were older age (OR 9; p = 0.03), higher NIHSS (OR 28; p = 0.02), intracranial stenosis (OR 10; p = 0.04) and embolic stroke (large-artery atherosclerosis and cardioembolism on TOAST classification) (OR 7; p = 0.06). MES were not independently associated with short-term functional outcome, long-term mortality or future vascular events. CONCLUSIONS: MES are moderately frequent following acute ischemic stroke. Microemboli-monitoring helps to better classify the stroke etiology. However, the presence MES did not have any prognostic significance in this study. PMID- 20831779 TI - Partial third nerve palsy after Measles Mumps Rubella vaccination. AB - BACKGROUND: Measles Mumps Rubella (MMR) vaccination is known to cause some serious adverse events, such as fever, rash, gland inflammation and neurologic disorders. These include third and sixth cranial nerve palsies. RESULTS: The case reported describes a partial recurrent oculomotor palsy associated with systemic symptoms following MMR vaccination in a healthy young child. The oculomotor palsy did not recover completely during the follow-up. CONCLUSIONS: Most of the times, measles, mumps and rubella cause mild illness and discomfort; but can also have serious or fatal sequelae. MMR vaccination has been proved to be safe and to reduce significantly the number of reported infections due to these viruses. However, significant adverse events can occur and paediatricians and public health operators should be aware of this aspect. PMID- 20831780 TI - Survival and health status of DOTS tuberculosis patients in rural Lao PDR. AB - BACKGROUND: Contact tracing of tuberculosis (TB) patients is rarely performed in low-income countries. Our objective was to assess the outcome of and compliance with directly observed treatment (DOTS) of TB patients over a 3 year period in rural Lao PDR. METHODS: We performed a retrospective cohort study in which we enrolled TB patients who started DOTS treatment at Attapeu Provincial Hospital. We traced, through hospital records, all patients in their residential village. We conducted a standardized questionnaire with all TB patients and performed physical and anthropometric examinations as well as evaluations of compliance through counting of treatment pills at home and at the health facilities. RESULTS: Of 172 enrolled TB patients (sex ratio female/male: 0.52, mean age: 46.9 years +/- 16.9), 26 (15.1%) died. These had a lower weight at the start (34.6 vs. 40.8 kg, p < 0.001) and were less compliant (91.6% vs. 19.2%, p < 0.001) than survivors. Low compliance was associated with poor accessibility to health care (p = 0.01) and symptomatic improvement (p = 0.02). Survivors had persistently poor health status. They were underweight (54.7%), and still had clinical symptoms (53.5%), including dyspnoea (28.8%) and haemoptysis (9.5%). CONCLUSION: Our study suggests a lower rate of survival than expected from official statistics. Additionally, it showed that follow-up of TB patients is feasible although the patients lived in very remote area of Laos. Follow-up should be strengthened as it can improve patient compliance, and allow contact tracing, detection of new cases and collection of accurate treatment outcome information. PMID- 20831781 TI - Periodic pattern detection in sparse boolean sequences. AB - BACKGROUND: The specific position of functionally related genes along the DNA has been shown to reflect the interplay between chromosome structure and genetic regulation. By investigating the statistical properties of the distances separating such genes, several studies have highlighted various periodic trends. In many cases, however, groups built up from co-functional or co-regulated genes are small and contain wrong information (data contamination) so that the statistics is poorly exploitable. In addition, gene positions are not expected to satisfy a perfectly ordered pattern along the DNA. Within this scope, we present an algorithm that aims to highlight periodic patterns in sparse boolean sequences, i.e. sequences of the type 010011011010... where the ratio of the number of 1's (denoting here the transcription start of a gene) to 0's is small. RESULTS: The algorithm is particularly robust with respect to strong signal distortions such as the addition of 1's at arbitrary positions (contaminated data), the deletion of existing 1's in the sequence (missing data) and the presence of disorder in the position of the 1's (noise). This robustness property stems from an appropriate exploitation of the remarkable alignment properties of periodic points in solenoidal coordinates. CONCLUSIONS: The efficiency of the algorithm is demonstrated in situations where standard Fourier-based spectral methods are poorly adapted. We also show how the proposed framework allows to identify the 1's that participate in the periodic trends, i.e. how the framework allows to allocate a positional score to genes, in the same spirit of the sequence score. The software is available for public use at http://www.issb.genopole.fr/MEGA/Softwares/iSSB_SolenoidalApplication.zip. PMID- 20831782 TI - Routine resite of peripheral intravenous devices every 3 days did not reduce complications compared with clinically indicated resite: a randomised controlled trial. AB - BACKGROUND: Peripheral intravenous device (IVD) complications were traditionally thought to be reduced by limiting dwell time. Current recommendations are to resite IVDs by 96 hours with the exception of children and patients with poor veins. Recent evidence suggests routine resite is unnecessary, at least if devices are inserted by a specialised IV team. The aim of this study was to compare the impact of peripheral IVD 'routine resite' with 'removal on clinical indication' on IVD complications in a general hospital without an IV team. METHODS: A randomised, controlled trial was conducted in a regional teaching hospital. After ethics approval, 362 patients (603 IVDs) were randomised to have IVDs replaced on clinical indication (185 patients) or routine change every 3 days (177 patients). IVDs were inserted and managed by the general hospital medical and nursing staff; there was no IV team. The primary endpoint was a composite of IVD complications: phlebitis, infiltration, occlusion, accidental removal, local infection, and device-related bloodstream infection. RESULTS: IVD complication rates were 68 per 1,000 IVD days (clinically indicated) and 66 per 1,000 IVD days (routine replacement) (P = 0.86; HR 1.03; 95% CI, 0.74-1.43). Time to first complication per patient did not differ between groups (KM with log rank, P = 0.53). There were no local infections or IVD-related bloodstream infections in either group. IV therapy duration did not differ between groups (P = 0.22), but more (P = 0.004) IVDs were placed per patient in the routine replacement (mean, 1.8) than the clinical indication group (mean, 1.5), with significantly higher hospital costs per patient (P < 0.001). CONCLUSIONS: Resite on clinical indication would allow one in two patients to have a single cannula per course of IV treatment, as opposed to one in five patients managed with routine resite; overall complication rates appear similar. Clinically indicated resite would achieve savings in equipment, staff time and patient discomfort. There is growing evidence to support the extended use of peripheral IVDs with removal only on clinical indication. REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR) Number ACTRN12608000421336. PMID- 20831783 TI - Analyzing the regulation of metabolic pathways in human breast cancer. AB - BACKGROUND: Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. METHODS: For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. RESULTS: Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. CONCLUSION: We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment. PMID- 20831784 TI - Differential detection of alternatively spliced variants of Ciz1 in normal and cancer cells using a custom exon-junction microarray. AB - BACKGROUND: Ciz1 promotes initiation of mammalian DNA replication and is present within nuclear matrix associated DNA replication factories. Depletion of Ciz1 from normal and cancer cells restrains entry to S phase and inhibits cell proliferation. Several alternative splicing events with putative functional consequences have been identified and reported, but many more variants are predicted to exist based on publicly available mRNAs and expressed sequence tags. METHODS: Here we report the development and validation of a custom exon and exon junction microarray focused on the human CIZ1 gene, capable of reproducible detection of differential splice-variant expression. RESULTS: Using a pair of paediatric cancer cell lines and a pool of eight normal lines as reference, the array identified expected and novel CIZ1 splicing events. One novel variant (delta 8-12) that encodes a predicted protein lacking key functional sites, was validated by quantitative RT-PCR and found to be over-represented in a range of other cancer cell lines, and over half of a panel of primary lung tumours. CONCLUSIONS: Expression of CIZ1 delta 8-12 appears to be restricted to cancer cells, and may therefore be a useful novel biomarker. PMID- 20831785 TI - Assessment of nerve involvement in the lumbar spine: agreement between magnetic resonance imaging, physical examination and pain drawing findings. AB - BACKGROUND: Detection of nerve involvement originating in the spine is a primary concern in the assessment of spine symptoms. Magnetic resonance imaging (MRI) has become the diagnostic method of choice for this detection. However, the agreement between MRI and other diagnostic methods for detecting nerve involvement has not been fully evaluated. The aim of this diagnostic study was to evaluate the agreement between nerve involvement visible in MRI and findings of nerve involvement detected in a structured physical examination and a simplified pain drawing. METHODS: Sixty-one consecutive patients referred for MRI of the lumbar spine were - without knowledge of MRI findings - assessed for nerve involvement with a simplified pain drawing and a structured physical examination. Agreement between findings was calculated as overall agreement, the p value for McNemar's exact test, specificity, sensitivity, and positive and negative predictive values. RESULTS: MRI-visible nerve involvement was significantly less common than, and showed weak agreement with, physical examination and pain drawing findings of nerve involvement in corresponding body segments. In spine segment L4 5, where most findings of nerve involvement were detected, the mean sensitivity of MRI-visible nerve involvement to a positive neurological test in the physical examination ranged from 16-37%. The mean specificity of MRI-visible nerve involvement in the same segment ranged from 61-77%. Positive and negative predictive values of MRI-visible nerve involvement in segment L4-5 ranged from 22 78% and 28-56% respectively. CONCLUSION: In patients with long-standing nerve root symptoms referred for lumbar MRI, MRI-visible nerve involvement significantly underestimates the presence of nerve involvement detected by a physical examination and a pain drawing. A structured physical examination and a simplified pain drawing may reveal that many patients with "MRI-invisible" lumbar symptoms need treatment aimed at nerve involvement. Factors other than present MRI-visible nerve involvement may be responsible for findings of nerve involvement in the physical examination and the pain drawing. PMID- 20831786 TI - Immunohistochemical approach to the pathogenesis of clinical cases of bovine Herpesvirus type 5 infections. AB - Meningoencephalitis by Herpesvirus type 5 (BoHV-5) in cattle has some features that are similar to those of herpetic encephalitis in humans and other animal species. Human Herpesvirus 3 (commonly known as Varicella-zoster virus 1), herpes simplex viruses (HSV), and equid Herpesvirus 1 (EHV-1) induce an intense inflammatory, vascular and cellular response. In spite of the many reports describing the histological lesions associated with natural and experimental infections, the immunopathological mechanisms for the development of neurological disorder have not been established. A total of twenty calf brains were selected from the Veterinary School, University of Sao Paulo State, Aracatuba, Brazil, after confirmation of BoHV-5 infection by virus isolation as well as by a molecular approach. The first part of the study characterized the microscopic lesions associated with the brain areas in the central nervous system (CNS) that tested positive in a viral US9 gene hybridization assay. The frontal cortex (Fc), parietal cortex (Pc), thalamus (T) and mesencephalon (M) were studied. Secondly, distinct pathogenesis mechanisms that take place in acute cases were investigated by an immunohistochemistry assay. This study found the frontal cortex to be the main region where intense oxidative stress phenomena (AOP-1) and synaptic protein expression (SNAP-25) were closely related to inflammatory cuffs, satellitosis and gliosis, which represent the most frequently observed neurological lesions. Moreover, MMP-9 expression was shown to be localized in the leptomeninges, in the parenchyma and around mononuclear infiltrates (p < 0.0001). These data open a new perspective in understanding the role of the AOP-1, MMP-9 and SNAP-25 proteins in mediating BoHV-5 pathogenesis and the strategies of host-virus interaction in order to invade the CNS. PMID- 20831789 TI - The non-pathogenic mycobacteria M. smegmatis and M. fortuitum induce rapid host cell apoptosis via a caspase-3 and TNF dependent pathway. AB - BACKGROUND: The HIV pandemic raised the potential for facultative-pathogenic mycobacterial species like, Mycobacterium kansasii, to cause disseminating disease in humans with immune deficiencies. In contrast, non-pathogenic mycobacterial species, like M. smegmatis, are not known to cause disseminating disease even in immunocompromised individuals. We hypothesized that this difference in phenotype could be explained by the strong induction of an innate immune response by the non-pathogenic mycobacterial species. RESULTS: A comparison of two rapid-growing, non-pathogenic species (M. smegmatis and M. fortuitum) with two facultative-pathogenic species (M. kansasii and M. bovis BCG) demonstrated that only the non-pathogenic bacteria induced strong apoptosis in human THP-1 cells and murine bone marrow-derived macrophages (BMDM) and dendritic cells (BMDD). The phospho-myo-inositol modification of lipoarabinomannan (PI-LAM) isolated from non-pathogenic species may be one of the cell wall components responsible for the pro-inflammatory activity of the whole bacteria. Indeed, PI LAM induces high levels of apoptosis and IL-12 expression compared to the mannosyl modification of LAM isolated from facultative-pathogenic mycobacteria. The apoptosis induced by non-pathogenic M. smegmatis was dependent upon caspase-3 activation and TNF secretion. Consistently, BALB/c BMDM responded by secreting large amounts of TNF upon infection with non-pathogenic but not facultative pathogenic mycobacteria. Interestingly, C57Bl/6 BMDM do not undergo apoptosis upon infection with non-pathogenic mycobacteria despite the fact that they still induce an increase in TNF secretion. This suggests that the host cell signaling pathways are different between these two mouse genotypes and that TNF is necessary but not sufficient to induce host cell apoptosis. CONCLUSION: These results demonstrate a much stronger induction of the innate immune response by non-pathogenic versus facultative-pathogenic mycobacteria as measured by host cell apoptosis, IL-12 and TNF cytokine induction. These observations lend support to the hypothesis that the strong induction of the innate immune response is a major reason for the lack of pathogenicity in fast-growing mycobacteria. PMID- 20831787 TI - Characterisation of COPD heterogeneity in the ECLIPSE cohort. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex condition with pulmonary and extra-pulmonary manifestations. This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort (ECLIPSE). METHODS: We studied 2164 clinically stable COPD patients, 337 smokers with normal lung function and 245 never smokers. In these individuals, we measured clinical parameters, nutritional status, spirometry, exercise tolerance, and amount of emphysema by computed tomography. RESULTS: COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function. Co-morbidities were more prevalent in COPD patients than in controls, and occurred to the same extent irrespective of the GOLD stage. The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness, health status, presence of co-morbidity, exercise capacity and number of exacerbations reported in the year before the study. The distribution of these variables within each GOLD stage was wide. Even in subjects with severe airflow obstruction, a substantial proportion did not report symptoms, exacerbations or exercise limitation. The amount of emphysema increased with GOLD severity. The prevalence of bronchiectasis was low (4%) but also increased with GOLD stage. Some gender differences were also identified. CONCLUSIONS: The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease. PMID- 20831790 TI - Cost-effectiveness of injury prevention - a systematic review of municipality based interventions. AB - BACKGROUND: Injuries are a major cause of mortality and morbidity which together result in avoidable societal costs. Due to limited resources, injury prevention interventions need to demonstrate cost-effectiveness to justify their implementation. However, the existing knowledge in this area is limited. Consequently, a systematic review is needed to support decision-making and to assist in the targeting of future research. The aim of this review is to critically appraise the published economic evidence of injury prevention interventions at the municipal level. METHODS: A search strategy was developed to focus a literature search in PubMed, Embase, Cochrane and NHS EED. Studies were eligible for inclusion if they were economic evaluations of injury prevention interventions that could be implemented by municipalities; had a relevant comparison group; did not include any form of medication or drug use; and were assessed as having at least an acceptable quality from an economic point of view. Articles were screened in three steps. In the final step, studies were critically appraised using a check-list based on Drummond's check-list for assessing economic evaluations. RESULTS: Of 791 potential articles 20 were accepted for inclusion. Seven studies showed net savings; four showed a cost per health score gained; six showed both savings and a cost per health score gained but for different time horizons and populations; and three showed no effect. The interventions targeted a range of areas such as traffic safety, fire safety, hip fractures, and sport injuries. One studied a multi-targeted community-based program. Only six articles used effectiveness data generated within the study. CONCLUSIONS: The results indicate that there are injury prevention interventions that offer good use of societal resources. However, there is a lack of economic evidence surrounding injury prevention interventions. This lack of evidence needs to be met by further research about the economic aspects of injury prevention interventions to improve the information available for decision-making. PMID- 20831791 TI - Lower prevalence of hip fractures in foreign-born individuals than in Swedish born individuals during the period 1987-1999. AB - BACKGROUND: This is the first longitudinal study with a 22-year follow-up, based on a national and complete sample, to determine whether the prevalence of hip fracture and the age when it occurs are influenced by migration and by being foreign-born. Cultural background and environmental factors such as UV-radiation and lifestyle during childhood and adolescence may influence the risk of a hip fracture event later in life. Differences in prevalence might occur between the indigenous population and those who have migrated to a country. METHODS: The study was based on national population data. The study population consisted of 321,407 Swedish-born and 307,174 foreign-born persons living in Sweden during the period 1987-1999. RESULTS: Foreign-born individuals had a reduced risk of hip fracture, with odds ratios (ORs) of 0.47-0.77 for men and 0.42-0.88 for women. Foreign-born women had the hip fracture event at a higher age on average, but a longer time spent in Sweden was associated with a small but significant increase in risk. CONCLUSIONS: We found that there was a reduced risk of hip fracture in all foreign-born individuals, and that the hip fracture event generally happened at a higher age in foreign-born women. Migration must therefore be considered in relation to the prevalence and risk of hip fracture. Migration can therefore have a positive effect on one aspect of the health of a population, and can influence and lower the total cost of healthcare due to reduced risk and prevalence of hip fracture. PMID- 20831792 TI - Genetic and diet effects on Ppar-alpha and Ppar-gamma signaling pathways in the Berlin Fat Mouse Inbred line with genetic predisposition for obesity. AB - BACKGROUND: The Berlin Fat Mouse Inbred (BFMI) line is a new mouse model for obesity, which was long-term selected for high fatness. Peroxisome proliferator activated receptors (PPARs) are involved in the control of energy homeostasis, nutrient metabolism and cell proliferation. Here, we studied the expression patterns of the different Ppar genes and the genes in the PPAR pathway in the BFMI line in comparison to physiological changes. RESULTS: At the age of 10 weeks, the BFMI mice exhibited marked obesity with enlarged adipocytes and high serum triglycerides concentrations in comparison to the often used mouse line C57BL/6 (B6). Between these two lines, gene expression analyses revealed differentially expressed genes belonging to the PPAR pathway, in particular genes of the lipogenesis and the fatty acid transport. CONCLUSION: Surprisingly, the Ppar-alpha gene expression was up-regulated in liver and Ppar-gamma gene expression was down-regulated in the white adipose tissue, indicating the activation of a mechanism that counteracts the rise of obesity. PMID- 20831793 TI - Extensive loss of translational genes in the structurally dynamic mitochondrial genome of the angiosperm Silene latifolia. AB - BACKGROUND: Mitochondrial gene loss and functional transfer to the nucleus is an ongoing process in many lineages of plants, resulting in substantial variation across species in mitochondrial gene content. The Caryophyllaceae represents one lineage that has experienced a particularly high rate of mitochondrial gene loss relative to other angiosperms. RESULTS: In this study, we report the first complete mitochondrial genome sequence from a member of this family, Silene latifolia. The genome can be mapped as a 253,413 bp circle, but its structure is complicated by a large repeated region that is present in 6 copies. Active recombination among these copies produces a suite of alternative genome configurations that appear to be at or near "recombinational equilibrium". The genome contains the fewest genes of any angiosperm mitochondrial genome sequenced to date, with intact copies of only 25 of the 41 protein genes inferred to be present in the common ancestor of angiosperms. As observed more broadly in angiosperms, ribosomal proteins have been especially prone to gene loss in the S. latifolia lineage. The genome has also experienced a major reduction in tRNA gene content, including loss of functional tRNAs of both native and chloroplast origin. Even assuming expanded wobble-pairing rules, the mitochondrial genome can support translation of only 17 of the 61 sense codons, which code for only 9 of the 20 amino acids. In addition, genes encoding 18S and, especially, 5S rRNA exhibit exceptional sequence divergence relative to other plants. Divergence in one region of 18S rRNA appears to be the result of a gene conversion event, in which recombination with a homologous gene of chloroplast origin led to the complete replacement of a helix in this ribosomal RNA. CONCLUSIONS: These findings suggest a markedly expanded role for nuclear gene products in the translation of mitochondrial genes in S. latifolia and raise the possibility of altered selective constraints operating on the mitochondrial translational apparatus in this lineage. PMID- 20831794 TI - The proliferation, apoptosis, invasion of endothelial-like epithelial ovarian cancer cells induced by hypoxia. AB - BACKGROUND: Epithelial ovarian cancer is one of the most malignant cancers in women because metastasis occurs in the most of patients by the time of diagnosis. Cancer cells have strong capacity to form angiogenesis or vasculogenic mimicry, which plays the major role in its malignant phenotype. Vasculogenic mimicry might contribute to the failure of the angiogenesis-targeted therapy strategies. Under the microenvironment of the tumor, hypoxia is the most common phenomena because of the vast energy and oxygen consuming. In the present study, the endothelial like cells induced by hypoxia from SKOV-3 and ES-2 ovarian cancer cells were harvested to investigate the changes in their biological behaviors. METHODS: The endothelial-like cells from SKOV-3 and ES-2 cells were harvested by laser capture microdissection. The biological behaviors of the endothelial-like cells, including proliferation, cell cycle, apoptosis, invasion and telomerase activity were determined by MTT, FCM, Transwell chamber and TRAP-ELISA methods. HIF-1alpha is the most important factor for the behavior changes under hypoxic condition. Some other genes relative to biological behaviors are also changes following the changes of HIF-1alpha. In order to elucidate the underlying mechanisms for these changes by hypoxia, the relative genes expressions including HIF-1alpha, CyclinD1, Flk-1, VEGF, p53 and V-src were determined by real-time PCR. RESULTS: SKOV-3 and ES-2 cells were resistant to hypoxia by adoption of proliferation, apoptosis, differentiation and invasion. Combined with other studies, the more poorly cancer cells differentiate, the more strongly cells are resistant to hypoxia, the more possible to form vasculogenic mimicry. The changes in the expression of HIF-1alpha, and HIF-1alpha-dependent VEGF, Flk-1, Cyclin D1, and HIF-1alpha-independent p53 have been involved in this process. CONCLUSIONS: HIF 1alpha took an important role in the behavioral changes of SKOV-3 and ES-2 cells by hypoxia. At the same time, other mechanisms were also involved in this process. PMID- 20831795 TI - Brain architecture of the largest living land arthropod, the Giant Robber Crab Birgus latro (Crustacea, Anomura, Coenobitidae): evidence for a prominent central olfactory pathway? AB - BACKGROUND: Several lineages within the Crustacea conquered land independently during evolution, thereby requiring physiological adaptations for a semi terrestrial or even a fully terrestrial lifestyle. Birgus latro Linnaeus, 1767, the giant robber crab or coconut crab (Anomura, Coenobitidae), is the largest land-living arthropod and inhabits Indo-Pacific islands such as Christmas Island. B. latro has served as a model in numerous studies of physiological aspects related to the conquest of land by crustaceans. From an olfactory point of view, a transition from sea to land means that molecules need to be detected in gas phase instead of in water solution. Previous studies have provided physiological evidence that terrestrial hermit crabs (Coenobitidae) such as B. latro have a sensitive and well differentiated sense of smell. Here we analyze the brain, in particular the olfactory processing areas of B. latro, by morphological analysis followed by 3 D reconstruction and immunocytochemical studies of synaptic proteins and a neuropeptide. RESULTS: The primary and secondary olfactory centers dominate the brain of B. latro and together account for ca. 40% of the neuropil volume in its brain. The paired olfactory neuropils are tripartite and composed of more than 1,000 columnar olfactory glomeruli, which are radially arranged around the periphery of the olfactory neuropils. The glomeruli are innervated ca. 90,000 local interneurons and ca. 160,000 projection neurons per side. The secondary olfactory centers, the paired hemiellipsoid neuropils, are targeted by the axons of these olfactory projection neurons. The projection neuron axonal branches make contact to ca. 250.000 interneurons (per side) associated with the hemiellipsoid neuropils. The hemiellipsoid body neuropil is organized into parallel neuropil lamellae, a design that is quite unusual for decapod crustaceans. The architecture of the optic neuropils and areas associated with antenna two suggest that B. latro has visual and mechanosensory skills that are comparable to those of marine Crustacea. CONCLUSIONS: In parallel to previous behavioral findings that B. latro has aerial olfaction, our results indicate that their central olfactory pathway is indeed most prominent. Similar findings from the closely related terrestrial hermit crab Coenobita clypeatus suggest that in Coenobitidae, olfaction is a major sensory modality processed by the brain, and that for these animals, exploring the olfactory landscape is vital for survival in their terrestrial habitat. Future studies on terrestrial members of other crustacean taxa such as Isopoda, Amphipoda, Astacida, and Brachyura will shed light on how frequently the establishment of an aerial sense of olfaction evolved in Crustacea during the transition from sea to land. Amounting to ca. 1,000,000, the numbers of interneurons that analyse the olfactory input in B. latro brains surpasses that in other terrestrial arthropods, as e.g. the honeybee Apis mellifera or the moth Manduca sexta, by two orders of magnitude suggesting that B. latro in fact is a land-living arthropod that has devoted a substantial amount of nervous tissue to the sense of smell. PMID- 20831796 TI - Trazodone for the treatment of fibromyalgia: an open-label, 12-week study. AB - BACKGROUND: Despite its frequent use as a hypnotic, trazodone has not been systematically assessed in fibromyalgia patients. In the present study have we evaluated the potential effectiveness and tolerability of trazodone in the treatment of fibromyalgia. METHODS: A flexible dose of trazodone (50-300 mg/day), was administered to 66 fibromyalgia patients for 12 weeks. The primary outcome measure was the Pittsburgh Sleep Quality Index (PSQI). Secondary outcome measures included the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI), the Hospital Anxiety and Depression Scale (HADS), the Brief Pain Inventory (BPI), the Short-Form Health Survey (SF-36), and the Patients' Global Improvement Scale (PGI). Trazodone's emergent adverse reactions were recorded. Data were analyzed with repeated measures one-way ANOVA and paired Student's t test. RESULTS: Trazodone markedly improved sleep quality, with large effect sizes in total PSQI score as well on sleep quality, sleep duration and sleep efficiency. Significant improvement, although with moderate effect sizes, were also observed in total FIQ scores, anxiety and depression scores (both HADS and BDI), and pain interference with daily activities. Unexpectedly, the most frequent and severe side effect associated with trazodone in our sample was tachycardia, which was reported by 14 (21.2%) patients. CONCLUSIONS: In doses higher than those usually prescribed as hypnotic, the utility of trazodone in fibromyalgia management surpasses its hypnotic activity. However, the emergence of tachycardia should be closely monitored. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov number NCT-00791739. PMID- 20831797 TI - Epidemiologic surveillance of nosocomial infections in a Pediatric Intensive Care Unit of a developing country. AB - BACKGROUND: Nosocomial Infections (NI) are a frequent and relevant problem. The purpose of this study was to determine the epidemiology of the three most common NI in a Pediatric Intensive Care Unit from a developing country. METHODS: We performed a prospective study in a single Pediatric Intensive Care Unit during 12 months. Children were assessed for 3 NI: bloodstream infections (BSI), ventilator associated pneumonia (VAP) and urinary tract infections (UTI), according to Center for Disease Control criteria. Use of devices (endotracheal tube [ETT], central venous catheter [CVC] and urinary catheter [UC]) was recorded. RESULTS: Four hundred fourteen patients were admitted; 81 patients (19.5%) developed 85 NIs. Density of incidence of BSI, VAP and UTI was 18.1, 7.9 and 5.1/1000 days of use of CVC, ETT and UC respectively. BSI was more common in children with CVCs than in those without CVCs (20% vs. 4.7%, p < 0.05). Candida spp. was the commonest microorganism in BSI (41%), followed by Coagulase-negative Staphylococcus (17%). Pseudomonas (52%) was the most common germ for VAP and Candida (71%) for UTI. The presence of NI was associated with increased mortality (38.2% vs. 20.4% in children without NI; p < 0.001) and the median length of ICU stay (23 vs. 6 days in children without NI; p < 0.001). Children with NI had longer average hospital stay previous to diagnosis of this condition (12.3 vs. 6 days; p < 0.001). CONCLUSIONS: One of every 5 children acquires an NI in the PICU. Its presence was associated with increased mortality and length of stay. At the same time a longer stay was associated with an increased risk of developing NI. PMID- 20831798 TI - Pain acceptance and personal control in pain relief in two maternity care models: a cross-national comparison of Belgium and the Netherlands. AB - BACKGROUND: A cross-national comparison of Belgian and Dutch childbearing women allows us to gain insight into the relative importance of pain acceptance and personal control in pain relief in 2 maternity care models. Although Belgium and the Netherlands are neighbouring countries sharing the same language, political system and geography, they are characterised by a different organisation of health care, particularly in maternity care. In Belgium the medical risks of childbirth are emphasised but neutralised by a strong belief in the merits of the medical model. Labour pain is perceived as a needless inconvenience easily resolved by means of pain medication. In the Netherlands the midwifery model of care defines childbirth as a normal physiological process and family event. Labour pain is perceived as an ally in the birth process. METHODS: Women were invited to participate in the study by independent midwives and obstetricians during antenatal visits in 2004-2005. Two questionnaires were filled out by 611 women, one at 30 weeks of pregnancy and one within the first 2 weeks after childbirth either at home or in a hospital. However, only women having a hospital birth without obstetric intervention (N = 327) were included in this analysis. A logistic regression analysis has been performed. RESULTS: Labour pain acceptance and personal control in pain relief render pain medication use during labour less likely, especially if they occur together. Apart from this general result, we also find large country differences. Dutch women with a normal hospital birth are six times less likely to use pain medication during labour, compared to their Belgian counterparts. This country difference cannot be explained by labour pain acceptance, since - in contrast to our working hypothesis - Dutch and Belgian women giving birth in a hospital setting are characterised by a similar labour pain acceptance. Our findings suggest that personal control in pain relief can partially explain the country differences in coping with labour pain. For Dutch women we find that the use of pain medication is lowest if women experience control over the reception of pain medication and have a positive attitude towards labour pain. In Belgium however, not personal control over the use of pain relief predicts the use of pain medication, but negative attitudes towards labour. CONCLUSIONS: Apart from individual level determinants, such as length of labour or pain acceptance, our findings suggest that the maternity care context is of major importance in the study of the management of labour pain. The pain medication use in Belgian hospital maternity care is high and is very sensitive to negative attitudes towards labour pain. In the Netherlands, on the contrary, pain medication use is already low. This can partially be explained by a low degree of personal control in pain relief, especially when co-occurring with positive pain attitudes. PMID- 20831799 TI - Genome-wide search identifies Ccnd2 as a direct transcriptional target of Elf5 in mouse mammary gland. AB - BACKGROUND: The ETS transcription factor Elf5 (also known as ESE-2) is highly expressed in the mammary gland and plays an important role in its development and differentiation. Indeed studies in mice have illustrated an essential role for Elf5 in directing alveologenesis during pregnancy. Although the molecular mechanisms that underlie the developmental block in Elf5 null mammary glands are beginning to be unraveled, this investigation has been hampered by limited information about the identity of Elf5-target genes. To address this shortcoming, in this study we have performed ChIP-cloning experiments to identify the specific genomic segments that are occupied by Elf5 in pregnant mouse mammary glands. RESULTS: Sequencing and genomic localization of cis-regulatory regions bound by Elf5 in vivo has identified several potential target genes covering broad functional categories. A subset of these target genes demonstrates higher expression levels in Elf5-null mammary glands suggesting a repressive functional role for this transcription factor. Here we focus on one putative target of Elf5, the Ccnd2 gene that appeared in our screen. We identify a novel Elf5-binding segment upstream of the Ccnd2 gene and demonstrate that Elf5 can transcriptionally repress Ccnd2 by directly binding to the proximal promoter region. Finally, using Elf5-null mammary epithelial cells and mammary glands, we show that loss of Elf5 in vivo leads to up regulation of Ccnd2 and an altered expression pattern in luminal cells. CONCLUSIONS: Identification of Elf5-targets is an essential first step in elucidating the transcriptional landscape that is shaped by this important regulator. Our studies offer new toolbox in examining the biological role of Elf5 in mammary gland development and differentiation. PMID- 20831800 TI - An algorithm for automated closure during assembly. AB - BACKGROUND: Finishing is the process of improving the quality and utility of draft genome sequences generated by shotgun sequencing and computational assembly. Finishing can involve targeted sequencing. Finishing reads may be incorporated by manual or automated means. One automated method uses targeted addition by local re-assembly of gap regions. An obvious alternative uses de novo assembly of all the reads. RESULTS: A procedure called the bounding read algorithm was developed for assembly of shotgun reads plus finishing reads and their constraints, targeting repeat regions. The algorithm was implemented within the Celera Assembler software and its pyrosequencing-specific variant, CABOG. The implementation was tested on Sanger and pyrosequencing data from six genomes. The bounding read assemblies were compared to assemblies from two other methods on the same data. The algorithm generates improved assemblies of repeat regions, closing and tiling some gaps while degrading none. CONCLUSIONS: The algorithm is useful for small-genome automated finishing projects. Our implementation is available as open-source from http://wgs-assembler.sourceforge.net under the GNU Public License. PMID- 20831801 TI - Which is the best method of sterilization of tumour bone for reimplantation? A biomechanical and histopathological study. AB - INTRODUCTION: Sterilization and re-usage of tumour bone for reconstruction after tumour resection is now gaining popularity in the East. This recycle tumour bone needs to be sterilized in order to eradicate the tumour cells before re implantation for limb salvage procedures. The effect of some of these treatments on the integrity and sterility of the bone after treatment has been published but there has yet been a direct comparison between the various methods of sterilization to determine the one method that gives the best tumour kill without compromising the bone's structural integrity. METHOD: This study was performed to evaluate the effect of several sterilization methods on the mechanical behavior of human cortical bone graft and histopathology evaluation of tumour bone samples after being processed with 4 different methods of sterilization. Fresh human cortical tumour bone is harvested from the diaphyseal region of the tumour bone were sterilized by autoclave (n =10); boiling (n =10); pasteurization (n =10); and irradiation (n =10). There were also 10 control specimens that did not receive any form of sterilization treatment. The biomechanical test conducted were stress to failure, modulus and strain to failure, which were determined from axial compression testing. Statistical analysis (ANOVA) was performed on these results. Significance level (alpha) and power (beta) were set to 0.05 and 0.90, respectively. RESULTS: ANOVA analysis of 'failure stress', 'modulus' and 'strain to failure' demonstrated significant differences (p < 0.05) between treated cortical bone and untreated specimens under mechanical loading.'Stress to failure' was significantly reduced in boiled, autoclaved and irradiated cortical bone samples (p < 0.05). 'Modulus' detected significant differences in the boiled, autoclaved and pasteurization specimens compared to controls (p < 0.05). 'Strain to failure' was reduced by irradiation (p < 0.05) but not by the other three methods of treatments.Histopathology study revealed no viable tumour cell in any of four types of treatment group compared to the untreated control group. CONCLUSIONS: Sterilization of cortical bone sample by pasteurization and to a lesser extent, irradiation does not significantly alter the mechanical properties when compared with untreated samples. Mechanical properties degrade with the use of high temperature for sterilization (boiling). All methods of sterilization gave rise to 100 percent tumour kill. PMID- 20831802 TI - Molecular characterization of partial-open reading frames 1a and 2 of the human astroviruses in South Korea. AB - Human astroviruses (HAstVs) are among the major causes of gastroenteritis in South Korea. In this study, the partial regions of the open reading frame (ORF) 1a and ORF2 genes of HAstVs from gastroenteritis patients in nine hospitals were sequenced, and the molecular characterization of the viruses was revealed. 89 partial nucleotide sequences of ORF1a and 88 partial nucleotide sequences of ORF2 were amplified from 120 stool specimens. Phylogenetic analysis showed that most of the nucleotide sequences of ORF1a and ORF2 were grouped with HAstV type 1 but had evolutionary genetic distance compared with the reference sequences, such as the HAstV-1 prototype, Dresden strain, and Oxford strain. According to the phylogenetic analysis, some nucleotide sequences including SE0506041, SE0506043, and SE0506058, showed the discrepancy of the genotypes, but there was no proof of recombination among the HAstV types. In conclusion, this study showed that the dominant HAstV isolated from the Seoul metropolitan area in 2004-2005 was HAstV type 1, and that Korean HAstV-1 had the genetic distance in evolution compared with the reference sequences of HAstVs. Lots of nucleotide sequences of the ORF1a and ORF2 genes of HAstV will be useful for studying for the control and prevention of HAstV gastroenteritis in South Korea. PMID- 20831803 TI - Membranous nephropathy and lupus-like syndrome after hematopoietic cell transplantation: a case report. AB - INTRODUCTION: The kidney is increasingly recognised as a target organ of chronic graft-versus-host disease after hematopoietic cell transplantation in the context of the development of the nephrotic syndrome. Chronic graft-versus-host disease is associated with autoimmune phenomena similar, but not identical, to those observed in various rheumatologic disorders, implicating autoimmunity as an important component of the disease. CASE PRESENTATION: We report the case of a 57 year-old Caucasian man who developed the nephrotic syndrome due to membranous nephropathy in association with recurrent chronic graft-versus-host disease, along with a lupus-like syndrome manifested with pancytopenia, hair loss, positive anti-DNA antibodies and sub-epithelial and mesangial immune deposits. To the best of our knowledge, this is the first case reported in the literature. The nephrotic syndrome subsided soon after he was treated with a short course of cyclosporin with steroids. Unfortunately he died seven months later due to a relapse of leukemia. CONCLUSIONS: Our case report confirms the notion that chronic graft-versus-host disease is characterized by the appearance of autoimmune phenomena similar, but not identical, to those seen in autoimmune diseases. The decision for more immunosuppression has to be weighed against the need for preservation of the graft versus leukemia phenomenon. PMID- 20831804 TI - Identification of response-modulated genetic interactions by sensitivity-based epistatic analysis. AB - BACKGROUND: High-throughput genomics has enabled the global mapping of genetic interactions based on the phenotypic impact of combinatorial genetic perturbations. An important next step is to understand how these networks are dynamically remodelled in response to environmental stimuli. Here, we report on the development and testing of a method to identify such interactions. The method was developed from first principles by treating the impact on cellular growth of environmental perturbations equivalently to that of gene deletions. This allowed us to establish a novel neutrality function marking the absence of epistasis in terms of sensitivity phenotypes rather than fitness. We tested the method by identifying fitness- and sensitivity-based interactions involved in the response to drug-induced DNA-damage of budding yeast Saccharomyces cerevisiae using two mutant libraries - one containing transcription factor deletions, and the other containing deletions of DNA repair genes. RESULTS: Within the library of transcription factor deletion mutants, we observe significant differences in the sets of genetic interactions identified by the fitness- and sensitivity-based approaches. Notably, among the most likely interactions, only ~50% were identified by both methods. While interactions identified solely by the sensitivity-based approach are modulated in response to drug-induced DNA damage, those identified solely by the fitness-based method remained invariant to the treatment. Comparison of the identified interactions to transcriptional profiles and protein-DNA interaction data indicate that the sensitivity-based method improves the identification of interactions involved in the DNA damage response. Additionally, for the library containing DNA repair mutants, we observe that the sensitivity-based method improves the grouping of functionally related genes, as well as the identification of protein complexes, involved in DNA repair. CONCLUSION: Our results show that the identification of response-modulated genetic interactions can be improved by incorporating the effect of a changing environment directly into the neutrality function marking the absence of epistasis. We expect that this extension of conventional epistatic analysis will facilitate the development of dynamic models of gene networks from quantitative measurements of genetic interactions. While the method was developed for growth phenotype, it should apply equally well for other phenotypes, including the expression of fluorescent reporters. PMID- 20831805 TI - The importance of examining movements within the US health care system: sequential logit modeling. AB - BACKGROUND: Utilization of specialty care may not be a discrete, isolated behavior but rather, a behavior of sequential movements within the health care system. Although patients may often visit their primary care physician and receive a referral before utilizing specialty care, prior studies have underestimated the importance of accounting for these sequential movements. METHODS: The sample included 6,772 adults aged 18 years and older who participated in the 2001 Survey on Disparities in Quality of Care, sponsored by the Commonwealth Fund. A sequential logit model was used to account for movement in all stages of utilization: use of any health services (i.e., first stage), having a perceived need for specialty care (i.e., second stage), and utilization of specialty care (i.e., third stage). In the sequential logit model, all stages are nested within the previous stage. RESULTS: Gender, race/ethnicity, education and poor health had significant explanatory effects with regard to use of any health services and having a perceived need for specialty care, however racial/ethnic, gender, and educational disparities were not present in utilization of specialty care. After controlling for use of any health services and having a perceived need for specialty care, inability to pay for specialty care via income (AOR = 1.334, CI = 1.10 to 1.62) or health insurance (unstable insurance: AOR = 0.26, CI = 0.14 to 0.48; no insurance: AOR = 0.12, CI = 0.07 to 0.20) were significant barriers to utilization of specialty care. CONCLUSIONS: Use of a sequential logit model to examine utilization of specialty care resulted in a detailed representation of utilization behaviors and patient characteristics that impact these behaviors at all stages within the health care system. After controlling for sequential movements within the health care system, the biggest barrier to utilizing specialty care is the inability to pay, while racial, gender, and educational disparities diminish to non-significance. Findings from this study represent how Americans use the health care system and more precisely reveals the disparities and inequalities in the U.S. health care system. PMID- 20831806 TI - Relationship of family caregiver burden with quality of care and psychopathology in a sample of Arab subjects with schizophrenia. AB - BACKGROUND: Although the burden experienced by families of people with schizophrenia has long been recognized as one of the most important consequences of the disorder, there are no reports from the Arab world. Following the example of the five-nation European (EPSILON) study, we explored the following research question: How does the relationship between domains of caregiving (as in the Involvement Evaluation Questionnaire--IEQ-EU) and caregiver psychic distress on the one hand, and caregiver's/patient's socio-demographics, clinical features and indices of quality of care, on the other hand, compare with the pattern in the literature? METHOD: Consecutive family caregivers of outpatients with schizophrenia were interviewed with the IEQ-EU. Patients were interviewed with measures of needs for care, service satisfaction, quality of life (QOL) and psychopathology. RESULTS: There were 121 caregivers (66.1% men, aged 39.8). The IEQ domain scores (total: 46.9; tension: 13.4; supervision: 7.9; worrying: 12.9; and urging: 16.4) were in the middle of the range for the EU data. In regression analyses, higher burden subscale scores were variously associated with caregiver lower level of education, patient's female gender and younger age, as well as patient's lower subjective QOL and needs for hospital care, and not involving the patient in outdoor activities. Disruptive behavior was the greatest determinant of global rating of burden. CONCLUSION: Our results indicate that, despite differences in service set-up and culture, the IEQ-EU can be used in Kuwait as it has been used in the western world, to describe the pattern of scores on the dimensions of caregiving. Differences with the international data reflect peculiarities of culture and type of service. Despite generous national social welfare provisions, experience of burden was the norm and was significantly associated with patient's disruptive behavior. The results underscore the need for provision of community-based programs and continued intervention with the families in order to improve the quality of care. PMID- 20831807 TI - Paroxysmal autonomic instability with dystonia in a patient with tuberculous meningitis: a case report. AB - INTRODUCTION: This case report describes an extremely rare combination of paroxysmal autonomic instability with dystonia and tuberculous meningitis. Paroxysmal autonomic instability with dystonia is normally associated with severe traumatic brain injury. CASE PRESENTATION: A 69-year-old man of Indonesian descent was initially suspected of having a community-acquired pneumonia, which was seen on chest X-ray and computed tomography of the chest. However, a bronchoscopy showed no abnormalities. He was treated with amoxicillin-clavulanic acid in combination with ciprofloxacin. However, nine days after admission he was disorientated and complained of headache. Neurological examination revealed no further abnormalities. A lumbar puncture revealed no evidence of meningitis. He was then transferred to our hospital. At that time, initial cultures of bronchial fluid for Mycobacterium tuberculosis turned positive, as well as polymerase chain reaction for Mycobacterium tuberculosis. Later, during his stay in our intensive care unit, he developed periods with hypertension, sinus tachycardia, excessive transpiration, decreased oxygen saturation with tachypnea, pink foamy sputum, and high fever. This constellation of symptoms was accompanied by dystonia in the first days. These episodes lasted approximately 30 minutes and improved after administration of morphine, benzodiazepines or clonidine. Magnetic resonance imaging showed an abnormal signal in the region of the hippocampus, thalamus and the anterior parts of the lentiform nucleus and caudate nucleus. CONCLUSIONS: In patients with (tuberculous) meningitis and episodes of extreme hypertension and fever, paroxysmal autonomic instability with dystonia should be considered. PMID- 20831808 TI - The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. AB - BACKGROUND: Malignant brain tumors affect people of all ages and are the second leading cause of cancer deaths in children. While current treatments are effective and improve survival, there remains a substantial need for more efficacious therapeutic modalities. The ketogenic diet (KD) - a high-fat, low carbohydrate treatment for medically refractory epilepsy - has been suggested as an alternative strategy to inhibit tumor growth by altering intrinsic metabolism, especially by inducing glycopenia. METHODS: Here, we examined the effects of an experimental KD on a mouse model of glioma, and compared patterns of gene expression in tumors vs. normal brain from animals fed either a KD or a standard diet. RESULTS: Animals received intracranial injections of bioluminescent GL261 luc cells and tumor growth was followed in vivo. KD treatment significantly reduced the rate of tumor growth and prolonged survival. Further, the KD reduced reactive oxygen species (ROS) production in tumor cells. Gene expression profiling demonstrated that the KD induces an overall reversion to expression patterns seen in non-tumor specimens. Notably, genes involved in modulating ROS levels and oxidative stress were altered, including those encoding cyclooxygenase 2, glutathione peroxidases 3 and 7, and periredoxin 4. CONCLUSIONS: Our data demonstrate that the KD improves survivability in our mouse model of glioma, and suggests that the mechanisms accounting for this protective effect likely involve complex alterations in cellular metabolism beyond simply a reduction in glucose. PMID- 20831809 TI - Unlocking the "Black box": internal female genitalia in Sepsidae (Diptera) evolve fast and are species-specific. AB - BACKGROUND: The species-specificity of male genitalia has been well documented in many insect groups and sexual selection has been proposed as the evolutionary force driving the often rapid, morphological divergence. The internal female genitalia, in sharp contrast, remain poorly studied. Here, we present the first comparative study of the internal reproductive system of Sepsidae. We test the species-specificity of the female genitalia by comparing recently diverged sister taxa. We also compare the rate of change in female morphological characters with the rate of fast-evolving, molecular and behavioral characters. RESULTS: We describe the ectodermal parts of the female reproductive tract for 41 species representing 21 of the 37 described genera and define 19 morphological characters with discontinuous variation found in eight structures that are part of the reproductive tract. Using a well-resolved molecular phylogeny based on 10 genes, we reconstruct the evolution of these characters across the family [120 steps; Consistency Index (CI): 0.41]. Two structures, in particular, evolve faster than the rest. The first is the ventral receptacle, which is a secondary sperm storage organ. It accounts for more than half of all the evolutionary changes observed (7 characters; 61 steps; CI: 0.46). It is morphologically diverse across genera, can be bi-lobed or multi-chambered (up to 80 chambers), and is strongly sclerotized in one clade. The second structure is the dorsal sclerite, which is present in all sepsids except Orygma luctuosum and Ortalischema albitarse. It is associated with the opening of the spermathecal ducts and is often distinct even among sister species (4 characters; 16 steps; CI: 0.56). CONCLUSIONS: We find the internal female genitalia are diverse in Sepsidae and diagnostic for all species. In particular, fast-evolving structures like the ventral receptacle and dorsal sclerite are likely involved in post-copulatory sexual selection. In comparison to behavioral and molecular data, the female structures are evolving 2/3 as fast as the non-constant third positions of the COI barcoding gene. They display less convergent evolution in characters (CI = 0.54) than the third positions or sepsid mating behavior (CICOI = 0.36; CIBEHAV = 0.45). PMID- 20831810 TI - A cross-sectional survey of compliance with national guidance for alcohol consumption by children: measuring risk factors, protective factors and social norms for excessive and unsupervised drinking. AB - BACKGROUND: The Chief Medical Officer for England has developed the first guidance in England and some of the first internationally on alcohol consumption by children. Using the most recent iteration of a large biennial survey of schoolchildren we measure the extent to which young people's drinking fell within the guidelines just prior to their introduction and the characteristics of individuals whose drinking does not; how alcohol related harms relate to compliance; and risk factors associated with behaving outside of the guidance. METHODS: A cross-sectional survey was conducted utilising a self-completed questionnaire with closed questions. A total of 11,879 schoolchildren, aged 15-16 years, from secondary schools in North West England participated in the study. Data were analysed using chi square and conditional logistic regression. RESULTS: Alcohol consumption is an established norm by age 15 years (81.3%). Acute alcohol related violence, regretted sex and forgetfulness were experienced by significantly fewer children drinking within the guidance (than outside of it). Over half of drinkers (54.7%) reported routinely drinking more heavily than guidance suggests (here >= 5 drinks/session >= 1 month), or typically drinking unsupervised at home or at a friend's home when parents were absent (57.4%). Both behaviours were common across all deprivation strata. Children with greater expendable incomes were less likely to consume within guidance and reported higher measures for unsupervised, frequent and heavy drinking. Although drinking due to peer pressure was associated with some measures of unsupervised drinking, those reporting that they drank out of boredom were more likely to report risk related drinking behaviours outside of the guidance. CONCLUSIONS: Successful implementation of guidance on alcohol consumption for children could result in substantial reductions in existing levels of alcohol related harms to young people. However, prolonged social marketing, educational and parental interventions will be required to challenge established social norms in heavy and unsupervised child drinking across all social strata. Policy measures to establish a minimum price for alcohol and provide children with entertaining alternatives to alcohol should also increase compliance with guidance. PMID- 20831811 TI - Assessing disease disclosure in adults with cystic fibrosis: the Adult Data for Understanding Lifestyle and Transitions (ADULT) survey Disclosure of disease in adults with cystic fibrosis. AB - BACKGROUND: As more patients with cystic fibrosis (CF) reach adulthood and participate in age-appropriate activities (e.g. employment, dating), disclosure of medical status becomes more important. This study assessed rates of disclosure and its perceived impact on relationships using the Adult Data for Understanding Lifestyle and Transitions (ADULT) online survey. METHODS: Adults with CF participated in the survey via the United States national network of CF Centers. Descriptive and inferential statistics were utilized. RESULTS: Participants (n = 865) were more likely to disclose to relatives (94%) and close friends (81%) than to dating partners (73%), bosses/supervisors/teachers (51%) or co-workers (39%). Respondents generally reported a neutral/positive effect on relationships following disclosure. Negative effects of disclosure were infrequent, but more likely with dating partners or bosses/supervisors/teachers. Results also indicated that disclosure may be influenced by severity of lung disease and gender, with those having normal/mild lung disease less likely to disclose their diagnosis to both co-workers (p < 0.01) and bosses/supervisors/teachers (p < 0.01), and women being more likely to disclose to close friends (p < 0.0001) and dating partners (p < 0.05) than men. CONCLUSIONS: Most adults with CF disclosed their disease to relatives and close friends. Individuals with severe CF lung disease were more likely to disclose their diagnosis to coworkers and supervisors/teachers. It may be helpful to provide support for disclosure of disease in situations such as employment and dating. PMID- 20831812 TI - Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients. AB - BACKGROUND: New biomarkers that replace or are used in conjunction with the current ovarian cancer diagnostic antigen, CA125, are needed for detection of ovarian cancer in the presurgical setting, as well as for detection of disease recurrence. We previously demonstrated the upregulation of leucine-rich alpha-2 glycoprotein-1 (LRG1) in the sera of ovarian cancer patients compared to healthy women using quantitative mass spectrometry. METHODS: LRG1 was quantified by ELISA in serum from two relatively large cohorts of women with ovarian cancer and benign gynecological disease. The expression of LRG1 in ovarian cancer tissues and cell lines was examined by gene microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, immunocytochemistry and mass spectrometry. RESULTS: Mean serum LRG1 was higher in 58 ovarian cancer patients than in 56 healthy women (89.33 +/- 77.90 vs. 42.99 +/- 9.88 ug/ml; p = 0.0008) and was highest among stage III/IV patients. In a separate set of 193 pre-surgical samples, LRG1 was higher in patients with serous or clear cell ovarian cancer (145.82 +/- 65.99 ug/ml) compared to patients with benign gynecological diseases (82.53 +/- 76.67 ug/ml, p < 0.0001). CA125 and LRG1 levels were moderately correlated (r = 0.47, p < 0.0001). LRG1 mRNA levels were higher in ovarian cancer tissues and cell lines compared to their normal counterparts when analyzed by gene microarray and RT-PCR. LRG1 protein was detected in ovarian cancer tissue samples and cell lines by immunocytochemistry and Western blotting. Multiple iosforms of LRG1 were observed by Western blot and were shown to represent different glycosylation states by digestion with glycosidase. LRG1 protein was also detected in the conditioned media of ovarian cancer cell culture by ELISA, Western blotting, and mass spectrometry. CONCLUSIONS: Serum LRG1 was significantly elevated in women with ovarian cancer compared to healthy women and women with benign gynecological disease, and was only moderately correlated with CA125. Ovarian cancer cells secrete LRG1 and may contribute directly to the elevated levels of LRG1 observed in the serum of ovarian cancer patients. Future studies will determine whether LRG1 may serve as a biomarker for presurgical diagnosis, disease recurrence, and/or as a target for therapy. PMID- 20831813 TI - Cesarean and VBAC rates among immigrant vs. native-born women: a retrospective observational study from Taiwan Cesarean delivery and VBAC among immigrant women in Taiwan. AB - BACKGROUND: Cultural and ethnic roots impact women's fertility and delivery preferences This study investigated whether the likelihood of cesarean delivery, primary cesarean, and vaginal delivery after cesarean (VBAC) varies by maternal national origin. METHODS: We conducted a nation-wide, population-based, observational study using secondary data from Taiwan. De-identified data were obtained on all 392,246 singleton live births (>=500 g; >=20 weeks) born to native-born Taiwanese, Vietnamese and mainland Chinese-born mothers between January 1, 2006 and December 31, 2007 from Taiwan's nation-wide birth certificate data. Our analytic samples consisted of the following: for overall cesarean likelihood 392,246 births, primary cesarean 336,766 (excluding repeat cesarean and VBAC), and VBAC 55,480 births (excluding primary cesarean and vaginal births without previous cesarean). Our main outcome measures were the odds of cesarean delivery, primary cesarean delivery and VBAC for Vietnamese and Chinese immigrant mothers relative to Taiwanese mothers, using multiple regression analyses to adjust for maternal and neonatal characteristics, paternal age, institutional setting, and major obstetric complications. RESULTS: Unadjusted overall cesarean, primary cesarean, and VBAC rates were 33.9%, 23.0% and 4.0% for Taiwanese, 27.6%, 20.1% and 5.0% for mainland Chinese, and 19.3%, 13.9 and 6.1% for Vietnamese respectively. Adjusted for confounders, Vietnamese mothers were less likely than native-born Taiwanese to have overall and primary cesarean delivery (OR = 0.59 and 0.58 respectively), followed by Chinese mothers (both ORs = 0.90 relative to native-born Taiwanese). Vietnamese mothers were most likely to have successful VBAC (OR = 1.58), followed by Chinese mothers (OR = 1.25). CONCLUSION: Immigrant Vietnamese and Chinese mothers have lower odds of cesarean and higher VBAC odds than native-born Taiwanese, consistent with lower cesarean rates prevailing in their home countries (Vietnam 10.1%; mainland China 20%-50% rural and urban respectively). PMID- 20831814 TI - Programmed cell death 4 loss increases tumor cell invasion and is regulated by miR-21 in oral squamous cell carcinoma. AB - BACKGROUND: The tumor suppressor Programmed Cell Death 4 (PDCD4) has been found to be under-expressed in several cancers and associated with disease progression and metastasis. There are no current studies characterizing PDCD4 expression and its clinical relevance in Oral Squamous Cell Carcinoma (OSCC). Since nodal metastasis is a major prognostic factor in OSCC, we focused on determining whether PDCD4 under-expression was associated with patient nodal status and had functional relevance in OSCC invasion. We also examined PDCD4 regulation by microRNA 21 (miR-21) in OSCC. RESULTS: PDCD4 mRNA expression levels were assessed in 50 OSCCs and 25 normal oral tissues. PDCD4 was under-expressed in 43/50 (86%) OSCCs, with significantly reduced mRNA levels in patients with nodal metastasis (p = 0.0027), and marginally associated with T3-T4 tumor stage (p = 0.054). PDCD4 protein expression was assessed, by immunohistochemistry (IHC), in 28/50 OSCCs and adjacent normal tissues; PDCD4 protein was absent/under-expressed in 25/28 (89%) OSCCs, and marginally associated with nodal metastasis (p = 0.059). A matrigel invasion assay showed that PDCD4 expression suppressed invasion, and siRNA-mediated PDCD4 loss was associated with increased invasive potential of oral carcinoma cells. Furthermore, we showed that miR-21 levels were increased in PDCD4-negative tumors, and that PDCD4 expression may be down-regulated in OSCC by direct binding of miR-21 to the 3'UTR PDCD4 mRNA. CONCLUSIONS: Our data show an association between the loss of PDCD4 expression, tumorigenesis and invasion in OSCC, and also identify a mechanism of PDCD4 down-regulation by microRNA-21 in oral carcinoma. PDCD4 association with nodal metastasis and invasion suggests that PDCD4 may be a clinically relevant biomarker with prognostic value in OSCC. PMID- 20831815 TI - Cancer in children residing near nuclear power plants: an open question. AB - BACKGROUND: Global warming and the established responsibility of the anthropogenic emissions of greenhouse gases represent a strong push towards the construction of new nuclear power plants (NPPs) to cope with the growing energy needs. The toxicity of nuclear waste associated with the extreme difficulty of their disposal and increase in cancer mortality and incidence following occupational radiation exposure are considered the only health problems. METHODS: A search of scientific articles and government documents published since January 1, 1980 to July 1, 2010 was performed to evaluate cancer rate and mortality in residents, particularly children, in the vicinity of NPPs. RESULTS: A recent well conducted state-of-the-art case-control study of childhood cancers in the areas around German NPPs (KiKK study) showed a statistically significant cancers (2.2 fold increase in leukemia and a 1.6-fold increase in solid tumor) among children under five years of age living in the inner 5 km circle around NPPs when compared to residence outside this area. These findings have been confirmed by two meta analyses. Nevertheless, other UK, France, Spain and Finland studies did not find cancer incidence and/or death increase near NPPs. CONCLUSIONS: Increased cancer risk near NPPs remains in fact an open question. The stronger evidence from the KiKK study suggests there may well be such increases at least in children regardless of the country in which nuclear reactors are located. In fact, few months ago the U.S. Nuclear Regulatory Commission has asked the National Academy of Sciences (NAS) to perform a state-of-the-art study on cancer risk for populations surrounding NPPs. PMID- 20831816 TI - Regulated degradation of the APC coactivator Cdc20. AB - BACKGROUND: Cdc20 is a highly conserved activator of the anaphase-promoting complex (APC), promoting cell-cycle-regulated ubiquitination and proteolysis of a number of critical cell-cycle-regulatory targets including securin and mitotic cyclins. APC-Cdc20 activity is tightly regulated, and this regulation is likely important for accurate cell cycle control. One significant component of Cdc20 regulation is thought to be Cdc20 proteolysis. However, published literature suggests different mechanisms and requirements for Cdc20 proteolysis. The degree to which Cdc20 proteolysis is cell-cycle regulated, the dependence of Cdc20 proteolysis on Cdc20 destruction boxes (recognition sequences for APC-mediated ubiqutination, either by Cdc20 or by the related Cdh1 APC activator), and the need for APC itself for Cdc20 proteolysis all have been disputed to varying extents. In animals, Cdc20 proteolysis is thought to be mediated by Cdh1, contributing an intrinsic order of APC activation by Cdc20 and then by Cdh1. One report suggests a Cdh1 requirement for Cdc20 proteolysis in budding yeast; this idea has not been tested further. RESULTS: We characterized Cdc20 proteolysis using Cdc20 expressed from its endogenous locus; previous studies generally employed strongly overexpressed Cdc20, which can cause significant artifacts. We analyzed Cdc20 proteolysis with or without mutations in previously identified destruction box sequences, using varying methods of cell cycle synchronization, and in the presence or absence of Cdh1. Cdc20 instability is only partially dependent on destruction boxes. A much stronger dependence on Cdh1 for Cdc20 proteolysis was observed, but Cdh1-independent proteolysis was also clearly observed. Cdc20 proteolysis independent of both destruction boxes and Cdh1 was especially detectable around the G1/S transition; Cdh1-dependent proteolysis was most notable in late mitosis and G1. CONCLUSIONS: Cdc20 proteolysis is under complex control, with different systems operating at different points in the cell cycle. This complexity is likely to explain apparent conflicts in previously published literature on this subject. A major mode of control of Cdc20 proteolysis occurs in late mitosis/early G1 and is Cdh1-dependent, as in animal cells; this mode may contribute to the known sequential activation of the APC by Cdc20 followed by Cdh1. An independent mode of Cdc20 proteolysis, independent of destruction boxes and Cdh1, occurs at G1/S; we do not know the mechanism or function of this mode of proteolysis, but speculate that it may contribute to sharpening and restricting activation of APC-Cdc20 to early mitosis. PMID- 20831817 TI - Characterization of tetracycline modifying enzymes using a sensitive in vivo reporter system. AB - BACKGROUND: Increasing our understanding of antibiotic resistance mechanisms is critical. To enable progress in this area, methods to rapidly identify and characterize antibiotic resistance conferring enzymes are required. RESULTS: We have constructed a sensitive reporter system in Escherichia coli that can be used to detect and characterize the activity of enzymes that act upon the antibiotic, tetracycline and its derivatives. In this system, expression of the lux operon is regulated by the tetracycline repressor, TetR, which is expressed from the same plasmid under the control of an arabinose-inducible promoter. Addition of very low concentrations of tetracycline derivatives, well below growth inhibitory concentrations, resulted in luminescence production as a result of expression of the lux genes carried by the reporter plasmid. Introduction of another plasmid into this system expressing TetX, a tetracycline-inactivating enzyme, caused a marked loss in luminescence due to enzyme-mediated reduction in the intracellular Tc concentration. Data generated for the TetX enzyme using the reporter system could be effectively fit with the known Km and kcat values, demonstrating the usefulness of this system for quantitative analyses. CONCLUSION: Since members of the TetR family of repressors regulate enzymes and pumps acting upon almost every known antibiotic and a wide range of other small molecules, reporter systems with the same design as presented here, but employing heterologous TetR-related proteins, could be developed to measure enzymatic activities against a wide range of antibiotics and other compounds. Thus, the assay described here has far reaching applicability and could be adapted for high-throughput applications. PMID- 20831818 TI - Evaluation of multicomponent recombinant vaccines against Actinobacillus pleuropneumoniae in mice. AB - BACKGROUND: Porcine contagious pleuropneumonia (PCP) is a highly contagious disease that is caused by Actinobacillus pleuropneumoniae (APP) and characterized by severe fibrinous necrotizing hemorrhagic pleuropneumonia, which is a severe threat to the swine industry. In addition to APP RTX-toxins I (ApxI), APP RTX toxin II (ApxII), APP RTX-toxin III (ApxIII) and Outer membrane protein (OMP), there may be other useful antigens that can contribute to protection. In the development of an efficacious vaccine against APP, the immunogenicities of multicomponent recombinant subunit vaccines were evaluated. METHODS: Six major virulent factor genes of APP, i.e., apxI, apxII, apxIII, APP RTX-toxins IV (apxIV), omp and type 4 fimbrial structural (apfa) were expressed. BALB/c mice were immunized with recombinant ApxI ( rApxI), recombinant ApxII (rApxII), recombinant ApxIII (rApxIII) and recombinant OMP (rOMP) (Group I); rApxI, rApxII, rApxIII, recombinant ApxIV (rApxIV), recombinant Apfa (rApfa) and rOMP (Group II); APP serotype 1 (APP1) inactivated vaccine (Group III); or phosphate-buffered saline (PBS) (Control group), respectively. After the first immunization, mice were subjected to two booster immunizations at 2-week intervals, followed by challenge with APP1 Shope 4074 and APP2 S1536. RESULTS: The efficacy of the multicomponent recombinant subunit vaccines was evaluated on the basis of antibody titers, survival rates, lung lesions and indirect immunofluorescence (IIF) detection of APP. The antibody level of Group I was significantly higher than those of the other three groups (P < 0.05). The survival rate of Group I was higher than that of Groups II and III (P < 0.05) and the control (P < 0.01). Compared with the other three groups, the lungs of Group I did not exhibit obvious hemorrhage or necrosis, and only showed weak and scattered fluorescent dots by IIF detection. CONCLUSION: The result indicates that the multicomponent recombinant subunit vaccine composed of rApxI, rApxII, rApxIII and rOMP can provide effective cross-protection against homologous and heterologous APP challenge. PMID- 20831819 TI - 'ZP domain' of human zona pellucida glycoprotein-1 binds to human spermatozoa and induces acrosomal exocytosis. AB - BACKGROUND: The human egg coat, zona pellucida (ZP), is composed of four glycoproteins designated as zona pellucida glycoprotein-1 (ZP1), -2 (ZP2), -3 (ZP3) and -4 (ZP4) respectively. The zona proteins possess the archetypal 'ZP domain', a signature domain comprised of approximately 260 amino acid (aa) residues. In the present manuscript, attempts have been made to delineate the functional significance of the 'ZP domain' module of human ZP1, corresponding to 273-551 aa fragment of human ZP1. METHODS: Baculovirus-expressed, nickel nitrilotriacetic acid affinity chromatography purified 'ZP domain' of human ZP1 was employed to assess its capability to bind and subsequently induce acrosomal exocytosis in capacitated human spermatozoa using tetramethyl rhodamine isothiocyanate conjugated Pisum sativum Agglutinin in absence or presence of various pharmacological inhibitors. Binding characteristics of ZP1 'ZP domain' were assessed employing fluorescein isothiocyanate (FITC) labelled recombinant protein. RESULTS: SDS-PAGE and immunoblot characterization of the purified recombinant protein (both from cell lysate as well as culture supernatant) revealed a doublet ranging from ~35-40 kDa. FITC- labelled 'ZP domain' of ZP1 binds primarily to the acrosomal cap of the capacitated human spermatozoa. A dose dependent increase in acrosomal exocytosis was observed when capacitated sperm were incubated with recombinant 'ZP domain' of human ZP1. The acrosome reaction mediated by recombinant protein was independent of Gi protein-coupled receptor pathway, required extra cellular calcium and involved both T- and L-type voltage operated calcium channels. CONCLUSIONS: Results described in the present study suggest that the 'ZP domain' module of human ZP1 has functional activity and may have a role during fertilization in humans. PMID- 20831820 TI - Role of surface charge and oxidative stress in cytotoxicity of organic monolayer coated silicon nanoparticles towards macrophage NR8383 cells. AB - BACKGROUND: Surface charge and oxidative stress are often hypothesized to be important factors in cytotoxicity of nanoparticles. However, the role of these factors is not well understood. Hence, the aim of this study was to systematically investigate the role of surface charge, oxidative stress and possible involvement of mitochondria in the production of intracellular reactive oxygen species (ROS) upon exposure of rat macrophage NR8383 cells to silicon nanoparticles. For this aim highly monodisperse (size 1.6 +/- 0.2 nm) and well characterized Si core nanoparticles (Si NP) were used with a surface charge that depends on the specific covalently bound organic monolayers: positively charged Si NP-NH2, neutral Si NP-N3 and negatively charged Si NP-COOH. RESULTS: Positively charged Si NP-NH2 proved to be more cytotoxic in terms of reducing mitochondrial metabolic activity and effects on phagocytosis than neutral Si NP N3, while negatively charged Si NP-COOH showed very little or no cytotoxicity. Si NP-NH2 produced the highest level of intracellular ROS, followed by Si NP-N3 and Si NP-COOH; the latter did not induce any intracellular ROS production. A similar trend in ROS production was observed in incubations with an isolated mitochondrial fraction from rat liver tissue in the presence of Si NP. Finally, vitamin E and vitamin C induced protection against the cytotoxicity of the Si NP NH2 and Si NP-N3, corroborating the role of oxidative stress in the mechanism underlying the cytotoxicity of these Si NP. CONCLUSION: Surface charge of Si-core nanoparticles plays an important role in determining their cytotoxicity. Production of intracellular ROS, with probable involvement of mitochondria, is an important mechanism for this cytotoxicity. PMID- 20831821 TI - An ethnobotanical survey of plants used to manage HIV/AIDS opportunistic infections in Katima Mulilo, Caprivi region, Namibia. AB - Katima Mulilo has the highest burden of HIV/AIDS in Namibia. Due to several constraints of the antiretroviral therapy programme, HIV-infected persons still use ethnomedicines to manage AIDS-related opportunistic infections. Despite the reliance on plants to manage HIV/AIDS in Katima Mulilo, there have been no empirical studies to document the specific plant species used by traditional healers to treat AIDS-related opportunistic infections. In this study, an ethnobotanical survey was conducted to record the various plant families, species, and plant parts used to manage different HIV/AIDS-related opportunistic infections in Katima Mulilo, Caprivi region, Namibia. The results showed that a total of 71 plant species from 28 families, mostly the Combretaceae (14%), Anacardiaceae (8%), Mimosaceae (8%), and Ebanaceae (7%), were used to treat conditions such as herpes zoster, diarrhoea, coughing, malaria, meningitis, and tuberculosis. The most plant parts used were leaves (33%), bark (32%), and roots (28%) while the least used plant parts were fruits/seeds (4%). Further research is needed to isolate the plants' active chemical compounds and understand their modes of action. PMID- 20831822 TI - Health-related quality of life, and its determinants, among older people in rural Vietnam. AB - BACKGROUND: The proportion of people in Vietnam aged 60 and above has increased rapidly in recent decades. However, there is a lack of evidence, particularly in rural settings, on their health-related quality of life (HRQoL) within the context of socioeconomic changes and health-sector reform in the country. This study assesses the level and determinants of HRQoL in a rural district in order to provide evidence for designing and implementing appropriate health policies. METHODS: In 2007, 2,873 people aged 60+ living in 2,240 households randomly selected from the FilaBavi demographic surveillance site (DSS) were interviewed using a generic EQ-5D questionnaire to assess their HRQoL. Socioeconomic characteristics of the people and their households were extracted from the DSS's re-census that year, and the EQ-5D index was calculated based on the time trade off tariff. Multilevel-multivariate linear regression analysis was performed to measure the affect of socioeconomic factors on HRQoL. RESULTS: The EQ-5D index at old age was found to be 0.876 (95%CI: 0.870-0.882). Age between 60-69 or 70-79 years, position as household head, working until old age, literacy, and belonging to better wealth quintiles are determinants of higher HRQoL. Ageing has a primary influence on the deterioration of HRQoL at older ages, mainly due to reduction in physical rather than mental functions. Educational disparity in HRQoL is low, and exists mostly between basic and higher levels of education. Being a household head and working at old age are advantageous for attaining better quality of life in physical rather than psychological terms. Economic conditions affect HRQoL through sensory rather than physical utilities. Long-term living conditions more likely affect HRQoL than short-term economic conditions. CONCLUSIONS: HRQoL at old age is at a high level, and varies substantially according to socioeconomic factors. Its determinants should be addressed in social and health policies designed to improve health of older people, especially among the most vulnerable groups. PMID- 20831823 TI - Alterations in Vitamin D signalling and metabolic pathways in breast cancer progression: a study of VDR, CYP27B1 and CYP24A1 expression in benign and malignant breast lesions. AB - BACKGROUND: Breast cancer is a heterogeneous disease associated with different patient prognosis and responses to therapy. Vitamin D has been emerging as a potential treatment for cancer, as it has been demonstrated that it modulates proliferation, apoptosis, invasion and metastasis, among others. It acts mostly through the Vitamin D receptor (VDR) and the synthesis and degradation of this hormone are regulated by the enzymes CYP27B1 and CYP24A1, respectively. We aimed to study the expression of these three proteins by immunohistochemistry in a series of breast lesions. METHODS: We have used a cohort comprising normal breast, benign mammary lesions, carcinomas in situ and invasive carcinomas and assessed the expression of the VDR, CYP27B1 and CYP24A1 by immunohistochemistry. RESULTS: The results that we have obtained show that all proteins are expressed in the various breast tissues, although at different amounts. The VDR was frequently expressed in benign lesions (93.5%) and its levels of expression were diminished in invasive tumours (56.2%). Additionally, the VDR was strongly associated with the oestrogen receptor positivity in breast carcinomas. CYP27B1 expression is slightly lower in invasive carcinomas (44.6%) than in benign lesions (55.8%). In contrast, CYP24A1 expression was augmented in carcinomas (56.0% in in situ and 53.7% in invasive carcinomas) when compared with that in benign lesions (19.0%). CONCLUSIONS: From this study, we conclude that there is a deregulation of the Vitamin D signalling and metabolic pathways in breast cancer, favouring tumour progression. Thus, during mammary malignant transformation, tumour cells lose their ability to synthesize the active form of Vitamin D and respond to VDR-mediated Vitamin D effects, while increasing their ability to degrade this hormone. PMID- 20831824 TI - Case report of MR perfusion imaging in sinking skin flap syndrome: growing evidence for hemodynamic impairment. AB - BACKGROUND: The syndrome of the sinking skin flap (SSSF) with delayed sensorimotor deficits after craniectomy is not well known and often neglected. Among various postulated causes, there is evidence that disturbed brain perfusion may be related to the observed symptoms, and that cranioplasty reliably alleviates these symptoms. We report a case of sinking skin flap syndrome (SSFS) with recovery from neurological sensorimotor deficits after cranioplasty correlated with pre- and postsurgical MR brain perfusion studies. CASE PRESENTATION: A 42-year-old woman presented with slowly progressive sensorimotor paresis of her left arm after decompressive extensive craniectomy due to subarachnoid hemorrhage four months ago. Her right cranium showed a "sinking skin flap". After cranioplastic repair of her skull defect, the patient fully recovered from her symptoms. Before cranioplasty, reduced brain perfusion in the right central cortical region was observed in MR-perfusion images. After cranioplasty, a marked increase in brain perfusion was observed which correlated with objective clinical recovery. CONCLUSION: There is increasing evidence that impaired blood flow is responsible for delayed motor deficits in patients with sinking skin flap syndrome in the area of compressed brain regions. Symptoms should be evaluated by brain perfusion imaging complementing surgical decision making. PMID- 20831825 TI - Mechanisms of oxidative stress and alterations in gene expression by Libby six mix in human mesothelial cells. AB - BACKGROUND: Exposures to an amphibole fiber in Libby, Montana cause increases in malignant mesothelioma (MM), a tumor of the pleural and peritoneal cavities with a poor prognosis. Affymetrix microarray/GeneSifter analysis was used to determine alterations in gene expression of a human mesothelial cell line (LP9/TERT-1) by a non-toxic concentration (15*10(6) MUm2/cm2) of unprocessed Libby six-mix and negative (glass beads) and positive (crocidolite asbestos) controls. Because manganese superoxide dismutase (MnSOD; SOD2) was the only gene upregulated significantly (p < 0.05) at both 8 and 24 h, we measured SOD protein and activity, oxidative stress and glutathione (GSH) levels to better understand oxidative events after exposure to non-toxic (15*10(6) MUm2/cm2) and toxic concentrations (75*10(6) MUm2/cm2) of Libby six-mix. RESULTS: Exposure to 15*10(6) MUm2/cm2 Libby six-mix elicited significant (p < 0.05) upregulation of one gene (SOD2; 4-fold) at 8 h and 111 gene changes at 24 h, including a 5-fold increase in SOD2. Increased levels of SOD2 mRNA at 24 h were also confirmed in HKNM-2 normal human pleural mesothelial cells by qRT-PCR. SOD2 protein levels were increased at toxic concentrations (75*10(6) MUm2/cm2) of Libby six-mix at 24 h. In addition, levels of copper-zinc superoxide dismutase (Cu/ZnSOD; SOD1) protein were increased at 24 h in all mineral groups. A dose-related increase in SOD2 activity was observed, although total SOD activity remained unchanged. Dichlorodihydrofluorescein diacetate (DCFDA) fluorescence staining and flow cytometry revealed a dose- and time-dependent increase in reactive oxygen species (ROS) production by LP9/TERT-1 cells exposed to Libby six-mix. Both Libby six-mix and crocidolite asbestos at 75*10(6) MUm2/cm2 caused transient decreases (p < 0.05) in GSH for up to 24 h and increases in gene expression of heme oxygenase 1 (HO-1) in LP9/TERT-1 and HKNM-2 cells. CONCLUSIONS: Libby six-mix causes multiple gene expression changes in LP9/TERT-1 human mesothelial cells, as well as increases in SOD2, increased production of oxidants, and transient decreases in intracellular GSH. These events are not observed at equal surface area concentrations of nontoxic glass beads. Results support a mechanistic basis for the importance of SOD2 in proliferation and apoptosis of mesothelial cells and its potential use as a biomarker of early responses to mesotheliomagenic minerals. PMID- 20831826 TI - Configural frequency analysis as a method of determining patients' preferred decision-making roles in dialysis. AB - BACKGROUND: Numerous studies examined factors in promoting a patient preference for active participation in treatment decision making with only modest success. The purpose of this study was to identify types of patients wishing to participate in treatment decisions as well as those wishing to play a completely active or passive role based on a Germany-wide survey of dialysis patients; using a prediction typal analysis method that defines types as configurations of categories belonging to different attributes and takes particularly higher order interactions between variables into account. METHODS: After randomly splitting the original patient sample into two halves, an exploratory prediction configural frequency analysis (CFA) was performed on one-half of the sample (n = 1969) and the identified types were considered as hypotheses for an inferential prediction CFA for the second half (n = 1914). 144 possible prediction types were tested by using five predictor variables and control preferences as criterion. An alpha adjustment (0.05) for multiple testing was performed by the Holm procedure. RESULTS: 21 possible prediction types were identified as hypotheses in the exploratory prediction CFA; four patient types were confirmed in the confirmatory prediction CFA: patients preferring a passive role show low information seeking preference, above average trust in their physician, perceive their physician's participatory decision-making (PDM)-style positive, have a lower educational level, and are 56-75 years old (Type 1; p < 0.001) or > 76 years old (Type 2; p < 0.001). Patients preferring an active role show high information seeking preference, a higher educational level, and are < 55 years old. They have either below average trust, perceive the PDM-style negative (Type 3; p < 0.001) or above average trust and perceive the PDM-style positive (Type 4; p < 0.001). CONCLUSIONS: The method prediction configural frequency analysis was newly introduced to the research field of patient participation and could demonstrate how a particular control preference role is determined by an association of five variables. PMID- 20831827 TI - The pituri story: a review of the historical literature surrounding traditional Australian Aboriginal use of nicotine in Central Australia. AB - The harmful outcomes of nicotine self administration have been the focus of sustained global health education campaigns that have targeted tobacco smoking and to a lesser extent, smokeless tobacco use. 'Smokeless tobacco' infers that the nicotine is not burnt, and administration can be through a range of methods including chewing.The chewing of wild tobacco plants (Nicotiana spp.) is practiced across a broad inland area of Central Australia by traditional Aboriginal groups. Collectively these plants are known by a variety of names - one common name being 'pituri'. This is the first paper to examine the historical literature and consider the linkage between pituri use and health outcomes. Using a narrative approach, this paper reviews the literature generated since 1770 surrounding the term pituri and the behaviours associated with its use. The review examines the scientific literature, as well as the diaries and journals of nineteenth century explorers, expedition notes, and early Australian novels to expound the scientific evidence and broaden the sense of understanding related to pituri, particularly the behavioural elements. The evaluation considers the complexities of ethnobotany pertaining to language and distance and the ethnopharmacology of indigenous plant usage. The review compares the use of burnt and smokeless tobacco to pituri and establishes the foundation for research into the clinical significance and health outcomes of pituri use. Additionally, this review provides contemporary information for clinicians providing care for patients who chew pituri. PMID- 20831828 TI - Emerging role of radiation induced bystander effects: Cell communications and carcinogenesis. AB - Ionizing radiation is an invaluable diagnostic and treatment tool used in various clinical applications. On the other hand, radiation is a known cytotoxic with a potential DNA damaging and carcinogenic effects. However, the biological effects of low and high linear energy transfer (LET) radiations are considerably more complex than previously thought. In the past decade, evidence has mounted for a novel biological phenomenon termed as "bystander effect" (BE), wherein directly irradiated cells transmit damaging signals to non-irradiated cells thereby inducing a response similar to that of irradiated cells. BE can also be induced in various cells irrespective of the type of radiation, and the BE may be more damaging in the longer term than direct radiation exposure. BE is mediated either through gap-junctions or via soluble factors released by irradiated cells. DNA damage response mechanisms represent a vital line of defense against exogenous and endogenous damage caused by radiation and promote two distinct outcomes: survival and the maintenance of genomic stability. The latter is critical for cancer avoidance. Therefore, efforts to understand and modulate the bystander responses will provide new approaches to cancer therapy and prevention. This review overviews the emerging role of BE of low and high LET radiations on the genomic instability of bystander cells and its possible implications for carcinogenesis. PMID- 20831829 TI - Intraabdominal and retroperitoneal soft-tissue sarcomas--outcome of surgical treatment in primary and recurrent tumors. AB - BACKGROUND: Surgery is the only curative treatment for intraabdominal and retroperitoneal sarcoma (IaRS). Little is known about how to treat patients with recurrence. We here report the outcome in primary and recurrent sarcoma treated at the Sarcoma Center in Aarhus, Denmark. METHODS: All patients evaluated for IaRS from June 1998 to May 2008 were enrolled and data on symptoms, signs, means of diagnosis, extent of surgery, perioperative complications, mortality and long time survival were registered. Primary and first-recurrence sarcomas were analyzed separately. RESULTS: Sixty-five of 73 primary and 22 of 28 first recurrence IaRS had surgery. Fifty-three (82%) and 11 (50%) patients achieved radical R0 resection. Age and radicality of surgery were independent predictors of death, while recurrence of sarcoma was not. Perioperative mortality was 2.3%. 5-year survival was 70.2% for primary and 51.8% for first-recurrent sarcomas. However, patients with radical surgery had 5-year survival of over 70% in both the primary and recurrent group. CONCLUSIONS: The radicality of surgery is the most important prognostic factor. Patients with recurrence have an equally good prognosis as those with primary sarcoma if radicality is achieved and such surgery should not be considered only as a palliative effort. PMID- 20831830 TI - Removal of metallic tracheobronchial stents in lung transplantation with flexible bronchoscopy. AB - BACKGROUND: Airway complications are among the most challenging problems after lung transplantation, and Self-Expandable Metallic Stents (SEMS) are used to treat airway complications such as stenosis or malacia at the bronchial anastomosis sites. Several transplantation centers are reluctant to use SEMS since their removal is sometimes needed and usually requires the use of rigid bronchoscopy under general anesthesia. The objective of the current report is to describe our experience in SEMS retrieval by flexible bronchoscopy under conscious sedation. METHODS: A retrospective review was done of patients requiring tracheobronchial stent placement after lung transplantation in which the SEMS had to be removed. The retrieval procedure was done by flexible bronchoscopy on a day-care ambulatory basis. RESULTS: Between January 2004 and January 2010, out of 305 lung transplantation patients, 24 (7.8%) underwent SEMS placement. Indications included bronchial stenosis in 20 and bronchomalacia in 4. In six patients (25%) the SEMS had to be removed due to excessive granulation tissue formation and stent obstruction. The average time from SEMS placement to retrieval was 30 months (range 16-48 months). The stent was completely removed in five patients and partially removed in one patient; no major complications were encountered, and all patients were discharged within 3 hours of the procedure. In all procedures, new SEMS was successfully re-inserted thereafter. CONCLUSIONS: The retrieval of SEMS in patients that underwent lung transplantation can be effectively and safely done under conscious sedation using flexible bronchoscopy on a day-care basis, this observation should encourage increasing usage of SEMS in highly selected patients. PMID- 20831831 TI - The Neural/Immune Gene Ontology: clipping the Gene Ontology for neurological and immunological systems. AB - BACKGROUND: The Gene Ontology (GO) is used to describe genes and gene products from many organisms. When used for functional annotation of microarray data, GO is often slimmed by editing so that only higher level terms remain. This practice is designed to improve the summarizing of experimental results by grouping high level terms and the statistical power of GO term enrichment analysis. Here, we propose a new approach to editing the gene ontology, clipping, which is the editing of GO according to biological relevance. Creation of a GO subset by clipping is achieved by removing terms (from all hierarchal levels) if they are not functionally relevant to a given domain of interest. Terms that are located in levels higher to relevant terms are kept, thus, biologically irrelevant terms are only removed if they are not parental to terms that are relevant. RESULTS: Using this approach, we have created the Neural-Immune Gene Ontology (NIGO) subset of GO directed for neurological and immunological systems. We tested the performance of NIGO in extracting knowledge from microarray experiments by conducting functional analysis and comparing the results to those obtained using the full GO and a generic GO slim. NIGO not only improved the statistical scores given to relevant terms, but was also able to retrieve functionally relevant terms that did not pass statistical cutoffs when using the full GO or the slim subset. CONCLUSIONS: Our results validate the pipeline used to generate NIGO, suggesting it is indeed enriched with terms that are specific to the neural/immune domains. The results suggest that NIGO can enhance the analysis of microarray experiments involving neural and/or immune related systems. They also directly demonstrate the potential such a domain-specific GO has in generating meaningful hypotheses. PMID- 20831832 TI - Isolation and characterization of a virus (CvV-BW1) that infects symbiotic algae of Paramecium bursaria in Lake Biwa, Japan. AB - BACKGROUND: We performed an environmental study of viruses infecting the symbiotic single-celled algae of Paramecium bursaria (Paramecium bursaria Chlorella virus, PBCV) in Lake Biwa, the largest lake in Japan. The viruses detected were all Chlorella variabilis virus (CvV = NC64A virus). One of them, designated CvV-BW1, was subjected to further characterization. RESULTS: CvV-BW1 formed small plaques and had a linear DNA genome of 370 kb, as judged by pulsed field gel electrophoresis. Restriction analysis indicated that CvV-BW1 DNA belongs to group H, one of the most resistant groups among CvV DNAs. Based on a phylogenetic tree constructed using the dnapol gene, CvV was classified into two clades, A and B. CvV-BW1 belonged to clade B, in contrast to all previously identified virus strains of group H that belonged to clade A. CONCLUSIONS: We conclude that CvV-BW1 composes a distinct species within C. variabilis virus. PMID- 20831833 TI - Membrane proteomic analysis of pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer is one of the most aggressive human tumors due to its high potential of local invasion and metastasis. The aim of this study was to characterize the membrane proteomes of pancreatic ductal adenocarcinoma (PDAC) cells of primary and metastatic origins, and to identify potential target proteins related to metastasis of pancreatic cancer. METHODS: Membrane/membrane associated proteins were isolated from AsPC-1 and BxPC-3 cells and identified with a proteomic approach based on SDS-PAGE, in-gel tryptic digestion and liquid chromatography with tandem mass spectrometry (LC-MS/MS). X! Tandem was used for database searching against the SwissProt human protein database. RESULTS: We identified 221 & 208 proteins from AsPC-1 and BxPC-3 cells, respectively, most of which are membrane or membrane-associated proteins. A hundred and nine proteins were found in both cell lines while the others were present in either AsPC-1 or BxPC-3 cells. Differentially expressed proteins between two cell lines include modulators of cell adhesion, cell motility or tumor invasion as well as metabolic enzymes involved in glycolysis, tricarboxylic acid cycle, or nucleotide/lipid metabolism. CONCLUSION: Membrane proteomes of AsPC-1 (metastatic) and BxPC-3 (primary) cells are remarkably different. The differentially expressed membrane proteins may serve as potential targets for diagnostic and therapeutic interventions. PMID- 20831834 TI - Excluding pulmonary embolism in primary care using the Wells-rule in combination with a point-of care D-dimer test: a scenario analysis. AB - BACKGROUND: In secondary care the Wells clinical decision rule (CDR) combined with a quantitative D-dimer test can exclude pulmonary embolism (PE) safely. The introduction of point-of-care (POC) D-dimer tests facilitates a similar diagnostic strategy in primary care.We estimated failure-rate and efficiency of a diagnostic strategy using the Wells-CDR combined with a POC-D-dimer test for excluding PE in primary care.We considered ruling out PE safe if the failure rate was <2% with a maximum upper confidence limit of 2.7%. METHODS: We performed a scenario-analysis on data of 2701 outpatients suspected of PE. We used test characteristics of two qualitative POC-D-dimer tests, as derived from a meta analysis and combined these with the Wells-CDR-score. RESULTS: In scenario 1 (SimpliRed-D-dimer sensitivity 85%, specificity 74%) PE was excluded safely in 23.8% of patients but only by lowering the cut-off value of the Wells rule to <2. (failure rate: 1.4%, 95% CI 0.6-2.6%)In scenario 2 (Simplify-D-dimer sensitivity 87%, specificity 62%) PE was excluded safely in 12.4% of patients provided that the Wells-cut-off value was set at 0. (failure rate: 0.9%, 95% CI 0.2-2.6%) CONCLUSION: Theoretically a diagnostic strategy using the Wells-CDR combined with a qualitative POC-D-dimer test can be used safely to exclude PE in primary care albeit with only moderate efficiency. PMID- 20831836 TI - EXercising with Computers in Later Life (EXCELL) - pilot and feasibility study of the acceptability of the Nintendo(r) WiiFit in community-dwelling fallers. AB - BACKGROUND: Falls management programmes have been instituted to attempt to reduce falls. This pilot study was undertaken to determine whether the Nintendo(r) WiiFit was a feasible and acceptable intervention in community-dwelling older fallers. FINDINGS: Community-dwelling fallers over 70 years were recruited and attended for computer-based exercises (n = 15) or standard care (n = 6). Balance and fear of falling were assessed at weeks 0, 4 and 12. Participants were interviewed on completion of the study to determine whether the intervention was acceptable.Eighty percent of participants attended 75% or more of the exercise sessions. An improvement in Berg Score was seen at four weeks (p = 0.02) and in Wii Age at 12 weeks (p = 0.03) in the intervention group. There was no improvement in balance scores in the standard care group. CONCLUSION: WiiFit exercise is acceptable in self-referred older people with a history of falls. The WiiFit has the potential to improve balance but further work is required. TRIAL REGISTRATION: ClinicalTrials.gov - NCT01082042. PMID- 20831835 TI - 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine ameliorates age-related spatial memory deterioration by preventing neuronal cell death. AB - BACKGROUND: Accumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways. Endoplasmic reticulum (ER) stress-induced neuronal apoptosis, on the other hand, is a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage. The present study examined the effects of 1,2-dilinoleoyl-sn-glycero-3 phosphoethanolamine (DLPhtEtn), a phospholipid, on ER stress-induced neuronal death and age-related cognitive disorders. METHODS: PC-12 cell viability was assayed before and after treatment with amyloid-beta(1-40) peptide or thapsigargin in the presence and absence of DLPhtEtn. A series of behavioral tests were performed for senescence-accelerated mouse-prone 8 (SAMP8) mice after 7-month oral administration with polyethylene glycol (PEG) or DLPhtEtn and then, the number of hippocampal neurons was counted. RESULTS: Amyloid-beta(1-40) peptide or thapsigargin is capable of causing ER stress-induced apoptosis. DLPhtEtn (30 MUM) significantly inhibited PC-12 cell death induced by amyloid beta(1-40) peptide or thapsigargin. In the water maze test, oral administration with DLPhtEtn (1 mg/kg) for 7 months (three times a week) significantly shortened the prolonged retention latency for SAMP8 mice. In contrast, DLPhtEtn had no effect on the acquisition and retention latencies in both the open field test and the passive avoidance test for SAMP8 mice. Oral administration with DLPhtEtn (1 mg/kg) for 7 months prevented a decrease in the number of hippocampal neurons for SAMP8 mice. CONCLUSION: The results of the present study show that DLPhtEtn ameliorates age-related spatial memory decline without affecting motor activities or fear memory, possibly by protecting hippocampal neuronal death. DLPhtEtn, thus, might exert its beneficial action against senile dementia and neurodegenerative diseases such as Alzheimer disease. PMID- 20831837 TI - Patient- and provider-related determinants of generic and specific health-related quality of life of patients with chronic systolic heart failure in primary care: a cross-sectional study. AB - BACKGROUND: Identifying the determinants of health-related quality of life (HRQOL) in patients with systolic heart failure (CHF) is rare in primary care; studies often lack a defined sample, a comprehensive set of variables and clear HRQOL outcomes. Our aim was to explore the impactof such a set of variables on generic and disease-specific HRQOL. METHODS: In a cross-sectional study, we evaluated data from 318 eligible patients. HRQOL measures used were the SF-36 (Physical/Mental Component Summary, PCS/MCS) and four domains of the KCCQ (Functional status, Quality of life, Self efficacy, Social limitation). Potential determinants (instruments) included socio-demographical variables (age, sex, socio-economic status: SES), clinical (e.g. NYHA class, LVEF, NT-proBNP levels, multimorbidity (CIRS-G)), depression (PHQ-9), behavioural (EHFScBs and prescribing) and provider (e.g. list size of and number. of GPs in practice) variables. We performed linear (mixed) regression modelling accounting for clustering. RESULTS: Patients were predominantly male (71.4%), had a mean age of 69.0 (SD: 10.4) years, 12.9% had major depression, according to PHQ-9. Across the final regression models, eleven determinants explained 27% to 55% of variance (frequency across models, lowest/highest beta): Depression (6*, -0.3/-0.7); age (4*, -0.1/-0.2); multimorbidity (4*, 0.1); list size (2*, -0.2); SES (2*, 0.1/0.2); and each of the following once: no. of GPs per practice, NYHA class, COPD, history of CABG surgery, aldosterone antagonist medication and Self-care (0.1/-0.2/-0.2/0.1/-0.1/-0.2). CONCLUSIONS: HRQOL was determined by a variety of established individual variables. Additionally the presence of multimorbidity burden, behavioural (self-care) and provider determinants may influence clinicians in tailoring care to individual patients and highlight future research priorities. PMID- 20831838 TI - The Worksite Health Promotion Capacity Instrument (WHPCI): development, validation and approaches for determining companies' levels of health promotion capacity. AB - BACKGROUND: The Worksite Health Promotion Capacity Instrument (WHPCI) was developed to assess two key factors for effective worksite health promotion: collective willingness and the systematic implementation of health promotion activities in companies. This study evaluates the diagnostic qualities of the WHPCI based on its subscales Health Promotion Willingness and Health Promotion Management, which can be used to place companies into four different categories based on their level of health promotion capacity. METHODS: Psychometric evaluation was conducted using exploratory factor and reliability analyses with data taken from a random sample of managers from n = 522 German information and communication technology (ICT) companies. Receiver operating characteristic (ROC) analyses were conducted to determine further diagnostic qualities of the instrument and to establish the cut-off scores used to determine each company's level of health promotion capacity. RESULTS: The instrument's subscales, Health Promotion Willingness and Health Promotion Management, are based on one dimensional constructs, each with very good reliability (Cronbach's alpha = 0.83/0.91). ROC analyses demonstrated satisfactory diagnostic accuracy with an area under the curve (AUC) of 0.76 (SE = 0.021; 95% CI 0.72-0.80) for the Health Promotion Willingness scale and 0.81 (SE = 0.021; 95% CI 0.77-0.86) for the Health Promotion Management scale. A cut-off score with good sensitivity (71%/76%) and specificity (69%/75%) was determined for each scale. Both scales were found to have good predictive power and exhibited good efficiency. CONCLUSIONS: Our findings indicate preliminary evidence for the validity and reliability of both subscales of the WHPCI. The goodness of each cut-off score suggests that the scales are appropriate for determining companies' levels of health promotion capacity. Support in implementing (systematic) worksite health promotion can then be tailored to each company's needs based on their current capacity level. PMID- 20831839 TI - Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women. AB - BACKGROUND: Considerably little is known about the biological role and clinical significance of androgen receptor expression in breast cancer. The objectives of this study were to characterize AR-CAG repeat genotypes in a cohort of women with breast cancer and to determine the influence of AR on response to neoadjuvant chemotherapy and clinical outcome. MATERIALS AND METHODS: Genotyping of the AR CAG repeat region was done on 70 patients and 80 healthy aged- matched female controls. To assess response to NACT, tissue samples from 30 LABC cases were evaluated quantitatively by real time for AR mRNA expression. The clinical response was correlated with both the pre and post chemotherapy AR expression. The CAG alleles did not show differences between cases and controls when the mean of short, long and average length of both CAG alleles was considered. However, analysis when done defining short allele as CAGn < 20 (AR1) and the long as CAGn >= 20 (AR2), risk was found associated with AR2 allele with marginal significance (P = 0.09). Stratification by age of onset, FH, stage, grade ER and AR status failed to reveal any association with breast cancer risk. Genotype carriers with >= 20 CAGn showed decrease of AR mRNA expression although significance could not be established (P = 0.47). Tumours in responders had the higher AR mRNA expression levels in pre neo-adjuvant chemotherapy condition (p < 0.02) which got reduced after neoadjuvant chemotherapy and the difference was found to be significant (P = 0.014). CONCLUSIONS: Although, expansion of the CAGn in the AR gene doesn't show any major effect on breast cancer risk, patients with positive AR expression, pre neoadjuvant chemotherapy, were found to be good responders and a decrease in mRNA level of AR gene related to the chemotherapy-induced apoptosis could serve as an important independent predictor of response to NACT. PMID- 20831841 TI - Tranexamic acid in cardiac surgery: is there a cause for concern? AB - The withdrawal of marketing approval for aprotinin resulted in more clinicians administering tranexamic acid to patients at increased risk of bleeding and adverse outcome. The latest in a series of retrospective analyses of observational data is published in Critical Care and suggests an increase in mortality, when compared to data from the aprotinin era, in those patients having surgery when a cardiac chamber is opened. The added observation of an increase in cerebral excitatory phenomena (seizure activity) with tranexamic acid has a known mechanism and questions if such patients should be given this drug. PMID- 20831840 TI - Three periods of one and a half decade of ischemic stroke susceptibility gene research: lessons we have learned. AB - Candidate gene association studies, linkage studies and genome-wide association studies have highlighted the role of genetic factors in the development of ischemic stroke. This research started over a decade ago, and can be separated into three major periods of research. In the first wave classic susceptibility markers associated with other diseases (such as the Leiden mutation in Factor V and mutations in the prothrombin and 5,10-methylenetetrahydrofolate reductase (MTHFR) genes) were tested for their role in stroke. These first studies used just a couple of hundred samples or even less. The second and still ongoing period bridges the two other periods of research and has led to a rapid increase in the spectrum of functional variants of genes or genomic regions, discovered primarily in relation to other diseases, tested on larger stroke samples of clinically better stratified patients. Large numbers of these alleles were originally discovered by array-based genome-wide association studies. The third period of research involves the direct array screening of large samples; this approach represents significant progress for research in the field. Research into susceptibility genes for stroke has taught us that careful stratification of patients is critical, that susceptibility alleles are often shared between diseases, and that not all susceptibility factors that associate with clinical traits that are themselves risk factors for stroke (such as increase of triglycerides) necessarily represent susceptibility for stroke. Research so far has been mainly focused on large- and small-vessel associated stroke, and knowledge on other types of stroke, which represent much smaller population samples, is still very scarce. Although some susceptibility allele tests are on the palette of some direct-to-consumer companies, the clinical utility and clinical validity of these test results still do not support their use in clinical practice. PMID- 20831842 TI - From GWAS to the clinic: risk factors for intracranial aneurysms. AB - Subarachnoid hemorrhage (SAH) from a ruptured intracranial aneurysm is a devastating subset of stroke, occurring in relatively young people (mean age around 50 years) of whom around a third die within the initial weeks after the bleed. Environmental and genetic risk factors both have a role in SAH. A recent genome-wide association study of intracranial aneurysms in Finnish, Dutch and Japanese cohorts totaling 5,891 cases and 14,181 controls identified three new loci strongly associated with intracranial aneurysms on chromosomes 18q11.2 and 10q24.32, and replicated two previously found loci on chromosomes 8q11.23-q12.1 and 9p21.3. However, these five intracranial aneurysm risk loci identified so far explain only up to 5% of the familial risk of intracranial aneurysms, which makes genetic risk prediction tests currently unfeasible for intracranial aneurysms. New approaches, including identification of causal variants, rare variants and copy number variants, such as insertions and deletions, may improve genetic risk prediction for SAH and intracranial aneurysms. This may lead to diagnostic tools for identifying individuals at increased risk for aneurysm formation and rupture of aneurysms. In this way, genetic diagnostic tools will identify the people who will benefit most from screening by imaging studies for aneurysms and those who are most likely to benefit from preventive treatment of incidentally discovered aneurysms. PMID- 20831843 TI - Relationship between growth behaviour, micro and macroscopic morphologies and freezing sensitivity of the ripening starter Geotrichum candidum is strain specific and mostly related to the morphotypes: the arthrospores/hyphae parameter. AB - Microscopic conformation, growth behaviour and freezing sensitivity of seven strains of Geotrichum candidum, a ripening starter, were studied and compared according to their macroscopic morphotypes. It has been shown that the thallus forming units (TFU)*ml-1/OD600nm ratio as a function of time is an interesting parameter to follow G. candidum sporulation through the growth behaviour. Microscopic conformation, growth behaviour and freezing sensitivity are clearly strain specific and mostly related to their corresponding morphotypes "yeast", "mould" or "intermediate". The two "mould" strains that sporulate weakly (UCMA103, UCMA499) showed a low survival rate to freezing stress whereas the "yeast" strains expressed a significant resistance owing to the arthrospore abundance. Interestingly, one strain (UCMA96) which appeared on solid medium in accord with the "mould" morphotype respond similarly to freezing stress. PMID- 20831844 TI - Major lipids and fatty acids in the liver and rumen fluid of the goat (Capra hircus) infected with the trematode Paramphistomum cervi. AB - The present study records the occurrence of major lipid fractions and their fatty acids in a digenetic trematode parasite Paramphistomum cervi, and the rumen fluid and liver of the goat (Capra hircus). The amount of neutral lipids (NL), glycolipids (GL) and phospholipids (PL) of goat liver, rumen fluid and of the parasite shows that the rumen fluid is rich in NL, which is also in maximum quantity in the parasite, while the liver is rich in PL followed by NL. The number of fatty acids of total lipids (TL), NL and PL is greater in the parasite than those of the liver and rumen fluid. The number of fatty acids of GL is higher in the liver than in the parasite and the rumen fluid. Comparison of unsaturated fatty acid (UFA), C18 total and C18 UFA of TL, NL, GL and PL of the liver, rumen fluid and the parasite shows that the amount of C18 UFA is higher in P. cervi in all the lipid fractions, except for GL, than in the rumen fluid and the liver. The results reveal that P. cervi absorbs a greater number of fatty acids than its host. PMID- 20831845 TI - Validation of self-reported hearing loss using television volume. AB - OBJECTIVE: To assess the diagnostic utility of using television volume as a marker for hearing loss. STUDY DESIGN: Prospective study using a self administered questionnaire. SETTING: ENT and audiology out-patient departments in the north of England. PARTICIPANTS: One hundred and seventeen patients with a history of hearing loss, undergoing pure tone audiometry for the first time. MAIN OUTCOME MEASURES: sensitivity, specificity, diagnostic accuracy, and positive and negative predictive value of television volume as a marker of hearing loss. RESULTS: The data indicated that if the patient (or their partner or parent) reported viewing television with an increased volume, then there was a 68 per cent chance of the patient having a hearing loss of 25 dB or more. Patients reporting increased television volume had a mean hearing loss of 35 dB. Increased television volume had a sensitivity of 81 per cent and a specificity of 52 per cent as a predictor of hearing loss. Patients who increased their television volume to watch news programmes had an average hearing loss of 41 dB; increased television volume for news programmes had a sensitivity of 75 per cent and a specificity of 71 per cent as a predictor of hearing loss. CONCLUSIONS: Television volume is a useful marker of hearing loss in situations where audiometry is unavailable, for instance in a primary care setting. However, it is not a very specific test. PMID- 20831846 TI - Cholesteatoma imaging using modified echo-planar diffusion-weighted magnetic resonance imaging. AB - INTRODUCTION: Imaging of cholesteatomas can be useful especially in cases of recurrent disease. Computed tomography scans have been recommended before primary surgery, but cholesteatoma tissue looks similar to inflammatory tissue. Diffusion weighted magnetic resonance imaging is both sensitive and specific in detecting cholesteatoma, which appears as a bright signal on a dark background. Non-echo planar diffusion-weighted magnetic resonance imaging is superior to routine echo planar diffusion-weighted magnetic resonance imaging as it minimises susceptibility artefacts; however, the addition of this facility involves expensive magnetic resonance scanner upgrading. METHOD: To avoid the cost of such upgrading, we modified our echo-planar diffusion-weighted magnetic resonance imaging parameters and then scanned 15 consecutive cases of suspected cholesteatoma or suspected recurrent cholesteatoma. RESULTS: Imaging results correlated well with clinical and/or operative findings. CONCLUSION: These results indicate that software adjustments can enable echo-planar diffusion weighted magnetic resonance imaging to detect cholesteatomas reliably, and as effectively as non-echo-planar diffusion-weighted magnetic resonance imaging. This discovery has the potential to facilitate reliable delayed post-operative screening of canal wall up mastoidectomies, avoiding the need for a 'second look' procedure. PMID- 20831847 TI - Determinants of induced abortion: an analysis of individual, household and contextual factors in Rajasthan, India. AB - In the developing world, little is known about the risk and precipitating factors for abortion, due to a dearth of community-based surveys. Most analyses of determinants of induced abortion consider only a small set of household and individual socio-demographic factors and treat abortion as an isolated outcome, which ignores its relationship with prior reproductive health behaviours and experiences. In this paper, data from a cross-sectional survey of abortion knowledge, attitudes and practices among 2571 currently married women of reproductive age in Rajasthan, India, were used to examine contextual-, household and individual-level determinants of abortion. Bivariate probit models, which jointly determine the probability of pregnancy and the conditional probability of abortion, were used to reflect the probability of abortion as a result of interrelated and sequential events. Increased socioeconomic status and life-cycle factors were associated with both the probability of pregnancy and with the conditional likelihood of abortion. Women who reported personal networks were also more likely to terminate pregnancies, particularly if their network members purportedly had abortion experience. Community knowledge of sex-selective abortion also exerted a significant positive effect on the propensity to terminate a pregnancy. For rural women only, community beliefs regarding spousal consent requirements pre-abortion were also significantly associated with abortion. PMID- 20831848 TI - The parasite community of the nase Chondrostoma nasus (L. 1758) from Austrian rivers. AB - Between April 2003 and November 2006 a total of 191 individuals of the predominantly herbivorous fish species nase Chondrostoma nasus (L. 1758) were examined for parasites from six river sites in Austria. The following parasite taxa were recovered--Ciliata: Trichodina sp., Chilodonella piscicola, Ichthyophthirius multifiliis; Myxozoa: Myxobolus muelleri (cysts) and Myxobolus sp. (cysts); Monogenea: Dactylogyrus vistulae, D. chondrostomi and Dactylogyrus spp., Gyrodactylus sp., Diplozoon paradoxum; Digenea: Diplostomum spathaceum (larv.) and Tylodelphis clavata (larv.); Cestoda: Caryophyllaeus laticeps; Acanthocephala: Pomphorhynchus laevis; Bivalvia: Unio sp. (Glochidia); Crustacea: Lamproglena pulchella; Hirudinea: Piscicola geometra. The only taxa occurring at all sample sites were Dactylogyrus spp., which was also the dominant taxon at most sites, and Myxobolus muelleri, both from the gills of the fish. This is the first record of the parasite community of the nase in Austria. PMID- 20831849 TI - Frontal sinus models and onlay templates in osteoplastic flap surgery. AB - OBJECTIVE: Precise delineation of the extent of frontal sinus pneumatisation is a crucial step in osteoplastic flap frontal sinus surgery. The authors present a novel method of achieving this objective. METHODS: First, models of the frontal area are generated using three-dimensional printing based on pre-operative computed tomography image data. These models are then used to create an onlay template of the frontal sinus, which is used intra-operatively. RESULTS: In a series of 10 patients undergoing osteoplastic flap frontal sinus surgery, the described frontal sinus templates were consistently accurate to within 1 mm. CONCLUSION: Frontal sinus templates are potentially useful adjuncts to current techniques employed to guide frontal sinus surgery. PMID- 20831850 TI - Endaural meatoplasty: the Whipps Cross technique. AB - OBJECTIVE: To describe our technique of endaural meatoplasty for mastoid surgery, and to publish an online video demonstration. METHOD: After the endaural incision, a skin incision is accurately marked over the anterior conchal bowl, identified by pushing the anti-helix anteriorly. This should meet the line of the endaural incision superiorly and extend inferiorly to the lower anterior edge of the conchal cartilage. After performing the incision, a segment of conchal cartilage is removed. The soft tissue meatoplasty is facilitated by resecting a triangular segment of skin and underlying soft tissue medial to the conchal incision (on which it is based). The free edges are closed with absorbable sutures after the (attico)mastoidectomy. RESULTS: We have used this method on 64 patients over the past two years. Satisfactory functional and cosmetic outcomes were achieved in all. CONCLUSION: Our technique is simple, easy to learn, quick and effective in helping to achieve our goal of a dry mastoid cavity with an adequate meatoplasty. PMID- 20831851 TI - Managing calcified canal systems: audiovisual presentation. PMID- 20831852 TI - Impact of periodontitis on the diabetes-related inflammatory status. AB - Wide-ranging activation of the innate immune system causing chronic low-grade inflammation is closely involved not only in the pathogenesis of type 2 diabetes mellitus and its complications, through an ongoing cytokine-induced acute-phase response, but also in the pathogenesis of periodontal diseases, whereby cytokines play a central role in the host's response to the periodontal biofilm. Although there is extensive knowledge about the pathways through which diabetes affects periodontal status, less is known about the impact of periodontal diseases on the diabetes-related inflammatory state. This review attempts to explain the immunobiological connection between periodontal diseases and type 2 diabetes mellitus, exploring the mechanisms through which periodontal infection can contribute to the low-grade general inflammation associated with diabetes (thus aggravating insulin resistance) and discussing the impact of periodontal treatment on glycemic control in people living with both diabetes and periodontal disease. PMID- 20831853 TI - Creating a research network of general dental practitioners: lessons learned from a pilot project. PMID- 20831854 TI - Fixed-term work and violence at work. AB - OBJECTIVES: This study investigated the effect of a fixed-term job contract on encounters of violence at work. We assumed that fixed-term employees encountered more violence or threats of violence at their work than permanent employees. METHODS: This study is based on 3 large statistical data sets: (a) the Work and Health surveys carried out by the Finnish Institute of Occupational Health in 1997-2006 (n=7,519); (b) the so-called Victim study carried out by Statistics Finland in 2006, where 4088 working people were interviewed about victimization resulting in injuries and violence; and (c) another study from Statistics Finland, which interviewed 4 392 wage-earners about their working conditions in 2008. RESULTS: One of the 3 data sets showed that fixed-term employees encountered more violence at work than permanent employees, whereas the other 2 did not show any difference between different contract groups. CONCLUSIONS: Our hypothesis concerning greater violence encounters among fixed-term employees was not confirmed. PMID- 20831855 TI - From innovation to application: social-ecological context, diagnostics, drugs and integrated control of schistosomiasis. AB - Compared to malaria, tuberculosis and HIV/AIDS, schistosomiasis remains a truly neglected tropical disease. Schistosomiasis, perhaps more than any other disease, is entrenched in prevailing social-ecological systems, since transmission is governed by human behaviour (e.g. open defecation and patterns of unprotected surface water contacts) and ecological features (e.g. living in close proximity to suitable freshwater bodies in which intermediate host snails proliferate). Moreover, schistosomiasis is intimately linked with poverty and the disease has spread to previously non-endemic areas as a result of demographic, ecological and engineering transformations. Importantly though, thanks to increased advocacy there is growing awareness, financial and technical support to control and eventually eliminate schistosomiasis as a public health problem at local, regional and global scales. The purpose of this review is to highlight recent progress made in innovation, validation and application of new tools and strategies for research and integrated control of schistosomiasis. First, we explain that schistosomiasis is deeply embedded in social-ecological systems and explore linkages with poverty. We then summarize and challenge global statistics, risk maps and burden estimates of human schistosomiasis. Discovery and development research pertaining to novel diagnostics and drugs forms the centrepiece of our review. We discuss unresolved issues and emerging opportunities for integrated and sustainable control of schistosomiasis and conclude with a series of research needs. PMID- 20831857 TI - The activity of phosphate-dependent glutaminase from the rat small intestine is modulated by ADP and is dependent on integrity of mitochondria. AB - The effect of adenine nucleotides and phosphate on rat small intestine phosphate dependent glutaminase (PDG) activity was investigated in intact mitochondria. Disruption of the integrity of mitochondria by sonication or freeze-thawing resulted in loss of enzyme activity. ADP was the strongest adenine nucleotide activator of the enzyme giving a V(max) that was over 5-fold of that for AMP or ATP. The sigmoid activation curve of PDG by ADP became hyperbolic in presence ATP. ADP also lowered the K(m) for glutamine and increased V(max) and these effects were further enhanced by the presence of ATP. Activation of PDG by phosphate and ADP was not completely additive suggesting some antagonism between the activators. There was no clear relationship between changing ATP/ADP ratios and PDG activity in presence of a constant concentration of phosphate. However, ratios of approximately 1:4 and 4:1 gave the highest and lowest activities, respectively. The pH dependence of PDG activity was affected by phosphate concentration and results suggest that the divalent ion is the activating species. PMID- 20831856 TI - gamma-Glutamyl transpeptidase is a heavily N-glycosylated heterodimer in HepG2 cells. AB - The cell surface enzyme gamma-glutamyl transpeptidase (GGT) is expressed by human hepatocellular carcinomas (HCCs). HCCs arise from malignant transformation of hepatocytes and are the most common form of primary liver cancer. Identification of tumor-specific, post-translational modifications of GGT may provide novel biomarkers for HCC. The HepG2 cell line, derived from a human HCC, has been used extensively in studies of liver cancer. However, the use of this cell line for studies of GGT have been stymied by reports that HepG2 cells do not process the GGT propeptide into its heterodimeric subunits. The data in this study demonstrate that HepG2 cells do, in fact, produce the mature heterodimeric form of GGT. Immunohistochemical and immunoaffinity analyses provide direct evidence that, in HepG2 cells, GGT is properly localized to the bile canaliculi. Three independent, experimental approaches demonstrate that GGT in HepG2 cells is comprised of two subunits that are more heavily N-glycosylated than GGT from normal human liver tissue. These data directly contradict the dogma in the field. These data support the use of HepG2 cells as a model system for analyzing tumor specific changes in the post-translational modifications of GGT. PMID- 20831858 TI - Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport. AB - The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/Per-ARNT-Sim domain transcription factor, which is activated by various xenobiotic ligands. AHR is known to be abundant in liver tissue and to be associated with hepatic steatosis. However, it has not yet been elucidated how the activation of AHR promotes hepatic steatosis. The aim of this study is to clarify the role of AHR in hepatic steatosis. The intraperitoneal injection of 3-methylcholanthrene (3MC), a potent AHR ligand, into C57BL/6J mice significantly increased the levels of triglycerides and six long-chain monounsaturated fatty acids in the livers of mice, resulting in hepatic microvesicular steatosis. 3MC significantly enhanced the expression level of fatty acid translocase (FAT), a factor regulating the uptake of long-chain fatty acids into hepatocytes, in the liver. In an in vitro experiment using human hepatoma HepG2 cells, 3MC increased the expression level of FAT, and the downregulation of AHR by AHR siRNA led to the suppression of 3MC induced FAT expression. In addition, the mRNA level of peroxisome proliferator activated receptor (PPAR) alpha, an upstream factor of FAT, was increased in the livers of 3MC-treated mice. Taking together, AHR activation induces hepatic microvesicular steatosis by increasing the expression level of FAT. PMID- 20831859 TI - The identity of the transient proton loading site of the proton-pumping mechanism of cytochrome c oxidase. AB - Cellular respiration is driven by cytochrome c oxidase (CcO), which reduces oxygen to water and couples the released energy to proton pumping across the mitochondrial or bacterial membrane. Proton pumping in CcO involves proton transfer from the negatively charged side of the membrane to a transient proton loading or pump site (PLS), before it is ejected to the opposite side. Although many details of the reaction mechanism are known, the exact location of the PLS has remained elusive. We report here results from combined classical molecular dynamics simulations and continuum electrostatic calculations, which show that the hydrogen-bonded system around the A-propionate of heme a3 dissociates reversibly upon reduction of heme a. The dissociation increases the pK(a) value of the propionate to a value above ~9, making it accessible for redox-state dependent protonation. The redox state of heme a is of key importance in controlling proton leaks by polarizing the PLS both statically and dynamically. These findings suggest that the propionate region of heme a3 fulfills the criteria of the pump site in the proton translocation mechanism of CcO. PMID- 20831860 TI - Quantitative analysis of influenza M2 channel blockers. AB - The influenza M2 H(+) channel enables the concomitant acidification of the viral lumen upon endosomic internalization. This process is critical to the viral infectivity cycle, demonstrated by the fact that M2 is one of only two targets for anti-flu agents. However, aminoadamantyls that block the M2 channel are of limited therapeutic use due to the emergence of resistance mutations in the protein. Herein, using an assay that involves expression of the protein in Escherichia coli with resultant growth retardation, we present quantitative measurements of channel blocker interactions. Comparison of detailed K(s) measurements of different drugs for several influenza channels, shows that the swine flu M2 exhibits the highest resistance to aminoadamantyls of any channel known to date. From the perspective of the blocker, we show that rimantadine is consistently a better blocker of M2 than amantadine. Taken together, such detailed and quantitative analyses provide insight into the mechanism of this important and pharmaceutically relevant channel blocker system. PMID- 20831861 TI - GABAergic compensation in connexin36 knock-out mice evident during low-magnesium seizure-like event activity. AB - Gap junctions within the cerebral cortex may facilitate cortical seizure formation by their ability to synchronize electrical activity. To investigate this, one option is to compare wild-type (WT) animals with those lacking the gene for connexin36 (Cx36 KO); the protein that forms neuronal gap junctions between cortical inhibitory cells. However, genetically modified knock-out animals may exhibit compensatory effects; with the risk that observed differences between WT and Cx36 KO animals could be erroneously attributed to Cx36 gap junction effects. In this study we investigated the effect of GABA(A)-receptor modulation (augmentation with 16MUM etomidate and blockade with 100MUM picrotoxin) on low magnesium seizure-like events (SLEs) in mouse cortical slices. In WT slices, picrotoxin enhanced both the amplitude (49% increase, p=0.0006) and frequency (37% increase, p=0.005) of SLEs; etomidate also enhanced SLE amplitude (18% increase, p=0.003) but reduced event frequency (25% decrease, p<0.0001). In Cx36 KO slices, the frequency effects of etomidate and picrotoxin were preserved, but the amplitude responses were abolished. Pre-treatment with the gap junction blocker mefloquin in WT slices did not significantly alter the drug responses, indicating that the reduction in amplitude seen in the Cx36 KO mice was not primarily mediated by their lack of interneuronal gap junctions, but was rather due to pre-existing compensatory changes in these animals. Conclusions from studies comparing seizure characteristics between WT and Cx36 KO mice must be viewed with a degree of caution because of the possible confounding effect of compensatory neurophysiological changes in the genetically modified animals. PMID- 20831862 TI - A metric-based analysis of the contribution of spike timing to contrast and motion direction coding by single neurons in macaque area MT. AB - Spike timing is thought to contribute to the coding of motion direction information by neurons in macaque area MT. Here, we examined whether spike timing also contributes to the coding of stimulus contrast. We applied a metric-based approach to spike trains fired by MT neurons in response to stimuli that varied in contrast, or direction. We assessed the performance of three metrics, D(spike) and D(product) (containing spike count and timing information), and the spike count metric D(count). We analyzed responses elicited during the first 200 msec of stimulus presentation from 205 neurons. For both contrast and direction, the large majority of neurons showed the highest mutual information using D(spike), followed by D(product), and D(count). This was corroborated by the performance of a theoretical observer model at discriminating contrast and direction using the three metrics. Our results demonstrate that spike timing can contribute to contrast coding in MT neurons, and support previous reports of its potential contribution to direction coding. Furthermore, they suggest that a combination of spike count with periodic and non-periodic spike timing information (contained in D(spike), but not in D(product) and D(count) which are insensitive to spike counts and timing respectively) provides the largest coding advantage in spike trains fired by MT neurons during contrast and direction discrimination. PMID- 20831863 TI - The phonemic restoration effect reveals pre-N400 effect of supportive sentence context in speech perception. AB - The phonemic restoration effect refers to the tendency for people to hallucinate a phoneme replaced by a non-speech sound (e.g., a tone) in a word. This illusion can be influenced by preceding sentential context providing information about the likelihood of the missing phoneme. The saliency of the illusion suggests that supportive context can affect relatively low (phonemic or lower) levels of speech processing. Indeed, a previous event-related brain potential (ERP) investigation of the phonemic restoration effect found that the processing of coughs replacing high versus low probability phonemes in sentential words differed from each other as early as the auditory N1 (120-180 ms post-stimulus); this result, however, was confounded by physical differences between the high and low probability speech stimuli, thus it could have been caused by factors such as habituation and not by supportive context. We conducted a similar ERP experiment avoiding this confound by using the same auditory stimuli preceded by text that made critical phonemes more or less probable. We too found the robust N400 effect of phoneme/word probability, but did not observe the early N1 effect. We did however observe a left posterior effect of phoneme/word probability around 192-224 ms-clear evidence of a relatively early effect of supportive sentence context in speech comprehension distinct from the N400. PMID- 20831864 TI - Serum osteocalcin is related to abdominal obesity in Korean obese and overweight men. AB - BACKGROUND: Growing evidence suggests a link between body composition and serum osteocalcin. Here we examined such an association between serum osteocalcin and body composition in Korean obese men. METHODS: Eighty-six men, aged 20 to 76 years, who visited the obesity clinic at the Division of Family Medicine, Severance hospital, Seoul, Korea were recruited for this study. Abdominal fat computed tomography (CT) scans were performed to measure the visceral fat area (VFA) and subcutaneous fat area (SFA). RESULTS: Serum osteocalcin levels were negatively correlated with age, VFA, and VFA/SFA ratio. In addition, serum osteocalcin levels were significantly decreased in obese and overweight subjects with visceral obesity (12.7+/-3.2) compared to those without visceral obesity (18.6+/-4.9). Multiple regression analysis showed that serum osteocalcin levels were associated with VFA in obese and overweight men after adjustment for age, insulin resistance, current smoking, alcohol consumption and adiposity indices. CONCLUSION: Osteocalcin was inversely related to visceral obesity in Korean obese and overweight men. These results suggest cross-talk between bone and adipose tissue. PMID- 20831865 TI - Re: Post-treatment circulating plasma BMP6 mRNA and H3K27 methylation levels discriminate metastatic prostate cancer from localized disease. PMID- 20831866 TI - Traceability to a common standard for protein measurements by immunoassay for in vitro diagnostic purposes. AB - BACKGROUND: There is a lot of confusion about the meaning of "measuring a protein in biological fluids" for in-vitro diagnostic purposes. This is due to a lack of understanding of metrological concepts and of acceptance of a pragmatic metrological concept for mixture analysis. METHODS: We describe the metrological concepts that apply to measurement of proteins. We propose a pragmatic reference measurement system for protein analysis. We investigate the feasibility of the approach with TSH as example. RESULTS: The reference measurement system for a protein should be viewed as a dynamic continuum from discovery to translation into an SI-component. A quasi surrogate component-mixture may be defined by recommendations for epitopes that immunoassays should recognize. The all procedure trimmed mean is proposed as surrogate reference measurement procedure. Traceability is established by transfer of the IU of an WHO standard to a panel of commutable sera. Investigation of the TSH-example showed that the approach may be feasible. CONCLUSIONS: The proposed pragmatic concept would be a major step towards traceability of protein measurements by immunoassay. It would allow a staged introduction of standardization during the continuum from discovery of a protein to full scientific understanding and transformation to the SI-unit. PMID- 20831868 TI - Focus on molecules: Pitx3. PMID- 20831867 TI - Cellular inhibitor of apoptosis (cIAP1) is down-regulated during retinal ganglion cell (RGC) maturation. AB - Apoptosis, is the main type of cell death that occurs in ageing and neurodegenerative disease, such as glaucoma. This study therefore characterises the expression profile of caspases (pro-apoptosis) and inhibitors of apoptosis (IAPs; anti-apoptosis) during maturation of the Brown Norway rat retina between 6 weeks and >24 weeks and also examines concomitant changes in expression of tumor necrosis factor receptor associated factor 2 (TRAF2). The expression profiles of caspases (initiator caspases 8, 9 and effector caspases 6, 7, 3) and inhibitors of apoptosis (IAPs) (Neuronal IAP), cellular IAP1 and 2 (cIAP1/2), X-chromosome linked IAP (XIAP), Survivin, Bruce and Livin) were examined in retinae from 6 weeks and >24 weeks old BN rats using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, Western blotting and immunofluoroscence analysis. Caspase expression was not altered significantly during the study interval. IAP expression showed a general reduction during maturation of BN retina, which was statistically significant for cIAP1. cIAP1 reduction was confirmed by Western blotting and immunoflouroscence and was restricted to cells in the retinal ganglion cell layer (RGCL). Accumulation of TRAF2 was observed in the RGCL accompanying the down-regulation of cIAP1 observed. Our results suggest that cells in the mature RGCL may have a greater susceptibility to cell death compared to their younger counterparts and this may be due in part to a reduction in activation of survival pathways involving IAPs and TRAFs. PMID- 20831869 TI - A disulfide driven domain swap switches off the activity of Shigella IpaH9.8 E3 ligase. AB - We show that the monomeric form of Shigella IpaH9.8 E3 ligase catalyses the ubiquitination of human U2AF35 in vitro, providing a molecular mechanism for the observed in vivo effect. We further discover that under non-reducing conditions IpaH9.8 undergoes a domain swap driven by the formation of a disulfide bridge involving the catalytic cysteine and that this dimer is unable to catalyse the ubiquitination of U2AF35. The crystal structure of the domain-swapped dimer is presented. The redox inactivation of IpaH9.8 could be a mechanism of regulating the activity of the IpaH9.8 E3 ligase in response to cell damage so that the host cell in which the bacteria resides is maintained in a benign state suitable for bacterial survival. PMID- 20831870 TI - Predicted bacteriorhodopsin from Exiguobacterium sibiricum is a functional proton pump. AB - The predicted Exigobacterium sibiricum bacterirhodopsin gene was amplified from an ancient Siberian permafrost sample. The protein bacteriorhodopsin from Exiguobacterium sibiricum (ESR) encoded by this gene was expressed in Escherichia coli membrane. ESR bound all-trans-retinal and displayed an absorbance maximum at 534nm without dark adaptation. The ESR photocycle is characterized by fast formation of an M intermediate and the presence of a significant amount of an O intermediate. Proteoliposomes with ESR incorporated transport protons in an outward direction leading to medium acidification. Proton uptake at the cytoplasmic surface of these organelles precedes proton release and coincides with M decay/O rise of the ESR. PMID- 20831871 TI - Binding of Bacillus thuringiensis Cry1A toxins with brush border membrane vesicles of maize stem borer (Chilo partellus Swinhoe). AB - Maize stem borer (Chilo partellus) is a major insect pest of maize and sorghum in Asia and Africa. Bacillus thuringiensis (Bt) delta-endotoxins have been found effective against C. partellus, both in diet-overlay assay and in transgenic plants. Gene stacking as one of the resistance management strategies in Bt maize requires an understanding of receptor sharing and binding affinity of delta endotoxins. In the present study, binding affinity of three fluorescein isothiocyanate labeled Cry1A toxins showed high correlation with the toxicity of respective delta-endotoxins. Competitive binding studies showed that Cry1Ab toxins share some of the binding sites with Cry1Aa and Cry1Ac with low affinity and that Cry1Ab may have additional binding sites that are unavailable to the other two toxins tested. PMID- 20831873 TI - A game dynamic model for delayer strategies in vaccinating behaviour for pediatric infectious diseases. AB - Several studies have found that some parents delay the age at which their children receive pediatric vaccines due to perception of higher vaccine risk at the recommended age of vaccination. This has been particularly apparently during the Measles-Mumps-Rubella scare in the United Kingdom. Under a voluntary vaccination policy, vaccine coverage in certain age groups is a potentially complex interplay between vaccinating behaviour, disease dynamics, and age specific risk factors. Here, we construct an age-structured game dynamic model, where individuals decide whether to vaccinate according to imitation dynamics depending on age-dependent disease prevalence and perceived risk of vaccination. Individuals may be timely vaccinators, delayers, or non-vaccinators. The model exhibits multiple equilibria and a broad range of possible dynamics. For certain parameter regimes, the proportion of timely vaccinators and delayers oscillate in an anti-phase fashion in response to oscillations in infection prevalence. Under an exogenous change to the perceived risk of vaccination as might occur during a vaccine scare, the model can also capture an increase in delayer strategists similar in magnitude to that observed during the Measles-Mumps-Rubella vaccine scare in the United Kingdom. Our model also shows that number of delayers steadily increases with increasing severity of the scare, whereas it saturates to specific value with increases in duration of the scare. Finally, by comparing the model dynamics with and without the option of a delayer strategy, we show that adding a third delayer strategy can have a stabilizing effect on model dynamics. In an era where individual choice--rather than accessibility--is becoming an increasingly important determinant of vaccine uptake, more infectious disease models may need to use game theory or related techniques to determine vaccine uptake. PMID- 20831872 TI - Loop-swapped chimeras of the agouti-related protein and the agouti signaling protein identify contacts required for melanocortin 1 receptor selectivity and antagonism. AB - Agouti-related protein (AgRP) and agouti signaling protein (ASIP) are homologs that play critical roles in energy balance and pigmentation, respectively, by functioning as antagonistic ligands at their cognate melanocortin receptors. Signaling specificity is mediated in part through receptor binding selectivity brought about by alterations in the cysteine-rich carboxy-terminal domains of the ligands. AgRP binds with high affinity to the melanocortin 3 receptor and the melanocortin 4 receptor, but not to the melanocortin 1 receptor (MC1R), whereas ASIP binds with high affinity to all three receptors. This work explores the structural basis for receptor selectivity by studying chimeric proteins developed by interchanging loops between the cysteine-rich domain of ASIP and the cysteine rich domain of AgRP. Binding data demonstrate that melanocortin 4 receptor responds to all chimeras and is therefore highly tolerant of gross loop changes. By contrast, MC1R responds primarily to those chimeras with a sequence close to that of wild-type ASIP. Further analysis of binding and functional data suggests that the ASIP C-terminal loop (a six-amino-acid segment closed by the final disulfide bond) is essential for high-affinity MC1R binding and inverse agonism. Comparison with previously published molecular models suggests that this loop makes contact with the first extracellular loop of MC1R through a series of key hydrophobic interactions. PMID- 20831874 TI - Understanding hepatitis C viral dynamics with direct-acting antiviral agents due to the interplay between intracellular replication and cellular infection dynamics. AB - The current paradigm for modeling viral kinetics and resistance evolution after treatment initiation considers only the level of circulating virus and cellular infection (CI model), while the intra-cellular level is disregarded. This model was successfully used to explain HIV dynamics and Hepatitis C virus (HCV) dynamics during interferon-based therapy. However, in the new era of direct acting antiviral agents (DAAs) against HCV, viral kinetics is characterized by a more rapid decline of the wild-type virus as well as an early emergence of resistant strains that jeopardize the treatment outcome. Although the CI model can be extended to describe these new kinetic patterns, this approach has qualitative and quantitative limitations. Instead, we suggest that a more appropriate approach would consider viral dynamics at the cell infection level, as done currently, as well as at the intracellular level. Indeed, whereas in HIV integrated DNA serves as a static replication unit and mutations occur only once per infected cell, HCV replication is deeply affected by DAAs and furthermore processes of resistance evolution can occur at the intra-cellular level with a faster time-scale. We propose a comprehensive model of HCV dynamics that considers both extracellular and intracellular levels of infection (ICCI model). Intracellular viral genomic units are used to form replication units, which in turn synthesize genomic units that are packaged and secreted as virions infecting more target cells. Resistance evolution is modeled intra-cellularly, by different genomic- and replication-unit strains with particular relative-fitness and drug sensitivity properties, allowing for a rapid resistance takeover. Using the ICCI model, we show that the rapid decline of wild-type virus results from the ability of DAAs to destabilize the intracellular replication. On the other hand, this ability also favors the rapid emergence, intracellularly, of resistant virus. By considering the interaction between intracellular and extracellular infection we show that resistant virus, able to maintain a high level of intracellular replication, may nevertheless be unable to maintain rapid enough de novo infection rate at the extracellular level. Hence this model predicts that in HCV, and contrary to our experience with HIV, the emergence of productively resistant virus may not systematically prevent from a viral decline in the long-term. Thus, the ICCI model can explain the transient viral rebounds observed with DAA treatment as well as the viral resistance found in most patients with viral relapse at the end of DAA combination therapy. PMID- 20831876 TI - A high-accuracy protein structural class prediction algorithm using predicted secondary structural information. AB - One major problem with the existing algorithm for the prediction of protein structural classes is low accuracies for proteins from alpha/beta and alpha+beta classes. In this study, three novel features were rationally designed to model the differences between proteins from these two classes. In combination with other rational designed features, an 11-dimensional vector prediction method was proposed. By means of this method, the overall prediction accuracy based on 25PDB dataset was 1.5% higher than the previous best-performing method, MODAS. Furthermore, the prediction accuracy for proteins from alpha+beta class based on 25PDB dataset was 5% higher than the previous best-performing method, SCPRED. The prediction accuracies obtained with the D675 and FC699 datasets were also improved. PMID- 20831875 TI - Synergistic effects in the designs of neuraminidase ligands: analysis from docking and molecular dynamics studies. AB - Docking and molecular dynamics were used to study the nine ligands (see Scheme 1) at the neuraminidase (NA) active sites. Their binding modes are structurally and energetically different, with details given in the text. Compared with 1A (oseltamivir carboxylate), the changes of core template or/and functional groups in the other ligands cause the reductions of interaction energies and numbers of H-bonds with the NA proteins. Nonetheless, all these ligands occupy the proximity space at the NA active sites and share some commonness in their binding modes. The fragment approach was then used to analyze and understand the binding specificities of the nine ligands. The contributions of each core template and functional group were evaluated. It was found that the core templates rather than functional groups play a larger role during the binding processes; in addition, the binding qualities are determined by the synergistic effects of the core templates and functional groups. Among the nine ligands, 1A (oseltamivir carboxylate) has the largest synergistic energy and its functional groups fit perfectly with the NA active site, consistent with the largest interaction energy, numerous H-bonds with the NA active-site residues as well as experimentally lowest IC(50) value. Owing to the poorer metabolizability than oseltamivir, large contribution of the benzene core template and fine synergistic effects of the functional groups, the 4-(N-acetylamino)-5-guanidino-3-(3 pentyloxy)benzoic acid should be an ideal lead compound for optimizing NA drugs. PMID- 20831877 TI - A unified approach to the Richards-model family for use in growth analyses: why we need only two model forms. AB - This paper advances a unified approach to the modeling of sigmoid organismal growth. There are numerous studies on growth, and there have been several proposals and applications of candidate models. Still, a lack of interpretation of the parameter values persists and, consequently, differences in growth patterns have riddled this field. A candidate regression model as a tool should be able to assess and compare growth-curve shapes, systematically and precisely. The Richards models constitute a useful family of growth models that amongst a multitude of parameterizations, re-parameterizations and special cases, include familiar models such as the negative exponential, the logistic, the Bertalanffy and the Gompertz. We have reviewed and systemized this family of models. We demonstrate that two specific parameterizations (or re-parameterizations) of the Richards model are able to substitute, and thus to unify all other forms and models. This unified-Richards model (with its two forms) constitutes a powerful tool for an interpretation of important characteristics of observed growth patterns, namely, [I] maximum (relative) growth rate (i.e., slope at inflection), [II] age at maximum growth rate (i.e., time at inflection), [III] relative mass or length at maximum growth rate (i.e., relative value at an inflection), [IV] value at age zero (i.e., birth, hatching or germination), and [V] asymptotic value (i.e., adult weight or length). These five parameters can characterize uniquely any sigmoid-growth data. To date most studies only compare what is referred to as the "growth-rate constant" or simply "growth rate" (k). This parameter can be interpreted as neither relative nor actual growth rate, but only as a parameter that affects the slope at inflection. We fitted the unified Richards and five other candidate models to six artificial data sets, generated from the same models, and made a comparison based on the corrected Akaike's Information Criterion (AICc). The outcome may in part be the result of the random generation of data points. Still, in conclusion, the unified-Richards model performed consistently well for all data sets, despite the penalty imposed by the AICc. PMID- 20831878 TI - Positive and negative modulation of circadian activity rhythms by mGluR5 and mGluR2/3 metabotropic glutamate receptors. AB - Glutamate released from retinal ganglion cells conveys information about the daily light:dark cycle to master circadian pacemaker neurons within the suprachiasmatic nucleus that then synchronize internal circadian rhythms with the external day-length. Glutamate activation of ionotropic glutamate receptors in the suprachiasmatic nucleus is well established, but the function of the metabotropic glutamate receptors that are also located in this nucleus is not known. Therefore, in this study we evaluated agonists and antagonists acting at orthosteric or allosteric sites for mGluR5 and mGluR2/3 metabotropic glutamate receptors for their ability to modulate light-induced phase advances and delays of hamster circadian activity rhythms. mGluR5 allosteric antagonists fenobam, MPEP and MTEP, each 10 mg/kg, potentiated light-induced phase advances of hamster circadian activity rhythms, while the mGluR5 agonists CHPG, (S)-3,5-DHPG or positive allosteric modulator CDPPB had no effect. Neither mGluR5 agonists nor antagonists had any effect on light-induced phase delays of activity rhythms. The competitive mGluR2/3 antagonist LY341495, 10 mg/kg, also potentiated light induced phase advances, but inhibited light-induced phase delays. The mGluR2/3 agonists LY354740 and LY404039 were without effect on phase advances while a third agonist LY379268, 10 mg/kg, inhibited both light-induced advances and delays. Finally, mGluR2/3 agonists LY379268 and LY404039 also inhibited light induced phase delays of activity rhythms. These results suggest that during light induced phase advances, mGluR2/3 and mGluR5 receptors act to negatively modulate the effects of light on the circadian pacemaker or its output(s). mGluR5 receptors do not appear to be involved during light-induced phase delays. In contrast, the role for mGluR2/3 receptors during phase delays is more complicated as both agonists and antagonists inhibit light-induced phase delays. Dysfunctions in human circadian rhythms have been implicated in some forms of depression, and metabotropic glutamate receptor ligands, which are also being evaluated for antidepressant activity, are shown here to be capable of modifying light-induced phase shifts of circadian activity rhythms. PMID- 20831879 TI - Uptake and cytotoxicity of chitosan nanoparticles in human liver cells. AB - Despite extensive research into the biomedical and pharmaceutical applications of nanoparticles, and the liver being the main detoxifying organ in the human body, there are limited studies which delineate the hepatotoxicity of nanoparticles. This paper reports on the biological interactions between liver cells and chitosan nanoparticles, which have been widely recognised as biocompatible. Using the MTT assay, human liver cells were shown to tolerate up to 4h of exposure to 0.5% w/v of chitosan nanoparticles (18+/-1 nm, 7.5+/-1.0 mV in culture medium). At nanoparticle concentrations above 0.5% w/v, cell membrane integrity was compromised as evidenced by leakage of alanine transaminase into the extracellular milieu, and there was a dose-dependent increase in CYP3A4 enzyme activity. Uptake of chitosan nanoparticles into the cell nucleus was observed by confocal microscopic analysis after 4h exposure with 1% w/v of chitosan nanoparticles. Electron micrographs further suggest necrotic or autophagic cell death, possibly caused by cell membrane damage and resultant enzyme leakage. PMID- 20831880 TI - Prevalence and risk determinants of HIV-1 and HIV-2 infections in pregnant women in Bissau. AB - OBJECTIVES: To analyse the risk determinants of HIV-1 and HIV-2 infections in pregnant women in Bissau. METHODS: Pregnant women attending the antenatal clinics of Bissau between January 2002 and June 2006 were consecutively tested unless they opted out. RESULTS: Among 23,869 tested women the overall prevalence of HIV 1 was 5.7%, that of HIV-2 was 2.4%, and these included the 0.7% prevalence of HIV 1 and HIV-2 duals. The main factors associated with the risk of HIV-1 infection were older age, occupation and number of sexual partners. Beafada and Mandinga ethnic groups were at greater risk of presenting HIV-1, and Bijago and Papel at lower risk. The factors associated with the risk of HIV-2 were age, literacy and occupation; the Beafada were at greater risk than the other ethnic groups. CONCLUSIONS: The prevalence of HIV-2 infection decreased overtime, whereas that of HIV-1 infection remained substantially stable, but was higher than that observed in previous studies. The rapid decline in the rates of HIV-2 infection suggests that many of the factors that allowed its exponential growth in the past have now been partially removed, and that sexual and vertical transmission have not been sufficient to maintain and extend the epidemic. PMID- 20831881 TI - Post-therapy paradoxical response in immunocompetent patients with lymph node tuberculosis. PMID- 20831882 TI - The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). AB - OBJECTIVES: Solithromycin (formerly CEM-101) is a novel fluoroketolide with potent activity against bacterial pathogens that are susceptible or resistant to other MLS(B)-ketolide agents. The objective of this study was to assess the activity of solithromycin and comparator antimicrobials against a large number and variety of contemporary clinical bacterial pathogens collected in the United States (USA) and Europe during 2009. METHOD: During 2009, a total of 10,670 non duplicated clinical isolates were collected from 52 medical centers located in the USA (27 centers; 6228 isolates) and Europe (25 centers; 4442 isolates). Susceptibility testing and interpretation were performed using CLSI reference methods. RESULTS: Among 1363 Streptococcus pneumoniae isolates, 99.9% of the strains displayed solithromycin MIC values at <=0.5 mg/L, and 100% were inhibited at an MIC of 1 mg/L. Solithromycin demonstrated activity and potency against Haemophilus influenzae comparable to azithromycin (MIC(50), 1 mg/L and MIC(90), 2 mg/L) and was very potent against all 313 Moraxella catarrhalis isolated (MIC(50), 0.06 mg/L and MIC(90), 0.12 mg/L). Against 4729 Staphylococcus aureus isolates, solithromycin (MIC(50), 0.06 mg/L and MIC(90), >4 mg/L) activity was greater against methicillin-susceptible isolates (MIC(50), 0.06 mg/L and MIC(90), 0.06 mg/L) compared to methicillin-resistant isolates (MIC(50), 0.06 mg/L and MIC(90), >4 mg/L). Solithromycin was very active against all 757 beta-haemolytic streptococci (MIC(50), <=0.03 mg/L and MIC(90), 0.06 mg/L) and 310 viridans group streptococci (MIC(50), <=0.03 mg/L and MIC(90), 0.06 mg/L) evaluated. CONCLUSION: This contemporary surveillance study utilizing clinical isolates shows that solithromycin exhibits favorable in vitro potency and spectrum of activity against bacterial pathogens most frequently isolated in community-acquired respiratory tract (CA-RTI) and skin and skin structure infections (SSSI). PMID- 20831883 TI - Concentrated epidemics of HIV, HCV, and HBV among Afghan refugees. PMID- 20831884 TI - Spike detection in human muscle sympathetic nerve activity using a matched wavelet approach. AB - Sympathetic nerve recordings associated with blood pressure regulation can be recorded directly using microneurography. A general characteristic of this signal is spontaneous burst activity of spikes (action potentials) separated by silent periods against a background of considerable Gaussian noise. During measurement with electrodes, the raw muscle sympathetic nerve activity (MSNA) signal is amplified, band-pass filtered, rectified and integrated. This integration process removes information regarding action potential content and their discharge properties. This paper proposes a new method for detecting action potentials from the raw MSNA signal to enable investigation of post-ganglionic neural discharge properties. The new method is based on the design of a mother wavelet that is matched to an actual mean action potential template extracted from a real raw MSNA signal. To detect action potentials, the new matched wavelet is applied to the MSNA signal using a continuous wavelet transform following a thresholding procedure and finding of a local maxima that indicates the location of action potentials. The performance of the proposed method versus two previous wavelet based approaches was evaluated using (1) real MSNA recorded from seven healthy participants and, (2) simulated MSNA. The results show that the new matched wavelet performs better than the previous wavelet-based methods that use a non matched wavelet in detecting action potentials in the MSNA signal. PMID- 20831885 TI - Hetero-dimerization of serotonin 5-HT(2A) and dopamine D(2) receptors. AB - In the present study, detailed information is presented on the hetero dimerization of the serotonin 5-HT(2A) receptor and the dopamine D(2) receptor. Biophysical approaches (fluorescence spectroscopy as well as fluorescence lifetime microscopy) were used to determine the degree of fluorescence resonance energy transfer (FRET) between cyan and yellow fluorescent protein labeled receptor variants co-expressed in human embryonic kidney 293 cells (HEK293). Recorded data demonstrate the existence of energy transfer between the wild-type forms of 5-HT(2A)R and D(2)R, pointing toward the formation of hetero-5 HT(2A)R/D(2)R dimers and homo-5-HT(2A)R/5-HT(2A)R dimers. Moreover, the present study investigates the role of specific motifs (one containing adjacent arginine residues (217RRRRKR222) in the third intracellular loop (ic3) of D(2)R, and the other consisting of acidic glutamate residues (454EE455) in the C-tail of (5 HT(2A)R) in the formation of noncovalent complexes between these receptors. Our results suggest that these regions of 5-HT(2A)R and D(2)R may be involved in the interaction between these two proteins. On the other hand, the above-mentioned motifs do not play an important role in the homo-dimerization of these receptors. Furthermore, we estimated the influence of specific receptor ligands on the dimerization processes. Agonists (DOI and quinpirole) and antagonists (ketanserin and butaclamol) cause different effects on FRET efficiency depending on whether homo- or hetero-complexes are present. These data may have therapeutic implications, since (using the immunofluorescence double labeling protocols) the co-localization of these two receptors was demonstrated in the medial prefrontal cortex and pars reticulate of the substantia nigra of the rat brain. PMID- 20831886 TI - Critical role of molecular imaging for substantially improved anticancer therapy. PMID- 20831887 TI - Intravesical drug delivery: Challenges, current status, opportunities and novel strategies. AB - The urinary bladder has certain unique anatomical features which enable it to form an effective barrier to toxic substances diffusing from the urine into the blood. The barrier function is due to the epithelial surface of the urinary bladder, the urothelium, which has characteristic umbrella cells, joined by tight junctions and covered by impenetrable plaques, as well as an anti-adherent mucin layer. Diseases of the urinary bladder, such as bladder carcinomas and interstitial cystitis, cause acute damage to the bladder wall and cannot be effectively treated by systemic administration of drugs. Such conditions may benefit from intravesical drug delivery (IDD), which involves direct instillation of drug into the bladder via a catheter, to attain high local concentrations of the drug with minimal systemic effects. IDD however has its limitations, since the permeability of the urothelial layer is very low and instilled drug solutions become diluted with urine and get washed out of the bladder during voiding, necessitating repeated infusions of the drug. Permeation enhancers serve to overcome these problems to some extent by using electromotive force to enhance diffusion of the drug into the bladder wall or chemical molecules, such as chitosan, dimethylsulphoxide, to temporarily disrupt the tight packing of the urothelium. Nanotechnology can be integrated with IDD to devise drug-encapsulated nanoparticles that can greatly improve chemical interactions with the urothelium and enhance penetration of drugs into the bladder wall. Nanocarriers such as liposomes, gelatin nanoparticles, polymeric nanoparticles and magnetic particles, have been found to enhance local drug concentrations in the bladder as well as target diseased cells. Intravesical drug carriers can be further improved by using mucoadhesive biomaterials which are strongly adhered to the urothelial cell lining, thus preventing the carrier from being washed away during urine voiding. This increases the residence time of the drug at the target site and enables sustained delivery of the drug over a prolonged time span. Polymeric hydrogels, such as the temperature sensitive PEG-PLGA-PEG polymer, have been used to develop in situ gelling systems to deliver drugs into the bladder cavity. Recent advances and future prospects of biodegradable nanocarriers and in situ gels as drug delivery agents for intravesical drug delivery are reviewed in this paper. PMID- 20831888 TI - Barrier analysis of periocular drug delivery to the posterior segment. AB - Periocular administration is a potential way of delivering drugs to their targets in posterior eye segment (vitreous, neural retina, retinal pigment epithelium (RPE), choroid). Purpose of this study was to evaluate the role of the barriers in periocular drug delivery. Permeation of FITC-dextrans and oligonucleotides in the bovine sclera was assessed with and without Pluronic gel in the donor compartment. Computational model for subconjunctival drug delivery to the choroid and neural retina/vitreous was built based on clearance concept. Kinetic parameters for small hydrophilic and lipophilic drug molecules, and a macromolecule were obtained from published ex vivo and in vivo animal experiments. High negative charge field of oligonucleotides slows down their permeation in the sclera. Pluronic does not provide adequate rate control to modify posterior segment drug delivery. Theoretical calculations for subconjunctival drug administration indicated that local clearance by the blood flow and lymphatics removes most of the drug dose which is in accordance with experimental results. Calculations suggested that choroidal blood flow removes most of the drug that has reached the choroid, but this requires experimental verification. Calculations at steady state using the same subconconjunctival input rate showed that the choroidal and vitreal concentrations of the macromolecule is 2-3 orders of magnitude higher than that of small molecules. The evaluation of the roles of the barriers augments to design new drug delivery strategies for posterior segment of the eye. PMID- 20831889 TI - Long-term oral-appliance therapy in obstructive sleep apnea: a cephalometric study of craniofacial changes. AB - OBJECTIVES: The aim of this randomized controlled study was to cephalometrically assess possible changes in craniofacial morphology associated with long-term use of an adjustable oral-appliance compared with continuous positive airway pressure (CPAP) in patients with the obstructive sleep apnea/hypopnea syndrome (OSAHS). In addition, we wanted to study the relationship between these possible changes and the degree of mandibular protrusion associated with oral-appliance therapy. METHODS: Fifty-one patients were randomized to oral-appliance therapy and 52 patients to CPAP therapy. At baseline and after follow-up (2.3+/-0.2 years), a lateral cephalogram of all patients was made in maximum intercuspation to determine relevant cephalometric variables. Both baseline and follow-up cephalograms were traced digitally whereupon cephalometric variables were compared. Changes in craniofacial morphology between the oral-appliance- and CPAP group were evaluated with a linear regression analysis. RESULTS: Compared with CPAP, long-term use of an oral-appliance resulted in small but significant (dental) changes. Overbite and overjet decreased, 1.0 (+/-1.5)mm and 1.7 (+/ 1.6)mm, respectively. Furthermore we found a retroclination (-2.0 (+/-2.8) degrees ) of the upper incisors and a proclination (3.7 (+/-5.4) degrees ) of the lower incisors. Moreover, the lower- and total anterior facial height increased significantly, 0.8 (+/-1.5)mm and 0.9 (+/-1.4)mm, respectively. No changes in skeletal variables were found. Linear regression analysis revealed that the decrease in overbite was associated with the mean mandibular protrusion during follow-up (B=-0.029, SE=0.014, p<0.05). CONCLUSIONS: Oral-appliance therapy should be considered as a life long treatment, and there is a risk of craniofacial changes to occur. Therefore, patients treated with an oral appliance, need a thorough follow-up by a dentist or dental-specialist experienced in the field of dental sleep medicine. PMID- 20831890 TI - Molecular property-binding affinity relationship of flavonoids for common rat plasma proteins in vitro. AB - The structural difference of flavonoids strongly affects the binding process with plasma proteins. This work in here mainly concerns about the molecular property binding affinity relationship of dietary flavonoids for common rat plasma proteins (CRPP). The magnitudes of binding constants between flavonoids and CRPP were within the range of 10(4)-10(5) L/mol and the number of binding sites (n) was determined as 1.02 +/- 0.19. These data were much smaller than the affinities between flavonoids and purified bovine and human serum albumins. The hydroxylation on rings A, B and C of flavonoids significantly affected the binding affinity. The glycosylation of dietary flavonoids decreased the binding affinity and the C2=C3 double bond hardly affected it. The galloylated catechins have higher binding affinities for CRPP than non-galloylated catechins. Flavonoids played as a hydrogen bond acceptor when bound to CRPP. The flavonoids with high topological polar surface areas (TPSA) are bound tightly while those with low TPSA are not. PMID- 20831891 TI - Ceramides with 2-hydroxylated, very long-chain polyenoic fatty acids in rodents: From testis to fertilization-competent spermatozoa. AB - Sphingolipids from rodent testis and spermatozoa are known to contain non hydroxylated (N-) and 2-hydroxylated (2-OH) very-long-chain polyunsaturated fatty acids (VLCPUFA). In this study, the contribution of species with each type of fatty acids to the total ceramides (Cer) and sphingomyelins (SM) was investigated in rat and mouse testis and in rat spermatozoa. The major VLCPUFA in both lipids of testis were N- and 2-OH versions of 28:4n-6, 30:5n-6 and 32:5n-6 in the rat, and predominantly of 30:5n-6 in the mouse. Absent altogether from rat pre-puberal testes, SM and Cer with N-VLCPUFA appeared 10 days earlier than those with 2-OH VLCPUFA in postnatal development, in association with germ cell differentiation. Conversely, in adult fertile rats that were gradually deprived of germ cells in vivo after treatment with doxorubicin, SM and Cer with N-VLCPUFA decreased earlier than their 2-OH counterparts, and neither was present in aspermatogenic testes. In rat epididymal spermatozoa, the content of Cer prevailed over that of SM and 2-OH VLCPUFA prevailed over N-VLCPUFA in both lipids. In mature gametes, the acrosomal reaction resulted in an almost complete hydrolysis of the species of SM that contain both types of VLCPUFA to produce the corresponding Cer. Ceramides are biosynthetic precursors of SM in the testis, but themselves final products in spermatozoa. VLCPUFA-rich SM and Cer are thus produced in germ cells with the teleological objective of fulfilling their ultimate physiological role in spermatozoa that are apt and ready to fertilize an oocyte. PMID- 20831892 TI - Nucleus accumbens and impulsivity. AB - The multifaceted concept of impulsivity implies that different impulsivity aspects, mediated by different neural processes, influence behavior at different levels. The nucleus accumbens (NAc) is a key component of the neural processes regulating impulsivity. In this review, we discuss the findings of lesion studies in animals and functional imaging studies in humans focusing on the role of the NAc in impulsivity. Evidence supports that the extent and pattern of involvement of the NAc, and its subregions, the core and the shell, vary among different facets of impulsivity. Data from imaging studies reviewed in this article suggest the involvement of the ventral striatum/NAc in impulsive choice. Findings of animal studies indicate that lesions of the NAc core subregion facilitated impulsivity in tasks involving intertemporal choice, and promoted a risk-averse, less impulsive, tendency in tasks involving options with probability differences. Modification of neurotransmitter activity, especially of dopamine, which is proposed to underlie the changes observed in functional imaging studies, has been shown to influence afferent input pattern in the NAc and the generation of the behavioral output. Parameters of behavioral tasks reflecting response inhibition function are altered by neurochemical interventions and local electrical stimulation in both the core and the shell subregions. In toto, NAc's pattern of neuronal activity, either genetically determined or acquired, has a critical impact on the interindividual variation in the expression of impulsivity. Nevertheless, the NAc is not the only substrate responsible for impulsivity and it is not involved in each facet of impulsivity to the same extent. PMID- 20831893 TI - Cdc25A-driven proliferation regulates CD62L levels and lymphocyte movement in response to interleukin-7. AB - OBJECTIVE: Interleukin-7 (IL-7) is a multifunctional cytokine and a promising immunotherapeutic agent. However, because transient T-cell depletion is an immediate outcome of IL-7 administration at supraphysiological doses, we investigated the mechanism by which the IL-7 proliferative signal transduced through Cdc25A, a key activator of cyclin-dependent kinases, could modulate lymphocyte movement. MATERIALS AND METHODS: Employing novel methods of manipulating Cdc25A gene expression, combined with in vitro and in vivo evaluation of IL-7 application, we assessed the expression of activation and homing markers and identified the mechanism by which IL-7 could induce T-cell expansion and alter lymphocyte motility. RESULTS: Constitutively active Cdc25A drove T-cell proliferation independently of IL-7 and resulted in an activated phenotype (CD69(hi), CD44(hi)). Conversely, inhibition of Cdc25A resulted in decreased proliferation, reduced expression of activation markers, and upregulation of the lymph node homing molecule, CD62L, which promoted cell adhesion when engaged by ligand. We found that IL-7 prevented the nuclear translocation of the transcription factor, Foxo1, in a manner dependent on the activity of Cdc25A, resulting in decreased levels of CD62L. In vivo administration of IL-7 decreased lymph node cellularity, while treatment with IL 7, premixed with a neutralizing IL-7 antibody (M25), increased total lymph node cells--with more nuclear Foxo1 detected in cells from mice receiving IL-7 + M25. CONCLUSIONS: These results are consistent with the model that IL-7 drives Cdc25A mediated T-cell proliferation, which prevents the nuclear translocation of Foxo1, leading to reduced expression of CD62L and the migration of T cells into circulation. PMID- 20831894 TI - Annexin A3 is associated with cell death in lactacystin-mediated neuronal injury. AB - Massive neuronal apoptosis and accumulation of protein aggregates in the cortex and hippocampus of the brain are hallmarks of several neurodegenerative disorders, indicating ubiquitin proteasome system (UPS) dysfunction. Lactacystin, a classical proteasome inhibitor, is used to simulate ubiquitin proteasome system dysfunction in neurons to mimic pathological features of neurodegenerative disorders. Based on Western blot analyses, we reported for the first time that annexin A3 (AnxA3) is not only endogenously expressed in mouse cortical neurons but also more importantly, by gene expression microarray and real-time RT-PCR that it is greatly transcriptional up-regulated to approximately 11- and 15-fold, respectively in murine primary cortical neurons with 1MUM lactacystin for 24h. Up regulation of AnxA3 expression occurred after 12-15h post-lactacystin treatment, which corresponded with the onset of neuronal injury, with approximately 25% of the neurons being non-viable by that time interval. Western blot analysis with anti-AnxA3 antibodies further validated that up-regulation of AnxA3 only occurs with onset of neuronal death, and not with the onset of proteasome inhibition, which occurs at 4.5h post-lactacystin treatment. Over-expression studies suggested AnxA3 might be involved in death promotion during lactacystin-mediated neuronal death, since caspase-3 activation was significantly stronger upon neuronal AnxA3 over-expression. We propose AnxA3 up-regulation may have significant relevance in the elucidation of neurodegenerative pathophysiology. PMID- 20831895 TI - Superior graft-versus-leukemia effect associated with transplantation of haploidentical compared with HLA-identical sibling donor grafts for high-risk acute leukemia: an historic comparison. AB - The outcomes of an historic comparison of 117 consecutive, high-risk, acute leukemia patients undergoing hematopoietic stem cell transplantation (HSCT) from HLA-mismatched/haploidentical donors (HID, n = 81) or HLA-identical sibling donors (ISD, n = 36) without the use of in vitro T cell depletion (TCD), between the period of January 2005 and April 2009 were compared. Full engraftment was achieved in 98% of patients in the HID group and 97% in the ISD group. The cumulative incidences of grades II-IV acute graft-versus-host disease (aGVHD) in the HID and ISD cohorts were 49% and 24%, respectively (P = .014) with a relative risk (RR) of 2.99 (1.25-7.21) (P = .014). The incidence of chronic GVHD (cGVHD) did not differ significantly between the 2 cohorts. The 2-year cumulative incidence of relapse was significantly lower in HID (26%) than in ISD patients (49%) (P = .008). The 2-year cumulative incidence of nonrelapse mortality (NRM) was comparable in recipients of HID (34%) and ISD grafts (38%) (P = .85). The 3 year probability of overall survival (OS) was higher in HID patients (42%) than in ISD (20%) (P = .048) patients. Our comparisons suggest that HID transplants can achieve a stronger graft-versus-leukemia (GVL) effect than ISD for high-risk acute leukemia patients. PMID- 20831897 TI - Evidence of B cell immune responses to acute lymphoblastic leukemia in murine allogeneic hematopoietic stem cell transplantation recipients treated with donor lymphocyte infusion and/or vaccination. AB - These experiments explored mechanisms of control of acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation using a murine model of MHC-matched, minor histocompatibility antigen-mismatched transplantation. The central hypothesis examined was that addition of active vaccination against leukemia cells would substantially increase the effectiveness of allogeneic donor lymphocyte infusion (DLI) against ALL present in the host after transplantation. Although vaccination did increase the magnitude of type I T cell responses against leukemia cells associated with DLI, it did not lead to substantial improvement in long-term survival. Analysis of immunologic mechanisms of leukemia progression demonstrated that the failure of vaccination was not because of antigen loss in leukemia cells. However, analysis of survival provided surprising findings that, in addition to very modest type I T cell responses, a B cell response that produced antibodies that bind leukemia cells was found in long term survivors. The risk of death from leukemia was significantly lower in recipients that had higher levels of such antibodies. These studies raise the hypothesis that stimulation of B cell responses after transplantation may provide a novel way to enhance allogeneic graft-versus-leukemia effects associated with transplantation. PMID- 20831898 TI - Dynamics and flexibility of G-protein-coupled receptor conformations and their relevance to drug design. AB - G-protein coupled receptors (GPCRs) are seven helical transmembrane proteins with functional diversity and form the largest superfamily of drug targets. The functional diversity of these receptors stems from the conformational flexibility of the receptor, the nature of the ligand activating the receptor, and the intracellular protein that the receptor couples to. A molecular level understanding of the influence of each of these factors will greatly aid the design of functional selective drugs. In this review, the current state of our understanding of the conformational flexibility and dynamics of class A GPCRs derived from a confluence of biophysical and computational techniques is elucidated. PMID- 20831896 TI - Early lymphocyte recovery and outcomes after umbilical cord blood transplantation (UCBT) for hematologic malignancies. AB - Rapid lymphocyte recovery after bone marrow or peripheral blood transplantation is associated with improved survival. However, the impact of early lymphocyte recovery has not been examined after umbilical cord blood transplant (UCBT). We evaluated lymphocyte recovery in 360 consecutive patients with hematologic malignancy that underwent UCBT between 2001 and 2007. Uniform myeloablative (MA), reduced intensity conditioning (RIC) and graft-versus-host disease prophylaxis regimens were used. In multivariate analysis, an absolute leukocyte count (ALC) >200 * 10(6)/L at day 30 (n = 73) after MA conditioning was associated with superior 2-year overall survival (OS) (73% versus 61%; P = .02) (relative risk [RR]: 2.29; 95% confidence interval [CI]: 1.15-4.56), progression-free survival (PFS) (68% versus 54%; P = .05) (RR: 1.96; 95% CI: 0.99-3.86) and less transplant related mortality (8% versus 28%, P < .01) (RR: 4.38; 95% CI: 1.65-11.60) compared to <=200 * 10(6)/L (n = 43). Similarly, an ALC >200 * 10(6)/L at day 42 (n = 105) after RIC was associated with superior 2-year OS (59% versus 41%, P < .01) (RR: 2.10; 95% CI: 1.3-3.41) and PFS (46% versus 36%, P = .05) (RR: 1.58; 95% CI: 1.01-2.49) compared to <=200 * 10(6)/L (n = 55). There was no significant relationship between ALC and relapse. Rapid lymphocyte recovery early after UCBT predicts better survival in patients with hematologic malignancies. PMID- 20831899 TI - The CpA135 gene as a marker to identify Cryptosporidium species infecting humans. AB - Of the 22 species currently recognized as valid in the Cryptosporidium genus, C. parvum and C. hominis account for most cases of human infections worldwide. However, C. meleagridis, C. canis, C. felis, C. suis, C. muris, as well as the cervine, rabbit and monkey Cryptosporidium genotypes, have also been recognized as the etiologic cause of both sporadic and epidemic cryptosporidiosis in humans. Molecular methods are necessary to distinguish species and genotypes of Cryptosporidium, due to the lack of reliable morphological variations. The aim of this work was to determine the genetic polymorphisms in a fragment of the A135 gene in isolates of C. parvum, C. hominis, C. meleagridis, C. canis, C. muris, C. andersoni and the Cryptosporidium cervine genotype. Primers were designed on conserved regions identified on a multiple alignment of the C. parvum, C. hominis and C. muris sequences, the three species for which information is available at the genome level. PCR amplification and direct sequencing of a 576 bp fragment revealed the presence of numerous single nucleotide polymorphisms (SNPs) among the species/genotype tested. The genetic variability was exploited to design a PCR-RFLP assay useful for a rapid identification of the most important human pathogens in the genus Cryptosporidium. PMID- 20831900 TI - Endoscopic ultrasound does not accurately stage early adenocarcinoma or high grade dysplasia of the esophagus. AB - BACKGROUND & AIMS: Patients with esophageal high-grade dysplasia or mucosal esophageal cancer can be successfully treated by endoscopy. We performed a systematic review of the literature to determine whether endoscopic ultrasound (EUS) correctly predicts the T-stage of early esophageal cancers, compared with pathology specimens obtained by using endoscopic mucosal resection (EMR) or surgery. METHODS: Standard systematic review methods were used to perform reference searches, determine eligibility, abstract data, and analyze data. When possible, individual patient-level data were abstracted, in addition to publication-level aggregate data. RESULTS: Twelve studies had sufficient information to abstract and review for quality; 8 had individual patient-level data (n = 132). Compared with surgical or EMR pathology staging, EUS had T-stage concordance of 65%, including all studies (n = 12), but only 56% concordance when limited to individual patient-level data. Factors such as initial biopsy pathology (high-grade dysplasia vs early-stage cancer) did not appear to affect the concordance of staging between EUS and EMR/surgical staging. CONCLUSIONS: EUS is not sufficiently accurate in determining the T-stage of high-grade dysplasias or superficial adenocarcinomas; other means of staging, such as EMR, should be used. PMID- 20831901 TI - Duration of pain is correlated with elevation in liver function tests in patients with symptomatic choledocholithiasis. AB - BACKGROUND & AIMS: We assessed the temporal relationship between abdominal pain and elevation in liver function tests (LFTs) in patients with acute symptomatic choledocholithiasis. METHODS: Retrospective study of patients that presented within 12 hours of pain onset and were subsequently found to have choledocholithiasis. RESULTS: We identified 40 patients with complete medical records. Levels of aspartate and alanine aminotransferases (AST and ALT) correlated with duration of pain (Pearson correlation, r = 0.633 and 0.622 respectively, P < .001 for both); the correlation was not as strong for gamma glutamyl transpeptidase (GGT) (r = 0.326, P = .046) and was not significant for alkaline phosphatase or bilirubin. This temporal association was stronger in patients that had undergone cholecystectomy versus those with intact gallbladders (for ALT, r = 0.603 vs r = 0.311, respectively). Eighteen patients, evaluated within 6 hours of pain, had normal or minimal alterations in LFTs; transabdominal ultrasound was abnormal in 6 (sensitivity 33.3%). All had repeat LFTs within 24 hours (mean 10.3 +/- 6.9 hours later) and large increases in ALT and aspartate aminotransferase levels (mean 10.5- and 6.8-fold respectively; P < .01 for both), intermediate increases in glutamyl transpeptidase levels, (mean 4-fold, P < .05), and no changes in alkaline phosphatase levels. This significant increase in LFTs was the only indication of biliary pathology before endoscopy in 11/18 patients. CONCLUSIONS: Increasing duration of pain is associated with increasing LFTs (particularly transaminases) in patients with acute symptomatic choledocholithiasis. Patients with normal LFTs and ultrasound upon presentation should have repeat LFTs if biliary pain is suspected. The absence of significant biochemical abnormalities within the first 24 hours makes the diagnosis of symptomatic choledocholithiasis unlikely. PMID- 20831902 TI - Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas. AB - BACKGROUND & AIMS: Differences in efficacy of radiofrequency ablation (RFA) and surgical resection (SR) are not clear for patients with hepatocellular carcinoma (HCC). METHODS: From 2002 to 2007, 419 patients with HCCs <=5 cm were enrolled consecutively in the study. Among these patients, 190 and 229 patients received RFA and SR, respectively, as their first treatment. Factors were analyzed in terms of overall survival and recurrence by multivariate analysis and propensity score matching analysis. RESULTS: The SR group had younger age, a higher male-to female ratio, higher prevalence of hepatitis B virus, lower prevalence of hepatitis C virus, better liver function reserve, and larger tumor size than the RFA group. The cumulative 5-year overall survival rates were 79.3% in the SR group and 67.4% in the RFA group. During the follow-up period, tumors recurred in 244 patients in a median time of 14.5 +/- 15.7 months. Before propensity-score matching, the RFA group had shorter overall survival time (P = .009) and higher tumor recurrence rate (P < .001) than the SR group. After matching, RFA was comparable to SR in overall survival time (P = .519), but the RFA group still had a greater incidence of tumor recurrence (P < .001). In patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 HCC, RFA was as effective as SR for overall survival time and recurrence. CONCLUSIONS: Patients with small HCCs have a higher rate of tumor recurrence following RFA than surgery, but overall survival rates are comparable between therapies. RFA is as effective as surgery in patients with BCLC stage 0 HCC. PMID- 20831903 TI - Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. AB - BACKGROUND & AIMS: There are few data available about the prevalence or effects of cirrhosis in patients with hepatocellular carcinoma (HCC) from viral hepatitis. We compared patients with HCC and hepatitis B virus (HBV) or hepatitis C virus (HCV) infections to determine the proportions of cirrhosis in each group, virologic and tumor characteristics, and overall survival. METHODS: This analysis included patients with HBV (n = 64) or HCV (n = 118) infection who were diagnosed with HCC at the Mayo Clinic in Rochester, Minnesota from 1994-2008; groups were matched for age and sex. The diagnosis of cirrhosis was based on histology and, if histologic information was insufficient or unavailable, clinical indicators that included ascites or varices, thrombocytopenia or splenomegaly, and radiographic configuration of cirrhosis. Virologic characteristics, tumor stage, and patient survival were also assessed. RESULTS: The prevalence of histologic cirrhosis was 88% among patients with HBV infection and 93% among those with HCV infection (P = .46). When the most inclusive criteria for cirrhosis were applied, cirrhosis was present in 94% of patients with HBV and 97% with HCV (P = .24). Among HCV patients, 5.2% were negative for HCV RNA after antiviral treatment; 63.4% of HBV patients had HBV DNA <2000 IU/mL with or without treatment. Patients with HBV tended to have less surveillance and more advanced stages of HCC, without differences in survival from those with HCV infection (P = .75). CONCLUSIONS: Most patients with HCC and chronic viral hepatitis had evidence of cirrhosis, including those with HBV infection and those without active viral replication. PMID- 20831904 TI - Alterations in the expression of the Atp7a gene in the early postnatal development of the mosaic mutant mice (Atp7a mo-ms) - An animal model for Menkes disease. AB - Copper is a trace element that is essential for the normal growth and development of all living organisms. In mammals, the ATP7A Cu-transporting ATPase is a key protein that is required for the maintenance of copper homeostasis. In both humans and mice, the ATP7A protein is coded by the X-linked ATP7A/Atp7a gene. Disturbances in copper metabolism caused by mutations in the ATP7A/Atp7a gene lead to severe metabolic syndromes Menkes disease in humans and the lethal mottled phenotype in mice. Mosaic is one of numerous mottled mutations and may serve as a model for a severe Menkes disease variant. In Menkes patients, mutations in the ATP7A gene often result in a decreased level of the normal ATP7A protein. The aim of this study was to analyse the expression of the Atp7a gene in mosaic mutants in early postnatal development, a critical period for starting copper supplementation therapy in both Menkes patients and mutant mice. Using real-time quantitative RT-PCR, we analysed the expression of the Atp7a gene in the brain, kidney and liver of newborn (P0.5) and suckling (P14) mice. Our results indicate that in mosaic P0.5 mutants, the Atp7a mRNA level is decreased in all analysed organs in comparison with wild-type animals. In two week-old mutants, a significant decrease was observed only in the kidney. In contrast, their hepatic level of Atp7a tended to be higher than in wild-type mice. We speculate that disturbance in the expression of the Atp7a gene and, consequently, change in the copper concentration of the organs, may contribute to the early fatal outcome of mosaic males. PMID- 20831905 TI - Controlled DNA "damage" and repair in hypoxic signaling. AB - Hypoxia, a fundamental stimulus in biology and medicine, uses reactive oxygen species (ROS) as second messengers. A surprising target of hypoxia-generated ROS is specific bases within hypoxic response elements (HREs) of the VEGF and other hypoxia-inducible genes. Oxidative modifications coincide with the onset of mRNA accumulation and are localized to transcriptionally active mono-nucleosomes. The oxidative base modifications are removed by the base excision DNA repair pathway for which one of its components, the bifunctional transcriptional co-activator and DNA endonuclease Ref-1/Ape1, is critical for transcription complex assembly. Mimicking the effect of hypoxia by introducing an abasic site in an oligonucleotide model of the VEGF HRE, altered transcription factor binding, enhanced sequence flexibility, and engendered more robust reporter gene expression. These observations suggest that controlled DNA "damage" and repair, mediated by ROS used as second messengers and critically involving the base excision pathway of DNA repair, respectively, are important for hypoxia-induced transcriptional activation. PMID- 20831906 TI - Redox regulation of guanylate cyclase and protein kinase G in vascular responses to hypoxia. AB - The production of cGMP by the soluble form of guanylate cyclase (sGC) in bovine pulmonary arteries (BPA) is controlled by cytosolic NADPH maintaining reduced thiol and heme sites on sGC needed for activation by NO, and the levels of Nox oxidase-derived superoxide and peroxide that influence pathways regulating sGC activity. Our recent studies in BPA suggest that the activities of peroxide metabolizing pathways in vascular smooth muscle potentially determine the balance between sGC stimulation by peroxide and a cGMP-independent activation of cGMP dependent protein kinase (PKG) by a disulfide-mediated subunit dimerization. Cytosolic NADPH oxidation also appears to function in BPA through its influence on protein thiol redox control as an additional mechanism promoting vascular relaxation through PKG activation. These processes regulating PKG may participate in decreases in peroxide and increases in NADPH associated with contraction of BPA to hypoxia and in cytosolic NADPH oxidation potentially mediating bovine coronary artery relaxation to hypoxia. PMID- 20831907 TI - Insights into the mechanism of dihydropyrimidine dehydrogenase from site-directed mutagenesis targeting the active site loop and redox cofactor coordination. AB - In mammals, the pyrimidines uracil and thymine are metabolised by a three-step reductive degradation pathway. Dihydropyrimidine dehydrogenase (DPD) catalyses its first and rate-limiting step, reducing uracil and thymine to the corresponding 5,6-dihydropyrimidines in an NADPH-dependent reaction. The enzyme is an adjunct target in cancer therapy since it rapidly breaks down the anti cancer drug 5-fluorouracil and related compounds. Five residues located in functionally important regions were targeted in mutational studies to investigate their role in the catalytic mechanism of dihydropyrimidine dehydrogenase from pig. Pyrimidine binding to this enzyme is accompanied by active site loop closure that positions a catalytically crucial cysteine (C671) residue. Kinetic characterization of corresponding enzyme mutants revealed that the deprotonation of the loop residue H673 is required for active site closure, while S670 is important for substrate recognition. Investigations on selected residues involved in binding of the redox cofactors revealed that the first FeS cluster, with unusual coordination, cannot be reduced and displays no activity when Q156 is mutated to glutamate, and that R235 is crucial for FAD binding. PMID- 20831908 TI - Kinetic studies of Gly28:Ser mutant form of Bacillus pumilus lipase: changes in k(cat) and thermal dependence. AB - Lipases are useful catalysts for a wide variety of industrial purposes. Herein we report the stability and thermal dependence of the activity of wild-type Bacillus pumilus lipase (BplA) and four site-directed mutants designed to improve its thermal stability. The Gly28:Ser mutation produces a dramatic four-fold increase in its k(cat) and a remarkable increase in its stability. While the increase in k(cat) is temperature-independent, the increase in stability shows that the resultant interactions of this mutation have a strong enthalpic component. Thermal dependence of stability, k(cat), K(M) and k(cat)/K(M) were analysed to gain insight on the structural effects of mutations on BplA. Our results are consistent with a gain in enzyme mobility for those mutants displaying enhanced catalytic properties; the analysis of thermal dependence of kinetic parameters indicates that the mutations did not change either the catalytic mechanism or the rate-limiting step of catalysis. PMID- 20831909 TI - Human cervical spine ligaments exhibit fully nonlinear viscoelastic behavior. AB - Spinal ligaments provide stability and contribute to spinal motion patterns. These hydrated tissues exhibit time-dependent behavior during both static and dynamic loading regimes. Therefore, accurate viscoelastic characterization of these ligaments is requisite for development of computational analogues that model and predict time-dependent spine behavior. The development of accurate viscoelastic models must be preceded by rigorous, empirical evidence of linear viscoelastic, quasi-linear viscoelastic (QLV) or fully nonlinear viscoelastic behavior. This study utilized multiple physiological loading rates (frequencies) and strain amplitudes via cyclic loading and stress relaxation experiments in order to determine the viscoelastic behavior of the human lower cervical spine anterior longitudinal ligament, the posterior longitudinal ligament and the ligamentum flavum. The results indicated that the cyclic material properties of these ligaments were dependent on both strain amplitude and frequency. This strain amplitude-dependent behavior cannot be described using a linear viscoelastic formulation. Stress relaxation experiments at multiple strain magnitudes indicated that the shape of the relaxation curve was strongly dependent on strain magnitude, suggesting that a QLV formulation cannot adequately describe the comprehensive viscoelastic response of these ligaments. Therefore, a fully nonlinear viscoelastic formulation is requisite to model these lower cervical spine ligaments during activities of daily living. PMID- 20831910 TI - An in vivo characterization of colostrum protein uptake in porcine gut during early lactation. AB - Understanding the bioactive roles of colostrum proteins has gained much attention, and in particular, their potential use in human and veterinary medicine has been extensively studied. However, studies of bioactivity have mainly been conducted in vitro, but it has not yet been well characterized at the individual protein level which colostrum components are internalized by the intestinal tissue of the neonate. The aim of this study was to characterize the in vivo processing of porcine colostrum in the gastrointestinal tract, and describe which of the potential bioactive proteins can be observed in the small intestinal tissue, and therefore may be functionally important. Using 2D-LC-MS/MS analysis we mapped the proteins in porcine colostrum. The colostrum proteins were then traced in the stomach content, as well as in the small intestinal tissue of 5 piglets suckled for 24h. For comparison, we also mapped the proteins present in the intestinal tissue of a newborn piglet that had not received colostrum. This analysis allowed us to identify the colostrum proteins that are internalized and retained in the tissue from the small intestine, indicating their functional importance. Our studies have shown that in early lactation, some colostrum proteins are protected against proteolytic degradation in the stomach. Furthermore, colostrum proteins with immuno-protective, antimicrobial or other bioactive functions are more prone to uptake in the small intestine than the caseins and beta-lactoglobulin, which are amongst the most abundant in colostrum. PMID- 20831911 TI - Combined peptides of human enterovirus 71 protect against virus infection in mice. AB - Human enterovirus 71 (EV71) is a cause of hand, foot and mouth disease (HMFD) in children under 6 years old, and could cause serious neurological complications in some patients. Numerous large outbreaks of EV71 caused HMFD have occurred recently in Asia, especially in China. The cross-reactivity of EV71 with human brain tissue was observed and the cross-reactivity inducing regions were identified in previously study, which suggested that there were two regions in structural proteins of virus should be avoided in the vaccine. Six peptides without cross-reactivity were selected and combined into three vaccine candidates and applied in further evaluation in neonatal mice. The Vac6 comprising the peptides of P(70-159), P(140-249), P(324-443) and P(746-876) of the structural proteins could provide effective protection on pups against virus infection, as shown in viral copies detection and histopathology examination. Immunohistochemical staining results indicated that Vac6 had no cross-reactivity with human brain tissues. Our results suggested that Vac6 could have potential clinical value against EV71 epidemics caused mainly by C4 strains in the mainland of China. PMID- 20831912 TI - Cost-effectiveness of Ontario's pandemic vaccine program. PMID- 20831913 TI - Rabies vaccines: WHO position paper--recommendations. AB - This article presents the WHO recommendations on the use of rabies vaccines excerpted from the recently published Rabies vaccines: WHO position paper. This document replaces the WHO position paper entitled Rabies vaccines WHO position paper published in the Weekly Epidemiological Record in December 2007. Footnotes to this paper provide a limited number of core references; their abstracts as well as a more comprehensive list of references may be found at http://www.who.int/immunization/documents/positionpapers/en/index.html. Grading tables which assess the quality of scientific evidence for key conclusions are also available through this link and are referenced in the position paper. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This updated paper reflects the recent recommendations of WHO's Strategic Advisory Group of Experts on immunization, or SAGE. PMID- 20831915 TI - Comment on the contribution by Weycker et al., "Cost of routine immunization of young children against rotavirus infection with Rotarix (r) versus RotaTeq (r)". PMID- 20831914 TI - Candidate hepatitis C vaccine trials and people who inject drugs: challenges and opportunities. AB - People who inject drugs (PWID) are at high risk of HCV. Limited evidence of the effectiveness of prevention interventions and low uptake of treatment in this group highlight the need for increased investment in biomedical interventions, notably safe and efficacious vaccines. While several candidates are currently in development, field trials in PWID present challenges, including ethical issues associated with trial literacy, informed consent and standards of care. Significant biological and social factors and differences between HIV and HCV suggest that HCV warrants targeted vaccine preparedness research to lay the groundwork for successful implementation of future trials. PMID- 20831916 TI - Targeted microbeads for attraction and induction of specific innate immune response in the tumor microenvironment. AB - Antitumor activity of molecules and cells of the innate immune system has been reported. Here we propose a method for targeting preferred innate immune cells and magnifying their tumoricidal effect at the tumor microenvironment, by modular multiple-component complexes (termed TILTAN). As a model, micro-scale complexes were assembled carrying monoclonal anti-HER2 antibodies, lipopolysaccharide and/or mannose. The complexes showed high binding capacity to HER2-positive cancer cells in vitro, high induction of interleukin-1 RNA transcription by the activated monocytes and ability to mediate monocytes' attachment to HER2-positive cells. TILTAN treatment was found safe in in vivo testing and induced change in interleukin-1 RNA transcription in tumors xenografts. We thus present a new vision of targeting a desired innate immune response to the tumor microenvironment. PMID- 20831917 TI - Profiles of B and T cell immune responses elicited by different forms of the hepatitis B virus surface antigen. AB - Gene-based hepatitis B virus (HBV) vaccines have been proposed as a novel approach to improve the immunogenicity toward non-responders and to allow for protection against potential viral escape mutants. Furthermore, there is significant interest in using DNA or viral vector vaccines to serve as therapeutic agents to treat chronic HBV infections that are resistant to existing drug therapies. However, the key protective antigen of HBV, the surface protein (HBsAg), can be expressed in three different sizes due to its multiple translational initiation sites: small, middle, and large forms of HBsAg. It is not clear whether the immunogenicity of these HBsAg is same, especially their ability to elicit HBsAg-specific B cell and T cell immune responses in addition to the traditional serum HBsAg-specific antibody responses. In the current study, the immunogenicity of three forms of HBsAg DNA vaccines was analyzed individually in a mouse model. Our results indicated that different forms of the HBsAg have unique immunogenicity profiles and this information is useful for the selection of optimal gene-based HBV vaccines for further improved prophylactic and therapeutic applications. PMID- 20831918 TI - Vascular smooth muscle contractility assays for inflammatory and immunological mediators. AB - The blood vessels are one of the important target tissues for the mediators of inflammation and allergy; further cytokines affect them in a number of ways. We review the use of the isolated blood vessel mounted in organ baths as an important source of pharmacological information. While its use in the bioassay of vasoactive substances tends to be replaced with modern analytical techniques, contractility assays are effective to evaluate novel synthetic drugs, generating robust potency and selectivity data about agonists, partial agonists and competitive or insurmountable antagonists. For instance, the human umbilical vein has been used extensively to characterize ligands of the bradykinin B(2) receptors. Isolated vascular segments are live tissues that are intensely reactive, notably with the regulated expression of gene products relevant for inflammation (e.g., the kinin B(1) receptor and inducible nitric oxide synthase). Further, isolated vessels can be adapted as assays of unconventional proteins (cytokines such as interleukin-1, proteases of physiopathological importance, complement-derived anaphylatoxins and recombinant hemoglobin) and to the gene knockout technology. The well known cross-talks between different cell types, e.g., endothelium-muscle and nerve terminal-muscle, can be extended (smooth muscle cell interaction with resident or infiltrating leukocytes and tumor cells). Drug metabolism and distribution problems can be modeled in a useful manner using the organ bath technology, which, for all these reasons, opens a window on an intermediate level of complexity relative to cellular and molecular pharmacology on one hand, and in vivo studies on the other. PMID- 20831919 TI - Gymnasterkoreayne F inhibits osteoclast formation by suppressing NFATc1 and DC STAMP expression. AB - Osteoclasts are multinucleated cells that have a unique role in bone degradation. Modulation of osteoclast formation and/or its activity is an important approach for the treatment of bone-destructive diseases such as osteoporosis and rheumatoid arthritis. In this study, Gymnasterkoreayne F (GK-F), a natural compound isolated from Gymnaster koraiensis, was found to inhibit osteoclast differentiation from primary bone marrow-derived macrophages (BMMs) in a dose dependent manner. The inhibition occurred through the suppression of nuclear factor of activated T cells c1 (NFATc1) expression, which then led to the decreased levels of osteoclastogenic markers, including Cathepsin K and tartrate resistant acid phosphatase (TRAP). In addition, GK-F abolished pre-osteoclast fusion induced by the receptor activator of nuclear factor kappa B ligand (RANKL), lipopolysaccharide (LPS) and TNF-alpha. Reflecting its inhibitory effects on cell-cell fusion, GK-F attenuated the gene expression of an essential molecule of osteoclast fusion, the dendritic cell-specific transmembrane protein (DC-STAMP). Furthermore, GK-F inhibited the bone resorptive activity of differentiated osteoclasts through its ability to block RANKL-induced actin ring formation. The effect was associated with a significant decrease in the induction of beta3 integrin expression, which is an essential regulator of osteoclast cytoskeletal function. Taken together, these results suggest that GK-F might be useful as a therapeutic agent for bone resorption-related diseases. PMID- 20831920 TI - Alzheimer disease. Foreward. PMID- 20831922 TI - Preface update of dental local anesthesia. PMID- 20831923 TI - Local anesthetics: pharmacology and toxicity. AB - The development of safe and effective local anesthetic agents has possibly been the most important advancement in dental science to occur in the last century. The agents currently available in dentistry are extremely safe and fulfill most of the characteristics of an ideal local anesthetic. These local anesthetic agents can be administered with minimal tissue irritation and with little likelihood of inducing allergic reactions. A variety of agents are available that provide rapid onset and adequate duration of surgical anesthesia. This introductory article provides a brief update of the clinical pharmacology of local anesthetic agents and formulations used in dentistry at present. PMID- 20831924 TI - The use of local anesthetic agents in medicine. AB - Local anesthetics are commonly used in both dentistry and medicine. These drugs are also used in some office-based medical practices. Except for minor procedures, most physicians who require complicated nerve blocks rely on anesthesiologists to administer the local anesthesia. Both ester and amide local anesthetics are routinely used in medical practice. This article reviews the types and uses of local anesthesia in anesthesiology. PMID- 20831925 TI - Long-acting local anesthetics and perioperative pain management. AB - Although the use of long-acting local anesthetics has become a useful therapeutic approach for managing peri- and postoperative pain, recent evidence reveals unexpected outcomes. This article reviews the clinical use of long-acting local anesthetics, presents current clinical research findings, and makes recommendations for their use. PMID- 20831926 TI - Infiltration anesthesia in the mandible. AB - Infiltration is preferred to regional block techniques in the maxilla as the former offers a number of advantages. This paper considers the evidence for the efficacy of infiltration anesthesia in the mandible in the adult dentition, both as a primary and as a supplemental method. PMID- 20831927 TI - Phentolamine mesylate for accelerating recovery from lip and tongue anesthesia. AB - Phentolamine mesylate, at dosages from 0.4 to 0.8 mg in adults and adolescents and at dosages from 0.2 to 0.4 mg in children aged 4 to 11 years, has been proven to be safe and effective for the reversal of soft tissue anesthesia (lip and tongue numbness) and the associated functional deficits resulting from a local dental anesthetic injection containing a vasoconstrictor. Its ability to block a adrenergic receptors on blood vessels induces vasodilation and enhances the redistribution of the local anesthetic away from the injection site. The low dosages administered for dental local anesthetic reversal in all likelihood accounts for the lack of significant cardiovascular effects that are associated with the medical use of the drug for hypertensive conditions associated with catecholamine excess. PMID- 20831928 TI - Efficacy of articaine formulations: quantitative reviews. AB - In 2000, the US Food and Drug Administration (FDA) approved the use of 4% articaine with epinephrine 1:100,000, and with epinephrine 1:200,000 in 2006. Articaine has been commonly compared with its predecessor, lidocaine hydrochloride. Since its introduction in 1948, lidocaine has maintained a status as the most widely used local dental anesthetic in most countries. Proven efficacy with low allergenicity and toxicity over long-term clinical use and research have confirmed the value and safety of this drug. Thus, it became the gold standard to which all new local anesthetics are compared. Despite the gold standard status of lidocaine, numerous reports and editorials have supported and recognized the use of articaine. PMID- 20831929 TI - Allergic reactions to local anesthetic formulations. AB - True allergic reactions to local anesthetics are rare adverse reactions. At the most, they represent less than 1% of all adverse local anesthetic reactions. When true allergic reactions have been confirmed, the reactions are most commonly the type I anaphylactic and type IV delayed hypersensitivity responses. The type I immediate hypersensitivity reactions are the most severe and may be life threatening. In the event a potential allergic reaction occurs in a dental office, the dentist needs to properly evaluate the events leading up to the reaction and provide a differential diagnosis. A referral should be given to any patient when an allergic reaction cannot be ruled out as an intravascular injection, toxic overdose, psychogenic reaction, or an idiosyncratic event. PMID- 20831921 TI - Alzheimer disease. PMID- 20831930 TI - Acquired methemoglobinemia revisited. AB - Dentistry has two medications in its pain management armamentarium that may cause the potentially life-threatening disorder methemoglobinemia. The first medications are the topical local anesthetics benzocaine and prilocaine. The second medication is the injectable local anesthetic prilocaine. Acquired methemoglobinemia remains a source of morbidity and mortality in dental and medical patients despite the fact that it is better understood now than it was even a decade ago. It is in the interest of all dental patients that their treating dentists review this disorder. The safety of dental patients mandates professional awareness. PMID- 20831931 TI - Ocular complications associated with local anesthesia administration in dentistry. AB - The most widely used method for controlling pain during dental procedures is the intraoral administration of local anesthetics in close proximity to a specific nerve or fiber to obtund nerve conduction. The most commonly anesthetized nerves in dentistry are branches or nerve trunks associated with the maxillary and mandibular divisions of the trigeminal nerve (cranial nerve V). However, other nerves may be inadvertently affected by intraoral local anesthesia injections, resulting in anesthetic complications of structures far from the oral cavity. Practitioners should be aware of potential ocular complications following intraoral injections in dentistry. These complications include oculomotor paralysis and vision loss. The knowledge of these conditions and their potential cause should alert the dentist to the importance of appropriate injection techniques and an understanding of management protocol. PMID- 20831932 TI - Beta-adrenergic blocking agents and dental vasoconstrictors. AB - A clinically significant interaction between epinephrine or levonordefrin with nonselective beta-adrenergic blocking agents, although apparently rare in the dental setting, is potentially serious and can lead to significant hypertension with a concomitant reflex bradycardia. Based on the results of epinephrine infusion studies, the severity of the interaction seems dose related; small epinephrine doses cause less of a pressor response than larger doses. The interaction can be seen after intraoral submucosal injections but is generally of a smaller magnitude, at least with only 1 or 2 cartridges of lidocaine plus 1:100,000 epinephrine. However as demonstrated by 1 case report, some individuals are hypersensitive to this interaction. Inadvertent intravascular injections of local anesthetic plus vasoconstrictor and the use of high doses of vasoconstrictor are likely to result in a more pronounced response. Patients with significant cardiovascular disease may be especially vulnerable to the most serious sequelae resulting from the pressor reactions of the drug combination. PMID- 20831933 TI - Local anesthetic use in the pregnant and postpartum patient. AB - The use of systemically absorbed drugs in the gravid and in the lactating patient is of concern to the dentist. This article reviews concerns for the health and safety of the mother, developing fetus, and neonate involving local anesthetics. The available literature on the use of local anesthetics for dentistry in the pregnant and postpartum patient is also reviewed. In addition, the physiology of the pregnant and postpartum woman is discussed because this is essential to understanding potential interplay with local anesthesia and the stress of a dental appointment. PMID- 20831934 TI - Paresthesias in dentistry. AB - Alterations to normal oral sensory function can occur following restorative and surgical dental procedures. Paresthesia is defined as an abnormal sensation, such as burning, pricking, tickling, or tingling. Paresthesias are one of the more general groupings of nerve disorders known as neuropathies. This article reviews the extent of this oral complication as it relates to dental and surgical procedures, with specific emphasis on paresthesias associated with local anesthesia administration. This review establishes a working definition for paresthesia as it relates to surgical trauma and local anesthesia administration, describes the potential causes for paresthesia in dentistry, assesses the incidence of paresthesias associated with surgery and local anesthesia administration, addresses the strengths and weaknesses in research findings, and presents recommendations for the use of local anesthetics in clinical practice. PMID- 20831935 TI - Needle phobia: etiology, adverse consequences, and patient management. AB - Needle phobia has profound health, dental, societal, and legal implications, and severe psychological, social, and physiologic consequences. There is genetic evidence for the physiologic response to needle puncture, and a significant familial psychological component, showing evidence of inheritance. Needle phobia is also a learned behavior. The dental practitioner must recognize patients with needle phobia before the administration of local anesthetics to identify patients who are potentially reactive and to prevent untoward sequelae. Needle phobia is highly associated with avoidance behavior, and the dentist must exhibit compassion and respect. To avoid bradycardia, hypotension, unconsciousness, convulsions, and possibly asystole, oral premedication with benzodiazepines or other antianxiety agents must be considered for patients who are needle phobic. Management of needle phobiaeinduced syncope includes perioperative monitoring, oxygen administration, positioning, atropine, and vasopressors. PMID- 20831936 TI - Needle breakage: incidence and prevention. AB - Since the introduction of nonreusable, stainless steel dental local anesthetic needles, needle breakage has become an extremely rare complication of dental local anesthetic injections. But although rare, dental needle breakage can, and does, occur. Review of the literature and personal experience brings into focus several commonalities which, when avoided, can minimize the risk of needle breakage with the fragment being retained from occurring. PMID- 20831937 TI - Advanced techniques and armamentarium for dental local anesthesia. AB - Computer-controlled local anesthetic delivery (C-CLAD) devices and systems for intraosseous (IO) injection are important additions to the dental anesthesia armamentarium. C-CLAD using slow infusion rates can significantly reduce the discomfort of local anesthetic infusion, especially in palatal tissues, and facilitate palatal approaches to pulpal nerve block that find special use in cosmetic dentistry, periodontal therapy, and pediatric dentistry. Anesthesia of single teeth can be obtained using either C-CLAD intraligamentary injections or IO injections. Supplementary IO anesthesia is particularly suited for providing effective pain control of teeth diagnosed with irreversible pulpitis. PMID- 20831938 TI - Local anesthesia administration by dental hygienists. AB - Within the last 30 years, the role of dental hygienists has expanded to include the administration of local anesthesia. Several studies have been performed to assess practice characteristics and effectiveness of these changes in state licensure regulations. Findings indicate an acceptance of this expansion in dental hygiene practice; however, the delegation of this pain control procedures remains controversial. To address this controversy, the authors have reviewed of current literature to assess the practice of local anesthesia administration by dental hygienists. PMID- 20831939 TI - Pheromones. Preface. PMID- 20831941 TI - Female perception of male body odor. AB - Olfaction is one of the most crucial forms of communication among nonhuman animals. Historically, olfaction has been perceived as being of limited importance for humans, but recent research has documented that not only do humans have sensitive olfactory abilities, but also odors have the potential to influence our physiology and behavior. This chapter reviews research on olfactory communication among humans, focusing on the effects of male bodily odors on female physiology and behavior. The process of body odor production and the detection of olfactory signals are reviewed, focusing on potential sex differences in these abilities. The effects of male body odors on female physiological and behavioral effects of body odors are considered. Finally, with specific regard to female mate choice, evidence regarding the influence of the major histocompatibility complex and fluctuating asymmetry on male olfactory cues is reviewed. PMID- 20831940 TI - Functional neuronal processing of human body odors. AB - Body odors carry informational cues of great importance for individuals across a wide range of species, and signals hidden within the body odor cocktail are known to regulate several key behaviors in animals. For a long time, the notion that humans may be among these species has been dismissed. We now know, however, that each human has a unique odor signature that carries information related to his or her genetic makeup, as well as information about personal environmental variables, such as diet and hygiene. Although a substantial number of studies have investigated the behavioral effects of body odors, only a handful have studied central processing. Recent studies have, however, demonstrated that the human brain responds to fear signals hidden within the body odor cocktail, is able to extract kin specific signals, and processes body odors differently than other perceptually similar odors. In this chapter, we provide an overview of the current knowledge of how the human brain processes body odors and the potential importance these signals have for us in everyday life. PMID- 20831942 TI - Current issues in the study of androstenes in human chemosignaling. AB - We review research on the 16-androstenes and their special claim, born originally of the finding that androstenes function as boar pheromones, to be human chemosignals. Microbial fauna in human axillae act upon the 16-androstenes to produce odorous volatiles. Both individual variation and sex differences in perception of these odors suggest that they may play a role in mediating social behavior, and there is now much evidence that they modulate changes in interpersonal perception, and individual mood, behavior, and physiology. Many of these changes are sensitive to the context in which the compounds are experienced. However, many key outstanding questions remain. These include identification of the key active compounds, better quantification of naturally occurring concentrations and understanding how experimentally administered concentrations elicit realistic effects, and elucidation of individual differences (e.g., sex differences) in production rates. Until such issues are addressed, the question of whether the androstenes play a special role in human interactions will remain unresolved. PMID- 20831943 TI - Mammary odor cues and pheromones: mammalian infant-directed communication about maternal state, mammae, and milk. AB - Neonatal mammals are exposed to an outstandingly powerful selective pressure at birth, and any mean to alleviate their localization effort and accelerate acceptance to orally grasp a nipple and ingest milk should have had advantageous consequences over evolutionary time. Thus, it is essential for females to display a biological interface structure that is sensorily conspicuous and executively easy for their newborns. Females' strategy to increase the conspicuousness of nipples could only exploit the newborns' most advanced and conserved sensory systems, touch and olfaction, and selection has accordingly shaped tactilely and olfactorily conspicuous mammary structures. This evolutionary modification has worked either by affecting structural features of mammaries or indirectly by affecting maternal behavioral propensities to create olfactory traces on them. These predictions are considered here in mammalian cases that have received empirical attention among marsupials, rodents, lagomorphs, ungulates, carnivores, and primates. It appears that broadcasting chemical cues and/or signals from the mammae is a pan-mammalian reproductive strategy to pilot neonatal arousal, motivation and attraction to the mother, provide assistance in localizing and orally grasping the mammae, and boost up learning. But the ways by which these chemical cues are produced and assembled on the mammae are both diverse between species and complex within species, offering an outstanding opportunity for comparative analyses in chemical communication. PMID- 20831944 TI - Exposure to female pheromones during pregnancy causes postpartum anxiety in mice. AB - The postpartum period is associated with an increased incidence of pathological anxiety, exerting a substantial burden on both the mother and the baby. We have shown that pharmacological suppression of prolactin in early pregnancy decreases maternal neurogenesis to cause postpartum anxiety. The present data demonstrate that physiological suppression of prolactin secretion through exposure to unfamiliar female pheromones throughout pregnancy prevented the normal postpartum attenuation of anxiety in mice, resulting in high anxiety relative to postpartum controls. Female pheromone-exposed mice also showed severely impaired maternal behavior in an anxiogenic situation. Mice exposed to female pheromones had decreased serum prolactin levels in early pregnancy, resulting in an ablation of the normal increase of neurogenesis on day 7 of pregnancy. These data demonstrate that low serum prolactin levels in early pregnancy, whether induced pharmacologically or as a physiological consequence of exposure to unfamiliar female pheromones, result in failure to show the normal adaptive decrease in anxiety after birth. This provides new insight into possible mechanisms that might underlie postpartum anxiety in women. PMID- 20831946 TI - Chemosensory function of the amygdala. AB - The chemosensory amygdala has been traditionally divided into two divisions based on inputs from the main (olfactory amygdala) or accessory (vomeronasal amygdala) olfactory bulbs, supposedly playing different and independent functional roles detecting odors and pheromones, respectively. Recently, there has been increased anatomical evidence of convergence inputs from the main and accessory bulbs in some areas of the amygdala, and this is correlated with functional evidence of interrelationships between the olfactory and the vomeronasal systems. This has lead to the characterization of a third division of the chemosensory amygdala, the mixed chemosensory amygdala, providing a new perspective of how chemosensory information is processed in the amygdaloid complex, in particular in relation to emotional behaviors. In this chapter, we analyze the anatomical and functional organization of the chemosensory amygdala from this new perspective. Finally, the evolutionary changes of the chemosensory nuclei of the mammalian amygdala are discussed, paying special attention to the case of primates, including humans. PMID- 20831945 TI - Major urinary protein regulation of chemical communication and nutrient metabolism. AB - The major urinary protein (MUP) family members contain a conserved beta-barrel structure with a characteristic central hydrophobic pocket. They are secreted by the liver and excreted into the urine. MUPs bind via their central pockets to volatile pheromones or other lipophilic molecules, and regulate pheromone transportation in the circulation, excretion in the kidney, and release into the air from urine marks. MUPs are highly polymorphic, and the MUP profiles in urine function as individual identity signatures of the owners. The MUP signatures are detected by the main and accessory olfactory systems and trigger adaptive behavioral responses and/or developmental processes. Circulating MUPs serve as a metabolic signal to regulate glucose and lipid metabolism. Recombinant MUP1 markedly ameliorates hyperglycemia and glucose intolerance in mice with type 2 diabetes. MUP1 suppresses hepatic gluconeogenesis and promotes energy expenditure in skeletal muscle by stimulating mitochondrial biogenesis and function. MUPs are unique members of the lipocalin superfamily that mediate both chemical and metabolic signaling. PMID- 20831947 TI - TRPC channels in pheromone sensing. AB - Pheromone recognition relies on an amplification cascade that is triggered by pheromone binding to G protein-coupled receptors (GPCR). The first step in translation of GPCR activation by pheromones in the vomeronasal organ and main olfactory epithelium (MOE) into a cellular response is the activation of a transient receptor potential (TRP) family member, TRPC2 [Zufall, F., Ukhanov, K., Lucas, P., Liman, E. R., and Leinders-Zufall, T. (2005). Neurobiology of TRPC2: From gene to behavior. Pflugers Arch.451, 61-71; Yildirim, E., and Birnbaumer, L. (2007). TRPC2: Molecular biology and functional importance. Handb. Exp. Pharmacol. 53-75]. The members of the canonical (TRPC) family of TRP channels mediate membrane permeability, specifically, Ca(2+) influx into the cytoplasm in response to activation of GPCR and tyrosine kinase receptors by hormones, neurotransmitters, and growth factors [Nilius, B. (2007). TRP channels in disease. Biochim. Biophys. Acta1772, 805-812; Venkatachalam, K., and Montell, C. (2007). TRP channels. Annu. Rev. Biochem.76, 387-417]. Mechanisms of their activation have been the focus of intense interest during the last decade. The data obtained from studies of TRPC2 have resulted in a better understanding of ion channel physiology and led to novel paradigms in modern cell biology [Lucas, P., Ukhanov, K., Leinders-Zufall, T., and Zufall, F. (2003). A diacylglycerol gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: Mechanism of pheromone transduction. Neuron40, 551-561; Stowers, L., Holy, T. E., Meister, M., Dulac, C., and Koentges, G. (2002). Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science295, 1493-1500; Leypold, B. G., Yu, C. R., Leinders-Zufall, T., Kim, M. M., Zufall, F., and Axel, R. (2002). Altered sexual and social behaviors in trp2 mutant mice. Proc. Natl. Acad. Sci. USA99, 6376-6381]. Although TRPC2 activation by pheromones presents one of the most straightforward examples of physiological function of TRPC channels, the molecular aspects of its activation are not well understood (Yildirim, E., and Birnbaumer, L. (2007). TRPC2: Molecular biology and functional importance. Handb. Exp. Pharmacol. 53-75). It is natural to expect that better understanding of TRPC2 activation mechanisms will lead to breakthroughs in understanding ion channel activation mechanisms, as well as applied behavioral pharmacology. The present review is focused on the current knowledge of TRPC2 physiology with a specific focus on TRPC activation mechanisms. PMID- 20831948 TI - Alarm pheromones-chemical signaling in response to danger. AB - Many animals respond to the threat of predation by producing alarm signals that warn other individuals of the presence of danger or otherwise reduce the success of predators. While alarm signals may be visual or auditory as well as chemical, alarm pheromones are common, especially among insects and aquatic organisms. Plants too emit chemical signals in response to attack by insect herbivores that recruit the herbivores' natural enemies and can induce preparations for defense in neighboring plants (or other parts of the same plant). In this chapter, we discuss our current understanding of chemical alarm signaling in a variety of animal groups (including social and presocial insects, marine invertebrates, fish, and mammals) and in plants. We also briefly discuss the exploitation of alarm pheromones as foraging cues for natural enemies. We conclude with a brief discussion of the potential exploitation of alarm signaling to achieve the applied goal of managing pest species. PMID- 20831949 TI - Odorant-binding proteins in insects. AB - Our understanding of the molecular and biochemical mechanisms that mediate chemoreception in insects has been greatly improved after the discovery of olfactory and taste receptor proteins. However, after 50 years of the discovery of first insect sex pheromone from the silkmoth Bombyx mori, it is still unclear how hydrophobic compounds reach the dendrites of sensory neurons in vivo across aqueous space and interact with the sensory receptors. The presence of soluble polypeptides in high concentration in the lymph of chemosensilla still poses unanswered questions. More than two decades after their discovery and despite the wealth of structural and biochemical information available, the physiological function of odorant-binding proteins (OBPs) is not well understood. Here, I review the structural properties of different subclasses of insect OBPs and their binding to pheromones and other small ligands. Finally, I discuss current ideas and models on the role of such proteins in insect chemoreception. PMID- 20831950 TI - Drosophila CheB proteins involved in gustatory detection of pheromones are related to a human neurodegeneration factor. AB - The Drosophila CheBs proteins are expressed in a variety of sexually dimorphic subsets of taste hairs, some of which have been directly implicated in pheromone detection. Their remarkable collection of expression patterns suggests that CheBs have specialized roles in gustatory detection of pheromones. Indeed, mutations in the CheB42a gene specifically alter male response to female-specific cuticular hydrocarbons. Furthermore, CheBs belong to the large ML (MD-2-like) superfamily of lipid-binding proteins and share amino acids with an essential role in the function of human GM2-activator protein (GM2-AP), a protein whose absence results in neurodegeneration and death. As GM2-AP binds specifically to the GM2 ganglioside, we have proposed that CheB42a and other CheBs function by interacting directly with the lipid-like cuticular hydrocarbons of Drosophila melanogaster and modulating their detection by transmembrane receptors. Here I review the current knowledge of the CheB family and discuss possible models for their function. PMID- 20831951 TI - Volatile signals during pregnancy. AB - Scents play a key role in mediating reproductive interactions in many vertebrates including mammals. Nowadays, several studies indicate that humans seem to use remarkably olfactory communication and are even able to produce and perceive pheromones. Furthermore, over the past several years, it became increasingly clear that pheromone-like chemical signals probably play a role in offspring identification and mother recognition. Recently developed technical procedures (solid-phase microextraction and dynamic headspace extraction) now allow investigators to characterize volatile compounds with high reliability. We analyzed the volatile compounds in sweat patch samples collected from the para axillary and nipple-areola regions of women during pregnancy and after childbirth. We hypothesized that, at the time of birth and during the first weeks of life, the distinctive olfactory pattern of the para-axillary area is probably useful to newborn babies for recognizing and distinguishing their own mother, whereas the characteristic pattern of the nipple-areola region is probably useful as a guide to nourishment. PMID- 20831952 TI - Olfactory sensitivity: functioning in schizophrenia and implications for understanding the nature and progression of psychosis. AB - Prefrontal neural processes maturing during neurodevelopment parallel normal improvement in higher order olfactory processing (identification) from childhood. Hence, disorders of adolescence such as schizophrenia that implicate prefrontal regions are associated with olfactory identification deficits in the presence of relatively intact lower order olfactory processing capacity (sensation) and mediating neural processes (limbic system). Understanding the linear neural trajectory of olfactory processing can assist in detecting the location, nature, and extent of early compromise of circuitry implicated in neurodevelopmental disorders such as psychosis. More recently, relatively discreet odorant sensitivity problems in schizophrenia have been described and these appear related to secretion of malodorous compounds. These findings have significant implications for future genetic prediction of this disorder. PMID- 20831953 TI - Olfactory systems in mate recognition and sexual behavior. AB - Olfactory signals play an important role so that breeding efforts are synchronized with appropriate social and environmental circumstances. In this context, the mammalian olfactory system is characterized by the existence of several olfactory subsystems that have evolved to process olfactory information. While the vomeronasal (or accessory) olfactory system is usually conceived as being involved in the processing of pheromonal signals due to its close connections with the reproductive hypothalamus, the main olfactory system is, by contrast, considered as a general analyzer of volatile chemosignals, especially those that are used for the social identification of conspecifics. In fact, several recent sets of experiments suggest that both the main and accessory olfactory systems have the ability to process partly overlapping pheromonal chemosignals and that both systems converge at a downstream level of pheromonal processing. As a consequence, both systems have the ability to support complimentary aspects in mate discrimination and sexual behavior. However, the relative roles played by these systems and their interactions are at present still far from being understood. PMID- 20831954 TI - Communication by olfactory signals in rabbits: its role in reproduction. AB - Rabbits use a variety of olfactory signals to transmit information related with reproduction. Such cues are produced in skin glands (submandibular, anal, Harder's, lachrymal, preputial) and the mammary gland-nipple complex. Some signals are transmitted by active behaviors, for example, chin-marking, urination, and defecation, while others are transmitted passively (e.g., mammary pheromone (MP) and inguinal gland secretions). We show that sex steroids regulate: chinning frequency and the chin gland's size, weight and secretory activity in bucks and does by acting on specific brain regions or on the chin gland, respectively. The "mammary pheromone," identified in milk as 2-methyl-but 2-enal, is essential for guiding the pups to the nipples, but its origin (mammary gland, ventral skin, nipple) remains to be determined. Estradiol, progesterone, and prolactin regulate the emission of an olfactory cue that also triggers nipple search behavior in the pups, but its chemical identity and relation with the MP are unclear. PMID- 20831955 TI - Chemical communication and reproduction in the gray short-tailed opossum (Monodelphis domestica). AB - The gray short-tailed opossum is one of the most widely studied of all marsupials and an important model for study of olfactory communication, particularly as it relates to pheromonal activation of reproduction. Males respond to differentially to female skin gland secretions and urine from anestrous females, while females respond only skin gland secretions, particularly that of the suprasternal gland. Divergent responses by male and female opossums to odors from these different body sources are most likely related to sex-specific production and deposition of chemical signals in this species. Female opossums do not have an estrous cycle but are stimulated to estrus by male pheromone. Females nuzzle scent marks from male suprasternal gland secretions, and thereby facilitate delivery of a nonvolatile estrus-inducing pheromone to the chemosensory epithelium of vomeronasal organ. Neuroendocrine correlates of pheromonal induction of estrus include elevated plasma estradiol and upregulation of progesterone receptors in hypothalamic regions that control reproductive behavior. PMID- 20831956 TI - Pheromones in a superorganism: from gene to social regulation. AB - Analogous to the importance of hormones in controlling organism homoeostasis, pheromones play a major role in the regulation of group homoeostasis at the social level. In social insects, pheromones coordinate the association of "unitary" organisms into a coherent social unit or so called "superorganism." For many years, honey bees have been a convincing model for studying pheromone regulation of social life. In addition, with the recent sequencing of its genome, a global view of pheromone communication is starting to emerge, and it is now possible to decipher this complex chemical language from the molecular to the social level. We review here the different pheromones regulating the main biological functions of the superorganism and detail their respective action on the genome, physiology and behavior of nestmates. Finally, we suggest some future research that may improve our understanding of the remarkably rich syntax of pheromone communication at the social level. PMID- 20831957 TI - Unraveling the pheromone biosynthesis activating neuropeptide (PBAN) signal transduction cascade that regulates sex pheromone production in moths. AB - Studies over the past three decades have demonstrated that female moths usually produce sex pheromones as multicomponent blends in which the ratios of the individual components are precisely controlled, making it possible to generate species-specific pheromone blends. Most moth pheromone components are de novo synthesized from acetyl-CoA in the pheromone gland (PG) through modifications of fatty acid biosynthetic pathways. Pheromone biosynthesis activating neuropeptide (PBAN), a neurohormone produced by a cephalic organ (subesophageal ganglion) stimulates sex pheromone biosynthesis in the PG via an influx of extracellular Ca(2+). In recent years, we have expanded our knowledge of the precise mechanisms underlying silkmoth (Bombyx mori) sex pheromone production by characterizing a number of key molecules. In this review, we want to highlight our efforts in elucidating these mechanisms in B. mori and to understand how they relate more broadly to lepidopteran sex pheromone production in general. PMID- 20831958 TI - Pheromones in social wasps. AB - Social wasps need an efficient communication system to coordinate their members in the numerous activities of the colony. In this regard, the chemical channel is the most utilized by social wasps to transfer information in intraspecific (pheromones) and interspecific (allomones) communication. In this chapter, we reviewed the main chemical substances which mediate recognition between colony members and coordinate nest defense, alarm and recruitment. Due to their central role in the colonial life, the majority of pheromones have been identified and their functions have been deeply investigated in many species. On the contrary, sex pheromones which are the most studied in insects, have been quite neglected in social wasps. PMID- 20831959 TI - New pheromones and insect control strategies. AB - A survey of the new environmentally safe strategies used for insect control is presented. The survey includes mating disruption, pheromone antagonists as chemical communication inhibitors, pheromones and plant-based volatiles, attractant-and-kill, and push-pull strategies. Important successes have been obtained, particularly in mating disruption with significant reduction in pesticide use in low to moderate pest infestations. One important factor of concern is the high cost of semiochemicals and formulations containing them in comparison to the conventional insecticide treatments, and a combined effort by scientists, producers, and farmers should be made to reduce the cost of application of these semiochemicals. PMID- 20831960 TI - Pheromones and exocrine glands in Isoptera. AB - Termites are eusocial insects that have a peculiar and intriguing system of communication using pheromones. The termite pheromones are composed of a blend of chemical substances and they coordinate different social interactions or activities, including foraging, building, mating, defense, and nestmate recognition. Some of these sociochemicals are volatile, spreading in the air, and others are contact pheromones, which are transmitted by trophallaxis and grooming. Among the termite semiochemicals, the most known are alarm, trail, sex pheromones, and hydrocarbons responsible for the recognition of nestmates. The sources of the pheromones are exocrine glands located all over the termite body. The principal exocrine structures considered pheromone-producing glands in Isoptera are the frontal, mandibular, salivary or labial, sternal, and tergal glands. The frontal gland is the source of alarm pheromone and defensive chemicals, but the mandibular secretions have been little studied and their function is not well established in Isoptera. The secretion of salivary glands involves numerous chemical compounds, some of them without pheromonal function. The worker saliva contains a phagostimulating pheromone and probably a building pheromone, while the salivary reservoir of some soldiers contains defensive chemicals. The sternal gland is the only source of trail-following pheromone, whereas sex pheromones are secreted by two glandular sources, the sternal and tergal glands. To date, the termite semiochemicals have indicated that few molecules are involved in their chemical communication, that is, the same compound may be secreted by different glands, different castes and species, and for different functions, depending on the concentration. In addition to the pheromonal parsimony, recent studies also indicate the occurrence of a synergic effect among the compounds involved in the chemical communication of Isoptera. PMID- 20831961 TI - Aphid pheromones. AB - Aphids are the main insect pests of agricultural crops in temperate regions causing major economic losses. Although broad-spectrum insecticides are available for control, alternative and more targeted methods are needed due to insecticide resistance and increasing environmental pressures. An alternative control method for aphids is to exploit their pheromones, which have been extensively studied in recent years. For example, aphids release alarm pheromones in response to natural enemy attack and these could be used to deter aphids from the crops. Sex pheromones have also been identified which could be used to interfere males locating conspecific females (oviparae), as well as for manipulating natural enemies. Several hypotheses relating to how species integrity is maintained via the aphid sex pheromone have been proposed. The composition and behavioral activity of these pheromones, and how their use could be implemented in integrated pest management systems to control aphids, is discussed. PMID- 20831962 TI - Recent advances in methyl eugenol and cue-lure technologies for fruit fly detection, monitoring, and control in Hawaii. AB - Worldwide, an important aspect of invasive insect pest management is more effective, safer detection and control systems. Phenyl propanoids are attractive to numerous species of Dacinae fruit flies. Methyl eugenol (ME) (4-allyl-1, 2 dimethoxybenzene-carboxylate), cue-lure (C-L) (4-(p-acetoxyphenyl)-2-butanone), and raspberry ketone (RK) (4-(p-hydroxyphenyl)-2-butanone) are powerful male specific lures. Most evidence suggests a role of ME and C-L/RK in pheromone synthesis and mate attraction. ME and C-L/RK are used in current fruit fly programs for detection, monitoring, and control. During the Hawaii Area-Wide Pest Management Program in the interest of worker safety and convenience, liquid C L/ME and insecticide (i.e., naled and malathion) mixtures were replaced with solid lures and insecticides. Similarly, Male Annihilation Technique (MAT) with a sprayable Specialized Pheromone and Lure Application Technology (SPLAT), in combination with ME (against Bactrocera dorsalis, oriental fruit fly) or C-L/RK (against B. cucurbitae, melon fly), and the reduced-risk insecticide, spinosad, was developed for area-wide suppression of fruit flies. The nontarget effects of ME and C-L/RK to native invertebrates were examined. Although weak attractiveness was recorded to flower-visiting insects, including bees and syrphid flies, by ME, effects to native Drosophila and other Hawaiian endemics were found to be minimal. These results suggested that the majority of previously published records, including those of endemic Drosophilidae, were actually for attraction to dead flies inside fruit fly traps. Endemic insect attraction was not an issue with C-L/RK, because B. cucurbitae were rarely found in endemic environments. PMID- 20831963 TI - Oviposition pheromones in haematophagous insects. AB - Pheromones influencing oviposition behavior in females of haematophagous insects have been the interest of recent past by many group of scientists working on oviposition pheromones. Finding and choosing a good site for oviposition is a challenging task for females of haematophagous insects, especially in those insects which does not have the parental care. Their decisions have far-reaching and profound consequences for the life history of the offspring. In such blood feeding insects, the choice of oviposition site is affected by pheromones, which may function either as deterrents or stimulants in short range, while they may also act as repellents or attractants in long range perception. During the location of a suitable oviposition site for egg laying or a potential host for blood feeding, haematophagous insects mainly use olfactory and visual cues. These pheromones are produced by the ovipositing female or by conspecific larvae co occurring with gravid females. Adult females detect oviposition pheromones by odor receptors on the antennae, as well as by contact chemoreceptors on tarsi, mouthparts and antennae. Different cues exploited by gravid females from a diversified arena include egg, larva, habitat, microbes, infusions and plant produced volatiles influence the oviposition behavior. Traps baited with pheromones, infusions, and insecticides shall be promising tools for monitoring and control of target insect using integrated vector management strategies. PMID- 20831964 TI - The association between quality of life and stuttering. PMID- 20831965 TI - Fluency disorders and life quality: subjective wellbeing vs. health-related quality of life. AB - It seems intuitive that people with a fluency disorder, such as stuttering, must experience a low life quality. Yet this is not necessarily so. Whether measured life quality is lower depends on several factors, the most important of these being methodological. This is because the disciplines of medicine and the social sciences utilize quite different technologies to measure the construct. Within medicine, health-related quality of life (HRQOL) is measured through constellations of perceived symptoms. Thus, if the symptoms chosen to represent HRQOL match the pathological characteristics of the fluency disorder, the relationship is self-fulfilling. Psychology, on the other hand, uses subjective wellbeing to represent life quality. Here, the relationship between symptoms and perceived life quality is much less certain. It is proposed that this partial disconnection is due to the presence of a homeostatic system which manages subjective wellbeing in an attempt to keep it positive. The paper that follows examines the construct of life quality from both disciplinary perspectives, and then reports on the findings from each discipline in relation to fluency disorders. It is concluded there is no necessary link between fluency disorders and life quality provided subjective wellbeing is used as the indicator variable. EDUCATIONAL OBJECTIVES: The reader will be able to describe: (i) contemporary issues in quality of life measurement; (ii) the relationship between fluency disorders and life quality; (iii) the conceptual limitations of health-related quality of life. PMID- 20831966 TI - Health-related quality of life in people with aphasia: implications for fluency disorders quality of life research. AB - It is increasingly important that clinicians address the health-related quality of life (HRQOL) of adults with communication disorders in clinical practice. The overall aim of this paper is to draw conclusion about the suitability of the Short Form 36 Health Survey for the communication disorders of aphasia and stuttering. This study reports on the impact of post-stroke aphasia on 30 Australian older adults' HRQOL. It also comments on the capacity of the SF-36 to measure HRQOL in this population, specifically whether it is sensitive to the three known determinants of post-stroke HRQOL - emotional, physical and social functioning. Comparisons with other data are made to assist interpretation of the SF-36 subscale scores: with 75 older adults with no history of neurological conditions; and with data from the 1995 National Health Survey data. The main findings are: (1) adults with post-stroke aphasia have similar HRQOL to their peers on six subscales, but significantly lower Role emotional and Mental health HRQOL; (2) a substantial number of aphasic adults reported depressive mood; and (3) aphasic adults with depressive mood have significantly worse HRQOL on six subscales than aphasic adults without depressive mood, but similar Role emotional and Body pain HRQOL. In conclusion, stroke and aphasia have minimal impact on older adults' HRQOL as measured by the SF-36, which conflicts with an established evidence base of the negative consequences of aphasia on life. Thus, the SF-36 is not advisable for use with aphasic adults. Implications of these findings for aphasia and stuttering are discussed. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) describe the impact of aphasia and depressive mood on quality of life; (b) compare the impact of aphasia on the quality of life of adults to adults who do not have aphasia; (c) describe the similarities and differences between quality of life of adults with aphasia and adults who stutter; and (d) describe the strengths and limitations of the SF-36 as a measure of quality of life in adults who stutter versus adults with aphasia. PMID- 20831967 TI - Assessing quality of life in stuttering treatment outcomes research. AB - Stuttering can affect many aspects of a person's life. People who stutter report that they experience negative reactions to stuttering, difficulty communicating in key situations, diminished satisfaction with life, and a reduced ability to achieve their goals in life. Unfortunately, most treatment outcomes studies have focused on changes in the observable characteristics of stuttering, with significantly fewer studies examining the broader consequences of stuttering. This paper proposes that evaluation of stuttering treatment outcomes can be enhanced through assessment of impact of stuttering on a speaker's quality of life. A means of assessing quality of life is described, based on the Overall Assessment of the Speaker's Experience of Stuttering (OASES; Yaruss & Quesal, 2006, 2008). The OASES is a multi-dimensional assessment instrument built upon the World Health Organization's International Classification of Functioning, Disability, and Health (ICF; WHO, 2001; see also Yaruss & Quesal, 2004). One section of the OASES is designed to assess specific aspects of quality of life in individuals who stutter. Preliminary data from two ongoing studies involving the OASES are briefly summarized in order to demonstrate: (a) that individuals who stutter do report an adverse impact on their quality of life as a result of stuttering and (b) that quality of life can improve following treatment for stuttering. It is recommended that future stuttering treatment outcomes studies directly examine the broader consequence of stuttering by focusing, in part, on quality of life. EDUCATIONAL OBJECTIVES: After reading this article, the participant will be able to: (1) describe some of the adverse consequences of stuttering reported by individuals who stutter; (2) define quality of life as it relates to the study of the stuttering disorder; (3) explain the value of assessing quality of life in stuttering treatment outcomes research. PMID- 20831968 TI - An investigation into the personal financial costs associated with stuttering. AB - Stuttering has been found to deteriorate quality of life in psychological, emotional and social functioning domains. It is reasonable to assume then that stuttering would also be associated with economic consequences that may also challenge quality of life. Remarkably, the personal financial costs associated with stuttering in adults has rarely if ever been explored or investigated in the fluency disorders field. This study involved an assessment of the personal costs of stuttering and an investigation into determinants that may influence spending. Two hundred adults who stutter participated in this study. Findings indicated that the average total cost was around $5,500 (median cost $4,165) in 2007/08 Australian dollars over a 5-year period. Major financial items included costs of direct and indirect treatments for stuttering, self-help, stuttering related conferences, and technology. Financial costs were not significantly influenced by the sex of the person, annual income, or by how severe the person stuttered. However, those individuals younger than 60 years old spent significantly more on treatment related costs, while those with elevated levels of social anxiety spent significantly less than those with lower levels of social anxiety. Quality of life implications associated with stuttering are discussed. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) describe the method for assessing the direct financial costs of stuttering over a 5-year period; (b) describe the financial personal cost of stuttering for adults who stutter; (c) describe the relationship between factors like sex, age, severity of stuttering and financial costs; and (d) describe the relationship between social anxiety and the financial cost of stuttering. PMID- 20831969 TI - Relationships among linguistic processing speed, phonological working memory, and attention in children who stutter. AB - Relatively recently, experimental studies of linguistic processing speed in children who stutter (CWS) have emerged, some of which suggest differences in performance among CWS compared to children who do not stutter (CWNS). What is not yet well understood is the extent to which underlying cognitive skills may impact performance on timed tasks of linguistic performance. The purpose of this study was to explore possible relationships between measures of linguistic processing speed and two aspects of cognition: phonological working memory and attention. Participants were 9 CWS and 14 CWNS between the ages of 3;6 and 5;2. Children participated in a computerized picture naming task (an index of linguistic processing speed) and a nonword repetition task (an index of phonological working memory). Parents completed a temperament behavior questionnaire, from which information about the children's attentional skills was collected. Findings revealed that the groups did not differ from each other on speed of picture naming or attention; however, the CWS performed significantly worse in nonword repetition. In addition, after partialling out the effects of age, (a) for CWS only, there was a significant negative relationship between picture naming speed and nonword repetition; (b) there were no significant relationships for either group between aspects of attention and picture naming speed; and (c) only the CWNS showed a significant relationship between nonword repetition and focused attentional skills. These results underscore the need to consider the underlying skills associated with lexically related aspects of language production when examining the task performances of CWS and CWNS. EDUCATIONAL OBJECTIVES: The reader will be able to: (a) summarize findings from previous studies examining the speech and language performance of children who do (CWS) and do not stutter (CWNS); (b) describe findings of previous studies related to nonword repetition and attention in CWS; (c) compare the results of the present study with previous work in this area; and (d) discuss speculations concerning the relationship between linguistic processing speed, phonological working memory, and attention in CWS and CWNS. PMID- 20831970 TI - Word-final prolongations in an adult male with neurofibromatosis type 1. AB - A case of word-final prolongations occurring in an adult male with neurofibromatosis type 1 is reported. Speech samples were collected in five different speech modalities (i.e. spontaneous speech, monologue, repetition, automatic series and reading) and subsequently analyzed in a semi-automatic manner using Praat software. Results on the frequency, nature and distribution of the word-final prolongations are presented. The possible pathogenesis of these word-final disfluencies and their relation to stuttering is discussed. EDUCATIONAL OBJECTIVES: The reader will be able to: (1) describe the characteristics of word-final prolongations as displayed by an adult male with neurofibromatosis type 1 and (2) discuss the possible pathogenesis of these word final prolongations and their relation to stuttering. PMID- 20831972 TI - University students' explanations for their descriptions of people who stutter: an exploratory mixed model study. AB - Semantic differential instruments are often used to assess fluent speakers' attitudes toward people who stutter (PWS). Such instruments are prone to response bias and often lack the power to explain respondents' general impressions of PWS. To address these concerns 149 fluent university students completed an open-ended questionnaire in which they described PWS and provided an explanation for their descriptions. A mixed model design with a qualitative emphasis allowed for thematic as well as quantitative data analysis. The results suggest that individuals may have simultaneously positive and negative attitudes toward PWS regardless of gender or familiarity with PWS. Multiple explanations were provided and took into account personal and societal reactions to stuttering. Fluent speakers appear to perceive PWS as being likeable individuals who are poor communicators, a combination of high-warmth and low-competence that elicits pity and passive harm from listeners according to social psychologists (Cuddy et al., 2008). The implications of these findings and future research directions are discussed. EDUCATIONAL OBJECTIVES: After reading this article, the reader will be able to: (1) describe issues of concern related to the measurement of attitudes toward PWS; (2) describe how mixed (qualitative and quantitative) designs can contribute to a deeper understanding of fluent speakers' attitudes toward PWS; and (3) discuss how the ways in which fluent speakers' thoughts about stuttering and PWS can influence their emotions and behaviors when in the presence of someone who stutters. PMID- 20831973 TI - Measurement of trained speech patterns in stuttering: interjudge and intrajudge agreement of experts by means of modified time-interval analysis. AB - Improved fluency after stuttering therapy is usually measured by the percentage of stuttered syllables. However, outcome studies rarely evaluate the use of trained speech patterns that speakers use to manage stuttering. This study investigated whether the modified time interval analysis can distinguish between trained speech patterns, fluent speech, and stuttered speech. Seventeen German experts on stuttering judged a speech sample on two occasions. Speakers of the sample were stuttering adults, who were not undergoing therapy, as well as participants in a fluency shaping and a stuttering modification therapy. Results showed satisfactory inter-judge and intra-judge agreement above 80%. Intervals with trained speech patterns were identified as consistently as stuttered and fluent intervals. We discuss limitations of the study, as well as implications of our findings for the development of training for identification of trained speech patterns and future outcome studies. EDUCATIONAL OBJECTIVES: The reader will be able to (a) explain different methods to measure the use of trained speech patterns, (b) evaluate whether German experts are able to discriminate intervals with trained speech patterns reliably from fluent and stuttered intervals and (c) describe how the measurement of trained speech patterns can contribute to outcome studies. PMID- 20831971 TI - Overreliance on auditory feedback may lead to sound/syllable repetitions: simulations of stuttering and fluency-inducing conditions with a neural model of speech production. AB - This paper investigates the hypothesis that stuttering may result in part from impaired readout of feedforward control of speech, which forces persons who stutter (PWS) to produce speech with a motor strategy that is weighted too much toward auditory feedback control. Over-reliance on feedback control leads to production errors which if they grow large enough, can cause the motor system to "reset" and repeat the current syllable. This hypothesis is investigated using computer simulations of a "neurally impaired" version of the DIVA model, a neural network model of speech acquisition and production. The model's outputs are compared to published acoustic data from PWS' fluent speech, and to combined acoustic and articulatory movement data collected from the dysfluent speech of one PWS. The simulations mimic the errors observed in the PWS subject's speech, as well as the repairs of these errors. Additional simulations were able to account for enhancements of fluency gained by slowed/prolonged speech and masking noise. Together these results support the hypothesis that many dysfluencies in stuttering are due to a bias away from feedforward control and toward feedback control. EDUCATIONAL OBJECTIVES: The reader will be able to (a) describe the contribution of auditory feedback control and feedforward control to normal and stuttered speech production, (b) summarize the neural modeling approach to speech production and its application to stuttering, and (c) explain how the DIVA model accounts for enhancements of fluency gained by slowed/prolonged speech and masking noise. PMID- 20831975 TI - How many heart failure nurses are enough? PMID- 20831974 TI - Utterance complexity and stuttering on function words in preschool-age children who stutter. AB - The purpose of the present investigation was to examine the relation between utterance complexity and utterance position and the tendency to stutter on function words in preschool-age children who stutter (CWS). Two separate studies involving two different groups of participants (Study 1, n=30; Study 2, n=30) were conducted. Participants were preschool-age CWS between the age of 3, 0 and 5, 11 who engaged in 15-20min parent-child conversational interactions. From audio-video recordings of each interaction, every child utterance of each parent child sample was transcribed. From these transcripts, for each participant, measures of language (e.g., length and complexity) and measures of stuttering (e.g., word type and utterance position) were obtained. Results of Study 1 indicated that children stuttered more frequently on function words, but that this tendency was not greater for complex than simple utterances. Results of Study 2, involving the assessment of utterance position and MLU quartile, indicated that that stuttering was more likely to occur with increasing sentence length, and that stuttering tended to occur at the utterance-initial position, the position where function words were also more likely to occur. Findings were taken to suggest that, although word-level influences cannot be discounted, utterance-level influences contribute to the loci of stuttering in preschool-age children, and may help account for developmental changes in the loci of stuttering. EDUCATIONAL OBJECTIVES: The reader will learn about and be able to: (a) describe the influence of word type (function versus content words), and grammatical complexity, on disfluent speech; (b) compare the effect of stuttering frequency based on the position of the word in the utterance; (c) discuss the contribution of utterance position on the frequency of stuttering on function words; and (d) explain possible reasons why preschoolers stutter more frequently on function words than content words. PMID- 20831976 TI - Fulminant fatal swine influenza (H1N1): Myocarditis, myocardial infarction, or severe influenza pneumonia? AB - The swine influenza (H1N1) pandemic began in Mexico and rapidly spread worldwide. As is the case with pandemic influenza A, the majority of early deaths have been in young healthy adults. The complications of pandemic H1N1 have been reported from several centers. Noteworthy has been the relative rarity of bacterial coinfection in bacterial pneumonia in hospitalized adults with H1N1 pneumonia. Simultaneous bacterial community-acquired pneumonia due to methicillin-sensitive Staphylococcus aureus or community-acquired methicillin resistant S. aureus and subsequent bacterial community-acquired pneumonia due to S. pneumoniae or Haemophilus influenzae have been reportedly rare (0.4%-4% of well-documented cases). Cardiac complications of H1N1 infection have been uncommon. Young healthy adults without a cardiac history who have H1N1 and chest pain usually have either acute myocardial infarction or acute myocarditis. Cardiac symptomatology with H1N1 often overshadows pulmonary manifestations, that is, influenza pneumonia. With H1N1 pneumonia, clinicians should be alert for otherwise unexplained tachycardia or chest pain that may represent acute myocardial infarction or myocarditis. We present a case of rapidly fatal H1N1 in a young adult treated with oseltamivir and peramivir. He was initially tachycardic, thought to represent myocarditis. He subsequently became hypotensive and expired. At autopsy there was cardiomegaly present but there were no signs of acute myocardial infarction or myocarditis. Pathologically, he died of severe H1N1 pneumonia and not bacterial pneumonia. PMID- 20831977 TI - Human movement across the lifespan: learning, synergies and disease, 9th Motor Control and Human Skill Conference. PMID- 20831978 TI - Vaccidents and adversomics. PMID- 20831979 TI - Tumor specific low pH environments enhance the cytotoxicity of lovastatin and cantharidin. AB - In tumor cell masses, the extracellular pH decreases below 6.5. The effect of external acidic pH on the efficacy of 24 chemical compounds including molecular targeted inhibitors and anti-tumor reagents was investigated in human cancer cells. Lovastatin showed no cytotoxicity in mesothelioma or pancreatic carcinoma cells at concentrations up to 10 MUM and pH around 7.4, but 10 MUM lovastatin decreased the survival of these cells below 40% at acidic pH. Lovastatin inhibits HMG-CoA reductase, resulting in a decrease in the levels of cholesterol and prenylated proteins. An inhibitor of the former pathway showed pH-independent cytotoxic activity, whereas an inhibitor of the latter pathway had stronger activity at acidic pH. The inhibitory efficacy of cantharidin also increased at acidic pH. On the other hands, no pH dependency or slightly impaired efficacy at low pH conditions was observed in other 20 reagents, and especially, the activity of aphidicolin was suppressed under acidic conditions. These results suggested that screening under acidic conditions would be useful for developing new chemotherapeutic reagents. PMID- 20831980 TI - Trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells. AB - The intracellular androgen metabolism and cell activity in prostate cancer cells with mutated (LNCaP-FGC) or wild-type (VCaP) androgen receptors in the presence of trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase, were examined. Trilostane suppressed the intracellular production of androstenedione, testosterone, and dihydrotestosterone from dehydroepiandrosterone in LNCaP-FGC cells. In both LNCaP-FGC and VCaP cell types, the prostate-specific antigen (PSA) levels in media were increased by trilostane alone in a concentration-dependent manner. Both cells pretreated with trilostane showed a dose-dependent decrease in PSA production with bicalutamide (P<0.001). Trilostane should be used with particular concern when treating prostate cancer. PMID- 20831981 TI - A small oxazine compound as an anti-tumor agent: a novel pyranoside mimetic that binds to VEGF, HB-EGF, and TNF-alpha. AB - A novel pyranoside mimetic compound, DMBO (2-(2,6-difluorophenyl)-5-(4 methoxyphenyl)-1-oxa-3-azaspiro[5.5]undecane), was designed and synthesized. The sugar mimicking behavior of DMBO was addressed by its ability to bind several growth factors/cytokines such as vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor (HB-EGF), and tumor necrosis factor (TNF)-alpha as demonstrated by the recently developed surface plasmon resonance assay. DMBO exhibited strong anti-proliferation activity in vitro against tumor cells including a highly metastatic murine osteosarcoma cell line LM8G7 that secretes VEGF as well as two human ovarian cell lines, OVSAHO and SKOV-3, which secrete TNF-alpha and HB-EGF respectively. Furthermore, DMBO inhibited the metastatic activity to the mouse liver of LM8G7 cells injected from a lateral tail vein, and affected the heparan-degrading activity of LM8G7 cells. Here, we report that DMBO acts as a human heparanase inhibitor in vitro possibly as a substrate mimetic. DMBO also inhibited the migration and invasion of LM8G7 cells and angiogenic events such as endothelial cell proliferation, migration and capillary tube-like formation in vitro. More prominently, the administration of DMBO with heparin resulted in synergistic anti-tumor effects in mouse modelofosteosarcoma. These preclinical data shows the potential anti-cancer effects of DMBO. PMID- 20831982 TI - Microsatellite instability with promoter methylation and silencing of hMLH1 can regionally occur during progression of gastric carcinoma. AB - Microsatellite instability (MSI) is known to result from inactivation of mismatch repair genes largely by promoter methylation. However, the methylation usually accumulates time-dependently. To know whether MSI can be acquired later in tumorigenesis, we examined intratumoral heterogeneity of MSI and promoter methylation of hMLH1 after immunohistochemical screening for heterogeneous expression of hMLH1 in 55 cases of gastric carcinomas. We demonstrated for the first time that MSI-H can develop from MSI-L or the absence of MSI due to time dependent accumulation of DNA methylation during progression of early-stage gastric carcinomas. The resultant replication errors may play a role in enhancing invasive activity. PMID- 20831984 TI - Endovascular repair of ruptured aortic aneurysms using carbon dioxide contrast angiography. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) has become a common approach to the management of ruptured abdominal aortic aneurysms (rAAA). The use of iodinated contrast during EVAR for rAAA has several disadvantages, including contrast nephropathy, potential allergic response, and the need for high-pressure injection. We evaluated the use of carbon dioxide (CO(2)) as the primary contrast agent for endovascular repair of ruptured aortic aneurysms. METHODS: Between December 2007 and July 2009, we retrospectively reviewed our experience with patients undergoing endovascular repair of rAAA, with CO(2)as the principal contrast agent, and compared them with patients who underwent EVAR using iodinated contrast. RESULTS: Four patients underwent endovascular repair of rAAA with CO(2) angiography (group 1) and seven with iodinated contrast (group 2). The mean age of the patients was not different between groups (p = 0.353). Patients in group 1 received a mean of 443 +/- 99 mL of CO(2) and 4.3 +/- 8.5 mL of iodinated contrast. Patients in group 2 received 110.2 +/- 37.6 mL of iodinated contrast (p < 0.001). Overall mortality was not different between group 1 (0.0%) and group 2 (28.6%, p = 0.491). In patients who survived to discharge, the change in creatinine between admission and discharge was greater in group 2 although not statistically significant (0.25 +/- 0.19 mg/dL for group 1 vs. 0.58 +/- 0.25 mg/dL for group 2, p = 0.066). There was no significant difference in length of stay between group 1 (intensive care unit, 1.00 +/- 0.82 days; hospital, 4.25 +/- 0.96 days) and group 2 (intensive care unit, 3.60 +/- 3.44 days; hospital, 9.00 +/- 6.60 days). CONCLUSIONS: Endovascular repair of rAAA using CO(2) as a contrast agent is technically feasible and safe. The potential benefits of CO(2) angiography support the continued use of CO(2) in cases of ruptured aneurysms. Further studies are necessary to determine whether CO(2) improves survival and limits the progression of renal dysfunction after endovascular repair of rAAA. PMID- 20831985 TI - A 5-year evaluation using the talent endovascular graft for endovascular aneurysm repair in short aortic necks. AB - BACKGROUND: Although endovascular aneurysm repair has been shown to be an effective way to treat abdominal aortic aneurysm (AAA), certain anatomic characteristics such as a short aortic neck, limit its applicability. Initially, commercially available devices were approved only for the treatment of AAA with an aortic neck length >= 15 mm. The purpose of this study was to evaluate the outcomes of the recently approved Talent endograft for AAAs with a short aortic neck length (10-15 mm). METHOD: Data were obtained from the prospective, nonrandomized, multicenter Talent enhanced Low Profile Stent Graft System trial which enrolled patients between February 2002 and April 2003. A total of 154 patients with adequate preoperative imaging were identified for this study. Subgroup analyses were performed for AAA with 10-15 mm aortic neck and those with >15 mm neck. Safety and effectiveness endpoints were evaluated at 30 days, 1 year, and 5 years postprocedure. RESULTS: Patients treated with aortic neck lengths of 10-15 mm (n = 35) and those with >15 mm (n = 102) had similar age, gender, and risk factor profile. Both groups had similar preoperative aneurysm morphology in terms of maximum aneurysm size, degree of neck angulation, or proximal neck diameter. There were no statistically significant differences in freedom from major adverse events and mortality rates at 30 and 365 days. Similarly, there was no difference in the effectiveness endpoints at 12 months. At 5 years, there was no difference in migration rate, endoleaks, or change in aneurysm diameter from baseline. In addition, there is no difference in freedom from aneurysm-related mortality (94% vs. 99%). CONCLUSIONS: AAAs with short aortic necks (10-15 mm) and otherwise suitable anatomy for endovascular repair can be safely and effectively treated with the Talent endograft with excellent 1 and 5 year outcomes. PMID- 20831986 TI - Midterm results of the Zenith endograft in relation to neck length. AB - BACKGROUND: Successful endovascular repair of abdominal aortic aneurysms (AAAs) requires specific infrarenal neck anatomy to allow for a durable seal and fixation. This is a single-center study reviewing outcomes in relation to neck length after placement of a Zenith endograft. METHODS: Retrospective single center review of all AAAs electively repaired with a Zenith endograft during a recent 5-year period. Patients were divided into those with infrarenal necks 4-15 mm in length and those >15 mm using center line measurements. Clinical outcomes and follow-up computed tomography scans were reviewed. RESULTS: Between 2003 and 2008, 318 patients underwent elective repair of an infrarenal AAA with the Zenith endograft. Of 318 patients, 68 (21.4%) had necks measuring 4-15 mm in length and 250 (79.5%) had necks measuring >15 mm. Overall early mortality was 0.9% (p = 0.11) and the rate of type II endoleaks was 19% (p = 0.11); neither differed between the groups. Four patients in each group had immediate proximal type I endoleaks, which resolved spontaneously in two patients in each group. The remaining two in each group required further intervention (two endovascular and two conversion to open repair). Type I endoleaks and reinterventions did not differ statistically between groups (p = 0.06). On further analysis, those patients requiring reintervention or conversion for type I endoleaks had other unattractive neck features (large diameter, angulation). There have been no instances of new type I endoleaks during 5-yearfollow-up period. CONCLUSION: These midterm results indicate that patients with shorter infrarenal necks can be treated as effectively as those with longer necks with the Zenith endograft unless these necks are tortuous or wide. PMID- 20831987 TI - The posterior approach in the treatment of popliteal artery aneurysm: feasibility and analysis of outcome. AB - BACKGROUND: This review evaluates the results of our 18-year experience with surgical treatment of popliteal artery aneurysms (PAAs), examining the effects of the variables of clinical presentations, surgical technique, graft material, and runoff on operative results in the management of popliteal aneurysms. METHODS: We reviewed 49 PAAs consecutively repaired in 35 patients. We preferentially use, if possible, the posterior approach for repair of popliteal aneurysms. We repaired aneurysms passing above the Hunter canal using a medial approach to allow for adequate exposure of the proximal neck of the aneurysm. We separately analyzed the results of patients who underwent the posterior approach (group A) and those that underwent the medial approach (group B). Primary, primary assisted, and secondary patency were established using life-tables analysis. RESULTS: In our experience, the posterior approach was used in 38 repairs (77.6%), followed by graft interposition (group A). PAAs were asymptomatic in 29 (59.2%) of 49 cases. Among 20 symptomatic PAAs, nine (18.4%) caused intermittent claudication, one (2.0%) caused rest pain and trophic wound, and the remaining 10 limbs (20.4%) presented with acute ischemia and limb threat. A total of 11 popliteal aneurysms (22.4%) required repair with a medial approach (group B) because the extension of the aneurysm was proximal to the adductor hiatus. The primary patency rates at 6 and 8 years were 94.3 and 83.8%, respectively, for group A and 100% (p = .43) and 19.1% (p = .001) for group B, the respective assisted primary patency rates were 97.3 and 86.3%, in group A and 100% (p = .43) and 19.1% (p = .001) for group B. The secondary patency rates at 6 months and 8 years were 97.3 and 97.3%, respectively, in group A and 90.9% (p = .34) and 77.9% (p = .05) in group B. Amputation occurred in two (4.1%) of 49 limbs and 30-day postoperative mortality was 2.0% (1/49 patients). There was no statistical difference in amputation rate in symptomatic and asymptomatic limbs, and in group A and B. CONCLUSION: We believe that the posterior approach is the gold standard surgical therapy to treat PPAs not extending above the Hunter canal. In our experience, the posterior approach was possible in 77.6% of cases. It has excellent patency and prevents further aneurysm expansion by completely interrupting the collateral circulation to the aneurysm sac. In contrast, the posterior approach had a slightly higher tibial nerve injury (p = .43), especially during the learning curve. The preoperative symptoms and the use of venous material for reconstruction affect significantly long-term patency. PMID- 20831988 TI - Long-term outcome of endovascular popliteal artery aneurysm repair. AB - BACKGROUND: Popliteal artery aneurysms have traditionally been repaired with an open surgical approach. However, endovascular popliteal artery repair (EVPAR) has been used in selected patients because of its less invasive nature. In this report, we present our long-term outcomes for EVPAR. METHODS: Retrospective review of all patients who underwent EVPAR at a single academic institution between September 2002 and March 2006. These patients were evaluated for patency, need for secondary intervention, amputation-free survival, and overall survival. RESULTS: A total of 15 limbs in 13 patients were treated with EVPAR during the study period. All EVPAR were performed using the Viabahn((r)) endoprostheses, with an average of 1.67 stents per limb. The mean age of the patients was 74.6 years (range, 66-84). Technical success was achieved in 100% and all limbs had initial postoperative ankle-arm indices of >= 1.0. Mean duration of follow-up was 54 months (range, 42-70). Two patients died of unrelated causes at 3 and 38 months with intact limbs, and one patient was lost to follow-up. Two limbs developed type I or III endoleaks, and were successfully treated with additional endovascular stent placement, resulting in a primary patency rate of 84.6% and secondary patency rate of 100%. There were no instances of limb loss during the follow-up period, yielding both amputation-free survival and overall survival rates of 85.7%. CONCLUSIONS: Long-term follow-up of this cohort of EVPAR patients suggests that in selected patients, this is a durable technique, capable of achieving excellent patency rates and limb preservation. Further large-scale clinical trials are warranted to help define optimal candidates for this technique. PMID- 20831989 TI - Batroxobin for prevention of restenosis in diabetic patients after infrapopliteal arterial angioplasty: a small randomized pilot trial. AB - BACKGROUND: We designed a small randomized clinical trial to prospectively test the hypothesis that batroxobin is more effective than aspirin alone to prevent restenosis in patients with diabetes undergoing angioplasty of infrapopliteal arteries. METHODS: After a successful angioplasty, a total of 52 diabetic patients with symptomatic infrapopliteal obstructions were randomized to either the treated group (n = 26) or the control group (n = 26). Patients in the treated group received 5 IU batroxobin through an intravenous drip once every alternate day, for a total of six doses. The primary end point was restenosis and reocclusion, which was documented by magnetic resonance angiography or duplex scanning at 12-month follow-up. The clinical symptoms relief and ankle-brachial index (ABI) were compared before and after the procedure, and during follow-up. Kaplan-Meier curves were constructed to evaluate restenosis or reocclusion-free, limb salvage, and amputation-free rates. RESULTS: Restenosis and reocclusion occurred in 22.0% and 34.5% lesions in the treated and the control group, respectively (p = 0.0307). Statistical differences were observed between the ABI before the angioplasty procedure(p < 0.05) and the ABI at the 12-month follow-up (p = 0.0094) of the two groups. Clinical symptoms improvement and tissue healing occurred in 23 and 19 patients in the batroxobin group and the control group, respectively (p = 0.0544). Twelve months after angioplasty, Kaplan-Meier analysis showed that the restenosis and reocclusion-free rate was 74.0% and 54.8%, the limb salvage rate was 96.2% and 92.3%, and the amputation-free rate was 84.6% and 84.6%, in the treated and control group, respectively. CONCLUSION: This pilot trial revealed that batroxobin usage was effective in preventing restenosis and reocclusion after infrapopliteal arterial angioplasty, and it might provide better clinical symptoms relief; however, it did not report preferable limb salvage or amputation-free rates. PMID- 20831990 TI - Fate of popliteal artery aneurysms after exclusion and bypass. AB - BACKGROUND: Treatment of popliteal aneurysm (PA) includes exclusion and bypass graft. In excluded sac, persistent flow through collateral arteries (endoleak) could result in aneurysm growth. METHODS: We retrospectively reviewed PA treated by exclusion and bypass, using duplex ultrasound or computed tomography (CT) scans to demonstrate the presence of residual flow and sac growth. RESULTS: Between 1997 and 2007, we treated 53 PAs in 46 patients by ligation and bypass grafting using polytetrafuoroethylene (PTFE) or saphenous vein. The mean PA diameter preoperatively was 33.4 mm (range, 20-70 mm). At a mean follow-up period of 35 months, 75% (n = 40) PA showed a decrease in mean transverse diameter, from 33.4 to 27.3 mm (p < 0.001). In 17% patients (n = 9), aneurysm sac size remained unchanged, whereas in 8% (n = 4) it increased (mean, 4.5 mm). In six cases (11%), persistent sac flow was revealed by Duplex or TC scan. One patient with a large aneurysm that increased by 50% underwent endoaneurysmorrhaphy through a posterior approach because of symptoms related to local compression. No rupture occurred in follow-up period. The cumulative Kaplan-Meier patency rate at 12, 36, and 60 months were 86%, 76%, and 69%, respectively. Limb salvage rate at 5 years was 92%. Cumulative patency rate at 60 months in the group with popliteal artery unchanged or increased resulted significantly lower than the group with aneurismal sac decreased (30% vs. 84%; p < 0.001). Multivariate analysis did not show correlation between risk factors or preoperative aneurysm diameter, and increased or decreased sac size. CONCLUSIONS: In our results, aneurysm sac growth exists but is low, and a persistent sac flow was not correlated to increased sac size. In view of these results, we believe that medial approach for popliteal artery reconstruction can be used because the aneurysm increase is low and the risk of rupture is not important. No decrease of sac size was otherwise significantly correlated to graft patency. PMID- 20831991 TI - Early carotid surgery in patients after acute ischemic stroke: is it safe? A retrospective analysis in a single center between early and delayed/deferred carotid surgery on 285 patients. AB - BACKGROUND: The early risk of stroke after transient ischemic attack (TIA)/stroke is of the order of 5-10% at 1 week and 10-20% at 3 months. Even if carotid endarterectomy (CEA) is the treatment of choice in symptomatic internal carotid artery stenosis, the timing of carotid intervention after acute stroke is not yet codified. The authors want to determinate whether early CEA is safely carried out in the first few hours (<48 hours) successive to the nondebilitating neurological event and whether the outcome (TIA/stroke/death) in these cases is comparable with the results of those treated by delayed/deferred surgery (range, 48 hours-24 weeks). METHODS: In 4 years, the authors performed 1,184 CEA (285 symptomatic). Five groups were formed from 285 symptomatic patients, according to interval between TIA/stroke onset and performance of CEA: G1, less than 48 hours; G2, 48 hours-2 weeks; G3, 2-4 weeks; G4, 4-8 weeks; G5, 8-24 weeks. Surgery was never performed on patients with disabling neurological deficit (modified Rankin Scale, 5) at the time of admittance, cerebral lesions greater than 3 cm at magnetic resonance/computed tomography scan, presence or suspect of parenchymal hemorrhage associated with ischemic damage, condition considered unfit for surgery (American Society of Anesthesiology classification grade V), and occlusion of the cerebral middle artery. Neurological and diagnostic examinations (duplex-scanning and computed tomography/magnetic resonance scan) were used in determining the selection for early CEA. RESULTS: Cumulative TIA/stroke/death rate after CEA was 3.8% (11/285) and at 30 days was 2.8% (8/285). The cumulative TIA rate after CEA and at 30 days was 0% (0/285). The cumulative stroke rate after CEA was 3.5% (10/285) and at 30 days was 2.4% (7/285). The cumulative death rate after CEA and at 30 days was 0.3% (1/285). Stroke rate after CEA in each group was: G1 4.2% (3/70); G2 3.2% (2/61); G3 0% (0/22); G4 3.4% (1/29); G5 3.8% (4/103). Any statistically significant difference between G1 and the other four groups was not detected with regard to postoperative stroke: G1 (4.2%) versus G2 (3.2%), p = 0.7641; G1 (4.2%) versus G3 (0%), p = 0.7648; G1 (4.2%) versus G4 (3.4%), p = 0.8473; G1 (4.2%) versus G5 (3.8%), p = 0.8952. No hemorrhagic stroke was detected after early CEA. The type of anesthesia and the use of a shunt didn't show any significant difference between the five groups. CONCLUSIONS: The analysis of these records suggests that early CEA in the acute post stroke phase, for patients clinically selected, does not result in greater complications than when performed delayed or deferred . Furthermore, the advantage of early CEA is the reduction of recurrent strokes, as untreated patients present a higher incidence of neurological events. PMID- 20831992 TI - Sizing for endovascular aneurysm repair: clinical evaluation of a new automated three-dimensional software. AB - BACKGROUND: To assess the reproducibility and accuracy of the sizing procedure before aortic endograft implantation using new sizing automated software as compared with standard radiological procedures. METHODS: On the basis of original spiral-computed tomography images, the sizing of 32 patients with abdominal aortic aneurysm treated by endovascular aneurysm repair (EVAR) was retrospectively compared. The first sizing was performed by a radiologist using a standard workstation (General electrics) and software (Advanced vessel analysis). The second was performed twice by two surgeons using a personal computer with automatic three-dimensional sizing software (Endosize; Therenva, Rennes, France). All diameters and lengths required before EVAR were measured (17 items). Moreover, 13 qualitative criteria regarding EVAR feasibility, including neck length, were compared. Intra- and interobserver variability with Endosize, as well as the variability between the two measurement methods were analyzed using the intraclass correlation coefficient (ICC) and Bland and Altman's method. Qualitative variables were analyzed using Fischer's exact test and kappa coefficient. RESULTS: Intraobserver variability with Endosize proved to be efficient. None of the ICCs were lower than 0.9, and more than 90% of the absolute differences between two measurements were less than 2 mm. Interobserver variability with Endosize was assessed in a similar manner. Measurement variability of vessel diameters was less marked than that of vessel lengths. This trend was observed for all datasets. Comparison of the two measurement methods demonstrated a good correlation (minimum ICC = 0.697; maximum ICC = 0.974), although less so than that observed using Endosize. Mean time consumption using Endosize was 13.1 +/- 4.53 minutes (range: 7.2-32.7). Analysis of the alarm sets demonstrated a high agreement between observers (kappa coefficient = 0.81). CONCLUSIONS: Sizing using the Endosize software is as reliable as conventional radiological procedures. Sizing by surgeons using an automated, user-friendly, and mobile tool appears to be reproducible. PMID- 20831993 TI - Endovascular abdominal aortic aneurysm repair using an anatomical fixation technique and concomitant suprarenal orientation: results of a prospective, multicenter trial. AB - BACKGROUND: Endovascular repair of abdominal aortic aneurysms with the Endologix Powerlink System has been shown to be a safe and effective alternative to open surgery in patients having an aortic neck diameter of up to 26 mm. We report the mid-term outcomes of an endovascular repair approach wherein the infrarenal bifurcated stent graft was placed at the aortoiliac bifurcation, with concomitant placement of a proximal extension having suprarenal orientation for proximal sealing. METHODS: Between 2006 and 2008, eight US sites enrolled 44 consecutive eligible patients presenting with abdominal aortic aneurysm in a prospective, single arm pivotal trial approved by the Food and Drug Administration. Each patient received a Powerlink infrarenal bifurcated stent graft through anatomical fixation at the aortoiliac bifurcation and a suprarenal extension to achieve proximal sealing. Analysis of the primary endpoint (proximal type I endoleak) was evaluated using contrast-enhanced computed tomography scans at 30 days, with on going long-term follow-up for safety and treatment effectiveness. RESULTS: Patients (89% male) presented at a mean age of 70 +/- 10 years with mean maximal aneurysm sac diameter of 5.5 cm. Challenging infrarenal aortic neck anatomy was present in 93% of patients. Technical success was 100% over a mean procedure time of 129 minutes. No aneurysm-related deaths, conversions, ruptures, migrations, or type III or IV endoleaks have been observed. The majority of endoleaks (80%) observed to date are type II. Currently, the primary clinical success rate is 93%. Two endovascular secondary procedures have been performed for resolution of type IA or type IB endoleak, and one surgical intervention was performed for resolution of limb occlusion. Significant reduction in sac diameter is observed to up to 2 years. CONCLUSIONS: The combination of an anatomically-fixed Powerlink infrarenal bifurcated stent graft and a suprarenal proximal extension safely and effectively excludes aneurysms in eligible patients. Longer term follow-up will determine the durability of these findings. PMID- 20831994 TI - Surgical or endovascular treatment for chronic mesenteric ischemia: a multicenter study. AB - BACKGROUND: To evaluate treatment options for patients with chronic mesenteric ischemia in the United Kingdom. METHODS: Early and late outcomes of patients with chronic mesenteric ischemia who underwent bypass or percutaneous angioplasty (PTA) in 12 centers were compared on an intention-to-treat basis. RESULTS: A total of 76 patients underwent 101 procedures (PTA 49; bypass 52). Of these, 36 had a PTA first, and 40 had a bypass first. Among those who underwent a primary PTA, nine required a subsequent bypass. Three patients who underwent a primary bypass also required a graft PTA, and three patients required further surgery. Patients who underwent a primary PTA were found to be significantly older and tended to have greater comorbidities. As compared with PTA, primary bypasses were more frequently undertaken in an urgent manner or as an emergency (43% vs. 8%). Perioperative morbidity for bypass was significantly greater than that for PTA (32% vs. 6%). Overall, 30-day mortality for bypass tended to be greater than that for PTA (13% vs. 4%; n.s.), but was similar for patients treated electively in the two groups (4% vs. 3%). Cumulative 1- and 5-year survival (bypass: 85%, 63%; PTA: 67%, 31%) and primary patency (bypass: 81%, 69%; PTA: 54%, 32%) rates were found to be significantly better after primary bypass. CONCLUSIONS: Treatment preferences were center-dependent. Symptomatic recurrence was found to be less frequent and patency rates were better after a primary bypass. PTA may be a viable alternative in patients with significant comorbidities. PMID- 20831995 TI - Long-term outcome of inferior vena cava filter placement in patients undergoing gastric bypass. AB - BACKGROUND: It has been well established that inferior vena cava (IVC) filter placement at the time of open gastric bypass (OGB) surgery in patients with a body mass index of more than 55 kg/m(2) reduces both the pulmonary embolism rate and the perioperative mortality. However, little is known about the long-term effects of IVC filter placement in this particular group of patients. METHODS: Over an 8-year period, a total of 571 morbid obese patients underwent OGB procedures, and 58 (10%) of them required placement of an IVC filter before their procedure. All IVC filters were placed percutaneously through a femoral vein approach using a portable OEC fluoroscope. Types of IVC filters used in our study included the TrapEase (n = 35), Simon-Nitinol (n = 9), Greenfield (n = 2), and Bard Recovery (n = 12). RESULTS: Of the 58 patients who required an IVC placement, 56 remained free of any thromboembolic phenomena over the 8-year period (range, 1-8 years). The remaining two patients developed deep venous thrombosis. One patient was successfully treated with intravenous heparin and a 6 month course of Coumadin. She had complete resolution of her deep venous thrombosis and was incidentally noted to have a prothrombin 20210 gene mutation. The other patient, who had multiple gastric bypass complications, could not be successfully treated with intravenous heparin and thus progressed on to complete IVC thrombosis. She developed phlegmasia cerulea dolens and required bilateral above-the-knee amputations. She subsequently died 3 months after her procedures. CONCLUSION: It appears that IVC filter placement at the time of OGB surgery is a relatively benign intervention with a maximal benefit. A note of caution should be exerted for those obese patients who have a hypercoagulable disorder and for those who have complications related to the gastric bypass. An aggressive posture, which may consist of immediate anticoagulation after their procedures (only when it is deemed safe), should be advocated in this small sub-group of morbid obese patients. PMID- 20831996 TI - Spontaneous recanalization of an occluded internal carotid artery. AB - Recanalization after extracranial internal carotid artery (ICA) occlusion is a rare phenomenon and the natural history of the disease is largely unknown. There have been few cases reported in the published data, including early recanalization after a cerebrovascular accident (CVA). We report a case of a 74 year-old man who presented with a CVA and a history of multiple CVAs in the past, the last episode being a year ago. Multiple imaging modalities, including duplex scans, computerized tomographic angiograms, and fluoroscopy-guided angiogram of bilateral carotid arteries, showed occlusion of the left ICA in the past. The duplex scan performed 8 months later demonstrated late spontaneous recanalization of the occluded left ICA. The patient underwent successful carotid endarterectomy. The pathophysiology, natural history, and possible surveillance strategy are discussed in this case report. PMID- 20831997 TI - Endovascular repair of carotid artery pseudoaneurysm after carotid endarterectomy with self-expanding covered stents-a long-term follow-up. AB - A 66-year-old Caucasian man with type 2 diabetes mellitus, peptic ulcer disease, peripheral vascular disease, and a 70% symptomatic carotid stenosis underwent a successful carotid endarterectomy with intraoperative shunting and Dacron patch closure in October 2000. Three months later, he developed a pseudoaneurysm at the site of the surgical repair. This was successfully treated with endovascular covered stents and has continued to remain patent at 9-year follow-up. Carotid artery pseudoaneurysms are secondary to trauma, infection, or previous surgery. Open surgical repair has been the treatment of choice for these pseudoaneurysms. However, open repairs are difficult and carry a high morbidity. Thus, endovascular therapy is a valid treatment for carotid artery pseudoaneurysm. Reviewing the published data, this is the first case report with successful endovascular covered stent placement for a carotid pseudoaneurysm with 9-year follow-up. PMID- 20831998 TI - Renal artery thrombosis caused by stent fracture: the risk of undiagnosed renal artery entrapment. AB - We report a case of renal artery thrombosis resulting from a stent fracture in a patient with a solitary functional kidney. It was successfully revascularized by surgical repair despite renal ischemia lasting more than 48 hours. This article illustrates the danger of generalizing endovascular stenting in renal artery disease regardless of the etiology. Renal artery entrapment must be kept in mind as a possible cause of renal artery stenosis. Treatment of compressive pathologies with stenting can lead to stent failure. Surgery remains the best approach for the treatment of this type of lesion. PMID- 20831999 TI - Covered stent treatment for an aneurysm of a saphenous vein graft to the common carotid artery. AB - Aneurysmal degeneration of a saphenous vein graft is a rare complication and, so far, only three cases involving a carotid artery have been described. We report the case of a patient with a cervical neoplasm presenting carotid invasion, who underwent en bloc tumor resection and carotid reconstruction with a saphenous vein graft. Six years later, during follow-up, an aneurysm of the carotid graft was detected. Endovascular intervention was performed using a covered stent. Three years after this intervention, the patient was found to be asymptomatic, and computed tomography showed that the covered stent was patent, without complications. PMID- 20832000 TI - Endovascular stent-graft repair for spontaneous dissection of infra-renal abdominal aorta. AB - Abdominal aortic dissection (AAD) is a rare pathology and potentially causes rupture or other serious complications. This case report details our experience in endovascular aneurysm repair for AAD in a patient who had a history of coronary bypass surgery. Circumferential dissection of terminal aorta showed stenosis of true lumen as well as blood flow present in the pseudolumen. Using Zenith AAA endovascular device, the entry site was closed and the pseudolumen was thrombosed successfully. In the present report, published data on AAD were reviewed and endovascular aneurysm repair as a treatment option has been discussed as well. PMID- 20832001 TI - Late-onset congestive heart failure in a patient with a 58-year-old huge traumatic carotid-jugular fistula and pseudoaneurysm: endovascular treatment with a stent-graft. AB - We report a case of successful stent-graft endovascular treatment of a huge traumatic carotid-jugular fistula with a pseudoaneurysm that had resulted from a bullet injury. A 77-year-old man with a pulsatile neck mass came to our hospital complaining of dyspnea and chest pain at rest; about 58 years ago, a gunshot accident had inflicted a penetrating bullet wound on the right side of his neck. Computerized tomography angiogram had demonstrated a huge vascular mass protruding into the right anterior neck with a pseudoaneurysm. The calcified pseudoaneurysm had an oval-shaped opening in the right common carotid artery, with a large base into the right internal jugular vein. Echocardiography showed deteriorating congestive heart failure, wherein left ventricular (LV) enlargement with a LV end-diastolic diameter of 6.1 cm, severe tricuspid valve regurgitation, and LV ejection fraction of 60% was seen. The surgical approach was considered risky because of the severe deformity of the native vasculature, the severe calcified pseudoaneurysm, and the context of advanced age with congestive heart failure. Thus, we decided to treat this patient with endovascular devices. Fortunately, a stent-graft was delivered successfully across the carotid-jugular fistula and immediate follow-up angiogram demonstrated a small filling defect at the base of stent-graft representing thrombus. The follow-up computerized tomography angiograms obtained 2 weeks and 4 months later further demonstrated a patent stent-graft, no evidence of thrombus progression, and no abnormal shunt flow. The patient did not experience any neurologic complications nor did he show any evidence of pulmonary embolism for 8 months. PMID- 20832003 TI - Inferior vena cava filters. PMID- 20832002 TI - How to manage the left subclavian artery during endovascular stenting for thoracic aortic dissection? An assessment of the evidence. AB - BACKGROUND: Despite the publication of recent guidelines for management of the left subclavian artery (LSA) during endovascular stenting procedures of the thoracic aorta, specific management for those presenting with dissection remains unclear. This systematic review attempts to address this issue. METHODS: Systematic assessment of the published data on thoracic aorta dissection was performed identifying 46 studies, which incorporated 1,275 patients. Primary outcomes included the prevalence of left arm ischemia, stroke, spinal cord ischemia, endoleak, stent migration, and mortality. Outcomes were compared between patients with and without LSA coverage and revascularization incorporating factors such as the number of stents used, length of aorta covered, urgency of intervention, and type of dissection (acute or chronic). Statistical pooling techniques, chi(2) tests, and Fisher's exact testing were used for group comparisons. RESULTS: As compared with other outcomes, LSA coverage without revascularization in the presence of aortic dissection is much more likely to be complicated by left arm ischemia (prevalence increased from 0.0% to 4.0% [p = 0.021]), stroke (prevalence increased from 1.4% to 9.0% [p = 0.009]), and endoleak (prevalence increased from 4.0% to 29.3% [p = 0.001]). However, revascularization was not shown to reverse these effects. Longer aortic coverage (>= 150 mm) was associated with an increased prevalence of spinal cord ischemia (from 1.3% to 12.5% [p = 0.011]) and mortality (from 1.3% to 15.6% [p = 0.003]). CONCLUSION: In patients undergoing endovascular stenting for thoracic aortic dissection, in cases where LSA coverage is necessary, revascularization should be considered before the procedure to avoid complications such as left arm ischemia, stroke, and endoleak, and where feasible, an appropriate preoperative assessment should be carried out. PMID- 20832004 TI - Diameter-reducing wire to facilitate deployment of a modified Zenith fenestrated stent graft. AB - BACKGROUND: Modified fenestrated stent grafts have been used for compassionate treatment of large complex aortic aneurysms in high-risk patients who do not have access to a manufactured device and are not candidates for conventional open surgical repair. Accurate device design and precise implantation are key components of the procedure. A technique of device modification with diameter reducing wire is described to facilitate catheterization of side branches. METHODS: The modified Cook Zenith stent graft was created using reinforced fenestrations with gold nitinol markers. The stainless steel wire, which secures the top cap into the uncovered stent, was partially withdrawn, retrieved, and redirected externally through-and-through the fabric of the stent graft. Each Z stent was constrained using the stainless steel wire for support and by two nonlocking prolene loops. The constrained stent graft was 30% narrower than the unconstrained device, which allowed flow between the stent graft and the aortic wall, as well as longitudinal and rotational movement of the stent graft. After successful catheterization of the fenestrations, balloon-expandable stent grafts were advanced over hydrophilic sheaths, and the stainless steel diameter-reducing wire was removed with full expansion of the Z-stents to its unconstrained diameter. The fenestrations were stented with balloon-expandable stent grafts, followed by placement of iliac limbs CONCLUSION: The use of a diameter-reducing wire allows longitudinal and rotational movement to the modified fenestrated stent graft and facilitates side branch catherization in patients in whom there is misalignment between the fenestration and the origin of the target vessel. PMID- 20832005 TI - Artifact free T2*-weighted imaging at high spatial resolution using segmented EPI sequences. AB - The aim of this work was the development of novel measurement techniques that acquire high resolution T2*-weighted datasets in measurement times as short as possible without suffering from noticeable blurring and ghosting artifacts. Therefore, two new measurement techniques were developed that acquire a smoother k-space than generic multi shot echo planar imaging sequences. One is based on the principle of echo train shifting, the other on the reversed gradient method. Simulations and phantom measurements demonstrate that echo train shifting works properly and reduces artifacts in multi shot echo planar imaging. For maximum SNR efficiency this technique was further improved by adding a second contrast. Both contrasts can be acquired within a prolongation in measurement time by a factor of 1.5, leading to an SNR increase by approximately 2. Furthermore it is demonstrated that the reversed gradient method remarkably reduces artifacts caused by a discontinuous k-space weighting. Assuming sequence parameters as feasible for fMRI experiments, artifact free T2*-weighted images with a matrix size of 256 * 256 leading to an in-plane resolution in the submillimeter range can be obtained in about 2s per slice. PMID- 20832006 TI - Radiobiological effect based treatment plan optimization with the linear quadratic model. AB - As an approach towards more biology-oriented treatment planning for external beam radiation therapy, we present the incorporation of local radiation damage models into three dimensional treatment planning. This allows effect based instead of dose based plan optimization which could potentially better match the biologically relevant tradeoff between target and normal tissues. In particular, our approach facilitates an effective comparison of different fractionation schemes. It is based on the linear quadratic model to describe the biological radiation effect. Effect based optimization was integrated into our inverse treatment planning software KonRad, and we demonstrate the resulting differences between conventional and biological treatment planning. Radiation damage can be analyzed both qualitatively and quantitatively in dependence of the fractionation scheme and tissue specific parameters in a three dimensional voxel based system. As an example the potential advantages as well as the associated risks of hypofractionation for prostate cancer are analyzed and visualized with the help of effective dose volume histograms. Our results suggest a very conservative view regarding alternative fractionation schemes since uncertainties in biological parameters are still too big to make reliable clinical predictions. PMID- 20832007 TI - Improving the performance of direct Monte Carlo optimization for large tumor volumes. AB - Direct Monte Carlo Optimization (DMCO) is a powerful method for dose optimization with Monte Carlo accuracy and direct aperture optimization with simulated annealing. Recently, we presented quasi intensity modulated arc therapy (qIMAT), a step-and-shoot technique that simulates a rotational technique by using a high number of beams and reducing the number of segments. In the present work, we applied a combination of both techniques to optimize an anal cancer case. Because of the limited memory of standard computers, two techniques for reducing the size of the inverse kernel (IK) were investigated. The standard deviation degradation technique (SDDT) and the reduced resolution technique (RRT) were applied to a 7 field IMRT plan on the CarPet phantom. Several IKs with an estimated standard deviation (SD) of the MC-calculation of 5%, 10% and 15% and another three IKs with voxel size of 4, 8 and 16mm were calculated. All IKs were optimized with DMCO; after optimization, a final dose calculation with 5% SD and 4mm resolution was carried out. SDDT was a better compromise between plan quality and IK-size reduction than RRT. PTV homogeneity and dose sparing to the OAR was almost identical for SDDT, while for RRT the quality was degraded by low resolution. Therefore, SDDT was applied to the anal cancer case. The IK-file of a quasi-IMAT plan with 30 beams was calculated with XVMC with 15% SD and a voxel size of 4mm. After optimization with DMCO using one segment per beam, a final dose calculation with 2% variance was performed. By comparing the DVHs of qIMAT with a 7-field IMRT (commercial therapy planning system) and with a 7-field IMRT (DMCO), qIMAT showed considerably advantages over IMRT in OARs dose sparing. In this way, the DMCO optimization with qIMAT of complex cases with large treatment volumes, such as anal cancer, are possible. Furthermore, for anal cancer, the comparison of qIMAT with IMRT showed that qIMAT can improve the plan quality. PMID- 20832008 TI - Dose-response relationship for lung cancer induction at radiotherapy dose. AB - Cancer induction after radiation therapy is a severe side effect. It is therefore of interest to predict the probability of second cancer appearance for the treated patient. Currently there is large uncertainty about the shape of the dose response relationship for carcinogenesis for most cancer types at high dose levels. In this work a dose-response relationship for lung cancer is derived based on (i) the analysis of lung cancer induction after Hodgkin's disease, (ii) a cancer risk model developed for high doses including fractionation based on the linear quadratic model, and (iii) the reconstruction of treatment plans for Hodgkin's patients treated with radiotherapy. The fitted model parameters for an alpha/beta=3 Gy were alpha=0.061Gy(-1) and R=0.84. The value for alpha is in agreement with analysis of normal tissue complications of the lung after radiation therapy. The repopulation/repair parameter R is large, but seems to be characteristic for lung tissue which is sensitive with regard to fractionation. Lung cancer risk is according to this model for small doses consistent with the finding of the A-bomb survivors, has a maximum at doses of around 15 Gy and drops off only slightly at larger doses. The predicted EAR for lung after radiotherapy of Hodgkin's disease is 18.4/10000PY which can be compared to the findings of several epidemiological studies were EAR for lung varies between 9.7 and 21.5/10000PY. PMID- 20832009 TI - Theoretical models for dynamic shape factors and lung deposition of small particle aggregates originating from combustion processes. AB - A theoretical model was developed which allows the generation of irregularly shaped aggregate particles due to the stepwise joining of spherical components with variable diameters. The mathematical approach is mainly thought to act as a supporting tool for the simulation of the transport and deposition behaviour of combustion aerosols in the atmosphere and the human respiratory tract. In combination with aggregate construction essential particle parameters (dynamic shape factor chi, aerodynamic diameter d(ae)) are computed using the model. As a main result of aggregate generation, an increasing particle size, expressed by an increasing number of spherical components, leads to an enhancement of chi and d(ae), whereby values of the first parameter range from 2 to 70. Deposition of small aggregates (sizes between 2 and 200nm) in the human respiratory tract is commonly marked by high rates of bronchial particle accumulation (40-60%) and declined rates of extrathoracic (20-30%) and alveolar accumulation (2-15%). Concerning aggregate deposition by airway generation, increased cluster size causes a significant decrease of particle accumulation in the proximal airways, whilst accumulation in the intermediate to distal airways is dramatically enhanced. The model was validated using experimental deposition data of tobacco smoke. An excellent correspondence between experimental and theoretical results was found. PMID- 20832010 TI - From the editor's desk: poems from a garden so sweet. PMID- 20832011 TI - Special issue on Steroids in Obesity and Diabetes. PMID- 20832012 TI - Introduction: DNA repair and radiotherapy targeting: an overview. PMID- 20832013 TI - DNA repair targeting and radiotherapy: a focus on the therapeutic ratio. AB - Radiotherapy (RT) results in the production of a variety of ionizing radiation induced lesion in DNA. Specific pathways of DNA repair are required to repair the variety of lesions, which include DNA single-strand breaks (SSBs), DNA double strand breaks (DSBs), DNA base alterations, and DNA-DNA or DNA-protein cross links. Nonrepaired DNA damage can lead to normal and tumor cell death via apoptosis, mitotic catastrophe, autophagy, or terminal growth arrest senescence. Targeting the sensing and repair of DNA damage is an exciting concept. This must be combined with precision RT to limit the volume of irradiated normal tissue, including the use of image-guided radiotherapy (IGRT) and brachytherapy. The therapeutic ratio of combined targeting of DNA combined with RT could also be preserved using biological approaches and includes the following: (1) the documentation of relative defects in DNA damage sensing and repair in malignant cells; (2) the preferential use of certain DNA repair pathways (eg, base excision repair or homologous recombination) in malignant tissues compare with normal tissues; (3) the targeting of repair defects in chronically hypoxic cells; and (4) optimal scheduling of a DNA repair inhibitor in the neoadjuvant, concurrent, or adjuvant combined treatment settings. In this review, we discuss the general rationale and the optimal timing and duration of DNA repair inhibition during fractionated RT with the emphasis on preserving the therapeutic ratio of cancer treatment. PMID- 20832014 TI - Use of gammaH2AX and other biomarkers of double-strand breaks during radiotherapy. AB - The rapid phosphorylation of histone H2AX at serine 139 (gammaH2AX) serves as a sensitive marker for DNA double-strand breaks induced by ionizing radiation or other genotoxic agents. The potential clinical applications of gammaH2AX detection in tissues from cancer patients during fractionated radiotherapy and the sensitivity for detection of in vivo drug effects on radiation-induced DNA damage responses (DDRs) are discussed. The quantification of gammaH2AX foci in the nuclei of peripheral blood lymphocytes allows estimation of the applied integral body dose by conformal radiotherapy to tumors in different sites of the body. The limits of precision of biodosimetry in peripheral blood lymphocytes with a gammaH2AX assay shortly after radiation exposure are shown. The high sensitivity of the in vitro radiation dose-gammaH2AX foci response allows monitoring of drug effects on DDR pathways after in vivo drug exposure and in vitro irradiation. Drugs are under clinical investigation that modify radiation induced damage response. If interindividual or intertumoral differences in drug sensitivity exist, the measurement of radiation-induced foci formation and resolution after in vivo drug exposure and in vitro or in vivo irradiation of a cellular probe can serve as a functional assay that may predict the individual gain of a combination therapy. Validation by prospective studies is needed. PMID- 20832015 TI - Single nucleotide polymorphisms of DNA repair genes as predictors of radioresponse. AB - Radiation therapy is a key modality in the treatment of cancer. Substantial progress has been made in unraveling the molecular events which underpin the responses of malignant and surrounding normal tissues to ionizing radiation. An understanding of the genes involved in processes such as DNA double-strand break repair, DNA damage response, cell-cycle control, apoptosis, cellular antioxidant defenses, and cytokine production, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Experimental approaches, such as candidate SNP association studies, genome-wide association studies, and massively parallel sequencing are being proposed to address these questions. We present a focused review of the evidence supporting an association between SNPs in DNA repair genes and radioresponse in normal tissues and tumors. Although preliminary results indicate possible associations, there are methodological weaknesses in many of the studies, and independent validation of SNPs as biomarkers of radioresponse in much larger cohorts will likely require research cooperation through international consortia. PMID- 20832016 TI - Targeting base excision repair as a sensitization strategy in radiotherapy. AB - Cellular DNA repair determines survival after ionizing radiation. Human tumors commonly exhibit aberrant DNA repair since they drive mutagenesis and chromosomal instability. Recent reports have shown alterations in the base excision repair (BER) and single strand break repair (SSBR) pathways in human tumors. Here we review these reports with respect to radiation sensitivity and the attempts to target such tumor-specific BER/SSBR aberrations. These aberrations can alter cellular resistance to therapeutic agents, including radiation. Some strategies therefore aim to counteract the radioresistance mediated by such aberrant DNA repair. Other strategies aim to exploit the dependence of the tumor, but not the normal cells, on backup repair mechanisms after radiation, therefore increasing the therapeutic window. Such tumor-targeted radiosensitization holds promise for increasing the efficacy of radiotherapy. PMID- 20832018 TI - The E2F1/Rb and p53/MDM2 pathways in DNA repair and apoptosis: understanding the crosstalk to develop novel strategies for prostate cancer radiotherapy. AB - Both the p53- and E2F1-signaling pathways are defective in almost all types of tumors, suggesting very important roles for their signaling networks in regulating the process of tumorigenesis and therapy response. Studies on Radiation Therapy Oncology Group tissue samples have identified aberrant expression of p53, MDM2 (an E3 ubiquitin ligase that targets p53 for proteosomal degradation), and p16 (an upstream regulator of retinoblastoma and hence E2F1 in prostate cancer); abnormal expression of these biomarkers has been associated with clinical outcome after radiotherapy +/- androgen deprivation therapy. Although the proapoptotic properties of p53 are well documented, a relatively new aspect of p53 function as an active mediator of prosurvival signaling pathways is now emerging. E2F1 is a transcription factor that possesses both proapoptotic and prosurvival properties. Thus, the role of E2F1 in the process of tumorigenesis versus apoptosis is a contested issue that needs to be resolved. Furthermore, the role of E2F1 in DNA repair is being increasingly recognized. Thus, novel approaches to curb the prosurvival and DNA repair capability of E2F1 while promoting apoptotic function are of interest. In this review, we discuss the challenges involved in targeting the p53/E2F1 pathways and the crosstalk networks, and further propose potential therapeutic strategies for prostate cancer management. PMID- 20832017 TI - Targeting nonhomologous end-joining through epidermal growth factor receptor inhibition: rationale and strategies for radiosensitization. AB - DNA double-strand breaks (DSBs) are the most lethal type of DNA damage induced by ionizing radiation or chemotherapeutic drugs used to eradicate cancer cells. The ability of cancer cells to effectively repair DSBs significantly influences the outcome of therapeutic regimens. Therefore, a new and important area of clinical cancer research is the development of DNA repair inhibitors that can be used as radio- or chemosensitizers. Nonhomologous end joining (NHEJ) is the predominant pathway for the repair of radiation-induced DSBs. A series of recent reports indicates that the epidermal growth factor receptor (EGFR) or its downstream components may modulate NHEJ through direct interaction with the DNA repair enzyme, DNA-dependent protein kinase. Because EGFR is overexpressed or activated in many cancers, these findings provide a compelling rationale for combining radiotherapy with therapies that block EGFR or its downstream signaling components. In this review, we delineate how these novel connections between a cell-surface receptor (EGFR) and a predominantly nuclear event (NHEJ) provide vulnerable nodes that can be selectively targeted to improve cancer therapy. PMID- 20832019 TI - Enhancing radiotherapy through a greater understanding of homologous recombination. AB - Radiotherapy for the treatment of cancer can cause a wide range of cellular effects, the most biologically potent of which is the double-strand break in DNA. The process of repairing DNA double-strand breaks involves 1 of 2 major mechanisms: nonhomologous end joining or homologous recombination. In this review, we review the molecular mechanisms of homologous recombination, in particular as it relates to the repair of DNA damage from ionizing radiation. We also present specific situations in which homologous recombination may be dysfunctional in human cancers and how this functional abnormality can be recognized. We also discuss the therapeutic opportunities that can be exploited based on deficiencies in homologous recombination at various steps in the DNA repair pathway. Side-by-side with these potential therapeutic opportunities, we review the contemporary clinical trials in which strategies to exploit these defects in homologous recombination can be enhanced by the use of radiotherapy in conjunction with biologically targeted agents. We conclude that the field of radiation oncology has only scratched the surface of a potentially highly efficacious therapeutic strategy. PMID- 20832020 TI - Poly(ADP-ribose) polymerase inhibition as a model for synthetic lethality in developing radiation oncology targets. AB - DNA double-strand breaks (DSBs) induced during clinical radiotherapy are potent inducers of cell death. Poly(ADP-ribose) polymerase (PARP)-1 is a 113-kD nuclear protein that binds to both single- and double-strand DNA breaks and is actively involved in DNA single-strand break repair and base excision repair. Recently, potent and specific chemical inhibitors of PARP activity have been developed that are effective tumor cell radiosensitizers in vitro and in vivo. Because of synthetic lethality, PARP inhibitors may be highly effective as a single agent in patients whose tumors have germline or somatic defects in DNA damage and repair genes (eg, ATM, BRCA1, BRCA2, and NBS1) or defects in genes involved in phosphatase and tensin homolog gene (PTEN) signaling. Defects in specific DNA repair pathways also appear to enhance the radiosensitizing effects of PARP inhibition. In addition to inherent genetics, tumor cells may also be preferentially sensitized to radiotherapy by diverse mechanisms, including proliferation-dependent radiosensitization, targeting of the endothelium and tumor vasculature, and increased sensitivity to PARP inhibitors within repair deficient hypoxic cells. Because biologically active doses of PARP inhibitors caused minimal toxicity in phase I to II clinical trials, careful scheduling of these agents in combination with radiotherapy may maintain the therapeutic ratio and increase tumor radiocurability. PMID- 20832021 TI - The tumor microenvironment and DNA repair. AB - Genetic instability is one of the hallmarks of cancer cells. As tumors grow, they progressively acquire mutations that ultimately allow them to invade normal tissues and metastasize to distant sites. This increased propensity for mutation also leads to cancers that are resistant to therapeutic intervention. Recent evidence has shown that the tumor microenvironment plays a major role in the etiology of this phenomenon; as tumors are exposed to repeated cycles of hypoxia and reoxygenation, they downregulate a number of DNA repair pathways, thus leading to genetic instability. Understanding the mechanisms involved in this process may provide insights into the development of novel treatment strategies. PMID- 20832022 TI - Dose reduction in CT: the time is now. PMID- 20832023 TI - Feasibility of dose reduction using novel denoising techniques for low kV (80 kV) CT enterography: optimization and validation. AB - RATIONALE AND OBJECTIVES: The aim of this study was to optimize and validate projection-space denoising (PSDN) strategies for application to 80-kV computed tomographic (CT) data to achieve 50% dose reduction. MATERIALS AND METHODS: Image data obtained at 80 kV (mean CT dose index volume, 7.9 mGy) from dual-source, dual-energy CT enterographic (CTE) exams in 42 patients were used. For each exam, nine 80 kV image data sets were reconstructed using PSDN (three levels of intensity) with or without image-based denoising and compared to commercial reconstruction kernels. For optimization, qualitative analysis selected optimal denoising strategies, with quantitative analysis measuring image contrast, noise, and sharpness (full width at half maximum bowel wall thickness, maximum CT number gradient). For validation, two radiologists examined image quality, comparing low dose 80-kV optimally denoised images to full-dose mixed-voltage images. RESULTS: PSDN algorithms generated the best 80-kV image quality (41 of 42 patients), while the commercial kernels produced the worst (39 of 42) (P < .001). Overall, 80-kV PSDN approaches resulted in higher contrast (mean, 332 vs 290 Hounsfield units), slightly less noise (mean, 20 vs 26 Hounsfield units), but slightly decreased image sharpness (relative bowel wall thickness, 1.069 vs 1.000) compared to full dose mixed-voltage images. Mean image quality scores for full-dose CTE images were 4.9 compared to 4.5 for optimally denoised half-dose 80-kV CTE images and 3.1 for nondenoised 80-kV CTE images (P < .001). CONCLUSION: Optimized denoising strategies improve the quality of 80-kV CTE images such that CT data obtained at 50% of routine dose levels approaches the image quality of full-dose exams. PMID- 20832024 TI - Radiologists' perceptions of computer aided detection versus double reading for mammography interpretation. AB - RATIONALE AND OBJECTIVES: The aim of this study was to examine radiologists' use and perceptions of computer-aided detection (CAD) and double reading for screening mammography interpretation. MATERIALS AND METHODS: A mailed survey of 257 community radiologists participating in the national Breast Cancer Surveillance Consortium was used to assess perceptions and practices related to CAD and double reading. Latent class analysis was used to classify radiologists' overall perceptions of CAD and double reading on the basis of their agreement or disagreement with specific statements about CAD and double reading. RESULTS: Most radiologists (64%) reported using CAD for more than half the screening mammograms they interpreted, but only <5% reported double reading that much. More radiologists perceived that double reading improved cancer detection rates compared to CAD (74% vs 55% reported), whereas fewer radiologists thought that double reading decreased recall rates compared to CAD (50% vs 65% reported). Radiologists with the most favorable perceptions of CAD were more likely to think that CAD improved cancer detection rates without taking too much time compared to radiologists with the most unfavorable overall perceptions. In latent class analysis, an overall favorable perception of CAD was significantly associated with the use of CAD (81%), a higher percentage of workload in screening mammography (80%), academic affiliation (71%), and fellowship training (58%). Perceptions of double reading that were most favorable were associated with academic affiliation (98%). CONCLUSIONS: Radiologists' perceptions were more favorable toward double reading by a second clinician than by a computer, although fewer used double reading in their own practice. The majority of radiologists perceived both CAD and double reading at least somewhat favorably, although for largely different reasons. PMID- 20832025 TI - Navigated liver biopsy using a novel soft tissue navigation system versus CT guided liver biopsy in a porcine model: a prospective randomized trial. AB - RATIONALE AND OBJECTIVES: The aim of this prospective, randomized animal study was to compare a new computer guided needle-based navigation system for liver biopsy with conventional computed tomography (CT)-guided liver biopsy. Computer navigated interventions provide continuous needle tracking during motion and deformation from patient respiration and movement. MATERIALS AND METHODS: Twenty artificial tumors of about 5 mm in diameter were injected into the livers of five pigs, each at a different site. Each tumor was targeted by conventional CT-guided and computer navigated intervention. Intervention was considered complete after successful tumor biopsy. Data on procedure time, number of CT scans performed, accuracy, and success rate were recorded. RESULTS: All tumors (100%) were biopsied successfully. Mean procedural time was comparable between the two techniques (20 +/- 9 minutes conventional versus 20 +/- 8 minutes navigation). Mean number of CT scans were 1.2 +/- 0.4 with navigation and 6.1 +/- 3.8 with the conventional technique (P < .01). The dose-length product in the conventional group was significantly higher (212 +/- 116 mGy * cm) than in the navigated group (78 +/- 22 mGy * cm; P < .001). Mean number of capsule penetrations was 4 +/- 1 with navigation versus 2 +/- 1 with the conventional technique (P < .001). CONCLUSION: Computer-navigated liver biopsy may provide a promising and innovative device for easy, rapid, and successful liver biopsies with low morbidity. Further technical improvements and clinical studies in humans are required. PMID- 20832027 TI - High-quality CT colonography can detect nonpolypoid colorectal neoplasm (NP-CRN) science or rhetoric? PMID- 20832028 TI - Rad-path course at the AFIP. PMID- 20832029 TI - Geriatric cruise. PMID- 20832030 TI - [Critic analysis of a comparative meta-analysis on the morbidity, functional and carcinologic results after radical prostatectomy according to surgical approach. Work of cancerology committee of the French urological association]. AB - Surgical approach for radical prostatectomy is even today a subject of debate in the urologic community. Many comparative studies between retropubic and laparoscopic approach (robotic assisted or not) were reported since 10 years without being able to decide between the supporters of retropubic or laparoscopic approach. The committee of cancer research of the French urological association took hold this question after a recent meta-analysis publication on this subject. Although imperfect, this meta-analysis exists and permits to conclude partially on the advantages and the inconveniences supposed for each surgical approach. Regarding morbidity after radical prostatectomy, the only significant difference reported concerns the hemorrhagic risk in favour of the laparoscopic approach. Regarding oncologic results, the only exploitable data concern positive surgical margins rate, which is identical whatever surgical approach. Concerning the functional results, no difference was reported in the literature between different surgical approaches. PMID- 20832031 TI - [The primary disorder of sphincter relaxation or Fowler's syndrome]. AB - The primary disorder of sphincter relaxation or Fowler's syndrome constitutes the first cause of urinary retention in young women after ruling neurological, iatrogenic and local origins out. It includes painless urinary retention, polycystic ovaries in more than 50% of the cases, high maximum urethral closure pressure, increase in sphincter volume and striated urethral sphincter electromyography abnormalities. So far, the only treatment restoring micturation in this condition is sacral neuromodulation. PMID- 20832032 TI - [Nutrition, dietary supplements and prostate cancer]. AB - Prostate cancer is becoming the most common cancer in men. In parallel, role of diet as contributing or protector factor of prostate cancer is supported by experimental studies, clinical observations and intervention studies. Among the prostate cancer risk factor, role of energy intake, especially saturated fat, has been demonstrated. Similarly, omega-3, lycopene, pomegranate juice and vitamin D protective role have been shown. Informed and educated population is necessary to limit energy intake and promote consumption of foods potentially protective. PMID- 20832033 TI - [Transurethral needle ablation Prostiva for treating symptomatic benign prostatic hyperplasia: a review]. AB - Benign prostatic hyperplasia (BPH) is a common disease affecting a large proportion of men older than 50 years. There are multiple treatment options for BPH including medications, minimally invasive options such as transurethral needle ablation (Tuna) and transurethral microwave therapy (TUMT), and more invasive options such as transurethral laser vaporization and transurethral resection of the prostate (TURP). The minimally invasive options induce thermal injury to the BPH adenoma with a lower risk of permanent side effects than TURP. Tuna treatment is a minimally invasive technique of BPH which can be carried out in ambulatory surgery and which is effective for urinary symptoms with little risk of morbidity. It is an alternative to medical treatment and does not replace planned surgical treatment. Available evidence suggests that Tuna is a relatively effective and safe technique. It significantly improves BPH parameters but it does not reach the same level efficacy and long-lasting success as TURP. Also the Tuna procedure compares favourably to combination medical therapy for the treatment of BPH on a cost basis. alpha-Blocker monotherapy is less costly than Tuna for 5 years, while the cost of 5alpha-reductase inhibitor monotherapy is approximately equivalent to that of Tuna for 5 years. From the payer's perspective, the break-even point between the Tuna((r)) procedure and combination medical management occurs after approximately 2 years 7 months of treatment. PMID- 20832034 TI - [Characterization and outcome of renal cancers <= 4cm treated by surgery]. AB - PURPOSE: In a retrospective study, we described the characteristics and the outcome of renal cancers less than or equal to 4cm treated by surgical excision. MATERIAL: Two hundred and eighty four cancers less than or equal to 4cm on preoperative CT scan (T1a) were extracted from our database. We studied, the presence of symptoms, the ECOG and ASA scores, the size, the histological type and the Fuhrman grade. The follow up was clinical, biological and radiological. RESULTS: The mean age was 60.8 years. 21% of patients were symptomatic. The renal capsule was intact in 182 cases (64.08%), the urinary tract in 267 cases (94.01%). Seven patients (2.46%) were metastatic with tumors greater than or equal to pT3a. The most common histological types were the conventional renal cell carcinoma (78.52%) and the papillary renal cell carcinoma (16.55%). 76.06%. of the tumors were low grade. With a median of 66.9 months, 33 patients died (11.61%) . For N0M0 patients, with a median of 59.3 months, three specific deaths (1.19%) and 17 deaths from other causes (6.77%) were observed. The average survival of N0M0 group was 227.2 months. CONCLUSION: The renal cell carcinoma less than or equal to 4cm was a heterogeneous group including locally advanced and aggressive or metastatic tumors. For localized forms, surgical excision provided an effective long-term treatment regardless the histological type or the tumor grade. PMID- 20832035 TI - [Transvaginal repair of genital prolapse using the Prolift technique: a prospective study]. AB - OBJECTIVE: To evaluate the efficacy and to report the follow-up of transvaginal repair of genital prolapse using a tension free vaginal mesh. PATIENTS AND METHODS: Twenty-eight women were treated for genital prolapse with the Prolift technique and followed prospectively. Preoperative prolapse treatment, associated treatment, complications were reported. Postoperatively, efficacy and complications were reported. Patients were examined at one, three, six and 12 months then yearly. Treatment failure defined as Pelvic Organ Prolapse Quantification (POP-Q) stage II or more. RESULTS: The mean age was 68 years. The median follow-up was 12 months. Ten (35%) and 14 (50%) patients had a stage II and III/IV cystocele respectively. Nineteen (67%) patients had stage II/III rectocele. We reported one bladder injury (3.5%) sutured during surgery and one haematoma (3.5%) requiring secondary management. Important buttock pain appeared in two patients (7%) treated with a total mesh on day 1 and 6 weeks after surgery respectively. They were both relieved after cutting one posterior arm of the mesh. De novo stress incontinence appeared in one (3.5%) patient and urgency in two (7%) patients. Mesh exposure occurred in one (3.5%) patient requiring a minimal surgical management. One patient (3.5%) declared dyspareunia. Success was reached in 96.5% patients. CONCLUSION: The transvaginal mesh was a safe and efficient technique to treat genital prolapse. PMID- 20832036 TI - [Input from a specialized nurse consultation in the management of detrusor overactivity treated with intradetrusor injections of botulinum toxin in urology department. Pilot study]. AB - OBJECTIVES: To adapt in daily practice, in a urology department, recommendations for good clinical practice for follow-up of neurological patients with neurogenic detrusor overactivity treated with injections of botulinum toxin type A by involving a referent nurse in neuro-urology. METHOD: A nurse consultation in neuro-urology has been created in June 2007 to intervene at each follow-up consultation at D0, D8, D45, then by phone until reappearance of functional signs to organize a new injection of botulinum toxin. This pilot study evaluated the faisability, the input on clinical workload, and the benefit on relationship between the patient and the caregiver. RESULTS: An improvement of the quality of care has been given to the patient since first contact to follow-up. The number of neurological patient transfers and waiting time between the recurrence of functional signs and new therapeutic care were reduced. The number of medical consultations has been reduced saving time to redistribute on other activities. Knowledge improvement and privileged relationship with the patient and the doctor were reported by the referent nurse. CONCLUSION: The participation of a referent nurse in neuro-urology has improved the quality of care of these patients from first contact to follow-up and has allowed adaptation of the recommendations in the practice of caring of an urology department. PMID- 20832037 TI - [Robot-assisted radical prostatectomy: Perioperative complications, pathological results and functional results during the learning curve]. AB - OBJECTIVE: We report our experiences regarding the peri- and postoperative complications as well as pathological and functional results of robot-assisted radical prostatectomy during the implementation phase and the learning curve of the technique. MATERIAL: All clinical, paraclinical, as well as peri- and postoperative events of the first 102 patients were filed. Postoperative complications were classified according to the Clavien classification. Regarding functional results, continence was defined as the use of 0 pads or one pad for security reasons. Erectile function was classified into absence of spontaneous erections, erections insufficient for sexual intercourse and erections sufficient for sexual intercourse. RESULTS: Median procedure time was 240min, blood-loss 400mL and transfusion rate 2%. Overall, 7.8% of all patients had perioperative complications, 13.7% had minor and 4.9% had mayor post operative complications. The overall positive surgical margin rate was 16.0%. At 12month, 87% of all patients were continent and 21.1% had spontaneous erections and 47.4% had sexual intercourse. CONCLUSION: Patients treated during the implementation phase of robot-assisted radical prostatectomy show rates of peri- and postoperative complications, as well as pathological and functional results comparable to the results of centers of excellence published in the literature. PMID- 20832038 TI - [Are the rules of "evidence based medicine" strictly followed in the field of robot-assisted laparoscopic radical prostatectomy?]. PMID- 20832039 TI - [Local recurrence of renal carcinoma after laparoscopic partial nephrectomy]. AB - We report the case of an early local recurrence after a laparoscopic partial nephrectomy (LPN) for a Furhman grade 1-2 clear cell renal carcinoma (CCRC). CT scan at 6 months revealed a local recurrence. An open total nephrectomy was performed. There were six nodules in the perirenal fat from a grade 3 CCRC. Twenty-six months after the LPN, the patient had a wound recurrence, which was surgically removed. Four months after the wound recurrence, the patient had pulmonary, liver and adrenal glands metastasis. He received an oral treatment with sunitinib. At 4 months after the initiation of the sunitinib, he had a total response. PMID- 20832040 TI - [What can hide a hydrocele?]. AB - The catheter migration after ventriculoperitoneal shunt (VPS) for hydrocephalus is a very rare complication. It is caused by a disconnection or rupture of the catheter. Then, this one can be exteriorized through the anus or the mouth. We report here the case of catheter exteriorization after VPS through the peritoneovaginal duct diagnosed during the hydrocele surgical cure, two years after VPS insertion. The children with VPS require a regular clinical surveillance and a radiographic control of the hydrocephalus valve track, once per year. PMID- 20832041 TI - [Goldman Antopol syndrome associated with bilateral congenital severe factor V deficiency]. AB - Antopol-Goldman lesions are extremely rare. This kind of lesion is a subepithelial pelvic hematoma. This syndrome is certainly of rare occurrence and that is why a differential diagnosis of urothelial cancer in young patients who had problems with clotting must be raised. We reported a case of a 43-year-old haemophiliac with a severe congenital factor V deficit and presenting a bilateral and asynchronous Antopol Goldman syndrome. The diagnosis has been based on CT scans. The subepithelial aetiology bleeding has been shown on selective renal arteriography that allowed to cover a micro-aneurysm through the setting up of a vascular stent and a selective embolization. PMID- 20832042 TI - A paradigm shift for plastic meetings. PMID- 20832043 TI - Dyspareunia associated with paraurethral banding in the transobturator sling. PMID- 20832044 TI - Contemporary perspectives on vaginal pH and lactobacilli. AB - Ever since the pH of the vagina was found to be much more acidic than blood and interstitial fluids, a belief going back more than a century has persisted that the vagina is protected from pathogenic organisms by the high level of hydronium ions present. A corollary of this belief is that the pH of the vagina and antipathogen activity is due to colonizing Lactobacilli. Unfortunately, this dogma lacks empirical research support. The vaginal pH is determined by the interplay between vaginal physiological processes and microbiology. An acidic vaginal pH and Lactobacilli are components of multiple defense mechanisms active in protection against infection in the lower female genital tract. PMID- 20832045 TI - Repeat teen birth: does delivery mode make a difference? AB - OBJECTIVE: We sought to evaluate the association between the rate of repeat adolescent births and mode of delivery. STUDY DESIGN: This was a retrospective cohort study of 899 adolescents delivering in Rhode Island. Repeat birth rates were calculated and compared between adolescents delivering their first baby via cesarean vs vaginally. Fisher's exact test, Wilcoxon rank sum test, and survival analysis methods were utilized. RESULTS: Total repeat birth rate within 2 years was 15.9% with 17.4% for the cesarean cohort and 15.6% for the vaginal birth cohort (relative risk, 1.12; 95% confidence interval, 0.77-1.62). Median duration to repeat birth in the cesarean cohort was 20 months; for the vaginal birth cohort it was 17.6 months. CONCLUSION: Repeat birth within 2 years of index birth for teen mothers whose first birth was a cesarean vs vaginal delivery was not statistically different; the trend in time to next delivery may give us information about when to direct interventions to prevent second pregnancies. PMID- 20832047 TI - Significance of modified Glasgow prognostic score as a useful indicator for prognosis of patients with gastric carcinoma. AB - BACKGROUND: The significance of the Glasgow prognostic score (GPS), an inflammation-based prognostic score, as an indicator of aggressiveness in gastric carcinoma has not been investigated fully. METHODS: Two hundred thirty-two patients with gastric carcinoma were enrolled. Patients who had both an elevated C-reactive protein (>1.0 mg/dL) and hypoalbuminemia (<3.5 g/dL) were allocated a traditional GPS (TGPS) of 2. Patients who had one of these abnormal values were allocated a TGPS of 1, and patients who had neither were allocated a TGPS of 0. RESULTS: There existed a significant difference between the survival of adjacent groups of patients when examined using the TGPS (P = .05 for TGPS 0 vs 1 and P = .006 for TGPS 1 vs 2). Multivariate analysis based on TGPS demonstrated that TGPS (P = .020) and tumor stage (P = .0007) proved to be independent prognostic indicators for worse prognosis. CONCLUSIONS: The preoperative measurement of an inflammation-based prognostic score can demonstrate a strict stratification for the prognosis of patients with gastric carcinoma. PMID- 20832048 TI - Development of an objective evaluation tool to assess technical skill in laparoscopic colorectal surgery: a Delphi methodology. AB - BACKGROUND: Laparoscopic colorectal surgery (LCS) is an advanced procedure for which no objective tools exist to assess technical skill. The aim of this study was to determine expert consensus regarding items required on a rating scale for LCS, using a Delphi technique. METHODS: Experts rated the substeps of LCS from 1 to 5. Responses were returned to the panel until consensus (Cronbach's alpha >= .80) was reached. Substeps that 80% of experts rated as >=4 were included in the final instrument. RESULTS: Initially, alpha values were .81 for sigmoid colectomy, .77 for right (medial-to-lateral) colectomy, and .74 for the lateral to-medial approach. In the second round, alpha values were .83 for medial-to lateral right colectomy and .82 for lateral-to-medial colectomy. CONCLUSIONS: The Delphi method allowed the determination of consensus regarding the essential steps to be included in a tool designed to measure technical competence in LCS. PMID- 20832049 TI - Massive pneumoperitoneum after esophagectomy. AB - A 79-year-old man presented for routine follow-up computed tomography after esophagectomy (reconstruction had been done by intrathoracic esophagogastrostomy) had been performed 18 months earlier for thoracic esophageal cancer (pT2, pN1, M0, stage IIB according to International Union Against Cancer classification). Although he had no symptoms, plain abdominal radiography and computed tomography revealed massive pneumoperitoneum and a small right pneumothorax. On the day after admission, upper gastrointestinal endoscopy showed no ulcers or strictures of the remnant esophagus, gastric tube, and duodenum. Air was released by spontaneous rupture of blebs in the right lung, after which it passed through the esophageal hiatus, which had been opened at the time of esophagectomy, and accumulated in the abdominal cavity. The origin of the gas can be understood from the postoperative anatomic changes, as can the mechanism of air retention in the abdominal cavity. When a patient has a history of operation, accurate understanding of operative procedure and postoperative anatomic change may provide a clue to appropriate diagnosis. PMID- 20832050 TI - The influence of race on the development of acute lung injury in trauma patients. AB - BACKGROUND: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are sequelae of severe trauma. It is unknown if certain races are at greater risk of developing ALI/ARDS, and once established, if there are racial differences in the severity of lung injury or mortality. METHODS: Retrospective cohort study of 4,397 trauma patients (1,831 Caucasians, 871 African-Americans, 886 Hispanics, and 809 Asian/Pacific Islanders) requiring intensive care unit (ICU) admission between 1996 and 2007 at an urban Level I trauma center. RESULTS: African-American patients were most likely to present in shock with penetrating trauma and receive a massive transfusion. The incidence of ALI/ARDS was similar by race (P = .99). Among patients who developed ALI/ARDS, there was no evidence to support a difference in partial pressure of oxygen in arterial blood to fraction of inspired oxygen (Pao(2)/Fio(2)) (P = .33), lung injury score (P = .67), or mortality (P = .78) by race. CONCLUSIONS: Despite differences in baseline characteristics, the incidence of ALI/ARDS, severity of lung injury, and mortality were similar by race. PMID- 20832051 TI - Evolution of locoregional treatment for peritoneal carcinomatosis: single-center experience of 308 procedures of cytoreductive surgery and perioperative intraperitoneal chemotherapy. AB - BACKGROUND: Peritoneal carcinomatosis imposes an enormous clinical burden to the oncologic community. This study reports the patterns of care of the locoregional approach of cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy as a curative procedure for peritoneal carcinomatosis from the experience of a single tertiary center in Australia. METHODS: We performed a review of clinical records from a prospective database of patients who were treated at the St George Hospital Peritoneal Surface Malignancy Program according to a standard protocol. RESULTS: A total of 308 CRS were performed in 249 patients with peritoneal surface malignancy; the mean age was 53 years and 55% were women. Over the years, we expanded the age limit for treatment (P = .03), reduced intensive care unit stays (P = .04), reduced amount of blood transfusion (P = .03), treated patients with a higher peritoneal cancer index (P < .001), achieved higher rates of complete cytoreduction (P = .003), increased use of PIC (P < .001), and improved complication rate (P = .02) and mortality rate (P = .01). The median survival of patients treated over the years also improved (P = .001). CONCLUSIONS: We show the maturity of the treatment of peritoneal carcinomatosis with CRS and perioperative intraperitoneal chemotherapy in our institution after an initial learning curve with expansion of the selection criteria, improved perioperative outcomes, improved surgical results, and long term survival outcomes. PMID- 20832052 TI - Catastrophizing: a predictive factor for postoperative pain. AB - BACKGROUND: postsurgical pain is a major cause of delayed recovery and discharge after surgery. A significant proportion of patients develop chronic postsurgical pain, which affects their quality of life. Cognitive and psychological factors are reported to play a significant role in the severity of reported postsurgical pain. High levels of catastrophizing are associated with a heightened pain experience and appear to contribute to the development of chronic pain. This article describes the concept of pain catastrophizing, its association with postsurgical pain, and its potential role in the management of postsurgical pain and postsurgical quality of life. METHODS: data for this review were identified from MEDLINE, EMBASE, and PsycINFO. Reference lists of selected articles were cross-searched for additional literature. RESULTS: High catastrophizing levels were found to be associated with increased pain severity, increased incidence of development of chronic pain, and poorer quality of life after surgery. There was no consensus on the relation between catastrophizing and analgesia consumption. CONCLUSIONS: identifying and reducing catastrophizing levels can help to optimize pain management in surgical patients. PMID- 20832053 TI - Surgical treatment of hydatid disease of the liver: 25 years of experience. AB - BACKGROUND: The aim of this study was to evaluate the results of conservative and radical treatment of liver hydatid disease. METHODS: Records of patients who underwent surgery for liver hydatid disease between 1980 and 2005 were reviewed. Outcomes measured were operative morbidity and mortality, hospital stay, and recurrence. RESULTS: Two hundred fourteen patients underwent conservative treatment (external drainage, marsupialization, omentoplasty), and 240 had radical surgery (hepatic resection, cystopericystectomy). Operative morbidity was 79.9% and 16.2% for conservative and radical procedures, respectively (P < .001). Operative mortality was 6.5% for conservative procedures and 9.2% for radical procedures (P = .3). The recurrence rate was 30.4% in patients having conservative surgery and 1.2% in patients undergoing radical surgery (P < .001). No recurrences occurred in patients with clear cysts after conservative surgery. CONCLUSIONS: Cystopericystectomy was a safe and effective procedure that achieved excellent immediate and long-term results. Hepatic resection should be considered only in exceptional cases, because it involves the unnecessary sacrifice of healthy hepatic parenchyma. Conservative surgery and alternative procedures should be restricted to the treatment of clear cysts and to patients who cannot undergo radical surgery. PMID- 20832054 TI - Recurrent skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus requiring operative debridement. AB - BACKGROUND: The aim of this study was to examine clinical factors associated with the recurrence of community-onset skin and soft tissue infections caused by methicillin-resistant Staphylococcus aureus. METHODS: An observational case comparison study based on a retrospective review of medical records was conducted in a public health system. All patients with community-onset skin and soft tissue infections caused by methicillin-resistant S aureus who underwent operative debridement from January 1999 to December 2003 were included. The outcome of interest was recurrence within 1 year. RESULTS: Two hundred fifty-three patients met the criteria for inclusion. Fifty-three (21%) patients returned with recurrent episodes. These patients were compared with 200 patients (79%) who did not develop recurrence. On multivariate analysis, factors independently predictive of recurrence were medical history of abscess requiring surgical debridement within the previous year (adjusted odds ratio, 2.6; 95% confidence interval, 1.4-5.0; P = .002) and obesity (adjusted odds ratio, 3.4; 95% confidence interval, 1.4-8.8; P = .008). CONCLUSIONS: Patients with obesity or histories of methicillin-resistant S aureus infection are at significantly increased risk for recurrent soft tissue infection. PMID- 20832055 TI - Association between the oxytocin receptor gene and amygdalar volume in healthy adults. AB - BACKGROUND: Recent studies have suggested that oxytocin affects social cognition and behavior mediated by the oxytocin receptor (OXTR) in amygdala in humans as well as in experimental animals. Genetic studies have revealed a link between the OXTR gene and the susceptibility to autism spectrum disorders (ASD), especially in the social dysfunctional feature of ASD. METHODS: We examined the relationship between amygdala volume measured with manual tracing methodology and seven single nucleotide polymorphisms and one haplotype-block in OXTR, which were previously reported to be associated with ASD, in 208 socially intact Japanese adults with no neuropsychiatric history or current diagnosis. RESULTS: The rs2254298A allele of OXTR was significantly associated with larger bilateral amygdala volume. The rs2254298A allele effect on amygdala volume varied in proportion to the dose of this allele. The larger the number of rs2254298A alleles an individual had, the larger their amygdala volume. Such an association was not observed with hippocampal volume or with global brain volumes, including whole gray, white matter, and cerebrospinal-fluid space. Furthermore, two three-single nucleotide polymorphism haplotypes, including rs2254298G allele, showed significant associations with the smaller bilateral amygdala volume. CONCLUSIONS: The present results suggest that OXTR might be associated with the susceptibility to ASD, especially in its aspects of social interaction and communication mediated by a modulation of amygdala development, one of the most distributed brain regions with high density of OXTR. Furthermore, amygdala volume measured with magnetic resonance imaging could be a useful intermediate phenotype to uncover the complex link between OXTR and social dysfunction in ASD. PMID- 20832056 TI - Genome-wide association study of schizophrenia in a Japanese population. AB - BACKGROUND: Genome-wide association studies have detected a small number of weak but strongly supported schizophrenia risk alleles. Moreover, a substantial polygenic component to the disorder consisting of a large number of such alleles has been reported by the International Schizophrenia Consortium. METHOD: We report a Japanese genome-wide association study of schizophrenia comprising 575 cases and 564 controls. We attempted to replicate 97 markers, representing a nonredundant panel of markers derived mainly from the top 150 findings, in up to three data sets totaling 1990 cases and 5389 controls. We then attempted to replicate the observation of a polygenic component to the disorder in the Japanese and to determine whether this overlaps that seen in UK populations. RESULTS: Single-locus analysis did not reveal genome-wide support for any locus in the genome-wide association study sample (best p = 6.2 * 10(-6)) or in the complete data set in which the best supported locus was SULT6B1 (rs11895771: p = 3.7 * 10(-5) in the meta-analysis). Of loci previously supported by genome-wide association studies, we obtained in the Japanese support for NOTCH4 (rs2071287: p(meta) = 5.1 * 10(-5)). Using the approach reported by the International Schizophrenia Consortium, we replicated the observation of a polygenic component to schizophrenia within the Japanese population (p = .005). Our trans Japan-UK analysis of schizophrenia also revealed a significant correlation (best p = 7.0 * 10(-5)) in the polygenic component across populations. CONCLUSIONS: These results indicate a shared polygenic risk of schizophrenia between Japanese and Caucasian samples, although we did not detect unequivocal evidence for a novel susceptibility gene for schizophrenia. PMID- 20832058 TI - Effect of magnesium chloride (2:1 electrolyte) on the aqueous solution behavior of some saccharides over the temperature range of 288.15-318.15 K: a volumetric approach. AB - Infinite-dilution standard partial molar volumes, V(2)(0), for various mono-, di , and trisaccharides, and their derivatives (methyl glycosides) at molalities ranging from 0.04 to 0.12 mol kg(-1) in aqueous solutions of magnesium chloride of 0.5, 1.0, 2.0, and 3.0 mol kg(-1), have been evaluated over a range of temperatures from 288.15 to 318.15 K by density measurements employing a vibrating-tube densimeter. These data have been utilized to determine the corresponding standard partial molar volumes of transfer, Delta(t)V(2)(0), of saccharides and methyl glycosides from water to aqueous magnesium chloride solutions. The Delta(t)V(2)(0) values have been found to be positive, and their magnitudes increase with an increasing concentration of magnesium chloride in all cases. Partial molar expansion coefficients, (?V(2)(0)/?T)(P) and second derivatives thereof, (?(2)V(2)(0)/?T(2))(P) have been estimated. The magnitude of V(2)(0) values increases with an increase in temperature, indicating that hydration effects in solutions are strongly sensitive to temperature. Pair and higher order volumetric interaction coefficients (V(AB), V(ABB)) have also been obtained from Delta(t)V(2)(0) values by using the McMillan-Mayer theory. The various parameters have been discussed in terms of the solute (saccharide or methyl glycoside)-co-solute (magnesium chloride) interactions and are thus used to understand the mixing effects due to these interactions. These results have been compared with those earlier reported in the presence of electrolytes. An attempt is made to interpret the volumetric properties data in terms of the stereochemistry of the solutes. PMID- 20832057 TI - Attention-deficit/hyperactivity phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) may result from delayed establishment of corticolimbic circuitry or perturbed dopamine (DA) neurotransmission. Despite the widespread use of stimulants to treat ADHD, little is known regarding their long-term effects on neurotransmitter levels and metabolism. Cyclin-dependent kinase 5 (Cdk5) regulates DA signaling through control of synthesis, postsynaptic responses, and vesicle release. Mice lacking the Cdk5-activating cofactor p35 are deficient in cortical lamination, suggesting altered motor/reward circuitry. METHODS: We employed mice lacking p35 to study the effect of altered circuitry in vivo. Positron emission tomography measured glucose metabolism in the cerebral cortex using 2-deoxy-2-[18F] fluoro-d-glucose as the radiotracer. Retrograde dye tracing and tyrosine hydroxylase immunostains assessed the effect of p35 knockout on the medial prefrontal cortex (PFC), especially in relation to mesolimbic circuit formation. We defined the influence of Cdk5/p35 activity on catecholaminergic neurotransmission and motor activity via examination of locomotor responses to psychostimulants, monoamine neurotransmitter levels, and DA signal transduction. RESULTS: Here, we report that mice deficient in p35 display increased glucose uptake in the cerebral cortex, basal hyperactivity, and paradoxical decreased locomotion in response to chronic injection of cocaine or methylphenidate. Knockout mice also exhibited an increased susceptibility to changes in PFC neurotransmitter content after chronic methylphenidate exposure and altered basal DAergic activity in acute striatal and PFC slices. CONCLUSIONS: Our findings suggest that dysregulation of Cdk5/p35 activity during development may contribute to ADHD pathology, as indicated by the behavioral phenotype, improperly established mesolimbic circuitry, and aberrations in striatal and PFC catecholaminergic signaling in p35 knockout mice. PMID- 20832059 TI - Vitamin A deficiency alters splenic dendritic cell subsets and increases CD8(+)Gr 1(+) memory T lymphocytes in C57BL/6J mice. AB - Vitamin A-deficient populations have impaired T cell-dependent antibody responses. Dendritic cells (DCs) are the most proficient antigen-presenting cells to naive T cells. In the mouse, CD11b(+) myeloid DCs stimulate T helper (Th) 2 antibody immune responses, while CD8alpha(+) lymphoid DCs stimulate Th1 cell mediated immune responses. Therefore, we hypothesized that vitamin A-deficient animals would have decreased numbers of myeloid DCs and unaffected numbers of lymphoid DCs. We performed dietary depletion of vitamin A in C57BL/6J male and female mice and used multicolor flow cytometry to quantify immune cell populations of the spleen, with particular focus on DC subpopulations. We show that vitamin A-depleted animals have increased polymorphonuclear neutrophils, lymphoid DCs, and memory CD8(+) T cells and decreased CD4(+) T lymphocytes. Therefore, vitamin A deficiency alters splenic DC subpopulations, which may contribute to skewed immune responses of vitamin A-deficient populations. PMID- 20832060 TI - Modeling human performance in statistical word segmentation. AB - The ability to discover groupings in continuous stimuli on the basis of distributional information is present across species and across perceptual modalities. We investigate the nature of the computations underlying this ability using statistical word segmentation experiments in which we vary the length of sentences, the amount of exposure, and the number of words in the languages being learned. Although the results are intuitive from the perspective of a language learner (longer sentences, less training, and a larger language all make learning more difficult), standard computational proposals fail to capture several of these results. We describe how probabilistic models of segmentation can be modified to take into account some notion of memory or resource limitations in order to provide a closer match to human performance. PMID- 20832061 TI - Dorsal cortical comminution as a predictor of redisplacement of distal radius fractures in children. AB - BACKGROUND: The purpose of this study was to evaluate the various factors, which could contribute towards redisplacement of distal radius fractures, including comminution of the dorsal cortex of the distal radius, treated in our department. METHODS: In this retrospective study, we evaluated the risk of redisplacement of distal radius fractures in our department and also looked at the probable factors predisposing to this risk. A total of 134 fractures(129 children) were included in the study after exclusions. The variables that were assessed as possible causes of redisplacement were age, gender, fracture pattern (apex), degree of initial displacement,presence/absence of comminution, presence/absence of ulnar fracture, grade of surgeon, quality of initial reduction and Cast index. RESULTS: After excluding the fractures without a known outcome, 124 fractures (120 children) were available for analysis. The average age of children was 10.6 years (range 2-16 years) with more boys (89)than girls (31). Redisplacement after an initial reduction occurred in 30 children (24%). Six of these children(4.8% of the entire study group) required further intervention. The factors associated with an increased risk of redisplacement were complete initial displacement of fracture (p = 0.02),dorsal bayonet fracture pattern(p = 0.007), presence of comminution (p = 0.001) and the quality of the initial reduction (p = 0.002).Forward stepwise logistic regression analysis revealed comminution at the fracture site to be the most significant factor associated with redisplacement, increasing the odds of redisplacement by 5.82 (95%confidence interval (CI): 2.08 16.22, p = 0.001). There seemed to be a trend towards a reduced risk of redisplacement when K-wiring was done in the presence of comminution (p = 0.12). CONCLUSION: The presence of dorsal cortical comminution at the fracture site on initial radiographs should alert the treating surgeon to a significantly higher risk of redisplacement and supplemental K-wiring should be considered in this situation. PMID- 20832062 TI - Atorvastatin inhibits oxidative stress via adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients. AB - BACKGROUND: Interventional treatment with atorvastatin lowered the circulating levels of the catalytic core of NADPH oxidase, namely sgp91(phox), but the underlying mechanism is still undefined. AIM: To test the hypothesis that the inhibitory effect on oxidative stress, induced by Atorvastatin, could be mediated by adiponectin. METHODS AND RESULTS: We compared 36 patients with polygenic hypercholesterolemia and 18 healthy subjects. Patients were randomized to either a low-fat diet (Group A) or low-fat diet plus atorvastatin 10 mg/day (Group B) for 30 days. Lower serum adiponectin levels and higher lipid profile, gp91(phox) serum levels, urinary isoprostanes, platelet oxygen free radicals, characterized patients. After 30 days of treatment, group B showed higher levels of adiponectin which is inversely correlated to reduced levels of sgp91(phox), urinary isoprostanes and platelet oxygen free radicals (p<0.001). In in vitro model, adiponectin dosages between 5 and 10 ng/ml inhibited p47(phox) translocation to gp91(phox) and soluble gp91(phox) cleavage indicating its ability in inhibiting the assembly of NADPH oxidase subunits on cell membrane and in turn the enzymatic system activation. CONCLUSION: This study provides the first evidence that in patients higher APN serum levels are associated with gp91(phox) down-regulation. APN-mediated gp91(phox) reduction could be one of the mechanisms involved in atorvastatin's antioxidant effect. PMID- 20832063 TI - Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. AB - BACKGROUND: Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date. METHODS AND RESULTS: We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 +/- 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 +/- 1.11 mmol/L for those with 18 or more (P for trend<0.0001). The association with TC levels was slightly stronger when the weighted GRS that weighted the magnitude of allelic effects was used. CONCLUSION: A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels. PMID- 20832064 TI - Association of CD40 ligand levels in the culprit coronary arteries with subsequent prognosis of acute myocardial infarction. AB - OBJECTIVE: CD40 ligand (CD40L) plays a crucial role in atherogenesis and plaque destabilization. The purpose of this study was to clarify the association of CD40L levels in the culprit coronary arteries (CA) with the subsequent cardiovascular events in patients with acute myocardial infarction (AMI). METHODS: We enrolled 68 patients with AMI whose CA were treated using thrombectomy devices. Blood samples were collected from the peripheral veins (PV), the ascending aortae (AO) and CA. RESULTS: CD40L levels in the CA were significantly greater than those in the PV and AO. Statistical analyses revealed that CD40L levels in CA correlated positively with the corrected TIMI frame counts and maximal serum creatine kinase-MB in throughout clinical course, and inversely with myocardial blush grade and left ventricular ejection fraction 6 months after AMI. In logistic regression analyses, the group with high CD40L levels in CA was associated with an 8.58-fold increase in the odds of a cardiovascular event rate compared with the group with low CD40L levels. CONCLUSIONS: In patients with AMI, enhanced CD40L levels in CA might affect myocardial perfusion, myocardial damage, and subsequent cardiovascular events, and could be a predictive marker for the prognosis of AMI. PMID- 20832065 TI - Relation between retinol, retinol-binding protein 4, transthyretin and carotid intima media thickness. AB - OBJECTIVE: Retinol is transported in a complex with retinol-binding protein 4 (RBP4) and transthyretin (TTR) in the circulation. While retinol is associated with various cardiovascular risk factors, the relation between retinol, RBP4, TTR and carotid intima media thickness (IMT) has not been analysed yet. METHODS: Retinol, RBP4 and TTR were measured in 96 individuals and their relation to mean and maximal IMT was determined. RESULTS: Mean IMT correlated with RBP4 (r=0.335, p<0.001), retinol (r=-0.241, p=0.043), RBP/TTR ratio (r=0.254, p=0.025) and retinol/RBP4 ratio (r=-0.549, p<0.001). Adjustment for age, sex, BMI, blood pressure, HDL/total cholesterol ratio, triglyceride, diabetes and smoking revealed that the retinol/RBP4 ratio was strongly and independently associated with mean IMT. Similar results were found for maximal IMT, which included the measurement of plaques. CONCLUSION: The data support that the transport complex of vitamin A is associated with the IMT, an established parameter of atherosclerosis. Changes in RBP4 saturation with retinol may link renal dysfunction and insulin resistance to atherosclerosis. PMID- 20832066 TI - Chronic kidney disease is associated with increased carotid artery stiffness without morphological changes in participants of health check-up programs. AB - BACKGROUND AND METHODS: Patients with chronic kidney disease (CKD) show a much higher risk of cardiovascular disease. However, the mechanisms underlying this association and the impact of CKD on behaviors of the vascular walls have not been fully clarified. Using ultrasonography, this study investigated associations of CKD (estimated glomerular filtration rate <60 ml/min/1.73 m(2) and/or presence of proteinuria) with both elasticity (stiffness beta index) of the carotid artery and intimal atherosclerotic changes in participants of health check-up programs (n=3406, 63% men; mean age, 58.8 years). RESULTS: Stiffness beta was significantly higher in CKD subjects (7.49 +/- 0.14) than in non-CKD subjects (6.87 +/- 0.05, P<0.001). This significant difference was maintained in a multiple adjusted model including conventional risk factors such as hypertension, diabetes mellitus, dyslipidemia, smoking and obesity (7.20 +/- 0.14 vs. 6.91 +/- 0.05, P=0.043). No significant differences in intima-media complex thickness or plaque score were seen between CKD and non-CKD subjects. CONCLUSION: In participants of health check-up programs, CKD was associated with increased carotid arterial stiffness without intimal disease, independently of conventional risk factors. These findings indicate that CKD may predispose the carotid arteries to earlier development of arteriosclerosis, characterized by increased arterial stiffness. PMID- 20832067 TI - Relationship between HDL3 subclasses and waist circumferences on the prevalence of metabolic syndrome: KMSRI-Seoul Study. AB - OBJECTIVE: Limited information is available on the association of HDL subtypes and the risk of metabolic syndrome (MetSyn). The objective of the present study was to investigate the association of HDL subspecies with the prevalence of MetSyn in new outpatients. METHODS: Five hundred forty-one new outpatients (366 males and 175 females) were enrolled in two hospitals participating in the KMSRI Seoul Study. The new criteria for the Korean MetSyn based on the 2005 KHANES were used. Medical questionnaires, anthropometric measurements, 3-day recall dietary assessments, and blood biomarker analyses were performed. Unconditional logistic regression models were used to estimate crude and odds ratios (ORs) and 95% confidence intervals (CIs) with multivariate adjustments. The proportions of HDL subtypes were measured after subtypes were identified by 4-30% gradient gel electrophoresis. RESULTS: Of the subjects, 50.8% were classified as MetSyn; blood pressure (BP) and fasting blood sugar (FBS) among the five criteria did not differ by gender. Increasing the HDL(2b) subtype significantly reduced the risk of MetSyn in males and females. The association of small size HDL(3b) with the risk of MetSyn was stronger in females than in males: adjusted ORs (95% CIs) for the 3rd tertile of HDL(3b) compared to the 1st tertile were 3.79 (CI, 2.00-7.18) in males and 11.2 (CI, 2.1-59.6) in females. However, a decreased waist circumference (WC), BP, and triglycerides (TG) were observed with increased large HDL particles in males. CONCLUSIONS: Small-sized HDL was associated with increased MetSyn risk factors and closely related to WC, BP, TG, and HOMA-IR, particularly in males. PMID- 20832068 TI - Calcitonin gene-related peptide inhibits angiotensin II-induced endothelial progenitor cells senescence through up-regulation of klotho expression. AB - BACKGROUND: It has been shown that angiotensin II (Ang II) is able to accelerate endothelial progenitor cells (EPCs) senescence through induction of oxidative stress. Calcitonin gene-related peptide (CGRP), a major neurotransmitter of the capsaicin-sensitive sensory nerves, protects endothelial function. Whether CGRP protects against EPCs senescence is unknown. METHODS AND RESULTS: In cord-derived EPCs, the effects of CGRP on Ang II-induced cell senescence were evaluated by exogenous application of CGRP and rutaecarpine (to stimulate the endogenous CGRP production) or by over-expression of CGRP. The anti-senescence mechanisms of CGRP on EPCs were investigated either by applying CGRP antagonist or by silence of klotho, an anti-aging protein. The results showed that both CGRP and klotho mRNA expression were reduced in Ang II-induced senescent EPCs. Exogenous application of CGRP inhibited Ang II-induced EPCs senescence by down-regulating the expression of NADPH oxidase and reactive oxygen species production. Similarly, rutaecarpine or CGRP I over-expression also inhibited Ang II-induced EPCs senescence. The effects of CGRP and rutaecarpine were reversed by CGRP(8-37), a select antagonist of CGRP receptor and capsazepine, a selective antagonist of transient receptor potential vanilloid 1, respectively. Furthermore, gene silence of klotho markedly attenuated the anti-senescence effect of CGRP on EPCs. CONCLUSIONS: The results suggest that CGRP can counteract Ang II-induced EPCs senescence through down-regulating the expression of NADPH oxidase and reactive oxygen species production and increasing the production of klotho. PMID- 20832069 TI - Development of a multi-residue analytical method, based on liquid chromatography tandem mass spectrometry, for the simultaneous determination of 46 micro contaminants in aqueous samples. AB - A multi-residue analytical method based on high-performance liquid chromatographic separation, electrospray ionization with tandem mass spectrometric detection (HPLC/MS-MS) was developed for the simultaneous analysis of 46 basic, neutral and acidic compounds covering a wide range of polarity (logK(OW)<0-5.9). The compound list included selected iodinated contrast media, analgesics, anti-inflammatories, stimulants, beta-blockers, antibiotics, lipid regulators, anti-histamines, psychiatric drugs, herbicides, corrosion inhibitors and the gastric acid regulator pantoprazole. The main feature of the presented method was a simultaneous solid phase extraction (SPE) of all analytes followed by simultaneous separation and detection by HPLC/MS-MS with electrospray ionization in both positive and negative polarization within the same chromatogram. Optimization of electrospray drying gas temperature resulted in using a temperature gradient on the ion source. Six different polymeric sorbents for SPE were compared with respect to recoveries, taking into account the specific surface of each sorbent. Method quantitation limits (MQL) in surface and seawater ranged from 1.2 to 28 ng/L, in wastewater from 5.0 to 160 ng/L, respectively. In order to demonstrate the applicability of the method, river water, treated wastewater and seawater were analyzed. PMID- 20832070 TI - Ultra-high-performance liquid chromatography fingerprinting method for chemical screening of metabolites in cultivation broth. AB - A fingerprinting method for chemical screening of microbial metabolites, potential antibiotics, in spent cultivation broths is described. The method is based on high-throughput ultra-high-performance liquid chromatography (UHPLC) separation with UV detection (photodiode array detector). Thirteen antibiotic standards and four cultivation broths were used for the method development. The comparison of ten liquid-liquid and solid phase extraction protocols for sample clean-up and pre-concentration revealed that Oasis HLB C18 sorbent gives the best recoveries. The Acquity BEH C18 chromatographic column was chosen for the samples separation with respect to its universality, selectivity, efficiency and robustness. The method is presented by two 3D fingerprints for every sample that was obtained under different, acidic and alkaline, UHPLC conditions. The acidic mobile phase consisted of 0.5% phosphoric acid with methanol and the alkaline mobile phase of 1mM ammonium formate, pH 9 with acetonitrile. Each pair of 3D fingerprints includes the following physico-chemical information: polarity (retention time), presence and characterization of chromophores (UV spectra), compound concentration (detector response), and acid-base properties (influence of different pH of the aqueous parts of mobile phases on retention times). The sample extraction and method validation were assessed with relative standard deviation (RSD) of 0.5, 5.0 and 20.0% for retention times, peak areas and minor compound peak areas, respectively. PMID- 20832071 TI - A simple hollow fiber renewal liquid membrane extraction method for analysis of sulfonamides in honey samples with determination by liquid chromatography-tandem mass spectrometry. AB - A sensitive and precise analysis using hollow fiber renewal liquid membrane (HFRLM) extraction followed by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) is described for determination of five sulfonamides in honey samples. In this procedure, the organic solvent introduced directly into the sample matrix extracts the sulfonamides and carries them over the polypropylene porous membrane. An organic solvent is immobilized inside the polypropylene porous membrane, leading to a homogeneous phase. The stripping phase at higher pH in the lumen of the membrane promotes the ionization of the target compounds releasing them to this phase. The most important parameters affecting the extraction efficiency were optimized by multivariable designs (pH and sample mass, pH and buffer for stripping phase, extraction temperature and time, type and volume of extractor solvent and use of salt to saturate the sample). Detection limits in the range of 5.1-27.4 MUg kg(-1) and linearity coefficient of correlation higher than 0.987 were obtained for the target analytes. The results obtained for the proposed method show that HFRLM-LC-MS/MS can be used for determination of the five sulfonamides studied in honey samples with excellent precision, accuracy, practicality and short analysis time. PMID- 20832072 TI - Evaluation of tea tree oil quality and ascaridole: a deep study by means of chiral and multi heart-cuts multidimensional gas chromatography system coupled to mass spectrometry detection. AB - The natural-like assessment of essential oils is a demanding task due to the growing trend toward adulterations. Usually chiral chromatography was used for this purpose due to the capability of assessing stereospecificity which is directly related to the enzymatic pathways of each plant species. On the other hand, the quality of an essential oil involves also the evaluation of its oxidative state, mainly connected with the age and storage conditions. In fact, some modifications in the chemical profile of the oil can occur if not properly preserved. Alterations of the components due to oxidative reactions lead to the formation of peroxides, endoperoxides and epoxides, such as ascaridole and 1,2,4 trihydroxymenthane, usually present in very low amount, formed by the oxidation of terpinen-4-ol and alpha-terpinene, respectively. Therefore, in the present research, the quality of Australian Tea Tree oil (Melaleuca alternifolia (Maiden & Betche) Cheel, Myrtaceae) was investigated by means of a multi heart-cut multidimensional gas chromatographic system coupled to a mass spectrometer detector and by conventional enantio-GC. The MDGC system allowed the complete separation of the compounds of interest transferred from the first column to a second dimension based on a different separation mechanism. The MS detector at the end of the second column provided the identification of the peaks with high similarity values because of their high purities after the multidimensional separation. Method validation was carried out, in order to use this procedure for routine application, monitoring the repeatability of 1D retention times and 2D peak areas, LoD and LoQ. Finally, enantiomeric ratios for chiral compounds were established to support quality data obtained. PMID- 20832073 TI - Effective liquid-liquid extraction method for analysis of pyrethroid and phenylpyrazole pesticides in emulsion-prone surface water samples. AB - The distribution of pyrethroid and phenylpyrazole pesticides in the water environment has raised public concerns because of their potential risks to ecosystem and human health. However, co-extraction of emulsifier type compounds (by liquid-liquid extraction, LLE) present in environmental samples can present a challenge for quantifying typically low concentrations of pesticides. Several methods were evaluated for breaking emulsions in problematic environmental surface water samples extracted by LLE using methylene chloride. Target pesticides included 11 typical pyrethroid and phenylpyrazole pesticides commonly used in agricultural and landscape insect pest control. The most effective method was selected for validation in fortification studies with GC-ECD analysis. The average recoveries of spiked pyrethroid and phenylpyrazole pesticides were 88.2 123.4% for water samples with moderate emulsions and 93.0-117.4% for water samples with severe emulsions. Recoveries of the pesticides ranged 81.0-126.4% (water samples with moderate emulsions) and 95.9-110.6% (water samples with severe emulsions) for lowest fortification level (5-20 ngL(-1)), 88.2-123.4% (water samples with moderate emulsions) and 93.0-117.4% (water samples with severe emulsions) for middle fortification level (10-40 ngL(-1)), and 90.2-119.9% (water samples with moderate emulsions) and 91.2-105.9% (water samples with severe emulsions) for highest fortification level (50-200 ngL(-1)). Relative standard deviations of pesticide recoveries were usually < 10%. Results indicate that this method is a robust and reproducible option for LLE of pyrethroid and phenylpyrazole pesticides from emulsion-prone surface water samples. PMID- 20832074 TI - Diffuse sorption modeling: Ionic adsorption on silica. AB - The Poisson-Boltzmann equation was applied to simulation of published data on adsorption of bivalent metal ions on silica. The surface charge of silica was approximated with the basic Stern model (without coordinate binding of sodium ions). It was found that the adsorption of alkaline-earth metal ions is closely consistent with the Poisson-Boltzmann equation; i.e., it may be completely explained by electrostatic attraction in the diffuse layer. Adsorption in the diffuse layer was also found important for some heavy metals, such as cadmium. PMID- 20832075 TI - Hydrodynamic properties of rigid fractal aggregates of arbitrary morphology. AB - The hydrodynamic properties of rigid fractal aggregates are key ingredients in understanding the governing mechanism of their motion and the properties of their suspensions. In the present work we outline explicit equations for the estimation of the complete set of hydrodynamic properties of arbitrary shaped aggregates made of uniform sized spherical primary particles. The rigid body motion equations are coupled to Stokesian dynamics model to derive hydrodynamic rigid body properties. A wide library of clusters consisting of fractal aggregates of different morphologies (d(f)=1.8-3.0) and spheroidal clusters of different axes ratios with broad range of number of constitutive spheres (N(sphere)=10-1000) was used. Using the developed hydrodynamic rigid body properties' equations quantities such as the hydrodynamic radii of translational (R(H)) and rotational (R(omega)) motion, and all hydrodynamic information for each cluster, contained in its grand resistance matrix, are found. Furthermore, the relations between different hydrodynamic properties of average clusters and their morphology are investigated. In the effort to introduce a simplified model that accurately reproduces the complex hydrodynamic behavior of a fractal cluster, two approaches are discussed, namely, an equivalent sphere model and an equivalent ellipsoid model. The predicted hydrodynamic properties from both approaches, which can be computed exactly, closely match those of the clusters, for all cluster masses and morphologies, with the equivalent ellipsoid model being more effective whenever the cluster anisotropy is crucial. Therefore, this simplified approach provides an effective tool to predict the behavior of any cluster with complex structure. PMID- 20832076 TI - MnO(x)/TiO(2) composite nanoxides synthesized by deposition-precipitation method as a superior catalyst for NO oxidation. AB - A series of MnO(x)/TiO(2) composite nanoxides were prepared by deposition precipitation (DP) method, and the sample with the Mn/Ti ratio of 0.3 showed a superior activity for NO catalytic oxidation to NO(2). The maximum NO conversion over MnO(x)(0.3)/TiO(2)(DP) could reach 89% at 250 degrees C with a GHSV of 25,000h(-1), which was much higher than that over the catalyst prepared by conventional wet-impregnation (WI) method (69% at 330 degrees C). Characterization results including XRD, HRTEM, FTIR, XPS, H(2)-TPR, NO-TPD and Nitrogen adsorption-desorption implied that the higher activity of MnO(x)(0.3)/TiO(2)(DP) could be attributed to the enrichment of well-dispersed MnO(x) on the surface and the abundance of Mn(3+) species. Furthermore, DRIFT investigations and long-time running test indicated that NO(2) came from the decomposition of adsorbed nitrogen-containing species. PMID- 20832077 TI - Evaluation of alternative comonomers for the production of ASE and HASE thickeners. AB - Methyl methacrylate (MMA), n-butyl acrylate (BA) and 2-ethyl hexyl acrylate (EHA) were evaluated as alternatives to ethyl acrylate (EA) in the composition of methacrylic acid (MAA)-EA copolymers for the production of hydrophobically modified alkali soluble emulsions (HASE). In addition, the impact of Sipomer BEM and PLEX 6954-0 as associative monomers (AM) on the properties of the final HASE products was evaluated. EHA gave reasonable results as a replacement comonomer for alkali soluble emulsion (ASE) synthesis and applications. However, it was not possible to obtain transparent thickened solutions without provoking significant flocculation losses during the synthesis of HASE products that incorporated EHA. MAA-BA and MAA-MMA formulations produced ASE and HASE copolymers with 0.5mol.% AM, which presented high transparency and viscosity levels. When comparing the two AM, it was found that the longer the hydrophobic tail, the higher the apparent viscosity, but the lower the transparency of the final product. PMID- 20832078 TI - Insights into H(4)SiO(4) surface chemistry on ferrihydrite suspensions from ATR IR, Diffuse Layer Modeling and the adsorption enhancing effects of carbonate. AB - Silicic acid (H(4)SiO(4)) adsorbs at the ferrihydrite-water interface as monomeric or oligomeric surface silicate complexes.ATR-IR spectra were used to determine the proportions of monomeric and oligomeric surface silicate as a function of pH and Si surface concentrations (Gamma(Si)) for H(4)SiO(4) in ferrihydrite suspensions.At each pH the proportion of adsorbed silicate present as monomers decreased as Gamma(Si) increased while at a given Gamma(Si) the proportion of adsorbed silicate present as monomers was higher at higher pH. ATR IR spectra for ferrihydrite suspensions in combination with the adsorption isotherm data were used to calibrate the Diffuse Layer Model (DLM) to describe H(4)SiO(4) adsorption as monomers and oligomers on ferrihydrite surface sites (=FeOH). Using a set of reactions that were consistent with the ATR-IR spectra the DLM could accurately describe the H(4)SiO(4) adsorption isotherms, the distribution of surface monomeric and oligomeric silicates, and the decrease in surface potential with Gamma(Si).The reactions included the formation of monomeric complexes (=FeH((3-n))SiO(4)((-n))) and trimeric silicate complexes formed between two surface sites(=Fe(2)H((6-n))Si(3)O(10)((-n))). This oligomer stoichiometry is consistent with previous studies suggesting the surface silicate oligomer is formed by a solution H(4)SiO(4) bridging two adjacent adsorbed monomers to form a linear trimer. This study also showed that carbonate can enhance H(4)SiO(4) adsorption between pH 9 and 11. The data were consistent with formation of an outer-sphere complex between a solution H(3)SiO(4)(-) and a protonated adsorbed carbonate species which is analogous to the mechanism by which carbonate enhances the goethite adsorption of sulfate. PMID- 20832079 TI - Cu-doped TiO(2) nanoparticles for photocatalytic disinfection of bacteria under visible light. AB - Two percent Cu-doped TiO(2) nanoparticles were prepared by a modified ammonia evaporation-induced synthetic method, calcined at 450 degrees C, and characterized by powder X-ray diffraction, energy dispersive X-ray analysis, ESR spectroscopy, scanning electron microscopy, UV-visible diffuse reflectance spectrum, photoluminescence spectroscopy, and electrochemical impedance spectroscopy. Doping shifts the optical absorption edge to the visible region but increases the charge-transfer resistance and decreases the capacitance. Under visible light, the composite nanoparticles very efficiently catalyze the disinfection of Escherichia coli. The prepared oxide is selective in photocatalysis; under UV light, its photocatalytic activity to degrade sunset yellow, rhodamine B, and methylene blue dyes is less than that of the undoped one. PMID- 20832080 TI - Applying zeta potential measurements to characterize the adsorption on montmorillonite of organic cations as monomers, micelles, or polymers. AB - A systematic study was carried out to characterize the adsorption of organic cations as monomers, micelles, or polymers on montmorillonite by monitoring zeta potential (xi) as a function of cation loading on the clay. In general, the clay's xi became less negative as cation loading increased. A fairly good linear correlation between adsorption of organic cations on the clay, up to the cation exchange capacity (CEC) of the clay, and xi potential of the composites was fitted. However, when the adsorption of the larger cation exceeded the CEC, a nonlinear increase in xi was measured. The degree of this increase corresponds to the cation size and affinity to the clay (in the order surfactant1000 MUg/L for paracetamol. Anaerobic treatment was only suitable to remove the majority of paracetamol (>90%). Metoprolol was partly removed (67%) during aerobic treatment. Deconjugation could have affected the removal efficiency of ibuprofen as concentrations even increased during anaerobic treatment and only after the anammox treatment 77% of ibuprofen was removed. The presence of persistent micro pollutants (diclofenac, carbamazepine and cetirizine), which are not susceptible for biodegradation, makes the application of advanced physical and chemical treatment unavoidable. PMID- 20832098 TI - Enhanced nitrogen removal from pharmaceutical wastewater using SBA-ANAMMOX process. AB - Efficient biological nitrogen removal from pharmaceutical wastewater has been focused recently. The present study dealt with the treatment of colistin sulfate and kitasamycin manufacturing wastewater through anaerobic ammonium oxidation (ANAMMOX). The biotoxicity assay on luminescent bacterium Photobacterium phosphoreum (T3 mutation) showed that the pharmaceutical wastewater imparted severe toxicity with a relative luminosity of 3.46% +/- 0.45%. During long-term operation, the cumulative toxicity from toxic pollutants in wastewater resulted in the performance collapse of conventional ANAMMOX process. A novel ANAMMOX process with sequential biocatalyst (ANAMMOX granules) addition (SBA-ANAMMOX process) was developed by combining high-rate ANAMMOX reactor with sequential biocatalyst addition (SBA). At biocatalyst addition rate of 0.025 g VSS (L wastewater)(-1) day(-1), the nitrogen removal rate of the process reached up to 9.4 kg N m(-3) day(-1) in pharmaceutical wastewater treatment. The effluent ammonium concentration was lower than 50 mg N L(-1), which met the Discharge Standard of Water Pollutants for Pharmaceutical Industry in China (GB 21903 2008). The application of SBA-ANAMMOX process in refractory ammonium-rich wastewater is promising. PMID- 20832099 TI - Solubility of uranium and thorium from a healing earth in synthetic gut fluids: a case study for use in dose assessments. AB - The aim of this case study was to estimate the bioaccessibility of uranium ((238)U) and thorium ((232)Th) from a healing earth by analysing the solubility of these radionuclides in synthetic gastric and intestinal fluids. An easy applicable in vitro test system was used to investigate the fractional mobilization of the soil contaminants being potentially available for absorption under human in vivo conditions. These findings provided the basis for a prospective dose assessment. The solubility experiments were performed using two different in vitro digestion methods. The concentrations of (238)U and (232)Th in the solutions extracted from the soil were measured by inductively coupled plasma mass spectrometry (ICP-MS). The dissolved fractions in the synthetic gastrointestinal fluid ranged in average from 10.3% to 13.8% for (238)U and from 0.3% to 1.6% for (232)Th, respectively, depending on the digestion method. Subsequently, the committed effective doses from intake of (238)U and (232)Th after ingestion of the healing earth during 1 year were evaluated for adult persons. Thereby ingestion dose coefficients calculated as a function of bioaccessibility were used. The dose assessments ranged between 4.3 * 10(-7)-1.9 * 10(-6) Sv y(-1) for (238)U and 5.6 * 10(-7)-3.3 * 10(-6) Sv y(-1) for (232)Th, respectively. On the basis of the assumptions and estimations made, the present work indicates a relatively low radiation risk due to (238)U and (232)Th after internal exposure of the healing earth. PMID- 20832100 TI - Trans-generational and neonatal humoral immune responses in West Greenland sledge dogs (Canis familiaris) exposed to organohalogenated environmental contaminants. AB - Previous investigations in the Arctic have suggested OHC (organohalogen contaminant) induced immune toxic effects on e.g. polar bears (Ursus maritimus). We therefore studied the dietary impact from minke whale blubber (Balaenoptera acutorostrata), rich in polyunsaturated fatty acids and OHCs, on the humoral immunity of 7 captive West Greenland sledge dog (Canis familiaris) bitches and their 4 pups constituting a sentinel model species for polar bears. A control group was composed of 8 bitches and their 5 pups all fed pork (Suis scrofa) fat. The study included serum IgG measurements (bitches and pups) and specific immune responses towards tetanus toxoid (bitches) and diphtheria toxoid (pups) as well as influenza virus (pups). The analyses showed that IgG concentrations were non significantly lowest in exposed bitches and pups (t-test: all p>0.05). In addition, significant lower antibody response was detected in exposed pups immunized with influenza virus at age 3 months (t-test: both p<0.05). No clear group differences were found for tetanus toxoid in bitches and diphtheria toxoid in pups. The results suggest that the humoral immune system of sledge dogs may be suppressed by the dietary blubber composition of OHCs and polyunsaturated fatty acids while a larger follow-up study is recommended in order to investigate this relationship further. PMID- 20832101 TI - Current evidence of the management of undifferentiated spondyloarthritis: a systematic literature review. AB - OBJECTIVE: To examine the efficacy of available drugs in undifferentiated spondyloarthritis (u-SpA). METHODS: Systematic review of studies retrieved from Medline (1961-July 2009), Embase (1961-July 2009), and Cochrane Library (up to July 2009). A complementary hand search was also performed. The selection criteria were as follows: (population) u-SpA patients; (intervention) nonsteroidal anti-inflammatory agents, disease-modifying antirheumatic drugs, anti-tumor necrosis factor alpha, anakinra, abatacept, biphosphonates, or thalidomide; (outcome) pain, function, structural damage and quality of life; (study design) randomized controlled trials (RCT), cohort studies, and case reports; (level of evidence) according to The Oxford Centre for Evidence-based Medicine (update 2009). An additional narrative review was performed to analyze the effects of drug therapies in patients with spondyloarthritis according new Assessment of Spondyloarthritis International Society criteria. RESULTS: The following 7 studies were included: 2 RCT, 1 cohort study, and 4 case reports, which included 117 patients with u-SpA (mostly young men). No evidence related to the effect of nonsteroidal anti-inflammatory agents or disease-modifying antirheumatic drugs on u-SpA patients was found. Infliximab and etanercept showed some benefit regarding clinical outcomes, function, and quality of life. Two RCT reported important benefit of infliximab and adalimumab also in patients with predominantly axial spondyloarthritis. Rifampicin plus doxycycline improved some clinical outcomes but ciprofloxacin had no benefit. Anecdotal positive evidence was reported with pamidronate. No serious adverse events were reported in the retrieved studies. CONCLUSION: Low-quality evidence suggests a benefit of tumor necrosis factor alpha blockers in u-SpA and good-quality evidence in predominantly axial spondyloarthritis. The use of antibiotics remains controversial. High-quality trials are needed to definitively assess the effect of available drugs in these patients. PMID- 20832102 TI - Kisspeptin-10 inhibits bone-directed migration of GPR54-positive breast cancer cells: Evidence for a dose-window effect. AB - OBJECTIVES: The KiSS-1 gene product is absent or expressed at low level in metastatic breast cancer compared with their nonmetastatic counterparts. A deca peptide derived from the KiSS-1 gene product, designated kisspeptin-10 (Kp-10), activates a receptor coupled to Galphaq subunits (GPR54 or KiSS-1R). In this study we have analyzed whether Kp-10 treatment affects bone-directed migration of GPR54-positive breast cancer cells. METHODS: GPR54 expression was analyzed using immune cytochemistry. Bone-directed breast cancer cell invasion was measured by assessment of the breast cancer cell migration rate through an artificial basement membrane. Chemokine receptor CXCR4 and stromal cell-derived factor-1 (SDF-1) mRNA expression was quantified using semi-quantitative RT-PCR. CXCR4 protein expression and SDF-1 protein secretion were measured using the western blot technique. RESULTS: Breast cancer cell invasion was increased when cocultured with MG63 osteoblast-like cells. Treatment with KP-10 reduced the ability to invade a reconstituted basement membrane and to migrate in response to the cellular stimulus. This effect was significant in a dose-window of 10-9 M to 10-11 M. Searching for the molecular mechanisms we found that KP-10 treatment significantly reduces expression of the chemokine receptor CXCR4 by the breast cancer cells. In addition, expression and secretion of its ligand SDF-1 by the MG63 cells were significantly reduced. Furthermore, SDF-1-induced CXCR4 signaling was down-regulated. CONCLUSIONS: These data represent the first report that KP-10 inhibits bone-directed migration of GPR54-positive breast cancer cells. In addition, we found evidence for a KP-10 dose-window effect. Furthermore, the SDF 1/CXCR4 system seems to be involved in the anti-migratory action of KP-10. PMID- 20832103 TI - Endometrial effects of exemestane compared to tamoxifen within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial: results of a prospective gynecological ultrasound substudy. AB - OBJECTIVES: This study prospectively assessed the effects of exemestane and tamoxifen on the endometrium in patients receiving adjuvant treatment for postmenopausal hormone receptor-positive breast cancer within the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) trial. METHODS: Patients were randomized to receive tamoxifen or exemestane. In a prespecified trial subprotocol, patients underwent transvaginal ultrasound to assess endometrial thickness at baseline and during a 1- to 3-year treatment period. RESULTS: Among 143 evaluable patients, there were no cases of endometrial thickness >10 mm with exemestane, vs. 11 cases with tamoxifen (p < 0.0003). There was a significant difference between the treatment groups regarding time to endometrial thickness >10mm, in favour of exemestane (p < 0.0001). Time to endometrial thickness > 5 mm was significantly longer for exemestane than for tamoxifen (p < 0.0001). Median time to endometrial thickness > 5 mm or censoring was 583 days in the exemestane group versus 315 days in the tamoxifen group. There were also significantly fewer incidences of endometrial thickness > 5 mm at month 6 and month 12 with exemestane compared to tamoxifen (tamoxifen: 6% and 2%; exemestane: 29% and 39%, respectively). After 12 months, mean increases in endometrial thickness from baseline were 2.64 mm and 6.0mm in the exemestane and tamoxifen groups, respectively (p < 0.0006). Moreover, 17 histologically confirmed endometrial changes were observed in the tamoxifen group, vs. one in the exemestane group. CONCLUSIONS: Exemestane was associated with significantly less endometrial thickening than tamoxifen during adjuvant endocrine therapy for postmenopausal hormone receptor-positive breast cancer. PMID- 20832104 TI - Vascular endothelial growth factor gene polymorphisms and ovarian cancer survival. AB - OBJECTIVES: We sought to evaluate the effect of polymorphisms in the VEGF (Vascular Endothelial Growth Factor) gene on overall survival in ovarian cancer patients. METHODS: A sample of 319 women diagnosed with primary invasive epithelial ovarian cancer in Australia between 1985 and 1997, recruited as incident cases, were genotyped for four VEGF single nucleotide polymorphisms (three tagSNPs and one functional SNP) using the Sequenom MassARRAY platform. A SNP found to be associated with ovarian cancer survival in this sample set was then evaluated in two independent datasets in an attempt to replicate the association. RESULTS: VEGF tagSNPs rs3025033 and rs2146323 were not associated with ovarian cancer survival in the Australian sample. Ovarian cancer patients homozygous for tagSNP rs833068 or the functional SNP rs2010963 displayed significantly shortened overall survival in the Australian sample (HR 2.09, 95% CI 1.16-3.78), an effect most apparent in the first 5years after diagnosis. This association was not replicated in two independent datasets. CONCLUSIONS: Findings from this study provide no evidence that rs3025033 and rs2146323 VEGF polymorphisms are associated with ovarian cancer survival. Although homozygous carriers of the tagSNP rs833068 experienced significantly worse survival in our Australian dataset, we were unable to replicate this in two independent datasets. PMID- 20832105 TI - Poly(ADP-ribose) polymerase 1 participates in the phase entrainment of circadian clocks to feeding. AB - Circadian clocks in peripheral organs are tightly coupled to cellular metabolism and are readily entrained by feeding-fasting cycles. However, the molecular mechanisms involved are largely unknown. Here we show that in liver the activity of PARP-1, an NAD(+)-dependent ADP-ribosyltransferase, oscillates in a daily manner and is regulated by feeding. We provide biochemical evidence that PARP-1 binds and poly(ADP-ribosyl)ates CLOCK at the beginning of the light phase. The loss of PARP-1 enhances the binding of CLOCK-BMAL1 to DNA and leads to a phase shift of the interaction of CLOCK-BMAL1 with PER and CRY repressor proteins. As a consequence, CLOCK-BMAL1-dependent gene expression is altered in PARP-1-deficient mice, in particular in response to changes in feeding times. Our results show that Parp-1 knockout mice exhibit impaired food entrainment of peripheral circadian clocks and support a role for PARP-1 in connecting feeding with the mammalian timing system. PMID- 20832106 TI - The effect of Electro Discharge Machining (EDM) on the corrosion resistance of dental alloys. AB - OBJECTIVE: The aim of the present study was to evaluate the effect of Electro Discharge Machining (EDM) on the corrosion resistance of two types of dental alloys used for fabrication of implant retained superstructures. METHODS: Two groups of specimens were prepared from a Co-Cr (Okta-C) and a grade II cpTi (Biotan) alloys respectively. Half of the specimens were subjected to EDM with Cu electrodes and the rest were conventionally finished (CF). The corrosion resistance of the alloys was evaluated by anodic polarization in Ringer's solution. Morphological and elemental alterations before and after corrosion testing were studied by SEM/EDX. Six regions were analyzed on each surface before and after corrosion testing and the results were statistically analyzed by paired t-test (a=0.05). RESULTS: EDM demonstrated inferior corrosion resistance compared to CF surfaces, the latter being passive in a wider range of potential demonstrating higher polarization resistance and lower I(corr) values. Morphological alterations were found before and after corrosion testing for both materials tested after SEM analysis. EDX showed a significant decrease in Mo, Cr, Co, Cu (Co-Cr) and Ti, Cu (cpTi) after electrochemical testing plus an increase in C. SIGNIFICANCE: According to the results of this study the EDM procedure decreases the corrosion resistance of both the alloys tested, increasing thus the risk of possible adverse biological reactions. PMID- 20832107 TI - Rejection, feeling bad, and being hurt: using multilevel modeling to clarify the link between peer group aggression and adjustment. AB - The association between affiliating with aggressive peers and behavioral, social and psychological adjustment was examined. Students initially in 3rd, 4th, and 5th grade (N = 427) were followed biannually through 7th grade. Students' peer nominated groups were identified. Multilevel modeling was used to examine the independent contributions of adolescents' typical peer context (between-person effect) and changes in peer context (within-person effects) to adolescents' adjustment. Typically affiliating with aggressive groups and affiliating with more aggressive groups than usual predicted higher aggression for all youth. Typically affiliating with aggressive groups predicted negative adjustment (lower social preference and self-worth, higher victimization) for girls but neutral or positive adjustment for boys. Although typical peer context was consistently associated with adjustment, changes in peer context predicted small changes in adjustment for several outcomes. Results underscored the need to adopt a more differentiated picture of adolescents' dynamic peer context and its association with normative development. PMID- 20832108 TI - Polymer surface functionalities that control human embryoid body cell adhesion revealed by high throughput surface characterization of combinatorial material microarrays. AB - High throughput materials discovery using combinatorial polymer microarrays to screen for new biomaterials with new and improved function is established as a powerful strategy. Here we combine this screening approach with high throughput surface characterization (HT-SC) to identify surface structure-function relationships. We explore how this combination can help to identify surface chemical moieties that control protein adsorption and subsequent cellular response. The adhesion of human embryoid body (hEB) cells to a large number (496) of different acrylate polymers synthesized in a microarray format is screened using a high throughput procedure. To determine the role of the polymer surface properties on hEB cell adhesion, detailed HT-SC of these acrylate polymers is carried out using time of flight secondary ion mass spectrometry (ToF SIMS), X ray photoelectron spectroscopy (XPS), pico litre drop sessile water contact angle (WCA) measurement and atomic force microscopy (AFM). A structure-function relationship is identified between the ToF SIMS analysis of the surface chemistry after a fibronectin (Fn) pre-conditioning step and the cell adhesion to each spot using the multivariate analysis technique partial least squares (PLS) regression. Secondary ions indicative of the adsorbed Fn correlate with increased cell adhesion whereas glycol and other functionalities from the polymers are identified that reduce cell adhesion. Furthermore, a strong relationship between the ToF SIMS spectra of bare polymers and the cell adhesion to each spot is identified using PLS regression. This identifies a role for both the surface chemistry of the bare polymer and the pre-adsorbed Fn, as-represented in the ToF SIMS spectra, in controlling cellular adhesion. In contrast, no relationship is found between cell adhesion and wettability, surface roughness, elemental or functional surface composition. The correlation between ToF SIMS data of the surfaces and the cell adhesion demonstrates the ability to identify surface moieties that control protein adsorption and subsequent cell adhesion using ToF SIMS and multivariate analysis. PMID- 20832109 TI - Periodontal regeneration using engineered bone marrow mesenchymal stromal cells. AB - Regeneration of lost periodontium is a challenge in that both hard (alveolar bone, cementum) and soft (periodontal ligament) connective tissues need to be restored to their original architecture. Bone marrow mesenchymal stromal cells (BM-MSCs) appear to be an attractive candidate for connective tissue regeneration. We hypothesized that BM-MSCs are able to sense biological cues from the local microenvironment and organize appropriately to contribute to the regeneration of both soft and hard periodontal connective tissues. To test this hypothesis, we transplanted GFP(+) rat BM-MSCs expanded ex vivo on microcarrier gelatin beads into a surgically created rat periodontal defect. After three weeks, evidence of regeneration of bone, cementum and periodontal ligament was observed in both transplanted and control animals. However, the animals that received BM-MSCs regenerated significantly greater new bone. In addition, the animals that had received the cells and beads transplant had significantly more appropriately orientated periodontal ligament fibers, indicative of functional restoration. Finally, donor-derived BM-MSCs were found integrated in newly formed bone, cementum and periodontal ligament, suggesting that they can directly contribute to the regeneration of cells of these tissues. PMID- 20832110 TI - Cell behavior on extracellular matrix mimic materials based on mussel adhesive protein fused with functional peptides. AB - Adhesion of cells to surfaces is a basic and important requirement in cell culture and tissue engineering. Here, we designed artificial extracellular matrix (ECM) mimics for efficient cellular attachment, based on mussel adhesive protein (MAP) fusion with biofunctional peptides originating from ECM materials, including fibronectin, laminin, and collagen. Cellular behaviors, including attachment, proliferation, spreading, viability, and differentiation, were investigated with the artificial ECM material-coated surfaces, using three mammalian cell lines (pre-osteoblast, chondrocyte, and pre-adipocyte). All cell lines examined displayed superior attachment, proliferation, spreading, and survival properties on the MAP-based ECM mimics, compared to other commercially available cell adhesion materials, such as poly-L-lysine and the naturally extracted MAP mixture. Additionally, the degree of differentiation of pre osteoblast cells on MAP-based ECM mimics was increased. These results collectively demonstrate that the artificial ECM mimics developed in the present work are effective cell adhesion materials. Moreover, we expect that the MAP peptide fusion approach can be extended to other functional tissue-specific motifs. PMID- 20832111 TI - Phenotype and functional analysis of human monocytes-derived dendritic cells loaded with a carbosilane dendrimer. AB - Dendritic cells (DCs) play a major role in development of cell-mediated immunotherapy due to their unique role in linking innate and adaptive immunities. In spite of improvement in this area, strategies employing ex vivo generated DCs have shown limited efficacy in clinical trials. Dendrimers have been proposed as new carriers for drug delivery in aim to ameliorate DCs antigen loading that is a pivotal point in DCs approaches. In this study, we have investigated the phenotypic and functional characteristics of human monocytes-derived dendritic cells after HIV-derived peptides uptake in vitro. We have found that iDCs and mDCs were able to capture efficiently water soluble carbosilane (CBS) dendrimer 2 G-NN16 and did not induce changes in maturation markers levels at the DCs surface. Therefore, CBS 2 G-NN16-loaded mDCs migrated as efficiently as unloaded DCs towards CCL19 or CCL21. Furthermore, DCs viability, activation of allogenic naive CD4 + T cells by mDCs and secretion of cytokines were not significantly changed by 2 G-NN16 loading. Summing up, our data indicate that CBS 2 G-NN16 has no negative effects on the pivotal properties of DCs in vitro. It should therefore be feasible to further develop this antigen loading strategy for clinical use in immunotherapy against viral infections. PMID- 20832113 TI - Protein kinases reduce mitochondrial Ca2+ uptake through an action on the outer mitochondrial membrane. AB - Cytosolic Ca(2+) signal induces mitochondrial Ca(2+) uptake that has far-reaching effect on several cellular functions. We have previously shown in H295R cells that the transfer of cytosolic Ca(2+) signal into mitochondria is attenuated by the simultaneous activation of p38 MAPK and novel-type PKC isoforms (Szanda et al. (2008) [1], Koncz et al. (2009) [2]). In the present study we show that (i) kinase-mediated inhibition of mitochondrial Ca(2+) uptake persists after clamping or dissipation of the mitochondrial membrane potential; (ii) kinase activation increases the [Ca(2+)] required for half-maximal Ca(2+) uptake rate in permeabilized cells; (iii) inhibition of the Ca(2+) uptake by the kinases is dependent on an intact mitochondrial outer membrane; (iv) when p38 MAPK and novel type PKC isoforms are activated, the outer mitochondrial membrane may limit Ca(2+) diffusion even in the low micromolar [Ca(2+)] range. These findings confirm the concept that the outer mitochondrial membrane impedes mitochondrial Ca(2+) uptake by reducing the availability of Ca(2+) at the transport sites (i.e. the inner mitochondrial membrane), and suggest that Ca(2+) transport through the outer membrane is controlled by the activity of p38 MAPK and novel-type PKC isoforms. PMID- 20832112 TI - Alterations in gene expression of human vascular endothelial cells associated with nanotopographic cues. AB - Human cells in vivo are exposed to a topographically rich, 3-dimenisional environment which provides extracellular cues initiating a cascade of biochemical signals resulting in changes in cell behavior. One primary focus of our group is the development of biomimetic substrates with anisotropic nanoscale topography to elucidate the mechanisms by which physical surface cues are translated into biochemical signals. To investigate changes in gene expression as a result of nanotopographic cues, Human Umbilical Vein Endothelial Cells (HUVECs) were cultured on chemically identical flat and 400 nm pitch nanogrooved surfaces. After 12 h, RNA was harvested for an Affymetrix HG U133 Plus 2.0 gene array. Of over 47,000 possible gene probes, 3171 had at least a two-fold difference in expression between the control flat and 400 nm pitch. The gene ontology groups with the most significant increase in expression are involved in protein modification and maintenance, similar to cells upregulating chaperone and protein synthesis genes in response to physical stresses. The most significant decreases in expression were observed with cell cycle proteins, including cyclins and checkpoint proteins. Extracellular matrix proteins, including integrins, collagens, and laminins, are almost uniformly downregulated on the 400 nm pitch surfaces compared to control. The downregulation of one of these genes, integrin beta 1, was confirmed via quantitative PCR. Together, these gene array data, in addition to our studies of cell behavior on nanoscale surfaces, contribute to our understanding of the signaling pathways modulated by topographical surface cues. PMID- 20832114 TI - Plasma neuropeptide Y levels differ in distinct diabetic conditions. AB - Neuropeptide Y (NPY) is an important hormone in appetite regulation. Although the contribution of NPY to metabolic disease has been previously demonstrated, there are only a few reports addressing NPY plasma levels under distinct diabetic conditions. In this study we evaluated NPY plasma levels in diabetes mellitus type 2 (DM2) patients with (n=34) and without (n=34) diabetic polyneuropathy (PNP) and compared these with age and gender matched healthy controls (n=34). We also analyzed NPY plasma levels in gestational diabetes mellitus (GDM) patients with age and pregnancy-week matched controls with normal glucose tolerance (NGT). NPY concentration was determined using a commercially available radioimmunoassay kit. In addition, metabolic parameters of DM2 and GDM patients were recorded. One way ANOVA tests with appropriate post hoc corrections showed elevated levels of NPY in DM2 patients with and without PNP when compared with those of healthy controls (122.32+/-40.86 and 117.33+/-29.92 vs. 84.65+/-52.17 pmol/L; p<0.001, p<0.005, respectively). No significant difference was observed between diabetic patients with and without PNP. The NPY levels were similar in the GDM group and in pregnant women with NGT (74.87+/-14.36 vs. 84.82+/-51.13 pmol/L, respectively). Notably, the NPY concentration correlated positively with insulin levels in DM2 patients (R=0.35, p<0.01). Our data suggest a potential involvement of circulating NPY in DM2 pathology. PMID- 20832115 TI - Response of Eisenia fetida to the application of different organic wastes in an aluminium-contaminated soil. AB - The effects of amending Al-contaminated soils with municipal solid waste compost (MSW), poultry manure (PM) and cow manure (CM) on Al toxicity and morphological alterations and biochemical enzymes of the earthworm Eisenia fetida were investigated in an incubation spiking experiment. Al(NO(3))(3) was added to a soil at rates equivalent to 0, 50 and 100 mg Al kg(-1). In order to apply the same amount of organic matter (OM), soil samples were mixed with MSW, PM and CM at a rate of 10%, 7.6% and 5.8%, respectively. Earthworm cocoon number, average weight of cocoon and number of juveniles per cocoon were measured after 30 days of incubation, whereas weight, Al concentration and available Al, as well cellulase and glutathione-S-transferase activities of earthworms were measured after 3, 15, 30, 60, 90 and 120 days. Reproductive and enzymatic activities of earthworms decreased with increasing the rate of Al applied. The inhibition of weight, enzyme activities and Al concentration of earthworm was lower in organically amended soils than in unamended soils. At the end of the incubation, earthworm weight and enzymatic activities in highly contaminated soils increased and Al concentration in earthworm tissues decreased as the relative amount of humic acids applied to soil increased, following the order unamended soil0.05). We demonstrated an association between the onset of exacerbation and the severity of obstruction (FEV(1)) (r=-0.360; P=0.037), eosinophils in sputum (r=-0.399; P=0.029), albumin (r=-0.442; P=0.013), and IL(8) in sputum (r=0.357; P=0.038). CONCLUSIONS: The results suggest a rapid inflammatory response, both neutrophilic and eosinophilic, in the asthmatic exacerbation. However, the swelling in the bronchi may play an important role in the initial inflammatory response in the exacerbations depending of time of onset. PMID- 20832160 TI - Embryology and anatomy of the vulva: the female orgasm and women's sexual health. AB - Sexual health is vital to overall well-being. Orgasm is a normal psycho physiological function of human beings and every woman has the right to feel sexual pleasure. The anatomy of the vulva and of the female erectile organs (trigger of orgasm) is described in human anatomy textbooks. Female sexual physiology was first described in Dickinson's textbook in 1949 and subsequently by Masters and Johnson in 1966. During women's sexual response, changes occur in the congestive structures that are essential to the understanding of women's sexual response and specifically of their orgasm. Female and male external genital organs arise from the same embryologic structures, i.e. phallus, urogenital folds, urogenital sinus and labioscrotal swellings. The vulva is formed by the labia majora and vestibule, with its erectile apparatus: clitoris (glans, body, crura), labia minora, vestibular bulbs and corpus spongiosum. Grafenberg, in 1950, discovered no "G-spot" and did not report an orgasm of the intraurethral glands. The hypothetical area named "G-spot" should not be defined with Grafenberg's name. The female orgasm should be a normal phase of the sexual response cycle, which is possible to achieve by all healthy women with effective sexual stimulation. Knowledge of the embryology, anatomy and physiology of the female erectile organs are important in the field of women's sexual health. PMID- 20832161 TI - Abdominal surgical incisions and perioperative morbidity among morbidly obese women undergoing cesarean delivery. AB - OBJECTIVE: To test the hypothesis that there is no difference in perioperative morbidity and the type of uterine incisions between vertical skin incisions (VSI) and low transverse skin incisions (LTSI) at the time of cesarean delivery in morbidly obese women. STUDY DESIGN: Retrospective cohort study of morbidly obese women (BMI > 35 kg/m(2)) who underwent cesarean delivery between June 2004 and December 2006. RESULTS: During the study, 424 morbidly obese women underwent cesarean section. Patients with VSI were older (31.0 +/- 6.2 years vs. 26.7 +/- 5.8 years), heavier (48.2 +/- 9.1 kg/m(2) vs. 41.7 +/- 6.7 kg/m(2)), and more likely to have a classical than a low transverse uterine incision (65.9% vs. 7.3%), p < 0.001. After controlling for confounders, women with VSI did not have an increase in perioperative morbidity, but underwent more vertical uterine incisions (adjusted odds ratio = 18.49, 95% CI: 6.44, 53.07). CONCLUSION: VSI and LTSI are safe in morbidly obese patients undergoing cesarean section, but there is a tendency for increased vertical uterine incisions in those who underwent VSI. PMID- 20832162 TI - The efficacy and tolerability of short-term low-dose estrogen-only add-back therapy during post-operative GnRH agonist treatment for endometriosis. AB - OBJECTIVE: To evaluate the efficacy and tolerability of a low-dose estrogen-only regimen as a short-term add-back therapy during post-operative GnRH agonist (GnRHa) treatment of patients with endometriosis. STUDY DESIGN: Retrospective cohort study. One hundred seventeen women of reproductive age who were treated with post-operative GnRHa after conservative laparoscopic surgery for endometrioma were eligible for this study. The patients were divided into two groups: group A (n = 56) received tibolone (2.5mg) between 2002 and 2004 and group B (n = 61) received estradiol valerate (1mg) between 2005 and 2007 as an add-back therapy for five months, beginning at the time of the second injection of a GnRHa. The incidence of hypoestrogenic symptoms and the degree of pelvic pain according to a verbal rating scale (VRS) scoring system, the incidence and patterns of uterine bleeding during add-back therapy, the endometrial thickness by ultrasonography two months after the last GnRHa treatment, and the serum CA 125 level were evaluated. RESULTS: The incidence of uterine bleeding, hypoestrogenic symptoms such as hot flashes and sweating, and pelvic pain did not differ significantly between the two treatment groups. However, the endometrium was thicker in group A than group B (p = 0.022). In group B, the frequency of uterine bleeding was lower from the second month after starting add-back therapy than in group A, but without statistical significance (at the sixth month, p = 0.086). CONCLUSION: The low-dose estrogen-only regimen was efficacious and tolerable as a short-term add-back therapy during post-operative GnRHa treatment after surgery for endometriosis. PMID- 20832163 TI - Characterization of methane, benzene and toluene-oxidizing consortia enriched from landfill and riparian wetland soils. AB - The microbial oxidations of methane (M) and volatile organic compounds (VOCs) were compared with those of M and VOCs alone after enriching soil samples with M and/or VOCs. Landfill cover and riparian wetland soils from which M and VOCs were simultaneously emitted were selected as representative samples. Benzene (B) and toluene (T) were employed as the model VOCs. With the landfill soil consortia, the rate of M oxidation decreased from 4.15-5.56 to 2.26-3.42 MUmol g-dry soil( 1)h(-1) in the presence of both B and T, but with the wetland soil consortia the rate of M oxidation (3.09 MUmol g-dry soil(-1)h(-1)) in the mixture of M as well as both B and T was similar to that of M alone (3.04 MUmol g-dry soil(-1)h(-1)). Compared with the methanotrophic community with M alone, the portion of type II methanotrophs was greater in the landfill consortia; whereas, the proportion in wetland consortia was less in the presence of both B and T. The oxidations of B and T were stimulated by the presence of M with both the landfill and wetland consortia. There were no correlations between the oxidation rate of M and those of B and T with the gene copy numbers of pmoA and tmoA responsible for the oxidations. PMID- 20832164 TI - The sedimentation of mixed cultures used in the treatment of effluents generated from terrestrial fuel distribution terminals. AB - This study evaluated the use of coagulants (ferric chloride and aluminium sulphate) and an anionic polyelectrolyte (polyacrylamide) in the settling of a mixed culture (C(1)), which was used for the biodegradation of hydrocarbons present in effluent of fuel distribution terminals contaminated with diesel oil and gasoline. In preliminary investigations conducted in jar tests, the optimal concentrations of coagulant were obtained for further studies. After preliminary tests, biodegradation was evaluated in a central composite design (CCD) with varying concentrations of ferric chloride and polyelectrolyte. Ferric chloride and polyelectrolyte concentrations ranged from 77.9 to 422.12 mg/L and 0.0 to 3.2mg/L, respectively. The responses monitored in CCD experiments included the sludge volume index (SVI), turbidity, and specific rate of oxygen uptake (SOUR), where values of 100mL/g, 840 nephelometric turbidity unit (NTU) and 58 mg O(2)/gh, respectively, were obtained. Subsequently, biodegradation was monitored in a sequencing batch reactor (SBR). The results indicated that within five cycles, total petroleum hydrocarbon (TPH) removal increased from 75 +/- 1.0% to 79 +/- 0.5%, while the volatile suspended solids (VSS) increased from 1300 to 2500 mg/L. PMID- 20832165 TI - Mechanism of uranium (VI) removal by two anaerobic bacterial communities. AB - The mechanism of uranium (VI) removal by two anaerobic bacterial consortia, recovered from an uncontaminated site (consortium A) and other from an uranium mine (consortium U), was investigated. The highest efficiency of U (VI) removal by both consortia (97%) occurred at room temperature and at pH 7.2. Furthermore, it was found that U (VI) removal by consortium A occurred by enzymatic reduction and bioaccumulation, while the enzymatic process was the only mechanism involved in metal removal by consortium U. FTIR analysis suggested that after U (VI) reduction, U (IV) could be bound to carboxyl, phosphate and amide groups of bacterial cells. Phylogenetic analysis of 16S rRNA showed that community A was mainly composed by bacteria closely related to Sporotalea genus and Rhodocyclaceae family, while community U was mainly composed by bacteria related to Clostridium genus and Rhodocyclaceae family. PMID- 20832166 TI - Gamma radiolysis of alachlor aqueous solutions in the presence of hydrogen peroxide. AB - The enhanced effect of gamma irradiation with hydrogen peroxide (H(2)O(2)) for alachlor degradation in an aqueous solution was first investigated in this study. The combination of gamma irradiation and H(2)O(2) led to an enhanced effect, which remarkably increased the degradation efficiency of alachlor and the total organic carbon (TOC) removal. At a dose of 200 Gy, the degradation degree of the alachlor solution reached 81.7 and 99.2% under H(2)O(2) concentrations of 0 and 0.1 MUM, respectively. In addition, the TOC removal efficiencies of the alachlor under initial H(2)O(2) concentrations of 0, 0.5 and 1.0 MUM were 59.5, 74.8 and 83.8%, respectively, at an absorbed dose of 20 k Gy. However, for higher H(2)O(2) concentrations (greater than 1 MUM), the alachlor degradation was reduced because OH radicals were scavenged by the H(2)O(2). The biodegradability of alachlor solutions prior to and after treatment by gamma irradiation was also assessed using the Closed Bottle Test (CBT). The results showed enhanced biodegradability of alachlor with increasing absorbed doses. PMID- 20832167 TI - Accumulation and tolerance characteristics of cadmium in a halophytic Cd hyperaccumulator, Arthrocnemum macrostachyum. AB - The potential of the extreme halophyte Arthrocnemum macrostachyum was examined to determine its tolerance and ability to accumulate cadmium for phytoremediation purposes. A glasshouse experiment was designed to investigate the effect of cadmium from 0 to 1.35 mmol l(-1) on the growth and the photosynthetic apparatus of A. macrostachyum by measuring chlorophyll fluorescence parameters, gas exchange and photosynthetic pigment concentrations. We also determined ash, cadmium, calcium, copper, iron, manganese, magnesium, phosphorous, sodium, and zinc concentrations, and C/N ratio. A. macrostachyum demonstrated hypertolerance to cadmium stress; it did not show phytotoxicity at shoot concentration as high as 70 mg kg(-1). The bioaccumulator factors exceeded the critical value (1.0) for all Cd treatments, and the transport factors indicated that this species has higher ability to transfer Cd from roots to shoots at lower Cd concentrations. At 1.35 mmol l(-1) Cd A. macrostachyum showed 25% biomass reduction after a month of treatment. Long-term effects of cadmium on the growth were mainly determined by variations in net photosynthetic rate (P(N)). Reductions in P(N) could be accounted by higher dark respiration and lower pigment concentrations. Finally, A. macrostachyum has the basic characteristics of a Cd-hyperaccumulator and may be useful for restoring Cd-contaminated sites. PMID- 20832168 TI - Performance evaluation of organic emulsion liquid membrane on phenol removal. AB - The percentage removal of phenol from aqueous solution by emulsion liquid membrane and emulsion leakage was investigated experimentally for various parameters such as membrane:internal phase ratio, membrane:external phase ratio, emulsification speed, emulsification time, carrier concentration, surfactant concentration and internal agent concentration. These parameters strongly influence the percentage removal of phenol and emulsion leakage. Under optimum membrane properties, the percentage removal of phenol was as high as 98.33%, with emulsion leakage of 1.25%. It was also found that the necessity of carrier for enhancing phenol removal was strongly dependent on the internal agent concentration. PMID- 20832169 TI - Biological treatment of PAH-contaminated sediments in a Sequencing Batch Reactor. AB - The technical feasibility of a sequential batch process for the biological treatment of sediments contaminated by polycyclic aromatic hydrocarbons (PAHs) was evaluated through an experimental study. A bench-scale Sediment Slurry Sequencing Batch Reactor (SS-SBR) was fed with river sediments contaminated by a PAH mixture made by fluorene, anthracene, pyrene and crysene. The process performance was evaluated under different operating conditions, obtained by modifying the influent organic load, the feed composition and the hydraulic residence time. Measurements of the Oxygen Uptake Rates (OURs) provided useful insights on the biological kinetics occurring in the SS-SBR, suggesting the minimum applied cycle time-length of 7 days could be eventually halved, as also confirmed by the trend observed in the volatile solid and total organic carbon data. The removal efficiencies gradually improved during the SS-SBR operation, achieving at the end of the study rather constant removal rates above 80% for both 3-rings PAHs (fluorene and anthracene) and 4-ring PAHs (pyrene and crysene) for an inlet total PAH concentration of 70 mg/kg as dry weight (dw). PMID- 20832170 TI - Chromium VI adsorption on cerium oxide nanoparticles and morphology changes during the process. AB - In this study, suspended cerium oxide nanoparticles stabilized with hexamethylenetetramine were used for the removal of dissolved chromium VI in pure water. Several concentrations of adsorbent and adsorbate were tested, trying to cover a large range of possible real conditions. Results showed that the Freundlich isotherm represented well the adsorption equilibrium reached between nanoparticles and chromium, whereas adsorption kinetics could be modeled by a pseudo-second-order expression. The separation of chromium-cerium nanoparticles from the medium and the desorption of chromium using sodium hydroxide without cerium losses was obtained. Nanoparticles agglomeration and morphological changes during the adsorption-desorption process were observed by TEM. Another remarkable result obtained in this study is the low toxicity in the water treated by nanoparticles measured by the Microtox((r)) commercial method. These results can be used to propose this treatment sequence for a clean and simple removal of drinking water or wastewater re-use when a high toxicity heavy metal such as chromium VI is the responsible for water pollution. PMID- 20832171 TI - Pain behavior in the formalin test persists after ablation of the great majority of C-fiber nociceptors. AB - Although the formalin test is a widely used model of persistent pain, the primary afferent fiber types that underlie the cellular and behavioral responses to formalin injection are largely unknown. Here we used a combined genetic and pharmacological approach to investigate the effect of ablating subsets of primary afferent nociceptors on formalin-induced nocifensive behaviors and spinal cord Fos protein expression. Intrathecal capsaicin-induced ablation of the central terminals of TRPV1+neurons greatly reduced the behavioral responses and Fos elicited by low-dose (0.5%) formalin. In contrast, genetic ablation of the MrgprD expressing subset of non-peptidergic unmyelinated afferents, which constitute a largely non-overlapping population, altered neither the behavior nor the Fos induced by low-dose formalin. Remarkably, nocifensive behavior following high dose (2%) formalin was unchanged in mice lacking either afferent population, or even in mice lacking both populations, which together make up the great majority of C-fiber nociceptors. Thus, at high doses, which are routinely used in the formalin test, formalin-induced "pain" behavior persists in the absence of the vast majority of C-fiber nociceptors, which points to a contribution of a large spectrum of afferents secondary to non-specific formalin-induced tissue and nerve damage. PMID- 20832172 TI - Experimental and theoretical study of electron density and structure factors in CoSb3. AB - We refine two low-order structure factors of the skutterudite CoSb3 using convergent beam electron diffraction. The relatively large unit cell of this material causes the disks to overlap and introduces a series of challenges in the refinement procedure. These challenges and future work-arounds are discussed. The refined structure factors F200 and F600 are compared to X-ray diffraction and density functional calculated values, the latter calculated using two different functionals. Both relaxed and experimental lattice parameters are tested to explicitly highlight the impact of the lattice geometry and atomic position on the structure factors. PMID- 20832173 TI - Bloch wave symmetries in electron diffraction: applications to Friedels law, Gjonnes-Moodie lines and refraction at interfaces. AB - We classify the point symmetries at the different points in the Brillouin zone for the 17 two-dimensional space groups and the symmetries of the Bloch waves for the 10 two-dimensional crystallographic point groups. Simple examples involving breakdown of Friedels law, Gjonnes-Moodie lines, and reflection and refraction at interfaces are presented. PMID- 20832174 TI - Identification of novel Cryptosporidium species in aquarium fish. AB - Little is known about the prevalence and genotypes of Cryptosporidium in fish. The present study investigated the prevalence of Cryptosporidium species in 200 aquarium fish of 39 different species in Western Australia by PCR amplification at the 18S rRNA locus. A total of 21 positives were detected by PCR (10.5% prevalence) from 13 different species of fish. Nineteen of these isolates were successfully sequenced. Of these, 12 were similar or identical to previously described species/genotypes of Cryptosporidium, while the remaining seven isolates appeared to represent three novel species. PMID- 20832176 TI - Race and sex associations to weight concerns among urban African American and Caucasian smokers. AB - This study compared general weight concerns (Drive for Thinness, Body Dissatisfaction, and Cognitive Restraint) and smoking-specific weight concerns among adult African American and Caucasian women and men smokers enrolled in a smoking cessation clinical trial. Participants were 119 African Americans (73 female) and 182 Caucasians (90 female). Results revealed that general weight concerns were higher in Caucasians versus African Americans, and in women compared with men but there were no race by sex interactions. Drive for Thinness and Body Dissatisfaction was higher in women compared with men, and Cognitive Restraint was highest in Caucasian women. Finally, smoking-specific weight concerns were higher in Caucasian women than both Caucasian and African American men, with African American women intermediate. Results indicate that while Caucasian women preparing to quit smoking exhibited the highest levels of concern about weight, smoking-specific weight concerns, and certain sub-components of general weight concerns were also prevalent among African Americans and Caucasians. Future research is needed to elucidate how race and sex differences in weight concerns may impact smoking cessation. PMID- 20832177 TI - Therapeutic potential of interleukin-6 antagonism in bipolar disorder. AB - Bipolar disorder (BD) is a chronic, severe, and highly disabling psychiatric disorder. Its underlying neurobiology remains largely unclear. A significant body of evidence indicates that inflammatory activation expressed by increased cytokines is relevant in its pathophysiology. IL-6 is one of the most important cytokines involved in the pathogenesis of immune and inflammatory disorders. Several studies recently showed increased levels of IL-6 in manic and depressive episodes and also during euthymia in subjects with BD. Tocilizumab is an IL-6 receptor antagonist being marketed for the treatment of rheumatoid arthritis and Castleman's disease. In this article we discuss the possibility that tocilizumab may have a therapeutic role in treatment of BD through its anti-inflammatory action. PMID- 20832178 TI - Diarrhea Predominant Irritable Bowel Syndrome (IBS-D): fact or fiction. AB - Diarrhea Predominant Irritable Bowel Syndrome IBS (IBS-D) and functional diarrhea constitute 50% of cases treated by gastroenterology specialists and a significant proportion of those treated in a primary physicians practice. The size of the problem and the difficulty in successfully addressing these entities has frustrated patients and physicians alike. The presented data delineates work-up, final diagnoses and clinical outcomes in the largest single clinical retrospective study of 303 patients with an initial presentation of IBS-D and functional diarrhea. Results indicate that 298 (98%) patients were found to have a diagnosis different from the initial presentation of IBS-D, and 204 (68%) of the patients studied had conditions related to treatable bile acid abnormalities. After identifying these clinical diagnoses and instituting appropriate therapy, 98% of these patients had a favorable response, as measured by a decrease in the number of bowel movements to less than three per day and a significant change in the consistency of the stools. This finding is dramatically different from the poor response generally experienced from conventional therapy for IBS-D and functional chronic diarrhea. The data presented in this study substantiates the hypothesis that IBS-D and functional diarrhea do not exist as true clinical entities and explains the previous lack of satisfactory therapeutic response. Symptoms experienced by these patients were caused by a collection of different clinical conditions bunched up under this "umbrella" diagnosis of IBS-D. Once these separate entities were identified and appropriately addressed, the clinical response was quite impressive and encouraging. The implication of this hypothesis could be of vital importance because of the number of those suffering from these symptoms. PMID- 20832179 TI - Pretreatment apparent diffusion coefficient of the primary lesion correlates with local failure in head-and-neck cancer treated with chemoradiotherapy or radiotherapy. AB - PURPOSE: This study was performed to evaluate whether the apparent diffusion coefficient (ADC) of a primary lesion correlates with local failure in primary head-and-neck squamous cell carcinoma (HNSCC) treated with chemoradiotherapy or radiotherapy. METHODS AND MATERIALS: We retrospectively studied 38 patients with primary HNSCC (12 oropharynx, 20 hypopharynx, 4 larynx, 2 oral cavity) treated with chemoradiotherapy or radiotherapy with radiation dose to gross tumor volume equal to or over 60 Gy and who underwent pretreatment magnetic resonance imaging, including diffusion-weighted imaging. Ten patients developed local failure during follow-up periods of 2.0 to 9.3 months, and the remaining 28 showed local control during follow-up periods of 10.5 to 31.7 months. The variables that could affect local failure (age, tumor volume, ADC, T stage, N stage, dose, treatment method, tumor location, and overall treatment time) were analyzed using logistic regression analyses for all 38 patients and for 17 patients with Stage T3 or T4 disease. RESULTS: In univariate logistic analysis for all 38 cases, tumor volume, ADC, T stage, and treatment method showed significant (p < 0.05) associations with local failure. In multivariate analysis, ADC and T stage revealed significance (p < 0.01). In univariate logistic analysis for the 17 patients with Stage T3 or T4 disease, ADC and dose showed significant (p < 0.01) associations with local failure. In multivariate analysis, ADC alone showed significance (p < 0.05). CONCLUSIONS: The results suggest that pretreatment ADC, along with T stage, is a potential indicator of local failure in HNSCC treated with chemoradiotherapy or radiotherapy. PMID- 20832180 TI - Multi-institutional Phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities. AB - PURPOSE: Proton beam therapy (PBT) is theoretically an excellent modality for external beam radiotherapy, providing an ideal dose distribution. However, it is not clear whether PBT for prostate cancer can clinically control toxicities. The purpose of the present study was to estimate prospectively the incidence of late rectal toxicities after PBT for organ-confined prostate cancer. METHODS AND MATERIALS: The major eligibility criteria included clinical Stage T1-T2N0M0; initial prostate-specific antigen level of <=20 ng/mL and Gleason score <=7; no hormonal therapy or hormonal therapy within 12 months before registration; and written informed consent. The primary endpoint was the incidence of late Grade 2 or greater rectal toxicity at 2 years. Three institutions in Japan participated in the present study after institutional review board approval from each. PBT was delivered to a total dose of 74 GyE in 37 fractions. The patients were prospectively followed up to collect the data on toxicities using the National Cancer Institute-Common Toxicity Criteria, version 2.0. RESULTS: Between 2004 and 2007, 151 patients were enrolled in the present study. Of the 151 patients, 75, 49, 9, 17, and 1 had Stage T1c, T2a, T2b, T2c, and T3a, respectively. The Gleason score was 4, 5, 6, and 7 in 5, 15, 80 and 51 patients, respectively. The initial prostate-specific antigen level was <10 or 10-20 ng/mL in 102 and 49 patients, respectively, and 42 patients had received hormonal therapy and 109 had not. The median follow-up period was 43.4 months. Acute Grade 2 rectal and bladder toxicity temporarily developed in 0.7% and 12%, respectively. Of the 147 patients who had been followed up for >2 years, the incidence of late Grade 2 or greater rectal and bladder toxicity was 2.0% (95% confidence interval, 0-4.3%) and 4.1% (95% confidence interval, 0.9-7.3%) at 2 years, respectively. CONCLUSION: The results of the present prospective study have revealed a valuable piece of evidence that PBT for localized prostate cancer can achieve a low incidence of late Grade 2 or greater rectal toxicities. PMID- 20832181 TI - Contrast-enhanced [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography for staging and radiotherapy planning in patients with anal cancer. AB - PURPOSE: The practice of surgical staging and treatment of anal cancer has been replaced by noninvasive staging and combined modality therapy. For appropriate patient management, accurate lymph node staging is crucial. The present study evaluated the feasibility and diagnostic accuracy of contrast-enhanced [(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG)-positron emission tomography/computed tomography (PET/CT) for staging and radiotherapy planning of anal cancer. METHODS AND MATERIALS: A total of 22 consecutive patients (median age, 61 years old) with anal cancer underwent complete staging evaluation including physical examination, biopsy of the primary tumor, and contrast enhanced (ce)-PET/CT. Patients were positioned as they would be for their subsequent radiotherapy. PET and CT images were evaluated independently for detectability and localization of the primary tumor, pelvic and inguinal lymph nodes, and distant metastasis. The stage, determined by CT or PET alone, and the proposed therapy planning were compared with the stage and management determined by ce-PET/CT. Data from ce-PET/CT were used for radiotherapy planning. RESULTS: ce-PET/CT revealed locoregional lymph node metastasis in 11 of 22 patients (50%). After simultaneous reading of PET and CT data sets by experienced observers, 3 patients (14%) were found to have sites of disease not seen on CT that were identified on PET. Two patients had sites of disease not seen on PET that were identified on CT. In summary, 2 patients were upstaged, and 4 patients were downstaged due to ce-PET/CT. However, radiotherapy fields were changed due to the results from ce-PET/CT in 23% of cases compared to CT or PET results alone. CONCLUSIONS: ce-PET/CT is superior to PET or CT alone for staging of anal cancer, with significant impact on therapy planning. PMID- 20832182 TI - Quality of life after whole pelvic versus prostate-only external beam radiotherapy for prostate cancer: a matched-pair comparison. AB - PURPOSE: Comparison of health-related quality of life after whole pelvic (WPRT) and prostate-only (PORT) external beam radiotherapy for prostate cancer. METHODS AND MATERIALS: A group of 120 patients (60 in each group) was surveyed prospectively before radiation therapy (RT) (time A), at the last day of RT (time B), at a median time of 2 months (time C) and >1 year after RT (time D) using a validated questionnaire (Expanded Prostate Cancer Index Composite). All patients were treated with 1.8- to 2.0-Gy fractions up to 70.2 to 72.0 Gy with or without WPRT up to 45 to 46 Gy. Pairs were matched according to the following criteria: age+/-5 years, planning target volume+/-10 cc (considering planning target volume without pelvic nodes for WPRT patients), urinary/bowel/sexual function score before RT+/-10, and use of antiandrogens. RESULTS: With the exception of prognostic risk factors, both groups were well balanced with respect to baseline characteristics. No significant differences were found with regard to urinary and sexual score changes. Mean bladder function scores reached baseline levels in both patient subgroups after RT. However, bowel function scores decreased significantly more for patients after WPRT than in those receiving PORT at all times (p<0.01, respectively). Significant differences were found for most items in the bowel domain in the acute phase. At time D, patients after WPRT reported rectal urgency (>once a day in 15% vs. 3%; p=0.03), bloody stools (>=half the time in 7% vs. 0%; p=0.04) and frequent bowel movements (>two on a typical day in 32% vs. 7%; p<0.01) more often than did patients after PORT. CONCLUSION: In comparison to PORT, WPRT (larger bladder and rectum volumes in medium dose levels, but similar volumes in high dose levels) was associated with decreased bowel quality of life in the acute and chronic phases after treatment but remained without adverse long-term urinary effects. PMID- 20832183 TI - Prevalence of neuropathic pain in radiotherapy oncology units. AB - PURPOSE: Neuropathic pain (NP) in cancer patients severely impacts quality of life. Radiotherapy (RT) may cause NP, and at the same time, cancer patients visit RT units for pain relief. NP prevalence at these sites and current analgesic treatment should be assessed to improve management. METHODS AND MATERIALS: This epidemiological, prospective, multicenter study was undertaken to assess NP prevalence, according to Douleur Neuropathique 4 questions questtionaire (DN4) test results, and analgesic management in cancer pain patients visiting RT oncologic units. Secondary analyses assessed NP etiology and pain intensity (using the Brief Pain Inventory-Short Form) and impact (using the Hospital Anxiety and Depression Scale (HADS), Medical Outcomes Study [MOS] for Sleep, and the Health Survey Short Form-12). RESULTS: A total of 1,098 patients with any kind of pain were registered. NP prevalence was 31.1% (95% confidence interval, 28.4%--33.9%); 291 NP patients (mean age, 62.2 +/-12.5 years and 57.7% men) were eligible for study; 49% of patients were overweight. The most frequent tumors were those of breast and lung, and stage IIIB was the most common cancer stage. The tumors caused 75% of NP cases. Anxiety, sleepiness, and depression were common. At 8 weeks, pain intensity and interference with daily activities decreased significantly for 50.8% of responders. Depression and anxiety (p < 0.0001) scores on the Physical Component Summary and Mental Component Summary measures (p < 0.0001) and all MOS-Sleep subscales, except for snoring, improved significantly. The percentage of satisfied patients increased from 13.8% to 87.4% (p < 0.0001) with the current analgesic treatment, which meant a 1.2- and 6-fold increase (p < 0.0001) in narcotic analgesics and anticonvulsants, respectively, compared to previous treatment. CONCLUSIONS: NP is highly prevalent at RT oncology units, with sleepiness, anxiety, and depression as frequent comorbidities. There is a need to improve management of NP with increased use of more specific NP-targeting drugs. PMID- 20832184 TI - Image-guided localization accuracy of stereoscopic planar and volumetric imaging methods for stereotactic radiation surgery and stereotactic body radiation therapy: a phantom study. AB - PURPOSE: To evaluate the positioning accuracies of two image-guided localization systems, ExacTrac and On-Board Imager (OBI), in a stereotactic treatment unit. METHODS AND MATERIALS: An anthropomorphic pelvis phantom with eight internal metal markers (BBs) was used. The center of one BB was set as plan isocenter. The phantom was set up on a treatment table with various initial setup errors. Then, the errors were corrected using each of the investigated systems. The residual errors were measured with respect to the radiation isocenter using orthogonal portal images with field size 3 * 3 cm(2). The angular localization discrepancies of the two systems and the correction accuracy of the robotic couch were also studied. A pair of pre- and post-cone beam computed tomography (CBCT) images was acquired for each angular correction. Then, the correction errors were estimated by using the internal BBs through fiducial marker-based registrations. RESULTS: The isocenter localization errors (MU +/-sigma) in the left/right, posterior/anterior, and superior/inferior directions were, respectively, -0.2 +/- 0.2 mm, -0.8 +/- 0.2 mm, and -0.8 +/- 0.4 mm for ExacTrac, and 0.5 +/- 0.7 mm, 0.6 +/- 0.5 mm, and 0.0 +/- 0.5 mm for OBI CBCT. The registration angular discrepancy was 0.1 +/- 0.2 degrees between the two systems, and the maximum angle correction error of the robotic couch was 0.2 degrees about all axes. CONCLUSION: Both the ExacTrac and the OBI CBCT systems showed approximately 1 mm isocenter localization accuracies. The angular discrepancy of two systems was minimal, and the robotic couch angle correction was accurate. These positioning uncertainties should be taken as a lower bound because the results were based on a rigid dosimetry phantom. PMID- 20832185 TI - Use of 3.0-T MRI for stereotactic radiosurgery planning for treatment of brain metastases: a single-institution retrospective review. AB - PURPOSE: To investigate the efficacy of 3.0-T magnetic resonance imaging (MRI) for detecting brain metastases for stereotactic radiosurgery (SRS) planning. METHODS AND MATERIALS: All adult patients scheduled for SRS treatment for brain metastases at our institution between October 2005 and January 2008 were eligible for analysis. All patients underwent radiosurgery treatment planning 3.0-T MRI on the day of scheduled radiosurgery and a diagnostic 1.5-T MRI in the days or weeks prior to radiosurgery for comparison. Both scans were interpreted by neuroradiologists who reported their findings in the radiology reports. We performed a retrospective review of the radiology reports to determine the number of brain metastases identified using each MRI system. RESULTS: Of 254 patients scheduled for treatment from October 2005 to January 2008, 138 patients had radiology reports that explicitly described the number of metastases identified on both scans. With a median interval of 17 days (range, 1-82) between scans, the number of metastases detected using 1.5-T MRI system ranged from 1 to 5 and from 1 to 8 using the 3.0 T-MRI system. Twenty-two percent of patients were found to have a greater number of metastases with the 3.0 T-MRI system. The difference in number of metastases detected between the two scans for the entire cohort ranged from 0 to 6. Neither histology (p = 0.52 by chi-sq test) nor time between scans (p = 0.62 by linear regression) were significantly associated with the difference in number of metastases between scans. CONCLUSIONS: The 3.0-T MRI system appears to be superior to a 1.5-T MRI system for detecting brain metastases, which may have significant implications in determining the appropriate treatment modality. Our findings suggest the need for a prospectively designed study to further evaluate the use of a 3.0 T-MRI system for stereotactic radiosurgery planning in the treatment of brain metastases. PMID- 20832186 TI - Evaluation of four techniques using intensity-modulated radiation therapy for comprehensive locoregional irradiation of breast cancer. AB - PURPOSE: To establish optimal intensity-modulated radiation therapy (IMRT) techniques for treating the left breast and regional nodes, using moderate deep inspiration breath hold. METHODS AND MATERIALS: We developed four IMRT plans of differing complexity for each of 10 patients following lumpectomy for left breast cancer. A dose of 60 Gy was prescribed to the boost planning target volume (PTV) and 52.2 Gy to the breast and supraclavicular, infraclavicular, and internal mammary nodes. Two plans used inverse-planned beamlet techniques: a 9-field technique, with nine equispaced axial beams, and a tangential beamlet technique, with three to five ipsilateral beams. The third plan (a segmental technique) used a forward-planned multisegment technique, and the fourth plan (a segmental blocked technique) was identical but included a block to limit heart dose. Dose- volume histograms were generated, and metrics chosen for comparison were analyzed using the paired t test. RESULTS: Mean heart and left anterior descending coronary artery doses were similar with the tangential beamlet and segmental blocked techniques but higher with the segmental and 9-field techniques (mean paired difference of 15.1 Gy between segmental and tangential beamlet techniques, p < 0.001). Substantial volumes of contralateral tissue received dose with the 9 field technique (mean right breast V2, 58.9%; mean right lung V2, 75.3%). Minimum dose to >=95% of breast PTV was, on average, 45.9 Gy with tangential beamlet, 45.0 Gy with segmental blocked, 51.4 Gy with segmental, and 50.2 Gy with 9-field techniques. Coverage of the internal mammary region was substantially better with the two beamlet techniques than with the segmental blocked technique. CONCLUSIONS: Compared to the 9-field beamlet and segmental techniques, a tangential beamlet IMRT technique reduced exposure to normal tissues and maintained reasonable target coverage. PMID- 20832187 TI - Positional reproducibility of pancreatic tumors under end-exhalation breath-hold conditions using a visual feedback technique. AB - PURPOSE: To assess positional reproducibility of pancreatic tumors under end exhalation (EE) breath-hold (BH) conditions with a visual feedback technique based on computed tomography (CT) images. METHODS AND MATERIALS: Ten patients with pancreatic cancer were enrolled in an institutional review board-approved trial. All patients were placed in a supine position on an individualized vacuum pillow with both arms raised. At the time of CT scan, they held their breath at EE with the aid of video goggles displaying their abdominal displacement. Each three-consecutive helical CT data set was acquired four times (sessions 1-4; session 1 corresponded to the time of CT simulation). The point of interest within or in proximity to a gross tumor volume was defined based on certain structural features. The positional variations in point of interest and margin size required to cover positional variations were assessed. RESULTS: The means +/ standard deviations (SDs) of intrafraction positional variations were 0.0 +/- 1.1, 0.1 +/- 1.2, and 0.1 +/- 1.0 mm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively (p = 0.726). The means +/- SDs of interfraction positional variations were 0.3 +/- 2.0, 0.8 +/- 1.8, and 0.3 +/- 1.8 mm in the LR, AP, and SI directions, respectively (p = 0.533). Population-based margin sizes required to cover 95th percentiles of the overall positional variations were 4.7, 5.3, and 4.9 mm in the LR, AP, and SI directions, respectively. CONCLUSIONS: A margin size of 5 mm was needed to cover the 95th percentiles of the overall positional variations under EE-BH conditions, using this noninvasive approach to motion management for pancreatic tumors. PMID- 20832189 TI - Adenoviral E4orf3 and E4orf6 proteins, but not E1B55K, increase killing of cancer cells by radiotherapy in vivo. AB - PURPOSE: Radiotherapy is widely used for treatment of many tumor types, but it can damage normal tissues. It has been proposed that cancer cells can be selectively sensitized to radiation by adenovirus replication or by using radiosensitizing transgenes. Adenoviral proteins E1B55K, E4orf3, and E4orf6 play a role in radiosensitization, by targeting the Mre11, Rad50, and NBS1 complex (MRN) and inhibiting DNA double-strand break (DSB) repair. We hypothesize that combined with irradiation, these adenoviral proteins increase cell killing through the impairment of DSB repair. METHODS AND MATERIALS: We assessed the radiosensitizing/additive potential of replication-deficient adenoviruses expressing E1B55K, E4orf3, and E4orf6 proteins. Combination treatments with low dose external photon beam radiotherapy were studied in prostate cancer (PC-3MM2 and DU-145), breast cancer (M4A4-LM3), and head and neck cancer (UT-SCC8) cell lines. We further demonstrated radiosensitizing or additive effects in mice with PC-3MM2 tumors. RESULTS: We show enhanced cell killing with adenovirus and radiation combination treatment. Co-infection with several of the viruses did not further increase cell killing, suggesting that both E4orf6 and E4orf3 are potent in MRN inhibition. Our results show that adenoviral proteins E4orf3 and E4orf6, but not E1B55K, are effective also in vivo. Enhanced cell killing was due to inhibition of DSB repair resulting in persistent double-strand DNA damage, indicated by elevated phospho-H2AX levels at 24 h after irradiation. CONCLUSIONS: This knowledge can be applied for improving the treatment of malignant tumors, such as prostate cancer, for development of more effective combination therapies and minimizing radiation doses and reducing side effects. PMID- 20832188 TI - Effect of irradiation on microvascular endothelial cells of parotid glands in the miniature pig. AB - PURPOSE: To evaluate the effect of irradiation on microvascular endothelial cells in miniature pig parotid glands. METHODS AND MATERIALS: A single 25-Gy dose of irradiation (IR) was delivered to parotid glands of 6 miniature pigs. Three other animals served as non-IR controls. Local blood flow rate in glands was measured pre- and post-IR with an ultrasonic Doppler analyzer. Samples of parotid gland tissue were taken at 4 h, 24 h, 1 week, and 2 weeks after IR for microvascular density (MVD) analysis and sphingomyelinase (SMase) assay. Histopathology and immunohistochemical staining (anti-CD31 and anti-AQP1) were used to assess morphological changes. MVD was determined by calculating the number of CD31- or AQP1-stained cells per field. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay was used to detect apoptotic cells. The activity of acid and neutral Mg(2+)-dependent SMase (ASMase and NSMase, respectively) was also assayed. RESULTS: Local parotid gland blood flow rate decreased rapidly at 4 h post-IR and remained below control levels throughout the 14-day observation period. Parotid MVD also declined from 4 to 24 hours and remained below control levels thereafter. The activity levels of ASMase and NSMase in parotid glands increased rapidly from 4 to 24 h post-IR and then declined gradually. The frequency of detecting apoptotic nuclei in the glands followed similar kinetics. CONCLUSIONS: Single-dose IR led to a significant reduction of MVD and local blood flow rate, indicating marked damage to microvascular endothelial cells in miniature pig parotid glands. The significant and rapid increases of ASMase and NSMase activity levels may be important in this IR-induced damage. PMID- 20832190 TI - [Late vaginal mesh exposure after prolapse repair]. AB - Mesh exposure is the major complication of vaginal prolapse repair. Incidence rates are variable according to the series. Mesh exposure usually occurs during the year following the intervention. We report here the first case of a patient with a late exposure of an anterior vaginal mesh 4 years after a surgical cystocele repair. The mesh has been easily removed at the operative theatre by vaginal approach. PMID- 20832191 TI - [Acute human herpesvirus 6 (HHV-6) infections: when and how to treat?]. AB - The pathogenicity of human herpesvirus 6 (HHV-6) still raises numerous questions. Acute HHV-6 infections correspond to primary infections, reactivations or exogenous reinfections. The expression of related clinical symptoms is highly variable but may be extremely severe, particularly among immunocompromised patients. The prototypic severe disease associated with these infections is limbic encephalitis occurring in stem cell transplant recipients. The diagnosis of acute HHV-6 infections relies on the quantitation of viral load in whole blood by means of quantitative PCR. The demonstration of HHV-6 causative role in the genesis of clinical symptoms requires additional investigations such as the search for HHV-6 DNA in cerebrospinal fluid in case of encephalitis. The chromosomal integration of HHV-6 DNA is a rare event among HHV-6-infected subjects but may alter the interpretation of virological results. Therapy with ganciclovir, foscarnet or cidofovir has not yet clear indications but, at the current stage of knowledge, only concerns the treatment of highly symptomatic infections. The usefulness of prophylactic or pre-emptive antiviral chemotherapy has not yet been convincingly demonstrated. Treatment efficacy must be checked through a clinical and virological follow up, based in part on quantitative PCR approaches. Controlled studies are urgently needed with the goal of evaluating the cost-effectiveness of HHV-6 follow up and therapy in different clinical situations. PMID- 20832192 TI - [Medical genetics]. PMID- 20832193 TI - [Interest of real-time PCR Xpert MRSA/SA on GeneXpert((r)) DX System in the investigation of staphylococcal bacteremia]. AB - AIM OF THE STUDY: Recently, a rapid, fully automated real-time PCR test has become available for detection of Staphylococcus aureus in positive blood cultures, Xpert MRSA/SA blood culture. This study was defined to evaluate the use of this product in our hospital setting to assist in optimizing antibiotic treatment. MATERIALS AND METHODS: Over a period of 18months (from February 2008 to July 2009), 51 positive blood cultures were examined for Staphylococcus using the Xpert MRSA/SA assay on the GeneXpert((r)) System. The PCR results were transferred to the clinician as soon as available. The presence of empirical antibiotic therapy was noted and modified if necessary after discussions between the clinician and the infectious disease specialist. RESULTS: Twenty-three blood bottles were positive for S. aureus, two were resistant to methicillin. Twenty eight were coagulase negative staphylococci. No discrepancy between identification (S. aureus) and methicillin resistance was observed. Thirty-two samples had clinically significant bacteremia (23 S. aureus and nine coagulase negative staphylococci). Sixteen (50%) of these patients had received inappropriate antibiotic therapy (11 without antibiotic therapy, five with betalactam antibiotics). For these patients, an appropriate antibiotic therapy was prescribed according to these results. Sixteen patients had adequate empirical antibiotic therapy at the time of receiving the PCR result. Among these 16 patients, eight switches were performed from broad-spectrum treatment to a more restrictive antistaphylococcal treatment. Of the 19 patients with a nonclinically relevant coagulase negative staphylococci infection, four were already on antibiotics for other infections and these treatments were not modified. Empirical treatment could be avoided in 13 patients who had a clinical presentation consistent with staphylococcal bacteremia (multiple sores, history of carrying methicllin-resistant or susceptible S. aureus infection, presence of intravascular material or prosthesis). CONCLUSION: The real-time PCR Cepheid Xpert MRSA/SA on GeneXpert((r)) DX System has become an essential tool in our laboratory enhancing the reports of positive blood cultures for staphylococci. This test is fast (50min) and reliable. It allows optimization of antibiotic therapy in hospital. PMID- 20832194 TI - [Antibacterial activity against 224 clinical bacterial strains of JCA 250 and JCA 251 compounds containing essential oils provided from Aroma Technologies research]. AB - OBJECTIVE: It was to determine the antibacterial spectrum of JCA 250 and JCA 251, two naturally occurring compounds from Aroma Technologies research, on a bacterial population isolated from clinical infections. METHOD: Two hundred and twenty-four bacterial strains were tested. The minimum inhibitory concentrations (MIC) of JCA 250 and JCA 251 were determined by agar dilution method. Tests were performed in triplicate. RESULTS: The mean MIC was 0.20% for JCA 250 and 0.15% for JCA 251. JCA 251 regularly exhibited greater activity. All Enterobacteriaceae were inhibited at concentrations less or equal to 0.15% for JCA 250 or JCA 251. For strict aerobes, the MIC values were more spread out. Two Pseudomonas aeruginosa strains differed from the population with JCA 251 MIC of 0.25 and 0.40%. Concerning Gram-positive cocci, all the strains were inhibited with less or equal to 0.25% of compound. The most resistant population were the Enterococci and the Lactobacilli, with MIC more or equal to 0.2% for JCA 250 or JCA 251. Anaerobes showed MIC closely grouped for a heterogeneous bacterial group. One Propionibacterium sp. strain came apart from the group and was inhibited with a MIC of 0.5%. CONCLUSION: The overall results showed an interesting antibacterial activity on bacteria isolated from clinical samples. Most of the bacterial strains were inhibited at a concentration of 0.2%. The highest mean values were obtained for commensal bacteria from the flora, which is of particular interest in this study. PMID- 20832195 TI - [Prevalence of Candida parapsilosis, C. orthopsilosis and C. metapsilosis in candidemia over a 5-year period at Nantes hospital and in vitro susceptibility to three echinocandins by E-test(r)]. AB - AIM OF THE STUDY: To determine the prevalence of C. parapsilosis sensu stricto, C. orthopsilosis and C. metapsilosis among candidemia at Nantes University Hospital and to evaluate the in vitro susceptibility of the isolates against three echinocandin drugs (caspofungin, micafungin and anidulafungin). MATERIAL AND METHODS: Retrospective study (march 2004 to july 2009) of 178 cases of candidemia corresponding to 183 Candida spp. strains identified by means of routine phenotypical methods. Re-identification of C. parapsilosis sensu lato isolates was performed by ITS rDNA sequencing analysis. Minimal inhibitory concentrations (MIC) were determined by E-test((r)). All echinocandin non susceptible isolates (MIC>2 MUg/mL) were analyzed for the presence/absence of FKS1 mutations associated with resistance. RESULTS: During this period, C. parapsilosis sensu lato was responsible for 27 candidemia, ranging at the second most common Candida species after C. albicans (n=99, 54.1%). Neither isolates belong to C. orthopsilosis nor C. metapsilosis. According to the literature, all the isolates displayed high MICs against the three echinocandin drugs. All the isolates displayed both susceptibility (MIC <= 2 MUg/mL) and a good agreement between MICs read at 24h and 48 h for caspofungin and micafungin (MIC(50)=0.75 MUg/mL, MIC(90)=1.5 MUg/mL). Surprisingly, whereas most of the strains were susceptible to anidulafungin at 24h (MIC(50)=1 MUg/mL, MIC(90)=1.5 MUg/mL), 14 (52 %) displayed non-susceptibility, despite the lack of mutation associated with resistance on FKS1, when reading was performed at 48 h (MIC(50)=3 MUg/mL, MIC(90)=12 MUg/mL). CONCLUSION: Prevalence of C. orthopsilosis and C. metapsilosis in patients with candidemia is low at Nantes University Hospital. The difficulty encountered with MIC reading by E-test((r)) are discussed. PMID- 20832196 TI - Directly observed antiretroviral therapy improves adherence and viral load in drug users attending methadone maintenance clinics: a randomized controlled trial. AB - OBJECTIVE: To determine if directly observed antiretroviral therapy (DOT) is more efficacious than self-administered therapy for improving adherence and reducing HIV viral load (VL) among methadone-maintained opioid users. DESIGN: Two-group randomized trial. SETTING: Twelve methadone maintenance clinics with on-site HIV care in the Bronx, New York. PARTICIPANTS: HIV-infected adults prescribed combination antiretroviral therapy. MAIN OUTCOMES MEASURES: Between group differences at four assessment points from baseline to week 24 in: (1) antiretroviral adherence measured by pill count, (2) VL, and (3) proportion with undetectable VL (< 75 copies/ml). RESULTS: Between June 2004 and August 2007, we enrolled 77 participants. Adherence in the DOT group was higher than in the control group at all post-baseline assessment points; by week 24 mean DOT adherence was 86% compared to 56% in the control group (p < 0.0001). Group differences in mean adherence remained significant after stratifying by baseline VL (detectable versus undetectable). In addition, during the 24-week intervention, the proportion of DOT participants with undetectable VL increased from 51% to 71%. CONCLUSIONS: Among HIV-infected opioid users, antiretroviral DOT administered in methadone clinics was efficacious for improving adherence and decreasing VL, and these improvements were maintained over a 24-week period. DOT should be more widely available to methadone patients. PMID- 20832197 TI - Factors associated with attendance in 12-step groups (Alcoholics Anonymous/Narcotics Anonymous) among adults with alcohol problems living with HIV/AIDS. AB - BACKGROUND: Despite the value of 12-step meetings, few studies have examined factors associated with attendance among those living with HIV/AIDS, such as the impact of HIV disease severity and demographics. OBJECTIVE: This study examines predisposing characteristics, enabling resources and need on attendance at Alcoholic Anonymous (AA) and Narcotics Anonymous (NA) meetings among those living with HIV/AIDS and alcohol problems. METHODS: Secondary analysis of prospective data from the HIV-Longitudinal Interrelationships of Viruses and Ethanol study, a cohort of 400 adults living with HIV/AIDS and alcohol problems. Factors associated with AA/NA attendance were identified using the Anderson model for vulnerable populations. Generalized estimating equation logistic regression models were fit to identify factors associated with self-reported AA/NA attendance. RESULTS: At study entry, subjects were 75% male, 12% met diagnostic criteria for alcohol dependence, 43% had drug dependence and 56% reported attending one or more AA/NA meetings (past 6 months). In the adjusted model, female gender negatively associated with attendance, as were social support systems that use alcohol and/or drugs, while presence of HCV antibody, drug dependence diagnosis, and homelessness associated with higher odds of attendance. CONCLUSIONS: Non-substance abuse related barriers to AA/NA group attendance exist for those living with HIV/AIDS, including females and social support systems that use alcohol and/or drugs. Positive associations of homelessness, HCV infection and current drug dependence were identified. These findings provide implications for policy makers and treatment professionals who wish to encourage attendance at 12-step meetings for those living with HIV/AIDS and alcohol or other substance use problems. PMID- 20832198 TI - Can Hepatitis C virus treatment be used as a prevention strategy? Additional model projections for Australia and elsewhere. AB - Zeiler et al. (2010) use a simple model to project the potential prevention utility of using pegylated interferon and ribavirin to treat active injecting drug users (IDUs) for HCV infection. Their analysis shows that increasing the level of HCV treatment in Australia could dramatically reduce the prevalence of HCV infection among IDUs. We argue that their projections are under-estimating the possible impact of HCV treatment because their assumed prevalence of active HCV infection in Australia is too high (assumed prevalence of acute plus chronic is 60%) and their model effectively assumes a treatment efficacy of 33%. We replicate their model and show that if these issues are corrected (assuming 45% prevalence of active HCV infection, i.e. ~60% antibody prevalence and 50% treatment efficacy), then substantially greater impact can be achieved. In addition, we show that the effect of HCV treatment on the primary prevention of HCV increases in populations with lower background HCV prevalence. We also query their finding that HCV treatment should be preferentially targeted to IDUs not on methadone maintenance treatment. PMID- 20832201 TI - The two-component regulatory system CiaRH contributes to the virulence of Streptococcus suis 2. AB - Two-component regulatory systems (TCSs) are widely distributed among bacteria and enable the organisms to make coordinated changes in gene expression in response to a variety of environmental stimuli. In this work, we constructed a mutant strain of the TCS CiaRH and measured its virulence in vitro and in vivo. Compared with the wild type strain, the mutant strain exhibited a significant decrease in adherence to epithelial cells Hep-2 and PIEC. Furthermore, the deletion of CiaRH not only enhanced the bactericidal activity of RAW264.7 macrophage against Streptococcus suis 2, but also increased blood clearance of S. suis 2 in vivo. More importantly, the mutant was attenuated in vivo in CD1 mice and pigs, with reduced mortality, morbidity and impaired bacterial growth observed in specific organs. These results suggest that the CiaRH is required for S. suis 2 virulence. PMID- 20832202 TI - The impact of consanguinity on neonatal and infant health. AB - Marriage between biological relatives is widely popular in many parts of the world, with over 1000 million people living in countries where 20-50+% of unions are contracted between couples related as second cousins or closer. Consanguinity is, however, a controversial topic, in part due to public misunderstanding, complicated by often exaggerated past estimates of the adverse health outcomes. While some consanguineous couples are at high risk of conceiving a child with a genetic disorder, they are a small minority. Thus a multi-population meta analysis has indicated an excess infant death rate of 1.1% in the progeny of first cousins, and even this figure may be compromised by inadequate control for non-genetic variables. The benefits as well as the disadvantages of consanguineous marriage are assessed and discussed, with specific consideration given to the health of migrant communities in Western countries, among whom first cousin marriage remains preferential. PMID- 20832200 TI - Validity of a demand curve measure of nicotine reinforcement with adolescent smokers. AB - High or inelastic demand for drugs is central to many laboratory and theoretical models of drug abuse, but it has not been widely measured with human substance abusers. The authors used a simulated cigarette purchase task to generate a demand curve measure of nicotine reinforcement in a sample of 138 adolescent smokers. Participants reported the number of cigarettes they would purchase and smoke in a hypothetical day across a range of prices, and their responses were well-described by a regression equation that has been used to construct demand curves in drug self-administration studies. Several demand curve measures were generated, including breakpoint, intensity, elasticity, P(max), and O(max). Although simulated cigarette smoking was price sensitive, smoking levels were high (8+ cigarettes/day) at prices up to 50c per cigarette, and the majority of the sample reported that they would purchase at least 1 cigarette at prices as high as $2.50 per cigarette. Higher scores on the demand indices O(max) (maximum cigarette purchase expenditure), intensity (reported smoking level when cigarettes were free), and breakpoint (the first price to completely suppress consumption), and lower elasticity (sensitivity of cigarette consumption to increases in cost), were associated with greater levels of naturalistic smoking and nicotine dependence. Greater demand intensity was associated with lower motivation to change smoking. These results provide initial support for the validity of a self-report cigarette purchase task as a measure of economic demand for nicotine with adolescent smokers. PMID- 20832203 TI - Cryopreservation of ovarian tissue: an emerging technology for female germline preservation of endangered species and breeds. AB - Many hundreds of exotic species and domestic animal breeds have been lost over the course of the last few decades. In order to avoid a similar fate to other animals threatened with extinction, it is crucial to develop and apply rescue strategies to ensure their survival for the future. One option as a safeguard measure is the cryopreservation of the main source of female gametes enclosed within the ovary: the primordial follicles. So far, there are three options to cryopreserve small ovarian follicles: whole ovary, ovarian cortical tissue or isolated follicles, with the use of slow freezing or vitrification methods. After cryopreservation, the harvested material can be transplanted or cultured, with the aim to produce mature fertilizable oocytes. The objective of this review is to summarize the current status of the cryopreservation of ovarian tissue in domestic species and non-endangered wild mammals as model for threatened and endangered species and breeds, and to provide new insights into techniques that can be applied in the future. PMID- 20832204 TI - Use of a stochastic simulation model to assess effects of diagnostic specificity of systems for detecting ovulating cows on herd reproductive performance in year round calving dairy herds. AB - Many automated systems for detecting ovulating cows in dairy herds require decisions when designing algorithms and selecting cutpoints that require a compromise between diagnostic sensitivity (probability of classifying an ovulating cow as ovulating) and diagnostic specificity [daily probability of not classifying a non-ovulating cow (whether open or pregnant but not yet diagnosed as pregnant) as ovulating]. Because sensitivity must be moderately high, this compromise often results in specificity below 100%. However, little is understood about the effects of reduced specificity on herd reproductive performance. A stochastic model was developed that simulates the reproductive process in a year round calving dairy herd to assess effects of changes in specificity at various combinations of sensitivity and conception rate (proportion of inseminations resulting in pregnancy) on herd reproductive measures of economic importance. The model included effects of inseminations in pregnant cows on probability of conceptus loss, and variation in the interval from conceptus loss to next ovulation (i.e. the next opportunity to reconceive). Using moderate assumptions of the probability of conceptus loss following insemination in pregnant cows, reductions in specificity from 99.9 to 99.5, 99, 98 and 97%, resulted in decreases in mean 100 day in-calf rate (100DICR; the proportion of cows with a positive pregnancy diagnosis to an insemination on or before 100 days since calving) of 1.2, 3.3, 6.8 and 9.7 percentage points, respectively. These same reductions in Sp resulted in increases in mean 200 day not in-calf rate (200DNICR; the proportion of cows with negative pregnancy diagnosis results to all inseminations on or before 200 days since calving) of 0.5, 1.6, 3.6 and 6 percentage points, and increases in mean number of inseminations per calving (Insems/Calving; the total number of inseminations in the herd divided by the number of cows that recalved) by factors of 1.2, 1.5, 2.1 and 2.8, respectively. The relationship between specificity for detecting ovulating cows and the 100DICR, 200DNICR and Insems/Calving was sensitive to changes in the probability of conceptus loss following inseminations in pregnant cows. However, even with conservative assumptions, specificity still had important effects on 100DICR and 200DNICR. Varying parameters for the interval from conceptus loss to next ovulation had little effect on the relationships between specificity and these measures. These results demonstrate that specificity is an important consideration when designing algorithms and selecting cutpoints in automated systems for detecting ovulating cows. Low specificity not only increases Insems/Calving but also prolongs intervals from calving to the establishment of a sustained pregnancy resulting in substantial reductions in 100DICR and increases in 200DNICR. This model could assist when determining economically optimal combinations of ovulation detection sensitivity and specificity when developing automated systems for selecting ovulating cows in commercial herds. PMID- 20832205 TI - Modelling female reproductive function in farmed animals. AB - Impaired reproduction in farmed animals is a major cost to agriculture, and this is exacerbated by the implementation of intensive production systems. Addressing this has been the focus of a significant body of research. While considerable advances have been made in biological experiments and understanding, a systems insight into the mechanisms that underlie reproductive function in mammals is needed. Mathematical modelling offers a means to develop a systems approach to reproduction by coalescing information and predicting outcomes of interventions. There has been steady progress in the development of mathematical models addressing various issues of reproduction over the last decade, from cell signalling pathways through to herd management. We review these developments and their insights as well as their limitations. In addition, we identify other areas that need development, and how modelling might usefully contribute to these areas of reproduction science. PMID- 20832207 TI - Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry profiling of trace constituents of condom lubricants in the presence of biological fluids. AB - The use of condoms in sexual assault cases has become increasingly common due to the heightened awareness of the use of DNA as evidence in criminal investigations. The ability to identify and differentiate the polymers and additives found in lubricant residues can provide investigators leads and insights as to the perpetrator of a sexual assault. Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS) is ideal for detecting condom lubricants and additives; the instrument is capable of surveying analytes across a wide mass range and is a preferred technique for the analysis of polymers. Three MALDI-TOF-MS methods directed toward the detection and differentiation of condom and personal lubricant residues, as well as their mixtures with biological fluids, were developed and compared: (a) a sample premixed with aqueous matrix; (b) a sample premixed with an ionic liquid matrix; and (c) a layering method that incorporates a cationization reagent. Of the three, the layered method that utilized sodium chloride as a cationization reagent showed the best sensitivity and selectivity. This method allowed for the segregation of the various lubricant formulas into a discrete number of groups. Infrared spectroscopy was used to support and clarify the MALDI data. Principal component analysis was used to further demonstrate the ability of this method to segregate various lubricant types into a limited number of classes. Additionally, lubricant residues could be detected in the presence of biological fluids down to a fraction of a percent. PMID- 20832206 TI - Bacterial contamination of ram semen, antibiotic sensitivities, and effects on sperm quality during storage at 15 degrees C. AB - This study was designed to determine the degree and type of bacterial contamination of ejaculated semen samples in fertile rams and its consequences on sperm quality during storage. In experiment 1, 68 ejaculates from 36 rams were divided into two aliquots, one of which was used for bacterial culture, while the other one was diluted, stored at 15 degrees C and assessed for plasma membrane integrity and motility at 0, 24 and 48h after dilution. From the 68 ejaculates, 66 were positive for aerobic bacteria, including 20 species of bacteria from 14 genera. The most frequently isolated bacteria were Escherichia coli, Proteus mirabilis, Enterobacter cloacae, Staphylococcus epidermis, and Staphylococcus aureus species. These 5 bacteria were present in 97% of all contaminated samples. All contaminant bacteria were found to be sensitive to gentamicin and to ceftiofur, with variable percentages of resistance to the other antibiotics evaluated. In samples with total enterobacteria count lower than 100 colony forming units (CFU)/ml, higher proportions of motile and progressive sperm and higher velocities of spermatozoa were observed at different times during storage. In experiment 2, pure cultures of the most frequently isolated bacteria were individually added to fresh semen samples of low contamination and tested for their effects on sperm quality during storage at 15 degrees C. Semen with E. coli showed a drastic reduction in motility, velocity and viability during storage. This reduction was also significant, but less drastic, in semen with E. cloacae and P. mirabilis, whereas it was partial and less pronounced in the other groups (S. epidermidis and S. aureus). In conclusion, the contamination of ram semen with enterobacterial species reduced sperm quality during storage at 15 degrees C, and the antibiotics gentamicin and ceftiofur showed the higher antimicrobial activities. PMID- 20832208 TI - Improved DCT-based detection of copy-move forgery in images. AB - Techniques for digital image tampering are becoming more and more sophisticated and widespread. Copy-move forgery is one of the tampering techniques that are frequently used. In this paper, an improved DCT-based method is developed to detect this specific artifact. Firstly, the image is divided into fixed-size overlapping blocks and, DCT is applied to each block to represent its features. Truncating is employed to reduce the dimension of the features. Then the feature vectors are lexicographically sorted and, duplicated image blocks will be neighboring in the sorted list. Thus duplicated image blocks will be compared in the matching step. To make the method more robust, a scheme to judge whether two feature vectors are similar is imported. Experiment results demonstrated that the proposed method can detect the duplicated regions even when an image was distorted by JPEG compression, blurring or additive white Gaussian noise. PMID- 20832209 TI - Uniqueness in the forensic identification sciences--fact or fiction? AB - Fingerprint analysts, firearms and toolmark examiners, and forensic odontologists often rely on the uniqueness proposition in order to support their theory of identification. However, much of the literature claiming to have proven uniqueness in the forensic identification sciences is methodologically weak, and suffers flaws that negate any such conclusion being drawn. The finding of uniqueness in any study appears to be an overstatement of the significance of its results, and in several instances, this claim is made despite contrary data being presented. The mathematical and philosophical viewpoint regarding this topic is that obtaining definitive proof of uniqueness is considered impossible by modern scientific methods. More importantly, there appears to be no logical reason to pursue such research, as commentators have established that uniqueness is not the essential requirement for forming forensic conclusions. The courts have also accepted this in several recent cases in the United States, and have dismissed the concept of uniqueness as irrelevant to the more fundamental question of the reliability of the forensic analysis. PMID- 20832210 TI - L-arginine is effective in stroke-like episodes of MELAS associated with the G13513A mutation. AB - We report a case involving a 15-year-old boy with MELAS (G13513A mutation) who developed several stroke-like episodes in a short period of time. Intravenous administration of l-arginine during the acute phase of the stroke-like episodes reduced symptoms immediately, and oral supplementation of l-arginine successfully prevented further stroke-like episodes. This is the first report on effective l arginine therapy in MELAS associated with the G13513A mutation. PMID- 20832211 TI - [Popliteal venous thrombosis associated with a false aneurysm revealing femoral exostosis in a child]. AB - Recent unprovoked and symptomatic thrombosis of the left popliteal vein was diagnosed in a 9-year-old girl. Treatment with low-molecular-weight heparin was initiated in association with vitamin K antagonist (INR 2.5), and compressive stockings. Two and a half months later, the ultrasound examination revealed a false aneurysm of the left distal superficial femoral artery. Knee X-rays showed a distal femoral exostosis. MRI clarified the relationship between the false aneurysm and the exostosis. Bone scintigraphy eliminated multiple exostoses. Resection of the false aneurysm associated with end-to-end femoro-popliteal saphenous bypass and exostosectomy in the same operative time were performed. On histopathological examination there was no sign of malignant transformation. Vascular complications of exostoses are infrequent and the association with deep venous thrombosis and false aneurysm is exceptional. This case report illustrates the contribution of knee X-rays to unravel this unusual clinical presentation. PMID- 20832212 TI - [Pandemic influenza A/H1N1v, pregnancy and vaccination]. AB - Seasonal flu is potentially more severe during pregnancy especially when it occurs in the last three months. Pregnant women were shown to be especially exposed to severe forms of the flu and death in the first weeks of the pandemic influenza A/H1N1v. For the first time in history, adequate vaccines were available in the early phase of the pandemic and recommended by WHO as a priority for pregnant women. In France, vaccination with the non-adjuvanted vaccine (Panenza(r)) was recommended after three months of pregnancy. However, the pandemic vaccines were discredited by the mass media and the population even before they were available. This was due to several factors, and especially to the lack of information on the vaccine and its potential toxicity and, in case of pregnancy, potential risk of adverse fetal events, despite the fact that available data shows the seasonal flu vaccine is effective and well tolerated in pregnant women. This article aimed to provide decisional elements for influenza A/H1N1v vaccination in pregnant women. PMID- 20832213 TI - [Epstein-Barr virus and cytomegalovirus primary infections: a comparative study in 52 immunocompetent adults]. AB - OBJECTIVE: The objective of this study was to compare epidemiological, clinical, and biological data of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) primary infections in immunocompetent adults, admitted in the infectious disease department of the Reims Teaching Hospital between 2000 and 2005. PATIENTS AND METHODS: Inclusion criteria were the presence of anti-VCA IgM antibodies or the presence of CMV specific IgM antibodies and the absence of any other positive serology. Differences in reported percentage were compared with a Khi(2) test or Fischer's exact test, when appropriate. Continuous variables were compared with the Mann-Whitney Test. RESULTS: There were no significant changes over the years in the numbers of EBV (n=32) and CMV (n=20) primary infections. The patient's mean age was 22.7 years (14-48 years) in EBV primary infections and 38.6 years (13-66 years) in CMV primary infections (P<0.01). The clinical variables significantly associated with primary EBV infection were sore throat and cervical lymphadenopathy (P<0.01). Arthromyalgia and respiratory manifestations were less frequent in EBV primary infection (P<0.01). The biological variables significantly associated with EBV primary infection were a marked alanine aminotransferase elevation and a marked lymphocytosis with atypical lymphocytes (P<0.001). Thrombopenia was less frequently associated with EBV primary infection (P<0.001). CONCLUSION: Clinical and biological presentations of EBV and CMV primary infections were similar. The simultaneous serologic diagnosis of these two infections remains necessary to provide a specific diagnosis, for the most efficient patient care. PMID- 20832214 TI - [Two cases of Fanconi's syndrome induced by tenofovir in the Ivory Coast]. PMID- 20832215 TI - Circulating free tumor DNA and colorectal cancer. AB - Cancer is characterized by multiple somatic genetic and epigenetic alterations that could be useful as molecular markers for detecting tumor DNA in different bodily fluids. In patients with various diseases as well as in healthy subjects, circulating plasma and serum carry small amounts of non-cell-bound DNA. In this free circulating DNA, tumor-associated molecular alterations can be detected in patients who have cancer. In many instances, the alterations identified are the same as those found in the primary tumor tissue, thereby suggesting tumor origin from a fraction of the circulating free DNA. In fact, various types of DNA alterations described in colorectal cancer have been detected in the circulating free DNA of patients with colorectal cancer. These alterations include KRAS2, APC and TP53 mutations, DNA hypermethylation, microsatellite instability (MSI) and loss of heterozygosity (LOH). Also, advances in polymerase chain reaction (PCR) based technology now allow the detection and quantification of extremely small amounts of tumor-derived circulating free DNA in colorectal cancer patients. The present report summarizes the literature available so far on the mechanisms of circulating free DNA, and on the studies aimed at assessing the clinical and biological significance of tumor-derived circulating free DNA in colorectal cancer patients. Thus, tumor-derived circulating free DNA could serve as a marker for the diagnosis, prognosis and early detection of recurrence, thereby significantly improving the monitoring of colorectal cancer patients. PMID- 20832216 TI - Sociogeographical factors associated with participation in colorectal cancer screening. AB - BACKGROUND/AIM: Sociodemographic factors associated with colorectal cancer screening participation have been extensively analysed although few, if any, studies have focused on regional/geographical factors as determinants of non participation rates. The purpose of this study was to investigate the effects of individual and geographical determinants on the variable participation rates seen for colorectal cancer screening. METHODS: The study population comprised 183,978 individuals in the first round of screening and 175,596 in the second round, all of whom were residents of the city of Marseille in France. The influence of age, gender and regional/geographical characteristics, such as proportion of migrants and property prices per square meter, on participation rates was assessed by multilevel analysis. RESULTS: The participation rate was lower for men (0.85; 95% CI: 0.83-0.86), and higher for those aged 65-69 years. Univariate analysis showed that participation rates were significantly different across the 16 municipal districts of Marseille (range: 22.8-36.7%; OR: 1.97; 95% CI: 1.86-2.08). On multivariate analysis, having a higher proportion of migrants in the district population was still associated with lower participation (OR: 0.96; 95% CI: 0.95 0.97). CONCLUSION: In addition to individual factors, regional/geographical factors appear to be relevant determinants of participation rates in urban colorectal cancer screening programs. PMID- 20832217 TI - False bisalbuminemia and hyperalphafetoproteinemia. AB - The capillary electrophoresis is a very powerful separation method offering a high degree of resolution. However, certain interferences can be detected giving transitory shoulders or peaks. We report the case of a serum protein electrophoresis performed with Capillarys (Sebia) in a 68-year-old patient, hospitalized for cancer of the head of the pancreas, which showed an important shoulder in the migratory range of albumin, simulating bisalbuminemia. An interference with alphafetoprotein was proven explaining this electrophoretic aspect. PMID- 20832218 TI - A fulminant colitis index greater or equal to 8 is not predictive of colectomy risk in infliximab-treated moderate-to-severe ulcerative colitis attacks. AB - INTRODUCTION: In severe attacks of ulcerative colitis (UC) treated with intravenous corticosteroids, a fulminant colitis index (FCI) greater or equal to 8 has been associated with a greater likelihood of colectomy (72 vs 16% with an FCI<8). This retrospective study aimed to assess the accuracy of such an association in infliximab-treated patients with moderate-to-severe bouts of UC. PATIENTS AND METHODS: The study was based on the medical files of 43 patients who had received at least one infusion of infliximab to treat moderate-to-severe UC (partial Mayo Clinic score). Remission and clinical response were also assessed using the partial Mayo score. The accuracy of an FCI greater or equal to 8 to predict the likelihood of colectomy was assessed by calculating the sensitivity, specificity, positive and negative predictive values, Yule's Q coefficient, Youden's index and statistical significance (Chi(2) test). RESULTS: After treatment with infliximab, 10 patients were in remission (23.3%), 21 (48.8%) had a clinical response, four (9.3%) had treatment failure (without, however, requiring colectomy) and eight (18.6%) had a colectomy. Calculation of the above mentioned indicators revealed that an FCI greater or equal to 8 was not an indicator of the risk of colectomy in this patient population, and found that only an FCI greater or equal to 16 was statistically significant. However, low values for sensitivity, positive predictive value and Youden's index preclude the clinical application of this latter result. CONCLUSION: In patients treated with infliximab for moderate-to-severe UC attacks, the FCI is not a predictor of colectomy. In such patients, the factors predictive of a response to treatment or likelihood of colectomy, currently acknowledged with corticosteroid treatment, need to be further assessed for infliximab treatment. PMID- 20832219 TI - CT colonography: role of a second reader CAD paradigm in the initial training of radiologists. AB - PURPOSE: To evaluate the influence of CAD for the evaluation of CT colonography (CTC) datasets by inexperienced readers during the attendance of a dedicated hands-on training course. METHOD AND MATERIALS: Twenty-seven radiologists inexperienced in CTC (11 with no CTC training at all, 16 having previously reviewed no more than 10 CTC cases overall) attended a hands-on training course based on direct teaching on fifteen workstations (four Advantage Windows 4.4 with Colon VCAR software, GE; six CADCOLON, Im3D; five ColonScreen (Toshiba/Voxar) with ColonCADTM API, Medicsight). During the course, readers were instructed to analyze 26 CTC cases including 38 colonic lesions obtained through low-dose MDCT acquisitions, consisting of 12 polyps sized less than 6 mm, 9 polyps sized between 6 and 10 mm, 12 polyps sized between 11 mm and 30 mm, and 5 colonic masses sized>3 cm. CTC images were reviewed by each reader both in 2D and 3D mode, respectively by direct evaluation of native axial images and MPR reconstructions, and virtual endoscopy or dissected views. Each reader had 15 min time for assessing each dataset without CAD, after which results were compared with those provided by CAD software. Global rater sensitivity for each lesion size before and after CAD usage was compared by means of two-tailed Student's t test, while sensitivity of each single reader before and after CAD usage was assessed with the McNemar test. RESULTS: For lesions sized<6 mm, global rater sensitivity was 0.1852+/-0.1656 (mean+/-SD) before CAD-assisted reading and 0.2345+/-0.1761 after CAD (p=0.0018). For lesions sized 6-9 mm, sensitivity was 0.2870+/-0.1016 before CAD-assisted reading and 0.3117+/-0.1099 after CAD (p=0.0027). For lesions sized 10-30 mm, sensitivity was 0.5308+/-0.2120 before CAD-assisted reading and 0.5637+/-0.2133 after CAD (p=0.0086), while for lesions sized>30 mm, sensitivity before CAD-assisted reading was 0.3556+/-0.3105 and did not change after CAD usage (p=1). Sensitivity of each single rater did not significantly differ before and after CAD for any lesion size category (McNemar test, p>0.05). Specificity was not significantly different before and after CAD for any lesion size (>96% for all size categories). CONCLUSION: CAD usage led to increased overall sensitivity of inexperienced readers for all polyps sizes, except for lesions>30 mm, but sensitivity of individual raters was not significantly higher compared with CAD-unassisted reading. PMID- 20832220 TI - Percutaneous CT-guided biopsy of the musculoskeletal system: results of 2027 cases. AB - INTRODUCTION: Biopsy of the musculoskeletal system is useful in the management of bone lesions particularly in oncology but they are often challenging procedures with a significant risk of complications. Computed tomography (CT)-guided needle biopsies may decrease these risks but doubts still exist about their diagnostic accuracy. This retrospective analysis of the experience of a single institution with percutaneous CT-guided biopsy of musculoskeletal lesions evaluates the results of these biopsies for bone lesions either in the appendicular skeleton or in the spine, and defines indications. MATERIALS AND METHODS: We reviewed the results of 2027 core needle biopsies performed over the past 18 years at the authors' institution. The results obtained are subject of this paper. RESULTS: In 1567 cases the correct diagnosis was made with the first CT-guided needle biopsy (77.3% accuracy rate), in 408 cases the sample was not diagnostic and in 52 inadequate. Within 30 days these 408 patients underwent another biopsy, which was diagnostic in 340 cases with a final diagnostic accuracy of 94%. Highest accuracy rates were obtained in primary and secondary malignant lesions. Most false negative results were found in cervical lesions and in benign, pseudotumoral, flogistic, and systemic pathologies. There were 22 complications (18 transient paresis, 3 haematomas, 1 retroperitoneal haematoma) which had no influence on the treatment strategy, nor on patient outcome. CONCLUSION: This technique is reliable and safe and should be considered nowadays the gold standard for biopsies of the musculoskeletal system. PMID- 20832221 TI - Quantification of aortic valve area at 256-slice computed tomography: comparison with transesophageal echocardiography and cardiac catheterization in subjects with high-grade aortic valve stenosis prior to percutaneous valve replacement. AB - PURPOSE: The purpose of this study was to compare planimetric aortic valve area (AVA) measurements from 256-slice CT to those derived from transesophageal echocardiography (TEE) and cardiac catheterization in high-risk subjects with known high-grade calcified aortic stenosis. METHODS AND MATERIALS: The study included 26 subjects (10 males, mean age: 79+/-6; range, 61-88 years). All subjects were clinically referred for aortic valve imaging prior to percutaneous aortic valve replacement from April 2008 to March 2009. Two radiologists, blinded to the results of TEE and cardiac catheterization, independently selected the systolic cardiac phase of maximum aortic valve area and independently performed manual CT AVA planimetry for all subjects. Repeated AVA measurements were made to establish CT intra- and interobserver repeatability. In addition, the image quality of the aortic valve was rated by both observers. Aortic valve calcification was also quantified. RESULTS: All 26 subjects had a high-grade aortic valve stenosis (systolic opening area <1.0 cm(2)) via CT-based planimetry, with a mean AVA of 0.62+/-0.18. In four subjects, TEE planimetry was precluded due to severe aortic valve calcification, but CT-planimetry was successfully performed with a mean AVA of 0.46+/-0.23 cm(2). Mean aortic valve calcium mass score was 563.8+/-526.2 mg. Aortic valve area by CT was not correlated with aortic valve calcium mass score. A bias and limits of agreement among CT and TEE, CT and cardiac catheterization, and TEE and cardiac catheterization were -0.07 [ 0.37 to 0.24], 0.03 [-0.49 to 0.55], 0.12 [-0.39 to 0.63]cm(2), respectively. Differences in AVA among CT and TEE or cardiac catheterization did not differ systematically over the range of measurements and were not correlated with aortic valve calcium mass score. CONCLUSION: Planimetric aortic valve area measurements from 256-slice CT agree well with those derived from TEE and cardiac catheterization in high-risk subjects with known high-grade calcified aortic stenosis. PMID- 20832222 TI - MRS study of the effects of minocycline on markers of neuronal and microglial integrity in ALS. AB - OBJECTIVE: Magnetic resonance spectroscopy (MRS) allows to monitor brain metabolites noninvasively in amyotrophic lateral sclerosis (ALS). The objective of this study was to use MRS to monitor the effect of minocycline treatment (200 mg/day) over a short period (6 weeks) on the brain metabolites in the precentral gyrus and brainstem in newly diagnosed ALS patients. METHODS: Ten ALS patients (not on riluzole treatment) were recruited and submitted to single-voxel proton MRS longitudinal examinations (1) before minocycline treatment, (2) 3 weeks and (3) 6 weeks after initiation of treatment. RESULTS: Results did not show the expected decrease of N-acetylaspartate/creatine (NAA/Cr) in the precentral gyrus, and an increased NAA/Cr ratio in the brainstem suggested neuronal recovery. The myo-inositol (mI)/Cr ratio was unchanged in the precentral gyrus, but increased in the brainstem, indicating a glial reaction. CONCLUSIONS: MRS results suggest that minocycline treatment could be beneficial in the early stages of ALS. PMID- 20832223 TI - Cardiovascular remodeling after AVF surgery in rats assessed by a clinical MRI scanner. AB - PURPOSE: To evaluate a cardiovascular magnetic resonance imaging (MRI) technique which allows the longitudinal analysis of cardiovascular remodeling in a rodent femoral arteriovenous fistula (AVF) model by means of a clinical scanner. MATERIALS AND METHODS: Eight rats underwent femoral AVF surgery and four rats served as controls. Vascular and cardiac morphology as well as cardiac function was assessed from Week 3 to 12 using contrast-enhanced, time-resolved magnetic resonance angiography (MRA) and cardiac MRI (cine gradient-echo sequence) at 3 T in one imaging session. RESULTS: Arteriovenous surgery resulted in progressive venous dilation and a subsequent cardiac adaptation. This procedure led to downstream vasodilation of the iliac vein and inferior vena cava of 179% and 188%, respectively (3 weeks). To accommodate the increased returning blood volume, cardiac output (CO) increased significantly (P=.014; 6 weeks). This was caused by increased end-diastolic volume (EDV), stroke volume (SV) and heart rate (HR) consistent with an increased volume load. A continuous increase in heart weight peaked at 12 weeks. This increase combined with a distinct end-diastolic left ventricular dilation implied eccentric hypertrophy. CONCLUSION: Small rodent MRI is feasible and clearly depicts fistula maturation and cardiac alterations. This technique proved to be a valuable tool for longitudinal in vivo monitoring in this model, which strongly resembles clinical findings in hemodialysis patients. PMID- 20832224 TI - Numerical solutions to the time-dependent Bloch equations revisited. AB - The purpose of this study was to demonstrate a simple and fast method for solving the time-dependent Bloch equations. First, the time-dependent Bloch equations were reduced to a homogeneous linear differential equation, and then a simple equation was derived to solve it using a matrix operation. The validity of this method was investigated by comparing with the analytical solutions in the case of constant radiofrequency irradiation. There was a good agreement between them, indicating the validity of this method. As a further example, this method was applied to the time-dependent Bloch equations in the two-pool exchange model for chemical exchange saturation transfer (CEST) or amide proton transfer (APT) magnetic resonance imaging (MRI), and the Z-spectra and asymmetry spectra were calculated from their solutions. They were also calculated using the fourth/fifth order Runge-Kutta-Fehlberg (RKF) method for comparison. There was also a good agreement between them, and this method was much faster than the RKF method. In conclusion, this method will be useful for analyzing the complex CEST or APT contrast mechanism and/or investigating the optimal conditions for CEST or APT MRI. PMID- 20832225 TI - Noninvasive evaluation of cerebral glioma grade by using multivoxel 3D proton MR spectroscopy. AB - OBJECTIVE: To determine whether metabolite ratios in multivoxel 3D proton MR spectroscopy (1H MRS) is different between low-grade and high-grade gliomas and may be useful for glioma grading. MATERIALS AND METHODS: Thirty-nine patients (23 male and 16 female; 22-75 years old; mean age, 44.92+/-12.65 years) suspected of having gliomas underwent 3D 1H MRS examinations. Metabolite ratios [choline (Cho)/creatine (Cr), N-acetylaspartate (NAA)/Cr and Cho/NAA] were measured. Tumor grade was determined by using the histopathologic grading. Receiver operating characteristic analysis of metabolite ratios was performed, and optimum thresholds for tumor grading were determined. The resulting sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for identifying high-grade gliomas were calculated. RESULTS: Diagnostic-quality 3D 1H MRS with readily quantifiable Cho, Cr and NAA peaks was obtained in 94.87% of the cases. The Cho/Cr and Cho/NAA ratios were significantly higher in high grade than in low-grade glioma (P<.001), whereas the NAA/Cr ratios were significantly lower in high-grade than in low-grade glioma (P<.001). Receiver operating characteristic analysis demonstrated a threshold value of 2.04 for Cho/Cr ratio to provide sensitivity, specificity, PPV and NPV of 84.00%, 83.33%, 91.30% and 71.43%, respectively. Threshold value of 2.20 for Cho/NAA ratio resulted in sensitivity, specificity, PPV and NPV of 88.00%, 66.67%, 84.62% and 72.73%, respectively. Overall diagnostic accuracy was not statistically significantly different between Cho/Cr and Cho/NAA ratios (chi2=0.093, P=.76). CONCLUSION: Metabolite ratios of low-grade gliomas were significantly different from high-grade gliomas. Cho/Cr and Cho/NAA ratios could have the superior diagnostic performance in predicting the glioma grade. PMID- 20832227 TI - Paradoxical high signal intensity of hepatocellular carcinoma in the hepatobiliary phase of Gd-EOB-DTPA enhanced MRI: initial experience. AB - PURPOSE: To describe the paradoxical high signal intensity of hepatocellular carcinoma (HCC) in the hepatobiliary phase on gadolinium-ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: A database search was performed to identify cases of HCC that showed unusual prolonged enhancement in the hepatobiliary phase of Gd-EOB-DTPA MRI. All patients received 3.0-T liver MRI including precontrast T1-weighted images, T2-weighted images and a post Gd-EOB-DTPA-enhanced dynamic study. The signal intensity of HCC was measured at pre-enhanced, arterial, portal, delayed and hepatobiliary phase using regions of interest. Radiologic and pathologic correlation was performed for the paradoxically prolonged enhancing portion of HCC in the hepatobiliary phase. RESULTS: Four patients (all male, age range 44-70; mean 57.5 years) were included in this study. All patients showed HCC lesions that were low signal intensity (SI) on T1-WI, high SI on T2-WI, enhanced in arterial phase, and washed-out in delayed phase. All cases showed paradoxically high SI in hepatobiliary phase, which was unusual for HCC. Pathologically, they were all diagnosed as well-differentiated HCC with prominent cytoplasm and a bile secreting appearance. CONCLUSION: HCC may demonstrate the prolonged high signal intensity at the hepatobiliary phase on Gd-EOB-DTPA enhanced MRI. These HCCs tended to be highly differentiated and to have prominent bile secretion. PMID- 20832226 TI - Reduction of breast density following tamoxifen treatment evaluated by 3-D MRI: preliminary study. AB - This study analyzed the change in breast density in women receiving tamoxifen treatment using 3-D MRI. Sixteen women were studied. Each woman received breast MRI before and after tamoxifen. The breast and the fibroglandular tissue were segmented using a computer-assisted algorithm, based on T1-weighted images. The fibroglandular tissue volume (FV) and breast volume (BV) were measured and the ratio was calculated as the percent breast density (%BD). The changes in breast volume (DeltaBV), fibroglandular tissue volume (DeltaFV) and percent density (Delta%BD) between two MRI studies were analyzed and correlated with treatment duration and baseline breast density. The DeltaFV showed a reduction in all 16 women. The Delta%BD showed a mean reduction of 5.8%. The reduction of FV was significantly correlated with baseline FV (P<.001) and treatment duration (P=.03). The percentage change in FV was correlated with duration (P=.049). The reduction in %BD was positively correlated with baseline %BD (P=.02). Women with higher baseline %BD showed more reduction of %BD. Three-dimensional MRI may be useful for the measurement of the small changes of DeltaFV and Delta%BD after tamoxifen. These changes can potentially be used to correlate with the future reduction of cancer risk. PMID- 20832228 TI - Determination of oxaceprol in rat plasma by LC-MS/MS and its application in a pharmacokinetic study. AB - A sensitive method for the quantification of oxaceprol in rat plasma using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. Sample pretreatment involved a simple protein precipitation by the addition of 60 MUL of acetonitrile-methanol (1:2, v/v) to 20 MUL plasma sample volume. Separation was achieved on a Dikma ODS-C18 (5 MUm, 150 mm * 4.6mm) reversed-phase column at 40 degrees C with acetonitrile/0.1% formic acid-4mM ammonium acetate in water (35:65,v/v) at a flow rate of 0.6mL/min. Detection was performed using an electrospray ionization (ESI) operating in negative ion multiple reaction monitoring (MRM) mode by monitoring the ion transitions from m/z 172 -> 130 (oxaceprol) and m/z 153 -> 109 (protocatechuic acid, internal standard). The calibration curve of oxaceprol in plasma showed good linearity over the concentration range of 1.25-800 ng/mL. The limit of detection and limit of quantification were 0.400 ng/mL and 1.25 ng/mL, respectively. Intra- and inter day precisions in all samples were within 15%. There was no matrix effect. The validated method was successfully applied to a preclinical pharmacokinetic study of oxaceprol in rats. After oral administration of 20mg/kg oxaceprol to rats, the main pharmacokinetic parameters T(max), C(max), T(1/2), V(z/F) and AUC(0-t) were 1.4h, 1.2 MUg/mL, 2.3h, 19.7 L/kg and 3.4 mg h/L, respectively. PMID- 20832229 TI - Determination of aqueous stability and degradation products of series of coumarin dimers. AB - The stability in aqueous solution of five classes of coumarin dimers (I-V, compounds 1-29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the alpha-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay. PMID- 20832230 TI - Problem-solving treatment in general practice residency: a focus group study of registrars' views. AB - OBJECTIVE: General practitioner (GP) registrars often express the need for more expertise of non-pharmacological treatments for patients with mental health problems. Problem-solving treatment (PST) could be an attractive option. We aimed to explore GP registrars' views on PST-training during residency and on the actual use of PST in general practice. METHODS: We performed a qualitative study with four focus groups, interviewing 18 Dutch registrars who had been trained in PST during residency. Data were analysed according to the principles of constant comparative analysis. RESULTS: Registrars thought that PST-training during residency was feasible, interesting and helpful, but found that it took too much time in everyday practice and was not a GP's task. All registrars, however, said they would use specific elements in a variety of consultations, for instance concretising problems, brainstorming about practical solutions, and activating patients. CONCLUSION: Registrars regarded PST-training during residency feasible and helpful. In daily practice they would apply specific elements of the treatment. PRACTICE IMPLICATIONS: We recommend residency programmes to offer training in PST or another psychological treatment with comparable elements. Training should fit in with the registrars' needs and level of training and experience. PMID- 20832231 TI - Iliofemoral venous thrombosis from external compression by a vesical diverticulum. AB - Twenty six percent to 47% of venous thromboembolisms (VTE) are classified as idiopathic. Deep venous thrombosis (DVT) due to external compression of the venous system by various lesions has been reported in the literature. Identification of such lesions may obviate the need for prolonged anticoagulation and prevent recurrence. An important step in the evaluation of cases with iliofemoral thrombosis is to obtain computed tomography (CT) of the abdomen and pelvis to identify any potential pathology. We report a case of acute unilateral iliofemoral DVT caused by external compression from a vesical diverticulum. The CT scan played a crucial role in the diagnosis and guided management. PMID- 20832232 TI - Circulating B lymphocytes producing autoantibodies to endothelial cells play a role in the pathogenesis of Takayasu arteritis. AB - OBJECTIVE: Takayasu arteritis (TA) is an autoimmune disease with an unclear etiology and pathophysiology. An antibody-mediated inflammatory response is a known feature of this disease, however, the role of circulating B-lymphocyte production of such antibodies is not known. The objective of this study is to characterize in vitro production of autoimmune antibodies by B-lymphocytes from patients with TA and to examine differences related to disease activity. METHODS: Peripheral blood samples were taken from 72 patients with TA and 50 age-matched controls. Among the patients with TA, 42 had active disease while 31 had inactive disease. The Sharma modified criteria were used for diagnosis, and the National Institutes of Health criteria were used for TA activity assessment. Levels of autoantibodies in culture supernatant of circulating B-lymphocytes, including anti-endothelial cell antibody (AECA), anti-cardiolipin antibody (ACA), anti beta(2) glycoprotein-I antibody (abeta2GPI), and anti-annexin V antibody (AAVA), were assayed by enzyme-linked immunosorbent assay (ELISA) in each participant. RESULTS: In vitro levels of AECA, ACA, abeta2GPI, and AAVA from circulating B lymphocytes were significantly increased in TA patients compared with controls (AECA: 0.6 +/- 0.36 vs 0.18 +/- 0.09, P < .001; ACA: 0.69 +/- 0.22 vs 0.54 +/- 0.13, P < .001; abeta2GPI: 0.99 +/- 0.19 vs 0.83 +/- 0.07, P< .001; AAVA: 0.62 +/ 0.26 vs 0.41 +/- 0.44, P < .001). In vitro levels of AECA, ACA, and AAVA from circulating B-lymphocytes in active TA were higher than those in inactive TA (AECA: 0.85 +/- 0.29 vs 0.28 +/- 0.10, P < .001; ACA: 0.79 +/- 0.21 vs 0.56 +/- 0.15, P < .001; AAVA: 0.82 +/- 0.16 vs 0.36 +/- 0.06, P < .001). No difference was found in the in vitro level of abeta2GPI between active TA and inactive TA (1.01 +/- 0.17 vs 0.96 +/- 0.22, P = .115). In vitro levels of AECA, ACA, and AAVA from circulating B-lymphocytes in inactive TA showed no statistic difference with those in controls (AECA: 0.28 +/- 0.10 vs 0.18 +/- 0.09, P = .096; ACA: 0.56 +/- 0.15 vs 0.54 +/- 0.13, P = .699; AAVA: 0.36 +/- 0.06 vs 0.41 +/- 0.44, P = .200). In vitro levels of abeta2GPI in inactive TA were higher than those in controls (0.96 +/- 0.22 vs 0.83 +/- 0.07, P < .001). CONCLUSIONS: This study characterizes in vitro production of autoantibodies by circulating B-lymphocytes from patients with TA. Differences in production from those with active versus inactive disease suggest that phenotypic alterations in this cell type may play an important role in pathogenesis. PMID- 20832233 TI - Aortic rupture after spinal correction for scoliosis in the presence of a thoracic stent graft. AB - Corrective surgery for scoliosis often results in a lengthening of the spinal column and relative change of the position of the adjacent anatomical structures such as the aorta. The extent of these anatomical changes could be affected by the presence of a rigid aortic stent graft in the descending thoracic aorta. We present a case of aortic rupture after spinal correction for scoliosis in a 56 year-old female with a thoracic aortic stent graft. Extensive elongation of the aorta with concentration of the stress forces at the lower margin of the stent graft resulted in a weakening of the aortic wall and subsequent rupture. PMID- 20832234 TI - Multicystic peritoneal mesothelioma: outcomes and patho-biological features in a multi-institutional series treated by cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC). AB - AIM: This retrospective multi-institutional study addresses the role of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of multicystic peritoneal mesothelioma (MCPM). MCPM is an uncommon tumour with uncertain malignant potential and no current standard therapy. Additionally, poorly defined pathological and biological features of this disease were investigated. METHODS: Twelve patients with MCPM underwent 14 procedures of cytoreduction and HIPEC in two Italian referral centres. Nine patients had recurrent disease after previous debulking (one operation in six patients, two in two, four in one). Biological markers related to mesothelioma origin and clinical features were assessed by immunohistochemical studies. RESULTS: Median follow-up was 64 months (range 5-148). Optimal cytoreduction (residual tumour nodules <=2.5 mm) was performed in all the procedures. One grade IV postoperative complication (NCI/CTCAE v.3.0) and no operative death occurred. All the patients are presently alive with no evidence of disease, including two patients who underwent the procedure twice, due to locoregional disease recurrence. Five- and ten-year progression-free survival was 90% and 72%, accounting for a. statistically significant difference (P = 0.0001) with progression-free survival following previous debulking surgery (median 11 months; range 2-31). All cases showed low proliferative activity assessed by mitotic rate and Ki-67 expression. CONCLUSIONS: MCPM is a borderline tumour with a high propensity to local-regional recurrence. Definitive tumour eradication by means of cytoreduction and HIPEC seems more effective than debulking surgery in preventing disease relapse. Low mitotic rate and poor Ki-67 expression might be related to the peculiar behaviour of MCMP. PMID- 20832235 TI - [Haemodynamic monitoring or output cardiac monitoring?]. PMID- 20832236 TI - [The role of rFVIIa in treatment of severe postpartum haemorrhage: to evaluate the risk/benefit ratio]. PMID- 20832237 TI - [Bullous pemphigoid]. AB - Bullous pemphigoid is the most frequent autoimmune bullous skin disease and affects subjects who are about 80 years old. The risk factors are neurological degenerative diseases, poor Karnovski's status and some drugs (aldactone and neuroleptics). Typically, the disease consists of itching eczematous or urticarial sheets, surmounted by blisters. The blisters heal without scars. Mouth and head are rarely involved. The diagnostic is made by histological examination . It shows a subepidermal blister with some degree of dermal infiltrate with lymphocytes and eosinophils. Direct immunofluorescence reveals a linear pattern of IgG deposition along the basal membrane, which signs the diagnosis. Indirect immunofluorescence detecting anti-basal membrane antibodies is of poor diagnostic value. New tests detecting BPAg 2 antibodies by enzyme-linked immunosorbant assay (ELISA) seems to be good markers for disease activity and prognosis. Recommended treatment is topical corticosteroids (clobetasol propionate cream) for several months. It has been showed to be more effective and less dangerous than oral corticotherapy in severe forms of bullous pemphigoid. Corticosteroid sparing agents like methotrexate or mycophenolate mofetil are sometimes used because of cutaneous or systemic side effect of strong and protracted topical corticosteroid therapy. The management of these patients shall be done by specialized and coordinated staff in order to bring the best care. PMID- 20832238 TI - [Stenting in superficial femoral artery and usCRP: Multicentric study SAFE in 255 patients]. AB - OBJECTIVE: To evaluate mid-term primary patency of the femoral artery stenting in correlation with usCRP level and characteristics of the population, morphological aspect of the lesions and interventional techniques. METHODS: Patients were prospectively included in a multicenter study (18 centers in France) after stenting (SMART, Cordis Johnson & Johnson, Issy-les-Moulineaux, France) of the superficial femoral artery (SFA). Inclusion and exclusion criteria were based on recommendations and every day practice of the centers. RESULTS: Thus 255 patients (183 men; mean age: 69 years; range 44-92) were included. Technical success of the SFA stenting was 100% without any complications and primary angiographic success 97%. usCRP level increased significantly (p < 0.05) between before and 24h after SFA stenting. In the subgroup of patients without initial inflammation (n = 157), usCRP increased significantly (p < 0.05) in the group of patient with initial thrombosis and additional intervention (graft, amputation, angioplasty on other arterial bed) in the same procedure compared to the remaining patients. Restenosis rate was 12.4% (26/209 patients) at 7 +/- 2 months. Before stenting, usCRP level was not predictive of a restenosis, whereas after stenting, an increase of the 24h usCRP level was significantly higher in the subgroup of patient with an occlusion at mid-term (8 patients; p < 0.05). CONCLUSION: This study demonstrated good patency at 7 months of SFA stenting with nitinol SMART with an increase of the usCRP level 24h after stenting in favour of the presence of an occlusion at mid-term follow-up. PMID- 20832239 TI - [Schnitzler syndrome: A dramatic improvement with anakinra]. PMID- 20832240 TI - Avoiding pitfalls in mammographic interpretation. AB - There is a public misconception that screening mammography detects all breast malignancies. The objective of this pictorial essay is to review classic mammographic features of malignancy that, if missed, could potentially result in malpractice litigation. By identifying radiologic themes, we attempt to improve awareness about the imaging characteristics of a variety of subtle malignancies. PMID- 20832241 TI - Working memory structure in 10- and 15-year old children with mild to borderline intellectual, disabilities. AB - The validity of Baddeley's working memory model within the typically developing population, was tested. However, it is not clear if this model also holds in children and adolescents with mild to, borderline intellectual disabilities (ID; IQ score 55-85). The main purpose of this study was therefore, to explore the model's validity in this population. Several verbal and visuo-spatial STM and WM tasks, were administered to 115 children with mild to borderline ID (mean age 10 years) and to 98, adolescents with mild to borderline ID (mean age 15). Structural equation modeling (LISREL) shows, that Baddeley's working memory model does not fit the data of the 10-year and 15-year old, participants. Principal components analyses on the other hand show a hazy pattern with on the one, side an indication for a 'general' component with loadings of visuo-spatial short-term memory and, working memory tasks and a separate verbal short-term memory component. On the other hand there, is also an indication of a modality specific memory structure; a visuo-spatial- versus a verbal, component. A straight-forward dichotomy between STM and WM indicates apparently an, oversimplification, at least it is for children and adolescents with mild to borderline ID. PMID- 20832242 TI - Gradient vector flow with mean shift for skin lesion segmentation. AB - Image segmentation is an important task in the analysis of dermoscopy images since the extraction of skin lesion borders provides important cues for accurate diagnosis. In recent years, gradient vector flow based algorithms have demonstrated their merits in image segmentation. However, due to the compromise of internal and external energy forces within the partial differential equation these methods commonly lead to under- or over-segmentation problems. In this paper, we introduce a new mean shift based gradient vector flow (GVF) algorithm that drives the internal/external energies towards the correct direction. The proposed segmentation method incorporates a mean shift operation within the standard GVF cost function. Theoretical analysis proves that the proposed algorithm converges rapidly, while experimental results on a large set of diverse dermoscopy images demonstrate that the presented method accurately determines skin lesion borders in dermoscopy images. PMID- 20832243 TI - Effect of topical honey on limitation of radiation-induced oral mucositis: an intervention study. AB - Radiation therapy for oral carcinoma is therapeutically useful in dose of at least 6000 cGy but causes mucositis that severely interferes with oral function. The literature indicates that honey appears to promote wound healing, so the authors investigated whether its anti-inflammatory properties might limit the severity of radiation-induced oral mucositis. A single-blinded, randomized, controlled clinical trial was carried out to compare the mucositis-limiting qualities of honey with lignocaine. A visual assessment scale permitted scoring of degrees of mucositis and statistical evaluation of the results was performed using the chi(2) test. Only 1 of 20 patients in the honey group developed intolerable oral mucositis compared with the lignocaine group, indicating that honey is strongly protective (RR=0.067) against the development of mucositis. The proportion of patients with intolerable oral mucositis was lower in the honey group and this was statistically significant (p=0.000). Honey applied topically to the oral mucosa of patients undergoing radiation therapy appears to provide a distinct benefit by limiting the severity of mucositis. Honey is readily available, affordable and well accepted by patients making it useful for improving the quality of life in irradiated patients. PMID- 20832244 TI - Power modulation contrast enhanced ultrasound for postoperative perfusion monitoring following free tissue transfer in head and neck surgery. AB - This feasibility study evaluated whether contrast enhanced ultrasound (CEU) was able to assess free flap perfusion following free tissue transfer in the head and neck region. Thirty-six patients underwent standard clinical monitoring (SCM) and CEU postoperatively. The time taken for each technique to detect flap failure was recorded. Qualitative CEU analysis by visual assessment predicted survival in 30/30 (100%) and failure in 5/6 (83%) flaps with sensitivity, specificity, positive (PPV) and negative (NPV) predictive values of 100, 86, 97 and 100%, respectively. Quantitative CEU measurement of blood volume (alpha) values within healthy perfused flaps was over 60 times higher than in failing flaps (8.25+/ 2.82dB vs. 0.12+/-0.17dB, respectively, P<0.0001). If a cut-off alpha value of <1.5dB was used to predict future flap failure, the accuracy of the test was 100% (sensitivity, specificity, PPV, NPV). If a cut-off alpha value of >1.9dB indicated flap success, the PPV and NPV are 100%. Following surgery, SCM took 76 (+/-15) h to detect flap failure compared with 18 (+/-38) h with CEU (P<0.05). CEU is highly accurate in its ability to distinguish between perfused and failing flaps. The technique is quick (<10min) and capable of imaging all flap types. PMID- 20832245 TI - Maxillofacial prosthetic rehabilitation in the UK: a survey of maxillofacial prosthetists' and technologists' attitudes and opinions. AB - Maxillofacial prostheses are constructed by maxillofacial prosthetists and technologists (MPTs), as an alternative treatment when maxillofacial defects cannot be surgically fulfilled. A questionnaire was conducted surveying 220 MPTs working in all UK maxillofacial units about their opinions, attitudes, and experience regarding several aspects related to maxillofacial silicone prostheses. Numbers and percentages of maxillofacial prostheses, their retention method, serviceability, reduced serviceability causes, and digital technologies (DT) used in constructing prostheses were analysed. Thousand hundred and ninety three prostheses were constructed (42% ocular, 31% auricular, 13% orbital, 12% nasal, 1% composite, more than one facial prosthesis). Adhesives commonly retained orbital (48%) and nasal (45%) prostheses. Implant-retained bars commonly retained auricular prostheses (70%). Ocular prostheses were entirely retained by undercuts. Implant-retained prostheses remained serviceable for twice as long (19 24 months) as adhesive-retained prostheses (7-12 months). Causes for prosthesis replacement included colour changes (71%), poor maintenance (41%), and silicone tear (37%). Thirty-one percent of MPTs used DT computer software and programs for designing and constructing maxillofacial prostheses. In conclusion, adhesives, implant-retained bars and magnets are commonly used retentive methods. Prosthesis failure is caused mainly by colour change, poor maintenance, silicone tear and delamination. Different DTs are used by one-third of MPTs. PMID- 20832246 TI - SAPHO syndrome with TMJ involvement: review of the literature and case presentation. AB - Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare group of sterile, inflammatory osteoarticular disorders classically associated with skin manifestations. The etiology is unknown but probably involves genetic, infectious, and immunological components. The characteristic feature of the disease is found in the bone lesions, which typically involve the anterior chest wall and axial skeleton. In the literature review, six case reports discussed involvement of the TMJ. Treatment of SAPHO is geared toward symptom management as there is no cure. Surgery for mandibular lesions is usually a last resort as results are reported to be temporary with symptoms recurring within a year. Surgery appears to be performed early after diagnosis of TMJ related pathology; probably because lesions affecting the TMJ involve some limitation in mouth opening with varying degrees of ankylosis. The authors provide a literature review and describe a case of SAPHO syndrome with ankylosis of the left TMJ. The patient was treated with joint reconstruction using a patient-fitted total joint prosthesis (TMJ Concepts Inc., Ventura CA) in single stage surgery. This paper is the first to report maxillary involvement in SAPHO syndrome. PMID- 20832247 TI - Autotransplantation of two maxillary premolars in a free vascularized fibula reconstructed mandible. AB - A 10-year-old female patient with a fibula transplant in her left hemimandible due to ameloblastoma treatment was referred for combined orthodontic and surgical planning and treatment to observe and prevent expected asymmetric facial development and malocclusion, because the premolars and molars on the left side of the mandible were missing. The patient had an Angle Class II malocclusion and arch length discrepancy in the upper jaw. The two second premolars in the maxilla were transplanted into the neomandible to create occlusion on the left side and retention for orthodontic treatment. Clinical and radiological examination 3 months postoperatively showed good integration of both premolars without pocket formation. After 4 months, active orthodontic treatment with fixed appliances was started to create sufficient arch space in the upper jaw for both canines to erupt and to extrude and for the transplanted premolars in the lower jaw to rotate and align into the planned positions. This case report demonstrates that autotransplantation of premolars into a fibula transplant can be a successful dental rehabilitation procedure. PMID- 20832248 TI - Rethinking the genetic basis for comorbidity of schizophrenia and type 2 diabetes. AB - The co-occurrence of schizophrenia (SCZ) and type 2 diabetes mellitus (T2D) has been well documented. This review article focuses on the hypothesis that the co occurrence of SCZ and T2D may be, at least in part, driven by shared genetic factors. Previous genetic studies of T2D and SCZ evidence have disclosed a number of overlapped risk loci. However, the putative common genetic factors for SCZ and T2D remain inconclusive due to inconsistent findings. A systemic review of methods of identifying genetic loci contributing to the comorbidity link between SCZ and T2D is hence needed. In the current review article, we have discussed several different approaches to localizing the shared susceptibility genes for these two diseases. To begin with, one could start with probing the gene involved in both glucose and dopamine metabolisms. Additionally, hypothesis-free genome wide association studies (GWAS) may provide more clues to the common genetic basis for these two diseases. Genetic similarities inferred from GWAS may shed some light on the genetic mechanism underlying the comorbidity link between SCZ and T2D. Meanwhile, endophenotypes (e.g., adiponectin level in T2D and working memory in SCZ) may serve as alternative phenotypes that are more directly influenced by genes than target diseases. Hence, endophenotypes of these diseases may be more tractable to identification. To summarize, novel approaches are needed to dissect the complex genetic basis of the comorbidity of SCZ and T2D. PMID- 20832249 TI - The case for including Attenuated Psychotic Symptoms Syndrome in DSM-5 as a psychosis risk syndrome. AB - The American Psychiatric Association Task Force on DSM-5 has recently proposed consideration of Attenuated Psychotic Symptoms Syndrome as a new diagnosis, based on nearly 15 years of prospective research in centers across the globe. The condition is also known as "psychosis risk syndrome," "at-risk mental state," "ultra-high risk," and "putative prodrome." We review evidence favoring its inclusion as a new diagnosis in DSM-5 and report new preliminary findings on DSM IV diagnoses in current clinical use for these patients and on results of diagnostic interviews in unselected volunteers. The main evidence supporting inclusion is: (1) the patients are currently ill, (2) the patients are at high risk for getting worse, (3) no DSM-IV diagnosis accurately captures their current illness or future risk, (4) the diagnosis has been made with reliability and validity in the research setting, and (5) placement in DSM-5 would help promote the needed treatment and prevention research to enable articulation of a standard of care to benefit these patients and their families. Potential harms can be minimized by patient, family, and provider education. It will be important to demonstrate through well-designed field trials whether the diagnostic criteria can be used with reliability in everyday clinical practice. PMID- 20832250 TI - Preventive effect of chemical peeling on ultraviolet induced skin tumor formation. AB - BACKGROUND: Chemical peeling is one of the dermatological treatments available for certain cutaneous diseases and conditions or improvement of cosmetic appearance of photoaged skin. OBJECTIVES: We assessed the photochemopreventive effect of several clinically used chemical peeling agents on the ultraviolet (UV) irradiated skin of hairless mice. METHODS: Chemical peeling was done using 35% glycolic acid dissolved in distilled water, 30% salicylic acid in ethanol, 10% or 35% trichloroacetic acid (TCA) in distilled water at the right back of UV irradiated hairless mice every 2 weeks in case of glycolic acid, salicylic acid, and 10% TCA and every 4 weeks in case of 35% TCA for totally 18 weeks after the establishment of photoaged mice by irradiation with UVA+B range light three times a week for 10 weeks at a total dose of 420 J/cm(2) at UVA and 9.6 J/cm(2) at UVB. Tumor formation was assessed every week. Skin specimens were taken from treated and non-treated area for evaluation under microscopy, evaluation of P53 expression, and mRNA expression of cyclooxygenase (COX)-2. Serum level of prostaglandin E(2) was also evaluated. RESULTS: All types of chemical peeling reduced tumor formation in treated mice, mostly in the treated area but also non treated area. Peeling suppressed clonal retention of p53 positive abnormal cells and reduced mRNA expression of COX-2 in treated skin. Further, serum prostaglandin E(2) level was decreased in chemical peeling treated mice. CONCLUSIONS: These results indicate that chemical peeling with glycolic acid, salicylic acid, and TCA could serve tumor prevention by removing photodamaged cells. PMID- 20832251 TI - MRI correlates of episodic memory in Alzheimer's disease, mild cognitive impairment, and healthy aging. AB - Episodic memory is a core feature of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Impaired episodic memory in AD results from the dysfunction of an integrated network and involves both gray and white matter pathologies. We explored the neural correlates of episodic memory in AD, MCI and healthy aging by correlating a measure of episodic memory with hippocampal volume and fractional anisotropy (FA) and mean diffusivity (MD) of the cingulum and fornix. Episodic memory was associated with hippocampal volume and MD of the cingulum and fornix. In contrast, there were fewer significant associations between episodic memory and FA. These findings support a relationship between episodic memory and hippocampal circuitry, and suggest that MD is a more sensitive marker of decreased white matter integrity in the study of AD and MCI than FA. Furthermore, MD was significantly associated with hippocampal volume, indicating that white matter pathology is not completely independent of gray matter pathology. However, the pattern of diffusivity differences in AD and MCI implies a more complex pathology than simply Wallerian degeneration. PMID- 20832252 TI - Paracingulate sulcus asymmetry; sex difference, correlation with semantic fluency and change over time in adolescent onset psychosis. AB - The left paracingulate sulcus (PCS) is longer than the right and the adjacent cortex is activated by the generation of words. In adult patients with chronic schizophrenia the anatomical asymmetry is reduced. In 35 controls and 38 adolescents with schizophrenia or schizoaffective disorder (mean age = 16 years) we found that semantic verbal fluency correlated with leftward PCS asymmetry in controls but not in patients. At intake, PCS length did not differ between patients and controls, but at follow-up (13 controls, 10 patients, mean age = 18 years) PCS asymmetry (comprising both increasing left and decreasing right length) increased significantly, the increase was greater in males than in females, and there was a trend for a diagnosis * sex * side * time interaction such that in controls leftward PCS asymmetry increased, while in patients of both sexes there was convergence toward symmetry. Thus sulcal anatomy develops differentially in the two sexes during adolescence, and the pattern of asymmetric sex-dependent change over time may distinguish patients with psychosis from controls. Greater change in asymmetry during adolescence may explain earlier age of onset in males and greater deficits in verbal fluency. PMID- 20832253 TI - Callosal microstructural abnormalities in Alzheimer's disease and alcoholism: same phenotype, different mechanisms. AB - Magnetic resonance (MRI) and diffusion tensor imaging (DTI) data were acquired in 13 Alzheimer's disease (AD) patients, 15 elderly alcoholics, and 32 elderly controls. Midsagittal area, length, dorsoventral height, fractional anisotropy (FA), and mean diffusivity (MD) of the total corpus callosum and volume of the lateral ventricles were measured; area, FA, and MD were also determined for the callosal genu, body, and splenium. On DTI, both patient groups had lower FA and higher MD than controls in all callosal regions. On MRI, both patient groups had smaller genu than controls; additional size deficits were present in the alcoholism group's callosal body and the AD group's splenium. The callosal arch was higher in the AD but not the alcoholic group compared with controls. The two patient groups had larger ventricles than controls, and the AD group had larger ventricles than the alcoholic group. Callosal area correlated with its height, and callosal FA and MD correlated with ventricular volume in AD, whereas callosal area correlated only with FA in alcoholics. In AD, the disruption of the callosal integrity, which was associated with distorted callosal shape, was related to ventricular dilation, which has been shown in twin studies to be under a multitude of genetic, polygenetic, and environmental influences. Conversely, in alcoholism, disruption of callosal microstructural integrity was related to shrinkage of the corpus callosum itself. PMID- 20832255 TI - Depression severity is correlated to the integrity of white matter fiber tracts in late-onset major depression. AB - Cerebral white matter lesions (WMLs) are believed to play an important role in a subset of major depression (MD). We aimed to describe the impact of WMLs on white matter pathways in MD using diffusion tensor imaging (DTI) and magnetization transfer imaging. As a novel approach, we used DTI tractography to assess pathways intersected by WMLs. We examined 22 patients with late-onset MD and 22 age- and gender-matched controls. Parametric maps of fractional anisotropy (FA), apparent diffusion coefficient (ADC), and magnetization transfer ratio (MTR) were obtained to describe tissue integrity. The association between depression severity and the tract-specific localization of WMLs was analyzed on a voxel-by voxel basis. We showed a significant positive association between depression severity and fiber tracts intersected by WMLs in the left superior longitudinal fasciculus and the right uncinate fasciculus. In both groups, WMLs had significantly lower FA and MTR, and higher ADC than both the tracts they intersected and the normal-appearing white matter (NAWM). In turn, the tracts intersected by WMLs had significantly lower FA and higher ADC than the NAWM. In conclusion, depression severity correlates with the tract-specific localization of WMLs. WMLs have a pronounced effect on white matter integrity in the pathways they intersect. PMID- 20832254 TI - Regional cortical gray matter thickness differences associated with type 2 diabetes and major depression. AB - The purpose of this study was to examine the effect of type 2 diabetes with major depression on cortical gray matter using magnetic resonance imaging and cortical pattern matching techniques. We hypothesized that diabetic subjects and depressed diabetic subjects would demonstrate decreased cortical gray matter thickness in prefrontal areas as compared to healthy control subjects. Patients with type 2 diabetes (n=26) and patients with diabetes and major depression (n=26) were compared with healthy controls (n=20). Gray matter thickness across the entire cortex was measured using cortical pattern matching methods. All subjects with diabetes demonstrated decreased cortical gray matter thickness in the left anterior cingulate region. Additionally, depressed diabetic subjects showed significant cortical gray matter decreases in bilateral prefrontal areas compared with healthy controls. Correlations between clinical variables and cortical gray matter thickness revealed a significant negative relationship with cerebrovascular risk factors across all three groups, most consistently in the left dorsomedial prefrontal cortex. A significant positive relationship between performance on attention and executive function tasks and cortical gray matter thickness predominantly in left hemisphere regions was also seen across all subjects. Depression and diabetes are associated with significant cortical gray matter thinning in medial prefrontal areas. PMID- 20832256 TI - Subcortical and cortical gray matter differences between Kraepelinian and non Kraepelinian schizophrenia patients identified using voxel-based morphometry. AB - The long-term outcome of schizophrenia patients may differ depending on their brain structure. This would be reflected in significant structural differences between poor-outcome (i.e., Kraepelinian) and non-Kraepelinian patients. To assess this possibility, we have evaluated the degree of deviation in brain structure in Kraepelinian patients with respect to controls and non-Kraepelinian schizophrenia patients. We used voxel-brain morphometry (VBM) to assess the differences in gray matter volume across the brain in the Kraepelinian group with respect to the healthy controls and non-Kraepelinian patients. Twenty-six Kraepelinian and 18 non-Kraepelinian schizophrenia patients and 41 healthy controls were included. With respect to the healthy controls, the Kraepelinian patients showed a very significant decrease in gray matter in the frontal, occipital, and limbic cortices, and, at a subcortical level, bilaterally in the striatum and thalamus. In comparison with the non-Kraepelinian patients, the Kraepelinian individuals continued to show a similar subcortical decrease. Thus, Kraepelinian patients may be characterized by a distinct pattern of brain abnormalities, in particular, in subcortical regions. PMID- 20832257 TI - AFM characterization of spin-coated multilayered dry lipid films prepared from aqueous vesicle suspensions. AB - We present a detailed AFM study on multilayered dry lipid films prepared from aqueous vesicle suspensions. Different preparation techniques were applied in order to optimize the preparation of homogeneous lipid films of various film thicknesses. Suspensions of preformed DOPC/DPPC vesicles were adsorbed onto indium tin oxide-coated glass coverslips, a substrate also commonly employed for the formation of giant liposomes. We found that the homogeneity of the lipid films could substantially be improved when applying a spin-coating step during the film preparation. These films were much more homogeneous than those prepared by conventional drop-casting and in addition the film thickness could be controlled. When using a combination of vesicle adsorption and spin-coating the quality and thickness of the films depended crucially on the lipid concentration of the vesicle suspension, the adsorption temperature and the adsorption time. For lipid films prepared by direct spin-coating the lipid concentration and the applied spin-coating sequence were critical parameters for the quality and thickness of the deposited lipid films. PMID- 20832258 TI - Electrochemical investigation of methyl parathion at gold-sodium dodecylbenzene sulfonate nanoparticles modified glassy carbon electrode. AB - A gold/sodium dodecylbenzene sulfonate nanoparticles modified glassy carbon electrode (nano-Au/SDBS/GCE) was electrochemically fabricated with a constant potential at -0.4V. The obtained nano-Au/SDBS/GCE was characterized with scanning electronic microscopy, X-ray photoelectron spectroscopy and electrochemical techniques. Electrochemical behaviors of methyl parathion at the nano-Au/SDBS/GCE were thoroughly investigated. Compared to the unmodified electrode, the peak current obviously increased and the oxidation peak potential negatively shifted. These changes indicated that the composite nanoparticles possess good electrocatalytic performance on the electrochemical reaction of methyl parathion. Experimental parameters such as deposition time, pH value and accumulation conditions were optimized. Under optimum conditions, the peak current corresponding to the oxidation of the hydroxylamine group was found in a good linear relationship with the methyl parathion concentration. In addition, a calibration curve with excellent linearity was obtained in the concentration range from 5.0*10(-7)molL(-1) to 1.0*10(-4)molL(-1) with an estimated detection limit of 8.6*10(-8)molL(-1) (S/N=3). The successful determination of methyl parathion in real samples demonstrated the usefulness and potential applications of this method. PMID- 20832259 TI - Chitosan as a potential amendment to remediate metal contaminated soil - a characterisation study. AB - The potential of chitosan, a fishery waste-based material, as a soil amendment to clean-up metal contaminated soil was investigated. Chitosan was treated using glutaraldehyde (GLA), epichlorohydrin (ECH) and ethylene glycol diglycidyl ether (EGDE) as cross-linking reagents to enhance its chemical stability in acidic media and to improve its physical properties. Cross-linking treatment had significant effects on chitosan surface area, pore diameter, surface morphology and crystallinity. Interaction with Ag(I), Pb(II) and Cu(II) decreased the crystallinity of the materials and changed their surface morphology significantly. FTIR analysis confirmed that N and O atoms served as binding sites for the metal ions. Chitosan and treated chitosans were able to bind metal ions, even in the presence of K(+), Cl(-) and NO(3)(-), which are dominant ions in soil. Therefore, remediation of metal contaminated soil using chitosan and cross linked treated chitosans as soil amendments is feasible. PMID- 20832261 TI - Cytochrome c provokes the weakening of zwitterionic membranes as measured by force spectroscopy. AB - Cytochrome c (cyt c) is a small soluble protein from the intermembrane space of mitochondria. This protein is essential because it transfers electrons between two membrane complexes of the respiratory chain. In fact, during this transfer, the positively charged amino-acid residues surrounding the heme in the protein structure allow the cyt c to interact properly with the anionic part of other molecules: mainly the cardiolipin-rich membrane of mitochondria and respiratory complexes. We have previously shown that besides its interaction with anionic lipids, the cyt c is also able to cross neutral lipid membranes. In this work, with the help of AFM and punch-through experiments, we have measured the force required to penetrate the membrane in the fluid and in the gel phases with or without cyt c molecules. In the presence of cyt c molecules, the structures generated by the interaction with the protein were considerably weakened, which led to the desorption of the fluid bilayer and to a considerable loss of cohesion of the gel phase. These results show the usefulness of punch-through experiments in determining the changes of membrane properties in the presence of external agents. PMID- 20832262 TI - Novel pH-sensitive non-ionic surfactant vesicles: comparison between Tween 21 and Tween 20. AB - Drug delivery systems using vesicular carriers such as liposomes or niosomes, have distinct advantages over conventional dosage forms because the vesicles can act as drug containing reservoirs and the modification of the vesicular compositions or surface properties can adjust the drug release rate and/or the affinity for the target site. In recent years, niosomes have been the object of growing scientific attention as an alternative potential drug delivery system to conventional liposomes. The aim of present work was firstly to determine the critical micelle concentration (CMC) and then to analyze the capability of polysorbate 21 (Tween 21) to form niosomal formulations. Non-ionic surfactant vesicles were prepared using Tween 21 and cholesterol (CHOL) at equimolar ratio (15 mM:15 mM) by employing the "film" technique. Cholesterol was used to complete the hydrophobic moiety of single alkyl chain non-ionic surfactant for vesicle formation. Dynamic light scattering was used to determine the size, zeta (zeta) potential, polydispersity index and colloidal stability of the niosomal formulation. The vesicles were also characterized for their microviscosity and pH sensitivity using fluorescent probes. The present work led to a simple, but positive result in pharmaceutical technology area. In particular, we have shown that the Tween 21:CHOL vesicles (i) are a homogenous and monodisperse vesicular population; (ii) are characterized by dimension compatible with the transport of drugs across biological barriers especially those whose diameter is about 100nm; (iii) shows a good stability at least 90 days at 4 degrees C and (iv) are pH sensitive systems. In conclusion, this niosomal formulation could be used as pH sensitive nanodevices for delivery of drugs to pathological tissues, which exhibit an acidic environment as compared to normal tissues. PMID- 20832263 TI - An in situ formed biodegradable hydrogel for reconstruction of the corneal endothelium. AB - Biodegradable hydrogels are important biomaterials for tissue engineering and drug delivery. For the purpose of corneal regenerative medicine, we describe an in situ formed hydrogel based on a water-soluble derivative of chitosan, hydroxypropyl chitosan (HPCTS), and sodium alginate dialdehyde (SAD). Periodate oxidized alginate rapidly cross-links HPCTS due to Schiff's base formation between the available aldehyde and amino groups. Hydrogel cytotoxicity, degradability and histocompatibility in vivo were examined. The potential of the composite hydrogel for corneal endothelium reconstruction was demonstrated by encapsulating corneal endothelial cells (CECs) to grow on Descemet's membranes. The results demonstrate that the composite hydrogel was both non-toxic and biodegradable and that CECs transplanted by the composite hydrogel could survive and retain normal morphology. These results provide an opportunity for corneal endothelium reconstruction based on tissue engineering by the in situ formed composite hydrogel. PMID- 20832264 TI - Morphological studies on two marine colepid ciliates from Qingdao, China, Nolandia orientalis spec. nov. and Pinacocoleps similis (Kahl, 1933) comb. nov. (Ciliophora, Colepidae). AB - Recent studies have revealed that the "lower" marine ciliates are far more diverse than previously suspected. During a survey on the ciliate fauna in coastal waters of Qingdao, northern China, we have isolated about 30 new or poorly known taxa. In the present study two colepid species are investigated, Nolandia orientalis spec. nov. and Pinacocoleps similis (Kahl, 1933) comb. nov. (basionym: Coleps similis Kahl, 1933). Their morphology and infraciliature are documented based on living observations and silver impregnations. The new species Nolandia orientalis differs from the type species N. nolandi mainly in the structure of tier plates. The structure of the tier plates was also the basis for transferring Coleps similis Kahl, 1933 to the genus Pinacocoleps and for three further new combinations: Pinacocoleps heteracanthus (Noland, 1937) comb. nov. (basionym: Coleps heteracanthus Noland, 1937), P. spiralis (Noland, 1937) comb. nov. (basionym Coleps spiralis Noland, 1937) and Pinacocoleps arenarius (Bock, 1952) comb. nov. (basionym: Coleps arenarius Bock, 1952). PMID- 20832265 TI - Comparison of electronic portal imaging and cone beam computed tomography for position verification in children. AB - AIM: To compare the accuracy of radiotherapy set-up using an electronic portal imaging device (EPID) versus megavoltage cone beam computed tomography (MV-CBCT) in paediatric patients. MATERIALS AND METHODS: In total, 204 pairs of EPID and MV CBCT were carried out for 72 patients in the first 3 treatment days and weekly thereafter. RESULTS: For the whole group, the mean systematic EPID set-up errors were 1.8 (+/-1.7), 1.6 (+/-1.3), 1.4 (+/-1.5) mm and 2.3 (+/-1.7), 1.6 (+/-1.3), 2.4 (+/-1.6) mm for MV-CBCT in the longitudinal, lateral and vertical directions, respectively, whereas the mean EPID random errors were 2.0 (+/-1.7), 1.4 (+/ 1.5), 1.2 (+/-1.6) and 1.9 (+/-1.5), 1.5 (+/-1.3), 2.1 (+/-1.7) mm for MV-CBCT in the longitudinal, lateral and vertical directions, respectively. For systematic errors of head and neck patients, there was a statistically significant difference in the lateral and vertical directions (P=0.027, 0.003), whereas in the non-head and neck patients there was a statistically significant difference in the lateral direction only (P=0.031). In head and neck patients, the mean random errors were significantly different in the vertical and lateral directions, whereas in non-head and neck patients, they were significantly different in the vertical direction only. The larger values alternate between the two modalities. The systematic and random errors (detected by EPID and MV-CBCT) were significantly correlated in almost all direction in all tumour sites. CONCLUSIONS: The comparison between set-up error in EPID and MV-CBCT was not in favour of any of the two modalities. However, the two modalities were strongly correlated but fairly agreed and the differences between the shifts reported were small and hardly influenced the recommended planning target volume margin. PMID- 20832266 TI - Hepatoprotective treatment attenuates oxidative damages induced by carbon tetrachloride in rats. AB - The present study evaluated the hepatoprotective effect of an N-acetyl dl methionine+choline chloride+caffeine+thiamine hydrochloride+nicotinamide+pyridoxine hydrochloride compound at doses of 0.2, 0.6 and 1.0 mL/kg of b.w., and the assessment was done by the investigation of serum enzymatic activity, metabolic functions of the liver and histophatological changes in female Wistar rats, which were subjected to experimental intoxication with CCl(4). One hundred and nineteen rats were randomly distributed into 17 groups, performing five different treatments, being evaluated seven animals per treatment in four periods: 2, 4, 6 and 8 days after CCl(4)-induced intoxication. Treated rats with the hepatoprotective medicine (HM) presented a significant reduction in infiltration of inflammatory cells, steatosis, necrosis and liver congestion when compared to non-treated rats (control). Beside these results, the treatment showed a positive effect on circulatory alterations in the intoxicated animals, with reduction of spleen and renal congestion, as well as, promotion of a significant improvement in ALT, AST, LDH, ALP, GGT enzymatic serum activity reduction and in recovering liver function regarding the metabolism of urea, triglycerides and glucose. These findings indicate therapeutic usefulness of the compound when administered at dose 0.6 and 1.0 mL/kg of b.w. in female Wistar rats. PMID- 20832267 TI - Healing effect of quince seed mucilage on T-2 toxin-induced dermal toxicity in rabbit. AB - This study was performed to examine the healing effects of creams prepared from quince seed mucilage on dermal toxicity induced by T-2 toxin. Creams were prepared from quince seed mucilage in eucerin base as 5, 10, and 15% (w/w). To induce dermal toxicity, 100 MUg T-2 toxin was dissolved in 12 MUl methanol and applied on the shaved skin of rabbit for 2 consecutive days. A separate group received only solvent (methanol). On the third day, the prepared creams were applied on the skin lesions twice a day until complete healing was occurred. Healing, was defined by decreased wound margin, treatment erythema and blisters. Time required for healing was 14, 14, 12, 10, and 9 days for groups of no treatment, eucerin, quince seed cream 5%, 10%, and 15%, respectively. Results obtained by this study shows that quince seed mucilage (15%) has more and better healing effects on dermal toxicity caused by T-2 toxin comparing to no treatment or eucerin cream without mucilage. PMID- 20832268 TI - Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non alcoholic steatohepatitis. AB - The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. PMID- 20832269 TI - Protective role of curcumin in nephrotoxic oxidative damage induced by vancomycin in rats. AB - Vancomycin (VAN) is a glycopeptide antibiotic which is active against gram positive bacteria including methicillin resistant Staphylococci. Free radicals are involved in the pathogenesis of vancomycin-induced nephrotoxicity. Therefore, the present study was conducted to investigate the antioxidant potential of curcumin (CUR) against the nephrotoxicity of vancomycin in male rats. Animals used in this study were divided into four groups; the first group was used as control, the second, third and fourth groups were treated orally with curcumin (200 mg/kg BW/day), vancomycin (200 mg/kg BW/day, i.p.), vancomycin plus curcumin, respectively. Curcumin was administered 2 weeks before and 1 week simultaneously with vancomycin. Results showed that thiobarbituric acid reactive substances (TBARS) in plasma and kidney tissue were significantly increased after vancomycin administration. While, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in plasma and kidney tissue and the content of glutathione (GSH) in kidney tissue were decreased compared to control. Vancomycin significantly increased the levels of urea and creatinine. The presence of curcumin with vancomycin caused reduction in induction levels of TBARS in plasma and kidney, urea and creatinine. It ameliorated vancomycin induced decrease in the activities of antioxidant enzymes and GSH. The presence of curcumin with vancomycin alleviated its nephrotoxic effects. It can be concluded that curcumin has beneficial influences and could be able to antagonize vancomycin nephrotoxicity. PMID- 20832270 TI - Differential toxicity of Mn2+ and Mn3+ to rat liver tissues: oxidative damage, membrane fluidity and histopathological changes. AB - Toxicity due to overexposure to manganese (Mn) is becoming increasingly prevalent. Mn-induced neurodegenerative toxicity has been demonstrated, but little is known concerning the adverse effects of the element on the liver. Under physiological conditions, manganese primarily exists as divalent manganese (Mn(2+)) and trivalent manganese (Mn(3+)). The present study was designed to evaluate and compare the effects of Mn(2+) and Mn(3+) on oxidative hepatic damage, membrane fluidity and histopathological changes in rats. Rats exposed to Mn(2+) or Mn(3+) (2.0mg Mn/kg body weight) showed significant inhibition of superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, as well as decreased levels of glutathione (GSH) and increased levels of malondialdehyde (MDA) in liver tissues. We also showed a significant inhibition of SOD activity and increased MDA levels in hepatocyte nuclei. We also observed reduced Na(+),K(+)-ATPase activity, increased MDA levels and decreased plasma membrane fluidity, which was accompanied by an increase of fluorescence anisotropy (r) values, in hepatic plasma membranes. In addition, Mn(2+) and Mn(3+) both caused histopathological changes, such as mononuclear cell infiltration, congestion, enlargement of the veins and sinusoids, hepatocellular damage, necrotic changes, mitochondrial hyperplasia, swelling and vacuolization, as determined by light and electron microscopy. Taken together, these data suggest that both Mn(2+) and Mn(3+) inhibit the normal physiological functioning of the liver. Under the experimental conditions used, the adverse effects of Mn(2+) were more severe than those of Mn(3+). PMID- 20832271 TI - Is sexual body shape dimorphism consistent in aquatic and terrestrial chelonians? AB - Comparisons between aquatic and terrestrial species provide an opportunity to examine how sex-specific adaptations interact with the environment to influence body shape. In terrestrial female tortoises, selection for fecundity favors the development of a large internal abdominal cavity to accommodate the clutch; in conspecific males, sexual selection favors mobility with large openings in the shell. To examine to what extent such trends apply in aquatic chelonians we compared the body shape of males and females of two aquatic turtles (Chelodina colliei and Mauremys leprosa). In both species, females were larger than males. When controlled for body size, females exhibited a greater relative internal volume and a higher body condition index than males; both traits potentially correlate positively with fecundity. Males were more streamlined (hydrodynamic), and exhibited larger openings in the shell providing more space to move their longer limbs; such traits probably improve mobility and copulation ability (the males chase and grab the female for copulation). Overall, although the specific constraints imposed by terrestrial and aquatic locomotion shape the morphology of chelonians differently (aquatic turtles were flatter, hence more hydrodynamic than terrestrial tortoises), the direction for sexual shape dimorphism remained unaffected. Our main conclusion is that the direction of sexual shape dimorphism is probably more consistent than sexual size dimorphism in the animal kingdom. PMID- 20832272 TI - Association between concentration of trace elements in serum and bronchial asthma among Japanese general population. AB - BACKGROUND AND AIMS: A number of previous studies had revealed the association between trace elements in serum and bronchial asthma. However, only a few researches had focused on serum concentration of trace elements in a general population. In this study, an association between trace elements in serum and bronchial asthma was investigated in a general population. METHODS: Subjects were 1025 volunteers (385 males and 640 females between ages 19 and 82 years old) who had participated in the Iwaki Health Promotion Project 2005. Bronchial asthma was diagnosed based on the European Community Respiratory Health Survey II according to the self-questionnaires on health conditions of subjects. The serum concentrations of certain trace elements (manganese, copper, zinc, selenium and iron) were measured and compared. Also, an association between serum trace elements level and neutrophil-related functions (oxidative burst activity, phagocytic activity, serum opsonic activity) were determined. RESULTS: In males, no significant differences were seen in any serum trace elements concentrations. In females, serum zinc level was significantly higher in bronchial asthma group than in control. A positive correlation was seen between serum concentration of zinc and serum opsonic activity in both genders. CONCLUSIONS: In female asthmatics, increase of oxidative stress was suggested to be caused by superoxide dismutase pathway (elimination system of reactive oxygen species) rather than serum opsonic activity (production system of reactive oxygen species from neutrophils) pathway, as the zinc concentration in bronchial asthma group was higher than that in control. PMID- 20832273 TI - Effect of selenium on carbimazole-induced testicular damage and oxidative stress in albino rats. AB - Carbimazole is an antithyroid drug used in treatment of hyperthyroidism. The present investigation studied the effect of carbimazole on testicular activity in albino rats and the ameliorative role of selenium. Treating rats with carbimazole (1.35 mg/kg b.w) daily for 8 weeks caused reduction in the body and testes weight. Moreover, the diameters of the seminiferous tubules and heights of their germinal epithelium were significantly reduced. Testes of treated rats showed many histological alterations included congestion of blood vessels, hemorrhage, degeneration of interstitial tissue and degeneration of spermatogenic cells with apoptosis and necrosis. Histochemical results revealed reduction in polysaccharides, total proteins and nucleic acids contents in testicular tissue. In addition, the level of testosterone, luteinizing hormone (LH), T(3), T(4) and thyroid stimulating hormone (TSH) was significantly decreased in sera of treated animals. Moreover, a high lipid peroxidation with a decrease in the enzymatic antioxidant status, superoxide dismutase (SOD) and catalase (CAT) was recorded in testes homogenate. Treating animals with carbimazole and selenium showed an improvement in the histological structure as well as histochemical components of the testis with an increase in the number of spermatogenic cells. There was an increase in testosterone, LH, T(3), T(4) and TSH levels. Moreover, administration of selenium led to decrease in malondialdehyde and increase in catalase and superoxide dismutase activities. It is suggested that the curative effect of selenium against testicular damage induced by carbimazole may be due to its antioxidant properties. PMID- 20832274 TI - How thymic antigen presenting cells sample the body's self-antigens. AB - Our perception of the scope self-antigen availability for tolerance induction in the thymus has profoundly changed over the recent years following new insights into the cellular and molecular complexity of intrathymic antigen presentation. The diversity of self-peptide display is on the one hand afforded by the remarkable heterogeneity of thymic antigen presenting cells (APCs) and on the other hand by the endowment of these cells with unconventional molecular pathways. Recent studies show that each APC subset appears to carry its specific antigen cargo as a result of cell-type specific features: firstly, transcriptional control (i.e. promiscuous gene expression in medullary thymic epithelial cells); secondly, antigen processing (i.e. proteasome composition and protease sets); thirdly, intracellular antigen sampling (i.e. autophagy in thymic epithelial cells) and fourthly, extracellular antigen sampling (i.e. immigrating dendritic cells sampling extrathymic milieus). The combinatorial expression patterns of these attributes in distinct APC subsets result in a self-peptide display partly unique to the cortex mediating positive selection and to the medulla mediating tolerance induction. PMID- 20832275 TI - Cellular mechanisms regulating epithelial morphogenesis and cancer invasion. AB - The cellular mechanisms driving mammalian epithelial morphogenesis are of significant fundamental and practical interest. Historically, these processes have been difficult to study directly, owing to the opacity and relative inaccessibility of mammalian tissues. Recent experimental advances in timelapse imaging and in 3D organotypic culture have enabled direct observation of epithelial morphogenesis. In the mammary gland, branching morphogenesis is observed to proceed through a novel form of collective epithelial migration. The active unit of morphogenesis is a multilayered epithelium with reduced apico basal polarity, within which cells rearranged vigorously. From within this multilayered state, new ducts initiate and elongate into the matrix without leading cellular extensions or dedicated leaders. We discuss the implications of these findings on our understanding of epithelial morphogenesis in other organs and in cancer progression. PMID- 20832276 TI - Waste management activities and carbon emissions in Africa. AB - This paper summarizes research into waste management activities and carbon emissions from territories in sub-Saharan Africa with the main objective of quantifying emission reductions (ERs) that can be gained through viable improvements to waste management in Africa. It demonstrates that data on waste and carbon emissions is poor and generally inadequate for prediction models. The paper shows that the amount of waste produced and its composition are linked to national Gross Domestic Product (GDP). Waste production per person is around half that in developed countries with a mean around 230 kg/hd/yr. Sub-Saharan territories produce waste with a biogenic carbon content of around 56% (+/-25%), which is approximately 40% greater than developed countries. This waste is disposed in uncontrolled dumps that produce large amounts of methane gas. Greenhouse gas (GHG) emissions from waste will rise with increasing urbanization and can only be controlled through funding mechanisms from developed countries. PMID- 20832277 TI - A glucose sensor protein for continuous glucose monitoring. AB - In vivo continuous glucose monitoring has posed a significant challenge to glucose sensor development due to the lack of reliable techniques that are non- or at least minimally-invasive. In this proof-of-concept study, we demonstrated the development of a new glucose sensor protein, AcGFP1-GBPcys-mCherry, and an optical sensor assembly, capable of generating quantifiable FRET (fluorescence resonance energy transfer) signals for glucose monitoring. Our experimental data showed that the engineered glucose sensor protein can generate measurable FRET signals in response to glucose concentrations varying from 25 to 800 MUM. The sensor developed based on this protein had a shelf-life of up to 3 weeks. The sensor response was devoid of interference from compounds like galactose, fructose, lactose, mannose, and mannitol when tested at physiologically significant concentrations of these compounds. This new glucose sensor protein can potentially be used to develop implantable glucose sensors for continuous glucose monitoring. PMID- 20832278 TI - Next generation microfluidic platforms for high-throughput protein biochemistry. AB - DNA technologies such as cloning, DNA microarrays, and next generation sequencing have transformed the life sciences. Protein technologies on the other hand have not seen such explosive progress. This is mainly due to the inherent difficulty of working with proteins because of their manifold physical characteristics as opposed to the well behaved and well understood DNA polymer. Recent technological advancements have increased the throughput of protein biochemistry to levels where it is becoming of interest to systems biology. Here I review methods for high-throughput in situ synthesis and characterization of proteins and their integration with microfluidic devices. In the near future, the use of gene synthesis, microfluidic based protein synthesis and characterization will give rise to a resurgence of protein biochemistry in the current world of high throughput genomics. PMID- 20832279 TI - A comparison of a Neuropen monofilament and ethyl chloride for assessing loss of touch sensation during combined spinal-epidural anaesthesia for caesarean section. AB - BACKGROUND: Before caesarean section is performed under regional anaesthesia the block should be assessed, preferably using a touch stimulus. What constitutes a touch stimulus remains unclear. The aim of this study was to compare a Neuropen monofilament with ethyl chloride in the assessment of touch. METHODS: Forty women undergoing elective caesarean section received combined spinal-epidural anaesthesia. The upper dermatome spread was assessed using touch to a monofilament and ethyl chloride and cold to ethyl chloride at 5, 10, 15 and 20 min after intrathecal injection and again at the end of surgery. Visual analogue pain scores and Apgar scores were collected. RESULTS: Two one-sided test analysis demonstrated equivalence for Neuropen touch and ethyl chloride touch within one dermatome (P<0.0001). Wilcoxon post tests showed that Neuropen touch was marginally lower than ethyl chloride touch (P=0.0056). The median level of block to touch using both stimuli was below T5 at all time points. Pain scores had a median value of 0 cm and Apgar scores were 10 in all infants at 10 min. CONCLUSION: Data from this study suggest that a Neuropen monofilament and ethyl chloride are equivalent when used to assess a block to touch. However, subtle differences in the level of block to touch indicate that sensory level assessments should state the stimulus used. As the block to touch was below T5 at all time points, when opioids are added to local anaesthetics, T5 might no longer represent a necessary goal to ensure the absence of pain during caesarean section. PMID- 20832280 TI - Minimum effective dose of spinal ropivacaine with and without fentanyl for postpartum tubal ligation. AB - BACKGROUND: Ropivacaine may be the ideal spinal anesthetic for postpartum tubal ligation due to its medium duration of action, low incidence of side effects and possibly reduced post-anesthetic care unit (PACU) stay. METHODS: Two prospective up-down sequential allocation studies were performed using hyperbaric spinal ropivacaine via a combined spinal-epidural anesthetic technique for patients undergoing postpartum tubal ligation. The first study was performed using an initial dose of 12.5 mg hyperbaric ropivacaine, which was adjusted in testing intervals of 0.5 mg. The second study used an initial dose of 16 mg hyperbaric ropivacaine, a testing interval of 1.0mg, and a fixed dose of fentanyl 10 MUg. The need to supplement the block with intravenous or epidural agents was defined as a failure. Failures were treated with epidural lidocaine. RESULTS: The first and second studies recruited 24 and 17 patients, respectively. The median effective dose (ED50) for hyperbaric spinal ropivacaine was 16.4 mg (95% CI 13.7 19) with an ED95 estimate of 21.9 mg. The median effective dose of spinal ropivacaine with fentanyl 10 MUg was 17.0 mg (95% CI 15.4-18.7) with an ED95 estimate of 21.3 mg. When data were combined, the overall ED50 for ropivacaine was 16.7 mg (95% CI 15.1-18.4) with an ED95 estimate of 22.5 mg (95% CI 16.3 28.8). A T8 block was not achieved in 4 patients receiving spinal ropivacaine alone, and 1 patient receiving spinal ropivacaine with fentanyl. The majority (82%) of patients who did not receive epidural local anesthetic supplementation had recovery of motor block within 60 min following PACU admission. CONCLUSION: Spinal hyperbaric ropivacaine 22 mg with or without fentanyl 10 MUg could be used for postpartum tubal ligation surgery. PMID- 20832281 TI - Bloodless trilogy? Anesthesia, obstetrics and interventional radiology for cesarean delivery. PMID- 20832282 TI - A randomized comparison of automated intermittent mandatory boluses with a basal infusion in combination with patient-controlled epidural analgesia for labor and delivery. AB - BACKGROUND: Automated mandatory boluses (AMB), when used in place of a continuous basal infusion, have been shown to reduce overall local anesthetic consumption without compromising analgesic efficacy in patient-controlled epidural analgesia (PCEA). We hypothesized that our PCEA+AMB regimen could result in a reduction of breakthrough pain requiring epidural supplementation in comparison with PCEA with a basal infusion (PCEA+BI). METHODS: We recruited sixty-two healthy ASA I nulliparous parturients in early labor. The parturients were randomized to receive 0.1% ropivacaine+fentanyl 2 MUg/mL either via PCEA+BI (PCEA with basal continuous infusion of 5mL/h) or PCEA+AMB (PCEA with AMB of 5 mL every hour instead of a basal infusion) immediately following successful induction of combined spinal-epidural (CSE) analgesia. Block characteristics, incidence of breakthrough pain requiring epidural supplementation, side effects, obstetric outcomes, Apgar scores and overall maternal satisfaction with analgesia were noted. RESULTS: The time-weighted hourly consumption of ropivacaine (PCEA and clinician supplementation for breakthrough pain) was significantly lower in the PCEA+AMB group (mean=7.6 mL, SD 3.2) compared to the PCEA+BI group (mean=9.3 mL, SD 2.5; P<0.001). The mean time to first PCEA self-bolus following CSE was significantly longer in the PCEA+AMB group compared to the PCEA+BI group (268 min vs. 104 min; P<0.001). Parturients in Group PCEA+AMB also gave higher satisfaction scores. The incidence of breakthrough pain was similar in both groups. CONCLUSION: PCEA+AMB, when compared to PCEA+BI, confers greater patient satisfaction and a longer duration of effective analgesia after CSE despite reduced analgesic consumption. PMID- 20832283 TI - Maternal critical care: what's in a name? PMID- 20832284 TI - Structural and functional plasticity of the cytoplasmic active zone. AB - The presynaptic active zone (AZ) membrane is the site where vesicle fusion mediates information transfer between connected neurons. Reaching into the cytoplasm, an electron-dense cytomatrix (CAZ) is found to decorate the AZ membranes. CAZ architectures are meant not only to regulate the synaptic vesicle exocycle/endocycle, but also to structurally stabilize the presynaptic site. The CAZ is composed of a set of large scaffold proteins, many of which are evolutionarily conserved. Recently, several signaling factors controlling the developmental assembly of CAZs were found by unbiased genetics in Drosophila and Caenorhabditis elegans. At the same time, post-translational modification of CAZ proteins was implicated in changing the strength of mammalian brain synapses. Studying how processes of structural and functional CAZ plasticity get integrated within circuit remodeling remains an important challenge. PMID- 20832285 TI - The genetics of neurodevelopmental disease. AB - The term neurodevelopmental disorder encompasses a wide range of diseases, including recognizably distinct syndromes known to be caused by very rare mutations in specific genes or chromosomal loci, and also much more common disorders such as schizophrenia, autism spectrum disorders, and idiopathic epilepsy and mental retardation. After decades of frustration, the past couple of years have suddenly seen tremendous progress in unravelling the genetics of these common disorders. These findings have led to a paradigm shift in our conception of the genetic architecture of common neurodevelopmental disease, highlighting the importance of individual, rare mutations and overlapping genetic aetiology of various disorders. They have also converged on specific neurodevelopmental pathways, providing insights into pathogenic mechanisms. PMID- 20832287 TI - New technologies. PMID- 20832286 TI - Synaptic organizing complexes. AB - A number of synaptogenic factors induce presynaptic or postsynaptic differentiation when presented to axons or dendrites. Many such factors participate in bidirectional trans-synaptic adhesion complexes. Axonal neurexins interacting in an isoform-specific code with multiple dendritic partners (neuroligins, LRRTMs, or Cbln-GluRdelta), and axonal protein tyrosine phosphatase receptors interacting with dendritic NGL-3, nucleate local networks of high affinity protein-protein interactions leading to aligned presynaptic and postsynaptic differentiation. Additional secreted target-derived factors such as fibroblast growth factors and glial-derived factors such as thrombospondin bind specific axonal or dendritic receptors stimulating signal transduction mechanisms to promote selective aspects of synapse development. Together with classical adhesion molecules and controlled by transcriptional cascades, these synaptogenic adhesion complexes and secreted factors organize the molecular composition and thus functional properties of central synapses. PMID- 20832288 TI - Genetic dissection of axon regeneration. AB - Axon regeneration has long been studied in vertebrate model organisms and neuronal cultures. Recent development of axon regeneration paradigms in genetic model organisms, such as Caenorhabditis elegans, Drosophila and zebrafish, has opened an exciting field for in vivo functional dissection of regeneration pathways. Studies in these organisms have discovered essential genes and pathways for axon regrowth. The conservation of these genes crossing animal phyla suggests mechanistic relevance to higher organisms. The power of genetic approaches in these organisms makes large-scale genetic and pharmacological screens feasible and can greatly accelerate the mechanistic understanding of axon regeneration. PMID- 20832289 TI - Adhesion and signaling between neurons and glial cells in Drosophila. AB - Trans-cellular communication relies on a complex interplay of cell-cell adhesion and signaling induced by diffusible molecules. This is particularly evident for neuron-glia interaction in the nervous system. The small, relative number of glial cells in combination with well-established genetic techniques predestines Drosophila as a powerful model to dissect the molecular basis of neuron-glia interaction. We are discussing homophilic and heterophilic adhesion systems that ensure proper interaction of neurons and glial cells as well as prominent signaling cascades regulating various aspects of coordinated neuron-glial development. The combination of these results in instructive signals governing proper nervous system development and function. PMID- 20832290 TI - The dynamic cytoskeleton: backbone of dendritic spine plasticity. AB - Dendritic spines are small actin-rich protrusions on the surface of dendrites whose morphological and molecular plasticity play key roles in learning and memory. Both the form and function of spines are critically dependent on the actin cytoskeleton. However, new research, using electron microscopy and live cell super-resolution microscopy indicates that the actin cytoskeleton is more complex and dynamic than originally thought. Also, exciting recent studies from several labs indicate that microtubules, once thought to be restricted to the dendrite shaft, can make excursions into the most distal regions of dendritic spines. Moreover, microtubule invasions of spines appear to be associated with changes in synaptic activity. Thus, it is likely that dynamic interactions between microtubules and actin filaments within dendritic spines play important roles in dendritic spine plasticity. PMID- 20832291 TI - The BMP signaling pathway at the Drosophila neuromuscular junction and its links to neurodegenerative diseases. AB - The Drosophila neuromuscular junction (NMJ) has recently provided new insights into the roles of various proteins in neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Multiple Sclerosis (MS) Hereditary Spastic Paraplegia (HSP), and Huntington's Disease (HD). Several developmental signaling pathways including WNT, MAPK and BMP/TGF beta signaling play important roles in the formation and growth of the Drosophila NMJ. Studies of the fly homologues of genes that cause neurodegenerative disease at the NMJ have resulted in a better understanding of the roles of these proteins in vivo. These studies may shed light on the pathological mechanisms of these diseases, with implications for reduced BMP/TGF-beta signaling in ALS, SMA and HD and increased signaling in HSP and MS. PMID- 20832292 TI - Biosynthetic enzymes of unusual microbial sugars. AB - The biological importance of proteins and nucleic acids in the natural world is undeniable, and research efforts on these macromolecules have often overshadowed those directed at carbohydrates. It is now known, however, that carbohydrates not only play roles in energy storage and plant cell wall structure, but are also intimately involved in such processes as fertilization, the immune response, and cell adhesion. Indeed, recent years have seen an explosion in research efforts directed at uncovering and understanding new sugar moieties. The dideoxysugars and trideoxysugars, which are synthesized by a variety of bacteria, fungi, and plants, represent an especially intriguing class of carbohydrates. They are found, for example, on the lipopolysaccharides of some Gram-negative bacteria or on antibacterial agents such as erythromycin. Many of them are formed from simple monosaccharides such as glucose-6-phosphate or fructose-6-phosphate via a myriad of enzymatic reactions including acetylations, aminations, dehydrations, epimerizations, reductions, and methylations. In this review we focus on the recent structural investigations of the bacterial N-acetyltransferases and the PLP-dependent aminotransferases that function on nucleotide-linked sugar substrates. PMID- 20832293 TI - Down-regulation of the miRNA master regulators Drosha and Dicer is associated with specific subgroups of breast cancer. AB - Down-regulation of Drosha and Dicer has been suggested to be of prognostic value in some cancers. The aims of our study were to investigate the down-regulation of Drosha and Dicer in breast cancers and its associations with clinicopathological features, molecular subtypes and outcome. Drosha and Dicer expression was assessed with real-time RT-PCR in 245 patients with breast cancer receiving adjuvant anthracycline-based chemotherapy and compared to expression levels of normal breast tissue. Drosha down-regulation was observed in 18% of cases and was associated with high grade, high Ki-67, lack of Bcl2 expression, HER2 over expression and gene amplification and TOPO2A gene amplification. Dicer down regulation was found in 46% of cases and was associated with lack of expression of ER, PR and Bcl2 and with high grade, high Ki-67, triple-negative and basal like phenotypes. Drosha and Dicer were concurrently down-regulated in 15% of cases and significantly associated with high grade and high Ki-67 index. No significant associations between down-regulation of Drosha and/or Dicer and outcome were observed. Our results suggest that down-regulation of Drosha and/or Dicer is not robustly associated with the outcome of breast cancer patients treated with adjuvant anthracycline-based chemotherapy but preferentially observed in distinct subgroups of breast cancer. PMID- 20832294 TI - Suppression of ovarian function in combination with an aromatase inhibitor as treatment for advanced breast cancer in pre-menopausal women. AB - Trials have shown superiority of aromatase inhibitors (AIs) over tamoxifen for post-menopausal oestrogen receptor-positive advanced breast cancer (ER+ABC). We previously reported the use of goserelin plus anastrozole (G+A) as second-line endocrine therapy for pre-menopausal ER+ABC. We report clinical and endocrine data from G+A as first-line systemic therapy. Thirty-six patients (median age=44 years) with metastatic (N=28) and locally advanced disease were administered G+A for >=6 months (unless progressed prior). Some (N=13) received further therapy with goserelin plus another AI (steroidal), exemestane (G+E). Serial serum hormone assays (oestradiol, dehydroepiandrosterone sulphate, testosterone, follicle stimulating hormone and luteinising hormone) were performed. Twenty-four patients (67%) derived clinical benefit (CB) (5% complete response, 31% partial response, 31% stable disease for >=6 months) with median time to progression and duration of CB of 12 (2-47) and 24+(7-78+) months respectively. Ten patients were still receiving first-line G+A at analysis. Amongst 13 patients who went onto receive G+E, 38% achieved CB with a mean duration of 13+(7-32) months. Therapy was well tolerated with no withdrawals. The combination of G+A resulted in 98% reduction (from pre-treatment to 6-month) in median levels of oestradiol (from 574.5 pmol/L; inter-quartile range (IQR)=209-1426; (N=6) to 13.45 pmol/L; IOQ=5.5 31.5 (N=4) whilst the levels of other hormones had minimal fluctuations during therapy. The combinations of ovarian function suppression (using G) and AIs produce sustained CB and minimal side effects in pre-menopausal ER+ABC with significant reduction in oestradiol levels. Within the limitations of being a non randomised study, they should be considered in appropriate patients with hormone sensitive ABC. PMID- 20832295 TI - C-reactive protein; a potential marker of second cancer and cardiovascular disease in testicular cancer survivors? AB - INTRODUCTION: C-reactive protein (CRP) is a marker of cardiovascular disease (CVD). There is conflicting evidence regarding CRP as a marker of future cancer. We studied whether CRP predicts CVD and consecutive cancer in testicular cancer survivors (TCSs). PATIENTS AND METHODS: During 1998-2001, 586 TCSs with a high sensitivity CRP <= 10 mg/L were identified median 11 (4-21) years after treatment (FU-1). A second follow-up survey (FU-2) was conducted median 8 (6-9) years after FU-1. At FU-2 we obtained information about post-FU-1 CVD (cardiovascular death, nonfatal myocardial infarction, stroke, revascularisation or heart failure). Information about post-FU-1 non-germ cell cancer and cardiovascular death in all patients were retrieved from the Cancer Registry of Norway. RESULTS: After FU-1 31 (5.3%) of 586 patients developed non-germ cell cancer (excluding localised prostate cancer), while 28 (4.9%) developed CVD. Cox regression analyses showed that patients with CRP >=1.5mg/L had 2.21 (95% CI 1.04-4.70) times higher risk of developing non-germ cell cancer and 2.79 (95% CI 1.22-6.34) times higher risk for CVD compared to patients with CRP <1.5mg/L at FU-1. CONCLUSION: In long-term TCSs, CRP may serve as a potential marker of cardiovascular events and a second cancer. PMID- 20832296 TI - Advances in cancer surgery: natural orifice surgery (NOTES) for oncological diseases. AB - Natural orifice transluminal endoscopic surgery (NOTES) is a new concept that attempts to reduce the impact of surgery on the patient. In surgical oncology several studies have already revealed that a minimally invasive approach provides at least the same, if not a better, long-term outcome. One could hypothesize that a less invasive approach such as NOTES could further enhance such advantages. Since its initial description, NOTES has become clinical reality and today nearly every organ is accessible by a transluminal approach, in at least the experimental setting. Subsequent to published research, first clinical studies on NOTES in oncology were reported and the accuracy of transgastric peritoneoscopy for staging of pancreas cancer was shown to be similar to laparoscopy in humans. A NOTES gastro-jejunostomy via transgastric access has also been proposed to decrease invasiveness of palliative treatment of duodenal, biliary and pancreatic cancers. Colorectal cancer resection via transanal access would offer a clear-cut patient advantage over laparoscopic and would not be subject to the frequent criticism of violating an innocent second organ, as the colon or rectum is always breached in a colectomy. Natural orifice endoluminal therapies, such as endoscopic submucosal dissection, already have been clinically applied for several years. Improved techniques or instruments evolving from NOTES technology might enhance its widespread use for the treatment of early malignancies and thereby again will provide a tremendous benefit for the patient. Although still somewhat controversial, the subject of natural orifice surgery in oncological disease indicates that current laboratory efforts to introduce NOTES into cancer surgery could be ready for cautious clinical investigations. The final determination of patient benefit will need well-constructed prospective study. PMID- 20832297 TI - Sulfidogenic fluidized bed treatment of real acid mine drainage water. AB - The treatment of real acid mine drainage water (pH 2.7-4.3) containing sulfate (1.5-3.34 g/L) and various metals was studied in an ethanol-fed sulfate-reducing fluidized bed reactor at 35 degrees C. The robustness of the process was tested by increasing stepwise sulfate, ethanol and metal loading rates and decreasing feed pH and hydraulic retention time. Highest sulfate reduction rate (4.6g/L day) was obtained with feed sulfate concentration of 2.5 g/L, COD/sulfate ratio of 0.85 and HRT of 12 h. The corresponding sulfate and COD removal efficiencies were about 90% and 80%, respectively. The alkalinity produced in sulfidogenic ethanol oxidation neutralized the acidic mine water. Highest metal precipitation efficiencies were observed at HRT of 24 h, the percent metal removal being over 99.9% for Al (initial concentration 55 mg/L), Co (9.0 mg/L), Cu (49 mg/L), Fe (435 mg/L), Ni (3.8 mg/L), Pb (7.5 mg/L) and Zn (6.6 mg/L), and 94% for Mn (7.21 mg/L). PMID- 20832298 TI - Life cycle assessment of bioenergy systems: state of the art and future challenges. AB - The use of different input data, functional units, allocation methods, reference systems and other assumptions complicates comparisons of LCA bioenergy studies. In addition, uncertainties and use of specific local factors for indirect effects (like land-use change and N-based soil emissions) may give rise to wide ranges of final results. In order to investigate how these key issues have been addressed so far, this work performs a review of the recent bioenergy LCA literature. The abundance of studies dealing with the different biomass resources, conversion technologies, products and environmental impact categories is summarized and discussed. Afterwards, a qualitative interpretation of the LCA results is depicted, focusing on energy balance, GHG balance and other impact categories. With the exception of a few studies, most LCAs found a significant net reduction in GHG emissions and fossil energy consumption when bioenergy replaces fossil energy. PMID- 20832299 TI - Heterogeneous catalytic transesterification of phosphatidylcholine. AB - The transesterification of phosphatidylcholine (PC) via homogeneous and heterogeneous catalysis was investigated for the production of fatty acid methyl esters (FAME) i.e. biodiesel. Calcium methoxide and calcium oxide were used as heterogeneous catalysts, and KOH as a homogeneous catalyst for the transesterification of phosphatidylcholine (PC)--a polar phospholipid prevalent in eukaryotic organisms. The initial reaction rate was higher for KOH (24.23 g of FAME/g of catalyst.min) than for calcium methoxide (17.06 g of FAME/g of catalyst.min) and calcium oxide (1.06 g of FAME/g of catalyst.min). PC was then mixed with soybean oil at different proportions (i.e. 10%, 30% and 50%, PC10, PC30 and PC50, respectively) which was then used as the feedstock for transesterification using calcium methoxide. When the mass fraction of PC was increased in the feedstock reaction rate also increased. Phosphorus content of the FAME layer of PC100, PC50, PC30 and PC10 was 0.081, 0.041, 0.035 and 0.028% (w/w), respectively. PMID- 20832300 TI - Purification and characterization of glutaminase-free L-asparaginase from Pectobacterium carotovorum MTCC 1428. AB - An intracellular glutaminase-free L-asparaginase from Pectobacterium carotovorum MTCC 1428 was isolated to apparent homogeneity. The homotetramer enzyme has a molecular mass of 144.4 kDa (MALDI-TOF MS) and an isoelectric point of approximately 8.4. The enzyme is very specific for its natural substrate, L asparagine. The activity of L-asparaginase is activated by mono cations and various effectors including Na+, K+, L-cystine, L-histidine, glutathione and 2 mercaptoethanol whereas it is moderately inhibited by various divalent cations and thiol group blocking reagents. Kinetic parameters, Km, Vmax and kcat of purified L-asparaginase from P. carotovorum MTCC 1428 were found to be 0.657 mM, 4.45 U MUg(-1) and 2.751*10(3) s(-1), respectively. Optimum pH of purified L asparaginase for the hydrolysis of L-asparagine was in the range of 8.0-10.0, and its optimum temperature was found to be 40 degrees C. The purified L asparaginase has no partial glutaminase activity, which can reduce the possibility of side effects during the course of anti-cancer therapy. PMID- 20832301 TI - Isoform-selective inhibition of chrysin towards human cytochrome P450 1A2. Kinetics analysis, molecular docking, and molecular dynamics simulations. AB - Our kinetics studies demonstrated that the nature product chrysin exhibited a high inhibitory affinity of 54 nM towards human cytochrome P450 1A2 and was comparable to alpha-naphthoflavone (49 nM), whereas it represented a moderate affinity of 5225 nM against human cytochrome P450 2C9. However, it remains unclear how this inhibitor selectively binds 1A2. To better understand the isoform selectivity of chrysin, molecular docking and molecular dynamics simulations were performed. Chrysin formed a strong H-bond with Asp313 of 1A2. The stacking interactions with Phe226 also contributed to its tight binding to 1A2. The larger and much more open active site architectures of 2C9 may explain the weaker inhibitory affinity of chrysin towards 2C9. The predicted binding free energies suggest that chrysin preferred 1A2 (DeltaG(bind, pred)=-23.11 kcal/mol) to 2C9 (-20.41 kcal/mol). Additionally, the present work revealed that 7-hydroxy flavone bound to 1A2 in a similar pattern as chrysin and represented a slightly less negative predicted binding free energy, which was further validated by our kinetics analysis (IC(50)=240 nM). Results of the study can provide insight for designing novel isoform-selective 1A2 inhibitors. PMID- 20832302 TI - Synthesis of symmetrical thiol-adenosine conjugate and 5' thiol-RNA preparation by efficient one-step transcription. AB - A symmetrical transcription initiator containing two adenosines and conjugated thiol functionality (ThioAMP dimer) is chemically synthesized. Transcription in the presence of ThioAMP dimer under the T7 Phi2.5 promoter yields 5' thiol labeled RNA (5' HS-RNA) with up to 90% labeling efficiency, depending on the concentration ratio of ThioAMP dimer to ATP. The resulting 5' HS-RNA may be used directly or after thiopropyl Separose 6B affinity column purification. Biotinylation of 5' HS-RNA and formation of gold nanoparticle-RNA nanoplexes are demonstrated. PMID- 20832303 TI - Identification of the first non-peptidic small molecule inhibitor of the c-Abl/14 3-3 protein-protein interactions able to drive sensitive and Imatinib-resistant leukemia cells to apoptosis. AB - An in silico structure-based ligand design approach resulted in the identification of the first non-peptidic small molecule able to inhibit protein protein interactions between 14-3-3 and c-Abl. This compound shows an anti proliferative effect on human leukemia cells either sensitive or resistant to Imatinib, in consequence of the T315I mutation. It also mediates c-Abl release from 14-3-3 in a way similar to that found in response to Imatinib treatment. PMID- 20832304 TI - Validated predictive QSAR modeling of N-aryl-oxazolidinone-5-carboxamides for anti-HIV protease activity. AB - Validated predictive QSAR modeling was done on some N-aryl-oxazolidinone-5 carboxamides for higher anti-HIV protease activities. Stepwise regression developed significant models showing importance of atom based descriptors like RTSA indices, Wang-Ford charges and different whole molecular descriptors. The true predictabilities of QSAR models were justified by challenging these against an external dataset. A representative high active compound was predicted by this modeling. It showed that internal and external validations may lead to the same conclusion. PMID- 20832305 TI - Novel rhodanine derivatives induce growth inhibition followed by apoptosis. AB - We have designed and synthesized three novel compounds, 5-isopropylidiene derivatives of 3-dimethyl-2-thio-hydantoin (ITH-1), 3-ethyl-2-thio-2,4 oxazolidinedione (ITO-1), and 5-benzilidene-3-ethyl rhodanine (BTR-1), and have tested their chemotherapeutic properties. Our results showed that all three compounds induced cytotoxicity in a time- and concentration-dependent manner on leukemic cell line, CEM. Among the compounds tested, BTR-1 was 5- to 7-fold more potent than ITH-1 and ITO-1 when compared by trypan blue and MTT assays. IC(50) value of BTR-1 was estimated to be <10MUM. Both cell cycle analysis and tritiated thymidine assays revealed that BTR-1 affects DNA replication by inducing a block at S phase. BTR-1 treatment led to increased level of ROS production and DNA strand breaks suggesting activation of apoptosis for induction of cell death. PMID- 20832306 TI - Design and synthesis of a new class of malonyl-CoA decarboxylase inhibitors with anti-obesity and anti-diabetic activities. AB - A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes. PMID- 20832307 TI - Pyrazolobenzodiazepines: part I. Synthesis and SAR of a potent class of kinase inhibitors. AB - A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents. PMID- 20832308 TI - Ultrastructural changes in diaphragm neuromuscular junctions in a severe mouse model for Spinal Muscular Atrophy and their prevention by bifunctional U7 snRNA correcting SMN2 splicing. AB - In Spinal Muscular Atrophy (SMA), the SMN1 gene is deleted or inactivated. Because of a splicing problem, the second copy gene, SMN2, generates insufficient amounts of functional SMN protein, leading to the death of spinal cord motoneurons. For a "severe" mouse SMA model (Smn -/-, hSMN2 +/+; with affected pups dying at 5-7 days), which most closely mimicks the genetic set-up in human SMA patients, we characterise SMA-related ultrastructural changes in neuromuscular junctions (NMJs) of two striated muscles with discrete functions. In the diaphragm, but not the soleus muscle of 4-days old SMA mice, mitochondria on both sides of the NMJs degenerate, and perisynaptic Schwann cells as well as endoneurial fibroblasts show striking changes in morphology. Importantly, NMJs of SMA mice in which a modified U7 snRNA corrects SMN2 splicing and delays or prevents SMA symptoms are normal. This ultrastructural study reveals novel features of NMJ alterations - in particular the involvement of perisynaptic Schwann cells - that may be relevant for human SMA pathogenesis. PMID- 20832309 TI - Genetics, chromatin diminution, and sex chromosome evolution in the parasitic nematode genus Strongyloides. AB - BACKGROUND: When chromatin diminution occurs during a cell division a portion of the chromatin is eliminated, resulting in daughter cells with a smaller amount of genetic material. In the parasitic roundworms Ascaris and Parascaris, chromatin diminution creates a genetic difference between the soma and the germline. However, the function of chromatin diminution remains a mystery, because the vast majority of the eliminated DNA is noncoding. Within the parasitic roundworm genus Strongyloides, S. stercoralis (in man) and S. ratti (in rat) employ XX/XO sex determination, but the situation in S. papillosus (in sheep) is different but controversial. RESULTS: We demonstrate genetically that S. papillosus employs sex specific chromatin diminution to eliminate an internal portion of one of the two homologs of one chromosome pair in males. Contrary to ascarids, the eliminated DNA in S. papillosus contains a large number of genes. We demonstrate that the region undergoing diminution is homologous to the X chromosome of the closely related S. ratti. The flanking regions, which are not diminished, are homologous to the S. ratti autosome number I. Furthermore, we found that the diminished chromosome is not incorporated into sperm, resulting in a male-specific transmission ratio distortion. CONCLUSIONS: Our data indicate that on the evolutionary path to S. papillosus, the X chromosome fused with an autosome. Chromatin diminution serves to functionally restore an XX/XO sex-determining system. A consequence of the fusion and the process that copes with it is a transmission ratio distortion in males for certain loci. PMID- 20832310 TI - Prolonged prometaphase blocks daughter cell proliferation despite normal completion of mitosis. AB - The mitotic checkpoint maintains genomic stability by blocking the metaphase anaphase transition until all kinetochores attach to spindle microtubules [1, 2]. However, some defects are not detected by this checkpoint. With low concentrations of microtubule-targeting agents, the checkpoint eventually becomes satisfied, though the spindles may be short and/or multipolar [3, 4] and the fidelity of chromosome distribution and cleavage completion are compromised. In real life, environmental toxins, radiation, or chemotherapeutic agents may lead to completed but inaccurate mitoses. It has been assumed that once the checkpoint is satisfied and cells divide, the daughter cells would proliferate regardless of prometaphase duration. However, when continuously exposed to microtubule inhibitors, untransformed cells eventually slip out of mitosis after 12-48 hr and arrest in G1 [5-8] (see also [9]). Interestingly, transient but prolonged treatments with nocodazole allow completion of mitosis, but the daughter cells arrest in interphase [10, 11] (see also [9, 12]). Here we characterize the relationship between prometaphase duration and the proliferative capacity of daughter cells. Our results reveal the existence of a mechanism that senses prometaphase duration; if prometaphase lasts >1.5 hr, this mechanism triggers a durable p38- and p53-dependent G1 arrest of the daughter cells despite normal division of their mothers. PMID- 20832311 TI - Sexual dimorphism in the fly brain. AB - BACKGROUND: Sex-specific behavior may originate from differences in brain structure or function. In Drosophila, the action of the male-specific isoform of fruitless in about 2000 neurons appears to be necessary and sufficient for many aspects of male courtship behavior. Initial work found limited evidence for anatomical dimorphism in these fru+ neurons. Subsequently, three discrete anatomical differences in central brain fru+ neurons have been reported, but the global organization of sex differences in wiring is unclear. RESULTS: A global search for structural differences in the Drosophila brain identified large volumetric differences between males and females, mostly in higher brain centers. In parallel, saturating clonal analysis of fru+ neurons using mosaic analysis with a repressible cell marker identified 62 neuroblast lineages that generate fru+ neurons in the brain. Coregistering images from male and female brains identified 19 new dimorphisms in males; these are highly concentrated in male enlarged higher brain centers. Seven dimorphic lineages also had female-specific arbors. In addition, at least 5 of 51 fru+ lineages in the nerve cord are dimorphic. We use these data to predict >700 potential sites of dimorphic neural connectivity. These are particularly enriched in third-order olfactory neurons of the lateral horn, where we provide strong evidence for dimorphic anatomical connections by labeling partner neurons in different colors in the same brain. CONCLUSION: Our analysis reveals substantial differences in wiring and gross anatomy between male and female fly brains. Reciprocal connection differences in the lateral horn offer a plausible explanation for opposing responses to sex pheromones in male and female flies. PMID- 20832312 TI - Phosphorylation of eEF1A1 at Ser300 by TbetaR-I results in inhibition of mRNA translation. AB - BACKGROUND: Transforming growth factor beta (TGF-beta) is a potent inhibitor of cell proliferation that regulates cell functions by activating specific serine/threonine kinase receptors on the cell surface. Type I TGF-beta receptor (TbetaR-I) is essential for TGF-beta signaling, and substrates of TbetaR-I provide insights into molecular mechanisms of TGF-beta signaling. RESULTS: Here we identify eukaryotic elongation factor 1A1 (eEF1A1) as a novel substrate of TbetaR-I. We show that TbetaR-I phosphorylates eEF1A1 at Ser300 in vitro and in vivo. Ser300 was found to be important for aminoacyl-tRNA (aa-tRNA) binding to eEF1A1. Ser300 phosphorylation or mutations of Ser300 correlate with inhibition of protein synthesis in vitro and in vivo. We show that mimicking eEF1A1 phosphorylation at Ser300 results in inhibition of cell proliferation, and that mutations of Ser300 affect TGF-beta dependency in inhibition of protein synthesis and cell proliferation. Increased expression of eEF1A has been reported to enhance carcinogenesis. An analysis of human breast cancer cases revealed a decrease of eEF1A1 phosphorylation at Ser300 in malignant tumor cells as compared to epithelial cells in noncancerous tissues. CONCLUSIONS: Phosphorylation of eEF1A1 by TbetaR-I is a novel regulatory mechanism that provides a direct link to regulation of protein synthesis by TGF-beta, as an important component in the TGF beta-dependent regulation of protein synthesis and cell proliferation. PMID- 20832313 TI - Coupling of apoptosis and L/R patterning controls stepwise organ looping. AB - Handed asymmetry in organ shape and positioning is a common feature among bilateria, yet little is known about the morphogenetic mechanisms underlying left right (LR) organogenesis. We utilize the directional 360 degrees clockwise rotation of genitalia in Drosophila to study LR-dependent organ looping. Using time-lapse imaging, we show that rotation of genitalia by 360 degrees results from an additive process involving two ring-shaped domains, each undergoing 180 degrees rotation. Our results show that the direction of rotation for each ring is autonomous and strictly depends on the LR determinant myosin ID (MyoID). Specific inactivation of MyoID in one domain causes rings to rotate in opposite directions and thereby cancels out the overall movement. We further reveal a specific pattern of apoptosis at the ring boundaries and show that local cell death is required for the movement of each domain, acting as a brake-releaser. These data indicate that organ looping can proceed through an incremental mechanism coupling LR determination and apoptosis. Furthermore, they suggest a model for the stepwise evolution of genitalia posture in Diptera, through the emergence and duplication of a 180 degrees LR module. PMID- 20832314 TI - Great bowerbirds create theaters with forced perspective when seen by their audience. AB - Birds in the infraorder Corvida [1] (ravens, jays, bowerbirds) are renowned for their cognitive abilities [2-4], which include advanced problem solving with spatial inference [4-8], tool use and complex constructions [7-10], and bowerbird cognitive ability is associated with mating success [11]. Great bowerbird males construct bowers with a long avenue from within which females view the male displaying over his bower court [10]. This predictable audience viewpoint is a prerequisite for forced (altered) visual perspective [12-14]. Males make courts with gray and white objects that increase in size with distance from the avenue entrance. This gradient creates forced visual perspective for the audience; court object visual angles subtended on the female viewer's eye are more uniform than if the objects were placed at random. Forced perspective can yield false perception of size and distance [12, 15]. After experimental reversal of their size-distance gradient, males recovered their gradients within 3 days, and there was little difference from the original after 2 wks. Variation among males in their forced-perspective quality as seen by their female audience indicates that visual perspective is available for use in mate choice, perhaps as an indicator of cognitive ability. Regardless of function, the creation and maintenance of forced visual perspective is clearly important to great bowerbirds and suggests the possibility of a previously unknown dimension of bird cognition. PMID- 20832315 TI - Cellular organization of the neural circuit that drives Drosophila courtship behavior. AB - BACKGROUND: Courtship behavior in Drosophila has been causally linked to the activity of the heterogeneous set of ~1500 neurons that express the sex-specific transcripts of the fruitless (fru) gene, but we currently lack an appreciation of the cellular diversity within this population, the extent to which these cells are sexually dimorphic, and how they might be organized into functional circuits. RESULTS: We used genetic methods to define 100 distinct classes of fru neuron, which we compiled into a digital 3D atlas at cellular resolution. We determined the polarity of many of these neurons and computed their likely patterns of connectivity, thereby assembling them into a neural circuit that extends from sensory input to motor output. The cellular organization of this circuit reveals neuronal pathways in the brain that are likely to integrate multiple sensory cues from other flies and to issue descending control signals to motor circuits in the thoracic ganglia. We identified 11 anatomical dimorphisms within this circuit: neurons that are male specific, are more numerous in males than females, or have distinct arborization patterns in males and females. CONCLUSIONS: The cellular organization of the fru circuit suggests how multiple distinct sensory cues are integrated in the fly's brain to drive sex-specific courtship behavior. We propose that sensory processing and motor control are mediated through circuits that are largely similar in males and females. Sex-specific behavior may instead arise through dimorphic circuits in the brain and nerve cord that differentially couple sensory input to motor output. PMID- 20832316 TI - Animating the model figure. AB - In all branches of scientific inquiry, researchers build models that enable them to visualize, formulate and communicate their hypotheses to others. In cell biology, our conceptual understanding of a process is typically embodied in a model figure. These visual models should ideally represent pre-existing knowledge of molecular interactions, movement, structure and localization but, in reality, they often fall short. Cell biologists have begun to look to the use of three dimensional animation to visualize and describe complex molecular and cellular events. In addition to aiding teaching and communication, animation is emerging as a powerful tool for providing researchers with insight into the processes that they study. Two case studies focusing on the structure/function of the motor protein dynein and the structure of the centriole are discussed. PMID- 20832317 TI - Development of healthy children's feet--nine-year results of a longitudinal investigation of plantar loading patterns. AB - The purpose of the present study was to provide normative data for foot loading patterns and foot form parameters in order to support decisions about the normal or abnormal development of the growing foot during childhood. In a longitudinal design, 36 healthy German children were followed over the course of nine years. The children had a mean age of 14.6 +/- 1.8 months at the first appointment and 122.8 +/- 2.0 months at the last appointment. The children participated in 17 measurement appointments every 3, 6 or 12 months. Dynamic foot loading was evaluated with plantar pressure measurements during walking and static footprints were taken to determine changes in foot form. During the investigation period an increase of peak pressures of the total foot by 190%, of the relative maximum force of the total foot by 20% and the foot length by 90% was observed. A decrease for the relative maximum force under the midfoot (63%) and for the arch index (49%) could also be demonstrated. Furthermore, body height showed a significant influence on foot length and midfoot width. Body weight had a significant influence on the static parameter midfoot width. Between genders, boys showed a significant wider midfoot and a smaller forefoot contact area as compared to girls. The established database can be used as comparative values for clinical decisions about the normal foot development. PMID- 20832318 TI - Reliability of three-dimensional gait analysis in cervical spondylotic myelopathy. AB - BACKGROUND: Gait impairment is one of the primary symptoms of cervical spondylotic myelopathy (CSM). Detailed assessment is possible using three dimensional gait analysis (3DGA), however the reliability of 3DGA for this population has not been established. The aim of this study was to evaluate the test-retest reliability of temporal-spatial, kinematic and kinetic parameters in a CSM population. METHODS: Twelve patients with CSM (mean age 54 years) were consecutively recruited from a neurosurgery clinic. 3DGA was conducted on 2 separate days, less than 1 week apart, using the VICON((r)) 250 Motion Analysis. The average of 10 gait cycles was analysed. Reliability was assessed using the one-way random intraclass correlation coefficient (ICC), the standard error of measurement (SEM), and Bland-Altman limits of agreement (LOA). RESULTS: Temporal spatial parameters showed excellent reliability, with ICCs above 0.9 for speed, cadence, stride length, double support time, and step width. ICCs for kinematic parameters ranged from acceptable (0.62, peak knee flexion in stance) to excellent (0.95, total hip sagittal plane motion). The SEM for all kinematic parameters was below 4 degrees , with the exception of peak hip internal rotation (5.8 degrees ). Peak values were less reliable than the total range of motion in a plane. The majority of kinetic parameters showed excellent reliability (ICCs>0.85), with the exception of peak medio-lateral ground reaction force (ICC 0.12). CONCLUSIONS: This information will enhance the interpretation of gait scores for CSM patients, as an estimate of the change required to exceed measurement error is now available. PMID- 20832319 TI - Mucosal immunity in resource-limited setting: is the battle ground different? AB - In many developing countries, populations are under considerable pressure from high bacterial exposure on mucosal surfaces. Immune dysregulation in this setting is multifactorial and is driven by a range of environmental factors, undernutrition and coinfections such as measles, malaria and HIV. Disruption or subversion of respiratory-tract and intestinal epithelial barriers leads to increased invasion by mucosal pathogens and a high frequency of life-threatening bacterial disease. It is our opinion that a process of epithelial barrier dysfunction and immune dysregulation at these mucosal surfaces leads to the much higher rates of pneumonia, meningitis and severe sepsis seen in resource-limited countries. PMID- 20832320 TI - CheV: CheW-like coupling proteins at the core of the chemotaxis signaling network. AB - Microbes have chemotactic signaling systems that enable them to detect and follow chemical gradients in their environments. The core of these sensory systems consists of chemoreceptor proteins coupled to the CheA kinase via the scaffold or coupler protein CheW. Some bacterial chemotaxis systems replace or augment CheW with a related protein, CheV, which is less well understood. CheV consists of a CheW domain fused to a receiver domain that is capable of being phosphorylated. Our review of the literature, as well as comparisons of the CheV and CheW sequence and structure, suggest that CheV proteins conserve CheW residues that are crucial for coupling. Phosphorylation of the CheV receiver domain might adjust the efficiency of its coupling and thus allow the system to modulate the response to chemical stimuli in an adaptation process. PMID- 20832321 TI - Carotenoid biosynthesis in extremophilic Deinococcus-Thermus bacteria. AB - Bacteria from the phylum Deinococcus-Thermus are known for their resistance to extreme stresses including radiation, oxidation, desiccation and high temperature. Cultured Deinococcus-Thermus bacteria are usually red or yellow pigmented because of their ability to synthesize carotenoids. Unique carotenoids found in these bacteria include deinoxanthin from Deinococcus radiodurans and thermozeaxanthins from Thermus thermophilus. Investigations of carotenogenesis will help to understand cellular stress resistance of Deinococcus-Thermus bacteria. Here, we discuss the recent progress toward identifying carotenoids, carotenoid biosynthetic enzymes and pathways in some species of Deinococcus Thermus extremophiles. In addition, we also discuss the roles of carotenoids in these extreme bacteria. PMID- 20832322 TI - Mitochondrial inheritance in budding yeasts: towards an integrated understanding. AB - Recent advances in yeast mitogenomics have significantly contributed to our understanding of the diversity of organization, structure and topology in the mitochondrial genome of budding yeasts. In parallel, new insights on mitochondrial DNA (mtDNA) inheritance in the model organism Saccharomyces cerevisiae highlighted an integrated scenario where recombination, replication and segregation of mtDNA are intricately linked to mitochondrial nucleoid (mt nucleoid) structure and organelle sorting. In addition to this, recent discoveries of bifunctional roles of some mitochondrial proteins have interesting implications on mito-nuclear genome interactions and the relationship between mtDNA inheritance, yeast fitness and speciation. This review summarizes the current knowledge on yeast mitogenomics, mtDNA inheritance with regard to mt nucleoid structure and organelle dynamics, and mito-nuclear genome interactions. PMID- 20832323 TI - c-Met expression is associated with time to recurrence in patients with glioblastoma multiforme. AB - The aim of this study was to explore the difference in c-Met expression between primary and recurrent glioblastoma multiforme (GBM), and to determine whether the dysregulation of c-Met expression has a role in the malignant progression of GBM. Paired primary and recurrent GBM specimens from the same patient were evaluated using immunohistochemical analysis. The association between c-Met expression and progression-free survival time (PFST) was analyzed. There was a significant difference in c-Met expression between primary and recurrent tumors (p=0.020), and patients with tumors expressing c-Met at a higher level had a significantly shorter PFST (6.1 months vs. 11.5 months; p=0.026). Our study indicates that recurrent GBM express c-Met at a higher level and that c-Met overexpression is associated with shorter PFST in patients with GBM. These findings suggest that c Met potentially has an important role in the treatment of GBM. PMID- 20832324 TI - Lumbar microdiscectomy under epidural anaesthesia with the patient in the sitting position: a prospective study. AB - In a prospective study we compared the surgical outcome, length of hospital stay, complications and patient satisfaction for patients undergoing lumbar microdiscectomy (LM) under spinal anaesthesia (SA) in the sitting position (23 patients) to those of another cohort who underwent LM under general anaesthesia (GA) in the prone or genu-pectoral position during the same time period (238 patients). We aimed to determine: (i) if epidural anaesthesia is safe for lumbar microdiscectomy; and (ii) if placing the patient in a sitting position confers an advantage in performing the operation. For all patients we calculated the time from the end of the operation to the first spontaneous urination and to the first administration of analgesic drugs. Before being discharged, patients were asked to give an opinion on the quality of analgesia obtained by epidural anaesthesia and on the sitting position used. No patient had any complications linked to epidural anaesthesia and only one patient experienced a small dural tear as a surgical complication. Twenty of 23 patients expressed satisfaction with the level of analgesia obtained and only three considered it poor. All patients found the sitting position comfortable. Advantages of the sitting position for surgery include better comfort for the patient, potential to recreate a load condition similar to the one that takes place during orthostasis and a "cleaner" operative field that uses gravity to drain blood. Of greatest concern is the possibility of the patient developing a dural tear and subsequent leaking of cerebrospinal fluid, which could also be a source of surgical complications. Currently, epidural anaesthesia allows a reduction in anaesthetic and surgical times, anaesthetic complications and, consequently, hospitalization period. Further analysis of the sitting position for the patient during surgery is required to fully assess the advantages and disadvantages of this method. PMID- 20832325 TI - Technical note: easy graft passage without posterior portals in PCL reconstruction. AB - Graft passage during arthroscopically assisted, single-bundle transtibial PCL reconstruction is a technically demanding surgical procedure. We propose the use of a so called Deschamps clamp, originally designed for cerclage wire transport, in combination with a meniscal repair needle with an eye. This facilitates easy passage of a pull-through needle and obviates extensive debridement of the tibial insertion. Posterior portals are not needed. PMID- 20832326 TI - Synthesis and biological evaluation of a series of aromatic bisphosphonates. AB - Geminal bisphosphonates display varied biological activity depending on the nature of the substituents on the central carbon atom. For example, the nitrogenous bisphosphonates zoledronate and risedronate inhibit the enzyme farnesyl diphosphate synthase while digeranyl bisphosphonate has been shown to inhibit the enzyme geranylgeranyl diphosphate synthase. We now have synthesized isoprenoid bisphosphonates where an aromatic ring has been used to replace one of the isoprenoid olefins in an isoprenoid bisphosphonate and investigated the ability of these new compounds to impair protein geranylgeranylation within cells. Several of these new compounds are potent inhibitors of the enzyme geranylgeranyl diphosphate synthase. PMID- 20832327 TI - Microvascular bone grafting: a new long-term solution for intraosseous arteriovenous malformations of the mandible in children. AB - BACKGROUND: Intraosseous arteriovenous malformations (AVMs) in the maxillofacial area are rarely reported in the current literature. These malformations have been associated with severe hemorrhage resulting in significant morbidity and mortality. The recommended gold standard treatment of AVMs is an endovascular embolization, combined with surgery. Especially in children, disease management remains a challenge for the surgeon due to the process of bone growth. AIM: In this report, we describe our experience with a microvascular bone graft as another possible surgical technique for the treatment of intraosseous AVMs in children. PATIENT AND METHODS: A 15-year-old boy was admitted to our department with a life-threatening hemorrhage due to an AVM of the left mandible. The attempt of an ordinary tooth extraction had lead to the emergency. Several embolizations and surgical interventions were required. Finally, a bony reconstruction with a microvascular bone graft from the right iliac crest was performed in order to achieve a normal form and function of the mandible. Postoperative recovery of the patient was unremarkable, and no recurrence was reported. Dental rehabilitation and a good esthetic outcome were achieved by insertion of dental implants. RESULTS: The performed interventions resulted in a complete anatomic and clinical cure. CONCLUSION: We suggest microvascular bone grafts from the anterior iliac crest as a valuable alternative in the long-term treatment of intraosseous AVMs, especially for extensive defects and in children. PMID- 20832328 TI - Panel and patient perceptions of nasal aesthetics after secondary cleft rhinoplasty with versus without columellar grafting. AB - BACKGROUND: Cleft-lip nasal deformity alters patient's self-image, as well as posing unique challenges for the rhinoplastic surgeon. OBJECTIVES: The main purpose of this study was to compare the panel perceptions of nasal aesthetics following secondary cleft rhinoplasty with versus without caudal septal extension grafting (columella grafting). We also investigated whether patient's self assessment and satisfaction correlated with 4 other variables: (1) rhinoplasty techniques; (2) patients' age; (3) patients' gender; and (4) panel perceptions. METHODS: Using a cross-sectional study design, we enrolled a sample of adult laypersons and medical experts. The predictor variable was the rhinoplasty techniques (with/without columellar grafting). The outcome variable was the panel rankings of nasal aesthetics based on the photographs of 50 nonsyndromic cleft patients before and after the rhinoplasty. Other variables included the patient's subjective assessment and satisfaction, demographic and anatomic variables. Appropriate descriptive, uni- and bivariate statistics were calculated. The significance level was set at P<=0.05 and <0.05 for single- and two-tailed tests of hypothesis, respectively. RESULTS: The sample consisted of 507 laypersons and 51 professionals who gave comparative ratings (P>0.05). Columellar grafting was associated with higher rankings of postoperative nasal aesthetics (P =0.04). Most of the patients (90%) rated positive outcomes. Surgical techniques, patients' age and gender, and panel perceptions were not individually significantly associated with subjective measures and satisfaction. CONCLUSIONS: Our results suggest that caudal septal extension grafting improves the nasal aesthetics of the cleft patients, as judged by the panel. Patient's self-assessment seems unreliable to be used as an outcome measure. PMID- 20832329 TI - Maternal cigarette smoking and the associated risk of having a child with orofacial clefts in China: a case-control study. AB - BACKGROUND: We investigated whether maternal and paternal cigarette smoking during early pregnancy could increase the risk of delivering an infant with an orofacial cleft. METHODS: A case-control study was carried out in China. 304 infants born with an isolated nonsyndromic oral cleft and 453 non-malformed controls were recruited as participants and their exposure to smoke plus family history data were collected. RESULTS: The relative odds ratios of maternal smoking to cause an orofacial cleft in infant increased for 3.30 (95% CI, 1.17 9.33) in CLO and 3.12 (95% CI, 1.24-7.84) in CLP from 1 to 10 cigarettes per day before pregnancy. The unadjusted odds ratio is 3.64 (95% CI, 1.01-13.19) and the adjusted OR is 7.00 (95% CI, 1.44-34.13) in CLO from 1 to 10 cigarettes during the first trimester. Paternal smoking in the periconceptional period was strongly associated with all subtypes of CLP. The association with medium ETS (2-6h) at home or at work was strongest for infants with all OFCs in the periconceptional period from 1 month before pregnancy through the end of the first trimester. CONCLUSION: This study confirmed the modest association between maternal smoking and orofacial clefts. PMID- 20832330 TI - Tranexamic acid: an alternative to aprotinin as antifibrinolytic therapy in pediatric congenital heart surgery. AB - OBJECTIVE: There has been concern about the usage of aprotinin, an antifibrinolytic drug that was often used in pediatric cardiac surgery until 2006. At our center, these concerns led to the replacement of aprotinin with tranexamic acid for antifibrinolytic treatment. METHODS: In this retrospective observational study, two groups of pediatric patients were studied during two different periods, receiving either aprotinin (n=70) or tranexamic acid (n=70) upon cardiac surgery. Data were collected from children with cyanotic heart defects, children who weighed less than 10 kg, and children who underwent re operation. RESULTS: There was no difference in terms of blood loss or amount of erythrocyte concentrates and fresh frozen plasma transfused. Only the intraoperative amount of platelet concentrate received by children in the tranexamic acid group was 29 ml (p=0.013) higher. There was no significant difference in the length of stay at the intensive care unit, in renal function values, or in the rate of rethoracotomy. CONCLUSIONS: The results of this study suggest that tranexamic acid represents an adequate alternative to aprotinin in congenital cardiac surgery. PMID- 20832331 TI - Diagnosis of aortic-right ventricular tunnel by dual-source computed tomography. PMID- 20832332 TI - New advances in the understanding of the in-source decay fragmentation of peptides in MALDI-TOF-MS. AB - In-source decay (ISD) is a rapid fragmentation occurring in the matrix-assisted laser desorption/ionization (MALDI) source before the ion extraction. Despite the increasing interest for peptides de novo sequencing by ISD, the influence of the matrix and of the peptide itself is not yet fully understood. Here we compare matrices with high ISD efficiencies to gain deeper insight in the ISD fragmentation process(es). The major ISD fragments are the c- and z-ions, but other types of fragments are also observed, and their origin is studied here. Two main pathways lead to fragmentation in the source: a radical-induced pathway that leads to c-, z-, w-, and d-ions, and a thermally activated pathway that leads to y-, b-, and a-ions. A detailed analysis of the ISD spectra of selected peptides revealed that (1) the extents of the two in-source pathways are differently favored depending on the matrix used, that (2) the presence of a positive/negative charge on the radical-induced fragments is necessary for their observation in positive/negative mode, respectively, and that (3), for a same peptide, the patterns of the different types of fragments differ according to the matrix used. PMID- 20832334 TI - Acute compartment syndrome in a patient on extracorporeal support: utility of near-infrared spectroscopy. PMID- 20832333 TI - Epigenetic control of recombination in the immune system. AB - Immune receptor gene expression is regulated by a series of developmental events that modify their accessibility in a locus, cell type, stage and allele-specific manner. This is carried out by a programmed combination of many different molecular mechanisms, including region-wide replication timing, changes in nuclear localization, chromatin contraction, histone modification, nucleosome positioning and DNA methylation. These modalities ultimately work by controlling steric interactions between receptor loci and the recombination machinery. PMID- 20832335 TI - Predictors of cardiac troponin release after mitral valve surgery. AB - OBJECTIVES: Although cardiac troponin I (cTnI) measurement is used extensively as a marker of perioperative myocardial injury, limited knowledge exists in noncoronary artery bypass graft surgery. DESIGN: Observational study. SETTING: Single-center intensive care unit. INTERVENTION: None. PARTICIPANTS: One hundred eighty-five consecutive adult patients undergoing mitral valve surgery for predominant mitral regurgitation were enrolled and underwent measurement of cTnI at 24 hours after surgery. MEASUREMENTS AND MAIN RESULTS: CTnI release after mitral valve surgery was significantly associated with an adverse outcome. The optimal cTnI value for predicting adverse outcomes was 14 ng/mL. Univariate preoperative predictors of cTnI release were prior use of diuretics (p = 0.04) or a rheumatic (p = 0.006), ischemic (p = 0.004), or myxomatous (p = 0.005) etiology to mitral disease, whereas intraoperative variables predictive of cTnI release were cross-clamp time (p = 0.005), cardiopulmonary bypass time (p < 0.001), need for mitral valve replacement (p = 0.024), number of electrical cardioversions (p = 0.03), patent foramen ovale closure (p = 0.03), tricuspid valve repair (p = 0.04), need for epinephrine/norepinephrine (p = 0.004) or intra-aortic balloon pump (p = 0.03) in the operating room; and, finally, the surgeon who performed the surgery (p = 0.014). There were no postoperative predictors of excessive cTnI release. In multivariate analysis, the only predictors of cTnI release were the cardiopulmonary bypass time (odds ratio, 1.42; confidence intervals, 1.019-1.064; p = 0.001) and the infusion of epinephrine/norepinephrine in the operating room (odds ratio, 4.002; confidence intervals, 1.238-12.929; p = 0.02). CONCLUSIONS: After mitral surgery, the need for epinephrine/norepinephrine perioperatively and the cardiopulmonary bypass time independently predict a cTnI release significantly related to an adverse outcome. PMID- 20832336 TI - Transesophageal echocardiography in the diagnosis of hypoxia in the intensive care unit. PMID- 20832337 TI - An unusual cause of left ventricular outflow tract obstruction. PMID- 20832338 TI - Incidental and online learning of melodic structure. AB - The cognition of music, like that of language, is partly rooted in enculturative processes of implicit and incidental learning. Musicians and nonmusicians alike are commonly found to possess detailed implicit knowledge of musical structure which is acquired incidentally through interaction with large samples of music. This paper reports an experiment combining the methodology of artificial grammar learning with musical acquisition of melodic structure. Participants acquired knowledge of grammatical melodic structures under incidental learning conditions in both experimental and untrained control conditions. Subsequent analysis indicates a large effect of unsupervised online learning in the experimental and control group throughout the course of the testing phase suggesting an effective ongoing learning process. Musicians did not outperform nonmusicians, indicating that musical expertise is not advantageous for the learning of a new, unfamiliar melodic system. Confidence ratings suggest that participants became aware of the knowledge guiding their classification performance despite the incidental learning conditions. PMID- 20832339 TI - gammadelta T cells enhance autoimmunity by restraining regulatory T cell responses via an interleukin-23-dependent mechanism. AB - Mice that lack interleukin-23 (IL-23) are resistant to T cell-mediated autoimmunity. Although IL-23 is a maturation factor for T helper 17 (Th17) cells, a subset of gammadelta T cells expresses the IL-23 receptor (IL-23R) constitutively. Using IL-23R reporter mice, we showed that gammadelta T cells were the first cells to respond to IL-23 during experimental autoimmune encephalomyelitis (EAE). Although gammadelta T cells produced Th17 cell associated cytokines in response to IL-23, their major function was to prevent the development of regulatory T (Treg) cell responses. IL-23-activated gammadelta T cells rendered alphabeta effector T cells refractory to the suppressive activity of Treg cells and also prevented the conversion of conventional T cells into Foxp3(+) Treg cells in vivo. Thus, IL-23, which by itself has no direct effect on Treg cells, is able to disarm Treg cell responses and promote antigen specific effector T cell responses via activating gammadelta T cells. PMID- 20832340 TI - Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. AB - Monocytes are effectors of the inflammatory response to microbes. Human CD14(+) monocytes specialize in phagocytosis and production of reactive oxygen species and secrete inflammatory cytokines in response to a broad range of microbial cues. Here, we have characterized the functions of human monocytes that lack CD14 (CD14(dim)) and express CD16. CD14(dim) monocytes were genetically distinct from natural killer cells. Gene expression analyses indicated similarities with murine patrolling Gr1(dim) monocytes, and they patrolled the endothelium of blood vessels after adoptive transfer, in a lymphocyte function-associated antigen-1 dependent manner. CD14(dim) monocytes were weak phagocytes and did not produce ROS or cytokines in response to cell-surface Toll-like receptors. Instead, they selectively produced TNF-alpha, IL-1beta, and CCL3 in response to viruses and immune complexes containing nucleic acids, via a proinflammatory TLR7-TLR 8-MyD88 MEK pathway. Thus, CD14(dim) cells are bona fide monocytes involved in the innate local surveillance of tissues and the pathogenesis of autoimmune diseases. PMID- 20832341 TI - Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. AB - Tumor necrosis factor (TNF) receptor-associated factor 3 (TRAF3) functions downstream of multiple TNF receptors and receptors that induce interferon-alpha (IFN-alpha), IFN-beta, and IFN-lambda production, including Toll-like receptor 3 (TLR3), which is deficient in some patients with herpes simplex virus-1 encephalitis (HSE). Mice lacking TRAF3 die in the neonatal period, preventing direct investigation of the role of TRAF3 in immune responses and host defenses in vivo. Here, we report autosomal dominant, human TRAF3 deficiency in a young adult with a history of HSE in childhood. The TRAF3 mutant allele is loss-of expression, loss-of-function, dominant-negative and associated with impaired, but not abolished, TRAF3-dependent responses upon stimulation of both TNF receptors and receptors that induce IFN production. TRAF3 deficiency is associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN. Thus, TLR3-mediated immunity against primary infection by HSV-1 in the central nervous system is critically dependent on TRAF3. PMID- 20832342 TI - Determining object boundaries from MR images with sub-pixel resolution: towards in-line inspection with a mobile tomograph. AB - This work evaluates the performance of edge-detection algorithms to determine the sample geometry with high spatial accuracy from low-resolution MR images. In particular, we show that by applying such numerical methods it is possible to reconstruct the internal and external contours of the object with a spatial precision that surpasses the nominal spatial resolution of the image by more than one order of magnitude. Special attention is paid to find the spatial resolution and signal-to-noise ratio required by the described numerical methodology to achieve a desired spatial accuracy. Finally, we discuss the potential application of this image processing approach for in-line quality control of extruded rubber materials, where micrometer spatial precision has to be achieved from images measured in short experimental times. The results presented here prove that the sensitivity of mobile MRI sensors is enough to achieve the spatial accuracy required to proof check the production of extruded rubber fittings in acceptable experimental times. PMID- 20832343 TI - Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: the unsolved paradox. AB - INTRODUCTION: In aromatic L-amino acid decarboxylase (AADC) deficiency, a neurotransmitter biosynthesis defect, paradoxical normal or increased levels of urinary dopamine have been reported. Genotype/phenotype correlations or alternative metabolic pathways may explain this remarkable finding, but were never studied systematically. METHODS: We studied the mutational spectrum and urinary dopamine levels in 20 patients with AADC-deficiency. Experimental procedures were designed to test for alternative metabolic pathways of dopamine production, which included alternative substrates (tyramine and 3 methoxytyrosine) and alternative enzymes (tyrosinase and CYP2D6). RESULTS/DISCUSSION: In 85% of the patients the finding of normal or increased urinary levels of dopamine was confirmed, but a relation with AADC genotype could not be identified. Renal microsomes containing CYP2D were able to convert tyramine into dopamine (3.0 nmol/min/g protein) but because of low plasma levels of tyramine this is an unlikely explanation for urinary dopamine excretion in AADC-deficiency. No evidence was found for the production of dopamine from 3 methoxytyrosine. Tyrosinase was not expressed in human kidney. CONCLUSION: Normal or increased levels of urinary dopamine are found in the majority of AADC deficient patients. This finding can neither be explained by genotype/phenotype correlations nor by alternative metabolic pathways, although small amounts of dopamine may be formed via tyramine hydroxylation by renal CYP2D6. CYP2D6 mediated conversion of tyramine into dopamine might be an interesting target for the development of new therapeutic strategies in AADC-deficiency. PMID- 20832344 TI - A randomized study comparing isotope and echocardiography stress testing in the screening of silent myocardial ischaemia in type 2 diabetic patients. AB - AIMS: This study aimed to compare the positive predictive value (PPV) of stress myocardial scintigraphy (SPECT) and of dobutamine echocardiography (DE) in the diagnosis of significant coronary artery stenosis (CAD) in asymptomatic type 2 diabetic patients, and to assess long-term clinical outcomes according to silent myocardial ischaemia (SMI) screening. METHODS: A total of 204 asymptomatic type 2 diabetic patients at high cardiovascular (CV) risk were prospectively randomized to undergo either SPECT (n=104) or DE (n=100). Coronary angiography was proposed in cases of SMI, with revascularization of suitable lesions. Intensive treatment of CV risk factors was prescribed for all patients. Death and myocardial infarction (MI) were recorded during the 3-year follow-up. RESULTS: Clinical characteristics were similar in the two testing groups. The prevalence of SMI and significant CAD were 13% and 4%, respectively, in the SPECT group vs 11% and 5%, respectively, in the DE group (not significant [NS]). The PPV for the detection of significant CAD was 29% for SPECT and 45% for DE (NS). Seven patients (3%) underwent initial revascularization. The 3-year rate of CV death and MI was 2.5%, and similar in both groups. CONCLUSION: Rates of SMI and significant CAD in asymptomatic high-risk type 2 diabetic patients receiving intensive care of risk factors are low, and SPECT and DE are similar in the detection of SMI and CAD. Coronary revascularization and intensive CV risk-factor therapy are associated with a low rate of adverse CV events at 3 years, whichever stress test was used. PMID- 20832345 TI - [Septate uteri: must we treat all of them?]. AB - Septate uterus is the most common female genital malformation. It can be responsible for recurrent miscarriages and infertility. Hysteroscopic septoplasty is an effective procedure. It can prevent abortions and probably increase fertility. The hysteroscopic section of the septum has become a simple and safe technique, with the use of small hysteroscopes and that of bipolar energy with trained surgeons. These are the reasons why hysteroscopic septoplasty can be proposed to women with septate uterus and a desire for pregnancy. PMID- 20832346 TI - Non-invasive assessment of corneal endothelial permeability by means of electrical impedance measurements. AB - The permeability of the corneal endothelial layer has an important role in the correct function of the cornea. Since ionic permeability has a fundamental impact on the passive electrical properties of living tissues, here it is hypothesized that impedance methods can be employed for assessing the permeability of the endothelial layer in a minimally invasive fashion. Precisely, the main objective of the present study is to develop and to analyze a minimally invasive method for assessing the electrical properties of the corneal endothelium, as a possible diagnostic tool for the evaluation of patients with endothelial dysfunction. A bidimensional model consisting of the main corneal layers and a four-electrode impedance measurement setup placed on the epithelium has been implemented and analyzed by means of the finite elements method (FEM). In order to obtain a robust indicator of the permeability of the endothelium layer, the effect of the endothelium electrical properties on the measured impedance has been studied together with reasonable variations of the other model layers. Simulation results show that the impedance measurements by means of external electrodes are indeed sufficiently sensitive to the changes in the electrical properties of the endothelial layer. It is concluded that the method presented here can be employed as non-invasive method for assessing endothelial layer function. PMID- 20832347 TI - Dynamic posturography in evaluation of balance in patients of Parkinson's disease with normal pull test: concept of a diagonal pull test. AB - OBJECTIVES: To assess subclinical balance impairment in patients of Parkinson's disease (PD) with normal "pull test", using dynamic posturography. METHODS: Twenty PD patients (H&Y stage 2) and 20 matched healthy controls were studied. The patients were evaluated in best 'ON' state using UPDRS and Dynamic Posturography. The latter measured dynamic balance indices and limits of stability (LOS) in 8 directions: forward (FW), backward (BW), right (RT), left (LT), forward-right (FW-RT), forward-left (FW-LT), backward-right (BW-RT) and backward-left (BW-LT). RESULTS: The dynamic balance indices and total LOS scores did not differ significantly between PD and controls. Direction-wise analysis of LOS showed significantly lower scores (suggesting impaired balance) in PD compared to controls only in FW-RT (21.2 +/- 13.8 vs 34.5 +/- 17.5, p=0.005) and BW-LT (20.8 +/- 9.8 vs 31.8 +/- 15.1, p=0.018) directions. In LOS test, controls had better stability in FW than BW (p=0.002) and on RT than LT directions (p=0.0005). Analysis in diagonal directions showed greater stability in FW-RT than FW-LT, in BW-LT than BW-RT, in FW-RT than BW-RT, and BW-LT than FW-LT directions. Though PD patients maintained greater stability in FW direction like controls, they lost the advantage in other directions. CONCLUSIONS: Despite normal "pull test", PD patients had subclinical direction-specific balance impairment, more apparent in forward-right and backward-left directions. This information may be useful in modifying the standard "pull test" with addition of pull in diagonal directions for detection of early balance impairment. PMID- 20832348 TI - Elucidating the changing socio-spatial dynamics of neighborhood effects on adult obesity risk in Taiwan from 2001 to 2005. AB - Obesity poses a significant health threat in industrialized countries, with its incidence increasing steadily in Taiwan. This study addresses how neighborhood contexts influence individuals, using a multilevel spatial analysis of obesity risk from 2001 to 2005. A priority concern was whether contextual influences on health are limited to the immediate neighborhood or extend to a wider geographical area. The results led to the following conclusions. First, neighborhood factors related to obesity risk are likely to operate over a broad geographical area and are not limited to the focal neighborhood of residence. Second, a geographically based epidemiological change in the likelihood of obesity risk was observed from 2001 to 2005 in Taiwan. Third, the spatial lag model revealed significant spatial spillover of obesity risk in the study area in 2005. Policy interventions are recommended for the neighborhoods associated with the strong spillover effect. The results demonstrate that, in addition to enhancing the accuracy of prediction regarding the effects of neighborhood factors on obesity, incorporating spatial dynamics at the neighborhood level can encourage the development of contextually sensitive policy interventions. PMID- 20832349 TI - The Rice Kinase Phylogenomics Database: a guide for systematic analysis of the rice kinase super-family. AB - Determination of gene function is particularly problematic when studying large gene families because redundancy limits the ability to assess the contributions of individual genes experimentally. Phylogenomics is a phylogenetic approach used in comparative genomics to predict the biological functions of members of large gene-families by assessing the similarity among gene products. In this report, we describe the application of the Rice Kinase Database for elucidating functions of individual members of this gene family. PMID- 20832350 TI - Characterizing contact lens-related dryness symptoms in a cross-section of UK soft lens wearers. AB - PURPOSE: To estimate the prevalence of and factors associated with contact lens related dryness symptoms in a large population of soft contact lens patients in the UK. METHODS: Soft contact lens (CL) wearers (n=932) from 12 UK clinical sites were queried regarding CL history and wearing experience by a self-administered questionnaire. A new score using Contact Lens Dry Eye Questionnaire (CLDEQ) items was used where CL-related dry eye (CL-DE)=frequency of 'sometimes', 'frequently', or 'constantly' plus intensity 3-5; NoCL-DE=frequency of 'never' or 'rarely' and intensity 0-1; Marginal CL-DE, all other categories. Data were analyzed across categories, P-values <0.05 significant. RESULTS: The prevalence of CL-DE was: CL DE=31%, Marginal CL-DE=13% and NoCL-DE=56%. Wearers with CL-DE had significantly lower typical comfort (CL-DE=7.0 +/- 1.9; Marginal=7.6 +/- 1.9; NoCL-Dry=8.7 +/- 1.8, P<0.001), end-of-day comfort (CL-DE=4.9 +/- 2.5; Marginal=6.1 +/- 2.0; NoCL DE=7.8 +/- 2.1, P<0.001) and shorter comfortable wearing times in hours (CL DE=9.1 +/- 4.4; Marginal=9.8 +/- 3.6; NoCL-DE=12.4 +/- 5.1, P<0.001). Positive CL DE status was significantly more likely among toric lens wearers (n=129) compared to spherical lens wearers (43% vs. 30%, P=0.04). Lens material class, lens care system and gender were not significantly related to CL-DE status. Of the CL-DE group, only 38% had been diagnosed with dry eye and 47% self-assessed as dry eye. Use of artificial tears, CLs for dryness, ointments/gels and warm compresses differed between groups according to CL-DE status (P<0.001, all comparisons). CONCLUSIONS: The survey provided useful data regarding the current status symptoms among UK soft CL wearers. The CL-DE score predicted patients' wearing experience; poorer comfort, shorter comfortable wearing time and increased use of treatments. PMID- 20832351 TI - Enzymatic activity in disordered states of proteins. AB - Although disordered proteins are able to carry out a variety of different functions, particularly those involved in signalling and regulation, they have been observed to perform catalysis only in a small number of cases. The presence of structural disorder is indeed expected to be poorly compatible with enzymatic catalysis, which requires a well-organised environment in the active site of the enzyme in order to facilitate the formation of the transition state of the chemical reaction to be catalysed. Despite this stringent requirement, current evidence suggests that certain partially disordered proteins could be catalytically active by becoming structured in the regions of their active sites, even if their overall states retain a significant degree of conformational heterogeneity. This type of mechanism, however, does not appear to be not very common, perhaps because the time required to the conformational search within a disordered state to establish a catalytic environment in the presence of the substrate should not be longer than the overall turnover time required for optimal function. In addition, the catalytic environment should be maintained for long enough despite the structural fluctuations to enable the catalytic reaction to take place. As some partially unstructured proteins have been reported to be capable of overcoming these severe limitations and act as enzymes, their study can increase our general understanding of the mechanism of enzymatic catalysis, as well as extend our ability to control the range of functions that can be performed by disordered proteins. PMID- 20832352 TI - Tumors on chips: oncology meets microfluidics. AB - Despite over 2 million papers published on cancer so far, malignancy still remains a puzzlingly complex disease with overall low survival rates. Expanding our knowledge of the molecular mechanisms of malignancy and of resistance to therapy is crucial in guiding the successful design of anti-cancer drugs and new point-of-care diagnostics. The up-and-coming microfluidic Lab-on-a-Chip (LOC) technology and micro-total analysis systems (MUTAS) are arguably the most promising platforms to address the inherent complexity of cellular systems with massive experimental parallelization and 4D analysis on a single cell level. This review discusses the emerging applications of microfluidic technologies and their advantages for cancer biology and experimental oncology. We also summarize the recent advances in miniaturized systems to study cancer cell microenvironment, cancer cytomics, and real-time (4D) pharmacological screening. Microfabricated systems, such as cell microarrays, together with on-chip label-less cytometry, and micro-sorting technologies, are all highlighted with the view of describing their potential applications in pharmacological screening, drug discovery, and clinical oncology. It is envisaged that microfluidic solutions may well represent the platform of choice for next generation in vitro cancer models. PMID- 20832353 TI - The voyage of the microbial eukaryote. AB - Although genome data from unicellular marine eukaryotes is sparse, sequences from several supergroups have initiated an era of genome-enabled research aimed at understanding gene function, evolution, and adaptation in non-traditional model protists. Trends in genomic content within and between different lineages are emerging, including phylogenetically anomalous patterns, sometimes resulting from horizontal gene transfer. Some such genes have nutrient uptake and metabolism roles suggesting that bacterial and eukaryotic microbes have similar cellular mineral-environmental constraints. Many 'accessory genome' components are of unknown function, but low gene copy numbers combined with small genomes make protists ideal for systems biology. Cultured and uncultured protists are providing insights to ecology, ancestral features and the role of cooption in development of complex traits. Various protists harbor features important in sexuality and multicellularity once believed to have originated in metazoans or other multicellular taxa. PMID- 20832354 TI - Photoionization of psoralen derivatives in micelles: Imperatorin and alloimperatorin. AB - The fluorescence properties of psoralen derivatives, 8-methoxypsoralen (8-MOP), imperatorin (IMP) and alloimperatorin (ALLOI), were investigated in various solvent and micellar solutions. The variation in intensity and maxima of the fluorescence in micellar solutions suggest that psoralens are located in the micelle-water interface region. Radical cations and hydrated electrons were generated by photoionization in micellar solution upon excitation at 266 nm. A nonlinear relationship between transient yield and photon fluency was obtained for each compound, indicating that a two-photon mechanism is predominant in the photoionization of the sensitizers. The photoionization efficiencies are significantly higher in anionic sodium dodecyl sulfate (SDS) than in cationic cetyltrimethylammonium bromide (CTAB) micelles, reflecting the influence of micelle charge on the efficiency of the separation of the photoproduced charge carriers. The photoionization efficiencies of IMP and ALLOI are similar. PMID- 20832355 TI - Vibrational spectroscopic study and NBO analysis on bis(4-amino-5-mercapto-1,2,4 triazol-3-yl) methane using DFT method. AB - In this work, we report a combined experimental and theoretical study on molecular structure, vibrational spectra, NBO analysis of bis(4-amino-5-mercapto 1,2,4-triazol-3-yl) methane (BAMTM). The FT-Raman and FT-IR spectra of BAMTM were recorded in the solid phase. The molecular geometry, harmonic vibrational frequencies and bonding features of BAMTM in the ground state have been calculated by using density functional method (B3LYP) with standard 6-31G(d, p) basis set. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. Finally the theoretical spectrograms for FT-IR and FT-Raman spectra of the title molecule have been constructed which show good agreement with recorded spectra. PMID- 20832356 TI - Performance characteristics of the Cavidi ExaVir viral load assay and the ultra sensitive P24 assay relative to the Roche Monitor HIV-1 RNA assay. AB - BACKGROUND: The Cavidi viral load assay and the ultra-sensitive p24 antigen assay (Up24 Ag) have been suggested as more feasible alternatives to PCR-based HIV viral load assays for use in monitoring patients infected with HIV-1 in resource limited settings. OBJECTIVES: To describe the performance of the Cavidi ExaVir LoadTM assay (version 2.0) and two versions of the Up24 antigen assay and to characterize their agreement with the Roche Monitor HIV-1 RNA assay (version 1.5). STUDY DESIGN: Observational study using a convenience sample of 342 plasma specimens from 108 patients enrolled in two ACTG clinical trials to evaluate the performance characteristics of the Up24 Ag assay using two different lysis buffers and the Cavidi ExaVir LoadTM assay. RESULTS: In analysis of agreement with the Roche assay, the Cavidi assay demonstrated superiority to the Up24 Ag assays in accuracy and precision, as well as sensitivity, specificity, and positive and negative predictive values for HIV-1 RNA >= 400, >= 1000 and >= 5000 copies/mL. Logistic performance curves indicated that the Cavidi assay was superior to the Up24 assays for viral loads greater than 650 copies/mL. CONCLUSIONS: The results suggest that the Cavidi ExaVir Load assay could be used for monitoring HIV-1 viral load in resource-limited settings. PMID- 20832357 TI - High-throughput screening of improved protease inhibitors using a yeast cell surface display system and a yeast cell chip. AB - Protease-targeted inhibitors have been promising pharmaceuticals. Here, we combined a yeast cell surface display system with a yeast cell chip for the high throughput screening of protease inhibitors, and succeeded in improving the activity of a protease inhibitor. PMID- 20832358 TI - Standardising analysis of carbon monoxide rebreathing for application in anti doping. AB - Determination of total haemoglobin mass (Hbmass) via carbon monoxide (CO) depends critically on repeatable measurement of percent carboxyhaemoglobin (%HbCO) in blood with a hemoximeter. The main aim of this study was to determine, for an OSM3 hemoximeter, the number of replicate measures as well as the theoretical change in percent carboxyhaemoglobin required to yield a random error of analysis (Analyser Error) of <=1%. Before and after inhalation of CO, nine participants provided a total of 576 blood samples that were each analysed five times for percent carboxyhaemoglobin on one of three OSM3 hemoximeters; with approximately one-third of blood samples analysed on each OSM3. The Analyser Error was calculated for the first two (duplicate), first three (triplicate) and first four (quadruplicate) measures on each OSM3, as well as for all five measures (quintuplicates). Two methods of CO-rebreathing, a 2-min and 10-min procedure, were evaluated for Analyser Error. For duplicate analyses of blood, the Analyser Error for the 2-min method was 3.7, 4.0 and 5.0% for the three OSM3s when the percent carboxyhaemoglobin increased by two above resting values. With quintuplicate analyses of blood, the corresponding errors reduced to .8, .9 and 1.0% for the 2-min method when the percent carboxyhaemoglobin increased by 5.5 above resting values. In summary, to minimise the Analyser Error to ~<=1% on an OSM3 hemoximeter, researchers should make >=5 replicates of percent carboxyhaemoglobin and the volume of CO administered should be sufficient increase percent carboxyhaemoglobin by >=5.5 above baseline levels. PMID- 20832359 TI - Assessment of symptom control in patients with cancer in Northwestern Turkey. AB - AIM: The main purpose of this cross-sectional study was to compare symptoms occurring before and after chemotherapy treatment and to investigate the factors affecting those symptoms. The secondary purpose was to determine the most commonly occurring symptoms experienced by the patients with cancer after chemotherapy. METHODS: Fifty inpatients and outpatients receiving chemotherapy for the first time with various cancer diagnoses and hospitalized in the oncology unit of Trakya University Medical Faculty Hospital between July 2006 and April 2007 were attended to the study. Data were collected using the Edmonton Symptom Assessment Scale (ESAS). RESULTS: It was discovered that symptoms of fatigue, nausea, loss of appetite, impaired sense of well-being, changes in skin and nails, stomatitis and numbness in hands among chemotherapy patients increased by a statistically significant margin after treatment (p<0.05). Post-chemotherapy symptoms increased markedly (p<0.05) among patients within groups determined by age, gender, marital status, stage of cancer and date of diagnosis. Cross-group comparisons of post-chemotherapy participants analyzed in terms of marital status, clinical stage of disease, and date of diagnosis revealed that fewer symptoms (drowsiness and shortness of breath) increased compared to other symptoms measured along with treatment (p<0.05). CONCLUSION: We conclude that by considering personal characteristic (i.e. age, gender, etc.) as well as disease related characteristics (i.e. clinical stage of the disease, etc.), individual nursing care might significantly contribute to the alleviation and management of symptoms. PMID- 20832360 TI - Brk/PTK6 signaling in normal and cancer cell models. AB - Breast tumor kinase (Brk), also termed PTK6, is known to function in cell-type and context-dependent processes governing normal differentiation. However, in tumors in which Brk is overexpressed, this unusual soluble tyrosine kinase is emerging as a mediator of cancer cell phenotypes, including increased proliferation, survival, and migration. Nuclear and cytoplasmic substrates phosphorylated by Brk include a collection of regulatory RNA-binding proteins, adaptor molecules that link Brk to signaling pathways generally associated with the activation of growth factor receptors, and Signal Transducers and Activators of Transcription (STAT) molecules that are direct regulators of gene expression. Understanding Brk-dependent regulation of these key signaling pathways and how they influence cancer cell behavior is predicted to inform the development of improved 'targeted' cancer therapies and may provide insight into ways to avoid chemo-resistance to established treatments. PMID- 20832361 TI - Basic and translational applications of engineered MHC class I proteins. AB - Major histocompatibility complex (MHC) class I molecules can be engineered as single chain trimers (SCTs) that sequentially incorporate all three subunits of the fully assembled proteins, namely peptide, beta2 microglobulin, and heavy chain. SCTs have been made with many different MHC-peptide complexes and are used as novel diagnostic and therapeutic reagents, as well as probes for diverse biological questions. Here, we review the recent and diverse applications of SCTs. These applications include new approaches to enumerate disease-related T cells, DNA vaccines, eliciting responses to pre-assembled MHC-peptide complexes, and unique probes of lymphocyte development and activation. Future applications of SCTs will be driven by their further engineering and the ever-expanding identification of disease-related peptides using chemical, genetic and computational approaches. PMID- 20832362 TI - Impaired Toll-like receptor 7 and 9 signaling: from chronic viral infections to cancer. AB - HIV-1, hepatitis B virus, hepatitis C virus, and human papillomavirus type 16 cause persistent infections that frequently precede cancer development. Virions of these viruses are weak inducers of interferon-alpha and impair Toll-like receptor (TLR)9 function. Loss of TLR9 responsiveness also occurs in tumors without viral etiology such as breast, ovary, and head and neck carcinomas. Recent reports have suggested that viruses and components of the tumor microenviroment interact with regulatory receptors on plasmacytoid dendritic cells (pDCs) to impair TLR7 and TLR9 signaling, and to downregulate TLR9 gene expression. The limited responsiveness of pDCs might contribute to reduced innate immune responses during chronic viral infections and oncogenesis, and represent a target for new therapeutic approaches based on TLR agonists. PMID- 20832363 TI - Non-vertebrate models to study parasite invasion of the central nervous system. AB - Infections of the central nervous system due to neuroparasites have contributed significantly to morbidity and mortality. In part, this is because of our incomplete understanding of parasite traversal of the blood-brain barrier, a key step in the development of central nervous system infections, and the lack of available drugs that can cross the blood-brain barrier to gain entry into the brain to kill parasites. The novel in vitro, ex vivo, and in vivo models of the blood-brain barrier can offer strategies to elucidate the physical barriers, cellular mechanisms and molecular elements participating from both sides of parasite-host interactions leading to neuropathogenesis. Improving our knowledge of these core processes might elevate the efficiency of therapy of diseases caused by them. PMID- 20832364 TI - Mycobacterium tuberculosis strains with the Beijing genotype demonstrate variability in virulence associated with transmission. AB - Phylogenetic analysis has shown that Beijing genotype strains can be grouped into at least 7 different sublineages. We aimed to test the hypothesis that the virulence of Beijing genotype strains differed among members of the different sublineages and that the level of virulence correlated with their ability to spread and cause disease. BALB/c mice were infected with Beijing strains representative of the different lineages and of different epidemiological characteristics (transmitted vs. non-transmitted). Survival times, lung pathology, bacterial load and immunology kinetics were evaluated at defined intervals post-infection. Transmissibility was determined by co-housing infected and uninfected mice in close contact for 1-2 months. The results show that mice infected with the highly transmitted Beijing strains began showing mortality 3 weeks post-infection and all had died by 5 weeks, suggesting high virulence phenotypes. In contrast, >80% of mice infected with the non-transmitted strains survived 4 months post-infection, suggesting low virulence phenotypes. Our co housing transmission model confirmed these virulence phenotypes. Extensive tissue damage and the induction of lower levels of IFNgamma and iNOS expression, as well as high but ephemeral TNFalpha expression were associated with the high virulence phenotype. In contrast, minimal tissue damage and progressive expression of IFNgamma and TNFalpha were associated with the low virulence phenotype. Both virulence phenotypes induced similar levels of IL-4 expression during the early stages of infection after which the high virulence strain induced significantly higher levels of IL-4 expression. In conclusion, this study demonstrates that Beijing genotype strains display a spectrum of virulence phenotypes in mice which mimic their epidemiological characteristics. Both transmissible and non transmissible strains may exist in the same sublineage. PMID- 20832365 TI - Reduction of HIV incidence in men who have sex with men. PMID- 20832366 TI - Effectiveness of five artemisinin combination regimens with or without primaquine in uncomplicated falciparum malaria: an open-label randomised trial. AB - BACKGROUND: Artemisinin-combination therapy (ACT) is recommended as first-line treatment of falciparum malaria throughout the world, and fixed-dose combinations are preferred by WHO; whether a single gametocytocidal dose of primaquine should be added is unknown. We aimed to compare effectiveness of four fixed-dose ACTs and a loose tablet combination of artesunate and mefloquine, and assess the addition of a single gametocytocidal dose of primaquine. METHODS: In an open label randomised trial in clinics in Rakhine state, Kachin state, and Shan state in Myanmar (Burma) between Dec 30, 2008, and March 20, 2009, we compared the effectiveness of all four WHO-recommended fixed-dose ACTs (artesunate-mefloquine, artesunate-amodiaquine, dihydroartemisinin-piperaquine, artemether-lumefantrine) and loose artesunate-mefloquine in Burmese adults and children. Eligible patients were those who presented to the clinics with acute uncomplicated Plasmodium falciparum malaria or mixed infection, who were older than 6 months, and who weighed more than 5 kg. Treatments were randomised in equal numbers within blocks of 50 and allocation was in sealed envelopes. All patients were also randomly assigned to receive either a single dose of primaquine 0.75 mg base/kg or not. Patients were followed up for 63 days. Treatment groups were compared by analysis of variance and multiple logistic regression. The primary outcome was the 63 day recrudescence rate. This study is registered with clinicaltrials.gov, number NCT00902811. FINDINGS: 155 patients received artesunate-amodiaquine, 162 artemether-lumefantrine, 169 artesunate-mefloquine, 161 loose artesunate mefloquine, and 161 dihydroartemisinin-piperaquine. By day 63 of follow-up, 14 patients (9.4%; 95% CI 5.7-15.3%) on artesunate-amodiaquine had recrudescent P falciparum infections, a rate significantly higher than for artemether lumefantrine (two patients; 1.4%; 0.3-5.3; p=0.0013), fixed-dose artesunate mefloquine (0 patients; 0-2.3; p<0.0001), loose artesunate-mefloquine (two patients; 1.3%; 0.3-5.3; p=0.0018), and dihydroartemisinin-piperaquine (two patients 1.3%; 0.3-5.2%; p=0.0012). Hazard ratios for re-infection (95% CI) after artesunate-amodiaquine were 3.2 (1.3-8.0) compared with the two artesunate mefloquine groups (p=0.01), 2.6 (1.0-6-0) compared with artemether-lumefantrine (p=0.04), and 2.3 (0.9-6.0) compared with dihydroartemisinin-piperaquine (p=0.08). Mixed falciparum and vivax infections were common: 129 (16%) had a mixed infection at presentation and 330 (41%) patients had one or more episodes of Plasmodium vivax infection during follow-up. The addition of a single dose of primaquine (0.75 mg/kg) reduced P falciparum gametocyte carriage substantially: rate ratio 11.9 (95% CI 7.4-20.5). All regimens were well tolerated. Adverse events were reported by 599 patients, most commonly vomiting and dizziness. Other side-effects were less common and were not related to a specific treatment. INTERPRETATION: Artesunate-amodiaquine should not be used in Myanmar, because the other ACTs are substantially more effective. Artesunate-mefloquine provided the greatest post-treatment suppression of malaria. Adding a single dose of primaquine would substantially reduce transmission potential. Vivax malaria, not recurrent falciparum malaria, is the main complication after treatment of P falciparum infections in this region. FUNDING: Medecins sans Frontieres (Holland) and the Wellcome Trust Mahidol University Oxford Tropical Medicine Research Programme. PMID- 20832367 TI - Population-based HIV-1 incidence in France, 2003-08: a modelling analysis. AB - BACKGROUND: Routine national incidence testing with enzyme immunoassay for recent HIV-1 infections (EIA-RI) has been done in France since January, 2003. From the reported number of HIV infections diagnosed as recent, and accounting for testing patterns and under-reporting, we aimed to estimate the incidence of HIV infection in France in 2003-08. METHODS: We analysed reports from the French National Institute for Public Health Surveillance for patients who were newly diagnosed with HIV between January, 2003, and December, 2008. Missing data were imputed with multiple imputation. Patients were classified with non-recent or recent infection on the basis of an EIA-RI test, which was calibrated with serial measurements from HIV seroconverters from the French ANRS-PRIMO cohort. We used an adapted stratified extrapolation approach to calculate the number of new HIV infections in men who have sex with men (MSM), injecting drug users (IDUs), and heterosexual men and women by nationality. Population sizes were obtained from the national census and national behavioural studies. FINDINGS: After accounting for under-reporting, there were 6480 (95% CI 6190-6780) new diagnoses of HIV infection in France in 2008. We estimate that there were 6940 (6200-7690) new HIV infections in 2008, suggesting an HIV incidence of 17 per 100 000 person-years. In 2008, there were 3550 (3040-4050) new infections in heterosexuals (incidence of 9 per 100 000 person-years), 3320 (2830-3810) in MSM (incidence of 1006 per 100 000 person-years), and 70 (0-190) in IDUs (incidence of 86 per 100 000 person years). Overall HIV incidence decreased between 2003 and 2008 (p<0.0001), but remained comparatively high and stable in MSM. INTERPRETATION: In France, HIV transmission disproportionately affects certain risk groups and seems to be out of control in the MSM population. Incidence should be tracked to monitor transmission dynamics in the various population risk groups and to help to target and assess prevention strategies. FUNDING: French National Institute for Public Health Surveillance (InVS) and French National Agency for Research on AIDS and Viral Hepatitis (ANRS). PMID- 20832368 TI - Maximising the public health benefit of antimalarials. PMID- 20832369 TI - Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency. AB - Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRalphabeta+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID. PMID- 20832370 TI - The evaluation of catechins that contain a galloyl moiety as potential HIV-1 integrase inhibitors. AB - Four catechins with the galloyl moiety, including catechin gallate (CG), epigallocatechin gallate (EGCG), gallocatechin gallate (GCG), and epicatechin gallate (ECG), were found to inhibit HIV-1 integrase effectively as determined by our ELISA method. In our docking study, it is proposed that when the HIV-1 integrase does not combine with virus DNA, the four catechins may bind to Tyr143 and Gln148, thus altering the flexibility of the loop (Gly140-Gly149), which could lead to an inhibition of HIV-1 integrase activity. In addition, after combining HIV-1 integrase with virus DNA, the four catechins may bind between the integrase and virus DNA, consequently, disrupt this interaction. Thus, the four catechins may reduce the activity of HIV-1 integrase by disrupting its interaction with virus DNA. The four catechins have a highly cooperative inhibitory effect (IC50=0.1 MUmol/L). Our study suggests that catechins with the galloyl moiety could be a novel and effective class of HIV-1 integrase inhibitors. PMID- 20832371 TI - Generation and analysis of expressed sequence tags from adductor muscle of Japanese scallop Mizuhopecten yessoensis. AB - A normalized cDNA library was constructed from the adductor muscle of M. yessoensis and acquired 4595 high quality expressed sequence tags (ESTs). After clustering and assembly of the ESTs, 3061 unigenes containing 654 contigs and 2407 singletons were identified. The contig length ranged from 266 bp to 2364 bp and the average length of these contigs was 544 bp. Blastx nonredundant protein database analysis showed that 1522 unigenes had significant homology to known genes (E value <= 10-5). By comparing to Clusters of Orthologous Groups (COG) categories, 460 unigenes were annotated (E value <=10(-10)). Using Kyoto Encyclopedia of Genes and Genomes (KEGG), 345 of 3061 unigenes were assigned into 103 pathways (E value <= 10-5). For InterProScan searches, 1237 unigenes were annotated containing 727 different types of protein domains. 941 of the 1237 unigenes were annotated for Gene Ontology (GO) classification using Uniprot2GO associations in any category (biological, cellular, and molecular). By sequences comparability and analysis of Blastx NCBI nonredundant protein database and KEGG, 66 unigenes were identified that may be involved in genetic information processing based on the known knowledge. The study provides a material basis as useful information for the genomic analysis of shellfish. PMID- 20832372 TI - Limb gigantism, neurofibromatosis and royal heredity in the Ancient World 2500 years ago: Achaemenids and Parthians. PMID- 20832373 TI - Criss cross mastopexy. PMID- 20832374 TI - Improved A1C by switching to continuous subcutaneous insulin infusion from injection insulin therapy in type 2 diabetes: A retrospective claims analysis. AB - AIMS: This study was a real-world, retrospective evaluation of the clinical effectiveness of switching to continuous subcutaneous insulin infusion (CSII) among managed care enrollees with type 2 diabetes for whom multiple daily injections (MDI) had presumably failed. METHODS: Administrative claims with integrated A1C values from a large and geographically diverse health plan were analyzed. RESULTS: Statistically significant A1C reductions (from the baseline period to follow-up period, mean follow-up 17 months) were achieved with CSII. Among subjects using a long-acting and rapid-acting insulin regimen at baseline, A1C decreased to mean follow-up A1C by 0.8% and to minimum follow-up A1C by 1.2% (p<0.001). The proportion of subjects at target (A1C<7%) increased significantly from baseline to follow-up (8.4-22.9% [using mean A1C] and 32.8% [using minimum A1C]; both p<0.001). The rate of severe hypoglycemic events was similar from baseline to follow-up. CONCLUSIONS: CSII was associated with significant reductions in A1C without an increase in hypoglycemic events in insulin-taking people with type 2 diabetes, including subjects previously using a long-acting and rapid-acting insulin regimen. PMID- 20832376 TI - [Segmental arterial mediolysis and renovascular hypertension]. AB - Segmental arterial mediolysis (SAM) is a rare nonarteriosclerotic, noninflammatory vascular disease of unknown origin that causes vascular occlusion or massive life-threatening intraabdominal hemorrhages. SAM is an acute disease. The initial injurious phase consist in mediolysis, then evolves in chronic vascular lesions. Diagnostic criteria are histologic, but rarely accessible apart from surgical complications. To our knowledge, there is no recommendation concerning therapy and follow-up of these patients. In our patient, we were interested in the atypical clinical presentation with renovascular hypertension, and the coexistence of acute and chronic vascular lesions that suppose the existence of recurrences in the evolution of this disease. We are interested also in the link that might exist between renal infarct and SAM, SAM's chronic vascular lesions and fibromuscular dysplasia vascular lesions. PMID- 20832375 TI - Correlates of depression among people with diabetes: The Translating Research Into Action for Diabetes (TRIAD) study. AB - AIM: The broad objective of this study was to examine multiple dimensions of depression in a large, diverse population of adults with diabetes. Specific aims were to measure the association of depression with: (1) patient characteristics; (2) outcomes; and (3) diabetes-related quality of care. METHODS: Cross-sectional analyses were performed using survey and chart data from the Translating Research Into Action for Diabetes (TRIAD) study, including 8790 adults with diabetes, enrolled in 10 managed care health plans in 7 states. Depression was measured using the Patient Health Questionnaire (PHQ-8). Patient characteristics, outcomes and quality of care were measured using validated survey items and chart data. RESULTS: Nearly 18% of patients had major depression, with prevalence 2-3 times higher among patients with low socioeconomic status. Pain and limited mobility were strongly associated with depression, controlling for other patient characteristics. Depression was associated with slightly worse glycemic control, but not other intermediate clinical outcomes. Depressed patients received slightly fewer recommended diabetes-related processes of care. CONCLUSIONS: In a large, diverse cohort of patients with diabetes, depression was most prevalent among patients with low socioeconomic status and those with pain, and was associated with slightly worse glycemic control and quality of care. PMID- 20832377 TI - Non-syndromic cleft lip and palate: could stress be a causal factor? AB - The aetiology of non-syndromic cleft lip and palate has as yet not been clearly defined. Familial relationships, environmental toxins and nutritional status have all been considered without conclusive results, although in some studies a potential link between non-syndromic cleft lip and palate and any one or more of these factors has been proposed. Elevated stress, particularly an extended term of traumatic stress, can lead to oxidative damage at the cellular level via hypothalamus-pituitary-adrenal (HPA) axis dysregulation, high cortisol and cytokine production. The effect of this hormonal shift is to re-direct the blood supply to the mother's muscles, thereby reducing the supply to the placenta, causing a potential nutritional deficiency which may then result in a genetic alteration in the foetus. Mothers with a child aged two years or younger who had been born with a cleft, who were members of CleftPals, a family support group, volunteered to be participants in this qualitative study. The research first called for a survey to be completed by the mother and this was then followed by an interview conducted by the researcher. The study involved families living in the three eastern States of Australia. The results suggest that physical and/or emotional stress may well be implicated in clefting. While little work has been done in considering stress as a causal factor, the existing literature suggests, as does this study, that elevated stress levels at, or soon after, conception appear to affect foetal development. PMID- 20832378 TI - Reliable genetic identification of burnt human remains. AB - The identification of severely burnt human remains by genetic fingerprinting is a common task in forensic routine work. In cases of extreme fire impact, only hard tissues (bones, teeth) may be left for DNA analysis. DNA extracted from burnt bone fragments may be highly degraded, making an amplification of genetic markers difficult or even impossible. Furthermore, heavily burnt bones are very prone to contamination with external DNA. We investigated whether authentic DNA profiles can be generated from human bones showing different stages of fire induced destruction (well preserved, semi-burnt, black burnt, blue-grey burnt, blue-grey white burnt). DNA was extracted from 71 bone fragments derived from 13 individuals. Obtained genetic patterns (STRs and mtDNA sequences) were compared to the genetic pattern of the respective bodies. Our results show that the identification via DNA analysis is reliably and reproducibly possible from well preserved and semi-burnt bones. In black burnt bones the DNA was highly degraded and in some cases no nuclear DNA was left, leaving mitochondrial DNA analysis as an option. Blue-grey burnt bones lead only sporadically to authentic profiles. The investigation of blue-grey-white burnt bones barely led to reliable results. PMID- 20832379 TI - Metal-on-metal bearings total hip arthroplasty: the cobalt and chromium ions release concern. AB - With certain concerns recently reported on metal-on-metal bearing couples in total hip arthroplasty, this study's objective is to review the current knowledge concerning release of metal ions and its potential consequences. Each metal-on metal implant presents different tribological properties. The analytical techniques for metals are accurate and the Co ion rates seem acceptable up to 2 MUg/L. A delayed type IV hypersensitivity reaction (atypical lymphocytic vasculitis-associated lesion [ALVAL]) may be the source of arthroplasty failure. Idiosyncratic, it remains unpredictable even using cutaneous tests and apparently is rare (0.3%). Today, there are no scientific or epidemiologic data supporting a risk of carcinogenesis or teratogenesis related to the use of a metal-on-metal bearings couple. Solid pseudotumors nearly exclusively are observed with resurfacing procedures, carrying a high annual revision rate in women under 40 years of age, occurring particularly in cases of acetabular malposition and with use of cast molded Cr-Co alloys. Osteolysis manifests through complete and progressive radiolucent lines or through cavitary lesions stemming from ALVAL type alterations or impingement problems or implant incompatibility. The formation of wear debris exceeding the biological tolerance is possible with implant malposition, subluxation, and jamming of the femoral head in cases of cup deformity. Moreover, each implant presents different metal ion production; assessment of their performance and safety is required before their clinical use. With the knowledge available today, metal-on-metal bearing couples are contraindicated in cases of metal allergies or end stage renal dysfunction and small size resurfacing should cautiously be used. PMID- 20832380 TI - Pelvic reorientation osteotomies and acetabuloplasties in children. Surgical technique. AB - The objectives of pelvic osteotomies are to improve femoral head coverage and coxofemoral joint stability. The most currently used osteotomies can be divided into reorientation osteotomies (Salter and Pol le Coeur triple osteotomy) and acetabuloplasties (Pemberton and Dega). All these osteotomies share an identical installation on the table and bikini-type incision. The Salter osteotomy uses a single osteotomy line located at the inferior gluteal line. The Pol Le Coeur triple pelvic osteotomy combines innominate osteotomies of the iliopubic and ischiopubic rami via a genitofemoral approach (inguinal). In these two reorientation osteotomies, the acetabulum tilts in retroversion, improving the anterior and lateral coverage but reducing the posterior coverage. In the Pemberton acetabuloplasty, the osteotomy line is incomplete. It begins anteriorly between the iliac spines and ends posteriorly immediately above the triradiate cartilage. The posterior part of the ilium remains intact. The Pemberton acetabuloplasty causes retroversion and plicature of the acetabulum responsible for reducing its diameter. Anterior and lateral coverage of the femoral head is improved and posterior coverage remains unchanged. In the Dega acetabuloplasty, the osteotomy line is incomplete. It begins laterally above the acetabulum and terminates just above the triradiate cartilage. The medial part of the ilium remains intact. The Dega acetabuloplasty reduces the diameter of the acetabulum and improves overall femoral head coverage (anterior, lateral, and posterior). PMID- 20832381 TI - Open wedge high tibial osteotomies: Calcium-phosphate ceramic spacer versus autologous bonegraft. AB - INTRODUCTION: Valgus tibial osteotomy (VTO) is a well-known procedure for the treatment of medial compartment femoro-tibial osteoarthritis. Good and very good results have been reported with calcium phosphate wedges, which avoid the inconveniences of autologous grafts use. The hypothesis of this study is that with equivalent results in the treatment of osteoarthritis of the knee, the use of calcium phosphate wedges (BMCaPh) to fill the bone defect created by osteotomy would result in fewer specific complications and less pain associated with autologous grafts (AUTO) harvesting. PATIENTS AND METHODS: This prospective, controlled, randomised study included one arm that received a macroporous, biphasic calcium phosphate wedge (BMCaPh group) and one arm that received an autologous tricortical graft (AUTO group) for filling. The same plate with locked screws was used for fixation in all cases. All patients underwent at least two years of clinical and radiographic post-operative follow-up. RESULTS: Forty patients were included. Loss of correction occurred in six of the twenty-two patients in the BMCaPh group (27%), resulting in three early surgical revisions, compared to one loss of correction in the AUTO group. Lateral cortical hinge tears were a risk factor for loss of correction for the entire cohort and in the BMCaPh group. (relative risk 13.3 [1.9-92]. Moreover, union took significantly longer and pain lasted significantly longer in the BMCaPh group, although results were comparable at 6 months. DISCUSSION: A significant number of undesirable events (loss of correction) occurred in this study, limiting the number of included patients. Nevertheless, the results show that although there was no difference in the two groups for overall complications, number of revisions all causes combined, or clinical results, filling with BMCaPh was less tolerated and increased the risk of loss of correction when local mechanical conditions of the knee were unfavourable (lateral cortical hinge tears). Moreover, although it is not possible to draw a conclusion because of methodology bias in this study, early weight-bearing resumption on the knee also seemed to favour these complications. LEVEL OF EVIDENCE: Level II. Prospective randomized study. PMID- 20832382 TI - Congenital scoliosis: a frontal plane evaluation of 251 operated patients 14 years old or older at follow-up. AB - INTRODUCTION: Congenital scoliosis, carrying an incidence between 0.5 and 1 per 1000 births, raise the problem of their evolutive potential. HYPOTHESIS: Some predictive factors for the evolution of scoliotic curvature due to congenital vertebral malformation (CVM) can be found. MATERIAL AND METHODS: This was a retrospective multicenter study of 251 patients, at least 14 years old when evaluated at end of follow-up, with CVM and spinal deformity predominating in the frontal plane. RESULTS: 38.8% of patients showed associated neurologic, visceral or orthopedic abnormalities. CVM was single in 60.6%, double in 20.3%, triple in 6.4% and multiple in 12.7% of cases. 34.1% of CVMs were thoracic. Congenital scoliosis curvature was single in 88.8% of patients, double in 10% and triple in 1.2%. Mean curvature angle was 31.7 degrees at diagnosis (range, 0-105 degrees ) and 41.3 degrees preoperatively (range, 10-105 degrees ). Sixty-one patients showed associated kyphosis. Mean change in postoperative curvature angle over follow-up was 1.6 degrees (range, -20 degrees to 38 degrees ) in the 73 patients managed by arthrodesis, -0.4 degrees (-24 degrees to 30 degrees ) in the 64 managed by epiphysiodesis, and 0.4 degrees (-18 degrees to 35 degrees ) in the 49 managed by hemivertebral (HV) resection. Results were found to correlate significantly with age at surgery for patients managed by epiphysiodesis, but not for those managed by HV resection or arthrodesis. DISCUSSION: More than 30% of congenital scolioses involve associated intraspinal abnormality. All CVM patients should therefore undergo medullary and spinal MRI to assess the CVM in all three planes, and the medullary canal and its content. The evolution of scoliotic curvature induced by CVM is hard to predict. Several factors are to be taken into account: CVM type, number and location, and patient age. Curvature progression may be slow or very fast. It accelerates during the peak of puberty, stabilizing with bone maturity. Surgery is mandatory in evolutive scoliosis. Four procedures may be recommended, according to type of CVM and especially to patient age: arthrodesis, convex epiphysiodesis, HV resection or rib distraction. Surgery seeks to correct the spinal deformity induced by the CVM and prevent compensatory curvature and neurologic complications, while conserving sagittal and frontal spinal balance and sparing as many levels as possible. In case of HV involvement, the procedure of choice is CVM resection, which provides 87.5% good results in this indication; the procedure is relatively safe, conservative of spinal levels, and without age limit. LEVEL OF EVIDENCE: Level IV. Retrospective study. PMID- 20832383 TI - Relationship between strength and functional indexes (Rowe and Walch-Duplay scores) after shoulder surgical stabilization by the Latarjet technique. AB - INTRODUCTION: The rotator cuff muscles help stabilize the glenohumeral joint. Postoperative recovery of rotator cuff muscle strength appears to be an important factor for optimal joint stabilization and the resumption of professional and/or sports activities. OBJECTIVE: To study the relationship between internal rotator (IR) and external rotator (ER) muscle strength, shoulder function and the resumption of sports activities (as typically evaluated with functional scores) following surgical stabilization with the Bristow-Latarjet procedure in cases of chronic shoulder instability. PATIENTS AND METHODS: Twenty patients with anterior, post-traumatic, chronic shoulder instability were included prospectively in a cohort study. The Rowe and Walch-Duplay functional scores were rated for the operated shoulder and the isokinetic IR and ER peak torque values were evaluated with a Con-Trex((r)) dynamometer before surgery and then 3, 6 and 21 months afterwards. The isokinetic evaluation was performed (at 180 degrees /s, 120 degrees /s and 60 degrees /s) in the seated position, with the arms in 45 degrees of abduction and 30 degrees of antepulsion in the plane of the scapula. RESULTS: There were no significant postoperative correlations between shoulder function (as judged by the Rowe and Walch-Duplay scores) and IR or ER muscle strength. CONCLUSION: This study did not provide evidence for a correlation between IR and ER muscle strength and functional scores after surgical stabilization of the shoulder. However, it is necessary to objectively measure the rotator cuff strength recovery to adequate the strengthening of rotator muscle prior to the resumption of sports activities. Isokinetic strength assessment may thus be a valuable decision support tool for the resumption of sports activities and would complement the functional scores studied here. PMID- 20832384 TI - Illness patterns prior to diagnosis of lymphoma: analysis of UK medical records. AB - BACKGROUND: Increased understanding of the relationship between lymphomas and co morbidities is likely to provide valuable insights into the natural history of these disorders. METHODS: 761 cases with lymphoma (310 diffuse large B-cell [DLBCL]; 226 follicular [FL]; and 225 Hodgkin [HL]) and 761 unaffected age and sex matched controls were recruited and their histories of infection and non infection diagnoses in primary care records were compared using negative binomial regression. RESULTS: No differences were observed between the infectious illness patterns of DLBCL and FL cases and their matched controls over the 15 years preceding lymphoma diagnosis. A marked excess of infectious illness episodes was recorded for HL cases compared to their controls; evident at least a decade prior to HL diagnosis. For non-infectious consultations an excess of case over control visits emerged 4-6 years before DLBCL and FL diagnosis; no specific co-morbidity associations were found. No case-control differences for non-infectious conditions were apparent for HL. CONCLUSION: There are substantial variations in patterns of illness prior to diagnosis of the three lymphoma subtypes examined. The excess of infectious diagnoses prior to HL may point to underlying immune abnormality, but there was no suggestion of this for DLBCL and FL where a generalized excess of non-infectious conditions was evident. PMID- 20832385 TI - Ileal reservoir with ileo-anal anastomosis: long-term complications. AB - Coloproctectomy with ileo-anal anastomosis (CP-IAA) has been in use for 30 years. This intervention is the standard technique when surgery is indicated for familial adenomatous polyposis (FAP) and for ulcerative colitis (UC). Although the surgery is safe with mortality of less than 1%, it is associated with a morbidity of 18-70%. We thought a literature review about long-term complications would be enlightening. Pouchitis is the most common complication; it occurs in 70% of patients over 20 years follow-up; small bowel obstruction affects 25% of patients and pelvic sepsis occurs in 20-30% within 10 years. CP-IAA can impact the patient's sexual life due to erectile and ejaculatory dysfunction, dyspareunia, and incontinence of stool during sexual intercourse. Nevertheless, patients with long-standing UC describe an overall improvement in their sexual function after surgery. The failure rate varies from 3.5 to 15%; major causes of failure are sepsis, unrecognized Crohn's disease, and poor functional results. Cases of dysplasia and cancer have been reported in the reservoir, but more particularly when there is retained colonic glandular mucosa. The transitional zone should be monitored whenever there are risk factors for colon neoplasia. The relatively high morbidity of CP-IAA should not overshadow the good functional results of this technique. PMID- 20832386 TI - Programme for ultrasound diagnoses and treatment with albendazole of cystic echinococcosis in asymptomatic carriers: 10 years of follow-up of cases. AB - Cystic echinococcosis is an endemic disease in the Province of Rio Negro, Argentina. Ultrasound surveys carried out in 1984 found prevalence rates of 5.6% in children between 6 and 14 years of age. OBJECTIVE: To describe and to evaluate the results of the strategy applied in school children by hospital services of the Province of Rio Negro with regard to diagnosis, treatment and monitoring of cystic echinococcosis and to evaluate simultaneously the results of the control program against cystic echinococcosis. MATERIALS AND METHODS: In 1997 ultrasound was chosen to carry out population surveys and the medical treatment criteria for the detected cases were standardized. The population under study involved 5745 students in the first survey and 22,793 in subsequent studies. The detected cases were classified according to Gharbi's scheme. A treatment algorithm was defined based only on monitoring ("watch and wait"), albendazole, surgery (open or laparoscopic) or mini-invasive procedures, according to type, location and size of the cyst. Information was also obtained on cases notified to the Health System between 1980 and 2008. RESULTS: In the first survey, 70 carriers (1.2%) were detected; of these, 25 started albendazole treatment (35.7%) and only 3 (4.3%) underwent surgery. Ten years after treatment, 60.1% of 42 cases, presented Types IV and V cysts and 14.5% presented total involution of their cysts. In subsequent studies, 87 (0.4%) cases were detected, 49 of which started albendazole treatment (56.3%) and 9 underwent surgery (10.3%). The incidence rate of cystic echinococcosis cases decreased from 38*100,000 in 1980 to 3.7*100,000 in 2008. DISCUSSION: A strong decrease in cystic echinococcosis was obtained although persistent levels of transmission were maintained. The cases produced under these conditions are diagnosed by means of ultrasound surveys and are treated using a plan based on albendazole and monitoring by the Health System during a period of 10 years. PMID- 20832387 TI - Adenosine receptors and vascular inflammation. AB - Epidemiological studies have shown a positive correlation between poor lung function and respiratory disorders like asthma and the development of adverse cardiovascular events. Increased adenosine (AD) levels are associated with lung inflammation which could lead to altered vascular responses and systemic inflammation. There is relatively little known about the cardiovascular effects of adenosine in a model of allergy. We have shown that A(1) adenosine receptors (AR) are involved in altered vascular responses and vascular inflammation in allergic mice. Allergic A(1)wild-type mice showed altered vascular reactivity, increased airway responsiveness and systemic inflammation. Our data suggests that A(1) AR is pro-inflammatory systemically in this model of asthma. There are also reports of the A(2B) receptor having anti-inflammatory effects in vascular stress; however its role in allergy with respect to vascular effects has not been fully explored. In this review, we have focused on the role of adenosine receptors in allergic asthma and the cardiovascular system and possible mechanism(s) of action. PMID- 20832388 TI - The vesicle-to-micelle transformation of phospholipid-cholate mixed aggregates: a state of the art analysis including membrane curvature effects. AB - We revisited the vesicle-to-micelle transformation in phosphatidylcholine-cholate mixtures paying special attention to the lipid bilayer curvature effects. For this purpose, we prepared unilamellar vesicles with different starting sizes (2r(v)=45-120nm). We then studied mixtures of the unilamellar vesicles (1-8mmol kg(-1)) and sodium cholate (0-11.75mmolkg(-1)) by static and dynamic light scattering. The transformation generally comprises at least two, largely parallel phenomena; one increases and the other decreases the average mixed aggregate size. In our view, cholate first induces bilayer fluctuations that lead to vesicle asphericity, and then to lipid bilayer poration followed by sealing/reformation (or fusion). The cholate-containing mixed bilayers, whether in vesicular or open form, project thread-like protrusions with surfactant enriched ends even before complete bilayer solubilisation. Increasing cholate concentration promotes detachment of such protrusions (i.e. mixed micelles formation), in parallel to further softening/destabilising of mixed amphipat bilayers over a broad range of concentrations. Vesicles ultimately fragment into mixed thread-like micelles. Higher cholate relative concentrations yield shorter thread-like mixed micelles. Most noteworthy, the cholate-induced bilayer fluctuations, the propensity for large aggregate formation, the transformation kinetics, and the cholate concentration ensuring complete lipid solubilisation all depend on the starting mean vesicle size. The smallest tested vesicles (2r(v)=45nm), with the highest bilayer curvature, require ~30% less cholate for complete solubilisation than the largest tested vesicles (2r(v)=120nm). PMID- 20832389 TI - Mutation spectrum and frequency of the RHO gene in 248 Chinese families with retinitis pigmentosa. AB - Mutations in the rhodopsin gene (RHO) are suggested to be the most common cause of autosomal dominant retinitis pigmentosa (RP). However, the exact spectrum and frequency of RHO mutations in different forms of RP has not been well defined, especially in Chinese populations. In this study, direct cycle sequencing was used to analyze all five coding exons and adjacent intronic regions of RHO in 248 Chinese probands with different forms of non X-linked RP. Eight heterozygous nucleotide changes were detected, including two novel mutations (c.628G>T, p.Val210Phe; c.945C>G, p.Asn315Lys) and six known mutations (c.527C>T, p.Ser176Phe; c.568G>T, p.Asp190Tyr; c.768_770delCAT, p.Ile256del; c.1040C>T, p.Pro347Leu; c.310G>A, p.Val104Ile; c.895G>T, p.Ala299Ser), in 14 probands (nine isolated cases, three from autosomal dominant families, and three from autosomal recessive families). Of the eight mutations, seven were missense changes and one was a small deletion. Six may be pathogenic mutations, and two others (c.310G>A, c.895G>T) may not be causative on their own. The p.Ala299Ser change was present in six of the 248 probands with RP but only in one of 384 normal controls, while the p.Val104Ile was present in two probands but none of the 384 controls. Our results demonstrate an overview of the spectrum and frequency of RP RHO mutations in a Chinese population and emphasize that RHO mutations in isolated RP are not uncommon. PMID- 20832390 TI - Involvement of ROS in chlorogenic acid-induced apoptosis of Bcr-Abl+ CML cells. AB - Chlorogenic acid (Chl) has been reported to possess a wide range of biological and pharmacological properties including induction of apoptosis of Bcr-Abl(+) chronic myeloid leukemia (CML) cell lines and clinical leukemia samples via inhibition of Bcr-Abl phosphorylation. Here we studied the mechanisms of action of Chl in greater detail. Chl treatment induced an early accumulation of intracellular reactive oxygen species (ROS) in Bcr-Abl(+) cells leading to downregulation of Bcr-Abl phosphorylation and apoptosis. Chl treatment upregulated death receptor DR5 and induced loss of mitochondrial membrane potential accompanied by release of cytochrome c from the mitochondria to the cytosol. Pharmacological inhibition of caspase-8 partially inhibited apoptosis, whereas caspase-9 and pan-caspase inhibitor almost completely blocked the killing. Knocking down DR5 using siRNA completely attenuated Chl-induced caspase 8 cleavage but partially inhibited apoptosis. Antioxidant NAC attenuated Chl induced oxidative stress-mediated inhibition of Bcr-Abl phosphorylation, DR5 upregulation, caspase activation and CML cell death. Our data suggested the involvement of parallel death pathways that converged in mitochondria. The role of ROS in Chl-induced death was confirmed with primary leukemia cells from CML patients in vitro as well as in vivo in nude mice bearing K562 xenografts. Collectively, our results establish the role of ROS for Chl-mediated preferential killing of Bcr-Abl(+) cells. PMID- 20832391 TI - Akti-1/2, an allosteric inhibitor of Akt 1 and 2, efficiently inhibits CaMKIalpha activity and aryl hydrocarbon receptor pathway. AB - Deregulation of the phosphatidylinositol 3 (PI3) kinase/Akt pathway, resulting in enhanced Akt activity, is one of the most frequent changes in human cancer. Akt has therefore attracted significant attention as an anticancer target in recent years and many Akt inhibitors have been identified, especially Akti-1/2, a non ATP competitive inhibitor of Akt isoforms 1 and 2. In this study, our results suggest that caution may be required when using Akti-1/2 as a specific inhibitor of Akt since it perfectly inhibits Ca(2+)/CaM-dependent protein kinase (CaMK) Ialpha activity. Akti-1/2 was thus able to inhibit recombinant CaMKIalpha activity as efficiently as the CaMK inhibitor KN-93. Moreover, Akti-1/2 prevented the nuclear translocation of aryl hydrocarbon receptor (AhR) in MCF-7 cells in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure, which has been demonstrated to require CaMKI activity. In addition, our results, obtained with a large panel of structurally-unrelated PI3K inhibitors, make unlikely any contribution of PI3K/Akt activity to the AhR pathway. To the best of our knowledge, this is the first report showing that Akti-1/2 has off-target effects at concentration equipotent with Akt inhibition. This may impact on the therapeutic application of Akti-1/2 and structurally-related compounds. PMID- 20832392 TI - MUC1 expression and its association with other aetiological factors and localization to mitochondria in preneoplastic and neoplastic gastric tissues. AB - BACKGROUND: The molecular events that underlie the conversion of normal human gastric epithelium into adenocarcinoma are poorly understood. MUC1 overexpression and localization in mitochondria might confer cancer cells with attenuation of stress induced apoptosis. We studied MUC1 expression pattern, interaction with HSP70 and localization in mitochondria in preneoplastic and neoplastic human gastric tissues. METHODS: Immunohistochemistry and Western blot were used to study MUC1 expression pattern and localization in mitochondria. Coimmunoprecipitation was used to study MUC1 interaction with HSP70. MUC1 expression was correlated with other causative features including erbB2 expression. RESULTS: MUC1 was expressed in 75.8% (147/194). MUC1 overexpression was detected in 50.0% (19/38 cases) dysplasia and 58.2% (32/55 cases) adenocarcinoma tissues. MUC1-CT-HSP70 interaction was seen in 71.66% (43/60 cases) and MUC1 localized to mitochondria in 33.33% (5/15) dysplasia samples and in 47.05% (8/17) adenocarcinoma samples. MUC1 expression showed significant association with smoking (chi(2)=5.945; p<0.015), alcohol consumption (chi(2)=4.055; p<0.044) and erbB2 positivity (chi(2)=10.75; p<0.001). MUC1 expression did not show appreciable association with age (chi(2)=0.15; p<0.698), sex (chi(2)=0.22; p<0.640) or Helicobacter pylori infection (chi(2)=3.06; p<0.080). CONCLUSIONS: Significant correlation was found between MUC1 expression and smoking, alcohol and erbB2 expression. MUC1 showed aberrant expression in dysplasia and adenocarcinoma stages. MUC1 cytosolic tail was bound by HSP70 in all the stages but MUC1-CT was found to localize in mitochondria only in dysplasia and adenocarcinoma. MUC1-CT localization to mitochondria in dysplasia and adenocarcinoma might aid in the attenuation of epithelial stress response induced loss of polarity. PMID- 20832393 TI - Hemoglobin A1c: assessment of three POC analyzers relative to a central laboratory method. AB - BACKGROUND: Glycosylated hemoglobin evaluation is very important for assessing the control of diabetes. Since the use of point-of-care (POC) devices for monitoring HbA1c is increasing, it is important to determine how these devices compare in relation to instrumentation used in the central laboratory (CL). METHODS: Eighty-eight randomly selected samples previously analyzed using the Bio Rad VariantTM II Hemoglobin Testing System were run on three POC Analyzers (Siemens DCA VantageTM Analyzer, Axis-Shield AfinionTM AS100 Analyzer, and Bio Rad In2itTM Analyzer). RESULTS: All POC instruments showed good correlation to the CL method (R(2)>0.95 for all methods). HbA1c levels obtained using Variant II (mean=7.9; 95% CI=7.5-8.3%) and In2it (mean=7.9; 95% C.I.=7.5-8.2%) instruments were found to have no statistical mean difference (p=0.21), while the values obtained using DCA Vantage (mean=7.2% C.I.=6.9-7.5%) and Afinion (mean=7.3% C.I.=7.0-7.6%) instruments were different (p<0.001) from those of the CL method. The Afinion and DCA Vantage instruments increasingly underestimated the HbA1c compared to the CL as the HbA1c values increased. These differences were even more striking when the estimated average glucose is calculated. CONCLUSIONS: Despite significant variation of results among the POC instruments evaluated relative to the CL method and pending resolution of HbA1c standardization issues, we conclude that all of the POC instruments can be used for HbA1c determination if clinicians are given instrument specific reference ranges. PMID- 20832394 TI - Cranial vasculature in zebrafish forms by angioblast cluster-derived angiogenesis. AB - Formation of embryonic vasculature involves vasculogenesis as endothelial cells differentiate and aggregate into vascular cords and angiogenesis which includes branching from the existing vessels. In the zebrafish which has emerged as an advantageous model to study vasculogenesis, cranial vasculature is thought to originate by a combination of vasculogenesis and angiogenesis, but how these processes are coordinated is not well understood. To determine how angioblasts assemble into cranial vasculature, we generated an etsrp:GFP transgenic line in which GFP reporter is expressed under the promoter control of an early regulator of vascular and myeloid development, etsrp/etv2. By utilizing time-lapse imaging we show that cranial vessels originate by angiogenesis from angioblast clusters, which themselves form by the mechanism of vasculogenesis. The two major pairs of bilateral clusters include the rostral organizing center (ROC) which gives rise to the most rostral cranial vessels and the midbrain organizing center (MOC) which gives rise to the posterior cranial vessels and to the myeloid and endocardial lineages. In Etsrp knockdown embryos initial cranial vasculogenesis proceeds normally but endothelial and myeloid progenitors fail to initiate differentiation, migration and angiogenesis. Such angioblast cluster-derived angiogenesis is likely to be involved during vasculature formation in other vertebrate systems as well. PMID- 20832395 TI - Tbx18 and Tbx15 null-like phenotypes in mouse embryos expressing Tbx6 in somitic and lateral plate mesoderm. AB - Members of the T-box family of transcription factors play essential roles in cell type specification, differentiation, and proliferation during embryonic development. All T-box family members share a common DNA binding domain - the T domain - and can therefore recognize similar sequences. Consequently, T-box proteins that are co-expressed during development have the potential to compete for binding at downstream targets. In the mouse, Tbx6 is expressed in the primitive streak and presomitic mesoderm, and is sharply down-regulated upon segmentation of the paraxial mesoderm. We sought to determine the phenotypic and molecular consequences of ectopically expressing Tbx6 within the segmented paraxial mesoderm and its derivatives using a 3-component transgenic system. The vertebral column, ribs, and appendicular skeleton were all affected in these embryos, which resembled Tbx18 and Tbx15 null embryos. We hypothesize that these phenotypes result from competition between the ectopically expressed Tbx6 and the endogenously expressed Tbx18 and Tbx15 at the binding sites of target genes. In vitro luciferase transcriptional assays provide further support for this hypothesis. PMID- 20832396 TI - Drosophila vitelline membrane assembly: a critical role for an evolutionarily conserved cysteine in the "VM domain" of sV23. AB - The vitelline membrane (VM), the oocyte proximal layer of the Drosophila eggshell, contains four major proteins (VMPs) that possess a highly conserved "VM domain" which includes three precisely spaced, evolutionarily conserved, cysteines (CX7CX8C). Focusing on sV23, this study showed that the three cysteines are not functionally equivalent. While substitution mutations at the first (C123S) or third (C140S) cysteines were tolerated, females with a substitution at the second position (C131S) were sterile. Fractionation studies showed that sV23 incorporates into a large disulfide linked network well after its secretion ceases, suggesting that post-depositional mechanisms are in place to restrict disulfide bond formation until late oogenesis, when the oocyte no longer experiences large volume increases. Affinity chromatography utilizing histidine tagged sV23 alleles revealed small sV23 disulfide linked complexes during the early stages of eggshell formation that included other VMPs, namely sV17 and Vml. The early presence but late loss of these associations in an sV23 double cysteine mutant suggests that reorganization of disulfide bonds may underlie the regulated growth of disulfide linked networks in the vitelline membrane. Found within the context of a putative thioredoxin active site (CXXS) C131, the critical cysteine in sV23, may play an important enzymatic role in isomerizing intermolecular disulfide bonds during eggshell assembly. PMID- 20832397 TI - Coffin-Lowry syndrome: a role for RSK2 in mammalian neurogenesis. AB - Coffin-Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)-activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS. PMID- 20832398 TI - Intestinal effects of lipopolysaccharide in rabbit are mediated by cyclooxygenase 2 through p38 mitogen activated protein kinase. AB - The mediators of the pathophysiological symptoms of septic shock are not completely understood. The intracellular signalling mechanisms of lipopolysaccharide (LPS)-induced effects need further investigation. This study investigates (1) the role of COX-2 in the effect of LPS on (a) the KCl, acetylcholine and prostaglandin E2-induced contractions of rabbit duodenum and (b) the oxidative stress status in plasma and intestine and (2) the relationship between p38 MAPK and COX-2 expression in rabbit duodenum. Rabbits were injected i.v. with either (1) saline, (2) LPS, (3) SB203580, a p38 MAPK inhibitor, (4) SB203580+LPS, (5) NS-398, a COX-2 inhibitor or (6) NS-398+LPS. Contractility studies were performed by suspending pieces of duodenum in an organ bath in the direction of longitudinal and circular smooth muscle fibres. The formation of products of oxidative damage to proteins (carbonyls) and lipids [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] was quantified in intestinal tissue and plasma. The protein expression of COX-2 was measured by western blot. The KCl, acetylcholine and prostaglandin E2-induced contractions decreased with LPS. In addition, LPS increased the levels of carbonyls and MDA+4-HDA in plasma and duodenum as well as COX-2 expression in duodenal tissue. All these effects were blocked by NS-398. The p38 MAPK inhibitor SB203580 blocked the effect of LPS on COX-2 expression. These results suggest that the effect of LPS on KCl, acetylcholine and prostaglandin E2-induced contractions in the rabbit duodenum and oxidative stress might be mediated by an increase in COX-2 expression through the p38 MAPK pathway. PMID- 20832399 TI - Acute ligand-independent Src activation mimics low EGF-induced EGFR surface signalling and redistribution into recycling endosomes. AB - Src, a non-receptor tyrosine kinase, is a key signal transduction partner of epidermal growth factor (EGF) receptor (EGFR). In human breast cancer, EGFR and Src are frequently over-expressed and/or over-activated. Although reciprocal activation is documented, mechanisms underlying Src:EGFR interactions are incompletely understood. We here exploited ts/v-Src thermo-activation in MDCK monolayers to test whether acute Src activation impacts on signalling and trafficking of non-liganded EGFR. We found that thermo-activation caused rapid Src recruitment to the plasma membrane, concomitant association with EGFR, and its phosphorylation at Y845 and Y1173 predominantly at the cell surface. Like low EGF concentrations, activated Src (i) decreased EGF surface binding without affecting the total EGFR pool; (ii) triggered EGFR endocytosis via clathrin coated vesicles; (iii) and led to its sequestration in perinuclear/recycling endosomes with avoidance of multivesicular bodies and lysosomal degradation. Combined Src activation and EGF were synergistic for EGFR-Y845 and -Y1173 phosphorylation at some endosomes. We conclude that acute effects of Src in MDCK cells may mimic those of low EGF on EGFR activation and redistribution. Src:EGFR interactions may be sufficient to trigger EGFR activation and might contribute to its local signalling, without requiring either soluble extracellular signal or receptor over-expression. PMID- 20832400 TI - CGGBP1 is a nuclear and midbody protein regulating abscission. AB - Abscission marks the completion of cell division and its failure is associated with delayed cytokinesis and even tetraploidization. Aberrant abscission and consequential ploidy changes can underlie various diseases including cancer. Midbody, a transient structure formed in the intercellular bridge during telophase, contains several proteins including Aurora kinase B (AURKB), which participate in abscission. We report here an unexpected expression pattern and function of the transcription repressor protein CGG triplet repeat-binding protein 1 (CGGBP1), in normal human fibroblasts. We show that CGGBP1, a chromatin associated protein, trans-localizes to spindle midzone and midbodies in a manner similar to that of AURKB. CGGBP1 depletion resulted in a cell cycle block at G2, characterized by failure of cells to undergo mitosis and also reduced entry into S phase. Consistent with its presence in the midbodies, live microscopy showed that CGGBP1 deficiency caused mitotic failure at abscission resulting in tetraploidy, which could be rescued by CGGBP1 overexpression. These results show that CGGBP1 is a bona fide midbody protein required for normal abscission and mitosis in general. PMID- 20832401 TI - Loss of retinal function in aged DBA/2J mice - New insights into retinal neurodegeneration. AB - The DBA/2J mouse is a common animal model of glaucoma. The intraocular pressure increases with age, and retinal ganglion cells (RGC) degenerate, usually starting at an age of approximately six months. In this study, we used two-year-old DBA/2J mice presuming an end-point of RGC degeneration. We investigated visual function in these animals using electroretinography (ERG) and visual evoked potentials (VEP), and we checked the number of remaining RGC by retrograde staining. Almost no RGC were left in the retina, and VEP were hardly recordable. Surprisingly, also ERG amplitudes of scotopic a-waves and b-waves, photopic b-waves and oscillatory potentials were decreased significantly by approximately 40% compared to amplitudes measured in age-matched C57BL/6J mice. The latencies were not changed in DBA/2J mice compared to C57BL/6J mice, and so were the ratios between amplitudes of a-waves, b-waves and oscillatory potentials. Our results indicate that, in addition to degeneration of RGC, also photoreceptors are affected by pathological processes in the eye caused by the mutations present in DBA/2J mice. PMID- 20832402 TI - Olfactory ensheathing cells from the nose: clinical application in human spinal cord injuries. AB - Olfactory mucosa, the sense organ of smell, is an adult tissue that is regenerated and repaired throughout life to maintain the integrity of the sense of smell. When the sensory neurons of the olfactory epithelium die they are replaced by proliferation of stem cells and their axons grow from the nose to brain assisted by olfactory ensheathing cells located in the lamina propria beneath the sensory epithelium. When transplanted into the site of traumatic spinal cord injury in rat, olfactory lamina propria or purified olfactory ensheathing cells promote behavioural recovery and assist regrowth of some nerves in the spinal cord. A Phase I clinical trial demonstrated that autologous olfactory ensheathing cell transplantation is safe, with no adverse outcomes recorded for three years following transplantation. Autologous olfactory mucosa transplantation is also being investigated in traumatic spinal cord injury although this whole tissue contains many cells in addition to olfactory ensheathing cells, including stem cells. If olfactory ensheathing cells are proven therapeutic for human spinal cord injury there are several important practical issues that will need to be solved before they reach general clinical application. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20832403 TI - A synthetic cannabinoid agonist promotes oligodendrogliogenesis during viral encephalitis in rats. AB - Chronic CNS infection by several families of viruses can produce deficits in prefrontal cortex (PFC) and striatal function. Cannabinoid drugs have been long known for their anti-inflammatory properties and their ability to modulate adult neuro and gliogenesis. Therefore, we explored the effects of systemic administration of the cannabinoid agonist WIN55,212-2(WIN) on prefrontal cortex (PFC) and striatal cytogenesis in a viral model of CNS injury and inflammation based on Borna Disease (BD) virus encephalitis. Active BrdU(+) progenitor populations were significantly decreased 1 week after BrdU labeling in BD rats [p<0.001 compared to uninfected (NL) controls] while less than 5% of BrdU(+) cells colabeled for BDV protein. Systemic WIN (1mg/kg i.p. twice daily*7 days) increased the survival of BrdU(+) cells in striatum (p<0.001) and PFC of BD rats, with differential regulation of labeled oligodendroglia precursors vs microglia/macrophages. WIN increased the percentage of BrdU(+) oligodendrocyte precursor cells and decreased BrdU(+) ED-1-labeled phagocytic cells, without producing pro- or antiviral effects. BDV infection decreased the levels of the endocannabinoid anandamide (AEA) in striatum (p<0.05 compared to NL rats), whereas 2-AG levels were unchanged. Our findings indicate that: 1) viral infection is accompanied by alterations of AEA transmission in the striatum, but new cell protection by WIN appears independent of its effect on endocannabinoid levels; and 2) chronic WIN treatment alters the gliogenic cascades associated with CNS injury, promoting oligodendrocyte survival. Limiting reactive gliogenesis and macrophage activity in favor of oliogodendroglia development has significance for demyelinating diseases. Moreover, the ability of cannabinoids to promote the development of biologically supportive or symbiotic oligodendroglia may generalize to other microglia-driven neurodegenerative syndromes including NeuroAIDS and diseases of aging. PMID- 20832404 TI - Olfactory ensheathing cells enhance Schwann cell-mediated anatomical and functional repair after sciatic nerve injury in adult rats. AB - Sciatic nerve injury results in axon damage, muscle degeneration, and loss of function. We compared the potential of Schwann cell (SC), olfactory ensheathing cell (OEC), or mixed SC/OEC transplants for anatomical and functional restoration after adult rat sciatic nerve transection. The cells were seeded into a 20mm long macroporous poly(dl-lactide-co-glycolide) acid conduit and grafted between the sciatic nerve stumps. Some rats received a conduit without cells (controls) or an autologous nerve graft, the clinical standard of care. Compared with SC transplants, axon regeneration was 25% less with OEC transplants but 28% more with SC/OEC transplants. Gastrocnemius muscle restoration was similar with a SC or OEC transplant and 35% better with a SC/OEC transplant. With SC transplants, motor and sensory function recovery and electrophysiological outcomes were similar as with OEC transplants and 33% better with SC/OEC transplants. Compared with the mixed SC/OEC transplants, axon regeneration was 21% better and gastrocnemius muscle restoration was 18% better with autologous peripheral nerve transplants, but these improvements did not translate into increased function and electrophysiological outcomes. Our results revealed that OEC synergistically improve SC mediated sciatic nerve repair. The data emphasized the promise of SC/OEC transplants as artificial nerves for peripheral nerve repair. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20832405 TI - (18)F-FECNT: validation as PET dopamine transporter ligand in parkinsonism. AB - The positron emission tomography (PET) tracer 2beta-carbomethoxy-3beta-(4 chlorophenyl)-8-(2-[18F]-fluoroethyl)-nortropane ((18)F-FECNT) is a highly specific ligand for dopamine transporter (DAT) that yields higher peak striatum to-cerebellum ratios and offers more favorable kinetics than most (18)F radiolabeled DAT ligands currently available. The goal of this study is to validate the use of (18)F-FECNT as a PET radiotracer to assess the degree of striatal dopamine terminals denervation and midbrain dopaminergic cell loss in MPTP-treated parkinsonian monkeys. Three rhesus monkeys received weekly injections of MPTP (0.2-0.5 mg/kg) for 21 weeks, which resulted in the progressive development of a moderate level of parkinsonism. We carried out (18)F FECNT PET at baseline (twice; 10 weeks apart) and at week 21 post-MPTP injections. Postmortem stereological cell counts of dopaminergic neurons in the ventral midbrain, and intensity measurements of DAT and tyrosine hydroxylase (TH) immunoreactivity in the striatum were performed and correlated with striatal and ventral midbrain PET data. Three additional monkeys were used as controls for midbrain dopaminergic cell counts, and striatal DAT or TH immunoreactivity measurements. The correlation and coefficient of variance between (18)F-FECNT test-retest specific uptake ratios were 0.99 (R2) and 2.65%, respectively. The (18)F-FECNT binding potential of the ventral midbrain and striatal regions was tightly correlated with postmortem stereological cell counts of nigral dopaminergic neurons (R2=0.91), and striatal DAT (R2=0.83) or TH (R2=0.88) immunoreactivity intensity measurements. These findings demonstrate that (18)F FECNT is a highly sensitive PET imaging ligand to quantify both striatal dopamine denervation and midbrain dopaminergic cell loss associated with parkinsonism. PMID- 20832406 TI - Neurophysiological and neuropathological characterization of new murine models of chemotherapy-induced chronic peripheral neuropathies. AB - Cisplatin, paclitaxel and bortezomib belong to some of the most effective families of chemotherapy drugs for solid and haematological cancers. Epothilones represent a new family of very promising antitubulin agents. The clinical use of all these drugs is limited by their severe peripheral neurotoxicity. Several in vivo rat models have reproduced the characteristics of the peripheral neurotoxicity of these drugs. However, since only a very limited number of cancer types can be studied in immunocompetent rats, these animal models do not represent an effective way to evaluate, at the same time, the antineoplastic activity and the neurotoxic effects of the anticancer compounds. In this study, we characterized the neurophysiological impairment induced by chronic chemotherapy treatment in BALB/c mice, a strain suitable for assessing the activity of anticancer treatments. At the end of a 4-week period of treatment with cisplatin, paclitaxel, epothilone-B or bortezomib, sensory and sensory/motor nerve conduction velocities (NCV) were determined in the caudal and digital nerves and dorsal root ganglia (DRG) and sciatic nerves were collected for histopathological analysis. The electrophysiological studies revealed that all the compounds caused a statistically significant reduction in the caudal NCV, while impairment of the digital NCV was less severe. This functional damage was confirmed by the histopathological observations evidencing axonal degeneration in the sciatic nerve induced by all the drugs associated with pathological changes in DRG induced only by cisplatin and bortezomib. These results confirm the possibility to use our models to combine the study of the antineoplastic activity of anticancer drugs and of their toxic effects on the peripheral nervous system in the BALB/c mouse strain. PMID- 20832407 TI - Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection. AB - Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4(+) T lymphocyte proliferation and IFN-gamma production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses. PMID- 20832408 TI - Decreased glutamic acid decarboxylase mRNA expression in prefrontal cortex in Parkinson's disease. AB - Parkinson's disease (PD) patients typically suffer from motor disorders but mild to severe cognitive deficits can also be present. Neuropathology of PD primarily involves loss of dopaminergic neurons in the substantia nigra, pars compacta, although more widespread pathology from the brainstem to the cerebral cortex occurs at different stages of the disease. Cognitive deficits in PD are thought to involve the cerebral cortex, and imaging studies have identified the dorsolateral prefrontal cortex (DLPFC) as a possible site for some of the symptoms. GABAergic neurons in the cerebral cortex play a key role in the modulation of pyramidal neurons and alterations in muscimol binding to GABA(A) receptors have been reported in Brodmann area 9 (BA9) of the prefrontal cortex in PD patients (Nishino et al., 1988). In order to further assess the likelihood that GABAergic activity is altered in the prefrontal cortex in PD, gene expression of the 67 kilodalton isoform of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD67 encoded by the GAD1 gene), was examined in BA9 of post mortem brains from 19 patients and 20 controls using isotopic in situ hybridization histochemistry. GAD67 mRNA labeling was examined and quantified on X-ray films and emulsion radioautographs. We show that GAD67 mRNA labeling is significantly lower in PD compared to control cases. Analysis of emulsion radioautographs indicates that GAD67 mRNA labeling is decreased in individual neurons and is not paralleled by a decrease in the number of GAD67 mRNA-labeled neurons. Analysis of expression data from a microarray study performed in 29 control and 33 PD samples from BA9 confirms that GAD67 expression is decreased in PD. Another finding from the microarray study is a negative relationship between GAD67 mRNA expression and age at death. Altogether, the results support the possibility that GABAergic neurotransmission is impaired in the DLPFC in PD, an effect that may be involved in some of the behavioral deficits associated with the disease. PMID- 20832409 TI - Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture. AB - The higher risk factor for Amyotrophic Lateral Sclerosis (ALS) among Italian soccer players is a question that is still debated. One of the hypotheses that have been formulated to explain a possible link between ALS and soccer players is related to the abuse of dietary supplements and drugs for enhancing sporting performance. In particular, it has been reported that branched-chain amino acids (BCAAs) are widely used among athletes as nutritional supplements. To observe the possible effect of BCAAs on neuronal electrical properties, we performed electrophysiological experiments on Control cultured cortical neurons and on neurons after BCAA treatment. BCAA-treated neurons showed hyperexcitability and rapamycin was able to suppress it and significantly reduce the level of mTOR, Akt and p70S6 phosphorylation. Interestingly, the hyperexcitability previously reported in cortical neurons from a genetic mouse model of ALS (G93A) was also reversed by rapamycin treatment. Moreover, both G93A and valine-treated neurons presented significantly higher levels of Pp70S6 when compared to control neurons, strongly indicating the involvement of this substrate in ALS pathology. Finally, we performed electrophysiological experiments on motor cortex slices from Control and G93A mice and those fed with a BCAA-enriched diet. We observed that neuron excitability was comparable between G93A and BCAA-enriched diet mice, but was significantly higher than in Control mice. These findings, besides strongly indicating that BCAAs specifically induce hyperexcitability, seem to suggest the involvement of p70S6 substrate in ALS pathology. PMID- 20832410 TI - Schistosoma mansoni: In vitro schistosomicidal activity of piplartine. AB - Schistosomiasis is one of the world's greatly neglected tropical diseases, and its control is largely dependent on a single drug, praziquantel. Here, we report the in vitro effect of piplartine, an amide isolated from Piper tuberculatum (Piperaceae), on Schistosoma mansoni adult worms. A piplartine concentration of 15.8 MUM reduced the motor activity of worms and caused their death within 24h in a RPMI 1640 medium. Similarly, the highest sub-lethal concentration of piplartine (6.3 MUM) caused a 75% reduction in egg production in spite of coupling. Additionally, piplartine induced morphological changes on the tegument, and a quantitative analysis carried out by confocal microscopy revealed an extensive tegumental destruction and damage in the tubercles. This damage was dose dependent in the range of 15.8-630.2 MUM. At doses higher than 157.6 MUM, piplartine induced morphological changes in the oral and ventral sucker regions of the worms. It is the first time that the schistosomicidal activity has been reported for piplartine. PMID- 20832411 TI - Impact of acute and chronic stressor experiences on heart atrial and brain natriuretic peptides in response to a subsequent stressor. AB - The impact of stressful events on processes related to cardiovascular functioning might vary with previous stressor experiences, just as such sensitization effects have been detected with respect to several neurochemical and hormonal processes. The present investigation assessed the impact of a psychosocial stressor on factors directly or indirectly related to cardiovascular functioning among CD-1 mice that had previously experienced an acute or chronic stressor regimen. These factors included plasma variations of atrial and brain natriuretic peptides (ANP and BNP, respectively), inflammatory cytokines in plasma, mRNA expression of natriuretic peptides and inflammatory cytokines in the ventricles, and norepinephrine (NA) levels and utilization within the locus coeruleus, a brain region implicated in cardiac functioning. A social stressor (exposure to a dominant mouse) increased NE levels and utilization within the locus coeruleus, plasma corticosterone, cytokine and ANP levels. Among mice initially exposed to an acute stressor (restraint), NE utilization, ventricular ANP mRNA expression, and plasma interleukin-6 (IL-6) concentrations were markedly increased by the subsequent social stressor. In chronically stressed mice some of the effects of the social stressor were dampened, including changes of plasma corticosterone, locus coeruleus NE utilization, as well as plasma and ventricular IL-6 mRNA expression. Conversely, plasma ANP was markedly enhanced by the combined stressor events as was ventricular BNP and IL-1beta mRNA expression. It seems that stressors may profoundly influence (sensitize or desensitize) on factors that could influence cardiovascular functioning. It remains to be determined whether these actions would be translated as pathophysiological outcomes. PMID- 20832412 TI - Modeling immune complex-mediated autoimmune inflammation. AB - A number of autoimmune diseases are thought to feature a particular type of self sustaining inflammation, caused by the deposition of immune complexes (IC) in the inflamed tissue and a consequent activation of local effector cells. The persistence of this inflammation is due to a positive feedback loop, where autoantigen particles released as part of the tissue damage caused by the inflammation stimulate autoreactive B cells, leading to the formation of further immune complexes and their subsequent deposition. We present a mathematical model for the exploration of IC-mediated autoimmune inflammation and its clinical implications. We characterize the possible differences between normal individuals and those susceptible to such inflammation, and show that both random perturbations and bifurcations can lead to disease onset. Our model explains how defects in the mechanisms responsible for cellular debris clearance contribute to the development of disease, in agreement with empirical evidence. Moreover, we show that parameters governing the dynamics of immune complexes, such as their clearance rate, have an even stronger effect in determining the behavior of the system. We demonstrate the existence of hysteresis, implying that once IC mediated autoimmune inflammation is triggered, its long-term suppression may be difficult to achieve. Our results can serve to guide the development of novel therapies to autoimmune diseases involving this type of inflammation. PMID- 20832413 TI - The role of renal aquaporin 2 in the alleviation of dehydration associated with diabetic polyuria in KKAy mice. AB - AIMS: Polyuria is a symptom that appears in association with diabetes mellitus. Because sustained polyuria causes serious dehydration, it is believed that the body has a compensating mechanism to alleviate dehydration. In the present study, the role of renal aquaporin 2 (AQP2) in the compensating mechanism was investigated in KKAy mice, a type 2 diabetes model. MAIN METHODS: The renal AQP2 expression levels in KKAy mice aged between 5 and 24 weeks were determined using Western blotting. The hypothalamic vasopressin mRNA expression levels also were measured by real-time RT-PCR. Insulin was subcutaneously administered to 11-week old KKAy mice twice a day for 7 days. After insulin treatment, the renal AQP2 protein expression and the hypothalamic vasopressin mRNA expression were measured. KEY FINDINGS: The urinary volumes of 5- and 12-week-old KKAy mice were 1.5 +/- 0.3 mL and 9.5 +/- 1.2 mL, respectively. The inner medullary AQP2 protein expression of 12-week-old KKAy mice was approximately 2.5-fold higher than that of 5-week-old KKAy mice. The hypothalamic vasopressin mRNA expression of 12-week old KKAy mice was approximately twice that of 5-week-old KKAy mice. Insulin treatment in KKAy mice resulted in a significant reduction in the plasma glucose level, urinary volume, and inner medullary AQP2 protein and hypothalamic vasopressin mRNA expression. SIGNIFICANCE: The present study demonstrated that AQP2 is a renal functional molecule of vasopressin that controls urinary volume and that AQP2 in the kidney increases to alleviate dehydration due to type 2 diabetes with polyuria. PMID- 20832414 TI - Simulation of evolution implemented in the mutualistic symbioses towards enhancing their ecological efficiency, functional integrity and genotypic specificity. AB - We created the mathematical model for the evolution of the Efficiency of Mutualistic Symbioses (EMS) which was estimated as the microsymbiont impacts on the host's reproductive potential. Using the example of rhizobia-legume interaction, the relationships were studied between EMS and Functional Integrity of Symbiosis (FIS) which is represented as a measure for concordance of changes in the partners' genotypic frequencies under the environmental fluctuations represented by the minor deviations of the systemic model parameters. The FIS indices correlate positively with EMS values suggesting an enhancement of FIS via the natural selection operating in the partners' populations in favor of high EMS. Due to this selection, nodular habitats may be closed for colonization by the non-beneficial bacterial strains and the Genotypic Specificity of Mutualism (GSM) in partners' interactions is enhanced: the selective advantage of host specific vs non-host-specific mutualists is increasing. The novelty of our model is to suggest a selective background for macroevolutionary events reorganizing the structure and functions of symbiotic systems and to present its evolution as a result of shifting the equilibrium between different types of mutualists under the impacts of the symbiosis-stipulated modes of natural selection. PMID- 20832415 TI - The lack of target specificity of small molecule anticancer kinase inhibitors is correlated with their ability to damage myocytes in vitro. AB - Many new targeted small molecule anticancer kinase inhibitors are actively being developed. However, the clinical use of some kinase inhibitors has been shown to result in cardiotoxicity. In most cases the mechanisms by which they exert their cardiotoxicity are not well understood. We have used large scale profiling data on 8 FDA-approved tyrosine kinase inhibitors and 10 other kinase inhibitors to a panel of 317 kinases in order to correlate binding constants and kinase inhibitor binding selectivity scores with kinase inhibitor-induced damage to neonatal rat cardiac myocytes. The 18 kinase inhibitors that were the subject of this study were: canertinib, dasatinib, dovitinib, erlotinib, flavopiridol, gefitinib, imatinib, lapatinib, midostaurin, motesanib, pazopanib, sorafenib, staurosporine, sunitinib, tandutinib, tozasertib, vandetanib and vatalanib. The combined tyrosine kinase and serine-threonine kinase selectivity scores were highly correlated with the myocyte-damaging effects of the kinase inhibitors. This result suggests that myocyte damage was due to a lack of target selectivity to binding of both tyrosine kinases and serine-threonine kinases, and was not due to binding to either group specifically. Finally, the strength of kinase inhibitor binding for 290 kinases was examined for correlations with myocyte damage. Kinase inhibitor binding was significantly correlated with myocyte damage for 12 kinases. Thus, myocyte damage may be multifactorial in nature with the inhibition of a number of kinases involved in producing kinase inhibitor-induced myocyte damage. PMID- 20832416 TI - Spatial frequency discrimination learning in normal and developmentally impaired human vision. AB - Perceptual learning effects demonstrate that the adult visual system retains neural plasticity. If perceptual learning holds any value as a treatment tool for amblyopia, trained improvements in performance must generalize. Here we investigate whether spatial frequency discrimination learning generalizes within task to other spatial frequencies, and across task to contrast sensitivity. Before and after training, we measured contrast sensitivity and spatial frequency discrimination (at a range of reference frequencies 1, 2, 4, 8, 16 c/deg). During training, normal and amblyopic observers were divided into three groups. Each group trained on a spatial frequency discrimination task at one reference frequency (2, 4, or 8 c/deg). Normal and amblyopic observers who trained at lower frequencies showed a greater rate of within task learning (at their reference frequency) compared to those trained at higher frequencies. Compared to normals, amblyopic observers showed greater within task learning, at the trained reference frequency. Normal and amblyopic observers showed asymmetrical transfer of learning from high to low spatial frequencies. Both normal and amblyopic subjects showed transfer to contrast sensitivity. The direction of transfer for contrast sensitivity measurements was from the trained spatial frequency to higher frequencies, with the bandwidth and magnitude of transfer greater in the amblyopic observers compared to normals. The findings provide further support for the therapeutic efficacy of this approach and establish general principles that may help develop more effective protocols for the treatment of developmental visual deficits. PMID- 20832417 TI - Trends in leisure-, transport-, and work-related physical activity in Canada 1994 2005. AB - BACKGROUND: In Canada, data show adults had a lower energy intake in 2004 than in 1972. Data also show adults expended more energy through leisure-time physical activity in 2000 than in 1981. On the other hand, the prevalence of overweight and obesity (combined) rose from 49.2% to 59.1% between 1978 and 2004. PURPOSE: This study aimed to chart trends in leisure-, transport-, and work-related physical activity in Canada between 1994 and 2005. METHODS: We used nationally representative data from the three National Population Health Surveys (1994, 1996, and 1998) and the three Canadian Community Health Surveys (2000, 2003, and 2005) (a repeated cross-sectional design). Sample sizes ranged from n=17626 (in 1994) to n=132,221 (in 2005). RESULTS: Between 1994 and 2005, men became less inactive during leisure time (-9.94% [9.89%-9.98%]), less inactive during transports (-15.31% [15.26%-15.35%]), and more inactive at work (+5.18% [5.14% 5.22%]). Similar results were found for women. CONCLUSIONS: Declining levels of physical activity at work may help explain the rising prevalence of overweight and obesity in Canada. PMID- 20832418 TI - Self-rated health according to amount, intensity and duration of leisure time physical activity. AB - OBJECTIVE: To examine the dose-response relationship between leisure time physical activity (LTPA) and self-rated health. METHODS: A survey (n=18,058) representative of the population aged 18-64years of Madrid (Spain) conducted between 2000 and 2008. A questionnaire on the frequency and duration of numerous activities was used to assess the total amount, the intensity, and the duration of LTPA. Self-rated health was classified as optimal or sub-optimal (fair/bad/very bad). Analyses were performed using logistic regression. RESULTS: Compared with no LTPA, active people in the lowest quintile for total amount of LTPA showed an odds ratio (OR) of sub-optimal health of 0.69; a linear dose response relationship (p<0.001) was observed, with the OR gradually decreasing to 0.49 in the highest quintile of LTPA. There was an inverse gradient for LTPA intensity adjusted for energy expenditure, so that the OR of sub-optimal health was 0.69 for light LTPA, 0.60 for moderate, and 0.48 for vigorous (p linear trend <0.001). For the same duration, the frequency of optimal health increases with the intensity of LTPA. CONCLUSIONS: The total amount of LTPA shows a graded and continuous association with better self-rated health. The benefits of LTPA on self-rated health increase with the intensity of the activity. PMID- 20832419 TI - Awareness of the background rate of sudden cardiac death during mass immunization with pandemic H1N1 influenza vaccines increases the intended vaccination rate. PMID- 20832420 TI - Prohibitin as an oxidative stress biomarker in the eye. AB - Identification of biomarker proteins in the retina and retinal pigment epithelium (RPE) under oxidative stress may imply new insights into signaling mechanisms of retinal degeneration at the molecular level. Proteomic data from an in vivo mice model in constant light and an in vitro oxidative stress model are compared to controls under normal conditions. Our proteomic study shows that prohibitin is involved in oxidative stress signaling in the retina and RPE. The identity of prohibitin in the retina and RPE was studied using 2D electrophoresis, immunohistochemistry, western blot, and mass spectrometry analysis. Comparison of expression levels with apoptotic markers as well as translocation between mitochondria and the nucleus imply that the regulation of prohibitin is an early signaling event in the RPE and retina under oxidative stress. Immunohistochemical analysis of murine aged and diabetic eyes further suggests that the regulation of prohibitin in the RPE/retina is related to aging- and diabetes-induced oxidative stress. Our proteomic approach implies that prohibitin in the RPE and the retina could be a new biomarker protein of oxidative stress in aging and diabetes. PMID- 20832421 TI - Determination of serum triglyceride by enzyme electrode using covalently immobilized enzyme on egg shell membrane. AB - A mixture of commercial lipase, glycerol kinase and glycerol-3-phosphate oxidase was co-immobilized onto egg shell membrane through covalent coupling. A method is described for fabrication of a triglyceride (TG) biosensor using egg shell membrane bound enzymes. The biosensor measured current, i.e. flow of electrons generated from H(2)O(2), maximally when polarized at 0.4V. The biosensor showed optimum response within 10 sec at pH 7.0 and 35 degrees C. The current was in proportion to concentration of TG in the range 0.56-2.25 mM. An amperometric method was developed for determination of TG employing this enzyme electrode. The minimum detection limit of the method was 0.28 mM. The analytic recovery of added TG was 95.00% and 96.50%. Within batch and between batch coefficients of variations (CV) were <2.14% and <3.48% respectively. A good correlation (r=0.985) was obtained between serum TG level by standard enzymic colorimetric method and the present method. Serum substances such as urea, uric acid, glucose, cholesterol, ascorbic acid and pyruvic acid had no interference. The enzyme electrode was used 200 times over a period of 70 days without any considerable loss of activity, when stored at 4 degrees C. PMID- 20832422 TI - A novel plasmid for delivering genes into mammalian cells with noninvasive food and commensal lactic acid bacteria. AB - Using food and commensal lactic acid bacteria (LAB) as vehicles for DNA delivery into epithelial cells is a new strategy for vaccine delivery or gene therapy. However, present methods for DNA delivery with LAB have suffered low efficiency. Our goal was to develop a new system to deliver DNA into epithelial cells with high efficiency using food and commensal LAB. An Escherichia coli-LAB shuttle plasmid, pLKV1, for DNA delivery into eukaryotic cells was constructed. Two reporter plasmids with green and red fluorescent protein genes were also constructed to monitor the uptake of protein and DNA, respectively. Bacteria delivering these reporter plasmids into Caco-2 cells were monitored by fluorescence microscopy. Several methods that weaken the bacterial cell wall prior to co-culture with Caco-2 cells were evaluated for their role in the improvement of gene transfer efficiency. Treating Streptococcus gordonii with penicillin and lysozyme greatly increased its rate of gene delivery to mammalian cells compared to untreated control bacteria, while glycine pretreatment promoted the highest gene transfer rate for Lactococcus lactis. Uptake of green fluorescent bacteria by Caco-2 cells showed that the cell wall-weakening treatment promoted the internalization of the noninvasive bacteria into Caco-2 cells. In conclusion, we have developed a noninvasive system using LAB as a vehicle for vaccine delivery or gene therapy, and tested this system in vitro with Caco-2 cells. PMID- 20832423 TI - Threat-detection in child development: an evolutionary perspective. AB - Evidence for developmental aspects of fear-targets and anxiety suggests a complex but stable pattern whereby specific kinds of fears emerge at different periods of development. This developmental schedule seems appropriate to dangers encountered repeatedly during human evolution. Also consistent with evolutionary perspective, the threat-detection systems are domain-specific, comprising different kinds of cues to do with predation, intraspecific violence, contamination-contagion and status loss. Proper evolutionary models may also be relevant to outstanding issues in the domain, notably the connections between typical development and pathology. PMID- 20832424 TI - Manganese exposure inhibits the clearance of extracellular GABA and influences taurine homeostasis in the striatum of developing rats. AB - Manganese (Mn) accumulation in the brain has been shown to alter the neurochemistry of the basal ganglia. Mn-induced alterations in dopamine biology are fairly well understood, but recently more evidence has emerged characterizing the role of gamma-aminobutyric acid (GABA) in this dysfunction. The purpose of this study was to determine if the previously observed Mn-induced increase in extracellular GABA (GABA(EC)) was due to altered GABA transporter (GAT) function, and whether Mn perturbs other amino acid neurotransmitters, namely taurine and glycine (known modulators of GABA). Extracellular GABA, taurine, and glycine concentrations were collected from the striatum of control (CN) or Mn-exposed Sprague-Dawley rats using in vivo microdialysis, and the GAT inhibitor nipecotic acid (NA) was used to probe GAT function. Tissue and extracellular Mn levels were significantly increased, and the Fe:Mn ratio was decreased 36-fold in the extracellular space due to Mn-exposure. NA led to a 2-fold increase in GABA(EC) of CNs, a response that was attenuated by Mn. Taurine responded inversely to GABA, and a novel 10-fold increase in taurine was observed after the removal of NA in CNs. Mn blunted this response and nearly abolished extracellular taurine throughout collection. Striatal taurine transporter (Slc6a6) mRNA levels were significantly increased with Mn-exposure, and Mn significantly increased (3)H Taurine uptake after 3-min exposure in primary rat astrocytes. These data suggest that Mn increases GABA(EC) by inhibiting the function of GAT, and that perturbed taurine homeostasis potentially impacts neural function by jeopardizing the osmoregulatory and neuromodulatory functions of taurine in the brain. PMID- 20832425 TI - Information technology solutions for integration of biomolecular and clinical data in the identification of new cancer biomarkers and targets for therapy. AB - The quest for new cancer biomarkers and targets for therapy requires not only the aggregation and analysis of heterogeneous biomolecular data but also integration of clinical data. In this review we highlight information technology solutions for the integration of biomolecular and clinical data and focus on a solution at the departmental level, i.e., decentralized and medium-scale solution for groups of labs working on a specific topic. Both, hardware and software requirements are described as well as bioinformatics methods and tools for the data analysis. The highlighted IT solutions include storage architecture, high-performance computing, and application servers. Additionally, following computational approaches for data integration are reviewed: data aggregation, integrative data analysis including methodological aspects as well as examples, biomolecular pathways and network reconstruction, and mathematical modelling. Finally, a case study in cancer immunology including the used computational methods is shown, demonstrating how IT solutions for integrating biomolecular and clinical data can help to identify new cancer biomarkers for improving diagnosis and predicting clinical outcome. PMID- 20832426 TI - Adenoviral-mediated Cre expression effectively suppresses GlyT1 binding in the thalamic area of GlyT1 conditional knock-out mice. AB - To properly understand the function of genes of neurological interest, in vivo manipulation in the adult is essential, particularly when the target gene is involved in brain development. Moreover, since the physiological effects of target protein may be region-specific, targeting a distinct brain region could be required to dissect these effects in specific brain locations. Infection of somatic tissues of transgenic mice bearing loxP-flanked gene sequences with a viral vector expressing Cre recombinase provides a means of allowing flexible spatio-temporal control of target gene expression. Viral vector-mediated Cre expression could be used to mediate localized gene modulation in a specific brain region. In the present study this technology was applied to the glycine transporter type-1 (GlyT1) protein which is responsible for the uptake of synaptic glycine in the forebrain and has been implicated as a therapeutic target for the treatment of schizophrenia. Since GlyT1 is widely expressed in glial cells, we employed an adenoviral-based vector (Ad5) to deliver Cre protein, due to the preferentially transduction of glial cells by adenoviral vectors in rodent brain. We show significant reduced GlyT1 binding specifically in the thalamic area of conditional GlyT1 (GlyT1c) transgenic mice injected with Ad5-Cre virus, as measured by GlyT1 autoradiography. In conclusion, we demonstrated the validity of viral vector-mediated delivery of Cre to loxP targeted transgenic mice as a novel strategy to investigate target gene function in selected subregions of the adult brain, which provides a valuable technique to investigate gene function both in normal physiology and in disease models. PMID- 20832427 TI - A multiscale analysis of the temporal characteristics of resting-state fMRI data. AB - In this paper, we conduct an investigation of the null hypothesis distribution for functional magnetic resonance imaging (fMRI) time series using multiscale analysis tools, SiZer (significance of zero crossings of the derivative) and wavelets. Most current approaches to the analysis of fMRI data assume simple models for temporal (short term or long term) dependence structure. Such simplifications are to some extent necessary due to the complex, high-dimensional nature of the data, but to date there have been few systematic studies of the dependence structures under a range of possible null hypotheses, using data sets gathered specifically for that purpose. We aim to address some of these issues by analyzing the detrended data with a long enough time horizon to study possible long-range temporal dependence. Our multiscale approach shows that even for resting-state data, data, i.e. "null" or ambient thought, some voxel time series cannot be modeled by white noise and need long-range dependent type error structure. This finding suggests the use of different time series models in different parts of the brain in fMRI studies. PMID- 20832428 TI - Batch prepared protein standards for cerebrospinal fluid (CSF) biomarkers for neurodegeneration. AB - Immuno-assays are increasingly used for quantification of protein biomarkers for neurodegeneration. It has been proposed to use such cerebrospinal fluid (CSF) protein biomarkers as diagnostic tests for Alzheimer's disease. In two recent world-wide validation studies we found the analytical accuracy to be poor (inter laboratory coefficient of variation, CV>10%) for CSF tau protein, CSF phospho-tau protein, CSF amyloid beta protein and the CSF neurofilament light chain protein. Retrospectively we suspected that the lack of preparation of accurate and consistent protein standards may have been one reason for the poor inter laboratory CV. Here we confirm this hypothesis prospectively under standardised and optimised conditions. The CVs for CSF tau, CSF phospho-tau and CSF amyloid beta of individually prepared standards are 8%, 12% and 12% compared to significantly lower CVs for batch prepared standards (5%, 8%, 7%, respectively, p<0.05). This issue will need to be solved in order to ensure that the attempts to include these CSF protein biomarkers either as a diagnostic tool or a secondary outcome measure for treatment trials will be successful. PMID- 20832429 TI - Multi-limb acquisition of motor evoked potentials and its application in spinal cord injury. AB - The motor evoked potential (MEP) is an electrical response of peripheral neuro muscular pathways to stimulation of the motor cortex. MEPs provide objective assessment of electrical conduction through the associated neural pathways, and therefore detect disruption due to a nervous system injury such as spinal cord injury (SCI). In our studies of SCI, we developed a novel, multi-channel set-up for MEP acquisition in rat models. Unlike existing electrophysiological systems for SCI assessment, the set-up allows for multi-channel MEP acquisition from all limbs of rats and enables longitudinal monitoring of injury and treatment for in vivo models of experimental SCI. The article describes the development of the set up and discusses its capabilities to acquire MEPs in rat models of SCI. We demonstrate its use for MEP acquisition under two types of anesthesia as well as a range of cortical stimulation parameters, identifying parameters yielding consistent and reliable MEPs. To validate our set-up, MEPs were recorded from a group of 10 rats before and after contusive SCI. Upon contusion with moderate severity (12.5mm impact height), MEP amplitude decreased by 91.36+/-6.03%. A corresponding decline of 93.8+/-11.4% was seen in the motor behavioral score (BBB), a gold standard in rodent models of SCI. PMID- 20832431 TI - Impaired neural stem/progenitor cell proliferation in streptozotocin-induced and spontaneous diabetic mice. AB - Diabetes mellitus is associated with adverse complications in many organ systems including the brain. Accumulating evidence indicates that diabetes, regardless of its type, impairs adult neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC). However, the effects of the disease on neurogenesis in the subventricular zone (SVZ) are not well established. We induced diabetes in male NOD/SCID (non obese diabetic/severe combined immunodeficiency) mice and C57BL/6 mice with a single intraperitoneal injection of streptozotocin (STZ). On day 7 or day 21 after STZ injection mice received the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) for labeling of proliferative cells. Mice were sacrificed 24h later and brain coronal sections were stained with anti-BrdU antibodies. Neural stem/progenitor cell (NSC/NPC) proliferation, as revealed by BrdU-labeled cells, was markedly decreased in the subgranular zone of the DG in STZ-treated diabetic mice. A similar reduction of NSC/NPC proliferation was seen in the SVZ. Reduced DG and SVZ cell proliferation was also found in diabetic NOD mice, a model of spontaneous diabetes, and the reduction was attenuated by bilateral adrenalectomy (Adx). Adx did not alter blood glucose or insulin levels in either prediabetic or diabetic NOD mice, but Adx partly increased mRNA levels of hippocampal and SVZ brain-derived neurotrophic factor (BDNF), a crucial regulator of NSC/NPC proliferation. Moreover, NOD and NOD/SCID mice showed a more rapid reduction of NSC/NPC proliferation than C57BL/6 mice in response to diabetes. Thus, we conclude that diabetes inhibits cell proliferation in both the SVZ and HPC, and inhibition was associated with elevated glucocorticoid levels and reduced BDNF expression. PMID- 20832430 TI - Stress-induced changes in c-Fos and corticotropin releasing hormone immunoreactivity in the amygdala of the spontaneously hypertensive rat. AB - The present study was undertaken to test the hypothesis that dysregulation of the amygdala contributes to the exaggerated autonomic response to stress in an animal model of essential hypertension. Spontaneously hypertensive (SHR) and normotensive Wistar male rats were chronically instrumented and exposed to 20 min of either air jet stress (AJS) or air noise alone (CON). AJS induced a significant increase in both heart rate and arterial pressure that was greater in the SHR. AJS induced a significant increase in c-Fos-like immunoreactivity (FLI) throughout the caudal-rostral extent of the basolateral, medial, and central (CEA) subnuclei of the amygdala. Differences in FLI between strains were localized to the rostral CEA and the SHR expressed significantly less FLI. AJS also induced a significant increase in the number of corticotrophin releasing hormone (CRH) positive neurons in the CEA. Differences between strains were localized to the caudal CEA and the number of CRH-positive cells was significantly greater in the SHR. The stress-induced increase in CRH labeling in caudal CEA of the SHR was coupled to a greater increase in FLI in the rostral locus coeruleus (LC) of the SHR versus the Wistar. AJS also induced significant increases in FLI in several hypothalamus subnuclei, but no strain-related differences were identified. These results suggest for the first time that dysregulation of CRH-positive cells in the caudal CEA and reduced excitation and/or exaggerated inhibition of rostral CEA neurons may contribute to the exaggerated cardiovascular response to stress in the SHR, possibly through descending modulation of the rostral LC. PMID- 20832432 TI - Effects of valproate on neurotransmission associated with ryanodine receptors. AB - To clarify the antiepileptic mechanisms of valproate (VPA), we determined the effects of acute and sub-acute administrations of VPA on ryanodine receptor (RyR) associated hippocampal releases of GABA and glutamate using microdialysis, as well expression of mRNA and protein of RyR subtypes in the rat hippocampus. Acute administration of therapeutic-relevant VPA did not affect the hippocampal extracellular levels of GABA or glutamate, whereas sub-acute administration increased GABA level without affecting that of glutamate. Perfusion with ryanodine increased the hippocampal extracellular level of glutamate (ryanodine concentration range: 1-1000MUM) concentration-dependently; however, that of GABA was increased by 1-100MUM ryanodine concentration-dependently but the stimulatory effects of 1000MUM ryanodine on GABA release was not observed. Both acute and sub acute administrations of therapeutic-relevant VPA inhibited ryanodine-induced responses of hippocampal extracellular glutamate level without affecting that of GABA. Especially, both acute and sub-acute administrations of VPA prevented the breakdown of GABA release induced by 1000MUM ryanodine. Sub-acute administration of therapeutically-relevant dose VPA weakly increased RyR mRNA expression but we could not detect the changes of RyR protein expression in rat hippocampus. These results suggest that VPA inhibited the neurotransmitter release associated with RyR without affecting the expression of RyR protein. Therefore, the antiepileptic action of VPA seems to be mediated, at least in part, by an increase in basal GABA release and inhibition of RyR-associated glutamate release. PMID- 20832433 TI - Withdrawal from methylphenidate increases neural reactivity of dorsal midbrain. AB - Ritalin (methylphenidate hydrochloride, MP) is a non-amphetamine psychostimulant and is the drug of choice to treat children and adults diagnosed with the attention deficit hyperactivity disorder (ADHD). Several studies have demonstrated that rats treated with MP during early developmental stage exhibit alterations in anxiety-related processes such as an increased response to stressful stimuli and elevated plasma levels of corticosterone. Accordingly, the present study was designed to further characterize the neural and behavioral consequences of withdrawal from MP in adult rats and its influence on the neural reactivity of the dorsal midbrain. After initial exposure to an elevated plus maze (EPM), brainstem neural activation, elicited by exposure to EPM aversive cues, was analyzed using a Fos-protein immunolabeling technique. Additional independent groups of animals were submitted to electrical stimulation of the dorsal column (DPAG) or the startle response procedure, in order to verify the influence of withdrawal from MP on the expression of unconditioned fear induced by DPAG activation and the effects of or withdrawal from MP on motor response, respectively. Our results provide new findings about the influence of MP treatment in adult rats, showing that, after a sudden MP treatment-break, increased anxiety, associated with the neural sensitization of anxiety-related regions, ensues. PMID- 20832434 TI - The interaction between PRRSV and the late gestation pig fetus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) crosses the placenta during late gestation and productively infects the fetus. Virus replication and cytokine responses were measured in tissues of fetuses recovered at 109-112 days of gestation, just prior to parturition. At the time of recovery, gross anatomical abnormalities were evident in both infected and non-infected fetuses from the infected dams. Virus isolation and immunohistochemistry identified the thymus as the primary site of virus replication. Steady state RT-PCR amplification of inflammatory, Th1 and Th2 cytokines, showed elevated IFN-gamma and TNF-alpha mRNAs in tissues from infected fetuses, which corresponded to elevated cytokine proteins in serum but not amniotic fluid. Further evidence for induction of immunity was found in the hyperplastic response of lymph nodes, which included the development of germinal centers occupied CDw75+ B cells. Collectively, these data support the notion that the immunocompetent fetus is capable of initiating an antiviral response, which is compartmentalized within the infected fetus. Furthermore, fetal pathology may not be a direct result of virus replication in the fetus. PMID- 20832435 TI - The VP37 protein of Broad bean wilt virus 2 induces tubule-like structures in both plant and insect cells. AB - VP37 protein of Broad bean wilt virus 2 (BBWV-2) is a multifunctional protein that binds single-strand nucleic acids, interacts with viral coat protein (CP) and potentiates the virus cell-to-cell movement in its host plant. In this study, tubule-like structures filled with virus-like particles were observed by Electron Microscopy in plasmodesmata in walls of Chenopodium quinoa leaf cells infected with BBWV-2. Immunogold labeling using VP37 protein specific antibody demonstrates that the VP37 is a component of the tubular structures. When VP37 was fused with the green fluorescent protein (VP37-GFP) and expressed in BY-2 protoplasts or in insect Tn cells, green fluorescent tubules of various lengths were produced, protruding from the surface of the expressing cells. These findings suggest that the movement of BBWV-2 between cells is mediated by the tubular structures that contain the VP37 protein, and the VP37 protein itself is capable of inducing these tubule-like structures in cells. Our results also suggest that the plant and insect cell factors involved in the tubule formation have conserved features. PMID- 20832436 TI - Collecting accurate secondary foodscape data. A reflection on the trials and tribulations. AB - In a special issue of the American Journal of Preventive Medicine (2009, 36(4S)), themed around the measurement of food and physical activity environments, Brownson, Hoehner, Day, Forsyth, and Sallis (2009, 118) made a plea for increased attention to be paid to the difficulties and complexities associated with the gathering of secondary data, and its subsequent refinement for use. Some of the peculiarities involved with the gathering and refining of secondary data, in particular data on the locations of food outlets in North East England are discussed in this paper. 'Foodscape' data is often invoked in Geographical Information Systems (GIS) based studies that seek to explore the geography of food availability/access in relation to outcomes such as obesity. However, results from a GIS-based analysis are only as strong as the data utilised. This paper explores the time consuming negotiations, possible expense and probable stress of acquiring foodscape data from a robust source (Local Councils within the North East Government Office Region (GOR), UK), considerations that may unfortunately influence the potential scope of research projects. Furthermore, this paper extends its remit to discuss the clerical issues that plague the 'tidying up' of such secondary information. The paper will conclude by discussing how the time intensive sourcing and subsequent 'cleaning' of accurate secondary information is likely to be worthwhile, but will note that it is naive to assume that (a) 'gatekeepers' will understand the necessity of your research and will thus cooperate accordingly, and (b) that the use of secondary data exonerates the researcher from 'getting their hands dirty'. The paper also concludes by highlighting the disconnect between the high quality research that is so frequently called for, and the lack of robust data sets that are available for use in these investigations. PMID- 20832437 TI - Convenience food products. Drivers for consumption. AB - Convenience is one of the big trends in the food business. The demand for convenience food products is steadily increasing; therefore, understanding convenience food consumption is an important issue. Despite being vital properties of convenience food, saving time and effort have not been very successful constructs for predicting convenience food consumption. To examine a wide range of possible drivers for convenience food consumption, the present study uses a convenience food frequency questionnaire that asks about consumption behavior. A paper-and-pencil questionnaire was sent out to a representative sample of people in German-speaking Switzerland and yielded N = 918 complete datasets from persons mainly responsible for buying and preparing food in the household. The various convenience food products could be categorized into four groups, which we labeled as highly processed food items, moderately processed food items, single components, and salads. Fifteen drivers were found to have a significant impact either on total convenience consumption or on one of the identified categories. Strong predictors were age, concern about naturalness, nutrition knowledge, and cooking skills. PMID- 20832438 TI - Predicting consumers' intention to consume ready-to-eat meals. The role of moral attitude. AB - This study investigates the usefulness of integrating moral attitude into the Theory of Planned Behavior (TPB) model when predicting intention to consume ready to-eat (RTE) meals. Questionnaire data were gathered in three countries: Norway (N = 112), The Netherlands (N = 99), and Finland (N = 134) in spring 2009. A stepwise hierarchical regression was conducted, and the analyses showed that moral attitude is an important predictor of RTE-meal consumption. The feeling of moral obligation, operationalised as a negative feeling of guilt, had a negative effect on peoples' intention to consume ready meals in all the three countries tested, and the explained variance (R2) for TPB increased when moral was added as an explanatory factor. However, although the test showed significant results for the effect of attitude towards behavior and moral in all countries, non significant results were observed for the effect of subjective norm in both The Netherlands and Norway when moral attitude was included to the TPB-model, indicating cultural differences in the social pressure towards ready meal consumption. PMID- 20832439 TI - Regular consumption of a cereal breakfast. Effects on mood and body image satisfaction in adult non-obese women. AB - Breakfast has psychological and nutritional benefits due to physiological mechanisms and expectations about health impact. Beliefs people hold about calories in food can adversely affect mood and body-image satisfaction and such adverse reactions can be predicted by body mass index. The objectives were to test the effect of consuming isocaloric breakfasts, appearing different in calorie content, on appetite, mood and body-image satisfaction, and to assess impact on daily nutrient intake. One-hundred-and-twenty-three women were randomly assigned to eat a cereal or muffin breakfast which "appeared" different in calorie content while unaware they were isocaloric. Participants estimated calories of breakfast, appetite, mood, and body-image satisfaction on a daily basis for seven-days. The cereal breakfast was perceived to be lower in calories, made participants fuller, happier, relaxed, and more satisfied about weight and body compared to the muffin breakfast. Differences in estimated daily fibre and micronutrient intake were compatible with the design. Breakfasts were isocaloric yet the cereal breakfast was rated lower in calories and produced more positive psychological reactions. This evidence indicates the power of perceptions of foods to influence important attributes of health and well-being which could be valuable in dietary interventions where mood and body image satisfaction affect outcome. PMID- 20832440 TI - How weight-related cues affect food intake in a modeling situation. AB - In a standard modeling experiment, a naive participant eats in the presence of an experimental confederate who has been instructed to eat a lot or a little. Results from such experiments show that people eat more when eating companions eat more and less when eating companions eat less. This modeling effect has been shown to be highly powerful. In the current report, two studies demonstrate that the effect is moderated when participants are exposed to weight-related cues. In Study 1, a body-weight scale was present in the experimental room; in Study 2, a weight-related verbal statement was uttered. Results of both of the chocolate tasting studies show that without the weight-related cues, participants consumed more chocolate when the confederate ate a large quantity than when she ate little. However, in the sessions including the weight-related cues, participants ate little chocolate, regardless of how much the confederate consumed. Weight related cues might function as primes that elicit cognitions about body weight and these cognitions might, unbeknownst to the individual, render him or her more vigilant concerning food intake, thereby decreasing consumption. PMID- 20832441 TI - When reduced fat increases preference. How fat reduction in nutrition tables and numeracy skills affect food choices. AB - Zero-fat products may be good alternatives to regular-fat products for consumers who are watching their health. In a choice experiment, we investigated whether consumers were willing to consume zero-fat products on the basis of nutrition tables and whether numeracy skills affected this decision. We presented respondents with the same two products in three choice tasks, reducing the fat content at each choice. Product A always contained less fat than Product B. The participants could choose one of the two products or none. Most respondents favoured the lower-fat products over the higher-fat products. However, after a fat reduction to almost zero, significantly more respondents chose the fattier alternative than in the first choice. A fat reduction to zero further reduced the relative preference for the lower-fat product in favour of the fattier alternative. Many consumers thus seem unwilling to consume zero-fat products. Respondents lower in numeracy seemed to differentiate less between regular- and reduced-fat products than those higher in numeracy. We discuss the implications of these findings for food producers. PMID- 20832442 TI - Assessing the natural variability in crop composition. AB - The number of evaluations of the nutrient composition of food and feed crops has increased over the past 15years due to the introduction of new crops using the tools of modern biotechnology. The composition of these crops has been extensively compared with conventional (non-transgenic) controls as an integral part of the comparative safety assessment process. Following guidelines outlined in the Organization of Economic Co-operation and Development (OECD) Consensus Documents, most of these studies have incorporated field trials at multiple geographies and a diverse range of commercially available varieties/hybrids that are analyzed to understand natural variability in composition due to genetic and environmental influences. Using studies conducted in the US, Argentina and Brazil over multiple growing seasons, this report documents the effect of geography, growing season, and genetic background on soybean composition where fatty acids and isoflavones were shown to be particularly variable. A separate investigation of 96 different maize hybrids grown at three locations in the US demonstrated that levels of free amino acids, sugars/polyols, and molecules associated with stress response can vary to a greater degree than that observed for more abundant components. The International Life Sciences Institute (ILSI) crop composition database has proven to be an important resource for collecting and disseminating nutrient composition data to promote a further understanding of the variability that occurs naturally in crops used for food and feed. PMID- 20832444 TI - Straight gyrus morphology in first-episode schizophrenia-spectrum patients. AB - Previous studies on the straight gyrus have shown inconsistent results in first episode schizophrenia. In the present study, straight gyrus morphometry in first episode schizophrenia-spectrum patients was investigated by using a region-of interest methodology. 141 schizophrenia-spectrum patients and 81 healthy subjects were studied. Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using BRAINS2. The main resulting measurements were straight gyrus gray matter volume and cortical surface area. Patients with schizophrenia-spectrum disorders did not significantly differ from controls in the straight gyrus morphometric variables evaluated (p>0.115). There was neither significant group-by-side (p>0.199) or group-by-gender interaction (p>0.096). Clinical variables were not significantly related with straight gyrus morphology. Our results, based on a large and representative sample, do not confirm the presence of significant straight gyrus morphometric anomalies in schizophrenia spectrum disorders, after controlling for potential confounding variables. PMID- 20832443 TI - Fear conditioning fragments REM sleep in stress-sensitive Wistar-Kyoto, but not Wistar, rats. AB - Pavlovian conditioning is commonly used to investigate the mechanisms of fear learning. Because the Wistar-Kyoto (WKY) rat strain is particularly stress sensitive, we investigated the effects of a psychological stressor on sleep in WKY compared to Wistar (WIS) rats. Male WKY and WIS rats were either fear conditioned to tone cues or received electric foot shocks alone. In the fear conditioning procedure, animals were exposed to 10 tones (800 Hz, 90 dB, 5s), each co-terminating with a foot shock (1.0 mA, 0.5s), at 30-s intervals. In the shock stress procedure, animals received 10 foot shocks at 30-s intervals, without tones. All subjects underwent a tone-only test both 24h (Day 1) and again two weeks (Day 14) later. Rapid eye movement sleep (REMS) continuity was investigated by partitioning REMS episodes into single (inter-REMS episode interval >3 min) and sequential (interval <= 3 min) episodes. In the fear conditioned group, freezing increased from baseline in both strains, but the increase was maintained on Day 14 in WKY rats only. In fear-conditioned WKY rats, total REMS amount increased on Day 1, sequential REMS amount increased on Day 1 and Day 14, and single REMS amount decreased on Day 14. Alterations were due to changes in the number of sequential and single REMS episodes. Shock stress had no significant effect on REMS microarchitecture in either strain. The shift toward sequential REMS in fear-conditioned WKY rats may represent REMS fragmentation, and may provide a model for investigating the neurobiological mechanisms of sleep disturbances reported in posttraumatic stress disorder. PMID- 20832445 TI - Spermatotoxicity, biochemical changes and histological alteration induced by gossypol in testicular and hepatic tissues of male rats. AB - Gossypol acetic acid (GAA) displays anti-fertility and antioxidant behavior. The efficacies of different doses of gossypol acetic acid were investigated in male albino rats. Rats were allocated into four groups: control group and three GAA treated groups (2-4), that were injected with GAA (5, 10, 20mg/kg BW, respectively), through inrtaperitonial injection. Treatment of GAA was found to elicit a significant decrease in sperm counting, sperm motility, serum levels of testosterone, luteinizing hormone and follicle-stimulating hormone, whereas, the activities of testicular 17beta-hydroxysteroid dehydrogenase and 17-ketosteroid reductase were increased. The activities of serum transaminases and alkaline phosphatase and hepatic glutathione peroxidase; glutathione reductase, superoxide dismutase and glutathione S-transferase and the level of hepatic glutathione were elevated. While, the lipid peroxidation end product; malondialdehyde, nitric oxide, and lipid profile and the activity of hepatic cytochrome P450 were decreased in GAA-treated rats. The histological analysis of liver and testicular tissues showed sever hepatocyte damage in addition to abnormal localization of hepatocytic nuclei. Also, the testicular pathology of GAA-treated rats showed depressed spermatogensis, sertoli cell toxicity and degeneration of seminiferous tubules. PMID- 20832446 TI - Development of stably transfected human and rat hepatoma cell lines for the species-specific assessment of xenobiotic response enhancer module (XREM) dependent induction of drug metabolism. AB - Based on our current knowledge, PXR holds a key position in the induction of a selective battery of enzymes and transporters of drug metabolism. In order to prevent serious adverse drug effects or unpredicted drug-drug interactions (DDI), it is compulsory to investigate the possible inducing potency of drugs under development. Furthermore, analysis of the inducing potency of environmental pollutants and new or manufactured chemicals is part of toxicological risk assessment. In non-transfected human HepG2 and rat H4IIE hepatoma cells, we examined the characteristics of expression of 45 genes involved in drug metabolism. A few gene products such as CYP2B6 or CYP3A4 mRNA were prominent in HepG2 cells while their major rat counterparts were, e.g., CYP2B3 or CYP3A1/3A3. Furthermore, a number of xenobiotic receptors including PXR were expressed in both cell lines. A number of genes were regulated in a cell type and species specific manner after incubation with the prototypical PXR agonists rifampicin or dexamethasone, respectively. Then, we established cell-based reporter gene assays for screening for PXR-dependent induction of drug metabolism. HepG2 and H4IIE cells were stably transfected with a reporter gene containing PXR responsive elements (XREMs) which mediate the induction of PXR target genes such as CYP3A enzymes. With both stable cell lines the CYP inducers clotrimazole, dexamethasone, omeprazole, phenobarbital, rifampicin, as well as the drug candidate EMD 392949 and the brominated flame retardants hexabromocylododecane (HBCD) and a pentabromodiphenyl ether (pentaBDE) mixture were screened. In the human HepG2-XREM3 and rat H4IIE-XREM3 cells, clotrimazole and HBCD were found as common activators of the human and rat PXR whereas pentaBDE was more effective with the human cell system. Omeprazole and phenobarbital did not induce the rat PXR-dependent reporter gene expression in H4IIE-XREM3 cells, while a moderate increase was found in HepG2-XREM3 cells. EMD 392949 also acted as inducer in human but not in rat cells confirming in vivo observations. In summary, the established PXR-dependent in vitro system allows the simultaneous, fast, and species-specific screening of chemicals, environmental contaminants, food ingredients and drugs for CYP3A induction in cells of human and rat origin. PMID- 20832447 TI - The face of effort: frowning muscle activity reflects effort during a physical task. AB - It is a common observation that exertion of effort is associated with a specific facial expression. However, this facial expression has never been quantified during physical tasks and its relationship with effort is unknown. The aims of the present study were to measure frowning muscle activity during a physical task with electromyography (EMG) and to investigate the relationship between facial EMG and effort. Effort was experimentally manipulated by increasing task difficulty and inducing muscle weakness. Twenty men performed leg extensions with four relative workloads. The fatigue group (n=10) repeated the leg extensions after fatiguing eccentric exercise, and the control group repeated just the leg extensions. Facial EMG amplitude, ratings of perceived effort (RPE), and leg EMG amplitude increased significantly with increasing task difficulty and with muscle fatigue. Facial EMG, RPE, and leg EMG all correlated significantly. The results suggest that frowning muscle activity reflects effort during physical tasks. PMID- 20832448 TI - A disposition to reappraise decreases anterior insula reactivity during anxious anticipation. AB - Across individuals there is variability in one's inherent tendency to reappraise emotional events in everyday life, which may be related to how worried one becomes in the presence of an anticipated aversive event. The extent to which this natural tendency to reappraise has neurobiological correlates during anxious anticipation is unknown. Neuroimaging research indicates that responses in the anterior insula precede anticipated aversive events and appear to represent one's affective feeling state of anxious anticipation. Successful cognitive reappraisal should weaken this anticipatory insula response. Here, functional magnetic resonance images were acquired while participants completed an anticipation task. We found increased anterior insula activation during aversive anticipation and a negative association between anxious anticipatory right anterior insula reactivity and dispositional reappraisal. Thus, even without the instruction to reappraise, individuals high in dispositional reappraisal tended to have a reduced anticipatory insula response to aversive stimuli, thereby down-regulating a neural substrate for aversive anticipation. PMID- 20832449 TI - Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets. AB - Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS). OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor beta and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction. PMID- 20832450 TI - Effects of exposure to a time-varying 1.5 T magnetic field on the neurotransmitter-activated increase in intracellular Ca(2+) in relation to actin fiber and mitochondrial functions in bovine adrenal chromaffin cells. AB - BACKGROUND: It has been reported that exposure to electromagnetic fields influences intracellular signal transduction. We studied the effects of exposure to a time-varying 1.5 T magnetic field on membrane properties, membrane cation transport and intracellular Ca(2+) mobilization in relation to signals. We also studied the mechanism of the effect of exposure to the magnetic field on intracellular Ca(2+) release from Ca(2+) stores in adrenal chromaffin cells. METHODS: We measured the physiological functions of ER, actin protein, and mitochondria with respect to a neurotransmitter-induced increase in Ca(2+) in chromaffin cells exposed to the time-varying 1.5 T magnetic field for 2h. RESULTS: Exposure to the magnetic field significantly reduced the increase in [Ca(2+)]i. The exposure depolarized the mitochondria membrane and lowered oxygen uptake, but did not reduce the intracellular ATP content. Magnetic field-exposure caused a morphological change in intracellular F-actin. F-actin in exposed cells seemed to be less dense than in control cells, but the decrease was smaller than that in cytochalasin D-treated cells. The increase in G-actin (i.e., the decrease in F-actin) due to exposure was recovered by jasplakinolide, but inhibition of Ca(2+) release by the exposure was unaffected. CONCLUSIONS AND GENERAL SIGNIFICANCE: These results suggest that the magnetic field-exposure influenced both the ER and mitochondria, but the inhibition of Ca(2+) release from ER was not due to mitochondria inhibition. The effect of eddy currents induced in the culture medium may indirectly influence intracellular actin and suppress the transient increase in [Ca(2+)]i. PMID- 20832451 TI - Treatment with sildenafil prevents impairment of learning in rats born to pre eclamptic mothers. AB - Pre-eclampsia is an important hypertensive pregnancy disorder and a main cause of maternal and fetal morbidity and mortality. Children born from mothers with pre eclampsia may present cognitive deficits. The mechanisms leading to this cognitive impairment remain unclear and no treatments to improve it have been tested. Pre-eclampsia is associated with impaired regulation of the nitric oxide 3'-5'guanosine monophosphate cyclic (cGMP) pathway, which modulates some cognitive functions. We hypothesized that alterations in the NO-cGMP pathway would be involved in the mechanisms leading to cognitive impairment in rats born to pre-eclamptic mothers and that treatment with sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, could restore their cognitive function. To test these hypotheses, we used an animal model of pre-eclampsia in rats: pregnant rats treated with l-nitro-arginine methyl ester, an inhibitor of nitric oxide synthase. Using this model, we assessed: (1) whether rats born to pre-eclamptic mothers show reduced learning ability and/or altered motor activity or coordination when they are 2 months-old; (2) whether cognitive impairment is associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo; and (3) whether treatment of the mothers with sildenafil prevents this cognitive and motor alterations. The results reported show that the ability to learn a conditional discrimination task in a Y maze is reduced in rats born to pre-eclamptic mothers. This impairment was associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo, as assessed by microdialysis in freely moving rats. Treatment with sildenafil restores the function of this pathway and learning ability. PMID- 20832452 TI - Parkinsonian impairment correlates with spatially extensive subthalamic oscillatory synchronization. AB - The local strength of pathological synchronization in the region of the subthalamic nucleus (STN) is emerging as a possible factor in the motor impairment of Parkinson's Disease (PD). In particular, correlations have been repeatedly demonstrated between treatment-induced suppressions of local oscillatory activity in the beta frequency band and improvements in motor performance. However, a mechanistic role for beta activity is brought into question by the difficulty in showing a correlation between such activity at rest and the motor deficit in patients withdrawn from medication. Here we recorded local field potential (LFP) activity from 36 subthalamic regions in 18 patients undergoing functional neurosurgery for the treatment of PD. We recorded directly from the contacts of the deep brain stimulation (DBS) electrodes as they were introduced in successive 2 mm steps, and assessed phase coherence as a measure of spatially extended, rather than local, oscillatory synchronization. We found that phase coherence in the beta frequency band correlated with the severity of Parkinsonian bradykinesia and rigidity, both in the limbs and axial body. Such correlations were frequency and site specific in so far as they were reduced when the lowermost contact of the DBS electrode was above the dorsal STN. Correlations with limb tremor occurred at sub-beta band frequencies and were more lateralized than those between beta activity and limb bradykinesia and rigidity. Phase coherence could account for up to ~25% of the variance in motor scores between sides and patients. These new data suggest that the strength of spatially extended oscillatory synchronization, as well as the strength of local synchronization, may be worthwhile incorporating into modelling studies designed to inform surgical targeting, post-operative stimulation parameter selection and closed-loop stimulation regimes in PD. In addition, they strengthen the link between pathological synchronization and the different motor features of Parkinsonism. PMID- 20832453 TI - Subnuclear organization of parabrachial efferents to the thalamus, amygdala and lateral hypothalamus in C57BL/6J mice: a quantitative retrograde double labeling study. AB - The present study investigated the subnuclear organization of collateralized efferent projection patterns from the mouse parabrachial nucleus (PbN), the second taste relay in rodents, to higher gustatory centers, including the ventroposteromedial nucleus of the thalamus (VPMpc), central nucleus of the amygdala (CeA) and lateral hypothalamus (LH). We made injections of the retrograde tracer red and green latex microspheres into the VMPpc and CeA (VPMpc CeA group), VMPpc and LH (VPMpc-LH group) or CeA and LH (CeA-LH group, n=6 for each group). Injections into these areas preferentially resulted in retrograde labeling in the ipsilateral PbN in all groups. Cells projecting to the VPMpc, CeA, and LH were generally found in all subnuclei, but were differentially distributed. VPMpc-projecting cells predominated in gustatory-related subnuclei, CeA-projecting neurons predominated in the external lateral (el) subnucleus, and concentrated labeling was observed in the dorsal lateral subnucleus (dl) following LH injection. Double-labeled neurons were found for all groups, almost entirely ipsilaterally and primarily in the medial (m), waist area (wa), ventral lateral (vl) and el subnuclei. These results suggest that PbN neurons in different subdivisions have different projection and collateralization patterns to the VPMpc, CeA and LH. Functional implications of these projections are discussed with an emphasis on their roles in taste. PMID- 20832454 TI - Inhibition of central angiotensin II-induced pressor responses by hydrogen peroxide. AB - Hydrogen peroxide (H(2)O(2)), important reactive oxygen species produced endogenously, may have different physiological actions. The superoxide anion (O(2)(.-)) is suggested to be part of the signaling mechanisms activated by angiotensin II (ANG II) and central virus-mediated overexpression of the enzyme superoxide dismutase (that dismutates O(2)(.-) to H(2)O(2)) reduces pressor and dipsogenic responses to central ANG II. Whether this result might reflect elevation of H(2)O(2) rather than depletion of O(2)(.-) has not been addressed. Here we investigated the effects of H(2)O(2) injected intracerebroventricularly (i.c.v.) or ATZ (3-amino-1,2,4-triazole, a catalase inhibitor) injected intravenously (i.v.) or i.c.v. on the pressor responses induced by i.c.v. injections of ANG II. Normotensive male Holtzman rats (280-320 g, n=5-13/group) with stainless steel cannulas implanted in the lateral ventricle were used. Prior injection of H(2)O(2) (5 MUmol/1 MUl) or ATZ (5 nmol/1 MUl) i.c.v. almost abolished the pressor responses induced by ANG II (50 ng/1 MUl) also injected i.c.v. (7 +/- 3 and 5 +/- 3 mm Hg, respectively, vs. control: 19 +/- 4 mm Hg). Injection of ATZ (3.6 mmol/kg b.wt.) i.v. also reduced central ANG II-induced pressor responses. Injections of H(2)O(2) i.c.v. and ATZ i.c.v. or i.v. alone produced no effect on baseline arterial pressure. Central ANG II, H(2)O(2) or ATZ did not affect heart rate. The results show that central injections of H(2)O(2) and central or peripheral injections of ATZ reduced the pressor responses induced by i.c.v. ANG II, suggesting that exogenous or endogenous H(2)O(2) may inhibit central pressor mechanisms activated by ANG II. PMID- 20832455 TI - Hippocampal alpha7 nicotinic receptors modulate memory reconsolidation of an inhibitory avoidance task in mice. AB - CF-1 male mice were trained in an inhibitory avoidance (IA) task using either a mild or a high footshock (0.8 or 1.2 mA, 50 Hz, 1 s). A retention test was given 48 h later. Immediately after the retention test, mice were given intra-dorsal hippocampus infusions of either choline (Ch, an alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonist, 0.08-1.30 MUg/hippocampus), or methyllycaconitine (MLA, an alpha7nAChR antagonist, 1.0-30.0 MUg/hippocampus). Memory retention was tested again 24 h later. Methyllycaconitine impaired retention performance regardless of footshock intensity and its effects were long lasting. Ch impaired retention performance only in those mice trained with a high footshock. On the contrary, Ch enhanced retention performance when mice were trained with a mild footshock. These effects were long lasting and dose- and time-dependent. Retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects could not be attributable to non-specific effects of the drugs. Methyllycaconitine effects were dose-dependently reversed by choline, suggesting that MLA and Ch interact at the alpha7nAChR. Altogether, results suggest that hippocampal alpha7nAChRs play a critical role in reconsolidation of an IA response in mice, and may also have important implications for dynamic memory processes. This is the first presentation, to our knowledge, indicating that a specific receptor (alpha7nAChR) is able to modulate consolidated memories after retrieval. PMID- 20832456 TI - Carbonyl side-chain of catechol compounds is a key structure for the suppression of copper-associated oxidative DNA damage in vitro. AB - Catechol is possibly carcinogenic to humans (International Agency for Research on Cancer, IARC). The key mechanism could include its oxidative DNA-damaging effect in combination with reductive-oxidative metals like Cu. We found that DNA damage was suppressed by introducing an alpha-carbonyl group to catechol at C4-position to produce carbonyl catechols. During the oxidative DNA-damaging process, catechols but not carbonyl catechols were oxidized to o-quinone; however, coexisting Cu(II) was reduced to Cu(I). Carbonyl catechols were possibly arrested at the oxidation step of semiquinones in the presence of Cu(II). Cu(I)-binding to DNA was stronger than Cu(II)-binding, on the basis of the circular dichroism spectral change. None of the carbonyl catechols induced such change, suggesting sequestration of Cu(I) from DNA. Solid-phase extraction experiments and spectrophotometric analyses showed the formation of semiquinone chelates with Cu(I). Thus, chelate formation could explain the suppression mechanism of the Cu catechol-dependent DNA damage by terminating the reduction-oxidation cycle. Structural modifications such as introducing an alpha-carbonyl group to catechol at C4-position would contribute to reducing the risk and improving industrial and medical potentials of aromatic/phenolic compounds sustaining our daily lives. PMID- 20832457 TI - Challenging the requirement for chronic fish toxicity studies on formulated plant protection products. AB - Ecotoxicity testing of pesticide active ingredients and formulated plant protection products (PPPs) prior to their commercial use is required by authorities around the world. Such studies are important for the conduct of risk assessments to protect wildlife and the environment, but they should only be conducted when their use is scientifically justified. One test of questionable scientific merit is the chronic fish toxicity test when conducted with formulated PPPs, which is a potential requirement under European legislation: chronic exposure to the formulated product per se rarely occurs in the environment and therefore it is generally not possible to use the data from chronic formulation studies in a meaningful risk assessment. A recent survey of European crop protection companies to explore the scientific merits and regulatory drivers for chronic fish toxicity studies has shown that current practice in deciding on the need for chronic fish toxicity testing of formulated PPPs varies substantially between companies. The most commonly cited reason for conducting such studies was solely to meet regulatory requirements. We conclude that chronic formulation testing is rarely if ever scientifically justified, and recommend that the forthcoming revision of the EU Aquatic Toxicology Guidance Document takes account of this by including a requirement that justification must be provided for conducting the test, rather than the current situation where the onus is on the registrant to provide a justification for not conducting the test. PMID- 20832458 TI - Early increases in transglutaminase activity and polyamine levels in a Mallory Denk body mouse model. AB - Rodents treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) are a model of two hepatic toxic manifestations: porphyria and the appearance of hepatic cytoplasmic protein aggregates (Mallory-Denk Bodies, MDBs). MDBs are induced after long-term DDC feeding, consist primarily of keratins 8 and 18, and contain glutamine-lysine cross-links generated by transglutaminases (TGs). TGs are Ca(2+) dependent enzymes which catalyze the formation of covalent bonds between proteins and between proteins and polyamines. The aim of the current study was to investigate the time-course of TG hepatic activity in CF1 male mice either acutely or chronically treated with DDC and to correlate this activity with polyamine and porphyrin levels. On day 3 of the treatment, statistically significant increases in TG activity (75%), porphyrin content (6740%) and spermidine levels (73%) were observed. Although not statistically significant, at this time point putrescine levels showed an increase of 52%. The highest TG activity was observed on day 30 (522%), while porphyrin levels were still gradually increasing by day 45 (37,000%). From day 7 of the treatment and until the end of the experiment, putrescine levels remained increased (781%). Spermine levels were not affected by the treatment. The DDC-induced increases in putrescine and spermidine levels herein reported seem to be an early event contributing to the stimulation of liver TG activity, and thus to the promotion of cross-linking reactions between keratin proteins. This in turn would contribute to the formation of protein aggregates, which would lead to the appearance of MDBs. Due to the pro-oxidant and antioxidant properties of polyamines, it is possible to speculate that putrescine and spermidine may also participate at several levels in the oxidative stress processes associated with MDB formation. PMID- 20832459 TI - Use of the gammaH2AX assay for assessing the genotoxicity of polycyclic aromatic hydrocarbons in human cell lines. AB - The development of in vitro genotoxic assays as an alternative method to animal experimentation is of growing interest in the context of the implementation of new regulations on chemicals. However, extrapolation of toxicity data from in vitro systems to in vivo models is hampered by the fact that in vitro systems vary in their capability to metabolize chemicals, and that biotransformation can greatly influence the experimental results. Therefore, much attention has to be paid to the cellular models used and experimental conditions. Polycyclic aromatic hydrocarbons (PAHs) are carcinogenic ubiquitous pollutants. Human exposure to PAHs is mainly from food origin. In this study, a detailed analysis of the biotransformation capabilities of three human cell lines commonly used for in vitro testing (HepG2, ACHN and Caco-2) was undertaken using 3 model PAHs (benzo(a)pyrene [B(a)P], fluoranthene [FLA] and 3-methylcholanthrene [3-MC]). Concomitantly the genotoxicity of these PAHs was investigated in different cell lines, using a new genotoxic assay (H2AX) in 96-well plates. The metabolic rates of B(a)P, FLA and 3-MC were similar in HepG2 and Caco-2 cell lines, respectively, though with the production of different metabolites. The ACHN cell line was shown to express very limited metabolic capabilities. We demonstrated that the PAHs having a high metabolic rate (B(a)P and 3-MC) were genotoxic from 10(-7) molar in both HepG2 and Caco-2 cells. The present study shows that H2AX measurement in human cell lines competent for the metabolism, is an efficient and sensitive genotoxic assay requiring less cells and time than other currently available tests. PMID- 20832460 TI - UVA-induced cyototoxicity and DNA damaging potential of benz (e) acephenanthrylene. AB - The toxicity of benz (e) acephenanthrylene (BeA) has been studied earlier with regard to the carcinogenicity of its metabolites, but its phototogenotoxicity is not well understood. Present study aimed to analyze the photodynamic response of BeA in human skin cell line (A375) under ambient environmental intensity of UVA (1.40 mW/cm(2)). Kinetic of BeA showed that the highest intracellular uptake of BeA occurred after 24h of incubation. Cell viability, generation of reactive oxygen species (ROS), oxidative stress and DNA damage induced by BeA under UVA irradiation were assessed. BeA generates singlet oxygen ((1)O(2)), superoxide anion radical (O(2)(i-)) and hydroxyl radical (iOH) in a concentration-dependent manner. It was observed that glutathione reduced (GSH) and catalase activity were decreased while DNA damage and cell death were induced significantly (P>0.01) as concentration of BeA increased. Thus our results suggest that BeA may be phototoxic as well as photogenotoxic under UVA irradiation. PMID- 20832461 TI - The effect of bamboo extract on hepatic biotransforming enzymes--findings from an obese-diabetic mouse model. AB - AIM OF THE STUDY: Bamboo leaves are used as a component in traditional Chinese medicine for the anti-inflammatory function. Our previous studies have demonstrated that an ethanol/water extract from Phyllostachys edulis ameliorated obesity-associated chronic systemic inflammation in mice, and therefore relieving the symptoms of type 2 diabetes. The aim of this project was to further investigate the effects of this bamboo extract on hepatic biotransformation enzymes in both lean and obese mice, as an initial step in the toxicological evaluation of using this traditional medicine in obese/diabetic population. MATERIALS AND METHODS: Male C57BL/6J mice were randomized to 4 groups and fed standard (10% kcal from fat) diet with or without bamboo extract supplementation at a dose of 10 gram per kilogram diet (n=10 and n=9, respectively), or high fat (45% kcal from fat) diet with or without bamboo extract (n=8 and N=7, respectively). The dietary treatment lasted for 6 months. Subsequently, the activities and expression of the major Phase I and II hepatic biotransformation enzymes were assessed in subcellular fractions from murine livers. RESULTS: Three groups of mice, lean bamboo extract-supplemented, obese/diabetic, and bamboo extract-supplemented obese/diabetic, showed greater activities of cytochromes P450 1a2 and 3a11 compared to control but no changes in the expression level of these proteins. For Phase II enzymes, bamboo extract supplementation in lean mice caused decreased glutathione-S-transferase activity (-12%) and greater uridine diphosphate glucuronosyltransferase activity (+46%), but had no effect on sulfotransferase activity. Conversely, the obese/diabetic condition itself increased glutathione-S-transferase and uridine diphosphate glucuronosyltransferase activities, but decreased total sulfotransferase activity and sulfotransferase 2a1 expression. CONCLUSIONS: Bamboo extract and obesity/diabetes show significant independent effects on hepatic biotransformation as well as interaction effects in mice. These changes may alter the clearance of endo- and xenobiotics, including bamboo extract itself, hence this effect should be carefully considered in the medicinal application of bamboo extract as it has potential to alter its own metabolism and that of other medications concurrently administered to obese diabetic patients. PMID- 20832462 TI - Inhibitory effect of Sanguisorba officinalis ethanol extract on NO and PGE2 production is mediated by suppression of NF-kappaB and AP-1 activation signaling cascade. AB - AIM OF THE STUDY: Sanguisorba officinalis, a well known valuable medicinal plant in Korea, China and Japan used traditionally for the treatment of inflammatory and metabolic diseases such as diarrhea, chronic intestinal infections, duodenal ulcers, and bleeding. Recent studies have revealed that its aqueous or ethanolic extracts exhibit a variety of pharmacological activities such as anti-oxidative, anti-cancer, anti-lipid peroxidation, anti-atherogenic, and vasorelaxant effects. Systematic studies on the anti-inflammatory effect of this plant and its molecular mechanisms have not yet been fully investigated. Ethanol extract of Sanguisorba officinalis (So-EE) the lipopolysaccharide (LPS)-stimulated macrophages and production of inflammatory mediators were employed to assess these properties. RESULTS: So-EE significantly suppressed the production of nitric oxide (NO) and prostaglandin (PG) E(2) from LPS-activated RAW264.7 cells and peritoneal macrophages in a dose-dependent manner. This extract effectively diminished the mRNA levels of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2, implying that the blockade is generated at the transcriptional level. So EE strongly blocked the activation and translocation of NF-kappaB and AP-1 by suppressing the upstream kinases including inhibitor of kappaBalpha (IkappaBalpha), IkappaBalpha kinase (IKK), Akt (protein kinase B), phosphoinositide-dependent kinase 1 (PDK1), p85/phosphoinositide-3-kinase (PI3K), and mitogen activated protein kinase (MAPK) such as extracellular signal regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Moreover, So-EE suppressed the phosphorylation of Src, its kinase activity, and complex formation between Src and p85. CONCLUSION: This study suggests that So-EE has a potent anti inflammatory activity mediated by NF-kappaB, and AP-1 inhibitory properties linked to the suppression of Src and MAPK activation. PMID- 20832463 TI - Ethnopharmacological use of babassu (Orbignya phalerata Mart) in communities of babassu nut breakers in Maranhao, Brazil. AB - AIM OF THE STUDY: Products derived from the palm tree Orbignya phalerata Mart, a species popularly known in Brazil as babassu, are used for the treatment of different diseases such as rheumatism, ulcers and inflammatory processes. The objective of this study was to perform a sociodemographic survey among communities of babassu nut breakers in the region of Medio Mearim, Esperantinopolis, Maranhao, Brazil, and to evaluate the frequency and main forms of therapeutic use of babassu products and subproducts. MATERIALS AND METHODS: A semiquantitative method was used for the survey, with the application of semistructured interviews consisting of closed and semi-open questions. The data were analyzed using the SPSS 16.0 software for Windows (2007). RESULTS: The results showed that 82% of female nut breakers had a household income of less than US$ 280.00 and only 2% earned more than US$ 500.00. With respect to race and educational level, 61% of the interviewed women were mulattoes and 33% had a low educational level. The babassu-derived products most frequently used for medicinal purposes were the mesocarp, a residue called "borra", and oil. The mesocarp flour was used by 90% of nut breakers for the treatment of gastritis and inflammation and by 77% for leukorrhea. Babassu residue was mainly used for the treatment of wounds (60%) and the oil was used for woundhealing (16%) and leukorrhea (8%). CONCLUSIONS: In conclusion, the products derived from babassu are used for the treatment of gastritis, leukorrhea and wounds. In addition, most of the interviewed subjects apply these products topically. PMID- 20832464 TI - East African discourses on khat and sex. AB - AIM OF THE STUDY: The study aims to review and analyse the varied East African discourses on the effects of khat use on libido, fertility, transmission of HIV, prostitution and rape. MATERIALS AND METHODS: The data were gathered between 2004 and 2009 in Kenya and Uganda. Between 2004 and 2005 across Kenya and Uganda a broad survey approach was adopted, involving identification of and travel to production areas, interviews with producers and consumers in rural and urban settings. In addition, a survey of 300 Ugandan consumers was carried out in late 2004. Between 2007 and 2009, an in-depth study of khat production, trade and consumption was conducted in Uganda. This study also employed a mixture of methods, including key informant interviews participant-observation and a questionnaire survey administered to 210 khat consumers. RESULTS: Khat is associated, by consumers and its detractors alike, with changes in libido and sexual performance. Although there is no evidence to support their claims, detractors of khat use argue that khat causes sexual violence, causes women to enter sex work, and that chewing causes the spread of sexually transmitted diseases, including the HIV virus. CONCLUSIONS: In East Africa the discourse on khat and sex has led to consumption of the substances being associated by many people with uncontrolled sexual behaviour. There is no evidence that khat use fuels promiscuity, commercial sex, sexually transmitted diseases or rape. The current discourse on khat and sex touches on all these topics. Local religious and political leaders invoke khat use as a cause of what they argue is a breakdown of morals and social order. In Kenya and Uganda it is women khat consumers who are seen as sexually uncontrolled. In Uganda, the argument is extended even to men: with male khat chewers labelled as prone to commit rape. PMID- 20832465 TI - Redox imbalance influence in the myocardial Akt activation in aged rats treated with DHEA. AB - This study examined, in young and old (3 and 24 month-old, respectively) healthy Wistar rats, the in vivo effect of DHEA (10 mg/kg body weight) administered subcutaneously for 5 weeks. Reduced (GSH) and oxidized (GSSG) glutathione levels, glucose-6-phosphate dehydrogenase (G6PDH), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and thioredoxin (Trx) reductase activities, hydrogen peroxide steady-state concentration and Nrf2, GST, Trx-1, Akt and p-Akt expressions were assessed in heart tissue. DHEA treatment significantly increased GST activity in 3 and 24 month-old treated groups. The aging factor diminished hydrogen peroxide concentration and Nrf2 expression, independently of treatment. However, the aging process increased GST, Akt and p-Akt expressions in both 24 month-old groups. The aged group responded differently to DHEA respective to GSSG content, GPx activity and p-Akt concentration. Further studies are needed to form conclusions about the efficacy and safety of DHEA replacement in the elderly, and to better understand DHEA's net effect on oxidative stress parameters and its modulation of signaling cascades. PMID- 20832466 TI - The role of mitochondria in Drosophila aging. AB - Understanding how alterations in mitochondrial function in different cells and tissues impacts the aging process remains one of the greatest challenges facing biogerontologists. Here, we discuss the recent upsurge in research in this area using the fruit fly Drosophila melanogaster as a model system. Topics that are discussed include age-related changes in mitochondrial function, mitochondrial oxidative stress and lifespan, life extension mediated by moderate knock-down of genes important for mitochondrial electron transport chain (ETC) function, and the relationship between dietary restriction and ETC activity. Finally, we review recent approaches to supplement the endogenous fly ETC with a single-subunit mitochondrial respiratory enzyme from yeast. PMID- 20832467 TI - The immune recovery function of sleep - tracked by neutrophil counts. PMID- 20832469 TI - Pathogenic effects of a novel mutation (c.664_681del) in KCNQ4 channels associated with auditory pathology. AB - Hearing loss is a common communication disorder caused by various environmental and genetic factors. Hereditary hearing loss is very heterogeneous, and most of such cases involve sensorineural defects in the auditory pathway. There are currently 57 known autosomal dominant non-syndromic hearing loss (DFNA) loci, and the causative genes have been identified at 22 of these loci. In the present study, we performed a genome-wide linkage analysis in a Korean family segregating autosomal dominant hearing loss. We observed linkage on chromosome 1p34, and at this locus, we detected a novel mutation consisting of an 18 nucleotide deletion in exon 4 of the KCNQ4 gene, which encodes a voltage-gated potassium channel. We carried out a functional in vitro study to analyze the effects of this mutation (c.664_681del) along with two previously described KCNQ4 mutations, p.W276S and p.G285C. Although the c.664_681del mutation is located in the intercellular loop and the two previously described mutations, p.W276S and p.G285C, are located in the pore region, all mutants inhibit normal channel function by a dominant negative effect. Our analysis indicates that the intercellular loop is as significant as the pore region as a potential site of pathogenic effects on KCNQ4 channel function. PMID- 20832470 TI - Optimization of skin permeation and distribution of ibuprofen by using nanostructures (coagels) based on alkyl vitamin C derivatives. AB - In this investigation two vitamin C-based -6-O-ascorbic acid esters (ASC12 and ASC16), able to form liquid-crystal structures (coagels) was evaluated for their potential usefulness to promote the permeation and distribution of ibuprofen (IBU). Two coagel formulations and the same coagels added of polyethylene glycol (PEG-400) were assayed in comparison with a commercial product (Arfen(r)) by using hairless rat skin as model. The ASC16 and ASC12 derivatives gave rise to stable supramolecular assemblies in water and in water/PEG mixtures (coagels), allowing the solubilization of IBU (0.85%) and producing a IBU controlled release systems, as evidenced by the dynamic dialyse test: the n values were near 1.0, indicative of a linear kinetic, for all coagel formulations, except for the ASC12PEG/C formulation (n=1.51). Our results evidenced the enhancement activity of coagels and the synergic effect of the combination with PEG: all coagels showed a higher amount of IBU permeated through the skin compared to commercial Arfen(r) with an enhancement factor of 52.94 and 21.53 for ASC12PEG/C and ASC16/C respectively. Otherwise, coagels formulations appeared to produce a low IBU depot in the skin and in the same order of magnitude in epidermis and derma, in spite of significant increase of IBU cutaneous permeation. The positive synergic effect of the coagel-PEG mixtures was demonstrated by the high amount of IBU accumulated in the upper skin layers. The effect of the coagels on the IBU skin permeation and distribution depending on their hydro-lipophilic character could allow a rational design and an optimization of topical formulations. PMID- 20832468 TI - Epigenetics and psychoneuroimmunology: mechanisms and models. AB - In this Introduction to the Named Series "Epigenetics, Brain, Behavior, and Immunity" an overview of epigenetics is provided with a consideration of the nature of epigenetic regulation including DNA methylation, histone modification and chromatin re-modeling. Illustrative examples of recent scientific developments are highlighted to demonstrate the influence of epigenetics in areas of research relevant to those who investigate phenomena within the scientific discipline of psychoneuroimmunology. These examples are presented in order to provide a perspective on how epigenetic analysis will add insight into the molecular processes that connect the brain with behavior, neuroendocrine responsivity and immune outcome. PMID- 20832471 TI - Transformation of a series of saturated isomeric steroidal diols by Aspergillus tamarii KITA reveals a precise stereochemical requirement for entrance into the lactonization pathway. AB - Four isomers of 5alpha-androstan-3,17-diol have been transformed by the filamentous fungus Aspergillus tamarii, an organism which has the ability to convert progesterone to testololactone in high yield through an endogenous four step enzymatic pathway. The only diol handled within the lactonization pathway was 5alpha-androstan-3alpha,17beta-diol which, uniquely underwent oxidation of the 17beta-alcohol to the 17-ketone prior to its Baeyer-Villiger oxidation and the subsequent production of 3alpha-hydroxy-17a-oxa-D-homo-5alpha-androstan-17 one. This demonstrated highly specific stereochemical requirements of the 17beta hydroxysteroid dehydrogenase for oxidation of this specific steroidal diol to occur. In contrast, the other three diols were transformed within the hydroxylation pathway resulting in functionalization at C-11beta. Only 5alpha androstan-3beta,17alpha-diol could bind to the hydroxylase in multiple binding modes undergoing monohydroxylation in 6beta and 7beta positions. Evidence from this study has indicated that hydroxylation of saturated steroidal lactones may occur following binding of ring-D in its open form in which an alpha-alcohol is generated with close spatial parity to the C-17alpha hydroxyl position. All metabolites were isolated by column chromatography and were identified by (1)H, (13)C NMR and DEPT analysis and further characterized using infra-red, elemental analysis and accurate mass measurement. PMID- 20832472 TI - On the formation and nature of the imidazoline I2 binding site on human monoamine oxidase-B. AB - An allosteric binding site with high affinity for imidazoline I(2) ligands has been proposed to exist on monoamine oxidase-B (MAO-B). However, enzyme inhibition only occurs at ligand concentrations far higher than are required to saturate this site. We here confirm previous reports that inactivation of recombinant human MAO-B with tranylcypromine results in the formation of a high affinity I(2) site on the enzyme, measured as an increase in binding of [(3)H]2-BFI. Incubation of MAO-B with 2-phenylethylamine, an endogenous trace amine and MAO-B substrate, resulted in a progressive loss of enzyme activity, increased enzyme mass, distinct spectral changes and, as was observed with tranylcypromine, a parallel increase in high affinity binding of [(3)H]2-BFI. Kinetic studies of the mechanism by which 2-BFI inhibits MAO-B activity suggested binding of 2-BFI, at micromolar concentrations, to a site distinct from the active site on at least two forms of the pure enzyme, probably corresponding to oxidised and reduced enzyme states. Studies with mutant enzymes revealed a pattern of changes consistent with binding of 2-BFI to the substrate entrance channel of human MAO B. Structural data confirm that high affinity binding of I(2) ligands occurs within the entrance channel of inactive enzyme, while lower affinity binding at the same location in catalytically active enzyme results in mixed inhibition of MAO-B activity. High affinity I(2) sites may form in vivo due to inactivation of a portion of MAO-B during amine oxidation, while the low affinity I(2) site on active enzyme is a target for novel MAO-B inhibitor drugs. PMID- 20832473 TI - Slow down of actin depolymerization by cross-linking molecules. AB - The ability to control the assembly and disassembly dynamics of actin filaments is an essential property of the cellular cytoskeleton. While many different proteins are known which accelerate the polymerization of monomers into filaments or promote their disintegration, much less is known on mechanisms which guarantee the kinetic stability of the cytoskeletal filaments. Previous studies indicate that cross-linking molecules might fulfill these stabilizing tasks, which in addition facilitates their ability to regulate the organization of cytoskeletal structures in vivo. The effect of depolymerization factors on such structures or the mechanism which leads finally to their disintegration remain unknown. Here, we use multiple depolymerization methods in order to directly demonstrate that cross-linking and bundling proteins effectively suppress the actin depolymerization in a concentration dependent manner. Even the actin depolymerizing factor cofilin is not sufficient to facilitate a fast disintegration of highly cross-linked actin networks unless molecular motors are used simultaneously. The drastic modification of actin kinetics by cross-linking molecules can be expected to have wide-ranging implications for our understanding of the cytoskeleton, where cross-linking molecules are omnipresent and essential. PMID- 20832474 TI - Teleost intestinal immunology. AB - Teleosts clearly have a more diffuse gut associated lymphoid system, which is morphological and functional clearly different from the mammalian GALT. All immune cells necessary for a local immune response are abundantly present in the gut mucosa of the species studied and local immune responses can be monitored after intestinal immunization. Fish do not produce IgA, but a special mucosal IgM isotype seems to be secreted and may (partly) be the recently described IgZ/IgT. Fish produce a pIgR in their mucosal tissues but it is smaller (2 ILD) than the 4 5 ILD pIgR of higher vertebrates. Whether teleost pIgR is transcytosed and cleaved off in the same way needs further investigation, especially because a secretory component (SC) is only reported in one species. Teleosts also have high numbers of IEL, most of them are CD3-E+/CD8-alpha+ and have cytotoxic and/or regulatory function. Possibly many of these cells are TCRgammadelta cells and they may be involved in the oral tolerance induction observed in fish. Innate immune cells can be observed in the teleost gut from first feeding onwards, but B cells appear much later in mucosal compartments compared to systemic sites. Conspicuous is the very early presence of putative T cells or their precursors in the fish gut, which together with the rag-1 expression of intestinal lymphoid cells may be an indication for an extra-thymic development of certain T cells. Teleosts can develop enteritis in their antigen transporting second gut segment and epithelial cells, IEL and eosinophils/basophils seem to play a crucial role in this intestinal inflammation model. Teleost intestine can be exploited for oral vaccination strategies and probiotic immune stimulation. A variety of encapsulation methods, to protect vaccines against degradation in the foregut, are reported with promising results but in most cases they appear not to be cost effective yet. Microbiota in fish are clearly different from terrestrial animals. In the past decade a fast increasing number of papers is dedicated to the oral administration of a variety of probiotics that can have a strong health beneficial effect, but much more attention has to be paid to the immune mechanisms behind these effects. The recent development of gnotobiotic fish models may be very helpful to study the immune effects of microbiota and probiotics in teleosts. PMID- 20832475 TI - Hemolysin EthA in Edwardsiella tarda is essential for fish invasion in vivo and in vitro and regulated by two-component system EsrA-EsrB and nucleoid protein HhaEt. AB - Edwardsiella tarda is a Gram-negative pathogen for hemorrhagic septicemia in fish. Recently, two-component system (TCS) EsrA-EsrB in E. tarda has been found to play key roles in regulating type III secretion system (TTSS) and type VI secretion system (T6SS). In this study, a markedly attenuated DeltaesrB mutant was investigated to exhibit enhanced cell-invasion capability, as well as the increased cytotoxicity of its extracellular products (ECPs). Compared with the parental strain, the DeltaesrB mutant unexpectedly displayed the significantly increased hemolytic activity, and the restoration of hemolysin production was observed in the complemented strain esrB(+). A hemolysis-associated 147 kDa protein, EthA, was found to be up-regulated in the ECPs of DeltaesrB. The deletion of ethA gene in E. tarda wild type and DeltaesrB strains drastically decreased their capacities in internalization of epithelial papilloma of carp (EPC) cells. These results indicated that the increased production of EthA was responsible for the enhanced cell-invasion related capabilities in DeltaesrB. Furthermore, the expression of EthA in DeltaesrB exhibited a temperature-induced manner, and a nucleoid protein Hha(Et) was identified to mediate ethA expression by directly binding to its promoter. These results demonstrated that the virulence determinant EthA was fully required for invasion abilities of E. tarda and was subjected to the control of a complicated and precisely regulated network primed for its invasion, colonization and infection process in fish. PMID- 20832476 TI - Exploring the neural correlates of goal-directed action and intention understanding. AB - Because we are a cooperative species, understanding the goals and intentions of others is critical for human survival. In this fMRI study, participants viewed reaching behaviors in which one of four animated characters moved a hand towards one of two objects and either (a) picked up the object, (b) missed the object, or (c) changed his path halfway to lift the other object. The characters included a human, a humanoid robot, stacked boxes with an arm, and a mechanical claw. The first three moved in an identical, human-like biological pattern. Right posterior superior temporal sulcus (pSTS) activity increased when the human or humanoid robot shifted goals or missed the target relative to obtaining the original goal. This suggests that the pSTS was engaged differentially for figures that appeared more human-like rather than for all human-like motion. Medial frontal areas that are part of a protagonist-monitoring network with the right pSTS (e.g., Mason and Just, 2006) were most engaged for the human character, followed by the robot character. The current data suggest that goal-directed action and intention understanding require this network and it is used similarly for the two processes. Moreover, it is modulated by character identity rather than only the presence of biological motion. We discuss the implications for behavioral theories of goal-directed action and intention understanding. PMID- 20832477 TI - Large-scale EEG/MEG source localization with spatial flexibility. AB - We propose a novel approach to solving the electro-/magnetoencephalographic (EEG/MEG) inverse problem which is based upon a decomposition of the current density into a small number of spatial basis fields. It is designed to recover multiple sources of possibly different extent and depth, while being invariant with respect to phase angles and rotations of the coordinate system. We demonstrate the method's ability to reconstruct simulated sources of random shape and show that the accuracy of the recovered sources can be increased, when interrelated field patterns are co-localized. Technically, this leads to large scale mathematical problems, which are solved using recent advances in convex optimization. We apply our method for localizing brain areas involved in different types of motor imagery using real data from Brain-Computer Interface (BCI) sessions. Our approach based on single-trial localization of complex Fourier coefficients yields class-specific focal sources in the sensorimotor cortices. PMID- 20832478 TI - Dissociable contributions of prefrontal cortex and the hippocampus to short-term memory: evidence for a 3-state model of memory. AB - Behavioral research has yielded conflicting results regarding the architecture of short-term memory (STM). Whereas a consensus has emerged that within STM a single chunk within the focus of attention (FA) has a privileged status, it is unclear whether further distinctions exist. One proposal is that outside of FA, memory is all of one sort with a continuous progression from STM to long-term memory (LTM). On the other hand, sharp performance drop-offs when STM is loaded with more than 4+/-1 items suggest distinctions between STM and LTM. We use functional magnetic resonance imaging (fMRI) to adjudicate between these theories. A neural triple dissociation provided evidence for a 3-state model of memory. Critically, prefrontal cortex was selectively enhanced to retrieval from activated portions of LTM whereas the hippocampus was associated with retrieval of items within putative 4+/-1 capacity limits. We hypothesize that the associative properties of the hippocampus serve to inter-relate information actively maintained in STM which not only promotes strong STM, but also lays the foundations for subsequent LTM. By contrast, information not actively maintained in mind requires top-down retrieval processes mediated by the prefrontal cortex. These data provide key insights into the architecture of STM and its relationship to LTM. PMID- 20832479 TI - Early influence of prior experience on face perception. AB - Inferring someone's personality from his or her photograph is a pervasive and automatic behavior that takes place even if no reliable information about one's character can be derived solely from facial features. This illustrates nicely the idea that perception is not a passive process, but rather an active combination of current sensory inputs with endogenous knowledge derived from prior experience. To understand how and when neural responses to faces can be modulated by prior experience, we recorded magneto-encephalographic (MEG) responses to new faces, before and after subjects were exposed for a short period of 15-20 min to an experimentally induced association between a facial feature (inter-eye distance) and a response (personality judgment). In spite of the absence of any observable response bias following such a short reinforcement phase, our experimental manipulation influenced neural responses to faces as early as 60-85 ms. Source localization of magneto-encephalographic signals, confirmed by intracranial recordings, suggests that prior experience modulates early neural processing along two initially independent neural routes, one initiated in an anterior system that includes the orbitofrontal cortex and the temporal poles, and the second one involving face-sensitive regions in the ventral visual pathway. The two routes are both active as early as 60 ms but engage in reciprocal interactions only later, between 135 and 160 ms. These experimental findings support recent models assuming the existence of a fast anterior pathway activated in parallel with the ventral visual system which would link prior experience with current sensory inputs. PMID- 20832480 TI - Myelin water and T(2) relaxation measurements in the healthy cervical spinal cord at 3.0T: repeatability and changes with age. AB - Multiecho T(2) relaxation measurements offer specific information about myelin content through the myelin water fraction (MWF), as well as about the water environments through the intra- and extra-cellular (IE), and global, geometric mean T(2) (GMT(2)) times. While these measurements have yielded new insights into brain development and pathologies, they have yet to be thoroughly investigated in the spinal cord. The goals of this study were: (1) to apply a new 3D multiecho T(2) relaxation measurement in the cervical spine with sufficient axial resolution to distinguish grey and white matter; (2) to perform a pilot reliability assessment of the resulting MWF and GMT(2) measures in a target population; and (3) to detect differences in these measures between a younger cohort (20-30 years of age) and an older cohort (50-75 years of age) of healthy adults. The results demonstrated that the MWF in younger healthy adults follows the known pattern of lower myelin content in grey matter (mean (95% confidence interval)) (0.049 (0.030-0.067)) as compared to white matter (0.296 (0.275 0.317), p<0.001). The reliability coefficients were 0.65 and 0.82 for the MWF in the dorsal (DC) and lateral column (LC) white matter, respectively; 0.79 and 0.52 for the IE GMT(2); and 0.74 and 0.73 for the global GMT(2). Significantly lower MWF were found in the older adults than in the younger adults (DC p=0.014; LC p=0.012), as well as lower IE GMT(2) times (DC p=0.008; LC p=0.042), however, the global GMT(2) times did not show any differences. These changes in MWF and IE GMT(2) times, but not in global GMT(2) times, indicate that multiecho T(2) relaxation measures are sensitive to changes in myelin integrity and cell morphology that may not be apparent on conventional T(2) weighted images. PMID- 20832481 TI - Cortical processing of head- and eye-gaze cues guiding joint social attention. AB - Previous fMRI experiments showed an involvement of the STS in the processing of eye-gaze direction in joint attention. Since head-gaze direction can also be used for the assessment of another person's attentional focus, we compared the mechanisms underlying the processing of head- and eye-gaze direction using a combined psychophysical and fMRI approach. Subjects actively followed the head- or eye-gaze direction of a person in a photograph towards one of seven possible targets by moving their eyes. We showed that the right posterior superior temporal sulcus (STS) as well as the right fusiform gyrus (FSG) were involved in both processing of head- as well as eye-gaze direction. Another finding was a bilateral deactivation of a distinct area in the middle STS (mSTS) as well as the left anterior STS (aSTS), that was stronger when subjects followed eye-gaze direction than when they followed head-gaze direction. We assume that this deactivation is based on an active suppression of information arising from the distracting other directional cue, i.e. head-gaze direction in the eye-gaze direction task and eye-gaze direction in the head-gaze direction task. These results further support the hypothesis that the human equivalent of the gaze sensitive area in monkeys lies in more anterior parts of the STS than previously thought. PMID- 20832482 TI - Structural brain alterations in patients with major depressive disorder and high risk for suicide: evidence for a distinct neurobiological entity? AB - Major depressive disorder (MDD) is associated with a considerably increased risk for suicide. There is evidence to suggest that a predisposition to suicidal behavior may exist which is independent of the disorder itself. Furthermore, suicide attempters with mood disorders have an up to sixfold higher rate of suicidal behavior in first-degree relatives than non-suicidal patients. Genetic and nongenetic factors may play a role in the familial transmission of suicidal behavior. One of these factors may be neurobiological alterations, the knowledge about which is still limited. The main goal was therefore to study morphometric brain abnormalities in the hypothesized fronto-limbic network in depressed patients with high risk for suicide in contrast to non-high risk depressed patients. 15 patients with MDD and with own suicidal behavior and/or with suicidal behavior in first-degree relatives defined as a high risk group, 15 depressed patients with non-high risk for suicide and 30 matched healthy controls participated in the study. We applied the voxel-based morphometry protocol to structural T1-weighted volumes. Patients with high risk for suicide showed significantly decreased gray matter density in a fronto-striato-limbic network in contrast to matched healthy controls and in caudate and rostral anterior cingulate cortex in contrast to non-high risk patients. In the latter patient group no significant gray matter alterations were detected. This new finding provides evidence for structural brain alterations in depressed patients with high risk for suicide in a brain network strongly involved in emotional and motivational control reflecting a potentially distinct neurobiological entity. PMID- 20832483 TI - Process-specific prefrontal contributions to episodic encoding and retrieval of tastes: a functional NIRS study. AB - The neural basis of memory subprocesses, encoding and retrieval, have been extensively examined in functional neuroimaging studies. However, the cortical substrates of taste memory, which form an important part of our episodic memory, have rarely been explored in humans. Previously, we have used functional near infrared spectroscopy (fNIRS) and found activation of the lateral prefrontal cortex (LPFC) related to taste encoding. The method used in the current study allowed brain monitoring while participants tasted liquid taste-stimuli in upright positions. Here, using the same system, we examined the LPFC activity of 28 healthy volunteers during both the encoding and the retrieval of taste memory. The contrast between the retrieval and eyes-closed-resting conditions revealed activation in the bilateral LPFC. This activation was significantly larger than that for encoding in the bilateral frontopolar and right dorso-LPFC regions, particularly in the right hemisphere (N=28, P<0.05, FDR corrected), exhibiting right hemispheric dominance. Our findings are in line with the hemispheric encoding/retrieval asymmetry (HERA) model, which proposes a process-specific prefrontal contribution to memory function. PMID- 20832484 TI - Electrocortical activity is coupled to gait cycle phase during treadmill walking. AB - Recent findings suggest that human cortex is more active during steady-speed unperturbed locomotion than previously thought. However, techniques that have been used to image the brain during locomotion lack the temporal resolution necessary to assess intra-stride cortical dynamics. Our aim was to determine if electrocortical activity is coupled to gait cycle phase during steady-speed human walking. We used electroencephalography (EEG), motion capture, and a force measuring treadmill to record brain and body dynamics while eight healthy young adult subjects walked on a treadmill. Infomax independent component analysis (ICA) parsed EEG signals into maximally independent component (IC) processes representing electrocortical sources, muscle sources, and artifacts. We calculated a spatially fixed equivalent current dipole for each IC using an inverse modeling approach, and clustered electrocortical sources across subjects by similarities in dipole locations and power spectra. We then computed spectrograms for each electrocortical source that were time-locked to the gait cycle. Electrocortical sources in the anterior cingulate, posterior parietal, and sensorimotor cortex exhibited significant (p<0.05) intra-stride changes in spectral power. During the end of stance, as the leading foot was contacting the ground and the trailing foot was pushing off, alpha- and beta-band spectral power increased in or near the left/right sensorimotor and dorsal anterior cingulate cortex. Power increases in the left/right sensorimotor cortex were more pronounced for contralateral limb push-off (ipsilateral heel-strike) than for ipsilateral limb push-off (contralateral heel-strike). Intra-stride high-gamma spectral power changes were evident in anterior cingulate, posterior parietal, and sensorimotor cortex. These data confirm cortical involvement in steady-speed human locomotion. Future applications of these techniques could provide critical insight into the neural mechanisms of movement disorders and gait rehabilitation. PMID- 20832486 TI - The neural network sustaining the crossmodal processing of human gender from faces and voices: an fMRI study. AB - The aim of this fMRI study was to investigate the cerebral crossmodal interactions between human faces and voices during a gender categorization task. Twelve healthy male participants took part to the study. They were scanned in 4 runs that contained 3 conditions consisting in the presentation of faces, voices or congruent face-voice pairs. The task consisted in categorizing each trial (visual, auditory or associations) according to its gender (male or female). The subtraction between the bimodal condition and the sum of the unimodal ones showed that categorizing face/voice associations according to their gender produced unimodal activations of the visual (right calcarine sulcus) and auditory regions (bilateral superior temporal gyri), and specific supramodal activations of the left superior parietal gyrus and the right inferior frontal gyrus. Moreover, psychophysiological interaction analyses (PPI) revealed that both unimodal regions were inter-connected and connected to the prefrontal gyrus and the putamen, and that the left parietal gyrus had an enhanced connectivity with a parieto-premotor circuit involved in the crossmodal control of attention. This fMRI study showed that the crossmodal auditory-visual categorization of human gender is sustained by a network of cerebral regions highly similar to those observed in our previous studies examining the crossmodal interactions involved in face/voice recognition (Joassin et al., 2010). This suggests that the crossmodal processing of human stimuli requires the activation of a network of cortical regions, including both unimodal visual and auditory regions and supramodal parietal and frontal regions involved in the integration of both faces and voices and in the crossmodal attentional processes, and activated independently from the task to perform or the cognitive level of processing. PMID- 20832485 TI - Fractionating verbal episodic memory in Alzheimer's disease. AB - The aim of this study was to determine the neural correlates of different stages of episodic memory function and their modulation by Alzheimer's disease (AD). Several decades of work has supported the role of the medial temporal lobes (MTL) in episodic memory function. However, a more recent work, derived in part from functional neuroimaging studies, has suggested that other brain structures make up a large-scale network that appears to support successful encoding and retrieval of episodic memories. Furthermore, controversy exists as to whether dissociable MTL regions support qualitatively different aspects of memory (hippocampus: contextual memory or 'recollection'; perirhinal/lateral entorhinal cortex: item memory or 'familiarity'). There is limited neuropsychological support for these models and most work in AD only has examined free recall memory measures. We studied the relationship between performance on different stages of the Rey Auditory Verbal Learning Test (AVLT), a 15-item word list learning task, and structural MRI measures in mild AD patients. Structural measures included hippocampal volume and cortical thickness of several ROIs known to undergo atrophy in AD. Correlation and multiple regression analyses, controlling for age, education, and gender, were performed in 146 mild AD patients (MMSE 23.3+/-2.0). To evaluate the robustness of these relationships, similar analyses were performed with additional standardized verbal memory measures. Early immediate recall trials (e.g. Trial 1 of the AVLT) were not associated with the size of MTL regions, but correlated most strongly with inferior parietal, middle frontal gyrus, and temporal pole ROIs. After repeated exposure (e.g. Trial 5 of the AVLT), immediate recall was correlated with both MTL and a similar distribution of isocortical structures, but most strongly the temporal pole. For delayed recall, only the hippocampus correlated with performance. In contrast, for delayed recognition discrimination, the perirhinal/entorhinal cortex correlated more strongly than the hippocampus; no other isocortical regions were strongly associated with performance. Convergent results were found for immediate and delayed trials of other memory tests. The current results suggest that a richer understanding of the memory deficits in AD can be gained by examining multiple measures, which tap different aspects of memory function. Furthermore, the present findings are consistent with models hypothesizing different stages of verbal list learning map onto dissociable brain regions. These data have implications for understanding the anatomic basis of processes underlying episodic memory, particularly related to a division of labor within the medial temporal lobes and within the large-scale MTL-cortical memory network. PMID- 20832488 TI - In vivo functional near-infrared spectroscopy measures mood-modulated cerebral responses to a positive emotional stimulus in sheep. AB - The affective state of an animal, which is thought to reflect its welfare, consists of both short-term emotional reactions and long-term general mood. Because this state is generated and processed by the brain, we used non-invasive measurement of such brain activity as a novel indicator variable and investigated the interplay of mood and short-term emotional reactions in animals. We developed a wireless sensor for functional near-infrared spectroscopy (fNIRS), which assesses cortical perfusion changes, and consequently neuronal activity. Mood differences were induced by barren and enriched housing in a total of nine sheep and we observed their brain reaction in response to the positive situation of being groomed. We detected a decrease in cerebral oxyhaemoglobin concentration ([O(2)Hb]) which persisted during grooming. The localisation of the decrease in the brain did not depend on the site where the stimulus was applied. Also, the intensity of the response did not depend on the intensity of the grooming stimulus and a sham stimulus did not evoke an [O(2)Hb] response as seen with a grooming stimulus. Thus, we conclude that the observed haemodynamic brain response was unlikely to reflect pure somato-sensory information. We then found that the amplitude of the [O(2)Hb] response was larger if sheep were in a supposedly more negative mood. This contradicts the common assumption that negative mood generally taints reactions to emotional stimuli. Our results also demonstrate the potential of fNIRS for assessing affective states in freely moving animals. PMID- 20832487 TI - Time-to-event voxel-based techniques to assess regional atrophy associated with MCI risk of progression to AD. AB - OBJECTIVE: When using imaging to predict time to progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), time-to-event statistical methods account for varying lengths of follow-up times among subjects whereas two-sample t-tests in voxel-based morphometry (VBM) do not. Our objectives were to apply a time-to-event voxel-based analytic method to identify regions on MRI where atrophy is associated with significantly increased risk of future progression to AD in subjects with MCI and to compare it to traditional voxel-level patterns obtained by applying two-sample methods. We also compared the power required to detect an association using time-to-event methods versus two-sample approaches. METHODS: Subjects with MCI at baseline were followed prospectively. The event of interest was clinical diagnosis of AD. Cox proportional hazards models adjusted for age, sex, and education were used to estimate the relative hazard of progression from MCI to AD based on rank-transformed voxel-level gray matter density (GMD) estimates. RESULTS: The greatest risk of progression to AD was associated with atrophy of the medial temporal lobes. Patients ranked at the 25th percentile of GMD in these regions had more than a doubling of risk of progression to AD at a given time point compared to patients at the 75th percentile. Power calculations showed the time-to-event approach to be more efficient than the traditional two-sample approach. CONCLUSIONS: We present a new voxel-based analytic method that incorporates time-to-event statistical methods. In the context of a progressive disease like AD, time-to-event VBM seems more appropriate and powerful than traditional two-sample methods. PMID- 20832489 TI - A novel approach to the human connectome: ultra-high resolution mapping of fiber tracts in the brain. AB - Signal transmission between different brain regions requires connecting fiber tracts, the structural basis of the human connectome. In contrast to animal brains, where a multitude of tract tracing methods can be used, magnetic resonance (MR)-based diffusion imaging is presently the only promising approach to study fiber tracts between specific human brain regions. However, this procedure has various inherent restrictions caused by its relatively low spatial resolution. Here, we introduce 3D-polarized light imaging (3D-PLI) to map the three-dimensional course of fiber tracts in the human brain with a resolution at a submillimeter scale based on a voxel size of 100 MUm isotropic or less. 3D-PLI demonstrates nerve fibers by utilizing their intrinsic birefringence of myelin sheaths surrounding axons. This optical method enables the demonstration of 3D fiber orientations in serial microtome sections of entire human brains. Examples for the feasibility of this novel approach are given here. 3D-PLI enables the study of brain regions of intense fiber crossing in unprecedented detail, and provides an independent evaluation of fiber tracts derived from diffusion imaging data. PMID- 20832491 TI - Efficacy of a single dose hepatitis B depot vaccine. AB - A single dose formulation of a novel hepatitis B vaccine, consisting of an adjuvant emulsion of liposomes in oil was produced at a manufacturing scale and delivered to rabbits. This single dose vaccine generated a significantly higher antibody response than two doses of an alum-adjuvanted control vaccine in the short term, and was as effective as three doses of the control vaccine in the long term. PMID- 20832490 TI - Social vision: sustained perceptual enhancement of affective facial cues in social anxiety. AB - Heightened perception of facial cues is at the core of many theories of social behavior and its disorders. In the present study, we continuously measured electrocortical dynamics in human visual cortex, as evoked by happy, neutral, fearful, and angry faces. Thirty-seven participants endorsing high versus low generalized social anxiety (upper and lower tertiles of 2104 screened undergraduates) viewed naturalistic faces flickering at 17.5 Hz to evoke steady state visual evoked potentials (ssVEPs), recorded from 129 scalp electrodes. Electrophysiological data were evaluated in the time-frequency domain after linear source space projection using the minimum norm method. Source estimation indicated an early visual cortical origin of the face-evoked ssVEP, which showed sustained amplitude enhancement for emotional expressions specifically in individuals with pervasive social anxiety. Participants in the low symptom group showed no such sensitivity, and a correlational analysis across the entire sample revealed a strong relationship between self-reported interpersonal anxiety/avoidance and enhanced visual cortical response amplitude for emotional, versus neutral expressions. This pattern was maintained across the 3500 ms viewing epoch, suggesting that temporally sustained, heightened perceptual bias towards affective facial cues is associated with generalized social anxiety. PMID- 20832492 TI - Differential effect of CD4+Foxp3+ T-regulatory cells on the B and T helper cell responses to influenza virus vaccination. AB - The T-regulatory (T-reg) cells restrict the T-cell functions in various viral infections including influenza infection. However little is known about the effect of T-regs in influenza vaccination. Herein, we found that immunization of BALB/c mice with a prototype of UV-inactivated influenza PR8/A/34 virus vaccine expanded the CD4(+)Foxp3(+) T-reg pool and fostered the development of virus specific CD4(+)Foxp3(+) T-reg cells. Increasing the size of Foxp3(+) T-reg pool did not alter the primary PR8-specific B-cell response, but it did suppress the primary and memory PR8-specific T helper responses induced by vaccination. In contrast, the vaccination-induced T helper cell response was augmented in the absence of CD4(+)Foxp3(+) T-reg cells. Since CD4 T helper cells contribute to anti-influenza protection, therapeutic "quenching" of T-reg function prior to vaccination may enhance the efficacy of influenza vaccination. PMID- 20832493 TI - Construction of Neospora caninum stably expressing TgSAG1 and evaluation of its protective effects against Toxoplasma gondii infection in mice. AB - Toxoplasma gondii and Neospora caninum are closely related apicomplexan parasites. The surface antigen 1 of T. gondii (TgSAG1) is a major immunodominant antigen and, therefore, is considered to be a good candidate for the development of an effective recombinant vaccine against toxoplasmosis. In this study, N. caninum stably expressing the TgSAG1 gene (Nc/TgSAG1) was constructed using pyrimethamine-resistant DHFR-TS and GFP genes as double-selection markers. The expression level, molecular weight, and antigenic property of recombinant TgSAG1 expressed by the Nc/TgSAG1 were similar to those of the native TgSAG1. The mice immunized with Nc/TgSAG1 induced TgSAG1-specific Th1-dominant immune responses and protected the mice from a lethal challenge infection with T. gondii. These results indicate that N. caninum may provide a new tool for the production of a live recombinant vector vaccine against toxoplasmosis in animals. To our knowledge, this is the first report to evaluate the usefulness of N. caninum based live vaccine. PMID- 20832494 TI - Effect of influenza vaccination on hospitalizations in persons aged 50 years and older. AB - OBJECTIVE: To estimate influenza vaccine effectiveness (VE) in preventing hospitalizations in persons over 50 years of age. DESIGN: We performed a retrospective, population based study, using a "difference-in-differences" approach to determine the association between hospitalization and prior vaccination. We examined this association when influenza was not circulating and compared it to the association found when influenza was circulating. VE was estimated from the difference in the association between hospitalization and prior vaccination, inside vs. outside influenza seasons. SETTING: Kaiser Permanente in Northern California. PATIENTS: Health plan members aged 50 years and older during the September 1997 to August 2008 study period, when there were about 68,000 pneumonia hospitalizations in 10 million person-years. RESULTS: Vaccination was associated with lower risk of hospitalization for pneumonia and influenza, even before flu season, presumably due to unmeasured confounders. When influenza arrived the hospitalization-vaccination association strengthened, yielding an adjusted VE estimate of 12.4% (95% CI: 1.6-22.0) in persons aged 50 64, and 8.5% (95% CI: 3.3-13.5) in those aged 65 years and older. There was no significant effect on hospitalizations for ischemic heart disease (IHD), congestive heart failure (CHF), cerebrovascular disease (CVD), or trauma. CONCLUSIONS: Influenza vaccination has a modest but significant effect on prevention of hospitalization for pneumonia and influenza in persons 50 years of age and older. PMID- 20832495 TI - Adverse reaction of influenza A (H1N1) 2009 virus vaccination in pregnant women and its effect on newborns. AB - Pregnant women are reluctant to be vaccinated during their pregnancy. Their main concern is the safety of influenza vaccine. We investigated the adverse reactions of pregnant women who received the influenza A (H1N1) 2009 virus vaccination and also conditions of neonates of the vaccinated women. Various adverse reactions developed after vaccination, but the symptoms were mild and resolved within several days without requiring any treatment or hospitalization. PMID- 20832496 TI - Detection of recent hybridization between sympatric Chilean Puya species (Bromeliaceae) using AFLP markers and reconstruction of complex relationships. AB - The Chilean Puya species constitute a monophyletic group, co-occurring in different species combinations within the country and displaying a remarkable morphological variability. Here, we studied the importance of recent hybridization and introgression in the group and reconstructed the complex inter- and intraspecific relationships. Amplified fragment length polymorphism (AFLP) analysis, including 109 accessions of all Chilean Puya species and four putative hybrids, yielded 984 characters. Three main genetic groups were revealed, with the chilensis group (P. chilensis, P. gilmartiniae, P. boliviensis) diverging first, and the alpestris (P. alpestris, P. berteroniana) and coerulea group (P. venusta, P. coerulea) forming sister groups. STRUCTURE analyses confirmed a hybrid origin of morphologically intermediate individuals, and detected several additional hybrids. Hybrids were found between the chilensis and alpestris group, and between the alpestris and coerulea group. Exclusion of hybrids improved phylogenetic reconstructions. The study demonstrates that the detection of hybrids within Bromeliaceae can be difficult based on morphological characters alone and that efficient reproductive barriers may only slowly establish, leading to hybridization between closely related sympatric species. The importance of hybridization for the rapid diversification of Puya is discussed. PMID- 20832497 TI - Amygdala conditioning modulates sensory input to the cerebellum. AB - Localization of emotional learning in the amygdala and discrete motor learning in the cerebellum provides empirical means to study the mechanisms mediating the interaction between fast emotional and slow motor learning. Behavioral studies have demonstrated that fear conditioning facilitates the motor conditioning. The present study tests the hypothesis that the amygdala output induces this facilitation by increasing the salience of the conditioned stimulus (CS) representation in the pontine nucleus (PN) input to the cerebellum. Paired trials of CS-US (unconditioned stimulus) were applied to anesthetized rats, a condition that allows for amygdala-based fear conditioning but not cerebellar-based motor conditioning. Multiple unit recordings in the PN served to assess the salience of the CS. Results showed that CS-US conditioning increased the PN-reactivity to the CS. Lidocaine-induced reversible inactivation of the amygdala prevented the facilitatory effect of conditioning on the PN-reactivity to the CS. These findings suggest that the amygdala-based conditioned responses reach the PN and increase the salience of the CS signal there, perhaps facilitating cerebellar conditioning. This facilitatory effect of the amygdala may be conceptualized under the 'two-stage theory of learning', which predicts that emotional learning in the first stage accelerates the motor learning in the second stage. We hereby demonstrate the physiological mechanism through which fast emotional learning in the first stage facilitates slow cerebellar learning in the second stage. PMID- 20832499 TI - Virus-host protein interactions in RNA viruses. AB - RNA viruses exhibit small-sized genomes that only encode a limited number of viral proteins, but still establish complex networks of interactions with host cell components. Here we summarize recent reports that aim at understanding general features of RNA virus infection networks at the protein level. PMID- 20832498 TI - Nrg1/ErbB signaling networks in Schwann cell development and myelination. AB - Neuregulin-1 (Nrg1) provides a key axonal signal that regulates Schwann cell proliferation, migration and myelination through binding to ErbB2/3 receptors. The analysis of a number of genetic models has unmasked fundamental mechanisms underlying the specificity of the Nrg1/ErbB signaling axis. Differential expression of Nrg1 isoforms, Nrg1 processing, and ErbB receptor localization and trafficking represent important regulatory themes in the control of Nrg1/ErbB function. Nrg1 binding to ErbB2/3 receptors results in the activation of intracellular signal transduction pathways that initiate changes in Schwann cell behavior. Here, we review data that has defined the role of key Nrg1/ErbB signaling components like Shp2, ERK1/2, FAK, Rac1/Cdc42 and calcineurin in development of the Schwann cell lineage in vivo. Many of these regulators receive converging signals from other cues that are provided by Notch, integrin or G protein coupled receptors. Signaling by multiple extracellular factors may act as key modifiers and allow Schwann cells at different developmental stages to respond in distinct manners to the Nrg1/ErbB signal. PMID- 20832500 TI - The immunoregulatory properties of oncolytic myxoma virus and their implications in therapeutics. AB - Myxoma virus (MYXV) is a poxvirus with a strict rabbit-specific host-tropism for pathogenesis. The immunoregulatory factors encoded by MYXV can suppress some functions of immune effectors from other species. We review their mechanisms of action, implications in therapeutics and the potential to improve MYXV as an oncolytic agent in humans. PMID- 20832501 TI - Fighting mycobacterial infections by antibiotics, phytochemicals and vaccines. AB - Buruli ulcer is a neglected disease caused by Mycobacterium ulcerans and represents the world's third most common mycobacterial infection. It produces the polyketide toxins, mycolactones A, B, C and D, which induce apoptosis and necrosis. Clinical symptoms are subcutaneous nodules, papules, plaques and ulcerating oedemae, which can enlarge and destroy nerves and blood vessels and even invade bones by lymphatic or haematogenous spread (osteomyelitis). Patients usually do not suffer from pain or systematic inflammation. Surgery is the treatment of choice, although recurrence is common and wide surgical excisions including healthy tissues result in significant morbidity. Antibiotic therapy with rifamycins, aminoglycosides, macrolides and quinolones also improves cure rates. Still less exploited treatment options are phytochemicals from medicinal plants used in affected countries. Vaccination against Buruli ulcer is still in its infancy. PMID- 20832502 TI - A scoring system to predict readmission of patients with acute pancreatitis to the hospital within thirty days of discharge. AB - BACKGROUND & AIMS: Reducing rapid readmission of patients after discharge could improve quality of treatment and reduce costs. Little is known about clinical predictors of early readmission for acute pancreatitis (AP). We developed a strategy to identify and stratify patients with AP at risk for readmission within 30 days of discharge. METHODS: We derived and validated a model in a cohort of patients hospitalized with AP from June 2005-October 2009. Early readmission was defined as admission to the hospital or reevaluation in the emergency department within 30 days of discharge. The cohort was divided into a derivation cohort (admitted June 2005-December 2007, n = 248) and a validation cohort (admitted January 2008-October 2009, n = 198). A weighted scoring system was developed using logistic regression for the prediction of early readmission. Accuracy was assessed by area under the receiver-operator characteristic (ROC) curve analysis. RESULTS: Of the total patients, 21% (92/446) had early readmission. Multivariable analysis identified the following discharge characteristics as independent risk factors for early readmission: gastrointestinal symptoms, eating less than a solid diet, pancreatic necrosis, treatment with antibiotics, and pain (P < .05). Weighted risk scores stratified patients into groups of low, moderate, and high risk for early readmission: 4%, 15%, and 87%, respectively, in the derivation cohort and 5%, 18%, and 68%, respectively, in the validation cohort. Area under the ROC curve demonstrated an accurate prediction (c-statistic = 0.83). CONCLUSIONS: We created a scoring system that accurately predicts which patients with AP have high and low risk of readmission within 30 days of discharge. PMID- 20832503 TI - Adjusted significance levels for subgroup analyses in clinical trials. AB - Subgroup analyses in clinical trials are becoming increasingly important. In cancer research more and more targeted therapies are explored and probably only a portion of the whole population will benefit from them. Subgroups of interest can be analyzed in several ways, but a correction of the type I error probability is needed in order to appropriately draw conclusions. Often a conservative Bonferroni approach is taken where the total significance level is distributed (equally or unequally) over the analysis including all patients (overall analysis) and the subgroup analysis. However, more efficient methods are available that take into account the correlation that exists between the test statistics for the overall and the subgroup analysis. The latter approaches are very appealing but have not found their way into practice. The aim of this paper is to show that these methods are the same as the methods used when dealing with interim analyses, i.e., group sequential methods, and hence standard software can be used to calculate the appropriate significance levels. Further, we show that this correction can be applied even when the size of the subgroup is unknown until the end of the trial. Using a simulation study with survival data, we also show that the familywise error rate is well controlled, even with small sample sizes. We hope that this will promote the use of these methods in future cancer clinical trials. PMID- 20832504 TI - Application of AFM and optical biosensor for investigation of complexes formed in P450-containing monooxygenase systems. AB - Atomic force microscopy (AFM) allows to visualize and count the individual protein molecules and their complexes within multiprotein systems. On the other hand, optical biosensor (OB) provides information on complex formation kinetics as well as complex lifetime (tau(LT)) and affinity. Comparison of complex lifetime tau(LT) with the time required for enzyme's catalytic cycle (tau(cat)) enables to characterize productive complexes and distinguish them from non productive ones. Both these approaches were applied for the analysis of the three cytochrome P450-containing monooxygenase systems: cytochrome P450 101, cytochrome P450 11A1 and cytochrome P450 2B4. By using AFM, the formation of binary and ternary protein complexes was registered in all the three systems. OB analysis enabled to kinetically characterize these binary and ternary complexes. It was shown that the binary complexes putidaredoxin reductase (PdR)/putidaredoxin (Pd) and Pd/cytochrome P450 101 (P450 101) formed within the P450 101 system and, also, the binary complexes adrenodoxin reductase (AdR)/adrenodoxin (Ad) and Ad/cytochrome P450 11A1 (P450 11A1) formed within the P450 11A1 system are non productive (deadlock). At the same time, the ternary PdR/Pd/P450 101 and AdR/Ad/P450 11A1 complexes proved to be productive. The binary cytochrome P450 reductase (Fp)/cytochrome P450 2B4 (2B4) complexes and the ternary Fp/2B4/cytochrome b5 (b5) complexes formed within P450 2B4 system were productive. PMID- 20832505 TI - Electrochemical deposition of conducting polymer coatings on magnesium surfaces in ionic liquid. AB - A conducting polymer-based smart coating for magnesium (Mg) implants that can both improve the corrosion resistance of Mg and release a drug in a controllable way is reported. As the ionic liquid is a highly conductive and stable solvent with a very wide electrochemical window, the conducting polymer coatings can be directly electrodeposited on the active metal Mg in ionic liquid under mild conditions, and Mg is highly stable during the electrodeposition. The electrodeposited poly(3,4-ethylenedioxythiophene) (PEDOT) coatings on Mg are uniform and can significantly improve the corrosion resistance of Mg. In addition, the PEDOT coatings can load the anti-inflammatory drug dexamethasone during the electrodeposition, which can be subsequently released upon electric stimulation. PMID- 20832506 TI - Polymeric endoaortic paving: Mechanical, thermoforming, and degradation properties of polycaprolactone/polyurethane blends for cardiovascular applications. AB - Polymeric endoaortic paving (PEAP) is a process by which a polymer is endovascularly delivered and thermoformed to coat or "pave" the lumen of the aorta. This method may offer an improvement to conventional endoaortic therapy in allowing conformal graft application with reduced risk of endoleak and customization to complex patient geometries. Polycaprolactone (PCL)/polyurethane (PU) blends of various blend ratios were assessed as a potential material for PEAP by characterizing their mechanical, thermoforming and degradation properties. Biaxial tension testing revealed that the blends' stiffness is similar to that of aortic tissue, is higher for blends with more PCL content, and may be affected by thermoforming and degradation. Tubes of blends were able to maintain a higher diameter increase after thermoforming at higher PCL content and higher heating temperatures; 50/50 blend tubes heated to 55 degrees C were able to maintain 90% of the diameter increase applied. Delamination forces of the blends ranged from 41 to 235 N m-2. In a Pseudomonas lipase solution, the 50/50 blend had a 94% lower degradation rate than pure PCL, and the 10/90 blend exhibited no degradation. These results indicate that PEAP, consisting of a PCL/PU blend, may be useful in developing the next generation of endoaortic therapy. PMID- 20832507 TI - Polymer chain scission, oligomer production and diffusion: a two-scale model for degradation of bioresorbable polyesters. AB - This paper presents a computer model for the biodegradation of polyesters such as poly(lactic acid), poly(glycolic acid) and their copolymers. The model can take polymer details such as molecular weight distribution, different end and random scission rates and copolymer ratio as input data. A multi-scale approach is developed: polymer chain scission and oligomer production which occur at the molecular scale are modelled using a kinetic Monte Carlo scheme, oligomer diffusion which occurs at the device scale is modelled using a diffusion equation, and the two are connected at the finite difference nodes of the diffusion equation. The two-scale model can be used to predict the temporal evolution and spatial distribution of molecular weight distribution in a device as well as the weight loss as a function of time. It is shown that the kinetic Monte Carlo scheme can accurately predict the effect of copolymer ratio on the degradation rate. Grizzi and co-workers observed in their experiments that a PLA film 0.3mm thick degrades much more slowly than one that is 2mm thick. The numerical study shows that the conceptional reaction diffusion model suggested by Grizzi et al. needs to be extended in order to explain the size effect fully. PMID- 20832508 TI - Methyl-beta-cyclodextrin modified vascular prosthesis: Influence of the modification level on the drug delivery properties in different media. AB - A textile polyester vascular graft was modified with methyl-beta-cyclodextrin (MebetaCD) to obtain a new implant capable of releasing antibiotics directly in situ at the site of operation over a prolonged period and thereby prevent post operative infections. We investigated the influence of the curing parameters (time and temperature) that allow control of the degree of functionalization (DF) of the support by MebetaCD. The inclusion of ciprofloxacin (CFX) in the MebetaCD cavity was observed in solution by two-dimensional (1)H NMR spectroscopy. The amount of CFX loaded on the modified graft increased with DF. Depending on the release medium (water, phosphate-buffered saline, or human plasma) and the DF of the prostheses, different kinetic profiles of release of CFX were obtained. The sustained release of CFX in human plasma was shown by microbiological assays that indicated prolonged antimicrobial activity against Staphylococcus aureus and Escherichia coli. Viability tests demonstrated the non-toxicity of MebetaCD to an epithelial cell line (HPMEC), although a decrease in endothelial cell number was observed on the functionalized prosthesis, probably due to the roughness of the coating and also to the nature of the MebetaCD polymer present on the surface of the fibers. PMID- 20832509 TI - 1.3 Mb de novo deletion in chromosome band 3q29 associated with normal intelligence in a child. AB - We report on a 6 and 9/12 year-old male patient with a de novo chromosome 3q29 microdeletion identified by BAC array comparative genomic hybridization assay (aCGH), with accompanying normal 46,XY high-resolution chromosome analysis. The patient has language-based learning disabilities and behavioral features consistent with diagnoses of autism and attention deficit hyperactivity disorder (ADHD) of the inattentive type. He also displays some other features previously associated with chromosome 3q29 microdeletion such as an elongated face, long fingers, and joint laxity. Most notably our patient, per formal IQ testing, was not found to have frank mental retardation as has been previously reported among patients with chromosome 3q29 terminal deletion, but rather our patient has demonstrated an average full-scale IQ result. Our report further expands the phenotypic spectrum of the rare chromosome 3q29 microdeletion syndrome to include the possibility of normal intelligence as corroborated by formal, longitudinal psycho-educational testing. PMID- 20832510 TI - Model organism proteomics. PMID- 20832511 TI - TNF-alpha stimulates alkaline phosphatase and mineralization through PPARgamma inhibition in human osteoblasts. AB - The aims of the present study were to determine whether prostaglandins (PGs) and PPARgamma are involved in the stimulation of tissue-non-specific alkaline phosphatase (TNAP) activity and mineralization by TNF-alpha in human osteoblasts. We used osteoblasts differentiated from MSCs from three different donors and MG 63 osteoblast-like cells. Inhibition of prostaglandin synthesis with the cyclooxygenase (COX) inhibitor indomethacin or the specific COX-2 blocker NS-398 abolished mineralization in the absence and presence of 1 ng/ml of TNF-alpha, suggesting that PGs were involved. The TNAP inhibitor levamisole abolished TNF alpha effects on mineralization, suggesting that PGs were involved in TNAP expression and mineralization. TNF-alpha stimulated expression of COX-2 and PG E synthase before that of TNAP, but expression of PG D synthase later suggesting that PGE2 and PGF2alpha but not 15d-PGJ2 were involved in TNF-alpha effects. However, both PGE2 and PGF2alpha dose-dependently inhibited mineralization indicating that endogenous PG are required for mineralization but that TNF-alpha does not increase mineralization by increasing PG synthesis. Interestingly, TNF alpha inhibited PPARgamma expression and binding activity to PPRE consensus sequences independently of 15d-PGJ2. Inhibition of PPARgamma activity with GW 9662 mimicked TNF-alpha effects in MG-63 cells, indicating that TNF-alpha stimulates mineralization by inhibiting PPARgamma in osteoblasts. In MSC-derived osteoblast cultures, inhibition of PPARgamma dropped TNAP expression and mineralization. Treatment of MG-63 cells with conditioned media from MSC-derived osteoblasts or MSC-derived adipocytes treated or not with GW-9662 revealed that TNF-alpha inhibition of PPARgamma in undifferentiated MSCs and/or adipocytes was responsible for the decreased expression of TNAP in osteoblasts. In conclusion, TNF-alpha increases TNAP expression and stimulates mineralization by inhibiting PPARgamma in osteoblasts, but PPARgamma in adipocytes or undifferentiated MSCs controls the secretion of a factor leading to TNAP stimulation in osteoblasts. PMID- 20832512 TI - Bisphosphonates in Paget's disease. AB - Paget's disease is the best example of a common high turnover bone disease. A review of the early use of bisphosphonates in the treatment of this condition shows that many of the fundamental therapeutic issues were identified using drugs which by today's standards were far from ideal. Over the succeeding decades there has been a steady increase in potency culminating in the introduction of intravenous zoledronic acid which is capable of inducing long term remissions which were unthinkable when bisphosphonates were first introduced. PMID- 20832513 TI - Potential renal acid load may more strongly affect bone size and mass than volumetric bone mineral density. PMID- 20832514 TI - The Fracture and Immobilization Score (FRISC) for risk assessment of osteoporotic fracture and immobilization in postmenopausal women--A joint analysis of the Nagano, Miyama, and Taiji Cohorts. AB - INTRODUCTION: We aimed to (i) explore risk factors for major osteoporotic fracture or immobilization; (ii) develop a prediction model that can be used to assess the risk of fracture and immobilization; and (iii) assess external validity of the final model. METHODS: A total of 1787 postmenopausal Japanese women were followed in a hospital-based cohort study. Endpoints included the annual incidence of major osteoporotic fracture and immobilization. For each endpoint, multivariate Poisson regression models were fitted separately and risk factors were screened through backward variable selection. The predictive accuracy of the final model (FRISC) was evaluated in two independent community based cohorts. RESULTS: Over a median follow-up of 5.3 years, a total of 383 major osteoporotic fractures (279 clinical vertebral, 44 hip, 60 distal forearm) and 83 immobilizations occurred in the developmental dataset. Backward variable selection confirmed that the following are risk factors for major osteoporotic fracture: age, weight, prior fracture, back pain, and lumbar bone mineral density (BMD). Age, prior fracture and dementia were significant risk factors for immobilization. Hosmer-Lemeshow tests did not indicate any significant deviation between the observed fracture frequency and prediction from the FRISC in the independent validation dataset. The C statistic for the FRISC was 0.727 (95% confidence interval: 0.660 to 0.794) and was higher than that for BMD alone significantly (p=0.03). CONCLUSIONS: We developed a novel prediction model for fracture and immobilization, FRISC, and the clinical risk factors in the FRISC allows better identification of populations at high risk of fracture than BMD alone. A web application is available at http://www.biostatistics.jp/prediction/frisc. PMID- 20832515 TI - Effect of the inosine 5'-monophosphate dehydrogenase inhibitor BMS-566419 on renal fibrosis in unilateral ureteral obstruction in rats. AB - Chronic allograft nephropathy (CAN) is a major cause of late allograft loss. One morphological characteristic of CAN is renal interstitial fibrosis. Mycophenolate mofetil (MMF), the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitor, has been reported to attenuate the progression of renal interstitial fibrosis. However, the question of whether the newly synthesized IMPDH inhibitors with structures different from MMF have an antifibrotic effect remains unanswered. We evaluated the antifibrotic effects of BMS-566419, a chemically synthesized IMPDH inhibitor, using an experimental rat model, unilateral ureteral obstruction (UUO), in comparison with those of MMF. Expression levels of monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta1 (TGF beta1), which play important roles in UUO-induced renal fibrosis, were also investigated to determine the mechanism by which BMS-566419 affects the progression of renal fibrosis. After 14 days of UUO, interstitial fibrosis was frequently observed in the renal cortex of rats administered vehicle control. BMS 566419 by oral administration showed a significant and dose-dependent suppressive effect on UUO-induced renal fibrosis in histopathological experiments. BMS-566419 treatment also decreased collagen content, as indicated by hydroxyproline concentration, and the expression of collagen type 1 mRNA. BMS-566419 also decreased the expression of mRNA for both MCP-1 and TGF-beta1. The antifibrotic effects of treatment with BMS-566419 at 60 mg/kg seemed comparable to those with MMF at 40 mg/kg. These results suggest that BMS-566419 and other chemically synthesized IMPDH inhibitors have beneficial pharmacological effects similar to those of MMF, and are potential pharmaceutical candidates in the treatment of fibrotic renal disease, including CAN. PMID- 20832517 TI - Results of kidney transplantation from donors after cardiac death. AB - Confronting the organ donor shortage, many transplant centers around the world increasingly use donors after cardiac death (DCD). Over the past 20 years, follow up studies in kidney recipients comparing DCD and donors after brain death (DBD) have shown comparable long-term graft function and survival. As a consequence, DCD programs should be continued and expanded, for these donors constitute a potential solution to the imbalance between the numbers of end-stage kidney disease patients on waiting lists versus available kidney grafts. DCD kidneys do not necessarily signify suboptimal grafts; they may merit to be allocated the same as DBD grafts. PMID- 20832518 TI - Predonation quality of life and early postdonation safety of older living renal donors in China. AB - BACKGROUND: Studies on the safety of older living renal donors are lacking in China. METHODS: We observed 142 consecutive living renal donors before and early after (7 days) the operation. There were no prisoners used as donors or recipients. Subjects were divided into 2 groups: older than 50 years of age (n = 40) or younger age (n = 102). We compared differences in early safety between the 2 groups. RESULTS: There were no significant differences in 8 aspects of the predonation quality of life using the SF-36 questionnaire, except for physical function (P < .001). Zero hour biopsies performed on 52 kidneys showed 15 to display abnormal renal tissues (28.85%), which was significantly greater among the older age group (P = .034). The perioperative indexes were similar between the 2 groups; however, the hospital stay was longer in the older group (P = .034). Compared with the younger group, the older group generally showed a lower creatinine clearance (CCr; P < .001), higher cystatin c (P = .006), and similar serum creatinine (Scr) preoperatively, conditions that persisted at 7 days postoperatively. Although the increased Scr and reduced CCr were present in all donors, the changes in Scr and CCr were similar between the 2 groups. Differences in urinary micro-albumin and proteinuria before and after operation were not significantly different for both groups. CONCLUSIONS: Increased use of older living kidney donors in China may be a safe strategy to meet the demand for transplantation. However, long-term outcomes need further follow-up. PMID- 20832519 TI - Risk factors for delayed graft function after hand-assisted laparoscopic donor nephrectomy. AB - BACKGROUND: Delayed graft function (DGF) has a negative effect on the results of living-donor kidney transplantation. OBJECTIVE: To investigate potential risk factors for DGF. METHODS: This prospective study included 200 consecutive living donors and their recipients between January 2002 and July 2007. Delayed graft function was defined as need for dialysis within the first postoperative week. RESULTS: Delayed graft function was diagnosed in 12 patients (6%). Intraoperative complications occurred in 10 donors (5%), and postoperative complications in 24 donors (13.5%). One-year kidney graft survival with vs without DGF was 52% and 98%, respectively (P < .002). In donors, 2 univariate risk factors for DGF identified were lower counts per second at peak activity during scintigraphy, and multiple renal veins. In recipients, only 2 or more kidney transplantations and occurrence of an acute rejection episode were important factors. At multivariate analysis, increased risk of DGF was associated with the presence of multiple renal veins (odds ratio, 151.57; 95% confidence interval, 2.53-9093.86) and an acute rejection episode (odds ratio, 78.87; 95% confidence interval, 3.17 1959.62). CONCLUSION: Hand-assisted laparoscopic donor nephrectomy is a safe procedure. The presence of multiple renal veins and occurrence of an acute rejection episode are independent risk factors for DGF. PMID- 20832520 TI - Living donor renal transplantation using grafts with multiple arteries procured by laparoscopic nephrectomy. AB - OBJECTIVE: Kidney grafts with multiple renal arteries (MRAs) are not uncommon, but they do make transplantation more difficult. Laparoscopic graft nephrectomy has become the standard; however, the safety and reliability must be maintained for both a donor and a recipient even in case of MRAs. This study evaluated the short-term outcomes of living donor renal transplant using grafts with MRAs procured by laparoscopic nephrectomy. PATIENTS AND METHODS: This study reviewed all living donor kidney transplantations performed from January 2008 to June 2009, which were divided into 3 groups according to the number of renal graft arteries. The serum creatinine level, warm ischemic time (WIT), rewarming time, total ischemic time (TIT), operative time, acute rejection episodes, and complications in each group were evaluated. RESULTS: The serum creatinine level showed no difference among the groups. Longer TIT was observed in the MRAs group, but WIT and rewarming time did not differ. The acute rejection rate was not different. There were no vessel complications in any donors and recipients. CONCLUSION: Harvesting kidney grafts with MRAs by laparoscopic nephrectomy requires a longer TIT; however, transplantation can be performed safely and reliably for both donors and recipients. PMID- 20832521 TI - Factors associated with changes in coagulation profiles after living donor hepatectomy. AB - BACKGROUND: Hepatic resection may be associated with postoperative coagulopathy. However, there is limited information about the predictors affecting coagulopathy after donor hepatectomy. We evaluated the contributors of maximal changes in prothrombin time (PT), activated thromboplastin time (aPTT), and platelet count in the development of postoperative coagulopathy. METHODS: We retrospectively analyzed 864 living donors, all of whom received general anesthesia using desflurane, isoflurane, or sevoflurane. A coagulation derangement was defined as one or more of the following events postoperatively: peak PT >1.5 international normalized ratio (INR; highest quartile of PT), peak aPTT >46 seconds (highest quartile of aPTT), or nadir platelet count <100 * 10(9)/L. Factors were evaluated by univariate and multivariate logistic regression analysis to identify predictors of coagulopathy. RESULTS: Mean postoperative peak PT, peak aPTT, and nadir platelet count were 1.4 +/- 0.2 INR, 43.8 +/- 23.7 seconds, and 155.9 +/- 37.3 * 10(9)/L, respectively, with 39.4% of donors being at the risk for coagulation derangement. Multivariate logistic regression analysis revealed that predictors of such derangement included anesthesia duration, remnant liver volume, and body mass index (BMI). However, coagulation derangement was not independently associated with age, gender, volatile anesthetics, central venous pressure, fatty change in the liver, estimated blood loss, or intraoperative hypotensive episodes. CONCLUSION: We found that long anesthesia duration, low BMI, and small remnant liver volume were predictors of coagulation derangement. These results provide a better understanding of risk factors affecting changes in coagulation profiles after living donor hepatectomy. PMID- 20832522 TI - Kidney grafts from HCV-positive donors: advantages and disadvantages. AB - The Organ Procurement and Transplantation Network database (2001-2006) was reviewed for kidney transplant (KT) recipients, to evaluate the effects of use of grafts from donors positive for hepatitis C virus (HCV) on recipient outcome. Data for 76,787 de novo adult KT recipients were included in the analysis. Serologic tests revealed HCV positivity in 6.25% of cadaver kidneys and 2.97% of living-donor kidneys. Median follow-up in patients still alive was 36 months. At multivariable Cox regression analysis in recipients of cadaver kidney, HCV serostatus was significantly associated with overall and graft survival (both P < .001), with a hazard ratio for HCV-positive patients of 1.43 for overall survival and 1.48 for graft survival. Similar results were obtained for living-donor kidney recipients. Recipients of HCV-positive organs tended to be male and African American and to have a shorter waiting time. Infection was the most commonly reported cause of death in recipients of organs from HCV-positive donors. In patients willing to accept HCV-positive grafts (929 [25.6%]), waiting time was significantly shortened (P < .001). However, this benefit was offset by decreased patient survival (P < .001) and graft survival (P = .007). PMID- 20832523 TI - Vasopressor agents after experimental brain death: effects of dopamine and vasopressin on vitality of the small gut. AB - BACKGROUND: Both congenital and acquired short bowel syndrome frequently leads to the necessity for long-term parenteral nutrition, which in turn may lead to any of several complications or death. Transplantation of the small bowel from brain dead organ donors has been successfully performed over the last years. However, systemic blood pressure and blood perfusion to the splanchnic area decrease rapidly after brain death, which comprises the vitality of the small bowel. OBJECTIVE: To evaluate the differences between dopamine and low-dose vasopressin on perfusion and vitality of the small bowel after brain death. METHODS: Fifteen pigs were randomized into 3 groups: vasopressin (n = 6), dopamine (n = 6), or control (n = 3). Brain death was induced via stepwise filling of an epidural balloon. When the hypotensive phase was achieved, vasopressin, maximum dose of 0.04 IU/kg/h, or dopamine, maximum dose of 20 MUg/kg/min, was administered for 5 hours with the objective of increasing mean arterial blood pressure by 15 mm Hg. RESULTS: Target blood pressure was achieved in the vasopressin group but not the dopamine group. Vasopressin reduced cardiac output, superior mesenteric artery (SMA) blood flow and oxygen delivery, and systemic oxygen delivery and consumption, and increased oxygen extraction. Dopamine increased SMA blood flow, and had no effect on systemic oxygen delivery or consumption. CONCLUSIONS: Vasopressin reversed hypotension but compromised both the systemic and SMA blood flow. Vasopressin was associated with inadequate oxygen delivery, estimated from decreased oxygen delivery and increased oxygen extraction. These adverse effects were not observed with dopamine. PMID- 20832524 TI - Role of vascular endothelial growth factor in protection of intrahepatic cholangiocytes mediated by hypoxic preconditioning after liver transplantation in rats. AB - OBJECTIVE: To investigate the effect on intrahepatic cholangiocytes mediated by hypoxic preconditioning (HP) after liver transplantation and the role of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: This experiment was based on a model of rat orthotopic liver autotransplantation. Sprague-Dawley rats were randomly divided into 3 groups: normal control, autotransplantation (AT), and HP. The HP group was subjected to 8% oxygen atmosphere for 90 minutes before surgery. At 6, 12, 24, and 48 hours after autotransplantation, the rats were killed for testing .Serum total bilirubin, direct bilirubin, and alkaline phosphatase concentrations were determined. The microstructure of cholangiocytes and the ultramicrostructure of cholangioles were determined. Immunohistochemistry was used to detect the expression of VEGF and the proliferation rate of cholangiocytes. RESULTS: Total bilirubin, direct bilirubin, and alkaline phosphatase concentrations in the AT group increased considerably more than in the HP group during the entire interval (P < .05). Light microscopy demonstrated that the microstructure of cholangiocytes in the AT group was damaged more seriously than in the HP group. At transmission electron microscopy, the ultramicrostructure of cholangioles was changed more obviously than in the HP group. The expression of VEGF on cholangiocytes and the proliferation rate of cholangiocytes were higher in the HP group than in the AT group over the entire experiment (P < .05). CONCLUSION: Hypoxic preconditioning has a protective effect on cholangiocytes after liver autotransplantation. The mechanism may be related to HP-induced overexpression of VEGF on cholangiocytes. PMID- 20832525 TI - Diluted blood reperfusion as a model for transplantation of ischemic rat livers: alanine aminotransferase is a direct indicator of viability. AB - Donors after cardiac death present a significant pool of untapped organs for transplantation, and use of machine perfusion strategies has been an active focus area in experimental transplantation. However, despite 2 decades of research, a gold standard has yet to emerge for machine perfusion systems and protocols. Whole blood reperfusion has been used as a surrogate for organ transplantation, especially as a model for the short-term response posttransplantation, and for optimization of perfusion systems. Although it is known that there is a strong correlation between liver function in whole-blood reperfusion and survival, the exact nature of these correlations, and to what extent they can be considered as an indicator of viability for transplantation/recipient survival, remain unclear. In this work, we demonstrate that diluted whole-blood reperfusion can be used as a direct model for transplantation of ischemic rat liver grafts. Specifically, we show that recipient survival can be predicted based simply on the value of alanine aminotransferase during perfusion, providing quantitative criteria of viability for use in this animal model. These results indicate that in the rat model graft survival is highly correlated with hepatocellular damage. PMID- 20832526 TI - Clinical analysis of living related renal transplantation with donors older than 50 years in China. AB - OBJECTIVE: The objective of this study was to investigate whether kidney grafts from living related donors older than 50 years were safe for the donors and recipients in the long term. METHODS: One hundred seven living related donor kidney transplantations were performed in our center from April 1994 to December 2007. No prisoners or organs from prisoners were used in the collection of these data. Donors were divided into 2 groups: >50 years of age (range, 51-78 years), designated as the study group, and <=50 years of age (range, 21-50 years), designated as the control groups. The mean time of follow-up was 49 months (range, 12-180 months). Clinical data were compared, including donor serum creatinine (Scr) levels, glomerular filtration rates (GFR) before and after the procedures operative complications, and postoperative short-term and long-term recovery of renal function in recipients as well as their complications and recipient and kidney survivals. RESULTS: All operations were successfully performed. Before the operation, the mean Scr and GFR were 82.16 +/- 10.86 umol/L and 85.82 +/- 6.26 mL/min, respectively, in the study group versus 78.66 +/- 10.41 umol/L and 88.74 +/- 9.44 mL/min, respectively, in the control group. There were no significant differences in mean Scr or GFR values between the groups at various preoperative or postoperative times (P > .05). No severe perioperative complications occurred, and no subsequent renal function failure was observed upon long-term follow-up of donors in the 2 groups. Comparisons of recipient age, gender ratio, duration on dialysis, HLA matches, cold/warm ischemia times, and immunosuppression therapy showed a correlations between the 2 groups. Mean Scr levels of recipients, which were compared from 1 week to 3 years following surgery, were slightly higher among the control than the study group, but the difference was not significant (P > .05). There were no significant differences between the study and control groups in 1-,3-,5-, and 8-year recipient/graft survival rates (P > .05). CONCLUSIONS: Long-term follow-up showed that transplantations using grafts from donors older than 50 years of age yielded similar results to those with younger donors. PMID- 20832527 TI - Outcome of the using older donors for kidney transplantation;Gazi University, Ankara experience. AB - The extreme organ shortage in Turkey has led to expansion of living and diseased donors. We retrospectively analyzed patient data to determine the outcomes of elderly donors. Among 210 donors, 28 (13.3%) were atleast >=55 years old. In this group, 17 were from living and 11 from diseased donors. Mean cold ischemia time was 68 +/- 21 minutes. The immunosuppressive protocol consisted of induction therapy (simulect 20 mg on days 0 and 4) and immunosuppression with calcineurin inhibitors, mycophenolic acid, and steroids. Nine patients (32.6%) with delayed graft function (DGF) required transient hemodialysis. None of the recipients or their grafts were lost due to surgical complications. We noted 5 acute rejection episodes which were all reversed by pulse steroids. Mean creatinine levels at 1, 3, and 5 years were 1.7, 2.1 and 2.3 mg/dL respectively. Patient and graft survivals at 1, 3, and 5 years were 100%, 96%, and 92% and 100%, 92%, and 92%, respectively. Although 3.6% of recipients displayed DGF, it did not affect graft outcomes. In conclusion, kidney transplantation from older donors should be considered to be an option for kidney transplantation. PMID- 20832528 TI - Association between the heme oxygenase-1 promoter polymorphism and renal transplantation outcome in Greece. AB - BACKGROUND: Heme oxygenase-1 (HO-1) is the enzyme that catabolizes heme into carbon monoxide, biliverdin, and free iron. The induction of this enzyme is an important cytoprotective mechanism, which occurs as an adaptive and beneficial response to a wide variety of oxidant stimuli. HO-1 has recently been suggested to protect transplants from ischemia/reperfusion and immunologic injury. HO-1 inducibility is mainly modulated by a (GT)(n) repeat polymorphism in the promoter region, and has been shown that short repeats (S) are associated with greater upregulation of HO-1, compared with long repeats (L). In the present study we investigated the influence of this HO-1 gene polymorphism on clinical outcome after transplantation and on renal transplant function. METHODS: DNA from 175 donor/recipient pairs who underwent transplantation between October 2002 and June 2007 was genotyped. We divided the HO-1 alleles into 2 subclasses, the S <= 27 repeats and L > 27 repeats. RESULTS: There has been significant relevance between the genotype of the donor and the outcome of the graft, as far as recipients with normal graft function and recipients with deteriorated graft function are concerned (P = .021). In patients with normal graft function, grafts from L homozygotes were found in 24%, whereas in patients with deteriorated function, grafts from L-homozygotes exhibited in higher rate (50%). Neither the donor's nor the recipient's polymorphism influenced the graft survival (log-rank test P = .228 for the donors and log-rank test P = 0.844 for the recipients). There was no evidence of a gene-dose effect on graft survival (P = .469). Recipients of allografts from S-carriers donors had significantly lower serum creatinine levels at 24 months compared with recipients of allografts from L-homozygotes donors (P = .016). PMID- 20832529 TI - Time of occurrence of kidney acute antibody-mediated allograft rejection/acute cellular rejection and cell senescence: implications for function outcome. AB - BACKGROUND: Late versus early acute antibody-mediated rejection (AAMR) or acute cellular rejection (ACR) episodes are associated with poorer kidney function and graft survival. We explored whether cell senescence upon detection of AAMR +/- ACR contributes to these results. METHODS: We reviewed the renal transplant database of 2 Institutions. Biopsies performed for acute graft dysfunction from January 2000 to March 2007 were analyzed for morphological criteria of AAMR with or without ACR (n = 17 from 17 patients). Immunoperoxidase staining for p16(INK4B) was performed on the remaining paraffin-embedded tissue in 9 of 17 cases. The average number of positive cells/high power field (HPF) was calculated in every case. Cases with rejection were grouped according to the time of presentation: early (<3 months n = 8) versus late (>3 months; n = 9). Graft function was obtained using the Modification of Diet in Renal Disease (mDRD) glomerular filtration rate estimate (eGFR) before, during rejection, and at the last visit, to calculate DeltaeGFR. RESULTS: Nuclear expression of p16(INK4B) was 12.2 +/- 11.3 cells/HPF in 4 of 8 biopsies performed at a median of 23 (range = 4 80) days (early AAMR +/- ACR), and 59.8 +/- 51.3 cells/HPF in 5 of 9 biopsies performed at a median of 1171 (range = 279-3210) days (late AAMR +/- ACR). eGFR before rejection was 48.5 +/- 7.6 mL/min, and 43.7 +/- 4.3 mL/min for early and late rejection episodes, respectively (P = not significant [NS]). DeltaeGFR of 12.5 +/- 25.9 mL/min (early rejection), and -13.7 +/- -12.3 mL/min (late rejection), versus last follow-up visit (P = .02) occurred at a median of 143.9 +/- 94.1 and 69.6 +/- 35.1 weeks after the rejection episodes, respectively. CONCLUSIONS: Even though the number of biopsies analyzed for p16(INK4a) was small, it was evident that the number of cells expressing this marker of senescence was higher among biopsy specimens obtained with late rejection episodes. This finding suggests the presence of injuries prior to the rejection episode. The significantly lower eGFR at last follow-up in the late rejection group may translate to a reduced capacity of the repair process to sustain nephron function. PMID- 20832530 TI - Optimized technique in needle biopsy protocol shown to be of greater sensitivity and accuracy compared to wedge biopsy. AB - BACKGROUND: Kidney biopsy is an important tool in determining allograft suitability for transplantation. Most deceased-donor renal biopsies performed today in the United States are wedge biopsies (WBs), with core needle biopsies being performed only by a minority of organ procurement organizations (OPOs). The lack of a gold standard in tissue sampling and tissue evaluation has prompted our OPO to find a more sensitive biopsy method as well as a more accurate pathology evaluation protocol to reassess expanded-criteria donor kidneys. METHODS: Between the months of March 2007 and June 2008, the New York Organ Donor Network OPO imported 226 kidneys. These kidneys had been previously biopsied by the originating OPOs utilizing the WB method. All 226 kidneys were rebiopsied by our preservation team using the optimized needle biopsy technique (ONBT) and then evaluated by the pathologists of the Transplant Pathology Laboratory of the Mount Sinai Hospital. RESULTS: Histologic findings from both types of biopsies were compared in the following parameters: glomerular yield, percentage of obsolete glomeruli, tubular interstitial scarring, arterial intimal fibrosis and acute tubular necrosis. Difference in glomerular yield between WB and ONBT was not statistically significant (P = .1736). ONBT detected more tubular interstitial scarring and arterial intimal fibrous narrowing than WB (P = .00). No statistical difference was found between the two biopsy methods in identifying acute tubular necrosis. CONCLUSION: The data suggest that there were no statistical differences in sample reliability between ONBT and WB. However, ONBT was found to be significantly more sensitive in identifying allograft tubular interstitial scarring as well as intimal fibrous narrowing. Overall this study provides proof that ONBT is a more reliable and accurate method compared to WB in identifying important parameters of renal allograft. PMID- 20832531 TI - Third and fourth kidney transplant: still a reasonable option. AB - INTRODUCTION: At present, a second kidney transplant is considered an established therapeutic option for patients who have lost a previous graft. Second transplants show similar graft survival as first transplants. A debate exists about the benefit of submitting the patient to a third or fourth renal transplant, or to maintain dialysis. OBJECTIVE: We sought to analyze graft and patient survivals as well as associated variables and surgical complications of third and fourth transplantations. MATERIAL AND METHODS: From July 1985 to December 2008, we performed 74 third and 8 fourth transplantations among 2763 cases. We prospectively collected the variables of age, gender, graft origin, hyperimmunization, time on dialysis, location, bench surgery, acute rejection episodes, graft survival, and operative complications. RESULTS: Third and fourth trasplantations were performed in 49 men and 33 women, with an overall mean age of 40.26 years who were on dialysis for an average of 126.89 months before transplantation. Mean graft survivals of their first and second grafts were 35.6 and 50.1 months, respectively. Acute or chronic rejection was reason for renal failure in 71% and 75% of cases, respectively. Patient survivals at 1 and 5 years were 92.7% and 90.6%, for third and both 85.7% for the fourth transplantation. The third and fourth transplantations showed 1- and 5-year graft survivals of 88% and 76.4% and 71.4% and 42.9%, respectively. Sixty-eight cases underwent cadaveric donor and 14 living donor (mean age, 42.1 years) transplantations. Nine patients were hyperimmunized. In 60 cases, we used the left kidney. Orthotopic kidney transplantation was performed in 15 cases; heterotopic transplant to the right iliac fossa in 40 and in the left iliac fossa in 17 cases. Arterial bench surgery was necessary in 6 cases and venous in 3. We performed 3 hepatorenal and 1 cardiorenal transplantation. The complications included 29 cases (35.4%) of postoperative acute tubular necrosis, 14 of acute rejection episodes (17.1%); 12 of perirenal hematoma (14.6%); 1 urinary fistula (1.2%); 4 lymphocele (4.9%); 2 ureteral stenosis (2.4%); variables arterial kink requiring surgery (1.2%), and 1 venous thrombosis with graft loss (1.2%). The 4 patients who died in the perioperative period succumbed to intravascular disseminated coagulation (n = 1) cardiac failure (n = 2), and septic shock (n = 1). Induction antibody therapy, hyperimmunized status, or operative complications were not independent prognostic factors for patient or graft survival. CONCLUSIONS: Third or fourth renal transplantations constitute a valid therapeutic option with reasonable short- and long-term patient and graft survivals. Although orthotopic kidney transplantation was used in selected patients, we preferred an iliac fossa approach for most. PMID- 20832532 TI - Evaluation of cinacalcet HCl treatment after kidney transplantation. AB - BACKGROUND: Hyperparathyroidism often remains or develops after kidney transplantation. Vitamin D sterol used as treatment for an elevated parathyroid hormone (PTH) level and associated bone disease may be contraindicated due to hypercalcemia. The calcimimetic cinacalcet HCl (cinacalcet), which lowers PTH and calcium (Ca) in chronic kidney disease patients, may represent an alternate therapeutic modality. METHODS: This multicenter, retrospective, observational study examined 41 kidney transplant patients receiving cinacalcet for >=3 months starting >=3 months posttransplantation. Levels of intact PTH, Ca, and phosphorus (P) were examined during the assessment phase (3-6 months after initiation). RESULTS: Median PTH decreased 21.8% during the assessment phase (P < .001), with 32.5% of patients exhibiting a >=30% decrease in PTH from baseline. Median Ca decreased 6.8% (P < .0001). Median serum P rose 10.0% (P = .0124), but remained within normal limits. The estimated glomerular filtration rate was stable throughout the study. CONCLUSIONS: Cinacalcet may be useful for the treatment of hyperparathyroidism after kidney transplantation. Randomized, prospectively designed clinical trials are required to confirm these results. PMID- 20832533 TI - Correlation between HLA and posttransplantation diabetes mellitus in the Han population in South China. AB - BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is a common metabolic complication in renal transplant recipients. Some studies have revealed predisposing or protective HLA genes for PTDM. OBJECTIVE: To describe the characteristics of PTDM in patients in the south of China. METHODS: The present study included 195 living-donor kidney transplant recipients. Informed consent was obtained from all participants, and the study was approved by our Institutional Ethics Committee. Each donor-recipient pair was related. Twenty-two patients had PTDM, whereas 173 did not. The frequency of each HLA phenotype was compared between these 2 groups. The 195 patients were divided into 2 groups according to immunosuppression regimen, a cyclosporine group and a tacrolimus group, and the incidence of PTDM was compared between the groups. Patients were then subdivided into 2 groups according to age, an elderly group (age 40 years or older) and a younger group (age younger than 40 years), and the incidence of PTDM was calculated and compared between these 2 groups. RESULTS: HLA-A30 and HLA-DR7 seem to be predisposing genes for PTDM in patients in the south of China; Low dosages of calcineurin inhibitors were used in our center, There was no significant difference in the incidence of PTDM between the CsA and Tac groups; The incidence of PTDM in the elderly group was significantly higher than that in the younger group. CONCLUSION: Patients receiving HLA-A30 and HLA-DR7 antigens, and elderly patients are at higher risk of developing PTDM. Tacrolimus does not significantly increase the incidence of PTDM. PMID- 20832534 TI - Effect of apolipoprotein E gene polymorphism on serum lipid level before and after renal transplantation. AB - OBJECTIVE: To investigate the effect of apolipoprotein E (ApoE) gene polymorphism on lipid metabolism among renal transplant recipients before and after transplantation. No prisoners or organs from prisoners were used in this study. METHODS: ApoE gene polymorphism was detected with polymerase chain reaction restriction fragment length polymorphism; serum lipid levels were measured with biochemical methods. RESULTS: Serum lipid levels in the recipients were increased significantly at 3 months after renal transplantation, and further elevated at 6 months and 1 year. The recipients with higher total serum cholesterol (TC) and triglyceride (TG) levels only accounted for 2.9% and 7.6%, respectively, before renal transplantation; but for 28.6% and 46.7%, respectively, at 3 months (P < .01); 40.0% and 59.0% at 6 months; and 42.9% and 62.9% at 12 months. ApoE gene polymorphism showed no statistical difference in ApoE allele or ApoE genotype between the control and the study groups. The effect of ApoE genotype on serum lipid levels was different between controls and recipients either before or after renal transplantation. The levels of serum TC, TG, low-density lipoprotein cholesterol, ApoB, ApoE were: (epsilon)2/2+(epsilon)2/3; (epsilon)3/3; (epsilon)3/4+(epsilon)4/4 from low to high in controls and recipients before transplantation, but the levels of TG and ApoE reversed among recipients after renal transplantation. CONCLUSION: Renal transplant recipients are liable to develop hyperlipidemia, particularly hypertriglyceridemia among recipients with ApoE genotypes (epsilon)2/2 or (epsilon)2/3. PMID- 20832535 TI - Bone disease in renal transplantation and pleotropic effects of vitamin D therapy. AB - Osteoporosis, osteopenia, and osteonecrosis are common in renal transplant recipients. In this study, we evaluated relationship between bone mineral density (BMD) and posttransplant duration; creatinine clearance; serum levels of glucose, calcium, phosphorus, alkaline phosphatase, vitamin D (vitD), parathormone, magnesium, C telopeptide, osteocalcin, lipids, and vit D therapy. Eighty five subjects included in this study had a mean age of 36.25 +/- 10.5 years. At least at 6-month intervals we measured femoral neck (FN) and lumbar vertebra (LV) by DEXA and biochemical parameters. VitD was prescribed in 57 patients (vitDG). The mean duration of posttransplantation follow-up was 9.82 +/- 2.72 months. T scores (TS) of FN and LV were normal in 29.4% and 21.2%; osteopenia in 56.5% and 49.4%; and osteoporosis in 12.1% and 29.4% of patients, respectively. Upon follow-up, TS improved significantly from -1.58 to -1.46 in FN and from -1.88 to -1.70 in LV (P < .05 for both). In patients receiving vitDG, TS improved significantly from 1.74 to -1.61 on FN and from -2.16 to -1.97 on LV (P < .05 for both). Osteocalcin and vitDG levels decreased in all patients (P < .05 for all). Blood urea nitrogen and serum creatinine increased (P < .05). In VitDG cohort, triglyceride levels decreased (P < .05) with unchanged blood glucose values; but among the other patients, triglycerides were unchanged but glucose levels had increased (P < .05). Bone disease including osteopenia or osteoporosis was observed among 70%. During the follow-up period, BMD increased significantly from baseline at 9.82 +/ 2.72 months. VitD therapy caused more prominent improvements in BMD and decreases in serum triglycerides as well as mutigated the increase in blood glucose. PMID- 20832536 TI - Molecular epidemiology of Epstein-Barr virus in adult kidney transplant recipients. AB - In transplant recipients, Epstein-Barr virus (EBV) infection may be related to posttransplantation lymphoproliferative disorders (PTLD), the most important risk factors for which are the patient's serostatus before transplantation and the level of immunosuppression. Herein, we have evaluated the impact of EBV in adult kidney transplant recipients by prospectively investigating its molecular epidemiology in 855 consecutive whole blood samples obtained from 290 patients. EBV-DNA monitoring by real-time polymerase chain reaction (PCR) was performed at 3-month intervals in the first year after transplantation and subsequently once a year. Moreover, we studied 55 healthy, non-transplant recipient, blood donors. PCR for EBV-DNA results were positive in 99/855 samples (11.6%) obtained from 72/290 patients (24.8%) versus none from healthy control subjects (P < .05). There were no differences in the prevalence of EBV-DNA positivity regarding demographic characteristics, underlying pathology leading to transplantation, renal function, and immunosuppressive protocol. Only 4 patients showed a viral load of >2,000 genome equivalents/mL whole blood at >12 months; no patient developed PTLD. In conclusion, although the occurrence of EBV-DNA positivity was frequent, it was usually at low levels of viral load, confirming that adult kidney graft recipients are at a low risk of developing PTLD. PMID- 20832537 TI - Influence of long-term dialysis treatment on operative complications after renal transplantation. AB - BACKGROUND: We sought to assess the influence of long-term dialysis treatment on operative complications after kidney transplantation. METHODS: We identified and prospectively followed 2 groups of patients who underwent renal transplantation: group I were on dialysis <5 years and group II, >15 years. We compared the groups regarding mismatches, residual diuresis, operative and medical complications, as well as duration of hospitalization after transplantation. RESULTS: Groups I and II included 36 and 24 patients with 33.3% and 45.8% female of mean ages at transplantation of 49 (range, 9-73) and 45 (range, 27-56) years, respectively. Group I contained 9 seniors and 4 subjects <18 years. There were no significant differences in mean donor age, number of marginal donors, mismatches, postoperative bleeding, wound infections, urine leakage, or duration of hospitalization. However, the number of postoperative lymphoceles was significantly higher in group II: 5 (20.8%) versus 1 (2.7%) (P = .01). Graftectomy was performed in 2 group II patients including 1 primary graft nonfunction, and another for recurrent focal segmental glomerulosclerosis. CONCLUSION: Our results suggested that the duration of dialysis treatment was not a significant factor for postoperative complications and prolonged hospital stay, except for an increased risk of lymphocele formation. PMID- 20832538 TI - Signal transducer and activator of transcription 1 and matrix metalloproteinase 3 genetic expression and clinical significance on urothelial tumors after renal transplantation. AB - OBJECTIVE: The objective of this study was investigate signal transducer and activator of transcription 1 and matrix metalloproteinase 3 genetic expression and clinical significance on urothelial carcinoma after renal transplantation. METHODS: This study included 51 patients with histopathologically proven urothelial carcinoma, 16 of whom had undergone renal transplantation, and 35 others who had not and served as a control group. Human genome oligo-arrays were used to analyze the gene expression spectrum of the tumors. STAT1 and MMP3 expression in urothelial carcinoma was determined using real-time-polymerase chain reaction (RT-PCR) and immunohistochemistry staining. No prisoners or organs from prisoners were used in this study. RESULTS: Among the transplantation group, 35 genes were up-regulated. The functions of 23 genes were known or partly known. Additionally, 76 genes were down-regulated in the transplantation group. The function of 46 genes was known or partly known. Pathway analysis of differences in gene expression between the groups revealed 23 groups of pathways that exhibited statistical significance (P < .05). The differences in the levels of expression of STAT1 and MMP3 were significant (P < .05). CONCLUSIONS: Differences in gene expression profiles of STAT1 and MMP3 exist between patients who have and those who have not undergone renal transplantation. STAT1 and MMP3 may be potential targets for the chemoprevention of posttransplantation urothelial carcinoma. PMID- 20832539 TI - Dermatologic findings in renal transplant recipients: Possible effects of immunosuppression regimen and p53 mutations. AB - OBJECTIVE: To analyze the dermatologic lesions and possible effects of immunosuppression treatment and p53 gene mutations on dermatologic findings in renal transplant recipients. MATERIALS AND METHODS: The study included 163 renal transplant recipients. After dermatologic examination, cultures, and histopathologic and genetic analyses were performed. A single-strand conformation polymorphism technique was used to analyze p53 gene mutations. Patients were categorized into 3 groups according to time since the transplantation procedure. Results were analyzed using the chi(2) test, using a software program (SPSS version 13.0; SPSS, Inc, Chicago, Illinois). RESULTS: Mean (SD) age of the 163 transplant recipients (65 women and 98 men) was 40 (11) years, and posttransplantation follow-up was 65 (55) months. The most frequently observed drug-related lesion was hypertrichosis, in 46 of 150 patients. Of 115 lesions, the most commonly observed were verruca vulgaris (n = 34) from viruses, and pityriasis versicolor (n = 21) from superficial fungal infections. Of the total group, 20 patients (12.2%) were mutation carriers. Compared with the entire cohort, the group with premalignant lesions demonstrated more p53 mutations (11% vs 50%; P = .004). Patients given cyclosporine therapy exhibited more premalignant or malignant cutaneous lesions compared with patients who received other agents (P = .03). CONCLUSION: Patients carrying p53 mutations developed a malignant lesion in the late posttransplantation period, which suggests the importance of prediction of risk. PMID- 20832540 TI - Targeting risk factors for impaired wound healing and wound complications after kidney transplantation. AB - BACKGROUND: Because of potent immunosuppression, impaired wound healing and complications are frequent features after kidney transplantation (KTx). OBJECTIVE: To investigate the incidence and nature of impaired wound healing and complications at a single transplantation center in Norway. PATIENTS: Of 226 patients who underwent KTx, 199 (87%) were followed up prospectively for 1 year (2005) via close and meticulous wound inspection. RESULTS: The study revealed a high rate of wound complications (200-250/y) in a high-volume center. Fifty-four patients (27%) experienced prolonged wound healing, defined as gaps, secretions, or wound complications, at 3 to 5 weeks posttransplantation, and 41 patients (21%) had impaired wound healing, defined as gaps, secretions, or wound complications after 5 weeks posttransplantation. In total, 50 patients (25%) required surgical or radiologic reintervention. Complications included lymphocele in 29 patients (14.6%), wound dehiscence in 16 (8.0%), bleeding or hematoma in 10 (5.0%), and infection in 9 (4.5%). Risk factors associated with wound complications included recipient older than 60 years, body mass index greater than 30, hemoglobin concentration less than 10 g/dL, albumin concentration less than 36 g/dL, duration of surgery more than 200 minutes, no subcutaneous sutures, and sirolimus or everolimus therapy. At nominal and logistic regression analysis, recipient older than 60 years, body mass index greater than 30, and no subcutaneous sutures were independent risk factors. CONCLUSION: Risk factor analysis and previous documentation suggest that wound complications might be counteracted using the following measures: subcutaneous sutures, predialysis transplantation, sealing or ligation of lymphatic trunks, prophylactic fenestration, reduction of corticosteroid load, and avoiding sirolimus/everolimus therapy. PMID- 20832541 TI - Sirolimus-induced isometric tubular vacuolization: a new sirolimus histopathologic manifestation. AB - The clinical and pathological experience with sirolimus is limited at this time. In this study, we report severe isometric vacuolization of the proximal tubules after sirolimus therapy in two kidney transplant patients. Patient 1 is a hepatitis C virus-positive, 30-year-old African American man who had end-stage renal disease (ESRD) of unknown etiology. Patient 2 is a 62-year-old white woman with ESRD due to unknown etiology. Both patients were initially placed on tacrolimus, mycophenolic acid, and prednisone immunosuppressive therapy. These patients were switched to sirolimus at 1 and 5 month posttransplant, respectively, due to the development of new-onset hyperglycemia and an elevated serum creatinine. Both patients presented with acute renal failure and high sirolimus levels at 5 years (patient 1) and 10 months posttransplant (patient 2). Biopsies of their kidney transplants showed widespread isometric tubular cytoplasmic vacuolization and severe arterial hyalinosis. Acute renal insufficiency improved after sirolimus dose reduction. In this case report, we introduce a new morphological appearance after sirolimus therapy of isometric cytoplasmic vacuolization of the renal tubules and severe arterial hyalinosis, similar to that seen in calcineurin inhibitor induced tubular toxicity. PMID- 20832542 TI - Gynecologic symptoms and sexual function in female kidney allograft recipients. AB - BACKGROUND: There is little information in the literature about changing menstrual patterns, sexuality, and fertility after kidney transplantation. The purpose of this study was to describe gynecologic symptoms, menstrual characteristics, sexual functions, details of pregnancies and gynecologic care before and after women underwent renal transplantation. METHODS: A detailed Turkish questionnaire was prepared for gynecologic evaluation. Fifty women of reproductive age who underwent renal transplantation took part in this study. The questionnaires were filled out at the time of the postoperative follow-up. RESULTS: The mean age and body mass index of all study participants at the time of interview was 33.9 years (range, 18-52) and 23.5 kg/m(2) (range, 16.5-33.3), respectively. There were no differences between bleeding between periods, heavy period, painful period, and period duration before and after transplantation. Eight women left active working life after grafting on their own accord. Thirteen women ceased sexual activity after transplantation. None of the women reported pregnancy after grafting. A total of 98% of women reported that they were never instructed about regular gynecologic care. CONCLUSION: We found that restrictions in the lives of women with transplanted kidneys included ceasing sexual activity and leaving active working life and that these were due to fear of possible organ damage. Women with transplanted kidneys must be informed about posttransplant sex life and the requirement for regular examinations by a gynecologist. Hence, close collaborations should be formed between patients, primary care physicians, and gynecologists. PMID- 20832543 TI - Erectile dysfunction in living donor kidney transplant recipients associated with chronic hepatitis B infection. AB - OBJECTIVES: The objectives of this study were to investigate the prevalence of erectile dysfunction (ED) among living donor kidney transplant (LDKT) recipients associated with chronic hepatitis B infection in China and to assess the effect of successful LDKT to improve ED. MATERIALS AND METHODS: From January 2006 to May 2009, erectile function of 26 LDKT recipients associated with chronic hepatitis B infection (Group 1) was evaluated predialysis, during dialysis, and at 6 months posttransplantation using the International Index of Erectile Function, version 5 (IIEF-5). We enrolled 61 age-matched LDKT recipients without hepatitis B/C infection as a control group (Group 2). RESULTS: The prevalences of ED in Group 1 at predialysis, on dialysis, and 6 months posttransplantation were 23.1%, 80.7%, and 65.3%, respectively. Among Group 2, it was 4.9%, 72.1%, and 41.0%, respectively. The difference in ED between groups was significant at predialysis (P = .031) and 6 months posttransplantation (P = .037). Compared with the dialysis stage, the prevalence of ED at 6 months posttransplantation was significantly decreased in Group 2 (72.1% vs 41.0%; P = .001), but it was not significantly difference from Group 1 (80.7% vs 65.3%; P = .211). CONCLUSIONS: The incidence of ED among hepatitis B recipients was higher than among hepatitis B/C-negative patients at the predialysis and posttransplantation stages. Kidney transplantation is a key treatment to reduce the prevalence of ED among hepatitis B/C-negative recipients, but not those with hepatitis B. PMID- 20832544 TI - Does hepatorenal syndrome affect the result of liver transplantation? Clinical observations. AB - Hepatorenal syndrome (HRS) is a reversible, functional renal failure that occurs in patients with advanced hepatic failure. However, the reported rates of complete recovery of renal function and patient survivals after orthotopic liver transplantation (OLT) are variable. The aim of this study was to compare the outcomes after OLT between patients with HRS and those without HRS (no-HRS). We established exclusion criteria to select study patients who underwent OLT in a single center between January 2005 and October 2008. The exclusion criteria included the following: (1) malignancy, (2) <18 years of age, (3) other than primary OLT, (4) ABO mismatch or hemophilia, (5) no liver cirrhosis, and (6) survival >1 month after OLT. We selected 71 subjects, including 8 HRS and 63 no HRS patients. No significant differences were observed in the estimated glomerular filtration rate (eGFR) between the 2 groups except for a lower eGFR on the day of and 1 month after OLT in the HRS group: 108.3 +/- 40.5 versus 31.4 +/- 14.1 mL/min and 85.4 +/- 15.0 versus 57.3 +/- 12.1 mL/min (P = .000 and P = .014, respectively). The renal function of 6/7 HRS patients who survived >1 year improved. The 1-year patient survival rate after OLT in HRS patients was similar to that without HRS: 95% versus 86% (P = .37). We concluded that HRS had minimal effects on patient survival and return of acceptable renal function. PMID- 20832545 TI - Peritransplant monitoring of immune cell function in adult living donor liver transplantation. AB - PURPOSE: We evaluated the clinical utility of peritransplant in vitro assays of immune cell function in adult living donor liver transplant (LDLT) recipients. METHODS: In particular, we measured immune cell function, using the ImmuKnow assay, in 107 adult LDLT recipients and 200 potential living liver donors (control group) admitted to our center between July 2008 and January 2009. RESULTS: In the control group, the mean proportion of T-helper/inducer cells was 36.8% +/- 8.2%. The degree of immune response was strong in 12%, moderate in 77%, and low in 11%. In the study group, the degree of immune response within the first month was strong in 4.6%, moderate in 38.2%, and low in 57.2%, thus significantly lower than in the control group (P < .001). ImmuKnow results and tacrolimus levels did not show a significant correlation (r(2) = .002, P = .392). Although six patients showed biopsy-proven acute cellular rejection, none showed a strong immune response. Patients with overt infection showed a lower immune response. CONCLUSIONS: These results indicate that peritransplant assessment of immune response using the ImmuKnow assay does not reliably predict the occurrence of acute rejection. Additional studies are necessary to accurately assess the clinical utility of immune response monitoring. PMID- 20832546 TI - Timing of conversion to mammalian target of rapamycin inhibitors is crucial in liver transplant recipients with impaired renal function at transplantation. AB - BACKGROUND: Renal dysfunction, primarily related to long-term use of calcineurin inhibitor-based immunosuppression, is the most common complication after liver transplantation. OBJECTIVE: To evaluate whether liver transplant recipients with impaired kidney function at transplantation can benefit from early conversion to mammalian target of rapamycin inhibitor therapy (mTORi) compared with patients with late induction of mTORi-based therapy. MATERIALS AND METHODS: Between 2003 and 2008, therapy was changed to an mTORi-based regimen in 57 patients. Patients were divided into 4 groups: group 1, early conversion (<=3 months after orthotopic liver transplantation) to mTORi therapy, and with impaired perioperative renal function; group 2, early conversion to mTORi therapy, and with normal perioperative renal function; group 3, late conversion to mTORi therapy, and with impaired perioperative renal function; and group 4, late conversion to mTORi therapy, and with normal perioperative renal function. RESULTS: One month after conversion, the mean (SD) increase in calculated glomerular filtration rate in groups 1 (early conversion) and 3 (late conversion) was comparable: 8 (9) mL/min vs 7 (10) mL/min. At month 3, the increase in calculated glomerular filtration rate between groups 1 and 3 was significant (15 [11] mL/min vs 9 [15] mL/min; P = .04), an effect that persisted at month 6 (16 [12] mL/min vs 10 [12] mL/min; P = .05) and month 12 (22 [14] mL/min vs 12 [15] mL/min; P = .04). CONCLUSION: In liver transplant recipients with perioperatively impaired renal function, early conversion to mTORi therapy should be performed because this approach seems to be more effective in improving long-term renal function. PMID- 20832547 TI - Cardiovascular risk factors and immunosuppressive regimen after liver transplantation. AB - Cardiovascular and metabolic diseases represent important long-term complications after liver transplantation (LT), impairing long-term and disease-free survivals. A few mechanisms underlie the development of those complications, but the role of immunosuppressive drugs is major. Although several patients develop temporary metabolic diseases, which normalize after a short postoperative period and do not need long-term drug therapy, the incidences of de novo long-lasting arterial hypertension, hyperlipidemia, and diabetes mellitus are high during the first year after LT. The aim of this retrospective study was to evaluate new-onset arterial hypertension, hyperlipidemia, or diabetes among 100 LT patients at a single institution. We used chi-square statistical analysis to compare incidences during tacrolimus versus cyclosporine therapy. Hypertension did not seem to be more strongly related to tacrolimus than to cyclosporine, nor did diabetes, whereas there was a difference for the development of hyperlipidemia. PMID- 20832548 TI - Sirolimus in liver transplant recipients: a large single-center experience. AB - Sirolimus (SRL) is a newer immunosuppressant whose possible benefits and side effects in comparison to calcineurin inhibitors (CNIs) still have to be addressed in the liver transplantation setting. We report the results of the use of SRL in 86 liver transplant recipients, 38 of whom received SRL as the main immunosuppressant in a CNI-sparing regimen. Indications for the use of SRL were: impaired renal function (n = 32), CNI neurotoxicity (n = 16), hepatocellular carcinoma (HCC) at high risk of recurrence (n = 21), recurrence of HCC (n = 6), de novo malignancies (n = 4), cholangiocarcinoma (n = 1), and the need to reinforce immunosuppression (n = 6). Among patients on SRL-based treatment, four episodes of acute rejection were observed, three of which occurred during the first postoperative month. Renal function significantly improved when sirolimus was introduced within the third postoperative month, while no change was observed when it was introduced later. Neurological symptoms resolved completely in 14/16 patients. The 3-year recurrence-free survival of patients with HCC on SRL was 84%. Sixty-two patients developed side effects that required drug withdrawal in seven cases. There was a reduced prevalence of hypertension and new-onset diabetes among patients under SRL. In conclusion, SRL was an effective immunosuppressant even when used in a CNI-sparing regimen. It was beneficial for patients with recently developed renal dysfunction or neurological disorders. PMID- 20832549 TI - Effect of right ventricular dysfunction on dynamic preload indices to predict a decrease in cardiac output after inferior vena cava clamping during liver transplantation. AB - BACKGROUND: Dynamic preload indices such as stroke volume variation (SVV) and pulse pressure variation (PPV) have yielded false-positive results in patients with right ventricular (RV) dysfunction. We therefore assessed the effect of RV dysfunction on dynamic indices to predict the decrease in cardiac output (CO) during liver transplantation. METHODS: Hemodynamic parameters were measured before and after inferior vena cava (IVC) clamping in 52 recipients. The RV dysfunction was defined as an RV ejection fraction (RVEF) <= 30%. The area under the receiver operating characteristic curve (AUC) sufficient to detect changes in CO (DeltaCO) >= 20% after IVC clamping in recipients was calculated. RESULTS: Recipients with RVEF <= 30% did not show significant increases in SVV or PPV despite having DeltaCO >= 20%. In recipients with RVEF > 30%, the threshold value and AUC of SVV predicting a decrease in CO were 10% and 0.755 (compared with an AUC of 0.5, P = .011), respectively, whereas those for PPV were 10% and 0.767 (P = .007), respectively. However, in recipients with RVEF <= 30%, the threshold value and AUC of SVV were 10% and 0.638 (P = .305), respectively, whereas those for PPV were 12% and 0.684 (P = .159), respectively. CONCLUSIONS: These results suggest that dynamic preload indices may not be sufficiently sensitive to detect a CO decrease in liver transplant recipients with RV dysfunction, emphasizing the importance of evaluating RV function when determining the predictability of dynamic indices. PMID- 20832550 TI - Thromboelastography-guided transfusion decreases intraoperative blood transfusion during orthotopic liver transplantation: randomized clinical trial. AB - OBJECTIVE: To test in a prospective randomized study the hypothesis that use of thromboelastography (TEG) decreases blood transfusion during major surgery. MATERIAL AND METHODS: Twenty-eight patients undergoing orthotopic liver transplantation were recruited over 2 years. Patients were randomized into 2 groups: those monitored during surgery using point-of-care TEG analysis, and those monitored using standard laboratory measures of blood coagulation. Specific trigger points for transfusion were established in each group. RESULTS: In patients monitored via TEG, significantly less fresh-frozen plasma was used (mean [SD], 12.8 [7.0] units vs 21.5 [12.7] units). There was a trend toward less blood loss in the TEG-monitored patients; however, the difference was not significant. There were no differences in total fluid administration and 3-year survival. CONCLUSION: Thromboelastography-guided transfusion decreases transfusion of fresh frozen plasma in patients undergoing orthotopic liver transplantation, but does not affect 3-year survival. PMID- 20832551 TI - Serum vasopressin concentrations during orthotopic liver transplantation. AB - BACKGROUND: We report measurements of the temporal response of serum vasopressin concentrations in the period after reperfusion of the liver graft during orthotopic liver transplantation (OLT). METHODS: Vasopressin concentrations were determined in 11 adult patients undergoing OLT by radioimmunoassay of samples collected after induction, at 5 minutes prior to reperfusion, and at 10, 20, 30, 40, 50, 60, 90, and 120 minutes after reperfusion. RESULTS: Pre-incision vasopressin concentrations ranged from <0.5 to 2.6 pg/mL (reference serum vasopressin, <1.7 pg/mL). Overall, levels increased before reperfusion, but fell thereafter. Individual patients manifested elevated levels during the period after reperfusion. Values immediately before reperfusion exhibited most variability, ranging from 0.8 to 40 pg/mL (median, 15; interquartile range [IQR], 4-29) Median vasopressin concentrations 10 minutes postreperfusion were 7.6 pg/mL (IQR, 3-27). Only 3 of the 11 patients failed to generate vasopressin levels >20 pg/mL. In each of these patients, hemodynamics were satisfactory without the need for additional pressor infusion. Maximum vasopressin concentration measured in any patient was 85 pg/mL. There was no correlation between vasopressin concentration and mean blood pressure or systemic vascular resistance index. CONCLUSION: Vasopressin concentrations during OLT vary widely and are elevated periodically during the anhepatic and postreperfusion stages, with no apparent relationship between vasopressin concentrations and blood pressure. Although vasopressin concentrations were not as high as those measured during some other clinical situations, these data suggest that a relative vasopressin deficiency is not a direct cause of hypotension during OLT. PMID- 20832552 TI - Influence of immunosuppressive drugs on the development of CD4(+)CD25(high) Foxp3(+) T cells in liver transplant recipients. AB - INTRODUCTION: Many studies suggest that CD4(+)CD25(high) T regulatory cells (Tregs) have a crucial role in downregulating the immune response to alloantigens. In this study, we investigated the possible influence of immunosuppressive therapy, including rapamycin and calcineurin inhibitors (CNIs; tacrolimus), on level of Tregs in liver allograft recipients. MATERIALS AND METHODS: We assessed 47 liver transplant recipients with stable liver function for >=2 years, dividing them into 2 groups: Patients receiving rapamycin (n = 15), and those receiving tacrolimus (n=32). Thirty-eight, age-matched healthy subjects were used as normal controls. We examined the expression of CD4, CD25, and Foxp3 in peripheral blood T cells. Flow cytometry was performed with a FACSCalibur instrument with data analysis using Cell Quest software. RESULTS: Rapamycin significantly increased the prevalence of Tregs, including the percentage of CD4(+)CD25(high) T cells in total lymphocytes and among total CD4(+) T cells, compared with the healthy subjects and the CNI group. The prevalence of Tregs in the CNIs group was significantly lower than that of controls. Foxp3 was expressed in >95% of CD4(+)CD25(high)T cells, whereas it was in <20% of CD4(+)CD25(low) T cells and not expressed among CD4(+)CD25(-) T cells. CONCLUSIONS: Immunosuppressive therapy (rapamycin or CNIs) may have a different roles in tolerance induction among liver transplant recipients. Namely, rapamycin promoted the induction of a profile consistent with alloantigen tolerance; CNIs hampered this progression. PMID- 20832553 TI - Introduction of mycophenolate mofetil in maintenance liver transplant recipients: what can we expect? Results of a 10-year experience. AB - BACKGROUND: Mycophenolate mofetil (MMF) is a cornerstone immunosuppressive drug after liver transplantation (OLT). The aim of this study was to evaluate the long term results of the addition of MMF in maintenance OLT recipients. METHODS: From 1996 to 2006, MMF was introduced because of (1) histologic features of rejection or (2) calcineurin inhibitor (CNI) toxicity in order to reduce CNI dosage. RESULTS: The study population included 208 patients (median, age 54 +/- 9 years), with a median delay between OLT and MMF introduction of 54 +/- 43 months. The median dosage of MMF was 1180 mg/d at the end of follow-up. After a median follow up of 50 +/- 26 months, 26.4% of the patients taking MMF did present >=1 side effect and MMF discontinuation rate was 13.8% (transient in 3.8%). The main side effects were digestive disorders (45%), pruritus +/- rash +/- mucitis (12.7%), and myelosuppression (16.4%). MMF was withdrawn because of digestive disorders (17.2%), pruritus +/- rash +/- mucitis (17.2%), and myelosuppression (24.1%). The mean glomerular filtration rate as calculated by the Cockcroft-Gault formula value significantly increased after the introduction of MMF (58.1 vs 71.4 mL/min; paired t-test; P < .01). Improvement of renal function was significantly associated with initial association with tacrolimus (vs cyclosporine), initial trough level of cyclosporine (not tacrolimus), delay between OLT and MMF introduction, and age of renal impairment. CONCLUSION: Our results suggest that the introduction of MMF in OLT maintenance recipients is efficient and well tolerated (one quarter of the patients presented significant side effects, leading to treatment discontinuation in 10% of the patients). PMID- 20832554 TI - The technique and outcomes of branch-patch arterial reconstruction in living donor liver transplantation. AB - BACKGROUND: Although living donor liver transplantation (LDLT) is now an established therapeutic modality for end-stage liver disease, technical dilemmas exist. The pretransplant imaging findings may not clearly define the surgical anatomy of the hepatic artery (HA), especially its diameter. A tiny artery (<2 mm) has always been found during the hilar dissection. Its size is discrepant to the diameter to the recipient arterial stump. The aim of this paper was to report a hepatic arterial reconstruction technique for small diameter (<2 mm) vessels in a partial liver graft. METHODS: Since January 2002 to May 2007, we performed 9 LDLT with small hepatic arteries (<2 mm), which were analyzed retrospectively for this report. In this technique, we transect the donor hepatic artery proximally and distally to the tiny graft artery, take off and create a patch for arterial anastomosis. Computed tomographic angiography is used to evaluate the vascular anatomy and to measure the diameter of the graft HAs. RESULTS: All donors were discharged without any vascular complications. One donor experienced a bile leakage from the dissections plane of the liver, which was treated by draining the abdominal cavity. Eight of the 9 patients survived without evidence of hepatic artery thrombosis during 32 months (range, 14-72); one subject died due to cytomegalovirus infection. CONCLUSION: The arterial reconstruction technique enabled use of tiny arteries, eliminating the problems of diameter discrepancy without increasing donor complications. PMID- 20832555 TI - Quality of life and psychologic distress of recipients after adult living-donor liver transplantation (LDLT)-A study from mainland China. AB - This cross-sectional study investigated potential factors impacting quality of life in 125 recipients after living-donor liver transplantation (LDLT). Health related quality of life (HRQoL) was measured by using the Chinese version of Medical Outcomes Study Short Form-36 (SF-36), and psychologic symptoms by using the Symptom Checklist-90-Revised (SCL-90-R). Clinical and demographic data were collected from the records of the Chinese Liver Transplant Registry and via questionnaire. A total of 102 recipients (81.6%) completed the questionnaires. All SF-36 domain scores (except the mental health score) were lower in the study than in the general population of Sichuan. The mental quality of life was significantly lower in female than in male subjects (P = .000). Regarding the role-physical (P = .016), social functioning (P = .000), and role-emotional (P = .004) domains, recipients >1 year after transplantation scored higher than those <1 year. Bodily pain scores were lower in recipients with prior acute liver failure than those with hepatic carcinoma or hepatic cirrhosis (P = .032). Social functioning was poorer in recipients with than in those without complications (P = .039). Mental component summary scale (MCS) scores and some of physical component summary scale (PCS) significantly correlated with symptom dimension scores of the SCL-90-R (P < .05). In conclusion, gender, time since transplant, etiology of disease, complications, occupation, and some psychologic symptoms were possible factors influencing postoperative HRQoL of LDLT recipients. PMID- 20832556 TI - Safety and effectiveness of intensive insulin protocol use in post-operative liver transplant recipients. AB - There is a paucity of data regarding the safety and utility of strict glycemic control in patients undergoing orthotopic liver transplantation (OLT). Although control of hyperglycemia may theoretically be beneficial, concerns exist regarding the effect of iatrogenic hypoglycemia on graft function. We performed a retrospective observational study evaluating the impact of the introduction of a nurse-initiated glycemic control protocol on OLT recipients cared for in a single intensive care unit (ICU). The medical records of 84 OLT recipients in 2003 (Preprotocol group) and 77 recipients in 2007 (Protocol group) were reviewed. Data regarding demographics, medical history, physiology, perioperative anesthesia and surgical events, ICU stay, graft function, and mortality were abstracted. Glucose values on admission to ICU, at 2, 6, 12, 18, and 24 hours after surgery, and at 4 am on the morning after OLT were recorded. Patients in the Protocol group achieved better and faster glycemic control. The odds ratio for severe hyperglycemia (glucose >250 mg/dL) in the Protocol group was 0.16 (95% confidence interval, 0.09-0.28). Hypoglycemia was not observed. The 1-year mortality was 5.3% in the Preprotocol and 6.0% in the Protocol group (P = .86). The rate of graft loss was low, and there was no difference in the incidence of graft failure between the Preprotocol and Protocol groups. We conclude that nurse initiated and -directed glycemic control protocols can be safely and effectively used in the early period after OLT, though we did not identify a beneficial effect on graft function. PMID- 20832557 TI - Comparison of the molecular adsorbent recirculating system and plasmapheresis for patients with graft dysfunction after liver transplantation. AB - BACKGROUND: Graft dysfunction after liver transplantation (OLT) is a life- threatening condition. Molecular adsorbent recirculating system (MARS) or plasmapheresis (PLP) may be effective supportive therapy of graft dysfunction for patients who cannot undergo retransplantation. The aim of this study was to compare the effects of MARS and PLP in patients with graft dysfunction after OLT. METHODS: Between January 2002 and July 2007, 31 OLT recipients who experienced graft dysfunction, defined as hyperbilirubinemia (>10 mg/dL) without bile duct obstruction and/or presence of hepatic encephalopathy, were treated with MARS or PLP. Biochemical and hemodynamic data and survival were compared in MARS and PLP groups. RESULTS: Fifteen patients were treated with 41 MARS sessions and 16 with 105 PLP sessions. After a single MARS session, patients showed significant reductions in creatinine, urea nitrogen, bilirubin, and ammonia. After a single PLP session, patients showed significant improvements in prothrombin time, bilirubin, alanine aminotransferase, alkaline phosphatase, and albumin. After the completion of treatment, Both MARS and PLP significantly improved bilirubin values. at 90 days there were no differences in overall survival rates; 53% in MARS versus 56% in PLP. CONCLUSION: Both MARS and PLP are alternative supportive treatments for graft dysfunction after OLT. PMID- 20832558 TI - Outcomes of patients who develop symptomatic Clostridium difficile infection after solid organ transplantation. AB - Clostridium difficile-associated diarrhea is the most common cause of hospital associated diarrhea in the UK. Infection can produce a spectrum of manifestations from mild diarrhea to toxic megacolon, colonic perforation, and death. The aim of this study was to evaluate the outcomes of patients who developed symptomatic Clostridium difficile infection (CDI) within the first year after solid organ transplantation. Between 2004 and 2007, we performed 682 transplantation: 433 from deceased-donor kidney, 143 live-donor kidney, 18 pancreas-only, and 88 simultaneous kidney and pancreas transplants. Within the first year of transplantation, 24 patients developed symptomatic CDI. No single risk factor or antimicrobial agent was associated with acquiring infection. Among this group, 2 patients developed toxic megacolon requiring subtotal colectomy and recovered. Although 5 patients who developed CDI died within the first year, CDI was not the primary cause of death. The overall mortality of patients who developed CDI within the first year of transplantation accounted for 0.7% of all transplanted patients. Increased awareness of CDI and barrier nursing can minimize the impact of CDI on the morbidity and mortality associated with transplantation. Patients should be informed of the risk of CDI during consenting for transplantation, because the 3.5% incidence is more common than that of graft loss due to thrombosis. PMID- 20832559 TI - Cytomegalovirus infection after liver transplantation incidence, risks, and benefits of prophylaxis. AB - BACKGROUND: Cytomegalovirus (CMV) infection and related disease is a feared complication after liver transplantation. Antiviral prophylaxis is recommended in clinical practice guidelines depending on the CMV status of both donor and recipient as well as the individual risk profile. METHODS: We retrospectively analyzed 211 liver transplant recipients with respect to the incidence of CMV infection after transplantation, the influence of donor and recipient CMV status, and the effect of antiviral prophylaxis. In addition, the underlying liver disease and immunosuppressive regimen were compared with the incidence of CMV infection. Patients were divided into 4 groups according to CMV donor/recipient (D/R) profile: group A (D-/R-) 28 patients (13.3%), group B (D-/R+) 64 patients (30.3%), group C (D+/R+) 79 patients (37.4%), and group D (D+/R-) 40 patients (19.0%). RESULTS: CMV infection was observed in 17.9%, 29.7%, 24.1%, and 22.5% of the patients, respectively, with no significant difference in infection rates between the groups. CMV infection occurred in 5 patients (17.9%) in the presumed low-risk profile (group A), despite an antiviral prophylaxis in 4 out of these 5 patients. In contrast, CMV infection occurred in only 9/40 patients (22.5%) in the presumed high-risk profile (group D). The most frequent infection rates were found in groups B and C (R+ groups). After successful treatment of CMV infection, no recurrence was detected. Underlying liver disease or immunosuppressive protocol had no influence on CMV infection. CONCLUSION: Approximately one fourth of patients will acquire CMV infection after liver transplantation independent of donor/recipient status. Surprisingly, antiviral prophylaxis does not seem to be sufficient to reduce this proportion of patients, either in presumed high-risk or in presumed low-risk situations. PMID- 20832560 TI - Graft loss and poor outcomes after living-donor liver transplantation owing to arterioportal shunts caused by liver needle biopsies. AB - BACKGROUND: Arterioportal shunts (APS) are well-known critical complications after liver transplantation (OLT). The aims of this study were to assess the frequency and causes of APS after OLT and to analyze APS patients with poor outcomes. PATIENTS: We evaluated 1415 OLT recipients retrospectively investigating APS cases. RESULTS: APS were detected in at least 9 patients (0.6%). All patients with APS had a history of posttransplant invasive procedures; percutaneous transhepatic cholangio drainage (n = 6) or needle biopsy (LNB; n = 3). Two patients with poor outcomes showed proximal APS caused by LNBs. The other 7 patients with distal APSs, showed stable conditions. Imaging findings in the 2 proximal APS patients revealed drastic changes in graft hemodynamics. Although they finally underwent re-OLT, their outcomes were poor, owing to fatal complications associated with advanced collaterals. CONCLUSION: We concluded that even careful LNBs can cause APS at unexpected points. Earlier, more aggressive treatments are required, especially for proximal APS patients. PMID- 20832561 TI - Simultaneous pancreas-kidney transplantation: which organ should be transplanted first? AB - Simultaneous pancreas-kidney transplantation (SPKT) has been accepted as treatment for type I diabetic patients with end-stage renal disease. Its success depends largely on the surgical technique. This study sought to compare groups of SPKT with initial pancreas implantation versus initial kidney implantation. From December 2000 to September 2006, 151 SPKT were performed by a single center. In 85 cases, the pancreas was implanted first (group 1), and in 66 cases the order was inverted (group 2). Variables were implantation sequence, pancreas and kidney ischemia time, donor age, venous drainage, previous donor peritoneal dialysis, and recipient age and gender. Outcome variables included pancreas vascular thrombosis, 3-month graft survival, 3-month patient survival, pancreas rejection episodes, intra-abdominal infection, diabetes control and reoperations. We observed a 10.6% incidence of vascular thrombosis in group 1 but none in group 2 (P = .005). In groups 1 and 2, the 3-month pancreas survivals were 74.1% and 89.4% (P = .022), and the mean hospital stays were 24.3 and 15.8 days, respectively (P = .002). Our results suggested that, when 2 different teams are involved in SPKT, with >1 exposure and the need for retractor replacement, the kidney should be transplanted first, because the pancreas may be damaged during the surgical procedure. PMID- 20832562 TI - Outcomes after simultaneous pancreas and kidney transplantation and the discriminative ability of the C-peptide measurement pretransplant among type 1 and type 2 diabetes mellitus. AB - BACKGROUND: Earlier studies reporting outcomes after pancreas transplantation have included a combination of C-peptide cutoffs and clinical criteria to classify type 2 diabetes mellitus (T2DM). However, because the kidney is the major site for C-peptide catabolism, C-peptide is unreliable to discriminate the type of diabetes in patients with kidney disease. METHODS: To improve the discriminative power and better classify the type of diabetes, we used a composite definition to identify T2DM: presence of C-peptide, negative glutamic acid decarboxylase antibody, absence of diabetic ketoacidosis, and use of oral hypoglycemics. Additionally among T2DM patients with end-stage renal disease (ESRD), body mass index of <30 kg/m(2) and use of <1 u/kg of insulin per day were selection criteria for suitablity for simultaneous pancreas and kidney transplantation (SPKT). We compared graft and patient survival between T1DM and T2DM after SPKT. RESULTS: Our study cohort consisted of 80 patients, 10 of whom were assigned as T2DM based on our study criteria. Approximately 15% of patients with T1DM had detectable C-peptide. Cox regression survival analyses found no significant differences in allograft (pancreas and kidney) or patient survival between the 2 groups. The mean creatinine clearance at 1 year estimated by the modification of Diet in Renal Disease (MDRD) equation was not significantly different between the 2 groups. Among those with 1 year of follow-up, all patients with T2DM had glycosylate hemoglobin of <6.0 at 1 year versus 92% of those with T1DM. CONCLUSION: SPKT should be considered in the therapeutic armamentarium for renal replacement in selected patients with T2DM and ESRD. Use of C-peptide measurements for ESRD patients can be misleading as the sole criterion to determine the type of diabetes. PMID- 20832563 TI - Cartilage oligomeric matrix protein-angiopoientin-1 enhances angiogenesis of isolated islet and maintains normoglycemia following transplantation. AB - Islet transplantation (ITx) has potential as a therapy for patients with type 1 diabetes. For successful engraftment and insulin independence, the transplanted islets must establish an adequate, stable blood supply. Angiopoientin-1 (Ang1) is a specific growth factor that induces vascularization via the Tie2 or Tie1 receptor. In this study, we used an in vitro angiogenesis assay to evaluate islet function following transplantation and the effect of the Ang1 variant cartilage oligomeric matrix protein (COMP) Ang1 on isolated islets. The enhanced function of islets transduced with COMP-Ang1 was also confirmed in a streptozotocin (STZ) induced diabetic mice model. In a three-dimensional collagen-based culture system, the transduction of COMP-Ang1 into islets significantly increased angiogenesis compared with the bacterial-beta-galactosidase (LacZ)-transduced controls and an intact, nontransduced islet negative control group. COMP-Ang1 transduced islets also attenuated hyperglycemia in syngeneic diabetic C57BL/6 mice and enhanced glucose tolerance by areas under the curves of intraperitoneal glucose tolerance tests. These findings demonstrated the capacity of COMP-Ang1 to promote revascularization in cultured islets, which may contribute to successful transplantation in vivo. PMID- 20832564 TI - Suppressor of cytokine signaling 1 inhibits apoptosis of islet grafts through caspase 3 and apoptosis-inducing factor pathways in rats. AB - A significant portion of pancreatic islet grafts can be destroyed by apoptosis, failing to engraft in the early period after transplantation. Recently, we observed that overexpression of suppressor of cytokine signaling 1 (SOCS1) in islet grafts achieved an antiapoptotic effect, prolonging graft survival in a rat transplant model. Caspase 3 is the central executioner caspase that is activated by upstream cascades in a caspase-dependent apoptosis pathway. Apoptosis inducing factor (AIF) is a key protein that can be released from mitochondria, translocating to the nucleus in the caspase-independent apoptosis pathway. In this study, we investigated whether these two pathways were involved in cytoprotection afforded by SOCS1 on islet grafts. We used a chimeric adenovirus vector (Ad5F35-SOCS1) to enhance SOCS1 expression in isolated Sprague-Dawley rat islets, which were transplanted into recipients experiencing streptozotocin induced diabetes. We analyzed the expressions of active (cleaved) caspase 3 and AIF on islets. The Ad5F35-SOCS1-infected islets with higher SOCS1 expression showed decreased levels of active caspase 3 and intranuclear AIF after treatment with tumor necrosis factor-alpha and cycloheximide in vitro. The diabetic recipients transplanted with Ad5F35-SOCS1-infected islets showed longer periods of normoglycemia versus recipients transplanted with mock-infected islets (P < .05) due to prolonged graft survival. A histological analysis indicated that the Ad5F35-SOCS1-infected islet grafts displayed decreased caspase 3 activation and AIF translocation (to nucleus) in the early posttransplant period. These results demonstrated that the expression of SOCS1 in islet grafts protected them from apoptosis through caspase 3 dependent and AIF caspase-independent-pathways. PMID- 20832565 TI - Prolongation of islet graft survival using concomitant transplantation of islets and vascular endothelial cells in diabetic rats. AB - BACKGROUND: The transplantation of isolated islets of Langerhans is nearing acceptance as treatment of type 1 diabetes mellitus. Because the arterial and venous connections of the pancreas are disrupted during islet isolation, islets must be revascularized after transplantation. OBJECTIVE: To observe whether increased numbers of vascular endothelial cells in islets can affect the angiogenesis and function of the grafts. MATERIALS AND METHODS: Rats with streptozocin-induced diabetes were divided into 3 groups. The rats in group 1 received islet grafts under the capsule of the left kidney; rats in group 2 received combined vascular endothelial cell and islet transplants; and rats in group 3 served as controls. After the transplantation procedure, blood glucose and insulin concentrations were evaluated daily. Hematoxylin-eosin and immunohistochemical staining was used to detect expression of vascular endothelial growth factor antibodies in the diabetic rat kidneys. The mean microvascular density was also calculated. RESULTS: At 3 days posttransplantation, blood glucose and insulin concentrations returned to normal in group 2, however, they declined only slightly in group 1, and moderate hyperglycemia was present. There was a significant difference in blood glucose and insulin concentrations between the 2 groups after 3 days (P < .05). The mean (SD) microvascular density in group 2 was markedly higher than that in group 1 (12.58 [1.81] vs 10.38 [0.97] P = .04). CONCLUSION: This study suggests that concomitant transplantation of isolated islets with endothelial cells can prolong islet graft survival in diabetic rats. PMID- 20832566 TI - Intramedullary cavity as implantation site for bioartifical pancreas: preliminary in vivo study. AB - BACKGROUND: The intramedullary cavity is a widely distributed well-vascularized microenvironment capable of sustaining grafts, and is a potential site for islet transplantation. The bone marrow offers sufficient space that may also be suitable for bioartificial pancreas (BAP) implantation. OBJECTIVE: To evaluate the feasibility of bone marrow as an implantation site for BAPs. MATERIALS AND METHODS: A calcium phosphate cement chamber satisfies the criteria for immunoisolation. Mouse insulinoma cells were suspended with agarose gel and enclosed in a calcium phosphate cement chamber to create a BAP, which was implanted in the intramuscular space in diabetic swine or the intramedullary cavity in diabetic dogs. Blood glucose and C-peptide concentrations were determined perioperatively. RESULTS: In the swine, the mean +/- SD blood glucose concentration decreased from 413 +/- 24 mg/dL to 285 +/- 47 mg/dL, and was maintained in the range of 285 to 336 mg/dL for 15 days. It increased to 368 to 450 mg/dL after the BAPs were implanted in the intramuscular space. In the dogs, the blood glucose concentration decreased from 422 +/- 32 mg/dL to 247 +/- 52 mg/dL, and was maintained in the range of 247 to 347 mg/dL after the BAPs were implanted in the intramedullary cavity. The C-peptide concentration increased from 6.1 +/- 2.8 pmol/L to 104.7 +/- 16.4 pmol/L when the BAPs were implanted in the intramedullary cavity. CONCLUSION: This study indicates superior effectiveness of BAPs implanted in the intramedullary cavity compared with the intramuscular space. This observation may be attributed to the greater oxygen tension in the bone marrow. The BAPs in direct contact with the circulatory system receive sufficient blood flow for function and survival. This preliminary study demonstrates that the intramedullary cavity may be an implantation site for BAP transplantation. PMID- 20832567 TI - Histologic features of cytomegalovirus enteritis in small bowel allografts. AB - BACKGROUND: Cytomegalovirus (CMV) is one of the most common viral infections to affect solid organ transplant patients, most frequently owing to reactivation of a latent infection as a result of immunosuppression. CMV enteritis (CE) may enter into the differential diagnosis of acute rejection in biopsies of small bowel (SB) allografts, where differentiation is important due to disparate therapies. OBJECTIVE: The aim of this study was to identify histologic features in SB allografts that may suggest CE. METHODS: The case files for a single institution were queried for all cases of SB mucosal biopsies with cells positive by CMV immunoperoxidase staining. Morphologic and clinical information was reviewed. RESULTS: Six biopsies demonstrating immunoperoxidase-confirmed CE were identified in a retrospective review of the records of a single institution. A common predisposing factor was the administration of high-dose steroids within a month before CE diagnosis. Most cases (66%) displayed a demarcated area of villous/crypt loss with an abundance of plasma cells and lymphocytes and a paucity of eosinophils. One case showed an acute enteritis-like pattern of injury, corresponding with a higher number of CMV-positive cells. CMV inclusions were visible on hematoxylin-eosin stains in all but 1 case. In no case were histologic criteria for acute cellular rejection met. CONCLUSIONS: The presence of circumscribed area of mucosal injury with few eosinophils or an acute enteritis pattern should prompt the identification of viral inclusions or the acquisition of a CMV immunostain. PMID- 20832568 TI - Acute rejection of small intestine allografts is associated with increased expression of toll-like receptors. AB - Although outcomes after intestinal transplantation have steadily improved owing to advances in immunosuppressive therapy, operative techniques, and postoperative medical management, rejection of the intestinal allograft continues to be a major clinical problem and constitutes the primary reason for graft loss. Although the adaptive immune system has been the major focus of investigation regarding regulation of rejection of the intestinal allograft, the role of the innate immune system has recently become of increased interest. We hypothesized that microbial products of the microflora associated with the intestinal allograft may engage the Toll-like receptor pathway of the innate immune system to potentiate alloimmune responses and rejection of the allograft. To investigate this, we established a murine model for orthotopic intestinal transplantation and allograft rejection. Using this model, we show that the expression of Toll-like receptor 2 is increased 50-fold and the expression of Toll-like receptor 4 is increased 200-fold during rejection of the allograft. We then performed survival studies that showed increased survival of mice, which had the Toll-like receptor knocked out. These preliminary studies suggest an important role for in innate immune system in acute rejection of the small intestinal allografts, and as such represents an emerging and promising area of investigation. PMID- 20832569 TI - Resting alveolar gas tensions as a mortality prognosticator in chronic heart failure. AB - BACKGROUND: Increased end-tidal oxygen (ET-O(2)) and decreased end-tidal carbon dioxide (ET-CO(2)) gas tensions are noninvasively measurable correlates of ventilatory inefficiency, leading to increased ventilatory requirements relative to gas exchange among patients with chronic heart failure (CHF). We investigated the prognostic value of ET-O(2) and ET-CO(2) as predictors of CHF mortality. METHODS: We measured resting ET-O(2) and ET-CO(2) electrochemically in 134 patients with symptomatic CHF in the supine position. We used Kaplan-Meier analysis, Cox proportional hazard models, and receiver operating characteristic curves to test our hypothesis. RESULTS: At a median follow-up of 16.5 months, 32 patients had died. ET-O(2) levels were increased (P = .001) and ET-CO(2) levels decreased (P = .002) with increased New York Heart Association class (I-IV). Survivors showed lower ET-O(2) (121 vs 118 mm Hg; P = .021) and higher ET-CO(2) (33.2 vs 32.1 mm Hg; P = .032) levels than nonsurvivors. Patients with ET-O(2) values >=121 mm Hg and/or ET-CO(2) values <31 mm Hg had an increased risk of death with hazard ratios of 2.93 (95% confidence interval [CI], 1.43-6.01) and 2.47 (95% CI, 1.23-4.97), respectively. Kaplan-Meier estimates for follow-up mortality with ET-O(2) >=121 mm Hg and/or ET-CO(2) <31 mm Hg were 83.8% (vs 60.1%; P = .0014) and 80.3% (vs 60.2%; P = .0061), respectively. Areas under the receiver operating characteristic curves for prediction of death with ET-O(2) and ET-CO(2) were both significant and similar to that of echocardiographic left ventricular function. CONCLUSIONS: In CHF, high levels of ET-O(2) and low levels of ET-CO(2) are associated with increased mortality. We suggest that the measurements may be useful prognostic markers for risk stratification. PMID- 20832570 TI - Effect of blood product transfusion-induced tolerance on incidence of cardiac allograft rejection. AB - BACKGROUND: Blood product transfusion has been successfully used in solid-organ transplantation to induce tolerance. Whether a similar protective effect of blood product transfusion exists in heart transplantation is controversial. OBJECTIVE: To investigate the effect of cellular blood product transfusion within 2 weeks posttransplantation on the incidence of cellular and antibody-mediated rejection. PATIENTS AND METHODS: Patients were grouped on the basis of number of blood transfusions; group 1 received no transfusions, and groups 2, 3, and 4 each received an incremental number of transfusion units. All endomyocardial biopsy samples were routinely studied using immunofluorescence in the first 12 weeks posttransplantation. RESULTS: Baseline characteristics including age, sex, body mass index, history of diabetes, donor characteristics, and pretransplantation laboratory values were similar except that group 4 had a higher rate of previous sternotomy and longer ischemic time during transplantation. Approximately 9200 endomyocardial biopsy samples composed the data. Short- and long-term freedom from the International Society for Heart & Lung Transplantation grade 3A or higher cellular rejection and from antibody-mediated rejection were comparable between groups. CONCLUSIONS: Blood transfusions within the first 2 weeks post transplantation do not seem to confer any protective effect against posttransplantation cellular rejection or antibody- mediated rejection. Whether other unmeasured confounding factors mask their effect requires further prospective studies. PMID- 20832571 TI - Sirolimus is associated with impaired hematopoiesis in heart transplant patients? A retrospective analysis. AB - BACKGROUND: Proliferation signal inhibitors may adversely impact bone marrow function. We sought to describe the impact of sirolimus on hemoglobin and erythropoiesis in heart transplant recipients. METHODS: We have conducted a single-center, retrospective analysis of all heart transplant patients treated with sirolimus. We measured serum hemoglobin (Hb) at baseline and at 3 months to determine the prevalence of anemia and change in Hb after sirolimus initiation. We also characterized hematologic profile of patients to gain insights into the effects of sirolimus on erythropoiesis. RESULTS: There were 84 patients included in the study. The prevalence of anemia increased from 71% to 75% after sirolimus initiation. Anemic patients were more likely to be male (P = .026) and have worse renal function (glomerular filtration rate 49 +/- 27 vs 70 +/- 42 mL/min; P = .012). A >=20 g/L drop in Hb was observed in 25% of the overall cohort. Patients investigated for anemia (n = 67) had a low Hb (111 +/- 24 g/L), normal mean corpuscular volume (87 +/- 47 FL), and low serum iron levels (10 +/- 5 MUmol/L) and transferrin saturation (0.22 +/- 0.12). Serum ferritin was variable (263 +/- 370 MUg/L). Bone marrow evaluation in 19 patients revealed adequate marrow iron stores in all cases. CONCLUSION: Anemia is prevalent in heart transplant patients treated with sirolimus and increases over time. Patients have a characteristic hematologic profile suggestive of anemia of chronic disease and functional iron deficiency. PMID- 20832572 TI - Atrial flutter after heart transplantation: mechanism and catheter ablation. AB - BACKGROUND: Atrial flutter is a frequent arrhythmia after heart transplantation, but little is known about its mechanism and treatment. We report the results of an electrophysiologic study in patients with atrial flutter after orthotopic heart transplantation, describing its mechanism and demonstrating the acute and long-term efficacy of catheter ablation for treating this arrhythmia. METHODS: We included 14 patients with symptomatic atrial flutter after orthotopic heart transplantation. All of them underwent an electrophysiologic study to determine the mechanism of the arrhythmia and catheter ablation when possible. RESULTS: Counterclockwise right atrial circuit around the tricuspid annulus involving the cavotricuspid isthmus was demonstrated in 13 patients (86%). Catheter ablation of the isthmus was performed with good acute results in all but 1. During a mean follow-up of 24 +/- 17 months, recurrent atrial flutter was documented in 3 patients and atrial fibrillation in 2. In another patient, we demonstrated a left atrial origin. CONCLUSIONS: The most common mechanism of atrial flutter in heart transplant recipients is a counterclockwise circuit around the tricuspid annulus involving the cavotricuspid isthmus. Catheter ablation of the isthmus between tricuspid annulus and posterior atrial suture line represents an effective treatment in these patients. This condition may be avoided by changing the surgical technique to a bicaval anastomosis. PMID- 20832573 TI - Gastroesophageal reflux disease is associated with an increased rate of acute rejection in lung transplant allografts. AB - PURPOSE: Gastric fundoplication (GF) for gastroesophageal reflux disease (GERD) may protect against the progression of chronic rejection in lung transplant (LT) recipients. However, the association of GERD with acute rejection episodes (ARE) is uncertain. This study sought to identify if ARE were linked to GERD in LT patients. METHODS: This single-center retrospective observational study, of patients transplanted from January 1, 2000, to January 31, 2009, correlated results of pH probe testing for GERD with ARE (>=International Society for Heart and Lung Transplantation A1 or B1). We compared the rates of ARE among patients with GERD (DeMeester Score > 14.7) versus without GERD as number of ARE per 1,000 patient-days after LT. Patients undergoing GF prior to LT were excluded. RESULTS: The analysis included 60 LT subjects and 9,249 patient-days: 33 with GERD versus 27 without GERD. We observed 51 ARE among 60 LT recipients. The rate of ARE was highest among patients with GERD: 8.49 versus 2.58, an incidence density ratio (IDR) of 3.29 (P = .00016). Upon multivariate negative binomial regression modeling, only GERD was associated with ARE (IDR 2.15; P = .009). Furthermore, GERD was associated with multiple ARE (36.4% vs 0%; P < .0001) and earlier onset compared with patients without GERD: ARE proportion at 2 months was 0.55 versus 0.26 P = .004). CONCLUSION: In LT recipients, GERD was associated with a higher rate, multiple events, and earlier onset of ARE. The efficacy of GF to reduce ARE among patients with GERD needs further evaluation. PMID- 20832574 TI - Lung transplantation for severe antineutrophilic cytoplasmic antibody-associated vasculitis. AB - Antineutrophil cytoplasmic antibody-associated vasculitis is a life-threatening disorder for which medical therapy has greatly improved survival. However, there is still significant mortality associated with antineutrophil cytoplasmic antibody-associated vasculitis. Little data exists on the utility of lung transplantation for patients, especially with an acute and severe form of this disease. Herein, we report successful lung transplantation for a patient with life-threatening pulmonary hemorrhage and respiratory failure as a consequence of this pulmonary renal syndrome. PMID- 20832575 TI - The impact of bone marrow fibrosis on the outcome of hematopoietic stem cell transplantation. AB - We retrospectively analyzed the data of 175 patients who underwent autologous (n = 69) or allogeneic hematopoietic stem cell transplantation (HCT) (n = 106) including 19 (27.5%) and 38 (35.8%) recipients who had bone marrow fibrosis (BMF) prior to transplantation, respectively. We investigated the effects of BMF on engraftment, graft-versus-host disease (GVHD), early posttransplant complications, and survival. Pretransplantation BMF did not delay engraftment and showed no impact either on early posttransplant complications or on the development of acute and/or chronic GVHD. Probability of 1-year overall survival (OS) and progression-free survival (PFS) of autologous HCT recipients were similar, namely 76.7% versus 88.6% (P > .005) and 26.33% versus 16.5% (P > .05) among patients with versus without fibrosis, respectively. In allogeneic HCT recipients, the probability of 1-year OS was 35.2% among patients with versus 48.9% among those without fibrosis (P = .004) PFS at 1 year was inferior among allogeneic HCT recipients with BMF: 27.8% versus 51.2% (P = .0008). Cox regression analysis revealed BMF to be independently associated with age, Sorror comorbidity index, primary disease, and disease status during HCT (P = .045). PMID- 20832576 TI - Vascular endothelium changes after conditioning in hematopoietic stem cell transplantation: role of cyclophosphamide and busulfan. AB - Vascular endothelial injury, a feature of some complications of hematopoietic stem cell transplantation (HSCT), is characterized by increased endothelial cells. We investigated that classical pretreatment drugs in HSCT could result in vascular endothelial injury in mice. Six-to eight-week-old female BALB/c mice were divided into a control group, a cyclophosphamide group (60 mg/kg per day for 2 days) and a busulfan group (4 mg/kg per day for 4 days). We observed the general state of health and regularly counted the number of white blood cells. Circulating endothelial cells and their progenitors were estimated by flow cytometry. Morphologic endothelial changes were analyzed with optical and transmission electron microscopy. After conditioning with cyclophosphamide or busulfan, white blood cells fell to a low number with injuries noted on hematoxylin and eosin-stained pathology sections. Circulating endothelial cells and their progenitors peaked significantly higher than in the control group. Vascular endothelial injuries were observed in the 2 experimental groups by transmission electron microscopy. These data support the hypothesis the vascular endothelial injury occurs during conditioning with cyclophosphamide or busulfan for HSCT, with simultaneous mobilization of endothelial progenitor cells. PMID- 20832577 TI - Micafungin does not influence the concentration of tacrolimus in patients after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: Tacrolimus is commonly used in stem cell transplant recipients for prophylaxis of graft-vs-host disease. Micafungin is widely used as a strong antifungal agent in empirical therapy in patients with febrile neutropenia. Both tacrolimus and micafungin are substrates of cytochrome P450 3A4 in vitro. Therefore, there is risk of drug interaction with concomitant administration of these drugs. OBJECTIVE: To estimate the drug interaction of tacrolimus and micafungin by evaluating the pharmacokinetics in 6 patients who had undergone allogeneic stem cell transplantation. RESULTS: The mean (SD) concentration-dose ratio of tacrolimus in all patients at 1, 4, 8, and 24 hours after concomitant administration of micafungin was 607 +/- 306, 653 +/- 328, 699 +/- 340 and 671 +/ 403 (ng/mL)/(mg/kg/d), respectively, and without micafungin was 756 +/- 314 (ng/mL)/(mg/kg/d). The percentage of the concentration-dose ratio in patients treated with tacrolimus and micafungin vs patients treated with tacrolimus alone was 98%, 105%, 112%, and 108% at 1, 4, 8, and 24 hours, respectively. For both tacrolimus and micafungin, the 90% confidence intervals for the primary pharmacokinetic parameters (ie, the concentration-dose ratio at each point) ranged from 80% to 125%. CONCLUSION: We conclude that there is no drug interaction between tacrolimus and concomitantly administered micafungin in stem cell transplantation recipients. PMID- 20832578 TI - Microdystrophin delivery in dystrophin-deficient (mdx) mice by genetically corrected syngeneic MSCs transplantation. AB - Cell transplantation and gene therapy are two promising therapeutical approaches for the treatment on Duchenne Muscular Dystrophy (DMD). However, both strategies have met many hurdles, mainly because of the absence of an efficient systemic delivery system on gene therapy and immune reactionns on cell transplantation. In this project, we investigated the strategy based on combination of these two basic ones, ie, transplantation of transgene-corrected mdx mesenchymal stem cells (MSCs) into mdx mice to cure DMD. The MSCs isolated from male mdx mice were transduced with recombinant adenovirus including human microdystrophin gene and labeled with BrdU were transplanted into female mdx mice, the Chimerism with the sex-determinant Y chromosome and human microdystrophin expression were detected. Simultaneously, the plasma creatine kinase (CK) activity, the improvement with the muscles' pathology and contractile propertie were evaluated. The results clearly demonstrated that some human dystrophin and BrdU expression collectively were detected in some muscles of transplanted mdx mice. Moreover, the CK activity and percentage of centrally nucleated fiber (CNF) decreased slightly after transplanation. Regrettably, the protective effect on contraction-induced injury in TA and diaphragm muscles wasn't significantly improvement after transplantation. Our results suggested, if enhancement on the efficiency with cell transplantation, that the transplantation of autologous MSCs corrected by dystrophin may be a form to treat DMD patients in future. PMID- 20832579 TI - The impact of early rehabilitation on the duration of hospitalization in patients after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: We examined the relationship between the improved physical activity by early rehabilitation and the duration of hospitalization among patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Thirteen allo-HSCT patients with myeloablative conditioning regimens (group A) and 13 patients with nonmyeloablative conditioning regimens (group B) were assessed retrospectively in this study. All patients received physical exercise immediately after neutrophil engraftment at the class 10,000 bioclean room (class 10,000). The mean daily steps at class 10,000 were measured as a substitute for the amount of physical activity, and the duration of hospitalization as one of the clinical outcomes. RESULTS: The degree of physical activity showed a negative correlation with the duration of hospitalization in group A (r = -.71; P = .0071), regardless of complications such as acute graft-versus-host disease, infections, and cytomegalovirus reactivation. However, there was no significant association in group B (r = .09; P = .77). CONCLUSION: The improved physical activity through early rehabilitation may be an independent, favorable prognostic factor for allo-HSCT patients with myeloablative conditioning regimens. PMID- 20832580 TI - Streptozotocin-induced diabetic rat-derived bone marrow mesenchymal stem cells have impaired abilities in proliferation, paracrine, antiapoptosis, and myogenic differentiation. AB - BACKGROUND: Diabetes has been widely recognized as a major risk factor for cardiovascular disease. With the development of the regenerative medicine, autologous bone marrow-derived mesenchymal stem cells (BMSCs), transplantation can effectively improve cardiac function after myocardial infarction. However, the BMSCs used in most previous studies are derived from young or normal donors. Little is know about the biological characters change of BMSCs in diabetes mellitus. METHODS: BMSCs were taken from the streptozotocin (STZ)-induced diabetic rats and normal control rats. Cell proliferation was evaluated by CCK-8 assay. Production of vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-1 were measured by enzyme-linked immunosorbent assay. Apoptosis under hypoxia and serum deprivation culture conditions were detected by Hoechst 33342 stain and flow cytometry. Myogenic differentiation, induced by 5 azacytidine was assessed by using immunocytochemical staining for the expression of sarcomeric alpha-actin and desmin. RESULTS: Diabetic rat models were successfully induced by intraperitoneal injection of STZ. The proliferative abilities of BMSCs derived from diabetic rats decreased significantly compared with that from normal rats (P < .05). Similar results were also presented in the cytokines (VEGF and IGF-1) release (P = .02 and P < .01, respectively) that the ability of antiapoptosis and myogenic differentiation decreased obviously between diabetes group and the normal control group (P < .01). CONCLUSION: BMSCs from STZ induced diabetic rats could be successfully harvested and expanded in vitro culture condition; their morphology was very similar to normal control group, with minor changes. However, the proliferative and differentiation properties of diabetic BMSCs, as well as cytokine release and antiapoptosis ability, were significantly impaired. PMID- 20832581 TI - Correlation between the immature characteristics of umbilical cord blood-derived mesenchymal stem cells and engraftment of hematopoietic stem cells in NOD/SCID mice. AB - Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSC) facilitate the engraftment of human (h) hematopoietic stem cells when transplanted simultaneously in animal and human studies. However, the type of MSCs that preferentially enhance the engraftment of HSCs is unknown. Recent studies have shown that MSCs derived from a single source are heterogeneous in terms of cell size, morphology, proliferation rate, and differentiation potential. This study was designed to investigate the properties of UCB-MSCs, which influence the engraftment of hHSCs in a NOD/SCID mouse model. We categorized MSCs as being the most effective (UCB-352 MSCs) or the least effective (UCB-156 MSCs) at promoting the homing and engraftment of HSCs, and compared the characteristics of these 2 MSC populations. We observed that the 2 populations showed differences in characteristics typical of immature MSCs, and related to proliferation potential. We showed that UCB-352 MSCs, which proliferate quickly, preferentially enhanced the engraftment of HSCs in NOD/SCID mice. In addition, we observed differences in the pattern of both PODXL and Oct4 expression, and in the levels of cytokines such as SDF-1 and SCF using flow cytometry and membrane arrays. The more effective UCB-352 MSCs expressed higher levels of PODXL and Oct4, which were associated with immaturity, than did the UCB-156 MSCs. Furthermore, UCB-352 cells secreted greater levels of SDF-1 and SCF, both of which are required for hematopoiesis. We propose that the proliferation potential of UCB-MSCs, coupled with their immature characteristics, may serve as a novel standard to promote the homing and engraftment of HSCs. PMID- 20832582 TI - Mast cell protease 6 is required for allograft tolerance. AB - It has been shown that mast cells (MC) are absolutely required for transplant acceptance. However, only a few of the numerous mediators produced by MC have been proposed as potential mechanisms for the observed immunosuppression. The role of proteases in acquired immune tolerance as such has not yet been addressed. In this study, we have shown the requirement for MC protease 6 (MCP6), an MC-specific tryptase, to establish tolerance toward an allogeneic skin graft. The substrate for MCP6 is interleukin (IL)-6, cytokine generally considered to indicate transplant rejection. Herein we have shown an inverse correlation between MCP6 and IL-6. High expression of MCP6 is accompanied by low levels of IL 6 when the allograft is accepted, whereas low expression of MCP6 in combination with high levels of IL-6 are observed in rejecting grafts. Moreover, tolerance toward an allogeneic graft cannot be induced in MCP6(-/-) mice. Rejection observed in these mice was comparable to that of MC-deficient hosts; it is T-cell mediated. These findings suggest that MCP6 actively depletes the local environment of IL-6 to maintain tolerance. PMID- 20832583 TI - Eotaxin/CCL11 levels correlate with myocardial fibrosis and mast cell density in native and transplanted rat hearts. AB - INTRODUCTION: Myocardial fibrosis contributes to hemodynamic and cardiac functional alterations commonly observed posttransplantation. Cardiac mast cells (MC) have been linked to fibrosis in posttransplantation hearts. Eotaxin, which has been shown to be involved in fibrogenesis, has been demonstrated to be increased in production in cardiac macrophages. The aim of our study was to correlate myocardial fibrosis during heart transplant rejection in the rat with eotaxin/chemokine [c-c motif] ligand 11 (CCL11) expression, and with various subtypes of infiltrating cardiac MC, namely connective-type MC (CTMC) and mucosa type MC (MMC). METHODS: We used tissues from 2 previous studies of ongoing acute rejection in allogeneic Brown-Norway to Lewis rat and an isogeneic Brown-Norway to Brown-Norway heterotopic heart transplantation models under cyclosporin/prednisolone immunosuppression. Collagen fibrils were stained with Masson's trichrome with myocardial fibrosis expressed as percent fibrotic area per total section area. Eotaxin/CCL11 previously measured in heart tissue using enzyme-linked immunosorbent assay (ELISA) was correlated with the extent of myocardial fibrosis. We compared values from native hearts (n = 4) as well as transplants on days 5, 16, and 28 (n = 4 in each group). RESULTS: The area of myocardial fibrosis was significantly increased in the allogeneic compared with the isogeneic group at day 16 (38% vs 21%) and at day 28 (49% vs 22%) after transplantation. Myocardial fibrosis correlated significantly with eotaxin/CCL11 concentrations and the density of MMC, but not with CTMC in heart tissue. CONCLUSIONS: Eotaxin-triggered MC infiltration of the heart may contribute to myocardial fibrosis after transplantation. Targeting eotaxin/CCL11 with monoclonal antibodies, such as bertilimumab, could reduce MC infiltration, possibly resulting in decreased myocardial fibrosis and improved contractile function after heart transplantation. PMID- 20832584 TI - An experimental approach toward chronic pulmonary allograft rejection: Orthotopic lung versus heterotopic tracheal segment transplantation in rats. AB - BACKGROUND: Despite the impact of chronic rejection (CR) on long-term outcomes, clinically relevant experimental models are sparse, often including a design of subcutaneous implantation of tracheal segments. However, this latter site lacks anatomic correlation, adequate perfusion, and ventilatory function. In this study, we compared the spatial and sequential course of CR in models of orthotopic single lung transplantation (LT) versus heterotopically implanted tracheal segments in rats. METHODS: We performed 30 orthotopic left single LTs from Fisher 344 (F344) to Wistar Kyoto (WKY) rats for comparison with the outcomes of 3 tracheal segments implanted subcutaneously in every recipient. As a control group, 3 syngeneic tracheal segments were implanted into 12 WKY rats. For histopathologic examinations, tracheal segments and pulmonary allografts were harvested between days 1 and 112 and between weeks 4 and 18, respectively. RESULTS: Allogeneic tracheal segments showed rapid fragmentation of the respiratory epithelium, with complete luminal occlusion by week 4, whereas the lumen in isografts remained unobstructed. In contrast, bronchioles from orthotopically transplanted lungs did not show epithelial changes before week 14. However, marked lymphocytic sequestration into bronchioles occurred by week 8 with sequential destruction of all layers of the small airways, with loss of respiratory epithelium by week 16. CONCLUSIONS: Based on the different histomorphologic dynamics of CR, direct comparison between those 2 models is limited. When investigating CR in future studies, initial findings based on tracheal implantation experiments should be expanded in the site of orthotopic pulmonary transplantation. PMID- 20832585 TI - Effect of pyruvate and HEPES on rat lung allograft acidosis and cell death after long-term hypothermic storage. AB - BACKGROUND: We have previously demonstrated that adding pyruvate to Perfadex increased graft metabolism during 24-hour storage and improved reperfusion lung function. This increased metabolism was associated with progressively lower pH of the storage solution during the preservation interval. OBJECTIVE: To determine whether more effective pH regulation would result in further improvements in lung survival after hypothermic storage. MATERIALS AND METHODS: Rat lungs were stored for 24 hours in Perfadex, Perfadex with HEPES (N-2-hydroxyethylpiperazine propanesulfonic acid) buffer, pyruvate-modified Perfadex, and pyruvate-modified Perfadex with HEPES. Change in pH in the storage solution was measured. Structural lung injury was evaluated using hematoxylin-eosin stained tissue sections. Cell death was quantified by measuring necrotic cells using trypan blue exclusion and apoptotic cells via the TUNEL (terminal deoxynucleotide transferase mediated deoxyuridine triphosphate nick-end labeling) assay. RESULTS: Lungs stored in Perfadex demonstrated the greatest degree of cell death. Lungs in the Pyruvate group exhibited decreased cell death despite greater acidosis. The addition of HEPES reduced cell death and preservation solution acidosis in both Perfadex and pyruvate-modified Perfadex (P < .05). Almost all cell death resulted from necrosis. Adding pyruvate to the preservation solution increases acid formation during storage, but decreases cell death. HEPES ameliorates this acidosis and decreases allograft cell destruction. CONCLUSION: Increasing the preservation solution buffering capacity may be a simple strategy for improving lung preservation for transplantation. PMID- 20832586 TI - Combined application of blocking antibodies and MicroRNA interference in inhibiting CD44 expression. AB - BACKGROUND: We sought to explore the effect of CD44 targeting on the tolerance to memory cell-mediated graft rejection. METHODS: We developed a cardiac transplantation model in nude mice and administered anti-CD44 monoclonal antibodies (mAbs) to these mice. Then, we used anti-CD44 mAb and CD44-interfering microRNA (miRNA) to inhibit CD44 expression in vitro. RESULTS: The median survival time (MST) associated with multiple intraperitoneal injections was >100 days, whereas that associated with CD4(+) Tm cells blocked CD44 and that associated with a single intraperitoneal injection of anti-CD44 mAb was 11 and 10.3 days, control group was 5.5 days. The inhibition effect of the anti-CD44 mAb in 3T3 cells significantly reduced with cell proliferation. Used CD44 miRNA in 3T3 cells, the most obvious inhibition effect of mRNA appeared at 48 hours after transfection and the inhibition decreased subsequently. In combination, antibody mediated blocking and miRNA showed some synergistic effects. CONCLUSION: The inhibition of CD44 can significantly prolong the MST in memory models. The inhibition effect of combined application showed limitations with regard to cell proliferation and duration of action, but the short-term synergistic effect of the combined approach was stronger than the effects of individual approaches. PMID- 20832587 TI - Hepatoprotective effect of an immortal human fetal hepatic cell transplantation on CCL(4)-induced acute liver injury in mice. AB - Hepatocyte transplantation has been widely confirmed in the animal model experiments as an effective method for treatment of fulminant hepatic failure. However, the lack of donor organs remains a major problem. One solution is the development of transplantable hepatocytes. Herein we have transplanted intraperitoneally an established immortalized human fetal hepatic cell line (HL 7702) into CCl(4)-treated mice with acute liver injury to determine whether they provided life-saving metabolic support. The results showed lower levels of blood ammonia and higher content of liver albumin (P < .05) after HL-7702 transplantation versus nontransplanted controls at days 3 and 7. Histologic examination showed the transplantation group to be less affected at day 7 with no difference at day 14. In conclusion, an established immortal human fetal hepatic cell line may be a promising cell source providing life-saving metabolic support as a bioartificial liver device for the treatment of acute liver injury. PMID- 20832588 TI - Establishment of a porcine model for lobar lung auto-transplantation. AB - OBJECTIVE: The aim of this study was to develop a porcine model of left single lung auto-transplantation. METHODS: Eighteen 50-kg male domestic pigs underwent left pneumonectomy and lobar lung auto-transplantation (left lower lobe). Each animal was allocated to a perfusion protocol during surgery: group I, cold saline (n = 6); group II, cold heparin (n = 6); and group III, cold Euro-Collins (n = 6). We measured changes of partial pressure of oxygen in pulmonary vein blood (PvO(2)), partial pressure of carbon dioxide in pulmonary vein blood (PvCO(2)), lung compliance, and mean pulmonary artery pressure. RESULTS: The postoperative survival rate was 100%. PvO(2), PvCO(2), mean pulmonary artery pressure, and lung compliance of the left lower lobe showed a significant difference between the saline and the heparin groups or the Euro-Collins group (P < .05), whereas there was no significant difference between the heparin and the Euro-Collins groups. CONCLUSION: Compared with other species, humans and pigs show remarkable anatomical and physiological similarity. It is useful experimental animal model to evaluate pulmonary function and grafting protocols following lobar lung transplantation. PMID- 20832589 TI - Serial monitoring of B-type natriuretic Peptide in management of heart failure after liver transplantation in a patient with Budd-Chiari syndrome: case report. AB - Liver transplantation (LT) is an effective treatment option in patients with Budd Chiari syndrome and end-stage liver disease. However, the procedure may lead to a sudden increase in cardiac preload, which in turn may cause heart failure. Although assays of B-type natriuretic peptide (BNP) are increasingly used in diagnosis, management, and prediction of heart failure, the role of BNP after LT has not been well defined. Herein, we describe the case of a 56-year-old woman with Budd-Chiari syndrome who underwent LT and in whom heart failure was successfully managed using serial monitoring of BNP concentrations. The BNP concentration increased to 1735 pg/mL on postoperative day 4, and decreased to 180 pg/mL on postoperative day 19, at which time inotropic agents were discontinued. PMID- 20832590 TI - Successful treatment of invasive mucormycosis in a liver transplant patient by arm amputation. AB - Mucormycosis is an uncommon but frequently fatal infectious complication after solid organ transplantation. We describe successful treatment of invasive mucormycosis in a liver transplant recipient by wound debridement, a right above elbow arm amputation, and antifungal medications. Early recognition, prompt operative intervention, and initiation of an appropriate antifungal treatment are very important in the management of mucormycosis, a potentially life-threatening infection. PMID- 20832591 TI - Macrophage-dominant sialadenitis in human T-cell leukemia virus type I-associated myelopathy after living-donor liver transplantation. AB - A 64-year-old man who suffered from human T-cell leukemia virus type I (HTLV-I) associated myelopathy (HAM) after living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus infection complained of xerostomia. Although exocrine function test results were positive, autoantibodies including anti-SS-A/SS-B antibodies and sialography showed negative findings. Labial salivary gland biopsy revealing infiltration of 60 counts of mononuclear cells (MNCs) in minor salivary glands led to a diagnosis of Sjogren's syndrome-like sialadenitis. Immunohistochemistry demonstrated dominant CD68 staining and major histocompatibility complex class II on the surface of infiltrating MNCs. Herein we have reported a rare condition of macrophage-dominant sialadenitis in a patient with HAM after LDLT. PMID- 20832592 TI - Combined liver-kidney transplantation complicated by intraoperative discovery of a bronchobiliary fistula. AB - Herein, we report the case of an intraoperative diagnosis of bronchobiliary fistula during combined liver-kidney transplantation because of polycystic disease. The diagnosis necessitated changes in surgical and anesthesiologic management and in the overall medical decision-making process. Emergent isolation of the affected lung was instituted to mitigate a large air leak and ensure adequate respiratory exchange, and to enable surgical repair. The kidney transplantation procedure was delayed for a few hours, enabling hemodynamic and respiratory stabilization in the intensive care unit before conditions were deemed adequate to proceed. The posttransplantation course was complicated but eventually successful, and the patient recovered both liver and kidney function. At a later evaluation, we realized that diagnosis of bronchobiliary fistula could have been made preoperatively had the chest radiograph been interpreted correctly and had the clinicians involved had a higher degree of suspicion for this complication of polycystic liver disease. PMID- 20832593 TI - Acute allograft renal failure with marked hyperuricemia developing during mizoribine administration: a case report with review of the literature. AB - Mizoribine (MZ) is a potent immunosuppressant used in conjunction with other immunosuppressants to prevent and treat allograft rejection after organ transplantation. Although hyperuricemia is the most common side effect of MZ, there are no case reports of acute allograft renal failure associated with MZ. This report describes a patient who developed acute allograft renal failure and hyperuricemia during MZ treatment. Accordingly, MZ treatment was terminated, hemodialysis was initiated, and allopurinol was administered. Hemodialysis was necessary only once. The patient's condition improved with these treatments, and renal function recovered. Care should be taken during treatment with MZ to avoid latent renal dysfunction. Monitoring of serum uric acid levels was necessary. Moreover, it may be necessary to consider discontinuation of MZ and initiation of hemodialysis in cases of transient renal dysfunction. No prisoners were used and no organs from prisoners were used in the study. PMID- 20832594 TI - Post-kidney transplantation lymphocele due to a lymphatic filariasis. AB - Lymphocele is a well-known complication of renal transplantation. Presenting symptoms are nonspecific; most patients are entirely asymptomatic. Herein, we have reported a case of lymphocele due to an asymptomatic lymphatic Wuchereria bancrofti filariasis with deterioration of graft function. A 53-year-old man with end-stage renal disease secondary to vascular disease was admitted 40 days after transplantation with vague, isolated abdominal pain. An abdomen and pelvis ultrasound examination demonstrated a cystic structure in the renal hilus. Graft function deteriorated, so the patient underwent puncture of the lymphocele followed by povidone iodine sclerotherapy. In the percutaneous drainage, we noted a fine whitish strand 4-mm thick similar to the shape of the stent, a part of which seemed to go into the transplantation fossa. Parasitological examination showed an adult female worm of W bancrofti measuring 6 cm. The test for microfilaremia was negative. The patient was treated for 10 days with a combination of Ivermectin and Albendazole associated with Doxycycline. The collection rapidly decreased after worm treatment. This case describes a post renal transplantation lymphocele due to asymptomatic lymphatic filariasis. PMID- 20832595 TI - Cost of paid transplantation abroad: possible donor-origin early multiple myeloma in a renal transplant recipient treated using bortezomib. AB - The incidence of cancer is greater in transplant recipients compared with the general population. Posttransplantation lymphoproliferative disorder (PTLD) is the second most common cancer in these patients. Non-Hodgkin lymphoma is most commonly observed, and multiple myeloma (PTLD-MM) accounts for less than 4% of PTLDs. Most reported PTLD-MM is of recipient origin, and to date, few cases of donor-origin PTLD-MM have been reported. Bortezomib is a protease inhibitor that has been used successfully to treat multiple myeloma. Herein, we describe the case of a patient in whom multiple myeloma developed shortly after paid living unrelated renal transplantation performed abroad (in Egypt). The patient had no apparent risk factors for PTLD-MM. Thus, it was supposed that PTLD-MM was of donor origin, considering its early development, lack of recipient risk factors, and no available donor medical status. To our knowledge, this report is the first to describe the use of bortezomib in this setting. Although bortezomib plus dexamethasone therapy resulted in hematologic remission, the patient remained dialysis-dependent. PMID- 20832596 TI - Successful bone marrow transplantation reveals the lack of endothelial progenitor cells mobilization in a patient with critical limb ischemia: a case report. AB - Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease. PMID- 20832599 TI - Editorial comment. PMID- 20832597 TI - RE: Emergency liver transplantation after umbilical hernia repair: A case report. PMID- 20832600 TI - Editorial comment. PMID- 20832602 TI - Editorial comment. PMID- 20832603 TI - Editorial comment. PMID- 20832605 TI - Editorial comment. PMID- 20832606 TI - Editorial comment. PMID- 20832607 TI - Editorial comment. PMID- 20832609 TI - Editorial comment. PMID- 20832610 TI - Should preservable parenchyma, and not tumor size, be the main determinant of the feasibility of partial nephrectomy? PMID- 20832611 TI - Editorial comment. PMID- 20832613 TI - Editorial comment. PMID- 20832615 TI - Editorial comment. PMID- 20832617 TI - Editorial comment. PMID- 20832618 TI - Editorial comment. PMID- 20832620 TI - Editorial comment. PMID- 20832622 TI - Editorial comment. PMID- 20832624 TI - Editorial comment. PMID- 20832625 TI - Editorial comment. PMID- 20832629 TI - Editorial comment. PMID- 20832627 TI - Editorial comment. PMID- 20832631 TI - Editorial comment. PMID- 20832632 TI - Editorial comment. PMID- 20832634 TI - Editorial comment. PMID- 20832636 TI - Editorial comment. PMID- 20832637 TI - Editorial comment. PMID- 20832639 TI - Editorial comment. PMID- 20832640 TI - Editorial comment. PMID- 20832643 TI - Editorial comment. PMID- 20832644 TI - Re: Linden RA et al.: Technique of outpatient placement of intraprostatic fiducial markers before external beam radiotherapy (Urology 2009;73:881-886). PMID- 20832646 TI - Re: Hsieh MH et al.: Outcomes and cost analysis of pyeloplasty for antenatally diagnosed ureteropelvic junction obstruction using Markov models (Urology 2008;72:794-799). PMID- 20832647 TI - Re: Lotan y et al.: Are urologists fairly reimbursed for complex procedures: failure of 22 modifier? (Urology 2008;72:494-497). PMID- 20832650 TI - Preface. Genetics of neurologic and psychiatric diseases. PMID- 20832651 TI - Clinical screening and genetic testing. AB - Clinical screening is most effective in diseases in which the disease is in its earliest form and may not have symptoms or signs but can be readily diagnosed with an inexpensive, noninvasive test. This article discusses the general principles of genetic disease architecture that can guide screening and diagnostic approaches for all of the cardiomyopathies and inherited diseases. It addresses how the genetic architecture of the trait guides, and how clinical characteristics of the disease influence, a clinical screening approach. PMID- 20832652 TI - Approaches to the patient with neurogenetic disease. AB - The clinical practice of neurogenetics is complex, challenging, and rewarding. Several guidelines are helpful. This article briefly focuses on 8 aspects of clinical neurogenetics, namely (1) factors suggesting the presence of a genetic disease, (2) nonspecific categories that may be hiding neurogenetic diseases, (3) importance of family history, (4) assessment of sporadic cases, (5) genetic counseling, (6) genetic testing, (7) available information resources, and (8) integration of the clinical neurogenetic strategy. PMID- 20832653 TI - Methods: genetic epidemiology. AB - Given the potential benefits of gene identification in psychiatry, genetic epidemiology has become a mainstream discipline within the field. This article discusses the main tools for gene discovery. The focus is on the designs and analytic approaches for each of these methods. Because most gene discovery has now moved to genetic association studies, and most recently to genome-wide association studies, the focus is on methods for this design. Also highlighted are the current challenges of genetic epidemiology as a prelude to future approaches that may be applied to psychiatric disorders in the coming years. PMID- 20832654 TI - Genetics of psychiatric disorders methods: molecular approaches. AB - The practice of psychiatry has long suffered from the limited information available on the biological basis of mental disorders. This limitation is now coming to an end. Advances in DNA analysis technologies and in our understanding of the human genome, together with our new knowledge of the properties of the genome and significant efforts toward generating large patient and control sample collections, have paved the way for successful genome-wide association studies. As a result, reports now appear in the literature every week identifying new genes for complex disorders. Next-generation sequencing methods, combined with the results of association and perhaps linkage studies, will help us uncover missing heritability factors, achieve a better understanding of the genetic aspects of psychiatric disease, and devise the best strategies for incorporating genetics in the service of patients. PMID- 20832655 TI - Predictive and diagnostic genetic testing in psychiatry. AB - The recent advent of commercially available genetic tests for the diagnosis of several mental illnesses has led to intense controversy amongst the psychiatric research community. In this article the authors review these developments, and contrast these with the growing evidence from genomewide association studies that highly heritable psychiatric conditions such as schizophrenia are due to the contributions and interaction of multiple allelic variants, each of small effect size. There is also evidence for the contribution of some highly penetrant rare de novo copy number variants, though the lack of disease specificity for these is of concern. This article outlines the prerequisites for predictive and diagnostic genetic tests, such as clinical validity and utility, and reviews the opportunity that genetic tests for mental illnesses present. As the scientific discourse on genetic tests for complex disorders is not limited to psychiatry, the authors outline current thoughts on the significance of genome-wide association studies across health, and the phenomenon of direct-to-consumer tests in medicine. The attitudes and understanding of patients, families, and clinicians about the future (currently hypothetical) scenario of psychiatric genetic tests are discussed, as is the potential for such testing to increase, rather than diminish stigma. Finally, recommendations on the future development and availability of genetic tests in psychiatry are provided. PMID- 20832656 TI - Genetics of addictions. AB - Addictions include a group of common, heritable psychiatric illnesses that have multiple psychiatric and medical comorbidities. Robust genetic associations have been found for alcohol dependence, nicotine dependence, and cocaine dependence. Common genetic associations have been found between alcohol dependence and aerodigestive cancers and between nicotine dependence and lung disease. These associations highlight the importance of understanding the genetics of substance dependence in the context of its multiple medical and psychiatric comorbidities. PMID- 20832657 TI - The neurobiology of anxiety disorders: brain imaging, genetics, and psychoneuroendocrinology. AB - Anxiety disorders are highly comorbid with each other and with major depressive disorder. As syndromes, anxiety and mood disorders share many symptoms, and several treatments are effective for both. Despite this overlap, there exist many distinguishing features that support the continued classification of individual anxiety disorders that are distinct from each other and from major depression. The goal of this article is to describe the key biological similarities and differences between anxiety disorders. PMID- 20832658 TI - Genetics of personality disorders. AB - This article on genetic contributions to the etiology of personality disorders broadly follows the Diagnostic and Statistical Manual of Mental Disorders classification. Until recently, relatively few genetic studies of personality disorders as defined by this system had been published. The review begins by evaluating the current evidence for genetic influences on the Diagnostic and Statistical Manual of Mental Disorders axis II disorders. Psychiatric genetics has for a long time been moving beyond simple quantitative genetic studies. One of the most exciting directions in psychiatric genetics is the rapidly developing field of molecular genetic studies, aiming to identify specific genes correlated with psychiatric phenotypes. Personality disorders, like most other psychiatric diagnostic categories, are etiologically complex, which implies that they are influenced by several genes and several environmental factors. The interplay between genes and the environment is receiving increasing attention, and is addressed in relation to both quantitative and molecular methods. Finally, future directions are discussed. PMID- 20832659 TI - Advances on the genetics of Mendelian idiopathic epilepsies. AB - Genetic factors play an increasingly recognized role in idiopathic epilepsies. Since 1995, positional cloning strategies in multigenerational families with autosomal dominant transmission have revealed 11 genes (KCNQ2, KCNQ3, CHRNA4, CHRNA2, CHRNB2, SCN1B, SCN1A, SCN2A, GABRG2, GABRA1, and LGI1) and numerous loci for febrile seizures and epilepsies. To date, all genes with the exception of LGI1, encode neuronal ion channel or neurotransmitter receptor subunits. Molecular approaches have revealed great genetic heterogeneity, with most genes remaining to be identified. One of the major challenges is now to understand phenotype-genotype correlations. This review focuses on the current knowledge on the molecular basis of these rare mendelian autosomal dominant forms of idiopathic epilepsies. PMID- 20832660 TI - The promise and reality of pharmacogenetics in psychiatry. AB - Existing psychotropic medications for the treatment of mental illnesses, including antidepressants, mood stabilizers, and antipsychotics, are clinically suboptimal. They are effective in only a subset of patients or produce partial responses, and they are often associated with debilitating side effects that discourage adherence. There is growing enthusiasm in the promise of pharmacogenetics to personalize the use of these treatments to maximize their efficacy and tolerability; however, there is still a long way to go before this promise becomes a reality. This article reviews the progress that has been made in research toward understanding how genetic factors influence psychotropic drug responses and the challenges that lie ahead in translating the research findings into clinical practices that yield tangible benefits for patients with mental illnesses. PMID- 20832661 TI - Pharmacogenetics and schizophrenia. AB - The wide interindividual variability in clinical response and tolerability of antipsychotic medications has led investigators to postulate that these variabilities may be under genetic control. Although not always consistent, there are promising indications from emergent pharmacogenetic studies that efficacy of antipsychotic medications for the various symptom domains of psychopathology in schizophrenia may be genetically regulated. This is an encouraging approach. Moreover, there are also suggestive findings that the side-effect profiles of second-generation antipsychotic medications and their propensity to cause weight gain and glucose and lipid abnormalities as well as tardive dyskinesia may be related to pharmacogenetic factors in this patient population. Ultimately, such approaches could drive choices of antipsychotic medication based on the likelihood of clinical response and development of side effects in light of a particular patient's genetic profile. In the future, this targeted approach (personalized medicine) may become informative for clinicians choosing an antipsychotic medication for an individual patient with schizophrenia. PMID- 20832662 TI - How safe is safe? Risk in radiotherapy. PMID- 20832663 TI - Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer. AB - PURPOSE: To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer. RESULTS AND DISCUSSION: We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR. CONCLUSIONS: The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole. PMID- 20832664 TI - Automated weekly replanning for intensity-modulated radiotherapy of cervix cancer. AB - PURPOSE: The adoption of intensity-modulated radiotherapy (IMRT) to treat cervical malignancies has been limited in part by complex organ and tumor motion during treatment. This study explores the limits of a highly adaptive, small margin treatment scenario to accommodate this motion. In addition, the dosimetric consequences of organ and tumor motion are modeled using a combination of deformable registration and fractional dose accumulation techniques. METHODS AND MATERIALS: Thirty-three cervix cancer patients had target volumes and organs-at risk contoured on fused, pretreatment magnetic resonance-computed tomography images and weekly magnetic resonance scans taken during treatment. The dosimetric impact of interfraction organ and target motion was compared for two hypothetical treatment scenarios: a 3-mm margin plan with no replanning, and a 3-mm margin plan with an automated replan performed on the updated weekly patient geometry. RESULTS: Of the 33 patients, 24 (73%) met clinically acceptable target coverage (98% of the clinical target volume receiving at least 95% of the prescription dose) using the 3-mm margin plan without replanning. The range in dose to 98% of the clinical target volume across all patients was 7.9% of the prescription dose if no replanning was performed. After weekly replanning, this range was tightened to 2.6% of the prescription dose and all patients met clinically acceptable target coverage while maintaining organ-at-risk dose sparing. CONCLUSIONS: The dosimetric impact of anatomical motion underscores the challenges of applying IMRT to treat cervix cancer. An appropriate adaptive strategy can ensure target coverage for small-margin IMRT treatments and maintain favorable organ-at-risk dose sparing. PMID- 20832665 TI - Biochemical disease-free rate and toxicity for men treated with iodine-125 prostate brachytherapy with d(90) >=180 Gy. AB - PURPOSE: Iodine-125 ((125)I) prostate brachytherapy is planned with a prescribed dose of 145 Gy and minimal dose received by 90% of the prostate (D(90)) of 120 125% (174-181 Gy). We examined the clinical outcomes and toxicity profile of men receiving a D(90) (isodose enclosing 90% of the prostate) of >=180 Gy. METHODS AND MATERIALS: Between March 1999 and May 2006, 129 men (17% of our total brachytherapy population) treated with (125)I monotherapy for Stage T1-T2 prostate cancer received a D(90) >=180 Gy. Implants were performed using transrectal ultrasonography and fluoroscopic guidance. The 1-month postplan dosimetry used magnetic resonance imaging-computed tomography fusion. The minimal follow-up was 2 years. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events toxicity scale, version 3. RESULTS: The median patient age was 63 years (range, 50-76), and the pretreatment prostate-specific antigen level was 5.5 ng/mL (range, 0.6-13.5). The Gleason score was <=6 in 125 patients and was 7 in 4 patients. The median follow up period was 40 months (range, 24-111), and the median D(90) was 186 Gy. The median minimal dose received by 30% of the urethra was 203 Gy, and the median rectal volume receiving a minimum of 100% of the prescribed dose was 0.81 cm(3). Acute Grade 2 genitourinary toxicity was seen in 5.4% and late Grade 2 in 7%. Late urinary retention (Grade 3) was seen in 2 patients (1.5%). Grade 1 rectal bleeding occurred in 9.3% and Grade 2 in 2.3%. On univariate logistic regression analysis, none of the clinical and dosimetric parameters predicted for rectal bleeding. Of 110 men who were potent before treatment, 81% remained potent 5 years after treatment. Three biochemical failures and only one local failure developed. The 5-year biochemical no evidence of disease rate using the "nadir plus 2" definition was 96.8%. CONCLUSION: A D(90) of >=180 Gy is associated with excellent biochemical disease-free survival and acceptable toxicity. PMID- 20832666 TI - Response to "Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: Results from three Canadian centers"(Int J Radiat Oncol Biol Phys 2009;75:193-197). PMID- 20832669 TI - Optimizing benefits of local control in breast cancer. PMID- 20832670 TI - In regards to Dennis and Duncan: Radiation oncology in undergraduate medical education: a literature review (Int J Radiat Oncol Biol Phys 2010;76:649-655). PMID- 20832672 TI - When Is a "BED" not a "BED"?-When it is an EQD2: In regard to Buyyounouski et al. (Int J Radiat Oncol Biol Phys 2010;76:1297-1304). PMID- 20832673 TI - Strain typing of acetic acid bacteria responsible for vinegar production by the submerged elaboration method. AB - Strain typing of 103 acetic acid bacteria isolates from vinegars elaborated by the submerged method from ciders, wines and spirit ethanol, was carried on in this study. Two different molecular methods were utilised: pulsed field gel electrophoresis (PFGE) of total DNA digests with a number of restriction enzymes, and enterobacterial repetitive intergenic consensus (ERIC) - PCR analysis. The comparative study of both methods showed that restriction fragment PFGE of SpeI digests of total DNA was a suitable method for strain typing and for determining which strains were present in vinegar fermentations. Results showed that strains of the species Gluconacetobacter europaeus were the most frequent leader strains of fermentations by the submerged method in the studied vinegars, and among them strain R1 was the predominant one. Results showed as well that mixed populations (at least two different strains) occurred in vinegars from cider and wine, whereas unique strains were found in spirit vinegars, which offered the most stressing conditions for bacterial growth. PMID- 20832674 TI - Comparison of inactivation of Listeria monocytogenes within a biofilm matrix using chlorine dioxide gas, aqueous chlorine dioxide and sodium hypochlorite treatments. AB - The present research compared the effect of chlorine dioxide (CD) gas, aqueous CD and aqueous sodium hypochlorite (SHC) treatments on the inactivation of a five strain mixture of Listeria monocytogenes - containing biofilms. Four day old biofilms were developed on a stainless steel (SS 304) coupon by using a mixture of five cultures of L. monocytogenes (Scott A, N1-227, 103M, 82 and 311) using a 100% relative humidity (RH) dessicator for incubation at room temperature (22 +/- 2 degrees C). After biofilm development, coupons were rinsed and dried for 2 h and treated with 0.3 mg/l CD gas at 75% RH, 7 mg/l of aqueous CD and 50 mg/l SHC. Initial log(10) population of biofilm cells before CD gas, aqueous CD and SHC treatment was 4.80, 5.09 and 4.95 log(10) CFU/cm(2). The Weibull model was used to fit non-linear survivor curves. Treatments and time points of 0.3 mg/l CD gas and 7 mg/l aq. CD solution were significantly different (p < 0.05). A 10 min treatment of 0.3 mg/l CD gas, 7 mg/l of aq. CD, and 50 mg/l SHC resulted in reductions of 3.21, 3.74 and 3.09 log(10) CFU/cm(2), respectively. At 10 min, all treatments were not statistically different (p > 0.05). Low levels of CD (0.3 mg/l CD gas and 7 mg/l aq. CD solution) for 10 min resulted in similar log reductions compared to 50 mg/l SHC. PMID- 20832675 TI - Antiviral effects of cranberry juice and cranberry proanthocyanidins on foodborne viral surrogates--a time dependence study in vitro. AB - Cranberry juice (CJ) and cranberry proanthocyanidins (PAC) are widely known for their antibacterial, antiviral, and pharmacological activities. The effect of CJ and cranberry PAC on the infectivity of foodborne viral surrogates, murine norovirus (MNV-1), feline calicivirus (FCV-F9), MS2 (ssRNA) bacteriophage, and phiX-174 (ssDNA) bacteriophage after 0 min to 1h at room temperature was evaluated. Viruses at titers of ~5log(10)PFU/ml were mixed with equal volumes of CJ at pH 2.6, CJ at pH 7.0, 0.30 mg/ml CJ PAC, 0.60mg/ml PAC, or water and incubated for 0, 10, 20, 30, 40, 50 min, and 1h at room temperature. Infectivity was determined using standard plaque assays. The viral reduction rates of the four tested viruses were found to vary considerably. Among the tested viruses, FCV-F9 titers were decreased the most by ~5log(10)PFU/ml within 30 min. MS2 titers were decreased the least by only ~1log(10)PFU/ml after 1h with CJ at pH 2.6 and 0.30 mg/ml PAC, and ~0.5log(10)PFU/ml with CJ at pH 7.0 and 0.15 mg/ml PAC. MNV-1 and phi-X174 showed comparable titer reductions which was between that of FCV-F9 and MS2. In most cases, viral reduction within the first 10 min of treatment accounted for >=50% of the total reduction. Transmission electron microscopy on FCV-F9 treated with CJ and PAC revealed structural changes. This study shows potential of using natural bioactive compounds for controlling foodborne viral diseases. Further studies are necessary to elucidate the mechanism of action of CJ components and to understand the differences in viral titer reduction profiles. PMID- 20832676 TI - Prevalence of and risk factors for Campylobacter spp. contamination of broiler chicken carcasses at the slaughterhouse. AB - A study was conducted in 2008 to estimate the prevalence and identify the risk factors for Campylobacter spp. contamination of broiler carcasses during the slaughtering process. A pool of 10 caeca and one carcass were collected from 425 batches of broiler chickens slaughtered in 58 French slaughterhouses over a 12 month period. Potential risk factors were identified according to the Campylobacter contamination status of carcasses and processing variables identified from questionnaires. The statistical analysis took into account confounding factors that have already been associated with the presence of Campylobacter on carcasses such as the slaughter age of the chicken or seasonal variations. Campylobacter spp. were isolated from 77.2% of caeca (95% CI 73.2 to 81.2) and from 87.5% of carcasses (95% CI 84.4 to 90.7). A multiple logistic regression showed 4 parameters as significant risk factors (p < 0.05) for contamination: (I) batches were not the first to be slaughtered in the logistic schedule (OR = 3.5), (II) temperature in the evisceration room was higher than 15 degrees C (OR = 3.1), (III) dirty marks on carcasses after evisceration were visible (OR = 2.6) and (IV) previous thinning of the flocks, from which slaughtered batches came, had occurred at the farm (OR = 3.3). This last result highlighted the need for sanitary precautions to be taken when catching birds for transport. At the slaughterhouse, evisceration seemed to be the operation contributing most to the spread of contamination. Effective risk management solutions could include the systematic external rinsing of carcasses after evisceration and the implementation of slaughtering schedules according to the Campylobacter contamination status of flocks. PMID- 20832677 TI - Lactic acid bacteria community dynamics and metabolite production of rye sourdough fermentations share characteristics of wheat and spelt sourdough fermentations. AB - Four spontaneous rye sourdough fermentations were performed over a period of ten days with daily back-slopping. Samples taken at all refreshment steps were used for culture-dependent and culture-independent characterization of the microbiota present. Furthermore, an extensive metabolite target analysis was performed through a combination of various chromatographic methods, including liquid chromatography coupled to mass spectrometry (LC/MS) and gas chromatography coupled to mass spectrometry (GC/MS). Spearman's rank correlation coefficients were calculated and a principal component analysis (PCA) was performed on the data obtained in this study combined with data obtained previously for wheat and spelt sourdoughs. In general, the establishment of a stable microbial ecosystem occurred through a three-phase evolution, with mainly Lactobacillus plantarum and Lactobacillus fermentum dominating the rye sourdough ecosystems. PCA revealed that ornithine and mannitol were positively correlated with rye sourdoughs, contributing to bacterial competitiveness at the onset of sourdough production. Wheat and spelt sourdoughs showed a high degree of similarity, although certain compounds (e.g. indolelactic acid) appeared to be specific for spelt sourdoughs. The production of amino acid metabolites, mainly hydroxy acids (e.g. phenyllactic acid) and alcohols (e.g. 3-methyl-1-butanol), contributed to the equilibration of the redox balance and further enhanced the competitiveness of dominant species in stable sourdoughs. PMID- 20832678 TI - Use of high-concentration-short-time chlorine dioxide gas treatments for the inactivation of Salmonella enterica spp. inoculated onto Roma tomatoes. AB - Salmonella outbreaks have been recently linked to the consumption of fresh tomatoes. Thus, there is a need to develop systems that reduce the risk of microbial contamination to increase product shelf-life and keep fresh fruit attributes. The objectives of this study were to evaluate high-concentration short-time chlorine dioxide gas treatments effects on Salmonella-inoculated Roma tomatoes and determine the optimal treatment conditions for microbial inactivation and shelf-life extension. Effects of ClO(2) concentration (2, 5, 8 and 10mg/l) and exposure time (10, 30, 60, 120 and 180 s) on inoculated Roma tomatoes were studied. Salmonella enterica strains, serotype Montevideo, Javiana and Baildon, were used to experimentally inoculate the food product. After ClO(2) treatments, tomatoes were stored at room temperature for 28 days. Inherent microbial population, change in tomato color, and chlorine dioxide gas residuals were evaluated. ANOVA analysis showed that both ClO(2) concentration and treatment time were significant (p<0.01) for Salmonella inactivation. Surviving Salmonella populations of 3.09, 2.17 and 1.16 logCFU/cm(2) were obtained treating tomatoes with 8 mg/l ClO(2) for 60 s, 10 mg/l ClO(2) for 120 s, and 10 mg/l for 180 s, respectively (initial Salmonella population: 6.03+/-0.11 log CFU/cm(2)). The selected treatments significantly reduced background microflora (p<0.05), while fruit color and residual contents were not significantly different (p>0.05), as compared to the control. Results suggest the potential for high concentration-short-time treatments ClO(2) gas as an effective pathogen inactivation technology for large-scale produce packing operations. PMID- 20832679 TI - Alicyclobacillus acidoterrestris in pasteurized exotic Brazilian fruit juices: isolation, genotypic characterization and heat resistance. AB - In this study, the population of Alicyclobacillus spp. was estimated in pasteurized exotic Brazilian fruit juices using the most probable number (MPN) technique followed by biochemical tests. Pasteurized passion fruit (n = 57) and pineapple (n = 50) juices were taken directly from Brazilian manufacturers. While Alicyclobacillus spp. was isolated from passion fruit juice, the microorganism was not found in any pineapple juice samples. A higher incidence of Alicyclobacillus was observed in samples taken in June and July (dry months in Brazil) in comparison to the other months (March, April, May and August), and the highest Alicyclobacillus counts were recovered from these samples(>23 MNP/100 mL). Sixteen (n = 16) Alicyclobacillus strains were typed using the randomly amplified polymorphic DNA method (RAPD-PCR). RAPD-PCR revealed great genetic similarity between the passion fruit juice strains and Alicyclobacillus acidoterrestris DSM 2498. The heat resistance of three isolates was determined, and the mean D(95 degrees ) (1.7 min) and z (7.6 degrees C) values in the passion fruit juice were not significantly different (p > 0.05) from those obtained for the DSM 2498 strain (D(95 degrees ) = 1.5 min and z = 7.1 degrees C). This is the first report on the isolation of A. acidoterrestris from exotic fruit juices such as passion fruit juice. It is worth pointing out the importance of applying good agricultural practices in the field and applying controls for the fruit selection and washing steps, as well as controlling the time/temperature conditions for pasteurization so as to reduce the incidence and chances of A. acidoterrestris spoilage in these juices. PMID- 20832680 TI - Presence of non-Saccharomyces yeasts in cellar equipment and grape juice during harvest time. AB - The purpose of this study was to analyze the presence of different yeasts in the facilities of four wineries from the D.O.Ca. Rioja region in Spain. The study was conducted through the identification of the yeasts via the PCR-RFLP technique of the ITS region of rDNA. The diversity of non-Saccharomyces yeasts found in wineries has previously only been studied to a limited extent, despite the fact that these yeasts take part both in the start of spontaneous fermentation and in the changes which occur in the wines during their subsequent conservation. Most earlier studies carried out on cellar ecosystems have focussed on the clonal diversity of Saccharomyces cerevisiae. The results obtained in this study indicated that the presence of non-Saccharomyces yeasts in facilities is higher than that of the S. cerevisiae, with percentages of over 60% in all the wineries analyzed. Yeasts belonging to 10 genera and 18 species were isolated, but the only genera present in all four wineries were Cryptococcus, Pichia, and Saccharomyces. The Zygosaccharomyces bailii yeast responsible for taint was detected in one cleaned winery, in both the winemaking equipment and the fermenting must. It was also noted that the quantity and type of yeasts present in the facilities are related to the product used for cleaning them. It is also necessary to point out that the cleaning of the cellars prior to the reception of the grapes does not completely eliminate the yeasts present, so that these can subsequently become part of the vinification process. PMID- 20832681 TI - Lactic acid bacteria population dynamics during minced beef storage under aerobic or modified atmosphere packaging conditions. AB - A total of 266 lactic acid bacteria (LAB) have been isolated from minced beef stored at 0, 5, 10 and 15 degrees C aerobically and under modified atmosphere packaging consisting of 40% CO(2)-30% O(2)-30% N(2) in the presence MAP (+) and absence MAP (-) of oregano essential oil. Sequencing of their 16S rRNA gene along with presence of the katA gene demonstrated dominance of the LAB microbiota by Leuconostoc spp. during aerobic storage at 5, 10 and 15 degrees C, as well as during MAP (-) and MAP (+) storage at 10 and 15 degrees C; Lactobacillus sakei prevailed during aerobic storage at 0 degrees C, as well as at MAP (-) and MAP (+) storage at 0 and 5 degrees C. The sporadic presence of other species such as Leuconostoc mesenteroides, Weisella viridescens, Lactobacillus casei and Lactobacillus curvatus has also been determined. Pulsed-Field Gel Electrophoresis of high molecular weight genomic DNA revealed the dynamics of the isolated LAB strains. Prevalence of Leuconostoc spp. was attributed to one strain only. On the other hand, packaging conditions affected Lb. sakei strain spoilage dynamics. PMID- 20832682 TI - Distribution of dimorphic yeast species in commercial extra virgin olive oil. AB - Recent microbiological research has demonstrated the presence of a rich microflora mainly composed of yeasts in the suspended fraction of freshly produced olive oil. Some of the yeasts are considered useful as they improve the organoleptic characteristics of the oil during preservation, whereas others are considered harmful as they can damage the quality of the oil through the hydrolysis of the triglycerides. However, some dimorphic species can also be found among the unwanted yeasts present in the oil, considered to be opportunistic pathogens to man as they have often been isolated from immunocompromised hospital patients. Present research demonstrates the presence of dimorphic yeast forms in 26% of the commercial extra virgin olive oil originating from different geographical areas, where the dimorphic yeasts are represented by 3-99.5% of the total yeasts. The classified isolates belonged to the opportunistic pathogen species Candida parapsilosis and Candida guilliermondii, while among the dimorphic yeasts considered not pathogenic to man, the Candida diddensiae species was highlighted for the first time in olive oil. The majority of the studied yeast strains resulted lipase positive, and can consequently negatively influence the oil quality through the hydrolysis of the triglycerides. Furthermore, all the strains showed a high level of affinity with some organic solvents and a differing production of biofilm in "vitro" corresponded to a greater or lesser hydrophobia of their cells. Laboratory trials indicated that the dimorphic yeasts studied are sensitive towards some components of the oil among which oleic acid, linoleic acid and triolein, whereas a less inhibiting effect was observed with tricaprilin or when the total polyphenols extracted from the oil were used. The observations carried out on a scanning electron microscope (SEM), demonstrated the production of long un-branched pseudohyphae in all the tested dimorphic yeasts when cultivated on nutrient deficient substrates. PMID- 20832683 TI - Exploitation of Acha (Digitaria exiliis) and Iburu (Digitaria iburua) flours: chemical characterization and their use for sourdough fermentation. AB - This study aimed at characterizing the chemical and microbiological composition of Acha (Digitaria exiliis) and Iburu (Digitaria iburua) flours and at exploiting their potential for sourdough fermentation. Both the flours had a gross composition similar to other cereals. As shown by two-dimensional electrophoresis analysis, Acha flour had a higher number of prolamins with respect to Iburu flour. The opposite was found for the number of glutelin spots. The concentration of total free amino acids of Iburu flour was higher than that of Acha flour (1348+/-34 vs. 100+/-20 mg/kg). Pediococcus pentosaceus was the dominant species in both the flours. Several isolates were used to ferment Acha or Iburu flours. After 8h fermentation at 30 degrees C, pH ranged from 3.41 to 3.83 and from 4.20 to 4.66 for Acha and Iburu sourdoughs, respectively. The highest values of TTA and concentration of lactic acid were found in almost all Iburu sourdoughs. The synthesis of acetoin and gamma-amino butyric acid (GABA) was only found in Iburu sourdoughs. Data from the kinetics of acidification, synthesis of lactic and acetic acids, acetoin, and liberation of total free amino acids were elaborated by Principal Component Analysis. Sourdoughs from Acha and Iburu flour were clearly differentiated. PMID- 20832684 TI - Combined pH and high hydrostatic pressure effects on Lactococcus starter cultures and Candida spoilage yeasts in a fermented milk test system during cold storage. AB - The combined effects of high pressure processing (HPP) and pH on the glycolytic and proteolytic activities of Lactococcus lactis subsp. lactis, a commonly used cheese starter culture and the outgrowth of spoilage yeasts of Candida species were investigated in a fermented milk test system. To prepare the test system, L. lactis subsp. lactis C10 was grown in UHT skim milk to a final pH of 4.30 and then additional samples for treatment were prepared by dilution of fermented milk with UHT skim milk to pH levels of 5.20 and 6.50. These milk samples (pH 4.30, 5.20 and 6.50) with or without an added mixture of two yeast cultures, Candida zeylanoides and Candida lipolytica (10(5) CFU mL(-1) of each species), were treated at 300 and 600 MPa (<=20 degrees C, 5 min) and stored at 4 degrees C for up to 8 weeks. Continuing acidification by starter cultures, as monitored during storage, was substantially reduced in the milk pressurised at pH 5.20 where the initial titratable acidity (TA) of 0.40% increased by only 0.05% (600 MPa) and 0.10% (300 MPa) at week 8, compared to an increase of 0.30% in untreated controls. No substantial differences were observed in pH or TA between pressure treated and untreated milk samples at pH 4.30 or 6.50. The rate of proteolysis in milk samples at pH values of 5.20 and 6.50 during storage was significantly reduced by treatment at 600 MPa. Treatment at 600 MPa also reduced the viable counts of both Candida yeast species to below the detection limit (1 CFU mL(-1)) at all pH levels for the entire storage period. However, samples treated at 300 MPa showed recovery of C. lipolytica from week 3 onwards, reaching 10(6)-10(7) CFU mL(-1) by week 8. In contrast, C. zeylanoides did not show any recovery in any of the pressure-treated samples during storage. PMID- 20832685 TI - The effects of X-ray radiation on Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica and Shigella flexneri inoculated on whole Roma tomatoes. AB - In the last two decades several foodborne disease outbreaks associated with produce were reported. Tomatoes, in particular, have been associated with several multi-state Salmonella outbreaks. Inactivation of inoculated Escherichia coli O157:H7, Listeria monocytogenes, Salmonella enterica and Shigella flexneri on whole Roma tomato surfaces by X-ray at 0.1, 0.5, 0.75, 1.0, and 1.5 kGy was studied. The main purpose of this study was to achieve a 5 log reduction in consistent with the recommendations of the National Advisory Committee on Microbiological Criteria for Foods. Moreover, the effect of X-ray on inherent microflora (mesophilic counts, psychrotrophic counts and yeast and mold counts) of untreated and treated Roma tomatoes, during storage at ambient temperature (22 degrees C) for 20 days was also determined. Mixtures of three or two strains of each tested organism was spot inoculated (100 MUl) onto the surface of Roma tomatoes (approximately 7-9 log per tomato), separately, and air-dried, followed by treatment with X-ray doses at 22 degrees C and 55-60% relative humidity. Surviving bacterial populations on tomato surfaces were evaluated using a nonselective medium (tryptic soy agar) with a selective medium overlay for each bacteria; E. coli O157:H7 (CT-SMAC agar), L. monocytogenes (MOA), and S. enterica and S. flexneri (XLD). Treatment with X-ray significantly reduced the population of the tested pathogens on whole Roma tomato surfaces, compared with the control. Approximately 4.2, 2.3, 3.7 and 3.6 log CFU reduction of E. coli O157:H7, L. monocytogenes, S. enterica and S. flexneri per tomato were achieved by treatment with 0.75 kGy X-ray, respectively. More than a 5 log CFU reduction per tomato was achieved at 1.0 or 1.5 kGy X-ray for all tested pathogens. Furthermore, treatment with X-ray significantly reduced the inherent microflora on Roma tomatoes. Inherent levels were significantly (p<0.05) lower than the control sample throughout storage for 20 days. PMID- 20832686 TI - Effect of Capsicum carotenoids on growth and aflatoxins production by Aspergillus flavus isolated from paprika and chilli. AB - The aim of this study was to determine the effect of a carotenoid mixture (Capsantal FS-30-NT), containing capsanthin and capsorubin, on growth and aflatoxins (AF) production of AF-producing Aspergillus flavus isolates. Each isolate, previously isolated from paprika and chilli, was inoculated on Czapek Yeast extract Agar (CYA) medium supplemented with different amounts of capsantal (0-1%) and incubated at 10, 15 and 25 degrees C during 21 days. Growth rates and lag phases were obtained, and AF production was determined at 7, 14 and 21 days. None of the isolates grew at 10 degrees C and one isolate (UdLTA 3.193) hardly grew at 15 degrees C. Capsantal addition had no effect over lag phases and growth rates at 15 degrees C. At 25 degrees C capsantal reduced growth rates and increased lag phases. However, the effect of capsantal on AF production was inconclusive, because it depended on temperature or time, and most of the times it was not significant. Low temperature has been a crucial factor in AF production, regardless of the capsantal concentration tested. Industrial storage temperature for paprika and chilli use to be approximately 10 degrees C, so if this temperature is maintained mould growth and AF production should be prevented. PMID- 20832687 TI - Variation of microbial load and visual quality of ready-to-eat salads by vegetable type, season, processor and retailer. AB - Microbial components and visual quality were determined on 1158 consumer units of ready-to-eat salads from several processors, two per each of 579 process lots, with residual shelf-life varying around a mode of five days, collected over 19 months in the years 2006-2008 from retail stores of two Italian cities close to a major producing and processing area. The salads were mainly baby leaf of single species (lettuce, arugula, spinach, lamb's lettuce), with approximately 10% of the lots made up by mixes of 2-4 species. One unit per lot was analyzed on the day of collection and the other at the consume-by date. No Salmonella or Listeria monocytogenes was found (detection limit: presence in 25 g). Escherichia coli was detected in 27% of the lots (detection limit: 5 cfu/g), with probability of occurrence and counts highest in Autumn and for lettuce and arugula. Average visual quality was higher and other components of the microbial load were lower in Winter and Spring compared to Summer and Autumn (-0.6 log cfu/g of total aerobic counts, -1.3 log cfu/g of coliforms, -0.6 log cfu/g of yeasts and moulds). Lactic acid bacteria were detected more frequently in Spring and Summer (up to 50% of the lots). The rate of increase of microbial populations during shelf life was not affected by the level of initial contamination. At the consume by date total aerobic count exceeded 7.2 log cfu/g for 50% of the lots and 7.7 log cfu/g for 25%. Salads from the biggest processor and retailer showed slightly higher visual quality scores, lower odds of E. coli occurrence and lower microbial loads. Visual quality scores showed significant negative relationships with the levels of lactic acid bacteria, coliforms and total viable counts. PMID- 20832688 TI - Occurrence of biogenic amine-forming lactic acid bacteria in wine and cider. AB - A collection of 810 lactic acid bacteria (LAB) strains isolated from wine and cider was screened for potential biogenic amine (BA) producers by combining molecular and phenotypic approaches. A newly developed multiplex PCR method allowed for the simultaneous detection of four genes involved in the production of histamine (histidine decarboxylase, hdc), tyramine (tyrosine decarboxylase, tyrdc) and putrescine (via either ornithine decarboxylase, odc, or agmatine deiminase, agdi) while TLC and HPLC analysis allowed for BA-production determination. One hundred and fifty-eight LAB strains were monitored by the molecular/phenotypic double approach and revealed a good correlation between genotypic and phenotypic data. Eighteen per cent of the tested strains were positive for at least one BA target gene with up to three detected simultaneously, in particular amongst Lactobacillus brevis and Lactobacillus hilgardii isolates for the tyrdc and agdi genes. The most frequent gene corresponded to the agdi gene detected in 112 strains (14% of all LAB strains) of 10 different LAB species. The tyrdc gene was detected in 67 strains represented by 7 different LAB species (8% overall), especially those isolated from wine. Lower levels of hdc(+) (2% of strains) and especially odc(+) (0.5% of strains) strains were observed. Interestingly, species that have never been described to carry BA-producing pathway genes were identified in this study. Furthermore, only one cadaverine-producer was detected and corresponded to Lactobacillus 30a, a collection strain not found in fermented beverages, although cadaverine is commonly detected in wines. PMID- 20832689 TI - Interactions between bacterial isolates from modified-atmosphere-packaged artisan type cooked ham in view of the development of a bioprotective culture. AB - Growth and metabolite production of three dominant bacterial isolates (Carnobacterium divergens 3M14, Leuconostoc carnosum 3M42, and Brochothrix thermosphacta RMS6) from modified-atmosphere-packaged (MAP), artisan-type cooked ham were assessed for their interactions in view of the development of a bioprotective culture. During monoculture experiments in cooked ham simulation medium, Leuc. carnosum 3M42 converted the available glucose into lactic acid and ethanol, whereas the two other strains produced additional metabolites such as acetic acid and 3-methyl-1-butanol. When grown in co-culture, Leuc. carnosum 3M42 suppressed the growth and metabolism of B. thermosphacta RMS6. In contrast, a co culture of the latter bacterium with C. divergens 3M14 led to a variety of spoilage-related metabolic compounds. Subsequently, experiments with a commercial cooked ham product indicated that Leuc. carnosum 3M42 dominated the meat matrix and improved acceptability of the product over time, hence acting as a bioprotective culture for MAP, artisan-type cooked ham. PMID- 20832690 TI - From undefined red smear cheese consortia to minimal model communities both exhibiting similar anti-listerial activity on a cheese-like matrix. AB - Starting from one undefined cheese smear consortium exhibiting anti-listerial activity (signal) at 15 degrees C, 50 yeasts and 39 bacteria were identified by partial rDNA sequencing. Construction of microbial communities was done either by addition or by erosion approach with the aim to obtain minimal communities having similar signal to that of the initial smear. The signal of these microbial communities was monitored in cheese microcosm for 14 days under ripening conditions. In the addition scheme, strains having significant signals were mixed step by step. Five-member communities, obtained by addition of a Gram negative bacterium to two yeasts and two Gram positive bacteria, enhanced the signal dramatically contrary to six-member communities including two Gram negative bacteria. In the erosion approach, a progressive reduction of 89 initial strains was performed. While intermediate communities (89, 44 and 22 members) exhibited a lower signal than initial smear consortium, eleven- and six-member communities gave a signal almost as efficient. It was noteworthy that the final minimal model communities obtained by erosion and addition approaches both had anti-listerial activity while consisting of different strains. In conclusion, some minimal model communities can have higher anti-listerial effectiveness than individual strains or the initial 89 micro-organisms from smear. Thus, microbial interactions are involved in the production and modulation of anti-listerial signals in cheese surface communities. PMID- 20832691 TI - The determination of viable counts in probiotic cultures microencapsulated by spray-coating. AB - An assessment of various methods to determine viable counts (CFU) in freeze-dried and dried microencapsulated (ME) probiotic cultures was carried out. Microencapsulation was done by spray-coating of dried Lactobacillus rhamnosus R0011 or Bifidobacterium longum ATCC 15708 cultures with fat. Rehydration of the ME powders was incomplete when they were added to water and gently agitated. As a result analytical methods based on vortexing of rehydrated ME cultures and which did not incorporate a high-shear homogenization (HSH) step underestimated the viable counts. The CFU of ME cultures were identical when methods using either blender or generator probes high-shear homogenization (HSH) were carried out. Furthermore HSH reduced the variability of the CFU results of both free-cell and ME cultures by a factor of three. The addition of an emulsifier (Tween 80) in the rehydrating medium to dissolve fat did not improve CFU counts when generator probes were used for HSH. The presence of fat in the ME product, or when added to the rehydration medium, improved CFU counts of B. longum but not of L. rhamnosus. PMID- 20832692 TI - Comparison of recovery methods for the enumeration of injured Listeria innocua cells under isothermal and non-isothermal treatments. AB - This study compares the feature of different media with the combination of selective with non-selective media in a TAL method for recovery of Listeria innocua cells exposed to thermal treatments. Experiments were conducted in broth at constant temperature (52.5 and 65.0 degrees C) and pH (4.5 and 7.5) conditions, using NaCl or glycerol to adjust water activity to 0.95. Four different media were used in bacterial cell enumeration: (i) a non-selective medium - TSAYE, (ii) two selective media - TSAYE + 5%NaCl and Palcam Agar and (iii) TAL medium (consisting of a layer of Palcam Agar overlaid with one of TSAYE). Two food products were used as case studies aiming at comparison of results obtained on selective and TAL media enumeration. Parsley samples were inoculated with L. innocua and subjected to posterior thermal treatments both under isothermal (52.5, 60.0 and 65.0 degrees C) and non-isothermal (heating rate of 1.8 degrees C/min from 20.0 to 65.0 degrees C) conditions. The recovery capability of TAL method was also studied when a pre-cooked frozen food (i.e. meat pockets) was fried (oil temperature of ~180 degrees C). TAL method proved to be better than Palcam Agar in terms of capability to recover injured cells and was effective in L. innocua enumeration when non-sterile samples were analysed. PMID- 20832693 TI - Survival of Lactobacillus rhamnosus strains in the upper gastrointestinal tract. AB - In the present study six probiotic Lactobacillus rhamnosus strains were investigated for their ability to survive in the human upper gastrointestinal tract through a dynamic gastric model of digestion. MRS broth was used as delivery vehicle and survival was investigated during in vitro gastric and gastric plus duodenal digestion. Results highlighted that all tested strains showed good survival rate during both gastric and duodenal digestion. In particular, three strains exhibited a great survival showing a recovery percentage in the range between 117 and 276%. In agreement with survival data, high lactic acid production was detected for all strains, confirming their metabolic activity during digestion. PMID- 20832694 TI - Molecular ecology and polyphasic characterization of the microbiota associated with semi-dry processed coffee (Coffea arabica L.). AB - This work was aimed at isolating and identifying the microbiota present during the semi-dry method of coffee processing using polyphasic methods and to evaluate microbial diversity with PCR-DGGE. Samples of Coffea arabica L. were collected during different processing stages in southern Minas Gerais, Brazil. The bacterial and fungal isolates were phenotypically characterised and grouped according to the ARDRA technique, in which the 16-23S and ITS1-5.8S regions of the rDNA were sequenced for species identification. The bacterial counts varied from 3.7 to 7 log CFU g(-1). The yeast counts ranged from 3.4 to 6.9 log CFU g( 1), and the filamentous fungal population varied from 2 to 3.7 log CFU g(-1). Bacillus subtilis, Escherichia coli, Enterobacter agglomerans, Bacillus cereus and Klebsiella pneumoniae were the predominant bacteria detected during the processing of the coffee, and Pichia anomala, Torulaspora delbrueckii and Rhodotorula mucilaginosa were the dominant yeasts. All of the yeast and bacterial species detected by PCR-DGGE were isolated using culture-dependent methods, with the exception of one uncultivable bacterial species. Aspergillus was the most common genus among the filamentous fungal isolates. The use of polyphasic methods allowed a better characterization of the microbiota that is naturally present in semi-dry processed coffee. PMID- 20832695 TI - Wilderness Medical Society Roundtable Report. Recommendations on the use of epinephrine in outdoor education and wilderness settings. PMID- 20832696 TI - Effectors of visual search efficacy on the Allegheny Plateau. AB - BACKGROUND: Although lost-person search managers try to direct search efforts quantitatively, it has historically been difficult to quantify the efficacy of search efforts accurately. The effective-sweep-width (ESW) methodology represents an avenue for accomplishing this goal but has not yet been widely disseminated among practitioners. METHODS: We obtained ESW values in the summer and winter in a typical disturbed-forest environment in southwest Pennsylvania. We used nonparametric statistics to compare individual ESW values for two types of search objects detected by 18 summer and 20 winter searchers, cumulating the P values for similar comparisons and correcting for false discovery via a stepped method. RESULTS: We detected robust differences (all at P <.001) associated with search object color, season, and vegetation thickness. In contrast with earlier studies, we found a significant correlation between individual searchers' ESWs for different search objects and different types of vegetation (P <.001). We also found that adolescent searchers had significantly lower ESW values than adults (P = .002). Apparently significant positive correlations between time spent on the course or field search experience and ESW disappeared when teens were excluded from the comparisons. CONCLUSIONS: These results (the first comparison of seasonal ESW effects in identical terrain) represent the first statistical demonstration that the ESW methodology provides more than enough resolution to answer fundamental questions about the efficacy of visual search for lost persons by human searchers. They also add support to the imperative of operationally disseminating these methods among search-and-rescue practitioners, and offer some initial operational lessons for search managers. PMID- 20832697 TI - Injury incidence and predictors on a multiday recreational bicycle tour: The Register's Annual Great Bike Ride Across Iowa, 2004 to 2008. AB - OBJECTIVE: The "Register's Annual Great Bike Ride Across Iowa" (RAGBRAI) is a 7 day recreational bicycle ride with more than 10,000 participants covering 500 miles. The heat and humidity of late July in Iowa, the prevalence of amateur riders, and the consumption of alcohol can combine creating the potential for a significant number of injuries. The purpose of this study is to determine the type, quantity, and severity of injuries on RAGBRAI and gather data on the factors related to these incidents. METHODS: This retrospective chart review examined ambulance "run sheets" for patients requiring transport to the hospital from the bike route between 2004 and 2008. These run sheets included name, age, chief complaint, anatomic location of injuries, medications administered, procedures performed, and a full narrative describing the initial scene, patient's account of the incident, services provided, and ongoing condition of the patient while en route to the hospital. Chi-square tests, Pearson's correlation tests, and t tests were applied to determine significant statistical outcomes. RESULTS: From 2004 to 2008, Care Ambulance Inc provided on-route medical services for 419 RAGBRAI participants. Of these participants, 190 (45.3%) required transport to a local hospital by Care Ambulance Inc. Females were more likely to require transport, as they comprised 46.3% of transported patients while only representing 35% of all RAGBRAI participants (P = .001). For men, increasing age was a significant predictor of transport, particularly males between the ages of 60 and 69 years old (P = .01). Of the 148 run sheets where mechanism of incident was documented, 114 incidents were caused by rider factors (77.0%), 29 by road factors (19.6%), and 5 by bicycle factors (3.4%). Higher heat indexes were correlated with an increased number of dehydration cases (r = 0.979, P = .02). Of participants who reported with minor injuries to a mobile first aid station and did not require transport, 90.1% had not imbibed any alcohol. Bony injuries were more common above the waistline as 39/45 (86.7%) fractures occurred to the clavicle, shoulder/proximal humerus, hand, or head. The most common bony injury each year of RAGBRAI was a clavicle fracture, which represented 44.4% of all recorded fractures from 2004 to 2008. Lacerations and abrasions were also more common above the waist, as 63.5% (127/200) of soft tissue injuries requiring treatment were either to the head or upper extremities. No specific event day showed any correlation with increased injury (P >.05). CONCLUSIONS: This study suggests that females and older males are more likely to require transport for injuries sustained on RAGBRAI, the majority of injuries occur around the head and upper extremities, dehydration case load is correlated with heat index, and that incidents are usually caused by rider factors. This research could be used by multiday recreational bicycle tour organizers to continue educating riders on riding carelessness and etiquette and prepare medical services for certain quantities and types of injuries. PMID- 20832698 TI - An analysis of sea kayaking incidents in New Zealand 1992-2005. AB - OBJECTIVES: The objective of this study was to investigate trends, medical problems, and contributory factors that occurred in 50 sea kayaking incidents in New Zealand between October 1992 and September 2005. There are currently very limited validated data available worldwide about the epidemiology of sea kayaking incidents. The research will raise awareness of how these events happened and their potential for serious harm. It will assist kayakers to manage their sport safely. METHODS: This was a retrospective epidemiological study of incident reports originally collected by Paul Caffyn for the Kiwi Association of Sea Kayakers (KASK). Variables investigated in this study were geographic location, month, year, participant demographics, incident severity, type of kayak and trip, environmental conditions, safety gear carried, medical problems, cause of deaths, and contributory factors. Tables and graphs were developed to analyze the results. RESULTS: Incidents occurred around New Zealand throughout the year, often in rough seas in offshore winds. More people were involved in September. Fifty-six percent of incidents involved groups; 20% were overseas tourists and 72% were recreational private trips. Eighty-five percent of participants were male, mostly aged 24 to 39 years old, and 48% had little or no experience. The severity of incidents increased with time. Severity was lower for women. Severity was higher in calm conditions and light winds, when the capsized kayaker became separated from the kayak, and when a personal flotation device (PFD) was not worn. Fishing incidents had a higher severity and involved inexperienced kayakers. Human factors contributed to most if not all incidents and occurred more frequently than physical events. Where medical problems were reported, hypothermia and sprains were common. Collision with a powered vessel was often fatal. The study was limited because it was based on relatively small numbers, was unlikely to capture all incidents in New Zealand, and denominator data were unknown. CONCLUSIONS: All incidents were complex events with many variables interacting in different ways and all had the potential to be serious and life threatening. Human actions were more important than physical events and young men were most often involved. Staying with the kayak after capsizing and wearing a PFD may have reduced the severity of an incident. PMID- 20832699 TI - The lack of associations between alleles at the hypoxia-inducible factor 1A C1772T loci and responses to acute hypoxia. AB - OBJECTIVE: The aim of this study was to investigate the associations between alleles of the hypoxia-inducible factor 1A (HIF1A) C1772T polymorphism and several physiological responses to hypoxia, including the hypoxic ventilatory response (HVR), and serum erythropoietin (EPO), arterial oxygen saturation (Sao2), and acute mountain sickness (AMS) responses during 8 hours of exposure to normobaric hypoxia. METHODS: A total of 76 males participated in the study; 52 participants completed an 8-hour exposure to 12.7% oxygen, during which time Sao2, EPO concentrations, and AMS scores were measured, while 62 individuals took part in an HVR trial (in total 38 individuals completed both protocols). DNA was obtained from leukocytes, and a 346-bp fragment of the HIF1A gene containing the C1772T polymorphism was amplified using polymerase chain reaction. Fragments were sequenced to reveal individual genotypes, and the associations between HIF1A genotype and EPO, Sao2, AMS responses to hypoxia and HVR were examined. RESULTS: The magnitude of the hypoxic responses was highly variable between individuals. The increase in participants' EPO responses ranged from 89% to 388% of baseline values following hypoxia, while Sao2 values during the exposure ranged from 71% to 89%. The HVR ranged from -0.04 to +2.18 L x min(-1) x Sao2 %(-1) among participants. No significant differences in EPO, Sao2, AMS, or HVR results were observed between the HIF1A CC genotype and the combined CT/TT genotype group. CONCLUSION: In this study, the HIF1A C1772T polymorphism does not appear to influence EPO, Sao2, or AMS responses during acute hypoxic exposure, or the magnitude of the HVR. PMID- 20832700 TI - Spontaneous endogenous core temperature rewarming after cooling due to snow burial. AB - OBJECTIVE: To measure afterdrop and rewarming in subjects placed in a hypothermia wrap immediately after extrication from 60 minutes of snow burial. METHODS: We measured esophageal core body temperature (Tes) in 6 subjects buried in compacted snow (mean density 39%) for up to 60 minutes at an altitude of 2450 m while breathing with an AvaLung (Black Diamond Equipment, Salt Lake City, UT). Mean snow temperature was -3.5 +/- 1.0 degrees C and mean air temperature was 0 +/- 2 degrees C. Subjects wore a 1-piece Gore-Tex suit over medium weight Capilene underwear with a hood, face mask, goggles, mittens, and boots. After extrication from snow burial subjects were immediately placed in a hypothermia wrap. Tes was measured for an additional 60 minutes as subjects rewarmed by shivering. RESULTS: Tes cooling rate during snow burial was 0.84 +/- 0.3 degrees C/h during a mean burial time of 58 +/- 4 minutes. Tes afterdrop (0.77 +/- 0.4 degrees C) occurred 12 +/- 8 minutes after extrication from snow burial at a cooling rate of 4.0 +/- 0.8 degrees C/h (P <.001 Tes snow burial vs afterdrop cooling rate). Rewarming rate was 1.1 +/- 0.3 degrees C/h over the subsequent 48 +/- 8 minutes (P = 0.045 snow burial cooling vs rewarming rate). CONCLUSION: Afterdrop rate increased about 4-fold as compared to snow burial cooling rate for a transient time period in subjects who were placed immediately into an insulating hypothermia wrap. Spontaneous endogenous rewarming increased core body temperature at a slightly higher rate than it decreased during snow burial. These findings suggest that field rewarming of mildly hypothermic and shivering avalanche burial victims is possible, but they should be insulated quickly to limit significant afterdrop. PMID- 20832701 TI - Prospective, double-blind, randomized, placebo-controlled comparison of acetazolamide versus ibuprofen for prophylaxis against high altitude headache: the Headache Evaluation at Altitude Trial (HEAT). AB - OBJECTIVE: High altitude headache (HAH) is the most common neurological complaint at altitude and the defining component of acute mountain sickness (AMS). However, there is a paucity of literature concerning its prevention. Toward this end, we initiated a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya designed to compare the effectiveness of ibuprofen and acetazolamide for the prevention of HAH. METHODS: Three hundred forty-three healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. Outcome measures included headache incidence and severity, AMS incidence and severity on the Lake Louise AMS Questionnaire (LLQ), and visual analog scale (VAS). RESULTS: Two hundred sixty five of 343 subjects completed the trial. HAH incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%; P = .95), and both agents were significantly more effective than placebo (45.3%; P = .01). AMS incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%; P = .34), and both agents were significantly more effective than placebo (28.6%; P = .03). In fully compliant participants, moderate or severe headache incidence was similar when treated with acetazolamide (3.8%) or ibuprofen (4.7%; P = .79), and both agents were significantly more effective than placebo (13.5%; P = .03). CONCLUSIONS: Ibuprofen and acetazolamide were similarly effective in preventing HAH. Ibuprofen was similar to acetazolamide in preventing symptoms of AMS, an interesting finding that implies a potentially new approach to prevention of cerebral forms of acute altitude illness. PMID- 20832702 TI - Chemical oxygen generation: Evaluation of the Green Dot Systems, Inc portable, nonpressurized emOx device. AB - OBJECTIVE: To evaluate the performance of the emOx emergency powdered oxygen portable nonpressurized delivery system. This device produces oxygen through chemical reaction and is marketed for emergency first aid use until professional medical assistance is available. METHODS: Seven unmanned trials were conducted under standard laboratory conditions. Measures included oxygen flow, reaction canister external wall temperature, delivered gas temperature, and delivered gas relative humidity. RESULTS: The mean oxygen flow was 1.75 +/- 1.58 L x min(-1) (mean +/- SD) with a total yield of 40.4 +/- 2.6 L. Oxygen flow increased slowly and with substantial variability between reactant groups, exceeding 2.0 L x min( 1) after 15.7 +/- 6.4 minutes of operation. Oxygen flow briefly peaked at 5.93 +/ 0.56 L x min(-1) at 17.8 +/- 7.9 minutes before rapidly falling to zero. The mean oxygen fraction was 0.81 +/- 0.28, exceeding 0.96 in 10.7 +/- 2.9 minutes. The reaction canister external wall temperature reached 54.7 +/- 7.4 degrees C. Delivered gas temperature varied little from ambient. Delivered gas relative humidity surpassed 75% in 8 +/- 3 minutes and 90% in 15 +/- 5 minutes of operation. CONCLUSIONS: A readily available, high concentration oxygen supply could have utility to manage many conditions in advance of the arrival of professional emergency medical services (EMS). Unfortunately, the highly variable activation time and low average oxygen flow rate make the rapid deployment value of the emOx equivocal. The limited total oxygen yield makes it inappropriate for conditions demanding significant oxygen resources. Advancement in oxygen concentrator systems likely holds far more promise than powdered chemical oxygen generation for first aid and emergency medical applications. PMID- 20832703 TI - Orbital subperiosteal hematoma from scuba diving. AB - Only a few cases of nontraumatic orbital subperiosteal hematoma due to scuba diving have been reported, and this is the first of such cases that underwent surgical intervention. This injury results from negative pressure within the face mask, suctioning orbital tissues into the mask after incomplete equilibration of pressure on descent. Valsalva maneuver is a second mechanism implicated in the etiology of this injury. Recognition of this injury is of the utmost importance because vision loss is a possible complication if there is compression of the optic nerve or increased intraocular pressure. In many cases of nontraumatic orbital hematoma, conservative management is adequate; however, this case was an exception due to worsening exam findings. Divers may be able to prevent this injury by frequent and gentle equilibration of mask pressure on descent. PMID- 20832704 TI - Extensor hood syndrome--osteophytic irritation of digital extensor tendons in rock climbers. AB - OBJECTIVE: Injuries to the flexor tendons and flexor tendon pulleys are frequently reported in rock climbers. Osteoarthritic changes with bone spurs are also well known. We report on the less commonly described extensor tendon irritation caused by such osteophytes. METHODS: Thirteen high-level rock climbers (12 men, 1 woman; average age 33.8 years [range 17-55]; average years of climbing experience 19 [range 5-30]; average climbing level 10.2) with extensor hood irritation caused by dorsally located osteophytes of proximal interphalangeal (n = 10) or distal interphalangeal joints (n = 3) were evaluated and managed. Twelve climbers received conservative therapy and 1 climber was treated surgically. RESULTS: Before treatment, the climbers were unable to achieve their normal climbing ability due to extensor tendon irritations with resultant effusion noted in the ultrasound examinations. After conservative treatment, and in 1 case surgery, all patients achieved their previous climbing ability. CONCLUSION: While all climbers were able to achieve their former climbing level after treatment, the condition is progressive and the osteoarthritic changes will likely cause further problems for these individuals in the future. Extensor hood irritation must be considered in the differential diagnosis of finger pain in rock climbers. PMID- 20832705 TI - Non-avalanche-related snow immersion deaths: tree well and deep snow immersion asphyxiation. AB - Non-avalanche-related snow immersion death (NARSID), or snow immersion asphyxiation, is a significant winter mountain hazard for skiers and snowboarders. This phenomenon occurs predominately in western North America, where large tree wells and deep snowpacks develop. Although statistics are difficult to procure, snow immersion asphyxiation has resulted in more than 70 documented deaths in the past 2 decades. The primary purpose of this review is to examine the existing literature on NARSID to help prevent such dangerous accidents through educating wilderness medicine professionals and fostering public awareness. The exact duration of burial to time of death and the cause of death are not precisely known but can be postulated from accident reports, experimental snow burial studies, and avalanche literature. In most cases, death probably occurs within 15 to 30 minutes from the time of burial. However, survival after prolonged burial in a tree well and deep snow is possible. The cause of death is asphyxiation, probably due to one of the mechanisms that produce asphyxia in avalanche burial victims: positional asphyxia, airway obstruction, or carbon dioxide displacement asphyxia. Prevention of snow immersion asphyxiation begins with skiers and snowboarders staying within the limits of their skills, using the proper tools for deep powder, staying in control at all times, and employing a buddy system. A skier or snowboarder who falls near or into a tree well should tuck, roll, and try to land upright, grab the tree trunk or a branch, and yell or blow a whistle to alert partners. If buried upside down, the person should stay calm and create an air pocket, which is probably of paramount importance. Skiers and snowboarders should use avalanche safety equipment to lessen the risk of snow submersion asphyxiation. PMID- 20832706 TI - A mystery infection. PMID- 20832707 TI - Heads on learning. PMID- 20832708 TI - Effective tick removal with a fishing line knot. PMID- 20832709 TI - Presumptive Latrodectus bite with ileus and myocardial involvement. PMID- 20832710 TI - Avalanche triage: are two birds in the bush better than one in the hand? PMID- 20832712 TI - Physiological demands of hiking the Grand Canyon. PMID- 20832713 TI - Medicinal alcohol for exercise-associated hyponatremia? PMID- 20832715 TI - Recycling cohesin rings by deacetylation. AB - In this issue of Molecular Cell, Beckouet et al. (2010) and Borges et al. (2010) identify the enzyme responsible for cohesin deacetylation in anaphase and show that de novo acetylation is required for cohesion establishment in the next cell cycle. PMID- 20832716 TI - Old yeast can't handle the noise. AB - In this issue of Molecular Cell, Feser et al. (2010) show that aging yeast lose chromatin-associated histones and, furthermore, that correcting this deficiency robustly enhances replicative life span, indicating that loss of normal chromatin packing contributes to the aging process. PMID- 20832717 TI - Epigenetic networks and miRNAs in stem cells and cancer. AB - Stem-like cells in human cancer (CSCs) have multiple properties of embryonic stem cells (ESCs). In this issue, Iliopoulos et al. (2010) identify molecular mechanisms that link miRNAs to epigenetic states and drive CSCs, contributing to tumor aggressiveness. PMID- 20832718 TI - Evolution of central carbon metabolism. AB - Organisms share a common core to their metabolic networks. But what determined this: chance, chemical necessity, or evolutionary optimization? In this issue of Molecular Cell, Noor et al. (2010) provide new evidence for selection of a network with optimal features from a broader set of possibilities. PMID- 20832719 TI - CST meets shelterin to keep telomeres in check. AB - Telomere protection in budding yeast requires the heterotrimer named CST (for Cdc13-Stn1-Ten1). Recent data show that CST components are conserved and required for telomere stability in a wide range of eukaryotes, even those utilizing the shelterin complex to protect their telomeres. A common function of these proteins might be to stimulate priming at the C-strand gap that remains after telomerase elongation, replication termination, and terminal processing. In light of the budding yeast situation, another conserved function of CST might well be the regulation of telomerase. The cohabitation at telomeres of CST and shelterin components highlights the complexity of telomere biology. PMID- 20832720 TI - Hos1 deacetylates Smc3 to close the cohesin acetylation cycle. AB - Cohesion between sister chromatids is mediated by the chromosomal cohesin complex. In budding yeast, cohesin is loaded onto chromosomes during the G1 phase of the cell cycle. During S phase, the replication fork-associated acetyltransferase Eco1 acetylates the cohesin subunit Smc3 to promote the establishment of sister chromatid cohesion. At the time of anaphase, Smc3 loses its acetylation again, but the Smc3 deacetylase and the possible importance of Smc3 deacetylation are unknown. Here, we show that the class I histone deacetylase family member Hos1 is responsible for Smc3 deacetylation. Cohesin is protected from deacetylation while bound to chromosomes but is deacetylated as soon as it dissociates from chromosomes at anaphase onset. Nonacetylated Smc3 is required as a substrate for cohesion establishment in the following cell cycle. Our results complete the description of an Smc3 acetylation cycle and provide unexpected insight into the importance of de novo Smc3 acetylation for cohesion establishment. PMID- 20832721 TI - An Smc3 acetylation cycle is essential for establishment of sister chromatid cohesion. AB - Sister chromatid cohesion is thought to involve entrapment of sister DNAs by a tripartite ring composed of the cohesin subunits Smc1, Smc3, and Scc1. Establishment of cohesion during S phase depends on acetylation of Smc3's nucleotide-binding domain (NBD) by the Eco1 acetyl transferase. It is destroyed at the onset of anaphase due to Scc1 cleavage by separase. In yeast, Smc3 acetylation is reversed at anaphase by the Hos1 deacetylase as a consequence of Scc1 cleavage. Smc3 molecules that remain acetylated after mitosis due to Hos1 inactivation cannot generate cohesion during the subsequent S phase, implying that cohesion establishment depends on de novo acetylation during DNA replication. By inducing Smc3 deacetylation in postreplicative cells due to Hos1 overexpression, we provide evidence that Smc3 acetylation contributes to the maintenance of sister chromatid cohesion. A cycle of Smc3 NBD acetylation is therefore an essential aspect of the chromosome cycle in eukaryotic cells. PMID- 20832722 TI - Comprehensive, fine-scale dissection of homologous recombination outcomes at a hot spot in mouse meiosis. AB - In mammalian meiosis, only a small fraction of programmed DNA double-strand breaks are repaired as interhomolog crossovers (COs). To analyze another product of meiotic recombination, interhomolog noncrossovers (NCOs), we performed high resolution mapping of recombination events at an intensely active mouse hot spot in F1 hybrids derived from inbred mouse strains. We provide direct evidence that the vast majority of repair events are interhomolog NCOs, consistent with models in which frequent interhomolog interactions promote accurate chromosome pairing. NCOs peaked at the center of the hot spot but were also broadly distributed throughout. In some hybrid strains, localized zones within the hot spot were highly refractory to COs and showed elevated frequency of coconversion of adjacent polymorphisms in NCOs, raising the possibility of double-strand gap repair. Transmission distortion was observed in one hybrid, with NCOs providing a significant contribution. Thus, NCO recombination events play a substantial role in mammalian meiosis and genome evolution. PMID- 20832723 TI - The chromodomains of the Chd1 chromatin remodeler regulate DNA access to the ATPase motor. AB - Chromatin remodelers are ATP-driven machines that assemble, slide, and remove nucleosomes from DNA, but how the ATPase motors of remodelers are regulated is poorly understood. Here we show that the double chromodomain unit of the Chd1 remodeler blocks DNA binding and activation of the ATPase motor in the absence of nucleosome substrates. The Chd1 crystal structure reveals that an acidic helix joining the chromodomains can pack against a DNA-binding surface of the ATPase motor. Disruption of the chromodomain-ATPase interface prevents discrimination between nucleosomes and naked DNA and reduces the reliance on the histone H4 tail for nucleosome sliding. We propose that the chromodomains allow Chd1 to distinguish between nucleosomes and naked DNA by physically gating access to the ATPase motor, and we hypothesize that related ATPase motors may employ a similar strategy to discriminate among DNA-containing substrates. PMID- 20832724 TI - Elevated histone expression promotes life span extension. AB - Changes to the chromatin structure accompany aging, but the molecular mechanisms underlying aging and the accompanying changes to the chromatin are unclear. Here, we report a mechanism whereby altering chromatin structure regulates life span. We show that normal aging is accompanied by a profound loss of histone proteins from the genome. Indeed, yeast lacking the histone chaperone Asf1 or acetylation of histone H3 on lysine 56 are short lived, and this appears to be at least partly due to their having decreased histone levels. Conversely, increasing the histone supply by inactivation of the histone information regulator (Hir) complex or overexpression of histones dramatically extends life span via a pathway that is distinct from previously known pathways of life span extension. This study indicates that maintenance of the fundamental chromatin structure is critical for slowing down the aging process and reveals that increasing the histone supply extends life span. PMID- 20832725 TI - PARP-1 regulates chromatin structure and transcription through a KDM5B-dependent pathway. AB - PARP-1 is an abundant nuclear enzyme that regulates gene expression, although the underlying mechanisms are unclear. We examined the interplay between PARP-1, histone 3 lysine 4 trimethylation (H3K4me3), and linker histone H1 in the chromatin-dependent control of transcription. We show that PARP-1 is required for a series of molecular outcomes at the promoters of PARP-1-regulated genes, leading to a permissive chromatin environment that allows loading of the RNA Pol II machinery. PARP-1 does so by (1) preventing demethylation of H3K4me3 through the PARylation, inhibition, and exclusion of the histone demethylase KDM5B; and (2) promoting the exclusion of H1 and the opening of promoter chromatin. Upon depletion of PARP-1, these outcomes do not occur efficiently. Interestingly, cellular signaling pathways can use the regulated depletion of PARP-1 to modulate these chromatin-related molecular outcomes. Collectively, our results help to elucidate the roles of PARP-1 in the regulation of chromatin structure and transcription. PMID- 20832726 TI - A feed-forward circuit controlling inducible NF-kappaB target gene activation by promoter histone demethylation. AB - Activation of transcription from a silenced state is crucial to achieve specific gene expression in many biological contexts. Methylation of lysine 9 on histone H3 (H3K9) is widely associated with transcriptional silencing, and its disappearance is linked to the activation of several inflammatory genes by NF kappaB. Here we describe that this event is controlled by a feed-forward circuit catalyzed by the activity of the histone demethylase Aof1 (also known as Lsd2/Kdm1b). We find that Aof1 is required for removal of dimethyl H3K9 at specific promoters, and thereby it controls stimulus-induced recruitment of NF kappaB and gene expression. However, Aof1 is itself recruited by interaction with the c-Rel subunit of NF-kappaB, which is found at low levels associated with promoters in unstimulated cells. Thus, at these tightly regulated genes, NF kappaB functions both as a transcriptional activator and as an upstream targeting signal that marks promoters to be derepressed by histone demethylation. PMID- 20832727 TI - Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. AB - In an inducible oncogenesis model, the miR-200 family is inhibited during CSC formation but not transformation, and inhibition of miR-200b increases CSC formation. Interestingly, miR-200b directly targets Suz12, a subunit of a polycomb repressor complex (PRC2). Loss of miR-200 during CSC formation increases Suz12 expression, Suz12 binding, H3-K27 trimethylation, and Polycomb-mediated repression of the E-cadherin gene. miR-200b expression or Suz12 depletion blocks the formation and maintenance of mammospheres, and in combination with chemotherapy suppresses tumor growth and prolongs remission in mouse xenografts. Conversely, ectopic expression of Suz12 in transformed cells is sufficient to generate CSCs. The miR-200b-Suz12-cadherin pathway is important for CSC growth and invasive ability in genetically distinct breast cancer cells, and its transcriptional signature is observed in metastatic breast tumors. The interaction between miR-200 and Suz12 is highly conserved, suggesting that it represents an ancient regulatory mechanism to control the growth and function of stem cells. PMID- 20832728 TI - Decapping activators in Saccharomyces cerevisiae act by multiple mechanisms. AB - Eukaryotic mRNA degradation often occurs in a process whereby translation initiation is inhibited and the mRNA is targeted for decapping. In yeast cells, Pat1, Scd6, Edc3, and Dhh1 all function to promote decapping by an unknown mechanism(s). We demonstrate that purified Scd6 and a region of Pat1 directly repress translation in vitro by limiting the formation of a stable 48S preinitiation complex. Moreover, while Pat1, Edc3, Dhh1, and Scd6 all bind the decapping enzyme, only Pat1 and Edc3 enhance its activity. We also identify numerous direct interactions between Pat1, Dcp1, Dcp2, Dhh1, Scd6, Edc3, Xrn1, and the Lsm1-7 complex. These observations identify three classes of decapping activators that function to directly repress translation initiation and/or stimulate Dcp1/2. Moreover, Pat1 is identified as critical in mRNA decay by first inhibiting translation initiation, then serving as a scaffold to recruit components of the decapping complex, and finally activating Dcp2. PMID- 20832729 TI - A dual E3 mechanism for Rub1 ligation to Cdc53. AB - In ubiquitin-like protein (UBL) cascades, a thioester-linked E2~UBL complex typically interacts with an E3 enzyme for UBL transfer to the target. Here we demonstrate a variant mechanism, whereby the E2 Ubc12 functions with two E3s, Hrt1 and Dcn1, for ligation of the UBL Rub1 to Cdc53's WHB subdomain. Hrt1 functions like a conventional RING E3, with its N terminus recruiting Cdc53 and C terminal RING activating Ubc12~Rub1. Dcn1's "potentiating neddylation" domain (Dcn1(P)) acts as an additional E3, reducing nonspecific Hrt1-mediated Ubc12~Rub1 discharge and directing Ubc12's active site to Cdc53. Crystal structures of Dcn1(P)-Cdc53(WHB) and Ubc12 allow modeling of a catalytic complex, supported by mutational data. We propose that Dcn1's interactions with both Cdc53 and Ubc12 would restrict the otherwise flexible Hrt1 RING-bound Ubc12~Rub1 to a catalytically competent orientation. Our data reveal mechanisms by which two E3s function synergistically to promote UBL transfer from one E2 to a target. PMID- 20832731 TI - Central carbon metabolism as a minimal biochemical walk between precursors for biomass and energy. AB - Central carbon metabolism uses a complex series of enzymatic steps to convert sugars into metabolic precursors. These precursors are then used to generate the entire biomass of the cell. Are there simplifying principles that can explain the structure of such metabolic networks? Here we address this question by studying central carbon metabolism in E. coli. We use all known classes of enzymes that work on carbohydrates to generate rules for converting compounds and for generating possible paths between compounds. We find that central carbon metabolism is built as a minimal walk between the 12 precursor metabolites that form the basis for biomass and one precursor essential for the positive net ATP balance in glycolysis: every pair of consecutive precursors in the network is connected by the minimal number of enzymatic steps. Similarly, input sugars are converted into precursors by the shortest possible enzymatic paths. This suggests an optimality principle for the structure of central carbon metabolism. The present approach may be used to study other metabolic networks and to design new minimal pathways. PMID- 20832730 TI - Rictor forms a complex with Cullin-1 to promote SGK1 ubiquitination and destruction. AB - The Rictor/mTOR complex (also known as mTORC2) plays a critical role in cellular homeostasis by phosphorylating AGC kinases such as Akt and SGK at their hydrophobic motifs to activate downstream signaling. However, the regulation of mTORC2 and whether it has additional function(s) remain largely unknown. Here, we report that Rictor associates with Cullin-1 to form a functional E3 ubiquitin ligase. Rictor, but not Raptor or mTOR alone, promotes SGK1 ubiquitination. Loss of Rictor/Cullin-1-mediated ubiquitination leads to increased SGK1 protein levels as detected in Rictor null cells. Moreover, as part of a feedback mechanism, phosphorylation of Rictor at T1135 by multiple AGC kinases disrupts the interaction between Rictor and Cullin-1 to impair SGK1 ubiquitination. These findings indicate that the Rictor/Cullin-1 E3 ligase activity is regulated by a specific signal relay cascade and that misregulation of this mechanism may contribute to the frequent overexpression of SGK1 in various human cancers. PMID- 20832732 TI - Clinical problems in diabetic pregnancy. PMID- 20832733 TI - Disturbances in lipid metabolism in diabetic pregnancy - Are these the cause of the problem? AB - The most common neonatal complication of gestational diabetes (GDM) is macrosomia. During early pregnancy an accumulation of maternal fat depots occurs followed by increased adipose tissue lipolysis and subsequent hyperlipidaemia, which mainly corresponds to increased triglycerides (TG) in all circulating lipoproteins. In GDM women, the enhanced insulin resistance and decreased oestrogens are responsible for the reported wide range of dyslipidaemic conditions. In GDM, decreased proportion of long chain polyunsaturated fatty acids in fetus plasma could result from decreased supply, impaired placental transfer or even altered intrauterine metabolism. A positive correlation between maternal TG and neonatal body weight or fat mass has been found in GDM. Augmented oxidative stress and altered adipokines have also been found, with an adverse outcome even in normoglycaemic conditions. Thus, although additional studies are required, overall these findings indicate that altered maternal lipid metabolism rather than hyperglycaemia constitutes a risk for macrosomia in GDM. PMID- 20832734 TI - Vitamin D and pregnancy: An old problem revisited. AB - Vitamin D has historically been considered to play a role solely in bone and calcium metabolism. Human disease associations and basic physiological studies suggest that vitamin D deficiency is plausibly implicated in adverse health outcomes including mortality, malignancy, cardiovascular disease, immune functioning and glucose metabolism. There is considerable evidence that low maternal levels of 25 hydroxyvitamin D are associated with adverse outcomes for both mother and fetus in pregnancy as well as the neonate and child. Vitamin D deficiency during pregnancy has been linked with a number of maternal problems including infertility, preeclampsia, gestational diabetes and an increased rate of caesarean section. Likewise, for the child, there is an association with small size, impaired growth and skeletal problems in infancy, neonatal hypocalcaemia and seizures, and an increased risk of HIV transmission. Other childhood disease associations include type 1 diabetes and effects on immune tolerance. The optimal concentration of 25 hydroxyvitamin D is unknown and compounded by difficulties in defining the normal range. Whilst there is suggestive physiological evidence to support a causal role for many of the associations, whether vitamin D deficiency is a marker of poor health or the underlying aetiological problem is unclear. Randomised controlled trials of vitamin D supplementation with an appropriate assessment of a variety of health outcomes are required. PMID- 20832735 TI - Developmental programming and diabetes - The human experience and insight from animal models. AB - Children born to mothers, rather than to fathers, with type 1 diabetes (type 1 DM) or type 2 diabetes (type 2 DM) may have a greater susceptibility to diabetes and obesity in later life, inferring a role for in utero or early post-natal influences on the developing child. This review summarises the studies contributing to this hypothesis, noting some of the controversies including the potential for residual confounding and the influence of maternal BMI. Animal models demonstrate that maternal hyperglycaemia leads to persistent disorders of offspring pancreatic beta cell secretory capacity, abnormal insulin signaling in insulin-sensitive tissues and abnormal development of the hypothalamus, associated with aberrant control of energy regulation and obesity in adult life. Prospective studies, particularly follow-up of children born to diabetic mothers participating in RCTs of improved glycemic control are needed to accurately assess the transgenerational influences of maternal diabetes and to evaluate mechanisms inferred from animal data. PMID- 20832736 TI - Screening for hyperglycaemia in pregnancy: Consensus and controversy. AB - Policy decisions on whether to implement screening programmes depend on whether the proposed programmes meet a set of criteria laid down by the World Health Organization. Screening for hyperglycaemia in pregnancy (HGP) does not meet all the criteria. However the case for screening has been strengthened by a number of recent developments, including: rising prevalence of HGP because of increasing maternal age and BMI; the results of the Hyperglycaemia and Adverse Pregnancy Outcomes study, showing that adverse effects of HGP are seen over a wider range of plasma glucose levels than previously thought; two large trials which showed the benefits of treating lesser degrees of HGP; trials showing that metformin and glibenclamide were effective and safe alternatives to immediate insulin in those without good control on lifestyle measures alone. However uncertainties remain around the threshold for treatment, and on the best screening strategy. PMID- 20832737 TI - The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome. AB - Obesity has reached pandemic proportions and is of growing concern worldwide. Adverse health outcomes associated with a raised body mass index present the greatest challenge currently facing clinicians across all disciplines. Obesity is a chronic illness which is associated with metabolic disease, nutritional deficiency, musculoskeletal complications and cancer. These obesity-related health issues extend to pregnancy where they are responsible for producing a variety of medical and obstetric complications resulting in an increased incidence of maternal and fetal adverse outcomes. Management of diet, gestational diabetes and gestational and inter-gestational weight may improve outcomes in women who are obese during pregnancy. Specific recommendations for the management of obesity in pregnancy have recently been published. PMID- 20832738 TI - Type 2 diabetes in pregnancy - An increasing problem. AB - The worldwide epidemic in type 2 diabetes has been associated with an increased diagnosis in young adults. This has lead to a rapid rise in the number of pregnancies complicated by type 2 diabetes. Studies have shown risk of serious adverse outcome, including congenital malformation and perinatal mortality, is the same, or increased, in type 2 diabetes compared to type 1 diabetes. Despite improved glycaemic control in type 2 diabetes compared to type 1 diabetes, rates of perinatal morbidity, including preterm birth and macrosomia, appear to be similar. Risk factors associated with poor pregnancy outcome in women with type 2 diabetes include obesity, ethnicity and poor pregnancy preparation. This review will cover practical aspects of management of type 2 diabetes before, during and after pregnancy, including prepregnancy care, safety of oral hypoglycaemic agents, glycaemic management during labour, and choice of effective contraception. PMID- 20832739 TI - Maturity onset diabetes of the young and pregnancy. AB - Three and a half decades after the clinical description of "Maturity Onset Diabetes of the Young" (MODY), and despite its low prevalence, important knowledge has been gathered concerning its genetic basis, molecular pathways, clinical phenotypes and pharmacogenetic issues. This knowledge has proved to be important not only for the attention of subjects carrying a mutation but also for the insight provided in Type 2 diabetes mellitus. In recent years, a shift from the term "MODY" to "monogenic diabetes" has taken place, the latter term being a better and more comprehensive descriptor. We stick to the "old" term because information on other types of monogenic diabetes and pregnancy is scarce. In this review we perform an overview of the entity, the prevalence rates reported in women with gestational diabetes mellitus and the specific impact of each type on pregnancy outcome. PMID- 20832740 TI - Onset of autoimmune type 1 diabetes during pregnancy: Prevalence and outcomes. AB - Although this has been recently challenged, gestational diabetes mellitus (gestational diabetes) is still defined as an "impairment of glucose tolerance with onset or first recognition during pregnancy". According to this definition, all pathophysiological conditions leading to beta cell deficiency may reveal as gestational diabetes, due to the physiological insulin resistance associated with pregnancy. In rare patients, gestational diabetes is associated with the presence of islet autoantibodies and with a high risk of progression to overt type 1 diabetes after delivery. This condition has often been compared to the Latent Autoimmune Diabetes in Adults. The frequency of islet autoantibodies in gestational diabetes has been assessed in many studies, but data about the clinical presentation of this subtype and about its prognosis are few. We review these studies and discuss the links of autoimmune gestational diabetes with type 1 diabetes mellitus. PMID- 20832741 TI - Metformin treatment for Type 2 diabetes in pregnancy? AB - Metformin lowers blood glucose by reducing hepatic glucose output, increasing insulin sensitivity and enhancing peripheral glucose uptake. Metformin is widely used in women with Type 2 diabetes of child-bearing age, many of whom become pregnant. Studies to date in Type 2 diabetes in pregnancy, gestational diabetes and polycystic ovarian syndrome are reassuring. Metformin is not considered teratogenic. There is sufficient evidence that metformin is safe used throughout pregnancy, with no worsening of obstetric or perinatal outcomes. Women may benefit from the lesser weight gain. The long-term risks to the offspring remain inadequately researched, with no evidence of harm up to 2 years, and no suggestions of later complications in countries using metformin for many years. Metformin is recommended for use in pregnancies complicated by Type 2 diabetes, but women should be informed of the evidence regarding its associated risks and benefits to enable an informed choice over its use. PMID- 20832742 TI - Hypertension in diabetic pregnancy: impact and long-term outlook. AB - Hypertensive disorders in pregnancy can be chronic, pregestational or just diagnosed before the 20th week, or newly diagnosed in the second half of pregnancy. Any type of hypertension is more frequent in diabetic pregnancies with a different distribution among different types of diabetes. Most of the evidence is for pre-eclampsia associated with a marked increase in primary caesarean section, preterm birth and more need for neonatal intensive care. Different risk factors and pregnancy outcomes would support the hypothesis that pre-eclampsia and gestational hypertension might be largely separate entities, but this position is not unanimously accepted. Chronic hypertension increases with age and duration of diabetes, predicting increased rates of prematurity and neonatal morbidity, especially when associated with superimposed pre-eclampsia. Long-term consequences are observed in women whose pregnancy was complicated by hypertension such as chronic hypertension and cardiovascular diseases. PMID- 20832743 TI - The future role for a diabetes specialist midwife. AB - In the United Kingdom diabetes is now the most common, pre-existing medical disorder in pregnancy [Jincoe A. Diabetes: monitoring maternal and fetal wellbeing. Br J Midwifery 2006;14(2):91-4], and still continues to have associated risks for the mother, fetus and neonate [Confidential Enquiry into Maternal and Child Health. Diabetes in pregnancy: are we providing the best care? Findings of a national enquiry: England, Wales and Northern Ireland. London: CEMACH; 2007]. Worldwide diabetes is becoming more prevalent [Macfarlane A. Diabetes and pregnancy. Br Med J 2006;333(7560):157-8] and there is the added new phenomenon of the increase in Type 2 diabetes in the childbearing population. The midwifery role in such pregnancies has come under question as some units have Diabetes Specialist Midwives and some do not and midwifery care is presently varied [Miller A. Diabetes: lessons for midwives. Pract Midwife 2005;8(11):4-5]. This review will specifically seek to address the midwifery role in relation to this client group with complex needs. It will explore how a specialist midwifery post could have an impact on improving care, how the role is developing and future perspectives. Aspects on how midwifery care is delivered to women with diabetes in the United Kingdom will be discussed and a brief international insight relayed. PMID- 20832744 TI - Obstetric problems in diabetic pregnancy - The role of fetal hypoxia. AB - Perinatal mortality has not decreased over the last two decades in pregestational diabetic pregnancies. Stillbirth rate is 4-6 times and neonatal mortality 2-4 times higher in diabetic than in non-diabetic pregnancies despite modern electronic fetal surveillance methods. Majority of late stillbirths are "unexplained", many of which are presumably caused by fetal hypoxia. Both experimental and clinical studies have shown that fetal hyperglycaemia and hyperinsulinaemia can independently cause fetal hypoxia, which ultimately can lead to fetal death. Poor glycaemic control is associated with perinatal complications. Sharp increases in amniotic fluid erythropoietin levels indicate fetal hypoxia in diabetic pregnancy. Fetal erythropoietin concentrations correlate directly with maternal HbA(1c) levels. It is therefore important to maintain near-normal glycaemic level throughout pregnancy. Measurement of amniotic fluid erythropoietin level is a new way to detect fetal hypoxia antenatally. Sufficiently large controlled studies are needed before definitive answer of the clinical utility of amniotic fluid erythropoietin measurements in diabetic pregnancies can be determined. PMID- 20832745 TI - Gestational diabetes guidelines in a HAPO world. AB - The impact of gestational diabetes on maternal and fetal health has been increasingly recognized. However, universal consensus on the diagnostic methods and thresholds has long been lacking. Published guidelines from major societies differ considerably from one another, ranging in recommendations from aggressive screening to no routine screening at all. As a result, real-world practice is equally varied. The recently published Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, and two randomized controlled trials evaluating treatment of mild maternal hyperglycemia, have served to confirm the findings of smaller, nonrandomized studies solidifying the link between maternal hyperglycemia and adverse perinatal outcomes. In response to these studies, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) has formulated new guidelines for screening and diagnosis of diabetes in pregnancy. Key components of the IADPSG guidelines include the recommendation to screen high-risk women at the first encounter for pre-gestational diabetes, to screen universally at 24-28 weeks' gestation, and to screen with use of the 75-g oral glucose tolerance test interpreting abnormal fasting, 1-h, and 2-h plasma glucose concentrations as individually sufficient for the diagnosis of gestational diabetes. Furthermore, to translate the continuous association between maternal glucose and adverse outcomes demonstrated in the HAPO cohort, they recommend thresholds for positive screening tests at which the odds of elevated birth weight, cord C-peptide, and fetal percent body fat are 1.75 relative to odds of those outcomes at mean glucose values. Opponents to the IADPSG recommendations will likely be those who favor risk-based screening in addition to those who endorse the 50-g glucose challenge test followed by the 100-g oral glucose tolerance test as a more cost effective, familiar, and possibly, well-validated screening tool. Others may argue that the diagnostic thresholds chosen by the IADPSG are arbitrary and will continue to miss many cases of abnormal glucose metabolism and therefore leave open the possibility of adverse perinatal outcomes due to untreated gestational diabetes. Finally, the potential economic impact of the IADPSG guidelines are unknown, and with minimal long-term data yet available on the offspring of the HAPO cohort, a true cost-effectiveness analysis will be difficult to perform accurately. Given these potential points of contention, the responses of professional and international groups to the IADPSG guidelines are difficult to gauge. Regardless, these guidelines serve to advance the discussion on appropriate screening and diagnosis of diabetes in pregnancy. PMID- 20832747 TI - SNPing Away at Cancer. PMID- 20832746 TI - Cancer metabolism: is glutamine sweeter than glucose? PMID- 20832748 TI - The Meaning of 21 in the MicroRNA world: perfection rather than destruction? PMID- 20832749 TI - Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. AB - Rho GTPases impact a number of activities important for oncogenesis. We describe a small molecule inhibitor that blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NF-kappaB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation. PMID- 20832750 TI - A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. AB - MDM2, a negative regulator of p53, is elevated in many cancers that retain wild type p53. A single nucleotide polymorphism (SNP) in the human MDM2 promoter increases the affinity of Sp1 resulting in elevated MDM2 levels. We generated mice carrying either the MDM2(SNP309T) or the MDM2(SNP309G) allele to address the impact of MDM2(SNP309G) on tumorigenesis. Mdm2(SNP309G/G) cells exhibit elevated Mdm2 levels, reduced p53 levels, and decreased apoptosis. Importantly, some Mdm2(SNP309G/G) mice succumbed to tumors before 1 year of age, suggesting that this allele increases tumor risk. Additionally, the Mdm2(SNP309G) allele potentiates the tumor phenotype and alters tumor spectrum in mice inheriting a p53 hot-spot mutation. These data provide causal evidence for increased cancer risk in carriers of the Mdm2(SNP309G) allele. PMID- 20832751 TI - An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction. AB - In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. To study the physiological significance of the RP-Mdm2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of Mdm2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-Mdm2 interaction significantly accelerates EMU-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-Mdm2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis. PMID- 20832752 TI - In silico analysis of kinase expression identifies WEE1 as a gatekeeper against mitotic catastrophe in glioblastoma. AB - Kinases execute pivotal cellular functions and are therefore widely investigated as potential targets in anticancer treatment. Here we analyze the kinase gene expression profiles of various tumor types and reveal the wee1 kinase to be overexpressed in glioblastomas. We demonstrate that WEE1 is a major regulator of the G(2) checkpoint in glioblastoma cells. Inhibition of WEE1 by siRNA or small molecular compound in cells exposed to DNA damaging agents results in abrogation of the G(2) arrest, premature termination of DNA repair, and cell death. Importantly, we show that the small-molecule inhibitor of WEE1 sensitizes glioblastoma to ionizing radiation in vivo. Our results suggest that inhibition of WEE1 kinase holds potential as a therapeutic approach in treatment of glioblastoma. PMID- 20832753 TI - Pharmacological inhibition of BMK1 suppresses tumor growth through promyelocytic leukemia protein. AB - BMK1 is activated by mitogens and oncogenic signals and, thus, is strongly implicated in tumorigenesis. We found that BMK1 interacted with promyelocytic leukemia protein (PML), and inhibited its tumor-suppressor function through phosphorylation. Furthermore, activated BMK1 notably inhibited PML-dependent activation of p21. To further investigate the BMK-mediated inhibition of the tumor suppressor activity of PML in tumor cells, we developed a small-molecule inhibitor of the kinase activity of BMK1, XMD8-92. Inhibition of BMK1 by XMD8-92 blocked tumor cell proliferation in vitro and significantly inhibited tumor growth in vivo by 95%, demonstrating the efficacy and tolerability of BMK1 targeted cancer treatment in animals. PMID- 20832754 TI - The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. AB - It was previously shown that the NF-kappaB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch induced NF-kappaB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. PMID- 20832755 TI - Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21. AB - Lung cancer is the leading cause of cancer-related deaths in the world, and non small-cell lung cancer (NSCLC) accounts for 80% of cases. MicroRNA-21 (miR-21) expression is increased and predicts poor survival in NSCLC. Although miR-21 function has been studied in vitro with cancer cell lines, the role of miR-21 in tumor development in vivo is unknown. We utilize transgenic mice with loss-of function and gain-of-function miR-21 alleles combined with a model of NSCLC to determine the role of miR-21 in lung cancer. We show that overexpression of miR 21 enhances tumorigenesis and that genetic deletion of miR-21 partially protects against tumor formation. MiR-21 drives tumorigenesis through inhibition of negative regulators of the Ras/MEK/ERK pathway and inhibition of apoptosis. PMID- 20832756 TI - Neurolaw or Frankenlaw? The thought police have arrived. PMID- 20832757 TI - Strange contagions: of laughter, jumps, jerks, and mirror neurons. PMID- 20832758 TI - The aversion of scientists to leading edge areas until they are "proven". PMID- 20832759 TI - Descartes' carton--On plausibility. PMID- 20832760 TI - Environmentally caused cancers are underestimated. PMID- 20832761 TI - Bee gone: The breakdown of ecosystems, and the social devastation that must inevitably follow. PMID- 20832762 TI - Nonlocality, intention, and observer effects in healing studies: laying a foundation for the future. AB - All research domains are based upon epistemological assumptions. Periodic reassessment of these assumptions is crucial because they influence how we interpret experimental outcomes. Perhaps nowhere is this reassessment needed more than in the study of prayer and intention experiments. For if positive results from this field of research are sustained, the reality of nonlocal consciousness must be confronted. This paper explores the current status of healing and intention research, citing a number of major studies and using the "Study of the Therapeutic Effects of Intercessory Prayer (STEP) in Cardiac Bypass Surgery Patients: A Multicenter Randomized Trial of Uncertainty and Certainty of Receiving Intercessory Prayer" as a case study of this line of research. The paper argues that the dose-dependent model typical of drug trials, and adopted for use in the STEP and other studies, is not the optimal model for intention healing research, and critiques this approach in detail, citing apposite research from which we draw our recommendations and conclusions. The paper suggests that the usual assumptions concerning blindness and randomization that prevail in studies using the pharmacological model must be reappraised. Experimental data suggest that a nonlocal relationship exists among the various individuals participating in a study, one which needs to be understood and taken seriously. We argue that it is important to account for and understand the role of both local and nonlocal observer effects, since both can significantly affect outcome. Research is presented from an array of disciplines to support why the authors feel these issues of linkage, belief, and intention are so important to a successful, accurate, and meaningful study outcome. Finally, the paper offers suggestions for new lines of research and new protocol designs that address these observer-effect issues, particularly the nonlocal aspects. The paper finally suggests that if these effects occur in intention studies, they must necessarily exist in all studies, although in pharmacological studies they are often overshadowed by the power of chemical and biological agents. PMID- 20832763 TI - The efficacy and cost effectiveness of integrative medicine: a review of the medical and corporate literature. AB - Data supporting the efficacy and cost effectiveness of an integrative approach to healthcare comes from three sources: medical research conducted at universities, studies carried out by corporations developing employee wellness programs, and pilot projects run by insurance companies. The integrative approaches being studied place the patient at the center of the care and address the full range of physical, emotional, mental, social, spiritual, and environmental influences that affect a person's health. Most importantly, they promote prevention by engaging the whole person in the attainment of a personalized lifestyle that supports health. A review of the medical, corporate, and payer literature reveals that, to start, immediate and significant health benefits and cost savings could be realized throughout our healthcare system by utilizing three integrative strategies: (1) integrative lifestyle change programs for those with chronic disease, (2) integrative interventions for people experiencing depression, and (3) integrative preventive strategies to support wellness in all populations. PMID- 20832764 TI - Johrei, a Japanese healing technique, enhances the growth of sucrose crystals. AB - The effect of Johrei treatment on the crystallization of sucrose from supersaturated solutions was studied in comparison with the crystallization in untreated solutions. This work was performed assuming that Johrei enhances the natural mechanisms of equilibrium restoration in biological and nonbiological systems. The crystallization in Johrei-treated solutions as judged by statistical analysis was found to be faster than the crystallization in untreated solutions. A discussion is presented about the mechanisms possibly involved. PMID- 20832765 TI - Evidence-based management of herb-drug interaction in cancer chemotherapy. AB - The fact that many cancer patients take herbal medicine, including Chinese herbal medicine, together with chemotherapy is well known. The potential for side effects resulting from concurrent use of these two different treatment modalities requires physicians to be aware of the potential risks and benefits that might arise. This study searched available evidence for herb-drug interaction in cancer therapy and identified 168 articles. Little direct evidence for such interaction could be found, whereas there is some indirect evidence for benefit. Hence, most of the concern about herb-drug interaction in chemotherapy appears to be theoretical. To resolve this discrepancy, evidence-based studies should be undertaken to document the positive and/or negative effects of the concomitant use of herbs with anticancer chemotherapeutic drugs. As evidence accumulates, it would be helpful to set up an internationally accessible database to document the use of Chinese medicine herbs with anticancer drugs. Once this information is collected, efforts should be made to educate health care professionals and patients about the use of Chinese herbal medicine together with Western drugs in treating cancer. PMID- 20832766 TI - An exploratory study of the effect of acupuncture on self-efficacy for women seeking fertility support. AB - OBJECTIVE: The aim of this study was to examine the effect of acupuncture on self efficacy for women receiving acupuncture for fertility support. DESIGN: Pretest and posttest measurement of infertility self-efficacy was conducted in this prospective observational study. SETTING: Subjects were recruited from three acupuncture practices in South Eastern Australia. PARTICIPANTS: Women aged 18 to 45 years presenting for acupuncture treatment for natural conception or as an adjunct to assisted reproductive technology participated in this study. Consecutive new patients were invited to take part if they were planning a minimum of four acupuncture treatments as part of a current episode of care. OUTCOME MEASURES: Measurement at baseline and post-acupuncture treatment was performed with the infertility self-efficacy (ISE) scale. RESULTS: Seventeen women met the entry criteria for the study, 15 (88%) entered the study, 13 (76%) completed both questionnaires. We found a significant increase in total ISE scores from baseline and after four acupuncture treatments (N = 13; t [12] = 3.15, P = .008). Four women showed clinically significant improvement on ISE total scores using the significant change index. CONCLUSIONS: We have preliminary data suggesting that acupuncture improves self-efficacy and psychological coping for women experiencing delays with falling pregnant. Further rigorous research is needed to examine the overall therapeutic effect from acupuncture to support women while undergoing the stressful repetitive process of assisted reproductive technology or natural fertility, and to examine the role of outcome and self efficacy expectations. PMID- 20832767 TI - Integrative healthcare education: alive, well, and diligently preparing students for 21st century medicine. PMID- 20832768 TI - [Clinical characteristics of tinnitus in Meniere's disease]. AB - INTRODUCTION: Meniere's disease is characterised by vertigo, hearing loss and tinnitus. Various studies assess the problem of vertigo and audition deficit in Meniere's disease, but only a few of these relate to the clinical characteristics of tinnitus, the aim of this study. MATERIAL AND METHODS: A transversal descriptive study of the behaviour of tinnitus in 88 patients in different stages of Meniere's disease treated in a tertiary hospital was carried out. The different characteristics of disease were analysed: intensity was evaluated with an analogue-visual scale, subjective tonality through tonal shade references, the impact on the patient's quality of life was tested by a self-appraisal questionnaire, and competence level was evaluated with the Tinnitus Handicap Inventory. Epidemiologic factors, personal records, hearing thresholds and evolution in the number of vertiginous crises in the previous six months were also taken into account. RESULTS: The average time of evolution of the disease was 15.4 years. The results evidence the development of tinnitus of moderate intensity (5/10) and low frequency (46%), with a slight impact on quality of life. Worsening in the quality of life related to hearing affectation and/or advanced stages of the disease was also observed. We identified high frequency tonality, a medical record of depression and youth as unfavourable prognostic factors. There was no relationship found with the years of evolution of the disease or with the number of vertigo crises. CONCLUSION: In large samples of long evolution Meniere's disease, patients do not perceive tinnitus as a problem that produces serious impairment in their quality of life. PMID- 20832769 TI - The role of testing realism on experimentally obtained stereotype strength. AB - It has been shown (Hoffmann 2009) that pencil-and-paper tests, when used to determine stereotype strength, may yield data quite different to that obtained from hardware tests. The purpose of this research was to determine the level of realism required in order to have stereotypes that are consistent with real-world values. It is surprising that there does not appear to be any published research addressing this problem; all previous researches have considered either paper/pencil or hardware tests or sometimes both, but no level of simulation in between these techniques. In order to determine the effect of level of testing realism, a specific example was chosen to test, that of water tap operation stereotypes. Tests used verbal questioning, photographs of tap arrangements, a partial hardware arrangement and finally a full hardware setup. The results of these four levels of realism were very different and illustrated that, only with a full realistic simulation, did participants respond as might be expected in a real-world environment, illustrating the importance of testing realism when determining population stereotypes. This result has strong implications for product designers when selecting appropriate layouts of displays and controls and the linkages relating these. PMID- 20832770 TI - Effect of cognitive load on speech prosody in aviation: Evidence from military simulator flights. AB - Mental overload directly affects safety in aviation and needs to be alleviated. Speech recordings are obtained non-invasively and as such are feasible for monitoring cognitive load. We recorded speech of 13 military pilots while they were performing a simulator task. Three types of cognitive load (load on situation awareness, information processing and decision making) were rated by a flight instructor separately for each flight phase and participant. As a function of increased cognitive load, the mean utterance-level fundamental frequency (F0) increased, on average, by 7 Hz and the mean vocal intensity increased by 1 dB. In the most intensive simulator flight phases, mean F0 increased by 12 Hz and mean intensity, by 1.5 dB. At the same time, the mean F0 range decreased by 5 Hz, on average. Our results showed that prosodic features of speech can be used to monitor speaker state and support pilot training in a simulator environment. PMID- 20832771 TI - Differential induction of collagens by mechanical stress in human periodontal ligament cells. AB - OBJECTIVE: Excessive mechanical stress (MS) during hyperocclusion is known to result in destruction of periodontal tissues and alveolar bone, leading to occlusal trauma. Collagens are extracellular matrix components that are encoded by more than 30 different genes. They are classified into three types: fibril forming, fibril-associated with interrupted triple helices (FACIT), and non fibril forming collagens. Although MS is known to affect COL I, little is known about its effects on other types of collagens in the periodontal ligament (PDL). We hypothesised that MS could induce expression of the three different types of collagens, thus protecting against occlusal trauma. DESIGN: The aim of this study was to investigate intermittent uniaxial stretching-induced collagen expression in PDL cells using DNA microarray, polymerase chain reaction, and western blotting analysis. We compared changes in collagen expression caused by MS stimulation and osteogenic stimulation, and examined relationships between expression of collagen and their digestive enzymes, matrix metalloproteases (MMPs). RESULTS: Expression of both fibril-forming and FACIT collagens was transiently decreased in the initial phase after MS, while the expression of non fibril-forming collagens was gradually increased. MS for 3-7 days resulted in gradual upregulation of all three types of collagen. Furthermore, the expression of fibril- and non-fibril-forming collagens was reciprocally related to expression of MMPs. In contrast, expression of all three types of collagen was slightly upregulated during osteogenesis. CONCLUSION: The MS-induced expression patterns of fibril-forming and FACIT collagens suggest changes in the composition of the extracellular matrix to increase the resistance of PDL cells to hyperocclusal force. PMID- 20832772 TI - Chloride channels regulate chondrogenesis in chicken mandibular mesenchymal cells. AB - Voltage gated chloride channels (ClCs) play an important role in the regulation of intracellular pH and cell volume homeostasis. Mutations of these genes result in genetic diseases with abnormal bone deformation and body size, indicating that ClCs may have a role in chondrogenesis. In the present study, we isolated chicken mandibular mesenchymal cells (CMMC) from Hamburg-Hamilton (HH) stage 26 chick embryos and induced chondrocyte maturation by using ascorbic acid and beta glycerophosphate (AA-BGP). We also determined the effect of the chloride channel inhibitor NPPB [5-nitro-2-(3-phenylpropylamino) benzoic acid] on regulation of growth, differentiation, and gene expression in these cells using MTT and real time PCR assays. We found that CLCN1 and CLCN3-7 mRNA were expressed in CMMC and NPPB reduced expression of CLCN3, CLCN5, and CLCN7 mRNA in these cells. At the same time, NPPB inhibited the growth of the CMMC, but had no effect on the mRNA level of cyclin D1 and cyclin E (P>0.05) with/without AA-BGP treatment. AA-BGP increased markers for early chondrocyte differentiation including type II collagen, aggrecan (P<0.01) and Sox9 (P<0.05), whilst had no effect on the late chondrocyte differentiation marker type X collagen. NPPB antagonized AA-BGP induced expression of type II collagen and aggrecan (P<0.05). Furthermore, NPPB downregulated type X collagen (P<0.05) with/without AA-BGP treatment. We conclude that abundant chloride channel genes in CMMC play important roles in regulating chondrocyte proliferation and differentiation. Type X collagen might function as a target of chloride channel inhibitors during the differentiation process. PMID- 20832773 TI - Enamel development in primary molars from children with familial dysautonomia. AB - OBJECTIVES: Familial dysautonomia (FD) is an autosomal recessive disorder, classified as a hereditary sensory and autonomic neuropathy type III, associated with growth defects affecting postnatal development. This study analysed prenatal and postnatal enamel development and postnatal calcification in upper second primary molars from FD children in comparison with healthy controls. The postnatal enamel of FD was also examined histologically for manifestation of growth insults. DESIGN: The analyses were carried out on two ground sections, connecting buccal and palatinal cusp tips of mesial and distal cusps. The measurements included apical location of neonatal line, width and percentage of prenatal enamel. Chemical analyses were performed using an energy dispersive X ray spectrometer. RESULTS: The prenatal proliferative phase and prenatal apposition rate of enamel were faster on the distal cusps in FD. The postnatal enamel thickness was similar in both groups. The phosphate content of FD teeth was significantly higher and the Ca/P ratio was significantly lower. Postnatal traumatic lines were observed in all FD children and in only one healthy child. CONCLUSIONS: FD upper primary second molars showed thicker prenatal enamel formation in comparison to healthy and other syndromes and better mineralisation. All FD primary molars showed large number of postnatal traumatic lines, implicating severe traumatic episodes during the first year of life. PMID- 20832774 TI - Characterization of uniformly and atom-specifically (13)C-labeled heparin and heparan sulfate polysaccharide precursors using (13)C NMR spectroscopy and ESI mass spectrometry. AB - The biological actions of heparin and heparan sulfate, two structurally related glycosaminoglycans, depend on the organization of the complex heparanome. Due to the structural complexity of the heparanome, the sequence of variably sulfonated uronic acid and glucosamine residues is usually characterized by the analysis of smaller oligosaccharide and disaccharide fragments. Even characterization of smaller heparin and heparan sulfate oligosaccharide or disaccharide fragments using simple 1D (1)H NMR spectroscopy is often complicated by the extensive signal overlap. (13)C NMR signals, on the other hand, overlap less and therefore, (13)C NMR spectroscopy can greatly facilitate the structural elucidation of the complex heparanome and provide finer insights into the structural basis for biological functions. This is the first report of the preparation of anomeric carbon-specific (13)C-labeled heparin and heparan sulfate precursors from the Escherichia coli K5 strain. Uniformly (13)C- and (15)N-labeled precursors were also produced and characterized by (13)C NMR spectroscopy. Mass spectrometric analysis of enzymatically fragmented disaccharides revealed that anomeric carbon specific labeling efforts resulted in a minor loss/scrambling of (13)C in the precursor backbone, whereas uniform labeling efforts resulted in greater than 95% (13)C isotope enrichment in the precursor backbone. These labeled precursors provided high-resolution NMR signals with great sensitivity and set the stage for studying the heparanome-proteome interactions. PMID- 20832775 TI - Production of furans from rice straw by single-phase and biphasic systems. AB - 5-Hydroxymethylfurfural (HMF) and furfural, both of which can be derived from renewable sources, are key components for the production of different chemicals and fuels. In this study, rice straw, a cheap, abundant, and mainly unused agricultural waste, is converted to furans by a dilute acid hydrolysis process. The highest yield of HMF in a single-phase hydrolysis was 15.3 g/kg straw, attained at 180 degrees C during 3 h with 0.5% sulfuric acid, while the maximum yield of furfural, 59 g/kg straw, was obtained at 150 degrees C during 5 h. Different extracting solvents, including 2-PrOH, 1-BuOH, methyl isobutyl ketone (MIBK), and acetone at 180 degrees C for 3 h as well as tetrahydrofuran (THF) at 150 degrees C for 5 h were examined in biphasic systems. Use of the solvents generally improved the production of HMF compared to the single aqueous phase process. The best results of HMF production, more than 59 g/kg straw, were obtained in the systems containing either 2-PrOH or 1-BuOH. Using THF as an extracting solvent, a relatively high furfural yield, 118.2 g/kg straw, was obtained, and 96% of furfural produced in this system was extracted into THF during the process. PMID- 20832776 TI - Moraxella catarrhalis Lgt2, a galactosyltransferase with broad acceptor substrate specificity. AB - The genetic basis of lipo-oligosaccharide (LOS) biosynthesis for the bacterium Moraxella catarrhalis has been elucidated and functions suggested for each of the glycosyltransferases. In this study we have expressed and characterised one of these enzymes, the putative galactosyltransferase Lgt2(B/C). The lgt2(B/C) gene was amplified from M. catarrhalis, expressed in Escherichia coli, and Lgt2(B/C) was purified. Analysis of its glycosyltransferase catalytic activity ascertained the pH and temperature optima. The donor specificity and acceptor specificity were examined and they showed that Lgt2(B/C) is a galactosyltransferase with relatively broad acceptor specificity with optimal activity in the presence of exogenous Mg(2+). PMID- 20832777 TI - Probing anion-cellulose interactions in imidazolium-based room temperature ionic liquids: a density functional study. AB - The interactions of the cellulose molecule with several anions, including acetate , alkyl phosphate, tetrafluoroborate and hexafluorophosphate anions which are most commonly involved in the imidazolium ionic liquids (ILs), have been studied by performing density functional theory calculations. Based on calculated geometries, energies, IR characteristics, and electronic properties of the cellulose-anion complexes, it is found that the strength of interactions of anions with cellulose follows the order: acetate anion>alkyl phosphate anion>tetrafluoroborate anion>hexafluorophosphate anion, which is consistent with the experimentally observed solubility trend of cellulose in the corresponding imidazolium-based ILs. The present study may provide basic aids to some extent for understanding the dissolution behavior of cellulose in the imidazolium-based ILs. PMID- 20832778 TI - Facile synthesis of glycosylated Fmoc amino acid building blocks assisted by microwave irradiation. AB - The synthesis of glycosylated Fmoc amino acids by reaction of mono- and disaccharide peracetates with Fmoc amino acids having free carboxyl groups was rapidly promoted by Lewis acids (SnCl(4), BF(3).Et(2)O) under microwave irradiation. The products are useful building blocks for the synthesis of glycopeptides. PMID- 20832779 TI - Importance of lipid rafts for lysophosphatidylcholine-induced caspase-1 activation and reactive oxygen species generation. AB - Lipid rafts play an important role in regulating cellular processes and functions. Here, we demonstrate that in microglia stimulated with the pro inflammatory lipid lysophosphatidylcholine (LPC), caspase-1 activation and NADPH oxidase activity depend on intact lipid rafts. Disruption of lipid rafts with methyl-beta-cyclodextrin, fumonisin B1 or nystatin prevented LPC-stimulated caspase-1 activation and reactive oxygen species (ROS) production, whereas LPC induced Na(+) influx remained unaffected. Since ROS regulate caspase-1 activity in LPC-stimulated microglia, the effects of lipid raft-disrupting agents on caspase-1 activation can be related to their inhibition of NADPH oxidase-mediated ROS production. PMID- 20832780 TI - In vitro and in vivo interactions of aluminum on NTPDase and AChE activities in lymphocytes of rats. AB - Al adjuvants are used in vaccines to increase the immune response. NTPDase and AChE play a pivotal role and act in the regulation of the immune system. The effect of Al exposure in vitro and in vivo on NTPDase and AChE activities in the lymphocytes of rats was determined. In vitro, ATP hydrolysis was decreased by 20.4% and 17.3% and ADP hydrolysis was decreased by 36.5% and 34.8%, in groups D and E, respectively, when compared to the control. AChE activity was increased by 157.3%, 152.5%, 74.7% and 90.8% in groups B, C, D, and E, respectively, when compared to the control. In vivo, ATP hydrolysis was increased by 85% and 86% and ADP hydrolysis was increased by 104.2% and 74%, in Al plus citrate and Al groups, respectively, when compared to the control. AChE activity was increased by 50.7% in Al plus citrate and by 28.6% in Al groups, when compared to the control. Our results show that Al exposure both in vitro and in vivo altered NTPDase and AChE activities in lymphocytes. These results may demonstrate the ability of Al to elicit the immune system, where NTPDase and AChE activities can act as purinergic and cholinergic markers in lymphocytes. PMID- 20832781 TI - Sources of variability in children's language growth. AB - The present longitudinal study examines the role of caregiver speech in language development, especially syntactic development, using 47 parent-child pairs of diverse SES background from 14 to 46 months. We assess the diversity (variety) of words and syntactic structures produced by caregivers and children. We use lagged correlations to examine language growth and its relation to caregiver speech. Results show substantial individual differences among children, and indicate that diversity of earlier caregiver speech significantly predicts corresponding diversity in later child speech. For vocabulary, earlier child speech also predicts later caregiver speech, suggesting mutual influence. However, for syntax, earlier child speech does not significantly predict later caregiver speech, suggesting a causal flow from caregiver to child. Finally, demographic factors, notably SES, are related to language growth, and are, at least partially, mediated by differences in caregiver speech, showing the pervasive influence of caregiver speech on language growth. PMID- 20832782 TI - Detection of seizures in EEG using subband nonlinear parameters and genetic algorithm. AB - Detection of seizures in EEG can be challenging because of myogenic artifacts and might be time-consuming. In this study, we propose a method using subband nonlinear parameters and genetic algorithm for automatic seizure detection in EEG. In the experiment, the discrete wavelet transform was used to decompose EEG into five subband components. Nonlinear parameters were extracted and employed as the features to train the support vector machine with linear kernel function (SVML) and radial basis function kernel function (SVMRBF) classifiers. A genetic algorithm (GA) was used for selecting the effective feature subset. The seizure detection sensitivities of the SVML and the SVMRBF with GA are 90.8% and 94.0%, respectively. The sensitivity of SVMRBF increases to 95.8% by using GA for weight adjustment. Moreover, the proposed method is capable of discriminating the interictal EEG of epileptic subjects from the normal EEG, which is considered difficult, yet crucial, in clinical services. PMID- 20832783 TI - Fully automatic brain extraction algorithm for axial T2-weighted magnetic resonance images. AB - In this paper we propose two brain extraction algorithms (BEA) for T2-weighted magnetic resonance imaging (MRI) scans. The T2-weighted image is first filtered with a low pass filter (LPF) to remove or subdue the background noise. Then the image is diffused to enhance the brain boundaries. Using Ridler's method a threshold value for intensity is obtained. Using the threshold value a rough binary brain image is obtained. By performing morphological operations and using the largest connected component (LCC) analysis, a brain mask is obtained from which the brain is extracted. This method uses only 2D information of slices and is named as 2D-BEA. The concept of LCC failed in few slices. To overcome this problem, 3D information available in adjacent slices is used which resulted in 3D BEA. Experimental results on 20 MRI data sets show that the proposed 3D-BEA gave excellent results. The performance of this 3D-BEA is better than 2D-BEA and other popular methods, brain extraction tool (BET) and brain surface extractor (BSE). PMID- 20832784 TI - The anatomy of the callosal and visual-association pathways in high-functioning autism: a DTI tractography study. AB - There is increasing recognition that many of the core behavioral impairments that characterize autism potentially emerge from poor neural synchronization across nodes comprising dispersed cortical networks. A likely candidate for the source of this atypical functional connectivity in autism is an alteration in the structural integrity of intra- and inter-hemispheric white matter (WM) tracts that form large-scale cortical networks. To test this hypothesis, in a group of adults with high-functioning autism (HFA) and matched control participants, we used diffusion tensor tractography to compare the structural integrity of three intra-hemispheric visual-association WM tracts, the inferior longitudinal fasciculus (ILF), the inferior fronto-occipito fasciculus (IFOF) and the uncinate fasciculus (UF), with the integrity of three sub-portions of the major inter hemispheric fiber tract, the corpus callosum. Compared with the control group, the HFA group evinced an increase in the volume of the intra-hemispheric fibers, particularly in the left hemisphere, and a reduction in the volume of the forceps minor (F-Mi) and body of the corpus callosum. The reduction in the volume of the F-Mi also correlated with an increase in repetitive and stereotypical behavior as measured by the Autism Diagnostic Interview. These findings suggest that the abnormalities in the integrity of key inter- and intra-hemispheric WM tracts may underlie the atypical information processing observed in these individuals. PMID- 20832785 TI - Developmental attentional dyslexia. AB - Attentional dyslexia is a reading deficit in which letters migrate between neighboring words, but are correctly identified and keep their correct relative position within the word. Thus, for example, fig tree can be read as fig free or even tie free. This study reports on 10 Hebrew-speaking individuals with developmental attentional dyslexia and explores in detail the characteristics of their between-word errors. Each participant read 2290 words, presented in word pairs: 845 horizontally presented word pairs, 240 vertically presented word pairs, and 60 nonword pairs. The main results are that almost all migrations preserve the relative position of the migrating letter within the word, indicating that the between-word position can be impaired while the within-word position encoding remains intact. This result is also supported by the finding that the participants did not make many letter position errors within words. Further analyses indicated that more errors occur in longer words, that most migrations occur in final letters (which are the leftmost letters in Hebrew), and that letters migrate both horizontally and vertically, and more frequently from the first to the second word in horizontal presentation. More migrations occurred when the result of migration was an existing word. Similarity between words in a pair did not increase error rates, and more migrations occurred when the words shared fewer letters. The between-word errors included the classic errors of migration of a letter between words, but also omission of one instance of a letter that appeared in the same position in the two words, an error that constituted a considerable percentage of the between-word errors, and intrusion of a letter from one word to the corresponding position in the neighboring word without erasing the original letter in the same position. PMID- 20832786 TI - A response to Delistraty et al. (2010) "Radiological risk from consuming fish and wildlife to Native Americans on the Hanford Site (USA)". PMID- 20832787 TI - Individual exposure to air pollution and lung function in Korea: spatial analysis using multiple exposure approaches. AB - Interpolation methods can estimate individual-level exposures to air pollution from ambient monitors; however, few studies have evaluated how different approaches may affect health risk estimates. We applied multiple methods of estimating exposure for several air pollutants. We investigated how different methods of estimating exposure may influence health effect estimates in a case study of lung function data, forced expiratory volume in 1s (FEV1), and forced vital capacity (FVC), for 2102 cohort subjects in Ulsan, Korea, for 2003-2007. Measurements from 13 monitors for particulate matter <10 MUm (PM(10)), ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide were used to estimate individual-level exposures by averaging across values from all monitors, selecting the value from the nearest monitor, inverse distance weighting, and kriging. We assessed associations between pollutants and lung function in linear regression models, controlling for age, sex, and body mass index. Cross validation indicated that kriging provided the most accurate estimated exposures. FVC was associated with all air pollutants under all methods of estimating exposure. Only ozone was associated with FEV1. An 11 ppb increase in lag-0-2 8-h maximum ozone was associated with a 6.1% (95% confidence interval 5.0, 7.3%) decrease in FVC and a 0.50% (95% confidence interval 0.03, 0.96%) decrease in FEV1, based on kriged exposures. Central health effect estimates were generally higher using exposures based on averaging across all monitors or kriging. Results based on the nearest monitor approach had the lowest variance. Findings suggest that spatial interpolation methods may provide better estimates than monitoring values alone by reflecting the spatial variability of individual-level exposures and generating estimates for locations without monitors. PMID- 20832788 TI - [Mini nutritional assessment (MNA) as nutrition screening tool in internal medicine. Advantages and disadvantages]. AB - OBJECTIVE: To evaluate the nutritional status of the elderly hospitalized patient with the Mini Nutritional Assessment (MNA), its relationship with length of hospital stay and mortality, the incidence of malnutrition during hospitalization and to evaluate the applicability of MNA in an Internal Medicine Department of an acute care hospital. MATERIAL AND METHODS: A prospective study on the nutritional status of patients of 65 years or older admitted to hospital in an Internal Medicine Department was performed in 106 consecutive patients. In all patients a MNA test, an anthropometric (weight, height, body mass index, skinfold), and biochemical (cholesterol, lymphocytes, albumin) evaluation were performed; outcome, age, institutionalization, Charlson index and Barthel index were recorded. RESULTS: Mean age of the patients was 81+/-7 years, Charlson index 2.3+/-1.9 and Barthel index 74.9+/-30.8. Mean weight was 64.5+/-10.6kg, BMI 26+/ 3.9, and weight loss in the previous 3 months 1.17+/-2.92kg. Mean length of hospital stay was 11.1+/-9.8, and mortality was 5.7%. Prevalence of malnutrition, assessed by MNA, was 4.7%, and 36.8% of the patients were at risk of malnutrition. Malnourished patients have a longer length of hospital stay, higher Barthel and Charlson indexes. There are no conclusive differences in mortality. Incidence of malnutrition during hospitalization was between 2.43 and 15.68%. CONCLUSIONS: Malnutrition increases length of hospital stay, rate of complications and costs. The clinicians responsible for the patient should perform nutrition evaluation at hospital admission and repeat it during the hospitalization, using simple screening tools that incorporate an explicit nutrition intervention plan. PMID- 20832789 TI - [Longevity and genotype apoE 2/3 in a family from Tierra de Campos]. PMID- 20832790 TI - [Ischemic stroke secondary to pulmonary arteriovenous fistula. Utility of the transcranial Doppler]. PMID- 20832791 TI - [Musculoskeletal ultrasound utility in the diagnosis of gout]. PMID- 20832792 TI - [Guillain-Barre syndrome secondary to H1N1 influenza vaccine]. PMID- 20832793 TI - [Conservative management of an old condition: Acute phlegmonous gastritis]. PMID- 20832794 TI - [Clarifications on the syndrome of inappropriate secretion of antidiuretic hormone produced by prostate cancer]. PMID- 20832795 TI - Predictive factors for cutting-out in femoral intramedullary nailing. AB - BACKGROUND: Femoral intramedullary nailing is currently one of the most frequent surgical treatments for extracapsular hip-fracture fixation. Cutting-out of the lag screw is the main complication of this technique, but only few studies have approached the cutting-out focussed on femoral nailing. The aim of this study was to confirm in patients treated with intramedullary nailing not only with regard to previous reports about the association of cutting-out with technical factors, but also with regard to clinical factors not previously studied. METHODS: Case control study of all patients sustaining a cut-out of the femoral nail was carried out and a control sample was randomly selected among all extracapsular hip-fracture patients during the study period (2005-2008). All clinical and technical variables were collected from medical records. Orthopaedic Trauma Association (AO/OTA) fracture classification, Singh Osteoporosis Index of the contralateral hip and the American Society of Anaesthesiology (ASA) criteria for preoperative clinical status were used. Statistical assessment included bivariant analysis and multivariant logistic regression analysis. RESULTS: A total of 916 hip-fracture cases were treated in the study period: 33 of them (3.6%) were identified as suffering cutting-out, and 315 controls fulfilling inclusion criteria were also recruited. No statistical differences were found in age, sex or other socio-demographic variables between the two groups. Bivariant analysis showed significant differences between groups in technical variables (tip-apex distance, suboptimal placement of lag screw, fracture diastasis, inadequate fixation quality and distal static locking) and in clinical variables (osteoporosis severity, right hip affected, better previous ability for walking and better preoperative ASA status). Multivariant logistic regression analysis showed significant association only for tip-apex distance and inadequate fixation quality. Differences in distal static locking were close to statistical significance. CONCLUSIONS: The strongest predictor of cutting-out in femoral nailing is tip-apex distance. This study suggests that distal static locking and other clinical conditions play an important role in this fixation failure. PMID- 20832796 TI - Economic evaluation of nurse staffing and nurse substitution in health care: a scoping review. AB - OBJECTIVE: Several systematic reviews have suggested that greater nurse staffing as well as a greater proportion of registered nurses in the health workforce is associated with better patient outcomes. Others have found that nurses can substitute for doctors safely and effectively in a variety of settings. However, these reviews do not generally consider the effect of nurse staff on both patient outcomes and costs of care, and therefore say little about the cost-effectiveness of nurse-provided care. Therefore, we conducted a scoping literature review of economic evaluation studies which consider the link between nurse staffing, skill mix within the nursing team and between nurses and other medical staff to determine the nature of the available economic evidence. DESIGN: Scoping literature review. DATA SOURCES: English-language manuscripts, published between 1989 and 2009, focussing on the relationship between costs and effects of care and the level of registered nurse staffing or nurse-physician substitution/nursing skill mix in the clinical team, using cost-effectiveness, cost-utility, or cost-benefit analysis. Articles selected for the review were identified through Medline, CINAHL, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Google Scholar database searches. REVIEW METHODS: After selecting 17 articles representing 16 unique studies for review, we summarized their main findings, and assessed their methodological quality using criteria derived from recommendations from the guidelines proposed by the Panel on Cost-Effectiveness in Health Care. RESULTS: In general, it was found that nurses can provide cost effective care, compared to other health professionals. On the other hand, more intensive nurse staffing was associated with both better outcomes and more expensive care, and therefore cost effectiveness was not easy to assess. CONCLUSIONS: Although considerable progress in economic evaluation studies has been reached in recent years, a number of methodological issues remain. In the future, nurse researchers should be more actively engaged in the design and implementation of economic evaluation studies of the services they provide. PMID- 20832797 TI - Hydrogenated phosphatidylcholine supplementation reduces hepatic lipid levels in mice fed a high-fat diet. AB - The ability of the fatty acid composition of dietary phosphatidylcholine (PC) to affect hepatic lipid levels was investigated in C57BL/6 mice (n=8-10 per group) by feeding: (1) a high-fat semi-purified diet (HF), (2) HF diet supplemented with 1.25 wt% soy PC (SPC), (3) HF with 1.25 wt% hydrogenated soy PC (SPCH), (4) HF with 1.25 wt% egg PC (EPC), and (5) HF with 1.25 wt% hydrogenated egg PC (EPCH). The polyunsaturated fatty acid content (C18:2+C18:3+C20:4) of soy, egg and hydrogenated PC was 70%, 20% and 0%, respectively. Total liver lipid was significantly lower in SPCH and EPCH vs. HF (8.7 +/- 0.1 and 8.5 +/- 0.5 vs. 11.8 +/- 0.6g/100, P<0.05), but not in SPC or EPC. SPCH and EPCH had significantly lower levels of hepatic cholesterol (-52% and -53% vs. HF, respectively). Bioactive lipids (i.e., sphingomyelin and ceramide) were also lower in the liver of SPCH and EPCH rather than in SPC or EPC. Hepatic expression of genes controlling fatty acid synthesis and catabolism were not significantly affected by dietary PC. However, hepatic expression of HMGCR, LDLR and SREBP2 was higher and that of ABCA1, ABCG5 and ABCG8 was reduced in SPCH and EPCH vs. HF. These results demonstrate that hydrogenated PC supplementation reduces hepatic lipid levels in mice fed a high-fat diet supporting the concept that the ability of dietary PC to lower hepatic lipid levels is not due to its content of polyunsaturated fatty acids. PMID- 20832798 TI - The evaporation of positive genetic association findings. When time has come to go. PMID- 20832799 TI - High-fat diet without excess calories induces metabolic disorders and enhances atherosclerosis in rabbits. AB - OBJECTIVE: Excess intake of a high-fat diet (HFD) is associated with obesity and metabolic syndrome, which are major risk factors for cardiovascular disease. However, it is unclear whether consumption of an HFD at a normal calorific range would be detrimental to metabolism or affect the development of atherosclerosis. Here, we tested the hypothesis that consumption of a normal-calorie HFD would impair lipid metabolism, insulin sensitivity, and blood pressure. METHODS AND RESULTS: Rabbits fed with an HFD containing either 3% (15% kcal from fat) or 10% (25.8% kcal from fat) coconut oil were compared with control rabbits fed with a standard chow diet (9.3% kcal from fat). All rabbits consumed an equal amount of calories of their respective food. However, HFD feeding induced marked metabolic disorders including increased plasma levels of free fatty acids, insulin resistance, and hypertension compared with control rabbits. Metabolic disorders were more pronounced in 10%-HFD-fed rabbits than 3%-HFD-fed rabbits. To examine whether these disorders affected the development of atherosclerosis, two HFD groups were further fed with a diet containing 0.3% cholesterol for another 18 weeks. We found that 10%-HFD group showed a prominent accumulation of adipose tissue and developed 2-fold greater aortic atherosclerosis than 3%-HFD group. CONCLUSIONS: These results suggest that consuming an HFD containing even a normal number of calories can cause insulin resistance, hypertension, and adipose accumulation even without obesity. High amounts of fat in diets apparently accelerate the development of atherosclerosis. PMID- 20832801 TI - Genetic variants in adipose triglyceride lipase influence lipid levels in familial combined hyperlipidemia. AB - OBJECTIVE: Familial combined hyperlipidemia (FCHL) has been associated with abnormalities in fatty acid metabolism. The adipose triglyceride lipase (PNPLA2) plays a pivotal role in the turnover of fatty acids in adipose tissue and liver. This study was designed to evaluate whether selected PNPLA2 variants may influence the susceptibility to FCHL or its lipid-related traits. METHODS: Four SNPs within the PNPLA2 gene (rs7925131, rs7942159, rs66460720 and the nonsynonymous P481L) were selected based on previous association with decreased plasma levels of free fatty acids (FFA) and total triglycerides (TG) and their high frequency (MAF>0.25). These SNPs were genotyped in 214 FCHL individuals from 83 families and in 103 controls and the corresponding haplotypes were reconstructed. RESULTS: No association between individual SNPs and the FCHL trait was observed. However, two PNPLA2 haplotypes were associated with lower risk of FCHL (P<0.004 after Bonferroni's correction). Compared to the others, these haplotypes were related to lower TG (118.9 +/- 66.8 vs. 197.1 +/- 114.7 mg/dl; P=0.001) and higher HDL-C (62.3 +/- 15.8 vs. 51.0 +/- 15.0 mg/dl; P<0.005). In a subgroup of studied subjects (n=63) protective haplotypes were also associated with lower FFA levels (0.33 +/- 0.11 vs. 0.46 +/- 0.18 mEq/L; P<0.05). These effects were independent from age, BMI and HOMA(IR). CONCLUSION: These data demonstrate that variants within PNPLA2 may modulate the TG component of FCHL trait, thus implicating PNPLA2 as modifier gene in this lipid disorder. They also suggest a potential role of PNPLA2 in the metabolism of TG-rich lipoproteins. PMID- 20832800 TI - Angiopoietins, abdominal aortic aneurysm and atherosclerosis. AB - Abdominal aortic aneurysm (AAA) and atherosclerosis are common causes of mortality and morbidity in an aging population. Angiogenesis is believed to contribute to the development and progression of these diseases. Angiopoietins (angpts) are known to be important regulators of angiogenesis. Angpts can also influence inflammation and have been shown to possess both pro-atherosclerotic and atheroprotective effects. This review explores the potential roles that the angpts play in the development and progression of AAA and atherosclerosis. PMID- 20832802 TI - Rendering edge enhancement tactile phenomenon by friction variation in dynamic touch. AB - Variable friction tactile displays have been recently used to render virtual textures and gratings. Neural basis of perceptual mechanism of detection of edge like features resulting in discrimination of virtual gratings during active touching these tactile actuators is studied using a finite-element biomechanical model of human fingertip. The predicted neural response of the mechanoreceptors, i.e. the computed strain energy density at the location of selected mechanoreceptors as a measure of neural discharge rate of the corresponding receptors, to local reduction of friction between fingerpad and surface are shown to exhibit a similar shape as the edge enhancement phenomenon, particularly in a sudden burst at the boundary of variable friction regions. This phenomenon is supposed to account for the illusion of virtual edges rendered through the modification of contact forces. The presence of this sudden burst under varied model parameters was investigated. It was shown that while the appearance of this phenomenon in simulation results was invariant to model parameters, associated alteration of the edge enhancement ratio might be considered for the purpose of the tuning of the variable friction tactile display. PMID- 20832803 TI - Exercise of mechanisms for dynamic stability control increases stability performance in the elderly. AB - Old adults show a decreased recovery performance compared to young ones after unexpected perturbations increasing the risk of falls. Therefore, the purpose of the present study was to examine the effect of a specific training of mechanisms responsible for dynamic stability on the recovery performance of old adults after simulated forward falls and the contribution of muscle strength exercise. 38 old adults (two experimental groups each n=13 and a control group, n=12) participated in the study. Group 1 exercised the mechanisms responsible for dynamic stability like increase in base of support and counter-rotating segments around the centre of mass by practicing specific tasks including these mechanisms. Group 2 exercised these mechanisms of dynamic stability and muscle strength. The exercise volume was equal in both interventions (14 weeks, two times per week and ~ 1.5h per session). Stability performance has been examined by simulated forward falls before and after the intervention. The two experimental groups improved in a similar extent (~ 35%) their ability to regain balance during forward falls after the intervention. The reason was a faster increase in base of support. Further, the performance enhancement was related to an increase in the rate of hip moment generation. Exercising the mechanisms responsible for dynamic stability control in old adults affects their ability to regain balance after forward falls. A faster utilization of these mechanisms due to improved neuromuscular coordination resulted in the significant performance enhancement. PMID- 20832804 TI - A transversely isotropic constitutive model of excised guinea pig spinal cord white matter. AB - Narrowing of the spinal canal generates an amalgamation of stresses within the spinal cord parenchyma. The tissue's stress state cannot be quantified experimentally; it must be described using computational methods, such as finite element analysis. The objective of this research was to propose a compressible, transversely isotropic constitutive model, an augmentation of the isotropic Mooney-Rivlin hyperelastic strain energy function, to describe the guinea pig spinal cord white matter. Model parameters were derived from a combination of inverse finite element analysis on transverse compression experiments and least squared error analysis applied to quasi-static longitudinal tensile tests. A comparison of the residual errors between the predicted response and the experimental measurements indicated that the transversely isotropic constitutive law that incorporates an offset stretch reduced the error by a factor of four when compared to other commonly used models. PMID- 20832805 TI - In vivo gait analysis in a mouse femur fracture model. AB - Although the mouse has become a preferred species for molecular studies on fracture healing, gait analysis after fracture fixation and during bone healing has not yet been performed in mice. Herein, we introduce a novel technique for gait analysis in mice and report the change of motion pattern after fracture and fixation. A standardized femur fracture was stabilized by a common pin. The non fractured tibia was additionally marked with a pin, allowing continuous analysis of the tibio-femoral angle by digital video-radiography. Dynamic gait analysis was performed at day fourteen after surgery in a radio-opaque running wheel. Fracture fixation resulted in a significantly reduced range and maximum of the tibio-femoral angle compared to non-fractured controls. This was associated with a significantly reduced stride length. Because stride frequency was slightly increased and, thus, stride time diminished, stride velocity was not significantly reduced compared to controls. Thus, our study demonstrates distinct alterations of the gait of mice at 2 weeks after femur fracture and stabilization. Our results support the need of gait analysis in fracture healing studies to assess the animals' well-being. PMID- 20832806 TI - Unique selectivity windows using selective displacers/eluents and mobile phase modifiers on hydroxyapatite. AB - A detailed study was carried out to combine the unique selectivity of ceramic hydroxyapatite (CHA) with the separation power of selective displacement chromatography. A robotic liquid handling system was employed to carry out a parallel batch screen on a displacer library made up of analogous compounds. By incorporating positively charged, metal chelating and/or hydrogen bonding groups into the design of the displacer, specific interaction sites on CHA were targeted, thus augmenting the selectivity of the separation. The effect of different mobile phase modifiers, such as phosphate, sulfate, lactate and borate, were also investigated. Important functional group moieties and trends for the design of CHA displacers were established. Selective batch separations were achieved between multiple protein pairs which were unable to be resolved using linear gradient techniques, demonstrating the applicability of this technique to multiple protein systems. The specific interaction moieties used on the selective displacer were found to dictate which protein was selectively displaced in the separation, a degree of control not possible using a mono-interaction type resin in displacement chromatography. Mobile phase modifiers were also shown to play a crucial role, augmenting the selectivity of a displacer in a synergistic fashion. Column separations were carried out using selective displacers and mobile phase modifiers identified in the batch experiments, and baseline separation of the previously unresolved protein pairs was achieved. Further, the elution order in these systems was able to be reversed while still maintaining baseline separations. This work establishes a new class of separations which combine the selectivities of multi-modal resins, displacers/eluents, and mobile phase modifiers to create unique selectivity windows unattainable using traditional modes of operation. PMID- 20832807 TI - First approach based on direct ultrasonic assisted enzymatic digestion and capillary-high performance liquid chromatography for the peptide mapping of soybean proteins. AB - This work proposes, for the first time, the use of a high intensity ultrasonic probe to accelerate the tryptic digestion of soybean proteins. Different digestion parameters were optimized: protein extracting solution, reduction, and alkylation conditions (time, concentration, and temperature), trypsin:protein ratio, and ultrasonic conditions (sonication amplitude and time). Separation of peptide profiles was carried out by capillary-HPLC. The effect of the variation of chromatographic conditions (elution gradient, column temperature, and injection volume) on peptide separation was also studied using two capillary-HPLC columns with different column diameters and particle sizes. Moreover, samples were focused at the top of the column in order to obtain an increasing sensitivity without loss of efficiency. This method was successfully applied to the profiling of soybean peptides from transgenic and non-transgenic soybeans and from different pigmented beans commercialized as soybeans. PMID- 20832808 TI - Measurement of bubble size distribution in a gas-liquid foam using pulsed-field gradient nuclear magnetic resonance. AB - Pulsed-field gradient nuclear magnetic resonance, previously used for measuring droplet size distributions in emulsions, has been used to measure bubble size distributions in a non-overflowing pneumatic gas-liquid foam that has been created by sparging propane into an aqueous solution of 1.5g/l (5.20mM) SDS. The bubble size distributions measured were reproducible and approximated a Weibull distribution. However, the bubble size distributions did not materially change with position at which they were measured within the froth. An analysis of foam coarsening due to Ostwald ripening in a non-overflowing foam indicates that, for the experimental conditions employed, one would not expect this to be a significant effect. It is therefore apparent that the eventual collapse of the foam is due to bubble bursting (or surface coalescence) rather than Ostwald ripening. This surface coalescence occurs because of evaporation from the free surface of the foam. An analytical solution for the liquid fraction profile for a certain class of non-overflowing pneumatic foam is given, and a mean bubble size that is appropriate for drainage calculations is suggested. PMID- 20832809 TI - Smart hollow microspheres of chondroitin sulfate conjugates and magnetite nanoparticles for magnetic vector. AB - Smart hollow microspheres composed of vinyled-chondroitin sulfate conjugates (CSpi) and magnetite nanoparticles were obtained by the intermediate of a multiple emulsion in absence of a surfactant, attributable to stabilizing properties of the CS. It was formed an oil-water multiple emulsion in which the CS played a role as an anionic stabilizer for magnetite nanoparticles via complexation. Iron oxides were bonded to the microspheres by the formation of a complex of Fe(3+) ions on the crystalline phase with oxygen atoms at the carboxyl groups without their magnetic properties being affected. The average crystal size of embedded magnetite nanoparticles was approximately 16.5nm, indicative of a good dispersion in microspheres. Furthermore, the introduction of iron oxides resulted in microspheres with a higher diameter and a narrower particle size distribution. PMID- 20832810 TI - Droplet impact upon a wet surface with varied fluid and surface properties. AB - The transition boundaries of various regimes characterizing the impact outcomes of a droplet upon a liquid layer of small thickness were investigated experimentally. With careful control of film thickness, the onset of these regimes in terms of a Weber number (We), which expresses the ratio between the droplet inertia and surface force, specifically when the layer depth is smaller than the droplet diameter, has been further clarified, as compared to prior studies. Several turning, non-monotonic trends between We and the film thickness normalized by the droplet diameter, H, were thus identified as H?1. Furthermore, by adding various percentages of glycerine, the effects of liquid viscosity were revealed, which inhibited disintegration into secondary droplets. We also added surfactant to change the surface tension, leading to further complication of the collision outcome that would be related to the interaction between the crater and the bottom surface. The material effect of the solid surface was hence studied for further demonstration of such interplays. The results showed that increasing viscosity would essentially delay the occurrence of these transitions whereas reducing surface tension might encourage the onset. Therefore a possibility of using additives to manipulate the collision outcomes, while not changing much the constituent fluid properties, is presented. PMID- 20832811 TI - Paramedics as decision makers on the activation of the catheterization laboratory in the presence of acute ST-elevation myocardial infarction. AB - MATERIALS AND METHODS: To minimize delays in time to reperfusion in an urban suburban North Carolina County, Guilford County Emergency Medical Services (EMS) and Moses Cone Hospital, Greensboro, NC, have collaborated to use the acquisition of 12-lead electrocardiographs and their paramedic interpretation to initiate the catheterization laboratory team and cardiologist; independent of over read by a physician. The study population of 91 patients was divided into the catheterization laboratory activation by EMS and catheterization laboratory activation by the emergency department physician (ED-MD) groups, and also by EMS and self-transported groups. RESULTS: The EMS group had shorter median time intervals from hospital door to percutaneous coronary intervention (PCI) with balloon inflation than those patients who self-transported to the hospital. Also, patients who were treated during the EMS activation of the catheterization laboratory phase had shorter median hospital door to PCI times than those who were treated during ED-MD activation of the catheterization laboratory. CONCLUSION: The time from hospital arrival to PCI with balloon inflation was significantly shorter during the period in which EMS activated the catheterization laboratory than during the period the laboratory was activated by hospital staff. Thus, paramedics with quality electrocardiogram interpretation training and education can identify patients with acute ST-elevation myocardial infarction and properly activate the catheterization laboratory. PMID- 20832812 TI - Ischemic etiology for adenosine-sensitive fascicular tachycardia. AB - Adenosine-responsive ventricular tachycardias (VTs) typically occur in patients without structural heart disease; and thus, its association with myocardial ischemia is rare. In this case report, we describe a patient who had demonstrable ischemia along the anterolateral wall of the left ventricle and who developed a VT that was clinically terminated with adenosine. Surface electrocardiogram demonstrated a monomorphic VT with a right bundle-branch block morphology and a rightward axis configuration, and electrophysiologic testing showed atrioventricular dissociation upon atrial pacing and retrograde His waves following induction of VT. These findings localized the patient's VT to the left anterior fascicle, an anatomical region that coincided with the patient's territory of ischemia. We describe the electrophysiologic testing involved in elucidating the patient's tachyarrhythmia, and we provide a brief discussion of the pathogenesis and clinical features of adenosine-sensitive VT. Our case demonstrates that heterogeneous mechanisms of VT are operative in patients with ischemic heart disease. PMID- 20832813 TI - Electrocardiographic predictors of culprit artery in acute inferior ST elevation myocardial infarction. AB - BACKGROUND: In acute inferior ST-segment elevation myocardial infarction (STEMI), multiple electrocardiographic algorithms have been proposed to predict the culprit artery. Our purpose is to review these and compare them to ST depression in lead aVR to predict culprit artery in inferior STEMI. METHODS: In 106 patients with acute inferior STEMI who underwent emergent coronary angiography, we correlated electrocardiographic and angiographic findings pertaining to the culprit artery. We then reviewed the algorithms proposed by Fiol et al and Tierala et al, and applied them and our own from Kanei et al using ST depression in aVR for predicting the left circumflex artery (LCx) as the culprit, to the population. Finally, we compared the sensitivities and specificities of the respective algorithms for predicting the culprit artery. RESULTS: The sensitivity and specificity of ST depression in lead aVR to predict LCx as the culprit were 53% and 86%, respectively, and 86% and 55%, respectively for predicting the right coronary artery (RCA) as the culprit. When their algorithms were applied to our population, the sensitivities and specificities of Fiol et al and Tierala et al were slightly higher. CONCLUSION: Compared to other proposed algorithms, ST depression in aVR is a simple method with satisfactory sensitivity and specificity to predict the culprit artery in inferior STEMI. PMID- 20832814 TI - Effects of electrode placement errors in the EASI-derived 12-lead electrocardiogram. AB - In this study, we assess the effects of electrode placement error on the EASI derived 12-lead electrocardiogram (ECG). The study data set consisted of 744 body surface potential map (BSPM) recordings. The BSPMs, each of which was made up of 117 leads, were recorded from a mixture of healthy, myocardial infarction, and left ventricular hypertrophy subjects. The BSPMs were interpolated to increase the number of data points in the region of the EASI recording electrodes I, E, and A and the precordial leads. This facilitated 3 experiments. Firstly, recording sites I, E, and A were simultaneously moved +/-5 cm vertically, in 0.5 cm increments, from their correct locations. Secondly, recording sites I and A were moved horizontally, again up to +/-5 cm, in 0.5 cm increments. Finally, all 6 precordial leads were moved vertically in 0.5 cm increments up to +/-5 cm. At each movement step, the resulting 12-lead ECG was compared with the original 12 lead ECG. Root mean square error was determined along with the absolute difference in J-point amplitude. Although the EASI leads were found to be less sensitive to electrode misplacement than the standard precordial leads, it was found that when precordial leads were moved up to +/-3 cm vertically, the resulting 12-lead ECG more accurately resembled the original 12-lead ECG than a 12-lead ECG reconstructed from accurately positioned EASI leads. Further work is required to establish the effects of electrode misplacement beyond the +/-5 cm limits assessed in this study. PMID- 20832815 TI - Telemedicine fighting acute coronary syndromes. AB - INTRODUCTION: Telemedicine allows exchange of information and has therefore become an important tool for optimizing patient treatment in the field of cardiology. Transmission of electrocardiograms (ECGs) from the prehospital setting to the receiving hospital is the most widespread technology in the prehospital setting. Providing a diagnostic ECG from patients with acute coronary syndromes to health care professionals with decision-making power has proven pivotal for an early diagnosis, ideal triage, and initiation of reperfusion therapy of the large group of patients presenting with ST-elevation myocardial infarction (STEMI). This urgent triage could be expanded to several diagnosis in cardiology, primarily the non-ST-elevation presenters. PURPOSE: The purpose of the present article is to briefly describe the history the teletransmitted ECG and some of the recent results obtained when used in routine practice for acute triage and referral for primary percutaneous coronary intervention. CONCLUSIONS: Transmitting 12-lead ECGs from the community directly to attending cardiologists should become routine. Time to reperfusion in STEMI has decreased, explaining much of the observed decrease in STEMI mortality. This technology allows for increasingly complex and individualized prehospital medical care and could be expanded to a broader number of cardiovascular diagnoses. PMID- 20832816 TI - Role of the surface electrocardiogram in developing countries. AB - The surface electrocardiogram (ECG) is a basic cardiac investigation delivering information not only regarding heart rhythm but also regarding ischemic disease, effects of hypertension, congenital syndromes, and cardiomyopathies. These may determine decisions regarding follow-up investigations or treatment. The ECG fulfils several characteristics of a good screening test: it is rapid, is noninvasive, requires minimal technical expertise to perform, and is inexpensive. However, its interpretation requires highly trained physicians. In industrialized nations, the test is performed routinely in outpatient clinics and hospitals frequently in conjunction with further cardiac imaging. Developing nations confront a different situation. Urbanized segments may access ECG testing similarly to industrialized countries. However, in a country such as India, 80% of population is rural and poor. Less than 30% of physicians are rurally located, and most are primary care physicians. Access to medical care is limited by sparse and underresourced medical facilities and personnel, poorer socioeconomic status, ignorance of disease, and lack of motivation to seek health care. The ECG may be the only affordable cardiac test for this population, but poor communications (transport, telephone) hamper access. Initiatives to overcome these obstacles are being undertaken in some model situations. For example in Bangalore, India, use of mobile vans equipped with satellite terminals (aided by the Indian Space Research Organization) permits transmission of ECGs from rural points to central urban hospitals for physician interpretation. The physician community has responsibilities of improving the diagnostic yield from the ECG. Rural communities have a different spectrum of diseases with lesser coronary artery disease and greater incidence of valvular disease. The ECG has different roles in these diseases. (In contrast, urban communities in the same country experience diseases of industrialized nations.) Electrocardiogram interpretation also needs to account for different "normal" values in different ethnic groups: there is a surprising dearth of such data in groups other than African Americans. This is essential for interpretation of abnormality. Development of additional sophisticated analyses from ECG data may guide more selective use of expensive and invasive therapies. For example, risk stratification for defibrillator implant may be enhanced by use of T-wave alternans and heart rate variability. In China, ischemia monitoring with 12-lead Holters is performed due to lack of availability of a chest pain clinic. Innovative measures in electrocardiography are required for improving health care delivery in developing nations. PMID- 20832817 TI - Torsades: adjacent and triggering electrocardiographic events. AB - Torsades de pointes (TdP) is a particular variant of ventricular arrhythmia associated with the long QT syndrome. The background of the latter is essentially 2-fold: patients under treatment with QT-prolonging drugs and subjects with congenital ionopathies. A third category is composed of subjects with both of these backgrounds. The fundamental feature of TdP is its provocation by pause related augmentation of the repolarizing TU wave. The substrate electrocardiogram (ECG) shows prominent U waves in regular rhythm. The exaggeration of the U wave voltage following a pause is more marked the longer the pause and, for a given pause, more marked the faster the prepause rate. The pause-related sequences figure frequently adjacent to that which actually triggers the attack of TdP and continues to be seen after the event, serving to advise the physician as to the diagnosis, even following cardiac resuscitation, so that preventive measures can be taken (pacing, intravenous magnesium sulfate, or infusion with isoproterenol). The U wave of the regular rhythm ECG may show amplitude instability: an especially tall U triggering a premature ventricular complexe (PVC) that then in turn generates a pause-related sequence. TU alternans is common. Because these patients may not be in a monitored bed, recognition of pause-related phenomena in a patient with a long QT requires the ECG reader of the day to alert the floor as to the running danger. The mechanism of the pause-related TU augmentation is the generation of early afterdepolarizations. PMID- 20832818 TI - The normal electrocardiogram in the newborn and neonatal period and its progression. AB - Description of the progression of the normal newborn and neonatal electrocardiogram (ECG) in the first year of life include dare the mechanisms for the changes in the muscle masses of the pulmonary and systemic circulations and the resulting affect on the electrocardiogram included also is a description of the T wave detailed as well is a description from data from northern Italy of the QT interval using a large population base. PMID- 20832819 TI - Unnecessary arrhythmia monitoring and underutilization of ischemia and QT interval monitoring in current clinical practice: baseline results of the Practical Use of the Latest Standards for Electrocardiography trial. AB - PURPOSE: The purpose of the study was to examine the appropriate use of arrhythmia, ischemia, and QTc interval monitoring in the acute care setting. METHODS: We analyzed baseline data of the Practical Use of the Latest Standards for Electrocardiography (PULSE) trial, a multisite randomized clinical trial evaluating the effect of implementing electrocardiographic monitoring practice standards. Research nurses reviewed medical records for indications for monitoring and observed if arrhythmia, ischemia, and QT interval monitoring was being done on 1816 patients in 17 hospitals. RESULTS: Almost all (99%) patients with an indication for arrhythmia monitoring were being monitored, but 85% of patients with no indication were monitored. Of patients with an indication for ischemia monitoring, 35% were being monitored; but 26% with no indication were being monitored for ST-segment changes. Only 21% of patients with an indication for QT interval monitoring had a QTc documented, but 18% of patients with no indication had a QTc documented. CONCLUSION: Our data show evidence of inappropriate monitoring: undermonitoring for ischemia and QTc prolongation and overmonitoring for all 3 types of monitoring, especially arrhythmia monitoring. PMID- 20832820 TI - Ventricular arrhythmia is predicted by sum absolute QRST integralbut not by QRS width. AB - BACKGROUND: There is a controversy regarding the association between QRS width and ventricular arrhythmias (VAs). We hypothesized that predictive value of the QRS width could be improved if QRS width were considered in the context of the sum magnitude of the absolute QRST integral in 3 orthogonal leads sum absolute QRST integral (SAI QRST). We explored correlations between QRS width, SAI QRST, and VA in primary prevention implantable cardioverter-defibrillator (ICD) patients with structural heart disease. METHODS: Baseline orthogonal electrocardiograms were recorded at rest in 355 patients with implanted primary prevention ICDs (mean age, 59.5 +/- 12.4 years; 279 male [79%]). Patients were observed prospectively at least 6 months; appropriate ICD therapies because of sustained VA served as end points. The sum magnitude of the absolute QRST integral in 3 orthogonal leads (SAI QRST) was calculated. RESULTS: During a mean follow-up of 18 months, 48 patients had sustained VA and received appropriate ICD therapies. There was no difference in baseline QRS width between patients with and those without arrhythmia (114.9 +/- 32.8 vs 108.9 +/- 24.7 milliseconds; P = .230). SAI QRST was significantly lower in patients with VA at follow-up than in patients without VA (102.6 +/- 27.6 vs 112.0 +/- 31.9 mV.ms; P = 0.034). Patients with SAI QRST (<=145 mV.ms) had a 3-fold higher risk of ventricular tachycardia (VT)/ventricular fibrillation (VF) (hazard ratio [HR], 3.25; 95% confidence interval [CI], 1.59-6.75; P = .001). In the univariate analysis, QRS width did not predict VT/VF. In the bivariate Cox regression model, every 1 millisecond of incremental QRS widening with a simultaneous 1 mV.ms SAI QRST decrease raised the risk of VT/VF by 2% (HR, 1.02; 95% CI, 1.01-1.03; P = .005). CONCLUSION: QRS widening is associated with ventricular tachyarrhythmia only if accompanied by low SAI QRST. PMID- 20832821 TI - Cardiac resynchronization therapy or sequential pacing in failing Mustard? AB - The atrial switch (Mustard, Senning procedures) was one of the treatments of choice for repair of transposition of the great arteries from the early 1960s to the mid-1980s. A significant proportion of patients with atrial switch develops systemic (right) ventricular failure. A series of surgical therapeutic options exists to manage cardiac failure in this setting, and, more recently proposed, cardiac resynchronization therapy. We describe case report of a 30-year-old woman with congenital heart disease (CHD) and previous Mustard procedure who underwent upgrading from single chamber to dual-chamber pacemaker. The narrower native QRS did not correlate with a better synchrony status nor with a better cardiac output. Functional evaluation confirmed a better performance in DDD mode with short atrioventricular delay and broad QRS. Some echocardiographic and electrocardiographic parameters, such as ejection fraction and QRS duration, well established in adults' heart for selection of candidates to cardiac resynchronization therapy, are much less studied in CHD. Postoperative CHD may provide unique patterns of asynchrony with poorly predictable hemodynamic outcome. PMID- 20832822 TI - Neurology education in Latin America and the World Federation of Neurology. AB - The World Federation of Neurology (WFN) is the international body representing the specialty of neurology in more than 100 countries/regions of the globe. The WFN was organized as a federation of national neurologic societies in 1957. A primary goal of the WFN is to assist low-resource countries in providing meaningful education for its neurologic health care providers and thus improve the neurologic health of its citizens. During the last decade the WFN has promoted the Neurology Education in Latin America establishing different strategies. PMID- 20832823 TI - Stroke severity in concomitant cardiac sources of embolism in patients with atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF), which is the most common etiology of cardioembolic stroke, may be accompanied by other cardiac sources of embolism. The heterogeneity and multiplicity of the cardiac sources of embolism may influence stroke severity via formation of thrombi with heterogenous compositions, ages, and sizes. We investigated among stroke patients with AF whether stroke severity is different between patients with concomitant potential cardiac sources of embolism and those without. METHODS: The subjects for this study were consecutive patients with cerebral infarction and AF who underwent transesophageal echocardiography during a 10-year period. The definitions and determination of high- and medium-risk potential cardiac sources of embolism were based on the Trial of Org 10172 in Acute Stroke Treatment classification. Initial stroke severity and infarct sizes were compared between patients with concomitant potential cardiac sources of embolism and those without. RESULTS: Of the 266 patients enrolled, 181 (68.0%) had one or more concomitant potential cardiac sources of embolism. Left atrial thrombus and spontaneous echo contrast were most common. Patients with concomitant potential cardiac sources of embolism had a higher median score on the initial National Institute of Health Stroke Scale (6 vs. 3, p=0.005) and a larger infarction diameter (45.4+/-31.3 mm vs. 35.5+/-26.6 mm, p=0.002) than those without. Occlusion of the symptomatic arteries was more frequently detected in patients with concomitant potential cardiac sources of embolism. CONCLUSIONS: Stroke patients with AF frequently had concomitant potential cardiac sources of embolism, and strokes were more severe in them. PMID- 20832824 TI - Epileptic nystagmus: description of a pediatric case with EEG correlation and SPECT findings. AB - Epileptic nystagmus (EN) describes repetitive eye movements that result from seizure activity. We describe a patient with EN and vertigo first noted at the age of 4 yr and 10 mo. Brain MRI did not show anomalies. Ictal EEG recordings revealed epileptic activity during three episodes of horizontal, left-beating nystagmus not crossing the midline. Ictal 99mTc-ECD SPECT demonstrated the presence of active foci in multiple cerebral regions including bilateral prefrontal, bilateral parieto-temporo-occipital and the left parieto-insular vestibular areas. A wide area of hypoperfusion was also evident in the right hemisphere, prevailing in the parieto-occipital regions and the medial prefrontal gyrus. Topiramate was started at a dose of 2 mg/kg/d with complete seizure control after 14 d. EEG and SPECT were repeated after a seizure-free period of 1 mo; disappearance of epileptic activity and modification of cerebral perfusion were evident. This case reaffirms the cortical origin and involvement of temporo occipital and frontal cortex in the genesis of saccadic epileptic nystagmus. Rapid complete control of clinical events coincided with the normalization of EEG and improvement of the SPECT pattern. PMID- 20832825 TI - Sleep later, remember now: the importance of sleep research on the occurrence of sudden unexpected death in epilepsy. PMID- 20832826 TI - Perioperative outcomes of thoracoscopic anatomic resections in patients with limited pulmonary reserve. AB - BACKGROUND: Preoperative pulmonary function tests are used to assess operability for either lobectomy or pneumonectomy. Current guidelines for defining high-risk patients for anatomic lung resection on the basis of these tests were developed in the era of open thoracotomy. We studied the outcomes of such high-risk patients after video-assisted thoracoscopic surgical resections to assess the performance of these guidelines. METHODS: Records of all patients who underwent anatomic resection from 2001 to 2009 at a single institution were queried for pulmonary function and perioperative outcomes. Patients with predicted postoperative forced expiratory volume in 1 second or predicted postoperative lung carbon dioxide diffusing capacity less than 40% were considered to have limited pulmonary reserve. Perioperative outcomes of patients with limited pulmonary reserve who underwent thoracoscopic resection were documented and compared with those of similar patients who underwent open resection. RESULTS: Of 600 patients assessed, 70 had limited pulmonary reserve according to our criteria. Forty-seven of them underwent thoracoscopic resection. This cohort had excellent outcomes, with mortality of 2.1%, pneumonia rate of 4.3%, and discharge independence rate of 95.7%. Relative to contemporary patients undergoing open resection (N=23, including 12 conversions), patients undergoing thoracoscopic resection had lower incidence of pneumonia (4.3% vs. 21.7%, P<.05) and shorter intensive care unit stay (2 vs 4 days, P=.05). CONCLUSIONS: Patients with marginal lung function tolerate thoracoscopic anatomic resection well. Reassessment of the traditional pulmonary function test guidelines for operability is warranted in the current era of thoracoscopic lung surgery. PMID- 20832827 TI - Williams-Beuren syndrome: an unusual cause of neonatal and infantile coarctation. PMID- 20832828 TI - Up to 6-year follow-up after pulmonary vein isolation for persistent/permanent atrial fibrillation: importance of sinus node function. AB - OBJECTIVE: Sinus node dysfunction is commonly associated with atrial fibrillation. There is little information about the long-term results of pulmonary vein isolation in relation to sinus node function. The present study was conducted to investigate whether sinus node dysfunction affects the late outcome of pulmonary vein isolation in patients with persistent/permanent atrial fibrillation. METHODS: Among 76 consecutive patients with persistent/permanent atrial fibrillation who had undergone cut-and-sew pulmonary vein isolation, 66 patients without evidence of intra-atrial thrombus by transesophageal echography, and who were able to tolerate cardioversion, were enrolled. Sinus node recovery time after cardioversion was examined intraoperatively. All of the patients underwent valvular surgery concomitantly (mitral in 62). RESULTS: Sinus node dysfunction was detected in 18 patients. These patients had a significantly lower f wave voltage in V(1) of the electrocardiogram and a larger cardiothoracic ratio than patients with normal sinus node function. Hospital mortality was 3%, and 3 late deaths were observed. Follow-up was conducted for up to 72 months (mean 30 months), with a 100% complete follow-up rate. There were no significant differences in actuarial survival and freedom from cardiac events between patients with normal and abnormal sinus node function. No thromboembolic events occurred. A significantly higher proportion of patients with normal sinus node function (82%) were free of atrial fibrillation at 4 years than patients with sinus node dysfunction (25%; P < .0001). CONCLUSIONS: The atrial fibrillation cure rate after pulmonary vein isolation may be influenced by sinus node function in both the early and late stages. Although further examinations are required, pulmonary vein isolation may be an adequate treatment for persistent/permanent atrial fibrillation in patients with normal sinus node function. PMID- 20832829 TI - Effects of rosiglitazone on abnormal lipid kinetics in HIV-associated dyslipidemic lipodystrophy: a stable isotope study. AB - HIV-associated dyslipemic lipodystrophy (HADL) is a heterogeneous syndrome of fat redistribution, hypertriglyceridemia, and insulin resistance, associated with markedly accelerated rates of lipolysis, intraadipocyte and intrahepatic reesterification, and very low-density lipoprotein-triglyceride synthesis and release. The objective of the study was to determine if rosiglitazone can ameliorate these lipid kinetic defects in patients with HADL. Infusions of [(13)C(1)]palmitate and [(2)H(5)]glycerol were used to measure total and net lipolysis, adipocyte and hepatic reesterification, and plasma free fatty acid (FFA) oxidation in 9 men with HADL, before and after 3 months of treatment with rosiglitazone (8 mg/d). Rosiglitazone treatment significantly increased both total lipolysis (R(a) FFA(total) from 3.37 +/- 0.40 to 4.57 +/- 0.68 mmol FFA per kilogram fat per hour, P < .05) and adipocyte reesterification (1.25 +/- 0.35 to 2.43 +/- 0.65 mmol FFA per kilogram fat per hour, P < .05). However, there was no change in net lipolysis (R(a) FFA(net) 2.47 +/- 0.43 to 2.42 +/- 0.37 mmol FFA per kilogram fat per hour), plasma FFA oxidation (0.30 +/- 0.046 to 0.32 +/- 0.04 mmol FFA per kilogram lean body mass per hour), or FFA flux available for hepatic reesterification (0.59 +/- 0.07 to 0.56 +/- 0.10 mmol FFA per kilogram fat per hour). There were significant decreases in fasting plasma insulin concentrations and insulin resistance, but not in fasting plasma lipid or glucose concentrations. There was a significant decrease in waist to hip ratio (0.98 +/- 0.02 to 0.95 +/- 0.02, P < .05) consistent with a significant increase in hip circumference (0.93 +/- 0.02 to 0.95 +/- 0.02 m, P < .05), without change in waist circumference. Rosiglitazone significantly increased adipocyte reesterification and improved insulin sensitivity, but the potential benefit of these changes was compromised by increase in total lipolysis. Combining rosiglitazone with agents designed to blunt lipolysis could expand depleted peripheral adipose depots in patients with HIV lipodystrophy. PMID- 20832830 TI - A lipase inhibitor monoterpene and monoterpene glycosides from Monarda punctata. AB - An 80% acetone extract of Monarda punctata showed an inhibitory effect on lipase activity in isolated mouse plasma in vitro and carvacrol was obtained as the active constituent. It had an IC50 value of 4.07 mM invitro and suppressed elevations in blood triacylglycerol levels in olive oil-loaded mice. Furthermore, from the whole plant, 22 compounds were isolated. Six monoterpene glycosides, a flavone glucuronide, and other known compounds were identified based on the results of spectroscopic analyses. PMID- 20832831 TI - Neurocytoprotective effects of the bioactive constituents of Pueraria thomsonii in 6-hydroxydopamine (6-OHDA)-treated nerve growth factor (NGF)-differentiated PC12 cells. AB - Chronic neurodegenerative disorders are having an increasing impact on public health as human longevity increases. Parkinson's disease (PD) is a degenerative disorder of the central nervous system and is characterized by motor system disorders resulting in loss of dopamine-producing brain cells. Pueraria thomsonii Benth. (Fabaceae) is an herbal medicine that has traditionally been used as an antipyretic agent. In the present study, the active constituents, daidzein and genistein, were isolated from P. thomsonii. Both compounds exhibited neurocytoprotective effects against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in nerve growth factor (NGF)-differentiated PC12 cells. Neither daidzein nor genistein affected 6-OHDA-induced cellular reactive oxygen species (ROS) generation according to flow cytometric analysis. Rather, they inhibited caspase-8 and partially inhibited caspase-3 activation, providing a protective mechanism against 6-OHDA-induced cytotoxicity in NGF-differentiated PC12 cells. The present results imply that daidzein and genistein may be useful in the development of future strategies for the treatment of PD. PMID- 20832832 TI - Sexual risk behaviour of rural-to-urban migrant taxi drivers in Dhaka, Bangladesh: a cross-sectional behavioural survey. AB - OBJECTIVES: Human immunodeficiency virus (HIV) research in Bangladesh has mainly focused on key vulnerable groups (e.g. sex workers, drug users). In order to develop appropriate HIV prevention strategies in an evolving epidemic, there is a need for evidence on sexual practices in other population groups. This research aims to describe the prevalence of risky behaviours and factors affecting sexual behaviour/practices among rural-to-urban migrant taxi drivers in Dhaka. STUDY DESIGN: Cross-sectional study. METHODS: This paper reports on the cross-sectional survey component of a mixed methods research study amongst migrant workers in Bangladesh. The sample (n = 437) comprised rural-to-urban migrant taxi drivers in Dhaka (aged 18-35 years). The survey data were analysed statistically using Statistical Package for the Social Sciences. RESULTS: Very high levels of pre- and extramarital sexual behaviour were found (84% and 51%, respectively) amongst the sample (n = 437). The reported sexual activity included high levels of risky/unsafe sex in the past year: 64% of the sample reported sex with multiple commercial sex partners (mean = 13.21), and 21.7% reported sex with other males/transgenders (mean = 2.53). Protection against risk was low: 78.2% reported that their last commercial sexual encounter was unprotected, and only 5.6% used condoms consistently. Multivariate analysis revealed that the odds of risky sexual behaviour were higher in migrant men who were not married (odds ratio 35.3, P < 0.001) and married men who were living apart from their spouses (odds ratio 41.7, P < 0.001). Additionally, reported risk behaviours were significantly associated with frequency of home visits, duration of separation from spouse and alcohol consumption. Thus, male migration without family or spouse appears to be a key driver of risky sexual practices. CONCLUSIONS: This study provides important new information for understanding the dynamics of sexual behaviour in Bangladesh, and suggests that migrant men should be a key population for HIV prevention efforts. Nonetheless, the fact that most men were having unprotected sex with sex workers reinforces the importance of continuing to target interventions towards commercial sex contexts. PMID- 20832833 TI - Quit attempts and intention to quit cigarette smoking among Medicaid recipients in the USA. AB - OBJECTIVES: To examine the effect of Medicaid coverage of tobacco dependence treatments (TDT) on quitting attempts and intention to quit by Medicaid recipient smokers. STUDY DESIGN: Multiple cross-sectional study. METHOD: Data from the national 1996-2007 Tobacco Use Supplements to the Current Population Survey in the USA were analysed (n=6585). Measures included self-reported quit attempts during the last 12 months, and serious intention to quit in the next 6 months and in the next 30 days. RESULTS: In the baseline model, Medicaid coverage of TDT was associated with attempted quitting [odds ratio (OR) 1.23, 95% confidence interval (CI) 1.05-1.45], intention to quit in the next 6 months (OR 1.32, 95% CI 1.09 1.59) and intention to quit in the next 30 days (OR 1.27, 95% CI 1.01-1.58). After controlling for cigarette taxes and the antismoking sentiment index for each state, the magnitude became smaller and the association was only statistically significant for intention to quit in the next 6 months. CONCLUSIONS: Covering smoking cessation aids and eliminating copayments with Medicaid can encourage more quitting attempts and facilitate intentions to quit. PMID- 20832834 TI - Injury prevention: a strategic priority for environmental health? AB - Injury results from the acute transfer of energy (or the acute lack of a vital element) from the environment to human tissue. It is thus, ipso facto, an 'environmental health' issue par excellence. This paper argues that injury consequently deserves consideration as a major strategic priority by environmental health professionals. Two international agreements concerning children's health and the environment have major implications for safety. The Children's Environmental Health Action Plan for Europe (CEHAPE) and the European Environmental Health Strategy make reference to the need for improved evidence and greater co-operation between the environmental and health sectors. CEHAPE is particularly relevant to safety as it focuses on four regional priority goals, the second of which refers to the prevention and reduction of health consequences from injuries by promoting safe, secure and supportive human settlements for all children. The natural strategic 'home' for injury prevention may therefore lie within environmental health, a domain from which it has generally been excluded. In support of this assertion, Scotland's recent policy initiative on the environment and human health 'Good Places, Better Health' is cited, where injury in children up to 8 years of age is one of four child health priorities being tackled during its initial implementation. An important test of the initiative may be its capacity to inform policy, practice and research in the field of injury prevention and safety promotion. If successful, it will help to validate the environmental health approach to a field that remains relatively neglected by public agencies, policy makers, practitioners and researchers. PMID- 20832835 TI - Readability levels of health pamphlets distributed in hospitals and health centres in Athens, Greece. AB - OBJECTIVES: Health literacy is important in the medical and social sciences due to its impact on behavioural and health outcomes. Nevertheless, little is known about it in Greece, including patients' level of understanding health brochures and pamphlets distributed in Greek hospitals and clinics. STUDY DESIGN: Observational study in the greater metropolitan area of Athens, Greece. METHODS: Pamphlets and brochures written in the Greek language were collected from 17 hospitals and healthcare centres between the spring and autumn of 2006. Readability of pamphlets using the Flesch-Kincaid, Simple Measure of Gobbledygook (SMOG) and Fog methods was calculated based on a Greek readability software. RESULTS: Out of 70 pamphlets collected from 17 hospitals, 37 pamphlets met the criteria for the study. The average readability level of all scanned pamphlets was ninth to 10th grade, corresponding to a readability level of 'average'. A highly significant difference (P<0.001) was found between private and public hospitals using the Flesch-Kincaid and SMOG readability scales. Pamphlets from private hospitals were one grade more difficult than those from public hospitals. CONCLUSION: Approximately 43.7% of the Greek population aged >=20 years would not be able to comprehend the available pamphlets, which were found to have an average readability level of ninth to 10th grade. Further research examining readability levels in the context of health literacy in Greece is warranted. This effort paves the way for additional research in the field of readability levels of health pamphlets in the Greek language, the sources of health information, and the level of understanding of key health messages by the population. PMID- 20832836 TI - Mutations of an antibody binding energy hot spot on domain III of the dengue 2 envelope glycoprotein exploited for neutralization escape. AB - Previous crystallographic studies have identified a total of 11 DENV-2 envelope protein domain III (ED3) residues (K305, F306, K307, V308, V309, K310, I312, Q325, P364, K388, and N390) that interacted, through both side- and main-chain contacts, with the Fab of a dengue virus (DENV) subcomplex-specific neutralizing monoclonal antibody (MAb) 1A1D-2 (Lok et al., 2008). Here, we used DENV-2 recombinant ED3 mutants of the MAb 1A1D-2 structural epitope residues to determine the functional epitope of this MAb. The side-chains of residues K307, K310 and I312 were determined to be functionally critical for MAb binding, and thus constitute a hot spot of binding energy for MAb 1A1D-2 on the DENV-2 ED3. Overall, these findings demonstrate that only a subset of the amino acid residue side-chains within the structural epitope of MAb 1A1D-2 define a functional epitope on the DENV-2 ED3 that is essential for MAb binding and neutralization escape. PMID- 20832837 TI - Kinetics of electro-oxidation of ammonia-N, nitrites and COD from a recirculating aquaculture saline water system using BDD anodes. AB - The viability of the electro-oxidation technology provided with boron doped diamond (BDD) electrodes for the treatment and reuse of the seawater used in a Recirculating Aquaculture System (RAS) was evaluated in this work. The influence of the applied current density (5-50 A m(-2)) in the removal of Total Ammonia Nitrogen (TAN), nitrite and chemical oxygen demand (COD) was analyzed observing that complete TAN removal together with important reductions of the other considered contaminants could be achieved, thus meeting the requirements for reuse of seawater in RAS systems. TAN removal, mainly due to an indirect oxidation mechanism was described by a second order kinetics while COD and nitrite removal followed zero-th order kinetics. The values of the kinetic constants for the anodic oxidation of each compound were obtained as a function of the applied current density (k(TAN) = 7.86 * 10(-5) . exp(6.30 * 10(-2) J); kNO2 = 3.43 * 10(-2) J; k(COD) = 1.35 * 10(-2) J). The formation of free chlorine and oxidation by-products, i.e., trihalomethanes (THMs) was followed along the electro-oxidation process. Although a maximum concentration of 1.7 mg l(-1) of total trihalomethanes was detected an integrated process combining electrochemical oxidation in order to eliminate TAN, nitrite and COD and adsorption onto activated carbon to remove the residual chlorine and THMs is proposed, as an efficient alternative to treat and reuse the seawater in fish culture systems. Finally, the energy consumption of the treatment has been evaluated. PMID- 20832838 TI - Evaluating the influence of process parameters on soluble microbial products formation using response surface methodology coupled with grey relational analysis. AB - Soluble microbial products (SMPs) present a major part of residual chemical oxygen demand (COD) in the effluents from biological wastewater treatment systems, and the SMP formation is greatly influenced by a variety of process parameters. In this study, response surface methodology (RSM) coupled with grey relational analysis (GRA) method was used to evaluate the effects of substrate concentration, temperature, NH(4)(+)-N concentration and aeration rate on the SMP production in batch activated sludge reactors. Carbohydrates were found to be the major component of SMP, and the influential priorities of these factors were: temperature>substrate concentration > aeration rate > NH(4)(+)-N concentration. On the basis of the RSM results, the interactive effects of these factors on the SMP formation were evaluated, and the optimal operating conditions for a minimum SMP production in such a batch activated sludge system also were identified. These results provide useful information about how to control the SMP formation of activated sludge and ensure the bioreactor high-quality effluent. PMID- 20832839 TI - Effect of weathering treatment on the fractionation and leaching behavior of copper in municipal solid waste incinerator bottom ash. AB - This work describes the effect of weathering of fresh quenched municipal solid waste incinerator (MSWI) bottom ash on the fractionation and leaching behavior of Cu. A sequential extraction procedure was used to characterize the fractionation of Cu in the fresh and weathered MSWI bottom ash samples. It showed that the organic matter bound fraction of Cu decreased drastically from 69% to 37% during the weathering treatment, while the residual fraction, Fe-Mn oxides bound fraction, carbonate bound fraction and exchangeable fraction increased from 24% to 54%, 3% to 4%, 2% to 3% and 2% to 3%, respectively. Furthermore, two standard leaching procedures, synthetic precipitation leaching procedure (SPLP) and toxicity characteristic leaching procedure (TCLP), were carried out on the fresh and weathered samples. The leaching of Cu was attenuated with the process of weathering treatment in the SPLP procedure, but was enhanced in the TCLP procedure. The results suggested that the weathering treatment could change the fractionation and leaching behavior of Cu in MSWI bottom ash. Further research is required to correlate weathering of ash and mobility of Cu. PMID- 20832840 TI - Seasonal variability of physiological and biochemical aspects of chromium accumulation in outdoor-grown Salvinia minima. AB - Seasonal variations in physiological and biochemical parameters of the aquatic fern Salvinia minima exposed to different Cr(VI) concentrations were studied. Growth, photosynthetic pigments, soluble carbohydrates, sucrose-related enzymes, lipid peroxidation, phenolics, and Cr accumulation in floating and submerged leaves were analyzed. Cr content was lower in winter than in summer, indicating that active metabolic events occurred in metal uptake. Leaf number and metal concentration factor were higher in summer than in winter. Relative growth rate (R(n)) indicated that growth was more affected by Cr in winter than in summer. Biochemical parameters showed great seasonal variations under increasing Cr. Hexose, starch, malondialdehyde and phenolic contents were greatest in winter, but R(n) and protein values were lowest. Sucrose content was highest in summer floating leaves. A great seasonal variability was observed in sucrose-related enzymes with the highest activities occurring in winter lipoxygenase was much higher in winter than in summer, indicating a strong lipid peroxidation. Results indicate that in Salvinia Cr causes seasonal perturbations in carbohydrate metabolism and oxidative stress by altering both sucrose-related enzymes and lipoxygenase activities. Variability in physiological and biochemical parameters seems to indicate that in outdoor conditions different mechanisms, in terms of Cr accumulation and tolerance, may occur in S. minima during summer and winter. PMID- 20832841 TI - Separation and aquatic toxicity of enantiomers of the organophosphorus insecticide O-ethyl O-4-nitrophenyl phenylphosphonothioate (EPN). AB - Enantioselectivity in separation and toxicity of chiral pesticides has become important research areas in environmental science, because these studies give a deeper insight into the environmental effect of chiral pesticides. In this study, enantiomeric separation of the organophosphorus pesticide and acaricide O-ethyl O 4-nitrophenyl phenylphosphonothioate (EPN) was investigated by chiral high performance liquid chromatography (HPLC) with two chiral stationary phases. The racemate and separated enantiomers of EPN were tested for aquatic toxicities assay using Daphnia magna and zebrafish (Danio rerio) embryo test. The enantiomers of EPN were completely separated on Chiralpak AD and Chiralpak AS columns coupled with a circular dichroism detector at 236 nm. Better separations were achieved with lower temperatures (e.g., 20 degrees C) and lower levels of polar modifiers (e.g., 1%). A significant difference was found between the enantiomers in their acute aquatic toxicity; the (+)-enantiomer was about 10 times more toxic than its antipode. On the contrary, the (-)-enantiomer induced crooked body, yolk sac edema and pericardial edema significantly more than (+) enantiomer in the zebrafish embryo test. These results suggest that biological toxicity of chiral pesticides should be assessed by using their individual enantiomers with more comprehensive methods. PMID- 20832842 TI - Enhancement of pyrene removed from contaminated soils by Bidens maximowicziana. AB - The research utilized Bidens maximowicziana along with pyrene-degrading bacteria to evaluate their potential in cleaning up pyrene contamination. The removal of pyrene from the planted soil was obviously higher than that from the unplanted soils. After 50 d of B. maximowicziana growth, the average removal ratio of pyrene in planted soil was 79%, which was 28% higher than that of pyrene in unplanted soil. In contrast to other plants, both roots and shoots of B. maximowicziana could accumulate a large amount of pyrene from the soil and pyrene uptake increased with the soil pyrene concentration. Through analysis of pathways of pyrene removal, this enhanced removal of pyrene by plant-microbial association might be mainly the result of B. maximowicziana-promoted microbial degradation. Both the catalase and polyphenol oxidase activities in soil were higher in planted soil than those in unplanted soil. And the bacteria populations in soil, especially in rhizosphere, were also inspired by the growth of B. maximowicziana. These could be explained by the rhizosphere effect. Therefore, bio-removal of pyrene in the contaminated soils was feasible using B. maximowicziana. PMID- 20832843 TI - Photocatalytic oxidation of natural organic matter surrogates and the impact on trihalomethane formation potential. AB - Natural organic matter (NOM) consists of a complex mixture of organics and acts as precursors for a range of disinfection by-products (DBPs) including trihalomethanes (THMs). The characteristics of these precursors are still not well identified and here we have used a range of NOM surrogates that allows us to investigate how the characteristics of NOM relate to treatability with photocatalytical oxidation. Nine surrogates of NOM (five amino acids, two carbohydrates, two phenolic compounds) were evaluated and the impact of retention time on dissolved organic carbon (DOC) and trihalomethane formation potential (THMFP) measured. Adsorption of the compounds onto TiO(2) was evaluated and electrostatic forces played a significant role in their removal although photocatalytic oxidation was found to be unselective. DOC and THMFP decreased significantly with retention time except for l-leucine where the by-products formed during photocatalytic oxidation were significantly more reactive with chlorine than the parent compound. PMID- 20832845 TI - The new chronology of the Ceprano calvarium (Italy). PMID- 20832846 TI - Concentrations and determinants of organochlorine levels among pregnant women in Eastern Spain. AB - Persistent organic pollutants (POPs) comprise a large variety of toxic substances with ample distribution. While exposure to these toxins occurs mainly through diet, maternal POP levels may be influenced by certain sociodemographic, environmental, or lifestyle factors. This is important given that these substances may have adverse effects on fetal development. The aim of this study is to examine the sociodemographic, environmental, lifestyle, and dietary determinants of the levels of hexachlorobenzene (HCB), b-hexachlorocyclohexane (b HCH), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (4,4'-DDT), 1,1-dichloro-2,2 bis(4-chlorophenyl)ethylene (4,4'-DDE), and polychlorinated biphenyls (PCB congeners 118, 138, 153, 180) measured in the blood of pregnant women participating in a mother-child cohort study conducted in Valencia (Spain). The study population consisted of 541 pregnant women who formed part of the INMA (Childhood and the Environment) cohort (2004-2006). POP levels were determined in blood taken during the 12th week of pregnancy with the aid of gas chromatography with electron capture detection. Sociodemographic, environmental, and dietary information was obtained from a questionnaire. Multivariate Tobit regression models were constructed in order to assess the association between POP levels and selected covariates. The results showed that all the women had detectable levels of at least one of these compounds while in 43% of the subjects, all eight compounds were detected. The compounds found in the greatest number of women were 4,4'-DDE (100%) and PCBs 153 and 180 (95%). The most important determinants of high POP levels were the mother's age, country of origin, increased body mass index, and number of weeks of breastfeeding after previous pregnancies. With regard to diet, 4,4'-DDT and 4,4'-DDE levels increased with the intake of meat, fruit, and cereal. PCB 153 levels increased with the intake of seafood. The levels of HCB, b-HCH, 4,4'-DDT, and 4,4'-DDE observed in this study were slightly higher than in other studies, whereas the PCB levels were similar. PMID- 20832847 TI - Mast cell activation by fibrinogen-related homologous c-terminal peptides (haptides) modulates systemic blood pressure. AB - BACKGROUND: Haptides are a family of short peptides homologous to C-termini sequences of fibrinogen chains beta and gamma (haptides Cbeta and preCgamma, respectively) which were previously shown to penetrate and bind cells. OBJECTIVES: This work investigates the systemic effect of the haptides with possible clinical implications. METHODS: Intra-arterial monitoring in rats recorded the haptides' effects on systemic blood pressure. In parallel, their effect was also tested in vitro on isolated rat peritoneal mast cells and on human mast cells. RESULTS: Intra-arterial monitoring in rats showed that intravenous administration of low haptides concentrations (35-560 MUg/kg rat) caused a shocklike behavior with transient decrease in the systolic and diastolic blood pressure by up to 55% (P < .05) in a dose-dependent manner and a minor increase in their heart rate. Randomly scrambled sequences of the haptides had no such effect, suggesting a specific interaction with receptors. Intravenous administration of blockers to histamine receptors H1 and H2 before haptides administration attenuated this effect. Furthermore, in vitro incubation of human LAD2 mast cell line or isolated rat peritoneal mast cells with the haptides caused degranulation of the mast cells. We found that the haptides Cbeta and preCgamma activated mast cells causing histamine release, resulting in a steep decrease in blood pressure, comparable to anaphylactic shock. CONCLUSION: In treating vascular occlusive diseases, massive fibrinolysis is induced, and haptide-containing sequences are released. We suggest that treatment with histamine receptor blockers or with mast cell stabilizing agents in such pathological conditions may overcome this effect. PMID- 20832848 TI - Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. AB - BACKGROUND: Most infants developing atopic dermatitis have a low risk for atopy. Primary prevention of atopic dermatitis is difficult. OBJECTIVE: To assess the effect of supplementation of an infant and follow-on formula with prebiotic and immunoactive oligosaccharides on the occurrence of atopic dermatitis in the first year of life. METHODS: Healthy term infants from 5 European countries with low atopy risk were recruited before the age of 8 weeks, either having started with formula feeding or being on full breast-feeding (breast-feeding group). Formula fed infants were randomized to feeding with a regular formula containing a specific mixture of neutral oligosaccharides and pectin-derived acidic oligosaccharides (prebiotic formula group) or regular formula without oligosaccharides (control formula group). RESULTS: A total of 414 infants were randomized to the prebiotic group and 416 infants to the control group. A total of 300 infants were followed in the breast-feeding group. Up to the first birthday, atopic dermatitis occurred in significantly fewer infants from the prebiotic group (5.7%) than from the control group (9.7%; P = .04). The cumulative incidence of atopic dermatitis in the prebiotic group was in the low range of the breast-feeding group (7.3%). In a Cox regression model, the rate of atopic dermatitis was significantly lower by 44% in the prebiotic group versus the control group (P = .04). The number needed to prevent 1 case of atopic dermatitis by supplementation of prebiotics was 25 infants. CONCLUSION: Formula supplementation with a specific mixture of oligosaccharides was effective as primary prevention of atopic dermatitis in low atopy risk infants. PMID- 20832849 TI - Mechanisms of tolerance to parental parathyroid tissue when combined with human allogeneic thymus transplantation. AB - BACKGROUND: The induction of tolerance toward third-party solid organ grafts with allogeneic thymus tissue transplantation has not been previously demonstrated in human subjects. OBJECTIVE: Infants with complete DiGeorge anomaly (having neither thymus nor parathyroid function) were studied for conditions and mechanisms required for the development of tolerance to third-party solid organ tissues. METHODS: Four infants who met the criteria received parental parathyroid with allogeneic thymus transplantation and were studied. RESULTS: Two of 3 survivors showed function of both grafts but subsequently lost parathyroid function. They demonstrated alloreactivity against the parathyroid donor in mixed lymphocyte cultures. For these 2 recipients, parathyroid donor HLA class II alleles were mismatched with the recipient and thymus. MHC class II tetramers confirmed the presence of recipient CD4(+) T cells with specificity toward a mismatched parathyroid donor class II allele. The third survivor has persistent graft function and lacks alloreactivity toward the parathyroid donor. All parathyroid donor class II alleles were shared with either the recipient or the thymus graft, with minor differences between the parathyroid (HLA-DRB1*1104) and thymus (HLA DRB1*1101). Tetramer analyses detected recipient T cells specific for the parathyroid HLA-DRB1*1104 allele. Alloreactivity toward the parathyroid donor was restored with low doses of IL-2. CONCLUSION: Tolerance toward parathyroid grafts in combined parental parathyroid and allogeneic thymus transplantation requires matching of thymus tissue to parathyroid HLA class II alleles to promote negative selection and suppression of recipient T cells that have alloreactivity toward the parathyroid grafts. This matching strategy may be applied toward tolerance induction in future combined thymus and solid organ transplantation efforts. PMID- 20832850 TI - Polymerization stress, shrinkage and elastic modulus of current low-shrinkage restorative composites. AB - OBJECTIVE: To compare currently available low-shrinkage composites with others regarding polymerization stress, volumetric shrinkage (total and post-gel), shrinkage rate and elastic modulus. METHODS: Seven BisGMA-based composites (Durafill/DU, Filtek Z250/FZ, Heliomolar/HM, Aelite LS Posterior/AP, Point 4/P4, Filtek Supreme/SU, ELS/EL), a silorane-based (Filtek LS, LS), a urethane-based (Venus Diamond, VD) and one based on a dimethacrylate-derivative of dimer acid (N'Durance, ND) were tested. Polymerization stress was determined in 1-mm high specimens inserted between two PMMA rods attached to a universal testing machine. Total volumetric shrinkage was measured using a mercury dilatometer. Maximum shrinkage rate was used as a parameter of the reaction speed. Post-gel shrinkage was measured using strain-gages. Elastic modulus was obtained by three-point bending. Data were submitted to one-way ANOVA/Tukey test (p=0.05), except for elastic modulus (Kruskal-Wallis). RESULTS: Composites ranked differently for total and post-gel shrinkage. Among the materials considered as "low-shrinkage" by the respective manufacturers, LS, EL and VD presented low post-gel shrinkage, while AP and ND presented relatively high values. Polymerization stress showed a strong correlation with post-gel shrinkage except for LS, which presented high stress. Elastic modulus and shrinkage rate showed weak relationships with polymerization stress. SIGNIFICANCE: Not all low-shrinkage composites demonstrated reduced polymerization shrinkage. Also, in order to effectively reduce polymerization stress, a low post-gel shrinkage must be associated to a relatively low elastic modulus. PMID- 20832851 TI - Shade compatibility of esthetic restorative materials--A review. AB - OBJECTIVES: The objectives of this study were to review the shade compatibility of esthetic restorative materials and to provide a visual method to harmonize the color of them. METHODS: Published reports on the color ranges and distributions of shade guides, color differences between restorative materials and the referenced shade guides, and those between the identical shade designated restorative materials were reviewed. RESULTS: Several limitations in shade guides should be considered in color matching such as (1) color ranges and distributions of shade guides are different from those of human teeth, (2) arrangements of shade tabs in shade guides are not ideally logical, and (3) color of marketed esthetic restorative materials and the referenced shade tabs is significantly different. Color coordinates of restorative materials of the identical shade designations vary by the kind and brand of the restorative materials. Color differences between restorative materials and the referenced shade guides and those between the identical shade designated restorative materials are generally higher than perceptible limits. A visual color harmonization method was suggested, and the considerations for the instrumental color harmonization were provided. SIGNIFICANCE: Visual color matching would result in color mismatching by the kind and brand of the restorative materials. The first step to improve the color matching performance would be the harmonization of the color of restorative materials with those of the corresponding shade tabs. PMID- 20832852 TI - Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data. AB - BACKGROUND: Results from randomised controlled trials have shown a higher short term risk of stroke associated with carotid stenting than with carotid endarterectomy for the treatment of symptomatic carotid stenosis. However, these trials were underpowered for investigation of whether carotid artery stenting might be a safe alternative to endarterectomy in specific patient subgroups. We therefore did a preplanned meta-analysis of individual patient data from three randomised controlled trials. METHODS: Data from all 3433 patients with symptomatic carotid stenosis who were randomly assigned and analysed in the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial, the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) trial, and the International Carotid Stenting Study (ICSS) were pooled and analysed with fixed-effect binomial regression models adjusted for source trial. The primary outcome event was any stroke or death. The intention-to-treat (ITT) analysis included all patients and outcome events occurring between randomisation and 120 days thereafter. The per-protocol (PP) analysis was restricted to patients receiving the allocated treatment and events occurring within 30 days after treatment. FINDINGS: In the first 120 days after randomisation (ITT analysis), any stroke or death occurred significantly more often in the carotid stenting group (153 [8.9%] of 1725) than in the carotid endarterectomy group (99 [5.8%] of 1708, risk ratio [RR] 1.53, [95% CI 1.20 1.95], p=0.0006; absolute risk difference 3.2 [1.4-4.9]). Of all subgroup variables assessed, only age significantly modified the treatment effect: in patients younger than 70 years (median age), the estimated 120-day risk of stroke or death was 50 (5.8%) of 869 patients in the carotid stenting group and 48 (5.7%) of 843 in the carotid endarterectomy group (RR 1.00 [0.68-1.47]); in patients 70 years or older, the estimated risk with carotid stenting was twice that with carotid endarterectomy (103 [12.0%] of 856 vs 51 [5.9%] of 865, 2.04 [1.48-2.82], interaction p=0.0053, p=0.0014 for trend). In the PP analysis, risk estimates of stroke or death within 30 days of treatment among patients younger than 70 years were 43 (5.1%) of 851 patients in the stenting group and 37 (4.5%) of 821 in the endarterectomy group (1.11 [0.73-1.71]); in patients 70 years or older, the estimates were 87 (10.5%) of 828 patients and 36 (4.4%) of 824, respectively (2.41 [1.65-3.51]; categorical interaction p=0.0078, trend interaction p=0.0013]. INTERPRETATION: Stenting for symptomatic carotid stenosis should be avoided in older patients (age >=70 years), but might be as safe as endarterectomy in younger patients. FUNDING: The Stroke Association. PMID- 20832853 TI - A combinatorial screening of human fibroblast responses on micro-structured surfaces. AB - Biomaterial surfaces structured with topographical features have been predicted to play an important role in the next generation of biomedical implants. Specific trends with regard to the influence of the topographical effect on cellular behavior are however challenging to establish due to differences in the topographical features and geometries in the various studies. Here, we demonstrate the use of a highly versatile combinatorial screening approach to identify the effect of 169 distinct surface topographies, consisting of pillars, on fibroblast proliferation and mechanical response. Altering the inter-pillar gap size of the structures revealed a significant change in fibroblast proliferation and identified obvious stress-induced changes in the cytoskeleton and focal adhesion morphology. Larger (4-6 MUm) inter-pillar gap sizes reduced fibroblast proliferation and elicited a strong elongation leading to a disruption of the actin cytoskeleton anchored primarily to focal adhesions located between the pillars. Smaller (1-2 MUm) inter-pillar gap sizes, on the contrary, caused the fibroblasts to proliferate comparable to cells on a non-structured surface with cells having a clear actin cytoskeleton attached to focal adhesions located mostly on top of the pillars. The approach reveals a strong correlation between the exact topographical periodicities and cellular responses such as cell proliferation, cell morphology and focal adhesion. PMID- 20832854 TI - Death signal transduction induced by co-immobilized TNF-alpha plus IFN-gamma and the development of polymeric anti-cancer drugs. AB - Based on our earlier work on the apoptosis in HeLa cells induced by TNF-alpha plus IFN-gamma, we investigate how the co-immobilized TNF-alpha plus IFN-gamma promotes the signal transduction of HeLa cells. It is found that the free TNF alpha plus IFN-gamma has much stronger capability than the co-immobilized TNF alpha plus IFN-gamma in binding with apoptosis signaling receptors TNFR1, which allows an argument that the co-immobilized TNF-alpha plus IFN-gamma can modulate the death pathway of HeLa cells. Subsequently, we determine the cell membrane surface receptor with which the co-immobilized TNF-alpha plus IFN-gamma binds, and probe the expression of death receptor which induces the apoptosis pathway upstream protein FADD and TRADD. Our results reveal that the death signal transduction, induced by the co-immobilized TNF-alpha plus IFN-gamma, is mainly realized via the IFN-gamma signaling pathway rather than the TNF-alpha one. In addition, the transcription of STAT1 plus its Serine 727 and Tyrosine 701 phosphorylation is not the pre-requisite for inducing the cell death signal transduction. It is thus suggested that the co-immobilized TNF-alpha plus IFN gamma promotes the activation of some unknown key markers in response to IFN gamma, and the binding of the co-immobilized TNF-alpha plus IFN-gamma with some other TNF-alpha receptors results in enhanced programmed cell death in HeLa cells. PMID- 20832855 TI - Using growth factor arrays and micropatterned co-cultures to induce hepatic differentiation of embryonic stem cells. AB - The success in driving embryonic stem cells towards hepatic lineage has been confounded by the complexity and cost of differentiation protocols that employ large quantities of expensive growth factors (GFs). Instead of supplementing culture media with soluble GFs, we investigated cultivation and differentiation of mouse embryonic stem cells (mESCs) on printed arrays of GFs. Hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF) and bone morphogenetic protein (BMP4) were mixed in solution with fibronectin and collagen (I) and then printed onto silane-modified glass slides to form 500 MUm diameter protein spots. mESCs were cultured on top of GF spots for up to 12 days and analyzed by RT-PCR and immunostaining at different time points. The stem cells residing on HGF containing combinations of GFs exhibited requisite features of hepatic differentiation including pronounced loss in pluripotency (Oct4), transient (up and down) expression of endoderm (Sox17) and upregulation of early hepatic markers--albumin and alpha-fetoprotein. The hepatic differentiation was enhanced further by adding hepatic stellate cells to surfaces that already contained mESCs on GF spots. A combination of co-culture with non-parenchymal liver cells and the optimal GF stimulation was found to induce endoderm and hepatic phenotype earlier and to a much greater extent than the GF arrays or micropatterned co-cultures used individually. While this paper investigated hepatic differentiation of mouse ESCs, our findings and stem cell culture approaches are likely to be relevant for human ESC cultivation. Overall, the platform combining printed GF arrays and heterotypic co-cultures will be broadly applicable for identifying the composition of the microenvironment niche for ESC differentiation into various tissue types. PMID- 20832856 TI - Cord coiling, umbilical cord insertion and placental shape in an unselected cohort delivering at term: relationship with common obstetric outcomes. AB - BACKGROUND: The position of the placental cord insertion, its shape and cord coiling are thought to be associated with perinatal outcome. This study derives indices describing the relationship of cord insertion to the placental centre, the shape of the placenta and cord coiling in placentas from unselected term pregnancies. Further, we investigate these indices in pregnancies affected by pre eclampsia (PET), pregnancy induced hypertension (PIH), gestational diabetes mellitus (GDM) and delivery of a small for gestational age (SGA) baby. DESIGN/METHODOLOGY: Eight hundred and sixty one unselected women with singleton pregnancy delivering at 37-42 weeks were prospectively recruited to this study. Placental axes and their relationship with the cord insertion were measured using digital photography and proprietary software. From these, the cord centrality (distance of umbilical cord insertion from the centre) and placental eccentricity (deviation of the placental shape from circular) were derived. The cord coiling index (number of coils in the cord divided by the length of cord in cm) was also calculated from manual measurements. RESULTS: The mean value of cord centrality index was 0.36 (SD = 0.21) and of placental eccentricity 0.49 (SD = 0.17). Left direction of umbilical cord coiling was more common than right (79% vs 16.4%) The mean cord coiling index was 0.20 (SD = 0.09) coils/cm. The indices were constant between 37 and 42 weeks and were no different in the non-affected population compared to women with pre-eclampsia (n = 17), PIH, (n = 27), GDM (n = 38) or delivery of an SGA baby (n = 54). CONCLUSION: The cord centrality index that we derive suggests that the cord insertion is most commonly 'off centre', and eccentricity index that the placental shape is elliptical. Therefore, contrary to widely held belief, the cord does not normally insert centrally nor is the placenta normally round in shape. There is a preponderance of left sided coiling. There was no difference for any of the indices between the non-affected pregnancies and pregnancies affected by pre-eclampsia, PIH, GDM and SGA. PMID- 20832857 TI - DNA methylation contributes to the tissue-specific expression of the rPL-Iv gene. AB - To understand the tissue-specific expression of the rat placental lactogen-I variant (rPL-Iv) gene, we investigated the methylation pattern of the 5'-flanking region of this gene in various rat tissues. We report that the 5'-flanking region of the rPL-Iv gene was hypomethylated in placenta that expressed the gene and hypermethylated in those tissues that did not express the gene. Moreover, the intron region of the rPL-Iv gene was hypomethylated in the placenta, but hypermethylated in the liver, kidney and pituitary. Although there are 5 CpG sites and the density of CpG dinucleotide is lower within 2 kb of the rPL-Iv 5' flanking region, the methylated promoter reporter gene produced strong repression in the transcriptional activity of the gene. In addition, the 5'-flanking and intron regions of the rPL-Iv gene were hypomethylated on day 12 of gestation, and the methylation pattern in the placenta remained unchanged from mid-pregnancy until term. The entire genomic region of the rPL-Iv gene might be hypermethylated in tissues other than the placenta, within which its methylated status repress expression of the placenta-specific rPL-Iv gene. Interestingly, the methylation status of the intron region of the rPL-Iv in proliferating Rcho-1 cells was changed to the unmethylated status on day 8 and 12 of differentiation of Rcho-1 cells. These results demonstrate that demethylation in the rPL-Iv upstream region was induced at an early stage of placental development, and once the 5'-flanking region of the rPL-Iv had been demethylated, its status on the rPL-Iv genomic region was continued during pregnancy. Taken together, these results suggest that DNA methylation is responsible for the silencing of tissue-specific genes in non expressing cells, while defined combinations of trophoblast factors dictate the expression of unmethylated rPL-Iv gene in placenta trophoblast cells. PMID- 20832858 TI - Low-dose Nilotinib can maintain complete molecular remissions in FIP1L1/PDGFRA positive hypereosinophilic syndrome. PMID- 20832859 TI - Coagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy in newly diagnosed multiple myeloma. AB - Patients with multiple myeloma (MM) are at relatively high risk of developing thromboembolic event (TEE), especially during treatment with immunomodulatory agents. We characterized coagulation profiles and evaluate the incidence of TEE associated with the combination therapy of bortezomib-thalidomide-dexamethasone (VTD) in Chinese patients with newly diagnosed MM. The results indicated that the platelet count and platelet aggregation induced by the agonists were decreased after a short exposure to bortezomib in vivo. The incidence of TEE was low in VTD therapy for an overall rate of 3%. We do not recommend routine thromboprophylaxis for VTD therapy in Chinese patients with MM. PMID- 20832860 TI - Early assessment of treatment response in patients with AML using [(18)F]FLT PET imaging. AB - Assessment of treatment response in acute leukemia is routinely performed after therapy via bone marrow biopsy. We investigated the use of positron emission tomography (PET) for early assessment of treatment response in patients with acute myeloid leukemia (AML), using the proliferation marker 3'-deoxy-3' [(18)F]fluoro-l-thymidine (FLT). Eight adult AML patients receiving induction chemotherapy underwent whole-body FLT PET/CT scans acquired at different time points during therapy. Patients who entered complete remission (CR) exhibited significantly lower FLT uptake in bone marrow than those patients with resistant disease (RD). In bone marrow, mean and maximum standardized uptake values were 0.8, 3.6 for CR and 1.6, 11.4 for RD, p<0.001. FLT PET results for CR and RD patients were independent of assessment time point, suggesting that FLT PET scans acquired as early as 2 days after chemotherapy initiation may be predictive of clinical response. This pilot study suggests that FLT PET imaging during induction chemotherapy may serve as an early biomarker of treatment response in AML. PMID- 20832861 TI - Variability of responses in the crucian carp Carassius carassius from two Ukrainian ponds determined by multi-marker approach. AB - The aim of this study was to evaluate the health status of the comparatively tolerant fish Carassius carassius over three seasons in an area characterized by spontaneous human activities. Sites near the springs of a river (site Z) and downstream of a river (site B) in Western Ukraine were selected. According to the centroid grouping analysis, the biochemical and morphological indices allowed the fish to be distinguished according to season more than to site. The level of nuclear abnormalities was low in fish from both sites. However C. carassius inhabiting site B showed a lower metal-binding capacity of MTs in relation to fish from site Z. This was combined with high levels of MT protein (particularly in the liver), and reduced glutathione (GSH) and redox state of GSH (particularly in the gills), which might confer some advantages to fish inhabiting this site. The levels of ethoxyresorufin-O-deethylase, glutathione-S-transferase, cholinesterase and vitellogenin-like proteins indicated significant but intermittent inter-site differences. In summer, oxidative damage due to a high level of lipid peroxidation, and low superoxide dismutase and catalase activities was observed in fish from site B, and in autumn, it was observed in the gills of fish from site Z. The relationship between MT protein levels and antioxidant defense and the lack of a positive relationship between MT levels and their metal binding capacity was confirmed by principal component analysis. PMID- 20832862 TI - An evaluation of volatile compounds released from containers commonly used in circulation of sports beverages. AB - In an effort to identify and quantify important volatile organic compounds (VOCs) released from sports beverage containers commonly used for storage and distribution, three brands of sports beverages with poly ethylene terephthalate (PET) and metal cans were analyzed through headspace-solid phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS). Out of 80 volatile compounds identified from all container types, I-limonene recorded the highest concentration (34.3-118 pmol mol(-1)) along with 12 other VOCs detected most frequently (more than 3 out of all 6 products) such as 2-methyl-6-methylene-2,7 octadiene, alpha-terpineol, decanaldehyde, and p-isopropyltoluene. When each container was filled up with water and analyzed after a long-term storage (49 days), a total of 14 VOCs were detected. According to our analysis, all the VOCs detected from either beverage or container materials were below the safety limits prescribed previously by diverse agencies. However, an extension of these analyses may be necessary for other beverage types, as certain VOCs can be migrated from container materials. PMID- 20832863 TI - Fish embryo toxicity of carbamazepine, diclofenac and metoprolol. AB - Frequently measured pharmaceuticals in environmental samples were tested in fish embryo toxicity (FET) tests with Danio rerio, based on the draft OECD test protocol. In this FET test 2-h-old zebrafish embryos were exposed for 72 h to carbamazepine, diclofenac and metoprolol to observe effects on embryo mortality, gastrulation, somite formation, tail movement and detachment, pigmentation, heartbeat, malformation of head, otoliths and heart, scoliosis, deformity of yolk, and hatching success at 24, 48 and 72 h. We found specific effects on growth retardation above 30.6 mg/l for carbamazepine, on hatching, yolk sac and tail deformation above 1.5mg/l for diclofenac, and on scoliosis and growth retardation above 12.6 mg/l for metoprolol. Scoring all effect parameters, the 72 h-EC(50) values were: for carbamazepine 86.5mg/l, for diclofenac 5.3mg/l and for metoprolol 31.0mg/l (mean measured concentrations). In conclusion, our results for carbamazepine and metoprolol are in agreement with other findings for aquatic toxicity, and also fish embryos responded in much the same way as rat embryos did. For diclofenac, the FET test performs comparably to Early Life Stage testing. PMID- 20832864 TI - Comment on "Long-term prognosis of transient left ventricular ballooning syndrome and cancer". PMID- 20832865 TI - GroEL provides protection against Bacillus anthracis infection in BALB/c mice. AB - Heat shock proteins (Hsps) of the HSP60 and HSP70 family are highly conserved and essential to all living organisms. Hsps are immunodominant in numerous microbial infections and have been investigated for their vaccine potential. We investigated the immunogenicity and protective efficacy of GroEL and DnaK of B. anthracis in murine model. Both Hsps were found to be highly immunogenic with mixed antibody response (both IgG1 and IgG2a), indicating stimulation of both humoral and cell-mediated immunity. Cytokine profile also confirmed robust T-cell response with increase in lymphocyte proliferation. Immunization with GroEL conferred 100% protection to mice against B. anthracis infection whereas DnaK couldn't provide protection. PMID- 20832866 TI - Bipolar disorder patients have similar levels of education but lower socio economic status than the general population. AB - BACKGROUND: There is conflicting evidence regarding the educational level and its importance for social and occupational functioning in bipolar disorder (BD). The aim of this study was to investigate how educational achievement relates to function in BD compared with the general population, and which clinical factors are associated with level of education. METHODS: Hospitalized patients with DSM IV BD (N=257; 69.3% BD I; 25.7% BD II; 5.1 BD NOS; 51.4% females) were consecutively recruited from mental health clinics throughout Norway and compared with a geographically matched reference sample from the general population (N=56,540) on levels of education, marital status, income, and disability benefits. Further analyses of association were carried out using logistic regression analyses. RESULTS: A significantly higher proportion of subjects in the BD group than in the reference group was single, had low income, or was disabled. No between-group difference was found in educational level. In the reference group education was inversely correlated with the risk of being disabled, but no such relationship was found in the BD group. Rapid cycling and recurring depressive episodes were the only clinical characteristics associated with low educational level. LIMITATIONS: Acutely admitted patients might not be representative for milder forms of disease. CONCLUSIONS: Despite similar levels of education, BD patients had lower social and occupational function than the general population, and no association was found between education and disability for BD patients. PMID- 20832867 TI - Atypical pattern of rod electroretinogram modulation by recent light history: a possible biomarker of seasonal affective disorder. AB - Our goal was to challenge both normal controls and patients with seasonal affective disorders (SAD) to various light histories and then measure their retinal response modulation using the electroretinogram (ERG) in both winter and summer. In winter and summer, 11 normal controls and 12 SAD patients were exposed to three different light conditions for 1 h (10,000, 100 and 5 lux) followed by an ERG. Groups showed similar ERG amplitudes in the 100 lux condition. Compared with the 100-lux condition, in controls, the ERG response was significantly increased in the 5-lux condition; in SAD, it was significantly decreased in the 10,000-lux condition. This pattern was present in both seasons. This is the first time a retinal response modulation anomaly has been observed in SAD patients in both the depressed and euthymic states. Retinal response modulation may represent an interesting biomarker of the disease for future research. PMID- 20832868 TI - Neuropsychological functioning in adult bipolar disorder and ADHD patients: a comparative study. AB - Bipolar disorder (BD) and adult attention deficit hyperactivity disorder (ADHD) usually manifest with shared clinical symptoms, proving quite challenging to thoroughly differentiate one from another. Previous research has characterized these two disorders independently, but no study compared both pathologies from a neuropsychological perspective. The aim of this study was to compare the neuropsychological profile of adult ADHD and BD with each other and against a control group, in order to understand the way in which comprehensive cognitive assessment can contribute to their discrimination as distinct clinical entities as well as their differential diagnosis. All groups were successfully matched for age, sex, years of education, and premorbid IQ. Participants were assessed with an extensive neuropsychological battery evaluating multiple domains. Compared to controls, BD patients had a poorer performance on immediate verbal memory tasks. Both clinical groups exhibited significantly lower scores than controls on the recognition phase of verbal and non-verbal memory tasks, as well as on a task of executive functioning with high working memory demand. Noticeably, however, ADHD had significantly better performance than BD on the recognition phase of both the Rey list memory task and the Rey Figure. The better performance of ADHD patients over BD may reflect the crucial role of the executive component on their memory deficits and gives empirical support to further differentiate the neuropsychological profile of BD and adult ADHD patients in clinical practice. PMID- 20832869 TI - The role of non-HLA single nucleotide polymorphisms in multiple sclerosis susceptibility. AB - Multiple sclerosis (MS) is the most common neurological disease of the central nervous system affecting young adults. While the etiology of the disease is still unknown, epidemiological and genetics studies have shown a significant inherited component involved in MS pathogenesis. Single nucleotide polymorphisms (SNPs) associated with MS have been recently evaluated by two main groups of high throughput genotyping analyses: candidate gene approaches and genome-wide association studies (GWAS). Although both types of studies have identified polymorphisms in the human leukocyte antigen (HLA) region as the strongest susceptibility loci for MS, recent investigations have identified a broad spectrum of non-HLA genes prominently associated with MS. This review will focus on recent findings in non-HLA genes as well as their SNPs which have shown high linkage to MS as a genetic-based disorder. Understanding of non-HLA polymorphisms will help elucidate the signalling aberrations involved in MS development and may help to identify novel, personalized approaches to therapy. PMID- 20832870 TI - Blood-brain barrier disruption and enhanced vascular permeability in the multiple sclerosis model EAE. AB - Multiple sclerosis (MS) is a demyelinating disease characterized by the breakdown of the blood-brain barrier (BBB), and accumulation of inflammatory infiltrates in the central nervous system. Tight junctions are specialized cell-cell adhesion structures and critical components of the BBB that have previously been shown to be abnormally distributed in MS tissue. To evaluate whether experimental autoimmune encephalomyelitis (EAE) provides a suitable model for this aspect of MS disease, we examined the expression and distribution of ZO-1 over the course of disease in EAE. We observed a dramatic relocalization of ZO-1 which precedes overt clinical disease and correlates with the sites of inflammatory cell accumulation. Treatment of in vitro cultures of murine brain endothelial cells with components of EAE induction provided similar findings, with relocalization of ZO-1 and increased permeability of endothelial monolayers. BBB disruption in the EAE model appears to parallel disease progression in MS, with direct effects on the cerebrovascular endothelium, making it an ideal tool for future evaluation of tight junction breakdown and repair in MS-like pathology. PMID- 20832871 TI - PFAPA syndrome in children: A meta-analysis on surgical versus medical treatment. AB - OBJECTIVE: To compare the range of medical and surgical therapies for children with PFAPA syndrome. METHODS: A literature search was performed using Medline, Embase, Ovid and Cochrane databases for studies between 1987 and 2010 that compared PFAPA treatment in children (surgical versus medical). Random-effect meta-analytical techniques were conducted for the outcome measures. RESULTS: The use of antibiotics and cimetidine in PFAPA syndrome are ineffective. However, there is evidence that the use of steroids is effective in the resolution of symptoms. Tonsillectomy (+/- adenoidectomy) as a treatment of PFAPA was found to be an effective intervention for resolution of symptoms (P<0.00001). Meta analysis of surgery versus cimetidine and surgery versus antibiotics demonstrated that surgery is a significantly more effective treatment for PFAPA syndrome. A comparison of treatment with steroids or surgery did not show any statistically significant difference, confirming the effectiveness of both therapies for the resolution of PFAPA syndrome (P=0.83). CONCLUSIONS: The most effective non surgical therapy is corticosteroids. However, they do not prevent future fever cycles. The results of this meta-analysis showed that tonsillectomy (+/- adenoidectomy) is the most effective intervention for long-term resolution of PFAPA syndrome symptoms. PMID- 20832873 TI - Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain. AB - The extracellular matrix (ECM) of the central nervous system is well recognized as a migration and diffusion barrier that allows for the trapping and presentation of growth factors to their receptors at the cell surface. Recent data highlight the importance of ECM molecules as synaptic and perisynaptic scaffolds that direct the clustering of neurotransmitter receptors in the postsynaptic compartment and that present barriers to reduce the lateral diffusion of membrane proteins away from synapses. The ECM also contributes to the migration and differentiation of stem cells in the neurogenic niche and organizes the polarized localization of ion channels and transporters at contacts between astrocytic processes and blood vessels. Thus, the ECM contributes to functional compartmentalization in the brain. PMID- 20832872 TI - Parenting and plasticity. AB - As any new parent knows, having a baby provides opportunities for enrichment, learning and stress - experiences known to change the adult brain. Yet surprisingly little is known about the effects of maternal experience, and even less about the effects of paternal experience, on neural circuitry not directly involved in parenting. Here we discuss how caregiving and the accompanying experiential and hormonal changes influence the hippocampus and prefrontal cortex, brain regions involved in cognition and mood regulation. A better understanding of how parenting impacts the brain is likely to help in devising strategies for treating parental depression, a condition that can have serious cognitive and mental health consequences for children. PMID- 20832874 TI - Evaluating the function of calcium antagonist on the Cd-induced stress in sperm of Russian sturgeon, Acipenser gueldenstaedtii. AB - In the current study, the sperm of Russian sturgeon (Acipenser gueldenstaedtii) was used to evaluate the roles of Verapamil (VRP), a calcium channel blocker, against cadmium (Cd)-induced stress. Sturgeon sperm were exposed for 2h at 50MUg/L VRP, 5.0MUg/L Cd, the mixture of 50MUg/L VRP+5.0MUg/L Cd, 50MUg/L Cd and the mixture of 50MUg/L VRP+50MUg/L Cd. After exposure, the sperm motility parameters (motility and velocity), oxidative stress levels (lipid peroxidation [LPO] and carbonyl protein [CP]) and antioxidant enzyme activities (superoxide dismutase [SOD], glutathione reductase [GR], glutathione peroxidase [GPx]) were measured in sturgeon sperm. Compared to the control, Cd-induced stress was apparent as reflected by depressed motility parameters, induced oxidative stress and inhibited antioxidant enzyme activities at both Cd concentrations. In the presence of VRP, Cd-induced stress was reduced in sturgeon sperm, especially all the measured parameters in the sperm exposed at 5.0MUg/L Cd returned to control levels, expect for the sperm motility. The present results indicate that VRP can reduce the Cd-induced stress in sturgeon sperm and suggest that using of sperm in vitro assays may provide a novel and efficient means for evaluating the effects of residual metals in the aquatic environment of sturgeon. PMID- 20832875 TI - Age-related muscle atrophy in the lower extremities and daily physical activity in elderly women. AB - This study investigated the relationship between age-related declines in muscle thickness of the lower extremities and daily physical activity in elderly women. The subjects comprised 20 young women and 17 elderly women residing in a nursing home. Lower limb muscle thickness was measured by B-mode ultrasound with the following 10 muscles; gluteus maximus, gluteus medius, gluteus minimus, psoas major, rectus femoris, vastus lateralis, vastus intermedius, biceps femoris, gastrocnemius and soleus. Daily physical activity was evaluated using life-space assessment (LSA) which assessed the life-space level, degree of independence, and frequency of attainment. Muscle thickness in the gluteus maximus, gluteus medius, gluteus minimus, psoas major, rectus femoris, vastus lateralis, vastus intermedius, biceps femoris and gastrocnemius, but not soleus, was significantly greater in the young group than the elderly group. The greatest rates of age related loss of skeletal muscle mass in the lower limbs showed in the psoas major, while the smallest loss showed in soleus muscle. Only the gluteus medius was significantly associated with the LSA score (r = 0.528, p < 0.05) in elderly women. These results suggest that the reduction in skeletal mass with age is smaller in soleus muscle, and that the age-related decline in gluteus medius muscle is influenced by daily physical activity. PMID- 20832876 TI - Imbalance between pro-angiogenic and anti-angiogenic factors in rheumatic and mixomatous mitral valves. AB - BACKGROUND: A balance between angiogenic and anti-angiogenic factors is critical in tissue development, tissue repair and homeostasis. Aberrant angiogenesis has been implicated in several pathologic conditions, including valvular heart disease. The aim of this study was to ascertain the pathogenetic role of angiogenesis in rheumatic and mixomatous mitral valve diseases. METHODS: Leaflets from mixomatous (n=20) and rheumatic (n=20) mitral valves removed from surgical patients, and normal mitral valve (n=6) obtained at autopsy were collected. Immunohistochemical studies were performed on sequential valve sections, evaluating CD31, CD34, alpha smooth muscle actin (alpha-SMA), vascular endothelial growth factor (VEGF), VEGF receptor-1 (VEGFR1), VEGF receptor-2 (VEGFR-2), and chondromodulin-I (Chm-I). RESULTS: Immunohistochemistry revealed significant differences among groups in CD31 (p=0.001), CD34 (p<0.001), alpha-SMA (p<0.001), VEGF (p<0.001), VEGFR1 (p=0.007), VEGFR2 (p=0.011), and Chm-I (p<0.001) expressions. Rheumatic valves demonstrated a severe up-regulation and down-regulation in pro-angiogenic and anti-angiogenic factors, respectively, compared with mixomatous and normal mitral valves. On the contrary, mixomatous valves showed a significant up-regulation of anti-angiogenic factors with respect to rheumatic and normal valves. CONCLUSIONS: These findings provide evidence that an imbalance between pro-angiogenic and anti-angiogenic factors is implicated in mitral valve disease. Pro-angiogenic factors are up-regulated in rheumatic disease, while anti-angiogenic ones in mixomatous mitral valves. PMID- 20832877 TI - Atorvastatin prevents mesenchymal stem cells from hypoxia and serum-free injury through activating AMP-activated protein kinase. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are the optimal candidate of treating myocardial infarction; however, the lower survival ratio of implanted cell discourages the advantages of this treatment. Recent studies have displayed statins, which exert pleiotropic effects on the cardiovascular system partially through the increase in endothelial nitric oxide synthase (eNOS) activity, could increase the livability of cells under hypoxia and serum-free (H/SF) conditions. AMP-activated protein kinase (AMPK) is the essential part in keeping the balance of energy production and metabolism in various tissues, which is the dominant factor modulating the programmed cell death. Therefore, we hypothesized that atorvastatin could protect MSCs from H/SF injury through AMPK-eNOS pathway. METHODS AND RESULTS: Stained with Annexin V/propidine iodine (PI), we found atorvastatin (0.001 MUM-10 MUM) reduced apoptosis of porcine bone marrow-derived MSCs cultured in H/SF condition; however, this effect was obstructed by compound C, an inhibitor of AMPK. This trend was similar as what bax protein, a pro apoptosis protein, showed analyzed by Western blotting; whereas the bcl-2 protein, an anti-apoptosis protein, increased in atorvastatin treated cells. Meanwhile, MSCs treated with atorvastatin increased phosphorylation of AMPK and eNOS. The uptrend was partially inhibited by compound C. CONCLUSIONS: Atorvastatin can activate AMPK and the phosphorylation of AMPK results in eNOS activated, which provides a novel explanation for the multi-effect of statins on cardiovascular system. PMID- 20832878 TI - The impact of early compared to late morning hours on brachial endothelial function and long-term cardiovascular events in healthy subjects with no apparent coronary heart disease. AB - BACKGROUND: Adverse cardiovascular events (CVE) tend to peak during early morning post-waking hours. Our objective was to explore a possible correlation between early and late morning hours and flow-mediated dilation (FMD), and whether early morning FMD reduction contributes to a circadian pattern of cardiac and vascular vulnerability. METHODS: Brachial FMD was prospectively assessed in 268 consecutive healthy subjects, 169 (63%) men, mean age 53 +/- 11 years, without any concomitant medications. Following an overnight fast, FMD and endothelium independent nitroglycerin-mediated vasodilation were assessed using high resolution ultrasound. All subjects were followed up by phone every 6 months for combined CVE, which included all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions. RESULTS: The cohort was divided into Group A with FMD performed immediately post-waking, between 6:00 and 10:00 am [n=151 (56%) subjects], and Group B after 10:00 am [n=117 (46%) subjects]. Although both groups were comparable regarding baseline brachial artery diameter and the prevalence of risk factors, FMD was significantly lower in Group A compared with Group B subjects (10.4 +/- 3.4% vs. 13.5 +/- 3.5%, p=0.007, respectively). In a mean follow-up of 45 +/- 21 months, the composite CVEs were significantly more common in subjects with <=(n=128) vs. >(n=140) the median FMD of 11.3% [18/128 (14.1%) vs. 1/140 (0.7%), p=0.007, respectively]. Furthermore, FMD independently predicted long-term adverse CVE. CONCLUSIONS: FMD is blunted in early compared to late morning post-waking hours, and independently predicts long-term adverse CVE in healthy subjects with no apparent heart disease. PMID- 20832879 TI - From "one medicine" to "one health" and systemic approaches to health and well being. AB - Faced with complex patterns of global change, the inextricable interconnection of humans, pet animals, livestock and wildlife and their social and ecological environment is evident and requires integrated approaches to human and animal health and their respective social and environmental contexts. The history of integrative thinking of human and animal health is briefly reviewed from early historical times, to the foundation of universities in Europe, up to the beginning of comparative medicine at the end of the 19th century. In the 20th century, Calvin Schwabe coined the concept of "one medicine". It recognises that there is no difference of paradigm between human and veterinary medicine and both disciplines can contribute to the development of each other. Considering a broader approach to health and well-being of societies, the original concept of "one medicine" was extended to "one health" through practical implementations and careful validations in different settings. Given the global health thinking in recent decades, ecosystem approaches to health have emerged. Based on complex ecological thinking that goes beyond humans and animals, these approaches consider inextricable linkages between ecosystems and health, known as "ecosystem health". Despite these integrative conceptual and methodological developments, large portions of human and animal health thinking and actions still remain in separate disciplinary silos. Evidence for added value of a coherent application of "one health" compared to separated sectorial thinking is, however, now growing. Integrative thinking is increasingly being considered in academic curricula, clinical practice, ministries of health and livestock/agriculture and international organizations. Challenges remain, focusing around key questions such as how does "one health" evolve and what are the elements of a modern theory of health? The close interdependence of humans and animals in their social and ecological context relates to the concept of "human-environmental systems", also called "social-ecological systems". The theory and practice of understanding and managing human activities in the context of social-ecological systems has been well-developed by members of The Resilience Alliance and was used extensively in the Millennium Ecosystem Assessment, including its work on human well-being outcomes. This in turn entails systems theory applied to human and animal health. Examples of successful systems approaches to public health show unexpected results. Analogous to "systems biology" which focuses mostly on the interplay of proteins and molecules at a sub-cellular level, a systemic approach to health in social-ecological systems (HSES) is an inter- and trans-disciplinary study of complex interactions in all health-related fields. HSES moves beyond "one health" and "eco-health", expecting to identify emerging properties and determinants of health that may arise from a systemic view ranging across scales from molecules to the ecological and socio-cultural context, as well from the comparison with different disease endemicities and health systems structures. PMID- 20832880 TI - The growth of public health expenditures in OECD countries: do government ideology and electoral motives matter? AB - This paper empirically evaluates whether government ideology and electoral motives influenced the growth of public health expenditures in 18 OECD countries over the 1971-2004 period. The results suggest that incumbents behaved opportunistically and increased the growth of public health expenditures in election years. Government ideology did not have an influence. These findings indicate (1) the importance of public health in policy debates before elections and (2) the political pressure towards re-organizing public health policy platforms especially in times of demographic change. PMID- 20832881 TI - Patently unpatentable: implications of the Myriad court decision on genetic diagnostics. AB - The recent decision in the case Association for Molecular Pathology et al. v. United States Patent and Trademark Office et al. shocked the biotechnology industry. Although the case could be overturned on appeal, it will probably change how gene patents are written. The effects of the decision might be most strongly felt in the short term by clinical laboratories that develop new genetic tests based on single genes. However, evidence suggests that patents are less effective as an incentive to innovate in the field of genetic diagnostics than for pharmaceuticals. In addition, as genomic technologies move towards whole genome analysis, policy arguments for patent protection for single genes become less compelling. It is clear that the intellectual property model challenged by the Myriad decision will have to be replaced if new genetic technologies are to achieve their full potential in promoting 'the progress of science and useful arts'. PMID- 20832882 TI - Developments in nitrile and amide biotransformation processes. AB - Nitrile and amide bioconversions have received attention through their ability to provide a range of commercially important chemicals. These bioconversions are mediated by distinct process strategies. Here, the processes performance is discussed, and the use of whole cells, cell extracts and enzymes as biocatalysts is compared. Additionally, the benefits of biocatalyst reuse through immobilization have been identified and immobilization matrices utilized for these bioconversions evaluated. Exploitation and commercial development will depend on optimization of the process performance and the capacity for scale-up in addition to the biocatalytic potential. High substrate concentrations and biocatalyst stability and reuse through immobilization strategies provide driving forces towards more efficient process kinetics. Membrane immobilization is specifically highlighted as a route to maximize process performance. PMID- 20832883 TI - The role of ethics in science and engineering. AB - It is generally thought that science and engineering should never cross certain ethical lines. The idea connects ethics to science and engineering, but it frames the relationship in a misleading way. Moral notions and practices inevitably influence and are influenced by science and engineering. The important question is how such interactions should take place. Anticipatory ethics is a new approach that integrates ethics into technological development. PMID- 20832884 TI - Esophagus in-field: a new predictor for esophagitis. AB - PURPOSE: To define optimization parameters for limiting esophageal toxicity with concurrent chemoradiation (CRT) for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A retrospective analysis of patients treated with concurrent chemoradiation at the Dana-Farber/Brigham and Women's Hospital Cancer Center was done with IRB approval. All patients were treated with concurrent CRT. All patients underwent 3-D conformal radiotherapy planned with ECLIPSE (Varian, Palo Alto, CA) treatment planning system. Patients had their esophagus contoured in two ways: the entire esophagus (Esoph) and esophagus in-field (Esoph(in)). Together with clinical variables, dose volume metrics including mean dose, V5-V60 of both structures (Esoph and Esoph(in)) were analyzed for correlation with acute esophagitis (>= grade 3) and late esophageal stricture. The analyses and graphics were completed using R (R Development Core Team, 2006). Logistic regression analysis was used to assess the relationships between dosimetric factors and swallowing complications while controlling for non-dosimetric variables. RESULTS: 109 patients were studied between 2000 and 2006. 25% of patients had grade 3 or greater acute esophagitis. 5/109 (5.5%) had late esophageal stricture with a six month actuarial risk of stricture of 6.5% (95% CI=1-11%). Mean dose and V45-V60 for both Esoph and Esoph(in) significantly correlated with development of acute esophagitis. V55 and V60 for both Esoph and Esoph(in) significantly correlated with development of stricture. On Multivariate analysis V55 of the Esoph and Esoph(in) was most predictive of toxicity. Limiting the V55 Esoph(in) to 50% was the best cut-point for acute esophagitis. CONCLUSIONS: In the setting of concurrent CRT, V55 of the Esoph or Esoph(in) is the best predictor of acute esophagitis. PMID- 20832885 TI - Association of TGF-beta1 and XPD polymorphisms with severe acute radiation induced esophageal toxicity in locally advanced lung cancer patients treated with radiotherapy. AB - PURPOSE: Radiation-induced esophageal toxicity (RIET) is a dose-limiting toxicity in lung cancer patients receiving radiotherapy. Accumulating evidence indicates that DNA repair and the cytokine pathways play essential roles in radiation induced diseases. Genetic polymorphisms of genes in these pathways may affect gene function and/or gene expression and lead to different treatment-related esophageal toxicity. MATERIALS AND METHODS: This study investigated the association of 21 polymorphisms in 14 genes, with the occurrence of >= grade 2 acute RIET. Genotypes were analyzed among 213 stage III lung cancer patients receiving radiotherapy. RESULTS: We used Cox proportional hazard model to examine the effects of genotypes on >= grade 2 acute RIET risk and Kaplan-Meier estimator to compare effects of different genotypes on such risk. Multivariate analysis showed that CT or TT genotype of TGF-beta1-509C/T polymorphism was associated with a significantly higher RIET risk (adjusted hazard ratio [HR]=2.47; 95% confidence interval (CI)=1.17-5.24; P=0.018, or HR=3.86; 95% CI=1.50-9.92; P=0.005), respectively, compared with the CC genotype. Moreover, Lys/Gln+Gln/Gln genotypes of XPD Lys751Gln polymorphism were also associated with a significantly decreased RIET risk (adjusted HR=0.55; 95% CI=0.32-0.96; P=0.030). CONCLUSIONS: This report, for the first time, examined the influence of inherited variation in the DNA repair and the cytokine pathways on RIET. PMID- 20832886 TI - Increased biomass production of industrial bakers' yeasts by overexpression of Hap4 gene. AB - HAP4 encodes a transcriptional activator of respiration-related genes and so, redirection from fermentation to respiration flux should give rise to an increase in biomass production in Saccharomyces cerevisiae transformants that overexpress HAP4. With this aim, three bakers' yeasts, that is, V1 used for lean doughs, its 2-deoxy-D-glucose resistant derivative DOG21, and V3 employed for sweet doughs, were transformed with integrative cassettes that carried HAP4 gene under the control of constitutive promoter pTEF2; in addition VTH, DTH and 3TH transformants were selected and characterized. Transformants showed increased expression of HAP4 and respiration-related genes such as QCR7 and QCR8 with regard to parental, and similar expression of SUC2 and MAL12; these genes are relevant in bakers' industry. Invertase (Suc2p) and maltase (Mal12p) activities, growth and sugar consumption rates in laboratory (YPD) or industrial media (MAB) were also comparable in bakers' strains and their transformants, but VTH, DTH and 3TH increased their final biomass production by 9.5, 5.0 and 5.0% respectively as compared to their parentals in MAB. Furthermore, V1 and its transformant VTH had comparable capacity to ferment lean doughs (volume increase rate and final volume) while V3 and its transformant 3TH fermented sweet doughs in a similar manner. Therefore transformants possessed increased biomass yield and appropriate characteristics to be employed in bakers' industry because they lacked drug resistant markers and bacterial DNA, and were genetically stable. PMID- 20832887 TI - The prevalence and risk factors for coeliac disease among children and adolescents with type 1 diabetes mellitus. AB - AIMS: Our aim was to determine in children with T1DM the prevalence of positive antibodies against tissue transglutaminase (anti-tTG IgA) as indices of coeliac disease (CD), as well as its clinical presentation, its determinants and its association with thyroid (anti-TG, anti-TPO) and pancreatic b-cell autoimmunity (anti-GAD). METHODS: The study included 105 children and adolescents with T1DM, aged (mean+/-SD) 12.44+/-4.76 years, with a T1DM duration of 4.41+/-3.70 years. RESULTS: Fifty of our patients (47.6%) were positive for anti-GAD, 9/105 (8.6%) for anti-tTG IgA and 21/105(20%) for anti-thyroid antibodies. The anti-tTG IgA (+) children, in comparison with the rest of the study population, were of younger age (9.31 vs. 12.74 years, p=0.038), shorter diabetes duration (2.16 vs. 4.62 years, p=0.056) and had mild growth impairment (height SDS: -0.55 vs. +0.20, p=0.055). Univariate logistic regression analysis revealed that the presence of anti-tTG IgA (+) was associated with younger age and shorter T1DM duration. Only 5/9 (55.6%) children with high titres of anti-tTG IgA developed mild gastrointestinal symptoms or growth retardation and had histological findings typical of CD. CONCLUSIONS: The prevalence of anti-tTG IgA positivity among T1DM children was 8.6% and its occurrence was associated with younger age and short diabetes duration. Since CD presents in T1DM patients asymptomatically or with non-specific symptoms, periodic autoantibody screening is necessary for its early diagnosis. PMID- 20832888 TI - The eight-item Morisky Medication Adherence Scale MMAS: translation and validation of the Malaysian version. AB - AIMS: To translate and examine the psychometric properties of the Malaysian version of the Morisky Medication Adherence Scale (MMAS) among patients with type 2 diabetes. METHODS: A standard "forward-backward" procedure was used to translate MMAS into Malay language. It was later validated on a convenience sample of 223 type 2 diabetes outpatients between May and September 2009. Reliability was tested for internal consistency. Validity was confirmed using convergent and known group validity. RESULTS: Employing the recommended scoring method, the mean+/-SD of MMAS scores was 6.13+/-1.72. Moderate internal consistency was found (Cronbach's alpha=0.675), the test-retest reliability value was 0.816 (p<0.001). A positive correlation between the eight- and four-item MMAS was found (r=0.792; p<0.01). A significant relationship between MMAS categories and HbA1c categories (chi(2)=20.261; p>=0.001) was found. The MMAS sensitivity and specificity, with positive and negative predictive values were 77.61%, 45.37%, 46.84% and 76.56%, respectively. CONCLUSIONS: The findings of this validation study indicate that the Malaysian version of the MMAS is a reliable and valid measure of medication adherence which can now be used. PMID- 20832889 TI - Osteocalcin and atherosclerosis: a complex relationship. AB - The relationship between OC and atherosclerosis in different clinical situations confirms the interplay that exists among bone cells and vascular system. The recently demonstrated effects of OC on glucose metabolism and visceral fat in healthy subjects and T2DM patients, contribute to the knowledge of the role of OC in the pathogenesis of cardiovascular disease. PMID- 20832890 TI - CD95 is a key mediator of invasion and accelerated outgrowth of mouse colorectal liver metastases following radiofrequency ablation. AB - BACKGROUND & AIMS: Recently, we have shown that micro-metastases, in the hypoxic transition zone surrounding lesions generated by radiofrequency ablation (RFA), display strongly accelerated outgrowth. CD95 is best known for its ability to induce apoptosis but can also promote tumorigenesis in apoptosis-resistant tumor cells. Therefore, we tested whether CD95 signaling plays a role in accelerated outgrowth of colorectal liver metastases following RFA. METHODS: Hypoxia-induced invasion was assessed in three-dimensional EGFP-expressing C26 tumor cell cultures by confocal microscopy. CD95 localization was tested by immunofluorescence. Invasion and outgrowth of liver metastases following RFA were analyzed by post-mortem confocal microscopy and by morphometric assessment of tumor load. Neutralization of CD95L was performed by using antibody MFL4. CD95 was suppressed by lentiviral RNA interference. The role of host CD95L was assessed using gld mice. RESULTS: Micro-metastases in the hypoxic transition zone following RFA displayed a highly invasive phenotype and increased expression of CD95 and CD95L. Hypoxia-induced tumor cell invasion in vitro increased the expression of CD95 and CD95L and induced translocation of CD95 to the invasive front. In vitro invasion, metastasis invasion, and accelerated tumor growth in the transition zone were strongly suppressed by neutralizing CD95L or by suppressing tumor cell CD95. In contrast, metastasis invasion and outgrowth were unaffected in gld mice. CONCLUSIONS: Hypoxia causes autocrine activation of CD95 on colorectal tumor cells, thereby promoting local invasion and accelerated metastasis outgrowth in the hypoxic transition zone following RFA. Further pre clinical work is needed to assess the role of CD95L neutralization, either alone or in combination with chemotherapy, in limiting aggressive recurrence of liver metastases following RFA. PMID- 20832891 TI - Molecular pathology of Wilson's disease: a brief. PMID- 20832892 TI - Two decades of reforms. Appraisal of the financial reforms in the Russian public healthcare sector. AB - This paper reviews the empirical evidence on the outcomes of the financial reforms in the Russian public healthcare sector. A systematic literature review identified 37 relevant publications that presented empirical evidence on changes in quality, equity, efficiency and sustainability in public healthcare provision due to the Russian public healthcare financial reforms. Evidence suggests that there are substantial inter-regional inequalities across income groups both in terms of financing and access to public healthcare services. There are large efficiency differences between regions, along with inter-regional variations in payment and reimbursement mechanisms. Informal and quasi-formal payments deteriorate access to public healthcare services and undermine the overall financing sustainability. The public healthcare sector is still underfinanced, although the implementation of health insurance gave some premises for future increases of efficiency. Overall, the available empirical data are not sufficient for an evidence-based evaluation of the reforms. More studies on the quality, equity, efficiency and sustainability impact of the reforms are needed. Future reforms should focus on the implementation of cost-efficiency and cost-control mechanisms; provide incentives for better allocation and distribution of resources; tackle problems in equity in access and financing; implement a system of quality controls; and stimulate healthy competition between insurance companies. PMID- 20832893 TI - Relationship between catastrophic health expenditures and household incomes and expenditure patterns in South Korea. AB - OBJECTIVES: The compositions of health expenditures by households in South Korea with and without catastrophic health expenditures were compared. Also, relationships between catastrophic health expenditures and household incomes, and between such health expenditures and expenditure patterns were explored. METHODS: Data from the 2006 South Korean Household Income & Expenditure Survey, a representative survey of 90,696 households were analyzed. We used a double-hurdle model to assess each income source and expenditure category. The independent variable was the presence of catastrophic health expenditure. RESULTS: After adjusting for household characteristics, the results showed that earned, business, and property incomes were significantly lower, but transfer and loan incomes were significantly higher in households with catastrophic health expenditures than in those without such health expenditures. All consumption categories, other than health expenditure, were significantly lower in households with catastrophic health expenditures than in those without catastrophic health expenditures. This suggests that households with catastrophic health expenditures faced challenges in offset by the potentially excessive health expenditure and may have been obliged to reduce consumption of other items. CONCLUSIONS: The expansion of insurance coverage and lowering of out-of-pocket rates in the South Korean Health Insurance benefits could be a necessary first step in protecting households from the occurrence of health related economic catastrophes. PMID- 20832894 TI - A multicenter phase II study of belotecan, a new camptothecin analogue, as a second-line therapy in patients with small cell lung cancer. AB - Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan as a second-line therapy in patients with small cell lung cancer (SCLC). Patients who were previously treated for SCLC were entered into the study. Belotecan was given by daily intravenous infusion for five consecutive days, every three weeks. Twenty five patients were enrolled in this study. On an intention-to-treat basis, belotecan induced an overall response rate of 24%, a median overall survival of 9.9 months, a median time to progression of 2.2 months, and a 1-year survival rate of 38.3%. Grade 3/4 neutropenia developed in 88.0% of patients and grade 3/4 thrombocytopenia in 40.0%. Nonhematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerated as a second-line agent in patients with SCLC. PMID- 20832895 TI - Exercise interventions following surgery for non-small cell lung cancer (NSCLC): the need for future randomised controlled trials. PMID- 20832896 TI - A chronic obstructive pulmonary disease related signature in squamous cell lung cancer. AB - The epidemiological relationship between squamous cell lung cancer (SCC) and chronic obstructive pulmonary disease (COPD), both smoking-related diseases, suggests that they have also a genetic basis. We compared 35 SCC patients with and without COPD with whole-genome gene expression profiles of laser microdissected tissue. Validation of differential expression was performed for 25 genes using quantitative (q)RT-PCR. Subsequently, we performed array-based CGH on the same tumor samples. We found that 374 probes were differentially expressed in SCC from patients with and without COPD. Forty-four probes were derived from genes with mitochondrial functions and 34 probes were located on 5q. All these probes showed a lower expression level in SCC from non-COPD patients. For a random selection of 25 mitochondrial and 5q genes, we confirmed the differential expression by qRT-PCR. Loss of 3p, 5q and 9p was observed, via array-CGH, to be more frequent in SCC from non-COPD patients as compared to SCC from COPD patients. Combination of chromosomal aberrations and the location of the differentially expressed genes showed significant association for loss of the 5q31.2-31.3 region and reduced expression of the 5q genes. In conclusion, a more frequent loss of 5q and a low expression of genes located on 5q in SCC tumors of non-COPD patients compared to tumors from COPD patients was identified suggesting that different oncogenetic pathways are operational in patients with and without COPD. PMID- 20832897 TI - Involved field radiotherapy for locally advanced non-small cell lung cancer: isolated mediastinal nodal relapse. AB - The current standard of care for locally advanced inoperable non-small cell lung cancer is high dose radiotherapy with concurrent chemotherapy. We report on a patient with stage IIIA NSCLC treated with concurrent chemoradiotherapy on the primary tumor and the 18-fluorodeoxyglucose positron emission tomography ((18)FDG PET) positive hilar and mediastinal lymph nodes. Six months after treatment this patient developed a single isolated contralateral mediastinal nodal relapse outside but in the proximity of the irradiated target volume. This patient was successfully re-irradiated to this isolated nodal relapse after reconstruction of the dose given to the localisation of this regional recurrence. This case describes the clinical problem of a regional recurrence after involved field radiotherapy that occasionally occurs. A possible explanation for those regional recurrences is an under staging of extension of the disease because the time interval between the staging (18)FDG-PET-CT scan and the start of the irradiation was too long. If the time-interval is 4 weeks or more, we strongly recommend a new (18)FDG-PET-CT because of the possibility of upstaging of the disease. PMID- 20832898 TI - Do consistent individual differences in metabolic rate promote consistent individual differences in behavior? AB - Consistent individual differences (CIDs) in behavior are a widespread phenomenon in animals, but the proximate reasons for them are unresolved. We discuss evidence for the hypothesis that CIDs in energy metabolism, as reflected by resting metabolic rate (RMR), promote CIDs in behavior patterns that either provide net energy (e.g. foraging activity), and/or consume energy (e.g. courtship activity). In doing so, we provide a framework for linking together RMR, behavior, and life-history productivity. Empirical studies suggest that RMR is (a) related to the capacity to generate energy, (b) repeatable, and (c) correlated with behavioral output (e.g. aggressiveness) and productivity (e.g. growth). We conclude by discussing future research directions to clarify linkages between behavior and energy metabolism in this emerging research area. PMID- 20832899 TI - Interactions in the pollen-specific receptor-like kinases-containing signaling network. AB - The pollen-specific receptor-like kinases (PRKs) from Solanum lycopersicum, LePRK1 and LePRK2, are believed to be involved in the regulation of pollen germination and pollen tube growth. They appear to be part of a multimeric complex in which the transmembranic LePRKs presumably have a key position in transducing exogenous signals through the plasma membrane. Here, we focused on extra- and intracellular interactions involving the LePRKs. We show in yeast two hybrid experiments a cross-interaction of putative PRK-ligands, the oligomerization of LePRK2 and a direct contact of LePRKs to activated Rho proteins of plants (ROPs). Moreover, we observed that pollen-specific RopGEFs, which catalyze ROP activation and may be regulated by PRK interaction, are active in vitro while autoinhibition seems to occur in vivo. We suggest that activation of RopGEFs as a checkpoint in PRK signal transduction is a more complex event including further components in planta. Our findings point to some new aspects in PRK-mediated signal transduction implying a LePRK2 complex with different signaling activity and a further direct control of LePRKs by activated ROP. PMID- 20832900 TI - RIP3 and AtKinesin-13A - a novel interaction linking Rho proteins of plants to microtubules. AB - RIP3 belongs to a group of recently identified proteins, classified as the ICR/RIP family whose members were described to interact with Rho proteins of plants (ROPs). Our in vivo and in vitro data demonstrate that RIP3 is a true ROP effector, interacting specifically with the active form of ROPs. We found that RIP3 has properties and cellular roles different from the previously described RIP family member ICR1/RIP1. We show that RIP3 is localized at microtubules and interacts with the kinesin-13 family member AtKinesin-13A, suggesting a role for RIP3 in microtubule reorganization and a possible function in ROP-regulated polar growth. PMID- 20832901 TI - Modifications of Miccoli minimally invasive thyroidectomy for the low-volume surgeon. AB - OBJECTIVE: The objective of the study was to describe our experience with modifications of the Miccoli minimally invasive thyroidectomy. DESIGN: Planned analysis of a prospectively maintained database was undertaken after Institutional Review Board approval. METHODS: Demographic and surgical data were obtained and analyzed with attention to age, sex, pathology, incision lengths, and complications. RESULTS: From a single-surgeon series of 785 consecutive thyroidectomies, 178 patients were identified who underwent an endoscopic minimally invasive thyroidectomy. A series of modifications of the classic Miccoli technique evolved over a period of 4 years and include presurgical factors (patient marking in holding area, intubation with laryngeal EMG tube using videolaryngoscope, rotation of operating table away from anesthesia), intraoperative principles (use of operative loupes, slave monitor, laryngeal nerve monitoring, and novel instrumentation; identification of the medial cleft and ligation of superior pedicle bundle using ultrasonic technology; avoidance of clips), and postoperative techniques (deep extubation, laryngeal endoscopy, outpatient management, and oral calcium supplementation). CONCLUSIONS: A minimally invasive endoscopic thyroidectomy is possible even in a practice with moderate surgical volumes by using several techniques that facilitate the performance of this procedure. A high success rate and low complication rate can be achieved, resulting in improved patient satisfaction. PMID- 20832902 TI - Benign paroxysmal positional vertigo following whiplash injury: a myth or a reality? AB - OBJECTIVE: The aim of the study was to evaluate the true incidence, diagnosis, and treatment of benign paroxysmal positional vertigo (BPPV) arising after whiplash injury and to distinguish this type of posttraumatic vertigo from other types of dizziness complained after trauma. METHODS: This was a retrospective study comprising patients referred to our center after whiplash injury. The patients were evaluated with neurotologic examination including bedside and instrumental tests. A Dizziness Handicap Inventory evaluating the symptoms of patients was submitted before and after treatment and was evaluated. The BPPV patients were separately evaluated from those with cervicogenic vertigo, and a comparison between our data about idiopathic BPPV was done. RESULTS: Eighteen patients of whiplash who had BPPV were evaluated. The mean age was 38.2 years. BPPV was the cause of vertigo in 33.9% of total whiplash patients. In 16 cases, the posterior semicircular canal was involved; the lateral semicircular canal was involved in 2 cases. The instrumental neurotologic assessment did not show any alteration of either vestibulospinal reflexes or dynamic ocular movements. Duration of symptoms before treatment ranged from 3 to 26 days. A total of 55.5% of patients had relief from their symptoms after first repositioning maneuver. The Dizziness Handicap Inventory score improved in all patients treated with repositioning maneuvers, but no difference emerged with idiopathic BPPV data. CONCLUSION: BPPV after whiplash injury could be unveiled with a simple bedside examination of peripheral vestibular system, and a treatment could be done in the same session. The diagnosis of posttraumatic BPPV is not different from the idiopathic form, but the treatment may require more maneuvers to achieve satisfactory results. PMID- 20832903 TI - Chronic rhinosinusitis in the setting of other chronic inflammatory diseases. AB - OBJECTIVES: The objectives of the study were to determine the prevalence of chronic rhinosinusitis (CRS) overall and its 2 phenotypic variants, CRS with and without polyposis (NP), in patients with chronic inflammatory comorbidities including autoimmune disorders, inflammatory bowel disease, and atopic dermatitis. These findings were compared with data in patients with asthma. Patients with hypertension were also used as a reference group to estimate the incidence of CRS in a group with regular medical follow-up. STUDY DESIGN: A retrospective, cross-sectional query of a large tertiary care electronic medical record database was performed. RESULTS: Electronic medical record database prevalence of CRS in patients with hypertension was 4.4%. The prevalence of CRS was 18% in asthma (P < .0001), 7% in atopic dermatitis, 3.5% in inflammatory bowel disease, and ranged from 1.4% to 5.9% in autoimmune disorders. The frequency of CRS patients exhibiting the NP phenotype was similarly low in patients with autoimmune disease and hypertension, but was significantly greater in patients with asthma (P < .0001), inflammatory bowel disease (P = .033), and atopic dermatitis (P = .049), CONCLUSIONS: These findings suggest similar prevalence of overall CRS in patients with autoimmune disease and inflammatory bowel disease, and background rates as estimated by observations in hypertension patients. Inflammatory bowel disease and atopic dermatitis patients with CRS exhibit some skewing toward the NP phenotype, as do asthmatics, where this association is well known. PMID- 20832904 TI - Primary cartilage tympanoplasty: our technique and results. AB - Cartilage has shown to be a promising graft material to close tympanic membrane perforations. However, due to its rigid quality, doubts are raised regarding its sound conduction properties. It has been suggested that acoustic benefit may be obtained by thinning the cartilage. We describe our innovative method for harvesting tragal cartilage from the same endaural incision and also describe preparation of the graft by slicing it. We present our 3-year experience of shield cartilage type 1 tympanoplasty using sliced tragal cartilage-perichondrium composite graft. AIM: The aim of this study was to prove the success rate of our technique of shield cartilage tympanoplasty using sliced tragal cartilage graft in terms of functional and anatomic results. STUDY DESIGN: Retrospective analysis of type 1 cartilage tympanoplasties using sliced tragal cartilage was carried out in MIMER Medical College and Sushrut ENT Hospital during May 2005 to January 2008 with a minimum follow-up of 2 years. METHOD AND MATERIALS: A total of 223 ears were operated by our technique. RESULTS: The overall success rate of our technique was 98.20% in terms of perforation closure and air bone gap closure within 7.06 +/- 3.39 dB. The success rates in the various age group are as follows: 11 to 20 years, 97.67%; 21 to 40 years, 99.12%; and 41 to 60 years, 96.96%. CONCLUSION: Our technique of type 1 cartilage tympanoplasty achieves good anatomic and functional results. PMID- 20832905 TI - Completion thyroidectomy: fact or fiction? PMID- 20832906 TI - 2-Aminoethoxydiphenyl borate administration into the nostril alleviates murine allergic rhinitis. AB - OBJECTIVE: Orai1 is the pore-forming subunit of the Ca(2+) release-activated Ca(2+) channels and plays a key role in the store-operated Ca(2+) entry. However, little is known about the function of this pathway in allergic rhinitis (AR). In this study, we examined whether the intervention of Orai1 pathway was capable of controlling IgE-mediated allergic reactions by using AR mice models. MATERIALS AND METHODS: We used Western blotting and real-time reverse transcription polymerase chain reaction to evaluate Orai1 expression in nasal mucosa and nasal associated lymphoid tissue (NALT) of normal, control, and 2-aminoethoxydiphenyl borate (2-APB)-treated mice. In addition, we analyzed concentrations of nasal lavage fluid leukotriene C4 (LTC4), eosinophil cation protein (ECP), ovalbumin specific IgE, and interleukin-4 (IL-4) through enzyme-linked immunosorbent assay and measured messenger RNA (mRNA) levels of LTC4 synthase and ECP in nasal mucosa, and germline CE transcription and IL-4 mRNA in NALT by using real-time reverse transcription polymerase chain reaction among groups. RESULTS: 2 Aminoethoxydiphenyl borate administration into the nostril reduced numbers of sneezing and nasal rubbing as well as counts of invasive eosinophils in treated mice compared with those in control ones. Furthermore, the administration suppressed Orai1 expression in nasal mucosa and NALT of treated mice compared with that of control ones. Similarly, 2-APB treatment restrained nasal lavage fluid LTC4, ECP, ovalbumin-specific IgE, and IL-4 and their corresponding mRNAs in the previously mentioned tissues of treated mice in comparison with those of control ones. CONCLUSION: Our results indicate that 2-APB treatment effectively alleviates murine AR through pleiotropic activities. PMID- 20832907 TI - Pneumolabyrinth after cochlear implantation in large vestibular aqueduct syndrome: a case report. PMID- 20832908 TI - Prevalence of extramucosal fungal elements in sinonasal polyposis: a mycological and pathologic study in an Egyptian population. AB - OBJECTIVE AND HYPOTHESIS: The objective of the study was to define the true incidence of fungal elements in the nasal and sinus mucous in cases of chronic rhinosinusitis (CRS) with bilateral polyposis compared with normal controls-in an Egyptian African population-via mycological and histologic techniques. STUDY DESIGN: This study was conducted prospectively on 100 patients with the clinical diagnosis of CRS with bilateral nasal polyposis. Fifty volunteers with no history of nasal or paranasal sinus disease served as a control group. RESULTS AND CONCLUSION: The postulated criteria for the diagnosis of allergic fungal sinusitis were present in 92% of CRS with polyposis, suggesting that fungi are involved in the disease process of most CRS patients. PMID- 20832909 TI - Reducing methotrexate errors. PMID- 20832910 TI - Iatrogenesis, frailty, and geriatric syndromes. AB - Older adults are at risk for iatrogenesis, especially if they are frail and have 1 or more geriatric syndromes. Iatrogenic events do not occur only in acute care; in nursing homes they affect 65% of residents annually. It is therefore likely that they are occurring in assisted living communities, though perhaps called by another name. Most commonly, iatrogenesis is an adverse drug event or reaction. Knowing more about the characteristics of frailty and the contributing factors to geriatric syndrome(s), assisted living nurses can be better prepared to monitor, detect, describe, and communicate an iatrogenic event or outcome. This article describes the signs and symptoms of atypical presentation of illness that can mask or are associated with iatrogenesis. Evidence-based assessment instruments are suggested for each geriatric syndrome. PMID- 20832911 TI - Effects of age on navigation strategy. AB - Age differences in navigation strategies have been demonstrated in animals, with aged animals more likely to prefer an egocentric (route) strategy and younger animals more likely to prefer an allocentric (place) strategy. Using a novel virtual Y-maze strategy assessment (vYSA), the present study demonstrated substantial age differences in strategy preference in humans. Older adults overwhelmingly preferred an egocentric strategy, while younger adults were equally distributed between egocentric and allocentric preference. A preference for allocentric strategy on the Y-maze strategy assessment was found to benefit performance on an independent assessment (virtual Morris water task) only in younger adults. These results establish baseline age differences in spatial strategies and suggest this may impact performance on other spatial navigation assessments. The results are interpreted within the framework of age differences in hippocampal structure and function. PMID- 20832913 TI - Putting age-associated changes in neurogenesis in their place. AB - Individual differences in cognitive aging are, in some cases, correlated with changes in molecular markers at the neuronal level. However, the use of simple correlations to analyze data across multiple age groups has a number of potential pitfalls. When young animals differ from aged animals on both of the dependent variables being assessed with a correlation analysis, the age difference often accounts for the detection of a relationship between the 2 measures. When the age groups are analyzed discretely, the data may exhibit a completely different trend, as suggested in a recent Commentary. In addition to reconsidering the interpretation of recently published data on the relationship between age-related deficits in cognition and hippocampal neurogenesis, the demands of the task should be taken into account when evaluating the contributions of newly-generated neurons. PMID- 20832914 TI - [Influenza, flu, "Spanish flu", "swine flu" and other controversies in the naming of viruses: the "politically incorrect" side of virology]. PMID- 20832915 TI - Structural modification of a specific antimicrobial lead against Helicobacter pylori discovered from traditional Chinese medicine and a structure-activity relationship study. AB - Psoralen (1a) was found to be a specific and potent antimicrobial lead against Helicobacter pylori (H. pylori) from a traditional Chinese medicine (TCM) in the bioassay directed isolation. A series of structurally diverse analogues of 1a were thus designed and synthesized to improve the antimicrobial potency, some of which showed more potent activities than the lead compound (1a) against H. pylori. Among them, compound 25a is 16-fold stronger (MIC = 0.39 MUg/mL) than 1a (MIC = 6.25 MUg/mL), and is even potent than the positive control metronidazole (MIC = 0.50 MUg/mL). The in vitro antimicrobial activities against H. pylori of these structurally diverse analogues based on the scaffold of 1a have also led to an outline of structure-activity relationship. PMID- 20832916 TI - Structure activity relationship studies of imidazo[1,2-a]pyrazine derivatives against cancer cell lines. AB - Designed novel imidazo[1,2-a]pyrazine based inhibitors, synthesized by condensing alpha-aminopyrazines with alpha-halocarbonyl compounds followed by electrophilic substitutions. Cytotoxic effects on four cancer cell lines evaluated. Based on preliminary data, imidazo[1,2-a]pyrazine template redesigned to improve activity. PMID- 20832917 TI - The preparation of bi-functional organophosphine oxides as potential antitumor agents. AB - Following our previously reported pyridinyl phosphine oxides as antitumor agents, we targeted the commercially available C(2)-axial chiral organophosphine ligand catalysts, such as 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) 1 and 2,2',6,6'-tetramethoxy-4,4'-bis(diphenylphosphino)-3,3'-bipyridine (P-Phos) 2 as a convenient source for producing organophosphine oxides as antitumor leads. Their corresponding chiral and racemic bi-phosphine oxides 3 and 4 can be obtained easily through a simple oxidation step with hydrogen peroxide, and their antitumor activities towards human hepatocellular carcinoma Hep3B cell line were reported. We found out that compound 3 shows stronger antitumor activity than that of 4, where axial chirality cannot improve their activity. Further athymic nude mice Hep3B xenograft model demonstrates the attractive in vivo antitumor potential of 3. PMID- 20832918 TI - [Hepatic granulomas]. AB - Liver granulomas are histopathologically defined and associated with various liver and non-livers disorders. There are five main causes of liver granulomatosis: primary biliary cirrhosis, tuberculosis, sarcoidosis, B and C viral hepatitis, and drug related. In the other cases, not associated with an underlying systemic granulomatous disease, a systematic diagnostic approach should be used to identify less common etiologies. After a careful diagnostic work-up, a long-term follow-up of patients with undetermined liver granulomatosis is mandatory as it may be a presenting feature of liver lymphoma. PMID- 20832919 TI - [New modalities of renin-angiotensin system inhibition: Renin inhibitors and active immunization against angiotensin II]. PMID- 20832920 TI - In-field radon measurement in water: a novel approach. AB - This paper presents a novel approach of measuring radon in-water in the field by inserting a MEDUSA gamma-ray detector into a 210 L or 1000 L container. The experimental measurements include investigating the effect of ambient background gamma-rays on in-field radon measurement, calibrating the detector efficiency using several amounts of KCl salt dissolved in tap water, and measuring radon in borehole water. The results showed that there is fairly good agreement between the field and laboratory measurements of radon in water, based on measurements with Marinelli beakers on a HPGe detector. The MDA of the method is 0.5 Bq L-1 radon in-water. PMID- 20832921 TI - Factor structure of the Prenatal Distress Questionnaire. AB - OBJECTIVE: to explore the factor structure of the Prenatal Distress Questionnaire (PDQ), which aims to assess worries and concerns related to pregnancy. DESIGN: cross-sectional survey of 263 low-risk pregnant women attending a regional maternity centre in Northern Ireland. Participants completed the PDQ and a series of questions on socio-demographic characteristics between 22 and 28 weeks of gestation. Exploratory factor analysis was conducted using principal axis factoring with promax rotation. FINDINGS: analysis of individual questionnaire items showed that items exploring concerns about healthy diet, irritating physical symptoms, and anxiety about labour and birth evoked the highest reported stress in low-risk pregnant women. Exploratory factor analysis of all 12 items making up the PDQ identified three factors: concerns about birth and the baby, concerns about weight/body image, and concerns about emotions and relationships. CONCLUSIONS: the PDQ is a short, easy-to-complete questionnaire that has good face, concurrent validity and internal consistency. In this study, the three factors identified from the 12 items making up the PDQ are in keeping with factors found in other pregnancy-specific measures of stress and anxiety, and with data from descriptive studies. Current research suggests that PDQ has the potential to identify and allow for clinical intervention that might prevent preterm labour and postnatal complications associated with pregnancy-specific stress. IMPLICATIONS FOR PRACTICE: awareness of what makes women anxious can help midwives to target specific aspects of pregnancy-specific stress and to introduce relevant support. PMID- 20832922 TI - The emerging evidence for Narrative Exposure Therapy: a review. AB - Individuals who have experienced multiple traumatic events over long periods as a result of war, conflict and organised violence, may represent a unique group amongst PTSD patients in terms of psychological and neurobiological sequelae. Narrative Exposure Therapy (NET) is a short-term therapy for individuals who have PTSD symptoms as a result of these types of traumatic experiences. Originally developed for use in low-income countries, it has since been used to treat asylum seekers and refugees in high-income settings. The treatment involves emotional exposure to the memories of traumatic events and the reorganisation of these memories into a coherent chronological narrative. This review of all the currently available literature investigates the effectiveness of NET in treatment trials of adults and also of KIDNET, an adapted version for children. Results from treatment trials in adults have demonstrated the superiority of NET in reducing PTSD symptoms compared with other therapeutic approaches. Most trials demonstrated that further improvements had been made at follow-up suggesting sustained change. Treatment trials of KIDNET have shown its effectiveness in reducing PTSD amongst children. Emerging evidence suggests that NET is an effective treatment for PTSD in individuals who have been traumatised by conflict and organised violence, even in settings that remain volatile and insecure. PMID- 20832923 TI - Moral distress experienced by health care professionals who provide home-based palliative care. AB - Health care providers regularly encounter situations of moral conflict and distress in their practice. Moral distress may result in unfavorable outcomes for both health care providers and those in their care. The purpose of this study was to examine the experience of moral distress from a broad range of health care occupations that provide home-based palliative care as the initial step of addressing the issue. A critical incident approach was used in qualitative interviews to elicit the experiences on moral distress from 18 health care providers drawn from five home visiting organizations in south central Ontario, Canada. Most participants described at least two critical incidents in their interview generating a total of 47 critical incidents. Analyses of the critical incidents revealed 11 issues that triggered moral distress which clustered into three themes, (a) the role of informal caregivers, b) challenging clinical situations and (c) service delivery issues. The findings suggest that the training and practice environments for health care providers need to be designed to recognize the moral challenges related to day-to-day practice. PMID- 20832924 TI - Mediating processes in bereavement: the role of rumination, threatening grief interpretations, and deliberate grief avoidance. AB - Limited research so far has examined coping processes that mediate between risk factors and bereavement outcome. Knowledge of these pathways is important, since it helps establish why some bereaved persons are more vulnerable than others and suggests possibilities for intervention. In this international longitudinal study, three potentially critical mediators, namely rumination, threatening grief interpretations and deliberate grief avoidance, were examined in relationship to previously established risk factors (e.g., expectedness of the death, attachment style) and four major outcome variables (grief, depressive symptoms, emotional loneliness and positive mood). Individuals who were recently bereaved (maximum 3 years) filled in questionnaires at three points in time. Results showed that rumination and--to a somewhat lesser extent--threatening grief interpretations played an important role in mediating the effects of various risk factors on outcomes. However, the contribution of these two mediators was dependent on the specific risk factor and outcome measure under consideration. For example, whereas the effect of neuroticism on grief was mediated by both processes (to the extent of 73%), the effect of neuroticism on positive mood was only mediated by rumination and to a smaller extent (23%). A few risk factors, such as current financial situation and spirituality, were not mediated by either coping strategy. Implications of these findings are discussed. PMID- 20832925 TI - Acute caffeine consumption enhances the executive control of visual attention in habitual consumers. AB - Recent work suggests that a dose of 200-400 mg caffeine can enhance both vigilance and the executive control of visual attention in individuals with low caffeine consumption profiles. The present study seeks to determine whether individuals with relatively high caffeine consumption profiles would show similar advantages. To this end, we examined the effects of four caffeine doses (0 mg, 100 mg, 200 mg, 400 mg) on low- and high-level visual attention in individuals with high consumption profiles (n=36), in a double-blind study using a repeated measures design. Results from the Attention Network Test indicated that caffeine enhanced both vigilance and the executive control of visual attention, but only at the highest administered dose (400 mg). We demonstrate that in habitual consumers high doses of caffeine can produce beneficial changes in visual attention. These results carry implications for the theorized interactions between caffeine, adenosine and dopamine in brain regions mediating visual attention. PMID- 20832926 TI - [Geographical variations in the prevalence of COPD in Spain: relationship to smoking, death rates and other determining factors]. AB - BACKGROUND: The EPI-SCAN study (Epidemiologic Study of COPD in Spain), conducted from May 2006 to July 2007, determined that the prevalence of COPD in Spain according to the GOLD criteria was 10.2% of the 40 to 80 years population. Little is known about the current geographical variation of COPD in Spain. OBJECTIVES: We studied the prevalence of COPD, its under-diagnosis and under-treatment, smoking and mortality in the eleven areas participating in EPI-SCAN. COPD was defined as a post-bronchodilator FEV1/FVC ratio <0.70 or as the lower limit of normal (LLN). RESULTS: The ratio of prevalences of COPD among the EPI-SCAN areas was 2.7-fold, with a peak in Asturias (16.9%) and a minimum in Burgos (6.2 %) (P<0.05). The prevalence of COPD according to LLN was 5.6% (95% CI 4.9-6.4) and the ratio of COPD prevalence using LLN was 3.1-fold, but with a peak in Madrid-La Princesa (10.1%) and a minimum in Burgos (3.2%) (P<0.05). The ranking of prevalences of COPD was not maintained in both sexes or age groups in each area. Variations in under-diagnosis (58.6% to 72.8%) and under-treatment by areas (24.1% to 72.5%) were substantial (P<0.05). The prevalence of smokers and former smokers, and cumulative exposure as measured by pack-years, and the age structure of each of the areas did not explain much of the variability by geographic areas. Nor is there any relation with mortality rates published by Autonomous Communities. CONCLUSION: There are significant variations in the distribution of COPD in Spain, either in prevalence or in under-diagnosis and under-treatment. PMID- 20832927 TI - [Relationship between lower respiratory tract infections in the first year of life and the development of asthma and wheezing in children]. AB - INTRODUCTION: There is limited knowledge on the relationship between lower respiratory tract infections (LRTI) and asthma and wheezing during infancy, as there are few studies with prospective design, birth cohort and in non selected population. The objectives of the present study were to determine the prevalence of asthma and recurrent wheezing in childhood and to analyse the relationship between LTRI during the first year of life and the development of asthma and/or wheezing in childhood. PATIENTS AND METHODS: Prospective birth cohort study conducted in the Hospital del Mar (Barcelona). We recruited 487 children, followed up from the pregnancy to the 6th year of life. As outcomes we studied: the presence of asthma and wheezing. As independent variables we studied: LTRI occurring during the first year of life, and some covariables including, among others: prematurity, birth weight, maternal history of asthma and atopy, breastfeeding, prenatal exposure to tobacco. RESULTS: The asthma prevalence at 6 year of age was 9.3%. The variables associated with the development of asthma were LTRI, prematurity, atopic mother and formula breastfeeding. LTRI during the first year of life were also related with early recurrent wheezing and persistent wheezing. CONCLUSIONS: Our results confirm that LTRI during the first year of life are related to the diagnosis of asthma and with the clinical phenotypes of early wheezing and persistent wheezing. These results are in accordance with the concept that LTRI occurring during a critical period of development, as are the first years of life, have an important role on in the later development of asthma and recurrent wheezing. PMID- 20832928 TI - [Community acquired pneumonia. New guidelines of the Spanish Society of Chest Diseases and Thoracic Surgery (SEPAR)]. PMID- 20832929 TI - Levator defects are associated with prolapse after pelvic floor surgery. AB - OBJECTIVES: Pelvic organ prolapse recurrence after pelvic floor surgery is a common problem. This study was designed to assess whether avulsion defects of the puborectalis muscle are associated with recurrent pelvic organ prolapse and its symptoms. STUDY DESIGN: We retrospectively evaluated 737 data sets of patients who had presented to a tertiary urogynaecology unit with symptoms of pelvic floor dysfunction. All underwent a standardised interview including a surgical history, a clinical examination and 4D pelvic floor ultrasound. Avulsion injury was diagnosed on tomographic ultrasound. The prevalence of pelvic organ prolapse and its symptoms was calculated for patients with previous hysterectomy and previous anti-incontinence and prolapse surgery, with and without confirmed avulsion injury. RESULTS: Out of 737 patients, 248 (33.6%) reported a previous hysterectomy, 165 patients (22.4%) had undergone incontinence or prolapse procedures, 106 (14.4%) reported a previous anterior colporrhaphy, and 45 patients (6.1%) had undergone a colposuspension in the past. In all four groups avulsion injury was significantly associated with objective prolapse (relative risks between 2.3 and 3.3, odds ratios between 3.4 and 6). Symptoms of prolapse were significantly associated with avulsion injury post hysterectomy, incontinence or prolapse procedures and after anterior colporrhaphy. CONCLUSIONS: Avulsion injury of the puborectalis muscle is associated with prolapse in women with previous pelvic floor surgery. PMID- 20832930 TI - WHIPPET: a novel tool for prioritizing invasive plant populations for regional eradication. AB - Large geographic areas can have numerous incipient invasive plant populations that necessitate eradication. However, resources are often deficient to address every infestation. Within the United States, weed lists (either state-level or smaller unit) generally guide the prioritization of eradication of each listed species uniformly across the focus region. This strategy has several limitations that can compromise overall effectiveness, which include spending limited resources on 1) low impact populations, 2) difficult to access populations, or 3) missing high impact populations of low priority species. Therefore, we developed a novel science-based, transparent, analytical ranking tool to prioritize weed populations, instead of species, for eradication and tested it on a group of noxious weeds in California. For outreach purposes, we named the tool WHIPPET (Weed Heuristics: Invasive Population Prioritization for Eradication Tool). Using the Analytic Hierarchy Process that included expert opinion, we developed three major criteria, four sub-criteria, and four sub-sub-criteria, taking into account both species and population characteristics. Subject matter experts weighted and scored these criteria to assess the relative impact, potential spread, and feasibility of eradication (major criteria) for 100 total populations of 19 species. Species-wide population scores indicated that conspecific populations do not necessarily group together in the final ranked output. Thus, priority lists based solely on species-level characteristics are less effective compared to a blended prioritization based on both species attributes and individual population and site parameters. WHIPPET should facilitate a more efficacious decision-making process allocating limited resources to target invasive plant infestations with the greatest predicted impacts to the region under consideration. PMID- 20832931 TI - A framework for sustainable invasive species management: Environmental, social, and economic objectives. AB - Applying the concept of sustainability to invasive species management (ISM) is challenging but necessary, given the increasing rates of invasion and the high costs of invasion impacts and control. To be sustainable, ISM must address environmental, social, and economic factors (or "pillars") that influence the causes, impacts, and control of invasive species across multiple spatial and temporal scales. Although these pillars are generally acknowledged, their implementation is often limited by insufficient control options and significant economic and political constraints. In this paper, we outline specific objectives in each of these three "pillars" that, if incorporated into a management plan, will improve the plan's likelihood of sustainability. We then examine three case studies that illustrate how these objectives can be effectively implemented. Each pillar reinforces the others, such that the inclusion of even a few of the outlined objectives will lead to more effective management that achieves ecological goals, while generating social support and long-term funding to maintain projects to completion. We encourage agency directors and policy-makers to consider sustainability principles when developing funding schemes, management agendas, and policy. PMID- 20832932 TI - Is LESS/NOTES really more? PMID- 20832933 TI - Scale-up of BDD anode system for electrochemical oxidation of phenol simulated wastewater in continuous mode. AB - Scale-up of boron-doped diamond (BDD) anode system is significant to the practical application of electrochemical oxidation in bio-refractory wastewater treatment. In this study, the performance of a smaller BDD anode (24 cm(2)) system in continuous mode electrochemical oxidation of phenol simulated wastewater was first investigated and well described by the response surface methodology (RSM). Furthermore, the RSM was extended to examine the scale-up feasibility of BDD anode systems with similar configurations. It was demonstrated that both COD degradation efficiency and specific energy consumption could be expected at the same level even as the system was enlarged over 100 times, which implied that BDD anode system could be successfully scaled up through controlling the same retention time, current density, initial COD, and conductivity conditions. Based on this study, a larger BDD anode (2904 cm(2)) system was constructed and systematic measurements were made on its performance in electrochemical oxidation of phenol simulated wastewater. Very good agreement was found between measured and predicted results by RSM. At the optimized conditions, the larger BDD anode system could easily reduce the COD of phenol simulated wastewater from 633 mg L(-1) to 145 mg L(-1) (<150 mg L(-1), National Discharge Standard of China) during 80 min with specific energy consumption only 31 kWh kgCOD(-1). PMID- 20832934 TI - Using heavy metals to detect the human disturbances spatial scale on Chinese Yellow Sea coasts with an integrated analysis. AB - An integrated approach involving landuse patterns obtained from landuse data and heavy metal contents of the top 10 cm surface soil layer samplings was proposed to detect the characteristic spatial scale of non-point source human disturbances on the Yellow Sea coast in China. Circular plots, with radii of 200, 500, 1000, 1500, and 2000 m were set up to represent five spatial scales. We proposed a human impact index (HII) using the landuse data to model the human disturbances. Multivariate statistics of the 10 heavy metals, Cr, Co, Fe, Mn, Ni, V, Zn, Cu, Ti, and Sr, were done. Finally curve estimation between HII and heavy metals was also done. The results showed that: (1) multivariate statistics, including principal component analysis, cluster analysis and the 1-tailed Pearson correlation analysis showing that elements Cr, Cu, Fe, Mn, Ni, V, Zn, and Co could be interpreted as anthropogenic elements and (2) of all the heavy metals showing statistical significance from the curve estimation, in general, the 1000 m scale HII had the best modeling result. We concluded that the characteristic spatial scale of human disturbances on Yellow Sea coast might be 1000 m. PMID- 20832935 TI - Selective recovery of copper, nickel and zinc from ashes produced from Saccharomyces cerevisiae contaminated biomass used in the treatment of real electroplating effluents. AB - The aim of this work was to seek an environmentally friendly process for recycling metals from biomass-sludges generated in the treatment of industrial wastewaters. This work proposes a hybrid process for selective recovery of copper, nickel and zinc from contaminated biomass of Saccharomyces cerevisiae, used in the bioremediation of electroplating effluents. The developed separation scheme comprised five consecutive steps: (1) incineration of the contaminated biomass; (2) microwave acid (HCl) digestion of the ashes; (3) recovery of copper from the acid solution by electrolysis at controlled potential; (4) recycle of nickel, as nickel hydroxide, by alcalinization of the previous solution at pH 14; (5) recovery of zinc, as zinc hydroxide, by adjusting the pH of the previous solution at 10. This integrated approach allowed recovering each metal with high yielder (>99% for all metals) and purity (99.9%, 92% and 99.4% for copper, nickel and zinc, respectively). The purity of the metals recovered allows selling them in the market or being recycled in the electroplating process without waste generation. PMID- 20832936 TI - Decolorization and biodegradation of Reactive Blue 13 by Proteus mirabilis LAG. AB - The decolorization and biodegradation of Reactive Blue 13 (RB13), a sulphonated reactive azo dye, was achieved under static anoxic condition with a bacterial strain identified as Proteus mirabilis LAG, which was isolated from a municipal dump site soil near Lagos, Nigeria. This strain decolorized RB13 (100mg/l) within 5h. The formation of aromatic amine prior to mineralization was supported by Fourier transform infrared spectrometry (FTIR), which revealed the disappearance of certain peaks, particularly those of the aromatic C-H bending at 600-800 cm( 1). Gas chromatography-mass spectrophotometry (GCMS) analysis of the dye metabolite showed the presence of sodium-2(2-formyl-2-hydroxyvinyl) benzoate, with a tropylium cation as its base peak, this suggested the breakage of naphthalene rings in RB13. The detection of azoreductase and laccase activities suggested the enzymatic reduction of azo bonds prior to mineralization. In addition, phytotoxicity studies indicated the detoxification of RB13 to non-toxic degradation products by this strain of P. mirabilis LAG. PMID- 20832937 TI - Single and binary adsorption of reactive dyes from aqueous solutions onto clinoptilolite. AB - The adsorption of Reactive Blue 21 (RB21) and Reactive Red 195 (RR195) onto clinoptilolite type natural zeolite (ZEC) has been investigated at 298.15K. The uptake of single and binary reactive dyes from aqueous solutions has been determined by UV-vis spectroscopy. Two mono-component (RB21 and RR195) and binary component (RB21 with RR195, and RR195 with RB21), isotherms were determined. The mono-component Langmuir isotherm model was applied to experimental data and the isotherm constants were calculated for RB21 and RR195 dyes. The monolayer coverage capacities of clinoptilolite for RB21 and RR195 dyes in single solution system were found as 9.652 and 3.186 mg/g, respectively. Equilibrium adsorption for binary systems was analyzed by using the extended Langmuir models. The rate of kinetic processes of single and binary dye systems onto clinoptilolite was described by using two kinetics adsorption models. The pseudo-second-order model was the best choice among the kinetic models to describe the adsorption behaviour of single and binary dyes onto clinoptilolite. PMID- 20832938 TI - Adsorption of etheramine on kaolinite: a cheap alternative for the treatment of mining effluents. AB - The results of laboratory experiments aimed at determining the influence of physicochemical parameters on the adsorption of etheramine (adsorbate) on white, pink and yellow kaolinites (adsorbent) are presented. The adsorption of etheramine was favoured at pH 10.0 under conditions where the initial concentration of etheramine was 200 mg l(-1) and the ratio of adsorbent to volume of etheramine solution was 1:100 g ml(-1). Equilibrium adsorption was attained within 30 min and the efficiencies of removal of etheramine by white, pink and yellow kaolinite were 77%, 80% and 69%, respectively. The adsorption isotherms of the kaolinites were determined under optimum conditions and with adsorbate in the concentration range of 0-4000 mg l(-1). The amounts of etheramine adsorbed per unit mass of adsorbent were 33.03, 34.32 and 23.11 mg g(-1) for white, pink and yellow kaolinites, respectively. The adsorption of etheramine on kaolinites was better fitted to the Langmuir rather than the Freundlich isotherm, and could be explained by a pseudo-second-order kinetic model. It is concluded that kaolinites offer significant potential in the treatment of effluents originating from the processing of lower grade iron ores by froth flotation. PMID- 20832939 TI - Rapid and simple low density miniaturized homogeneous liquid-liquid extraction and gas chromatography/mass spectrometric determination of pesticide residues in sediment. AB - A simple, rapid and environmentally friendly analytical methodology is developed for extraction of pesticides (diazinon, chlorpyrifos and trifluralin) from sediment samples based on a technique called low density miniaturized homogenous liquid-liquid extraction (LDMHLLE) prior gas chromatography mass spectrometry determination. The method based on homogeneous liquid-liquid extraction with methanol containing n-hexane as a solvent of lower density than water (n-hexane). After addition of water, n-hexane solvent immediately forms a distinct water immiscible phase at the top of the vial, which can be easily separated and injected to the GC/MS instrument for quantification. Acquisition was performed in the selected ion monitoring mode. The limits of detection were estimated for the individual pesticides as 3S(b) (three times of the standard deviation of baseline) of the measured chromatogram for pesticides. The proposed method is very fast, simple, and sensitive without any need for stirring and centrifugation and applied to real sediment samples, successfully. PMID- 20832940 TI - Micellar-enhanced ultrafiltration of zinc in synthetic wastewater using spiral wound membrane. AB - In the present study, micellar-enhanced ultrafiltration (MEUF) was used to remove Zn(2+) from synthetic wastewater by the spiral-wound ultrafiltration membrane. The effects of different operating conditions on the separation performance of membrane were investigated. It was found that the transmembrane pressure has the largest influence on the permeate flux, but it has negligible effect on the rejection coefficient. Furthermore, sodium dodecyl sulfate (SDS) feed concentrations, SDS-Brij35 mixed micelles concentration and solution pH have a major influence on the rejection coefficient and negative effect on the permeate flux due to concentration polarization layer formation. Also, the results showed that the permeate flux and removal efficiency of zinc by anionic surfactant (SDS) MEUF depends on the ligand-to-Zn(2+) ratio extremely. In general, MEUF by spiral wound ultrafiltration membrane has good rejection of Zn(2+)under different operating conditions, as the rejections were higher than 98.0%. However, application of single anionic surfactant at relatively low concentration is more efficient than mixed surfactants and MEUF was not practical when the wastewater is intensively acidic. PMID- 20832941 TI - Self-reported somatosensory symptoms of neuropathic pain in fibromyalgia and chronic widespread pain correlate with tender point count and pressure-pain thresholds. AB - Widespread pain and pain hypersensitivity are the hallmark of fibromyalgia, a complex pain condition linked to central sensitization. In this study the painDETECT questionnaire (PDQ), validated to identify neuropathic pain and based on pain quality items, was applied in a cross-sectional sample of patients with chronic widespread pain (CWP). The aims of the study were to assess the patient reported sensory neuropathic symptoms by PDQ and to correlate these with tender point (TP) count and pressure-pain thresholds. Eighty-one patients (75 F, 6 M) with CWP (ACR-criteria) filled in the PDQ. Manual TP examination was conducted according to ACR guidelines. Computerized cuff pressure algometry was used for the assessment of pressure-pain detection thresholds (PDT, unit: kPa) and pressure-pain tolerance thresholds (PTT, unit: kPa). Mean TP count was 14.32 (range: 2-18), mean PDQ score 22.75 (range: 5-37). Mean PDT was 8.8 kPa (range: 2 36) and mean PTT 30.9 kPa (range: 4-85). Deep-tissue hyperalgesia was the predominant somatosensory symptom reported in 83%, but other neuropathic symptoms were also frequent, e.g. burning 51% and prickling 47%. Statistically significant correlations were found between PDQ score and TP count: r=0.35 (p<0.01), and PDQ score and PDT: r=0.45 (p<0.01), and PTT: r=0.43 (p<0.01). The study indicates that pain in CWP has neuropathic features, and that the presence and number of tender points are associated with neuropathic pain symptoms. A high mean PDQ score was found to correlate with TP count and pressure-pain thresholds. The PDQ may become a useful tool assisting in the identification of central sensitization in patients with CWP and in the future diagnostic assessment fibromyalgia. PMID- 20832942 TI - Sensitized peripheral nociception in experimental diabetes of the rat. AB - Painful neuropathy is a common complication of diabetes. Particularly in the early stage of diabetic neuropathy, patients are characterized by burning feet, hyperalgesia to heat, and mechanical stimuli, as if residual nociceptors were sensitized. Such symptoms are barely explained by common pathophysiological concepts of diabetic neuropathy. Diabetes was induced in Wistar rats by streptozotocin (STZ). After 4 weeks behavioral testing (Plantar test, Randall Selitto) was conducted. Basal and stimulated release of calcitonin gene-related peptide (CGRP), Substance P (SP) and prostaglandin E(2) (PGE(2)) from isolated skin and sciatic nerve were assessed by enzyme immunoassays. Electrophysiological properties of identified nociceptors under hyperglycemic, hypoxic, and acidotic conditions were investigated using the skin-nerve preparation. The diabetic rats showed hyperalgesia to heat and pressure stimulation. The basal CGRP/SP release was reduced, but chemical stimulation with bradykinin induced greater release of SP, CGRP and PGE(2) than in control animals. In contrast, capsaicin-stimulated CGRP release was reduced in sciatic nerves. Hypoxia per se lowered von Frey thresholds of most C-nociceptors to half. Hyperglycemic hypoxia induced ongoing discharge in all diabetic but not control C-fibers which was further enhanced under acidosis. Sensory and neurosecretory nociceptor functions are sensitized in diabetes. Diabetic C-fibers show exaggerated sensitivity to hyperglycemic hypoxia with and without additional acidosis, conditions that are thought to mimic ischemic episodes in diabetic nerves. Ongoing C-fiber discharge is known to induce spinal sensitization. Together with altered receptor and ion channel expressions this may contribute to painful episodes in diabetic neuropathy. PMID- 20832943 TI - Dropouts and sub-groups--statistics can help but not cure. PMID- 20832944 TI - First report of infection of Lutzomyia longipalpis by Leishmania (Leishmania) infantum from a naturally infected cat of Brazil. AB - In recent years, cases of feline visceral leishmaniasis (FVL) have been described in different countries. In urban areas, domestic cats are suggested as possible alternative reservoirs of Leishmania (L.) infantum, the causal agent of visceral leishmaniasis (VL). This paper reports the first case of infection of Lutzomyia longipalpis by L. infantum of a naturally infected cat from Brazil through xenodiagnosis. The presence of a cat with FVL and its infectivity to the natural vector in Belo Horizonte city, an endemic area of VL in Brazil, suggests the need for further studies to determine the rate of occurrence of FVL among domestic cats and the infectivity ratio of L. longipalpis in endemic areas, and what is the role of these animals in the epidemiology of the disease. PMID- 20832946 TI - Association of a common mineralocorticoid receptor gene polymorphism with salivary cortisol in healthy adults. AB - A common polymorphism of the mineralocorticoid receptors (MR) gene has been associated with cortisol levels after dexamethasone. However, if and how this MR gene variant affects basal cortisol secretion throughout the day is unknown. The aim of our study was to examine the association between the MR gene polymorphism 2G/C (rs2070951) and salivary cortisol measured at four time points during the day in the Stress, Atherosclerosis, and ECG Study (STRATEGY). We recruited healthy adults from the general population (n=133, distributed equally across four age groups, 30-70 years). Salivary cortisol was assessed at 0800, 1200, 1600 and 2200 h. We found a significant effect of genotype indicating that homozygous G allele carriers had higher overall salivary cortisol levels (F=4.5, p=0.01). Furthermore, we found a significant time * group interaction indicating that the group effect was predominantly driven by higher 0800 h salivary cortisol levels in G/G homozygotes (F=2.9, p=0.02). Participants homozygous for the G allele also had greater area under the curve (AUC) cortisol secretion compared to C allele carriers (F=6.4, p=0.01). Our findings suggest that being homozygous for the G allele of the MR gene polymorphism -2G/G is associated with higher cortisol levels in healthy adults, especially in the morning during peak cortisol secretion. This polymorphism may contribute to the interindividual variability in stress responsiveness and might be involved in stress-related disorders. PMID- 20832947 TI - Social anxiety and marijuana-related problems: the role of social avoidance. AB - BACKGROUND: People with elevated social anxiety seem vulnerable to marijuana related impairment. Yet little work has examined core facets of social anxiety that may be especially related to marijuana-related problems. METHOD: The present study examined the relationships between current (past three months) marijuana related problems and two aspects of social anxiety (fear in social situations and social avoidance) among current (N=102) marijuana users. RESULTS: Although both social fear and social avoidance were significantly correlated with marijuana related problems, only social avoidance was uniquely related to marijuana problems (after controlling for social fear, sex, negative affect, alcohol problems, and marijuana use frequency). Sex moderated the relationship between social avoidance and marijuana-related problems such that men with greater social avoidance exhibited the greatest severity of marijuana-related problems. CONCLUSIONS: Avoidance of social situations appears robustly related to marijuana related problems. This finding has important implications for theoretical models that can inform treatment of co-occurring social anxiety and marijuana problems. PMID- 20832948 TI - Differential diagnosis of acute rejection and chronic cyclosporine nephropathy after rat renal transplantation by detection of endothelial microparticles (EMP). AB - Endothelial microparticles (EMP) are small vesicles smaller than 1.0MUm, released from endothelial cells (EC) during their activation and (or) apoptosis. The assay of the level of elevated EMP is a new approach to evaluate the dysfunction of endothelial cell. EMP can be classified into several types according to their membrane molecular, and the levels of various types of EMP may be different. As the most cost-effective immunodepressant, cyclosporine A (CsA) has been used widely in organ transplantation. But its dose is hard to control, under medication may cause the acute rejection (AR) and overdose may cause chronic cyclosporine nephropathy (CCN). The cyclosporine A (CsA) caused CCN and the AR caused renal injury after renal transplantation are both vascular diseases related with endothelial dysfunction, and up to now, there is still no effective method to distinguish the two kinds of diseases. Owing to distinct pathogenesis of the two kinds of vascular diseases, the level of each type of EMP originated from vascular endothelial cells may be different. We hypothesize that maybe we can distinguish them by detecting the different levels of some types of EMP which is also related with vascular disease, and we propose to prove our hypothesis through animal experiment. If our hypothesis is proved, it will be more helpful for clinicians to adjust the dose of CsA promptly according to the differential diagnosis of the two kinds of diseases. PMID- 20832949 TI - Endotoxaemia in the pathogenesis of cytopenias in liver cirrhosis. Could oral antibiotics raise blood counts? AB - Cytopenias are frequently observed in patients with cirrhosis and are associated with increased morbidity. In particular, thrombocytopenia can impact routine care of patients with cirrhosis by potentially postponing or interfering with diagnostic and therapeutic procedures including liver biopsy and medically indicated or elective surgery. The pathogenesis of cytopenias in cirrhosis remains largely unknown. Historically, the concept of hypersplenism has long been associated with the cirrhosis-related hematological disorders but was never proven. On the other hand, intestinal bacterial overgrowth and altered gut permeability in cirrhotic patients lead to increased translocation of bacteria and endotoxin into the portal circulation. The impaired phagocytic function of the reticuloendothelial system together with the portosystemic shunting allow endotoxin to reach the systemic circulation and high concentrations of circulating endotoxin are found in cirrhotic patients even with no clinical evidence of infection and correlate with the severity of liver disease. Endotoxin activates monocytes and promotes the release of proinflammatory cytokines. Indeed, serum levels of interleukin-1, interleukin-6, tumor necrosis factor alpha, and interferon-gamma are elevated in patients with cirrhosis in proportion to the severity of liver disease. Endotoxaemia stimulates the vascular production of nitric oxide (NO) directly or indirectly via the cytokine cascade, and correlates with serum NO metabolite levels in cirrhosis. Several lines of evidence strongly suggest that endotoxaemia may reduce peripheral blood counts either directly or through the release of cytokines and NO. Previous studies in experimental models of cirrhosis and cirrhotic patients have demonstrated that long-term administration of oral antibiotics such as trimethoprim sulfamethoxazole, norfloxacin, and rifaximin can reduce bacterial translocation and circulating levels of endotoxin, TNF-alpha, IL-6, and NO. We hypothesize that endotoxaemia plays a pivotal role in the pathogenesis of cytopenias in cirrhosis and that intestinal decontamination could raise peripheral blood counts by the suppression of endotoxaemia and the inhibition of cytokine and NO production. PMID- 20832950 TI - How to assess osteoporosis management efficacy? PMID- 20832951 TI - Is neuromuscular relaxation of rocuronium prolonged in patients with obstructive jaundice? AB - Rocuronium is an aminosteroid non-depolarizing neuromuscular relaxant, which is metabolized in the liver and excreted through bile. The duration of neuromuscular blockade of rocuronium at equipotent bolus dose may be prolonged and variable in patients with liver and kidney failure. However, very few studies have been reported its pharmacodynamics in patients with obstructive jaundice. We propose that the effect of rocuronium is prolonged in patients with obstructive jaundice, and a caution should be taken in monitoring postoperative residual neuromuscular blockade. PMID- 20832952 TI - Application of high pressure processing to reduce verotoxigenic E. coli in two types of dry-fermented sausage. AB - The effect of high pressure processing (HPP) on the survival of verotoxigenic Escherichia coli (VTEC) in two types of Norwegian type dry-fermented sausages was studied. Two different types of recipes for each sausage type were produced. The sausage batter was inoculated with 6.8 log(10) CFU/g of VTEC O103:H25. After fermentation, drying and maturation, slices of finished sausages were vacuum packed and subjected to two treatment regimes of HPP. One group was treated at 600 MPa for 10 min and another at three cycles of 600 MPa for 200 s per cycle. A generalized linear model split by recipe type showed that these two HPP treatments on standard recipe sausages reduced E. coli by 2.9 log(10) CFU/g and 3.3 log(10) CFU/g, respectively. In the recipe with higher levels of dextrose, sodium chloride and sodium nitrite E. coli reduction was 2.7 log(10) CFU/g in both treatments. The data show that HPP has a potential to make the sausages safer and also that the effect depends somewhat on recipe. PMID- 20832953 TI - [Prenatal diagnosis of hyperechogenic kidneys: A study of 17 cases]. AB - OBJECTIVES: To evaluate the prenatal diagnosis and the prognostic value of ultrasound in case of fetal hyperechogenic kidneys. PATIENTS AND METHODS: Seventeen prenatally diagnosed cases of hyperechogenic kidneys were retrospectively reviewed at the University Hospital of Lille from 1997 to 2008. The clinical and ultrasound data were compared to the postnatal follow-up and the long-term prognosis. RESULTS: The aetiologies are nine recessive polycystic kidney diseases, three dominant, two Bardet-Biedl syndromes and three cases of transient renal hyperechogenicity. No renal ultrasonographic criterion is specific of aetiology. Five pregnancies were terminated. We observed one neonatal death and 11 survivors (median follow-up: 30months) including two infants with hypertension. All oligohydramnios (n=8) were associated with poor prenatal outcomes (terminations of pregnancy, neonatal death or hypertension) compared to the other nine with normal amniotic fluid volume (nine children symptom-free). Kidneys less or equal to +4 S.D. and a normal amniotic fluid volume were associated with a good prognosis (n=7, seven symptom-free). CONCLUSION: The fetal kidneys characteristics on prenatal ultrasound fail to provide an accurate etiological diagnosis. Only congenital defects and family history adjust the aetiology. Amniotic fluid volume and fetal kidney size are the best prenatal predictors of outcome. PMID- 20832954 TI - Cochrane systematic reviews in the field of addiction: what's there and what should be. AB - The Cochrane Drugs and Alcohol Group aims to produce, update, and disseminate systematic reviews on the prevention, treatment, and rehabilitation of problematic drug and alcohol use. The objective of the present paper was to summarize the main characteristics of the published systematic reviews in the field of drug and alcohol dependence, in terms of the topics covered, methods used to produce the reviews, and available evidence. By January 2010, the Group had published 52 reviews with 694 primary studies included out of 2059 studies considered for inclusion. Of these publications, 44% were published in 12 journals, including Drug and Alcohol Dependence (11%) with the highest number of publications, and 68% were conducted in North America. The majority of included studies (90%) were randomized controlled trials. Evaluating their methodological quality, we found that allocation concealment methods were not properly described in the majority of studies (18% adequate, 73% unclear, 9% inadequate). The percentage of interventions shown to be beneficial varied according to the substance considered: 42% for opioids, 37% for alcohol, 14% for psychostimulants, 7% for polydrugs, and 33% for prevention. Furthermore, 75% of the reviews provided specific information on further research needs. Cochrane reviews provide information on the most effective treatments, particularly in the area of opioid and alcohol dependence, and help clarify areas for further research. PMID- 20832955 TI - Menstrual cycle phase at quit date and smoking abstinence at 6 weeks in an open label trial of bupropion. AB - BACKGROUND: Quit attempts may have different outcomes based on menstrual cycle phase on quit day. This is the first preliminary study examining whether smoking cessation outcomes vary by menstrual cycle phase of quit date in women receiving a 6-week open trial of sustained release (SR) bupropion. METHODS: Thirty-three treatment-seeking premenopausal women were studied. Abstinence outcomes were compared for women quitting during the luteal versus follicular phase. RESULTS: Women receiving bupropion SR whose self-selected quit date occurred in the luteal phase had significantly higher rates of point prevalence abstinence during the final week of a 6-week post-quit treatment period than women quitting in the follicular phase (62.5% versus 29.4%; p<0.05). A similar, but non-significant, pattern of findings was demonstrated for continuous abstinence during the treatment phase and for point prevalence abstinence at 3-month follow-up. CONCLUSIONS: Women receiving bupropion SR were significantly more likely to be abstinent at treatment completion if quitting occurred during the luteal phase. This is consistent with recent findings of outcome related to cycle phase at quit date in the absence of pharmacotherapy, and differs from findings utilizing nicotine replacement. Results add to emerging data suggesting that smoking cessation interventions with varying mechanisms of action may result in different outcomes for premenopausal women based on gonadal hormones at quit date. PMID- 20832956 TI - The recent prevalence of bovine leukemia virus (BLV) infection among Japanese cattle. AB - A seroepidemiological survey of bovine leukemia virus (BLV) infection was conducted in Japan in 2007 using an enzyme-linked immunosorbent assay (ELISA) and an agar gel immunodiffusion (AGID) test. A total of 5420 cattle (dairy, 3966; breeding beef, 797; fattening beef, 657) from 209 farms in seven prefectures in Japan were tested. The overall prevalence of BLV infection was 28.6%. The prevalence of BLV infection in dairy cattle (34.7%) was higher than for both fattening beef cattle (7.9%) and breeding beef cattle (16.3%). Age-specific prevalence showed that BLV prevalence increased with age in all types of cattle and was notably different between dairy and beef cattle under 1 year of age. Among 207 farms, 141 herds (68.1%) had one or more positive animals. The proportion of these positive farms was significantly higher among dairy farms (79.1%) than among beef breeding farms (39.5%) and beef fattening farms (51.9%) (P<0.001). Dairy farms (40.5%) also showed a significantly higher within-herd prevalence than beef breeding (27.4%) and fattening (14.9%) farms (P=0.001). This study indicated that BLV is more widely spread in dairy cattle than in beef breeding cattle in Japan. Given the prevalence of BLV infection in dairy and beef cattle was 8- and 1.7-fold higher, respectively, than rates previously found in 1980-1982, BLV appears to be spreading particularly among the dairy cattle population during the last two decades. Further investigation is required to determine the risk factors necessary to control BLV infection that take into account the different farming practices that exist between dairy and beef sectors. PMID- 20832957 TI - Evaluation of genes involved in prostaglandin action in equine endometrium during estrous cycle and early pregnancy. AB - The aim was to evaluate expression of genes involved in the biosynthesis of prostaglandins (PTG), Prostaglandin H Synthase-1 (PTGS1) and PTGS2, PGF synthase (PTGFS), and PGE synthase (PTGES), PGF receptor (PTGFR), PGE receptors (PTGER2 and PTGER4), prostaglandin transporter (SLCO2A1) and hydroxyprostaglandin dehydrogenase-15 (HPGD). Endometrial biopsies were obtained from mares on day of ovulation (d0, n=4), late diestrus (LD, n=4), early luteolysis (EL, n=4) and after luteolysis (AL, n=4) during the cycle. Stages of the cycle were confirmed by plasma progesterone concentrations measured daily and ultrasound examinations. Biopsies were also taken on days 14 (P14; n=4), 15 (P15, n=4), 18 (P18, n=4) and 22 (P22; n=4) of pregnancy. Relative mRNA expressions were quantified using real time RT-PCR. A mixed model was fitted on the normalized data and least significant difference test (alpha=0.05) was employed. Expression of PTGS1 mRNA was low throughout the estrous cycle and early days of pregnancy, but upregulated on P18 and P22. PTGS2 expression was increased on EL, but it was suppressed by pregnancy on P15, P18, and P22. PTGFS expression was upregulated in both cyclic and pregnant mares compared to d0 and its level was the highest on LD. PTGFR expression was transiently increased on LD and EL and was suppressed during early pregnancy. Both PTGES and PTGER2 expressions were increased on LD, EL, and early pregnancy, but were decreased after the luteolysis in cyclic mares as they remained high on P18 and P22. PTGER4 expression did not change throughout the cycle and early pregnancy. Levels of HPGD and SLCO2A1 were significantly increased only on P22. In conclusion, PTGS2 expression increases around the time of luteolysis and concurrent upregulation of PTGFS and PTGES indicates that equine endometrium has increased capability of PTG production around the time of luteolysis. However, pregnancy reduces PTGS2 expression, but maintains the high levels of PTGES during early pregnancy along with PTGER2 while PTGFR expression was suppressed. These findings suggest that possible luteotrophic action of PGE2 is required in early equine pregnancy. PTGS1 is only upregulated later in the early pregnancy suggesting that it is not involved in luteolysis, but could be the main PTGS enzyme at this time during early pregnancy. An increase in HPGD and SLCO2A1 levels on P22 indicates a tight regulation of PTG action by pregnancy. PMID- 20832958 TI - Forensic aspects of the 2009 Victorian Bushfires Disaster. AB - The 2009 Victorian Bushfires Disaster started on a record hot day in February 2009 and resulted in over 300 separate fires with a death toll of 173 and over 400 presentations to hospital emergency departments. This occurred a little over a week after a heat wave in which over 400 people were thought to have died prematurely in southeastern Australia. The Victorian Institute of Forensic Medicine in collaboration with the police force and the State Coroner's Office and over 100 colleagues from all over Australia, Indonesia, New Zealand and Japan implemented a DVI process based on Interpol guidelines to identify the deceased persons. CT scanning was conducted on all remains collected and played a pivotal role in the identification processes in conjunction with experts in pathology, anthropology, forensic odontology and molecular biology. This paper outlines the scale of the disaster and the work, from a forensic medical perspective, to identify the deceased. PMID- 20832959 TI - Choice of approach for revision surgery in cases with recurring chronic otitis media with cholesteatoma after the canal wall up procedure. AB - OBJECTIVES: Cholesteatoma has a tendency to recur if not properly eradicated. This study sought to investigate and compare the outcome of the canal wall up (CWU) versus the canal wall down (CWD) procedure for recurrent cholesteatoma after initial canal preserving surgery. METHODS: Between January 1990 and August 2007, 42 patients who underwent a revision tympanomastoidectomy for a recurred cholesteatoma were analyzed retrospectively. All patients initially underwent the canal wall up procedure. Recurrence rates, audiologic outcomes, and the extent of recurrent/residual cholesteatoma were investigated, and the revision surgical methods were compared. RESULTS: The mean follow-up duration was 10 years (range, 13 months-15.6 years). The CWD procedure was performed in 29 (69%) patients with a recurred cholesteatoma and the CWU procedure in 13 (31%) as a first revision procedure. CWD surgeries were performed in more severe cases. A second revision surgery was required in five (12%) patients. Extended cholesteatoma recurrences were observed even among cases with a lower disease stage at the time of primary surgery. The second recurrence rate was significantly higher in the CWU group than the CWD group (p=0.026). The 8-year disease-free follow-up rate in the CWD group was significantly higher than the CWU group (p=0.002). Postoperative AB gap closure was significantly better in the CWU group than CWD group (p=0.001). CONCLUSION: The CWD procedure is a safer and more successful method for controlling recurrent cholesteatoma. Thus, surgeons should not be hesitant to perform the CWD procedures for revision cases. PMID- 20832960 TI - Release of proteolytic activity following reduction in therapeutic human serum albumin containing products: detection with a new neoepitope endopeptidase immunoassay. AB - Botulinum type A toxin (BoNT/A) is defined by its specific endopeptidase cleavage of SNAP25 between Gln(197) and Arg(198) under reducing conditions. The neurotoxin is widely used for therapeutic or cosmetic purposes, but should not contain other toxin serotypes or unwanted protease activities. Using a neoepitope endopeptidase immunoassay, additional cleavage between Arg(198) and Ala(199) was detected with a range of therapeutic BoNT/A products confirming an earlier report of an unidentified proteolytic component. By developing the assay and making it insensitive to BoNT/C1, any activity due to the type C1 toxin was excluded. Therapeutic preparations consist of ng quantities of toxin protein which are typically stabilised by 0.125-30 mg of HSA. An excellent correlation (R(2)=0.993) between HSA content per vial and measured activity was obtained within the therapeutic BoNT/A products tested. No activity was detected in any of the non albumin formulated preparations, thereby identifying HSA as the source of the unknown protease for the first time. To investigate the cause of this activity, either as an intrinsic molecular activity of albumin or due to an albumin associated purification contaminant, further studies on a variety of commercial plasma-derived HSA products or recombinant HSA materials free from potential plasma contaminants were carried out. The measured proteolytic levels were highly consistent amongst preparations, and could all be partially inhibited by the presence of zinc and blocked by PKSI-527 and aprotinin. By contrast, the data did not support the role of plasmin, kallikrein, trypsin, alpha(2)-antiplasmin plasmin complexes or HSA purification contaminants, PKA (prekallikrein activator) or kallikrein-like activity. Taken together, these findings indicate a new intrinsic proteolytic activity of the albumin molecule revealed under reducing conditions as the source of the unexpected Arg-Ala cleaving activity. PMID- 20832961 TI - Measurement of lumefantrine and its metabolite in plasma by high performance liquid chromatography with ultraviolet detection. AB - Artemether-lumefantrine (ARM-LUM) has in recent years become the first-line treatment for uncomplicated malaria in many Sub-Saharan African countries. Vigorous monitoring of the therapeutic efficacy of this treatment is needed. This requires high-quality studies following standard protocols; ideally, such studies should incorporate measurement of drug levels in the study patients to exclude the possibility that insufficient drug levels explain an observed treatment failure. Several methods for measuring lumefantrine (LUM) in plasma by HPLC are available; however, several of these methods have some limitations in terms of high costs and limited feasibility arising from large required sample volumes and demanding sample preparation. Therefore, we set out to develop a simpler reversed phase high performance liquid chromatography (RP-HPLC) method based on UV detection for simultaneous measurement of LUM and its major metabolite the desbutyl LUM (DL) in plasma. Halofantrine was used as an internal standard. Liquid-liquid extraction of samples was carried out using hexane-ethyl acetate (70:30, v/v). Chromatographic separation was carried out on a Synergi Polar-RP column (250 mm * 300 mm, particle size 4 MUm). The mobile phase consisted of acetonitrile-0.1M ammonium acetate buffer adjusted to pH 4.9 (85:15%, v/v). Absorbance of the compounds was monitored at 335 nm using a reference wavelength of 360 nm. Absolute extraction recovery for LUM and DL were 88% and 90%, respectively. Inter- and intraday coefficients of variation for LUM and DL were <= 10%. The lower limits of quantification for LUM and DL were 12.5 and 6.5 ng/ml, respectively. After validation, the methodology was transferred to a local laboratory in Tanga Tanzania and samples from a small subset of malaria patients were analysed for LUM. The method appears to be applicable in settings with limited facilities. PMID- 20832962 TI - Development of liquid chromatographic enantiomer separation methods and validation for the estimation of (R)-enantiomer in eslicarbazepine acetate. AB - Chiral separation method development was carried out for eslicarbazepine acetate and its (R)-enantiomer on diverse chiral stationary phases. Better chiral selectivity was observed on cellulose tris-(3,5-dichlorophenylcarbamate) immobilized column (Chiralpak IC-3). Under polar organic mode (POM), with 100% acetonitrile as mobile phase and 0.5 ml/min flow, a resolution close to three was achieved. With normal phase (NP) mobile phase consisting dichloromethane:ethanol (90:10, v/v) and 1.0 ml/min flow, a resolution close to six was achieved. Detection was done by UV at 220 and 240 nm respectively. Both the methods were found to be robust and were validated with respect to robustness, precision, linearity, limit of detection, limit of quantification and accuracy. The proposed methods are suitable for the accurate estimation of (R)-enantiomer in bulk drug samples up to 0.1% when a 1mg/ml analyte test solution is chromatographed. PMID- 20832963 TI - Inhibitory effects of ticagrelor compared with clopidogrel on platelet function in patients with acute coronary syndromes: the PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy. AB - OBJECTIVES: The PLATO (PLATelet inhibition and patient Outcomes) PLATELET substudy aimed to compare the antiplatelet effects of clopidogrel and ticagrelor in patients with acute coronary syndromes. BACKGROUND: The PLATO study demonstrated superiority of ticagrelor over clopidogrel in the prevention of ischemic events in patients with acute coronary syndromes. METHODS: Patients were randomized to receive either clopidogrel (300- to 600-mg loading dose [LD], 75 mg/day) or ticagrelor (180-mg LD, 90 mg twice daily). The effects of maintenance therapy were studied in 69 patients pre- and 2 to 4 h post-dose after at least 28 days. The LD effect was studied in 24 clopidogrel-naive patients. Light transmittance aggregometry (adenosine diphosphate 5 to 20 MUM), VerifyNow P2Y12, and VASP phosphorylation assays were performed. RESULTS: During maintenance therapy, ticagrelor achieved greater suppression of platelet reactivity compared with clopidogrel. The mean maximum light transmittance aggregometry responses (adenosine diphosphate 20 MUM) post-maintenance dose were 44+/-15% for clopidogrel and 28+/-10% for ticagrelor (p<0.001). High platelet reactivity was seen more frequently in the clopidogrel group. Proton pump inhibitor use was associated with higher platelet reactivity with clopidogrel but not ticagrelor. The ticagrelor LD also achieved greater inhibition of platelet aggregation compared with the clopidogrel LD. CONCLUSIONS: Ticagrelor achieves greater antiplatelet effect than clopidogrel in patients with acute coronary syndromes, both in the first hours of treatment and during maintenance therapy. PMID- 20832964 TI - Penetrating cardiac injury from a wooden knitting needle. PMID- 20832965 TI - Torsion of epiploic appendages: an overlooked cause of acute abdomen. PMID- 20832966 TI - Constipation in a 7-year-old boy: congenital band causing a strangulated small bowel and pulseless electrical activity. AB - BACKGROUND: Constipation in pediatric patients is a common diagnosis in the emergency department (ED) and may occasionally arise from a significant underlying illness. OBJECTIVE: To discuss a rare cause of constipation that led to a strangulated small bowel and cardiac arrest. CASE REPORT: A 7-year-old boy presented in pulseless electrical activity. The patient had been seen in the ED 2 days prior with the complaint of abdominal pain, which was diagnosed as constipation. The boy had emigrated from Mexico 18 months earlier. The patient was resuscitated in the ED and taken emergently to the operating room. During surgery he was discovered to have a congenital abdominal adhesive band that led to a strangulated small bowel. He suffered subsequent multi-organ failure, including hypoxic ischemic encephalopathy, and was hospitalized for 5 months. One month after discharge he was improving and being followed by multiple providers. CONCLUSION: Congenital adhesive bands, although rare, may be life-threatening anomalies. We present this case to increase awareness of this condition among emergency physicians. PMID- 20832967 TI - Droperidol analgesia for opioid-tolerant patients. AB - BACKGROUND: Patients with acute and chronic pain syndromes such as migraine headache, fibromyalgia, and sickle cell disease represent a significant portion of emergency department (ED) visits. Certain patients may have tolerance to opioid analgesics and often require large doses and prolonged time in the ED to achieve satisfactory pain mitigation. Droperidol is a unique drug that has been successfully used not only as an analgesic adjuvant for the past 30 years, but also for treatment of nausea/vomiting, psychosis, agitation, sedation, and vertigo. OBJECTIVES: In this review, we examine the evidence supporting the use of droperidol for analgesia, adverse side effects, and controversial United States (US) Food and Drug Administration (FDA) black box warning. DISCUSSION: Droperidol has myriad pharmacologic properties that may explain its efficacy as an analgesic, including: dopamine D2 antagonist, dose-dependent GABA agonist/antagonist, alpha2 adrenoreceptor agonist, serotonin antagonist, histamine antagonist, muscarinic and nicotinic cholinergic antagonist, anticholinesterase activity, sodium channel blockade similar to lidocaine, and MU opiate receptor potentiation. CONCLUSION: Droperidol is an important adjuvant for patients who are tolerant to opioid analgesics. The FDA black box warning does not apply to doses below 2.5 mg. PMID- 20832968 TI - Testicle ischemia resulting from an inguinal hernia. AB - BACKGROUND: Scrotal pain in the emergency department (ED) should be evaluated rapidly for sources that may cause irreversible testicular ischemia. OBJECTIVES: This case report discusses a patient presenting with a large inguinal hernia causing testicle ischemia. CASE REPORT: A 48-year-old man with a 1-year history of a large right-sided indirect inguinal hernia was transferred to the ED from the ultrasound laboratory after the patient experienced acute onset of severe right-sided testicular pain. The radiologist urgently called the attending emergency physician to notify him of ultrasound findings that showed compromised vascular flow to the right testicle. Urology and General Surgery were consulted immediately. The patient was placed in a supine position and reduction of the large hernia was attempted. After approximately 15 min of manual pressure, the herniated bowel was reduced back into the abdominal cavity and the patient experienced immediate relief of his symptoms. CONCLUSIONS: Scrotal ultrasound was repeated, and vascular flow to his right testicle was found to be re-established. This case highlights a rare presentation of acute onset of testicular ischemia caused by vascular compression from a large indirect inguinal hernia in an adult male. PMID- 20832969 TI - Communication in the context of long-distance family caregiving: an integrated review and practical applications. AB - OBJECTIVE: Understanding how geographic distance impacts how individuals communicatively negotiate family caregiving is important for a number of reasons. Though long-distance caregiving (LDC) is a growing phenomenon with serious relational and health implications, this topic has yet to be approached from a communication perspective. In this review, LDC is thus considered as a communication context to offer caregiving scholars practical applications for contributing to this emerging research area. METHODS: Review of the literature from 1999 to 2009 that studied aspects of distance caregiving communication obtained through searching Academic Search Premier, EBSCO, Communication and Mass Media Complete, PsycArticles, PsycInfo, PubMed/Medline, and Health Source: Nursing/Academic Edition online databases. RESULTS: Eight published original research studies were included in the review. CONCLUSION: The extent to which LDC communication is studied by caregiving researchers has the potential to provide helpful guidance for distant caregivers and care recipients to achieve successful health and relational outcomes. PRACTICE IMPLICATIONS: Upon reviewing distance caregiving communication research findings, four applications are discussed: (1) defining distance as a subjective experience; (2) encouraging the use of mediated communication in LDC; and examining (3) interpersonal conflict and (4) topic avoidance processes in the LDC context. PMID- 20832970 TI - Content of text messaging immunization reminders: what low-income parents want to know. AB - OBJECTIVE: The purpose of this project was to gather preliminary data on preferred content for text reminders sent to low-income parents. METHODS: A brief, IRB-approved survey was administered to 200 consecutive English-speaking parents of children under 6 years old at a Pediatric Residency clinic. Because text messages can hold only limited content, parents were given three example texts ranging from very basic to very specific information and asked to select the information they would wish to receive. RESULTS: Of the 190 parents (95%) who responded, 22.1% (42) were Hispanic and 76.3% (145) were non-Hispanic. Over 80% (153) received Medicaid. Of the 79.5% (151) of respondents interested in receiving text messages who responded to the question regarding content, nearly 50% (74) preferred Option 2, with the remaining respondents divided between Option 1 (43) and Option 3 (35). Results differed significantly between Hispanic and non-Hispanic respondents (chi(2)(2)=6.36, p=0.042). CONCLUSION: The majority of parents preferred a message containing the child's name, specific immunization information and physician information. However, Hispanic respondents were significantly more likely to endorse an option that included additional information. PRACTICE IMPLICATIONS: Text messaging may be an optimal vehicle for provider-patient communication, however cultural differences should be considered when developing messages. PMID- 20832972 TI - Role of lymph node dissection in the treatment of urothelial carcinoma of the upper urinary tract: multi-institutional relapse analysis and immunohistochemical re-evaluation of negative lymph nodes. AB - AIM: To determine the role of lymph node dissection (LND) in the treatment of urothelial carcinoma (UC) of the upper urinary tract (UUT). PATIENTS AND METHODS: [Study-1] A retrospective multi-institutional study evaluated 293 patients undergoing predominantly nephroureterectomy for UC of the UUT. Of 293 patients, 267 patients had pure UC and 26 demonstrated other histological components. Regarding the pathological node status, 130 patients had pN0 disease, 141 patients had pNx disease and 22 patients had pN+ disease. The sites of initial recurrence and time to first recurrence were reviewed. The sites of recurrence were classified as locoregional or distant recurrence. The relationship between node status and future recurrence was analyzed. [Study-2] Fifty-one patients treated by nephroureterectomy at Hokkaido University Hospital were included. All had LND and all LNs were negative on hematoxylin and eosin staining. We re evaluated the presence of micrometastasis in LND specimens by anti-cytokeratin immunohistochemistory. RESULTS: [Study-1] Of 293 patients, 76 developed disease relapse. Regional lymph node recurrence was the most common site (34 patients). On multivariate analyses that adjusted for the effect of tumor stage and tumor grade, pNx (skipping LND) was an adverse factor not only for locoregional recurrence, but also for distant relapse. [Study-2] Immunohistochemistry identified micrometastases in 7 (14%) of 51 patients. Regarding survival, 5 of these 7 patients with micrometastases were alive at last follow-up. CONCLUSIONS: On relapse analysis, skipping LND was an adverse factor not only for locoregional recurrence, but also for distant relapse. Immunohistochemistry detected micrometastases in about 14% of patients previously diagnosed as pN0. These findings further support a potential therapeutic benefit of LND by eliminating micrometastases. PMID- 20832971 TI - Estimating statistical power for open-enrollment group treatment trials. AB - Modeling turnover in group membership has been identified as a key barrier contributing to a disconnect between the manner in which behavioral treatment is conducted (open-enrollment groups) and the designs of substance abuse treatment trials (closed-enrollment groups, individual therapy). Latent class pattern mixture models (LCPMMs) are emerging tools for modeling data from open-enrollment groups with membership turnover in recently proposed treatment trials. The current article illustrates an approach to conducting power analyses for open enrollment designs based on the Monte Carlo simulation of LCPMM models using parameters derived from published data from a randomized controlled trial comparing Seeking Safety to a Community Care condition for women presenting with comorbid posttraumatic stress disorder and substance use disorders. The example addresses discrepancies between the analysis framework assumed in power analyses of many recently proposed open-enrollment trials and the proposed use of LCPMM for data analysis. PMID- 20832973 TI - [Iatrogenic oesophageal perforation following the use of a bougie]. PMID- 20832974 TI - [Perfusion brain SPECT and Alzheimer disease]. AB - Alzheimer Disease (AD) is the most frequent cause of degenerative dementia. There is an asymptomatic phase of the disease. Brain single photon computed tomography (SPECT) is a simple way to investigate the cerebral blood flow. Alzheimer's disease is characterized by hypoperfusion in the medial temporal, associative posterior parietal cortex and frontal cortex. Brain SPECT could also have an interest in the early detection of amnesic mild cognitive impairment (MCI) patients with a high risk of conversion to AD. Indeed, the hypoperfusion of the associative parietal cortex in MCI patients is considered predictive of a rapid conversion to AD. Different scintigraphic patterns of neurodegenerative dementias could be used for their differential diagnosis. PMID- 20832976 TI - [Evolution of care of patients needing a total knee replacement]. AB - Clinical efficiency of total knee arthroplasty (TKA) is demonstrated. During the last 10 years, evaluation of the result by the patient himself took a central place. From a technical point of view, minimal invasive surgery as well as computer assisted surgery showed interesting developments. Pain control and well designed rehabilitation protocols are the mandatory key points for optimal care. PMID- 20832975 TI - [Dermatitis herpetiformis]. AB - Dermatitis herpetiformis is a subepidermal autoimmune acquired blistering skin disorder that is associated with intestinal gluten sensitivity. The multifactorial pathogenesis associated genetic background with Major histocompatibility complex II molecules (HLA-DQ2 and HLA-DQ8), its absence has a great negative predictive value and environmental factor with gluten consumption. There is also an increased incidence of autoimmune disorders. Skin lesions are small vesicles and/or bullae, with pruritus, located at the extensor surface of the elbows, proximal forearms and the buttocks. Gastrointestinal manifestations are rare. The biopsies from uninvolved skin establish the diagnostic with a deposition of IgA in the dermal papillae for direct immunofluorescence and in a representative lesion classically neutrophil micro-abcesses within the papillary dermis. The differential diagnosis is clinical with other causes of pruritus and histological with the linear IgA bullous dermatosis. Usually the treatment begin with dapsone for symptomatic skin lesions, it can be considered like a therapeutic test. A gluten-free diet is the treatment of choice and reduce the risk of lymphoma, the major complication. PMID- 20832977 TI - Your patient has symptomatic fibroids and would like to have a baby: what treatment should you advise? PMID- 20832978 TI - Either called "chemobrain" or "chemofog," the long-term chemotherapy-induced cognitive decline in cancer survivors is real. AB - CONTEXT: In recent years, there is growing evidence in the medical literature to support an association between administration of commonly used chemotherapeutic agents and an increased risk for cognitive impairment. OBJECTIVES: We herein critically summarize data relating to the pathophysiological mechanisms by which chemotherapy may induce cognitive impairment in patients surviving from solid tumors. The clinical and epidemiological characteristics and the proposed management strategies to counter chemotherapy-induced cognitive impairment (CICI) also are presented. METHODS: References for this review were identified by searches of PubMed from 1995 until December 2009 with related terms. RESULTS: Both the pathogenetic mechanisms and the overall clinical nature of CICI remain vaguely defined. Findings indicate that CICI is a relatively common event that, in most of the cases, remains underdiagnosed, thereby adversely affecting the quality of life of patients with cancer. Effective pharmacological interventions toward the symptomatic or prophylactic management of CICI also are lacking. CONCLUSION: Either called "chemobrain" or "chemofog," the long-term CICI in cancer survivors is real. The need for multidisciplinary care interventions toward a timely diagnosis and management of CICI is clearly warranted. PMID- 20832979 TI - Keeping the patient at the center of patient- and family-centered care. AB - The practice of palliative care typically refers to the focus of treatment as the patient and family. Tending to the needs of both patients and their families is usually good, but what should clinicians do when they perceive the best interests, needs, or treatment preferences of the patient are in conflict with those of the family or other surrogate? Physicians may be able to suppress the inevitable moral cognitive dissonance of such circumstances, write orders, and walk away, but other health care professionals, especially nurses, may not have it so easy. This article suggests practical steps to obviate conflict in such circumstances before offering an ethical analysis focusing on notions of autonomy, beneficence, and true caring for patients, especially those near the end of life. The limitations of surrogate decision makers are considered and legal liability concerns are briefly explored, ultimately leading to the conclusion that keeping the patient at the center is sine qua non of patient- and family-centered care. PMID- 20832980 TI - Perceived success in addressing end-of-life care needs of low-income elders and their families: what has family conflict got to do with it? AB - The purpose of this study was to examine the predictors of perceived success in addressing the end-of-life care needs of low-income older adults and their family members. Perceived success is defined as the clinician's subjective assessment of the extent to which end-of-life care needs of the patient and family have been met by the interdisciplinary team. The results are drawn from a larger longitudinal multimethod case study designed to understand how end-of-life care is provided to a diverse group of frail elders in an innovative, fully "integrated," managed care program. Data were generated from 120 social work surveys detailing care experiences and outcomes particular to 120 elder deaths. Significant predictors of perceived success for addressing patient needs included patient care needs (beta=0.17, P<=0.05), race (beta=0.19, P<=0.05), patient preferences elicited (beta=0.29, P<=0.01) and honored (beta=0.20, P<=0.05), and family conflict (beta=-0.24, P<=0.01). Significant predictors of perceived success for addressing family needs included family care needs (beta=0.30, P<=0.001), team and administrative resources (beta=0.19, P<=0.01), patient preferences honored (beta=0.16, P<=0.05), quality of relationship with patient (beta=0.27, P<=0.001) and family (beta=0.23, P<=0.01), and family conflict (beta= 0.31, P<=0.001). This study provides preliminary evidence of differential correlates and predictors of perceived success for addressing patient and family needs, highlighting the detrimental influence of family conflict. Future research is needed to better understand the kinds of assessment and intervention protocols that might prevent or ameliorate conflict and enhance structures and process-of care variables to facilitate more successful outcomes. PMID- 20832981 TI - Methylnaltrexone in the treatment of opioid-induced constipation in cancer patients receiving palliative care: willingness-to-pay and cost-benefit analysis. AB - CONTEXT: When laxative regimens have failed, methylnaltrexone may be indicated for the relief of opioid-induced constipation (OIC) in patients with advanced illness receiving palliative care. OBJECTIVES: A cost-benefit analysis (CBA), based on a willingness-to-pay (WTP) approach, was performed to determine if methylnaltrexone should be added to the formulary list of drugs being reimbursed by third-party payers in Canada for the treatment of cancer patients in palliative care suffering from OIC. METHODS: The WTP study had two components: a decision board explaining treatment options (Component A) and a questionnaire to measure individual WTP using a bidding game approach (Component B). Component A had two options: Option 1 (laxatives only) and Option 2 (laxatives+methylnaltrexone injection). Only participants choosing Option 2 were invited to complete Component B. The results of the WTP survey were then incorporated into a CBA. Within a hypothetical cohort, additional monthly premiums that individuals were willing to pay for methylnaltrexone were compared with the monthly costs to the insurer for providing methylnaltrexone to all patients who would potentially be using it. RESULTS: Four hundred one Canadians, of age 18 years and older, were surveyed and yielded a WTP in additional monthly insurance premiums of Canadian dollar (CAD) $8.65 (95% confidence interval: CAD$6.17-CAD$11.13). The CBA resulted in additional CAD$89,307 with a cost of CAD$139,840 and benefits of CAD$229,147. A set of 10,000 Monte Carlo simulations resulted in average CBA savings of CAD$145,011 with a 99.86% probability of dominance. CONCLUSION: The present CBA provides pharmacoeconomic evidence for the adoption of methylnaltrexone for treating OIC in terminally ill cancer patients. PMID- 20832983 TI - Use of palliative care services and general practitioner visits at the end of life in The Netherlands and Belgium. AB - CONTEXT: At the end of life, some personalized and specialized care is required. The way that general practitioner (GP) visits and palliative care services at the end of life are organized in different countries may impact the frequency of care provision. However, nationwide data on the prevalence of these interventions and comparisons among countries are scarce. OBJECTIVES: To compare the frequency of GP visits and use of palliative care services at the end of life in two European countries and identify the associated factors. METHODS: In 2007, two mortality follow-back studies were conducted simultaneously in The Netherlands and Belgium, using existing Sentinel GP networks and similar standardized procedures. Within the one-year period, all registered patients who died at home or in a care home were selected. RESULTS: From the data of 543 registered patients, GP visits were more frequent at the end of life in The Netherlands than in Belgium: the mean number of GP visits in the last week of life was 5.1 vs. 3.2 (home) and 4.4 vs. 2.3 (care home). Conversely, palliative care services in the last three months of life were used more frequently in Belgium than in The Netherlands: 78% vs. 41% (home) and 39% vs. 5% (care homes). The differences between countries remained consistent despite correcting for possible confounders. Having more frequent GP visits at home was associated with cancer-related deaths both in The Netherlands and Belgium. CONCLUSION: Independent of the differences in patient populations (at home and care home) between countries, there are more frequent GP visits at the end of life in The Netherlands and greater use of palliative care services in Belgium. PMID- 20832982 TI - Caregiver-assisted coping skills training for lung cancer: results of a randomized clinical trial. AB - CONTEXT: Lung cancer is one of the most common cancers in the United States and is associated with high levels of symptoms, including pain, fatigue, shortness of breath, and psychological distress. Caregivers and patients are adversely affected. However, previous studies of coping skills training (CST) interventions have not been tested in patients with lung cancer nor have systematically included caregivers. OBJECTIVES: This study tested the efficacy of a caregiver assisted CST protocol in a sample of patients with lung cancer. METHODS: Two hundred thirty-three lung cancer patients and their caregivers were randomly assigned to receive 14 telephone-based sessions of either caregiver-assisted CST or education/support involving the caregiver. Patients completed measures assessing pain, psychological distress, quality of life (QOL), and self-efficacy for symptom management; caregivers completed measures assessing psychological distress, caregiver strain, and self-efficacy for helping the patient manage symptoms. RESULTS: Patients in both treatment conditions showed improvements in pain, depression, QOL, and self-efficacy, and caregivers in both conditions showed improvements in anxiety and self-efficacy from baseline to four-month follow-up. Results of exploratory analyses suggested that the CST intervention was more beneficial to patients/caregivers with Stage II and III cancers, whereas the education/support intervention was more beneficial to patients/caregivers with Stage I cancer. CONCLUSION: Taken together with the broader literature in this area, results from this study suggest that psychosocial interventions can lead to improvements in a range of outcomes for cancer patients. Suggestions for future studies include the use of three-group designs (e.g., comparing two active interventions with a standard-care control) and examining mechanisms of change. PMID- 20832985 TI - Palliative sedation, not slow euthanasia: a prospective, longitudinal study of sedation in Flemish palliative care units. AB - CONTEXT: Palliative sedation remains a much debated and controversial issue. The limited literature on the topic often fails to answer ethical questions concerning this practice. OBJECTIVES: The aim of this study was to describe the characteristics of patients who are being sedated for refractory symptoms in palliative care units (PCUs) from the time of admission until the day of death. METHODS: A prospective, longitudinal, descriptive design was used to assess data in eight PCUs. The total sample consisted of 266 patients. Information on demographics, medication, food and fluid intake, decision making, level of consciousness, and symptom experience were gathered by nurses and researchers three times a week. If patients received palliative sedation, extra information was gathered. RESULTS: Of all included patients (n=266), 7.5% received palliative sedation. Sedation started, on average, 2.5 days before death and for half of these patients, the form of sedation changed over time. At the start of sedation, patients were in the end stage of their illness and needed total care. Patients were fully conscious and had very limited oral food or fluid intake. Only three patients received artificial fluids at the start of sedation. Patients reported, on average, two refractory symptoms, the most important ones being pain, fatigue, depression, drowsiness, and loss of feeling of well-being. In all cases, the patient gave consent to start palliative sedation because of increased suffering. CONCLUSION: This study revealed that palliative sedation is only administered in exceptional cases where refractory suffering is evident and for those patients who are close to the ends of their lives. Moreover, this study supports the argument that palliative sedation has no life-shortening effect. PMID- 20832984 TI - Coping profiles common to older African American cancer survivors: relationships with quality of life. AB - CONTEXT: Cancer survivors use distinct sets of coping behaviors that vary in their associations with psychological health and quality of life. However, existing research has largely focused on Caucasian and middle-class subjects. OBJECTIVES: This study explores whether clusters with differing coping profiles could be identified among older African American cancer survivors and whether these profiles varied on cultural factors and physical, psychological, and relationship well-being. METHODS: Four hundred forty-nine older African American cancer survivors recruited from outpatient oncology clinics completed a questionnaire booklet containing the Ways of Helping Questionnaire (WHQ), the Brief Index of Race-Related Stress, the Religious Involvement Scale, Mutuality Scale, and the Short Form-12 Health Survey Questionnaire. A k-means cluster analysis was conducted using the WHQ. RESULTS: Four distinct coping profiles were identified and labeled as high coping, low encouraging healthy behaviors, low coping, and strong/distracting behaviors. Coping profiles were associated with participant's gender, age, and living-alone status. Controlling for these demographic differences, the coping profiles were associated with religiosity; experiences with racism; and physical, psychological, and relationship well being. CONCLUSIONS: The findings from this study lend support for examining coping profiles and health outcomes among African American cancer survivors. This research also suggests that these profiles vary on cultural factors. This information should prove useful to researchers as they develop culturally appropriate interventions for this underserved population. PMID- 20832986 TI - Evaluation of central serotonin sensitivity in breast cancer survivors with cancer-related fatigue syndrome. AB - CONTEXT: Increased central serotonin sensitivity is hypothesized to contribute toward the development of cancer-related fatigue syndrome (CRFS). OBJECTIVES: To compare the responses of breast cancer survivors with or without CRFS to the buspirone challenge test (an index of central serotonin sensitivity). METHODS: Disease-free women who had successfully completed treatment for early-stage breast cancer were assessed. On the basis of the diagnostic interview for CRFS and a structured psychiatric interview, women were classified as either "cases" of CRFS or "controls." Women with comorbid psychiatric diagnoses were excluded. Volunteers underwent a challenge test using buspirone (a serotonin-selective agonist) using a double-blind, randomized, placebo-controlled protocol. Cortisol and prolactin responses were assessed at hourly intervals for the four hours after administration of buspirone. RESULTS: Fourteen cases of CRFS and 28 controls participated in the study. There were no significant differences in baseline or stimulated cortisol release after buspirone challenge. There were differences neither in basal prolactin levels in the two groups nor in the total prolactin response to buspirone (as measured using the area under the curve). In patients with CRFS, peak prolactin response occurred at 120 minutes and sustained until 180 minutes post buspirone. In controls, peak prolactin response occurred at 60 minutes and then began to decline. CONCLUSIONS: This study has demonstrated the utility and acceptability of buspirone as a probe of central serotonin sensitivity in this population. No evidence was found for alterations in central serotonin sensitivity in patients with CRFS. Conclusions are tentative, however, because poor recruitment resulted in a small sample and an underpowered comparison. PMID- 20832987 TI - A multicenter study comparing two numerical versions of the Edmonton Symptom Assessment System in palliative care patients. AB - CONTEXT: The Edmonton Symptom Assessment System (ESAS) is a widely used, self report symptom intensity tool for assessing nine common symptoms in palliative care, with ratings ranging from 0 (none, best) to 10 (worst). Based on a "think aloud" study of 20 advanced cancer patients, the ESAS was revised (ESAS-r). OBJECTIVES: To compare the consistency of patients' symptom ratings and obtain patient perspectives regarding ease of understanding and completion between the ESAS and ESAS-r. METHODS: Cognitively intact patients (n=160) were recruited from eight palliative care sites in Canada and Switzerland, using cross-sectional sampling (20 per site). Consenting patients completed the ESAS, ESAS-r, and a structured interview. Intraclass correlation coefficients (ICCs) were calculated to assess rating consistency. RESULTS: In total, 1046 patients were screened. One hundred sixty were enrolled and evaluable (female 51%, median age 61 [range 34 92], lung cancer 26%, gastrointestinal cancer 22%). Mean ESAS scores ranged from 1.2 (nausea, standard deviation [SD] 2.1) to 4.3 (appetite, SD 3.3). ICCs ranged from 0.65 to 0.83, with lowest scores (<0.8) for drowsiness, appetite, and well being. Although most patients rated both versions as very easy or easy to understand and complete, the ESAS-r was significantly easier to understand than the ESAS (P=0.008). Significantly, more patients preferred the ESAS-r (39%) than the ESAS (14%, P<0.001) because of its definitions, clarity, and format. CONCLUSION: The ESAS-r retains core elements of the ESAS, with improved interpretation and clarity of symptom intensity assessment. It represents the next generation of ESAS development, with further validation recommended for drowsiness, appetite, and well-being. PMID- 20832988 TI - The Driving Behavior Survey: scale construction and validation. AB - Although long recognized in the clinical literature, problematic behavior characteristic of anxious drivers has received little empirical attention. The current research details development of a measure of anxious driving behavior conducted across three studies. Factor analytic techniques identified three dimensions of maladaptive behaviors across three college samples: anxiety-based performance deficits, exaggerated safety/caution behavior, and anxiety-related hostile/aggressive behavior. Performance deficits evidenced convergent associations with perceived driving skill and were broadly related to driving fear. Safety/caution behaviors demonstrated convergence with overt travel avoidance, although this relationship was inconsistent across studies. Safety/caution scores were associated specifically with accident- and social related driving fears. Hostile/aggressive behaviors evidenced convergent relationships with driving anger and were associated specifically with accident related fear. Internal consistencies were adequate, although some test-retest reliabilities were marginal in the unselected college sample. These data provide preliminary evidence for utility of the measure for both research and clinical practice. PMID- 20832990 TI - Self-compassion is a better predictor than mindfulness of symptom severity and quality of life in mixed anxiety and depression. AB - Mindfulness has received considerable attention as a correlate of psychological well-being and potential mechanism for the success of mindfulness-based interventions (MBIs). Despite a common emphasis of mindfulness, at least in name, among MBIs, mindfulness proves difficult to assess, warranting consideration of other common components. Self-compassion, an important construct that relates to many of the theoretical and practical components of MBIs, may be an important predictor of psychological health. The present study compared ability of the Self Compassion Scale (SCS) and the Mindful Attention Awareness Scale (MAAS) to predict anxiety, depression, worry, and quality of life in a large community sample seeking self-help for anxious distress (N = 504). Multivariate and univariate analyses showed that self-compassion is a robust predictor of symptom severity and quality of life, accounting for as much as ten times more unique variance in the dependent variables than mindfulness. Of particular predictive utility are the self-judgment and isolation subscales of the SCS. These findings suggest that self-compassion is a robust and important predictor of psychological health that may be an important component of MBIs for anxiety and depression. PMID- 20832989 TI - Age of onset of social anxiety disorder in depressed outpatients. AB - Onset of social anxiety disorder (SAD) often precedes that of major depressive disorder (MDD) in patients with this comorbidity pattern. The current study examined the association between three SAD onset groups (childhood, adolescent, adulthood) and clinical characteristics of 412 psychiatric outpatients diagnosed with MDD and SAD based on a semi-structured diagnostic interview. Childhood and adolescent SAD onset groups were more likely to report an onset of MDD prior to age 18 and have made at least one prior suicide attempt compared to the adulthood onset group. The childhood SAD onset group also was more likely to have chronic MDD, poorer past social functioning, and an increased hazard of MDD onset compared to the adulthood onset group. Findings suggest that patients with an onset of SAD in childhood or adolescence may be particularly at risk for a more severe and chronic course of depressive illness. PMID- 20832991 TI - GABA inhibition modulates NMDA-R mediated spike timing dependent plasticity (STDP) in a biophysical model. AB - Spike timing dependent plasticity (STDP) has been demonstrated in various neural systems of many animals. It has been shown that STDP depends on the target and the location of the synapse and is dynamically regulated by the activity of adjacent synapses, the presence of postsynaptic calcium, presynaptic GABA inhibition or the action of neuromodulators. Recent experimental evidence has reported that the profile of STDP in the CA1 pyramidal neuron can be classified into two types depending on its dendritic location: (1) A symmetric STDP profile in the proximal to the soma dendrites, and (2) an asymmetric one in the distal dendrites. Bicuculline application revealed that GABA(A) is responsible for the symmetry of the STDP curve. We investigate via computer simulations how GABA(A) shapes the STDP profile in the CA1 pyramidal neuron dendrites when it is driven by excitatory spike pairs (doublets). The model constructed uses calcium as the postsynaptic signaling agent for STDP and is shown to be consistent with classical long-term potentiation (LTP) and long-term depression (LTD) induced by several doublet stimulation paradigms in the absence of inhibition. Overall, simulation results provide computational evidence for the first time that the switch between the symmetrical and the asymmetrical STDP operational modes is indeed due to GABA inhibition. Furthermore, gamma frequency inhibition and not theta one is responsible for the transition from asymmetry-to-symmetry. The resulted symmetrical STDP profile is centered at +10 ms with two distinct LTD tails at -10 and +40 ms. Finally, the asymmetry-to-symmetry transition is strongly dependent on the strength (conductance) of inhibition and its relative onset with respect to pre- and postsynaptic spike stimulation. PMID- 20832992 TI - Border detection in dermoscopy images using hybrid thresholding on optimized color channels. AB - Automated border detection is one of the most important steps in dermoscopy image analysis. Although numerous border detection methods have been developed, few studies have focused on determining the optimal color channels for border detection in dermoscopy images. This paper proposes an automatic border detection method which determines the optimal color channels and performs hybrid thresholding to detect the lesion borders. The color optimization process is tested on a set of 30 dermoscopy images with four sets of dermatologist-drawn borders used as the ground truth. The hybrid border detection method is tested on a set of 85 dermoscopy images with two sets of ground truth using various metrics including accuracy, precision, sensitivity, specificity, and border error. The proposed method, which is comprised of two stages, is designed to increase specificity in the first stage and sensitivity in the second stage. It is shown to be highly competitive with three state-of-the-art border detection methods and potentially faster, since it mainly involves scalar processing as opposed to vector processing performed in the other methods. Furthermore, it is shown that our method is as good as, and in some cases more effective than a dermatology registrar. PMID- 20832993 TI - Surgical management of persistent oromandibular dystonia of the temporalis muscle. AB - A rare case of unifocal oromandibular dystonia of the temporalis muscle is presented. It was treated with surgical myotomy when initial botulinum toxin A therapy failed after 3 years of repeated injections. PMID- 20832994 TI - Efficacy and safety of nicorandil therapy in patients with acute heart failure. AB - BACKGROUND: Nicorandil is a vasodilator that both opens potassium channels and has nitrate effects. The administration of nitrate is the gold standard for the treatment of acute heart failure (AHF). However, there have been few reports regarding the usefulness of nicorandil for the treatment of AHF. Therefore, we evaluated the efficacy of intravenous administration of nicorandil in patients with AHF. METHODS: A total of 31 AHF patients were enrolled, and randomized into either the nicorandil group (n=16) or control group (n=15). Nicorandil was started with a bolus injection of 100 MUg/kg, and the continuous injection of 60 100 MUg/kg/h within 30 min after admission, which continued for 5 days. There were no limitations in the treatment of AHF except for nicorandil use. B-type natriuretic peptide (BNP) and N-terminal-pro-BNP (NT-pro-BNP) were measured on admission (Day 1), Day 3, and Day 7. RESULTS: BNP significantly decreased in the nicorandil group on Day 3 (502.4 +/- 406.9 pg/ml) from Day 1 (1397.0 +/- 1617.5 pg/ml), however, no significant decrease was observed in the control group. NT pro-BNP tended to decrease on Day 3 (7316.7 +/- 10,187.5 pg/ml, p=0.06) and significantly decreased on Day 7 (5702.9 +/- 6468.8 pg/ml) from Day 1 (11,270.0 +/- 12,388.5 pg/ml) in the nicorandil group, however there were no changes in the control group. When patients from nicorandil group were classified into a high systolic blood pressure (SBP) group (baseline SBP >140 mm Hg, n=10) and low SBP group (baseline SBP <140 mmHg, n=6), a significant decrease was observed in SBP from Day 1 to Day 3 in both groups. CONCLUSIONS: Intravenous administration of nicorandil can decrease serum cardiac stress markers, and was shown to be effective in AHF patients. Furthermore, nicorandil improved the hemodynamics in the patients with high SBP, and the drug could be safely administered to AHF patients with low SBP. PMID- 20832995 TI - Impulsivity and sensation seeking in cannabis abusing patients with schizophrenia. PMID- 20832996 TI - Association between duration of untreated psychosis and brain morphology in schizophrenia within the Northern Finland 1966 Birth Cohort. AB - BACKGROUND: Duration of untreated psychosis (DUP) has been linked with poor prognosis and changes in the brain structure in schizophrenia at least at the beginning of the disease, but it is still unknown whether DUP relates to brain morphometry in the longer term. Our aim was to analyze the relation between DUP and the brain structure in schizophrenia in the general population, after several years of illness. METHODS: Brains of subjects with psychosis from the Northern Finland 1966 Birth Cohort (NFBC 1966) were scanned with MRI during 1999-2001 after an 11-year follow-up. DUP was assessed from medical records and regressed against global and local tissue density measurements. The brain morphometric and the DUP information were available for 46 subjects with DSM-III-R schizophrenia. RESULTS: The DUP did not correlate with volumes of the total gray or white matter or the cerebrospinal fluid. The length of DUP associated positively with reduced densities of the right limbic area and the right hippocampus. CONCLUSIONS: Long DUP was slightly associated with reductions of gray matter densities in the limbic area and especially the hippocampus after several years follow-up, supporting the hypothesis that, compared to short DUP, long DUP might be a marker of different disease trajectories including subtle morphometric changes. PMID- 20832998 TI - Regulatory B cells in skin and connective tissue diseases. AB - While B cells are generally considered to be positive regulators of humoral immune responses due to their ability to differentiate into plasmablasts/plasma cells and produce antibodies, B cells also modulate immune responses through antigen presentation and cytokine secretion. Moreover, "regulatory B cells" that suppress immune responses have been recognized as an important new component of the immune system. In mice, the function of regulatory B cells is almost exclusively dependent on IL-10. The cell-surface phenotype of murine IL-10 producing regulatory B cells is reported to be CD1d(hi)CD5(+) or CD1d(hi)CD21(hi)CD23(+)IgM(hi), and thus their phenotype overlaps with that of CD5(+) B-1a cells, CD1d(hi)CD21(hi)CD23(lo)IgM(hi) marginal zone (MZ) B cells, and CD1d(hi)CD21(hi)CD23(hi)IgM(hi) T2-MZ precursor B cells. Contrary to earlier work that suggested a minor role for B cells in contact hypersensitivity, regulatory B cells are now known to have a critical inhibitory functions in this type of immune response. Furthermore, studies using murine disease models have demonstrated that regulatory B cells play a significant role in autoimmune connective tissue diseases such as rheumatoid arthritis and systemic lupus erythematosus, as well as organ-specific autoimmune diseases including experimental autoimmune encephalomyelitis and inflammatory bowel disease. In comparison to mouse regulatory B cells, little is known regarding their human counterparts. One recent study demonstrates that human CD19(+)CD24(hi)CD38(hi) B cells possess regulatory capacity. Clarifying the molecular mechanisms by which regulatory B cells suppress immune responses will be of great benefit in the development of new B cell-targeted therapeutic strategies. PMID- 20832997 TI - The role of the insula in schizophrenia. AB - Involvement of the insular cortex is a common finding in neuroanatomical studies of schizophrenia, yet its contribution to disease pathology remains unknown. This review describes the normal function of the insula and examines pathology of this region in schizophrenia. The insula is a cortical structure with extensive connections to many areas of the cortex and limbic system. It integrates external sensory input with the limbic system and is integral to the awareness of the body's state (interoception). Many deficits observed in schizophrenia involve these functions and may relate to insula pathology. Furthermore, reports describing deficits caused by lesions of the insula parallel deficits observed in schizophrenia. Examples of insula-related functions that are altered in schizophrenia include the processing of both visual and auditory emotional information, pain, and neuronal representations of the self. The last of these functions, processing representations of the self, plays a key role in discriminating between self-generated and external information, suggesting that insula dysfunction may contribute to hallucinations, a cardinal feature of schizophrenia. PMID- 20833000 TI - Update on the global spread of dengue. AB - The global spread of dengue fever within and beyond the usual tropical boundaries threatens a large percentage of the world's population, as human and environmental conditions for persistence and even spread are present in all continents. The disease causes great human suffering, a sizable mortality from dengue haemorrhagic fever and its complications, and major costs. This situation has worsened in the recent past and may continue to do so in the future. Efforts to decrease transmission by vector control have failed, and no effective antiviral treatment is available or foreseeable on the immediate horizon. A safe and effective vaccine protective against all serotypes of dengue viruses is sorely needed. PMID- 20832999 TI - The potential use of protein kinase D inhibitors for prevention/treatment of epidermal tumors. AB - BACKGROUND: The serine/threonine kinase protein kinase D (PKD) has been proposed to be a pro-proliferative, anti-differentiative signal in epidermal keratinocytes. Indeed, the phorbol ester tumor promoter, 12-O tetradecanoylphorbol 13-acetate (TPA) induces biphasic PKD activation, which mirrors the biphasic response of initial differentiation followed by proliferation and tumor promotion seen in TPA-treated keratinocytes in vitro and epidermis in vivo. OBJECTIVE: Our objective was to test the idea that PKD's pro proliferative and/or anti-differentiative effects in keratinocytes contribute to TPA-induced tumorigenesis. METHODS: Using western analysis and assays of keratinocyte proliferation and differentiation, we investigated the effect of inhibitors of PKD on keratinocyte function. RESULTS: We found that overexpression of a constitutively active PKD mutant increased, and of a dominant-negative PKD mutant decreased, keratinocyte proliferation. A recently described selective PKD inhibitor showed low potency to inhibit keratinocyte proliferation or PKD activation. Therefore, we tested the ability of known only relatively selective PKD inhibitors on keratinocyte function and protein kinase activation. H89 {N-[2 (p-bromocinnamylamino) ethyl]-5-isoquinoline-sulfonamide}, a reported inhibitor of PKD and cAMP-dependent protein kinase, enhanced the effect of a differentiating agent on a marker of keratinocyte differentiation. Another reported non-selective PKD inhibitor, resveratrol stimulated differentiation and inhibited proliferation. The protein kinase C/PKD inhibitor Go6976 blocked the increase in proliferation (as measured by DNA specific activity) induced by chronic TPA without affecting the initial TPA-elicited differentiation. CONCLUSION: Our results support the idea that relatively selective PKD inhibitors, such as Go6976, H89 and resveratrol, might be useful for preventing/treating epidermal tumorigenesis without affecting keratinocyte differentiation. PMID- 20833001 TI - Regional gray and white matter volume abnormalities in obsessive-compulsive disorder: a voxel-based morphometry study. AB - Previous studies have demonstrated both functional and structural abnormalities in the frontal-striatal-thalamic circuits in obsessive-compulsive disorder (OCD). The purpose of this study was to assess volume abnormalities not only of gray matter (GM), but also of white matter (WM) in patients with OCD using voxel-based morphometry (VBM). Subjects consisted of 23 patients with OCD and 26 normal control subjects. All patients were drug-free for at least 2 weeks before the study. Three-dimensional T1-weighed MR images were obtained in all subjects. Optimized voxel-based morphometry was performed to detect structural difference between the two groups. The patients with OCD demonstrated a significant reduction of GM volume in the bilateral medial prefrontal cortex, right premotor area, right orbitofrontal cortex (OFC), right dorsolateral prefrontal cortex, and bilateral temporal and occipital regions. The OCD patients also showed a significant WM volume increase in the right anterior limb of the internal capsule, right orbitofrontal region, and a significant WM volume reduction in the left anterior cingulate gyrus. Our findings are consistent with previous studies implicating dysfunction of the frontal cortex including the OFC. The results suggested that WM volume abnormalities in the orbitofrontal region, anterior limb of the internal capsule, and anterior cingulate gyrus would imply abnormalities in the pathways of frontal-striatal circuits. PMID- 20833002 TI - Biomimetic synthesis of silver nanoparticles by Citrus limon (lemon) aqueous extract and theoretical prediction of particle size. AB - In the present study, silver nanoparticles were rapidly synthesized at room temperature by treating silver ions with the Citrus limon (lemon) extract. The effect of various process parameters like the reductant concentration, mixing ratio of the reactants and the concentration of silver nitrate were studied in detail. In the standardized process, 10(-2)M silver nitrate solution was interacted for 4h with lemon juice (2% citric acid concentration and 0.5% ascorbic acid concentration) in the ratio of 1:4 (vol:vol). The formation of silver nanoparticles was confirmed by Surface Plasmon Resonance as determined by UV-Visible spectra in the range of 400-500 nm. X-ray diffraction analysis revealed the distinctive facets (111, 200, 220, 222 and 311 planes) of silver nanoparticles. We found that citric acid was the principal reducing agent for the nanosynthesis process. FT-IR spectral studies demonstrated citric acid as the probable stabilizing agent. Silver nanoparticles below 50 nm with spherical and spheroidal shape were observed from transmission electron microscopy. The correlation between absorption maxima and particle sizes were derived for different UV-Visible absorption maxima (corresponding to different citric acid concentrations) employing "MiePlot v. 3.4". The theoretical particle size corresponding to 2% citric acid concentration was compared to those obtained by various experimental techniques like X-ray diffraction analysis, atomic force microscopy, and transmission electron microscopy. PMID- 20833003 TI - Staining proteins: a simple method to increase the sensitivity of ellipsometric measurements in adsorption studies. AB - This communication describes a simple way to improve the sensitivity of spectroscopic ellipsometry, when applied to monitor the adsorption of proteins to solid surfaces. The method described herein is based on the reaction of a commercially available dye (Coomassie brilliant blue G) with the adsorbed proteins and the subsequent analysis by spectroscopic ellipsometry. In order to demonstrate the potential advantages of this method, the adsorption of bovine serum albumin to an antifouling coating was also investigated. According to our results, the modification with the dye significantly affects the optical properties of the adsorbed protein layer, which can be represented using a simple optical model (Lorentz). In general, the proposed modification increases the sensitivity of the detection by 2.5 +/- 0.4-fold and enables the analysis of thin layers of adsorbed protein not obtainable by conventional methods. These results particularly reveal the importance of the proposed modification for the evaluation of low adsorbing substrates and antifouling coatings. PMID- 20833004 TI - Smart swelling biopolymer microparticles by a microfluidic approach: synthesis, in situ encapsulation and controlled release. AB - This paper reports a microfluidic synthesis of biopolymer microparticles aiming at smart swelling. Monodisperse aqueous emulsion droplets comprising biopolymer and its cross-linking agent were formed in mineral oil and solidified in the winding microfluidic channels by in situ chaotic mixing, which resulted in internal chemical gelation for hydrogels. The achievement of pectin microparticles from in situ mixing pectin with its cross-linking agent, calcium ions, successfully demonstrates the reliability of this microfluidic synthesis approach. In order to achieve hydrogels with smart swelling, the following parameters and their impacts on the swelling behaviour, stability and morphology of microparticles were investigated: (1) the type of biopolymers (alginate or mixture of alginate and carboxymethylcellulose, A-CMC); (2) rapid mixing; (3) concentration and type of cross-linking agent. Superabsorbent microparticles were obtained from A-CMC mixture by using ferric chloride as an additional external cross-linking agent. The in situ encapsulation of a model protein, bovine serum albumin (BSA), was also carried out. As a potential protein drug-delivery system, the BSA release behaviours of the biopolymer particles were studied in simulated gastric and intestinal fluids. Compared with alginate and A-CMC microparticles cross-linked with calcium ions, A-CMC microparticles cross-linked with both calcium and ferric ions demonstrate a significantly delayed release. The controllable release profile, the facile encapsulation as well as their biocompatibility, biodegradability, mucoadhesiveness render this microfluidic approach promising in achieving biopolymer microparticles as protein drug carrier for site-specific release. PMID- 20833005 TI - [Epidemics of gastroenteritis caused by norovirus in Parisian children]. AB - During the months of October and November 2006-2008, norovirus was detected in the stools of 14 children hospitalized with acute diarrhea (no sapovirus). Nine of these noroviruses belonged to a unique GGII4 strain, which produced severe clinical symptoms, present only in 2007 and 2008 and absent in 2006. This strain, identified in Europe mainly in the elderly, seems to be on the rise in children in the Paris area over the past few years. PMID- 20833006 TI - Toxicity of methimazole on femoral bone in suckling rats: alleviation by selenium. AB - AIMS: Selenium has a pharmacological properties and it is well considered as an antioxidant. The present study investigated the potential ability of selenium, used as a nutritional supplement, to alleviate bone impairments in suckling rats whose mothers were treated with methimazole, an antithyroid drug. MAIN METHODS: Female Wistar rats were randomly divided into four groups of six each: group I served as control which received standard diet; group II were rendered hypothyroid by administration of methimazole (250 mg L(-1) in their drinking water); group III received both methimazole (250 mg L(-1) in their drinking water) and selenium (0.5 mg kg(-1) of diet); group IV received 0.5 Na(2)SeO(3) mg kg(-1) of diet. Treatments were started from the 14th day of pregnancy until day 14 after delivery. KEY FINDINGS: Methimazole treatment decreased femur length and weight in 14-day-old rats, when compared to controls. Femur antioxidant enzyme activities, superoxide dismutase, catalase and glutathione peroxidase decreased. Lipid peroxidation recorded an increase revealed by high femur malondialdehyde levels. Methimazole also caused a significant decrease in calcium and phosphorus levels in bone. Yet, in plasma and urine, they increased and decreased inversely. Besides, plasma total tartrate-resistant acid phosphatase was enhanced, while total alkaline phosphatase was reduced. Co-administration of selenium through diet improved the biochemical parameters cited above. Nevertheless, distorted histoarchitecture revealed in hypothyroid rat femur was alleviated by Se treatment. SIGNIFICANCE: The present study suggests that selenium is an important protective element that may be used as a dietary supplement protecting against bone impairments. PMID- 20833007 TI - Iron uptake by Caco-2 cells following in vitro digestion: effects of heat treatments of pork meat and pH of the digests. AB - The present in vitro studies report on iron uptake by Caco-2 cells from pepsin and pepsin+pancreatin-digested pork meat proteins at pH values between 4.6 and 7 mimicking conditions in the duodenum and the proximal jejunum, respectively. Heat treatment of the pork meat resulted in increased iron uptake from pepsin-digested samples to Caco-2 cells at pH 4.6. The major enhancing effects on iron uptake by Caco-2 cells were observed after pepsin digestion in the pH range 4.6-6.0, whereas the pepsin+pancreatin-digested samples resulted in negligible iron uptake in Caco-2 cells at pH 7. Thus, the results emphasize the importance of separating pepsin-digested and pepsin+pancreatin-digested proteins during in vitro studies on iron availability. Furthermore, the present results showed the pH dependency of iron uptake anticipated. The enhancing effect of ascorbic acid was verified by increased iron uptake from pepsin-digested pork meat samples at pH 4.6, while no effect of ascorbic acid was observed at pH 7 in pepsin+pancreatin-digested samples. PMID- 20833008 TI - Effects of zinc pre-treatment on blood glutathione, serum zinc and kidney histological organisation in male rats exposed to cadmium. AB - The effects of sub-chronic exposure to cadmium (Cd) on the blood glutathione, serum zinc and on the kidney histological organisation in rats as well as the possible protective role of zinc (Zn) are the object of this study. For this purpose, 60 male Wistar rats (8 weeks old) were divided into three groups: the first group was exposed to Cd in the form of CdCl(2), administered in five doses (each of 0.4 mg Cd/kg b.w.) on days 5, 10, 15, 20 and 25, giving a total dose of 2mg Cd/kg b.w., i.p.; the second group was simultaneously exposed to Zn and Cd with the same timeline and the same doses of Cd as the first group but with, in addition, injections of Zn in the form of ZnCl(2), administered in doses of 0.8 mg Zn/kg b.w., giving a total dose of 4 mg Zn/kg b w, i.p.; a control group received 0.5 mL of physiological saline in an identical manner. Intoxication with Cd was followed by a significant decrease in blood glutathione, increase in oxidized glutathione as well as histological damage in kidneys. Pre-treatment with Zn exhibited a protective role against Cd toxicity with a significant decrease in serum zinc content. This fact may be explained by an excessive use of zinc in metallothionein synthesis as a cadmium detoxification agent. PMID- 20833009 TI - No altered blood pressure and serum markers of oxidative stress after a long time dietary fish oil in the genetically 9 month-old type-2 diabetes Zucker rat. AB - In this study, we investigated the effect of a high n-3 fatty acid diet (eicosapentaenoic and docosahexaenoic acids) in Zucker obese and lean rats on blood pressure in association with physiological parameters, serum biochemistry and oxidative stress analysis. After 150 days of treatment, dietary fish oil supplementation in Zucker obese rats (9 months of age) reduces bodyweight gain and serum triglyceridemia and nitrite levels, increases serum glucose and angiotensin converting enzyme activity, but does not alter blood pressure, cholesterol levels and serum markers of oxidative stress (malondialdehyde, glutathione), compared to the Zucker rats fed control diet. According to these results, we can consider that after 150 days of treatment, fish oil is not enough to regulate parameters involved in the metabolic syndrome, such as cholesterolemia and blood pressure, in a 9 month-old genetically type-2 diabetes rat. PMID- 20833010 TI - Staging of non-small cell lung cancer (NSCLC): a review. AB - Lung cancer remains the most common cause of cancer-related mortality in Scotland, accounting for 28.9% of all cancer deaths in 2007. (1) Current guidelines recommend assessment of patient fitness and operability by a multi disciplinary team when selecting management options. (2-6) Two of the most important prognostic markers are the stage of disease and ECOG performance status. The most commonly used cancer staging system is the tumour, node, metastasis (TNM) staging system, which is maintained by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). In 1998, the International Association for the Study of Lung Cancer (IASLC) established The Lung Cancer Staging Project, collecting data on over 100,000 patients diagnosed with lung cancer between 1990-2000 worldwide, in order to revise the 6th edition TNM staging system for non-small cell lung cancer (NSCLC).(7) The 7th edition was published in late 2009. This review of staging in NSCLC, includes a summary of the different staging techniques currently available and the 7th edition TNM staging system for NSCLC.(8). PMID- 20833011 TI - Developmental control of cell growth and division in Drosophila. AB - In single-celled life forms, the rate of cell growth and division is principally determined by the availability of nutrients. Multicellular organisms operate very differently, with cell growth and division also under the control of developmental programs that instruct cell behaviour according to a cell's position and orientation relative to others, and according to the mechanical forces that the cell experiences. In the fruit fly Drosophila, these three inputs have been shown to act via signalling pathways, transcription factors and microRNAs to regulate the rate of cell growth and division and can also act upon the mitotic spindle to control the orientation of cell division. PMID- 20833012 TI - A finite element simulation of biological conversion processes in landfills. AB - Landfills are the most common way of waste disposal worldwide. Biological processes convert the organic material into an environmentally harmful landfill gas, which has an impact on the greenhouse effect. After the depositing of waste has been stopped, current conversion processes continue and emissions last for several decades and even up to 100years and longer. A good prediction of these processes is of high importance for landfill operators as well as for authorities, but suitable models for a realistic description of landfill processes are rather poor. In order to take the strong coupled conversion processes into account, a constitutive three-dimensional model based on the multiphase Theory of Porous Media (TPM) has been developed at the University of Duisburg-Essen. The theoretical formulations are implemented in the finite element code FEAP. With the presented calculation concept we are able to simulate the coupled processes that occur in an actual landfill. The model's theoretical background and the results of the simulations as well as the meantime successfully performed simulation of a real landfill body will be shown in the following. PMID- 20833013 TI - Surface functionalization of electrospun nanofibers for detecting E. coli O157:H7 and BVDV cells in a direct-charge transfer biosensor. AB - Electrospinning is a versatile and cost effective method to fabricate biocompatible nanofibrous materials. The novel nanostructure significantly increases the surface area and mass transfer rate, which improves the biochemical binding effect and sensor signal to noise ratio. This paper presents the electrospinning method of nitrocellulose nanofibrous membrane and its antibody functionalization for application of bacterial and viral pathogen detection. The capillary action of the nanofibrous membrane is further enhanced using oxygen plasma treatment. An electrospun biosensor is designed based on capillary separation and conductometric immunoassay. The silver electrode is fabricated using spray deposition method which is non-invasive for the electrospun nanofibers. The surface functionalization and sensor assembly process retain the unique fiber morphology. The antibody attachment and pathogen binding effect is verified using the confocal laser scanning microscope (CLSM) and scanning electronic microscope (SEM). The electrospun biosensor exhibits linear response to both microbial samples, Escherichia coli O157:H7 and bovine viral diarrhea virus (BVDV) sample. The detection time of the biosensor is 8 min, and the detection limit is 61 CFU/mL and 10(3)CCID/mL for bacterial and viral samples, respectively. With the advantage of efficient antibody functionalization, excellent capillary capability, and relatively low cost, the electrospinning process and surface functionalization method can be implemented to produce nanofibrous capture membrane for different immuno-detection applications. PMID- 20833014 TI - An embedded portable biosensor system for bacterial concentration detection. AB - Microbial screening is a primary concern for many products. Traditional techniques based on standard plate count (SPC) are accurate, but time consuming. Furthermore, they require a laboratory environment and qualified personnel. The impedance technique (IT) looking for changes in the electrical characteristics of the sample under test (SUT) induced by bacterial metabolism represents an interesting alternative to SPC since it is faster (3-12h vs. 24-72 h for SPC) and can be easily implemented in automatic form. With this approach, the essential parameter is the time for bacteria concentration to reach a critical threshold value (about 10(7) cfu mL(-1)) capable of inducing significant variations in the SUT impedance, measured by applying a 100 mV peak-to-peak 200 Hz sinusoidal test signal at time intervals of 5 min. The results of this work show good correlation between data obtained with the SPC approach and with impedance measurements lasting only 3h, in the case of highly contaminated samples (10(6) cfu mL(-1)). Furthermore, this work introduces a portable system for impedance measurements composed of an incubation chamber containing the SUT, a thermoregulation board to control the target temperature and an impedance measurement board. The mix of cheap electronics and fast detection time provides a useful tool for microbial screening in industrial and commercial environments. PMID- 20833015 TI - Biological investigation using a shear horizontal surface acoustic wave sensor: small "click generated" DNA hybridization detection. AB - We have used a 104 MHz lithium tantalate (LiTaO(3)) surface acoustic wave (SAW) sensor to investigate DNA probes grafting and their further hybridization with natural and click generated (Cg-DNA) oligonucleotides. Natural DNA targets of different strand lengths, tosyl-di(tri, tetra) thymidine and azido-di(tri, tetra) thymidine oligonucleotides were tested. In our case, and besides the follow-up of a 34mer DNA hybridization, we detected complementarity between natural DNA probes and azido-tetra-thymidine for the first time, whereas previous hybridization studies reported a minimal of 10-mer oligonucleotides recognition length. We also demonstrated that contrarily to natural DNA, the synthesized oligonucleotides present stable bonds with complementary DNA strands. Frequency responses of both grafting and hybridization have shown the same shape: an exponential decay with different time constants, (187+/-1)s and (68+/-19) s for grafting and hybridization respectively. We have also shown that recognition between DNA strands and tetranucleotide analogues is comparable to natural 34mer DNA bases and presents the same time constant within uncertainties. PMID- 20833016 TI - A novel nitromethane biosensor based on biocompatible conductive redox graphene chitosan/hemoglobin/graphene/room temperature ionic liquid matrix. AB - A novel amperometric biosensor for nitromethane (CH(3)NO(2)) based on immobilization of graphene (GR), chitosan (CS), hemoglobin (Hb) and room temperature ionic liquid (IL) on a glassy carbon electrode (GCE) was developed for the first time. The surface morphologies of a set of representative membranes were characterized by means of scanning electron microscopy (SEM). The electrochemical performance of the biosensor was evaluated by cyclic voltammetry (CV) and chronoamperometry. A pair of stable and well-defined redox peaks of Hb with a formal potential of -0.240 V was observed at the GR-CS/Hb/GR/IL/GCE. The effects of phosphate buffer pH, scan rate, and temperature on the biosensor were investigated to provide optimum analytical performance. Moreover, several electrochemical parameters, e.g., the heterogeneous electron transfer rate constant (k(s)), were calculated in detail. The presence of both GR and IL not only dramatically facilitated the electron transfer of Hb, but also greatly enhanced electrocatalytic activity towards CH(3)NO(2). The apparent Michaelis Menten constant was down to 0.16 MUM, indicating that the biosensor possessed high affinity to CH(3)NO(2). Besides this, the proposed biosensor exhibited fast amperometric response (<5s), low detection limit (6.0 * 10(-10)M), and excellent long-time storage stability for the determination of CH(3)NO(2). PMID- 20833017 TI - Fiber-optic particle plasmon resonance sensor for detection of interleukin-1beta in synovial fluids. AB - A facile and label-free biosensing method has been developed for determining an osteoarthritis concerned cytokine, interleukin-1beta (IL-1beta), in synovial fluids. The biosensing technique, fiber-optic particle plasmon resonance (FOPPR), is based on gold nanoparticles-modified optical fiber where the gold nanoparticle surface has been modified by a mixed self-assembled monolayer for further conjugation of anti-IL-1beta antibody and minimization of nonspecific adsorption. Upon binding of IL-1beta to anti-IL-1beta on the gold nanoparticle surface, the absorbance of the gold nanoparticle layer on the optical fiber changes and the signal change is enhanced through multiple total internal reflections along the optical fiber. Results show that the detection of IL-1beta in synovial fluid by this sensor agrees quantitatively with the clinically accepted enzyme-linked immunosorbent assay (ELISA) method but a much shorter analysis time is required (<10 min). The sensor response versus log concentration of IL-1beta was linear (r=0.9947) over the concentration range of 0.050-10 ng/mL and a limit of detection (LOD) of 21 pg/mL (1.2 pM) was achieved. Such a LOD for IL-1beta (17 kDa) represents a major advancement in the field of real-time monitoring of low molecular weight proteins in complex biological fluids. PMID- 20833018 TI - Electrochemical detection of DNA hybridization based on signal DNA probe modified with Au and apoferritin nanoparticles. AB - A novel and ultrasensitive electrochemical approach for sequence-specific DNA detection based on signal dual-amplification with Au NPs and marker-loaded apoferritin NPs was reported. Target DNA was sandwiched between capture DNA coupled to magnetic beads and signal DNA self-assembled on Au NPs which were incorporated with marker-loaded apoferritin NPs. Subsequent electrochemical stripping analysis of the electroactive markers released from apoferritin NPs in acidic buffers provided a means to quantify the concentration of target DNA. In this means, one target signal could be transformed into multiple redox signals of the markers since a single Au NP could be loaded with dozens of apoferritin NPs, and an apoferritin NP could be loaded with thousands of markers. Under the optimum conditions, the linear range was from 2.0 * 10(-16) to 1.0 * 10(-14)M and the detection limit was 5.1 * 10(-17)M by using the cadmium as a model marker. The proposed DNA biosensor not only exhibited excellent sensitivity but also had good reproducibility and selectivity against two-base mismatched DNA. PMID- 20833019 TI - Tuberculosis infection of the talonavicular joint. AB - Isolated tuberculosis osteomyelitis affecting the foot is extremely rare. Symptoms are nonspecific and haematological investigations are often unhelpful making diagnosis difficult. We report the case of a 41-year-old female who presented with a 7-month history of a painful hindfoot following a minor ankle sprain. Inflammatory markers were mildly raised and initial radiographs showed only some mild narrowing of the talonavicular joint. MRI scanning suggested osteomyelitis centred over the talonavicular joint. Open biopsy confirmed areas of caseous necrosis but no acid-fast bacilli were seen. The final diagnosis was confirmed with culture of mycobacterium tuberculosis. A good recovery was seen following debridement and commencement of anti-tuberculosis chemotherapy. Unless an awareness of this condition exists, the diagnosis and therefore the appropriate treatment can often be delayed which may lead to significant consequences for the patient. PMID- 20833020 TI - Upward tibiotalar dislocation without fracture: A case report. AB - Pure tibiotalar dislocations without associated fracture are rare. The authors report a case of an unusual closed tibiotalar dislocation without fracture involving proximal ascension of the talus. Immediate closed reduction was performed. Repair of the disrupted medial ligament was performed and one syndesmosis screw inserted, followed by 6 weeks of immobilization. After 1 year of follow-up, functional results were excellent. PMID- 20833023 TI - Effect of OPRM variant on labor analgesia and post-cesarean delivery analgesia. PMID- 20833024 TI - Normal urine output after elective caesarean section: an observational study. AB - BACKGROUND: When monitoring postoperative urine output there is no guidance specific to obstetrics. Factors such as peri-operative oxytocin infusions add further complexity. Our aim was to determine a normal range for urine output after elective caesarean section under neuraxial anaesthesia. METHODS: Sixty women were recruited and for 24h from the time of urethral catheterisation, we recorded urine output and fluid input. We also measured intra-operative blood loss, use of prophylactic oxytocin infusion and markers of renal function. Data were compared with Mann-Whitney U-tests or paired t tests. RESULTS: Oxytocin infusions were used in 45 women (75%). Median (95% CI) urine output in the first 6h was 0.8 (0.4-1.9) mL kg(-1)h(-1) in women receiving oxytocin compared to 1.4 (0.7-2.2)mL kg(-1)h(-1) in those who did not (P=0.02). Urine output for all women at 12 and 18 h was 2.0 (0.7-5.7) and 1.9 (0.5-4.5)mL kg(-1)h(-1). Blood loss was 0.4 (0.2-0.8)L in women with oxytocin infusions and 0.3 (0.1-0.4)L in those without (P=0.003). Mean (SD) pre- and postoperative urine osmolality was 622.5 (185.7) and 293.0 (135.1) mosm/kg, respectively (P<0.0001). CONCLUSIONS: Urine output varied widely between subjects, especially after the first 6h and was further reduced by the use of oxytocin infusion. This may have been a direct effect or related to increased blood loss in this group. Oxytocin use should be accounted for when setting a minimum postoperative urine output. We also found high pre-operative urine osmolalities suggesting significant dehydration. PMID- 20833025 TI - Obstetric anaesthesia and transverse myelitis. PMID- 20833026 TI - Peripartum cardiac chest pain and troponin rise. AB - The incidence of myocardial ischaemia is increasing in the obstetric population. This has been attributed to several factors including greater maternal age, the increasing incidence of obesity and diabetes, and the growing population of patients with grown-up congenital heart disease who now reach adulthood and become pregnant. A number of cases of myocardial ischaemia in pregnant women have been documented, during and after delivery, for which no cause has been established. We present a case of a nulliparous woman who developed cardiac chest pain, bradycardia, hypertension and a raised troponin I after vaginal delivery of twin boys at 36 weeks of gestation. Ischaemic electrocardiogram changes were noted. Detailed investigations demonstrated a normal coronary circulation. A patent foramen ovale was found on bubble echocardiography. PMID- 20833027 TI - Factors influencing cesarean delivery operative times: a prospective observational cohort study. AB - BACKGROUND: This study aimed to determine the distribution of operative delivery times for uncomplicated parturients undergoing elective cesarean delivery with neuraxial anesthesia. A secondary aim was to explore patient and surgical factors associated with longer cesarean delivery times. METHODS: A prospective observational study of 331 parturients undergoing elective cesarean delivery with neuraxial anesthesia was conducted. Factors examined included age, body mass index, ethnicity, number of previous cesarean deliveries, stretch mark and scar severity and surgical experience. RESULTS: Operative times ranged from 13 to 108 min with a mean (SD) of 43.4 (+/-15.7) min. Only 6 (1.8%) parturients had operative times >90 min and none were converted to general anesthesia. As the number of previous cesarean deliveries increased, the mean operative time increased linearly from 39.5 (+/-13.0) min in subjects with no previous cesarean deliveries to 52.8 (+/-18.1) min in subjects with 3 or 4 previous cesarean deliveries (P<0.0005). For parturients with previous cesarean deliveries, operative times were longer for those with scar scores > or =5 than for those with scores <5 (P<0.01). Stretch mark scores were not associated with operative times. Tubal ligation prolonged the total operative time by a mean of 7 min (P<0.0005), and attending staff required a mean of 6 more min than residents or fellows (P<0.01). There was no correlation between operative times, age and body mass index and little variation with ethnicity. CONCLUSIONS: These findings identify previous cesarean deliveries, increased scar intensity, tubal ligation and surgical experience as factors that increase operative times for cesarean delivery. The data also suggest that neuraxial anesthesia lasting 90 min should provide adequate analgesia for most uncomplicated parturients undergoing elective cesarean delivery. PMID- 20833029 TI - Cardiac output and fluid replacement in a Jehovah's Witness with severe postpartum hemorrhage. PMID- 20833030 TI - Postpartum headache. AB - Headache is a common puerperal complaint. A wide variety of factors can be involved, ranging from hormonal shifts, physiological changes, and peripartum procedures that may precipitate, worsen, or cause troublesome headache. The differential diagnosis of postpartum headache is broad and potentially daunting to the various clinicians caring for the postpartum patient. It often requires further neurological consultation or imaging to resolve. This review will focus on the main causes of postpartum headache, their incidence, and clinical presentation. Causes of postpartum headache that will be covered include benign primary headache disorders such as migraine and tension type headache as well as secondary headache disorders such as postdural puncture headache, stroke, and venous sinus thrombosis. A structured approach to headache evaluation in the postpartum patient will be presented to help differentiate the possible causes of headache. PMID- 20833031 TI - Control of movements and temporal discounting of reward. AB - Let us assume that the purpose of any movement is to position our body in a more rewarding state. People and other animals discount future reward as a function of time. Recent results suggest that there is a correlation between changes in this reward temporal discount function and changes in saccadic velocity and duration. These results suggest that each movement carries a cost because its duration delays acquisition of reward. The value that the brain assigns to the stimulus, and the rate at which it discounts this value in time, form a cost that appears to influence the motor commands that move our body. PMID- 20833032 TI - The conformation and structure of GAGs: recent progress and perspectives. AB - The glycosaminoglycan (GAG) family of linear sulphated polysaccharides are involved in most regulatory processes in the extracellular matrix of higher organisms. The relationship between GAG substitution pattern and activity, however, remains unclear and experimental evidence suggests that subtle conformational factors play an important role. The difficulty of modelling these complex charged molecules shifts the burden of investigation towards experimental techniques. Recent advances in complementary physical-chemical, particularly spectroscopy-based approaches are reviewed, together with methods for analysing the resulting complex data. The prospects for combining some of these approaches and fitting them into the wider context of interactions, are also discussed. PMID- 20833033 TI - False-positive Human Papillomavirus DNA tests in cervical screening: it is all in a definition. AB - AIM: Based on data from randomised controlled trials (RCT) on primary cervical screening, it has been reported that the problem of more frequent false-positive tests in Human Papillomavirus (HPV) DNA screening compared to cytology could be overcome. However, these reports predominantly operated with a narrow definition of a (false-)positive test. The aim of this paper was to illustrate how the narrow definition affected the measured adverse effects of HPV DNA screening compared with cytology screening. METHODS: In the European RCT data, we measured the impact of the narrow definition of a positive screening test on the published relative positive predictive values (PPV), an indicator of the relative frequency of false-positive screening tests. RESULTS: Using the trialists' definitions of positive screening tests, HPV screening combined with cytology triage had relative PPVs of 0.87 (95% confidence interval (CI): 0.60-1.26) for >= CIN3 based on Swedish RCT data, and 0.78 (0.52-1.16) for >= CIN2 in the Italian Phase 1 RCT (25-34 years). These PPVs changed to 0.44 (0.30-0.64) and 0.51 (0.33-0.79), respectively, when all positive HPV or cytology screening tests were accounted for. In the Finnish RCT data, HPV screening using the cut-off point of >= 10 pg/ml had a relative PPV of 0.27 (0.15-0.50) for >= CIN3, which changed to 1.84 (0.99-3.41). CONCLUSION: The relative PPV was incorrectly estimated in six out of seven studies. In three of those six studies, the relative PPV changed significantly after inclusion of the previously erroneously excluded false positive HPV or cytology tests. PMID- 20833034 TI - ABO blood group and cancer. AB - BACKGROUND: ABO blood type has been associated with various malignancies, including pancreatic cancer. Our aim was to study this association using data from a hospital-based tumour registry. METHODS: From the tumour registry, we retrieved data from 15,359 cancer patients treated during 2000-2003 at the European Institute of Oncology (Milan, Italy), with defined ABO blood type. We performed a case-control analysis, comparing the distribution of ABO blood types of patients with each specific form of cancer against that of patients with other forms of cancer. We also reviewed the literature and performed a meta-analysis on the association between ABO blood group and pancreatic cancer. RESULTS: We observed a significantly lower frequency of blood type O in patients with exocrine pancreatic cancer compared to patients with other forms of cancer (29% versus 44%; P<0.001; odds ratio (OR), 0.53; 95% confidence intervals (CI), 0.33 0.83). This association was confirmed by the meta-analysis of seven prior studies (summary relative risk, 0.79; 95% CI, 0.70-0.90). No association was found for endocrine pancreatic cancer or for cancer originating in other organs. CONCLUSIONS: Our data suggest that the association between ABO blood group and cancer is limited to exocrine pancreas malignancy. PMID- 20833035 TI - A class of novel conjugates of substituted purine and Gly-AA-OBzl: synthesis and evaluation of orally analgesic activity. AB - Aimed at the chemotherapy of chronic pain two kinds of analgesic pharmacophores, substituted purine and Gly-AA-OBzl, were coupled via a five-step-reaction procedure and 19 novel conjugates N-[2-chloro-9-(tetrahydropyran-2-yl)-9H-purin-6 yl]-N-cyclopropylglycylamino acid benzylesters were provided. On mouse-tail flick model their in vivo analgesic activities were assayed. The results indicate that introducing Gly-OC(2)H(5) into the 6-position of the substituted purine leads to ambiguous increase of the analgesic activity, while introducing Gly-AA-OBzl into this position leads to significant increase of the analgesic activity. PMID- 20833036 TI - Thienopyrimidines as beta3-adrenoceptor agonists: hit-to-lead optimization. AB - Resulting from a vHTS based on a pharmacophore alignment on known beta3 adrenoceptor ligands, an aryloxypropanolamine scaffold comprising a thienopyrimidine moiety was further optimized as a human beta3-AR agonist, yielding a lead compound with an excellent cellular activity of EC(50)=20 pM, selectivity over hbeta1- and hbeta2-adrenoceptors and a promising safety profile. PMID- 20833037 TI - Design and synthesis of substrates for newborn screening of Maroteaux-Lamy and Morquio A syndromes. AB - In continued efforts to develop enzymatic assays for lysosomal storage diseases appropriate for newborn screening laboratories we have synthesized novel and specific enzyme substrates for Maroteaux-Lamy (MPS VI) and Morquio A (MPS IVA) diseases. The sulfated monosaccharide derivatives were found to be converted to product by the respective enzyme in blood from healthy patients but not by blood from patients with the relevant lysosomal storage disease. The latter result shows that the designed substrates are highly selective for the respective enzymes. PMID- 20833038 TI - Discovery of pyrrolopyridazines as novel DGAT1 inhibitors. AB - A new structural class of DGAT1 inhibitors was discovered and the structure activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 MUM to 48 nM. PMID- 20833040 TI - Quantitative screening of EGF receptor-binding peptides by using a peptide library with multiple fluorescent amino acids as fluorescent tags. AB - EGF receptor-binding peptides could be found by a peptide screening method using fifteen fluorescent amino acids as fluorescent tags. Of 225 peptides, we found an 8-mer peptide containing a dipeptide unit, Y-F, which was the strongest binding peptide to the EGF receptor. PMID- 20833039 TI - Novel azulene-based derivatives as potent multi-receptor tyrosine kinase inhibitors. AB - A series of azulene-based derivatives were synthesized as potent inhibitors for receptor tyrosine kinases such as FMS-like tyrosine kinase 3 (FLT-3). Systematic side chain modification of prototype 1a was carried out through SAR studies. Analogue 22 was identified from this series and found to be one of the most potent FLT-3 inhibitors, with good pharmaceutical properties, superior efficacy, and tolerability in a tumor xenograft model. PMID- 20833041 TI - Design of an orally efficacious hydroxyethylamine (HEA) BACE-1 inhibitor in a preclinical animal model. AB - In this Letter, we describe our efforts to design HEA BACE-1 inhibitors that are highly permeable coupled with negligible levels of permeability-glycoprotein activity. These efforts culminate in producing 16 which lowers Alphabeta by 28% and 32% in the cortex and CSF, respectively, in the preclinical wild type Hartley guinea pig animal model when dosed orally at 30mpk BID for 2.5days. PMID- 20833042 TI - Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors. AB - The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed. PMID- 20833043 TI - Investigation of 4-piperidinols as novel H3 antagonists. AB - Compounds containing a substituted 4-piperidinol core have been found to be potent antagonists of the human H(3) receptor. The compounds exhibited up to a 60 fold preference for inhibiting the human H(3) receptor over the mouse and showed a low binding affinity for the hERG channel. PMID- 20833044 TI - Synthesis and antiviral evaluation of alpha-D-2',3'-didehydro-2',3'-dideoxy-3'-C hydroxymethyl nucleosides. AB - We have identified a selective S(N)2' reaction triggered by iodide ion that leads to the ring-opening of 2,2'-anhydro-alpha-nucleosides. By applying the method, we have synthesized alpha-D-2',3'-didehydro-2',3'-dideoxy-3'-C-hydroxymethyl nucleosides, designed as potential antiviral agents. PMID- 20833045 TI - Branching enzyme deficiency/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular genetic studies. AB - The fatal infantile neuromuscular presentation of branching enzyme deficiency (glycogen storage disease type IV) due to mutations in the gene encoding the glycogen branching enzyme, is a rare but probably underdiagnosed cause of congenital hypotonia. We report an infant girl with severe generalized hypotonia, born at 33 weeks gestation who required ventilatory assistance since birth. She had bilateral ptosis, mild knee and foot contractures and echocardiographic evidence of cardiomyopathy. A muscle biopsy at 1 month of age showed typical polyglucosan storage. The autopsy at 3.5 months of age showed frontal cortex polymicrogyria and polyglucosan bodies in neurons of basal ganglia, thalamus, substantia innominata, brain stem, and myenteric plexus, as well as liver involvement. Glycogen branching enzyme activity in muscle was virtually undetectable. Sequencing of the GBE1 gene revealed a homozygous 28 base pair deletion and a single base insertion at the same site in exon 5. This case confirms previous observations that GBE deficiency ought to be included in the differential diagnosis of congenital hypotonia and that the phenotype correlates with the 'molecular severity' of the mutation. PMID- 20833047 TI - Recycling endosomes in apical plasma membrane domain formation and epithelial cell polarity. AB - Recycling endosomes have taken central stage in the intracellular sorting and polarized trafficking of apical and basolateral plasma membrane components. Molecular players in the underlying mechanisms are now emerging, including small GTPases, class V myosins and adaptor proteins. In particular, defects in the expression or function of these recycling endosome-associated and endosome regulating proteins have been implicated in cell surface polarity defects and diseases, including microvillus inclusion disease, arthrogryposis-renal dysfunction-cholestasis syndrome, and virus susceptibility. Key findings are that recycling endosomes recruit and deliver core polarity proteins to lateral cell surfaces and initiate the biogenesis of apical plasma membrane domains and epithelial cell polarity. Here, we review recent data that implicate recycling endosomes in the establishment and maintenance of epithelial cell polarity. PMID- 20833046 TI - Dicing with dogma: de-branching the lamellipodium. AB - The primary event in the movement of a migrating eukaryotic cell is the extension of cytoplasmic sheets termed lamellipodia composed of networks of actin filaments. Lamellipodia networks are thought to arise through the branching of new filaments from the sides of old filaments, producing a dendritic array. Recent studies by electron tomography have revealed the three dimensional organization of lamellipodia and show, contrary to previous evidence, that actin filaments do not form dendritic arrays in vivo. These findings signal a reconsideration of the structural basis of protrusion and about the roles of the different actin nucleating and elongating complexes involved in the process. PMID- 20833048 TI - Is vertical postural orientation in weightlessness correlated with the subjects' perceptual typology? AB - It was proposed to investigate whether the central nervous system is able to select the most appropriate reference frame for controlling subjects' vertical orientation in response to severe environmental constraints such as microgravity and support perturbations. The question addressed was whether the subjects, regardless of their perceptual typology, might be able to use the same visual reference frame to control their vertical orientation. Fifteen subjects were asked to perform a sit-to-stand (STS) task under microgravity. Subjects were seated on a chair with their feet fixed to a horizontal or forwards tilted support (20 degrees ). When the support was tilted the subjects' ankles were placed at an angle of 110 degrees . Two main findings emerged from this study. First, in all the experimental conditions, the results obtained showed that the subjects' controlled their postural orientation fairly correctly but not very precisely, since a bias was systematically observed in their head and trunk orientation. In other words, changes in their ankle angles and the absence of gravity only slightly disturbed their vertical body orientation, and when these two constraints were applied concomitantly, their effects were not cumulative. Secondly, contrary to our initial hypothesis, the subjects' postural orientation performances were not correlated with the perceptual typology. All the subjects preferentially used the visual reference frame to control their vertical postural orientation. The present findings confirm that the proprioceptive dominance of visual independent (VI) subjects enhances their ability to select the most appropriate reference frame to deal with inter-sensory disturbances such as those consisting here of microgravity combined with proprioceptive perturbations imposed at ankle level. PMID- 20833049 TI - The efficacy of routine hyperventilation for seizure activation during prolonged video-electroencephalography monitoring. AB - Hyperventilation (HV) is considered to be one of the activation procedures that provokes epileptic potentials and clinical seizures. However, the true clinical yield of HV is not well established. We retrospectively reviewed the records of all patients admitted to JFK Hospital, Edison, New Jersey, between October 2001 and December 2004 for long-term video-electroencephalography (EEG). A total of 475 patients (193 males; 282 females; age range 5-89 years) were included in the study. All patients underwent routine 3-minute HV as part of the evaluation of their clinical episodes. During the initial assessment, 165 patients did not experience a seizure event, 92 had non-epileptic events, 16 experienced psychogenic non-epileptic seizures (PNES) and six had a clinical event. During HV, of the 43 patients who had primary generalized epilepsy, nine had an abnormal EEG and two experienced seizures; however, out of the 159 patients who had partial seizures, only one patient demonstrated an abnormal EEG. Our study demonstrates that routine HV generally has a very low yield in our Epilepsy Monitoring Unit. This finding also lends support to the idea that partial seizures are relatively resistant to HV activation. PMID- 20833050 TI - Electroencephalographic abnormalities in baclofen-induced encephalopathy. AB - We report a patient in whom the characteristic electroencephalographic features of baclofen intoxication are highlighted and emphasize the role of electrographic abnormalities in the diagnosis of this condition. PMID- 20833051 TI - Recurrent dissociation of the tibial insert after mini-subvastus posterior stabilized total knee arthroplasty: a case report. AB - We report here on an unusual case of recurrent dissociation of a polyethylene tibial insert from its metal baseplate after high-flex posterior-stabilized (PS) Genesis II total knee arthroplasty with using the mini-subvastus approach. After the 1st episode of dissociation, which had happened 1 month after the primary surgery, we changed the tibial insert and found damages on the dovetails and the post of the retrieved insert. Unfortunately, the patient suffered the same dissociation 1 month after the tibial insert was changed. This case illustrates that incomplete seating of the insert due to limited surgical exposure and anterior impingement of the high-flex PS post may contribute to the risk of dissociation. PMID- 20833052 TI - Potential application of thymidylate kinase in nucleoside analogue activation in Plasmodium falciparum. AB - Plasmodium falciparum thymidylate kinase (PfTMPK) shows a broad range of substrate tolerance when compared to the corresponding human enzyme. Besides 2' deoxythymidine monophosphate (dTMP), PfTMPK can phosphorylate 3'-azido-2',3' dideoxythymidine monophosphate (AZTMP) very efficiently. In contrast, human thymidylate kinase (hTMPK) is 200 times less active towards AZTMP. We were interested to see if we could use PfTMPK to activate 3'-azido-2',3' deoxythymidine (AZT) derivatives as a strategy to treat malaria. P. falciparum lacks a pyrimidine nucleoside kinase which usually activates nucleoside and nucleoside analogues to the corresponding monophosphates. Therefore, several prodrug analogues of AZT and related nucleoside monophosphates were prepared and analysed for antiparasitic activity. The prodrugs showed an increase in activity over the parent nucleoside analogues, which showed no inhibition of parasite growth at the concentration tested. The evidence here reported provides a strategy that could be exploited for further anti-malarial design. PMID- 20833053 TI - Intermolecular interaction and morphology investigation of drug loaded ABA triblock copolymers with different hydrophilic/lipophilic ratios. AB - Copolymers with different hydrophilic/lipophilic ratios (HLR) were used to optimize the compatibility between polymer as drug carrier and quercetin as lipophilic drug. Synthesis of amphiphilic triblock copolymers (TC) of poly(butylene adipate)-poly(ethylene glycol)-poly(butylene adipate) (PBA-PEG-PBA) with different PBA molecular weights is the first approach for this purpose. Polymerization and structural features of the polymers were analyzed by different characterization techniques (GPC, (1)H NMR and FT-IR). Formation of hydrophobic and hydrophilic domains with different ratios in the ABA-triblock copolymers was studied by (1)H NMR. The sunflower-like nanoparticles were prepared by self assembling of the amphiphilic copolymers in the aqueous solution. The hydrophobic PBA segments formed the central solid-like core which stabilized by the hydrophilic PEG rings. The optimum HLR for these copolymers was determined on the basis of drug release time and profile, obtained from freeze-dried nanoparticle powders. The results indicated that optimum HLR for the sustained quercetin release obtained at higher molecular weight of polyesteric domains. Zeta potential measurements showed that the nanoparticle size was close related to the initial concentrations of the nanoparticle dispersions and the compositions of the triblock copolymers. Moreover, TEM pictures showed that the nanocarriers morphologies were changed by changing HLR of triblock copolymers. The PBA-PEG-PBA nanoparticles also showed good drug loading properties, suggesting that they were very suitable as delivery devices for hydrophobic drugs. PMID- 20833054 TI - Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent. AB - A class of cyclic acyldepsipeptide antibiotics collectively known as the enopeptins has recently attracted much attention because of their activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These antibiotics are further distinguished by their novel mechanism of action in which they bind and deregulate the tightly controlled activity of the cytoplasmic protease ClpP. Although the natural products have poor pharmacological properties, a synthetic derivative called acyldepsipeptide 4 (ADEP 4) showed remarkable antibacterial activity both in vitro and in mouse models of bacterial infections. A novel route to the ADEP 4 peptidolactone core structure, featuring the Joullie-Ugi three-component reaction, was developed. This multicomponent reaction and a related multicomponent reaction, the Ugi four-component reaction, were used to prepare analogs that were designed using the principles of conformational analysis. These cyclic acyldepsipeptides were tested for their activity against drug-resistant, clinical isolates of Staphylococci and Enterococci. One ADEP 4 analog in which the pipecolate was replaced by 4-methyl pipecolate exhibited in vitro antibacterial activity against Enterococci that was fourfold higher than the parent compound. PMID- 20833055 TI - Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2 d]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation. AB - We synthesized a series of pyrrolo[3,2-d]pyrimidine derivatives and evaluated their application as type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase. Incorporation of a diphenylurea moiety at the C4 position of the pyrrolo[3,2-d]pyrimidine core via an oxygen linker resulted in compounds that were potent inhibitors of VEGFR2 kinase. Of these derivatives, compound 20d showed the strongest inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells (HUVEC). The co-crystal structure of 20d and VEGFR2 revealed that 20d binds to the inactive form of VEGFR2. Further studies indicated that 20d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited PDGFR and Tie-2 kinases. Oral administration of the hydrochloride salt of 20d at 3mg/kg/day showed potent inhibition of tumor growth in a DU145 human prostate cancer cell xenograft nude mouse model. PMID- 20833056 TI - Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring. AB - Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7 deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 MUM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 MUM, MIC isoniazid 0.28 MUM and MIC PA-824 0.44 MUM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low oxygen-recovery assay (LORA) >= 60 MUM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli. PMID- 20833057 TI - Synthesis and evaluation of original amidoximes as antileishmanial agents. AB - An original series of amidoxime derivatives was synthesized using manganese(III) acetate, Buchwald-Hartwig and Heck reactions. Two amidoximes (39 and 52) showed interesting in vitro activities toward Leishmania donovani promastigotes, exhibiting 8.3 and 8.8 MUM IC(50) values. Moreover, the cytotoxicity of these compounds was evaluated on human THP1 cells, giving access to the corresponding selectivity index. Among the 25 tested compounds, amidoximes 38 and 39 and diamidoximes 50 and 52 exhibited a better selectivity index than pentamidine used as a drug compound reference. PMID- 20833058 TI - Molecular characterization of RsMPK2, a C1 subgroup mitogen-activated protein kinase in the desert plant Reaumuria soongorica. AB - Reaumuria soongorica (Pall.) Maxim. is a short woody shrub widely found in semi arid areas of China, and can survive severe environmental stresses. To understand its potential signaling transduction pathway in stress tolerance, we investigated the participation of mitogen-activated protein kinases (MAPKs) as possible mediators of abiotic stresses. A novel MAP kinase cDNA (RsMPK2) that encodes a 374 amino acid protein was isolated from R. soongorica. RsMPK2 belongs to the C1 subgroup, which is still functionally uncharacterized compared to groups A and B; and contains all 11 of the conserved MAPK subdomains and the TEY phosphorylation motif. RsMPK2 is expressed in vegetative (root, stem, leaf and callus) and reproductive (flower) organs. The transcripts of RsMPK2 were rapidly accumulated at high levels when R. soongorica was subjected to dehydration, salinity conditions and treatment with abscisic acid or hydrogen peroxide. Growth analysis of Escherichia coli (srl::Tn10) cells transformed with pPROEXHT-RsMPK2 showed that the expression products of RsMPK2 do not act as an osmoprotectant. But, the inhibition of RsMPK2 expression by the inhibitor U0126 induced a decrease of antioxidant enzyme activity under stresses, indicating that RsMPK2 is involved in the regulation of the antioxidant defense system in the response to stress signaling. PMID- 20833059 TI - Determinants of success of surgical innovation. PMID- 20833060 TI - [(18)F]Fluorodeoxyglucose positron emission tomography-computerized tomography and lung cancer: a significant referral bias exists. AB - OBJECTIVE: [(18)F]Fluorodeoxyglucose positron emission tomography-computerized tomography (PET-CT) scan is a tool widely used in the diagnosis and staging of lung cancer. Referral bias is present when the results of a diagnostic study affect the decision to proceed with definitive testing. This bias artificially increases the sensitivity and decreases the specificity, and may inappropriately alter the decision to undergo definitive testing. The accuracy of PET-CT scan in suspected lung cancer and the role of referral bias were investigated. METHODS: From January 2005 through June 2007, 584 consecutive patients undergoing PET-CT scan for suspected lung cancer were studied. Endpoints measured included qualitative and quantitative results of PET-CT scans and pathologic results from patients, who underwent invasive procedures for diagnosis, staging and/or therapy. A positive PET scan was defined as one in which the standard uptake value (SUV) was greater than 2.5. A standard mathematical model, based on overall results of PET-CT scan in all patients, was used to create adjustments to account for the effect of referral bias. RESULTS: A total of 414 (71%) of PET-CT scans were reported as positive, while 170 (29%) were negative. Attempt at tissue diagnosis occurred in 417 patients (71%); surgical intervention was performed in 246 (42%). Whereas 86% (355/414) of patients with a positive PET-CT scan underwent tissue sampling, only 36% (62/170) with a negative PET-CT scan had an attempt (p<.001). In patients with a positive study, a higher SUV was associated with an attempt at tissue diagnosis (p<.001). Before adjustment, the sensitivity and specificity of the PET-CT scan for any cancer were 87% and 43%. After adjustment, sensitivity fell to 75%, while specificity rose to 64%. The unadjusted sensitivity of PET-CT scan for detecting mediastinal disease was only 79%. CONCLUSIONS: The estimate of the accuracy of PET-CT scan is significantly influenced by referral bias, and a strong reliance is placed on its results. Furthermore, patients with a positive PET-CT scan are more likely to undergo tissue sampling as the SUV increases. Given the relatively low sensitivity of the PET-CT scan in detecting disease and its poor performance in the mediastinum, the PET-CT scan may have too high an impact on the decision to undergo further invasive diagnostic procedures. Patients should not be deferred from tissue sampling based solely on a negative PET-CT scan. PMID- 20833061 TI - On the efficiency of the long wavelength minor bacteriochlorophyll groups in the vicinity of reaction centers. AB - The role of minor chlorophyll and bacteriochlorophyll groups in excitation delivery to reaction centers and subsequent trapping in them was analyzed by means of PC-modeling. The analysis of general type of photosynthetic units and, in particular, those resembling typical photosystems of purple bacteria, has revealed some types of structures in which the presence of minor BChl fractions in the vicinity of reaction centers did increase the efficiency of the useful energy trapping. In some cases the spectral range of optimal energy conversion is broadened. PMID- 20833062 TI - Nursing clinical practice guidelines to improve care for people undergoing percutaneous coronary interventions. AB - AIM: The aim of this paper is to present a set of nursing clinical practice guidelines for individuals undergoing percutaneous coronary interventions (PCIs) together with a summary of the evidence to support these recommendations. BACKGROUND: Percutaneous coronary intervention is a common procedure requiring expert nursing care delivered within an interdisciplinary team. Although evidence based medical practice guidelines exist, they include minimal information to guide nursing-specific care. GUIDELINES DEVELOPMENT: The guidelines development process used a framework of the patient journey. Three steps leading up to this paper were undertaken: (1) a comprehensive literature review; (2) a consensus development workshop; and (3) a modified Delphi technique to refine the guideline recommendations. SUMMARY: Clinical practice guidelines to support interventional cardiology nursing care are limited. This paper represents an important contribution toward meeting this need. IMPLICATIONS FOR PRACTICE: These guidelines, developed within a context of Australian and New Zealand nursing practice, provide an important foundation to enable benchmarking and ongoing developing clinical practice standards. PMID- 20833063 TI - Development of a T(H)17 immune response during the induction of murine syngeneic graft-versus-host disease. AB - Syngeneic graft-versus-host disease (SGVHD) develops following lethal irradiation, reconstitution with syngeneic bone marrow (BM) and treatment with a 21 day course of the immunosuppressive agent cyclosporine A (CsA). Clinical symptoms of SGVHD appear 2-3 weeks post-CsA with inflammation occurring in the colon and liver. Previously we have demonstrated that CD4(+) T cells and a T helper cell type 1 cytokine response (T(H)1) are involved in the development of SGVHD associated intestinal inflammation. Studies have recently discovered an additional T cell lineage that produces IL-17 and is termed T(H)17. It has been suggested that inflammatory bowel disease is a result of a T(H)17 response rather than a T(H)1 response. This study was designed to investigate T(H)17 involvement in SGVHD-associated colitis. Following induction of SGVHD, the levels of T(H)17 and T(H)1 cytokine mRNA and protein were measured in control and SGVHD animals. In vivo cytokine neutralization was performed to determine the role of the prototypic T(H)17 cytokine, IL-17, in the disease process. We found that during CsA-induced murine SGVHD there was an increase in both T(H)17 and T(H)1 mRNA and cytokines within the colons of diseased mice. The administration of an anti-mouse IL-17A mAb did not alter the course of disease. However, neutralization of IL-17A resulted in an increased production of IL-17F, a related family member, with an overlapping range of effector activities. These results demonstrate that in the pathophysiology of SGVHD, there is a redundancy in the T(H)17 effector molecules that mediate the development of SGVHD. PMID- 20833064 TI - Pilot study of interleukin-17 producing cells in synovial fluid monocytes of patients with systemic lupus erythematosus. PMID- 20833065 TI - Epigenetic and 3-dimensional regulation of V(D)J rearrangement of immunoglobulin genes. AB - V(D)J recombination is a crucial component of the adaptive immune response, allowing for the production of a diverse antigen receptor repertoire (Ig and TCR). This review will focus on how epigenetic regulation and 3-dimensional (3D) interactions may control V(D)J recombination at Ig loci. The interplay between transcription factors and post-translational modifications at the Igh, Igkappa, and Iglambda loci will be highlighted. Furthermore, we propose that the spatial organization and epigenetic boundaries of each Ig loci before and during V(D)J recombination may be influenced in part by the CTCF/cohesin complex. Taken together, the many epigenetic and 3D layers of control ensure that Ig loci are only rearranged at appropriate stages of B cell development. PMID- 20833066 TI - Intravenous administration of equine-derived whole IgG antivenom does not induce early adverse reactions in non-envenomed horses and cows. AB - Administration of antivenoms to treat snakebite envenomings has the potential risk of inducing early adverse reactions. The mechanisms involved in these reactions are unclear. In this study, polyspecific antivenom consisting of whole IgG purified from equine plasma by caprylic acid precipitation was administered intravenously to non-envenomed horses (n = 47) and cows (n = 20) at a dose of 0.4 mL/kg. It has been reported that, in humans, this formulation (administered at a dose of 0.4 mL/kg) induces mild noticeable early adverse reactions, such as fever, vomiting, diarrhea, urticaria, generalized rash, tachypnea or tachycardia, in about 15-20% of the patients. Unexpectedly, none of the animals receiving antivenom in our study showed any evidence of early adverse reaction. Moreover, no late adverse reactions, i.e. serum sickness, were observed during 40 days after antivenom administration. Unlike studies performed in envenomed humans, our present results were obtained in a group of non-envenomed individuals. It is concluded that, in addition to the physicochemical characteristics of the formulation, other unknown factors must determine the occurrence of adverse reactions in snakebite envenomed humans treated with equine-derived antivenoms. PMID- 20833067 TI - Defining new categories of pregnancy intention in African-American women. AB - OBJECTIVE: Half of all U.S. pregnancies are categorized as unintended at conception, but concerns persist that existing measures of pregnancy intention do not adequately reflect the complexities of reproductive desires and preferences. We explored new strategies for categorizing viewpoints toward future pregnancy focusing on young, low-income, African-American women, and assessed the stability of these viewpoints over time. For pregnancies that occurred during the study, we examined the utility of the newly derived categories for predicting retrospective measures of intendedness. METHODS: Data were collected using Q-methodology, a technique for eliciting subjective viewpoints and identifying shared patterns among individuals. African-American women ages 15 to 25 and at risk for pregnancy were recruited at clinics serving low-income populations. The women sorted statements reflecting attitudes and preferences regarding future pregnancy into a distribution on a continuum from "least true for me" to "most true for me." We used by-person factor analysis to derive latent viewpoints. RESULTS: We identified six factors each reflecting a unique viewpoint about future pregnancy. These were a pregnancy seeking factor, one reflecting both ambivalence and low reproductive control, and four reflecting pregnancy avoidance, with distinctions around social support, reproductive control, and desired pregnancy timing. Distribution of factors differed by age group, as well as by retrospective categorization of pregnancy intention for those women who became pregnant during the study. CONCLUSION: Our categories provide a nuanced reflection of women's points of view about future pregnancies, and, with further validation, may prove useful for predicting or preventing contraceptive nonuse, undesired conceptions, and associated adverse outcomes. PMID- 20833068 TI - Patient predictors of colposcopy comprehension of consent among English- and Spanish-speaking women. AB - PURPOSE: patients with limited English proficiency may be at increased risk for diminished understanding of clinical procedures. This study sought to assess patient predictors of comprehension of colposcopy information during informed consent and to assess differences in understanding between English and Spanish speakers. METHODS: between June and August 2007, English- and Spanish-speaking colposcopy patients at two Boston hospitals were surveyed to assess their understanding of the purpose, risks, benefits, alternatives, and nature of colposcopy. Patient demographic information was collected. FINDINGS: there were 183 women who consented to participate in the study. We obtained complete data on 111 English speakers and 38 Spanish speakers. English speakers were more likely to have a higher education, greater household income, and private insurance. Subjects correctly answered an average of 7.91 +/- 2.16 (72%) of 11 colposcopy survey questions. English speakers answered more questions correctly than Spanish speakers (8.50 +/- 1.92 [77%] vs 6.21 +/- 1.93 [56%]; p < .001). Using linear regression to adjust for confounding variables, we found that language was not significantly associated with greater understanding (p = .46). Rather, education was the most significant predictor of colposcopy knowledge (p < .001). CONCLUSION: many colposcopy patients did not understand the procedure well enough to give informed consent. The observed differences in colposcopy comprehension based on language were a proxy for differences in education. Education, not language, predicted subjects' understanding of colposcopy. These results demonstrate the need for greater attention to patients' educational background to ensure adequate understanding of clinical information. PMID- 20833069 TI - General and arthritis-specific barriers to moderate physical activity in women with arthritis. AB - BACKGROUND: most women with arthritis are insufficiently active, despite the health benefits derived from participation in moderate physical activity (MPA). Understanding perceived barriers that make it difficult for women with arthritis to be active is needed to inform interventions. Barriers are often assessed through investigator-provided lists, containing mainly general, personal, and situational barriers, common across populations (e.g., lack of time). However, identifying an encompassing range of problematic barriers that challenge women's activity participation is needed. Such barriers may be general and arthritis specific (e.g., pain). Problematic barriers may be best identified through assessment of whether individuals actually experience these barriers (i.e., are present) and, for present barriers, their extent of limitation on activity. Thus, the primary study purpose was to examine whether the presence of general and arthritis-specific barrier categories and the limitation of these overall categories were significant predictors of participation in MPA among women with arthritis (n = 248). METHODS: on-line measures of barriers and MPA were completed. FINDINGS: a multiple regression model predicting activity was significant (r(2)(adjusted) = .22; p < .01). Both arthritis-specific and general barrier limitation were the strongest predictors of activity. Arthritis-specific personal barriers were reported as being present most often (e.g., pain). CONCLUSION: interventions should identify problematic barriers, taking into account the extent to which both general and disease-specific barriers limit activity, and then target their alleviation through the use of coping strategies as a way to improve activity adherence and health among women with arthritis. PMID- 20833070 TI - The role of lumbopelvic posture in pelvic floor muscle activation in continent women. AB - This study was undertaken to determine the effect of changing standing lumbopelvic posture on pelvic floor muscle (PFM) activation amplitude and timing and the resultant vaginal manometry values recorded during static and dynamic tasks. Sixteen nulliparous, continent women between the ages of 22 and 41 years performed five tasks (quiet standing, maximal effort cough, Valsalva manoeuvre, maximum voluntary contraction (MVC) of the PFMs, and a load-catching task) in three different standing postures (normal lumbopelvic posture, hyperlordosis and hypolordosis). Electromyographic (EMG) data were recorded from the PFMs bilaterally using a PeriformTM vaginal probe coupled to DelsysTM Bagnoli-8 EMG amplifiers. In separate trials, vaginal manometry was obtained using a PeritronTM perineometer. Lumbopelvic angle was recorded simultaneously with EMG and vaginal manometry using an OptotrakTM 3D motion analysis system to ensure that subjects maintained the required posture throughout the three trials of each task. All data were filtered using a moving 100 ms RMS window and peak values were determined for each trial and task. Repeated-measures analyses of variance were performed on the peak PFM EMG, intra-vaginal pressure amplitudes, and lumbopelvic angles as well as activation onset data for the cough and load-catching tasks. There was significantly higher resting PFM activity in all postures in standing as compared to supine, and in the standing position, there was higher resting PFM activity in the hypo-lordotic posture as compared to the normal and hyperlordotic postures. During the MVC, cough, Valsalva, and load-catching tasks, subjects generated significantly more PFM EMG activity when in their habitual posture than when in hyper- or hypo-lordotic postures. Conversely, higher peak vaginal manometry values were generated in the hypo-lordotic posture for all tasks in all cases. These results clearly indicate that changes in lumbopelvic posture influence both the contractility of the PFMs and the amount of vaginal pressure generated during static postures and during dynamic tasks. Lumbopelvic posture does not, however, appear to have a significant effect on the timing of PFM activation during coughing or load-catching tasks. PMID- 20833071 TI - Benefits of staple food restriction for Japanese obese patients with chronic kidney disease: a pilot study. AB - OBJECTIVE: We conducted a pilot study to assess the effects of dietary intervention on metabolic risk factors and renal parameters in obese patients with chronic kidney disease (CKD). METHODS: We studied 19 obese patients with CKD at our outpatient clinic. The diet selected for this study restricted only their staple food intake, with no change in the side dish component of their meals. We studied neither the lifestyles of the patients nor the activities that they were involved in. We examined changes in clinical and laboratory parameters at baseline and after consumption of the diet. RESULTS: After 2 and 6 months of staple food restriction, changes in body weight were found to be -3.6% +/- 3.9% and -3.4% +/- 4.7%, respectively. Of the 19 patients, the body weights of 9 decreased by >3% (range: 3.4% to 17.1%) from baseline to follow-up at 6 months. After 6 months of following the diet, these 9 patients showed marked reductions in blood pressure, homeostasis model assessment insulin resistance, and triglycerides, when compared with the remaining 10 patients with stable body weights; however, for proteinuria and estimated glomerular filtration rate they reported having values similar to the 10 patients with stable body weights. CONCLUSIONS: Weight reduction associated with a lowered insulin resistance was reported in obese patients with CKD after 6 months of staple food restriction; however, further studies need to be conducted to confirm the presence of other possible renal benefits. PMID- 20833072 TI - Unintentional weight loss is an independent predictor of mortality in a hemodialysis population. AB - OBJECTIVE: This study investigated common components of classification of nutrition screening risk in the prediction of clinical end-points (mortality and morbidity) in hemodialysis patients over a 3-year period (2005 to 2008). DESIGN: This was a retrospective cohort study. SETTING: This study was conducted at a Hemodialysis centre. PARTICIPANTS: The study included patients on maintenance hemodialysis in June 2005. INTERVENTION: Assessment of nutrition risk was carried out using components of Protein-Energy Wasting criteria. MAIN OUTCOME MEASURE: Clinical outcome at the 3-year follow-up (June 2008) was measured as mortality and morbidity (as unplanned hospital admissions). Risk of mortality was investigated independent of comorbidities, age, gender, ethnicity, and dialysis vintage using Cox proportional hazards model. RESULTS: A total of 217 patients met the inclusion criteria (143 male [66%]; age, 60.5 +/- 15.6 years). Patients who lost >=5% body weight in the 6 months before the study commenced, had a 3 fold (Hazard Ratio = 3.0; 95% confidence interval: 1.2 to 7.5) independent greater risk of death (P = .02). Low serum albumin (<38 g/L) resulted in higher morbidity and mortality; however, this was not statistically significant when adjusted for confounders. Body mass index was only available in 64% (138 of 217) of the cohort at baseline, and was not related to clinical outcome at the 3-year follow-up. CONCLUSION: Unintentional weight loss is independently predictive of clinical outcome in this cohort of dialysis patients. It is recommended that nutrition screening tools include weight loss as a key component in classification of risk and for prioritizing patient care. PMID- 20833073 TI - Design and development of a dialysis food frequency questionnaire. AB - OBJECTIVES: Periodic assessment of dietary intake across a given dialysis population may help to improve the clinical outcomes related to nutrients such as dietary protein, phosphorus, or potassium. Although dietary recalls and food records are used to assess dietary intake at individual level and over shorter periods, food frequency questionnaires (FFQ) are used to rank subjects of a given population according to their nutrient intake over longer periods. DESIGN: To modify and refine the conventional Block FFQ to develop a specific FFQ for dialysis patients. SETTING: A total of 8 DaVita outpatient dialysis clinics in Los Angeles area, which participated in the "Nutrition and Inflammation in Dialysis Patients" study. PATIENTS: The study included 154 patients undergoing maintenance hemodialysis (MHD). MAIN OUTCOME MEASURE: Dietary intake of participating MHD patients using a 3-day food record, supplemented by a person-to person dietary interview, to capture food intake over the last hemodialysis treatment day of the week and the 2 subsequent nondialysis days. RESULTS: Analyses of the food records identified the key contributors to the daily nutrient intake in the 154 participating MHD patients. A "Dialysis-FFQ" was developed to include approximately 100 food items representing the total food intake of 90% of the patients of the "Nutrition and Inflammation in Dialysis Patients" study population. Distinctions were made in several food items on the basis of key nutritional issues, such as protein, phosphorus, and potassium, in dialysis patients. CONCLUSIONS: We have developed a "Dialysis FFQ" to compare and rank dialysis patients according to their diverse nutrient intake. Although the Dialysis-FFQ may be a valuable tool to compare dialysis patients and to identify those who ingest higher or lower amounts of a given nutrient, studies are needed to examine the utility of the Dialysis-FFQ for nutritional assessment of dialysis patients. PMID- 20833074 TI - Effects of renal-specific oral supplementation in malnourished hemodialysis patients. AB - BACKGROUND: Protein-energy malnutrition is still a problem in patients with chronic renal failure, especially during replacement renal therapy. The chronic inflammatory status in these patients intensifies the malnutrition, as well as making treatment more complicated. The aim of the present study was to estimate the influence of oral supplementation on the nutritional status of malnourished hemodialysis (HD) patients depending on the existence of an inflammatory state. METHODS: To study the influence of oral supplementation on nutrition status, 30 HD patients with protein-energy malnutrition characteristics and 25 well nourished HD patients were enrolled in the study. Malnourished HD patients were prescribed Renilon 7.5 at an oral intake dose of 125 mL twice a day for 3 months. The nutritional status was characterized based on body mass index, Subjective Global Assessment score, serum albumin and prealbumin concentrations. The intensity of the inflammatory state was determined by C-reactive protein and interleukin-6. Serum concentrations of leptin and adiponectin were also measured. RESULTS: After 3 months of supplementation, malnourished patients had an increase in prealbumin, albumin, and leptin concentrations. No statistically significant differences were observed between patients lacking inflammation and those with inflammation. CONCLUSIONS: The results indicate an improvement in the nutritional status of HD patients who were prescribed an oral supplementation. Furthermore, patients with inflammatory state characteristics also benefited from Renilon 7.5 treatment. PMID- 20833075 TI - Marine n-3 polyunsaturated fatty acids in patients with end-stage renal failure and in subjects without kidney disease: a comparative study. AB - OBJECTIVE: Patients with end-stage renal disease treated with chronic hemodialysis (HD) are reported to have low levels of marine n-3 polyunsaturated fatty acids (PUFA) in plasma and cell membranes compared with healthy subjects. The aim of this study was to investigate whether n-3 PUFA levels in plasma and cells are lower in HD patients as compared with subjects without kidney disease. RESEARCH DESIGN: A comparative study was carried out. SETTING: This study was carried out at the Departments of Nephrology and Cardiology, Aalborg Hospital, Aarhus University Hospital, Denmark. PARTICIPANTS: This study consisted of 2 study populations comprising HD patients and 5 study populations comprising subjects without kidney disease. INTERVENTION: The fatty acid distribution in plasma phospholipids and platelet phospholipids was measured using gas chromatography. MAIN OUTCOME MEASURE: Eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA) levels in plasma or serum phospholipids and platelet phospholipids in HD patients were compared with n-3 PUFA levels in subjects without kidney disease. RESULTS: EPA and DHA were lower and AA/EPA was higher in plasma/serum phospholipids in HD patients than in subjects without kidney disease. Similarly, higher AA and AA/EPA and lower EPA and DHA levels were found in platelet phospholipids of HD patients. Adjustment for gender, age, and habitual intake of fish and fish oil supplements did not change these results. CONCLUSION: HD patients have lower n-3 PUFA levels in plasma and cells compared with subjects without kidney disease. PMID- 20833076 TI - Evaluation of metabolic risk marker in obesity-related glomerulopathy. AB - OBJECTIVE: Insulin resistance is a common metabolic abnormality, which increases the risk of renal events in obesity. The present study is aimed to examine the relation between metabolic factors and obesity-related glomerulopathy (ORG), and then compare the risk markers of insulin resistance for clinical prediction. METHODS: A total of 112 cases with proven renal ORG and 135 age- and gender matched lean controls were included. The degree of proteinuria, endogenous creatinine clearance rate, body mass index, amylin, fasting glucose, insulin, lipid and lipoprotein concentrations were measured during the steady state. RESULTS: The patients with ORG were clinically characterized by increased body mass index and proteinuria, with higher levels of amylin, homeostasis model assessment of insulin resistance (HOMA-IR), insulin, glucose, and lipid proteins when compared with the lean controls. Multiple logistic regression analysis revealed that amylin and HOMA-IR were significantly associated with the prevalence of ORG. In patients with ORG, proteinuria level correlated with amylin, total cholesterol, fasting insulin, and HOMA-IR. Moreover, proteinuria correlated positively with HOMA-IR and amylin in a multiple regression analysis. In addition, the endogenous creatinine clearance rate did not correlate with any metabolic marker. CONCLUSION: This study suggested that screening for HOMA-IR might have predictive value for renal damage in obese patients. In addition to insulin resistance, amylin also showed positive effects on evaluation of such renal impairment. PMID- 20833077 TI - Anti-inflammatory properties of high-density lipoprotein cholesterol in chronic hemodialysis patients: impact of intervention. AB - OBJECTIVE: Levels of high-density lipoprotein (HDL) cholesterol as well as its functional roles are suppressed in chronic kidney disease because of ongoing chronic microinflammatory state. We hypothesized that intervention aimed at reducing inflammation may improve the levels and activity of HDL cholesterol as well as survival of our patients. METHODS: In this prospective follow-up study, we selected 67 patients (33 women, 34 men) on chronic hemodialysis (23.5 months [range, 10 to 34], aged 67.5 years [range, 39 to 90 years]). Targeted examination for asymptomatic infective foci or poor function of arterio-venous (AV)-fistula was carried out after a detailed initial clinical examination in all patients. Individual intervention was performed according to examination results. Blood was drawn for analysis of HDL cholesterol; interleukin-6, its soluble receptor, monocyte chemoattractant protein 1 (MCP-1), total iron binding capacity, and high sensitivity C-reactive protein at the beginning of the study and after 3 months. The patients were then closely followed up for 2 years during which the occurrence and cause of death was registered. RESULTS: A significant decrease of inflammatory parameters (Interleukin-6: 4.9 vs. 1.1 pg/mL, P > .001 and MCP-1: 397 vs. 310 pg/mL, P = .02) and increase of HDL cholesterol (1.22 +/- 0.55 vs. 1.33 +/- 0.55; P = .003) was seen in the entire study population. No difference in survival was found between the different interventional groups. The 2-year death rate was 37%. On using Kaplan-Meier analysis, a significantly better survival in patients with increase of HDL cholesterol (77% vs. 50%; P = .013) and/or a decrease of MCP-1 (81% vs. 53%; P = .04) was found after 3 months of intervention. CONCLUSIONS: It was concluded that individually aimed intervention may improve levels of HDL cholesterol and MCP-1. Changes in these 2 parameters can predict the 2-year survival rates of patients. PMID- 20833078 TI - Relationship between chronic kidney disease and white matter hyperintensities on magnetic resonance imaging. AB - Renal dysfunction may be related to cerebral small-vessel disease. This study aimed to assess the relationship between mild renal dysfunction and various white matter hyperintensities on magnetic resonance imaging (MRI). A total of 2106 subjects (1368 men and 738 women; mean age, 56 +/- 10 years) without a history of stroke were enrolled in the study. Kidney function was evaluated in terms of estimated glomerular filtration rate (eGFR), calculated using the relationship 194Cr(-1.094) * age(-0.287) * 0.739 (if female), where Cr is serum creatinine concentration. White matter hyperintensity on T2-weighted MRI was classified as deep and/or subcortical white matter hyperintensity (DSWMH), periventricular hyperintensity (PVH), or asymptomatic cerebral infarction (ACI). The prevalence of ACI, DSWMH, and PVH was significantly correlated with degree of eGFR reduction; in the subgroups with eGFR >= 90, 60~89, and <60 mL/min/1.73 m(2), the following prevalences were found: ACI, 7%, 6%, and 16%; DSWMH, 18%, 21%, and 37%; PVH: 7%, 10%, and 21%. The odds ratios for ACI, DSWMH, and PVH of eGFR <60 mL/min/1.73 m(2) were significantly increased, to 2.11 (95% confidence interval [CI], 1.23-3.61; P = .006), 2.26 (1.53-3.34; P < .001), and 2.81 (1.67-4.72; P < .001), respectively. Our data indicate that mild renal dysfunction may be associated with an increase in cerebral small-vessel disease independent of hypertension. PMID- 20833079 TI - Seizures and epilepsy in patients with a posterior circulation infarct. AB - Seizures occur mainly in patients with cortical infarcts in the anterior circulation. Those related to a posterior circulation infarct (POCI) are considered rare. This study investigated the characteristics of patients with seizures related to a POCI. A total of 180 consecutive patients admitted with a POCI had a 2- to 7-year follow-up; 24 of them (13.6%) developed seizures. Vascular risk factors, etiology and extension of the infarct, degree of neurologic impairment, and outcome were compared in the patients with and without seizures. Complex partial type seizure was the most common presentation. Stroke characteristics were largely the same in the patients with and without seizures. History of a previous stroke was noted in 62.5% of the seizure group and in 17.9% of the nonseizure group (P < .001). Clinical outcome was worse in the seizure group (P = .004). The relative incidence of seizures in patients with a POCI was not lower than that in the overall stroke population. The high incidence of recurrent stroke is the main risk factor for seizures in patients with a POCI. The seizures themselves are responsible for the increased dependence rate. PMID- 20833080 TI - Hemifacial spasm, glossodynia, and dolichoectasia of the basilar artery. AB - The case of a 77-year-old hypertensive man presenting with hemifacial spasm and glossodynia is reported. Imaging studies revealed gross dolichoectasia of the vertebrobasilar arterial system with pontine compression. It is suggested that the neurologic symptoms most likely resulted from pontine compression, rather than from any compression of the cranial nerves. PMID- 20833081 TI - Prestroke anticoagulation and paroxysmal type are correlated with favorable outcome in ischemic stroke patients with atrial fibrillation. AB - Paroxysmal atrial fibrillation (AF), which often precedes permanent AF, is reported to be a risk factor for milder ischemic stroke. We assessed whether the type of AF and prestroke treatment with an anticoagulant were associated with physical disabilities in patients with AF-related acute ischemic stroke. We identified 162 consecutive acute ischemic stroke patients with AF who were admitted to our hospital over a 3-year period. Disability was measured using the modified Rankin Scale (mRS) at the time of discharge and was categorized according to favorable clinical outcome (mRS score 0-2). Of the 162 patients, 71 (43.8%) had paroxysmal AF and 91 had permanent AF. Fifty-six patients (34.6%) had been treated with a prophylactic anticoagulant. A total of 103 patients (63.6%) had a favorable outcome. Multivariate logistic analysis revealed that paroxysmal AF (odds ratio [OR], 1.58; P = .0187), prestroke anticoagulation treatment (OR, 1.95; P = .0019), and noncardiogenic embolism (OR, 2.20; P = .0073) were independent factors associated with a favorable clinical outcome. Our data indicate that paroxysmal AF and prestroke anticoagulation treatment are independently associated with favorable clinical outcome at the time of hospital discharge in patients with AF. PMID- 20833082 TI - Cannabis-related myocardial infarction and cardioembolic stroke. AB - We report a 33-year-old man with a history of chronic cannabis use who sustained myocardial infarction followed by cerebral infarction after a recent significant increase in cannabis use. This is the first case of cannabis-associated stroke of probable cardioembolic origin. PMID- 20833083 TI - Cognitive functioning in the acute phase poststroke: a predictor of discharge destination? AB - Cognitive dysfunction occurs in more than half of stroke survivors and can have far-reaching consequences for functioning in daily life. Assessment of cognitive function can play a major role in determining the appropriate discharge destination after a hospital stay. The present study aimed to determine the feasibility of cognitive screening in the acute phase poststroke and to investigate whether this cognitive screening can accurately predict discharge destination to either a dependent or an independent living situation. A total of 287 patients with a first-ever cerebral stroke consecutively admitted to a stroke unit of a general hospital were eligible for the study. All patients underwent neuropsychological screening, consisting of the Mini-Mental State Examination (MMSE), Cognitive Screening Test (CST), and Clock-Drawing Test, within 7 days poststroke. Screening was feasible in 73.2% of the patients. Logistic regression analysis showed that the Barthel Index (BI) score (ie, ability to perform activities of daily living) could predict the discharge destination with 47% explained variance when age and BI score were taken into account. Adding the 3 cognitive tests to the model with age and BI improved the explained variance substantially (53%), with a significant contribution of BI and CST. Cognitive screening in the acute phase poststroke appeared to be feasible and capable of supporting the decision of whether to discharge a patient to home or to a dependent living situation. Functional status improved the predictive value of the model; the MMSE was not suitable for prediction. A comprehensive set of various predictors, including cognition, is recommended to support discharge planning. PMID- 20833084 TI - Intravenous thrombolysis in an elderly patient with acute ischemic stroke masking aortic dissection. AB - Before thrombolytic treatment for acute ischemic stroke is undertaken, conditions associated with increased risk of hemorrhagic complications, such as an acute aortic dissection (AAD), should be excluded. We report an 80-year-old woman with acute ischemic stroke as the sole clinical manifestation of AAD who was treated with intravenous (IV) tissue plasminogen activator (tPA). She had no history of hypertension or any signs or symptoms suggestive of AAD. After IV tPA infusion was started, carotid color-coded duplex sonography demonstrated proximal left common carotid artery dissection suggestive of AAD. Infusion of tPA was stopped, and subsequent computed tomography angiography confirmed Stanford type A aortic dissection. In this case, prompt neurosonologic evaluation helped us make an appropriate diagnosis and avoid complications related to treatment. Neurosonologic evaluation should be considered as soon as possible in all patients with acute ischemic stroke, especially when thrombolytic treatment is being considered. PMID- 20833085 TI - Recurrent posterior circulatory emboli from a mildly stenosed bicuspid aortic valve. AB - Bicuspid aortic valve (BAV) is a common condition but is only rarely associated with embolic complications. We describe a 42-year-old man with recurrent posterior circulatory ischemic strokes that resulted in ataxia and cognitive impairment. Transesophageal echocardiography demonstrated a BAV with mild stenosis, moderate calcification, and a dilated ascending aorta. The degree of calcification and the valve phenotype might be important factors implicating the BAV as a rare cause of ischemic stroke. PMID- 20833086 TI - Cerebral venous sinus thrombosis presenting as transient ischemic attacks in a case with homozygous mutations of MTHFR A1298C and CG677T. AB - We report a case with recurrent, transient attacks of slurred speech, weakness, and numbness of the right half of the face and the right arm without seizure activity, accompanied by headache and double vision. Neurologic examination revealed bilateral papilledema and right abducens palsy. Brain magnetic resonance imaging revealed thrombosis of the dural venous sinuses and the cortical veins, with no evidence of parenchymal lesion. Homozygous mutations were found for methylenetetrahydrofolate reductase (MTHFR) A1298C and MTHFR CG677T. Anticoagulation with heparin and warfarin resulted in prompt cessation of the transient attacks, as well as the signs and symptoms of increased intracranial pressure. This report documents that, although rare, transient ischemic attacks can result from cerebral venous thrombosis. PMID- 20833087 TI - Strong association between a new marker of hemolysis and glomerulopathy in sickle cell anemia. AB - To perform a precise evaluation of the hemolytic status of patients with sickle cell anemia (SCA), advanced red blood cell parameters provided by the last generation analyzers were investigated in a series of SCA patients. The search for precise markers of hemolysis was performed to identify if patients so exposed develop organic complications related to a postulated hemolysis-linked endothelial dysfunction. Red blood cell survival was evaluated by the ratio between mature red blood cell (RBC) and reticulocyte (RET) hemoglobin (RBC-Hb/RET Hb). In comparison with serum lactate dehydrogenase (LDH) and total bilirubin, the log (RBC-Hb/RET-Hb) was identified as the most discriminant hematological parameter to evaluate hemolysis. Furthermore, by combining this parameter with LDH, we defined a composite variable, which we called CVar, that is highly correlated with albuminuria and might constitute a powerful new marker of risk for this complication. PMID- 20833088 TI - Animal traction and transport in the 21st century: getting the priorities right. PMID- 20833089 TI - Effects of local lidocaine treatment before and after median nerve injury on mechanical hypersensitivity and microglia activation in rat cuneate nucleus. AB - This study examined the relationship between microglia activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. We also investigated effects of local lidocaine pre- and post-treatment on microglia activation and development of hypersensitivity in this model. By immunohistochemistry and immunoblotting, little immunoreactivity of OX-42, a microglia activation marker, was detected in the CN of normal rats. As early as 1 day after CCI, there was a significant increase in OX-42 immunoreactivity in the lesion side of CN, which reached a maximum at 14 days. Microinjection of minocycline, a microglia activation inhibitor, into the CN 1 day after CCI attenuated injury-induced behavioral hypersensitivity in a dose dependent manner. Furthermore, the animals received 1%, 2% or 5% lidocaine 15 min prior to median nerve CCI (pre-treatment), 5h (early post-treatment) or 1 day (late post-treatment) after median nerve CCI. Pre-treatment and early post treatment with 2% and 5% lidocaine, but not 1% lidocaine, attenuated OX-42 immunoreactivity and behavioral hypersensitivity following median nerve injury. Late post-treatment with 1%, 2%, or 5% lidocaine failed to decrease OX-42 immunoreactivity and mechanical hypersensitivity in CCI rats. In conclusion, median nerve injury-induced microglia activation in the CN modulated development of behavioral hypersensitivity. High-concentration lidocaine was effective in decreasing microglia activation in the CN and in attenuating neuropathic pain sensations at the early stage following nerve injury, when microglia had not yet been activated. PMID- 20833090 TI - Single crystals of DPPH grown from diethyl ether and carbon disulfide solutions - crystal structures, IR, EPR and magnetization studies. AB - Single crystals of the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) obtained from diethyl ether (ether) and carbon disulfide (CS2) were characterized by the X ray diffraction, IR, EPR and SQUID magnetization techniques. The X-ray structural analysis and IR spectra showed that the DPPH form crystallized from ether (DPPH1) is solvent free, whereas that one obtained from CS2 (DPPH2) is a solvate of the composition 4DPPH.CS2. Principal values of the g-tensor were estimated by the X band EPR spectroscopy at room and low (10 K) temperatures. Magnetization studies revealed the presence of antiferromagnetically coupled dimers in both types of crystals. However, the way of dimerization as well as the strength of exchange couplings are different in the two DPPH samples, which is in accord with their crystal structures. The obtained results improved parameters accuracy and enabled better understanding of properties of DPPH as a standard sample in the EPR spectrometry. PMID- 20833091 TI - An electromagnetic reverse method of coil sensitivity mapping for parallel MRI - theoretical framework. AB - In this paper, a novel sensitivity mapping method is proposed for the image domain parallel MRI (pMRI) technique. Instead of refining raw sensitivity maps by means of conventional image processing operations such as polynomial fitting, the presented method determines coil sensitivity profiles through an iterative optimization process. During the algorithm implementation the optimization cost function is defined as the difference between the raw sensitivity profile and the desired profile. The minimization is governed by the physics of low-frequency electromagnetic and reciprocity theories. The performance of the method was theoretically investigated and compared with that of a traditional polynomial fitting, against a range of system noise levels. It was found that, the new method produces high-fidelity sensitivity profiles with noise amplitudes, measured as root mean square deviation an order of magnitude less than that of the polynomial fitting method. Using the sensitivity profiles generated by our method, SENSE (sensitivity encoding) reconstructions produce significantly less image artefacts than conventional methods. The successful implementation of this method has far-reaching implications that accurate sensitivity mapping is not only important for parallel reconstruction, but also essential for its transmission analogy, such as Transmit SENSE. PMID- 20833092 TI - [Results in assisted reproductive techniques: interpretation and function]. AB - The modes of expression in assisted reproductive techniques are numerous. The delivery rate per started cycle must include the deliveries issued of thawed embryos transfer. The birth rates per patient are a different modality of great interest for the crude as well as the actuarial cumulative delivery rates. But all these data should be interpreted within their context: selection of patients or health policy. The disparity of expression of results comes from the function of these results. Scientific analysis, public health, monitoring quality and prognostic value are the four main purposes justifying differentiated expression modes. PMID- 20833093 TI - A lumped-parameter model of the cerebrospinal system for investigating arterial driven flow in posttraumatic syringomyelia. AB - Fluid transport in syringomyelia has remained enigmatic ever since the disease was first identified some three centuries ago. However, accumulating evidence in the last decade from animal studies implicates arterial pulsations in syrinx formation. In particular, it has been suggested that a phase difference between the pressure pulse in the spinal subarachnoid space and the perivascular spaces, due to a pathologically disturbed cerebrospinal fluid (CSF) or blood supply, could result in a net influx of CSF into the spinal cord (SC). A lumped-parameter model is developed of the cerebrospinal system to investigate this conjecture. It is found that although this phase-lag mechanism may operate, it requires the SC to have an intrinsic storage capacity due to the collapsibility of the contained venous reservoir. This net flux is associated with a higher mean pressure in the SC than the SSS which is maintained in the periodic steady state. According to our simulations the mechanical perturbations of arachnoiditis exacerbate the phase-lag effect, which may be partially alleviated by the presence of a posttraumatic syrinx and more completely by a syringo-subarachnoid shunt. PMID- 20833094 TI - Comparison of oscillometric pulse amplitude envelopes recorded from the locally compressed radial arteries. AB - Simultaneously recorded oscillometric envelopes, obtained pneumo- and photoplethysmographically from a small local pad-type pneumatic cuff on the left and from a larger cuff on the right radial artery, were compared in 17 healthy subjects. For oscillometric estimation, specific fixed ratios based on evidence in the literature were used. The obtained envelopes for each person were shifted and aligned at the point of upper arm mean arterial pressure for this person, thus eliminating the brachial-to-radial mean blood pressure gradient and possible left-right difference. In this way, the shape of differently recorded envelopes as a determinant of the accuracy of oscillometric estimation was studied. Results showed an advantage of photoplethysmographically compared to pneumoplethysmographically recorded envelopes. For a smaller cuff (diameter 40mm), the mean difference in mmHg 'oscillometric estimate minus auscultatory reference' and standard deviation were in the case of photo recording for systolic and diastolic pressures -0.6 (6.3) and 1.2 (3.4), respectively. In the case of pneumo recording, these parameters were considerably larger, being 12.1 (11.9) and -6.2 (10.9), respectively. For a larger cuff the same tendency was revealed. Photo recording was found to be less sensitive to alterations in the cuff size and characteristic ratios. PMID- 20833095 TI - Consistency of the blind source separation computed with five common algorithms for magnetoencephalogram background activity. AB - Blind source separation (BSS) is widely used to analyse brain recordings like the magnetoencephalogram (MEG). However, few studies have compared different BSS decompositions of real brain data. Those comparisons were usually limited to specific applications. Therefore, we aimed at studying the consistency (i.e., similarity) of the decompositions estimated for real MEGs from 26 subjects using five widely used BSS algorithms (AMUSE, SOBI, JADE, extended-Infomax and FastICA) for five epoch lengths (10s, 20s, 40s, 60s and 90s). A statistical criterion based on Factor Analysis was applied to calculate the number of components into which each epoch would be decomposed. Then, the BSS techniques were applied. The results indicate that the pair of algorithms 'AMUSE-SOBI', followed by 'JADE FastICA', provided the most similar separations. On the other hand, the most dissimilar outcomes were computed with 'AMUSE-JADE' and 'SOBI-JADE'. The BSS decompositions were more similar for longer epochs. Furthermore, additional analyses of synthetic signals supported the results of the real MEGs. Thus, when selecting BSS algorithms to explore brain signals, the techniques offering the most different decompositions, such as AMUSE and JADE, may be preferred to obtain complementary, or at least different, perspectives of the underlying components. PMID- 20833096 TI - Correlation technique and least square support vector machine combine for frequency domain based ECG beat classification. AB - The present work proposes the development of an automated medical diagnostic tool that can classify ECG beats. This is considered an important problem as accurate, timely detection of cardiac arrhythmia can help to provide proper medical attention to cure/reduce the ailment. The proposed scheme utilizes a cross correlation based approach where the cross-spectral density information in frequency domain is used to extract suitable features. A least square support vector machine (LS-SVM) classifier is developed utilizing the features so that the ECG beats are classified into three categories: normal beats, PVC beats and other beats. This three-class classification scheme is developed utilizing a small training dataset and tested with an enormous testing dataset to show the generalization capability of the scheme. The scheme, when employed for 40 files in the MIT/BIH arrhythmia database, could produce high classification accuracy in the range 95.51-96.12% and could outperform several competing algorithms. PMID- 20833097 TI - Visual hallucinations and associated factors in Chinese patients with Parkinson's disease: roles of RBD and visual pathway deficit. PMID- 20833098 TI - PIFs: pivotal components in a cellular signaling hub. AB - A small subset of basic helix-loop-helix transcription factors called PIFs (phytochrome-interacting factors) act to repress seed germination, promote seedling skotomorphogenesis and promote shade-avoidance through regulated expression of over a thousand genes. Light-activated phytochrome molecules directly reverse these activities by inducing rapid degradation of the PIF proteins. Here, we review recent advances in dissecting this signaling pathway and examine emerging evidence that indicates that other pathways also converge to regulate PIF activity, including the gibberellin pathway, the circadian clock and high temperature. Thus PIFs have broader roles than previously appreciated, functioning as a cellular signaling hub that integrates multiple signals to orchestrate regulation of the transcriptional network that drives multiple facets of downstream morphogenesis. The relative contributions of the individual PIFs to this spectrum of regulatory functions ranges from quantitatively redundant to qualitatively distinct. PMID- 20833099 TI - A proposal for kinetic proof reading by ISWI family chromatin remodeling motors. AB - ATP-dependent chromatin remodeling motors play fundamental roles in nuclear processes by regulating access to DNA. Yet compared to other cellular motors less is known about how these motors couple the energy of ATP to alter their substrates. Here we use recent studies on a key chromatin remodeling motor from the ISWI class, human ACF and its yeast counterpart, ISW2, to propose a model for how these motors use ATP to read structural cues presented by nucleosomal substrates. Substantial earlier work has shown that ACF activity is strongly regulated by the length of the DNA flanking a nucleosome as well as by the histone H4 tail. Recent bulk and single-molecule studies of human ACF suggest that this complex functions as a dimeric motor. These studies, together with studies of yeast ISW2 imply that at least two types of ATP hydrolysis events accompany each cycle of nucleosome movement. We propose that ISWI motors may employ a kinetic proof reading type of mechanism to favor action on nucleosomes that are poised to be in condensed chromatin while inhibiting action on nucleosomes that are in fully active or fully condensed chromatin. PMID- 20833100 TI - Polymer complexes. LIII. Supramolecular coordination modes and structural of novel sulphadrug complexes. AB - Novel polymer complexes of copper(II), palladium(II), platinum(II) and cadmium(II) containing homopolymer [4-acrylamido benzene sulphonyl guanidine; (HL)] and various anions (SO42-, CH3COO-, NO3-, Br- or Cl-) have been designed and carried out. Their structures were investigated by elemental analyses, spectral (IR, UV-vis, 1H NMR and ESR) and magnetic moments. The modes of interactions between the ligand and the metals were discussed, where oxygen (of O=S=O group) and nitrogen atom [of imino nitrogen (NH/N) of the guanidine group] are involved in chelation. The homopolymer shows two types of coordination behaviour. In mononuclear polymer complexes 4 and 6-10, it acts as a neutral bidentate ligand chelated through the NH and O atoms, whereas in the polymer complexes 1-3, 5 and 11, monobasic bidentate ligand is coordinated through the -N and -O atoms. The poly-chelates are of 1:1/1:2 (metal-homopolymer) stoichiometry and exhibit four coordination. On the basis of electronic spectral data and magnetic susceptibility measurement square planar geometry has been proposed. The ESR spectral data provided information about their structure on the basis Hamiltonian parameters and degree of covalency. From the electron paramagnetic resonance and spectral data, the orbital reduction factors were calculated. PMID- 20833101 TI - A new synthetic route, characterization and vibrational studies of manganese hypophosphite monohydrate at ambient temperature. AB - The manganese hypophosphite monohydrate (Mn(H2PO2)2.H2O) was synthesized by using the energy saving method in acetone medium for controlling the exothermic process of H2 gas releasing. The thermal analysis (TG/DTG/DTA), atomic absorption spectrophotometry (AAS) and X-ray powder diffraction (XRD) were employed to characterize this compound. These methods confirm the formula of the title compound. The SEM data in this work agree well with the previously reported work. The vibrational behavior was studied by using the FTIR and FT Raman methods. The correlation field splitting analysis of H2O in Mn(H2PO2)2.H2O symbolized as C2v) C1-C2h5 and C2v-C(i)-C2h5) suggested the number of vibrational modes to be: Gamma(vib,H2O)=3A(g)+3B(g)+3A(u)+3B(u). While the case of hypophosphite anion can be suggested to exhibit 16 (infrared) [A(u)(8)+B(u)(8)] and 18 Raman [A(g)(9)+B(g)(9)] bands which agree well with the observed FT IR spectra. However, the Raman spectra could not be fully identified. The coupling between these modes with the appropriate vibrations of neighboring species at each sites in the unit cell can further influence the vibrational spectra. PMID- 20833102 TI - Spectroscopic, magnetic and thermal studies of Co(II), Ni(II), Cu(II) and Zn(II) complexes of 3-acetylcoumarin-isonicotinoylhydrazone and their antimicrobial and anti-tubercular activity evaluation. AB - Co(II), Ni(II), Cu(II) and Zn(II) complexes with a new heterocyclic Schiff base derived by the condensation of isonicotinoylhydrazide and 3-acetylcoumarin have been synthesized. 1H, 13C and 2D HETCOR NMR analyses confirm the formation of title compound and existence of the same in two isomeric forms. The metal complexes were characterized on the basis of various spectroscopic techniques like electronic, EPR, IR, 1H and 13C NMR studies, elemental analysis, magnetic properties and thermogravimetric analysis, and also by the aid of molar conductivity measurements. It is found that the Schiff base behaves as a monobasic tridentate ligand coordinating in the imidol form with 1:1 metal to ligand stoichiometry. Trigonal bipyramidal geometry has been assigned for Ni(II) and Cu(II) complexes, while tetrahedral for Co(II) and Zn(II) complexes. The compounds were subjected to antimicrobial and anti-tubercular activity screening using serial broth dilution method and Minimum Inhibitory Concentration (MIC) is determined. Zn(II) complex has shown significant antifungal activity with an MIC of 6.25 MUg/mL while Cu(II) complex is noticeable for antibacterial activity at the same concentration. Anti-TB activity of the ligand has enhanced on complexation with Co(II) and Ni(II) ions. PMID- 20833103 TI - Dichroic ATR-FTIR spectroscopy on oriented alpha-helical poly(l-lysine) multilayered with polyanions. AB - The preparation and spectroscopic and microscopic characterization of oriented polyelectrolyte multilayers (PEM) interesting for defined nanostructured functional materials and surfaces are reviewed. Oriented PEM were generated by consecutively adsorbing alpha-helical poly(l-lysine) (PLL) and oppositely charged polyanions like poly(vinylsulfate) (PVS) or poly(styrene sulfonate) (PSS) at silicon substrates texturized by parallel nanoscopic surface grooves, respectively. Dichroic Attenuated Total Reflexion Fourier Transform Infrared (ATR FTIR) spectroscopy was used to study the conformation and macromolecular order of stiff polyelectrolytes within PEM. High order parameters up to S=0.82 (S=1 for high, S=0 for low order) were obtained from the dichroic ratios of the Amide I and Amide II bands suggesting a significant alignment of charged alpha-helical polypeptides in PEM. For PEM consisting of PLL/polyanion the S values significantly increased with increasing molecular weight of PLL and with decreasing molecular weight of the polyanion. These spectroscopic findings were supported by SFM images on PEM-PLL/PVS with high molecular PLL and PEM-PLL/PSS with low molecular PSS, which both showed anisotropically oriented worm-like structures, while PEM-PLL/PVS with low molecular PLL and PEM-PLL/PSS with high molecular PSS showed no orientation features. PMID- 20833104 TI - Effect of predefined order sets and usability problems on efficiency of computerized medication ordering. AB - OBJECTIVES: To study the effect of predefined order sets on the efficiency of computerized medication ordering, and to analyze the effect of different types of usability problems on ordering efficiency. METHODS: Crossover study to comparing the efficiency of two methods of ordering (with and without use of predefined order sets) in a laboratory setting using a computerized physician order entry system (CPOE). The excess number of mouse clicks and keystrokes (the difference in number of mouse clicks and keystrokes needed by each physician and the minimally required numbers to accomplish the ordering tasks) for each method was measured and per physician, occurrences of usability problems during the task sessions were recorded. Observed usability problems were categorized using Zhang et al.'s heuristic principles of good user interface design. The effect of different types of usability problems on the excess number of mouse clicks and keystrokes was statistically analyzed. RESULTS: The median excess number of mouse clicks and keystrokes needed by physicians was 6.2 times lower in the method with predefined order sets (p<0.01). The excess number of mouse clicks and keystrokes was significantly increased by vague and erroneous system messages with a factor of 2.62 (95% CI 2.24-3.07), the use of unfamiliar language and terminology by a factor of 1.28 (95% CI 1.14-1.43), and non-informative system feedback by a factor of 1.15 (95% CI 1.03-1.28), respectively. Other categories of usability problems had little influence on ordering efficiency. CONCLUSIONS: Predefined order sets can improve the efficiency of computerized ordering by reducing the excess number of mouse clicks and keystrokes. However, the efficiency of computerized ordering can be significantly impaired by usability problems due to vague and incorrect system messages, unfamiliar language, and non-informative system feedback. PMID- 20833105 TI - Bartonella spp.: throwing light on uncommon human infections. AB - After 2 decades of Bartonella research, knowledge on transmission and pathology of these bacteria is still limited. Bartonella spp. have emerged to be important pathogens in human and veterinary medicine. For humans, B. henselae is considered to represent the most relevant zoonotic Bartonella species and is responsible for cat scratch disease, bacillary angiomatosis, and other disorders. Over the years, many Bartonella species have been isolated from humans, cats, dogs, and other mammals, and infections range from an asymptomatic state (e.g., animal-specific species) to even life-threatening diseases (e.g., Oroya fever). It is obvious that the analysis of pathogenicity mechanisms underlying Bartonella infections is needed to increase our understanding of how these pathogens adapt to their mammalian hosts resulting in acute or chronic diseases. PMID- 20833106 TI - Assessment of cytogenetic damage and oxidative stress in personnel occupationally exposed to the pulsed microwave radiation of marine radar equipment. AB - Due to increased usage of microwave radiation, there are concerns of its adverse effect in today's society. Keeping this in view, study was aimed at workers occupationally exposed to pulsed microwave radiation, originating from marine radars. Electromagnetic field strength was measured at assigned marine radar frequencies (3 GHz, 5.5 GHz and 9.4 GHz) and corresponding specific absorption rate values were determined. Parameters of the comet assay and micronucleus test were studied both in the exposed workers and in corresponding unexposed subjects. Differences between mean tail intensity (0.67 vs. 1.22) and moment (0.08 vs. 0.16) as comet assay parameters and micronucleus test parameters (micronuclei, nucleoplasmic bridges and nuclear buds) were statistically significant between the two examined groups, suggesting that cytogenetic alterations occurred after microwave exposure. Concentrations of glutathione and malondialdehyde were measured spectrophotometrically and using high performance liquid chromatography. The glutathione concentration in exposed group was significantly lower than in controls (1.24 vs. 0.53) whereas the concentration of malondialdehyde was significantly higher (1.74 vs. 3.17), indicating oxidative stress. Results suggests that pulsed microwaves from working environment can be the cause of genetic and cell alterations and that oxidative stress can be one of the possible mechanisms of DNA and cell damage. PMID- 20833107 TI - HNF4alpha--role in drug metabolism and potential drug target? AB - Hepatocyte nuclear factor 4alpha (HNF4alpha) is a highly conserved member of the nuclear receptor superfamily of ligand-dependent transcription factors. It is best known as a master regulator of liver-specific gene expression, especially those genes involved in lipid transport and glucose metabolism. However, there is also a growing body of work that indicates the importance of HNF4alpha in the regulation of genes involved in xenobiotic and drug metabolism. A recent study identifying the essential fatty acid linoleic acid (LA, C18:2) as the endogenous, reversible ligand for HNF4alpha suggests that HNF4alpha may also be a potential drug target and that its activity may be regulated by diet. This review will discuss the role of HNF4alpha in drug metabolism, including the genes it regulates, the factors that regulate its activity, and its potential as a drug target. PMID- 20833108 TI - Hypo-osmotic swelling test identifies individual spermatozoa with minimal DNA fragmentation. AB - One concern during intracytoplasmic sperm injection (ICSI) is that selected spermatozoa may have increased levels of DNA damage; however, the available testing for this is largely destructive in nature and therefore unsuitable as a tool for sperm selection. One alternative selection process that has previously achieved pregnancies is the hypo-osmotic swelling test (HOST). This study reports that low HOST values of neat semen samples were significantly (P<0.001) associated with increased DNA damage identified by the DNA fragmentation index (DFI) from the sperm chromatin structure assay as well as the TdT-mediated dUTP nick-end labelling (TUNEL) assay. The HOST value was highly predictive of an abnormal DFI value by receiver operating characteristic curve analysis (P<0.001). Furthermore, when individual spermatozoa were assessed for both HOST status and DNA fragmentation by TUNEL, the key HOST-induced tail-swelling grades D, E and F were most commonly associated with high HOST values and were significantly (P<0.001) associated with minimal DNA damage regardless of the DNA status of the ejaculate. The application of HOST may be a valuable tool in the routine identification and selection of viable, DNA-intact individual spermatozoa for ICSI after further research to demonstrate its efficacy and safety. PMID- 20833109 TI - Ex-premature infant boys with hypospadias are similar in size to age-matched, ex premature infant boys without hypospadias. AB - OBJECTIVE: Studies have postulated that hypospadias, prematurity, and low birth weight are linked by defects in androgen signaling. To determine whether premature, hypospadiac boys are small and remain so, we compared their size at birth and at hypospadias repair to premature boys who underwent post-neonatal circumcision. METHODS: We identified premature boys admitted to Texas Children's Hospital who underwent either hypospadias repair or circumcision after 4 months of age. Age, weight, and height at birth and surgery were recorded. RESULTS: Fifty-four boys had hypospadias and 34 did not. For hypospadiac boys, the mean birth weight and age, height, and weight at surgery were lower than for boys without hypospadias. More importantly, length-for-age and weight-for-age percentiles were also lower for hypospadiac boys. When subset analysis was performed on boys younger than 2 years at surgery, however, there were no significant differences in height or weight between hypospadiac and non hypospadiac boys. CONCLUSION: Our series suggests that premature, hypospadiac boys are born smaller than age-matched, non-hypospadiac controls. However, there were no age-corrected size differences between hypospadiac and non-hypospadiac boys at surgery. This implies that hypospadiac boys exhibit post-neonatal 'rebound' growth. Global growth deficits, if any, do not persist in hypospadiac boys. PMID- 20833110 TI - Open letter (and invitation) to the pharmaceutical industry: "no, we cannot just present your slide deck ...". PMID- 20833111 TI - Association between carbamazepine-induced cutaneous adverse drug reactions and the HLA-B*1502 allele among patients in central China. AB - The aim of this study was to investigate the association between carbamazepine (CBZ)-induced cutaneous adverse drug reactions (cADRs) and the HLA-B*1502 allele among patients from central China. Eight patients with Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), 28 with mild maculopapular eruptions (MPEs), 50 CBZ-tolerant controls, and 71 healthy volunteers were recruited. HLA genotyping was performed using the polymerase chain reaction sequence-based typing (SBT) method. As a result, the HLA-B*1502 allele was observed at the following rates: (1) 100% (8/8) among those with CBZ-induced SJS/TEN, (2) 10.7% (3/28) among those with CBZ-induced MPEs; (3) 8.0% (4/50) among CBZ-tolerant controls; (4) 8.5% (6/71) among healthy volunteers. The eight patients with SJS/TEN positive for the HLA-B*1502 allele had an odds ratio (OR) of 184 compared with CBZ-tolerant controls. There was no significant difference in frequency between patients with MPEs and CBZ-tolerant controls (P>0.05). Thus, CBZ-induced SJS/TEN, but not MPEs, is strongly associated with HLA-B*1502. Testing for HLA B*1502 should be recommended for patients from central China prior to initial CBZ treatment. PMID- 20833112 TI - Adding injury to insult: seizure-related injuries. PMID- 20833114 TI - Electrochemistry of the antibacterial and antifungal drug nitroxoline and its determination in bulk form, pharmaceutical formulation and human blood. AB - Nitroxoline has been reduced at the mercury electrode in buffered solutions (pH 2 11) in two irreversible cathodic steps. The first step was attributed to reduction of -NO(2) group to the hydroxylamine stage and the second one to reduction-saturation of the C=N double bond. DC-polarographic and various adsorptive stripping voltammetric methods were developed for determination of nitroxoline in bulk form. Limits of quantitation of 1.02*10(-6), 3.05*10(-8), 9.01*10(-9), and 9.12*10(-10)M nitroxoline were achieved by means of the developed DC-polarography, differential-pulse-, linear-sweep-, and square-wave adsorptive cathodic stripping voltammetric methods, respectively. All these electroanalytical methods were successfully applied for determination of nitroxoline in its Nibiol((r)) tablets. While only the developed adsorptive stripping voltammetry methods were successfully applied for determination of the drug in spiked human serum and for pharmacokinetic studies in real human plasma. The analysis was carried out without interference from common excipients and without the necessity for prior extraction or interaction with any reagent during the analysis. PMID- 20833115 TI - Species distribution of Burkholderia cepacia complex isolates in cystic fibrosis and non-cystic fibrosis patients in New Zealand. AB - Burkholderia cepacia complex (Bcc) isolates from 39 CF patients and 25 non-CF patients in New Zealand were speciated and characterised using the multilocus sequence typing (MLST) scheme for Bcc. B. multivorans predominated in CF patients (31/39, 79.5%) and in non-CF patients (7/25, 28%). Sequence types (ST) with an international distribution were identified (27/64, 42.2%) among the New Zealand Bcc isolates. MLST revealed a high level of diversity among Bcc isolates in CF patients indicating a lack of person-to-person transmission. Non-CF patients showed less diversity in MLST types, however, individuals with shared STs were geographically and chronologically separated. The use of MLST analysis allows continued surveillance of isolates with the potential to identify outbreaks. The identification of internationally distributed strains may provide an indicator of the relative transmissibility and infectivity of these strains and warrants further investigation. PMID- 20833116 TI - Biological monitoring and analytical toxicology in occupational and environmental medicine. PMID- 20833117 TI - Nature, nurture and socioeconomic policy-what can we learn from molecular genetics? AB - Many countries use public resources to compensate individuals with genetic disorders, identified by behaviors/symptoms such as chronic diseases and disabilities. This paper draws attention to molecular genetic research which may provide a new dimension to our understanding of how socioeconomic outcomes are generated. We provide an overview of the recently emerging evidence of gene environment interaction effects. This literature points out specific areas where policies may compensate groups of individuals carrying genetic risks, without the need to identify anyone's genetic endowments. Moreover, epigenetics studies, which concern heritable changes in gene functions that occur independently of the DNA sequence, have shown that environments may affect heritable traits across generations. It means that policies which neutralize adverse environments may also increase intergenerational mobility, given that genetic and/or environmental risk factors are more common in socially disadvantaged groups. PMID- 20833118 TI - Long-term treatment of hepatorenal syndrome as a bridge to liver transplantation. AB - BACKGROUND/AIMS: Terlipressin plus albumin is first-line treatment for hepatorenal syndrome (HRS). Therapy lasts from a few days to two weeks, whereas the efficacy and safety of long-term administration remain unsettled. METHODS: We describe our experience of prolonged terlipressin and albumin treatment as a bridge to liver transplantation in three patients with cirrhosis and recurrent HRS. RESULTS: The length of treatment ranged from 62 days to eight months. Attempts to suspend terlipressin or to switch treatment to midodrine plus octreotide were consistently associated with a deterioration of serum creatinine and oliguria. No major side-effects were observed. All patients were transplanted, but two died from peri-operative complications. CONCLUSIONS: These clinical cases suggest that long-term terlipressin administration in selected patients with recurrent HRS awaiting liver transplantation may represent an option to prevent irreversible renal failure and the need for dialysis until an organ becomes available. PMID- 20833119 TI - [Multifocal epithelial hyperplasia: a familial case]. AB - Multifocal epithelial hyperplasia (MEH), or Heck disease, is a disease of the oral mucosa rarely seen in Spain. It is caused by the human papillomavirus (HPV), and is mainly associated with types 13 and 32. It appears in childhood (3-18 years) and a higher prevalence is reported in women and certain ethnic groups (American Indians and Eskimos). It consists of a benign, asymptomatic epithelial proliferation in the form of multiple papules of 3-10mm with a normal oral mucosa colour. The case involves an Ecuadorian male of 14 years, with papulous lesions in the oral mucosa with onset at 4 years of age. His 32 year-old mother had identical lesions. CONCLUSION: We present two members of an ecuadorian family with MEH. Although it is a rare disease in Spain, we must take this disease into account, given the increase in the immigrant population in Spain. PMID- 20833120 TI - Deep venous thrombosis associated with acute hematogenous osteomyelitis in children. AB - INTRODUCTION: Deep venous thrombosis (DVT) is rare in children. It may complicate acute hematogenous osteomyelitis (AHO). OBJECTIVE: The present study assessed the incidence of DVT in community-acquired AHO, and compared clinical and laboratory characteristics with AHO without DVT. PATIENTS AND METHODS: A prospective study included patients treated for community-acquired AHO between April 2007 and December 2009. RESULTS: Seventy patients were included: mean age, 7.7 years. Seven developed DVT. All involved Staphylococcus aureus. The isolated Staphylococcus aureus was significantly more often methicillin-resistant than methicillin-susceptible (p=0.04). C-reactive protein, erythrocyte sedimentation rate, positive blood culture and incidence of pulmonary staphylococcus were significantly higher in patients with DVT. These patients also had significantly more febrile days. One patient with DVT died from severe refractory respiratory failure. DISCUSSION: DVT was observed in 10% of cases of community-acquired AHO. DVT was associated with more severe onset, with extensive local disease. Surgery was often needed to drain a subperiosteal abscess. DVT can cause invasive and life-threatening infection through septic emboli, particularly to the lungs. LEVEL OF EVIDENCE: Level III. PMID- 20833121 TI - Esophageal perforations. AB - The incidence of esophageal perforation (EP) has risen with the increasing use of endoscopic procedures, which are currently the most frequent causes of EP. Despite decades of clinical experience, innovations in surgical technique and advances in intensive care management, EP still represents a diagnostic and therapeutic challenge. EP is a devastating event and mortality hovers close to 20%. Ambiguous presentations leading to misdiagnosis and delayed treatment and the difficulties in management are responsible for the high morbidity and mortality rates. A high variety of treatment options are available ranging from observational medical therapy to radical esophagectomy. The potential role of interventional endoscopy and the use of stents for the treatment of EP seem interesting but remain to be evaluated. Surgical primary repair, with or without reinforcement, is the preferred approach in patients with EP. Prognosis is mainly determined by the cause, the location of the injury and the delay between perforation and initiation of therapy. PMID- 20833122 TI - The development of persistent duck hepatitis B virus infection can be prevented using antiviral therapy combined with DNA or recombinant fowlpoxvirus vaccines. AB - We recently reported the development of a successful post-exposure combination antiviral and "prime-boost" vaccination strategy using the duck hepatitis B virus (DHBV) model of human hepatitis B virus infection. The current study aimed to simplify the vaccination strategy and to test the post-exposure efficacy of combination therapy with the Bristol-Myers Squibb antiviral drug, entecavir (ETV) and either a single dose of DHBV DNA vaccines on day 0 post-infection (p.i.) or a single dose of recombinant fowlpoxvirus (rFPV-DHBV) vaccines on day 7 p.i. Whilst untreated control ducks infected with an equal dose of DHBV all developed persistent and wide spread DHBV infection of the liver, ducks treated with ETV combined with either the DHBV DNA vaccines on day 0 p.i. or the rFPV-DHBV vaccines on day 7 p.i. had no detectable DHBV-infected hepatocytes by day 14 p.i. and were protected from the development of persistent DHBV infection. PMID- 20833123 TI - Seed pods of the carob tree Ceratonia siliqua are a favored sugar source for the mosquito Aedes albopictus in coastal Israel. AB - The sugar feeding of Aedes albopictus was studied. In outdoor cages they fed avidly on carob (Ceratonia siliqua L., Caesalpiniaceae) seed pods soiled with sugary exudates. Feeding was either from the surface or by piercing the tissue which is indicated by the presence of plant tissue residues in the gut. More than 90% were sugar positive and about a third had plant tissue residues in the gut after overnight exposure. Similar exposure to clean undamaged seed pods resulted in about two thirds sugar positive mosquitoes and all of these had plant-tissue residues in the gut. In an irrigated, field site, with abundance of sugar sources in the summer 68% of the females and 75% of the males were sugar positive whereas, 1.2% of the females and no males had plant tissue in the gut. The proportion of sugar positive mosquitoes was similar in the autumn and plant tissue was not found in 150 females and 13 males. In the dry site in the summer 42% females and 33% males were sugar positive while 22% females and 33% males contained plant tissue. In the autumn 73% females and 80% males were sugar positive while 2% females and none of the males contained plant tissue. PMID- 20833124 TI - Nuclear magnetic resonance-based quantification of organic diphosphates. AB - Phosphorylated compounds are ubiquitous in life. Given their central role, many such substrates and analogs have been prepared for subsequent evaluation. Prior to biological experiments, it is typically necessary to determine the concentration of the target molecule in solution. Here we describe a method where concentrations of stock solutions of organic diphosphates and bisphosphonates are quantified using (31)P nuclear magnetic resonance (NMR) spectroscopy with standard instrumentation using a capillary tube with a secondary standard. The method is specific and is applicable down to a concentration of 200 MUM. The capillary tube provides the reference peak for quantification and deuterated solvent for locking. PMID- 20833125 TI - Structure and mechanism of action of a de novo antimicrobial detergent-like peptide. AB - The K4 peptide (KKKKPLFGLFFGLF) was recently demonstrated to display good antimicrobial activities against various bacterial strains and thus represents a candidate for the treatment of multiple-drug resistant infections. In this study, we use various techniques to study K4 behaviour in different media: water, solutions of detergent micelles, phospholipid monolayers and suspension of phospholipid vesicles. First, self-assembly of the peptide in water is observed, leading to the formation of spherical objects around 10nm in diameter. The addition of micelles induces partial peptide folding to an extent depending on the charge of the detergent headgroups. The NMR structure of the peptide in the presence of SDS displays a helical character of the hydrophobic moiety, whereas only partial folding is observed in DPC micelles. This peptide is able to destabilize the organization of monolayer membranes or bilayer liposomes composed of anionic lipids. When added on small unilamellar vesicles it generates larger objects attributed to mixed lipid-peptide vesicles and aggregated vesicles. The absence of calcein leakage from liposomes, when adding K4, underlines the original mechanism of this linear amphipathic peptide. Our results emphasize the importance of the electrostatic effect for K4 folding and lipid destabilization leading to the microorganisms' death with a high selectivity for the eukaryotic cells at the MIC. Interestingly, the micrographs obtained by electronic microscopy after addition of peptide on bacteria are also consistent with the formation of mixed lipid-peptide objects. Overall, this work supports a detergent like mechanism for the antimicrobial activity of this peptide. PMID- 20833126 TI - Drosophila CG10527 mutants are resistant to juvenile hormone and its analog methoprene. AB - Juvenile hormone (JH) is critical for development, metamorphosis, and reproduction in insects. While the physiological importance of JH has been appreciated for decades, its biosynthetic pathway and molecular action remain poorly understood. Drosophila CG10527 encodes a protein with high homology to crustacean farnesoic acid methyltransferase (FAMeT) that converts farnesoic acid to methyl farnesoate (MF), a precursor of JH, but its in vivo functions remain unclear. Here we report that CG10527 is expressed widely in secondary cells in the male accessory glands, in ovarian follicle cells, and in glial cells in the nervous system. Furthermore, CG10527 is expressed abundantly in the corpora allata where JH is synthesized. To understand the physiological functions of CG10527, we generated specific CG10527 deletions. Phenotypic analysis showed that CG10527 null mutants are fully viable and fertile in both sexes, indicating that CG10527 is not essential for survival and fertility. Surprisingly, CG10527 mutants showed no defects in the biosynthesis of MF and JH. However, CG10527 mutants were 3-5 times more resistant than wild-type flies to topically applied MF and JH as well as the JH analog methoprene at both sub-lethal and lethal doses. Taken together, our data indicate that Drosophila CG10527 plays little, if any, role in JH biosynthesis but may participate in the JH signaling pathway. PMID- 20833127 TI - Oxidative modifications impair albumin quantification. AB - BACKGROUND: Hypoalbuminemia is a measure of malnutrition, inflammation and a predictor of mortality in uremia. It is controversial whether albumin levels per se are associated with the clinical outcomes in uremic patients. The co occurrence of hypoalbuminemia and oxidative stress in hemodialysis (HD) patients led us to hypothesize that oxidative modifications of albumin decrease its detection and influence albumin quantification. METHODS: Albumin levels are determined in clinical laboratories mainly by the bromocresol green (BCG) spectrophotometric assay. The detection of serum albumin was investigated in HD patients and in healthy controls using an "albumin-detection index", defined as the ratio between BCG read-out (albumin-specific) to total albumin. The detection efficacy of albumin was also investigated in vitro, after glycoxidation, HOCl mediated-oxidation, and metal-catalyzed-oxidation. Oncotic pressure was measured to assess albumin function. RESULTS: The albumin-detection index of patients was significantly lower compared with controls, correlating negatively with oxidative stress markers (serum advanced oxidation protein products-AOPP and glycoxidized serum albumin) and positively with serum albumin levels. The albumin-detection index was also decreased after in vitro oxidation. CONCLUSIONS: The study shows, both in vivo and in vitro, decreased detection of oxidized albumin by a commonly used clinical assay, thus providing the molecular link between oxidative stress and hypoalbuminemia. Oxidative stress as reflected by hypoalbuminemia, rather than actual albumin levels, may be related to cardiovascular morbidity outcomes in HD patient. PMID- 20833128 TI - Pyrosequencing enhancement for better detection limit and sequencing homopolymers. AB - Pyrosequencing is a DNA sequencing technique based on sequencing-by-synthesis enabling rapid and real-time sequence determination. Although ample genomic research has been undertaken using pyrosequencing, the requirement of relatively high amount of DNA template and the difficulty in sequencing the homopolymeric regions limit its key advantages in the applications directing towards clinical research. In this study, we demonstrate that pyrosequencing on homopolymeric regions with 10 identical nucleotides can be successfully performed with optimal amount of DNA (0.3125-5 pmol) immobilized on conventional non-porous Sepharose beads. We also validate that by using porous silica beads, the sequencing signal increased 3.5-folds as compared to that produced from same amount of DNA immobilized on solid Sepharose beads. Our results strongly indicate that with optimized quantity of DNA and suitable solid support, the performance of pyrosequencing on homopolymeric regions and its detection limit has been significantly improved. PMID- 20833129 TI - Understanding gene essentiality by finely characterizing hubs in the yeast protein interaction network. AB - The centrality-lethality rule, i.e., high-degree proteins or hubs tend to be more essential than low-degree proteins in the yeast protein interaction network, reveals that a protein's central position indicates its important function, but whether and why hubs tend to be more essential have been heavily debated. Here, we integrated gene expression and functional module data to classify hubs into four types: non-co-expressed non-co-cluster hubs, non-co-expressed co-cluster hubs, co-expressed non-co-cluster hubs and co-expressed co-cluster hubs. We found that all the four hub types are more essential than non-hubs, but they also show different enrichments in essential proteins. Non-co-expressed non-co-cluster hubs play key role in organizing different modules formed by the other three hub types, but they are less important to the survival of the yeast cell. Among the four hub types, co-expressed co-cluster hubs, which likely correspond to the core components of stable protein complexes, are the most essential. These results demonstrated that our classification of hubs into four types could better improve the understanding of gene essentiality. PMID- 20833130 TI - Global regulator H-NS and lipoprotein NlpI influence production of extracellular DNA in Escherichia coli. AB - Extracellular DNA (eDNA) is a structural component of the polymeric matrix of biofilms from different species. Different mechanisms for DNA release have been proposed including lysis of cells, lysis of DNA-containing vesicles, and DNA secretion. Here, a genome-wide screen of 3985 non-lethal mutations was performed to identify genes whose deletion alters eDNA release in Escherichia coli. Deleting nlpI, yfeC, and rna increased eDNA from planktonic cultures while deleting hns and rfaD decreased eDNA production. The lipoprotein NlpI negatively affects eDNA release since the overexpression of nlpI decreases eDNA 16 fold while deleting nlpI increases eDNA threefold. The global regulator H-NS is required for eDNA production since DNA was not detected for the hns mutant and production of H-NS restored eDNA production to wild-type levels. Therefore our results suggest that secretion may play a role in eDNA release in E. coli since the effect of the hns deletion on cell lysis (slight decrease) and membrane vesicles (threefold increase) does not account for the reduction in eDNA. PMID- 20833131 TI - In vivo differential effects of fasting, re-feeding, insulin and insulin stimulation time course on insulin signaling pathway components in peripheral tissues. AB - BACKGROUND: Components of the insulin receptor signaling pathway are probably some of the best studied ones. Even though methods for studying these components are well established, the in vivo effects of different fasting regimens, and the time course of insulin receptor phosphorylation and that of its downstream components in insulin-sensitive peripheral tissues have not been analyzed in detail. RATIONALE: When assessing insulin signaling, it may be beneficial to drive insulin levels as low as possible by performing an overnight fast before injecting a supra-physiological dose of insulin. Recent studies have shown however that 5 or 6 h fast in mice is sufficient to assess physiological responses to insulin and/or glucose in glucose tolerance tests, insulin tolerance tests and euglycemic hyperinsulinemic clamp studies. Moreover, mice are nocturnal feeders, with ~70% of their daily caloric intake occurring during the dark cycle, and their metabolic rate is much higher than humans. Therefore, an overnight fast in mice is closer to starvation than just food withdrawal. Thus our aim was to assess insulin signaling components from the insulin receptor to downstream targets IRS1, Akt/PKB, GSK3, Erk1/2 and ribosomal protein S6 in muscle, liver and adipose tissue in 5 h versus 16 h (overnight) fasted mice, and the time course (0 30 min) of these phosphorylation events. We also assessed whether re-feeding under 5 h and 16 h fasting conditions was a more robust stimulus than insulin alone. CONCLUSIONS: Our study determines that a short food withdrawal from mice, for a period of 5 h, results in a similar insulin-stimulated response in phosphorylation events as the long overnight fast, presenting a more physiological experimental set up. We also demonstrate that in vivo, insulin stimulated phosphorylation of its signaling components is different between different peripheral tissues, and depending on the tissue(s) and protein(s) of interest, an appropriate time course should be chosen. PMID- 20833132 TI - Increased transient receptor potential vanilloid type 1 (TRPV1) channel expression in hypertrophic heart. AB - The aim of this study was to compare the expression of transient receptor potential vanilloid type 1 (TRPV1) channels in hypertrophic hearts from transgenic mice showing overexpression of the catalytic subunit alpha of protein phosphatase 2A alpha (PP2Ac alpha) with wild-type mice and with TRPV1-/- mice. Transcripts of TRPV1, matrix metalloproteinase 9 (MMP9), discoidin domain receptor family, member 2 (DDR-2), atrial natriuretic peptide (ANP), GATA 4, and regulatory microRNA (miR-21) were analyzed using quantitative real-time PCR. Ventricle-to-body-weight-ratio was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1-/- mice (8.6+/-1.3mg/g; 5.4+/-0.3mg/g; and 5.4+/-0.4mg/g; respectively; p<0.05 by Kruskal-Wallis test). TRPV1 transcripts were significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice (1.7+/-0.2 arbitrary units vs. 0.8+/-0.1 arbitrary units; p<0.05). TRPV1 protein expression was also significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice. A significant linear correlation was observed between TRPV1 transcripts and the ventricle-to-body-weight-ratio (Spearman r=0.78; p<0.05). The expression of DDR-2 was significantly higher in PP2Ac alpha transgenic mice compared to wild-type mice and TRPV1 knockout mice. The expression of miR21 was significantly higher in PP2Ac alpha transgenic mice compared with TRPV1-/- mice (0.103+/-0.018 (PP2Ac alpha transgenic mice); 0.089+/ 0.009 (wild-type mice); and 0.045+/-0.013 (TRPV1-/- mice), respectively; p<0.05). Masson Goldner staining revealed that PP2Ac alpha transgenic mice showed increased heart fibrosis compared with TRPV1 knockout mice. The study suggests an important role of TRPV1 in the pathogenesis of genetically associated heart hypertrophy. PMID- 20833133 TI - Modulation of neutrophil apoptosis by murine pulmonary microvascular endothelial cell inducible nitric oxide synthase. AB - Neutrophils contribute significantly to ALI (acute lung injury) through adhesion to pulmonary microvascular endothelial cells (PMEC), trans-PMEC migration and alveolar infiltration. Trans-PMEC migration delays expression of neutrophil apoptosis, which promotes intra-alveolar neutrophil survival and neutrophil mediated ALI. We assessed the role of neutrophil vs PMEC inducible nitric oxide (NO) synthase (iNOS) in modulating neutrophil apoptosis. Apoptosis of wild-type vs iNOS-/- neutrophils was quantified by microscopy and FACS annexin-V binding. In a murine model of ALI, neutrophils isolated by BAL(broncho-alveolar lavage) from iNOS-/- mice had increased expression of apoptosis after 24h culture ex vivo than wild-type neutrophils (15.2+/-3.3 vs 3.0+/-0.4%, mean+/-sd, p<0.01). Apoptosis rates of isolated bone marrow iNOS+/+ vs iNOS-/- neutrophils were similar under basal and LPS/IFN-gamma stimulation, and following LPS/IFN-gamma stimulated trans-PMEC migration. Apoptosis of both iNOS+/+ and iNOS-/- neutrophils was inhibited by trans-PMEC migration only across iNOS+/+ PMEC (1.6+/ 0.3 and 1.5+/-0.3%, respectively; p<0.05 for each vs non-migrated neutrophils) but not across iNOS-/- PMEC (4.3+/-1 and 3.1+/-0.6%, respectively). PMEC iNOS dependent inhibition of neutrophil apoptosis was independent of changes in neutrophil caspase-3 activity. We conclude that PMEC iNOS, but not neutrophil iNOS, has an important inhibitory effect on neutrophil apoptosis during trans PMEC neutrophil migration, which is independent of caspase-3 activity. Further studies will define the mechanism of PMEC iNOS-dependent inhibition of neutrophil apoptosis and assess the potential relevance of this phenomenon in human neutrophils and ALI. PMID- 20833134 TI - Activation of the unfolded protein response by a cataract-associated alphaA crystallin mutation. AB - alphaA-crystallin is a lens chaperone that plays an essential role in the transparency and refractive properties of the lens. Mutations in alphaA crystallin have been associated with the development of hereditary cataracts. The R49C mutation of alphaA-crystallin (alphaA-R49C) was identified in a four generation Caucasian family with hereditary cataracts. The alphaA-R49C protein forms larger-than-normal oligomers in the lens and has decreased solubility. This aberrant alphaA-R49C oligomerization suggests that protein folding is altered. However, whether activation of the unfolded protein response (UPR) occurs during crystallin mutation-induced cataract formation and whether the UPR causes cell death under these conditions is unclear. We investigated UPR activation in an in vivo mouse model of alphaA-R49C using immunoblot analysis of lens extracts. We found that expression of the endoplasmic reticulum (ER) chaperone, BiP, was 5 fold higher in homozygous alphaA-R49C lenses than in wild type lenses. Analysis of proteins typically expressed during the UPR revealed that ATF-4 and CHOP levels were also higher in homozygous lenses than in wild type lenses, while the opposite was true of ATF-6 and XBP-1. Taken together, these findings show that mutation of alphaA-crystallin induces activation of the UPR during cataract formation. They also suggest that the UPR is an important mediator of cell death observed in homozygous alphaA-R49C lenses. PMID- 20833135 TI - AHNAK1 and AHNAK2 are costameric proteins: AHNAK1 affects transverse skeletal muscle fiber stiffness. AB - The AHNAK scaffold PDZ-protein family is implicated in various cellular processes including membrane repair; however, AHNAK function and subcellular localization in skeletal muscle are unclear. We used specific AHNAK1 and AHNAK2 antibodies to analyzed the detailed localization of both proteins in mouse skeletal muscle. Co localization of AHNAK1 and AHNAK2 with vinculin clearly demonstrates that both proteins are components of the costameric network. In contrast, no AHNAK expression was detected in the T-tubule system. A laser wounding assay with AHNAK1-deficient fibers suggests that AHNAK1 is not involved in membrane repair. Using atomic force microscopy (AFM), we observed a significantly higher transverse stiffness of AHNAK1-/- fibers. These findings suggest novel functions of AHNAK proteins in skeletal muscle. PMID- 20833136 TI - Reduction of Nup107 attenuates the growth factor signaling in the senescent cells. AB - Hypo-responsiveness to growth factors is a fundamental feature of cellular senescence. In this study, we found markedly decreased level of Nup107, a key scaffold protein in nuclear pore complex assembly, in senescent human diploid fibroblasts as well as in organs of aged mice. Depletion of Nup107 by specific siRNA in young human diploid fibroblasts prevented the effective nuclear translocation of phosphorylated extracellular signal-regulated kinase (ERK) following epidermal growth factor (EGF) stimulation, and decreased the expression of c-Fos in consequence. The disturbances in ERK signaling in Nup107 depleted cells closely mirror the similar changes in senescent cells. Knockdown of Nup107 in anaplastic oligodendroglioma cells caused cell death, rather than growth retardation, indicating a greater sensitivity to Nup107 depletion in cancer cells than in normal cells. These findings support the notion that Nup107 may contribute significantly to the regulation of cell fate in aged and transformed cells by modulating nuclear trafficking of signal molecules. PMID- 20833137 TI - A family of cell-adhering peptides homologous to fibrinogen C-termini. AB - A family of cell-adhesive peptides homologous to sequences on different chains of fibrinogen was investigated. These homologous peptides, termed Haptides, include the peptides Cbeta, preCgamma, and CalphaE, corresponding to sequences on the C termini of fibrinogen chains beta, gamma, and alphaE, respectively. Haptides do not affect cell survival and rate of proliferation of the normal cell types tested. The use of new sensitive assays of cell adhesion clearly demonstrated the ability of Haptides, bound to inert matrices, to mediate attachment of different matrix-dependent cell types including normal fibroblasts, endothelial, and smooth muscle cells. Here we present new active Haptides bearing homologous sequences derived from the C-termini of other proteins, such as angiopoietin 1&2, tenascins C&X, and microfibril-associated glycoprotein-4. The cell adhesion properties of all the Haptides were found to be associated mainly with their 11 N-terminal residues. Mutated preCgamma peptides revealed that positively charged residues account for their attachment effect. These results suggest a mechanism of direct electrostatic interaction of Haptides with the cell membrane. The extended Haptides family may be applied in modulating adhesion of cells to scaffolds for tissue regeneration and for enhancement of nanoparticulate transfection into cells. PMID- 20833138 TI - Histone demethylase LSD1 is required to induce skeletal muscle differentiation by regulating myogenic factors. AB - During myogenesis, transcriptional activities of two major myogenic factors, MyoD and myocyte enhancer factor 2 (Mef2) are regulated by histone modifications that switch on and off the target genes. However, the transition mechanism from repression to activation modes of histones has not been defined. Here we identify that lysine specific demethylase 1, (LSD1) is responsible for removing the repressive histone codes during C2C12 mouse myoblast differentiation. The potent role of LSD1 is suggested by the increment of its expression level during myogenic differentiation. Moreover, by performing co-immunoprecipitation and ChIP assay, physically interaction of LSD1 with MyoD and Mef2 on the target promoters was identified. Their interactions were resulted in upregulation of the transcription activities shown with increased luciferase activity. Interruption of demethylase activity of LSD1 using shRNA or chemical inhibitor, pargyline, treatment led to aberrant histone codes on myogenic promoters during skeletal muscle differentiation. We also demonstrate that inhibition of LSD1 impairs C2C12 mouse myoblast differentiation. Our results show for the first time the regulatory mechanism of myogenesis involving histone demethylase. Altogether, the present study suggests a de-repression model and expands the understanding on the dynamic regulation of chromatin during myogenesis. PMID- 20833139 TI - Torque generation by one of the motor subunits of heterotrimeric kinesin-2. AB - Heterotrimeric kinesin-2 motors transport intraflagellar transport (IFT) particles from the base to the tip of the axoneme to assemble and maintain cilia. These motors are distinct in containing two non-identical motor subunits together with an accessory subunit. We evaluated the significance of this organization by comparing purified wild type kinesin-2 holoenzymes that support IFT in vivo, with mutant trimers containing only one type of motor domain that do not support IFT in vivo. In motility assays, wild type kinesin-2 moved microtubules (MTs) at a rate intermediate between the rates supported by the two mutants. Interestingly, one of the mutants, but not the other mutant or the wild type protein, was observed to drive a persistent counter-clock-wise rotation of the gliding MTs. Thus one of the two motor domains of heterotrimeric kinesin-2 exerts torque as well as axial force as it moves along a MT, which may allow kinesin-2 to control its circumferential position around a MT doublet within the cilium. PMID- 20833140 TI - Human kidney anion exchanger 1 interacts with adaptor-related protein complex 1 MU1A (AP-1 mu1A). AB - Kidney anion exchanger 1 (kAE1) mediates chloride (Cl-) and bicarbonate (HCO3-) exchange at the basolateral membrane of kidney alpha-intercalated cells. Impaired trafficking of kAE1 leads to defect of the Cl-/HCO3- exchange at the basolateral membrane and failure of proton (H+) secretion at the apical membrane, causing a kidney disease--distal renal tubular acidosis (dRTA). To gain a better insight into kAE1 trafficking, we searched for proteins physically interacting with the C terminal region of kAE1 (Ct-kAE1), which contains motifs crucial for intracellular trafficking, by a yeast two-hybrid (Y2H) system. An adaptor-related protein complex 1 MU1A (AP-1 mu1A) subunit was found to interact with Ct-kAE1. The interaction between either Ct-kAE1 or full-length kAE1 and AP-1 mu1A were confirmed in human embryonic kidney (HEK) 293T by co-immunoprecipitation, affinity co-purification, co-localization, yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA) and GST pull-down assay. The interacting site for AP-1 mu1A on Ct-kAE1 was found to be Y904DEV907, a subset of YXXO motif. Interestingly, suppression of endogenous AP-1 mu1A in HEK 293T by small interfering RNA (siRNA) decreased membrane localization of kAE1 and increased its intracellular accumulation, suggesting for the first time that AP-1 mu1A is involved in the kAE1 trafficking of kidney alpha-intercalated cells. PMID- 20833141 TI - G protein-mediated Ca2+-sensitization of CPI-17 phosphorylation in arterial smooth muscle. AB - CPI-17 is a unique phosphoprotein that specifically inhibits myosin light chain phosphatase in smooth muscle and plays an essential role in agonist-induced contraction. To elucidate the in situ mechanism for G protein-mediated Ca2+ sensitization of CPI-17 phosphorylation, alpha-toxin-permeabilized arterial smooth muscle strips were used to monitor both force development and CPI-17 phosphorylation in response to GTPgammaS with varying Ca2+ concentrations. CPI-17 phosphorylation increased at unphysiologically high Ca2+ levels of pCa <= 6. GTPgammaS markedly enhanced the Ca2+ sensitivity of CPI-17 steady-state phosphorylation but had no enhancing effect under Ca2+-free conditions, while the potent PKC activator PDBu increased CPI-17 phosphorylation regardless of Ca2+ concentration. CPI-17 phosphorylation induced by pCa 4.5 alone was markedly inhibited by the presence of PKC inhibitor but not ROCK inhibitor. In the presence of calyculin A, a potent PP1/PP2A phosphatase inhibitor, CPI-17 phosphorylation increased with time even under Ca2+-free conditions. Furthermore, as Ca2+ concentration increased, so did CPI-17 phosphorylation rate. GTPgammaS markedly enhanced the rate of phosphorylation of CPI-17 at a given Ca2+. In the absence of calyculin A, either steady-state phosphorylation of CPI-17 under Ca2+ free conditions in the presence of GTPgammaS or at pCa 6.7 in the absence of GTPgammaS was negligible, suggesting a high intrinsic CPI-17 phosphatase activity. In conclusion, cooperative increases in Ca2+ and G protein activation are required for a significant activation of total kinases that phosphorylate CPI 17, which together overcome CPI-17 phosphatase activity and effectively increase the Ca2+ sensitivity of CPI-17 phosphorylation and smooth muscle contraction. PMID- 20833142 TI - Solution NMR structure of the V27A drug resistant mutant of influenza A M2 channel. AB - The M2 protein of influenza A virus forms a proton-selective channel that is required for viral replication. It is the target of the anti-influenza drugs, amantadine and rimantadine. Widespread drug resistant mutants, however, has greatly compromised the effectiveness of these drugs. Here, we report the solution NMR structure of the highly pathogenic, drug resistant mutant V27A. The structure reveals subtle structural differences from wildtype that maybe linked to drug resistance. The V27A mutation significantly decreases hydrophobic packing between the N-terminal ends of the transmembrane helices, which explains the looser, more dynamic tetrameric assembly. The weakened channel assembly can resist drug binding either by destabilizing the rimantadine-binding pocket at Asp44, in the case of the allosteric inhibition model, or by reducing hydrophobic contacts with amantadine in the pore, in the case of the pore-blocking model. Moreover, the V27A structure shows a substantially increased channel opening at the N-terminal end, which may explain the faster proton conduction observed for this mutant. Furthermore, due to the high quality NMR data recorded for the V27A mutant, we were able to determine the structured region connecting the channel domain to the C-terminal amphipathic helices that was not determined in the wildtype structure. The new structural data show that the amphipathic helices are packed much more closely to the channel domain and provide new insights into the proton transfer pathway. PMID- 20833143 TI - Myocardial regeneration potential of adipose tissue-derived stem cells. AB - Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the underlying mechanisms for beneficial effect on cardiac function, and safety issues. PMID- 20833144 TI - Cytochrome c oxidase loses catalytic activity and structural integrity during the aging process in Drosophila melanogaster. AB - The hypothesis, that structural deterioration of cytochrome c oxidase (CcO) is a causal factor in the age-related decline in mitochondrial respiratory activity and an increase in H2O2 generation, was tested in Drosophila melanogaster. CcO activity and the levels of seven different nuclear DNA-encoded CcO subunits were determined at three different stages of adult life, namely, young-, middle-, and old-age. CcO activity declined progressively with age by 33%. Western blot analysis, using antibodies specific to Drosophila CcO subunits IV, Va, Vb, VIb, VIc, VIIc, and VIII, indicated that the abundance these polypeptides decreased, ranging from 11% to 40%, during aging. These and previous results suggest that CcO is a specific intra-mitochondrial site of age-related deterioration, which may have a broad impact on mitochondrial physiology. PMID- 20833145 TI - Arsenic transfer between metallothionein proteins at physiological pH. AB - As3+ bound to the two-domain, recombinant human metallothionein (isoform 1a) is stable at pH 7 and translocates via protein-protein interactions to other metallothionein proteins. The data show As3+ transfer from the two-domain beta alpha-hMT to binding sites in the isolated apo-beta-hMT and apo-alpha-hMT. Under conditions of equilibrium, apo- and partially-metallated species coexist indicating that noncooperative demetallation of the As(6)-betaalpha-hMT occurrs. As3+ transfer under conditions (pH 7) where the free As3+ ion is not stable, provides evidence that Cd2+ and Zn2+ transfer may also take place through protein protein interactions and that partially metallated Cd-MT and Zn-MT would be stable. PMID- 20833146 TI - Raldh3 expression in diabetic islets reciprocally regulates secretion of insulin and glucagon from pancreatic islets. AB - We have previously reported that obesity-induced diabetes developed in high-fat diet (HFD)-fed BDF1 mice. This is caused by insufficient insulin response to an excess glucose load. In this study, we have shown that the enhanced expression of retinaldehyde dehydrogenase 3 (Raldh3) causes functional disorders of pancreatic islets in diabetic mouse models. In the pancreatic islets of HFD-induced diabetic BDF1 mice and spontaneously diabetic C57BL/KsJ(db/db) mice, gene expression analysis with oligonucleotide microarray revealed a significant increase in Raldh3 expression. Exposure to a culture medium containing a higher glucose concentration (25 mM) significantly increased Raldh3 expression in murine MIN6 and alphaTC1 clone 9 cells, which derived from the alpha and beta-cells of pancreatic islets, respectively. Overexpression of Raldh3 reduced the insulin secretion in MIN6 cells, and surprisingly, increased the glucagon secretion in alphaTC1 clone 9 cells. Furthermore, the knockdown of Raldh3 expression with siRNA decreased the glucagon secretion in alphaTC1 clone 9 cells. Raldh3 catalyzes the conversion of 13-cis retinal to 13-cis retinoic acid and we revealed that 13-cis retinoic acid significantly reduces cell viability in MIN6 and alphaTC1 clone 9 cells, but not in cells of H4IIEC3, 3T3-L1, and COS-1 cell lines. These findings suggest that an increasing expression of Raldh3 deregulates the balanced mechanisms of insulin and glucagon secretion in the pancreatic islets and may induce beta-cell dysfunction leading to the development of type 2 diabetes. PMID- 20833147 TI - Interaction of novel hybrid compounds with the D3 dopamine receptor: Site directed mutagenesis and homology modeling studies. AB - The dopamine D3 receptor has been implicated as a potential target for drug development in various complex psychiatric disorders including psychosis, drug dependence, and Parkinson's disease. In our overall goal to develop molecules with preferential affinity at D3 receptors, we undertook a hybrid drug development approach by combining a known dopamine agonist moiety with a substituted piperazine fragment. In the present study, three compounds produced this way with preferential D3 agonist activity, were tested at D3 receptors with mutations in the agonist binding pocket of three residues known to be important for agonist binding activity. At S192A and T369V, the hybrid agonist compounds produced an interaction profile in [(3)H]spiperone binding assays similar to that of the parent 5-OH-DPAT and 7-OH-DPAT molecules. The loss of affinity at the S192A mutant was most prominent for 5-OH-DPAT and its corresponding hybrid compound D237. D110N did not show any radioligand binding. Homology modeling indicated that 7-OH-DPAT-derived D315 uniquely shares H-bonding with Tyr365 which produced favorable interaction and no loss of H-bonding in the S192A mutant, suggesting that agonist activity may not be solely controlled by residues in the binding pocket. PMID- 20833148 TI - Organ-specific carboxylesterase profiling identifies the small intestine and kidney as major contributors of activation of the anticancer prodrug CPT-11. AB - The activation of the anticancer prodrug CPT-11, to its active metabolite SN-38, is primarily mediated by carboxylesterases (CE). In humans, three CEs have been identified, of which human liver CE (hCE1; CES1) and human intestinal CE (hiCE; CES2) demonstrate significant ability to hydrolyze the drug. However, while the kinetic parameters of CPT-11 hydrolysis have been measured, the actual contribution of each enzyme to activate the drug in biological samples has not been addressed. Hence, we have used a combination of specific CE inhibition and conventional chromatographic techniques to determine the amounts, and hydrolytic activity, of CEs present within human liver, kidney, intestinal and lung specimens. These studies confirm that hiCE demonstrates the most efficient kinetic parameters for CPT-11 activation, however, due to the high levels of hCE1 that are expressed in liver, the latter enzyme can contribute up to 50% of the total of drug hydrolysis in this tissue. Conversely, in human duodenum, jejunum, ileum and kidney, where hCE1 expression is very low, greater than 99% of the conversion of CPT-11 to SN-38 was mediated by hiCE. Furthermore, analysis of lung microsomal extracts indicated that CPT-11 activation was more proficient in samples obtained from smokers. Overall, our studies demonstrate that hCE1 plays a significant role in CPT-11 hydrolysis even though it is up to 100-fold less efficient at drug activation than hiCE, and that drug activation in the intestine and kidney are likely major contributors to SN-38 production in vivo. PMID- 20833149 TI - Marine natural products targeting phospholipases A2. AB - Phospholipases A(2) (PLA(2)s) form a family of enzymes catalyzing the hydrolysis of membrane phospholipids into arachidonic acid, which is the major precursor of pro-inflammatory eicosanoids. As a result, PLA(2)s have been considered as potential targets in anti-inflammatory drug discovery. Marine natural products are a rich source of bioactive compounds, including PLA(2) inhibitors. Here, we review the properties of marine PLA(2) inhibitors identified since the first discovery of PLA(2) inhibitory activity in the marine natural product manoalide in the mid 1980s. PMID- 20833150 TI - AP-1 inhibitory peptides attenuate in vitro cortical neuronal cell death induced by kainic acid. AB - This study has assessed the neuroprotective efficacy of five AP-1 inhibitory peptides in an in vitro excitotoxicity model. The five AP-1 inhibitory peptides and controls of the JNK inhibitor peptide (JNKI-1D-TAT) and TAT cell-penetrating peptide were administered to primary cortical neuronal cultures prior to kainic acid exposure. All five AP-1 inhibitory peptides and JNKI-1D-TAT provided significant neuroprotection from kainic acid induced neuronal cell death. Kainic acid exposure induced caspase and calpain activation in neuronal cultures, with caspase-induced cleavage of alpha-fodrin reduced by administration of the AP-1 inhibitory peptides. Sequence analysis of the AP-1 inhibitory peptides did not reveal the presence of any secondary structures; however two peptides shared 66% amino-acid sequence homology. As a result, truncated sequences were designed and synthesised to identify the active region of the peptides. All truncated peptides were significantly neuroprotective following kainic acid and glutamate exposure. We have shown for the first time the neuroprotective efficacy of full-length and truncated AP-1 inhibitory peptides in kainic acid and glutamate neuronal excitotoxicity models. The identification of therapeutic targets, such as the AP 1 complex, is an important step for the development of pharmaceuticals to reduce neuronal loss in disorders with a prevalence of excitotoxic cell death such as epilepsy, cerebral ischaemia, and traumatic brain injury. PMID- 20833151 TI - Connexin36 knockout mice display increased sensitivity to pentylenetetrazol induced seizure-like behaviors. AB - OBJECTIVE: Large-scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions. To explore roles for connexin36 (Cx36) gap junctions in seizures, we examined the seizure threshold of connexin36 knockout (Cx36KO) mice using a pentylenetetrazol (PTZ) model. METHODS: Mice (2-3months old) with Cx36 wildtype (WT) or Cx36KO genotype were treated with vehicle or 10-40mg/kg of the convulsant PTZ by intraperitoneal injection. Seizure and seizure-like behaviors were scored by examination of video collected for 20min. Quantitative real-time PCR (QPCR) was performed to measure potential compensatory neuronal connexin (Cx30.2, Cx37, Cx43 and Cx45), pannexin (PANX1 and PANX2) and gamma-aminobutyric acid type A (GABA(A)) receptor alpha1 subunit gene expression. RESULTS: Cx36KO animals exhibited considerably more severe seizures; 40mg/kg of PTZ caused severe generalized (>=grade III) seizures in 78% of KO, but just 5% of WT mice. A lower dose of PTZ (20mg/kg) induced grade II seizure-like behaviors in 40% KO vs. 0% of WT animals. There was no significant difference in either connexin, pannexin or GABA(A) alpha1 gene expression between WT and KO animals. CONCLUSION: Increased sensitivity of Cx36KO animals to PTZ-induced seizure suggests that Cx36 gap junctional communication functions as a physiological anti-convulsant mechanism, and identifies the Cx36 gap junction as a potential therapeutic target in epilepsy. PMID- 20833152 TI - Synergistic benefits of erythropoietin and simvastatin after traumatic brain injury. AB - Simvastatin and recombinant human erythropoietin (rhEpo) are implicated as potential therapeutic candidates for traumatic brain injury (TBI). Prominent effects of simvastatin include its anti-inflammatory, neurotrophic and neuroregenerative actions studied in various models of neuronal injury. On the other hand, rhEpo has been shown to promote cell survival mechanisms by producing anti-apoptotic and cell proliferative actions. Beneficial effects of rhEpo and statin monotherapies have been well studied. However, there are no reports showing combined use of rhEpo and statins after TBI. This investigation examined if combined efficacy of cell proliferative ability of rhEpo along with the neuroregenerative ability of simvastatin will render maximum recovery in a controlled cortical impact (CCI) mouse model of TBI. Results showed that compared to baseline TBI, rhEpo was more effective than simvastatin in promoting cell proliferation while simvastatin was more effective than rhEpo in restoring axonal damage following TBI. Combined treatment with simvastatin and rhEpo maximally restored axonal integrity while simultaneously inducing greater proliferation of newly formed cells resulting in better functional recovery after TBI than either alone. This is the first study showing the efficacy of erythropoietin-simvastatin combinational therapeutic approach in achieving greater structural and cognitive recovery after TBI. PMID- 20833153 TI - Neuroprotection in experimental stroke in the rat with an IgG-erythropoietin fusion protein. AB - Erythropoietin (EPO) is a potent neuroprotective agent that could be developed as a new treatment for stroke. However, the blood-brain barrier (BBB) is intact in the early hours after stroke when neuroprotection is still possible, and EPO does not cross the intact BBB. To enable BBB transport, human EPO was re-engineered as an IgG-EPO fusion protein, wherein the IgG part is a monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb acts as a BBB molecular Trojan horse to ferry the fused EPO across the BBB via transport on the BBB insulin receptor. The HIRMAb part of the HIRMAb-EPO fusion protein does not recognize the rat insulin receptor. However, the EPO part of the fusion protein does recognize the rat EPO receptor. Therefore, the neuroprotective properties of the HIRMAb-EPO fusion protein were investigated with a permanent middle cerebral artery occlusion model in the rat. The HIRMAb-EPO fusion protein was injected into the ipsilateral brain under stereotaxic guidance. High doses of the HIRMAb EPO fusion protein (61pmol) completely eliminated both cortical and sub-cortical infarction. Lower doses of the fusion protein (4.5pmol) eliminated the cortical infarct with no significant effect on sub-cortical infarct. The neurologic deficit was reduced by 35% and 90%, respectively, by the 4.5 and 61pmol doses of the HIRMAb-EPO fusion protein. In conclusion, these studies demonstrate the biological activity of the HIRMAb-EPO fusion protein in the brain in vivo, and that EPO retains neuroprotective properties following fusion to the HIRMAb BBB Trojan horse. PMID- 20833154 TI - Enlarged right superior temporal gyrus in children and adolescents with autism. AB - The superior temporal gyrus has been implicated in language processing and social perception. Therefore, anatomical abnormalities of this structure may underlie some of the deficits observed in autism, a severe neurodevelopmental disorder characterized by impairments in social interaction and communication. In this study, volumes of the left and right superior temporal gyri were measured using magnetic resonance imaging obtained from 18 boys with high-functioning autism (mean age=13.5+/-3.4years; full-scale IQ=103.6+/-13.4) and 19 healthy controls (mean age=13.7+/-3.0years; full-scale IQ=103.9+/-10.5), group-matched on age, gender, and handedness. When compared to the control group, right superior temporal gyral volumes was significantly increased in the autism group after controlling for age and total brain volume. There was no significant difference in the volume of the left superior temporal gyrus. Post-hoc analysis revealed a significant increase of the right posterior superior temporal gyral volume in the autism group, before and after controlling for age and total brain volume. Examination of the symmetry index for the superior temporal gyral volumes did not yield statistically significant between-group differences. Findings from this preliminary investigation suggest the existence of volumetric alterations in the right superior temporal gyrus in children and adolescents with autism, providing support for a neuroanatomical basis of the social perceptual deficits characterizing this severe neurodevelopmental disorder. PMID- 20833155 TI - Distribution of 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor expression in rat trigeminal and dorsal root ganglia neurons: relevance to the selective anti migraine effect of triptans. AB - Triptans, acting as serotonin, 5-HT(1B/1D/1F), receptor agonists, provide an effective and established treatment option in migraine and cluster headache. Clinical observations suggest a relatively specific effect of these compounds on primary headache disorders, but not in other pain syndromes. The mechanism of this specificity, however, is not well understood. Hence, we systematically studied primary sensory ganglia in rat to determine if the peripheral distribution of 5HT(1B/1D/1F) receptors showed any anatomical difference that would account for the specificity of clinical effect. Rat primary afferent and sensory ganglia neurons--trigeminal ganglia (Vg), and dorsal root ganglia (DRG): C(2), C(5), T(5), L(5)--were examined using paraffin-embedded, slide-bound tissue sections reacted with specific primary antibodies for rat 5-HT(1B, 1D) and (1F) receptors in a peroxidase-based immunohistochemical method. Immunoreactivity specific for all three serotonergic receptor subtypes was demonstrated in the five peripheral nervous system regions examined and quantitated. There was a good agreement for 5-HT(1B) and 5-HT(1D) receptors to that previously demonstrated in Vg and DRG L(5), while this was the first characterisation for 5-HT(1F) receptor in any of the five regions, as well as for 5-HT(1B) and 5HT(1D) receptors in DRG C(2), C(5) and T(5). In summary, all three 5-HT receptors are equally represented in Vg and the DRGs examined. We conclude that the triptans are theoretically able to bind to receptors at each level of the peripheral neuraxis without any apparent anatomical preference for the head. PMID- 20833156 TI - Heme oxygenase-1 signals are involved in preferential inhibition of pro inflammatory cytokine release by surfactin in cells activated with Porphyromonas gingivalis lipopolysaccharide. AB - Porphyromonas gingivalis is considered the major pathogen of periodontal disease, which leads to chronic inflammation in oral tissues. P. gingivalis-produced lipopolysaccharide (LPS) is a key factor in the development of periodontitis. It is established that surfactin produced by Bacillus subtilis confers anti inflammatory properties. However, the underlying mechanisms responsible for surfactin-induced anti-inflammatory actions in the context of periodontitis are poorly understood. In this study, we investigated whether surfactin affected P. gingivalis LPS-induced pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and IL-12, and determined that it significantly inhibited their production. Surfactin-mediated inhibition was mainly due to blocked activation of P. gingivalis LPS-triggered nuclear factor kappaB. We also examined whether the regulatory effect of surfactin on P. gingivalis LPS-stimulated human THP-1 macrophages was mediated by the induction of heme oxygenase-1 (HO-1) signals, and determined that surfactin also induced HO 1 mRNA and protein expression via activation of Nrf-2. Additionally, we found that small interfering RNA-mediated knock-down of Nrf-2 significantly inhibited surfactin-induced HO-1 expression. Furthermore, inhibition of phosphoinositide 3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) significantly decreased surfactin-induced HO-1 expression, which is consistent with the suggestion that surfactin-induced HO-1 expression occurs via PI3K/Akt, ERK, and Nrf-2. Treatment with a selective inhibitor of HO-1 reversed the surfactin mediated inhibition of pro-inflammatory cytokines, suggesting that surfactin induces anti-inflammatory effects by activating Nrf-2-mediated HO-1 induction via PI3K/Akt and ERK signaling. Collectively, these observations support the potential of surfactin as a candidate in strategies to prevent caries, periodontitis, or other inflammatory diseases. PMID- 20833157 TI - Haplophytin-A induces caspase-8-mediated apoptosis via the formation of death inducing signaling complex in human promyelocytic leukemia HL-60 cells. AB - Haplophytin-A (10-methoxy-2,2-dimethyl-2,6-dihydro-pyrano[3,2-c]quinolin-5-one), a novel quinoline alkaloid, was isolated from the Haplophyllum acutifolium. In this study, we investigated the effect of haplophytin-A on the apoptotic activity and the molecular mechanism of action in human promyelocytic leukemia HL-60 cells. Treatment with haplophytin-A (50MUM) induced classical features of apoptosis, such as, DNA fragmentation, DNA ladder formation, and the externalization of annexin-V-targeted phosphatidylserine residues in HL-60 cells. In addition, haplophytin-A triggered the activations of caspase-8, -9, and -3, and the cleavage of poly (ADP-ribose) polymerase (PARP) in HL-60 cells. In addition, haplophytin-A caused the loss of mitochondrial membrane potential (DeltaPsi(m)) and the release of cytochrome c and Smac/DIABLO to the cytosol, and modulated the expression levels of Bcl-2 family proteins. We further demonstrated that knockdown of caspase-8 using its siRNA inhibited the mitochondrial translocation of tBid, the activations of caspase-9 and caspase-3, and subsequent DNA fragmentation by haplophytin-A. Furthermore, haplophytin-A-induced the formation of death-inducing signaling complex (DISC) and then activated caspase-8 in HL-60 cells. During haplophytin-A-induced apoptosis, caspase-8-stimulated tBid provide a link between the death receptor-mediated extrinsic pathway and the mitochondria- mediated intrinsic pathway. Taken together, these results suggest that the novel compound haplophytin-A play therapeutical role for leukemia via the potent apoptotic activity through the extrinsic pathway, involving the intrinsic pathway. PMID- 20833158 TI - Mitochondrial dysfunction and biotransformation of beta-carboline alkaloids, harmine and harmaline, on isolated rat hepatocytes. AB - The cytotoxic effects and biotransformation of harmine and harmaline, which are known beta-carboline alkaloids and potent hallucinogens, were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to harmine caused not only concentration (0-0.50mM)- and time (0-3h)-dependent cell death accompanied by the formation of cell blebs and the loss of cellular ATP, reduced glutathione, and protein thiols but also the accumulation of glutathione disulfide. Of the other analogues examined, the cytotoxic effects of harmaline and harmol (a metabolite of harmine) at a concentration of 0.5mM were less than those of harmine. The loss of mitochondrial membrane potential and generation of oxygen radical species in hepatocytes treated with harmine were greater than those with harmaline and harmol. In the oxygen consumption of mitochondria isolated from rat liver, the ratios of state-3/state-4 respiration of these beta-carbolines were decreased in a concentration-dependent manner. In addition, harmine resulted in the induction of the mitochondrial permeability transition (MPT), and the effects of harmol and harmaline were less than those of harmine. At a weakly toxic level of harmine (0.25mM), it was metabolized to harmol and its monoglucuronide and monosulfate conjugates, and the amounts of sulfate rather than glucuronide predominantly increased with time. In the presence of 2,5-dichloro-4-nitrophenol (50MUM; an inhibitor of sulfotransferase), harmine-induced cytotoxicity was enhanced, accompanied by decrease in the amount of harmol-sulfate conjugate, due to an increase in the amount of unconjugated harmol and the inhibition of harmine loss. Taken collectively, these results indicate that (a) mitochondria are target organelles for harmine, which elicits cytotoxicity through mitochondrial failure related to the induction of the MPT, mitochondrial depolarization, and inhibition of ATP synthesis; and (b) the toxic effects of harmine are greater than those of either its metabolite harmol or its analogue harmaline, suggesting that the onset of harmine-induced cytotoxicity may depend on the initial and/or residual concentrations of harmine rather than on those of its metabolites. PMID- 20833159 TI - Brassinosteroids cause cell cycle arrest and apoptosis of human breast cancer cells. AB - Brassinosteroids (BRs) are plant hormones that appear to be ubiquitous in both lower and higher plants. Recently, we published the first evidence that some natural BRs induce cell growth inhibitory responses in several human cancer cell lines without affecting normal non-tumor cell growth (BJ fibroblasts). The aim of the study presented here was to examine the mechanism of the antiproliferative activity of the natural BRs 28-homocastasterone (28-homoCS) and 24 epibrassinolide (24-epiBL) in human hormone-sensitive and -insensitive (MCF-7 and MDA-MB-468, respectively) breast cancer cell lines. The effects of 6, 12 and 24h treatments with 28-homoCS and 24-epiBL on cancer cells were surveyed using flow cytometry, Western blotting, TUNEL assays and immunofluorescence analyses. The studied BRs inhibited cell growth and induced blocks in the G(1) cell cycle phase. ER-alpha immunoreactivity was uniformly present in the nuclei of control MCF-7 cells, while cytoplasmic speckles of ER-alpha immunofluorescence appeared in BR-treated cells (IC(50), 24h). ER-beta was relocated to the nuclei following 28-homoCS treatment and found predominantly at the periphery of the nuclei in 24 epiBL-treated cells after 24h of treatment. These changes were also accompanied by down-regulation of the ERs following BR treatment. In addition, BR application to breast cancer cells resulted in G(1) phase arrest. Furthermore, TUNEL staining and double staining with propidium iodide and acridine orange demonstrated the BR mediated induction of apoptosis in both cell lines, although changes in the expression of apoptosis-related proteins were modulated differently by the BRs in each cell line. The studied BRs seem to exert potent growth inhibitory effects via interactions with the cell cycle machinery, and they could be highly valuable leads for agents for managing breast cancer. PMID- 20833160 TI - Handling reactive metabolite positives in drug discovery: What has retrospective structure-toxicity analyses taught us? AB - Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) as opposed to the parent molecules from which they are derived are thought to be responsible for the pathogenesis of some IADRs, procedures (RM trapping/covalent binding) are being incorporated into the discovery screening funnel early-on to assess the risk of RM formation. Utility of the methodology in structure-toxicity relationships and scope in abrogating RM formation at the lead optimization stage are discussed in this article. Interpretation of the output from RM assessment assays, however, is confounded by the fact that many successfully marketed drugs are false positives. Therefore, caution must be exercised in deprioritizing a compound based on a positive result, so that the development of a useful and potentially profitable compound won't be unnecessarily halted. Risk mitigation strategies (e.g., competing detoxication pathways, low daily dose, etc.) when selecting RM positives for clinical development are also reviewed. PMID- 20833161 TI - The surface organization of diacylglycerol pyrophosphate and its interaction with phosphatidic acid at the air-water interface. AB - Diacylglycerol pyrophosphate (DGPP), a phosphorylated form of phosphatidic acid (PA), gained attention recently due to its role as signaling lipid. However, little is known about its surface organization and potential impact on membrane mediated function. In this work we investigated the interfacial behavior of Langmuir monolayers formed with pure DGPP and of its mixtures with PA. We found that changes of the subphase pH affect the surface behavior of DGPP. At pH 8, DGPP forms liquid expanded monolayers with a compressibility modulus of about 60mNm-1 at collapse. On acidic solutions, the compressibility modulus increases to 90mNm-1 and the average molecular area is smaller. At pH 8, DGPP and its precursor PA form thermodynamically favored topographically homogeneous non-ideal mixtures. The interaction among these lipids leads to a non-ideal diminution of the mean molecular area and consequently, to an increase of the compressibility modulus, with variations of the surface electrostatics. The favorable interaction of PA and DGPP, leading to changes of the film packing suggest that DGPP may act as a structural signal transducer in membrane-mediated cellular processes. PMID- 20833162 TI - The paraoxonase L55M and Q192R gene polymorphisms and myocardial infarction in a Tunisian population. AB - OBJECTIVES: In the present study, we examined a possible association between the PON1 Q192R and L55M polymorphisms and myocardial infarction (MI) in a sample of the Tunisian population. DESIGN AND METHODS: Three hundred and ten patients with MI and 375 controls were recruited. Paraoxonase gene polymorphisms at codon 192 and 55 were analyzed by PCR-RFLP. RESULTS: Genotype distributions and allele frequencies of L55M were similar among the control and MI groups. For the Q192R polymorphism patients with MI had significantly higher frequency of the RR genotype compared to controls [17.1% vs. 10.9%; OR (95% CI), 1.93 (1.24-3.02); p=0.004]. The MI patient group showed a significantly higher frequency of the R allele compared to the controls [38% vs. 30%; chi(2)=10.74, p=0.001]. The association between the PON1 Q192R polymorphism and MI remained significant after adjustment for other well-established cardiovascular risk factors. CONCLUSIONS: The present study showed a significant and independent association between the PON1 Q192R polymorphism (presence of R allele) and MI in the Tunisian population. PMID- 20833163 TI - Oxidative stress biomarkers and chromogranin A in uremic patients: effects of dialytic treatment. AB - OBJECTIVE: To evaluate oxidative stress in uremia and dialysis and chromogranin A, a stress hormone that could be related to oxidative processes. METHODS: Plasma oxidative stress biomarkers (-SH, 8-OHdG, and ox-LDL) and chromogranin A were measured in 89 outpatients (21 uremic patients, 17 in peritoneal dialysis, and 51 in haemodialysis), and in 18 subjects with normal renal function. RESULTS: -SH groups were significantly reduced in heamodialysis, peritoneal, and uremic patients as compared with the control group (p=0.01), while 8-OHdG was increased (p<0.01). No differences were observed for ox-LDL. Chromogranin A was increased in uremic, peritoneal and haemodialysis patients (p<0.01), showing a positive correlation to 8-OHdG (p<0.01). CONCLUSION: Oxidative stress biomarkers and chromogranin A levels differ between control subjects when compared to both uremic and dialysis patients. No differences were observed between uremic and dialysis patients, suggesting that uremia is the major source of the increase in oxidative stress and CgA levels in patients with end stage renal disease. PMID- 20833164 TI - Effects of antioxidants on post-thawed bovine sperm and oxidative stress parameters: antioxidants protect DNA integrity against cryodamage. AB - This study was conducted to determine the effects of methionine, inositol and carnitine on sperm (motility, abnormality, DNA integrity and in vivo fertility) and oxidative stress parameters (lipid peroxidation, total glutathione and antioxidant potential levels) of bovine semen after the freeze-thawing process. Nine ejaculates, collected with the aid of an artificial vagina twice a week from each Simmental bovine, were included in the study. Each ejaculate, splitted into seven equal groups and diluted in Tris-based extender containing methionine (2.5 and 7.5 mM), carnitine (2.5 and 7.5 mM), inositol (2.5 and 7.5 mM) and no additive (control), was cooled to 5 degrees C and then frozen in 0.25 ml straws. Frozen straws were then thawed individually at 37 degrees C for 20s in a water bath for the evaluation. The extender supplemented with 7.5 mM doses of carnitine and inositol led to higher subjective motility percentages (61.9+/-1.3% and 51.3+/-1.6%) compared to the other groups. The addition of methionine and carnitine at doses of 2.5 and 7.5 mM and inositol at doses of 7.5mM provided a greater protective effect in the percentages of total abnormality in comparison to the control and inositol 2.5 mM (P < 0.001). As regards CASA motility, 7.5 mM carnitine (41.6+/-2.9% and 54.2+/-4.9%) and inositol (34.9+/-2.0% and 47.3+/ 2.2%) caused insignificant increases in CASA and total motility in comparison to the other groups. All of the antioxidants at 2.5 and 7.5 mM resulted in lower sperm with damaged DNA than that of control, thus reducing the DNA damage (P < 0.05). No significant differences were observed in CASA progressive motility and sperm motion characteristics among the groups. In fertility results based on 59 day non-returns, no significant differences were observed in non-return rates among groups. As regards biochemical parameters, supplementation with antioxidants did not significantly affect LPO and total GSH levels in comparison to the control group (P > 0.05). The maintenance of AOP level in methionine 2.5 mM was demonstrated to be higher (5.06+/-0.38 mM) than that of control (0.96+/ 0.29 mM) following the freeze-thawing (P < 0.001). Supplementation with these antioxidants prior to the cryopreservation process protected the DNA integrity against the cryodamage. Furthermore, future research should focus on the molecular mechanisms of the antioxidative effects of the antioxidants methionine, carnitine and inositol during cryopreservation. PMID- 20833165 TI - Over-expression of ERp29 attenuates doxorubicin-induced cell apoptosis through up regulation of Hsp27 in breast cancer cells. AB - The endoplasmic reticulum protein 29 (ERp29) has a critical role in regulating protein folding, maturation and secretion. However, its role in carcinogenesis remains elusive. Recently, we reported that ERp29 is a novel tumor suppressor and regulates mesenchymal-epithelial transition in MDA-MB-231 breast cancer cells. Here, we investigated whether ERp29 plays a role in the response of breast cancer cells to chemotherapeutic agents. We found that expression of ERp29 increased the resistance to doxorubicin, but not cisplatin and paclitaxel, and decreased the doxorubicin-induced cell apoptosis in MDA-MB-231 cells, whereas knockdown of ERp29 in MCF-7 cells increased the doxorubicin cytotoxicity. A proteomics study identified up-regulation of Hsp27 and down-regulation of stathmin-1, galectin and prohibitin in the doxorubicin-resistant, ERp29 over-expressing MDA-MB-231 cells. Further, we demonstrated that ERp29 up-regulated expression of Hsp27 by down regulating eukaryotic translational initiation factor 2alpha (eIF2alpha). When Hsp27 was knocked down by siRNA in the doxorubicin-resistant, ERp29 over expressing MDA-MB-231 cells and parental MCF-7 cells, cell viability was significantly decreased and doxorubicin-induced cell apoptosis was enhanced. These results indicate that Hsp27 is involved in the ERp29-mediated resistance to doxorubicin. Therefore, targeting of Hsp27, with a combination of other chemotherapeutic agents, is a rational strategy in treating doxorubicin-resistant cancer cells. PMID- 20833166 TI - Gold nanoparticles downregulate VEGF-and IL-1beta-induced cell proliferation through Src kinase in retinal pigment epithelial cells. AB - Proliferative vitreo retinopathy (PVR) is one of the ocular complications, marked by the enhanced proliferation of various cells including retinal pigment epithelial cells (RPE). The aim of the present study is to analyze the effect of gold nanoparticles (Au-NP) on vascular endothelial growth factor (VEGF) and interleukin-1 beta (IL-1beta)-induced cell spreading, migration and proliferation in RPE cells. Au-NP (300 nM) significantly blocked the VEGF-and IL-1beta-induced cell spreading, migration and proliferation in bovine RPE cells (BRPEs). To elucidate the signaling mechanism of VEGF- and IL-1beta-induced cell proliferation, BRPEs were treated with PP2, a Src inhibitor. Further, to clarify the possible involvement of the Src pathway on the inhibitory effect of Au-NPs, transient transfection assay was performed using dominant negative (DN) and constitutively active (CA) mutant plasmid of Src kinase. The results showed that VEGF and IL-1beta exert their proliferative effects through the activation of Src kinase whereas CA Src rescued the inhibitory effect of Au-NP in presence or absence of VEGF and IL-1beta in BRPEs. Further, an in vitro kinase assay was performed to identify the status of Src phosphorylation at Y419. We found that VEGF and IL-1beta increased Src phosphorylation in BRPEs and Au-NP blocked the VEGF- and IL-1beta-induced Src phosphorylation at Y419. Taken together, our result suggests that Au-NP could effectively inhibit the VEGF- and IL-1beta induced proliferation and migration by suppressing the Src kinase pathway in BRPEs and Au-NP might act as an effective therapeutic agent for the treatment of ocular diseases such as proliferative vitreo retinopathy. PMID- 20833167 TI - Sex differences in the benefits of rehabilitative training during adolescence following neonatal hypoxia-ischemia in rats. AB - Much effort and many resources are being devoted to rehabilitative programs for children with disabilities caused by neonatal hypoxic-ischemic encephalopathy without clear evidence of the efficacy of such programs. We recently reported that rehabilitative training tasks during adolescence improve spatial learning impairment following neonatal hypoxic-ischemic injury in rats without histological improvement. In the present study we focused on sex differences. Wister rat pups were exposed to a unilateral hypoxic-ischemic insult at 7 days of age. Six weeks after hypoxia-ischemia, rehabilitative training tasks were started. The tasks consisted of the plus maze, the eight-arm radial maze, and the choice reaction time task. Sixteen weeks after the insult, the water maze task was performed to evaluate spatial learning ability. Afterwards, we morphologically examined brain injury. Our rehabilitative training significantly improved swimming time and length in females (P<0.01) but not in males. Likewise, the training ameliorated infarct areas in the injured cerebral hemisphere in females but not in males (P<0.01). These results suggest that it may be important to develop and evaluate cognitive rehabilitation programs for children with brain injury on the basis of gender. PMID- 20833168 TI - Toxoplasma gondii: inhibitory activity and encystation effect of securinine and pyrrolidine derivatives on Toxoplasma growth. AB - Securinine, an alkaloid originally isolated from Securinega suffruticosa, exhibits a wide range of biological activities, including anti-malarial activity. Along with securinine, 10 pyrrolidine derivatives, generated via the retrosynthesis of (-)-securinine, were selected and tested for their inhibitory activity against Toxoplasma gondii growth in vitro. Anti-Toxoplasma activity correlated to hydrophobicity of the tested compounds. Three pyrrolidine derivatives along with securinine inhibit Toxoplasma proliferation at the micromolar range. These compounds act on parasite proliferation in different capacities, either by slowing the growth rate or inhibiting invasion of host cells. Securinine induces bradyzoite differentiation at comparable levels to treatment with alkali media in vitro. PMID- 20833169 TI - Statin therapy improves sustained virologic response among diabetic patients with chronic hepatitis C. AB - BACKGROUND & AIMS: Patients with chronic hepatitis C infection are 2- to 3-fold more likely to develop type 2 diabetes, which reduces their chances of achieving a sustained virologic response (SVR). To identify differences in predictors of SVR in patients with and without diabetes who received combination antiviral therapy, we conducted a retrospective analysis of a national Veterans Affairs administrative database. METHODS: We analyzed data from the Veterans Affairs Medical SAS Datasets and Decision Support System for entire cohort and separately for diabetic patients (n = 1704) and nondiabetic patients (n = 6589). Significant predictors of SVR were identified by logistic regression analysis. RESULTS: Diabetic patients had a lower SVR compared with nondiabetic patients (21% vs 27%, respectively, P < .001). Diabetic patients had higher clustering of previously established negative predictors of SVR. On multivariate analysis of diabetic patients for SVR, the positive predictors were higher low-density lipoprotein (odds ratio [OR], 1.45; P = .0129), use of statin (OR, 1.52; P = .0124), and lower baseline viral load (OR, 2.31; P < .001), whereas insulin therapy (OR, 0.7; P = .0278) was a negative predictor. Diabetic patients on statins had higher pretreatment viral loads (log 6.2 vs 6.4, respectively, P = .006) but better early virologic response. There was a graded inverse relationship between Hemoglobin A1c and SVR rate (P = .0482). This relationship was significant among insulin users (P = .0154) and non-significant among metformin users (P = .5853). CONCLUSIONS: Statin use was associated with an improved SVR among both diabetic patients and nondiabetic patients receiving combination antiviral therapy. Diabetic patients who received insulin achieved lower SVR compared with those not receiving insulin. Poor diabetes control was associated with lower SVR rates. PMID- 20833171 TI - Fox defecation behaviour in relation to spatial distribution of voles in an urbanised area: An increasing risk of transmission of Echinococcus multilocularis? AB - Urbanisation of alveolar echinococcosis is a new phenomenon that has been highlighted during the last few decades. It has thus become necessary to understand the dynamics of transmission of Echinococcus multilocularis in urbanised areas. Spatial heterogeneity of infection by E. multilocularis has been explained as the result of a multifactorial dependence of the transmission in which the factors depend on the scale of the investigation. The aim of this study was to assess, in an urbanised area, the effect of such environmental factors as season, habitat type and the level of urbanisation, on the availability of two major intermediate hosts (Microtus spp. and Arvicola terrestris), the distribution of red fox faeces and the distribution of E. multilocularis as determined by detection of coproantigens in faeces. Results of the study revealed higher densities of Microtus spp. in rural than in peri-urban areas. Moreover this species was highly aggregated in urban wasteland. Arvicola terrestris densities did not appear to be linked to the level of urbanisation or to the type of habitat studied. Distribution of faeces was positively linked to distance walked and to Microtus spp. and A. terrestris distributions whatever the level of urbanisation. Such a distribution pattern could enhance the transmission cycle in urban areas. The Copro-ELISA test results on faeces collected in the field revealed that ODs were significantly negatively correlated with the abundance of A. terrestris. The larger population densities of Microtus spp. found in urban wastelands and the well known predominance of Microtus spp. in the red fox diet in the region suggest that Microtus spp. may play a key role in urban transmission of the parasite in the study area. PMID- 20833170 TI - Population diversity and multiplicity of infection in Theileria annulata. AB - The tick-borne apicomplexan parasite Theileria annulata is endemic in many sub tropical countries and causes the bovine disease tropical theileriosis. Although the parasite is known to be highly diverse, detailed information is lacking on the genetic structure of natural populations and levels of multiplicity of infection in the cattle host. With the widespread deployment of live attenuated vaccines and the emergence of drug-resistant parasites in the field, it is vital to appreciate the factors which shape genetic diversity of the parasite both within individual hosts and in the wider population. This study addresses these issues and represents an extensive genetic analysis of T. annulata populations in two endemic countries utilising a high-throughput adaptation of a micro- and mini satellite genotyping system. Parasite material was collected from infected cattle in defined regions of Turkey and Tunisia to allow a variety of analyses to be conducted. All animals (n=305) were found to harbour multiple parasite genotypes and only two isolates shared an identical predominant multi-locus profile. A modelling approach was used to demonstrate that host age, location and vaccination status play a measurable role in determining multiplicity of infection in an individual animal. Age was shown to positively correlate with multiplicity of infection and while positive vaccination status exerted a similar effect, it was shown to be due not simply to the presence of the immunising genotype. Importantly, no direct evidence was found for the immunising genotype spreading or recombining within the local parasite community. Genetic analysis confirmed the tentative conclusion of a previous study that the parasite population appears to be, in general, panmictic. Nevertheless, evidence supporting linkage disequilibrium and a departure from panmixia was uncovered in some localities and a number of explanations for these findings are advanced. PMID- 20833172 TI - Interspecific differences in carotenoid content and sensitivity to UVB radiation in three acanthocephalan parasites exploiting a common intermediate host. AB - Few endoparasite species are pigmented. Acanthocephalans are an exception however, with several species being characterised by yellow to orange colouration both at the immature (cystacanth) and adult stages. However, the functional and adaptive significance of carotenoid-based colourations in acanthocephalans remains unclear. One possibility is that the carotenoid content of acanthocephalan cystacanths acts as a protective device against ultra-violet radiation (UVR) passing through the translucent cuticle of their crustacean hosts. Indeed, acanthocephalans often bring about behavioural changes in their aquatic intermediate hosts that can increase their exposure to light. Carotenoid composition and damage due to ultra-violet - B (UVB) radiation were investigated in three acanthocephalan parasite species that induce contrasting behavioural alterations in their common intermediate host, the crustacean amphipod Gammarus pulex. The fish acanthocephalans Pomphorhynchus laevis and Pomphorhynchus tereticollis both induce a positive phototaxis in gammarids, such that infected hosts spend more time out of shelters, while remaining benthic. The bird acanthocephalan Polymorphus minutus, on the other hand, induces a negative geotaxis, such that infected hosts typically swim close to the water surface, becoming more exposed to UV radiation. We show that differences in cystacanth colouration between acanthocephalan species directly reflect important differences in carotenoid content. The two fish parasites exhibit a contrasting pattern, with P. tereticollis harbouring a large diversity of carotenoid pigments, whereas P. laevis is characterised by a lower carotenoid content consisting mainly of lutein and astaxanthin. The highest carotenoid content is found in the bright orange P.minutus, with a predominance of esterified forms of astaxanthin. Exposure to UVB radiation revealed a higher susceptibility in P. laevis larvae compared with P. tereticollis and P. minutus, in terms of sublethality (decreased evagination rate) and of damage to DNA (increased cyclobutane pyrimidine dimers production). Although we found important and correlated interspecific differences in carotenoid composition and tolerance to high UVB radiation, our results do not fully support the hypothesis of adaptive carotenoid-based colourations in relation to UV protection. An alternative scenario for the evolution of carotenoid accumulation in acanthocephalan parasites is discussed. PMID- 20833173 TI - Social and environmental determinants of malaria in space and time in Viet Nam. AB - The malaria burden in Viet Nam has been in decline in recent decades, but localised areas of high transmission remain. We used spatiotemporal analytical tools to determine the social and environmental drivers of malaria risk and to identify residual high-risk areas where control and surveillance resources can be targeted. Counts of reported Plasmodium falciparum and Plasmodium vivax malaria cases by month (January 2007-December 2008) and by district were assembled. Zero inflated Poisson regression models were developed in a bayesian framework. Models had the percentage of the district's population living below the poverty line, percent of the district covered by forest, median elevation, median long-term average precipitation, and minimum temperature included as fixed effects, and terms for temporal trend and residual district-level spatial autocorrelation. Strong temporal and spatial heterogeneity in counts of malaria cases was apparent. Poverty and forest cover were significantly associated with an increased count of malaria cases but the magnitude and direction of associations between climate and malaria varied by socio-ecological zone. There was a declining trend in counts of malaria cases during the study period. After accounting for the social and environmental fixed effects, substantial spatial heterogeneity was still evident. Unmeasured factors which may contribute to this residual variation include malaria control activities, population migration and accessibility to health care. Forest-related activities and factors encompassed by poverty indicators are major drivers of malaria incidence in Viet Nam. PMID- 20833174 TI - Validation of an adiponectin immunoassay in human skeletal muscle biopsies. AB - Adiponectin is an insulin-sensitizing adipocytokine that circulates in plasma as multimeric isoforms, including trimers, hexamers and high molecular weight complexes. Although adiponectin multimers have previously been measured by Western blot, this remains a relatively delicate technique that is often hampered by high background or multiple bands. We validated a commercially available ELISA, designed to measure total (low, middle and high molecular weight) human adiponectin concentration in cell culture supernatants, serum and plasma, for its proper use in skeletal muscle biopsies obtained in patients with chronic heart failure and healthy controls. PMID- 20833175 TI - Flow cytometry of intestinal intraepithelial lymphocytes in celiac disease. AB - This article reviews the multiple uses of flow cytometry in the diagnosis, monitoring and research of celiac disease, the most prevalent chronic autoimmune gastrointestinal disease. The phenotyping of intraepithelial lymphocytes (IELs) is of clinical relevance in the diagnosis of the disease given the characteristic features of elevated CD3+ IELs (alphabeta and gammadelta TcR) and the decrease in CD3- IELs. IEL biomarkers are also useful in the assessment of the response to the gluten-free diet and, importantly, in the diagnosis of the severe complications of celiac disease: refractory celiac disease and enteropathy associated T-cell lymphoma. Novel applications of flow cytometry for the detection of anti-transglutaminase antibodies (a validated biomarker of celiac disease) and of gluten (the triggering antigen of the autoimmune process) are also discussed. The assessment of diagnostic and prognostic biomarkers by flow cytometry in celiac disease is performed routinely in a growing number of centers and it is an example of the versatility of this technique and its applicability to the research and clinical study of solid tissues. PMID- 20833176 TI - A simple two-step purification procedure for the iC3b binding collectin conglutinin. AB - Bovine conglutinin is a serum protein involved in innate immunity. It binds calcium dependently to iC3b, a product of the complement component C3 deposited on cell surfaces, immune complexes or artificial surfaces after complement activation. We here present a simple and efficient two-step procedure for the purification of conglutinin. In the first step, bovine serum is incubated with non-coupled chromatographic TSK beads at 37 degrees C to allow complement activation and iC3b deposition on the beads and subsequent binding of conglutinin to iC3b. Conglutinin is then eluted from the beads by EDTA. In the second step, conglutinin is separated from iC3b and IgM by ion-exchange chromatography. This purification procedure yielded 81 MUg of conglutinin per ml of serum with a recovery of 61.2%. Surface plasmon resonance analysis showed that the purified conglutinin had a high affinity for mannan (K(d)=2.3-3.2 nM). SDS-PAGE and time resolved immunofluorometric assays showed that the conglutinin was not contaminated with other serum collectins such as collectin-43 or mannan-binding lectin. PMID- 20833177 TI - Anti-BSA antibodies are a major cause of non-specific binding in insulin autoantibody radiobinding assays. AB - Insulin autoantibodies (IAA) are usually the first risk-markers detected during the type 1 diabetes prodrome, but precise measurement is difficult as insulin binding is often low. Non-specific binding (NSB) of (125)I-labelled insulin necessitates competitive displacement with unlabelled insulin to demonstrate specificity. NSB varies with different batches of label, suggesting that it is caused by impurities in the label. Addition of bovine serum albumin (BSA) can reduce NSB, so we investigated whether BSA antibodies cause lack of specificity in IAA assays. Samples from patients with newly-diagnosed type 1 diabetes, healthy schoolchildren previously found to have raised (125)I-insulin binding (>= 0.4 units) and IAA-negative schoolchildren were re-assayed for IAA by radiobinding microassay using commercial (125)I-insulin with and without 1g/dl BSA added to the buffer. Of 100 patients, 68 were IAA-positive on re-assay with BSA compared to 72 without BSA (p=0.125). Of 154 schoolchildren who previously had raised (125)I-insulin binding, only 45 had (125)I-insulin binding >= 0.4 units on re-assay with BSA compared to 90 without BSA (p<0.001). Following competitive displacement with unlabelled insulin, 40 were IAA-positive with BSA compared to 48 without BSA (p=0.02). No IAA-negative schoolchildren were IAA positive on re-assay. Levels of NSB were associated with antibodies binding (125)I-BSA and purification of labelled insulin reduced NSB. Addition of BSA to assay buffer improves the screening efficiency of the IAA assay without reducing disease sensitivity in patients. High titre BSA antibodies interfere with IAA measurement because of (125)I-BSA present in some insulin labels. Improved purification of insulin labels should obviate the need for competitive displacement. PMID- 20833178 TI - A novel method for the detection of antibodies to adalimumab in the presence of drug reveals "hidden" immunogenicity in rheumatoid arthritis patients. AB - Production of anti drug antibodies (ADA) in adalimumab treated RA patients is associated with reduced serum adalimumab levels and less clinical response. However, most current assays to measure ADA are unable to detect ADA in complex with adalimumab. Thus, ADA is only measured if antibody production exceeds drug levels in the serum, meaning that ADA formation is underestimated. The aim of this study is to develop a method to detect ADA in the presence of drug. A pH shift-anti-idiotype Antigen binding test (PIA) was used to enable ADA measurement in the presence of adalimumab. ADA-adalimumab complexes were dissociated by acid treatment and addition of excess rabbit anti-idiotype-F(ab) before neutralization. Rabbit anti-idiotype-F(ab) blocks reformation of ADA-drug complexes by competing with patient ADA for adalimumab binding. Released ADA are measured by an antigen binding test (ABT). The PIA enabled detection of ADA in the presence of large excess of adalimumab and was used to measure ADA in 30 adalimumab treated rheumatoid arthritis (RA) patients during the first 28 weeks of treatment. It revealed ADA in 21 out of 30 tested patients, while the ABT detected ADA in only 5 patients. Indicating that an immunogenic reaction towards adalimumab is present in the majority of adalimumab treated patients. PMID- 20833179 TI - Evaluation of heterophilic antibody blocking agents in reducing false positive interference in immunoassays for IL-17AA, IL-17FF, and IL-17AF. AB - IL-17AA, IL-17FF, and IL-17AF are proinflammatory cytokines that have been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). In order to measure the levels of these cytokines in synovial fluid and serum samples from RA patients, immunoassays specific for IL-17AA, FF, and AF were developed. Although these assays could tolerate up to 50% pooled normal human serum, false positive reactivity was problematic in patient samples suggesting interference from heterophilic antibodies. We therefore evaluated the ability of several commercially available heterophilic antibody blocking agents to reduce false positive reactivity by testing them against samples that were confirmed as false positives in the IL-17AA, FF, and AF assays. Several of the blockers performed well, including HBR-1, HBR-9, HBR-11, HBR-Plus, Serum Cytokine Assay Diluent, and IIR. We chose to move forward using IIR blocker for sample analysis and verified that IIR had no effect on the assay standard curves and did not affect IL-17 quantitation in plasma from ex vivo stimulated human whole blood. IL-17FF and IL-17AF were below the limits of quantitation of the assays (12.3 and 10.5pg/ml, respectively) in synovial fluid and serum samples from patients with RA and osteoarthritis (OA). For the more sensitive IL-17AA assay (1.6pg/ml limit of quantitation), low levels of IL-17AA were measurable in 48% of RA synovial fluid samples (mean, 7.9pg/ml; median, <1.6pg/ml; range, <1.6 29.7pg/ml; n=23) but not in synovial fluid from patients with OA (n=33). For serum samples, however, IL-17AA was below the limit of detection for both RA and OA patients. When these same serum samples were analyzed in the absence of a heterophilic antibody blocker, false positive reactivity yielded apparent mean IL 17AA levels of 43.3pg/ml (28% positive; n=50) and 14.8pg/ml (12% positive; n=50) for RA and OA patients, respectively, results that could potentially be interpreted as consistent with disease biology. These studies demonstrate the importance of ensuring that HAb interference is well controlled, particularly when measuring low concentrations of cytokines in samples from patients with autoimmune disease. PMID- 20833180 TI - Metal-enhanced PicoGreen fluorescence: application to fast and ultra-sensitive pg/ml DNA quantitation. AB - In this paper we provide both a theoretical and experimental analysis of the sensitivity of a DNA quantitation assay using a fluorescent chromophore which non covalently binds dsDNA. It is well-known that the range of DNA concentrations available for fluorescence quantitation depends on the concentration of the chromophore, its affinity for nucleic acids, the binding site size on DNA and the ratio between the fluorescence intensity of the chromophore when bound to DNA compared to free chromophore in solution. We present experimental data obtained for a PicoGreen (PG)/DNA quantitation assay, which is in complete agreement with the results of our theoretical analysis. Experimentally measured PG-fluorescence intensity vs DNA concentration functions were fitted by a derived analytical expression, in which parameters of PG binding to DNA and chromophore fluorescence properties were included. We show that silver nanoparticles significantly increase the ratio between the fluorescence of PG bound to DNA and free PG, due to the metal-enhanced fluorescence effect (MEF), which enhances the lower limit of detectability of DNA concentrations by several orders of magnitude. An additional order of magnitude increase of PG/DNA assay sensitivity (~1 pg/ml) can be achieved by decreasing the PG concentration. We show herein that the use of MEF substrates in surface assays has a profound effect on assay sensitivity. PMID- 20833181 TI - The localization of two mimic epitopes of lipopolysaccharide binding protein and the preparation of their tandem multiple antigen peptide. AB - OBJECTIVE: To screen and identify two mimic epitopes in the inflammatory site of lipopolysaccharide binding protein (LBP), and to synthesize and purify their corresponding mimic epitope four branched peptide (multiple antigen peptide, MAP). METHOD: Using an anti-full length LBP monoclonal antibody as the target molecule, the amino acid sequences of the exogenous peptides were deduced by combining several different techniques including: affinity screening of the phage display peptide library, the lipopolysaccharide (LPS) binding activity assay and competitive inhibition test, cytokine production inhibition, flow cytometry, and DNA sequencing. Basic Local Alignment Search Tool (BLAST) software was used to compare the resulting peptide sequences with the primary structure sequence of the LBP molecule, and thus the amino acid sequences for two mimic inflammatory epitopes for the binding of LBP and LPS were determined. Additionally, the two target sequences were coupled, and the 9-fluorenylmethyloxycarbonyl (FMOC) solid phase synthesis method was used to synthesize the 24aa peptide. The design program of the multiple antigen peptide (MAP) was used to couple the four tandem peptides with lysine as the core base to produce the branch like structure, and thus, the four branched peptide was synthesized and purified. RESULTS: Fourteen phage clones (C) with competitive LPS binding activity with LBP were successfully obtained. Among these, the amino acid sequences of the peptides in C2, C19, C57, C77, C85 and C91 showed a homology of more than 90% to the primary structure of LBP. However, the amino acid sequences of C29 and C90, WKAQKRFMKKSG and LKTRKLFWKYKD, respectively, did not show homology to the primary structure of LBP, which were determined to be mimic epitopes of the inflammatory sites in LBP. Further synthesis of the 24aa peptide using FMOC solid-phase synthesis and MAP modification were carried out, the four branched peptide was synthesized and purified, and the purity was found to be higher than 95%. The purified peptide was subjected to mass spectrometry analysis and amino acid analysis, and its molecular weight (3102.77 kDa) and amino acid composition were in accordance with theoretical values. CONCLUSION: The amino acid sequence for two mimic epitopes of the inflammatory site of LBP were determined to be WKAQKRFMKKSG and LKTRKLFWKYKD. The MAP was successfully prepared simultaneously and is able to be used as the core antigen protein for the formulation of vaccines. This knowledge will help in future investigations of the functional characteristics of LBP protein, and enhance exploration into new pathways for the prevention and treatment of LPS inflammatory diseases. PMID- 20833182 TI - Responses of diploid and triploid Pacific oysters Crassostrea gigas to Vibrio infection in relation to their reproductive status. AB - Several Vibrio species are known to be pathogenic to the Pacific oyster Crassostrea gigas. Survival varies according to pathogen exposure and high mortality events usually occur in summer during gametogenesis. In order to study the effects of gametogenetic status and ploidy (a factor known to affect reproduction allocation in oysters) on vibriosis survival, we conducted two successive experiments. Our results demonstrate that a common bath challenge with pathogenic Vibrio splendidus and Vibrio aestuarianus on a mixture of mature, spawning and non-mature oysters can lead to significant mortality. Previous bath challenges, which were done using only non-mature oysters, had not produced mortality. Immunohistochemical analyses showed the affinity of Vibrio for gonadic tissues, highlighting the importance of sexual maturity for vibriosis infection processes in oysters. Mortality rate results showed poor repeatability between tanks, however, in this bath challenge. We then tested a standardized and repeatable injection protocol using two different doses of the same combination of two Vibrio species on related diploid and triploid oysters at four different times over a year. Statistical analyses of mortality kinetics over a 6-day period after injection revealed that active gametogenesis periods correspond to higher susceptibility to vibriosis and that there is a significant interaction of this seasonal effect with ploidy. However, no significant advantage of triploidy was observed. Triploid oysters even showed lower survival than diploid counterparts in winter. Results are discussed in relation to differing energy allocation patterns between diploid and triploid Pacific oysters. PMID- 20833183 TI - Molecular cloning of a C-type lectin with two CRD domains from the banana shrimp Fenneropenaeus merguiensis: early gene up-regulation after Vibrio harveyi infection. AB - A diverse class of pattern-recognition proteins called lectins play important roles in shrimp innate immunity. A novel C-type lectin gene (FmLC) was cloned from the hepatopancreas of banana shrimp Fenneropenaeus merguiensis by means of PCR and 5' and 3' rapid amplification of cDNA ends (RACE). The full-length cDNA consists of 1118 bp with one 1002 bp open reading frame, encoding 333 amino acids. Its deduced amino acid sequence contains a putative signal peptide of 20 amino acids. FmLC contains two carbohydrate recognition domains, CRD1 and CRD2, that share only 30% identity with each other. The first CRD comprises a QPD motif with specificity for binding galactose and a single Ca(2+) binding site, while the second CRD consists of an EPN motif for a mannose-specific binding site. FmLC had a close evolutionary relationship to other dual-CRD lectins of penaeid shrimp. Expression results showed that transcripts of FmLC were detected only in the hepatopancreas, none was found in other tissues. After challenging either whole shrimp or hepatopancreas tissue fragments with Vibrioharveyi, the expression of FmLC was up-regulated. This indicates that FmLC is inducible and may be involved in a shrimp immune response to recognize potential bacterial pathogens. PMID- 20833184 TI - Taking the pulse of ribosome assembly in vivo. PMID- 20833185 TI - Scorpion venom complexity fractal analysis. Its relevance for comparing venoms. AB - We analyzed the venom elution pattern of 15 scorpions species. Data were scanned at 1 Hz and stored digitally. Approximate fractal dimension (D) [Sevcik (1998)] was calculated for minutes 0-60 of the elutions. D was calculated for either the whole time range, or calculated using a window of 500 points, which was displaced by one time increment recursively, and stored [(t(i),D(i)) sets]. We avoid the term complexity as much as possible since defining complexity is difficult; instead we propose the term contortedness and represent it by the variable Q=D-1. To compare venom contortednesses of different species, a phase plot with their (t(i),Q(i)) sets was constructed and determination coefficient (d(s)) were calculated squaring the Spearman rank correlation coefficient. (t(i),Q(i)) sets of several elutions of the same species were averaged and compared with other species finding that some were amazingly similar (Tityus clathratus vs Tityus caripitensis, d(s) = 0.813). Tityus discrepans was similar to 6 of 8 species of the same genus (d(s) ranging from 0.23 to 0.49), and also similar to Centruroides gracilis and Chactas laevipes (d(s) 0.54 and 0.49, respectively). Serendipitously,T. discrepans was chosen many years ago to produce anti-Tityus antivenom in Venezuela; perhaps the clinical success in neutralizing the venom of the other known Venezuelan Tityus, stems from the mimetism of this venom with the remaining species' venom. PMID- 20833186 TI - A three-compartment model of the C-peptide-insulin dynamic during the DIST test. AB - Dynamic insulin sensitivity (SI) tests often utilise model-based parameter estimation. This research analyses the impact of expanding the typically used two compartment model of insulin and C-peptide kinetics to incorporate a hepatic third compartment. The proposed model requires only four C-peptide assays to simulate endogenous insulin production (uen), greatly reducing the cost and clinical burden. Sixteen subjects participated in 46 dynamic insulin sensitivity tests (DIST). Population kinetic parameters are identified for the new compartment. Results are assessed by model error versus measured data and repeatability of the identified SI. The median C-peptide error was 0% (IQR: -7.3, 6.7)%. Median insulin error was 7% (IQR: -28.7, 6.3)%. Strong correlation (r=0.92) existed between the SI values of the new model and those from the original two-compartment model. Repeatability in SI was similar between models (new model inter/intra-dose variability 3.6/12.3% original model -8.5/11.3%). When frequent C-peptide samples may be available, the added hepatic compartment does not offer significant diagnostic, repeatability improvement over the two compartment model. However, a novel and successful three-compartment modelling strategy was developed which provided accurate estimation of endogenous insulin production and the subsequent SI identification from sparse C-peptide data. PMID- 20833187 TI - Waist circumference leads to prolonged microvascular reactive hyperemia response in young overweight/obese women. AB - OBJECTIVES: Previous data in our laboratory have shown microvascular dysfunction in normoglycaemic subjects with metabolic syndrome (MS). In a step further, we have investigated which clinical parameters related or not to MS would elicit microvascular dysfunction and the need of diagnosing MS for the establishment of microcirculatory impairment in overweight/obese women. METHODS: Nineteen lean [23.6+/-3.1years, body mass index (BMI) 21.9+/-1.8kg/m(2)] and 59 overweight/obese [24.6+/-3.7years; BMI 34.4+/-5.9kg/m(2)] sedentary non-smoking women, divided in overweight/obese without (MS negative, n=36) and obese with MS (MS positive, n=23) were evaluated. Blood biochemistry, HOMA-IR index and anthropometric variables were determined. Morphological (capillary diameters) and functional [functional capillary density, red blood cell velocity (RBCV) at baseline and peak and time (TRBCV(max)) to reach it during post-occlusive reactive hyperemia after 1min ischemia] microcirculatory variables were examined by nailfold videocapillaroscopy. RESULTS: Compared to controls, overweight/obese MS negative and obese MS positive presented longer TRBCV(max); the presence of two MS components was sufficient to prolong it and the MS diagnosis did not add any significant impairment to the microcirculation. Among clinical parameters investigated, a direct relationship between TRBCV(max) and waist circumference and insulin concentrations was found. CONCLUSION: Our results have shown that microvascular dysfunction is independent of metabolic syndrome diagnosis and could be predicted by the waist circumference on young overweight/obese women, reinforcing the relationship between obesity-related microvascular/metabolic disturbances. PMID- 20833188 TI - Conservation and diversity of MutS proteins. AB - The homologues of MutS, mismatch repair protein, exist in all prokaryotes, with the exception of Actinobacteria, Mollicutes and part of the Archaea. Multiple alignments of 316 MutS amino acid sequences from 169 species revealed conserved residues and sequence motifs distinguishing MutS homologues. All MutS homologues show high conservation within the ATPase domain. MutS1, the homologue responsible for DNA mismatch recognition, is common in Archaea and Bacteria. MutS1 is distinguished by the N-terminal mismatch binding domain containing the GXFXE motif shared by all MutS1 homologues and MSH6 homologues in eukaryotes. Less common than MutS1, MutS2, the suppressor of homologous recombination, is rendered distinctive by the C-terminal Smr endonuclease domain containing the conserved HGXG motif. MutS1 and MutS2 are of enormous significance in maintaining genome integrity. The functions of the other homologues: MutS2-like, MutS3, MutS4, and MutS5 have not yet been found. Each of these homologues exists in a narrower range of taxonomic groups than MutS1 or MutS2 and has neither the mismatch binding nor the Smr domain. The number of different MutS homologues in a single organism usually ranges from one to four; there are rarely five and six only occur exceptionally. The diversity of MutS types and structures begs the question as to how this diversity influenced the evolution of genomes. PMID- 20833189 TI - Effects of head rotation on space- and word-based reading errors in spatial neglect. AB - Patients with right hemisphere lesions often omit or misread words on the left side of a text or the beginning letters of single words which is termed neglect dyslexia (ND). Two types of reading errors are typically observed in ND: omissions and word-based reading errors. The prior are considered as space-based omission errors on the contralesional side of the page, while the latter can be viewed as a kind of stimulus- or word-based reading errors where leftsided parts of a single perceptual entity (the word) are neglected. The head, trunk and eyes are part of a hypothetical egocentric reference frame that is aligned around our body and divides space into a left and right hemispace. Previous neglect studies have shown that head- and trunk-orientation significantly influence contralesional neglect. An open question is whether such egocentric manipulations also influence omissions and word-based errors in paragraph reading in ND. The current study investigated in a sample of right-hemisphere lesioned patients with ND vs. without ND and matched healthy control subjects the influence of head rotation (HR) on both types of reading errors using controlled indented paragraph reading tests. Passive leftward HR significantly reduced omission errors on the left side of the text in ND, but had no effect on word-based reading errors. In conclusion egocentric manipulations like HR only appear to influence space-based attentional processes in neglect evident as omissions in paragraph reading but have no impact on those attentional processes involved in word identification evident as word-based errors in paragraph reading. PMID- 20833190 TI - Faces are special but not too special: spared face recognition in amnesia is based on familiarity. AB - Most current theories of human memory are material-general in the sense that they assume that the medial temporal lobe (MTL) is important for retrieving the details of prior events, regardless of the specific type of materials. Recent studies of amnesia have challenged the material-general assumption by suggesting that the MTL may be necessary for remembering words, but is not involved in remembering faces. We examined recognition memory for faces and words in a group of amnesic patients, which included hypoxic patients and patients with extensive left or right MTL lesions. Recognition confidence judgments were used to plot receiver operating characteristics (ROCs) in order to more fully quantify recognition performance and to estimate the contributions of recollection and familiarity. Consistent with the extant literature, an analysis of overall recognition accuracy showed that the patients were impaired at word memory but had spared face memory. However, the ROC analysis indicated that the patients were generally impaired at high confidence recognition responses for faces and words, and they exhibited significant recollection impairments for both types of materials. Familiarity for faces was preserved in all patients, but extensive left MTL damage impaired familiarity for words. These results show that face recognition may appear to be spared because performance tends to rely heavily on familiarity, a process that is relatively well preserved in amnesia. In addition, the findings challenge material-general theories of memory, and suggest that both material and process are important determinants of memory performance in amnesia. PMID- 20833191 TI - Attentional engagement deficits in dyslexic children. AB - Reading acquisition requires, in addition to appropriate phonological abilities, accurate and rapid selection of sublexical orthographic units by attentional letter string parsing. Spatio-temporal distribution of attentional engagement onto 3-pseudoletter strings was studied in 28 dyslexic and 55 normally reading children by measuring attentional masking (AM). AM refers to an impaired identification of the first of two sequentially presented masked objects (O1 and O2). In the present study, O1 was always centrally displayed, whereas the location of O2 (central or lateral) and the O1-O2 interval were manipulated. Dyslexic children showed a larger AM at the shortest O1-O2 interval and a sluggish AM recovery at the longest O1-O2 interval, as well as an abnormal lateral AM. More importantly, these spatio-temporal deficits of attentional engagement were selectively present in dyslexics with poor phonological decoding skills. Our results suggest that an inefficient spatio-temporal distribution of attentional engagement - probably linked to a parietal lobule dysfunction - might selectively impair the letter string parsing mechanism during phonological decoding. PMID- 20833192 TI - Bimanual crossed-uncrossed difference and asynchrony of normal, anterior- and totally-split-brain individuals. AB - This study investigated interhemispheric transfer in ten normal, four anterior-, and four totally-split-brain individuals, through measures of manual asynchrony and bimanually-recorded crossed-uncrossed difference (CUD). The CUD relied on the difference between crossed and uncrossed responses whereas the asynchrony measure relied on the reaction time difference between the two responding hands. Manipulations of sensory and attentional factors were assessed for both measures. We found a normal CUD (3.8 ms) along with an exacerbated and more variable asynchrony for partial split-brain individuals (40.8 ms) compared to normal individuals (CUD: 0.4 ms, asynchrony: 13.8 ms). In turn, the CUD of total split brain individuals (20.4 ms) was larger than that of partial split-brain and normal individuals. Also, the asynchrony of total split-brain individuals (57.6 ms) was larger and more variable than that of normal individuals, and more variable than that of partial split-brain individuals. We interpret these results as behavioural evidence of independent mechanisms underlying the CUD and bimanual synchronization, as well as evidence of the joint involvement of both the anterior and the posterior portions of the corpus callosum in bimanual coordination. PMID- 20833193 TI - Anticipation of body-scaled action is modified in anorexia nervosa. AB - Patients with anorexia nervosa frequently believe they are larger than they really are. The precise nature of this bias is not known: is it a false belief related to the patient's aesthetic and emotional attitudes towards her body? Or could it also reflect abnormal processing of the representation of the body in action? We tested this latter hypothesis by using a body-scaled action anticipation task in which 25 anorexics and 25 control participants had to judge whether or not an aperture was wide enough for them to pass through. The anticipation of body-scaled action was severely disturbed in anorexic patients; they judged that they could not pass through an aperture, even when it was wide enough (i.e. they behave as if their body was larger than in reality). The abnormally high "passability ratio" (the critical aperture size to shoulder width ratio) was also correlated with the duration of illness and the degree of body concern/dissatisfaction. Our results suggest that body size overestimation in anorexia nervosa is not solely due to psycho-affective factors but rather suggest impaired neural processing of body dimensions that might take its source in parietal networks. PMID- 20833194 TI - Auditory-somatosensory multisensory interactions in humans: dissociating detection and spatial discrimination. AB - Simple reaction times (RTs) to auditory-somatosensory (AS) multisensory stimuli are facilitated over their unisensory counterparts both when stimuli are delivered to the same location and when separated. In two experiments we addressed the possibility that top-down and/or task-related influences can dynamically impact the spatial representations mediating these effects and the extent to which multisensory facilitation will be observed. Participants performed a simple detection task in response to auditory, somatosensory, or simultaneous AS stimuli that in turn were either spatially aligned or misaligned by lateralizing the stimuli. Additionally, we also informed the participants that they would be retrogradely queried (one-third of trials) regarding the side where a given stimulus in a given sensory modality was presented. In this way, we sought to have participants attending to all possible spatial locations and sensory modalities, while nonetheless having them perform a simple detection task. Experiment 1 provided no cues prior to stimulus delivery. Experiment 2 included spatially uninformative cues (50% of trials). In both experiments, multisensory conditions significantly facilitated detection RTs with no evidence for differences according to spatial alignment (though general benefits of cuing were observed in Experiment 2). Facilitated detection occurs even when attending to spatial information. Performance with probes, quantified using sensitivity (d'), was impaired following multisensory trials in general and significantly more so following misaligned multisensory trials. This indicates that spatial information is not available, despite being task-relevant. The collective results support a model wherein early AS interactions may result in a loss of spatial acuity for unisensory information. PMID- 20833195 TI - Combined effect of wavelength and polarization in double-pass retinal images in the human eye. AB - A polychromatic double-pass setup was developed to study the effects of wavelength and polarization on retinal image quality. The results show that the central part of the images was similar for all wavelengths (543, 633 and 780 nm) and polarization states. However, the image tails increased significantly when using infrared light for all the polarization states used. For the set of subjects involved in the study, ocular diattenuation presented individual differences, however significant changes were not found across the different wavelengths. Moreover the Stokes vectors providing the maximum intensity transmittance varied across subjects and corresponded to elliptically polarized light. These non-negligible diattenuation effects might affect the performance of clinical devices which only take into account ocular birefringence. PMID- 20833196 TI - Inhibitory effects of alprazolam on the development of acute experimental autoimmune encephalomyelitis in stressed rats. AB - The progression and development of multiple sclerosis (MS) has long been hypothesized to be associated with stress. Benzodiazepines have been observed to reduce negative consequences of stress on the immune system in experimental and clinical models, but there are no data on their effects on MS, or experimental autoimmune encephalomyelitis (EAE), a model for human MS. We designed experiments conducted to ascertain whether alprazolam could modify the clinical, histological and neuroendocrine manifestations of acute EAE in Lewis rats exposed to a chronic auditory stressor. EAE was induced by injection of an emulsion of MBP and complete Freund's adjuvant containing Mycobacterium tuberculosis H37Ra. Stress application and treatment with drugs (placebo or alprazolam) were initiated 5days before inoculation and continued daily for the duration of the experiment (days 14 or 34 postinoculation).Our results show significant increases in the severity of neurological signs, the histological lesions of the spinal cord (inflammation), and the corticosterone plasmatic levels in stressed rats compared to those non-stressed ones. Treatment with alprazolam reversed the adverse effects of stress. These findings could have clinical implications in patients suffering from MS treated with benzodiazepines, so besides the psychopharmacological properties of alprazolam against stress, it has beneficial consequences on EAE. PMID- 20833197 TI - Hypothalamic cocaine- and amphetamine-regulated transcript peptide is reduced and fails to modulate feeding behavior in rats with chemically-induced mammary carcinogenesis. AB - Cocaine- and amphetamine-regulated transcript peptide (CART) is a major anorectic agent present in the hypothalamus. We investigated the possible role of CART in mammary cancer-induced anorexia and body weight loss in rats. Mammary carcinogenesis was induced in the female Sprague-Dawley rats by intraperitoneal injection of N-methyl-N-nitrosourea (MNU). Following administration of MNU, rats progressively showed a reduction in food intake and body weight. Fourteen weeks after MNU treatment, rats were injected daily with CART or CART-antibody intracerebroventricularly for 5days, and food intake and body weight were monitored (g) before the next injection time-point. In normal rats, while a distinct anorexia and weight loss was observed following CART administration, injection of CART-antibody produced opposite effects. However, both the agents failed to produce any significant alterations in food intake and body weight of mammary tumor-bearing animals. An immunohistochemical application of antibodies against CART to the brain sections of cancerous rats showed a reduced immunoreactivity in the hypothalamic dorsomedial, ventromedial, lateral, paraventricular and arcuate nuclei. The results suggest that, cancerous condition might down-regulate the CART system in the hypothalamus. Alternatively, reduction in hypothalamic CART activity might be a counter-regulatory strategy to reverse food under-consumption or body mass erosion. PMID- 20833198 TI - Cognitive motor interference while walking: a systematic review and meta analysis. AB - Dual-task methodology has been increasingly used to assess cognitive motor interference while walking. However, whether the observed dual-task-related gait changes are systematically related to methodological variations remains unclear and researchers still lack knowledge of what cognitive task to use in different groups for clinical purposes or for research. We systematically reviewed experimental studies that measured gait performance with and without performing concurrent cognitive task. Our results suggest that cognitive tasks that involve internal interfering factors seem to disturb gait performance more than those involving external interfering factors. Meta-analysis results show that the overall effect of different cognitive tasks was prominent in gait speed. In healthy participants, meta-regression analysis suggests strong associations between age and speed reduction under dual-task conditions and between the level of cognitive state and speed reduction under dual-task conditions. Standardizing research methodologies, as well as improving their ecological validity, enables better understanding of dual-task-related gait changes in different populations and improves, in turn, our understanding of neural mechanisms and gait control in general in content. PMID- 20833199 TI - Human threat management systems: self-protection and disease avoidance. AB - Humans likely evolved precautionary systems designed to minimize the threats to reproductive fitness posed by highly interdependent ultrasociality. A review of research on the self-protection and disease avoidance systems reveals that each system is functionally distinct and domain-specific: each is attuned to different cues; engages different emotions, inferences, and behavioral inclinations; and is rooted in somewhat different neurobiological substrates. These systems share important features, however. Each system is functionally coherent, in that perceptual, affective, cognitive, and behavioral processes work in concert to reduce fitness costs of potential threats. Each system is biased in a risk-averse manner, erring toward precautionary responses even when available cues only heuristically imply threat. And each system is functionally flexible, being highly sensitive to specific ecological and dispositional cues that signal greater vulnerability to the relevant threat. These features characterize a general template useful for understanding not only the self-protection and disease avoidance systems, but also a broader set of evolved, domain-specific precautionary systems. PMID- 20833200 TI - Understanding higher level gait disturbances in mild dementia in order to improve rehabilitation: 'last in-first out'. AB - Predicting and anticipating disturbances in higher level gait is particularly relevant for patients with dementia as higher level gait appears to be closely related to higher level cognitive functioning. A phenomenon that could contribute to the understanding and prediction of disturbances in higher level gait and gait related motor activity in the various subtypes of dementia is paraphrased as 'last in-first out'. 'Last in-first out' refers to the principle that neural circuits that mature late in development are the most vulnerable to neurodegeneration. The strength of relating symptoms to the 'last in-first out' principle is that a future symptom can be predicted and anticipated in a therapeutic way, even if the disease process has not already started. Therefore, the aim of this review is to provide new strategies for rehabilitation of higher level gait disturbances in dementia based upon the 'last in-first out' principle. These new strategies emerge from five neural networks: the superior longitudinal fasciculus, the uncinate fasciculus, the fronto-cerebellar and fronto-striatal connections, and the cingulum. PMID- 20833201 TI - Aspergillus galactomannan antigen assay in bronchoalveolar lavage fluid for diagnosis of invasive pulmonary aspergillosis. AB - OBJECTIVES: A recently developed bronchoalveolar lavage (BAL) galactomannan (GM) assay shows promising results. We evaluated the diagnostic performance of this assay and analyzed risk factors for false-positive results. METHODS: A prospective cohort study was performed in a tertiary hospital over a 9-month period. We reviewed all adult patients who underwent GM assays of BAL. Patients were categorized with proven, probable, or possible invasive pulmonary aspergillosis (IPA) according to revised EORTC/MSG definitions. Each patient with a false-positive BAL GM result was matched with three patients with true-negative BAL GM result, and the risk factors for false-positive BAL GM results were determined. RESULTS: Of 359 enrolled patients, 22 (6%) were diagnosed with IPA (1 proven, 17 probable, and 4 possible). Of the 22 patients with IPA, 17 (77%) had already received antifungal agents before the BAL GM assay was conducted. At an index cutoff value of >=0.5, the BAL GM assay had a sensitivity of 64% (95% CI 41%-83%) and a specificity of 89% (95% CI 85%-92%). However, at an index cutoff value of >=0.2, the BAL GM assay had a sensitivity of 86% (95% CI 65%-97%) and a specificity of 74% (95% CI 69%-79%). Of the 52 patients with positive BAL GM assay (>=0.5), 25 (7%) were false-positives. Univariate and multivariate analysis revealed that treatment with piperacillin-tazobactam or ampicillin-sulbactam was associated with false-positive BAL GM results. CONCLUSIONS: The BAL GM assay appears promising for the diagnosis of IPA. However, treatment with certain antibiotics may interfere with the results of the BAL GM assay. PMID- 20833202 TI - Chronological and biological age in HIV infection. PMID- 20833203 TI - Methods for detection and differentiation of existing and new crinivirus species through multiplex and degenerate primer RT-PCR. AB - A method was developed for rapid identification and differentiation of both known and novel crinivirus species involving both multiplex and degenerate reverse transcription-polymerase chain reaction (RT-PCR). The multiplex method can discriminate among known criniviruses infecting vegetable and small fruit crops, and rapidly identify viruses associated with disease symptoms, as well as identification of mixed crinivirus infections. Four host groups for multiplex detection of criniviruses were selected based on the types of crops where specific criniviruses would be expected to occur. Each detection group contained three to four crop-specific primers designed to the same region of the gene encoding the highly conserved RNA-dependent RNA polymerase gene (RdRp) of criniviruses for rapid, single-reaction determination of which crinivirus(es) may be infecting a plant. Degenerate reverse primers used for RT and in PCR were designed to amplify all members of each host group, and were coupled with species specific forward primers resulting in four separate single-reaction cocktails for detection of most criniviruses sequenced to date, whether present in single or mixed virus infections. Additional viruses can be added to multiplex detection by adjustment of primer concentration for balanced detection of target viruses. In order to identify unknown putative criniviruses or those for which sequence information is not yet available, a genus-wide, universal degenerate primer set was developed. These primers also targeted the crinivirus RdRp gene, and amplify a wide range of crinivirus sequences. Both detection systems can be used with most RNA extraction methods, and with RT-PCR reagents common in most laboratories. PMID- 20833204 TI - Evaluation of 30 commercial assays for the detection of antibodies to HIV in China using classical and Bayesian statistics. AB - The purpose of this study was to evaluate the 30 commercial HIV-antibody (HIV-Ab) assays in the nationwide assessment program of China using classical and Bayesian statistical methods. The classical estimates of sensitivity and specificity varied from 95.9% to 100% and from 94.6% to 100%, respectively. The proportions of assays with 100% sensitivity and with 100% specificity reached 63.3% (19/30) and 3.3% (1/30), respectively. Using the Bayesian logit hierarchical model, the overall estimates of sensitivity and specificity were 99.8% (95% Bayesian credible interval [BCI]: 99.4-100%) and 98.1% (95% BCI: 97.4-98.7%), respectively, for the 17 ELISAs under evaluation. For the 13 rapid assays, the corresponding overall estimates were reported to be 99.2% (95% BCI: 98.5-99.8%) and 98.4% (95% BCI: 97.8-98.9%), respectively. In addition, given the prevalences of HIV infection among the general population of China and the intravenous drug user group in China, the positive predictive values were estimated for each individual assay in the framework of the two schools of statistical thought. Furthermore, by comparing the two types of estimates, it is concluded that the two types of statistical methods were complementary for the evaluation of very accurate HIV-Ab assays. PMID- 20833205 TI - Use of filter carrier technique to measure the persistence of avian influenza viruses in wet environmental conditions. AB - A germ carrier technique was adapted for the determination of the persistence of influenza viruses in moist environments. The technique was employed with 3 low pathogenic avian influenza viruses (H4N6, H5N1, and H6N8), one human influenza virus (H1N1), and two model viruses (NDV and ECBO) in lake water at five different temperatures (30, 20, 10, 0, and -10 degrees C). Viral quantitation was carried out at regular intervals on cell culture for a maximum duration of 16 weeks. Serial data were analyzed by linear regression model to calculate T-90 values (time required for one log reduction in the virus titer). Persistence of all of the viruses was highest at -10 degrees C followed by 0, 10, 20, and 30 degrees C. At -10 degrees C, the single freeze-thaw cycle resulted in an abrupt decline in the virus titer, followed by long term persistence. Generally, influenza viruses persisted shorter than model viruses while ECBO has the highest survival time in lake water. Individual influenza viruses differed in their persistence at all temperatures. The findings of the present study suggest that AIV can remain infectious in lake water for extended periods of time at low temperatures. PMID- 20833206 TI - Simplified screening method for detecting oseltamivir resistant pandemic influenza A (H1N1) 2009 virus by a RT-PCR/restriction fragment length polymorphism assay. AB - The sudden emergence of the pandemic influenza A (H1N1) 2009 virus in early 2009 has resulted in a rapid transmission of this virus worldwide. Within a short time span, sporadic cases infected with this virus that shows oseltamivir resistance have also been reported. These resistant viruses have an amino acid change from histidine to tyrosine at position 275 (H275Y) of the neuraminidase gene. In this study, a reverse transcriptase PCR/restriction fragment length polymorphism (RT PCR/RFLP) assay was developed to detect the H275Y mutation. Resistant and sensitive viruses could be differentiated using the RFLP patterns. This RT PCR/RFLP assay is a simple method and also very specific and sensitive for detecting the H275Y mutation of pandemic influenza A (H1N1) 2009 viruses, and can be used in resource-limited settings. PMID- 20833207 TI - Repetitive administration of aripiprazole enhances locomotor response to methamphetamine in mice. AB - Dopamine receptor partial agonists have been proposed as potential candidate agents to treat psycho-stimulant abuse. Aripiprazole is a dopamine D2/D3 receptor partial agonist that is currently used as an antipsychotic drug in clinical settings. This study aimed to examine whether aripiprazole can suppress the methamphetamine-induced locomotor response in mice that is used as an indicator for potential clinical use. In ICR mice pre-exposed to methamphetamine (1mg/kg subcutaneous injection once daily for 7 days), we found that mice receiving repetitive treatments with aripiprazole (1, 5, and 10mg/kg, respectively; intraperitoneal injection once daily for 1 week) showed a significantly enhanced locomotor response upon re-exposure to methamphetamine (0.5mg/kg), compared with animals that received a vehicle treatment. Furthermore, we found that methamphetamine-naive mice receiving repetitive treatment with aripiprazole (5mg/kg intraperitoneal injection once daily for 1 week) also showed a significantly enhanced locomotor response to acute challenge with methamphetamine (0.5mg/kg), compared with animals receiving the vehicle treatment. The enhanced locomotor response to methamphetamine in both methamphetamine-pre-exposed and methamphetamine-naive mice lasted at least four weeks in this study. Our data suggest that aripiprazole may enhance the effects of methamphetamine, so caution should be exercised when prescribing to individuals with histories of stimulant use. PMID- 20833208 TI - GW1929: a nonthiazolidinedione PPARgamma agonist, ameliorates neurological damage in global cerebral ischemic-reperfusion injury through reduction in inflammation and DNA fragmentation. AB - Transient global cerebral ischemia results in acute neurodegeneration in selective brain areas. Global cerebral ischemic-reperfusion (IR) injury induced selective hippocampal damage results into various neurobehavioral deficits including spatial memory and learning deficiencies. In this study, we have investigated the protective effects of a nonthiazolidinedione PPARgamma agonist, N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine (GW1929), against global cerebral IR injury induced neurobehavioral deficits and brain damage in gerbils. Bilateral carotid artery occlusion induced global cerebral ischemia in gerbils resulted in neurological deficits, hyperlocomotion, reduced response latency in passive avoidance test and hippocampal damage. Hippocampal neurodegeneration after cerebral IR injury was also associated with significant increase in iNOS and MMP-9 immunoreactivity along with TNFalpha and IL-6 levels. Massive apoptotic DNA fragmentation as evident from increased TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick end labelling)-positive cells was also observed in the CA1 hippocampal region of IR challenged gerbils. GW1929 treatment significantly ameliorated cerebral IR induced neurological symptoms, hyperlocomotion, cognitive deficits and hippocampal neuronal damage in CA1 hippocampus region in gerbils. Significant reduction in IR injury induced iNOS and MMP-9 immunoreactivity, TNFalpha and IL-6 levels and apoptotic DNA fragmentation was also observed with GW1929 treatment. Pioglitazone, thiazolidinedione PPARgamma agonist also exhibited similar effects on inflammatory parameters after global cerebral IR injury. In summary, this study demonstrates neuroprotective effects of GW1929 in global cerebral IR injury induced neurobehavioral deficits and brain pathology which may be attributed to reduced inflammation and apoptotic DNA fragmentation, suggesting therapeutic potential of PPARgamma agonists in cerebral IR injury. PMID- 20833209 TI - Biochemical characterization of Plasmodium falciparum dipeptidyl aminopeptidase 1. AB - Dipeptidyl aminopeptidase 1 (DPAP1) is an essential food vacuole enzyme with a putative role in hemoglobin catabolism by the erythrocytic malaria parasite. Here, the biochemical properties of DPAP1 have been investigated and compared to those of the human ortholog cathepsin C. To facilitate the characterization of DPAP1, we have developed a method for the production of purified recombinant DPAP1 with properties closely resembling those of the native enzyme. Like cathepsin C, DPAP1 is a chloride-activated enzyme that is most efficient in catalyzing amide bond hydrolysis at acidic pH values. The monomeric quaternary structure of DPAP1 differs from the homotetrameric structure of cathepsin C, which suggests that tetramerization is required for a cathepsin C-specific function. The S1 and S2 subsite preferences of DPAP1 and cathepsin C were profiled with a positional scanning synthetic combinatorial library. The S1 preferences bore close similarity to those of other C1-family cysteine peptidases. The S2 subsites of both DPAP1 and cathepsin C accepted aliphatic hydrophobic residues, proline, and some polar residues, yielding a distinct specificity profile. DPAP1 efficiently catalyzed the hydrolysis of several fluorogenic dipeptide substrates; surprisingly, however, a potential substrate with a P2-phenylalanine residue was instead a competitive inhibitor. Together, our biochemical data suggest that DPAP1 accelerates the production of amino acids from hemoglobin by bridging the gap between the endopeptidase and aminopeptidase activities of the food vacuole. Two reversible cathepsin C inhibitors potently inhibited both recombinant and native DPAP1, thereby validating the use of recombinant DPAP1 for future inhibitor discovery and characterization. PMID- 20833210 TI - Jagged/Notch signalling is required for a subset of TGFbeta1 responses in human kidney epithelial cells. AB - The Jagged/Notch pathway has been implicated in TGFbeta1 responses in epithelial cells in diabetic nephropathy and other fibrotic conditions in vivo. Here, we identify that Jagged/Notch signalling is required for a subset of TGFbeta1 stimulated gene responses in human kidney epithelial cells in vitro. TGFbeta1 treatment of HK-2 and RPTEC cells for 24h increased Jagged1 (a Notch ligand) and Hes1 (a Notch target) mRNA. This response was inhibited by co-incubation with Compound E, an inhibitor of gamma-secretase (GSI), an enzyme required for Notch receptor cleavage and transcription regulation. In both cell types, TGFbeta1 responsive genes associated with epithelial-mesenchymal transition such as E cadherin and vimentin were also affected by gamma-secretase inhibition, but other TGFbeta1 targets such as connective tissue growth factor (CTGF) and thrombospondin-1 (THBS1) were not. TGFbeta1-induced changes in Jagged1 expression preceded EMT-associated gene changes, and co-incubation with GSI altered TGFbeta1 induced changes in cell shape and cytoskeleton. Transfection of cells with the activated, cleaved form of Notch (NICD) triggered decreased expression of E cadherin in the absence of TGFbeta1, but did not affect alpha-smooth muscle actin expression, suggesting differential requirements for Notch signalling within the TGFbeta1-responsive gene subset. Increased Jagged1 expression upon TGFbeta1 exposure required Smad3 signalling, and was also regulated by PI3K and ERK. These data suggest that Jagged/Notch signalling is required for a subset of TGFbeta1 responsive genes, and that complex signalling pathways are involved in the crosstalk between TGFbeta1 and Notch cascades in kidney epithelia. PMID- 20833211 TI - Activities of alpha-asarone in various animal seizure models and in biochemical assays might be essentially accounted for by antioxidant properties. AB - Anticonvulsant properties of alpha-asarone were studied in mice at three doses with different toxicity. The 100mg/kg dose decreased both treadmill performance and locomotor activity, caused hypothermia, and potentiated pentobarbital-induced sleep. The last two effects and no toxicity were observed at 60 and 22mg/kg, respectively. In chemical (pentylenetetrazole, picrotoxin, N-methyl-D-aspartate, pilocarpine) and electrical (maximal electroshock) seizure tests, neither seizures nor death were prevented by 60 mg/kg alpha-asarone which, however, exhibited protective-like effects (delay in the onset of clonic and/or tonic seizures and/or in the death of mice). Magnesium deficiency-dependent audiogenic seizures responded to non-toxic doses of alpha-asarone (60 mg/kg and less): 22 mg/kg protecting 50% of tested animals. Because these seizures respond to both anti-seizure and antioxidant compounds, antioxidant properties of alpha-asarone were studied, indicating 5 Units of superoxide dismutase-like activity per mg alpha-asarone. Treatment of mice by alpha-asarone (daily dose of 100mg/kg during 7 days) induced brain antioxidant enzymes (superoxide dismutase, glutathione peroxidase and reductase) in striatum and hippocampus and to a lesser extent in cortex. In view of recent findings about deleterious roles of chronic inflammatory/oxidant stresses in human epilepsy outcome, antioxidant and inductive properties of alpha-asarone are proposed to be coherent bases for traditional clinical efficacy. PMID- 20833212 TI - Identification of dispensable nucleotide sequence in 3' untranslated region of porcine reproductive and respiratory syndrome virus. AB - The 3' untranslated region (UTR) of porcine arterivirus genome plays a pivotal role for virus replication, yet the properties of 3' UTR remain largely undefined. We conducted site-directed mutagenesis to the 3' UTR of the type II porcine reproductive and respiratory syndrome virus (PRRSV). Serial deletions of the 3' UTR showed that at least 40 nucleotides immediately following the ORF7 stop codon were dispensable for the viability of PRRSV in cultured cells. We then constructed a chimeric PRRSV cDNA clone using type II PRRSV as the backbone containing the 3' UTR from the type I PRRSV. The chimeric virus was viable and shared similar properties with the parental virus. Our results provided the first description of the 40nt dispensable region in type I PRRSV 3' UTR, and further predicted structure demonstrated that the high-order structure of 3' UTR might play significant roles in its function. PMID- 20833213 TI - Biological characterization and complete genomic sequence of Apium virus Y infecting celery. AB - A celery isolate of Apium virus Y (ApVY-Ce) from diseased plants in a commercial field in California was characterized. The experimental host range of the virus included 13 plant species in the families Apiaceae, Chenopodiaceae and Solanaceae. Almost all infected plant species showed foliar chlorosis and distortion or severe stunting and systemic chlorosis. ApVY-Ce was transmitted to all 10 host species in the Apiaceae by green peach aphids. It reacted with the potyvirus group antibody and Celery mosaic virus (CeMV) antiserum. The complete genomic sequence of ApVY-Ce was determined to be 9917 nucleotides, excluding the 3' poly(A) tail, and it comprises a large open reading frame encoding a polyprotein of 3184 amino acid residues. Its genomic organization is typical of potyviruses, and contains conserved motifs found in the genus Potyvirus. Comparisons with available genomic sequences of other potyviruses indicate that ApVY-Ce shares 26.1-52.9% identities with species of the existing genera and unassigned viruses in the Potyviridae at the polyprotein sequence level. Extensive phylogenetic analysis based on the 3'-partial sequences confirms that ApVY-Ce is most closely related to CeMV and is a distinct species of the genus Potyvirus. PMID- 20833214 TI - Advanced fluorescence microscopy methods illuminate the transfection pathway of nucleic acid nanoparticles. AB - A great deal of attention in biopharmacy and pharmaceutical technology is going to the development of nanoscopic particles to efficiently deliver nucleic acids to target cells. Despite the great potential of nucleic acids for treatment of various diseases, progress in the field is fairly slow. One of the causes is that development of suitable nanoscopic delivery vehicles is hampered by insufficient knowledge of their physicochemical and biophysical properties during the various phases of the transfection process. To address this issue, in the past decade we have developed and applied advanced fluorescence microscopy techniques that can provide a better insight in the transport and stability of nanoparticles in various biological media. This mini-review discusses the basic principles of fluorescence recovery after photobleaching (FRAP), fluorescence correlation spectroscopy (FCS) and single particle tracking (SPT), and gives an overview of studies in which we have employed these techniques to characterize the transport and stability of nucleic acid containing nanoparticles in extracellular media and in living cells. PMID- 20833215 TI - Conserved regions of the Plasmodium falciparum rhoptry-associated protein 3 mediate specific host-pathogen interactions during invasion of red blood cells. AB - Invasion of red blood cells (RBCs) by the Plasmodium falciparum malaria merozoite is mediated by parasite surface molecules and proteins contained within apical organelles that are capable of recognizing receptors on the membrane of RBCs. The identification and characterization of these P. falciparum invasion-associated proteins is the first step for unveiling potential new drug and vaccine target molecules to eradicate this deadly disease. Among the exclusive set of malarial vaccine candidates, the members of the rhoptry-associated protein (RAP) family have been associated with the parasite's binding to and invasion of RBCs. Remarkably, the third member of this family (named RAP-3) has been recently detected on the surface of non-infected RBCs exposed to free merozoites, therefore suggesting the participation of this protein during RBC infection. In this study, the sequence of RAP-3 was finely mapped using synthetic peptides in order to identify which are the specific binding regions involved in RAP3-RBC interactions. Two high-activity binding peptides (HABPs) established high affinity interactions with RBC surface molecules of about 27-90 kDa, which were differentially affected by different enzymatic treatments. RAP-1 and RAP-2 HABPs inhibited binding of RAP-3 HABPs to different extents, thus suggesting the recognition of similar binding sites on RBC membrane, as well as ability of RAP-3 HABPs to inhibit P. falciparum infection in vitro. Altogether, these functional analyses of RAP-3 HABPs strongly suggest a potential role for this protein in RBC invasion, and highlight its HABPs as potential targets to develop a fully protective minimal subunit-based malarial vaccine. PMID- 20833216 TI - Bombesin and neurotensin exert antiproliferative effects on oval cells and augment the regenerative response of the cholestatic rat liver. AB - The regenerative capacity of the cholestatic liver is significantly attenuated. Oval cells are hepatic stem cells involved in liver's regeneration following diverse types of injury. The present study investigated the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation as well as on hepatocyte and cholangiocyte proliferation and apoptosis in the cholestatic rat liver. Seventy male Wistar rats were randomly divided into five groups: controls, sham operated, bile duct ligated (BDL), BDL+BBS (30 MUg/kg/d), BDL+NT (300 MUg/kg/d). Ten days later, alpha-fetoprotein (AFP) mRNA (in situ hybridization), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphologic features of oval cells that were cytokeratin-19(+) and AFP mRNA(+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes and cholangiocytes were determined. Alanine aminotransferase (ALT) levels and hepatic oxidative stress (lipid peroxidation and glutathione redox state) were also estimated. The neuropeptides BBS and NT significantly reduced ALT levels and hepatic oxidative stress. Both agents exerted similar and cell type-specific effects on oval cells, hepatocytes and cholangiocytes: (a) oval cell proliferation and accumulation in the cholestatic liver was attenuated, (b) hepatocyte proliferation was increased along with a decreased rate of their apoptosis and (c) cholangiocyte proliferation was attenuated and their apoptosis was increased. These observations might be of potential value in patients with extrahepatic cholestasis. PMID- 20833217 TI - Structure-activity studies of GmSubPep, a soybean peptide defense signal derived from an extracellular protease. AB - GmSubPep, a 12-amino acid peptide isolated from soybean leaves, induces the expression of genes in soybean suspension-cultured cells that encode proteins involved in defense against pathogens. The peptide is derived from an extracellular subtilisin-like protease (subtilase) and binds a putative cell surface receptor that initiates a defense signaling cascade. Interaction of the peptide with its receptor results in alkalinization of soybean suspension cell media which can be utilized to analyze the kinetics of receptor binding. Substitutions of alanine at each of the 12 amino acid positions revealed that the amino acids at positions 10 (arginine) and 12 (histidine) were essential for activity. Both analogs were able to reduce the physiological effects of GmSubPep associated with receptor binding. Deletion of the C-terminal histidine [GmSubPep(1-11)] abolished the alkalinizing activity and this peptide was also a strong competitor for receptor binding. Deletion of N-terminal amino acids from GmSubPep caused a sequential loss of activity with no alkalinizing activity for GmSubPep(4-12). However, the N-terminal deleted peptides did not compete with GmSubPep for receptor binding. Further modifications at the arginine-10 position indicated that an ionizable proton was not essential for activity as an attenuated response was found for a citrulline substitution. Substitution of the histidine-12 with methylated histidine at position N-1 of the imidazole group abolished activity, whereas substitution at N-3 was completely active, indicating that the N-3 analog retains important receptor binding properties. This study indicates that the extreme C-terminal of GmSubPep has important signal transduction properties while the C-terminal is essential for receptor interaction. PMID- 20833218 TI - mRNA expression of corticotropin-releasing factor and urocortin 1 after restraint and foot shock together with alprazolam administration. AB - Corticotropin-releasing factor (CRF) is expressed in the paraventricular nucleus of the hypothalamus (PVN), and act centrally to provoke stress-like autonomic and behavioral responses. Urocortins 1-3 are additional ligands to the CRF receptors 1 and 2. Ucn 1 neurons are primarily concentrated in the Edinger-Westphal (EW) nucleus and also have been associated with stress responses. It is also known that UCN 1 respond in different ways depending on the stressor presented. Benzodiazepines can act via the CRF peptidergic system and chronic administration of alprazolam does not interfere with CRF mRNA expression in the PVN, but significantly increase Ucn 1 mRNA expression in the EW. The aim of our study was to investigate the relationship between different stressor stimuli, foot shock (FS) and restraint (R), and the mRNA expression of CRF and Ucn 1 in the PVN and EW using alprazolam (A). We employed fos activation and in situ hybridization. Restraint group presented increased fos-ir and CRF mRNA expression in the PVN compared to FS group. The stress responses of R group were prevented by A. In the EW, fos-ir was higher in the FS group than in the R group, whereas Ucn 1 mRNA expression was higher in the R group than in the FS group. Alprazolam significantly increased fos-ir and Ucn 1 mRNA expression in both groups. Our results show that PVN and EW respond in different ways to the same stressors. Furthermore, EW of stressed animals replies in a complementary way comparing to PVN with the use of Alprazolam. PMID- 20833219 TI - Plasma levels of kisspeptins in postmenopausal Chinese women do not show substantial elevation. AB - The menopause, defined as the permanent cessation of menstruation resulting from ovarian failure, is characterized by elevated levels of serum gonadotropins. Recent studies have demonstrated that the gonadotropin hypersecretion in postmenopausal women is secondary to increase of KiSS-1 mRNA from the hypothalamus neurons, which encoded kisspeptin peptides. The present study was designed to determine whether plasma kisspeptins levels are altered in postmenopausal women. Blood samples were taken from 145 postmenopausal women, 35 young women and 30 pregnant women control in the first trimester. The plasma concentration of kisspeptins, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) was measured using immunoassay kits. Results indicated that plasma kisspeptins levels in postmenopausal women had higher than those in young women (5.25+/-0.36; 4.48+/-0.34 pmol/L), but no significant difference was found between the two groups (p=0.179). Plasma FSH and LH levels were significantly higher in postmenopausal women (124.67+/-12.78, 57.14+/-3.57 mIu/mL) than those in young women (9.23+/-2.78, 7.56+/-2.71 mIu/mL, p<0.001). However, Plasma kisspeptins levels were not significantly correlated to FSH and LH in postmenopausal women (r=-0.23, 0.324; p=0.927, 0.176, respectively), and also there was no any correlation between plasma kisspeptins and E2 in postmenopausal women (r=-0.065; p=0.792). Collectively, there was no significant difference in plasma kisspeptins levels between postmenopausal and young women. Our result suggested that kisspeptins' role during menopause might mainly act in central rather than peripheral system and it could not be currently used as a clinical marker for menopause. PMID- 20833221 TI - Impact of global cerebral ischemia on K+ channel expression and membrane properties of glial cells in the rat hippocampus. AB - Astrocytes and NG2 glia respond to CNS injury by the formation of a glial scar. Since the changes in K(+) currents in astrocytes and NG2 glia that accompany glial scar formation might influence tissue outcome by altering K(+) ion homeostasis, we aimed to characterize the changes in K(+) currents in hippocampal astrocytes and NG2 glia during an extended time window of reperfusion after ischemic injury. Global cerebral ischemia was induced in adult rats by bilateral, 15-min common carotid artery occlusion combined with low-pressure oxygen ventilation. Using the patch-clamp technique, we investigated the membrane properties of hippocampal astrocytes and NG2 glia in situ 2 hours, 6 hours, 1 day, 3 days, 7 days or 5 weeks after ischemia. Astrocytes in the CA1 region of the hippocampus progressively depolarized starting 3 days after ischemia, which coincided with decreased Kir4.1 protein expression in the gliotic tissue. Other K(+) channels described previously in astrocytes, such as Kir2.1, Kir5.1 and TREK1, did not show any changes in their protein content in the hippocampus after ischemia; however, their expression switched from neurons to reactive astrocytes, as visualized by immunohistochemistry. NG2 glia displayed increased input resistance, decreased membrane capacitance, increased delayed outwardly rectifying and A-type K(+) currents and decreased inward K(+) currents 3 days after ischemia, accompanied by their proliferation. Our results show that the membrane properties of astrocytes after ischemia undergo complex alterations, which might profoundly influence the maintenance of K(+) homeostasis in the damaged tissue, while NG2 glia display membrane currents typical of proliferating cells. PMID- 20833220 TI - gamma2-Melanocyte stimulation hormone (gamma2-MSH) truncation studies results in the cautionary note that gamma2-MSH is not selective for the mouse MC3R over the mouse MC5R. AB - The melanocortin system has been implicated in a multitude of physiological pathways including obesity, satiety, energy homeostasis, sexual behavior, pigmentation, sodium regulation, hypertension, and many others. Based upon studies of the endogenous melanocortin receptor agonists at the cloned human melanocortin receptor proteins, it was concluded that the gamma-MSH related agonist ligands are selective for the MC3 versus the MC4 and MC5 receptors. In attempts to understand and identify the specific amino acids of gamma2-MSH important for MC3R selectivity, we have performed N- and C-terminal truncation studies and pharmacologically characterized twenty-eight ligands at the mouse MC1 and MC3-5 melanocortin receptors. The C-terminal Trp-Asp9-Arg10-Phe11 residues are important for nM potency at the mMC3R and the Arg7-Trp8 residues are important for mMC5R nM potency. We observed the unanticipated results that several of the C-terminal truncated analogs possessed nM agonist potency at the mMC3 and mMC5Rs which lead us to perform a comparative side-by-side study of the mouse and human MC5R. These data resulted in MUM gamma2-MSH analog potency at the hMC5R, consistent with previous reports, however at the mMC5R, nM gamma2-MSH analog potency was observed. Thus, these data support the hypothesis of important species specific differences in gamma-MSH related ligand potency at the rodent versus human MC5R subtype that is critical for the interpretation of in vivo rodent physiological studies. These results prompted us to examine the affects of a peripherally administered melanocortin agonist on hypothalamic gene expression levels of the MC3R, MC4R, and MC5R. The super potent non-selective NDP-MSH agonist was administered i.p. and resulted in significantly decreased levels of mMC3R and mMC5R hypothalamic mRNA versus saline control. These data provide for the first time data demonstrating peripherally administered NDP-MSH can modify hypothalamic melanocortin receptor expression levels. PMID- 20833222 TI - Intact glucosinolates modulate hepatic cytochrome P450 and phase II conjugation activities and may contribute directly to the chemopreventive activity of cruciferous vegetables. AB - The currently accepted view is that the chemopreventive activity of glucosinolates is exclusively mediated by their degradation products, such as isothiocyanates. In the present study, evidence is presented for the first time that intact glucosinolates can modulate carcinogen-metabolising enzyme systems. The glucosinolates glucoraphanin and glucoerucin were isolated from cruciferous vegetables and incubated with precision-cut rat liver slices. Both glucosinolates elevated the O-dealkylations of methoxy- and ethoxyresorufin, markers for CYP1 activity; supplementation of the incubation medium with myrosinase, the enzyme that converts glucosinolates to their corresponding isothiocyanates, abolished these effects. Moreover, both glucoerucin and glucoraphanin increased the apoprotein levels of microsomal CYP1A1, CYP1A2 and CYP1B1. At higher concentrations, both glucosinolates enhanced quinone reductase activity, whereas glucoraphanin also elevated glutathione S-transferase; in this instance, however, supplementation of the incubation medium with myrosinase exacerbated the inductive effect. Finally, both glucosinolates increased modestly cytosolic quinone reductase, GSTalpha and GSTMU protein levels, which became more pronounced when myrosinase was added to the incubations with the glucosinolate. It may be inferred that intact glucosinolates can modulate the activity of hepatic carcinogen-metabolising enzyme systems and this is likely to impact on the chemopreventive activity linked to cruciferous vegetable consumption. PMID- 20833223 TI - Memory related dysregulation of hippocampal function in major depressive disorder. AB - Hippocampal abnormalities have frequently been associated with major depressive disorder (MDD), however evidence of a functional hippocampal deficit has remained illusive. Here, functional magnetic resonance imaging (fMRI) is employed in conjunction with an associative memory paradigm to investigate functional irregularities of the hippocampus during the encoding process. The use of a focussed analytical approach and a behavioural task targeted to hippocampal function confirmed the hypothesis that the normal modulation of hippocampal activation by encoding strength is dysregulated in MDD. Further analysis demonstrated that this impairment of function was specific to the hippocampus. A double dissociation between groups in the hippocampus and intraparietal sulcus indicates that compensatory mechanisms may exist. These results show that MDD is associated with a dysregulation of hippocampal function that cannot be explained in terms of overall brain state or motivational stance and provides an important link between memory impairments and hippocampal changes in MDD. PMID- 20833224 TI - Glucocorticoids and circadian clock control of cell proliferation: at the interface between three dynamic systems. AB - The circadian clock, an endogenous timekeeper that regulates daily rhythms of physiology, also influences the dynamic release of glucocorticoids. The release of glucocorticoids is characteristically pulsatile and is further modulated in a circadian fashion. A circadian pacemaker in the brain regulates daily rhythms of hypothalamic-pituitary-adrenal axis and autonomic nervous system activity that both influence glucocorticoid release from the adrenal gland. This systemic regulation interacts with rhythms in the adrenal gland itself that are driven by its own circadian clock. One function of glucocorticoids is the regulation of cell proliferation. Depending on the tissue, this can involve both negative and positive regulation of a variety of processes, including cell differentiation and cell death. Cell proliferation is also under circadian control, and recent evidence suggests that this regulation may involve glucocorticoid signalling. Here, we review the dynamic processes participating in the interplay between the circadian clock, glucocorticoids and cell proliferation, and we discuss the potential implications for therapy. PMID- 20833225 TI - Alpha-conotoxin ImI disrupts central control of swimming in the medicinal leech. AB - Medicinal leeches (Hirudo spp.) swim using a metachronal, front-to-back undulation. The behavior is generated by central pattern generators (CPGs) distributed along the animal's midbody ganglia and is coordinated by both central and peripheral mechanisms. Here we report that a component of the venom of Conus imperialis, alpha-conotoxin ImI, known to block nicotinic acetyl-choline receptors in other species, disrupts swimming. Leeches injected with the toxin swam in circles with exaggerated dorsoventral bends and reduced forward velocity. Fictive swimming in isolated nerve cords was even more strongly disrupted, indicating that the toxin targets the CPGs and central coordination, while peripheral coordination partially rescues the behavior in intact animals. PMID- 20833226 TI - Frontal EEG asymmetry: the effects of sustained walking in the elderly. AB - Numerous studies have been made in recent years addressing the effect of physical exercise on brain cortical activity and changes in mood. This research, however, was restricted to inadequate study designs in the elderly. In these times of an aging society, with the daily increasing interest in the benefits of physical exercise, investigations of the interrelationships of psycho-physiological elements of physical exercise seem to be progressively necessary. Using the model of frontal asymmetry, we hypothesized, that physical exercise by elderly persons at a self-selected pace increases left frontal alpha activity and is associated with a shift in mood to the positive. An electroencephalography (EEG) on two frontal positions (Fp1, Fp2) was made before and after walking at a self-selected pace for 45-60min and the state of the respective moods noted. The equation (right-left)/(right+left) was used to calculate frontal asymmetry as a marker of approach-related emotions. Key findings after walking were (1) a shift of the alpha-1 (7.5-10.0Hz) activation towards the right frontal brain areas as well as (2) an improvement in mood. Based on the frontal asymmetry model, an increase in the alpha-1 activation (p<0.05) might be associated with approach-related emotions. In conclusion, there is reason to believe that physical exercise programmes, as commonly practiced by the elderly, have beneficial effects on their general feeling of well-being. We were able to demonstrate this in this pilot study by applying only a comparatively simple and economically viable method. PMID- 20833227 TI - Electrophysiological correlates of brand names. AB - EEG coherence has been used extensively in the investigation of language processing of different words categories. In contrast, relatively less is known about EEG coherence pattern of processing brand names. The present study aimed to investigate EEG coherence pattern associated with brand names in English and Chinese. EEG coherence of 32 healthy normal participants during 4 reading conditions, including concrete English words, concrete Chinese characters, English brand names and their translated Chinese brand names, were computed and compared. Regardless whether it was in English or Chinese, brand names were generally associated with higher intrahemispheric beta coherence in both the left and right hemispheres than concrete words or characters. Compared to English brand names, Chinese brand names demonstrated increased interhemispheric theta coherence in the frontal and temporal cortical regions. These results suggest that brand names tend to be processed through semantic routes. Similar to proper names and nonwords, they are represented in the lexical systems of both hemispheres. In addition, English and Chinese brand names are processed similarly at the semantic level and the difference in EEG coherence patterns associated with English and Chinese brand names is more likely due to phonological and orthographic processing that are associated with English and Chinese, respectively. PMID- 20833228 TI - Lack of the cerebral peduncle involvement in a series of adult supratentorial AVM: a diffusion tensor imaging study. AB - Congenital as arteriovenous malformation(AVM) is, most patients with AVM would be asymptomatic until adults. During the past 2 years, 23 cases of adult supratentorial AVM patients had DTI after admission. The region of interest was placed in the cerebral peduncle. Their FA value and fiber number was compared with those of cavernous malformation (CM) and tumor (glioma and meningioma). In the AVM group, there was no significant difference in FA of the cerebral peduncle (ipsilateral 0.758+/-0.055 versus contralateral 0.755+/-0.049; P>0.05) and fiber number (319.6+/-82.9 versus 304.7+/-89.1; P>0.05). In the CM group, FA of the cerebral peduncle on ipsilateral side (0.711+/-0.092) was significantly lower than that of contralateral side (0.768+/-0.043) (P<0.01). Similar result was in fiber number of the CM group (251+/-82.1 versus 307.3+/-77.0; P<0.05). In tumor group, FA of ipsilateral side (0.713+/-0.084) was lower than that of contralateral (0.751+/-0.052) without significant difference. There was no significant difference in fiber number between ipsilateral and contralateral sides in the tumor group (308.9+/-112.4 versus 287.9+/-62.4). Unlike non-AVM lesions (CM and tumor), FA value and fiber number of the ipsilateral cerebral peduncle is less influenced in the AVM group. The lack of the cerebral peduncle involvement indicates that there is plasticity of white matter in AVM. PMID- 20833229 TI - Impulse inhibition in people with Internet addiction disorder: electrophysiological evidence from a Go/NoGo study. AB - We investigated response inhibition in people with Internet addiction disorder (IAD) by recording event-related brain potentials during a Go/NoGo task. Twelve IAD-afflicted and 12 normal university students participated in the study. Results show that the IAD group exhibited lower NoGo-N2 amplitude, higher NoGo-P3 amplitude, and longer NoGo-P3 peak latency than the normal group. The results also suggest that the IAD students had lower activation in the conflict detection stage than the normal group; thus, they had to engage in more cognitive endeavors to complete the inhibition task in the late stage. In addition, the IAD students showed less efficiency in information processing and lower impulse control than their normal peers. PMID- 20833230 TI - Ovarian steroid regulation of the midbrain corticotropin releasing factor and urocortin systems in macaques. AB - A significant number of postmenopausal women report increased anxiety and vulnerability to stress, which has been linked to decreased secretion of ovarian steroids. Communication between the serotonin system and the corticotropin releasing factor (CRF) system determines stress sensitivity or resilience. This study examines the effects of the ovarian steroids, estradiol (E) and progesterone (P) on the CRF system components that impact serotonin neurons in the midbrain of nonhuman primates. Ovariectomized rhesus macaques were treated with placebo, E alone for 1 month, or E supplemented with P for the last 2 weeks. Quantitative (q)RT-PCR and immunocytochemistry were employed. E+/-P treatment decreased CRF-R1 and increased CRF-R2 gene expression in hemi-midbrain blocks and in laser captured serotonin neurons. Also in hemi-midbrains, E treatment increased urocortin 1 (UCN1) and CRFBP gene expression, but supplemental P treatment reversed these effects. E+/-P decreased CRF fiber density in the dorsal, interfascicular and median raphe nuclei and decreased CRF-R1 immunostaining in the dorsal raphe. E increased CRF-R2 immunostaining in the dorsal and median raphe. E+/-P increased UCN1 immunostaining in the cell bodies and increased UCN1 fiber density in the caudal linear nucleus. Estrogen receptor beta (ERbeta), but not ERalpha was detected in the nucleus of UCN1-positive neurons. While the mechanism of ovarian hormone regulation of the midbrain CRF system requires further investigation, these studies clearly demonstrate another pathway by which ovarian hormones may have positive effects on anxiety and mood regulation. PMID- 20833231 TI - Remyelination after cuprizone induced demyelination is accelerated in mice deficient in the polysialic acid synthesizing enzyme St8siaIV. AB - Polysialic acid (PSA) is a carbohydrate polymer added post-translationally on the neural cell adhesion molecule (NCAM) affecting its adhesion properties. It has been suggested that the presence of PSA in demyelinated lesions in multiple sclerosis could prevent axon-glia interactions inhibiting spontaneous remyelination. The enzyme St8siaIV is one of the two polysialyltransferases responsible for PSA synthesis, and it is predominantly active during adult life. Here we treated 8-10-weeks old St8siaIV deficient and wild-type mice for 5 weeks with cuprizone, which is a reliable model for de- and remyelination in the corpus callosum and cortex. Developmental myelination of the St8siaIV knock-out mice was not disturbed and adult mice showed normal myelin protein expression. Demyelination did not differ between transgenic and wild-type mice but early myelin protein re-expression and thus remyelination were accelerated in St8siaIV knock-out mice during the first week after withdrawal of the toxin. This was mainly due to enhanced oligodendrocyte precursor cells (OPC) differentiation and to a lesser extent to OPC recruitment. These data are proof of principle that PSA expression interferes at least to some extent with remyelination in vivo. PMID- 20833232 TI - Developmental changes in brain connectivity assessed using the sleep EEG. AB - Adolescence represents a time of significant cortical restructuring. Current theories posit that during this period connections between frequently utilized neural networks are strengthened while underutilized synaptic connections are discarded. The aim of the present study was to examine the developmental evolution of connectivity between brain regions using the sleep EEG. All-night sleep EEG recordings in two longitudinal cohorts (children and teens) followed at 1.5-3 year intervals and one cross-sectional cohort (adults) were analyzed. The children and teen cohorts were 9/10 and 15/16 years at the initial assessment; ages of the adults were 20 to 23 years. Intrahemispheric, interhemispheric, and diagonal coherence was measured between all six possible pairings of two central (C3/A2 and C4/A1) and two occipital (O2/A1 and O1/A2) derivations during slow wave, stage 2, and, REM sleep. Within-subjects analyses were performed for the children and teen cohorts, and a linear regression analysis was performed across every assessment of all cohorts. Within-subject analyses revealed a maturational increase in coherence for both age cohorts, though the frequencies, sleep states, and regions differed between cohorts. Regression analysis across all age cohorts showed an overall linear increase in left and right intrahemispheric coherence for all sleep states across frequencies. Furthermore, coherence between diagonal electrode pairs also increased in a linear manner for stage 2 and REM sleep. No age-related trend was found in interhemispheric coherence. Our results indicate that sleep EEG coherence increases with age and that these increases are confined to specific brain regions. This analysis highlights the utility of the sleep EEG to measure developmental changes in brain maturation. PMID- 20833233 TI - Reducing chimera formation during PCR amplification to ensure accurate genotyping. AB - Measurements of population diversity are fundamental to the reconstruction of the evolutionary and epidemiological history of organisms. Commonly used protocols to measure population diversity using the polymerase chain reaction (PCR) are prone to the introduction of artificial chimeras. These are often difficult to detect and can confound the correct interpretation of results due to the false generation of recombinants when the underlying DNA sample contains multiple distinct templates. This study presents a standardised procedure to suppress the formation of artificial chimeras during PCR amplification. The solution is based on the accurate determination of the efficiency and end point of the log-linear phase of a PCR. This procedure will facilitate the generation of data sets that more accurately reflect the underlying population diversity rather than artifacts introduced by the process itself. PMID- 20833234 TI - Ocular discomfort by environmental and personal risk factors altering the precorneal tear film. AB - Ocular discomfort (e.g. burning, dry and itching eyes) is among top 2 symptoms in office environments. The ophthalmological explanation is aqueous-deficient dry eye and evaporative dry eye and exposure to allergens, while indoor air pollutants causing chemesthesis generally is the rationale of the indoor environmental community. Review of salient environmental, occupational, and personal risk factors, that alter the precorneal tear film (PTF), reveals at least three mechanisms resulting in ocular discomfort. First, the PTF structure is altered by a physical process that increases the emission rate of aqua loss resulting in hyperosmolarity, gland dysfunctions, and associated discomfort. Second, the structural composition of the outermost lipid layer of the PTF is altered by aggressive aerosols and combustion products, both indoors and outdoors, that facilitate loss of aqua, and possibly chemesthesis. Third, strong sensory irritating pollutants cause chemesthesis by trigeminal stimulation. In general, organic and inorganic indoor air pollutant concentrations are too low causing chemesthesis, but the odor may cause reported discomfort. The total risk of ocular discomfort is exacerbated by physical alteration of the PTF by visual tasking and climate conditions (low humidity, high temperature, and draft); further, personal factors like age, gender and use of certain medication also influence the overall stability of the PTF. PMID- 20833235 TI - Effects of rooibos (Aspalathus linearis) on oxidative stress and biochemical parameters in adults at risk for cardiovascular disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In South Africa, the plant Aspalathus linearis (Brum.f) Dahlg. (Fabaceae) is traditionally used as a "tea" referred to as rooibos or redbush. This plant has been listed as a medicinal plant based mostly on anecdotal evidence. AIMS OF THE STUDY: Despite a long history of traditional use in South Africa, very little scientific data are available from controlled clinical trials confirming its popular use. The aim of the present study was to investigate the effect of rooibos on biochemical and oxidative stress parameters in adults at risk for cardiovascular disease. MATERIALS AND METHODS: After a washout period of 2 weeks, 40 volunteers consumed six cups of fermented/traditional rooibos daily for 6 weeks, followed by a control period. Blood biochemical parameters indicative of antioxidant activity and content (total polyphenols), lipid peroxidation (conjugated dienes - CDs, thiobarbituric acid reactive substances - TBARS), redox status (total glutathione - tGSH, ratio of reduced to oxidized glutathione - GSH:GSSG), lipid profile (total cholesterol, low density lipoprotein - LDL and high density lipoprotein - HDL cholesterol and triacylglycerol levels) and liver and kidney function were measured at the end of each study period. RESULTS: Plasma antioxidant capacity was not altered, but plasma total polyphenol levels increased significantly after rooibos consumption compared with the control levels (from 79.8+/-16.9 mg/L to 89.8+/-14.1 mg/L). Significant decreases in plasma markers of lipid peroxidation were found after rooibos consumption, as reported by levels of CDs (167.3+/-29.5 nmol/mL vs. 108.8+/-20.1 nmol/mL) and TBARS (1.9+/-0.6 MUmol/L vs. 0.9+/-0.3 MUmol/L). Reduced glutathione (797+/-238 MUmol/L vs. 1082+/-140 MUmol/L) and the GSH:GSSG ratio (41+/-14 vs. 76+/-17) were both significantly increased after consumption of rooibos. The lipid profiles showed that rooibos consumption, compared with the control values, significantly decreased serum LDL-cholesterol (4.6+/-1.3 mmol/L vs. 3.9+/-0.7 mmol/L) and triacylglycerols (1.7+/-0.8 mmol/L vs. 1.2+/-0.7 mmol/L), while HDL-cholesterol (0.9+/-0.1 mmol/L vs. 1.2+/-0.2 mmol/L) was significantly increased. CONCLUSION: Confirming its popular use, consumption of fermented, traditional rooibos significantly improved the lipid profile as well as redox status, both relevant to heart disease, in adults at risk for developing cardiovascular disease. PMID- 20833236 TI - Anti-diabetic activity and stability study of the formulated leaf extract of Zizyphus spina-christi (L.) Willd with the influence of seasonal variation. AB - AIM OF THE STUDY: The present study aimed to evaluate the anti-diabetic activity of Zizyphus spina-christi leaf extract (200 mg/kg b.w.), plain and formulated in STZ-diabetic rats. Percentage yield of extracts, marker yield (christinin-A) and antihyperglycemic potencies, depending on seasonal variation were investigated. The chemical stability, study of storage conditions, shelf life T90 prediction of both plain extract and formulated soft gelatin capsules by accelerated studies were studied. MATERIAL AND METHODS: Changes in all studied parameters after oral administration of Z. spina-christi extract for 28 days were reported. Seasonal variation affecting yield and activities was studied. Flavonoid contents were HPLC evaluated. The capsules were stored at 30, 40 and 50 degrees C [75% relative humidity] and their residual christinin-A content was assayed for 24 weeks. Christinin-A chemical degradation was monitored by HPLC stability indicating method previously validated. Possible physical examination was checked by dissolution test of the content of the capsules using dissolution tester USP XXIV. RESULT: Oral administration of Z. spina-christi leaf extract, plain and formulated for 28 days reduced blood glucose level with significant increase in serum insulin and C-peptide levels. Marked elevation in total antioxidant capacity with normalization of percentage of glycated hemoglobin (HbA1C%) was reported. Moreover, they succeeded to reduce the elevated blood lactate level and to elevate the reduced blood pyruvate content of diabetic rats. In line with amelioration of the diabetic state, Zizyphus extract, plain and formulated restored liver and muscle glycogen content together with significant decrease of hepatic glucose-6-phosphatase and increase in glucose-6-phosphate dehydrogenase activities. In vitro experiments showed a dose-dependent inhibitory activity of Zizyphus extract against alpha-amylase enzyme with (IC(50)) at 0.3 mg/ml. Such finding has been supported by the in vivo suppression of starch digestion and absorption by Zizyphus extract in normal rats. The flavonoids content of the formulated leaves (collected during June 2009) were found to be 11.5 MUg/g of the dry plant material (expressed as quercetin) and 58.8 MUg/g of the dry plant material (expressed as rutin). The shelf life for the capsules stored at 30, 40 and 50 degrees C [75% relative humidity] for plain and formulated extract were calculated to be 66.90 and 70.74 weeks, respectively. CONCLUSION: The current work revealed that Z. spina-christi leaf extract, plain and formulated, improved glucose utilization in diabetic rats by increasing insulin secretion which may be due to both saponin and polyphenols content and controlling hyperglycemia through attenuation of meal-derived glucose absorption that might be attributed to the total polyphenols. Studies showed that leaves are preferably collected from June to October. Finally, the release followed the Higuchi kinetic model, indicating diffusion dominated drug release with no drop in the dissolution values throughout the test period. PMID- 20833237 TI - (Re-)activation of neurons in aging and dementia: lessons from the hypothalamus. AB - Our hypothesis is that there is 'wear and tear' in the brain, which is the basis of the process of aging, but that stimulation of brain function may slow down brain aging and diminish the risk for neurodegenerative diseases such as Alzheimer's disease (AD), possibly by activating repair mechanisms. Evidence supporting this hypothesis is presented in this review. During normal aging and in AD, cell loss is not as prominent a phenomenon as is often presumed. In fact, unaltered neuronal numbers have been reported in many brain areas in AD, e.g. in the nucleus basalis of Meynert (NBM) where the number of large neurons decreases while that of small neurons increases. Decreased neuronal activity is an essential characteristic of AD, and a substantial decrease of cerebral glucose metabolism may even precede cognitive impairments. Some hypothalamic neurons remain intact and active during the process of aging, others become even hyperactive, which may lead to disorders. Arginine vasopressin (AVP) levels were found to be higher in the elderly than in young subjects. There is an age related, sex-dependent activation of the AVP neurons in the supraoptic nucleus (SON) and in the paraventricular nucleus (PVN), which may be the basis of analogous changes in the prevalence of hypertension and hyponatraemia in the elderly. No significant functional loss of magnocellular hypothalamic neurosecretory neurons were found in the SON or PVN in AD. The activity of the corticotrophin releasing hormone (CRH) neurons in the hypothalamic PVN is the basis for the activity of the hypothalamo-pituitary-adrenal (HPA) axis, which is activated during aging in a sex-dependent way, and even more activated in AD. The activated HPA axis is a risk for depression. Environmental stimulation increases brain reserve. An increase in time spent on intellectual activities was associated with a significant decrease in probability to get AD, and occupation has even a stronger indication of diminished risk for dementia. A series of observations showed that a dysfunctional clock may underlie the disordered rhythms in AD. Additional bright light improved the rest-activity rhythms, while giving bright light and/or melatonin to AD patients ameliorated the progression of cognitive and noncognitive symptoms. This implies that neurons affected by AD can still be reactivated if the right stimuli are applied. Unknown diffusible factors from the neural stem cells improve the survival of aged and degenerating neurons in postmortem human brain slice cultures. Gene therapy with nerve growth factor aimed at the NBM showed metabolic activation of various brain regions. A microarray study of the prefrontal cortex in the course of AD revealed an increased expression of genes related to synaptic activity and changes in plasticity during the very early pre-symptomatic stages, which is proposed to represent a coping mechanism against increased soluble beta-amyloid levels. In brief, these examples of the 'use it or lose it' principle during the course of aging or AD now provide novel targets for the development of therapeutic strategies aiming at the prevention and treatment of AD. PMID- 20833238 TI - Telomere/telomerase dynamics within the human immune system: effect of chronic infection and stress. AB - Aging of the immune system is a major factor responsible for the increased severity of infections, reduced responses to vaccines, and higher cancer incidence in the elderly. A major category of stressors that contribute to the alterations within the T lymphocyte compartment is the family of herpes viruses. These viruses, usually acquired early in life, persist for many decades and drive certain T cells to the end stage of replicative senescence, which is characterized by a variety of phenotypic and functional changes, including altered cytokine profile, resistance to apoptosis, and shortened telomeres. Indeed, high proportions of senescent CD8 (cytotoxic) T lymphocytess are associated with latent cytomegalovirus (CMV) infection in the elderly, and are part of a cluster of immune biomarkers that are associated with early mortality. Similar cells accumulate at younger ages in persons chronically infected with HIV 1. In addition to persistent viral infection, psychological stress as well as oxidative stress can also contribute to the generation of senescent dysfunctional T lymphocytes. Strategies such as cell culture manipulation of replicative senescence, as well as lifestyle and stress reduction techniques are discussed in terms of possible approaches to enhance immune function in older persons. This review highlights the importance of using humans in studies on immunosenescence and telomere/telomerase dynamics, since model organisms employed in other facets of aging research are not subject to the particular factors that cause the striking age-related reconfiguration of the human immune system. PMID- 20833239 TI - Early-life origin of adult disease: evidence from natural experiments. AB - Until the present time, disease susceptibility was believed to be determined solely by the genetic information carried in the DNA sequence. In recent years, however, it has become clear that epigenetic rearrangements play an equally essential role in the disease development and that this process, particularly at key developmental stages, is very susceptible to environmental modulations. The extensive studies, both human and animal, have shown that early-life environment is probably the most important causal component in the etiology of some diseases including cancer as well as metabolic and cardiovascular disorders. This review considers the natural experiment-based evidence regarding the developmental origin of human adult disease. PMID- 20833240 TI - HPA axis responsiveness to stress: implications for healthy aging. AB - The major neuroendocrine response mediating stress adaptation is activation of the hypothalamic pituitary adrenal axis, with stimulation of corticotropin releasing hormone (CRH) and vasopressin (VP) from parvocellular neurons of the hypothalamic paraventricular nucleus, leading to stimulation of pituitary ACTH secretion and increases in glucocorticoid secretion from the adrenal cortex. Basal production and transient increases during stress of glucocorticoids and its hypothalamic regulators are essential for neuronal plasticity and normal brain function. While activation of the HPA axis is essential for survival during stress, chronic exposure to stress hormones can predispose to psychological, metabolic and immune alterations. Thus, prompt termination of the stress response is essential to prevent negative effects of inappropriate levels of CRH and glucocorticoids. This review addresses the regulation of HPA axis activity with emphasis on the mechanisms of termination of CRH transcription, which is a critical step in this process. In addition, the actions by which glucocorticoids, CRH and VP can affect the aging process will be discussed. PMID- 20833241 TI - Perinatal effect of methamphetamine on nociception in adult Wistar rats. AB - Methamphetamine is a psychostimulant drug which causes the release of monoamine neurotransmitters. Although drugs of abuse are known to have analgesic effects, there is a lack of evidence regarding the effect of prenatal exposure to methamphetamine on nociception in adulthood. Adult Wistar rats whose mothers had received daily exposure to methamphetamine (5 mg/kg; s.c.) or saline, during gestation or gestation and lactation periods, were examined for: (1) gender differences in nociception; (2) an association between nociception and gross motor behavior in the plantar test; (3) effects of cross-fostering on nociception; and (4) analgesic effects of an acute injection of methamphetamine (1 mg/kg s.c.). Nociception was tested using the plantar test on postnatal days 85-90. Prenatal methamphetamine increased sensitivity to pain on forelimbs (p<0.0001) and hind limbs (p<0.05) in females only. Prenatal methamphetamine treated male rats fostered by adoptive injection stressed mothers had higher sensitivity to pain than prenatally injection stressed rats fostered by methamphetamine treated mothers (p<0.05). Acute methamphetamine induced analgesia faster in prenatally methamphetamine exposed rats than in controls. In all groups, analgesia increased in the cranio-caudal direction (p<0.0001). From our behavioral data it can be concluded that exposure to methamphetamine during the prenatal period completely dissociates the relationship between nociception and intensity of overall behavior observed in intact animals in adulthood. Thus, our results indicate that perinatal exposure to psychostimulants may have long-term impact on several functions related to dopaminergic system. PMID- 20833243 TI - Influence of age on reactivity to diverse emotional challenges in low- and high anxiety rats. AB - Studies have revealed that the extent of reactivity of high-anxiety rats to diverse challenges is different than low-anxiety rats and have provided important insights into the psychopathology of anxiety. Various factors intervene to allow defensive mechanisms to react to diverse threatening challenges, including ontogeny and the nature of the emotional challenge (e.g., conditioned vs. unconditioned). The present study investigated the extent to which a particular type of fear extrapolates to other emotional responses to diverse threatening challenges. Groups of 30- and 60-day-old rats were assigned to low freezing behavior (LFB) and high freezing behavior (HFB) groups using the contextual fear conditioning paradigm and subjected to either the fear-potentiated startle (FPS) test, novelty-induced ultrasound vocalizations (USVs) or elevated plus-maze (EPM) tests. At 30 days of age, HFB rats exhibited greater FPS than LFB rats. In contrast, prior selection of HFB and LFB did not affect the performance of 30-day old animals in the EPM and novelty-induced USVs. Sixty-day-old animals exhibited a performance deficit in all three tests. These data suggest that the performance of young rats in animal models of anxiety parallels their selection as LFB and HFB in the contextual fear conditioning paradigm. However, the increased fear like behavior exhibited by the 60-day-old HFB rats may elicit performance deficits in conditioned and unconditioned fear tests. These results suggest that the interaction between hyperanxiety and age may cause a performance deficit despite the animals' increased fear-like behavior when facing emotional challenges, thus resembling psychiatric patients in many respects. PMID- 20833242 TI - Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. AB - Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders. PMID- 20833244 TI - Three phases of DiGeorge/22q11 deletion syndrome pathogenesis during brain development: patterning, proliferation, and mitochondrial functions of 22q11 genes. AB - DiGeorge, or 22q11 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by deletion of a minimum of 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one, some, or all of these genes--particularly during development. Nevertheless, the normal functions of 22q11 genes in the embryo or neonate, and their contribution to developmental pathogenesis that must underlie 22q11DS are not well understood. Our data suggests that a substantial number of 22q11 genes act specifically and in concert to mediate early morphogenetic interactions and subsequent cellular differentiation at phenotypically compromised sites--the limbs, heart, face and forebrain. When dosage of a broad set of these genes is diminished, early morphogenesis is altered, and initial 22q11DS phenotypes are established. Thereafter, functionally similar subsets of 22q11 genes--especially those that influence the cell cycle or mitochondrial function--remain expressed, particularly in the developing cerebral cortex, to regulate neurogenesis and synaptic development. When dosage of these genes is diminished, numbers, placement and connectivity of neurons and circuits essential for normal behavior may be disrupted. Such disruptions likely contribute to vulnerability for schizophrenia, autism, or attention deficit/hyperactivity disorder seen in most 22q11DS patients. PMID- 20833245 TI - Virological and clinico-pathological features of orf virus infection in experimentally infected rabbits and mice. AB - Many aspects of the biology of orf virus (ORFV) infection remain poorly understood and attempts to establish animal models have yielded conflicting and non-reproducible results. We herein describe the characterization of ORFV infection and disease in rabbits and mice. A protocol of intradermal inoculation was employed to inoculate 10(8.5)TCID50/mL of ORFV strain IA-82 in the skin of ears, of the back and labial commissures. All inoculated rabbits presented a clinical course characterized by erythema, macules, papules/vesicles or pustules that eventually dried originating scabs. Local signs started around days 3 and 4 post-inoculation (pi) and lasted 3-10 days. Virus was recovered from lesions between days 2 and 14pi. Histological examination of lesions revealed focal proliferative dermatitis with ballooning degeneration and eosinophilic intracytoplasmic inclusion bodies in keratinocytes, histological hallmarks of contagious ecthyma in sheep. A similar, albeit milder clinical course occurred in 5/10 inoculated mice; virus was recovered from lesions from three animals. Inoculated lambs - used as controls - developed severe lesions of contagious ecthyma. VN tests performed at day 28pi failed to detect neutralizing antibodies in all inoculated animals. In contrast, convalescent rabbit sera were positive by ELISA at dilutions from 100 to 400. These results show that rabbits are susceptible to ORFV infection and thus may be used to study selected aspects of ORFV biology. PMID- 20833246 TI - Interleukin (IL)-1 and IL-6 regulation of neural progenitor cell proliferation with hippocampal injury: differential regulatory pathways in the subgranular zone (SGZ) of the adolescent and mature mouse brain. AB - Current data suggests an association between elevations in interleukin 1 (IL 1)alpha, IL-1beta, and IL-6 and the proliferation of neural progenitor cells (NPCs) following brain injury. A limited amount of work implicates changes in these pro-inflammatory responses with diminished NPC proliferation observed as a function of aging. In the current study, adolescent (21day-old) and 1year-old CD 1 male mice were injected with trimethyltin (TMT, 2.3mg/kg, i.p.) to produce acute apoptosis of hippocampal dentate granule cells. In this model, fewer 5 bromo-2'-deoxyuridine (BrdU)+ NPC were observed in both naive and injured adult hippocampus as compared to the corresponding number seen in adolescent mice. At 48h post-TMT, a similar level of neuronal death was observed across ages, yet activated ameboid microglia were observed in the adolescent and hypertrophic process-bearing microglia in the adult. IL-1alpha mRNA levels were elevated in the adolescent hippocampus; IL-6 mRNA levels were elevated in the adult. In subgranular zone (SGZ) isolated by laser-capture microdissection, IL-1beta was detected but not elevated by TMT, IL-1a was elevated at both ages, while IL-6 was elevated only in the adult. Naive NPCs isolated from the hippocampus expressed transcripts for IL-1R1, IL-6Ralpha, and gp130 with significantly higher levels of IL-6Ralpha mRNA in the adult. In vitro, IL-1alpha (150pg/ml) stimulated proliferation of adolescent NPCs; IL-6 (10ng/ml) inhibited proliferation of adolescent and adult NPCs. Microarray analysis of SGZ post-TMT indicated a prominence of IL-1a/IL-1R1 signaling in the adolescent and IL-6/gp130 signaling in the adult. PMID- 20833248 TI - High-hydrostatic pressure technique is an effective method for the preparation of PVA-heparin hybrid gel. AB - To develop an antithrombotic material for preparation of small-diameter vascular graft, we describe a novel method to prepare a poly(vinyl alcohol) (PVA)-heparin hydrogels prepared by high-hydrostatic pressure (HHP, 980 MPa), which is designed for sustained release of heparin. Antithrombogenic test revealed that HHP method would not affect the antithrombin III (ATIII) activity of the released heparin. The distribution of heparin in the polymer matrix was homogeneous than freeze thawing gel, due to the fast gelling affect of PVA which takes approximately 10 min for gel formation. The formation of intra- and intermolecular hydrogen bonds between PVA chains has trapped the heparin inside, suppressing the phase separation between PVA and heparin. Furthermore, evenly distribution of heparin induced the formation of heparin and PVA molecular complex, which brought the sustained release of heparin from the PVA despite the high swelling ratio. Our results show that it is possible to prepare a PVA-heparin hybrid gel which can be applied as an effective material for an antithrombotic system without using any chemical agent. PMID- 20833249 TI - Thiolated hydroxyethylcellulose: synthesis and in vitro evaluation. AB - In recent years, thiomers have received considerable interest due to advantageous characteristics, such as improved mucoadhesive and permeation enhancing properties. Thiolated polymers, however, are characterized by an ionic charge which represents for various applications a great limitation. The aim of this study was therefore to synthesize a novel thiolated polymer not exhibiting ionizable groups. Hydroxyethylcellulose (HEC) was chosen as polymer backbone. The chemical modification was achieved by the replacement of hydroxyl groups on the carbohydrate structure with thiol moieties, using thiourea as thiolating reagent. The resulting thiolated hydroxyethylcellulose (HEC-SH) was characterized in vitro regarding its gelling properties, swelling behaviour, mucoadhesion on freshly excised porcine intestinal mucosa and permeation enhancing effect across rat intestinal mucosa. The new thiomer displayed up to 131.58 +/- 11.17 MUmol thiol groups per gram polymer, which are responsible for the observed in situ gelling capacity. The swelling behaviour and the mucoadhesive properties of tablets based on HEC-SH were 1.5-fold and 4-fold improved compared with unmodified HEC, respectively. The permeation enhancing effect of 0.5% (m/v) HEC-SH on rhodamine 123 (Rho-123) transport was 1.9-fold improved compared with buffer only. According to these results, HEC-SH seems to represent a promising tool for the development of in situ gelling, mucoadhesive delivery systems with permeation enhancing properties. PMID- 20833247 TI - Altered T cell responses in children with autism. AB - Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2-5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFalpha, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or T(H)1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and T(H)2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3(+), CD4(+) and CD8(+) T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder. PMID- 20833250 TI - Genetic variation and risk of chronic lymphocytic leukaemia. AB - Chronic lymphocytic leukaemia (CLL) is the most common form of lymphoid malignancy in Western countries, accounting for around a quarter of all leukaemias. Evidence from epidemiological and family studies have provided evidence for familial clustering of CLL compatible with inherited genetic predisposition to CLL. Direct evidence for genetic susceptibility has been provided by a recent genome wide association study of CLL which has identified common variants at 10 different loci which influence CLL risk. Here we review the current knowledge regarding the allelic architecture of susceptibility to CLL and what the currently identified risk loci are telling us regarding disease aetiology. PMID- 20833251 TI - Tuning the differentiation of periosteum-derived cartilage using biochemical and mechanical stimulations. AB - OBJECTIVE: In this study, we aim at tuning the differentiation of periosteum in an organ culture model towards cartilage, rich in collagen type II, using combinations of biochemical and mechanical stimuli. We hypothesize that addition of TGF-beta will stimulate chondrogenesis, whereas sliding indentation will enhance collagen synthesis. DESIGN: Periosteum was dissected from the tibiotarsus of 15-day-old chick embryos. Explants were embedded in between two agarose layers, and cultured without stimulation (control), with biochemical stimulation (10 ng/ml TGF-beta1), with mechanical stimulation (sliding indentation), or both biochemical and mechanical stimulations. Sliding indentation was introduced as a method to induce tensile tissue strain. Analysis included quantification of DNA, collagen and GAG content, conventional histology, and immunohistochemistry for collagen type I and II at 1 or 2 weeks of culture. RESULTS: Embedding the periosteal explants in between agarose layers induced cartilage formation, confirmed by synthesis of sGAG and collagen type II. Addition of TGF-beta1 to the culture medium did not further enhance this chondrogenic response. Applying sliding indentation only to the periosteum in between agarose layers enhanced the production of collagen type I, leading to the formation of fibrous tissue without any evidence of cartilage formation. However, when stimulated by both TGF-beta1 and sliding indentation, collagen production was still enhanced, but now collagen type II, while sGAG was found to be similar to TGF-beta1 or unloaded samples. CONCLUSIONS: The type of tissue produced by periosteal explants can be tuned by combining mechanical stimulation and soluble factors. TGF-beta1 stimulated a chondrocyte phenotype and sliding indentation stimulated collagen synthesis. Such a combination may be valuable for improvement of the quality of tissue-engineered cartilage. PMID- 20833252 TI - Endoglin differentially regulates TGF-beta-induced Smad2/3 and Smad1/5 signalling and its expression correlates with extracellular matrix production and cellular differentiation state in human chondrocytes. AB - OBJECTIVE: Transforming growth factor-beta (TGF-beta) plays a critical role in cartilage homeostasis and deregulation of its signalling is implicated in osteoarthritis (OA). TGF-beta isoforms signal through a pair of transmembrane serine/threonine kinases known as the type I and type II TGF-beta receptors. Endoglin is a TGF-beta co-receptor that binds TGF-beta with high affinity in the presence of the type II TGF-beta receptor. We have previously shown that endoglin is expressed in human chondrocytes and that it forms a complex with the TGF-beta signalling receptors. However, the functional significance of endoglin expression in chondrocytes is unknown. Our objective was to determine whether endoglin regulates TGF-beta/Smad signalling and extracellular matrix (ECM) production in human chondrocytes and whether its expression varies with chondrocyte differentiation state. METHOD: Endoglin function was determined by overexpression or antisense morpholino/siRNA knockdown of endoglin in human chondrocytes and measuring TGF-beta-induced Smad phosphorylation, transcriptional activity and ECM production. Alterations in endoglin expression levels were determined during subculture-induced dedifferentiation of human chondrocytes and in normal vs OA cartilage samples. RESULTS: Endoglin enhances TGF-beta1-induced Smad1/5 phosphorylation and inhibits TGF-beta1-induced Smad2 phosphorylation, Smad3 driven transcriptional activity and ECM production in human chondrocytes. In addition, the enhancing effect of endoglin siRNA knockdown on TGF-beta1-induced Smad3-driven transcription is reversed by ALK1 overexpression. Furthermore, endoglin levels are increased in chondrocytes following subculture-induced dedifferentiation and in OA cartilage as compared to normal cartilage. CONCLUSION: Together, our results suggest that endoglin regulates the balance between TGF-beta/ALK1/Smad1/5 and ALK5/Smad2/3 signalling and ECM production in human chondrocytes and that endoglin may represent a marker for chondrocyte phenotype. PMID- 20833253 TI - Differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in brain structures of rats selected for low and high anxiety in basal and fear stimulated conditions, in a model of contextual fear conditioning. AB - In this paper we used a model of individual differences in fear responses in rats selected according to their low and high freezing response in the contextual fear test and termed these animals "low- and high anxiety" rats, respectively. We studied differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in the brain structures of low (LR) and high (HR) anxiety rats subjected to extinction trials and re-learning of a conditioned fear response. We found different patterns of spontaneous (western blotting) and fear-stimulated expression of alpha-2 subunits and gephyrin (western blotting and immunocytochemistry) in brain structures of HR and LR animals. Increased basal concentrations of alpha-2 subunits in the amygdala were observed in HR rats (compared to unconditioned control group). The density of alpha-2 subunits in the amygdala negatively correlated with freezing response duration in the aversive context on re-learning in the same group of animals. This finding supports data on the role of GABA-A receptor alpha-2 subunits in the amygdala in modulation of anxiety-like behaviour. Western blotting revealed that exposure of HR animals to fear-conditioned context upon re-test of the conditioned fear test elevated the concentration of alpha-2 subunits in the amygdala and prefrontal cortex. In addition, immunocytochemistry showed that conditioned fear increased the number of cells co-expressing alpha-2 subunits and gephyrin in the basolateral amygdala and dentate gyrus of the hippocampus in the HR group. Together, these findings suggest that animals that are more vulnerable to stress differ in the intracellular mechanisms that control GABA-A receptor trafficking in limbic structures (hippocampus and amygdala), which are involved in the control of emotional behaviour. These data indicate a possible mechanism for the variable effects of benzodiazepines among patients with anxiety disorders. The obtained data may also help to better explain the neurobiological mechanisms that operate in clinical situations where anxious patients subjected to exposure therapy are exposed to an aversive, contextual and conditioning stimulus. PMID- 20833254 TI - Protective role of sulforaphane against oxidative stress mediated mitochondrial dysfunction induced by benzo(a)pyrene in female Swiss albino mice. AB - Recent focus of cancer chemoprevention is on intermediate biomarkers capable of detecting early changes that can be correlated with inhibition of carcinogenic initiation and progression. The present study aimed to delineate in vivo anti initiating mechanisms of orally administered sulforaphane (SFN) with special reference to mitochondrial dysfunction in target (lungs) and non-target (liver) tissues employing benzo(a)pyrene [B(a)P] as the model carcinogen. The recent revival of interest in the study of mitochondria has been stimulated by the evidence that genetic and/or metabolic alterations in this organelle lead to a variety of human diseases including cancer. These alterations could be either causative or contributing factors. Hence the activities of mitochondrial specific enzymes of TCA cycle and the electron transport complexes were analyzed in the experimental groups to assess the ATP production. Short-term tests such as the assessment of antioxidant status and reactive oxygen species (ROS)-induced lipid peroxidation, are widely used in the detection and evaluation of anticarcinogens. The assessment of mitochondrial lipid peroxidation along with the antioxidant status proved worthy for the correlation to the degree of damage. The induction of cancer was confirmed by the immunohistochemistry for Bcl-2. The results prove sulforaphane to be very successful in combating the oxidative stress mediated mitochondrial dysfunction in experimental lung carcinogenesis induced by benzo(a)pyrene. PMID- 20833255 TI - Key role of the RhoA/Rho kinase system in pulmonary hypertension. AB - Pulmonary hypertension (PH) is a general term comprising a spectrum of pulmonary hypertensive disorders which have in common an elevation of mean pulmonary arterial pressure (mPAP). The prototypical form of the disease, termed pulmonary arterial hypertension (PAH), is a rare but lethal syndrome with a complex aetiology characterised by increased pulmonary vascular resistance (PVR) and progressive elevation of mPAP; patients generally die from heart failure. Current therapies are inadequate and median survival is less than three years. PH due to chronic hypoxia (CH) is a condition separate from PAH and is strongly associated with chronic obstructive pulmonary disease (COPD). An early event in the pathogenesis of this form of PH is hypoxic pulmonary vasoconstriction (HPV), an acute homeostatic process that maintains the ventilation-perfusion ratio during alveolar hypoxia. The mechanisms underlying HPV remain controversial, but RhoA/Rho kinase (ROK)-mediated Ca2+-sensitisation is considered important. Increasing evidence also implicates RhoA/ROK in PASMC proliferation, inflammatory cell recruitment and the regulation of cell motility, all of which are involved in the pulmonary vascular remodelling occurring in all forms of PH. ROK is therefore a potential therapeutic target in treating PH of various aetiologies. Here, we examine current concepts regarding the aetiology of PAH and also PH due to CH, focusing on the contribution that RhoA/ROK-mediated processes may make to their development and on ROK inhibitors as potential therapies. PMID- 20833256 TI - Snail transcription factors in keratinocytes: Enough to make your skin crawl. AB - Keratinocytes are the cells in vertebrates that form the frontline barrier to the environment, and are also the most common origin of human cancer. They normally retain tight cell-cell adhesion and low motility, allowing them to terminally differentiate as they stratify. However, they must be able to respond to tissue damage by migrating into and across wounds. This requires reduced mutual adhesion, suppressed terminal differentiation and increased motility, processes driven by the Snail family of transcriptional repressors. The quantity, location and activity of Snail proteins are regulated by growth factors and cytokines to mediate these responses and invoke an inflammatory response. Subversion of these same pathways can promote carcinoma invasion and metastasis. Signaling network facts: * Snail1 and Snail2 in keratinocytes are important in promoting migration, inflammation and carcinogenesis, and suppressing terminal differentiation. * Extracellular stimuli, including TGFR and EGFR ligands, regulate Snails transcriptionally, via SMAD and MAPK pathways, and post-translationally, by modulating GSK3 and PAK1 activity, which determine Snail stability and intracellular location. * Snails directly repress transcription of genes important for cell-cell adhesion and cornified envelope formation. * Down regulation of epithelial cadherins by Snails allows LIMDPs to relocate from adherens junctions to the cytoplasm, where they stimulate MAPK pathways, and to the nucleus, where they bind directly to Snails and act as corepressors. * Snail2 is essential for re-epithelialization of healing wounds and can be up-regulated in the keratinocytes at wound margins by p38, ERK1/2 and ERK5 MAPKs, and the arylhydrocarbon receptor. * Further information on signaling related to Snail proteins can be found online at KEGG: http://www.genome.jp/kegg-bin/show pathway?hsa04520 http://www.genome.jp/kegg-bin/show_pathway?hsa04350 http://www.genome.jp/kegg-bin/show pathway?hsa04012. PMID- 20833257 TI - The International Journal of Biochemistry & Cell Biology. Preface. PMID- 20833258 TI - CD48: A co-stimulatory receptor of immunity. AB - The CD48 molecule is a glycosyl-phosphatidyl-inositol (GPI)-anchored cell-surface protein of the CD2 family of molecules. Originally described on virally-induced B cells, CD48 has been found on various hematopoietic cells, and its expression is regulated by viral and bacterial products and immune-associated proteins. CD48 binds CD2 and other molecules, yet its high-affinity ligand in both mouse and human systems is 2B4. Despite its lack of an intracellular domain, stimulation of CD48 induces rearrangement of signaling factors in lipid rafts, Lck-kinase activity, and tyrosine phosphorylation. As an adhesion and co-stimulatory molecule, CD48 induces numerous effects in B and T lymphocytes, natural killer cells, mast cells, and eosinophils. Some of these depend upon cell-cell interactions via 2B4-CD48 binding. The structural and phenotypic characteristics of CD48, and its role in physiological and pathophysiological processes, are reviewed herein. Possible CD48-based applications for immune-impaired and inflammatory disorders are discussed as well. PMID- 20833259 TI - Substrate profiling and aldehyde dismutase activity of the Kvbeta2 subunit of the mammalian Kv1 potassium channel. AB - Voltage-dependent potassium channels (Kv) are involved in various cellular signalling processes by governing the membrane potential of excitable cells. The cytosolic face of these alpha subunit-containing channels is associated with beta subunits that can modulate channel responses. Surprisingly, the beta subunit of the mammalian Kv1 channels, Kvbeta2, has a high level of sequence homology with the aldo-keto reductase (AKR) superfamily of proteins. Recent studies have shown that Kvbeta2 can catalyze the reduction of aldehydes and, most significantly, that channel function is modulated when Kvbeta2-bound NADPH is concomitantly oxidized. As a result, the redox chemistry of this subunit is crucial to understanding its role in K(+) channel modulation. The present study has extended knowledge of the substrate profile of this subunit using a single turnover fluorimetric assay. Kvbeta2 was found to catalyse the reduction of aromatic aldehyde substrates such as 2, 3 and 4-nitrobenzaldehydes, 4-hydroxybenzaldehyde, pyridine 2-aldehyde and benzaldehyde. The presence of an electron withdrawing group at the position para to the aldehyde in aromatic compounds facilitated reduction. Aliphatic aldehydes proved to be poor substrates. We devised a simple HPLC-based assay to identify Kvbeta2 reaction products. Using this assay we showed, for the first time, that Kvbeta2 can catalyze a slow aldehyde dismutation reaction using 4-nitrobenzaldehyde as substrate and have identified the products of this reaction. The ability of Kvbeta2 to carry out both an aldehyde reduction and a dismutation reaction is discussed in the light of current thinking on the role of redox chemistry in channel modulation. PMID- 20833260 TI - Protein kinases: Signaling molecules controlling ovarian functions. AB - The present focus survey represents a review of current knowledge concerning involvement of protein kinases in control of basic ovarian functions in mammals. Ovarian cells produce a number of protein kinases, whose expression depends on type of cells, their state and action of hormones and other protein kinases. A number of protein kinases are involved in control of ovarian cell proliferation, apoptosis, oocyte maturation, hormone release, reception and response to hormones, as well as in mediating action of hormones on these ovarian functions. Protein kinases and their regulators could be used for characterization, prediction and control of ovarian folliculogenesis and atresia, corpus luteum functions, oocyte maturation, fertility, release of hormones, response of ovarian structures to hormonal regulators, as well as for treatment of some reproductive disorders. PMID- 20833261 TI - Neuronal networks of nicotine addiction. AB - Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors. The main effects of nicotine associated with smoking are nicotinic receptor activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction. PMID- 20833262 TI - Pyroglutamate-Abeta: role in the natural history of Alzheimer's disease. AB - The accumulation of amyloid-beta (Abeta) peptides is believed to be a central contributor to the neurodegeneration typically seen in Alzheimer's disease (AD) brain. Abeta extracted from AD brains invariably possesses extensive truncations, yielding peptides of differing N- and C-terminal composition. Whilst Abeta is often abundant in the brains of cognitively normal elderly people, the brains of AD patients are highly enriched for N-terminally truncated Abeta bearing the pyroglutamate modification. Pyroglutamate-Abeta (pE-Abeta) has a higher propensity for oligomerisation and aggregation than full-length Abeta, potentially seeding the accumulation of neurotoxic Abeta oligomers and amyloid deposits. In addition, pE-Abeta has increased resistance to clearance by peptidases, causing these peptides to persist in biological fluids and tissues. The extensive deposition of pE-Abeta in human AD brain is under-represented in many transgenic mouse models of AD, reflecting major differences in the production and processing of Abeta peptides in these models compared to the human disease state. PMID- 20833263 TI - Personalized medicine: potential impact on the biopharmaceutical industry. PMID- 20833264 TI - Salvage of oxidized guanine derivatives in the (2'-deoxy)ribonucleotide pool as source of mutations in DNA. AB - Recent evidence suggests that salvage of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8 oxodG) and 8-oxo-7,8-dihydro-guanine (8-oxoGua) can contribute substantially to levels of 8-oxoGua in DNA and RNA. However, it remains to be determined if this mechanism contributes to mutagenesis and disease. This review covers the predominant methods for detecting 8-oxoGua and its derivatives, summarizes some of the relevant recent DNA repair studies and discusses the mechanisms for metabolism of oxidized guanine derivatives in the (2'-deoxy)ribonucleoside and (2'-deoxy)ribonucleotide pools. PMID- 20833265 TI - Field evaluation of the MM3-SERO ELISA for detection of anti-Fasciola IgG antibodies in milk samples from individual cows and bulk milk tanks. AB - We carried out a field evaluation of the MM3-SERO ELISA for the diagnosis of Fasciola hepatica infection, by analysing serum and milk samples from individual cows and samples from bulk milk tanks. The diagnostic performance of the assay was assessed with serum samples from all 257 cows in eight fluke-free herds, and 240 cows with natural fasciolosis (diagnosed in vivo and/or post-mortem). Assay performance for individual milk samples was determined by analysis of paired serum and milk samples from 947 lactating cows from 33 F. hepatica-infected farms. The diagnostic usefulness of the assay for bulk tank milk was evaluated by analysis of bulk milk from infected (33) and non-infected (35) farms. For serum samples, the sensitivity, specificity and diagnostic accuracy of the assay were respectively 99.2% (95% CI: 97.0%-99.9%), 100% (95% CI: 98.6%-100%) and 0.997 (95% CI: 0.987-1.000). The only two infected animals in which serum antibodies were not detected had very low parasitic burdens (with only 2 and 3 flukes observed). The performance of the MM3 SERO ELISA for individual milk samples was similar to that for serum samples, and the stepwise linear regression revealed a strong correlation between the results for the milk samples and the serum samples (R(2)=0.84; p<0.001). The agreement between results obtained with pairs of serum and milk samples was very high: there was matching classification in 96% (910/947) of paired samples (kappa=0.92; p<0.001). Individual milk samples may therefore be used, instead of serum samples, in the MM3-SERO ELISA, for reliable detection of seropositive cows. Testing bulk tank milk samples enabled detection of infected herds, even when the within-herd prevalence of infection was as low as 12%. We conclude that the MM3-SERO ELISA is a sensitive and highly specific test for serodiagnosis of bovine fasciolosis, and can be used with individual samples of either serum or milk. Use of the assay with bulk milk samples enables estimation of the within-herd prevalence of infection. PMID- 20833266 TI - Relation between renal function and response to cardiac resynchronization therapy in Multicenter Automatic Defibrillator Implantation Trial--Cardiac Resynchronization Therapy (MADIT-CRT). AB - BACKGROUND: Cardiorenal interactions have been shown to affect outcome in heart failure patients but were not related to response to cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to test our hypothesis that assessment of markers of prerenal failure may help identify mildly symptomatic HF patients with diminished effective circulating blood volume who will benefit from CRT. METHODS: The benefit of CRT with a defibrillator (CRT-D) as compared with defibrillator-only therapy in reducing the risk of HF or death was assessed by renal function parameters (including serum creatinine [SCr], blood urea nitrogen [BUN], and the ratio of BUN to SCr [BUN:SCr], dichotomized at median values and into approximate quartiles) among 1,803 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy. RESULTS: Multivariate analysis showed that the benefit of CRT-D was inversely related to SCr levels and directly related to BUN levels. Combined assessment of the two renal function parameters showed a significant difference in the benefit of CRT-D between patients with low (<= 18 mg/dL, HR = 0.85, P = .28) and elevated (> 18 mg/dL, HR = 0.46, P < .001) BUN:SCr (P-value for interaction = .005). Consistently, the benefit of CRT-D was significantly increased with increasing quartiles of BUN:SCr (Q(1): HR = 1.06 [P = .79], Q(2): HR = 0.64 [P = .04], Q(3): HR = 0.47 [P < .001], Q(4): HR = 0.44 [P < .001]; P value for trend = .005). CONCLUSIONS: In MADIT-CRT, patients with an elevated ratio of BUN to SCr experienced a significantly greater reduction in the risk of HF or death with CRT-D therapy as compared with patients with a low ratio. These findings suggest an association between prerenal function and response to CRT. PMID- 20833267 TI - Optical imaging of the heart: Seeing below the surface. PMID- 20833268 TI - Proarrhythmic risk of embryonic stem cell-derived cardiomyocyte transplantation in infarcted myocardium. AB - BACKGROUND: Cellular replacement strategies using embryonic stem cells (ESCs) and their cardiac derivatives are emerging as novel experimental therapeutic paradigms for the treatment of post-myocardial infarction (MI) left ventricular (LV) dysfunction; however, their potential proarrhythmic risk remains unclear. OBJECTIVE: The purpose of this study was to investigate the functional effect and proarrhythmic risk of ESC transplantation in a mouse model of MI. METHODS: We compared the functional effects and proarrhythmic risk of direct intramyocardial transplantation of 3 * 10(5) undifferentiated mouse ESCs (MI+ESC group, n = 33) and mouse ESC-derived cardiomyocytes (MI+ESC-CM group, n = 40) versus culture medium (MI group, n = 33) at the infarct border zone in a mouse model of acute MI. LV performance was assessed with serial cardiac magnetic resonance imaging (MRI) at 1 and 3 week(s) post-MI, and invasive LV pressure measurement was assessed (dP/dt) at 4 weeks before sacrifice for histological examination. Furthermore, electrophysiological study was also performed in another set of animals in each group (n = 24) to assess for proarrhythmias after transplantation. RESULTS: In vitro cellular electrophysiological study demonstrated that ESC-CMs exhibit arrhythmogenesis including automaticity, lengthened action potential duration, and depolarized resting membrane potential. At 4 weeks, the MI+ESC-CM group (21/40, 53%) had a higher mortality rate compared with those in the MI group (10/33, 30%, P = .08) and in the MI+ESC group (7/33, 21%, P = .012). Electrophysiological study showed a significantly higher incidence of inducible ventricular tachyarrhythmias in the MI+ESC-CM group (13/24, 54%) compared with in the MI group (6/24, 21%, P = .039) and in the MI+ESC group (5/24, 21%, P = .017). Cardiac MRI showed similar improvement in LV ejection fraction in the MI+ESC and MI+ESC-CM groups compared with in the MI group at 1 week (27.5% +/- 3.8%; 30.3% +/- 5.2% vs. 12.4% +/- 1.4%; P < .05) and 3 weeks (29.8% +/- 3.9%; 27.0% +/- 4.8% vs. 10.6% +/- 2.8%; P < .05) post-MI, respectively. Furthermore, invasive hemodynamic assessment at 4 weeks showed significant similar improvement in LV +dP/dt in the MI+ESC (2,644 +/- 391 mmHg/s, P < .05) and MI+ESC-CM groups (2,539 +/- 389 mmHg/s; P < .05) compared with in the MI group (2,042 +/- 406 mmHg/s). CONCLUSIONS: Our results demonstrate that transplantation of undifferentiated ESCs and ESC-CMs provides similar improvement in cardiac function post-MI. However, transplantation of ESC-CMs is associated with a significantly higher prevalence of inducible ventricular tachyarrhythmias and early mortality than transplantations with ESCs. PMID- 20833269 TI - Genetic diversity in strains of Helicobacter pylori from India and their relatedness to strains from other parts of the world. AB - Helicobacter pylori is predominantly transmitted within families and infection occurs mostly in early childhood, frequently leading to persistent infection lifelong. In the present study, genetic diversity of Helicobacter pylori among North and South Indian isolates was evaluated. 16S rDNA, cagA, vacA and iceA genes were amplified followed by sequencing of respective amplicons for diversity analysis. Result of PCR assay showed that status of pathogenicity genes varied among strains from Varanasi and Hyderabad. Phylogenetic analysis based on 16S rDNA sequences showed clustering of Hyderabad and Varanasi strains in separate groups, pointing to significant diversity. Additionally, phylogenetic analysis revealed that most of the Varanasi strains shared homology with the strains from Taiwan except for two isolates which matched with an isolate from Brazil. On the other hand majority of the Hyderabad strains showed relatedness with strains from Brazil except one which showed homology with one strain from Taiwan. In conclusion our results show that genetic diversity among H. pylori isolates is widely prevalent regardless of the region from which they are isolated. More interestingly, phylogenetic analysis suggests that the Indian strains of H. pylori show close homology to those from Taiwan and/or Brazil. PMID- 20833270 TI - A 15-year analysis of molecular epidemiology of avian infectious bronchitis coronavirus in China. AB - A comprehensive study of the epidemiology and pathogenicity of infectious bronchitis virus (IBV) in China was carried out by molecular characterization of the S1 gene from 46 isolates obtained for this study and 174 reference strains isolated over a 15-year period. Nine types were found according to sequence analysis and phylogenetic study of the S1 gene. The co-circulation of multiple IBV types and the ongoing emergence of IBV variants are the epidemiological challenges in China. Factors contributing to the continual emergence include mutations, insertions and deletions in the S1 protein genes; recombination between local IBV strains circulating in chicken flocks in China; and recombination between local strains and vaccine strains. Vaccination-challenge analysis between circulating field strains and Mass-type H120 vaccine indicated the need to develop new vaccines from local IBV strains. These results also emphasize the importance of continued IBV surveillance in China. PMID- 20833271 TI - Antibodies to ribosomal P proteins in lupus nephritis: a surrogate marker for a better renal survival? AB - OBJECTIVE: To define if antibodies to ribosomal P proteins disclose a better lupus nephritis long-term survival. METHODS: Sixty consecutive SLE patients with biopsy-proven nephritis (2004 ISN/RPS) were evaluated for renal survival parameters. Inclusion criteria were at least one serum sample at: renal flares, biopsy, and last follow-up until 2008. Anti-P was detected by ELISA/immunoblot and anti-dsDNA by indirect immunofluorescence/ELISA. RESULTS: Eleven patients (18%) with anti-P+ (without anti-dsDNA) during renal flare were compared to 49 (82%) persistently negative for anti-P throughout the study. At the final follow up post-biopsy (6.3+/-2.5 vs. 6.8+/-2.4 years, p=0.36), the comparison of anti P+/anti-dsDNA- with anti-P- group revealed a trend to lower mean creatinine levels (0.9+/-0.3 vs. 2.3+/-2.1 mg/dl, p=0.07), lower frequency of dialysis (0% vs. 35%, p=0.025), and higher frequency of normal renal function (91% vs. 53%, p=0.037). The overall renal survival was significantly higher in anti-P+/anti dsDNA- compared to anti-P- (11.0+/-4.5 vs. 9.2+/-4.5 years, p=0.033), anti dsDNA+/anti-P- (vs. 8.7+/-4.7 years, p=0.017), and anti-P-/anti-dsDNA- (vs. 9.8+/ 4.3 years, p=0.09) groups. CONCLUSION: Our data supports the notion that anti-P antibody in the absence of anti-dsDNA during nephritis flares is a valuable marker to predict a better long-term renal outcome in lupus patients. PMID- 20833272 TI - The meaning of anti-Ro and anti-La antibodies in primary Sjogren's syndrome. AB - Anti-SSA/Ro and anti-La/SSB are the hallmark antibodies in primary Sjogren's syndrome (pSS), being present in 60-70%. These antibodies have been associated with an earlier disease onset, glandular dysfunction and extraglandular manifestations as well as with other B cells activation markers. In addition an immunogenetic background is important for the autoantibody formation, having a stronger association with HLA-DR2 and HLA-DR3. Anti-Ro/SSA and anti-La/SSB antibodies are useful in the diagnosis of pSS and help to identify more "active" patients, however their association with response to treatment is unclear. Herein we review the evidence regarding the association of these antibodies with HLA background, demographic, clinical, glandular dysfunction, other serologic features and response to treatment in patients with pSS. PMID- 20833274 TI - K(+) and Ca2(+) dependence of inspiratory-related rhythm in novel "calibrated" mouse brainstem slices. AB - Recently developed transversal newborn rat brainstem slices with "calibrated" rostrocaudal margins unraveled novel features of rhythmogenic inspiratory active pre-Botzinger complex (preBotC) neural networks (Ballanyi and Ruangkittisakul, 2009). For example, slice rhythm in physiological (3 mM) superfusate K(+) is depressed by modestly raised Ca2(+) and restored by raised K(+). Correspondingly, we generated here calibrated preBotC slices from commonly used newborn C57BL/6 mice in which rostrocaudal extents of respiratory marker structures, e.g., the inferior olive, turned out to be smaller than in newborn rats. Slices of 400-600 MUm thickness with likely centered preBotC kernel ("m-preBotC slices") generated rhythm in 3 mM K(+) and 1mM Ca(2+) for several hours although its rate decreased to < 5 bursts/min after >1 h. Rhythm was stable at 8-12 bursts/min in 6-7 mM K(+), depressed by 2 mM Ca2(+), and restored by 9 mM K(+). Our findings provide the basis for future structure-function analyses of the mouse preBotC, whose activity depends critically on a "Ca(+)/K(+) antagonism" as in rats. PMID- 20833275 TI - A revisit to O2 sensing and transduction in the carotid body chemoreceptors in the context of reactive oxygen species biology. AB - Oxygen-sensing and transduction in purposeful responses in cells and organisms is of great physiological and medical interest. All animals, including humans, encounter in their lifespan many situations in which oxygen availability might be insufficient, whether acutely or chronically, physiologically or pathologically. Therefore to trace at the molecular level the sequence of events or steps connecting the oxygen deficit with the cell responses is of interest in itself as an achievement of science. In addition, it is also of great medical interest as such knowledge might facilitate the therapeutical approach to patients and to design strategies to minimize hypoxic damage. In our article we define the concepts of sensors and transducers, the steps of the hypoxic transduction cascade in the carotid body chemoreceptor cells and also discuss current models of oxygen- sensing (bioenergetic, biosynthetic and conformational) with their supportive and unsupportive data from updated literature. We envision oxygen sensing in carotid body chemoreceptor cells as a process initiated at the level of plasma membrane and performed by a hemoprotein, which might be NOX4 or a hemoprotein not yet chemically identified. Upon oxygen-desaturation, the sensor would experience conformational changes allosterically transmitted to oxygen regulated K+ channels, the initial effectors in the transduction cascade. A decrease in their opening probability would produce cell depolarization, activation of voltage dependent calcium channels and release of neurotransmitters. Neurotransmitters would activate the nerve endings of the carotid body sensory nerve to convey the information of the hypoxic situation to the central nervous system that would command ventilation to fight hypoxia. PMID- 20833273 TI - Reactive oxygen species and the brain in sleep apnea. AB - Rodents exposed to intermittent hypoxia (IH), a model of obstructive sleep apnea (OSA), manifest impaired learning and memory and somnolence. Increased levels of reactive oxygen species (ROS), oxidative tissue damage, and apoptotic neuronal cell death are associated with the presence of IH-induced CNS dysfunction. Furthermore, treatment with antioxidants or overexpression of antioxidant enzymes is neuroprotective during IH. These findings mimic clinical cases of OSA and suggest that ROS may play a key causal role in OSA-induced neuropathology. Controlled production of ROS occurs in multiple subcellular compartments of normal cells and de-regulation of such processes may result in excessive ROS production. The mitochondrial electron transport chain, especially complexes I and III, and the NADPH oxidase in the cellular membrane are the two main sources of ROS in brain cells, although other systems, including xanthine oxidase, phospholipase A2, lipoxygenase, cyclooxygenase, and cytochrome P450, may all play a role. The initial evidence for NADPH oxidase and mitochondrial involvement in IH-induced ROS production and neuronal injury unquestionably warrants future research efforts. PMID- 20833277 TI - Recombinant human sperm-specific glyceraldehyde-3-phosphate dehydrogenase: structural basis for enhanced stability. AB - Sperm-specific glyceraldehyde-3-phosphate dehydrogenase (GAPDS) is bound to the fibrous sheath of the sperm flagellum through the hydrophobic N-terminal domain of the enzyme molecule. Expression of human GAPDS in E.coli cells yields inactive and insoluble protein. Presumably, the N-terminal domain prevents correct folding of the full-length recombinant enzyme. To obtain GAPDS in a soluble and active form, a recombinant enzyme lacking in 68 amino acids of the N-terminal domain (dN GAPDS) was expressed in E.coli cells. Purified dN-GAPDS was shown to be a protein of 9.3 nm in diameter (by dynamic light scattering), which is close to the size of the muscle tetrameric glyceraldehyde-3-phosphate dehydrogenase (8.6 nm). The catalytic properties of the protein differed a little from those of the muscle glyceraldehyde-3-phoshate dehydrogenase. However, compared to muscle glyceraldehyde-3-phoshate dehydrogenase, dN-GAPDS exhibited enhanced thermostability (the transition midpoints values are 60.8 and 67.4 degrees C, respectively) and was much more resistant towards action of guanidine hydrochloride (inactivation constants are 2.45+/-0.018 and 0.118 +/- 0.008 min( 1), respectively). The enhanced stability of dN-GAPDS is likely to be related to some specific features of the GAPDS structure compared to that of the muscle enzyme: 1) reduced number of solvent-exposed salt bridges; 2) 2 additional buried salt bridges; and 3) 6 additional proline residues in GAPDS meeting the "proline rule". It is assumed that high stability of the sperm-specific GAPDS is of importance for the efficiency of fertilization. PMID- 20833276 TI - Sleep fragmentation attenuates the hypercapnic (but not hypoxic) ventilatory responses via adenosine A1 receptors in awake rats. AB - Sleep fragmentation (SF) and intermittent hypoxia and hypercapnia are the primary events associated with obstructive sleep apnea (OSA). We previously found that SF eliminates ventilatory long-term facilitation and attenuates poikilocapnic hypoxic ventilatory responses (HVR). This study examined the effect of SF on isocapnic HVR and hypercapnic ventilatory responses (HCVR), and investigated the time course of and the role of adenosine A1 receptors in these SF effects in conscious adult male Sprague-Dawley rats. SF was achieved by periodic, forced locomotion in a rotating drum (30 s rotation/90 s stop for 24 h). Ventilation during baseline, isocapnic hypoxia (11% O2 plus 4% CO2) and hypercapnia (6% CO2) was measured using plethysmography. About 1h after 24h SF, resting ventilation, arterial blood gases and isocapnic HVR (control: 169.3 +/- 11.5% vs. SF: 170.0 +/ 10.3% above baseline) were not significantly changed, but HCVR was attenuated (control: 172.8 +/- 17.5% vs. SF: 129.5 +/- 9.6%; P = 0.003). This attenuated HCVR then returned spontaneously to the control level ~4 h after SF (168.9 +/- 12.1%). This HCVR attenuation was also reversed (184.0 +/- 17.5%) by systemic injection of the adenosine A1 receptor antagonist 8-CPT (2.5 mg/kg) shortly after SF, while 8-CPT at this dose had little effect on HCVR in control rats (169.9 +/- 11.8%). Collectively, these results suggest that: (1) 24 h SF does not change isocapnic HVR but causes an attenuation of HCVR; and (2) this attenuation lasts for only a few hours and requires activation of adenosine A1 receptors. PMID- 20833278 TI - Stability of the domain interface contributes towards the catalytic function at the H-site of class alpha glutathione transferase A1-1. AB - Cytosolic glutathione transferases (GSTs) are major detoxification enzymes in aerobes. Each subunit has two distinct domains and an active site consisting of a G-site for binding GSH and an H-site for an electrophilic substrate. While the active site is located at the domain interface, the role of the stability of this interface in the catalytic function of GSTs is poorly understood. Domain 1 of class alpha GSTs has a conserved tryptophan (Trp21) in helix 1 that forms a major interdomain contact with helices 6 and 8 in domain 2. Replacing Trp21 with an alanine is structurally non-disruptive but creates a cavity between helices 1, 6 and 8 thus reducing the packing density and van der Waals contacts at the domain interface. This results in destabilization of the protein and a marked reduction in catalytic activity. While functionality at the G-site is not adversely affected by the W21A mutation, the H-site becomes more accessible to solvent and less favorable for the electrophilic substrate 1-chloro-2,4-dinitrobenzene (CDNB). Not only does the mutation result in a reduction in the energy for stabilizing the transition state formed in the S(N)Ar reaction between the substrates GSH and CDNB, it also compromises the ability of the enzyme to form and stabilize a transition state analogue (Meisenheimer complex) formed between GSH and 1,3,5-trinitrobenzene (TNB). The study demonstrates that the stability of the domain-domain interface plays a role in mediating the catalytic functionality of the active site, particularly the H-site, of class alpha GSTs. PMID- 20833280 TI - The Drosophila melanogaster sperm proteome-II (DmSP-II). AB - Advances in mass spectrometry technology, high-throughput proteomics and genome annotations have resulted in significant increases in our molecular understanding of sperm composition. Using improved separation and detection methods and an updated genome annotation, a re-analysis of the Drosophila melanogaster sperm proteome (DmSP) has resulted in the identification of 956 sperm proteins. Comparative analysis with our previous proteomic dataset revealed 766 new proteins and an updated sperm proteome containing a total of 1108 proteins, termed the DmSP-II. This expanded dataset includes additional proteins with predicted sperm functions and confirms previous findings concerning the genomic organization of sperm loci. Bioinformatic and protein network analyses demonstrated high quality and reproducibility of proteome coverage across three replicate mass spectrometry runs. The use of whole-cell proteomics in conjunction with characterized phenotypes, functional annotations and pathway information has advanced our systems level understanding of sperm proteome functional networks. PMID- 20833281 TI - Tuning acetylation levels with HAT activators: therapeutic strategy in neurodegenerative diseases. AB - Neurodegenerative diseases, such as polyglutamine-related diseases, amyotrophic lateral sclerosis, and Alzheimer's disease are accompanied by transcriptional dysfunctions, leading to neuronal death. It is becoming more evident that the chromatin acetylation status is impaired during the lifetime of neurons, by a common mechanism related to the loss of function of histone acetyltransferase (HAT) activity. Notably, the HAT termed cAMP response element binding protein (CREB)-binding protein (CBP) was shown to display neuroprotective functions. Several other HATs have now been shown to participate in basic but vital neuronal functions. In addition, there is increasing evidence of several HATs (including CBP), as essential regulators of neuronal plasticity and memory formation processes. In order to counteract neuronal loss and/or memory deficits in neurodegenerative diseases, the current therapeutic strategies involve the use of small molecules antagonizing histone deacetylase (HDAC) activity (i.e. HDAC inhibitors). Although this strategy lacks specificity, some of these molecules display promising therapeutic properties. With the rapidly evolving literature on HATs and their respective functions in neuronal survival and memory formation, it seems essential to envisage direct stimulation of the acetyltransferase function as a new therapeutic tool in neurodegenerative diseases. In this review, we will highlight the present understanding and the future prospects of such therapeutic approach. PMID- 20833282 TI - We need to talk about Kelvingrove.... PMID- 20833283 TI - Neoadjuvant chemotherapy in advanced ovarian cancer: what kind of evidence is needed to convince US gynaecological oncologists? PMID- 20833279 TI - Advances in resuscitation strategies. AB - Shock, regardless of etiology is characterized by decreased delivery of oxygen and nutrients to the tissues and our interventions are directed towards reversing the cellular ischemia and preventing its consequences. The treatment strategies that are most effective in achieving this goal obviously depend upon the different types of shock (hemorrhagic, septic, neurogenic and cardiogenic). This brief review focuses on the two leading etiologies of shock in the surgical patients: bleeding and sepsis, and addresses a number of new developments that have profoundly altered the treatment paradigms. The emphasis here is on new research that has dramatically altered our treatment strategies rather than the basic pathophysiology of shock. PMID- 20833284 TI - Hepatitis E vaccine: why wait? PMID- 20833285 TI - Providing paediatric palliative care in Kenya. PMID- 20833286 TI - The power of praise. PMID- 20833287 TI - Philip Morris versus Uruguay: health governance challenged. PMID- 20833288 TI - Even low-dose lead exposure is hazardous. PMID- 20833289 TI - Ending inequities in access to effective pain relief? PMID- 20833291 TI - Sakena Yacoobi: leader for Afghan women's health and education. PMID- 20833292 TI - Clinical assessment incorporating a personal genome. PMID- 20833293 TI - Neglected hepatitis E and typhoid vaccines. PMID- 20833295 TI - Flexible sigmoidoscopy to prevent colorectal cancer. PMID- 20833296 TI - Flexible sigmoidoscopy to prevent colorectal cancer. PMID- 20833299 TI - Childhood mortality due to respiratory syncytial virus. PMID- 20833300 TI - Effect of vitamin A supplementation on maternal survival. PMID- 20833301 TI - Corruption in health systems. PMID- 20833303 TI - Introduction of European priority review vouchers to encourage development of new medicines for neglected diseases. AB - Every year 1 billion people worldwide are affected by traditionally neglected diseases, such as malaria, tuberculosis, leishmaniasis, and lymphatic filariasis, which impose tremendous public health burdens. Governments, foundations, and drug manufacturers have, however, started to support development of new treatments. European Union Member States have been leaders in implementing so-called push mechanisms (payment for drug development) and pull funding (reward for output), such as the advance market commitment, which creates a market for vaccines by guaranteeing prices. We propose an additional step that could be taken to encourage development of medicines for neglected diseases. A priority review voucher scheme, as is already in place in the USA, would reward a manufacturer that developed a new medicine for neglected diseases with a voucher that could be redeemed for priority review of a future medicine, probably a potential blockbuster drug. Unlike the US system a European voucher would also accelerate pricing and reimbursement decisions. This scheme would be likely to provide substantial benefits to voucher holders, society, and public health organisations. PMID- 20833304 TI - How many lives does an ulcerative colitis patient have? PMID- 20833305 TI - [The Spanish Journal of Nuclear Medicine enters the competitive scene of global scientific communication]. PMID- 20833306 TI - Quick guide. Paternally transmitted parasites. PMID- 20833307 TI - Gene regulation: enhancers stepping out of the shadow. AB - The expression of many animal genes has been shown to be controlled by two- rather than one--enhancers with similar regulatory content. Such enhancer redundancy ensures robustness of gene expression under adverse environmental or genetic conditions. PMID- 20833308 TI - Female meiosis: coming unglued with age. AB - Chromosome abnormalities in humans are strikingly associated with increasing maternal age. Studies in mice implicate loss of chromosome cohesion as an important cause of age-related meiotic errors in the oocyte. PMID- 20833309 TI - Visual system: how does blindsight arise? AB - Some patients can discriminate unseen visual stimuli within a field defect caused by damage to the primary visual cortex. The pathways for this 'blindsight' have never been established, but recent studies implicate hitherto overlooked cells in the thalamic LGN. PMID- 20833310 TI - Gene silencing: small RNAs control RNA polymerase II elongation. AB - Short interfering RNAs trigger histone silencing marks and stalling of RNA polymerase II at their genomic target sites through a mechanism termed transcriptional gene silencing (TGS). The Argonaute protein NRDE-3, along with NRDE-2, are needed for TGS in C. elegans. TGS also inhibits elongation and controls alternative splicing in mammalian cells. PMID- 20833311 TI - Signal transduction: bacterial thermometer works by measuring membrane thickness. AB - Cells detect external chemical stimuli by directly binding a signaling molecule, but the strategies used by cells to detect and respond to non-chemical cues have been mysterious. Recent work suggests that a bacterial protein detects changes in environmental temperature by physically measuring membrane thickness. PMID- 20833312 TI - Memory: reconsolidation allows modification of motor memories. AB - A recent study using non-invasive transcranial magnetic stimulation has revealed how specific brain processing during memory reactivation makes possible the modification of existing memories that is required for motor learning. PMID- 20833313 TI - Phenotypic plasticity: different teeth for different feasts. AB - A polyphenism in the nematode Pristionchus pacificus involves the development of different feeding structures in response to an environmental cue, providing a genetic model species for investigating ecologically relevant phenotypic plasticity. PMID- 20833314 TI - Axon regeneration: electrical silencing is a condition for regrowth. AB - A recent study in primary sensory neurons shows that electrical activity- mediated through L-type voltage-gated calcium channels--could suppress axon growth after injury. PMID- 20833315 TI - Binocular rivalry: neurons unwire when they can't simultaneously fire. AB - Binocular rivalry, where very different monocular images appear to alternate, changes its perceptual characteristics over time. New evidence suggests that this results from synaptic weakening or decoupling of neurons that are prevented from firing together. PMID- 20833316 TI - Jacob and Monod: from operons to EvoDevo. PMID- 20833317 TI - Evolution of complex gene regulatory circuits by addition of refinements. AB - How do complex gene regulatory circuits evolve? These circuits involve many interacting components, which work together to specify patterns of gene expression. They typically include many subtle mechanistic features, but in most cases it is unclear whether these features are essential for the circuit to work at all, or if instead they make a functional circuit work better. In the latter case, such a feature is here termed 'dispensable', and it is plausible that the feature has been added at a late stage in the evolution of the circuit. This review describes experimental tests of this question, using the phage lambda gene regulatory circuit. Several features of this circuit are found to be dispensable, in the sense that the circuitry works without these features, though not as well as the wild type. In some cases, second-site suppressor mutations are needed to confer near-normal behavior in the absence of such a feature. These findings are discussed here in the context of a two-stage model for evolution of gene regulatory circuits. In this model, a circuit evolves by assembly of a primitive or basic form, followed by adjustment of parameters and addition of qualitatively new features. Pathways are suggested for the addition of such features to a more basic form. Selected examples in other systems are described. Some of the dispensable features of phage lambda may be evolutionary refinements. Finding that a feature is dispensable, however, does not prove that it is a late addition - it is possible that it was essential early in evolution, and became dispensable as the circuit evolved. Conversely, a late addition might have become essential. As ongoing work provides additional examples of dispensable features, it may become clearer how often they represent refinements. PMID- 20833318 TI - Hierarchical evolution of the bacterial sporulation network. AB - Genome sequencing of multiple species makes it possible to understand the main principles behind the evolution of developmental regulatory networks. It is especially interesting to analyze the evolution of well-defined model systems in which conservation patterns can be directly correlated with the functional roles of various network components. Endospore formation (sporulation), extensively studied in Bacillus subtilis, is driven by such a model bacterial network of cellular development and differentiation. In this review, we analyze the evolution of the sporulation network in multiple endospore-forming bacteria. Importantly, the network evolution is not random but primarily follows the hierarchical organization and functional logic of the sporulation process. Specifically, the sporulation sigma factors and the master regulator of sporulation, Spo0A, are conserved in all considered spore-formers. The sequential activation of these global regulators is also strongly conserved. The feed forward loops, which are likely used to fine-tune waves of gene expression within regulatory modules, show an intermediate level of conservation. These loops are less conserved than the sigma factors but significantly more than the structural sporulation genes, which form the lowest level in the functional and evolutionary hierarchy of the sporulation network. Interestingly, in spore-forming bacteria, gene regulation is more conserved than gene presence for sporulation genes, while the opposite is true for non-sporulation genes. The observed patterns suggest that, by understanding the functional organization of a developmental network in a model organism, it is possible to understand the logic behind the evolution of this network in multiple related species. PMID- 20833319 TI - Evolution of transcription networks--lessons from yeasts. AB - That regulatory evolution is important in generating phenotypic diversity was suggested soon after the discovery of gene regulation. In the past few decades, studies in animals have provided a number of examples in which phenotypic changes can be traced back to specific alterations in transcriptional regulation. Recent advances in DNA sequencing technology and functional genomics have stimulated a new wave of investigation in simple model organisms. In particular, several genome-wide comparative analyses of transcriptional circuits across different yeast species have been performed. These studies have revealed that transcription networks are remarkably plastic: large scale rewiring in which target genes move in and out of regulons through changes in cis-regulatory sequences appears to be a general phenomenon. Transcription factor substitution and the formation of new combinatorial interactions are also important contributors to the rewiring. In several cases, a transition through intermediates with redundant regulatory programs has been suggested as a mechanism through which rewiring can occur without a loss in fitness. Because the basic features of transcriptional regulation are deeply conserved, we speculate that large scale rewiring may underlie the evolution of complex phenotypes in multi-cellular organisms; if so, such rewiring may leave traceable changes in the genome from which the genetic basis of functional innovation can be detected. PMID- 20833320 TI - Transcriptional enhancers in animal development and evolution. AB - Regulatory DNAs serve as templates to bring weakly interacting transcription factors into close proximity so they can work synergistically to switch genes on and off in time and space. Most of these regulatory DNAs are enhancers that can work over long distances--a million base pairs or more in mammals--to control gene expression. Critical enhancers are sometimes even found within the introns of neighboring genes. This review summarizes well-defined examples of enhancers controlling key processes in animal development. Potential mechanisms of transcriptional synergy are discussed with regard to enhancer structure and contemporary ChIP-sequencing assays, whereby just a small fraction of the observed binding sites represent bona fide regulatory DNAs. Finally, there is a discussion of how enhancer evolution can produce novelty in animal morphology and of the prospects for reconstructing transitions in animal evolution by introducing derived enhancers in basal ancestors. PMID- 20833322 TI - Using synthetic biology to understand the evolution of gene expression. AB - The evolution of phenotype is often based on changes in gene expression rather than changes in protein-coding sequence. Gene expression is controlled by complex networks of interacting regulators that act through a variety of biochemical mechanisms. Perturbation of these networks can have profound effects on the fitness of organisms. This highlights an important challenge: the investigation of whether the mechanisms and network architectures we observe in Nature evolved in response to selective pressure--and, if so, what that pressure might have been -or whether the architectures are a result of non-adaptive forces. Synthetic biologists aim to construct artificial genetic and biological systems to increase our understanding of Nature as well as for a number of biotechnological applications. In this review, I will highlight how engineering 'synthetic' control of gene expression provides a way to test evolutionary hypotheses. Synthetic biology might allow us to investigate experimentally the evolutionary paths not taken by extant organisms. PMID- 20833321 TI - Transcriptional repression: conserved and evolved features. AB - The regulation of gene expression by transcriptional repression is an ancient and conserved mechanism that manifests itself in diverse ways. Here we summarize conserved pathways for transcriptional repression prevalent throughout all forms of life, as well as indirect mechanisms that appear to have originated in eukaryotes, consistent with the unique chromatin environment of eukaryotic genes. The direct interactions between transcriptional repressors and the core transcriptional machinery in bacteria and archaea are sufficient to generate a sophisticated suite of mechanisms that provide flexible control. These direct interactions contrast with the activity of corepressors, which provide an additional regulatory control in eukaryotes. Their modulation of chromatin structure represents an indirect pathway to downregulate transcription, and their diversity and modulation provide additional complexity suited to the requirements of elaborate eukaryotic repression patterns. New findings indicate that corepressors are not necessarily restricted to generating a single stereotypic output, but can rather exhibit diverse functional responses depending on the context in which they are recruited, providing a hitherto unsuspected additional source of diversity in transcriptional control. Mechanisms within eukaryotes appear to be highly conserved, with novel aspects chiefly represented by addition of lineage-specific corepressor scaffolds that provide additional opportunities for recruiting the same core machinery. PMID- 20833323 TI - Evolution of eukaryotic DNA methylation and the pursuit of safer sex. AB - Cytosine methylation is an ancient process with conserved enzymology but diverse biological functions that include defense against transposable elements and regulation of gene expression. Here we will discuss the evolution and biological significance of eukaryotic DNA methylation, the likely drivers of that evolution, and major remaining mysteries. PMID- 20833324 TI - Improved probabilistic inference as a general learning mechanism with action video games. AB - Action video game play benefits performance in an array of sensory, perceptual, and attentional tasks that go well beyond the specifics of game play [1-9]. That a training regimen may induce improvements in so many different skills is notable because the majority of studies on training-induced learning report improvements on the trained task but limited transfer to other, even closely related, tasks ([10], but see also [11-13]). Here we ask whether improved probabilistic inference may explain such broad transfer. By using a visual perceptual decision making task [14, 15], the present study shows for the first time that action video game experience does indeed improve probabilistic inference. A neural model of this task [16] establishes how changing a single parameter, namely the strength of the connections between the neural layer providing the momentary evidence and the layer integrating the evidence over time, captures improvements in action-gamers behavior. These results were established in a visual, but also in a novel auditory, task, indicating generalization across modalities. Thus, improved probabilistic inference provides a general mechanism for why action video game playing enhances performance in a wide variety of tasks. In addition, this mechanism may serve as a signature of training regimens that are likely to produce transfer of learning. PMID- 20833325 TI - Solar radiation and human health. PMID- 20833326 TI - Cardiopulmonary bypass--reducing the stress. PMID- 20833327 TI - Giant unruptured calcified aneurysm of non-coronary sinus of valsalva. PMID- 20833328 TI - Prologue to the volume: Endocrine tumors and their genetics, a perspective. PMID- 20833329 TI - Multiple endocrine neoplasia type 1 (MEN1). AB - Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal-dominant disorder characterised by the occurrence of tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene, consists of 10 exons that encode a 610-amino acid protein referred to as Menin. Menin is predominantly a nuclear protein that has roles in transcriptional regulation, genome stability, cell division and proliferation. Germ-line mutations usually result in MEN1 or occasionally in an allelic variant referred to as Familial Isolated Hyperparathyroidism (FIHP). MEN1 tumours frequently have loss of heterozygosity (LOH) of the MEN1 locus, which is consistent with a tumour suppressor role of MEN1. Furthermore, somatic abnormalities of MEN1 have been reported in MEN1 and non-MEN1 endocrine tumours. To date, over 1300 mutations have been reported, and the majority (>70%) of these are predicted to lead to truncated forms of Menin. The mutations are scattered throughout the >9 kb genomic sequence of the MEN1 gene. Four, which consist of c.249_252delGTCT (deletion at codons 83-84), c.1546_1547insC (insertion at codon 516), c.1378C>T (Arg460Ter) and c.628_631delACAG (deletion at codons 210-211) have been reported to occur frequently in 4.5%, 2.7%, 2.6% and 2.5% of families, respectively. However, a comparison of the clinical features in patients and their families with the same mutations reveals an absence of phenotype-genotype correlations. The majority of MEN1 mutations are likely to disrupt the interactions of Menin with other proteins and thereby alter critical events in cell cycle regulation and proliferation. PMID- 20833330 TI - Multiple endocrine neoplasia type 2. AB - Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant cancer syndrome with major components of medullary thyroid carcinoma (MTC), pheochromocytoma and hyperparathyroidism. The disease is caused by germline mutations of the RET proto-oncogene. Subtypes of MEN 2 include MEN 2A, MEN 2B and familial MTC (FMTC) which differ in pattern of additional lesions or--in FMTC- lack of pheochromocytoma. In 2009, after extensive review of the literature, the guidelines of the American Thyroid Association made several recommendations regarding clinical and genetic diagnostic testing and treatment options. In this article, the recently published literature is reviewed and concerns regarding future perspectives are added. In particular, a critical handling of rare DNA variants and double mutations is necessary. Up to now, mutation-specific risk profiles and mutation-associated treatment recommendations are unavailable. We emphasise the need for approved centres for treatment of patients affected by MEN 2, not only adults but young children as well. As a high level of skill is required for endoscopic adrenal-sparing surgery, surgeons should declare their expertise before operating such patients. Registry-based follow-up should be mandatory including documentation of short- and long-term outcome in order to provide valid data for future counselling of patients with MEN 2. PMID- 20833331 TI - Clinical and molecular genetics of Carney complex. AB - Carney complex (CNC) is a rare multiple familial neoplasia syndrome that is characterized by multiple types of skin tumors and pigmented lesions, endocrine neoplasms, myxomas and schwannomas and is inherited in an autosomal dominant manner. Clinical and pathologic diagnostic criteria are well established. Over 100 pathogenic variants in the regulatory subunit type 1A (RI-A) of the cAMP dependent protein kinase (PRKAR1A) have been detected in approximately 60% of CNC patients, most leading to R1A haploinsufficiency. Other CNC-causing genes remain to be identified. Recent studies provided some genotype-phenotype correlations in CNC patients carrying PRKAR1A-inactivating mutations, which provide useful information for genetic counseling and/or prognosis; however, CNC remains a disease with significant clinical heterogeneity. Recent mouse and in vitro studies have shed light into how R1A haploinsufficiency causes tumors. PRKAR1A defects appear to be weak tumorigenic signals for most tissues; Wnt signaling activation and cell cycle dysregulation appear to be important mediators of the tumorigenic effect of a defective R1A. PMID- 20833332 TI - VHL disease. AB - von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. In this review, we present a synopsis of clinical features of the disease and emphasise unique aspects of VHL syndrome in the paediatric population. Genotype-phenotype associations based on the risk of phaeochromocytoma have pointed to the existence of additional, HIF-independent functions of VHL that remain underexplored. We also examine the progress on these pleiotropic roles of VHL, which contribute to explain clinical features of VHL disease. These advances have important translational implications and are likely to offer a new host of therapeutic options to individuals affected by the disease in the future. PMID- 20833333 TI - SDH-related pheochromocytoma and paraganglioma. AB - Pheochromocytoma and paraganglioma are rare tumors of adrenals as well as the sympathetic and parasympathetic paraganglia. Clinical presentation of these tumors depends on localization, secretory profile and malignant potential. Four distinct syndromes--PGL1-4--are related to mutations in the succinate dehydrogenase gene--mitochondrial complex involved in electron transfer and Krebs cycle. Here we describe etiology, genetics, as well as clinical aspects of SDH related tumors. We also describe recent discoveries in HIF-related pathway of tumorigenesis and mutations in new SDH-related genes that have improved our understanding of this disease. PMID- 20833334 TI - MEN-4 and other multiple endocrine neoplasias due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. AB - Cyclin-dependent kinase inhibitors (CDKIs) are known targets to become deregulated in various tumour types, including endocrine tumours. Typically, these cell cycle regulators are somatically inactivated in sporadic endocrine tumours. Recently, it became known that certain CDKI genes cause inherited susceptibility to endocrine neoplasia. Multiple endocrine neoplasia type 4 (MEN4) emerged as a novel form of multiple endocrine neoplasia, caused by mutations in the CDKI gene CDKN1B/p27(Kip1). The MEN4 phenotype remains unclear, but all MEN4 patients identified thus far present with parathyroid involvement, and less typically with pituitary adenomas and other endocrine features. Moreover, the CDKI gene CDKN2C/p18(INK4C) has been also implicated in endocrine neoplasia susceptibility. This review presents the recent advances in these novel MEN related states and summarises the current knowledge of how these CDKIs may be implicated in endocrine neoplasia. In addition, it briefly presents data from Cdkn1b/p27(Kip1) and Cdkn2c/p18(INK4C) murine models, which strongly support the protective role of these inhibitors against endocrine tumourigenesis. PMID- 20833335 TI - Endocrine tumours in neurofibromatosis type 1, tuberous sclerosis and related syndromes. AB - Neurofibromatosis type 1 (NF-1) and tuberous sclerosis complex (TSC) are two familial syndromes known as phakomatoses that may be associated with endocrine tumours. These hereditary cutaneous conditions affect the central nervous system and are characterised by the development of hamartomas. Over the past 20 years, there have been major advances in our understanding of the molecular basis of these diseases. Both NF-1 and TSC are disorders of unregulated progression through the cell cycle, in which causative genes behave as tumour suppressor genes. The pathogenesis of these familial syndromes is linked by the shared regulation of a common pathway, the protein kinase mammalian target of rapamycin (mTOR). Additional related disorders that also converge on the mTOR pathway include Peutz-Jeghers syndrome and Cowden syndrome. All of these inherited cancer syndromes are associated with characteristic skin findings that offer a clue to their recognition and treatment. The discovery of mTOR inhibitors has led to a possible new therapeutic modality for patients with endocrine tumours as part of these familial syndromes. PMID- 20833337 TI - The genetics of pituitary adenomas. AB - Pituitary adenomas are one of the most frequent intracranial tumors with a prevalence of clinically-apparent tumors close to 1:1000 of the general population. They are clinically significant because of hormone overproduction and/or tumor mass effects in addition to the need for neurosurgery, medical therapies and radiotherapy. The majority of pituitary adenomas have a sporadic origin with recognized genetic mutations seldom being found; somatotropinomas are an exception, presenting frequent somatic GNAS mutations. In this and other phenotypes, tumorigenesis could possibly be explained by altered function of genes implicated in cell cycle regulation, growth factors or their receptors, cell-signaling pathways, specific hormonal factors or other molecules with still unclear mechanisms of action. Genetic changes, such as allelic loss or gene amplification, and epigenetic changes, usually by promoter methylation, have been implicated in abnormal gene expression, but alternative mechanisms may be present. Familial cases of pituitary adenomas represent 5% of all pituitary tumors. MEN1 mutations cause multiple endocrine neoplasia type 1 (MEN1), while the Carney complex (CNC) is characterized by mutations in the protein kinase A regulatory subunit-1alpha (PRKAR1A) gene or changes in a locus at 2p16. Recently, a MEN1-like condition, MEN4, was found to be related to mutations in the CDKN1B gene. The clinical entity of familial isolated pituitary adenomas (FIPA) is characterized by genetic defects in the aryl hydrocarbon receptor interacting protein (AIP) gene in about 15% of all kindreds and 50% of homogenous somatotropinoma families. Identification of familial cases of pituitary adenomas is important as these tumors may be more aggressive than their sporadic counterparts. PMID- 20833336 TI - Mouse models of endocrine tumours. AB - Since the onset of the genomic era, there has been tremendous progress in identifying the genetic causes of endocrine tumours. Although this knowledge is valuable in its own right, understanding the molecular basis of tumourigenesis allows the development of new therapies targeted at the causative defects. Understanding the connection between genotype and phenotype is a complex process, which can only be partially understood from the analysis of primary tumours or from the studies of cells in vitro. To bridge this gap, genetically modified mice have been developed to allow molecular dissection of the relevant defects in an intact organism. In this article, we discuss the status of genetic modelling for hereditary and sporadic endocrine tumourigenesis with a goal towards providing a view of how this technology will be of future benefit to clinicians developing specifically targeted therapies for endocrine tumours. PMID- 20833338 TI - Familial predisposition to adrenocortical tumors: clinical and biological features and management strategies. AB - The incidence of adrenocortical tumors (ACTs) is increased in several familial cancer syndromes resulting from abnormalities in genes that encode transcription factors implicated in cell proliferation, differentiation, senescence, apoptosis, and genomic instability. These include P53, MEN1, APC, and PRKAR1A. Adenomas are the most common ACTs, but adrenocortical carcinomas occur rarely as well. The clinical manifestations of ACTs, which result from increased secretion of adrenocortical hormones, are similar in the familial and sporadic forms of the disease. However, their management may differ because of unique aspects of the constitutional syndromes. The analysis of gene expression profiles of ACTs in these constitutional syndromes have contributed to our understanding of adrenal tumorigenesis and revealed new molecular diagnostic and prognostic markers and candidate genes for targeted therapies. This chapter summarizes the clinical and biological features, pathogenesis, and management strategies for ACTs that develop in patients with familial cancer syndrome. PMID- 20833339 TI - Clinical and molecular genetics of parathyroid neoplasms. AB - Primary hyperparathyroidism (HPT) results from the excessive secretion of parathyroid hormone from parathyroid tumours. While most HPT is sporadic, it is associated with a familial syndrome in a minority of cases. The study of these syndromes has helped define the pathophysiology of both familial and sporadic parathyroid neoplasms. Investigation of kindred with multiple endocrine neoplasia type 1 (MEN1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT) led to the discovery of the tumour suppressor genes MEN1 and HRPT2. We now recognise that somatic mutations in MEN1 and HRPT2 tumour suppressor genes are frequent events in sporadic parathyroid adenomas and carcinomas, respectively. Parathyroid tumours in the MEN2A syndrome result from mutational activation of the RET oncogene. The CCND1/PRAD1 oncogene was discovered by analysis of sporadic parathyroid tumours. Studies of familial isolated HPT and analysis of chromosomal loss and gain in parathyroid tumours suggest that other genes relevant to parathyroid neoplasia await identification. PMID- 20833341 TI - New kid on the block? Autoimmune pancreatitis. PMID- 20833342 TI - New developments in colorectal cancer screening. Preface. PMID- 20833340 TI - Familial testicular germ cell tumours. AB - This article defines familial testicular germ cell tumours (FTGCTs) as testicular germ cell tumours (TGCTs) diagnosed in at least two blood relatives, a situation which occurs in 1-2% of all cases of TGCT. Brothers and fathers of TGCT patients have an 8-10- and 4-6-fold increased risk of TGCT, respectively, and an even higher elevated risk of TGCT in twin brothers of men with TGCT has been observed, suggesting that genetic elements play an important role in these tumours. Nevertheless, previous linkage studies with multiple FTGCT families did not uncover any high-penetrance genes and it has been concluded that the combined effects of multiple common alleles, each conferring a modest risk, might underlie FTGCT. In agreement with this assumption, recent candidate gene-association analyses have identified the chromosome Y gr/gr deletion and mutations in the PDE11A gene as genetic modifiers of FTGCT risk. Moreover, two genome-wide association studies of predominantly sporadic but also familial cases of TGCT have identified three additional susceptibility loci, KITLG, SPRY4 and BAK1. Notably, all five loci are involved in the biology of primordial germ cells, representing the cell of origin of TGCT, suggesting that the tumours arise as a result of disturbed testicular development. PMID- 20833343 TI - The dimensions of the CRC problem. AB - Colorectal cancer is a significant health problem, the importance of which will increase substantially in the coming years, both in more, as well as in less developed regions of the world. The present paper describes the dimensions of the problem from an epidemiologic viewpoint as well as from the perspective of policy makers and professionals seeking to control the disease. Currently, colorectal cancer is the third most common cancer and the fourth most common cause of cancer deaths worldwide, with 1.2 million estimated cases and 609,000 estimated deaths in 2008. Based on demographic trends, the annual incidence is expected to increase by nearly 80% to 2.2 million cases over the next two decades and most of this increase will occur in the less developed regions of the world (62%). These regions are ill equipped to deal with the rapidly increasing demand for cancer treatment resulting from population growth and higher life expectancy. Concerted efforts to control colorectal cancer are therefore of great importance worldwide. They will require allocation of additional resources and should be based on an appropriate balance between prevention, diagnosis and treatment. PMID- 20833344 TI - Reprint of: the natural history of adenomas. AB - It is well known that adenomas represent the morphologically categorised precursor of the vast majority of colorectal cancers. Only few adenomas actually develop invasive cancer (progressive adenomas), although every adenoma has the capacity of malignant evolution. Most adenomas stabilise their progression or even regress. Easily identifiable but widely ranged pathological features (size, architectural growth, type, grade and gross organisation of dysplasia) are predictive of their natural history in terms of potential of cancerisation and duration of the adenoma-carcinoma sequence. Knowledge of the biological machineries sustaining the progression rates and times could be crucial to refine the natural history assumptions in screening modelling. PMID- 20833345 TI - Targeting risk groups for screening. AB - Currently colorectal cancer (CRC) screening guidelines are based on age and to some extent on family history of screenees only. Potentially CRC screening could be also customised according to gender, race, ethnicity, smoking habits, presence of obesity, diabetes and metabolic syndrome. The factors that could be individually modified are: choice of screening test, age of initiation of screening and screening intervals. Gender is probably the easiest factor to be included. One of the professional societies has already included the race into guidelines in order to lower the age of starting screening in African-Americans. Targeting persons at higher than average-risk aims at optimising the use of available resources. However, an important drawback of such approach exists; it is the risk of making guidelines too complex and incomprehensible for both eligible screenees and physicians. PMID- 20833346 TI - Evidence for colorectal cancer screening. AB - The incidence of colorectal cancer (CRC) has been increasing during the past decades, and the lifetime risk for CRC in industrialised countries is about 5%. CRC is a good candidate for screening, because it is a disease with high prevalence, has recognised precursors, and early treatment is beneficial. This paper outlines the evidence for efficacy from randomised trials for the most commonly used CRC screening tests to reduce CRC incidence and mortality in the average-risk population. Four randomised trials have investigated the effect of guaiac-based fecal occult blood screening on CRC mortality, with a combined CRC mortality risk reduction of 15-17% in an intention-to-screen analysis, and 25% for those people who attended screening. Flexible sigmoidoscopy screening has been evaluated in three randomised trials. The observed reduction in CRC incidence varied between 23 and 80%, and between 27 and 67% for CRC mortality, respectively (intention-to-screen analyses) in the trials with long follow-up time. No randomised trials exist in other CRC screening tools, included colonoscopy screening. FOBT and flexible sigmoidoscopy are the two CRC screening methods which have been tested in randomised trials and shown to reduce CRC mortality. These tests can be recommended for CRC screening. PMID- 20833347 TI - Simulation of colorectal cancer screening: what we do and do not know and does it matter. AB - Simulation modelling is increasingly used to inform decision-making on screening, including colorectal cancer screening strategies. The strength of simulation is its ability to handle complexity and to identify the implications of uncertainty in a formal, documented, reproducible and consistent way. Important specific uncertainties concerning colorectal cancer screening are the dwell time of adenomas and the associated sensitivity of the various tests. Concerning these issues, for distal colorectal neoplasia, knowledge has been greatly increased by the recent availability of the once only sigmoidoscopy randomised trial results. Other uncertainties concern the quality of life effects of screening, diagnostic and surveillance colonoscopies, and the true total costs of the various screening modalities in a routine high throughput efficient setting. A limitation of simulation of screening is that complexity leads to lack of insight and understanding into the models used, and therefore a lack of sound criticism, acceptance and use amongst decision makers. Modellers are currently focussing on ways to make models and the implications of assumptions more transparent. Thus it is important to further develop the quality and acceptability of simulation, especially that for colorectal cancer screening. PMID- 20833349 TI - Quality assurance of endoscopy in colorectal cancer screening. AB - This chapter explores the concept of quality assurance of colorectal cancer screening. It argues that effective quality assurance is critical to ensure that the benefits of screening outweigh the harms. The three key steps of quality assurance, definition of standards, measurement of standards and enforcement of standards, are explained. Quality is viewed from the perspective of the patient and illustrated by following the path of patients accessing endoscopy within screening services. The chapter discusses the pros and cons of programmatic versus non-programmatic screening and argues that quality assurance of screening can and should benefit symptomatic services. Finally, the chapter emphasises the importance of a culture of excellence underpinned by continuous quality improvement and effective service leadership. PMID- 20833348 TI - Cost-effectiveness of colorectal cancer screening - an overview. AB - There are several modalities available for a colorectal cancer (CRC) screening program. When determining which CRC screening program to implement, the costs of such programs should be considered in comparison to the health benefits they are expected to provide. Cost-effectiveness analysis provides a tool to do this. In this paper we review the evidence on the cost-effectiveness of CRC screening. Published studies universally indicate that when compared with no CRC screening, all screening modalities provide additional years of life at a cost that is deemed acceptable by most industrialized nations. Many recent studies even find CRC screening to be cost-saving. However, when the alternative CRC screening strategies are compared against each other in an incremental cost-effectiveness analysis, no single optimal strategy emerges across the studies. There is consensus that the new technologies of stool DNA testing, computed tomographic colonography and capsule endoscopy are not yet cost-effective compared with the established CRC screening tests. PMID- 20833350 TI - Does participation to screening unintentionally influence lifestyle behaviour and thus lifestyle-related morbidity? AB - Cancer is a leading cause of death worldwide and the burden could be reduced by evidence-based strategies for the primary prevention of cancer, the early detection of malignancies and more adequate treatment of cancer patients. Previous research has shown that lifestyle factors are associated with common cancers and that several cancer screening programmes are cost-effective in reducing cancer-specific mortality. But, some recent studies reported that participants of screening programs might unintentionally change their lifestyle. Cancer screening might be a teachable moment or, on the other hand, have a false health certificate effect. Despite that the evidence is scarce, cancer screening might have opportunities for lifestyle improvements, although a possible health certificate effect still remains. Integrated approaches to combine primary and secondary prevention have the potential to optimise the efforts to improve cancer prevention and survival. More research is warranted to investigate evidence-based approaches. PMID- 20833351 TI - Performance improvements of stool-based screening tests. AB - Stool testing is a widely accepted, non-invasive, technique for colorectal cancer (CRC) screening. Guaiac-based faecal occult blood test (gFOBT) screening has been proven to decrease CRC-related mortality; however gFOBT is hampered by a low sensitivity. Faecal immunochemical tests (FITs) have several advantages over gFOBT. First of all, FIT has a better sensitivity and higher uptake. Furthermore, the quantitative variant of the FIT allows choices on cut-off level for test positivity according to colonoscopy resources available, personal risk profile, and/or intended detection rate in the screened population. Stool-based DNA (sDNA) tests aiming at the detection of specific DNA alterations may improve detection of CRC and adenomas compared to gFOBT screening, but large-scale population based studies are lacking. This review focuses on factors influencing test performance of those three stool based screening tests. PMID- 20833352 TI - Performance improvements of imaging-based screening tests. AB - Endoscopic and radiologic tests appear to be more accurate than stool-tests in detecting advanced neoplasia because of direct visualisation of colorectal mucosa. Further technological advances are expected to improve the performance and acceptability of these tests. Several attempts at increasing the adenoma detection rate of colonoscopy have been tested, and in vivo histologic differentiation between neoplastic and hyperplastic polyps may lead to substantial saving in economic and medical resources. Low-volume and non cathartic bowel preparations may improve CT colonography acceptability, whilst computer-aided detection and low-dose protocols may result in a higher accuracy and safety of this procedure. Despite the lack of ionising radiation, significant drawbacks will likely to limit the role of MR colonography in screening programs. Colon capsule endoscopy appears to be a safe and technically feasible procedure. The suboptimal accuracy of the first generation seems to be substantially improved by the second generation of this device. PMID- 20833353 TI - How to enhance physician and public acceptance and utilisation of colon cancer screening recommendations. AB - Colorectal Cancer (CRC) screening delivery is a multidisciplinary undertaking, aiming at reducing mortality from and incidence of CRC without adversely affecting the health status of participants. The adoption of a public health perspective involves commitment to ensure equity of access and sustainability of the program over time. We reviewed available evidence concerning predictors of CRC screening uptake and the impact of interventions to improve adoption of screening using conceptual frameworks defining the role of determinants of preventive behaviours and the reach and target of interventions. The results of this review indicate that policy measures aimed at supporting screening delivery, as well as organisational changes, influencing the operational features of preventive services, need to be implemented, in order to allow individual's motivation to be eventually realised. To ensure coverage and equity of access and to maximise the impact of the intervention, policies aimed at implementing organised programs should be adopted, ensuring that participation in screening and any follow-up assessment should not be limited by financial barriers. Participants and providers beliefs may determine the response to different screening modalities. To achieve the desired health impact, an active follow-up of people with screening abnormalities should be implemented, supported by the introduction of infrastructural changes and multidisciplinary team work, which can ensure sustainability over time of effective interventions. Continuous monitoring as well as the adoption of plans to evaluate for program effectiveness represent crucial steps in the implementation of a successful program. PMID- 20833354 TI - Colorectal cancer screening in an expanding panorama of screening programmes. AB - Cervical and breast cancer screening programmes have been introduced in times when both the professional requirements for evidence based medicine and public demand for quantification of benefits may have been less explicit. The World Health Organisation has recommended cancer screening only for cervix, breast and colorectal cancer (CRC) - the latter leaving health authorities with a choice between a multitude of screening methods of which the efficacy has been proven only for fecal occult blood testing (FOBT). Although we are far from seeing the perfect screening method and screening programme, cost effectiveness for CRC screening has been estimated at least as cost-effective as established programmes for cervix and breast cancer screening. Established and imminent screening programmes should be considered as natural platforms for randomised trial with commitment and responsibility to continuously improve the quality and effectiveness of the screening service provided. PMID- 20833355 TI - Signaling defects and the nuclear envelope in progeria. AB - Hutchinson-Gilford progeria syndrome is a rare childhood genetic disorder with features of accelerated aging. In this issue, Hernandez et al. observe decreased Wnt signaling and extracellular matrix gene expression in a murine model of the disease, suggesting potential therapeutic strategies and further emphasizing the nuclear envelope's role in signal transduction. PMID- 20833356 TI - Multiclassifier proteomics to define complexes yields new chromosomal proteins. AB - In a recent issue of Cell, Ohta et al. report a method of quantitative proteomics coupled with bioinformatic analysis for the identification of associated components in complex mixtures. Using this approach, they assayed the protein composition of mitotic chromosomes, identifying 4029 associated proteins, 562 of which are previously uncharacterized. PMID- 20833357 TI - It's not just sex. AB - The dosage of X and Y chromosome genes varies systematically in males and females. In mammals, X inactivation largely compensates for this, but in this issue of Developmental Cell, Wijchers et al. show that the expression of hundreds of autosomal genes is still influenced by sex chromosome dosage, independently of physiological sex. PMID- 20833358 TI - pRb, a switch between bone and brown fat. AB - Calo et al. (2010) recently reported that the absence of the transcriptional regulator pRb enhances differentiation of mesenchymal precursors toward the brown adipocyte lineage in detriment of osteoblast and white fat populations. These findings may have therapeutic implications for cancer and bone and metabolic disease. PMID- 20833359 TI - A cellular view of Nf2 in liver homeostasis and tumorigenesis. AB - How liver adjusts and stabilizes its size is unsolved so far; the answers to this question may also provide insights into mechanisms of hepatocarcinogenesis. Two recent papers suggest a role for Merlin/Nf2 in control of liver cell turnover, but results appear conflicting at first glance. PMID- 20833360 TI - A zyxin-mediated mechanism for actin stress fiber maintenance and repair. AB - To maintain mechanical homeostasis, cells must recognize and respond to changes in cytoskeletal integrity. By imaging live cells expressing fluorescently tagged cytoskeletal proteins, we observed that actin stress fibers undergo local, acute, force-induced elongation and thinning events that compromise their stress transmission function, followed by stress fiber repair that restores this capability. The LIM protein zyxin rapidly accumulates at sites of strain-induced stress fiber damage and is essential for stress fiber repair and generation of traction force. Zyxin promotes recruitment of the actin regulatory proteins alpha actinin and VASP to compromised stress fiber zones. alpha-Actinin plays a critical role in restoration of actin integrity at sites of local stress fiber damage, whereas both alpha-actinin and VASP independently contribute to limiting stress fiber elongation at strain sites, thus promoting stabilization of the stress fiber. Our findings demonstrate a mechanism for rapid repair and maintenance of the structural integrity of the actin cytoskeleton. PMID- 20833361 TI - Rho-kinase directs Bazooka/Par-3 planar polarity during Drosophila axis elongation. AB - Cell rearrangements shape the Drosophila embryo via spatially regulated changes in cell shape and adhesion. We show that Bazooka/Par-3 (Baz) is required for the planar polarized distribution of myosin II and adherens junction proteins and polarized intercalary behavior is disrupted in baz mutants. The myosin II activator Rho-kinase is asymmetrically enriched at the anterior and posterior borders of intercalating cells in a pattern complementary to Baz. Loss of Rho kinase results in expansion of the Baz domain, and activated Rho-kinase is sufficient to exclude Baz from the cortex. The planar polarized distribution of Baz requires its C-terminal domain. Rho-kinase can phosphorylate this domain and inhibit its interaction with phosphoinositide membrane lipids, suggesting a mechanism by which Rho-kinase could regulate Baz association with the cell cortex. These results demonstrate that Rho-kinase plays an instructive role in planar polarity by targeting Baz/Par-3 and myosin II to complementary cortical domains. PMID- 20833362 TI - Chiral forces organize left-right patterning in C. elegans by uncoupling midline and anteroposterior axis. AB - Left-right (LR) patterning is an intriguing but poorly understood process of bilaterian embryogenesis. We report a mechanism for LR patterning in C. elegans in which the embryo uncouples its midline from the anteroposterior (AP) axis. Specifically, the eight-cell embryo establishes a midline that is tilted rightward from the AP axis and positions more cells on the left, allowing subsequent differential LR fate inductions. To establish the tilted midline, cells exhibit LR asymmetric protrusions and a handed collective movement. This process, termed chiral morphogenesis, involves differential regulation of cortical contractility between a pair of sister cells that are bilateral counterparts fate-wise and is activated by noncanonical Wnt signaling. Chiral morphogenesis is timed by the cytokinetic furrow of a neighbor of the sister pair, providing a developmental clock and an unexpected signaling interaction between the contractile ring and the adjacent cells. PMID- 20833363 TI - Functional coupling between the extracellular matrix and nuclear lamina by Wnt signaling in progeria. AB - The segmental premature aging disease Hutchinson-Gilford Progeria (HGPS) is caused by a truncated and farnesylated form of Lamin A. In a mouse model for HGPS, a similar Lamin A variant causes the proliferative arrest and death of postnatal, but not embryonic, fibroblasts. Arrest is due to an inability to produce a functional extracellular matrix (ECM), because growth on normal ECM rescues proliferation. The defects are associated with inhibition of canonical Wnt signaling, due to reduced nuclear localization and transcriptional activity of Lef1, but not Tcf4, in both mouse and human progeric cells. Defective Wnt signaling, affecting ECM synthesis, may be critical to the etiology of HGPS because mice exhibit skeletal defects and apoptosis in major blood vessels proximal to the heart. These results establish a functional link between the nuclear envelope/lamina and the cell surface/ECM and may provide insights into the role of Wnt signaling and the ECM in aging. PMID- 20833364 TI - Extended-synaptotagmin-2 mediates FGF receptor endocytosis and ERK activation in vivo. AB - Targeting of activated plasma membrane receptors to endocytic pathways is important in determining the outcome of growth factor signaling. However, the molecular mechanisms are still poorly understood. Here, we show that the synaptotagmin-related membrane protein E-Syt2 is essential for rapid endocytosis of the activated FGF receptor and for functional signal transduction during Xenopus development. E-Syt2 depletion prevents an early phase of activated FGF receptor endocytosis that we show is required for ERK activation and the induction of the mesoderm. E-Syt2 interacts selectively with the activated FGF receptor and with Adaptin-2, and is required upstream of Ras activation and of receptor autophosphorylation for ERK activation and the induction of the mesodermal marker Xbra. The data identify E-Syt2 as an endocytic adaptor for the clathrin-mediated pathway whose function is conserved in human and suggest a broader role for the E-Syt subfamily in growth factor signaling. PMID- 20833365 TI - FGF9 suppresses meiosis and promotes male germ cell fate in mice. AB - Sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. Previous studies have established that retinoic acid (RA) triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis, whereas in the developing testis, the enzyme CYP26B1 degrades RA and germ cells are not induced to enter meiosis. Using in vitro and in vivo models, we demonstrate that fibroblast growth factor 9 (FGF9) produced in the fetal testis acts directly on germ cells to inhibit meiosis; in addition, FGF9 maintains expression of pluripotency-related genes and upregulates markers associated with male germ cell fate. We conclude that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors. PMID- 20833366 TI - Hopx and Hdac2 interact to modulate Gata4 acetylation and embryonic cardiac myocyte proliferation. AB - Regulation of chromatin structure via histone modification has recently received intense attention. Here, we demonstrate that the chromatin-modifying enzyme histone deacetylase 2 (Hdac2) functions with a small homeodomain factor, Hopx, to mediate deacetylation of Gata4, which is expressed by cardiac progenitor cells and plays critical roles in the regulation of cardiogenesis. In the absence of Hopx and Hdac2 in mouse embryos, Gata4 hyperacetylation is associated with a marked increase in cardiac myocyte proliferation, upregulation of Gata4 target genes, and perinatal lethality. Hdac2 physically interacts with Gata4, and this interaction is stabilized by Hopx. The ability of Gata4 to transactivate cell cycle genes is impaired by Hopx/Hdac2-mediated deacetylation, and this effect is abrogated by loss of Hdac2-Gata4 interaction. These results suggest that Gata4 is a nonhistone target of Hdac2-mediated deacetylation and that Hdac2, Hopx, and Gata4 coordinately regulate cardiac myocyte proliferation during embryonic development. PMID- 20833367 TI - Histone demethylase JmjD2A regulates neural crest specification. AB - The neural crest is a multipotent stem cell-like population that is induced during gastrulation, but only acquires its characteristic morphology, migratory ability, and gene expression profile after neurulation. This raises the intriguing possibility that precursors are actively maintained by epigenetic influences in a stem cell-like state. Accordingly, we report that dynamic histone modifications are critical for proper temporal control of neural crest gene expression in vivo. The histone demethylase, JumonjiD2A (JmjD2A/KDM4A), is expressed in the forming neural folds. Loss of JmjD2A function causes dramatic downregulation of neural crest specifier genes analyzed by multiplex NanoString and in situ hybridization. Importantly, in vivo chromatin immunoprecipitation reveals direct stage-specific interactions of JmjD2A with regulatory regions of neural crest genes, and associated temporal modifications in methylation states of lysine residues directly affected by JmjD2A activity. Our findings show that chromatin modifications directly control neural crest genes in vertebrate embryos via modulating histone methylation. PMID- 20833368 TI - The matrix protein hnRNP U is required for chromosomal localization of Xist RNA. AB - In XX female mammals, one of the two X chromosomes is epigenetically inactivated to equalize gene expression with XY males. The formation of the inactive X chromosome (Xi) is regulated by an X-linked long noncoding RNA Xist, which accumulates on the entire length of the chromosome in cis and induces heterochromatin formation. However, the mechanism by which Xist RNA "paints" the Xi has long remained elusive. Here, we show that a matrix protein hnRNP U/SP120/SAF-A is required for the accumulation of Xist RNA on the Xi. Xist RNA and hnRNP U interact and upon depletion of hnRNP U, Xist RNA is detached from the Xi and diffusely localized into the nucleoplasm. In addition, ES cells lacking hnRNP U expression fail to form the Xi. We propose that the association with matrix proteins is an essential step in the epigenetic regulation of gene expression by Xist RNA. PMID- 20833369 TI - Sexual dimorphism in mammalian autosomal gene regulation is determined not only by Sry but by sex chromosome complement as well. AB - Differences between males and females are normally attributed to developmental and hormonal differences between the sexes. Here, we demonstrate differences between males and females in gene silencing using a heterochromatin-sensitive reporter gene. Using "sex-reversal" mouse models with varying sex chromosome complements, we found that this differential gene silencing was determined by X chromosome complement, rather than sex. Genome-wide transcription profiling showed that the expression of hundreds of autosomal genes was also sensitive to sex chromosome complement. These genome-wide analyses also uncovered a role for Sry in modulating autosomal gene expression in a sex chromosome complement specific manner. The identification of this additional layer in the establishment of sexual dimorphisms has implications for understanding sexual dimorphisms in physiology and disease. PMID- 20833370 TI - [The French stroke national programme, the PRM practitioner and the brain-damaged patient]. PMID- 20833371 TI - Epithelial sensing of fungal invasion. AB - The mechanisms discriminating mucosal colonization from invasion by Candida albicans are unclear. In this issue, Moyes et al. show that epithelial cells discriminate between colonizing yeasts and invading hyphae by mechanisms involving c-Fos and MKP1 phosphatase, opening up new avenues for understanding the pathophysiology of mucosal fungal infections. PMID- 20833372 TI - Stopping HPVs dead in their tracts. AB - Vaccines are currently available to prevent infection of the genital tract and subsequent disease for some human papillomavirus (HPV) types, and attempts to develop broadly cross-reactive HPV vaccines are progressing. A recently developed murine model of cervicovaginal HPV infection examines the mechanisms by which antibodies prevent infection in vivo. PMID- 20833373 TI - G-CSF and CD34+ progenitor cells in hematopoietic grafts: too fertile for human cytomegalovirus. AB - Smith et al. (2010) establish a humanized mouse model of latent host and cellular tropism of human cytomegalovirus (HCMV) infection and examine the effects of granulocyte-colony stimulating factor (GCSF) on human cytomegalovirus (HCMV) reactivation in vivo. HCMV-infected circulating CD34(+) myeloid cells populate end organs such as the liver and differentiate into cells capable of supporting lytic infection. PMID- 20833374 TI - A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. AB - Discriminating between commensal and pathogenic states of opportunistic pathogens is critical for host mucosal defense and homeostasis. The opportunistic human fungal pathogen Candida albicans is also a constituent of the normal oral flora and grows either as yeasts or hyphae. We demonstrate that oral epithelial cells orchestrate an innate response to C. albicans via NF-kappaB and a biphasic MAPK response. Activation of NF-kappaB and the first MAPK phase, constituting c-Jun activation, is independent of morphology and due to fungal cell wall recognition. Activation of the second MAPK phase, constituting MKP1 and c-Fos activation, is dependent upon hypha formation and fungal burdens and correlates with proinflammatory responses. Such biphasic response may allow epithelial tissues to remain quiescent under low fungal burdens while responding specifically and strongly to damage-inducing hyphae when burdens increase. MAPK/MKP1/c-Fos activation may represent a "danger response" pathway that is critical for identifying and responding to the pathogenic switch of commensal microbes. PMID- 20833375 TI - Immune inhibitory ligand CD200 induction by TLRs and NLRs limits macrophage activation to protect the host from meningococcal septicemia. AB - Macrophage activation is essential for protection against bacterial pathogens but needs to be regulated to prevent damage to the host. We show a key role for the immune inhibitory receptor CD200R and its ligand CD200 in the context of infection with the Gram-negative human pathogen Neisseria meningitidis. N. meningitidis induced CD200 but downregulated CD200R on macrophages in a manner dependent on Neisserial lipopolysaccharide, Toll-like receptor-4 (TLR-4), and the MyD88 pathway but independent of a known Neisserial receptor, scavenger receptor A (SR-A). Agonists of the pattern-recognition receptors nucleotide oligomerization domain 2 (NOD2) and NACHT-LRR protein 3 (NALP3) also induced CD200. The NF-kappaB member c-Rel was essential for TLR-, NOD2-, and NALP3 mediated induction of CD200. CD200(-/-) animals showed higher lethality in response to experimental meningococcal septicemia, induced higher levels of proinflammatory cytokines, and recruited increased numbers of activated leukocytes, despite comparable bacterial clearance. Thus CD200 is induced by TLR , NOD2-, and NALP3-mediated pathways, limiting their function and protecting the host from excessive inflammation. PMID- 20833376 TI - Structural and functional analysis of prehistoric lentiviruses uncovers an ancient molecular interface. AB - Lentiviruses are widespread in a variety of vertebrates, often associated with chronic disease states. However, until the recent discovery of the prehistoric endogenous lentiviruses in rabbits (RELIK) and lemurs (PSIV), it was thought that lentiviruses had no capacity for germline integration and were only spread horizontally in an exogenous fashion. The existence of RELIK and PSIV refuted these ideas, revealing lentiviruses to be present in a range of mammals, capable of germline integration, and far more ancient than previously thought. Using Gag sequences reconstructed from the remnants of these prehistoric lentiviruses, we have produced chimeric lentiviruses capable of infecting nondividing cells and determined structures of capsid domains from PSIV and RELIK. We show that the structures from these diverse viruses are highly similar, containing features found in modern-day lentiviruses, including a functional cyclophilin-binding loop. Together, these data provide evidence for an ancient capsid-cyclophilin interaction preserved throughout lentiviral evolution. PMID- 20833377 TI - In vivo mechanisms of vaccine-induced protection against HPV infection. AB - Using a human papillomavirus (HPV) cervicovaginal murine challenge model, we microscopically examined the in vivo mechanisms of L1 virus-like particle (VLP) and L2 vaccine-induced inhibition of infection. In vivo HPV infection requires an initial association with the acellular basement membrane (BM) to induce conformational changes in the virion that permit its association with the keratinocyte cell surface. By passive transfer of immune serum, we determined that anti-L1 antibodies can interfere with infection at two stages. Similarly to active VLP immunization, transfer of high L1 antibody concentrations prevented BM binding. However, in the presence of low concentrations of anti-L1, virions associated with the BM, but to the epithelial cell surface was not detected. Regardless of the concentration, L2 vaccine-induced antibodies allow BM association but prevent association with the cell surface. Thus, we have revealed distinct mechanisms of vaccine-induced inhibition of virus infection in vivo. PMID- 20833378 TI - The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. AB - Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcgamma receptors (FcgammaR). We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. All mAbs enhanced infection at subneutralizing concentrations. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent FcgammaR binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue. PMID- 20833379 TI - Granulocyte-colony stimulating factor reactivates human cytomegalovirus in a latently infected humanized mouse model. AB - Human cytomegalovirus (HCMV) is a significant cause of morbidity and mortality in organ transplant recipients. The use of granulocyte-colony stimulating factor (G CSF)-mobilized stem cells from HCMV seropositive donors is suggested to double the risk of late-onset HCMV disease and chronic graft-versus-host disease in recipients when compared to conventional bone marrow transplantation with HCMV seropositive donors, although the etiology of the increased risk is unknown. To understand mechanisms of HCMV transmission in patients receiving G-CSF-mobilized blood products, we generated a NOD-scid IL2Rgamma(c)(null)-humanized mouse model in which HCMV establishes latent infection in human hematopoietic cells. In this model, G-CSF induces the reactivation of latent HCMV in monocytes/macrophages that have migrated into organ tissues. In addition to establishing a humanized mouse model for systemic and latent HCMV infection, these results suggest that the use of G-CSF mobilized blood products from seropositive donors pose an elevated risk for HCMV transmission to recipients. PMID- 20833380 TI - Enterobacteriaceae act in concert with the gut microbiota to induce spontaneous and maternally transmitted colitis. AB - Disruption of homeostasis between the host immune system and the intestinal microbiota leads to inflammatory bowel disease (IBD). Whether IBD is instigated by individual species or disruptions of entire microbial communities remains controversial. We characterized the fecal microbial communities in the recently described T-bet(-/-) *Rag2(-/-) ulcerative colitis (TRUC) model driven by T-bet deficiency in the innate immune system. 16S rRNA-based analysis of TRUC and Rag2( /-) mice revealed distinctive communities that correlate with host genotype. The presence of Klebsiella pneumoniae and Proteus mirabilis correlates with colitis in TRUC animals, and these TRUC-derived strains can elicit colitis in Rag2(-/-) and WT adults but require a maternally transmitted endogenous microbial community for maximal intestinal inflammation. Cross-fostering experiments indicated a role for these organisms in maternal transmission of disease. Our findings illustrate how gut microbial communities work in concert with specific culturable colitogenic agents to cause IBD. PMID- 20833381 TI - Intensive current transfer in membrane systems: modelling, mechanisms and application in electrodialysis. AB - Usually in electrochemical systems, the direct current densities not exceeding the limiting current density are applied. However, the recent practice of electrodialysis evidences the interest of other current modes where either the imposed direct current is over the limiting one or a non-constant asymmetrical (such as pulsed) current is used. The paper is devoted to make the mechanisms of mass transfer under these current regimes more clear. The theoretical background for mathematical modelling of mass transfer at overlimiting currents is described. Four effects providing overlimiting current conductance are examined. Two of them are related to water splitting: the appearance of additional charge carriers (H(+) and OH(-) ions) and exaltation effect. Two others are due to coupled convection partially destroying the diffusion boundary layer: gravitational convection and electroconvection. These effects result from formation of concentration gradients (known as concentration polarization) caused by the current flowing under conditions where ionic transport numbers are different in the membrane and solution. Similar effects take place not only in electrodialysis membrane systems, but in electrode ones, in electrophoresis and electrokinetic micro- and nanofluidic devices such as micropumps. The relation of these effects to the properties of the membrane surface (the chemical nature of the fixed groups, the degree of heterogeneity and hydrophobicity, and the geometrical shape of the surface) is analyzed. The interaction between the coupled effects is studied, and the conditions under which one or another effect becomes dominant are discussed. The application of intensive current modes in electrodialysis, the state-of-the-art and perspectives, are considered. It is shown that the intensive current modes are compatible with new trends in water treatment oriented towards Zero Liquid Discharge (ZLD) technologies. The main idea of these hybrid schemes including pressure- and electro-driven processes as well as conventional methods is to provide the precipitation of hardness salts before the membrane modules and that of well dissolved salts after. PMID- 20833382 TI - Existing models fail to predict sepsis in an obstetric population with intrauterine infection. AB - OBJECTIVE: Multiple scoring systems exist to identify inpatients who are at risk for clinical deterioration. None of these systems have been evaluated in an obstetric population. We examined the Systemic Inflammatory Response syndrome (SIRS) and Modified Early Warning score (MEWS) criteria in pregnant women with chorioamnionitis. STUDY DESIGN: This was an 18-month retrospective analysis of patients with chorioamnionitis. SIRS and MEWS scores were calculated; clinical outcomes were ascertained, and test characteristics were calculated for the primary outcome of sepsis, intensive care unit transfer, or death. RESULTS: Nine hundred thirteen women with chorioamnionitis were identified. Five women experienced sepsis; there was 1 death. Five hundred seventy-five of the 913 women (63%) met SIRS criteria (95% confidence interval, 59.8-66.2%; positive predictive value, 0.9%). Ninety-two of the 913 women (10.3%) had a MEWS score of >= 5 (95% confidence interval, 8.3-12.2%; positive predictive value, 0.05%). CONCLUSION: SIRS and MEWS criteria do not identify accurately patients who are at risk for intensive care unit transfer, sepsis, or death among pregnant women with intrauterine infection and should not be used in an obstetric setting. PMID- 20833383 TI - Decreased proportion of peripheral blood vascular endothelial growth factor expressing T and natural killer cells in preeclampsia. AB - OBJECTIVE: The purpose of this study was to determine the proportion of circulating T and natural killer (NK) cells that express intracellular vascular endothelial growth factor (VEGF) in women with preeclampsia compared to those with a normal pregnancy. STUDY DESIGN: In all, 24 preeclamptic patients and 30 healthy pregnant women were involved in this case-control study. Intracellular VEGF expression of unstimulated lymphocytes was determined with flow cytometric examination. RESULTS: In healthy pregnant women, the majority of both T and NK cells expressed VEGF in their cytoplasma (median, 79.9%; 25-75 percentile, 73.7 87.0 and median, 78.3%; 25-75 percentile, 64.1-85.3, respectively). Furthermore, CD4(+) helper and CD8(+) cytotoxic T cells showed a similar pattern of VEGF expression in normal pregnancy. However, the proportion of VEGF-expressing peripheral blood T (both helper and cytotoxic) and NK cells was markedly decreased in preeclampsia (for T cells: median, 51.6%; 25-75 percentile, 40.1 60.0; P < .001; for NK cells: median, 45.2%; 25-75 percentile, 27.4-64.0; P < .001). CONCLUSION: Our results suggest decreased production of VEGF by circulating T and NK cells in preeclampsia, which might contribute to the development of the generalized endothelial dysfunction characteristic of the maternal syndrome of the disease. PMID- 20833384 TI - Maternal depressive symptoms, serum folate status, and pregnancy outcome: results of the Amsterdam Born Children and their Development study. AB - OBJECTIVE: The objective was to explore whether different levels of depressive symptoms in pregnant women and their serum folate status combined were associated with the gestational age and birthweight of their offspring. STUDY DESIGN: Data were derived from pregnant women in Amsterdam who completed a questionnaire covering depressive symptoms (Center for Epidemiological Studies Depression Scale) and from whom blood samples were taken to determine serum folate status. Only live-born singletons were included (n = 4044) in the multivariate regression analysis. RESULTS: When adjusted for potential confounders, only the association between major depressive symptoms and gestational age remained significant (-0.2 weeks; 95% confidence interval, -0.4 to -0.1). Women with depressive symptoms and low folate status (7.6%) experienced the shortest gestational age (38.6 weeks) and lowest birthweight (3270 g) (there was no significant interaction). CONCLUSION: Depressive symptoms were associated with shorter gestational age and related lower birthweight. The study results underline the importance of folic acid intake specifically in women suffering from depressive symptoms. PMID- 20833385 TI - Testing for methylated PCDH10 or WT1 is superior to the HPV test in detecting severe neoplasms (CIN3 or greater) in the triage of ASC-US smear results. AB - OBJECTIVE: Management of equivocal Papanicolaou smear result remains to be challenging even with the aid of human papillomavirus test. Recently, 3 novel methylation-silenced genes, PAX1, WT1, and PCDH10, have been found to be specifically associated with cervical cancer. We compared the performances of methylation test of these genes with human papillomavirus tests in triage of equivocal Papanicolaou smear result. STUDY DESIGN: Two hundred twenty-two women with Papanicolaou smear results of atypical cells of undetermined significance nested to a multicenter, nation-wide cohort (the T1899 cohort) were studied. Status of cervical neoplasm was diagnosed with colposcopic biopsy. Status of gene methylation was determined by methylation-specific polymerase chain reaction. High-risk human papillomavirus DNA was detected by polymerase chain reaction reverse line blot hybridization and Hybrid Capture 2. RESULTS: Cervical intraepithelial neoplasm 1, cervical intraepithelial neoplasm 2, cervical intraepithelial neoplasm 3, carcinoma in situ, carcinoma, and normal cervix were diagnosed in 58, 17, 14, 10, 1, and 120 women, respectively. Methylation of PCDH10, WT1, and PAX1 was highly associated with the severity of cervical neoplasm (P < 10-9, < 10-7, and < 10-5, respectively). In comparison with a negative test result, the odds ratio (95% confidence intervals) for cervical intraepithelial neoplasm 3 or more severe neoplasms for women tested positive for methylation of these 3 genes were 26.4 (9.0-77.3), 18.1 (6.9-47.2), and 10.3 (4.1 25.9), respectively; whereas those positive for human papillomavirus polymerase chain reaction and Hybrid Capture 2 were 10.5 (3.5-31.9) and 5.6 (2.3-21.4). In triage for atypical cells of undetermined significance, each methylation test had less colposcopy referral and false-positive rates, but higher false-negative rate than the human papillomavirus tests. With a combination test of PCDH10 or WT1 methylation, a comparable false-negative rate (P = .62) but much less false positive rate (P = .002) and colposcopy referral rate (P < 10-6) were achieved. CONCLUSION: In triage of atypical cells of undetermined significance Papanicolaou smear results, methylation test of WT1 and PCDH10 is superior to human papillomavirus test in this multicenter cohort. Comparing to current human papillomavirus triage, the new test has only one third of false positivity and half of colposcopy referral, with no compromise of the sensitivity in diagnosis of cervical intraepithelial neoplasm 3 or more severe neoplasms. PMID- 20833386 TI - Change in spine height measurements following sustained mid-range and end-range flexion of the lumbar spine. AB - Workers lose height during the day. Flexion-based exercises and body positions are commonly prescribed to unload the spine and prevent back pain. Lumbar extension positions have been researched and result in an increase in spine height. End-range lumbar extension postures increase spine height to a greater extent than mid-range lumbar extension postures, but these positions are not always tolerated by patients with lumbar conditions. No study to date has investigated the effect of end-range versus mid-range lumbar flexion postures on spine height changes. The purpose of this study was to investigate the effects of two techniques commonly used in clinical settings to unload the lumbar intervertebral disc (IVD) segments through increasing spine height in: (1) a sidelying mid-range lumbar flexion position; and (2) a sidelying end-range lumbar flexion position. A total of 20 asymptomatic women and 21 asymptomatic men with a mean age of 23.8 years (+/-2.5) participated in the study. Subjects were randomized systematically into 2 groups to determine the order of testing position. Measurements were taken with a stadiometer in the sitting position to detect change in spine height after each position. Results of the paired t-tests indicated that compared to the spine height in sitting, the sidelying end-range lumbar flexion position resulted in a statistically significant (p < .001) mean spine height gain of 4.78 mm (+/-4.01) while the sidelying mid-range lumbar flexion position resulted in a statistically significant (p < .001) mean spine height gain of 5.84 mm (+/-4.4). No significant difference between the height changes observed following the two sidelying positions was found (p = .22). Sidelying lumbar flexion positions offer valuable alternatives to lumbar extension positions to increase spine height, possibly through increasing hydration levels of the lumbar IVD and could be proposed as techniques to offset spinal shrinkage and the biomechanical consequences of sustained loads. PMID- 20833387 TI - Musculoskeletal symptoms among mobile hand-held device users and their relationship to device use: A preliminary study in a Canadian university population. AB - The study aims were, in a population of university students, staff, and faculty (n = 140), to: 1) determine the distribution of seven measures of mobile device use; 2) determine the distribution of musculoskeletal symptoms of the upper extremity, upper back and neck; and 3) assess the relationship between device use and symptoms. 137 of 140 participants (98%) reported using a mobile device. Most participants (84%) reported pain in at least one body part. Right hand pain was most common at the base of the thumb. Significant associations found included time spent internet browsing and pain in the base of the right thumb (odds ratio 2.21, 95% confidence interval 1.02-4.78), and total time spent using a mobile device and pain in the right shoulder (2.55, 1.25-5.21) and neck (2.72, 1.24 5.96). Although this research is preliminary, the observed associations, together with the rising use of these devices, raise concern for heavy users. PMID- 20833388 TI - Ergonomics contribution to chemical risks prevention: An ergotoxicological investigation of the effectiveness of coverall against plant pest risk in viticulture. AB - The purpose of this article is to present the contribution of a trans disciplinary approach focused on ergonomics and chemical risk control. We shall more precisely discuss how such an approach carried out in the field of agricultural work has made it possible to highlight serious shortcomings in the effectiveness of the coveralls that are supposed to protect vineyard workers from pesticides. The study results, as well as the whistle-blow that followed have questioned the control and prevention measures used until then. The aforementioned trans-disciplinary approach gathers knowledge and methods from epidemiology, industrial hygiene, occupational health and safety and ergonomics. Ergonomics were central in the development of the approach as it connected task and activity analysis with contamination measurements. Lastly, the first results that were obtained have been confirmed and reused by the AFSSET (Agence Francaise de Securite Sanitaire Environnement et Travail, the French governmental agency in charge of environmental health and occupational health and safety issues) regarding the agricultural sector but also for all other situations in which workers use coveralls as protection against chemical risks. PMID- 20833389 TI - Knockdown of fucosyltransferase III disrupts the adhesion of circulating cancer cells to E-selectin without affecting hematopoietic cell adhesion. AB - Adhesive interactions between selectins and their ligands play an essential role during cancer extravasation. Fucosylation of these proteins by fucosyltransferases, or FUTs, is critical for their functions. Using quantitative RT-PCR, we demonstrated that FUT4 and FUT7 are the predominant FUTs expressed in hematopoietic cell line, while FUT3 is heavily expressed by multiple cancer cell lines including the prostate cancer cell line MDA PCa2b. Knockdown of FUT3 expression in MDA PCa2b cells by small interference RNA (siRNA) significantly reduced FUT3 expression. Cell-surface sialyl Lewis antigens were largely abolished. Cell adhesion and cell rolling on the blood vessel wall were simulated by perfusing cancer cells through microtubes coated with recombinant human E selectin. At physiological levels of wall shear stress, the number of flowing cancer cells recruited to the microtube surface was dramatically reduced by FUT3 knockdown. Higher rolling velocity was also observed, which is consistent with reduced E-selectin binding activity. Interestingly, FUT3 siRNA treatment also significantly reduced the cell growth rate. Combined with the novel siRNA delivery platform recently developed in our laboratory, FUT3 siRNA could be a promising conjunctive therapy aiming at reducing the metastatic virulence of circulating epithelial cancer cells. PMID- 20833390 TI - Expedient synthesis of coumarin-coupled triazoles via 'click chemistry' leading to the formation of coumarin-triazole-sugar hybrids. AB - Coumarin-based triazoles were synthesized from 3-azidomethylcoumarin and a terminal acetylenic compound. Uncatalysed thermal conditions result in a mixture of both 1,4- and 1,5-regioisomers or the thermodynamically more stable 1,4 regioisomer, whereas the Cu(I)-catalysed reaction affords only the favourable 1,4 regioisomer. B3LYP/6-31G(d) level of theory has been used to calculate geometry and frequency features of the reactants, transition states (TSs) and products. Computational studies further reveal that 1,4-regioisomeric products are more favourable and also thermodynamically more stable compared to the 1,5 regioisomers. PMID- 20833391 TI - [Use of adhesive mesh in hernioplasty compared to the conventional technique. Results of a randomised prospective study]. AB - INTRODUCTION: The use of meshes made with reabsorbable materials and structures that allow them to be fixed to the tissue without sutures, is considered as a therapeutic possibility in inguinal hernioplasty, reducing surgical times and supposedly improving pain and post-operative recovery. MATERIAL AND METHODS: A prospective randomised study of patients intervened for inguinal hernia between March 2009 and March 2010. Those patients subjected to hernia repair with a self adhesive mesh (Parietene Progrip((r))) were placed in the in the SA (self adhesive) group, and those subjected to hernia repair with a polypropylene mesh fixed with a monofilament suture in the CL (Classic Lichenstein) group. Complications and pain, using the visual analogue scale, were evaluated over 7 days. RESULTS: A total of 90 patients were divided into 2 groups of 45. The mean age was 60 y and 49 years, respectively, with the mean size of the hernia defect being 3cm, and approximately 60% were indirect hernias. The time of fixing the mesh and the overall surgery time was lower in the SA group than in the LC group: 56s versus 3min and 52s, and 17min and 45s versus 20min and 10s, respectively. There were no differences in hospital stay, complications or post-operative pain. CONCLUSION: The use of this type of mesh reduces the time of fixing the prosthesis and the total surgical time, with no effect on early post-operative pain or surgical complications compared to hernioplasty with a polypropylene mesh fixed with a monofilament suture. PMID- 20833393 TI - Response to a commentary by Makhijani et al. on a research report by Delistraty et al. (2010). PMID- 20833394 TI - Lymphocyte sub-population cell counts are associated with the metabolic syndrome and its components in the Vietnam Experience Study. AB - OBJECTIVE: The metabolic syndrome (MetS) increases the risk of cardiovascular disease morbidity and mortality. MetS is also associated with increases in the number of circulating white blood cells. Lymphocyte sub-population counts have also been implicated in cardiovascular disease; this analysis will examine whether or not they are associated with MetS. METHODS: Participants were 4255 Vietnam-era US veterans. From military service files, telephone interviews, and a medical examination, occupational, socio-demographic, and health data were collected. MetS was ascertained from: body mass index; fasting blood glucose or a diabetes medication; blood pressure or a diagnosis of hypertension; HDL cholesterol; and triglyceride levels. Circulating T, T4, T8 and B lymphocytes cell numbers were determined by flow cytometry. RESULTS: In fully adjusted logistic regression analyses, high lymphocyte sub-population counts were associated with an increased risk of MetS: T cells, OR=2.68, 95%CI 1.99-3.61, p<.001; T4 cells, OR=2.37, 95%CI 1.78-3.15, p<.001; T8 cells, OR=1.79, 95%CI 1.43 2.24, p<.001; B cells, OR=1.82, 95%CI 1.51-2.19, p<.001. High lymphocyte sub population numbers were also associated with an increased likelihood of possessing each of the MetS components, as well as the number of components possessed. CONCLUSIONS: These results extend previous research which has largely been confined to total white blood cell or overall lymphocyte counts. If the present associations arise in prospective research, it is possible that simple lymphocyte cell counts could provide an additional prognostic indicator of risk for MetS. PMID- 20833395 TI - Group X secretory phospholipase A(2) augments angiotensin II-induced inflammatory responses and abdominal aortic aneurysm formation in apoE-deficient mice. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a complex vascular disease characterized by matrix degradation and inflammation and is a major cause of mortality in older men. Specific interventions that prevent AAA progression remain to be identified. In this study, we tested the hypothesis that Group X secretory phospholipase A(2) (GX sPLA(2)), an enzyme implicated in inflammatory processes, mediates AAA. METHODS AND RESULTS: GX sPLA(2) was detected by immunostaining in human aneurysmal tissue and in angiotensin II (Ang II)-induced AAAs in apolipoprotein E-deficient (apoE(-/-)) mice. GX sPLA(2) mRNA was increased significantly (11-fold) in abdominal aortas of apoE(-/-) mice in response to Ang II infusion. To define the role of GX sPLA(2) in experimental AAAs, apoE(-/-) and apoE(-/-) x GX sPLA(2)(-/-) (GX DKO) mice were infused with Ang II for either 10 (n=7) or 28 (n=24-26) days. Deficiency of GX sPLA(2) significantly reduced the incidence and severity of AAAs, as assessed by ultrasound measurements in vivo of aortic lumens and by computer-assisted morphometric analyses ex vivo of external diameter. Results from gene expression profiling indicated that the expression of specific matrix metalloproteinases and inflammatory mediators was blunted in aortas from GX DKO mice compared to apoE(-/ ) mice after 10-day Ang II infusion. Ang II induction of cyclooxygenase-2, interleukin-6, matrix metalloproteinase (MMP)-2, MMP-13 and MMP-14 was reduced significantly in GX DKO mice compared to apoE(-/-) mice. CONCLUSION: GX sPLA(2) promotes Ang II-induced pathological responses leading to AAA formation. PMID- 20833396 TI - Muscle contributions to whole-body sagittal plane angular momentum during walking. AB - Walking is a complex dynamic task that requires the regulation of whole-body angular momentum to maintain dynamic balance while performing walking subtasks such as propelling the body forward and accelerating the leg into swing. In human walking, the primary mechanism to regulate angular momentum is muscle force generation. Muscles accelerate body segments and generate ground reaction forces that alter angular momentum about the body's center-of-mass to restore and maintain dynamic stability. In addition, gravity contributes to whole-body angular momentum through its contribution to the ground reaction forces. The purpose of this study was to generate a muscle-actuated forward dynamics simulation of normal walking to quantify how individual muscles and gravity contribute to whole-body angular momentum in the sagittal plane. In early stance, the uniarticular hip and knee extensors (GMAX and VAS), biarticular hamstrings (HAM) and ankle dorsiflexors (TA) generated backward angular momentum while the ankle plantar flexors (SOL and GAS) generated forward momentum. In late stance, SOL and GAS were the primary contributors and generated angular momentum in opposite directions. SOL generated primarily forward angular momentum while GAS generated backward angular momentum. The difference between muscles was due to their relative contributions to the horizontal and vertical ground reaction forces. Gravity contributed to the body's angular momentum in early stance and to a lesser extent in late stance, which was counteracted primarily by the plantar flexors. These results may provide insight into balance and movement disorders and provide a basis for developing locomotor therapies that target specific muscle groups. PMID- 20833397 TI - Finite element sub-modeling analyses of damage to enamel at the incisor enamel/adhesive interface upon de-bonding for different orthodontic bracket bases. AB - This study investigates the micro-mechanical behavior associated with enamel damage at an enamel/adhesive interface for different bracket bases subjected to various detachment forces using 3-D finite element (FE) sub-modeling analysis. Two FE macro-models using triangular and square bracket bases subjected to shear, tensile and torsional de-bonding forces were established using MUCT images. Six enamel/adhesive interface sub-models with micro- resin tag morphology and enamel rod arrangement were constructed at the corresponding stress concentrations in macro-model results. The boundary conditions for the sub-models were determined from the macro-model results and applied in sub-modeling analysis. The enamel and resin cement stress concentrations for triangular and square bases were observed at the adhesive bottom towards the occlusal surface under shear force and at the mesial and distal side planes under tensile force. The corresponding areas under torsional force were at the three corners of the adhesive for the triangular base and at the adhesive bottom toward/off the occlusal surface for the square base. In the sub-model analysis, the concentration regions were at the resin tag base and in the region around the etched holes in the enamel. These were perfectly consistent with morphological observations in a parallel in vitro bracket detachment experiment. The critical de-bonding forces damaging the enamel for the square base were lower than those of the triangular base for all detached forces. This study establishes that FE sub-modeling can be used to simulate the stress pattern at the micro-scale enamel/adhesive interface, suggesting that a square base bracket might be better than a triangular bracket. A de-bonding shear force can detach a bracket more easily than any other force with a lower risk of enamel loss. PMID- 20833398 TI - Size exclusion chromatography and viscometry in paper degradation studies. New Mark-Houwink coefficients for cellulose in cupri-ethylenediamine. AB - The paper deals with the application of size exclusion chromatography (SEC) for the studies of paper degradation phenomena. The goal is to solve some of the technical problems connected with the calibration of multi-detector SEC system and to find the correlation between SEC and viscometric results of degree of polymerization of cellulose. The results gathered for the paper samples degraded by acidic air pollutant (NO(2)) are used as an example of SEC-MALLS application. From the correlation between intrinsic viscosities and absolute value of molecular masses obtained with SEC/MALLS (Multi Angle Laser Light Scattering) technique, Mark-Houwink coefficients for cellulose in cupri-ethylenediamine solution were determined. Thus obtained coefficients were used for the determination of viscometric degree of polymerization (molecular mass) of the aged samples. An excellent correlation was found between the chromatographic values of molecular masses obtained with SEC-UV/VIS detection and the viscometric ones utilizing the improved values of Mark-Houwink coefficients. PMID- 20833399 TI - Isotachophoresis-based sample preparation of cellulases in sugarcane juice using bovine serum albumin as a model protein. AB - The foremost requirement of quantification of cellulases expressed in genetically modified sugarcane is an efficient sample clean-up. This work investigates the feasibility of isotachophoresis for this purpose. An electrolyte system comprising a leading electrolyte of 10mM formic acid at pH 9.0 and a terminating electrolyte of 10mM beta-alanine was devised and used to perform isotachophoresis of cellulases. The use of a simple front cutting method removed a majority of interfering species in the juice, thereby resulting in the formation of a distinct zone of desired proteins. In comparison to techniques such as ultrafiltration and liming, the analysis time and loss of desired proteins was lower when the sample was prepared by using isotachophoresis. Hence, isotachophoresis was an ideal choice for purification of the proteins in question from the remaining components in the juice. PMID- 20833400 TI - Effects of an exercise program in children with cystic fibrosis: are there differences between females and males? AB - OBJECTIVE: To investigate the adaptive responses of an in-patient exercise program in children with cystic fibrosis (CF) and evaluate the effects of sex. STUDY DESIGN: In total, 158 female and 186 male subjects with CF (age, 12 to 43 years) were studied during a 6-week rehabilitation course. A maximal incremental cycling test was used to determine exercise capacity and responses after 6 weeks of exercise training. Measures included lung function, peak oxygen uptake, peak workload, and peak heart rate. RESULTS: Lung function values were lower in males (P < .05). Females had a lower aerobic capacity (P < .05) at the beginning and at the end of the exercise training program. Similar training effects (P > .05) were seen between sexes in peak oxygen uptake (mL/min, mL/kg/min) and peak heart rate (beats/min) but not in peak workload (Watts, W/kg). CONCLUSIONS: The exercise program improved the fitness level similarly in females and males with CF. Basic physiological sex differences were still seen at the beginning and end of the training, despite the better lung function in females. Moreover, the finding suggested that fitness level and not lung function determined the response to training in CF, with those who were less fit at baseline having the largest response to training. PMID- 20833401 TI - Cerebellar hemorrhage on magnetic resonance imaging in preterm newborns associated with abnormal neurologic outcome. AB - OBJECTIVE: To investigate the relationship between cerebellar hemorrhage in preterm infants seen on magnetic resonance imaging (MRI), but not on ultrasonography, and neurodevelopmental outcome. STUDY DESIGN: Images from a cohort study of MRI in preterm newborns were reviewed for cerebellar hemorrhage. The children were assessed at a mean age of 4.8 years with neurologic examination and developmental testing using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition. RESULTS: Cerebellar hemorrhage was detected on both ultrasonography and MRI in 3 of the 131 preterm newborns evaluated, whereas smaller hemorrhages were seen only on MRI in 10 newborns (total incidence, 10%). Adjusting for gestational age at birth, intraventricular hemorrhage, and white matter injury, cerebellar hemorrhage detectable solely by MRI was associated with a 5-fold increased odds of abnormal neurologic examination compared with newborns without cerebellar hemorrhage (outcome data in 74%). No association with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition score was found. CONCLUSIONS: Cerebellar hemorrhage is not uncommon in preterm newborns. Although associated with neurologic abnormalities, hemorrhage seen only on MRI is associated with much more optimistic outcomes than that visible on ultrasonography. PMID- 20833402 TI - Inactivation of the gene katA or sodA affects the transient entry into the viable but non-culturable response of Staphylococcus aureus in natural seawater at low temperature. AB - We have investigated the fate of Staphylococcus aureus by starving the cells and maintaining them in natural seawater at 22 and 4 degrees C. At 22 degrees C, cells developed a long-term survival state where about 0.037% of the initial population remained culturable over more than 7 months, whereas at 4 degrees C, bacteria lost culturability and transiently entered into the viable but non culturable state (VBNC). However, after 22 days of entry into the VBNC state, the number of viable cells detected via the direct viable count method decreased significantly. We show here that mutational inactivation of catalase (KatA) or superoxide dismutase (SodA) rendered strains hypersensitive to seawater stress at 4 degrees C and consequently, part of the seawater lethality on S. aureus at low temperature is mediated by reactive oxygen species (ROS) during microcosm survival process. Shifting the temperature from 4 to 22 degrees C of totally non culturable wild-type cells induced a partial recovery of the population. However, deficiencies in catalase or superoxide dismutase prevent resuscitation ability. PMID- 20833403 TI - Does use of tropical beaches by tourists and island residents result in damage to fringing coral reefs? A case study in Moorea French Polynesia. AB - Although coral reefs worldwide are subject to increasing global threats, humans also impact coral reefs directly through localized activities such as snorkeling, kayaking and fishing. We investigated five sites on the northern shore of Moorea, French Polynesia, and quantified the number of visitors on the beach and in shallow water. In field surveys, we measured total coral cover and colony sizes of two common genera, Porites and Acropora, a massive and branching morphology, respectively. One site, which hosted over an order of magnitude more people than the other four, had significantly less total coral cover and supported very little branching Acropora. In addition, size frequency distributions of both the branching and massive genera were skewed toward smaller colony sizes at the high use site. Our results demonstrated that the use of tropical beaches may result in less coral cover, with branching colonies rare and small. PMID- 20833404 TI - Public health status and influence factors after 2008 Wenchuan earthquake among survivors in Sichuan province, China: cross-sectional trial. AB - OBJECTIVES: On 12 May 2008, an earthquake with a magnitude of 8.0 on the Richter scale struck in Sichuan province, China. After the disaster, approximately 5 million people were living in temporary shelters. The objectives of this study were: (1) to provide the basic information on public health outcomes among the survivors; (2) to compare these outcomes between counties affected to differing extents by the earthquake; and (3) to identify important policies and programmes associated with public health outcomes. STUDY DESIGN: Cross-sectional multicluster sample surveys were employed using data collected from two counties. METHODS: Cross-sectional surveys were conducted in August 2008 in two counties in Sichuan province. The study outcomes [physical component summary (PCS) and mental component summary (MCS)] were measured using Short Form-12. Independent demographic, socio-economic and trauma exposure variables were also measured. Multivariate regression analysis was conducted to investigate associations between the independent variables and PCS and MCS outcomes. RESULTS: In total, 3862 interviews were completed in the two counties. The mean PCS score was 37.6 [95% confidence interval (95% CI 35.13-41.97) in Beichuan county and 45.4 (95% CI 44.30-45.95) in Langzhong county. MCS scores were 36.8 (95% CI 33.61-40.71) in Beichuan county and 49.6 (95% CI 49.69-50.01) in Langzhong county, well below the instrument norm of 50. Variables with negative associations with physical or mental health included: female gender, living in a temporary shelter, higher income, deaths among family/friends, family property damaged and illness within the past 2 weeks. Higher frequencies of trauma exposure (more than six trauma exposure events) showed a strong significant negative association with PCS and MCS in both counties. CONCLUSIONS: Interventions should be designed to focus on people without a household income (or a lower income), living in shelters or temporary houses. Governments should support income-generating activities and improve living conditions and public health status. PMID- 20833405 TI - [Neuroradiology in Spain]. PMID- 20833406 TI - Heterocellular induction of interferon by negative-sense RNA viruses. AB - The infection of cells by RNA viruses is associated with the recognition of virus PAMPs (pathogen-associated molecular patterns) and the production of type I interferon (IFN). To counter this, most, if not all, RNA viruses encode antagonists of the IFN system. Here we present data on the dynamics of IFN production and response during developing infections by paramyxoviruses, influenza A virus and bunyamwera virus. We show that only a limited number of infected cells are responsible for the production of IFN, and that this heterocellular production is a feature of the infecting virus as opposed to an intrinsic property of the cells. PMID- 20833407 TI - The influence of operating conditions on the efficiency of vapor phase hydrogen peroxide in the degradation of 4-(dimethylamino)benzaldehyde. AB - Vapor phase hydrogen peroxide (VPHP) nowadays finds more and more applications especially as a bio-decontamination agent for enclosed areas. Although this oxidizing agent logically offers a potential for the degradation of hazardous chemical contaminants, the information on the utilization within this area is very limited. The main objective of this study was to examine in detail the influence of basic operational (temperature, concentration of VPHP, relative humidity, condensation) and other conditions (e.g. amount of contaminant, the effect of UV radiation) on the efficiency of the VPHP process for the degradation of the selected model substance, i.e. 4-(dimethylamino)benzaldehyde. For this purpose, a series of different VPHP "wet" decontamination cycles (with a visible condensation) were carried out and compared. The obtained results clearly proved that VPHP could be utilized for the degradation of 4-(dimethylamino)benzaldehyde, however it was necessary to regard this process as a multi-parametric, in which all operational conditions played significant roles, while the molecular distribution of H(2)O and H(2)O(2) at first constituted the key factor for a successful degradation of contaminants on the surface. In order to achieve the highest decomposition efficiency of 4-(dimethylamino)benzaldehyde by the wet VPHP process, it appeared to be necessary to decrease the initial relative humidity in the relevant enclosed area (ideally up to 5%) before the introduction of VPHP and carry out this decontamination procedure ideally at 25 degrees C and maintain the VPHP concentration higher than 500 ppm. Furthermore, it was found that the addition of UV radiation had a positive role on VPHP efficiency (in the best case, the degradation rate increased up to 1.5 times compared to using the sole VPHP). The monitoring of the concentration of VPHP within an enclosed facility is a good tool for the monitoring of the degradation of chemical contaminants by this agent. PMID- 20833408 TI - Biodegradation of carbendazim by a novel actinobacterium Rhodococcus jialingiae djl-6-2. AB - A novel actinobacterial strain Rhodococcus jialingiae djl-6-2 capable of using carbendazim (MBC) as the sole carbon and nitrogen source for growth was used to investigate its metabolism pathway of MBC. The HPLC and MS/MS analysis showed that MBC was hydrolyzed to 2-aminobenzimidazole (2-AB) and then converted to benzimidazole or 2-hydroxybenzimidazole (2-HB). The conversion of 2-AB was inhibited by NH(4)NO(3). The benzene ring of 2-HB was further opened through meta (extradiol) catechol cleavage. The inoculation of strain djl-6-2 to MBC contaminated soil resulted in a higher degradation rate than noninoculated soil, which indicated the potential of strain djl-6-2 in bioremediation of MBC polluted soil. PMID- 20833409 TI - Electrochemical abatement of the antibiotic sulfamethoxazole from water. AB - The electrochemical abatement of the antibiotic sulfamethoxazole (SMX) from aqueous solutions at pH 3.0 has been carried out by anodic oxidation and electro Fenton (EF) processes with H(2)O(2) electrogeneration. The electrolyses have been performed using a small, undivided cell equipped with a Pt or thin film boron doped diamond (BDD) anode and a carbon-felt cathode. The higher performance of the EF process with 0.2mM Fe(2+) in a BDD/carbon felt cell is demonstrated. This is due to the higher production of ()OH radicals, as well as to the simultaneous degradation at the anode surface and in the bulk solution. At low current, the oxidation at the anode was predominant; at high current, SMX was pre-eminently degraded in the bulk. SMX was quickly destroyed under all the conditions tested, following pseudo first-order kinetics; however, the almost total removal of the total organic carbon was only achieved in the BDD/carbon felt cell. The reaction by-products were quantified by chromatographic techniques and thus, the reaction pathway for the mineralization of SMX by EF has been elucidated. Hydroxylation of SMX on the sulfanilic ring is suggested as the first step, followed by the formation of p-benzoquinone and 3-amino-5-methylisoxazole. Their oxidative cleavage led to the formation of five carboxylic acids that were finally mineralized to CO(2); the release of NH(4)(+), NO(3)(-), and SO(4)(2-) accounted for almost 100% of the initial nitrogen and sulfur content. The absolute rate constants for the oxidative degradation of SMX and the detected aromatic by products have also been determined. PMID- 20833410 TI - Comprehensive assessment of pine needles as bioindicators of PAHs using multivariate analysis. The importance of temporal trends. AB - The importance of the annual and seasonal trends associated to the polycyclic aromatic hydrocarbons (PAHs) biomonitoring by pine needles are studied with a comprehensive use of univariate and multivariate analysis tools. For this purpose, four pine needle sampling campaigns (winter, spring, summer and autumn 2007) were carried out in 29 sites from Portugal. Needles from Pinus pinaster Ait. and Pinus pinea L. trees were collected from all year-classes available in each tree, corresponding to the different shoots of needles coming out every spring and the results of both species were treated separately. Annual trends of polycyclic aromatic hydrocarbons (PAHs) contamination indicate a general increase from the least to the most exposed year-classes, for all seasons. The mean values for the sum of 16PAHs ranged from 71 +/- 33 ngg(-1) (dry weight - dw) for new year (2007) needles in the summer to 514 +/- 317 ngg(-1) (dw) for 2-year needles (2005) in the spring for P. pinea, and between 90 +/- 50 ngg(-1) (dw) for new year (2007) needles in the summer and 1212 +/- 436 ngg(-1) (dw) for 3-year needles (2004) in summer for P. pinaster. The seasonal evolution shows the highest concentrations in the winter, then declining to the lowest levels in the summer and rising again from summer to autumn. Principal component analysis confirmed differences between seasons and needle year-classes, more visible for P. pinea samples. The cooler seasons have more affinity towards the lighter more abundant PAHs, as do the older needles. Differences between both pine species are also evident. PMID- 20833411 TI - Mortality from cold waves in Castile--La Mancha, Spain. AB - INTRODUCTION: As is known, the effects of extreme temperatures on mortality are characterised by an annual periodicity, with a rise centred in the winter months. The most recent epidemiological studies show that mortality caused by cold waves is, in many cases, comparable to that caused by the severest heat waves. This study sought to quantify the rise in mortality due to extreme cold and the factors that determine the relationship between these variables in Castile-La Mancha (Spain). METHODS: We examined the effect of extreme winter temperature on daily non accidental cause mortality in Castile - La Mancha from 1975 to 2003, for all ages. Quantitative analyses were performed using ARIMA models, with other covariates, such as influenza, pressure trends, relative humidity, and cold wave duration and chronological number. RESULTS: There were two mortality peaks: a short-term peak (with a lag of 3 to 7 days); and a longer term peak (of under two weeks). Excess mortality during cold waves was around 10% per degree centigrade below the threshold temperature for all the provinces except Guadalajara, where an increase of only 4.61% was detected. Mortality increased in response to rises in cold-wave duration and relative humidity. Cold waves occurring at the end of the "winter" season caused the greatest mortality. CONCLUSIONS: This study confirms that daily mortality in Castile - La Mancha increases during cold waves. Efficient cold-wave prevention plans must therefore be implemented. Such plans should be based on in-depth knowledge of the causes that underlie and modulate the relationship between low temperatures and health effects. PMID- 20833412 TI - Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. AB - INTRODUCTION: Because the risk of venous thromboembolism (VTE) associated with progestin is uncertain, we tested oral contraceptives, estrogen and progestin as independent VTE risk factors. MATERIALS AND METHODS: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN women with objectively-diagnosed incident VTE over the 13-year period, 1988-2000 (n=726) and one to two Olmsted County women per case matched on age, event year and duration of prior medical history (n=830), and reviewed their complete medical history in the community for previously-identified VTE risk factors (i.e., hospitalization with or without surgery, nursing home confinement, trauma/fracture, leg paresis, active cancer, varicose veins and pregnancy/postpartum), and oral contraceptive, oral estrogen, and oral or injectable progestin exposure. Using conditional logistic regression we tested these hormone exposures as VTE risk factors, both unadjusted and after adjusting for previously-identified VTE risk factors. RESULTS: In unadjusted models, oral contraceptives, progestin alone, and estrogen plus progestin were significantly associated with VTE. Individually adjusting for body mass index (BMI) and previously-identified VTE risk factors, these effects remained essentially unchanged except that progestin alone was not associated with VTE after adjusting for active cancer. Considering only case-control pairs without active cancer, progestin alone was positively but non-significantly associated with VTE (OR=2.49; p=0.16). Adjusting for BMI and previously-identified VTE risk factors including active cancer, oral contraceptives, estrogen alone, and progestin with or without estrogen were significantly associated with VTE. CONCLUSIONS: Oral contraceptives, estrogen alone, estrogen plus progestin, and progestin with or without estrogen are independent VTE risk factors. PMID- 20833413 TI - PTEN-loss and nuclear atypia of EIN in endometrial biopsies can predict the existence of a concurrent endometrial carcinoma. AB - AIM: The objective of the present study was to evaluate whether nuclear atypia or PTEN-loss in endometrial intraepithelial neoplasia (EIN), could help to predict in endometrial curettage material, the prevalence of concurrent carcinoma in hysterectomy specimens. MATERIALS AND METHODS: This retrospective single institution study included women who were diagnosed with endometrial hyperplasia (simple or complex) and underwent hysterectomy within 12weeks from the initial diagnosis without interval treatment. All endometrial curettage slides were reviewed by three experienced pathologists and only cases that fulfilled the criteria of EIN were used for further analysis. For each case, the nuclear atypia and the immunohistochemically detected expression of PTEN were evaluated. The hysterectomy slides were also reviewed and the findings were used in the subsequent analysis. RESULTS: Out of 83 cases that were enrolled in the study, 33 (39.76%), had a concurrent endometrial carcinoma. Nuclear atypia in EIN cases with a final histology of endometrial cancer was found in 31 out of 33 cases (93.94%) but only in 27 out of 50 benign cases (54%). There was no PTEN-loss in 8 out of 33 EIN cases (24.24%) that proved to be cancer and 22 out of 50 EIN cases (44%) that proved to be benign. Either atypia or PTEN-loss or both were found in 33/33 (100%) cancer cases and in 39/50 (78%) benign cases; this difference was statistically significant (Fisher exact test, p < 0.05). CONCLUSION: PTEN-loss, as an independent variable, was not found to be a predictor of endometrial cancer in the final histology. However, biopsies presented with EIN, featuring nuclear atypia and recognized as PTEN-null are more likely to be finally diagnosed with endometrial cancer. PMID- 20833414 TI - Restoration of spermatogenesis after transplantation of c-Kit positive testicular cells in the fowl. AB - Transplantation of male germ line cells into sterilized recipients has been used in mammals for conventional breeding as well as for transgenesis. We have previously adapted this approach for the domestic chicken and we present now an improvement of the germ cell transplantation technique by using an enriched subpopulation of c-Kit-positive spermatogonia as donor cells. Dispersed c-Kit positive testicular cells from 16 to 17 week-old pubertal donors were transplanted by injection directly into the testes of recipient males sterilized by repeated gamma irradiation. We describe the repopulation of the recipient's testes with c-Kit positive donor testicular cells, which resulted in the production of functional heterologous spermatozoa. Using manual semen collection, the first sperm production in the recipient males was observed about nine weeks after the transplantation. The full reproduction cycle was accomplished by artificial insemination of hens and hatching of chickens. PMID- 20833415 TI - High-throughput gender identification of three Columbidae species using melting curve analysis. AB - The objective was to perform high-throughput gender identification of three Columbidae species (Columba livia, Columba pulchricollis, and Streptopelia tranquebarica). Although the chromo-helicase-DNA binding protein (CHD)-based Griffiths P2/P8 primer set resolved the amplicon products of these species in 3% agarose gel electrophoresis, it was unsuitable for molecular gender identification using the melting curve analysis (MCA) curve for high-throughput analysis. After sequencing the CHD-Z and CHD-W genes for these species, we redesigned a female-specific CHD-W primer (dove-W) and a female/male (or CHD Z/CHD-W)-common primer (dove-ZW) to combine with the Griffiths P2 primer to generate two PCR amplicons with different lengths (P2/dove-W and P2/dove-ZW for 252- and 104-bp, respectively). Melting temperature (Tm) values for P2/dove-W and P2/dove-ZW amplicons were determined and resolved in MCA at approximately 79.0~79.5 and 77.5 degrees C, respectively. Accordingly, females contained two Tm peaks, whereas males contained one. In conclusion, melting curve analysis (MCA) using our proposed primer sets was a robust gender identification method for the three Columbidae species tested. PMID- 20833416 TI - Endocrine and milt response of Senegalese sole, Solea senegalensis, males maintained in captivity. AB - Improving fertilization success in captive Senegalese sole broodstocks has been a challenge in the last years. Recent reports suggest that low sperm volume and quality could be one of the reasons leading to poor fertilization rates, although further studies are needed to reach a conclusive explanation. Here, we report on several experiments focused on this issue. Seasonal profiles of plasma androgen levels (testosterone and 11-ketotestosterone) and sperm production and quality parameters were assessed, although no statistical correlations among them were identified. The response of males to female presence/absence was also analyzed. Long-term isolation from females decreased male androgen levels at the peak of the reproductive period, suggesting some kind of disrupting effects on the endocrine system. On the other hand, short-term exposure of previously isolated males to ripe females decreased androgen levels, possibly reflecting a rapid steroidogenic shift promoting final maturation of spermatozoa, and increased sperm viability, motility and velocity, thus, supporting the concept of positive effects of female contact on male sole performance. Further evidence sustaining the relevant female-to-male communication in sole reproduction was obtained after treating the females with progestagen 17alpha,20beta-dihydroxy-4-pregnen-3-one (regarded as pre-ovulatory pheromone in fish) and registering a significant increase in sperm viability, velocity and motility in surrounding males. Finally, we found that a single administration of a 20 MUg/kg GnRH analogue in males was effective in stimulating androgen release and sperm quality, although the effects were transient and thus, the use of sustained hormone delivery methods were suggested for improving efficiency. Our results point to velocity, viability, and motility as the most sensitive parameters in sole sperm, although further studies will have to evaluate whether these parameters have any relation with fertilization success in captive broodstocks of this important aquaculture species. PMID- 20833417 TI - Egg yolk plasma can replace egg yolk in stallion freezing extenders. AB - Hen egg yolk is normally used as a cryoprotective agent in semen freezing extenders, but its use has sanitary and practical disadvantages. Moreover the protection afforded by egg yolk has not yet been completely elucidated. The objective of this study was to compare the egg yolk plasma fraction to whole egg yolk in stallion freezing extender. Plasma contains mainly Low Density Lipoproteins (LDL), which are widely presumed to be the cryoprotective agent in egg yolk. Plasma can be produced on an industrial scale, sterilised by gamma irradiation and incorporated in a ready-to-use extender (our ultimate objective). Plasma samples were subjected to different doses of gamma-irradiation (3, 5, 10 kGy) without dramatic chemical changes that may affect their cryoprotective properties. Stallion semen was frozen with whole egg yolk as a control and with sterilised egg yolk plasma. A fertility trial was conducted on a total of 70 mares' cycles. Fertility per cycle was 60% after insemination of semen frozen in our control extender containing egg yolk (EY), compared to 69% for the extender containing sterilised egg yolk plasma (EYP) (P > 0.05). Post-thaw motility and membrane integrity of spermatozoa were also analysed. Motility parameters were not significantly different between extenders except for the variable VAP (for EY versus EYP, VAP: 63 MUm.s(-1) versus 59 MUm.s(-1), a, b: P < 0.001; PROG: 41% versus 39%, RAP30: 56% versus 54%; RAP40: 51% versus 48%, P > 0.05). Membrane integrity was better preserved in EY than in EYP but the difference between extenders was small (P < 0.05). Our results demonstrated that sterilised egg yolk plasma has the potential to replace egg yolk in stallion freezing extender. This experiment led to the development of a ready-to-use extender called INRA Freeze((r)) (IMV-Technologies, France). PMID- 20833418 TI - Ovulation rate, embryo mortality and intrauterine growth retardation in obese swine with gene polymorphisms for leptin and melanocortin receptors. AB - The Mediterranean Iberian pigs are obese genotypes, due to a leptin resistance syndrome related to leptin receptor gene polymorphisms. The Iberian pig is affected by a lower prolificacy when compared to lean breeds, and thus may constitute a good animal model for adverse effects of obesity in reproductive performance. The present study determined possible differences in rates of ovulation and embryo implantation and later incidence of embryo mortality and intrauterine growth retardation (IUGR) in sows of Iberian breed (n = 23) and highly-prolific lean commercial crosses (Large White * Landrace, n = 17) at two critical periods of swine pregnancy: Day 21 (just after achievement of trophoblast attachment) and Day 35 (just after completion of the transition from late embryo to early foetal stage). Two different reproductive performances were identified in the Iberian breed; 58.3% of the females had lower ovulation rates than LWxL (13.2 +/- 2.3 vs 22.5 +/- 1.6, P < 0.05), but 41.7% had a similar number of ovulations (18.2 +/- 3.9). However, those Iberian sows having high ovulatory rates showed a high incidence of regression of corpora lutea and embryo losses between Days 21 and 35, which was not found in Iberian females with low ovulation rates; therefore, the number of viable embryos was similar in both Iberian groups (8.2 +/- 1.0 and 8.4 +/- 1.0) and lower that in highly-prolific LWxL (14.8 +/- 1.8, P < 0.05). At Day 35, a total of 167 conceptuses (73 LWxL and 94 IB) were evaluated for IUGR. The LWxL conceptuses were longer and wider than Iberian (69.5 +/- 0.1 and 64.4 +/- 0.1 vs 49.9 +/- 0.1 and 41.9 +/- 0.1 mm, P < 0.0001). However, Iberian conceptuses were heavier than LWxL (107.4 +/- 6.6 vs 68.6 +/- 2.4 g) due to a lower quantity of fluids and a higher development of the placental tissues in comparison to the embryo itself. In conclusion, current study indicates a bimodal effect of obese genotypes on reproductive performances, either by lowering ovulation rate or by increased embryo losses in the first third of pregnancy. PMID- 20833419 TI - Determination of glutation peroxidase and superoxide dismutase activities in canine seminal plasma and its relation with sperm quality and lipid peroxidation post thaw. AB - Lipid peroxidation (LPO) of dog spermatozoa was assessed in fresh semen and in samples of the same ejaculates after freezing and thawing. Particular attention was paid to individual differences in the susceptibility to LPO and its possible relationship with freezeability. Innate levels of LPO were low in fresh spermatozoa but increased after thawing in one of the dogs included in our study. The level of lipid peroxidation in fresh spermatozoa was not correlated with that of thawed spermatozoa. Negative correlations were detected between the activity in seminal plasma of GPx and sperm velocities post thaw (P < 0.01), however SOD activity was positively correlated with the percentage of linear motile sperm post thaw (P < 0.05). PMID- 20833420 TI - Cryopreservation of in vitro produced bovine embryos: effects of lipid segregation and post-thaw laser assisted hatching. AB - The objective was to determine if lipid segregation, with or without post-thaw laser assisted hatching (LAH) of in vitro produced (IVP) bovine embryos, would enhance in vitro survivability and development 24 h post-thaw. On Day 6 of culture (Day 0 = IVF), in vitro produced bovine embryos were divided into three developmental stages: 32-cell (n = 78), compact morula (CM n = 223), and blastocyst (n =56). Embryos within each stage were allocated to the following treatments prior to cryopreservation in 1.5M ethylene glycol: no treatment (Control), 7.5 MUg/mL Cytochalasin B for 20 min (CB), or CB with centrifugation (16,000 * g) for 20 min (CBCF). All CB treatments were extended to include embryo freezing. Immediately post-thaw, one-half of the CBCF and Control groups were subjected to zona pellucida drilling (LAH), using the XY Clone(r) system, creating groups CBCFLAH and LAH, respectively. All thawed embryos were cultured for 24 h and evaluated. No treatment differences were observed for either post thaw survival or 24 h development. Within the CM stage, CBCFLAH and LAH exhibited a greater number of both total and live cells than Control (total: 69.4, 69.3, 53.0, live: 56.4, 54.7, 39.3 respectively; P < 0.05). In conclusion, LAH post thaw alone or in combination with CBCF improved embryo viability following cryopreservation. PMID- 20833421 TI - Strategies to improve pregnancy per insemination using sex-sorted semen in dairy heifers detected in estrus. AB - The objective was to improve pregnancy per artificial insemination (P/AI; 35-42 d after AI) in virgin Jersey heifers bred by AI of sex-sorted semen after being detected in estrus. Giving 100 MUg of GnRH at first detection of estrus, with AI 12 h later, did not affect P/AI in Experiment I [GnRH = 47.2% (100/212) vs. No GnRH = 51.7% (104/201); P = 0.38] or Experiment II [GnRH = 53.1% (137/258) vs. No GnRH = 48.6% (122/251); P = 0.43]. In these two experiments, estrus detection was done with tail-head chalk or a HeatWatch((r)) system, respectively. In Experiment III, a single insemination dose (2.1 * 106 sperm) 12 h after estrus detection (n = 193), a double dose at 12 h (n = 193), or a double dose involving insemination 12 and 24 h after estrus detection (n = 190) did not affect P/AI (87/193 = 45.1%, 85/193 = 44.0%, and 94/190 = 49.5%, respectively; P = 0.51). However, P/AI was influenced by the number of AI service (First, 115/208 = 55.3%(a); Second, 94/204 = 46.1%(a); and Third, 57/165 = 34.8%(b); P = 0.004). In Experiment IV, the P/AI of heifers inseminated from 12 to 16 h after the onset of estrus (40/106 = 37.7%) was less (P = 0.03) than those inseminated from 16.1 to 20 h (85/164 = 51.8%), and 20.1 to 24 h (130/234 = 55.6%). However, the P/AI for heifers inseminated from 24.1 to 30 h (61/134 = 45.5%) did not differ from that of any other interval. In conclusion, in Jersey heifers inseminated with sex-sorted semen, P/AI was not significantly affected by giving GnRH at detection of estrus or a double insemination dose, but it was higher with AI 16.1 to 24 h vs. 12 to 16 h after the onset of estrus. PMID- 20833422 TI - Intracervical application of hyaluronan improves cervical relaxation in the ewe. AB - Artificial insemination (AI) using frozen semen is a key method to enable rapid genetic improvement but its use in the sheep industry is currently limited by poor fertility. Laparoscropic AI is most effective but has not gained popularity due to cost and welfare considerations. Transcervical intrauterine AI (TCAI) may offer a practical alternative but the complex anatomy of the ovine cervix limits adequate penetration of the inseminating pipette. Hyaluronan (HA) is a glycoaminoglycan whose content in the cervix increases at oestrus and which may contribute to the degree of natural relaxation observed at this time. This study investigated the effect of intracervical application of HA on the depth of cervical penetration in sheep. Oestrus was synchronised on three occasions in 48 Welsh mountain ewes with progesterone sponges and PMSG. Each animal initially served as its own untreated control. Ewes were subsequently treated intracervically with 25 mg of: (2i) low molecular weight (MW) HA; (2ii) high MW HA or (2iii) both low and high MW HA (n = 16/group) at 52 h after sponge removal or with low MW HA at: (3i) 50 h; (3ii) 52 h or (3iii) both 50 h and 52 h. Depth of cervical penetration measured at 54 h was increased from 1.22 cm to 3.66 cm by treatment with low MW HA (P <= 0.001), with no differences between the number of treatments (1 or 2) or the time at which the HA was administered (50 or 52 h). High MW HA alone or together with low MW HA had no effect. In conclusion, intracervical application of low MW HA 52 h after sponge removal increases cervical penetration up to 3.4cm to allow TCAI in sheep. PMID- 20833423 TI - Neither plasma progesterone concentrations nor exogenous eCG affects rates of ovulation or pregnancy in fixed-time artificial insemination (FTAI) protocols for puberal Nellore heifers. AB - The objective was to evaluate the effects of plasma progesterone (P4) concentrations and exogenous eCG on ovulation and pregnancy rates of pubertal Nellore heifers in fixed-time artificial insemination (FTAI) protocols. In Experiment 1 (Exp. 1), on Day 0 (7 d after ovulation), heifers (n = 15) were given 2 mg of estradiol benzoate (EB) im and randomly allocated to receive: an intravaginal progesterone-releasing device containing 0.558 g of P4 (group 0.5G, n = 4); an intravaginal device containing 1 g of P4 (group 1G, n = 4); 0.558 g of P4 and PGF(2alpha) (PGF; 150 MUg d-cloprostenol, group 0.5G/PGF, n = 4); or 1 g of P4 and PGF (group 1G/PGF, n = 3). On Day 8, PGF was given to all heifers and intravaginal devices removed; 24 h later (Day 9), all heifers were given 1 mg EB im. In Exp. 2, pubertal Nellore heifers (n = 292) were treated as in Exp. 1, with FTAI on Day 10 (30 to 36 h after EB). In Exp. 3, pubertal heifers (n = 459) received the treatments described for groups 0.5G/PGF and 1G/PGF and were also given 300 IU of eCG im (groups 0.5G/PGF/eCG and 1G/PGF/eCG) at device removal (Day 8). In Exp. 1, plasma P4 concentrations were significantly higher in heifers that received 1.0 vs 0.588 g P4, and were significantly lower in heifers that received PGF on Day 0. In Exp. 2 and 3, there were no significant differences among groups in rates of ovulation (65-77%) or pregnancy (Exp. 2: 26-33%; Exp. 3: 39-43%). In Exp. 3, diameter of the dominant ovarian follicle on Day 9 was larger in heifers given 0.558 g vs 1.0 g P4 (10.3 +/- 0.2 vs 9.3 +/- 0.2 mm; P < 0.01). In conclusion, lesser amounts of P4 in the intravaginal device or PGF on Day 0 decreased plasma P4 from Days 1 to 8 and increased diameter of the dominant follicle on Day 9. However, neither of these nor 300 IU of eCG on Day 8 significantly increased rates of ovulation or pregnancy. PMID- 20833424 TI - New technique to quantify the lipid composition of lipid droplets in porcine oocytes and pre-implantation embryos using Nile Red fluorescent probe. AB - The principal objective of this study was to develop a novel method based on confocal microscopy and a solvatochromic fluorescent dye, Nile red (NR) to quantify the main types of lipids in a single mammalian oocyte and embryo. We hypothesize that NR staining followed by the decomposition of NR-spectra identifies and quantifies the triglycerides, phospholipids, and cholesterol in a single oocyte and embryo. We analyzed the lipid droplets in porcine oocytes and pre-implantation embryos up to the hatched blastocyst stage developed in vivo and in cultured blastocysts. The emission spectrum of NR-stained mixture of different lipid types is a convolution of several component spectra. The principal component analysis (PCA) and a multivariate curve resolution-alternating least squares method (MCR-ALS) allowed to decompose the emission spectrum and quantify the relative amount of each lipid type present in mixture. We reported here that the level of the triglycerides, phospholipids and cholesterol in lipid droplets significantly decreases by 17.7%, 26.4% and 23.9%, respectively, from immature to mature porcine oocytes. The content of triglycerides and phospholipids remains unchanged in droplets of embryos from the zygote up to the morula stage. Then the triglyceride level decreases in the blastocyst by 15.1% and in the hatched blastocyst by 37.3%, whereas the amount of phospholipids decreases by 10.5% and 12.5% at the blastocyst and hatched blastocyst stages, respectively. In contrast, the content of cholesterol in droplets does not change during embryo cleavage. The lipid droplets in the blastocyst produced in vivo contain lower amounts of triglycerides (by 26.1%), phospholipids (by 14.2%) and cholesterol (by 34.8%) than those in the blastocyst cultured in NCSU-23 medium. In conclusion, our new technique is suitable to quantify the content of triglycerides, phospholipids and cholesterol in individual mammalian oocytes and embryos. Our findings indicate an important role for lipids during porcine oocyte maturation and early embryonic development, and suggest an altered lipid metabolism in cultured embryos. PMID- 20833425 TI - The Australian alcopops tax revisited. PMID- 20833426 TI - The Millennium Development Goals: a cross-sectoral analysis and principles for goal setting after 2015 Lancet and London International Development Centre Commission. PMID- 20833427 TI - Toxicity assessment of sediments from three European river basins using a sediment contact test battery. AB - The toxicity of four polluted sediments and their corresponding reference sediments from three European river basins were investigated using a battery of six sediment contact tests representing three different trophic levels. The tests included were chronic tests with the oligochaete Lumbriculus variegatus, the nematode Caenorhabditis elegans and the mudsnail Potamopyrgus antipodarum, a sub chronic test with the midge Chironomus riparius, an early life stage test with the zebra fish Danio rerio, and an acute test with the luminescent bacterium Vibrio fischeri. The endpoints, namely survival, growth, reproduction, embryo development and light inhibition, differed between tests. The measured effects were compared to sediment contamination translated into toxic units (TU) on the basis of acute toxicity to Daphnia magna and Pimephales promelas, and multi substance Potentially Affected Fractions of species (msPAF) as an estimate for expected community effects. The test battery could clearly detect toxicity of the polluted sediments with test-specific responses to the different sediments. The msPAF and TU-based toxicity estimations confirmed the results of the biotests by predicting a higher toxic risk for the polluted sediments compared to the corresponding reference sediments, but partly having a different emphasis from the biotests. The results demonstrate differences in the sensitivities of species and emphasize the need for data on multiple species, when estimating the effects of sediment pollution on the benthic community. PMID- 20833428 TI - Lead-induced phytotoxicity mechanism involved in seed germination and seedling growth of wheat (Triticum aestivum L.). AB - The mechanism of lead-inhibitory effects on seed germination and seedling growth was investigated in wheat cv. Xihan 2 subjected to different Pb(NO(3))(2) concentrations. High concentrations of lead and exogenous H(2)O(2) significantly inhibited seed germination and the growth of roots and shoots. Dimethylthiourea, catalase or diphenylene iodonium could reverse lead-inhibitory effects on seed germination. Significant elevated H(2)O(2) generation was observed in germinating seeds exposed to lead. Analysis using fluorescent dye 2',7' dichlorodihydrofluorescein diacetate showed significantly increased H(2)O(2) level in the root tissue in response to lead treatment. Nitric oxide (NO) donor sodium nitroprusside could alleviate the Pb-inhibitory effects on seed germination and shoot growth, which was blocked by guanylyl cyclase inhibitor methylene blue. Therefore, NADH-dependent generation of extracellular H(2)O(2) is responsible for Pb-inhibitory effect on seed germination, the protection of exogenous NO against lead toxicity involved in seed germination and seedlings shoot growth may be associated with cGMP signaling pathway. PMID- 20833429 TI - Short-term mercury exposure affecting the development and antioxidant biomarkers of Japanese flounder embryos and larvae. AB - This study investigated the acute and sub-lethal toxicities of waterborne mercuric chloride to Japanese flounder (Paralichthys olivaceus) embryos and larvae. Acute toxicity tests indicated that the 48-h LC(50) values of mercury to the embryos and larvae were 48.1 (32.8-63.6) and 99.4 (72.9-147.0) MUg L(-1), respectively. Mercury could cause low hatching success, delayed hatching process, reduced growth at concentrations >=20 MUg L(-1), and induce reduced survival and higher morphological malformations at concentrations >=40 MUg L(-1) in the embryos and larvae. In sub-lethal toxicity test, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and malondialdehyde (MDA) contents of the larvae were significantly increased, while glutathione-S transferase (GST) was decreased by 10 days of 0-10 MUg Hg(2+)L(-1) exposure. These findings suggested that the hatching, survival, growth and antioxidant biomarkers of the flounder were sensitive to the highest mercury concentrations and could thereby serve as potential biomarkers for evaluating mercury contamination in the aquatic environment. PMID- 20833430 TI - Phytoremediation of mercury in pristine and crude oil contaminated soils: Contributions of rhizobacteria and their host plants to mercury removal. AB - The rhizospheric soils of three tested legume crops: broad beans (Vicia faba), beans (Phaseolus vulgaris) and pea (Pisum sativum), and two nonlegume crops: cucumber (Cucumis sativus) and tomato, (Lycopersicon esculentum) contained considerable numbers (the magnitude of 10(5)g(-1) soil) of bacteria with the combined potential for hydrocarbon-utilization and mercury-resistance. Sequencing of the 16S rRNA coding genes of rhizobacteria associated with broad beans revealed that they were affiliated to Citrobacter freundii, Enterobacter aerogenes, Exiquobacterium aurantiacum, Pseudomonas veronii, Micrococcus luteus, Brevibacillus brevis, Arthrobacter sp. and Flavobacterium psychrophilum. These rhizobacteria were also diazotrophic, i.e. capable of N(2) fixation, which makes them self-sufficient regarding their nitrogen nutrition and thus suitable remediation agents in nitrogen-poor soils, such as the oily desert soil. The crude oil attenuation potential of the individual rhizobacteria was inhibited by HgCl(2), but about 50% or more of this potential was still maintained in the presence of up to 40 mgl(-1) HgCl(2). Rhizobacteria-free plants removed amounts of mercury from the surrounding media almost equivalent to those removed by the rhizospheric bacterial consortia in the absence of the plants. It was concluded that both the collector plants and their rhizospheric bacterial consortia contributed equivalently to mercury removal from soil. PMID- 20833431 TI - Formulation of water-dispersible nanopermethrin for larvicidal applications. AB - The formulation of water dispersible nanopermethrin was investigated for its larvicidal property. Nanopermethrin was prepared using solvent evaporation of oil in water microemulsion, which was obtained by mixing an organic and aqueous phase. The mean particle size of nanodispersion in water was 151 +/- 27 nm. X-ray diffraction (XRD) of nanopermethrin showed it was amorphous. Larvicidal studies were carried out against Culex quinquefasciatus and the results were compared with bulk permethrin. The LC(50) of nanopermethrin to Cx. quinquefasciatus was 0.117 mg/L. The LC(50) of bulk permethrin to Cx. quinquefasciatus was 0.715 mg/L. Nanopermethrin may be a good choice as a potent and selective larvicide for Cx. quinquefasciatus. PMID- 20833432 TI - The secular trend of suicide rate and the socio-economic, media, and climatic factors in Taiwan, 1976-2009: a population-based study. AB - INTRODUCTION: The purpose of the present study was to explore the relationship between the secular trend of the suicide rate and the socio-economic, media, and climatic factors in Taiwan during 1976-2009. METHODS: The yearly suicide death rate, socio-economic (spouseless population, aged population, labor participation rate, unemployment rate, and gross national production), media (newspapers, television sets, and personal computer) densities, and climatic (temperature, rainfall, and sunshine) factors were gathered. Pearson's correlation coefficients between variables were calculated, and stepwise multiple regression analysis was conducted. RESULTS: Percentage of the spouseless and elderly population, labor participation rate, unemployment rate, and densities of newspapers and personal computer were significantly associated with suicide rate. Multiple regression chose spouseless population, labor participation rate, and unemployment rate to explain 96.1% of the variance of the suicide rate (F((3,22))=178.996, p=0.000). CONCLUSIONS: Socio-economic factors are important for the secular trend of suicide, while medium densities also play some roles. PMID- 20833433 TI - Prefrontal brain asymmetry and pre-menstrual dysphoric disorder symptomatology. AB - BACKGROUND: Pre-menstrual dysphoric disorder (PMDD), a dysphoric form of pre menstrual syndrome, is included as a diagnosis for further study in the DSM-IV-TR (APA, 2000). The present study investigated whether a marker of risk for major depressive disorder (MDD), prefrontal brain asymmetry, also characterizes women with PMDD. METHODS: In a sample of 25 college women with PMDD symptomatology and 25 matched controls, resting frontal electroencephalographic (EEG) activity was assessed on four occasions within a two-week span. RESULTS: Across several frontal sites women with PMDD had relatively less left than right prefrontal brain activity, consistent with a diathesis-stress model for menstrual-related dysphoria. CONCLUSIONS: The findings suggest an overlap in the risk profile for MDD and PMDD. PMID- 20833434 TI - Does psychomotor retardation define a clinically relevant phenotype of unipolar depression? AB - BACKGROUND: The recognition and assessment of psychomotor retardation may have implications for better definition of the clinical phenotypes of depression. The aim of this study was to assess the clinical correlates of psychomotor retardation endorsed at any time during the patients' lifetime (LPR). METHODS: The study sample included 291 patients with non-psychotic major depressive disorder (MDD) participating in the clinical trial, "Depression: The Search for Treatment-Relevant Phenotypes." Psychomotor retardation was measured using a factor derived from the Mood Spectrum Self-Report (MOODS-SR) assessment. Using a pre-defined cut-off score on the lifetime psychomotor retardation (LPR) factor of the MOODS-SR, participants were classified into high and low scorers. Logistic regression analysis was used to evaluate the relationship between LPR and subthreshold bipolarity. RESULTS: Compared to low scorers, participants with high scores on the LPR factor had greater severity of depression and more bipolarity indicators. CONCLUSIONS: The MOODS-SR appears to be helpful to identify clinical phenotypes of unipolar depression and to highlight the usefulness of a lifetime approach to the assessment of psychopathology in the characterisation of patients with unipolar depression. PMID- 20833435 TI - Defensive startle response to emotional social cues in social anxiety. AB - Potentiation of fear-related defense behaviours coordinated by the amygdala in response to environmental threat characterizes several anxiety disorders. We compared eye-blink startle responses to startle probes delivered during the presentation of emotional and neutral social cues in high and low generalized social anxiety. Socially anxious individuals exhibited larger startle responses to emotional (positive and negative) relative to neutral social cues, compared to non-anxious individuals. PMID- 20833436 TI - The microanatomy of the palatine tonsils of the buffalo (Bos bubalus). AB - The palatine tonsils play a key role in initiating immune responses against antigens entering the body through the mouth. They are also replication sites of some pathogens. There is no data available about the structure of the palatine tonsils of the Egyptian water buffalo. Therefore, palatine tonsils of 14 clinically healthy buffalo bulls (2-3 years old) were examined macroscopically and microscopically using light, and transmission electron microscopes. The tonsils had an elongated kidney shape with a central invagination (tonsillar fossa) containing a single macroscopic opening leading to a small central cavity (tonsillar sinus). A number of macroscopic crypts originated from this sinus (internal crypts). Besides the tonsillar fossa, also small macroscopic crypts (external crypts) were present. The tonsils were enclosed by a thin connective tissue capsule and septa divided the tonsils into incomplete lobes. Within these encapsulated organs mucous glands were very obvious. Each crypt was highly branched and lined with stratified squamous non-keratinized epithelium. Several lymphoid cells infiltrated between the epithelial cells forming patches of lymphoepithelium. The crypt lumen contained lymphocytes, neutrophils and erythrocytes. Lymph nodules with clear germinal centers extended under the epithelial surface. Diffusely distributed lymphocytes were found in the narrow interfollicular region. High endothelial venules, interdigitating dendritic cells, macrophages and plasma cells were observed among the diffuse lymphocytes. Lymphatics filled with lymphocytes drained the tonsils. PMID- 20833437 TI - Intelligibility of hearing impaired children as judged by their parents: A comparison between children using cochlear implants and children using hearing aids. AB - OBJECTIVES: The aim of this study was to determine the intelligibility of prelingually deaf children with cochlear implants (CI) as judged by their own parents, and to compare these results with prelingually hearing impaired children using hearing aids (HA) and normally hearing (NH) children. The authors hypothesised that subjects using conventional hearing aids would have poorer intelligibility judgements compared to NH and CI children. METHODOLOGY: This is a comparative study of 24 prelingually deaf CI children (m.a. 8.3 years), 24 prelingually hearing impaired HA children (m.a. 9.0 years) and 25 NH children. Recorded speech samples at word-, sentence- and story-level were perceptually judged by two speech pathologists and the child's main caregiver (the mother in most cases) using a five-point hierarchical scale. In addition, the sample of each child was transcribed by the child's main caregiver. The investigators counted and determined a percentage of words correctly understood. RESULTS: The judgements of the speech pathologists and the transcriptions of the mothers were not different between the CI and NH children, although the mothers tended to judge their CI child to be less intelligible. The HA children on the other hand, showed a mean intelligibility inferior to NH and CI children, as demonstrated by the judgements of the mothers and speech pathologists as well as by the percentages of correctly identified words by the mothers. CONCLUSION: The intelligibility of the prelingually deaf CI children is very close to the intelligibility of NH children, while the HA children still show a decreased mean intelligibility. PMID- 20833438 TI - Chronic otitis media in mucopolysaccharidosis may not be due to Eustachian tube dysfunction. PMID- 20833439 TI - Mass vaccination as a complementary tool in the control of a severe outbreak of bovine brucellosis due to Brucella abortus in Extremadura, Spain. AB - We report the evolution of an outbreak of bovine brucellosis (Brucella abortus) in the region of Extremadura (Spain) involving more than 1000 herds and nearly 40,000 animals. S19 vaccination of young cattle combined with a test and slaughter strategy did not result in a rapid decrease in herd prevalence and animal incidence; these parameters showed a constant decreasing trend only when a combination of restriction of cattle movements, increased test frequency, S19 vaccination and mass RB51 vaccination (with yearly revaccinations) were applied to all susceptible populations. These measures were applied for 5 years; abortions following RB51 vaccination of pregnant cows were limited to the first inoculation and the involvement of the vaccine strain could only be demonstrated in 78 out of 897 abortions. Our results demonstrate the usefulness - and lack of significant side effects - of RB51 mass vaccination as a complementary tool to control bovine brucellosis outbreaks in areas where the disease cannot be contained using more conservative approaches. PMID- 20833440 TI - RNAi and small interfering RNAs in human disease therapeutic applications. AB - Small interfering RNAs (siRNAs) have been shown to effectively downregulate gene expression in human cells, giving them potential to eradicate disease. Prospects for clinical applications are discussed in this review, along with an overview of recent history and our current understanding of siRNAs used for therapeutic application in human diseases, such as cancer and viral infections. Over recent years, progress has been made in lipids, ligands, nanoparticles, polymers and viral vectors as delivery agents and for gene-based expression of siRNA to enhance the efficacy and specificity of these methods while at the same time reducing toxicity. It has become apparent that given the recent advances in chemistry and delivery, RNAi will soon prove to be an important and widely used therapeutic modality. PMID- 20833441 TI - Autoantibodies in type 1 diabetes. AB - Type 1 diabetes is an autoimmune disease manifested by an autoimmune attack on the pancreatic beta-islet cells. It is also known that Type 1 diabetes is associated with other autoimmune diseases. The aim of the present study was to seek autoantibodies in the serum of people with Type 1 diabetes. PMID- 20833442 TI - Perceived risk and the willingness to enroll in a diabetes prevention lifestyle intervention in Arab-Americans. AB - The purpose was to examine whether self-reported perceived risk predicts willingness to enroll in DPP-adapted lifestyle intervention in Arab-Americans. Results document a positive relationship between perceived risk and willingness to engage in diabetes prevention activities. These findings imply that educational interventions communicating risk may improve adoption of diabetes preventative efforts. PMID- 20833443 TI - High prevalence of glucose intolerance in Japanese patients with peripheral arterial disease. PMID- 20833444 TI - Intermittent etanercept therapy in pediatric patients with psoriasis. AB - BACKGROUND: Stopping and restarting etanercept is well tolerated in adult psoriasis, but little is known about intermittent use in pediatric psoriasis. OBJECTIVE: We sought to assess safety and efficacy of etanercept administered intermittently in children with psoriasis. METHODS: At study entry, patients were 4 to 17 years old with moderate to severe stable plaque psoriasis (Psoriasis Area and Severity Index [PASI] score >= 12). After an initial 12-week, double-blind period and a 24-week, open-label period, eligible patients (ie, achieved 75% improvement in PASI response from baseline [PASI 75]) were re-randomized to a 12 week, double-blind withdrawal-retreatment period: patients received placebo (withdrawal) or etanercept as long as they maintained PASI 75; otherwise, they were retreated with open-label etanercept (retreatment). RESULTS: The 138 patients who entered the withdrawal-retreatment period were re-randomized equally between placebo and etanercept. In the group treated with blinded or open-label etanercept, 52 of 65 (80%; observed data) patients maintained or regained PASI 75 at the end of the 12-week period. In all, 45 of 64 (70%) patients on blinded etanercept maintained PASI 75 at every study visit during the 12-week period, compared with 35 of 65 (54%) patients who did so on blinded placebo. No patient had a serious adverse event, serious infection, or withdrew from study because of an adverse event. LIMITATIONS: Small study and short observation period are limitations. CONCLUSION: During the final 12-week withdrawal-retreatment period of this 48-week study, intermittent etanercept therapy appeared safe, with no patients experiencing a serious adverse event or serious infection, and effective, with 80% of patients on etanercept maintaining or regaining PASI 75 at the end of the 12-week period. PMID- 20833445 TI - Excess costs associated with common healthcare-associated infections in an Iranian cardiac surgical unit. AB - Healthcare-associated infection (HCAI) following open heart surgery is not only a major cause of mortality and morbidity, but also carries higher costs. There are limited data on the additional costs due to HCAI in non-western countries. To estimate the direct cost of the four most common HCAIs in an Iranian sample, we studied 1191 patients admitted for elective open heart surgery. HCAIs were defined using the National Nosocomial Infections Surveillance criteria (Centers for Disease Control and Prevention, Atlanta, GA, USA). The financial costs of length of stay per day in hospital, paraclinical services, medications, instruments, and operating room were provided by the hospital's finance department. The contribution of HCAI to excess direct medical costs in patients with HCAI was assessed by multivariable linear regression. In the study population, the mean age was 57.3+/-11.9 years, 857 (72.0%) were men, and 64 (5.4%) developed HCAI. In total there were 73 infections of which the most common was surgical site infection (49.3%), followed by urinary tract infection (20.5%), bloodstream infection (16.5%), and pneumonia (13.7%). After adjustment for other confounders HCAI remained associated with excess direct medical costs (beta=1707.06, SE=90.84; P < 0.001). The medical costs in patients with HCAI were almost twice those in patients without HCAI. More than half of the excess cost was attributable to prolonged hospitalisation. PMID- 20833447 TI - [Do primary care doctors empathise with pregnant women?]. PMID- 20833446 TI - Effects of ApoE4 and maternal history of dementia on hippocampal atrophy. AB - We applied an automated hippocampal segmentation technique based on adaptive boosting (AdaBoost) to the 1.5 T magnetic resonance imaging (MRI) baseline and 1 year follow-up data of 243 subjects with mild cognitive impairment (MCI), 96 with Alzheimer's disease (AD), and 145 normal controls (NC) scanned as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). MCI subjects with positive maternal history of dementia had smaller hippocampal volumes at baseline and at follow-up, and greater 12-month atrophy rates than subjects with negative maternal history. Three-dimensional maps and volumetric multiple regression analyses demonstrated a significant effect of positive maternal history of dementia on hippocampal atrophy in MCI and AD after controlling for age, ApoE4 genotype, and paternal history of dementia, respectively. ApoE4 showed an independent effect on hippocampal atrophy in MCI and AD and in the pooled sample. PMID- 20833448 TI - The reputation and professional identity of family medicine practice according to medical students: a Spanish case study. AB - OBJECTIVE: Over the last decade, family medicine has been progressively rejected by medical students as a career choice in many Western countries. Our objective is to contribute to a better understanding of this phenomenon by examining the reputation of and identification processes with family medicine by medical students. DESIGN: A qualitative case study. METHODS: Focus groups and document analysis were used for generating empirical material. Focus groups (n=6) were conducted (2008-2009). Thematic analysis was adopted as the technique for analyzing data gathered. SETTING: A faculty of medicine of a Spanish university. PARTICIPANTS: Second and sixth year undergraduate medical students (N=48). RESULTS: Family medicine appears to be largely devalued as a professional activity, among medical students, being viewed as a monotonous and non technological medical practice with no intellectual challenge. Such a negative view, which already appears in early stages of medical training, leads to a lack of identification with this medical practice by students. CONCLUSION: Misconceptions about the practice of family medicine, created and reproduced in health care system and societal contexts, encourage the practice of specialized medicine. In addition, the academic environment appears to promote organ- and disease-based medical knowledge, which goes against the holistic and patient centered approach characteristic of the practice of family medicine. In order to improve the reputation of family medicine and for it to be considered as an attractive career path by medical students, it is recommended that family medicine is developed as an academic medical field, and that improvements are made in the conditions and status of this medical practice within the health care system. PMID- 20833449 TI - [Incidence rate of community acquired pneumonia in a population cohort registered in BIFAP]. AB - OBJECTIVE: To estimate the incidence rate (IR) of community acquired pneumonia (CAP) using the information in the Primary Healthcare database in Spain. DESIGN: Retrospective study (2003-2007) using the information registered in the Database for Pharmaco-Epidemiological Research in Primary Care (BIFAP). STUDY POPULATION: Subjects aged 20 to 79 years old, were followed up until the occurrence of a pneumonia episode, death, age of 80, or the end of the study, whichever came first. CASE SELECTION: A computerised search was performed to detect suggestive cases of pneumonia using ICPC codes (International Classification of Primary Care) and free text. The computerised histories were manually reviewed in order to identify those cases fulfilling the CAP's determined definition. ANALYSE: IR of pneumonia was computed by age, sex and season. The percentage of hospitalisation was estimated. These results were compared with the IR from the United Kingdom using THIN database (The Health Improvement Network). RESULTS: IR of CAP was 2.69 per 1000 persons-year (IR women=2.29; IR men=3.16) with BIFAP database, and 32 % of the CAP cases were hospitalised. In United Kingdom, IR was 1.07 per 1000 persons-year (IR women=0.93; IR men=1.22) and 17% of CAP were hospitalised. CONCLUSION: The BIFAP computerised Primary Care database is useful to estimate the incidence rate of CAP in Spain, as well as to compare the results with those obtained using other European computerised Primary Care databases. PMID- 20833450 TI - A convenient synthesis of 13N-labelled azo compounds: a new route for the preparation of amyloid imaging PET probes. AB - In the present paper, a fast and automated method for the synthesis of (13)N labelled azo compounds is reported for the first time. The labelling strategy is based on trapping [(13)N]NO(2)(-) in an anion exchange resin. The reaction with primary aromatic amines in acidic media led to the formation of the corresponding diazonium salts, which were further reacted with aromatic amines and alcohols to yield the corresponding (13)N-labelled azo derivatives with good radiochemical conversion (40.0-58.3%). Good radiochemical yields (20.4-47.2%, decay corrected) and radiochemical purities (>99.9%) were obtained after purification by HPLC. Such methodology can be easily applied to the preparation of a wide range of (13)N-labelled azo derivatives by adequate selection of the non-radioactive precursors. PMID- 20833451 TI - Synthesis and cytotoxicity evaluation of novel 1,4-disubstituted 1,2,3-triazoles via CuI catalysed 1,3-dipolar cycloaddition. AB - A facile and highly efficient method for the regioselective synthesis of 1,4 disubstituted 1,2,3-triazoles (beta-keto 1,2,3-triazoles) in good to excellent yields from in-situ generated beta-ketoazides and terminal alkynes through Cu(I) catalyzed 1,3 dipolar cycloaddition is described. This reaction proceeds smoothly either in water or in a 1:1 mixture of water and acetone at room temperature without use of any additive. The synthesized compounds were screened for their cytotoxicity in A549 (Lung Cancer), HT-29 (Colon Cancer), He La (Cervical Cancer) using MTT assay that exhibited significant cytotoxicity at modest doses. PMID- 20833452 TI - Synthesis, characterization and cytotoxicity of mixed-ligand complexes of palladium(II) with aromatic diimine and 4-toluenesulfonyl-L-amino acid dianion. AB - Eight new palladium(II) complexes (1a-2d) with 4-toluenesulfonyl-l-amino acid dianion and diimine (bipy and phen) have been synthesized and characterized by elemental analysis, IR, UV, (1)H NMR, (13)C NMR and mass spectra techniques. Crystal structure of the complex (2d) has been determined by X-ray diffraction analysis. The cytotoxicity was tested by MTT and SRB assays. The results indicate that the complexes (1a-2d) have selectivity against tested carcinoma cell lines. The complex (2c) has the best cytotoxicity among the eight complexes, moreover its cytotoxicity is better than that of cisplatin against BGC-823, Bel-7402 and KB cell lines. It suggests that both aromatic diimine and 4-toluenesulfonyl-L amino acid have important effect on cytotoxicity. PMID- 20833453 TI - Crystal structures, DNA-binding and cytotoxic activities studies of Cu(II) complexes with 2-oxo-quinoline-3-carbaldehyde Schiff-bases. AB - Three novel 2-oxo-quinoline-3-carbaldehyde Schiff-bases and their Cu(II) complexes were synthesized. The molecular structures of Cu(II) complexes were determined by X-ray crystal diffraction. The DNA-binding modes of the complexes were also investigated by UV-vis absorption spectrum, fluorescence spectrum, viscosity measurement and EB-DNA displacement experiment. The experimental evidences indicated that the ligands and Cu(II) complexes could interact with CT DNA (calf-thymus DNA) through intercalation, respectively. Comparative cytotoxic activities of ligands and Cu(II) complexes were also determined by MTT [3-(4,5 dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide] and SRB (sulforhodamine B) methods. The results showed that the three Cu(II) complexes exhibited more effective cytotoxic activity against HL60 cells and HeLa cells than corresponding ligands. Also, CuL(3) showed higher cytotoxic activity than CuL(1) and CuL(2). PMID- 20833454 TI - Synthesis and in vitro antibacterial activity of fluoroquinolone derivatives containing 3-(N'-alkoxycarbamimidoyl)-4-(alkoxyimino) pyrrolidines. AB - A series of novel 7-[3-(N'-alkoxycarbamimidoyl)-4-(alkoxyimino)pyrrolidin-1-yl] fluoroquinolone derivatives were designed, synthesized and characterized by (1)H NMR, MS and HRMS. These fluoroquinolones were screened for their in vitro antibacterial activity. Most of them exhibit good potency in inhibiting the growth of Staphylococcus aureus and Staphylococcus epidermidis (MIC: 0.06-4.00 MUg/mL). The activity of compounds 33 and 43 against S. aureus including MRSA and S. epidermidis including MRSE (MIC: 0.06-0.125 MUg/mL) is more than or comparable to the reference drugs levofloxacin and gemifloxacin. In addition, compound 33 is 32 and 16-32 fold more potent than both the reference drugs against Enterococcus faecium 08-7 and Klebsiella pneumoniae 09-22, respectively. PMID- 20833455 TI - The impact of an integrated pharmacology and medicines management curriculum for undergraduate adult nursing students on the acquisition of applied drug/pharmacology knowledge. AB - AIMS: To investigate the efficacy of a 14-month integrated pharmacology and medicines management curriculum for undergraduate nursing students on the acquisition of applied drug/pharmacology knowledge. BACKGROUND: Despite considerable debate regarding nurses' ability to be able to fulfill their medication management responsibilities, little is known about how nurses should be educated in medicines management. METHODS: Two groups of nursing students were compared. The first group were exposed to the usual curriculum (control group), whilst a second group experienced a new integrated pharmacology and medicines management curriculum (intervention group) (N=120). The impact of the curriculum on applied drug knowledge was assessed using a 69 item short answer questionnaire relating to a vignette. Students also undertook a 42 item on-line test exploring principles of pharmacokinetics. Students were also asked to self-rate their knowledge using a four point likert scale which asked how confident they were in relation to the prescribed medication regime. The data were collected in July 2008. The intervention group was exposed to an integrated curriculum approach, whilst the control group undertook periods of supervised practice within a clinical environment supported with a workbook and practice assessment learning outcomes. RESULTS/FINDINGS: Students exposed to an integrated approach to pharmacology and medicines management demonstrated superior pharmacokinetic knowledge and were more able to apply drug knowledge to the patient vignettes than the control group. CONCLUSION: An early introduction of an integrated approach to the teaching and assessing of pharmacological processes improves students' drug knowledge prior to qualification. A sound preparation will help to ensure safe and effective medicines management care for patients and will prepare nurses for post graduate education and further training. PMID- 20833456 TI - Transfer factors of polonium from soil to parsley and mint. AB - Transfer factors of (210)Po from soil to parsley and mint have been determined. Artificial polonium isotope ((208)Po) was used as a tracer to determine transfer factor of Po from soil to plant in pot experiments. Two plant growing systems were used for this study namely, an outdoor system and a sheltered system by a polyethylene tent. (208)Po and (210)Po were determined in soil and different parts of the studied plants (stem and leaf), using alpha spectroscopy. The results have shown that there was a clear uptake of (208)Po by roots to leaves and stems of both plants. Higher values of transfer factors using the (210)Po activity concentrations than the (208)Po activity concentration were observed. Transfer factors of (210)Po from soil to parsley varied between 20 * 10-2 and 50 * 10-2 and 22 * 10-3 and 67 * 10-3 in mint, while (208)Po transfer factors varied between 4 * 10-2 and 12 * 10-2 for parsley and 10 * 10-2 and 22 * 10-2 in mint. Transfer factors of Po were higher in those plants grown in the sheltered system than in the open system; about 75% of Po was transferred from atmosphere to parsley parts using the two systems. Ratios of transferred Po from soil to mint stem and leaf in the sheltered system were higher by 2 times from those in the open system. PMID- 20833457 TI - Variation of radiation level and radionuclide enrichment in high background area. AB - Significantly high radiation level and radionuclide concentration along Quilon beach area of coastal Kerala have been reported by several investigators. Detailed gamma radiation level survey was carried out using a portable scintillometer. Detailed studies on radionuclides concentration in different environmental matrices of high background areas were undertaken in the coastal areas of Karunagapalli, Kayankulam, Chavara, Neendakara and Kollam to study the distribution and enrichment of the radionuclides in the region. The absorbed gamma dose rates in air in high background area are in the range 43-17,400nGyh-1. Gamma radiation level is found to be maximum at a distance of 20m from the sea waterline in all beaches. The soil samples collected from different locations were analysed for primordial radionuclides by gamma spectrometry. The activity of primordial radionuclides was determined for the different size fractions of soil to study the enrichment pattern. The highest activity of (232)Th and (226)Ra was found to be enriched in 125-63MU size fraction. The preferential accumulation of (40)K was found in <63MU fraction. The minimum (232)Th activity was 30.2Bqkg-1, found in 1000-500MU particle size fraction at Kollam and maximum activity of 3250.4Bqkg-1 was observed in grains of size 125-63MU at Neendakara. The lowest (226)Ra activity observed was 33.9Bqkg-1 at Neendakara in grains of size 1000 500MU and the highest activity observed was 482.6Bqkg-1 in grains of size 125 63MU in Neendakara. The highest (40)K activity found was 1923Bqkg-1 in grains of size <63MU for a sample collected from Neendakara. A good correlation was observed between computed dose and measured dose in air. The correlation between (232)Th and (226)Ra was also moderately high. The results of these investigations are presented and discussed in this paper. PMID- 20833458 TI - Measuring the quality of documented care given by Swedish midwives during birth. AB - OBJECTIVES: To measure the extent to which documented Swedish midwifery care for low-risk labour and birth followed the World Health Organization's (WHO) recommendations for care in normal birth, and to compare midwifery care given to women who's labours were classified as low and high risk. STUDY DESIGN: A retrospective examination of midwifery and medical records, 144 from women with low-risk births and 54 from women with high-risk births, for aspects of pregnancy, labour and birth using a validated instrument based on WHO's recommendations. SETTING: Southern Sweden. OUTCOME MEASUREMENTS: Care given in accordance with WHO's four categories of practice and changes in risk group during the birth process. FINDINGS: Care interventions not recommended by WHO, such as routine establishment of an intravenous route, routine amniotomy during the first stage, continuous electronic fetal monitoring and pharmacological methods of pain relief, were widespread in the records. Documented care differed little between the labours of women at low risk and high risk. The midwives at the unit under study did not routinely carry out risk assessment. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The mode of care was one of readiness for medical intervention. The act of carrying out risk assessments at the time of the woman's admission may affect awareness of the level of care offered to birthing women, and thus help to reduce the number and variety of practices not recommended by WHO. PMID- 20833459 TI - The 'quit' smoker and stillbirth risk: a review of contemporary literature in the light of findings from a case-control study. AB - OBJECTIVE: to identify existing literature which addresses the topic of detecting, assessing and intervening when a pregnant woman who has quit smoking relapses. This literature review was conducted in the light of findings of a case control study which suggest that a quit smoking status is associated with increased risk of late stillbirth (odds ratio 3.03, 95% confidence interval 1.27 7.24, p = 0.01). METHOD: a structured review was conducted to identify literature related to quitting smoking in early pregnancy, prevalence and likelihood of relapse, possible methods for detecting smoking resumption, potential intervention strategies for the relapsed smoker and the societal burden of continuing to smoke in pregnancy. FINDINGS: there is a wide variety of evidence for the effectiveness of intervention strategies aimed at assisting women to quit smoking during pregnancy. However, few studies have specifically aimed to identify strategies to assist those women who report quitting in early pregnancy to maintain that status throughout pregnancy. CONCLUSIONS: in light of the results of the case-control study and this literature review, it is important that changes are made to prenatal care in order to enable midwives to better identify women who are struggling with abstinence or who resume smoking during pregnancy. IMPLICATIONS FOR PRACTICE: midwives should discuss and monitor smoking status with women at every prenatal visit. If a midwife finds that a woman has relapsed into smoking, they can be offered a range of quit smoking intervention strategies, including referral to a dedicated cessation service, counselling support, alternative therapies and, perhaps, nicotine replacement therapy. Further research aimed at identifying the extent of relapse among these women and the impact this may have on pregnancy outcome is warranted. Research to ascertain the most appropriate interventions to prevent relapse is also needed. PMID- 20833460 TI - Men's sexual orientation and suicide: evidence for U.S. adolescent-specific risk. AB - There is strong consensus in the research literature that adolescent and adult men who report same-sex sexual orientations, identities, and behaviors are at higher risk for suicide. Recent studies of general adolescent suicide risk have identified developmental trajectories that peak during the teenage years. Because the adolescent years are characterized by the development and heightened awareness of gender roles and sexual scripts closely tied to dominant cultural ideals of masculinity and heterosexuality, an adolescent-focused developmental trajectory for suicide risk might be particularly relevant for males with adolescent same-sex sexual orientations. We provide the first prospective examination of adolescent-specific risk for suicidality based on adolescent same sex sexual orientation using data from the United States, the National Longitudinal Study of Adolescent Health. Tracing suicide ideation and attempts across four assessments from adolescence (Wave 1 average age 15.3 years) to young adulthood (Wave 4 average age 28.2), we documented that the risk for suicidal thoughts and attempts for adolescent same-sex attracted males is developmental in nature. Specifically, the risk for suicidal thoughts and attempts for males with same-sex attractions is largely limited to the adolescent years. These results offer new insights for suicide prevention and intervention for male adolescents and adults with same-sex sexual orientations. PMID- 20833461 TI - Understanding boys': thinking through boys, masculinity and suicide. AB - In the UK, the media are reporting increasing rates of childhood suicide, while highlighting that increasing numbers of pre-adolescent boys (in relation to girls) are diagnosed as mentally ill. In response, academic, professional and political commentators are explaining this as a consequence of gender. One way of doing this has been to apply adult defined understandings of men and masculinities to the attitudes and behaviours of pre-adolescent boys. As a consequence, explanations of these trends point to either 'too much' masculinity, such as an inability to express feelings and seek help, or 'not enough' masculinity that results in isolation and rejection from significant others, such as peer groups. Using a discourse analysis of semi-structured interviews with 28 children aged 9-13 (12 male, 16 females) and 12 school staff at a school in North East England, this article questions the viability of using normative models of masculinity as an explanatory tool for explaining boys' behaviours and suggests that researchers in the field of gender and suicide consider how boys' genders may be constituted differently. We develop this argument in three ways. First, it is argued that studies that use masculinity tend to reduce the formation of gender to the articulation of power across and between men and other men and women. Second, we argue that approaches to understanding boys' behaviours are simplistically grafting masculinity as a conceptual frame onto boy's attitudes and behaviours. In response, we suggest that it is important to re-think how we gender younger boys. The final section focuses specifically on the ways that boys engage in friendships. The significance of this section is that we need to question how notions of communication, integration and isolation, key features of suicide behaviours, are framed through the local production of friendships. PMID- 20833462 TI - Anxiety sensitivity as a predictor of anxiety and pain related to third molar removal. AB - PURPOSE: Anxiety sensitivity (AS) refers to the fear of anxiety-related symptoms resulting from beliefs that such sensations have negative somatic, social, or psychological consequences. The aim of the present study was to investigate whether AS can predict both anticipated and experienced pain and state and trait anxiety related to third molar removal. MATERIALS AND METHODS: Data were collected from 160 patients who had completed measures of anxiety sensitivity, including the Anxiety Sensitivity Index, the short form of the Fear of Dental Pain questionnaire, the short form of the Dental Anxiety Inventory, and numeric rating scales to assess the anticipated anxiety and pain. Postoperatively, patients were asked to rate their experienced anxiety and pain during treatment, first immediately after surgery and again after 2 days and after 1 week. RESULTS: AS was significantly associated with the severity of dental trait anxiety. However, multiple stepwise regression analysis revealed that AS did not significantly predict anticipated and experienced anxiety and pain beyond that of state anxiety and fear of dental pain. State anxiety was the single best predictor of trait anxiety and pain, followed by the fear of dental pain. CONCLUSIONS: In the present study, AS did not predict anxiety and pain related to third molar removal. One possible explanation is that most measures were taken postoperatively, a period in which anticipatory anxiety is irrelevant. PMID- 20833463 TI - Deterioration of myocardial injury due to dexmedetomidine administration after myocardial ischaemia. AB - AIM: Dexmedetomidine is a highly selective alpha-2 adrenergic agonist used perioperatively. Dexmedetomidine's cardioprotective effect after myocardial ischaemia remains unknown. In this study, we administered dexmedetomidine after ischaemia to investigate its ability to protect the cardiac muscle from ischaemia reperfusion injury in isolated rat hearts. METHODS: After a 30-min stop of perfusion, isolated rat hearts underwent reperfusion for 120 min. At the initiation of reperfusion, dexmedetomidine was administered for 25 min at concentrations of 0 nM (control group), 1 nM (Dex 1 group), and 10 nM (Dex 10 group). Yohimbine (an alpha-2 adrenergic antagonist) was administered in the manner as above in another group of isolated rat hearts at a concentration of 1 MUM without dexmedetomidine (Yoh group) and at 1 MUM with 10 nM dexmedetomidine (Yoh+Dex 10 group). The area of infarction was measured using 2,3,5 triphenyltetrazolium staining. RESULTS: Dexmedetomidine administration did not influence haemodynamics or the coronary flow (CF), but did increase the myocardial infarct size. Neither concentration of dexmedetomidine affected the infarct size as the Dex 1 and Dex 10 groups had almost the same infarct size. The infarct size was 40.5+/-2.9% in the control group, 60.9+/-5.3% in the Dex 1 group, and 60.9+/-2.8% in the Dex 10 group. The infarct size was reduced in the yohimbine groups. The infarct size was 39.2+/-3.3% in the Yoh+Dex 10 group and 45.0+/-3.2% in the Yoh group. CONCLUSION: Dexmedetomidine administration does not influence haemodynamics or CF, but does increase the cardiac infarct size. alpha 2 Adrenergic stimulation may induce this mechanism. PMID- 20833464 TI - Regional cerebral oxygen saturation predicts poor neurological outcome in patients with out-of-hospital cardiac arrest. PMID- 20833465 TI - A novel androgen receptor gene mutation in a Chinese patient with complete androgen insensitivity syndrome. AB - OBJECTIVE: To identify the underlying androgen receptor gene mutation in a Chinese patient with typical symptoms of complete androgen insensitivity syndrome. STUDY DESIGN: A Chinese female phenotype with 46, XY karyotype was diagnosed because of primary amenorrhea. Mutations were determined by polymerase chain reaction followed by DNA sequencing. RESULTS: DNA sequencing of the androgen receptor gene showed a G2439T transition causing E442X mutation in exon 1 in the patient with complete androgen insensitivity syndrome. The E442X mutation was a new de novo non-sense mutation in exon 1 of the androgen receptor gene. This non-sense mutation is located in the N-terminal transactivation domain and leads to a predicted truncated protein of 441 amino acids with loss of the end part of the N-terminal transactivation domain, and the DNA-binding and ligand binding domain. CONCLUSION: This E442X non-sense point mutation has not been described previously in cases of androgen insensitivity syndrome, and could lead to the synthesis of a short truncated non-functional androgen receptor probably responsible for the phenotype of complete androgen insensitivity syndrome in the affected individual. Gonadectomy should be planned to eliminate the risk of gonadal malignancy. PMID- 20833466 TI - JMarinas: a simple tool for the environmentally sound management of small marinas. AB - A novel index for the preliminary evaluation of the distribution of pollutants in the harbor environment (Small Marinas Pollution Risk) is proposed. An associated Environmental Decision Support System (JMarinas) has been developed which implements the Multiple Attribute Decision Making theory (MADM) and uses the harbor's map as geographical support for computations. The MADM matrix is built considering various attributes of the marina and is calculated using both qualitative and quantitative data. Jmarinas has been applied to two small marinas along the Ligurian coast (Marina degli Aregai and Portosole) during the winter and summer seasons. Results show good spatial and temporal resolution and are in agreement with observations. For further quantitative assessment of performance, we refer to Irene et al. (2010). PMID- 20833467 TI - The influence of reducing conditions on the dissolution of a Mn-rich slag from pyrometallurgical recycling of alkaline batteries. AB - The redox potential (Eh) is a key parameter for controlling the release of elements from solid materials. Nevertheless, this parameter is seldom taken into account during risk assessment studies within any regulatory framework. We studied the incidence of redox changes to the solid materials using two batch procedures: i) a gradient of redox conditions obtained using sodium ascorbate solutions at various concentrations; ii) N(2) bubbling in water. These experiments were performed on two Mn-rich slag samples coming from a pyrometallurgical plant that recycles alkaline batteries. Both samples differed slightly in their chemical composition and solid characterization (i.e. presence of Mn oxide) and presented different behaviours. The present study focused on the release of the main slag elements (i.e. Mn and Si) chosen as indicators of the dissolution of primary silicate phases. Solid phase analyses (SEM-EDS and XRD) were coupled with the monitoring of elements in leachates in order to understand their behaviour and the mechanisms involved. The results indicated that the solid composition plays an important role in the release mechanisms. The presence of Mn oxide enhanced the mobilization of Mn in the greatest reducing conditions (-320 +/- 5 mV/SHE), to the extent that 42% of the total Mn was leached. This demonstrated the significance in studying the solid phases (using SEM-EDS and XRD) before and after any leaching experiment. From a laboratory practice point of view, it was easier to use sodium ascorbate and allowed, in our case, greater reducing conditions to be reached. PMID- 20833468 TI - Application of sequential extraction analysis to electrokinetic remediation of cadmium, nickel and zinc from contaminated soils. AB - An enhanced electrokinetic process for the removal of cadmium (Cd), nickel (Ni) and zinc (Zn) from contaminated soils was performed. The efficiency of the chelate agents nitrilotriacetic acid (NTA), diethylenetriaminepentaacetic acid (DTPA) and diaminocycloexanetetraacetic acid (DCyTA) was examined under constant potential gradient (1.23 V/cm). The results showed that chelates were effective in desorbing metals at a high pH, with metal-chelate anion complexes migrating towards the anode. At low pH, metals existing as dissolved cations migrated towards the cathode. In such conflicting directions, the metals accumulated in the middle of the cell. Speciation of the metals during the electrokinetic experiments was performed to provide an understanding of the distribution of the Cd, Ni and Zn. The results of sequential extraction analysis revealed that the forms of the metals could be altered from one fraction to another due to the variation of physico-chemical conditions throughout the cell, such as pH, redox potential and the chemistry of the electrolyte solution during the electrokinetic treatment. It was found that binding forms of metals were changed from the difficult type to easier extraction type. PMID- 20833469 TI - Toxic interaction of thionine to deoxyribonucleic acids: elucidation of the sequence specificity of binding with polynucleotides. AB - The sequence specificity of the intercalative DNA damage of the phenothiazine dye thionine has been investigated by absorbance, fluorescence, circular dichroism and viscosity studies using four synthetic polynucleotides, poly(dA-dT).poly(dA dT), poly(dA).poly(dT), poly(dG-dC).poly(dG-dC) and poly(dG).poly(dC). Strong hypochromic-bathochromic effects in absorbance and quenching in fluorescence were observed that showed strong binding of thionine to these polynucleotides. Scatchard plots revealed non-cooperative binding and analysis by McGhee-von Hippel equation provided the affinity values in the order of 10(5)M(-1). The binding clearly revealed the high preference of thionine to the alternating GC sequences followed by the homo GC sequences. The AT polynucleotides had lower binding affinities but the alternating AT sequences had higher affinity compared to the homo stretches. The results of ferrocyanide quenching studies in fluorescence and viscosity experiments conclusively proved the intercalation of thionine while circular dichroic studies provided evidence for the structural perturbations associated with the sequence specific intercalative binding. The sequence specificity of the intercalative damage of thionine to deoxyribonucleic acid is advanced from this study. PMID- 20833470 TI - Simulation of micellar enhanced ultrafiltration by multiple solute model. AB - Multiple solute ultrafiltration models in micellar enhanced ultra filtration (MEUF) have been studied, for experimental results of selective separation of Cu (II) and Co (II) with anionic surfactant, sodium dodecyl sulfate (SDS) and imino diacetic acid (IDA) as chelating agent using synthetic waste water. This model is based on mass balance analysis coupled with the filtration theory, resistance-in series model and gel polarization model. This model is characterized by the parameters, membrane resistance R(m), membrane permeability P(m), back transport coefficient K(b), K(bi) and mass transfer coefficient k(i). These parameters are estimated by using the Levenberg-Marquardt method coupled with the Gauss-Newton algorithm. Due to cross currents caused by the superficial velocity, some solutes are removed from the membrane surface and go into the bulk known as back transport effect. Hence back transport coefficient plays significant role in explaining the extent of micellization. The simulation results show a good agreement with the experimental data of permeate quality and flux. The consideration of negligible gel thickness is suitable for dilute solutions. PMID- 20833471 TI - Using resin supported nano zero-valent iron particles for decoloration of Acid Blue 113 azo dye solution. AB - In this study, a synthesized cation exchange resin supported nano zero-valent iron (NZVI) complex forming NZVI-resin was proposed for the decoloration of an azo dye Acid Blue 113 (AB 113), taking into account reaction time, initial dye concentration, NZVI dose and pH. From results, the successful decoloration of the AB 113 solution was observed using a NZVI-resin. Increasing the iron load to 50.8 mg g(-1), the removal efficiencies of the AB 113 concentration increased exponentially. With an initial dye concentration of 100 mg l(-1) and nano iron load of 50.8 mg g(-1), the best removal efficiencies were obtained at 100 and 12.6% for dye concentration and total organic carbon, respectively. Color removal efficiency was dependent on initial dye concentration and iron load. Moreover, the removal rates followed modified pseudo-first order kinetic equations with respect to dye concentration. Thus, the observed removal rate constants (k) were 0.137-0.756 min(-1) by NZVI loads of 4.9-50.8 mg g(-1). Consequently, the NZVI resin performed effectively for the decoloration of AB 113 azo dye, offering great potential in the application of NZVI-resins in larger scale column tests and further field processes. PMID- 20833472 TI - Disentangling the complex relations among caregiver and adolescent responses to adolescent chronic pain. AB - The social context surrounding chronic pain is important, particularly in the case of pain in adolescents, where caregivers can be a key influence on adolescent social and physical activities. In general, greater adolescent difficulties are related to greater caregiver difficulties, and vice versa, although the strength of these relations has not been consistent across studies. Further, existing analyses have not evaluated more complex multivariate models involving both direct and indirect relations among adolescents and caregivers. There is consequently a lack of clarity in this area. The present analyses represent an initial attempt at explicating more precisely how adolescent and caregiver behaviors in response to pain influence adolescent functioning. Initially, a hypothetical model was constructed that included caregiver pain management behaviors, as well as adolescent and caregiver psychosocial responses to pain. The adequacy of this model was first evaluated with Pearson correlations and then with structural equation modelling using data from 120 adolescent caregiver dyads. After some modification of the model to allow for adequate fit with the data, findings indicated that caregiver variables were only indirectly related to adolescent functioning via adolescent psychosocial responses to pain. This indirect relation may explain previous inconsistency across studies. Perhaps more importantly, the model tested may allow for an improved understanding of the complex relations among adolescents and caregivers factors. Finally, the need to adequately understand caregiver experiences in response to adolescent pain is highlighted and calls for appropriate intervention in young people struggling with chronic pain are reinforced within these analyses. PMID- 20833474 TI - The daily impact of pain from metastatic breast cancer on spousal relationships: a dyadic electronic diary study. AB - Women with metastatic breast cancer (MBC) experience high levels of emotional distress and pain. Although individuals often rely on their intimate partners to provide physical and emotional support when they are in pain, the daily impact of pain on the spousal relationship in the context of advanced cancer is unclear. To understand how relationships are affected by pain, 57 MBC patients and their partners completed electronic diary assessments 6 times a day for 14 days. Patients and partners rated the patient's pain, their own mood (circumplex adjectives), the provision/receipt of social support, and the degree to which cancer interfered with their relationship. Multilevel mediation models with the couple as the unit of analysis were estimated. Partners and patients reported greater relationship interference when patients experienced more pain and less aroused (i.e., more tired, less peppy, less active) mood. Greater tired mood during the day accounted for 17% and 82% of the association between patients' morning pain and their evening ratings of emotional and physical support from their partners, respectively. Partners did not directly respond to patients' pain by providing emotional or physical support; however, they were more likely to provide support when patients experienced more tired and less active mood as a consequence of their pain. Results suggest that one way that pain may wear on couples' relationships is through its adverse effects on patients' daily mood. They also suggest that partners may base their provision of support on their perception of the adverse effects of pain on patients' aroused mood. PMID- 20833475 TI - Endocannabinoid involvement in endometriosis. AB - Endometriosis is a disease common in women that is defined by abnormal extrauteral growths of uterine endometrial tissue and associated with severe pain. Partly because how the abnormal growths become associated with pain is poorly understood, the pain is difficult to alleviate without resorting to hormones or surgery, which often produce intolerable side effects or fail to help. Recent studies in a rat model and women showed that sensory and sympathetic nerve fibers sprout branches to innervate the abnormal growths. This situation, together with knowledge that the endocannabinoid system is involved in uterine function and dysfunction and that exogenous cannabinoids were once used to alleviate endometriosis-associated pain, suggests that the endocannabinoid system is involved in both endometriosis and its associated pain. Herein, using a rat model, we found that CB1 cannabinoid receptors are expressed on both the somata and fibers of both the sensory and sympathetic neurons that innervate endometriosis's abnormal growths. We further found that CB1 receptor agonists decrease, whereas CB1 receptor antagonists increase, endometriosis-associated hyperalgesia. Together these findings suggest that the endocannabinoid system contributes to mechanisms underlying both the peripheral innervation of the abnormal growths and the pain associated with endometriosis, thereby providing a novel approach for the development of badly-needed new treatments. PMID- 20833476 TI - Genetic diversity of piroplasms in plains zebra (Equus quagga burchellii) and Cape mountain zebra (Equus zebra zebra) in South Africa. AB - Seventy EDTA blood samples collected from plains zebra (Equus quagga burchellii) and Cape mountain zebra (Equus zebra zebra) were screened for the presence of piroplasm parasite DNA using quantitative T. equi-specific and B. caballi specific TaqMan real-time PCR (qPCR) tests. T. equi parasite DNA was detected in 60 samples, 19 of which were also positive for B. caballi. Approximately 1480bp of the piroplasm 18S rRNA gene was amplified and sequenced from 17 samples, while the V4 hypervariable region of the 18S rRNA gene was amplified, cloned and sequenced from 31 samples. BLASTN analysis revealed that all of the sequences obtained were most similar to T. equi genotypes and not B. caballi genotypes. Although Babesia parasites were present in some of these samples, as indicated by qPCR, the parasitaemia may have been too low to allow detection by cloning of PCR products from a mixed infection. Sequence analyses of both the full-length and the V4 hypervariable region of the T. equi 18S rRNA gene revealed the existence of 13 new T. equi sequences from zebra, confirming the existence of sequence heterogeneity in the rRNA genes of the parasites that cause equine piroplasmosis, and further suggesting that there may be additional, as yet unidentified, T. equi and B. caballi 18S rRNA sequences present in the horse and zebra populations in South Africa. The occurrence of previously unrecognized sequence variation could pose a potential problem in the implementation of diagnostic tests targeting the 18S rRNA gene. PMID- 20833477 TI - Burns and fire disasters from leaking petroleum pipes in Lagos, Nigeria: an 8 year experience. AB - INTRODUCTION: Petroleum products are mostly inflammable and require strict regulations for safe handling. This study characterises the epidemiology of people who sustained burns from leaking petroleum pipes in Lagos, Nigeria. Risk factors for the leaks were determined and proposals for preventive measures made. MATERIALS AND METHODS: Records of burn patients treated in our hospital from June 1999 to September 2004 were studied and victims of petroleum pipeline fires treated from October 2004 to May 2007 interviewed. RESULTS: Nine incidents of pipeline fire disasters occurred during the study period. A total of 646 victims sustained 100% burns and died at the disaster sites. Deliberate pipeline damage caused explosions in 55.6% of the cases and spontaneous ruptures in 44.4%. Forty eight patients were admitted to our hospital for major burns from pipeline explosions. Their ages ranged from 15 to 50 years with a mean of 25.36 +/- 5.62 years. The total body surface area (TBSA) involved in burns ranged from 31% to 100% with a mean of 75.71 +/- 18.60. Over 40% of the patients had burns beyond 80% TBSA. Mortality rate was 67.3%. Poverty, irregular supply and high prices of petroleum products were responsible for the deliberate pipeline damage and lack of maintenance and surveillance for the spontaneous ruptures. CONCLUSION: The incidents of fire disasters from broken petroleum pipelines increased over the study period with considerable mortality. Programmes to reduce poverty, regular product supply, pipeline maintenance and surveillance may reduce the occurrence of the disasters. PMID- 20833478 TI - Moving towards dose individualization of tyrosine kinase inhibitors. AB - Molecular targeted therapies with tyrosine kinase inhibitors (TKIs) have been a recent breakthrough in cancer treatment. These small molecules are mainly used at a fixed dose ignoring the possible need for dose individualization. Fixed dosing may indeed result in suboptimal treatment or excessive toxicity considering the high inter-individual variability in the pharmacokinetics (PK) of these therapies. The PK, toxicity and efficacy of ten commonly used molecular targeted anti-cancer therapies were reviewed in order to optimize their prescription. A wide interpatient variability in the pharmacokinetics of these small molecules is demonstrated. Moreover associations between certain toxicities and the treatment efficacy have also been demonstrated for some agents, such as erlotinib and skin rash, that may be used as a surrogate marker. Other biomarkers intended to substitute for a clinical endpoint have been described for some TKIs and may be useful for dose individualization. Promising alternatives to fixed dosing were explored such as therapeutic drug monitoring, genotype and phenotype adjusted dosing, and toxicity-adjusted dosing. Prospective studies are needed to validate these methods so that dosing algorithms may be developed in the near future in order to personalize therapeutics to the individual needs of each cancer patient. PMID- 20833479 TI - Administration of serotonin inhibitor p-Chlorophenylalanine induces pessimistic like judgement bias in sheep. AB - Judgement bias has potential as a measure of affective state in animals. The serotonergic system may be one mechanism involved with the formation of negative judgement biases. It was hypothesised that depletion of brain serotonin would induce negative judgement biases in sheep. A dose response trial established that 40 mg/kg of p-Chlorophenylalanine (pCPA) administered to sheep for 3 days did not affect feeding motivation or locomotion required for testing judgement biases. Thirty Merino ewes (10 months old) were trained to an operant task for 3 weeks. Sheep learnt to approach a bucket when it was placed in one corner of the testing facility to receive a feed reward (go response), and not approach it when in the alternate corner (no-go response) to avoid a negative reinforcer (exposure to a dog). Following training, 15 sheep were treated with pCPA (40 mg/kg daily) for an extended duration (5 days). Treated and control sheep were tested for judgement bias following 3 and 5 days of treatment, and again 5 days after cessation of treatment. Testing involved the bucket being presented in ambiguous locations between the two learnt locations, and the response of the sheep (go/no-go) measured their judgement of the bucket locations. Following 5 days of treatment, pCPA-treated sheep approached the most positive ambiguous location significantly less than control sheep, suggesting a pessimistic-like bias (treatment * bucket location interaction F(1,124.6)=49.97, p=0.011). A trend towards a significant interaction was still evident 5 days after the cessation of pCPA treatment (p=0.068), however no significant interaction was seen on day 3 of testing (p=0.867). These results support the suggestion that judgement bias is a cognitive measure of affective state, and that the serotonergic pathway may be involved. PMID- 20833480 TI - Sex differences amongst dependent heroin users: histories, clinical characteristics and predictors of other substance dependence. AB - INTRODUCTION AND AIMS: To examine differences in the characteristics and histories of male and female dependent heroin users, and in the clinical characteristics associated with multiple substance dependence diagnoses. DESIGN AND METHODS: 1513 heroin dependent participants underwent an interview covering substance use and dependence, psychiatric history, child maltreatment, family background, adult violence and criminal history. Family background, demographic and clinical characteristics were analysed by sex. Ordinal regression was used to test for a relationship between number of substance dependence diagnoses and other clinical variables. RESULTS: Women were more likely to experience most forms of child maltreatment, to first use heroin with a boyfriend or partner, to experience ongoing adult violence at the hands of a partner, and to have a poorer psychiatric history than men. Males had more prevalent lifetime substance dependence diagnoses and criminal histories and were more likely to meet the criteria for ASPD. Predictors of multiple substance dependence diagnoses for both sexes were mental health variables, antisocial behaviour, childhood sexual abuse, victim of adult violence, younger age at first cannabis use and overdose. As the number of dependence diagnoses increased, clinical and behavioural problems increased. Childhood emotional neglect was related to increasing dependence diagnoses for females but not males, whereas PTSD was a significant predictor for males but not females. DISCUSSION AND CONCLUSIONS: Mental health problems, other substance dependence, childhood and adult trauma were common in this sample, with sex differences indicating different treatment needs and possible different pathways to heroin dependence for men and women. PMID- 20833481 TI - Appetitive and regulatory processes in young adolescent drinkers. AB - Dual-process models of addiction propose that alcohol (mis)use develops because of an imbalance between a fast automatic appetitive system, in which stimuli are valued in terms of their emotional and motivational significance and a slower controlled regulatory system, which acts on deliberate considerations. This study focused on the automatic and regulatory processes that are involved in the early stages of young adolescent alcohol use. Participants were 43 young adolescent drinkers, who completed an explicit alcohol valence measure, two versions of an Affective Simon Task (AST), a working memory task and an alcohol use questionnaire. Alcohol use was associated with relatively positive self-reported valence of alcohol pictures, especially for adolescents with lower inhibition capacity. The Affective Simon Tasks did not show stronger automatic approach tendencies in heavier drinkers. This study suggests that in early stages of alcohol use appetitive valence is a more important stimulator for the initiation of alcohol use than automatic approach tendencies, and supports the view that young adolescents with low inhibition capacity are especially at risk for developing alcohol misuse. Prevention therefore should be focused on reducing the attractive valence of alcoholic drinks and strengthening the cognitive control of at-risk children. PMID- 20833482 TI - Hydroxyurea (therapeutics and mechanism): metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications. AB - During a century, hydroxyurea has received much attention in relation to its physiological properties. This review mainly deals with the metabolism, mechanism, cell signaling, therapeutic properties, bioactivity, receptors, and toxicity. Metabolism provides insight concerning the mechanism. Carbamoyl nitroso is an intermediate, based on ease of oxidation of the parent and subsequent formation of nitroxyl and nitric oxide. Carbamoyl nitroso bears structural and electrochemical similarity to acyl nitroso from hydroxamic acids, to the phenylhydroxylamine-nitrosobenzene couple, and to alpha-dicarbonyls. Carbamoyl nitroso may be involved in electron transfer, reactive oxygen species formation, and oxidative stress. Cell signaling plays a significant role in the biological action. The therapeutic properties are discussed with emphasis on cancer, sickle cell disease, HIV, skin, and genes. Promise as a practical medicine is indicated by clinical trials. Toxicity is also included. Carbamoyl nitroso, nitroxyl, nitric oxide, and metal complexes of the parent drug are designated the main actors in the physiological effects. The mechanistic theme is in keeping with prior reports in Medical Hypotheses. PMID- 20833483 TI - Lipoxin A4 may function as an endogenous anti-arrhythmic molecule. AB - Cardiac arrhythmias cause significant morbidity and mortality in patients with coronary heart disease, hypertension, and congestive cardiac failure and in the elderly. Inflammation, oxidative injury, altered myocyte metabolism, extracellular matrix remodeling and fibrosis initiate and perpetuate cardiac arrhythmias, especially atrial fibrillation. Enhanced myeloperoxidase (MPO) activity by infiltrating activated leukocytes could bind to myocardial cells and cause fibrosis resulting in the initiation and progression of arrhythmias. Supplementation of eicosapentaenoic and docosahexaenoic acids (EPA and DHA, respectively) suppresses arrhythmias. EPA and DHA form precursors to anti inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins that are known to suppress inflammation, have anti-fibrotic actions and inhibit MPO activity. Hence, it is likely that leukocyte and/or myocardial deficiency of EPA and DHA and consequent reduced formation of lipoxins, resolvins, protectins and maresins enhance inflammation and MPO activity that leads to myocardial damage and fibrosis and initiation and progression of cardiac arrhythmias. Based on these evidences, I propose that lipoxins, resolvins and protectins function as endogenous anti-arrhythmic molecules and their stable synthetic analogs could be useful in the management of cardiac arrhythmias. PMID- 20833484 TI - Packaging-specific influence of chitosan on color stability and lipid oxidation in refrigerated ground beef. AB - We examined the influence of chitosan on lipid oxidation and color stability of ground beef stored in different modified atmosphere packaging (MAP) systems. Ground beef patties with chitosan (1%) or without chitosan (control) were packaged either in high-oxygen MAP (HIOX; 80% O(2)+20% CO(2)), carbon monoxide MAP (CO; 0.4% CO+19.6% CO(2)+80% N(2)), vacuum (VP), or aerobic packaging (PVC) and stored at 1 degrees C. Chitosan increased (P<0.05) redness of patties stored in PVC and CO, whereas it had no effect (P>0.05) in HIOX. Chitosan patties demonstrated lower (P<0.05) lipid oxidation than controls in all packaging. Control patties in PVC and HIOX exhibited greater (P<0.05) lipid oxidation than those in VP and CO, whereas chitosan patties in different packaging systems were not different (P>0.05) from each other. Our findings suggested that antioxidant effects of chitosan on ground beef are packaging-specific. PMID- 20833485 TI - Genetic variability and phylogeny of Torque teno sus virus 1 (TTSuV1) and 2 (TTSuV2) based on complete genomes. AB - Thirteen genomes of Torque teno sus virus 1 (TTSuV1) and 2 (TTSuV2) were obtained to examine the diversity and evolution of swine TTVs. Despite the low nucleotide identity reported, the genomic organization and transcriptional profiles of TTVs are similar. The nucleotide diversity for TTSuV1 was higher than TTSuV2, and the pattern of mutation among the ORFs was also different. Phylogenetic and genetic analyses support the proposed division of TTV into two species. TTSuV1 showed high levels of variability (>30%), with three different types (the third described for the first time) that may display a geographical structure. In contrast, TTSuV2 showed lower levels of variability (<15%), and no different types could be described. Larger values for the ratios of synonymous (dS) to non synonymous (dN) base substitutions (dS/dN) were reported for the ORFs pointing to a certain level of selective constraint in TTV genomes. PMID- 20833486 TI - The how (and why) of disease registers. AB - A disease register is central to the understanding of clinical outcomes but the principles underpinning register design are not always apparent. My group developed, implemented and analysed outcomes using cystic fibrosis (CF) registers in Scotland (~500 patients, 1992-1995), the UK (~7000 patients, 1995-2006) and more recently across Europe (~30 000 patients, 2006-2009). The key design principles are summarised and exemplified using the process required to add new diseases such as CF to neonatal screening programmes to illustrate pitfalls in the complex path from screening to timely entry into specialist CF care. The disciplines of screening and specialist CF disease therapy are very different and our findings may be relevant for the evaluation of the fragile links in the complex patient journey. Should these links fail, they have the potential to delay the entry of a screened baby into therapy after testing positive for a preventable disease. PMID- 20833487 TI - Biochemical characterization and sperm motility parameters of ostrich (Struthio camelus) semen. AB - The aim of the study was to obtain baseline values for biochemical parameters of ostrich seminal plasma and sperm motility parameters measured by CASA. Biochemical characteristics of ostrich semen included a high protein concentration (29.3 +/- 9.1g/l) and high amidase (280.6 +/- 130.8 U/l) and LDH activity (1880.0 +/- 983.6 U/l). On the other hand antioxidant, superoxide dismutase, anti-proteinase and acid phosphatase activity were low. Biochemical parameters of semen were variable. Motility of ostrich sperm was characterized by low linearity (23.0 +/- 6.2%). The quality of undiluted semen stored at room temperature deteriorated within an hour due to agglutination and gelation. On the other hand, ostrich semen could be stored up to 4h at 5 degrees C without loss of motility after which loss of motility occurred but could be partially mitigated using semen extenders (EK and Ovodyl). PMID- 20833488 TI - The effect of dietary soy supplementation compared to estrogen and placebo on menopausal symptoms: a randomized controlled trial. AB - OBJECTIVES: To compare the effects of daily ingestion of dietary soy supplementation, low-dose hormone therapy (HT) and placebo on psychological, somatic and urogenital symptoms in postmenopausal women. STUDY DESIGN: A double blind, randomized, controlled trial. Sixty healthy, symptomatic, postmenopausal women of 40-60 years of age were allocated to use dietary soy supplementation (containing 90 mg of isoflavone) or HT (1mg estradiol and 0.5mg norethisterone acetate) or placebo. MAIN OUTCOME MEASURES: the Menopause Rating Scale (MRS) was used to assess menopausal symptoms at baseline and after 16 weeks of treatment. Intention-to-treat analyses were performed using the chi-square test, Fisher's exact test, the Kruskal-Wallis non-parametric test and analysis of variance (ANOVA). RESULTS: No statistically significant differences were found between the groups with respect to baseline clinical and sociodemographic characteristics. The psychological, somatic and urogenital symptoms analyzed in the MRS improved during treatment in all the groups, except for urogenital symptoms in the placebo group in which no significant changes were detected. Comparison between groups revealed a statistically significant improvement in somatic symptoms (hot flashes and muscle pain) in the users of HT (-45.6%) and dietary soy supplementation ( 49.8%). Urogenital symptoms (vaginal dryness) improved significantly in HT users (-38.6%) and in users of the dietary soy supplementation (-31.2%). There was no statistically significant difference between the groups with respect to overall MRS score or to scores obtained in the psychological symptoms subscale. CONCLUSION: Dietary soy supplementation may constitute an effective alternative therapy for somatic and urogenital symptoms of the menopause. PMID- 20833489 TI - Preeclampsia as a female-specific risk factor for chronic hypertension. AB - Preeclampsia is a complication of pregnancy that has also long term effects on maternal health. Several epidemiologic studies have shown an increased risk for cardiovascular morbidity (relative risk [RR] 2.3) and mortality (RR 2.3) in women after a history of preeclampsia. The chance to develop chronic hypertension afterwards is twofold to 10 times higher in affected women, compared with women after normotensive pregnancies. As hypertension is a major cardiovascular risk factor, early detection and treatment is mandatory to reduce the risk of future cardiovascular disease. Data on (cost)-effectiveness of cardiovascular screening programs in women after preeclampsia are currently lacking and there are no recommendations yet for prevention in the guidelines. We recommend regularly preventive blood pressure measurements after high risk pregnancies. More research is needed to identify women who will profit most of early intervention. PMID- 20833490 TI - Primary peritoneal mesothelioma: case series and literature review. AB - Primary peritoneal mesothelioma is a rare and aggressive tumour. We present six consecutive cases treated by our institution in the last three years. All were between 56-65 years old and only one gave a history of direct contact with asbestos. Four of the patients showed a thrombocytosis on presentation but other blood tests and evaluation of ascitic fluid were normal. In all cases, the diagnosis was made through investigation of mixed abdominal symptoms with CT scanning and laparoscopic biopsy. Despite the use of modern chemotherapy, response to treatment was unpredictable, with survival from ten weeks to three years. PMID- 20833491 TI - Noninvasive visualization of microvessels using diffraction enhanced imaging. AB - The architecture of the vascular network is crucial because almost every disease alters the morphology of the blood vessel. Although existing imaging technique can provide vessel images, microvessels will not be discerned without the use of contrast agents. Furthermore, conventional imaging technique can only provide the outline of the vessels due to the restriction of spatial resolution. In this study, a novel imaging technique, diffraction enhanced imaging (DEI), is applied to the observation of microvessels in mouse hepatic fibrosis samples. With high spatial resolution and contrast of biological soft tissues, DEI is a non-invasive synchrotron-based imaging technique and does not require contrast agents. Particularly, this article highlights the exploration of the objects inside microvessels. A segment of blood vessel, which is obstructed by a blood clot, is under quantitative assessment and the result provides a precise description of vessel stenosis. Additionally, as one of the application of the diffraction enhanced imaging, blood stream simulation is carried out on the three-dimensional model of the vessel. It proves that this imaging technique has great value in evaluating hemodynamics and histopathology of microvascular diseases. PMID- 20833492 TI - Dual energy CTA of the carotid bifurcation: advantage of plaque subtraction for assessment of grade of the stenosis and morphology. AB - OBJECTIVES: Calcifications adjacent to the vessel lumen often limit the assessment of stenoses at the carotid bifurcation in 3D multi intensity projection images (3D-MIP) using conventional single energy CT. Aim of the study was to evaluate the diagnostic value of 3D-MIP images after subtraction of bone and calcified plaques (PBS) using dual energy CT for the assessment of carotid bifurcation stenoses. MATERIALS AND METHODS: 36 patients with a total of 46 stenoses at the carotid bifurcation were examined with a dual energy CT system. Grade of the stenoses and plaque morphology were assessed in axial multi planar projections (axMPR) and freely rotatable 3D-MIP images before and after PBS and compared with results from DSA. RESULTS: Grade of the stenosis could be evaluated in all 46 cases in DSA, axMPR and 3D-MIP after PBS. However, in 25 cases grade of the stenosis was not assessable prior to PBS. The average grade of the stenosis increased from DSA (81.4%) to axMPR (83.5%) to 3D-MIP before and after PBS (86.5% and 85.6%). The amount of pseudo-occlusions increased in concordance with the grade of the stenosis (0<9<16). Using 3D-MIP reconstructions, plaque morphology could be evaluated in 32/46 stenoses before PBS and in 44/46 cases after PBS. CONCLUSIONS: PBS facilitated the evaluation of grade of the stenosis in all cases. Nevertheless, after PBS stenoses were overrated in 3D-MIP in comparison to DSA and axMPR. Moreover, plaque morphology, as an independent risk factor for stroke, can be evaluated even in calcified plaques after PBS. Therefore dual energy CTA with plaque subtraction has the potential to identify patients with vulnerable plaques better than conventional CTA. PMID- 20833493 TI - Semiquantitative assessment of focal cartilage damage at 3T MRI: a comparative study of dual echo at steady state (DESS) and intermediate-weighted (IW) fat suppressed fast spin echo sequences. AB - PURPOSE: The aim of the study was to compare semiquantitative assessment of focal cartilage damage using the dual echo at steady state (DESS)- and intermediate weighted (IW) fat suppressed (fs) sequences at 3T MRI. METHODS: Included were 201 subjects aged 35-65 with frequent knee pain. MRI was performed with the same sequence protocol as in the Osteoarthritis Initiative (OAI): sagittal IW fs, triplanar DESS and coronal IW sequences. Cartilage status was scored according to the WORMS system using all five sequences. A total of 243 focal defects were detected. In an additional consensus reading, the lesions were evaluated side-by side using only the sagittal DESS and IW fs sequences. Lesion conspicuity was graded from 0 to 3, intrachondral signal changes adjacent to the defect were recorded and the sequence that depicted the lesion with larger diameter was noted. Wilcoxon signed-rank tests, controlled for clustering by person, were used to examine differences between the sequences. RESULTS: 37 (17.5%) of the scorable lesions were located in the medial tibio-femoral (TF), 48 (22.7%) in the lateral TF and 126 (59.7%) in the patello-femoral compartment. 82.5% were superficial and 17.5% full-thickness defects. Conspicuity was superior for the IW sequence (p<0.001). The DESS sequence showed more associated intrachondral signal changes (p<0.001). In 103 (48.8%) cases, the IW fs sequence depicted the lesions as being larger (p<0.001). CONCLUSIONS: The IW fs sequence detected more and larger focal cartilage defects than the DESS. More intrachondral signal changes were observed with the DESS. PMID- 20833494 TI - Is herniography useful and safe? AB - 117 consecutive herniograms were reviewed for patients who had symptoms suggestive of hernia but with no evidence or inconclusive findings on physical examination. The traditional approach has been to explore patients with suspected occult hernias. The aim of this study was to assess the impact of herniography in minimizing needless groin exploration and to evaluate its safety. Thirty-three herniograms were positive and showed unilateral and bilateral inguinal hernias. There were no false positive examinations and two false negative examinations. No complications were present. Patients with positive herniograms were explored, and operative findings correlated well with herniographic findings. Twenty-four patients were referred to other specialities. Follow-up in clinic and telephone interviews showed symptomatic improvement in the majority of patients. Herniography is useful in evaluating obscure groin pain and occult hernias. It is a safe procedure and more cost effective than a negative exploration or diagnostic laparoscopy. PMID- 20833495 TI - Convertible pneumatic actuator for magnetic resonance elastography of the brain. AB - Here we present a novel pneumatic actuator design for brain magnetic resonance elastography (MRE). Magnetic resonance elastography is a phase contrast technique capable of tracing strain wave propagation and utilizing this information for the calculation of mechanical properties of materials and living tissues. In MRE experiments, the acoustic waves are generated in a synchronized way with respect to image acquisition, using various types of mechanical actuators. The unique feature of the design is its simplicity and flexibility, which allows reconfiguration of the actuator for different applications ranging from in vivo brain MRE to experiments with phantoms. Phantom and in vivo data are presented to demonstrate actuator performance. PMID- 20833496 TI - Evaluation of time-intensity curves in ductal carcinoma in situ (DCIS) and mastopathy obtained using dynamic contrast-enhanced magnetic resonance imaging. AB - PURPOSE: The aim of this study was to retrospectively evaluate the ability of dynamic, contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate between ductal carcinoma in situ (DCIS) and mastopathy by analyzing their signal intensities (SIs). METHODS: After the pre-contrast MRI was performed using a 1.5 T MRI system, DCE-MRI was performed four times following intravenous administration of contrast medium. We set the volumes of interest (VOIs) on the tumor and normal mammary gland and obtained the SIs in these VOIs. We calculated the entropy (EPY) in the pre-contrast (EPY0) and four post-contrast scans (EPY1, EPY2, EPY3, and EPY4 for the first, second, third and fourth scans, respectively) using the volume histogram method, and the wash-in (WR(in)) and washout rates (WR(out)) according to the Breast-Imaging Reporting and Data System developed by the American College of Radiology. We also calculated the early slope (Slope(early)) from the pre- and post-contrast SIs in the tumor and normal gland. We evaluated the usefulness of the above parameters for differentiating between DCIS and mastopathy using the area under the receiver operating characteristic curve (Az). RESULTS: There were significant differences in EPY2 (P=.009), EPY3 (P=.017), EPY4 (P=.034), WR(in) (P=.036), WR(out) (P=.019), and Slope(early) (P=.002) between DCIS and mastopathy. The average Az values were 0.67, 0.52, 0.64, 0.63, 0.67 and 0.70 for EPY2, EPY3, EPY4, WR(in), WR(out) and Slope(early), respectively. CONCLUSION: We evaluated the usefulness of various parameters calculated from SIs obtained by DCE-MRI for differentiating between DCIS and mastopathy. Our results suggested that Slope(early) is more useful than EPYs, WR(in) and WR(out). PMID- 20833497 TI - Diffusion tensor image up-sampling: a registration-based approach. AB - Diffusion weighted images (DWI), from which the corresponding diffusion tensor images (DTI) are estimated, are commonly acquired with anisotropic discretizations. Traditional methods to up-sample diffusion weighted images generally rely on scene-based interpolation and do not exploit structural information from the images. In this study, a DTI up-sampling framework is presented that incorporates the underlying anatomical shape information by means of non-rigid inter-slice registration. A strategy is proposed to reorient the interpolated tensor in order to maintain its proper orientation. Tests on phantom as well as on real data sets show that the proposed method is able to produce better results compared to scene based interpolation methods in terms of the accuracy of DWI/DTI interpolation, especially when diffusion tensor orientation is taken into account. PMID- 20833498 TI - Apparent diffusion coefficient of line scan diffusion image in normal prostate and prostate cancer--comparison with single-shot echo planner image. AB - PURPOSE: This retrospective study was designed to evaluate the apparent diffusion coefficient (ADC) of line scan diffusion images (LSDI) in normal prostate and prostate cancer. Single-shot echo planner images (SS-EPI) were used for comparison. MATERIALS AND METHODS: Twenty prostate tumors were examined by conventional MRI in 14 patients prior to radical prostatectomy. All patients were examined with a 1.5-T MR imager (Signa CV/i ver. 9.1 GE Medical System Milwaukee, WI, USA). Diffusion-weighted MR imaging (DWI) using LSDI was performed with a pelvic phased-array coil, with b values of 5 and 800 s/mm2. DWI using SS-EPI was performed with a body coil, with b values of 0 and 800 s/mm2. The ADCs of each sequence for 14 normal prostate and 20 prostate cancers were histopathologically assessed. Signal-to-noise ratio (SNR) on DWI was estimated and compared for each sequence. RESULTS: The mean ADCs (+/-S.D.) of normal peripheral zones (PZ), transition zones (TZ) and cancer (in 10-3 mm2/s) that used LSDI were 1.42+/-0.12, 1.23+/-0.10 and 0.79+/-0.19, respectively. Those that used SS-EPI were 1.76+/ 0.26, 1.38+/-0.20 and 1.05+/-0.27, respectively. Using unpaired t test (P<.05), we found a significant difference in each sequence between normal tissue (both PZ and TZ) and the cancer. Paired t test (P<.05) also registered a significant difference between LSDI and SS-EPI. Mean SNR for DWI using LSDI was 16.49+/-5.03, while the DWI using SS-EPI was 18.85+/-9.26. The difference between the SNR of each sequence was not statistically significant by paired t test. CONCLUSION: We found that ADCs using LSDI and SS-EPI showed similar tendencies in the same patients. However, in all regions, LSDI ADCs had smaller standard deviations than SS-EPI ADCs. PMID- 20833499 TI - Evaluation of noncirrhotic hepatic parenchyma with and without significant portal vein stenosis using diffusion-weighted echo-planar MR on the basis of multiple perfusion-components theory. AB - To determine whether diffusion-weighted echo-planar MR images are sensitive to liver perfusion difference. Noncirrhotic livers of 71 patients (43 males, 28 females; age range, 22-87 years; mean, 61 years) without (n=51) and with (n=20) significant (>70%) portal vein stenosis (accompanying proximal hepatic arterial stenosis and/or biliary tract obstruction in 10) by tumors were examined with diffusion-weighted echo-planar sequences (modified for b factors of 1, 28, 66, 288 and 600 s/mm2). On the basis of multiple-perfusion-components theory, i.e., assuming logarithm of signal intensity for liver perfusion is linearly attenuated versus logarithm of a smaller b factor, we defined the slope of the line as the perfusion-related D' value. The D' values of these livers were calculated from images with b factors of 1, 28, and 66 s/mm2. The livers' apparent diffusion coefficient values for diffusion (ADC(d) values) were calculated from images with b factors of 288 and 600 s/mm2. The livers with significant portal vein stenosis had statistically lower mean D' values than the livers without portal vein stenosis (P<.001 on the Mann-Whitney U test). However, there was no significant difference in ADC(d) values between these liver types (P>.05). The D' value calculated from diffusion-weighted echo-planar sequences with plural smaller b factors may be sensitive to liver perfusion difference. PMID- 20833500 TI - Management of branch-duct intraductal papillary mucinous neoplasms of the pancreas: observation with MR imaging. AB - PURPOSE: To evaluate the clinical outcomes of conservative management by observation with MRI of patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs). MATERIALS AND METHODS: Twenty-three consecutive patients, who were followed up by MRI with magnetic resonance cholangiopancreatography (MRCP) over a period of more than 9 months after initial MRI examinations, were enrolled in this study. On MRI, number of lesions, the maximum diameter of BD IPMNs, lesion location, the presence of associated dilatation of main pancreatic duct (MPD), the presence of enhancing mural nodules within the lesion and the presence of interval change were retrospectively reviewed on initial and follow up MR images in consensus by two radiologists. All patients were evaluated to search for evidence of malignant progression of disease. RESULTS: The follow-up period ranged from 10 to 96 months (mean, 37 months). On initial MRI with MRCP, a total of 39 lesions were found in 23 patients. The maximum diameter of BD-IPMNs ranged between 6 and 32 mm, with a mean of 12 mm. Thirty-four lesions (87%) of 19 patients remained unchanged in the maximum diameter. Five lesions (13%) of four patients showed an increase in the maximum diameter. Enhancing mural nodules were not found in any individual, neither on the initial MRI study nor on the follow up studies. There was no patient who had evidence of local aggressive growth of tumor or evidence of metastases to distant sites. CONCLUSION: Our study suggests that branch-duct IPMNs without enhancing mural nodules are essentially benign and should be managed nonoperatively through observation by MRI. PMID- 20833501 TI - Non-neural BOLD variability in block and event-related paradigms. AB - Block and event-related stimulus designs are typically used in fMRI studies depending on the importance of detection power or estimation efficiency. The extent of vascular contribution to variability in block and event-related fMRI BOLD response is not known. With scaling, the extent of vascular variability in the fMRI-BOLD response during block and event-related design tasks was investigated. Blood oxygen level-dependent (BOLD) contrast data from healthy volunteers performing a block design motor task and an event-related memory task requiring performance of a motor response were analyzed from the regions of interest (ROIs) surrounding the primary and supplementary motor cortices. Average BOLD signal change was significantly larger during the block design compared to the event-related design. In each subject, BOLD signal change across voxels in the ROIs had higher variation during the block design task compared to the event related design task. Scaling using the resting state fluctuation of amplitude (RSFA) and breath-hold (BH), which minimizes BOLD variation due to vascular origins, reduced the within-subject BOLD variability in every subject during both tasks but significantly reduced BOLD variability across subjects only during the block design task. The strong non-neural source of intra- and intersubject variability of BOLD response during the block design compared to event-related task indicates that study designs optimizing for statistical power through enhancement of the BOLD contrast (for, e.g., block design) can be affected by enhancement of non-neural sources of BOLD variability. PMID- 20833502 TI - Synchronous resection for colorectal liver metastases: the future. AB - Colorectal Cancer is a common malignancy. Many patients have metastatic disease at presentation and a significant proportion subsequently go onto develop metastatic disease, following surgery for the primary disease. Some groups advocate that synchronous metastatic disease should be resected at the same time as the primary, whereas others believe that outcomes are better following delayed resection for metastatic disease. The following review aims to outline the arguments in favour of both and to suggest some broad guidelines. PMID- 20833503 TI - [Guide for the use of jet-ventilation during ENT and oral surgery]. AB - The aim of this synthesis was to give recommendations on the use of jet ventilation during ENT surgical and endoscopy procedures. Literature was collected from PUBMED and analysed by the members of French association of anaesthesiologists in ENT surgery, all skilled in this field. Presentation of these recommendations was given during the general assembly held in Reims, the 15th May 2009. Jet-ventilation is especially indicated during upper airway endoscopy and laryngeal invasive endoscopic surgery. Furthermore, transtracheal jet ventilation is included on most of difficult oxygenation and difficult intubation algorithm. The main risk of jet-ventilation is pulmonary barotrauma when expiration of injected gas is impeded by an upper airway obstruction. Failure and complications of tracheal puncture are rare when performed by experimented operators. Clinical use of jet ventilation requires a dedicated device. Practice of jet ventilation without intubation may be dangerous when applied without control of driving pressure and end expiratory tracheal pressure. Every anaesthetist should be familiar with transtracheal ventilation since they may face a "cannot ventilate cannot intubate" situation. Upper airway endoscopy and laryngeal surgery are the ideal field for training jet ventilation, even more so as this technique offers perfect operative conditions. To apply this project, jet ventilation should be used more frequently in routine practice. To maintain skill, regular use of these techniques is required. PMID- 20833504 TI - Effectiveness and tolerability of amidotrizoate for the treatment of constipation resistant to laxatives in advanced cancer patients. AB - CONTEXT: Constipation is a common problem for advanced cancer patients, and is generally inadequately treated. OBJECTIVES: The aim of this study was to prospectively evaluate the effectiveness and tolerability of amidotrizoate (AM) in patients unresponsive to current laxatives. METHODS: A consecutive sample of advanced cancer patients was surveyed. Inclusion criteria were no bowel movements for three days despite receiving regular doses of senna or lactulose. AM 50 mL was administered orally; the dose could be repeated the day after, based on clinical judgment and/or patients' preference. Age, sex, primary tumor, previous abdominal surgery, chemotherapy and radiotherapy performed in the previous month, and the use of opioids were recorded. Nausea, the presence of early satiety, and fluid and food intake also were measured. Time to first bowel movement was recorded, and adverse effects attributable to AM. RESULTS: Ninety-nine patients were surveyed (36 women/63 men). The mean age was 65.7 years (SD+/-12.2) and the mean Karnofsky score was 46.8 (SD+/-9.4). Patients had no bowel movement for a mean of four days (SD+/-1.8, range 3-15 days). A total of 80.8% of patients were receiving opioids in doses of mean daily oral morphine equivalents of 164 mg (SD+/-235). After AM administration (mean 9.9+/-6.5 hours), 44.4% of patients had a bowel movement within 24 hours. This effect was associated with significant improvement of other symptoms and was independent of age (P=0.513), gender (P=0.090), Karnofsky status (P=0.979), days of constipation (P=0.198), concomitant chemotherapy (P=0.098) or radiotherapy (P=0.414), the use of opioids (P=0.361), opioid doses (P=0.420), and primary tumor (P=0.231). The treatment was more effective in patients who had previous abdominal surgery (HR=3.33). CONCLUSION: AM was found to be an easy and inexpensive breakthrough medication to induce a bowel movement in about 45% of advanced cancer patients not responsive to common laxatives, with limited and acceptable adverse effects. PMID- 20833505 TI - Imaging atrial septal defects by real-time three-dimensional transesophageal echocardiography: step-by-step approach. AB - BACKGROUND: There are currently no standardized three-dimensional (3D) transesophageal echocardiographic (TEE) views of the interatrial septum and atrial septal defects (ASDs). Without a standardized approach, it is difficult to ascertain the important anatomic relationships (such as the location of the aortic rim of an ASD), to perform relevant measurements (such as the size of an ASD or the size of its rims), or to guide the deployment of catheters and devices during atrial septal closure. METHODS: Using a 3D TEE matrix-array transducer, 706 TEE studies were performed over a 14-month period. The purpose of the study was to develop a standardized protocol for anatomically correct orientation of 3D TEE images of the interatrial septum and ASDs. RESULTS: Among 706 TEE studies, there were 23 patients with ASDs, representing 3.3% of the study population. Eighteen patients had secundum ASDs, two had primum ASDs, and three had sinus venosus ASDs of the superior vena cava type. A protocol for properly orienting 3D TEE images of the interatrial septum and ASDs was developed. When the images are acquired at an angle of 0 degrees , the septum is properly oriented by the tilt up-then-left maneuver. The initial 3D TEE image in first tilted up to reveal the right atrial side of the septum. Then the image is tilted 180 degrees around its vertical axis to reveal the left atrial side of the septum; the aortic rim is on the left, the superior vena cava on the top, and the right-sided pulmonary vein ostia on the right side of the screen. For acquisitions at a higher angle, the rotate-left-in-z-axis maneuver is used. The image is first tilted up to reveal the right atrial side of the septum, as in the tilt-up-then-left maneuver. The image is then rotated counterclockwise in the z axis until the superior vena cave is at 12 o'clock. Finally, the image is tilted 180 degrees around its vertical axis to reveal the left atrial side of the septum. CONCLUSIONS: The use of standardized tilt-up-then-left and rotate-left-in-z-axis maneuvers enhances the diagnosis of ASDs, ascertains the important anatomic relationships of ASDs to surrounding structures, and facilitates communication between echocardiographers obtaining 3D TEE images and interventional cardiologists or cardiac surgeons performing ASD closures. PMID- 20833506 TI - Real-time three-dimensional transesophageal echocardiographic imaging of cor triatriatum and persistent left superior vena cava. AB - The authors describe the case of a 54-year-old woman with the association of two rare congenital cardiac anomalies: cor triatriatum and persistent left superior vena cava with the special characteristic of direct drainage to the right atrium. Real-time three-dimensional transesophageal echocardiography offered a comprehensive anatomic and functional evaluation of these infrequent entities. PMID- 20833507 TI - Diagnostic value of segmental longitudinal strain by automated function imaging in coronary artery disease without left ventricular dysfunction. AB - BACKGROUND: The aim of this study was to investigate the role of segmental longitudinal strain for the diagnosis of coronary artery disease (CAD) assessed by automated function imaging. METHODS: One hundred fifty-two subjects (mean age, 63 +/- 12 years; 77 men) referred for assessment of cardiac function under suspicion of CAD were recruited for this study. Patients with left ventricular dysfunction or with acute coronary syndromes were excluded. RESULTS: Peak systolic global longitudinal strain (GLS) was significantly decreased in patients with CAD. Peak segmental longitudinal strain difference (LSD) and its ratio to peak systolic GLS were significant higher in patients with CAD. The areas under receiver operating characteristic curves for the diagnosis of CAD were 0.813 for peak systolic GLS, 0.851 for the number of abnormal segments, 0.805 for peak segmental LSD, and 0.862 for the ratio of peak segmental LSD to peak systolic GLS. Using 1.0 as a cutoff point for the ratio of peak segmental LSD to peak systolic GLS, sensitivity was 77.3% and specificity 79.2%. CONCLUSIONS: This study suggests that it may be possible to assess CAD with strain by automated function imaging, but further larger scale studies are needed to confirm this. PMID- 20833508 TI - Pulmonary embolus caused by Suttonella indologenes prosthetic endocarditis in a pulmonary homograft. AB - A 28-year-old Cambodian man with a history of congenital heart disease presented with a 6-month history of increasing fatigue, night sweats, and weight loss. His surgical history included two Blalock-Taussig shunts, ventricular septal defect closure, and placement of a pulmonary valve conduit via a Rastelli procedure. Echocardiographic and cardiac computed tomographic studies revealed a vegetation in the pulmonary homograft. Blood cultures grew gram-negative rods that were eventually identified as Suttonella indologenes. The patient underwent a prolonged course of intravenous antibiotics, which was complicated by septic pulmonary embolism that clinically resolved. Bacterial endocarditis caused by aerobic gram-negative organisms is uncommon. The authors report the first case of S. indologenes endocarditis in a patient with complex congenital heart disease. PMID- 20833509 TI - The Sgp3 locus derived from the 129 strain is responsible for enhanced endogenous retroviral expression in macroH2A1-deficient mice. AB - The endogenous retroviral envelope glycoprotein, gp70, implicated in murine lupus nephritis is secreted by hepatocytes, and its expression is largely regulated by the Sgp3 (serum gp70 production 3) locus derived from lupus-prone mice. Because of the localization of the macroH2A1 gene encoding macroH2A histone variants within the Sgp3 interval and of an up-regulated transcription of endogenous retroviral sequences in macroH2A1-deficient C57BL/6 (B6) mice, we investigated whether macroH2A1 is a candidate gene for Sgp3. macroH2A1-deficient B6 mice carrying the 129-derived Sgp3 locus, which was co-transferred with the 129 macroH2A1 mutant gene, displayed increased levels of serum gp70 and hepatic retroviral gp70 RNAs comparable to those of B6.NZB-Sgp3 congenic mice bearing the Sgp3 locus of lupus-prone NZB mice. In contrast, the abundance of retroviral gp70 RNAs in macroH2A1-deficient 129 mice was not elevated at all as compared with wild-type 129 mice. Furthermore, Sgp3 subcongenic B6 mice devoid of the NZB derived macroH2A1 gene displayed an Sgp3 phenotype identical to that of B6.NZB Sgp3 congenic mice carrying the NZB-derived macroH2A1 gene, thus excluding macroH2A1 as a candidate Sgp3 gene. Collectively, our data indicate that enhanced transcription of endogenous retroviral sequences observed in macroH2A1-deficient B6 mice is not a result of the macroH2A1 mutation, but due to the presence of the 129-derived Sgp3 locus. In contrast, the effect of a macroH2A1 knockout mutation on the expression of several non-retroviral cellular genes was very similar on the B6 and 129 backgrounds, indicating that these effects were due to the macroH2A1 knockout. PMID- 20833510 TI - Transgenic overexpression of anti-double-stranded DNA autoantibody and activation of Toll-like receptor 4 in mice induce severe systemic lupus erythematosus syndromes. AB - Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease characteristized by the presence of autoantibodies against double-stranded DNA (anti-dsDNA) in sera at high levels. Bacterial infections in SLE are associated with higher morbidity and mortality. Our goal was to observe the interaction between these 2 factors in the pathogenesis of lupus. We generated transgenic mice with monoclonal anti-dsDNA to investigate the development of lupus. By challenging the mice in vitro and in vivo with Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPS), we were able to examine the role of bacterial infection in SLE. In our study, the transgenic mice with a secreted form of anti dsDNA were found to have higher levels of anti-nuclear antibodies, anti-dsDNA, blood urea nitrogen, and proteinuria. The splenocytes of the mice stimulated with LPS secreted more anti-dsDNA, IFN-gamma, and IL-10. After injecting them with LPS in vivo, we further found higher immune complex depositions and IL-10 in the kidneys of the transgenic mice. Moreover, the LPS-injected transgenic mice had higher mortality rate. This is the first transgenic model to demonstrate that only 2 risk factors, pathogenic anti-dsDNA and TLR4 activation, induce severe SLE syndromes in normal mice through the overproduction of IL-10 and IFN-gamma. These findings imply that anti-dsDNA and bacterial infections have pivotal roles in the pathogenesis of SLE; the inhibition of TLR4 may be regarded as a therapeutic target. PMID- 20833511 TI - Immediate, single stage, truly anatomic zirconia implant in lower molar replacement: a case report with 2.5 years follow-up. AB - This report demonstrates the clinical use of a modified, truly anatomic, root analogue zirconia implant for immediate replacement of a two-rooted, left first mandibular molar. A 50-year-old female patient with chronic apical periodontitis of the left mandibulary first molar was referred and the tooth was extracted. The mesial root had to be removed surgically due to a root fracture. A truly anatomical, root identical, roughened zirconia implant modified by macro retentions was manufactured and placed into the extraction socket by tapping 7 days later. After 4 months a composite crown was cemented in place. No complications occurred during the healing period. A good functional and aesthetic result was achieved with minimal bone resorption and soft tissue recession at 30 months follow-up. This report describes the successful clinical use of an immediate, single stage, truly anatomical root-analogue zirconia implant for replacement of a two-rooted tooth. Significant modifications such as macro retentions yielded primary stability and excellent osseointegration. This novel approach is minimally invasive, respects the underlying anatomy, aids socket prevention, is time- and cost-saving with good patient acceptance as there is no need for bone drilling, sinus lift, bone augmentation or other traumatic procedures. PMID- 20833512 TI - Effects of aripiprazole and haloperidol on progression to schizophrenia-like behavioural abnormalities and apoptosis in rodents. AB - Aripiprazole (APZ) is considered a first-line medication for treating first and multiple episodes of schizophrenia, but its effect on preventing the progressive pathophysiology of schizophrenia remains unclear. This study examined the hypothesis that APZ blocks enhanced glutamate release in the medial prefrontal cortex (mPFC) during psychotic episodes of schizophrenia, thereby preventing progression of the pathophysiology. We examined effects of APZ on methamphetamine (METH)-induced increases in glutamate levels in the mPFC, and on repeatedly administered METH-induced progression to schizophrenia-like behavioural abnormalities involving cross-sensitization to the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, deficit of prepulse inhibition (PPI), and expression of TUNEL-positive cells. Additionally, we compared the preventive effects of APZ to those of a conventional antipsychotic: haloperidol (HPD). Results show that APZ (1.0 and 3.0 mg/kg) and HPD (0.1 mg/kg) each blocked METH (2.5 mg/kg)-induced increases in glutamate levels in the mPFC. Furthermore, APZ (3.0 mg/kg) and HPD (0.1 mg/kg), when co-administered repeatedly with METH, each prevented progression to schizophrenia-like behavioural and neuropathological abnormalities. Repeated co-administration of APZ (3.0 mg/kg) with saline did not induce apoptosis, although HPD (0.1 mg/kg) with saline did induce apoptosis. These results indicate that APZ and HPD prevented progressive pathophysiology, which is related to increased glutamate levels, and indicate that repeated administration of HPD, but not APZ, induced apoptosis under conditions without increased glutamate levels. These findings suggest the importance of using APZ and HPD in the appropriate stages of the glutamate-related pathophysiology of schizophrenia. PMID- 20833513 TI - Proteomic expression analysis of mycosis fungoides (MF) skin tissues: overexpressions of SOD2, S100A8 and FABP5 in MF. PMID- 20833514 TI - Effects on cognitive functioning after olanzapine-ziprasidone crossover in recent onset schizophrenia. AB - INTRODUCTION: To enhance functional outcome in schizophrenia improvement of cognitive symptoms is crucial. EXPERIMENTAL PROCEDURES: Using a comprehensive test battery, this follow-up examines cognitive effects in patients with recent onset schizophrenia after a change of medication following insufficient clinical response and intolerance. RESULTS: After eight weeks cognitive outcomes had not improved in the patients having switched from olanzapine to ziprasidone (n=11; mean dose 136 mg) nor in those having switched from ziprasidone to olanzapine (n=10; mean 16 mg), while the symptoms of patients maintaining olanzapine (n=18; mean 10.9 mg) or ziprasidone (n=18; mean 88.9 mg) treatment had not improved further. DISCUSSION: The findings suggest that also in early-stage schizophrenia the antipsychotics tested affect cognitive symptoms similarly. PMID- 20833515 TI - Effect of cytomegalovirus infection on temporal lobe development in utero: quantitative MRI studies. AB - Several environmental factors, including viral infections during fetal development, are known to increase the risk of schizophrenia. Cytomegalovirus (CMV) is the main cause of viral congenital infection. Since changes in temporal lobe structures are a consistent finding in imaging studies of adult schizophrenics, we investigated possible derangement in temporal lobe development in CMV infected fetuses. Abdominal MRI (1.5 T) was performed using a single-shot fast spin echo T2-weighted sequence. MRI volumetry was employed to measure brain and temporal lobe size in 27 CMV infected fetuses and 52 gestational age matched controls in utero. The ratio of temporal lobe to whole brain was computed for each fetus and group comparisons were performed using Student's t-test or ANOVA. Temporal lobe volumes, normalized to whole brain and co-varied with gestational age; were significantly smaller in fetuses infected with CMV compared to uninfected fetuses. (Infected group mean +/- SEM: 0.086 +/- 0.006, controls: 0.113 +/- 0.003, p<0.0001). Infection during the 1st and 2nd trimester had a more pronounced effect than infection during the 3rd trimester. Infected fetuses with no MRI findings had significantly lower temporal lobe/whole brain ratios than controls (0.092 +/- 0.008, p<0.01, N=11) and the lowest ratios were observed in fetuses with overt findings such as cysts or gray matter heterotopy (0.067 +/- 0.015). These results demonstrate the ability of quantitative fetal brain MRI to detect previously unreported, specific deficits in brain development in CMV infected fetuses, which, in conjunction with other genetic and environmental factors, may contribute to the risk of developing schizophrenia later in life. PMID- 20833516 TI - Endovascular techniques in palliative care. AB - Most palliative care patients will require multidisciplinary management to optimise symptom control. This overview will show that endovascular procedures are an important consideration in many cases. These procedures can be used primarily, or more commonly, as an adjunct to other therapy modalities. Catheter, wire and modern imaging technology allow interventional radiologists to treat a wide, and growing, spectrum of conditions. Percutaneous endovascular procedures allow for minimal discomfort and rapid recovery, ideal for palliative care patients. Many symptoms (or life-threatening conditions) can be treated with endovascular techniques. This discussion aims to demonstrate the increasing spectrum of endovascular interventions and review the evidence available. This overview cannot provide an exhaustive list of possible procedures, but covers most aspects and should reinforce the evidence base for intervention in this field. We have included a section on the technical aspects of endovascular intervention, including the use of sedoanalgesia, and post-embolisation syndrome. Embolisation of bleeding tumours, including bronchial artery embolisation and symptomatic renal tumour embolisation, is a fairly well-established technique. Embolisation of symptomatic skeletal metastases has shown good results. Covered stent grafting of ruptured or threatened arteries is an evolving field that has benefited from developments in stent graft technology and design. Symptomatic, unresectable liver tumours can be embolised with good results. Stent insertion in the superior vena cava produces dramatic relief of superior vena cava syndrome. Advanced malignancy predisposes to venous thrombosis; caval filtration is discussed together with venous thrombectomy. PMID- 20833517 TI - Folic acid induces acute renal failure (ARF) by enhancing renal prooxidant state. AB - Systemic administration of folic acid (FA) in mice was used for studying the pathogenesis associated with acute renal failure (ARF). However, the mechanism by which FA induces ARF remains poorly understood. The present study therefore, was planned to investigate the effect of folic acid administration on prooxidant state and associated ultrastructural changes in renal tissue. Balb/c male mice of 4-6 weeks old were divided into control and two folic acid treatment groups (Groups A and B). The animals in group A were administered intraperitoneal injection of folic acid (100 mg kg(-1) body weight) for a period of 7 consecutive days while the animal in group B were administered a single intraperitoneal dose of folic acid (250 mg kg(-1) body weight). The renal tissues were collected and used for the analyses of lipid peroxidative indices and activities of antioxidant enzymes in renal tissues. To corroborate biochemical findings scanning electron microscopy (SEM) in renal tissue was studied. Folic acid treated animals demonstrated marked renal hypertrophy accompanied by severe impairment of renal function. Glutathione levels (GSH) and antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) levels were significantly decreased and LPO levels increased following FA treatment. SEM results further substantiated the observed biochemical changes as evident by severe inflammation in glomeruli, swelling in primary and secondary pedicels, blebbing in villi, and tremendous deprivation of erythrocytes (RBCs) in FA treated kidneys. The present study therefore suggests that acute administration of folic acid leads to the generation of oxidative stress and altered membrane architecture responsible for folic acid induced ARF. PMID- 20833518 TI - Letter on behalf of the European College of Veterinary Clinical Pathology in response to the article "International Recommendations for Training Future Toxicologic Pathologists Participating in Regulatory-Type, Nonclinical Toxicity Studies". PMID- 20833519 TI - The time course of myonuclear accretion during hypertrophy in young adult and older rat plantaris muscle. AB - To investigate whether accretion of myonuclei precedes or follows the increase in fibre cross-sectional area and whether this time course is affected by age, left plantaris muscle of 5- and 25-month-old male Wistar rats was overloaded by denervation of its synergists for 1, 2 or 4 weeks. Contralateral plantaris muscle served as control. Myonuclei were counted in haematoxylin-stained cross-sections. While hypertrophy (33% in young adult) became significant after 2 weeks overload (p<0.01), the myonuclear number was increased only at 4 weeks of overload (p<0.001). The time course and magnitude of hypertrophy were similar in young adult and older rats. Older muscles contained 26% more myonuclei per mm fibre length (p=0.001) and had a 10-fold larger proportion of central myonuclei (p<0.001) than young adult muscles. In conclusion, our data indicate that muscle fibre hypertrophy precedes the acquisition of new myonuclei and that the ability to develop hypertrophy is not attenuated or delayed in 25-month-old rat muscle. PMID- 20833520 TI - Acetylcholinesterase inhibition in cognition-relevant brain areas of mice treated with a nootropic Amazonian herbal (Marapuama). AB - The goal of acetylcholinesterase inhibitors (AChEIs) used to treat Alzheimer's patients is an improvement in cholinergic transmission. While currently available AChEIs have limited success, a huge impediment to the development of newer ones is access to the relevant brain areas. Promnesic, anti-amnesic and AChEI properties were identified in a standardized ethanol extract from Ptychopetalum olacoides (POEE), a medicinal plant favored by the elderly in Amazon communities. The purpose of this study was to provide conclusive evidence that orally given POEE induces AChE inhibition in brain areas relevant to cognition. Histochemistry experiments confirmed that the anticholinesterase compound(s) present in POEE are orally bioavailable, inducing meaningful AChE inhibition in the hippocampus CA1 (~33%) and CA3 (~20%), and striatum (~17%). Ellman's colorimetric analysis revealed that G1 and G4 AChE isoforms activities were markedly inhibited (66 and 72%, respectively) in hippocampus and frontal cortex (50 and 63%, respectively), while G4 appeared to be selectively inhibited (72%) in the striatum. Western blotting showed that POEE did not induce significant changes in the AChE immunocontent suggesting that its synthesis is not extensively modified. This study provides definitive proof of meaningful anticholinesterase activity compatible with the observed promnesic and anti-amnesic effects of POEE in mice, reaffirming the potential of this extract for treating neurodegenerative conditions where a hypofunctioning cholinergic neurotransmission is prominent. Adequate assessment of the safety and efficacy of this extract and/or its isolated active compound(s) are warranted. PMID- 20833521 TI - Preventive effect of silymarin in cerebral ischemia-reperfusion-induced brain injury in rats possibly through impairing NF-kappaB and STAT-1 activation. AB - Silymarin and silibinin are bioactive components isolated from Silybum marianum. They have been reported to exhibit anti-oxidative and anti-inflammatory effects. Many studies revealed that drugs with potent anti-inflammatory potential can protect animals against inflammation-associated neurodegenerative disease, e.g., stroke. In this current work we established an animal model of acute ischemic stroke injury by inducing cerebral ischemic/reperfusion (CI/R) in rats to elucidate whether silymarin or silibinin can protect animals from CI/R injury. Pretreatment with silymarin, but not silibinin, dose-dependently (1-10MUg/kg, i.v.) reduced CI/R-induced brain infarction by 16-40% and improved neurological deficits in rats with a stroke. Elevated pathophysiological biomarkers for CI/R induced brain injury, including lipid peroxidation, protein nitrosylation, and oxidative stress, were all reduced by silymarin. In addition, expression of inflammation-associated proteins (e.g., inducible nitric oxide synthase, cyclooxygenase-2 and myeloperoxidase), and transcriptional factors (e.g., nuclear factor (NF)-kappa B and signal transducer and activator of transcription (STAT) 1), as well as production of proinflammatory cytokine (e.g., interleukin-1beta and tumor necrosis factor-alpha) was all significantly prevented by silymarin. Furthermore, an in vitro study on microglial BV2 cells showed that silymarin could inhibit nitric oxide and superoxide anion production, possibly by interfering with NF-kappaB nuclear translocation/activation. Likewise, silymarin pretreatment also inhibited IkappaB-alpha degradation and NF-kappaB nuclear translocation in brain tissues of ischemic rats. Our results reveal that silymarin, but not its active component silibinin, protected rats against CI/R induced stroke injury by amelioration of the oxidative and nitrosative stresses and inflammation-mediated tissue injury through impeding the activation of proinflammatory transcription factors (e.g., NF-kappaB and STAT-1) in the upregulation of proinflammatory proteins and cytokines in stroke-damaged sites. In conclusion, silymarin displays beneficial effects of preventing inflammation related neurodegenerative disease, e.g., stroke, which needs further investigation and clinical evidences. PMID- 20833522 TI - The acute administration of eicosapentaenoic acid is neuroprotective after spinal cord compression injury in rats. AB - The aim of the present study was to investigate the effects of treatment with eicosapentaenoic acid (EPA) after spinal cord compression injury in adult rats. Saline or EPA (250 nmol/kg) was administered intravenously 30 min after compression injury. Locomotor recovery was assessed daily using the BBB open field locomotor score. One week after injury, animals were sacrificed and the spinal cord tissue containing the compression epicenter, and the adjacent rostral and caudal segments, was immunostained using specific markers for neurons, oligodendrocytes, axonal injury, and macrophages/microglia. Administration of EPA resulted in decreased axonal injury and increased neuronal and oligodendrocyte survival, in the lesion epicenter and adjacent tissue. The behavioural assessment mirrored the neuroprotective effects and showed a significantly improved functional recovery in animals treated with EPA compared to the saline-treated controls over the 7-day period. These observations suggest that EPA has neuroprotective properties when administered after spinal cord trauma. PMID- 20833523 TI - Non-MHC antigenic targets of the humoral immune response in transplantation. AB - There is a growing body of data supporting a role for non-HLA antibodies in acute and chronic rejection of solid organ transplants. While many of these non-HLA antigens remain poorly defined, the principal antigenic targets are expressed on cells of the allograft including endothelium and epithelium. These non-HLA antigens are classified as either alloantigens, such as the major histocompatibility complex class I chain-related gene A (MICA) or MICB, or tissue specific autoantigens such as vimentin, cardiac myosin (CM), collagen V (Col V), agrin, and angiotensin II receptor type I (AT1). Herein we provide an overview of the non-MHC antigenic targets that have been implicated in graft rejection and discuss the interplay between alloimmunity and autoreactivity in graft rejection. PMID- 20833524 TI - mTOR signalling and metabolic regulation of T cell differentiation. AB - T cells constantly monitor energy status and nutrient levels in order to adjust metabolic pathways according to their nutritional status and other environmental stimuli. It is increasingly evident that the regulation of cellular metabolism is tightly coupled to T cell differentiation that ultimately determines the cellular fate. The mammalian target of Rapamycin (mTOR) pathway has emerged as a key player in sensing these nutritional/energetic signals and in addition, acts as a major integrator of growth factor induced signals, so placing mTOR at the core of a signalling network controlling metabolism and cellular fate. The mTOR pathway has been shown to play an important role in determining the differentiation of CD4(+) T cells into inflammatory and regulatory subsets, in the induction of anergy, in the development of CD8(+) memory T cells and the regulation of T cell trafficking. PMID- 20833525 TI - Conferences and journal: a virtuous interaction. PMID- 20833526 TI - 13C metabolic flux analysis in complex systems. AB - Experimental determination of in vivo metabolic rates by methods of (13)C metabolic flux analysis is a pivotal approach to unravel structure and regulation of metabolic networks, in particular with microorganisms grown in minimal media. However, the study of real-life and eukaryotic systems calls for the quantification of fluxes also in cellular compartments, rich media, cell-wide metabolic networks, dynamic systems or single cells. These scenarios drastically increase the complexity of the task, which is only partly dealt by existing approaches that rely on rigorous simulations of label propagation through metabolic networks and require multiple labeling experiments or a priori information on pathway inactivity to simplify the problem. Albeit qualitative and largely driven by human interpretation, statistical analysis of measured (13)C patterns remains the exclusive alternative to comprehensively handle such complex systems. In the future, this practice will be complemented by novel modeling frameworks to assay particular fluxes within a network by stable isotopic tracer for targeted validation of well-defined hypotheses. PMID- 20833527 TI - The 30 min decision to delivery time is unrealistic in morbidly obese women. PMID- 20833528 TI - The 30 minute decision to delivery time is unrealistic in morbidly obese women. PMID- 20833529 TI - Herpes simplex meningitis after accidental dural puncture during epidural analgesia for labour. PMID- 20833530 TI - Neuraxial anaesthesia for caesarean section in a patient with narcolepsy and cataplexy. AB - We report the management of a morbidly obese parturient suffering from narcolepsy with cataplexy who presented for caesarean section. Her symptoms were controlled by modafinil and fluoxetine. We administered epidural anaesthesia successfully; surgery was uneventful and recovery was uncomplicated. We discuss some of the issues surrounding parturients with narcolepsy including drug therapy and choice of anaesthetic technique. PMID- 20833531 TI - The effect of adding magnesium sulphate to epidural bupivacaine and fentanyl in elective caesarean section using combined spinal-epidural anaesthesia: a prospective double blind randomised study. AB - BACKGROUND: Combined spinal-epidural anaesthesia is commonly used for elective caesarean section. Intrathecal injection produces rapid onset with minimal doses of local anaesthetic and epidural administration can be used to prolong the block. Our study examined the effects of adding magnesium sulphate to epidural bupivacaine and fentanyl in patients undergoing elective caesarean section using combined spinal-epidural anaesthesia. METHODS: Women ASA physical status I or II at term were recruited. All received 2 mL intrathecal 0.5% hyperbaric bupivacaine, 10 mL epidural 0.25% plain bupivacaine with fentanyl 100 MUg, and were randomly allocated to receive either 10 mL of epidural 0.9% sodium chloride or 10 mL epidural 5% magnesium sulphate. The quality of surgical anaesthesia, incidence of hypotension, Apgar scores, intraoperative pain assessment, onset of postoperative pain, sedation scores and side effects were recorded in the postoperative period. RESULTS: Ninety women were recruited. There was no difference in the time taken for the block to reach T4 sensory level, time to reach the highest level of sensory block, time interval between first neuraxial injection and onset of surgery between the groups. Women who received magnesium had greater motor block and muscle relaxation (P<0.05). Apgar scores were 7 or more in almost all neonates in both groups. There was no significant difference in the incidence of hypotension, nausea and vomiting and duration of motor blockade between the groups. Women who received magnesium showed less shivering and later onset of post operative pain (P<0.05). CONCLUSION: The addition of magnesium to epidural bupivacaine and fentanyl in women undergoing elective caesarean section with combined spinal-epidural anaesthesia improved intraoperative conditions and the quality of postoperative analgesia. PMID- 20833532 TI - Acute respiratory distress syndrome associated with H1N1 influenza during pregnancy. PMID- 20833533 TI - Semi-automated reconstruction of neural circuits using electron microscopy. AB - Reconstructing neuronal circuits at the level of synapses is a central problem in neuroscience, and the focus of the nascent field of connectomics. Previously used to reconstruct the C. elegans wiring diagram, serial-section transmission electron microscopy (ssTEM) is a proven technique for the task. However, to reconstruct more complex circuits, ssTEM will require the automation of image processing. We review progress in the processing of electron microscopy images and, in particular, a semi-automated reconstruction pipeline deployed at Janelia Farm. Drosophila circuits underlying identified behaviors are being reconstructed in the pipeline with the goal of generating a complete Drosophila connectome. PMID- 20833534 TI - Sexual dimorphism in olfactory signaling. AB - What makes males and females behave differently? Although genetic master regulators commonly underlie physical differences, sexually dimorphic behavior is additionally influenced by sensory input such as olfactory cues. Olfaction requires both ligands for signaling and sensory neural circuits for detection. Specialized subsets of each interact to generate gender-dimorphic behavior. It has long been accepted that males and females emit sex-specific odor compounds that function as pheromones to promote stereotypic behavior. Significant advances have now been made in purifying and isolating several of these sex-specific olfactory ligands. In contrast, the neural mechanisms that enable a gender dimorphic response to these odors remain largely unknown. However, first progress has been made in identifying components of sexually dimorphic olfactory circuits in both Drosophila and the mouse. PMID- 20833535 TI - The accuracy of the sentinel node procedure after excision biopsy in squamous cell carcinoma of the vulva. AB - INTRODUCTION: Restricting inguinofemoral lymphadenectomy to patients with malignant nodes would reduce treatment-related morbidity in vulval cancer patients. A prospective study was conducted to determine the diagnostic accuracy of the Sentinel Lymph Node (SLN) procedure in vulval cancer patients referred following either diagnostic or excision biopsy. METHODS: Patients with clinical stage I and II squamous cell carcinoma of the vulva underwent SLN identification with peri-scar/lesional injection of (99m)Technetium-labelled nanocolloid (pre operative lymphoscintigraphy and intra-operative use of a hand-held probe) and intra-operative blue dye. Radical excision of the vulval tumour or scar and formal inguinofemoral lymphadenectomy was then performed as necessary. SLN were processed separately and further examined at multiple levels to exclude micrometastases (H&E/cytokeratin staining) if negative on routine analysis. Clinical follow-up was carried out to identify and treat recurrences or treatment related morbidity. RESULTS: Thirty-two women took part. Fifteen were referred following excision biopsy and seventeen following diagnostic biopsy of their primary vulval tumour. One or more SLN was successfully detected intra operatively in 31 patients (97%) and 45 groins. An SLN could not be identified intra-operatively in one case (re-excision of scar). On average, more SLN were identified in patients with their primary vulval lesion in situ compared with those whose tumour had previously been excised (2.6 vs. 1.8, p = 0.03). Midline tumours were more likely (15/17) than lateral tumours (1/15) to have bilateral SLN identified pre-operatively. Two patients with midline tumours previously excised had unilateral SLN. Seven patients (23%) and ten groins had inguinofemoral lymph node metastases. The SLN procedure correctly identified inguinofemoral metastases in six patients (nine groins). In one case (midline tumour, re-excision of scar) the sentinel node was positive on one side but false negative on the other. CONCLUSIONS: The SLN procedure may be used to identify malignant groins in selected patients with vulval cancer. The extent to which previous vulval surgery might influence the accuracy of the SLN procedure deserves further investigation. PMID- 20833536 TI - Two-step biodiesel production from Calophyllum inophyllum oil: optimization of modified beta-zeolite catalyzed pre-treatment. AB - In this study, a two-step process was developed to produce biodiesel from Calophyllum inophyllum oil. Pre-treatment with phosphoric acid modified beta zeolite in acid catalyzed esterification process preceded by transesterification which was done using conventional alkali catalyst potassium hydroxide (KOH). The objective of this study is to investigate the relationship between the reaction temperatures, reaction time and methanol to oil molar ratio in the pre-treatment step. Central Composite Design (CCD) and Response Surface Methodology (RSM) were utilized to determine the best operating condition for the pre-treatment step. Biodiesel produced by this process was tested for its fuel properties. PMID- 20833537 TI - Catalytic reactive distillation process development for 1,1 diethoxy butane production from renewable sources. AB - Some acetals can be produced from renewable resources (bioalcohols) and seem to be good candidates for different applications such as oxygenated diesel additives. In the present case the production of 1,1 diethoxy butane from bioethanol and butanal is presented. Butanal can be obtained from biobutanol following a partial oxidation or a dehydrogenation process. In this paper innovative process development about the synthesis of the mentioned acetal including catalytic reactive distillation experimental and simulation results will be presented and discussed. Katapak SP modules containing Amberlyst 47 resin were used as structured catalytic packings. This reactive system allowed reaching higher conversions than the equilibrium ones at the same temperatures. All the experimental data gathered allowed to tune a simulation model for the reactive distillation operation which showed a fairly good behavior in order to perform initial 1,1 diethoxy butane production process design studies. PMID- 20833538 TI - Optimization of bio-diesel production from soybean and wastes of cooked oil: combining dielectric microwave irradiation and a SrO catalyst. AB - This work offers an optimized method in the transesterification of pristine (soybean) oil and cooked oil to bio-diesel, based on microwave dielectric irradiation as a driving force for the transesterification reaction and SrO as a catalyst. This combination has demonstrated excellent catalytic activity and stability. The transesterification was carried out with and without stirring. According to 1H NMR spectroscopy and TLC results, this combination accelerates the reaction (to less than 60 s), maintaining a very high conversion (99%) and high efficiency. The catalytic activity of SrO under atmospheric pressure in the presence of air and under the argon atmosphere is demonstrated. The optimum conversion of cooked oil (99.8%) is achieved under MW irradiation of 1100 W output with magnetic stirring after only 10 s. The optimum method decreases the cost of bio-diesel production and has the potential for industrial application in the transesterification of cooked oil to bio-diesel. PMID- 20833539 TI - Carbonyl reductase SCRII from Candida parapsilosis catalyzes anti-Prelog reaction to (S)-1-phenyl-1,2-ethanediol with absolute stereochemical selectivity. AB - An (S)-specific carbonyl reductase (SCRII) was purified to homogeneity from Candida parapsilosis by following an anti-Prelog reducing activity of 2 hydroxyacetophenone. Peptide mass fingerprinting analysis shows SCRII belongs to short-chain dehydrogenase/reductase family. Its coding gene was cloned and overexpressed in Escherichia coli. The recombinant SCRII displays the similar enzymatic characterization and catalytic properties to SCR. It catalyzes the enantioselective reduction of 2-hydroxyacetophenone to (S)-1-phenyl-1,2 ethanediol with excellent optical purity of 100% in higher yield than SCR. Based on the sequence-structure alignment, several single-point mutations inside or adjacent to the substrate-binding loop or active site were designed. With respect to recombinant native SCRII, the A220 and E228 mutations almost lost enantioselectivity towards 2-hydroxyacetophenone reduction. The catalytic efficiencies (kcat/Km) for the A220 or E228 variants are <7% that of the unmutated enzyme. This work provides an excellent catalyst for enantiopure alcohol preparation and the lethal mutations of A220 and E228 suggest their importance in substrate-binding and/or catalysis. PMID- 20833540 TI - Ethanol fermentation from Jerusalem artichoke powder using Saccharomyces cerevisiae KCCM50549 without pretreatment for inulin hydrolysis. AB - A strain of Saccharomyces cerevisiae, KCCM50549, was found to efficiently ferment the inulin-containing carbohydrates in Jerusalem artichoke without acidic or enzymatic pretreatment prior to fermentation. S. cerevisiae KCCM50549 could utilize almost completely the fructo-oligosaccharides present in Jerusalem artichoke (up to degree of polymerization (DP) of 15), in contrast to the other S. cerevisiae strain such as NCYC625 that fermented the fructo-oligosaccharides with DP of up to around six. Inulin-fermenting S. cerevisiae KCCM50549 produced c.a. 1.6 times more ethanol from Jerusalem artichoke compared with S. cerevisiae NCYC625. Direct ethanol fermentation of Jerusalem artichoke flour at 180 g/L without any supplements or pretreatments by S. cerevisiae KCCM50549 in a 5 L jar fermentor yielded 36.2 g/L of ethanol within 36 h. The conversion efficiency of inulin-type sugars to ethanol was 70% of the theoretical ethanol yield. PMID- 20833541 TI - Feasibility study of a Great Lakes bioenergy system. AB - A bioenergy production and delivery system built around the Great Lakes St. Lawrence Seaway (GLSLS) transportation corridor was assessed for its ability to mitigate energy security and climate change risks. The land area within 100 km of the GLSLS and associated railway lines was estimated to be capable of producing at least 30 Mt(dry) yr(-1) of lignocellulosic biomass with minimal adverse impacts on food and fibre production. This was estimated to be sufficient to displace all of the coal-fired electricity in Ontario plus more than 620 million L of green diesel (equivalent to 5.3% of diesel consumption in GLSLS provinces). Lifecycle greenhouse gas emissions were 88% and 76% lower than coal-fired power and conventional diesel, respectively. Production costs of $120 MWh(-1) for power and up to $30 GJ(-1) ($1.1 L(-1)) for green diesel were higher than current market prices, but a value for low-carbon energy would narrow the price differential. PMID- 20833542 TI - Peripheral but crucial: a hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) for potent and selective inhibition of neuronal nitric oxide synthase. AB - Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr(706), Leu(337), and Met(336)) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met(336), as well as the pi-pi stacking interaction between the pyridinyl motif and the side chain of Tyr(706) are important for the high potency and selectivity of these nNOS inhibitors. PMID- 20833543 TI - Synthesis and biological evaluation of novel triptolide analogues for anticancer activity. AB - Three types of novel triptolide analogues with 9,11-olefin (3-5), five-membered unsaturated lactam ring (6-7) or A/B cis ring junction (8-14) were synthesized. Although with 9,11-olefin instead of 9,11-beta-epoxide, compound 4a was much more active than the parent natural triptolide (1) with the lowest IC(50) value of 0.05nM for SKOV-3 cells, clearly challenging the traditional viewpoint on the necessity of 9,11-beta-epoxide group of triptolide. In addition, structure activity relationships for three classes of compounds were studied. PMID- 20833544 TI - Plasma-mediated release of morphine from synthesized prodrugs. AB - Two morphine prodrugs ('PDA' and 'PDB') were synthesized and the kinetics of esterase-mediated morphine release from these prodrugs were determined when incubated with plasma from different animal species. Morphine was rapidly released from PDA by all species plasma with the maximum reached within 5-10min; the released morphine was biologically active as determined by an in vitro cAMP assay. The morphine was released from PDB at a slower and species-dependent rate (mouse>rat>guinea pig>human). Morphine's release from PDB appeared to be mediated by carboxyl esterases as the release was inhibited by the carboxyl esterase inhibitor benzil. PDA nor PDB induce cytotoxicity in the neuronal cell lines SK NSH and SH-SY5Y. The carboxyl and amino functional moieties present on the linker portions of PDA and PDB, respectively, may facilitate their conjugation to nanoparticles to tailor morphine pharmacokinetics and specific targeting. These studies suggest the potential clinical utility of these prodrugs for morphine release at desired rates by administration of their mixture at selected ratios. PMID- 20833545 TI - Bottromycin derivatives: efficient chemical modifications of the ester moiety and evaluation of anti-MRSA and anti-VRE activities. AB - Novel bottromycin derivatives were synthesized from bottromycin A(2) via a hydrazide derivative as a common intermediate. Seventeen derivatives were subjected to in vitro evaluation against drug-resistant gram-positive bacteria. Some compounds showed potent anti-MRSA and anti-VRE activity, as did bottromycin A(2). Notably, a propyl ketone derivative exhibited good antibacterial activity with excellent metabolite stability. PMID- 20833546 TI - Paraoxon, 4-nitrophenyl phosphate and acetate are substrates of alpha- but not of beta-, gamma- and zeta-carbonic anhydrases. AB - Carbonic anhydrases (CAs, EC 4.2.1.1) belonging to alpha-, beta-, gamma- and zeta classes and from various organisms, ranging from the bacteria, archaea to eukarya domains, were investigated for their esterase/phosphatase activity with 4 nitrophenyl acetate, 4-nitrophenyl phosphate and paraoxon as substrates. Only alpha-CAs showed esterase/phosphatase activity, whereas enzymes belonging to the beta-, gamma- and zeta-classes were completely devoid of such activity. Paraoxon, the metabolite of the organophosphorus insecticide parathione, was a much better substrate for several human/murine alpha-CA isoforms (CA I, II and XIII), with k(cat)/K(M) in the range of 2681.6-4474.9M(-1)s(-1), compared to 4-nitrophenyl phosphate (k(cat)/K(M) of 14.9-1374.4M(-1)s(-1)). PMID- 20833547 TI - Structure-based design of imidazo[1,2-a]pyrazine derivatives as selective inhibitors of Aurora-A kinase in cells. AB - Co-crystallisation of the imidazo[1,2-a]pyrazine derivative 15 (3-chloro-N-(4 morpholinophenyl)-6-(pyridin-3-yl)imidazo[1,2-a]pyrazin-8-amine) with Aurora-A provided an insight into the interactions of this class of compound with Aurora kinases. This led to the design and synthesis of potent Aurora-A inhibitors demonstrating up to 70-fold selectivity in cell-based Aurora kinase pharmacodynamic biomarker assays. PMID- 20833548 TI - Three-dimensional kinematics during deep-flexion kneeling in mobile-bearing total knee arthroplasty. AB - We performed an in vivo radiographic analysis of tibiofemoral and polyethylene (PE) insert motions during weight-bearing kneeling beyond 120 degrees of flexion in one high-flexion knee arthroplasty design to determine if kinematics changed over time and if axial rotation occur between the PE insert and the tibial baseplate. Twenty knees implanted with a posterior-stabilized rotating-platform (RP) knee arthroplasty were postoperatively evaluated at 3, 6, and 12 months. The averaged flexion angles were 122 degrees , 129 degrees , and 131 degrees at 3, 6, and 12 months, respectively, showing that the improvement of flexion was achieved up to 6 months. The femoral condyles translated posteriorly from extension to maximum flexion. There was a significant increase in AP translation of femoral lateral condyle in the maximum flexion kneeling between 12 months and the two other intervals (p=0.0003 at 3 months and p=0.016 at 6 months), while no differences in those of medial condyle between all intervals. Almost all rotation occurred at the surface between the tibial baseplate and the PE insert (p=0.0479 at 3 months, p=0.0008 at 6 months, and p=0.0479 at 12 months), almost no rotation occurred at the surface between the PE insert and the femoral component. There were significant increases in the amount of internal rotation angle during full flexion between the tibial component and the PE insert up to 12 months. Knees implanted with this RP knee arthroplasty design show deep-flexion knee kinematics that are consistent with the implant design intent. PMID- 20833549 TI - The effectiveness of minimally invasive total knee arthroplasty to preserve quadriceps strength: a randomized controlled trial. AB - We performed a single-center, randomized, double-blind study to compare muscle strength in patients who had undergone primary total knee arthroplasty (TKA), performed using either a minimally invasive or a conventional surgical technique. We evaluated 30 knees in healthy age-matched subjects, 22 knees after conventional TKA (conventional group), and 23 knees after minimally invasive surgery TKA (MIS group). The Hospital for Special Surgery (HSS) score, Oxford knee score (OKS), and isokinetic (60o/s) muscle strength were evaluated the day before surgery and 3, 6, and 12 months after surgery. HSS and OKS improved significantly over time during follow-up (p<0.001), but there was no significant difference between the groups (p>0.05). The extensor peak torque (EPT) and flexor peak torque (FPT) improved significantly over time (p<0.001) and EPT was greater in the MIS group than in the conventional group during the follow-up period (p<0.05). There was no difference in FPT and the hamstring-to-quadriceps ratio between the groups. Although MIS patients had a significant deficit in extensor strength following TKA, compared with healthy controls, this approach offers a significant improvement in extensor muscle strength over conventional surgery. These results suggest that the MIS approach results in better outcomes with regard to maintaining extensor strength than the conventional surgical approach. PMID- 20833550 TI - Synthesis and anti-HIV-1 evaluation of phosphonates which mimic the 5' monophosphate of 4'-branched 2',3'-didehydro-2',3'-dideoxy nucleosides. AB - Synthesis of the 4'-ethynyl and 4'-cyano phosphonates 8-11, which mimic the 5' monophosphate of 4'-branched 2',3'-didehydro-2',3'-dideoxy nucleosides, was investigated by employing the 3',4'-unsaturated nucleosides (13 and 28) as the starting material. The synthesis was initiated by the electrophilic addition of NIS/(EtO)(2)P(O)CH(2)OH to these unsaturated nucleosides. After introduction of the 2',3'-double bond, the 4'-hydroxylmethyl group of the resulting adducts was transformed into the ethynyl or cyano group. While the 4'-cyano phosphonates 9 and 11 were not sufficiently stable to be isolated, the 4'-ethynyl counterparts (8 and 10) were obtained as their mono-ammonium salts. The adenine derivative 8 showed almost comparable anti-HIV-1 activity to that of d4T. PMID- 20833551 TI - N-phenyl-N'-[4-(5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenyl]ureas as novel inhibitors of VEGFR and FGFR kinases. AB - We have recently reported the discovery of pyrrolo[3,2-d]pyrimidine derivatives 1a and 1b as potent triple inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Tie-2 kinases. To identify compounds having strong inhibitory activity against fibroblast growth factor receptor (FGFR) kinase, further modification was conducted using the co-crystal structure analysis of VEGFR2 and 1b. Among the compounds synthesized, urea derivative 11l having a piperazine moiety on the terminal benzene ring showed strong inhibitory activity against FGFR1 kinase as well as VEGFR2 kinase. A binding model of 11l complexed with VEGFR2 suggested that the piperazine moiety forms additional interactions with Ile1025 and His1026. PMID- 20833552 TI - Changes in antioxidant systems in soybean as affected by Sclerotinia sclerotiorum (Lib.) de Bary. AB - Changes in antioxidant systems in soybean [Glycine max (L.) Merr., Fabaceae] genotypes infected with Sclerotinia sclerotiorum were studied 12, 24, 48 and 72h after inoculation. Generation of superoxide and hydroxyl radicals was evaluated together with the production of malonyldialdehyde, main end product of lipid peroxidation. Several enzymatic and non-enzymatic parameters were monitored as well, such as the activity of antioxidant enzymes superoxide dismutase and pyrogallol and guaiacol peroxidases, reduced glutathione, soluble proteins and total carotenoids content. Results showed that genotypes expressed oxidative burst as well as different antioxidant systems in response to biotic stress caused by pathogen invasion. It has been confirmed that, although hypersensitive cell death is efficient against biotrophic pathogens, it does not protect soybean plants against infection by the necrotrophic pathogen such as S. sclerotiorum. Still, some genotypes showed distinctive and combined activity of several biochemical parameters which may point to further directions in exploring host pathogen relations and lead to selection and production of new genotypes with higher levels of tolerance. PMID- 20833553 TI - Simultaneous maxillary sinus lifting and implant placement with autogenous parietal bone graft: outcome of 17 cases. AB - The aim of this study was to retrospectively evaluate the surgical technique of sinus floor elevation with autogenous parietal bone grafting in conjunction with immediate dental implants for the reconstruction of the maxilla in deficient maxillary alveolar ridges. Seventeen patients who underwent sinus floor elevation with bone graft from the parietal bone between 2005 and 2007 were included in the study. Cases of extremely deficient bone level in the alveolar ridge<4mm were included in the study. Seventy-seven implants (49 Staumann(r), 24 Replace(r) and 4 Ankylos(r)) with different length and diameter were placed immediately after the graft was placed. Strict oral hygiene was required for the patients. Presurgical and postsurgical panoramic radiographs were taken. A high-quality reconstruction with an increase in lifted sinus bone height was achieved with parietal bone particulates. Seventy-three implants were clinically osseointegrated and four implants were lost giving a success rate 94.8%. No correlation was found between failure and the surgery. The encouraging results of this study suggest that the technique of reconstruction of the sinus floor and the resorbed alveolar ridge using an autogenous parietal bone graft is reliable, giving the surgeon the opportunity to successfully perform immediate implant placement in more difficult and deficient maxillary alveolar bone height. PMID- 20833554 TI - Early removal of the chest tube after complete video-assisted thoracoscopic lobectomies. AB - OBJECTIVE: Chest tubes induce morbidity such as pain, decrease mobility, increase the risk of infection, and prolong the length of hospital stays. This study evaluates a chest-tube protocol containing a high-drainage threshold and a short time period of drainage. METHODS: A retrospective study was performed with data collected from all elective complete video-assisted thoracoscopic (c-VATS) (bi )lobectomies between March 2006 and December 2009. All patients had one chest tube, postoperatively. The chest tube was removed if there was no air leakage and there was a drainage volume of 400 ml (24 h)(-1) or less. We aimed to remove the chest tube on postoperative day 1. RESULTS: This series consists of 110 lobectomies and six bilobectomies. The median duration of chest-tube placement was 1.0 day. In 58.8% of patients (confidence interval (CI) 95%: 49.5-68.0), the drain was removed within 24 h of operation and in 82.5% (CI 95%: 74.2-88.7) within 48 h. In six (6.2%) patients, subcutaneous emphysema developed while the drain was still in place, and was treated with removal of the drain. Persistent air leakage was seen in four (3.4%) patients. One (0.9%) persisting pneumothorax was diagnosed. A pneumothorax after removal of the drain was not diagnosed. No major complications developed in 98 patients (84.5%). The median day of discharge was postoperative day 4. CONCLUSIONS: This study shows it is safe, after c-VATS (bi-)lobectomy, to remove the chest tube within 24 h in 58.8%, and within 48 h in 82.5% of patients. As was also shown in other studies, this leads to shorter length of hospital stays, lower costs, and most importantly, reduces patient morbidity without the added risk of complications. PMID- 20833555 TI - Type 1 congenital pulmonary airway malformation with a complication of abnormal blood vessel. PMID- 20833556 TI - Rib approximation without intercostal nerve compression reduces post-thoracotomy pain: a prospective randomized study. AB - OBJECTIVE: One of the most important considerations in the care of thoracic surgery patients is the control of pain, which leads to increased morbidity and relevant mortality. METHODS: Between February and May 2009, 60 patients undergoing full muscle-sparing posterior minithoracotomy were prospectively randomized into two groups, according to the thoracotomy closure techniques. In the first group (group A), two holes were drilled into the sixth rib using a hand perforator, and sutures were passed through the holes in the sixth rib and were circled from the upper edge of the fifth rib, thereby compressing the intercostal nerve underneath the fifth rib. In the second group (group B), the intercostal muscle underneath the fifth rib was partially dissected along with the intercostal nerve, corresponding to the holes on the sixth rib. Two 1/0 polyglactin (Vicyrl) sutures were passed through the holes in the sixth rib and above the intercostal nerve. RESULTS: There were 30 patients in each group. The visual analog score, observer verbal ranking scale (OVRS) scores for pain, and Ramsay sedation scores were used to follow-up on postoperative analgesia and sedation. The von Frey hair test was used to evaluate hyperalgesia of the patients. The patients in group B had lower visual analog scores at rest and during coughing. The patients in group B had lower OVRS scores than group A patients. The groups were not statistically different in terms of the Ramsay sedation scores and von Frey hair tests. CONCLUSIONS: Thoracotomy closure by a technique that avoids intercostal nerve compression significantly decreases post thoracotomy pain. PMID- 20833557 TI - The intracorporeal use of 2-octyl cyanoacrylate resin to control air leaks after lung resection. AB - OBJECTIVE: To describe the outcome of patients who had 2-octyl cyanoacrylate used as an adjunct to control air leaks after lung resection by application directly onto the visceral pleura. METHODS: A retrospective review of these patients from 2007 to 2009 from a single surgeon's practice. RESULTS: Seven challenging patients had 2-octyl cyanoacrylate used to control difficult air leaks after lung resection. The indications included lack of standard sealants in patients with emphysematous lung that would not hold suture and vast air leaks after decortications or extensive nonanatomic resections in patients that would not tolerate the loss of tidal volume. All air leaks sealed immediately and none of the patients left the operating theater with an air leak, including three patients who underwent difficult decortications for empyema. All patients recovered uneventfully, except one patient who died from acute respiratory distress syndrome. His postmortem examination revealed that the resin remained intact on the lung without signs of degradation after being in an intracorporeal environment for weeks. There were no complications nor toxicity directly related to the 2-octyl cyanoacrylate resin. CONCLUSIONS: 2-Octyl cyanoacrylate is extremely effective in immediately controlling air leaks, with the results being seen instantly. It dries quickly, does not wash off the lung, and remains intact on the visceral pleura for several weeks. 2-Octyl cyanoacrylate deserves additional testing as an adjunct to control air leaks after lung resection. PMID- 20833558 TI - Impact of lobectomy for non-small-cell lung cancer on respiratory function in octogenarian patients with mild to moderate chronic obstructive pulmonary disease. AB - OBJECTIVE: To assess the long-term impact of standard lobectomy on respiratory function in octogenarian patients with mild/moderate chronic obstructive pulmonary disease (COPD). METHODS: We reviewed all octogenarians (n=38), who underwent lobectomy for stage I-II non-small-cell lung cancer (NSCLC) from 2000 to 2006. Inclusion criteria were: Tiffenau index<0.7, no adjuvant therapies, smoking cessation after surgery, spirometric data available after 12+/-3 months from surgery in the absence of relapsing disease. RESULTS: After excluding 14 patients (three died perioperatively), 24 fulfilled the inclusion criteria. The median preoperative forced expiratory volume in 1s (FEV1) was 80% (range 56.7 100%). The mean change in FEV1 after lobectomy resulted in a loss of 11% (range 32% to +7%, p=0.004). Considering two groups on the basis of median FEV1 (group 1: FEV1<=80%, group 2: FEV1>80%), mean FEV1 loss after surgery was 7.9% in group 1 and 14.9% in group 2, respectively (p=0.17). No statistical differences were found between the two groups in changes after surgery of forced vital capacity (FVC), arterial oxygen and carbon-dioxide tension. Diffusion capacity of the lung for carbon monoxide (DLCO)% loss was significantly higher in group 2 compared with group 1 (-22.5% vs +1.5%, p=0.001). Six patients showed an improvement of postoperative FEV1: all had a preoperative FEV1 less than 60%, an upper or homogeneous pattern of emphysema, and received an upper lobectomy. In group 2, the FEV1 loss was not affected by the type of lobectomy whereas in group 1, the resection of lower lobe was associated to a major FEV1 loss (-14.5% vs +5.3%, p=0.05). CONCLUSIONS: Octogenarians with lower preoperative FEV1% have a better late preservation of pulmonary function after lobectomy. Upper lobectomy seems to produce a lung-volume reduction effect, leading to an improvement in the expiratory volume in patients with higher airflow obstruction. PMID- 20833559 TI - Developments in the systemic treatment of endometrial cancer. AB - Systemic treatment represents the cornerstone of endometrial cancer management in advanced, relapsed and metastatic disease, which is still characterized by poor prognosis. Progestins remain an effective option for patients with low grade, estrogen and/or progesterone receptor positive disease, with some of them achieving prolonged survival. Platinum compounds, anthracyclines and more recently taxanes have been implemented in combination regimens achieving response rates more than 50% and resulting in overall survival above 1 year in randomized trials. Adjuvant chemotherapy with the same agents may be useful for patients with early stage disease and high-risk features, such as high grade or non endometrioid histology. Combination of chemotherapeutic agents with radiotherapy remains investigational. Hematologic, cardiac toxicity and neurotoxicity represent the main concern of chemotherapy and increase the risk for treatment related morbidity and death, especially in pretreated patients bearing substantial co-morbidities. The gradual elucidation of the molecular aspects of endometrial carcinogenesis has led to the development of novel, selective antineoplastic agents, targeting specific molecular pathways and mediators of signal transduction implemented in cell proliferation, survival and angiogenesis. In the current review, we report on the recent advances regarding systemic therapy of endometrial carcinoma with special emphasis on results of large, randomized phase III clinical trials. Biomarkers with potent prognostic significance or predictive value for response to treatment are presented and novel molecular agents showing promising results in early clinical trials are discussed. PMID- 20833560 TI - The treatment of propofol induced the TGF-beta1 expression in human endothelial cells to suppress endocytosis activities of monocytes. AB - Propofol anesthesia and sedation are known to downregulate the functions of many hematopoietic cells, such as macrophages and neutrophils, in vivo. However, the effects of propofol on secretion of the regulatory cytokine transforming growth factor beta1 (TGF-beta1) in vivo are unknown. In this study, the effects of propofol on TGF-beta1 expression in human peripheral blood mononuclear cells, umbilical vein endothelial cells (HUVECs), lymphocytes (Jurkat) and monocytes (THP-1) were tested. Moreover, these sera were also tested for regulatory activity on monocyte endocytosis with or without treatment with the TGF-beta1 pathway inhibitor SB431542. Propofol raised levels of both total and activated TGF-beta1 in propofol-treated patient sera after surgical operations. Furthermore, propofol induced secretion of latent TGF-beta1 in HUVEC cells and enhanced TGF-beta1 activation in THP-1 and Jurkat cells in vitro. Additionally, sera from propofol-treated patients suppressed monocyte endocytosis ex vivo, an effect that was abrogated by the TGF-beta1 pathway inhibitor SB431542. PMID- 20833561 TI - Old acid, new chemistry. Negative metal anions generated from alkali metal oxalates and others. AB - A brief search in Sci Finder for oxalic acid and oxalates will reward the researcher with a staggering 129,280 hits. However, the generation of alkali metal and silver anions via collision-induced dissociation of the metal oxalate anion has not been previously been reported, though Tian and coworkers recently investigated the dissociation of lithium oxalate. The exothermic decomposition of alkali metal oxalate anion to carbon dioxide in the collision cell of a triple quadrupole mass spectrometer leaves no place for the electron to reside, resulting in a double electron-transfer reaction to produce an alkali metal anion. This reaction is facilitated by the negative electron affinity of carbon dioxide and, as such, the authors believe that metal oxalates are potentially unique in this respect. The observed dissociation reactions for collision with argon gas (1.7-1.8 * 10(-3) mbar) for oxalic acid and various alkali metal oxalates are discussed and summarized. Silver oxalate is also included to demonstrate the propensity of this system to generate transition-metal anions, as well. PMID- 20833562 TI - Ultrasonography as a tool to study afferent feedback from the muscle-tendon complex during human walking. AB - In humans, one of the most common tasks in everyday life is walking, and sensory afferent feedback from peripheral receptors, particularly the muscle spindles and Golgi tendon organs (GTO), makes an important contribution to the motor control of this task. One factor that can complicate the ability of these receptors to act as length, velocity and force transducers is the complex pattern of interaction between muscle and tendinous tissues, as tendon length is often considerably greater than muscle fibre length in the human lower limb. In essence, changes in muscle-tendon mechanics can influence the firing behaviour of afferent receptors, which may in turn affect the motor control. In this review we first summarise research that has incorporated the use of ultrasound-based techniques to study muscle-tendon interaction, predominantly during walking. We then review recent research that has combined this method with an examination of muscle activation to give a broader insight to neuromuscular interaction during walking. Despite the advances in understanding that these techniques have brought, there is clearly still a need for more direct methods to study both neural and mechanical parameters during human walking in order to unravel the vast complexity of this seemingly simple task. PMID- 20833563 TI - Reliability of spike and turn variables of surface EMG during isometric voluntary contractions of the biceps brachii muscle. AB - The present study was performed to investigate the reliability of initial value and the rate of change of eight spike and turn variables in biceps brachii muscle of eleven subjects during sustained isometric voluntary contractions. Three levels of contraction were studied: 20%, 50% and 80% of the maximal voluntary contraction (MVC) level. Reliability was investigated using the intraclass correlation coefficient (ICC) and the standard error of measurement (SEM) of the estimates for each subject. The reliability of the spike and turn variables was compared with four classical variables (ARV: average rectified value, RMS: root mean square MDF: median frequency and MNF: mean frequency) for the same recorded signals. Tukey's HSD (honestly significant difference) test was applied to detect significant differences at the 95% confidence level (p<0.05) between the %MVC levels for each of the eight variables. The main findings of this study can be summarized as follows: (i) the initial value estimation with eight spike and turn variables showed good reliability but the estimation of rate of change showed poor reliability. (ii) The reliability of the classical variables for estimation of the initial value was slightly lower than that of the spike and turn variables, but the four classical variables showed better reliability than the spike and turn variables for estimation of the slope. (iii) The initial values of the amplitude variables (MTA: mean turn amplitude and MSA: mean spike amplitude) increased and the rate of changes of the frequency variables (MTF: mean turn frequency, MSF: mean spike frequency and ZC: zero-crossing) decreased significantly when the contraction level increased from 20% MVC to 80% MVC. PMID- 20833564 TI - Clinicoradiologic features of vertebrobasilar dolichoectasia in stroke patients. AB - The prevalence and implications of vertebrobasilar dolichoectasia (VBD), a causative arteriopathy of stroke are unclear in Asian stroke patients. Through a comparative study of VBD and non-VBD stroke patients, we aimed to elucidate the clinicoradiologic features of VBD patients in Japan. A total of 481 consecutive patients (302 men and 179 women) with acute stroke were admitted to our department between 2007 and 2008. Of these 481 inpatients, 374 (231 men and 143 women) had brain infarct (BI), and 107 (71 men and 36 women) had brain hemorrhage (BH). We reviewed medical records, and VBD was diagnosed by magnetic resonance angiography. Cardiovascular disease (CVD) risk profile, modified Rankin scale score at 30 days poststroke, and stroke lesions were compared among 4 groups: the VBD BI group, the VBD BH group, the non-VBD BI group, and the non-VBD BH group. The diameter, height, and lateral displacement of the basilar artery (BA) were analyzed in the VBD patients. Statistical analyses used multivariate logistic regression analysis. VBD was found in 37 patients (34 men and 3 women). Mean age (+/- SD) was 64.4 +/- 14.7 years (63.4 +/- 14.6 years in men and 65.3 +/- 6.1 years in women). Twenty-four patients (21 men and 3 women) had BI, and 13 men had BH. There were significant male preferences in VBD BI (P < .01) and VBD BH patients (P < .01). Mean age (+/- SD) was 67.7 +/- 14.3 years in BI patients and 56.7 +/- 12.7 years in BH patients. The VBD BH men were significantly younger than the non-VBD BH men (P < .05) and VBD BI men (P < .01). Frequency of current smoking was significantly greater in VBD BI patients compared with non-VBD BI patients (P < .05). Other CVD risk factors did not differ among the 4 groups. Mean modified Rankin Scale score was significantly higher in VBD BH men compared with non-VBD BH men and VBD BI men (P < .01). The height and lateral displacement of the BA were scored more severely in BH patients than in BI patients (P < .01), but BA diameter did not differ between BH and BI patients. The frequency of pontine infarct and hemorrhage was 3-fold greater in VBD BI (P < .05) and VBD BH patients (P < .005) compared with non-VBD BI and BH patients. Our findings indicate a VBD prevalence of 7.7% in stroke patients, 6.4% in BI patients, and 12.1% in BH patients. Our clinicoradiologic analyses suggest male predominance, younger onset of BH, and higher frequency of pontine lesions in VBD patients. Significant BA changes and poor outcome of stroke were found in patients with hemorrhagic VBD rather than ischemic VBD. Thus, more attention should be paid to risk and care of BH in VBD patients, in addition to those of BI. PMID- 20833565 TI - The case for the comparator model as an explanation of the sense of agency and its breakdowns. AB - I compare Frith and colleagues' influential comparator account of how the sense of agency is elicited to the multifactorial weighting model advocated by Synofzik and colleagues. I defend the comparator model from the common objection that the actual sensory consequences of action are not needed to elicit the sense of agency. I examine the comparator model's ability to explain the performance of healthy subjects and those suffering from delusions of alien control on various self-attribution tasks. It transpires that the comparator model needs case-by case adjustment to deal with problematic data. In response to this, the multifactorial weighting model of Synofzik and colleagues is introduced. Although this model is incomplete, it is more naturally constrained by the cases that are problematic for the comparator model. However, this model may be untestable. I conclude that currently the comparator model approach has stronger support than the multifactorial weighting model approach. PMID- 20833566 TI - Does total joint replacement or arthrodesis of the first metatarsophalangeal joint yield better functional results? A systematic review of the literature. AB - As first metatarsophalangeal joint arthrodesis is generally considered to be a successful procedure for the treatment of hallux rigidus, many surgeons question the usefulness of total joint replacement. In an effort to elucidate the clinical evidence, we undertook a systematic review of the literature comparing the functional outcomes of arthrodesis and joint replacement in first metatarsophalangeal surgery. Using multiple search engines and medical subject headings, 10 articles were eligible for inclusion: 5 featured arthrodesis and 5 featured total joint replacement. The American Orthopaedic Foot and Ankle Society Hallux metatarsophalangeal-interphalangeal score was used in all articles. The mean age at operation was 53 years for joint replacement patients and 55 for those undergoing joint arthrodesis. Most patients in all studies were female. There was a significant increase from pre- to postoperative scores in both procedures. The median postoperative score for joint replacement was 83/100 (range 74-95) and 82/100 (range 78-89) for arthrodesis. The median revision rate in joint replacements was 7% (range 0%-10%) and 0% (range 0%-12%) for arthrodesis. This systematic review reveals that arthrodesis achieves better functional outcomes than total joint replacement. The operative techniques and prostheses for joint replacements are however still in an early stage of development and advances still need to be achieved to produce a more successful and anatomical prosthesis that could be functionally superior to an arthrodesis. PMID- 20833567 TI - Tendon adhesion after percutaneous repair of the Achilles tendon: a case report. AB - Percutaneous repair of the Achilles tendon is known to minimize tendon adhesions and wound complication through a minimally invasive technique. The usually reported complications are sural nerve injury and inadequate contact of the tendon stumps, which can lead to rerupture or tendon lengthening. We experienced an interesting case of Achilles tendon adhesion after percutaneous repair, which had been initially misdiagnosed as a rerupture. To our knowledge, this is the only report of Achilles tendon adhesion as a complication after percutaneous repair, which stresses the importance of functional postoperative rehabilitation. PMID- 20833568 TI - Plexiform schwannoma of the foot: a review of the literature and case report. AB - Plexiform schwannoma is a rare variety of benign nerve sheath tumor that is usually confined to the head and neck or trunk. In this article, we describe the case of a plexiform schwannoma of the foot in an adult male. In addition to a review of the literature, we discuss diagnostic characteristics and differentiators for this tumor, an approach to surgical treatment, including reconstruction of the plantar foot defect after tumor extirpation, and why it is important for practicing foot and ankle surgeons to differentiate plexiform schwannoma from other similar tumors. PMID- 20833569 TI - Radiographic angles in hallux valgus: comparison between manual and computer assisted measurements. AB - Radiographic angles are used to assess the severity of hallux valgus deformity, in preoperative planning, assessing postoperative outcomes, and in comparing results between interventions. The manual method to measure these angles has been shown to be prone to errors and to be time consuming. Computer programs are now available to assist in angular measurements. This study was undertaken to compare the reliability and time taken between the 2 methods. A total of 30 radiographs were used from a population of patients with hallux valgus deformity. The radiographs were digitized for computer-assisted measurements. The technical error of measurement (TEM) was calculated for intra- and interobserver data to assess the error in angular measurement with both methods. The technical error of measurement was lower with the computer-assisted method, suggesting that this method is more reliable. Furthermore, the time taken was also reduced with this method. PMID- 20833570 TI - [The caring of family members in the intensive care units from the Jean Watson perspective]. AB - This article presents a brief reflection on the caring of families in the Intensive Care Units. To address this issue, Jean Watson, one of the most important theoreticians on nursing of our days, has been taken as a reference. Watson was chosen because it is possible to understand perfectly the need to contemplate the family within the holistic care of critical patients from his theory. Thus, it is proposed to carry out an investigation that studies the care of the family members of the critical patient based on the idea of Watson's caring theory. To understand this approach, the theory of caring is analyzed and evaluated according to the guide produced by McEwen in 2007. PMID- 20833571 TI - Evidence of Chagas disease in seronegative Brazilian patients with megaesophagus. AB - BACKGROUND: After 100 years of research, Chagas disease (CD) remains an important public health problem in Latin America. The symptomatic chronic phase is usually characterized by cardiac or digestive involvement and diagnosis currently relies on the measurement of Trypanosoma cruzi-specific antibodies produced in response to the infection. However, the detection of parasite DNA in seronegative persons has been reported. METHODS: The prevalence of CD in a population with esophageal disorders was assessed by conventional serology. We also detected T. cruzi DNA in blood samples of seronegative and inconclusive patients by nested polymerase chain reaction (N-PCR). RESULTS: The seroprevalence of CD determined by conventional serologic tests (indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA)) was 79% in 513 patients with esophageal disorders. Out of 41 blood samples, N-PCR was positive in 31 (76%) cases for which serology was negative or inconclusive. CONCLUSIONS: As all patients presented with clinical signs suggestive of the digestive form of CD and most of them were born in endemic areas, we highlight the importance of improving diagnosis of the disease and the implications for blood bank screening. Our data suggest that N PCR is effective in the detection of T. cruzi DNA in patients with inconclusive or negative serology, and it may eventually be useful in the determination of the etiology of megaesophagus. PMID- 20833572 TI - Determinants of health-related quality of life in Parkinson's disease: a systematic review. AB - This systematic review critically evaluates the literature to identify the demographic and clinical factors that predict the health-related quality of life (HRQOL) of people with Parkinson's disease (PD). Understanding how these factors relate to HRQOL in people with PD may assist clinicians minimise the functional and social impact of the disease by optimising their assessment and clinical decision making processes. A tailored search strategy in six databases identified 29 full-text reports that fulfilled the pre-defined inclusion and exclusion criteria. The quality of included studies was assessed by two independent reviewers using a customized assessment form. A best-evidence synthesis was used to summarise the demographic and clinical factors that were examined in relation to HRQOL. Depression was the most frequently identified determinant of HRQOL in people with idiopathic PD. Disease severity and disease disability were also found to be predictive of poor HRQOL outcomes in many studies. The motor symptoms that contributed most often to overall life quality were gait impairments and complications arising from medication therapy. To minimise the impact of PD on HRQOL, it may be necessary to consider the extent to which demographic factors and motor and non-motor symptoms contribute to life quality. PMID- 20833573 TI - A tale of two cities: residential context and risky behavior among adolescents in Los Angeles and Chicago. AB - This article evaluates whether the at-risk behavior of adolescents is differentially influenced by community context across two metropolitan areas. Our focus is on Latino youth in particular. The data come from the Los Angeles Family and Neighborhood Survey (L.A.FANS) and the Project on Human Development in Chicago Neighborhoods (PHDCN). Multi-level models are employed to estimate the effects of community-level influences on adolescent risky behavior in Los Angeles and Chicago. Neighborhood-level influences on the at-risk behavior of youth are found to operate similarly across the two cities, such that native-born children of Latino immigrants are at greatest risk of problem behavior in co-ethnic highly segregated neighborhoods in both Los Angeles and Chicago. Similar patterns are observed for African-Americans, particularly in Chicago and Non-Latino Whites in both cities. We argue that the findings are best interpreted through a segregation framework. Members of each racial/ethnic group appear to exhibit negative health risk behaviors when they reside in areas that are disproportionately populated with their co-ethnic peers. PMID- 20833574 TI - Shootward and rootward: peak terminology for plant polarity. PMID- 20833575 TI - Algal diseases: spotlight on a black box. AB - Like any other living organisms, algae are plagued by diseases caused by fungi, protists, bacteria or viruses. As aquaculture continues to rise worldwide, pathogens of nori or biofuel sources are becoming a significant economic burden. Parasites are also increasingly being considered of equal importance with predators for ecosystem functioning. Altered disease patterns in disturbed environments are blamed for sudden extinctions, regime shifts, and spreading of alien species. Here we review the biodiversity and impact of pathogens and parasites of aquatic primary producers in freshwater and marine systems. We also cover recent advances on algal defence reactions, and discuss how emerging technologies can be used to reassess the profound, multi-faceted, and so far broadly-overlooked influence of algal diseases on ecosystem properties. PMID- 20833576 TI - Evolutionary conservation of the transcriptional network regulating secondary cell wall biosynthesis. AB - The ability to make secondary cell walls was a pivotal step for vascular plants in their conquest of dry land. Here, we review recent molecular and genetic studies that reveal that a group of Arabidopsis (Arabidopsis thaliana) secondary wall-associated NAC domain transcription factors are master switches regulating a cascade of downstream transcription factors, leading to activation of the secondary wall biosynthetic program. Close homologs of the Arabidopsis secondary wall NACs and their downstream transcription factors exist in diverse taxa of vascular plants and some are functional orthologs of their Arabidopsis counterparts. There is evidence to suggest that the secondary wall NAC-mediated transcriptional regulation of secondary wall biosynthesis is a conserved mechanism throughout vascular plants. PMID- 20833578 TI - Alcohol drinking and laryngeal cancer: overall and dose-risk relation--a systematic review and meta-analysis. AB - Alcohol drinking is a known risk factor for laryngeal cancer. However, little information is available on the risk associated with light alcohol drinking. To address this issue, we conducted a meta-analysis using two methods: (i) random effects models with reconstruction of alcohol consumption categories and calculation of risk estimates associated with predefined consumption levels using Hamling method and (ii) random-effects meta-regression models. The PubMed database was searched for all case-control or cohort studies published in the English language on the association between alcohol consumption and risk of laryngeal cancer. Forty studies (38 case-control, 2 cohort) reporting on at least three levels of consumption were included. Overall, alcohol drinking versus non drinking was associated with an approximately 2-fold increase in risk of laryngeal cancer (RR=1.90; 95% CI: 1.59-2.28). While light alcohol drinking (>=1 drink/day) did not show any significant association with risk of laryngeal cancer (12 studies. RR=0.88; 95% CI: 0.71-1.08), moderate drinking (>1 to <4drinks/day) was associated with a 1.5-fold increase in risk (35 studies. RR=1.47; 95% CI: 1.25-1.72) and heavy drinking (?4drinks/day) was associated with a 2.5-fold increased risk (33 studies. RR=2.62; 95% CI: 2.13-3.23). Subgroup analyses for studies that adjusted for main potential confounding factors (age, sex, and tobacco use) and several further subgroup analyses showed similar results, which suggest the robustness of the results. PMID- 20833579 TI - Feasibility and efficacy study of weekly cisplatin with concurrent intensity modulated radiation therapy for nasopharyngeal carcinoma: preliminary results. AB - The aim of this study was to assess the feasibility and efficacy of a weekly cisplatin 40 mg/m(2) regimen in patients with nasopharyngeal carcinoma treated concurrently with definitive intensity-modulated radiation therapy (IMRT). The primary endpoints were treatment compliance and acute toxicities. Twenty-two patients with newly diagnosed NPC were recruited in this phase II trial. All patients received definitive IMRT concurrently with weekly cisplatin 40 mg/m(2) for six cycles. The treatment technique was split-field IMRT (SF-IMRT) before August 2009 and whole-field IMRT (WF-IMRT) thereafter. The median follow-up time was 15.1 months (range, 1.5-30 months). No patients experienced regional recurrence or distant metastasis. One patient developed local recurrence. One patient died of non-malignant disease. For all patients, the 1-year overall survival, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival were 95.5%, 95.5%, 100%, and 100%, respectively. All patients received the full dose of RT. Twenty-one patients (95.5%) completed all six cycles of chemotherapy (CHT). Three patients experienced treatment delay. Of them, one had CHT delay, and the other two had IMRT delay. No treatment related death was found. Acute toxicities were generally mild or moderate. Grade 3 and 4 toxicities accounted for less than 10% of overall occurrence in each corresponding category except for a relatively higher rate in stomatitis (Grade 3, 27%). Renal function impairment was not found. Weekly cisplatin with concurrent IMRT appears to be feasible and effective in treating NPC patients and these findings warrant further investigation. PMID- 20833581 TI - Nitrate, ammonium, and potassium sensing and signaling. AB - Plants acquire numerous nutrients from the soil. In addition, nutrients elicit many physiological and morphological responses especially in roots. Recently, there has been significant progress in identifying the sensing and regulatory mechanisms of several essential nutrients. In this review, we describe the newly identified signaling components of nitrate, ammonium, and potassium, focusing specifically on the initial sensing steps. PMID- 20833577 TI - Aminoglycoside modifying enzymes. AB - Aminoglycosides have been an essential component of the armamentarium in the treatment of life-threatening infections. Unfortunately, their efficacy has been reduced by the surge and dissemination of resistance. In some cases the levels of resistance reached the point that rendered them virtually useless. Among many known mechanisms of resistance to aminoglycosides, enzymatic modification is the most prevalent in the clinical setting. Aminoglycoside modifying enzymes catalyze the modification at different -OH or -NH2 groups of the 2-deoxystreptamine nucleus or the sugar moieties and can be nucleotidyltransferases, phosphotransferases, or acetyltransferases. The number of aminoglycoside modifying enzymes identified to date as well as the genetic environments where the coding genes are located is impressive and there is virtually no bacteria that is unable to support enzymatic resistance to aminoglycosides. Aside from the development of new aminoglycosides refractory to as many as possible modifying enzymes there are currently two main strategies being pursued to overcome the action of aminoglycoside modifying enzymes. Their successful development would extend the useful life of existing antibiotics that have proven effective in the treatment of infections. These strategies consist of the development of inhibitors of the enzymatic action or of the expression of the modifying enzymes. PMID- 20833582 TI - Human bocavirus in children: mono-detection, high viral load and viraemia are associated with respiratory tract infection. AB - BACKGROUND AND OBJECTIVES: Human bocavirus 1 (HBoV1) has recently been detected in children with respiratory tract infections (RTI). In order to study whether HBoV1 can cause RTI, we investigated its presence in children with upper RTI (URTI), lower RTI (LRTI) and a control group of children without RTI. STUDY DESIGN: Nasopharyngeal aspirates (NPA) and blood samples were collected from children admitted to hospital with RTI from 6 June 2007 to 28 February 2009 (n=1154), and from children admitted for elective surgery who had no RTI (n=162). Using polymerase chain reaction (PCR), the NPAs were examined for 17 infectious agents including HBoV1. Blood samples were tested with HBoV1-PCR only. RESULTS: HBoV1 was detected in NPAs from 10% of patients and 17% of controls. Adjusted for age, gender and the presence of other viruses, HBoV1 was not associated with RTI. In the HBoV1-positive NPAs, at least one other virus was detected in 75% and the virus appeared alone in 25%. Adjusted for age and gender, the detection of HBoV1 as the sole virus was associated with RTI, but not with LRTI. Viraemia was found only in children with RTI. The study showed that it was associated with RTI and LRTI. A high HBoV1-load was associated with LRTI, but not with RTI. No interactions between HBoV1 and other infectious agents were found. CONCLUSIONS: Our data support the hypothesis that HBoV1 causes RTI in children, because detection of HBoV1 alone, viraemia and high viral load are associated with RTI and/or LRTI in this age group. However, HBoV1 is common in healthy children. PMID- 20833583 TI - Could differential virological characteristics account for ongoing viral replication and insidious damage of the brain during HIV 1 infection of the central nervous system? AB - Neurocognitive disorders due to human immunodeficiency virus type 1 (HIV-1) infection have been reported in 25-60% of cases,(1-3) despite a sustained viral response in peripheral blood while on highly active anti-retroviral therapy (HAART). A possible reason may be that the central nervous system (CNS) is less accessible for anti-retroviral agents, therefore this sanctuary site can provide a reservoir for ongoing HIV-1 replication. Mutations conferring resistance to anti-retroviral drugs may predominate in compartments where drug levels are suboptimal. This review provides an overview on the literature regarding the development of resistance mutations and the sensitivity for co-receptors in CNS. Mutations caused by the anti-retroviral drugs with the lowest intracerebral penetration would be expected to be found in higher percentages in the CNS than in the periphery of the human body. However, few studies have been performed that can confirm or reject this claim. Zidovudine, the anti-retroviral drug with the best intracerebral penetration, has been studied to some extent. This drug indeed induces resistance mutations in blood as well as the CNS. HAART induces a switch from HIV that uses co-receptor CRR5 to HIV that uses co-receptor CXCR4. This switch may appear later in the CNS compartment compared to the periphery. However, current literature shows conflicting evidence. In conclusion, the current understanding of HIV-strain evolution under drug pressure in sanctuary sites like CNS is incomplete. Therefore, more research is needed in order to establish the role of these sites in the development of drug resistant mutants under adequate HAART. PMID- 20833584 TI - Neurofeedback training in ADHD: more news on specificity. PMID- 20833585 TI - An assessment of indoor air concentrations and health risks of volatile organic compounds in three primary schools. AB - Concentrations of volatile organic compounds (VOCs), including formaldehyde, in classrooms, kindergartens, and outdoor playgrounds of three primary schools were measured in spring, winter, and fall terms in Izmir, Turkey. A health-risk assessment was conducted for odor detection, sensory irritation, chronic toxic effects, and cancer. Active sampling was applied for VOCs and formaldehyde on Tenax TA and DNPH tubes, respectively. VOCs were analyzed in a thermal desorption GC-MS system. Formaldehyde analysis was performed using an HPLC instrument. Benzene, toluene, and formaldehyde were the most abundant compounds with 95th percentile indoor air concentrations of 29, 87, and 106 MUg/m(3), respectively. Naphthalene and xylenes followed them with an order of magnitude lower concentrations. Two isomers of dichlorobenzene (1,3 and 1,4) were the other notable compounds. The concentrations were utilized to classify the indoor air pollutants with respect to potential health effects. In addition, carcinogenic and chronic toxic risks were estimated using Monte-Carlo simulation. Formaldehyde appears to be the most concerning pollutant with high chronic toxic and carcinogenic risk levels according to the health assessment followed by naphthalene, benzene, and toluene due to their chronic effects. PMID- 20833586 TI - Evaluating the link between the management of clinical waste in the National Health Service (NHS) and the risk of the spread of infections: A case study of three hospitals in England. AB - This study aimed to evaluate waste management practices in three case study NHS Trusts in England and the potential risks of the spread of pathogens causing healthcare associated infections (HCAIs). Using a combination of microbiological techniques, interviews and questionnaire surveys, four target microbes were studied, namely: meticillin resistant Staphylococcus aureus (MRSA), meticillin sensitive Staphylococcus aureus (MSSA), Clostridium difficile (C. difficile) and vancomycin-resistant enterococci (VRE). Waste Flow Diagrams (WFDs) were used to map the flow of the waste. While there was a perceived link between the management of the waste and the spread of the microbes by staff, none of the target organisms were isolated. The findings suggest that when the waste is properly contained and managed that it should not pose a significant risk in terms of the spread of the four bacteria tested in this study. In addition, the results demonstrate that there is a need for staff perceptions and beliefs to be addressed in the development of policies and training related to infection control and its link to waste management. PMID- 20833587 TI - Methodological and practical application issues in exercise prescription using the heart rate reserve and oxygen uptake reserve methods. AB - Exercise intensity is an important aspect of enhancing health-related fitness. Relationships between the percentages of heart rate reserve (%HRR), maximal oxygen uptake (%VO(2max)) and oxygen uptake reserve (%VO2R) have been proposed as being effective for exercise intensity prescription. The present paper reviewed experimental studies published between 1966 and 2010, which investigated the relationships between the %HRR, %VO(2max) and %VO2R. The following aspects were focused upon: (a) comparisons of the relationships between %HRR, %VO(2max) and %VO2R at different exercise intensities; (b) methodological differences in determining resting VO2 and VO(2max) and associated effects on the above relationships; (c) applicability of the %HRR-%VO(2max) and %HRR-%VO2R relationships for exercise prescription. Fifteen studies published between 1997 and 2010 met inclusion criteria. Five studies observed the %HRR-%VO2R relationship, while the others also investigated the %HRR-%VO(2max) relationship. Six studies found that the %HRR was closer to the %VO2R than the %VO(2max). Most studies did not satisfy the recommended methodological criteria for assessing the resting VO2, or used incremental test protocols which may have underestimated VO(2max). None investigated the stability of the %HRR-%VO2R relationship in training conditions, such as during prolonged submaximal exercise. In conclusion, many of the reviewed studies presented methodological limitations that compromised their results in relation to the application of the %HRR-%VO2R relationship for prescribing aerobic training. PMID- 20833588 TI - Should pre-participation cardiovascular screening for competitive athletes be introduced in Australia? A timely debate in a sport-loving nation. AB - Pre-participation screening of all competitive athletes is recommended in some countries and mandated in others to prevent sudden cardiac death in predisposed athletes. Whilst the prevalence of some conditions, which are screened for such as coronary artery anomalies and long QT syndromes, are stable across different populations, the prevalence of underlying conditions such as hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia shows considerable geographic variability. Evidence exists that screening reduces sudden death, but the potential negative impact of exclusion from sport has not been quantified. Australia has a high rate of participation in sport and needs to consider whether screening is feasible, effective and affordable. It is difficult to make this decision currently as there is little information about the scope of the problem in Australia and whether the prevalence of underlying conditions which predispose to sudden cardiac death is similar or different to that in other countries. We review the evidence for and against screening and propose that systematic collection of Australian data is required before routine pre-participation screening can be introduced in Australia. PMID- 20833589 TI - Increased production through parasite control: can ancient breeds of sheep teach us new lessons? AB - With a rising world population and economic development, the global demand for meat, milk and other animal products is increasing dramatically. Controlling parasitic diseases in livestock, in particular helminth infections, could rapidly improve productivity and resource utilization. There is a growing interest in indigenous ruminant breeds because these animals have adapted to survive with minimal maintenance in the presence of high exposure to parasite infection. Recent findings on the mechanisms of parasite resistance in indigenous breeds are discussed, and the possibility that such studies may lead to new insight into the immunity and control of parasites proposed. These findings have important implications for the preservation of poorly characterized local indigenous breeds. PMID- 20833590 TI - Secondary prevention of stroke: can we do better than aspirin? PMID- 20833592 TI - Formative and process evaluations of a cognitive-behavioral therapy and mindfulness intervention for people with epilepsy and depression. AB - People with chronic diseases are at high risk for depression, resulting in a need for effective and accessible treatment options. Project UPLIFT is a program based on cognitive-behavioral therapy and mindfulness that is aimed at reducing depressive symptoms among people with epilepsy. It is designed to be delivered to small groups of people over the phone or Internet. This study describes the formative and process evaluations of Project UPLIFT; the purpose of these evaluations was to assess the acceptability and feasibility of the program, looking at both the program components and delivery methods. The formative evaluation, conducted prior to program implementation, included nine participants in three focus groups. The process evaluation included qualitative comments and responses to the Client Satisfaction Questionnaire from 38 Project UPLIFT pilot study participants. Overall, the results from both evaluations indicate that participants felt that Project UPLIFT was acceptable and perceived to be beneficial. PMID- 20833593 TI - Counterpoint: there is a dose-response relationship in the low-dose rate brachytherapy management of prostate cancer. PMID- 20833594 TI - Antibiotic hypersensitivity in CF: drug-induced life-threatening hemolytic anemia in a pediatric patient. AB - Adverse reactions to antibiotics in patients with cystic fibrosis (CF) are a growing concern. We report the case of a pediatric patient with CF with multiple comorbidities and a history of drug reactions, who developed life-threatening piperacillin-induced immune hemolytic anemia. We review drug-induced hemolytic anemia (DIIHA) in particular, and antibiotic hypersensitivity in CF in general, including the frequency, pathogenesis, and risk factors. Finally, we discuss the treatment options and propose an algorithm for the management of drug-induced hypersensitivity reactions in patients with CF. PMID- 20833595 TI - Mealtime interactions in families of a child with cystic fibrosis: a meta analysis. AB - BACKGROUND: A meta-analysis was performed to examine differences in family mealtimes between families with and without a child with CF. Both global measures of family functioning during the mealtime and parent-child micro behaviors specific to feeding were compared to determine if one class of mealtime behaviors is more strongly affected. METHODS: Of 41 studies identified, 10 studies across 4 independent samples met the criteria for study inclusion. All studies included observational methodology. The mean sample age ranged from 18.6 months to 8 years and 6 months. The total aggregate sample size was 230 participants, 119 with CF and 111 comparison children. RESULTS: Families with children with CF encounter more difficulties during mealtimes than comparison families, and the effects on overall family functioning are greater than for parent-child micro feeding behaviors. CONCLUSION: Findings suggest that future interventions should focus on the broader family context as well as behaviors specific to feeding. PMID- 20833596 TI - Preventing the development of body issues in adolescent girls through intervention with their mothers. AB - The purpose of this study was to test the efficacy of the Healthy Girls Project, an ecologically based, targeted prevention program aimed at discouraging the development of body-related problems in middle-school girls via an intervention directly and only with their mothers. Participants were 31 seventh- and eighth grade girls and their mothers. The empirically based intervention comprised a series of 4 weekly workshops that had both interactive psychoeducational components and behavioral components (e.g., homework to do with daughters, modeling activities). The study design was experimental, with mother-daughter dyads randomly assigned to either the intervention group or a wait-list control group. Daughters completed pretest (i.e., pre-workshop) measures, posttest measures, and, 3 months later, follow-up measures. Results indicated that at both posttest and follow-up, girls whose mothers were in the intervention group perceived less pressure from their mothers to be thin. At follow-up, these girls also showed a lower drive for thinness. Results were mixed regarding group differences in body dissatisfaction levels at posttest and at follow-up. Results are discussed in terms of their implications for targeted prevention efforts aimed at girls during their middle-school years. PMID- 20833597 TI - A combined fluorescence and microcomputed tomography system for small animal imaging. AB - Fluorescence molecular tomography (FMT) plays an important role in studying physiological and pathological processes of small animals in vivo at molecular level. However, this technique suffers from relatively low spatial resolution. To complement the problem, there has been a strong demand for providing functional and morphological analysis at the same time. In this paper, we proposed a hybrid full-angle free-space FMT and X-ray micro-cone-beam computed tomography (CT) (micro-CBCT) prototype system, providing both functional and anatomical images. During the whole acquisition, the two subsystems acquire projection images (fluorescence and CT) synchronously to keep consistent body position without moving the animals. The acquired datasets are intrinsically coregistered in the corresponding coordinate and identified geometry. Tomographic fluorescence and CT images are reconstructed using normalized Born-based spatial regularization and Feldkamp-Davis-Kress methods, respectively. The experimental results of both phantom and in vivo mouse preliminarily validate the accuracy and performance of the integrated system. PMID- 20833591 TI - Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. AB - BACKGROUND: The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS: Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1.33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS: Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2.76% (n=82) in the cilostazol group and 3.71% (n=119) in the aspirin group (hazard ratio 0.743, 95% CI 0.564-0.981; p=0.0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0.77%, n=23) than on aspirin (1.78%, n=57; 0.458, 0.296-0.711; p=0.0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION: Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING: Otsuka Pharmaceutical. PMID- 20833598 TI - Calculation of forward and backward arterial waves by analysis of two pressure waveforms. AB - We developed a technique to calculate forward and backward arterial waves from proximal and distal pressure waveforms. First, the relationship between the waveforms is represented with an arterial tube model. Then, the model parameters are estimated via least-squares fitting. Finally, the forward and backward waves are calculated using the parameter estimates. Thus, unlike most techniques, the arterial waves are determined without a more difficult flow measurement or an experimental perturbation. We applied the technique to central aortic and femoral artery pressure waveforms from anesthetized dogs during drug infusions, volume changes, and cardiac pacing. The calculated waves predicted an abdominal aortic pressure waveform measurement more accurately (2.4 mmHg error) than the analyzed waveforms (5.3 mmHg average error); reliably predicted relative changes in a femoral artery flow measurement (14.7% error); and changed as expected with selective vasoactive drugs. The ratio of the backward- to forward-wave magnitudes was 0.37 +/- 0.05 during baseline. This index increased by ~50% with phenylephrine and norepinephrine, decreased by ~60% with dobutamine and nitroglycerin, and changed little otherwise. The time delay between the waves in the central aorta was 175 +/- 14 ms during baseline. This delay varied by +/-~25% and was inversely related to mean pressure. PMID- 20833599 TI - Computational acceleration for MR image reconstruction in partially parallel imaging. AB - In this paper, we present a fast numerical algorithm for solving total variation and l(1) (TVL1) based image reconstruction with application in partially parallel magnetic resonance imaging. Our algorithm uses variable splitting method to reduce computational cost. Moreover, the Barzilai-Borwein step size selection method is adopted in our algorithm for much faster convergence. Experimental results on clinical partially parallel imaging data demonstrate that the proposed algorithm requires much fewer iterations and/or less computational cost than recently developed operator splitting and Bregman operator splitting methods, which can deal with a general sensing matrix in reconstruction framework, to get similar or even better quality of reconstructed images. PMID- 20833600 TI - Multiperiodicity of periodically oscillated discrete-time neural networks with transient excitatory self-connections and sigmoidal nonlinearities. AB - The existing approaches to the multistability and multiperiodicity of neural networks rely on the strictly excitatory self-interactions of neurons or require constant interconnection weights. For periodically oscillated discrete-time neural networks (DTNNs), it is difficult to discuss multistable dynamics when the connection weights are periodically oscillated around zero. By using transient excitatory self-interactions of neurons and sigmoidal nonlinearities, we develop an approach to investigate multiperiodicity and attractivity of periodically oscillated DTNNs with time-varying and distributed delays. It shows that, under some new criteria, there exist multiplicity results of periodic solutions which are locally or globally exponentially stable. Computer numerical simulations are performed to illustrate the new theories. PMID- 20833601 TI - Structured max-margin learning for inter-related classifier training and multilabel image annotation. AB - In this paper, a structured max-margin learning algorithm is developed to achieve more effective training of a large number of inter-related classifiers for multilabel image annotation application. To leverage multilabel images for classifier training, each multilabel image is partitioned into a set of image instances (image regions or image patches) and an automatic instance label identification algorithm is developed to assign multiple labels (which are given at the image level) to the most relevant image instances. A K-way min-max cut algorithm is developed for automatic instance clustering and kernel weight determination, where multiple base kernels are seamlessly combined to address the issue of huge intra-concept visual diversity more effectively. Second, a visual concept network is constructed for characterizing the inter-concept visual similarity contexts more precisely in the high-dimensional multimodal feature space. The visual concept network is used to determine the inter-related learning tasks directly in the feature space rather than in the label space because feature space is the common space for classifier training and image classification. Third, a parallel computing platform is developed to achieve more effective learning of a large number of inter-related classifiers over the visual concept network. A structured max-margin learning algorithm is developed by incorporating the visual concept network, max-margin Markov networks and multitask learning to address the issue of huge inter-concept visual similarity more effectively. By leveraging the inter-concept visual similarity contexts for inter-related classifier training, our structured max-margin learning algorithm can significantly enhance the discrimination power of the inter-related classifiers. Our experiments have also obtained very positive results for a large number of object classes and image concepts. PMID- 20833602 TI - On the selection of optimal feature region set for robust digital image watermarking. AB - A novel feature region selection method for robust digital image watermarking is proposed in this paper. This method aims to select a nonoverlapping feature region set, which has the greatest robustness against various attacks and can preserve image quality as much as possible after watermarked. It first performs a simulated attacking procedure using some predefined attacks to evaluate the robustness of every candidate feature region. According to the evaluation results, it then adopts a track-with-pruning procedure to search a minimal primary feature set which can resist the most predefined attacks. In order to enhance its resistance to undefined attacks under the constraint of preserving image quality, the primary feature set is then extended by adding into some auxiliary feature regions. This work is formulated as a multidimensional knapsack problem and solved by a genetic algorithm based approach. The experimental results for StirMark attacks on some benchmark images support our expectation that the primary feature set can resist all the predefined attacks and its extension can enhance the robustness against undefined attacks. Comparing with some well-known feature-based methods, the proposed method exhibits better performance in robust digital watermarking. PMID- 20833603 TI - Blind deconvolution using generalized cross-validation approach to regularization parameter estimation. AB - In this paper, we propose and present an algorithm for total variation (TV)-based blind deconvolution. Both the unknown image and blur can be estimated within an alternating minimization framework. With the generalized cross-validation (GCV) method, the regularization parameters associated with the unknown image and blur can be updated in alternating minimization steps. Experimental results confirm that the performance of the proposed algorithm is better than variational Bayesian blind deconvolution algorithms with Student's-t priors or a total variation prior. PMID- 20833604 TI - Restoration of Poissonian images using alternating direction optimization. AB - Much research has been devoted to the problem of restoring Poissonian images, namely for medical and astronomical applications. However, the restoration of these images using state-of-the-art regularizers (such as those based upon multiscale representations or total variation) is still an active research area, since the associated optimization problems are quite challenging. In this paper, we propose an approach to deconvolving Poissonian images, which is based upon an alternating direction optimization method. The standard regularization [or maximum a posteriori (MAP)] restoration criterion, which combines the Poisson log likelihood with a (nonsmooth) convex regularizer (log-prior), leads to hard optimization problems: the log-likelihood is nonquadratic and nonseparable, the regularizer is nonsmooth, and there is a nonnegativity constraint. Using standard convex analysis tools, we present sufficient conditions for existence and uniqueness of solutions of these optimization problems, for several types of regularizers: total-variation, frame-based analysis, and frame-based synthesis. We attack these problems with an instance of the alternating direction method of multipliers (ADMM), which belongs to the family of augmented Lagrangian algorithms. We study sufficient conditions for convergence and show that these are satisfied, either under total-variation or frame-based (analysis and synthesis) regularization. The resulting algorithms are shown to outperform alternative state-of-the-art methods, both in terms of speed and restoration accuracy. PMID- 20833605 TI - What's in the pool? A comprehensive identification of disinfection by-products and assessment of mutagenicity of chlorinated and brominated swimming pool water. AB - BACKGROUND: Swimming pool disinfectants and disinfection by-products (DBPs) have been linked to human health effects, including asthma and bladder cancer, but no studies have provided a comprehensive identification of DBPs in the water and related that to mutagenicity. OBJECTIVES: We performed a comprehensive identification of DBPs and disinfectant species in waters from public swimming pools in Barcelona, Catalonia, Spain, that disinfect with either chlorine or bromine and we determined the mutagenicity of the waters to compare with the analytical results. METHODS: We used gas chromatography/mass spectrometry (GC/MS) to measure trihalomethanes in water, GC with electron capture detection for air, low- and high-resolution GC/MS to comprehensively identify DBPs, photometry to measure disinfectant species (free chlorine, monochloroamine, dichloramine, and trichloramine) in the waters, and an ion chromatography method to measure trichloramine in air. We assessed mutagenicity with the Salmonella mutagenicity assay. RESULTS: We identified > 100 DBPs, including many nitrogen-containing DBPs that were likely formed from nitrogen-containing precursors from human inputs, such as urine, sweat, and skin cells. Many DBPs were new and have not been reported previously in either swimming pool or drinking waters. Bromoform levels were greater in brominated than in chlorinated pool waters, but we also identified many brominated DBPs in the chlorinated waters. The pool waters were mutagenic at levels similar to that of drinking water (approximately 1,200 revertants/L-equivalents in strain TA100-S9 mix). CONCLUSIONS: This study identified many new DBPs not identified previously in swimming pool or drinking water and found that swimming pool waters are as mutagenic as typical drinking waters. PMID- 20833606 TI - Genotoxic effects in swimmers exposed to disinfection by-products in indoor swimming pools. AB - BACKGROUND: Exposure to disinfection by-products (DBPs) in drinking water has been associated with cancer risk. A recent study (Villanueva et al. 2007; Am J Epidemiol 165:148-156) found an increased bladder cancer risk among subjects attending swimming pools relative to those not attending. OBJECTIVES: We evaluated adults who swam in chlorinated pools to determine whether exposure to DBPs in pool water is associated with biomarkers of genotoxicity. METHODS: We collected blood, urine, and exhaled air samples from 49 nonsmoking adult volunteers before and after they swam for 40 min in an indoor chlorinated pool. We estimated associations between the concentrations of four trihalomethanes (THMs) in exhaled breath and changes in micronuclei (MN) and DNA damage (comet assay) in peripheral blood lymphocytes before and 1 hr after swimming; urine mutagenicity (Ames assay) before and 2 hr after swimming; and MN in exfoliated urothelial cells before and 2 weeks after swimming. We also estimated associations and interactions with polymorphisms in genes related to DNA repair or to DBP metabolism. RESULTS: After swimming, the total concentration of the four THMs in exhaled breath was seven times higher than before swimming. The change in the frequency of micronucleated lymphocytes after swimming increased in association with higher exhaled concentrations of the brominated THMs (p = 0.03 for bromodichloromethane, p = 0.05 for chlorodibromomethane, p = 0.01 for bromoform) but not chloroform. Swimming was not associated with DNA damage detectable by the comet assay. Urine mutagenicity increased significantly after swimming, in association with the higher concentration of exhaled bromoform (p = 0.004). We found no significant associations with changes in micronucleated urothelial cells. CONCLUSIONS: Our findings support potential genotoxic effects of exposure to DBPs from swimming pools. The positive health effects gained by swimming could be increased by reducing the potential health risks of pool water. PMID- 20833607 TI - Short-term changes in respiratory biomarkers after swimming in a chlorinated pool. AB - BACKGROUND: Swimming in chlorinated pools involves exposure to disinfection by products (DBPs) and has been associated with impaired respiratory health. OBJECTIVES: We evaluated short-term changes in several respiratory biomarkers to explore mechanisms of potential lung damage related to swimming pool exposure. METHODS: We measured lung function and biomarkers of airway inflammation [fractional exhaled nitric oxide (FeNO), eight cytokines, and vascular endothelial growth factor (VEGF) in exhaled breath condensate], oxidative stress (8-isoprostane in exhaled breath condensate), and lung permeability [surfactant protein D (SP-D) and the Clara cell secretory protein (CC16) in serum] in 48 healthy nonsmoking adults before and after they swam for 40 min in a chlorinated indoor swimming pool. We measured trihalomethanes in exhaled breath as a marker of individual exposure to DBPs. Energy expenditure during swimming, atopy, and CC16 genotype (rs3741240) were also determined. RESULTS: Median serum CC16 levels increased from 6.01 to 6.21 microg/L (average increase, 3.3%; paired Wilcoxon test p = 0.03), regardless of atopic status and CC16 genotype. This increase was explained both by energy expenditure and different markers of DBP exposure in multivariate models. FeNO was unchanged overall but tended to decrease among atopics. We found no significant changes in lung function, SP-D, 8-isoprostane, eight cytokines, or VEGF. CONCLUSIONS: We detected a slight increase in serum CC16, a marker of lung epithelium permeability, in healthy adults after they swam in an indoor chlorinated pool. Exercise and DBP exposure explained this association, without involving inflammatory mechanisms. Further research is needed to confirm the results, establish the clinical relevance of short-term serum CC16 changes, and evaluate the long-term health impacts. PMID- 20833608 TI - Evaluating the evidence for over-the-counter alternatives for relief of hot flashes in menopausal women. AB - OBJECTIVE: To review the literature on alternative over-the-counter (OTC) therapies for the treatment of hot flashes in menopausal women. DATA SOURCES: A literature search was conducted using PubMed, International Pharmaceutical Abstracts, and Medline from inception to June 2010, combining the term hot flash individually with black cohosh, isoflavones, red clover, soy, vitamin E, ginseng, dong quai, evening primrose oil, wild yam, kava, and melatonin. All publication types including human participants and published in English were eligible for review. These articles, relevant abstracts, and additional references were used to collect pertinent data. STUDY SELECTION AND DATA EXTRACTION: Clinical trials comparing the above single-ingredient agents with placebo or active treatment were selected. In addition, only studies assessing the effects of these single ingredient agents on vasomotor symptoms in menopausal women were included. DATA SYNTHESIS: Since the Women's Health Initiative and Heart and Estrogen/Progestin Replacement Study II, women have sought lifestyle changes and other drug therapies as alternatives to menopausal hormone therapy to relieve hot flashes associated with menopause. The currently available literature is conflicting in regard to efficacy and does not support the use of alternative OTC therapies for hot flash management associated with menopause. In addition, long-term safety data are lacking for any of these therapies. CONCLUSION: Women should be encouraged to implement therapeutic lifestyle changes to assist them with hot flash management. Based on the current literature, alternative OTC therapies do not have consistent, beneficial data to support their use in hot flash management. PMID- 20833609 TI - Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke prevention. AB - OBJECTIVE: To review the available literature on the effects of angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs) or combinations of these agents on stroke outcomes in hypertensive patients. DATA SOURCES: A Medline search was conducted using the search terms stroke and antihypertensives, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers from 1985 to August 17, 2009. STUDY SELECTION: Randomized controlled clinical trials with at least 400 randomized patients were selected if at least one of the treatment arms used a CCB, ACEI, or ARB to evaluate stroke outcomes in hypertensive patients. DATA SYNTHESIS: The prevalence of stroke is high in the United States, accounting for approximately 150,000 deaths per year. Early identification and treatment of hypertension to quickly achieve blood pressure reduction is critical in the prevention of stroke. Many trials have provided evidence that CCBs, ACEIs, and ARBs are effective in stroke prevention. Most patients require two or more antihypertensive drugs to achieve blood pressure goals. Because of their complementary actions, combination antihypertensive therapy with a renin-angiotensin-aldosterone system (RAAS) blocker and a CCB may help reduce stroke incidence to a greater extent than either of the monotherapies. CONCLUSION: A growing body of clinical trial data suggest that aggressive combination antihypertensive therapy, including a RAAS blocker and CCB, may help reduce stroke incidence. Fixed-dose combination therapy is an important consideration in optimizing blood pressure control and patient adherence to therapy in stroke prevention. PMID- 20833611 TI - Safer use of medications through risk evaluation and mitigation strategies: Academy perspectives. PMID- 20833613 TI - Tobacco users' perceptions of a brief tobacco cessation intervention in community pharmacies. AB - OBJECTIVE: To explore factors affecting tobacco users' perceived appropriateness of a brief and proactive tobacco cessation counseling program, ask, advise, and refer (AAR), at community pharmacies. DESIGN: Inductive thematic analysis. SETTING: Southern Wisconsin during fall 2008. PATIENTS: 24 tobacco users who had recently received brief and proactive tobacco cessation counseling at a community pharmacy. INTERVENTION: Semistructured telephone interviews conducted by primary author. MAIN OUTCOME MEASURES: Perceptions of a brief and proactive tobacco cessation counseling program conducted at community pharmacies. RESULTS: In conducting the thematic analysis, eight distinct themes were identified. Display of information and resources at pharmacies for use by tobacco users as needed was identified as the most predominant theme and was found to be most helpful by many respondents. Other themes identified in decreasing order of prevalence were: tobacco users' perceptions of the role of pharmacists in health care, tobacco users' belief that smoking could interact with a current medication or health condition, tobacco users' sensitivity toward their tobacco use behavior or being told what to do, nonconfrontational and friendly approach of pharmacists, tobacco users' readiness to quit at the time of AAR counseling, tobacco user initiation of tobacco use discussion, and tobacco users' belief that tobacco use is bad. CONCLUSION: Overall, this qualitative investigation suggests that several factors might influence tobacco users' perceived appropriateness of AAR counseling at community pharmacies. AAR might be well received by tobacco users and pharmacy patrons as long as it is done in a professional and respectful manner. PMID- 20833614 TI - Tobacco treatment practices of pharmacists in Montana. AB - OBJECTIVES: To assess the tobacco treatment practices of Montana pharmacists, evaluate pharmacist interest in addressing tobacco use, and identify perceived barriers to delivery of tobacco cessation services. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: Montana in February 2007. PARTICIPANTS: 192 pharmacists attending an annual continuing professional education program. INTERVENTION: Attendees at 11 meeting sites throughout the state completed the survey. MAIN OUTCOME MEASURES: Pharmacists' use of the U.S. Clinical Practice Guideline 5 A's (ask, advise, assess, assist, and arrange) in regard to tobacco cessation services. RESULTS: Of program attendees, 76% (192 of 253) completed the 35-item survey. More than one-half (58%) of respondents were men, and 90% were white. Respondents were licensed for a median of 22.5 years and dispensed a median of 1,000 prescriptions per week. The percent of pharmacists who treated one or more patients using the 5 A's in the preceding 30 days were as follows: asked about tobacco use, 39%; advised to quit smoking, 54%; assessed for readiness to quit smoking, 36%; assisted with quitting (i.e., cessation counseling), 46%; assisted with advice to use nonprescription cessation medication, 62%; assisted with advice to use prescription cessation medication, 54%; arranged for a follow-up appointment for additional counseling, 6%; and referred to a tobacco quit line, 23%. Most respondents (58%) reported that providing cessation services within routine practice was moderately or highly feasible. The most frequently cited barriers to providing cessation services included lack of time (52%), reimbursement (26%), and training (19%). CONCLUSION: Few Montana pharmacists are routinely asking patients about tobacco use in a typical month. However, the majority of pharmacists reported that it would be feasible to provide more tobacco cessation activities within routine pharmacy practice. Addressing barriers related to workload, reimbursement, and training would likely increase the number of pharmacists who provide tobacco cessation services. PMID- 20833615 TI - Individual- and neighborhood-level factors associated with nonprescription counseling in pharmacies participating in the New York State Expanded Syringe Access Program. AB - OBJECTIVE: To determine the individual- and neighborhood-level predictors of frequent nonprescription in-pharmacy counseling. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: New York City (NYC) during January 2008 to March 2009. INTERVENTION: 130 pharmacies registered in the Expanded Syringe Access Program (ESAP) completed a survey. PARTICIPANTS: 477 pharmacists, nonpharmacist owners/managers, and technicians/clerks. MAIN OUTCOME MEASURES: Frequent counseling on medical conditions, health insurance, and other products. RESULTS: Technicians were less likely than pharmacists to provide frequent counseling on medical conditions or health insurance. Regarding neighborhood-level characteristics, pharmacies in areas of high employment disability were less likely to provide frequent health insurance counseling and pharmacies in areas with higher deprivation were more likely to provide counseling on other products. CONCLUSION: ESAP pharmacy staff members are a frequent source of nonprescription counseling for their patients in disadvantaged neighborhoods of NYC. These findings suggest that ESAP pharmacy staff may be amenable to providing relevant counseling services to injection drug users and warrant further investigation. PMID- 20833616 TI - Factors influencing community pharmacists' enrollment in a state prescription monitoring program. AB - OBJECTIVES: To determine factors influencing enrollment for community pharmacists registered and not registered in Ohio's prescription monitoring program (PMP), the Ohio Automated Rx Reporting System (OARRS); to identify association of OARRS enrollment with demographics, availability of Internet access at work, educational background, and/or previous PMP education received; and to compare knowledge of OARRS for enrollees versus nonenrollees. DESIGN: Descriptive, nonexperimental, cross-sectional study. SETTING: Ohio in November and December 2008. PARTICIPANTS: Pharmacists licensed and living in Ohio with a valid e-mail address on file with the state board of pharmacy. INTERVENTION: Online survey developed and administered via Zoomerang. MAIN OUTCOME MEASURE: Factors influencing enrollment for community pharmacists registered and not registered with OARRS. RESULTS: 2,511 complete responses were recorded, and 1,434 respondents indicated community pharmacy as their primary practice setting. Pharmacists not registered with OARRS noted "time available to access the OARRS report" as the top factor influencing their decision not to enroll in OARRS. Pharmacists registered with OARRS noted "being able to assist with decreasing doctor shopping" as the top factor influencing their decision to enroll in OARRS. CONCLUSION: Factors influencing enrollment as indicated by pharmacists not registered with OARRS should be the primary focus of initial efforts to increase enrollment. PMID- 20833617 TI - Evaluation of nonprescription syringe sales in San Francisco. AB - OBJECTIVE: To determine the experiences, practices, and challenges associated with nonprescription syringe sales (NPSS) among pharmacists whose pharmacies were enrolled in the Disease Prevention Demonstration Project in San Francisco, CA. METHODS: Self-administered survey mailed to 69 pharmacies and interviews with pharmacists and technicians. RESULTS: A total of 55 of 69 pharmacies (80%) returned the survey, and eight pharmacy managers and three pharmacy technicians were interviewed in person. Of pharmacists, 72% reported none or very few problems with NPSS in the previous year, although surveys and interviews illustrated challenges associated with NPSS in terms of time management, educating patients about syringe disposal, and understanding patient preferences for syringes. Of pharmacists, 62% reported NPSS to no more than 10 to 20 patients per week and 67% collected more than 400 syringes in the previous year. One-third of pharmacists perceived that their pharmacies were located in areas where drug activity was high and that the majority of NPSS patients injected illegal drugs. CONCLUSION: Access to sterile syringes is a prominent public health issue, and pharmacists can play an important role in injection drug user (IDU) education and disease prevention. This evaluation suggests that pharmacies are selling nonprescription syringes to individuals perceived to be IDUs with no major problems. Additional evaluations from health department programs are needed to demonstrate the efficacy of NPSS in California. PMID- 20833618 TI - Pharmaceuticals in drinking water: local analysis of the problem and finding a solution through awareness. AB - OBJECTIVES: To evaluate public awareness of pharmaceuticals in drinking water and to develop educational efforts to promote awareness in our community. METHODS: A review of the literature was conducted to gain a full perspective of the current issue. Questionnaires, interviews, and website feedback were used to assess awareness of the problem and the most commonly used medication disposal methods. In addition, educational flyers were created to disseminate information to the public. RESULTS: The questionnaires were completed by a total of 96 respondents. Of respondents employed in health care, 72% had previous knowledge of pharmaceutical medications being found in our local (Charleston, SC) water supply, and of respondents not employed in health care, 54% had previous knowledge. For those with previous knowledge, 7% disposed of medications in the toilet or sink, 38% used the trash, and 36% used multiple methods. Of respondents indicating no previous knowledge, 3% disposed of medications in the toilet or sink, 35% used the trash, and 42% used multiple methods. CONCLUSION: Public awareness of pharmaceuticals in drinking water and educational efforts focusing on proper disposal of medications are essential in helping to reduce drinking water contamination. PMID- 20833619 TI - Preventing unintended pregnancy: pharmacists' roles in practice and policy via partnerships. AB - OBJECTIVES: To review the literature regarding pharmacists' roles in preventing unintended pregnancy, review the relevant laws and policies in the United States to describe pharmacists' and/or pharmacy's role in policy development related to unintended pregnancy, and identify partners who pharmacists can work with in this public health area. DATA SOURCES: A systematic review was conducted focusing on the role of pharmacists in unintended pregnancy. For practice, articles were identified in Medline through July 1, 2009, using MeSH and keywords. For policy, two authors examined the current status of access issues related to over-the counter (OTC) status and collaborative practice agreements. Partners were identified in the reviews and authors' experiences. DATA EXTRACTION: English language, U.S.-based articles that contained either qualitative or quantitative data or were review articles addressing pharmacist interventions, pharmacists' knowledge and attitudes regarding contraception, and pharmacists' comfort and ability to counsel on preventing unintended pregnancy were included. DATA SYNTHESIS: Some improvements to emergency contraception (EC) access in pharmacies have occurred during the previous decade. Studies focused on counseling, pharmacist provision of depot reinjection, and pharmacist initiation of oral contraceptives were positive. No studies linked increased contraceptive access in pharmacies to lower pregnancy rates. In terms of policy, the literature described three access-related areas, including (1) EC and conscience clauses, (2) collaborative practice agreements, and (3) changes in prescription to OTC status. Pharmacists' partnerships may include physicians/clinicians, local health departments, family-planning organizations, nongovernmental organizations, and colleges of pharmacy. CONCLUSION: Currently, pharmacists may increase access to contraceptives primarily via EC and use of collaborative practice agreements to initiate and/or continue hormonal contraceptives. New practice models should be implemented in community or clinic practices as allowed by collaborative practice regulations in each state. We encourage researchers and practitioners to consider a community approach in their endeavors by working with numerous types of primary care providers and organizations to explore ways to increase contraceptive access. PMID- 20833620 TI - From dispensing to disposal: the role of student pharmacists in medication disposal and the implementation of a take-back program. AB - OBJECTIVES: To decrease the amount of pharmaceuticals present in our community's water supply, reduce the accidental and intentional ingestion of pharmaceuticals, and increase awareness of proper medication disposal. SETTING: Knoxville, TN, from November 2008 to November 2009. PRACTICE DESCRIPTION: Medication and thermometer collection events were held at various community retail establishments. Community officials and students collaborated to plan advertising, implementation, and appropriate medication and thermometer disposal. Event volunteers set up easily accessible tents and tables in high-traffic areas to collect unused medications, mercury thermometers, and recyclable medication bottles. PRACTICE INNOVATION: Student pharmacists worked cooperatively with community partners to collect unused medications and exchange thermometers. MAIN OUTCOME MEASURES: Pounds of recyclables collected, pounds of medications collected, and number of thermometers exchanged. RESULTS: The events increased community awareness of appropriate medication disposal and pharmacists' roles in safe use of medications. From November 2008 to November 2009, more than 1,100 pounds of unwanted medications were collected through events and the drop box. Additionally, more than 470 pounds of recyclable packaging material was collected and 535 mercury thermometers exchanged. CONCLUSION: Student pharmacists can partner with community officials and businesses to provide safe and appropriate medication and mercury thermometer disposal. PMID- 20833621 TI - Adverse event associated with a change in nonprescription syringe sale policy. AB - OBJECTIVE: To report and describe the possible correlation of a change in syringe sale policy at a community pharmacy with an adverse clinical outcome. SETTING: Providence, RI, in summer 2009. PATIENT DESCRIPTION: 27-year-old white woman with a long-standing history of chronic relapsing opiate addiction and human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. CASE SUMMARY: The patient presented to the hospital emergency department with 5 days of severe diffuse pain, swelling in her hands and feet, and several days of rigors with fevers, sweats, and chills. She was diagnosed with sepsis resulting from a disseminated methicillin-resistant Staphylococcus aureus (MRSA) infection. The patient was treated with intravenous antibiotics, neurosurgical drainage of an epidural abscess, intensive care unit care for 1 week, and acute hospitalization for 8 weeks. MAIN OUTCOME MEASURES: Not applicable. RESULTS: A few weeks before the patient was hospitalized, pharmacists at her local neighborhood pharmacy decided to stop selling syringes in packages of 10. Instead, syringes were sold at a minimum quantity of 100. The patient did not know where to obtain sterile syringes and began reusing syringes. CONCLUSION: The patient introduced pathogenic bacteria from her skin into her bloodstream through unsafe injection practices. The change in syringe sale policy at her local pharmacy likely inadvertently contributed to this severe and life-threatening situation. Consideration of the implications of syringe sale policy must include an understanding of the barriers that influence individual pharmacist's decisions regarding particular store policies that affect over-the-counter syringe sales. Legalized sale of nonprescription syringes in community pharmacies alone is not enough to curb the epidemic of unsafe injection practices in the United States. All medical risks that are inherent in the use of unsafe syringes, including blood-borne viral pathogens (e.g., HIV, HCV) and bacterial infections (e.g., MRSA), should be considered. PMID- 20833622 TI - Diabetes care: model for the future of primary care. AB - OBJECTIVE: To review relevant trends threatening primary care and the evidence supporting use of nonphysicians in primary and chronic care of patients with diabetes. DATA SOURCES: Current medical and pharmacy literature as selected by authors. SUMMARY: The care needed by patients with diabetes does not fit well into our current medical model for primary care, and an adequate supply of physicians is not likely to be available for primary care roles in coming years. Patients with diabetes who are placed on evidence-based regimens, are educated about their disease, are coached in ways that motivate them to lose weight and adopt other therapeutic lifestyle changes, and are adhering to and persisting with therapy will soon have improved clinical parameters. These quickly translate into fewer hospitalizations and emergency department visits. A growing body of literature supports the use of pharmacists and other nonphysicians in meeting the needs of patients with diabetes. Pharmacists should join nurse practitioners, specially trained nurses, and physician assistants as integral members of the health care team in providing care to patients with diabetes and, by logical extension, other chronic conditions. CONCLUSION: Demand for primary care is likely to outstrip the available supply of generalist physicians in the coming years. In addition to nurse practitioners and physician assistants, pharmacists should be considered for key roles in future interdisciplinary teams that triage and provide direct care to patients, including those with diabetes and other chronic conditions. PMID- 20833624 TI - Clifton Joseph Latiolais (1926-1995): enthusiasm for excellence. PMID- 20833625 TI - Did a wolf cry 'pandemic'? PMID- 20833626 TI - New drugs: Denosumab, dienogest/estradiol valerate, and polidocanol. PMID- 20833627 TI - Science snippets. Cost containment and schizophrenia, patient satisfaction, and medication information. PMID- 20833628 TI - Genomewide characterization of the light-responsive and clock-controlled output pathways in Lotus japonicus with special emphasis of its uniqueness. AB - During the last decade, tremendous progress has been made in understanding the molecular mechanisms underlying the plant circadian clock in Arabidopsis thaliana, mainly taking advantage of the availability of its entire genomic sequence. It is also well understood how the clock controls the photomorphogenesis of seedlings, including the shade avoidance response, and how the clock controls the photoperiodic flowering time in the spring annual long days herb A. thaliana. Based on this, here we attempt to shed light on these clock-controlled fundamental and physiological events in Lotus japonicus, which is a perennial temperate legume with a morphological nature quite different from Arabidopsis. In the Lotus database, we first compiled as many clock-, light-, and flowering-associated coding sequences as possible, which appear to be orthologous or homologous to the Arabidopsis counterparts. Then we focused on the PHYTOCHROME INTERACTING FACTOR4 (PIF4)-mediated photomorphogenic pathway and the FLOWERING LOCUS T (FT)-mediated photoperiodic flowering pathway. It was shown in L. japonicus that the putative LjPIF4 homologue is expressed in a manner dependent on the circadian clock, and the putative LjFT orthologue is expressed coincidentally and especially in the long-days conditions, as in the case of A. thaliana. LjFT is capable of promoting flowering in A. thaliana, whereas the function of LjPIF4 seems to be divergent to a certain extent from that of AtPIF4. These results are discussed with emphasis on the intriguing differences between these model plant species. PMID- 20833629 TI - Programmed cell death of the megagametophyte during post-germinative growth of white spruce (Picea glauca) seeds is regulated by reactive oxygen species and the ubiquitin-mediated proteolytic system. AB - The megagametophyte of white spruce (Picea glauca) seeds undergoes programmed cell death following seed germination. This process is characterized by distinct morphological and biochemical features, such as DNA fragmentation and the induction of proteases. Biphasic production of hydrogen peroxide was detected in the megagametophyte following seed germination. ROS scavengers or inhibitors of ROS production decreased caspase-like protease activity and slowed the progression of cell death. One catalase (CAT) of white spruce reacted with antibodies directed against cotton-seed CAT. The corresponding CAT gene was cloned and compared with the catalase genes of other plant species. The activity of the white spruce CAT enzyme was stimulated by tyrosine phosphorylation. The phosphorylated CAT was subjected to ubiquitination and degraded by the proteasome. Furthermore, the proteasome inhibitor MG132 inhibited the degradation of CAT and delayed cell death. These results suggest that the interplay of CAT and the ubiquitin-mediated proteolytic system is critical in the control of ROS production and subsequent cell death. PMID- 20833630 TI - Mechanisms of control of microRNA biogenesis. AB - MicroRNAs (miRNAs) are a class of ~22 nt non-coding RNAs that control diverse biological functions in animals, plants and unicellular eukaryotes by promoting degradation or inhibition of translation of target mRNAs. miRNA expression is often tissue specific and developmentally regulated. Aberrant expression of miRNAs has been linked to developmental abnormalities and human diseases, including cancer and cardiovascular disorders. The recent identification of mechanisms of miRNA biogenesis regulation uncovers that various factors or growth factor signalling pathways control every step of the miRNA biogenesis pathway. Here, we review the mechanisms that control the regulation of miRNA biogenesis discovered in human cells. Further understanding of the mechanisms that control of miRNA biogenesis may allow the development of tools to modulate the expression of specific miRNAs, which is crucial for the development of novel therapies for human disorders derived from aberrant expression of miRNAs. PMID- 20833631 TI - MitoGenesisDB: an expression data mining tool to explore spatio-temporal dynamics of mitochondrial biogenesis. AB - Mitochondria constitute complex and flexible cellular entities, which play crucial roles in normal and pathological cell conditions. The database MitoGenesisDB focuses on the dynamic of mitochondrial protein formation through global mRNA analyses. Three main parameters confer a global view of mitochondrial biogenesis: (i) time-course of mRNA production in highly synchronized yeast cell cultures, (ii) microarray analyses of mRNA localization that define translation sites and (iii) mRNA transcription rate and stability which characterize genes that are more dependent on post-transcriptional regulation processes. MitoGenesisDB integrates and establishes cross-comparisons between these data. Several model organisms can be analyzed via orthologous relationships between interspecies genes. More generally this database supports the 'post transcriptional operon' model, which postulates that eukaryotes co-regulate related mRNAs based on their functional organization in ribonucleoprotein complexes. MitoGenesisDB allows identifying such groups of post-trancriptionally regulated genes and is thus a useful tool to analyze the complex relationships between transcriptional and post-transcriptional regulation processes. The case of respiratory chain assembly factors illustrates this point. The MitoGenesisDB interface is available at http://www.dsimb.inserm.fr/dsimb_tools/mitgene/. PMID- 20833632 TI - Asymmetric DNA recognition by the OkrAI endonuclease, an isoschizomer of BamHI. AB - Restriction enzymes share little or no sequence homology with the exception of isoschizomers, or enzymes that recognize and cleave the same DNA sequence. We present here the structure of a BamHI isoschizomer, OkrAI, bound to the same DNA sequence (TATGGATCCATA) as that cocrystallized with BamHI. We show that OkrAI is a more minimal version of BamHI, lacking not only the N- and C-terminal helices but also an internal 3(10) helix and containing beta-strands that are shorter than those in BamHI. Despite these structural differences, OkrAI recognizes the DNA in a remarkably similar manner to BamHI, including asymmetric contacts via C terminal 'arms' that appear to 'compete' for the minor groove. However, the arms are shorter than in BamHI. We observe similar DNA-binding affinities between OkrAI and BamHI but OkrAI has higher star activity (at 37 degrees C) compared to BamHI. Together, the OkrAI and BamHI structures offer a rare opportunity to compare two restriction enzymes that work on exactly the same DNA substrate. PMID- 20833633 TI - Coupling of transcription and replication machineries in lambda DNA replication initiation: evidence for direct interaction of Escherichia coli RNA polymerase and the lambdaO protein. AB - Transcription proceeding downstream of the lambda phage replication origin was previously shown to support initial steps of the lambda primosome assembly in vitro and to regulate frequency and directionality of lambda DNA replication in vivo. In this report, the data are presented indicating that the RNA polymerase beta subunit makes a direct contact with the lambdaO protein, a replication initiator of lambda phage. These results suggest that the role of RNA polymerase during the initiation of lambda phage DNA replication may be more complex than solely influencing DNA topology. Results demonstrated in this study also show that gyrase supercoiling activity stimulates the formation of a complex between lambdaO and RNA polymerase, suggesting that the introduction of negative supercoils by DNA gyrase, besides lowering the energy required for DNA strand separation, may play an additional role in modeling protein-protein interactions at early steps of DNA replication initiation. PMID- 20833634 TI - Walking of antitumor bifunctional trinuclear PtII complex on double-helical DNA. AB - The trinuclear BBR3464 ([{trans-PtCl(NH(3))(2)}(2)u-(trans Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+)) belongs to the polynuclear class of platinum-based anticancer agents. DNA adducts of this complex differ significantly in structure and type from those of clinically used mononuclear platinum complexes, especially, long-range (Pt, Pt) intrastrand and interstrand cross-links are formed in both 5'-5' and 3'-3' orientations. We show employing short oligonucleotide duplexes containing single, site-specific cross-links of BBR3464 and gel electrophoresis that in contrast to major DNA adducts of clinically used platinum complexes, under physiological conditions the coordination bonds between platinum and N7 of G residues involved in the cross links of BBR3464 can be cleaved. This cleavage may lead to the linkage isomerization reactions between this metallodrug and double-helical DNA. Differential scanning calorimetry of duplexes containing single, site-specific cross-links of BBR3464 reveals that one of the driving forces that leads to the lability of DNA cross-links of this metallodrug is a difference between the thermodynamic destabilization induced by the cross-link and by the adduct into which it could isomerize. The rearrangements may proceed in the way that cross links originally formed in one strand of DNA can spontaneously translocate from one DNA strand to its complementary counterpart, which may evoke walking of the platinum complex on DNA molecule. PMID- 20833635 TI - HIV-1 RT-dependent DNAzyme expression inhibits HIV-1 replication without the emergence of escape viruses. AB - DNAzymes are easier to prepare and less sensitive to chemical and enzymatic degradation than ribozymes; however, a DNA enzyme expression system has not yet been developed. In this study, we exploited the mechanism of HIV-1 reverse transcription (RT) in a DNA enzyme expression system. We constructed HIV-1 RT dependent lentiviral DNAzyme expression vectors including the HIV-1 primer binding site, the DNA enzyme, and either a native tRNA (Lys-3), tR(M)DtR(L), or one of two truncated tRNAs (Lys-3), tR(M)DDeltaARMtR(L) or tR(M)D3'-endtR(L). Lentiviral vector-mediated DNAzyme expression showed high levels of inhibition of HIV-1 replication in SupT1 cells. We also demonstrated the usefulness of this approach in a long-term assay, in which we found that the DNAzymes prevented escape from inhibition of HIV. These results suggest that HIV-1 RT-dependent lentiviral vector-derived DNAzymes prevent the emergence of escape mutations. PMID- 20833637 TI - Positioning to get out of meiosis: the asymmetry of division. AB - BACKGROUND: During meiosis, mammalian oocytes undergo two successive cell divisions without an intermediate replicative phase. This brief period, called 'meiotic maturation', is crucial for the formation of an egg capable of being fertilized and of generating viable and euploid offspring. METHODS: We review our current knowledge of the cellular and molecular mechanisms that control asymmetry and appear to be shared between mammalian species, as well as the associated misfunctions that impair the formation of functional female gametes. RESULTS AND CONCLUSIONS: The two successive divisions that comprise mammalian oogenesis are asymmetric. They lead to the formation of small polar bodies and the large and polarized egg. This asymmetry depends upon the dynamic organization of the oocyte cytoskeleton during both divisions. During meiosis I, microfilaments and associated molecules ensure the targeting of the microtubule spindle at the oocyte periphery. During meiosis II, they anchor the spindle under the plasma membrane. In parallel, the cortex overhanging the spindle is dramatically reorganized. Establishment and maintenance of this cortical domain are crucial for the completion of fertilization. Loss of this differentiated area is characteristic of ageing or low-quality gametes and associated with increased maternal age or post-ovulatory ageing. PMID- 20833636 TI - p53 activates the PANK1/miRNA-107 gene leading to downregulation of CDK6 and p130 cell cycle proteins. AB - The tumor suppressor p53 is a central regulator of cell-cycle arrest and apoptosis by acting as a transcription factor to regulate numerous genes. We identified all human p53-regulated mRNAs by microarray analyses and searched for protein-coding genes which contain intronic miRNAs. Among others, this analysis yielded the panthothenate kinase 1 (PANK1) gene and its intronic miRNA-107. We showed that miRNA-107 and PANK1 are coregulated by p53 in different cell systems. The PANK1 protein, which catalyzes the rate-limiting step of coenzyme A biosynthesis, is also upregulated by p53. We observed that p53 directly activates PANK1 and miRNA-107 transcription through a binding site in the PANK1 promoter. Furthermore, p53 is recruited to the PANK1 promoter after DNA damage. In order to get more insight into miRNA-107 function we investigated its potential target genes. Cell-cycle regulators are significantly enriched among predicted miRNA-107 targets. We found miRNA-107-dependent regulation of two important regulators of G(1)/S progression, CDK6 and the RB-related 2 gene RBL2 (p130). CDK6 and p130 proteins are downregulated upon miRNA-107 expression. Our results uncover a novel miRNA-dependent signaling pathway which leads to downregulation of cell cycle proteins in the absence of transcriptional repression. PMID- 20833638 TI - Oral contraceptives and risk of endometriosis: a systematic review and meta analysis. AB - BACKGROUND: Combined oral contraceptives (OCs) inhibit ovulation, substantially reduce the volume of menstrual flow and may hypothetically interfere with implantation of refluxed endometrial cells. The aim of this review is to establish if OC use influences the risk of endometriosis. METHODS: We performed a MEDLINE search to identify all studies published in the last four decades (January 1970 to January 2010) in the English language on the relationship between OC exposure and risk of endometriosis. Two authors abstracted data on standardized forms. RESULTS: We identified 608 potentially relevant studies and 18 studies (6 cross-sectional, 7 case-control and 5 cohort) were selected. Pooling of the results derived from all the included reports independently from study design, yielded a common relative risk of 0.63 [95% confidence interval (CI), 0.47-0.85] for current OC users, 1.21 (95% CI, 0.94-1.56) for past users and 1.19 (95% CI, 0.89-1.60) for ever users. Methodological drawbacks, such as uncertain temporal relationship between exposure and outcome in cross-sectional studies and suboptimal selection of controls in case-control studies, limit the quality of the available evidence. CONCLUSIONS: The risk of endometriosis appears reduced during OC use. However, it is not possible to exclude the possibility that the apparent protective effect of OC against endometriosis is the result of postponement of surgical evaluation due to temporary suppression of pain symptoms. Confounding by selection and indication biases may explain the trend towards an increase in risk of endometriosis observed after discontinuation, but further clarification is needed. To date, the hypothesis of recommending OCs for primary prevention of endometriosis does not seem sufficiently substantiated. PMID- 20833639 TI - Exercise therapy in polycystic ovary syndrome: a systematic review. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 8-12% of women. Lifestyle modification, including increased physical activity, is the first-line approach in managing PCOS. A systematic review was performed to identify and describe the effect of exercise as an independent intervention on clinical outcomes in PCOS. METHODS: Five databases were searched with no time limit. A pre-specified definition of PCOS was not used. Studies were included if exercise therapy (aerobic and/or resistance) could be evaluated as an independent treatment against a comparison group. Outcomes measured included cardiovascular risk factors [insulin resistance (IR), lipid profiles, blood pressure and weight] and reproductive measures (ovulation, menstrual regularity and fertility outcomes). Quality analysis was performed based on the Cochrane Handbook of Systematic Reviews and the Quality of Reporting of Meta-Analyses checklist. RESULTS: Eight manuscripts were identified (five randomized controlled trials and three cohort studies). All studies involved moderate intensity physical activity and most were of either 12 or 24 weeks duration with frequency and duration of exercise sessions ranging between studies. The most consistent improvements included improved ovulation, reduced IR (9-30%) and weight loss (4.5 10%). Improvements were not dependant on the type of exercise, frequency or length of exercise sessions. CONCLUSIONS: Exercise-specific interventions in PCOS are limited. Studies vary considerably in design, intensity and outcome measures; therefore conclusive results remain elusive. Larger, optimally designed studies are needed to both gain insights into the mechanisms of exercise action and to evaluate the public health impact of exercise of PCOS. PMID- 20833643 TI - Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: a definitive study using only bone-erosive ACPA-negative rheumatoid arthritis. AB - OBJECTIVES: ACPA is a highly specific marker for RA. It was recently reported that ACPA can be used to classify RA into two disease subsets, ACPA-positive and ACPA-negative RA. ACPA-positive RA was found to be associated with the HLA-DR shared epitope (SE), but ACPA negative was not. However, the suspicion remained that this result was caused by the ACPA-negative RA subset containing patients with non-RA diseases. We examined whether this is the case even when possible non RA ACPA-negative RA patients were excluded by selecting only patients with bone erosion. METHODS: We genotyped HLA-DRB1 alleles for 574 ACPA-positive RA, 185 ACPA-negative RA (including 97 erosive RA) and 1508 healthy donors. We also tested whether HLA-DR SE is associated with RF-negative or ANA-negative RA. RESULTS: ACPA-negative RA with apparent bone erosion was not associated with SE, supporting the idea that ACPA-negative RA is genetically distinct from ACPA positive RA. We also tested whether these subsets are based on autoantibody producing activity. In accordance with the ACPA-negative RA subset, the RF negative RA subset showed a clearly distinct pattern of association with SE from the RF-positive RA. In contrast, ANA-negative as well as ANA-positive RA was similarly associated with SE, suggesting that the subsets distinguished by ACPA are not based simply on differences in autoantibody production. CONCLUSIONS: ACPA negative erosive RA is genetically distinct from ACPA-positive RA. PMID- 20833644 TI - Safety and efficacy of etanercept therapy in ankylosing spondylitis patients undergoing phacoemulsification surgery. PMID- 20833645 TI - Strumpellin is a novel valosin-containing protein binding partner linking hereditary spastic paraplegia to protein aggregation diseases. AB - Mutations of the human valosin-containing protein gene cause autosomal-dominant inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia. We identified strumpellin as a novel valosin-containing protein binding partner. Strumpellin mutations have been shown to cause hereditary spastic paraplegia. We demonstrate that strumpellin is a ubiquitously expressed protein present in cytosolic and endoplasmic reticulum cell fractions. Overexpression or ablation of wild-type strumpellin caused significantly reduced wound closure velocities in wound healing assays, whereas overexpression of the disease-causing strumpellin N471D mutant showed no functional effect. Strumpellin knockdown experiments in human neuroblastoma cells resulted in a dramatic reduction of axonal outgrowth. Knockdown studies in zebrafish revealed severe cardiac contractile dysfunction, tail curvature and impaired motility. The latter phenotype is due to a loss of central and peripheral motoneuron formation. These data imply a strumpellin loss-of-function pathogenesis in hereditary spastic paraplegia. In the human central nervous system strumpellin shows a presynaptic localization. We further identified strumpellin in pathological protein aggregates in inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, various myofibrillar myopathies and in cortical neurons of a Huntington's disease mouse model. Beyond hereditary spastic paraplegia, our findings imply that mutant forms of strumpellin and valosin-containing protein may have a concerted pathogenic role in various protein aggregate diseases. PMID- 20833646 TI - Phospholipase C beta 1 deficiency is associated with early-onset epileptic encephalopathy. AB - The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-beta 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-beta 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-beta 1 in the index case. Linkage to the phospholipase C-beta 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-beta 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-beta 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C beta 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy. PMID- 20833647 TI - Cardiac-specific leptin receptor deletion exacerbates ischaemic heart failure in mice. AB - AIMS: the obesity-related adipokine, leptin, has multiple actions on peripheral organs, including the mitigation of adverse cardiovascular outcomes after myocardial infarction (MI). Although we recently demonstrated that leptin, its receptor, and downstream signalling are up-regulated in the heart after MI, the significance of intact cardiomyoctye leptin signalling is unknown. Therefore, our objective was to generate a cardiomyocyte-specific leptin receptor knock-out (ObRKO) mouse to determine whether worse cardiac outcomes after MI result from impaired leptin signalling in cardiomyocytes. METHODS AND RESULTS: tamoxifen inducible ObRKO mice were subjected to experimental MI or sham surgeries and studied after 1 month. After MI, ObRKO mice displayed a loss of cardiac signal transducer and activator of transcription (STAT) 3 and adenosine monophosphate activated protein kinase (AMPK) signalling. Worse survival and cardiac morbidity were also seen in the ObRKO mouse post-MI, including decreased contractile function and glycolytic metabolism, and increased left ventricular dilation, hypertrophy, collagen deposition, matrix metalloproteinase activity, apoptosis, and inflammation. Treatment of ObRKO mice post-MI with an ObR-independent AMPK activator improved cardiac function and restored many of these maladaptive processes to wild-type levels. CONCLUSION: these data indicate that leptin signalling mitigates cardiac injury in the post-MI failing heart by acting directly on cardiomyocytes to increase STAT3 and AMPK activation, to decrease cardiac hypertrophy, apoptosis, and inflammation, and to limit deleterious changes in cardiac structure, function, and glycolytic metabolism. PMID- 20833648 TI - Mitochondria-specific transgenic overexpression of connexin-43 simulates preconditioning-induced cytoprotection of stem cells. AB - AIMS: We previously reported that preconditioning of stem cells with insulin-like growth factor-1 (IGF-1) translocated connexin-43 (Cx-43) into mitochondria, causing cytoprotection. We posit that these preconditioning effects could be simulated by mitochondria-specific overexpression of Cx-43. METHODS AND RESULTS: During IGF-1-induced preconditioning of C57black/6 mouse bone marrow stem cell antigen-1(+) (Sca-1(+)) cells, Cx-43 was mainly translocated onto the mitochondrial inner membrane, which was abrogated by an extracellular signal regulated kinases 1 and 2 (ERK1/2) blocker PD98059. To investigate the role of mitochondrial Cx-43, we successfully designed a vector coding for full-length mouse Cx-43 with a mitochondria-targeting sequence (mito-Cx-43) and cloned into a shuttle vector (pShuttle-IRES-hrGFP-1) for mitochondria-specific overexpression of Cx-43 (mito-Cx-43). Sca-1(+) cells with mito-Cx-43 reduced cytosolic accumulation of cytochrome c, lowered caspase-3 activity, and improved survival during index oxygen-glucose deprivation as determined by terminal deoxynucleotidyl transferase dUTP nick-end labelling and lactate dehydrogenase assays. Computational analysis revealed a B-cell lymphoma-2 (Bcl-2) homology domain-3 (BH3) motif in Cx-43 with a conserved pattern of amino acids consistent with the Bcl-2 family that regulated cytochrome c release. Moreover, computational secondary structure prediction indicated an extended alpha-helix in this region, a known condition for BH3-driven protein-protein interactions. CONCLUSION: Cx-43 translocation into mitochondria during preconditioning was ERK1/2-dependent. Expression of mito-Cx-43 simulated the cytoprotective effects of preconditioning in stem cells. Structural features of Cx-43 were shared with the Bcl-2 family as determined by computational analysis. PMID- 20833649 TI - Cigarette smoking induces vascular proliferative disease through the activation of Egr-1. PMID- 20833650 TI - C-kit+ cardiac progenitors exhibit mesenchymal markers and preferential cardiovascular commitment. AB - AIMS: The heart contains c-kit(+) progenitors that maintain cardiac homeostasis. Cardiac c-kit(+) cells are multipotent and give rise to myocardial, endothelial and smooth muscle cells, both in vitro and in vivo. C-kit(+) cells have been thoroughly investigated for their stem cell activity, susceptibility to stress conditions and ageing, as well as for their ability to repair the infarcted heart. Recently, expression of mesenchymal stem cell (MSC) markers and MSC differentiation potency have been reported in cardiac progenitor cells. Based on this evidence, we hypothesized that c-kit(+) cells may have phenotypic and functional features in common with cardiac MSCs. METHODS AND RESULTS: Culture of cells obtained from enzymatic dissociation of heart auricle fragments produced a fast-growing fibroblast-like population expressing mesenchymal markers. C-kit(+) cells co-expressing MSC markers were identified in this population, sorted by flow cytometry and cultured in the presence or the absence of unselected cardiac cells from the same patients. Subsets of c-kit(+) cells also co-expressed MSCs markers in vivo, as detected by immunofluorescence analysis of auricle tissue. Ex vivo expanded c-kit(+) cells produced osteoblasts and adipocytes, although less preferentially than bone marrow-derived MSCs, possessed vascular smooth muscle cell features and were induced to differentiate into endothelium-like and cardiac like cells. CONCLUSION: In line with previous findings, our results indicate that c-kit(+) cardiac progenitors are primitive stem cells endowed with multilineage differentiation ability. They further suggest a possible relationship between these cells and a heart-specific MSC population with cardiovascular commitment potential. PMID- 20833652 TI - Human cardiac and bone marrow stromal cells exhibit distinctive properties related to their origin. AB - AIMS: Bone marrow mesenchymal stromal cell (BMStC) transplantation into the infarcted heart improves left ventricular function and cardiac remodelling. However, it has been suggested that tissue-specific cells may be better for cardiac repair than cells from other sources. The objective of the present work has been the comparison of in vitro and in vivo properties of adult human cardiac stromal cells (CStC) to those of syngeneic BMStC. METHODS AND RESULTS: Although CStC and BMStC exhibited a similar immunophenotype, their gene, microRNA, and protein expression profiles were remarkably different. Biologically, CStC, compared with BMStC, were less competent in acquiring the adipogenic and osteogenic phenotype but more efficiently expressed cardiovascular markers. When injected into the heart, in rat a model of chronic myocardial infarction, CStC persisted longer within the tissue, migrated into the scar, and differentiated into adult cardiomyocytes better than BMStC. CONCLUSION: Our findings demonstrate that although CStC and BMStC share a common stromal phenotype, CStC present cardiovascular-associated features and may represent an important cell source for more efficient cardiac repair. PMID- 20833651 TI - Ablation of phospholamban and sarcolipin results in cardiac hypertrophy and decreased cardiac contractility. AB - AIMS: Improving the sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA) function has clinical implications in treating heart failure. The present study aimed to determine the effect of constitutive activation of the SERCA pump on cardiac contractility in normal mice and during pressure-overload-induced cardiac hypertrophy. METHODS AND RESULTS: The SERCA pump was constitutively activated in both atrial and ventricular chambers of the mouse heart by ablating its key regulators, phospholamban (PLN) and sarcolipin (SLN). The double-knockout (dKO) mice for PLN and SLN showed increased SERCA pump activity, Ca(2+) transients and SR Ca(2+) load, and developed cardiac hypertrophy. Echocardiographic measurements showed that the basal cardiac function was not affected in the young dKO mice. However, the cardiac function worsened upon ageing and when subjected to pressure overload. CONCLUSION: Our studies suggest that the constitutive activation of the SERCA pump is detrimental to cardiac function. Our findings also emphasize the need for dynamic regulation of the SERCA pump by PLN and/or SLN to maintain cardiac contractility in normal conditions and during pathophysiological states. PMID- 20833653 TI - Chemical structure of beta-galactofuranose-containing polysaccharide and O-linked oligosaccharides obtained from the cell wall of pathogenic dematiaceous fungus Fonsecaea pedrosoi. AB - Fonsecaea pedrosoi is the main etiologic agent of chromoblastomycosis, usually occurring in tropical and subtropical areas. The cell wall components of pathogenic microorganisms behave as an antigen and/or ligand of the innate immune response. The cells of F. pedrosoi reacted with the alpha-galactopyranose-binding lectin (Griffonia simplicifolia lectin 1B4 isolectin, GSL 1B4), as well as the alpha-mannose-binding lectin, concanavalin A. The cell wall glycoprotein was isolated from conidial cells of F. pedrosoi, and its structure was analyzed by (1)H-nuclear magnetic resonance (NMR) and (13)C-NMR experiments. The N-linked polysaccharide moiety consists of a backbone beta-1,6-linked galactofuranose and alpha-1,6-linked mannose polymers, both of which are substituted with alpha-1,2 linked glucose side-chains. Furthermore, the glycoprotein contained a large amount of O-linked oligosaccharides, especially a hexaose that constituted approximately 20% of the glycoprotein. Unexpectedly, the hexaose had a highly branched structure which consisted of galactofuranose, galactopyranose, glucose and mannose residues as follows: An anti-F. pedrosoi antibody specifically reacted with the cells of F. pedrosoi, whereas other fungal cells that contain galactofuranose residues did not react. The reactivity of the antibody was strongly inhibited by the branched hexaose, suggesting that the characteristic structure of the O-linked hexaose involves the antigenic specificity of the cells. PMID- 20833654 TI - Mapping of numerous disease-associated expression polymorphisms in primary peripheral blood CD4+ lymphocytes. AB - Genome-wide association studies of human gene expression promise to identify functional regulatory genetic variation that contributes to phenotypic diversity. However, it is unclear how useful this approach will be for the identification of disease-susceptibility variants. We generated gene expression profiles for 22 184 mRNA transcripts using RNA derived from peripheral blood CD4+ lymphocytes, and genome-wide genotype data for 516 512 autosomal markers in 200 subjects. We screened for cis-acting variants by testing variants mapping within 50 kb of expressed transcripts for association with transcript abundance using generalized linear models. Significant associations were identified for 1585 genes at a false discovery rate of 0.05 (corresponding to P-values ranging from 1 * 10(-91) to 7 * 10(-4)). Importantly, we identified evidence of regulatory variation for 119 previously mapped disease genes, including 24 examples where the variant with the strongest evidence of disease-association demonstrates strong association with specific transcript abundance. The prevalence of cis-acting variants among disease-associated genes was 63% higher than the genome-wide rate in our data set (P = 6.41 * 10(-6)), and although many of the implicated loci were associated with immune-related diseases (including asthma, connective tissue disorders and inflammatory bowel disease), associations with genes implicated in non-immune related diseases including lipid profiles, anthropomorphic measurements, cancer and neurologic disease were also observed. Genetic variants that confer inter individual differences in gene expression represent an important subset of variants that contribute to disease susceptibility. Population-based integrative genetic approaches can help identify such variation and enhance our understanding of the genetic basis of complex traits. PMID- 20833655 TI - Genome-wide association study identifies genetic determinants of warfarin responsiveness for Japanese. AB - Warfarin is a commonly used anticoagulant, whose dose needs to be determined for each individual patient owing to large inter-individual variability in its therapeutic dose. Although several clinical and genetic variables influencing warfarin dose have been identified, uncovering additional factors are critically important for safer use of warfarin. Through a genome-wide association study, we identified single-nucleotide polymorphism (SNP) rs2108622 [cytochrome P450, family 4, subfamily F, polypeptide 2 (CYP4F2)] as a genetic determinant of warfarin responsiveness for Japanese. Stratifying subjects who have been pre classified according to the genotypes of SNP rs10509680 [cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)] and SNP rs9923231 [vitamin K epoxide reductase complex subunit 1 (VKORC1)], based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin. Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age, body surface area, status of amiodarone co-administration and genotypes of SNPs in the CYP2C9 and VKORC1 genes improved the model's predictability to 43.4%. In this study, the association of CYP4F2 with warfarin dose of the Japanese has been established for the first time. Besides, a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co administration status was suggested for the Japanese. Our study also implied that common SNPs other than those in the CYP2C9, VKORC1 and CYP4F2 genes that show strong effect on the therapeutic warfarin dose might not exist. PMID- 20833656 TI - Management of lower gastrointestinal bleeding: endoscopist or radiologist? PMID- 20833657 TI - Strong interaction between the effects of alcohol consumption and smoking on oesophageal squamous cell carcinoma among individuals with ADH1B and/or ALDH2 risk alleles. AB - BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is considered a difficult cancer to cure. The detection of environmental and genetic factors is important for prevention on an individual basis. OBJECTIVE: To identify groups at high risk for OSCC by simultaneously analysing both genetic and environmental risk factors. Methods A multistage genome-wide association study of OSCC in Japanese individuals with a total of 1071 cases and 2762 controls was performed. RESULTS: Two associated single-nucleotide polymorphisms (SNPs), as well as smoking and alcohol consumption, were evaluated as genetic and environmental risk factors, respectively, and their interactions were also evaluated. Risk alleles of rs1229984 (ADH1B) and rs671 (ALDH2) were highly associated with OSCC (odds ratio (OR)=4.08, p=4.4*10(-40) and OR=4.13, p=8.4*10(-76), respectively). Also, smoking and alcohol consumption were identified as risk factors for OSCC development. By integrating both genetic and environmental risk factors, it was shown that the combination of rs1229984 and rs671 risk alleles with smoking and alcohol consumption was associated with OSCC. Compared with subjects with no more than one environmental or genetic risk factor, the OR reached 146.4 (95% CI 50.5 to 424.5) when both environmental and genetic risk factors were present. Without the genetic risks, alcohol consumption did not correlate with OSCC. In people with one or two genetic risk factors, the combination of alcohol consumption and smoking increased OSCC risk. CONCLUSIONS: Analysis of ADH1B and ALDH2 variants is valuable for secondary prevention of OSCC in high-risk patients who smoke and drink alcohol. In this study, SNP genotyping demonstrated that the ADH1B and/or ALDH2 risk alleles had an interaction with smoking and, especially, alcohol consumption. These findings, if replicated in other groups, could demonstrate new pathophysiological pathways for the development of OSCC. PMID- 20833658 TI - Association of the G-protein and alpha2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial. AB - OBJECTIVE: Clonidine is an alpha(2)-adrenoceptor agonist which, by coupling with G-protein, has been proposed as an alternative treatment for refractory ascites of patients with cirrhosis for several years. Genetic polymorphisms of beta adrenoceptor and angiotensin II type 1 receptor blockers have been reported to affect drug response in patients with cirrhosis. This study evaluated the clonidine-diuretic response rate, favourable predictors and genetic components of the clonidine-diuretic response in patients with cirrhosis with refractory ascites. METHODS: 270 patients with cirrhosis with refractory ascites were randomised equally into two treatment groups to receive diuretics alone or the clonidine-diuretics association. The primary end point was clonidine-diuretic response rate. Secondary end points were mean daily dose of diuretics, times of paracentesis, ascites-related readmission and 1-year survival rate. RESULTS: Good clonidine responders had better natriuresis and diuresis as well as a significant decrease in abdominal circumference, plasma renin, aldosterone and norepinephrine levels. The overall clonidine-diuretics response rate was 55-60%. In patients with cirrhosis, the prevalence of ARDA(2)C WD/DD and GNB3 CT/TT genotypes was 71% and 77%, respectively. Among the responders, 71% of patients with cirrhosis had the ARDA(2)C WD/DD genotype and 67% has the GNB3 CT/TT genotype. Besides higher baseline norepinephrine levels, the presence of both ARDA(2)C WD/DD and GNB3 CT/TT genotypes showed a positive predictive value of 82% and a negative predictive value of 79% for good clonidine response. CONCLUSIONS: These results suggest that neurohormonal and genetic testing may be used as predictive factors for the additive effects of clonidine on the diuresis and natriuresis effects of diuretics in patients with cirrhosis with refractory ascites. PMID- 20833659 TI - High detection rate of adenomas in familial colorectal cancer. AB - BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population. PMID- 20833661 TI - Liver dysfunction in patients with IBD under immunosuppressive treatment: do we need to fear? PMID- 20833662 TI - Serum fibrosis markers to predict clinical and histological progression in hepatitis C non-responders. PMID- 20833663 TI - Metabolic syndrome: relevant for all types of chronic liver diseases? PMID- 20833668 TI - Factors associated with undernutrition among children in a rural district of Kelantan, Malaysia. AB - The aim of the study was to identify the factors associated with undernutrition indicators in children 5 years and younger in a rural community in Malaysia. A total of 295 children and their carers were selected from community clinics based on a multistage sampling method. Pretested questionnaire, anthropometric measurement, and dietary assessment were used for data collection. There was 69% stunting, 63.4% underweight, 40% wasting, and 26.8% with mid-upper-arm circumference (MUAC) for age below a z score of -2 among children. In all, 10 factors were found to be associated with different indicators of undernutrition. Age was the only factor that had association with all the undernutrition indicators. Total household income and total expenditure showed significant association with underweight. Birth weight was reported to have significant association with underweight, stunting, and low MUAC-for-age. The findings suggest that the factors of undernutrition were different for different indicators of undernutrition and thus give a more comprehensive picture on factors contributing to acute and chronic malnutrition. PMID- 20833669 TI - The Third National Health and Morbidity Survey: prevalence of obesity, and abdominal obesity among the Malaysian elderly population. AB - Obesity is an emerging public health threat in the elderly population in developing countries. Hence, the Third National Health and Morbidity Survey has assessed 4746 individuals aged 60 years and older recruited through a household survey to determine the prevalence of adiposity using body mass index and waist circumference. The national's prevalence of overweight and obesity in men was 29.2% (95% confidence interval [CI] = 27.2-31.3) and 7.4% (95% CI = 6.4-8.6), respectively. However, the prevalence decreased with age. The figures in women were 30.3% (95% CI = 28.5-32.1) and 13.8% (95% CI = 12.5-15.2), respectively. The prevalence of abdominal obesity was 21.4% (95%CI = 20.2-22.6), with 7.7% (95% CI = 6.7-9.0) in men and 33.4% (95% CI = 31.4-35.3) in women. Predictors of adiposity include the following: Malay and Indian ethnicity, higher education level, higher household income, from urban area, and being married. In conclusion, adiposity affects about one third of the Malaysian elderly population, especially those of the younger age group, women, and those with higher socioeconomic status. PMID- 20833671 TI - The health benefits of urban green spaces: a review of the evidence. AB - BACKGROUND: Urban development projects can be costly and have health impacts. An evidence-based approach to urban planning is therefore essential. However, the evidence for physical and non-physical health benefits of urban green space is unclear. METHODS: A literature search of academic and grey literature was conducted for studies and reviews of the health effects of green space. Articles found were appraised for their relevance, critically reviewed and graded accordingly. Their findings were then thematically categorized. RESULTS: There is weak evidence for the links between physical, mental health and well-being, and urban green space. Environmental factors such as the quality and accessibility of green space affects its use for physical activity. User determinants, such as age, gender, ethnicity and the perception of safety, are also important. However, many studies were limited by poor study design, failure to exclude confounding, bias or reverse causality and weak statistical associations. CONCLUSION: Most studies reported findings that generally supported the view that green space have a beneficial health effect. Establishing a causal relationship is difficult, as the relationship is complex. Simplistic urban interventions may therefore fail to address the underlying determinants of urban health that are not remediable by landscape redesign. PMID- 20833672 TI - Measurement of the indoor and outdoor (220)Rn (thoron) equilibrium factor: application to lung dose. AB - A miniature four-chamber alpha track detector was developed that measures both (222)Rn (radon) and (220)Rn (thoron), in duplicate. Using this detector and the previous long-term measurements of the (220)Rn decay products (212)Pb, and (212)Bi, an equilibrium factor, F(eq), is derived for both outdoor and indoor (220)Rn environments (0.004+/-0.001 outdoors and 0.04+/-0.01 indoors). The lung airway dose can then be calculated from a dose factor from UNSCEAR that requires the equilibrium equivalent thoron concentration (EEC), i.e. the product of F(eq) and the (220)Rn gas concentration. The lung dose from thoron in domestic or occupational surveys is often overlooked. The values of F(eq) for thoron in several published studies are in general agreement with the values reported here. Thus, a long-term alpha track measurement of thoron multiplied by an appropriate indoor or outdoor equilibrium factor yields the EEC, which can be used to assess bronchial lung dose. PMID- 20833673 TI - Risk assessment of baseline outdoor gamma dose rate levels study of natural radiation sources in Bursa, Turkey. AB - Within the scope of this study, gamma radiation dose rate measurements have been carried out in the province of Bursa. The mean outdoor (terrestrial and cosmic) gamma dose rate in this area was 90 nGy h(-1). The cosmic gamma dose rate was measured to be 16 nGy h(-1) at the Iznik lake in the region. The mean annual effective dose due to outdoor gamma radiations was determined to be 110.4 uSv. The collective effective dose equivalent was calculated to be 3.21 * 10(2) man Sv per year. The average relative excess lifetime risk of fatal cancer was calculated at 4.50 * 10(-4) for the people living in the city. The activity concentrations of natural radionuclides such as (238)U series, (232)Th series, (40)K and fission products like (137)Cs in surface soil samples were measured by using an HPGe-based gamma spectrometry system. The mean activity concentration of (238)U series, (232)Th series, (40)K and (137)Cs were found to be 55.9 Bq kg(-1) for (226)Ra, 23.6 Bq kg(-1) for (214)Pb, 22.5 Bq kg(-1) for (214)Bi, 31.3 Bq kg( 1) for (208)Tl, 32.9 Bq kg(-1) for (228)Ac, 430 Bq kg(-1) for (40)K and 5.4 Bq kg(-1) for (137)Cs. The radiation hazards associated with the radionuclides were estimated at an average of 136 Bq kg(-1) by calculating the radium equivalent activity (Ra(eq)). The mean calculated value of the external hazard index (H(ex)) for the soil was found to be 0.37. PMID- 20833674 TI - Doses in human organs due to alpha, beta and gamma radiations emitted by thoron progeny in the lung. AB - This work consists of two parts. In the first part, the doses in the human lung per unit exposure to thoron progeny, the dose conversion factor (DCF), was calculated. Dependence of the DCF on various environmental and subject-related parameters was investigated. The model used in these calculations was based on ICRP 66 recommendations. In the second part, the human lungs were considered as the source of beta and gamma radiation which target the other organs of the human body. The DCF to other organs was obtained as 20 uSv WLM(-1), which is larger than the DCF for radon progeny, which was 13 uSv WLM(-1). This is a consequence of the longer half-life of the relevant thoron progeny than that of the radon progeny. It is interesting to note that after the lungs, where the radiation source is actually located, muscle tissue receives the largest dose. PMID- 20833675 TI - Estimation of indoor (220)Rn progeny concentrations with (220)Rn measurements. AB - For estimating indoor thoron ((220)Rn) progeny concentrations with (220)Rn measurements, both theoretical studies and field measurements were carried out in this work. Based on the theoretical study, it was found that the exhalation rate of (220)Rn (E(Tn)) could be optimally assessed with the (220)Rn concentration measured at a point of 50 cm far from the source wall, and the equilibrium equivalent thoron concentration (EETC) could be further estimated with the E(Tn) and the area of wall surface as well as the room volume. Field measurements testified that the estimated EETCs were in general agreement with the directly measured results with an average ratio of 0.87 +/- 0.12. The new method developed in this study is thought to be preferable for long-term and large-scale surveys of indoor EETC. PMID- 20833676 TI - Characteristic and performance of a simple thoron chamber. AB - For calibration and intercomparison experiments, a thoron chamber with an inner volume of 300 l was designed based on a programmable constant temperature and humidity testing device in this work. The commercial lantern mantles enriched with (232)Th were used as the (220)Rn source and the mantles were set in 3*3*3 points of lattice style inside the chamber. Experimental studies showed that (220)Rn concentrations in the chamber could be easily controlled and adjusted from about 0.5 to 80 kBq m(-3) through manual settings of the relative humidity and temperature, and the spatial distribution of (220)Rn in the chamber was fairly homogeneous. PMID- 20833677 TI - Long-term determination of airborne radon progeny concentrations using LR 115 detectors and the effects of thoron. AB - The 'proxy equilibrium factor' (F(p)) method has been developed for long-term determination of airborne radon progeny concentrations using LR 115 solid-state nuclear track detectors. In this paper, the effects of (220)Rn on the F(p) method have been studied. The correction to the track density was related to a parameter alpha which was the ratio of the sum of activity concentrations of alpha-particle emitting radionuclides in the (220)Rn decay chain to the activity concentration of (220)Rn alone. Under commonly encountered circumstances, alpha could not be smaller than 2. An attempt was made to verify this using the exposure chamber at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. A most interesting observation of alpha < 2 for very high (220)Rn concentrations and very low equilibrium factors for (220)Rn in the exposure chambers was made. A possible explanation was the substantial deposition of (216)Po under the extreme conditions inside the exposure chambers. PMID- 20833678 TI - Evaluation of the calibration parameters of radiochromic films for patient dosimetry in interventional radiology. AB - The study aims to analyse the effects of beam energy, dose fractionation, response homogeneity, long-term fading and response sensitivity of radiochromic films. It also investigates the effect of the scanner, ambient temperature and storage conditions on the response of the films. The radiochromic films were irradiated at various air kerma from 20 mGy to about 8 Gy. Results showed that the response of the films is not energy dependent for low doses ranging from 300 to 700 mGy (coefficient of variation = 5-12%) but starts to show a slight dependence for high doses above 2 Gy (coefficient of variation = 20%). There is no significant difference (4%) in optical densities (OD) and pixel values when doses were fractionated and when using scanner with and without warm-up lamp. The curve fitting of OD and pixel values for the sensitivity test at different kilovolt potential gave an r(2) value of 0.99. PMID- 20833679 TI - Considerations in screeneing/measuring children with internal/external contamination. AB - The National Internal Radiation Assessment Section, which operates the Canadian National Calibration Reference Centre for Bioassay and In Vivo Monitoring, has field deployable equipment for emergency response. A substantial part of this toolkit is a set of portal monitors that can be used to quickly screen people into 'uncontaminated' and 'contaminated'. The former term refers to a person who has <60 kBq (empirical practical detection limit) of activation/fission products and the latter group is contaminated by that amount or more. Previous work has focused on how to process large numbers of people quickly and methodologies have been previously published; however, it was assumed that the group being monitored was composed of healthy adults. When applying these methods to children, a number of shortcomings have been identified. PMID- 20833680 TI - Radioactivity monitoring in ground level air in Belgrade urban area. AB - Concentrations of beryllium-7 ((7)Be), lead-210 ((210)Pb) and caesium-137 ((137)Cs) were measured at two sites in the city of Belgrade (Serbia). One monitoring site was located in the central city area with heavy traffic and the other within the Institute of Nuclear Sciences Vinca, in the suburbs. Presented data cover the period 2004-9. Activity of the radionuclides was determined on an HPGe detector (Canberra, relative efficiency 23 %) by standard gamma spectrometry. Activities of (7)Be and (210)Pb exhibit a similar seasonal pattern. The mean monthly concentrations of (7)Be did not exceed 7 mBq m(-3). The maxima are correlated with the seasonal increase in temperature, whereas the minima are linearly correlated with the amount of precipitation. The activity of (210)Pb was below 0.9 mBq m(-3). The activities of both radionuclides were very low in winters and were largely affected by precipitation and snow coverage. Concentrations of (137)Cs were mainly below the limit of detection. PMID- 20833681 TI - Measurement of the (212)Pb particle size distribution indoors. AB - A new device has been developed for the measurement of the (212)Pb particle size distribution indoors. This device consists of two wire screens and a back-up filter with a diameter of 2.0 cm. The sampling flow rate is typically 3.0 l min( 1). After 3-h sampling time and 6-h waiting time, a CR-39 detector is used for the registration of the alpha particles from the (212)Pb, deposited on the wire screens and the filter, respectively. It appears clear from field measurements that there are no appreciable differences among the particle size distributions from different dwellings within the same location and under the same climate conditions. However, the (212)Pb particle size distributions from the countryside dwellings have different results from those of the city dwellings. PMID- 20833682 TI - Preliminary indoor thoron measurements in high radiation background area of southeastern coastal Orissa, India. AB - This paper presents the preliminary results of radon and thoron measurements in the houses of Chhatrapur area of southeastern coast of Orissa, India. This area is one of the high radiation background radiation areas in India, which consists of monazite sand as the source of thoron. Both active and passive methods were employed for the measurements. Radon and thoron concentrations were measured in the houses of Chhatrapur area using twin cup radon dosemeters, RAD7 and radon thoron discriminative detector (Raduet). Thoron progeny concentration was also measured in the houses using deposition rate measurements. Radon and thoron concentrations in the houses of study area were found to vary from 8 to 47 Bq m( 3) and the below detection level to 77 Bq m(-3), respectively. While thoron progeny concentration in these houses ranges between 0.17 and 4.24 Bq m(-3), preliminary investigation shows that the thoron concentration is higher than radon concentration in the houses of the study area. The thoron progeny concentration was found to be comparatively higher, which forms a base for further study in the area. The comparison between the results of various techniques is presented in this paper. PMID- 20833683 TI - CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case control study. AB - AIMS: despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. METHODS AND RESULTS: the selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (OR(adj): 1.7, 95% CI: 1.0-2.6, P = 0.018 and OR(adj): 2.4, 95% CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (OR(adj): 2.5, 95% CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (OR(adj): 3.3, 95% CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. CONCLUSION: carriage of the loss of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI. PMID- 20833684 TI - Prospective evaluation of two recruitment strategies for a randomized controlled cancer prevention trial. AB - PURPOSE: To evaluate two recruitment strategies used during the full-scale randomized, placebo-controlled Selenium and Vitamin E Cancer Prevention Trial (SELECT) at one clinical center. BACKGROUND: Recruitment of participants to cancer prevention trials is challenging and costly and more efficient methods are needed. METHODS: SELECT participants were males >=60 years old who were solicited with two recruitment strategies. In the control strategy, potential participants, identified through purchased mailing lists, were sent a SELECT invitation letter. In the 'spouse' strategy, letters were sent to married postmenopausal women already participating in the Women's Health Initiative (WHI) at our clinical center asking them to provide an enclosed SELECT invitation letter (identical to the one in the control strategy) to the 'man in her life'. Our hypothesis was that SELECT recruitment of men would be enhanced by this indirect mailing to their spouses already participating in a similar program. RESULTS: In the control strategy, 183,315 invitation letters were mailed to 60,000 men; cumulative response was 2.16%; 600 men ultimately enrolled in SELECT (15.1% of respondents) for a mailing recruitment cost of $259 per participant. In the spouse strategy, 800 women participating in WHI clinical studies had husbands; of the 2214 invitation letters mailed to this group of women, cumulative response was 2.75%; 34 men ultimately enrolled in SELECT (55.7% of respondents) for a mailing recruitment cost of $59 per participant. LIMITATION: Process information on how invitation letters were handled in the spouse strategy was not collected. CONCLUSION: A direct mail recruitment strategy was successful in recruiting men to a cancer prevention trial. A recruitment strategy involving indirect mailing to married women participating in a similar research program in the same center did not increase initial response substantially, but a higher proportion of respondents ultimately entered the prevention trial. PMID- 20833685 TI - Device closure of patent ductus arteriosus: optimal guidance by transaortic phased-array imaging. AB - In many institutions, device closure of patent ductus arteriosus (PDA) in adult patients is only performed once to twice per year. This report describes an interventional PDA closure procedure being effectively assisted by transaortic phased-array imaging, also known as intracardiac echocardiography (ICE). This way, well-known advantages of ICE as are lowering of radiation exposure and fluoroscopy time can potentially be transferred to PDA device closure. PMID- 20833686 TI - Expressions of RANKL/RANK and M-CSF/c-fms in root resorption lacunae in rat molar by heavy orthodontic force. AB - The differentiation and functions of osteoclasts are regulated by receptor activator of nuclear factor-kappaB (RANK)/receptor activator of nuclear factor kappaB ligand (RANKL) system that stimulates osteoclasts formation. Macrophage colony-stimulating factor (M-CSF) is also essential for osteoclastogenesis. A recent immunocytochemical study reported that RANKL/RANK and M-CSF/c-fms were localized in the periodontal ligament of rat molars during experimental orthodontic tooth movement. The present study focused on the expressions of RANKL/RANK and M-CSF/c-fms in root resorption area during experimental tooth movement in rats. Forty 6-week-old male Wistar rats were subjected to an orthodontic force of 10 or 50 g with a closed coil spring (wire size: 0.005 inch, diameter: 1/12 inch) ligated to the maxillary first molar cleat by a 0.008 inch stainless steel ligature wire to induce a mesial tipping movement of the upper first molars. Experimental tooth movement was undertaken for 10 days. Each sample was sliced into 6 MUm continuous sections in a horizontal direction and prepared for haematoxylin and eosin (H and E) and immunohistochemistry staining for tartrate-resistant acid phosphatase (TRAP), RANK, RANKL M-CSF, and c-fms in root resorption area. Statistical analysis was carried out using a Mann-Whitney U-test with a significance level of P<0.01. On days 7 and 10, immunoreactivity for RANKL/RANK and M-CSF/c-fms was detected in odontoclasts with an orthodontic force of 50 g, but not 10 g. Therefore, RANKL/RANK and M-CSF/c-fms systems may be involved in the process of root resorption by heavy orthodontic force. PMID- 20833687 TI - Posterior approach white line advancement ptosis repair: the evolving posterior approach to ptosis surgery. AB - INTRODUCTION: We describe a surgical technique for ptosis correction in moderate to good levator function involving advancement of the levator aponeurosis via a transconjunctival posterior approach without resection of Muller's muscle. We present our experience of and the results from this method, and review the evolution of posterior approach ptosis surgery. PURPOSE: To assess the efficacy and predictability of posterior approach white line advancement ptosis repair. METHODS: Retrospective analysis of all patients with primary aponeurotic ptosis undergoing posterior-approach repair using white line advancement between December 2007 and June 2008. We describe a technique whereby after dissection of the Muller's conjunctiva composite flap, the levator aponeurosis is advanced with double-armed sutures through the white line, then through the tarsus and out through the skin. RESULTS: There were 112 ptosis procedures during this period, of which 71 eyelids of 41 patients were eligible for inclusion. There were 14 men and 27 women. The mean age was 63.76 (range 24-87) years. Minimum follow up was 3 months (range 12-43 weeks). Of the 71 procedures, 42 were combined with a blepharoplasty. Sixty-two achieved their desired lid height, contour and symmetry (87.3% success rate). No patients were overcorrected. Success rate in the phenylephrine-positive group (42/71) was 88.1% compared with 100% in phenylephrine-negative group (4/71). CONCLUSIONS: We present a modified approach to ptosis correction via a posterior approach. It has a high success rate and good cosmetic outcome. It is technically straightforward and easy to learn. PMID- 20833688 TI - The issue of studying the effect of interventions in renal replacement therapy -- to what extent may we be deceived by selection and competing risk? AB - Patients with chronic kidney disease (CKD) who live up to renal replacement therapy (RRT) are a selected group of patients with a high mortality risk. The aim of this paper is to contribute a potential epidemiological explanation as to why therapeutic interventions - targeting specific causes of death - of which the effectiveness has been shown in the general population may not have a similar impact in a highly selected population like RRT patients. In this perspective, selection processes over the course of renal disease progression as well as the potential 'dilution' of an effect in the presence of highly increased mortality from other causes need attention. We suggest that the results from well-conducted high-quality studies in incident RRT patients without or with only very limited in- and exclusion criteria are likely the ones best qualified to be extrapolated to other RRT populations. PMID- 20833689 TI - Unravelling fibrosis: two newcomers and an old foe. PMID- 20833690 TI - Toward a psychological science of advanced technology design for older adults. AB - OBJECTIVES: Technology represents advances in knowledge that change the way humans perform tasks. Ideally, technology will make the task easier, more efficient, safer, or perhaps more pleasurable. Unfortunately, new technologies can sometimes make a task more difficult, slower, dangerous, or perhaps more frustrating. Older adults interact with a variety of technologies in the course of their daily activities and thus products should be designed to be used by people of varying ages. METHODS: In this article, we provide an overview of what psychology has to offer to the design of technology-from understanding what people need, to identifying their preferences for design characteristics, and to defining their capabilities and limitations that will influence technology interactions. RESULTS: We identify how research in the field of psychology and aging has advanced understanding of technology interactions and how research on technology interactions can inform theories of aging. DISCUSSION: Design for aging involves understanding the unique capabilities and limitations of older adults; identifying their needs, preferences, and desires for technology in their lives; and involving them in the design process. PMID- 20833691 TI - Interleukin-18 among atrial fibrillation patients in the absence of structural heart disease. AB - AIMS: Inflammation plays a role in the genesis and perpetuation of atrial fibrillation (AF). Interleukin (IL)-18 is a pleiotropic proinflammatory cytokine with a central role in the inflammatory cascade. We hypothesize that the circulating IL-18 concentration is elevated in AF patients. METHODS AND RESULTS: In a case-control study design, 56 cases with AF and 26 controls were enrolled. All AF cases were categorized into paroxysmal and persistent AF or lone AF and AF with hypertension. Circulating levels of IL-18, tumour necrosis factor-alpha, high-sensitivity C-reactive protein, matrix metalloproteinase (MMP)-9, and tissue inhibitor of MMP-1 were measured. In adjusted analyses, only age, MMP-9, and IL 18 were independently associated with AF, in which IL-18 had the most significant association (P = 0.0011, standardized estimate &bgr = 1.76, OR = 1.02, 95% confidence interval: 1.01-1.03). Interleukin-18 levels in persistent AF patients were higher than those in paroxysmal ones (P = 0.0011). Patients who developed AF within 24 h prior to sampling displayed a higher level of IL-18 than those with sinus rhythm (P = 0.0027). Interleukin-18 was positively correlated with left atrial diameter (r = 0.33, P = 0.0117). CONCLUSION: This study documents the elevated IL-18 in AF patients. Interleukin-18 may be superior to other inflammatory markers which are known to be elevated in AF. PMID- 20833692 TI - The prognosis of implantable defibrillator patients treated with cardiac resynchronization therapy: comorbidity burden as predictor of mortality. AB - AIMS: Comorbidity, such as myocardial infarction, diabetes, and renal failure, plays a pivotal role in the prognosis of a patient with arrhythmias. However, data on the prognostic impact of comorbiditiy in heart failure patients with cardiac resynchronization therapy and defibrillation (CRT-D) are scarce. The purpose of this study was to determine the impact of comorbidity on survival in CRT-D patients. METHODS AND RESULTS: The study population consisted of 463 heart failure patients who received a CRT-D between 1999 and 2008 in Rotterdam and Basel. The Charlson comorbidity index (CCI) is often used as an adjusting variable in prognostic models. The Cox proportional hazards analysis was performed to determine the independent effect of comorbidity on survival. During a median follow-up of 30.5 months, 85 patients died. Mortality rates at 1 and 7 years were 6.3 and 32.3%. Cumulative incidence of implantable cardioverter defibrillator (ICD) therapy at 7 years was 50%, and death without ICD therapy was observed in 9% of patients. At least three comorbid conditions were observed in 81% of patients. Patients who died had a higher CCI score compared with those who survived (3.9 +/- 1.5 vs. 2.9 +/- 1.5; P < 0.001). An age-adjusted CCI score >= 5 was a predictor of mortality (hazard ratio 3.69, 95% CI 2.06-6.60; P < 0.001) independent from indication for ICD therapy, and from ICD interventions during the clinical course. CONCLUSION: Comorbidity is often present in heart failure patients, and a high comorbidity burden was a significant predictor of mortality in CRT-D recipients. Comorbidity cannot predict appropriate ICD therapy. Death without prior ICD therapy occurs in a minor proportion of patients. PMID- 20833693 TI - How many atrial fibrillation ablation candidates have an underlying supraventricular tachycardia previously unknown? Efficacy of isolated triggering arrhythmia ablation. AB - AIMS: Supraventricular tachycardia may trigger atrial fibrillation (AF). The aim of the study was to evaluate the prevalence of supraventricular tachycardia (SVT) inducibility in patients referred for AF ablation and to evaluate the effects of SVT ablation on AF recurrences. METHODS AND RESULTS: Two hundred and fifty-seven patients (185 males; mean age: 53.4 +/- 14.6 years) referred for AF ablation were studied. In all patients only AF relapses had been documented in the clinical history. Twenty-six patients (10.1%; mean age: 43.4 +/- 13.3 years; 17 males) had inducible SVT during electrophysiological study and underwent an ablation targeted only at SVT suppression. Ablation was successful in all 26 patients. The ablative procedures are: 12 slow-pathway ablations for atrioventricular nodal re entrant tachycardia; 9 concealed accessory pathway ablations for atrioventricular re-entrant tachycardia; and 5 focal ectopic atrial tachycardia ablations. No recurrences of SVT were observed during the follow-up (21 +/- 11 months). Two patients (7.7%) showed recurrence of at least one episode of AF. Patients with inducible SVT had less structural heart disease and were younger than those without inducible SVT (interventricular septum thickness: 8.4 +/- 1.6 vs. 11.0 +/ 1.4 mm, P < 0.01; left atrial diameter: 37.0 +/- 3.0 vs. 44.0 +/- 2.2 mm, P < 0.01; age: 43.4 +/- 13.3 vs. 57.3 +/- 11.2 years, P < 0.01). Prevalence of paroxysmal AF was higher in patients with inducible SVT when compared with those with only AF (84.6 vs. 24.6%, P < 0.01). CONCLUSION: A significant proportion of candidates to AF ablation are inducible for a SVT. SVT ablation showed a preventive effect on AF recurrences. Those patients should be selected for simpler ablation procedures tailored only on the triggering arrhythmia suppression. PMID- 20833694 TI - Insight into evolution of Bordetella pertussis from comparative genomic analysis: evidence of vaccine-driven selection. AB - Despite high vaccine coverage, pertussis incidence has increased substantially in recent years in many countries. A significant factor that may be contributing to this increase is adaptation to the vaccine by Bordetella pertussis, the causative agent of pertussis. In this study, we first assessed the genetic diversity of B. pertussis by microarray-based comparative genome sequencing of 10 isolates representing diverse genotypes and different years of isolation. We discovered 171 single nucleotide polymorphisms (SNPs) in a total of 1.4 Mb genome analyzed. The frequency of base changes was estimated as one per 32 kb per isolate, confirming that B. pertussis is one of the least variable bacterial pathogens. We then analyzed an international collection of 316 B. pertussis isolates using a subset of 65 of the SNPs and identified 42 distinct SNP profiles (SPs). Phylogenetic analysis grouped the SPs into six clusters. The majority of recent isolates belonged to clusters I-IV and were descendants of a single prevaccine lineage. Cluster I appeared to be a major clone with a worldwide distribution. Typing of genes encoding acellular vaccine (ACV) antigens, ptxA, prn, fhaB, fim2, and fim3 revealed the emergence and increasing incidence of non-ACV alleles occurring in clusters I and IV, which may have been driven by ACV immune selection. Our findings suggest that B. pertussis, despite its high population homogeneity, is evolving in response to vaccination pressure with recent expansion of clones carrying variants of genes encoding ACV antigens. PMID- 20833695 TI - The XPD subunit of TFIIH is required for transcription-associated but not DNA double-strand break-induced recombination in mammalian cells. AB - Mutations in the XPD gene can give rise to three phenotypically distinct disorders: xeroderma pigmentosum (XP), trichothiodystrophy (TTD) or combined XP and Cockayne syndrome (CS) (XP/CS). The role of Xeroderma Pigmentosum group D protein (XPD) in nucleotide excision repair explains the increased risk of skin cancer in XP patients but not all the clinical phenotypes found in XP/CS or TTD patients. Here, we describe that the XPD-defective UV5 cell line is impaired in transcription-associated recombination (TAR), which can be reverted by the introduction of the wild-type XPD gene expressed from a vector. UV5 cells are defective in TAR, despite having intact transcription and homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Interestingly, we find reduced spontaneous HR in XPD-defective cells, suggesting that transcription underlies a portion of spontaneous HR events. We also report that transcription coupled repair (TCR)-defective cells, mutated in the Cockayne syndrome B (CSB) protein, have a defect in TAR, but not in DSB-induced HR. However, the TAR defect may be associated with a general transcription defect in CSB-deficient cells. In conclusion, we show a novel role for the XPD protein in TAR, linking TAR with TCR. PMID- 20833696 TI - Developmental vitamin D deficiency and risk of schizophrenia: a 10-year update. AB - There is an urgent need to generate and test candidate risk factors that may explain gradients in the incidence of schizophrenia. Based on clues from epidemiology, we proposed that developmental vitamin D deficiency may contribute to the risk of developing schizophrenia. This hypothesis may explain diverse epidemiological findings including season of birth, the latitude gradients in incidence and prevalence, the increased risk in dark-skinned migrants to certain countries, and the urban-rural gradient. Animal experiments demonstrate that transient prenatal hypovitaminosis D is associated with persisting changes in brain structure and function, including convergent evidence of altered dopaminergic function. A recent case-control study based on neonatal blood samples identified a significant association between neonatal vitamin D status and risk of schizophrenia. This article provides a concise summary of the epidemiological and animal experimental research that has explored this hypothesis. PMID- 20833697 TI - Grasping in the dark activates early visual cortices. AB - We have previously demonstrated that the primary motor and somatosensory cortices of monkeys are somatotopically activated for action-observation as are for action generation, indicating that the recruitment of learned somatosensory-motor representations underlies the perception of others' actions. Here we examined the effects of seen and unseen actions on the early visual cortices, to determine whether stored visual representations are employed in addition to the somatosensory-motor ones. We used the quantitative (14)C-deoxyglucose method to map the activity throughout the cortex of the occipital operculum, lunate, and inferior occipital sulci of "rhesus monkeys" who reached to grasp a 3D object either in the light or in the dark or who observed the same action executed by another subject. In all cases, the extrastriate areas V3d and V3A displayed marked activation. We suggest that these activations reflect processing of visuospatial information useful for the reaching component of action, and 3D object-related information useful for the grasping part. We suggest that a memorized visual representation of the action supports action-recognition, as well as action-execution in complete darkness when the object and its environment are invisible. Accordingly, the internal representation that serves action cognition is not purely somatosensory-motor but also includes a visual component. PMID- 20833698 TI - Lateralization of speech production starts in sensory cortices--a possible sensory origin of cerebral left dominance for speech. AB - Speech production is a left-lateralized brain function, which could arise from a left dominance either in speech executive or sensory processes or both. Using functional magnetic resonance imaging in healthy subjects, we show that sensory cortices already lateralize when speaking is intended, while the frontal cortex only lateralizes when speech is acted out. The sequence of lateralization, first temporal then frontal lateralization, suggests that the functional lateralization of the auditory cortex could drive hemispheric specialization for speech production. PMID- 20833703 TI - Exploring physician perceptions of the impact of emotions on behaviour during interactions with patients. AB - BACKGROUND: There is relatively little research on affective influences on physician behaviour, especially on prescribing and referrals. Affects include transitory moods and lasting emotions. OBJECTIVES: We explored physician perceptions of the impact of four mood states on perceived rates of five behaviours: talking with patients, prescribing medications and referrals for laboratory tests, diagnostic tests and specialists. We also examined whether burnout modified the impact of moods on behaviour. METHODS: A total of 188 family physicians responded anonymously to a self-reporting questionnaire that assessed the perceived rate of behaviours when in a positive, negative, tired and nervous mood and burnout level. RESULTS: Five analyses of variance with repeated measures on mood states and contrast analyses computed the effects of mood and burnout on the behaviours. The mood factor was found significant for each of the behaviours, in all P < 0.001. The respondents reported that on good mood compared with negative mood days, they talked more, prescribed less and referred less. The burnout factor was also significant: high compared with low burnout physicians had higher perceived rates of all referral behaviours. Significant mood * burnout interactions indicated that the effects of mood were stronger among high compared with low burnout physicians. CONCLUSIONS: The physicians perceived that their moods had different effects on different behaviours: the negative mood decreased talking and increased prescribing and referral behaviours and vice versa for the positive mood. Burnout intensified the effects of moods. The incremental effects of negative moods and burnout may impair quality of health care and may be costly to health services. PMID- 20833704 TI - Psychosocial risk factors for chronic low back pain in primary care--a systematic review. AB - BACKGROUND: Low back pain (LBP) is a major public health problem, often encountered in primary care. Guidelines recommend early identification of psychosocial factors that could prevent recovery from acute LBP. METHODS: To review the evidence on the prognostic value of psychosocial factors on transition from acute to chronic non-specific LBP in the adult general population. Systematic review is the design of the study. A systematic search was undertaken for prospective studies dealing with psychosocial risk factors for poor outcome of LBP in primary care, screening PubMed, PsychInfo and Cochrane Library databases. The methodological quality of studies was assessed independently by two reviewers using standardized criteria before analysing their main results. RESULTS: Twenty-three papers fulfilled the inclusion criteria, covering 18 different cohorts. Sixteen psychosocial factors were analysed in three domains: social and socio-occupational, psychological and cognitive and behavioural. Depression, psychological distress, passive coping strategies and fear-avoidance beliefs were sometimes found to be independently linked with poor outcome, whereas most social and socio-occupational factors were not. The predictive ability of a patient's self-perceived general health at baseline was difficult to interpret because of biomedical confounding factors. The initial patient's or care provider's perceived risk of persistence of LBP was the factor that was most consistently linked with actual outcome. CONCLUSION: Few independent psychosocial risk factors have been demonstrated to exist. Randomized clinical trials aimed at modifying these factors have shown little impact on patient prognosis. Qualitative research might be valuable to explore further the field of LBP and to define new management strategies. PMID- 20833705 TI - Lost in interpretation: the use of interpreters in research on mental ill health. AB - BACKGROUND: The literature concerning interpretation in research primarily concentrates on rigorous techniques to eliminate bias. This article analyses other significant issues that arise when interpreters participate in research. MATERIAL: Empirical examples are drawn from a research project concerning mental ill health in a multicultural neighbourhood. DISCUSSION: Interpreters influence interview data in ways commonly unnoticed by researchers. One often-overlooked factor is that languages are dynamic and interpreters are not instruments. CONCLUSION: Research conducted with an interpreter is a complex undertaking. Solely relying on checklists to improve methodological rigour can result in a false sense of the material's validity. PMID- 20833706 TI - Reasons for participation in group-based type 2 diabetes self-management education. A qualitative study. AB - AIMS: To investigate reasons for participating in group-based diabetes self management education (DSME) for patients with type 2 diabetes. METHODS: A qualitative study using focus groups and individual semi-structured interviews was conducted with 22 patients attending seven different groups in Central Norway. RESULTS: Patients with diabetes described two main reasons for attending DSME; experiencing practical problems and feeling insecure. These reasons differed by affecting the patients in two ways - practically or emotionally. Practical problems and feeling insecure both originated from lack of or contradictory information and from lack of contact with other patients with diabetes. This affected the patients' everyday lives in important areas such as diet, medication, social settings and lifestyle changes. CONCLUSIONS: The underlying reason for participating in a DSME was the participants' experience of having insufficient information about their diabetes, which led to practical problems and emotional insecurity. Being aware of the patients' reasons for participating can help professionals keep a focus which is more consistent with patients' needs. PMID- 20833707 TI - Effect of N-acetyl cysteine and alpha-linolenic acid on sulfur mustard caused impairment of in vitro endothelial tube formation. AB - Sulfur mustard (SM), an alkylating chemical warfare agent, leads to tissue damage, including inflammation, blister formation, and impaired wound healing. Especially wound healing is of concern because after SM exposure, wound healing is prolonged. In this study, we focused on the effect of SM (30 and 100MUM) on endothelial tube formation, apoptosis, and proliferation in mouse embryoid bodies (EBs), which provide an appropriate model for investigating vasculogenesis and angiogenesis. EBs were exposed to SM for 30 min on day 0, 3, or 6 of EBs' growth, were allowed to grow until day 7, then fixed, and immunostained (PECAM-1, Ki67, and activated caspase-3). SM significantly decreased endothelial tube formation compared with unexposed EBs. Additionally, we observed a significant increase of apoptosis. As the formation of reactive oxygen species (ROS) is discussed to be involved in the pathophysiology of SM toxicity, we evaluated the effect of ROS scavengers (alpha-linolenic acid [ALA] and N-acetyl cysteine [NAC]) in the same experimental setup. Temporary effects of both scavengers could be detected, in particular NAC seemed to have temporary significant positive effects on endothelial tube formation in 100MUM SM-exposed EBs. ALA augmented proliferation when administered after 30MUM SM exposure on day 3, whereas NAC treatment on day 0 decreased apoptosis induced by 100MUM SM. Taken together, our findings pointed to a negative effect of SM on vascularization and endothelial tube formation. ROS scavengers NAC and ALA showed temporary, but not long-lasting, rescuing effects regarding endothelial tube formation after SM exposure. PMID- 20833708 TI - The use of in vitro toxicity data and physiologically based kinetic modeling to predict dose-response curves for in vivo developmental toxicity of glycol ethers in rat and man. AB - At present, regulatory assessment of systemic toxicity is almost solely carried out using animal models. The European Commission's REACH legislation stimulates the use of animal-free approaches to obtain information on the toxicity of chemicals. In vitro toxicity tests provide in vitro concentration-response curves for specific target cells, whereas in vivo dose-response curves are regularly used for human risk assessment. The present study shows an approach to predict in vivo dose-response curves for developmental toxicity by combining in vitro toxicity data and in silico kinetic modeling. A physiologically based kinetic (PBK) model was developed, describing the kinetics of four glycol ethers and their embryotoxic alkoxyacetic acid metabolites in rat and man. In vitro toxicity data of these metabolites derived in the embryonic stem cell test were used as input in the PBK model to extrapolate in vitro concentration-response curves to predicted in vivo dose-response curves for developmental toxicity of the parent glycol ethers in rat and man. The predicted dose-response curves for rat were found to be in concordance with the embryotoxic dose levels measured in reported in vivo rat studies. Therefore, predicted dose-response curves for rat could be used to set a point of departure for deriving safe exposure limits in human risk assessment. Combining the in vitro toxicity data with a human PBK model allows the prediction of dose-response curves for human developmental toxicity. This approach could therefore provide a means to reduce the need for animal testing in human risk assessment practices. PMID- 20833710 TI - Contribution of lysine 11-linked ubiquitination to MIR2-mediated major histocompatibility complex class I internalization. AB - The polyubiquitin chain is generated by the sequential addition of ubiquitin moieties to target molecules, a reaction between specific lysine residues that is catalyzed by E3 ubiquitin ligase. The Lys(48)-linked and Lys(63)-linked polyubiquitin chains are well established inducers of proteasome-dependent degradation and signal transduction, respectively. The concept has recently emerged that polyubiquitin chain-mediated regulation is even more complex because various types of atypical polyubiquitin chains have been discovered in vivo. Here, we demonstrate that a novel complex ubiquitin chain functions as an internalization signal for major histocompatibility complex class I (MHC I) membrane proteins in vivo. Using a tetracycline-inducible expression system and quantitative mass spectrometry, we show that the polyubiquitin chain generated by the viral E3 ubiquitin ligase of Kaposi sarcoma-associated herpesvirus, MIR2, is a Lys(11) and Lys(63) mixed-linkage chain. This novel ubiquitin chain can function as an internalization signal for MHC I through its association with epsin1, an adaptor molecule containing ubiquitin-interacting motifs. PMID- 20833709 TI - The glutaredoxin GLRX-21 functions to prevent selenium-induced oxidative stress in Caenorhabditis elegans. AB - Selenium is an essential micronutrient that functions as an antioxidant. Yet, at higher concentrations, selenium is pro-oxidant and toxic. In extreme cases, exposures to excess selenium can lead to death or selenosis, a syndrome characterized by teeth, hair and nail loss, and nervous system alterations. Recent interest in selenium as an anti- tumorigenic agent has reemphasized the need to understand the mechanisms underlying the cellular consequences of increased selenium exposure. We show here, that in the nematode, Caenorhabditis elegans, selenium has a concentration range in which it functions as an antioxidant, but beyond this range it exhibits a dose- and time-dependent lethality. Oxidation-induced fluorescence emitted by the dye, carboxy-H(2)DCFDA, indicative of reactive oxygen species formation was significantly higher in animals after a brief exposure to 5mM sodium selenite. Longer-term exposures lead to a progressive selenium-induced motility impairment that could be partially prevented by coincident exposure to the cellular antioxidant-reduced glutathione. The C elegans glrx-21 gene belongs to the family of glutaredoxins (glutathione dependent oxidoreductases) and the glrx-21(tm2921) allele is a null mutation that renders animals hypersensitive for the selenium-induced motility impairment, but not lethality. In addition, the lethality of animals with the tm2921 mutation exposed to selenium was unaffected by the addition of reduced glutathione, suggesting that GLRX-21 is required for glutathione to moderate this selenium induced lethality. Our findings provide the first description of selenium-induced toxicity in C elegans and support its use as a model for elucidating the mechanisms of selenium toxicity. PMID- 20833711 TI - Sulforaphane activates heat shock response and enhances proteasome activity through up-regulation of Hsp27. AB - It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid beta-induced cytotoxicity. Here, we report that SFN activates heat shock transcription factor 1-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27 overexpressing cells but absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells, in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN induced proteasome activity. This is the first report to show that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1 Nrf2 pathway, may contribute to cytoprotection. PMID- 20833712 TI - Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS1-associated tight junction protein. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic cause of kidney failure, characterized by the development of renal cysts. ADPKD is caused by mutations of the polycystin-1 (PC1) or polycystin-2 (PC2) genes. PC2 encodes a Ca(2+)-permeable cation channel, and its dysfunction has been implicated in cyst development. The transcriptional coactivator with PDZ binding motif (TAZ) is required for the integrity of renal cilia. Its absence results in the development of renal cysts in a knock-out mouse model. TAZ directly interacts with PC2, and it has been suggested that another yet unidentified PDZ domain protein may be involved in the TAZ/PC2 interaction. Here we describe a novel interaction of TAZ with the multi-PDZ-containing PALS1 associated tight junction protein (PATJ). TAZ interacts with both the N-terminal PDZ domains 1-3 and the C-terminal PDZ domains 8-10 of PATJ, suggesting two distinct TAZ binding domains. We also show that the C terminus of PC2 strongly interacts with PDZ domains 8-10 and to a weaker extent with PDZ domains 1-3 of PATJ. Finally, we demonstrate that both TAZ and PATJ impair PC2 channel activity when co-expressed with PC2 in oocytes of Xenopus laevis. These results implicate TAZ and PATJ as novel regulatory elements of the PC2 channel and might thus be involved in ADPKD pathology. PMID- 20833713 TI - Ethanol-induced HO-1 and NQO1 are differentially regulated by HIF-1alpha and Nrf2 to attenuate inflammatory cytokine expression. AB - Oxidative stress plays an important role in alcohol-induced inflammation and liver injury. Relatively less is known about how Kupffer cells respond to oxidative stress-induced expression of heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase (NQO1) to blunt inflammation and liver injury. We showed that Kupffer cells from ethanol-fed rats and ethanol-treated rat Kupffer cells and THP-1 cells displayed increased mRNA expression of HO-1, NQO1, and hypoxia-inducible factor-1alpha (HIF-1alpha). Our studies showed that silencing with HIF-1alpha and JNK-1 siRNAs attenuated ethanol-mediated mRNA expression of HO-1, but not NQO1, whereas Nrf2 siRNA attenuated the mRNA expression of both HO 1 and NQO1. Additionally, JunD but not JunB formed an activator protein-1 (AP-1) oligomeric complex to augment HO-1 promoter activity. Ethanol-induced HO-1 transcription involved antioxidant response elements, hypoxia-response elements, and an AP-1 binding motif in its promoter, as demonstrated by mutation analysis of the promoter, EMSA, and ChIP. Furthermore, livers of ethanol-fed c-Jun(fl/fl) mice showed reduced levels of mRNA for HO-1 but not of NQO1 compared with ethanol fed control rats, supporting the role of c-Jun or the AP-1 transcriptional complex in ethanol-induced HO-1 expression. Additionally, attenuation of HO-1 levels in ethanol-fed c-Jun(fl/fl) mice led to increased proinflammatory cytokine expression in the liver. These results for the first time show that ethanol regulates HO-1 and NQO1 transcription by different signaling pathways. Additionally, up-regulation of HO-1 protects the liver from excessive formation of inflammatory cytokines. These studies provide novel therapeutic targets to ameliorate alcohol induced inflammation and liver injury. PMID- 20833714 TI - Folic acid remodels chromatin on Hes1 and Neurog2 promoters during caudal neural tube development. AB - The mechanism(s) behind folate rescue of neural tube closure are not well understood. In this study we show that maternal intake of folate prior to conception reverses the proliferation potential of neural crest stem cells in homozygous Splotch embryos (Sp(-/-)) via epigenetic mechanisms. It is also shown that the pattern of differentiation seen in these cells is similar to wild-type (WT). Cells from open caudal neural tubes of Sp(-/-) embryos exhibit increased H3K27 methylation and decreased expression of KDM6B possibly due to up-regulation of KDM6B targeting micro-RNAs such as miR-138, miR-148a, miR-185, and miR-339-5p. In our model, folate reversed these epigenetic marks in folate-rescued Sp(-/-) embryos. Using tissue from caudal neural tubes of murine embryos we also examined H3K27me2 and KDM6B association with Hes1 and Neurog2 promoters at embryonic day E10.5, the proliferative stage, and E12.5, when neural differentiation begins. In Sp(-/-) embryos compared with WT, levels of H3K27me2 associated with the Hes1 promoter were increased at E10.5, and levels associated with the Neurog2 promoter were increased at E12.5. KDM6B association with Hes1 and Neurog2 promoters was inversely related to H3K27me2 levels. These epigenetic changes were reversed in folate-rescued Sp(-/-) embryos. Thus, one of the mechanisms by which folate may rescue the Sp(-/-) phenotype is by increasing the expression of KDM6B, which in turn decreases H3K27 methylation marks on Hes1 and Neurog2 promoters thereby affecting gene transcription. PMID- 20833715 TI - Structure of dimeric F1F0-ATP synthase. AB - The structure of the dimeric ATP synthase from yeast mitochondria was analyzed by transmission electron microscopy and single particle image analysis. In addition to the previously reported side views of the dimer, top view and intermediate projections served to resolve the arrangement of the rotary c(10) ring and the other stator subunits at the F(0)-F(0) dimeric interface. A three-dimensional reconstruction of the complex was calculated from a data set of 9960 molecular images at a resolution of 27 A. The structural model of the dimeric ATP synthase shows the two monomers arranged at an angle of ~45 degrees , consistent with our earlier analysis of the ATP synthase from bovine heart mitochondria (Minauro Sanmiguel, F., Wilkens, S., and Garcia, J. J. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 12356-12358). In the ATP synthase dimer, the two peripheral stalks are located near the F(1)-F(1) interface but are turned away from each other so that they are not in contact. Based on the three-dimensional reconstruction, a model of how dimeric ATP synthase assembles to form the higher order oligomeric structures that are required for mitochondrial cristae biogenesis is discussed. PMID- 20833716 TI - Differential anti-APOBEC3G activity of HIV-1 Vif proteins derived from different subtypes. AB - Antiretroviral cytidine deaminase APOBEC3G, which is abundantly expressed in peripheral blood lymphocytes and macrophages, strongly protects these cells against HIV-1 infection. The HIV-1 Vif protein overcomes this antiviral effect by enhancing proteasome-mediated APOBEC3G degradation and is key for maintaining viral infectivity. The 579-bp-long vif gene displays high genetic diversity among HIV-1 subtypes. Therefore, it is intriguing to address whether Vif proteins derived from different subtypes differ in their viral defense activity against APOBEC3G. Expression plasmids encoding Vif proteins derived from subtypes A, B, C, CRF01_AE, and CRF02_AG isolates were created, and their anti-APOBEC3G activities were compared. Viruses produced from cells expressing APOBEC3G and Vif proteins from different subtypes showed relatively different viral infectivities. Notably, subtype C-derived Vif proteins tested had the highest activity against APOBEC3G that was ascribed to its increased binding activity, for which the N terminal domain of the Vif protein sequences was responsible. These results suggest that the biological differences of Vif proteins belonging to different subtypes might affect viral fitness and quasispecies in vivo. PMID- 20833717 TI - Amyloid-binding small molecules efficiently block SEVI (semen-derived enhancer of virus infection)- and semen-mediated enhancement of HIV-1 infection. AB - Semen was recently shown to contain amyloid fibrils formed from a self-assembling peptide fragment of the protein prostatic acid phosphatase. These amyloid fibrils, termed semen-derived enhancer of virus infection, or SEVI, have been shown to strongly enhance HIV infectivity and may play an important role in sexual transmission of HIV, making them a potential microbicide target. One novel approach to target these fibrils is the use of small molecules known to intercalate into the structure of amyloid fibrils, such as derivatives of thioflavin-T. Here, we show that the amyloid-binding small molecule BTA-EG(6) (the hexa(ethylene glycol) derivative of benzothiazole aniline) is able to bind SEVI fibrils and effectively inhibit both SEVI-mediated and semen-mediated enhancement of HIV infection. BTA-EG(6) also blocks the interactions of SEVI with HIV-1 virions and HIV-1 target cells but does not cause any inflammation or toxicity to cervical epithelial cells. These results suggest that an amyloid binding small molecule may have utility as a microbicide, or microbicidal supplement, for HIV-1. PMID- 20833718 TI - Distinct MHC class II molecules are associated on the dendritic cell surface in cholesterol-dependent membrane microdomains. AB - Very small amounts of MHC class II-peptide complexes expressed on the surface of antigen-presenting cells (APCs) are capable of stimulating antigen-specific CD4 T cells. There is intense interest to elucidate the molecular mechanisms by which these small amounts of MHC-II can cluster, cross-link T cell receptors, and promote T cell proliferation. We now demonstrate that a significant fraction of the total pool of MHC-II molecules on the surface of dendritic cells is physically associated in macromolecular aggregates. These MHC-II/MHC-II interactions have been probed by co-immunoprecipitation analysis of the MHC-II I A molecule with the related I-E molecule. These molecular associations are maintained in gentle detergents but are disrupted in harsh detergents such as Triton X-100. MHC-II I-A/I-E interactions are disrupted when plasma membrane cholesterol is extracted using methyl beta-cyclodextrin, suggesting that lipid raft microdomains are important mediators of these MHC-II interactions. Although it has been proposed that tetraspanin proteins regulate molecular clustering, aggregation, and co-immunoprecipitation in APCs, genetic deletion of the tetraspanin family members CD9 or CD81 had no effect on MHC-II I-A/I-E binding. These data demonstrate that the presence of distinct forms of MHC-II with plasma membrane lipid rafts is required for MHC-II aggregation in APCs and provides a molecular mechanism allowing dendritic cells expressing small amounts of MHC-II peptide complexes to cross-link and stimulate CD4 T cells. PMID- 20833719 TI - Human beta-synuclein rendered fibrillogenic by designed mutations. AB - Filamentous inclusions made of alpha-synuclein are found in nerve cells and glial cells in a number of human neurodegenerative diseases, including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. The assembly and spreading of these inclusions are likely to play an important role in the etiology of common dementias and movement disorders. Both alpha-synuclein and the homologous beta-synuclein are abundantly expressed in the central nervous system; however, beta-synuclein is not present in the pathological inclusions. Previously, we observed a poor correlation between filament formation and the presence of residues 73-83 of alpha-synuclein, which are absent in beta synuclein. Instead, filament formation correlated with the mean beta-sheet propensity, charge, and hydrophilicity of the protein (global physicochemical properties) and beta-strand contiguity calculated by a simple algorithm of sliding averages (local physicochemical property). In the present study, we rendered beta-synuclein fibrillogenic via one set of point mutations engineered to enhance global properties and a second set engineered to enhance predominantly beta-strand contiguity. Our findings show that the intrinsic physicochemical properties of synucleins influence their fibrillogenic propensity via two distinct but overlapping modalities. The implications for filament formation and the pathogenesis of neurodegenerative diseases are discussed. PMID- 20833720 TI - Insight into the mechanism of human herpesvirus 7 U21-mediated diversion of class I MHC molecules to lysosomes. AB - The U21 open reading frame from human herpesvirus-7 encodes a membrane protein that associates with and redirects class I MHC molecules to the lysosomal compartment. The mechanism by which U21 accomplishes this trafficking excursion is unknown. Here we have examined the contribution of localization, glycosylation, domain structure, and the absence of substrate class I MHC molecules on the ability of U21 to traffic to lysosomes. Our results suggest the existence of a cellular protein necessary for U21-mediated rerouting of class I MHC molecules. PMID- 20833721 TI - The isolation and characterization of glycosylated phosphoproteins from herring fish bones. AB - Past studies of bone extracellular matrix phosphoproteins such as osteopontin and bone sialoprotein have yielded important biological information regarding their role in calcification and the regulation of cellular activity. Most of these studies have been limited to proteins extracted from mammalian and avian vertebrates and nonvertebrates. The present work describes the isolation and purification of two major highly glycosylated and phosphorylated extracellular matrix proteins of 70 and 22 kDa from herring fish bones. The 70-kDa phosphoprotein has some characteristics of osteopontin with respect to amino acid composition and susceptibility to thrombin cleavage. Unlike osteopontin, however, it was found to contain high levels of sialic acid similar to bone sialoprotein. The 22-kDa protein has very different properties such as very high content of phosphoserine (~270 Ser(P) residues/1000 amino acid residues), Ala, and Asx residues. The N-terminal amino acid sequence analysis of both the 70-kDa (NPIMA(M)ETTS(M)DSKVNPLL) and the 22-kDa (NQDMAMEASSDPEAA) fish phosphoproteins indicate that these unique amino acid sequences are unlike any published in protein databases. An enzyme-linked immunosorbent assay revealed that the 70-kDa phosphoprotein was present principally in bone and in calcified scales, whereas the 22-kDa phosphoprotein was detected only in bone. Immunohistological analysis revealed diffusely positive immunostaining for both the 70- and 22-kDa phosphoproteins throughout the matrix of the bone. Overall, this work adds additional support to the concept that the mechanism of biological calcification has common evolutionary and fundamental bases throughout vertebrate species. PMID- 20833723 TI - Monovalency unleashes the full therapeutic potential of the DN-30 anti-Met antibody. AB - Met, the high affinity receptor for hepatocyte growth factor, is one of the most frequently activated tyrosine kinases in human cancer and a validated target for cancer therapy. We previously developed a mouse monoclonal antibody directed against the extracellular portion of Met (DN-30) that induces Met proteolytic cleavage (receptor "shedding") followed by proteasome-mediated receptor degradation. This translates into inhibition of hepatocyte growth factor/Met mediated biological activities. However, DN-30 binding to Met also results in partial activation of the Met kinase due to antibody-mediated receptor homodimerization. To safely harness the therapeutic potential of DN-30, its shedding activity must be disassociated from its agonistic activity. Here we show that the DN-30 Fab fragment maintains high affinity Met binding, elicits efficient receptor shedding and down-regulation, and does not promote kinase activation. In Met-addicted tumor cell lines, DN-30 Fab displays potent cytostatic and cytotoxic activity in a dose-dependent fashion. DN-30 Fab also inhibits anchorage-independent growth of several tumor cell lines. In mouse tumorigenesis assays using Met-addicted carcinoma cells, intratumor administration of DN-30 Fab or systemic delivery of a chemically stabilized form of the same molecule results in reduction of Met phosphorylation and inhibition of tumor growth. These data provide proof of concept that monovalency unleashes the full therapeutic potential of the DN-30 antibody and point at DN-30 Fab as a promising tool for Met-targeted therapy. PMID- 20833724 TI - Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice. AB - The immune system is complex, with multiple layers of regulation that serve to prevent the production of self-antigens. One layer of regulation involves regulatory T cells (Tregs) that play an essential role in maintaining peripheral self-tolerance. Patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis have decreased levels of HDL, suggesting that apoA-I concentrations may be important in preventing autoimmunity and the loss of self-tolerance. In published studies, hypercholesterolemic mice lacking HDL apoA-I or LDLr(-/-), apoA-I(-/-) (DKO), exhibit characteristics of autoimmunity in response to an atherogenic diet. This phenotype is characterized by enlarged cholesterol-enriched lymph nodes (LNs), as well as increased T cell activation, proliferation, and the production of autoantibodies in plasma. In this study, we investigated whether treatment of mice with lipid-free apoA-I could attenuate the autoimmune phenotype. To do this, DKO mice were first fed an atherogenic diet containing 0.1% cholesterol, 10% fat for 6 weeks, after which treatment with apoA-I was begun. Subcutaneous injections of 500 MUg of lipid-free apoA-I was administered every 48 h during the treatment phase. These and control mice were maintained for an additional 6 weeks on the diet. At the end of the 12 week study, DKO mice showed decreased numbers of LN immune cells, whereas Tregs were proportionately increased. Accompanying this increase in Tregs was a decrease in the percentage of effector/effector memory T cells. Furthermore, lipid accumulation in LN and skin was reduced. These results suggest that treatment with apoA-I reduces inflammation in DKO mice by augmenting the effectiveness of the LN Treg response. PMID- 20833725 TI - GDP-bound and nucleotide-free intermediates of the guanine nucleotide exchange in the Rab5.Vps9 system. AB - Many GTPases regulate intracellular transport and signaling in eukaryotes. Guanine nucleotide exchange factors (GEFs) activate GTPases by catalyzing the exchange of their GDP for GTP. Here we present crystallographic and biochemical studies of a GEF reaction with four crystal structures of Arabidopsis thaliana ARA7, a plant homolog of Rab5 GTPase, in complex with its GEF, VPS9a, in the nucleotide-free and GDP-bound forms, as well as a complex with aminophosphonic acid-guanylate ester and ARA7.VPS9a(D185N) with GDP. Upon complex formation with ARA7, VPS9 wedges into the interswitch region of ARA7, inhibiting the coordination of Mg(2+) and decreasing the stability of GDP binding. The aspartate finger of VPS9a recognizes GDP beta-phosphate directly and pulls the P-loop lysine of ARA7 away from GDP beta-phosphate toward switch II to further destabilize GDP for its release during the transition from the GDP-bound to nucleotide-free intermediates in the nucleotide exchange reaction. PMID- 20833722 TI - Identification of anhydrobiosis-related genes from an expressed sequence tag database in the cryptobiotic midge Polypedilum vanderplanki (Diptera; Chironomidae). AB - Some organisms are able to survive the loss of almost all their body water content, entering a latent state known as anhydrobiosis. The sleeping chironomid (Polypedilum vanderplanki) lives in the semi-arid regions of Africa, and its larvae can survive desiccation in an anhydrobiotic form during the dry season. To unveil the molecular mechanisms of this resistance to desiccation, an anhydrobiosis-related Expressed Sequence Tag (EST) database was obtained from the sequences of three cDNA libraries constructed from P. vanderplanki larvae after 0, 12, and 36 h of desiccation. The database contained 15,056 ESTs distributed into 4,807 UniGene clusters. ESTs were classified according to gene ontology categories, and putative expression patterns were deduced for all clusters on the basis of the number of clones in each library; expression patterns were confirmed by real-time PCR for selected genes. Among up-regulated genes, antioxidants, late embryogenesis abundant (LEA) proteins, and heat shock proteins (Hsps) were identified as important groups for anhydrobiosis. Genes related to trehalose metabolism and various transporters were also strongly induced by desiccation. Those results suggest that the oxidative stress response plays a central role in successful anhydrobiosis. Similarly, protein denaturation and aggregation may be prevented by marked up-regulation of Hsps and the anhydrobiosis-specific LEA proteins. A third major feature is the predicted increase in trehalose synthesis and in the expression of various transporter proteins allowing the distribution of trehalose and other solutes to all tissues. PMID- 20833726 TI - Regulatory network identification by genetical genomics: signaling downstream of the Arabidopsis receptor-like kinase ERECTA. AB - Gene expression differences between individuals within a species can be largely explained by differences in genetic background. The effect of genetic variants (alleles) of genes on expression can be studied in a multifactorial way by the application of genetical genomics or expression quantitative trait locus mapping. In this paper, we present a strategy to construct regulatory networks by the application of genetical genomics in combination with transcript profiling of mutants that are disrupted in single genes. We describe the network identification downstream of the receptor-like kinase ERECTA in Arabidopsis (Arabidopsis thaliana). Extending genetical genomics on the Landsberg erecta/Cape Verde Islands (Ler/Cvi) recombinant inbred population with expression profiling of monogenic mutants enabled the identification of regulatory networks in the so far elusive ERECTA signal transduction cascade. We provide evidence that ERECTA is the causal gene for the major hotspot for transcript regulation in the Arabidopsis Ler/Cvi recombinant inbred population. We further propose additional genetic variation between Ler and Cvi in loci of the signaling pathway downstream of ERECTA and suggest candidate genes underlying these loci. Integration of publicly available microarray expression data of other monogenic mutants allowed us to link ERECTA to a downstream mitogen-activated protein kinase signaling cascade. Our study shows that microarray data of monogenic mutants can be effectively used in combination with genetical genomics data to enhance the identification of genetic regulatory networks. PMID- 20833727 TI - Multiple roles of soluble sugars in the establishment of Gunnera-Nostoc endosymbiosis. AB - Gunnera plants have the unique ability to form endosymbioses with N(2)-fixing cyanobacteria, primarily Nostoc. Cyanobacteria enter Gunnera through transiently active mucilage-secreting glands on stems. We took advantage of the nitrogen (N) limitation-induced gland development in Gunnera manicata to identify factors that may enable plant tissue to attract and maintain cyanobacteria colonies. Cortical cells in stems of N-stressed Gunnera plants were found to accumulate a copious amount of starch, while starch in the neighboring mature glands was nearly undetectable. Instead, mature glands accumulated millimolar concentrations of glucose (Glc) and fructose (Fru). Successful colonization by Nostoc drastically reduced sugar accumulation in the surrounding tissue. Consistent with the abundance of Glc and Fru in the gland prior to Nostoc colonization, genes encoding key enzymes for sucrose and starch hydrolysis (e.g. cell wall invertase, alpha-amylase, and starch phosphorylase) were expressed at higher levels in stem segments with glands than those without. In contrast, soluble sugars were barely detectable in mucilage freshly secreted from glands. Different sugars affected Nostoc's ability to differentiate motile hormogonia in a manner consistent with their locations. Galactose and arabinose, the predominant constituents of polysaccharides in the mucilage, had little or no inhibitory effect on hormogonia differentiation. On the other hand, soluble sugars that accumulated in gland tissue, namely sucrose, Glc, and Fru, inhibited hormogonia differentiation and enhanced vegetative growth. Results from this study suggest that, in an N-limited environment, mature Gunnera stem glands may employ different soluble sugars to attract Nostoc and, once the cyanobacteria are internalized, to maintain them in the N(2)-fixing vegetative state. PMID- 20833728 TI - Digital gene expression signatures for maize development. AB - Genome-wide expression signatures detect specific perturbations in developmental programs and contribute to functional resolution of key regulatory networks. In maize (Zea mays) inflorescences, mutations in the RAMOSA (RA) genes affect the determinacy of axillary meristems and thus alter branching patterns, an important agronomic trait. In this work, we developed and tested a framework for analysis of tag-based, digital gene expression profiles using Illumina's high-throughput sequencing technology and the newly assembled B73 maize reference genome. We also used a mutation in the RA3 gene to identify putative expression signatures specific to stem cell fate in axillary meristem determinacy. The RA3 gene encodes a trehalose-6-phosphate phosphatase and may act at the interface between developmental and metabolic processes. Deep sequencing of digital gene expression libraries, representing three biological replicate ear samples from wild-type and ra3 plants, generated 27 million 20- to 21-nucleotide reads with frequencies spanning 4 orders of magnitude. Unique sequence tags were anchored to 3'-ends of individual transcripts by DpnII and NlaIII digests, which were multiplexed during sequencing. We mapped 86% of nonredundant signature tags to the maize genome, which associated with 37,117 gene models and unannotated regions of expression. In total, 66% of genes were detected by at least nine reads in immature maize ears. We used comparative genomics to leverage existing information from Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) in functional analyses of differentially expressed maize genes. Results from this study provide a basis for the analysis of short-read expression data in maize and resolved specific expression signatures that will help define mechanisms of action for the RA3 gene. PMID- 20833729 TI - Genome structures and halophyte-specific gene expression of the extremophile Thellungiella parvula in comparison with Thellungiella salsuginea (Thellungiella halophila) and Arabidopsis. AB - The genome of Thellungiella parvula, a halophytic relative of Arabidopsis (Arabidopsis thaliana), is being assembled using Roche-454 sequencing. Analyses of a 10-Mb scaffold revealed synteny with Arabidopsis, with recombination and inversion and an uneven distribution of repeat sequences. T. parvula genome structure and DNA sequences were compared with orthologous regions from Arabidopsis and publicly available bacterial artificial chromosome sequences from Thellungiella salsuginea (previously Thellungiella halophila). The three-way comparison of sequences, from one abiotic stress-sensitive species and two tolerant species, revealed extensive sequence conservation and microcolinearity, but grouping Thellungiella species separately from Arabidopsis. However, the T. parvula segments are distinguished from their T. salsuginea counterparts by a pronounced paucity of repeat sequences, resulting in a 30% shorter DNA segment with essentially the same gene content in T. parvula. Among the genes is SALT OVERLY SENSITIVE1 (SOS1), a sodium/proton antiporter, which represents an essential component of plant salinity stress tolerance. Although the SOS1 coding region is highly conserved among all three species, the promoter regions show conservation only between the two Thellungiella species. Comparative transcript analyses revealed higher levels of basal as well as salt-induced SOS1 expression in both Thellungiella species as compared with Arabidopsis. The Thellungiella species and other halophytes share conserved pyrimidine-rich 5' untranslated region proximal regions of SOS1 that are missing in Arabidopsis. Completion of the genome structure of T. parvula is expected to highlight distinctive genetic elements underlying the extremophile lifestyle of this species. PMID- 20833730 TI - TNFalpha and IFNgamma synergistically enhance transcriptional activation of CXCL10 in human airway smooth muscle cells via STAT-1, NF-kappaB, and the transcriptional coactivator CREB-binding protein. AB - Asthmatic airway smooth muscle (ASM) expresses interferon-gamma-inducible protein 10 (CXCL10), a chemokine known to mediate mast cell migration into ASM bundles that has been reported in the airways of asthmatic patients. CXCL10 is elevated in patients suffering from viral exacerbations of asthma and in patients with chronic obstructive pulmonary disease (COPD), diseases in which corticosteroids are largely ineffective. IFNgamma and TNFalpha synergistically induce CXCL10 release from human ASM cells in a steroid-insensitive manner, via an as yet undefined mechanism. We report that TNFalpha activates the classical NF-kappaB (nuclear factor kappaB) pathway, whereas IFNgamma activates JAK2/STAT-1alpha and that inhibition of the JAK/STAT pathway is more effective in abrogating CXCL10 release than the steroid fluticasone. The synergy observed with TNFalpha and IFNgamma together, however, did not lie at the level of NF-kappaB activation, STAT-1alpha phosphorylation, or in vivo binding of these transcription factors to the CXCL10 promoter. Stimulation of human ASM cells with TNFalpha and IFNgamma induced histone H4 but not histone H3 acetylation at the CXCL10 promoter, although no synergism was observed when both cytokines were combined. We show, however, that TNFalpha and IFNgamma exert a synergistic effect on the recruitment of CREB-binding protein (CBP) to the CXCL10, which is accompanied by increased RNA polymerase II. Our results provide evidence that synergism between TNFalpha and IFNgamma lies at the level of coactivator recruitment in human ASM and suggest that inhibition of JAK/STAT signaling may be of therapeutic benefit in steroid-resistant airway disease. PMID- 20833731 TI - Ex3alphaERKO male infertility phenotype recapitulates the alphaERKO male phenotype. AB - Disruption of the Esr1 gene encoding estrogen receptor alpha (ERalpha) by insertion of a neomycin resistance gene (neo) into exon 2 (alphaERKO mice) was shown previously to cause infertility in male mice. While full-length ERalpha protein was not expressed in alphaERKO mice, alternative splicing resulted in the low-level expression of a truncated form lacking the N-terminus A/B domain and containing the DNA- and ligand-binding domains. Thus, it was unclear whether the reproductive phenotype in alphaERKO males was only due to the lack of full-length ERalpha or was affected by the presence of the variant ERalpha isoform. The present study examined male mice with deletion of exon 3 of Esr1 gene, lacking the DNA-binding domain, and null for ERalpha (Ex3alphaERKO). Dilation of some seminiferous tubules was apparent in male Ex3alphaERKO mice as early as postnatal day 10 and was pronounced in all tubules from day 20 onward. At 6 weeks of age, sperm numbers and sperm motility were lower in Ex3alphaERKO mice than in wild type (WT) mice, and the rete testis and efferent ductules were dilated. Mating studies determined that adult Ex3alphaERKO males were infertile and failed to produce copulatory plugs. Serum testosterone levels and Hsd17b3 and Cyp17a1 transcript levels were significantly higher, but serum estradiol, progesterone, LH, and FSH levels and Cyp19a1 transcript levels were not significantly different from those in WT mice. These results confirm and extend those seen in other studies on male mice with deletion of exon 3 of Esr1 gene. In addition, the reproductive phenotype of male Ex3alphaERKO mice recapitulated the phenotype of alphaERKO mice, strongly suggesting that the alphaERKO male infertility was not due to the presence of the DNA-binding domain in the truncated form of ERalpha and that full-length ERalpha is essential for maintenance of male fertility. PMID- 20833732 TI - NPY genes play an essential role in root gravitropic responses in Arabidopsis. AB - Plants can sense the direction of gravity and orient their growth to ensure that roots are anchored in soil and that shoots grow upward. Gravitropism has been studied extensively using Arabidopsis genetics, but the exact mechanisms for gravitropism are not fully understood. Here, we demonstrate that five NPY genes play a key role in Arabidopsis root gravitropism. NPY genes were previously identified as regulators of auxin-mediated organogenesis in a genetic pathway with the AGC kinases PID, PID2, WAG1, and WAG2. We show that all five NPY genes are highly expressed in primary root tips. The single npy mutants do not display obvious gravitropism defects, but the npy1 npy2 npy3 npy4 npy5 quintuple mutants show dramatic gravitropic phenotypes. Systematic analysis of all the npy double, triple, and quadruple combinations demonstrates that the five NPY genes all contribute to gravitropism. Our work indicates that gravitropism, phototropism, and organogenesis use analogous mechanisms in which at least one AGC kinase, one NPH3/NPY gene, and one ARF are required. PMID- 20833733 TI - Functional characterization and RNAi-mediated suppression reveals roles for hexose transporters in sugar accumulation by tomato fruit. AB - Hexoses accumulate to high concentrations (~ 200 mM) in storage parenchyma cells of tomato fruit. Hexoses are sourced from the fruit apoplasm as hydrolysis products of phloem-imported sucrose. Three hexose transporters (LeHT1, LeHT2, LeHT3), expressed in fruit storage parenchyma cells, may contribute to hexose uptake by these cells. An analysis of their full-length sequences demonstrated that all three transporters belong to the STP sub-family of monosaccharide transporters that localize to plasma membranes. Heterologous expression of LeHT1 (and previously LeHT2, Gear et al., 2000), but not LeHT3, rescued a hexose transport-impaired yeast mutant when raised on glucose or fructose as the sole carbon source. Biochemically, LeHT1, similarly to LeHT2, exhibited transport properties consistent with a high-affinity glucose/H(+) symporter. Significantly, LeHT1 and LeHT2 also functioned as low-affinity fructose/H(+) symporters with apparent K(m) values commensurate with those of fruit tissues. A substantial reduction (80-90%) in fruit expression levels of all LeHT genes by RNAi-mediated knockdown caused a 55% decrease in fruit hexose accumulation. In contrast, photoassimilate production by source leaves and phloem transport capacity to fruit were unaffected by transporter knockdown. Collectively, these findings demonstrate that LeHTs play key roles in driving accumulation of hexoses into storage parenchyma cells during tomato fruit development. PMID- 20833734 TI - Mapping of tonoplast intrinsic proteins in maturing and germinating Arabidopsis seeds reveals dual localization of embryonic TIPs to the tonoplast and plasma membrane. AB - We have mapped the expression of the tonoplast intrinsic protein (TIP) gene family members in Arabidopsis seeds by fluorescent protein tagging of their genomic sequences and confocal microscopy. Three isoforms (TIP1;1, TIP2;1, and TIP2;2) have distinct patterns of expression in maternal tissues (outer integument and placento-chalazal region). Two isoforms, TIP3;1 and the previously uncharacterized TIP3;2, are the only detectable TIPs in embryos during seed maturation and the early stages of seed germination. Throughout these developmental stages, both isoforms co-locate to the tonoplast of the protein storage vacuoles, but also appear to label the plasma membrane. Plasma membrane labeling is specific to TIP3;1 and TIP3;2, is independent of the position of the fluorescent protein tag, and appears to be specific to early seed maturation and early germination stages. We discuss these results in the context of the predicted distribution of aquaporins in Arabidopsis seeds. PMID- 20833735 TI - Post-translational derepression of invertase activity in source leaves via down regulation of invertase inhibitor expression is part of the plant defense response. AB - There is increasing evidence that pathogens do not only elicit direct defense responses, but also cause pronounced changes in primary carbohydrate metabolism. Cell-wall-bound invertases belong to the key regulators of carbohydrate partitioning and source-sink relations. Whereas studies have focused so far only on the transcriptional induction of invertase genes in response to pathogen infection, the role of post-translational regulation of invertase activity has been neglected and was the focus of the present study. Expression analyses revealed that the high mRNA level of one out of three proteinaceous invertase inhibitors in source leaves of Arabidopsis thaliana is strongly repressed upon infection by a virulent strain of Pseudomonas syringae pv. tomato DC3000. This repression is paralleled by a decrease in invertase inhibitor activity. The physiological role of this regulatory mechanism is revealed by the finding that in situ invertase activity was detectable only upon infection by P. syringae. In contrast, a high invertase activity could be measured in vitro in crude and cell wall extracts prepared from both infected and non-infected leaves. The discrepancy between the in situ and in vitro invertase activity of control leaves and the high in situ invertase activity in infected leaves can be explained by the pathogen-dependent repression of invertase inhibitor expression and a concomitant reduction in invertase inhibitor activity. The functional importance of the release of invertase from post-translational inhibition for the defense response was substantiated by the application of the competitive chemical invertase inhibitor acarbose. Post-translational inhibition of extracellular invertase activity by infiltration of acarbose in leaves was shown to increase the susceptibility to P. syringae. The impact of invertase inhibition on spatial and temporal dynamics of the repression of photosynthesis and promotion of bacterial growth during pathogen infection supports a role for extracellular invertase in plant defense. The acarbose-mediated increase in susceptibility was also detectable in sid2 and cpr6 mutants and resulted in slightly elevated levels of salicylic acid, demonstrating that the effect is independent of the salicylic acid-regulated defense pathway. These findings provide an explanation for high extractable invertase activity found in source leaves that is kept inhibited in situ by post-translational interaction between invertase and the invertase inhibitor proteins. Upon pathogen infection, the invertase activity is released by repression of invertase inhibitor expression, thus linking the local induction of sink strength to the plant defense response. PMID- 20833736 TI - The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel. AB - INTRODUCTION: Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease. METHODS: /Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications. RESULTS: All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered. DISCUSSION: The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile. PMID- 20833737 TI - An assessment of disease flare in patients with systemic lupus erythematosus: a comparison of BILAG 2004 and the flare version of SELENA. AB - AIMS: To compare the British Isles Lupus Assessment Group (BILAG) 2004, the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) flare index (SFI) and physician's global assessment (PGA) in assessing flares of disease activity in patients with systemic lupus erythematosus (SLE). METHODS: Sixteen patients with active SLE were assessed by a panel of 16 rheumatologists. The order in which the patients were seen was randomised using a 4*4 Latin square design. Each patient's flare status was determined at each assessment using the BILAG 2004 activity index; the SFI and a PGA. A group of five specialists designated each patient into severe, moderate, mild or no flare categories. RESULTS: The rate of complete agreement (95% CI) of the four individual examining physicians for any flare versus no flare was 81% (55% to 94%), 75% (49% to 90%) and 75% (49% to 90%) for the BILAG 2004 index, SELENA flare instrument and PGA, respectively. The overall agreement between flare defined by BILAG 2004 and the SFI was 81% and when type of flare was considered was 52%. Intraclass correlation coefficients (95% CI), as a measure of internal reliability, were 0.54 (0.32 to 0.78) for BILAG 2004 flare compared with 0.21 (0.08 to 0.48) for SELENA flare and 0.18 (0.06 to 0.45) for PGA. Severe flare was associated with good agreement between the indices but mild/moderate flare was much less consistent. CONCLUSIONS: The assessment of flare in patients with SLE is challenging. No flare and severe flare are identifiable but further work is needed to optimise the accurate 'capture' of mild and moderate flares. PMID- 20833738 TI - Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. AB - BACKGROUND: Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment. METHODS: A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months. RESULTS: The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out. CONCLUSIONS: Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance. PMID- 20833739 TI - Fertility and pregnancy outcomes following conservative treatment for placenta accreta. AB - BACKGROUND: The aim of this study was to estimate the fertility and pregnancy outcomes after successful conservative treatment for placenta accreta. METHODS: This retrospective national multicenter study included women with a history of conservative management for placenta accreta in French university hospitals from 1993 through 2007. Success of conservative treatment was defined by uterine preservation. Data were retrieved from medical files and telephone interviews. RESULTS: Follow-up data were available for 96 (73.3%) of the 131 women included in the study. There were eight women who had severe intrauterine synechiae and were amenorrheic. Of the 27 women who wanted more children, 3 women were attempting to become pregnant (mean duration: 11.7 months, range: 7-14 months), and 24 (88.9% [95% confidence interval (CI), 70.8-97.6%]) women had had 34 pregnancies (21 third-trimester deliveries, 1 ectopic pregnancy, 2 elective abortions and 10 miscarriages) with a mean time to conception of 17.3 months (range, 2-48 months). All 21 deliveries had resulted in healthy babies born after 34 weeks of gestation. Placenta accreta recurred in 6 of 21 cases [28.6% (95% CI, 11.3-52.2%)] and was associated with placenta previa in 4 cases. Post-partum hemorrhage occurred in four [19.0% (95% CI, 5.4-41.9%)] cases, related to placenta accreta in three and to uterine atony in one. CONCLUSIONS: Successful conservative treatment for placenta accreta does not appear to compromise the patients' subsequent fertility or obstetrical outcome. Nevertheless, patients should be advised of the high risk that placenta accreta may recur during future pregnancies. PMID- 20833741 TI - Human brucellosis. PMID- 20833740 TI - Acceptability and accuracy of a non-endoscopic screening test for Barrett's oesophagus in primary care: cohort study. AB - OBJECTIVES: To determine the accuracy and acceptability to patients of non endoscopic screening for Barrett's oesophagus, using an ingestible oesophageal sampling device (Cytosponge) coupled with immunocytochemisty for trefoil factor 3. DESIGN: Prospective cohort study. SETTING: 12 UK general practices, with gastroscopies carried out in one hospital endoscopy unit. PARTICIPANTS: 504 of 2696 eligible patients (18.7%) aged 50 to 70 years with a previous prescription for an acid suppressant (H(2) receptor antagonist or proton pump inhibitor) for more than three months in the past five years. MAIN OUTCOME MEASURES: Sensitivity and specificity estimates for detecting Barrett's oesophagus compared with gastroscopy as the ideal method, and patient anxiety (short form Spielberger state trait anxiety inventory, impact of events scale) and acceptability (visual analogue scale) of the test. RESULTS: 501 of 504 (99%) participants (median age 62, male to female ratio 1:1.2) successfully swallowed the Cytosponge. No serious adverse events occurred. In total, 3.0% (15/501) had an endoscopic diagnosis of Barrett's oesophagus (>=1 cm circumferential length, median circumferential and maximal length of 2 cm and 5 cm, respectively) with intestinal metaplasia. Compared with gastroscopy the sensitivity and specificity of the test was 73.3% (95% confidence interval 44.9% to 92.2%) and 93.8% (91.3% to 95.8%) for 1 cm or more circumferential length and 90.0% (55.5% to 99.7%) and 93.5% (90.9% to 95.5%) for clinically relevant segments of 2 cm or more. Most participants (355/496, 82%, 95% confidence interval 78.9% to 85.1%) reported low levels of anxiety before the test, and scores remained within normal limits at follow-up. Less than 4.5% (2.8% to 6.1%) of participants reported psychological distress a week after the procedure. CONCLUSIONS: The performance of the Cytosponge test was promising and the procedure was well tolerated. These data bring screening for Barrett's oesophagus into the realm of possibility. Further evaluation is recommended. PMID- 20833742 TI - Diagnosis and management of Barrett's oesophagus. PMID- 20833743 TI - Drug decriminalisation in Portugal. PMID- 20833744 TI - Non-endoscopic screening for Barrett's oesophagus. PMID- 20833745 TI - Diploma in old wives' tales medicine anyone? PMID- 20833746 TI - RNase L releases a small RNA from HCV RNA that refolds into a potent PAMP. AB - Triggering and propagating an intracellular innate immune response is essential for control of viral infections. RNase L is a host endoribonuclease and a pivotal component of innate immunity that cleaves viral and cellular RNA within single stranded loops releasing small structured RNAs with 5'-hydroxyl (5'-OH) and 3' monophosphoryl (3'-p) groups. In 2007, we reported that RNase L cleaves self RNA to produce small RNAs that function as pathogen-associated molecular patterns (PAMPs). However, the precise sequence and structure of PAMP RNAs produced by RNase L is unknown. Here we used hepatitis C virus RNA as substrate to characterize RNase L mediated cleavage products [named suppressor of virus RNA (svRNA)] for their ability to activate RIG-I like receptors (RLR). The NS5B region of HCV RNA was cleaved by RNase L to release an svRNA that bound to RIG-I, displacing its repressor domain and stimulating its ATPase activity while signaling to the IFN-beta gene in intact cells. All three of these RIG-I functions were dependent on the presence in svRNA of the 3'-p. Furthermore, svRNA suppressed HCV replication in vitro through a mechanism involving IFN production and triggered a RIG-I-dependent hepatic innate immune response in mice. RNase L and OAS (required for its activation) were both expressed in hepatocytes from HCV infected patients, raising the possibility that the OAS/RNase L pathway might suppress HCV replication in vivo. It is proposed that RNase L mediated cleavage of HCV RNA generates svRNA that activates RIG-I, thus propagating innate immune signaling to the IFN-beta gene. PMID- 20833748 TI - Surgeon is suspended for misleading his supervisor over his research. PMID- 20833749 TI - US court temporarily lifts ban on stem cell research. PMID- 20833750 TI - Scientists respond to UK business secretary's warning of cuts in research funding. PMID- 20833751 TI - European drug agency calls for more ethical trials in developing countries. PMID- 20833752 TI - Microarray analysis of gene expression during early development: a cautionary overview. AB - The rise of the 'omics' technologies started nearly a decade ago and, among them, transcriptomics has been used successfully to contrast gene expression in mammalian oocytes and early embryos. The scarcity of biological material that early developmental stages provide is the prime reason why the field of transcriptomics is becoming more and more popular with reproductive biologists. The potential to amplify scarce mRNA samples and generate the necessary amounts of starting material enables the relative measurement of RNA abundance of thousands of candidates simultaneously. So far, microarrays have been the most commonly used high-throughput method in this field. Microarray platforms can be found in a wide variety of formats, from cDNA collections to long or short oligo probe sets. These platforms generate large amounts of data that require the integration of comparative RNA abundance values in the physiological context of early development for their full benefit to be appreciated. Unfortunately, significant discrepancies between datasets suggest that direct comparison between studies is difficult and often not possible. We have investigated the sample handling steps leading to the generation of microarray data produced from prehatching embryo samples and have identified key steps that significantly impact the downstream results. This review provides a discussion on the best methods for the preparation of samples from early embryos for microarray analysis and focuses on the challenges that impede dataset comparisons from different platforms and the reasons why methodological benchmarking performed using somatic cells may not apply to the atypical nature of prehatching development. PMID- 20833753 TI - Increase of fecundity by probiotic administration in zebrafish (Danio rerio). AB - It is well known established that reproduction is sensitive to the state of energy reserves, and that there is a balance between energy homeostasis and fertility. In this view, this study examined the effects of the probiotic Lactobacillus rhamnosus, as a feed additive, on zebrafish (Danio rerio) fecundity. Ten days of probiotic treatment modulate the gene expression of neuropeptide hormones and metabolic signals, such as kiss1, kiss2 and leptin both at the CNS level and at the peripheral level. The increase in fecundity brought about by the probiotic was demonstrated by the higher number of ovulated eggs in vivo and by the higher germinal vesicle breakdown rate obtained with the in vitro maturation assay. The increase in oocyte maturation was associated with increased transcription of genes coding for signals which induce the maturation phase, such as lhcgr, cbr1l, and paqr8 genes, concomitant with a decreased transcription of genes coding for local factors which prevent oocyte maturation, such as tgfb1, gdf9, and bmp15. In conclusion, all these findings highlight the action of L. rhamnosus both on the endocrine system and at the local level by inducing oocyte maturation. The significance of the results herein obtained underlined the importance of diet in the reproductive process, supporting the hypothesis that feed additives can improve fecundity. Considering that the zebrafish has been clearly established as a vertebrate model for biomedical research, these results support the potentiality of feed additives such as probiotics, frequently used in the human diet, as a new technology to improve reproduction in all vertebrates, including humans. PMID- 20833754 TI - Hyaluronan inhibits postchemotherapy tumor regrowth in a colon carcinoma xenograft model. AB - Bone marrow hypoplasia and pancytopenia are among the most undesirable sequelae of chemotherapy for the treatment of cancer. We recently showed that hyaluronan (HA) facilitates hematopoietic recovery in tumor-free animals receiving chemotherapeutic agents. However, following a chemotherapeutic regimen in tumor bearing animals, it is possible that residual tumor cells might respond to systemic injections of HA. Thus, in this study, we investigated the effect of HA on the regrowth of residual tumor cells following chemotherapy. As a model, we used the HCT-8 human colon carcinoma cell line, which expresses the HA receptor CD44, binds exogenous HA, and is susceptible to a chemotherapy protocol containing irinotecan and 5-fluorouracil in a human/mouse xenograft model. HCT-8 cells were implanted in severe combined immunodeficient mice, followed by irinotecan/5-fluorouracil treatment. After three rounds of chemotherapy, residual tumors were allowed to regrow in the presence or absence of HA. The dynamics of tumor regrowth in the group treated with HA was slower compared with the control group. By week 5 after tumor implantation, the difference in the size of regrown tumors was statistically significant and correlated with lower proliferation and higher apoptosis in HA-treated tumors as compared with controls. This finding provides evidence that HA treatment does not stimulate but delays the growth of residual cancer cells, which is an important parameter in establishing whether the use of HA can enhance current chemotherapeutic strategies. PMID- 20833755 TI - Nanaomycin A selectively inhibits DNMT3B and reactivates silenced tumor suppressor genes in human cancer cells. AB - Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes. PMID- 20833756 TI - Long-term air pollution exposure and risk factors for cardiovascular diseases among the elderly in Taiwan. AB - OBJECTIVES: To investigate changes in blood pressure, blood lipids, blood sugar and haematological markers of inflammation associated with changes in long-term exposure to ambient air pollutants. METHODS: We conducted secondary analyses of data on blood pressure and blood biochemistry markers from the Social Environment and Biomarkers of Aging Study in Taiwan and air pollution data from the Taiwan Environmental Protection Administration in 2000. Associations of 1-year averaged criteria air pollutants (particulate matter with aerodynamic diameters <10 MUm (PM(10)) and <2.5 MUm (PM(2.5)), ozone (O(3)), nitrogen dioxide (NO(2)), sulfur dioxide and carbon monoxide) with systolic blood pressure, diastolic blood pressure, total cholesterol, triglycerides, high-density lipoprotein cholesterol, fasting glucose, haemoglobin A1c (HbA1c), interleukin 6 (IL-6) and neutrophils were explored by applying generalised additive models. RESULTS: After controlling for potential confounders, we observed that increased 1-year averaged particulate air pollutants (PM(10) and PM(2.5)) and NO(2) were associated with elevated blood pressure, total cholesterol, fasting glucose, HbA1c, IL-6 and neutrophils. Associations of increased 1-year averaged O(3) with elevated blood pressure, total cholesterol, fasting glucose, HbA1c and neutrophils were also observed. In particular, our two-pollutant models showed that PM(2.5) was more significantly associated with end-point variables than two gaseous pollutants, O(3) and NO(2). CONCLUSIONS: Changes in blood pressure, blood lipids, blood sugar and haematological markers of inflammation are associated with long-term exposure to ambient air pollutants. This might provide a link between air pollution and atherosclerotic cardiovascular diseases. PMID- 20833757 TI - The effects of timing on the cost-effectiveness of interventions for workers on sick leave due to low back pain. AB - OBJECTIVE: To examine the effects of different timing of structured interventions for workers on sick leave due to low back pain on return to work (RTW), and the consequences for costs and benefits. METHODS: Literature reviews were conducted to identify RTW curves and to estimate treatment effects, costs and benefits of structured interventions among workers on sick leave due to low back pain. RTW curves were mathematically described by Weibull functions and intervention effects, expressed by hazard ratios, were used to adjust these Weibull functions. Subsequently, these functions were used to evaluate the theoretical effects of interventions on reduction in number of days on sick leave and on the benefit cost ratio. RESULTS: The cost-benefits of a RTW intervention among workers on sick leave due to low back pain were determined by the estimated effectiveness of the intervention, the costs of the intervention, the natural course of RTW in the target population, the timing of the enrolment of subjects into the intervention, and the duration of the intervention. CONCLUSION: With a good RTW in the first weeks, the only early interventions likely to be cost-beneficial are inexpensive work-focused enhancements to early routine care, such as accommodating workplaces. Structured interventions are unlikely to have an additional impact on the already good prognosis when offered before the optimal time window at approximately 8 to 12 weeks. The generalisibility of the effectiveness of a RTW intervention depends on the comparability of baseline characteristics and RTW curves in target and source populations. PMID- 20833758 TI - Lung cancer mortality from exposure to chrysotile asbestos and smoking: a case control study within a cohort in China. AB - OBJECTIVE: To confirm the association between exposure to chrysotile asbestos and lung cancer risk and to demonstrate the combined effect of smoking and asbestos exposure. METHODS: A case-control study of 1139 asbestos workers identified 41 male lung cancer cases in 2001; each case was matched by age (+/-5 years) with five controls. Workers in seven workshops were categorised into high-, medium- and low-exposure subgroups, and conditional logistic regression was applied to estimate the odds ratios for lung cancer risk associated with the different exposure levels. Smoking, age at first exposure, and exposure duration were considered as covariates/confounding factors. A joint effect of asbestos exposure and smoking on lung cancer risk was analysed using a conditional logistical model. RESULTS: 54% of cases had high exposure and 24% low exposure, while 24% of controls had high exposure and 44% low exposure. Smoking was more common in cases (90%) than in controls (73%). The adjusted OR for lung cancer was 3.66 (95% CI 1.61 to 8.29) for high exposure and was elevated slightly for medium exposure (1.25; 95% CI 0.47 to 3.31). Smoking was related to lung cancer risk (OR 3.33; 95% CI 1.10 to 10.08). In comparison with the low-exposure non-smoking group, the OR for the high-exposure smoking group was 10.39 (1.34 to 82.45), in contrast to 5.23 (0.50 to 54.58) for high-exposure non-smoking workers. CONCLUSIONS: These results confirm the strong association between exposure to chrysotile asbestos and lung cancer risk, and support an interactive effect of asbestos exposure and smoking which is more than additive. PMID- 20833759 TI - Stress management interventions in the workplace improve stress reactivity: a randomised controlled trial. AB - OBJECTIVE: To examine the long-term effects of a stress management intervention (SMI) based on the effort-reward imbalance (ERI) model, on psychological and biological reactions to work stress. METHODS: 174 lower or middle management employees (99% male) were randomly assigned to an intervention or a waiting control group. The programme comprised 24 * 45 min group sessions (2 full days followed by two 4 * 45 min sessions within the next 8 months) on individual work stress situations. The primary endpoint was perceived stress reactivity (Stress Reactivity Scale, SRS), while secondary endpoints were salivary cortisol and alpha-amylase, anxiety and depression, and ERI. Assessments were repeated in 154 participants 1 year later. RESULTS: SRS score decreased in both groups. A two factor ANOVA with repeated measures showed a significant time * group effect (F=5.932; p=0.016) with the greater reduction in the intervention group. For SRS, the effect size (Cohen's d) after 1 year was d=0.416 in the intervention and d=0.166 in the control group. alpha-Amylase as a measure of sympathetic nervous system activation, decreased more strongly in the intervention group (area under the daytime curve and daytime slope: time * group effect p=0.076 and p=0.075). No difference was observed for cortisol. For depression, anxiety and ERI, improvements were higher in the intervention group but did not reach statistical significance. CONCLUSIONS: SMI based on work stress theory, is effective in reducing perceived stress reactivity and sympathetic activation in lower and middle management employees. Other mental health parameters and ERI show a tendency towards improvement. These beneficial effects are present 1 year later. PMID- 20833760 TI - The relationship between multiple myeloma and occupational exposure to six chlorinated solvents. AB - OBJECTIVES: Few studies have examined whether exposure to chlorinated solvents is associated with multiple myeloma. We evaluated associations between multiple myeloma and occupational exposure to six chlorinated solvents: 1,1,1 trichloroethane, trichloroethylene (TCE), methylene chloride (DCM), perchloroethylene, carbon tetrachloride and chloroform. METHODS: In-person interviews obtained occupational histories and information on jobs with likely solvent exposure. We assigned exposure metrics of probability, frequency, intensity and confidence using job-exposure matrices modified by job-specific questionnaire information. We used logistic regression to estimate ORs and 95% CIs for associations between multiple myeloma and ever exposure to each, and any, chlorinated solvent and analysed whether associations varied by duration and cumulative exposure. We also considered all occupations that were given the lowest confidence scores as unexposed and repeated all analyses. RESULTS: Risk of multiple myeloma was elevated for subjects ever exposed to 1,1,1-trichloroethane (OR (95% CI): 1.8 (1.1 to 2.9)). Ever exposure to TCE or DCM also entailed elevated, but not statistically significant, risks of multiple myeloma; these became statistically significant when occupations with low confidence scores were considered unexposed (TCE: 1.7 (1.0 to 2.7); DCM: 2.0 (1.2 to 3.2)). Increasing cumulative exposure to perchloroethylene was also associated with increasing multiple myeloma risk. We observed non-significantly increased multiple myeloma risks with exposure to chloroform; however, few subjects were exposed. CONCLUSIONS: Evidence from this relatively large case-control study suggests that exposures to certain chlorinated solvents may be associated with increased incidence of multiple myeloma; however, the study is limited by relatively low participation (52%) among controls. PMID- 20833761 TI - Neuroplastic changes within the brains of manganese-exposed welders: recruiting additional neural resources for successful motor performance. AB - BACKGROUND: In a previous study, regional delivery of manganese (Mn)ions within the brain revealed that the metal accumulates in the basal ganglia, where it induces degeneration of the globus pallidus. Degeneration of the basal ganglia impairs motor ability by compromising an important neural circuit involved in the regulation of motor control. Therefore, much research has been devoted to identifying a sensitive and non-invasive imaging marker to evaluate the functional correlates of Mn-related brain dysfunction. METHODS: We performed the first-ever sequential finger-tapping functional MRI (fMRI) experiment to investigate the behavioural significance of additionally recruited brain regions in welders with chronic Mn exposure. RESULTS: During the finger tapping task, activation of the bilateral primary sensorimotor cortex (SM1), bilateral supplementary motor area (SMA), bilateral dorsolateral premotor cortex, bilateral superior parietal cortex and ipsilateral dentate nucleus was higher in the welding group (42 welders) than in the control group (26 controls). The pallidal index correlated with the activation observed in the contralateral SM1 for the finger tapping task of the left hand. The fMRI variables correlated with motor behaviour. Grooved Pegboard performances (right hand) correlated with activation, as seen in the ipsilateral and contralateral SMAs obtained during the finger tapping task of the right hand. CONCLUSION: Our findings suggest that increased brain activation results from the compensational activation of ancillary cortical pathways, which ensures adequate motor function. PMID- 20833762 TI - Prevalence and correlates of regional pain and associated disability in Japanese workers. AB - OBJECTIVES: To assess the prevalence and correlates of regional pain and associated disability in four groups of Japanese workers. METHODS: As part of a large international survey of musculoskeletal symptoms (the CUPID study), nurses, office workers, sales/marketing personnel and transportation operatives in Japan completed a self-administered questionnaire (response rate 83%) covering experience of pain in six anatomical regions, associated disability and sickness absence, and various possible occupational and psychosocial risk factors for these outcomes. Associations with risk factors were assessed by logistic regression. RESULTS: Analysis was based on 2290 subjects. Rates of regional pain were generally less than in the UK, with a particularly low prevalence of wrist/hand pain among office workers (6% in past month). The strongest and most consistent risk factor for regional pain in the past month was tendency to somatise (ORs (95% CIs) for report of >= 2 versus 0 distressing somatic symptoms 3.1 (2.4 to 4.0) for low back pain, 2.8 (2.1 to 3.8) for shoulder pain, and 2.5 (1.6 to 4.1) for wrist/hand pain). Sickness absence for regional pain complaints in the past year was reported by 5% of participants, the major risk factor for this outcome being absence during the same period for other medical reasons (OR 3.7, 95% CI 2.4 to 5.8). CONCLUSIONS: Japanese office workers have markedly lower rates of wrist/hand pain than their UK counterparts. In Japan, as in Western Europe, somatising tendency is a major risk factor for regional pain. Sickness absence attributed to regional pain complaints appears to be much less common in Japan than in the UK, and to be driven principally by a general propensity to take sickness absence. PMID- 20833763 TI - Undergraduate performance in a domestic animal laboratory taught via distance education. AB - The objective of this study was to determine if laboratory modules of an undergraduate animal anatomy course offered in distance education (DistEd) format were as effective as face-to-face (F2F) format in helping students learn. Students (n = 159) completed an anatomy pretest as well as a presurvey to assess prior DistEd experience. Alternating each week, laboratory topics were presented either as F2F or as virtual DistEd laboratories. Two laboratory examinations were administered and included material from both laboratory formats (DistEd and F2F). Questions from the pretest were also included and used to generate the posttest scores. At the end of the semester, students completed a postsurvey to determine if DistEd was a viable alternative to F2F. Student grades on each examination were compared using an ANOVA model that included main effects of presentation method (DistEd, F2F), semester (fall, spring), and their interaction. Learning was evaluated based on the performances of students on pre- and posttests using unpaired t-tests. There was an increase (P < 0.0001) in anatomy post- vs. pretest scores for both semesters, indicative of student learning, although there was no effect of presentation method (F2F or DistEd). On exam 1, students achieved greater scores in fall 2008 (P < 0.0001) on material presented via DistEd compared with that presented as F2F. However, in spring 2009 students scored better on material presented as F2F. There was no effect of presentation method on exam 2 scores for either semester. Based on the postsurvey, 79.3% of students in fall 2008 and 52% of students from spring 2009 agreed that DistEd laboratories were a viable alternative to F2F laboratories. The results of this study support the conclusion that anatomy material can be taught effectively by distance education methods. PMID- 20833764 TI - Longissimus muscle transcriptome profiles related to carcass and meat quality traits in fresh meat Pietrain carcasses. AB - High quality pork is consumed as fresh meat, whereas other carcasses are used in the processing industry. Meat quality is determined measuring technical muscle variables. The objective of this research was to investigate the molecular regulatory mechanisms underlying meat quality differences of pork originating from genetically different Pietrain boars. Pietrain boars were approved for high meat quality using a DNA marker panel. Other Pietrain boars were indicated as average. Both groups produced litters in similar Pietrain sows. The LM were sampled from 9 carcasses produced by approved boars and 8 carcasses of average boars. Total RNA was isolated, and an equal portion of each sample was pooled to make a reference sample representing the mean of all samples. Each sample was hybridized on microarrays against the reference in duplicate using a dye swaps design. After normalization and subtraction of 2 times the background, only genes expressed in at least 5 carcasses were analyzed. For all analyses the mean of the M-values relative to the reference (i.e., fold change), were used. Sixteen genes showed significant linear or quadratic associations between gene expression and meat color (Minolta a* value, Minolta L* value, reflection, pH 24 h) after Bonferroni correction. All these genes had expression levels similar to the reference in all carcasses. Studying association between gene expression levels and meat quality using only genes with expression statistically differing from the reference in at least 5 carcasses revealed 29 more genes associating with the technological meat quality variables, again with meat color as a main trait. These associations were not significant after Bonferroni correction and explained less of the phenotypic variation in the traits. Bioinformatics analyses with The Database for Annotation, Visualization and Integrated Discovery (DAVID) using the list of genes with more than 2-fold changed expression level revealed that these genes were mainly found in muscle-specific processes, protein complexes, and oxygen transport, and located to muscle-specific cellular localizations. Pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed pathways related to protein metabolism, cellular proliferation, signaling, and adipose development differing between the 2 groups of carcasses. Approved meat carcasses showed less variation in gene expression. The results highlight biological molecular mechanisms underlying the differences between the high meat quality approved and average boars. PMID- 20833765 TI - Alpharma Beef Cattle Nutrition Symposium: predictability of feedlot cattle growth performance. AB - Predicting performance is vital to management and marketing decisions in commercial feedlots. Agreement between performance predicted from NE equations or empirical regression relationships and actual performance is generally very good, suggesting that factors affecting performance by finishing cattle are fairly well documented. The challenge for feedlot managers is to predict performance with limited information at the start of the feeding period. Data on sex and initial shrunk BW (ISBW) are typically available when cattle start on feed. Relationships between ISBW, sex, and performance were evaluated using 3,363 pen records collected over 4 yr from 3 commercial feedlots in the Texas Panhandle. Mixed model regression was used to account for random effects of feedlot * season * year and fixed effects of ISBW (range = 227 to 451 kg), sex (steer or heifer), and ISBW * sex (P < 0.10 for all variables evaluated). Previously developed equations indicated that with intercept and slope adjustments for sex, ISBW accounted for 76 and 84% of the variation in DMI and final shrunk BW (FSBW), respectively. Similarly, newly developed regression equations that included ISBW, sex, and ISBW * sex accounted for 46 and 81% of the variation in ADG and HCW, respectively. Initial BW was negatively related to G:F (R(2) = 0.22). Including early DMI data (DMI from d 8 to 28) increased R(2) and decreased prediction error for DMI, indicating that updating predictions with interim intake data might prove beneficial. An independent data set (781 lots of steers and heifers) collected during 1 yr from 2 Texas Panhandle feedlots was used to validate equations developed with the larger database. Dry matter intake predicted from ISBW and sex accounted for 69% of the variation in observed DMI (SE of prediction = 0.47; mean bias = 0.42 kg). Predicting DMI with ISBW, sex, and DMI from d 8 to 28 of the feeding period increased r(2) to 0.76 and slightly decreased the SE of prediction (0.42 kg), but the equation had a strong linear bias (-0.174; P < 0.001). The r(2) values for regression of observed on predicted ADG, G:F, FSBW, and HCW were 0.37, 0.08, 0.74, and 0.73, respectively, with positive mean bias (underprediction for all equations). Average daily gain calculated with NE equations from predicted DMI (ISBW and sex equation) and predicted FSBW had a similar r(2) (0.38) but less mean bias (-0.08 kg) than ADG predicted directly from ISBW and sex. Adjustments to equations for animal type, health, and management effects would likely improve predictions. Nonetheless, results suggest that predicting performance from initial BW with adjustments for steers vs. heifers should have considerable utility in practical settings. PMID- 20833766 TI - Evidence of major genes affecting resistance to bacterial cold water disease in rainbow trout using Bayesian methods of segregation analysis. AB - Bacterial cold water disease (BCWD) causes significant economic loss in salmonid aquaculture. We previously detected genetic variation for BCWD resistance in our rainbow trout population, and a family-based selection program to improve resistance was initiated at the National Center for Cool and Cold Water Aquaculture (NCCCWA). This study investigated evidence of major trait loci affecting BCWD resistance using only phenotypic data (without using genetic markers) and Bayesian methods of segregation analysis (BMSA). A total of 10,603 juvenile fish from 101 full-sib families corresponding to 3 generations (2005, 2007, and 2009 hatch years) of the NCCCWA population were challenged by intraperitoneal injection with Flavobacterium psychrophilum, the bacterium that causes BCWD. The results from single- and multiple-QTL models of BMSA suggest that 6 to 10 QTL explaining 83 to 89% of phenotypic variance with either codominant or dominant disease-resistant alleles plus polygenic effects may underlie the genetic architecture of BCWD resistance. This study also highlights the importance of polygenic background effects in the genetic variation of BCWD resistance. The polygenic heritability on the observed scale of survival status is slightly larger than that previously reported for rainbow trout BCWD resistance. These findings provide the basis for designing informative crosses for QTL mapping and carrying out genome scans for QTL affecting BCWD resistance in rainbow trout. PMID- 20833767 TI - Companion animals symposium: humanized animal models of the microbiome. AB - Humans and other mammals are colonized by trillions of microorganisms, most of which reside in the gastrointestinal tract, that provide key metabolic capabilities, such as the biosynthesis of vitamins and AA, the degradation of dietary plant polysaccharides, and the metabolism of orally administered therapeutics. Although much progress has been made by studying the human microbiome directly, comparing the human microbiome with that of other animals, and constructing in vitro models of the human gut, there remains a need to develop in vivo models where host, microbial, and environmental parameters can be manipulated. Here, we discuss some of the initial results from a promising method that enables the direct manipulation of microbial community structure, environmental exposures, host genotype, and other factors: the colonization of germ-free animals with complex microbial communities, including those from humans or other animal donors. Analyses of these resulting "humanized" gut microbiomes have begun to reveal 1) that key microbial activities can be transferred from the donor to the recipient animal (e.g., microbial reduction of cholesterol and production of equol), 2) that dietary shifts can affect the composition, gene abundance, and gene expression of the gut microbiome, 3) the succession of the microbial community in infants and ex-germ-free adult animals, and 4) the biogeography of these microbes across the length of gastrointestinal tract. Continued studies of humanized and other intentionally colonized animal models stand to provide new insight into not only the human microbiome, but also the microbiomes of our animal companions. PMID- 20833768 TI - Influence of processing method on comparative digestion of white corn versus conventional steam-flaked yellow dent corn in finishing diets for feedlot cattle. AB - Four Holstein steers (137 +/- 2 kg) with cannulas in the rumen and proximal duodenum were used in a 4 * 4 Latin square design to evaluate the influence of processing method on comparative digestion of white corn. Treatments consisted of a basal finishing diet containing 80% corn grain (DM basis) as 1) dry-rolled white corn (DRWC), 2) steam-flaked white corn (SFWC) with 0.36 kg/L flake density (SFWC36), 3) SFWC, 0.31 kg/L flake density (SFWC31), and 4) steam-flaked yellow corn (SFYC) with 0.31 kg/L flake density (SFYC31). Characteristics of ruminal, postruminal, and apparent total tract digestion of OM, starch, and N were similar (P >= 0.08) for SFYC31 and SFWC31 treatments. Decreasing flake density of white corn (from 0.36 to 0.31 kg/L) did not affect (P = 0.22) ruminal OM digestion, but increased (1.9%, P = 0.07) apparent total tract OM digestion. Compared with dry rolling, steam flaking white corn increased ruminal (9.4%, P = 0.05), postruminal (14.4%, P < 0.01), and apparent total tract OM digestion (8.2%, P < 0.01), reflecting corresponding increases in ruminal (13.3%, P < 0.01), postruminal (43%, P < 0.01), and apparent total tract (12.3%, P < 0.01) starch digestion. Apparent postruminal and apparent total-tract N digestion also were greater (6.5 and 5.6%, respectively, P = 0.04) for SFWC than for DRWC. The DE value of SFWC and SFYC diets was similar, averaging 3.39 Mcal/kg. The DE value of SFWC was greater (8.1%, P < 0.01) than that of DRWC. Ruminal pH (4 h postprandial) averaged 5.74 and was not affected (P >= 0.48) by dietary treatments. Compared with dry rolling, steam flaking markedly enhances the feeding value of white corn, with optimal flake density being less than 0.36 kg/L. Although white corn has greater vitreous endosperm content, characteristics of ruminal starch digestion and undegradable intake protein are similar to conventional yellow dent corn when processed to a similar flake density (0.31 kg/L). However, postruminal and apparent total tract starch digestion tends to be slightly less for flaked white corn than for yellow corn. PMID- 20833769 TI - The effect of selection for residual feed intake on general behavioral activity and the occurrence of lesions in Yorkshire gilts. AB - The objectives of this study were to determine the effect of selection for improved residual feed intake on behavior, activity, and lesion scores in gilts in their home pen. A total of 192 gilts were used, 96 from a line that had been selected for decreased residual feed intake over 5 generations (LRFI) and 96 from a randomly bred control line. Gilts were housed in 12 pens (16 gilts/pen; 0.82 m(2)/gilt) containing 8 gilts from each line in a conventional grow-finish unit. Twelve hours of video footage were collected on the day of placement and then every 4 wk for 3 more observational periods. Video was scored using a 10-min instantaneous scan sampling technique for 4 postures (standing, lying, sitting, and locomotion) and 1 behavior (at drinker). Categories of active (standing, locomotion, and at drinker) and inactive (sitting and lying) were also created. Lesion scores were collected 24 h after behavior collection had begun. The body of a gilt was divided into 4 regions, with each region receiving a score of 0 (0 lesions) to 3 (5+ lesions). All statistical analyses used Proc Mixed of SAS. Data were analyzed separately for the day of placement and the subsequent 3 rounds. General activity was summarized on a percentage basis by each posture and behavior and subjected to an arcsine square root transformation to normalize data and stabilize variance. Analysis was performed on each behavior and posture. Lesion scores for each region of the body were analyzed as repeated measures. There were no differences (P > 0.05) between genetic lines for all postures and the behavior at drinker on the day of placement. However, over subsequent rounds it was observed that LRFI gilts spent less (P = 0.03) time standing, more time sitting (P = 0.05), and were less active (P = 0.03) overall. Gilts from the LRFI line had decreased (P < 0.045) lesion scores on the day after placement. However, over subsequent rounds there were no (P > 0.05) differences between the genetic lines. In conclusion, on the day of placement there were no postural, behavior, or general activity differences between genetic lines, but LRFI gilts had decreased lesion scores. Behavioral differences were observed between genetic lines over subsequent rounds, with LRFI gilts becoming less active, but there were no differences in lesion scores. PMID- 20833770 TI - Influence of feed flavors and nursery diet complexity on preweaning and nursery pig performance. AB - In Exp. 1, 50 sows and their litters were used to determine the effects of adding a feed flavor to the creep diet on the proportion of pigs consuming creep feed ("eaters") and preweaning performance. Sows were blocked according to parity and date of farrowing and allotted to 2 experimental treatments: 1) litters fed a creep diet with no flavor (negative control) or 2) negative control diet with the feed flavor (Luctarom) included at 1,500 mg/kg. Both creep diets contained 1.0% chromic oxide and were offered ad libitum from d 18 until weaning at d 21. Adding flavor to the creep diet did not (P > 0.41) affect weaning weights, total BW gain, ADG, total creep feed intake, daily creep feed intake, or the proportion of creep feed eaters in whole litters. In Exp. 2, 480 weanling pigs (6.58 +/- 0.41 kg; 20 +/- 2 d) from Exp. 1 were randomly selected by preweaning treatment group, blocked by initial BW, and allotted to 1 of 8 treatments in a randomized complete block design to determine the interactive effects of preweaning exposure to flavor (exposed vs. unexposed), nursery diet complexity (complex vs. simple), and flavor addition to nursery diets (with vs. without flavor). Each treatment had 10 replications (pens) with 6 pigs per pen. Diets with flavor were supplemented with the flavor at 1,500 mg/kg in phase 1 diets and 1,000 mg/kg in phase 2 diets. A tendency for a 3-way interaction for ADG from d 5 to 10 (P = 0.10), 10 to 28 (P = 0.09), and 0 to 28 (P = 0.06) was observed. Postweaning ADG of pigs exposed to flavor in creep feed and fed flavored complex diets in the nursery was greater than pigs in any other treatment combination. Increasing diet complexity improved (P < 0.01) ADG and ADFI during both postweaning phases. Adding flavor to creep feed had no effect on G:F (P > 0.34) and pig BW (P > 0.45) in both postweaning periods. Adding flavor to starter diets tended to improve ADFI (P = 0.06) during d 0 to 5. In conclusion, adding flavor to the creep feed did not affect litter creep feed intake, the proportion of piglets consuming creep feed, or preweaning performance when creep was provided for 3 d before weaning. Preweaning exposure to feed flavor improved postweaning ADG in pigs fed complex diets supplemented with the same flavor but did not influence performance of pigs fed simple diets. PMID- 20833771 TI - Effects of ad libitum and restricted feed intake on growth performance and body composition of Yorkshire pigs selected for reduced residual feed intake. AB - Residual feed intake (RFI), defined as the difference in the observed and expected feed intake while accounting for growth and backfat, has gained much attention, but little is known about why pigs selected for reduced RFI are more efficient. To this end, a line of Yorkshire pigs selected for reduced RFI was developed. The objective of this study was to evaluate the 5th generation of this select line against a randomly selected control line for performance, carcass and chemical carcass composition, and overall efficiency toward the later part of the growth phase. Eighty barrows, 40 from each line, were paired by age (~132 d, P < 0.60) and BW (74.8 +/- 9.9 kg, P < 0.49) and randomly assigned to 1 of 4 feeding treatments in 10 replicates: 1) ad libitum, 2) 75% of ad libitum, 55% of ad libitum, and BW stasis, with weekly adjustments in intake to keep BW constant for each pig. Pigs were individually penned (group housing was used for selection) and on treatment for 6 wk. Initial BW did not differ between the lines (P < 0.49). The ad libitum select pigs consumed 10% less feed (P < 0.09) than the ad libitum control with no significant difference in BW (P < 0.80) and slight differences in carcass fat composition (P < 0.20) and backfat (P < 0.11), which resulted in significantly less carcass energy (P < 0.03). Under restricted feeding, the select line had an increase in BW (P = 0.10) while consuming the same ration of feed as the control line with no significant difference in chemical carcass composition and lighter visceral weights, which was significant for the 75% of ad libitum treatment (P < 0.01). Under BW stasis feeding the select line consumed 7.6% less feed overall (P = 0.21) and 18% less feed at the end of the 6 wk (P < 0.08), to maintain static BW with no significant difference in chemical carcass composition compared with the control line. Overall, the select line had lighter visceral weight (P < 0.02) and a greater dressing percentage (P < 0.03) compared with the control line. Using regression, the select line had reduced energy retention (P < 0.04) and feed energy utilization (P < 0.34); however, the select line appeared to have reduced maintenance requirements (P < 0.13). In conclusion, selection for reduced RFI decreases feed intake with no significant difference (P > 0.05) in growth performance, reduced backfat, increased dressing percentage, and reduced maintenance requirements. All of these traits are appealing to the producer and result in increased profits in the production setting. PMID- 20833772 TI - Ventricular remodeling and survival are more favorable for myocarditis than for idiopathic dilated cardiomyopathy in childhood: an outcomes study from the Pediatric Cardiomyopathy Registry. AB - BACKGROUND: Myocarditis is a cause of a new-onset dilated cardiomyopathy phenotype in children, with small studies reporting high rates of recovery of left ventricular (LV) function. METHODS AND RESULTS: The presenting characteristics and outcomes of children with myocarditis diagnosed clinically and with biopsy confirmation (n=119) or with probable myocarditis diagnosed clinically or by biopsy alone (n=253) were compared with children with idiopathic dilated cardiomyopathy (n=1123). Characteristics at presentation were assessed as possible predictors of outcomes. The distributions of time to death, transplantation, and echocardiographic normalization in the biopsy-confirmed myocarditis and probable myocarditis groups did not differ (P>=0.5), but both groups differed significantly from the idiopathic dilated cardiomyopathy group (all P<=0.003). In children with myocarditis, lower LV fractional shortening z score at presentation predicted greater mortality (hazard ratio, 0.85; 95% confidence interval, 0.73 to 0.98; P=0.03) and greater LV posterior wall thickness predicted transplantation (hazard ratio, 1.17; 95% confidence interval, 1.02 to 1.35; P=0.03). In those with decreased LV fractional shortening at presentation, independent predictors of echocardiographic normalization were presentation with an LV end-diastolic dimension z-score >2 (hazard ratio, 0.36; 95% confidence interval, 0.22 to 0.58; P<0.001) and greater septal wall thickness (hazard ratio, 1.16; 95% confidence interval, 1.01 to 1.34; P=0.04). CONCLUSIONS: Children with biopsy-confirmed or probable myocarditis had similar proportions of death, transplantation, and echocardiographic normalization 3 years after presentation and better outcomes than those of children with idiopathic dilated cardiomyopathy. In children with myocarditis who had impaired LV ejection at presentation, rates of echocardiographic normalization were greater in those without LV dilation and in those with greater septal wall thickness at presentation. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005391. PMID- 20833776 TI - Keratinocyte growth factor enhances barrier function without altering claudin expression in primary alveolar epithelial cells. AB - Keratinocyte growth factor (KGF) has efficacy in several experimental models of lung injury; however, the mechanisms underlying KGF's protective effect remain incompletely understood. This study was undertaken to determine whether KGF augments barrier function in primary rat alveolar epithelial cells grown in culture, specifically whether KGF alters tight junction function via claudin expression. KGF significantly increased alveolar epithelial barrier function in culture as assessed by transepithelial electrical resistance (TER) and paracellular permeability. Fluorescence-activated cell sorting of freshly isolated type 1 (AT1) and type 2 (AT2) cells followed by quantitative real-time RT-PCR revealed that more than 97% of claudin mRNA transcripts in these cells were for claudins-3, -4, and -18. Using cultured AT2 cells, we then examined the effect of KGF on the protein levels of the claudins with the highest mRNA levels: -3, -4, -5, -7, -12, -15, and -18. KGF did not alter the levels of any of the claudins tested, nor of zona occludens-1 (ZO-1) or occludin. Moreover, localization of claudins-3, -4, -18, and ZO-1 was unchanged. KGF did induce a marked increase in the apical perijunctional F-actin ring. Actin depolymerization with cytochalasin D blocked the KGF-mediated increase in TER without significantly changing TER in control cells. Together, these data support a novel mechanism by which KGF enhances alveolar barrier function, modulation of the actin cytoskeleton. In addition, these data demonstrate the complete claudin expression profile for AT1 and AT2 cells and indicate that claudins-3, -4, and 18 are the primary claudins expressed in these cell types. PMID- 20833777 TI - Tenascin-C deficiency attenuates TGF-beta-mediated fibrosis following murine lung injury. AB - Tenascin-C (TNC) is an extracellular matrix glycoprotein of unknown function that is highly expressed in adult lung parenchyma following acute lung injury (ALI). Here we report that mice lacking TNC are protected from interstitial fibrosis in the bleomycin model of ALI. Three weeks after exposure to bleomycin, TNC-null mice had accumulated 85% less lung collagen than wild-type mice. The lung interstitium of TNC-null mice also appeared to contain fewer myofibroblasts and fewer cells with intranuclear Smad-2/3 staining, suggesting impaired TGF-beta activation or signaling. In vitro, TNC-null lung fibroblasts exposed to constitutively active TGF-beta expressed less alpha-smooth muscle actin and deposited less collagen I into the matrix than wild-type cells. Impaired TGF-beta responsiveness was correlated with dramatically reduced Smad-3 protein levels and diminished nuclear translocation of Smad-2 and Smad-3 in TGF-beta-exposed TNC null cells. Reduced Smad-3 in TNC-null cells reflects both decreased transcript abundance and enhanced ubiquitin-proteasome-mediated protein degradation. Together, these studies suggest that TNC is essential for maximal TGF-beta action after ALI. The clearance of TNC that normally follows ALI may restrain TGF-beta action during lung healing, whereas prolonged or exaggerated TNC expression may facilitate TGF-beta action and fibrosis after ALI. PMID- 20833779 TI - The discussion section: your closing argument. PMID- 20833778 TI - Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes. AB - Both high tidal volume mechanical ventilation (HV) and hyperoxia (HO) have been implicated in ventilator-induced lung injury. However, patients with acute lung injury are often exposed to HO before the application of mechanical ventilation. The potential priming of the lungs for subsequent injury by exposure to HO has not been extensively studied. We provide evidence that HO (90%) for 12 h followed by HV (25 MUl/g) combined with HO for 2 or 4 h (HO-12h+HVHO-2h or -4h) induced severe lung injury in mice. Analysis of lung homogenates showed that lung injury was associated with cleavage of executioner caspases, caspases-3 and -7, and their downstream substrate poly(ADP-ribose) polymerase-1 (PARP-1). No significant lung injury or caspase cleavage was seen with either HO for 16 h or HV for up to 4 h. Ventilation for 4 h with HO (HVHO) did not cause significant lung injury without preexposure to HO. Twelve-hour HO followed by lower tidal volume (6 MUl/g) mechanical ventilation failed to produce significant injury or caspase cleavage. We also evaluated the initiator caspases, caspases-8 and -9, to determine whether the death receptor or mitochondrial-mediated pathways were involved. Caspase-9 cleavage was observed in HO-12h+HVHO-2h and -4h as well as HO for 16 h. Caspase-8 activation was observed only in HO-12h+HVHO-4h, indicating the involvement of both pathways. Immunohistochemistry and in vitro stretch studies showed caspase cleavage in alveolar epithelial cells. In conclusion, preexposure to HO followed by HV produced severe lung injury associated with alveolar epithelial cell apoptosis. PMID- 20833780 TI - Microbial communities and functional genes associated with soil arsenic contamination and the rhizosphere of the arsenic-hyperaccumulating plant Pteris vittata L. AB - To understand how microbial communities and functional genes respond to arsenic contamination in the rhizosphere of Pteris vittata, five soil samples with different arsenic contamination levels were collected from the rhizosphere of P. vittata and nonrhizosphere areas and investigated by Biolog, geochemical, and functional gene microarray (GeoChip 3.0) analyses. Biolog analysis revealed that the uncontaminated soil harbored the greatest diversity of sole-carbon utilization abilities and that arsenic contamination decreased the metabolic diversity, while rhizosphere soils had higher metabolic diversities than did the nonrhizosphere soils. GeoChip 3.0 analysis showed low proportions of overlapping genes across the five soil samples (16.52% to 45.75%). The uncontaminated soil had a higher heterogeneity and more unique genes (48.09%) than did the arsenic contaminated soils. Arsenic resistance, sulfur reduction, phosphorus utilization, and denitrification genes were remarkably distinct between P. vittata rhizosphere and nonrhizosphere soils, which provides evidence for a strong linkage among the level of arsenic contamination, the rhizosphere, and the functional gene distribution. Canonical correspondence analysis (CCA) revealed that arsenic is the main driver in reducing the soil functional gene diversity; however, organic matter and phosphorus also have significant effects on the soil microbial community structure. The results implied that rhizobacteria play an important role during soil arsenic uptake and hyperaccumulation processes of P. vittata. PMID- 20833781 TI - Bacteriophage PhiX174's ecological niche and the flexibility of its Escherichia coli lipopolysaccharide receptor. AB - To determine bacteriophage PhiX174's ecological niche, 783 Escherichia coli isolates were screened for susceptibility. Sensitive strains are diverse regarding their phylogenies and core lipopolysaccharides (LPS), but all have rough phenotypes. Further analysis of E. coli K-12 LPS mutants revealed that PhiX174 can use a wide diversity of LPS structures to initiate its infectious process. PMID- 20833782 TI - Screening for antifungal peptides and their modes of action in Aspergillus nidulans. AB - Many short cationic peptides have been identified as potent antimicrobial agents, but their modes of action are not well understood. Peptide synthesis on cellulose membranes has resulted in the generation of peptide libraries, while high throughput assays have been developed to test their antibacterial activities. In this paper a microtiter plate-based screening method for fungi has been developed and used to test nine antibacterial peptides against the model fungus Aspergillus nidulans. Microscopical studies using sublethal peptide concentrations caused defects in polarized growth, including increased branch formation and depolarized hyphae. We characterized the mode of action for one of our target peptides, Sub5 (12 amino acids), which has already been shown to possess pharmacological potential as an antibacterial agent and is able to interact with ATP and ATP dependent enzymes. The MIC for A. nidulans is 2 MUg/ml, which is in the same range as the MICs reported for bacteria. Fluorescein isothiocyanate (FITC) labeled Sub5 targeted the cytoplasmic membrane, particularly hyphal tips, and entered the cytoplasm after prolonged exposure, independent of endocytosis. Interestingly, Sub5 peptide treatment disturbed sterol-rich membrane domains, important for tip growth, at hyphal tips. A very similar peptide, FITC-P7, also accumulated on the cell membrane but did not have antibacterial or antifungal activity, suggesting that the cytoplasmic membrane is a first target for the Sub5 peptide; however, the antifungal activity seems to be correlated with the ability to enter the cytoplasm, where the peptides might act on other targets. PMID- 20833783 TI - Expression of active recombinant human tissue-type plasminogen activator by using in vivo polyhydroxybutyrate granule display. AB - Recombinant human tissue plasminogen activator (rPA) is a truncated version of tissue plasminogen activator (tPA), which contains nine disulfide bonds and is prone to forming inactive inclusion bodies when expressed in bacteria. To obtain functional rPA expression, we displayed the rPA on the surface of polyhydroxybutyrate (PHB) granules using phasin as the affinity tag. rPA was fused to the N terminus of the phasin protein with a thrombin cleavage site as the linker. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot analysis showed that rPA fusion was successfully displayed on the surface of PHB granules. An activity assay indicated that the rPA fusion is active. The in vivo surface display strategy for functional rPA expression in Escherichia coli is distinct for its efficient folding and easier purification and may be expanded to the expression of other eukaryotic proteins with complex conformation. PMID- 20833784 TI - Dihydrolipoamide dehydrogenases of Advenella mimigardefordensis and Ralstonia eutropha catalyze cleavage of 3,3'-dithiodipropionic acid into 3 mercaptopropionic acid. AB - The catabolism of the disulfide 3,3'-dithiodipropionic acid (DTDP) is initiated by the reduction of its disulfide bond. Three independent Tn5::mob-induced mutants of Advenella mimigardefordensis strain DPN7(T) were isolated that had lost the ability to utilize DTDP as the sole source of carbon and energy and that harbored the transposon insertions in three different sites of the same dihydrolipoamide dehydrogenase gene encoding the E3 subunit of the pyruvate dehydrogenase multi-enzyme complex of this bacterium (LpdA(Am)). LpdA(Am) was analyzed in silico and compared to homologous proteins, thereby revealing high similarities to the orthologue in Ralstonia eutropha H16 (PdhL(Re)). Both bacteria are able to cleave DTDP into two molecules of 3-mercaptopropionic acid (3MP). A. mimigardefordensis DPN7(T) converted 3MP to 3-sulfinopropionic acid, whereas R. eutropha H16 showed no growth with DTDP as the sole carbon source but was instead capable of synthesizing heteropolythioesters using the resulting cleavage product 3MP. Subsequently, the genes lpdA(Am) and pdhL(Re) were cloned, heterologously expressed in Escherichia coli applying the pET23a expression system, purified, and assayed by monitoring the oxidation of NADH. The physiological substrate lipoamide was reduced to dihydrolipoamide with specific activities of 1,833 mkat/kg of protein (LpdA(Am)) or 1,667 mkat/kg of protein (PdhL(Re)). Reduction of DTDP was also unequivocally detected with the purified enzymes, although the specific enzyme activities were much lower: 0.7 and 0.5 mkat/kg protein, respectively. PMID- 20833785 TI - Interaction of Bacillus thuringiensis vegetative insecticidal protein with ribosomal S2 protein triggers larvicidal activity in Spodoptera frugiperda. AB - Vegetative insecticidal protein (Vip3A) is synthesized as an extracellular insecticidal toxin by certain strains of Bacillus thuringiensis. Vip3A is active against several lepidopteran pests of crops. Polyphagous pest, Spodoptera frugiperda, and its cell line Sf21 are sensitive for lyses to Vip3A. Screening of cDNA library prepared from Sf21 cells through yeast two-hybrid system with Vip3A as bait identified ribosomal protein S2 as a toxicity-mediating interacting partner protein. The Vip3A-ribosomal-S2 protein interaction was validated by in vitro pulldown assays and by RNA interference-induced knockdown experiments. Knockdown of expression of S2 protein in Sf21 cells resulted in reduced toxicity of the Vip3A protein. These observations were further extended to adult fifth instar larvae of Spodoptera litura. Knockdown of S2 expression by injecting corresponding double-stranded RNA resulted in reduced mortality of larvae to Vip3A toxin. Intracellular visualization of S2 protein and Vip3A through confocal microscopy revealed their interaction and localization in cytoplasm and surface of Sf21 cells. PMID- 20833786 TI - Environmental factors shape sediment anammox bacterial communities in hypernutrified Jiaozhou Bay, China. AB - Bacterial anaerobic ammonium oxidation (anammox) is an important process in the marine nitrogen cycle. Because ongoing eutrophication of coastal bays contributes significantly to the formation of low-oxygen zones, monitoring of the anammox bacterial community offers a unique opportunity for assessment of anthropogenic perturbations in these environments. The current study used targeting of 16S rRNA and hzo genes to characterize the composition and structure of the anammox bacterial community in the sediments of the eutrophic Jiaozhou Bay, thereby unraveling their diversity, abundance, and distribution. Abundance and distribution of hzo genes revealed a greater taxonomic diversity in Jiaozhou Bay, including several novel clades of anammox bacteria. In contrast, the targeting of 16S rRNA genes verified the presence of only "Candidatus Scalindua," albeit with a high microdiversity. The genus "Ca. Scalindua" comprised the apparent majority of active sediment anammox bacteria. Multivariate statistical analyses indicated a heterogeneous distribution of the anammox bacterial assemblages in Jiaozhou Bay. Of all environmental parameters investigated, sediment organic C/organic N (OrgC/OrgN), nitrite concentration, and sediment median grain size were found to impact the composition, structure, and distribution of the sediment anammox bacterial community. Analysis of Pearson correlations between environmental factors and abundance of 16S rRNA and hzo genes as determined by fluorescent real time PCR suggests that the local nitrite concentration is the key regulator of the abundance of anammox bacteria in Jiaozhou Bay sediments. PMID- 20833787 TI - Differences in methylation at GATC sites in genomic DNA of Campylobacter coli from turkeys and swine. AB - A significant fraction (46/108, 43%) of swine isolates of Campylobacter coli but none of 81 isolates of C. coli from turkeys had genomic DNA that was resistant to digestion by MboI, suggesting methylation of adenines at GATC sites. No consistent association was noted between antimicrobial resistance and MboI resistance. Seven swine-associated multilocus sequence typing-based sequence types (STs) were detected among multiple isolates with MboI-resistant DNA. The data suggest host-associated DNA modification system(s) specific for adenine at GATC sites in C. coli from swine. PMID- 20833788 TI - Role of plant residues in determining temporal patterns of the activity, size, and structure of nitrate reducer communities in soil. AB - The incorporation of plant residues into soil not only represents an opportunity to limit soil organic matter depletion resulting from cultivation but also provides a valuable source of nutrients such as nitrogen. However, the consequences of plant residue addition on soil microbial communities involved in biochemical cycles other than the carbon cycle are poorly understood. In this study, we investigated the responses of one N-cycling microbial community, the nitrate reducers, to wheat, rape, and alfalfa residues for 11 months after incorporation into soil in a field experiment. A 20- to 27-fold increase in potential nitrate reduction activity was observed for residue-amended plots compared to the nonamended plots during the first week. This stimulating effect of residues on the activity of the nitrate-reducing community rapidly decreased but remained significant over 11 months. During this period, our results suggest that the potential nitrate reduction activity was regulated by both carbon availability and temperature. The presence of residues also had a significant effect on the abundance of nitrate reducers estimated by quantitative PCR of the narG and napA genes, encoding the membrane-bound and periplasmic nitrate reductases, respectively. In contrast, the incorporation of the plant residues into soil had little impact on the structure of the narG and napA nitrate reducing community determined by PCR-restriction fragment length polymorphism (RFLP) fingerprinting. Overall, our results revealed that the addition of plant residues can lead to important long-term changes in the activity and size of a microbial community involved in N cycling but with limited effects of the type of plant residue itself. PMID- 20833789 TI - Product-induced gene expression, a product-responsive reporter assay used to screen metagenomic libraries for enzyme-encoding genes. AB - A reporter assay-based screening method for enzymes, which we named product induced gene expression (PIGEX), was developed and used to screen a metagenomic library for amidases. A benzoate-responsive transcriptional activator, BenR, was placed upstream of the gene encoding green fluorescent protein and used as a sensor. Escherichia coli sensor cells carrying the benR-gfp gene cassette fluoresced in response to benzoate concentrations as low as 10 MUM but were completely unresponsive to the substrate benzamide. An E. coli metagenomic library consisting of 96,000 clones was grown in 96-well format in LB medium containing benzamide. The library cells were then cocultivated with sensor cells. Eleven amidase genes were recovered from 143 fluorescent wells; eight of these genes were homologous to known bacterial amidase genes while three were novel genes. In addition to their activity toward benzamide, the enzymes were active toward various substrates, including d- and l-amino acid amides, and displayed enantioselectivity. Thus, we demonstrated that PIGEX is an effective approach for screening novel enzymes based on product detection. PMID- 20833790 TI - Virus-bacterium coupling driven by both turbidity and hydrodynamics in an Amazonian floodplain lake. AB - The importance of viruses in aquatic ecosystem functioning has been widely described. However, few studies have examined tropical aquatic ecosystems. Here, we evaluated for the first time viruses and their relationship with other planktonic communities in an Amazonian freshwater ecosystem. Coupling between viruses and bacteria was studied, focusing both on hydrologic dynamics and anthropogenic forced turbidity in the system (Lake Batata). Samples were taken during four hydrologic seasons at both natural and impacted sites to count virus like particles (VLP) and bacteria. In parallel, virus-infected bacteria were identified and quantified by transmission electron microscopy (TEM). Viral abundance ranged from 0.5 * 107 +/- 0.2 * 107 VLP ml-1 (high-water season, impacted site) to 1.7 * 107 +/- 0.4 * 107 VLP ml-1 (low-water season, natural site). These data were strongly correlated with the bacterial abundance (r2 = 0.84; P < 0.05), which ranged from 1.0 * 106 +/- 0.5 * 106 cells ml-1 (high water, impacted site) to 3.4 * 106 +/- 0.7 * 106 cells ml-1 (low water, natural site). Moreover, the viral abundance was weakly correlated with chlorophyll a, suggesting that most viruses were bacteriophages. TEM quantitative analyses revealed that the frequency of visibly infected cells was 20%, with 10 +/- 3 phages per cell section. In general, we found a low virus-bacterium ratio (<7). Both the close coupling between the viral and bacterial abundances and the low virus-bacterium ratio suggest that viral abundance tends to be driven by the reduction of hosts for viral infection. Our results demonstrate that viruses are controlled by biological substrates, whereas in addition to grazing, bacteria are regulated by physical processes caused by turbidity, which affect underwater light distribution and dissolved organic carbon availability. PMID- 20833791 TI - Specific degradation of the mucus adhesion-promoting protein (MapA) of Lactobacillus reuteri to an antimicrobial peptide. AB - The intestinal flora of mammals contains lactic acid bacteria (LAB) that may provide positive health effects for the host. Such bacteria are referred to as probiotic bacteria. From a pig, we have isolated a Lactobacillus reuteri strain that produces an antimicrobial peptide (AMP). The peptide was purified and characterized, and it was unequivocally shown that the AMP was a well-defined degradation product obtained from the mucus adhesion-promoting protein (MapA); it was therefore termed AP48-MapA. This finding demonstrates how large proteins might inherit unexpected pleiotropic functions by conferring antimicrobial capacities on the producer. The MapA/AP48-MapA system is the first example where a large protein of an intestinal LAB is shown to give rise to such an AMP. It is also of particular interest that the protein that provides this AMP is associated with the binding of the bacterium producing it to the surface/lining of the gut. This finding gives us new perspective on how some probiotic bacteria may successfully compete in this environment and thereby contribute to a healthy microbiota. PMID- 20833792 TI - Secretion of flavins by three species of methanotrophic bacteria. AB - We detected flavins in the growth medium of the methanotrophic bacterium Methylocystis species strain M. Flavin secretion correlates with growth stage and increases under iron starvation conditions. Two other methanotrophs, Methylosinus trichosporium OB3b and Methylococcus capsulatus (Bath), secrete flavins, suggesting that flavin secretion may be common to many methanotrophic bacteria. PMID- 20833793 TI - Insights into the functionality of the putative residues involved in enterocin AS 48 maturation. AB - AS-48 is a 70-residue, alpha-helical, cationic bacteriocin produced by Enterococcus faecalis and is very singular in its circular structure and its broad antibacterial spectrum. The AS-48 preprotein consists of an N-terminal signal peptide (SP) (35 residues) followed by a proprotein moiety that undergoes posttranslational modifications to yield the mature and active circular protein. For the study of the specificity of the region of AS-48 that is responsible for maturation, three single mutants have been generated by site-directed mutagenesis in the as-48A structural gene. The substitutions were made just in the residues that are thought to constitute a recognition site for the SP cleavage enzyme (His 1, Met1) and in those involved in circularization (Met1, Trp70). Each derivative was expressed in the enterococcal JH2-2 strain containing the necessary native biosynthetic machinery for enterocin production. The importance of these derivatives in AS-48 processing has been evaluated on the basis of the production and structural characterization of the corresponding derivatives. Notably, only two of them (Trp70Ala and Met1Ala derivatives) could be purified in different forms and amounts and are characterized for their bactericidal activity and secondary structure. We could not detect any production of AS-48 in JH2-2(pAM401 81(His-1Ile)) by using the conventional chromatographic techniques, despite the high efficiency of the culture conditions applied to produce this enterocin. Our results underline the different important roles of the mutated residues in (i) the elimination of the SP, (ii) the production levels and antibacterial activity of the mature proteins, and (iii) protein circularization. Moreover, our findings suggest that His-1 is critically involved in cleavage site recognition, its substitution being responsible for the blockage of processing, thereby hampering the production of the specific protein in the cellular culture supernatant. PMID- 20833794 TI - Comparison of prostaglandin E2 receptor subtype 4 agonist and sulfasalazine in mouse colitis prevention and treatment. AB - Prodrugs of 5-aminosalicylic acid (5-ASA), such as sulfasalazine, have been the mainstay for the treatment and maintenance of inflammatory bowel disease (IBD) for decades, which is attributable to their antiadaptive immune activity. However, 5-ASA compromises regeneration of intestinal epithelia and induces apoptosis. The majority of patients eventually undergo colectomy. Agonists for the prostaglandin E(2) subtype 4 (EP4) receptor have been shown to protect epithelial barrier against colitis-inducing agents and could be valuable alternatives for sulfasalazine. Here, we compared sulfasalazine and a novel EP4 agonist for their abilities to prevent colitis induction and relieve symptoms of established colitis in a dextran sulfate sodium-indomethacin mouse model. The EP4 agonist dose-dependently alleviated weight loss in colitis mice. Compared with sulfasalazine at 100 mg/kg on the colitis induction model, the EP4 agonist at 0.2 mg/kg was superior in reducing colitis symptoms, preventing increase of innate immune cells, and ameliorating inflammation in colon. In mice with established colitis, sulfasalazine quickly reversed weight loss but with fading efficacy. The EP4 agonist, in contrast, had slow but sustained effects on body weight gain and was more efficacious in epithelial regeneration. Such temporal differences between sulfasalazine and the EP4 agonist actions seemingly led to no additive effect in combination therapy. In conclusion, the EP4 agonist would be more efficacious in the maintenance of remission because of both anti-innate immune responses and epithelial regeneration activity, whereas sulfasalazine would be more suitable for induction of remission because of its rapid onset of antiadaptive inflammation action. PMID- 20833795 TI - Two naturally occurring mutations in the type 1 melanin-concentrating hormone receptor abolish agonist-induced signaling. AB - The melanin-concentrating hormone (MCH) receptor type 1 (MCHR1) is a seven transmembrane domain protein that modulates orexigenic activity of MCH, the corresponding endogenous peptide agonist. MCH antagonists are being explored as a potential treatment for obesity. In the current study, we examined the pharmacological impact of 11 naturally occurring mutations in the human MCHR1. Wild-type and mutant receptors were transiently expressed in human embryonic kidney 293 cells. MCHR1-mediated, Galpha(i)-dependent signaling was monitored by using luciferase reporter gene assays. Two mutants, R210H and P377S, failed to respond to MCH. Five other variants showed significant alterations in MCH efficacy, ranging from 44 to 142% of the wild-type value. At each of the MCH responsive mutants, agonist potency and inhibition by (S)-methyl 3-((3-(4-(3 acetamidophenyl)piperidin-1-yl)propyl)carbamoyl)-4-(3,4-difluorophenyl)-6 (methoxymethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (SNAP-7941), an established MCHR1 small-molecule antagonist, were similar to wild type. To explore the basis for inactivity of the R210H and P377S mutants, we examined expression levels of these receptors. Assessment by enzyme-linked immunosorbent assay revealed that cell surface expression of both nonfunctional receptors was comparable with wild type. Overnight treatment with SNAP-7941, followed by washout of antagonist, enhanced MCH induced signaling by the wild-type receptor and restored MCH responsiveness of the P377S but not the R210H variant. It is of note that the two loss-of-function mutants were identified in markedly underweight individuals, raising the possibility that a lean phenotype may be linked to deficient MCHR1 signaling. Formal association studies with larger cohorts are needed to explore the extent to which signaling-deficient MCHR1 variants influence the maintenance of body weight. PMID- 20833796 TI - "There is no such thing as an accident," especially when people are drunk. AB - The intentionality bias is the tendency for people to view the behavior of others as intentional. This study tests the hypothesis that alcohol magnifies the intentionality bias by disrupting effortful cognitive abilities. Using a 2 * 2 balanced placebo design in a natural field experiment disguised as a food-tasting session, participants received either a high dose of alcohol (target BAC = .10%) or no alcohol, with half of each group believing they had or had not consumed alcohol. Participants then read a series of sentences describing simple actions (e.g., "She cut him off in traffic") and indicated whether the actions were done intentionally or accidentally. As expected, intoxicated people interpreted more acts as intentional than did sober people. This finding helps explain why alcohol increases aggression. For example, intoxicated people may interpret a harmless bump in a crowded bar as a provocation. PMID- 20833798 TI - Prospective study of the modified atkins diet in combination with a ketogenic liquid supplement during the initial month. AB - The modified Atkins diet is a high-fat, low-carbohydrate treatment for intractable childhood epilepsy. As data suggest that a stricter diet onset can be more effective, we added a ketogenic supplement to the modified Atkins diet during its initial month. Thirty children with intractable epilepsy were prospectively started on the modified Atkins diet in combination with a daily 400 calorie KetoCal shake. At 1 month, 24 (80%) children had >50% seizure reduction, of which 11 (37%) had >90% seizure reduction. There was no significant loss of efficacy during the second month after KetoCal was discontinued. The use of this ketogenic supplement increased daily fat intake and thus the ketogenic ratio (1.8:1 versus 1.0:1 in the modified Atkins diet alone, P = .0002), but did not change urinary or serum ketosis. The addition of a ketogenic supplement to the modified Atkins diet during its initial month appears to be beneficial. PMID- 20833797 TI - Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes. AB - Mitochondria play a central role in energy metabolism and cellular survival, and consequently mitochondrial dysfunction is associated with a number of human pathologies. Reversible protein phosphorylation emerges as a central mechanism in the regulation of several mitochondrial processes. In skeletal muscle, mitochondrial dysfunction is linked to insulin resistance in humans with obesity and type 2 diabetes. We performed a phosphoproteomics study of functional mitochondria isolated from human muscle biopsies with the aim to obtain a comprehensive overview of mitochondrial phosphoproteins. Combining an efficient mitochondrial isolation protocol with several different phosphopeptide enrichment techniques and LC-MS/MS, we identified 155 distinct phosphorylation sites in 77 mitochondrial phosphoproteins, including 116 phosphoserine, 23 phosphothreonine, and 16 phosphotyrosine residues. The relatively high number of phosphotyrosine residues suggests an important role for tyrosine phosphorylation in mitochondrial signaling. Many of the mitochondrial phosphoproteins are involved in oxidative phosphorylation, tricarboxylic acid cycle, and lipid metabolism, i.e. processes proposed to be involved in insulin resistance. We also assigned phosphorylation sites in mitochondrial proteins involved in amino acid degradation, importers and transporters, calcium homeostasis, and apoptosis. Bioinformatics analysis of kinase motifs revealed that many of these mitochondrial phosphoproteins are substrates for protein kinase A, protein kinase C, casein kinase II, and DNA dependent protein kinase. Our results demonstrate the feasibility of performing phosphoproteome analysis of organelles isolated from human tissue and provide novel targets for functional studies of reversible phosphorylation in mitochondria. Future comparative phosphoproteome analysis of mitochondria from healthy and diseased individuals will provide insights into the role of abnormal phosphorylation in pathologies, such as type 2 diabetes. PMID- 20833799 TI - Deletion of 14-3-3{varepsilon} and CRK: a clinical syndrome with macrocephaly, developmental delay, and generalized epilepsy. AB - Deletions of chromosome 17p13.3 result in neuronal migration defects such as isolated lissencephaly sequence and Miller-Dieker syndrome. LIS1 is the deleted gene within this region and is thought to directly cause isolated lissencephaly sequence and contribute to Miller-Dieker syndrome. Two additional genes (14-3 3epsilon and CRK) on the telomeric end of chromosome 17p reportedly contribute to the severe phenotype of Miller-Dieker syndrome. We report 2 patients with deletions of chromosome 17p13.3 involving the genes 14-3-3epsilon and CRK but not LIS1 with previously unreported, identical phenotypes of macrocephaly, small stature, dysmorphic features, generalized epilepsy, developmental delay, and nonspecific white matter changes. The findings in this report suggest that patients who have deletions of 14-3-3epsilon and/or CRK should be monitored closely for the development of seizures. PMID- 20833800 TI - SepL resembles an aberrant effector in binding to a class 1 type III secretion chaperone and carrying an N-terminal secretion signal. AB - Here we show that the type III secretion gatekeeper protein SepL resembles an aberrant effector protein in binding to a class 1 type III secretion chaperone (Orf12, here renamed CesL). We also show that short N-terminal fragments (<=70 amino acids) from SepL are capable of targeting fusion proteins for secretion and translocation. PMID- 20833801 TI - L-lysine catabolism is controlled by L-arginine and ArgR in Pseudomonas aeruginosa PAO1. AB - In comparison to other pseudomonads, Pseudomonas aeruginosa grows poorly in L lysine as a sole source of nutrient. In this study, the ldcA gene (lysine decarboxylase A; PA1818), previously identified as a member of the ArgR regulon of L-arginine metabolism, was found essential for L-lysine catabolism in this organism. LdcA was purified to homogeneity from a recombinant strain of Escherichia coli, and the results of enzyme characterization revealed that this pyridoxal-5-phosphate-dependent decarboxylase takes L-lysine, but not L-arginine, as a substrate. At an optimal pH of 8.5, cooperative substrate activation by L lysine was depicted from kinetics studies, with calculated K(m) and V(max) values of 0.73 mM and 2.2 MUmole/mg/min, respectively. Contrarily, the ldcA promoter was induced by exogenous L-arginine but not by L-lysine in the wild-type strain PAO1, and the binding of ArgR to this promoter region was demonstrated by electromobility shift assays. This peculiar arginine control on lysine utilization was also noted from uptake experiments in which incorporation of radioactively labeled L-lysine was enhanced in cells grown in the presence of L arginine but not L-lysine. Rapid growth on L-lysine was detected in a mutant devoid of the main arginine catabolic pathway and with a higher basal level of the intracellular L-arginine pool and hence elevated ArgR-responsive regulons, including ldcA. Growth on L-lysine as a nitrogen source can also be enhanced when the aruH gene encoding an arginine/lysine:pyruvate transaminase was expressed constitutively from plasmids; however, no growth of the ldcA mutant on L-lysine suggests a minor role of this transaminase in L-lysine catabolism. In summary, this study reveals a tight connection of lysine catabolism to the arginine regulatory network, and the lack of lysine-responsive control on lysine uptake and decarboxylation provides an explanation of L-lysine as a poor nutrient for P. aeruginosa. PMID- 20833802 TI - Analysis of the intact surface layer of Caulobacter crescentus by cryo-electron tomography. AB - The surface layers (S layers) of those bacteria and archaea that elaborate these crystalline structures have been studied for 40 years. However, most structural analysis has been based on electron microscopy of negatively stained S-layer fragments separated from cells, which can introduce staining artifacts and allow rearrangement of structures prone to self-assemble. We present a quantitative analysis of the structure and organization of the S layer on intact growing cells of the Gram-negative bacterium Caulobacter crescentus using cryo-electron tomography (CET) and statistical image processing. Instead of the expected long range order, we observed different regions with hexagonally organized subunits exhibiting short-range order and a broad distribution of periodicities. Also, areas of stacked double layers were found, and these increased in extent when the S-layer protein (RsaA) expression level was elevated by addition of multiple rsaA copies. Finally, we combined high-resolution amino acid residue-specific Nanogold labeling and subtomogram averaging of CET volumes to improve our understanding of the correlation between the linear protein sequence and the structure at the 2-nm level of resolution that is presently available. The results support the view that the U-shaped RsaA monomer predicted from negative-stain tomography proceeds from the N terminus at one vertex, corresponding to the axis of 3-fold symmetry, to the C terminus at the opposite vertex, which forms the prominent 6-fold symmetry axis. Such information will help future efforts to analyze subunit interactions and guide selection of internal sites for display of heterologous protein segments. PMID- 20833803 TI - Glycosylation of pilin and nonpilin protein constructs by Pseudomonas aeruginosa 1244. AB - PilO is an oligosaccharyl transferase (OTase) that catalyzes the O-glycosylation of Pseudomonas aeruginosa 1244 pilin by adding a single O-antigen repeating unit to the beta carbon of the C-terminal residue (a serine). While PilO has an absolute requirement for Ser/Thr at this position, it is unclear if this enzyme must recognize other pilin features. To test this, pilin constructs containing peptide extensions terminating with serine were tested for the ability to support glycosylation. It was found that a 15-residue peptide, which had been modeled on the C-proximal region of strain 1244 pilin, served as a PilO substrate when it was expressed on either group II or group III pilins. In addition, adding a 3 residue extension culminating in serine to the C terminus of a group III pilin supported PilO activity. A protein fusion composed of strain 1244 pilin linked at its C terminus with Escherichia coli alkaline phosphatase (which, in turn, contained the above-mentioned 15 amino acids at its C terminus) was glycosylated by PilO. E. coli alkaline phosphatase lacking the pilin membrane anchor and containing the 15-residue peptide was also glycosylated by PilO. Addition of the 3-residue extension did not allow glycosylation of either of these constructs. Site-directed mutagenesis of strain 1244 pilin residues of the C-proximal region common to the group I proteins showed that this structure was not required for glycosylation. These experiments indicate that pilin common sequence is not required for glycosylation and show that nonpilin protein can be engineered to be a PilO substrate. PMID- 20833804 TI - Functional characterization of a cyanobacterial OmpR/PhoB class transcription factor binding site controlling light color responses. AB - Complementary chromatic acclimation (CCA) allows many cyanobacteria to change the composition of their light-harvesting antennae for maximal absorption of different wavelengths of light. In the freshwater species Fremyella diplosiphon, this process is controlled by the ratio of red to green light and allows the differential regulation of two subsets of genes in the genome. This response to ambient light color is controlled in part by a two-component system that includes a phytochrome class photoreceptor and a response regulator with an OmpR/PhoB class DNA binding domain called RcaC. During growth in red light, RcaC is able to simultaneously activate expression of red light-induced genes and repress expression of green light-induced genes through binding to the L box promoter element. Here we investigate how the L box functions as both an activator and a repressor under the same physiological conditions by analyzing the effects of changing the position, orientation, and sequence of the L box. We demonstrate that changes in the local sequences surrounding the L box affect the strength of its activity and that the activating and repressing functions of the L box are orientation dependent. Also, the spacing between the L box and the transcription start site is critical for it to work as an activator, while its repressing role during light regulation requires additional upstream and downstream DNA sequence elements. The latter result suggests that the repressing function of RcaC requires it to operate in association with multiple additional DNA binding proteins, at least one of which is functioning as an activator. PMID- 20833805 TI - Genome sequence of the dioxin-mineralizing bacterium Sphingomonas wittichii RW1. AB - Pollutants such as polychlorinated biphenyls and dioxins pose a serious threat to human and environmental health. Natural attenuation of these compounds by microorganisms provides one promising avenue for their removal from contaminated areas. Over the past 2 decades, studies of the bacterium Sphingomonas wittichii RW1 have provided a wealth of knowledge about how bacteria metabolize chlorinated aromatic hydrocarbons. Here we describe the finished genome sequence of S. wittichii RW1 and major findings from its annotation. PMID- 20833806 TI - SpdR, a response regulator required for stationary-phase induction of Caulobacter crescentus cspD. AB - The cold shock protein (CSP) family includes small polypeptides that are induced upon temperature downshift and stationary phase. The genome of the alphaproteobacterium Caulobacter crescentus encodes four CSPs, with two being induced by cold shock and two at the onset of stationary phase. In order to identify the environmental signals and cell factors that are involved in cspD expression at stationary phase, we have analyzed cspD transcription during growth under several nutrient conditions. The results showed that expression of cspD was affected by the medium composition and was inversely proportional to the growth rate. The maximum levels of expression were decreased in a spoT mutant, indicating that ppGpp may be involved in the signalization for carbon starvation induction of cspD. A Tn5 mutant library was screened for mutants with reduced cspD expression, and 10 clones that showed at least a 50% reduction in expression were identified. Among these, a strain with a transposon insertion into a response regulator of a two-component system showed no induction of cspD at stationary phase. This protein (SpdR) was able to acquire a phosphate group from its cognate histidine kinase, and gel mobility shift assay and DNase I footprinting experiments showed that it binds to an inverted repeat sequence of the cspD regulatory region. A mutated SpdR with a substitution of the conserved aspartyl residue that is the probable phosphorylation site is unable to bind to the cspD regulatory region and to complement the spdR mutant phenotype. PMID- 20833807 TI - Proteomic analysis of Neorickettsia sennetsu surface-exposed proteins and porin activity of the major surface protein P51. AB - Neorickettsia sennetsu is an obligate intracellular bacterium of monocytes and macrophages and is the etiologic agent of human Sennetsu neorickettsiosis. Neorickettsia proteins expressed in mammalian host cells, including the surface proteins of Neorickettsia spp., have not been defined. In this paper, we isolated surface-exposed proteins from N. sennetsu by biotin surface labeling followed by streptavidin-affinity chromatography. Forty-two of the total of 936 (4.5%) N. sennetsu open reading frames (ORFs) were detected by liquid chromatography-tandem mass spectrometry (LC/MS/MS), including six hypothetical proteins. Among the major proteins identified were the two major beta-barrel proteins: the 51-kDa antigen (P51) and Neorickettsia surface protein 3 (Nsp3). Immunofluorescence labeling not only confirmed surface exposure of these proteins but also showed rosary-like circumferential labeling with anti-P51 for the majority of bacteria and polar to diffuse punctate labeling with anti-Nsp3 for a minority of bacteria. We found that the isolated outer membrane of N. sennetsu had porin activity, as measured by a proteoliposome swelling assay. This activity allowed the diffusion of L-glutamine, the monosaccharides arabinose and glucose, and the tetrasaccharide stachyose, which could be inhibited with anti-P51 antibody. We purified native P51 and Nsp3 under nondenaturing conditions. When reconstituted into proteoliposomes, purified P51, but not Nsp3, exhibited prominent porin activity. This the first proteomic study of a Neorickettsia sp. showing new sets of proteins evolved as major surface proteins for Neorickettsia and the first identification of a porin for the genus Neorickettsia. PMID- 20833808 TI - Latency of the lipid A deacylase PagL is involved in producing a robust permeation barrier in the outer membrane of Salmonella enterica. AB - Lipid A deacylase PagL, which detoxifies endotoxin, is latent in Salmonella enterica. This study determined the biological significance of this latency. PagL latency was beneficial for bacteria in producing a robust permeation barrier through lipid A modifications under host-mimetic conditions that induced the modification enzymes, including PagL. PMID- 20833809 TI - Residue histidine 669 is essential for the catalytic activity of Bacillus anthracis lethal factor. AB - The lethal factor (LF) of Bacillus anthracis is a Zn(2+)-dependent metalloprotease which plays an important role in anthrax virulence. This study was aimed at identifying the histidine residues that are essential to the catalytic activities of LF. The site-directed mutagenesis was employed to replace the 10 histidine residues in domains II, III, and IV of LF with alanine residues, respectively. The cytotoxicity of these mutants was tested, and the results revealed that the alanine substitution for His-669 completely abolished toxicity to the lethal toxin (LT)-sensitive RAW264.7 cells. The reason for the toxicity loss was further explored. The zinc content of this LF mutant was the same as that of the wild type. Also this LF mutant retained its protective antigan (PA) binding activity. Finally, the catalytic cleavage activity of this mutant was demonstrated to be drastically reduced. Thus, we conclude that residue His-669 is crucial to the proteolytic activity of LF. PMID- 20833810 TI - Regulation of a phage endolysin by disulfide caging. AB - In contrast to canonical phage endolysins, which require holin-mediated disruption of the membrane to gain access to attack the cell wall, signal anchor release (SAR) endolysins are secreted by the host sec system, where they accumulate in an inactive form tethered to the membrane by their N-terminal SAR domains. SAR endolysins become activated by various mechanisms upon release from the membrane. In its inactive form, the prototype SAR endolysin, Lyz(P1), of coliphage P1, has an active-site Cys covalently blocked by a disulfide bond; activation involves a disulfide bond isomerization driven by a thiol in the newly released SAR domain, unblocking the active-site Cys. Here, we report that Lyz(103), the endolysin of Erwinia phage ERA103, is also a SAR endolysin. Although Lyz(103) does not have a catalytic Cys, genetic evidence suggests that it also is activated by a thiol-disulfide isomerization triggered by a thiol in the SAR domain. In this case, the inhibitory disulfide in nascent Lyz(103) is formed between cysteine residues flanking a catalytic glutamate, caging the active site. Thus, Lyz(P1) and Lyz(103) define subclasses of SAR endolysins that differ in the nature of their inhibitory disulfide, and Lyz(103) is the first enzyme found to be regulated by disulfide bond caging of its active site. PMID- 20833811 TI - Role of cross talk in regulating the dynamic expression of the flagellar Salmonella pathogenicity island 1 and type 1 fimbrial genes. AB - Salmonella enterica, a common food-borne pathogen, differentially regulates the expression of multiple genes during the infection cycle. These genes encode systems related to motility, adhesion, invasion, and intestinal persistence. Key among them is a type three secretion system (T3SS) encoded within Salmonella pathogenicity island 1 (SPI1). In addition to the SPI1 T3SS, other systems, including flagella and type 1 fimbriae, have been implicated in Salmonella pathogenesis. In this study, we investigated the dynamic expression of the flagellar, SPI1, and type 1 fimbrial genes. We demonstrate that these genes are expressed in a temporal hierarchy, beginning with the flagellar genes, followed by the SPI1 genes, and ending with the type 1 fimbrial genes. This hierarchy could mirror the roles of these three systems during the infection cycle. As multiple studies have shown that extensive regulatory cross talk exists between these three systems, we also tested how removing different regulatory links between them affects gene expression dynamics. These results indicate that cross talk is critical for regulating gene expression during transitional phases in the gene expression hierarchy. In addition, we identified a novel regulatory link between flagellar and type 1 fimbrial gene expression dynamics, where we found that the flagellar regulator, FliZ, represses type 1 fimbrial gene expression through the posttranscriptional regulation of FimZ. The significance of these results is that they provide the first systematic study of the effect of regulatory cross talk on the expression dynamics of flagellar, SPI1, and type 1 fimbrial genes. PMID- 20833812 TI - Evidence that the supE44 mutation of Escherichia coli is an amber suppressor allele of glnX and that it also suppresses ochre and opal nonsense mutations. AB - Translational readthrough of nonsense codons is seen not only in organisms possessing one or more tRNA suppressors but also in strains lacking suppressors. Amber suppressor tRNAs have been reported to suppress only amber nonsense mutations, unlike ochre suppressors, which can suppress both amber and ochre mutations, essentially due to wobble base pairing. In an Escherichia coli strain carrying the lacZU118 episome (an ochre mutation in the lacZ gene) and harboring the supE44 allele, suppression of the ochre mutation was observed after 7 days of incubation. The presence of the supE44 lesion in the relevant strains was confirmed by sequencing, and it was found to be in the duplicate copy of the glnV tRNA gene, glnX. To investigate this further, an in vivo luciferase assay developed by D. W. Schultz and M. Yarus (J. Bacteriol. 172:595-602, 1990) was employed to evaluate the efficiency of suppression of amber (UAG), ochre (UAA), and opal (UGA) mutations by supE44. We have shown here that supE44 suppresses ochre as well as opal nonsense mutations, with comparable efficiencies. The readthrough of nonsense mutations in a wild-type E. coli strain was much lower than that in a supE44 strain when measured by the luciferase assay. Increased suppression of nonsense mutations, especially ochre and opal, by supE44 was found to be growth phase dependent, as this phenomenon was only observed in stationary phase and not in logarithmic phase. These results have implications for the decoding accuracy of the translational machinery, particularly in stationary growth phase. PMID- 20833813 TI - Legionella pneumophila strain 130b possesses a unique combination of type IV secretion systems and novel Dot/Icm secretion system effector proteins. AB - Legionella pneumophila is a ubiquitous inhabitant of environmental water reservoirs. The bacteria infect a wide variety of protozoa and, after accidental inhalation, human alveolar macrophages, which can lead to severe pneumonia. The capability to thrive in phagocytic hosts is dependent on the Dot/Icm type IV secretion system (T4SS), which translocates multiple effector proteins into the host cell. In this study, we determined the draft genome sequence of L. pneumophila strain 130b (Wadsworth). We found that the 130b genome encodes a unique set of T4SSs, namely, the Dot/Icm T4SS, a Trb-1-like T4SS, and two Lvh T4SS gene clusters. Sequence analysis substantiated that a core set of 107 Dot/Icm T4SS effectors was conserved among the sequenced L. pneumophila strains Philadelphia-1, Lens, Paris, Corby, Alcoy, and 130b. We also identified new effector candidates and validated the translocation of 10 novel Dot/Icm T4SS effectors that are not present in L. pneumophila strain Philadelphia-1. We examined the prevalence of the new effector genes among 87 environmental and clinical L. pneumophila isolates. Five of the new effectors were identified in 34 to 62% of the isolates, while less than 15% of the strains tested positive for the other five genes. Collectively, our data show that the core set of conserved Dot/Icm T4SS effector proteins is supplemented by a variable repertoire of accessory effectors that may partly account for differences in the virulences and prevalences of particular L. pneumophila strains. PMID- 20833814 TI - The two-component system BvrR/BvrS regulates the expression of the type IV secretion system VirB in Brucella abortus. AB - The pathogenesis of Brucella is related to the ability to multiply intracellularly, an event controlled by the two-component system BvrR/BvrS (TCS BvrRS) and the type IV secretion machinery VirB (T4SS VirB). We have hypothesized that the TCS BvrRS transcriptionally regulates the T4SS VirB. To test this hypothesis, we have compared the levels of VirB proteins in the wild-type strain Brucella abortus 2308 and mutant strains devoid of the sensor and regulator genes (bvrS and bvrR mutants, respectively). While the bvrR and bvrS mutants showed low levels of the VirB1, VirB5, VirB8, and VirB9 proteins, the same proteins were overexpressed in the bvrR mutant complemented with a plasmid carrying a functional bvrR gene. Quantitation of virB5 mRNA confirmed these data and indicated that the influence of the TCS BvrRS on the T4SS VirB occurs at the transcriptional level. The expression of the transcriptional activator VjbR also depended on the TCS BvrRS. In addition, we demonstrate a direct interaction between the promoter region of the VirB operon and the response regulator BvrR. Altogether these data demonstrate that the TCS BvrRS controls the expression of the T4SS VirB through direct and indirect mechanisms. PMID- 20833815 TI - Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection. AB - Signal transduction networks can be perturbed biochemically, genetically, and pharmacologically to unravel their functions. But at the systems level, it is not clear how such perturbations are best implemented to extract molecular mechanisms that underlie network function. Here, we combined pairwise perturbations with multiparameter phosphorylation measurements to reveal causal mechanisms within the signaling network response of cardiomyocytes to coxsackievirus B3 (CVB3) infection. Using all possible pairs of six kinase inhibitors, we assembled a dynamic nine-protein phosphorylation signature of perturbed CVB3 infectivity. Cluster analysis of the resulting dataset showed repeatedly that paired inhibitor data were required for accurate data-driven predictions of kinase substrate links in the host network. With pairwise data, we also derived a high-confidence network based on partial correlations, which identified phospho-IkappaBalpha as a central "hub" in the measured phosphorylation signature. The reconstructed network helped to connect phospho-IkappaBalpha with an autocrine feedback circuit in host cells involving the proinflammatory cytokines, TNF and IL-1. Autocrine blockade substantially inhibited CVB3 progeny release and improved host cell viability, implicating TNF and IL-1 as cell autonomous components of CVB3-induced myocardial damage. We conclude that pairwise perturbations, when combined with network-level intracellular measurements, enrich for mechanisms that would be overlooked by single perturbants. PMID- 20833816 TI - A binary search approach to whole-genome data analysis. AB - A sequence analysis-oriented binary search-like algorithm was transformed to a sensitive and accurate analysis tool for processing whole-genome data. The advantage of the algorithm over previous methods is its ability to detect the margins of both short and long genome fragments, enriched by up-regulated signals, at equal accuracy. The score of an enriched genome fragment reflects the difference between the actual concentration of up-regulated signals in the fragment and the chromosome signal baseline. The "divide-and-conquer"-type algorithm detects a series of nonintersecting fragments of various lengths with locally optimal scores. The procedure is applied to detected fragments in a nested manner by recalculating the lower-than-baseline signals in the chromosome. The algorithm was applied to simulated whole-genome data, and its sensitivity/specificity were compared with those of several alternative algorithms. The algorithm was also tested with four biological tiling array datasets comprising Arabidopsis (i) expression and (ii) histone 3 lysine 27 trimethylation CHIP-on-chip datasets; Saccharomyces cerevisiae (iii) spliced intron data and (iv) chromatin remodeling factor binding sites. The analyses' results demonstrate the power of the algorithm in identifying both the short up regulated fragments (such as exons and transcription factor binding sites) and the long--even moderately up-regulated zones--at their precise genome margins. The algorithm generates an accurate whole-genome landscape that could be used for cross-comparison of signals across the same genome in evolutionary and general genomic studies. PMID- 20833818 TI - Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci. AB - Inducible vancomycin resistance in enterococci is due to a sophisticated mechanism that combines synthesis of cell wall peptidoglycan precursors with low affinity for glycopeptides and elimination of the normal target precursors. Although this dual mechanism, which involves seven genes organized in two operons, is predicted to have a high fitness cost, resistant enterococci have disseminated worldwide. We have evaluated the biological cost of VanB-type resistance due to acquisition of conjugative transposon Tn1549 in Enterococcus faecium and Enterococcus faecalis. Because fitness was dependent on the integration site of Tn1549, an isogenic set of E. faecalis was constructed to determine the cost of inducible or constitutive expression of resistance or of carriage of Tn1549. A luciferase gene was inserted in the integrase gene of the transposon to allow differential quantification of the strains in cocultures and in the digestive tract of gnotobiotic mice. Both in vitro and in vivo, carriage of inactivated or inducible Tn1549 had no cost for the host in the absence of induction by vancomycin. In contrast, induced or constitutively resistant strains not only had reduced fitness but were severely impaired in colonization ability and dissemination among mice. These data indicate that tight regulation of resistance expression drastically reduces the biological cost associated with vancomycin resistance in Enterococcus spp. and accounts for the widespread dissemination of these strains. Our findings are in agreement with the observation that regulation of expression is common in horizontally acquired resistance and represents an efficient evolutionary pathway for resistance determinants to become selectively neutral. PMID- 20833817 TI - A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. AB - Autophagy is an intracellular turnover pathway. It has special relevance for neurodegenerative proteinopathies, such as Alzheimer disease, Parkinson disease, and Huntington disease (HD), which are characterized by the accumulation of misfolded proteins. Although induction of autophagy enhances clearance of misfolded protein and has therefore been suggested as a therapy for proteinopathies, neurons appear to be less responsive to classic autophagy inducers than nonneuronal cells. Searching for improved inducers of neuronal autophagy, we discovered an N(10)-substituted phenoxazine that, at proper doses, potently and safely up-regulated autophagy in neurons in an Akt- and mTOR independent fashion. In a neuron model of HD, this compound was neuroprotective and decreased the accumulation of diffuse and aggregated misfolded protein. A structure/activity analysis with structurally similar compounds approved by the US Food and Drug Administration revealed a defined pharmacophore for inducing neuronal autophagy. This pharmacophore should prove useful in studying autophagy in neurons and in developing therapies for neurodegenerative proteinopathies. PMID- 20833819 TI - The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia. AB - Recent data indicate that a variety of regulatory molecules active in embryonic development may also play a role in the regulation of early hematopoiesis. Here we report that the human Vent-like homeobox gene VENTX, a putative homolog of the Xenopus xvent2 gene, is a unique regulatory hematopoietic gene that is aberrantly expressed in CD34(+) leukemic stem-cell candidates in human acute myeloid leukemia (AML). Quantitative RT-PCR documented expression of the gene in lineage positive hematopoietic subpopulations, with the highest expression in CD33(+) myeloid cells. Notably, expression levels of VENTX were negligible in normal CD34(+)/CD38(-) or CD34(+) human progenitor cells. In contrast to this, leukemic CD34(+)/CD38(-) cells from AML patients with translocation t(8,21) and normal karyotype displayed aberrantly high expression of VENTX. Gene expression and pathway analysis demonstrated that in normal CD34(+) cells enforced expression of VENTX initiates genes associated with myeloid development and down-regulates genes involved in early lymphoid development. Functional analyses confirmed that aberrant expression of VENTX in normal CD34(+) human progenitor cells perturbs normal hematopoietic development, promoting generation of myeloid cells and impairing generation of lymphoid cells in vitro and in vivo. Stable knockdown of VENTX expression inhibited the proliferation of human AML cell lines. Taken together, these data extend our insights into the function of embryonic mesodermal factors in human postnatal hematopoiesis and indicate a role for VENTX in normal and malignant myelopoiesis. PMID- 20833820 TI - Effect of a quality-improvement intervention on end-of-life care in the intensive care unit: a randomized trial. AB - RATIONALE: Because of high mortality, end-of-life care is an important component of intensive care. OBJECTIVES: We evaluated the effectiveness of a quality improvement intervention to improve intensive care unit (ICU) end-of-life care. METHODS: We conducted a cluster-randomized trial randomizing 12 hospitals. The intervention targeted clinicians with five components: clinician education, local champions, academic detailing, clinician feedback of quality data, and system supports. Outcomes were assessed for patients dying in the ICU or within 30 hours of ICU discharge using surveys and medical record review. Families completed Quality of Dying and Death (QODD) and satisfaction surveys. Nurses completed the QODD. Data were collected during baseline and follow-up at each hospital (May 2004 to February 2008). We used robust regression models to test for intervention effects, controlling for site, patient, family, and nurse characteristics. MEASUREMENTS AND MAIN RESULTS: All hospitals completed the trial with 2,318 eligible patients and target sample sizes obtained for family and nurse surveys. The primary outcome, family-QODD, showed no change with the intervention (P = 0.33). There was no change in family satisfaction (P = 0.66) or nurse-QODD (P = 0.81). There was a nonsignificant increase in ICU days before death after the intervention (hazard ratio = 0.9; P = 0.07). Among patients undergoing withdrawal of mechanical ventilation, there was no change in time from admission to withdrawal (hazard ratio = 1.0; P = 0.81). CONCLUSIONS: We found this intervention was associated with no improvement in quality of dying and no change in ICU length of stay before death or time from ICU admission to withdrawal of life-sustaining measures. Improving ICU end-of-life care will require interventions with more direct contact with patients and families. Clinical trial registered with www.clinicaltrials.gov (NCT00685893). PMID- 20833821 TI - Strategic plan for lung vascular research: An NHLBI-ORDR Workshop Report. AB - The Division of Lung Diseases of the National Heart, Lung, and Blood Institute, with the Office of Rare Diseases Research, held a workshop to identify priority areas and strategic goals to enhance and accelerate research that will result in improved understanding of the lung vasculature, translational research needs, and ultimately the care of patients with pulmonary vascular diseases. Multidisciplinary experts with diverse experience in laboratory, translational, and clinical studies identified seven priority areas and discussed limitations in our current knowledge, technologies, and approaches. The focus for future research efforts include the following: (1) better characterizing vascular genotype-phenotype relationships and incorporating systems biology approaches when appropriate; (2) advancing our understanding of pulmonary vascular metabolic regulatory signaling in health and disease; (3) expanding our knowledge of the biologic relationships between the lung circulation and circulating elements, systemic vascular function, and right heart function and disease; (4) improving translational research for identifying disease-modifying therapies for the pulmonary hypertensive diseases; (5) establishing an appropriate and effective platform for advancing translational findings into clinical studies testing; and (6) developing the specific technologies and tools that will be enabling for these goals, such as question-guided imaging techniques and lung vascular investigator training programs. Recommendations from this workshop will be used within the Lung Vascular Biology and Disease Extramural Research Program for planning and strategic implementation purposes. PMID- 20833822 TI - Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation. AB - RATIONALE: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation. OBJECTIVES: To determine the potential benefit versus risk of sirolimus in lung transplantation. METHODS: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups. MEASUREMENTS AND MAIN RESULTS: One hundred eighty one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study. CONCLUSIONS: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906). PMID- 20833823 TI - Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. AB - RATIONALE: Mycobacterium massiliense has been recognized as a separate species from Mycobacterium abscessus; however, little is known regarding the clinical impact of this differentiation. OBJECTIVES: To compare clinical features and treatment outcomes between patients with M. abscessus lung disease and those with M. massiliense lung disease. METHODS: We performed molecular identification of stored clinical isolates of M. abscessus complex and compared clinical characteristics and treatment outcomes between 64 patients with M. abscessus lung disease and 81 patients with M. massiliense lung disease. MEASUREMENTS AND MAIN RESULTS: The clinical and radiographic manifestations of disease caused by each species were similar. Standardized combination antibiotic therapy, including a clarithromycin-containing regimen in combination with an initial 4-week course of cefoxitin and amikacin, was given to 57 patients (24 with M. abscessus and 33 with M. massiliense) for more than 12 months. The proportion of patients with sputum conversion and maintenance of negative sputum cultures was higher in patients with M. massiliense infection (88%) than in those with M. abscessus infection (25%; P < 0.001). Inducible resistance to clarithromycin (minimal inhibitory concentrations >= 32 MUg/ml) was found in all tested M. abscessus isolates (n = 19), but in none of the M. massiliense isolates (n = 28). CONCLUSIONS: Treatment response rates to combination antibiotic therapy including clarithromycin were much higher in patients with M. massiliense lung disease than in those with M. abscessus lung disease. The inducible resistance to clarithromycin could explain the lack of efficacy of clarithromycin-containing antibiotic therapy against M. abscessus lung disease. PMID- 20833824 TI - Increased proteolysis, myosin depletion, and atrophic AKT-FOXO signaling in human diaphragm disuse. AB - RATIONALE: Patients on mechanical ventilation who exhibit diaphragm inactivity for a prolonged time (case subjects) develop decreases in diaphragm force generating capacity accompanied by diaphragm myofiber atrophy. OBJECTIVES: Our objectives were to test the hypotheses that increased proteolysis by the ubiquitin-proteasome pathway, decreases in myosin heavy chain (MyHC) levels, and atrophic AKT-FOXO signaling play major roles in eliciting these pathological changes associated with diaphragm disuse. METHODS: Biopsy specimens were obtained from the costal diaphragms of 18 case subjects before harvest (cases) and compared with intraoperative specimens from the diaphragms of 11 patients undergoing surgery for benign lesions or localized lung cancer (control subjects). Case subjects had diaphragm inactivity and underwent mechanical ventilation for 18 to 72 hours, whereas this state in controls was limited to 2 to 4 hours. MEASUREMENTS AND MAIN RESULTS: With respect to proteolysis in cytoplasm fractions, case diaphragms exhibited greater levels of ubiquitinated protein conjugates, increased activity of the 26S proteasome, and decreased levels of MyHCs and alpha-actin. With respect to atrophic signaling in nuclear fractions, case diaphragms exhibited decreases in phosphorylated AKT, phosphorylated FOXO1, increased binding to consensus DNA sequence for Atrogin-1 and MuRF-1, and increased supershift of DNA-FOXO1 complexes with specific antibodies against FOXO1, as well as increased Atrogin-1 and MuRF-1 transcripts in whole myofiber lysates. CONCLUSIONS: Our findings suggest that increased activity of the ubiquitin-proteasome pathway, marked decreases in MyHCs, and atrophic AKT-FOXO signaling play important roles in eliciting the myofiber atrophy and decreases in diaphragm force generation associated with prolonged human diaphragm disuse. PMID- 20833825 TI - Palliative care for pulmonary patients. PMID- 20833826 TI - Peroxisome proliferator-activated receptors gamma coactivator-1alpha: master regulator of mitochondrial biogenesis and survival during critical illness? PMID- 20833827 TI - In-house neonatology: what are we waiting for? PMID- 20833828 TI - 24/7 neonatal intensive care unit attending physician coverage: a clash of missions. PMID- 20833829 TI - Mortality-risk profiling using Doppler leg scans in patients with pulmonary embolism. PMID- 20833830 TI - Prognostic significance of deep vein thrombosis in acute pulmonary embolism. PMID- 20833831 TI - Acute respiratory distress syndrome induced by pandemic H1N1 2009 influenza A virus infection. PMID- 20833832 TI - The lived experiences of children and adolescents with end-stage renal disease. AB - Relatively little is known about how children perceive and manage end-stage renal disease (ESRD) in daily life. To address this gap in the literature, the experiences and perceptions of children with ESRD were examined in this study. Study design comprised ethnographic interviews with 25 children and adolescents ages 7 to 18 years. Semistructured interviews were audiotaped, transcribed verbatim, and subjected to content analysis. Participants received a range of ESRD treatments including transplantation and dialysis. Findings indicate that ESRD has a profound impact on children. They described a range of challenges and experiences including not feeling "normal"; developing ESRD knowledge; frequent absence from school; gaining responsibility for ESRD care; relying on family, friends, and health care providers; and adjusting despite adversity. These findings depict a multifaceted, dynamic perspective engendered in tensions as children and adolescents grapple with adversity yet experience personal growth and resiliency. Implications and recommendations for clinical practice and research are discussed. PMID- 20833833 TI - Long-term survival of high tibial osteotomy for medial compartment osteoarthritis of the knee. AB - BACKGROUND: The management of degenerative arthritis of the knee in the younger, active patient presents a challenge to the orthopaedic surgeon. Surgical treatment options include high tibial osteotomy (HTO), unicompartmental knee arthroplasty, and total knee arthroplasty. PURPOSE: To examine the long-term survival of closing wedge HTO in a large series of patients up to 19 years after surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Four hundred fifty-five consecutive patients underwent lateral closing wedge HTO for medial compartment osteoarthritis between 1990 and 2001. Between 2008 and 2009, patients were contacted via telephone, and assessment included incidence of further surgery, current body mass index (BMI), Oxford Knee Score, and British Orthopaedic Association Patient Satisfaction Scale. Failure was defined as the need for revision HTO or conversion to unicompartmental knee arthroplasty or total knee arthroplasty. Survival analysis was completed using the Kaplan-Meier method. RESULTS: High tibial osteotomy survival was determined in 413 patients (91%). Of the 397 remaining living patients at the time of final review, 394 (99%) were contacted for follow-up via telephone interview. The probability of survival for HTO at 5, 10, and 15 years was 95%, 79%, and 56%, respectively. Multivariate regression analysis showed that age under 50 years (P = .001), BMI less than 25 (P = .006), and ACL deficiency (P = .03) were associated with better odds of survival. Mean Oxford Knee Score was 40 of 48 (range, 17-48). Overall, 85% of patients were enthusiastic or satisfied, and 84% would undergo HTO again at a mean 12 years of follow-up. CONCLUSION: High tibial osteotomy can be effective for periods longer than 15 years; however, results do deteriorate over time. Age less than 50 years, normal BMI, and ACL deficiency were independent factors associated with improved long-term survival of HTO. PMID- 20833834 TI - Responses against a subdominant CD8+ T cell epitope protect against immunopathology caused by a dominant epitope. AB - CD8(+) T cell responses are critical for the control of virus infections. Following infection, epitope-specific responses establish an unpredictable but reproducible pattern of dominance that is dictated by a large number of both positive and negative factors. Immunodomination, or diminution of subdominant epitope-specific responses by dominant epitopes, can play a substantial role in the establishment of epitope hierarchy. To determine the role of a dominant (K(d)M2(82-90)) and a subdominant (D(b)M(187-195)) epitope of respiratory syncytial virus in viral control and immunodomination, MHC-binding anchor residues in the two epitopes were mutated individually in recombinant infectious viruses, greatly reducing or deleting the epitope-specific CD8(+) T cell responses. Neither mutation negatively affected viral clearance in mice, and compensation by the unmutated epitope was seen in both cases, whereas compensation by five other subdominant epitopes was minimal. Mutation of the dominant K(d)M2(82-90) response resulted in effective viral clearance by the subdominant epitope with less illness, whereas mutation of the subdominant D(b)M(187-195) response resulted in overcompensation of the already dominant K(d)M2(82-90) epitope, and increased severity of illness. Increased illness was associated with poor functionality of the abundant population of CD8(+) T cells specific to the dominant K(d)M2(82-90) epitope, as measured by the percentage and magnitude of IFN-gamma production. These data demonstrate efficient viral clearance, and a protective effect of subdominant CD8(+) T cell responses. PMID- 20833835 TI - Lytic granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells. AB - Natural cytotoxicity is achieved by polarized release of perforin and granzymes at the NK cell-target cell immunological synapse. Signals for granule polarization and degranulation can be uncoupled in NK cells, which raises the question of their respective sensitivity to inhibitory receptors. Expression of either HLA-C or HLA-E on the human cell line 721.221 blocked granule polarization, degranulation, and CD16-dependent MIP-1alpha secretion by NK cell clones that expressed inhibitory receptors of matching HLA specificity. To test inhibition of signals for polarization and degranulation separately, Drosophila S2 cells expressing ICAM-1 with either HLA-C or HLA-E were used. CD16-dependent degranulation and MIP-1alpha secretion were not fully inhibited, suggesting that other receptor-ligand interactions, which occur with 721.221 cells, contribute to inhibition. In contrast, HLA-C or HLA-E on S2 cells coexpressing ICAM-1 or ULBP1 were sufficient to block granule polarization induced by either LFA-1 or NKG2D, even during concomitant CD16-dependent degranulation. Similarly, expression of a ligand for NKR-P1A on S2 cells inhibited granule polarization but not CD16 induced degranulation. Therefore, granule polarization, rather than degranulation, is the preferred target of inhibitory receptors in NK cells. PMID- 20833836 TI - Chemoattractant receptors and lymphocyte egress from extralymphoid tissue: changing requirements during the course of inflammation. AB - Memory/effector T cells traffic efficiently through extralymphoid tissues, entering from the blood and leaving via the afferent lymph. During inflammation, T cell traffic into the affected tissue dramatically increases; however, the dynamics and mechanisms of T cell exit from inflamed tissues are poorly characterized. In this study, we show, using both a mouse and a sheep model, that large numbers of lymphocytes leave the chronically inflamed skin. Many T cells capable of producing IFN-gamma and IL-17 also entered the draining afferent lymph, demonstrating that memory/effector T cells egress from sites of inflammation. Whereas efficient egress from acutely inflamed skin required lymphocyte-expressed CCR7, chronic inflammation promoted significant CCR7 independent exit as well. Lymphocyte exit at late time points of inflammation was sensitive to pertussis toxin but was only partially affected by the drug FTY720, implying the contribution of alternative chemoattractant receptors other than spingosine 1-phosphate receptor 1. Our data show that CCR7 is an important receptor for lymphocyte egress from both resting and inflamed extralymphoid tissues, but that alternative exit receptors come into play during chronic inflammation. PMID- 20833837 TI - Inhibition of NF-kappaB signaling in human dendritic cells by the enteropathogenic Escherichia coli effector protein NleE. AB - Intestinal dendritic cells (DCs) send processes between epithelial cells into the gut lumen to sample pathogens. Noninvasive enteropathogenic Escherichia coli (EPEC) colonize the gut using a type three secretion system (T3SS) to inject effector proteins into epithelial cells. We hypothesized that EPEC might also inject proteins into DC processes to dampen immune recognition. Using a T3SS linked fluorescence resonance energy transfer-based system we show that EPEC injects effectors into in vitro grown human myeloid DCs. Injected cells emit a blue signal due to cleavage of the green fluorescence resonance energy transfer based substrate CCF2/AM by beta-lactamase. When cultured with a mutant EPEC unable to translocate effector proteins, myeloid DCs show rapid activation of NF kappaB, secrete large amounts of proinflammatory cytokines and increase expression of CD80, CD83, and CD86, whereas wild-type EPEC barely elicits cytokine production and shuts off nuclear translocation of NF-kappaB p65. By deleting effector protein genes, we identified NleE as being critical for this effect. Expression of NleE in HeLa cells completely prevented nuclear p65 accumulation in response to IL1-beta, and luciferase production in an NF-kappaB reporter cell line. DCs cocultured with wild-type EPEC or NleE-complemented strains were less potent at inducing MLR. EPEC was also able to inject effectors into DCs sending processes through model gut epithelium in a transwell system and into Peyer's patch myeloid DCs. Thus, EPEC translocate effectors into human DCs to dampen the inflammatory response elicited by its own pathogen-associated molecular patterns. PMID- 20833838 TI - Innate immune proteins C1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. AB - Atherosclerosis is a chronic inflammatory disorder that is characterized by the accumulation of modified lipoproteins in the arterial intima. C1q and mannan binding lectin (MBL) are not only recognition components involved in activation of inflammation via the complement cascade, but they are also able to directly modulate phagocyte activation. Studies in C1q(-/-) and MBL(-/-) mice suggest that these molecules play a protective role in the early atherosclerotic lesion in the absence of, or prior to, expression of other complement components. However, in later stages, complement activation becomes an inappropriate inflammatory response, contributing to disease pathology. Therefore, to investigate possible molecular interactions of C1q and MBL in atherosclerotic lesions, we examined the influence of C1q and MBL in the clearance of native and modified lipoproteins by human monocytes and monocyte-derived macrophages. Both C1q and MBL are shown to bind and enhance the monocyte/monocyte-derived macrophage clearance of modified forms of low-density lipoprotein (LDL), including oxidized LDL and acetylated LDL, but not native LDL. Modified forms of LDL activate the classical complement pathway, but no lectin pathway activation was detected. Interestingly, monocytes that ingested modified LDL in the presence of C1q or MBL upregulated surface CD80 and CD31, as well as CCL2 chemokine gene expression. However, C1q and MBL also significantly reduced levels of free cholesterol accumulation in monocytes and human monocyte-derived macrophages that ingested oxidized LDL, while enhancing high-density lipoprotein-specific cholesterol efflux from these cells. These results suggest a novel pathway in which C1q and MBL influence removal and metabolism of atherogenic forms of LDL in the early stages of atherosclerosis. PMID- 20833839 TI - IL-1RL2 and its ligands contribute to the cytokine network in psoriasis. AB - Psoriasis is a common immune-mediated disease in European populations; it is characterized by inflammation and altered epidermal differentiation leading to redness and scaling. T cells are thought to be the main driver, but there is also evidence for an epidermal contribution. In this article, we show that treatment of mouse skin overexpressing the IL-1 family member, IL-1F6, with phorbol ester leads to an inflammatory condition with macroscopic and histological similarities to human psoriasis. Inflammatory cytokines thought to be important in psoriasis, such as TNF-alpha, IL-17A, and IL-23, are upregulated in the mouse skin. These cytokines are induced by and can induce IL-1F6 and related IL-1 family cytokines. Inhibition of TNF or IL-23 inhibits the increased epidermal thickness, inflammation, and cytokine production. Blockade of IL-1F6 receptor also resolves the inflammatory changes in human psoriatic lesional skin transplanted onto immunodeficient mice. These data suggest a role for IL-1F family members in psoriasis. PMID- 20833840 TI - GATA2 and Sp1 positively regulate the c-kit promoter in mast cells. AB - The c-kit gene is expressed in hematopoietic stem cells and lineage progenitor cells but is downregulated during cell development in most lineages, except for mast cells. In mast cells, high expression of c-kit is maintained during development, and c-Kit signaling is essential for mast cell development. To analyze the mechanisms by which c-kit gene expression are regulated in mast cells, we examined mast cell type-specific regulation of the c-kit promoter region. We observed that a GC-box in the c-kit promoter was critical for transcriptional activity and was bound to the transcription factor Sp1 as assessed using reporter assay and electrophoretic mobility assay. Chromatin immunoprecipitation assay and coexpression analyses showed that the transcription factor GATA2, which was recruited to the c-kit promoter in a mast cell-specific manner, in addition to Sp1, transactivated the c-kit promoter via the GC-box. Electrophoretic mobility assay and rechromatin immunoprecipitation assay indicated that GATA2 binds to the GC-box by forming a complex with Sp1. Introduction of Sp1 small interfering RNA significantly reduced the amount not only of Sp1 but also of GATA2 binding to the c-kit promoter in mast cells, resulting in suppression of c-kit transcription. Knockdown of GATA2 suppressed the recruitment of GATA2 toward the c-kit promoter, subsequently suppressing cell surface expression of c-Kit. These findings indicate that GATA2 and Sp1 play crucial roles in expression of the c-kit gene in mast cells. PMID- 20833841 TI - H1N1v influenza vaccine in Greek medical students. AB - BACKGROUND: We sought to investigate the penetration of the H1N1v vaccine in Greek medical students, as well as their approach to the vaccination. METHODS: A survey was conducted among the students of the University of Athens, School of Medicine, 1 month after the initiation of the vaccination programme. Participants were asked to fill in a questionnaire regarding their status of vaccination and their approach to the H1N1v vaccine. RESULTS: We handed a questionnaire to 1000 students (out of 1700 officially enrolled in the medical school) and retrieved 922 answers. Only 74 (8%) medical students had been vaccinated and 78 (9%) planned to (probably or definitely) do so in the future, while 641 (67%) would (probably or definitely) not get vaccinated. The highest coverage was among the sixth year students (37/234, 16%). The most common reasons for not having received the vaccine were perception of the disease as mild (387/848, 46%), and concern regarding long-term adverse events (370/848, 44%). Thirty percent (258/848) of the students doubted the vaccine's effectiveness, and 197 (23%) worried about possible short-term adverse events. One hundred and thirty-three respondents (16%) believed the whole story is a conspiracy while 102 (12%) reported to have had the flu. Almost half (43%) of the participants considered their knowledge on the subject inadequate. CONCLUSION: Our findings confirmed the low penetration of the H1N1 vaccine in Greece, as in most European countries, even in medical students. Better education of the students and the public might aid in increasing the immunization rates. PMID- 20833842 TI - Radiology education: a chronicle of support and success through the RSNA Research and Education Foundation. PMID- 20833843 TI - Lung cancer staging essentials: the new TNM staging system and potential imaging pitfalls. AB - Lung cancer is the leading cause of cancer-related deaths worldwide, with a dismal 5-year survival rate of 15%. The TNM (tumor-node-metastasis) classification system for lung cancer is a vital guide for determining treatment and prognosis. Despite the importance of accuracy in lung cancer staging, however, correct staging remains a challenging task for many radiologists. The new 7th edition of the TNM classification system features a number of revisions, including subdivision of tumor categories on the basis of size, differentiation between local intrathoracic and distant metastatic disease, recategorization of malignant pleural or pericardial disease from stage III to stage IV, reclassification of separate tumor nodules in the same lung and lobe as the primary tumor from T4 to T3, and reclassification of separate tumor nodules in the same lung but not the same lobe as the primary tumor from M1 to T4. Radiologists must understand the details set forth in the TNM classification system and be familiar with the changes in the 7th edition, which attempts to better correlate disease with prognostic value and treatment strategy. By recognizing the relevant radiologic appearances of lung cancer, understanding the appropriateness of staging disease with the TNM classification system, and being familiar with potential imaging pitfalls, radiologists can make a significant contribution to treatment and outcome in patients with lung cancer. PMID- 20833844 TI - Radiologic-pathologic correlation of ductal carcinoma in situ. AB - Ductal carcinoma in situ (DCIS) accounts for 20%-25% of breast cancers detected at screening mammography. The lesions are diverse and commonly are classified on the basis of their mammographic features and histologic characteristics such as nuclear grade and presence or absence of necrosis. The most common mammographic finding in DCIS is microcalcifications, but a low-grade lesion without necrosis is less likely to manifest with calcifications than either an intermediate- or a high-grade lesion. Other mammographic findings might include a mass or architectural distortion. Magnetic resonance (MR) imaging has higher sensitivity than mammography for the detection of DCIS and greater accuracy for depicting the extent of disease. The MR imaging appearance of DCIS depends primarily on the presence and extent of abnormal periductal or stromal vascularity. Nonmasslike enhancement, the most common MR imaging finding, is often seen in association with clumped internal enhancement. The enhancement kinetics in dynamic MR studies vary, and no kinetic pattern is pathognomonic of a particular nuclear grade of DCIS. However, the kinetic pattern at delayed imaging does appear to be correlated with the mammographic findings: Mass lesions show strong washout; fine pleomorphic, fine linear, and fine linear-branching calcifications demonstrate a plateau enhancement pattern; and amorphous calcifications exhibit persistent enhancement. Multidetector computed tomography might be a useful adjunct to MR imaging for preoperative mapping. PMID- 20833845 TI - US of breast masses categorized as BI-RADS 3, 4, and 5: pictorial review of factors influencing clinical management. AB - The Breast Imaging Reporting and Data System (BI-RADS) lexicon for ultrasonography (US) is based on the established lexicon used successfully in mammography and attempts to provide a common language to avoid ambiguity in interpreting, reporting, and teaching breast US. Proper and consistent use of the BI-RADS US lexicon has numerous advantages, including facilitating (a) communication of final assessment categories that clearly indicate management recommendations, (b) data tracking for self-audits, and (c) clinical review of outcome summaries. However, the literature to date does not include sufficient data on outcomes to validate clinical use of the BI-RADS US lexicon. In this article, a pictorial review of the BI-RADS US lexicon descriptors is provided, and specific cases from a retrospective review are used to highlight the challenges in using the BI-RADS US lexicon. With these examples, suggestions are offered for greater clarity in the use of this lexicon. The technical challenges in follow-up US imaging are described. The challenges in assigning final assessment categories are detailed, as well as the clinical factors that may influence decision making and the management of certain lesions. PMID- 20833847 TI - Imaging in pregnant patients: examination appropriateness. AB - A recurring source of contention between clinicians and radiologists continues to be examination appropriateness when imaging pregnant patients. With the multitude of references on potential radiation risks to the fetus, radiologists tend to be cautious and hesitant about exposing the fetus to radiation. This tendency is often interpreted by referring physicians as intrusion into and delay in the care of their patients. The risk burden of radiation exposure to the fetus has to be carefully weighed against the benefits of obtaining a critical diagnosis quickly and using a single tailored imaging study. In general, there is lower than expected awareness of radiation risks to the fetus from imaging pregnant patients. Modalities that do not use ionizing radiation, such as ultrasonography and magnetic resonance imaging, should be the preferred examinations for evaluating an acute condition in a pregnant patient. However, no examination should be withheld when an important clinical diagnosis is under consideration. Exposure to ionizing radiation may be unavoidable, but there is no evidence to suggest that the risk to the fetus after a single imaging study and an interventional procedure is significant. All efforts should be made to minimize the exposure, with consideration of the risk versus benefit for a given clinical scenario. PMID- 20833848 TI - Transvaginal US after bowel preparation for deeply infiltrating endometriosis: protocol, imaging appearances, and laparoscopic correlation. AB - Deeply infiltrating endometriosis (DIE) is a common gynecologic disease that is characterized by a difficult and delayed diagnosis. Radiologic mapping of the DIE lesion sites is crucial for case management, patient counseling, and surgical planning. Transvaginal ultrasonography (US) is the initial imaging modality for investigating DIE and has been the focus of several recent studies. DIE typically manifests at imaging as hypoechogenic nodules throughout the affected sites and thickening of the intestinal wall, with some lesions showing a mixed pattern due to cystic areas. Transvaginal US performed after bowel preparation improves the ability to diagnose intestinal lesions and provides invaluable details, including which layers of the intestine are affected and the distance between the lesion and the anal border. It is vital that radiologists be familiar with the technical aspects of this modality and with the US manifestations of DIE lesions. Transvaginal US performed after bowel preparation should be the first-line imaging modality for the evaluation of women with suspected endometriosis. PMID- 20833849 TI - PET/CT evaluation of cervical cancer: spectrum of disease. AB - The prognosis of invasive cervical cancer is based on the stage, size, and histologic grade of the primary tumor and the status of the lymph nodes. Assessment of disease stage is essential in determining proper management in individual cases. In the posttherapy setting, the timely detection of recurrence is essential for guiding management and may lead to increased survival. However, the official clinical staging system of the International Federation of Gynecology and Obstetrics has inherent flaws that may lead to inaccurate staging and improper management. Combined positron emission tomography (PET)/computed tomography (CT) represents a major technologic advance, consisting of two integrated complementary modalities whose combined strength tends to overcome their respective weaknesses. PET/CT has higher sensitivity and specificity than do conventional anatomic modalities and is valuable in determining the extent of disease and detecting recurrent or residual tumor. The combination of 2-[fluorine 18]fluoro-2-deoxy-d-glucose PET with intravenous contrast material-enhanced high resolution CT has proved useful for avoiding the interpretative weaknesses associated with either modality alone and in increasing the accuracy of staging or restaging. Nonetheless, accurate PET/CT interpretation requires a knowledge of the characteristics of disease spread or recurrence and an awareness of various imaging pitfalls if false interpretations are to be avoided. PMID- 20833850 TI - Diffusion-weighted imaging of peritoneal disease for noninvasive staging of advanced ovarian cancer. AB - Cross-sectional imaging of peritoneal carcinomatosis in patients with advanced ovarian cancer is important for appropriate management but can be compromised by the small size of cancer implants and the complexity of anatomic relationships. Diffusion-weighted imaging is a functional magnetic resonance (MR) imaging technique that exploits the restricted water mobility within hypercellular tumors to increase the contrast between these lesions and surrounding tissue. Its use improves the detection and delineation of peritoneal implants at both initial staging and follow-up. Moreover, diffusion-weighted imaging provides quantitative information about tissue cellularity that may be used to distinguish viable tumors from treatment-related changes. These data allow calculation of apparent diffusion coefficient (ADC) values, which, when considered in conjunction with biochemical and morphologic parameters, are helpful for assessing the effectiveness of treatment. The value of diffusion-weighted images is maximized when they are interpreted in comparison with anatomic MR images to avoid diagnostic pitfalls arising from normal hypercellular structures and neoplasms with low cellularity. When incorporating diffusion-weighted imaging into abdominal and pelvic MR studies, it is important to be aware of the strengths and limitations of the technique. Competence in data display methods and ADC calculations also helps improve the accuracy of image interpretation and may aid in the management of patients with advanced ovarian cancer. PMID- 20833851 TI - Renal pyramids: focused sonography of normal and pathologic processes. AB - In neonates and children, sonographic examinations of the renal pyramids may depict a spectrum of unique changes in echogenicity due to the effects of physiologic processes or a wide variety of pathologic processes that may affect the collecting ducts or interstitium of the pyramids. Focused sonographic evaluation of the pyramids with high-frequency transducers produces the most detailed images of the pyramids, revealing some appearances not previously reported, to the authors' knowledge. The authors highlight the clinical settings in which they have documented detailed changes in the echogenicity of the pyramids. The patterns of altered echogenicity alone may reflect a specific cause but in many instances are nonspecific, with clinical and biochemical correlation required to establish a more precise diagnosis. However, there is a lack of histologic data to completely explain the mechanism of many of these changes in echogenicity in all of the processes. As the authors have expanded their use of the focused sonographic technique, they have been able to depict altered echogenicity in the pyramids in greater numbers of children in whom an explanation for the changes is not always immediately apparent; for now, the cause must be considered idiopathic. More work is required to expand the use of this focused technique together with clinical, biochemical, and histologic correlation in an attempt to offer more complete explanations for the changes in echogenicity of the pyramids. PMID- 20833853 TI - The real "meaning" behind meaningful use. PMID- 20833852 TI - Hypertrophic cardiomyopathy: assessment with MR imaging and multidetector CT. AB - Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease. Its early detection is important because it is the most common cause of sudden cardiac death among young people. However, HCM is often a dilemma for clinicians because it manifests with diverse phenotypic expressions and clinical courses. With the advances in imaging technology, magnetic resonance (MR) imaging and multidetector computed tomography (CT) serve as suitable modalities for detecting and characterizing HCM and obtaining information for appropriate management of cases of HCM, although echocardiography is currently the most widely used modality. This article is an overview of the definition of HCM, its various phenotypes, risk stratification of HCM, and the potential application of cardiac MR imaging and multidetector CT for the assessment of HCM. PMID- 20833854 TI - Emergency imaging assessment of acute, nontraumatic conditions of the head and neck. AB - Patients often present to the emergency department with a wide variety of nontraumatic infectious, inflammatory, and neoplastic conditions of the head and neck. Because the use of cervical and neck computed tomography (CT) has become routine in the emergency setting, knowledge of the imaging findings of common acute conditions of the head and neck is essential to ensure an accurate diagnosis of these potentially life-threatening conditions, which include oral cavity infections, tonsillitis and peritonsillar abscess, sialadenitis, parotiditis, diskitis, thrombophlebitis, periorbital and orbital cellulitis, infectious cervical lymphadenopathy, and various neoplasms. Less common conditions that require rapid diagnosis and treatment include epiglottitis, invasive fungal sinusitis, angioedema, and deep neck abscess. Familiarity with these conditions enables the radiologist to make a prompt diagnosis, assess the extent of disease, and evaluate for potential complications. CT is the first-line imaging modality in the emergency setting; however, magnetic resonance imaging plays an important secondary role. PMID- 20833855 TI - FDG PET with contrast-enhanced CT: a critical imaging tool for laryngeal carcinoma. AB - Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has evolved to be an essential imaging modality in the evaluation of laryngeal carcinoma. Although the modality has limited utility in assessing the extent of the primary tumor, FDG PET has proved to be superior to anatomic modalities in the detection of lymph node and distant metastases. The role of FDG PET in the evaluation of patients with laryngeal tumors that are clinically classified as N0 has not shown consistent usefulness because of the innate resolution limitations of the camera. In the posttherapy setting, however, FDG PET has consistently demonstrated a high negative predictive value in the identification of recurrent disease, both during the course of therapy and during long-term follow-up. In addition, contrast material-enhanced computed tomography (CT) in conjunction with FDG PET has demonstrated a complementary role by allowing for superior anatomic coregistration and therefore more definitive diagnosis. There is sufficient evidence that with further advances in PET technology, this modality will likely become more useful in the detection of small lesions and occult nodal disease, as well as in guiding the management of laryngeal carcinoma. PMID- 20833856 TI - Multimodality imaging of peripheral neuropathies of the upper limb and brachial plexus. AB - The peripheral nerves of the upper limb are affected by a number of entrapment and compression neuropathies. These discrete syndromes involve the brachial plexus as well as the musculocutaneous, axillary, suprascapular, ulnar, radial, and median nerves. Clinical examination and electrophysiologic studies are the traditional mainstay of diagnostic work-up; however, ultrasonography and magnetic resonance imaging provide spatial information regarding the affected nerve and its surroundings, often assisting in narrowing the differential diagnosis and guiding treatment. Imaging is particularly valuable in complex cases with discrepant nerve function test results. Familiarity with the clinical features of various peripheral neuropathies of the upper extremity, the relevant anatomy, and the most common sites and causes of nerve entrapment assists in diagnosis and treatment. PMID- 20833857 TI - Scenes from the past: "Skeeter": Harlem Renaissance author's description of a young man's impression of a radiology examination room. PMID- 20833858 TI - Best cases from the AFIP: ameloblastoma and dentigerous cyst associated with impacted mandibular third molar tooth. PMID- 20833859 TI - Best cases from the AFIP: Wilms tumor in the setting of bilateral nephroblastomatosis. PMID- 20833860 TI - Basilar artery: another anatomic blind spot at brain imaging. PMID- 20833861 TI - An unusual cause for cough in an octogenarian. PMID- 20833862 TI - Cost-effectiveness of a day hospital falls prevention programme for screened community-dwelling older people at high risk of falls. AB - BACKGROUND: multifactorial falls prevention programmes for older people have been proved to reduce falls. However, evidence of their cost-effectiveness is mixed. DESIGN: economic evaluation alongside pragmatic randomised controlled trial. INTERVENTION: randomised trial of 364 people aged >=70, living in the community, recruited via GP and identified as high risk of falling. Both arms received a falls prevention information leaflet. The intervention arm were also offered a (day hospital) multidisciplinary falls prevention programme, including physiotherapy, occupational therapy, nurse, medical review and referral to other specialists. MEASUREMENTS: self-reported falls, as collected in 12 monthly diaries. Levels of health resource use associated with the falls prevention programme, screening (both attributed to intervention arm only) and other health care contacts were monitored. Mean NHS costs and falls per person per year were estimated for both arms, along with the incremental cost-effectiveness ratio (ICER) and cost effectiveness acceptability curve. RESULTS: in the base-case analysis, the mean falls programme cost was L349 per person. This, coupled with higher screening and other health-care costs, resulted in a mean incremental cost of L578 for the intervention arm. The mean falls rate was lower in the intervention arm (2.07 per person/year), compared with the control arm (2.24). The estimated ICER was L3,320 per fall averted. CONCLUSIONS: the estimated ICER was L3,320 per fall averted. Future research should focus on adherence to the intervention and an assessment of impact on quality of life. PMID- 20833863 TI - Age-associated differences in the gait pattern changes of older adults during fast-speed and fatigue conditions: results from the Baltimore longitudinal study of ageing. AB - OBJECTIVE: the present study investigated the effects of walking under different challenges and kinematics and kinetics generated during these activities and how these vary with age. We hypothesised that age-associated changes in gait speed and kinetics are more pronounced during fast-speed walking and post-activity walking, compared with usual-speed walking. METHODS: investigated walking under three conditions: (i) usual speed, (ii) fast speed and (iii) post-activity in 183 Baltimore Longitudinal Study of Aging participants (mean 73 +/- 9 years) who could walk unassisted. RESULTS: across all tasks, gait speed decreased with older age and this decline rate was exacerbated in the fast-speed walking task, compared with usual-speed walking (P < 0.001). Medial-lateral (ML) hip-generative mechanical work expenditure declined with age and the rate of decline was steeper for walking at fast speed and post-activity during hip extension (P = 0.032 and 0.027, respectively), compared with usual-speed walking. CONCLUSIONS: these findings indicate that older adults experience exacerbated declines in gait speed and ML control of the hip, which is explicitly evident during challenging walking. Exercise programmes aimed at improving gait speed and ML joint power from hip and ankle may help reverse age-associated changes in gait pattern among older adults. PMID- 20833864 TI - Telestroke: a concept in practice. PMID- 20833865 TI - Changes in the incidence of lower extremity amputations in individuals with and without diabetes in England between 2004 and 2008. AB - OBJECTIVE: To describe recent trends in the incidence of nontraumatic amputations among individuals with and without diabetes and estimate the relative risk of amputations among individuals with diabetes in England. RESEARCH DESIGN AND METHODS: We identified all patients aged >16 years who underwent any nontraumatic amputation in England between 2004 and 2008 using national hospital activity data from all National Health Service hospitals. Age- and sex-specific incidence rates were calculated using the total diabetes population in England every year. To test for time trend, we fitted Poisson regression models. RESULTS: The absolute number of diabetes-related amputations increased by 14.7%, and the incidence decreased by 9.1%, from 27.5 to 25.0 per 10,000 people with diabetes, during the study period (P > 0.2 for both). The incidence of minor and major amputations did not significantly change (15.7-14.9 and 11.8-10.2 per 10,000 people with diabetes; P = 0.66 and P = 0.29, respectively). Poisson regression analysis showed no statistically significant change in diabetes-related amputation incidence over time (0.98 decrease per year [95% CI 0.93-1.02]; P = 0.12). Nondiabetes-related amputation incidence decreased from 13.6 to 11.9 per 100,000 people without diabetes (0.97 decrease by year [0.93-1.00]; P = 0.059). The relative risk of an individual with diabetes undergoing a lower extremity amputation was 20.3 in 2004 and 21.2 in 2008, compared with that of individuals without diabetes. CONCLUSIONS: This national study suggests that the overall population burden of amputations increased in people with diabetes at a time when the number and incidence of amputations decreased in the aging nondiabetic population. PMID- 20833866 TI - A1C and diabetes diagnosis among Filipino Americans, Japanese Americans, and Native Hawaiians. AB - OBJECTIVE: To examine the sensitivity and specificity of A1C >= 6.5% to diagnose diabetes among Filipino Americans, Japanese Americans, and Native Hawaiians. RESEARCH DESIGN AND METHODS: This was a cross-sectional study among middle-aged adults without prior diagnosis of type 2 diabetes who completed a 2-h 75-g oral glucose tolerance test (OGTT) and A1C measures. RESULTS: The 933 participants had a mean age of 54.2 years, and 73% were women. A total of 425 (45.5%) subjects had impaired fasting glucose or impaired glucose tolerance, 145 (15.5%) had type 2 diabetes (by OGTT), and 83 (8.9%) had A1C >= 6.5%. The sensitivity and specificity of A1C >= 6.5% to define diabetes (by OGTT) was 40.0 and 96.8% and 68.9 and 95.3%, respectively (by fasting plasma glucose only). However, (64.8%) of Filipino and Japanese subjects with diabetes had isolated postchallenge hyperglycemia; AIC >= 6.5% sensitivity and specificity was 19.1 and 92.1%, respectively, to define isolated postchallenge hyperglycemia in the total sample. CONCLUSIONS: A1C >= 6.5% had low sensitivity and may delay diagnosis of type 2 diabetes without OGTT. This limitation is exacerbated by isolated postchallenge hyperglycemia in Asian Americans. PMID- 20833867 TI - Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. AB - OBJECTIVE: Previous observational studies have found an increased risk of acute pancreatitis among type 2 diabetic patients. However, limited information is available on this association and specifically on the role of antidiabetic treatment. Our aim, therefore, was to further assess the risk of acute pancreatitis in adult patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a population-based case-control analysis nested in a cohort of 85,525 type 2 diabetic patients and 200,000 diabetes-free individuals from the general population using data from The Health Improvement Network database. Subjects were followed up to ascertain incident cases of acute pancreatitis. RESULTS: We identified 419 cases of acute pancreatitis, 243 in the general population and 176 in the diabetes cohort. Incidence rates were 30.1 and 54.0 per 100,000 person-years in the general population and the diabetes cohort, respectively. In the cohort analysis, the adjusted incidence rate ratio of acute pancreatitis in diabetic patients versus that in the general population was 1.77 (95% CI 1.46-2.15). The magnitude of this association decreased with adjustment for multiple factors in the nested case-control analysis (adjusted odds ratio 1.37 [95% CI 0.99-1.89]). Furthermore, we found that the risk of acute pancreatitis was decreased among insulin-treated diabetic patients (0.35 [0.20 0.61]). CONCLUSIONS: Type 2 diabetes may be associated with a slight increase in the risk of acute pancreatitis. We also found that insulin use in type 2 diabetes might decrease this risk. Further research is warranted to confirm these associations. PMID- 20833869 TI - Age-associated changes in the subcellular localization of phosphorylated p38 MAPK in human granulosa cells. AB - p38 MAPK (p38) plays pivotal roles in aging and reproductive physiology. Nevertheless, involvement of p38 in female reproductive aging is uncertain. To improve knowledge of the role of p38 in age-associated reproductive failure, the expression and subcellular localization of phosphorylated p38 was investigated in human granulosa cells. p38 was 7-fold more activated in cells from older subjects than in those from younger subjects. Similar results were obtained in human granulosa-like KGN cells treated with hydrogen peroxide (H(2)O(2)). Interestingly, phosphorylated p38 was detected in the nucleus less frequently in older cells than in younger cells (Younger: 58.6%; Older: 29.8%, P< 0.01). Similarly cytoplasmic localization of phosphorylated p38 in KGN cells was observed after treatment with H(2)O(2). The activation and cytoplasmic localization of p38 in H(2)O(2)-treated KGN cells were blocked by N acetylcysteine and SB203580. Although the p38 activators, FSH and tumor necrosis factor-alpha, induced a similar localization of phosphorylated p38 in KGN cells, the expression and localization patterns of p38 were distinct from those in older granulosa cells and H(2)O(2)-treated KGN cells. These results indicate that the characteristic localization of p38 in older granulosa cells is induced by oxidative stress. PMID- 20833868 TI - Vibration perception threshold as a measure of distal symmetrical peripheral neuropathy in type 1 diabetes: results from the DCCT/EDIC study. AB - OBJECTIVE: To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy. RESEARCH DESIGN AND METHODS: VPT was determined in 1,177 adults with type 1 diabetes 13-14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction). RESULTS: Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71-0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy. CONCLUSIONS: VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest. PMID- 20833870 TI - Methylation status in the intragenic differentially methylated region of the IGF2 locus in Bos taurus indicus oocytes with different developmental competencies. AB - Oocyte quality is one of the most important aspects of in vitro embryo development. Extensive epigenetic programming must occur during oocyte growth and maturation. A specific DNA methylation pattern of the imprinted genes must be established on differentially methylated regions (DMR). The insulin-like growth factor 2 (IGF2) gene is an important growth factor, and it is imprinted in several mammalian species. The aim of this study was to evaluate the methylation pattern on the DMR of the last exon of IGF2 in immature and mature bovine oocytes with different developmental competencies. Mature oocytes from large follicles were less methylated (28.93%) than immature oocytes from large follicles (77.38% P = 0.002), and there was also a tendency towards lower methylation in mature oocytes from large follicles (28.93%) compared with mature oocytes from small follicles (52.58% P = 0.07). Immature oocytes from small and large follicles showed 53.85% (7/13) and 91.66% (11/12) hypermethylated sequences, respectively, whereas mature oocytes from small and large follicles showed 61.11% (11/18) and 40% (4/10), respectively. The hypomethylation pattern in mature oocytes from large follicles may be related to the higher competence of these oocytes. Our results suggest that the methylation pattern in this DMR may be a useful parameter to investigate as a molecular marker for oocyte competence in cattle and as a model for studies in other species. PMID- 20833871 TI - Molecular architecture and structural basis of allosteric regulation of eukaryotic phosphofructokinases. AB - Eukaryotic ATP-dependent 6-phosphofructokinases (Pfks) differ from their bacterial counterparts in a much more complex structural organization and allosteric regulation. Pichia pastoris Pfk (PpPfk) is, with ~ 1 MDa, the most complex and probably largest eukaryotic Pfk. We have determined the crystal structure of full-length PpPfk to 3.05 A resolution in the T state. PpPfk forms a (alphabetagamma)(4) dodecamer of D(2) symmetry with dimensions of 161 * 157 * 233 A mainly via interactions of the alpha chains. The N-terminal domains of the alpha and beta chains have folds that are distantly related to glyoxalase I, but the active sites are no longer functional. Interestingly, these domains located at the 2 distal ends of this protein along the long 2-fold axis form a (alphabeta)(2) dimer as does the core Pfk domains; however, the domains are swapped across the tetramerization interface. In PpPfk, the unique gamma subunit participates in oligomerization of the alphabeta chains. This modulator protein was acquired from an ancient S-adenosylmethionine-dependent methyltransferase. The identification of novel ATP binding sites, which do not correspond to the bacterial catalytic or effector binding sites, point to marked structural and functional differences between bacterial and eukaryotic Pfks. PMID- 20833872 TI - Poxytrins, a class of oxygenated products from polyunsaturated fatty acids, potently inhibit blood platelet aggregation. AB - Docosahexaenoic acid (DHA), an important component of marine lipids, exhibits anti-inflammatory activity related to some of its oxygenated metabolites, such as neuroprotectin/protectin D1 [NPD1/PD1; 10(R),17(S)-dihydroxy-docosa-4Z,7Z, 11E,13E,15Z,19Z-hexaenoic acid] produced through the 15-lipoxygenase pathway. However, other metabolites from DHA can be produced through this pathway, and other polyunsaturated fatty acids (PUFAs) of nutritional value may be oxygenated as well. Their biological activities remain unknown. Isomers of protectin D1 were synthesized using soybean lipoxygenase and tested for their ability to inhibit human blood platelet aggregation. A geometric isomer called PDX, previously described with the 11E,13Z,15E geometry, instead of 11E,13E,15Z in PD1, inhibited platelet aggregation at submicromolar concentrations when induced by either collagen, arachidonic acid, or thromboxane. The inhibition occurred at the level of both the cyclooxygenase activity and thromboxane receptor site. Interestingly, all the metabolites tested exhibiting the E,Z,E-conjugated triene were active, whereas E,E,Z trienes (as in PD1) or all-trans (E,E,E) trienes were inactive. We conclude that PDX and other oxygenated products from PUFAs of nutritional interest, having the E,Z,E-conjugated triene motif and collectively named poxytrins (PUFA oxygenated trienes), might have antithrombotic potential. PMID- 20833873 TI - Mitochondrial gamma-secretase participates in the metabolism of mitochondria associated amyloid precursor protein. AB - Intracellular amyloid-beta peptide (Abeta) has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondria were found to be the target both for amyloid precursor protein (APP) that accumulates in the mitochondrial import channels and for Abeta that interacts with several proteins inside mitochondria and leads to mitochondrial dysfunction. Here, we have studied the role of mitochondrial gamma-secretase in processing different substrates. We found that a significant proportion of APP is associated with mitochondria in cultured cells and that gamma-secretase cleaves the shedded C-terminal part of APP identified as C83 associated with the outer membrane of mitochondria (OMM). Moreover, we have established the topology of the C83 in the OMM and found the APP intracellular domain (AICD) to be located inside mitochondria. Our data show for the first time that APP is a substrate for the mitochondrial gamma-secretase and that AICD is produced inside mitochondria. Thus, we provide a mechanistic view of the mitochondria-associated APP metabolism where AICD, P3 peptide and potentially Abeta are produced locally and may contribute to mitochondrial dysfunction in AD. PMID- 20833874 TI - Surgical versus functional treatment for acute ruptures of the lateral ligament complex of the ankle in young men: a randomized controlled trial. AB - BACKGROUND: Some have recommended surgical treatment of Grade-III lateral ligament injuries in very active individuals with high functional demands on the ankle. The purpose of this study was to establish whether surgery provides better long-term results than functional treatment for acute ruptures of the lateral ligaments of the ankle. METHODS: Physically active Finnish men (mean age, 20.4 years) with an acute Grade-III lateral ligament rupture of the ankle were randomly allocated to surgical (n = 25) or functional (n = 26) treatment. Ligament injury was confirmed with stress radiographs. Surgical treatment comprised suture repair of the injured ligament(s) within the first week after injury. A below-the-knee plaster cast was worn for six weeks with full weight bearing. Functional treatment consisted of the use of an Aircast ankle brace for three weeks. The main outcome measures included final follow-up examinations, calculation of an ankle score, stress radiographs, and magnetic resonance imaging scans. RESULTS: Fifteen (60%) of twenty-five surgically treated patients and eighteen (69%) of twenty-six functionally treated patients returned for long-term follow-up (mean duration, fourteen years). All patients in both groups had recovered their preinjury activity level and reported that they could walk and run normally. The prevalence of reinjury was one of fifteen in the surgical group and seven of eighteen in the functional treatment group (risk difference: 32%; 95% confidence interval: 6% to 58%). The mean ankle score did not differ significantly between the groups (mean difference: 8.3 points; 95% confidence interval: -0.03 to 16.6 points). Stress radiographs revealed no difference between groups with regard to the mean anterior drawer (-1 mm in the surgical group and 0 mm in the functional treatment group; mean difference: 0.7 mm; 95% confidence interval: -1.4 to 2.7 mm) or mean tilt angle (0 degrees in both groups; mean difference: 0.1 degrees ; 95% confidence interval: -3.2 degrees to 3.5 degrees ). Grade-II osteoarthritis was observed on magnetic resonance images of four of the fifteen surgically treated patients and in none of the eighteen functionally treated patients (risk difference: 27%; 95% confidence interval: 4% to 49%). CONCLUSIONS: These findings indicate that, in terms of recovery of the preinjury activity level, the long-term results of surgical treatment of acute lateral ligament rupture of the ankle correspond with those of functional treatment. Although surgery appeared to decrease the prevalence of reinjury of the lateral ligaments, there may be an increased risk for the subsequent development of osteoarthritis. PMID- 20833875 TI - The phylogenetic placement of the non-phototrophic, Gram-positive thermophile 'Thermobaculum terrenum' and branching orders within the phylum 'Chloroflexi' inferred from gene order comparisons. AB - The phylogenetic position of an anaerobic, non-spore-forming thermophile 'Thermobaculum terrenum' was investigated on the basis of gene order data from completely sequenced bacterial genomes. Gene order data can be an excellent source of phylogenetic information. Shared gene arrangements are unlikely to have arisen by chance convergence. They are likely to reflect common ancestry. 'Thermobaculum terrenum' was found to share three gene arrangements that are present uniquely in genomes of members of the phylum 'Chloroflexi', indicating convincingly that 'Thermobaculum terrenum' is a member of this phylum. Branching orders within the phylum 'Chloroflexi' were inferred by identifying monophyletic groups of species, which were circumscribed by characteristic gene arrangements. The branching orders thus inferred were in good agreement with previously reported phylogenies based on single 16S rRNA gene sequences and on multiple protein sequences. The gene order comparisons revealed a close phylogenetic affinity of 'Thermobaculum terrenum' to Sphaerobacter thermophilus and Thermomicrobium roseum. PMID- 20833876 TI - Bacillus thermolactis sp. nov., isolated from dairy farms, and emended description of Bacillus thermoamylovorans. AB - A polyphasic taxonomic study was performed on 22 thermotolerant, aerobic, endospore-forming bacteria from dairy environments. Seventeen isolates were retrieved from raw milk, one from a filter cloth and four from grass, straw or milking equipment. These latter four isolates (R-6546, R-7499, R-7764 and R-7440) were identified as Bacillus thermoamylovorans based on DNA-DNA hybridizations (values above 70 % with Bacillus thermoamylovorans LMG 18084(T)) but showed discrepancies in characteristics with the original species description, so an emended description of this species is given. According to 16S rRNA gene sequence analysis and DNA-DNA hybridization experiments, the remaining 18 isolates (R 6488(T), R-28193, R-6491, R-6492, R-7336, R-33367, R-6486, R-6770, R-31288, R 28160, R-26358, R-7632, R-26955, R-26950, R-33520, R-6484, R-26954 and R-7165) represented one single species, most closely related to Bacillus thermoamylovorans (93.9 % 16S rRNA gene sequence similarity), for which the name Bacillus thermolactis is proposed. Cells were Gram-stain-positive, facultatively anaerobic, endospore-forming rods that grew optimally at 40-50 degrees C. The cell wall peptidoglycan type of strain R-6488(T), the proposed type strain, was A1gamma based on meso-diaminopimelic acid. Major fatty acids of the strains were C(16 : 0) (28.0 %), iso-C(16 : 0) (12.1 %) and iso-C(15 : 0) (12.0 %). MK-7 was the predominant menaquinone, and major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and some unidentified phospholipids. DNA G+C content was 35.0 mol%. Phenotypic properties allowed discrimination from other thermotolerant species of the genus Bacillus and supported the description of the novel species Bacillus thermolactis, with strain R-6488(T) ( = LMG 25569(T) = DSM 23332(T)) as the proposed type strain. PMID- 20833877 TI - Five novel Wickerhamomyces- and Metschnikowia-related yeast species, Wickerhamomyces chaumierensis sp. nov., Candida pseudoflosculorum sp. nov., Candida danieliae sp. nov., Candida robnettiae sp. nov. and Candida eppingiae sp. nov., isolated from plants. AB - On the basis of nucleotide divergences in the D1/D2 domain of the 26S rRNA gene and the internal transcribed spacers (ITS) domain of the rRNA gene, five novel yeast species, Wickerhamomyces chaumierensis sp. nov. (CBS 8565(T) = JCM 17246(T)), Candida pseudoflosculorum sp. nov. (CBS 8584(T) = JCM 17242(T)), Candida danieliae sp. nov. (CBS 8533(T) = JCM 17247(T)), Candida robnettiae sp. nov. (CBS 8580(T) = JCM 17243(T)) and Candida eppingiae sp. nov. (CBS 8586(T) = JCM 17241(T)), isolated from plants in Thailand and Guyana, are proposed in this study. PMID- 20833878 TI - Mycobacterium shinjukuense sp. nov., a slowly growing, non-chromogenic species isolated from human clinical specimens. AB - Seven isolates of a slowly growing, non-chromogenic Mycobacterium species were obtained from sputum and bronchial lavage fluid samples from elderly patients in different regions of Japan. These isolates were distinguished from related non tuberculous species by colony morphology, positive results for Tween hydrolysis, catalase at 68 degrees C, nitrate reductase and pyrazinamidase and negative results for semi-quantitative catalase, urease and arylsulfatase. The mycolic acid pattern obtained by HPLC revealed a single cluster of late-eluting mycolic acids similar to but different from those of Mycobacterium malmoense ATCC 29571(T). The 16S rRNA gene, 16S-23S internal transcribed spacer (ITS), rpoB and hsp65 sequences were unique in comparison with those of other mycobacteria. Comparison of 16S rRNA gene sequences showed that the isolates were most closely related to Mycobacterium tuberculosis H37Rv(T) (21 base differences in 1508 bp; 98.6 % 16S rRNA gene sequence similarity). A representative strain, GTC 2738(T), showed 91.9 % rpoB sequence similarity with Mycobacterium marinum strain M, 95 % hsp65 sequence similarity with Mycobacterium kansasii CIP 104589(T) and 81.1 % 16S-23S ITS sequence similarity with Mycobacterium gordonae ATCC 14470(T). Phylogenetic analysis of concatenated sequences of the 16S rRNA, rpoB and hsp65 genes showed that strain GTC 2738(T) was located on a distinct clade adjacent to M. tuberculosis, M. ulcerans and M. marinum, with bootstrap values of 81 %. DNA DNA hybridization demonstrated less than 70 % reassociation with type strains of genetically related species and supported the novel species status of the isolates. On the basis of this evidence, a novel species with the name Mycobacterium shinjukuense sp. nov. is proposed. The type strain, isolated from a sputum sample, is strain GTC 2738(T)( = JCM 14233(T) = CCUG 53584(T)). PMID- 20833879 TI - Nocardioides ultimimeridianus sp. nov. and Nocardioides maradonensis sp. nov., isolated from rhizosphere soil. AB - Two novel Gram-reaction-positive, rod-shaped actinobacterial strains, designated RP-B26(T) and RP-B30(T), were isolated from rhizosphere soil of a cliff associated plant (Peucedanum japonicum Thunb.) which was collected from Mara Island, Republic of Korea. The colonies of the isolates were circular, smooth, convex and moderately yellow-light-yellow in colour. 16S rRNA gene sequence analysis revealed that the isolates belonged to the family Nocardioidaceae and formed two distinct sublineages within the radiation of the genus Nocardioides. 16S rRNA gene sequence similarity between the isolates was 98.2 %. The closest phylogenetic neighbours of strain RP-B26(T) were Nocardioides humi DCY24(T) and Nocardioides kongjuensis A2-4(T) with 97.4 and 97.0 % 16S rRNA gene sequence similarity, respectively, whereas 16S rRNA gene sequence similarities between strain RP-B30(T) and N. humi DCY24(T) and N. kongjuensis A2-4(T) were 96.5 and 96.0 %, respectively. Both of the isolates contained ll-diaminopimelic acid as the diagnostic diamino acid in the cell walls. The predominant menaquinone was MK 8(H(4)). The polar lipids were phosphatidylinositol and phosphatidylglycerol. The fatty acid profiles of the isolates were characterized by the presence of saturated, unsaturated, 10-methyl and hydroxyl fatty acids, with small amounts of branched fatty acids. The DNA G+C contents of strains RP-B26(T) and RP-B30(T) were 73.0 and 71.7 mol%, respectively. Levels of DNA-DNA relatedness between the isolates were 44.9 +/- 1.5 % (thermal renaturation method) and 43.2 % (photobiotin-labelled method); the isolates showed low DNA-DNA relatedness values (<11 %) to the most closely related strain, N. humi KCTC 19265(T). On the basis of the phenotypic, genotypic and DNA-DNA hybridization data presented here, the isolates are considered to represent two novel species of the genus Nocardioides, for which the names Nocardioides ultimimeridianus sp. nov. (type strain RP-B26(T) = KCTC 19368(T) = DSM 19768(T)) and Nocardioides maradonensis sp. nov. (type strain RP-B30(T) = KCTC 19384(T) = DSM 19769(T)) are proposed. PMID- 20833880 TI - Description of Catellibacterium caeni sp. nov., reclassification of Rhodobacter changlensis Anil Kumar et al. 2007 as Catellibacterium changlense comb. nov. and emended description of the genus Catellibacterium. AB - A novel non-sporulating, non-motile, catalase- and oxidase-positive, strictly aerobic, Gram-negative, rod-shaped bacterial strain, designated DCA-1(T), was isolated from activated sludge collected from a butachlor wastewater treatment facility. The strain was able to degrade about 85 % of 100 mg butachlor l(-1) within 5 days of incubation. Growth occurred in the presence of 0-6 % (w/v) NaCl [optimum, 1 % (w/v) NaCl] and at pH 5.5-9.0 (optimum, pH 7.0) and 15-35 degrees C (optimum, 25-30 degrees C). Vesicular internal membrane structures and photoheterotrophic growth were not observed. The major respiratory quinone was ubiquinone 10 (Q-10) and the major cellular fatty acids were C(18 : 1)omega7c and 11-methyl C(18 : 1)omega7c. The genomic DNA G+C content of strain DCA-1(T) was 62.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequence comparison revealed that strain DCA-1(T) was a member of the family Rhodobacteraceae and was related most closely to the type strain of Catellibacterium aquatile (96.5 % sequence similarity). The combination of phylogenetic analysis, phenotypic characteristics and chemotaxonomic data supports the suggestion that strain DCA 1(T) represents a novel species of the genus Catellibacterium, for which the name Catellibacterium caeni sp. nov. is proposed. The type strain is DCA-1(T) ( = CGMCC 1.7745(T) = DSM 21823(T)). In addition, based on the characterization data obtained in this study, it is proposed that Rhodobacter changlensis should be reclassified as Catellibacterium changlense comb. nov. (type strain JA139(T) = DSM 18774(T) = CCUG 53722(T) = JCM 14338(T)). An emended description of the genus Catellibacterium is also presented. PMID- 20833881 TI - Rhizobium herbae sp. nov. and Rhizobium giardinii-related bacteria, minor microsymbionts of various wild legumes in China. AB - Seven Rhizobium strains associated with various legume species grown in different geographical regions of China were defined into four genomic groups related to Rhizobium giardinii, based upon ribosomal intergenic spacer RFLP, phylogenies of 16S rRNA and housekeeping (atpD, recA and glnII) genes, and DNA relatedness. Three strains in group I were classified as R. giardinii, as they showed high gene sequence similarities (>97 %) and DNA relatedness (64.3-67.5 %) to R. giardinii H152(T). Groups II, III and IV differed from all defined Rhizobium species based upon the consensus of all analyses. As group II contained two strains that originated from two distinct populations, we propose this group as a novel species, Rhizobium herbae sp. nov., with strain CCBAU 83011(T) ( = LMG 25718(T) = HAMBI 3117(T)) as the type strain. PMID- 20833882 TI - Persicivirga ulvanivorans sp. nov., a marine member of the family Flavobacteriaceae that degrades ulvan from green algae. AB - A rod shaped, Gram-stain-negative, chemo-organotrophic, heterotrophic, strictly aerobic, non-gliding bacterium, designated strain PLR(T), was isolated from faeces of the mollusc Aplysia punctata (Mollusca, Gastropoda) that had been fed with green algae belonging to the genus Ulva. The novel strain was able to degrade ulvan, a polysaccharide extracted from green algae (Chlorophyta, Ulvophyceae). The taxonomic position of strain PLR(T) was investigated by using a polyphasic approach. Strain PLR(T) was dark orange, oxidase-positive, catalase positive and grew optimally at 25 degrees C, at pH 7.5 and in the presence of 2.5 % (w/v) NaCl with an oxidative metabolism using oxygen as the electron acceptor. Nitrate could not be used as the electron acceptor. Strain PLR(T) had a Chargaff's coefficient (DNA G+C content) of 35.3 mol%. Phylogenetic analysis based on the sequence of the 16S rRNA gene placed the novel strain in the family Flavobacteriaceae (phylum 'Bacteroidetes'), within a clade comprising Stenothermobacter spongiae, Nonlabens tegetincola, Sandarakinotalea sediminis, Persicivirga xylanidelens and Persicivirga dokdonensis. The closest neighbours of strain PLR(T) were P. xylanidelens and P. dokdonensis, sharing 95.2 and 95.5 % 16S rRNA gene sequence similarity, respectively. Phylogenetic inference and differential phenotypic characteristics demonstrated that strain PLR(T) represents a novel species of the genus Persicivirga, for which the name Persicivirga ulvanivorans sp. nov. is proposed. The type strain is PLR(T) ( = CIP 110082(T) = DSM 22727(T)). PMID- 20833883 TI - Pontibacillus yanchengensis sp. nov., a moderately halophilic bacterium isolated from salt field soil. AB - A Gram-positive-staining, aerobic, moderately halophilic bacterium, designated strain Y32(T), was isolated from subsurface soil of the Sanwei salt field, Yancheng, Jiangsu province, South-east China. The cell-wall peptidoglycan type of strain Y32(T) was meso-diaminopimelic acid. The menaquinone was menaquinone-7 (MK 7). The major fatty acids were anteiso-C(15 : 0) and iso-C(15 : 0) and the DNA G+C content of strain Y32(T) was 40.3 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain Y32(T) was closely related to the type strains of the genus Pontibacillus. The 16S rRNA gene sequence similarities of strain Y32(T) with the type strains of species of the genus Pontibacillus were 97.8 % (Pontibacillus marinus KCTC 3917(T)), 96.9 % (Pontibacillus chungwhensis BH030062(T)), 96.8 % (Pontibacillus litoralis JSM 072002(T)) and 96.0 % (Pontibacillus halophilus JSM 076056(T)). DNA-DNA relatedness between strain Y32(T) and P. marinus KCTC 3917(T) was 42 %. On the basis of phenotypic, chemotaxonomic and phylogenetic evidences, strain Y32(T) was found to be affiliated to the genus Pontibacillus, but was clearly differentiated from other members of this genus. Strain Y32(T) represents a novel member of the genus, for which the name Pontibacillus yanchengensis sp. nov. is proposed. The type strain is Y32(T) ( = CGMCC 1.10680(T) = CCTCC AB209311(T) = NRRL B-59408(T)). PMID- 20833884 TI - Peptostreptococcus russellii sp. nov., isolated from a swine-manure storage pit. AB - Using a polyphasic approach, a taxonomic study was performed on seven strains of an unknown Gram-reaction-positive, non-spore-forming, obligately anaerobic coccus shaped bacterium, isolated from a swine-manure storage pit. Comparative 16S rRNA gene sequencing confirmed that all seven isolates were highly related to each other and formed a hitherto unknown lineage within the clostridial rRNA XI cluster of organisms. Pairwise analysis demonstrated that the novel organism was most closely related to Peptostreptococcus anaerobius CCUG 7835(T) and Peptostreptococcus stomatis CCUG 51858(T) with 16S rRNA gene sequence similarities of 95.5 and 93.0 %, respectively. The peptidoglycan type of the cell wall was determined to be A4alpha l-Lys-d-Asp and glucose, xylose and traces of mannose were detected as the cell-wall sugars. Based on biochemical, chemotaxonomic and phylogenetic evidence the unknown bacterium represents a new species of the genus Peptostreptococcus, for which the name Peptostreptococcus russellii sp. nov, is proposed. The type strain is RT-10B(T) ( = CCUG 58235(T) = NRRL B-59380(T) = DSM 23041(T)). PMID- 20833885 TI - Mycobacterium algericum sp. nov., a novel rapidly growing species related to the Mycobacterium terrae complex and associated with goat lung lesions. AB - A previously undescribed, rapid-growing, non-chromogenic Mycobacterium isolate from a goat lung lesion in Algeria is reported. Biochemical and molecular tools were used for its complete description and showed its affiliation to the Mycobacterium terrae complex. 16S rRNA, rpoB and hsp65 gene sequences were unique. Phylogenetic analyses showed a close relationship with M. terrae sensu stricto and Mycobacterium senuense. Culture and biochemical characteristics were generally similar to those of M. terrae and M. senuense. However, in contrast to M. terrae and M. senuense, the isolate was positive for urease production and had faster growth. The mycolic acid profile was distinct from those of M. terrae and M. senuense, thus further supporting the new taxonomic position of the isolate. We propose the name Mycobacterium algericum sp. nov. for this novel species. The type strain is TBE 500028/10(T) ( = Bejaia(T) = CIP 110121(T) = DSM 45454(T)). PMID- 20833886 TI - Bacillus alkalisediminis sp. nov., an alkaliphilic and moderately halophilic bacterium isolated from sediment of extremely shallow soda ponds. AB - Alkaliphilic strains characterized by optimal growth at pH 9.0 and 5 % (w/v) NaCl designated K1-25(T) and H3-93 were isolated from extremely shallow soda ponds located in Hungary. Cells of both strains were Gram-stain-positive, non-motile, straight rods and formed central, ellipsoidal endospores with swollen sporangia. The isolates were aerobic, catalase-positive, oxidase-negative and contained a peptidoglycan of type A1gamma based on meso-diaminopimelic acid. In both strains, menaquinone-7 (MK-7) was the predominant isoprenoid quinone and the major cellular fatty acids were anteiso-C(15 : 0) and iso-C(15 : 0). The DNA G+C contents of strains K1-25(T) and H3-93 were 39.0 and 36.3 mol%, respectively. 16S rRNA gene sequence-based phylogenetic analysis revealed 99.2 % similarity between strains K1-25(T) and H3-93 and the novel isolates had the highest similarities to Bacillus akibai 1139(T) (97.8 and 98.3 %, respectively), Bacillus wakoensis N 1(T) (97.0 and 97.4 %), Bacillus okhensis Kh10-101(T) (97.1 and 97.4 %) and Bacillus krulwichiae AM31D(T) (96.9 and 97.1 %). DNA-DNA hybridization between our strains and the type strains of closely related Bacillus species was lower than 70 %. Although DNA-DNA hybridization between strains K1-25(T) and H3-93 was 27 %, the phenotypic and chemotaxonomic data did not support the differentiation of these two strains into separate species. Therefore, they represent genomovars of a novel species, for which the name Bacillus alkalisediminis sp. nov. is proposed. The type strain is K1-25(T) ( = DSM 21670(T) = NCAIM B02301(T)). PMID- 20833887 TI - Leifsonia psychrotolerans sp. nov., a psychrotolerant species of the family Microbacteriaceae from Livingston Island, Antarctica. AB - A cold-tolerant, yellow-pigmented, Gram-positive, motile, facultatively anaerobic bacterial strain, LI1(T), was isolated from a moss-covered soil from Livingston Island, Antarctica, near the Bulgarian station St. Kliment Ohridski. Comparative 16S rRNA gene sequence-based phylogenetic analysis placed the strain in a clade with the species Leifsonia kafniensis KFC-22(T), Leifsonia pindariensis PON10(T) and Leifsonia antarctica SPC-20(T), with which it showed sequence similarities of 99.0, 97.9 and 97.9 %, respectively. DNA-DNA hybridization revealed a reassociation value of 2.7 % with L. kafniensis LMG 24362(T). The DNA G+C content of strain LI1(T) was 64.5 mol%. The growth temperature range was -6 to 28 degrees C, with optimum growth at 16 degrees C. Growth occurred in 0-5 % NaCl and at pH 4.5-9.5, with optimum growth in 1-2 % NaCl and at pH 5.5-6.5. The predominant fatty acids were anteiso-C(15 : 0), C(18 : 0) and iso-C(15 : 0). The polar lipids were phosphatidylglycerol and diphosphatidylglycerol. Physiological and biochemical tests clearly differentiated strain LI1(T) from L. kafniensis. Therefore, a novel cold-tolerant species within the genus Leifsonia is proposed: Leifsonia psychrotolerans sp. nov. (type strain LI1(T) = DSM 22824(T) = NCCB 100313(T)). PMID- 20833888 TI - Lactococcus lactis subsp. tructae subsp. nov. isolated from the intestinal mucus of brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss). AB - The species Lactococcus lactis currently includes three subspecies; L. lactis subsp. lactis and L. lactis subsp. cremoris, isolated from milk sources, and L. lactis subsp. hordniae, isolated from the leafhopper Hordnia circellata. In this study, three strains, designated L105(T), I3 and L101, were isolated from the intestinal mucus of brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss). These strains were closely related to members of the species Lactococcus lactis. Strain L105(T) showed 99.4 % 16S rRNA gene sequence similarity to that of the type strains L. lactis subsp. lactis NCDO 604(T) and L. lactis subsp. hordniae NCDO 2181(T) and showed 99.9 % similarity to the type strain Lactococcus lactis subsp. cremoris NCDO 607(T). Analysis of two housekeeping genes, rpoB and recA, confirmed the close relationship between the novel strains and L. lactis subsp. cremoris with similarities of 99.3 and 99.7 %, respectively. The three strains could, however, be differentiated from their closest relatives on the basis of several phenotypic characteristics, as was the case for L. lactis subsp. lactis and L. lactis subsp. hordniae, which were also closely related on the basis of 16S rRNA, rpoB and recA gene sequence similarities. The strains isolated in this study represent a new subspecies, for which the name Lactococcus lactis subsp. tructae subsp. nov. is proposed. The type strain is L105(T) ( = LMG 24662(T) = DSM 21502(T)). PMID- 20833889 TI - Pseudoteredinibacter isoporae gen. nov., sp. nov., a marine bacterium isolated from the reef-building coral Isopora palifera. AB - A Gram-negative, heterotrophic, marine bacterium, designated strain SW-11(T), was isolated from the reef-building coral Isopora palifera in Kenting, Taiwan. Cells were rods and were motile by a single polar flagellum. The strain grew at 10-45 degrees C (optimum, 30-35 degrees C), at pH 7.0-8.0 (optimum, pH 7.5) and with 2.0-4.0 % NaCl (optimum, 2.5-3.0 %). The polar lipids comprised phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, diphosphatidylglycerol and four unknown phospholipids. Isoprenoid quinones consisted of ubiquinone 9 (78.8 %) and ubiquinone 8 (21.1 %). Major cellular fatty acids were summed feature 3 (C(16 : 1)omega7c and/or C(16 : 1)omega6c; 22.3 %), C(17 : 1)omega8c (13.4 %), summed feature 8 (C(18 : 1)omega6c and/or C(18 : 1)omega7c; 13.1 %), C(16 : 0) (10.3 %) and anteiso-C(17 : 1)omega9c (10.0 %). The DNA G+C content was 51.6 mol%. 16S rRNA gene sequence analysis indicated that strain SW-11(T) belongs to the class Gammaproteobacteria and is a member of the order Alteromonadales. Strain SW-11(T) shared 93.2 % 16S rRNA gene sequence similarity with Teredinibacter turnerae T7902(T) and 92.1 % with Saccharophagus degradans 2-40(T), and can be further distinguished from these two related strains by distinct patterns of fatty acid content and differences in the polar lipid profile, the ability to utilize different compounds as carbon sources, the ability to degrade various compounds and differences in enzyme activities. The phylogenetic data and those from physiological, morphological and chemotaxonomic characterizations indicate that strain SW-11(T) represents a novel species and genus, for which the name Pseudoteredinibacter isoporae gen. nov., sp. nov. is proposed. The type strain of Pseudoteredinibacter isoporae is SW-11(T) ( = BCRC 17935(T) = LMG 25246(T)). PMID- 20833890 TI - Chryseomicrobium imtechense gen. nov., sp. nov., a new member of the family Planococcaceae. AB - A Gram-stain-positive, rod-shaped, yellow, non-motile, non-spore-forming, strictly aerobic bacterial strain, designated MW 10(T), was isolated from seawater of the Bay of Bengal, India, and was subjected to a polyphasic taxonomic study. Analysis of the 16S rRNA gene sequence revealed that strain MW 10(T) showed highest similarity to the type strains of Psychrobacillus psychrodurans (96.15 %) and Psychrobacillus psychrotolerans (96.01 %) and showed less than 96 % similarity to members of the genera Paenisporosarcina, Planococcus, Sporosarcina and Planomicrobium. Phylogenetic analysis based on the 16S rRNA gene sequence showed that strain MW 10(T) formed a clade separate from members of closely related genera. The morphological, physiological and chemotaxonomic characteristics of strain MW 10(T) differed from those of members of closely related genera. The major fatty acid in strain MW 10(T) was iso-C(15 : 0) and the menaquinones were MK-7 (48.4 %), MK-8 (32.3 %), MK-7(H(2)) (13.7 %) and MK-6 (5.6 %). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, an unknown phospholipid, an unknown lipid and an unknown glycolipid. The cell-wall peptidoglycan type was l Lys-d-Asp. The genomic DNA G+C content (53.4 mol%) of strain MW 10(T) was significantly different from those of members of closely related genera. On the basis of its morphological, physiological and chemotaxonomic characteristics as well as our phylogenetic analysis, we conclude that strain MW 10(T) is a member of a novel genus and species, for which the name Chryseomicrobium imtechense gen. nov., sp. nov., is proposed. The type strain of Chryseomicrobium imtechense is MW 10(T) ( = MTCC 10098(T) = JCM 16573(T)). PMID- 20833891 TI - A novel protein kinase localized to lipid droplets is required for droplet biogenesis in trypanosomes. AB - Ubiquitous among eukaryotes, lipid droplets are organelles that function to coordinate intracellular lipid homeostasis. Their morphology and abundance is affected by numerous genes, many of which are involved in lipid metabolism. In this report we identify a Trypanosoma brucei protein kinase, LDK, and demonstrate its localization to the periphery of lipid droplets. Association with lipid droplets was abrogated when the hydrophobic domain of LDK was deleted, supporting a model in which the hydrophobic domain is associated with or inserted into the membrane monolayer of the organelle. RNA interference knockdown of LDK modestly affected the growth of mammalian bloodstream-stage parasites but did not affect the growth of insect (procyclic)-stage parasites. However, the abundance of lipid droplets dramatically decreased in both cases. This loss was dominant over treatment with myriocin or growth in delipidated serum, both of which induce lipid body biogenesis. Growth in delipidated serum also increased LDK autophosphorylation activity. Thus, LDK is required for the biogenesis or maintenance of lipid droplets and is one of the few protein kinases specifically and predominantly associated with an intracellular organelle. PMID- 20833892 TI - Schizosaccharomyces pombe calmodulin, Cam1, plays a crucial role in sporulation by recruiting and stabilizing the spindle pole body components responsible for assembly of the forespore membrane. AB - Calmodulin in Schizosaccharomyces pombe is encoded by the cam1(+) gene, which is indispensable for both vegetative growth and sporulation. Here, we report how Cam1 functions in spore formation. We found that Cam1 preferentially localized to the spindle pole body (SPB) during meiosis and sporulation. Formation of the forespore membrane, a precursor of the plasma membrane in spores, was blocked in a missense cam1 mutant, which was viable but unable to sporulate. Three SPB proteins necessary for the onset of forespore membrane formation, Spo2, Spo13, and Spo15, were unable to localize to the SPB in the cam1 mutant although five core SPB components that were tested were present. Recruitment of Spo2 and Spo13 is known to require the presence of Spo15 in the SPB. Notably, Spo15 was unstable in the cam1 mutant, and as a result, SPB localization of Spo2 and Spo13 was lost. Overexpression of Spo15 partially alleviated the sporulation defect in the cam1 mutant. These results indicate that calmodulin plays an essential role in forespore membrane formation by stably maintaining Spo15, and thus Spo2 and Spo13, at the SPB in meiotic cells. PMID- 20833893 TI - Ras proteins have multiple functions in vegetative cells of Dictyostelium. AB - During the aggregation of Dictyostelium cells, signaling through RasG is more important in regulating cyclic AMP (cAMP) chemotaxis, whereas signaling through RasC is more important in regulating the cAMP relay. However, RasC is capable of substituting for RasG for chemotaxis, since rasG- cells are only partially deficient in chemotaxis, whereas rasC-/rasG- cells are totally incapable of chemotaxis. In this study we have examined the possible functional overlap between RasG and RasC in vegetative cells by comparing the vegetative cell properties of rasG-, rasC-, and rasC-/rasG- cells. In addition, since RasD, a protein not normally found in vegetative cells, is expressed in vegetative rasG- and rasC-/rasG- cells and appears to partially compensate for the absence of RasG, we have also examined the possible functional overlap between RasG and RasD by comparing the properties of rasG- and rasC-/rasG- cells with those of the mutant cells expressing higher levels of RasD. The results of these two lines of investigation show that RasD is capable of totally substituting for RasG for cytokinesis and growth in suspension, whereas RasC is without effect. In contrast, for chemotaxis to folate, RasC is capable of partially substituting for RasG, but RasD is totally without effect. Finally, neither RasC nor RasD is able to substitute for the role that RasG plays in regulating actin distribution and random motility. These specificity studies therefore delineate three distinct and none-overlapping functions for RasG in vegetative cells. PMID- 20833894 TI - Recognition of yeast by murine macrophages requires mannan but not glucan. AB - The first barrier against infection by Candida albicans involves fungal recognition and destruction by phagocytic cells of the innate immune system. It is well established that interactions between different phagocyte receptors and components of the fungal cell wall trigger phagocytosis and subsequent immune responses, but the fungal ligands mediating the initial stage of recognition have not been identified. Here, we describe a novel assay for fungal recognition and uptake by macrophages which monitors this early recognition step independently of other downstream events of phagocytosis. To analyze infection in live macrophages, we validated the neutrality of a codon-optimized red fluorescent protein (yEmRFP) biomarker in C. albicans; growth, hyphal formation, and virulence in infected mice and macrophages were unaffected by yEmRFP production. This permitted a new approach for studying phagocytosis by carrying out competition assays between red and green fluorescent yeast cells to measure the efficiency of yeast uptake by murine macrophages as a function of dimorphism or cell wall defects. These competition experiments demonstrate that, given a choice, macrophages display strong preferences for phagocytosis based on genus, species, and morphology. Candida glabrata and Saccharomyces cerevisiae are taken up by J774 macrophage cells more rapidly than C. albicans, and C. albicans yeast cells are favored over hyphal cells. Significantly, these preferences are mannan dependent. Mutations that affect mannan, but not those that affect glucan or chitin, reduce the uptake of yeast challenged with wild-type competitors by both J774 and primary murine macrophages. These results suggest that mannose side chains or mannosylated proteins are the ligands recognized by murine macrophages prior to fungal uptake. PMID- 20833895 TI - Extracellular secretion of overexpressed glycosylphosphatidylinositol-linked cell wall protein Utr2/Crh2p as a novel protein quality control mechanism in Saccharomyces cerevisiae. AB - Eukaryotic cells employ a variety of mechanisms to maintain protein quality control and homeostasis. Here we provide evidence that one such mechanism in Saccharomyces cerevisiae involves the regulated release of excess or misfolded proteins to the extracellular space. The overexpression of an epitope-tagged allele of the glycosylphosphatidylinositol (GPI)-linked cell wall protein Utr2/Crh2p (Utr2/Crh2-green fluorescent protein [GFP] or -hemagglutinin [HA]) causes endoplasmic reticulum (ER) stress and the secretion of Crh2-GFP/HA into the extracellular space. Secretion is dependent on two GPI-linked aspartyl proteases (Yps1p/2p) and components of the unfolded protein response (Ire1p and Hac1p) but is independent of ER-associated degradation (ERAD) components such as Hrd1p and Doa10p. Supporting the idea that this process represents a mechanism for protein quality control, the level of Crh2-HA is increased in strains lacking Bst1p, a protein required for the proteasomal degradation of GPI-linked proteins. Furthermore, secretion is dependent on Sec18p, indicating that it requires ER-to Golgi trafficking, and accordingly, Crh2-HA accumulates in the ER in ire1Delta and bst1Delta mutants by cycloheximide chase experiments. Since a fraction of Utr2/Crh2-GFP properly localizes to the cell wall in an ire1Delta mutant, extracellular secretion appears to occur through a pathway that is distinct from the normal GPI protein-trafficking pathway. Taken together, these data support a model in which the unfolded protein response (UPR)/yapsin-mediated extracellular release of overexpressed Utr2/Crh2-HA or -GFP is an alternative pathway for the removal of excess or misfolded secretory proteins functioning in parallel with proteasome-mediated degradation in S. cerevisiae. This model provides an explanation for the deleterious effects of Yps1/2p on the industrial production of some recombinant proteins in S. cerevisiae. PMID- 20833896 TI - Anaerobic expression of the ferredoxin-encoding FDX5 gene of Chlamydomonas reinhardtii is regulated by the Crr1 transcription factor. AB - The unicellular green alga Chlamydomonas reinhardtii has a complex anaerobic metabolism and reacts to hypoxic or anaerobic conditions with the induced expression of many genes. One gene which is upregulated particularly strongly is the FDX5 gene, encoding one of at least six ferredoxin isoforms in C. reinhardtii. Fdx5 is a typical plant-type 2Fe2S protein that is located in the chloroplast. The FDX5 promoter region contains three GTAC motifs, which are known to be the binding sites for copper response regulator 1 (Crr1) and other SQUAMOSA promoter binding proteins (SBPs). This study shows that two of these GTAC sites are essential to confer oxygen and also copper responsiveness to a reporter gene. The SBP domain of Crr1 is able to bind to both of these GTAC sites in in vitro binding assays. Moreover, in a Crr1-deficient C. reinhardtii strain, FDX5 is not expressed. These results clearly indicate that Crr1 is involved in the transcriptional regulation of the FDX5 gene in the absence of oxygen or copper. PMID- 20833897 TI - Psychiatry's role in teaching medical students, psychiatric residents, and colleague physicians about human sexuality. PMID- 20833898 TI - What has happened to teaching human sexuality in psychiatric training programs? PMID- 20833899 TI - Encompassing sexual medicine within psychiatry: pros and cons. AB - OBJECTIVE: This article examines the positive and negative aspects of psychiatry encompassing sexual medicine within its purview. METHODS: MEDLINE searches for the period between 1980 to the present were performed with the terms "psychiatry," "sexual medicine," and "sexual dysfunction." In addition, sexual medicine texts were reviewed for chapters relevant to this topic. RESULTS: Psychiatry, the only medical discipline trained to integrate both biological and psychological factors in making treatment decisions, has been minimally involved in the evolution of the multidisciplinary field known as sexual medicine. CONCLUSION: If psychiatry is to maintain a role in the diagnosis and treatment of sexual disorders, it is critical that its training programs include training in sexual medicine. PMID- 20833900 TI - Sexual health curricula in U.S. medical schools: current educational objectives. AB - OBJECTIVE: The authors identify the explicit and implicit objectives that shape decisions about what medical schools teach regarding human sexuality. METHODS: The authors reviewed relevant articles in journals, physician licensing examinations, and publications by professional organizations to identify learning objectives for human sexuality in undergraduate medical curricula. RESULTS: There is consensus about many of the attitudinal objectives and some of the skills medical students should acquire in sexual health. There is less consensus on the sexuality-related information student physicians need to master. The few common informational objectives focus narrowly on diagnosing sexual dysfunction and disease. CONCLUSION: The model sexual health curricula, licensing exams, and guidelines from professional organizations mainly focus on the pathological aspects of sexuality. Student physicians should master fundamental information on healthy sexual function and become familiar with the roles of practitioners in various therapeutic disciplines in addressing sexual concerns and enhancing patients' sexual functioning and well-being. Instruction should also address ways to incorporate this important topic in time-limited interactions with patients. PMID- 20833901 TI - Recommendations for teaching sexual health: how to ask and what to do with the answers. PMID- 20833902 TI - Addressing patient sexual orientation in the undergraduate medical education curriculum. AB - OBJECTIVE: This study aims to estimate the number of hours dedicated to lesbian, gay, bisexual, and transgender content in one medical school's undergraduate curriculum, compare it to the national average, and identify barriers to addressing this content. METHODS: Course and clerkship directors were asked to estimate how many hours they spent on lesbian, gay, bisexual, and transgender content, how many hours would be ideal, and what barriers they perceived to teaching this content. RESULTS: Faculty members identified lack of instructional time, lack of relevance to their course content, and lack of professional development on this topic as major barriers. There was a significant negative correlation (r(s)=-0.47, p=0.047) between "number of hours dedicated" and "perceived barriers to teaching this content." CONCLUSION: Course and clerkship directors who perceive more barriers to teaching lesbian, gay, bisexual, and transgender content report dedicating less time to its instruction, but the barriers they perceive can largely be mitigated through faculty development. PMID- 20833903 TI - Survey of sexual education among residents from different specialties. AB - OBJECTIVE: This study aims to determine how residents are being educated regarding sexual health, and it assesses attitudes toward sexual education and barriers to evaluating patients' sexuality. METHODS: An anonymous Internet survey was sent to 195 residents in family practice, internal medicine, obstetrics and gynecology, and psychiatry at a single site. RESULTS: One hundred seventeen surveys were completed, for a response rate of 60%. Participants reported a lack of formal education on sexual health. Although participants perceived their patients' sexuality as important and appeared to have the appropriate knowledge to evaluate sexual issues, they failed to inquire about sexual health regularly, especially for patients from non-Western cultures. Lack of comfort or confidence did not appear to impose major barriers to the evaluation of sexual health; instead, most respondents reported lack of time. CONCLUSION: Implementation of a formal curriculum will signal to residents that patients' sexuality is an important topic to address. PMID- 20833904 TI - Sexual education for psychiatric residents. AB - OBJECTIVE: The authors seek to promote sexuality curriculum development in departments of psychiatry. METHODS: The authors first focus on educational philosophy about what residents can be taught about sexual topics and then provide numerical and narrative resident evaluation data following a 6-month, half day per week rotation in a sexuality clinic. RESULTS: Curricula should begin by clarifying the dimensions of individual sexuality, conceptualizing the idea of the couple as the unit for understanding partnered sexual problems, providing opportunities to grow comfortable listening to sexual stories, and approaching etiology using the First Principle of Clinical Sexuality. Departments of psychiatry can evolve new approaches to teaching these topics with diverse methods including seminars, periodic lectures, case conferences, assigned books and journal articles, and discussion of the sexual implications of the patients cared for on other clinical rotations. CONCLUSION: More needs to be done nationally to prepare psychiatric residents to assess and treat sexual disorders, concerns, and problems. Curricular efforts need not require a sexuality expert. Existent faculty should be encouraged to develop their institution's initial approach, which inevitably will evolve toward greater comprehensiveness. PMID- 20833905 TI - Teaching sexual history-taking skills using the Sexual Events Classification System. AB - OBJECTIVE: The authors review the literature about educational programs for teaching sexual history-taking skills and describe novel techniques for teaching these skills. METHODS: Psychiatric residents enrolled in a brief sexual history taking course that included instruction on the Sexual Events Classification System, feedback on residents' video-recorded interviews with simulated patients, discussion of videos that simulated bad interviews, simulated patients, and a competency scoring form to score a video of a simulated interview. After the course, residents completed an anonymous survey to assess the usefulness of the experience. RESULTS: After the course, most residents felt more comfortable taking sexual histories. They described the Sexual Events Classification System and simulated interviews as practical methods for teaching sexual history-taking skills. CONCLUSION: The Sexual Events Classification System and simulated patient experiences may serve as a practical model for teaching sexual history-taking skills to general psychiatric residents. PMID- 20833906 TI - Sexual health education: a psychiatric resident's perspective. AB - OBJECTIVE: This report discusses psychiatric residents' perceptions of sexual health education and their opinions regarding curricular improvements. METHODS: An anonymous, web-based survey was sent to residents in one general psychiatry program (N=33). The response rate was 69.7%. RESULTS: Residents reported inadequate experience in multiple areas of sexual health. In every topic surveyed, 61.5% or more of the early residency group and 20% or more of the late residency group reported "none" or "too little" to both clinical and didactic experiences. Approximately one-half of residents responded that more time should be spent on every topic surveyed. The teaching modalities of didactics and outpatient clinical work were thought to provide the greatest educational benefit. CONCLUSION: Psychiatric residents value education regarding sexual health and would like more opportunities to learn about this topic. PMID- 20833907 TI - Sexual health competence of international medical graduate psychiatric residents in the United States. AB - OBJECTIVE: Currently in the United States, more than one in three psychiatric residents are international medical graduates (IMGs). In light of forecasts of physician shortages, this proportion is likely to continue growing. Although central to psychiatric care, sexual health competence levels of IMGs may be lower than those of U.S. graduates. METHODS: The authors conducted a nonsystematic review of the literature and online data to establish the learning needs of IMGs in this area. RESULTS: Data on five areas are summarized: demographic and sociocultural data of IMGs in the United States; the need for sexual medicine competence for practicing psychiatrists; how sexual health is currently taught in foreign medical schools; attitudes toward sexuality and sexual problems among physicians and patients of different cultures; and the management of sexual issues, including sexual boundaries, by IMGs. CONCLUSION: The authors found evidence suggesting that IMGs from areas most culturally dissimilar to the United States are likely to benefit from sexual medicine curricula in the context of cultural competence training. The diversity and resilience of IMGs are emphasized. Implications for immediate training and future research are outlined. PMID- 20833908 TI - Teaching professional boundaries to psychiatric residents. AB - OBJECTIVE: The authors demonstrate that the teaching of professional boundaries in psychiatry is an essential component of training to prevent harm to patients and to the profession. METHODS: The authors illustrate overarching principles that apply to didactic teaching in seminars and to psychotherapy supervision. RESULTS: The teaching of boundaries must be based in sound clinical theory and technique so that transference, countertransference, and frame theory are seen as interwoven with the concept of boundaries and must use case-based learning so that a "one-size-fits-all" approach is avoided. CONCLUSION: The emphasis in teaching should be on both the clinician's temptations and the management of the patient's wish to transgress therapeutic boundaries. PMID- 20833909 TI - Teaching psychiatric residents about paraphilic disorders. AB - OBJECTIVE: The author describes a program for psychiatric residents in evaluating patients with paraphilic disorders. METHODS: The program curriculum offers clinical education in paraphilic disorders and is organized by various perspectives within psychiatry, including the disease model, the life story, the dimensional perspective, and the behavioral perspective. RESULTS: Graduates of this program generally find this clinical and educational rotation very useful in their future work. CONCLUSION: To develop an effective teaching module for paraphilic disorders, programs need an interested and knowledgeable faculty and an adequate clinical experience. PMID- 20833910 TI - Teaching residents to recognize the impact of divorce. PMID- 20833911 TI - Psychiatrists' role in teaching human sexuality to other medical specialties. AB - OBJECTIVES: This article addresses the potential role for psychiatrists in teaching sexuality to other medical disciplines. METHODS: The authors searched PsycNet and PubMed/MEDLINE for pertinent articles and studies from the period between 1990 and 2009 using the terms human sexuality; teaching human sexuality; teaching methods; education and treatment in human sexuality; and medical practice. The senior author also drew on 20 years of experience teaching other medical specialists. RESULTS: Although few studies exist, the authors identified areas in which a psychiatrist might have particular teaching skills to impart: taking a sexual history; patient and physician communication; the partner's role; effects of depression on sexual health; sexual trauma and abuse; physical, intellectual, and developmental disabilities; sexual boundary issues; and working with gay, lesbian, bisexual, and transgendered persons. CONCLUSION: Psychiatrists deal with complex emotional issues and are alert to subtle emotional cues. They gather detailed histories, screen thoroughly for psychopathology, and consider the importance of interpersonal relationships. These attributes are potentially valuable when psychiatrists assist other specialists in addressing patients' sexual health. Psychiatrists with additional training in sexuality may be particularly adept in educating colleagues from other specialties. PMID- 20833912 TI - A multidisciplinary approach to sexual dysfunction in medical education. AB - OBJECTIVE: Addressing sexual health concerns in medical practice has been an emerging concept for the past two decades. However, there have been very few educational opportunities in medical training that would prepare future physicians for such a responsibility. Since assessing and treating sexual problems requires knowledge that encompasses many disciplines and requires skills typically not within the purview of medical training, the authors propose a multidisciplinary model that includes collaboration with sex therapists. METHODS: The authors review the extant literature on sexual health education in medical training. RESULTS: The authors describe an existing and evolving model at the University of Michigan which is based on several collaborative initiatives between the medical school, the psychiatry residency program, and several medical departments. CONCLUSION: The authors propose a collaborative training model that would facilitate future physicians' comfort with the subject and the acquisition of skills necessary to provide optimal care for patients who present with sexual health concerns. PMID- 20833913 TI - Sex therapy: advances in paradigms, nomenclature, and treatment. AB - OBJECTIVE: The author reviews the historical paradigms that have influenced the treatment of sexual problems, changes in the diagnostic nomenclature, and recent innovations in sex therapy. METHODS: The author reviews the literature and provides expert opinion. RESULTS: The author gives a historical overview of how theoretical models of understanding human sexuality have influenced treatment, describes the changes in sexual dysfunction nomenclature, and focuses on the combined medical and psychological treatment of sexual dysfunction. CONCLUSION: Sex therapy continues to evolve with new paradigms and definitions for understanding and diagnosing sexual problems and innovative methods of treating sexual problems. PMID- 20833914 TI - International perspective on teaching human sexuality. AB - OBJECTIVE: The authors outline international training programs in human sexuality. METHODS: The authors reviewed the international literature and Internet resources to identify key training opportunities and curricula, with particular emphasis on training opportunities for psychiatrists. RESULTS: The authors outline key resources and training courses outside the United States. CONCLUSION: Training in human sexuality, sexology, and sexual medicine is evolving across many clinical disciplines, but courses remain limited in number and far apart geographically. PMID- 20833915 TI - Lessons learned: what is happening to human sexuality education within psychiatry? PMID- 20833916 TI - A behavioral perspective on the biophysics of the light-dependent magnetic compass: a link between directional and spatial perception? AB - In terrestrial organisms, sensitivity to the Earth's magnetic field is mediated by at least two different magnetoreception mechanisms, one involving biogenic ferromagnetic crystals (magnetite/maghemite) and the second involving a photo induced biochemical reaction that forms long-lasting, spin-coordinated, radical pair intermediates. In some vertebrate groups (amphibians and birds), both mechanisms are present; a light-dependent mechanism provides a directional sense or 'compass', and a non-light-dependent mechanism underlies a geographical position sense or 'map'. Evidence that both magnetite- and radical pair-based mechanisms are present in the same organisms raises a number of interesting questions. Why has natural selection produced magnetic sensors utilizing two distinct biophysical mechanisms? And, in particular, why has natural selection produced a compass mechanism based on a light-dependent radical pair mechanism (RPM) when a magnetite-based receptor is well suited to perform this function? Answers to these questions depend, to a large degree, on how the properties of the RPM, viewed from a neuroethological rather than a biophysical perspective, differ from those of a magnetite-based magnetic compass. The RPM is expected to produce a light-dependent, 3-D pattern of response that is axially symmetrical and, in some groups of animals, may be perceived as a pattern of light intensity and/or color superimposed on the visual surroundings. We suggest that the light dependent magnetic compass may serve not only as a source of directional information but also provide a spherical coordinate system that helps to interface metrics of distance, direction and spatial position. PMID- 20833917 TI - Behaviour towards an unpreferred colour: can green flowers attract foraging hawkmoths? AB - Naive hawkmoths (Manduca sexta) learn from a single trial to approach and attempt to feed from an artificial flower of an innately unpreferred green colour even when a distractor flower with a preferred yellow colour is present. In some of the animals, the choice of the innately unpreferred colour during free-flight testing persists for several days despite not being rewarded and eventually leads to starvation. The results show that moths exhibit a very strong flower constancy that is not limited to the colours of nectar flowers. PMID- 20833918 TI - Source levels of echolocation signals vary in correlation with wingbeat cycle in landing big brown bats (Eptesicus fuscus). AB - Recordings of the echolocation signals of landing big brown bats with a two dimensional 16-microphone array revealed that the source level reduction of 7 dB per halving of distance is superimposed by a variation of up to 12 dB within single call groups emitted during the approach. This variation correlates with the wingbeat cycle. The timing of call emission correlates with call group size. First pulses of groups containing many calls are emitted earlier than first calls in groups with fewer calls or single calls. This suggests that the emission of pulse groups follows a fixed motor pattern where the information gained from the preceding pulse group determines how many calls will be emitted in the next group. Single calls and call groups are centred at the middle of the upstroke. Expiration is indicated by call emission. The pause between groups is centred at the middle of the downstroke and indicates inspiration. The hypothesis that the source level variation could be caused by changes in the subglottic pressure due to the contraction of the major flight muscles is discussed. PMID- 20833919 TI - Aerodynamic characteristics of flying fish in gliding flight. AB - The flying fish (family Exocoetidae) is an exceptional marine flying vertebrate, utilizing the advantages of moving in two different media, i.e. swimming in water and flying in air. Despite some physical limitations by moving in both water and air, the flying fish has evolved to have good aerodynamic designs (such as the hypertrophied fins and cylindrical body with a ventrally flattened surface) for proficient gliding flight. Hence, the morphological and behavioral adaptations of flying fish to aerial locomotion have attracted great interest from various fields including biology and aerodynamics. Several aspects of the flight of flying fish have been determined or conjectured from previous field observations and measurements of morphometric parameters. However, the detailed measurement of wing performance associated with its morphometry for identifying the characteristics of flight in flying fish has not been performed yet. Therefore, in the present study, we directly measure the aerodynamic forces and moment on darkedged-wing flying fish (Cypselurus hiraii) models and correlated them with morphological characteristics of wing (fin). The model configurations considered are: (1) both the pectoral and pelvic fins spread out, (2) only the pectoral fins spread with the pelvic fins folded, and (3) both fins folded. The role of the pelvic fins was found to increase the lift force and lift-to-drag ratio, which is confirmed by the jet-like flow structure existing between the pectoral and pelvic fins. With both the pectoral and pelvic fins spread, the longitudinal static stability is also more enhanced than that with the pelvic fins folded. For cases 1 and 2, the lift-to-drag ratio was maximum at attack angles of around 0 deg, where the attack angle is the angle between the longitudinal body axis and the flying direction. The lift coefficient is largest at attack angles around 30~35 deg, at which the flying fish is observed to emerge from the sea surface. From glide polar, we find that the gliding performance of flying fish is comparable to those of bird wings such as the hawk, petrel and wood duck. However, the induced drag by strong wing-tip vortices is one of the dominant drag components. Finally, we examine ground effect on the aerodynamic forces of the gliding flying fish and find that the flying fish achieves the reduction of drag and increase of lift-to drag ratio by flying close to the sea surface. PMID- 20833920 TI - Alternative developmental pathways associated with diapause regulated by temperature and maternal influences in embryos of the annual killifish Austrofundulus limnaeus. AB - Embryos of the annual killifish Austrofundulus limnaeus enter a state of developmental arrest termed diapause as part of their normal developmental program. Diapause can occur at two distinct developmental stages in this species, termed diapause II and III. When incubated at 25 degrees C, most embryos enter diapause II, whereas a small percentage of 'escape' embryos develop continuously past diapause II and enter diapause III. Control of entry into diapause II can be altered by maternal influences and the incubation environment experienced by the embryos. Young females produce a higher proportion of escape embryos than do older females. In addition, increasing the incubation temperature from 25 to 30 degrees C induces all embryos to escape from diapause. Surprisingly, escape embryos follow a different morphological and physiological developmental trajectory than do embryos that enter diapause II. Development of anterior structures is advanced compared with that of posterior structures in escape embryos when compared with embryos that will enter diapause II. The difference in timing of development for these two trajectories is consistent with changes observed between two species but is very atypical of variation observed within a species. Importantly, the two developmental pathways diverge early in development, during the segmentation period, when, according to evolutionary theory, constraint on developmental pathways should be relatively high. The possession of alternative developmental pathways in a vertebrate embryo is a novel finding, the ecological and evolutionary importance of which is still unknown, but potentially significant in terms of life-history evolution. PMID- 20833921 TI - The trade-off between growth rate and locomotor performance varies with perceived time until breeding. AB - Environmental circumstances can cause changes in early growth patterns that subsequently affect the adult phenotype. Here we investigated how different growth trajectories affected subsequent locomotor performance, and how such effects were influenced by the perceived time until the key life-history event of reproduction. Using juvenile three-spined sticklebacks Gasterosteus aculeatus, we show that a brief period of manipulated temperature in early life (independent of food supply) caused effects on skeletal growth trajectory not only during the manipulation itself, but also during a subsequent compensatory phase. The outcome of these changes was that fish in all treatment groups reached the same average size by sexual maturity, despite having different growth patterns. However, their growth trajectory had impacts on both pre-breeding swimming endurance and its decline over the course of the breeding season, such that swimming ability was negatively correlated with skeletal growth rate during the compensation period. We also show for the first time that 'negative compensation' (i.e. a decelerating growth trajectory) led to an improved swimming performance compared with steadily growing controls. Replicate experiments and photoperiod manipulations, moreover, revealed that the effects of growth rate on subsequent swimming performance were greater when the perceived time until the breeding season was shorter. These results show that the costs of accelerated or decelerated growth can last well beyond the time over which growth rates differ, and are affected by the time available until an approaching life history event such as reproduction, possibly because of the time available to repair the damage. PMID- 20833922 TI - Host gender and offspring quality in a flea parasitic on a rodent. AB - The quality of offspring produced by parent fleas (Xenopsylla ramesis) fed on either male or female rodent hosts (Meriones crassus) was studied. The emergence success, duration of development, resistance to starvation upon emergence and body size of the flea offspring were measured. It was predicted that offspring of fleas produced by parents that fed on male hosts (i) will survive better as pre imago, (ii) will develop faster, (iii) will live longer under starvation after emergence and (iv) will be larger than offspring of fleas fed on female hosts. The emergence success of pre-imaginal fleas was relatively high, ranging from 46.9% to 100.0% and averaging 78.4+/-3.0%, and was not affected by host gender. The duration of development of pre-imaginal fleas depended on the gender of the host of parents and differed between male and female offspring, with female fleas developing faster. Furthermore, male fleas developed faster if their parents fed on female rather than on male hosts, whereas no difference in the duration of development between host genders was found in female fleas. The time to death under starvation did not depend on the gender of either the flea or the host. A newly emerged flea, on average, lived 31.9+/-1.0 days without access to food. The relationship between host gender and body size of male flea offspring was the only effect that supported the predictions. An increase in body size in male fleas could increase their mating success and, ultimately, their fitness. PMID- 20833923 TI - Paralytic activity of lysophosphatidylcholine from saliva of the waterbug Belostoma anurum. AB - Lysophosphatidylcholine (LPC) is a major bioactive lipid that is enzymatically generated by phospholipase A(2) (PLA(2)). Previously, we showed that LPC is present in the saliva of the blood-sucking hemipteran Rhodnius prolixus and modulates cell-signaling pathways involved in vascular biology, which aids blood feeding. Here, we show that the saliva of the predator insect Belostoma anurum contains a large number of lipids with LPC accounting for 25% of the total phospholipids. A PLA(2) enzyme likely to be involved in LPC generation was characterized. The activity of this enzyme is 5-fold higher in Belostoma saliva than in other studied hemipterans, suggesting a close association with the predator feeding habits of this insect. Belostoma employs extra-oral digestion, which allows for ingestion of larger prey than itself, including small vertebrates such as amphibians and fish. Therefore, prey immobilization during digestion is essential, and we show here that Belostoma saliva and B. anurum saliva purified LPC have paralytic activity in zebrafish. This is the first evidence that lysophospholipids might play an important role in prey immobilization, in addition to contributing to blood feeding, and might have been an evolutionary acquisition that occurred long before the appearance of hematophagy in this animal group. PMID- 20833924 TI - Convergence of carbohydrate-biased intake targets in caged worker honeybees fed different protein sources. AB - The nutritional needs of bees are supplied by nectar carbohydrates and by protein and other nutrients in pollen but little is known of how bees achieve nutritional balance. Using newly emerged caged worker honeybees (Apis mellifera scutellata), we investigated whether bees maintain their intake target when confined to pairs of imbalanced complementary diets varying in protein to carbohydrate (P:C) ratio. Diets were formulated using three protein sources [casein, royal jelly or Feed Bee (a natural pollen substitute)] and sucrose. Within each protein type, honeybees switched between complementary diets and converged on the same P:C intake target. However, this target differed between protein types: P:C ratios were 1:12, 1:14 and 1:11 on casein, royal jelly and Feed-Bee diets, respectively. Except for an early peak in protein consumption on royal jelly diets, these strongly convergent ratios remained constant over the 14 day experiment. This is probably due to the absence of brood, reflected in relatively stable values measured for haemolymph protein concentration and hypopharyngeal gland activation in bees on Feed-Bee diets. Performance of caged workers was also assessed in terms of survival and ovarian activation. Survival was highest on casein diets and lowest on Feed-Bee diets but ovarian activation was highest on royal jelly diets and lowest on casein diets. This may be due to additional components in Feed-Bee and royal jelly (e.g. fatty acids), which are needed to activate the ovaries but also reduce survival. Nutrient intake of broodless workers is directly related to their own physiological requirements, and the strong carbohydrate bias may reflect the high metabolic rate of honeybees even under resting conditions. PMID- 20833925 TI - Hydrodynamic pumping by serial gill arrays in the mayfly nymph Centroptilum triangulifer. AB - Aquatic nymphs of the mayfly Centroptilum triangulifer produce ventilatory flow using a serial array of seven abdominal gill pairs that operates across a Reynolds numbers (Re) range from 2 to 22 during ontogeny. Net flow in small animals is directed ventrally and essentially parallel to the stroke plane (i.e. rowing), but net flow in large animals is directed dorsally and essentially transverse to the stroke plane (i.e. flapping). Detailed flow measurements based on Particle Image Velocimetry (PIV) ensemble-correlation analysis revealed that the phasing of the gills produces a time-dependent array of vortices associated with a net ventilatory current, a fluid kinematic pattern, here termed a 'phased vortex pump'. Absolute size of vortices does not change with increasing animal size or Re, and thus the vortex radius (R(v)) decreases relative to inter-gill distance (L(is)) during mayfly growth. Given that effective flapping in appendage array animals requires organized flow between adjacent appendages, we hypothesize that rowing should be favored when L(is)/R(v)<1 and flapping should be favored when L(is)/R(v)>1. Significantly, the rowing-to-flapping transition in Centroptilum occurs at Re~5, when the mean dynamic inter-gill distance equals the vortex radius. This result suggests that the Re-based rowing-flapping demarcation observed in appendage-array aquatic organisms may be determined by the relative size of the propulsive mechanism and its self-generated vortices. PMID- 20833926 TI - Peripheral modulation of pheromone response by inhibitory host compound in a beetle. AB - We identified several compounds, by gas chromatographic-electroantennographic detection (GC-EAD), that were antennally active in the bark beetle Ips typographus and also abundant in beetle-attacked spruce trees. One of them, 1,8 cineole (Ci), strongly inhibited the attraction to pheromone in the field. Single sensillum recordings (SSRs) previously showed olfactory receptor neurons (ORNs) on I. typographus antennae selectively responding to Ci. All Ci neurons were found within sensilla co-inhabited by a pheromone neuron responding to cis verbenol (cV); however, in other sensilla, the cV neuron was paired with a neuron not responding to any test odorant. We hypothesized that the colocalization of ORNs had a functional and ecological relevance. We show by SSR that Ci inhibited spontaneous activity of the cV neuron only in sensilla in which the Ci neuron was also present. Using mixtures of cV and Ci, we further show that responses to low doses (1-10 ng) of cV were significantly reduced when the colocalized Ci neuron simultaneously responded to high doses (1-10 MUg) of Ci. This indicated that the response of the Ci neuron, rather than ligand-receptor interactions in the cV neuron, caused the inhibition. Moreover, cV neurons paired with Ci neurons were more sensitive to cV alone than the ones paired with the non-responding ORN. Our observations question the traditional view that ORNs within a sensillum function as independent units. The colocalization of ORNs might sharpen adaptive responses to blends of semiochemicals with different ecological significance in the olfactory landscape. PMID- 20833927 TI - Angiogenesis of the uterus and chorioallantois in the eastern water skink Eulamprus quoyii. AB - We have discovered a modification of the uterus that appears to facilitate maternal-fetal communication during pregnancy in the scincid lizard Eulamprus quoyii. A vessel-dense elliptical area (VDE) on the mesometrial side of the uterus expands as the embryo grows, providing a large vascular area for physiological exchange between mother and embryo. The VDE is already developed in females with newly ovulated eggs, and is situated directly adjacent to the chorioallantois of the embryo when it develops. It is likely that signals from the early developing embryo determine the position of the VDE, as the VDE is off centre in cases where the embryo sits obliquely in the uterus. The VDE is not a modification of the uterus over the entire chorioallantoic placenta, as the VDE is smaller than the chorioallantois after embryonic stage 33, but expansion of the VDE and growth of the chorioallantois during pregnancy are strongly correlated. The expansion of the VDE is also strongly correlated with embryonic growth and increasing embryonic oxygen demand (Vo2). We propose that angiogenic stimuli are exchanged between the VDE and the chorioallantois in E. quoyii, allowing the simultaneous growth of both tissues. PMID- 20833928 TI - Effects of competitive prey capture on flight behavior and sonar beam pattern in paired big brown bats, Eptesicus fuscus. AB - Foraging and flight behavior of echolocating bats were quantitatively analyzed in this study. Paired big brown bats, Eptesicus fuscus, competed for a single food item in a large laboratory flight room. Their sonar beam patterns and flight paths were recorded by a microphone array and two high-speed cameras, respectively. Bats often remained in nearly classical pursuit (CP) states when one bat is following another bat. A follower can detect and anticipate the movement of the leader, while the leader has the advantage of gaining access to the prey first. Bats in the trailing position throughout the trial were more successful in accessing the prey. In this study, bats also used their sonar beam to monitor the conspecific's movement and to track the prey. Each bat tended to use its sonar beam to track the prey when it was closer to the worm than to another bat. The trailing bat often directed its sonar beam toward the leading bat in following flight. When two bats flew towards each other, they tended to direct their sonar beam axes away from each other, presumably to avoid signal jamming. This study provides a new perspective on how echolocating bats use their biosonar system to coordinate their flight with conspecifics in a group and how they compete for the same food source with conspecifics. PMID- 20833929 TI - The presence of UV wavelengths improves the temporal resolution of the avian visual system. AB - The ability to perceive rapid movement is an essential adaptation in birds, which are involved in rapid flight, pursuing prey and escaping predators. Nevertheless, the temporal resolution of the avian visual systems has been less well explored than spectral sensitivity. There are indications that birds are superior to humans in their ability to detect movement, as suggested by higher critical flicker frequencies (CFFs). It has also been implied, but not properly tested, that properties of CFF, as a function of light intensity, are affected by the spectral composition of light. This study measured CFF in the chicken, Gallus gallus L., using four different light stimuli - white, full-spectrum (white with addition of UV), yellow (590 nm) and UV (400 nm) - and four light intensity levels, adjusted to relative cone sensitivity. The results showed significantly higher CFF values for full-spectrum compared with white light, as well as a steeper rate of increase with intensity. The presence of UV wavelengths, previously demonstrated to affect mate choice and foraging, appears to be important also for detection of rapid movement. The yellow and UV light stimuli yielded rather similar CFFs, indicating no special role for the double cone in flicker detection. PMID- 20833930 TI - Polarization sensitivity in two species of cuttlefish - Sepia plangon (Gray 1849) and Sepia mestus (Gray 1849) - demonstrated with polarized optomotor stimuli. AB - The existence of polarization sensitivity (PS), most likely resulting from the orthogonal arrangement of microvilli in photoreceptors, has been proposed in cephalopods for some time, although it has rarely been examined behaviourally. Here, we tested the mourning cuttlefish, Sepia plangon, and the reaper cuttlefish, Sepia mestus, for polarization sensitivity using a large-field optomotor stimulus containing polarization contrast. Polaroid filter drums with stripes producing alternating e-vectors were rotated around free-moving animals. Polarized optomotor responses were displayed, and these responses were similar to those performed in response to a black-and-white, vertically-striped drum, whereas no responses were displayed to a plain polarizing control drum producing just a vertical e-vector. This indicates that the animals are able to see the contrast between adjacent stripes in the polarizing drum. To our knowledge, this is the first demonstration of functional polarization sensitivity in cuttlefish. PMID- 20833931 TI - Polarization sensitivity and retinal topography of the striped pyjama squid (Sepioloidea lineolata - Quoy/Gaimard 1832). AB - Coleoid cephalopods (octopus, cuttlefish and squid) potentially possess polarization sensitivity (PS) based on photoreceptor structure, but this idea has rarely been tested behaviourally. Here, we use a polarized, striped optokinetic stimulus to demonstrate PS in the striped pyjama squid, Sepioloidea lineolata. This species displayed strong, consistent optokinetic nystagmic eye movements in response to a drum with stripes producing e-vectors set to 0 deg, 45 deg, 90 deg and 135 deg that would only be visible to an animal with PS. This is the first behavioural demonstration of a polarized optokinetic response in any species of cephalopod. This species, which typically sits beneath the substrate surface looking upwards for potential predators and prey, possesses a dorsally shifted horizontal pupil slit. Accordingly, it was found to possess a horizontal strip of high-density photoreceptors shifted ventrally in the retina, suggesting modifications such as a change in sensitivity or resolution to the dorsal visual field. PMID- 20833932 TI - Control of tumbling during the locust jump. AB - Locust can jump precisely to a target, yet they can also tumble during the trajectory. We propose two mechanisms that would allow the locust to control tumbling during the jump. The first is that prior to the jump, locusts adjust the pitch of their body to move the center of mass closer to the intended thrust vector. The second is that contraction of the dorsolongitudinal muscles during the jump will produce torques that counter the torque produced by thrust. We found that locusts increased their take-off angle as the initial body pitch increased, and that little tumbling occurred for jumps that observed this relationship. Simulations of locust jumping demonstrated that a pitch versus take off angle relationship that minimized tumbling in simulated jumps was similar to the relationship observed in live locusts. Locusts were strongly biased to pitch head-upward, and performed dorsiflexions far more often than ventral flexions. The direction and magnitude of tumbling could be controlled in simulations by adjusting the tension in the dorsolongitudinal muscles. These mechanisms allowed the simulations to match the data from the live animals. Control of tumbling was also found to influence the control of jump elevation. The bias to pitch head upwards may have an evolutionary advantage when evading a predator and so make control of tumbling important for the locust. PMID- 20833933 TI - Behavioral and neurophysiological responses of an insect to changing ratios of constituents in host plant-derived volatile mixtures. AB - Ratios of compounds in host plant odors fluctuate with the phenological stage of the plant. In the present study, we investigated the effect of changing ratios of host plant volatile constituents on herbivore insect attraction and olfactory information processing. We tested a synthetic mixture of bioactive peach shoot volatiles with different concentrations of one of the mixture constituents, benzonitrile, on oriental fruit moth Cydia (=Grapholita) molesta females. Y-tube olfactometer bioassays showed that female attraction to the mixture was maintained while increasing the benzonitrile level up to 100 times. Further increases led to behaviorally ineffective mixtures. Then, we recorded odor-evoked neural activity patterns in the antennal lobes, the main olfactory center of the brain, using calcium imaging. Benzonitrile-containing mixtures elicited strong activation in two glomeruli, which were found to process mixture-related information in specific ways. Activation in one glomerulus directly paralleled behavioral effects of the different ratios tested whereas a deviating pattern was noted in the other glomerulus. Our results indicate that the ratio of constituents in a volatile mixture can be varied to a certain degree without reducing female attraction. Thus, volatile blends in nature might vary quantitatively within a certain range without affecting odor-guided host location. Neurophysiological results showed that the processing of mixture related information inside the antennal lobes is not uniform across glomeruli. Thus, final processing of this information probably takes place in higher-order brain centers. PMID- 20833934 TI - The muddles of medicine: a practical, clinical addendum to the biopsychosocial model. AB - BACKGROUND: The commonly-accepted "biopsychosocial model" does not always lend itself to the kind of pragmatic decisions that many clinical situations demand of physicians. OBJECTIVE: The authors attempt to identify and close gaps in the biopsychosocial model that hinder its application in certain real-life clinical situations. METHOD: The authors review some of the current and historical literature on the development and application of the biopsychosocial model, and argue the shortcomings of this modality in various clinical situations. RESULTS: The authors present three dicta to guide clinicians toward relevant areas of inquiry: 1) Think neuroanatomically; 2) Think existentially; and 3) Think "dirty;" that is, understand that patients and physicians sometimes work toward different goals. DISCUSSION: These dicta form an addendum to the biopsychosocial model, identifying and filling three specific, commonly-encountered gaps in that paradigm, which, ironically, is usually considered all-inclusive. PMID- 20833935 TI - Management of psychosis associated with a prolactinoma: case report and review of the literature. AB - BACKGROUND: Prolactinomas are the most common pituitary tumors; they are treated with dopamine agonists, which may cause psychotic symptoms as a side effect. Psychosis is treated with dopamine-receptor blockers that may result in elevated serum prolactin and symptomatic hyperprolactinemia. OBJECTIVE: The authors will review a case of a patient with a prolactinoma as well as schizophrenia and illustrate the management of psychosis in this case. METHOD: The review describes the management of prolactinoma, symptoms of hyperprolactinemia, and long-term effects of hyperprolactinemia. RESULTS: In the case presentation reviewed, the patient was finally discharged on risperidone long-acting injection and testosterone supplementation, with no growth of the adenoma after 3 years. DISCUSSION: This review provides recommendations and treatment strategy for management of prolactinoma in a patient with schizophrenia. PMID- 20833936 TI - Offensive language in the general hospital. AB - BACKGROUND: Offensive language (spoken by medical staff and by patients and their families) is often heard in the general hospital, but its manifestations and clinical implications have not been previously examined. OBJECTIVE: The authors sought to facilitate an understanding of the effects and treatment of offensive utterances and their downstream consequences. METHOD: The authors present a sampling of clinical vignettes that illustrate a variety of examples of hospital based events in which offensive language was used and discuss differential diagnoses and management strategies. RESULTS: Swearing can also be used as a psychological tool in the service of helping. Swearing may provide a channel of catharsis for aggressive drives and affects that have been building in either the doctor or the patient. DISCUSSION: Placing offensive behaviors, for example, use of profane language, in a biopsychosocial context can facilitate an understanding of the causes, effects, and treatment of these events. PMID- 20833937 TI - Symptom presentation, interventions, and outcome of emotionally-distressed patients in primary care. AB - BACKGROUND: Patients with psychosocial problems often present somatic symptoms in primary care. OBJECTIVE: The authors compare interventions and outcomes of emotionally-distressed patients by presenting physical disease, somatoform symptoms, or psychological symptoms. METHOD: General practitioners (N=191) documented data from 1,286 patients with psychosocial problems. Experts rated the presented reasons for encounter. RESULTS: Somatoform symptoms, as well as physical disease, result in patients' receiving physical treatments. Psychologically-oriented treatment is more likely with psychological presentation, but not significantly related to somatoform symptoms. CONCLUSION: These findings underline the importance of a specific treatment approach for patients with somatoform symptoms, so as to avoid inappropriate treatment. PMID- 20833938 TI - Reliability of self-reported nicotine use as determined by serum cotinine levels in patients referred for liver transplantation. AB - BACKGROUND: Smoking has been associated with a higher incidence of post-hepatic transplantation de novo noncutaneous neoplasms and vascular complications. There are conflicting reports regarding increased posttransplant mortality. OBJECTIVE: The authors sought to determine the reliability of patient-reported nicotine product use (NPU) in candidates for hepatic transplantation. METHOD: The authors performed a retrospective chart review of all patients referred for liver transplantation in a 12-month period. Each patient's report of recent or current nicotine product use through smoking, chewing tobacco, or nicotine replacement products, as obtained in interviews, was compared with the quantitative result of serum cotinine levels. RESULTS: Of 171 patients referred for liver transplant evaluation during a 12-month period, 17% reported ongoing NPU, and 83% denied it. Of the patients who denied recent NPU, 11% had serum cotinine levels reflective of active use. Of the patients reporting active NPU, 97% had positive cotinine levels. CONCLUSION: There was a high degree of reliability of patient self reported NPU, but detecting deceptive reporting is important in the selection of patients who will have long-term success with liver transplantation. PMID- 20833940 TI - Administration of olanzapine to prevent postoperative delirium in elderly joint replacement patients: a randomized, controlled trial. AB - BACKGROUND: Delirium is a serious postoperative condition for which few pharmacologic prevention trials have been conducted. OBJECTIVE: The authors tested the efficacy of perioperative olanzapine administration to prevent postoperative delirium in elderly patients after joint-replacement surgery. METHOD: The authors conducted a randomized, double-blind, placebo-controlled, prophylaxis trial at an orthopedic teaching hospital, enrolling 495 elderly patients age >=65 years, who were undergoing elective knee- or hip-replacement surgery; 400 patients received either 5 mg of orally-disintegrating olanzapine or placebo just before and after surgery. The primary efficacy outcome was the incidence of (DSM-III-R) delirium. RESULTS: The incidence of delirium was significantly lower in the olanzapine group than in the placebo group; this held true for both knee- and hip-replacement surgery. However, delirium lasted longer and was more severe in the olanzapine group. Advanced age, a high level of medical comorbidity, an abnormal albumin level, and having knee-replacement surgery were independent risk factors for postoperative delirium (Clinicaltrials.gov Identifier: NCT000699946). CONCLUSION: Administration of 10 mg of oral olanzapine perioperatively, versus placebo, was associated with a significantly lower incidence of delirium. These findings suggest that olanzapine prophylaxis of postoperative delirium may be an effective strategy. PMID- 20833939 TI - Prophylactic antidepressant treatment in patients with hepatitis C on antiviral therapy: a double-blind, placebo-controlled trial. AB - BACKGROUND: Approximately one-third of patients undergoing interferon-alpha (IFN alpha) therapy for treatment of the hepatitis C virus (HCV) develop major depression, which decreases functioning and may lead to the reduction or discontinuation of treatment. OBJECTIVE: The authors examined the efficacy of citalopram in preventing IFN-alpha-induced depression in HCV patients. METHOD: This was a randomized, controlled trial comparing citalopram with placebo in 39 HCV patients. RESULTS: The rate of IFN-alpha-induced depression in the sample was 15.4% (6/39). Randomization to citalopram did not decrease the statistical likelihood of developing IFN-alpha-induced depression (10.5% for citalopram vs. 20.0% for placebo). CONCLUSION: Citalopram does not prevent depression onset; however, an empirically-supported treatment recommendation for IFN-alpha-induced depression includes monitoring depressive symptoms throughout antiviral therapy and initiating psychiatric treatment at the initial signs of depression. PMID- 20833941 TI - Refeeding syndrome as an iatrogenic cause of delirium: a retrospective pilot study. AB - BACKGROUND: Refeeding syndrome describes a pattern of electrolyte disturbances occurring after the reintroduction of nutrition to the malnourished patient; it is often associated with delirium. OBJECTIVE: The authors investigated whether hospitalized elderly patients who develop delirium are more likely to have laboratory findings consistent with refeeding syndrome. METHOD: The authors conducted a retrospective chart review of 100 patients over age 60. Charts were examined for indications of delirium and refeeding syndrome. RESULTS: Significantly lower serum levels of magnesium and phosphate were found in patients with delirium. Delirium was not associated with any significant difference in levels of potassium. CONCLUSION: This study supports an association between delirium in elderly patients and electrolyte changes consistent with those seen in refeeding syndrome. PMID- 20833942 TI - Japanese version of the Delirium Rating Scale, Revised-98 (DRS-R98-J): reliability and validity. AB - BACKGROUND: Delirium is a common neuropsychiatric disorder in medical and surgical inpatients of all ages. It is associated with increased long-term mortality, longer length of hospital stay, poor functional recovery, and increased likelihood of nursing home placement. OBJECTIVE: The aim of this study was to investigate the reliability and the validity of the Japanese translation of the Delirium Rating Scale, Revised-98 (DRS-R-98). METHOD: Psychiatric consultation patients were assessed to compare groups of delirium, dementia, and non-delirium. RESULTS: Mean Total and Severity scores significantly distinguished delirium from the other groups. The scale had high interrater reliability and high internal consistency. Mean Severity scores during delirium differed from the posttreatment scores. Stratum-specific likelihood ratios showed that the DRS-R98 J is a reliable diagnostic tool. CONCLUSION: This study indicates that the Japanese version of the DRS-R-98 has high reliability and validity, and is a useful tool for assessing delirium among Japanese medically ill populations. PMID- 20833943 TI - Takotsubo cardiomyopathy after electroconvulsive therapy. AB - BACKGROUND: Takotsubo cardiomyopathy is a novel acute cardiac syndrome characterized by transient regional systolic dysfunction of the left-ventricular apex and mid-ventricle, with hyperkinesis of the basal left ventricular segments, which has been associated with severe emotional or physical stress. METHOD: This is the second published case report of takotsubo cardiomyopathy occurring in the setting of electroconvulsive therapy (ECT). RESULTS: The patient, a 52-year-old woman, experienced chest pain and discomfort shortly after ECT treatment. She was shown to have moderate left-ventricular dysfunction, with mid-cavity left ventricular hypo- to akinesis, and hyperkinesis in the basilar region, consistent with a diagnosis of takotsubo cardiomyopathy. There was full resolution of her symptoms within 48 hours of the initial event. DISCUSSION: This report highlights a previously undocumented complication of ECT and adds to the growing list of stressors responsible for cases of takotsubo cardiomyopathy. The prognosis is favorable, and recovery is generally complete, especially with early recognition of the syndrome and proper supportive treatment. PMID- 20833944 TI - Serotonin syndrome after a massive overdose of controlled-release paroxetine. AB - BACKGROUND: Serotonin syndrome is a condition resulting from an overabundance of serotonin at postsynaptic receptors. The syndrome usually responds to cyproheptadine and benzodiazepines. However, some patients do not respond to conventional treatment. OBJECTIVE: The authors report on the history and management of a patient, a 55-year-old man, who had taken a massive overdose of paroxetine, controlled-release. METHOD: The authors present a case report of history and treatment. Paroxetine levels were measured on Days 3 and 7 after admission, with rising values of the drug. The patient received a course of cyproheptadine and lorazepam, to which he was unresponsive, and he was transferred to the Medical Intensive Care Unit for heavy sedation. RESULTS: The patient had initially presented with minor symptoms of serotonin syndrome, but these quickly progressed in severity, and he eventually died from resulting complications: a pulmonary embolism 9 days after admission, despite appropriate prophylaxis with enoxaparin. CONCLUSION: The authors are the first to report on a paroxetine overdose of this magnitude, and they provide one of the few reports on a prolonged course of serotonin syndrome that was unresponsive to standard treatment. PMID- 20833945 TI - Treatment of recurrent Rapunzel syndrome and trichotillomania: case report and literature review. AB - BACKGROUND: Trichotillomania (obsession with one's hair) was first described in the literature over 100 years ago and was recognized by the American Psychiatric Association as a distinct disorder in 1987. OBJECTIVE: The authors discuss a rare presentation of a case of recurrent Rapunzel syndrome in a 37-year-old woman. METHOD: The authors present a biopsychosocial treatment plan for a therapeutic approach. RESULTS: This patient was unique for her relatively advanced age at onset, the recurrent nature, association with pancreatitis, and the consumption of artificial hair extensions, rather than her own hair. This patient presented with small-bowel obstruction requiring laparotomy. After surgery, she was evaluated by the psychiatric service; after discharge, she removed her hair extensions, continued to take her prescribed medication, attended a psychiatric program, and was monitored by family and friends. CONCLUSION: There are no definitive guidelines for treating trichotillomania. In this case, quetiapine, hair-extension removal, family involvement, and regular follow-up helped with the initial cessation of her hair consumption. Antidepressant treatment helped control the obsession while behavioral therapy and family involvement provided the means for habit-reversal training. PMID- 20833946 TI - Charles Bonnet syndrome as a manifestation of leptomeningeal metastases. PMID- 20833947 TI - Methylene blue and serotonin toxicity: definite causal link. PMID- 20833948 TI - Psychotic disorder as a manifestation of Graves' disease. PMID- 20833949 TI - Follow-up report: Self-amputation of the nipples and penis in a nonpsychotic, non gender-dysphoric man. PMID- 20833950 TI - Geophylogenies and the Map of Life. PMID- 20833951 TI - Sources of error inherent in species-tree estimation: impact of mutational and coalescent effects on accuracy and implications for choosing among different methods. AB - Discord in the estimated gene trees among loci can be attributed to both the process of mutation and incomplete lineage sorting. Effectively modeling these two sources of variation--mutational and coalescent variance--provides two distinct challenges for phylogenetic studies. Despite extensive investigation on mutational models for gene-tree estimation over the past two decades and recent attention to modeling of the coalescent process for phylogenetic estimation, the effects of these two variances have yet to be evaluated simultaneously. Here, we partition the effects of mutational and coalescent processes on phylogenetic accuracy by comparing the accuracy of species trees estimated from gene trees (i.e., the actual coalescent genealogies) with that of species trees estimated from estimated gene trees (i.e., trees estimated from nucleotide sequences, which contain both coalescent and mutational variance). Not only is there a significant contribution of both mutational and coalescent variance to errors in species-tree estimates, but the relative magnitude of the effects on the accuracy of species tree estimation also differs systematically depending on 1) the timing of divergence, 2) the sampling design, and 3) the method used for species-tree estimation. These findings explain why using more information contained in gene trees (e.g., topology and branch lengths as opposed to just topology) does not necessarily translate into pronounced gains in accuracy, highlighting the strengths and limits of different methods for species-tree estimation. Differences in accuracy scores between methods for different sampling regimes also emphasize that it would be a mistake to assume more computationally intensive species-tree estimation procedures that will always provide better estimates of species trees. To the contrary, the performance of a method depends not only on the method per se but also on the compatibilities between the input genetic data and the method as determined by the relative impact of mutational and coalescent variance. PMID- 20833952 TI - Cardiac myosin heavy chain gene regulation by thyroid hormone involves altered histone modifications. AB - The antithetical regulation of cardiac alpha- and beta-myosin heavy chain (MHC) genes by thyroid hormone (T(3)) is not well understood but appears to involve thyroid hormone interaction with its nuclear receptor and MHC promoters as well as cis-acting noncoding regulatory RNA (ncRNA). Both of these phenomena involve epigenetic regulations. This study investigated the extent that altered thyroid state induces histone modifications in the chromatin associated with the cardiac MHC genes. We hypothesized that specific epigenetic events could be identified and linked to cardiac MHC gene switching in response to a hypothyroid or hyperthyroid state. A hypothyroid state was induced in rats by propylthiouracil treatment (PTU), whereas a hyperthyroid (T(3)) was induced by T(3) treatment. The left ventricle was analyzed after 7 days for MHC pre-mRNA expression, and the chromatin was assessed for enrichment in specific histone modifications using chromatin immunoprecipitation quantitative PCR assays. At both the alpha-MHC promoter and the intergenic region, the enrichment in acetyl histone H3 at K9/14 (H3K9/14ac) and trimethyl histone H3 at K4 (H3K4me3) changed in a similar fashion. They were both decreased with PTU treatment but did not change under T(3), except at a location situated 5' to the antisense intergenic transcription start site. These same marks varied differently on the beta-MHC promoter. For example, H3K4me3 enrichment correlated with the beta-promoter activity in PTU and T(3) groups, whereas H3K9/14ac was repressed in the T(3) group but did not change under PTU. Histone H3K9me was enriched in chromatin of both the intergenic and alpha-MHC promoters in the PTU group, whereas histone H4K20me1 was enriched in chromatin of beta-MHC promoter in the normal control and T(3) groups. Collectively, these findings provide evidence that specific epigenetic phenomena modulate MHC gene expression in altered thyroid states. PMID- 20833953 TI - Antecedent hydrogen sulfide elicits an anti-inflammatory phenotype in postischemic murine small intestine: role of BK channels. AB - The objectives of this study were to determine the role of calcium-activated, small (SK), intermediate (IK), and large (BK) conductance potassium channels in initiating the development of an anti-inflammatory phenotype elicited by preconditioning with an exogenous hydrogen sulfide (H(2)S) donor, sodium hydrosulfide (NaHS). Intravital microscopy was used to visualize rolling and firmly adherent leukocytes in vessels of the small intestine of mice preconditioned with NaHS (in the absence and presence of SK, IK, and BK channel inhibitors, apamin, TRAM-34, and paxilline, respectively) or SK/IK (NS-309) or BK channel activators (NS-1619) 24 h before ischemia-reperfusion (I/R). I/R induced marked increases in leukocyte rolling and adhesion, effects that were largely abolished by preconditioning with NaHS, NS-309, or NS-1619. The postischemic anti inflammatory effects of NaHS-induced preconditioning were mitigated by BKB channel inhibitor treatment coincident with NaHS, but not by apamin or TRAM-34, 24 h before I/R. Confocal imaging and immunohistochemistry were used to demonstrate the presence of BKalpha subunit staining in both endothelial and vascular smooth muscle cells of isolated, pressurized mesenteric venules. Using patch-clamp techniques, we found that BK channels in cultured endothelial cells were activated after exposure to NaHS. Bath application of the same concentration of NaHS used in preconditioning protocols led to a rapid increase in a whole cell K(+) current; specifically, the component of K(+) current blocked by the selective BK channel antagonist iberiotoxin. The activation of BK current by NaHS could also be demonstrated in single channel recording mode where it was independent of a change in intracellular Ca(+) concentration. Our data are consistent with the concept that H(2)S induces the development of an anti adhesive state in I/R in part mediated by a BK channel-dependent mechanism. PMID- 20833954 TI - Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. AB - As a G protein-coupled receptor, the extracellular Ca(2+)-sensing receptor (CaSR) responds to changes not only in extracellular Ca(2+), but also to many other ligands. CaSR has been found to be expressed in the hearts and cardiovascular system. In this study, we confirmed that CaSR is expressed in mouse cardiomyocytes and showed that it is predominantly localized in caveolae. The goal of this study was to investigate whether CaSR plays a cardioprotective role in ischemic preconditioning (IPC). Hearts from C57BL/6J mice (male, 12-16 wk) were perfused in the Langendorff mode and subjected to the following treatments: 1) control perfusion; 2) perfusion with a specific CaSR antagonist, NPS2143; 3) IPC (four cycles of 5 min of global ischemia and 5 min of reperfusion); or 4) perfusion with NPS2143 before and during IPC. Following these treatments, hearts were subjected to 20 min of no-flow global ischemia and 120 min of reperfusion. Compared with control, IPC significantly improved postischemic left ventricular functional recovery and reduced infarct size. Although NPS2143 perfusion alone did not change the hemodynamic function and did not change the extent of postischemic injury, NPS2143 treatment abolished cardioprotection of IPC. Through immunoblot analysis, it was demonstrated that IPC significantly increased the levels of phosphorylated ERK1/2, AKT, and GSK-3beta, which were also prevented by NPS2143 treatment. Taken together, the distribution of CaSR in caveolae along with NPS2143-blockade of IPC-induced cardioprotective signaling suggest that the activation of CaSR during IPC is cardioprotective by a process involving caveolae. PMID- 20833955 TI - Cardiac angiotensin II: does it have a function? PMID- 20833956 TI - Wavelet analysis reveals heterogeneous time-dependent oscillations of individual mitochondria. AB - Mitochondrial inner membrane potential oscillations in cardiac myocytes synchronize under oxidative or metabolic stress, leading to synchronized whole cell oscillations. Gaining information about the temporal properties of individual mitochondrial oscillators is essential to comprehend the network's intrinsic spatiotemporal organization. We have developed methods to detect individual mitochondrial tetramethylrhodamine ethyl ester fluorescence oscillations and assess their dynamical properties using wavelet analysis. We demonstrate that these advanced signal processing tools can provide quantitative spatiotemporal information about intermitochondrial coupling. We have found that the mean frequency of selected groups of continuously oscillating mitochondria was 16.49 +/- 1.04 mHz, whereas the mean frequency in the normalized mean global wavelet spectrum was 22.84 +/- 1.80 mHz (n = 9 myocytes). In conclusion, this novel methodology will help shed new light on the dynamical properties of the mitochondrial network on the verge of synchronization. PMID- 20833957 TI - Short-term exercise training protects against doxorubicin-induced cardiac mitochondrial damage independent of HSP72. AB - Doxorubicin (Dox) is an antitumor agent used in cancer treatment, but its clinical use is limited due to cardiotoxicity. Although exercise training can defend against Dox-mediated cardiac damage, the means for this cardioprotection remain unknown. To investigate the mechanism(s) responsible for exercise training induced cardioprotection against Dox-mediated cardiotoxicity, we tested a two pronged hypothesis: 1) exercise training protects against Dox-induced cardiotoxicity by preventing Dox-mediated mitochondrial damage/dysfunction and increased oxidative stress and 2) exercise training-induced cardiac expression of the inducible isoform of the 70-kDa heat shock protein 72 (HSP72) is essential to achieve exercise training-induced cardioprotection against Dox toxicity. Animals were randomly assigned to sedentary or exercise groups and paired with either placebo or Dox treatment (i.e., 20 mg/kg body wt ip Dox hydrochloride 24 h before euthanasia). Dox administration resulted in cardiac mitochondrial dysfunction, activation of proteases, and apoptosis. Exercise training increased cardiac antioxidant enzymes and HSP72 protein abundance and protected cardiac myocytes against Dox-induced mitochondrial damage, protease activation, and apoptosis. To determine whether exercise-induced expression of HSP72 in the heart is required for this cardioprotection, we utilized an innovative experimental strategy that successfully prevented exercise-induced increases in myocardial HSP72 levels. However, prevention of exercise-induced increases in myocardial HSP72 did not eliminate the exercise-induced cardioprotective phenotype that is resistant to Dox-mediated injury. Our results indicate that exercise training protects against the detrimental side effects of Dox in cardiac myocytes, in part, by protecting mitochondria against Dox-mediated damage. However, this exercise-induced cardioprotection is independent of myocardial HSP72 levels. Finally, our data are consistent with the concept that increases in cardiac mitochondrial antioxidant enzymes may contribute to exercise-induced cardioprotection. PMID- 20833958 TI - Impaired flow-induced dilation of coronary arterioles of dogs fed a low-salt diet: roles of ANG II, PKC, and NAD(P)H oxidase. AB - Low-salt (LS) diet has been considered to be beneficial in the prevention and treatment of hypertension; however, it also increases plasma angiotensin (ANG) II and may cause adverse cardiovascular effects, such as endothelial dysfunction. We assessed endothelial function of coronary arterioles and vascular superoxide production, as a function of LS diet. Dogs were fed with LS (0.05% NaCl) or a normal-salt (NS, 0.65% NaCl) diet for 2 wk. There were threefold increases in plasma ANG II, associated with a 60% reduction in flow-induced dilation (FID) in coronary arterioles of LS compared with NS dogs. In vessels of NS dogs, FID was primarily mediated by nitric oxide (NO), as indicated by an eliminated FID by N(omega)-nitro-l-arginine methyl ester (l-NAME). In vessels of LS dogs, however, FID was eliminated. Administration of apocynin, a NAD(P)H oxidase inhibitor, partially restored FID and additional l-NAME eliminated FID. Generation of superoxide, measured with dihydroethidium, was significantly greater in vessels of LS than in NS dogs, which was further increased in response to ANG II or phorbol 12,13-dibutyrate, an agonist of protein kinase C (PKC). The enhanced superoxide was normalized by apocynin, losartan (a blocker of angiotensin type 1 receptor), and chelerythrine chloride (an antagonist of PKC). Western blotting indicated an upregulation of gp91(phox) and p47(phox), associated with increased expression of phosphorylated PKC in vessels of LS dogs. In separate experiments, dogs were fed simultaneously with LS and losartan (LS + Losa) for 2 wk. There was a significant increase in plasma ANG II in LS + Losa dogs, which, however, was associated with normal FID and gp91(phox) expression in coronary arterioles. In conclusion, LS led to endothelial dysfunction, as indicated by an impaired flow induced dilation caused by decreasing NO bioavailibility, a response that involves angiotensin-induced activation of PKC that, in turn, activates vascular NAD(P)H oxidase to produce superoxide. PMID- 20833959 TI - Local angiotensin II aggravates cardiac remodeling in hypertension. AB - Angiotensin II (ANG II) contributes to hypertension, cardiac hypertrophy, fibrosis, and dysfunction; however, it is difficult to separate the cardiac effect of ANG II from its hemodynamic action in vivo. To overcome the limitations, we used transgenic mice with cardiac-specific expression of a transgene fusion protein that releases ANG II from cardiomyocytes (Tg-ANG II) and treated them with deoxycorticosterone acetate (DOCA)-salt to suppress their systemic renin-angiotensin system. Using this unique model, we tested the hypothesis that cardiac ANG II, acting on the angiotensin type 1 receptor (AT(1)R), increases inflammation, oxidative stress, and apoptosis, accelerating cardiac hypertrophy and fibrosis. Male Tg-ANG II mice and their nontransgenic littermates (n-Tg) were uninephrectomized and divided into the following three groups: 1) vehicle-treated normotensive controls; 2) DOCA-salt; and 3) DOCA-salt + valsartan (AT(1)R blocker).Under basal conditions, systolic blood pressure (SBP) and cardiac phenotypes were similar between strains. In DOCA-salt hypertension, SBP increased similarly in both n-Tg and Tg-ANG II, and cardiac function did not differ between strains; however, Tg-ANG II had 1) greater ventricular hypertrophy as well as interstitial and perivascular fibrosis; 2) a higher number of deoxynucleotidyl-transferase-mediated dUTP nick end labeling positive cells and infiltrating macrophages; 3) increased protein expression of NADPH oxidase 2 and transforming growth factor-beta(1); and 4) downregulation of phosphatidylinositol 3-kinase (PI 3-kinase) and protein kinase B (Akt) phosphorylation. Valsartan partially reversed these effects in Tg-ANG II but not in n-Tg. We conclude that, when hemodynamic loading conditions remain unchanged, cardiac ANG II does not alter heart size or cardiac functions. However, in animals with hypertension, cardiac ANG II, acting via AT(1)R, enhances inflammation, oxidative stress, and cell death (most likely via downregulation of PI 3-kinase and Akt), contributing to cardiac hypertrophy and fibrosis. PMID- 20833960 TI - Delayed activation of caspase-independent apoptosis during heart failure in transgenic mice overexpressing caspase inhibitor CrmA. AB - Although caspase activation is generally thought to be necessary to induce apoptosis, recent evidence suggests that apoptosis can be activated in the setting of caspase inhibition. In this study, we tested the hypothesis that caspase-independent apoptotic pathways contribute to the development of heart failure in the absence of caspase activation. Acute cardiomyopathy was induced using a single dose of doxorubicin (Dox, 20 mg/kg) injected into male wild-type (WT) and transgenic (Tg) mice with a cardiac-specific expression of cytokine response modifier A (CrmA), a known caspase inhibitor. Early (6 day) survival was significantly better in CrmA Tg (81%) than WT (38%) mice. Twelve days after Dox injection, however, the mortality benefit had dissipated, and increased cardiac apoptosis was observed in both groups. There was, however, a significantly greater release of apoptosis-inducing factor (AIF) from mitochondria to cytosol in CrmA Tg compared with WT mice, which suggests that an enhancement of activation in caspase-independent apoptotic pathways had occurred. The administration of a poly(ADP-ribose) polymerase-1 inhibitor, 4-amino-1,8 naphthalimide (4-AN), to Dox-treated mice resulted in significantly improved cardiac function, a significant blockade of AIF released from mitochondria, and decreased cardiac apoptosis. There were also significantly improved survival in WT (18% without 4-AN vs. 89% with 4-AN) and CrmA Tg (13% without 4-AN vs. 93% with 4-AN) mice 12 days after Dox injection. In conclusion, these findings suggest that apoptosis can be induced in the heart lacking caspase activation via caspase-independent pathways and that enabling the inhibition of AIF activation may provide a significant cardiac benefit. PMID- 20833961 TI - Kinin B1 receptor upregulation by angiotensin II and endothelin-1 in rat vascular smooth muscle cells: receptors and mechanisms. AB - Oxidative stress upregulates the kinin B(1) receptor (B(1)R) in diabetes and hypertension. Since angiotensin II (ANG II) and endothelin-1 (ET-1) are increased in these disorders, this study aims at determining the role of these two prooxidative peptides in B(1)R expression in rat vascular smooth muscle cells (VSMC). In the A10 cell line and aortic VSMC, ANG II enhanced B(1)R protein expression in a concentration- and time-dependent manner (maximal at 1 MUM and 6 h). In A10 cells, ANG II (1 MUM) also increased B(1)R mRNA expression at 3 h and the activation of induced B(1)R with the agonist [Sar-d-Phe(8)]-des-Arg(9)-BK (10 nM, 5 min) significantly enhanced mitogen-activated protein kinase (MAPK1/2) phosphorylation. The enhancing effect of ANG II on B(1)R protein expression in A10 cells was normalized by the AT(1) (losartan) but not by the AT(2) (PD123319) receptor antagonist. Furthermore, it was inhibited by inhibitors of phosphatidylinositol 3-kinase (wortmannin) and NF-kappaB (MG132) but not of MAPK (PD098059). Whereas the ET(B) receptor antagonist (BQ788) had no effect, the ET(A) receptor antagonist (BQ123) blocked the effect of ANG II at 6-8 h but not at an early time point. BQ123 and BQ788 also blocked the increasing effect of ET 1 on B(1)R protein expression. Antioxidants (N-acetyl-l-cysteine and diphenyleneiodonium) abolished ANG II- and ET-1-increased B(1)R protein expression. In conclusion, B(1)R induction is linked to oxidative stress and activation of phosphatidylinositol 3-kinase and NF-kappaB. The newly synthesized B(1)R is functional and can activate MAPK signaling in VSMC. The effect of ANG II is mediated by the AT(1) receptor and the subsequent activation of ET(A) through ET-1 release. PMID- 20833962 TI - Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells. AB - We hypothesized that inhibition of the cGMP-specific enzyme phosphodiesterase 5A (PDE5A) promoted cGMP/protein kinase G (PKG) activity to condition stem cells for enhanced survival and proliferation. One-time tadalafil treatment (1 MUM for 30 min) of mesenchymal stem cells ((Tada)MSCs) provided sustained protection of cells for 36 h. Higher cGMP activity with concomitantly increased PKG1 activity was observed in (Tada)MSCs, which peaked within 12 h after tadalafil treatment. Pretreatment with PKG1 blockers (1 MUM KT-5823 or 20 nM K-252a) or transduction with adenoviral PKG1-short-hairpin RNA abolished tadalafil-induced cytoprotection of the cells. A higher proliferation rate was observed in (Tada)MSCs compared with nontreated MSCs ((Cont)MSCs). In a rat model of acute myocardial infarction, (Tada)MSCs transplanted 0 and 24 h after tadalafil treatment showed higher survival compared with (Cont)MSCs on day 2 and day 4 after engraftment. (Tada)MSCs transplanted 48 h after tadalafil treatment lost their protection on both day 2 and day 4 after engraftment, and their rate of survival was similar to (Cont)MSCs. Reduced terminal dUTP nick end-labeling positivity (P < 0.01 vs. (Cont)MSCs) and higher proliferation of (Tada)MSCs (P < 0.01 vs. (Cont)MSCs) was observed in the infarcted heart. Fluorescence immunostaining revealed neomyogenesis in both the infarct and peri-infarct areas. Blood vessel density was significantly increased in group 2 compared with group 1. Transthoracic echocardiographic heart function revealed significant preservation of the indexes of left ventricle contractility and attenuation of remodeling in (Tada)MSC engrafted animal hearts (group 2) compared with (Cont)MSCs (group 1). PDE5A inhibition using long-acting tadalafil is an innovative approach to promote stem cell survival and proliferation in the infarcted heart. PMID- 20833963 TI - Understanding exercise-induced hyperemia: central and peripheral hemodynamic responses to passive limb movement in heart transplant recipients. AB - To better characterize the contribution of both central and peripheral mechanisms to passive limb movement-induced hyperemia, we studied nine recent (<2 yr) heart transplant (HTx) recipients (56 +/- 4 yr) and nine healthy controls (58 +/- 5 yr). Measurements of heart rate (HR), stroke volume (SV), cardiac output (CO), and femoral artery blood flow were recorded during passive knee extension. Peripheral vascular function was assessed using brachial artery flow-mediated dilation (FMD). During passive limb movement, the HTx recipients lacked an HR response (0 +/- 0 beats/min, Delta0%) but displayed a significant increase in CO (0.4 +/- 0.1 l/min, Delta5%) although attenuated compared with controls (1.0 +/- 0.2 l/min, Delta18%). Therefore, the rise in CO in the HTx recipients was solely dependent on increased SV (5 +/- 1 ml, Delta5%) in contrast with the controls who displayed significant increases in both HR (6 +/- 2 beats/min, Delta11%) and SV (5 +/- 2 ml, Delta7%). The transient increase in femoral blood volume entering the leg during the first 40 s of passive movement was attenuated in the HTx recipients (24 +/- 8 ml) compared with controls (93 +/- 7 ml), whereas peripheral vascular function (FMD) appeared similar between HTx recipients (8 +/- 2%) and controls (6 +/- 1%). These data reveal that the absence of an HR increase in HTx recipients significantly impacts the peripheral vascular response to passive movement in this population and supports the concept that an increase in CO is a major contributor to exercise-induced hyperemia. PMID- 20833964 TI - Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner. AB - Acute increases in O-linked beta-N-acetylglucosamine (O-GlcNAc) levels of cardiac proteins exert protective effects against ischemia-reperfusion (I/R) injury. One strategy to rapidly increase cellular O-GlcNAc levels is inhibition of O GlcNAcase (OGA), which catalyzes O-GlcNAc removal. Here we tested the cardioprotective efficacy of two novel and highly selective OGA inhibitors, the NAG-thiazoline derivatives NAG-Bt and NAG-Ae. Isolated perfused rat hearts were subjected to 20 min global ischemia followed by 60 min reperfusion. At the time of reperfusion, hearts were assigned to the following four groups: 1) untreated control; 2) 50 MUM NAG-Bt; 3) 100 MUM NAG-Bt; or 4) 50 MUM NAG-Ae. All treatment groups significantly increased total O-GlcNAc levels (P < 0.05 vs. control), and this was significantly correlated with improved contractile function and reduced cardiac troponin I release (P < 0.05). Immunohistochemistry of normoxic hearts showed intense nuclear O-GlcNAc staining and higher intensity at Z-lines with colocalization of O-GlcNAc and the Z-line proteins desmin and vinculin. After I/R, there was a marked loss of both cytosolic and nuclear O-GlcNAcylation and disruption of normal striated Z-line structures. OGA inhibition largely preserved structural integrity and attenuated the loss of O-GlcNAcylation; however, nuclear O-GlcNAc levels remained low. Immunoblot analysis confirmed ~50% loss in both nuclear and cytosolic O-GlcNAcylation following I/R, which was significantly attenuated by OGA inhibition (P < 0.05). These data provide further support for the notion that increasing cardiac O-GlcNAc levels by inhibiting OGA may be a clinically relevant approach for ischemic cardioprotection, in part, by preserving the integrity of O-GlcNAc-associated Z-line protein structures. PMID- 20833965 TI - Pore mutants of HERG and KvLQT1 downregulate the reciprocal currents in stable cell lines. AB - We previously reported a transgenic rabbit model of long QT syndrome based on overexpression of pore mutants of repolarizing K(+) channels KvLQT1 (LQT1) and HERG (LQT2).The transgenes in these rabbits eliminated the slow and fast components of the delayed rectifier K(+) current (I(Ks) and I(Kr), respectively), as expected. Interestingly, the expressed pore mutants of HERG and KvLQT1 downregulated the remaining reciprocal repolarizing currents, I(Ks) and I(Kr), without affecting the steady-state levels of the native polypeptides. Here, we sought to further explore the functional interactions between HERG and KvLQT1 in heterologous expression systems. Stable Chinese hamster ovary (CHO) cell lines expressing KvLQT1-minK or HERG were transiently transfected with expression vectors coding for mutant or wild-type HERG or KvLQT1. Transiently expressed pore mutant or wild-type KvLQT1 downregulated I(Kr) in HERG stable CHO cell lines by 70% and 44%, respectively. Immunostaining revealed a severalfold lower surface expression of HERG, which could account for the reduction in I(Kr) upon KvLQT1 expression. Deletion of the KvLQT1 NH(2)-terminus did not abolish the downregulation, suggesting that the interactions between the two channels are mediated through their COOH-termini. Similarly, transiently expressed HERG reduced I(Ks) in KvLQT1-minK stable cells. Coimmunoprecipitations indicated a direct interaction between HERG and KvLQT1, and surface plasmon resonance analysis demonstrated a specific, physical association between the COOH-termini of KvLQT1 and HERG. Here, we present an in vitro model system consistent with the in vivo reciprocal downregulation of repolarizing currents seen in transgenic rabbit models, illustrating the importance of the transfection method when studying heterologous ion channel expression and trafficking. Moreover, our data suggest that interactions between KvLQT1 and HERG are mediated through COOH termini. PMID- 20833966 TI - Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. AB - Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are more complicated than in other organs, where loss of blood flow automatically leads to hypoxia. In this review, an extensive overview is given of the molecular and cellular mechanisms that are involved in the pathogenesis of lung ischemia-reperfusion injury and the possible therapeutic strategies to reduce or prevent it. In addition, the roles of neutrophils, alveolar macrophages, cytokines, and chemokines, as well as the alterations in the cell-death related pathways, are described in detail. PMID- 20833967 TI - Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation. AB - Epicatechin, a flavonoid, is a well-known antioxidant linked to a variety of protective effects in both humans and animals. In particular, its role in protection against cardiovascular disease has been demonstrated by epidemiologic studies. Low-dose epicatechin, which does not have significant antioxidant activity, is also protective; however, the mechanism by which low-dose epicatechin induces this effect is unknown. Our laboratory tested the hypothesis that low-dose epicatechin mediates cardiac protection via opioid receptor activation. C57BL/6 mice were randomly assigned to 1 of 10 groups: control, epicatechin, naloxone (nonselective opioid receptor antagonist), epicatechin + naloxone, naltrindole (delta-specific opioid receptor antagonist), epicatechin + naltrindole, norbinaltorphimine (nor-BNI, kappa-specific opioid receptor antagonist), epicatechin + nor-BNI, 5-hydroxydecanoic acid [5-HD, ATP-sensitive potassium channel antagonist], and epicatechin + 5-HD. Epicatechin (1 mg/kg) or other inhibitors (5 mg/kg) were administered by oral gavage or intraperitoneal injection, respectively, daily for 10 days. Mice were subjected to 30 min coronary artery occlusion followed by 2 h of reperfusion, and infarct size was determined via planimetry. Whole heart homogenates were assayed for downstream opioid receptor signaling targets. Infarct size was significantly reduced in epicatechin- and epicatechin + nor-BNI-treated mice compared with control mice. This protection was blocked by naloxone, naltrindole, and 5-HD. Epicatechin and epicatechin + nor-BNI increased the phosphorylation of Src, Akt, and IkappaBalpha, while simultaneously decreasing the expression of c-Jun NH(2) terminal kinase and caspase-activated DNase. All signaling effects are consistent with opioid receptor stimulation and subsequent cardiac protection. Naloxone, naltrindole, and 5-HD attenuated these effects. In conclusion, epicatechin acts via opioid receptors and more specifically through the delta-opioid receptor to produce cardiac protection from ischemia-reperfusion injury. PMID- 20833968 TI - Therapeutic effects of evasin-1, a chemokine binding protein, in bleomycin induced pulmonary fibrosis. AB - CC chemokines play an important role in the pathogenesis of idiopathic pulmonary fibrosis. Few studies have evaluated the efficacy of therapeutically targeting CC chemokines and their receptors during interstitial lung diseases. In the present study, the therapeutic effects of Evasin-1, a tick-derived chemokine-binding protein that has high affinity for CCL3/microphage inflammatory protein (MIP) 1alpha, was investigated in a murine model of bleomycin-induced lung fibrosis. CCL3/MIP-1alpha concentrations in lung homogenates increased significantly with time after bleomycin challenge, and this was accompanied by increased number of leukocytes and elevated levels of CCL2/monocyte chemoattractant protein (MCP)-1, CCL5/regulated upon activation, normal T cell expressed and secreted, TNF-alpha and transforming growth factor-beta(1), and pulmonary fibrosis. Administration of evasin-1 on a preventive (from the day of bleomycin administration) or therapeutic (from Day 8 after bleomycin) schedule decreased number of leukocytes in the lung, reduced levels of TNF-alpha and transforming growth factor-beta(1), and attenuated lung fibrosis. These protective effects were similar to those observed in CCL3/MIP-1alpha-deficient mice. In conclusion, targeting CCL3/MIP 1alpha by treatment with evasin-1 is beneficial in the context of bleomycin induced lung injury, even when treatment is started after the fibrogenic insult. Mechanistically, evasin-1 treatment was associated with decreased recruitment of leukocytes and production of fibrogenic cytokines. Modulation of CCL3/MIP-1alpha function by evasin-1 could be useful for the treatment of idiopathic pulmonary fibrosis. PMID- 20833969 TI - Sedentary behavior and cancer: a systematic review of the literature and proposed biological mechanisms. AB - BACKGROUND: Sedentary behavior (prolonged sitting or reclining characterized by low energy expenditure) is associated with adverse cardiometabolic profiles and premature cardiovascular mortality. Less is known for cancer risk. The purpose of this review is to evaluate the research on sedentary behavior and cancer, to summarize possible biological pathways that may underlie these associations, and to propose an agenda for future research. METHODS: Articles pertaining to sedentary behavior and (a) cancer outcomes and (b) mechanisms that may underlie the associations between sedentary behavior and cancer were retrieved using Ovid and Web of Science databases. RESULTS: The literature review identified 18 articles pertaining to sedentary behavior and cancer risk, or to sedentary behavior and health outcomes in cancer survivors. Ten of these studies found statistically significant, positive associations between sedentary behavior and cancer outcomes. Sedentary behavior was associated with increased colorectal, endometrial, ovarian, and prostate cancer risk; cancer mortality in women; and weight gain in colorectal cancer survivors. The review of the literature on sedentary behavior and biological pathways supported the hypothesized role of adiposity and metabolic dysfunction as mechanisms operant in the association between sedentary behavior and cancer. CONCLUSIONS: Sedentary behavior is ubiquitous in contemporary society; its role in relation to cancer risk should be a research priority. Improving conceptualization and measurement of sedentary behavior is necessary to enhance validity of future work. IMPACT: Reducing sedentary behavior may be a viable new cancer control strategy. PMID- 20833970 TI - Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia. AB - BACKGROUND AND AIMS: Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B (CTSB)-activatable imaging agents show high enzyme activity within intestinal tumors. METHODS: We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of CTSB. RESULTS: Among 558 participants, 457 (82%) had tumors that expressed CTSB (CTSB positive) and 101 (18%) had tumors that did not express CTSB (CTSB negative). CTSB expression was not associated with disease stage (P = 0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer-specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer-specific mortality of 1.99 (95% confidence interval, 1.19-3.34) and overall mortality of 1.71 (95% confidence interval, 1.16-2.50). CTSB expression was independently associated with KRAS (P = 0.01) and BRAF mutation (P = 0.04), but not microsatellite instability status, CpG island methylator phenotype status, PIK3CA mutation, LINE-1 methylation, TP53 expression, or PTGS2 (cyclooxygenase-2) expression. Among 123 individuals with adenomas, 91% expressed CTSB. CONCLUSIONS: As assessed by immunohistochemistry, CTSB is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer-specific and overall mortality. IMPACT: These results support the potential of CTSB a target for image detection of neoplastic lesions in humans. PMID- 20833971 TI - Meta-analysis of human papillomavirus infection concordance. AB - BACKGROUND: Estimates of human papillomavirus (HPV) concordance among sexual partners are important for various public health activities, from counseling individual patients to predicting the effect of HPV vaccination. METHODS: We systematically searched the PubMed and EMBASE databases for studies of HPV concordance among heterosexual couples published through 2008 in English. Two coders independently abstracted data using standardized forms. We integrated concordance data using random-effects meta-analysis. RESULTS: Thirty studies (33 study populations) that met inclusion criteria reported concordance data for 2,972 couples. Most studies were cross-sectional cohort studies conducted in Europe or Asia that used DNA hybridization to test for HPV, sometimes in conjunction with PCR. Overall, 25.5% (95% confidence interval, 17.2-36.1%) of couples were infected with 1 or more of the same HPV types. Among couples with both members HPV-positive, 63.2% (95% confidence interval, 49.1-75.3%) were infected with 1 or more of the same viral types. Positive concordance was higher for female partners of men with HPV infections than for male partners of women with HPV infections. Positive concordance was also higher for studies using PCR and for the few studies that recruited men with HPV-related disease. CONCLUSIONS: Sexual partners of HPV-infected individuals had high rates of HPV infection, suggesting a need for increased attention to this group. IMPACT: Our refined estimates of HPV concordance can inform clinical encounters and public health planning. Future HPV concordance studies should use more rigorous research designs, characterize their participants in greater detail, and study more meaningful populations. PMID- 20833972 TI - Urine concentrations of a tobacco-specific nitrosamine carcinogen in the U.S. population from secondhand smoke exposure. AB - BACKGROUND: The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanone (NNK) and its reduction product in the body, 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanol (NNAL), are potent pulmonary carcinogens. We have measured total NNAL in the U.S. population of tobacco users and nonsmokers exposed to secondhand smoke. METHODS: We measured total urinary NNAL (free NNAL plus its glucuronides following hydrolysis) by using a sensitive and specific high performance liquid chromatography/tandem mass spectrometry method. We calculated the percentage above the limit of detection, the 50th through 95th percentiles, and in some cases, geometric means for groups classified by age, gender, and race/ethnicity. RESULTS: Total urinary NNAL was measureable at or above its limit of detection (0.6 pg/mL) in 55% of the study participants, including 41% of nonsmokers. The population distribution of urinary NNAL included smoker and nonsmoker regions similar to the bimodal distribution of serum cotinine, and serum cotinine and total urinary NNAL were strongly correlated (r = 0.92; P < 0.001). Among nonsmokers, children had significantly higher concentrations of NNAL than did adults with the age of >=20 years (P < 0.001). CONCLUSIONS: Among National Health and Nutrition Examination Survey participants, total NNAL was found at measurable levels in the urine of 41% of nonsmokers and in 87.5% of those with substantial secondhand-smoke exposure (with serum cotinine concentrations of 0.1-10 ng/mL). Children with the age of 6 to 11 years had the highest NNAL concentrations among all nonsmokers. IMPACT: We describe for the first time the distribution of total urinary NNAL in the entire U.S. population, including smokers and nonsmokers. NNAL was detected in 41% of all nonsmokers. PMID- 20833973 TI - No effect of exercise on insulin-like growth factor-I, insulin, and glucose in young women participating in a 16-week randomized controlled trial. AB - INTRODUCTION: Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have been associated with increased risk of breast cancer. METHODS: We report our findings on the effects of 16 weeks of aerobic exercise on IGF axis proteins, insulin, glucose, and insulin resistance of 319 young sedentary women. Demographics, health surveys, body composition, dietary intake, and blood samples were collected at baseline and 16 weeks. IGF-I and IGFBP-1, IGFBP-2, and IGFBP-3 were measured by ELISA. RESULTS: Exercise adherence was 88%. The dropout rates for the exercise and control groups were 21.7% and 14.5%, respectively. There was a small significant change from baseline in IGFBP-3 concentrations. IGFBP-3 levels decreased in controls and increased in exercisers. The between-group difference was significant. No other changes were noted. CONCLUSION: Sixteen weeks of exercise had minimum or no effect on IGF proteins of young women. IMPACT: Our study supports findings from previous studies conducted in older populations and raises the question of what type of intervention is needed to change circulating levels of IGF proteins in humans. PMID- 20833974 TI - Some principles of research design in public health. 1961. PMID- 20833975 TI - Sequence variation at multiple loci influences red cell hemoglobin concentration. AB - A substantial genetic contribution underlies variation in baseline peripheral blood counts. We performed quantitative trait locus/loci analyses to identify chromosome regions harboring genes influencing red cell hemoglobin concentration using the cell hemoglobin concentration mean (CHCM), a directly measured parameter analogous to the mean cell hemoglobin concentration. Fourteen significant loci (gene symbols Chcmq1-Chcmq14) were detected. Seven of these influenced CHCM in a sex-specific fashion, and 2 showed significant interactive effects (epistasis). For quantitative trait locus/loci detected in multiple crosses, confidence intervals were narrowed using statistical and bioinformatic approaches. Two strong candidate genes emerged and were further analyzed: adult beta-globin (Hbb) for Chcmq3 on Chr 7, and transferrin (Trf) for Chcmq2 on Chr 9. High and low allele parental strains in crosses detecting Chcmq3 segregate 100% with the known ancestral haplotype blocks, hemoglobin (Hb) diffuse (Hbb(d)) and Hb single (Hbb(s)), respectively. Hbb(d) consists of nonidentical major and minor polypeptides and exhibits an increased positive charge relative to Hbb(s) due to the net loss of 2 negative residues in the Hbb(dminor) polypeptide, resulting in a pI of 7.85 versus 7.13. Thus, as shown in human erythrocytes, positively charged Hbs are associated with cell dehydration and increased CHCM in mouse erythrocytes. PMID- 20833976 TI - Transcription profiling in human platelets reveals LRRFIP1 as a novel protein regulating platelet function. AB - Within the healthy population, there is substantial, heritable, and interindividual variability in the platelet response. We explored whether a proportion of this variability could be accounted for by interindividual variation in gene expression. Through a correlative analysis of genome-wide platelet RNA expression data from 37 subjects representing the normal range of platelet responsiveness within a cohort of 500 subjects, we identified 63 genes in which transcript levels correlated with variation in the platelet response to adenosine diphosphate and/or the collagen-mimetic peptide, cross-linked collagen related peptide. Many of these encode proteins with no reported function in platelets. An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1 [leucine-rich repeat (in FLII) interacting protein 1]. Morpholino-based silencing in Danio rerio identified a modest role for commd7 and a significant effect for lrrfip1 as positive regulators of thrombus formation. Proteomic analysis of human platelet LRRFIP1-interacting proteins indicated that LRRFIP1 functions as a component of the platelet cytoskeleton, where it interacts with the actin-remodeling proteins Flightless-1 and Drebrin. Taken together, these data reveal novel proteins regulating the platelet response. PMID- 20833977 TI - GVHD after haploidentical transplantation: a novel, MHC-defined rhesus macaque model identifies CD28- CD8+ T cells as a reservoir of breakthrough T-cell proliferation during costimulation blockade and sirolimus-based immunosuppression. AB - We have developed a major histocompatibility complex-defined primate model of graft-versus-host disease (GVHD) and have determined the effect that CD28/CD40 directed costimulation blockade and sirolimus have on this disease. Severe GVHD developed after haploidentical transplantation without prophylaxis, characterized by rapid clinical decline and widespread T-cell infiltration and organ damage. Mechanistic analysis showed activation and possible counter-regulation, with rapid T-cell expansion and accumulation of CD8(+) and CD4(+) granzyme B(+) effector cells and FoxP3(pos)/CD27(high)/CD25(pos)/CD127(low) CD4(+) T cells. CD8(+) cells down-regulated CD127 and BCl-2 and up-regulated Ki-67, consistent with a highly activated, proliferative profile. A cytokine storm also occurred, with GVHD-specific secretion of interleukin-1 receptor antagonist (IL-1Ra), IL 18, and CCL4. Costimulation Blockade and Sirolimus (CoBS) resulted in striking protection against GVHD. At the 30-day primary endpoint, CoBS-treated recipients showed 100% survival compared with no survival in untreated recipients. CoBS treatment resulted in survival, increasing from 11.6 to 62 days (P < .01) with blunting of T-cell expansion and activation. Some CoBS-treated animals did eventually develop GVHD, with both clinical and histopathologic evidence of smoldering disease. The reservoir of CoBS-resistant breakthrough immune activation included secretion of interferon-gamma, IL-2, monocyte chemotactic protein-1, and IL-12/IL-23 and proliferation of cytotoxic T-lymphocyte-associated antigen 4 immunoglobulin-resistant CD28(-) CD8(+) T cells, suggesting adjuvant treatments targeting this subpopulation will be needed for full disease control. PMID- 20833978 TI - Progenitor cell dose determines the pace and completeness of engraftment in a xenograft model for cord blood transplantation. AB - Two critical concerns in clinical cord blood transplantation are the initial time to engraftment and the subsequent restoration of immune function. These studies measured the impact of progenitor cell dose on both the pace and strength of hematopoietic reconstitution by transplanting nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma-null (NSgamma) mice with lineage depleted aldehyde dehydrogenase-bright CD34(+) human cord blood progenitors. The progress of each transplant was monitored over an extended time course by repeatedly analyzing the peripheral blood for human hematopoietic cells. In vivo human hematopoietic development was complete. After long-term transplantation assays (>= 19 weeks), human T-cell development was documented within multiple tissues in 16 of 32 NSgamma mice. Human T-cell differentiation was active within NSgamma thymuses, as documented by the presence of CD4(+) CD8(+) T-cell progenitors as well as T-cell receptor excision circles. It is important to note that although myeloid and B-cell engraftment was detected as early as 4 weeks after transplantation, human T-cell development was exclusively late onset. High progenitor cell doses were associated with a robust human hematopoietic chimerism that accelerated both initial time to engraftment and subsequent T-cell development. At lower progenitor cell doses, the chimerism was weak and the human hematopoietic lineage development was frequently incomplete. PMID- 20833979 TI - Adaptation to anemia in hemoglobin E-beta thalassemia. AB - Hemoglobin E beta thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin Ebeta thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P(50) value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of beta thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value. PMID- 20833980 TI - In pediatric patients, age has more impact on dosing of vitamin K antagonists than VKORC1 or CYP2C9 genotypes. AB - Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P = .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations. PMID- 20833981 TI - Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. AB - The C-X-C-type chemokine Cxcl12, also known as stromal cell-derived factor-1, plays a critical role in hematopoiesis during fetal development. However, the functional requirement of Cxcl12 in the adult hematopoietic stem/progenitor cell (HSPC) regulation was still unclear. In this report, we developed a murine Cxcl12 conditional deletion model in which the target gene can be deleted at the adult stage. We found that loss of stroma-secreted Cxcl12 in the adult led to expansion of the HSPC population as well as a reduction in long-term quiescent stem cells. In Cxcl12-deficient bone marrow, HSPCs were absent along the endosteal surface, and blood cell regeneration occurred predominantly in the perisinusoidal space after 5-fluorouracil myelosuppression challenge. Our results indicate that Cxcl12 is required for HSPC homeostasis regulation and is an important factor for osteoblastic niche organization in adult stage bone marrow. PMID- 20833982 TI - Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy. AB - We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions. PMID- 20833983 TI - Small changes can have large impacts: health care overhaul should include child maltreatment prevention in primary care. PMID- 20833984 TI - Annual repeat rates of laparoscopic surgery: a marker of practice variation. AB - Use of laparoscopy is an area of interest owing to a previous report of significant numbers of repeat laparoscopic surgery in some women in Alberta, Canada. It was hypothesized that analyzing individual-woman rates of annual repeat procedures documents potential overuse of laparoscopic surgery. Administrative data concerning yearly individual specific laparoscopy experiences were obtained from Alberta Health and Wellness for the years 1996 to 2007. Rates of repeat diagnostic and operative laparoscopic procedures were determined for each fiscal year and analyzed using statistical process control methods. The rate of reoperation for an individual woman for both procedures has "special causes" of variation. Rates of reoperation within the fiscal year varied significantly. The reasons could include operating room access, initial clinical enthusiasm for new surgery, changing surgical skills, and changing processes in decision making. The presence of such variation will require policy initiatives to address high rates of annual repeat procedures. PMID- 20833985 TI - Piloting a method to measure satisfaction with HIV care. AB - This pilot study investigated the perception of the quality of health care received by 55 HIV-positive African Americans. A survey instrument, "The Quality of Care Through the Patient's Eyes"-HIV questionnaire (QUOTE-HIV), developed in the Netherlands, was used to collect quantitative data from the modified QUOTE HIV. Qualitative data are from 2 focus groups' perception discussions of the applicability of the QUOTE-HIV to HIV-positive African Americans. The study's purpose was to assess the usefulness of the questionnaire to identify patients' perceptions of quality health care. Results indicated that the QUOTE-HIV is a useful tool to assess HIV-positive African Americans' satisfaction and adequately covered all areas of concern discussed by both focus groups as components for measuring perceived quality of care. Most important, the QUOTE-HIV was found to be appropriate for assessing study participants' satisfaction with quality health care and assessing the receipt of quality health care from their respective providers. PMID- 20833986 TI - EHR implementation adversely affects performance on process quality measures in a community health center. PMID- 20833988 TI - Improvement of dietary quality with the aid of a low glycemic index diet in Asian patients with type 2 diabetes mellitus. AB - OBJECTIVES: This randomized controlled study was conducted to determine the effect of low glycemic index (GI) dietary advice on eating patterns and dietary quality in Asian patients with type 2 diabetes (T2DM). METHODS: Asian patients with T2DM (N = 104) were randomized into 2 groups that received either low GI or conventional carbohydrate exchange (CCE) dietary advice for 12 weeks. Nutritional prescriptions were based on the medical nutrition therapy for T2DM, with the difference being in the GI component of the carbohydrates. Dietary intake and food choices were assessed with the use of a 3-day food record. RESULTS: At week 12, both groups achieved the recommendations for carbohydrate (52 +/- 4% and 54 +/- 4% of energy) and fat (30 +/- 4% and 28 +/- 5% of energy) intake. There were no significant differences in the reported macronutrient intake in both groups. With the low GI diet, crude fiber and dietary calcium intake increased, while the dietary GI reduced. Subjects in the lowest dietary glycemic index/glycemic load (GI/GL) quartile consumed more parboiled/basmati rice, pasta, milk/dairy products, fruits, and dough, which are foods from the low GI category. There was a significant reduction in the hemoglobin A(1c) level at week 12 for patients in the lowest GI/GL quartile (Delta = -0.7 +/- 0.1%) compared with those in the highest GI/GL quartile (Delta = -0.1 +/- 0.2%). CONCLUSIONS: These results demonstrate the ability of low GI dietary advice to improve the dietary quality of Asian patients with T2DM. PMID- 20833989 TI - Hypoadiponectinemia is strongly associated with metabolic syndrome in Korean type 2 diabetes patients. AB - OBJECTIVE: To evaluate the relationship between serum adiponectin level, dietary intake, and metabolic syndrome (MetS) in type 2 diabetes mellitus (DM) patients, and to identify factors associated with serum adiponectin level. METHODS: A cross sectional study was performed using 789 type 2 DM patients (406 men and 383 women) 40-80 years old. Subjects were classified into 3 groups on the basis of serum adiponectin level. General characteristics and anthropometric, hematologic, and dietary data were obtained for each subject. RESULTS: The prevalence of hypoadiponectinemia (<4.0 ug/mL) was 57.4% in men and 32.4% in women. Serum adiponectin level was negatively correlated with body mass index (BMI), waist circumference, body fat percentage, and serum concentrations of insulin and triglyceride, and was positively correlated with high-density lipoprotein (HDL) cholesterol level. Even though the direct association of nutrient intake with serum adiponectin concentration was not strong, various contributing factors for hypoadiponectinemia were strongly correlated with micronutrient intake, such as calcium, iron, and niacin. Both sexes in the group with the lowest adiponectin concentration had a higher prevalence of MetS and MetS components than corresponding sexes in the group with the highest adiponectin concentration. CONCLUSIONS: Our findings show that hypoadiponectinemia is strongly associated with MetS in type 2 DM patients. Dietary intake may be indirectly associated with adiponectin levels through factors such as BMI, waist circumference, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), triglyceride, HDL cholesterol, and blood pressure. Therefore, our results suggest that manipulation of the level of adiponectin may prevent MetS and reduce the risk of cardiovascular disease in type 2 DM patients. PMID- 20833990 TI - Validation of a 3-dimensional laser body scanner for assessment of waist and hip circumference. AB - OBJECTIVES: To evaluate the reliability and validity of a 3-dimensional laser body scanner for estimation of waist and hip circumferences and waist:hip ratio. METHODS: Seventy women were evaluated for waist and hip circumference and waist:hip ratio via laser scanner and tape measure. In a subset of 34 participants, 8 repeated measures of laser scanning were performed for reproducibility analysis. Validity of the instrument was assessed by regression and Bland-Altman comparison of measures of waist and hip circumferences and waist:hip ratio to tape measure. RESULTS: Reproducibility analysis showed little difference between within-subjects measurements of circumferences (intraclass correlation coefficient >=0.992, p < 0.01). Evaluation of waist and hip circumferences measured by body scanning did not differ significantly from tape measure (p > 0.05). Bland-Altman analysis showed no bias between laser scanning and tape measure. CONCLUSION: These findings indicate that the 3-dimensional laser body scanner is a reliable and valid technique for the estimation of waist and hip circumferences as compared with tape measure. This instrument is promising as a quick and simple method of body circumference analysis. PMID- 20833991 TI - Almond consumption and cardiovascular risk factors in adults with prediabetes. AB - OBJECTIVE: The authors tested the hypothesis that in adults with prediabetes, an almond-enriched American Diabetes Association (ADA) diet improves measures of insulin sensitivity and other cardiovascular risk factors compared with an ADA nut-free diet. METHODS: DESIGN: Randomized parallel-group trial. SETTING: Outpatient dietary counseling and blood analysis. SUBJECTS: Sixty-five adult participants with prediabetes. INTERVENTION: Sixteen weeks of dietary modification featuring an ADA diet containing 20% of energy from almonds (approximately 2 oz per day). MEASURES OF OUTCOME: Outcomes included fasting glucose, insulin, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, TC:HDL-C, and HbA1c, which were measured at weeks 0, 8, and 16. Body weight, body mass index (BMI), waist circumference, blood pressure, and nutrient intake were measured at weeks 0, 4, 8, 12, and 16. RESULTS: The almond-enriched intervention group exhibited greater reductions in insulin (-1.78 uU/ml vs. +1.47 uU/ml, p = 0.002), homeostasis model analysis for insulin resistance (-0.48 vs. +0.30, p = 0.007), and homeostasis model analysis for beta-cell function (-13.2 vs. +22.3, p = 0.001) compared with the nut-free control group. Clinically significant declines in LDL-C were found in the almond-enriched intervention group (-12.4 mg/dl vs. -0.4 mg/dl) as compared with the nut-free control group. No changes were observed in BMI (-0.4 vs. -0.7 kg/m(2), p = 0.191), systolic blood pressure (-4.4 mm Hg vs. -3.5 mm Hg, p = 0.773), or for the other measured cardiovascular risk factors. CONCLUSIONS: An ADA diet consisting of 20% of calories as almonds over a 16-week period is effective in improving markers of insulin sensitivity and yields clinically significant improvements in LDL-C in adults with prediabetes. PMID- 20833992 TI - Pistachio nuts reduce triglycerides and body weight by comparison to refined carbohydrate snack in obese subjects on a 12-week weight loss program. AB - OBJECTIVE: There is a widely held view that, due to high fat content, snacking on nuts will lead to weight gain, ultimately causing unhealthy changes in lipid profiles. This study is designed to study the effects of pistachio snack consumption on body weight and lipid levels in obese participants under real world conditions. METHODS: Participants were randomly assigned to consume 1 of 2 isocaloric weight reduction diets for 12 weeks, with each providing 500 cal per day less than resting metabolic rate. Each diet included an afternoon snack of either 53 g (240 cal) of salted pistachios (n = 31) or 56 g of salted pretzels (220 cal; n = 28). RESULTS: Both groups lost weight during the 12-week study (time trend, p < 0.001), but there were significant differences in the changes in body mass index between the pretzel and pistachio groups (pistachio, 30.1 +/- 0.4 to 28.8 +/- 0.4 vs. pretzel, 30.9 +/- 0.4 to 30.3 +/- 0.5). At 6 and 12 weeks, triglycerides were significantly lower in the pistachio group compared with the pretzel group (88.04 +/- 9.80 mg/dL vs. 144.56 +/- 18.86 mg/dL, p = 0.01 at 6 weeks and 88.10 +/- 6.78 mg/dL vs. 132.15 +/- 16.76 mg/dL, p = 0.02 at 12 weeks), and there was a time trend difference between the 2 groups over the 12 weeks (p < 0.01). There were no significant differences in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, insulin, or glucose between the 2 groups. CONCLUSION: Pistachios can be consumed as a portion-controlled snack for individuals restricting calories to lose weight without concern that pistachios will cause weight gain. By comparison to refined carbohydrate snacks such as pretzels, pistachios may have beneficial effects on triglycerides as well. PMID- 20833993 TI - Lovastatin interacts with natural products to influence cultured hepatocarcinoma cell (hep-g2) growth. AB - OBJECTIVE: To assess the interaction of the hydroxy-3-methylglutaryl-coezyme A reductase inhibitor lovastatin individually and in combination with 3 natural plant compounds on hepatocarcinoma cell growth. METHODS: The cytotoxic effects of lovastatin in combination with epigallocatechin gallate (EGCG), capsaicin, and curcumin were investigated in cultured hepatocarcinoma cells (Hep-G2), and the interactions were depicted using an isobolographical analysis. RESULTS: All compounds tested reduced Hep-G2 cell growth to various degrees. In terms of individual cytotoxicity LC50 values, curcumin (55.5 +/- 7.6 umol/L) was found to be the most cytotoxic and had the lowest LC50, followed by lovastatin (62.3 +/- 5.34 umol/L), EGCG (82.1 +/- 15.1 umol/L), and capsaicin (199.5 +/- 11.72 umol/L). The individual LC50 values were used in a fix-fraction isobolographical analysis to predict the effect of combining lovastatin and the individual compounds. Experimentally derived LC50 values of 5 fractions containing fixed proportions of lovastatin to each of the 3 natural compounds allowed comparison of the experimentally derived LC50 to the predicted values depicted on the isobologram. CONCLUSION: Lovastatin in combination with capsaicin was found to be synergistic at all concentrations tested, and EGCG combinations produced both synergistic and additive results. Unexpectedly, lovastatin in combination with curcumin produced an antagonistic effect on cell growth, resulting in a greater concentration required than if the compounds were used individually. PMID- 20833994 TI - Erythrocyte n-3 is inversely correlated with serious psychological distress among the Inuit: data from the Nunavik health survey. AB - OBJECTIVE: A decrease in omega-3 (n-3) long-chain polyunsaturated fatty acids (LC PUFAs) and an increase in omega-6 (n-6) linoleic acid in the diet have been suggested as contributing factors in the pathogenesis of depression. The present study examined the relationship between red blood cell (RBC) n-3 and n-6 and serious psychological distress (SPD). METHODS: The authors analyzed data on 746 Inuit adults who took part in the 2004 Nunavik Inuit Health Survey. Fatty acids were quantified in RBC membranes. Psychological distress was measured by the Kessler 6-Item Scale (K6), a brief screening instrument for Diagnostic and Statistical Manual of Mental Disorders (fourth edition) mood disorders in the past 30 days. A score >=13 on the K6 has been established as a threshold to differentiate cases of SPD from noncases. STATISTICAL ANALYSIS: The risk of SPD according to RBC n-3 and n-6 was assessed by logistic regression analysis. Weighted estimates were calculated by the SUDAAN statistical package to account for the complex survey design. RESULTS: The 30-day prevalence rate of SPD was 12.4%. In SPD cases, mean n-3 LC-PUFAs were lower (7.81% +/- 0.24% [SEM] vs. 9.24% +/- 0.12%, p < 0.0001) and mean total n-6 was higher (27.3% +/- 0.36% vs. 25.9% +/- 0.15%, p = 0.0003) than in noncases. For each 1% increase in RBC n-3 LC PUFA, the odds ratio for SPD was 0.90 (95% confidence interval: 0.83, 0.99; p = 0.0248). However, neither individual n-6 FAs nor total n-6 was significantly associated (p >= 0.05) with SPD in multivariate analysis. CONCLUSIONS: In this study, the authors observed that n-3 LC-PUFAs in RBCs were inversely associated with SPD. The study's cross-sectional design implies that one cannot ascertain any causal relationship. The findings suggest that n-3 LC-PUFA consumption from the traditional Inuit diet deserves prospective analyses. PMID- 20833995 TI - Published predictive equations overestimate measured resting metabolic rate in young, healthy females. AB - OBJECTIVE: To compare resting metabolic rate (RMR) measured by indirect calorimetry versus RMR predicted by several published formulas in a sample of healthy young women. METHODS: RMR was measured using indirect calorimetry and predicted using 6 commonly used equations (Nelson, 1992; Mifflin, 1990; Owen, 1986; Schofield(Weight), 1985; Schofield(Weight and Height), 1985; Harris Benedict, 1919) in 47 reportedly healthy young females (age = 22.8 +/- 2.9 years; body mass index = 21.8 +/- 2.1 kg/m(2)). Comparisons between measured versus predicted RMR were conducted using paired t tests, and agreement using Pearson's correlation coefficient, analysis of variance, and the method of Bland-Altman. RESULTS: All 6 equations overestimated measured RMR by 140-738 kcal/d (all p < 0.001). The proportion of subjects for whom measured versus predicted RMR differed by +/-10% ranged from 74% (Nelson) to 100% (Harris-Benedict). The adjusted coefficients of determination (R(2)) between measured and predicted RMR ranged from 0.13 to 0.19 (all p < 0.05). Bland-Altman analysis R(2) values ranged from 0.03 (p = 0.233; Harris-Benedict) to 0.72 (p = 0.000; Owen). Given its continued popularity, we modified the Harris-Benedict equation (RMR(modified Harris-Benedict) (kcal/d) = 738 / (RMR(Harris-Benedict) - 738)). Doing so reduced the mean difference between measured and predicted RMR from +738 kcal/d to -0.53 kcal/d (p = 0.984). CONCLUSION: No equation performed well, and none should be used interchangeably with measured RMR. We recommend that a new equation be validated for, and prospectively tested in, young women. In the interim, RMR should be measured in this population or predicted using the modified Harris Benedict equation that we developed. PMID- 20833996 TI - Parental history lowers body mass index risk cutoff for hypertension among urban Indian adults. AB - OBJECTIVE: Parental history of hypertension, a commonly occurring nonmodifiable genetic risk factor, was examined for its influence on cutoff for body mass index (BMI) for identifying risk of hypertension. DESIGN: Data on BMI, body fat (%), blood pressure (BP), parental history of hypertension, and lifestyle factors were collected through a cross-sectional study. SETTING: Pune City, Maharashtra, India. SUBJECTS: Urban Indian adults (330 men and 306 women, aged 30-60 years). RESULTS: Age-related increases in prevalence of obesity and of hypertension (BP >= 140/90 mmHg or antihypertensive medication) were significant (p < 0.01 for all) in both sexes. Among nonobese subjects, age-adjusted systolic (SBP) and diastolic (DBP) blood pressure levels were significantly (p < 0.01) higher for those with positive parental history than for those without parental history, in both sexes. Adjusted odds ratios showed that obesity or positive parental history when considered in isolation increased the risk of hypertension (by 3 times in men and 5 times in women), while the presence of both increased it further (by 4 times in men and 10 times in women), indicating their synergistic influence. Further, the BMI cutoff obtained from receiver operating characteristic (ROC) analysis was lower by 1 to 1.5 units for subjects with parental history than for those without parental history, across different levels of sensitivity. CONCLUSIONS: Positive parental history lowers the BMI risk cutoff for hypertension. The implication is that parental history could be an important aid in developing preventive strategy for timely and early screening of individuals at risk of hypertension in many Asian populations in similar settings. PMID- 20833997 TI - A prospective study of work stressors and the common cold. AB - BACKGROUND: Psychological stress is a risk factor for infectious diseases. Although psychological stress at work is considered an important problem for many workers, there is little evidence for the effect of work-related stress on infectious diseases. AIMS: To investigate whether work-related stress affected the occurrence of the common cold in South Korean workers in small- to medium sized manufacturing companies. METHODS: We conducted a prospective study, involving 1241 workers. At the outset, we collected information regarding sociodemographic and work characteristics. At follow-up after 6 months, we asked subjects whether they had experienced common cold symptoms during the preceding 4 months. RESULTS: Male subjects experiencing stress at the outset were more likely to report having experienced the common cold at follow-up (odds ratios: high job demand group 1.74; 95% CI: 1.28-2.36; insufficient job control 1.42; 95% CI: 1.05 1.93; inadequate social support 1.40; 95% CI: 1.03-1.91). For females, no significant association between work stress and occurrence of the common cold was detected. CONCLUSIONS: Males experiencing work stress in job demand, job control and social support reported an increased occurrence of the common cold at follow up but this association was not seen in females. PMID- 20833998 TI - Increase in nematodirosis outbreaks among Scottish sheep flocks. PMID- 20833999 TI - Use of liquid carbon dioxide for whole-house gassing of poultry and implications for the welfare of the birds. AB - The use of liquid carbon dioxide (CO(2)) was evaluated as a means of culling a flock of five-week-old pullets in situ. It took five minutes and 20 seconds for sufficient liquid CO(2) to be injected (3.24 tonnes) to achieve the target concentration of 45 per cent CO(2). Although very low ambient temperatures were recorded (below -80 degrees C) during gassing, on the basis of postmortem reports and other data it is inferred that the birds died within minutes of exposure to the gas and before experiencing the extremely low temperatures recorded in the house. PMID- 20834000 TI - Retrospective study of Achilles mechanism disruption in 45 dogs. AB - Forty-five cases of canine Achilles mechanism disruption were reviewed, mostly involving medium-sized dogs, among which dobermanns, labradors and border collies were most commonly represented. Most cases were acute in onset (66.7 per cent), and were usually closed injuries (75.6 per cent). In the majority of cases, the damage involved all tendons (26.7 per cent), all tendons except the superficial digital flexor tendon (22.2 per cent), or the gastrocnemius alone (20 per cent). Damage most commonly occurred at the tendo-osseous junction (60 per cent), with injury occurring less commonly at the musculotendinous junction (20 per cent) or in the body of the tendon (13.3 per cent). A plantigrade posture was not predictive of involvement of specific tendons, but was more likely if the injury involved the musculotendinous junction. The most common method of treatment was a primary tendon repair using polydioxanone suture in a locking-loop pattern, with placement of a temporary calcaneotibial screw and cast. The outcome was not significantly influenced by whether the injury was open or closed, the duration of the injury, the tendons involved, or the method of repair. Complications were recorded in 16 cases (35 per cent), of which 10 were minor and six major. Complications were significantly more likely if the damage involved the body of the tendon. Long-term follow-up was available for 19 dogs; the outcome of surgery was considered to be good to excellent in 18 dogs. PMID- 20834001 TI - Estimated prevalence of Mycobacterium avium subspecies paratuberculosis infection in herds of dairy goats in France. AB - A study of the prevalence of Mycobacterium avium subspecies paratuberculosis (MAP) infection in dairy goats was carried out in France, using a serological ELISA. One hundred and five herds were randomly selected in different regions, and all the goats aged six months or older (11,847 goats) were sampled. An estimation had previously been made of the accuracy of the ELISA, and the Rogan Gladen estimator was used to convert apparent prevalence values into estimates of true prevalence values. Given that sensitivity and specificity at herd level are functions of sample size, and because the sizes of the herds varied considerably, the true prevalence of infection at herd level was estimated using a weighted average depending on the herd size stratum. At the level of the individual animal, the total true prevalence was estimated by applying a weighted average in accordance with the regional distribution of the animals in the target population. At herd level, apparent prevalence and estimated true prevalence were 55.2 and 62.9 per cent, respectively; at individual animal level they were 2.9 and 6.6 per cent, respectively. In herds that were seropositive for MAP, the average within-herd apparent prevalence was 5.9 per cent and the estimated average within-herd true prevalence was 11.1 per cent. PMID- 20834002 TI - Skin injuries identified in cattle and water buffaloes at livestock markets in Bangladesh. AB - Skin injuries were assessed in 560 imported and local cattle and water buffaloes at two livestock markets in Bangladesh. The body of each animal was divided into 11 anatomical regions, and abrasions, lacerations, penetrations, ulcerations, bleeding, swelling, hyperkeratosis and scars were recorded for each region. Among the 560 animals studied, 501 were found to have at least one injury. The prevalence of skin injuries was 89 per cent, with 84 per cent of the cattle and 99 per cent of the water buffaloes having obvious skin injuries. The most common types of injury were abrasions that were found in 73 per cent of the animals, followed by scars (50 per cent), and lacerations (41 per cent). Buffaloes had more abrasions (95 per cent), lacerations (57 per cent), swelling (15 per cent) and hyperkeratosis (32 per cent) compared with cattle, whereas scars (60 per cent) were more common in cattle (P<0.001). Within the 11 different anatomical regions, all types of injuries were present but in different proportions. The buttock region had a higher proportion of abrasions (36 per cent) followed by the hip, hindlimb and back regions. Penetration, ulceration, bleeding and swelling were present at lower frequencies in all regions. Causes for these injuries included rubbing against the inside wall of vehicles used for transportation and stock-handler abuse (59 per cent and 13 per cent, respectively). Buffaloes sustained more transport injuries than cattle, and the number of injuries was higher in imported than local animals. PMID- 20834003 TI - Isolated lateral meniscus tear in a boxer. PMID- 20834007 TI - Catalysing action against rabies. PMID- 20834008 TI - Mycoplasma agalactiae in Iberian ibex (Capra pyrenaica) in Spain. PMID- 20834009 TI - Severe generalised alopecia associated with demodicosis in a roe deer. PMID- 20834010 TI - From c-Photina mouse embryonic stem cells to high-throughput screening of differentiated neural cells via an intermediate step enriched in neural precursor cells. AB - The use of engineered mouse embryonic stem (mES) cells in high-throughput screening (HTS) can offer new opportunities for studying complex targets in their native environment, increasing the probability of discovering more meaningful hits. The authors have generated and developed a mouse embryonic stem cell line called c-Photina mES stably expressing a Ca(2+)-activated photoprotein as a reporter gene. This reporter cell line retains the ability to differentiate into any cell lineage and can be used for miniaturized screening processes in 384-well microplates. The c-Photina mES cell line is particularly well suited for the study of the pharmacological modulation of target genes that induce Ca(2+) mobilization. The authors differentiated this mES reporter cell line into neuronal cells and screened the LOPAC(1280) library monitoring the agonistic or antagonistic activities of compounds. They also demonstrate the possibility to generate and freeze bulk preparations of cells at an intermediate stage of differentiation and enriched in neural precursor cells, which retain the ability to form fully functional neural networks once thawed. The proposed cell model is of high value for HTS purposes because it offers a more physiological environment to the targets of interest and the possibility of using frozen batches of neural precursor cells. PMID- 20834011 TI - Genomic scans support repetitive continental colonization events during the rapid radiation of voles (Rodentia: Microtus): the utility of AFLPs versus mitochondrial and nuclear sequence markers. AB - Single locus studies might not resolve phylogenetic relationships and the evolutionary history of taxa. The analysis of multiple markers promises higher resolution, and congruence among loci may indicate that the phylogenies represent the underlying species history. Here, we examine the utility of a genome-wide approach based on amplified fragment length polymorphisms (AFLP) and several DNA sequence markers in resolving phylogenetic signals in the rapidly radiating rodent genus Microtus which produced about 70 vole species within the last 1.2-2 myr. The current Holarctic distribution of Microtus is assumed to have resulted from three independent colonization events out of Asia to North America, Europe, and northern Asia without subsequent colonization, which would have led to deep splits between species from different continents. We investigated this hypothesis of three single colonization events by reconstructing the phylogenetic relationships among species from all three continents based on data from the first exon of the nuclear arginine vasopressin receptor 1a gene (EXON1), an adjacent noncoding region and the mitochondrial cytochrome b gene. The phylogenetic patterns obtained from these sequence markers are contrasted to genome-wide data on more than 1800 amplified fragment length polymorphisms (AFLP) analyzed for the same samples. Our results show that the single sequence markers partially resolve the phylogenetic relationships within Microtus, but with some incongruence mostly between EXON1 and the other loci. However, deeper nodes of the radiation are only weakly supported and neither the combination of the markers nor additional nuclear sequences improved the resolution significantly. AFLPs provided much stronger support for major continent-specific clades, and show also that reciprocal monophyly of American and European voles is incomplete. Our results demonstrate that Microtus voles colonized the American and European continents each repeatedly in several independent events on similar colonization routes during their radiation. More generally, this study supports the suitability of AFLPs as an alternative to sequence markers to resolve the evolutionary history of rapidly radiating taxa. PMID- 20834016 TI - Tropical chronic pancreatitis: a historical perspective. PMID- 20834017 TI - Definitions are important and not all wheeze is asthma. PMID- 20834019 TI - Disability, environmental factors and non-fatal injury. AB - BACKGROUND: People with disabilities have high rates of non-fatal injury; they are also likely to experience environmental factors as barriers to functioning and participation in society. The reasons for the higher injury rates among those with disabilities have not been explained. OBJECTIVE: To determine if problems with environmental factors influence the higher rates of injury among disabled compared with non-disabled. DESIGN: Data from a population-based, random-digit dial cross-sectional telephone survey were analysed to evaluate whether environmental factors as measured by the Craig Hospital Inventory of Environmental Factors explained higher injury rates among those with disabilities compared with those without. A total of 2511 Colorado adults (1997 with no disability, 386 with moderate disability, and 128 with severe disability) were included in the sample. All rated their experience of environmental factors and reported injuries within the previous 12 months. Logistic regression analyses were conducted to evaluate whether environmental factors could be confounding factors in the association between disability and non-fatal injury. RESULTS: Disability and environmental barriers were independently associated with higher rates of injury. Environmental factors did attenuate the increased odds of experiencing an injury among those with severe disabilities, but these people continued to have significantly higher rates of injury after adjustment for environmental factors. The natural environment, social attitudes and policies were ranked highly as problems by all injured persons. CONCLUSION: Injury prevention efforts need to focus on reducing disability-related injuries and reducing environmental barriers for all. PMID- 20834020 TI - Who is Susan P Baker and why did she win the Calderone Prize? PMID- 20834021 TI - Gold for ubiquitin in Vancouver: First Conference on Proteomics of Protein Degradation and Ubiquitin Pathways held June 6-8, 2010 in Vancouver, University of British Columbia, organized By Lan Huang, Thibault Mayor, and Peipei Ping. AB - The rise of proteomics has had tremendous influence on analysis and understanding of the role of post-translational modifications in biological processes. The covalent attachment of small proteins like ubiquitin, SUMO,(1) or other ubiquitin like proteins (Ubls) is one class of post-translational modifications where proteomics has had notable impact. Various proteomics approaches, but in particular mass spectrometry-based analyses, have influenced the field and enabled significant advances over the past few years. The first meeting dedicated to proteomics of protein degradation and ubiquitin pathways showcased these advances and allowed a glimpse at future contributions of proteomics to this field. With its many attractive drug targets, the ubiquitin and proteasome system, as well as other proteolysis pathways, could offer new therapies for various human diseases including cancer and neurodegenerative disorders. The covalent linkage of ubiquitin to other proteins is catalyzed by the E1-E2-E3 cascade of enzymatic reactions whereby the many different E3 ubiquitin ligases provide substrate specificity to the process of protein ubiquitylation (1). Ubiquitylation is best known for targeting proteins for degradation by the proteasome, but other functions for ubiquitylation independent of proteolysis are also known. Likewise, modifications with SUMO or other Ubls generally do not regulate protein degradation but instead control subcellular localization, protein interactions, or change protein conformation and activity (2). The questions addressed by proteomics approaches to ubiquitylation and Ubl modifications are plentiful. They range from very specific, e.g. determination of the modified residue in a substrate protein, to complex, such as protein dynamics in proteome-wide ubiquitin (or Ubl) modification profiles (3). In either case, the rapid technological advancements (particularly in mass spectrometry instrumentation as well as quantitation and separation technologies) have allowed impressive progress, which was evident in the First Conference on Proteomics of Protein Degradation and Ubiquitin Pathways in Vancouver (http://ppdup.org/) (Fig. 1). PMID- 20834022 TI - Payment regulations for advanced practice nurses: implications for primary care. AB - The shortage of primary care providers (PCPs) in the United States may be worsened with health reform if more individuals receive health insurance coverage. Previous research suggests that Advanced Practice Registered Nurses (APRNs) can provide as high quality care and achieve the same health outcomes as physicians. However, APRNs are usually reimbursed at lower rates than physicians by both Medicare and Medicaid. Private health insurance regulations and Any Willing Provider laws vary from state to state but in general do little to facilitate the ability of APRNs to be reimbursed for their services or to be credentialed as PCPs. To maximize the utilization of APRNs as PCPs, the payment system should be remodeled. A clear regulatory framework and payment rationale are needed along with data on the type and complexity of care provided by various practitioners to increase efficiencies and improve access to health care. PMID- 20834023 TI - Vision, grit, and collaboration: how the Wisconsin Center for Nursing achieved both sustainable funding and established itself as a state health care workforce leader. AB - In 2001, a dedicated group of nurses from across Wisconsin came together to discuss how to create a state center of expertise on key nursing workforce issues. The result was the establishment of the Wisconsin Center for Nursing (WCN) in 2005. Since that time, through its statewide Board of Directors, WCN has clarified and targeted specific state workforce needs and identified gaps that exist in addressing those needs. During its five-year existence, WCN has received funding from a variety of sources, and volunteers have spent hundreds of hours working on behalf of the organization. Finding a sustainable base of funding for WCN has been a priority in order to ensure that the organization can hire permanent staff and invest in ongoing initiatives. In 2009, WCN was involved in developing a strategy that resolved both the issue of sustainability and the need to collect and analyze data on the nursing profession. A bill was passed by the Wisconsin legislature that required RNs and LPNs to complete a comprehensive survey every two years when they renew their state licenses. In addition, the legislature raised the licensure fee for RNs and LPNs and dedicated a portion to WCN to assist in the analysis of the newly-collected nursing workforce data and to develop a state-wide plan addressing the future of the Wisconsin nursing workforce. This article will include the history of the WCN and the details of its journey toward sustainability including accomplishments and lessons learned. PMID- 20834024 TI - The role of stenting the superior vena cava syndrome in patients with malignant disease. AB - Superior vena cava (SVC) obstruction occurs in patients with intrathoracic malignancies. Clinical symptoms can be distressing but presentation is insidious. We investigated the outcome of endovascular management for patients with SVC syndrome. We retrospectively reviewed the case histories of 17 patients (9 men) from January 2003 to June 2009. All patients had malignant disease. There were 24 interventions (2 patients with 2 interventions and 2 patients with 3 interventions). All had SVC stenosis over 90%. All patients were treated with intrathoracic angioplasty and stenting. All procedures were technically successful, and all patients had insertion of 10 to 18 mm diameter stents with symptom resolution in 16 patients. There were 2 occlusions at 1 and 6 weeks and 2 patients with restenosis (3 and 7 months). Endovascular intervention is technically feasible for SVC occlusion, relieves symptoms, and is a useful palliation measure. PMID- 20834025 TI - Determinants of lower extremity amputation or revascularization procedure in patients with peripheral artery diseases: a population-based investigation. AB - We used the National Health Insurance Claim data in Taiwan to evaluate determinants for nontraumatic lower extremity amputation (LEA) or peripheral revascularization procedures (PRP) in patients with peripheral artery diseases (PAD). We identified 14 241 patients. Sex-specific odds ratios of age, diabetes mellitus (DM), hypertension (HTN), coronary artery disease (CAD), cerebral vascular accident (CVA), or using cilostazol for LEA or PRP were explored. In patients with PAD, 14.3% of male and 7.4% of female had LEA; whereas 7.1% of male and 4.6% of female had PRP. Among male patients, HTN and CAD were significant risk factors for LEA, whereas DM and using cilostazol had protective roles. Findings in female patients were similar. For PRP, elderly patients had less such procedures. The risk/protective factors were similar. In conclusion, PAD patients having DM and using cilostazol had less LEA or PRP, whereas those having HTN and CAD had more LEA or PRP. PMID- 20834026 TI - Do novel risk biomarkers reflect the severity of peripheral arterial disease? AB - The association between novel atherosclerotic risk biomarkers and severity of peripheral arterial disease (PAD) was assessed. Patients (n = 133) with PAD were recruited. Established risk biomarkers including low- and high-density cholesterol, triglycerides, and blood pressure were measured. Novel risk biomarkers including plasma C-reactive protein, von Willebrand factor (vWF), interleukin 6, red cell folate (RCF), vitamin B12, total homocysteine (tHcy), and Hcy genotypes were also determined. The severity of PAD was evaluated, using ankle-brachial pressure index (ABPI), brachial-knee, and brachial-ankle pulse wave velocity (bk- and ba-PWV). Plasma tHcy and systolic blood pressure had a positive independent correlation with bk-PWV (beta = +0.56, P = .02 and beta = +0.38, P < .001, respectively). Red cell folate had an independent inverse correlation with bk-PWV (beta = -0.01, P = .01). Systolic blood pressure showed an independent positive correlation with ba-PWV only after adjustment for other risk biomarkers (beta = +0.1, P = .04). Novel markers, plasma tHcy, and RCF levels correlated with the severity of PAD. PMID- 20834027 TI - Fibrin d-dimer concentration, deep vein thrombosis symptom duration, and venous thrombus volume. AB - INTRODUCTION: To determine the relationship between fibrin D-dimer levels, symptom duration, and thrombus volume, consecutive patients with incident deep venous thrombosis (DVT) were evaluated. METHODS: In a cross-sectional study design, patient symptom onset was determined by careful patient questioning. Venous thrombosis was confirmed by compression duplex ultrasonography. Thrombus volume was estimated based on patient's femur length using a forensic anthropology method. Fibrin D-dimer was measured by latex immunoassay. RESULTS: 72 consecutive patients with confirmed leg DVT agreed to participate. The median symptom duration at the time of diagnosis was 10 days. The median D-dimer concentration was 1050 ng/dL. The median thrombus volume was 12.92 cm(3). D-Dimer levels correlated with estimated thrombus volume (P < .0006 CI 0.12-0.41; R(2) (adjusted) = .15) but not symptom duration, patient's age, or gender. CONCLUSIONS: Despite varying symptom duration prior to diagnosis, fibrin D-dimer remains a sensitive measure of venous thrombosis and correlates with thrombus volume. PMID- 20834028 TI - C-reactive protein, interleukin 6, and N-terminal pro-brain natriuretic peptide following cardioversion of atrial fibrillation: is there a role of biomarkers in arrhythmia recurrence? AB - AIMS: We investigated the role of high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), and N-terminal pro-brain natriuretic peptide (NTpro-BNP), in atrial fibrillation (AF) recurrence rate. METHODS: A total of 80 patients with first AF episode were studied prospectively. Echocardiography (ECG), Holter ECG, and measurements of hsCRP, IL-6, and NTproBNP were performed immediately post conversion and at 1 month. RESULTS: Recurrence was positively related to left atrial volume (P < .001), with no difference in NTpro-BNP, hsCRP, and IL-6. Decreased NTpro-BNP was observed in all at 1 month (P < .001, F = 63.4) and was positively related to left atrial volume (P < .01). In the lone AF subgroup, NTpro-BNP was lower and dropped significantly at 1 month (interaction F = 6.53, P < .01). CONCLUSIONS: Atrial volume was related to AF recurrence, whereas hsCRP, IL-6, and NTpro-BNP were not reliable for AF relapse. Relation of NTpro-BNP to left atrial volume could indicate a role in the atrial remodeling process. PMID- 20834029 TI - Monitoring of the anticoagulants argatroban and lepirudin: a comparison of laboratory methods. AB - Monitoring of direct inhibitors of thrombin (DTI) is critical for their safe and effective use as anticoagulants. We examined samples containing several concentrations of argatroban or lepirudin in reconstituted standard human plasma and plasma from medical outpatients and intensive care patients. Prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were determined using automated analyzers. Ecarin clotting time (ECT) was measured using a 10 IU/mL dilution of ecarin in 0.05 mol/L CaCl(2). Calibration curves were approximately linear for TT and ECT in samples containing argatroban and lepirudin, respectively. Activated partial thromboplastin curves reached a plateau at DTI concentrations >=2 ug/mL, suggesting that the aPTT may not reliably detect overdosing. Prothrombin time increased exponentially. A broad range of clotting times was seen in patient samples with all tests suggesting that individual morbidity and therapies may strongly influence test results and may lead to underestimation of DTI doses. PMID- 20834030 TI - Characteristics of prison hospice programs in the United States. AB - Hospice programs have emerged over the last 40 years as both an effective and humane practice for responding to terminal illnesses in the free society. More recently, hospice has diffused throughout state, federal, and municipal correctional systems. Thus, we sought via a mailed survey of the 69 known prison hospice programs in the United States (response rate of 62%) to determine how prison hospice programs were similar or dissimilar to hospices in the free society. Our findings suggest that prison hospices have a more stringent screening process for volunteers and require more volunteer training prior to interacting with a hospice patient. Prison hospice programs tend to follow both the National Prison Hospice Association and the GRACE Project guidelines. PMID- 20834031 TI - Self-efficacy, depression, and physical distress in males and females with cancer. AB - AIMS: to examine the relationship between self-efficacy with depression and physical distressing symptoms in males and females with cancer. METHODS: a total of 41 males and 49 females with cancer completed the General Perceived Self Efficacy Scale (GSE), depression scale, from the Hospital Anxiety and Depression Scale (HAD-D), and the MD Anderson Symptom Inventory (MDASI). RESULTS: correlations were found between depression and self-efficacy in males (r = -.501, P = .001) and females (r = -.588, P < .0005). The multivariate regression analysis revealed that education and depression could influence self-efficacy in male population. Urogenital versus breast cancer as well as depression seemed to influence females' self-efficacy. CONCLUSIONS: patients who had higher self efficacy had lower depressive symptoms. Men with depressive symptoms and women with breast cancer and depression are more likely to have low self-efficacy than patients with other cancer types. PMID- 20834032 TI - Qualitative analysis of consults by a pediatric advanced care team during its first year of service. AB - Phenomenologic analysis of initial consults provided during the first year of a new Pediatric Advanced Care Team (PACT) program provides essential understanding of the experience and inform program direction and future clinical research. Parents bring to the consult a desire to remain experts in their children's lives yet experience vulnerability as they seek assistance in making critical decisions often under conditions of disquieting uncertainty. Dynamic communication efforts involving the referring providers, PACT team members, and family are a key influence in facilitating consults' stated goals and in establishing the integrated palliative paradigm in a tertiary care environment. Validation was provided for a new research infrastructure that will function concurrently with the PACT clinical program in this rapidly evolving field. PMID- 20834033 TI - Factors associated with favorable attitudes toward end-of-life planning. AB - Planning for end-of-life (EOL) care can result in better patient outcomes and lowered health care costs. We hypothesized that knowledge and experiences with EOL care would influence patients' EOL planning (i.e., health care decisions, hospice use). Using an observational, cross-sectional design, we recruited a community sample of 331 South Floridians aged 18 to 84 (M = 44 years, SD = 14.95) to complete a questionnaire examining knowledge and opinions on EOL issues. Regression analyses showed that prior knowledge of living wills and hospice services were associated with more favorable attitudes toward hospice care, preference for limited medical interventions at EOL, and more comfort in communicating about death and dying. Patient education on EOL care may increase hospice use, enhance EOL planning, and improve patient outcomes. PMID- 20834034 TI - The positive attitudes and perceptions of care managers about advance directives. AB - In a previous intervention, we found that reminders from care managers failed to increase the number of their homebound older adult clients with advance directives. Thus, in the current study, we looked at the perceptions and attitudes of care managers about the need to discuss advance directives with their clients. Ninety-five care managers serving community-based nursing home eligible older adults completed an 18-question survey, which found that care managers overwhelmingly believe it is important to address advance directives. Only 3.2% reported that discussing advance directives is time consuming. No attitudinal barriers were identified. Given their positive attitudes about advance directives, care managers need educational interventions that will provide the knowledge and skills to interact effectively with clients who are resistant to addressing end-of-life issues. PMID- 20834035 TI - Feasibility of a webinar for coaching patients with chronic obstructive pulmonary disease on end-of-life communication. AB - RATIONALE: Previous research has shown that patients with chronic obstructive pulmonary disease (COPD) desire conversations about end-of-life wishes. However, most clinicians do not initiate these discussions. We explored whether educating patients via Web conferencing (webinar) would equip them with knowledge and skills to engage in conversations about end-of-life care. RESULTS: Prewebinar, 6 of the 7 patients had completed advanced care planning forms but only half had shared these with their clinicians. Most patients felt confident about discussing end-of-life preferences. At 3 months, all participants had taken further action on end-of-life planning. Five felt the webinar was an acceptable option if unable to participate in person. All patients voiced that adding a video stream would have promoted interaction in the context of these sensitive conversations. CONCLUSIONS: This pilot project demonstrated that a webinar to educate patients on end-of-life communication was acceptable for the majority of patients. Improvements in audio and video bandwidth may facilitate more interaction among virtual participants. This may be particularly useful for patient education on sensitive topics. PMID- 20834036 TI - The stresses of hospice volunteer work. AB - The purpose of this phenomenological study was to explore the interpretation of stress, the appraisal of the stressors, as well as the top stressors experienced by hospice volunteers. Individual semistructured interviews were conducted with 15 hospice volunteers. The interviews were digitally recorded, transcribed, and analyzed, using qualitative research methods. Although the results indicated that the hospice volunteers did not perceive their work as stressful, 2 main themes regarding challenging experiences did emerge. Hospice-related issues and personal issues were of concern to the volunteers. In addition, the timing of the stressors revealed that the most stress was felt at the beginning of their volunteer services, which has implications for hospice volunteer coordinators as they support their volunteers in the field. PMID- 20834037 TI - Reptile: representative tiling for short read error correction. AB - MOTIVATION: Error correction is critical to the success of next-generation sequencing applications, such as resequencing and de novo genome sequencing. It is especially important for high-throughput short-read sequencing, where reads are much shorter and more abundant, and errors more frequent than in traditional Sanger sequencing. Processing massive numbers of short reads with existing error correction methods is both compute and memory intensive, yet the results are far from satisfactory when applied to real datasets. RESULTS: We present a novel approach, termed Reptile, for error correction in short-read data from next generation sequencing. Reptile works with the spectrum of k-mers from the input reads, and corrects errors by simultaneously examining: (i) Hamming distance based correction possibilities for potentially erroneous k-mers; and (ii) neighboring k-mers from the same read for correct contextual information. By not needing to store input data, Reptile has the favorable property that it can handle data that does not fit in main memory. In addition to sequence data, Reptile can make use of available quality score information. Our experiments show that Reptile outperforms previous methods in the percentage of errors removed from the data and the accuracy in true base assignment. In addition, a significant reduction in run time and memory usage have been achieved compared with previous methods, making it more practical for short-read error correction when sampling larger genomes. AVAILABILITY: Reptile is implemented in C++ and is available through the link: http://aluru-sun.ece.iastate.edu/doku.php?id=software CONTACT: aluru@iastate.edu. PMID- 20834038 TI - Semi-supervised recursively partitioned mixture models for identifying cancer subtypes. AB - MOTIVATION: Patients with identical cancer diagnoses often progress differently. The disparity we see in disease progression and treatment response can be attributed to the idea that two histologically similar cancers may be completely different diseases on the molecular level. Methods for identifying cancer subtypes associated with patient survival have the capacity to be powerful instruments for understanding the biochemical processes that underlie disease progression as well as providing an initial step toward more personalized therapy for cancer patients. We propose a method called semi-supervised recursively partitioned mixture models (SS-RPMM) that utilizes array-based genetic and patient-level clinical data for finding cancer subtypes that are associated with patient survival. RESULTS: In the proposed SS-RPMM, cancer subtypes are identified using a selected subset of genes that are associated with survival time. Since survival information is used in the gene selection step, this method is semi-supervised. Unlike other semi-supervised clustering classification methods, SS-RPMM does not require specification of the number of cancer subtypes, which is often unknown. In a simulation study, our proposed method compared favorably with other competing semi-supervised methods, including: semi supervised clustering and supervised principal components analysis. Furthermore, an analysis of mesothelioma cancer data using SS-RPMM, revealed at least two distinct methylation profiles that are informative for survival. AVAILABILITY: The analyses implemented in this article were carried out using R (http://www.r.project.org/). CONTACT: devin_koestler@brown.edu; e_andres_houseman@brown.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20834039 TI - Oral laquinimod in patients with relapsing-remitting multiple sclerosis: 36-week double-blind active extension of the multi-centre, randomized, double-blind, parallel-group placebo-controlled study. AB - BACKGROUND: Laquinimod, an oral novel immunomodulator, was shown to reduce MRI measured disease activity in relapsing-remitting MS (RRMS) patients. OBJECTIVES: To determine whether the safety and efficacy profile of laquinimod, as shown in a placebo-controlled 36-week trial (LAQ/5062), is sustained and reproducible. METHODS: Two hundred and fifty seven patients entered the extension phase in which MRI was performed at the beginning and at the end of the active extension phase. Clinical assessments were performed at weeks 4, 12 and every 12 weeks thereafter. RESULTS: Two hundred and thirty nine (93%) patients completed the extension phase and 222 (86.3%) had a final scan available. Gadolinium-enhanced (GdE) T1 lesions were significantly reduced for patients switching from placebo to 0.3/ 0.6 mg doses (52%, p = 0.0006). In patients initially randomized to 0.6 mg in LAQ/5062 the reduction of MRI activity observed in the placebo-controlled phase was maintained in the extension. The proportion of GdE-free patients for those who switched from placebo increased from a baseline of 31% to 47% at the end of the extension phase (p = 0.01). The most prominent safety signal was elevations of liver enzymes, reversible in all cases. CONCLUSIONS: The good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day are confirmed in this extension study. PMID- 20834040 TI - Preservation of motor skill learning in patients with multiple sclerosis. AB - BACKGROUND: Several studies have demonstrated benefits of rehabilitation in multiple sclerosis (MS). However, the neuroscientific foundations for rehabilitation in MS are poorly established. OBJECTIVES: As rehabilitation and motor learning share similar mechanisms of brain plasticity, we test whether the dynamics of skill learning are preserved in MS patients relative to controls. METHODS: MS patients and controls learned a repeating sequence of hand movements and were assessed for short-term learning. Long-term learning was tested in another cohort of patients and controls practising the same sequence daily for two weeks. RESULTS: Despite differences in baseline performance, the dynamics and extent of improvements were comparable between MS and control groups for both the short- and long-term learning. Even the most severely damaged patients were capable of performance improvements of similar magnitude to that seen in controls. After one week of training patients performed as well as the controls at baseline. CONCLUSIONS: Mechanisms for short- and long-term plasticity may compensate for impaired functional connectivity in MS to mediate behavioural improvements. Future studies are needed to define the neurobiological substrates of this plasticity and the extent to which mechanisms of plasticity in patients may be distinct from those used for motor learning in controls. PMID- 20834041 TI - The prevalence of multiple sclerosis in central Italy. AB - BACKGROUND: The prevalence of multiple sclerosis varies considerably throughout the world. OBJECTIVE: To better define the prevalence of MS in central Italy. METHODS: This is a population-based study conducted in the province of Frosinone, which is situated in the Lazio region, central Italy. The selected prevalence day was 1 January 2007. A total of 467 patients, with a definite diagnosis of multiple sclerosis, were considered for crude, age- and sex-specific prevalence estimation. RESULTS: The overall crude prevalence rate was 95.0 cases per 100,000 (95% confidence interval (CI) 86.6-104.0). A significantly higher prevalence rate was recorded in females (134.9, 95% CI 121.0-150.1) than in males (53.3, 95% CI 44.4-63.3) (p = 0.001). Age-specific prevalence peaked in the 25-34 year, 35-44 year and 45-54 year age groups; moreover, it was found to increase up to the 35 44 year age group in males and the 45-54 year age group in females, decreasing thereafter. The female to male ratio was 2.6. CONCLUSIONS: The results confirm that MS occurs more frequently in central Italy than might be expected on the basis of the geographic-related distribution model, thus supporting the view that this is a high-risk area for the disease. PMID- 20834043 TI - Long-term effects on cortical excitability and motor recovery induced by repeated muscle vibration in chronic stroke patients. AB - BACKGROUND: Muscle vibration modifies corticomotor excitability in healthy subjects and reduces muscle tonus in stroke patients. OBJECTIVE: This study examined whether repeated muscle vibration (rMV) applied over the flexor carpi radialis (FCR) and biceps brachii (BB) can induce long-lasting changes, using transcranial magnetic stimulation (TMS), in patients with chronic stroke. METHODS: Thirty hemiparetic patients who offered at least minimal wrist and elbow isometric voluntary contractions were randomly assigned to either an experimental group, which received rMV in addition to physiotherapy (rMV + PT), or a control group that underwent PT alone. The following parameters of the FCR, BB, and extensor digitorum communis (EDC) were measured through TMS before, and 1 hour, 1 week, and 2 weeks after the end of intervention: resting motor threshold (RMT), map area, map volume, short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Muscle tonus and motor function were assessed on the same day as TMS. RESULTS: Pre-post analysis revealed a reduction in RMT and an increase in motor map areas occurred in the vibrated muscles only in the rMV + PT group, with an increase in map volumes of all muscles. Moreover, SICI increased in the flexors and decreased in the extensor. These neurophysiological changes lasted for at least 2 weeks after the end of rMV + PT and paralleled the reduction in spasticity and increase in motor function. A significant correlation was found between the degree of spasticity and the amount of intracortical inhibition. CONCLUSION: rMV with PT may be used as a nonpharmacological intervention in the neurorehabilitation of mild to moderate hemiparesis. PMID- 20834042 TI - Brain fatty acid-binding protein and omega-3/omega-6 fatty acids: mechanistic insight into malignant glioma cell migration. AB - Malignant gliomas (MG) are highly infiltrative tumors that consistently recur despite aggressive treatment. Brain fatty acid-binding protein (FABP7), which binds docosahexaenoic acid (DHA) and arachidonic acid (AA), localizes to sites of tumor infiltration and is associated with a poor prognosis in MG. Manipulation of FABP7 expression in MG cell lines affects cell migration, suggesting a role for FABP7 in tumor infiltration and recurrence. Here, we show that DHA inhibits and AA stimulates migration in an FABP7-dependent manner in U87 MG cells. We demonstrate that DHA binds to and sequesters FABP7 to the nucleus, resulting in decreased cell migration. This anti-migratory effect is partially dependent on peroxisome proliferator-activated receptor gamma, a DHA-activated transcription factor. Conversely, AA-bound FABP7 stimulates cell migration by activating cyclooxygenase-2 and reducing peroxisome proliferator-activated receptor gamma levels. Our data provide mechanistic insight as to why FABP7 is associated with a poor prognosis in MG and suggest that relative levels of DHA and AA in the tumor environment can make a profound impact on tumor growth properties. We propose that FABP7 and its fatty acid ligands may be key therapeutic targets for controlling the dissemination of MG cells within the brain. PMID- 20834044 TI - Crossover trial of subacute computerized aphasia therapy for anomia with the addition of either levodopa or placebo. AB - BACKGROUND: The effect of levodopa on recovery from aphasia is controversial. OBJECTIVE: To determine whether levodopa enhances the effect of intensive computer-assisted therapy (CAT) of anomia in the postacute stage of aphasia. METHODS: Double-blind multiple case study with intrasubject crossover design comparing the effect of levodopa (100 mg) versus placebo, each given for 2 weeks. SUBJECTS: Twelve patients with onset of aphasia from 2 to 9 weeks after stroke or traumatic brain injury were compared on naming performance on items trained and not trained with CAT. Subjects were randomized to either levodopa or placebo first, separated by a 1-week washout, and then switched to the other drug intervention for the second 2-week CAT intervention. The subjects also received routine aphasia therapies during these periods. RESULTS: All patients improved their naming performance for items trained by CAT in both periods (P = .001). No significant difference was found between the placebo and levodopa phases. CONCLUSION: Administration of levodopa for 2 weeks during the postacute stage of aphasia did not augment the positive effects of subacute intensive language treatment with CAT for a spoken naming task. PMID- 20834045 TI - Guided motor imagery in healthy adults and stroke: does strategy matter? AB - BACKGROUND: Motor imagery (MI) enhances physical performance and skill acquisition in healthy and neurorehabilitation populations, yet little is known about the use of strategies to guide MI. OBJECTIVES: To examine the relative effectiveness of visual, auditory, and combined (visual + auditory) cueing of an imagined finger abduction task on corticomotor excitability. METHODS: A total of 15 young (20-35 years) and 15 older people (over 55 years) and 10 people with chronic stroke, who could make voluntary movements of selected muscles, participated. Motor evoked potentials (MEPs, primary outcome) were measured following transcranial magnetic stimulation applied while participants imagined abducting their index finger under guidance of cueing strategies. Amplitudes of the MEPs from the first dorsal interosseous (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles were compared with rest, contrasted with MEPs elicited during active task performance, and expressed relative to rest to reflect facilitation. RESULTS: Cued MI enhanced MEPs in all groups, preferentially to the target FDI muscle. In stroke, APB was also facilitated. ADM was least affected by cueing. Analyses of simple effects of condition on FDI MEPs in each group revealed that visual cueing was most effective in young people, whereas auditory cueing was most effective in healthy older people and when directed at the nonparetic side in stroke ( P < .04). On the paretic side, strategies were equally effective. In all cases, MEPs were largest during physical performance. CONCLUSIONS: Cued MI augments corticomotor excitability associated with healthy and paretic muscles related to the imagined task. Age should be considered when selecting a cueing strategy for maximum effectiveness. PMID- 20834046 TI - An enriched environment improves sensorimotor function post-ischemic stroke. AB - OBJECTIVE: An enriched environment (EE) refers to conditions that facilitate or enhance sensory, cognitive, motor, and social stimulation relative to standard (laboratory) conditions. Despite numerous published studies investigating this concept in animal stroke models, there is still debate around its efficacy. The authors performed a systematic review and meta-analysis to determine the efficacy of an EE on neurobehavioral scores, learning, infarct size, and mortality in animal models of ischemic stroke. METHODS: Systematic review of controlled studies of the use of an EE in experimental stroke was conducted. Data extracted were analyzed using weighted mean difference meta-analysis. For pooled tests of neurobehavioral scores, a random effects standardized method was used. RESULTS: Animals recovering in an EE poststroke had mean neurobehavioral scores 0.9 standard deviations (95% confidence interval [CI] = 0.5-1.3; P < .001) above the mean scores of animals recovering in standard conditions and showed a trend toward improvement in learning (25.1% improvement; 95% CI = 3.7-46.6; P = .02). There was no significant increase in death. Animals exposed to an EE had 8.0% larger infarcts than control animals (95% CI = 1.8-14.1; P = .015). CONCLUSIONS: The results indicate significant improvements in sensorimotor function with EE poststroke but suggest a small increase in infarct volume. Clarification of the underlying mechanisms requires further study but should not overshadow the observed functional improvements and their application to clinical trials during stroke rehabilitation. PMID- 20834047 TI - Bantu-Khoisan interactions at the edge of the Bantu expansions: insights from southern Angola. AB - For a human population geneticist, an interest in Africa hardly requires an explanation. With the highest time depth of human history and over 2000 linguistic groups spreading across highly diverse geographical settings, Africa harbors a tremendous variety of genetic patterns that remain to be explained. My own interest in African populations started with Sao Tome, a tiny plantation island located at the heart of the Gulf of Guinea that was peopled by slaves imported from the adjacent areas of the mainland. Presently, I am still interested in insular populations related to the slave trade, like the Cape Verde Archipelago, facing Senegal. Moreover, I became involved in the study of genetic diversity of continental areas like Angola and Mozambique, lying at the southwestern and southeastern edges of the Bantu expansions, respectively. The area of Angola, in particular, is especially interesting for understanding the push of Bantu-speaking peoples out of the rain forest into the arid steppes of southwestern Africa. In southern Angola, the cultural and geographical proximity between Bantu and Khoisan cattle herders poses intriguing questions about the development of the relatively isolated Southwest African pastoral scene and the nature of the interactions between the vanguard of the Bantu expansions and the non-Bantu peoples from the desert. PMID- 20834048 TI - The very first time for JASs. PMID- 20834049 TI - Cognitive inferences in fossil apes (Primates, Hominoidea): does encephalization reflect intelligence? AB - Paleobiological inferences on general cognitive abilities (intelligence) in fossil hominoids strongly rely on relative brain size or encephalization, computed by means of allometric residuals, quotients or constants. Th is has been criticized on the basis that it presumably fails to reflect the higher intelligence of great apes, and absolute brain size has been favored instead. Many problems of encephalization metrics stem from the decrease of allometric slopes towards lower taxonomic level, thus making it difficult to determine at what level encephalization metrics have biological meaning. Here, the hypothesis that encephalization can be used as a good neuroanatomical proxy for intelligence is tested at two different taxonomic levels. A significant correlation is found between intelligence and encephalization only at a lower taxonomic level, i.e. on the basis of a low allometric slope, irrespective of whether species data or independent contrasts are employed. This indicates that higher-level slopes, resulting from encephalization grade shifts between subgroups (including hylobatids vs. great apes), do not reflect functional equivalence, whereas lower level metrics can be employed as a paleobiological proxy for intelligence. Thus, in accordance to intelligence rankings, lower-level metrics indicate that great apes are more encephalized than both monkeys and hylobatids. Regarding fossil taxa, encephalization increased during hominin evolution (particularly in Homo), but during the Miocene a significant shift towards higher encephalization (and inferred enhanced cognitive abilities) must have been also involved in the emergence of the great-ape-and-human clade (Hominidae). This is confirmed by the modern great-ape-like degree of encephalization displayed by the fossil great ape Hispanopithecus, which contrasts with the rather hylobatid-like degree of the stem hominoid Proconsul. The similarly low encephalization of Oreopithecus might result from secondary reduction under insularity conditions, but the australopith like degree of encephalization of Homo floresiensis seems incompatible with the cognitive abilities inferred from the stone tools attributed to this taxon. PMID- 20834050 TI - Metaplasticity and the human becoming: principles of neuroarchaeology. AB - Important recent developments in brain and cognitive sciences offer new avenues for productive cooperation between archaeology and neuroscience. Archaeologists can now learn more about the biological and neural substrates of the human cognitive abilities and use that knowledge to better define and identify their archaeologically visible traces and possible signatures. In addition, important questions and prevailing assumptions about the emergence of modern human cognition can be critically reviewed in the light of recent neuroscientific findings. Thus there is great prospect in the archaeology of mind for developing a systematic cross-disciplinary endeavor to map the common ground between archaeology and neuroscience, frame the new questions, and bridge the diverge analytical levels and scales of time. The term "neuroarchaeology" is introduced to articulate this rapidly developing field of cross-disciplinary research, focusing on questions and problems that emerge at the interface between brain and culture over the long- term developmental trajectories of human becoming. Neuroarchaeology aims at constructing an analytical bridge between brain and culture by putting material culture, embodiment, time and long term change at center stage in the study of mind. This paper presents a critical overview of this new research field and introduces the notion of "metaplasticity" to describe the enactive constitutive intertwining between neural and cultural plasticity. In this context, I summarize the main objectives, cross-disciplinary links, and theoretical grounding of this new approach to the archaeology of mind and outline some of the foundational issues and methodological challenges such a project might face. PMID- 20834051 TI - Genetics and southern African prehistory: an archaeological view. AB - Southern African populations speaking languages that are often - but inaccurately - grouped together under the label 'Khoisan' are an important focus of molecular genetic research, not least in tracking the early stages of human genetic diversification. This paper reviews these studies from an archaeological standpoint, concentrating on modern human origins, the introduction of pastoralism to southern Africa and admixture between the region's indigenous foragers and incoming Bantu-speaking farmers. To minimise confusion and facilitate correlation with anthropological, linguistic and archaeological data it emphasises the need to use ethnolinguistic labels accurately and with due regard for the particular histories of individual groups. It also stresses the geographically and culturally biased nature of the genetic studies undertaken to date, which employ data from only a few 'Khoisan' groups. Specific topics for which the combined deployment of genetic and archaeological methods would be particularly useful include the early history of Ju-Hoan- and Tuu-speaking hunter gatherers, the expansion of Khoe-speaking populations, the chronology of genetic exchange between hunter-gatherers and farmers, and the origins of the Sotho/Tswana- and Nguni-speaking populations that dominate much of southern Africa today. PMID- 20834052 TI - Molecular anthropology in the genomic era. AB - Molecular Anthropology is a relatively young field of research. In fact, less than 50 years have passed since the symposium "Classification and Human Evolution" (1962, Burg Wartenstein, Austria), where the term was formally introduced by Emil Zuckerkandl. In this time, Molecular Anthropology has developed both methodologically and theoretically and extended its applications, so covering key aspects of human evolution such as the reconstruction of the history of human populations and peopling processes, the characterization of DNA in extinct humans and the role of adaptive processes in shaping the genetic diversity of our species. In the current scientific panorama, molecular anthropologists have to face a double challenge. As members of the anthropological community, we are strongly committed to the integration of biological findings and other lines of evidence (e.g. linguistic and archaeological), while keeping in line with methodological innovations which are moving the approach from the genetic to the genomic level. In this framework, the meeting "DNA Polymorphisms in Human Populations: Molecular Anthropology in the Genomic Era" (Rome, December 3-5, 2009) offered an opportunity for discussion among scholars from different disciplines, while paying attention to the impact of recent methodological innovations. Here we present an overview of the meeting and discuss perspectives and prospects of Molecular Anthropology in the genomic era. PMID- 20834053 TI - Right handed Neandertals: Vindija and beyond. AB - Seven Vindija (Croatia) Neandertal teeth, dated about 32,000 years ago, were analyzed to determine patterning of scratches on the anterior teeth. Oblique scratches exclusively on the labial faces of incisors and canines represent a distinctive pattern, characteristic of hand directed, non-masticatory activities. At Vindija and elsewhere these scratches reveal activities, which were performed primarily with the right hand. The late Neandertals from Vindija, combined with other studies, show that European Neandertals were predominately right-handed with a ratio 15:2 (88.2%), a frequency similar to living people. Studies of teeth from Atapuerca extend this modern ratio to more than 500,000 years ago and increase the frequency of right- handers in the European fossil record to almost 94%. Species-wide, preferential right-handedness is a defining feature of modern Homo sapiens, tied to brain laterality and language with the 9:1 ratio of right- to left- handers - a reflection of the link between left hemispheric dominance and language. Up-to-date behavioral and anatomical studies of Neandertal fossils and the recent discovery of their possession of the FOXP2 gene indicate Neandertals (and, very likely, their European ancestors) had linguistic capacities similar to living humans. PMID- 20834054 TI - The association between dental mineralization and mandibular form: a study combining additive conjoint measurement and geometric morphometrics. AB - Studies have suggested that dental development substantially influences the variation of mandibular morphology and growth in primates. As a contribution to the methodology of such studies, we introduce a novel approach to quantifying the covariation between teeth and mandible. This was done showing fluctuations in the magnitude of this covariation within a sample of modern human mandibles at different postnatal ages. Dense CT- derived mandibular surface meshes of 73 females and 71 males, ranging in age from birth to adulthood, were processed by methods of geometric morphometrics. Each specimen's deciduous and permanent teeth were rated for mineralization stage. Form-space principal component analysis of the morphometric data was used to produce a single metric variable that best explains mandibular-form variation. This variable was then used to quantify the developing teeth, all together, through the use of the additive conjoint measurement method. This new metric variable corresponds to the dental prediction of the mandibular-form variation. Finally, we examine the covariation of the two over the full range of mineralization stages. We found a strikingly tight association between mandibular form and dental maturation up through the full emergence of the deciduous dentition (about age 2 years), followed by an equally striking decline in that association in later developmental stages, particularly for girls. The onset of the decline of the teeth-mandible relationship coincides with the onset time of the adult-like pattern of mastication and speech. The increasingly functional diversity may lead to more independence between dental development and mandibular growth than during the first two years. PMID- 20834055 TI - Not just a pretty song: an overview of the vocal repertoire of Indri indri. AB - The vocal behaviour of wild indris inhabiting the area near Andasibe was studied by means of all occurrence sampling. We provide a quantitative overview of the vocal repertoire of Indri indri, describing qualitative contextual information and quantitative acoustic analysis for all the utterances we recorded from adult individuals. Other than the song, the repertoire of Indri indri comprises 8 vocal types uttered by the adults. Future studies are necessary to explore whether vocalisations uttered in different contexts have different functions and how these functions relate to acoustic structure. PMID- 20834056 TI - New radiocarbon dates and isotope analysis of Neolithic human and animal bone from the Fontbregoua Cave (Salernes, Var, France). AB - This article presents the results of stable carbon and nitrogen isotope analysis carried out on 12 human and 13 animal bones from the Neolithic cave of Fonbregoua located in southern France. The stable isotope data shows that the humans had diets in which the protein sources were mainly from terrestrial animals. Six new radiocarbon dates on human bone indicate that the deposition of human remains at the site occurred during the Cardial phase (ca. 5450-5100 BCE cal.) as well as through to the transition to the middle Neolithic (ca. 5100-4800 BCE cal.). The isotopic human dietary patterns at Fontbregoua are similar to other Neolithic sites in the South-east of France and in Liguria (Italy), indicating similar dietary adaptations in this area during this period. Radiocarbon dates on humans from the site indicate that human burial practices at this site occurred over a long time period. PMID- 20834057 TI - Two case examples of pelvic fractures in medieval populations from central Europe. AB - Pelvic fractures are considered to be uncommon and difficult to treat, even in the modern medical literature. Serious and eventually life-threatening associated injuries may occur, requiring emergency abdominal, vascular or neurologic surgery. Pelvic fractures can also be managed non-operatively; however, a considerable dispute exists on the suitable management strategy. The treatment and healing of such injuries in the bioarchaeological record, is therefore of great interest for anthropological and medico-historical studies. Fractures of the pelvis are rarely reported in the anthropological literature either due to poor preservation of the innominate bone or lack of adequate examination. Here we present two cases of pelvic fractures observed on two adult male individuals from two European medieval sites. They differ in severity and in the pattern of healing. They are both adequately healed and probably had no acute life threatening consequences, which gives us some insight into the medical knowledge and means of management of past populations. PMID- 20834058 TI - Health and disease in a Roman walled city: an example of Colonia Iulia Iader. AB - The paper presents the results of the bioarchaeological study of a Roman period (3rd-5th century) skeletal sample from Zadar, Croatia with the focus on subadult stress indicators (cribra orbitalia and dental enamel hypoplasia) and indicators of non-specific infectious diseases (periostitis). The total frequency of cribra orbitalia, an indicator of iron deficiency anaemia, in Zadar is 20.1%. Half of the subadult skeletons from Zadar exhibit signs of cribra orbitalia, of which two are in active form. Adults not affected by cribra orbitalia lived on average 4.5 years longer than individuals affected by this pathological change. Total frequency of dental enamel hypoplasia in adults is 61.1% with somewhat higher frequency in females. The frequency of periostitis in subadults (66.7%) is significantly higher than in adults (30.4%). A positive correlation was established between cribra orbitalia and periostitis in males. The presented data suggest relatively low quality of life in Roman Zadar, most probably due to the overcrowding inside the walled city which led to deterioration of sanitary conditions and the occurrence of infectious diseases. PMID- 20834059 TI - The history and geography of the Y chromosome SNPs in Europe: an update. PMID- 20834060 TI - Key issues in the study of primate acoustic signals, an update. PMID- 20834061 TI - Measuring human energy expenditure and metabolic function: basic principles and methods. PMID- 20834062 TI - Interdisciplinary views on Molecular Anthropology in the Genomic Era. PMID- 20834067 TI - Joint influence of small-effect genetic variants on human longevity. AB - The results of genome-wide association studies of complex traits, such as life span or age at onset of chronic disease, suggest that such traits are typically affected by a large number of small-effect alleles. Individually such alleles have little predictive values, therefore they were usually excluded from further analyses. The results of our study strongly suggest that the alleles with small individual effects on longevity may jointly influence life span so that the resulting influence can be both substantial and significant. We show that this joint influence can be described by a relatively simple "genetic dose - phenotypic response" relationship. PMID- 20834068 TI - Novel roles for JNK1 in metabolism. AB - Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure. PMID- 20834069 TI - MIP/MTMR14 and muscle aging. PMID- 20834070 TI - Science and conscience. AB - Many historical facts, describing exploitation and discrimination of research subjects which have been justified by the importance of research aims, are known. Today the protection of the rights and safety of persons involved in biomedical research (research subjects) is the necessary precondition for contemporary biomedical researches and correspondingly, development of the science. An integral responsibility of researchers working in the field of biomedicine is to ensure the protection of safety and rights of research subjects. In Europe, as well as other countries of developed and partly in developing world, there is a relevant legislative basis of international agreements and national legislation which aims at protecting the research subject. Georgia possesses considerable legislative basis in this field which includes two obligatory instruments of Council of Europe and two national laws. Relevant legislation and ethical evaluation of biomedical research protocols involving human subjects by research ethics committees is an effective mechanism for protection of a research subject's safety and rights. In Georgia there already exist biomedical research ethics committees. Further, their amalgamation is necessary to increase their competence and regularity of activities through increasing the number of submitted research protocols as well as re-distribution of expertise (3-5 committees instead of existing 15-20 or more committees). All the researchers participating in biomedical research shall be educated on the issues of protection of rights of research subjects and contemporary principles of bioethics. The latter shall become an inseparable part of professional competence of researchers for which it is necessary to prepare and put into practice special training programmes (mural as well as distant courses). PMID- 20834071 TI - [Familial adenomatous polyposis of large intestine]. AB - At present the only treatment of familial diffuse polyposis is total colectomy and ileorectal anastomosis. Two cases of familial diffuse polyposis are analyzed. The first case: 18 year old man with diffuse polyposis of large intestine. The second case: 41 year old man with diffuse familial polyposis of large intestine, liver abscess in segment V, and fistula between the abscess and large intestine. In the both cases a radical proctocolectomy with the good, newest results. was done The patient underwent a proctocolectomy with the ileoanal anastomosis with S shaped ileal reservoir with an ileostoma. PMID- 20834072 TI - [Metabolic syndrome and risk factors for developing arterial hypertensia]. AB - Insulin Resistance and the resulting hyperinsulinemia is a collection of heart disease risk factors that increase the chance of developing arterial hypertensia- a key symptom of Metabolic Syndrome (MS). The basic role in pathogenesis of H at S belongs to insulin resistance (IR) and is caused by its compensative hyperinsulinemia (HI) in a combination with accompanying metabolic infringements. Beside this at S develops expressed dislipidemia--an increase of H level, the general XS, LPLD and decrease of LPHD. Recently one more theory of AH pathogenesis was discussed with adiposity according to which growth the AP is caused by increase of leptine level at these patients. Thus, pathogenesis of H at patients with metabolic variations and risk factors is very combined, varied and requires the differentiated and multilateral methods of treatment. PMID- 20834073 TI - The impact of thyroid diseases on bone metabolism and fracture risk. AB - Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. One of the leading causes of secondary osteoporosis are thyroid diseases; this fact carries special importance for Georgia because of thyroid disease prevalence in Georgian population. In the present article we discuss the mechanisms, by which thyroid hormones and thyroid stimulating hormone (TSH) act on bone. We also present the data of meta-analysis of large studies, which demonstrate the complex relationship between the thyroid diseases and bone mineral density as well as the fracture risk; namely by overt and subclinical thyrotoxicosis, hypothyroidism and the treatment with the suppressive doses of levothyroxine. Beside that, we review the related data and the possible reasons, why different treatment regimens of Grave's disease: conservative, operative and radioiodine are related to different fracture risks. Finally, we discuss briefly the practical aspects of the treatment of secondary osteoporosis, related with thyroid diseases. PMID- 20834074 TI - [Epidemiological assessment of the hepatitis B and C infectious disease markers in Baku and Nakhtchivan healthy population]. AB - Article is devoted to an estimation of spreading the subclinical infections caused with hepatitis B and C viruses among healthy adult inhabitants of Baku and Nakhchivan cities by detection of frequency of revealing serological markers of HBV (HBsAg) and HCV (anti-HCV) infections. The authors by the meta-analysis have generalized the results previously received in several seroepidemiological studies among healthy inhabitants of these cities and came to the conclusion that average HBsAg and anti-HCV detection rate have made--3.0 % and 4.0 %, accordingly. It has allowed believing that the Azerbaijan Republic can be classified as territory with moderate intensity of circulation of HBV and HCV. PMID- 20834075 TI - Unexpected non-seasonal increase of bacterial meningitis cases in Georgia in 2009. AB - In summer of 2009, During the period of 20-June - 31-August in total 32 patients with the clinical diagnosis of bacterial meningitis were hospitalized in two hospitals of Tbilisi (Center for Infectious Pathologies and Iashvili Child Clinic). Within a week's time (13 July-19 July) 9 persons with suspected cases of bacterial meningitis were hospitalized in both clinic. Our attention was attracted by the increased number of hospitalized patients within non-seasonal period. Goal of investigation was to establish the extent of the outbreak, to detect possible exposures, and to establish recommendations for prevention activities of disease. For laboratory confirmation cerebral spinal fluid biochemical and bacteriological (culturing) testing was used, but no single causative agent was isolated. To detect risk factors patients' were interviewed. 78.5% (25) of the hospitalized persons were under 14 years of age, and among them -70% (22) preschool children. The most common exposure identified through the interviews with patients included active or passive exposure to tobacco smoking (38%), an existence of the recent upper respiratory infection (31%), and attending crowded places (23%). Since causative agents were not isolated, we were not able to establish whether the increasing number of disease was caused from different etiologic pathogens or from single agent. We were not able to establish the presence of an outbreak since no single causative agent was isolated. Previous use of antibiotics remains the only likely reason for low detection of the pathogen. Detected risk-factors for distribution of disease were smoking, existence of the recent upper respiratory infection, and attending crowded places. In order to control increasing number of bacterial meningitis, improving basic laboratory diagnosis by implementing advanced methods that are not affected by the prior use of antibiotics, such as serological testing might be crucial, as well as increasing awareness of population about risk factors of bacterial meningitis and importance of early seeking medical care. PMID- 20834076 TI - Immunohistochemical expression of BRCA1 protein in invasive ductal carcinoma of the breast. AB - Immunohistochemically detected BRCA1 positivity has been reported to indicate the presence of full-length functional protein, while immunohistochemical negativity may be a result of sporadic BRCA1 mutation. We set out to study the immunohistochemical expression of BRCA1 protein in breast cancer and assess associations with lymph node status, histologic grade and expression of other biomarkers. We examined 100 patients aged from 21 to 71 years diagnosed with invasive ductal carcinoma. Immunohistochemistry was performed using anti-BRCA1, ER, PR, HER2/neu, and Ki-67 (MIB-1) antibodies. Cytoplasmic or nuclear cytoplasmic BRCA1 expression was identified in a total of 64 breast cancer patients. None of the breast cancer tissue samples showed solely nuclear BRCA1 immunoreactivity. BRCA1 expression was associated with higher histologic grade, and majority of BRCA1-positive patients were below 50 years of age. Most BRCA1 negative patients had intermediate grade tumors. BRCA1 expression was positively associated with ER and PR positivity, and negatively associated with HER2/neu overexpression. Although immunohistochemistry can be an inexpensive and valuable preliminary method for detecting the BRCA1 status, BRCA1 protein localization is a complex issue. Well designed studies are needed to further investigate the performance of various anti-BRCA1 antibodies in formalin- fixed paraffin-embedded tissue samples, assess their association with BRCA1 gene mutations and determine clinical usefulness of BRCA1 immunohistochemistry. PMID- 20834077 TI - [The influence of elektro-magnetic field on moving and emotional-motivate behaviour of animals in "open-field" and seratonus stimulate function effect]. AB - The aim of the work is detailed analysis of seratonus effect on moving and emotional-motivate behaviour of rats. The conducted quantative and qualitative analyzes show, that rats, feeded on with plant substance seratonus, are low emotional, manifestated with leas "urinaties" and "boluses" and high "grumming" effects. The plant substance seratonus is a function activity substance, takes off the emotional responsibility and takes an active part in metabolism of biological necessary components. The obtained data are very important from the point of assessment of the environment and individual sensitivity to the components contained in seratonus substances. PMID- 20834078 TI - [Hypoglycemic activity of berberin and extract obtained from the bark of Phellodendron lavalei, introduced in sub tropic areas of Georgia]. AB - The goal of this study was to evaluate hypoglycemic activity of Berberin and extract obtained from the bark of Phellodendron Lavalei, which is introduced in sub tropic areas of Georgia-Kobuleti. The study was carried out to reveal comparative hypoglycemic activity and acute toxicity of alkaloid Berberin and bark extract of Phellodendron Lavalei. Effects of Berberin hydrochloride and bark extract on blood glucose level was studied on mice. Measurement of blood glucose level was carried out on fasting animals using glucose meter "GlucoLab"--auto coding. The study showed that Berberin hydrochloride dose 150 mg/kg, extract (obtained from the bark of Phellodendron Lavalei) dose 400 mg/kg and glybenclamid dose 0.25 mg/kg practically decreased blood glucose level of mice in a same pattern. Received data allows us to suggest that Phellodendron Lavalei, introduced in sub tropic areas of Georgia contains active hypoglycemic components. In conclusion the possible use of Phellodendron Lavalei as a plant raw material for obtaining hypoglycemic substances needs to be decided after further study of efficacy, mechanism of action of extracts and active components of Phellodendron Lavalei on experimental models of diabetes mellitus. PMID- 20834079 TI - Peculiarities of circulatory system response on influence of modern tantalum manufacture factors in workers. AB - Objective of this study was to examine functional condition of cardiovascular system among workers at "Ulba Metallurgical Plant" JSC (located in Ust Kamenogorsk, Eastern Kazakhstan)--one of the world largest enterprises with the full production cycle from processing of tantalum containing raw materials to finished products. All workers that participated in the examination were divided into three groups: (I)--up to 5 years of occupation; (II)--from 5 to 9.9 years of occupation; and (III)--more than 10 years of occupation experience in the tantalum industry. The cardiovascular system, health concern and their contributing factors were assessed. In group I the factor of profitability of blood circulation was up to 3000 conventional units, which corresponds to the optimal fatigue; In group II the factor of profitability of blood circulation was increased up to 3525+/-327,3 conv. units--critical values zone. In group III the factor of profitability of blood circulation was up to 3000 conv. units. A relative improvement in the central hemodynamic indices compared with those in group II may be due to the development of adaptation. The assessments of functional condition of cardiovascular system among the workers specialize in different stages of tantalum production revealed the necessity of paying special attention at the cycle of tantalum processing and the years of work experience in an occupation. PMID- 20834080 TI - The macro-microscopic peculiarities of the human urinary bladder glands. AB - We studied the glands of the 130 persons, victims from the casual reasons (a trauma, an asphyxia, etc.) from newborn to senile age; we investigated different variants of a bladder glands forms, the changes in different parts of the organs wall (proximal, average, distal thirds) from the newborn period to senile age by the method of macro-microsopy and morphometry on the total preparations of urinary bladder. Glands preliminary have been stained by a solution 0,05% methylene dark blue with Sinelnicov's method and by hematoxilin and eozin. The glands were investigated with the application of stereo binocular microscope MBS 9. Statistical data processing included calculation of arithmetic-mean values, their errors, confidential intervals (excel). The view of the human urinary bladder glands in the macro-microscopy investigation is different. The glands have roundish, oval, ribbon forms. The form of the glands in the different parts of human urinary bladder (proximal, middle and distal) is difference. In the microtopography the glands have been proximal-distal changes; the quantity of glands increase from the proximal to distal portion. The human urinary bladder have many complex glands (the glands with 3, 4 and more beginnings parts) to the quantity in the distal part. PMID- 20834081 TI - A cost benefit analysis of elimination of kala-azar in Indian subcontinent: an example of Nepal. AB - BACKGROUND & OBJECTIVES: Visceral leishmaniasis, locally known as kala-azar (KA) has been considered as a major public health problem in Bangladesh, India and Nepal that affects 100,000 people per year with 147 million people at risk. Elimination of infectious disease is an ultimate goal of the public health system, therefore, the efforts have recently gained momentum from various organizations and governments to expand KA interventions in the endemic countries. The paper aims to estimate discounted net benefits and internal rate of return (IRR) to evaluate the economic feasibility for elimination of KA by utilizing available secondary information. METHODS: Cross-sectional data were collected from different sources to estimate societal costs of and benefits from KA interventions with a 13-year project period. Total costs are estimated based on the unit cost of inputs used for interventions. The benefits are derived from productivity change and resources saved due to reduction of KA incidence. Net benefits and IRRs are estimated based on standard procedures used in the field of economics, subsequently the sensitivity analysis is conducted. RESULTS: A total discounted net benefit of KA intervention is Nepalese Rupees (NRs) 65,287 million with 35% IRR. The result suggests that for every rupee invested in KA intervention at present will yield NRs 71 in future. The regional benefits from the interventions will be greater than the sum of benefits gained by the individual country due to its nature of public goods. CONCLUSION: Elimination of KA is a good investment opportunity for the Government and international partners involved in the health sector. PMID- 20834082 TI - Comparison of quinine and rabeprazole with quinine monotherapy in the treatment of uncomplicated falciparum malaria. AB - OBJECTIVE: This study was conducted to assess the effect of combination treatment of quinine and rabeprazole in the treatment of uncomplicated Plasmodium falciparum malaria. METHODS: The study included 50 patients of uncomplicated P. falciparum malaria. Group 1 (25 patients) received quinine and placebo (Q+P) while Group 2 (25 patients) received quinine and rabeprazole (Q+R). Diagnosis was confirmed by peripheral blood film (PBF) and rapid diagnostic test (RDT). Temperature was recorded every 6 h. All patients were followed-up on Days 7, 14, 21, 28 for detailed clinical and parasitological examination. RESULTS: A total of 20 patients in each group completed the treatment and followed-up for 28 days. While two patients in Group 1 (Q+P) and one patient in Group 2 (Q+R) were lost in follow-up; and seven (Q+P = 4, Q+R =3) patients were withdrawn from the study. Fever clearance time (FCT) of the two groups was also almost similar (Group 1 : 2 = 52.8 : 51.3 h). No statistically significant difference was observed in early treatment failure (ETF) either of the groups. None of the patients in both the groups showed late clinical failure (LCF) or late parasitological failure (LPF). However, there was a significant difference in the parasite clearance rates of the two groups (p<0.05). CONCLUSION: The study results suggest that addition of rabeprazole to quinine regimen resulted in an increase in the parasite elimination rate, which may be helpful in reducing the duration of treatment and increasing patient compliance. PMID- 20834083 TI - Comparative study of efficacy of artesunate plus cotrimoxazole and artesunate plus chloroquine in the treatment of malaria in Nigerian children: a preliminary report. AB - BACKGROUND & OBJECTIVES: The study was undertaken to evaluate the efficacy of cotrimoxazole plus artesunate and to compare the efficacy of this combination with that of artesunate plus chloroquine in the treatment of acute uncomplicated falciparum malaria in children. METHODS: Children aged between 0.5 and 12 yr with clinical and parasitological evidence of Plasmodium falciparum malaria were randomized to receive either artesunate plus cotrimoxazole or artesunate plus chloroquine. They were followed-up with clinical and parasitological assessment for a period of 14 days. RESULTS: In all, 57 out of 81 (31 in the artesunate plus cotrimoxazole group and 26 in artesunate plus chloroquine group) completed the study as per protocol and were evaluated. Pre-treatment clinical and parasitological parameters were similar in the two treatment groups. The time to clear fever and other symptoms were similar in the two groups 1.0 +/- 0 vs 1.14 +/- 0.38 (p > 0.05). Parasite clearance times were also similar; 1.65 +/- 0.49 days vs 1.58 +/- 0.67 days respectively for artesunate plus cotrimoxazole and artesunate plus chloroquine (p > 0.05). The cure rates on Day 14 were 100% for both artesunate plus cotrimoxazole and artesunate plus chloroquine groups. Both drug combinations were well-tolerated in the small population of children. CONCLUSION: These results indicate that artesunate plus cotrimoxazole has similar efficacy to artesunate plus chloroquine in the treatment of acute uncomplicated P. falciparum malaria in children resident in an endemic area of south-west Nigeria. PMID- 20834084 TI - Feasible choices in diagnostic methods of malaria. AB - BACKGROUND & OBJECTIVES: The present study was undertaken to find out a new easy method in the diagnosis of malaria by centrifuged buffy coat smear, which was found to be a feasible and reasonable procedure. METHODS: Blood samples collected from 120 patients suspected of malaria were subjected to all three diagnostic modalities-peripheral blood smear (PS), centrifuged buffy coat smear (CBCS) and antigen detection test using pLDH and aldolase (AG). RESULTS: The results of various methods were compared. It was seen that addition of centrifugation (i.e. CBCS) to conventional method of PS (i.e. thick and thin smears) improved its sensitivity from 85 to 93.3%. Antigen detection and CBCS were found superior to PS in sensitivity. CBCS gives combined sensitivity and specificity of both antigen and PS. CONCLUSION: CBCS is as sensitive as antigen test and as specific as PS in species identification. It is a reasonable and feasible procedure too. PMID- 20834085 TI - Knowledge, attitudes and practices about malaria in an urban community in south western Nigeria. AB - BACKGROUND & OBJECTIVES: Oyo is an urban community in Oyo state of south-western Nigeria and it is holoendemic for malaria. Information was collected on the knowledge, attitudes and practices (KAP) of inhabitants of Oyo town in relation to malaria. METHODS: A cross-sectional survey of 192 households with the aid of self- or researcher-administered questionnaires was carried out to identify factors associated with the disease in the area. RESULTS: About 93.2% (n=192) of respondents recognized mosquito bites as the cause of malaria. A small proportion of children (13.7%) and adults (5.3%) received prompt treatment; however, more adults (65.8%) got correct dosage of antimalarials than children (38.7%). About 90% of suspected malaria cases in children and adults were first treated at home with local herbs or drugs, purchased from medicine stores. The use of insecticide treated nets (ITNs) was scarce as only 16.7% of households used them for their children. Other reported malaria prevention methods include the use of insecticides (79.7%) and herbs (44.3%). In all, 17 (8.9%) of households did not have screening nets on their windows and 6.3% of 175 households with screening nets on their windows had rusty and torn nets. The level of education of heads of households was a strong predictor of positive malaria-related KAP. Window types and environmental hygiene were associated with prevalence of malaria in households. INTERPRETATION & CONCLUSION: The control of malaria cannot be achieved without full involvement of the affected communities; the available tools for control can only be effective and sustainable if the local communities are mobilized and empowered with knowledge. It is suggested that health education campaigns be intensified; chemist shop-keepers and mothers being important target groups. PMID- 20834086 TI - Experimental chemotherapy with Allium sativum (Liliaceae) methanolic extract in rodents infected with Leishmania major and Leishmania donovani. AB - BACKGROUND & OBJECTIVES: Several plant products have been tested and found to possess antileishmanial activity. The present study was undertaken to establish whether methanolic extract of Allium sativum Linn has antileishmanial activity in comparison to standard drugs. METHODS: Methanolic extract of A. sativum bulbs was screened for in vitro and in vivo antileishmanial activity against Leishmania major strain (NLB 145) and L. donovani strain (NLB 065). Pentostam and Amphotericin B were used as standard drugs. BALB/c mice and golden hamsters (Mesocricetus auratus) were used in in vivo studies on L. major and L. donovani respectively. RESULTS: The extract exhibited very low cytotoxicity (IC50 >450 MUg/ml) against Vero cells. The extract had significantly better (p <0.001) leishmanicidal activity against both species (IC50 34.22 MUg/ml to L. major, 37.41 MUg/ml to L. donovani) than Pentostam. However, the activity was significantly lower (p <0.001) than that of Amphotericin B against both the species. At a concentration of 250 MUg/ml, the extract induced the production of 60 MUM of nitric oxide, a ten-fold up-regulation in activated macrophages. The multiplication indices for L. major amastigotes treated in 100 MUg/ml were significantly different (p <0.05). Treatment with the extract, daily for 28 days led to a significant reduction (p <0.05) in footpad swelling in BALB/c mice; similar activity noticed in the treatment with standard drugs. The Leishman Donovan Units (LDU) for the extract treated animals were significantly higher (p <0.05) than those of standard drugs, but lower compared to the negative control. INTERPRETATION & CONCLUSION: Since the mechanism of action for the methanolic extract is apparently immunomodulatory, garlic compounds could be purified and tried as complementary medicine in the management of leishmaniases. PMID- 20834087 TI - The potential of the extracts of Tagetes minuta Linnaeus (Asteraceae), Acalypha fruticosa Forssk (Euphorbiaceae) and Tarchonanthus camphoratus L. (Compositae) against Phlebotomus duboscqi Neveu Lemaire (Diptera: Psychodidae), the vector for Leishmania major Yakimoff and Schokhor. AB - BACKGROUND & OBJECTIVES: Harmful effects of synthetic chemical insecticides including vector resistance, environmental pollution and health hazards have necessitated the current significance in the search for plant-based insecticide products that are environmentally safe and effective to leishmaniases control. The insecticidal activity of Tagetes minuta Linnaeus (Asteraceae), Acalypha fruticosa Forssk (Euphorbiaceae) and Tarchonanthus camphoratus L. (Compositae) extracts were investigated against Phlebotomus duboscqi Neveu Lemaire (Diptera: Psychodidae). METHODS: The extracts were prepared from dried aerial parts soaked in methanol and ethyl acetate twice until the filtrates became clear, filtered and dried out by rotary evaporation at 30-35 degrees C. The solid extracts obtained were later prepared into 2.5, 5 and 10 mg/ml. Two millilitres of the solutions were blotted on filter papers, which were dried overnight and placed into jars where adult sandflies were aspirated. Males and females were assayed separately. RESULTS & CONCLUSION: The extracts had significant mortality (p<0.05) in both males and females bioassays but were not significantly different between sexes. The extracts of Acalypha fruticosa and Tagetes minuta had significantly higher mortality rates than those of Tarchonanthus camphoratus and the different concentrations used showed significantly different mortality rates and 10 mg/ml was the most effective concentration. Cent percent mortality was obtained at 96 h of exposure to 5 and 10 mg/ml concentrations except for Tarchonanthus camphoratus which had a mortality of only 46.7% in 10 mg/ml bioassay. These extracts were found to be insecticidal to adult sandflies. PMID- 20834088 TI - Larval habitats of Aedes albopictus (Skuse) in rural areas of Calicut, Kerala, India. PMID- 20834089 TI - Mosquito larvicidal and phytochemical properties of Ervatamia coronaria Stapf. (Family: Apocynaceae). PMID- 20834090 TI - Laboratory evaluation of the biocontrol potential of Aphyosemion gularis against Anopheles larvae. PMID- 20834091 TI - Larvicidal efficacy of latex and extract of Calotropis procera (Gentianales: Asclepiadaceae) against Culex quinquefasciatus and Anopheles stephensi (Diptera: Culicidae). PMID- 20834092 TI - Entomological investigations during an outbreak of dengue fever in Lal Kuan town, Nainital district of Uttarakhand, India. PMID- 20834093 TI - Etravirine: clinical review of a treatment option for HIV type-1-infected patients with non-nucleoside reverse transcriptase inhibitor resistance. AB - Despite our progressive understanding of HIV type-1 (HIV-1) infection and the development of a number of antiretroviral agents to delay the onset of AIDS, there remains a need for agents with improved efficacy and safety. In particular, therapy options for treatment-experienced adult patients have been limited by the presence of drug-resistant virus, which often leads to a reduced virological response in these patients. The recently approved non-nucleoside reverse transcriptase inhibitor etravirine has demonstrated durable and superior efficacy over placebo and a favourable tolerability profile in HIV-1-infected, treatment experienced patients, offering a valuable new therapeutic option. This review examines the clinical development and drug profile of etravirine, placing it in the context of other antiretrovirals available for treatment-experienced patients. PMID- 20834094 TI - Clinical perspective on antiretroviral drug-drug interactions with the non nucleoside reverse transcriptase inhibitor etravirine. AB - Etravirine is an effective and well-tolerated recently approved non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV type-1-infected patients with previous antiretroviral treatment experience. Considering the importance of combining antiretrovirals for their optimal use in treating HIV, a number of drug drug interactions with etravirine and other antiretrovirals have been evaluated. Etravirine is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C9/CYP2C19 and P-glycoprotein, and although etravirine is metabolized by the CYP enzyme system, the extent of clinically relevant interactions with other antiretrovirals is limited. Etravirine can be combined with all currently available nucleoside/nucleotide reverse transcriptase inhibitors without dose adjustments, but not with other NNRTIs. Available data indicate that etravirine can be coadministered with most of the currently available ritonavir-boosted HIV protease inhibitors. Coadministration with tipranavir/ritonavir or unboosted HIV protease inhibitors is not recommended because of clinically relevant changes in exposure to etravirine or the coadministered HIV protease inhibitor, respectively. Etravirine can be coadministered with the integrase inhibitors elvitegravir/ritonavir or raltegravir, and with the fusion inhibitor enfuvirtide, without dose adjustments. Dose adjustment of the C-C chemokine receptor type-5 antagonist maraviroc is required, with the type of adjustment depending on whether a boosted HIV protease inhibitor is included in the regimen. In conclusion, etravirine can be combined with most antiretrovirals, with no clinically meaningful effect on drug exposure or safety/tolerability profiles. PMID- 20834095 TI - von Willebrand factor antigen: a novel on-treatment predictor of response to antiviral therapy in chronic hepatitis C genotypes 1 and 4. AB - BACKGROUND: Levels of von Willebrand factor antigen (vWF-Ag) increase during combination antiviral therapy of chronic hepatitis C (CHC). The present study investigates the association between these changes in vWF-Ag levels and response to treatment. METHODS: Changes in levels of vWF-Ag on antiviral combination treatment in 184 patients with CHC genotype 1 or 4 infections were measured prospectively and effect on response was studied. RESULTS: High on-treatment levels of vWF-Ag were associated with relapse (P<0.01) and low on-treatment levels with sustained virological response (SVR). Receiver operating characteristic curve analysis showed that vWF-Ag levels of <300% at week 12 of therapy have a positive predictive value (PPV) of 78% for SVR. In early virological response (EVR) patients, the PPV of vWF-Ag levels <300% at week 12 was 74%. An even higher PPV of 88% in complete EVRs (undetectable HCV RNA at week 12) was observed for the same cutoff value at week 12. CONCLUSIONS: On-treatment levels of vWF-Ag can be utilized as an additional predictive marker for response to antiviral therapy. This is especially relevant in EVR patients because EVR alone only has a PPV of 58-72% on SVR, which increased to 74%, when factoring in vWF-Ag levels <300% at week 12, and to 88% in complete EVRs; therefore, measurement of vWF-Ag levels at week 12 is helpful. EVR patients that are above the cutoff values for vWF-Ag that make SVR very probable might profit from an extension of therapy to 72 weeks. PMID- 20834096 TI - Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V. AB - BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme. PMID- 20834097 TI - A comprehensive surveillance of adamantane resistance among human influenza A virus isolated from mainland China between 1956 and 2009. AB - BACKGROUND: Adamantane-derived drugs have been used for treatment and prophylaxis of influenza A virus infection for many years worldwide. Rapid surveillance of antiviral drug resistance is important for appropriate clinical guideline development. Here, we retrospectively assessed adamantane resistance among different influenza A subtypes (H1N1, H3N2 and H5N1) over 53 years (1956-2009) in mainland China. METHODS: A total of 1,451 viruses, including 773 H3N2 viruses, 647 H1N1 viruses and 31 human H5N1 viruses, were analysed by matrix gene sequencing and assayed for drug resistance. RESULTS: Our results show that the prevalence of adamantane-resistant H3N2 viruses was low between 1956 and 2002, but substantially increased in 2003 to the extent that since 2006 all H3N2 viruses have been drug resistant. The percentage of adamantane-resistant H1N1 viruses also increased from 50.0% in 2004 to 98.7% in 2007; however, this decreased to 46.7% in 2009. Only three adamantane-resistant H5N1 viruses have been detected since 2003, when the first case of human H5N1 virus infection was detected in mainland China. Phylogenetic analysis demonstrated that the increase of adamantane-resistant isolates was caused by point mutations or intrasubtype reassortment instead of intersubtype reassortment. CONCLUSIONS: Because of the high percentage of adamantane-resistant H3N2 and H1N1 viruses in mainland China, the use of amantadine and rimantadine drugs for prophylaxis and treatment of current seasonal influenza A infection is not recommended. PMID- 20834098 TI - Inhibition of hepatitis B virus DNA replication by a thermostable interferon gamma variant. AB - BACKGROUND: Treatment of HBV chronic carriers using interferon (IFN)-alpha or nucleoside/nucleotide analogues fails to suppress viral infection. Type-II IFN gamma has been shown to inhibit HBV replication. The goal of the present work was to evaluate the antiviral efficacy against HBV of a thermostable IFN-gamma variant isolated using Massive Mutagenesis and thermoresistant selection (THR) technologies. METHODS: The thermostability of wild-type (wt) and S63C IFN-gamma was determined in vitro and in vivo. Activation of the IFN-gamma responsive element by wt and S63C IFN-gamma was tested using a luciferase assay. HepG2.2.15 cells constitutively expressing HBV were used to analyse the antiviral activity of wt and S63C IFN-gamma against HBV replication. Intracellular HBV DNA was detected by Southern blot and quantified by real-time PCR analyses. RESULTS: S63C IFN-gamma was shown to be more thermostable and had a longer half-life than wt IFN-gamma. Both wt and S63C IFN-gamma displayed a similar capacity to activate the IFN pathway. The treatment of HepG2.2.15 cells with wt or S63C IFN-gamma induced the inhibition of HBV viral replication. After heating, S63C IFN-gamma displayed better conservation of its antiviral activity against HBV when compared with wt IFN-gamma. CONCLUSIONS: These results confirm that the THR method can be used to isolate mutants with enhanced thermostability and demonstrate that a thermostable IFN-gamma variant presents antiviral properties against HBV replication. This molecule could provide a new strategy to treat patients who do not respond to antiviral therapy. PMID- 20834099 TI - Immune restoration and onset of new AIDS-defining events with combination antiretroviral therapy in HIV type-1-infected immigrants in the Netherlands. AB - BACKGROUND: We investigated differences in immune restoration and onset of new AIDS-defining events on combination antiretroviral therapy (cART) among HIV type 1 (HIV-1)-infected patients of different regional origin now living in the Netherlands. METHODS: Treatment-naive adults reaching plasma viral load (pVL)<400 copies/ml within 9 months of starting cART were selected from the Netherlands ATHENA cohort. CD4(+) T-cell response on cART was determined over 7 years using mixed models. CD4(+) T-cell counts were excluded from the analyses at the first of two consecutive measurements of pVL>=400 copies/ml following prior suppression to <400 copies/ml. Multivariate analyses included gender, age, CD4(+) T-cell count and pVL prior to cART, hepatitis coinfection, HIV-1 transmission and region of origin (Western Europe/North America [WN], sub-Saharan Africa [SSA], Southeast Asia [SEA], Latin America/Caribbean [LAC] or other). RESULTS: For 6,057 selected patients (WN 3,947, SSA 989, SEA 237, LAC 695 and other 189), median follow-up was 3.2 years (WN 3.3, SSA 2.9, SEA 3.2, LAC 2.7 and other 2.7). CD4(+) T-cell increase in the first 6 months of cART was lower in males than females (-26 cells/mm(3); P<0.0001) and in patients from SSA compared with WN (-36 cells/mm(3); P<0.0001). Because men from SSA started with lower CD4(+) T-cell counts than men from WN, they continued to lag behind and had lower absolute CD4(+) T-cell counts after 7 years of cART. Furthermore, cumulative tuberculosis incidence after 7 years of cART was higher in SSA compared with WN (4.5% versus 0.5%, hazard ratio 5.08, 95% confidence interval 2.22-11.60). CONCLUSIONS: HIV-1 infected immigrants from SSA have blunted immune restoration on fully suppressive cART and should be identified at an earlier disease stage. Our results call for more intensive screening for both latent and active tuberculosis in these patients. PMID- 20834100 TI - Incidence of liver cirrhosis in HIV-infected patients with chronic hepatitis B or C in the era of highly active antiretroviral therapy. AB - BACKGROUND: Longitudinal assessment of liver fibrosis with transient elastometry (TE) in patients with chronic viral hepatitis is becoming routine clinical practice in many clinics, as this procedure is non-invasive, easy to perform and relatively inexpensive, allowing early detection of cirrhosis. Herein, we examine the incidence of cirrhosis, using TE assessment, in HIV-infected individuals with chronic hepatitis B or C receiving highly active antiretroviral therapy (HAART). METHODS: A longitudinal study was performed on a cohort of HIV-infected patients with chronic hepatitis B or C who were followed since 2004 at Hospital Carlos III (Madrid, Spain) with periodic TE assessments. The primary outcome was the development of cirrhosis, defined as liver stiffness >12.5 KPa. RESULTS: A total of 508 HIV-infected patients were examined, of whom 54 developed liver cirrhosis during a mean +/-(SD) follow-up of 2.6 +/-1.0 years (overall incidence was 41.13 cases per 1,000 person-years). The risk of developing cirrhosis was significantly higher in 297 HCV-RNA-positive patients (either untreated or non-responders to hepatitis C therapy) compared with 55 patients who had cleared HCV with therapy (odds ratio 3.73, 95% confidence interval 1.06-13.17; P=0.04). By contrast, the risk of developing cirrhosis was low and similar in 24 HIV-HBV-coinfected patients under long-term suppressive HBV therapy (mainly tenofovir disoproxil fumarate), 132 HIV-infected patients without chronic liver disease and those who had cleared HCV with therapy. CONCLUSIONS: Development of liver cirrhosis in HIV infected individuals in the HAART era is mainly associated with active HCV coinfection. The risk of developing cirrhosis is negligible in patients who cleared HCV with therapy, as well as in HIV-HBV-coinfected patients on long-term suppressive tenofovir disoproxil fumarate therapy. PMID- 20834101 TI - Immune modulator and antiviral potential of dendritic cells pulsed with both hepatitis B surface antigen and core antigen for treating chronic HBV infection. AB - BACKGROUND: Commercially available prophylactic vaccines containing hepatitis B surface antigen (HBsAg), which are used to prevent HBV infections, are not as effective as a therapeutic immune modulator for treating patients with chronic hepatitis B (CHB). In this study, the immunogenicity of dendritic cells (DC) loaded with both HBsAg and hepatitis B core antigen (HBcAg) was tested in HBV transgenic mice (TM; 1.2HB-BS10) in vivo and in patients with CHB in vitro. METHODS: Spleen DC from HBV TM were cultured with a vaccine containing both HBsAg and HBcAg to produce HBsAg/HBcAg-pulsed DC. HBV TM were immunized twice at an interval of 4 weeks with HBsAg/HBcAg-pulsed DC and other immune modulators. Antibody titres to HBsAg (anti-HBs) were measured in sera. Antigen-specific T cells and cytotoxic T-lymphocytes (CTLs) in the spleen and liver were detected by lymphoproliferative and ELISPOT assays, respectively. HBsAg/HBcAg-pulsed human blood DC were cultured with autologous T-cells from CHB patients to assess their antigen-specific immune modulatory capacities. RESULTS: Significantly higher levels of anti-HBs, HBsAg-specific and HBcAg-specific T-cells and CTLs were detected in the spleen and liver of HBV TM immunized with HBsAg/HBcAg-pulsed DC compared with those immunized with other vaccine formulations (P<0.05). HBsAg/HBcAg-pulsed human blood DC also induced HBsAg- and HBcAg-specific proliferation of autologous T-cells from CHB patients. CONCLUSIONS: The immune modulatory capacities of HBsAg/HBcAg-pulsed DC in HBV TM in vivo, and in patients with CHB in vitro, inspire optimism about a clinical trial with this cell-based vaccine in patients with CHB. PMID- 20834102 TI - Z-FA-FMK as a novel potent inhibitor of reovirus pathogenesis and oncolysis in vivo. AB - BACKGROUND: Respiratory enteric orphan (reo)virus is a promising oncolytic viral candidate. Reoviral anticancer therapy is currently undergoing multiple clinical trials targeting various human cancers; however, there is no effective reoviral inhibitor that can be used to block unwanted reovirus replication during reoviral anticancer therapy. METHODS: Studies were conducted with transformed or normal cells in vitro and in vivo to characterize viral replication in the presence or absence of chemical inhibitors. RESULTS: We have identified a protease inhibitor that is very effective in the inhibition of viral replication. The dipeptide benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (Z-FA-FMK) effectively inhibited reovirus replication in a susceptible host and cured cells of a persistent infection with reovirus in vitro. Electron microscopic analysis of Z-FA-FMK treated cells revealed that internalized reovirus virions, retained in a perinuclear localization, no longer undergo further processing into viral factories following Z-FA-FMK treatment, suggesting that Z-FA-FMK specifically affects a reovirus virion maturation step. Animal studies showed that reovirus infection of Ras oncogenic tumours and host heart tissues is completely blocked by Z-FA-FMK treatment in severe combined immunodeficiency mice. CONCLUSIONS: Z-FA FMK is a very effective viral inhibitor that can prevent reovirus replication in vitro and reovirus-mediated myocarditis, as well as reovirus-mediated oncolysis, in vivo. A potential application of this drug for inhibition of reovirus infection is suggested. PMID- 20834103 TI - Analysis of immune selection as a potential cause for the presence of cleavage site mutation 431V in treatment-naive HIV type-1 isolates. AB - INTRODUCTION: HIV type-1 (HIV-1) protease (PR) and cleavage site (CS) mutations accumulate in protease-inhibitor-resistant isolates. HIV-1 CS mutation 431V is the most frequent treatment-associated CS mutation; however, little is known about its origin in treatment-naive HIV-1 isolates. Recently, it has been shown that the CS mutation 431V is located within the human leukocyte antigen (HLA) B*13-restricted cytotoxic T-lymphocyte (CTL) epitope RQANFLGKI (RI9). Therefore, we investigated whether the presence of CS mutation 431V might additionally be related to immune escape. METHODS: CTL recognition of RI9 and of RI9 variants carrying the 431V or the 436R mutation was analysed by ELISPOT in nine HLA-B*13 positive HIV-1-infected patients. Treatment-naive HIV-1-infected patients with primary drug-resistant HIV-1 isolates (n=58) or carrying 431V (n=4) were genotyped for HLA class I alleles. RESULTS: ELISPOT analysis showed different patterns of CTL recognition of RI9. CS mutation 431V could abrogate recognition by RI9-specific CTL in a subgroup of patients. Nevertheless, in our study, the occurrence of 431V in treatment-naive HIV-1 without primary drug resistance could not be explained by HLA-B*13-mediated immune selection. In patients with primary drug-resistant HIV-1 isolates, the frequency of HLA-B*13 was not increased and HLA-B*13 did not correlate with CS mutations 436R or 431V. CONCLUSIONS: HIV-1 CS mutation 431V can abrogate CTL recognition, indicating interactions between development of drug resistance and the CTL response. However, we could not find evidence that the presence of 431V in treatment-naive HIV-1 isolates with and without primary drug resistance is related to immune selection by HLA-B*13 or other HLA class I alleles. PMID- 20834104 TI - Self-reported adherence is more predictive of virological treatment response among patients with a lower tendency towards socially desirable responding. AB - BACKGROUND: Self-report is the most commonly used measure of adherence to highly active antiretroviral therapy, but typically shows weaker associations with virological treatment outcome than more objective adherence assessment methods. Socially desirable responding might hamper the validity of self-reported adherence. We investigated whether stratifying patients according to their socially desirable response set might improve the prediction of virological treatment response by self-reported adherence. METHODS: Patients enrolled in the focus group of the Dutch national cohort ATHENA completed a social desirability scale, four self-report adherence questions, and had their plasma HIV type-1 (HIV 1) RNA concentrations measured. We calculated odds ratios and 95% confidence intervals for self-reported non-adherence to predict HIV-1 RNA>50 copies/ml among patients with a lower or a higher tendency towards socially desirable responding. RESULTS: A total of 331 patients were included. Self-reported non-adherence was significantly predictive of HIV-1 RNA>50 copies/ml on three out of four questions among patients with lower socially desirable responding (n=198). Self-reported non-adherence did not predict HIV-1 RNA>50 copies/ml among patients with higher socially desirable responding (n=132). CONCLUSIONS: Stratifying patients according to their socially desirable response set improved the prediction of virological treatment response by self-reported adherence. This finding emphasizes the importance of discussing medication adherence with patients in a non-threatening and non-judgemental way that normalizes non-adherence in order to reduce socially desirable responding. PMID- 20834105 TI - Efficacy of tenofovir disoproxil fumarate/emtricitabine compared with emtricitabine alone in antiretroviral-naive HIV-HBV coinfection in Thailand. AB - BACKGROUND: Therapy for chronic hepatitis B with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) or emtricitabine (FTC) is currently recommended for HIV-HBV coinfection. However, there is limited randomized data on the efficacy of combined therapy with TDF and FTC, especially in antiretroviral (ARV)-naive patients. METHODS: This was a prospective randomized clinical trial comparing the efficacy of HBV monotherapy with FTC versus TDF/FTC combination therapy in ARV naive HIV-HBV coinfection. HIV-HBV-coinfected patients initiating ARV were randomized to either FTC/zidovudine/efavirenz (EFV; n=6) or TDF/FTC/EFV (n=10). The primary end point was the time-weighted area under the curve (TWAUC) of HBV DNA at 48 weeks. RESULTS: The median baseline CD4(+) T-cell count was 64 cells/MUl (interquartile range [IQR] 36-172), plasma HIV type-1 RNA was 4.90 log(10) copies/ml (IQR 4.58-5.44) and plasma HBV DNA was 8.76 log(10) copies/ml (IQR -8.45-8.82). A total of 11/16 (69%) patients were hepatitis B e antigen (HBeAg)-positive. The median TWAUC decrease in HBV DNA was -5.32 log(10) copies/ml in the TDF/FTC group compared with -3.25 log(10) copies/ml in the FTC group (P=0.03). At week 48, 90% of the TDF/FTC group and 33% of the FTC group had plasma HBV DNA<170 copies/ml (P=0.036, intention-to-treat analysis). HBeAg loss was observed in 4/11 (36%) HBeAg-positive patients. Hepatic flares were observed in 3/16 (19%) of patients. CONCLUSIONS: TDF/FTC combination therapy resulted in a significantly greater decrease in HBV DNA than FTC monotherapy, with a greater proportion of patients with undetectable HBV DNA at week 48. Our study supports the current recommendation of ARV containing TDF/FTC as the treatment of choice for patients with HIV-HBV coinfection. PMID- 20834106 TI - Emergence of intratreatment resistance to oseltamivir in pandemic influenza A H1N1 2009 virus. AB - BACKGROUND: Pandemic influenza A H1N1 2009 virus presents a new challenge to health authorities and communities worldwide. In Argentina, the outbreak was at its peak by the end of June 2009, during the southern winter. A systematic analysis of samples from patients with pandemic H1N1 2009 studied in our laboratory (Virology Laboratory, Hospital de Ninos R Gutierrez, Buenos Aires, Argentina) detected two patients presenting intratreatment emergence of the H275Y neuraminidase mutation, which confers resistance to oseltamivir. METHODS: Complementary DNAs, including the 275 codon, were obtained by reverse transcriptase PCR using viral RNAs extracted from nasopharyngeal or tracheal aspirates. Conventional sequencing and pyrosequencing were performed on each sample. In order to measure the virus susceptibility to oseltamivir, 50% inhibitory concentration determinations were performed by chemiluminescence. RESULTS: Sequential samples of two paediatric patients under oseltamivir treatment were analysed. Pretreatment samples were composed of 100% oseltamivir sensitive variants. In case 1, the oseltamivir-resistant variant was found 8 days after the beginning of treatment. In case 2, the viral population became resistant on the second day of treatment, with 83% of the viral population bearing the mutation and this reached 100% on the seventh day. CONCLUSIONS: We describe the intratreatment emergence of oseltamivir resistance in two paediatric patients. Pyrosequencing allowed us to detect variant mixtures, showing the transition of the viral population from sensitive to resistant. PMID- 20834107 TI - Antiviral treatment including entecavir plus tenofovir disoproxil fumarate for HBV reactivation following a rituximab-based regimen. AB - Entecavir and tenofovir disoproxil fumarate are potent and effective antiviral drugs that now represent recommended treatment options for chronic HBV infection. However, no or very limited clinical evidence is currently available on these drugs for the management of HBV reactivation in patients with haematological malignancies. Herein, we report a case of HBV reactivation in a patient with non Hodgkin's lymphoma following a rituximab-based regimen, and who was successfully treated with a combination antiviral treatment including entecavir and tenofovir disoproxil fumarate. PMID- 20834108 TI - Exploring a minimal two-component p53 model. AB - The tumor suppressor p53 coordinates many attributes of cellular processes via interlocked feedback loops. To understand the biological implications of feedback loops in a p53 system, a two-component model which encompasses essential feedback loops was constructed and further explored. Diverse bifurcation properties, such as bistability and oscillation, emerge by manipulating the feedback strength. The p53-mediated MDM2 induction dictates the bifurcation patterns. We first identified irradiation dichotomy in p53 models and further proposed that bistability and oscillation can behave in a coordinated manner. Further sensitivity analysis revealed that p53 basal production and MDM2-mediated p53 degradation, which are central to cellular control, are most sensitive processes. Also, we identified that the much more significant variations in amplitude of p53 pulses observed in experiments can be derived from overall amplitude parameter sensitivity. The combined approach with bifurcation analysis, stochastic simulation and sampling-based sensitivity analysis not only gives crucial insights into the dynamics of the p53 system, but also creates a fertile ground for understanding the regulatory patterns of other biological networks. PMID- 20834109 TI - Insulating electrodes: a review on biopotential front ends for dielectric skin electrode interfaces. AB - Insulating electrodes, also known as capacitive electrodes, allow acquiring biopotentials without galvanic contact with the body. They operate with displacement currents instead of real charge currents, and the electrolytic electrode-skin interface is replaced by a dielectric film. The use of insulating electrodes is not the end of electrode interface problems but the beginning of new ones: coupling capacitances are of the order of pF calling for ultra-high input impedance amplifiers and careful biasing, guarding and shielding techniques. In this work, the general requirements of front ends for capacitive electrodes are presented and the different contributions to the overall noise are discussed and estimated. This analysis yields that noise bounds depend on features of the available devices as current and voltage noise, but the final noise level also depends on parasitic capacitances, requiring a careful shield and printed circuit design. When the dielectric layer is placed on the skin, the present-day amplifiers allow achieving noise levels similar to those provided by wet electrodes. Furthermore, capacitive electrode technology allows acquiring high quality ECG signals through thin clothes. A prototype front end for capacitive electrodes was built and tested. ECG signals were acquired with these electrodes in direct contact with the skin and also through cotton clothes 350 um thick. They were compared with simultaneously acquired signals by means of wet electrodes and no significant differences were observed between both output signals. PMID- 20834110 TI - Effect of composition on the dielectric properties of hydrogels for biomedical applications. AB - The effect of composition on the dielectric properties of hydrogels for biomedical applications is experimentally investigated. The hydrogels, containing hydroxyethylcellulose (HEC), are characterized by means of the impedance spectroscopy technique. The real and imaginary parts of the electrical impedance of the hydrogels are determined for several concentrations of HEC, and of KCl, dissolved in it, for the frequency range of interest for biomedical applications. The results are compared with those corresponding to depurated water. The equivalent conductivity of the hydrogels is evaluated by performing measurements on samples of different thicknesses. With the limit of a small concentration of salt (<= 6%), the dependence of the electrical conductivity of the hydrogel on the salt concentration is linear. PMID- 20834111 TI - Impedance spectroscopy of conductive commercial hydrogels for electromyography and electroencephalography. AB - In biomedical applications such as the electroencephalogram, electrocardiogram and electromyogram, usually conductive hydrogels are applied to the skin providing a skin-electrode layer, with the aim of lowering contact impedance and improving the signal/noise ratio. It is important to know the electrical behavior of these materials, obtaining reliable values of their conductivity. It can be extracted by the whole cell impedance, which is affected not only by the bulk but also by the surface properties. The aim of the present work is to characterize the impedance of some currently available conductive hydrogels in the frequency range 5 Hz-1 MHz. For this purpose we have designed a novel cell, with silver electrodes, optical detection of the gap and guard ring. In this paper the results are compared with those obtained by means of a commercial cell with stainless steel electrodes, without a guard ring. In order to extract the different contributions of the bulk and the interface, we fitted the experimental data with a very simple model: the bulk properties are described by a single RC parallel, whereas the interface is represented by a constant phase element. PMID- 20834112 TI - Correlation between muscle electrical impedance data and standard neurophysiologic parameters after experimental neurogenic injury. AB - Previous work has shown that electrical impedance measurements of muscle can assist in quantifying the degree of muscle atrophy resulting from neuronal injury, with impedance values correlating strongly with standard clinical parameters. However, the relationship between such data and neurophysiologic measurements is unexplored. In this study, 24 Wistar rats underwent sciatic crush, with measurement of the 2-1000 kHz impedance spectrum, standard electrophysiological measures, including nerve conduction studies, needle electromyography, and motor unit number estimation (MUNE) before and after sciatic crush, with animals assessed weekly for 4 weeks post-injury. All electrical impedance values, including a group of 'collapsed' variables, in which the spectral characteristics were reduced to single values, showed reductions as high as 47.2% after sciatic crush, paralleling and correlating with changes in compound motor action potential amplitude, conduction velocity and most closely to MUNE, but not to the presence of fibrillation potentials observed on needle electromyography. These results support the concept that localized impedance measurements can serve as surrogate makers of nerve injury; these measurements may be especially useful in assessing nerve injury impacting proximal or axial muscles where standard quantitative neurophysiologic methods such as nerve conduction or MUNE cannot be readily performed. PMID- 20834113 TI - The predictive value of gastric reactance for postoperative morbidity and mortality in cardiac surgery patients. AB - No useful method to directly monitor the level of end organ tissue injury is currently available clinically. Gastric reactance has been proposed to measure changes in a tissue structure caused by ischemia. The purpose of this study was to assess whether gastric reactance is a reliable, clinically relevant predictor of complications and a potentially useful tool to assess hypoperfusion in cardiovascular surgery patients. The value of gastric reactance measurements, standard hemodynamic and regional perfusion variables, and scores to predict postoperative complications were compared in 55 higher risk cardiovascular surgery patients with cardiopulmonary bypass. Low frequency gastric reactance, X(L), had a significant predictive value of postoperative persistent shock requiring more than 48 h of vasopressors and associated complications, before, during and after surgery (p < 0.05). Results suggest that reactance is an earlier predictor of patients at risk than all other variables tested. Patients with a high reactance (X(L) > 26) before surgery had a significantly higher incidence of complications, higher mortality and more days in the ICU than patients with a low reactance (X(L) < 13). X(L) was found to be a reliable and clinically relevant measurement. These results justify further clinical research to explore how this information may be used to improve patient management. PMID- 20834114 TI - On the use of peripheral autonomic signals for binary control of body-machine interfaces. AB - In this work, the potential of using peripheral autonomic (PA) responses as control signals for body-machine interfaces that require no physical movement was investigated. Electrodermal activity, skin temperature, heart rate and respiration rate were collected from six participants and hidden Markov models (HMMs) were used to automatically detect when a subject was performing music imagery as opposed to being at rest. Experiments were performed under controlled silent conditions as well as in the presence of continuous and startle (e.g. door slamming) ambient noise. By developing subject-specific HMMs, music imagery was detected under silent conditions with the average sensitivity and specificity of 94.2% and 93.3%, respectively. In the presence of startle noise stimuli, the system sensitivity and specificity levels of 78.8% and 80.2% were attained, respectively. In environments corrupted by continuous ambient and startle noise, the system specificity further decreased to 75.9%. To improve the system robustness against environmental noise, a startle noise detection and compensation strategy were proposed. Once in place, performance levels were shown to be comparable to those observed in silence. The obtained results suggest that PA signals, combined with HMMs, can be useful tools for the development of body machine interfaces that allow individuals with severe motor impairments to communicate and/or to interact with their environment. PMID- 20834115 TI - Using Jensen's inequality to explain the role of regular calcium oscillations in protein activation. AB - Oscillations of cytosolic Ca(2 +) are very important for cellular signalling in excitable and non-excitable cells. The information of various extracellular stimuli is encoded into oscillating patterns of Ca(2 +) that subsequently lead to the activation of different Ca(2 +)-sensitive target proteins in the cell. The question remains, however, why this information is transmitted by means of an oscillating rather than a constant signal. Here we show that, in fact, Ca(2 +) oscillations can achieve a better activation of target proteins than a comparable constant signal with the same amount of Ca(2 +) used. For this we use Jensen's inequality that describes the relation between the function value of the average of a set of argument values and the average of the function values of the arguments from that set. We analyse the role of the cooperativity of the binding of Ca(2 +) and of zero-order ultrasensitivity, which are two properties that are often observed in experiments on the activation of Ca(2 +)-sensitive target proteins. Our results apply to arbitrary oscillation shapes and a very general decoding model, thus generalizing the observations of several previous studies. We compare our results with data from experimental studies investigating the activation of nuclear factor of activated T cells (NFAT) and Ras by oscillatory and constant signals. Although we are restricted to specific approximations due to the lack of detailed kinetic data, we find good qualitative agreement with our theoretical predictions. PMID- 20834116 TI - Local transport properties, morphology and microstructure of ZnO decorated SiO2 nanoparticles. AB - We report on a novel, surfactant free method for achieving nanocrystalline ZnO decoration of an SiO(2) nanoparticle at ambient temperature. The size distributions of the naked and decorated SiO(2) nanoparticles are measured by means of dynamic light scattering, and a monodisperse distribution is observed for each. The morphology and microstructure of the nanoparticles are explored using atomic force microscopy and high resolution transmission electron microscopy. Investigation of the optical properties of the ZnO decorated SiO(2) nanoparticles shows absorption at 350 nm. This blue shift in absorption as compared to bulk ZnO is shown to be consistent with quantum confinement effects due to the small size of the ZnO nanocrystals. Finally, the local electronic transport properties of the nanoparticles are explored by scanning conductance atomic force microscopy. A memristive hysteresis in the transport properties of the individual ZnO decorated SiO(2) nanoparticles is observed. Optical absorption measurements suggest the presence of oxygen vacancies, whose migration and annihilation appear to contribute to the dynamic conduction properties of the ZnO decorated nanoparticles. We believe this to be the first demonstration of a ZnO decorated SiO(2) nanoparticle, and this represents a simple yet powerful way of achieving the optical and electrical properties of ZnO in combination with the simplicity of SiO(2) synthesis. PMID- 20834117 TI - EuS nanocrystals: a novel synthesis for the generation of monodisperse nanocrystals with size-dependent optical properties. AB - A novel one-step solvothermal synthesis of stable colloidal EuS nanocrystals (NCs) is reported. The EuS NCs were synthesized in oleylamine directly from europium oleate and diethylammonium diethyldithiocarbamate in the presence of dodecanethiol and phenanthroline. The formation of single crystalline monodisperse EuS NCs, with sizes finely controlled by synthetic conditions, was confirmed by x-ray diffraction and high resolution transmission electron microscopy analysis. The exciton transition of EuS NCs blue-shifts to higher energies with decreasing particle sizes, as revealed by optical absorption and photoluminescence measurements. The feasibility of synthesizing monocrystalline EuS nanorods by solvothermal synthesis was also demonstrated, making them potentially viable materials for device applications. PMID- 20834118 TI - Enhanced microcontact printing of proteins on nanoporous silica surface. AB - We demonstrate porous silica surface modification, combined with microcontact printing, as an effective method for enhanced protein patterning and adsorption on arbitrary surfaces. Compared to conventional chemical treatments, this approach offers scalability and long-term device stability without requiring complex chemical activation. Two chemical surface treatments using functionalization with the commonly used 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde (GA) were compared with the nanoporous silica surface on the basis of protein adsorption. The deposited thickness and uniformity of porous silica films were evaluated for fluorescein isothiocyanate (FITC)-labeled rabbit immunoglobulin G (R-IgG) protein printed onto the substrates via patterned polydimethlysiloxane (PDMS) stamps. A more complete transfer of proteins was observed on porous silica substrates compared to chemically functionalized substrates. A comparison of different pore sizes (4-6 nm) and porous silica thicknesses (96-200 nm) indicates that porous silica with 4 nm diameter, 57% porosity and a thickness of 96 nm provided a suitable environment for complete transfer of R-IgG proteins. Both fluorescence microscopy and atomic force microscopy (AFM) were used for protein layer characterizations. A porous silica layer is biocompatible, providing a favorable transfer medium with minimal damage to the proteins. A patterned immunoassay microchip was developed to demonstrate the retained protein function after printing on nanoporous surfaces, which enables printable and robust immunoassay detection for point-of-care applications. PMID- 20834119 TI - Surface coating effects on the assembly of gold nanospheres. AB - Optical spectra and atomic force microscopy (AFM) images of individually selected spheres and mechanically assembled silica-coated gold nanosphere pairs were recorded. The shell served as a means of rigid control of the minimum spacing between the metal cores. The spectra of the assembled spheres were simulated using classical electrodynamics. The observed spectra resulted in superior characterization of the particle assembly geometry, relative to the AFM data. Experimental investigations regarding less-rigid polyvinylpyrrolidone (PVP) sphere coatings were also performed and some comparisons were made. PMID- 20834120 TI - Surface-enhanced Raman nanodomes. AB - We demonstrate a surface-enhanced Raman scattering (SERS) substrate consisting of a closely spaced metal nanodome array fabricated on flexible plastic film. We used a low-cost, large-area replica molding process to produce a two-dimensional periodic array of cylinders that is subsequently overcoated with SiO(2) and silver thin films to form dome-shaped structures. Finite element modeling was used to investigate the electromagnetic field distribution of the nanodome array structure and the effect of the nanodome separation distance on the electromagnetic field enhancement. The SERS enhancement from the nanodome array substrates was experimentally verified using rhodamine 6G as the analyte. With a separation distance of 17 nm achieved between adjacent domes using a process that is precisely controlled during thin film deposition, a reproducible SERS enhancement factor of 1.37 * 10(8) was demonstrated. The nanoreplica molding process presented in this work allows for simple, low-cost, high-throughput fabrication of uniform nanoscale SERS substrates over large surface areas without the requirement for high resolution lithography or defect-free deposition of spherical microparticle monolayer templates. PMID- 20834121 TI - Transforming insulating rutile single crystal into a fully ordered nanometer thick transparent semiconductor. AB - Rutile single crystals treated with ion-beam preferential etching (IBPE) are investigated with electrical transport and transmission electron microscopy. The initially insulating single crystals show the formation of an oxygen vacancy rich, highly ordered, thin conducting layer, below a crystalline rutile TiO(2) surface layer. Carrier concentrations of 10(19) cm(-3) and very high mobilities of the order of 300 cm(2) V(-1) s(-1) are observed in the nanolayers. The observations indicate that rutile single crystals can be effectively transformed into controlled conducting material using IBPE for creating a new breakthrough in transparent conducting media. PMID- 20834122 TI - Determination of rare earth elements (REES) in airborne particulate matter (APM) collected in Tokyo, Japan, and a positive anomaly of europium and terbium. AB - The determination of rare earth elements (REEs) in airborne particulate matter (APM) was conducted, and the distribution pattern of atmospheric REEs was evaluated in this study. The APM was collected in the center of Tokyo, Japan, where serious air pollution is always of concern. A cellulose acetate membrane filter was used to collect the APM because Ba and REEs contamination is lower than that in a quartz glass fiber filter. The REEs measurement was conducted by ICP-MS after the digestion of the APM by a microwave acid digestion procedure. The standard reference material (SRM) of NIST 1648 urban particulate matter was used to validate the accuracy of the analytical method. The analytical results for SRM well agreed with those of the reference and reported values. Consequently, the analytical method established in this study was applied to the determination of REEs in APM collected in Tokyo, Japan. The obtained REEs distribution pattern in the APM showed a positive anomaly of Tb and Eu. The La/Sm ratio, which is considered to be as a good indicator of the anthropogenic effect, in size-classified APM showed a high degree of the anthropogenic effect in fine APM with a diameter of <1.1 um. Emission sources of Tb, Eu and other REEs are discussed. PMID- 20834123 TI - Multifunctional separation mechanism on poly(oxyethylene) stationary phases in capillary liquid chromatography. AB - The retention behavior on poly(oxyethylene) (POE) chemically-bonded stationary phases was investigated in ion-exchange, reversed-phase (RP) and hydrophilic interaction (HILIC) modes in capillary liquid chromatography. The eluent cations fixed on the oxygen atoms of the POE chains by ion-dipole interaction worked as the anion-exchange sites for the separation of inorganic anions. Nonpolar analytes were retained on the POE stationary phases in the RP mode, while polar organic analytes were retained in the HILIC mode. Sodium alkyl sulfate dynamically modified on the stationary phase enhanced the hydrophobic property of the stationary phase. The effect of the oxyethylene unit number on the retention behavior was examined, and it was expected that the eluent cation is trapped among multiple POE chains by ion-dipole interaction. PMID- 20834124 TI - Enantiomeric separation by capillary electrochromatography on a sulfated poly beta-cyclodextrin modified silica-based monolith. AB - A sulfated poly beta-cyclodextrin (SPCD) modified silica-based monolithic column was prepared for enantiomeric separation. First, 2-hydroxy-3-allyloxy-propyl-beta cyclodextrin (allyl-beta-CD) was bonded onto a bifunctional reagent 3 (methacryloxy)propyltriethoxysilane (gamma-MAPS) modified silica-based monolith through radical polymerization; the column was then sulfated with chlorosulfonic acid. The SPCD chiral stationary phase resolved the boring problem associated with desalting when sulfated CDs were synthesized to act as chiral additives. The inorganic salt in the column introduced during the sulfating process could be easily removed by washing the column with water for some time. Chiral compounds investigated were successfully resolved into their enantiomers on the SPCD modified monolith in the capillary electrochromatography (CEC) mode. Due to the existence of the -SO(3)H group, electrosmotic flow (EOF) was obviously increased, and all of the separations could be carried out in 20 min with only a minor loss in the column efficiency and resolution. PMID- 20834125 TI - Sensor properties and surface characterization of silver-deposited SPR optical fibers. AB - The response curves and sensor properties of silver-deposited optical fibers with Ag film thicknesses of 20.0 - 80.0 nm based on surface plasmon resonance (SPR) were investigated. The response of the Ag-deposited optical fiber sensor depends on the thickness of the Ag film. The Ag-deposited optical fiber sensors show higher responses than those deposited with Au. The reflection properties of Ag films with thicknesses of 30.5 - 70.2 nm due to the SPR phenomenon were also measured and considered. The surfaces of these Ag films consist of various spherical grains with diameters of 30 - 90 nm and the surface height distribution is almost random, having a value of more than 8 nm. X-ray photoelectron spectroscopy (XPS) showed the presence of very thin (0.3 nm) native oxide layers on the Ag films. The Ag-deposited optical fiber sensor exhibited no change in the sensor properties following prolonged use for 4 months. The response curves of the Ag-deposited optical fiber sensors by use of SPR theoretical equations were calculated and compared with those obtained by experimentation. PMID- 20834126 TI - Surface-enhanced Raman scattering of 4-aminothiophenol adsorbed on silver nanosheets deposited onto cubic boron nitride films. AB - A simple method was found for the fabrication of silver nanosheets (AgNS) by the catalysis of gold nanoparticles (AuNP) on an amine-terminated cubic boron nitride (cBN) surface deposited on a Si(001) substrate in the presence of reductant. The morphology of the AgNS/AuNP/NH(2)-cBN/Si(001) sample was characterized by scanning electron microscopy and X-ray diffraction. The performance of the AgNS/AuNP/NH(2)-cBN/Si(001) sample as surface-enhanced Raman scattering (SERS) active substrate was evaluated by using 4-aminothiophenol (PATP) as the probe molecule. The SERS measurements showed that the maximum intensity was obtained on the AgNS/AuNP/NH(2)-cBN/Si(001) sample for 5 min silver deposition. Compared with the AuNP/NH(2)-cBN/Si(001) sample and a silver film/cBN/Si(001) prepared by the mirror reaction, the SERS signal of PATP was obviously improved on the above AgNS/AuNP/NH(2)-cBN/Si(001) film. The sensitivity and the stability of the AgNS/AuNP/NH(2)-cBN/Si(001) sample were also investigated. PMID- 20834127 TI - Improved solid-phase spectrometry for the microdetermination of total and dissolved phosphate. AB - Solid-phase spectrophotometry has been improved for the determination of the total and dissolved phosphate in water. The target phosphate-P at sub-ug dm(-3) to ug dm(-3) levels in a 20-cm(3) water sample was concentrated as the molybdenum blue species to 0.06 or 0.12 cm(3) using a Sephadex G-25 within 30 min, and gel beads were introduced to a 1.5-mm or 3-mm diameter flow cell having a 10-mm light path length. To minimize the error caused by any difference in the packing state of the gel beads in the cell for each measurement, the absorbances of the blue color were directly measured at 836 nm and at 450 nm using a UV-visible spectrophotometer. The absorbance difference (DeltaA) of the two wavelengths was used for determining the trace amounts of P. The sensitivity achieved by this procedure was higher by a factor of over 100 for a 20-cm(3) sample compared to that of the corresponding solution method using a 10-mm cell, and the detection limit was as low as 0.1 ug dm(-3). Higher sensitivity was obtained using 100 cm(3) water samples. Trace levels of the total and dissolved phosphate at sub-ug dm(-3) to ug dm(-3) levels in samples from mountainous small streams were directly determined without any preconcentration procedures. PMID- 20834128 TI - Analysis of photocatalytic reactions using a TiO(2) immobilized microreactor. AB - We have developed an analysis system for photocatalytic reactions, which utilizes a TiO(2) immobilized micro-capillary and a detection technique for dye concentration at arbitrary positions. In this study, we investigated the reaction processes for the photocatalytic decomposition of rhodamine 6G. This system allows the distinction of direct and secondary photocatalytic reactions under the same experimental conditions. The direct reaction occurs between adsorbed species and photoexcited electrons or holes, while the secondary reaction is induced by radicals, such as .OH, O(2)(+)., generated in water or ethanol. The entire reaction was studied by monitoring the dye concentration in the UV irradiated area, while only the secondary reaction was monitored outside the UV irradiated area. PMID- 20834129 TI - Flame atomic absorption spectrometry determination of trace amounts of nickel ions in water samples after ligandless ultrasound-assisted emulsification microextraction. AB - In the present work, a new ligandless-ultrasound-assisted emulsification microextraction (LL-USAEME) method was developed for preconcentration trace amounts of nickel as a prior step to its determination by flame atomic absorption spectrometry. Some factors influencing the extraction efficiency of nickel and its subsequent determination were studied and optimized, such as type and volume of the extraction solvent, pH, extraction time, extraction temperature and ionic strength. Under the optimal conditions, the calibration curve was linear over the range of 1.0 ng mL(-1) - 1.0 ug mL(-1) for nickel with R(2) = 0.9997. The detection limit was 0.34 ng mL(-1) in the original solution (3S(b)/m) and the relative standard deviation for 8 replicate determination of 0.3 ug mL(-1) nickel was +/-1.6%. The proposed method was successfully applied in the analysis of four real environmental water samples and good spiked recoveries over the range of 97 103% were obtained. PMID- 20834130 TI - In vitro and in vivo methods to measure the ceftriaxone distribution into the rat tail intervertebral disc. AB - To characterize the pathway of ceftriaxone penetration into intervertebral discs, rat-tail discs were collected and immersed in a ceftriaxone solution for an in vitro study. For this in vivo experiment, plasma and tail discs were collected 30 min after ceftriaxone administration (463.2 mg/kg, equal to 500 mg/kg disodium salt, iv). The ceftriaxone levels in the plasma and discs were determined with HPLC by a reversed-phase C18 column and a mobile phase of methanol and a 10 mM K(2)HPO(4) solution (pH 6.7) (21:79, v/v). The results indicate that ceftriaxone was undetectable by the in vitro model. The concentrations of ceftriaxone in plasma and in intervertebral discs were 147.4 +/- 21.2 and 4.0 +/- 1.7 ug/mL (as disodium salt), respectively. Our results suggest that a sufficient blood supply is required for the passive diffusion of ceftriaxone into intervertebral discs. The concentration ratio of ceftriaxone in intervertebral disc-to-plasma was about 2.7% at 30 min after ceftriaxone disodium administration (500 mg/kg, iv). PMID- 20834131 TI - Processing of the signal from detectors used in ion mobility spectrometry. AB - The output signal generated by detectors used in ion mobility spectrometry (IMS) is a time-dependent, small ionic current. To be able to take full advantage of information contained in this signal, adequate procedures of signal processing need to be utilized. Methods of spectrum filtration, peak separation, base-line correction as well as one- and two-dimensional integration applied in quantitative analysis are described. The effectiveness of the chosen methods was demonstrated on examples of experimental results obtained by IMS. Measurements were performed for spectra of reactant ions and sample ions generated by acetone, methyl tert-butyl ether (MTBE), dimethyl methylphosphonate (DMMP) and benzene. It was demonstrated that the proposed methods considerably improve the quality of the spectra, increase the selectivity of detection and reduce the uncertainty of quantitative measurements. PMID- 20834132 TI - Electrochemical modification of a graphite platform for a solid sampling electrothermal atomic absorption spectrometry of mercury. AB - An electrodeposited palladium and iridium/gold mixture has been investigated as a chemical modifier for mercury determination in environmental samples by solid sampling electrothermal atomic absorption spectrometry. Electrochemical procedures of platform surface modification performed in a cell with 20 ml of solution, and in a drop of modifier solution have been optimized. Simple electrolysis in a drop was found to be the most consistent, taking the reproducibility as the major criterion. A total mass of 250 ug of electrodeposited palladium or an iridium/gold mixture was used. The lifetime of 60 - 70 firings for a deposited iridium/gold mixture was smaller than that for palladium with a lifetime of 100 - 120 firings. The detection limit was 120 pg Hg. Different sample masses of between 0.1 and 10 mg were weighed into modified platforms according to the mercury content. The results obtained for mercury in environmental samples as soils, sediments and plant, using solid sampling and calibration against aqueous standards stabilized by potassium permanganate, were in good agreement with those achieved by using the thermal deposition of modifiers and with measurements by pyrolysis atomic absorption spectrometry with gold amalgamation. PMID- 20834133 TI - Mesoporous platinum electrodes for amperometric determination of sugars with anion exchange chromatography. AB - A simple amperometric detection (AD) method based on mesoporous platinum (Pt) electrodes has been developed for the determination of sugars (glucose, fructose, and sucrose) with high-performance anion-exchange chromatography (HPAEC). The amperometric detection is based on the direct oxidation of sugars on mesoporous Pt films formed on a gold electrode. The mesoporous Pt electrode (roughness factor of 243) sensitively responded to glucose, fructose, and sucrose in 80 mM sodium hydroxide solution as an alkaline mobile-phase for HPAEC. Under the optimum conditions, the limits of detection (S/N = 3) in these sugars were 0.24, 0.29, and 1.8 mM, for glucose, fructose, and sucrose, respectively. The reproducibility (relative standard deviation) of the measurements was less than 3.5%. The present method was applied to the determination of sugars in apple juice. The recoveries for all sugars ranged from 97 to 99%. PMID- 20834134 TI - A reusable capacitive immunosensor based on a CuS ultrathin film constructed by using a surface sol-gel technique. AB - A capacitive sensing method based on a CuS ultrathin film modified electrode prepared by a surface sol-gel technique has been developed for the direct detection of human IgA. The resulting CuS film was investigated with cyclic voltammetry (CV), impedance spectroscopy, and quartz crystal microbalance (QCM). CV and impedance examinations showed that the CuS film formed on the gold electrode surface was insulated, and was applicable to form an insulating layer of a capacitive immunosensor. With QCM measurements, the thickness of the CuS film was evaluated to be 5.8 nm. The capacitance change was greatly increased by a CuS nanofilm-based immunosensor, which was initiated by the recognition of an immobilized antibody and the target antigen. The capacitance of the immunosensor corresponding to the concentration of human IgA was investigated by potentiostatic-step measurements. A linear calibration curve was obtained in the range of 1.81 - 90.5 ng ml(-1) with a detection limit of 1.81 ng ml(-1). There were no obvious interferences from the nonspecific adsorption of other proteins. With nice reproducibility and regeneration capacity, the CuS ultrathin film modified immunosensor could be used for the detection of human IgA in serum samples with a recovery of 96.1 - 104.4%, showing its promising applicability and reliability. PMID- 20834135 TI - Traceable amino acid analyses of proteins and peptides by isotope-dilution mass spectrometry using precolumn derivatization reagent. AB - We have developed an accurate and traceable quantitation method of proteins and peptides by isotope-dilution mass spectrometry with the precolumn derivatization for hydrolyzed amino acid. This method utilized N-butylnicotinic acid N hydroxysuccinimide ester iodide as the derivatization reagent and C-30 reversed phase column for the separation. Quantitative results of porcine insulin and human serum albumin obtained from the hydrolyzed six or seven amino acids showed a good agreement, with less than 3% of the expanded uncertainties. This method allows more accurate and more robust amino acid analysis in comparison with non labeled methods. PMID- 20834136 TI - Retention behavior on aminoethyl-modified poly(p-phenylene terephthalamide) fiber stationary phases in gas chromatography. AB - Surface derivatization of Kevlar, poly(p-phenylene terephthalamide), fiber has been studied along with the evaluation of the surface characteristics of the chemically-modified fiber as the stationary phase in packed-capillary gas chromatography (GC). Several experimental parameters in the derivatization reaction have been optimized, and the retention behavior of the surface derivatized fibrous stationary phase has been investigated using various standard solutes, such as alkanes, alcohols and alkylbenzenes. By introducing aminoethyl functional groups onto the surface of the fibrous material, a specific selectivity for polar solutes has been observed. PMID- 20834138 TI - Expression of the stress-related genes for glutathione S-transferase and ascorbate peroxidase in the most-glycinin-deficient soybean cultivar Tousan205 during seed maturation. AB - Global analysis of gene expression profiles in most-glycinin-deficient cultivar Tousan205, was performed by DNA microarray analysis. It was confirmed that Tousan205 lacks mRNA expression of three glycinin subunit precursor genes, G1 (A1aB1x), G2 (A2B1a), and G5 (A3B4), and lacks G4 (A5A4B3) protein. Most glycinin subunits were deficient in mature seeds of Tousan205. We compared the gene expression of Tousan205 with those of parent cultivar, Tamahomare, which was used for crossbreeding of Tousan205. As a result, Tousan205 exhibited higher expression of some seed maturation proteins, and stress-related genes such as glutathione S-transferase and ascorbate peroxidase. This result indicates the possibility that the decrease of main storage protein, glycinin causes stress in soybean. PMID- 20834139 TI - Burkholderia vietnamiensis isolated from root tissues of Nipa Palm (Nypa fruticans) in Sarawak, Malaysia, proved to be its major endophytic nitrogen fixing bacterium. AB - Root-associating bacteria of the nipa palm (Nypa fruticans), preferring brackish water affected mud in Sarawak, Malaysia, were investigated. In a comparison of rhizobacterial microbiota between the nipa and the sago (Metroxylon sagu) palm, it was found that the nipa palm possessed a group of Burkholderia vietnamiensis as its main active nitrogen-fixing endophytic bacterium. Acetylene reduction by the various isolates of B. vietnamiensis was constant (44 to 68 nmol h(-1) in ethylene production rate) in soft gel medium containing 0.2% sucrose as sole carbon source, and the bacterium also showed motility and biofilm-forming capacity. This is the first report of endophytic nitrogen-fixing bacteria from nipa palm. PMID- 20834140 TI - The distribution of phosphatidyl-D-serine in the rat. AB - Phosphatidylserine plays an important role in cell membranes. We have reported the occurrence of phosphatidyl-D-serine (D-PS) in the rat cerebrum. Here, we describe the tissue distribution of D-PS in the rat. The D/D+L ratio of D-PS in the cerebrum was 0.9%, while no detectable amount of D-PS was detected in the cerebellum. D-PS was also found in the heart, spleen, lung, testis, liver, and kidney in a range of 0.05-0.7% (the D/D+L ratio). Thus, D-PS, even in small amounts, is localized to the cerebrum in the brain and is distributed to various tissues other than the brain in the rat. PMID- 20834141 TI - A yeast bioassay for androgenic and anti-androgenic compounds based on the NH2- and COOH-terminal interaction of androgen receptor. AB - Androgenic compounds induce an interaction between the NH(2)- and COOH-terminal regions (N-C interaction) of androgen receptor (AR). We describe a rapid yeast bioassay for androgenic and anti-androgenic compounds based on androgen-dependent beta-catenin-enhanced N-C interaction. The bioassay was also effective at detecting compounds that inhibit the N-C interaction in ways that do not involve binding to the ligand-binding domain. PMID- 20834142 TI - Functional analysis of the carbohydrate-binding module of an esterase from Neisseria sicca SB involved in the degradation of cellulose acetate. AB - An esterase gene from Neisseria sicca SB encoding CaeA, which catalyzes the deacetylation of cellulose acetate, was cloned. CaeA contained a putative catalytic domain of carbohydrate esterase family 1 and a carbohydrate-binding module (CBM) family 2. We constructed two derivatives, with and without the CBM of CaeA. Binding assay indicated that the CBM of CaeA had an affinity for cellulose. PMID- 20834143 TI - Identification of osteoclastic factors in the nuclear envelope of mature, multinucleated osteoclasts. AB - Multinucleation is indispensable to the bone-resorbing activity of mature osteoclasts. Nevertheless, little is known about the regulatory networks among multi-nuclei in a single mature osteoclast. For this reason, we purified osteoclastic factors from the nuclear envelope by two-dimensional gel electrophoresis. Two annexin family proteins and ferritin light chain 1 protein were identified as osteoclastic candidates. PMID- 20834144 TI - Fucoidan isolated from Laminaria angustata var. longissima induced macrophage activation. AB - We investigated macrophage activation by fucoidan from Laminaria angustata var. longissima in a murine macrophage cell line, RAW 264.7. The ratio of the chemical composition of the fucoidan was L-fucose:D-galactose:D-glucose:D-xylose:uronic acid:sulfate=1.00:0.54:0.08:0.08:0.64:0.87. The fucoidan induced production of nitric oxide, tumor necrosis factor-alpha, and interleukin-6 in RAW 264.7 cells. These results indicate that the fucoidan induced macrophage activation. PMID- 20834145 TI - Molecular cloning and characterization of gamma-glutamyltranspeptidase from Pseudomonas nitroreducens IFO12694. AB - gamma-glutamyltranspeptidase from Pseudomonas nitroreducens IFO12694 (PnGGT) exhibited higher hydrolytic activity than transfer activity, as compared with other gamma-glutamyltranspeptidases (GGTs). PnGGT showed little activity towards most of L-amino acids and towards glycyl-glycine, which is often used as a standard gamma-glutamyl accepter in GGT transfer reactions. The preferred substrates for PnGGT as a gamma-glutamyl accepter were amines such as methylamine, ethylamine, and isopropylamine. PMID- 20834146 TI - Concise synthesis of Valerena-4,7(11)-diene, a highly active sedative, from valerenic acid. AB - A concise synthesis of valerena-4,7(11)-diene with potent sedative activity was achieved in three steps involving, reduction of carboxylic acid, bromination of the resulting alcohol, and reduction of the bromide from valerenic acid in a 63% total yield. This synthetic method makes it possible to provide further materials for biological testing to realize comprehensive SAR studies. PMID- 20834147 TI - Protease-catalyzed monoacylation of 2-O-alpha-D-glucopyranosyl-L-ascorbic acid in three solvent systems. AB - 6-O-dodecanoyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acid (6-sDode-AA-2G) was synthesized from 2-O-alpha-D-glucopyranosyl-L-ascorbic acid and vinyl laurate with a protease from Bacillus subtilis in 30% dimethylformamide (DMF)/dioxane with a low water content. The addition of 3% (v/v) water to DMF/dioxane dramatically enhanced the 6-sDode-AA-2G synthesis. The optimum reaction conditions enabled 6-sDode-AA-2G to be synthesized in a yield of 38.1%. PMID- 20834148 TI - Isolation of N,N-dimethyl and N-methylserotonin 5-O-beta-glucosides from immature Zanthoxylum piperitum seeds. AB - Two serotonin derivatives, N,N-dimethylserotonin 5-O-beta-glucoside (1a) and N methylserotonin 5-O-beta-glucoside (1b) were isolated from immature seeds of Zanthoxylum piperitum. Their structures were determined by multi-step conversion reactions and spectroscopic analyses. Immature seeds of Z. piperitum contained extremely high levels of compounds 1a and 1b of approximately 0.29% and 0.15% (w/w), respectively. PMID- 20834149 TI - Possible link of a compositional change in intestinal microbiota with the anti allergic effect of fructo-oligosaccharides in NC/jic mice. AB - Food allergy was induced in two groups of NC/jic mice. Mice fed frucuto oligosaccharides showed fewer allergic symptoms than control diet-fed mice. The cecal microbiota compositions were clearly different between the two groups, and the difference was partly attributable to Clostridia possession. A possible link of the compositional change in intestinal micriobiota with the anti-allergic effect of fructo-oligosaccharides is suggested. PMID- 20834150 TI - Female sex pheromone of Glossosphecia romanovi (Lepidoptera: Sesiidae): identification and field attraction. AB - In field screening tests of synthetic pheromone candidates for Japanese sesiid species, a mixture of (3Z,13Z)-octadecadien-1-ol and (3Z,13Z)-octadecadienyl acetate successfully attracted male moths of Glossosphecia romanovi, a harmful pest of vine trees. The GC-EAD and GC-MS analyses of the pheromone gland extract revealed that the female moths produced the alcohol and acetate in a ratio of about 20:1, in addition to three other minor structure-related components. PMID- 20834151 TI - Metabolite profiling of Cheonggukjang, a fermented soybean paste, inoculated with various Bacillus strains during fermentation. AB - Metabolite profiling of Cheonggukjang inoculated with different Bacillus strains including Bacillus amyloliqueciens CH86-1, Bacillus licheniformis 58, and Bacillus licheniformis 67 during fermentation, was performed using gas chromatography-time of flight-mass spectrometry after derivatization, combined with multivariate statistical analysis. A total of 20 amino acids, 10 sugars, five sugar alcohols, and seven organic acids were identified in three Cheonggukjang samples. With fermentation time, most of the amino acids showed increasing amounts. On the other hand, most of the sugars including sucrose, fructose, and glucose decreasing patterns, and the amounts of organic acids varied. In order to observe differences in metabolites with fermentation time and inoculated Bacillus strains, principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were carried out, respectively. On PCA plots, some sugars and organic acids including sucrose, fructose, glucose, mannose, succinic acid, and malonic acid, as well as most of the amino acids, contributed mainly to differentiation of the Cheonggukjang samples fermentation time. On the other hand, on PLS-DA, mannose, xylose, glutamic acid, and proline were mainly responsible for differentiating the Cheonggukjang among into various inoculated strains. PMID- 20834152 TI - Identification and characterization of lipolytic enzymes from a peat-swamp forest soil metagenome. AB - In this work, a metagenomic library was generated from peat-swamp forest soil obtained from Narathiwat Province, Thailand. From a fosmid library of approximately 15,000 clones, six independent clones were found to possess lipolytic activity at acidic pH. Analysis of pyrosequencing data revealed six ORFs, which exhibited 34-71% protein similarity to known lipases/esterases. A fosmid clone, designated LP8, which demonstrated the highest level of lipolytic activity under acidic conditions and demonstrated extracellular activity, was subsequently subcloned and sequenced. The full-length lipase/esterase gene, estPS2, was identified. Its deduced amino acid was closely related to a lipolytic enzyme of an uncultured bacterium, and contained the highly conserved motif of a hormone-sensitive family IV lipase. The EstPS2 enzyme exhibited highest activity toward p-nitrophenyl butyrate (C4) at 37 degrees C at pH 5, indicating that it was an esterase with activity and secretion characteristics suitable for commercial development. PMID- 20834153 TI - Anti-asthmatic effects of an Amomum compactum extract on an ovalbumin (OVA) induced murine asthma model. AB - Despite ongoing intensive asthma research, the incidence of asthma is increasing worldwide. We investigated in this study the effects of Amomum compactum on ovalbumin (OVA)-induced asthma in a mouse model, and studied the possible mechanism for its anti-asthmatic action. Our data show that an A. compactum treatment markedly decreased the number of infiltrating eosinophils and the hypersecretion of mucus when compared with the effects on mice treated with OVA alone. The A. compactum treatment dose-dependently decreased the levels of reactive oxygen species (ROS) and T helper (Th)2 cytokines, including interleukin (IL)-4 and IL-5, in the bronchoalveolar lavage fluid (BALF), and a high dose of A. compactum effectively reduced the level of total immunoglobulin (Ig)E in the serum. Taken together, these data indicate that the administration of A. compactum may have potential therapeutic value when used as an adjuvant for the immunomodulatory treatment of allergic asthma. PMID- 20834154 TI - Characterization of oil bodies in adlay (Coix lachryma-jobi L). AB - Oil bodies were observed in cells of both embryo and aleurone layers of mature adlay grains (Coix lachryma-jobi L. var. ma-yuen Stapf). Stable oil bodies were successfully isolated from the adlay grains. Thin-layer chromatography revealed that the contents stored in the adlay oil bodies were mainly neutral lipids (>90% triacylglycerols and about 5% diacylglycerols). The integrity of the isolated oil bodies was presumably maintained via electronegative repulsion and steric hindrance provided by their surface proteins. Immunological cross-recognition using antibodies against sesame oil-body proteins indicated that two oleosin isoforms (termed oleosin-H and oleosin-L) and one caleosin were present in the adlay oil bodies. Full-length cDNA fragments encoding these three unique oil-body proteins were obtained by PCR cloning. MALDI-MS analyses confirmed that the three full-length cDNA fragments encoded the two oleosin isoforms and one caleosin observed in the oil bodies isolated from the adlay grains. PMID- 20834155 TI - Generation of a human anti-tumor necrosis factor-alpha monoclonal antibody by in vitro immunization with a multiple antigen peptide. AB - We developed the in vitro immunization method to induce antigen-specific immune responses in human peripheral blood mononuclear cells (PBMCs). However, when we used a peptide as sensitizing antigen, the antigen-specific immune response was found to be weak, and hence, we could not effectively obtain the antigen-specific antibody gene. In the present study, we attempted to improve the in vitro immunization method by augmenting the immune response to the peptide antigen. We used a multiple antigen peptide for sensitization. In vitro immunization of the multivalent antigen elicited a strong antigen-specific immune response in the PBMCs, and we succeeded in obtaining antigen-specific antibody genes by the phage display method. Further, by combining the variable-region genes and constant region genes of human IgG, we obtained four independent human monoclonal antibodies specific for tumor necrosis factor-alpha. This might be a good strategy for generating antigen-specific human monoclonal antibodies using a peptide antigen. PMID- 20834156 TI - Isolation and molecular characterization of a multicellular cyanobacterium, Limnothrix/Pseudanabaena sp. strain ABRG5-3. AB - A cyanobacterium, semi-filamentous multicellular strain ABRG5-3, was isolated and its unique nature was characterized. This axenic strain formed colonies and was motile on an agarose plate. The 16S rRNA gene of ABRG5-3 exhibited similarities to those of the Limnothrix and Pseudanabaena strains, which are known as filamentous and nonheterocystous cyanobacteria. Peaks in absorbance for the accumulation of chlorophyll a, phycocyanin, and phycoerythrin were observed in the cell extract. Natural separation of the pigments occurred in the supernatant of the autolysed cells. The cell lysis was promoted by osmotic shocks and lysozyme treatments. Chlorophyll a and total DNA were abundantly recovered from the cells. Analysis of the restriction-modification system for genomic DNA revealed novel diversity. Moreover, we made a successful attempt to create antibiotic-resistant strains by conjugation with a foreign plasmid, which indicates that strain ABRG5-3 is transformable. PMID- 20834157 TI - Increased ABCB1 expression in TP-110-resistant RPMI-8226 cells. AB - TP-110, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/TP-110) cells and elucidated their resistance mechanisms. The IC50 value for TP-110 cytotoxicity in the RPMI 8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug efflux pump. PMID- 20834158 TI - IgE-suppressive activity of (-)-matairesinol and its structure-activity relationship. AB - The IgE-suppressive activity of (-)-matairesinol is demonstrated, and the structure-activity relationship of (-)-matairesinol clarified. 3',4-Dihydroxy 3,4'-dimethoxylignano-9,9'-lactone showed higher IgE-suppressive activity than ( )-matairesinol without any cytotoxic activity. Some derivatives bearing a longer and more bulky alkoxy group at the 3 or 4 position showed IgE-accelerative activity. PMID- 20834159 TI - Effects of organic solvents on the reverse transcription reaction catalyzed by reverse transcriptases from avian myeloblastosis virus and Moloney murine leukemia virus. AB - The use of certain organic chemicals has been found to improve yields and specificity in PCR. In this study, we examined the effects of dimethyl sulfoxide (DMSO), formamide, and glycerol on the reverse transcription reaction catalyzed by reverse transcriptases (RTs) from avian myeloblastosis virus (AMV) and Moloney murine leukemia virus (MMLV). At 42 degrees C, DMSO at 24% v/v and formamide at 12-14% inhibited the cDNA synthesis reaction, but DMSO at 12% and formamide at 6 8% improved the efficiency of the cDNA synthesis reaction at low temperatures (25 34 degrees C). Glycerol at 10% improved the efficiency of the cDNA synthesis reaction at high temperatures (49-61 degrees C). The effects of DMSO and formamide appeared to be accompanied by decreases in the melting temperatures of the primers, and the effect of glycerol was due to increases in the thermal stabilities of AMV RT and MMLV RT. PMID- 20834160 TI - Regulatory mechanisms of Cordyceps sinensis on steroidogenesis in MA-10 mouse Leydig tumor cells. AB - Cordyceps sinensis (CS) is an herbal medicine that increases steroidogenesis in Leydig cells and improves male reproductive dysfunction. We have found that CS stimulates Leydig cell steroidogenesis through the protein kinase A and protein kinase C signaling pathways. In the present study, we sought to determine the mechanisms of CS-stimulated steroidogenesis in MA-10 mouse Leydig tumor cells. Using pharmacological approaches, we found that de novo protein synthesis, protein transcription, a calcium signal, and a mitochondria electrochemical gradient were required for CS-stimulated steroidogenesis in MA-10 cells. mRNA expression of steroidogenic acute regulatory protein was activated by CS. However, CS had an adversary effect on P450 side-chain cleavage enzyme activity, but not in 3beta-hydroxysteroid dehydrogenase enzyme, in regulating MA-10 cell steroidogenesis. In conclusion, de novo protein synthesis, increased steroidogenic acute regulatory protein mRNA expression, and the mitochondria electrochemical gradient were involved in CS-stimulated steroidogenesis in MA-10 cells. PMID- 20834161 TI - Application of an electrochemical NAD+ recycling system involving a string-like carbon fiber to an enzyme reactor. AB - A string-like carbon fiber was found to be very suitable as a working electrode material for direct electrochemical oxidation of beta-nicotinamide adenine dinucleotide reduced form (NADH), and direct use of it for an enzyme reactor was possible. The electrochemical NAD+ recycling system was applied to glucose dehydrogenase (GDH) and to the recombinant formate dehydrogenase (RFDH) reactors. The maximum oxidation current value increased to 3.9 mA in the case of the GDH reactor. The remaining GDH activity after the reaction for 10 h amounted to 57% of the initial level. The remaining NAD+ activity amounted to 78% of the initial level. The current efficiency was calculated to be 80%. Furthermore, RFDH, which was more stable than GDH, was applied to the system. The maximum current value reached 5.9 mA. The remaining RFDH activity after reaction for 10 h amounted to 81% of the initial level. The remaining NAD+ activity was 78% of the initial level. The current efficiency was calculated to be 73%. Based on these results, both the enzyme and NAD+ were found to be acceptably stable in the electrochemical NAD+ recycling system. PMID- 20834162 TI - The ALG-2 binding site in Sec31A influences the retention kinetics of Sec31A at the endoplasmic reticulum exit sites as revealed by live-cell time-lapse imaging. AB - ALG-2, a member of the penta-EF-hand protein family, interacts Ca2+-dependently with a COPII component, Sec31A. In this study, we first established HeLa cells stably expressing green fluorescent protein-fused ALG-2 (GFP-ALG-2) and red fluorescent protein-fused Sec31A (Sec31A-RFP). After inducing Ca2+-mobilization, the cytoplasmic distribution of GFP-ALG-2 changed from a diffuse to a punctate pattern, which extensively overlapped with the Sec31A-RFP-positive structures, indicating that ALG-2 is recruited to the endoplasmic reticulum exit sites (ERES) in living cells. Next, overlay experiments with biotin-labeled ALG-2 were done to dissect the ALG-2 binding site (ABS). They revealed that a sequence comprising amino acid residues 839-851 in the Pro-rich region was necessary and sufficient for direct binding to ALG-2. Finally, fluorescence recovery after photobleaching analysis indicated that the ABS deletion reduced the high-affinity population of Sec31A to the ERES, suggesting that the ABS is one of the key determinants of the retention kinetics of Sec31A at ERES. PMID- 20834163 TI - Inhibitory effect of Elephantopus mollis H.B. and K. extract on melanogenesis in B16 murine melanoma cells by downregulating microphthalmia-associated transcription factor expression. AB - In this study, the inhibitory effect of Elephantopus mollis H.B. and K. extract on melanogenesis in B16 murine melanoma cells was examined and possible mechanisms were elucidated. The melanin content in B16 cells decreased when they were treated with E. mollis extract. Inhibition was accompanied by reduced expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TRP1). Furthermore, the expression level of microphthalmia-associated transcription factor (MITF), a major transcriptional regulator of genes encoding melanogenic enzymes such as Tyr and Trp1, decreased as assessed by western blotting and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These results suggest that E. mollis extract reduces melanogenesis by downregulating Mitf expression, leading to reduced expression of Tyr and Trp1. In addition, melanocortin-1 receptor (MC1R) expression was downregulated by E. mollis extract, suggesting desensitization to alpha-melanocyte-stimulating hormone (alpha-MSH) of cells treated with the extract. PMID- 20834164 TI - Selective hydrolysis of the 3,6-anhydrogalacotosidic linkage in red algal galactan: a combination of reductive acid hydrolysis and anhydrous mercaptolysis. AB - Here we report a simple method for the structural analysis of red algal galactan containing 3,6-anhydrogalactose. Structural heterogeneity in the galactan was demonstrated by this method. For selective hydrolysis of 3,6-anhydrogalactosidic linkages in the galactan, conditions for reductive mild acid hydrolysis were examined by characterizing the resulting oligosaccharide alditols by anhydrous mercaptolysis. Residues other than alditols at the reducing ends, including labile 3,6-anhydrogalactose, were liberated quantitatively as diethyl dithioacetal derivatives, whereas alditols at the reducing ends were not derivatized and were liberated as alditols intact. The liberated sugars were then separated and measured quantitatively by gas-liquid chromatography. Heating of agarose in reductive hydrolysis with 0.3 M trifluoroacetic acid in the presence of an acid-stable reducing agent, 4-methyl morpholine borane, at 80 degrees C for 90 min and for 90 degrees C for 45 min was found to be optimum for the selective hydrolysis of 3,6-anhydrogalactosidic bonds, without detectable cleavage of other glycosidic bonds. PMID- 20834165 TI - Improvements in seasonal allergic disease with Lactobacillus plantarum No. 14. AB - We conducted two randomized, placebo-controlled, double-blind studies of Lactobacillus plantarum No. 14 (LP14) in female students with seasonal allergic diseases. We also examined the mitogenic activity and cytokine inducibility of LP14 using Peyer's patch cells and mesenteric lymph node cells of swine. For subjects who took 8.7*10(8) of LP14, a significant improvement in ocular symptom medication score was observed. In the placebo group, the T helper type 1 (Th1)/T helper type 2 (Th2) ratio tended to decrease after a 6-week intake period, while in the LP14 group, the percentage of Th1 cells significantly increased. Post intake eosinophil counts significantly increased in comparison to those at intake cessation in the placebo group, but it appeared to be suppressed in the LP14 group. There were no changes in fecal microflora. LP14 strongly induced the gene expression of Th1-type cytokines. This study indicates the clinical effects of LP14 on seasonal allergic diseases. PMID- 20834166 TI - Yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) accelerated the healing of acetic acid-induced gastric ulcer in rats. AB - We have reported that LG21 yogurt containing Lactobacillus gasseri OLL 2716 (LG21 yogurt) inhibits the formation of HCl-induced acute gastric lesions through the generation of prostaglandin E2. This study aimed to determine the role of viable Lactobacillus in the healing of acetic acid-induced chronic gastric ulcer. LG21 yogurt or gamma-ray radiated LG21 yogurt was administered orally twice a day for 10 d at a dose of 5 ml/kg. LG21 yogurt significantly accelerated the healing of the ulcer, but gamma-ray radiated LG21 yogurt did not. However, both yogurts significantly inhibited HCl-induced gastric erosive lesions and enhanced the generation of gastric mucosal prostaglandin E2. From the above results, it was found that viable bacteria are needed to accelerate the healing of chronic gastric ulcer, but not to inhibit gastric lesions. PMID- 20834167 TI - X-ray crystal structure of the DNA-binding domain of response regulator WalR essential to the cell viability of staphylococcus aureus and interaction with target DNA. AB - A bacterial two-component signal transduction system, WalK/WalR, is essential to the cell viability of Gram-positive bacteria and is therefore a potential target for the development of a new class of antibiotics. We have solved the X-ray crystal structure of the DNA-binding domain of the response regulator WalR (WalRc) from a Gram-positive pathogen Staphylococcus aureus, currently causing serious problems in public health through the acquisition of multi-drug resistance. The structure contains a winged helix-turn-helix motif and closely resembles those of WalRs of Bacillus subtilis and Enterococcus faecalis, and also that of PhoB of Escherichia coli. Gel mobility shift assays with mutant WalRs revealed specific interactions of WalR with the target DNA, as elaborated by in silico modeling of the WalRc-DNA complex. PMID- 20834168 TI - Effect of oxidized arachidonic acid and hexanal on the mouse taste perception of bitterness and umami. AB - The oxidization of fatty acids generates many volatile compounds forming an aroma, but little is known whether mammals use gustatory sense to detect the oxidized products as a taste or only use olfactory sense to detect as an aroma. We examined in this study the effect of aqueous extracts of the compounds from autoxidized arachidonic acid (AA) ethyl ester or hexanal which is the predominant component generated from oxidized AA by the anosmic mouse licking performance to a tastant. The addition of the water extract from oxidized AA or hexanal to a quinine hydrochloride (QHCl) solution decreased the anosmic mice licking frequency at several concentrations of QHCl. Hexanal also reduced the licking frequency of anosmic mice conditioned to avoid MSG at several concentrations of monosodium glutamate (MSG). These results suggest that hexanal would affect mouse taste perception to QHCl and MSG via the gustatory sensation. PMID- 20834169 TI - Biotransformation of cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid by plant cell cultures of Eucalyptus perriniana. AB - Biotransformations of phenylpropanoids such as cinnamic acid, p-coumaric acid, caffeic acid, and ferulic acid were investigated with plant-cultured cells of Eucalyptus perriniana. The plant-cultured cells of E. perriniana converted cinnamic acid into cinnamic acid beta-D-glucopyranosyl ester, p-coumaric acid, and 4-O-beta-D-glucopyranosylcoumaric acid. p-Coumaric acid was converted into 4 O-beta-D-glucopyranosylcoumaric acid, p-coumaric acid beta-D-glucopyranosyl ester, 4-O-beta-D-glucopyranosylcoumaric acid beta-D-glucopyranosyl ester, a new compound, caffeic acid, and 3-O-beta-D-glucopyranosylcaffeic acid. On the other hand, incubation of caffeic acid with cultured E. perriniana cells gave 3-O-beta D-glucopyranosylcaffeic acid, 3-O-(6-O-beta-D-glucopyranosyl)-beta-D glucopyranosylcaffeic acid, a new compound, 3-O-beta-D-glucopyranosylcaffeic acid beta-D-glucopyranosyl ester, 4-O-beta-D-glucopyranosylcaffeic acid, 4-O-beta-D glucopyranosylcaffeic acid beta-D-glucopyranosyl ester, ferulic acid, and 4-O beta-D-glucopyranosylferulic acid. 4-O-beta-D-Glucopyranosylferulic acid, ferulic acid beta-D-glucopyranosyl ester, and 4-O-beta-D-glucopyranosylferulic acid beta D-glucopyranosyl ester were isolated from E. perriniana cells treated with ferulic acid. PMID- 20834170 TI - Inhibitory effects of heartwood extracts of Broussonetia kazinoki Sieb on the development of atopic dermatitis in NC/Nga mice. AB - We investigated the effects of a topically applied extract of the heartwood of Broussonetia kazinoki Sieb (B. kazinoki) on atopic dermatitis (AD)-like skin lesions induced by an extract of the house-dust mite Dermatophagoides farina in NC/Nga mice. We found that topically applied B. kazinoki extract suppressed the histological manifestations of AD-like skin lesions, and decreased the levels of plasma immunoglobulin E (IgE) and interleukin-4 (IL-4) in the mice. Moreover, B. kazinoki inhibited the induction of thymus-and-activation-regulated chemokine (TARC/CCL17), macrophage-derived chemokine (MDC/CCL22), and regulated-on activation-normal T cell-expressed-and-secreted chemokine (RANTES/CCL5) in HaCaT cells activated by tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In conclusion, our results suggest that B. kazinoki extract has therapeutic advantages in the treatment of AD. PMID- 20834171 TI - Antioxidative activities of Oxindole-3-acetic acid derivatives from supersweet corn powder. AB - The components contributing to the antioxidative activity of supersweet corn powder (SSCP), which is commonly used in corn soup and snacks in Japan, were clarified and the effects investigated. 7-(O-beta-Glucosyloxy)oxindole-3-acetic acid (GOA) was found to be the component most strongly contributing to the 1,1 diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity of the 80% ethanol extract of SSCP, and the presence of its aglycone, 7-hydroxy-oxindole-3-acetic acid (HOA) was confirmed. GOA and HOA respectively contributed 35.1% and 10.5% to the DPPH radical-scavenging activity of the 80% ethanol extract of SSCP. Mice orally administered with HOA at doses of both 500 and 1500 mg/kg showed a significantly lower (p<0.05) level of thiobarbituric acid reactive substances (TBARS) in the plasma than the vehicle-treated control. These results suggest that GOA and HOA were at least partly involved in the antioxidative activity of SSCP in vitro and that HOA might have possessed antioxidative activity in vivo. PMID- 20834172 TI - SPME technique for analyzing headspace volatiles in fish miso, a Japanese fish meat-based fermented product. AB - The optimized conditions were evaluated for solid-phase microextraction (SPME) to investigate the headspace volatiles in fish miso, a Japanese fish meat-based fermented product. The influence on the efficiency for microextraction of such parameters as the sample size, isolation time and temperature, sensitivity and selectivity of several SPME fibers of different liquid phases as well as several extraction techniques was evaluated. Suitable reproducibility and sensitivity of SPME were achieved by combining carbowax/divenylbenzene of 65 um thickness as the liquid phase of SPME, 3 g of fish miso, 40 degrees C of isolation temperature and 40 min of isolation time. The headspace volatiles of fish miso prepared from spotted mackerel were analyzed under the optimized conditions. Although several volatiles contributed to fish miso, certain volatile esters might have played the greatest role in imparting the sweet-fruity aroma to the product. PMID- 20834173 TI - The biochemistry and molecular biology of xenobiotic polymer degradation by microorganisms. AB - Research on microbial degradation of xenobiotic polymers has been underway for more than 40 years. It has exploited a new field not only in applied microbiology but also in environmental microbiology, and has greatly contributed to polymer science by initiating the design of biodegradable polymers. Owing to the development of analytical tools and technology, molecular biological and biochemical advances have made it possible to prospect for degrading microorganisms in the environment and to determine the mechanisms involved in biodegradation when xenobiotic polymers are introduced into the environment and are exposed to microbial attack. In this review, the molecular biological and biochemical aspects of the microbial degradation of xenobiotic polymers are summarized, and possible applications of potent microorganisms, enzymes, and genes in environmental biotechnology are suggested. PMID- 20834174 TI - Regulation of T cell activation and anergy by the intensity of the Ca2+ signal in cooperation with other signals. AB - The results of our previous in vitro study indicated that the intensity of the Ca2+ signal could determine T cell activation and anergy. We show here that the T cell response of mice that had been treated with cyclosporine A during oral tolerance induction was higher than that of control mice, indicating that the Ca2+ signal could also determine T cell activation and tolerization in vivo. However, T cell activation was not apparent at any concentration of ionomycin, although a low dose of anti-CD3 monoclonal antibody (mAb) induced activation, while a high dose induced anergy in vitro. These results indicate that the balance between the Ca2+ signal and other signals which can also be induced by anti-CD3 stimulation, but not the actual intensity of the Ca2+ signal or the presence of co-stimulation, played an important role in regulating T cell activation and anergy. PMID- 20834175 TI - Flower color modification by engineering of the flavonoid biosynthetic pathway: practical perspectives. AB - The status quo of flavonoid biosynthesis as it relates to flower color is reviewed together with a success in modifying flower color by genetic engineering. Flavonoids and their colored class compounds, anthocyanins, are major contributors to flower color. Many plant species synthesize limited kinds of flavonoids, and thus exhibit a limited range of flower color. Since genes regulating flavonoid biosynthesis are available, it is possible to alter flower color by overexpressing heterologous genes and/or down regulating endogenous genes. Transgenic carnations and a transgenic rose that accumulate delphinidin as a result of expressing a flavonoid 3',5'-hydroxylase gene and have novel blue hued flowers have been commercialized. Transgenic Nierembergia accumulating pelargonidin, with novel pink flowers, has also been developed. Although it is possible to generate white, yellow, and pink-flowered torenia plants from blue cultivars by genetic engineering, field trial observations indicate difficulty in obtaining stable phenotypes. PMID- 20834176 TI - Cloning and overexpression of the xylitol dehydrogenase gene from Bacillus pallidus and its application to L-xylulose production. AB - The xylitol dehydrogenase gene (xdh) of Bacillus pallidus was cloned and overexpressed in Escherichia coli using pQE60 vector, for the first time. The open reading frame of 759 bp encoded a 253 amino acid protein with a calculated molecular mass of 27,333 Da. The recombinant xylitol dehydrogenase (XDH) was purified to homogeneity by three-step column chromatography, producing a single SDS-PAGE band of 28 kDa apparent molecular mass. The enzyme exhibited maximal activity at 55 degrees C in glycine-NaOH buffer pH 11.0, with 66% of initial enzyme activity retained after incubation at 40 degrees C for 1 h. In further application of the recombinant bacterium to L-xylulose production from xylitol (initial concentration 5%) using a resting cell reaction, 35% L-xylulose was produced within 24 h. This result indicates that this recombinant XDH is applicable in the large-scale production of L-xylulose. PMID- 20834177 TI - Melanogenesis inhibition due to NADH. AB - The effect of NADH on melanogenesis under aerobic conditions involves three types of reaction: (a) acting as tyrosinase substrate (a competitive substrate of L tyrosine and L-DOPA), (b) irreversible inactivation acting as a suicide substrate of tyrosinase, and (c) non-enzymatic reduction of o-dopaquinone by NADH. Under anaerobic conditions, NADH irreversibly inhibits the enzymatic forms met tyrosinase and deoxy-tyrosinase. In this paper, we kinetically characterize this coenzyme as it acts as a tyrosinase suicide substrate and propose a kinetic mechanism to explain its oxidation by tyrosinase. In addition, the compound is characterized as an irreversible inhibitor of met-tyrosinase and deoxy tyrosinase. PMID- 20834178 TI - Effect of corosolic acid on dietary hypercholesterolemia and hepatic steatosis in KK-Ay diabetic mice. AB - Corosolic acid (CA), contained in the leaves of the banaba plant (Lagerstroemia speciosa L.), is a pentacyclic triterpene, and has hypoglycemic effects. The effects of CA on dietary hypercholesterolemia and hepatic steatosis were assessed in KK-Ay mice, an animal model of type 2 diabetes. Two kinds of high cholesterol diet with or without 0.023% CA, were prepared for the study. KK-Ay mice were fed a normal diet (controls), the high cholesterol diet with CA (CA-mice) or that without CA (HC-mice) for 10 weeks. CA inhibited the mean blood cholesterol level by 32% (P<0.05) and the liver cholesterol content by 46% (P<0.05) compared with those of HC-mice 10 weeks after the start of dietary intake. Acutely, CA inhibited the mean blood cholesterol level 4 h after the administration of a high cholesterol cocktail in an oral cholesterol-loading test, compared with that of control mice (P<0.05). These results suggest that CA has some direct effects on the cholesterol absorption process in the small intestine. CA may inhibit the activity of cholesterol acyltransferase, which acts in the re-esterification of cholesterol in the small intestine, in type 2 diabetes. PMID- 20834179 TI - Effects of cyclohexenonic long-chain fatty alcohol in type 2 diabetic rat nephropathy. AB - We attempted to clarify the effects of cyclohexenonic long-chain fatty alcohol (CHLFA) on the alterations of type 2 diabetes-induced nephropathy. Forty-week-old male Goto-Kakizaki (GK) and Wistar rats were divided into four groups of 6 to 8 animals. Group A consisted of eight Wistar rats and served as an age-matched control group. Group B (7 GK rats) received no treatment and served as a diabetic group. Group C (6 GK rats) was treated daily with low-dose CHLFA (2 mg/ kg/body weight, subcutaneously) for 30 weeks, and Group D (6 GK rats) with high-dose CHLFA (8 mg/kg/body weight) for 30 weeks. At the end of the treatment period, urinary protein excretion, blood chemistry, renal histological, and immunohistological analyses were conducted. Although CHLFA administration did not influence serum glucose or insulin levels, it reversed diabetes-induced increases in urinary protein excretion and serum creatinine. Light microscopically, CHLFA treatment ameliorated the otherwise elevated glomerular sclerotic scores in the diabetic group.Immunohistochemically, increased expression of desmin and decreased expression of rat endothelial cell antigen-1 in the group with untreated diabetes both showed a reversal to control levels in the high-dose CHLFA treatment group. In conclusion, CHLFA may ameliorate type 2 diabetes induced nephropathy. PMID- 20834180 TI - Reduction of depression and anxiety by 4 weeks Hericium erinaceus intake. AB - Hericium erinaceus, a well known edible mushroom, has numerous biological activities. Especially hericenones and erinacines isolated from its fruiting body stimulate nerve growth factor (NGF) synthesis, which expects H. erinaceus to have some effects on brain functions and autonomic nervous system. Herein, we investigated the clinical effects of H. erinaceus on menopause, depression, sleep quality and indefinite complaints, using the Kupperman Menopausal Index (KMI), the Center for Epidemiologic Studies Depression Scale (CES-D), the Pittsburgh Sleep Quality Index (PSQI), and the Indefinite Complaints Index (ICI). Thirty females were randomly assigned to either the H. erinaceus (HE) group or the placebo group and took HE cookies or placebo cookies for 4 weeks. Each of the CES D and the ICI score after the HE intake was significantly lower than that before. In two terms of the ICI, "insentive" and "palpitatio", each of the mean score of the HE group was significantly lower than the placebo group. "Concentration", "irritating" and "anxious" tended to be lower than the placebo group. Our results show that HE intake has the possibility to reduce depression and anxiety and these results suggest a different mechanism from NGF-enhancing action of H. erinaceus. PMID- 20834181 TI - The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. AB - SMCT1 (slc5a8) is a sodium-coupled monocarboxylate transporter expressed in the brush border of enterocytes. It regulates the uptake of short-chain fatty acids (SCFAs) produced by bacterial fermentation in the large intestine. Another subtype, SMCT2 (slc5a12), is expressed abundantly in the small intestine, but its precise expression profile remains unknown. The present study using in situ hybridization method, immunohistochemistry, and quantitative PCR analysis examined the distribution and cellular localization of SMCT2 in the digestive tract of mice and compared the expression pattern with those of other transporters for monocarboxylates. While an abundant expression of SMCT2 was found in the jejunum, this was negligible in the duodenum, terminal ileum, and large intestine. In contrast, SMCT1 had predominant expression sites in the large bowel and terminal ileum. Subcellularly, SMCT2 was localized in the brush border of enterocytes in the intestinal villi-as is the case for SMCT1, suggesting its involvement in the uptake of food-derived monocarboxylates such as lactate and acetate. MCT (slc16) is a basolateral type transporter of the gut epithelium and conveys monocarboxylates in an H+-dependent manner. Since among the main subtypes of MCT family only MCT1 was expressed significantly in the small intestine, it is able to function as a counterpart to SMCT2 in this location. PMID- 20834182 TI - Consumption of bonito extract suppresses the decrease in cerebral blood flow in stroke-prone spontaneously hypertensive rats. AB - The effect of consuming bonito extract (BE) on cerebral blood flow was evaluated in stroke-prone spontaneously hypertensive rats (SHRSP), a cerebrovascular disease model. BE dissolved in drinking water was given to 5-week-old male SHRSP for 7 weeks. Tap water was given to the control group. At the age of 12 weeks, blood flow and vascular diameter were measured in the middle cerebral artery. Both cerebral blood flow and cerebral vessel width were greater in the BE group than in the control group. Also, stroke occurred in 7 (with death in 2) of the 8 animals in the control group but in none of the 6 animals in the BE group. To clarify its mechanism, the expressions of nitrogen oxide synthase (NOS) and the superoxide dismutase activity (SOD) in the brain were evaluated. NOS mRNA expression and SOD activity in the cerebrum were higher in the BE group. These results suggest that the consumption of BE suppresses the decrease of cerebral blood flow and reduces the risk of stroke to maintain vasorelaxation through the production of nitrogen oxide and suppression of active oxygen generation. PMID- 20834183 TI - The "Senobi" breathing exercise is recommended as first line treatment for obesity. AB - Neuroadrenergic abnormalities, including a predominant activity of parasympathetic nerve and blunted hormone secretion, are recognized in the overweight patients. This study aimed to examine whether the "Senobi" breathing method, a stretch-breathing exercise that we have developed, could activate or recover sympathetic nervous system activity that leads to the loss of body weight. Forty pre-menopausal women, aged 40 to 50 years, participated in this study. Twenty were healthy and the other 20 were overweight (body mass index>25 and body fat>30%). Sympathetic nerve activity was assessed using equipment that analyzes cardiac-beat variation, and several urinary hormone levels were examined before and 30 min after performing the "Senobi" breathing exercise. The average proportion of sympathetic nerve among healthy women during daytime hours (10:00 AM to 12:00 PM) was 62.6%+/-2.6%. On the other hand, that of overweight women was 33.5%+/-0.4%. After 1 min of the "Senobi" breathing, substantial up-regulation of sympathetic nerve activity and increased urinary hormone secretion were observed in the overweight women but not in the healthy controls. Moreover, after repeating the exercise for a month, the obese patients showed significant loss of body fat. The "Senobi" breathing exercise was found to be effective for weight loss in obesity possibly by regulating the autonomic nervous system and the hormone secretion. PMID- 20834184 TI - Normalized wall index specific and MRI-based stress analysis of atherosclerotic carotid plaques: a study comparing acutely symptomatic and asymptomatic patients. AB - BACKGROUND: Biomechanical stresses play an important role in determining plaque stability. Quantification of these simulated stresses can be potentially used to assess plaque vulnerability and differentiate different patient groups. METHODS AND RESULTS: 54 asymptomatic and 45 acutely symptomatic patients underwent in vivo multicontrast magnetic resonance imaging (MRI) of the carotid arteries. Plaque geometry used for nite element analysis was derived from in vivo MRI at the sites of maximum and minimum plaque burden. In total, 198 slices were used for the computational simulations. A pre-shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (ie, critical stress) was extracted for the selected slices and a comparison was performed between the 2 groups. Critical stress in the slice with maximum plaque burden is significantly higher in acutely symptomatic patients as compared to asymptomatic patients (median, inter quartile range: 198.0 kPa (119.8-359.0 kPa) vs 138.4 kPa (83.8-242.6 kPa), P=0.04). No significant difference was found in the slice with minimum plaque burden between the 2 groups (196.7 kPa (133.3-282.7 kPa) vs 182.4 kPa (117.2-310.6 kPa), P=0.82). CONCLUSIONS: Acutely symptomatic carotid plaques have significantly high biomechanical stresses than asymptomatic plaques. This might be potentially useful for establishing a biomechanical risk stratification criteria based on plaque burden in future studies. PMID- 20834185 TI - Erythropoietin prevention trial of coronary restenosis and cardiac remodeling after ST-elevated acute myocardial infarction (EPOC-AMI): a pilot, randomized, placebo-controlled study. AB - BACKGROUND: Erythropoietin (EPO) enhances re-endothelialization and anti apoptotic action. Larger clinical studies to examine the effects of high-dose EPO are in progress in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The aim of this multi-center pilot study was to investigate the effect of 'low-dose EPO' (6,000 IU during percutaneous coronary intervention (PCI), 24 h and 48 h) in 35 patients with a first ST-elevated AMI undergoing PCI who was randomly assigned to EPO or placebo (saline) treatment. Neointimal volume, cardiac function and infarct size were examined in the acute phase and 6 months later (ClinicalTrials.gov identifier: NCT00423020). No significant regression in in-stent neointimal volume was observed, whereas left ventricular (LV) ejection fraction was significantly improved (49.2% to 55.7%, P=0.003) and LV end-systolic volume was decreased in the EPO group (47.7 ml to 39.0 ml, P=0.036). LV end diastolic volume tended to be reduced from 90.2% to 84.5% (P=0.159), whereas in the control group it was inversely increased (91.7% to 93.7%, P=0.385). Infarction sizes were significantly reduced by 38.5% (P=0.003) but not in the control group (23.7%, P=0.051). Hemoglobin, peak creatine kinase values, and CD34(+)/CD133(+)/CD45(dim) endothelial progenitors showed no significant changes. No adverse events were observed during study periods. CONCLUSIONS: This is a first study demonstrating that short-term 'low-dose' EPO to PCI-treated AMI patients did not prevent neointimal hyperplasia but rather improved cardiac function and infarct size without any clinical adverse effects. PMID- 20834186 TI - Gender differences in the ST segment: effect of androgen-deprivation therapy and possible role of testosterone. AB - BACKGROUND: ST-segment elevation in a structurally normal heart is observed in Brugada- and early repolarization syndrome. The incidence of both syndromes is much higher in males than females. Clinical and basic studies suggest that testosterone plays an important role in ventricular repolarization. METHODS AND RESULTS: Standard surface 12-lead electrocardiograms recorded in 640 healthy subjects were studied (310 males, 330 females ranging in age from 5 to 89 years) (Study 1). The 3 ST levels (ST-J, -M, and -E) were measured in leads V(2) and V(5), which are representative of the right and left ventricles, respectively. The effect of androgen-deprivation therapy on the ST segment was also evaluated in 21 prostate cancer patients (Study 2). In both leads, the 3 ST levels were significantly higher in adult males than females (P<0.0001) due to a marked increase after puberty in males. As their age increased, males manifested a gradual reduction in the ST level in both leads; in females, there was a reduction in lead V(5) only. In both sexes, all 3 ST levels were significantly higher in lead V(2) than V(5) (P<0.0001). Androgen-deprivation therapy significantly decreased all 3 ST segments in both leads. CONCLUSIONS: Significant age- and gender differences in the ST segment in healthy adults were found, suggesting that testosterone modulates the early phase of ventricular repolarization. PMID- 20834187 TI - Lifestyle modification in metabolic syndrome and associated changes in plasma amino acid profiles. AB - BACKGROUND: Although lifestyle modification is the key treatment of metabolic syndrome (MetS), clinical data on the dynamical relationship between metabolic state and MetS has been limited. This study investigated the mutual correlations between demographic and biochemical variables, and the metabolic state based on the plasma amino acid (AA) concentrations, during a lifestyle modification for MetS. METHODS AND RESULTS: Japanese subjects, consisting of 54 patients with MetS [MetS(+)] and 35 persons without MetS [MetS(-)] were included in the study. Before a lifestyle modification program, the levels of glutamate metabolism related AA (Glu-mAA), aromatic AA metabolism-related AA (Aromatic-mAA) and alanine metabolism-related AA (Ala-mAA) were significantly higher, while those of glycine-serine-threonine metabolism-related AA (Gly-Ser-Thr-mAA) were significantly lower compared to those in MetS(-). After a lifestyle modification, significant reductions (P<0.05) in the BMI (-1.4 kg/m(2)), mean blood pressure ( 7.9 mmHg), hemoglobin A(1c) (-0.4%), and triglycerides (-30.6 mg/dl) were observed, and significant differences in the plasma AA levels between MetS(+) and MetS(-) were resolved. In addition, the diagnostic items of MetS were positively correlated with the levels of Glu-mAA, Ala-mAA, branched chain AA (BCAA)-mAA, Aromatic-mAA, and negatively correlated with the levels of Gly-Ser-Thr-mAA. CONCLUSIONS: As MetS subsided, the abnormality of mean plasma AA levels of the MetS(+) group returned to similar values as those in the MetS(-) group, suggesting a novel viewpoint regarding the metabolic mechanism of lifestyle modification. PMID- 20834188 TI - Effect of PMMA filler particles addition on the physical properties of resin composite. AB - The aim of this study was to evaluate the effect of additional polymethyl methacrylate (PMMA) fillers on the physical properties of experimental resin composites. PMMA particles (d=30 um) were added to an experimental methacrylate based resin composite in five concentrations of 0, 2.0, 4.8, 9.1, and 23.1 wt%. Properties such as contact angle, water sorption and compressive strength were measured and the fractured specimens were observed with a scanning electron microscope. The results showed that a small amount (2 wt%) of additional PMMA fillers inhibited the crack propagation and enhanced compressive strengths of the resin composites, without a significant change in water contact angle of surface or increased water sorption. However, in higher portions, the mechanical properties were not improved as a debonding at the interface between untreated fillers and the matrix, or failure within the organic filler could reduce the compressive yield strength of the composite. PMID- 20834189 TI - A transient increase of calcineurin phosphatase activity in living-donor kidney transplant recipients with acute rejection. AB - We describe the longitudinal follow-up of calcineurin activity and its clinical relevance in 4 de novo living-donor kidney transplant recipients treated with cyclosporine (n=1) or tacrolimus (n=3). The calcineurin activity in peripheral blood mononuclear cells was measured in combination with therapeutic drug monitoring during hospitalization. Serial blood samplings were performed after the oral administration of each drug to evaluate the temporal pharmacokinetic and pharmacodynamic profiles. Significant changes in enzyme activity were evaluated in relation to clinical outcomes. A nadir of calcineurin activity occurred at the maximum blood drug concentration within 4 h post-dose in most cases. Unlike cyclosporine, tacrolimus partially suppressed calcineurin activity throughout the dosing interval compared to the pre-dose level (cyclosporine, 62-67% inhibition; tacrolimus, 13-35% inhibition). Notably, calcineurin activity rapidly increased a few days before the onset of acute rejection in 2 patients, 1 receiving cyclosporine and 1 receiving tacrolimus, despite the achievement of therapeutic trough blood concentrations. These preliminary findings indicate that therapeutic monitoring of calcineurin activity in addition to the measurement of blood drug concentrations may be helpful to evaluate the pharmacodynamic effects of cyclosporine and tacrolimus early after renal transplantation. PMID- 20834190 TI - Dihydrofolate reductase gene intronic 19-bp deletion polymorphisms in a Japanese population. AB - Dihydrofolate reductase gene (DHFR) 19-bp deletion polymorphisms result in varied DHFR enzymatic activity affecting the risk for preterm delivery, spina bifida, and the efficacy of methotrexate (MTX). Ethnic differences in DHFR 19-bp polymorphisms may be responsible for the divergent findings in previous genetic studies. We compared genotype and allele frequency of DHFR intronic 19-bp deletion polymorphisms in ethnically homogenous East Asians (from Japan) and others by polymerase chain reaction assay conducted on 277 healthy Japanese individuals. The genotype distribution was as follows: wild/wild, 11.9% (n=33); wild/deletion, 40.1% (n=111); deletion/deletion, 48.0% (n=133). The frequencies of wild type and deletion alleles were 0.32 and 0.68, respectively. The obtained genotype distribution was consistent with those calculated by Hardy-Weinberg equilibrium. The genotype distribution and allele frequencies in the Japanese population were significantly different from those previously reported for other ethnic populations. Determination of intronic 19-bp deletion polymorphisms of DHFR may be useful for monitoring the efficacy and side effects of MTX for the treatment of diseases such as rheumatoid arthritis and childhood acute leukemia in the Japanese population because the frequency of the deletion allele is higher. PMID- 20834191 TI - Characterization of Thr-354 in the human sodium/iodide symporter (NIS) by site directed mutagenesis. AB - Sodium/iodide symporter (NIS) is the key molecule concentrating iodide in the thyroid gland. The first-described human NIS (hNIS) mutation to cause a complete iodide transport defect was the T354P mutation. The Thr-354 lies in the midst of the putative ninth transmembrane segment which is well-conserved within the members of the SLC5A transporter family. Here we have investigated the molecular function of Thr-354 using site-directed mutagenesis and found that T354S and T354A mutations result in significantly decreased iodide transport activity, 50 % and 2 % of wild-type hNIS. Our findings indicate that whereas Thr-354 is indispensable for the complete NIS activity, the beta-hydroxyl group accounts for half, and the alpha-helical structure alone contributes for one-fiftieth of wild type hNIS activity. PMID- 20834192 TI - Absolute value of bioelectrical impedance analysis-measured visceral fat area with obesity-related cardiovascular risk factors in Japanese workers. AB - AIM: The accumulation of Visceral fat is known to precede metabolic disorders and atherosclerosis. This study aimed to determine the relationships between body mass index (BMI), waist circumference (WC), estimated visceral fat area (eVFA) measured by bioelectrical impedance analysis (BIA), and obesity-related cardiovascular risk factors. METHODS: The study population was 2,870 middle-aged Japanese employees (males/females=2,322/ 548), who had undergone a health check up. RESULTS: In the receiver operating characteristic (ROC) curve, the cutoff levels yielding maximal sensitivity plus specificity for predicting the prevalence of >= 2 risks were, 24.5 kg/m(2) for BMI, 84.6 cm for WC, and 111 cm(2) for eVFA in males, and 23.6 kg/m(2), 81.5 cm, and 67 cm(2) in females. The average number of risk factors was over 1.0 in those with a BMI >= 25 kg/m(2) and with a WC >= 85 cm for males, >= 28 kg/m(2) and >= 95 cm respectively for females, and those with an eVFA >= 100 cm(2) for both males and females. In males, it was around 1.0 with cutoff levels of BMI, WC, and eVFA from the ROC curve. However, in females, it was around 0.6, because the prevalence of subjects with obesity and multiple risks was very low. CONCLUSIONS: These results suggested that the cutoff level for visceral fat reduction should be set based on an absolute value of risk factors, rather than a calculated value. In regular health check-up, it may be useful to set an absolute cutoff value for eVFA at 100 cm(2) as criteria to screen for multiple obesity-related cardiovascular risk factors. PMID- 20834193 TI - Very small low-density lipoprotein cholesterol level is a determinant of arterial stiffness in men with impaired glucose metabolism. AB - AIM: Pulse wave velocity (PWV), an estimate of arterial stiffness, is an important predictor of cardiovascular risk. The aim of this study was to investigate the relationship between lipoprotein subclasses and brachial-ankle PWV (baPWV). METHODS: A total of 131 apparently healthy Japanese men without a history of cardiovascular disease were divided into two groups: normal glucose metabolism (n =87) and impaired glucose metabolism (n =44). Cholesterol concentrations of major lipoproteins and their subclasses were determined by HPLC with gel permeation columns. RESULTS: In the normal glucose metabolism group, age, systolic blood pressure, and diastolic pressure were associated with increased baPWV, and a stepwise multiple linear regression analysis revealed that age (p =0.022) and systolic blood pressure (p < 0.001) were significantly independent determinants of baPWV. In the impaired glucose metabolism group, age (p =0.002), very small LDL cholesterol (p =0.012), systolic blood pressure (p =0.021), and the fasting plasma glucose concentration (p =0.038) were identified as independent determinants of baPWV, although a univariate analysis revealed significant relationships of several plasma lipid compositions or species to baPWV. CONCLUSIONS: In addition to aging, hypertension and glucose levels, very small LDL cholesterol levels appear to play an important role in the development of arterial stiffness in men with impaired glucose metabolism. PMID- 20834194 TI - Employee and employer support for workplace-based smoking cessation: results from an international survey. AB - OBJECTIVES: Workplace smoking cessation programs can increase smoking cessation rates, improve employee health, reduce exposure to second-hand smoke, and decrease costs. To assist with the development of such programs, we conducted a Global Workplace Smoking Survey to collect information on workplace attitudes towards smoking cessation programs. METHODS: Data were collected from 1,403 employers (smoking and non-smoking) and 3,525 smoking employees participating in surveys in 14 countries in Asia, Europe, and South America in 2007. Results were weighted to ensure that they were representative of smokers and employers at companies with the specified number of employees. RESULTS: More than two-thirds of employers (69%) but less than half of employees (48%) indicated that their company should help employees with smoking cessation. Approximately two-thirds of employees and 81% of employers overall felt that smoke-free policies encourage cessation, but fewer individuals from Europe (vs. from Asia or South America) agreed with this. In companies with a smoke-free policy, 76% of employees and 80% of employers felt that their policy had been somewhat, very, or extremely effective in motivating employees to quit or reduce smoking. Employers and employees differed substantially regarding appropriate methods for encouraging cessation, with more employees favouring financial incentives and more employers favouring education. CONCLUSIONS: Both employees and employers value smoke-free workplace programs and workplace cessation support activities, although many would like their companies to offer more support. These results will be useful for organizations exploring means of facilitating smoking cessation amongst employees. PMID- 20834195 TI - Regulation of maternal gene expression by MEK/MAPK and MPF signaling in porcine oocytes during in vitro meiotic maturation. AB - Mitogen-activated protein kinase (MAPK) and maturation/M phase promoting factor (MPF) play crucial roles in oocyte meiotic maturation in mammals. However, the underlying molecular mechanisms have not been addressed. In this study, the effects of the MEK/MAPK pathway inhibitor U0126 and the MPF inhibitor roscovitine on meiotic maturation and maternal gene expression in pig cumulus-oocyte complexes (COCs) and denuded oocytes (DOs) were investigated. Both inhibitors can reversibly block the resumption of meiosis in pig oocytes. COCs or DOs initially cultured in drug-free medium for 24 h and then transferred to medium containing U0126 showed normal progress to the Metaphase II stage (MII); (90.38 vs. 92.16% control group). In contrast, roscovitine treatment from 24 to 44 h significantly inhibited maturation of COCs and DOs. To explore the underlying molecular mechanisms, expression patterns and polyadenylation states of five representative maternal transcripts, cyclin B1, Cdc2, C-mos, GDF9 and BMP15, were examined by real-time PCR and poly(A)-test PCR (PAT assay). U0126 treatment resulted in aberrant expression of Cdc2 and GDF9, while roscovitine significantly maintained all five maternal transcripts at very high levels in treated COCs compared with the control group. The polyadenylation of these mRNAs increased as well. Furthermore, the experiments were repeated in DOs, and the results also indicated that both Cdc2 and GDF9 showed significantly higher expression in both mRNA and polyadenylation levels in the drug treatment groups. Together, these results provide the first demonstration in a mammalian system that MAPK and MPF play important roles in regulation of maternal gene expression during oocyte maturation. PMID- 20834196 TI - Trichostatin A promotes the development of bovine somatic cell nuclear transfer embryos. AB - We studied the effects of trichostatin A (TSA), a histone deacetylase inhibitor, on the development of bovine somatic cell nuclear transfer (SCNT) embryos by investigating (1) the optimal concentration and treatment time of TSA for development of bovine SCNT embryos, (2) the status of histone acetylation in TSA treated and control SCNT embryos and (3) the expression of histone acetylation- and deacetylation-related genes in TSA-treated and control SCNT embryos. We observed that 50 nM TSA-treatment for 20 h following fusion resulted in more efficient in vitro development of bovine SCNT embryos to the blastocyst stage. In regard to histone H4K5 acetylation, half of the control SCNT embryos faintly displayed histone H4K5 signals 30 min after electrofusion, while most of the TSA treated SCNT embryos displayed histone H4K5 signals within 30 min after electrofusion. Furthermore, the expressions of HDAC1 and HDAC2 in the blastocysts were significantly lower (P<0.05) in the TSA-treated SCNT than in the control SCNT. However, the expression of GCN5 and HAT1 did not differ between the TSA treated and control SCNT. In conclusion, we demonstrated that TSA-treatment after SCNT in bovine embryos can dramatically improve the practical applications of current cloning techniques. PMID- 20834197 TI - Characterization and identification of Erysipelothrix rhusiopathiae isolated from an unnatural host, a cat, with a clinical manifestation of depression. AB - Erysipelothrix rhusiopathiae is pathogenic for humans, many domestic animals and wild birds, but infectious cases with clinical symptoms in cats have not been reported. E. rhusiopathiae was recovered from a 4-month Russian blue breed cat with a very poor body condition score of 1 (BCS: 1/5). The isolate was typed as serotype 2b. Mice experimentally infected with the clinical isolate of E. rhusiopathiae through subcutaneous or intraperitoneal routes survived, and the organism was recovered from the spleen and synovial and pericardial fluids. Cats experimentally inoculated with the isolate either orally or subcutaneously survived but commonly exhibited depression and emaciation together with localized erythemal lesion of the skin accompanied by purulent ocular discharge. On hematological analysis, the number of total white blood cells was high compared with that in normal cats. Histological examination revealed congestion and moderate inflammation with focal necrosis. This observation may provide insight on E. rhusiopathiae infection in cats with the possible epidemiological significance and implications as a potential source of infection to other animals and humans. PMID- 20834198 TI - Serum heart-type fatty acid binding protein levels in acromegaly patients. AB - BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a major cytoplasmic low molecular weight protein and released into the circulation when the myocardium is injured. Previous studies have demonstrated that H-FABP is closely associated with acute coronary syndrome, hypertrophic and dilated cardiomyopathy, heart failure, stroke, obstructive sleep apnea syndrome, and pulmonary embolism. The aim of this study was to investigate serum H-FABP value in patients with acromegaly. METHODS AND RESULTS: We measured serum H-FABP levels in 30 consecutive patients with acromegaly, and 55 age-matched control subjects by using a sandwich enzymelinked immunosorbent assay. Serum H-FABP levels were significantly higher in patients with acromegaly than in control subjects (17.40 +/- 10.70, and 8.30 +/- 7.20, respectively) (p<0.001). A significant positive correlation was found by Spearman's correlation test between serum H-FABP levels and left ventricular end-systolic diameter (r=0.483, p=0.004). CONCLUSION: Patients with acromegaly have increased levels of H-FABP. Serum H-FABP levels might be a marker of myocardial performance in patients with acromegaly. PMID- 20834199 TI - Serum thyroxine and age--rather than thyroid volume and serum TSH--are determinants of the thyroid radioiodine uptake in patients with nodular goiter. AB - BACKGROUND: Radioiodine (131I) therapy is widely used for treatment of non-toxic goiters. A limitation for this treatment is a low thyroid radioiodine uptake (RAIU), often encountered in these patients. AIM: To estimate the impact of various factors on the thyroid RAIU. METHODS: We examined prospectively 170 patients (146 females; age range: 22-87 yrs) with nodular goiter (median 64 ml, range: 20-464 ml) selected for 131I therapy. Serum TSH was sub-normal in 42.4%. None were treated with anti-thyroid drugs. The thyroid RAIU was determined at 24h and 96 h. The goiter volume was measured by ultrasound (no.=127), or by magnetic resonance imaging (no.=43). RESULTS: The 24h and the 96 h RAIU were 34.2 +/- 9.8(SD)% (range: 11.4-66.0%) and 34.0 +/- 10.0% (range: 10.5-60.9%), respectively. Sixty-one patients had a 24h RAIU <30% and these individuals were older than patients with a 24h RAIU >= 30% (median 58 vs 51 yrs, p=0.02). These two subgroups did not differ significantly in other variables. Overall, the 24h RAIU was positively correlated to the serum (s) free T4-index (r=0.20, p=0.01), and negatively to age (r=-0.18, p=0.02), but not significantly related to serum TSH or thyroid volume. Age correlated positively with thyroid volume (r=0.31, p < 0.001). In a regression analysis, s-free T4-index and age remained as the only determinants of the 24h and the 96 h RAIU. CONCLUSIONS: In patients with a symptomatic nodular goiter, serum T4 and age are the major determinants of the thyroid RAIU. A sub-normal serum TSH is not a marker of a compromised thyroid RAIU but reflects that the iodine is confined to a few 'hot spots'. PMID- 20834200 TI - Serum thyroid hormones levels are significantly decreased in septic neonates with poor outcome. AB - The aim of this prospective study was to investigate the effects of thyroid hormone levels on the sepsis criteria and mortality in septic newborns. This study was performed at the Firat University Hospital Neonatal Intensive Care Unit. A group of septic newborns and a control group of healthy non-infected newborns were evaluated. Blood samples were obtained at onset from septic and healthy newborns and at 10th day of the antibiotic therapy from only septic newborns, and thereafter serum total T(3) (TT(3)), total T(4) (TT(4)), and TSH levels were determined. A total of 292 newborns were included in the study. Serum TT(3) levels at onset and at 10th day of the antibiotic therapy were 163.8+/-63.4 and 178.3+/-33.1 ng/dl, TT(4) levels were 6.9+/-2.2 and 11.0+/-2.6 mg/ml, and TSH levels were 3.8+/-2.1 and 4.0+/-2.5 MUU/ml, respectively in septic newborns. Serum TT3 levels were 180.3+/-47.6 ng/dl, TT(4) levels were 10.9+/-2.3 mg/ml, and TSH levels were 4.1+/-2.2 MUU/ml in healthy newborns. Serum TT(3), TT(4) levels of septic newborns were significantly decreased with respect to those of healthy newborns at onset and serum TT(4) levels was increased significantly after antibiotic therapy. To the best of our knowledge, this report is the first study to compare thyroid hormone levels in a large number of septic newborns and a healthy group. Our findings suggest that before and after treatment of neonatal sepsis a significant change is realized in thyroid hormone levels. PMID- 20834201 TI - Absence of primary hypothyroidism and goiter in Slc26a4 (-/-) mice fed on a low iodine diet. AB - BACKGROUND: Mutations in the SLC26A4 gene, coding for the anion transporter pendrin, are responsible for Pendred syndrome, characterized by congenital sensorineural deafness and dyshormonogenic goiter. The physiological role of pendrin in the thyroid is still unclear and the lack of a thyroid phenotype in some patients with SLC26A4 mutations and in Slc26a4 (-/-) mice indicate the existence of environmental or individual modifiers able to compensate for pendrin inactivation in the thyroid. Since pendrin can transport iodide in vitro, variations in iodide supply have been claimed to account for the thyroid phenotype associated with pendrin defects. AIM: The Slc26a4 (-/-) mouse model was used to test the hypothesis that iodide supply may influence the penetrance and expressivity of SLC26A4 mutations. MATERIALS AND METHODS: Slc26a4 (-/-) and (+/+) mice were fed up to 6 months on a standard or low iodine diet and were evaluated for thyroid structural abnormalities or biochemical hypothyroidism. RESULTS: A 27 fold iodide restriction induced similar modifications in thyroid histology, but no differences in thyroid size, T4 or TSH levels were observed between between Slc26a4 (-/-) and (+/+) mice, either in standard conditions and during iodine restriction. CONCLUSIONS: Iodide restriction is not able to induce a thyroid phenotype in Slc26a4 (-/-) mice. These experimental data, together with those coming from a review of familial Pendred cases leaving in regions either with low or sufficient iodide supply, support the idea that the expression of thyroid phenotype in Pendred syndrome is more powerfully influenced by individual factors than by dietary iodide. PMID- 20834202 TI - Motivational readiness for treatment in weight control programs: the TREatment MOtivation and REadiness (TRE-MORE) test. AB - BACKGROUND AND AIMS: The degree of motivation before starting the treatment represents a pre-treatment predictor of successful weight management. The aim of this study is to develop and validate a new self-reported questionnaire of motivation and readiness to change before starting a lifestyle modification program (the TREatment MOtivation and REadiness test) (TRE-MORE) for overweight patients. METHODS AND RESULTS: TRE-MORE was evaluated in a consecutive series of 129 obese patients attending our Outpatient Clinic. Validation of the questionnaire was performed through test-retest reliability, internal consistency, psychopathological correlates, and concurrent validity. Subjects have been evaluated by means of a clinical interview, and different self-reported questionnaires, assessing the eating specific and general psychopathology, and quality of life. TRE-MORE total and subscales scores showed good test-retest reliability and internal consistency. We identified 10 items grouped in 3 areas (obstacles and desire to overcome, taking care of themselves, and sharing the problems, current lifestyle). TREMORE scores were significantly correlated with eating specific psychopathology and quality of life measures. Univariate and Receiver Operating Characteristic curve analysis showed that TRE-MORE total and subscales scores represent a good model for predicting a weight loss >5% of the initial weight after 6 months of treatment. CONCLUSION: TRE-MORE represents a validated and easy-to-use questionnaire assessing at the meantime the treatment motivation and readiness with good predictive capacity for weight loss. PMID- 20834203 TI - Fallers choose an early transfer gaze strategy during obstacle avoidance in dual task condition. AB - BACKGROUND AND AIMS: The aim of the present study is to compare the gaze behavior between fallers and non-fallers during obstacle avoidance in dual-task conditions. METHODS: Nine older adults who had no experience of falling (mean age 79.9 +/- 5.4) and 9 older adults with known experience of falling (83.4 +/- 3.6) participated in the study. We examined their gaze behavior during obstacle avoidance in singletask (ST) and dual-task (DT) conditions. RESULTS: In the ST condition, compared with the faller group, the non-faller group showed no significant difference in timing of gaze transfer from the obstacle (faller: gaze transfer from obstacle when 1.6 +/- 1.1 steps before; non-faller: 1.9 +/- 0.7 steps before, p=0.493). In the DT condition, the faller group chose a transfer of gaze strategy significantly earlier than the non-faller group (faller: 2.7 +/- 1.4 steps before; non-faller: 1.6 +/- 0.5 steps before, p=0.008). CONCLUSION: Our findings suggest that fallers chose an early transfer of gaze strategy when challenged with an obstacle in DT conditions. PMID- 20834204 TI - Cardiac tumor issue overview. PMID- 20834205 TI - Evaluation of cardiac masses: the role of cardiovascular magnetic resonance. AB - Evaluation of known or suspected cardiac masses is a frequent and expanding indication for referral to the cardiac magnetic resonance (CMR) laboratory. Most patients will have undergone an initial echocardiogram that raised the suspicion of an abnormality. However, echocardiography suffers from several well-described limitations: restricted field of view; incomplete assessment of an invading cardiac mass due to an unfavourable patient body habitus; and limited ability to perform tissue characterization. The role of CMR in this setting is well established because of its ability to obtain a wide field of view, generate high contrast and spatial resolution, and perform multiplanar imaging, allowing precise demonstration and localization of a mass. In clinical practice, CMR serves several useful purposes. First, it is able to help discriminate between a true cardiac mass and a pseudomass. Second, tissue characterization by CMR can assist in generating a differential diagnosis, and can distinguish a cardiac neoplasm (which generally will require excision) from other conditions, such as intracardiac thrombus, lipomatous hypertrophy or benign lipomas (all of which generally do not require excision). Third, even when the etiology of a mass is known, CMR can provide useful information as to the extent of invasion into cardiac, as well as extracardiac structures, and associated findings. This article provides a general overview as to how CMR may be clinically useful to the practicing cardiovascular specialist. PMID- 20834206 TI - Three-dimensional echocardiography in the assessment of cardiac tumors: the added value of the extra dimension. AB - Echocardiography is the most frequently used imaging modality in the assessment of cardiac tumors. Historically, this evaluation had been based on the analysis of 2-dimensional (2D) echocardiographic sectors of the heart. The information obtained from orthogonal tomographic planes from several acoustic windows was used in an attempt to mentally reconstruct a model of how the tumor would actually look in 3 dimensions and how it would relate to its adjacent structures. New technology using matrix-array-transducers has permitted the development of real-time three-dimensional echocardiography (RT3DE), bringing cardiac imaging to a new dimension. Now it is possible to capture and analyze the entire volume of a cardiac tumor in a single cardiac cycle. This new imaging modality provides valuable clinical information that empowers echocardiographers with new levels of confidence in the diagnosis of heart disease. This manuscript discusses the added value of this new technology in the echocardiographic assessment of cardiac tumors. PMID- 20834207 TI - Benign cardiac tumors: a review. AB - Tumors of the heart are very uncommon and can occur as primary or secondary metastatic tumors. Metastatic tumors are over 40 times more common than primary cardiac tumors. Primary tumors of the heart are benign in 75% of cases and malignant in 25%. We first reported our institutional experience with all primary cardiac tumors in 2003. Of the 85 patients seen, 17 had malignant tumors (20%) and 68 had benign tumors (80%). These benign tumors and our subsequent experience form the basis of this report. PMID- 20834208 TI - Less invasive surgery for cardiac tumors. AB - Cardiac surgery has undergone remarkable changes in the last 2 decades. Percutaneous coronary interventions (PCI) were becoming increasingly sophisticated, and patients preferred these to the more durable but invasive option of surgery. Spurred by this, the evolution towards less invasive techniques in cardiac surgery was led by coronary bypass surgery, which of course involved operating on the surface of the heart. The development of less invasive techniques for valve surgery began in the mid-1990s, with advances made simultaneously in the United States and Europe. It became possible to operate inside the heart using techniques that spared the sternum partially or completely. The ability to access all the chambers of the heart with these techniques made it possible to deal with cardiac tumors as well. Less invasive advances in other surgical specialties preceded cardiac surgery and provided some of the ideas that were applied to the special problems of operating in the thorax and, in particular, on the heart. It was clear that there were 2 main groups of patients who would benefit from less invasive techniques in cardiac surgery: 1) patients who want it, including those who are the breadwinners or the main care providers in a family, and 2) patients who need it, mainly elderly, steroid dependent, debilitated, or deconditioned patients. This article offers an overview of the development of less invasive techniques in cardiac surgery and how they have been adapted for cardiac tumors. PMID- 20834209 TI - Malignant tumor overview. PMID- 20834210 TI - Pulmonary artery sarcoma. AB - Primary heart tumors are rare, and malignant primary heart tumors are only a small subset of these. Most primary malignant tumors are sarcomas arising from the cells of the structural elements of the heart such as blood vessels, muscle, connective tissue, fat and even bone. Unlike most malignancies, where cell type often dictates treatment choices and prognosis and is used for classification, the histology in primary cardiac sarcoma plays little role in determining therapeutic options or prognosis. We have found that anatomic location within the heart is the major determining factor in clinical presentation, treatment options and prognosis in cardiac sarcoma. Therefore, we accordingly classify primary cardiac sarcomas into right heart sarcomas, left heart sarcomas and pulmonary artery (PA) sarcomas. Since the first autopsy report of a primary PA sarcoma in 1923, there have been fewer than 250 cases reported in the English literature. Most of these reports have been single autopsy or case reports, and patient prognosis has generally been dismal. Since few institutions and even fewer individual physicians acquire much exposure to this disease, the diagnostic and treatment approaches have remained unresolved. Our cardiac sarcoma group working at the Methodist DeBakey Heart & Vascular Center and the MD Anderson Cancer Center has undertaken a systematic study of this disease, and operated on 9 patients using a radical resection with curative intent and multimodality approach. Based on this work, we have suggested a diagnostic strategy, treatment approach and staging system for primary PA sarcoma. A substantial improvement in patient survival over historical controls has also been demonstrated and will be discussed in this review. PMID- 20834211 TI - Right heart sarcomas. AB - Primary cardiac tumors are unusual, and primary cardiac sarcomas constitute a rare subset of these. In cardiac sarcoma, unlike many malignancies, the histologic cell type does appear to affect the treatment options or prognosis in a significant way. The presenting symptoms, treatment options and, indeed, prognosis are largely controlled by the tumor's anatomic location. We have proposed a classification system based on anatomic location that divides cardiac sarcoma into left heart, right heart and pulmonary artery sarcomas. In our experience, right heart sarcoma tends to be bulky, grow in a more exophitic manner, be more infiltrative, and metastasize earlier than left heart or pulmonary artery sarcoma. Right heart sarcoma also presents less often in congestive heart failure or with compromised hemodynamic status than left heart and pulmonary artery sarcoma, which are usually highly symptomatic at presentation. The prognosis for right heart sarcoma without surgery is dismal. Complete surgical resection remains the goal of therapy and the only treatment modality shown to increase survival. Complete surgical resection is complicated both by the bulky infiltrative nature of right heart sarcoma and the high incidence of metastatic disease at presentation. The current approach of our cardiac sarcoma group to right heart sarcoma has been to begin neoadjuvant chemotherapy once a definitive tissue diagnosis of sarcoma is achieved. After 4 to 6 rounds of chemotherapy, the patient is considered for surgical resection. This standardized treatment has been approved in our IRB protocol: a clinical trial to assess the safety and Efficacy of a novel radical tumor reSection Procedure used in conjunction with nEoadjuvant chemotheRapy to treat malignant primary right heart cardiac tumOrs - the ESPERO trial. This protocol is designed to compare our existing 24 index cases of surgical resection of right heart sarcoma using a nonstandardized treatment plan, with routine neoadjuvant chemotherapy, and a standardized treatment plan to see if the rate of microscopically complete resection can be improved from its current level of 33% and if this will improve patient survival. In this reveiw, we will discuss the experience with right heart sarcoma. PMID- 20834212 TI - Left heart sarcomas. AB - Primary tumors of the heart are uncommon, with roughly 75% benign and 25% malignant. Most of the malignant tumors are sarcomas and historically have had a very poor prognosis. These tumors tend to occur in young patients with a mean age of 40 years. Making a diagnosis of cardiac sarcoma can be difficult due to its rarity and the nature of the symptoms. For left heart sarcomas, almost all patients are symptomatic by the time the diagnosis has been made. Symptoms are dependent on the location and the extent of the tumor and are not related to tumor histology; similarly, histologic cell type has not been found to be related to prognosis in most studies. We therefore previously proposed a classification system for primary cardiac sarcoma based on anatomic location, dividing primary cardiac sarcoma into right heart, pulmonary artery and left heart sarcomas. Left heart sarcoma presents a technical anatomic challenge: the left atrium, being the posterior heart chamber, allows somewhat limited access using routine surgical approaches. The role of chemotherapy or radiotherapy remains unclear and unproven, leaving complete surgical resection as the only mode of therapy with a proven survival benefit. Our review of the published literature showed frequent local recurrence and poor long-term survival in left heart sarcomas. Our hypothesis was that the left atrium had limited anatomic accessibility for large complex resections and reconstructions, and this led cardiac surgeons to do a more limited tumor removal with an increased chance of local recurrence and a detrimental effect on survival. To address this technical challenge, our group introduced the surgical technique of cardiac explantation, ex vivo tumor resection, cardiac reconstruction, and subsequent cardiac reimplantation or cardiac autotransplantation for left heart sarcoma in an attempt to improve the completeness of local resection, decrease local recurrence, and extend patient survival. This review discusses the approach of the cardiac sarcoma group at the Methodist DeBakey Heart & Vascular Center and the MD Anderson Cancer Center to the diagnosis and treatment of left heart sarcoma, as well as our current patient outcomes. PMID- 20834213 TI - Systemic therapy for cardiac sarcomas. AB - Cardiac sarcomas create 2 risks: local problems and metastatic disease. Most frequently, the histologies are angiosarcoma and high-grade pleomorphic unclassified sarcoma (formerly called MFH or malignant fibrous histiocytoma). There is also a clinical-pathological entity without distinctive histological features of tumors that originate in the pulmonary artery and are referred to as pulmonary artery sarcomas or intimal sarcomas of the pulmonary artery. Conventional wisdom indicates that soft-tissue sarcomas are poorly responsive to chemotherapy. Luckily, that is not the case. Attempts to concentrate on the local problem only with therapies up to and including cardiac transplantation have been unsuccessful due to the high rate of fatal metastatic disease. PMID- 20834214 TI - RNAi screening for host factors involved in Vaccinia virus infection using Drosophila cells. AB - Viral pathogens represent a significant public health threat; not only can viruses cause natural epidemics of human disease, but their potential use in bioterrorism is also a concern. A better understanding of the cellular factors that impact infection would facilitate the development of much-needed therapeutics. Recent advances in RNA interference (RNAi) technology coupled with complete genome sequencing of several organisms has led to the optimization of genome-wide, cell-based loss-of-function screens. Drosophila cells are particularly amenable to genome-scale screens because of the ease and efficiency of RNAi in this system (1). Importantly, a wide variety of viruses can infect Drosophila cells, including a number of mammalian viruses of medical and agricultural importance (2,3,4). Previous RNAi screens in Drosophila have identified host factors that are required for various steps in virus infection including entry, translation and RNA replication (5). Moreover, many of the cellular factors required for viral replication in Drosophila cell culture are also limiting in human cells infected with these viruses (4,6,7,8, 9). Therefore, the identification of host factors co-opted during viral infection presents novel targets for antiviral therapeutics. Here we present a generalized protocol for a high-throughput RNAi screen to identify cellular factors involved in viral infection, using vaccinia virus as an example. PMID- 20834215 TI - Electron spin resonance micro-imaging of live species for oxygen mapping. AB - This protocol describes an electron spin resonance (ESR) micro-imaging method for three-dimensional mapping of oxygen levels in the immediate environment of live cells with micron-scale resolution(1). Oxygen is one of the most important molecules in the cycle of life. It serves as the terminal electron acceptor of oxidative phosphorylation in the mitochondria and is used in the production of reactive oxygen species. Measurements of oxygen are important for the study of mitochondrial and metabolic functions, signaling pathways, effects of various stimuli, membrane permeability, and disease differentiation. Oxygen consumption is therefore an informative marker of cellular metabolism, which is broadly applicable to various biological systems from mitochondria to cells to whole organisms. Due to its importance, many methods have been developed for the measurements of oxygen in live systems. Current attempts to provide high resolution oxygen imaging are based mainly on optical fluorescence and phosphorescence methods that fail to provide satisfactory results as they employ probes with high photo-toxicity and low oxygen sensitivity. ESR, which measures the signal from exogenous paramagnetic probes in the sample, is known to provide very accurate measurements of oxygen concentration. In a typical case, ESR measurements map the probe's lineshape broadening and/or relaxation-time shortening that are linked directly to the local oxygen concentration. (Oxygen is paramagnetic; therefore, when colliding with the exogenous paramagnetic probe, it shortness its relaxation times.) Traditionally, these types of experiments are carried out with low resolution, millimeter-scale ESR for small animals imaging. Here we show how ESR imaging can also be carried out in the micron-scale for the examination of small live samples. ESR micro-imaging is a relatively new methodology that enables the acquisition of spatially-resolved ESR signals with a resolution approaching 1 micron at room temperature(2). The main aim of this protocol-paper is to show how this new method, along with newly developed oxygen sensitive probes, can be applied to the mapping of oxygen levels in small live samples. A spatial resolution of ~30 x 30 x 100 MUm is demonstrated, with near micromolar oxygen concentration sensitivity and sub-femtomole absolute oxygen sensitivity per voxel. The use of ESR micro-imaging for oxygen mapping near cells complements the currently available techniques based on micro-electrodes or fluorescence/phosphorescence. Furthermore, with the proper paramagnetic probe, it will also be readily applicable for intracellular oxygen micro-imaging, a capability which other methods find very difficult to achieve. PMID- 20834216 TI - A cell-to-cell macromolecular transport assay in Planta utilizing biolistic bombardment. AB - Here, we present a simple and rapid protocol to detect and assess the extent of cell-to-cell macromolecular transport in planta. In this protocol, a fluorescently tagged-protein of interest is transiently expressed in plant tissue following biolistic delivery of its encoding DNA construct. The intra- and intercellular distribution of the tagged protein is then analyzed by confocal microscopy. We describe this technology in detail, providing step-by-step protocols to assay and evaluate the extent of symplastic protein transport in three plant species, Arabidopsis thaliana, Nicotiana benthamiana and N. tabacum (tobacco). PMID- 20834217 TI - The method of rodent whole embryo culture using the rotator-type bottle culture system. AB - Whole embryo culture (WEC) technique has been developed in 1950's by New and his colleagues, and applied for developmental biology (1). Although development and growth of mammalian embryos are critically dependent on the function of the placenta, WEC technique allows us to culture mouse and rat embryos ex vivo condition during limited periods corresponding to midgestation stages during embryonic day (E) 6.5-E12.5 in the mouse or E8.5-E14.5 in the rat (2, 3, 4). In WEC, we can directly target desired areas of embryos using fine glass capillaries because embryos can be manipulated under the microscope. Therefore, rodent WEC is very useful technique when we want to study dynamic developmental processes of postimplanted mammalian embryos. Up to date, several types of WEC systems have been developed (1). Among those, the rotator-type bottle culture system is most popular and suitable for long-term culture of embryos at midgestation, i.e., after E9.5 and E11.5 in the mouse and rat, respectively (1). In this video protocol, we demonstrate our standard procedures of rat WEC after E12.5 using a refined model of the original rotator system, which was designed by New and Cockroft (5, 6), and introduce various applications of WEC technique for studies in mammalian developmental biology. PMID- 20834218 TI - Direct tracheal instillation of solutes into mouse lung. AB - Intratracheal instillations deliver solutes directly into the lungs. This procedure targets the delivery of the instillate into the distal regions of the lung, and is therefore often incorporated in studies aimed at studying alveoli. We provide a detailed survival protocol for performing intratracheal instillations in mice. Using this approach, one can target delivery of test solutes or solids (such as lung therapeutics, surfactants, viruses, and small oligonucleotides) into the distal lung. Tracheal instillations may be the preferred methodology, over inhalation protocols that may primarily target the upper respiratory tract and possibly expose the investigator to potentially hazardous substances. Additionally, in using the tracheal instillation protocol, animals can fully recover from the non-invasive procedure. This allows for making subsequent physiological measurements on test animals, or reinstallation using the same animal. The amount of instillate introduced into the lung must be carefully determined and osmotically balanced to ensure animal recovery. Typically, 30-75 MUL instillate volume can be introduced into mouse lung. PMID- 20834219 TI - Intraperitoneal injection into adult zebrafish. AB - A convenient method for chemically treating zebrafish is to introduce the reagent into the tank water, where it will be taken up by the fish. However, this method makes it difficult to know how much reagent is absorbed or taken up per fish. Some experimental questions, particularly those related to metabolic studies, may be better addressed by delivering a defined quantity to each fish, based on weight. Here we present a method for intraperitoneal (IP) injection into adult zebrafish. Injection is into the abdominal cavity, posterior to the pelvic girdle. This procedure is adapted from veterinary methods used for larger fish. It is safe, as we have observed zero mortality. Additionally, we have seen bleeding at the injection site in only 5 out of 127 injections, and in each of those cases the bleeding was brief, lasting several seconds, and the quantity of blood lost was small. Success with this procedure requires gentle handling of the fish through several steps including fasting, weighing, anesthetizing, injection, and recovery. Precautions are required to minimize stress throughout the procedure. Our precautions include using a small injection volume and a 35G needle. We use Cortland salt solution as the vehicle, which is osmotically balanced for freshwater fish. Aeration of the gills is maintained during the injection procedure by first bringing the fish into a surgical plane of anesthesia, which allows slow operculum movements, and second, by holding the fish in a trough within a water-saturated sponge during the injection itself. We demonstrate the utility of IP injection by injecting glucose and monitoring the rise in blood glucose level and its subsequent return to normal. As stress is known to increase blood glucose in teleost fish, we compare blood glucose levels in vehicle-injected and non-injected adults and show that the procedure does not cause a significant rise in blood glucose. PMID- 20834220 TI - Assessment of cardiac function and energetics in isolated mouse hearts using 31P NMR spectroscopy. AB - Bioengineered mouse models have become powerful research tools in determining causal relationships between molecular alterations and models of cardiovascular disease. Although molecular biology is necessary in identifying key changes in the signaling pathway, it is not a surrogate for functional significance. While physiology can provide answers to the question of function, combining physiology with biochemical assessment of metabolites in the intact, beating heart allows for a complete picture of cardiac function and energetics. For years, our laboratory has utilized isolated heart perfusions combined with nuclear magnetic resonance (NMR) spectroscopy to accomplish this task. Left ventricular function is assessed by Langendorff-mode isolated heart perfusions while cardiac energetics is measured by performing (31)P magnetic resonance spectroscopy of the perfused hearts. With these techniques, indices of cardiac function in combination with levels of phosphocreatine and ATP can be measured simultaneously in beating hearts. Furthermore, these parameters can be monitored while physiologic or pathologic stressors are instituted. For example, ischemia/reperfusion or high workload challenge protocols can be adopted. The use of aortic banding or other models of cardiac pathology are apt as well. Regardless of the variants within the protocol, the functional and energetic significance of molecular modifications of transgenic mouse models can be adequately described, leading to new insights into the associated enzymatic and metabolic pathways. Therefore, (31)P NMR spectroscopy in the isolated perfused heart is a valuable research technique in animal models of cardiovascular disease. PMID- 20834221 TI - Isolation, enrichment, and maintenance of medulloblastoma stem cells. AB - Brain tumors have been suggested to possess a small population of stem cells that are the root cause of tumorigenesis. Neurosphere assays have been generally adopted to study the nature of neural stem cells, including those derived from normal and tumorous tissues. However, appreciable amounts of differentiation and cell death are common in cultured neurospheres likely due to sub-optimal condition such as accessibility of all cells within sphere aggregates to culture medium. Medulloblastoma, the most common pediatric CNS tumor, is characterized by its rapid progression and tendency to spread along the entire brain-spinal axis with dismal clinical outcome. Medulloblastoma is a neuroepithelial tumor of the cerebellum, accounting for 20% and 40% of intracranial and posterior fossa tumor in childhood, respectively. It is now well established that Shh signaling stimulates proliferation of cerebellar granule neuron precursors (CGNPs) during cerebellar development. Numerous studies using mouse models, in which the Shh pathway is constitutively activated, have linked Shh signaling with medulloblastoma. A recent report has shown that a subset of medulloblastoma cells derived from Patched1(LacZ/+) mice are cancer stem cells, which are capable of initiating and propagating tumors. Here we describe an efficient method to isolate, enrich and maintain tumor stem cells derived from several mouse models of medulloblastoma, with constitutively activated Shh pathway due to a mutation in Smoothened (hereon referred as SmoM2), a GPCR that is critical for Shh pathway activation. In every isolated medulloblastoma tissue, we were able to establish numerous highly proliferative colonies. These cells robustly expressed several neural stem cell markers such as Nestin and Sox2, can undergo serial passages (greater than 20) and were clonogenic. While these cultured tumor stem cells were relatively small, often bipolar with high nuclear to cytoplasmic ratio when cultured under conditions favoring stem cell growth, they dramatically altered their morphology, extended multiple cellular processes, flattened and withdrew from the cell cycle upon switching to a cell culture medium supplemented with 10% fetal bovine serum. More importantly, these tumor stem cells differentiated into Tuj1+ or NeuN+ neurons, GFAP+ astrocytes and CNPase+ oligodendrocytes, thus highlighting their multi-potency. Furthermore, these cells were capable of propagating secondary medulloblastomas when orthotopically transplanted into host mice. PMID- 20834222 TI - Strategies for study of neuroprotection from cold-preconditioning. AB - Neurological injury is a frequent cause of morbidity and mortality from general anesthesia and related surgical procedures that could be alleviated by development of effective, easy to administer and safe preconditioning treatments. We seek to define the neural immune signaling responsible for cold preconditioning as means to identify novel targets for therapeutics development to protect brain before injury onset. Low-level pro-inflammatory mediator signaling changes over time are essential for cold-preconditioning neuroprotection. This signaling is consistent with the basic tenets of physiological conditioning hormesis, which require that irritative stimuli reach a threshold magnitude with sufficient time for adaptation to the stimuli for protection to become evident. Accordingly, delineation of the immune signaling involved in cold-preconditioning neuroprotection requires that biological systems and experimental manipulations plus technical capacities are highly reproducible and sensitive. Our approach is to use hippocampal slice cultures as an in vitro model that closely reflects their in vivo counterparts with multi-synaptic neural networks influenced by mature and quiescent macroglia/microglia. This glial state is particularly important for microglia since they are the principal source of cytokines, which are operative in the femtomolar range. Also, slice cultures can be maintained in vitro for several weeks, which is sufficient time to evoke activating stimuli and assess adaptive responses. Finally, environmental conditions can be accurately controlled using slice cultures so that cytokine signaling of cold-preconditioning can be measured, mimicked, and modulated to dissect the critical node aspects. Cytokine signaling system analyses require the use of sensitive and reproducible multiplexed techniques. We use quantitative PCR for TNF-alpha to screen for microglial activation followed by quantitative real time qPCR array screening to assess tissue-wide cytokine changes. The latter is a most sensitive and reproducible means to measure multiple cytokine system signaling changes simultaneously. Significant changes are confirmed with targeted qPCR and then protein detection. We probe for tissue-based cytokine protein changes using multiplexed microsphere flow cytometric assays using Luminex technology. Cell-specific cytokine production is determined with double-label immunohistochemistry. Taken together, this brain tissue preparation and style of use, coupled to the suggested investigative strategies, may be an optimal approach for identifying potential targets for the development of novel therapeutics that could mimic the advantages of cold-preconditioning. PMID- 20834223 TI - Atmospheric-pressure molecular imaging of biological tissues and biofilms by LAESI mass spectrometry. AB - Ambient ionization methods in mass spectrometry allow analytical investigations to be performed directly on a tissue or biofilm under native-like experimental conditions. Laser ablation electrospray ionization (LAESI) is one such development and is particularly well-suited for the investigation of water containing specimens. LAESI utilizes a mid-infrared laser beam (2.94 MUm wavelength) to excite the water molecules of the sample. When the ablation fluence threshold is exceeded, the sample material is expelled in the form of particulate matter and these projectiles travel to tens of millimeters above the sample surface. In LAESI, this ablation plume is intercepted by highly charged droplets to capture a fraction of the ejected sample material and convert its chemical constituents into gas-phase ions. A mass spectrometer equipped with an atmospheric-pressure ion source interface is employed to analyze and record the composition of the released ions originating from the probed area (pixel) of the sample. A systematic interrogation over an array of pixels opens a way for molecular imaging in the microprobe analysis mode. A unique aspect of LAESI mass spectrometric imaging is depth profiling that, in combination with lateral imaging, enables three-dimensional (3D) molecular imaging. With current lateral and depth resolutions of ~100 MUm and ~40 MUm, respectively, LAESI mass spectrometric imaging helps to explore the molecular structure of biological tissues. Herein, we review the major elements of a LAESI system and provide guidelines for a successful imaging experiment. PMID- 20834224 TI - Direct analysis of single cells by mass spectrometry at atmospheric pressure. AB - Analysis of biochemicals in single cells is important for understanding cell metabolism, cell cycle, adaptation, disease states, etc. Even the same cell types exhibit heterogeneous biochemical makeup depending on their physiological conditions and interactions with the environment. Conventional methods of mass spectrometry (MS) used for the analysis of biomolecules in single cells rely on extensive sample preparation. Removing the cells from their natural environment and extensive sample processing could lead to changes in the cellular composition. Ambient ionization methods enable the analysis of samples in their native environment and without extensive sample preparation. The techniques based on the mid infrared (mid-IR) laser ablation of biological materials at 2.94 MUm wavelength utilize the sudden excitation of water that results in phase explosion. Ambient ionization techniques based on mid-IR laser radiation, such as laser ablation electrospray ionization (LAESI) and atmospheric pressure infrared matrix-assisted laser desorption ionization (AP IR-MALDI), have successfully demonstrated the ability to directly analyze water-rich tissues and biofluids at atmospheric pressure. In LAESI the mid-IR laser ablation plume that mostly consists of neutral particulate matter from the sample coalesces with highly charged electrospray droplets to produce ions. Recently, mid-IR ablation of single cells was performed by delivering the mid-IR radiation through an etched fiber. The plume generated from this ablation was postionized by an electrospray enabling the analysis of diverse metabolites in single cells by LAESI-MS. This article describes the detailed protocol for single cell analysis using LAESI-MS. The presented video demonstrates the analysis of a single epidermal cell from the skin of an Allium cepa bulb. The schematic of the system is shown in Figure 1. A representative example of single cell ablation and a LAESI mass spectrum from the cell are provided in Figure 2. PMID- 20834225 TI - Electroeluting DNA fragments. AB - Purified DNA fragments are used for different purposes in Molecular Biology and they can be prepared by several procedures. Most of them require a previous electrophoresis of the DNA fragments in order to separate the band of interest. Then, this band is excised out from an agarose or acrylamide gel and purified by using either: binding and elution from glass or silica particles, DEAE-cellulose membranes, "crush and soak method", electroelution or very often expensive commercial purification kits. Thus, selecting a method will depend mostly of what is available in the laboratory. The electroelution procedure allows one to purify very clean DNA to be used in a large number of applications (sequencing, radiolabeling, enzymatic restriction, enzymatic modification, cloning etc). This procedure consists in placing DNA band-containing agarose or acrylamide slices into sample wells of the electroeluter, then applying current will make the DNA fragment to leave the agarose and thus be trapped in a cushion salt to be recovered later by ethanol precipitation. PMID- 20834226 TI - Study glial cell heterogeneity influence on axon growth using a new coculture method. AB - In the central nervous system of all mammals, severed axons after injury are unable to regenerate to their original targets and functional recovery is very poor. The failure of axon regeneration is a combined result of several factors including the hostile glial cell environment, inhibitory myelin related molecules and decreased intrinsic neuron regenerative capacity. Astrocytes are the most predominant glial cell type in central nervous system and play important role in axon functions under physiology and pathology conditions. Contrast to the homologous oligodendrocytes, astrocytes are a heterogeneous cell population composed by different astrocyte subpopulations with diverse morphologies and gene expression. The functional significance of this heterogeneity, such as their influences on axon growth, is largely unknown. To study the glial cell, especially the function of astrocyte heterogeneity in neuron behavior, we established a new method by co-culturing high purified dorsal root ganglia neurons with glial cells obtained from the rat cortex. By this technique, we were able to directly compare neuron adhesion and axon growth on different astrocytes subpopulations under the same condition. In this report, we give the detailed protocol of this method for astrocytes isolation and culture, dorsal root ganglia neurons isolation and purification, and the co-culture of DRG neurons with astrocytes. This method could also be extended to other brain regions to study cellular or regional specific interaction between neurons and glial cells. PMID- 20834227 TI - Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks. AB - Single-stranded DNA constitutes an important early intermediate for homologous recombination and damage-induced cell cycle checkpoint activation. In Saccharomyces cerevisiae, efficient double-strand break (DSB) end resection requires several enzymes; Mre11/Rad50/Xrs2 (MRX) and Sae2 are implicated in the onset of 5'-strand resection, whereas Sgs1/Top3/Rmi1 with Dna2 and Exo1 are involved in extensive resection. However, the molecular events leading to a switch from the MRX/Sae2-dependent initiation to the Exo1- and Dna2-dependent resection remain unclear. Here, we show that MRX recruits Dna2 nuclease to DSB ends. MRX also stimulates recruitment of Exo1 and antagonizes excess binding of the Ku complex to DSB ends. Using resection assay with purified enzymes in vitro, we found that Ku and MRX regulate the nuclease activity of Exo1 in an opposite way. Efficient loading of Dna2 and Exo1 requires neither Sae2 nor Mre11 nuclease activities. However, Mre11 nuclease activity is essential for resection in the absence of extensive resection enzymes. The results provide new insights into how MRX catalyses end resection and recombination initiation. PMID- 20834228 TI - Cooperative functions of Chk1 and Chk2 reduce tumour susceptibility in vivo. AB - Although the linkage of Chk1 and Chk2 to important cancer signalling suggests that these kinases have functions as tumour suppressors, neither Chk1+/- nor Chk2 /- mice show a predisposition to cancer under unperturbed conditions. We show here that Chk1+/-Chk2-/- and Chk1+/-Chk2+/- mice have a progressive cancer-prone phenotype. Deletion of a single Chk1 allele compromises G2/M checkpoint function that is not further affected by Chk2 depletion, whereas Chk1 and Chk2 cooperatively affect G1/S and intra-S phase checkpoints. Either or both of the kinases are required for DNA repair depending on the type of DNA damage. Mouse embryonic fibroblasts from the double-mutant mice showed a higher level of p53 with spontaneous DNA damage under unperturbed conditions, but failed to phosphorylate p53 at S23 and further induce p53 expression upon additional DNA damage. Neither Chk1 nor Chk2 is apparently essential for p53- or Rb-dependent oncogene-induced senescence. Our results suggest that the double Chk mutation leads to a high level of spontaneous DNA damage, but fails to eliminate cells with damaged DNA, which may ultimately increase cancer susceptibility independently of senescence. PMID- 20834229 TI - Autocatalytic differentiation of epigenetic modifications within the Arabidopsis genome. AB - In diverse eukaryotes, constitutively silent sequences, such as transposons and repeats, are marked by methylation at histone H3 lysine 9 (H3K9me). Although selective H3K9me is critical for maintaining genome integrity, mechanisms to exclude H3K9me from active genes remain largely unexplored. Here, we show in Arabidopsis that the exclusion depends on a histone demethylase gene, IBM1 (increase in BONSAI methylation). Loss-of-function ibm1 mutation results in ectopic H3K9me and non-CG methylation in thousands of genes. The ibm1-induced genic H3K9me depends on both histone methylase KYP/SUVH4 and DNA methylase CMT3, suggesting interdependence of two epigenetic marks--H3K9me and non-CG methylation. Notably, IBM1 enhances loss of H3K9me in transcriptionally de repressed sequences. Furthermore, disruption of transcription in genes induces ectopic non-CG methylation, which mimics the loss of IBM1 function. We propose that active chromatin is stabilized by an autocatalytic loop of transcription and H3K9 demethylation. This process counteracts a similarly autocatalytic accumulation of silent epigenetic marks, H3K9me and non-CG methylation. PMID- 20834230 TI - Heat shock factor 1 ameliorates proteotoxicity in cooperation with the transcription factor NFAT. AB - Heat shock transcription factor 1 (HSF1) is an important regulator of protein homeostasis (proteostasis) by controlling the expression of major heat shock proteins (Hsps) that facilitate protein folding. However, it is unclear whether other proteostasis pathways are mediated by HSF1. Here, we identified novel targets of HSF1 in mammalian cells, which suppress the aggregation of polyglutamine (polyQ) protein. Among them, we show that one of the nuclear factor of activated T cells (NFAT) proteins, NFATc2, significantly inhibits polyQ aggregation in cells and is required for HSF1-mediated suppression of polyQ aggregation. NFAT deficiency accelerated disease progression including aggregation of a mutant polyQ-huntingtin protein and shortening of lifespan in R6/2 Huntington's disease mice. Furthermore, we found that HSF1 and NFAT cooperatively induce the expression of the scaffold protein PDZK3 and alphaB crystallin, which facilitate the degradation of polyQ protein. These results show the first mechanistic basis for the observation that HSF1 has a much more profound effect on proteostasis than individual Hsp or combination of different Hsps, and suggest a new pathway for ameliorating protein-misfolding diseases. PMID- 20834231 TI - Differences in signalling by directly and indirectly binding ligands in bacterial chemotaxis. AB - In chemotaxis of Escherichia coli and other bacteria, extracellular stimuli are perceived by transmembrane receptors that bind their ligands either directly, or indirectly through periplasmic-binding proteins (BPs). As BPs are also involved in ligand uptake, they provide a link between chemotaxis and nutrient utilization by cells. However, signalling by indirectly binding ligands remains much less understood than signalling by directly binding ligands. Here, we compared intracellular responses mediated by both types of ligands and developed a new mathematical model for signalling by indirectly binding ligands. We show that indirect binding allows cells to better control sensitivity to specific ligands in response to their nutrient environment and to coordinate chemotaxis with ligand transport, but at the cost of the dynamic range being much narrower than for directly binding ligands. We further demonstrate that signal integration by the chemosensory complexes does not depend on the type of ligand. Overall, our data suggest that the distinction between signalling by directly and indirectly binding ligands is more physiologically important than the traditional distinction between high- and low-abundance receptors. PMID- 20834232 TI - Crystal structures of human Ero1alpha reveal the mechanisms of regulated and targeted oxidation of PDI. AB - In the endoplasmic reticulum (ER) of eukaryotic cells, Ero1 flavoenzymes promote oxidative protein folding through protein disulphide isomerase (PDI), generating reactive oxygen species (hydrogen peroxide) as byproducts. Therefore, Ero1 activity must be strictly regulated to avoid futile oxidation cycles in the ER. Although regulatory mechanisms restraining Ero1alpha activity ensure that not all PDIs are oxidized, its specificity towards PDI could allow other resident oxidoreductases to remain reduced and competent to carry out isomerization and reduction of protein substrates. In this study, crystal structures of human Ero1alpha were solved in its hyperactive and inactive forms. Our findings reveal that human Ero1alpha modulates its oxidative activity by properly positioning regulatory cysteines within an intrinsically flexible loop, and by fine-tuning the electron shuttle ability of the loop through disulphide rearrangements. Specific PDI targeting is guaranteed by electrostatic and hydrophobic interactions of Ero1alpha with the PDI b'-domain through its substrate-binding pocket. These results reveal the molecular basis of the regulation and specificity of protein disulphide formation in human cells. PMID- 20834233 TI - Crystal structure of Lon protease: molecular architecture of gated entry to a sequestered degradation chamber. AB - Lon proteases are distributed in all kingdoms of life and are required for survival of cells under stress. Lon is a tandem fusion of an AAA+ molecular chaperone and a protease with a serine-lysine catalytic dyad. We report the 2.0-A resolution crystal structure of Thermococcus onnurineus NA1 Lon (TonLon). The structure is a three-tiered hexagonal cylinder with a large sequestered chamber accessible through an axial channel. Conserved loops extending from the AAA+ domain combine with an insertion domain containing the membrane anchor to form an apical domain that serves as a gate governing substrate access to an internal unfolding and degradation chamber. Alternating AAA+ domains are in tight- and weak-binding nucleotide states with different domain orientations and intersubunit contacts, reflecting intramolecular dynamics during ATP-driven protein unfolding and translocation. The bowl-shaped proteolytic chamber is contiguous with the chaperone chamber allowing internalized proteins direct access to the proteolytic sites without further gating restrictions. PMID- 20834235 TI - Presence of monoclonal T-cell populations in B-cell post-transplant lymphoproliferative disorders. AB - As has been previously shown, the lack of immune surveillance plays a major role in the unchecked proliferation of Epstein-Barr virus (EBV)-infected B cells in the pathogenesis of B-cell post-transplant lymphoproliferative disorders. We hypothesised that the lack of immune surveillance should possibly also affect T cells, and this should lead to subsequent emergence of T-cell clones. The presence of both B- and T-cell clones in post-transplant lymphoproliferative disorders samples has rarely been demonstrated in the past. We systematically evaluated 26 B-cell post-transplant lymphoproliferative disorder, 23 human immune deficiency virus-associated B-cell lymphoma and 10 immune-competent diffuse large B-cell lymphoma samples for B- and T-cell clonality (polymerase chain reaction and heteroduplex analysis using BIOMED-2 protocol), T-cell subsets (immunohistochemistry) and EBV association (in situ hybridisation using EBER). One-half of B-cell post-transplant lymphoproliferative disorders showed evidence of monoclonal T-cell expansion, and among the T cells present in the tissue samples, CD8-positive cells predominated. Although 9/13 (69%) B-cell post transplant lymphoproliferative disorders with the presence of monoclonal T-cell population had a CD4:CD8 ratio of <=0.4, 0/13 of the cases without monoclonal T cell expansion had a ratio <=0.4 (P = 0.002). Only 2/26 (8%) demonstrated significant cytological atypia in the CD3/CD8-positive cells. There was no association between EBV and presence of T-cell clones. T-cell clones were not identified in lymphomas other than B-cell post-transplant lymphoproliferative disorders. Among 53.8% cases of EBV-positive B-cell post-transplant lymphoproliferative disorders with associated clonal expansion of T-cells tested, none had EBV-positive T cells. We conclude that half of B-cell post-transplant lymphoproliferative disorders are associated with clonal expansion of CD8 positive T cells, most of which do not amount to the coexistence of a T-cell post transplant lymphoproliferative disorders. PMID- 20834234 TI - International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 1: specimen handling. AB - The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the handling and processing of radical prostatectomy specimens were coordinated by working group 1. Most uropathologists followed similar procedures for fixation of radical prostatectomy specimens, with 51% of respondents transporting tissue in formalin. There was also consensus that the prostate weight without the seminal vesicles should be recorded. There was consensus that the surface of the prostate should be painted. It was agreed that both the prostate apex and base should be examined by the cone method with sagittal sectioning of the tissue sample. There was consensus that the gland should be fully fixed before sectioning. Both partial and complete embedding of prostates was considered to be acceptable as long as the method of partial embedding is stated. No consensus was determined regarding the necessity of weighing and measuring the length of the seminal vesicles, the preparation of whole mounts rather than standardized blocks and the methodology for sampling of fresh tissue for research purposes, and it was agreed that these should be left to the discretion of the working pathologist. PMID- 20834236 TI - Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival. AB - In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray. Independent of their anatomical localization, the majority of KIT-mutated GISTs displayed a pure spindled phenotype (72%), with the remaining tumors showing an epithelioid/mixed growth pattern. In KIT-mutated GISTs from the stomach, the occurrence of an epithelioid/mixed growth pattern was significantly correlated with larger tumor diameters (P=0.005), higher mitotic counts (P=0.0001), high risk category (P=0.001), higher expression of the G2-phase cell-cycle marker cyclin B1 (P=0.04), higher expression of the G1 to M-phase proliferation marker Ki67 (P=0.02) and a significantly shorter disease-free survival (P=0.003) compared with tumors with pure spindled morphology. In contrast, there were no significant differences between pure spindled and epithelioid/mixed GISTs from the small/large bowel. Our findings indicate that the epithelioid/mixed phenotype in KIT-mutant gastric GISTs represents a secondary tumor growth pattern associated with tumor progression and adverse outcome, probably through accelerated G1/S-phase restriction point passage. PMID- 20834237 TI - Clinicopathological significance of calreticulin in breast invasive ductal carcinoma. AB - Calreticulin is a chaperone protein located in the lumen of the endoplasmic reticulum. The association of calreticulin with pathological conditions such as autoimmune disorders and certain types of cancer have been reported. However, little is known about its role in the pathogenesis of breast cancer. The aim of this study was to determine the expression of calreticulin in vitro and correlate its expression levels in breast cancer tissue samples with clinicopathological parameters. Calreticulin expression was evaluated in MCF-7 and MDA-MB-231 breast cancer cells by real-time RT-PCR, Western blot, immunohistochemistry, and immunofluorescence staining. Patient tissue microarrays were constructed from 228 breast cancer specimens for immunohistochemical analysis. The in vitro study showed a higher calreticulin expression in more aggressive MDA-MB-231 cells as compared with MCF-7 cells at both mRNA and protein levels. In all, 227 out of 228 breast cancer samples exhibited calreticulin staining in at least 5% of the cancer cells. Calreticulin immunostaining was observed to be localized to the cytoplasm of the cancer cells. Regression analysis of calreticulin immunostaining in the tissue microarrays revealed that its expression was positively correlated to logarithm of (log) tumor size (P=0.046) and development of distant metastasis (P=0.017). Multivariate analysis confirmed calreticulin expression as an independent predictor of log tumor size and occurrence of distant metastasis. The data suggest that calreticulin expression is associated with more advanced tumors and is a potential prognostic biomarker. PMID- 20834238 TI - Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases. AB - The high mobility group A (HMGA2) gene encodes a protein that alters chromatin structure and regulates the transcription of many genes; it is implicated in both benign and malignant neoplasias, but its rearrangements are a feature of development of several mesenchymal tumors. Given its implication in these tumors and particularly adipocytic tumors, and the availability of antibodies usable on paraffin-embedded tissues, we evaluated the immunohistochemical expression of this gene in a series of 1052 mesenchymal tumors. The objective was to define the value and limitations of HMGA2 immunohistochemical expression for histotyping, and compare with molecular data reported in the literature. We thus analyzed 880 cases on tissue microarray and 182 cases on whole sections (211 adipocytic tumors, 628 sarcomas, 213 benign mesenchymal tumors, and 10 normal adipose tissues). A nuclear immunostaining was detected in 86% of conventional and intramuscular lipomas, in 86% of well-differentiated liposarcomas and in 67% of dedifferentiated liposarcomas, as opposed to 16% of other benign adipose tumors and to 15% of non-well-differentiated liposarcoma/dedifferentiated liposarcoma sarcomas. Among benign mesenchymal tumors and lesions, it was detected in 90% of nodular fasciitis and in 88% of benign fibrous histiocytomas with respective specificities of 85 and 100%, and in 90% of aggressive angiomyxoma, contrary to other vulvovaginal tumor types, which expressed HMGA2 only rarely. The normal adipose tissue was always negative for HMGA2. Although not specific, immunohistochemical detection of the HMGA2 protein is helpful for the distinction of normal adipose tissue from well-differentiated lesions, particularly on biopsy or on re-excision. It is less sensitive than MDM2/CDK4 for dedifferentiated liposarcomas diagnosis, but it appears more specific to distinguish dedifferentiated liposarcomas from other poorly differentiated sarcomas. Finally, and may be more importantly, HMGA2 is useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors. PMID- 20834239 TI - WHO types A and AB thymomas: not always benign. AB - The 2004 WHO classification of thymic tumors recognizes five major subtypes of thymomas and thymic carcinoma. Subtypes A and AB thymomas are purported to be benign neoplasms, although prior studies have suggested a potential for malignant behavior. The purpose of this study was to assess the clinical behavior of A and AB thymomas identified from a large institutional pathologic database. A retrospective slide review of 500 thymic epithelial tumors identified 71 (~ 14%) cases of types A and AB thymomas. Clinical history and follow-up information were obtained through retrospective chart review. There were 38 and 33 cases of types A and AB thymomas, respectively. Complete follow-up data were available in 37 (52%) cases. Eighteen (49%) patients (type A, n=9 and type AB, n=9) had evidence of recurrent/metastatic disease at an average of 62 months (range from 6 to 244 months) after initial diagnosis. Survival curves for patients with types A and AB thymomas, with and without recurrences, show a statistically significant difference (P=0.001 and 0.005, respectively). Analysis of this large cohort confirms the potential for subtypes A and AB thymomas to show malignant behavior. Long-term clinical monitoring, therefore, appears to be justified in these cases. This study also shows the poor correlation between the WHO classification and tumor behavior. PMID- 20834240 TI - An improved prognostic model for stage T1a and T1b prostate cancer by assessments of cancer extent. AB - Treatment decisions on prostate cancer diagnosed by trans-urethral resection (TURP) of the prostate are difficult. The current TNM staging system for pT1 prostate cancer has not been re-evaluated for 25 years. Our objective was to optimise the predictive power of tumor extent measurements in TURP of the prostate specimens. A total of 914 patients diagnosed by TURP of the prostate between 1990 and 1996, managed conservatively were identified. The clinical end point was death from prostate cancer. Diagnostic serum prostate-specific antigen (PSA) and contemporary Gleason grading was available. Cancer extent was measured by the percentage of chips infiltrated by cancer. Death rates were compared by univariate and multivariate proportional hazards models, including baseline PSA and Gleason score. The percentage of positive chips was highly predictive of prostate cancer death when assessed as a continuous variable or as a grouped variable on the basis of and including the quintiles, quartiles, tertiles and median groups. In the univariate model, the most informative variable was a four group-split (<=10%, >10-25%, >25-75% and >75%); (HR=2.08, 95% CI=1.8-2.4, P<0.0001). The same was true in a multivariate model (DeltaX(2) (1 d.f.)=15.0, P=0.0001). The current cutoff used by TNM (<=5%) was sub-optimal (DeltaX(2) (1 d.f.)=4.8, P=0.023). The current TNM staging results in substantial loss of information. Staging by a four-group subdivision would substantially improve prognostication in patients with early stage disease and also may help to refine management decisions in patients who would do well with conservative treatments. PMID- 20835226 TI - Role of a ribosome-associated E3 ubiquitin ligase in protein quality control. AB - Messenger RNA lacking stop codons ('non-stop mRNA') can arise from errors in gene expression, and encode aberrant proteins whose accumulation could be deleterious to cellular function. In bacteria, these 'non-stop proteins' become co translationally tagged with a peptide encoded by ssrA/tmRNA (transfer-messenger RNA), which signals their degradation by energy-dependent proteases. How eukaryotic cells eliminate non-stop proteins has remained unknown. Here we show that the Saccharomyces cerevisiae Ltn1 RING-domain-type E3 ubiquitin ligase acts in the quality control of non-stop proteins, in a process that is mechanistically distinct but conceptually analogous to that performed by ssrA: Ltn1 is predominantly associated with ribosomes, and it marks nascent non-stop proteins with ubiquitin to signal their proteasomal degradation. Ltn1-mediated ubiquitylation of non-stop proteins seems to be triggered by their stalling in ribosomes on translation through the poly(A) tail. The biological relevance of this process is underscored by the finding that loss of Ltn1 function confers sensitivity to stress caused by increased non-stop protein production. We speculate that defective protein quality control may underlie the neurodegenerative phenotype that results from mutation of the mouse Ltn1 homologue Listerin. PMID- 20835227 TI - Checkpoint-dependent inhibition of DNA replication initiation by Sld3 and Dbf4 phosphorylation. AB - The initiation of eukaryotic DNA replication is regulated by three protein kinase classes: cyclin-dependent kinases (CDK), Dbf4-dependent kinase (DDK) and the DNA damage checkpoint kinases. CDK phosphorylation of two key initiation factors, Sld2 and Sld3, promotes essential interactions with Dpb11 (refs 2-4), whereas DDK acts by phosphorylating subunits of the Mcm2-7 helicase. CDK has an additional role in replication by preventing the re-loading of Mcm2-7 during the S, G2 and M phases, thus preventing origin re-firing and re-replication. During the G1 phase, both CDK and DDK are downregulated, which allows origin licensing and prevents premature replication initiation. Origin firing is also inhibited during the S phase when DNA damage or replication fork stalling activates the checkpoint kinases. Here we show that, analogous to the situation in the G1 phase, the Saccharomyces cerevisiae checkpoint kinase Rad53 inhibits both CDK- and DDK dependent pathways, which acts redundantly to block further origin firing. Rad53 acts on DDK directly by phosphorylating Dbf4, whereas the CDK pathway is blocked by Rad53-mediated phosphorylation of the downstream CDK substrate, Sld3. This allows CDK to remain active during the S phase in the presence of DNA damage, which is crucial to prevent re-loading of Mcm2-7 onto origins that have already fired. Our results explain how checkpoints regulate origin firing and demonstrate that the slowing of S phase by the 'intra-S checkpoint' is primarily due to the inhibition of origin firing. PMID- 20835228 TI - Inosine cyanoethylation identifies A-to-I RNA editing sites in the human transcriptome. AB - Adenosine-to-inosine (A-to-I) RNA editing is a post-transcriptional processing event involved in diversifying the transcriptome responsible for various biological processes. Although bioinformatic approaches have predicted a number of A-to-I editing sites in cDNAs, the human transcriptome is thought to still harbor large numbers of as-yet-unknown editing sites. Exploring new editing sites requires a biochemical method to accurately identify inosines on RNA strands. We here describe a chemical method to identify inosines, called inosine chemical erasing (ICE), that is based on cyanoethylation combined with reverse transcription. We carried out a large-scale verification of the ICE method focusing on 642 regions in human cDNA and identified 5,072 editing sites, including 4,395 new sites. Functional study revealed that A-to-I intronic editing in the SARS gene mediated by ADAR1 is involved in preventing aberrant exonization of Alu sequence into mature mRNA. PMID- 20835229 TI - Confinement-optimized three-dimensional T cell amoeboid motility is modulated via myosin IIA-regulated adhesions. AB - During trafficking through tissues, T cells fine-tune their motility to balance the extent and duration of cell-surface contacts versus the need to traverse an entire organ. Here we show that in vivo, myosin IIA-deficient T cells had a triad of defects, including overadherence to high-endothelial venules, less interstitial migration and inefficient completion of recirculation through lymph nodes. Spatiotemporal analysis of three-dimensional motility in microchannels showed that the degree of confinement and myosin IIA function, rather than integrin adhesion (as proposed by the haptokinetic model), optimized motility rate. This motility occurred via a myosin IIA-dependent rapid 'walking' mode with multiple small and simultaneous adhesions to the substrate, which prevented spurious and prolonged adhesions. Adhesion discrimination provided by myosin IIA is thus necessary for the optimization of motility through complex tissues. PMID- 20835231 TI - Highly sensitive flexible pressure sensors with microstructured rubber dielectric layers. AB - The development of an electronic skin is critical to the realization of artificial intelligence that comes into direct contact with humans, and to biomedical applications such as prosthetic skin. To mimic the tactile sensing properties of natural skin, large arrays of pixel pressure sensors on a flexible and stretchable substrate are required. We demonstrate flexible, capacitive pressure sensors with unprecedented sensitivity and very short response times that can be inexpensively fabricated over large areas by microstructuring of thin films of the biocompatible elastomer polydimethylsiloxane. The pressure sensitivity of the microstructured films far surpassed that exhibited by unstructured elastomeric films of similar thickness, and is tunable by using different microstructures. The microstructured films were integrated into organic field-effect transistors as the dielectric layer, forming a new type of active sensor device with similarly excellent sensitivity and response times. PMID- 20835230 TI - Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. AB - Interleukin 1beta (IL-1beta) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1beta. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1beta production in vitro. Processing of IL-1beta initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1beta in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP. PMID- 20835232 TI - Exciton antennas and concentrators from core-shell and corrugated carbon nanotube filaments of homogeneous composition. AB - There has been renewed interest in solar concentrators and optical antennas for improvements in photovoltaic energy harvesting and new optoelectronic devices. In this work, we dielectrophoretically assemble single-walled carbon nanotubes (SWNTs) of homogeneous composition into aligned filaments that can exchange excitation energy, concentrating it to the centre of core-shell structures with radial gradients in the optical bandgap. We find an unusually sharp, reversible decay in photoemission that occurs as such filaments are cycled from ambient temperature to only 357 K, attributed to the strongly temperature-dependent second-order Auger process. Core-shell structures consisting of annular shells of mostly (6,5) SWNTs (E(g)=1.21 eV) and cores with bandgaps smaller than those of the shell (E(g)=1.17 eV (7,5)-0.98 eV (8,7)) demonstrate the concentration concept: broadband absorption in the ultraviolet-near-infrared wavelength regime provides quasi-singular photoemission at the (8,7) SWNTs. This approach demonstrates the potential of specifically designed collections of nanotubes to manipulate and concentrate excitons in unique ways. PMID- 20835233 TI - Flexible electronics: Within touch of artificial skin. PMID- 20835234 TI - Controlled selectivity for palladium catalysts using self-assembled monolayers. AB - The selective reaction of one part of a bifunctional molecule is a fundamental challenge in heterogeneous catalysis and for many processes including the conversion of biomass-derived intermediates. Selective hydrogenation of unsaturated epoxides to saturated epoxides is particularly difficult given the reactivity of the strained epoxide ring, and traditional platinum group catalysts show low selectivities. We describe the preparation of highly selective Pd catalysts involving the deposition of n-alkanethiol self-assembled monolayer (SAM) coatings. These coatings improve the selectivity of 1-epoxybutane formation from 1-epoxy-3-butene on palladium catalysts from 11 to 94% at equivalent reaction conditions and conversions. Although sulphur species are generally considered to be indiscriminate catalyst poisons, the reaction rate to the desired product on a catalyst coated with a thiol was 40% of the rate on an uncoated catalyst. Interestingly the activity decreased for less-ordered SAMs with shorter chains. The behaviour of SAM-coated catalysts was compared with catalysts where surface sites were modified by carbon monoxide, hydrocarbons or sulphur atoms. The results suggest that the SAMs restrict sulphur coverage to enhance selectivity without significantly poisoning the activity of the desired reaction. PMID- 20835235 TI - Nanowire active-matrix circuitry for low-voltage macroscale artificial skin. AB - Large-scale integration of high-performance electronic components on mechanically flexible substrates may enable new applications in electronics, sensing and energy. Over the past several years, tremendous progress in the printing and transfer of single-crystalline, inorganic micro- and nanostructures on plastic substrates has been achieved through various process schemes. For instance, contact printing of parallel arrays of semiconductor nanowires (NWs) has been explored as a versatile route to enable fabrication of high-performance, bendable transistors and sensors. However, truly macroscale integration of ordered NW circuitry has not yet been demonstrated, with the largest-scale active systems being of the order of 1 cm(2) (refs 11,15). This limitation is in part due to assembly- and processing-related obstacles, although larger-scale integration has been demonstrated for randomly oriented NWs (ref. 16). Driven by this challenge, here we demonstrate macroscale (7*7 cm(2)) integration of parallel NW arrays as the active-matrix backplane of a flexible pressure-sensor array (18*19 pixels). The integrated sensor array effectively functions as an artificial electronic skin, capable of monitoring applied pressure profiles with high spatial resolution. The active-matrix circuitry operates at a low operating voltage of less than 5 V and exhibits superb mechanical robustness and reliability, without performance degradation on bending to small radii of curvature (2.5 mm) for over 2,000 bending cycles. This work presents the largest integration of ordered NW array active components, and demonstrates a model platform for future integration of nanomaterials for practical applications. PMID- 20835236 TI - A genome-wide association study for myopia and refractive error identifies a susceptibility locus at 15q25. AB - Myopia and hyperopia are at opposite ends of the continuum of refraction, the measure of the eye's ability to focus light, which is an important cause of visual impairment (when aberrant) and is a highly heritable trait. We conducted a genome-wide association study for refractive error in 4,270 individuals from the TwinsUK cohort. We identified SNPs on 15q25 associated with refractive error (rs8027411, P = 7.91 * 10-8). We replicated this association in six adult cohorts of European ancestry with a combined 13,414 individuals (combined P = 2.07 * 10 9). This locus overlaps the transcription initiation site of RASGRF1, which is highly expressed in neurons and retina and has previously been implicated in retinal function and memory consolidation. Rasgrf1(-/-) mice show a heavier average crystalline lens (P = 0.001). The identification of a susceptibility locus for refractive error on 15q25 will be important in characterizing the molecular mechanism responsible for the most common cause of visual impairment. PMID- 20835237 TI - Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal renal ciliopathy. AB - Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders. PMID- 20835238 TI - Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. AB - We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 * 10-10). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG. PMID- 20835239 TI - A genome-wide association study identifies a susceptibility locus for refractive errors and myopia at 15q14. AB - Refractive errors are the most common ocular disorders worldwide and may lead to blindness. Although this trait is highly heritable, identification of susceptibility genes has been challenging. We conducted a genome-wide association study for refractive error in 5,328 individuals from a Dutch population-based study with replication in four independent cohorts (combined 10,280 individuals in the replication stage). We identified a significant association at chromosome 15q14 (rs634990, P = 2.21 * 10-14). The odds ratio of myopia compared to hyperopia for the minor allele (minor allele frequency = 0.47) was 1.41 (95% CI 1.16-1.70) for individuals heterozygous for the allele and 1.83 (95% CI 1.42 2.36) for individuals homozygous for the allele. The associated locus is near two genes that are expressed in the retina, GJD2 and ACTC1, and appears to harbor regulatory elements which may influence transcription of these genes. Our data suggest that common variants at 15q14 influence susceptibility for refractive errors in the general population. PMID- 20835240 TI - Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. AB - The N-end rule pathway is a regulated proteolytic system that targets proteins containing destabilizing N-terminal residues (N-degrons) for ubiquitination and proteasomal degradation in eukaryotes. The N-degrons of type 1 substrates contain an N-terminal basic residue that is recognized by the UBR box domain of the E3 ubiquitin ligase UBR1. We describe structures of the UBR box of Saccharomyces cerevisiae UBR1 alone and in complex with N-degron peptides, including that of the cohesin subunit Scc1, which is cleaved and targeted for degradation at the metaphase-anaphase transition. The structures reveal a previously unknown protein fold that is stabilized by a novel binuclear zinc center. N-terminal arginine, lysine or histidine side chains of the N-degron are coordinated in a multispecific binding pocket. Unexpectedly, the structures together with our in vitro biochemical and in vivo pulse-chase analyses reveal a previously unknown modulation of binding specificity by the residue at position 2 of the N-degron. PMID- 20835241 TI - Gene-specific RNA polymerase II phosphorylation and the CTD code. AB - Phosphorylation of the RNA polymerase (Pol) II C-terminal domain (CTD) repeats (1 YSPTSPS-7) is coupled to transcription and may act as a 'code' that controls mRNA synthesis and processing. To examine the code in budding yeast, we mapped genome wide CTD Ser2, Ser5 and Ser7 phosphorylations and the CTD-associated termination factors Nrd1 and Pcf11. Phospho-CTD dynamics are not scaled to gene length and are gene-specific, with highest Ser5 and Ser7 phosphorylation at the 5' ends of well-expressed genes with nucleosome-occupied promoters. The CTD kinases Kin28 and Ctk1 markedly affect Pol II distribution in a gene-specific way. The code is therefore written differently on different genes, probably under the control of promoters. Ser7 phosphorylation is enriched on introns and at sites of Nrd1 accumulation, suggesting links to splicing and Nrd1 recruitment. Nrd1 and Pcf11 frequently colocalize, suggesting functional overlap. Unexpectedly, Pcf11 is enriched at centromeres and Pol III-transcribed genes. PMID- 20835242 TI - Structural basis of substrate recognition and specificity in the N-end rule pathway. AB - The N-end rule links the half-life of a protein to the identity of its N-terminal residue. Destabilizing N-terminal residues are recognized by E3 ubiquitin ligases, termed N-recognins. A conserved structural domain called the UBR box is responsible for their specificity. Here we report the crystal structures of the UBR boxes of the human N-recognins UBR1 and UBR2, alone and in complex with an N end rule peptide, Arg-Ile-Phe-Ser. These structures show that the UBR box adopts a previously undescribed fold stabilized through the binding of three zinc ions to form a binding pocket for type 1 N-degrons. NMR experiments reveal a preference for N-terminal arginine. Peptide binding is abrogated by N-terminal acetylation of the peptide or loss of the positive charge of the N-terminal residue. These results rationalize and refine the empirical rules for the classification of type 1 N-degrons. We also confirm that a missense mutation in UBR1 that is responsible for Johanson-Blizzard syndrome leads to UBR box unfolding and loss of function. PMID- 20835243 TI - Control of endothelial sprouting by a Tel-CtBP complex. AB - We show that the transcriptional repressor Tel plays an evolutionarily conserved role in angiogenesis: it is indispensable for the sprouting of human endothelial cells and for normal development of the Danio rerio blood circulatory system. Tel orchestrates endothelial sprouting by binding to the generic co-repressor, CtBP. The Tel-CtBP complex temporally restricts a VEGF (vascular endothelial growth factor)-mediated pulse of dll4 expression and thereby directly links VEGF receptor intracellular signalling and intercellular Notch-Dll4 signalling. It further controls branching by regulating expression of other factors that constrain angiogenesis such as sprouty family members and ve-cadherin. Thus, the Tel-CtBP complex conditions endothelial cells for angiogenesis by controlling the balance between stimulatory and antagonistic sprouting cues. Tel control of branching seems to be a refinement of invertebrate tracheae morphogenesis that requires Yan, the invertebrate orthologue of Tel. This work highlights Tel and its associated networks as potential targets for the development of therapeutic strategies to inhibit pathological angiogenesis. PMID- 20835244 TI - Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. AB - To better understand the mechanisms that regulate stem cell identity and function, we sought to identify genes that are preferentially expressed by stem cells and critical for their function in multiple tissues. Prdm16 is a transcription factor that regulates leukaemogenesis, palatogenesis and brown-fat development, but which was not known to be required for stem cell function. We demonstrate that Prdm16 is preferentially expressed by stem cells throughout the nervous and haematopoietic systems and is required for their maintenance. In the haematopoietic and nervous systems, Prdm16 deficiency led to changes in the levels of reactive oxygen species (ROS), depletion of stem cells, increased cell death and altered cell-cycle distribution. In neural stem/progenitor cells, Prdm16 binds to the Hgf promoter, and Hgf expression declined in the absence of Prdm16. Addition of recombinant HGF to Prdm16-deficient neural stem cells in cell culture reduced the depletion of these cells and partially rescued the increase in ROS levels. Administration of the anti-oxidant, N-acetyl-cysteine, to Prdm16 deficient mice partially rescued defects in neural stem/progenitor cell function and neural development. Prdm16 therefore promotes stem cell maintenance in multiple tissues, partly by modulating oxidative stress. PMID- 20835245 TI - Alternative expression analysis by RNA sequencing. AB - In alternative expression analysis by sequencing (ALEXA-seq), we developed a method to analyze massively parallel RNA sequence data to catalog transcripts and assess differential and alternative expression of known and predicted mRNA isoforms in cells and tissues. As proof of principle, we used the approach to compare fluorouracil-resistant and -nonresistant human colorectal cancer cell lines. We assessed the sensitivity and specificity of the approach by comparison to exon tiling and splicing microarrays and validated the results with reverse transcription-PCR, quantitative PCR and Sanger sequencing. We observed global disruption of splicing in fluorouracil-resistant cells characterized by expression of new mRNA isoforms resulting from exon skipping, alternative splice site usage and intron retention. Alternative expression annotation databases, source code, a data viewer and other resources to facilitate analysis are available at http://www.alexaplatform.org/alexa_seq/. PMID- 20835246 TI - Taming anxiety in laboratory mice. AB - Routine laboratory animal handling has profound effects on their anxiety and stress responses, but little is known about the impact of handling method. We found that picking up mice by the tail induced aversion and high anxiety, whereas use of tunnels or open hand led to voluntary approach, low anxiety and acceptance of physical restraint. Using the latter methods, one can minimize a widespread source of anxiety in laboratory mice. PMID- 20835247 TI - A quantitative targeted proteomics approach to validate predicted microRNA targets in C. elegans. AB - Efficient experimental strategies are needed to validate computationally predicted microRNA (miRNA) target genes. Here we present a large-scale targeted proteomics approach to validate predicted miRNA targets in Caenorhabditis elegans. Using selected reaction monitoring (SRM), we quantified 161 proteins of interest in extracts from wild-type and let-7 mutant worms. We demonstrate by independent experimental downstream analyses such as genetic interaction, as well as polysomal profiling and luciferase assays, that validation by targeted proteomics substantially enriched for biologically relevant let-7 interactors. For example, we found that the zinc finger protein ZTF-7 was a bona fide let-7 miRNA target. We also validated predicted miR-58 targets, demonstrating that this approach is adaptable to other miRNAs. We propose that targeted mass spectrometry can be applied generally to validate candidate lists generated by computational methods or in large-scale experiments, and that the described strategy should be readily adaptable to other organisms. PMID- 20835248 TI - Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1. AB - We propose that a C-type lectin receptor, SIGNR-1 (also called Cd209b), helps to condition dendritic cells (DCs) in the gastrointestinal lamina propria (LPDCs) for the induction of oral tolerance in a model of food-induced anaphylaxis. Oral delivery of BSA bearing 51 molecules of mannoside (Man(51)-BSA) substantially reduced the BSA-induced anaphylactic response. Man(51)-BSA selectively targeted LPDCs that expressed SIGNR1 and induced the expression of interleukin-10 (IL-10), but not IL-6 or IL-12 p70. We found the same effects in IL-10-GFP knock-in (tiger) mice treated with Man(51)-BSA. The Man(51)-BSA-SIGNR1 axis in LPDCs, both in vitro and in vivo, promoted the generation of CD4(+) type 1 regulatory T (Tr1) like cells that expressed IL-10 and interferon-gamma (IFN-gamma), in a SIGNR-1- and IL-10-dependent manner, but not of CD4(+)CD25(+)Foxp3(+) regulatory T cells. The Tr1-like cells could transfer tolerance. These results suggest that sugar modified antigens might be used to induce oral tolerance by targeting SIGNR1 and LPDCs. PMID- 20835249 TI - Clarke's column neurons as the focus of a corticospinal corollary circuit. AB - Proprioceptive sensory signals inform the CNS of the consequences of motor acts, but effective motor planning involves internal neural systems capable of anticipating actual sensory feedback. Just where and how predictive systems exert their influence remains poorly understood. We explored the possibility that spinocerebellar neurons that convey proprioceptive sensory information also integrate information from cortical command systems. Analysis of the circuitry and physiology of identified dorsal spinocerebellar tract neurons in mouse spinal cord revealed distinct populations of Clarke's column neurons that received direct excitatory and/or indirect inhibitory inputs from descending corticospinal axons. The convergence of these descending inhibitory and excitatory inputs to Clarke's column neurons established local spinal circuits with the capacity to mark or modulate incoming proprioceptive input. Together, our genetic, anatomical and physiological results indicate that Clarke's column spinocerebellar neurons nucleate local spinal corollary circuits that are relevant to motor planning and evaluation. PMID- 20835250 TI - ADF/cofilin-mediated actin dynamics regulate AMPA receptor trafficking during synaptic plasticity. AB - Dendritic spines undergo actin-based growth and shrinkage during synaptic plasticity, in which the actin depolymerizing factor (ADF)/cofilin family of actin-associated proteins are important. Elevated ADF/cofilin activities often lead to reduced spine size and immature spine morphology but can also enhance synaptic potentiation in some cases. Thus, ADF/cofilin may have distinct effects on postsynaptic structure and function. We found that ADF/cofilin-mediated actin dynamics regulated AMPA receptor (AMPAR) trafficking during synaptic potentiation, which was distinct from actin's structural role in spine morphology. Specifically, elevated ADF/cofilin activity markedly enhanced surface addition of AMPARs after chemically induced long-term potentiation (LTP), whereas inhibition of ADF/cofilin abolished AMPAR addition. We found that chemically induced LTP elicited a temporal sequence of ADF/cofilin dephosphorylation and phosphorylation that underlies AMPAR trafficking and spine enlargement. These findings suggest that temporally regulated ADF/cofilin activities function in postsynaptic modifications of receptor number and spine size during synaptic plasticity. PMID- 20835251 TI - Allosteric potentiation of glycine receptor chloride currents by glutamate. AB - Neuronal excitability in the CNS is primarily controlled by a balance between synaptic excitation and inhibition. In the brainstem and spinal cord, synaptic excitation and inhibition are mediated by the excitatory transmitter glutamate acting on ionotropic glutamate receptor-gated cationic channels and the inhibitory transmitter glycine acting on glycine receptor (GlyR)-gated chloride channels. We found that glutamate and its analog ligands potentiated GlyR mediated currents in both cultured spinal neurons and spinal cord slices of rats. This potentiation was not dependent on activation of any known glutamate receptor and manifested as an increase in single-channel open probability. Moreover, this glutamate potentiation was seen in HEK293 cells that transiently expressed GlyRs. Our data strongly suggest that glutamate allosterically potentiates GlyR-gated chloride channels, thereby blurring the traditional distinction between excitatory and inhibitory transmitters. Such a rapid homeostatic regulatory mechanism may be important for tuning functional balance between synaptic excitation and inhibition in the CNS. PMID- 20835252 TI - Ontogeny-recapitulating generation and tissue integration of ES cell-derived Purkinje cells. AB - Purkinje cells are the sole output neurons of the cerebellar cortex and their dysfunction causes severe ataxia. We found that Purkinje cells could be robustly generated from mouse embryonic stem (ES) cells by recapitulating the self inductive signaling microenvironments of the isthmic organizer. The cell-surface marker Neph3 enabled us to carry out timed prospective selection of Purkinje cell progenitors, which generated morphologically characteristic neurons with highly arborized dendrites that expressed mature Purkinje cell-specific markers such as the glutamate receptor subunit GluRdelta2. Similar to mature Purkinje cells, these neurons also showed characteristic spontaneous and repeated action potentials and their postsynaptic excitatory potentials were generated exclusively through nonNMDA glutamate receptors. Fetal transplantation of precursors isolated by fluorescence-activated cell sorting showed orthotopic integration of the grafted neurons into the Purkinje cell layer with their axons extending to the deep cerebellar nuclei and dendrites receiving climbing and parallel fibers. This selective preparation of bona fide Purkinje cells should aid future investigation of this important neuron. PMID- 20835253 TI - Visual fixations and the computation and comparison of value in simple choice. AB - Most organisms facing a choice between multiple stimuli will look repeatedly at them, presumably implementing a comparison process between the items' values. Little is known about the nature of the comparison process in value-based decision-making or about the role of visual fixations in this process. We created a computational model of value-based binary choice in which fixations guide the comparison process and tested it on humans using eye-tracking. We found that the model can quantitatively explain complex relationships between fixation patterns and choices, as well as several fixation-driven decision biases. PMID- 20835254 TI - A human mitochondriopathy caused by AIF mutation. PMID- 20835256 TI - Characterization of fertility related antisperm antibodies- a step towards causal treatment of immunological infertility and immuno-contraception. PMID- 20835257 TI - The 5-year functional outcomes after radical prostatectomy: a real-life experience in Korea. AB - We investigated the functional outcomes regarding erectile function and urinary continence up to 5 years following radical prostatectomy (RP) in a cohort of Korean men. We retrospectively analyzed the clinicopathologic data of 85 Korean men who received open uni- or bilateral nerve-sparing RP for clinically localized prostate cancer and were followed up for at least 5 years postoperatively. From medical records, patients' status regarding urinary and erectile function at baseline and postoperative followups after RP was assessed. At 24 and 60 months after RP, proportions of subjects continent (no pads used) were 89.4% and 97.6%, respectively (P = 0.007). Excluding subjects (n = 24) who preoperatively reported having severe erectile dysfunction or lacked relevant informations, proportions of subjects capable of having vaginal intercourse regardless of erectile aid usage were 47.5% and 37.7% at 24 and 60 months from RP, respectively (P = 0.022). Patient's age at surgery (P = 0.047) and salvage radiation therapy (P = 0.026) were observed to be significant predictors of having erections sufficient for intercourse at 60 months from RP in multivariate analysis. Our results showed that while patients' postoperative status regarding urinary continence at 2 years from RP is generally maintained or improved at 5 year point, erectile function was observed to significantly declined from 2 years to 5 years following RP. Such decline in erectile function following RP may be more significant among men who were relatively older at surgery or those who received salvage therapy during postoperative follow-ups. PMID- 20835258 TI - Ethical issues in penile transplantation. AB - This article provides an overview of the ethical issues associated with penile transplantation, a form of composite tissue allografting. There is only one reported case of human penile transplantation, and, as such, this technique is considered to be experimental. The ethical issues at stake involve both the graft donor and the graft recipient. With regard to the recipient, there are significant concerns relating to surgical risks and benefits, informed consent, body image (including surgical expectations and outcomes) and compliance. Donor issues may include family consent and privacy, as well as graft harvesting (leaving the donor cadaver without a penis). Many of these ethical issues can be explored during the recipient's assessment and consent process. Because no medium term or long-term outcome data for this procedure exist-only one such operation has ever been performed-the burdens and ethical issues concerning penile transplantation remain unknown. PMID- 20835259 TI - For cancers there is more to life than a longer G-strand. PMID- 20835260 TI - Diagnosis and treatment of hypogonadism in older men: proceed with caution. PMID- 20835261 TI - The role of TRPC6 in HGF-induced cell proliferation of human prostate cancer DU145 and PC3 cells. AB - Hepatocyte growth factor (HGF) is a glycoprotein that induces prostate cancer cell proliferation, migration and invasion. The activation of transient receptor potential canonical 6 (TRPC6) channels is considered important in promoting prostate cancer cell proliferation. In this study, we assessed the role of endogenous TRPC6 channels in the HGF-induced cell proliferation of prostate cancer. Reverse transcription-PCR and Western blotting were used to investigate TRPC6 expression. Electrophysiological techniques (whole-cell patch clamp configuration) and Ca(2+) imaging analysis were used to investigate the channel activity in cells. The effects of TRPC6 channels on cell cycle progression, cell apoptosis and cell growth were also examined. TRPC6 and c-MET were expressed in DU145 and PC3 cells. In addition, functional TRPC6 channels were present in DU145 and PC3 cells, and TRPC6 knockdown suppressed TRPC-like currents evoked by oleoyl 2-acetyl-sn-glycerol (OAG). Inhibition of TRPC6 channels in DU145 and PC3 cells abolished OAG- and HGF-induced Ca(2+) entry. Furthermore, inhibition of TRPC6 channels arrested DU145 and PC3 cells at the G(2)/M phase and suppressed HGF induced cell proliferation. Collectively, our results indicate that TRPC6 has an important role in HGF-induced DU145 and PC3 cell proliferation. PMID- 20835262 TI - The opening of maitotoxin-sensitive calcium channels induces the acrosome reaction in human spermatozoa: differences from the zona pellucida. AB - The acrosome reaction (AR), an absolute requirement for spermatozoa and egg fusion, requires the influx of Ca2(+) into the spermatozoa through voltage dependent Ca2(+) channels and store-operated channels. Maitotoxin (MTx), a Ca2(+) mobilizing agent, has been shown to be a potent inducer of the mouse sperm AR, with a pharmacology similar to that of the zona pellucida (ZP), possibly suggesting a common pathway for both inducers. Using recombinant human ZP3 (rhZP3), mouse ZP and two MTx channel blockers (U73122 and U73343), we investigated and compared the MTx- and ZP-induced ARs in human and mouse spermatozoa. Herein, we report that MTx induced AR and elevated intracellular Ca2(+) ([Ca2(+)](i)) in human spermatozoa, both of which were blocked by U73122 and U73343. These two compounds also inhibited the MTx-induced AR in mouse spermatozoa. In disagreement with our previous proposal, the AR triggered by rhZP3 or mouse ZP was not blocked by U73343, indicating that in human and mouse spermatozoa, the AR induction by the physiological ligands or by MTx occurred through distinct pathways. U73122, but not U73343 (inactive analogue), can block phospholipase C (PLC). Another PLC inhibitor, edelfosine, also blocked the rhZP3- and ZP-induced ARs. These findings confirmed the participation of a PLC-dependent signalling pathway in human and mouse zona protein-induced AR. Notably, edelfosine also inhibited the MTx-induced mouse sperm AR but not that of the human, suggesting that toxin-induced AR is PLC-dependent in mice and PLC independent in humans. PMID- 20835263 TI - Endothelial dysfunction induced by antibodies against angiotensin AT1 receptor in immunized rats. AB - AIM: To investigate the association between autoantibodies against angiotensin AT1 receptor (AT1-AAs) and endothelial dysfunction in vivo. METHODS: Rat models with AT1 receptor antibodies (AT1-Abs) were established by active immunization for nine months. Lactate dehydrogenase (LDH) activity was regarded as an indicator of cell necrotic death. Endothelin-1 (ET-1) in the sera of rats was determined and endothelium-dependent vasodilatation was detected in isolated thoracic aorta. Endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta endothelium was assessed using confocal microscopy. Coronary artery endothelial ultrastructure was observed. RESULTS: IgGs in the immunized group significantly increased the LDH activity (0.84+/-0.17 vs 0.39+/-0.12, P<0.01 vs vehicle group IgGs)in incubated human umbilical vein endothelial cells through AT1 receptor. Higher content of ET-1 occurred in the immunized rats than that of the vehicle group, and reached two peaks at month 3 (27+/-4 ng/L, P<0.01) and month 7 (35+/-5 ng/L, P<0.01), respectively. In addition, aortic endothelium dependent vasodilatation was attenuated; endothelial ICAM-1 level was markedly increased and cardiac capillary endothelium was damaged following immunization. CONCLUSION: Our study demonstrated that AT1-Abs contributed to endothelial dysfunction in vivo, which was a potential mechanism through which the antibodies play vital roles in related diseases. PMID- 20835264 TI - Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E deficient mice fed a "Western-style diet" by increasing PPAR alpha and gamma expression and reducing TC, MMP-9, and Cat S levels. AB - AIM: The examine the cardiac hypertrophy and fibrosis in apolipoprotein E deficient mice (ApoE-/- mice) fed a "Western-style diet" and the effect of simvastatin intervention. METHODS: Male ApoE-/- mice (n=36) were fed a "Western style diet" from the age of 8 weeks. After 16 weeks, they were randomly given either simvastatin (25 mg.kg-1.d-1) or normal saline (control group) by gavage for 8, 16, or 24 weeks. The left ventricular (LV) wall thickness and diameter of the myocardial cells were determined with Hematoxylin-Eosin stain, and the level of fibrosis of the myocardial matrix was assessed with Masson stain. Real-time quantitative polymerase chain reaction and Western blotting analysis were used to determine the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9), Cathepsin S (Cat S), and the peroxisome proliferator-activated receptors (PPARs) in the myocardium of ApoE-/- mice. RESULTS: ApoE-/- mice fed a "Western-style diet" showed an significant age-dependent increase in total cholesterol (TC), LV wall thickness, myocardial cell diameter and LV collagen content (P<0.05). The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05). Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05). CONCLUSION: ApoE-/- mice fed a "Western-style diet" had cardiac hypertrophy and fibrosis, which worsened with age. Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S. PMID- 20835265 TI - Inhibition of iNOS protects endothelial-dependent vasodilation in aged rats. AB - AIM: To examine whether iNOS contributes to endothelial dysfunction in aged rats. METHODS: Male Sprague Dawley rats were divided into three groups: young rats, aged rats treated with vehicle and aged rats treated with N-[3-(Aminomethyl) benzyl] acetamidine (1400W, 1 mg/kg, ip). Vasorelaxation was measured in isolated thoracic aorta. iNOS expression of thoracic aortic arteries was detected using immunohistochemistry and Western blot. Nitrotyrosine (a marker for peroxynitrite formation) content and expression in thoracic aortic tissue were determined using enzyme linked immunosorbent assay and immunohistochemistry. RESULTS: Maximal relaxation induced by acetylcholine (10-9 to 10-5 mol/L) in the aged rats treated with vehicle was significantly decreased (70%+/-15%, P<0.01), as compared with the young rats (95%+/-8%). However, the maximal relaxation induced by acidified NaNO2 (an endothelium-independent vasodilator) had no significant difference between the two groups. Moreover, iNOS and nitrotyrosine expression increased in the vessels of the aged rats. In the aged rats treated with 1400W (a highly selective iNOS inhibitor) nitrotyrosine expression was reduced and acetylcholine induced vasorelaxation was markedly improved (maximal relaxation was increased to 87%+/-8%, P<0.05), but the acidified NaNO2-induced vasorelaxation had no significant change. CONCLUSION: Our study demonstrated that inhibition of iNOS by 1400W increased endothelium-dependent vasodilation in aged rats. The mechanism was related with attenuation of peroxynitrite formation. PMID- 20835266 TI - Caveolae and caveolin-1 mediate endocytosis and transcytosis of oxidized low density lipoprotein in endothelial cells. AB - AIM: To explore the mechanisms involved in ox-LDL transcytosis across endothelial cells and the role of caveolae in this process. METHODS: An in vitro model was established to investigate the passage of oxidized low density lipoprotein (ox LDL) through a tight monolayer of human umbilical vein endothelial cells (HUVEC) cultured on a collagen-coated filter. Passage of DiI-labeled ox-LDL through the monolayer was measured using a fluorescence spectrophotometer. The uptake and efflux of ox-LDL by HUVEC were determined using fluorescence microscopy and HPLC. RESULTS: Caveolae inhibitors - carrageenan (250 MUg/mL), filipin (5 MUg/mL), and nocodazole (33 MUmol/L)-decreased the transport of ox-LDL across the monolayer by 48.9%, 72.4%, and 79.8% as compared to the control group. In addition, they effectively decreased ox-LDL uptake and inhibited the efflux of ox-LDL. Caveolin 1 and LOX-1 were up-regulated by ox-LDL in a time-dependent manner and decreased gradually after depletion of ox-LDL (P<0.05). After treatment HUVEC with ox-LDL and silencing caveolin-1, NF-kappaB translocation to the nucleus was blocked and LOX-1 expression decreased (P<0.05). CONCLUSION: Caveolae can be a carrier for ox LDL and may be involved in the uptake and transcytosis of ox-LDL by HUVEC. PMID- 20835268 TI - Matrine inhibits vascular smooth muscle cell proliferation by modulating the expression of cell cycle regulatory genes. AB - AIM: To investigate the effect of matrine on proliferation of vascular smooth muscle cells (VSMCs) and elucidate the underlying mechanisms. METHODS: Rat aortic VSMCs were cultured in medium supplemented with 10% fetal bovine serum and treated with various concentrations (0, 5, 10, 15, and 20 mg/L) of matrine for 72 h. VSMCs proliferation and cell cycle profiling were assessed using a methylene blue incorporation assay and flow cytometry, respectively. The underlying protein signaling mechanisms were determined using Western blot analysis of the expression levels of cell cycle regulatory genes, including p53, p21, p27, cyclin D1, cyclin E, cyclin-dependent kinase 2 and 4 (cdk2, cdk4), and phosphorylated Rb. The involvement of p21 and p27 pathways was further determined using small interfering RNA (siRNA) knockdown. RESULTS: Matrine inhibited VSMC proliferation in a dose-dependent manner by promoting G(1) arrest. The G(1) arrest was accompanied by up-regulation of p53 and p21 protein levels, and down-regulation of cyclin D1/cdk4, cyclin E/cdk2 and phosphorylated Rb protein levels. Matrine did not affect p27 expression. Furthermore, the anti-proliferative effect of matrine was abolished by silencing of p21, but not by silencing of p27. CONCLUSION: Our data indicate that matrine has an inhibitory effect on VSMC proliferation via up-regulation of the p53/p21 signaling pathway and modulation of other cell cycle regulatory genes. PMID- 20835267 TI - A novel model of cholesterol efflux from lipid-loaded cells. AB - Cholesterol efflux from lipid-loaded cells is a key athero-protective event that counteracts cholesterol uptake. The imbalance between cholesterol efflux and uptake determines the prevention or development of atherosclerosis. Many proteins and factors participate in the cholesterol efflux event. However, there are currently no systematic models of reverse cholesterol transport (RCT) that include most RCT-related factors and events. On the basis of recent research findings from other and our laboratories, we propose a novel model of one center and four systems with coupling transportation and networking regulation. This model represents a common way of cholesterol efflux; however, the systems in the model consist of different proteins/factors in different cells. In this review, we evaluate the novel model in vascular smooth muscle cells (VSMCs) and macrophages, which are the most important original cells of foam cells. This novel model consists of 1) a caveolae transport center, 2) an intracellular trafficking system of the caveolin-1 complex, 3) a transmembrane transport system of the ABC-A1 complex, 4) a transmembrane transport system of the SR-B1 complex, and 5) an extracelluar trafficking system of HDL/Apo-A1. In brief, the caveolin-1 system transports cholesterol from intracellular compartments to caveolae. Subsequently, both ABC-A1 and SR-B1 complex systems transfer cholesterol from caveolae to extracellular HDL/Apo-A1. The four systems are linked by a regulatory network. This model provides a simple and concise way to understand the dynamic process of atherosclerosis. PMID- 20835269 TI - Potentiation of EDHF-mediated relaxation by chloride channel blockers. AB - AIM: To investigate the involvement of Cl- channels in endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation in rat mesenteric arteries. METHODS: Cl- channel and K(ir) channel activities were studied using whole-cell patch clamping in rat mesenteric arterial smooth muscle cells. Isometric tension of arterial rings was measured in organ chambers. RESULTS: The volume-activated Cl- current in rat mesenteric arterial smooth muscle cells was abolished by Cl- channel blockers NPPB or DIDS. The EDHF-mediated vasorelaxation was potentiated by NPPB and DIDS. The EDHF response was diminished by a combination of apamin and charybdotoxin, which agreed with the hypothesis that EDHF response involves the release of K(+) via the Ca2(+)-activated K(+) channels in endothelial cells. The elevation of K(+) concentration in bathing solution from 1.2 mmol/L to 11.2 mmol/L induced an arterial relaxation, which was abolished by the combination of BaCl2 and ouabain. It is consistent to the hypothesis that K(+) activates K(+)/Na(+)-ATPase and inward rectifier K(+) (K(ir)) channels, leading to the hyperpolarization and relaxation of vascular smooth muscle. The K(+)-induced relaxation was augmented by NPPB, DIDS, or withdrawal of Cl- from the bathing solution, which could be reversed by BaCl2, but not ouabain. The potentiating effect of Cl- channel blockers on K(+)-induced relaxation was probably due to the interaction between Cl- channels and K(ir) channels. Moreover, the K(+)-induced relaxation was potentiated when the arteries were incubated in hyperosmotic solution, which is known to inhibit volume-activated Cl- channels. CONCLUSION: The inhibition of Cl- channels, particularly the volume-activated Cl- channels, may potentiate the EDHF-induced vasorelaxation through the K(ir) channels. PMID- 20835270 TI - Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression. AB - AIM: To investigate the expression of advanced glycation end products (AGEs) and their receptor RAGE in the livers and blood vessels of rats with non-alcoholic steatohepatitis (NASH) and the effect of pentoxifylline (PTX) on liver and artery function in rats with NASH. METHODS: Sprague-Dawley rats were fed a high-fat diet for 12 weeks and given PTX by gavage for 4 weeks. The effects of PTX on hepatic liver and vessel function as well as the expression of AGE and RAGE in rats with NASH were assessed. The intima-media thickness (IMT) of the aorta and carotid artery was evaluated using ultrasonography. RESULTS: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group. The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group. The IMT was reduced in NASH rats after treatment with PTX. Rats with NASH demonstrated higher AGE and RAGE protein levels in the liver and arteries compared with those of control rats. PTX treatment in NASH rats resulted in a decrease in AGE and RAGE protein levels in the liver and arteries compared with those in the NASH group. CONCLUSION: Early atherosclerosis was observed in rats with NASH induced by a 16 week high-fat diet. High expression of AGE and RAGE in the livers and arteries of rats with NASH may contribute to the pathogenesis of NASH and early atherosclerosis. PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression. PMID- 20835272 TI - [The power of vague formulations]. PMID- 20835273 TI - [Too many or too few admissions?]. PMID- 20835271 TI - Non-hematopoietic cells contribute to protective tolerance to Aspergillus fumigatus via a TRIF pathway converging on IDO. AB - Innate responses combine with adaptive immunity to generate the most effective form of anti-Aspergillus immune resistance. Whereas the pivotal role of dendritic cells in determining the balance between immunopathology and protective immunity to the fungus is well established, we determined that epithelial cells (ECs) also contributes to this balance. Mechanistically, EC-mediated protection occurred through a Toll-like receptor 3/Toll/IL-1 receptor domain-containing adaptor inducing interferon (TLR3/TRIF)-dependent pathway converging on indoleamine 2,3 dioxygenase (IDO) via non-canonical nuclear factor-kappaB activation. Consistent with the high susceptibility of TRIF-deficient mice to pulmonary aspergillosis, bone marrow chimeric mice with TRIF unresponsive ECs exhibited higher fungal burdens and inflammatory pathology than control mice, underexpressed the IDO dependent T helper 1/regulatory T cell (Th1/Treg) pathway and overexpressed the Th17 pathway with massive neutrophilic inflammation in the lungs. Further studies with interferon (IFN)-gamma, IDO or IL-17R unresponsive cells confirmed the dependency of immune tolerance to the fungus on the IFN-gamma/IDO/Treg pathway and of immune resistance on the MyD88 pathway controlling the fungal growth. Thus, distinct immune pathways contribute to resistance and tolerance to the fungus, to which the hematopoietic/non-hematopoietic compartments contribute through distinct, yet complementary, roles. PMID- 20835274 TI - [Abuse of pregabalin]. PMID- 20835275 TI - [Books and reviews criteria]. PMID- 20835276 TI - [Standards and medical records]. PMID- 20835278 TI - [Written information prior to interventions]. PMID- 20835279 TI - [Information flow--it's dangerous!]. PMID- 20835280 TI - [Survival in adults with acute lymphoblastic leukaemia]. AB - BACKGROUND: The Norwegian treatment protocol for acute lymphoblastic leukaemia in adults was introduced in 1982 and has undergone minor changes thereafter. Earlier studies from The South Eastern Norway Regional Health Authority have reported 50 % five-year overall survival in patients treated according to this protocol. This article presents survival data for Norwegian adults with acute lymphoblastic leukaemia on a national basis. MATERIAL AND METHODS: Data for all patients between 15 and 65 years, who were diagnosed with acute lymphoblastic leukaemia in the period 2000-2007 according to The Norwegian Registry for Acute Leukaemia and Lymphoblastic Lymphoma, and were treated with chemotherapy with a curative intent were analysed for survival. RESULTS: 128 patients were diagnosed with acute lymphoblastic leukaemia in the study period. The overall remission rate was 85.9 %. Five-year survival was 49.2 % overall, 31.4 % for patients 40 years or older and 62.6 % for those younger than 40 years. INTERPRETATION: These results are in line with previous Norwegian studies and show a five- year overall survival which is more than 10 % higher than that reported in international multicenter studies. One explanation can be that the Norwegian treatment program is more intensive than most treatment protocols used in other countries. PMID- 20835281 TI - [Acute myocardial infarction in Mid-Norway: transportation for thrombolytic treatment or primary percutaneous coronary intervention?]. AB - BACKGROUND: Occluded coronary arteries should be opened urgently in patients who have acute myocardial infarction and ST-elevation in ECG. When transport times are long, thrombolytic treatment is a good alternative to primary percutaneous coronary intervention (PCI). The purpose of this study was to assess choice of treatment strategy in cases where time after start of symptoms and transport time are decisive for the outcome. MATERIAL AND METHODS: A cohort study of 379 patients, who had myocardial infarction and ST-elevation, and were admitted to St. Olav's Hospital, Trondheim, Norway in the period 1.11.2007-31.1.2009. RESULTS: 268 patients (71 %) were treated with PCI, and 111 patients (29 %) with thrombolytic treatment. 173 patients (46 %) were transported by helicopter. The counties in Mid-Norway used markedly different treatment strategies for these patients. INTERPRETATION: Great regional differences were observed in the use of PCI and thrombolytic treatment in Mid-Norway. PMID- 20835282 TI - [Intravenous IgG for treatment of neuromuscular diseases]. AB - BACKGROUND: Highly purified IgG administered intravenously (IVIG) is used to treat many neurological diseases. MATERIAL AND METHODS: This review is based on articles identified through a search in PubMed and the authors' knowledge and experience within the field. RESULTS: The effect of IVIG has been best documented in the treatment of acute and chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy and acute exacerbation of myasthenia gravis. Some smaller studies support explorative IVIG treatment in other neurological diseases such as Lambert-Eaton myasthenic syndrome, paraproteinemic neuropathy, neuropathy caused by vasculitis, inflammatory myopathies and stiff-person syndrome. INTERPRETATION: IVIG affects the immune system in different ways. Documentation for the effect of such treatment in most neurological diseases remains sparse. PMID- 20835283 TI - [Emergency admissions from nursing homes to hospital at the end of life]. AB - BACKGROUND: Admissions from nursing homes to hospital at the end of life have not been previously studied in Norway. The goal of this project was to document acute admissions to a Norwegian hospital for patients who died within 48 hours after hospitalization. MATERIAL AND METHODS: This study is based on information recorded in patient charts for admissions to Haraldsplass Deaconess Hospital, Bergen in the period 1.10. 2007-30.9.2008. Patients who were admitted from nursing homes and died within 48 hours after admission to the hospital were eligible for inclusion. Cooperation between nursing homes and the hospital and whether patients received appropriate palliative care was analysed. RESULTS: 26 patients, mean age 85.3 years, were included in the study. All of them had internal medicine problems. 12 patients had been assessed by a physician before admission. 14 patients had a written referral from a doctor and 18 patients had a note from a nurse. For eight patients no information was given about what was expected from the hospital and for four patients there was no information about medication. No documentation was available about verbal contact between the institutions before the admissions. In the hospital, diagnostic procedures were used for 24 patients and potentially life-prolonging treatment was started for 23 patients. Morphine was prescribed for 18 patients. INTERPRETATION: The results show that nursing home residents have inadequate access to physicians, and indicate that competence concerning evaluation of critically ill patients in nursing homes must be improved. Hospital physicians used a treatment focus in their patient approach. The cooperation and communication between nursing homes and the hospital functioned badly. Palliative care should be improved both in the hospital and the nursing homes. PMID- 20835284 TI - [Discontinuation of prophylactic drugs to the elderly]. AB - Polypharmacy is common among the elderly and consequences may be adverse drug reactions, interactions and toxicity. At the same time it is well documented that elderly patients are suboptimally treated for conditions such as atrial fibrillation and osteoporosis. When assessing medical treatment one must take into account the remaining life expectancy, time to effect, complication risk related to not treating, risks related to adverse drug effects and interactions, patient preferences and treatment goals. PMID- 20835285 TI - [Family-focused neonatal care]. PMID- 20835288 TI - [Buy a uniform--support a nurse!]. PMID- 20835290 TI - Private ultrasonic whispering in moths. AB - Sound-producing moths have evolved a range of mechanisms to emit loud conspicuous ultrasounds directed toward mates, competitors and predators. We recently discovered a novel mechanism of sound production, i.e., stridulation of specialized scales on the wing and thorax, in the Asian corn borer moth, Ostrinia furnacalis, the male of which produces ultrasonic courtship songs in close proximity to a female (<2 cm). The signal is very quiet, being exclusively adapted for private communication. A quiet signal is advantageous in that it prevents eavesdropping by competitors and/or predators. We argue that communication via quiet ultrasound, which has not been reported previously, is probably common in moths and other insects. PMID- 20835291 TI - Cell polarity in plants: Linking PIN polarity generation mechanisms to morphogenic auxin gradients. AB - Auxin efflux carrier PIN proteins have been intensively investigated as they are the first polar cargos to be identified in plants with a direct relevance for plant patterning. Based on their polar localization; PIN proteins direct the intercellular flow of signaling molecule auxin and thus bear a rate limiting effect on the formation of auxin activity gradients. With this influence on directionality and extent of auxin transport PINs play crucial roles in plant body organization. Many factors such as vesicle trafficking regulator ARF-GEF GNOM, a kinase PINOID, a retromer complex and membrane sterol composition influence polar PIN localization. Recent work uncovers the mechanism that generates default PIN polarity. Real time PIN tracking reveals that PIN polarity is generated from initially non-polar secretion via endocytosis and subsequent polar recycling. In addition, the Rab5 endocytic pathway emerges to be important for polar PIN localization as Rab5 interference causes non-polar distribution of PINs. This non-polar distribution of PINs during embryogenesis transiently alters auxin activity gradients and changes organ identity by transforming embryonic leaf cells to root fates. These findings for the first time link PIN polarity based auxin activity gradient to cell fate decisions and thus demonstrate morphogen (a substance influencing cell fates on its concentration gradient) characters of auxin. They also suggest an auxin activity distribution-dependent sensing module that executes differential apical and basal developmental program during plant embryogenesis. PMID- 20835292 TI - Personal Wellbeing Index in a National Cohort of 87,134 Thai Adults. AB - Satisfaction with life correlates with other measures of subjective wellbeing and correlates predictably with individual characteristics and overall health. Social indicators and subjective wellbeing measures are necessary to evaluate a society and can be used to produce national indicators of happiness. This study therefore aims to help close the gap in wellbeing data for Thailand. The specific aims are to: (1) calculate the Thai PWI and domain scores using a large scale sample; (2) examine the level of life satisfaction of Thais when compared to international standards; (3) examine the Thai PWI and domains in relation to demographic, socioeconomic, and geographic characteristics. Our report derives from the findings on the Personal Wellbeing Index (PWI) in a large national cohort of Sukhothai Thammathirat Open University adult students living all over Thailand (n = 87,134). This Thai cohort had an overall PWI of 70.0 on a scale from 0 to 100 which is consistent with Western populations. The 'spirituality and religion' domain had the highest average score. 'Standard of living', 'future security' and 'achievement in life' made the largest contribution to overall 'satisfaction in life as a whole'. These domains also show a positive trend with increasing age, being married, higher income, more education, more household assets, and rural residence. The PWI will be an important tool for policymakers to understand the subjective wellbeing of population groups especially as Thailand is undergoing a political and economic transition. PMID- 20835294 TI - Understanding Change in Romantic Relationship Expectations of International Female Students from Turkey. AB - In the light of grounded theory, the authors explored change in romantic relationship expectations of international students. Twelve female graduate students from Turkey were interviewed and several themes were identified explaining the presence and absence of change in participants' attitudes toward romantic relationships. The findings are discussed in relation to acculturation and direction for future research is presented. PMID- 20835293 TI - Do Measured and Unmeasured Family Factors Bias the Association Between Education and Self-Assessed Health? AB - The association between educational attainment and self-assessed health is well established but the mechanisms that explain this association are not fully understood yet. It is likely that part of the association is spurious because (genetic and non-genetic) characteristics of a person's family of origin simultaneously affect one's educational attainment and one's adult health. In order to obtain an unbiased estimate of the association between education and health, we have to control for all relevant family factors. In practice, however, it is impossible to measure all relevant family factors. Sibling models are particularly appropriate in this case, because they control for the total impact of family factors, even if not all relevant aspects can be measured. I use data on siblings from a US study (MIDUS) and Dutch study (NKPS) to assess the total family impact on self-assessed health and, more importantly, to assess whether there is a family bias in the association between educational attainment and self assessed health. The results suggest that there is a substantial family effect; about 20% of the variation in self-assessed health between siblings can be ascribed to (measured and unmeasured) family factors. Measured family factors, such as parental education and father's occupation, could account only for a small part of the family effect. Furthermore, the results imply that it is unlikely that there is substantial bias due to family effects in the association between education and self-assessed health. This strengthens the conclusions from prior studies on the association between education and self-assessed health. PMID- 20835295 TI - The Legacy of Oil Spills. PMID- 20835296 TI - Recovery from Mercury Contamination in the Second Songhua River, China. AB - Mercury pollution in the Second Songhua River (SSR) was serious in the last century due to effluent from a chemical corporation. Effects of riverine self purification on mercury removal were studied by comparing monitoring data of mercury concentrations varieties in water, sediment, and fish in the past, about 30 years. The present work suggested that a river of such a size like the SSR possessed the potential ability to recover from mercury pollution under the condition that mercury sources were cut off, though it needs a very long time, which might be several decades or even a century of years. During the 30 years with no effluent containing mercury input, total mercury (T-Hg) of water and sediment in some typical segments, mostly near the past effluent outlet, had decreased radically but still higher than the background values, though the decrease amplitudes were over 90% compared with that in 1975. T-Hg had decreased by more than 90% in most fishes, but some were still not suitable for consumption. Methylmercury concentrations (MeHg) of water, sediment, and fish were higher or close to the background levels in 2004. In the coming decades, the purification processes in the SSR would be steady and slow for a long period. PMID- 20835297 TI - Stability of Cholesterol, 7-Ketocholesterol and beta-Sitosterol during Saponification: Ramifications for Artifact Monitoring of Sterol Oxide Products. AB - Cholesterol has been used to monitor artifact generation. Stability differences among cholesterol oxide products (COPs) and cholesterol in thermal and alkaline conditions are theorized. Thus, use of cholesterol may be unsuitable for detection of artifacts generated from COPs. Stability of cholesterol was compared to that of 7-ketocholesterol (7-keto) and beta-sitosterol (betaS) under various thermal and alkaline saponification conditions: 1 M methanolic KOH for 18 h at 24 degrees C (1 M18hr24 degrees C, Control), 18 h at 37 degrees C (1M18hr37 degrees C), 3 h at 45 degrees C (1M3hr45 degrees C), and 3.6 M methanolic KOH for 3 h at 24 degrees C (3.6M3hr24 degrees C). Trends indicated that cholesterol in solution was more stable than 7-keto under all conditions. Compared to betaS, cholesterol was more stable under all conditions except for 1M18hr37 degrees C for which stabilities were similar. Compounds were more labile in heat than alkalinity. Poor recoveries of 7-keto during cold saponification with high alkalinity were attributed to alkaline instability. 7-Keto, less stable than cholesterol, should be used to monitor artifact generation during screening of various methods that include thermal and alkaline conditions. In a preliminary analysis of turkey meat, more 3,5-7-one was generated from spiking with cholesterol than with 7-keto. PMID- 20835298 TI - Affirmative Challenges in Indigenous Resilience Research. PMID- 20835299 TI - DIRECTIONS IN INDIGENOUS RESILIENCE RESEARCH. AB - The last decade or so of research in Canada, reflected in this special issue, has increased our understanding of the distinction between Indigenous resilience and the research into Indigenous resilience.Measurement offers glimpses of resilience, mostly from the potentially distorted view of how resilient youth face specific adversity - adversity that is set by the funding opportunity: tobacco, substance abuse, suicide, or HIV infection. The driving role of funding has obvious problems; the priorities of funders may not be the priorities of communities and results can tell more about the funding opportunity than about resilience itself. Even so, this problem-focussed research has the very practical advantage of producing results geared to solutions.A major lesson of this body of work is that we should allow ourselves the space (and the modesty) to recognize that Aboriginal resilience is greater than we have been able to measure under specific funding opportunities. Even with this limitation, our results shows a large degree of specificity - what strengthens youth resilience to one type of adversity in one setting might well not work in another. Five proposals emerge from the findings. PMID- 20835300 TI - An Elder's View of Community Resilience. AB - This paper is an interview between Carrielynn Lund and Cree Elder Ruth Gladue on research and community resilience in her semi-remote, northern Alberta community. Ruth is a Cree Elder born "during the war years." She is married and has two girls, one boy, and "a few grandchildren." Ruth has worked as a Community Health Representative (CHR) and Licensed Practical Nurse (LPN) for over forty years. She lives in a semi-remote First Nations community in northern Alberta. PMID- 20835301 TI - Culturally Competent Service Provision Issues Experienced By Aboriginal People Living With HIV/AIDS. AB - Cultural identity is an important factor in how well Aboriginal people respond to HIV/AIDS prevention or, once diagnosed with HIV or AIDS, how it affects their health care. This study explores the cultural skills among service providers who see Aboriginal people living with HIV/AIDS (APHAs) and the perspectives of APHAs. The purpose is to better understand the wellness needs of APHAs and how culturally competent care affects health service access and use. Data collection included face-to-face semi-structured interviews with APHAs and focus groups/interviews with community-based and primary health professionals in five regions of Canada. Interviews and focus groups were voice-recorded, verbatim transcribed, and coded using Atlas.ti((r)) software. Thirty-five APHAs and fifty two service providers were reached. Two key themes were noticed:Active addictions are a major obstacle to adherence to HIV drug regimes. Half of APHA participants said addictions are a major factor. A similar portion noted intensified substance use was an initial coping strategy when diagnosed. A slightly smaller portion noted that addictions were dealt with soon after diagnosis in order to begin antiretroviral treatment. Service providers who inform, encourage, and support APHAs' choices are viewed as "culturally competent."Addictions and HIV must be "treated together," reflecting a holistic worldview of Aboriginal people. Programs that integrate addiction treatment with HIV/AIDS and service providers who encourage and support APHA's choices are viewed as "wise practice" models by both sets of study participants offering some convergence and a set of five wise practices are identified. PMID- 20835302 TI - Efficient Skeletonization of Volumetric Objects. AB - Skeletonization promises to become a powerful tool for compact shape description, path planning, and other applications. However, current techniques can seldom efficiently process real, complicated 3D data sets, such as MRI and CT data of human organs. In this paper, we present an efficient voxel-coding based algorithm for Skeletonization of 3D voxelized objects. The skeletons are interpreted as connected centerlines. consisting of sequences of medial points of consecutive clusters. These centerlines are initially extracted as paths of voxels, followed by medial point replacement, refinement, smoothness, and connection operations. The voxel-coding techniques have been proposed for each of these operations in a uniform and systematic fashion. In addition to preserving basic connectivity and centeredness, the algorithm is characterized by straightforward computation, no sensitivity to object boundary complexity, explicit extraction of ready-to parameterize and branch-controlled skeletons, and efficient object hole detection. These issues are rarely discussed in traditional methods. A range of 3D medical MRI and CT data sets were used for testing the algorithm, demonstrating its utility. PMID- 20835303 TI - Coping With Breast Cancer at the Nexus of Religiosity and Hawaiian Culture: Perspectives of Native Hawaiian Survivors and Family Members. AB - This article describes research to develop a breast health intervention for women in Hawaiian churches. Native Hawaiian women are disproportionately burdened by breast disease and tend to be diagnosed at advanced stages when treatment options are more limited. Research suggests that cultural conflict may be a factor in Hawaiian women's underutilization of conventional health services. Phenomenological approaches guided data collection and analysis to explore the influence of religiosity and ethnocultural tradition in coping with breast cancer. The overarching theme was kakou (we or us), which emphasized ways of coping oriented to the family collective and focused on family well-being. Findings offer a portal for understanding the lived experience of survivors and families in Hawaiian churches. Considerations are suggested for those practitioners assisting clients from collectivist-oriented cultures. PMID- 20835305 TI - Sublingual immunotherapy in allergic asthma: Current evidence and needs to meet. AB - Allergen-specific immunotherapy is aimed at modifying the natural history of allergy by inducing tolerance to the causative allergen. In its traditional, subcutaneous form, immunotherapy has complete evidence of efficacy in allergic asthma. However, subcutaneous immunotherapy (SCIT) has a major flaw in side effects, and especially in possible anaphylactic reactions, and this prompted the search for safer ways of administration of allergen extracts. Sublingual immunotherapy (SLIT) has met such need while maintaining a clinical efficacy comparable to SCIT. In fact, the safety profile, as outlined by a systematic revision of the available literature, was substantially free from serious systemic reactions. A number of meta-analyses clearly showed that SLIT is effective in allergic rhinitis by significantly reducing the clinical symptoms and the use of anti-allergic drugs, while the efficacy in allergic asthma is still debated, with some meta-analyses showing clear effectiveness but other giving contrasting results. Besides the efficacy on symptoms, the preventive activity and the cost-effectiveness are important outcomes of SLIT in asthma. The needs to meet include more data on efficacy in house dust mite asthma, optimal techniques of administration and, as previously done with SCIT, introduction of adjuvants able to enhance the immunologic response and use of recombinant allergens. PMID- 20835304 TI - Role of nitric oxide and its metabolites as potential markers in lung cancer. AB - Nitric oxide (NO) and reactive oxygen species (ROS) play important physiologic roles as mediators of signaling processes. However, high concentrations of NO and ROS result in damage to cellular and extracellular components. Excessive production of endogenous and/or exogenous ROS and NO is implicated in the pathogenesis of lung cancer. NO and its metabolites interact with ROS to generate potent nitrating agents leading to protein nitration, which is one of the several chemical modifications that occur during oxidative/nitrosative stress. Although there is considerable evidence in support of a role for NO in protein modifications and carcinogenesis, recent data suggest that NO has antagonistic cellular effects, leading to either promotion or inhibition of tumor growth. However, the role of NO in tumor biology is still poorly understood. This review demonstrates the role of NO and its metabolites as potential markers in lung cancer. PMID- 20835306 TI - Genomic and non-genomic actions of glucocorticoids in asthma. AB - Glucocorticoids are the mainstay of asthma therapy. They are primarily used to suppress airway inflammation, which is the central pathological change in asthmatic patients' airways. This is achieved by many different mechanisms. The classical mechanism is by suppression of the genetic transcription of many inflammatory cytokines that are key in asthma pathophysiology (transrepression). On the other hand, the transcription of certain inhibitory cytokines is activated by glucocorticoids (transactivation), a mechanism that also mediates many of the adverse effects of glucocorticoids. The onset of action through these mechanisms is often delayed (4-24 hours). Other mechanisms mediated through non-genomic pathways are increasingly appreciated. These are delivered in part by binding of glucocorticoids to nonclassical membrane-bound glucocorticoid receptors or by potentiating the alpha1-adrenergic action on the bronchial arterial smooth muscles, in addition to other mechanisms. These effects are characterized by their rapid onset and short duration of action. Understanding these different mechanisms will help in the development of new and better drugs to treat this common disease and to develop new improved strategies in our approach to its management. Here, the genomic and non-genomic mechanisms of actions of glucocorticoids in asthma are briefly reviewed, with special emphasis on the current updates of the non-genomic mechanisms. PMID- 20835307 TI - Reactive oxygen metabolites can be used to differentiate malignant and non malignant pleural efffusions. AB - OBJECTIVE: Increase in reactive oxygen metabolites (ROM) and free radicals is an important cause of cell injury. In this study, we investigated whether determination of ROM in pleural fluids of patients with malignant and non malignant pleural effusions can be used as a tumor marker indicating malignant effusions in the differential diagnosis. METHODS: Sixty subjects with exudative pleural effusion and 25 healthy individuals as the control group were included in the study. Of the subjects with pleural effusion, 50% were malignant and 50% were non-malignant. ROM was studied in the pleural fluids and sera of the subjects with pleural effusion and in the sera of those in the control group. The ROM values of smokers and non-smokers were compared in each group. The Student's t test and the Mann-Whitney U test were used in order to detect differences between groups for descriptive statistics in terms of pointed features. The statistical significance level was set at 5% in computations, and the computations were made using the SPSS (ver.13) statistical package program RESULTS: It was determined that the difference between the ROM values of subjects with malignant and non malign pleural effusions and the sera of the control group was significant in the malignant group compared to both groups (P = 0.0001), and the sera ROM values of patients with non-malignant pleural effusion were significant compared to the control group (P = 0.0001), and the ROM values of smokers were significant compared to non-smokers in each of the three groups (P = 0.0001). CONCLUSION: These findings indicate that sera ROM levels are increased considerably in patients with exudative effusions compared to that of the control group. This condition can be instructive in terms of serum ROM value being suggestive of exudative effusion in patients with effusions. Furthermore, the detection of pleural ROM values being significantly higher in subjects with malignant pleural effusions compared to non-malignant subjects suggests that ROM can be used as a tumor marker in the differential diagnosis of pleural effusions of unknown origin. PMID- 20835308 TI - Knowledge, attitude and practice of tobacco smoking by medical students in Riyadh, Saudi Arabia. AB - BACKGROUND: Tobacco consumption is associated with considerable negative impact on health. Health professionals, including future doctors, should have a leading role in combating smoking in the community. OBJECTIVES: The aims of the study were to assess the prevalence of smoking among medical students of newly established medical colleges in Riyadh city, the capital of Saudi Arabia, as well as to assess students' attitude, practice and their knowledge on the risk factors of tobacco consumption. METHODS: A cross-sectional, questionnaire-based study of students from two medical colleges in Riyadh, Saudi Arabia was carried out. The questionnaire used was anonymous, self-administered and developed mainly from Global Adult Tobacco Survey (GATS). RESULTS: A total of 215 students participated in this study. Forty students (19%) indicated that they smoke tobacco at the time of the study. All of them were males, which raise the prevalence among male students to 24%. Tobacco smoking was practiced by males more than females (P value <0.0001) and by senior more than junior students (<0.0001). About 94% of the study sample indicated that smoking could cause serious illnesses. About 90% of the students indicated that they would advice their patients to quit smoking in the future and 88% thought that smoking should be banned in public areas. Forty-four students (20%) thought that smoking has some beneficial effects, mainly as a coping strategy for stress alleviation. CONCLUSION: Despite good knowledge about the hazards of tobacco consumption, about 25% of the medical students in this study continue to smoke. The main reported reasons should be addressed urgently by policy-makers. Special efforts should be taken to educate medical students on the effective strategies in managing stress during their study as they thought that tobacco smoking could be used as a coping strategy to face such a stress. PMID- 20835309 TI - The emergence of Beijing genotype of Mycobacterium tuberculosis in the Kingdom of Saudi Arabia. AB - OBJECTIVE: To investigate the prevalence of Beijing genotype strains of Mycobacterium tuberculosis in the Kingdom of Saudi Arabia. METHODS: We analyzed the available data on a total of 1505 strains isolated during 2002-2005. RESULTS: Spoligotyping results revealed that Beijing family isolates represented 4.5% of all the isolates. Existence of Beijing clade is alarming as this family is known to be multi-drug resistant and transmissible. CONCLUSIONS: This study showed that the occurrence of Beijing genotype is associated with young age and drug resistance. The Beijing strains affected both Saudi nationals as well as migrants originating in Asia. The Beijing clade could be responsible for the ongoing transmission of tuberculosis within the community. PMID- 20835310 TI - Frontline gefitinib in advanced non-small cell lung cancer: Meta-analysis of published randomized trials. AB - OBJECTIVE: Gefitinib, a small molecule tyrosine kinase inhibitor, showed a substantial effect as a salvage treatment for patients with advanced non-small cell lung cancer (NSCLC) who had failed prior chemotherapy. Subsequent phase III trials in previously untreated patients have failed to demonstrate such benefit. It was later reported that gefitinib had a positive outcome when used in selected population. RATIONAL: The inconsistent results and the lack published meta analysis that systematically examined the overall efficacy of gefitinib in the frontline setting in such patients, have prompted the current meta-analysis. METHODS: We selected for analysis only those randomized, peer-reviewed clinical studies where the efficacy of gefitinib-based therapy (GBT) was investigated in chemotherapy naive patients with locally advanced or metastatic NSCLC. We also included studies where patients were randomized between gefitinib vs. placebo or none after initial chemoradiation or chemotherapy induction offered to all included patients. RESULTS: We identified seven eligible studies involving 2,646 and 1,939 patients randomized to GBT and to control arms, respectively. In mostly unselected population, GBT was not associated with higher objective response rate (ORR), progression-free survival (PFS) (hazard ratio [HR] = 0.97, 95% CI: 0.78 1.20, P = 0.78), or overall survival (OS) (HR = 1.04, 95% CI: 0.95-1.13, P = 0.45) as compared with control interventions. In a fraction of patients with known EGFR mutation status, GBT showed significantly higher ORR among patients with mutant EGFR (odds ratio [OR] = 2.81, 95% CI: 1.71-4.62, P < 0.0001); however, EGFR mutation was not associated with better PFS or OS with GBT. Nevertheless, patients receiving GBT experienced significant improvement in quality of life as compared with those in the control arms. CONCLUSION: We conclude that GBT cannot be recommended for frontline management of patients with advanced NSCLC in unselected patient population. PMID- 20835311 TI - Ghrelin, leptin, adiponectin, and resistin levels in sleep apnea syndrome: Role of obesity. AB - AIM: The aim of this study was to investigate the relationship among plasma leptin, ghrelin, adiponectin, resistin levels, and obstructive sleep apnea syndrome (OSAS). METHODS: Fifty-five consecutive newly diagnosed OSAS patients and 15 age-matched nonapneic controls were enrolled in this study. After sleep study between 8:00 AM and 9:00 AM on the morning, venous blood was obtained in the fasting state to measure ghrelin and adipokines. RESULTS: Serum ghrelin levels of OSAS group were significantly (P < 0.05) higher than those of the control group. No significant difference was noted in the levels of leptin, adiponectin, and resistin in OSAS group when compared to controls. There was a significant positive correlation between ghrelin and apnea-hypopnea index (AHI) (r = 0.237, P < 0.05) or the Epworth sleepiness scale (ESS) (r = 0.28, P < 0.05). There was also a significant positive correlation between leptin and body mass index (r = 0.592, P < 0.0001). No significant correlation was observed between leptin, adiponectin, resistin, and any polysomnographic parameters. CONCLUSION: Our findings demonstrated that serum ghrelin levels were higher in OSAS patients than those of control group and correlated with AHI and ESS. Further studies are needed to clarify the complex relation among OSAS, obesity, adipokines, and ghrelin. PMID- 20835312 TI - Pleural effusion following ventriculopleural shunt: Case reports and review of the literature. AB - Ventriculo-pleural shunt (VPLS) is an acceptable alternative in the management of hydrocephalus. Imbalance between the production and absorption of cerebrospinal fluid an lead to formation of pleural effusion in patient with VPLS and on occasion produce symptoms. Pleural effusion could be a transudate or a non specific exudate. We report our experience with this modality in relation to formation of pleural effusion and review the literature to make recommendation for its management. Information related to patients' demographics, smoking history, prior pulmonary and occupational history, indication, duration and complications of the VPLS and their management was gathered to substantiate current recommendation with our experience. PMID- 20835313 TI - Cilazapril-induced pleural effusion: A case report and review of the literature. AB - We describe an unusual case of lymphocytic pleural effusion associated with the use of cilazapril, a novel angiotensin-converting-enzyme inhibitor (ACEI). An 80 year-old male was prescribed cilazapril for hypertension. He subsequently presented with right chest pain and dry cough. He was found to have a lymphocytic pleural effusion on thoracentesis. Extensive workup, including open pleural biopsy, failed to reveal the etiology of the effusion. However, soon after the withdrawal of cilazapril, his clinical symptoms improved and the effusion disappeared. ACEI-induced pleural effusion has only been rarely reported. Drug induced pleural effusion should be considered when formulating the differential diagnosis in a patient receiving ACEI. PMID- 20835314 TI - Dangerous space emphysema after dental treatment. AB - We report the case of an elderly female patient who presented with dangerous space emphysema occurring after a dental procedure. This case presented a diagnostic and management dilemma because of the development of an unusual complication of dental disease. In our review of the medical literature, we were unable to find any cases with similar manifestations and clinical courses. PMID- 20835315 TI - A 60-year-old female with left shoulder pain. PMID- 20835316 TI - Concurrent sternal and pulmonary foci of Langerhans cell histiocytosis. PMID- 20835318 TI - Clinical and laboratory findings and therapeutic responses in children with nephrotic syndrome. AB - Nephrotic syndrome (NS) is a clinical entity characterized by massive loss of urinary protein leading to hypoproteinemia and edema. This prospective cross sectional study was performed on 44 children with idiopathic nephrotic syndrome (INS). The objectives were to study the clinical and biochemical parameters at the time of diagnosis of nephrotic syndrome and to study the histopathological distribution of different subtypes of INS and drug response pattern. There were 29 (66%) males and 15 females (34%). The mean age of NS was 4.87+/-3.24 years. Facial edema was found in 42 (95%), microscopic hematuria in 10 (23%), gross hematuria in 2 (4.5%), and hypertension in 5 (11.2%) of patients. In 17 children who underwent biopsy, focal segmental glomerulosclerosis was the most common pathologic finding (41%). Other subtypes included minimal change in three (18%), membranoproliferative glomerulonephritis in 1(5.8%), diffuse proliferative glomerulonephritis in 2 (11.6%), membranous glomerulonephritis in 1 (5.8%), and diffuse mesangial proliferation in 3 (17.5%) of cases. At the time of hospital admission, peritonitis were present in five (11.4%), pneumonia and upper respiratory infection (sinusitis) in eight (18%), cellulitis in two (4.5%). Among 44 children with NS, 29 (66%) were steroid sensitive cases, nine (20.5%) were steroid resistant and six (13.5%) were steroid dependent. Among patients with steroid sensitive NS, 37% were without relapsers, 38.8% frequent relapsers and 26.4% were infrequent relapsers. These results suggest that there are differences between season of incidence, response to treatment with corticosteroid and pathologic findings in our study and other studies in Iran and other countries. PMID- 20835317 TI - Can we reduce the cardiovascular risk in peritoneal dialysis patients? AB - Patients with end-stage renal disease (ESRD), including those treated with peritoneal dialysis (PD), have a high risk for death, particularly from cardiovascular (CV) causes. Traditional risk factors for CV disease - like hypertension, diabetes, and dyslipidemia - are highly prevalent, often severe, and more difficult to treat in dialysis patients. Development of strategies for CV risk reduction in dialysis patients is complicated by epidemiologic studies that demonstrate paradoxical associations of some of the traditional risk factors with mortality. The difficulty is enhanced by either a paucity or negative findings of studies that have tested risk modification by targeting traditional CV risk factors. It is also clear that neither the prevalence nor the severity of traditional risk factors explains the substantial increase in risk for death associated with ESRD; this has led to identification of several nontraditional risk factors. Among these, systemic inflammation, disordered mineral metabolism, and long-term CV risk from infectious complications appear the most promising. However, the evidence in favor of the importance of these risk factors is largely limited to observational studies. In this review, we present a critical analysis of the literature to assist the clinician to reduce the CV risk of ESRD patients treated with PD. PMID- 20835319 TI - A follow-up study of children with posterior urethral valve. AB - There are not many studies on long term follow up of children following surgery for posterior urethral valve in India. This study was done to assess the growth and renal function of children who had completed five years after surgery for posterior urethral valve at our hospital. Thirty children were included in this study. They were assessed retrospectively for the age and pattern of presentation, time of surgery and outcome. Outcomes measured were stunting, renal failure (GFR, tubular functions) and bladder functions. Fifty per cent of children were symptomatic five years after surgery with enuresis, dribbling, polyuria and recurrent urinary tract infection (UTI). GFR was <60 ml/m/1.73 m(2) in 33%. Growth failure, according to the World Health Organization (WHO) definition, was present in one-third of children. A low GFR was associated with growth failure. Poor bladder function evidenced by history of dribbling and significant residual urine was seen in one-third of patients. Residual hydronephrosis was seen in 74%. The most common presenting symptoms of PUV were poor urinary stream followed by recurrent UTI, poor weight gain, renal failure and abdominal mass. Eighty per cent of the study population had undergone surgery in infancy. Five years after surgery, 50% children were symptomatic; 30% had stunting. 33% had a GFR <60 ml/m/1.73 m(2) and a significantly greater degree of stunting than those with GFR >60 ml/m/1.73 m(2). Sonologically normal kidneys on follow-up were associated with a GFR above 60 ml/m/1.73 m(2). Poor bladder function was present in 30% of the children. Univariate analysis showed that statistically significant risk factors for decline in GFR in this study are oligohydramnios and surgery beyond the neonatal period. PMID- 20835320 TI - Percutaneous ultrasound-guided renal biopsy: A Libyan experience. AB - This study was done to assess the safety and efficacy of ultrasound-guided percutaneous renal biopsy (PRB), to ascertain the risk factors for complications and determine the optimal period of observation. The radiologist (A.M.) at the National Organ Transplant Centre, Central Hospital, Tripoli, Libya, performed 86 PRBs between February 1, 2006, and January 31, 2008, using an automated biopsy gun with 16-gauge needle. Coagulation profile was done in all the patients. All patients were kept on strict bed rest for six hours post-procedure. Eighty six renal biopsies were performed on 78 patients referred from rheumatology department and eight post-kidney transplant recipients; 23 were males with age range 15 - 56 years and 63 females with age range 16 - 66 years. A mean of 17.5 glomeruli were present in each specimen. A glomerular yield of less than five glomeruli was seen in four biopsies. Class I lupus nephritis (LN) was seen in 1 patient, class II lupus nephritis in 7 patients, class III LN in 13 patients and class IV LN in 29 patients. All the eight renal allografts were diagnosed as acute tubular necrosis or acute interstitial rejection. The risk of post-biopsy bleeding was higher in women, older patients and higher PTT. The overall complication rate was 5.8%. Three complications were observed within six hours of biopsy. No late complication was seen. PRB under real-time ultrasound-guidance is a safe and efficacious procedure to establish the histological diagnosis and should be done as out-patient procedure. Observation time of six hours post biopsy is optimal. PMID- 20835321 TI - Effectiveness of aminophylline prophylaxis of renal impairment after coronary angiography in patients with chronic renal insufficiency. AB - This study was done to investigate whether aminophylline reduces the incidence of contrast induced nephropathy (CIN) after coronary angioplasty. Sixty patients who had serum creatinine concentration of > 1.3 mg/dl randomly received 250 mg IV aminophylline or placebo 30 minutes before coronary angiography. Serum creatinine and blood urea nitrogen were determined immediately before (base line) and at 24 and 48 hours after administration of contrast medium. The primary end point was the incidence of CIN. The incidence of CIN was 20% in placebo group and 13.3% in aminophylline group; older age was significantly associated with CIN: In this study, we could not demonstrate the prophylactic effect of a single infusion of 250 mg aminophylline, 30 minutes before administration of contrast media. A larger trial that incorporates the evaluation of clinically relevant outcomes is required to more adequately assess the role for aminophylline in CIN prevention. PMID- 20835322 TI - Percutaneous nephrostomy by direct puncture technique: An observational study. AB - Percutaneous nephrostomy is the procedure of establishing a temporary drainage tract of the renal pelvi-calyceal system through the skin. This study aims to find out whether low cost trocar catheter can be a suitable substitute for the relatively high cost fluoroscopy/ultrasonography guided tract dilatation and tube insertion procedure. Percutaneous nephrostomy by the trocar catheter was performed in 126 patients. Under local anesthesia, a stab wound deep enough to traverse the muscle layer was made through which the trocar - catheter drainage set was inserted under ultrasonography guidance. About 179 procedures were performed in 126 patients. Primary technical success rate was 94%, major complication rate 1.6%, minor complication rate 11% and catheter related complications like catheter blockage or dislodgement were 13%. There was no procedure related mortality in our series. The ultrasonography-guided trocar, catheter nephrostomy, is a quick, safe and low cost procedure in selected cases of upper urinary tract obstruction. The primary technical success and complication rates are comparable to any other reported procedure and its low cost is particularly suitable for developing countries like India. PMID- 20835323 TI - Norwegian scabies in a renal transplant patient. AB - A variety of skin infections are encountered in postrenal transplant setting. Though bacterial and fungal infections are more common, surprises are in store for us sometimes. We describe a patient who underwent renal transplant two years ago, presenting with a painless, mildly pruritic expanding skin rash over abdomen. Histological examination of the skin biopsy showed that stratum corneum had multiple burrows containing larvae and eggs of Sarcoptes scabiei. The patient was treated with ivermectin 12 mg weekly once for 2 doses along with topical 5% permethrin and permethrin soap bath. There was remarkable improvement in the skin lesions with complete resolution in two weeks. Norwegian or crusted scabies is caused by massive infestation with Sarcoptes scabiei var. hominis. It can be rarely encountered in the post-transplant setting, which underscores the importance of early diagnosis and treatment before secondary bacterial infection sets in. PMID- 20835324 TI - Renal replacement lipomatosis: A rare type of renal pseudotumor. AB - Replacement lipomatosis of the kidney is the end result of severe atrophy of renal parenchyma with secondary marked proliferation of renal sinus and perirenal fatty tissue. Although ultrasonography may suggest the diagnosis, CT demonstrated the distinctive features most accurately. We report a case of renal replacement lipomatosis with coexistent xanthogranulomatous pyelonephritis and multiple perinephric and parietal wall collections. PMID- 20835325 TI - Complete remission of lambda light chain myeloma presenting with acute renal failure following treatment with bortezomib and steroids. AB - About one in five people with multiple myeloma produce only light chains. Patients with lambda light chain disease have a three times worse prognosis than kappa light chain disease. We report a case of lambda light chain deposition disease in a 35-year-old female who presented with acute renal failure requiring hemodialysis. She had complete recovery and is now in complete remission following treatment with bortezomib and steroids. PMID- 20835326 TI - Looking beyond the obvious: IgA nephropathy in a liver transplant recipient. AB - Seventeen years after a liver transplant for biliary atresia, an adolescent presented with renal failure. The serum level of cyclosporine was sub therapeutic; and, in spite of dosage adjustments, the patient's status did not improve. Given the patient's age, future renal transplant was a feasible consideration. However, this warranted investigation in the form of a renal biopsy in an attempt to confirm the underlying cause(s) of her renal failure. The renal biopsy revealed marked alteration in the renal anatomy due to IgA deposition, interstitial fibrosis, and hyaline arteriopathy. PMID- 20835327 TI - Marginal donor kidney in a marginal recipient: Five year follow-up. AB - The widening gap between demand and supply of organs became apparent as organ shortage became more severe. Organs previously considered unsuitable for transplantation are currently being used. Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by slow progressive cystic changes and deterioration of renal function. We provide our experience with an ADPKD patient who received a kidney from 38-year-old deceased donor ADPKD affected kidney for renal transplantation. PMID- 20835328 TI - Tubulointerstitial nephritis with uveitis syndrome: A case report and review of literature. AB - Tubulointerstitial nephritis with uveitis (TINU) syndrome is an unusual and under diagnosed cause of acute interstitial nephritis. The interstitial nephritis may precede, follow or develop concurrent to the uveitis. About 200 cases have been reported worldwide with only a single case reported from India. We report a 16 year-old male with TINU syndrome. PMID- 20835329 TI - A young boy with malignant hypertension and intracranial bleed. PMID- 20835330 TI - Bilateral renal lymphangioma - An incidental finding. PMID- 20835331 TI - Unilateral renal cystic disease. PMID- 20835332 TI - ACE polymorphism and diabetic nephropathy. PMID- 20835333 TI - Approach to urinary tract infections. PMID- 20835334 TI - Author's Reply. PMID- 20835335 TI - Angiotensin converting enzyme gene polymorphism in type 2 diabetics with nephropathy. PMID- 20835336 TI - Prevalence of lower urinary tract infection in South Indian type 2 diabetic subjects. PMID- 20835338 TI - The adiponectin/leptin ratio and metabolic syndrome in healthy korean adult males. PMID- 20835337 TI - O-GlcNAc Modification: Friend or Foe in Diabetic Cardiovascular Disease. AB - O-Linked beta-N-acetyl glucosaminylation (O-GlcNAcylation) is a dynamic post translational modification that occurs on serine and threonine residues of cytosolic and nuclear proteins in all cell types, including those involved in the cardiovascular system. O-GlcNAcylation is thought to act in a manner analogous to protein phosphorylation. O-GlcNAcylation rapidly cycles on/off proteins in a time scale similar to that for phosphorylation/dephosphorylation of proteins. Several studies indicate that O-GlcNAc might induce nuclear localization of some transcription factors and may affect their DNA binding activities. However, at the cellular level, it has been shown that O-GlcNAc levels increase in response to stress and augmentation of this response suppresses cell survival. Increased levels of O-GlcNAc have been implicated as a pathogenic contributor to glucose toxicity and insulin resistance, which are major hallmarks of type 2 diabetes and diabetes-related cardiovascular complications. Thus, O-GlcNAc and its metabolic functions are not yet well-understood; focusing on the role of O-GlcNAc in the cardiovascular system is a viable target for biomedical investigation. In this review, we summarize our current understanding of the role of O-GlcNAc on the regulation of cell function and survival in the cardiovascular system. PMID- 20835339 TI - Clinical Characteristics of Type 2 Diabetes Patients according to Family History of Diabetes. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) has a strong genetic component, and its prevalence is notably increased in the family members of T2DM patients. However, there are few studies about the family history of T2DM. We carried out this study to assess the influences of family history on clinical characteristics in T2DM patients. METHODS: This is a cross-sectional study involving 651 T2DM patients. Patient history and physical examination were performed and fasting blood was taken. If any first degree relative was diabetic, a family history of diabetes was considered to exist. RESULTS: Among the total 621 patients, 38.4% had a family history of diabetes. Patients with a family history had a younger age, higher weight, younger age at diagnosis and higher triglyceride level than did those without a family history. Dyslipidemia medication and metabolic syndrome were more prevalent in familial diabetes. Sex, blood pressure, previous treatment for diabetes, HbA1c, C-peptide, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol were not different between familial and non-familial diabetes. Upon multiple linear regression analysis, the family history of diabetes remained significantly associated with serum triglyceride level. CONCLUSION: In T2DM patients with a family history of diabetes, the disease tended to develop earlier. Metabolic syndrome and cardiovascular risk factors are more prevalent in familial T2DM than they were in non-familial T2DM. These results support the necessity of earlier screening for diabetes in family members of T2DM patients and more active prevention against cardiovascular disease in T2DM patients with a family history. PMID- 20835340 TI - Polymorphisms of the reg1alpha gene and early onset type 2 diabetes in the korean population. AB - BACKGROUND: The Reg gene has been reported to be expressed in regenerating islets and Reg1 protein to be up-regulated at an early stage of diabetes in mice. As human Reg1alpha is homologous with murine Reg1, we investigated whether common variants in Reg1alpha are associated with type 2 diabetes in the Korean population. METHODS: We sequenced the Reg1alpha gene to identify common polymorphisms using 24 Korean DNA samples. Of 11 polymorphisms found, five common ones (g.-385T>C [rs10165462], g.-36T>G [rs25689789], g.209G>T [rs2070707], g.1385C>G [novel], and g.2199G>A [novel]) were genotyped in 752 type 2 diabetic patients and 642 non-diabetic subjects. RESULTS: No polymorphism was associated with the risk of type 2 diabetes. However, g.-385C and g.2199A lowered the risk of early-onset type 2 diabetes, defined as a diagnosis in subjects whose age at diagnosis was 25 years or more but less than 40 years (odds ratio [OR], 0.721 [0.535 to 0.971] and 0.731 [0.546 to 0.977] for g.-385C and g.2199A, respectively) and g.1385G increased the risk of early-onset diabetes (OR, 1.398 [1.055 to 1.854]). Although adjusting for errors in multiple hypotheses-testing showed no statistically significant association between the three individual polymorphisms and early-onset diabetes, the haplotype H1, composed of g.-385C, g.1385C, and g.2199A, was associated with a reduced risk of early-onset diabetes (OR, 0.590 [0.396 to 0.877], P = 0.009). CONCLUSION: Polymorphisms in the Reg1alpha were not found to be associated with overall susceptibility to type 2 diabetes, though some showed modest associations with early-onset type 2 diabetes in the Korean population. PMID- 20835341 TI - The relationship of adiponectin/leptin ratio with homeostasis model assessment insulin resistance index and metabolic syndrome in apparently healthy korean male adults. AB - BACKGROUND: We investigated the relationships of adiponectin/leptin (A/L) ratio with cardiovascular risk factors, insulin resistance index, and metabolic syndrome (MS) in apparently healthy Korean male adults. METHODS: Sixty-eight male subjects were enrolled among the participants of an annual health check-up program (mean age, 55.1 years). Percent body fat (%) was measured using a bioelectric impedance analyzer. Serum leptin level was measured via radioimmunoassay, and adiponectin level was measured using an enzyme-linked immunosorbent assay. Homeostasis model assessment (HOMA)-insulin resistance (IR) index was calculated, and the presence of metabolic syndrome was assessed. RESULTS: Adiponectin, leptin, and A/L ratio showed significant correlations with percent body fat, lipid profile, and HOMA-IR. Mean leptin and HOMA-IR levels were significantly higher, while A/L ratio was significantly lower in subjects with MS. With increasing number of MS components, the mean values of leptin and HOMA IR increased and the A/L ratio decreased. In multiple regression analysis, HOMA IR was significantly correlated with triglyceride, fasting glucose, and A/L ratio, while A/L ratio was significantly correlated with body mass index and HOMA IR. HOMA-IR and A/L ratio were significant predictors for each other after adjustment for other factors. CONCLUSION: A/L ratio correlated well with lipid profile, HOMA-IR, and the presence and number of MS components in Korean male subjects. PMID- 20835342 TI - Effects of endurance exercise and high-fat diet on insulin resistance and ceramide contents of skeletal muscle in sprague-dawley rats. AB - BACKGROUND: We evaluated the effects of endurance exercise and a high-fat diet on insulin resistance and ceramide contents of skeletal muscle in Sprague-Dawley rats. METHODS: We randomly divided 32 rats into four groups: control (CON, n = 8), high fat diet (HF, n = 8), exercise (Ex, 24 m/min for 2 hours, 5 days/wk, n = 8), HF/Ex (n = 8). After 4-week treatments, plasma lipid profiles, glucose and insulin concentrations were measured. The triglycerides (TG), ceramide, and glucose transporter 4 (GLUT-4) contents were measured in the skeletal muscle. The rate of glucose transport was determined under submaximal insulin concentration during the muscle incubation. RESULTS: Free fatty acid levels were significantly higher in CON and HF than Ex (P = 0.032). Plasma glucose levels in HF were significantly higher than the two Ex groups (P = 0.002), and insulin levels were significantly higher in HF than in other three groups (P = 0.021). Muscular TG concentrations were significantly higher in HF than CON and Ex and also in HF/Ex than Ex, respectively (P = 0.005). Hepatic TG concentrations were significantly higher in HF than other three groups but Ex was significantly lower than HF/Ex (P = 0.000). Muscular ceramide content in HF was significantly greater than that in either Ex or HF/Ex (P = 0.031). GLUT-4 levels in CON and HF were significantly lower than those in Ex and HF/Ex (P = 0.009, P = 0.003). The glucose transport rate in submaximal insulin concentration was lower in CON than in either Ex or HF/Ex (P = 0.043), but not different from HF. CONCLUSION: This study suggests that high fat diet for 4 weeks selectively impairs insulin resistance, but not glucose transport rate, GLUT-4 and ceramide content in skeletal muscle per se. However, endurance exercise markedly affects the content of ceramide and insulin resistance in muscle. PMID- 20835343 TI - The Relationship between Lung Function and Metabolic Syndrome in Obese and Non Obese Korean Adult Males. AB - BACKGROUND: The existence of an association between lung function and metabolic syndrome (MetS) has been debated in cases involving non-obese subjects. To address this debate, we performed a cross-sectional study to investigate the association between lung function and MetS in both obese and non-obese populations. METHODS: The present study consisted of a total of 1,951 Korean male subjects. In this study group, we investigated relationships between lung function and MetS risk factors such as fasting serum glucose, systolic blood pressure (SBP), insulin resistance index, waist circumference (WC), and hemoglobin A(1C) level. RESULTS: Forced vital capacity (FVC) values were significantly lower in the MetS group compared with those of the non-MetS group. In both non-obese (body mass index [BMI] < 25 kg/m(2)) and obese subjects (BMI >= 25 kg/m(2)), fasting serum glucose, hemoglobin A(1C) level, insulin resistance index, SBP, WC, and the prevalences of diabetes and MetS were significantly higher in subjects in the lowest FVC quartile compared with those in the highest FVC quartile. Odds ratios for the presence of MetS risk factors, after adjusting for age and height, ranged from 1.21 to 1.39 (P < 0.01) for a one standard deviation decrease in FVC. CONCLUSION: The results of our study suggest that decreased vital capacity in Korean adult male subjects is associated with MetS, irrespective of obesity. PMID- 20835344 TI - Letter: effects of rosiglitazone on inflammation in Otsuka long-evans Tokushima Fatty rats (korean diabetes j 2010;34:191-9). PMID- 20835345 TI - Response: effects of rosiglitazone on inflammation in Otsuka long-evans Tokushima Fatty rats (korean diabetes j 2010;34:191-9). PMID- 20835346 TI - Erratum: Author's Name Correction. AB - [This corrects the article on p. 182 in vol. 34, PMID: 20617079.]. PMID- 20835347 TI - Standard Error Computations for Uncertainty Quantification in Inverse Problems: Asymptotic Theory vs. Bootstrapping. AB - We computationally investigate two approaches for uncertainty quantification in inverse problems for nonlinear parameter dependent dynamical systems. We compare the bootstrapping and asymptotic theory approaches for problems involving data with several noise forms and levels. We consider both constant variance absolute error data and relative error which produces non-constant variance data in our parameter estimation formulations. We compare and contrast parameter estimates, standard errors, confidence intervals, and computational times for both bootstrapping and asymptotic theory methods. PMID- 20835348 TI - Mindlessness Revisited: Sequential Request Techniques Foster Compliance by Draining Self-control Resources. AB - The present research extends previous findings suggesting that sequential request techniques, such as the Foot-in-the-Door (FITD) or Door-in-the-Face (DITF) technique, are primarily effective under conditions conducive of mindlessness. We forward that this mindlessness may be the product of the influence technique itself. More specifically, based on the notion of self-control as a limited resource, we hypothesize that actively responding to the initial request-phase of a FITD-compliance gaining procedure drains the target of his/her self-regulatory resources, thus creating the mindlessness so often observed in social influence settings. This resource depletion opens the door for compliance with the target request. The results were in line with these expectations. More specifically, we observed that active responding to an initial request of a FITD technique reduced the availability of self-regulatory resources. This state of resource depletion mediated the effect of the technique on behavioral compliance. In addition, the results of this study ruled out the alternate explanation that the effects were attributable to mood or a general tendency for acquiescence. PMID- 20835349 TI - Carotenoid fluorescence in Dunaliella salina. AB - Dunaliella salina is a halotolerant green alga that is well known for its carotenoid producing capacity. The produced carotenoids are mainly stored in lipid globules. For various research purposes, such as production and extraction kinetics, we would like to determine and/or localise the carotenoid globules in vivo. In this study, we show that the carotenoid-rich globules emit clear green fluorescence, which can be used in, for example, fluorescence microscopy (e.g. CLSM) to obtain pictures of the cells and their carotenoid content. PMID- 20835350 TI - Facilitating factors and barriers to the use of medications in publicly funded addiction treatment organizations. AB - OBJECTIVES: Publicly funded addiction treatment organizations have been slow to adopt pharmacotherapies. Few studies have examined the organizational factors associated with adoption of different types of medication in this treatment sector. This study identifies organization-level facilitators and barriers to the use of medications in publicly funded addiction treatment organizations. METHODS: Face-to-face interviews with a sample of 318 administrators of a representative sample of publicly funded addiction treatment centers in the US. RESULTS: Only 23.4% of programs reported using any of the five FDA-approved pharmacotherapies for treating addiction. An additional 14.3% of programs only used medications approved for the treatment of psychiatric disorders. Multivariate multinomial logistic regression results revealed that the odds of adoption of addiction pharmacotherapies were significantly greater in government-owned programs and in programs with more medical personnel. Programs that relied more heavily on non Medicaid public funding tended to be less likely to adopt addiction treatment medications. Greater contact with pharmaceutical representatives was positively associated with medication adoption. CONCLUSIONS: Current public funding policies and lack of access to medical personnel are barriers to the adoption of medications by publicly funded addiction treatment organizations. Efforts to promote adoption may also benefit from greater detailing activities by pharmaceutical representatives. These findings suggest that the large research investment devoted to developing addiction treatment medications may have limited public health impact due to the characteristics of publicly funded service delivery system as well as the limited attention given to this system by commercial purveyors of medications. PMID- 20835351 TI - Strategies to enhance umbilical cord blood stem cell engraftment in adult patients. AB - Umbilical cord blood (UCB) has been used successfully as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation in children and adults in the treatment of hematologic diseases. However, compared with marrow or mobilized peripheral blood stem cell grafts from adult donors, significant delays in the rates and kinetics of neutrophil and platelet engraftment are noted after UCB transplant. These differences relate in part to the reduced numbers of HSCs in UCB grafts. To improve the rates and kinetics of engraftment of UCB HSC, several strategies have been proposed, including ex vivo expansion of UCB HSCs, addition of third-party mesenchymal cells, intrabone delivery of HSCs, modulation of CD26 expression, and infusion of two UCB grafts. This article will focus on ex vivo expansion of UCB HSCs and strategies to enhance UCB homing as potential solutions to overcome the problem of low stem cell numbers in a UCB graft. PMID- 20835352 TI - Intrasexual Competition and Eating Restriction in Heterosexual and Homosexual Individuals. AB - Restrictive eating attitudes and behaviors have been hypothesized to be related to processes of intrasexual competition. According to this perspective, within sex competition for status serves the adaptive purpose of attracting mates. As such, status competition salience may lead to concerns of mating desirability. For heterosexual women and gay men, such concerns revolve around appearing youthful and thus, thinner. Following this logic, we examined how exposure to high-status and competitive (but not thin or highly attractive) same-sex individuals would influence body image and eating attitudes in heterosexual and in gay/lesbian individuals. Results indicated that for heterosexuals, intrasexual competition cues led to greater body image dissatisfaction and more restrictive eating attitudes for women, but not for men. In contrast, for homosexual individuals, intrasexual competition cues led to worse body image and eating attitudes for gay men, but not for lesbian women. These findings support the idea that the ultimate explanation for eating disorders is related to intrasexual competition. PMID- 20835354 TI - Fluorescent detection of phosphate anion by a highly selective chemosensor in water. AB - A macrocyclic dinuclear copper complex, [Cu(2) (II)(1)Br(4)].2H(2)O has been synthesized and characterized by X-ray crystallography, in which each metal ion is pentacoordinated in a square pyramidal environment and the macrocycle is folded to form a boat-shaped empty cavity. As studied by an indicator displacement assay, the dinuclear complex shows strong selectivity for phosphate over sulfate, nitrate, perchlorate and halides in water at physiological pH. PMID- 20835353 TI - Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery. AB - IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease biology, but emphasizes the importance of the rigor of the disease model. PMID- 20835355 TI - Depression, anxiety and alcohol abuse in a gastroenterology intensive care unit: prevalence and detection. AB - OBJECTIVES: To assess depression, anxiety, and alcohol abuse in a Gastroenterology ICU, and the level of its detection by the staff. METHOD: All patients consecutively admitted to the ICU during a six-month period, 18 or above, and staying >= 24 hours, were assessed with the Hospital Anxiety and Depression Scale (HADS) and the CAGE. Doctors and nurses assessed the type and severity of patients' morbidity. Data were analyzed with Student's t-test, Pearson's and Spearman's correlations for ordinal variables, chi-square for nominal variables, and multiple logistic regression. RESULTS: The 65 patients assessed had a mean age of 57, and were predominantly male (58.5%), married (72.3%), and retired (53.8%); 27.7% had a psychiatric history, 24.6% were on psychotropic drugs, and 32.3% had an alcohol intake above standards. Anxiety and depression HADS scores >= 8 were present in 29.2% and 35.4% of the patients, respectively; 20%, mainly men, scored positive on the CAGE. Women had significantly higher anxiety scores (=.012) than men but did not differ in depression. A psychiatric history was significantly associated with higher anxiety (p<.001) and depression (p=.007) scores, as well as being on psychotropic drugs regularly (p<.001; p=.03, respectively). Doctors diagnosed somatic illness in 48.8%, and somatic illness with psychiatric co-morbidity in 51%; for nurses the rates were, respectively, 41.5% and 58.6%. Doctors' and nurses' detection of psychiatric disorders were significantly associated with the HADS anxiety scores (p=.013; p=.001, respectively), and doctor's detection with depression (p=.046) scores. There were no significant associations between nurses' detection of psychiatric disorders and depression, and between both professional groups detection and alcohol abuse. CONCLUSION: High prevalence of depression, anxiety, and alcohol abuse in Gastroenterology ICU was confirmed. However, the level of detection by the staff was low and mainly when anxiety symptoms were present. PMID- 20835357 TI - Romantic attachment and subtypes/dimensions of jealousy. AB - The present study explored the possible relationship between romantic attachment and jealousy in 100 healthy subjects. The romantic attachment and jealousy were evaluated by means of, respectively, the "Experiences in Close Relationships" questionnaire (ECR), and the "Questionario della Gelosia" (QUEGE). The ECR anxiety scale was related to all QUEGE dimensions, while the ECR avoidance scale to three. Individuals with the preoccupied attachment style showed higher scores than secure subjects on the obsessionality, interpersonal sensitivity and fear of loss dimensions. Fearful-avoidant individuals had higher score than secure subjects on the fear of loss dimension only, while dismissing individuals had lower scores on the self-esteem dimension.These findings suggest that romantic attachment and jealousy are intertwined. PMID- 20835356 TI - Eating behaviour and body satisfaction in mediterranean children: the role of the parents. AB - Although the prevalence of fully expressed Eating Disorders is rare in young children, childhood eating disturbances are fairly common. Parents can play a facilitating role for the development of overweight and eating problems among their children. The aim of this study is to detect the possible relationships between children's eating attitudes and behaviour and the parents' beliefs about eating habits and body shape of their offspring.This survey was conducted in the area of Arezzo (Italy), on 900 children, aged 7-12, and on their parents/substitute caregivers. The Kids' Eating Disorder Survey questionnaire, and the CIBUS questionnaire were administered. A fully expressed Eating Disorder was diagnosed in two kids only. KEDS total score and weight/dissatisfaction subscale score positively correlated with parents' answers to the following CIBUS' items (How do you consider the body shape of your son/daughter? How much does your son/daughter eats? Have you ever thought of putting your son/daughter on a diet?). Positive correlations between the children BMI, desired BMI and the aforementioned CIBUS' items were found.The prevalence of formal Eating Disorders in children aged 7-12 is low. Children appear to be more preoccupied with their weight than with their body shape. Parents' beliefs about the offspring's body shape and eating habits have a relevant impact on children's eating attitudes and behaviour. PMID- 20835358 TI - How Much is Geriatric Caregivers Burnout Caring-Specific? Questions from a Questionnaire Survey. AB - SUMMARY: BACKGROUND AND AIMS: Research dealing with occupational strain and burnout in geriatric care is generally focused on the behavioral problems of the patient and/or the psychological traits or attitudes of the carers rather than on organizational functionality. This paper describes data from a survey of all geriatric professions, using the Stressful Events Questionnaire (SEQ), a tool that takes into account multiple dimensions that can affect the genesis of burnout, including the patient, the geriatric health care professional, and the health care organization. The aim of this study is to compare patterns of answers among different roles in geriatric care. METHOD: PATTERNS OF SEQ ANSWERS ARE DESCRIBED FOR THE ENTIRE SAMPLE AS WELL AS FOR WORKERS EXPERIENCING BURNOUT AND FOR EACH CARING PROFESSION INVESTIGATED: certified nursing assistants (CNAs), registered nurses and physicians/psychologists. RESULTS;: In general, carers refer more often as stressful the facility-related events; the only exception is that CNAs working in general hospital geriatric wards refer most often as stressful the patient-related events. The self-related events area seems to have a great importance for all professions. DISCUSSION: The specificity of gerontological burnout has to be discussed, to better define the role played by caring problems, including psychological attitudes of carers versus the role played by the institution and by the social situation of each worker. For CNAs, the interaction between educational background and the length of time spent as a CNA seems to be a critical topic. PMID- 20835359 TI - CXCR4 Tropic HIV-1 gp120 Inhibition of SDF-1alpha-Induced Chemotaxis Requires Lck and is Associated with Cofilin Phosphorylation. AB - OBJECTIVE: HIV gp120 is a pleiotropic protein present in the plasma and tissues of HIV-infected patients, which affects a variety of homeostatic functions. In this report, we examine the mechanism of how gp120 blocks CD4 T cells from migrating towards SDF-1alpha. METHODS: In vitro treatment of primary CD4 T cells with CXCR4 tropic gp120, SDF, and measurement of chemotaxis and cell signaling. RESULTS: gp120 signaling through CD4 receptor and Lck are required for its ability to inhibit chemotaxis induced by SDF, as demonstrated by CD4 receptor decoys, Lck inhibitors, as well as cells deficient in Lck, in which Lck expression is restored. Blocking Lck abrogates the ability of CXCR4 tropic gp120 to antagonize SDF-1alpha-induced chemotaxis. This inhibition is associated with cofilin phosphorylation, thereby providing a potential mechanism. CONCLUSION: We conclude that the ability of gp120 to inhibit SDF-1alpha-induced chemotaxis is mediated by the CD4 receptor and Lck signaling, potentially by promoting cofilin phosphorylation. PMID- 20835360 TI - RNA Genes: Retroelements and Virally Retroposable microRNAs in Human Embryonic Stem Cells. AB - Embryonic stem cells (ESCs) are capable of undergoing self-renewal, and their developmental ability is known as the stemness. Recently, microRNAs (miRNAs) as regulators have been isolated from ESCs. Although Dicer and DiGeorge syndrome critical region gene 8 (DGCR8) are essential factors for the biogeneration of miRNA, Dicer-knockout (KO) ESCs have showed to fail to express differentiation markers and DGCR8-KO ESCs have showed to be arrest in the G1 phase. Furthermore, Dicer-KO ESCs lost the ability to epigenetically silence retroelemtns (REs). REs are expressed and transposed in ESCs, whose transcripts control expression of miRNAs, and their transposable retroelement (TE) expression is, therefore related to ESC proliferation and differentiation, suggesting that the interplay between miRNAs and REs may have a deep responsibility for the stemness including a short G1/S transition and for RE regulation in ESCs. PMID- 20835361 TI - Spirometry Longitudinal Data Analysis Software (SPIROLA) for Analysis of Spirometry Data in Workplace Prevention or COPD Treatment. AB - Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Periodic spirometry is often recommended for individuals with potential occupational exposure to respiratory hazards and in medical treatment of respiratory disease, to prevent COPD or improve treatment outcome. To achieve the full potential of spirometry monitoring in preserving lung function, it is important to maintain acceptable precision of the longitudinal measurements, apply interpretive strategies that identify individuals with abnormal test results or excessive loss of lung function in a timely manner, and use the results for intervention on respiratory disease prevention or treatment modification. We describe novel, easy-to-use visual and analytical software, Spirometry Longitudinal Data Analysis software (SPIROLA), designed to assist healthcare providers in the above aspects of spirometry monitoring. Software application in ongoing workplace spirometry-based medical monitoring programs helped to identify increased spirometry data variability due to deteriorating test quality and subsequent improvement following interventions, and helped to enhance identification of individuals with excessive decline in lung function. PMID- 20835363 TI - Improved Syntheses of Precursors for PET Radioligands [F]XTRA and [F]AZAN. AB - Improved syntheses of 7-methyl-2-exo-[3'-(2-bromopyridin-3-yl)-5'-pyridinyl]-7 azabicyclo[2.2.1]heptanes (3) and 7-methyl-2-exo-[3'-(6-bromopyridin-2-yl)-5' pyridinyl]-7-azabicyclo[2.2.1]heptanes (4), precursors for PET radioligands [(18)F]XTRA (1) and [(18)F]AZAN (2), involving a key Stille coupling step followed by deprotection of Boc group and N-methylation are described. The new synthetic procedures provided the title compounds in more than 40% overall yields. PMID- 20835364 TI - Understanding Dermatan Sulfate-Heparin Cofactor II Interaction through Virtual Library Screening. AB - Dermatan sulfate, an important member of the glycosaminoglycan family, interacts with heparin cofactor II, a member of the serpin family of proteins, to modulate antithrombotic response. Yet, the nature of this interaction remains poorly understood at a molecular level. We report the genetic algorithm-based combinatorial virtual library screening study of a natural, high-affinity dermatan sulfate hexasaccharide with heparin cofactor II. Of the 192 topologies possible for the hexasaccharide, only 16 satisfied the "high-specificity" criteria used in computational study. Of these, 13 topologies were predicted to bind in the heparin-binding site of heparin cofactor II at a ~60 degrees angle to helix D, a novel binding mode. This new binding geometry satisfies all known solution and mutagenesis data and supports thrombin ternary complexation through a template mechanism. The study is expected to facilitate the design of allosteric agonists of heparin cofactor II as antithrombotic agents. PMID- 20835365 TI - How far and how fast can mushroom spores fly? Physical limits on ballistospore size and discharge distance in the Basidiomycota. AB - Active discharge of basidiospores in most species of Basidiomycota is powered by the rapid movement of a droplet of fluid, called Buller's drop, over the spore surface. This paper is concerned with the operation of the launch mechanism in species with the largest and smallest ballistospores. Aleurodiscus gigasporus (Russulales) produces the largest basidiospores on record. The maximum dimensions of the spores, 34 * 28 um, correspond to a volume of 14 pL and to an estimated mass of 17 ng. The smallest recorded basidiospores are produced by Hyphodontia latitans (Hymenochaetales). Minimum spore dimensions in this species, 3.5 * 0.5 um, correspond to a volume of 0.5 fL and mass of 0.6 pg. Neither species has been studied using high-speed video microscopy, but this technique was used to examine ballistospore discharge in species with spores of similar sizes (slightly smaller than A. gigasporus and slightly larger than those of H. latitans). Extrapolation of velocity measurements from these fungi provided estimates of discharge distances ranging from a maximum of almost 2 mm in A. gigasporus to a minimum of 4 um in H. latitans. These are, respectively, the longest and shortest predicted discharge distances for ballistospores. Limitations to the distances traveled by basidiospores are discussed in relation to the mechanics of the discharge process and the types of fruit-bodies from which the spores are released. PMID- 20835366 TI - The Fast Multipole Method and Fourier Convolution for the Solution of Acoustic Scattering on Regular Volumetric Grids. AB - The fast multipole method (FMM) is applied to the solution of large-scale, three dimensional acoustic scattering problems involving inhomogeneous objects defined on a regular grid. The grid arrangement is especially well suited to applications in which the scattering geometry is not known a priori and is reconstructed on a regular grid using iterative inverse scattering algorithms or other imaging techniques. The regular structure of unknown scattering elements facilitates a dramatic reduction in the amount of storage and computation required for the FMM, both of which scale linearly with the number of scattering elements. In particular, the use of fast Fourier transforms to compute Green's function convolutions required for neighboring interactions lowers the often-significant cost of finest-level FMM computations and helps mitigate the dependence of FMM cost on finest-level box size. Numerical results demonstrate the efficiency of the composite method as the number of scattering elements in each finest-level box is increased. PMID- 20835367 TI - The Benefits and Risks of Adolescent Employment. AB - Much controversy surrounds the consequences of adolescent paid work, with researchers coming to diverse conclusions about whether work is good, work is bad, work doesn't matter (the purported effects of employment are spurious, dependent on processes of selection), and work matters for some youth but not others, depending on their prior backgrounds and attributes and the contexts of their employment. This article summarizes findings from the Youth Development Study, a long-term, ongoing longitudinal study that has followed a community based panel from middle adolescence through early adulthood. The findings address this debate and support the final perspective-that the effects of teen employment on the successful transition to adulthood depend on its patterning through the years of high school (most invested, steady, sporadic, and occasional employment patterns) and its quality. Moreover, the YDS shows that patterns of teenage employment are linked to the social origins and motivations of youth upon entry to high school, and suggest that teenagers exercise agency as they build human capital during high school through education and work experience. The article concludes with a discussion of what parents, counselors, and others can do to help children make sound employment-related decisions during adolescence so as to assure effective career exploration and a successful school-to-work transition. PMID- 20835368 TI - 'THEY LIGHT THE CHRISTMAS TREE IN OUR TOWN': Reflections on Identity, Gender, and Adolescent Sports. AB - Sport occupies a prominent space in the public lives and private identities of US adolescents. Using the retrospective reflections of college students, this analysis explores two questions about sport-related identities during high school: Are 'athletes' and 'jocks' distinctly separate identities? Are these identities explicitly gendered? In four gender-segregated focus groups conducted in early 2005, 32 student-athletes from two upstate New York colleges discussed their high school experiences of sport, status, gender, and identity. Three primary themes developed with regard to differences between the 'jock' and 'athlete' archetypes: academic focus, teamwork, and cockiness/aggression. Examining the intersection of gender, high-status/high-profile sport, and identity in both popular cultural imagery and the personal experiences of the focus group discussants provided support for the thesis of a 'toxic jock' phenomenon. PMID- 20835369 TI - Diels-Alder routes to angularly halogenated cis-fused bicyclic ketones: Readily accessible cyclynone intermediates. AB - We have developed an efficient Lewis acid-catalyzed Diels-Alder route to a series of cis-fused bicyclic ketones bearing quaternary halogenation at the angular position. We have also developed a Diels-Alder based one-flask method for the regioselective preparation of TBS-protected 6-hydroxy tetralone and 5-hydroxy indanone derivatives. PMID- 20835370 TI - Defining a Clade by Morphological, Molecular and Toxinological Criteria: Distinctive Forms related to Conus praecellens A. Adams, 1854. AB - We carried out a definition of the species group to which Conus praecellens A. Adams 1854 belongs using a combination of comparative morphological data, molecular phylogeny based on standard genetic markers and toxinological markers. Prior to this work, Conus praecellens was generally postulated to belong to a clade of similarly high-spired, smaller Conusspecies such as Conus pagodus Kiener, 1845, Conus memiae (Habe & Kosuge, 1970) and Conus arcuatus Broderip & Sowerby, 1829. The molecular phylogeny and toxinological data demonstrate that these prior hypotheses are incorrect, and that instead, Conus praecellens is in a branch of Conus that includes Conus stupa (Kuroda, 1956), Conus stupella (Kuroda, 1956), Conus acutangulus Lamark, 1810 and surprisingly, some species that are morphologically strikingly different, Conus mitratus Sowerby, 1870 and Conus cylindraceus Broderip & Sowerby, 1830. A more careful analysis of the morphologically diverse forms assigned to Conus praecellens suggests that from the Philippine material alone, there are at least three additional undescribed species, Conus andremenezi, Conus miniexcelsus and Conus rizali. A reevaluation of protoconch/early teleoconch morphology also strongly suggests that Conus excelsus Sowerby III, 1908 is related to these species. Together, the different data suggest a clade including the 10 species above that we designate, the Turriconus (Shikama and Habe, 1968) (clade; there are additional distinctive forms within the clade that may be separable at the species level. The phylogenetic definition using the multidisciplinary approach described herein provides a framework for comprehensively investigating biodiverse lineages of animals, such as the cone snails. PMID- 20835362 TI - HSV Recombinant Vectors for Gene Therapy. AB - The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID- 20835371 TI - Differential effects of allosteric M(1) muscarinic acetylcholine receptor agonists on receptor activation, arrestin 3 recruitment, and receptor downregulation. AB - Muscarinic acetylcholine receptors (mAChRs) are drug targets for multiple neurodegenerative and neuropsychiatric disorders, but the full therapeutic potential of mAChR-targeted drugs has not been realized, mainly because of a lack of subtype-selective agonists. Recent advances have allowed the development of highly selective agonists that bind to an allosteric site on the M(1) mAChR that is spatially distinct from the orthosteric acetylcholine binding site, but less is known about the profile of intracellular signals activated by orthosteric versus allosteric M(1) mAChR agonists. We investigated the activation and regulatory mechanisms of two structurally distinct allosteric M(1) mAChR agonists, AC260584 and TBPB. We show that allosteric agonists potently activate multiple signal transduction pathways linked to the M(1) mAChR receptor but, compared to orthosteric agonists, much less efficiently recruit arrestin 3, a protein involved in regulation of G-protein coupled receptor signaling. Consistent with decreased arrestin recruitment, both allosteric agonists showed blunted responses in measurements of receptor desensitization, internalization, and downregulation. These results advance the understanding of mAChR biology and may shed light on unanticipated differences in the pharmacology of orthosteric vs. allosteric agonists that might be capitalized upon for drug development for the treatment of CNS diseases. PMID- 20835373 TI - Myocardial wall thickening from gated Magnetic Resonance images using Laplace's equation. AB - The aim of our work is to present a robust 3D automated method for measuring regional myocardial thickening using cardiac magnetic resonance imaging (MRI) based on Laplace's equation. Multiple slices of the myocardium in short-axis orientation at end-diastolic and end-systolic phases were considered for this analysis. Automatically assigned 3D epicardial and endocardial boundaries were fitted to short-axis and long axis slices corrected for breathold related misregistration, and final boundaries were edited by a cardiologist if required. Myocardial thickness was quantified at the two cardiac phases by computing the distances between the myocardial boundaries over the entire volume using Laplace's equation. The distance between the surfaces was found by computing normalized gradients that form a vector field. The vector fields represent tangent vectors along field lines connecting both boundaries. 3D thickening measurements were transformed into polar map representation and 17-segment model (American Heart Association) regional thickening values were derived. The thickening results were then compared with standard 17-segment 6-point visual scoring of wall motion/wall thickening (0=normal; 5=greatest abnormality) performed by a consensus of two experienced imaging cardiologists. Preliminary results on eight subjects indicated a strong negative correlation (r=-0.8, p<0.0001) between the average thickening obtained using Laplace and the summed segmental visual scores. Additionally, quantitative ejection fraction measurements also correlated well with average thickening scores (r=0.72, p<0.0001). For segmental analysis, we obtained an overall correlation of -0.55 (p<0.0001) with higher agreement along the mid and apical regions (r=-0.6). In conclusion 3D Laplace transform can be used to quantify myocardial thickening in 3D. PMID- 20835372 TI - Computer-aided diagnostic models in breast cancer screening. AB - Mammography is the most common modality for breast cancer detection and diagnosis and is often complemented by ultrasound and MRI. However, similarities between early signs of breast cancer and normal structures in these images make detection and diagnosis of breast cancer a difficult task. To aid physicians in detection and diagnosis, computer-aided detection and computer-aided diagnostic (CADx) models have been proposed. A large number of studies have been published for both computer-aided detection and CADx models in the last 20 years. The purpose of this article is to provide a comprehensive survey of the CADx models that have been proposed to aid in mammography, ultrasound and MRI interpretation. We summarize the noteworthy studies according to the screening modality they consider and describe the type of computer model, input data size, feature selection method, input feature type, reference standard and performance measures for each study. We also list the limitations of the existing CADx models and provide several possible future research directions. PMID- 20835375 TI - Generalized weighted likelihood density estimators with application to finite mixture of exponential family distributions. AB - The family of weighted likelihood estimators largely overlaps with minimum divergence estimators. They are robust to data contaminations compared to MLE. We define the class of generalized weighted likelihood estimators (GWLE), provide its influence function and discuss the efficiency requirements. We introduce a new truncated cubic-inverse weight, which is both first and second order efficient and more robust than previously reported weights. We also discuss new ways of selecting the smoothing bandwidth and weighted starting values for the iterative algorithm. The advantage of the truncated cubic-inverse weight is illustrated in a simulation study of three-components normal mixtures model with large overlaps and heavy contaminations. A real data example is also provided. PMID- 20835374 TI - The Associative Structure of Language: Contextual Diversity in Early Word Learning. AB - Previous studies demonstrated that statistical properties of adult generated free associates predict the order of early noun learning. We investigate an explanation for this phenomenon that we call the associative structure of language: early word learning may be driven in part by contextual diversity in the learning environment, with contextual diversity in caregiver speech correlating with the cue-target structure in adult free association norms. To test this, we examined the co-occurrence of words in caregiver speech from the CHILDES database and found that a word's contextual diversity-the number of unique word types a word co-occurs with in caregiver speech-predicted the order of early word learning and was highly correlated with the number of unique associative cues for a given target word in adult free association norms. The associative structure of language was further supported by an analysis of the longitudinal development of early semantic networks (from 16 to 30 months) using contextual co-occurrence. This analysis supported two growth processes: The lure of the associates, in which the earliest learned words have more connections with known words, and preferential acquisition, in which the earliest learned words are the most contextually diverse in the learning environment. We further discuss the impact of word class (nouns, verbs, etc.) on these results. PMID- 20835376 TI - The Suicide Prevention Continuum. AB - The suicide prevention continuum illustrates a practical approach to the complex issue of suicide prevention. The continuum evolved from discussions with two Aboriginal communities in Atlantic Canada about suicide and the different types of interventions available. The continuum offers a framework and reference tool to differentiate between the different stages of suicide risk. It illustrates where the Aboriginal Community Youth Resilience Network (ACYRN) fits into suicide prevention and how it contributes to prevention knowledge, capacity building, and policy development. PMID- 20835377 TI - Father, Son, Wife, Husband: Philanthropy as Exchange and Balance. AB - This essay attempts to use exchange and balance theories to explain philanthropy. For exchange, such theoretical components as attractions or rewards, costs, barriers and alternatives are invoked to make sense of the biography of a Chinese philanthropist in Hong Kong who donated two schools to remember his father and wife. The balance theory was also used, which argues that people do not seek to maximize their pleasure or to minimize their pain, but to balance, advancing one purpose or concern without neglecting the other-to enhance their well-being and to act morally. The essay argues that the case study method is most able to handle complex behaviour and complex lives. It concludes with a plea for more active use of social theory in research on philanthropy as moral and economic behavior embedded in the social contexts of family, marriage and community. PMID- 20835378 TI - Self-perceived Age and Attitudes Toward Marketing of Older Consumers in China. AB - Understanding consumer psychological characteristics and their impact on consumer behavior is an important foundation for business marketing strategies. Self perceived age has a great impact on older consumers' behavior. This article defines the gray market in China, investigates the factors that affect the differences between older consumers' self-perceived age and life age, and analyzes the influence of self-perceived age on older Chinese consumers' behavior. In this study, 1,120 older consumers were randomly selected from six cities in China. Findings show that over half of the respondents feel younger than their actual life age. Related marketing strategies are discussed. PMID- 20835379 TI - Education Financing of Rural Households in China. AB - The purpose of this paper was to examine children's education financing alternatives among households in rural China. Data on education financing was from a household survey conducted in three poverty villages in Guizhou, China. The difference in financing education by households was verified through non parametric testing. Findings show that private savings is dominant in financing education of children in school. Formal loans are almost absent even in the highest wealth group examined. The findings implied that the extension of financial services to children's education could motivate parents to send their children for more education, increase disposable income of rural households by reducing precautionary savings, and provide better-educated labors in rural China. PMID- 20835380 TI - The Importance of PRI Therapy for the Pastoral Counsellor. AB - It is not always easy for pastoral counsellors to help people change. Often people have become stuck in their ways. Recent developments in the field of brain research help explain why change is difficult. This article discusses Past Reality Integration Therapy (PRI), a psychotherapeutic method that integrates recent findings of brain research and offers an important addition to the work of (pastoral) counsellors and psychotherapists. The use of this approach with Dutch students in their pastoral training is presented. Furthermore the importance of this new method for counsellors themselves, their clients and their work is discussed and some overall conclusions about the method and its practical application are presented. PMID- 20835381 TI - Semi-Empirical Topological Method for Prediction of the Relative Retention Time of Polychlorinated Biphenyl Congeners on 18 Different HR GC Columns. AB - High resolution gas chromatographic relative retention time (HRGC-RRT) models were developed to predict relative retention times of the 209 individual polychlorinated biphenyls (PCBs) congeners. To estimate and predict the HRGC-RRT values of all PCBs on 18 different stationary phases, a multiple linear regression equation of the form RRT = a(o) + a(1) (no. o-Cl) + a(2) (no. m-Cl) + a(3) (no. p-Cl) + a(4) (V(M) or S(M)) was used. Molecular descriptors in the models included the number of ortho-, meta-, and para-chlorine substituents (no. o-Cl, m-Cl and p-Cl, respectively), the semi-empirically calculated molecular volume (V(M)), and the molecular surface area (S(M)). By means of the final variable selection method, four optimal semi-empirical descriptors were selected to develop a QSRR model for the prediction of RRT in PCBs with a correlation coefficient between 0.9272 and 0.9928 and a leave-one-out cross-validation correlation coefficient between 0.9230 and 0.9924 on each stationary phase. The root mean squares errors over different 18 stationary phases are within the range of 0.0108-0.0335. The accuracy of all the developed models were investigated using cross-validation leave-one-out (LOO), Y-randomization, external validation through an odd-even number and division of the entire data set into training and test sets. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1365/s10337-010-1696-5) contains supplementary material, which is available to authorized users. PMID- 20835382 TI - Angioscopic Evaluation of Neointimal Coverage of Coronary Stents. AB - Drug-eluting stents (DES) reduce coronary restenosis significantly; however, late stent thrombosis (LST) occurs, which requires long-term antiplatelet therapy. Angioscopic grading of neointimal coverage of coronary stent struts was established, and it was revealed that neointimal formation is incomplete and prevalence of LST is higher in DES when compared to bare-metal stents. It was also observed that the neointima is thicker and LST is less frequent in paclitaxel-eluting and zotarolimus-eluting stents than in sirolimus-eluting stents. Many new stents were devised and they are now under experimental or clinical investigations to overcome the shortcomings of the stents that have been employed clinically. Endothelial cells are highly anti-thrombotic. Neo endothelial cell damage is considered to be caused by friction between the cells and stent struts due to the thin neointima between them which might act as a cushion. Therefore, development of a DES that causes an appropriate thickness (around 100 MUm) of the neointima is a potential option with which to prevent neo endothelial cell damage and consequent LST while preventing restenosis. PMID- 20835383 TI - Demographic, Psychological, and Social Characteristics of Self-Identified Lesbian, Gay, and Bisexual Adults in a US Probability Sample. AB - Using data from a US national probability sample of self-identified lesbian, gay, and bisexual adults (N = 662), this article reports population parameter estimates for a variety of demographic, psychological, and social variables. Special emphasis is given to information with relevance to public policy and law. Compared with the US adult population, respondents were younger, more highly educated, and less likely to be non-Hispanic White, but differences were observed between gender and sexual orientation groups on all of these variables. Overall, respondents tended to be politically liberal, not highly religious, and supportive of marriage equality for same-sex couples. Women were more likely than men to be in a committed relationship. Virtually all coupled gay men and lesbians had a same-sex partner, whereas the vast majority of coupled bisexuals were in a heterosexual relationship. Compared with bisexuals, gay men and lesbians reported stronger commitment to a sexual-minority identity, greater community identification and involvement, and more extensive disclosure of their sexual orientation to others. Most respondents reported experiencing little or no choice about their sexual orientation. The importance of distinguishing among lesbians, gay men, bisexual women, and bisexual men in behavioral and social research is discussed. PMID- 20835384 TI - Are the affluent prepared to pay for the planet? Explaining willingness to pay for public and quasi-private environmental goods in Switzerland. AB - A large number of 'environmental justice' studies show that wealthier people are less affected by environmental burdens and also consume more resources than poorer people. Given this double inequity, we ask, to what extent are affluent people prepared to pay to protect the environment? The analyses are couched within the compensation/affluence hypothesis, which states that wealthier persons are able to spend more for environmental protection than their poorer counterparts. Further, we take into account various competing economic, psychological and sociological determinants of individuals' willingness to pay (WTP) for both public environmental goods (e.g., general environmental protection) and quasi-private environmental goods (e.g., CO(2)-neutral cars). Such a comprehensive approach contrasts with most other studies in this field that focus on a limited number of determinants and goods. Multivariate analyses are based on a general population survey in Switzerland (N = 3,369). Although income has a positive and significant effect on WTP supporting the compensation hypothesis, determinants such as generalized interpersonal trust that is assumed to be positively associated with civic engagement and environmental concern prove to be equally important. Moreover, we demonstrate for the first time that time preferences can considerably influence survey-based WTP for environmental goods; since investments in the environment typically pay off in the distant future, persons with a high subjective discount rate are less likely to commit. PMID- 20835385 TI - Metabolic constituents of grapevine and grape-derived products. AB - The numerous uses of the grapevine fruit, especially for wine and beverages, have made it one of the most important plants worldwide. The phytochemistry of grapevine is rich in a wide range of compounds. Many of them are renowned for their numerous medicinal uses. The production of grapevine metabolites is highly conditioned by many factors like environment or pathogen attack. Some grapevine phytoalexins have gained a great deal of attention due to their antimicrobial activities, being also involved in the induction of resistance in grapevine against those pathogens. Meanwhile grapevine biotechnology is still evolving, thanks to the technological advance of modern science, and biotechnologists are making huge efforts to produce grapevine cultivars of desired characteristics. In this paper, important metabolites from grapevine and grape derived products like wine will be reviewed with their health promoting effects and their role against certain stress factors in grapevine physiology. PMID- 20835387 TI - Parenting in an Individualistic Culture with a Collectivistic Cultural Background: The Case of Turkish Immigrant Families with Toddlers in the Netherlands. AB - Expanding our knowledge on parenting practices of immigrant families is crucial for designing culturally sensitive parenting intervention programs in countries with high immigration rates. We investigated differences in patterns of parenting between second-generation immigrant and native families with young children. Authoritarian and authoritative control and sensitivity of second-generation Turkish immigrant mothers of 2-year-old children (n = 70) and native Dutch mothers (n = 70) were observed in the home and in the laboratory. Controlling for maternal age and education, Turkish immigrant mothers were less supportive, gave less clear instructions to their children, were more intrusive and were less authoritative in their control strategies than native Dutch mothers. No differences were found in authoritarian control. In both ethnic groups supportive presence, clarity of instruction, authoritative control, and low intrusiveness loaded on one factor. No differences between ethnic groups were found in gender differentiated parenting. Maternal emotional connectedness to the Turkish culture was associated with less authoritative control, whereas more use of the Turkish language was related to more sensitivity. Even though mean level differences in parenting behaviors still exist between second-generation Turkish immigrant and native Dutch mothers, the patterns of associations between parenting behaviors were comparable for both groups. This suggests that existing parenting interventions for native families may be applicable to second-generation Turkish immigrants as well. PMID- 20835388 TI - Scholarship on Gender and Sport in Sex Roles and Beyond. AB - In this paper we critically review how research on girls or women and sport has developed over the last 35 years. We use a post-positivist lens to explore the content of the papers published in Sex Roles in the area of women, gender and sport and examine the shifts in how gender and sport have been conceptualized in these accounts. In order to initiate a broader dialogue about the scholarly analysis of gender and sport, we subsequently explore ideas inspired by feminist theorizing that have dominated/guided related research in other outlets over this time period but have received relatively little attention in papers published in Sex Roles. We conclude by briefly making suggestions for further research in this area. PMID- 20835386 TI - Saponins as cytotoxic agents: a review. AB - Saponins are natural glycosides which possess a wide range of pharmacological properties including cytotoxic activity. In this review, the recent studies (2005 2009) concerning the cytotoxic activity of saponins have been summarized. The correlations between the structure and the cytotoxicity of both steroid and triterpenoid saponins have been described as well as the most common mechanisms of action. PMID- 20835389 TI - Multivalent Antimicrobial Peptides as Therapeutics: Design Principles and Structural Diversities. AB - This review highlights the design principles, progress and advantages attributed to the structural diversity associated with both natural and synthetic multivalent antimicrobial peptides (AMPs). Natural homo- or hetero-dimers of AMPs linked by intermolecular disulfide bonds existed in the animal kingdom, but the multivalency strategy has been adopted to create synthetic branched or polymeric AMPs that do not exist in nature. The multivalent strategy for the design of multivalent AMPs provides advantages to overcome the challenges faced in clinical applications of AMPs, such as: stability, efficiency, toxicity, maintenance of activity in high salt concentrations and under physiological conditions, and importantly overcoming bacterial resistance which is currently a leading health problem in the world. The multivalency strategy is valuable for moving multivalent AMPs toward clinical applications. PMID- 20835390 TI - Ion mobility spectrometry for the rapid analysis of over-the-counter drugs and beverages. AB - In the pharmaceutical industry, there are increasing requirements for analytical methods in quality assessment for the production of drugs. In this investigation, ion mobility spectrometry (IMS) was used for the rapid qualitative separation and identification of active ingredients in generic over-the-counter drugs and food additives in beverages. The active ingredients determined in drugs were acetaminophen, aspartame, bisacodyl, caffeine, dextromethorphan, diphenhydramine, famotidine, glucosamine, guaifenesin, loratadine, niacin, phenylephrine, pyridoxine, thiamin, and tetrahydrozoline. Aspartame and caffeine were determined in beverages. Fourteen over-the-counter drugs and beverages were analyzed. Analysis times below 10 s were obtained for IMS, and reduced mobilities were reported for the first time for 12 compounds. A quadrupole mass spectrometer coupled to a mobility spectrometer was used to assure a correct peak assignation. The combination of fast analysis, low cost, and inexpensive maintenance of IMS instruments makes IMS an attractive technique for the qualitative determination of the active ingredients in over-the-counter drugs and food additives in manufacture quality control and cleaning verification for the drug and food industries. PMID- 20835391 TI - Penetration and Growth Rates of Mobile Phones in Developing Countries: An Analytical Classification. AB - This brief paper uses a simple arithmetic framework to classify and explain the performance of developing countries in closing the absolute digital divide. Four categories are created on the basis of two variables, namely, the penetration and rate of growth of mobile phones. The paper answers questions such as: Which countries do well and badly on both variables? Are the countries in these categories drawn from specific regions or similar income levels or is the distribution more random? How can similar countries from the same region appear in two diametrically opposite categories? What does this imply for policy? PMID- 20835392 TI - Measures of Inequality: Application to Happiness in Nations. AB - What is a good measure for happiness inequality? In the context of this question, we have developed an approach in which individual happiness values in a sample are considered as elements of a set and inequality as a binary relation on that set. The total number of inequality relations, each weighed by the distance on the scale of measurement between the pair partners, has been adopted as an indicator for the inequality of the distribution as a whole. For models in which the happiness occurs as a continuous latent variable, an analogous approach has been developed on the basis of differentials. In principle, this fundamental approach results in a (zero) minimum value, and, more importantly, also in a maximum value. In the case where happiness is measured using a k-points scale, the maximum inequality is obtained if all 1/2N sample members select the lowest possible rating (Eq. 1) and the other 1/2N the highest possible one (k). This finding even applies to the truly ordinal case, i.e., if the distances between the successive ratings on the scale are unknown. It is, however, impossible to quantify the inequality of some measured sample distribution, unless all distances of the k categories of the scale of measurement are known or at least estimated, either on an empirical basis or on the basis of assumptions. In general, the numerical application of the method to continuous distributions is very complicated. An exploration on the basis of a relatively simple model with a linear probability density function suggests that the inequality of a beta probability distribution with shape parameters a and b increases as the value of these parameters decreases. A contour plot, obtained by numerical integration, demonstrates this relationship in a quantitative way. This approach is applicable to judge the aptness of common statistics of dispersion, among which the standard deviation and the Gini coefficient. The former is shown to be more appropriate than the latter for measuring inequality of happiness within nations. PMID- 20835393 TI - Comparison of minimally invasive surgical approaches for hysterectomy at a community hospital: robotic-assisted laparoscopic hysterectomy, laparoscopic assisted vaginal hysterectomy and laparoscopic supracervical hysterectomy. AB - The study reported here compares outcomes of three approaches to minimally invasive hysterectomy for benign indications, namely, robotic-assisted laparoscopic (RALH), laparoscopic-assisted vaginal (LAVH) and laparoscopic supracervical (LSH) hysterectomy. The total patient cohort comprised the first 237 patients undergoing robotic surgeries at our hospital between August 2007 and June 2009; the last 100 patients undergoing LAVH by the same surgeons between July 2006 and February 2008 and 165 patients undergoing LAVHs performed by nine surgeons between January 2008 and June 2009; 87 patients undergoing LSH by the same nine surgeons between January 2008 and June 2009. Among the RALH patients were cases of greater complexity: (1) higher prevalence of prior abdominopelvic surgery than that found among LAVH patients; (2) an increased number of procedures for endometriosis and pelvic reconstruction. Uterine weights also were greater in RALH patients [207.4 vs. 149.6 (LAVH; P < 0.001) and 141.1 g (LSH; P = 0.005)]. Despite case complexity, operative time was significantly lower in RALH than in LAVH (89.9 vs. 124.8 min, P < 0.001) and similar to that in LSH (89.6 min). Estimated blood loss was greater in LAVH (167.9 ml) than in RALH (59.0 ml, P < 0.001) or LSH (65.7 ml, P < 0.001). Length of hospital stay was shorter for RALH than for LAVH or LSH. Conversion and complication rates were low and similar across procedures. Multivariable regression indicated that LAVH, obesity, uterine weight >=250 g and older age predicted significantly longer operative time. The learning curve for RALH demonstrated improved operative time over the case series. Our findings show the benefits of RALH over LAVH. Outcomes in RALH can be as good as or better than those in LSH, suggesting the latter should be the choice primarily for women desiring cervix-sparing surgery. PMID- 20835394 TI - The Public Acceptance of Voluntary Childlessness in the Netherlands: from 20 to 90 per cent in 30 years. AB - Within a relatively short period of 30 years, public acceptance of voluntary childlessness has increased enormously in the Netherlands. In this paper, we address two research questions, which we answer with data from 13 waves of the repeated cross-sectional survey Cultural Change in the Netherlands (CCN, 1965 1996). First, we investigate to what extent the increasing permissiveness is due to cohort replacement and to intra-cohort change. We find that between 1965 and 1980 the change is primarily due to intra-cohort (period) effects, whereas cohort replacement has become more important since 1980. Second, we address the question which social categories constitute the 10% of the population who do not accept voluntary childlessness. Church attendance-and not religiosity or religious socialization-turns out to be the most important factor. Low levels of income and education also negatively affect the acceptance of voluntary childless. PMID- 20835395 TI - Radiotherapy in the treatment of Graves ophthalmopathy-to do it or not? AB - To the objective of this study is to evaluate the role and toxicity of radiotherapy in the treatment of Graves ophthalmopathy. In the years 2000-2003, 121 patients with malignant exophthalmos were treated with radiotherapy of the retrobulbar area to the total dose of 20 Gy in ten fractions with a 6 MeV photon beam. The treatment was performed by the team of the Clinic of Oncology of the Jagiellonian University Medical College in Cracow. The radiotherapy was preceded by intravenous steroid therapy: methylprednisolone acetate administered at the dose of 2 g/week for four consecutive weeks. The highest efficacy, expressed as improvement of all ocular symptoms, was observed for the combined treatment. Female and non-diabetic patients responded positively to the combined treatment. Radiotherapy combined with steroid therapy in the treatment of Graves ophthalmopathy seems to be an effective treatment for strictly defined indications. In the treatment of Graves-Basedow disease, radiotherapy is a well tolerated treatment modality. Diabetes is a factor that worsens prognosis in Graves ophthalmopathy and female sex is a favourable factor for this condition. PMID- 20835396 TI - Ocular disease in patients with ANCA-positive vasculitis. AB - Anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis-the term recently applied to Wegener's granulomatosis-is a rare multi-system inflammation characterized by necrotizing granulomas and vasculitis. We investigated the ocular manifestations of this disease in a group of patients drawn from five inflammatory eye disease clinics across the United States. Of 8,562 persons with ocular inflammation, 59 individuals were diagnosed with ANCA-positive vasculitis; 35 males and 21 females, aged 16 to 96 years, were included in this study. Ocular diagnoses were scleritis (75.0%), uveitis (17.9%), and other ocular inflammatory conditions (33.9%) including peripheral ulcerative keratitis and orbital pseudotumor. Mean duration of ocular disease was 4.6 years. Oral corticosteroids and other systemic immunosuppressive agents were used by 85.7% and 78.5% of patients, respectively. Over time, patients with ANCA-positive vasculitis experienced 2.75-fold higher mortality than other patients with inflammatory eye disease. PMID- 20835397 TI - Sunscreens with Titanium Dioxide (TiO(2)) Nano-Particles: A Societal Experiment. AB - The risks of novel technologies, such as nano(bio)technology cannot be fully assessed due to the existing uncertainties surrounding their introduction into society. Consequently, the introduction of innovative technologies can be conceptualised as a societal experiment, which is a helpful approach to evaluate moral acceptability. This approach is illustrated with the marketing of sunscreens containing nano-sized titanium dioxide (TiO(2)) particles. We argue that the marketing of this TiO(2) nanomaterial in UV protective cosmetics is ethically undesirable, since it violates four reasonable moral conditions for societal experimentation (absence of alternatives, controllability, limited informed consent, and continuing evaluation). To remedy the current way nano sized TiO(2) containing sunscreens are utilised, we suggest five complementing actions (closing the gap, setup monitoring tools, continuing review, designing for safety, and regulative improvements) so that its marketing can become more acceptable. PMID- 20835398 TI - The Ambivalence of Promising Technology. AB - Issues of responsibility in the world of nanotechnology are becoming explicit with the emergence of a discourse on 'responsible development' of nanoscience and nanotechnologies. Much of this discourse centres on the ambivalences of nanotechnology and of promising technology in general. Actors must find means of dealing with these ambivalences. Actors' actions and responses to ambivalence are shaped by their position and context, along with strategic games they are involved in, together with other actors. A number of interviews were conducted with industrial actors with the aim of uncovering their ethical stances towards responsible development of nanotechnology. The data shows that standard repertoires of justification of nanotechnological development were used. Thus, the industrial actors fell back on their position and associated responsibilities. Such responses reinforce a division of moral labour in which industrial actors and scientists can focus on the progress of science and technology, while other actors, such as NGOs, are expected to take care of broader considerations, such as ethical and social issues. PMID- 20835399 TI - Lablab purpureus-A Crop Lost for Africa? AB - In recent years, so-called 'lost crops' have been appraised in a number of reviews, among them Lablab purpureus in the context of African vegetable species. This crop cannot truly be considered 'lost' because worldwide more than 150 common names are applied to it. Based on a comprehensive literature review, this paper aims to put forward four theses, (i) Lablab is one of the most diverse domesticated legume species and has multiple uses. Although its largest agro morphological diversity occurs in South Asia, its origin appears to be Africa. (ii) Crop improvement in South Asia is based on limited genetic diversity. (iii) The restricted research and development performed in Africa focuses either on improving forage or soil properties mostly through one popular cultivar, Rongai, while the available diversity of lablab in Africa might be under threat of genetic erosion. (iv) Lablab is better adapted to drought than common beans (Phaseolus vulgaris) or cowpea (Vigna unguiculata), both of which have been preferred to lablab in African agricultural production systems. Lablab might offer comparable opportunities for African agriculture in the view of global change. Its wide potential for adaptation throughout eastern and southern Africa is shown with a GIS (geographic information systems) approach. PMID- 20835401 TI - Potential signal to accommodation from the Stiles-Crawford effect and ocular monochromatic aberrations. AB - The purpose of this study is to determine if cues within the blurred retinal image due to the Stiles-Crawford (SC) effect and the eye's monochromatic aberrations can drive accommodation with a small pupil (3 mm) that is typical of bright photopic conditions.The foveal, psychophysical SC function (17 min arc) and ocular monochromatic aberrations were measured in 21 visually normal adults. The retinal image of a 10.2 min arc disc was simulated for spherical defocus levels of -1 D, 0 D and +1 D in each of four conditions consisting of combinations of the presence or absence of the individual SC function and monochromatic aberrations with a 3 mm pupil. Accommodation was recorded in eleven participants as each viewed the simulations through a 0.75-mm pinhole.The SC effect alone did not provide a significant cue to accommodation. Monochromatic aberrations provided a statistically significant but rather small cue to monocular accommodation. PMID- 20835402 TI - Synthesis of Ruthenium Boryl Analogues of the Shvo Metal-Ligand Bifunctional Catalyst. AB - Metal boryl complexes have received significant attention in the literature in recent years due to their role as key intermediates in a number of metal catalyzed borylation reactions. The ligand scaffold is known to have a significant impact on the observed reactivity of these metal boryl complexes. A synthetic strategy to access ruthenium boryl analogues of the Shvo metal-ligand catalysts is described. Heating a precursor to Shvo's catalyst (1) with bis(catecholato)diboron at 50 degrees C provided ruthenium boryl complex 3 [2,5 Ph(2)-3,4-Tol(2)(eta(5)-C(4)COBcat)Ru(CO)(2)Bcat] (Bcat = catecholatoboryl). Addition of bis(catecholato)diboron to complex 1 in the presence of a phenol results in ruthenium boryl complex5 [2,5-Ph(2)-3,4-Tol(2)(eta(5) C(4)COH)Ru(CO)(2)Bcat] at 22 degrees C in 30% isolated yield. A single crystal X ray analysis of complex 5 confirmed the assigned structure. An improved synthesis of ruthenium boryl complex 5 was developed by the in situ formation of complex 3 [2,5-Ph(2)-3,4-Tol(2)(eta(5)-C(4)COBcat)Ru(CO)(2)Bcat] followed by addition of the phenol, resulting in a 51% yield. PMID- 20835403 TI - Teeth Grinding: Is Emotional Stability related to Bruxism? AB - This study examines the association between personality traits and bruxism, the repetitive grinding or clenching of teeth. Community-dwelling participants (N = 470) had a comprehensive oral examination by a dentist and completed a dental history and personality questionnaires. Consistent with the literature on state anxiety and depression as antecedents of bruxism, Neuroticism-related traits were associated with self-reported teeth grinding. These traits were also associated with other oral complaints often associated with anxiety (jaw clicks, difficulty chewing food, and dry mouth), but not with more general oral health complaints (unhealthy gums, bleeding gums, and canker sores) or with dentist-assessed occlusal wear or tongue indentations. This study provides evidence for the association between Neuroticism and bruxism and other stress-related oral health symptoms. PMID- 20835400 TI - Lipoproteins and lipoprotein metabolism in periodontal disease. AB - A growing body of evidence indicates that the incidence of atherosclerosis is increased in subjects with periodontitis - a chronic infection of the oral cavity. This article summarizes the evidence that suggests periodontitis shifts the lipoprotein profile to be more proatherogenic. LDL-C is elevated in periodontitis and most studies indicate that triglyceride levels are also increased. By contrast, antiatherogenic HDL tends to be low in periodontitis. Periodontal therapy tends to shift lipoprotein levels to a healthier profile and also reduces subclinical indices of atherosclerosis. In summary, periodontal disease alters lipoprotein metabolism in ways that could promote atherosclerosis and cardiovascular disease. PMID- 20835404 TI - How the overlapping timescales for peptide binding and terrace exposure lead to non-linear step dynamics during growth of calcium oxalate monohydrate. AB - Using in situ atomic force microscopy (AFM), we investigate the inhibition of calcium oxalate monohydrate (COM) step growth by aspartic acid-rich peptides and find that the magnitude of the effect depends on terrace lifetime. We then derive a time dependent step-pinning model in which average impurity spacing depends on the terrace lifetime as given by the ratio of step spacing to step speed. We show that the measured variation in step speed is well fit by the model and allows us to extract the characteristic peptide adsorption time. The model also predicts that a crossover in the timescales for impurity adsorption and terrace exposure leads to bistable growth dynamics described mathematically by a catastrophe. We observe this behavior experimentally both through the sudden drop in step speed to zero upon decrease of supersaturation as well as through fluctuations in step speed between the two limiting values at the point where the catastrophe occurs. We discuss the model's general applicability to macromolecular modifiers and biomineral phases. PMID- 20835405 TI - Recognition memory reveals just how CONTRASTIVE contrastive accenting really is. AB - The effects of pitch accenting on memory were investigated in three experiments. Participants listened to short recorded discourses that contained contrast sets with two items (e.g. British scientists and French scientists); a continuation specified one item from the set. Pitch accenting on the critical word in the continuation was manipulated between non-contrastive (H* in the ToBI system) and contrastive (L+H*). On subsequent recognition memory tests, the L+H* accent increased hits to correct statements and correct rejections of the contrast item (Experiments 1-3), but did not impair memory for other parts of the discourse (Experiment 2). L+H* also did not facilitate correct rejections of lures not in the contrast set (Experiment 3), indicating that contrastive accents do not simply strengthen the representation of the target item. These results suggest comprehenders use pitch accenting to encode and update information about multiple elements in a contrast set. PMID- 20835406 TI - CFD simulations of enhanced condensational growth (ECG) applied to respiratory drug delivery with comparisons to in vitro data. AB - Enhanced condensational growth (ECG) is a newly proposed concept for respiratory drug delivery in which a submicrometer aerosol is inhaled in combination with saturated or supersaturated water vapor. The initially small aerosol size provides for very low extrathoracic deposition, whereas condensation onto droplets in vivo results in size increase and improved lung retention. The objective of this study was to develop and evaluate a CFD model of ECG in a simple tubular geometry with direct comparisons to in vitro results. The length (29 cm) and diameter (2 cm) of the tubular geometry were representative of respiratory airways of an adult from the mouth to the first tracheobronchial bifurcation. At the model inlet, separate streams of humidified air (25, 30, and 39 degrees C) and submicrometer aerosol droplets with mass median aerodynamic diameters (MMADs) of 150, 560, and 900 nm were combined. The effects of condensation and droplet growth on water vapor concentrations and temperatures in the continuous phase (i.e., two-way coupling) were also considered. For an inlet saturated air temperature of 39 degrees C, the two-way coupled numerical (and in vitro) final aerosol MMADs for initial sizes of 150, 560, and 900 nm were 1.75 MUm (vs. 1.23 MUm), 2.58 MUm (vs. 2.66 MUm), and 2.65 MUm (vs. 2.63 MUm), respectively. By including the effects of two-way coupling in the model, agreements with the in vitro results were significantly improved compared with a one-way coupled assumption. Results indicated that both mass and thermal two-way coupling effects were important in the ECG process. Considering the initial aerosol sizes of 560 and 900 nm, the final sizes were most influenced by inlet saturated air temperature and aerosol number concentration and were not largely influenced by initial size. Considering the growth of submicrometer aerosols to above 2 MUm at realistic number concentrations, ECG may be an effective respiratory drug delivery approach for minimizing mouth-throat deposition and maximizing aerosol retention in a safe and simple manner. However, future studies are needed to explore effects of in vivo boundary conditions, more realistic respiratory geometries, and transient breathing. PMID- 20835407 TI - Fluorometric assay of oleate-activated phospholipase D isoenzyme in membranes of rat nervous tissue and human platelets. AB - Phospholipase D plays a key role in the biosynthesis of phosphatidic acid, a second messenger involved in essential cellular processes. Oleate-activated phospholipase D was the first mammalian phospholipase D isoform to be discovered but is the least known. The study was aimed to test a fluorometric method of assessment of oleate-activated phospholipase D activity in different biological materials. The brain cortex of male Wistar rats, cultured rat brain astrocytes, and human platelets were processed to yield plasmatic membranes for experiments. To assess phospholipase D activity the modified fluorometric method was used. Previously, the method was used only to determine H2O2. In this enzyme-coupled assay phospholipase D activity is monitored indirectly using 10-acetyl-3,7 dihydroxyphenoxazine. First, phospholipase D cleaves exogenous phosphatidylcholine to yield choline and phosphatidic acid. Second, choline is oxidized by choline oxidase to betaine and H2O2. Finally, in the presence of horseradish peroxidase, H2O2 reacts with 10-acetyl-3,7-dihydroxyphenoxazine to generate the highly fluorescent product, resorufin. The concentration of resorufin was measured using excitation and emission at 560 nm and 590 nm, respectively. The proposed optimal parameters of the tested assay are 25 ug of rat brain cortex protein, 50 ug of rat brain astrocyte protein, and 50 ug of human platelet protein in a reaction volume of 200 uL, and 2 min enzymatic reaction at 37 degrees C. The fluorometric method may be applied to assay phospholipase D in different biological materials. PMID- 20835408 TI - Depletion of intracellular glutathione and increased lipid peroxidation mediate cytotoxicity of hematite nanoparticles in MRC-5 cells. AB - Particles generated from numerous anthropogenic and/or natural sources, such as crystalline alpha-Fe2O3 nanoparticles, have the potential to damage lung cells. In our study we investigated the effects of these nanoparticles (12.5 ug/ml) on lipid peroxidation and the antioxidative system in MRC-5 lung fibroblast cells following exposure for 24, 48 or 72h. Exposure to alpha-Fe2O3 nanoparticles increased lipid peroxidation by 81%, 189% and 110% after 24, 48 and 72h, respectively. Conversely, the reduced glutathione concentration decreased by 23.2% and 51.4% after 48 and 72h of treatment, respectively. In addition, an augmentation of the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase within the interval between 48-72h was noticed. Taking into account that the reduced glutathione level decreased and the malondialdehyde level, a lipid peroxidation product, remained highly increased up to 72h of exposure, it would appear that the MRC-5 antioxidant defense mechanisms did not efficiently counteract the oxidative stress induced by exposure to hematite nanoparticles. PMID- 20835423 TI - Transforming terpene feedstock into polyketide architecture. AB - The Cu-catalyzed synthesis of skipped 1,4-dienes from allylic acetates and vinyl Grignard reagents is key to bidirectional modifications of acyclic terpene acetates. As a result, trisubstituted double bond containing subunits can be readily transferred into complex polyketides from inexpensive bulk terpenes. PMID- 20835424 TI - Multi-component reactions involving group 6 Fischer carbene complexes: a source of inspiration for future catalytic transformations. AB - The ability of heteroatom stabilized Fischer carbene complexes (FCCs) to participate in multicomponent reactions (MCRs) has become a characteristic of such organometallics, particularly of chromium carbenes. This feature article updates the main results in this field during the last lustrum, highlighting the ability of FCCs for the construction of densely functionalized frameworks, mainly through the successive incorporation of unsaturated moieties (alkynes, CO ligands,...) in a sequential manner. Examples where up to seven components are coupled will be presented. PMID- 20835425 TI - alpha,alpha'-Dihydroxyketone formation using aromatic and heteroaromatic aldehydes with evolved transketolase enzymes. AB - Transketolase mutants have been identified that accept aromatic acceptors with good stereoselectivities, in particular benzaldehyde for which the wild type enzyme showed no activity. PMID- 20835426 TI - Real-time monitoring of relaxation and contractility of smooth muscle cells on a novel biohybrid chip. AB - Cardiovascular diseases represent the most common cause of death in industrialized countries. In this context vascular smooth muscle cells (SMCs) are a major key player that is involved in pathological processes like hypertension and atherosclerosis. Therefore the pharmaceutical industry is intensively investigated in developing non-destructive and label-free monitoring techniques for a quantitative detection of SMC characteristics in the field of active pharmaceutical development as well as clinical diagnostics. Hence, we developed a novel multiwell interdigital electrode sensor-array in standardized ANSI 96-well layout. Through optimization of electrode geometry and material as well as passivation/adhesion-layer we obtained a novel biohybrid chip for the sensitive and quantitative detection of SMC contractility as well as relaxation via impedance spectroscopy. For the validation of our multiwell sensor-array we established a SMC culture model derived from primary cells that is switchable from a non-contractile pathological to a functional contractile phenotype. Using the reference compounds acetylcholine (ACh) and amlodipine, we could quantify SMC contraction by an impedance decrease to 40% while SMC relaxation was detectable by an impedance increase to 110%. More strikingly we could monitor aging of the isolated SMC which arose by an attenuated contractility over successive passaging. Demonstrating the performance of our self-developed multiwell sensor array based impedance measurement setup we provide a suitable sensor-array coupled cell model to study the mechanisms that activated SMCs undergo in response to inflammatory mediators or vessel injury. PMID- 20835427 TI - A microfluidic approach for in vitro assessment of interorgan interactions in drug metabolism using intestinal and liver slices. AB - Over the past two decades, it has become increasingly clear that the intestine, in addition to the liver, plays an important role in the metabolism of xenobiotics. Previously, we developed a microfluidic-based in vitro system for the perifusion of precision-cut liver slices for metabolism studies. In the present study, the applicability of this system for the perifusion of precision cut intestinal slices, and for the sequential perifusion of intestinal and liver slices, all from rat, was tested to mimic the in vivo first pass situation. Intestinal and liver slices, exposed to the substrates 7-ethoxycoumarin (7-EC), 7 hydroxycoumarin (7-HC) and lidocaine (Li), exhibited similar metabolic rates in the biochip and in the well plates for periods of at least 3 h. The metabolic rate remained the same when two slices were placed in adjacent microchambers and perifused sequentially. In addition, the system has been adapted to sequentially perifuse intestinal and liver tissue slices in a two-compartment co-culture perfusion system with a continuous flow of medium. It becomes possible to direct metabolites or other excreted compounds formed by an intestinal slice in the first compartment to the second compartment containing a liver slice. The intestine does not influence liver metabolism for these substrates. The interplay between these two organs was demonstrated by exposing the slices to the primary bile acid, chenodeoxycholic acid (CDCA). CDCA induced the expression of fibroblast growth factor 15 (FGF15) in the intestinal slice, which resulted in a stronger down-regulation of the enzyme, cytochrome P450 7A1 (CYP7A1), in the liver slice in the second compartment than when the liver slice was exposed to CDCA in a single-microchamber biochip. We thus demonstrate in this paper that intestinal slices, in addition to liver slices, remain functional in the biochip under flow conditions, and that the two-microchamber biochip has great potential for the study of interorgan effects. This is the first example of the incorporation of both liver and intestinal slices in a microfluidic device. Use of this microfluidic system will improve our insight into interorgan interactions and elucidate as yet unknown mechanisms involved in toxicity, gene regulation and drug-drug interactions. PMID- 20835428 TI - Motile and non-motile sperm diagnostic manipulation using optoelectronic tweezers. AB - Optoelectronic tweezers was used to manipulate human spermatozoa to determine whether their response to OET predicts sperm viability among non-motile sperm. We review the electro-physical basis for how live and dead human spermatozoa respond to OET. The maximal velocity that non-motile spermatozoa could be induced to move by attraction or repulsion to a moving OET field was measured. Viable sperm are attracted to OET fields and can be induced to move at an average maximal velocity of 8.8 +/- 4.2 um s(-1), while non-viable sperm are repelled to OET, and are induced to move at an average maximal velocity of -0.8 +/- 1.0 um s(-1). Manipulation of the sperm using OET does not appear to result in increased DNA fragmentation, making this a potential method by which to identify viable non motile sperm for assisted reproductive technologies. PMID- 20835429 TI - Uniform cell seeding and generation of overlapping gradient profiles in a multiplexed microchamber device with normally-closed valves. AB - Generation of stable soluble-factor gradients in microfluidic devices enables studies of various cellular events such as chemotaxis and differentiation. However, many gradient devices directly expose cells to constant fluid flow and that can induce undesired responses from cells due to shear stress and/or wash out of cell-secreted molecules. Although there have been devices with flow-free gradients, they typically generate only a single condition and/or have a decaying gradient profile that does not accommodate long-term experiments. Here we describe a microdevice that generates several chemical gradient conditions on a single platform in flow-free microchambers which facilitates steady-state gradient profiles. The device contains embedded normally-closed valves that enable fast and uniform seeding of cells to all microchambers simultaneously. A network of microchannels distributes desired solutions from easy-access open reservoirs to a single output port, enabling a simple setup for inducing flow in the device. Embedded porous filters, sandwiched between the microchannel networks and cell microchambers, enable diffusion of biomolecules but inhibit any bulk flow over the cells. PMID- 20835430 TI - A microfluidic microprocessor: controlling biomimetic containers and cells using hybrid integrated circuit/microfluidic chips. AB - We present an integrated platform for performing biological and chemical experiments on a chip based on standard CMOS technology. We have developed a hybrid integrated circuit (IC)/microfluidic chip that can simultaneously control thousands of living cells and pL volumes of fluid, enabling a wide variety of chemical and biological tasks. Taking inspiration from cellular biology, phospholipid bilayer vesicles are used as robust picolitre containers for reagents on the chip. The hybrid chip can be programmed to trap, move, and porate individual living cells and vesicles and fuse and deform vesicles using electric fields. The IC spatially patterns electric fields in a microfluidic chamber using 128 * 256 (32,768) 11 * 11 MUm(2) metal pixels, each of which can be individually driven with a radio frequency (RF) voltage. The chip's basic functions can be combined in series to perform complex biological and chemical tasks and can be performed in parallel on the chip's many pixels for high-throughput operations. The hybrid chip operates in two distinct modes, defined by the frequency of the RF voltage applied to the pixels: Voltages at MHz frequencies are used to trap, move, and deform objects using dielectrophoresis and voltages at frequencies below 1 kHz are used for electroporation and electrofusion. This work represents an important step towards miniaturizing the complex chemical and biological experiments used for diagnostics and research onto automated and inexpensive chips. PMID- 20835431 TI - Kinetics of NF-kappaB nucleocytoplasmic transport probed by single-cell screening without imaging. AB - Transport of protein and RNA cargoes between the nucleus and cytoplasm (nucleocytoplasmic transport) is vital for a variety of cellular functions. The studies of kinetics involved in such processes have been hindered by the lack of quantitative tools for measurement of the nuclear and cytosolic fractions of an intracellular protein at the single cell level for a cell population. In this report, we describe using a novel method, microfluidic electroporative flow cytometry, to study kinetics of nucleocytoplasmic transport of an important transcription factor NF-kappaB. With data collected from single cells, we quantitatively characterize the population-averaged kinetic parameters such as the rate constants and apparent activation barrier for NF-kappaB transport. Our data demonstrate that NF-kappaB nucleocytoplasmic transport fits first-order kinetics very well and is a fairly reversible process governed by equilibrium thermodynamics. PMID- 20835432 TI - Antibody-protein A conjugated quantum dots for multiplexed imaging of surface receptors in living cells. AB - To use quantum dots (QDs) as fluorescent probes for receptor imaging, QD surface should be modified with biomolecules such as antibodies, peptides, carbohydrates, and small-molecule ligands for receptors. Among these QDs, antibody conjugated QDs are the most promising fluorescent probes. There are many kinds of coupling reactions that can be used for preparing antibody conjugated QDs. Most of the antibody coupling reactions, however, are non-selective and time-consuming. In this paper, we report a facile method for preparing antibody conjugated QDs for surface receptor imaging. We used ProteinA as an adaptor protein for binding of antibody to QDs. By using ProteinA conjugated QDs, various types of antibodies are easily attached to the surface of the QDs via non-covalent binding between the F(c) (fragment crystallization) region of antibody and ProteinA. To show the utility of ProteinA conjugated QDs, HER2 (anti-human epidermal growth factor receptor 2) in KPL-4 human breast cancer cells were stained by using anti-HER2 antibody conjugated ProteinA-QDs. In addition, multiplexed imaging of HER2 and CXCR4 (chemokine receptor) in the KPL-4 cells was performed. The result showed that CXCR4 receptors coexist with HER2 receptors in the membrane surface of KPL-4 cells. ProteinA mediated antibody conjugation to QDs is very useful to prepare fluorescent probes for multiplexed imaging of surface receptors in living cells. PMID- 20835433 TI - Analysis and hit filtering of a very large library of compounds screened against Mycobacterium tuberculosis. AB - There is an urgent need for new drugs against tuberculosis which annually claims 1.7-1.8 million lives. One approach to identify potential leads is to screen in vitro small molecules against Mycobacterium tuberculosis (Mtb). Until recently there was no central repository to collect information on compounds screened. Consequently, it has been difficult to analyze molecular properties of compounds that inhibit the growth of Mtb in vitro. We have collected data from publically available sources on over 300 000 small molecules deposited in the Collaborative Drug Discovery TB Database. A cheminformatics analysis on these compounds indicates that inhibitors of the growth of Mtb have statistically higher mean logP, rule of 5 alerts, while also having lower HBD count, atom count and lower PSA (ChemAxon descriptors), compared to compounds that are classed as inactive. Additionally, Bayesian models for selecting Mtb active compounds were evaluated with over 100 000 compounds and, they demonstrated 10 fold enrichment over random for the top ranked 600 compounds. This represents a promising approach for finding compounds active against Mtb in whole cells screened under the same in vitro conditions. Various sets of Mtb hit molecules were also examined by various filtering rules used widely in the pharmaceutical industry to identify compounds with potentially reactive moieties. We found differences between the number of compounds flagged by these rules in Mtb datasets, malaria hits, FDA approved drugs and antibiotics. Combining these approaches may enable selection of compounds with increased probability of inhibition of whole cell Mtb activity. PMID- 20835434 TI - Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context. AB - Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for murine B lymphoma A20 cell line. The peptide used in combination with the nanoporous nanoparticles allows an efficient in vivo targeting, a sustained release and a sensible therapeutic effect. PMID- 20835435 TI - Single light-emitting polymer nanofiber field-effect transistors. AB - We report on single nanofiber field-effect transistors made by the light-emitting polymer, poly(2-methoxy-5-(2-ethylhexoxy)-1,4-phenylenevinylene). We measure electrical performances comparable to or better than those of thin-film transistors by the same organic semiconductor, due to the molecular alignment induced by electrospinning, such as hole mobility of the order of 10(-3) cm(2) V( 1) s(-1) and on/off current ratios up to 780. In addition, we observe controllable photoluminescence intensity quenching by varying the gate voltage up to -40 V with device operation in the luministor mode. Single light-emitting polymer nanofiber transistors coupling electrical and optical functionalities open the way towards low cost and flexible one-dimensional switches and nanofiber based light-emitting transistors. PMID- 20835436 TI - Towards chirality-pure carbon nanotubes. AB - Current as-grown single-walled carbon nanotubes vary in diameter and chirality, which results in variations in their electronic and optical properties. Two approaches have been intensively studied to obtain chirality-pure nanotube structures and thus uniform properties for advanced applications. The first approach involves the post-synthesis separation according to the nanotubes' chiral vectors (n, m), and the second one involves direct synthes of carbon nanotubes with the same (n, m). This paper reviews the efforts along these two directions, with emphasis on the most recent progress of post-synthesis separation and the perspectives of controllable synthesis. PMID- 20835437 TI - Polyaniline-intercalated layered vanadium oxide nanocomposites--one-pot hydrothermal synthesis and application in lithium battery. AB - Polyaniline-intercalated layered vanadium oxide nanocomposites were successfully synthesized by an one-pot hydrothermal method and characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED), Fourier transform infrared spectroscopy (FT-IR), and Raman spectroscopy. The effects of reaction conditions, such as pH value of the precursor solution, reaction temperature and time, and the amount of aniline on the structure and morphology of the obtained samples, were systematically investigated. Based on the experimental results, an in situ intercalation-polymerization-exfoliation mechanism was put forward for the formation of layered nanocomposites. The application of the resulting layered nanocomposite as the cathode material in lithium battery was tested and the results showed that the polyaniline-intercalated layered vanadium oxide nanocomposite prepared at 140 degrees C had a good cycling performance and might act as a promising cathode material for high-energy-density rechargeable lithium batteries. PMID- 20835438 TI - A new CoFe(2)O(4)-Cr(2)O(3)-SiO(2) fluorescent magnetic nanocomposite. AB - A combined sonochemical co-precipitaion method has been developed for the synthesis of a CoFe(2)O(4)-Cr(2)O(3)-SiO(2) magnetic nanocomposite. The synthesis involved the pre-synthesis of CoFe(2)O(4)-Cr(2)O(3) nanoparticles, which were subsequently coated with SiO(2) by treatment with tetraethyl orthosilicate. It was observed that the as-prepared CoFe(2)O(4)-Cr(2)O(3)-SiO(2) nanocomposite exhibits photoluminescence properties without the addition of any external fluorescent marker. The fluorescent magnetic nanoparticles (FMNPs) had a typical diameter of 30 +/- 5 nm and a saturation magnetization of 5.1 emu g(-1) at room temperature. This as-prepared nanocomposite was used for staining cultured HeLa cells for fluorescence imaging. PMID- 20835439 TI - Oxide nanowire networks and their electronic and optoelectronic characteristics. AB - Oxide nanowire networks or oxide nanonets leverage some of the exceptional functionalities of one-dimensional nanomaterials along with the fault tolerance and flexibility of interconnected nanowires to creating exciting opportunities in large-area electronics as well as green energy systems. This paper reviews the electronic and optoelectronic properties of these networks and highlights their potential applications in field-effect transistors, optoelectronic devices, and solar cells. Techniques to grow nanowires and their subsequent integration into networks using contact printing and electrospinning are described. Electrical properties of field-effect transistors fabricated from contact printed nanowire networks are discussed, and means of integration of the nanowire networks of heterogenous materials that enable ambipolar device operation are outlined. Photocurrent properties of these nanowires are described, including the dye sensitization of large-bandgap SnO(2) nanowires. The final section deals with the advantages of employing nanowire networks in dye-sensitized solar cells and the dependence of solar cell performance on morphology and surface area. PMID- 20835440 TI - Chemical approaches towards single-species single-walled carbon nanotubes. AB - Small variations in diameter and chirality could bring striking changes in the electronic and optical properties of single-walled carbon nanotubes (SWCNTs). Therefore, SWCNTs of a specific diameter/chirality are required for many applications. In this review we provide an overview of the recent progress in various chemical approaches towards producing specific nanotubes. Issues regarding the structure of SWCNTs, characterization tools and various separation techniques are presented in this article. The benefits and limits of current chemical approaches are discussed and the perspectives of emerging strategies for achieving identical single-walled carbon nanotubes are highlighted. PMID- 20835441 TI - Impact of the colloidal state on the oriented attachment growth mechanism. AB - In the last five years, several excellent reviews about oriented attachment (OA) have evidenced the advances achieved in this research area, detailing the growth mechanism and the kinetic models. The main focus of this review is to examine the dependence of the OA mechanism on the colloidal state and to demonstrate how the colloidal state modifies the OA mechanism. Basically, we can define two main possible approaches to achieve self-organization or mutual orientation of adjacent nanocrystals. One is the effective collision of particles with mutual orientation controlled by the number of collisions. This type of growth occurs in a well dispersed colloidal suspension and results in a statistical growth process. The second way is through coalescence induced by particle rotation. This mechanism must be dominant in a weakly flocculated colloidal state in which there is significant interaction among particles. This type of process leads to the formation of complex structures. PMID- 20835442 TI - Ordered arrays of shape tunable CuInS(2) nanostructures, from nanotubes to nano test tubes and nanowires. AB - Well-aligned arrays of chalcopyrite CuInS(2) one dimensional nanostructures have been prepared in a controllable manner via a convenient wet-chemical approach using anodic aluminium oxide (AAO) as a hard template. Highly oriented CuInS(2) nanotubes, nano test tubes and nanowires arrays can be selectively grown by simply varying reaction conditions. Oleylamine (OLA) was found to play a key role in the synthesis and morphology control of the CuInS(2) product. The structure, morphology, composition and optical absorption properties of the as-prepared samples were characterized using X-ray powder diffraction, transmission electron microscopy, energy dispersive X-ray spectrometry, scanning electron microscopy and UV-Vis spectrophotometry. The formation mechanism of the CuInS(2) arrays is discussed. PMID- 20835443 TI - Ultrasmall near-infrared gold nanoclusters for tumor fluorescence imaging in vivo. AB - In this paper, we explore the possibility of using ultrasmall near-infrared (NIR) gold nanoclusters (AuNCs) as novel contrast imaging agents for tumor fluorescence imaging in vivo. The fluorescence imaging signal of the tail vein administrated AuNCs in living organisms can spectrally be well distinguished from the background with maximum emission wavelength at about 710 nm, and the high photostability of AuNCs promises continuous imaging in vivo. The uptake of AuNCs by the reticuloendothelial system is relatively low in comparison with other nanoparticle-based contrast imaging agents due to their ultrasmall hydrodynamic size (~2.7 nm). Through the body weight change analysis, the results show that the body weight of the mice administrated with AuNCs has not been changed obviously in comparison with that of the control mice injected with PBS. Furthermore, using MDA-MB-45 and Hela tumor xenograft models, in vivo and ex vivo imaging studies show that the ultrasmall NIR AuNCs are able to be highly accumulated in the tumor areas, thanks to the enhanced permeability and retention (EPR) effects. And the tumor-to-background ratio is about 15 for 6 h postinjection. The results indicate that the ultrasmall NIR AuNCs appear as very promising contrast imaging agents for in vivo fluorescence tumor imaging. PMID- 20835444 TI - Nanosegregated composites of an imidazolium salt and a layered inorganic compound: organization of both anions and cations in interlayer space. AB - The organization of an imidazolium salt in the interlayer space of a layered inorganic compound leads to the formation of nanosegregated composites. PMID- 20835446 TI - Influence of anion on the kinetics of copper island growth. AB - We compare the kinetics of copper island growth in the kinetic regime in the presence and absence of anion adsorption and show that the growth exponents are inconsistent with a direct attachment model. In sulfate solution, anion adsorption leads to instantaneous nucleation, equal lateral and vertical growth exponents, and suppressed vertical growth. In perchlorate solution, island growth is characterized by progressive nucleation, enhanced vertical growth, and different lateral and vertical growth exponents. Avrami analysis and analysis of the surface power spectra suggest that island growth is controlled by surface diffusion to the island perimeter. PMID- 20835445 TI - Self-aligned nanolithography by selective polymer dissolution. AB - We report a novel approach to the fabrication of self-aligned nanoscale trench structures in a thin polymer layer covering on conductive materials. By passing AC current through a polymer-coated nanowire in the presence of an appropriate solvent, a self-aligned nanotrench is formed in the polymer overlayer as a result of accelerated dissolution while the rest of the device remains covered. Similar results have been achieved for polymer-coated graphene ribbons. Such polymer protected devices in which only the active component is exposed should find important applications as electrical sensors in aqueous solutions, particularly in cases where parasitic ionic currents often obscure sensing signals. PMID- 20835447 TI - A reliable method for detecting complexed DNA in vitro. AB - Quantification of eluted nucleic acids is a critical parameter in characterizing biomaterial based gene-delivery systems. The most commonly used method is to assay samples with an intercalating fluorescent dye such as PicoGreen(r). However, this technique was developed for unbound DNA and the current trend in gene delivery is to condense DNA with transfection reagents, which interfere with intercalation. Here, for the first time, the DNA was permanently labeled with the fluorescent dye Cy5 prior to complexation, an alternative technique hypothesized to allow quantification of both bound and unbound DNA. A comparison of the two methods was performed by quantifying the elution of six different varieties of DNA complexes from a model biomaterial (collagen) scaffold. After seven days of elution, the PicoGreen(r) assay only allowed detection of three types of complexes (those formed using LipofectinTM and two synthesised copolymers). However, the Cy5 fluorescent labeling technique enabled detection of all six varieties including those formed via common transfection agents poly(ethylene imine), poly-L-lysine and SuperFectTM. This allowed reliable quantification of the elution of all these complexes from the collagen scaffold. Thus, while intercalating dyes may be effective and reliable for detecting double-stranded, unbound DNA, the technique described in this work allowed reliable quantification of DNA independent of complexation state. PMID- 20835448 TI - Ordered mesoporous carbon/alpha-alumina nanosheet composites. AB - Novel alpha-alumina crystalline nanosheets are used for the preparation of alumina-carbon composites, in which the latter component is phenolic resin-based ordered mesoporous carbon. A unique feature of these composites is perpendicular orientation of ordered mesopores of the carbon to the (001) facets of nonporous alpha-alumina nanosheets accompanied by significant enlargement of these mesopores in comparison to those present in the bulk carbon. PMID- 20835449 TI - A facile microwave-assisted Diels-Alder reaction of vinylboronates. AB - The Diels-Alder reaction of vinylboronates can be easily performed using microwave irradiation giving excellent yields of the cycloadducts. Pinacol vinylboronate was the reagent of choice due to its stability towards hydrolysis, operational simplicity and yields of Diels-Alder products. To the best of our knowledge, this is the first example of microwave-assisted Diels-Alder reaction of boron-substituted dienophiles. Subsequent in situ oxidation of the cycloadducts with alkaline hydrogen peroxide afforded the alcohols efficiently. PMID- 20835450 TI - Facile synthesis of 1,3,4-benzotriazepines and 1-arylamide-1H-indazoles via palladium-catalyzed cyclization of aryl isocyanates and aryl hydrazones under microwave irradiation. AB - A strategy involving palladium-catalyzed cyclization of halo-phenyl hydrazones and aryl isocyanates provides a convenient approach to the synthesis of 1,3,4 benzotriazepines (4) or 1-arylamide-1H-indazoles (5) in good isolated yields. Microwave irradiation was found to afford high reaction efficiency, while the choice of halophenyl hydrazone had an effect on the pathway of the reaction. PMID- 20835451 TI - Application of click-click chemistry to the synthesis of new multivalent RGD conjugates. AB - New multivalent RGD-containing macromolecules were designed by exploiting two orthogonal chemoselective ligations. They were next applied to a competitive cell adhesion assay and used for the non invasive optical imaging of tumour in small animals. PMID- 20835452 TI - CG base pair recognition within DNA triple helices by modified N-methylpyrrolo-dC nucleosides. AB - 3-Aminophenyl-modified analogues of the bicyclic nucleoside N-methyl-3H pyrrolo[2,3-d]pyrimidin-2(7H)-one were synthesised and incorporated directly into triplex-forming oligonucleotides in order to utilise their extended hydrogen bonding motif for recognition of the CG base pair. All analogues demonstrated strong binding affinity and very good selectivity for CG from pH 6.2 to 7.0; a marked improvement on previous modifications. PMID- 20835453 TI - Naturally occurring circular proteins: distribution, biosynthesis and evolution. AB - Circular proteins, i.e., proteins with a backbone comprised of a continuous and seamless circle of amino acids, have been discovered over the last 15 years in bacteria, plants, fungi and animals. They function as defence tools in the organisms in which they are expressed and are exceptionally stable. The cyclotides are the largest known family of circular proteins and are expressed by plants of the Violaceae (violet), Rubiaceae (coffee) and Cucurbitaceae (cucurbit) families, where they have a role in plant defence against insect predation. So far there are fewer examples of cyclic peptides in bacteria or animals but we suggest that cyclic peptides are an underdiscovered class of molecules and that many more will be discovered in the near future. There is much interest in understanding the mechanism of cyclization of circular proteins and the role of the cyclic backbone in defining structure and activity. In this review, the families of ribosomally synthesized cyclic proteins reported to date are described and their common features are examined, providing information on their distribution, biosynthesis and evolution. The unusual structure of circular proteins confers them with high stability, and makes them very interesting as scaffolds for drug design, and this has led to the re-engineering of linear proteins to stabilise them and use them for such applications. PMID- 20835454 TI - Rhodium-catalysed conjugate addition of arylboronic acids to enantiopure dehydroamino acid derivatives. AB - The rhodium-catalysed conjugate addition of arylboronic acids to an enantiopure acceptor derived from (R)-S-methylcysteine proceeds under substrate control to provide a range of functionalised phenylalanine derivatives with excellent stereocontrol via a highly diastereoselective protonation. PMID- 20835455 TI - Novel dialkoxytriazine-type glycosyl donors for cellulase-catalysed lactosylation. AB - Novel glycosidic compounds, 4,6-dialkoxy-1,3,5-triazin-2-yl beta-lactosides (DAT beta-Lac), have been prepared directly in water from lactose. The reaction was carried out on a laboratory scale without protecting the hydroxy groups of lactose. The resulting triazine derivatives were found to be recognized by endo beta1,4-glucanase III from Trichoderma reesei (EGIII). The EGIII-catalysed transglycosylation of 4,6-dimethoxy-1,3,5-triazine derivative (DMT-beta-Lac) with various glycosyl acceptors has successfully been demonstrated, affording the corresponding lactosylated products. PMID- 20835456 TI - Synthesis, transport activity, membrane localization, and dynamics of oligoester ion channels containing diphenylacetylene units. AB - Four new linear oligoesters containing a diphenylacetylene unit were prepared by fragment coupling sequences and the ion channel forming ability of the compounds was investigated. Activity in vesicles was very strongly controlled by overall length; the longest compound was effectively inactive. Planar bilayer studies established that all compounds are able to form channels, but that regular step changes in conductance depend on the location of the diphenylacetylene unit within the oligoester and on the electrolyte. The intrinsic fluorescence of the diphenylacetylene unit was used to probe aggregation and membrane localization. Both monomer (320 nm) and excimer (380 nm) emissions are quenched by copper ions; quenching of the excimer emission from an aqueous aggregate is very efficient. Time-dependent changes in the intensities of monomer and excimer emission show slow transfer of diphenylacetylene units from an aqueous aggregate to a membrane bound monomer with subsequent growth of emission from a membrane-bound excimer. The latter species is not quenched by aqueous copper ions. The implications of these species and processes for the mechanism of ion channel formation by simple oligoesters are discussed. PMID- 20835457 TI - Asymmetric synthesis of a tricyclic benzofuran motif: a privileged core structure in biologically active molecules. AB - An efficient synthetic strategy for the asymmetric synthesis of a hexahydrodibenzofuran core structure, with a quaternary stereogenic center, emerges by employing a chiral reduction using Corey's (S)-Me-CBS-oxazaborolidine reagent followed by a Mitsunobu reaction to set the stereochemistry. A Pd mediated intramolecular Heck reaction concludes the tricyclic core structure. Finally, a Pd/C catalyzed reduction yields the target molecule in 21% overall yield over 6 steps. PMID- 20835458 TI - Access to phosphoproteins and glycoproteins through semi-synthesis, Native Chemical Ligation and N->S acyl transfer. AB - Peptide thioesters are important tools for protein synthesis and semi-synthesis through their use in Native Chemical Ligation (NCL). NCL can be employed to assemble site-specifically modified proteins that can help elucidate the mechanisms of biomolecular processes. In this article we explore the compatibility of phosphopeptide synthesis and glycopeptide synthesis with thioester production through N->S acyl transfer. PMID- 20835459 TI - Reusable polystyrene-supported Pd catalyst for Mizoroki-Heck reactions with extremely low amounts of supported Pd. AB - In this communication, we report that by running Mizoroki-Heck reactions of various aryl iodides in toluene-DMF, only extremely low amounts of supported Pd (0.04 mequiv.) are required to obtain almost quantitative yields. The catalyst was reused successfully up to three times. PMID- 20835460 TI - Quantitative detection of conformational transitions in a calcium sensor protein by surface plasmon resonance. AB - We determined the conditions under which surface plasmon resonance can be used to monitor at real-time the Ca(2+)-induced conformational transitions of the sensor protein recoverin immobilized over a sensor chip. The equilibrium and the kinetics of conformational transitions were detected and quantified over a physiological range of Ca(2+) and protein concentrations similar to those found within cells. Structural analysis suggests that the detection principle reflects changes in the hydrodynamic properties of the protein and is not due to a mass effect. The phenomenon appears to be related to changes in the refractive index at the metal/dielectric interface. PMID- 20835461 TI - Identification of antibiotics using small molecule variable ligand display on gold nanoparticles. AB - Here we describe the use of simple 1-pot thiol exchange reactions to generate a library of mixed ligand-coated gold nanoparticles that was screened for antibiotic activity. A library of 120 nanoparticle conjugates was assembled and antibiotic activity toward E. coli was determined and found to depend upon the combination of thiols assembled onto the nanoparticles. The most active conjugate displayed 99.9% growth inhibition at 0.5 MUM. PMID- 20835465 TI - Lighting porphyrins and phthalocyanines for molecular photovoltaics. AB - The field of organic photovoltaics (OPV) represents one of the most promising technological areas. Porphyrins and phthalocyanines are perfectly suited for their integration in light energy conversion systems. These colored macrocycles exhibit very attractive physical properties, particularly very high extinction coefficients in the visible and near IR regions, where the maximum of the solar photon flux occurs, that is necessary for efficient photon harvesting, besides a rich redox chemistry, as well as photoinduced electron transfer and semiconducting capabilities. PMID- 20835466 TI - Substantial exchange coupling for {Mo-NCS-M} combination: illustration for 1-D [{Mo(NCS)6}{NiL}2(NCS)]n. AB - An antiferromagnetic interaction of J = -51 cm(-1) has been obtained in a NCS bridged {Mo(III)-Ni} compound (i.e. [{Mo(NCS)(6)}{NiL}(2)(NCS)](n)), a value twice as large as for the homologous {Cr(III)-Ni} derivative. The DFT calculated spin distribution on {Mo(NCS)(6)}(3-) reveals noticeable spin on the S atoms. PMID- 20835467 TI - Flavin-cyclodextrin conjugates as catalysts of enantioselective sulfoxidations with hydrogen peroxide in aqueous media. AB - beta-Cyclodextrin-flavin conjugates are highly efficient catalysts for the sulfoxidation of methyl phenyl sulfides with hydrogen peroxide in neat aqueous media operating at loadings down to 0.2 mol% and allowing for enantioselectivities up to 80% ee. PMID- 20835468 TI - Enzyme immobilisation on self-organised nanopatterned electrode surfaces. AB - A new method is described for immobilisation of enzymes on polymer-coated Pt islands. These islands are deposited on top of a SAM-covered Au(111) electrode by a combination of electroless and electrochemical deposition, which allows for a variation of island size and distance between the islands. Here we describe the immobilisation of pyranose-2-oxidase (P2Ox) and the catalytic response to D glucose on such a nanopatterned surface, which provides optimum access to the active centres of the enzyme. PMID- 20835469 TI - Ultramicroelectrode voltammetry and scanning electrochemical microscopy in room temperature ionic liquid electrolytes. AB - The high viscosity and unusual properties of room temperature ionic liquids (RTILs) present a number of challenges when performing steady-state voltammetry and scanning electrochemical microscopy in RTILs. These include difficulties in recording steady-state currents at ultramicroelectrode surfaces due to low diffusion coefficients of redox species and problems associated with unequal diffusion coefficients of oxidised and reduced species in RTILs. In this tutorial review, we highlight the recent progress in the use of RTILs as electrolytes for ultramicroelectrode voltammetry and SECM. We describe the basic principles of ultramicroelectrode voltammetry and SECM and, using examples from the recent literature, we discuss the conditions that must be met to perform steady-state voltammetry and SECM measurements in RTILs. Finally, we briefly discuss the electrochemical insights that can be obtained from such measurements. PMID- 20835470 TI - Intramolecular light induced activation of a Salen-Mn(III) complex by a ruthenium photosensitizer. AB - We have designed a molecular system consisting of a heteroleptic [Ru(bpy)(2)L](2+) chromophore covalently linked to a Mn(III)-Salen unit. We demonstrate the light induced oxidation of the Mn(III) center in this putative photo-catalyst assembly to a Mn(IV) high spin intermediate. Both oxidation states have been characterized by transient absorption and EPR techniques. PMID- 20835471 TI - Catalytic enantioselective synthesis of P-stereogenic compounds. AB - Catalytic enantioselective strategies have become synthetically useful to access P-stereogenic phosphines. To date, enantioselective desymmetrisations and dynamic kinetic resolutions dominate the field. Desymmetrisation strategies do not necessarily require the formation of a P-carbon or P-heteroatom bond. This approach has been validated with variable levels of success using organocatalysed asymmetric deprotonation (chiral diamine) or methylation (phase transfer catalysis), enzyme-mediated esterification, rhodium catalysed [2+2+2] cycloadditions and more recently molybdenum-based ring closing metathesis. The dynamic kinetic resolution of racemic P-templates relying on a P-C bond-forming event has been the object of extensive investigations, which have culminated with the arylation and alkylation (benzylation) of equilibrating diastereomeric palladium, platinum or ruthenium phosphido complexes. Although all these routes allow access to a myriad of highly interesting P-stereogenic compounds, the level of enantiocontrol is substrate- and reactant-dependent. Pleasingly, ee's up to 98% were obtained on selected systems. PMID- 20835472 TI - Isoquinoline-based chiral monodentate N-heterocyclic carbenes. AB - C(1)-symmetric isoquinoline-based chiral diaminocarbene ligands (MIQ) have been developed to block three quadrants of the metal coordination sphere, complementing C(2)-symmetric biisoquinoline-based ligands (BIQ). MIQ-Cu complexes catalyzed conjugate borylation of various alpha,beta-unsaturated amides in good yields (82-99%) and enantioselectivities (75-87% ee). PMID- 20835473 TI - Optically active liquid-crystalline fullerodendrimers from enantiomerically pure fulleropyrrolidines. AB - A synthetic methodology based on the 1,3-dipolar cycloaddition reaction was developed to design enantiomerically pure liquid-crystalline fullerodendrimers. PMID- 20835474 TI - A photoreactive crystalline quasiracemate. AB - Rationally designed racemic and quasiracemic sulfonamidecinnamic acids assemble to give hydrogen-bonded dimers with coplanar alignment of neighboring olefins. The quasiracemate phase contains near inversion-related motifs with chemically distinct components forming supramolecular heterodimers that undergo asymmetric photodimerization. PMID- 20835475 TI - Ligand-mediated self-assembly of polymer-enveloped gold nanoparticle chains and networks. AB - We demonstrate a universal approach to assemble gold nanoparticles (AuNPs) into ordered robust nanostructures. Colloidal AuNPs are partially coated by thiol containing ligands and then destabilised into anisotropic superstructures. In situ polymerization of the surface attached ligands produces enveloped nanoparticle networks with retained nanoplasmonic properties and enhanced stability. PMID- 20835476 TI - Principles and test methods for the determination of the activity of photocatalytic materials and their application to modified building materials. AB - Photocatalysts and photocatalytically modified materials based on titanium dioxide are used in a wide range of applications. Modified building materials are interesting for further research activities. These materials should be used as a substrate for photocatalysts to degrade a great variety of organic and inorganic pollutants like NO etc. Therefore methods to analyse the activity of these materials are necessary. Some national and international standards deal with photocatalytic degradation of different chemicals. However building materials show a different behaviour because pores and pH-values are not within their scope. Some standards and concepts were tested with building materials. A short overview of standards is given and some measurements are shown. PMID- 20835477 TI - Inhibitor screening of protein kinases using MALDI-TOF MS combined with separation and enrichment of phosphopeptides by TiO2 nanoparticle deposited capillary column. AB - A MALDI-TOF mass spectrometric method for rapid screening of protein tyrosine kinase (PTK) inhibitors has been developed. To circumvent the ion suppression of phosphorylated substrate peptides caused by the presence of high abundant non phosphorylated peptides in the enzymatic reaction mixtures, a separation and enrichment process of the phosphorylated peptides from complex mixtures was carried out by using an in-house fabricated TiO(2) nanoparticle-coated capillary column prior to the MS analysis. With a synthetic phosphopeptide (DAIpYAAPFAKKK), of which the sequence is similar to that of the substrate (EAIYAAPFAKKK) of the Abelson tyrosine kinase (Abl), as the internal standard, the signal ratio of the phosphorylated substrate to the standard detected by MALDI-TOF MS is linearly correlated with the molar ratio of the two phosphopeptides over the range of 0.3 to 3 with r(2) = 0.99. We validated the MS method by determining the IC(50) value of imatinib, an Abl inhibitor for clinical treatment of chronic myelogenous leukaemia (CML). The obtained IC(50) value (234 nM) is consistent with that determined by ELISA (291 nM). Then, six analogues of imatinib synthesized in our laboratory were screened using the method, giving rise to inhibitory potential results which are in good agreement with the docking analysis data. The developed method is sensitive, operationally simple, does not require isotope-labelling and is cost/time effective, providing an alterative method for rapid screening of PTK inhibitors as therapeutic agents for tumours. PMID- 20835478 TI - Long-lived emissive intra-ligand triplet excited states (3IL): next generation luminescent oxygen sensing scheme and a case study with red phosphorescent diimine Pt(II) bis(acetylide) complexes containing ethynylated naphthalimide or pyrene subunits. AB - The long-lived room temperature (RT) intra-ligand phosphorescence ((3)IL) of dbbpy Pt(II) bis(acetylide) (dbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine) complexes Pt-1 (lambda(em) = 629 nm, tau = 118 MUs, quantum yield phi = 17.5%) and Pt-3 (lambda(em) = 658 nm, tau = 73.6 MUs, phi = 2.1%) (dbbpy = 4,4'-di-tert butyl-2,2'-bipyridine), containing naphthalimide (NI) and pyrene subunits, respectively, were used for enhanced luminescent oxygen sensing, compared to the model complex dbbpyPt (bisphenylacetylide) (Pt-2, lambda(em) = 559 nm, tau = 0.7 MUs, phi = 49.6%) with the normal (3)MLCT excited state (metal-to-ligand-charge transfer). The luminescent lifetimes of Pt-1 and Pt-3 are greatly extended by 168 fold and 105-fold, respectively, when compared to that of Pt-2. The (3)IL features of the photoluminescence of Pt-1 and Pt-3 are supported by DFT/TDDFT calculations, which indicated a NI localized triplet excited state but a normal (3)MLCT/(3)LLCT excited state for Pt-2. The luminescent oxygen sensing properties of the complexes in solution as well as in polymer films were studied. In polymer films, the O(2) sensitivity of Pt-1 (quenching constant K(SV) = 0.085 Torr(-1)) and Pt-3 (K(SV) = 0.062 Torr(-1)) is 70-fold and 50-fold of Pt-2 (K(SV) = 0.0012 Torr(-1)), respectively. PMID- 20835479 TI - Synthesis and upconversion luminescence of BaY2F8:Yb3+/Er3+ nanobelts. AB - BaY(2)F(8):Yb(3+)/Er(3+) nanobelts were prepared with oleic acid as capping ligand. Under 980 nm excitation, the (2)H(9/2)->(4)I(15/2), (4)F(7/2) >(4)I(15/2), (2)H(11/2)->(4)I(15/2), (4)S(3/2)->(4)I(15/2), and (4)F(9/2) >(4)I(15/2) transitions were observed. The intensity ratio of (2)H(11/2)/(4)S(3/2)->(4)I(15/2) to (4)F(9/2)->(4)I(15/2) and (2)H(11/2) >(4)I(15/2) to (4)S(3/2)->(4)I(15/2) increased with increasing excitation power. PMID- 20835480 TI - Novel square pyramidal iron(III) complexes of linear tetradentate bis(phenolate) ligands as structural and reactive models for intradiol-cleaving 3,4-PCD enzymes: Quinone formation vs. intradiol cleavage. AB - The iron(iii) complexes of the bis(phenolate) ligands 1,4-bis(2-hydroxy-4-methyl benzyl)-1,4-diazepane H(2)(L1), 1,4-bis(2-hydroxy-4-nitrobenzyl)-1,4-diazepane H(2)(L2), 1,4-bis(2-hydroxy-3,5-dimethylbenzyl)-1,4-diazepane H(2)(L3) and 1,4 bis(2-hydroxy-3,5-di-tert-butylbenzyl)-1,4-diazepane H(2)(L4) have been isolated and studied as structural and functional models for 3,4-PCD enzymes. The complexes [Fe(L1)Cl] 1, [Fe(L2)(H(2)O)Cl] 2, [Fe(L3)Cl] 3 and [Fe(L4)Cl] 4 have been characterized using ESI-MS, elemental analysis, and absorption spectral and electrochemical methods. The single crystal X-ray structure of 3 contains the FeN(2)O(2)Cl chromophore with a novel square pyramidal (tau, 0.20) coordination geometry. The Fe-O-C bond angle (135.5 degrees ) and Fe-O bond length (1.855 A) are very close to the Fe-O-C bond angles (133, 148 degrees ) and Fe-O(tyrosinate) bond distances (1.81, 1.91 A) in 3,4-PCD enzyme. All the complexes exhibit two intense absorption bands in the ranges 335-383 and 493-541 nm, which are assigned respectively to phenolate (ppi) -> Fe(iii) (dsigma*) and phenolate (ppi) -> Fe(iii) (dpi*) LMCT transitions. The Fe(iii)/Fe(ii) redox potentials of 1, 3 and 4 (E(1/2), -0.882--1.010 V) are more negative than that of 2 (E(1/2), -0.577 V) due to the presence of two electron-withdrawing p-nitrophenolate moieties in the latter enhancing the Lewis acidity of the iron(iii) center. Upon adding H(2)DBC pretreated with two equivalents of Et(3)N to the iron(iii) complexes, two catecholate-to-iron(iii) LMCT bands (656, epsilon, 1030; 515 nm, epsilon, 1330 M( 1) cm(-1)) are observed for 2; however, interestingly, an intense catecholate-to iron(iii) LMCT band (530-541 nm) is observed for 1, 3 and 4 apart from a high intensity band in the range 451-462 nm. The adducts [Fe(L)(DBC)](-) generated from 1-4in situ in DMF/Et(3)N solution react with dioxygen to afford almost exclusively the simple two-electron oxidation product 3,5-di-tert butylbenzoquinone (DBQ), which is discerned from the appearance and increase in intensity of the electronic spectral band around 400 nm, and smaller amounts of cleavage products. Interestingly, in DMF/piperidine the amount of quinone product decreases and those of the cleavage products increase illustrating that the stronger base piperidine enhances the concentration of the catecholate adduct. The rates of both dioxygenation and quinone formation observed in DMF/Et(3)N solution vary in the order 1 > 3 > 4 < 2 suggesting that the ligand steric hindrance to molecular oxygen attack, the Lewis acidity of the iron(iii) center and the ability of the complexes to rearrange the Fe-O phenolate bonds to accommodate the catecholate substrate dictate the extent of interaction of the complexes with substrate and hence determine the rates of reactions. This is in line with the observation of DBSQ/H(2)DBC reduction wave for the adduct [Fe(L2)(DBC)](-) at a potential (E(1/2): -0.285 V) more positive than those for the adducts of 1, 3 and 4 (E(1/2): -0.522 to -0.645 V). PMID- 20835481 TI - Calcium phosphate growth beneath a polycationic monolayer at the air-water interface: effects of oscillating surface pressure on mineralization. AB - The self-assembly of the amphiphilic block copolymer poly(butadiene)-block-poly[2 (dimethylamino)ethyl methacrylate] at the air-water interface and the mineralization of the monolayers with calcium phosphate was investigated at different pH values. As expected for polyelectrolytes, the subphase pH strongly affects the monolayer properties. The focus of the current study, however, is on the effect of an oscillating (instead of a static) polymer monolayer on calcium phosphate mineralization. Monitoring of the surface pressure vs. mineralization time shows that the monolayer is quite stable if the mineralization is performed at pH 8. In contrast, the monolayer at pH 5 shows a measurable decrease of the surface pressure already after ca. 2 h of mineralization. Transmission electron microscopy reveals that mineralization at low pH under constant oscillation leads to small particles, which are arranged in circular features and larger entities with holes of ca. 200 nm. The larger features with the holes disappear as the mineralization is continued in favor of the smaller particles. These grow with time and form necklace-like architectures of spherical particles with a uniform diameter. In contrast, mineralization at pH 8 leads to very uniform particle morphologies already after 2 h. The mineralization products consist of a circular feature with a dark dot in the center. The increasing contrast of the precipitates in the electron micrographs with mineralization time indicates an increasing degree of mineralization vs. reaction time. The study therefore shows that mechanical effects on mineralization at interfaces are quite complex. PMID- 20835482 TI - Recent advances in DNA-based directed assembly on surfaces. AB - In the last decade, "small" and "integrated" have been keywords in the field of device fabrication as the desire to exploit nanoscale phenomena and make electronic, photonic and magnetic arrays has grown. In an effort to improve resolution and control costs, much work has been dedicated to developing alternatives to conventional microfabrication technology. For this purpose, biomolecular assembly and DNA nanotechnology in particular are appealing owing to their inherent size and capacity for molecular recognition. Herein, we review recent achievements in DNA-based directed assembly on substrates. These include novel methods for patterning and depositing nanomaterials on DNA-modified surfaces as well as using synthetic DNA nanostructures such as DNA tiles and origami as templates to direct the assembly of nanoscale components. Particular attention is paid to integrating self-assembly with top-down lithography, and some possible directions for future work are discussed. PMID- 20835483 TI - Stabilization of amorphous calcium carbonate by controlling its particle size. AB - Amorphous calcium carbonate (ACC) nanoparticles of different size are prepared using a flow system. Post-synthesis stabilization with a layer of poly[(alpha,beta)-dl-aspartic acid] leads to stabilization of the ACC, but only for particles <100 nm. Larger and uncoated particles readily convert into the crystalline forms of CaCO3. This shows that ACC is intrinsically stable below 100 nm. PMID- 20835485 TI - One-pot electrodeposition, characterization and photoactivity of stoichiometric copper indium gallium diselenide (CIGS) thin films for solar cells. AB - Herein we report the one-pot electrodeposition of copper indium gallium diselenide, CuIn(1-x)Ga(x)Se(2) (CIGS), thin films as the p-type semiconductor in an ionic liquid medium consisting of choline chloride/urea eutectic mixture known as Reline. The thin films were characterized by scanning electron microscopy with energy dispersive X-ray analysis, transmission electron microscopy, X-ray photoelectron spectroscopy, Raman microspectroscopy, and UV-visible spectroscopy. Based on the results of the characterizations, the electrochemical bath recipe was optimized to obtain stoichiometric CIGS films with x between 0.2 and 0.4. The chemical activity and photoreactivity of the optimized CIGS films were found to be uniform using scanning electrochemical microscopy and scanning photoelectrochemical microscopy. Low-cost stoichiometric CIGS thin films in one pot were successfully fabricated. PMID- 20835484 TI - PbSe nanocrystal growth as nanocubes and nanorods on peptide nanotubes via different directed-assembly pathways. AB - Pb-binding TAR-1 peptides (Ile-Ser-Leu-Leu-His-Ser-Thr) were covalently conjugated on a bolaamphiphile peptide nanotube substrate and the precursors of PbSe were incubated at room temperature. This resulted in the growth of highly crystalline PbSe nanocubes on this biomimetic cylindrical substrate. The growth mechanism to generate nanocubes occurs via the directed self-assembly of nanoparticles and then nanoparticle fusion. The peptide conformation and the cylindrical peptide nanotube substrate play important roles in the mesoscopic crystallization of PbSe nanocubes. Changing the buffer for the peptide immobilization process from 2-(N-morpholino)ethanesulfonic acid to phosphate induces a transformation in the nanocrystal shape from nanocube to nanorods. The conformational change of the TAR-1 peptide on the nanotubes due to the change in the buffer seems to be responsible for aggregating intermediate nanoparticles in different directions for the directed fusion and mesoscopic crystallization of PbSe into the different shapes. PMID- 20835486 TI - Isolation and reactivity of an unusually stable organoselenenyl azide. AB - The stabilities of a series of isolated covalent selenium(II) azides such as [2 [1-(3,5-dimethylphenyl)-2-naphthyl]-4,5-dihydro-4,4-dimethyloxazole]selenium azide (2a), [2-(4,4-dimethyl-2-oxazolinyl)phenyl]selenenyl azide (3a), [o-(2,6 diisopropylphenyl-iminomethinyl)phenyl]selenenyl azide (4a), [o-(R) (methylbenzyliminomethinyl)phenyl]selenenyl azide (5a) and o formylphenylselenenyl azide (6a) are rationalized; also the reactivity of first room temperature stable azide (2a) toward 1,3-cycloaddition has been explored. PMID- 20835487 TI - Engineered photoreceptors as novel optogenetic tools. AB - Cellular processes and indeed the survival of entire organisms crucially depend on precise spatiotemporal coordination of a multitude of molecular events. A new tool in cell biology is denoted "optogenetics" which describes the use of genetically encoded, light-gated proteins, i.e. photoreceptors, which perturb and control cellular and organismal behavior in a spatiotemporally exact manner. Photoreceptors resemble fluorescent reporter proteins such as GFP in being genetically encoded, non-invasive, and applicable to intact cells and organisms. They are explicitly intended to modulate activity; in contrast, fluorescent proteins generally do not disturb the processes under study. Fluorescent proteins have revolutionized cell biology because they allow the monitoring of such processes by imaging techniques that offer superb spatiotemporal resolution and sensitivity. Optogenetics extends these advantages to offer control. The scope of optogenetics has recently been expanded beyond the use of naturally occurring photoreceptors by the biologically-inspired design of engineered (or synthetic) photoreceptors. These photoreceptors are derived by fusion of one or more light absorbing sensor domains with an output or effector domain displaying the activity to be controlled. Here, we focus on the design and application of such engineered photoreceptors. We treat basic signaling principles and discuss the two photosensor classes which are currently most widely used in fusion-based design: LOV domains and phytochromes. Based on these principles, we develop general strategies for the engineering of photoreceptors. Finally, we review recently successful examples of the design and application of engineered photoreceptors. Our perspective provides guidelines for researchers interested in developing and applying novel optogenetic tools. PMID- 20835488 TI - Degradation of dichloroacetic acid in homogeneous aqueous media employing ozone and UVC radiation. AB - A tentative workable mechanism for dichloroacetic acid decomposition (DCA) in aqueous media employing ozone and UVC radiation has been developed. All experiments were made in a homogeneous medium under assured kinetic control regime. Under no circumstances did a headspace exist in the reactor volume. The starting point of the reaction with UVC radiation was always under the prerequisite of a confirmed state of initial equilibrium conditions for the mixture water-ozone-oxygen at 20 degrees C. The explored variables were: (i) DCA initial concentration, (ii) ozone concentration and (iii) fluence rate at the reactor window. The model comprises three parallel reactions: (1) direct photolysis, (2) direct ozonation and (3) ozone + UVC degradation. Complete DCA removal was achieved, and the mass balance, considering DCA disappearance and chloride ion formation, closed within very small error. The combination of ozone and UVC radiation produces a significant amount of hydrogen peroxide as an important reaction by-product. The direct photolysis can be well represented with a six step reaction sequence. The direct ozonation mechanism comprises 22 steps and, with the entire set of kinetic constants completed in this work, it is independent of the reaction pH in the range from 3 to 6.3. Lastly, the associated use of ozone and UVC radiation becomes necessary to consider the existence of radiation absorption by three species, namely DCA, ozone and hydrogen peroxide. The developed system, including the three parallel reactions, led to the proposal of a 37 step reaction mechanism. Finally the reaction kinetics, the mass balances and the radiation field corresponding to this complex system were rigorously modeled and the most significant features of the mathematical representation are briefly described. The simulation results rendered from this model agree very well with the measured experimental data. This outcome will be essential for deriving a complete reactor model that must be appropriate to describe, in the future, the more practical two-phase operating system. PMID- 20835489 TI - Lateral confinement effects on the structural properties of surfactant aggregates: SDS on graphene. AB - The structure of aqueous sodium dodecyl sulfate (SDS) surfactant aggregates formed on small graphene sheets and graphene nanoribbons has been studied using all-atom molecular dynamics simulations. Because the edges of the carbonaceous supports confine laterally the surfactant aggregates, by changing the size of the support (diameter of graphene sheets and width of graphene nanoribbons) it is possible to investigate lateral confinement effects on the aggregate morphology. The results are compared to those available on graphite, with no lateral confinement. Aqueous SDS aggregates were studied on 2.0 nm, 5.0 nm, and 10.0 nm circular graphene sheets and on 2.0 and 5.0 nm wide graphene nanoribbons. For the first time our results show that, because of lateral confinement provided by the graphene edges, SDS yields multiple layers, hemispheres, hemicylinders or multiple hemispheres depending on the graphene size and shape. Results are quantified in terms of morphology of the surfactant aggregates, order parameter of the adsorbed surfactant aggregates, and number of water molecules at contact with the carbonaceous support. PMID- 20835490 TI - Chemistry of anthracene-acetylene oligomers. XVII. Synthesis, structure, and dynamic behavior of 1,8-anthrylene pentamers and hexamers with acetylene linkers. AB - Three types of cyclic oligomers consisting of five or six 1,8-anthrylene units with acetylene linkers were synthesized by macrocyclization of the corresponding acyclic precursors with coupling reactions. DFT calculations at the M05/3-21G level revealed that the pentamers had a relatively rigid structure with strained alkyne carbons. Meanwhile, out of several possible conformers the hexamers preferred to take parallelogram-prism structures due to transannular pi...pi interactions, and conformational interconversions via rotation about the acetylene axes took place rapidly at room temperature. NMR spectra and electronic spectra are discussed on the basis of molecular structures. The enantiomers of the chiral hexamer with one diacetylene linker were resolved by chiral HPLC, and showed optical activity. PMID- 20835491 TI - The application of negative ion electrospray mass spectrometry for the sequencing of underivatized disulfide-containing proteins: insulin and lysozyme. AB - Negative ion electrospray mass spectra of the peptides produced by tryptic and chymotrypsin digests of bovine insulin, and from the tryptic digest of lysozyme identify at least 80% of the sequences of these proteins. In particular, negative ion mass spectrometry identifies and positions disulfide moieties, and is the method of choice for identifying this post-translational modification in these two proteins. Intramolecular disulfide functionality is identified by the fragmentation [(M - H)(-)- H(2)S(2)](-) in a digest peptide, and CID of that fragment anion provides amino acid sequencing information. Digest peptides containing an intermolecular disulfide structure undergo facile and diagnostic cleavages. Each cleavage produces a peptide fragment from which CID MS/MS data provide sequencing information. PMID- 20835492 TI - Agarose droplet microfluidics for highly parallel and efficient single molecule emulsion PCR. AB - An agarose droplet method was developed for highly parallel and efficient single molecule emulsion PCR. The method capitalizes on the unique thermoresponsive sol gel switching property of agarose for highly efficient DNA amplification and amplicon trapping. Uniform agarose solution droplets generated via a microfluidic chip serve as robust and inert nanolitre PCR reactors for single copy DNA molecule amplification. After PCR, agarose droplets are gelated to form agarose beads, trapping all amplicons in each reactor to maintain the monoclonality of each droplet. This method does not require cocapsulation of primer labeled microbeads, allows high throughput generation of uniform droplets and enables high PCR efficiency, making it a promising platform for many single copy genetic studies. PMID- 20835493 TI - A photoswitchable DNA-binding protein based on a truncated GCN4-photoactive yellow protein chimera. AB - Photo-controlled DNA-binding proteins promise to be useful tools for probing complex spatiotemporal patterns of gene expression in living organisms. Here we report a novel photoswitchable DNA-binding protein, GCN4(S)Delta25PYP, based on a truncated GCN4-photoactive yellow protein chimera. In contrast to previously reported designed photoswitchable proteins where DNA binding affinity is enhanced upon irradiation, GCN4(S)Delta25PYP dissociates from DNA when irradiated with blue light. In addition, the rate of thermal relaxation to the ground state, part of the PYP photocycle, is enhanced by DNA binding whereas in previous reported constructs it is slowed. The origins of this reversed photoactivity are analyzed in structural terms. PMID- 20835494 TI - Home health care for the elderly: associated factors and characteristics of access and health care. AB - OBJECTIVE: To assess factors associated with home health care for the elderly and its characteristics based on different care models, the Family Health Strategy and traditional primary care. METHODS: A population-based cross-sectional study was conducted in a representative sample of 1,593 individuals aged >60 years living in the urban area of the city of Bage, Southern Brazil, in 2008. A multistage sampling was carried out. Data was collected during individual interviews about access to services, providers' involvement, users' satisfaction and health status after care. Poisson regression model was used for estimating crude and adjusted prevalence ratios, their related 95% confidence intervals and p-values (Wald test). RESULTS: Home health care was statistically associated with prior history of stroke, signs of dementia and disability in activities of daily living. The family was requested 75% of home care visits. Medical doctors provided most of the care in traditional primary care settings while nursing staff provided most care within the Family Health Strategy. Approximately 78% of the elderly received care within 24 hours after the request and 95% of them positively evaluated the care received. Two thirds of the elderly reported improved health status. CONCLUSIONS: The variables associated with home health care were consistent with fragility indicators included in the Brazilian National Health Policy for the Elderly, reinforcing the role of this strategy for promoting equitable health care to elderly population. Users' satisfaction and the positive impact on their health status confirm home as a setting for providing care. PMID- 20835496 TI - The epidemiologic paradox of low birth weight in Brazil. AB - OBJECTIVE: To examine whether the low birth weight (LBW) paradox exists in Brazil. METHODS: LBW and cesarean section rates between 1995 and 2007 were estimated based on data from SINASC (Brazilian Live Births Database). Infant mortality rates (IMRs) were obtained using an indirect method that correct for underreporting. Schooling information was obtained from census data. Trends in LBW rate were assessed using joinpoint regression models. The correlations between LBW rate and other indicators were graphically assessed by lowess regression and tested using Spearman's rank correlation. RESULTS: In Brazil, LBW rate trends were non-linear and non-significant: the rate dropped from 7.9% in 1995 to 7.7% in 2000, then increased to 8.2% in 2003 and remained nearly steady thereafter at 8.2% in 2007. However, trends varied among Brazilian regions: there were significant increases in the North from 1999 to 2003 (2.7% per year), and in the South (1.0% per year) and Central-West regions (0.6% per year) from 1995 to 2007. For the entire period studied, higher LBW and lower IMRs were seen in more developed compared to less developed regions. In Brazilian States, in 2005, the higher the IMR rate, the lower the LBW rate (p=0.009); the lower the low schooling rate, the lower the LBW rate (p=0.007); the higher the number of neonatal intensive care beds per 1,000 live births, the higher the LBW rate (p=0.036). CONCLUSIONS: The low birth weight paradox was seen in Brazil. LBW rate is increasing in some Brazilian regions. Regional differences in LBW rate seem to be more associated to availability of perinatal care services than underlying social conditions. PMID- 20835495 TI - HIV rapid testing as a key strategy for prevention of mother-to-child transmission in Brazil. AB - OBJECTIVE: To assess the feasibility of HIV rapid testing for pregnant women at maternity hospital admission and of subsequent interventions to reduce perinatal HIV transmission. METHODS: Study based on a convenience sample of women unaware of their HIV serostatus when they were admitted to delivery in public maternity hospitals in Rio de Janeiro and Porto Alegre, Brazil, between March 2000 and April 2002. Women were counseled and tested using the Determine HIV1/2 Rapid Test. HIV infection was confirmed using the Brazilian algorithm for HIV infection diagnosis. In utero transmission of HIV was determined using HIV-DNA-PCR. There were performed descriptive analyses of sociodemographic data, number of previous pregnancies and abortions, number of prenatal care visits, timing of HIV testing, HIV rapid test result, neonatal and mother-to-child transmission interventions, by city studied. RESULTS: HIV prevalence in women was 6.5% (N=1,439) in Porto Alegre and 1.3% (N=3.778) in Rio de Janeiro. In Porto Alegre most of women were tested during labor (88.7%), while in Rio de Janeiro most were tested in the postpartum (67.5%). One hundred and forty-four infants were born to 143 HIV infected women. All newborns but one in each city received at least prophylaxis with oral zidovudine. It was possible to completely avoid newborn exposure to breast milk in 96.8% and 51.1% of the cases in Porto Alegre and Rio de Janeiro, respectively. Injectable intravenous zidovudine was administered during labor to 68.8% and 27.7% newborns in Porto Alegre and Rio de Janeiro, respectively. Among those from whom blood samples were collected within 48 hours of birth, in utero transmission of HIV was confirmed in 4 cases in Rio de Janeiro (4/47) and 6 cases in Porto Alegre (6/79). CONCLUSIONS: The strategy proved feasible in maternity hospitals in Rio de Janeiro and Porto Alegre. Efforts must be taken to maximize HIV testing during labor. There is a need of strong social support to provide this population access to health care services after hospital discharge. PMID- 20835497 TI - Socioeconomic predictors of child diet quality. AB - OBJECTIVE: To develop a diet quality index and to analyze socioeconomic factors associated with low child diet quality. METHODS: A cross-sectional study was performed with a representative sample of 1,282 children aged between seven and ten years, living in the city of Vitoria, Southeastern Brazil, in 2007. Children were randomly selected from 26 public schools and six private schools. Data on socioeconomic characteristics and life habits of children were obtained from a structured questionnaire, sent to homes and preferably completed by mothers. A food frequency questionnaire was created from studies performed with Brazilian children and tested in a public school. An index entitled Indice de Alimentacao do Escolar (ALES School Child Diet Index) was designed to assess diet quality, taking in consideration the nutritional recommendations for the Brazilian population and the habit of having breakfast. The association between diet quality and socioeconomic factors was analyzed using multinomial logistic regression. Adjusted odds ratios and 95% confidence intervals were estimated for the variables that remained in the model. RESULTS: According to the ALES index, approximately 41% of the children studied had low diet quality (boys= 37.7%, girls= 42.7%, p= 0.179). There were no significant differences between sex, age, maternal employment status and living with the mother and diet quality. The variables that remained associated with low diet quality were low maternal level of education (OR= 3.93; 95% CI: 2.58;5.99), father not present in the household (OR= 2.03; 95% CI: 1.68;2.99) and not having lunch at the table (OR= 1.47; 95% CI: 1.12;1.93). CONCLUSIONS: Low maternal level of education increased the probability of a child not consuming a good quality diet, whether due to lack of access to healthy foods and adequate information or poorer ability to discern what is healthy. PMID- 20835498 TI - Mortality prediction model using data from the Hospital Information System. AB - OBJECTIVE: To develop a hospital mortality prediction model based on data from the Hospital Information System of the Brazilian National Health System. METHODS: This was a cross-sectional study using data from 453,515 authorizations for hospital admission relating to 332 hospitals in Rio Grande do Sul, Southern Brazil in the year 2005. From the ratio between observed and expected deaths, the hospitals were ranked in an adjusted manner, and this was compared with the crude ranking of the mortality rate. Logistic regression was used to develop a predictive model for the likelihood of hospital mortality according to sex, age, diagnosis and use of an intensive care unit. Confidence intervals (95%) were obtained for the 206 hospitals with more than 365 hospital admissions per year. RESULTS: An index for the risk of hospital mortality was obtained. Ranking the hospitals using only the crude mortality rate differed from the ranking when it was adjusted according to the predictive likelihood model. Among the 206 hospitals analyzed, 40 of them presented observed mortality that was significantly greater than what was expected, while 58 hospitals presented mortality that was significantly lower than expected. Use of an intensive care unit presented the greatest weight in making up the risk index, followed by age and diagnosis. When the hospitals attended patients with widely differing profiles, the risk adjustment did not result in a definitive indication regarding which provider was best. Among this group of hospitals, those of large size presented greater numbers of deaths than would be expected from the characteristics of the hospital admissions. CONCLUSIONS: The hospital mortality risk index was shown to be an appropriate predictor for calculating the expected death rate, and it can be applied to evaluate hospital performance. It is recommended that, in comparing hospitals, the adjustment using the predictive likelihood model for the risk should be used, with stratification according to hospital size. PMID- 20835499 TI - Geographic expression of AIDS epidemic in Campinas, Southeastern Brazil, between 1980 and 2005. AB - OBJECTIVE: To analyze the spatial distribution of reported AIDS cases in adults and its association with living conditions in the city of Campinas, Southeastern Brazil. METHODS: Data on AIDS cases in men (n=2,945) and women (n=1,230) aged more than 13 years and living in Campinas, recorded in the SINAN (Brazilian Information System for Notifiable Diseases), were used to map the spatial distribution of this disease and the male:female ratio. Maps were constructed for the following periods: from 1980 to 1995, from 1996 to 2000, and from 2001 to 2005. The variables included in the analysis were address, sex and age. A weighted composite index was used to study living and health conditions in the area. Patients' home addresses were geocoded on a cartographic base, after correction and standardization according to a reference database of streets. A generalized additive model was adjusted to analyze the spatial distribution of the ratio of male:female cases in space, in the three study periods. RESULTS: The ratio of male:female cases was higher in areas with better living conditions (central) and around the prison (northwestern), where families of prisoners and former prisoners live temporarily, while this ratio was lower in the city suburbs (southwestern). CONCLUSIONS: The trends towards the AIDS epidemic affecting more women and poorer individuals were confirmed by the decrease in the ratio of male:female cases in the period, particularly in vulnerable and impoverished populations. Geographic information systems and spatial data analysis can be useful for AIDS control and surveillance actions. PMID- 20835500 TI - Atypical case of Mediterranean spotted fever. PMID- 20835501 TI - Bartonellosis diagnosis requires careful evaluation. PMID- 20835502 TI - Pyogenic liver abscess caused by community-acquired multidrug resistance Pseudomonas aeruginosa. PMID- 20835504 TI - The evaluation of bacteriology in perianal abscesses of 81 adult patients. AB - OBJECTIVE: Treatment of perianal abscesses requires prompt surgical drainage and antimicrobial therapy. However, we should encourage the selective use of antimicrobial agents on a case-by-case basis, especially because there is no evidence that uncomplicated perianal abscesses can be safely treated only with drainage. For this reason, it is important to identify the causative organisms; therefore, we accessed the microbiological analysis of these patients. PATIENTS AND METHODS: In this study, 81 consecutive adult patients with perianal abscesses, who presented at a university hospital in Diyarbakir from January 2004 to December 2006, were included. Clinical and laboratory data, and results of microbiological analysis were recorded. RESULTS: All specimens, except seven, yielded bacterial growth. Escherichia coli, Bacteriodes spp., coagulase-negative Staphylococci, and Staphylococcus aureus were the most common isolated organisms. CONCLUSION: In contrast to other investigators, this study demonstrated that aerobic organisms are the predominant isolates in these infections. PMID- 20835503 TI - Towards the complete eradication of mother-to-child HIV/HBV coinfection at Saint Camille Medical Centre in Burkina Faso, Africa. AB - The coinfection of HIV and hepatitis B virus (HBV) and their vertical transmission constitute a public health problem in sub-Saharan countries of Africa. The objectives of this research are: i) identify the pregnant women that are coinfected by HIV and HBV at Saint Camille Medical Centre; ii) use three antiretroviral drugs (zidovudine, nevirapine and lamivudine) to interrupt the vertical transmission of HIV and HBV from infected mothers; and iii) use the PCR technique to diagnose children who are vertically infected by these viruses in order to offer them an early medical assistance. At Saint Camille Medical Centre, 115 pregnant women, aged from 19 to 41 years, were diagnosed as HIV-positive and, among them, 14 coinfected with HBV. They had at least 32 weeks of amenorrhoea and all of them received the HAART, which contained lamivudine. Two to six months after childbirth, the babies underwent PCR diagnosis for HIV and HBV. The results revealed that, among these mothers, 64.4% were housewives, 36.5% were illiterates, and only 1.7% had a university degree. The rate of vertical transmission of HIV and HBV was 0.0% (0/115) and 21.4% (3/14), respectively. The 3 mothers who transmitted the HBV to their children had all HBsAg, HbeAg, and HBV DNA positive. An antiretroviral therapy that in addition to zidovudine and nevirapine includes lamivudine could, as in the present study, block or reduce the vertical transmission in HIV positive pregnant women who are coinfected with HBV. PMID- 20835505 TI - Genetic diversity of human immunodeficiency virus-1 isolates in Parana, Brazil. AB - OBJECTIVE: Because epidemiological data on circulating HIV subtypes among HIV positive patients in the state of Parana were not known until now, the aims of this study were to describe the genetic diversity profile of HIV-1 in treated patients in Parana, Brazil, and report the differences in protease (PR) and reverse transcriptase (RT) mutations in HIV-1 subtypes. PATIENTS AND METHODS: A cross-sectional study was conducted from 2003 to 2006. Plasma viral RNA of 389 patients was extracted and PR and RT genes were polymerase chain reaction amplified and sequenced. Sequences were subtyped and examined for antiretroviral resistance mutations. Data on gender of patient harboring the viruses and past history of antiretroviral treatment were also collected. RESULTS: Most viruses were either subtype B (61.44%) or subtype C (20.57%). Subtype C and F were more frequent in women (p < 0.00). The prevalence of subtypes was similar over the years studied. The most frequent RT mutations in all subtypes were M184V and mutations at codons 215, 41, 103, 67, 219, and 190. Mutations 41L, 210W, 215YF, and 74V were significantly more prevalent on subtype B, and the mutation 106M was significantly more prevalent on subtype C. The most frequent major PI mutations in all subtypes occurred at codons 46, 82, and 90. PR mutations 32I, 46I, and 84V were significantly more prevalent on subtype B. The minor PI mutations on codons 36, 93, and 63 were more prevalent on subtypes F, C, and B, respectively. CONCLUSION: We concluded that the predominant strain of HIV-1 in Parana is subtype B, followed by subtype C. Some mutations at PR and TR had subtype predominance in accordance with other authors' report. PMID- 20835506 TI - Barriers to treatment of hepatitis C in HIV/HCV coinfected adults in Brazil. AB - The objective of this study was to assess the prevalence of barriers to interferon treatment in a population of HIV/HCV coinfected patients. A cross sectional study was conducted at two AIDS Outpatient Clinics in Brazil. The study included all HIV infected patients followed at these institutions from January 2005 to November 2007. Medical records of 2,024 HIV-infected patients were evaluated. The prevalence of anti-HCV positive patients among them was 16.7%. Medical records of HCV/HIV coinfected patients were analyzed. 189 patients with the following characteristics were included in our study: mean age 43 years; male gender 65%; former IDUs (52%); HCV genotype 1 (66.4%); HCV genotype 3 (30.5%); median CD4+ T cell count was 340 cells/mm3. Among 189 patients included in the analyses, only 75 (39.6%) were considered eligible for HCV treatment. The most frequent reasons for non-treatment were: non-compliance during clinical follow-up (31.4%), advanced HIV disease (21.9%), excessive alcohol consumption or active drug use (18.7%), and psychiatric disorders (10.1%). CONCLUSIONS: In Brazil, as in elsewhere, more than half of HIV/HCV coinfected patients (60.4%) have been considered not candidates to received anti-HCV treatment. The main reasons may be deemed questionable: non-adherence, drug abuse, and psychiatric disease. Our results highlight the importance of multidisciplinary teams to optimize the access of coinfected patients to HCV treatment. PMID- 20835507 TI - Microbiological epidemiological history of meningococcal disease in Rio de Janeiro, Brazil. AB - The main objectives of the present study were to investigate the clinical and laboratory features of meningococcal disease in the city of Rio de Janeiro, Brazil, during the overlap of 2 epidemics in the 1990s. We conducted a study of a series of cases of meningococcal disease admitted in a Meningitis Reference Hospital. All clinical isolates available were analyzed by means of microbiological epidemiological markers. In 1990, Neisseria meningitidis serogroup B:4,7:P1.19,15, 1.7,1 sulfadiazine-resistant of the ET-5 complex emerged causing epidemic disease. Despite mass vaccination campaign (VaMengoc B+C(r)), the ET-5 clone remained hyperendemic after the epidemic peaked. In 1993 to 1995, an epidemic of serogroup C belonged to the cluster A4 overlapped, with a significant shift in the age distribution toward older age groups and an increase of sepsis. Serogroup C epidemics are a recurrent problem in Rio de Janeiro, which can be hindered with the introduction of a conjugate vaccine. We hope the data presented here brings useful information to discuss vaccines strategies and early management of suspected cases. PMID- 20835508 TI - Evaluation of procalcitonin and neopterin level in serum of patients with acute bacterial infection. AB - BACKGROUND: Fever as a common presenting complaint in pediatric patients can be due to various causes. Differentiating bacterial infection from other causes is important because the prompt use of antibiotics is critical in bacterial infection. Traditional markers of infection such as BT and WBC count may be unspecific and culture may be late or absent. CRP and Procalcitonin (PCT) have been considered to evaluate the evolution of infections and sepsis in patients presenting with SIRS. Neopterin has also been proposed to aid in the diagnosis of bacterial infection. In this study, we compared the value of the serum PCT, neopterin level, and WBC count for predicting bacterial infection and outcome in children with fever. METHODS: 158 pediatric (2-120-month-old) patients suspected to have acute bacterial infection, based on clinical judgment in which other causes of SIRS were ruled out were included in the study. WBC count with differential was determined and PCT and neopterin levels were measured. RESULTS: PCT level was higher in bacterial infection and patients who were complicated or expired. CONCLUSION: Rapid PCT test is superior to neopterin and WBC count for anticipating bacterial infection, especially in ED where prompt decision making is critical. PMID- 20835509 TI - Metabolic syndrome in HIV-infected patients receiving antiretroviral therapy in Latin America. AB - OBJECTIVE: To evaluate the prevalence of and the associated factors for metabolic syndrome (MS) among Latin American HIV-infected patients receiving antiretroviral therapy (ART) using baseline data from the RAPID II study. METHODS: A longitudinal study to evaluate the metabolic profile, cardiovascular disease (CVD) risk and associated treatment practices to reduce this risk has been conducted in seven Latin American countries (the RAPID II study). Adult HIV patients with at least six months of RT were enrolled. MS was defined following ATP-III criteria. Demographic and anthropometric data, serum biochemical and clinical parameters were compared in patients with and without MS using bivariate and multivariate analysis. RESULTS: A total of 4,010 patients were enrolled, 2,963 (74%) were males. Mean age (SD) was 41.9 (10.0) years. The prevalence of MS was 20.2%. Females had higher prevalence of MS than males (22.7% vs. 19.4%, p = 0.02). MS was driven by high triglycerides, low HDL-cholesterol and high blood pressure (HBP). Patients with MS had higher 10 year CVD risk: 22.2% vs. 7.4%, p < 0.001. Age (OR: 1.05 per year), female gender (OR: 1.29), family history of CVD (OR: 1.28), CD4 cell count (OR: 1.09 per 100 cell increase), and protease inhibitor based-ART (OR: 1.33) correlated with MS in the multivariate analysis. CONCLUSIONS: Prevalence of MS in this setting was similar to that reported from developed countries. MS was driven by high triglycerides, low-HDL and HBP, and it was associated with higher risk of CVD. Traditional risk factors, female gender, immune reconstitution, and protease inhibitor based-ART correlated with MS. PMID- 20835510 TI - The epidemiology of sepsis in a Brazilian teaching hospital. AB - OBJECTIVES: The objective of this study was to estimate disease incidence and mortality rate of sepsis in a tertiary public hospital. METHODS: Patients admitted to the Intensive Care Unit (ICU) in 2004 and 2005 were monitored for sepsis using an observational longitudinal study design. Patients were monitored daily for diagnostic criteria of sepsis, according to ACCP/SCCM Consensus Conference criteria, until either death or hospital discharge. RESULTS: During the study, we analyzed 1,179 patients. Systemic Inflammatory Response Syndrome (SIRS) was present in 1,048 (88.9%) patients on admission, and was associated with infection in 554 (47.0%) patients. Of these, sepsis was diagnosed in 30 (2.5%) patients, while severe sepsis was diagnosed in 269 (22.8%) patients, and septic shock was diagnosed in 255 (21.6%) patients. APACHE II and SOFA scores were higher in septic patients (p < 0.001), and the ensuing mortality rates were 32.8% (IC 95%: 21.6-45.7%) for patients with sepsis, 49.9% (IC 95%: 44.5-55.2%) for severe sepsis, and 72.7% (IC 95%: 68.1-76.9%) for septic shock. CONCLUSIONS: The data from our study revealed a high incidence of sepsis among hospitalized patients. Moreover, sepsis patients had a high rate of mortality. PMID- 20835511 TI - Comparative virulence of Scedosporium species in animal models. AB - Scedosporium species are an emerging opportunist group of fungi that have been found to cause infections in both immunocompetent and non-immunocompetent individuals. The infections are not regularly distributed among different countries of the world either because of improper identification or other geographical reasons. Strange as it may, disseminated systemic infections have only been reported in some specific countries. We used a mouse model of disseminated infection to assess if strains from Nigeria were virulent and compared it to a few other strains from other countries. S. apiospermum isolated from Nigeria were clearly less virulent than those obtained elsewhere. This may be the reason why this group of fungi has not been associated with specific clinical problems in Nigeria in particular and Africa in general. PMID- 20835512 TI - Distribution of filamentous fungi causing invasive fungal disease at the Haematological Unit, Hospital de Clinicas de Porto Alegre, Brazil. AB - Very limited data are available in the literature to elucidate the aetiology of invasive mould infections in Latin America. Here we report that Aspergillus species caused only half of such cases in a cohort study conducted over 21 months in a university hospital in Porto Alegre, Southern Brazil. Fusarium spp. were the second most prevalent moulds (20.7%), followed by Zygomycetes (13.8%). The importance of obtaining local epidemiological data for adequately guiding empirical antifungal therapy is reinforced. PMID- 20835513 TI - Risk factors related to hypertension among patients in a cohort living with HIV/AIDS. AB - INTRODUCTION: Studies disagree as to whether there is a greater prevalence of hypertension among HIV/AIDS patients and the role of antiretroviral therapy. OBJECTIVE: Evaluate the prevalence of hypertension and risk factors in a cohort of HIV-infected patients, with emphasis on antiretroviral therapy. METHOD: Case control study conducted at baseline of a cohort, between June/2007 and December/2008 in Pernambuco/Brazil. Blood pressure was classified as normal, prehypertension, and hypertension. RESULTS: Of 958 patients, 245 (25.6%) had hypertension (cases), 325 (33.9%) had prehypertension, and 388 (40.5%) were normotensive (controls). Comparison between hypertensive and normotensive patients showed that traditional factors, such as age > 40 (OR = 3.06, CI = 1.91 4.97), male gender (OR = 1.85, CI = 1.15-3.01), BMI > 25 (OR = 5.51, CI = 3.36 9.17), and triglycerides > 150 mg/dL (OR = 1.69, CI = 1.05-2.71), were independently associated with hypertension. Duration of antiretroviral therapy and CD4 > 200 cells/mm3 were associated with hypertension in univariate analysis, but did not remain in final model. Type of antiretroviral schema and lipodystrophy showed no association with hypertension. CONCLUSION: Hypertension in HIV/AIDS patients is partially linked to invariable factors, such as age and sex. Efforts should be directed toward controlling reversible factors, particularly excessive weight gain and unsuitable diet. PMID- 20835514 TI - Schistosoma mansoni: a rare cause of tubal infection. AB - S. haematobium is an important cause of urinary schistosomiasis, and symptomatic female genital infection is a common gynecological finding in areas where S. haematobium is prevalent. On the other hand, genital manifestations of intestinal schistosomas as S. mansoni are not frequent or are misdiagnosed. A case of a 40 year-old woman with abnormal uterine bleeding and asymptomatic tubal infection by S. mansoni identified in histological examination is presented. PMID- 20835515 TI - Acute HIV infection with rapid progression to AIDS. AB - Acute HIV infection is rarely recognized as the signs and symptoms are normally unspecific and can persist for days or weeks. The normal HIV course is characterized by a progressive loss of CD4+ cells, which normally leads to severe immunodeficiency after a variable time interval. The mean time from initial infection to development of clinical AIDS is approximately 8-10 years, but it is variable among individuals and depends on a complex interaction between virus and host. Here we describe an extraordinary case of a man who developed Pneumocisits jiroveci pneumonia within one month after sexual exposure to HIV-1, and then presented with 3 consecutive CD4 counts bellow 200 cells/mm3 within 3 months, with no other opportunistic disease. Although antiretroviral therapy (AZT+3TC+ATZ/r) was started, with full adherence of the patient, and genotyping indicating no primary antiretroviral resistance mutations, he required more than six months to have a CD4 restoration to levels above 200 cells/mm3 and 10 months to HIV-RNA to become undetectable. PMID- 20835516 TI - Spontaneous bacterial peritonitis caused by Streptococcus bovis: case report and review of the literature. AB - Spontaneous bacterial peritonitis (SBP) is a frequent and severe complication that occurs in patient with cirrhosis and ascites. It occurs in 10% to 30% of patients admitted to hospital. The organisms that cause SBP are predominantly enteric. Escherichia coli is the most frequent recovered pathogen, and Gram positive bacteria, mainly Staphylococcus spp., are being considered an emerging causative agent of SBP. Streptococcus bovis that may be found as part of the commensal bowel flora in about 10% of healthy adults constitute an uncommon cause of peritonitis that was first reported in 1994. We describe the first case of SBP at the University Hospital of Santa Maria (HUSM) caused by S. bovis, resistant to the antibiotics erythromycin and clindamycin (inducible clindamycin resistance detected by disk diffusion test using the D-zone test). PMID- 20835517 TI - Monoclonal gammopathy associated with visceral leishmaniasis. AB - Monoclonal gammopathy can accompany diverse conditions and is usually benign. It should be distinguished from monoclonal gammopathy of undetermined significance (MGUS) which can rarely turn malignant. Visceral leishmaniasis has only rarely been associated with monoclonal gammopathy. We describe the case of a 55-year-old male who had monoclonal gammopathy associated with visceral leishmanisais, which reversed with stibogluconate therapy. PMID- 20835518 TI - The emerging of the fifth malaria parasite (Plasmodium knowlesi): a public health concern? AB - After examining the most recent scientific evidences, which assessed the role of some malaria plasmodia that have monkeys as natural reservoirs, the authors focus their attention on Plasmodium knowlesi. The infective foci attributable to this last Plasmodium species have been identified during the last decade in Malaysia, in particular in the states of Sarawak and Sabah (Malaysian Borneo), and in the Pahang region (peninsular Malaysia). The significant relevance of molecular biology assays (polymerase chain reaction, or PCR, performed with specific primers for P. knowlesi), is underlined, since the traditional microscopic examination does not offer distinguishing features, especially when the differential diagnosis with Plasmodium malariae is of concern. Furthermore, Plasmodium knowlesi disease may be responsible of fatal cases, since its clinical presentation and course is more severe compared with those caused by P. malariae, paralleling a more elevated parasitemia. The most effective mosquito vector is represented by Anopheles latens; this mosquito is a parasite of both humans and monkeys. Among primates, the natural hosts are Macaca fascicularis, M. nemestina, M. inus, and Saimiri scirea. When remarking the possible severe evolution of P. knowlesi malaria, we underline the importance of an early recognition and a timely management, especially in patients who have their first onset in Western Hospitals, after journeys in Southeast Asian countries, and eventually participated in trekking excursions in the tropical forest. When malaria-like signs and symptoms are present, a timely diagnosis and treatment become crucial. In the light of its emerging epidemiological features, P. knowlesi may be added to the reknown human malaria parasites, whith includes P. vivax, P. ovale, P. malariae, and P. falciparum, as the fifth potential ethiologic agent of human malaria. Over the next few years, it will be mandatory to support an adequate surveillance and epidemiological network. In parallel with epidemiological and health care policy studies, also an accurate appraisal of the clinical features of P. knowlesi-affected patients will be strongly needed, since some preliminary experiences seem to show an increased disease severity, associated with increased parasitemia, in parallel with the progressive increase of inter-human infectious passages of this emerging Plasmodium. PMID- 20835519 TI - Osteomyelitis: a current challenge. AB - Over the last 30 years, the pathogenesis of osteomyelitis has almost been totally elucidated, and many factors responsible for the persistence of this infection have been identified. Numerous antimicrobial agents with distinct spectrums of action, pharmacokinetics, and pharmacodynamics have been used in its treatment. Surgical techniques, including muscle grafts, the Ilizarov technique, and antibiotic bone cements, have been applied. However, bone infections are still a challenge. Despite the importance of isolation and identification of microorganisms to determine the antimicrobial treatment of bone infections, there are few systematic national studies about the etiological profile of these diseases. This article describes the current knowledge of osteomyelitis and summarizes published national data based on the experience of different Orthopedic and Traumatology Services. In general, S. aureus was described as an important etiological agent; however, the difference in design of national studies makes a comparison between the prevalence of bone infection, the associated risk factors, and the different therapeutic approaches difficult. In conclusion, effort is necessary in order to stimulate systematic national studies in different Orthopedics and Traumatology Services to obtain a better consensus on preventive measures and therapies of bone infections. PMID- 20835520 TI - Nasal carriage of methicillin-resistant Staphylococcus aureus in university students. AB - In a study of university students, the percentage nasal carriage of Staphylococcus aureus was 40.8% (102/250). Of the isolates, MIC(50) of methicillin was 0.5 ug/mL and MIC(90) was 1 ug/mL. Six (5.8%) isolates were methicillin-resistant and carried the mecA gene. These results suggest that community-associated methicillin-resistant S. aureus may be spreading in Brazil. PMID- 20835521 TI - Methemoglobinemia and dapsone levels in patients with leprosy. AB - The objective of this work was to determine the methemoglobinemia and correlate with dapsone levels in multibacillary leprosy patients under leprosy multi-drug therapy. Thirty patients with laboratory and clinical diagnosis of multibacillary leprosy were enrolled. Dapsone was analyzed by high performance liquid chromatography and methemoglobinemia by spectrophotometry. The mean dapsone concentrations in male was 1.42 g/mL and in female was 2.42 g/mL. The mean methemoglobin levels in male was 3.09 ug/mL; 191%, and in female was 2.84 +/- 1.67%. No correlations were seen between dapsone levels and methemoglobin in male and female patients. Our results demonstrated that the dosage of dapsone in leprosy treatment does not promote a significant methemoglobinemia. PMID- 20835522 TI - Comparison of a rapid cytomegalovirus pp65 antigenemia assay revealed by immunofluorescence to an in-house assay revealed by immunoperoxidase for diagnosis in solid organ transplant recipient patients. AB - Cytomegalovirus (CMV) antigenemia is still one of the two major assays available for diagnosis and monitoring of CMV infections. A commercial rapid test recently available in Brazil for quantification of human cytomegalovirus pp65 antigenemia revealed by immunofluorescence technique was compared with the original in-house method revealed by immunoperoxidase in patients receiving solid organ transplants. Of 80 blood samples tested for CMV antigenemia, 34 (42.5%) were positive: commercial assay detected 33 (97%) and in-house assay detected 20 (58.8%) samples. The numbers of positive cells in the two assays were different, with a median of 4.5 and 12 positive cells obtained by in-house and commercial kit, respectively. Discrepancies between assays occurred in 15 specimens from patients with low-grade antigenemia (median 6 positive cells). The assay-time was reduced in approximately 50% compared to in-house methodology. In conclusion, besides comparable results obtained for both assays, the commercial antigenemia assay provides more rapid and sensitive results. PMID- 20835524 TI - Change the Qualis criteria! PMID- 20835523 TI - Atypical cutaneous mycobacteriosis caused by Mycobacterium avium complex. PMID- 20835525 TI - Characterization of oral cancer diagnostic delay in the state of Alagoas. AB - Oral cancer in Brazil still presents high levels of incidence and mortality bearing different traits throughout the national territory. In most of the cases the diagnosis is late; however there is a great possibility for cure when treated early on. AIM: to assess factors associated with the late diagnosis of oral cancer in the state of Alagoas. MATERIAL AND METHODS: a prospective cross sectional study was carried out in 74 patients, all of them diagnosed with oral squamous cell carcinoma in a hospital of Alagoas, between July of 2007 and September of 2008. A semi-structured interview was given, obtaining socio demographic data, the type of professional help sought, symptom onset, referrals and tumor clinical stage at the moment of diagnosis. RESULTS: According to the results obtained in this study, the patients usually sought professional medical help, rather than dental help when a lesion in the mouth appeared, being always referred to a specialist by the dentist, in advanced stages of the disease. CONCLUSIONS: This study suggests the need for continued education programs for the population and professionals aiming at the early identification of symptoms of the illness; however needing further studies. PMID- 20835526 TI - Audiological evaluation in workers exposed to noise and pesticide. AB - Noise-induced hearing loss has been studied for many years and today many experts also investigate the synergic action of chemical products, since they can be potentially ototoxic. AIM: to investigate the audiological findings in workers exposed to occupational noise and pesticide and to compare it to data from noise exposed workers. STUDY DESIGN: Clinical retrospective. MATERIAL AND METHOD: individuals that had been exposed to pesticide and noise (group I), and individuals that had been exposed to noise only (group II). RESULTS: The classification of the audiometric findings showed in that group I: 35% had normal hearing thresholds, 53.75% had degree 1 hearing loss and 11.25% had degree 2 hearing loss; and group II had 57.5% of normal hearing, 40% had degree 1 hearing loss and only 2.5% had degree 2 hearing loss. The analysis of the audiometric findings also showed a significant worsening after comparing groups I and II thresholds, in the frequency of 3 kHz on the left ear and 4 kHz on both ears. CONCLUSION: The analysis showed that group I had worse audiometric thresholds compared to group II. PMID- 20835527 TI - Prevalence of 35delG/GJB2 and del (GJB6-D13S1830) mutations in patients with non syndromic deafness from a population of Espirito Santo-Brazil. AB - Mutations in GJB2 gene are the leading cause of deafness in autosomal recessive inheritance, and the 35delG mutation is the most common in many ethnic groups. Besides the 35delG mutation in homozygosis, the mutation is also found in compound heterozygosis, coupled with other mutations in genes GJB2 and GJB6. AIM: To determine the prevalence of 35delG/GJB2 and del (GJB6-D13S1830) mutations in patients with sensorineural hearing impairment in residents from the Espirito Santo state, Brazil. MATERIALS AND METHODS: 77 unrelated individuals with moderate to profound sensorineural hearing loss were evaluated. The 35delG mutation was studied by PCR / RFLP; and the del (GJB6-D13S1830) mutation was screened by the technique of multiplex PCR. RESULTS: 88.3% had normal genotype for the studied mutations, 1.3% were compound heterozygotes, 3.9% homozygotic for the 35delG mutation, 6.5% heterozygotic for 35delG/GJB2. The frequency of 35delG/GJB2 and del (D13S1830/GJB6) alleles in the sample was 7.8% and 0.65%, respectively. CONCLUSION: The data confirmed the existence of the mutations studied in cases of sensorineural hearing loss in a population from Espirito Santo / Brazil. These findings reinforce the importance of genetic diagnosis, which can provide early treatment for children and genetic counseling for the affected families. PMID- 20835528 TI - Chloral hydrate to study auditory brainstem response. AB - Chloral Hydrate (CH) is a sedative and hypnotic drug used in pediatric procedures owing to the low depressive effect it has on the respiratory and cardiac systems. AIM: To assess the efficacy of the drug in performing ABR and to systematize its use. MATERIALS AND METHODS: A prospective cross-sectional study with 41 children without history of heart or lung disease. The initial dose of CH at 10% was 50 mg/Kg, with a boost dose of 6 mg/Kg administered 30 minutes later in cases in which there was no sedation. Drug effectiveness was established by sleep induction by 1 hour after the administration of the initial dose. Sleep occurrence was correlated with doses (50 mg or 56 mg/Kg), age, weight and gender. RESULTS: All the 41 children who participated in the study took 50 mg/kg of the agent and 23 of them slept within 30 minutes, 2 had respiratory complications, 16 had the 6 mg/Kg boost dose and 13 fell asleep after 30 minutes. The 56 mg/kg dose presented a statistically significant effect on sleep induction (p<0.05) when compared to the 50mg/kg dose. CONCLUSION: CH produced a satisfactory effect with 50 mg/Kg dose plus 6 mg/kg up to one hour after administration. Complications can occur regardless of the dose used. PMID- 20835529 TI - Long-term evaluation in aesthetic rhinoplasty in an academic referral center. AB - Plastic surgery is based on improving esthetic for the patient. In most services, the surgery outcome is evaluated in a subjective manner. AIM: to objectively assess the degree of patient satisfaction one year after rhinoplasty using the Rhinoplasty Outcome Evaluation questionnaire at a referral academic center. MATERIALS AND METHODS: 69 patients operated in the otorhinolaryngology service were selected. The patients were operated upon by third year residents during the period from January to December 2007 and answered the questionnaire translated by the authors of this study. RESULTS: we obtained a mean value of 73.25% of satisfaction for primary rhinoplasty and a mean value of 72.02% of satisfaction for secondary rhinoplasty. CONCLUSION: the level of satisfaction presented by the patients was considered to be very good. PMID- 20835531 TI - Auditory results from cochlear implants in elderly people. AB - According to data from the Brazilian Institute of Geography and Statistics, the elderly population grew 47.8% in the last decade in Brazil. A portion of this population has severe and/or profound hearing loss and do not benefit from conventional hearing aids. Thus, the use of cochlear implant is required. AIM: To analyze the benefits of cochlear implants in the elderly based on the comparison of primary auditory thresholds before and after the operation, discrimination of sentences in speech and in talking on the telephone. METHODOLOGY: Retrospective cohort study, analyzing medical records from patients aged over 60 years, users of cochlear implant for at least 1 year. RESULTS: Fourteen medical records were analyzed. Mean age of patients was 63.07 years. The mean pure tone thresholds between 500Hz, 1kHz, 2kHz and 4kHz before the implantation was 113dBHL. None of the patients, before operation, could discriminate sentences in open sets and only 3 scored 17% in closed sets sentence recognition. After one year of implantation, the mean sound field thresholds reached 34dBHL, and open set sentences recognition of 93.57%, while 71% of the patients had become able to have a conversation on the telephone. CONCLUSION: The elderly users of cochlear implant showed important outcomes, with significant improvement in understanding in the open set and in using the telephone. PMID- 20835530 TI - Nasal septal perforation closure with bacterial cellulose in rabbits. AB - Alloplastic materials can be used together with tissue and structure to close nasal septal perforation. AIM: to test cellulose use in the closure of septal perforation in rabbits and to compare fibrosis, inflammation, vascular congestion and graft integrity. MATERIALS AND METHODS: Fifteen rabbits. The rabbits were divided into two groups: CONTROL: Five rabbits and Bionext and fibrin glue Tissucol: Ten rabbits. Septal perforations were done in all of them. In the Bionext group the closure was performed with the placement of cellulose. RESULTS: Two rabbits died in the first week. Cellulose group: 2 closures without the cellulose in between the septum membrane and in 4 cases the graft stood in the middle of the perforation locked in place by the edges. No closure in the control group. CONCLUSION: There was no closure of the perforation of the nasal septum with the graft between the septum membranes. There was no statistically significant difference concerning acute inflammation, vascular congestion and fibrosis between the 2 groups. In cases in which the graft remained in place, there was no change in its integrity. It may be used as a substructure for re epithelization of the perforation edges. PMID- 20835532 TI - Pop-rock musicians: assessment of their satisfaction provided by hearing protectors. AB - Pop-rock musicians are at risk of developing hearing loss and other symptoms related to amplified music. AIM: The aim of the present study was to assess the satisfaction provided by the use of hearing protection in pop-rock musicians. STUDY DESIGN: Contemporary cohort study. MATERIALS AND METHODS: A study of 23 male pop-rock musicians, aged between 25 to 45 years. After audiological evaluation (pure tone audiometry, middle ear analysis, TEOAE and DPOAE) hearing protective devices were provided to be used for three months. After that musicians answered a satisfaction assessment questionnaire. RESULTS: The prevalence of hearing loss was of 21.7%. The most common complaints about the hearing protectors were: autophonia, pressure in the ears, interference in high frequencies perception and full time use of the hearing protector during concerts. There was a positive correlation between a reduction in tinnitus after the use of the HPD with the following complaints: tinnitus after beginning the career (p= 0.044), discomfort with the sound intensity in the work place (p= 0.009) and intolerance to loud sound (p= 0.029). CONCLUSIONS: There was a high prevalence of hearing loss and a positive tendency towards the use of the ear protector device among the sample population. PMID- 20835533 TI - Speech recognition according to the length of hearing aid use. AB - The use of hearing aids can provide plasticity to the hearing system as well as improve speech recognition as time goes by. AIM: To compare the influence of the length of hearing aid use on the benefit obtained with the hearing aids in adults and the elderly, new hearing aids users. MATERIALS AND METHODS: Prospective study with 40 individuals with mild to moderate-severe sensorineural hearing loss, gathered in 2 groups: Adults Group--13 people aged between 28 and 59 years old; and Elderly Group--27 people aged between 61 and 78 years old. These people were assessed 14 and 90 days after hearing aid fitting. Sentence recognition threshold in silence and under noise as well as the percentage indexes of sentences recognition in silence and under noise were obtained. RESULTS: The comparison between values obtained after 14 and 90 days of hearing aid use did not show statistically significant differences. When comparing values between the groups, no statistically significant difference was observed either. CONCLUSION: We did not find influences of the length of hearing aid use and the benefit obtained from using them; the results achieved by adults and the elderly were similar. PMID- 20835534 TI - Laryngeal and vocal analysis in bulimic patients. AB - Bulimia is an eating disorder classified as a mental disorder according to DSM IV. AIMS: The aim of the study was to evaluate vocal and laryngeal abnormalities in patients with bulimia compared to a control group. MATERIALS & METHODS: Study control group. Twenty-two women were evaluated, with an age range of 18 to 34 years old. Eleven diagnosed with purging bulimia and 11 in the control group. Both groups underwent an otolaryngological, perception and acoustic evaluation. The statistic analysis was done through a chi-square test and a Kruskall-Wallis non-parametric test, considering 5% as significance level. RESULTS: The bulimic group presented a higher prevalence of laryngeal abnormalities compared to the control group (p=0.000). The group with bulimia had higher GRBSI values (p=0.000) and A (p=0.022) of the GRBASI scale. The results of vocal acoustics analysis of the jitter, shimmer, PPQ and APQ were higher in the bulimic group (p=0.033). No statistical significance difference in the fundamental frequency and NHR were found between both groups. CONCLUSION: the bulimic patients in this study presented more laryngeal, acoustics and perception evaluation disorders when compared to a control group. PMID- 20835535 TI - Audiologic evaluation in patients with acquired hypothyroidism. AB - Hearing loss in hypothyroidism has been reported by many authors but its pathophysiology is unclear. AIMS: to study the audiological evaluation of patients with acquired hypothyroidism. MATERIALS AND METHODS: two groups were included: a hypothyroidism group (HG, n-30), and a control group (CG, n-30). Parameters studied: gender, time of hypothyroidism, comorbidities, cochleovestibular symptoms, biochemistry and hormonal exams (TSH, T4), tonal audiometry, TOAEs and BERA. RESULTS: all participants were women, 70% of the HG had Hashimoto thyroiditis, 60% of the HG had had the diagnostic of the hypothyroidism for at least five years. Depression and hypertension were frequent in HG. All HG patients had altered TSH values and 50% had diminished T4 values. Sensorineural hearing loss was detected in 22 ears from the HG and in seven from the CG. BERA was normal in the CG and altered in 10 ears from the HG, showing L-V increase. TOAEs were absent in 12 ears from the HG and in four from the CG. CONCLUSIONS: HG patients had more cochleovestibular symptoms, higher audiometric thresholds, increase in L-V in the BERA and absence or reduction in TOAEs amplitudes. Such alterations were not associated with THS and free T4 levels. PMID- 20835536 TI - Normative study of vocal acoustic parameters from children from 4 to 12 years of age without vocal symptoms: a pilot study. AB - Acoustic vocal analysis is a simple and fast method that allows to differentiate normal from changed voices. There are few studies that analyze normal acoustic vocal parameters at different age ranges in children. AIMS: To establish normative acoustic parameters of children's voice aged 4 to 12 years. METHODS: Two hundred and forty children were divided into four sub-groups by age: G1 (n 60; 4-5 years), G2 (n-60; 6-7 years), G3 (n-60; 8-9 years) and G4 (n-60; 10-12 years). The children's parents answered a questionnaire and the children were submitted to auditory acuity evaluation (Assessment of Transient Otoacoustic Emissions), acoustic vocal analyses, otorhinolaryngological and videolaryngoscopy exams. RESULTS: The normal values for the acoustic vocal parameters studied were established according to age range and gender. As age increased, there was a decrease of f0 and APQ and an increased in SPI with statistical difference of these parameters. The vocal parameters did not differ between genders until the age of 12. CONCLUSIONS: the characterization of the normative vocal patterns of children is an important reference for future studies. Some of the changes showed a direct relationship between age and a reduction of f0 and of APQ, and increase in SPI, with no difference between genders. PMID- 20835537 TI - A new score for tomographic opacification of paranasal sinuses in children. AB - Many score methods have been created to measure paranasal sinus abnormalities seen under CT scan. Currently, the Lund-Mackay staging system is widely accepted. However, its results may be affected by the development in children. AIM: To assess the precision and accuracy of a new tomography score, called "opacification-development ratio". It translates the percentage of sinus area that is opaque. MATERIALS AND METHODS: A cross-sectional study was prospectively conducted in patients ranging from 0-18 years of age who underwent CT scan assessment of rhinosinusitis. Two independent radiologists examined each scan twice, using both the Lund system and the ratio herein proposed. RESULTS: The opacification-development ratio reached substantial intra and inter-examiner agreement, similar to the Lund system (Kappa > 0.60). Considering the Lund system as the gold standard, the most accurate cut-off point was approximately 15 (sensitivity and specificity approach 90%). There was a strong linear correlation between the two methods (r > 90). CONCLUSIONS: opacification-development ratio is precise and correlates with the Lund system. A cut-off point set at 15 could be used to call a test positive. PMID- 20835538 TI - Intratympanic methylprednisolone as rescue therapy in sudden sensorineural hearing loss. AB - Treatment in sudden sensorineural hearing loss is a contentious issue, today, oral steroids are the most common choice and considered the best treatment option, but the use of intratympanic steroids has become an attractive alternative, especially in cases when systemic therapy fails, or to avoid the side effects of the systemic use of steroids. AIM: To describe the results of intratympanic methylprednisolone in idiopathic sudden sensorineural hearing loss after failure of oral prednisolone. METHODS: In a prospective study fourteen patients with idiopathic sudden sensorineural hearing loss were treated with intratympanic methylprednisolone after failing in the treatment with systemic steroids. Pretreatment and post-treatment audiometric evaluations including pure tone average (PTA) and speech reception thresholds (SRT) were analyzed. RESULTS: Ten from 14 patients treated with intra-tympanic methylprednisolone presented with hearing recovery > 20 dB in PTA or 20% in SRT. CONCLUSION: Three intratympanic injections of methylprednisolone improved pure-tone average or speech discrimination scores for a subset of sudden hearing loss subjects that failed to benefit from oral steroids. PMID- 20835539 TI - The knowledge of gynecologists and pediatricians from Recife public hospitals about high risk factors for deafness. AB - Hearing is one of the main forms of connection between human being and the environment; however, hearing loss is still diagnosed very late in Brazil, which directly interferes with the child's development. AIM: The aim of this study was to check the knowledge pediatricians and gynecologists have about the risk factors for the deafness, the way they acquired such knowledge and parent education about the subject. MATERIALS AND METHODS: We enrolled 119 doctors from three public hospitals of the city of Recife. An interview was applied, before and after the educational campaign on the matter. The study was descriptive, cross-sectional, case series-type. Data analysis was descriptive and inferential. RESULTS: The results showed that only 3 of the 18 hearing loss risk factors listed had gotten answers above 50% in the initial stage of the study and 53.84% of the professionals educated the families. All the answers had increased in the second stage. CONCLUSION: The results emphasize the need to pay more attention to this matter; therefore, primary care is an inexpensive and efficient way to fight hearing loss. PMID- 20835541 TI - Correlation analysis of hearing thresholds, validated questionnaires and psychoacoustic measurements in tinnitus patients. AB - One of the most criticized points in tinnitus clinical studies arise from the lack of consensus about measurement methods. AIM: To evaluate the correlation between audiometric thresholds, pitch matching (PM), minimum masking level (MML), Tinnitus Handicap Inventory (THI) and the Beck Depression Inventory (BDI) in tinnitus patients. STUDY DESIGN: Prospective, cross-sectional. MATERIALS AND METHODS: Subjects were submitted to tonal audiometry, PM and MML for tinnitus. They also filled out the THI and BDI. Data was statistically compared for correlation purposes between audiometric thresholds, psycho-acoustic measures and questionnaires. RESULTS: There was no statistically significant correlation between THI and MML, both in patients with BDI scores under and over 14 points. There was no statistically significant correlation between the worst hearing frequency and PM, as well as between the cut-off frequency and the PM in patients with descending hearing curves in their audiograms. CONCLUSIONS: There is no statistically significant correlation between psycho-acoustic measures (PM and MML), audiometric thresholds, THI and BDI. Tinnitus is a very complex symptom and isolated measures by psycho-acoustic methods; tinnitus and depression questionnaires are not satisfactory. PMID- 20835540 TI - Postoperative complications in implanted patients in the Cochlear Implant Program of Rio Grande do Norte-Brazil. AB - Cochlear implant surgery is regarded as safe for the auditory rehabilitation of individuals suffering from profound/severe hearing loss. Complications may arise from the surgery. The complications of implant cochlear surgery reflect the operation complexity, the skill of the surgical team and the inherent risks of the procedure itself. AIM: To establish and discuss the postoperative complications in implanted patients from the Cochlear Implant Program of Rio Grande do Norte-Brazil. STUDY DESIGN: Retrospective analysis. MATERIALS AND METHODS: This paper discusses the clinical records of 250 patients implanted between August 2000 to December 2008. All patients were implanted by the same surgeon. The postoperative complications were classified in minor as those that resolved with minimal or no treatment and major as those requiring additional surgery or hospitalization. RESULTS: In our sample, 33 patients (13.2%) had postoperative complications. Minor complications affected 20 cases (8.0%), while major complications occurred in 13 cases (5.2%). Hematomas, device failures and infections had the highest clinical relevance. CONCLUSION: This review reinstates the safety of the surgical procedure in relation to the possible occurrence of postoperative complications and emphasizes the need for continuous surgeon education and training. PMID- 20835542 TI - Audiological findings in patients treated with radiotherapy for head and neck tumors. AB - Radiotherapy has been widely used given its increase in the successful outcomes and cure of some cancers. AIM: To evaluate the functionality of the auditory system in patients who underwent radiotherapy treatment for head and neck tumors. MATERIALS AND METHODS: From May 2007 to May 2008, otorhinolaryngological and audiological evaluation (Pure Tone Audiometry (air and bone conduction), Speech Audiometry, Tympanometry, Acoustic Reflex testing and Distortion Product Otoacoustic Emissions) were performed in 19 patients diagnosed with head and neck neoplasia and treated with radiotherapy. Prospective case series study. RESULTS: 10.5% left ears and 26.3% right ears had bilateral hearing loss soon after radiotherapy according to ASHA criteria. CONCLUSIONS: Radiotherapy treatment for head and neck cancer has ototoxic effects. Early programs of auditory rehabilitation should be offered to these patients. PMID- 20835543 TI - Rhabdomyosarcoma of the head and neck: 24 cases and literature review. AB - Rhabdomyosarcoma (RMS) is a malignant tumor of soft tissues, more common in childhood, mainly located in the head and neck. It presents varied clinical and biological behavior and requires individualized management. AIM: To describe information on patients with head and neck RMS diagnosed and treated in a hospital, and to compare them to results in the literature. STUDY DESIGN: Descriptive and retrospective. MATERIALS AND METHODS: A retrospective analysis of data from 24 patients with head and neck rhabdomyosarcoma diagnosed and treated in a hospital from 1994 to 2008. RESULTS: The mean age was 7.79 years. According to gender, 54.17 % were males and 45.83 % were female. All patients underwent chemotherapy (CT), 62.5% of them also underwent radiotherapy (RT) and 16.67% were submitted to surgery. Of the 24 patients, 8 (33.3%) died, 6 (25%) were found free of neoplasia and 2 (8.3%) experienced tumor recurrence. CONCLUSION: The RMS of the head and neck often presents with nonspecific symptoms. Individualized multimodal therapy should be performed for these patients, including surgery, chemotherapy and radiotherapy. PMID- 20835544 TI - Thymus cyst: an option in the differential diagnosis of cervical-mediastinal tumors. PMID- 20835545 TI - Oral vascular leiomyoma with extensive calcification areas. PMID- 20835546 TI - Epithelial-myoepithelial carcinoma in the ventral surface of the tongue. PMID- 20835547 TI - Refractory otitis media as the first manifestation of Wegener's granulomatosis. PMID- 20835551 TI - NDRG1 protein overexpression in malignant thyroid neoplasms. AB - OBJECTIVES: The aim of this study was to examine the expression of the N-myc downstream-regulated gene 1 protein in benign and malignant lesions of the thyroid gland by immunohistochemistry. INTRODUCTION: N-myc downstream-regulated gene 1 encodes a protein whose expression is induced by various stimuli, including cell differentiation, exposure to heavy metals, hypoxia, and DNA damage. Increased N-myc downstream-regulated gene 1 expression has been detected in various types of tumors, but the role of N-myc downstream-regulated gene 1 expression in thyroid lesions remains to be determined. METHODS: A tissue microarray paraffin block containing 265 tissue fragments corresponding to normal thyroid, nodular goiter, follicular adenoma, papillary thyroid carcinoma (classical pattern and follicular variant), follicular carcinoma, and metastases of papillary and follicular thyroid carcinomas were analyzed by immunohistochemistry using a polyclonal anti- N-myc downstream-regulated gene 1 antibody. RESULTS: The immunohistochemical expression of N-myc downstream regulated gene 1 was higher in carcinomas compared to normal thyroid glands and nodular goiters, with higher expression in classical papillary thyroid carcinomas and metastases of thyroid carcinomas (P < 0.001). A combined analysis showed higher immunohistochemical expression of NDRG1 in malignant lesions (classical pattern and follicular variant of papillary thyroid carcinomas, follicular carcinomas, and metastases of thyroid carcinomas) compared to benign thyroid lesions (goiter and follicular adenomas) (P = 0.043). In thyroid carcinomas, N myc downstream-regulated gene 1 expression was significantly correlated with a more advanced TNM stage (P = 0.007) and age, metastasis, tumor extent, and size (AMES) high-risk group (P = 0.012). CONCLUSIONS: Thyroid carcinomas showed increased immunohistochemical N-myc downstream-regulated gene 1 expression compared to normal and benign thyroid lesions and is correlated with more advanced tumor stages. PMID- 20835550 TI - Growth of very low birth weight infants fed with milk from a human milk bank selected according to the caloric and protein value. AB - OBJECTIVE: To describe growth and clinical evolution of very low birth weight infants fed during hospital stay with milk from a human milk bank according to the caloric-protein value. METHOD: Forty very low birth weight infants were included: 10 were fed milk from their own mothers (GI), and 30 were fed human milk bank > 700 cal/L and 2 g/dL of protein. Growth curves were adjusted using nonlinear regression to the measured growth parameters. RESULTS: full enteral diet was reached in 6.3 days by GI and in 10.8 by GII; a weight of 2 kg was reached in 7.3 weeks for GI and in 7.8 for GII. In GI, 3/10 (33.3%) and in GII, 7/30 (23.3%) developed sepsis. Necrotizing enterocolitis did not occur in GI, but in 3/30 (10.0%) in GII. GI presented with urinary calcium > 4 mg/L in 1/10 (10.0%), urinary phosphorus (Pu) <1 mg/L in 10/10 (100%), and Ca/Cr >0.6 ratio in 1/10 (10.0%) of the cases; in GII, no children presented alterations of the urinary calcium or the Ca and Cr ratio, and Pu was <1 mg/L in 19/30 (63.3%). In terms of growth the 50th percentile for GI was a weight gain of 12.1 g/day (GI) vs. 15.8 g/day (GII), a length gain of 0.75 cm/week (GI) vs. 1.02 cm/week (GII), and a head circumference gain of 0.74 cm/week (GI) vs. 0.76 cm/week (GII). CONCLUSIONS: Human milk bank allowed a satisfactory growth and good clinical evolution for very low birth weight infants. PMID- 20835553 TI - Impact of glycemic control on the incidence of acute kidney injury in critically ill patients: a comparison of two strategies using the RIFLE criteria. AB - OBJECTIVE: To compare the renal outcome in patients submitted to two different regimens of glycemic control, using the RIFLE criteria to define acute kidney injury. INTRODUCTION: The impact of intensive insulin therapy on renal function outcome is controversial. The lack of a criterion for AKI definition may play a role on that. METHODS: Included as the subjects were 228 randomly selected, critically ill patients engaged in intensive insulin therapy or in a carbohydrate restrictive strategy. Renal outcome was evaluated through the comparison of the last RIFLE score obtained during the ICU stay and the RIFLE score at admission; the outcome was classified as favorable, stable or unfavorable. RESULTS: The two groups were comparable regarding demographic data. AKI developed in 52% of the patients and was associated with a higher mortality (39.4%) compared with those who did not have AKI (8.2%) (p<0.001). Renal function outcome was comparable between the two groups (p=0.37). We observed a significant correlation between blood glucose levels and the incidence of acute kidney injury (p=0.007). In the multivariate logistic regression analysis, only APACHE III scores higher than 60 were identified as an independent risk factor for unfavorable renal outcome. APACHE III scores>60, acute kidney injury and hypoglycemia were risk factors for mortality. CONCLUSION: Intensive insulin therapy and a carbohydrate-restrictive strategy were comparable regarding the incidence of acute kidney injury evaluated using RIFLE criteria. PMID- 20835552 TI - The effects of volatile induction and maintenance of anesthesia and selective spinal anesthesia on QT interval, QT dispersion, and arrhythmia incidence. AB - OBJECTIVE: The effects of sevoflurane general anesthesia and bupivacaine selective spinal anesthesia on QT dispersion (QTd) and corrected QT (QTc) interval were investigated. METHODS AND MATERIALS: This prospective, randomized, double-blind study was conducted between July and September 2009 in the Urology and General Surgery operating rooms. Forty ASA I-II patients undergoing noncardiac surgery were randomized into two groups: Group R (n=20) and Group V (n=20). In Group R, 5 mg bupivacaine was administered into the spinal space. Anesthesia induction in Group V was established with sevoflurane + 0.1 mg/kg vecuronium using the maximum vital capacity technique. Anesthesia was maintained with 2-3% sevoflurane + 50% N2O/O2 inhalation. All patients were tested with a 24 hour Holter ECG device. QT, QTc, and QTd intervals were measured using 12-lead ECG records at 1 and 3 minutes during preinduction, postinduction, postincision and postextubation periods. Mean arterial pressure (MAP), heart rate and ECG records were measured simultaneously. RESULTS: None of the patients displayed arrhythmia. There was no significant difference between the groups with regard to QTd values (p>0.05). However, QTc was longer in Group V than in Group R after the induction of anesthesia at 3 minutes, after the intubation at 1 and 3 minutes, and after the incision at 1 and 3 minutes. MAP and heart rate were generally higher in Group V (p<0.05). CONCLUSION: Although Volatile Induction and Maintenance of Anesthesia (VIMA) with sevoflurane might prolong the QTc interval and did not result in arrhythmia, selective spinal anesthesia with bupivacaine was not associated with alterations in the QT interval or arrhythmia. PMID- 20835554 TI - Manual for guided home exercises for osteoarthritis of the knee. AB - INTRODUCTION: Physiotherapy is one of the most important components of therapy for osteoarthritis of the knee. The objective of this prospective case series was to assess the efficiency of a guidance manual for patients with osteoarthritis of the knee in relation to pain, range of movement , muscle strength and function, active goniometry, manual strength test and function. METHODS: Thirty-eight adults with osteoarthritis of the knee (>or= 45 years old) who were referred to the physiotherapy service at the university hospital (Santa Casa de Misericordia de Sao Paulo) were studied. Patients received guidance for the practice of specific physical exercises and a manual with instructions on how to perform the exercises at home. They were evaluated for pain, range of movement, muscle strength and function. These evaluations were performed before they received the manual and three months later. Patients were seen monthly regarding improvements in their exercising abilities. RESULTS: The program was effective for improving muscle strength, controlling pain, maintaining range of movement of the knee joint, and reducing functional incapacity. DISCUSSION: A review of the literature showed that there are numerous clinical benefits to the regular practice of physical therapy exercises by patients with osteoarthritis of the knee(s) in a program with appropriate guidance. This study shows that this guidance can be attained at home with the use of a proper manual. CONCLUSIONS: Even when performed at home without constant supervision, the use of the printed manual for orientation makes the exercises for osteoarthritis of the knee beneficial. PMID- 20835555 TI - Comparison of quality of life, satisfaction with surgery and shoulder-arm morbidity in breast cancer survivors submitted to breast-conserving therapy or mastectomy followed by immediate breast reconstruction. AB - OBJECTIVES: This study was designed to compare the prevalence of shoulder-arm morbidity, patient satisfaction with surgery and the quality of life of women submitted to breast-conserving therapy or modified radical mastectomy and immediate breast reconstruction . METHODS: This study was a cross-sectional study of women who underwent breast-conserving therapy (n = 44) or modified radical mastectomy and immediate breast reconstruction (n = 26). Quality of life was evaluated with the SF-36 Health Survey Questionnaire. RESULTS: No differences were found in the prevalence of lymphedema. The movements that were most commonly affected by these procedures were abduction, flexion and external rotation. When the two groups were compared, however, we only found a statistically significant difference for the prevalence of restricted internal rotation, which occurred in 32% of women in the breast-conserving therapy group and 12% of those in the modified radical mastectomy and immediate breast reconstruction group (OR: 7.23; p = 0.03 following adjustment for potential confounding factors). No difference in quality of life or satisfaction with surgery was found between the two groups. CONCLUSIONS: These data suggest that the type of surgery did not affect the occurrence of lymphedema. Breast-conserving therapy, however, increased the risk of shoulder movement limitation. No differences were found between the two surgical techniques with respect to quality of life or satisfaction with surgery. PMID- 20835556 TI - Analysis of cardiac autonomic modulation in obese and eutrophic children. AB - INTRODUCTION: Obesity causes alterations in cardiac autonomic function. However, there are scarce and conflicting data on this function with regard to heart rate variability in obese children. OBJECTIVE: To compare the autonomic function of obese and eutrophic children by analyzing heart rate variability. METHODS: One hundred twenty-one children (57 male and 64 female) aged 8 to 12 years were distributed into two groups based on nutritional status [obese (n = 56) and eutrophic (ideal weight range; n = 65) according to the body mass index reference for gender and age]. For the analysis of heart rate variability, heart rates were recorded beat by beat as the children rested in the dorsal (prone) position for 20 minutes. Heart rate variability analysis was carried out using linear approaches in the domains of frequency and time. Either Student's t-test or the Mann-Whitney U-test was applied to compare variables between groups. Statistical significance was set at 5%. RESULTS: The SDNN, RMSSD, pNN50, SD1, SD2, LF and HF indices in milliseconds squared were lower among the obese children when compared to the eutrophic group. There were no alterations in the SD1/SD2 ratio, LF/HF ratio, LF index or HF index in normalized units. There was a significant difference between groups in the RR interval (R-to-R EKG interval). CONCLUSION: The obese children exhibited modifications in heart rate variability, characterized by a reduction in both sympathetic and parasympathetic activity. These findings stress the need for the early holistic care of obese children to avoid future complications. PMID- 20835557 TI - Clinical evaluation of the flotrac/Vigileo system for continuous cardiac output monitoring in patients undergoing regional anesthesia for elective cesarean section: a pilot study. AB - BACKGROUND: Spinal anesthesia for cesarean delivery may cause severe maternal hypotension and a decrease in cardiac output. Compared to assessment of cardiac output via a pulmonary artery catheter, the FloTrac/Vigileo system may offer a less invasive technique. The aim of this study was to evaluate cardiac output and other hemodynamic measurements made using the FloTrac/Vigileo system in patients undergoing spinal anesthesia for elective cesarean section. METHODS: A prospective study enrolling 10 healthy pregnant women was performed. Hemodynamic parameters were continuously obtained at 15 main points: admission to surgery (two baseline measurements), after preload, after spinal anesthesia administration and 4 time points thereafter (4, 6, 8 and 10 min after anesthesia), at skin and uterine incision, newborn and placental delivery, oxytocin administration, end of surgery, and recovery from anesthesia. Hemodynamic therapy was guided by mean arterial pressure, and vasopressors were used as appropriate to maintain baseline values. A repeated measures ANOVA was used for data analysis. RESULTS: There was a significant increase in heart rate and a decrease of stroke volume and stroke volume index up to 10 min after spinal anesthesia (P < 0.01). Importantly, stroke volume variation increased immediately after newborn delivery (P < 0.001) and returned to basal values at the end of surgery. Further hemodynamic parameters showed no significant changes over time. DISCUSSION AND CONCLUSIONS: No significant hemodynamic effects, except for heart rate and stroke volume changes, were observed in pregnant women managed with preload and vasopressors when undergoing elective cesarean section and spinal anesthesia. PMID- 20835558 TI - The effect of Helicobacter pylori eradication on macrophage migration inhibitory factor, C-reactive protein and fetuin-a levels. AB - OBJECTIVES: To determine the effect of Helicobacter pylori (H. pylori) eradication on blood levels of high-sensitivity C-reactive protein (hs-CRP), macrophage migration inhibitory factor and fetuin-A in patients with dyspepsia who are concurrently infected with H. pylori. METHODS: H.pylori infection was diagnosed based on the 14C urea breath test (UBT) and histology. Lansoprazole 30 mg twice daily, amoxicillin 1 g twice daily, and clarithromycin 500 mg twice daily were given to all infected patients for 14 days; 14C UBT was then re measured. In 30 subjects, migration inhibitory factor, fetuin-A and hs-CRP levels were examined before and after the eradication of H. pylori infection and compared to levels in 30 healthy subjects who tested negative for H. pylori infection. RESULTS: Age and sex distribution were comparable between patients and controls. Migration inhibitory factor and hs-CRP levels were higher, and fetuin-A levels were lower, in H. pylori-infected patients (p<0.05). Following eradication of H. pylori, migration inhibitory factor and hs-CRP levels were significantly decreased, whereas fetuin-A levels were increased. However, eradication of the organism did not change lipid levels (p>0.05). CONCLUSION: These findings suggest that H. pylori eradication reduces the levels of pro-inflammatory cytokines such as migration inhibitory factor and hs-CRP and also results in a significant increase in anti-inflammatory markers such as fetuin-A. PMID- 20835559 TI - The effect of chronic administration of L-arginine on the learning and memory of estradiol-treated ovariectomized rats tested in the morris water maze. AB - OBJECTIVE: The present study was carried out to evaluate the effect of L-arginine on the learning and memory of estradiol-treated ovariectomized (OVX) rats. METHODS: Forty-eight rats were divided into six groups: (1) sham, (2) OVX, (3) sham-Est, (4) OVX-Est, (5) sham-Est-LA, and (6) OVX-Est-LA. The animals of the sham-Est and OVX-Est groups were treated by weekly injection of estradiol valerate (2mg/kg). The sham-Est-LA and OVX-Est-LA groups were treated in the same manner but with an additional daily injection of L-arginine (200mg/kg). After eight weeks, animals of all groups were tested in the Morris water maze. The escape latency and path traveled to reach the platform were compared between groups. RESULTS: Time latency and path length in the OVX group were significantly higher than in the sham group (P<0.05). The OVX-Est group had a significantly shorter traveled path length and time latency compared to the OVX group (P<0.001). Time latency and path length in the sham-Est group was significantly higher than in the sham group (P<0.001). Time latency and path length in the OVX Est-LA group were significantly higher than in the OVX-Est group. CONCLUSIONS: These results allow us to propose that chronic treatment with estradiol enhances the spatial learning and memory of OVX rats, and that long term L-arginine treatment attenuates the effects of improvement produced by estradiol in OVX rats. PMID- 20835561 TI - Non-conventional emergency airway management. PMID- 20835560 TI - Metabolic and infectious pathologies in Brazilian medical literature: a review. AB - OBJECTIVE: This review of original reports on metabolic and infectious diseases that were recently published in Brazilian journals is designed to inform the readership of CLINICS about their content. METHODS: I conducted a search in PubMed for original research articles (clinical or basic research) recently published (2008-2009) by Brazilian medical and biological periodicals. Papers on metabolic pathologies were retrieved by searching for appropriate keywords such as metabolic syndrome and obesity. Papers on infectious disease were obtained by entering 15 different keywords for the most commonly occurring pathologies. Review articles, editorials, letters to the editor, and case reports were manually excluded. Selected titles were then categorized into appropriate sub categories. RESULTS: This search produced a total of 123 articles, which filtered down to 72 articles after eliminating editorials, review articles, letters to the Editor and case reports. Reviewed periodicals were Arquivos Brasileiros de Cardiologia, Arquivos Brasileiros de Endocrinologia e Metabologia, Brazilian Journal of Biological and Medical Research, Brazilian Journal of Infectious Diseases, Jornal de Pediatria, Jornal de Pneumologia, Revista da Associacao Medica Brasileira, Revista da Escola de Enfermagem da Universidade de Sao Paulo, and Sao Paulo Medical Journal. The articles were then briefly summarized. PMID- 20835562 TI - Pseudomyxoma peritonei syndrome 12 months after an intact resection of malignant mucocele of the appendix: a case report. PMID- 20835563 TI - Gastric wall abscess--an uncommon condition treated by an alternative form. PMID- 20835564 TI - Evidence based healthcare: encouraging the adoption of a new philosophy of care. PMID- 20835566 TI - Nanotechnology in ligature-induced periodontitis: protective effect of a doxycycline gel with nanoparticules. AB - OBJECTIVES: The aim of this study was to test the efficacy of a locally applied 8.5% nanostructured doxycycline (DOX) gel in preventing alveolar bone loss in experimental periodontal disease (EPD) in rats by using the tapping mode atomic force microscopy (AFM). MATERIAL AND METHODS: EPD was induced in 24 Wistar rats. Animals were treated with the doxycycline gel topically, immediately after EPD induction, and 3 times a day during 11 days. Four groups (n=6) were formed as follows: Naive group (animals not subjected to EPD nor treated); non-treated (NT) group (animals subjected to EPD, but not treated); vehicle gel (VG) group (animals subjected to EPD and treated with topical gel vehicle); and DOX group (test group): animals subjected to EPD and treated with the 8.5% DOX gel. In order to investigate topographical changes in histological sections, a novel simple method was used for sample preparation, by etching sections from paraffin embedded specimens with xylol. RESULTS: Comparing the AFM images, several grooves were observed on the surface of the alveolar bone and other periodontal structures in the NT and VG groups, with significantly greater depths when compared to the DOX group (p<0.05). CONCLUSIONS: Periodontal structures were brought into high relief confirming to be a simple and cost-effective method for AFM imaging with ultrastructural resolution. The doxycycline gel was able to afford periodontal surface preservation, with flatter grooves. PMID- 20835567 TI - Evaluation of care of dentoalveolar trauma. AB - OBJECTIVES: The aim of this study was to evaluate cases of dental trauma treated at the specialized center of Pontifical Catholic University of Parana, Curitiba, Brazil, during a period of 2 years. MATERIAL AND METHODS: A total of 647 patients were evaluated and treated between 2003 and 2005. Data obtained from each patient were tabulated and analyzed as to gender, age, etiology, time elapsed after the injury, diagnosis (type of trauma), and affected teeth. RESULTS: The results revealed that male individuals aged 7 to 13 years presented the highest prevalence of injury, and falling was the main causal factor. In most cases, the time elapsed between the accident and the first care ranged from 4 to 24 h. A total of 1,747 teeth were affected, with higher incidence of concussion/subluxation and coronal fracture, followed by lateral luxation and avulsion. The permanent maxillary central incisors were the most commonly affected teeth. CONCLUSION: The frequency and causes of dentoalveolar trauma should be investigated for identification of risk groups, treatment demands and costs in order to allow for the establishment of effective preventive measures that can reduce the treatment duration and costs for both patients and oral health services. PMID- 20835565 TI - pH-cycling models for in vitro evaluation of the efficacy of fluoridated dentifrices for caries control: strengths and limitations. AB - Despite a plethora of in situ studies and clinical trials evaluating the efficacy of fluoridated dentifrices on caries control, in vitro pH cycling models are still broadly used because they mimic the dynamics of mineral loss and gain involved in caries formation. This paper critically reviews the current literature on existing pH-cycling models for the in vitro evaluation of the efficacy of fluoridated dentifrices for caries control, focusing on their strengths and limitations. A search was undertaken in the MEDLINE electronic journal database using the keywords "pH-cycling", "demineralization", "remineralization", "in vitro", "fluoride", "dentifrice". The primary outcome was the decrease of demineralization or the increase of remineralization as measured by different methods (e.g.: transverse microradiography) or tooth fluoride uptake. Inclusion of studies, data extraction and quality assessment were undertaken independently and in duplicate by two members of the review team. Disagreements were solved by discussion and consensus or by a third party. One hundred and sixteen studies were included, of which 42 addressed specifically the comparison of dentifrices using different pH-cycling models. The other studies included meta-analysis or reviews, data about the effect of different fluoride sources on de-remineralization, different methods for analysis de remineralization and chemical variables and characteristics of dental hard tissues that might have influence on de-remineralization processes. Generally, the studies presented ability to detect known results established by clinical trials, to demonstrate dose-related responses in the fluoride content of the dentifrices, and to provide repeatability and reproducibility between tests. In order to accomplish these features satisfactorily, it is mandatory to take into account the type of substrate and baseline artificial lesion, as well as the adequate response variables and statistical approaches to be used. This critical review of literature showed that the currently available pH-cycling models are appropriate to detect dose-response and pH-response of fluoride dentifrices, and to evaluate the impact of new active principles on the effect of fluoridated dentifrices, as well as their association with other anti-caries treatments. PMID- 20835568 TI - Bone regeneration in surgically created defects filled with autogenous bone: an epifluorescence microscopy analysis in rats. AB - Although the search for the ideal bone substitute has been the focus of a large number of studies, autogenous bone is still the gold standard for the filling of defects caused by pathologies and traumas, and mainly, for alveolar ridge reconstruction, allowing the titanium implants installation. OBJECTIVES: The aim of this study was to evaluate the dynamics of autogenous bone graft incorporation process to surgically created defects in rat calvaria, using epifluorescence microscopy. MATERIAL AND METHODS: Five adult male rats weighing 200-300 g were used. The animals received two 5-mm-diameter bone defects bilaterally in each parietal bone with a trephine bur under general anesthesia. Two groups of defects were formed: a control group (n=5), in which the defects were filled with blood clot, and a graft group (n=5), in which the defects were filled with autogenous bone block, removed from the contralateral defect. The fluorochromes calcein and alizarin were applied at the 7th and 30th postoperative days, respectively. The animals were killed at 35 days. RESULTS: The mineralization process was more intense in the graft group (32.09%) and occurred mainly between 7 and 30 days, the period labeled by calcein (24.66%). CONCLUSIONS: The fluorochromes showed to be appropriate to label mineralization areas. The interfacial areas between fluorochrome labels are important sources of information about the bone regeneration dynamics. PMID- 20835569 TI - Comparison of hemodynamic effects of lidocaine, prilocaine and mepivacaine solutions without vasoconstrictor in hypertensive patients. AB - OBJECTIVE: Local anesthetic solutions with vasoconstrictors are not contraindicated in hypertensive patients, but due to their hemodynamic effects, local anesthetics without vasoconstrictors are mainly preferred by the clinicians. The aim of this study was to compare hemodynamic effects of three different local anesthetics without vasoconstrictors during tooth extraction in hypertensive patients. MATERIAL AND METHODS: Sixty-five mandibular molars and premolars were extracted in 60 hypertensive patients (29 females and 31 males; mean age: 66.95 +/- 10.87 years; range: 38 to 86 years old). Inferior alveolar and buccal nerve blocks were performed with 2% lidocaine hydrochloride (HCl), 2% prilocaine HCl or 3% mepivacaine HCl without vasoconstrictor. Hemodynamic parameters namely systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), saturation rate (SR), rate pressure product (RPP) and pressure rate quotient (PRQ) were investigated before and at different intervals after anesthetic injection. RESULTS: The hemodynamic effects of the three agents were similar to each other, although some significance was observed for DBP, MAP, RPP and PRQ values in the lidocaine, prilocaine and mepivacaine groups. CONCLUSION: Lidocaine, prilocaine and mepivacaine solutions without vasoconstrictor can be safely used in hypertensive patients. It is advisable that dental practitioners select anesthetic solutions for hypertensive patients considering their cardiovascular effects in order to provide patient comfort and safety. PMID- 20835570 TI - Influence of ferrule preparation with or without glass fiber post on fracture resistance of endodontically treated teeth. AB - OBJECTIVE: This study evaluated the effect of ferrule preparation (Fp) on the fracture resistance of endodontically treated teeth, restored with composite resin cores with or without glass fiber posts. MATERIAL AND METHODS: Forty-four bovine teeth were sectioned 19 or 17 mm (2 mm ferrule) from the apex, endodontically treated and assigned to four groups (n = 11): Group 1: Fp and post; Group 2: Fp and without post; Group 3: without Fp and with post; Group 4: without Fp and without post. All specimens were restored with composite resin core and metal crown. Specimens were subjected to fracture resistance testing in a universal testing machine at a crosshead speed of 0.5 mm/min. The data were analyzed by two-way ANOVA and Tukey's tests (alpha=0.05). RESULTS: The mean fracture resistance values were as follows: Group 1: 573.3 N; Group 2: 552.5 N; Group 3: 275.3 N; Group 4: 258.6 N. Significantly higher fracture resistance was found for the groups with Fp (p<0.001). CONCLUSION: There was no statistically significant interaction between the "Fp" and "post" factors (p = 0.954). The ferrule preparation increased the fracture resistance of endodontically treated teeth. However, the use of glass fiber post showed no significant influence on the fracture resistance. PMID- 20835571 TI - Fixed partial dentures in an up to 8-year follow-up. AB - Information on the longevity of fiber-reinforced composite fixed partial dentures (inlay FPDs) should be considered in the selection of materials, operative techniques and patient instructions related to prognosis and long-term cost effectiveness. OBJECTIVE: This study evaluated the long-term survival of fiber reinforced, adhesively-bonded composite prostheses placed in posterior teeth. MATERIALS AND METHODS: Twenty-one patients that received adhesively bonded polyethylene inlay FPDs in posterior teeth were selected from a private practice dental office and invited to evaluation. Of the eligible 21 patients, 13 (mean age 50.3 +/- 11.5 years) agreed to be enrolled as participants, providing 22 restorations, as several subjects presented more than one inlay FPD. One dentist placed all inlay FPDs using Ribbond as reinforcement and Tetric Ceram/Durafil or Charisma/Renamel composite combinations, according to manufacturer's instructions. Two independent calibrated operators performed the evaluation, using modified USPHS criteria. Survival functions of restorations were analyzed with Kaplan-Meier and Log Rank test (alpha = 0.05). RESULTS: The majority of restorations received A or B scores. Four (18.2%) inlay FPDs fractured among the 22 evaluated. The mean estimate survival rate was 7 years (95% CI: 5.9 to 8.1), and the overall percentage of survival was 81.8%. There were no significant differences (p>0.05) between composite combinations or tooth location considering all clinical aspects evaluated and survival functions. CONCLUSION: Posterior fiber-reinforced fixed partial dentures exhibited acceptable clinical performance after a period up to 8 years. PMID- 20835573 TI - Digital subtraction radiographic analysis of the combination of bioabsorbable membrane and bovine morphogenetic protein pool in human periodontal infrabony defects. AB - OBJECTIVES: This study assessed the bone density gain and its relationship with the periodontal clinical parameters in a case series of a regenerative therapy procedure. MATERIAL AND METHODS: Using a split-mouth study design, 10 pairs of infrabony defects from 15 patients were treated with a pool of bovine bone morphogenetic proteins associated with collagen membrane (test sites) or collagen membrane only (control sites). The periodontal healing was clinically and radiographically monitored for six months. Standardized pre-surgical and 6-month postoperative radiographs were digitized for digital subtraction analysis, which showed relative bone density gain in both groups of 0.034 +/- 0.423 and 0.105 +/- 0.423 in the test and control group, respectively (p>0.05). RESULTS: As regards the area size of bone density change, the influence of the therapy was detected in 2.5 mm2 in the test group and 2 mm2 in the control group (p>0.05). Additionally, no correlation was observed between the favorable clinical results and the bone density gain measured by digital subtraction radiography (p>0.05). CONCLUSIONS: The findings of this study suggest that the clinical benefit of the regenerative therapy observed did not come with significant bone density gains. Long-term evaluation may lead to a different conclusions. PMID- 20835572 TI - Effect of ageing and immersion in different beverages on properties of denture lining materials. AB - OBJECTIVES: To evaluate the color stability and hardness of two denture liners obtained by direct and indirect techniques, after thermal cycling and immersion in beverages that can cause staining of teeth. MATERIAL AND METHODS: Seventy disc shaped specimens (18 x 3 mm) processed by direct (DT) and indirect techniques (IT) were made from Elite soft (n=35) and Kooliner (n=35) denture liners. For each material and technique, 10 specimens were subjected to thermal cycling (3,000 cycles) and 25 specimens were stored in water, coffee, tea, soda and red wine for 36 days. The values of color change, Shore A hardness (Elite soft) and Knoop hardness (Kooliner) were obtained. The data were subjected to ANOVA, Tukey's multiple-comparison test, and Kruskal-Wallis test (P<0.05). RESULTS: The thermal cycling promoted a decrease on hardness of Kooliner regardless of the technique used (Initial: 9.09+/- 1.61; Thermal cycling: 7.77+/- 1.47) and promoted an increase in the hardness in the DT for Elite Soft (Initial: 40.63+/- 1.07; Thermal cycling: 43.53+/- 1.03); hardness of Kooliner (DT: 8.76+/- 0.95; IT: 7.70+/- 1.62) and Elite Soft (DT: 42.75+/- 1.54; IT=39.30+/- 2.31) from the DT suffered an increase after the immersion in the beverages. The thermal cycling promoted color change only for Kooliner in the IT. Immersion in the beverages did not promote color change for Elite in both techniques. The control group of the DT of Kooliner showed a significant color change. Wine and coffee produced the greatest color change in the DT only for Elite Soft when compared to the other beverages. CONCLUSION: The three variation factors promoted alteration on hardness and color of the tested denture lining materials. PMID- 20835574 TI - Influence of sodium hypochlorite and edta on the microtensile bond strength of a self-etching adhesive system. AB - Chemical substances used during biomechanical preparation of root canals can alter the composition of dentin surface and affect the interaction with restorative materials. OBJECTIVE: The purpose of this study was to evaluate the microtensile bond strength (uTBS) of a self-etching adhesive system to dentin irrigated with sodium hypochlorite (NaOCl) and ethylenediaminetetraacetic acid (EDTA). MATERIAL AND METHODS: Thirty human third molars were sectioned 3 mm below the occlusal surface, polished with 600- to 1200-grit silicon carbide papers, and randomly divided into 3 groups: G1 (control): no irrigating solution; G2: 1% NaOCl; and G3: 1% NaOCl followed by the application of 17% EDTA. The specimens received the self-etching adhesive system (XENO III - Dentsply), restored with microhybrid composite resin (Z250 - 3M ESPE), sectioned and trimmed to create 4 hourglass-shaped slabs of each tooth. The slabs were tested in microtensile strength in a universal testing machine (Emic DL 2000) at a crosshead speed of 0.5 mm/min until fracture. The results were analyzed statistically by ANOVA and Newman-Keuls test. RESULTS: Mean uTBS values and standard deviations in MPa were: G1 = 11.89 +/- 4.22; G2 = 19.41 +/- 5.32; G3 = 11.34 +/- 4.73. 1% NaOCl increased the adhesive resistance significantly (p<0.001/F=22.5763). The application of 1% NaOCl/17% EDTA resulted in statistically similar uTBS to the control group. CONCLUSIONS: None of the irrigants affected negatively the uTBS of XENO III to dentin. The use of 1% NaOCl alone resulted in higher bond strength than the other treatments. The combination of 1% NaOCl and 17% EDTA produced similar bond strength to that of untreated dentin. PMID- 20835575 TI - Construction of a copper stepwedge with aluminum equivalent mean gray values. AB - OBJECTIVES: To produce a copper (Cu) stepwedge with aluminum (Al) equivalent mean gray values (MGV). MATERIAL AND METHODS: The thicknesses of Cu steps that were equivalent to those of the Al were formulated using the X-ray attenuation properties of the materials. The Al and fabricated Cu stepwedges were radiographed, but the MGVs of the Cu stepwedge were mismatching to those of the Al. Using a mathematical function to adjust the pixel MGV of Cu stepwedge to those of the Al, new Cu stepwedges were created. In vitro iterations were performed until best approximation to Al was reached. RESULTS: The MGV of the Cu stepwedges fabricated by formularization were different than those of Al (p=0.001). Iteration method led to MGV similar to those of the Al stepwedge (p=0.207). CONCLUSIONS: Construction of a Cu stepwedge according to the basic rules of radiophysic failed to result in a stepwedge with similar radiodensity values to those of Al stepwedge. Further studies may use the formularization method only for prototype Cu wedge production, but consecutive iterations shall be compassed to obtain the best approximation to Al MGV. PMID- 20835576 TI - Class II malocclusion occlusal severity description. AB - OBJECTIVES: It is well known that the efficacy and the efficiency of a Class II malocclusion treatment are aspects closely related to the severity of the dental anteroposterior discrepancy. Even though, sample selection based on cephalometric variables without considering the severity of the occlusal anteroposterior discrepancy is still common in current papers. In some of them, when occlusal parameters are chosen, the severity is often neglected. The purpose of this study is to verify the importance given to the classification of Class II malocclusion, based on the criteria used for sample selection in a great number of papers published in the orthodontic journal with the highest impact factor. MATERIAL AND METHODS: A search was performed in PubMed database for full-text research papers referencing Class II malocclusion in the history of the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO). RESULTS: A total of 359 papers were retrieved, among which only 72 (20.06%) papers described the occlusal severity of the Class II malocclusion sample. In the other 287 (79.94%) papers that did not specify the anteroposterior discrepancy severity, description was considered to be crucial in 159 (55.40%) of them. CONCLUSIONS: Omission in describing the occlusal severity demands a cautious interpretation of 44.29% of the papers retrieved in this study. PMID- 20835578 TI - Effects of folk medicinal plant extract Ankaferd Blood Stopper on early bone healing. AB - OBJECTIVE: Several haemostatic agents are available for clinical use. Ankaferd Blood Stopper (ABS), a mixture of five medicinal plant extracts, has been used historically as a haemostatic agent. The aim of this in vivo study was to investigate the effects of ABS on early bone healing using a rat tibia defect model. MATERIAL AND METHODS: Sixteen male Wistar rats were randomized into two groups of 8 animals each. After deep anesthesia with ketamine, bone defects (3 mm diameter and 2 mm deep) were created in the right and left tibiae of all animals and either treated with 1 cc of ABS (Group 1) or left untreated (Group 2; control). Surgical areas were closed primarily. The animals were sacrificed on the 7th postoperative day and bone samples were collected from the tibias. The samples were examined histopathologically for infection, necrosis, fibrosis, new bone formation and foreign body reaction. The histomorphometric results were analyzed statistically by the chi square test, with the level of significance set at p<0.05. RESULTS: Significant differences were found in both groups in terms of inflammation, necrosis and new bone formation (p=0.001, p=0.0001, p=0.001). No foreign body reaction was observed in the experimental group. ABS application decreased fibrosis in the experimental group, but there were no statistically significant differences from the control group. CONCLUSIONS: Histopathologically, it was observed that the application of ABS decreased the occurrence of inflammation and necrosis, while increasing new bone formation in early bone healing period. Further in vitro and in vivo studies are necessary for evaluating the benefits and possible adverse effects of the application of this herbal product on wound healing. PMID- 20835577 TI - Effect of Aquatine Endodontic Cleanser on smear layer removal in the root canals of ex vivo human teeth. AB - OBJECTIVES: The purpose of this study was to measure and compare the root canal cleanliness and smear layer removal effectiveness of Aquatine Endodontic Cleanser (Aquatine EC) when used as an endodontic irrigating solution in comparison with 6% sodium hypochlorite (NaOCl). MATERIAL AND METHODS: Forty-five human teeth were randomly allocated to five treatment groups; the pulp chamber was accessed, cleaned, and shaped by using ProTaper and ProFile rotary instrumentation to an ISO size #40. The teeth were then processed for scanning electron microscopy, and the root canal cleanliness and removal of smear layer were examined. RESULTS: The most effective removal of smear layer occurred with Aquatine EC and NaOCl, both with a rinse of EDTA. CONCLUSIONS: Aquatine EC appears to be the first hypochlorous acid approved by the FDA to be a possible alternative to the use of NaOCl as an intracanal irrigant. Further research is needed to identify safer and more effective alternatives to the use of NaOCl irrigation in endodontics. PMID- 20835579 TI - Comparison of implant stability after different implant surface treatments in dog bone. AB - OBJECTIVES: The purpose of this investigation was to evaluate the effects of different implant surface treatments on implant stability in dog mandibles. MATERIAL AND METHODS: A total of 30 implants (Dentium Co, Seoul, Korea) were placed in 5 dog mandibles. Bone quality was assessed at each site. Implant stability was evaluated using 2 different methods. An Osstell resonance frequency analyzer (RFA) was used to determine the stability at baseline (day 1), and 3, 6 and 10 weeks after surgery. Animals were euthanized 10 weeks after implant installation. Specimens were obtained and submitted to the laboratory processing. Sections were stained with hematoxylin and eosin for histologic and histomorphometric analyses. All implantation sites in dog mandibles demonstrated bone types II and III. RESULTS AND CONCLUSIONS: All implants showed good primary stability at baseline in terms of insertion torque. The results of this study suggest that surface treatment may have significant effects on biological stability 3 weeks after implant placement. Further studies are needed to confirm these initial observations in poor quality bone. PMID- 20835580 TI - Microleakage in conservative cavities varying the preparation method and surface treatment. AB - OBJECTIVE: To assess microleakage in conservative class V cavities prepared with aluminum-oxide air abrasion or turbine and restored with self-etching or etch-and rinse adhesive systems. MATERIALS AND METHODS: Forty premolars were randomly assigned to 4 groups (I and II: air abrasion; III and IV: turbine) and class V cavities were prepared on the buccal surfaces. Conditioning approaches were: groups I/III - 37% phosphoric acid; groups II/IV - self-priming etchant (Tyrian SPE). Cavities were restored with One Step Plus/Filtek Z250. After finishing, specimens were thermocycled, immersed in 50% silver nitrate, and serially sectioned. Microleakage at the occlusal and cervical interfaces was measured in mm and calculated by a software. Data were subjected to ANOVA and Tukey's test (alpha=0.05). RESULTS: Marginal seal provided by air abrasion was similar to high speed handpiece, except for group I. There was SIGNIFICANT difference between enamel and dentin/cementum margins for to group I and II: air abrasion. The etch and-rinse adhesive system promoted a better marginal seal. At enamel and dentin/cementum margins, the highest microleakage values were found in cavities treated with the self-etching adhesive system. At dentin/cementum margins, high speed handpiece preparations associated with etch-and-rinse system provided the least dye penetration. CONCLUSION: Marginal seal of cavities prepared with aluminum-oxide air abrasion was different from that of conventionally prepared cavities, and the etch-and-rinse system promoted higher marginal seal at both enamel and dentin margins. PMID- 20835581 TI - Detection of selected bacterial species in intraoral sites of patients with chronic periodontitis using multiplex polymerase chain reaction. AB - OBJECTIVE: The aim of this study was to detect the prevalence of selected bacterial species in intraoral sites of patients with chronic periodontitis (CP) using multiplex polymerase chain reaction (PCR). METHODOLOGY: Samples were collected from the tongue dorsum, buccal mucosa, supragingival and subgingival plaque and saliva of 30 patients with untreated CP. Multiplex PCR was used to determine prevalence rates, which were then compared using a chi-square test. Significance level was set at p<0.05. Mean and standard deviation values were used to evaluate variations in prevalence according to site. RESULTS: The prevalence of S. mutans was 70% in saliva; 60% in samples collected from the tongue dorsum; 50% in samples collected from the buccal mucosa; 56.5% in the supragingival plaque; and 53.5% in the subgingival plaque. The prevalence of E. faecalis ranged from 3.5% to 13.5% in all intraoral microenvironment. The highest prevalence of P. gingivalis was found in subgingival plaque (53.5%), and of P. intermedia in supragingival plaque (33.5%), subgingival plaque (30%) and tongue dorsum (33.5%). The prevalence of bacteria did not vary significantly among the intraoral sites. CONCLUSIONS: All studied bacteria were identified in intraoral sites. S. mutans, P. gingivalis and P. intermedia had high prevalence rates, but the prevalence of E. faecalis was low. Multiplex PCR proved to be an adequate method for epidemiological studies. PMID- 20835583 TI - Changes in the tuberculosis profile in Brazil: a new reality? PMID- 20835582 TI - Management of a parotid sialocele in a young patient: case report and literature review. AB - Sialocele is a subcutaneous cavity containing saliva, caused by trauma or infection in the parotid gland parenchyma, laceration of the parotid duct or ductal stenosis with subsequent dilatation. It is characterized by an asymptomatic soft and mobile swelling on the parotid region. Imaging studies are useful and help establishing the diagnosis, such as sialography, ultrasonography, computed tomography and magnetic resonance imaging. This paper describes a recurrent case of a parotid sialocele in a young female patient. She presented a 6 cm x 5 cm swelling on the left parotid region. The ultrasonographic scan of the area revealed a hypoechoic ovoid well defined image suggesting a cyst. A sialography of the left parotid showed a cavitary sialectasia in a panoramic and anteroposterior view. A conservative management was adopted by percutaneous needle aspiration of the swelling, which was useful to provide material for analysis and helped healing. Dentists should be aware of this pathology and the importance in adopting a conservative treatment whenever it is possible. PMID- 20835584 TI - Change the qualis criteria! PMID- 20835585 TI - Prevalence and severity of wheezing in the first year of life. AB - OBJECTIVE: To determine the prevalence and severity of wheezing in infants, using the standardized protocol devised for the "Estudio Internacional de Sibilancias en Lactantes" (EISL, International Study of Wheezing in Infants), as well as to determine the relationship between such wheezing and physician-diagnosed asthma, in the first year of life. METHODS: Between March of 2005 and August of 2006, the EISL questionnaire was administered to the parents or legal guardians of infants undergoing routine procedures or immunization at public primary health care clinics in the southern part of the city of Sao Paulo, Brazil. RESULTS: Our sample comprised 1,014 infants (mean age = 5.0 +/- 3.0 months), 467 (46.0%) of whom had at least one wheezing episode, 270 (26.6%) having three or more such episodes, in their first year of life. The use of inhaled beta2 agonists, inhaled corticosteroids, or antileukotrienes, as well as the occurrence of nocturnal symptoms, difficulty breathing, pneumonia, emergency room visits, and hospitalization due to severe wheezing, was significantly more common among those with recurrent wheezing (p < 0.05). Physician-diagnosed asthma was reported for 35 (7.5%) of the 467 wheezing infants and was found to be associated with the use of inhaled corticosteroids, difficulty breathing during the attacks, and six or more wheezing episodes in the first year of life. However, less than 40% of those infants were treated with inhaled corticosteroids or antileukotrienes. CONCLUSIONS: In this study, the prevalence of wheezing episodes among infants in their first year of life was high and had an early onset. The proportion of infants diagnosed with and treated for asthma was low. PMID- 20835586 TI - Efficacy and safety of two dry-powder inhalers for the administration of mometasone furoate in asthma patients. AB - OBJECTIVE: Mometasone furoate (MF) is a new, potent synthetic inhaled corticosteroid. Worldwide, MF is administered via a dry-powder inhaler that contains multiple doses. As a preparation that would be more cost-effective, single-dose MF capsules were developed in Brazil. The objective of the present study was to evaluate the efficacy and safety of the two inhalers for MF administration in patients with asthma. METHODS: A randomized, multicenter, open label, parallel-group clinical trial involving 74 adult patients with moderate, persistent asthma who were randomized into two groups to receive approximately 400 ug of MF once a day for 60 days, either via the multiple-dose inhaler or via the newly developed single-dose inhaler. RESULTS: No significant differences were observed between the two groups regarding the primary endpoints (FEV1 and rescue medication use) or the secondary endpoints (morning PEF, tolerability, and safety, the last as assessed on the basis of hypothalamic-pituitary-adrenal axis function). CONCLUSIONS: The use of the single-dose inhaler developed in Brazil for MF administration is as effective and safe as is that of a standard inhaler in the treatment of patients with asthma. PMID- 20835587 TI - Field-test validation of the brazilian version of the Paediatric Asthma Quality of Life Questionnaire. AB - OBJECTIVE: To assess the psychometric properties of the official Brazilian Portuguese-language version of the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) in a representative group of Brazilian children and adolescents with asthma. METHODS: A total of 125 individuals with asthma, aged 8 17 years and being monitored at a pediatric pulmonology outpatient clinic in the city of Porto Alegre, Brazil, completed the PAQLQ. Validity was assessed by means of convergent validity (correlation between PAQLQ domains and those of the Pediatric Quality of Life Inventory (PedsQL) 4.0. Reliability was assessed by determining internal consistency (Cronbach's alpha coefficient), reproducibility (intraclass correlation coefficient), sensitivity to change (effect size), and discriminatory power (floor/ceiling effects). RESULTS: The mean age was 11 years, and 75 (60%) of the participants were male. The mean PAQLQ total score was 5.1, with floor/ceiling effects < 10%. Correlations between PAQLQ domains and the PedsQL 4.0 domains were acceptable (r = 0.37-0.40). The Cronbach's alpha coefficient for the total score was 0.93, ranging from 0.72 to 0.88 for the domains. The overall effect size was 0.60 (range: 0.45-0.60), whereas the overall intraclass correlation coefficient was 0.80 (range: 0.66-0.79). CONCLUSIONS: The official Brazilian Portuguese-language version of the PAQLQ showed good psychometric performance, confirming its cultural adequacy for use in Brazil. PMID- 20835588 TI - Should the bronchiectasis treatment given to cystic fibrosis patients be extrapolated to those with bronchiectasis from other causes? AB - OBJECTIVE: To profile the characteristics of adult patients with bronchiectasis, drawing comparisons between cystic fibrosis (CF) patients and those with bronchiectasis from other causes in order to determine whether it is rational to extrapolate the bronchiectasis treatment given to CF patients to those with bronchiectasis from other causes. METHODS: A retrospective analysis of the medical charts of 87 patients diagnosed with bronchiectasis and under follow-up treatment at our outpatient clinic. Patients who had tuberculosis (current or previous) were excluded. We evaluated the clinical, functional, and treatment data of the patients. RESULTS: Of the 87 patients with bronchiectasis, 38 (43.7%) had been diagnosed with CF, through determination of sweat sodium and chloride concentrations or through genetic analysis, whereas the disease was due to another etiology in 49 (56.3%), of whom 34 (39.0%) had been diagnosed with idiopathic bronchiectasis. The mean age at diagnosis was lower in the patients with CF than in those without (14.2 vs. 24.2 years; p < 0.05). The prevalence of symptoms (cough, expectoration, hemoptysis, and wheezing) was similar between the groups. Colonization by Pseudomonas aeruginosa or Staphylococcus aureus was more common in the CF patients (82.4 vs. 29.7% and 64.7 vs. 5.4%, respectively). CONCLUSIONS: The causes and clinical manifestations of bronchiectasis are heterogeneous, and it is important to identify the differences. It is crucial that these differences be recognized so that new strategies for the management of patients with bronchiectasis can be developed. PMID- 20835589 TI - Occurrence of hepatopulmonary syndrome in patients with cirrhosis who are candidates for liver transplantation. AB - OBJECTIVE: To determine the occurrence of hepatopulmonary syndrome (HPS) in patients with cirrhosis who are candidates for liver transplantation; to compare demographic, clinical, laboratory, and spirometric characteristics, as well as echocardiography results, arterial blood gas analysis, and severity of liver disease between the groups of patients with and without HPS; and to describe the occurrence of HPS in the subgroup of patients with cirrhosis and schistosomiasis mansoni (mixed liver disease). METHODS: Between January and November of 2007, we evaluated 44 patients under treatment at the Liver Transplant Outpatient Clinic of the Federal University of Pernambuco Hospital das Clinicas, in the city of Recife, Brazil. The diagnostic criteria for HPS were intrapulmonary vascular dilatation, identified by transthoracic echocardiography, and an alveolar arterial oxygen tension difference >or= 15 mmHg or a PaO2 < 80 mmHg. RESULTS: The mean age of the patients was 52 years, and 31 patients (70%) were male. The most common cause of cirrhosis was alcohol use. Schistosomiasis was present in 28 patients (64%). Of the 44 patients, 20 (45.5%) were diagnosed with HPS. No significant differences were found between those patients and the patients without HPS in terms of any of the characteristics studied. Of the 28 patients with cirrhosis and schistosomiasis, 10 (35.7%) were diagnosed with HPS. CONCLUSIONS: In the population studied, HPS was highly prevalent and did not correlate with any of the variables analyzed. PMID- 20835590 TI - Increased risk of respiratory symptoms and chronic bronchitis in women using biomass fuels in Nigeria. AB - OBJECTIVE: To determine whether respiratory symptoms and chronic bronchitis are associated with the use of biomass fuels (BMFs) among women residing in rural areas of the Ekiti State, in southwestern Nigeria. METHODS: From January to June of 2009, we carried out a cross-sectional study including 269 adult women. To collect data on sociodemographic status, type of fuel used for cooking in the household, respiratory symptoms, and smoking history, we used a questionnaire adapted from the European Community Respiratory Health Survey. All of the participants were invited to undergo spirometry. RESULTS: Of the 269 women in the study, 161 (59.9%) used BMFs for cooking. The proportion of women who reported respiratory symptoms was greater among those using BMFs than among those using a non-BMF-cough (13.7% vs. 3.7%); wheezing (8.7% vs. 2.8%); chest pain (7.5% vs. 1.9%); breathlessness (11.8% vs. 6.5%); nasal symptoms (9.3% vs. 4.6%); and chronic bronchitis (10.6% vs. 2.8%). Multivariate logistic regression analysis revealed that the use of BMFs was associated with the following variables: cough (OR = 4.82; p = 0.01); chronic bronchitis (OR = 3.75; p = 0.04); wheezing (OR = 2.22; p = 0.23); chest pain (OR = 3.82; p = 0.09); breathlessness (OR = 1.54; p = 0.35); and nasal symptoms (OR = 2.32; p = 0.20). All of the spirometric parameters evaluated (FEV1, FVC, FEV1/FVC ratio, and PEF) were lower in the women using BMFs than in those using a non-BMF. CONCLUSIONS: Our results underscore the need for women using BMFs in their households to replace them with a nontoxic type of fuel, such as electricity or gas. PMID- 20835591 TI - Does the BODE index correlate with quality of life in patients with COPD? AB - OBJECTIVE: To determine whether the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index correlates with health-related quality of life in patients with COPD. METHODS: We evaluated 42 patients with COPD, quantifying the following: lung function parameters; anthropometric variables; exercise capacity, with the six-minute walk test; dyspnea, with the modified Medical Research Council (MRC) scale; the BODE index; and quality of life, with the modified Saint George's Respiratory Questionnaire (mSGRQ). Patients were divided into two groups by disease severity: FEV1 >or= 50% and FEV1 < 50%. RESULTS: The mean BODE index was 2.58 +/- 1.17 and 4.15 +/- 1.81, respectively, for the FEV1 >or= 50% and FEV1 < 50% groups. There was a significant difference between the groups in terms of FEV1 and the FEV1/FVC ratio. There were moderate to significant correlations between the BODE index scores and all of the mSGRQ domains in the group of patients with FEV1 <50%. CONCLUSIONS: The BODE index score correlated with the scores of all of the mSGRQ domains in COPD patients with FEV1 < 50%. Therefore, COPD patients with FEV1 < 50% die sooner and have a poorer quality of life. PMID- 20835592 TI - Pulmonary function in children and adolescents with postinfectious bronchiolitis obliterans. AB - OBJECTIVE: To describe the pulmonary function in children and adolescents with postinfectious bronchiolitis obliterans (PIBO), as well as to evaluate potential risk factors for severe impairment of pulmonary function. METHODS: The pulmonary function of 77 participants, aged 8-18 years, was assessed by spirometry and plethysmography. The following parameters were analyzed: FVC; FEV1; FEF25-75%; FEV1/FVC; RV; TLC; RV/TLC; intrathoracic gas volume; and specific airway resistance (sRaw). We used Poisson regression to investigate the following potential risk factors for severe impairment of pulmonary function: gender; age at first wheeze; age at diagnosis; family history of asthma; tobacco smoke exposure; length of hospital stay; and duration of mechanical ventilation. RESULTS: The mean age was 13.5 years. There were pronounced decreases in FEV1 and FEF25-75%, as well as increases in RV and sRaw. These alterations are characteristic of obstructive airway disease. For the parameters that were the most affected, the mean values (percentage of predicted) were as follows: FEV1 = 45.9%; FEF25-75% = 21.5%; RV = 281.1%; RV/TLC = 236.2%; and sRaw = 665.3%. None of the potential risk factors studied showed a significant association with severely impaired pulmonary function. CONCLUSIONS: The patients with PIBO had a common pattern of severe pulmonary function impairment, characterized by marked airway obstruction and pronounced increases in RV and sRaw. The combination of spirometric and plethysmographic measurements can be more useful for assessing functional damage, as well as in the follow-up of these patients, than are either of these techniques used in isolation. Known risk factors for respiratory diseases do not seem to be associated with severely impaired pulmonary function in PIBO. PMID- 20835593 TI - Predicting reduced TLC in patients with low FVC and a normal or elevated FEV1/FVC ratio. AB - OBJECTIVE: To use clinical and spirometry findings in order to distinguish between the restrictive and nonspecific patterns of pulmonary function test results in patients with low FVC and a normal or elevated FEV1/FVC ratio. METHODS: We analyzed the pulmonary function test results of 211 adult patients submitted to spirometry and lung volume measurements. We used the clinical diagnosis at the time spirometry was ordered, together with various functional data, in order to distinguish between patients presenting with a "true" restrictive pattern (reduced TLC) and those presenting with a nonspecific pattern (normal TLC). RESULTS: In the study sample, TLC was reduced in 144 cases and was within the normal range in 67. The most common causes of a nonspecific pattern were obstructive disorders, congestive heart failure, obesity, bronchiolitis, interstitial diseases, and neuromuscular disorders. In patients given a working diagnosis of pulmonary fibrosis, pleural disease, or chest wall disease, the positive predictive value (PPV) for restriction was >or= 90%. In males, an FVC or= 0% between the FEV1% and the FVC% had a PPV for restriction of 89.5%. After performing logistic regression, we developed a point scale for predicting the restrictive pattern. CONCLUSIONS: In many patients with reduced FEV1, reduced FVC, and a normal FEV1/FVC ratio, the restrictive pattern can be identified with confidence through the use of an algorithm that takes the clinical diagnosis and certain spirometry measurements into account. PMID- 20835594 TI - Determination of total proteins and lactate dehydrogenase for the diagnosis of pleural transudates and exudates: redefining the classical criterion with a new statistical approach. AB - OBJECTIVE: To propose a new classification criterion for the differentiation between pleural exudates and transudates-quantifying total proteins in pleural fluid (TP-PF) and lactate dehydrogenase in pleural fluid (LDH-PF) exclusively-as well as to compare this new criterion with the classical criterion in terms of diagnostic yield. METHODS: This was an observational, cross-sectional study with a within-subject design, comprising 181 patients with pleural effusion treated at two university hospitals in the state of Rio de Janeiro, Brazil, between 2003 and 2006. The diagnostic parameters included in the classical criterion were identified, as were those included in the new criterion. RESULTS: Of the 181 patients, 152 and 29 were diagnosed with pleural exudates and pleural transudates, respectively. For the classical criterion, the sensitivity, specificity, and accuracy for the diagnosis of pleural exudates were, respectively, 99.8%, 68.6%, and 94.5%, whereas the corresponding values for the diagnosis of pleural transudates were 76.1%, 90.1%, and 87.6%. For the new criterion (cut-off points set at 3.4 g/dL for TP-PF and 328.0 U/L for LDH-PF), the sensitivity, specificity, and accuracy for the diagnosis of exudates were, respectively, 99.4%, 72.6%, and 99.2%, whereas the corresponding values for the diagnosis of transudates were 98.5%, 83.4%, and 90.0%. The accuracy of the new criterion for the diagnosis of pleural exudates was significantly greater than was that of the classical criterion (p = 0.0022). CONCLUSIONS: The diagnostic yield was comparable between the two criteria studied. Therefore, the new classification criterion can be used in daily practice. PMID- 20835595 TI - Clinical characteristics and evolution of non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis. AB - OBJECTIVE: To investigate the characteristics of and risk factors for mortality among non-HIV-infected immunocompromised patients with an in-hospital diagnosis of tuberculosis. METHODS: This was a two-year, retrospective cohort study of patients with an in-hospital diagnosis of tuberculosis. The predictive factors for mortality were evaluated. RESULTS: During the study period, 337 hospitalized patients were diagnosed with tuberculosis, and 61 of those patients presented with immunosuppression that was unrelated to HIV infection. Extrapulmonary tuberculosis was found in 47.5% of cases. In the latter group, the in-hospital mortality rate was 21.3%, and the mortality rate after discharge was 18.8%. One year survival was significantly higher among the immunocompetent patients than among the HIV patients (p = 0.008) and the non-HIV-infected immunocompromised patients (p = 0.015), although there was no such difference between the two latter groups (p = 0.848). Among the non-HIV-infected immunocompromised patients, the only factor statistically associated with mortality was the need for mechanical ventilation. Among the patients over 60 years of age, fibrosis/atelectasis on chest X-rays and dyspnea were more common, whereas fever and consolidations were less common. Fever was also less common among the patients with neoplasms. The time from admission to the initiation of treatment was significant longer in patients over 60 years of age, as well as in those with diabetes and those with end-stage renal disease. Weight loss was least common in patients with diabetes and in those using corticosteroids. CONCLUSIONS: The lower prevalence of classic symptoms, the occurrence of extrapulmonary tuberculosis, the delayed initiation of treatment, and the high mortality rate reflect the diagnostic and therapeutic challenges of tuberculosis in non-HIV-infected immunocompromised patients. PMID- 20835597 TI - Experimental model of isolated lung perfusion in rats: technique and application in lung preservation studies. AB - Small animal models are particularly suitable for lung preservation studies, because they are simple and cost-effective. This brief communication focuses on the technical description of an ex vivo lung perfusion model in rats by means of a commercially available apparatus, which was the first to be installed in a thoracic surgery research laboratory in Brazil. The model and its preparation, together with its applications for lung preservation studies, are described in detail. All technical details can also be seen in a video posted on the website of the Brazilian Journal of Pulmonology. PMID- 20835596 TI - Aminoguanidine reduces oxidative stress and structural lung changes in experimental diabetes mellitus. AB - We evaluated the effect of aminoguanidine on pulmonary oxidative stress and lung structure in an experimental model of diabetes mellitus. Thiobarbituric acid reactive substances (TBARS), histology and arterial blood gases were evaluated in animals with diabetes mellitus (DM group), animals with diabetes mellitus treated with aminoguanidine (DM+AG group), and controls. The TBARS levels were significantly higher in the DM group than in the control and DM+AG groups (2.90 +/- 1.12 vs. 1.62 +/- 0.28 and 1.68 +/- 0.04 nmol/mg protein, respectively), as was PaCO2 when compared with that of the control group (49.2 +/- 1.65 vs. 38.12 +/- 4.85 mmHg), and PaO2 was significantly higher in the control group (104.5 +/- 6.3 vs. 16.30 +/- 69.48 and 97.05 +/- 14.02 mmHg, respectively). In this experimental model of diabetes mellitus, aminoguanidine reduced oxidative stress, structural tissue alterations, and gas exchange. PMID- 20835598 TI - Heterogeneity in human IFN-gamma responses to clinical Mycobacterium tuberculosis strains. AB - Mycobacterium tuberculosis is one of the most successful human pathogens. Highly virulent strains, which are more easily transmitted than are less virulent strains, elicit variable immune responses. We evaluated the Th1 responses (IFN gamma production) in healthy volunteers after stimulation with various strains. Our results show that the individuals with negative tuberculin skin test (TST) results were not necessarily naive to all of the strains tested, whereas individuals with positive TST results did not respond to all of the strains tested. Drug-resistant strains induced a lower mean level of IFN-gamma production than did drug-sensitive strains. One possible practical application of this finding would be for the prediction of responses to treatment, in which it might be advantageous to have knowledge of the estimated IFN-gamma production elicited by a specific isolated strain. PMID- 20835599 TI - Portable monitoring devices in the diagnosis of obstructive sleep apnea: current status, advantages, and limitations. AB - Recent years have seen a growing interest in the use of portable monitoring devices for the diagnosis of obstructive sleep apnea syndrome. These have the potential to be used in lieu of the more complicated and uncomfortable alternative, polysomnography, which has long been considered to be the gold standard for the diagnosis of this relatively prevalent condition. Following their approval in 2008 by the Center of Medicare and Medicaid Services, the federal agency which administers Medicare and Medicaid in the United States, there has been extensive discussion about the utility and validity of these devices for use in the diagnosis of obstructive sleep apnea syndrome. Although there are various models of portable monitoring devices, the literature contains little information regarding how each device should be used in specific age groups, patients presenting comorbidities, and asymptomatic patients. Additionally, studies about the cost-effectiveness of this diagnostic method are scarce and conflicting. Therefore, this objective of this study was to review what has been learned about portable monitoring devices over time, as well as to examine the recent progress, advantages, limitations, and applications of these devices in the diagnosis of obstructive sleep apnea syndrome in different groups of patients. PMID- 20835600 TI - Bronchial thermoplasty in asthma. AB - Currently available treatments for asthma provide satisfactory control of the disease in most cases. However, a significant number of patients do not respond to such treatments (i.e., do not achieve effective symptom relief). One novel approach to treating asthma is bronchial thermoplasty, in which the airway smooth muscle is specifically and directly treated. This procedure delivers radiofrequency energy to the airways in order to reduce smooth muscle-mediated bronchoconstriction. In this article, we present the thermoplasty technique, summarizing the results of the major randomized clinical trials of the procedure, as well as discussing its mechanisms of action and potential adverse effects. We also propose strategies for the future clinical use of this new treatment. PMID- 20835601 TI - Severe paraquat poisoning: clinical and radiological findings in a survivor. AB - Paraquat is a nonselective contact herbicide of great toxicological importance, being associated with high mortality rates, mainly due to respiratory failure. We report the case of a 22-year-old male admitted to the emergency room with a sore throat, dysphagia, hemoptysis, and retrosternal pain after the ingestion of 50 mL of a paraquat solution, four days prior to admission. Chest CT scans revealed pulmonary opacities, pneumomediastinum, pneumothorax, and subcutaneous emphysema. The patient was submitted to two cycles of immunosuppressive therapy with cyclophosphamide, methylprednisolone, and dexamethasone. The pulmonary gas exchange parameters gradually improved, and the patient was discharged four weeks later. The clinical and tomographic follow-up evaluations performed at four months after discharge showed that there had been further clinical improvement. We also present a brief review of the literature, as well as a discussion of the therapeutic algorithm for severe paraquat poisoning. PMID- 20835602 TI - Giant cell tumor of the sternum. AB - We report the case of a 74-year-old female patient diagnosed with a giant cell tumor of the sternum. The clinical and radiological presentation was indicative of a primary tumor of the sternum. The patient underwent complementary tests and surgery. The pathological examination confirmed the diagnosis. Commonly observed in the long bones of the appendicular skeleton, this type of tumor is characterized by its local aggressiveness and metastatic potential. We also review the literature on the topic. PMID- 20835603 TI - Surgical treatment of lung malformations in pediatric patients. PMID- 20835604 TI - Immune homeostasis to microorganisms in the guts of triatomines (Reduviidae)--a review. AB - Bacteria, fungi and parasites are in constant contact with the insect gut environment and can influence different aspects of the host gut physiology. Usually, some of these microorganisms develop and survive in the digestive tract. Therefore, the gut environment must be able to tolerate certain populations of these organisms for the establishment of interactions between non-pathogenic bacteria, parasites and the gut. This review provides a brief overview of the biological and molecular mechanisms that microorganisms use to interact with the gut epithelia in mosquitoes and speculates on their significances for the development of bacteria and Trypanosoma cruzi in the guts of triatomines. PMID- 20835605 TI - Angiogenesis and experimental hepatic fibrosis. AB - Angiogenesis is a basic change occurring during repair by granulation tissue. This process seems to precede fibrosis formation in most types of chronic liver disease. To examine its presence and significance in different types of hepatic insults, this paper sought to identify the presence, evolution and peculiarities of angiogenesis in the most common experimental models of hepatic fibrosis. The characterization of cells, vessels and extracellular matrix and the identification of factors associated with endothelium (factor VIII RA), vascular basement membrane, other components of the vascular walls (actin, elastin) and the presence of the vascular-endothelial growth factor were investigated. The models examined included Capillaria hepatica septal fibrosis, whole pig serum injections, carbon tetrachloride administration, main bile duct ligation and Schistosoma mansoni infection. The first four models were performed in rats, while the last used mice. All models studied exhibited prominent angiogenesis. The most evident relationship between angiogenesis and fibrosis occurred with the C. hepatica model due to circumstances to be discussed. Special attention was paid to the presence of pericytes and to their tendency to become detached from the vascular wall and be transformed into myofibroblasts, which is a sequence of events that explains the decisive role angiogenesis plays in fibrosis. PMID- 20835606 TI - In vitro and in vivo effects of Enterococcus faecalis CECT7121 on Toxocara canis. AB - The aim of the present paper was to evaluate the larvicidal effect of Enterococcus faecalis CECT7121 (Ef7121) on the Toxocara canis cycle both in vitro and in vivo. For the in vitro experiments, T. canis larvae were incubated with the supernatants of Ef7121 (EI) and mutant Ef7121 (EIm), in a pre-culture of Ef7121 (EII) and in a fresh culture with Ef7121 (EIII) and the Ef7121 mutant strain (EIIIm). The viability of the larvae was calculated after a 48 h incubation. A significant reduction of the viability of T. canis larvae was observed in EI, EII and EIII. A decrease of this inhibitory effect was observed in EIm and EIIIm (p = 0.008). In the in vivo experiments, mice were orally inoculated with three doses of Ef7121. To study the probiotic persistence in the intestine, the animals were sacrificed every four days and their intestines were dissected. The initial average bacterial levels were 9.7 x 10(4) for Ef7121 (colony forming units/g). At the end of the assay the levels were 1.46 x 10(4). No bacterial translocation was detected in mesenteric lymphatic nodules and spleen. Ef7121 interference with the biological cycle was evaluated in mice challenged with T. canis. The interference was significant when the mice were challenged with probiotic and T. canis simultaneously (p = 0.001), but it was not significant when the challenge was performed 15 days after administration of the bacterial inoculum (p = 0.06). In conclusion, Ef7121 possessed in vitro and in vivo larvicidal activity. PMID- 20835607 TI - Chagas disease: serological and electrocardiographic studies in Wichi and Creole communities of Mision Nueva Pompeya, Chaco, Argentina. AB - Chagas disease, which is caused by Trypanosoma cruzi, affects nearly 16 million people in Latin America and causes 75-90 million people to be at risk of infection. The disease is urbanizing and globalizing due to frequent migrations. There are regions of high prevalence of infection, including the north-eastern provinces of Argentina and the entire phytogeographic region known as the Gran Chaco. In the province of Chaco, Argentina, there are places inhabited by native populations such as the Wichi and Toba communities, among others. Many Creole populations resulting from miscegenation with European colonists and immigrants coexist within these communities. It has been widely accepted that in the chronic phase of the disease, between 25-30% of individuals develop some form of cardiac disease, with the right bundle-branch block being the most typical condition described so far. The aim of this work was to study the prevalence of Chagas infection and its electrocardiographic profile in the Wichi and Creole populations of Mision Nueva Pompeya, in the area known as Monte Impenetrable in Chaco, to determine the prevalence and the pattern of heart diseases produced by Chagas disease in this region. PMID- 20835608 TI - Mycobacterium leprae downregulates the expression of PHEX in Schwann cells and osteoblasts. AB - Neuropathy and bone deformities, lifelong sequelae of leprosy that persist after treatment, result in significant impairment to patients and compromise their social rehabilitation. Phosphate-regulating gene with homologies to endopeptidase on the X chromosome (PHEX) is a Zn-metalloendopeptidase, which is abundantly expressed in osteoblasts and many other cell types, such as Schwann cells, and has been implicated in phosphate metabolism and X-linked rickets. Here, we demonstrate that Mycobacterium leprae stimulation downregulates PHEX transcription and protein expression in a human schwannoma cell line (ST88-14) and human osteoblast lineage. Modulation of PHEX expression was observed to a lesser extent in cells stimulated with other species of mycobacteria, but was not observed in cultures treated with latex beads or with the facultative intracellular bacterium Salmonella typhimurium. Direct downregulation of PHEX by M. leprae could be involved in the bone resorption observed in leprosy patients. This is the first report to describe PHEX modulation by an infectious agent. PMID- 20835609 TI - Sylvatic foci of the Chagas disease vector Triatoma infestans in Chile: description of a new focus and challenges for control programs. AB - Triatoma infestans is one of the main domestic vectors of Chagas disease. Reports of wild habitat occurrences have recently increased. In Chile, after a successful elimination campaign of T. infestans domestic infestation, a sylvatic focus was reported in bromeliads in the metropolitan region. Here, we report a new focus of sylvatic T. infestans inhabiting rock piles in the Valparaiso region in central Chile. All T. infestans captured were nymphal instars living among the stones, which were inhabited by several mammal species, along with the sylvatic triatomine vector Mepraia spinolai. We found a prevalence of infection with Trypanosoma cruzi of 36.54% in T. infestans, similar to the previous report for sylvatic specimens from bromeliads. Sylvatic populations of T. infestans should be studied at different geographic scales to elucidate their role in the maintenance of the sylvatic transmission cycle of T. cruzi and their possible role in threatening the domestic elimination of this vector. This information should be used to re-design the control programs in Chile to avoid the re establishment of the domestic cycle. PMID- 20835610 TI - Control of Mycobacterium fortuitum and Mycobacterium intracellulare infections with respect to distinct granuloma formations in livers of BALB/c mice. AB - Mycobacterium fortuitum is a rapidly growing nontuberculous Mycobacterium that can cause a range of diseases in humans. Complications from M. fortuitum infection have been associated with numerous surgical procedures. A protective immune response against pathogenic mycobacterial infections is dependent on the granuloma formation. Within the granuloma, the macrophage effector response can inhibit bacterial replication and mediate the intracellular killing of bacteria. The granulomatous responses of BALB/c mice to rapidly and slowly growing mycobacteria were assessed in vivo and the bacterial loads in spleens and livers from M. fortuitum and Mycobacterium intracellulare-infected mice, as well as the number and size of granulomas in liver sections, were quantified. Bacterial loads were found to be approximately two times lower in M. fortuitum-infected mice than in M. intracellulare-infected mice and M. fortuitum-infected mice presented fewer granulomas compared to M. intracellulare-infected mice. These granulomas were characterized by the presence of Mac-1+ and CD4+ cells. Additionally, IFN gammamRNA expression was higher in the livers of M. fortuitum-infected mice than in those of M. intracellulare-infected mice. These data clearly show that mice are more capable of controlling an infection with M. fortuitum than M. intracellulare. This capacity is likely related to distinct granuloma formations in mice infected with M. fortuitum but not with M. intracellulare. PMID- 20835611 TI - Polymorphisms IL10-819 and TLR-2 are potentially associated with sepsis in Brazilian patients. AB - Genetic variation in immune response is probably involved in the progression of sepsis and mortality in septic patients. However, findings in the literature are sometimes conflicting or their significance is uncertain. Thus, we investigated the possible association between 12 polymorphisms located in the interleukin-6 (IL6), IL10, TLR-2, Toll-like receptor-4 (TLR-4), tumor necrosis factor-alpha and tumor necrosis factor-beta (lymphotoxin alpha--LTA) genes and sepsis. Critically ill patients classified with sepsis, severe sepsis and septic shock and 207 healthy volunteers were analyzed and genotyped. Seven of the nine polymorphisms showed similar distributions in allele frequencies between patients and controls. Interestingly, our data suggest that the IL10-819 and TLR-2 polymorphisms may be potential predictors of sepsis. PMID- 20835612 TI - Helicobacter pylori transiently in the mouth may participate in the transmission of infection. AB - Helicobacter pylori infection is associated with peptic ulcer and gastric carcinoma. The oral cavity may be a reservoir for H. pylori; however, the results of studies on this subject are controversial. We employed single-step and nested polymerase chain reactions (PCR) to detect the presence of the vacA, ureA and 16S rDNA genes of H. pylori in the stomach, saliva and dental plaque of 30 subjects. The results were confirmed by sequencing. Nested 16S rDNA and ureA amplification was achieved in 80% of gastric, 30% of saliva and 20% of dental plaque specimens. Sequencing of 10, seven and four 16S rDNA products from stomach, saliva and dental plaque, respectively, showed > 99% identity with H. pylori. Sequencing of the other four oral cavity PCR products showed similarity with Campylobacter and Wolinella species. Additionally, the vacA genotype identified in the samples of different sites was the same within a given subject.H. pylori may be found in the oral cavity of patients with gastric infection, thus it could be a source of transmission. However, results obtained with detection methods based only on PCR should be interpreted with caution because other microorganisms that are phylogenetically very close to H. pylori are also present in the mouth. PMID- 20835613 TI - Susceptibility of Mycobacterium tuberculosis to first-line antimycobacterial agents in a Brazilian hospital: assessing the utility of the tetrazolium (MTT) microplate assay. AB - We conducted a cross-sectional, hospital-based study between January 2006-March 2008 to estimate the resistance of Mycobacterium tuberculosis to first-line drugs in patients with tuberculosis at a Brazilian hospital. We evaluated the performance of the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) microplate assay compared with the Bactec-MGIT 960 system for mycobacteria testing. The prevalence of resistance in M. tuberculosis was 6.7%. Multidrug-resistance [resistance to rifampicin (RMP) and isoniazid (INH)], INH resistance and streptomycin (SM)-resistance accounted for 1%, 3.8% and 3.8% of all resistance, respectively, and all isolates were susceptible to ethambutol (EM). The resistance was primary in four cases and acquired in three cases and previous treatment was associated with resistance (p = 0.0129). Among the 119 M. tuberculosis isolates, complete concordance of the results for INH and EM was observed between the MTT microplate and Bactec-MGIT 960TM methods. The observed agreement for RMP was 99% (sensitivity: 90%) and 95.8% for SM (sensitivity 90.9%), lower than those for other drugs. The MTT colourimetric method is an accurate, simple and low-cost alternative in settings with limited resources. PMID- 20835614 TI - Circulation of hantaviruses in the influence area of the Cuiaba-Santarem Highway. AB - We describe evidence of circulation of hantaviruses in the influence area of the Santarem-Cuiaba Highway (BR-163) in the Brazilian Amazon through the prevalence of specific antibodies against hantaviruses in inhabitants living in four municipalities of this area: Novo Progresso (2.16%) and Trairao (4.37%), in state of Para (PA), and Gua-ranta do Norte (4.74%) and Marcelandia (9.43%), in state of Mato Grosso. We also demonstrate the ongoing association between Castelo dos Sonhos virus (CASV) and hantavirus pulmonary syndrome (HPS) cases in the Castelo dos Sonhos district (municipality of Altamira, PA) and the first report of CASV in the municipalities of Novo Progresso and Guaranta do Norte. The results of this work highlight the risk for a possible increase in the number of HPS cases and the emergence of new hantavirus lineages associated with deforestation in this Amazonian area after the conclusion of paving works on BR-163 Highway. PMID- 20835615 TI - Genetic-morphometric variation in Culex quinquefasciatus from Brazil and La Plata, Argentina. AB - Variation among natural populations of Culex (Culex) quinquefasciatus Say is associated with different vectorial capacities. The species Cx. quinquefasciatus is present in the equatorial, tropical and subtropical zones in the Brazilian territory, with intermediate forms between Cx. quinquefasciatus and Culex pipiens occurring in regions of latitudes around 33 degrees -35 degrees S. Herein, we studied geographically distinct populations of Cx. quinquefasciatus by genetic characterization and analysis of intra-specific wing morphometrics. After morphological analysis, molecular characterization of Cx. quinquefasciatus and intermediate forms was performed by polymerase chain reaction of the polymorphic nuclear region of the second intron of the acetylcholinesterase locus. Additionally, the morphology of adult female wings collected from six locations was analyzed. Wing centroid sizes were significantly different between some geographical pairs. Mean values of R2/R2+3 differed significantly after pairwise comparisons. The overall wing shape represented by morphometric characters could be divided into two main groupings. Our data suggest that Brazilian samples are morphologically and genetically distinct from the Argentinean samples and also indicated a morphological distinction between northern and southern populations of Brazilian Cx. quinquefasciatus. We suggest that wing morphology may be used for preliminary assessment of population structure of Cx. quinquefasciatusin Brazil. PMID- 20835616 TI - Absence of domestic triatomine colonies in an area of the coastal region of Ecuador where Chagas disease is endemic. AB - Rhodnius ecuadoriensis is considered the second most important vector of Chagas disease in Ecuador. It is distributed across six of the 24 provinces and occupies intradomiciliary, peridomiciliary and sylvatic habitats. This study was conducted in six communities within the coastal province of Guayas. Triatomine searches were conducted in domestic and peridomestic habitats and bird nests using manual searches, live-bait traps and sensor boxes. Synantrhopic mammals were captured in the domestic and peridomestic habitats. Household searches (n = 429) and randomly placed sensor boxes (n = 360) produced no live triatomine adults or nymphs. In contrast, eight nymphs were found in two out of six searched Campylorhynchus fasciatus (Troglodytidae) nests. Finally, Trypanosoma cruzi DNA was amplified from the blood of 10% of the 115 examined mammals. Environmental changes in land use (intensive rice farming), mosquito control interventions and lack of intradomestic adaptation are suggested among the possible reasons for the lack of domestic triatomine colonies. PMID- 20835617 TI - Colonization by Helicobacter pylori of leprosy patients in Spain: immunomodulation to low molecular weight antigens of H. pylori. AB - We studied the prevalence of Helicobacter pylori in patients with leprosy and the effects of co-infection on the immune response to Helicobacter antigens in the polar groups of leprosy (lepromatous and tuberculoid). We showed that there is no difference in the prevalence of H. pylori in patients with leprosy as compared to a non-leprosy population. We also demonstrated that the immune response to low molecular weight H. pylori antigens (35, 26 and 19 kDa) differs in patients with lepromatous as compared to those with tuberculoid leprosy. In lepromatous leprosy, we show that there is a higher prevalence of the 35 and 26 kDa antigens, but a lower prevalence of the 19 kDa antigen. These immunological results are consistent with previous histopathological studies illustrating a more severe gastrointestinal inflammation in lepromatous patients; importantly, a response to the 35 kDa antigen is recognized as a marker for the development of ulcerative disease. PMID- 20835618 TI - Immune responses to gp82 provide protection against mucosal Trypanosoma cruzi infection. AB - The potential use of the Trypanosoma cruzi metacyclic trypomastigote (MT) stage specific molecule glycoprotein-82 (gp82) as a vaccine target has not been fully explored. We show that the opsonization of T. cruzi MT with gp82-specific antibody prior to mucosal challenge significantly reduces parasite infectivity. In addition, we investigated the immune responses as well as the systemic and mucosal protective immunity induced by intranasal CpG-adjuvanted gp82 vaccination. Spleen cells from mice immunized with CpG-gp82 proliferated and secreted IFN-gamma in a dose-dependent manner in response to in vitro stimulation with gp82 and parasite lysate. More importantly, these CpG-gp82-immunized mice were significantly protected from a biologically relevant oral parasite challenge. PMID- 20835619 TI - HIV/AIDS-associated visceral leishmaniasis in patients from an endemic area in Central-west Brazil. AB - An increase in morbidity associated with visceral leishmaniasis (VL) in human immunodeficiency virus (HIV)/AIDS patients has been described in Africa and the Mediterranean. Despite the high endemicity of VL and HIV-1/AIDS in Brazil, this association has not been thoroughly investigated. Our aim was to evaluate the epidemiologic and clinical characteristics of VL-HIV-1/AIDS cases from Central west [Mato Grosso do Sul (MS)] Brazil. Medical records of 23 VL-HIV-1/AIDS patients were reviewed. Patients were predominantly adult males (87%) and 34.8% of the patients were intravenous drug users (IVDU). Leishmaniasis was the first opportunistic infection in 60% of the HIV-1 patients. Fever occurred in all patients, although splenomegaly and hepatomegaly were absent in 21.7% of the cases. CD4+ T-cell counts were below 200 cells/mm(3) in 80% of the cases and the counts did not increase after clinical remission despite antiretroviral therapy. The first drug chosen to treat the cases was antimonial, but the therapeutic regimen was altered to amphotericin B in 12 of 17 cases due to side effects. Relapses were reported in 56.5% of the patients. IVDU may constitute an important risk factor for the transmission of both diseases in MS. VL-HIV-1/AIDS patients in MS share similar clinical characteristics as those from other endemic regions worldwide. Thus, these findings are critical for improving the surveillance of VL HIV/AIDS patients. PMID- 20835620 TI - Evaluation of local immune response to Fasciola hepatica experimental infection in the liver and hepatic lymph nodes of goats immunized with Sm14 vaccine antigen. AB - Protection against Fasciola hepatica in goats immunized with a synthetic recombinant antigen from Schistosoma mansoni fatty acid-binding protein 14 (rSm14) was investigated by assessing worm burdens, serum levels of hepatic enzymes, faecal egg count and hepatic damage, which was evaluated using gross and microscopic morphometric observation. The nature of the local immune response was assessed by examining the distribution of CD2+, CD4+, CD8+ and gamma'+ T lymphocytes along with IgG+, IL-4+ and IFN-gamma+ cells in the liver and hepatic lymph nodes (HLN). The goats used consisted of group 1 (unimmunized and uninfected), group 2 [infected control - immunized with Quillaia A (Quil A)] and group 3 (immunized with rSm14 in Quil A and infected), each containing seven animals. Immunization with rSm14 in Quil A adjuvant induced a reduction in gross hepatic lesions of 56.6% (p < 0.001) and reduced hepatic and HLN infiltration of CD2+, CD4+, CD8+ and gamma'+ T lymphocytes as well as IL-4+ and IFN-gamma+ cells (p < 0.05). This is the first report of caprine immunization against F. hepatica using a complete rSm14 molecule derived from S. mansoni. Immunization reduced hepatic damage and local inflammatory infiltration into the liver and HLN. However, considering that Quil A is not the preferential/first choice adjuvant for Sm14 immunization, further studies will be undertaken using the monophosphoryl lipid A-based family of adjuvants during clinical trials to facilitate anti-Fasciolavaccine development. PMID- 20835621 TI - Fibrinogen binds to nontoxigenic and toxigenic Corynebacterium diphtheriae strains. AB - The production of fibrinous exudates may play an important role in determining the outcome of bacterial infection. Although pseudomembrane formation is a characteristic feature of diphtheria, little is known about the fibrinogen (Fbn) binding properties of Corynebacterium diphtheriae strains and the influence of the gene that codes for diphtheria toxin (tox gene) in this process. In this study we demonstrated the ability of C. diphtheriae strains to bind to Fbn and to convert Fbn to fibrin. Bacterial interaction with rabbit plasma was evaluated by both slide and tube tests. Interaction of microorganisms with human Fbn was evaluated by both enzyme linked immunosorbent assay (ELISA) and fluorescein isothiocyanate-conjugated (FITC) Fbn binding assays. Nontoxigenic and toxigenic strains formed bacterial aggregates in the presence of plasma in the slide tests. The ability to convert Fbn to a loose web of fibrin in the plasma solution in the tube tests appeared to be a common characteristic of the species, including strains that do not carry the tox gene. Fbn binding to C. diphtheriae strains occurred at varying intensities, as demonstrated by the FITC-Fbn and ELISA binding assays. Our data suggest that the capacity to bind to Fbn and to convert Fbn to fibrin may play a role in pseudomembrane formation and act as virulence determinants of both nontoxigenic and toxigenic strains. PMID- 20835622 TI - Molecular characterization of adenoviruses from children presenting with acute respiratory disease in Uberlandia, Minas Gerais, Brazil, and detection of an isolate genetically related to feline adenovirus. AB - Human adenoviruses (HAdV) are a major cause of acute respiratory diseases (ARD), gastroenteritis, conjunctivitis and urinary infections. Between November 2000 April 2007, a total of 468 nasopharyngeal aspirate samples were collected from children with ARD at the Clinics Hospital of Uberlandia. These samples were tested by immunofluorescence assay (IFA) and 3% (14/468) tested positive for the presence of HAdV. By performing polymerase chain reaction (PCR) to detect HAdV DNA in samples that tested negative or inconclusive for all viruses identifiable by IFA (respiratory syncytial virus, parainfluenza viruses 1, 2 and 3, influenza viruses A and B and HAdV), as well as negative for rhinoviruses by reverse transcription-PCR, additional 19 cases were detected, for a total of 33 (7.1%) HAdV-positive samples. Nucleotide sequences of 13 HAdV samples were analyzed, revealing that they belonged to species B, C and E. Further analyses showed that species C (HAdV-2) was the most prevalent among the sequenced samples. To our knowledge, this is the first report describing the presence of HAdV-4 in Brazil. We also detected an isolate that was 100% identical to a part of the feline adenovirus hexon gene sequence. PMID- 20835623 TI - Growth, cysts and kinetics of Borrelia garinii (Spirochaetales: Spirochaetacea) in different culture media. AB - The aim of the present paper was to evaluate cyst formation and growth parameters of Borrelia garinii in a range of media differing in formulation and cost. A qualitative assessment of morphology and motility of B. garinii was conducted. All media were prepared aseptically and used in test tubes or Petri dishes. For each medium, the initial spirochete concentration was standardized to 10(3) spirochets/mL. The following culture media were suitable to grow B. garinii: Barbour-Stoenner-Kelly, brain heart infusion and PMR. Growth was minimal at six weeks post-inoculation and maximum spirochete density was observed between 9-12 weeks. Often, the cultures developed cysts of different sizes, isolated or in groups, with a spiraled portion of variable sizes, mainly in unfavorable culture media. Brazilian Lyme disease-like illness, also known as Baggio-Yoshinari syndrome (BYS), is a new and interesting emerging tick-borne disease, caused by Borrelia burgdorferi sensu lato spirochetes, only during its cystic forms. It has been assumed that the peculiar clinical and laboratory features of BYS are consequential to the absence of a human sucker Ixodes ricinus complex tick at risk areas in Brazil, supporting the concept that the borrelia phenotypic expression pattern is modified as it is transmitted through the host. PMID- 20835624 TI - HIV-1 RNA detection in the amniotic fluid of HIV-infected pregnant women. AB - This study is aimed at evaluating the potential to detect human immunodeficiency virus (HIV) in amniotic fluid (AF) collected at delivery from 40 HIV-positive pregnant women. Thirty patients had a plasma viral load (VL) below 1,000 copies/mL at delivery. VL was positive in three AF samples. No significant association was found between the HIV-1 RNA in AF and the maternal plasma samples. There was no HIV vertical transmission detected. PMID- 20835625 TI - Evaluation of Lionex TB kits and mycobacterial antigens for IgG and IgA detection in cerebrospinal fluid from tuberculosis meningitis patients. AB - To evaluate commercial Lionex TB together with four antigens of Mycobacterium tuberculosis (MPT-64, MT10.3, 16 kDa and 38 kDa) for IgG and IgA cerebrospinal fluid (CSF) detection in the diagnosis of tuberculosis meningitis (TBM) with CSF negative acid-fast bacilli staining, 19 cases of TBM, 64 cases of other infectious meningoencephalitis and 73 cases of other neurological disorders were tested by enzyme linked immunosorbent assay. IgA-MPT-64 and IgG Lionex showed the highest sensitivities, specificities, positive predictive value and negative predictive value (63.2%, 47.4%; 95%, 93.7%; 40%, 98% and 28.4%, 97.1%, respectively). However, while grey zone was 12.7% and 6%, respectively, lowering sensitivity but maintains high specificity (>or= 95%). High protein concentration in CSF was associated with antibody positivity CSF/HIV+ which did not influence the sensitivity of both tests. To our knowledge, this is the first description of IgA-MPT-64 and IgG Lionex antibodies in CSF-TBM and, although there is good specificity, adjustments are needed based on antigen composition to enhance sensitivity. PMID- 20835627 TI - Change the QUALIS criteria! PMID- 20835626 TI - Communication in oncology and bioethics. PMID- 20835628 TI - [Antibiotic prophylaxis reduces the incidence of infection and mortality in patients with necrotizing pancreatitis?]. PMID- 20835629 TI - [Smoking - part 3]. PMID- 20835631 TI - [Undergraduate research in Brazil and in medical courses]. PMID- 20835632 TI - Acute myocarditits in H1N1 influenza A virus infection. PMID- 20835633 TI - [Giant Neurocysticercosis: diagnosis and treatment]. PMID- 20835634 TI - Ethical issues of diagnosis disclosure and treatment in patients with genital or breast cancer. AB - OBJECTIVE: To verify how communication between physicians and patients takes place during diagnosis, treatment and prognosis of women with genital or breast cancer, using bioethics as a reference for analysis. METHODS: Descriptive/analytical epidemiological cross-sectional study of 120 patients randomly selected at Hospital de Base do Distrito Federal, Brazil. Patients were given a questionnaire with nine closed-ended questions distributed as follows: three related to diagnosis, four to treatment, and two to prognosis. RESULTS: The results showed that 73.3% of patients considered the quality of initial information received on the diagnosis of cancer as "negative"; 54.2% of patients understood information received on diagnosis and treatment; approximately 60% were aware of the prognosis of cancer; and less than 10% did not want additional information. However, for almost 40% of respondents, there was a problem in physician-patient communication regarding the process involving cancer. Age and extent of the disease did not influence the patients' degree of understanding about diagnosis, treatment, and prognosis. CONCLUSION: Communicating information about diagnosis, treatment and prognosis to patients with genital or breast cancer was adequate in about 60% of cases. However, problems were detected concerning the language used by physicians, lack of systematic consideration towards patient autonomy, and absence of mechanisms that could provide decision making power to patients. PMID- 20835635 TI - Correlation of respiratory muscle strength with anthropometric variables of normal-weight and obese women. AB - OBJECTIVE: To correlate anthropometric data and respiratory muscle strength (RMS) of normal-weight and obese women. METHODS: The sample consisted of 103 sedentary women, divided into two groups: 57 obese and 46 normal-weight women. Waist circumference (WC) and hip circumference (HC) were measured to calculate the waist-to-hip ratio (WHR), and maximal respiratory pressures (Pmax) were determined using an analog vacuum manometer to +/- 300 cm H2O. Body composition was measured using tetrapolar bioelectrical impedance analysis. Descriptive statistics was used for data analysis, in addition to the Student t test for independent samples, Pearson correlation, and stepwise multiple linear regression analysis. Significance level was set at p <= 0.05. RESULTS: The analysis showed significant differences in Pmax of normal-weight women (PImax = -73.04+/-16.55 cm H2O and PEmax = 79.67+/-18.89 cm H2O) and obese women (PImax = -85.00+/-21.69 cm H2O and PEmax = 103.86+/-20.35 cm H2O). Anthropometric and manometric variables showed no significant correlation in both groups. When analyzing the influence of bioelectrical impedance on RMS, a positive correlation was observed between lean body mass and PImax. CONCLUSION: Bioelectrical impedance and obesity showed a direct correlation with RMS. WC and WHR had no influence on RMS of obese women; however, a relevance to risk factors for associated diseases was observed. We believe that these results are due to an adjustment to excess body weight over the years. PMID- 20835636 TI - The SF-6D Brazil questionnaire: generation models and applications in health economics. AB - OBJECTIVE: Compare the preference measures derived from the SF-36, based on the two Brazilian versions of the Short Form 6 Dimensions questionnaire-Brazil (SF-6D Brazil). METHODS: Observational and transversal study. The following quality of life assessment instruments were applied: HAQ, SF-36, EQ-5D and SF-6D (1998 and 2002 versions). Descriptive statistics and correlation coefficients were used for data analysis. RESULTS: The study assessed 200 patients suffering from rheumatoid arthritis, with a mean age of 49.22 years, mean time with the disease of 11.16 years and mean HAQ score of 1.02. Preferences measured by the two versions of the SF-6D and by the EQ-5D showed significant correlations with one another, and Pearson coefficients ranged from 0.59 to 0.88 (p<0.01). CONCLUSION: The most current version of the SF-6D, based on the 2002 model, was found to be valid when compared to the version initially validated to Brazil and is a questionnaire alternative to assess preferences in economic analyses carried out in health care. PMID- 20835637 TI - Early detection of visual impairment and its relation to academic performance. AB - OBJECTIVE: To perform early detection of visual impairment in schoolchildren and to investigate its association with academic performance. METHODS: Cross sectional study using a sample of third-grade students from public elementary schools of the municipality of Juiz de Fora, state of Minas Gerais, Brazil. Students performed the visual acuity (VA) test using the Snellen chart. We also analyzed school records and administered a previously validated self-administered questionnaire. We considered that there was low VA when the VA value achieved using the chart was lower than or equal to 0.7, while poor academic performance was identified when the average grades of the last school year did not reach 60 points. RESULTS: We analyzed 222 students from five public schools. In terms of visual acuity, 31% of the students had impaired VA in the right eye and 29.8% of the students had impaired VA in the left eye. Our sample had 15.5% of students with fair or poor academic performance. Among the students with normal VA, 89.5% had satisfactory academic performance, while among those with impaired VA, only 75% achieved satisfactory performance (p = 0.015). CONCLUSION: The present study suggests that there is an association between low VA and poor academic performance in the sample assessed. PMID- 20835638 TI - Is there increase of STDs during Carnival? Time series of diagnoses in a STD clinic. AB - OBJECTIVE: Sexually transmitted diseases (STDs) are common reasons for seeking medical assistance. Media campaigns on STD/AIDS assume that exposure to risky sexual practices is greater during Carnival. The objective of this study was to analyze the temporal distribution of first appointments in a STD clinic from January 1993 to December 2005 to verify whether there is a seasonal increase in STD after Carnival. METHODS: A total of 2,646 medical records with a diagnosis of gonorrhea, syphilis, or trichomoniasis were selected among patients seeking medical assistance in the STD Unit of Universidade Federal Fluminense, Niteroi, Rio de Janeiro, Brazil. Statistical analysis was performed using month-to-month and year-to-year standardized average number of appointments during 13 years, in addition to smoothed time-series data using the Lowess method and the deterministic moving average method. RESULTS: July and August exhibited the largest number of gonorrhea and syphilis diagnoses, and June and July of trichomoniasis diagnoses. Gonorrhea had its peak value in May, with a falling trend until August. A constant number of syphilis diagnoses was observed between May and August, with smaller numbers in January and February and peak values in November. The seasonal pattern for trichomoniasis diagnosis showed peak values in July, with a consistent falling trend until December and an increase from January on. CONCLUSION: Carnival has no influence on the increase in the occurrence of gonorrhea, syphilis, and trichomoniasis in patients attending a STD clinic in Niteroi, Rio de Janeiro, Brazil. PMID- 20835639 TI - Biopharmaceutical industry-sponsored global clinical trials in emerging countries. AB - OBJECTIVE: To evaluate biopharmaceutical industry-sponsored clinical trials placed in countries previously described as emerging regions for clinical research, and potential differences for those placed in Brazil. METHODS: Data regarding recruitment of subjects for clinical trials were retrieved from www.clinicaltrials.gov on February 2nd 2009. Proportions of sites in each country were compared among emerging countries. Multiple logistic regressions were performed to evaluate whether trial placement in Brazil could be predicted by trial location in other countries and/or by trial features. RESULTS: A total of 8,501 trials were then active and 1,170 (13.8%) included sites in emerging countries (i.e., Argentina, Brazil, China, Czech Republic, Hungary, India, Mexico, Poland, Russia, South Korea, and South Africa). South Korea and China presented a significantly higher proportion of sites when compared to other countries (p<0.05). Multiple logistic regressions detected no negative correlation between placement in other countries when compared to Brazil. Trials involving subjects with less than 15 years of age, those with targeted recruitment of at least 1,000 subjects, and seven sponsors were identified as significant predictors of trial placement in Brazil. CONCLUSION: No clear direct competition between Brazil and other emerging countries was detected. South Korea showed the higher proportion of sites and ranked third in total number of trials, appearing as a major player in attractiveness for biopharmaceutical industry sponsored clinical trials. PMID- 20835640 TI - Randomized, comparative analysis between two tracheal suction systems in neonates. AB - OBJECTIVE: To quantify and compare variations in oxygen saturation throughout the suctioning procedure (before, during, and after) using two endotracheal suction systems: open suction system (OSS) vs. closed suction system (CSS). METHODS: A prospective randomized controlled study was carried out with 39 newborn infants of gestational age >= 34 weeks using pressure-limited, time-cycled, continuous flow mechanical ventilators. The infants were classified into two groups according to ventilatory parameters: Group I was ventilated using positive end expiratory pressure (PEEP) >= 5 cm H2O and mean airway pressure (MAP) >= 8 cm H2O; and Group II using PEEP < 5 cm H2O and MAP < 8 cm H2O. RESULTS: No statistically significant differences were observed when OSS and CSS were compared in both groups. There was a statistically significant improvement in post-procedure oxygen saturation in both groups. CONCLUSION: Both endotracheal suction systems can be used with no drawbacks of OSS in relation to CSS, provided the sample is similar to that of the present study. PMID- 20835641 TI - Violence and unsafe sexual practices in adolescents under 15 years of age. AB - OBJECTIVE: To identify factors associated with unprotected sexual activity in females under the age of 15 years. METHODS: Cross-sectional observational study of sexually active adolescents under the age of 15 seen at a public outpatient gynecology clinic. Data were collected by means of semi-structured interviews (personal information and data on sexuality), clinical examination, and laboratory tests for diagnosis of sexually transmitted infections. Data were analyzed by frequency testing, association of variables (with p <0.05) and multiple correspondence analysis. RESULTS: One hundred sexually active adolescents between the ages of 11 and 14 were interviewed and examined. Of these, 71% declared themselves black; one-third were behind in school; 80% began sexual activity before the age of 13; 58% reported having been victims of violence within the family environment, and 13% had suffered sexual abuse; 77% did not use condoms regularly; and 22% had STIs. Unprotected sexual activity was more frequent with first sexual intercourse before the age of 13, commercial sexual exploitation, multiple sexual partners, intrafamily violence and school delay, as well as black race, unexpected pregnancy, and STIs. CONCLUSION: The multiple types of violence suffered by teenagers, including structural, intrafamily, and sexual violence, increase their vulnerability to early, unprotected sexual activity and to STIs and unexpected pregnancy. The synergistic effects of poverty, low educational achievement, and low self-esteem reduces the odds that adolescents will build the tools required for self-protection and exposes them to further victimization outside the family environment. PMID- 20835642 TI - Perinatal outcome of twin pregnancies delivered in a teaching hospital. AB - OBJECTIVE: This study aimed to evaluate the perinatal outcome of twin pregnancies delivered in a tertiary teaching hospital according to chorionicity. METHODS: A retrospective study involving 289 twin pregnancies delivered from January 2003 to December 2006 was carried out. Maternal and perinatal data were obtained from hospital charts and delivery logs. Chorionicity was determined by ultrasonography or histopathological study. RESULTS: Incidence of twin gestations was 3.4% and 96.4% were spontaneously conceived. 60.5% were dichorionic (DC), 30.8% of monochorionic diamniotic (MCDA), 6.6% monochorionic monoamniotic (MCMA) and for 2.1% chorionicity was unknown. The mean gestation age at delivery was respectively 35.4, 33.6, 32.9 for DC, MCDA and MCMA. The mean birth weight was 2.171, 1.832 and 1.760 g respectively for DC, MC and MCMA. The proportion of fetuses delivered with less than 34 weeks in DC was of 21.7%, while in MCDA it was of 39.3% and in MCMA of 42.1%. Birth weight below the 10th centile occurred in 15.7% for DC, 22.5% for MCDA and 26.3% in MCMA. Congenital anomalies were observed in 21.3% in monochorionic and in 7.4% in the dichorionic. Length of hospital stay was shorter for DC when compared to MCDA and MCMA twins (13.1, 17.3 and 23.3 days, respectively). The proportion of twin pregnancies with both babies discharged alive were 85.7% in DC and 61.1% in MC. CONCLUSION: The rate of preterm deliveries and low birth weight is higher in monochorionic pregnancies when compared to dichorionic twins. However, when adjusted for complications such as fetal abnormalities and twin-twin transfusion syndrome, double survival rates were similar in the two groups. PMID- 20835643 TI - Analysis of prehospital care for stroke and acute myocardial infarction in the elderly population of Minas Gerais, Brazil. AB - OBJECTIVE: To analyze the association between prehospital components of the National Urgent Care Policy (Politica Nacional de Atencao as Urgencias, PNAU)- the Family Health Strategy (Estrategia de Saude da Familia, ESF) and the Mobile Emergency Care Service (Servico de Atendimento Movel de Urgencia, SAMU)--and indicators of morbidity and mortality from stroke and acute myocardial infarction (AMI) in the elderly population in preselected municipalities of the State of Minas Gerais, Brazil. METHODS: A longitudinal ecological study was carried out. Data analysis was performed using a series of multilevel regression models. Health indicators were analyzed from 2001 to 2007. RESULTS: Statistically significant associations were found between indicators of ESF coverage and presence of SAMU with indicators of stroke and AMI mortality, for both sexes, except for male AMI. Regarding hospital admission rates, the most consistent effects were identified for female AMI. CONCLUSION: The heterogeneity of the results points to an incipient stage of PNAU, which does not allow the observation of clear effects. This finding may also suggest that this policy has not yet been able to achieve its goals concerning the elderly. Further evaluation of PNAU is essential for the establishment of strategies that can enhance its effectiveness. PMID- 20835644 TI - The teaching of acupuncture in the University of Sao Paulo School of Medicine, Brazil. AB - OBJECTIVE: Since being introduced as an elective discipline (non-obligatory) in the second semester of 2002, acupuncture has been taught in the University of Sao Paulo School of Medicine. We conducted this study to verify interest and acceptance among under graduate medical students and to discern a positive influence contributing to improving their skills. METHODS: The study was conducted from 2002 to 2007 using descriptive statistical methods. RESULTS: The average number of students who concluded the discipline is 24.9 students per semester with an average number of medical students per semester of 87.5 (28% of all medical students in the 7th and 8th semesters). After a semester of basic training in acupuncture, only eight students per group are promoted (after selection) to the Medical Academic League of Acupuncture which lasts for two years. Every semester, all eight vacancies are filled. Among the students who concluded the course, 98% described course quality as good or very good, 85% considered themselves at least partially able to use acupuncture and 79% stated that the course influenced them in their medical education. CONCLUSION: There is a genuine interest to learn acupuncture, almost 30% of all students volunteer for a brief training in acupuncture while some of them choose additional training of two years due to the importance of acupuncture as part of professional skills. Results indicate that acupuncture should be included as an elective discipline for medical students. PMID- 20835645 TI - Clinical characteristics of a sample of patients with cat eye syndrome. AB - OBJECTIVE: Cat eye syndrome is considered a rare chromosome disease with a highly variable phenotype. The objective of this paper was to describe the clinical characteristics of a sample of patients with cat eye syndrome who were seen at our service. METHODS: This is a retrospective analysis of a sample of six patients with diagnoses of cat eye syndrome. All of these patients' karyotypes exhibited the presence of an additional marker chromosome, inv dup(22)(pter >q11.2::q11.2->pter). One patient also exhibited mosaicism with a lineage that had a normal chromosomal constitution. Clinical and follow-up data were collected from the patients' medical records. Fisher's exact test was used to compare the frequencies observed in our study with figures given in the literature (P<0.05). RESULTS: The main abnormalities observed were preauricular tags and/or pits and anal atresia (both observed in 83% of cases). Coloboma of the iris, an important finding with this syndrome, was observed in two cases (33%). Congenital heart disease was detected in four patients (67%) and the main defect found was interatrial communication (75%). Uncommon findings included hemifacial microsomia combined with unilateral microtia and biliary atresia. Just one of these patients died, from chylothorax and sepsis. CONCLUSION: The phenotype observed in cat eye syndrome is highly variable and may be superimposed on the phenotype of the oculo auriculo-vertebral spectrum. Although these patients usually have good prognosis, including from a neurological point of view, we believe that all patients with the syndrome should be assessed very early on for the presence of cardiac, biliary and anorectal malformations, which may avoid possible complications in the future, including patient deaths. PMID- 20835646 TI - Epidemiological and clinical aspects of pelvic endometriosis-a case series. AB - OBJECTIVE: To describe clinical and epidemiological aspects of patients with pelvic endometriosis who underwent laparoscopy at our service. METHODS: Retrospective study of 892 post-laparoscopy patients with histologically confirmed diagnosis of endometriosis. RESULTS: Mean age was 33.2 +/- 6.3 years, and 78.7% of patients were Caucasian. We found that 76.9% of women in the sample had a higher education. Most (56.5%) patients were nulliparous, and 62.2% reported dysmenorrhea as the chief complaint. Chronic pelvic pain was the most prevalent symptom, followed by deep dyspareunia, reported by 56.8% and 54.7% of patients respectively. Infertility was reported by 39.8% of the 892 patients in the sample. CONCLUSION: Endometriosis is most often diagnosed in the fourth decade of life. Patients with this condition present with multiple complaints, and must always undergo thorough questioning to properly guide diagnosis and monitor treatment results. PMID- 20835647 TI - The interaction between aromatase, metalloproteinase 2,9 and CD44 in breast cancer. AB - OBJECTIVE: This study intends to verify the expression levels and correlation of aromatase, matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9) and CD44 in ductal carcinoma in situ (DCIS) and infiltrating ductal carcinoma (IDC) when both are found in the same breast. METHODS: One hundred and ten cases were evaluated by tissue microarray (TMA) and immunohistochemically screened with anti-aromatase polyclonal antibodies, anti-MMP-2 monoclonal antibodies, anti-MMP 9 polyclonal antibodies and anti-CD44 monoclonal antibodies. RESULTS: Aromatase was expressed in IDC and DCIS in 63 (57.3%) and 60 (67%) of the cases respectively; MMP-2 was similarly expressed in IDC and DCIS in 15 (13.60%) cases; MMP-9 was positively expressed in IDC and DCIS in 83 (75.50%) and 82 (74.50%) cases, respectively; CD44 was positively expressed in IDC and DCIS in 49 (44.50%) and 48 (42.60%) of the cases, respectively; all of them were highly correlated (p<0,001). The correlation analysis found positive, statistically significant correlation, in IDC between aromatase and MMP-2 (p<0.001) and between aromatase and MMP-9 (p=0.034). Positive correlation between aromatase and MMP-2 (p<0.001) and between MMP-9 and CD44 (p=0.030) were found in DCIS. CONCLUSION: These results allow us to conclude that aromatase through local estrogen synthesis in breast tissue plays an important role in breast carcinogenesis, mainly influencing MMP-2 and MMP-9 which are important participants in tumor cell invasion and dependence of their connection to CD44 for action. PMID- 20835648 TI - CNPq-supported medical researchers: a comparative study of research areas. AB - OBJECTIVE: To assess the profile and scientific output of medical researchers supported by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) grants. METHODS: Data were extracted from the Lattes curricula of 411 medical researchers with active grants for the 2006-2008 period. The variables of interest were gender, institutional affiliation, scientific output, and advisership of undergraduate research fellows and master's and doctoral candidates. RESULTS: Researchers were predominantly male (68%) and recipients of category 2 grants (55.7%). Four Brazilian states (Sao Paulo, Rio de Janeiro, Rio Grande do Sul, and Minas Gerais) accounted for 90% of all researchers. Eight institutions accounted for roughly 80% of researchers in the sample, particularly USP (30.7%) and UNIFESP (17%). The study identified 30 areas of expertise for researchers. Median scientific output was 4.13 published articles per year (interquartile range, IQ, 2.9-5.8), or 2.23 per year (IQ, 1.4-3.2) after adjusting for articles published in Web of Science-indexed journals. The most productive areas in terms of indexed articles were Neuroscience (3.16 articles/year; IQ, 1.8-4.7) and Psychiatry (2.92; IQ, 1.73-4.5). CONCLUSION: Medical researchers are concentrated in the Southeast region of Brazil. The scientific output of most Brazilian researchers has increased over the past five years. An understanding of the profile of medical researchers in the country may aid development of effective strategies for qualitative improvement of scientific output. PMID- 20835649 TI - The role of selenoproteins in cancer. AB - Evidence has shown that metabolic disorders are common in tumor cells, leading to increased oxidative stress. The increase in the production of reactive oxygen species (ROS) associated with low antioxidant activity has been related to several types of cancer. Selenium, an antioxidant micronutrient, may function as an antimutagenic agent, preventing the malignant transformation of normal cells. A review of the literature was conducted based on a survey of articles published between 2000 and 2009 in the PubMed database; 39 articles that analyzed the relationship between cancer, oxidative stress and selenium supplementation were selected. The protective effect of this mineral is especially associated with its presence in the glutathione peroxidase and thioredoxin reductase, enzymes that are known to protect DNA and other cellular components against oxidative damage caused by ROS. Several studies have shown reduced expression of these enzymes in various types of cancer, especially when associated with low intake of selenium, which may increase the damage. Selenium supplementation appears to reduce the risk of some types of cancer by reducing oxidative stress and DNA damage. However, further studies are needed to clarify the adequate dose of selenium for each situation (sex, geographic location, and type of cancer). PMID- 20835650 TI - Febrile seizures: update on diagnosis and management. AB - Febrile seizures are a benign condition of childhood, and most children will have only one episode in their lifetime. Nevertheless, any seizure is a cause of major concern in the patient's family, and there is much discussion in the literature on when and whether to treat febrile seizures, as well as on what constitutes the best therapeutic approach. This review summarizes the current evidence and recommendations for diagnosis and management of patients with febrile seizures. PMID- 20835652 TI - [Depression among students from two nursing undergraduate programs: self assessment on health and associated factors]. AB - This study aimed to verify the prevalence of depression and associated factors among undergraduate nursing students. Descriptive research carried out in Ribeirao Preto with students from two undergraduate programs. INSTRUMENTS: Brazilian Economic Classification Criteria; Beck Depression Inventory; Quality of Life Assessment. It was performed bivariate and multivariate analysis of data. Ethical procedures were respected. Among the 114 subjects, most are women and single. Bachelor Program: 32% are aged less than 20 years old, from economic levels A2, B1 and B2 and 69,6% do not work. Teaching Diploma Program: 32,6% older than 25 years old, levels B2 and C and 75,8% work. Depression detected in 15,4% of the students at Bachelor's Program and 28,6% from the Teaching Diploma Program. The percentage of depression decreases as Teaching Diploma Program students' economical level increases. Mental self assessment carried out by student and program enrolled had significant prevalence rates. PMID- 20835653 TI - [Profile of patients with gynecological cancer under chemotherapy]. AB - A study of socio-epidemiological demographic profile of patients in chemotherapy for cancer in the Gynecology and Obstetrical Ward in HE- UFTM, presented in the period from 1998 to 2006. Retrospective study whose data collection was obtained from health records It was built a data base using Epi-Info. Data analysis considered simple distribution, mediacy with value between the maximum and the minimum and stand deviation. The sample was constituted of 321 health records; the more incident age group was 46 to 50 years-old; breast cancer was the most noticed cancer (45%); the chemotherapy most used was ciclofosfamida, in 173 treatments; had an increase in breast cancer. It was concluded that had a change in the patient's profile. PMID- 20835654 TI - [Aging, facing strategies of the aged and the consequences for family]. AB - This qualitative study seeks the understanding of the perception of the elderly, users of Basic Health Unit of Sao Paulo, on aging, coping strategies and impact on family. Interviews with three elderly people, from 71 to 90 years-old, were held from September 2007 to July'2008. Participants responded to questions under the Geriatric Depression Scale, Ecomapa, Genogram and Calgary model. From the Bardin analysis, we could determine three categories - the moment of realizing the life cycle; suffering the consequences of this time; facing the aging and old age. We believe in the continuity of studies that search for strategies with older people and their families in an attempt to improve life quality and family dynamics by the inclusion of entertainment, according to the possibilities offered to their communities. PMID- 20835655 TI - [Demands and control of work: implications in pediatric and neonatal intensive care units]. AB - To compare the demand and control over work of physicians and nurses working in pediatric and neonatal critical care units. Cross-sectional study with 37 doctors and 20 nurses. We used the Job Content Questionnarie. Physicians from the ICU Neonatal differ in social support received from the supervisor (p= 0.01) compared to the ICU Pediatric. ICU nurses of the Neonatal present job insecurity (p= 0.05). Physicians and nurses from the ICU Pediatric differ in control over the work, psychological demands of work, physical effort and support of the supervisor (p <0.05). Physicians and nurses from the ICU Neonatal show statistical differences in control over the work, physical effort and support of the supervisor (p<0.05). The work environment in the ICU'S presents high demand and low control over the work. PMID- 20835656 TI - [Life style, health aspects and work among truck drivers]. AB - Epidemiological study with the purpose of identify the demographic characteristics, health aspects and life style, amongst truck drivers were applied to 105 drivers from supply center of Campinas (fruit, vegetable, product wholesale market). The outcomes showed that all drivers interviewed were men, the majority were married, had kids, low study level and more than 30 years old. 54,2% reported abuse psychoactive drugs. The majority was aware of the importance of using condoms with casual partners; 47,5% reported relationship with casual partners and 86 always used condoms. Although the small sample analyzed, the results suggests that must be implemented health promotion actions and illness prevention public politics, including the development of customized educational interventions with in this professional group. PMID- 20835657 TI - [Meanings of research in the professional practice of clinical nurses]. AB - The aim of this study was to analyze the meanings given to investigative research by nurse clinicians enrolled in a research support group. The interpretive anthropology theoretical frame was used along with an ethnographic case study. Data was collected through semi-structured individual and group interviews, document and statement analysis as well as field diary notes. The statements of 36 participants were analyzed interpretively identifying four categories: activity's value, researching is learning, the movements about the activity, the activity is hard work that demands personal effort. We understand that once research training initiative is supported by the organization and desired by the nurse, it becomes a scientific-pedagogical strategy for academic nursing formation with positive repercussions to care assistance. PMID- 20835658 TI - [Understanding the intentions of actions of a multiprofessional teaching staff at a nursing undergraduate course]. AB - The objective of this study was to understand the intentions of actions of a nursing teaching staff and the ones from other healthcare areas at a nursing undergraduate course. Four teachers from each category were interviewed using the guiding question: What do you expect from your teaching action in this nursing course? It was used the social phenomenology by Alfred Schutz as the referential of analysis. It was revealed that the intention of actions from the teaching staff are working with the students seeing them as future professionals trying to make them reflect on their knowledge, attitudes and behaviors, hoping them to think in a critical way, make decisions and be technically competent. They also want to collaborate for the students' self-growth, believing that being a teaching staff member is being a researcher helping students to acquire investigative view and having intention to provide meaningful contends to students' personal and professional lives. PMID- 20835659 TI - [Linkages and challenges in the training of professional nurses]. AB - The objective of the study was to know the linkages and challenges between professional training and practice and the Curriculum Guidelines for Nursing Baccalaureate Degree Programs. It was a qualitative study, with 34 graduates in nursing, who answered an e-mailed questionnaire. Data analysis was based on Michael Foucault's discourse analysis. The ethical aspects were observed. Analysis showed three themes in graduates discourses - Unified Health System, generalist professional training and humanization. The study revealed an approximation of concepts and guidelines of the Curriculum Guidelines for Nursing Baccalaureate Degree Programs and of the Unified Health System with the reality of professional practice along with challenges in the training of professional nurses. PMID- 20835660 TI - [Noise and sounds in the neonatal unit]. AB - The purpose was to identify the causes of noise in the neonatal unit and measure its level in decibels. It is a descriptive study developed in a public institution in Fortaleza-Ceara. The data collection was conducted in the morning, afternoon and night periods from October/2004 through January/2005, though not direct observation, when we measured the Decibel Sound Pressure Level, through a decibelimeter. The results showed that the morning period presented high noise levels, mainly due to conversation between the people and due to water jet used for washing hands, with a maximum value of 80.4dB. The change of equipment in the night period presented maximum value of 78.1dB. We concluded that the average value of decibels in the NU was higher than the recommended by the ABNT. PMID- 20835661 TI - [Education in health: perspectives of the Family Health Strategy team under Paulo Freire's view]. AB - Qualitative study whose research subjects were the members of a Health Family Strategy. and has as purpose to know their perspectives about health education and presents them through the dialogical conception of Paulo Freire. In the circles of culture, four themes emerged: family health team, health education, health education practice in team work and how to improve the stock of existing health education, were encode, decode and critically unveiled its concepts, challenges, opportunities and expectations of their educational practices. The field research was the development of a Primary Care Unit of Health of Cachoeira do Campo, Minas Gerais. The results showed that health education is recognized by the subjects as a liability, but its practice is facing cultural barriers, and receives little emphasis in the daily work. PMID- 20835662 TI - [Ease of access revealed by users of the Single Health System]. AB - This study aimed to examine the perceptions of users about the ease of access to actions and services of the Single Health System (SHS). Qualitative study conducted with 24 users of SHS in a federal hospital in Rio de Janeiro. In collecting data was used the technique of semi-structured, the analysis was performed using the technique of analysis of thematic content. The Subjects recognize the access to various services of the SUS, as well as factors associated with such access, as the referral process, the luck and the belief in God. It was possible to verify the existence of a positive attitude about the health system, as well the identification of a set of its principles. PMID- 20835663 TI - [Nurse's role on basic health care regarding to the approach to drug addicted in Joao Pessoa, PB, Brazil]. AB - Qualitative study conducted with nurses from the Family Health Strategy in Joao Pessoa, PB, Brasil. The purpose was to investigate the nurses' role in the approach to the drug addict, analyzing the strategies of basic nursing care applied to them. The selection for the study followed the criterion for acceptance. The data were collected through a semi-structured interview, giving priority to participant's talks. One noticed the lack of professional training of the nurses in relation to the drug addiction, by restricting their actions to taking these users to more specialized services in mental health. It must redefine the attention, putting a new paradigm of health as a right and as a social community construction, from a global view of the processes of social interaction. PMID- 20835664 TI - [Prevention evaluation of HIV vertical transmission in Belo Horizonte, MG, Brazil]. AB - The study had as objective to analyze the prenatal care services offered by the East District's primary healthcare network of the city of Belo Horizonte as well as actions for the prevention of vertical transmission of HIV. It discussed the still significant rates of transmission of HIV in the presence of appropriate technologies for its prevention. Barriers directly related to problems in the early uptake of pregnant women and the institution of appropriate therapy in time were identified through univariate descriptive analysis considering Sisprenatal and Sinan databases. The involvement of managers and the training of professionals are essential for the correct direction of actions that enable the effective prevention of vertical transmission of HIV. PMID- 20835665 TI - [Family experience of dealing with sequels of the prematurity of a child]. AB - The objective of the study was to describe the experience of the family that lives with the sequels of prematurity in the first years of a child's life. That was qualitative study developed in Maringa, PR, Brazil, with eight families of children born from 1998 to 2008 at a University Hospital. Data was collected through open interviews carried out at the home of the families in the period from January to June 2006. The families of premature babies revealed the anguish and the suffering experienced when they found little by little, the limitations, differences and current sequels of prematurity. They emphasized that this experience can be translated as a long path in search of a better understanding of the whole process. PMID- 20835666 TI - [Nurses and the family of the patient with mental disorder]. AB - This qualitative study aimed at investigating how mental health nurses acquired knowledge about the theme family during their academic training, how they see families in their daily practice, and how should professional training be considering the presence of the family in the care setting. Data were collected using semistructured questionnaires. Six nurses were interviewed. Data analysis allowed the establishment of three theme categories: Academic and professional training absence of the family theme; the nurses' perception of the family with a mentally ill member; and a new vision of the family the role of teaching. During undergraduate education, nurses acquired little knowledge about the theme family; in the institutional routine, they praise the family as a participant of care; and indicate that the need for knowledge about families is based on the interdisciplinary character of education. PMID- 20835667 TI - [Professional autonomy in an atomic design: social representations of nurses]. AB - This work has the objective of describe and analyse the social representation of professional autonomy build by public health nurses. The methodology theoretical referencial was the Theory of Social Representation. Interviews were deeply made with 30 nurses of a city in state of Rio de Janeiro. The information was analysed by Alceste software. The results showed the professional autonomy drawing based on professional characteristics (responsibility is balance) and health programming as an important space to autonomy building. It can be concluded that autonomy process is under construction and that the existence of its representation. PMID- 20835668 TI - [Leucocituria in patients submitted to chemoteraphy and urine collection]. AB - The proposal of the study was to verify leucocituria frequency in carriers of gynecological cancer in chemotherapy (CT) and to identify practices in urine collection for exam. Descriptive transversal study carried out with ginecologyc cancer patients during chemotherapy sections. With semi-structured interview, it was identified urine collection technique and verified the results of exams accomplished before chemotherapy sections. Among 30 interviews, 80% related to collect urine correctly, 100% presented at last a mistake during the process. Leucocituria frequency was 30 episodes. The mistakes occurred mostly in genital cleaning and collection of the urinary jet. It infers that the erroneous form in the collection in addition to the neutropenia can be responsible for the leucocituria. PMID- 20835669 TI - [Overweight among adolescents from private schools in Fortaleza, CE, Brazil]. AB - The purpose of the study was to identify cases of overweight among adolescents in private schools in Fortaleza, Brazil. We investigated 794 students between 12 and 17 years old from 12 private schools, in the months March to June and August September 2007. The prevalence of overweight and obesity was 20% and 4%, respectively. Among the young people who watch TV while eat, the weight accumulated was higher and the cases of obesity was the double (p = 0, 000). About 28% of people who practiced regular physical activity were overweight (p <0, 001). In the fight against adolescent adiposity, to the nursing is primarily the preventive actions, because attenuate various pathological effects related to the accumulation of body weight. PMID- 20835670 TI - [Information system for supporting the Nursing Care Systematization]. AB - It is an unquestionable fact, the importance, relevance and necessity of implementing the Nursing Care Systematization in the different environments of professional practice. Considering it as a principle, emerged the motivation for the development of an information system to support the Nursing Care Systematization, based on Nursing Process steps and Human Needs, using the diagnoses language, nursing interventions and outcomes for professional practice documentation. This paper describes the methodological steps and results of the information system development - requirements elicitation, modeling, object relational mapping, implementation and system validation. PMID- 20835671 TI - [Teaching of nursing in Rio Grande do Sul in the 1950]. AB - The purpose of this research was to analyze how the undergraduate teaching of nursing in Rio Grande do Sul has constructed its knowledge, since the first course, as of the decade of 1950s. The survey has involved teaching nurses who have lived such period of our history, and the discourse analysis has been utilized for the documental analysis. The information data indicate, among them, the most integrated curriculum that seeks articulating theory/practice without fragmenting the knowledge and the teaching-learning relationship, wherein professors and students are subjects of such procedure. PMID- 20835672 TI - [Philosophical and theoretical basis for new conceptions of nursing care: contribution of the social poetic]. AB - This work identifies the application of the philosophical and theoretical basis of the social poetic in new conceptions of nursing care. Systematic review of 30 research works. Delimited categories: Dialogue in taking care of as technological instrument; To take care of in nursing as not invasive technology. In the new conceptions of to take care the client is considered the main target of the work in health. It was concluded that the social poetic basis were applied disclosing a perspective on the ethics of to take care, translated into respect with the clients and your knowledge for the self care, leads to the autonomy and solidarity between clients and professionals. The social poetic, as research method and social practice, discloses orienting aspects of a new perspective to be developed in nursing take care of. PMID- 20835673 TI - [Reflections on nursing assistance provided to the parturient]. AB - The objective of this bibliographic study is to identify the state of the art of production published in the area of obstetrics nursing involving the birth process, to contribute to future investigations, and to assist in reflection upon this theme. Data was collected through the bibliographic analysis of the LILACS, MEDLINE, Cochrane Library, and SciELO databases. Descriptors used: nurse midwives, childbirth work, normal childbirth, and Nursing care. Five studies were selected and later catalogued in bibliographic files. The themes selected were: professional regulation, care, assistance given, link established, educational actions, administrative activities, and difficulties. While the studies recognize this professional as a capacitated, legally backed professional who offers humanized assistance and thus reaffirms normal vaginal delivery, thus proportioning dignity, security, and autonomy to the delivering mother much still needs to written in order for the same autonomy and ethical-legal respect is acquired for health care professionals and clientele. PMID- 20835674 TI - [Maltreatmens against children and teenagers]. AB - The maltreatments against children and adolescents are admitted as a crescent phenomenon in world, but its knowledge are in building process due to its complexity. This study show a revising the literature with aims know and publicise epidemiological data about the violence against children and adolescents, discuss the knowledge about magnitude of this violence, the related factors and the consequences for victims. The literature show the range and magnitude violence against children and adolescents. Furthermore, studies reinforce the importance of recognizing the nature and reality of these events to form a diagnosis that helps elaborate and accomplish specific prevention and intervention policies. PMID- 20835675 TI - [Mental health in primary attention: needed constitution of competences]. AB - The family/people integrally attention is one of health services and professionals challenges, creating spaces for metal health in the primary level health attention. The aim of this study is to reflect about the constitution necessity of new knowledges/dones to the mental health at the primary attention, taking as perspective the competence referential. Essay developed since the historical assumptions ascertains that contextualize the Family Health Strategy and its interfaces with the psychosocial principles and some nurse background implications since the competence development theoretical intentions. We consider that reality transformation, with the health attention improvement asks for knowledges/dones constitution that attends to the psychosocial attention and the Unique Health System rules. PMID- 20835676 TI - [Teaching of oncology in nurse's education]. AB - The aim of the present study was to think the Oncology Course in the baccalaureate nursing curriculum pointing relevant issues about its introduction, considering professional training and qualification, labor market demand and a critical reflection about nurse's professional competences. Score is also the role of technology in helping training and education of new health professionals. PMID- 20835677 TI - [Therapeutic communication in perioperative care of mastectomy]. AB - The authors report their experience as teacher-nurse for years in oncologic hospital with the aim of enabling reflection on the development of nursing therapeutic communication at the hospital preoperative unit for mastectomized women. It was found that the practice of therapeutic communication becomes a favorable practice, because establish the nurse-patient relationship, with patient producing his own care. Understanding the fragility of the patient at this stage, the nurse takes commitment to predefine the nursing care in partnership, in order to meet the patient needs, aiming to, mainly, the autonomy of care. In this way, the authors present a proposal for nursing managed care based on a mutual relationship, human and participatory care. PMID- 20835678 TI - [Clinical and angiographic profile in coronary artery disease: hospital outcome with emphasis on the very elderly]. AB - BACKGROUND: knowing the risk factors and clinical manifestations of coronary artery disease (CAD) allows us to intervene more effectively with a particular population. OBJECTIVE: to identify clinical and angiographic profiles of patients undergoing cardiac catheterization, treated at a tertiary hospital and treated by percutaneous coronary interventions (PCI). METHODS: the study of 1,282 patients who underwent 1,410 cardiac catheterizations, selected from March/2007 to May/2008 from a database in a general hospital for diagnosis of coronary artery disease (CAD). Risk factors, indication for examination, technical details of PCI and in-hospital outcomes were prospectively collected. RESULTS: there were 688 (54.0%) males, mean age 65.4 +/- 10.9 years and 20.0% above 75 years age. The most frequent clinical condition was acute coronary syndrome (ACS) without ST segment elevation (STS) (38.7%). The multi artery CAD occurred in 46.4%, PCI was indicated in 464 patients, 547 target lesions were treated (type B2 or C, 86.0%), and of these, 14.0% treated with drug eluting stents. Among those with AMI with STS, primary PCI was performed in 19.0% of the patients, from these, 77.0% were transferred from the origin hospitals late (late PCI) and had not received prior thrombolytic, and 4.0% had PCI rescue. Angiographic success was achieved in 94.2% of PCIs. Death occurred in 5.6% of patients, with average age of 75.2 +/- 10.2 years. CONCLUSION: the prevalence of elderly (20.1% being > 75 years) and male was observed. From the risk factors for CAD, the most common were systemic hypertension and dyslipidemia. There was a predominance of ACS. Age > 75 years old, multiarterial CAD and chronic renal failure were predictors of in-hospital deaths. PMID- 20835679 TI - [Effect of physical activity and t-786C polymorphism in blood pressure and blood flow in the elderly]. AB - BACKGROUND: the T-786C polymorphism of the gene for endothelial nitric oxide synthase (eNOS) and superoxide anion production may reduce production and bioavailability of nitric oxide, affecting the degree of vasodilation. This effect can be reversed by exercise. OBJECTIVE: to investigate the influence of aerobic training and T-786C polymorphism in the concentrations of nitric oxide metabolites (NOx) in blood flow (BF) and blood pressure (BP). METHODS: thirty-two elderly pre-hypertensive women (59 +/- 6 years old) were divided into two groups according to the T-786C polymorphism (TT and TC + CC). We analyzed the concentrations of NOx (plasma) and blood flow by venous occlusion plethysmography at rest, 1, 2 and 3 minutes post-occlusion (BF-0, BF-1 BF-2 BF-3, respectively). Evaluations were performed before and after 6 months of a program of aerobic exercise. RESULTS: In the pre-training evaluations, NOx levels were lower in TC + CC group than in TT group. The TT group showed correlations between NOx and BF-0 (r = 0.6) and diastolic blood pressure (DBP) and BF-0 (r = -0.7), but no correlation was found in TC + CC group. In the post-training evaluations, there were correlations between NOx and BF-0 (r = 0.6) and the changes in NOx and DBP (r = -0.6) in TT group. There were also correlations between DBP and BF-1 (r = 0.8), DBP, and BF-2 (r = -0.6), DBP, and BF-3 (r = -0.6), in the changes between NOx and BF-1 (r = 0.8) and changes in NOx and DBP (r = -0.7) in TC + CC group. CONCLUSION: it was concluded that 6 months of aerobic exercise can increase the relationship between NO, BP and BF in elderly of allele C carriers. PMID- 20835680 TI - Relationship between depression, BNP levels and ventricular impairment in heart failure. AB - BACKGROUND: Depression is a common comorbidity in heart failure (HF); however, the mechanisms related to a poorer outcome of depressed patients with HF remain unclear. OBJECTIVE: To evaluate the role of severe depression in the outcome of patients with decompensated HF. METHODS: A total of 43 patients with advanced HF, EF < 40.0%, and hospitalized for cardiac compensation were consecutively studied. After history taking and physical examination, the patients underwent laboratory tests including BNP determination. After the diagnosis of depression was made, the Hamilton-D scale was applied. Severe depression was defined by a score equal to or greater than 18. The clinical and laboratory variables according to the presence or absence of severe depression were analyzed using logistic regression. The ROC curve defined the cut-off point for BNP. RESULTS: Severe or very severe depression was identified in 24 (55.8%) patients. Severely depressed patients did not differ from non-depressed patients as regards age, gender and renal function, but showed less cardiac impairment (EF 23.4 +/- 7.2% vs 19.5 +/- 5.2%; p = 0.046) and higher BNP levels (2,582.8 +/- 1,596.6 pg/ml vs 1,206.6 +/- 587.0 pg/ml; p < 0.001). However, patients with BNP levels higher than 1,100 pg/ml had a 12.0-fold higher chance (odds ratio [95% CI] = 2.61 - 55.26) of developing severe depression. CONCLUSION: Patients with severe depression showed a higher degree of neurohormonal stimulation despite their lower degree of ventricular dysfunction. The pathophysiological changes related to depression, leading to increased neurohormonal stimulation and cytokines, probably contributed to this more intense clinical manifestation even in the presence of less cardiac damage. PMID- 20835681 TI - [Relationship between leisure-time physical activity and blood pressure in adults]. AB - BACKGROUND: high blood pressure (BP) is found at epidemic levels in adults of industrialized societies, thereby favoring an increase in the risk of development of numerous cardiovascular pathologies. OBJECTIVE: to investigate the relationship between leisure-time physical activity (LTPA) and high systolic blood pressure (SBP)/diastolic blood pressure (DBP) in adults, in the city of Salvador, state of Bahia. METHODS: a cross-sectional study was conducted with a sample of 2,292 adults of both sexes, aged > 20 years. Those who engaged in physical activity during their leisure time were considered to be active in their free time. We used logistic regression analysis to estimate the odds ratio (OR), with confidence interval of 95%. RESULTS: after the adjustment for age and stratification by sex, the relationships between LTPA and SBP/DBP were: SBP = 0.86 (0.85 to 0.87) for females and 0.65 (0.64 to 0.66) for males; DBP = 0.94 (0.92 to 0.95) for females and 0.64 (0.63 to 0.65) for males. CONCLUSION: the results of this study are important to public health and they must be used to raise awareness of the relevance of LTPA to prevent high levels of SBP/DBP. PMID- 20835682 TI - [Heart rate variability and pulmonary infections after myocardial revascularization]. AB - BACKGROUND: heart rate variability (HRV) is a noninvasive diagnostic method used in the assessment of the autonomic modulation of the heart. The assessment of HRV using nonlinear dynamics methods in the preoperative period of surgical myocardial revascularization could be predictive of morbidity such as pulmonary infections in the postoperative period. OBJECTIVE: to evaluate the behavior of HRV using nonlinear dynamics in the preoperative period of surgical myocardial revascularization and its relation to the occurrence of pulmonary infections in the in-hospital postoperative period. METHODS: a total of 69 patients with coronary artery disease (mean age of 58.6 +/- 10.4 years) and indication for elective surgical myocardial revascularization were studied. In order to quantify the nonlinear dynamics of HRV, the following procedures were performed: detrended fluctuation analysis (DFA); analysis of the short (alpha1) and long-term (alpha2) components of DFA; approximate entropy (ApEn); Lyapunov exponent (LE); and Hurst exponent (HE) of time series of RR intervals of the ECG, as captured by the Polar S810i instrument on the day before surgery. RESULTS: at the cut-off levels set by the ROC curve, there was a significant difference between the groups with and without pulmonary infections in the postoperative period of myocardial revascularization for total DFA, approximate entropy and Lyapunov exponent with p = 0. 0309, p = 0.0307 and p = 0.0006, respectively. CONCLUSION: the nonlinear dynamics methods, at their respective cut-off levels, allowed for the identification of patients developing pulmonary infection in the postoperative period of surgical myocardial revascularization, thus suggesting that these methods may have a prognostic value for this group of patients. PMID- 20835684 TI - [Influence of genetic combinations on HDL-C levels in a Southern Brazilian population]. AB - BACKGROUND: low HDL-C levels are important predictors of coronary disease, the first cause of death worldwide. Many factors affect HDL-C levels, such as polymorphisms of genes encoding for key proteins of the reverse cholesterol transport pathway. OBJECTIVE: to investigate the influence of seven polymorphisms of the CETP, APOA1, ABCA1 and SCARB1 genes on HDL-C levels in a southern Brazilian population. METHODS: the polymorphisms were investigated in a sample of 500 individuals of European descent, but HDL-C levels from only 360 individuals were adjusted for cofactors using multiple linear regressions in the association study. The sample was divided in tertiles according to adjusted HDL-C levels, and allele and haplotype frequencies were compared between the 1st and 3rd tertiles of adjusted HDL-C levels. RESULTS: When combinations of risk alleles were tested, the frequency of allele combinations in three genes (haplotype 1 of APOA1 gene, variant 2S of SCARB1 gene, and allele B1 of CETP gene) was significantly higher in the lower tertile of adjusted HDL-C (28.3%) than in the upper tertile (14.9%; p=0.008), which indicated that the presence of these variants increased 2.26 times the chances of having HDL-C levels below 39.8 mg/dl. CONCLUSION: these markers, when studied separately, are expected to have a small influence on the characteristic under analysis, but greater influence was detected when the markers were studied in combination. In a population of southern Brazilians, our data showed a significant influence of variant combinations of APOA1, SCARB1 and CETP genes on HDL-c levels. PMID- 20835683 TI - [Electrocardiographic score: application in exercise test for the assessment of ischemic preconditioning]. AB - BACKGROUND: the time for 1.0 mm ST-segment depression (T-1.0mm) adopted to characterize ischemic preconditioning (IPC) in sequential exercise tests is consistent and reproducible; however, it has several limitations. OBJECTIVE: to apply an electrocardiographic score of myocardial ischemia in sequential exercise tests, comparing it to the conventional T-1.0 mm index. METHODS: sixty one patients with mean age of 62.2 +/- 7.5 years were evaluated; 86.9% were males. A total of 151 tests were analyzed, 116 of which were from patients who completed two assessment phases. The first phase comprised two sequential exercise tests for the documentation of IPC; the second phase, initiated one week later, comprised two more tests carried out under the effect of repaglinide. Two observers who were blind to the tests applied the score. RESULTS: Perfect inter and intraobserver agreement was found (Kendall tau-b = 0.96, p < 0.0001, and Kendall tau-b = 0.98, p < 0.0001, respectively). Values of sensitivity and specificity, negative predictive value, positive predictive value and accuracy were 72.41%, 89.29%, 75.8%, 87.5% and 81.0%, respectively. CONCLUSION: the ischemic score is a consistent and reproducible method for the documentation of IPC, and is a feasible alternative to T-1.0 mm. PMID- 20835685 TI - [Assessment of resistant hypertension with home blood pressure monitoring]. AB - BACKGROUND: ambulatory blood pressure monitoring (ABPM) is considered the gold standard for the diagnostic confirmation of resistant hypertension (RH). However, home blood pressure monitoring (HBPM) has been considered an option, because of its lower cost and greater comfort. OBJECTIVE: to compare the values obtained by HBPM with those obtained by ABPM in the identification of patients with resistant hypertension. METHODS: a total of 51 consecutive patients with resistant hypertension were selected. All were adults of both genders and were undergoing treatment in an outpatient referral clinic from January 2007 to September 2009. Casual office blood pressure (BP), 24-hour ABPM, and HBPM were performed according to current guidelines, with a maximum two-week interval between the methods. RESULTS: the comparison of ABPM (mean daytime) with HBPM showed a good correlation between them, both for systolic blood pressure (SBP) and for diastolic blood pressure (DBP): SBP r = 0.70, CI = 0.51-0.82, DBP r = 0.69, CI = 0.52-0.81. RH was confirmed by ABPM in 33 patients and by HBPM in 37, with no significant difference between the methods. CONCLUSION: according to the results obtained, we conclude that HBPM is a method that can be used as an alternative to ABPM for the diagnostic confirmation of RH. PMID- 20835687 TI - Evaluation of anti-Wnt/beta-catenin signaling agents by pGL4-TOP transfected stable cells with a luciferase reporter system. AB - Refractory and relapsed leukemia is a major problem during cancer therapy, which is due to the aberrant activation of Wnt/beta-catenin signaling pathway. Activation of this pathway is promoted by wingless (Wnt) proteins and induces co activator beta-catenin binding to lymphoid enhancer factor (LEF)/T-cell factor protein (TCF). To provide a convenient system for the screening of anti-Wnt/beta catenin agents, we designed a bi-functional pGL4-TOP reporter plasmid that contained 3X beta-catenin/LEF/TCF binding sites and a selectable marker. After transfection and hygromycin B selection, HEK 293-TOP and Jurkat-TOP stable clones were established. The luciferase activity in the stable clone was enhanced by the recombinant Wnt-3A (rWnt-3A; 100-400 ng/mL) and GSK3beta inhibitor (2'Z,3'E)-6 bromoindirubin-3'-oxime (BIO; 5 uM) but was inhibited by aspirin (5 mM). Using this reporter model, we found that norcantharidin (NCTD; 100 uM) reduced 80% of rWnt-3A-induced luciferase activity. Furthermore, 50 uM NCTD inhibited 38% of BIO induced luciferase activity in Jurkat-TOP stable cells. Employing 3H-thymidine uptake assay and Western blot analysis, we confirmed that NCTD (50 uM) significantly inhibited proliferation of Jurkat cells by 64%, which are the dominant beta-catenin signaling cells and decreased beta-catenin protein in a concentration-dependent manner. Thus, we established a stable HEK 293-TOP clone and successfully used it to identify the Wnt/beta-catenin signaling inhibitor NCTD. PMID- 20835686 TI - The neurobiology of infant maternal odor learning. AB - Infant rats must learn to identify their mother's diet-dependent odor. Once learned, maternal odor controls pups' approach to the mother, their social behavior and nipple attachment. Here we present a review of the research from four different laboratories, which suggests that neural and behavioral responses to the natural maternal odor and neonatal learned odors are similar. Together, these data indicate that pups have a unique learning circuit relying on the olfactory bulb for neural plasticity and on the hyperfunctioning noradrenergic locus coeruleus flooding the olfactory bulb with norepinephrine to support the neural changes. Another important factor making this system unique is the inability of the amygdala to become incorporated into the infant learning circuit. Thus, infant rats appear to be primed in early life to learn odors that will evoke approach responses supporting attachment to the caregiver. PMID- 20835688 TI - Reduced lung cancer mortality and exposure to synthetic fluids and biocide in the auto manufacturing industry. AB - OBJECTIVES: Water-based soluble and synthetic metalworking fluids (MWF) used in auto manufacturing may be contaminated by endotoxin from Gram-negative bacteria, a possible anticarcinogen via increased immuno-surveillance. The effectiveness of biocide, generally added to limit bacterial growth is unknown. We investigated whether an inverse relationship between lung cancer and synthetic MWF and biocide - as surrogates of endotoxin exposure - persisted in an extended follow-up of autoworkers. METHODS: A nested case-control analysis was performed within a retrospective cohort study of 46 399 auto manufacturing workers. Follow-up began in 1941 and was extended from 1985-1995. Mortality rate ratios (MRR) were estimated in Cox regression models for lung cancer as discrete and smoothed functions of cumulative exposure to synthetic MWF (mg/m (3)per year) and years exposed to biocide with both synthetic and soluble MWF. The analysis was also restricted to the subcohort hired on or after 1941 and stratified by follow-up period. RESULTS: The splines suggested a non-linear inverse exposure-response for lung cancer mortality with increasing endotoxin exposure. Overall, the greatest reduction in mortality was observed among those with the highest exposure [MRR 0.63, 95% confidence interval (95% CI) 0.39-0.98] at the 99 (th)percentile of exposure (15.8 mg/m (3)per year). Evidence for an inverse effect was limited to the earlier follow-up period. Effect modification by biocide was marginally significant (P=0.07); the protective effect of synthetic MWF was observed only for those who were co-exposed. CONCLUSIONS: The protective effect of synthetic MWF against lung cancer mortality persisted through the extended period of follow up, although attenuated, and was observed only among workers with co-exposure to biocide and synthetic MWF. PMID- 20835689 TI - Does stress at work make you gain weight? A two-year longitudinal study. AB - OBJECTIVES: Research concerning the association between stress at work and body mass index (BMI) has mainly focused on two models (ie, job demand-control and effort-reward imbalance) as predictors and mostly been cross-sectional. The aim of our study is to extend previous research in two ways. First, social stressors in the sense of social conflict and animosities at work - were included as an independent variable, arguing that they should be an especially promising predictor as they reflect a "social-evaluative threat". Second, a longitudinal design was employed with a two-year follow-up. In addition, the variables specified by the job demand-control model and the effort-reward imbalance model were assessed as well. METHODS: Participants comprised 72 employees (52 men, 20 women) from a Swiss service provider. Multiple regression analyses were used to predict BMI two years later with social stressors, effort-reward imbalance, demands, control, and the interaction of demands and control. Baseline BMI was controlled so that the dependent variable reflects the change in BMI over two years. RESULTS: Regression analyses revealed control and social stressors to be statistically significant predictors of follow-up BMI, while effort-reward imbalance was marginally significant. CONCLUSIONS: The results underscore the importance of social stressors and job control as predictors of stress-related impaired health. PMID- 20835690 TI - Reversible congestive heart failure in severe hypocalcemia. AB - We present a case of severe congestive left heart failure due to profound and long-term hypocalcemia caused by surgically induced hypoparathyroidism. Hypocalcemia as a potential contributor to heart failure should be included in the differential diagnosis of all patients with congestive heart failure who do not respond adequately to the usual treatment. By rapid correction of the serum calcium level unnecessary diagnostic and therapeutic measures might be avoided. In addition, being aware of and treating hypocalcemia is crucial since this kind of heart failure is completely reversible with calcium and vitamin D treatment.The pivotal role of calcium in molecular and cellular biology is well known, but its clinical importance in day-to-day practice is often underestimated. Although some cases of heart failure resulting from hypocalcemia secondary to hypoparathyroidism have been published in the last 20 years, this subject is still poorly documented in almost all current textbooks. PMID- 20835691 TI - [Modified two-rescuer resuscitation algorithm. Alternative for international missions of the German Armed Forces!]. AB - BACKGROUND: The aim of this study was to examine whether it is possible to perform resuscitation according to the present European Resuscitation Council (ERC) guidelines with a modified algorithm in the case of special, e.g. military, circumstances. On international missions of the German Armed Forces a rescue team only consists of an emergency physician and a paramedic. As the German Armed Forces require the same means of medical aid for all soldiers on every type of mission worldwide the algorithm must meet the ERC requirements. MATERIAL AND METHODS: In the study 20 medical teams specialized in resuscitation were examined. Of these teams 10 were from the German Armed Forces (the physician is a certified emergency physician) and 10 were civilian (the emergency physicians had up to 28 years experience). Each team was monitored as they performed resuscitation on a simulator for a period of 10 min. The patient's airway was secured by a laryngeal tube (LT) and over-the-head chest compressions were performed by the emergency physician. During resuscitation both team members held their position. In addition to comparing all results to the ERC guidelines both groups were analyzed separately and compared to each other. RESULTS: The median time needed for securing the airway was 17 s without any differences between the 2 groups. In 75% of the cases the time needed for successfully securing the airway on the first attempt was less than the allowed 30 s. In 5 cases (25%) the teams did not manage to successfully install the LT during the first attempt (4 failed attempts were performed by civilian teams and 1 by the military emergency teams); however, all 5 teams were successful at the second attempt. In the cases where the placement of the LT was not successful at the first attempt the time required for the final and successful placement was nevertheless less than 40 s. During the 10 min resuscitation procedure the hands-off fraction was on average 22.4%. No differences between the two groups were noted concerning the hands-off time (133.5 s for the civilian teams and 134.5 s for the teams of the German Armed Forces). The frequency of chest compressions was above the required 100/min (for the civilian teams 110/min and for the teams of the German Armed Forces 116.5/min). CONCLUSION: During military missions of the German Armed Forces there are no other options to perform resuscitation than by performing this procedure with only two rescuers. Using the algorithm in a modified way securing of the airway with an LT, the performance of over-the-head chest compressions and an effective resuscitation with advanced cardiac life support according to the ERC guidelines of 2005 are feasible even with 2 rescuers. Using the LT instead of endotracheal intubation to secure the airway particularly contributed to shortening the hands-off time. PMID- 20835692 TI - Spontaneously breathing anesthetized patients with a laryngeal mask airway: positive end-expiratory pressure does not improve oxygen saturation. AB - Spontaneous ventilation is a popular mode of ventilation for patients with the laryngeal mask airway (LMA). Studies have shown, however, that spontaneous ventilation impairs gas exchange and that assisting or controlling ventilation results in higher oxygen saturation. Atelectasis during general anesthesia is a well described mechanism which impacts on gas exchange. Positive end-expiratory pressure (PEEP) increases the lung volume available for gas exchange. This study investigated whether the application of PEEP leads to an improvement of oxygen saturation in unassisted spontaneously breathing patients with a LMA. A total of 80 adult patients under general anesthesia were prospectively randomized into two groups. Both groups were left to breathe spontaneously. In group 1 the adjustable pressure limiting (APL) valve was opened resulting in zero end-expiratory pressure. In group 2 the valve was set to a PEEP of +7 cm H2O. Oxygen saturation was measured by pulse oxymetry at four different phases: pre-induction, after induction and insertion of the LMA, during maintenance and in recovery. The application of PEEP did not improve oxygen saturation. In both groups the mean oxygen saturation was similar (97.2+/-1.8% in group 1 versus 97.2+/-1.9% in group 2, p=0.941) during maintenance. No effect on oxygen saturation in recovery could be found either (96.0+/-1.8% in group 1 versus 96.1+/-2.0% in group 2, p=0.952) and hemodynamics were unaffected by the application of PEEP. The application of a PEEP of +7 cm H2O with a LMA under spontaneous ventilation cannot be recommended. Limitations of our study were the selection of healthy patients and omitting pre oxygenation before induction which might have limited the development of atelectasis. In addition arterial partial pressure of oxygen (p(a)O2) measurements could have revealed subtle changes in oxygenation. PMID- 20835693 TI - [The role of erythropoietin in improvement of wound healing]. AB - Pleiotropic substances are characterized by their versatile and complex range of actions which makes them potential new active agents for the therapy of wounds. Besides its known effect to increase red blood cell production, the glycoprotein hormone erythropoietin (EPO) has been found to demonstrate a tissue protective effect in several other organs. The administration of EPO during skin wound healing is most likely essentially based on its cytopotective, proangiogenic, antiapoptotic and antiinflammatory effects. Herein EPO stimulates a coordinated interaction of different types of cells at a low or only a single dose. This review article aims to present the advantages and disadvantages of EPO administration in different experimental models to study the healing and regeneration processes of the skin and discusses possible clinical applications. PMID- 20835694 TI - [Total pelvic exenteration]. AB - Over the last decades total pelvic exenteration (TPE) has evolved into an established and safe surgical technique for locally advanced pelvic malignancies. Depending on the type of cancer 5 year overall survival rates of up to 66% and a satisfactory postsurgical quality of life have been reported. Currently infiltration of the pelvic side wall and resectable metastases are not necessarily a contraindication to a curative approach; furthermore, TPE can also be useful in palliative surgery. In locally recurrent rectal cancer TPE is the treatment of choice if the tumor is deemed resectable. A multidisciplinary diagnostic and therapeutic approach is of utmost importance, hence patients should be treated in specialized centers. PMID- 20835695 TI - [Transoral partial parathyroidectomy]. AB - Improvements in minimally invasive surgical techniques have resulted in the development of natural orifice transluminal endoscopic surgery (NOTES) to minimize operative trauma and perioperative morbidity. Considering the embryologic origin and development of the thyroid and parathyroid glands and their descent during embryogenesis into the final position in the neck, a transoral access to the thyroid region via a sublingual mucosal incision seems to be feasible. After implementation and improvement of a transoral access to the thyroid region in an animal model and human cadavers, we now report the first transoral excision of a parathyroid adenoma in a 37-year-old woman suffering from primary hyperparathyroidism. PMID- 20835696 TI - [Recommendations of the AGA (German-speaking Arthroscopy Association) on equipment of facilities, process quality and qualification of surgeons for arthroscopic interventions]. AB - Following closely the guidelines of the German Federal Medical Association for quality assurance of outpatient surgery, the AGA (German-speaking Arthroscopy Association) has formulated recommendations on quality standards in arthroscopic surgery. The surgical facility should implement a quality management system. Minimum standards of construction, apparatus, technical and hygiene facilities are included according to the directive of the German Federal Medical Association for quality assurance in outpatient surgery. General organizational requirements and process quality are described. These include the pre-operative diagnosis and therapy, outpatient surgery and anesthesia, the treatment after surgery and the assessment of the quality of the result. Requirements for the qualification of surgeons for authorization to independently execute arthroscopic services and training are formulated. The AGA recommends that in addition to the specialist status for authorization to independently execute arthroscopic services, the qualification "AGA arthroscopist" and for training of other doctors in the field of arthroscopic surgery, the qualification "AGA instructor" should be required. PMID- 20835697 TI - First direct evidence of hibernation in an eastern dwarf lemur species (Cheirogaleus crossleyi) from the high-altitude forest of Tsinjoarivo, central eastern Madagascar. AB - The nocturnal dwarf lemurs of Madagascar (genus Cheirogaleus) are the only primates known to be obligate hibernators. Although the physiology of hibernation has been studied widely in the western, small-bodied species, Cheirogaleus medius, no direct evidence of hibernation, i.e., body temperature recordings, has been reported for any of the three recognized eastern dwarf lemur species. We present skin temperature data collected by external collar transmitters from two eastern dwarf lemur individuals (Cheirogaleus crossleyi) captured in the high altitude forest of Tsinjoarivo, central-eastern Madagascar. Our study species is larger in body size than western dwarf lemurs and inhabits much colder environments. We present the first evidence of hibernation in an eastern dwarf lemur species, and we compare the results with data available for the western species. Although the hibernation period is shorter in dwarf lemurs from Tsinjoarivo, minimum body temperatures are lower than those reported for C. medius. Both individuals at Tsinjoarivo showed limited passive and extended deep hibernation during which they did not track ambient temperature as observed in most western dwarf lemurs. Because ambient temperatures at Tsinjoarivo never exceed 30 degrees C, dwarf lemurs have to experience arousals to maintain homeostasis during periods of hibernation. We show that large dwarf lemurs (>400 g) are capable of undergoing deep hibernation and suggest that cold, high altitude forests may render hibernation highly advantageous during periods of food scarcity. This study has implications for understanding the physiology of hibernation in small-bodied lemurs. PMID- 20835698 TI - [Seed migration to the vertebral venous plexus after prostate brachytherapy]. AB - We report on seed migration to the vertebral venous plexus after low dose rate prostate brachytherapy with (125)I. A 74-year-old man with T1c N0 M0 adenocarcinoma of the prostate with a Gleason score of 6 (3+3) and prostate specific antigen level of 14.94 ng/ml underwent interstitial prostate brachytherapy. Six weeks after treatment at the follow-up to determine aftercare a migrated seed was detected in the vertebral venous plexus and a second one in the right lung. No tissue damage around the migrated seeds was documented and the patient exhibited no clinical symptoms. PMID- 20835699 TI - [SILS, LESS, NOS, and Co. for minimally invasive kidney treatment: is less more?]. AB - BACKGROUND: Single-port surgery (LESS) is a new method of minimally invasive laparoscopic urology. These modern methods reduce the tissue trauma of the patient; however, high demands are placed on the surgeon. We report our initial clinical experience. MATERIAL AND METHODS: Eight patients with different pathologies in the abdomen and retroperitoneum (nephrectomy, renal cyst resection) were treated with an abdominal LESS access and two patients with vaginal NOS (natural orifice surgery) access. Previously, we obtained extensive experience with the setup and implementation in animal studies. The port placements were realized by various single-port systems in the paraumbilical region. RESULTS: All procedures were performed without conversion to an open surgical procedure. Two additional trocars were needed in the first single-port operation. The intra- and postoperative follow-up was uneventful in all patients. The average age of the patients was 58.9 years, the average operating time 131 min, the mean blood loss 70 ml, and the median body mass index 27. The postoperative evaluation of patient satisfaction revealed that all patients were perfectly satisfied. CONCLUSIONS: With appropriate experience and training of the whole team, single-port surgery is a safe and appropriate method for selected renal surgery. PMID- 20835700 TI - HbA1c: a useful cardiovascular risk marker in those without diabetes? PMID- 20835701 TI - Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age. AB - AIMS/HYPOTHESIS: The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism. METHODS: Mice deficient in CB2R (Cb2 ( -/- ) [also known as Cnr2]) were studied at different ages (2-12 months). Two-month old Cb2 (-/-) and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet. RESULTS: The lack of CB2R in Cb2 (-/-) mice led to greater increases in food intake and body weight with age than in Cb2 (+/+) mice. However, 12-month-old obese Cb2 (-/-) mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2 (-/-) mice were fed a high fat diet, reduced body weight gain and normal insulin sensitivity were observed. CONCLUSIONS/INTERPRETATION: These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance. PMID- 20835702 TI - Changing microbiological profile of pathogenic bacteria in diabetic foot infections: time for a rethink on which empirical therapy to choose? AB - AIMS/HYPOTHESIS: We studied the bacterial aetiology and antibiotic sensitivity pattern of diabetic foot ulcers in India. METHODS: Records of 447 hospitalised patients between 1991 and 2008 were retrospectively analysed between two time periods (before and after 1999) to compare bacterial aetiology and antimicrobial sensitivity patterns. The first three consecutive cultures from the same wound during treatment were evaluated. RESULTS: Of 1,632 cultures, 66% were polymicrobial, 23% monomicrobial and 11% sterile. In the monomicrobial group, 14% (n = 228) of cultures were Gram-negative, whereas 9% (n = 147) were Gram positive. The most common pathogens in the first culture were Pseudomonas aeruginosa (20.1%), Staphylococcus aureus (17.2%) and Escherichia coli (16.3%). Results for the third cultures showed persistence of P. aeruginosa (15.3%) and E. coli (14.2%). Gram-negative isolates dominated over Gram-positive ones (25.3% vs 15.1%, p < 0.05). Antibiotic sensitivity patterns before and after 1999 were: piperacillin-tazobactam 74% vs 66% (p < 0.005), imipenem 77% vs 85% (NS), cefoperazone-sulbactam 47% vs 44% (p < 0.005), amikacin 62% vs 78% (NS), ceftriaxone 41% vs 36% (p < 0.005), amoxicillin-clavulanate 51% vs 43% (p < 0.05) and clindamycin 43% vs 36% (p < 0.005), respectively. CONCLUSIONS/INTERPRETATION: Unlike in the West, in India Gram-negative bacteria were found to have always been dominant in the wounds of patients with diabetic foot infections. Infection with polymicrobial multidrug-resistant Gram-negative bacilli is common. The policy of empirical antimicrobial therapy at tertiary care needs to be changed. PMID- 20835703 TI - 3-hydroxy 3-methylglutaryl coenzyme A reductase: a new biomarker of fish exposure to water pollution. AB - The aim of this study was to identify a new putative biomarker in Salmo trutta exposed to water pollution. Variations in the levels of hepatic 3-hydroxy 3 methylglutaryl Coenzyme A reductase (HMG-CoAR), the rate-limiting enzyme of cholesterol biosynthesis, were compared to heat shock protein 70 and hypoxia inducible factor alpha, biomarkers of pollution exposure and lowered O2, respectively. The results confirm that HMG-CoAR levels increase in polluted water irrespective of water temperature or O2 content, indicating that HMG-CoAR could be used as a specific biomarker for water pollution. PMID- 20835704 TI - The local vasoconstriction of infant's skin following instillation of mydriatic eye drops. AB - BACKGROUND: Systemic absorption of eye drops is known to occur via the nasal mucosa, cornea, and conjunctiva. Diffusion of eye drops through the skin is previously unrecognized. Here, two cases are presented in which we observed skin pallor around the eyes after instillation of phenylephrine 2.5% drops. CASE 1: A 32-week gestational age premature infant had mydriatic eye drops instilled as part of retinopathy of prematurity screening. CASE 2: A term newborn dysmorphic infant underwent fundus examination to rule out ocular pathology. In both cases, discoloration of periorbital skin was observed 45 min following administration of drops. CONCLUSION: The risks of percutaneous toxicity must always be considered in children, especially in premature neonates, in whom the epidermal permeability barrier is frequently incompetent. Application of smaller drop size or wiping of overflowed drop from the skin may be useful to decrease the risk of systemic side effects. PMID- 20835705 TI - Palmitic acid induces the opening of a Ca2+-dependent pore in the plasma membrane of red blood cells: the possible role of the pore in erythrocyte lysis. AB - Earlier we found that in the presence of Ca(2+) palmitic acid (Pal) increases the nonspecific permeability of artificial (planar and liposomal) membranes and causes permeabilization of the inner mitochondrial membrane. An assumption was made that the mechanism of Pal/Ca(2+)-induced membrane permeabilization relates to the Ca(2+)-induced phase separation of Pal and can be considered as formation of fast-tightening lipid pores due to chemotropic phase transition in the lipid bilayer. In this article, we continue studying this pore. We have found that Pal plus Ca(2+) permeabilize the plasma membrane of red blood cells in a dose dependent manner. The same picture has been revealed for stearic acid (20 MUM) but not for myristic and linoleic acids. The Pal-induced permeabilization of erythrocytic membranes can also occur in the presence of Ba(2+) and Mn(2+) (200 MUM), but other bivalent cations (200 MUM Mg(2+), Sr(2+), Ni(2+), Co(2+)) are relatively ineffective. The formation of Pal/Ca(2+)-induced pores in the erythrocytic membranes has been found to result in the destruction of cells. PMID- 20835706 TI - The effect of isolated popliteus tendon complex injury on graft force in anterior cruciate ligament reconstructed knees. AB - Failure to diagnose injury to the posterolateral structures has been found to increase the forces experienced by the anterior cruciate ligament (ACL) and ACL grafts which may cause their subsequent failure. An isolated injury to the popliteus complex (PC) consisting of the popliteus tendon and popliteofibular ligament is not uncommon. Therefore, the purpose of this study was to discover if an isolated injury to the PC can significantly affect the forces experienced by the ACL graft under external loading conditions. We hypothesised that, under external tibial torque, the ACL graft will experience a significant increase in force, in knees with PC injury compared to the intact PC condition. Under varus tibial torque (10 N m), we observed minimal changes in the varus tibial rotation due to isolated sectioning of the PC in an ACL reconstructed knee (P > 0.05). Consequently, no significant increase in the ACL graft force was observed under varus tibial torque. In contrast, sectioning the PC resulted in a significant increase in the external tibial rotation compared to the intact PC knee condition under the external rotational tibial torque (5 N m) at all flexion angles (P < 0.05). These changes in kinematics under external tibial torque were manifested as elevated ACL graft forces at all selected flexion angles (P < 0.05). Prompt diagnosis of isolated PC injury and its treatment are warranted to prevent potential failure of ACL reconstruction. PMID- 20835707 TI - Montana's Clark Fork River Basin Task Force: a vehicle for integrated water resources management? AB - This article examines what is generally considered to be an unattainable goal in the western United States: integrated water resources management (IWRM). Specifically, we examine an organization that is quite unique in the West, Montana's Clark Fork River Basin Task Force (Task Force), and we analyze its activities since its formation in 2001 to answer the question: are the activities and contributions of the Task Force working to promote a more strongly integrated approach to water resources management in Montana? After reviewing the concepts underlying IWRM, some of the issues that have been identified for achieving IWRM in the West, and the Montana system of water right allocation and issues it faces, we adapt Mitchell's IWRM framework and apply it to the analysis of the Task Force's activities in the context of IWRM. In evaluating the physical, interaction, and protocol/planning/policy components of IWRM, we find that the Task Force has been contributing to the evolution of Montana's water resources management towards this framework, though several factors will likely continue to prevent its complete realization. The Task Force has been successful in this regard because of its unique nature and charge, and because of the authority and power given it by successive Montana legislatures. Also critical to the success of the organization is its ability to help translate into policy the outcomes of legal and quasi-judicial decisions that have impacted the state's water resources management agency. PMID- 20835708 TI - Invisible scar endoscopic dorsal approach thyroidectomy: a clinical feasibility study. AB - BACKGROUND: The aim of the present study was to test the safety and feasibility of the dorsal approach endoscopic thyroidectomy procedure in a prospective trial in humans, after the procedure had been developed ex vivo in human cadavers. METHODS: A total of 28 patients were enrolled for 30 unilateral procedures of thyroidectomy. Two cases were staged bilateral procedures. Patients presenting with suspicious cold nodules, hot nodules, or goiters were operated on under general anaesthesia. Skin incision is carried out on the scalp, behind the ear. Deep to the sternocleidomastoid muscle, but respecting the superficial cervical fascia, the preparation goes past the carotid triangle to reach the thyroid below the straight neck muscles. Postoperatively the patients underwent neurological assessment, vocal cord examination, clinical control for hemorrhage, and determination of serum levels of Ca(2+). RESULTS: Thirty unilateral procedures by the dorsal approach were carried out in 22 women and 6 men. There was 1 subtotal thyroidectomy and 29 total unilateral thyroidectomies with no conversions. There was one permanent recurrent laryngeal nerve (RLN) lesion and one postoperative hemorrhage. The size of the lobes removed ranged from 6 to 40 ml (mean: 18 ml). In four cases the specimen exceeded 38 ml. There was one multifocal papillary cancer requiring open surgical revision and lymphadenectomy. The other diagnoses were benign. All wounds healed by primary intention. Temporary impairment of cervical nerves was detected in six patients. It was possible to avoid access related problems by improving the patient's positioning on the operating table, omitting straight instruments, and respecting the superficial fascia before entering the carotid triangle. CONCLUSIONS: Hemithyroidectomy by the dorsal approach is feasible. It is a single surgeon, single port, gasless unilateral endoscopic technique with the option to go bilateral. PMID- 20835709 TI - [Characterization of ENU-mutant mice. Animal models for human diseases using morphological and molecular methods]. AB - Following sequencing of the human genome there are new challenges to decipher the knowledge concerning gene function and the role of gene interactions and pathways leading to disease. Mouse models have proven to be an ideal tool for this purpose. Point mutations induced by chemical mutagenesis by N-ethyl-N-nitrosourea (ENU) offer possibilities for the analysis of the phenotypic outcome of a single base pair exchange on the entire organism. The Munich ENU mouse mutagenesis project is part of the worldwide efforts to obtain mutations for each gene. The generation of new alleles or allelic series offers relevant insights into the relevance of single gene sections. Various mouse models for human diseases have been generated by a systematic large-scale genome-wide phenotyping screen in the last decade. This work illustrates how the implementation of the ENU mouse mutagenesis project with gene identification and parallel high-throughput screening is taking advantage of local cooperation with experienced phenotyping groups at the Helmholtz Zentrum Munchen, leading to major advances in the functional analysis of the mammalian genome. PMID- 20835711 TI - [2008 Annual Report of the German Pacemaker Registry: Cardiac Pacemaker Specialty Group and BQS Federal Quality Assurance Office gGmbH (manager: Dr. C. Veit), Dusseldorf]. PMID- 20835712 TI - [Curriculum and expert courses on pacemaker and ICD therapy]. AB - The curricula "Practice of Pacemaker Therapy" and "Practice of ICD Therapy" have been developed from practical experience with the first educational courses which are necessary to fulfill the German requirements of the medical products law which restricts the application of medical products to persons with the necessary education, knowledge and experience. The corresponding courses of competence under the auspices of the German Cardiac Society derive from this legal prerequisite. Competence refers to technical knowledge in cardiac implantable electrical devices (CIEDs) and understanding of possible dysfunctions as well as substantial knowledge on arrhythmia. The two curricula form the theoretical basis for the application of CIEDs. These courses represent an offer to cardiologists and all other physicians who wish to acquire and document competency in this field. A legal obligation to participate in these competency courses does not currently exist in Germany as long as evidence can be provided that this competency has been achieved by other means. Both curricula have proven to be comprehensive and practically highly useful and have been presented by highly committed specialists with expertise in this topic at a high level. Since 2005 some 2,000 physicians have been trained in courses on pacemaker therapy and more than 1,000 physicians in courses on ICD therapy with an ongoing high level demand to be expected in the future. PMID- 20835714 TI - Variables associated with odds of finishing and finish time in a 161-km ultramarathon. AB - We sought to determine the degree to which age, sex, calendar year, previous event experience and ambient race day temperature were associated with finishing a 100-mile (161-km) trail running race and with finish time in that race. We computed separate generalized linear mixed-effects regression models for (1) odds of finishing and (2) finish times of finishers. Every starter from 1986 to 2007 was used in computing the models for odds of finishing (8,282 starts by 3,956 individuals) and every finisher in the same period was included in the models for finish time (5,276 finishes). Factors associated with improved odds of finishing included being a first-time starter and advancing calendar year. Factors associated with reduced odds of finishing included advancing age above 38 years and warmer weather. Beyond 38 years of age, women had worse odds of finishing than men. Warmer weather had a similar effect on finish rates for men and women. Finish times were slower with advancing age, slower for women than men, and less affected by warm weather for women than for men. Calendar year was not associated with finish time after adjustment for other variables. PMID- 20835715 TI - Optimization of spray drying process for Bacillus thuringiensis fermented wastewater and wastewater sludge. AB - Response surface methodology was used to optimize spray drying process for producing biopesticide powders of Bacillus thuringiensis by using fermented broth of starch industry wastewater and wastewater sludge. Analysis of variance was carried out using number of viable spores in the powder as dependent variable. The determination coefficients of models were 92 and 94% for fermented broth of starch industry wastewater and wastewater sludge, respectively. Under the optimal conditions of the operational parameters of spray drying, the numbers of viable spores were 2.2 * 10(8) and 1.3 * 10(8) CFU/mg in the dry powders for starch industry wastewater and wastewater sludge respectively, with a loss of viable spores of 18 and 13% when compared with their respective fermented broths. The entomotoxicity (measured by the bioassay method) of the powders obtained under optimal conditions showed a loss of 28 and 18% when compared with the fermented broth of starch industry wastewater and wastewater sludge, respectively. The optimized results of spray drying were used for field application calculations. The volume of fermented broth required to produce powder formulated product when compared with the volume required for liquid formulation product in order to treat 1 ha of balsam fir was less and offered several advantages. PMID- 20835716 TI - Effects of intraoperative breaks on mental and somatic operator fatigue: a randomized clinical trial. AB - BACKGROUND: Intermittent work breaks are common in fields with high workload but not yet for surgeons during operations. We evaluated the effects of intraoperative breaks during complex laparoscopic surgery (5 min every half hour) on the surgeon. METHODS: Fifty-one operations were randomized to a scheme with intraoperative breaks and release of the pneumoperitoneum (intermittent pneumoperitoneum (IPP)) or conventional conduct (CPP). Stress hormones and alpha amylase were determined in the surgeon's saliva pre-, intra-, and postoperatively. Mental performance and error scores, musculoskeletal strain, and continuous ECG were secondary endpoints. RESULTS: Regular intraoperative breaks did not prolong the operation (IPP vs. CPP group: 176 vs. 180 min, p > 0.05). The surgeon's cortisol levels during the operation were reduced by 22 +/- 10.3% in the IPP vs. the CPP group (p < 0.05). There were significantly fewer (p < 0.05) intraoperative events in the IPP vs. the CPP group, which yielded higher alpha amylase peaks. The pre- to postoperative increase in the error rates of the bp concentration test was fourfold reduced in the IPP group (p = 0.052). The relevant locomotive strain-scores were grossly reduced by IPP (p < 0.001). CONCLUSIONS: Our data support the idea that work breaks during complex laparoscopic surgery can reduce psychological stress and preserve performance without prolongation of the operation time compared with the traditional work scheme. PMID- 20835717 TI - The impact of surgeon choice on the cost of performing laparoscopic appendectomy. AB - INTRODUCTION: While laparoscopic appendectomy (LA) can be performed using a myriad of techniques, the cost of each method varies. The purpose of this study is to analyze the effects of surgeon choice of technique on the cost of key steps in LA. METHODS: Surgeon operative notes, hospital invoice lists, and surgeon instrumentation preference sheets were obtained for all LA cases in 2008 at Cambridge Health Alliance (CHA). Only cases (N = 89) performed by fulltime staff general surgeons (N = 8) were analyzed. Disposable costs were calculated for the following components of LA: port access, mesoappendix division, and management of the appendiceal stump. The actual cost of each disposable was determined based on the hospital's materials management database. Actual hospital reimbursements for LA in 2008 were obtained for all payers and compared with the disposable cost per case. RESULTS: Disposable cost per case for the three portions analyzed for 126 theoretical models were calculated and found to range from US $81 to US $873. The surgeon with the most cost-effective preferred method (US $299) utilized one multi-use endoscopic clip applier for mesoappendix division, two commercially available pretied loops for management of the appendiceal stump, and three 5-mm trocars as their preferred technique. The surgeon with the least cost-effective preferred method (US $552) utilized two staple firings for mesoappendix division, one staple firing for management of the appendiceal stump, and 12/5/10-mm trocars for access. The two main payers for LA patients were Medicaid and Health Safety Net, whose total hospital reimbursements ranged from US $264 to US $504 and from US $0 to US $545 per case, respectively, for patients discharged on day 1. DISCUSSION: Disposable costs frequently exceeded hospital reimbursements. Currently, there is no scientific literature that clearly illustrates a superior surgical method for performing these portions of LA in routine cases. This study suggests that surgeons should review the cost implications of their practice and to find ways to provide the most cost-effective care without jeopardizing clinical outcome. PMID- 20835718 TI - Multimedia article. Sphincterotome stricturoplasty for long ampullary stenoses and benign biliary strictures (with video). AB - BACKGROUND: Long ampullary stenoses and fibrotic distal biliary strictures are not infrequently encountered during endoscopic retrograde cholangiopancreatography (ERCP). Instead of balloon dilation and stenting, we propose that these strictures can be managed with sphincterotome stricturoplasty (SS) during the initial ERCP. OBJECTIVE: To report our clinical experience with SS for benign distal biliary strictures. DESIGN: Review on prospectively collected data. PATIENTS: All (consecutive) patients who underwent ERCP and SS performed by the authors in a 12-month period. Long ampullary stenosis and/or distal biliary stricture is defined as significant narrowing of CBD from the level of duodenal wall into the common bile duct (CBD) after initial sphincterotomy. The upstream CBD is dilated. Despite adequate ES, contrast drainage is poor due to the downstream stricture. SS was performed using the same sphincterotome in slightly bowed position under endoscopic and fluoroscopic guidance. The cutting wire was placed parallel to the superior border within the stricture and incising the stenosis. In cases of relatively long strictures, during initial SS the majority of the cutting wire was inside the biliary opening. This differs from ES, where about one-third to one-half of the length of cutting wire is outside the ampulla. MEASUREMENTS: Clinical data, hospital course, procedure-related complication rates, and outcomes were prospectively collected in a database. RESULTS: During the study period, 308 ERCPs were performed. Benign and short (<=15 mm in length) distal biliary strictures were observed in 25 patients. Mean +/- SD stricture length was 7.4 +/- 3.0 mm. The presumed etiologies for these strictures were choledocholithiasis (n = 22) and postsphincterotomy stenosis (n = 3). There was no perforation, post-ERCP pancreatitis, postsphincterotomy bleeding, or cholangitis. To date, none of these patients who had SS have needed follow-up ERCP. LIMITATIONS: Single-operator experience, limited follow-up period. CONCLUSIONS: Compared with balloon stricturoplasty +/- biliary stenting, SS is a simple and cost-effective alternative option in managing long ampullary stenosis and/or distal fibrotic biliary stricture during the initial ERCP. PMID- 20835719 TI - Multimedia article. Successful endoscopic wire-guided balloon dilatation of angulated and tight ileal pouch strictures without fluoroscopy. AB - BACKGROUND: Ileal pouch strictures that are visually inaccessible by an endoscope may be balloon-dilated by exchange guide wire across the stricture with the aid of fluoroscopy. We present a technique of wire-guided balloon dilation without fluoroscopy to navigate strictures in the ileal pouch. METHODS: A 50-year-old Caucasian female presented with a 24-year history of ulcerative colitis (UC) with restorative proctocolectomy and ileal pouch anal anastomosis (IPAA) for 7 years. She developed Crohn's disease (CD) of the pouch with multiple strictures at the afferent limb of the pouch and a pouch-vaginal fistula. On pouchoscopy, the patient had two strictures at the distal neoterminal ileum, at 10 cm and 15 cm proximal to the pouch inlet. In retrospect, the distal stricture was angulated and 1 cm in length, and the proximal one was ulcerated and pinhole in size, which prevented the passage of an endoscope (9.8-mm single-channel, GIF-H180; Olympus Optical, Tokyo, Japan). The stricture number and locations were confirmed by retrograde water-soluble contrast X-ray. There was great difficulty in negotiating the strictures with balloon dilation and hence concern that blind passage of the balloon into the strictures might induce mucosal trauma or perforation. A controlled radial expansion (CRE) wire-guided balloon dilation catheter (CRE TM Single-Use Wire Guided Balloon Dilator; Boston Scientific Microvasive, Natick, MA) was introduced through the scope. Wire exchange technique was applied with help of our endoscopy nurse (A.O.). The guide wire was passed through the strictures without any resistance under endoscopy view. Subsequently, the balloon was introduced across the strictures, and both were successfully dilated to 16 mm (Videos 1 and 2). RESULTS: The procedure and postprocedure course were uneventful, and patient reported great symptomatic relief. CONCLUSION: Endoscopic guide-wire balloon dilation without fluoroscopic guidance appears to be feasible for CD-related strictures in experienced hands. PMID- 20835720 TI - Multimedia article. Navigated renal access using electromagnetic tracking: an initial experience. AB - BACKGROUND AND AIM: Navigation systems are promising tools for improving efficacy and safety in surgical endoscopy and other minimally invasive techniques. The aim of the current study is to investigate electromagnetic tracking (EMT) for navigated renal access in a porcine model. METHODS: For our proof-of-principle study we modified a recently established porcine ex vivo model. Via a ureteral catheter which was placed into the desired puncture site, a small sensor was introduced and located by EMT. Then, a tracked needle was navigated into the collecting system in a "rendezvous" approach. A total of 90 renal tracts were obtained in six kidneys using EMT, with a maximum of three punctures allowed per intervention. For each puncture, number of attempts to success, final distance to probe, puncture time, and localization were assessed. We compared absolute and relative frequencies using the chi-square test and applied the Mann-Whitney U test for continuous variables. RESULTS: No major problems were encountered performing the experiment. Access to the collecting system was successfully obtained after a single puncture in 91% (82/90) and within a second attempt in the remaining 9% (8/90). Thus, a 100% success rate was reached after a maximum of two punctures. Location of the calyx did not have a significant effect on success rate (p = 0.637). After a learning phase of 30 punctures, higher success rate (96% versus 83%; p = 0.041) was accomplished within shorter puncture time (14 versus 17 s; p = 0.049) and with higher precision (1.7 versus 2.8 mm; p < 0.001). CONCLUSIONS: With respect to other established techniques, use of EMT seems to decrease the number of attempts and procedural time remarkably. This might contribute to greater safety and efficacy when applied clinically. The presented approach appears to be promising, especially in difficult settings, provided that in vivo data support these initial results. PMID- 20835722 TI - Comparison of hemostatic properties between collagen and synthetic buttress materials used in staple line reinforcement in a swine splenic hemorrhage model. AB - INTRODUCTION: The use of staplers in gastrointestinal surgery is widespread, especially in advanced laparoscopic procedures. Staple line reinforcement with a buttress reduces bleeding and associated complications through a combination of factors. The intrinsic hemostatic properties of buttress materials have not been examined. This study examined the intrinsic hemostatic properties of two different types of material used in buttressing in an accepted hemostasis model that does not involve stapling or its effects by compression. MATERIALS: An acellular collagen buttress (Veritas) and a synthetic polymer buttress (Duet) were compared to two commonly used hemostatic agents, Syvek and Surgicel, with gauze as control. METHODS: In a swine capsular stripping hemostasis model, a 1 * 1 cm section of spleen capsule was removed and used as a source of bleeding, with one patch of material tested per bleeding site. A total of 51 wounds were created in five pigs (each patch n = 10, control n = 11). Hemostatic efficacy was assessed by quantitating the number of applications and total time needed for bleeding to stop. RESULTS: The mean time needed for hemostasis for Syvek and Veritas patches was significantly less than gauze, Duet and Surgicel (4.02, 4.51 vs. 8.97, 9.22, and 10.30 min respectively; p < 0.05). The Syvek and Veritas patches required significantly fewer applications than gauze, DuetTM and Surgicel (1.7, 2.2 vs. 4.1, 4.6, and 4.9 respectively; p < 0.01). CONCLUSIONS: The intrinsic hemostatic properties of different buttressing materials vary widely. In this study, a collagen buttress was significantly better at promoting hemostasis than the synthetic buttress material in a nonstapling model. This could be another factor to consider when choosing a buttress for staple line reinforcement. PMID- 20835721 TI - Preoperative ultrasound measurements predict the feasibility of gallbladder extraction during transgastric natural orifice translumenal endoscopic surgery cholecystectomy. AB - BACKGROUND: Extraction of a gallbladder through an endoscopic overtube during natural orifice translumenal endoscopic surgery (NOTES) transgastric cholecystectomy avoids potential injury to the esophagus. This study examined the rate of successful gallbladder specimen extraction through an overtube and hypothesized that preoperative ultrasound findings could predict successful specimen passage. METHODS: Gallbladder specimens from patients undergoing laparoscopic cholecystectomy were measured, and an attempt was made to pull the specimens through a commercially available overtube with an inner diameter of 16.7-mm. A radiologist blinded to the outcomes reviewed the available preoperative ultrasound measurements from these patients. Ultrasound dimensions including gallbladder length, width, and depth; wall thickness; common bile duct diameter; and size of the largest gallstone (LGS) were recorded. Multiple logistic regression analysis was performed to determine whether ultrasound findings and patient characteristics (age, body mass index [BMI], and sex) could predict the ability of a specimen to pass through the overtube. RESULTS: Of 57 patients, 44 (77%) who had preoperative ultrasounds available for electronic review were included in the final analysis. Gallstones were present in 35 (79%) of these 44 patients. Intraoperative gallbladder perforation occurred in 18 (41%) of the 44 patients, and 16 (36%) of the 44 gallbladders could be extracted through the overtube. Measurement of LGS was possible for 23 patients, and indeterminate gallstone size (IGS) was determined for 12 patients. The rate for passage of perforated versus intact gallbladders was similar (40% vs. 23%; p = 0.054). The LGS (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.02-1.33; p = 0.021) and IGS (OR, 22.97; 95% CI, 1.99-265.63; p = 0.025) predicted failed passage on multivariate logistic regression analysis. The passage rate was 80% for LGS smaller than 10 mm or no stones present, 18% for LGS 10 mm or larger, and 8% for IGS (p < 0.001). CONCLUSION: A majority of cholecystectomy specimens cannot pass through an endoscopic overtube. Preoperative ultrasound findings can predict successful specimen extraction. An IGS or a gallstone 10 mm or larger should be considered a relative contraindication to transgastric NOTES cholecystectomy. PMID- 20835723 TI - Development, validation and implementation of a monitoring tool for training in laparoscopic colorectal surgery in the English National Training Program. AB - INTRODUCTION: The National Training Program for laparoscopic colorectal surgery (LCS) provides supervised training to colorectal surgeons in England. The purpose of this study was to create, validate, and implement a method for monitoring training progression in laparoscopic colorectal surgery that met the requirements of a good assessment tool. METHODS: A generic scale for different tasks in LCS was created under the guidance of a national expert group. The scores were defined by the extent to which the trainees were dependent on support (1 = unable to perform, 5 = unaided (benchmark), 6 = proficient). Trainers were asked to rate their trainees after each supervised case; trainees completed a similar self assessment form. Construct validity was evaluated comparing scores of trainees at different experience levels (1-5, 6-10, 11-15, 16+) using the Wilcoxon signed rank test and ANOVA. Internal consistency was determined by Crohnbach's alpha, interrater reliability by comparing peer- and self-assessment (interclass correlation coefficient, ICC). Proficiency gain curves were plotted using CUSUM charts. RESULTS: Analysis included 610 assessments (333 by trainers and 277 by trainees). There was high interrater reliability (ICC = 0.867), internal consistency (alpha = 0.920), and construct validity [F(3,40) = 6.128, p < 0.001]. Detailed analysis of proficiency gain curves demonstrates that theater setup, exposure, and anastomosis were performed independently after 5 to 15 sessions, and the dissection of the vascular pedicle took 24 cases. Mobilization of the colon and of the splenic/hepatic flexure took more than 25 procedures. Median assessment time was 3.3 (interquartile range (IQR) 1-5) minutes and the tool was accepted as useful [median score 5 of 6 (IQR 4-5)]. DISCUSSION: A valid and reliable monitoring tool for surgical training has been implemented successfully into the National Training Program. It provides a description of an individualized proficiency gain curve in terms of both the level of support required and the competency level achieved. PMID- 20835724 TI - Initial experiences using robot-assisted central pancreatectomy with pancreaticogastrostomy: a potential way to advanced laparoscopic pancreatectomy. AB - BACKGROUND: Benign and borderline malignant pancreatic tumors are increasing. Function-preserving and minimally invasive pancreatectomy may be an ideal approach for these tumors. METHODS: The authors retrospectively evaluated their initial experiences with five consecutive robotic central pancreatectomies (CPs). They also compared the perioperative outcome for open CPs performed in their institution. RESULTS: The five women in the study had a median age of 45 years (range 36-64 years). A solid pseudopapillary tumor of the pancreas was found in four patients, and a pancreatic endocrine tumor was found in one patient. The tumor was relatively small (median size, 1.5 cm; range, 1-2 cm). All remnant pancreases were managed using pancreaticogastrostomy. The median operation time was 480 min (range 360-480 min), and the median estimated intraoperative bleeding was 200 ml (range 100-600 ml). No transfusion was given during the perioperative period. The median hospital stay was 12 days (range 9-28 days). Only one patient experienced postoperative pancreatic fistula (grade B), which was managed using the percutaneous drainage procedure. No operative morality was noted. In a comparative analysis with open CP, the robotic CP group demonstrated a smaller asymptomatic (17 out of 10 patients vs none, p = 0.026) tumor (5.9 +/- 6.4 vs 1.4 +/- 0.4 cm; p = 0.055), a longer operation time (286.5 +/- 90.2 vs 432.0 +/- 65.7 min, p = 0.013), and less intraoperative bleeding (432.0 +/- 65.7 vs 286.5 +/- 90.2 ml, p = 0.013). CONCLUSION: Central pancreatectomy can be selected carefully as an appropriate surgical option for benign and borderline malignant lesions limited to the pancreatic neck area. The robotic surgical system may allow surgeons to perform complex and difficult laparoscopic procedures more easily, effectively, and precisely. PMID- 20835725 TI - Defining the learning curve in laparoscopic paraesophageal hernia repair: a CUSUM analysis. AB - INTRODUCTION: There are numerous reports in the literature documenting high recurrence rates after laparoscopic paraesophageal hernia repair. The purpose of this study was to determine the learning curve for this procedure using the Cumulative Summation (CUSUM) technique. METHODS: Forty-six consecutive patients with paraesophageal hernia were evaluated prospectively after laparoscopic paraesophageal hernia repair. Upper GI series was performed 3 months postoperatively to look for recurrence. Patients were stratified based on the surgeon's early (first 20 cases) and late experience (>20 cases). The CUSUM method was then used to further analyze the learning curve. RESULTS: Nine patients (21%) had anatomic recurrence. There was a trend toward a higher recurrence rate during the first 20 cases, although this did not achieve statistical significance (33% vs. 13%, p = 0.10). However, using a CUSUM analysis to plot the learning curve, we found that the recurrence rate diminishes after 18 cases and reaches an acceptable rate after 26 cases. CONCLUSIONS: Surgeon experience is an important predictor of recurrence after laparoscopic paraesophageal hernia repair. CUSUM analysis revealed there is a significant learning curve to become proficient at this procedure, with approximately 20 cases required before a consistent decrease in hernia recurrence rate is observed. PMID- 20835726 TI - A totally laparoscopic distal gastrectomy with gastroduodenostomy (TLDG) for improvement of the early surgical outcomes in high BMI patients. AB - OBJECTIVE: To evaluate the effectiveness of totally laparoscopic distal gastrectomy with gastroduodenostomy (TLDG), we compared its early surgical outcomes with those of laparoscopy-assisted distal gastrectomy with gastroduodenostomy (LADG). METHODS: We retrospectively analyzed early surgical outcomes in 567 patients who underwent laparoscopic gastrectomy for gastric cancer between January 2009 and March 2010. The patients were divided into those with underwent TLDG and those with underwent LADG. Their surgical outcomes were analyzed according to the WHO Asia-Pacific Obesity classification. RESULTS: In overall patients, TLDG showed the significant results of early surgical outcomes. But more importantly, in the analysis of early surgical outcomes for obese patients, we found that TLDG could improve overall complication rate (p = 0.031), time to first flatus (p = 0.009), time to commencement of soft diet (p < 0.001), administration of analgesics (p = 0.019), pain score (Numeric Rating Scale, NRS), and hospital discharge (p = 0.003). CONCLUSIONS: We suggested that TLDG contributes to the improvement of early surgical outcomes. We further suggest that TLDG in obese patients could be the best way to improve early surgical outcomes, including the bowel movement, pain score, overall complication rate, and hospital discharge. PMID- 20835727 TI - Feasibility of laparoscopic partial gastrectomy with sentinel node basin dissection in a porcine model. AB - BACKGROUND: This study aimed to evaluate the technical feasibility and safety of laparoscopic partial full-thickness gastrectomy with extensive sentinel node basin (SB) dissection in a porcine model before its application to gastric cancer without lymph node metastasis. METHODS: A series of 10 pigs (30-37 kg) were used for a survival study approved by an animal use committee. The imaginary lesions were located in the greater curvature (n = 2), lesser curvature (n = 2), anterior wall (n = 2), posterior wall (n = 2), cardia (n = 1), and angle of the stomach (n = 1). The SBs were assumed to be located around each lesion in question. Laparoscopic partial gastrectomy and SB dissection were performed. Upper gastrointestinal series (UGIS) studies were performed with gastrograffin 5 days after the operation to detect possible stricture, leakage, and passage problems. The pigs were kept alive for 3 weeks, then killed. RESULTS: The procedure was completed for all the pigs. Nine gastric wedge resections and one segmental resection of the stomach with several SB dissections were performed. The mean operation time was 102 min (70-150 min). The postoperative mean weight gain was 3.19 kg. There was no perioperative morbidity or mortality. The UGIS studies failed to detect leakage and stricture, but all the pigs exhibited delayed gastric emptying. Necropsies did not detect procedure-related complications. CONCLUSIONS: As shown by a pig model, laparoscopic limited gastrectomy with SB dissection appears to be safe and technically feasible. PMID- 20835728 TI - Laparoscopic nonresectional suture rectopexy in the management of full-thickness rectal prolapse: substantive retrospective series. AB - BACKGROUND: Numerous surgical options exist for the correction of rectal prolapse, with the optimal choice remaining controversial. The laparoscopic approach has proved to be popular and effective. Concern exists about nonresectional rectopexy in the form of intractable postoperative constipation. The authors present their experience with nonresectional laparoscopic suture rectopexy. METHODS: All patients presenting with a full-thickness rectal prolapse between August 1994 and August 2009 who proved to be fit for a general anesthesia were offered a laparoscopic repair. Data were entered into a database, then prospectively and retrospectively analyzed. The data recorded included patient demographics, preoperative symptoms, conversion to open procedure, length of hospital stay, and postoperative complications. Preoperative Cleveland Clinic Incontinence Scores (CCIS) were calculated. Follow-up evaluation was by telephone questionnaire. Postoperative constipation, recurrence, and CCIS were noted. RESULTS: The series included 72 patients (71 women, 98%) with a median age of 72 years (range, 24-88 years). The median follow-up period was 48 months (range, 5 144 months). A total of 13 patients were lost to follow-up evaluation. The median operating time was 98 min (range, 35-200 min), and the median hospital stay was 2 days (range, 1-29 days). Three conversions to open procedure (5%) were performed. The median preoperative CCIS was 9.54 compared with 4.44 postoperatively (p = 0.024). The complications included one postoperative bleed requiring transfusion, one port-site abscess requiring incision and drainage, one postoperative retention of urine, and one chest infection. Postoperatively, 10 patients (17%) reported occasional constipation not requiring intervention, and an additional 10 patients (17%) reported more severe constipation, all managed successfully with regular laxatives. The patients followed up experienced six recurrences (9%). No postoperative deaths occurred. CONCLUSION: Laparoscopic abdominal suture rectopexy without resection is safe and effective for the treatment of full thickness rectal prolapse. PMID- 20835729 TI - Comparison of costs for video-assisted thoracic surgery lobectomy and open lobectomy for non-small cell lung cancer. AB - BACKGROUND: To promote the broad use of video-assisted thoracic surgery (VATS) for lobectomy (VATSL) in the management of lung cancer, it should be proved cost effective, especially in the current cost-sensitive climate. This study evaluated and compared the costs of VATSL and open lobectomy (OL) and analyzed how the surgeon's experience level with VATSL affected the cost. METHODS: In this study, 86 patients in a VATSL group and 97 patients in an OL group underwent surgery for lung cancer. Cost comparisons were performed for the VATSL and OL groups between patients who had no complications and patients with and without complications according to tumor location and the learning period of the surgeon. RESULTS: Postoperative complications occurred for 56 patients (30.6%) (14 VATSL vs 42 OL patients; p < 0.05). Patients who underwent VATSL had significant reductions in both chest tube duration (5.4 vs 9.1 days; p = 0.000) and length of hospital stay (7.1 vs 12.0 days; p = 0.000). The mean operation time for VATSL was not significantly longer than for OL (145.8 vs 136.4 min; p = 0.782). The total hospital cost (i.e., that paid by the patient and national insurance combined) was lower for VATSL than for OL according to comparisons both among all patients ($5,391 vs $5,593, respectively) and among only noncomplicated patients ($4,684 vs $4,769, respectively). In terms of tumor location, the total hospital cost for the VATSL group was lower than for the OL group when the surgery was performed on the right lower lobe (RLL), left upper lobe (LUL), and left lower lobe (LLL). The costs were not significantly different between the two learning periods of the surgeons, except for the cost of anesthesia. CONCLUSIONS: In Korea, VATSL for lung cancer had lower complication rates, shorter hospital stays, and lower total hospital costs than OL. PMID- 20835730 TI - Effect of laparoscopic esophagomyotomy on chest pain associated with achalasia and prediction of therapeutic outcomes. AB - BACKGROUND: The effect of myotomy for achalasia on chest pain has not been clarified. The current study aimed to investigate the therapeutic effect of laparoscopic myotomy on chest pain associated with achalasia and to identify prognostic factors for outcomes. METHOD: Between March 2005 and September 2008, 95 patients were available for detailed interviews and for assessment of clearance by timed barium esophagogram (TBE) before and after surgery. Of the 95 patients, 47 (24 men; mean age, 42.9 +/- 13.5 years) who experienced chest pain before surgery were studied. The subjects were asked in detail about dysphagia and chest pain before surgery and 6 months after surgery. The frequency and severity of the symptoms were graded on a scale of 0 to 4. In addition, the values obtained by multiplying the grade for frequency by the grades for severity of the two symptoms were defined as the dysphagia score and the chest pain score, respectively. The patients with chest pain scores of 0 after surgery were defined as group A and those with scores smaller than their preoperative scores as group B. The remaining patients with other scores were defined as group C. The background factors and clinical conditions of the three groups were compared. RESULTS: The mean chest pain score decreased from 5.0 +/- 3.2 to 1.0 +/- 1.6 (p < 0.001). The score after surgery was 0 for 27 patients and showed a decrease for 15 patients. Although the three groups did not differ in their characteristics, differences were noted in postoperative TBE factors (i.e., groups A and B had significantly shorter barium columns than group C at 1 and 5 min after surgery (p = 0.001). CONCLUSION: Laparoscopic myotomy had a therapeutic effect on chest pain associated with achalasia, and improvement in postoperative esophageal clearance may influence the therapeutic effect. PMID- 20835731 TI - A model for long-distance dispersal of boll weevils (Coleoptera: Curculionidae). AB - The boll weevil, Anthonomus grandis (Boheman), has been a major insect pest of cotton production in the US, accounting for yield losses and control costs on the order of several billion US dollars since the introduction of the pest in 1892. Boll weevil eradication programs have eliminated reproducing populations in nearly 94%, and progressed toward eradication within the remaining 6%, of cotton production areas. However, the ability of weevils to disperse and reinfest eradicated zones threatens to undermine the previous investment toward eradication of this pest. In this study, the HYSPLIT atmospheric dispersion model was used to simulate daily wind-aided dispersal of weevils from the Lower Rio Grande Valley (LRGV) of southern Texas and northeastern Mexico. Simulated weevil dispersal was compared with weekly capture of weevils in pheromone traps along highway trap lines between the LRGV and the South Texas/Winter Garden zone of the Texas Boll Weevil Eradication Program. A logistic regression model was fit to the probability of capturing at least one weevil in individual pheromone traps relative to specific values of simulated weevil dispersal, which resulted in 60.4% concordance, 21.3% discordance, and 18.3% ties in estimating captures and non-captures. During the first full year of active eradication with widespread insecticide applications in 2006, the dispersal model accurately estimated 71.8%, erroneously estimated 12.5%, and tied 15.7% of capture and non-capture events. Model simulations provide a temporal risk assessment over large areas of weevil reinfestation resulting from dispersal by prevailing winds. Eradication program managers can use the model risk assessment information to effectively schedule and target enhanced trapping, crop scouting, and insecticide applications. PMID- 20835732 TI - Using the greater omental flap to cover the cut surface of the liver for prevention of delayed gastric emptying after left-sided hepatobiliary resection: a prospective randomized controlled trial. AB - OBJECTIVE: The aim of this randomized controlled trial is to evaluate the effect on delayed gastric emptying (DGE) of using the greater omental flap to cover the cut surface of the liver after left-sided hepatobiliary resection. METHODS: From June 2007 to December 2008, all eligible patients were randomly assigned to either the greater omental flap group (OF group) or the control group (non-OF group). RESULTS: A total of 40 patients remained for final analysis. The incidence of DGE after left-sided hepatobiliary resection was 25%. The incidence of DGE showed no statistically significant differences between the OF group (10%) and the non-OF group (40%) (p = 0.065). The assessment of DGE using radiopaque rings revealed that changes over time in the gastric emptying ratio (GER, percentage of rings excreted from stomach) did not differ in a significant manner between the two groups. There were significant differences in changes over time in GER (p = 0.044) between the patients with and without DGE. The patients with DGE also showed higher GER at 5 h (p = 0.042) and at 6 h (p = 0.034) than those without DGE. CONCLUSIONS: Using the greater omental flap to cover the cut surface of the liver may reduce the incidence of DGE after left-sided hepatobiliary resection. Assessment using radiopaque markers may be useful to evaluate DGE. PMID- 20835733 TI - Different effect of HBV vaccine after liver transplantation between chronic HBV carriers and non-HBV patients who received HBcAb-positive grafts. AB - BACKGROUND: Combination of nucleos(t)ide analogue and anti-HBs immunoglobulin (HBIg) is the standard protocol for prevention of HBV reactivation after liver transplantation, but because of the extremely high cost of HBIg, HBV vaccine is tried as a much cheaper and potentially safer substitute. Here we show the different effect of HBV vaccine between chronic HBV carrier and non-HBV patients who received grafts from HBc antibody-positive donors. METHODS: Fifteen chronic HBV carriers and 6 non-HBV patients who received grafts from HBc antibody positive donors were included in this study. These patients received double dose of pre-S-containing HBV vaccine every month from later than 12 months after liver transplantation. Successful vaccination was defined as HBsAb >100 IU/l without HBIg administration for 3 months. RESULTS: None of the 15 chronic HBV carriers succeeded in maintaining high enough HBsAb titers. In contrast, 5 of 6 non-HBV patients with HBcAb-positive donors achieved HBsAb >100 IU/l without HBIg coadministration. Recipient HBV status (HBV carrier/non-HBV) was considered to have a stronger effect on vaccine success (p < 0.001) though recipient age (p = 0.006) was also selected as a significant factor. CONCLUSIONS: Recipient HBV status seems to be the most important factor affecting success of HBV vaccine after liver transplantation. In non-HBV patients who received grafts from HBcAb positive donors, HBV vaccination is an effective, cost-saving, and safe method for prevention of HBV reactivations. In contrast in chronic HBV patients, response rate was quite poor, so some modifications such as combination with adjuvant or modification of administration schedules should be considered. PMID- 20835734 TI - In vitro inactivation of feline calicivirus (FCV) by chemical disinfectants: resistance variation among field strains. AB - Several commercial products commonly used for disinfection against feline calicivirus (FCV) have been validated using the vaccine strain F9. However, little information is available regarding the resistance of field strains of FCV to chemical inactivation. In this study, disinfection experiments were performed either on two laboratory-adapted strains or on seven field isolates using three alcohol mixtures and one containing a chlorine compound. For each biocide tested, considerable variability was found among the strains in their susceptibility to inactivation, demonstrating that the effectiveness of disinfection depends not only on the type of chemical compound and exposure time, but also on the FCV strain. PMID- 20835735 TI - Comparative reactivity of serum samples from Argentinean HIV-infected patients with V3 peptides from subtype B or BF recombinants. AB - To analyze humoral cross-reactivity to V3 peptides from subtype B and BF recombinant forms, plasma samples from 50 HIV-1-infected patients were characterized by sequencing fragments of the env and pol genes. An in-house EIA was performed using peptides corresponding to the 15 central amino acids of the V3 loop of gp120 from subtypes B (MN, SF2) and F1 and a consensus peptide from Argentinean BF recombinants. No differences were found with respect to the infecting subtype, but significant differences were found among the peptides. Reactivity was higher against the MN and BF peptides in both groups infected with subtype B (n = 28) and BF (n = 22) recombinants than against subtype F1 and SF2 peptides. PMID- 20835736 TI - A pro-survival effect of polyamine depletion on norepinephrine-mediated apoptosis in cardiac cells: role of signaling enzymes. AB - Recent studies report that the primary transmitter of sympathetic nervous system norepinephrine (NE), which is actively produced in failing human heart, is able to induce apoptosis of rat cardiomyocytes. Apoptotic cell death of cardiomyocytes is involved in several cardiovascular diseases including ischemia, hypertrophy and heart failure, therefore representing a potential therapeutic target. The natural occurring polyamines, putrescine, spermidine and spermine, are biogenic amines involved in many cellular processes, including apoptosis. Thus, we have studied the involvement of polyamines in the apoptosis of cardiac cells induced by the treatment with NE. The results indicate that NE caused an early induction of the activity of ornithine decarboxylase (ODC), the first enzyme in polyamine biosynthesis, followed by a later increase of apoptotic cell death. This effect was prevented in the presence of alpha-difluoromethylornithine, an irreversible inhibitor of ODC. Moreover, the study of some key signal transduction pathways revealed an involvement of AMP-activated protein kinase, AKT and p38 mitogen activated protein kinases, in the modulation by polyamines of the response of cardiomyocytes to NE. In fact, polyamine-depleted cells showed an altered activation pattern of these kinases that may contrast apoptosis and appeared to result from a differential effect on the specific phosphatases that dephosphorylate and switch off these signaling proteins. In conclusion, these results indicate that in cardiac cells polyamines are involved in the execution of the death program activated by NE, and suggest that their apoptosis facilitating action is mediated by a network of specific phosphatases and kinases. PMID- 20835737 TI - Novel highly emissive non-proteinogenic amino acids: synthesis of 1,3,4 thiadiazolyl asparagines and evaluation as fluorimetric chemosensors for biologically relevant transition metal cations. AB - Highly emissive heterocyclic asparagine derivatives bearing a 1,3,4-thiadiazolyl unit at the side chain, functionalised with electron donor or acceptor groups, were synthesised and evaluated as amino acid-based fluorimetric chemosensors for metal cations, such as Cu2(+), Zn2(+), Co2(+) and Ni2(+). The results suggest that there is a strong interaction through the donor heteroatoms at the side chain of the various asparagine derivatives, with high sensitivity towards Cu2(+) in a ligand-metal complex with 1:2 stoichiometry. Association constants and detection limits for Cu2(+) were calculated. The photophysical and metal ion sensing properties of these asparagine derivatives confirm their potential as fluorimetric chemosensors and suggest that they can be suitable for incorporation into chemosensory peptidic frameworks. PMID- 20835738 TI - Short term effects of inpatient cognitive behavioral treatment of adolescents with anxious-depressed school absenteeism: an observational study. AB - This observational study examined the changes during inpatient cognitive behavioral treatment (CBT) of adolescents with chronic anxious-depressive school absenteeism with or without comorbid disruptive symptoms. 147 adolescents (aged 12-18 years) with a specific phobia or other anxiety disorder or a depressive episode or a mixed disorder of conduct and emotions and who had completely ceased to attend school or showed irregular school attendance underwent an inpatient cognitive-behavioral treatment. A further 16 patients aborted the treatment during the first day and were not included in the analyses. The treatment was manual guided and also included parents. Assessments were made pre-inpatient treatment, immediately post-inpatient treatment and at 2-month follow-up. School attendance was the primary outcome variable and secondary outcomes were composite scores of a range of adolescent- and parent-rated mental health problems. Overall, results show a considerable decline of school absenteeism and mental health problems during treatment and subsequent follow-up. Continuous school attendance was achieved by 87.1% of the sample at the end of inpatient treatment and by 82.3% at 2-month follow-up. Comorbid symptoms of anxiety, depression, disruptive and insufficient learning behavior were significantly reduced from pre to follow-up, with effect sizes for the composite scores ranging from 0.44 to 1.15 (p < 0.001). This large observational study in adolescents with school absenteeism and a mixture of emotional and disruptive symptoms is the first to show the benefits of inpatient therapy that included cognitive-behavioral therapy and access to a special school with expertise on teaching children and adolescents with psychiatric disorders. The results must be interpreted conservatively because of the lack of a control condition. PMID- 20835739 TI - Mesh erosion following laparoscopic incisional hernia repair. AB - Laparascopic mesh repair is a safe and effective method of surgically treating incisional hernia. However, such an approach may lead to specific complications of both laparoscopy and mesh placement. The mesh may migrate, become infected or erode into adjacent structures. We describe the case of a woman who underwent laparoscopic incisional hernia repair with subsequent erosion of the mesh into the bladder. PMID- 20835740 TI - Non-obstructed femoral hernia containing ascending colon, caecum, appendix and small bowel with concurrent bilateral recurrent inguinal hernia. AB - Femoral hernias, which are less common than inguinal hernias and more often found in females, occasionally contain more than just small intestine and omentum. Uncommon contents reported in femoral hernia sacs include caecum, appendix, Meckel's diverticulum (Littre hernia), testis, ovary, transverse colon and even stomach or kidney. Strangulation of femoral hernias containing appendix, small intestine and caecum, and Meckel's diverticulum are well reported in the literature. Here, we report a case of a male patient having bilateral femoral hernia with bilateral recurrent inguinal hernia. A huge, right-sided femoral hernia contained terminal ileum, appendix, caecum and ascending colon, which were irreducible but neither obstructed nor strangulated. The patient was operated on with a Pfannenstiel incision together with an infrainguinal incision. For reduction of content, an inguinal ligament was also incised. Bilateral preperitoneal, polypropylene mesh hernioplasty was performed along with rolled plug placement in the right femoral canal. The patient had an uneventful post operative recovery and no recurrence in 6 months of follow up. PMID- 20835741 TI - The role of streptococcal plasmin(ogen) binding in infective endocarditis. AB - The ability of viridans group streptococci (VGS) to bind human plasminogen and its subsequent activation into plasmin may contribute to the pathogenesis of streptococcal endocarditis. The increased proteolytic activity acquired through cell-bound plasmin may lead to a decreased stability of the streptococcal vegetation and possible embolisation. Twenty-two infective endocarditis isolates and 16 non-infective endocarditis isolates were screened for their ability to bind plasminogen through the quantification of its active form plasmin, using the colorimetric substrate D-Val-Leu-Lys p-nitroanilide. The species of the VGS assessed expressed a universal capability to bind human plasminogen, although they did so with differing affinities and independently of the site of isolation. PMID- 20835742 TI - Fungicidal activity of thymol and carvacrol by disrupting ergosterol biosynthesis and membrane integrity against Candida. AB - Natural isopropyl cresols have been reported to have antifungal activity. This work is an attempt to examine thymol and carvacrol against 111 fluconazole sensitive and -resistant Candida isolates. Insight into the mechanism of action was elucidated by flow cytometric analysis, confocal imaging and ergosterol biosynthesis studies. The susceptibility tests for the test compounds were carried out in terms of minimum inhibitory concentrations (MICs), disc diffusion assays and time-kill curves against all Candida isolates by employing standard protocols. Propidium iodide (PI) cell sorting has been investigated by flow cytometric analysis and confocal imaging. Haemolytic activity on human erythrocytes was studied to exclude the possibility of further associated cytotoxicity. Both compounds were found to be effective to varying extents against all isolates, including the resistant strains. In contrast to the fungistatic nature of fluconazole, our compounds were found to exhibit fungicidal nature. Significant impairment of ergosterol biosynthesis was pronouncedly induced by the test entities. Negligible cytoxicity was observed for the same compounds. Furthermore, it was observed that the positional difference of the hydroxyl group in carvacrol slightly changes its antifungal activity. Carvacrol and thymol show strong fungicidal effect against all of the Candida isolates. The mechanisms of action of these natural isopropyl cresols appear to originate from the inhibition of ergosterol biosynthesis and the disruption of membrane integrity. PMID- 20835743 TI - Endotoxin does not alter the pharmacokinetics of micafungin, but it impairs biliary excretion of micafungin via multidrug resistance-associated protein 2 (ABCC2/Mrp2) in rats. AB - Micafungin, a newly developed echinocandin-type antifungal agent, is widely used for the treatment of deep-seated fungal infections including those of Candida species and Aspergillus species. In the present study, the possible alterations in the pharmacokinetics and biliary excretion of micafungin were investigated in endotoxemic rats induced by Klebsiella pneumoniae endotoxin. Endotoxin (2 mg/kg) was injected intraperitoneally 24 h before an intravenous injection of micafungin (1 mg/kg). No significant differences in the plasma concentration-time curves and pharmacokinetic parameters of micafungin were observed between endotoxin-treated and endotoxin-untreated rats. When endotoxin-treated rats received a constant rate infusion of micafungin, the biliary clearance of micafungin was significantly decreased, whereas the steady-state plasma concentration did not change. By protein immunoblot analysis, a significant decrease in the expression of hepatic multidrug resistance-associated protein 2 (ABCC2/Mrp2), which is an efflux protein for micafungin, was observed in endotoxin-treated rats. These results suggest that endotoxin-induced decrease in the hepatobiliary excretion of micafungin is caused, at least in part, by the reduction of Mrp2-mediated hepatobiliary transport ability. The present study may provide information suggesting that micafungin can be used for patients with endotoxemia without the need for dosage adjustment. PMID- 20835744 TI - Revision total hip replacement: predictors of blood loss, transfusion requirements, and length of hospitalisation. AB - BACKGROUND: Revision total hip replacement (THR) is associated with increased blood loss and extended hospitalization. MATERIALS AND METHODS: We reviewed 146 patients who underwent revision THR to identify predictors of blood loss, transfusion requirements, and length of hospitalization. RESULTS: Blood loss was greater with increasing age and in men. Femoral and dual-component revision and revision of cemented hip components were also associated with greater blood loss. Transfusion requirements were greater in patients who had lower preoperative hemoglobin concentration and in patients undergoing dual-component revision. Length of hospitalization was significantly increased in patients who received transfusion but less in patients who underwent isolated acetabular-component hip revision. CONCLUSIONS: This study shows significantly greater blood loss in men, older patients, revision surgery of cemented implants, and dual-component revisions. More complex revision surgery and preoperative anemia are clearly associated with increased transfusion requirements and length of hospitalization. Identification and treatment of patients at higher risk of transfusion may guide likely transfusion requirements, shorten the length of hospitalization, and reduce the overall cost of treatment. PMID- 20835745 TI - Anterior cruciate ligament integrity in osteoarthritis of the knee in patients undergoing total knee replacement. AB - BACKGROUND: Anterior cruciate ligament (ACL) rupture has been implicated in the development of knee osteoarthritis (OA). This study aimed at determining the incidence of prior ACL deficiency in patients undergoing total knee replacement (TKR), the effect of prior ACL deficiency on function and the macroscopic and microscopic appearance of the ligament. MATERIALS AND METHODS: A total of 95 patients undergoing elective TKR for OA were recruited. Pre-operative knee assessment included questionnaires and KT1000 testing. The ACL was examined macroscopically at TKR in all patients, and 10 ACL specimens were examined histologically. RESULTS: The ACL was absent in 12% of the patients. There was no significant correlation between the pre-operative assessment or function and operative findings. The ACL samples all demonstrated degenerative change of varying severities. CONCLUSION: ACL deficiency is uncommon in patients undergoing TKR for OA, and does not worsen pre-operative function. PMID- 20835746 TI - Food perceptions in terms of health among Norwegian-Pakistani women participating in a culturally adapted intervention. AB - OBJECTIVE: To explore food perceptions in terms of health among Pakistani immigrant women, and if such perceptions could be altered through a culturally adapted intervention. METHODS: The study is a culturally adapted lifestyle intervention aiming at reducing diabetes risk among Pakistani women, Oslo, Norway. There were 198 participants (25-62 years) recruited through a multi recruitment strategy and randomly assigned into intervention and control groups. Data were collected through interviews with the help of a structured questionnaire with open-ended questions. RESULTS: Baseline data showed that many women emphasised vegetables (87%) and fish (52%) as important in a healthy diet, and perceived that the consumption of sugar (66%), oil (60%) and hard fat (39%) should be limited. After intervention, there was an increased proportion of women in the intervention group who perceived that consumption of sugar (p = 0.021) and white flour (p = 0.010) should be limited, in line with the emphasis of the intervention. CONCLUSIONS: Food perceptions in terms of health were generally in line with public dietary advice, however, with large variation among the women. A culturally adapted intervention had the potential to alter such perceptions. PMID- 20835747 TI - Hypertension and risk of death from external causes in the Physicians' Health Study enrollment cohort. AB - OBJECTIVES: To address the recent hypothesis that hypertension increases the risk of death from external causes. METHODS: We examined blood pressure and death from external causes among 82,037 male physicians who were screened for eligibility to enroll in the Physicians' Health Study. RESULTS: During up to 6.6 years of mortality follow-up, there were 304 deaths from external causes. No association was found overall, although we observed an increased risk of non-passive external causes of death, particularly death due to falls, which was independent of various lifestyle, medical, and pharmacological risk factors. CONCLUSIONS: The results of our study support this novel hypothesis. Further studies are needed to explore potential causal mechanisms between elevated BP and the risk of external death. PMID- 20835749 TI - Links between private habits, psychological stress and brain cancer: a case control pilot study in France. AB - Numerous studies have increasingly suggested that medical history and lifestyle factors could be involved in the increase of cancer risk in adults. The issue whether psychological factors can influence the development of cancer has been discussed for many years. In the field of brain cancer, psychological stress has not so far been investigated. We conducted a French case-control pilot study with 122 adult incident cases and 122 controls free of any cancer diagnosis, matched for age and gender, to investigate links between malignant primitive brain tumours (MPBT) and medical history, private habits and psychological stress. Data were collected through self-administered questionnaires, and person-to-person interviews. To complete the psychological stress assessment, 100-mm visual analog scales were used. After adjustment for confounders, we found no significant effect of head trauma, aspartame, tobacco or alcohol consumption, place (rural or urban) of residence, sociodemographic data, and experience of psychological stress at work/home. Our results showed a significant association between MPBT risk and major life events over the past 5 years before diagnosis (OR = 1.90, 95% CI 1.13-3.20), family histories of cancer (OR = 1.90, 95% CI 1.12-3.22), fresh vegetable and fruit intake (OR = 0.29, 95% CI 0.09-0.95), and skipped meals several times per week (OR = 0.35, 95% CI 0.16-0.77). The present study suggests the role of genetic factors in glioma risk, and also suggests that an acute and sudden psychological stress might influence MPBT appearance. Additional large clinical studies are needed to confirm these findings. PMID- 20835748 TI - The renaissance of continuous culture in the post-genomics age. AB - The development of continuous culture techniques 60 years ago and the subsequent formulation of theory and the diversification of experimental systems revolutionised microbiology and heralded a unique period of innovative research. Then, progressively, molecular biology and thence genomics and related high information-density omics technologies took centre stage and microbial growth physiology in general faded from educational programmes and research funding priorities alike. However, there has been a gathering appreciation over the past decade that if the claims of systems biology are going to be realised, they will have to be based on rigorously controlled and reproducible microbial and cell growth platforms. This revival of continuous culture will be long lasting because its recognition as the growth system of choice is firmly established. The purpose of this review, therefore, is to remind microbiologists, particularly those new to continuous culture approaches, of the legacy of what I call the first age of continuous culture, and to explore a selection of researches that are using these techniques in this post-genomics age. The review looks at the impact of continuous culture across a comprehensive range of microbiological research and development. The ability to establish (quasi-) steady state conditions is a frequently stated advantage of continuous cultures thereby allowing environmental parameters to be manipulated without causing concomitant changes in the specific growth rate. However, the use of continuous cultures also enables the critical study of specified transition states and chemical, physical or biological perturbations. Such dynamic analyses enhance our understanding of microbial ecology and microbial pathology for example, and offer a wider scope for innovative drug discovery; they also can inform the optimization of batch and fed batch operations that are characterized by sequential transitions states. PMID- 20835750 TI - Opportunities for clinical research in meningioma. AB - Meningiomas, when benign, are commonly treated with surgical resection alone. However, the optimal treatment for patients with subtotally resected or recurrent World Health Organization (WHO) grade I tumors, or WHO grade II and III tumors, regardless of the extent of resection, is not well defined, with both a paucity of high quality published evidence as well as a perceived minimal clinical effect for currently available interventions, specifically in terms of prolonging survival. In consideration of the size of the patient population with incompletely treated or non-benign meningiomas, there are opportunities for conducting high quality, prospective, multicenter clinical trials. In this review, we discuss a number of trials that were attempted and/or completed by cooperative groups or clinical consortia, and describe areas of clearly unmet need in terms of defining the optimal treatment regimens. Finally, we discuss ongoing efforts to develop new trials to more definitively address important therapeutic questions. PMID- 20835752 TI - Interaction of quercetin with copper ions: complexation, oxidation and reactivity towards radicals. AB - Quercetin, one of the most common dietary flavonols, was investigated in the presence of Cu(II) ions in methanolic solution in order to obtain some explanation on the mechanism interaction and its action against free radical mediated damage. The spectroscopic studies (UV-VIS, IR, ESI-MS) were used to assess the extent to which it undergo complex formation through chelation or modification through oxidation. The reaction of quercetin with Cu(II) resulted in the formation of 1:1 metal-ligand complex (lambda(max) = 436 nm) through the carbonyl oxygen and 3-OH group in C ring. Then quercetin is oxidized to the benzoquinone type products. The addition of EDTA destroyed the complex but did not regenerate the whole original spectrum of quercetin. From the other hand, the presence of EDTA inhibits formation of copper-quercetin complex and quercetin oxidation. The antioxidant activity of the Q + Cu solutions was evaluated by using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH?) radical scavenging method and from an electrochemical point of view. The complex is much more effective as free radical scaveninger than the free flavonoid. PMID- 20835751 TI - Effects of hypoxia on expression of a panel of stem cell and chemoresistance markers in glioblastoma-derived spheroids. AB - Tumor hypoxia has been attributed to play a crucial role in tumorigenesis and therapeutic resistance. Recently, it has been suggested that hypoxia leads to and maintains the undifferentiated state of tumor stem cells, thereby contributing to chemoresistance. The aim of the present study is to investigate the influence of hypoxia on the protein expression of a panel of stem cell and chemoresistance markers using in vivo-like multicellular tumor spheroids derived from a glioblastoma short-term culture with tumor stem cell properties (SJ-1) as well as a conventional glioblastoma cell line (U87). Spheroids were formed in 21% and 1% O(2) in serum-free medium. The immunohistochemical panel included hypoxia (HIF 1alpha, HIF-2alpha), proliferation (Ki-67), and stem cell markers (CD133, podoplanin, Bmi-1, nestin, Sox-2) as well as markers related to chemoresistance (MGMT, TIMP-1, Lamp-1, MRP1, MDR-1). As spheroids derived in hypoxia were smaller than in normoxia, a set of experiments was included in which the culturing time of hypoxic spheroids was extended to obtain equally sized spheroids. The results showed that expression of HIF-1alpha and HIF-2alpha was increased in hypoxia, whereas Ki-67 was reduced. Expression of stem cell markers CD133, podoplanin, Bmi 1, and nestin was increased in hypoxia, whereas Sox-2 was increased in SJ-1 only. TIMP-1 and Lamp-1 were increased in both SJ-1 and U87. In conclusion, the tumor cell phenotype related to stemness, and thereby potentially to chemoresistance, seems to depend on the oxygen tension, suggesting that development of therapeutic strategies targeting tumor stem cells should take oxygen tension into account. PMID- 20835753 TI - Effectiveness of in situ and ex situ conservation of crop diversity. What a Phaseolus vulgaris L. landrace case study can tell us. AB - The effectiveness of in situ (on-farm) and ex situ conservation strategies to maintain total genetic diversity was assessed in a threatened Phaseolus vulgaris L. landrace. Farmer seed lots (subpopulations) were sampled initially and then after in situ and ex situ multiplication (two locations). The number of plants used in the ex situ multiplications (120) was much larger than that normally used in germplasm bank procedures and the farmer seed lots were kept separate. In situ, the landrace was multiplied by each farmer with the usual population size. Eighty plants from the initial population, the in situ and the two ex situ multiplications were individually tested using 26 microsatellite markers. Most of the genetic parameters showed a consistent decline in the ex situ populations compared with the in situ population, with a notable loss of less frequent alleles. The differentiation among the farmer subpopulations increased when the multiplication took place outside of the adaptation area. Although 120 plants were multiplied in each ex situ cycle, a bottleneck effect was present. In addition, tests for neutrality detected three loci that are involved in pathogen response and are potentially under selective effects. The diversity conservation and the management practices of autogamous landrace crops are discussed. PMID- 20835754 TI - Comparison of microbial communities in pilot-scale bioreactors treating Bayer liquor organic wastes. AB - Western Australian bauxite deposits are naturally associated with high amounts of humic and fulvic materials that co-digest during Bayer processing. Sodium oxalate remains soluble and can co-precipitate with aluminium hydroxide unless it is removed. Removal of sodium oxalate requires a secondary crystallisation step followed by storage. Bioreactors treating oxalate wastes have been developed as economically and environmentally viable treatment alternatives but the microbial ecology and physiology of these treatment processes are poorly understood. Analysis of samples obtained from two pilot-scale moving bed biofilm reactors (MBBRs) and one aerobic suspended growth bioreactor (ASGB) using polymerase chain reaction- denaturing gradient gel electrophoresis of 16S rRNA genes showed that members of the alpha-, beta- and gamma-Proteobacteria subgroups were prominent in all three processes. Despite differing operating conditions, the composition of the microbial communities in the three reactors was conserved. MBBR2 was the only configuration that showed complete degradation of oxalate from the influent and the ASGB had the highest degradation rate of all three configurations. Several strains of the genus Halomonas were isolated from the bioreactors and their morphology and physiology was also determined. PMID- 20835755 TI - Journey in the Ostrinia world: from pest to model in chemical ecology. AB - The European corn borer Ostrinia nubilalis (ECB; Lepidoptera: Crambidae) is a widely recognized pest of agricultural significance over much of the northern hemisphere. Because of the potential value of pheromone-based control, there has been considerable effort devoted to elucidation of the ECB chemical ecology. The species is polymorphic regarding its female-produced pheromone. Partly because of this feature, over the years the ECB has become a model to study pheromone evolution. This review should assist in identifying new areas of pheromone research by providing an overview of the literature produced on this subject for the ECB since the late 1960's. PMID- 20835757 TI - Authoritative knowledge, the technological imperative and women's responses to prenatal diagnostic technologies. AB - Theories about authoritative knowledge (AK) and the technological imperative have received varying levels of interest in anthropological, feminist and science and technology studies. Although the anthropological literature abounds with empirical considerations of authoritative knowledge, few have considered both theories through an empirical, inductive lens. Data extracted from an earlier study of 30 women's responses to termination for fetal anomaly are reanalyzed to consider the women's views of, and responses to, prenatal diagnostic technologies (PNDTs). Findings indicate that a small minority embrace the societal portrayal of technology as univalently positive, while the majority have nuanced and ambivalent responses to the use of PNDTs. Further, the interface of authoritative knowledge and the technological imperative suggests that AK derives not only from medical provider status and technology use, but also from the adequacy and trustworthiness of the information. The issue of timing and uncertainty of the information also are interrogated for their impact on women's lives and what that can illuminate about the theories of AK and the technological imperative. PMID- 20835758 TI - The development of a methodology for examining the process of family communication of genetic test results. AB - It is important to study communication processes in families where members are undergoing testing for genetic conditions because the information received from such testing is crucial not just to the individual concerned but also to other members of the biological family. This topic has received little research attention, in part because of the complexities of methodology required. In this paper we present the development of a method specifically designed for the examination of the content and process of communication of genetic information in families. The method aims to maximize ecological validity as far as is possible. We describe how participants and other family members are recruited and how data were collected. We outline three main data analytic strategies: a graphic to show how genetic information changes as it flows from clinic and through the family, an intensive qualitative analysis of the meaning and impact of the genetic information to different family members, and an informative genogram which plots key family dynamics. This method will be illustrated in relation to a study of ten family-groups where one individual has been found to carry a genetic mutation predisposing them to hereditary breast and ovarian cancer. PMID- 20835756 TI - Role of lymphatic vessels in tumor immunity: passive conduits or active participants? AB - Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis. PMID- 20835759 TI - The aetiology of upper aerodigestive tract cancers among young adults in Europe: the ARCAGE study. AB - BACKGROUND: The incidence of cancers of the upper aerodigestive tract (UADT) is increasing throughout the world. To date the increases have been proportionally greatest among young people. Several reports have suggested that they often do not have a history of tobacco smoking or heavy alcohol consumption. OBJECTIVE: To determine the contribution of lifestyle factors to the etiology of UADT cancers occurring in those aged less than 50 years. METHODS: A case-control study was conducted in 10 European countries. Cases were cancers of the oral cavity and pharynx, larynx and esophagus, and hospital or population controls were age and sex matched. RESULTS: There were 356 cases younger than 50 years and 419 controls. Risk was strongly related to current smoking [odds ratio (OR) 5.5 95%; confidence interval (CI) (3.3, 9.2)], and risk increased with number of pack years smoked. Risk was also related to alcohol consumption for both current (OR 1.8; 0.97, 3.3) and past (OR 3.4; 1.6, 7.4) drinkers, and risk increased with number of drink-years. Persons frequently consuming fruits and vegetables were at significantly reduced risk. CONCLUSIONS: Risk factors already identified as being important for UADT cancers in adults are also important influences on risk in younger adults. The implication of these results is that the public health message in preventing UADT cancers remains the same to young and old alike. PMID- 20835761 TI - Dystocia in Friesian cows and its effects on postpartum reproductive performance and milk production. AB - A total of 1,243 records for 585 dairy Friesian cows from 1997-2004 were used to study the factors affecting dystocia and its effects on reproductive performance and milk production. The overall incidence of dystocia was 6.9%. The percentage of dystocia decreased with increasing live body weight, age, and parity of cows (P < 0.05); however, it increased with increasing birth weight of calves (P < 0.05). The highest percentage of dystocia was detected in winter season, but the least percentage was in summer season (P < 0.05). The percentage of incidence of dystocia was significantly (P < 0.05) higher with winter feeding compared to summer ration (8.2% vs. 5.1%). The percentage of incidence of dystocia was significantly (P < 0.05) higher with twinning than single calving (15.5% vs. 6.5%), while not significantly affected by the sex of born calves. Incidence of dystocia had adverse effects on reproductive performance and milk yield. The service interval, service period, days open, and calving interval were significantly (P < 0.05) longer in cows afflicted with dystocia compared to normal cows. The conception rate was lower (P < 0.05), but the number of service per conception was higher (P < 0.05) in cows afflicted with dystocia compared to normal cows (60.5% vs. 73.0% and 3.4 vs. 2.7, respectively). Average daily milk yield was lower (P < 0.05) by 1 kg for cows with incidence of dystocia compared to normal cows. PMID- 20835760 TI - Gene expression profiling in the submandibular gland, stomach, and duodenum of CAVI-deficient mice. AB - Carbonic anhydrase VI (CAVI) is the only secreted isozyme of the alpha-carbonic anhydrase family, which catalyzes the reversible reaction [Formula in text]. It appears that CAVI protects teeth and gastrointestinal mucosa by neutralizing excess acidity. However, the evidence for this physiological function is limited, and CAVI may have additional functions that have yet to be discovered. To explore the functions of CAVI more fully, we generated Car6 (-/-) mice and analyzed Car6 (-/-) mutant phenotypes. We also examined transcriptomic responses to CAVI deficiency in the submandibular gland, stomach, and duodenum of Car6 (-/-) mice. Car6 (-/-) mice were viable and fertile and had a normal life span. Histological analyses indicated a greater number of lymphoid follicles in the small intestinal Peyer's patches. A total of 94, 56, and 127 genes were up- or down-regulated in the submandibular gland, stomach, and duodenum of Car6 (-/-) mice, respectively. The functional clustering of differentially expressed genes revealed a number of altered biological processes. In the duodenum, the significantly affected biological pathways included the immune system process and retinol metabolic processes. The response to oxidative stress and brown fat cell differentiation changed remarkably in the submandibular gland. Notably, the submandibular gland, stomach, and duodenum shared one important transcriptional susceptibility pathway: catabolic process. Real-time PCR confirmed an altered expression in 14 of the 16 selected genes. The generation and of Car6 (-/-) mice and examination of the effects of CAVI deficiency on gene transcription have revealed several affected clusters of biological processes, which implicate CAVI in catabolic processes and the immune system response. PMID- 20835762 TI - Urban and rural immigrant Latino youths' and adults' knowledge and beliefs about mental health resources. AB - Immigrant Latino youth experience mental health problems in the U.S. Cultural beliefs and knowledge may influence help-seeking behaviors. Two hundred thirty four immigrant Latino respondents between 12 and 44 years of age completed a questionnaire assessing knowledge of and cultural beliefs regarding mental health resources for adolescents, symptoms, and help-seeking. Multivariate analyses showed that rural respondents were significantly less likely to know of mental health resources than urban-based immigrant Latinos. Knowledge and belief outcomes were also affected by age, gender, and length of time living in the community. Immigrant Latinos appear willing to seek professional help for mental health problems but may not know how to access this type of care, or may lack available services. Future research to inform interventions that increase awareness of accessible mental health services is suggested. Findings support systems-level changes including increased availability of culturally-specific mental health services, especially in rural areas. PMID- 20835763 TI - Newborn screening-progress and challenges. PMID- 20835764 TI - Impact of PVCs noted during coronary calcium scan on image quality and accuracy in subsequent coronary dual-source CT angiography. AB - The purpose of this study was to investigate the impact of the presence of one or more premature ventricular contractions (PVCs) during coronary calcium score scan (CS) on image quality and accuracy of subsequent dual-source coronary CT angiography (DS CCTA). Fifty-three out of 502 patients showed one or more PVCs during CS and built the study group. Sixty consecutively registered patients with sinus rhythm formed the control group. Two independent, blinded readers classified 1,723 coronary artery segments as being of diagnostic or non diagnostic image quality. All segments with diagnostic image quality were assessed for the presence for significant coronary artery stenosis. Accuracy was calculated using conventional angiography as standard of reference. The percentage of DS CCTA data sets with diagnostic image quality was significantly lower in the study group (79.2%) compared to the control group (90.6%, P < 0.05). The rate of coronary segment with diagnostic image quality was highly significant lower in the study group (89.5%; n = 723/808) compared to the control group (99.4%; n = 908/915; P < 0.001). However, accuracy did not differ in both groups. Significant correlation between non-diagnostic image quality and mean HR was only found in the study group (P = 0.019). The presence of one or more PVCs during CS does not affect accuracy but impairs image quality of subsequent DS CCTA. Mean HR is a predictor of non-diagnostic data sets only in the study group, suggesting more aggressive HR control could be beneficial. PMID- 20835765 TI - A comparison between plaque-based and vessel-based measurement for plaque component using volumetric intravascular ultrasound radiofrequency data analysis. AB - Although percent plaque components on plaque-based measurement have been used traditionally in previous studies, the impact of vessel-based measurement for percent plaque components have yet to be studied. The purpose of this study was therefore to correlate percent plaque components derived by plaque- and vessel based measurement using intravascular ultrasound virtual histology (IVUS-VH). The patient cohort comprised of 206 patients with de novo coronary artery lesions who were imaged with IVUS-VH. Age ranged from 35 to 88 years old, and 124 patients were male. Whole pullback analysis was used to calculate plaque volume, vessel volume, and absolute and percent volumes of fibrous, fibrofatty, necrotic core, and dense calcium. The plaque and vessel volumes were well correlated (r = 0.893, P < 0.001). There was a strong correlation between percent plaque components volumes calculated by plaque and those calculated by vessel volumes (fibrous; r = 0.927, P < 0.001, fibrofatty; r = 0.972, P < 0.001, necrotic core; r = 0.964, P < 0.001, dense calcium; r = 0.980, P < 0.001,). Plaque and vessel volumes correlated well to the overall plaque burden. For percent plaque component volume, plaque-based measurement was also highly correlated with vessel-based measurement. Therefore, the percent plaque component volume calculated by vessel volume could be used instead of the conventional percent plaque component volume calculated by plaque volume. PMID- 20835766 TI - Professional values: introduction to the theme. PMID- 20835767 TI - Intraoperative multispectral fluorescence imaging for the detection of the sentinel lymph node in cervical cancer: a novel concept. AB - PURPOSE: Real-time intraoperative near-infrared fluorescence (NIRF) imaging is a promising technique for lymphatic mapping and sentinel lymph node (SLN) detection. The purpose of this technical feasibility pilot study was to evaluate the applicability of NIRF imaging with indocyanin green (ICG) for the detection of the SLN in cervical cancer. PROCEDURES: In ten patients with early stage cervical cancer, a mixture of patent blue and ICG was injected into the cervix uteri during surgery. Real-time color and fluorescence videos and images were acquired using a custom-made multispectral fluorescence camera system. RESULTS: Real-time fluorescence lymphatic mapping was observed in vivo in six patients; a total of nine SLNs were detected, of which one (11%) contained metastases. Ex vivo fluorescence imaging revealed the remaining fluorescent signal in 11 of 197 non-sentinel LNs (5%), of which one contained metastatic tumor tissue. None of the non-fluorescent LNs contained metastases. CONCLUSIONS: We conclude that lymphatic mapping and detection of the SLN in cervical cancer using intraoperative NIRF imaging is technically feasible. However, the technique needs to be refined for full applicability in cervical cancer in terms of sensitivity and specificity. PMID- 20835768 TI - Obstructive and central sleep apnoea in Arnold-Chiari malformation: resolution following surgical decompression. PMID- 20835769 TI - Epworth sleepiness scale in obstructive sleep disordered breathing: the reliability and validity of the Thai version. AB - PURPOSES: The objectives of this study are to test the reliability and validity of the Thai version of the Epworth sleepiness scale (ESS) and to assess the relationship between the ESS score and the severity of obstructive sleep disordered breathing. METHODS: A total of 228 subjects (149 males and 79 females) were recruited. In order to check the discriminant validity of the ESS, we included 32 healthy volunteers and 39 patients with primary snoring to be the control groups and 126 patients with obstructive sleep apnea (OSA) confirmed by full polysomnography to be the disease groups. The test-retest reliability was investigated in 71 subjects. To check the responsiveness properties of the questionnaire, we asked a separate group of 31 patients who were successfully treated with either continuous positive airway pressure (CPAP) or upper airway surgery to complete the ESS before and after treatment at 3-6 months. RESULTS: The internal consistency demonstrated by Cronbach's alpha coefficients for standardized item was 0.87 and a range from 0.84 to 0.86 if some items were deleted. The test-retest reliability was shown by intra-class correlation coefficients of 0.79. There was a statistically significant difference between the mean of the ESS scores of the control groups (6.1 +/- 3.0) and the OSA patients (9.9 +/- 5.3) (p < 0.001). The ESS scores decreased significantly after a successful treatment with both CPAP and surgery (p < 0.001); however, there was no statistically significant difference among different severities of OSA. CONCLUSIONS: Our Thai version of the ESS showed an excellent internal consistency and test-retest reliability. It is able to discriminate between control subjects and OSA patients and to assess the response of treatment; however, it has a weak relationship with the apnea-hypopnea index. Therefore, we recommend use it to combine with more comprehensive clinical evaluation in obstructive sleep disordered breathing patients. PMID- 20835770 TI - Waist circumference predicts increased complications in rectal cancer surgery. AB - BACKGROUND: The impact of obesity on development of postoperative complications after gastrointestinal surgery remains controversial. This may be due to the fact that obesity has been calculated by body mass index, a measure that does not account for fat distribution. We hypothesized that waist circumference, a measure of central obesity, would better predict complications after high-risk gastrointestinal procedures. METHODS: Retrospective review of an institutional cancer database identified consecutive cases of men undergoing elective rectal resections. Waist circumference was calculated from preoperative imaging. RESULTS: From 2002 to 2009, 152 patients with mean age 65.2 +/- 0.75 years and body mass index 28.0 +/- 0.43 kg/m(2) underwent elective resection of rectal adenoma or carcinoma. Increasing body mass index was not significantly associated with risk of postoperative complications including infection, dehiscence, and reoperation. Greater waist circumference independently predicted increased risk of superficial infections (OR 1.98, 95% CI 1.19-3.30, p < 0.008) and a significantly greater risk of having one or more postoperative complications (OR 1.56, 95% CI 1.04-2.34, p < 0.034). CONCLUSIONS: Waist circumference, a measure of central obesity, is a better predictor of short-term complications than body mass index and can be used to identify patients who may benefit from more aggressive infection control and prevention. PMID- 20835771 TI - Gender-specific transfusion affects tumor-associated neutrophil: macrophage ratios in murine pancreatic adenocarcinoma. AB - INTRODUCTION: Perioperative blood transfusion has been linked to decreased survival for pancreas cancer. Noting clinical data associating female blood products with increased morbidity, our lab has demonstrated that transfusion of female blood augments metastatic events compared to male blood in an immunocompetent murine pancreatic cancer model. It has been suggested that tumor associated macrophages correlate with tumor progression by promoting angiogenesis. More recently, tumor-associated neutrophils have been implicated in aggressive tumor behavior. We hypothesize that differences in gender-specific transfusion-mediated pancreatic cancer progression are due to microenvironmental changes within the tumor. To test this hypothesis, we examined tumor-associated neutrophils and macrophage ratios in male and female mice with pancreatic cancer receiving blood transfusion from male or female donors. METHODS: C57/BL6 mice, age 7-9 weeks, underwent splenic inoculation with 2.5 * 10(5) PanO2 murine pancreatic adenocarcinoma cells. Mice were transfused on post-op day 7 with 1 ml/kg supernatant from day 42 male or female packed red cells. Necropsy was performed at 5 weeks or earlier for clinical deterioration, and tumors harvested. Frozen sections (5 um) were stained for neutrophils and macrophages by immunofluorescence. Data were analyzed using ANOVA; p <= 0.05 was used to determine significance; N >= 3 per group. RESULTS: Clinically, male mice had greater morbidity and mortality than female mice when receiving female blood products, with roughened hair coat, development of ascites and death due to bowel obstruction. In evaluating the tumor microenvironment from mice receiving female blood products, male mice were noted to have a greater neutrophil to macrophage ratio than female mice, 0.176 +/- 0.028 vs. 0.073 +/- 0.012, p = 0.03. When examining neutrophil to macrophage ratio in mice receiving male blood products, no difference was noted (p = 0.48). CONCLUSIONS: Male mice with pancreas cancer have greater morbidity than female mice when receiving female blood products. Furthermore, the difference in neutrophil to macrophage ratio suggests that gender-specific blood transfusion promotes aggressive tumor behavior in male mice via microenvironmental changes. These data warrant further study to delineate sex related differences in pancreatic cancer progression. PMID- 20835773 TI - A novel technique of partial splenectomy using radiofrequency ablation. AB - INTRODUCTION: Partial splenectomy has frequently been advocated to avoid the risk of overwhelming postsplenectomy sepsis. Concerns over adequate haemostasis during partial splenectomy, however, have limited its widespread use. We have previously reported our experience of using radiofrequency (RF) ablation to minimise blood loss during hepatic and splenic resections. METHODS: In this video, we illustrate the technique of partial splenectomy assisted by RF energy to minimise blood loss. PMID- 20835772 TI - Loss of alkalization in proximal esophagus: a new diagnostic paradigm for patients with laryngopharyngeal reflux. AB - INTRODUCTION: Cervical esophageal pH monitoring using a pH threshold of <4 in the diagnosis of laryngopharyngeal reflux (LPR) is disappointing. We hypothesized that failure to maintain adequate alkalization instead of acidification of the cervical esophagus may be a better indicator of cervical esophageal exposure to gastric juice. The aim of this study was to define normal values for the percent time the cervical esophagus is exposed to a pH >=7 and to use the inability to maintain this as an indicator for diagnosis of LPR. MATERIAL AND METHODS: Fifty nine asymptomatic volunteers had a complete foregut evaluation including pH monitoring of the cervical esophagus. Cervical esophageal exposure to a pH <4 was calculated, and the records were reanalyzed using the threshold pH >=7. The sensitivity of these two pH thresholds was compared in a group of 51 patients with LPR symptoms that were completely relieved after an antireflux operation. RESULTS: Compared to normal subjects, patients with LPR were less able to maintain an alkaline pH in the cervical esophagus, as expressed by a lower median percent time pH >= 7 (10.4 vs. 38.2, p < 0.0001). In normal subjects, the fifth percentile value for percent time pH >= 7 in the cervical esophagus was 19.6%. In 84% of the LPR patients (43/51), the percent time pH >= 7 were below the threshold of 19.6%. In contrast, 69% (35/51) had an abnormal test when the pH records were analyzed using the percent time pH < 4. Of the 16 patients with a false negative test using pH < 4, 11 (69%) were identified as having an abnormal study when the threshold of pH >= 7 was used. CONCLUSION: Normal subjects should have a pH >=7 in cervical esophagus for at least 19.6% of the monitored period. Failure to maintain this alkaline environment is a more sensitive indicator in the diagnosis of the LPR and identifies two thirds of the patients with a false negative test using pH <4. PMID- 20835774 TI - A novel method for establishment and characterization of extrahepatic bile duct epithelial cells from mice. AB - Culture of extrahepatic bile duct epithelial cells is a useful model to investigate physiology of extrahepatic bile duct epithelia and hepatobiliary disease mechanisms. The aim of this work was to establish and characterize a primary murine extrahepatic bile duct epithelial cell culture. Epithelial cells were isolated from extrahepatic bile ducts of BALB/c mice that were intraperitoneally injected with newborn bovine serum to induce the proliferation of extrahepatic bile ducts' epithelial cells and cultured on rat tail type I collagen-coated plastic culture flask containing DMEM/HamF12 with 10% FBS and 10 ng/ml epidermal growth factor at 37 degrees C in an incubator with 5% humidified CO(2). The cells showed typical morphologic characteristics of epithelial phenotypes with cobblestone appearance in monolayer within 5-6 d after culture; they were positive against anticytokeratin-19 immunostaining. Transmission electron microscopy showed typical bile duct epithelia with microvilli on the cytomembrane, Golgi complex, massive mitochondria, and rough endoplasmic reticulum in the cytoplasmic. The growth curve of the epithelial cells was determined by a MTT assay which showed a normal sigmoidal growth curve. This culture technique might be a reliable method for isolation, purification, and primary culture of extrahepatic bile duct epithelial cells that can serve as a model for in vitro studies on the pathophysiology of hepatobiliary diseases as well as pharmacological and toxicological targets relevant to hepatobiliary diseases. PMID- 20835775 TI - An improved method of cell culture system from eye stalk, hepatopancreas, muscle, ovary, and hemocytes of Penaeus vannamei. AB - Improved methods of cell culture from eye stalk, hepatopancreas, muscle, ovary, and hemocytes of shrimp (Penaeus vannamei) were established using synthetic media and shrimp muscle extract (SME). For hemocytes and ovarian cell cultures, Grace's insect medium supplemented with 10% (v/v) fetal bovine serum and 10% SME (v/v) showed enhanced attachment and proliferation of the cells. The hemocyte and ovarian cell cultures could be maintained for 48 and 66 days, respectively, and have been sub-cultured four and six times, respectively. Both ovary and hemocyte cell cultures contained primarily epithelial-like cells. Cells derived from ovary tissue grew preferably between 26 degrees C and 28 degrees C with 5% CO(2). Although the temperature preference of hemocyte cells was the same as ovarian cells, CO(2) supplementation did not show any difference in the growth of hemocyte cells. When the shrimp were injected with lipopolysaccharide (8 MUg/g of shrimp) and hemolymph was drawn 24 h post-injection, the in vitro multiplicity of hemocytes dramatically improved. The growth of eye stalk, hepatopancreas, and muscle-derived cells was much less compared to ovarian cells and hemocytes under the conditions described above. The optimal culture conditions for ovarian cells and hemocytes were also different from that for eye stalk, hepatopancreas, and muscle cell culture. The proliferation efficiencies of primary cultures of hepatopancreas, eyestalk, and muscle cells were about 30, 12, and <7 d, respectively. The improved culture conditions described here, particularly for hemocytes and ovary, will be very useful for in vitro studies involving viruses infecting shrimp and in shrimp genomic studies. PMID- 20835776 TI - Effect of 60 Hz magnetic fields on the activation of hsp70 promoter in cultured INER-37 and RMA E7 cells. AB - It has been reported that 50-60 Hz magnetic fields (MF) with flux densities ranging from microtesla to millitesla are able to induce heat shock factor or heat shock proteins in various cells. In this study, we investigated the effect of 60 Hz sinusoidal MF at 8 and 80 MUT on the expression of the luciferase gene contained in a plasmid labeled as electromagnetic field-plasmid (pEMF). This gene construct contains the specific sequences previously described for the induction of hsp70 expression by MF, as well as the reporter for the luciferase gene. The pEMF vector was transfected into INER-37 and RMA E7 cell lines that were later exposed to either MF or thermal shock (TS). Cells that received the MF or TS treatments and their controls were processed according to the luciferase assay system for evaluate luciferase activity. An increased luciferase gene expression was observed in INER-37 cells exposed to MF and TS compared with controls (p < 0.05), but MF exposure had no effect on the RMA E7 cell line. PMID- 20835777 TI - Organizational change: a way to increase colon, breast and cervical cancer screening in primary care practices. AB - Screening tests for colon, cervical and breast cancer remain underutilized despite their proven effectiveness in reducing morbidity and mortality. Stone et al. concluded that cancer screening is most likely to improve when a health organization supports performance through organizational changes (OC) in staffing and clinical procedures. OC interventions include the use of separate clinics devoted to prevention, use of a planned care visit, designation of non-physician staff for specific prevention activities and continuous quality improvement interventions. OBJECTIVES: To identify specific elements of OC interventions that increases the selected cancer screening rates. To determine to which extent practices bought into the interventions. METHODS: Eleven randomized controlled trials from January 1990 to June 2010 that instituted OC to increase cancer screening completion were included. Qualitative data was analyzed by using a framework to facilitate abstraction of information. For quantitative data, an outcome of measure was determined by the change in the proportion of eligible individuals receiving cancer screening services between intervention and control practices. The health prevention clinic intervention demonstrated a large increase (47%) in the proportion of completed fecal occult blood test; having a non-physician staff demonstrated an increase in mammography (18.4%); and clinical breast examination (13.7%); the planned care visit for prevention intervention increased mammography (8.8%); continuous quality improvement interventions showed mixed results, from an increase in performance of mammography 19%, clinical breast examination (13%); Pap smear (15%) and fecal occult blood test (13%), to none or negative change in the proportion of cancer screening rates. CONCLUSIONS: To increase cancer screening completion goals, OC interventions should be implemented tailored to the primary care practice style. Interventions that circumvent the physicians were more effective. We could not conclude whether or not continuous quality techniques were effective. Further research is needed to evaluate cost-effectiveness of these interventions. PMID- 20835778 TI - Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for the treatment of morbid obesity. A prospective study of 117 patients. AB - Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most widely used bariatric procedures today, and laparoscopic sleeve gastrectomy (LSG) as a single stage procedure for the treatment of morbid obesity is becoming increasingly popular. In this study, we prospectively compared both techniques in order to establish whether there is any superiority of one over the other based on morbidity and effectiveness. From January 2008 to December 2008, 117 obese patients with indication for bariatric surgery were assigned by patient choice after informed consent to either a LRYGB procedure (n = 75) or a LSG procedure (n = 42). We determined operative time, length of stay, morbidity, co-morbidity outcomes, and excess weight loss at 1 year postoperative. Both groups were comparable in age, sex, body mass index, and co-morbidities. Mean operative time of LSG was 82 min while LRYGB was 98 min (p < 0.05). Differences in length of stay, major complications, improvement in co-morbidities, and excess weight loss were not significant (p > 0.05). One year after surgery, average excess weight loss was 86% in LRYGB and 78.8% in LSG (p > 0.05). In the short term, both techniques are comparable regarding safety and effectiveness, so not one procedure is clearly superior to the other. PMID- 20835779 TI - Laparoscopic "gastrojejunal sleeve reduction" as a revision procedure for weight loss failure after roux-en-y gastric bypass. AB - BACKGROUND: Weight regain after Roux-en-Y gastric bypass (RYGB) is increasingly reported in the bariatric literature. Laparoscopic sleeve reduction of the gastrojejunal complex is a surgical option to revise a dilated gastric pouch. We report our short-term results. METHODS: Sleeve reduction entails serial firing of a linear stapler along the jejunal alimentary limb, across the gastric pouch and towards the left crus, with a bougie in place, thus, creating a new 20-25-cm reduced gastrojejunal complex. Data analyzed included age, body mass index (BMI), excess weight loss (EWL), comorbidity resolution, and any other simultaneous operative procedures. RESULTS: Fourteen patients were identified, all done laparoscopically. Nine underwent gastrojejunal sleeve reduction alone and five underwent additional lengthening of the Roux limb. There were no mortalities. Mean age at revision was 43 years (31-59). Mean BMI and EWL prior to revision were 35.5 +/- 4.0 kg/m2 and 48.9 +/- 15.8%, respectively. Nine of 14 patients (64%) had obesity-related comorbidities prior to the revision. Average BMI decrease was 2.7 kg/m2. Post-revision mean BMI and %EWL were 32.9 +/- 4.7 kg/m2 and 12.0 +/- 13.9%, respectively, with mean follow-up of 12 months. Three of nine patients (33%) experienced improvement and/or resolution of comorbidities. We did not find a significant difference between pre-and post-revision mean BMI and %EWL (p = 0.13) even after separately evaluating those patients who underwent Roux limb lengthening (p = 0.16). CONCLUSION: For RYGB patients who regained weight, laparoscopic gastrojejunal sleeve reduction does not seem to offer a major therapeutic benefit. Additional malabsorptive Roux lengthening also does not provide a significant benefit. Other options should be considered, such as placing a band on the gastric pouch or conversion to duodenal switch. PMID- 20835780 TI - Impact of laparoscopic adjustable gastric banding on pregnancy, maternal weight, and neonatal health. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a proven method for weight reduction. Less is known about pregnancies in patients after LAGB. METHODS: Information was gathered, through database and survey, on women who underwent LAGB at NYU Medical Center between 2001 and 2008 then became pregnant. RESULTS: Pregnancy occurred in 133 women, resulting in 112 babies, including six sets of twins. The average pre-pregnancy body mass index (BMI) was 32.7. Average weight gain was 11.5 kg, but was higher for those with pre-pregnancy BMI <30.0 compared to BMI >30.0 (16.4 vs 8.6 kg). Of singleton pregnancies, 89% were carried to full term, with cesarean section in 45%. Those with pre-pregnancy BMI <30.0 had a lower rate of cesarean section (35.71%), but it was not statistically significant (p = 0.55). Average birth weight was 3,268.6 g. Eight percent of babies from singleton pregnancies were low birth weight (<2,500 g), and seven percent were high birth weight (>4,000 g). Average Apgar scores at 1 and 5 min were 8.89 and 9.17. Four percent of patients developed gestational diabetes, and 5% developed pre-eclampsia. Band adjustments were performed in 71% of patients. Weight gain was higher in those who had their bands loosened in the first trimester (p = 0.063). Three patients had intrapartum band slips; one required surgery during pregnancy. CONCLUSIONS: LAGB is tolerable in pregnancy with rare intrapartum band slips. Weight gain is less in those with higher pre-pregnancy BMI and those who had their bands filled or not adjusted. Babies born to these mothers are as healthy as the general population. PMID- 20835781 TI - Enhanced production of L-arginine by expression of Vitreoscilla hemoglobin using a novel expression system in Corynebacterium crenatum. AB - Corynebacterium crenatum SYPA 5-5 is an aerobic and industrial L: -arginine producer. It was proved that the Corynebacterium glutamicum/Escherichia coli shuttle vector pJC1 could be extended in C. crenatum efficiently when using the chloramphenicol acetyltransferase gene (cat) as a reporter under the control of promoter tac. The expression system was applied to over-express the gene vgb coding Vitreoscilla hemoglobin (VHb) to further increase the dissolved oxygen in C. crenatum. As a result, the recombinant C. crenatum containing the pJC-tac-vgb plasmid expressed VHb at a level of 3.4 nmol g(-1), and the oxygen uptake rates reached 0.25 mg A(562)(-1) h(-1) which enhanced 38.8% compared to the wild-type strain. Thus, the final L: -arginine concentration of the batch fermentation reached a high level of 35.9 g L(-1), and the biomass was largely increased to 6.45 g L(-1), which were 17.3% and 10.5% higher than those obtained by the wild type strain, respectively. To our knowledge, this is the first report that the efficient expression system was constructed to introduce vgb gene increasing the oxygen and energy supply for L: -arginine production in C. crenatum, which supplies a good strategy for the improvement of amino acid products. PMID- 20835782 TI - The temporal stem in traumatic brain injury: preliminary findings. AB - The temporal stem (TS) of the temporal lobe is a major white matter (WM) region containing several major pathways that connect the temporal lobe with the rest of the brain. Because of its location, it may be particularly vulnerable to shear strain effects resulting from traumatic brain injury (TBI). A case vignette is presented in a patient with severe brain injury and focal TS pathology. Also, 12 severe TBI subjects unselected for TS pathology were compared to demographically matched, neurologically-intact controls using diffusion tensor imaging (DTI) to examine white matter tracts associated with the TS, including the inferior fronto occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), arcuate fasciculus (AF), cingulum bundle (CB) and the uncinate fasciculus (UF). For each tract, fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were computed and compared between the two groups and also examined in relationship to memory performance in the TBI subjects. Significant FA and ADC differences were observed in all tracts in the TBI patients compared to controls, with several relationships with memory outcome noted in the IFOF, ILF and AF. Based on these preliminary findings, the potential role of TBI-induced WM disconnection involving the TS is discussed as well as the relationship of TS damage to neurobehavioral outcome. The need for future studies specifically examining the role of TS injury in TBI is emphasized. PMID- 20835784 TI - Approach to establishment of a standard index for regional washout of a myocardial perfusion agent. AB - OBJECTIVE: Enhanced washout of (99m)Tc-SESTAMIBI (MIBI) is found in the myocardium in patients after acute myocardial infarction (AMI) or in those with serious angina. However, a standard index for washout evaluation in ischemic heart disease has not been established. We approached the establishment of a standard index for regional washout in ischemic heart disease and report the evaluation results of a newly developed washout evaluation method. METHODS: We made a polar map from short-axis myocardial SPECT images and developed a washout index (WO INDx) based on early and delayed images. The control group consisted of 10 healthy volunteers and a patient group of 43 patients with AMI or angina. Three nuclear cardiology specialists interpreted early and delayed images and visually graded the regional uptake of MIBI in 17 segments on a polar map, and the washout rate (WR) was compared with WO INDx. RESULTS: WO INDx and WR in the control group were 1.83 +/- 1.95 and 35.59 +/- 6.97, respectively. In the AMI cases the correlation of ejection fraction (EF) and WO INDx was -0.602, and the correlation of EF and WR was -0.346. The agreement between observers in the visual evaluation was high with excellent to moderate agreements. The ROC analysis was performed for WS2 with a washout score of 2 in the visual evaluation by Observers 1 to 3. The area under the ROC curve (AUC) was 0.934, 0.949 and 0.934 for WO INDx, respectively, and 0.681, 0.662 and 0.656 for WR, respectively, indicating that the AUC was higher for WO INDx. The sensitivity for WO INDx was 89.3, 88.9 and 96.3%, respectively, and the specificity was 88.2, 89.8 and 79.3%, respectively. The sensitivity for WR was 53.6, 52.8 and 51.9%, respectively, and the specificity was 87.5, 79.4 and 87.4%, respectively. These results suggested that WO INDx had higher reliability than WR in terms of sensitivity. CONCLUSIONS: The results suggested that the diagnosis using a new index, WO INDx, calculated from standardized percentage uptakes is more useful than that using the washout rate determined from the myocardial count in the MIBI washout evaluation. PMID- 20835783 TI - Contribution of discourse and morphosyntax skills to reading comprehension in Chinese dyslexic and typically developing children. AB - This study aimed at identifying important skills for reading comprehension in Chinese dyslexic children and their typically developing counterparts matched on age (CA controls) or reading level (RL controls). The children were assessed on Chinese reading comprehension, cognitive, and reading-related skills. Results showed that the dyslexic children performed significantly less well than the CA controls but similarly to RL controls in most measures. Results of multiple regression analyses showed that word-level reading-related skills like oral vocabulary and word semantics were found to be strong predictors of reading comprehension among typically developing junior graders and dyslexic readers of senior grades, whereas morphosyntax, a text-level skill, was most predictive for typically developing senior graders. It was concluded that discourse and morphosyntax skills are particularly important for reading comprehension in the non-inflectional and topic-prominent Chinese system. PMID- 20835785 TI - The role of quetiapine extended release in the treatment of bipolar depression. AB - Bipolar disorder is a common, recurrent, and chronic condition associated with significant morbidity and reduced longevity mainly due to the depressive pole of the illness. Despite the great need for effective therapies, relatively few randomized controlled trials have been conducted and, to date, only two agents have been approved by the United States Food and Drug Administration for treatment of bipolar depression (olanzapine/fluoxetine combination and quetiapine). Quetiapine is the first approved monotherapy for treatment of bipolar depression, and an extended-release (XR) form of quetiapine is now available. This once-daily, bioequivalent formulation represents a useful alternative for patients who cannot tolerate twice-daily, immediate-release (IR) quetiapine. Here, we summarize the evidence supporting the efficacy of quetiapine for treatment of bipolar depression, and also review the similarities and differences between the two formulations. Additional research on longer-term use of quetiapine XR is needed to establish the durability of therapeutic effects and tolerability over months or years of therapy, both alone and in combination with other mood stabilizers. Studies on the potential utility of lower doses of quetiapine XR and head-to-head studies to evaluate relative efficacy and cost effectiveness also are needed. PMID- 20835788 TI - [Abstracts of the 38th Congress of the German Society of Rheumatology. September 15-18, 2010. Hamburg, Germany]. PMID- 20835789 TI - Sequencing and genome assembly using next-generation technologies. AB - Several sequencing technologies have been introduced in recent years that dramatically outperform the traditional Sanger technology in terms of throughput and cost. The data generated by these technologies are characterized by generally shorter read lengths (as low as 35 bp) and different error characteristics than Sanger data. Existing software tools for assembly and analysis of sequencing data are, therefore, ill-suited to handle the new types of data generated. This paper surveys the recent software packages aimed specifically at analyzing new generation sequencing data. PMID- 20835786 TI - Hematologic effects of continuous flow left ventricular assist devices. AB - The extent of hematologic effects of the new continuous flow left ventricular assist devices (CF-LVAD) has not been studied. Recent clinical studies have demonstrated that hemolysis and thrombosis are not common during CF-LVAD support, however, the incidence of bleeding remains a concern. The rate of postoperative bleeding is similar to that of the prior generation pulsatile LVAD, but gastrointestinal bleeding due to angiodysplasia and arteriovenous malformations is more common and appears to be related to the blood flow rheology of these devices. New evidence suggests that acquired von Willebrand's disease develops in some patients due to the reduction in high molecular weight (HMW) multimers of von Willebrand's factor (vWF). Similar to acquired von Willebrand's disease seen in patients with aortic stenosis, the shear stress of the CF-LVAD may cause proteolysis of the HMW multimers of vWF. In addition to acquired von Willebrand's disease, there is activation of the fibrinolytic system and a loss of platelet numbers and function during CF-LVAD support. The hematologic responses during CF LVAD support are constantly changing, and antiplatelet therapy may need to be adjusted accordingly. Considerable research is needed to better define the complex hematologic effects during CF-LVAD support. Screening of patients for angiodysplasia and von Willebrand's disease before CF-LVAD implant may allow for effective preemptive treatment. Because bleeding causes significant morbidity for this population, more effective treatment strategies need to be developed. PMID- 20835790 TI - RNA structure prediction. AB - We give an overview of RNA structure predictions in this chapter. We discuss here the main approaches to RNA structure prediction: combinatorial approaches, comparative approaches, and kinetic approaches. The main algorithms and mathematical concepts such as transformational grammars will be briefly introduced. PMID- 20835791 TI - Normalization of gene-expression microarray data. AB - Expression microarrays are designed to quantify the amount of mRNA in a specific sample. However, this can only be done indirectly through quantifying the color intensities returned by labeled mRNA molecules bound to the array surface. Translating pixel intensities into transcript expression requires a series of computations, generically known as preprocessing and normalization steps. In this chapter, we introduce the basic concepts and methods, and illustrate them using data from three commonly used commercial platforms. PMID- 20835792 TI - Prediction of transmembrane topology and signal peptide given a protein's amino acid sequence. AB - Here, we describe transmembrane topology and signal peptide predictors and highlight their advantages and shortcomings. We also discuss the relation between these two types of prediction. PMID- 20835793 TI - Protein structure modeling. AB - The tertiary structure of proteins can reveal information that is hard to detect in a linear sequence. Knowing the tertiary structure is valuable when generating hypothesis and interpreting data. Unfortunately, the gap between the number of known protein sequences and their associated structures is widening. One way to bridge this gap is to use computer-generated structure models of proteins. Here we present concepts and online resources that can be used to identify structural domains in proteins and to create structure models of those domains. PMID- 20835795 TI - Automated protein NMR structure determination in solution. AB - The main drawback of protein NMR spectroscopy today is still the extensive amount of time required for solving a single structure. The main bottleneck in this respect is the manual evaluation of the experimental spectra. A clear solution to this challenge is the development of automated methods for this purpose. At the current stage of development, this goal has been almost or in a few cases fully reached for favorable cases such as well-behaved, stably folding smaller proteins below the 25 kDa range. For larger and/or more difficult molecules, the input of a human expert is still required. However, even here, automated routines will substantially speed up the structure determination process. In this report, we will summarize recent developments in this field and especially emphasize practical aspects important for a successful automated protein structure determination in solution. An important aspect closely related to structure determination is structure validation. Therefore, we devote a section to automated approaches for this topic. PMID- 20835796 TI - Computational tools in protein crystallography. AB - Protein crystallography emerged in the early 1970s and is, to this day, one of the most powerful techniques for the analysis of enzyme mechanisms and macromolecular interactions at the atomic level. It is also an extremely powerful tool for drug design. This field has evolved together with developments in computer science and molecular biology, allowing faster three-dimensional structure determination of complex biological assemblies. In recent times, structural genomics initiatives have pushed the development of methods to further speed up this process. The algorithms initially defined in the last decade for structure determination are now more and more elaborate, but the computational tools have evolved toward simpler and more user-friendly packages and web interfaces. We present here a modest overview of the popular software packages that have been developed for solving protein structures, and give a few guidelines and examples for structure determination using the two most popular methods, molecular replacement and multiple anomalous dispersion. PMID- 20835794 TI - Template-based protein structure modeling. AB - Functional characterization of a protein is often facilitated by its 3D structure. However, the fraction of experimentally known 3D models is currently less than 1% due to the inherently time-consuming and complicated nature of structure determination techniques. Computational approaches are employed to bridge the gap between the number of known sequences and that of 3D models. Template-based protein structure modeling techniques rely on the study of principles that dictate the 3D structure of natural proteins from the theory of evolution viewpoint. Strategies for template-based structure modeling will be discussed with a focus on comparative modeling, by reviewing techniques available for all the major steps involved in the comparative modeling pipeline. PMID- 20835797 TI - 3-D structures of macromolecules using single-particle analysis in EMAN. AB - Single-particle reconstruction is a methodology whereby transmission electron microscopy (TEM) is used to record images of individual monodisperse molecules or macromolecular assemblies, then sets of images of individual particles are computationally combined to produce a 3-D volumetric reconstruction. Ideally the TEM specimen will be prepared in vitreous ice (electron cryomicroscopy), but negative stain preparations may be used for lower resolution work. This technique has been demonstrated to produce structures at resolutions as high as ~ 4 A, though this is not yet typical. The reconstruction process is quite computationally intensive, and several software packages are available for this task. EMAN is one of the easier to master software suites for single-particle analysis. This protocol explains how to perform an initial low-resolution reconstruction using EMAN. PMID- 20835798 TI - Computational design of chimeric protein libraries for directed evolution. AB - The best approach for creating libraries of functional proteins with large numbers of nondisruptive amino acid substitutions is protein recombination, in which structurally related polypeptides are swapped among homologous proteins. Unfortunately, as more distantly related proteins are recombined, the fraction of variants having a disrupted structure increases. One way to enrich the fraction of folded and potentially interesting chimeras in these libraries is to use computational algorithms to anticipate which structural elements can be swapped without disturbing the integrity of a protein's structure. Herein, we describe how the algorithm Schema uses the sequences and structures of the parent proteins recombined to predict the structural disruption of chimeras, and we outline how dynamic programming can be used to find libraries with a range of amino acid substitution levels that are enriched in variants with low Schema disruption. PMID- 20835799 TI - Mass spectrometric protein identification using the global proteome machine. AB - Protein identification by mass spectrometry is widely used in biological research. Here, we describe how the global proteome machine (GPM) can be used for protein identification and for validation of the results. We cover identification by searching protein sequence collections and spectral libraries as well as validation of the results using expectation values, rho-diagrams, and spectrum databases. PMID- 20835800 TI - Unbiased detection of posttranslational modifications using mass spectrometry. AB - A major challenge in proteomics is to fully identify and characterize posttranslational modification (PTM) patterns present at any given time in cells, tissues, and organisms. Currently, the most frequently used method for identifying PTMs is tandem mass spectrometry combined with searching a protein sequence database. Although, database searching has been highly successful for the identification of proteins, it has a number of significant drawbacks for identification of modifications. The user needs to specify all expected modifications, and the search engine needs to consider all possible combinations of these modifications for all peptide sequences. If several potential modifications are considered, the search can take much longer than the data acquisition, creating a bottleneck in high-throughput analysis. In addition, the many possible assignments that need to be tested increase the noise and require better quality data for confident identification of modifications. Here, we describe a method for identifying both known and unknown PTM using mass spectrometry that does not suffer from these problems. The method is based on the observation that, in many samples, peptides are usually present both with and without modifications. By identifying the unmodified peptide with conventional database searches, the modified species of the peptide can be identified by searching for peptides with common and similar fragments as the unmodified peptide. After identifying both the modified and unmodified peptide, the elemental composition of the modification can be deduced if the mass accuracy of the precursor ion is sufficiently high. PMID- 20835801 TI - Protein quantitation using mass spectrometry. AB - Mass spectrometry is a method of choice for quantifying low-abundance proteins and peptides in many biological studies. Here, we describe a range of computational aspects of protein and peptide quantitation, including methods for finding and integrating mass spectrometric peptide peaks, and detecting interference to obtain a robust measure of the amount of proteins present in samples. PMID- 20835802 TI - Modeling experimental design for proteomics. AB - The complexity of proteomes makes good experimental design essential for their successful investigation. Here, we describe how proteomics experiments can be modeled and how computer simulations of these models can be used to improve experimental designs. PMID- 20835803 TI - A functional proteomic study of the Trypanosoma brucei nuclear pore complex: an informatic strategy. AB - The nuclear pore complex (NPC) is the sole mediator of transport between the nucleus and the cytoplasm. The NPC is composed of about 30 distinct proteins, termed nucleoporins or nups. The yeast (Rout et al., J Cell Biol 148:635-651, 2000) and mammalian (Cronshaw et al., J Cell Biol 158:915-927, 2002) NPC have been extensively studied. However, the two species are relatively closely related. Thus, to reveal details about NPC evolution, we chose to characterize the NPC of a distantly related organism, Trypanosoma brucei. We took a subcellular proteomic approach and used several complementary strategies to identify 865 proteins associated with the nuclear envelope. Over 50% of ~ 8,100 open reading frames of T. brucei have little or no known function because T. brucei is distantly related to model metazoa and fungi (Berriman et al., Science 309:416-422, 2005). By sequence similarity alone, we could identify only five nucleoporins. This chapter outlines our strategy to identify 17 additional nucleoporins as well as contribute functional annotation data to the T. brucei genome database. PMID- 20835804 TI - Inference of signal transduction networks from double causal evidence. AB - Here, we present a novel computational method, and related software, to synthesize signal transduction networks from single and double causal evidences. This is a significant and topical problem because there are currently no high throughput experimental methods for constructing signal transduction networks, and because the understanding of many signaling processes is limited to the knowledge of the signal(s) and of key mediators' positive or negative effects on the whole process. Our software NET-SYNTHESIS is freely downloadable from http://www.cs.uic.edu/~dasgupta/network-synthesis/ .Our methodology serves as an important first step in formalizing the logical substrate of a signal transduction network, allowing biologists to simultaneously synthesize their knowledge and formalize their hypotheses regarding a signal transduction network. Therefore, we expect that our work will appeal to a broad audience of biologists. The novelty of our algorithmic methodology based on nontrivial combinatorial optimization techniques makes it appealing to computational biologists as well. PMID- 20835805 TI - Reverse engineering gene regulatory networks related to quorum sensing in the plant pathogen Pectobacterium atrosepticum. AB - The objective of the project reported in the present chapter was the reverse engineering of gene regulatory networks related to quorum sensing in the plant pathogen Pectobacterium atrosepticum from micorarray gene expression profiles, obtained from the wild-type and eight knockout strains. To this end, we have applied various recent methods from multivariate statistics and machine learning: graphical Gaussian models, sparse Bayesian regression, LASSO (least absolute shrinkage and selection operator), Bayesian networks, and nested effects models. We have investigated the degree of similarity between the predictions obtained with the different approaches, and we have assessed the consistency of the reconstructed networks in terms of global topological network properties, based on the node degree distribution. The chapter concludes with a biological evaluation of the predicted network structures. PMID- 20835806 TI - Parameter inference and model selection in signaling pathway models. AB - To support and guide an extensive experimental research into systems biology of signaling pathways, increasingly more mechanistic models are being developed with hopes of gaining further insight into biological processes. In order to analyze these models, computational and statistical techniques are needed to estimate the unknown kinetic parameters. This chapter reviews methods from frequentist and Bayesian statistics for estimation of parameters and for choosing which model is best for modeling the underlying system. Approximate Bayesian computation techniques are introduced and employed to explore different hypothesis about the JAK-STAT signaling pathway. PMID- 20835807 TI - Genetic algorithms and their application to in silico evolution of genetic regulatory networks. AB - A genetic algorithm (GA) is a procedure that mimics processes occurring in Darwinian evolution to solve computational problems. A GA introduces variation through "mutation" and "recombination" in a "population" of possible solutions to a problem, encoded as strings of characters in "genomes," and allows this population to evolve, using selection procedures that favor the gradual enrichment of the gene pool with the genomes of the "fitter" individuals. GAs are particularly suitable for optimization problems in which an effective system design or set of parameter values is sought.In nature, genetic regulatory networks (GRNs) form the basic control layer in the regulation of gene expression levels. GRNs are composed of regulatory interactions between genes and their gene products, and are, inter alia, at the basis of the development of single fertilized cells into fully grown organisms. This paper describes how GAs may be applied to find functional regulatory schemes and parameter values for models that capture the fundamental GRN characteristics. The central ideas behind evolutionary computation and GRN modeling, and the considerations in GA design and use are discussed, and illustrated with an extended example. In this example, a GRN-like controller is sought for a developmental system based on Lewis Wolpert's French flag model for positional specification, in which cells in a growing embryo secrete and detect morphogens to attain a specific spatial pattern of cellular differentiation. PMID- 20835808 TI - [Limited toxicity of the pediculicides pyrethrin, pyrethroids, and permethrin]. PMID- 20835809 TI - [Dermal necrosis as cutaneous manifestation of heparin-induced thrombocytopenia II?]. AB - Most of the rare cases of skin necrosis following heparin injections are associated with the immunologically mediated form of heparin-induced thrombocytopenia II (HIT II). We present a 62-year- old woman who developed a necrotic abdominal lesion seven days after starting daily subcutaneous injections of the low molecular heparin enoxaparin. We detected circulating antibodies against the platelet factor 4-complex but no concomitant thrombocytopenia. An isolated, antibody-mediated thrombosis of dermal vessels is the likely underlying cause of the skin necrosis in HIT II. PMID- 20835810 TI - [Recurrent pyogenic granuloma. Treatment at difficult anatomic sites with the long-pulsed Nd:YAG laser (1064 nm)]. AB - Treatment of pyogenic granuloma is still difficult as lesions tend to recur. There are various means of treatment: surgical, cryotherapy, topical agents and various lasers. We successfully treated two recurrent pyogenic granulomas at difficult sites (on the tip of the finger and ear) using the Nd: YAG laser (1064 nm). Several treatments under local anesthesia were needed. The energy was increased until coagulation was visible. The laser treatment led to complete resolution. PMID- 20835811 TI - [Perianal streptococcal dermatitis caused by beta-hemolytic group G streptococci in two adults]. AB - Perianal streptococcal dermatitis is generally considered a childhood disorder caused by beta-hemolytic group A streptococci. It should also be considered in cases of therapy-refractory gluteal erythema in adults. We report two cases of perianal streptococcal dermatitis in adults. In both, the microbiological examination of the skin swabs showed beta-hemolytic group G streptococci. Therapy of choice is penicillin. PMID- 20835812 TI - [Necrotizing fasciitis caused by Acinetobacter baumannii : A case report]. AB - A 42-year-old man developed necrotizing fasciitis on the right leg. A multidrug resistant Acinetobacter baumannii was cultivated from the deep wound. Following therapy with imipenem and tobramycin as well as extensive debridement, the lesions improved slowly. A. baumannii is today an important cause of nosocomial infections, especially in intensive care units. PMID- 20835813 TI - Reanalyses of the historical series of UK variety trials to quantify the contributions of genetic and environmental factors to trends and variability in yield over time. AB - Historical datasets have much to offer. We analyse data from winter wheat, spring and winter barley, oil seed rape, sugar beet and forage maize from the UK National List and Recommended List trials over the period 1948-2007. We find that since 1982, for the cereal crops and oil seed rape, at least 88% of the improvement in yield is attributable to genetic improvement, with little evidence that changes in agronomy have improved yields. In contrast, in the same time period, plant breeding and changes in agronomy have contributed almost equally to increased yields of forage maize and sugar beet. For the cereals prior to 1982, contributions from plant breeding were 42, 60 and 86% for winter barley, winter wheat and spring barley, respectively. These results demonstrate the overwhelming importance of plant breeding in increasing crop productivity in the UK. Winter wheat data are analysed in more detail to exemplify the use of historical data series to study and detect disease resistance breakdown, sensitivity of varieties to climatic factors, and also to test methods of genomic selection. We show that breakdown of disease resistance can cause biased estimates of variety and year effects, but that comparison of results between fungicide treated and untreated trials over years may be a means to screen for durable resistance. We find the greatest sensitivities of the winter wheat germplasm to seasonal differences in rainfall and temperature are to summer rainfall and winter temperature. Finally, for genomic selection, correlations between observed and predicted yield ranged from 0.17 to 0.83. The high correlation resulted from markers predicting kinship amongst lines rather than tagging multiple QTL. We believe the full value of these data will come from exploiting links with other experiments and experimental populations. However, not to exploit such valuable historical datasets is wasteful. PMID- 20835814 TI - Microfluidic multi-analyte gradient generator. AB - A microfluidic device was developed to produce temporal concentration gradients of multiple analytes. Four on-chip pumps delivered pulses of three analytes and buffer to a 14-cm channel where the pulses were mixed to homogeneity. The final concentration of each analyte was dependent on the temporal density of the pulses from each pump. The concentration of each analyte was varied by changing the number of pump cycles from each reservoir while maintaining the total number of pump cycles per unit time to ensure a constant total flow rate in the device. To gauge the independent nature of each pump, sinusoidal waves of fluorescein concentration were produced from each pump with independent frequencies and amplitudes. The resulting fluorescence intensity was compared with a theoretical summation of the waves and the experimental data matched the theoretical waves within 1%, indicating that the pumps were operating independently and outputting the correct frequency and amplitude. The device was used to demonstrate the role of adenosine triphosphate-sensitive K(+) channels in glucose-stimulated increases in intracellular [Ca(2+)] in islets of Langerhans. Perfusion of single islets of Langerhans with combinations of glucose, diazoxide, and K(+) resulted in intracellular Ca(2+) patterns similar to what has been observed using conventional perfusion devices. The system will be useful in other studies with islets of Langerhans, as well as other assays that require the modulation of multiple analytes in time. PMID- 20835815 TI - Focused ultrasound-assisted acceleration of enzymatic hydrolysis of alkylphenols and 17beta-oestradiol glucuronide in fish bile. AB - According to the European Water Framework Directive (WFD), alkylphenols, such as octylphenols and nonylphenols, and 17beta-oestradiol are considered as priority or emerging pollutants, respectively, mainly due to their possible properties as endocrine-disrupting compounds (EDCs). EDCs are accumulated in liver, fat, kidney and bile in the glucuronide form. In order to determine the concentration of these compounds in bile, an enzymatic hydrolysis step is necessary. This step is usually long (~16 h), and in this sense, ultrasound probes were studied as a possible alternative energy source to accelerate this process. Enzymatic hydrolysis was reduced to 20 min using an ultrasound probe at one cycle and 10% of amplitude. For validation of analytical procedure, nonylphenol glucuronide (4NP-G), 4-tert-octylphenol glucuronide (4tOP-G) and 4-n-octylphenol glucuronide (4nOP-G) were synthesised while 17beta-oestradiol glucuronide (E2-G) was commercially available. Bile from thick-lip grey mullets (Chelon labrosus) was spiked with known amounts of 4NP-G, 4tOP-G, 4nOP-G and E2-G and submitted to the optimised procedure. Good recoveries (77-122%), precision in the 5% to 12% range and limits of detection, ranging from the low nanogramme per gramme level for 4tOP, 4nOP and E2 to the low microgramme per gramme level for nonylphenols, were obtained. The optimised method was applied for the determination of alkylphenol in the bile of thick-lip grey mullets fish bile from the Urdaibai estuary (UNESCO reserve of the Biosphere, Bay of Biscay), and high concentrations (2.3-14.2 MUg/g), such as those obtained in polluted areas, were measured. E2 was determined in the bile of thick-lip grey mullets, intraperitoneally injected with E2. PMID- 20835816 TI - Electrochemiluminescent aptamer biosensor for the determination of ochratoxin A at a gold-nanoparticles-modified gold electrode using N-(aminobutyl)-N ethylisoluminol as a luminescent label. AB - A highly selective electrochemiluminescent biosensor for the detection of target nephrotoxic toxin, ochratoxin A (OTA), was developed using a DNA aptamer as the recognition element and N-(4-aminobutyl)-N-ethylisoluminol (ABEI) as the signal producing compound. The electrochemiluminescent aptamer biosensor was fabricated by immobilizing aptamer complementary DNA 1 sequence onto the surface of a gold nanoparticle (AuNP)-modified gold electrode. ABEI-labeled aptamer DNA 2 sequence hybridized to DNA 1 and was utilized as an electrochemiluminescent probe. A decreased electrochemiluminescence (ECL) signal was generated upon aptamer recognition of the target OTA, which induced the dissociation of DNA 2 (ABEI labeled aptamer electrochemiluminescent probe) from DNA 1 and moved it far away from the electrode surface. Under the optimal conditions, the decreased ECL intensity was proportional to an OTA concentration ranging from 0.02 to 3.0 ng mL(-1), with a detection limit of 0.007 ng mL(-1). The relative standard deviation was 3.8% at 0.2 ng mL(-1) (n = 7). The proposed method has been applied to measure OTA in naturally contaminated wheat samples and validated by an official method. This work demonstrates the combination of a highly binding aptamer with a highly sensitive ECL technique to design an electrochemiluminescent biosensor, which is a very promising approach for the determination of small-molecule toxins. PMID- 20835817 TI - Isolation and sequence analysis of peptides from the skin secretion of the Middle East tree frog Hyla savignyi. AB - Novel peptides were identified in the skin secretion of the tree frog Hyla savignyi. Skin secretions were collected by mild electrical stimulation. Peptides were separated by reversed-phase high-performance liquid chromatography. Mass spectra were acquired by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS), and fragment ion spectra were obtained after collision-induced dissociation and electron capture dissociation. Peptides were analyzed by manual de novo sequencing and composition-based sequencing (CBS). Sequence analyses of three so far undescribed, structurally unrelated peptides are presented in this paper, having the sequences DDSEEEEVE-OH, P*EEVEEERJK-OH, and GJJDPJTGJVGGJJ-NH(2). The glutamate-rich sequences are assumed to be acidic spacer peptides of the prepropeptide. One of these peptides contains the modified amino acid hydroxyproline, as identified and localized by high-accuracy FTICR-MS. Combination of CBS and of experience-based manual sequence analysis as complementary and database-independent sequencing strategies resulted in peptide identification with high reliability. PMID- 20835818 TI - Fiber-optic pH detection in small volumes of biosamples. AB - Determining the pH values of microscopic plant samples may help to explain complex processes in plants, so it is an area of interest to botanists. Fiber optic probes with small dimensions can be used for this purpose. This paper deals with the fiber-optic detection of the pH values of droplets of plant xylem exudate based on ratiometric fluorescence intensity measurements with an internal reference. For this purpose, novel V-taper sensing probes with a minimum diameter of around 8 MUm were prepared that enable the delivery of fluorescence signal from the detection site on the taper tip to the detector. The taper tips were coated with pH-sensitive transducer (8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt; HPTS) and a reference [dichlorotris-(1,10-phenanthroline) ruthenium (II) hydrate (Ru-phen dichloride)] immobilized in a xerogel layer of propyltriethoxysilane and (3-glycidoxy)propyl trimethoxysilane. The prepared probes were sensitive to pH values mainly in the range from 6.0 to 9.0. In the pH range 6-9, the results were limited by measurement errors of about 0.2 pH units, and in the pH range 5-6 by measurement errors of about 0.5 pH units. Using the developed V-taper sensing probes, the pH values of in vivo and in vitro samples of small volumes (~6 MUl) of exudate were measured. The results were validated by comparison with conventional electrochemical pH measurements. PMID- 20835819 TI - Simultaneous measurement of three N-acylethanolamides in human bio-matrices using ultra performance liquid chromatography-tandem mass spectrometry. AB - Endocannabinoids including N-acylethanolamides (NAEs) are a family of lipid related signaling molecules implicated in many physiological and disease states which elicit their activities via the cannabinoid receptors. Anandamide (N arachidonoylethanolamine, AEA) is the most characterized endocannabinoid and has been detected in many tissues and bio-fluids including human plasma and the central nervous system. The endocannabinoid-like NAEs, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are described as entourage compounds because they illicit similar physiological effects to AEA but have little or no affinity for cannabinoid receptors. As entourage compounds, levels of these NAEs can greatly influence the efficacy of AEA yet there are few studies which measure these compounds in bio-fluids. Here we describe a rapid, highly sensitive, specific and highly reproducible ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the analysis of AEA, OEA, and PEA in human bio-fluids including plasma, serum, breast milk, and amniotic fluids. This validated method using deuterated (AEA-d(8), OEA-d(2), and PEA-d(4)) internal standards, represents an improvement over previous analyses in terms of run time (4 min), limit of detection (0.9 fmol on column for AEA and PEA and 4.4 fmol on column for OEA), precision (relative standard deviations of peak areas: 3.1% (AEA), 2.9% (OEA), and 5.4% (PEA) for 133 fmol on column) and accuracy (95.1 104.9%). The sensitivity and precision of the validated method described here suggests that this method is suitable for the analysis of AEA, OEA, and PEA in clinical samples and may be utilized for the investigation of bio-matrices containing limited amounts of NAEs. PMID- 20835820 TI - Whole-cell aquatic biosensors. AB - The use of various whole-cell organisms as tools for monitoring water contaminants is reviewed and evaluated. Their suitability and value for assessing a range of environmental problems from the impact of pollution, homeland defense issues, conservation, and the long-term degradation and recovery of ecosystems is discussed. Guidelines are provided for the choice of appropriate bioreporter organisms, transducers, and immobilization methods. Examples of the use of a broad spectrum of whole-cell bioreporters in assessing a variety of environmental problems are summarized. PMID- 20835821 TI - Correction of superior sulcus deformity with orbital fat anatomic repositioning and fat graft applied to retro-orbicularis oculi fat for Asian eyelids. AB - BACKGROUND: "Sunken eyelid" is a term used to describe a deeply sunken area between the upper eyelid and upper edge of the orbital bone. The condition frequently is accompanied by blepharoptosis. Correction of a "sunken eyelid" generally is performed with a fat graft. However, surgical limitations such as a movement dysfunction of the upper eyelid or irregular skin surface often are encountered using the grafting method previously reported. An open technique is believed to be more precise than a closed procedure, and satisfactory results may be achieved by repositioning the upper eyelid fat and applying a fat graft to the retro-orbicularis orbital fat (ROOF). METHODS: Fat was harvested from the medial thigh area using a 10-ml syringe with minimal pressure. During the upper eyelid surgery, the orbital fat was relocated between the conjoined tendon of the levator aponeurosis and the lower orbicularis oculi muscle and skin flap. The ROOF was verified, and fat grafting then was performed from the upper medial side to the lower lateral side and from the medial aspect to the lateral direction using an 18-gauge Coleman needle. The sunken eyelids were classified into grades 1 to 4 according to the sunken depth (i.e., the distance between the most inferior orbital rim and the site of the most sunken area). The amount of fat graft and the technique of incorporating the fat were different according to sunken depth. RESULTS: From January 2006 to June 2008, 50 Korean and Chinese patients (48 women and 2 men) underwent fat repositioning and ROOF fat grafting using an open technique. The patients ranged in age from 24 to 67 years. The mean observation period was 4.7 months. The amount of fat graft for each palpebra was 0.3 to 3.3 ml, and the mean graft amount was 1.4 ml. Satisfactory results were obtained for most of the patients, but four patients required additional surgery. The reasons for the secondary surgery were a translocation of the fat graft to a lower position forming a lump (2 patients) and undercorrection (2 patients). The rate of fat absorption was relatively low and the complications very few compared with surgical cases involving a noninvasive method. CONCLUSIONS: More precise treatment is possible by dividing the depressed area of the upper eyelid according to the stage. Satisfactory results were achieved by relocating the orbital fat using an open method and adjusting the ROOF fat graft according to the stage. PMID- 20835822 TI - Mesotherapy should not replace the surgical approach in the treatment of benign symmetric lipomatosis. PMID- 20835823 TI - Facial rejuvenation and improvement of malar projection using sutures with absorbable cones: surgical technique and case series. AB - BACKGROUND: Currently, the face can be reshaped with minimally invasive procedures. This report describes how the midface can be suspended by increasing the projection of the malar area, decreasing the nasolabial fold depth, and improving the jaw definition using 3-0 polypropylene sutures with absorbable cones (Silhouette Sutures). METHODS: Preoperative skin marks were made to indicate the four points on each side of the face where the sutures would exit through the skin: 1 cm lateral to the middle of the nasolabial fold, at the corner of the mouth, and on the line from the lateral corner of the lips to the angle of the mandible. The sutures were inserted through a 1.5-cm incision positioned in the temporal area. After insertion of the needle, the sutures were fixed to a small polypropylene mesh over the deep temporal fascia. RESULTS: A total of 316 patients were treated between January 2007 and December 2009. The results over a mean follow-up period of 18 months were good, with high patient satisfaction. All the complications experienced by 42 patients (13.3%) were minor and temporary including temporal area pain (7%), visible dermal pinching (3.5%), hematoma (1.3%), asymmetry (0.6%), and suture palpability (0.3%). There were no infections. CONCLUSIONS: Face-lifts were performed for 257 women with a mean age of 47 years and 59 men with a mean age of 49.5 years. This procedure can be performed for various age groups to rejuvenate and reshape the middle face. Men whose scars cannot be easily hidden due to baldness are good candidates as well. The technique led to stable results and only minor, temporary complications, with a high level of satisfaction among patients and surgeons. The longevity of the results beyond the mean follow-up period of 18 months needs to be determined. PMID- 20835824 TI - Reconstruction of nasal deformity in Wegener's granulomatosis: contraindication or benefit? AB - BACKGROUND: Saddle-nose deformity is a well-recognized stigma of patients affected by Wegener granulomatosis (WG). However, plastic surgical repair is seldom performed. In this study, the authors aimed to evaluate their own patients exclusively reconstructed by costal cartilage L-strut of the nose for this specific deformity. METHODS: During a 5-year-period, four women with an average age of 33 years underwent reconstructive rhinoplasty of their saddle-nose deformity caused by WG, which in every case was in remission regarding the nose at the time of surgery. Restoration of the nasal framework was performed by an L shaped rib cartilage graft. RESULTS: The external form and function of the newly reconstructed nose was preserved during an average follow-up period of 42 months for all the patients. No resorption of the rib cartilage graft was observed. A review of the literature found a total of 22 nasal reconstructions for patients affected by WG. CONCLUSION: According to this patient series and a review of the literature, external nasal reconstruction for patients affected by WG appears to be safe and effective if the disease is in remission before any operation. Despite concern that high-dose immune suppression therapy may increase the risk of failure in primary nasal dorsal repair, this could not be observed in the patients of this series, all of whom were receiving immunosuppressive medication. Therefore, nasal reconstruction to improve the physical appearance and thus the psychological well-being of these chronically ill patients seems to be justified. PMID- 20835825 TI - Augmentation mammoplasty in breasts with port-wine stains. Are these patients at increased risk of haematoma? A case report with comparative analysis. PMID- 20835826 TI - Three-dimensional radiofrequency tissue tightening: a proposed mechanism and applications for body contouring. AB - The use of radiofrequency energy to produce collagen matrix contraction is presented. Controlling the depth of energy delivery, the power applied, the target skin temperature, and the duration of application of energy at various soft tissue levels produces soft tissue contraction, which is measurable. This technology allows precise soft tissue modeling at multiple levels to enhance the result achieved over traditional suction-assisted lipectomy as well as other forms of energy such as ultrasonic and laser-generated lipolysis. PMID- 20835827 TI - The onlay folded flap (OFF): a new technique for nasal tip surgery. AB - BACKGROUND: In this article the onlay folded flap (OFF) is introduced as a new technique for reshaping, refining, supporting, and projecting the nasal tip by remodeling the cephalic portions of the lateral crura rather than canceling them. The surgical technique and the long-term outcomes are described. The indications, contraindications, advantages, and disadvantages are defined. METHODS: Forty patients were operated on for hypoprojected nasal tips. They had been followed for from 6 to 35 months (average = 13 months). None of the patients had thin skin, and none of them had previously undergone a rhinoplasty. Two symmetric lateral flaps are taken from the cephalic portions of the lateral crura and attached to the domal segments. The flaps' internal edges are carefully sutured together to form one flap. This is then rotated anteriorly over the original domes and fixed to them, before its distal portion is turned posteriorly over the first layer and fixed to it. The nasal tip projection was calculated for all patients before and 6 months after surgery using a personal method as a means of evaluating the gain in nasal tip projection in the postoperative period. RESULTS: Revision was necessary in only one patient to fix an unpleasant columellar scar. The average nasal tip projection gain 6 months after surgery was approximately 4 mm (range = 3-5 mm). The nasal tips were fine and stable in all patients. CONCLUSION: The OFF technique is recommended in primary rhinoplasty for reshaping, refining, and supporting the nasal tip and for increasing nasal tip projection (from 3 to 5 mm maximum) but only for people with normal or thick skin. It has many advantages and good postoperative results. PMID- 20835828 TI - Probiotic lactobacilli interfere with Streptococcus mutans biofilm formation in vitro. AB - In clinical studies, probiotic bacteria have decreased the counts of salivary mutans streptococci (MS). We compared the effects of probiotic Lactobacillus strains on the biofilm formation of Streptococcus mutans. The bacterial strains used included four S. mutans strains (reference strains NCTC 10449 and Ingbritt and clinical isolates 2366 and 195) and probiotic strains Lactobacillus rhamnosus GG, L. plantarum 299v, and L. reuteri strains PTA 5289 and SD2112. The ability of MS to adhere and grow on a glass surface, reflecting biofilm formation, was studied in the presence of the lactobacilli (LB). The effect of LB culture supernatants on the viability of the MS was studied as well. All of the LB inhibited the biofilm formation of the clinical isolates of MS (P < 0.001). The biofilm formation of the reference strains of MS was also inhibited by the LB, but L. plantarum and L. reuteri PTA 5289 showed a weaker inhibition when compared to L. reuteri SD2112 and L. rhamnosus GG. Viable S. mutans cells could be detected in the biofilms and culture media only when the experiments were performed with the L. reuteri strains. The L. reuteri strains were less efficient in killing the MS also in the tests performed with the culture supernatants. The pHs of the supernatants of L. reuteri were higher compared to those of L. rhamnosus GG and L. plantarum; P < 0.001. In conclusion, our results demonstrated that four commonly used probiotics interfered with S. mutans biofilm formation in vitro, and that the antimicrobial activity against S. mutans was pH-dependent. PMID- 20835829 TI - Changes in ffh, uvrA, groES and dnaK mRNA abundance as a function of acid adaptation and growth phase in Bifidobacterium longum BBMN68 isolated from healthy centenarians. AB - The acid adaption is commonly used as a strategy to enhance the acid tolerance of bifidobacteria. However, the acid tolerance response (ATR) mechanism elicited by this method is unclear. Real-time relative-quantitative PCR was applied to analyze the changes in the expressions of ffh, uvrA, groES, and dnaK involved in the ATR after acid-adaptation in Bifidobacterium longum BBMN68 in different growth phases. BBMN68 was cultured at a constant neutral pH during the whole growth phase. Without acid-adaptation, the survival ratios at the lethal pH 3.0 were 0.25% and 17% in the exponential and stationary phases, respectively. The genes ffh, uvrA, groES, and dnaK were significantly higher in the stationary phase than in the exponential phase. The results indicated that although there was no acid stress, the acid tolerance of cells was elevated from the exponential phase into stationary phase. After acid-adaptation at pH 5.0 for 120 min, the survival ratios of BBMN68 in the exponential and stationary phases were increased to 2.5 and 31%, respectively. In the exponential phase, ffh, uvrA groES, and dnaK were significantly decreased after acid-adaptation. In the stationary phase, after acid-adaptation for 15, 60, and 120 min, the genes uvrA, groES, and dnaK were significantly decreased, whereas, ffh was significantly up-regulated at 15 min, and then suppressed at 60 and 120 min after acid-adaptation. The results represented that the ATR in B. longum was different from other bacteria, and ffh may be the transient acid gene. PMID- 20835830 TI - Bacillus thuringiensis protein Cry6B (BGSC ID 4D8) is toxic to larvae of Hypera postica. AB - Insecticidal proteins produced by strains of Bacillus thuringenesis are specific toward target pests. One of the Bt proteins, Cry 1Ac has been used successfully for controlling crop predation by polyphagous pests Helicoverpa armigera. Structurally, Bt proteins consist of three domains; domain I and III are fairly homologous in various Bt proteins while domain II is hypervariable. The hypervariable domain II is believed to be responsible for specificity toward target pest. Successful deployment of Bt proteins requires knowledge of its specificity toward the insect. Various Bt proteins have been characterized for activity against coleopteran pests. Some Bt proteins of class Cry6 have been found to be active against potato weevil. We have evaluated the activity of Cry6B protein (BGSC-4D8) against lucerne weevil, Hypera postica, which is a major pest of forage crop Medicago sativa. Results revealed that the purified Cry6B protein is significantly active against the coleopteran pest with LC50 value 280 ng/MUl. The leaves coated with the purified Cry6 toxin were three times less damaged as compared with the negative control. PMID- 20835831 TI - Rule 3,000: a more reliable precursor to perceive vestibular schwannoma on MRI in screened asymmetric sensorineural hearing loss. AB - Nine different definitions of asymmetric sensorineural hearing loss (SNHL) have been reported in literature. The objectives of this study are to: (1) compare all these definitions of asymmetric SNHL; (2) measure the agreement between these definitions in detecting vestibular schwannoma (VS); and (3) determine the strongest association between an asymmetric SNHL definition and positive VS on magnetic resonance imaging (MRI). The study is a retrospective chart review in a tertiary care center. Cases were included if they were evaluated by an audiometric assessment and a posterior fossa MRI. Definitions of asymmetric SNHL reported in literature were applied to request for a further MRI investigation. The likelihood ratio (LR) for a positive test result (LR+) was the highest for the Rule 3,000 (2.91). On comparing all the other definitions with Rule 3,000, seven of the eight existing definitions have a kappa under the clinical usefulness threshold (Kappa < 0.6). When specification tests were applied, the Chi-square test identified Rule 3,000 with a highly significant P value (P < 0.0001). Rule 3,000, defined as asymmetric SNHL of 15 dB or more at the frequency 3,000 Hz, could serve as a universal referral guide for further MRI investigation. Results show that Rule 3,000 is more reliable to detect VS on MRI, a very simple rule that covers all the eight definitions of asymmetric SNHL reported in literature. This would help to reduce the number of negative MRI and to save time and money. If asymmetric SNHL is less than 15 dB, a biannual audiometry testing follow-up could be done. PMID- 20835832 TI - Head and neck squamous cell cancers: need for an organised time-bound surveillance plan. AB - Optimal care of patients with head and neck squamous cell cancer (HNSCC) involves a pre-determined period of post-treatment follow-up for the detection of recurrent or persistent disease, metastases and second primaries at the earliest opportunity. There is little evidence in literature as to whether the surveillance schemes should be based on patient survival, quality of life or cost adjusted parameters. This article aims at highlighting some of the issues pertinent to the optimization of surveillance strategies in HNSCC. PMID- 20835833 TI - Dose estimation for astronauts using dose conversion coefficients calculated with the PHITS code and the ICRP/ICRU adult reference computational phantoms. AB - Absorbed-dose and dose-equivalent rates for astronauts were estimated by multiplying fluence-to-dose conversion coefficients in the units of Gy.cm(2) and Sv.cm(2), respectively, and cosmic-ray fluxes around spacecrafts in the unit of cm(-2) s(-1). The dose conversion coefficients employed in the calculation were evaluated using the general-purpose particle and heavy ion transport code system PHITS coupled to the male and female adult reference computational phantoms, which were released as a common ICRP/ICRU publication. The cosmic-ray fluxes inside and near to spacecrafts were also calculated by PHITS, using simplified geometries. The accuracy of the obtained absorbed-dose and dose-equivalent rates was verified by various experimental data measured both inside and outside spacecrafts. The calculations quantitatively show that the effective doses for astronauts are significantly greater than their corresponding effective dose equivalents, because of the numerical incompatibility between the radiation quality factors and the radiation weighting factors. These results demonstrate the usefulness of dose conversion coefficients in space dosimetry. PMID- 20835834 TI - High-mobility group box 1 (HMGB1) as a master regulator of innate immunity. AB - Damage-associated molecular patterns (DAMPs) comprise intracellular molecules characterized by the ability to reach the extracellular environment, where they prompt inflammation and tissue repair. The high-mobility box group 1 (HMGB1) protein is a prototypic DAMP and is highly conserved in evolution. HMGB1 is released upon cell and tissue necrosis and is actively produced by immune cells. Evidence suggests that HMGB1 acts as a key molecule of innate immunity, downstream of persistent tissue injury, orchestrating inflammation, stem cell recruitment/activation, and eventual tissue remodeling. PMID- 20835835 TI - Factors predicting clinically significant fatigue in women following treatment for primary breast cancer. AB - Cancer-related fatigue is common, complex, and distressing. It affects 70-100% of patients receiving chemotherapy and a significant number who have completed their treatments. We assessed a number of variables in women newly diagnosed with primary breast cancer (BrCa) to determine whether biological and/or functional measures are likely to be associated with the development of clinically significant fatigue (CSF). Two hundred twenty-three women participated in a study designed to document the impact of the diagnosis and treatment of primary breast cancer on function. Forty-four had complete data on all variables of interest at the time of confirmed diagnosis but prior to treatment (baseline) and >= 9 months post-diagnosis. Objective measures and descriptive variables included history, physical examination, limb volume, hemoglobin, white blood cell count, and glucose. Patient-reported outcomes included a verbal numerical rating of fatigue (0-10, a score of >= 4 was CSF), five subscales of the SF-36, Physical Activity Survey, and Sleep Questionnaire. At baseline, the entire cohort (n = 223) and the subset (n = 44) were not significantly different for demographic, biological, and self-reported data, except for younger age (p = 0.03) and ER+ (p = 0.01). Forty five percent had body mass index (BMI) >= 25, 52% were post-menopause, and 52% received modified radical mastectomy, 39% lumpectomy, 52% chemotherapy, 68% radiation, and 86% hormonal therapy. Number of patients with CSF increased from 1 at baseline to 11 at >= 9 months of follow-up. CSF at >= 9 months significantly correlated with BMI >= 25, abnormal white blood cell count, and increase in limb volume and inversely correlated with vigorous activity and physical function (p < 0.05). Fatigue increases significantly following the treatment of BrCa. Predictors of CSF include high BMI and WBC count, increase in limb volume, and low level of physical activity. These are remediable. PMID- 20835836 TI - The practical challenges of recruitment and retention when providing psychotherapy to advanced breast cancer patients. AB - GOALS OF WORK: The goal of the present study was to investigate recruitment issues relevant to psychotherapy trials for metastatic cancer patients. First, we undertook a literature review of the psychotherapy intervention research for metastatic cancer patients. Second, we piloted pragmatic recruitment methods for a couples' intervention for women with metastatic breast cancer and their partners. METHODS: An extensive literature search was conducted to identify psychotherapy trials involving people with metastatic cancer published in peer reviewed journals. Study characteristics and recruitment methodologies were examined. In the pilot study, we trialled the recruitment strategies of approaching participants at outpatients' appointments, via letter, referral from the treating team and through direct advertising using two community support services. RESULTS: The literature search identified 1,905 potentially relevant articles, which were narrowed to 18 studies specifically involving metastatic cancer patients involving a professionally trained facilitator and a specified theoretical orientation. Limited information was found on recruitment rates and the success of recruitment strategies. Barriers to recruitment identified in the literature included degree of patient illness, lack of interest/perceived benefit, insufficient time, socio-demographic factors and negative clinician attitudes. Our pilot study identified 72 eligible couples of which 66 were approached. Our recruitment strategies resulted in six couples consenting (9.1%) but only three couples completing the study (4.5%). The main reasons for study refusal were the intervention was not needed, lack of interest, insufficient time, patient illness and travel distance. CONCLUSIONS: Recruitment for couple based psychotherapy interventions is challenging. More work is required on developing acceptable and feasible recruitment processes for metastatic cancer patients to be able to access support. PMID- 20835837 TI - Psychosocial needs of ethnic minority, inner-city, pediatric cancer patients. AB - PURPOSE: Limited data are available regarding the psychosocial impact of cancer on families of culturally diverse backgrounds living in medically underserved communities. The unique psychosocial needs of families of children with cancer from an ethnically diverse inner-city population is the focus of this study. METHODS: The prevalence of psychosocial needs among a multi-cultural, inner-city sample of children and adolescents with cancer and their parents was assessed using a modified version of the Psychosocial Needs Assessment Survey. All patients were recruited from the Children's Hospital at Montefiore located in Bronx, NY, a designated medically underserved community. RESULTS: Seventy-eight percent of parents reported unmet informational needs. The three most commonly endorsed informational needs by parents and children were regarding dietary management of acute side effects, late effects of having cancer and secondary cancer prevention. Less educated parents reported greater unmet supportive, practical, and spiritual needs than those with more education. Fathers had greater informational and practical needs than mothers and younger parents had more practical needs than older parents. Endorsement of spiritual needs was lower for both children and parents compared with supportive, informational, or practical needs. CONCLUSIONS: Given the high prevalence of reported unmet informational needs, efforts should be made to provide patients and families with education tailored to their informational needs and level of education. This population may benefit from psychoeducational interventions, including community based informational and peer support groups. Such interventions may augment efforts to lessen health gaps experienced in this population. PMID- 20835838 TI - Role of degenerated neuron density of dorsal root ganglion on anterior spinal artery vasospasm in subarachnoid hemorrhage: experimental study. AB - BACKGROUND: The spinal arteries are innervated by several systems that contribute to the control of spinal cord blood flow. The sensory fibers of upper cervical nerves have vasodilatatory effect on the anterior spinal arteries (ASA). Subarachnoid hemorrhage (SAH) causes severe vasospasm by various neurochemical mechanisms. We examined whether there is a relationship between the neuron density of the C3 dorsal root ganglion and the severity of ASA vasospasm in SAH. METHODS: This study was conducted on 20 rabbits. Four of them were used as baseline group. Experimental SAH has been applied to all of 16 animals by injecting homologous blood into cisterna magna. After 20 days of injection, ASA and C3 dorsal root ganglia (C3DRG) were examined histopathologically. ASA volume values and normal and degenerated neuron densities of C3DRG were estimated stereologically and the results were analyzed statistically. RESULTS: The mean ASA volume was 1.050+/-0.450 mm3, [corrected] and the mean neuronal density of C3DRG was 10,500 +/- 850 in all animals. The mean volume value of ASA was 0.970+/ 0.150 [corrected] mm3, and the normal neuron density of C3DRG fell to 8,600 +/- 400/mm3 in slight vasospasm group. In severe vasospasm-developed animals, mean volume value of ASA was 0.540+/-0.90 [corrected]mm3 and the normal neuron density of C3DRG fell to 5,500 +/- 360/mm3. An inverse relationship between the degenerated neuronal density of the C3DRG and ASA volume values may indicate the severity of ASA vasospasm. CONCLUSION: The neuron density of C3DRG may be an important factor on the regulation of ASA volume values and the continuation of spinal cord blood flow. Low neuron density of C3DRG may be considered as an important factor in the pathogenesis of severe ASA vasospasm in SAH. PMID- 20835839 TI - Microbial diversity in Tunisian geothermal springs as detected by molecular and culture-based approaches. AB - Prokaryotic diversities of 12 geothermal hot springs located in Northern, Central and Southern Tunisia were investigated by culture-based and molecular approaches. Enrichment cultures for both aerobic and anaerobic microorganisms were successfully obtained at temperatures ranging from 50 to 75 degrees C. Fourteen strains including four novel species were cultivated and assigned to the phyla Firmicutes (9), Thermotogae (2), Betaproteobacteria (1), Synergistetes (1) and Bacteroidetes (1). Archaeal or universal oligonucleotide primer sets were used to generate 16S rRNA gene libraries. Representative groups included Proteobacteria, Firmicutes, Deinococcus-Thermus, Thermotogae, Synergistetes, Bacteroidetes, Aquificae, Chloroflexi, candidate division OP9 in addition to other yet unclassified strains. The archaeal library showed a low diversity of clone sequences belonging to the phyla Euryarchaeota and Crenarchaeota. Furthermore, we confirmed the occurrence of sulfate reducers and methanogens by amplification and sequencing of dissimilatory sulfite reductase (dsrAB) and methyl coenzyme M reductase alpha-subunit (mcrA) genes. Altogether, we discuss the diverse prokaryotic communities arising from the 12 geothermal hot springs studied and relate these findings to the physico-chemical features of the hot springs. PMID- 20835841 TI - Conserved amino acids participate in the structure networks deputed to intramolecular communication in the lutropin receptor. AB - The luteinizing hormone receptor (LHR) is a G protein-coupled receptor (GPCR) particularly susceptible to spontaneous pathogenic gain-of-function mutations. Protein structure network (PSN) analysis on wild-type LHR and two constitutively active mutants, combined with in vitro mutational analysis, served to identify key amino acids that are part of the regulatory network responsible for propagating communication between the extracellular and intracellular poles of the receptor. Highly conserved amino acids in the rhodopsin family GPCRs participate in the protein structural stability as network hubs in both the inactive and active states. Moreover, they behave as the most recurrent nodes in the communication paths between the extracellular and intracellular sides in both functional states with emphasis on the active one. In this respect, non conservative loss-of-function mutations of these amino acids is expected to impair the most relevant way of communication between activating mutation sites or hormone-binding domain and G protein recognition regions. PMID- 20835840 TI - Transoral laser microsurgery for laryngeal cancer: a primer and review of laser dosimetry. AB - Transoral laser microsurgery (TLM) is an emerging technique for the management of laryngeal and other head and neck malignancies. It is increasingly being used in place of traditional open surgery because of lower morbidity and improved organ preservation. Since the surgery is performed from the inside working outward as opposed to working from the outside in, there is less damage to the supporting structures that lie external to the tumor. Coupling the laser to a micromanipulator and a microscope allows precise tissue cutting and hemostasis; thereby improving visualization and precise ablation. The basic approach and principles of performing TLM, the devices currently in use, and the associated dosimetry parameters will be discussed. The benefits of using TLM over conventional surgery, common complications and the different settings used depending on the location of the tumor will also be discussed. Although the CO(2) laser is the most versatile and the best-suited laser for TLM applications, a variety of lasers and different parameters are used in the treatment of laryngeal cancer. Improved instrumentation has lead to an increased utilization of TLM by head and neck cancer surgeons and has resulted in improved outcomes. Laser energy levels and spot size are adjusted to vary the precision of cutting and amount of hemostasis obtained. PMID- 20835843 TI - Feedback regulation of proteasome gene expression and its implications in cancer therapy. AB - Proteasomal protein degradation is one of the major regulatory mechanisms in the cell. Aberrant proteasome activity is directly related to the pathogenesis of many human diseases including cancers. How proteasome homeostasis is controlled is a fundamental question toward our understanding of proteasome dysregulation in cancer cells. The recent discovery of the Rpn4-proteasome negative feedback circuit provides mechanistic insight into the regulation of proteasome gene expression. This finding also has important implications in cancer therapy that uses small molecule inhibitors to target the proteasome. PMID- 20835842 TI - Kinetic and structural evidence of the alkenal/one reductase specificity of human zeta-crystallin. AB - Human zeta-crystallin is a Zn(2+)-lacking medium-chain dehydrogenase/reductase (MDR) included in the quinone oxidoreductase (QOR) family because of its activity with quinones. In the present work a novel enzymatic activity was characterized: the double bond alpha,beta-hydrogenation of medium-chain 2-alkenals and 3 alkenones. The enzyme is especially active with lipid peroxidation products such as 4-hydroxyhexenal, and a role in their detoxification is discussed. This specificity is novel in the QOR family, and it is similar to that described in the distantly related alkenal/one reductase family. Moreover, we report the X-ray structure of zeta-crystallin, which represents the first structure solved for a tetrameric Zn(2+)-lacking MDR, and which allowed the identification of the active site lining residues. Docking simulations suggest a role for Tyr53 and Tyr59 in catalysis. The kinetics of Tyr53Phe and Tyr59Phe mutants support the implication of Tyr53 in binding/catalysis of alkenal/one substrates, while Tyr59 is involved in the recognition of 4-OH-alkenals. PMID- 20835844 TI - The two-pore domain K+ channel TASK-1 is closely associated with brain barriers and meninges. AB - Impairment of the blood-brain barrier (BBB), the blood-cerebrospinal fluid (CSF) barrier and brain-CSF barrier has been implicated in neuropathology of several brain disorders, such as amyotrophic lateral sclerosis, cerebral edema, multiple sclerosis, neural inflammation, ischemia and stroke. Two-pore domain weakly inward rectifying K+ channel (TWIK)-related acid-sensitive potassium (TASK)-1 channels (K2p3.1; KCNK3) are among the targets that contribute to the development of these pathologies. For example TASK-1 activity is inhibited by acidification, ischemia, hypoxia and several signaling molecules released under pathologic conditions. We have used immuno-histochemistry to examine the distribution of the TASK-1 protein in structures associated with the BBB, blood-CSF barrier, brain CSF barrier, and in the meninges of adult rat. Dense TASK-1 immuno-reactivity (TASK-1-IR) was observed in ependymal cells lining the fourth ventricle at the brain-CSF interface, in glial cells that ensheath the walls of blood vessels at the glio-vascular interface, and in the meninges. In these structures, TASK-1-IR often co-localized with glial fibrillary associated protein (GFAP) or vimentin. This study provides anatomical evidence for localization of TASK-1 K+ channels in cells that segregate distinct fluid compartments within and surrounding the brain. We suggest that TASK-1 channels, in coordination with other ion channels (e.g., aquaporins and chloride channels) and transporters (e.g., Na+-K+-ATPase and Na+-K+-2Cl- and by virtue of its heterogeneous distribution, may differentially contribute to the varying levels of K+ vital for cellular function in these compartments. Our findings are likely to be relevant to recently reported roles of TASK-1 in cerebral ischemia, stroke and inflammatory brain disorders. PMID- 20835845 TI - Heat, pH induced aggregation and surface hydrophobicity of S. cerevesiae Ssa1 protein. AB - Heat shock protein 70 is a conserved protein among organisms. Hsp70 helps substrate proteins to fold correctly. Unfolded substrate proteins increase the probability of the aggregate formation. High level recombinant protein expression in biotechnology often leads insoluble inclusion bodies. To prevent aggregation and to obtain high levels of soluble proteins, Hsp co-expression with desired recombinant protein in yeast becomes a popular method. For this purpose, S. cerevesiae cytosolic Hsp70 (Ssa1) biochemical properties were characterized. Alteration of Ssa1 structure between ATP- and ADP-bound states regulates its function. Therefore, conformation-dependent Ssa1 hydrophobicity and as a result aggregation may also play a key role in Ssa1 function. Therefore, a combination of FTIR, acrylamide quenching, and ANS was used to investigate the effect of nucleotide binding on the structure of Ssa1. Ssa1 secondary structure alterations and hydrophobic properties in aqueous solutions with differing ionic strengths and temperature were also studied. PMID- 20835846 TI - A novel composition for the culture of human adipose stem cells which includes complement C3. AB - Adipose tissue is an easily accessible and abundant source of stem cells. Adipose stem cells (ASCs) are currently being researched as treatment options for repair and regeneration of damaged tissues. The standard culture conditions used for expansion of ASCs contain fetal bovine serum (FBS) which is undefined, could transmit known and unknown adventitious agents, and may cause adverse immune reactions. We have described a novel culture condition which excludes the use of FBS and characterised the resulting culture. Human ASCs were cultured in the novel culture medium, which included complement protein C3. These cultures, called C-ASCs, were compared with ASCs cultured in medium supplemented with FBS. Analysis of ASCs for surface marker profile, proliferation characteristics and differentiation potential indicated that the C-ASCs were similar to ASCs cultured in medium containing FBS. Using a specific inhibitor, we show that C3 is required for the survival of C-ASCs. This novel composition lends itself to being developed into a defined condition for the routine culture of ASCs for basic and clinical applications. PMID- 20835847 TI - Optimization of suture-free laser-assisted vessel repair by solder-doped electrospun poly(epsilon-caprolactone) scaffold. AB - Poor welding strength constitutes an obstacle in the clinical employment of laser assisted vascular repair (LAVR) and anastomosis. We therefore investigated the feasibility of using electrospun poly(epsilon-caprolactone) (PCL) scaffold as reinforcement material in LAVR of medium-sized vessels. In vitro solder-doped scaffold LAVR (ssLAVR) was performed on porcine carotid arteries or abdominal aortas using a 670-nm diode laser, a solder composed of 50% bovine serum albumin and 0.5% methylene blue, and electrospun PCL scaffolds. The correlation between leaking point pressures (LPPs) and arterial diameter, the extent of thermal damage, structural and mechanical alterations of the scaffold following ssLAVR, and the weak point were investigated. A strong negative correlation existed between LPP and vessel diameter, albeit LPP (484+/-111 mmHg) remained well above pathophysiological pressures. Histological analysis revealed that thermal damage extended into the medial layer with a well-preserved internal elastic lamina and endothelial cells. Laser irradiation of PCL fibers and coagulation of solder material resulted in a strong and stiff scaffold. The weak point of the ssLAVR modality was predominantly characterized by cohesive failure. In conclusion, ssLAVR produced supraphysiological LPPs and limited tissue damage. Despite heat induced structural/mechanical alterations of the scaffold, PCL is a suitable polymer for weld reinforcement in medium-sized vessel ssLAVR. PMID- 20835849 TI - Potent virucidal effect of pheophorbide a and pyropheophorbide a on enveloped viruses. AB - In this study, we evaluated the inhibitory effect of ethanol and aqueous extracts from a stem of Opuntia ficus indica on replication of three kinds of viruses: two enveloped viruses [herpes simplex virus type 2 (HSV-2), influenza A virus (IFV A)], and one non-enveloped virus [poliovirus type 1 (PV-1)]. Only ethanol extract from the cactus stem showed significant antiviral activity in vitro. Two chlorophyll derivatives, pheophorbide a and pyropheophorbide a, were isolated as active substances exhibiting potent virucidal effects on HSV-2 and IFV-A, but no activity against PV-1 was observed. These findings suggest that these active compounds might recognize specific glycoproteins of enveloped viruses, precluding their binding to host cell receptors and inhibiting viral infections. PMID- 20835848 TI - Cyclosporin A treatment and decreased fungal load/antigenemia in experimental murine paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb). The cyclosporin A (CsA) is an immunosuppressant drug that inhibits calcineurin and has been described as a potential antifungal drug. The present study investigated the effect of CsA on the immune response, fungal load/antigenemia in experimental murine PCM. It was used four groups of BALB/c mice: (a) infected with 1 x 105 Pb18 yeast cells (Pb), (b) infected and treated with CsA every other day 10 mg/kg of CsA (s.c.) during 30 days (Pb/CsA), (c) treated with CsA (CsA) and (d) no infected/treated (PBS). The immune response was evaluated by lymphocyte proliferation, DTH assays to exoAgs, ELISA for IgG anti-gp43 (specific immune responses) and cytokine serum levels (IFN-gamma, TNF-alpha, IL-4 and IL-10). Fungal load was determined by lung colony-forming units (CFU) counts, lung and liver histopathology analysis and antigenemia determined by inhibition-ELISA. As expected, CsA was able to inhibit the specific cellular and humoral immune response (P < 0.05), with decrease in serum IFN-gamma, TNF-alpha and IL-4 levels (P < 0.05). Cyclosporin A treatment also resulted in significantly decreased lung Pb CFU (P < 0.05) as well as a lower number of yeasts in the lung and liver (P < 0.05) by histopathology. In concordance, the decreased antigenemia was observed in Pb/CsA group (P < 0.05). In conclusion, even with immunosuppressive action, treatment with CsA results in decreased lung fungal load/antigenemia in experimental PCM in BALB/c mice. Further study is required to determine whether this represents less severe disease or protection by CsA. PMID- 20835850 TI - Components of convolvulin from Quamoclit * multifida. AB - Alkaline hydrolysis of the ether-insoluble resin glycoside (convolvulin) fraction of the seeds of Quamoclit * multifida (syn. Q. sloteri House, Convolvulaceae), a hybrid between Q. pennat and Q. coccinea, gave three new glycosidic acids (maltifidinic acids C, D, and E) along with three known glycosidic acids (quamoclinic acids B, C, and D) and four organic acids (2S-methylbutyric, tiglic, 2R,3R-nilic, and 7S-hydroxydecanoic acids). The structures of the new glycosidic acids were characterized on the basis of spectroscopic data as well as chemical evidence. PMID- 20835851 TI - Constituents with alpha-glucosidase and advanced glycation end-product formation inhibitory activities from Salvia miltiorrhiza Bge. AB - The 75% ethanol extract from roots of Salvia miltiorrhiza Bge. (Dan shen) afforded two new compounds, 3-hydroxy-2-(2'-formyloxy-1'-methylethyl)-8-methyl 1,4-phenanthrenedione (1), (8'R)-isosalvianolic acid C methyl ester (2), and 14 known compounds. Their structures were established on the basis of spectral analysis. The ability of the compounds to inhibit alpha-glucosidase activity and formation of advanced glycation end-products (AGEs) was evaluated. All compounds displayed various degrees of inhibitory effects against alpha-glucosidase; moreover, compounds 2, 6, 11, 14, and 16 exhibited much more potent inhibition against AGEs than the positive control (aminoguanidine, AG, IC(50) 0.11 MUM). This is the first time that compounds from this plant have been reported to have inhibitory activity against alpha-glucosidase. PMID- 20835852 TI - Utilization of resource leveling to optimize ERCP efficiency. AB - BACKGROUND: Optimizing endoscopy efficiency is becoming increasingly important. This study profiled ERCP availability and assessed resource leveling as a strategy to enhance efficiency. DESIGN: All ERCPs performed at an academic teaching hospital between January 2007 and December 2008 were reviewed. Procedure timeliness (time between admission and ERCP) and demand were analyzed to assess resource utilization. RESULTS: Data were recorded for 393 ERCPs. Profiling identified an unequal distribution of waiting times from admission to procedure due to restricted ERCP availability. Use of resource leveling methodology demonstrated that a small increase in procedure availability (one additional half day per week) would significantly reduce the hospital stay of ERCP patients. CONCLUSIONS: Resource leveling can be applied to balance procedure provision with demand to cope with fluctuations in demand. The impact of resource leveling can be truly measured only by implementing these changes and prospectively studying the effect. PMID- 20835853 TI - Data publishing and scientific journals: the future of the scientific paper in a world of shared data. PMID- 20835854 TI - Thiamine-responsive megaloblastic anemia syndrome. AB - Thiamine-responsive megaloblastic anemia (TRMA) syndrome usually associated with diabetes mellitus, anemia and deafness, due to mutations in SLC19A2, encoding a thiamine transporter protein. The onset of disease is usually seen during infancy or at early childhood and most of the TRMA patients are originated from consanguineous families. In this case, we report a 5-month-old boy who had diagnosis of TRMA during evaluations for his anemia and thrombocytopenia. The diagnosis of TRMA should be kept in mind in differential diagnosis of megaloblastic anemia especially in the populations where the consanguinity is frequent. PMID- 20835855 TI - Knowledge and attitudes in regard to pandemic influenza A(H1N1) in a multiethnic community of Malaysia. AB - BACKGROUND: Assessment of general public's knowledge and attitudes toward the development and prevention of new disease outbreaks is imperative because they have profound effects on health behaviors and may contribute to the control of the epidemic. PURPOSE: To investigate the level of knowledge and attitudes towards the influenza A(H1N1) outbreak across various ethnic groups and socio demographic backgrounds in Malaysia. METHOD: A cross-sectional, population-based, computer-assisted telephone interview exploring knowledge and attitudes regarding influenza A(H1N1) was conducted in Malaysia. Between July 11 and September 12, 2009, a total of 1,050 respondents were interviewed (response rate 69.3%). RESULTS: The mean total knowledge score for the overall sample was 7.30 (SD +/- 1.961) out of a possible score of 13 (Chinese had the highest scores, followed by Indians, then Malays). Some erroneous beliefs about the modes of transmission were identified. The majority of the participants (73.8%) perceived the A(H1N1) infection as often deadly. Despite the overestimation of the severity of A(H1N1) infection, high confidence in preventing infection and low perceived susceptibility of infection were reported. Influenza A(H1N1)-related stigma was prevalent and exhibited differences across ethnic groups. CONCLUSIONS: Findings suggest that provision of education and clear information are essential to correct the misconceptions, and increase perceived susceptibility to infection so that the general public will take precautions against A(H1N1) infection. PMID- 20835856 TI - The American Association of Clinical Endocrinologists/American College of Endocrinology (AACE/ACE) algorithm for managing glycaemia in patients with type 2 diabetes mellitus: comparison with the ADA/EASD algorithm. PMID- 20835857 TI - The combinatorics of medications precludes evidence-based algorithms for therapy. PMID- 20835858 TI - Hyperglycaemia-induced pro-inflammatory responses by retinal Muller glia are regulated by the receptor for advanced glycation end-products (RAGE). AB - AIMS/HYPOTHESIS: Up-regulation of the receptor for AGEs (RAGE) and its ligands in diabetes has been observed in various tissues. Here, we sought to determine levels of RAGE and one of its most important ligands, S100B, in diabetic retina, and to investigate the regulatory role of S100B and RAGE in Muller glia. METHODS: Streptozotocin-diabetes was induced in Sprague-Dawley rats. RAGE, S100B and glial fibrillary acidic protein (GFAP) were detected in retinal cryosections. In parallel, the human retinal Muller cell line, MIO-M1, was maintained in normal glucose (5.5 mmol/l) or high glucose (25 mmol/l). RAGE knockdown was achieved using small interfering RNA (siRNA), while soluble RAGE was used as a competitive inhibitor of RAGE ligand binding. RAGE, S100B and cytokines were detected using quantitative RT-PCR, western blotting, cytokine protein arrays or ELISA. Activation of mitogen-activated protein kinase (MAPK) by RAGE was determined by western blotting. RESULTS: Compared with non-diabetic controls, RAGE and S100B were significantly elevated in the diabetic retina with apparent localisation in the Muller glia, occurring concomitantly with upregulation of GFAP. Exposure of MIO-M1 cells to high glucose induced increased production of RAGE and S100B. RAGE signalling via MAPK pathway was linked to cytokine production. Blockade of RAGE prevented cytokine responses induced by high glucose and S100B in Muller glia. CONCLUSIONS/INTERPRETATION: Hyperglycaemia in vivo and in vitro exposure to high glucose induce upregulation of RAGE and its ligands, leading to RAGE signalling, which links to pro-inflammatory responses by retinal Muller glia. These data shed light on the potential clinical application of RAGE blockade to inhibit the progression of diabetic retinopathy. PMID- 20835859 TI - Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. AB - AIMS/HYPOTHESIS: Insulin analogues were developed to improve the pharmacological properties of injected insulin and to better mimic endogenous insulin output. However, certain insulin analogues have been suggested to display IGF-I-like biological activities. Furthermore, several recent epidemiological studies have suggested a potential increase in cancer risk for treatment of diabetes patients with long-acting analogue insulin glargine (A21Gly,B31Arg,B32Arg human insulin). Additional studies, however, reported no increased cancer risk. The purpose of the present study was to identify the receptor(s) and signal transduction pathways responsible for the biological actions of insulin glargine and insulin detemir (B29Lys[epsilon-tetradecanoyl],desB30 human insulin). METHODS: The colon cancer-derived cell line HCT116 was treated with increasing doses of insulin glargine, insulin detemir, regular insulin or IGF-I, and receptor activation was evaluated by immunoprecipitation assays. IGF-I receptor (IGF-IR) internalisation following insulin glargine treatment was assessed by confocal microscopy. Activation of the Akt and extracellular signal-regulated kinase pathways was evaluated by western blots. The anti-apoptotic effect of the analogues was measured by poly-(ADP ribose) polymerase antibody and annexin assays. RESULTS: We found evidence for dual activation of the insulin receptor and IGF-IR by the analogues. Dose-dependency experiments showed that insulin glargine was able to phosphorylate the IGF-IR at fivefold lower doses than those required to activate the insulin receptor. We also showed that insulin glargine can lead to prolonged activation of the receptors and therefore promote abnormal signalling. Confocal imaging experiments showed that insulin glargine, but not regular insulin induced IGF-IR internalisation similarly to IGF-I. Finally, both analogues displayed IGF I-like anti-apoptotic activities and stimulated cell cycle progression. CONCLUSIONS/INTERPRETATION: Our data indicate that insulin glargine and insulin detemir display atypical signalling activities that differ from those elicited by regular insulin and involve activation of the anti-apoptotic IGF-IR. PMID- 20835860 TI - The insulin dilemma in resource-limited countries. A way forward? AB - The International Insulin Foundation (IIF) has developed and validated a needs assessment instrument called the Rapid Assessment Protocol for Insulin Access (RAPIA) which has been used in seven countries in four continents to analyse the constraints to delivering effective continuing care for people with diabetes. One major contributor to the difficulties in availability of insulin is a failure to use the least costly sources and types of insulin and other effective drugs for diabetes. The purchase of insulins can consume as much as 10% of government expenditure on drugs, this being highly sensitive to the selection of newer analogue insulins as first-choice options, which cost between three and 13 times more than biosynthetic human insulin. Insulin cartridges for use with injection pens further add to costs. Similar considerations apply to most of the newer treatments for people with type 2 diabetes, which may cost up to 40 times more than metformin and sulfonylureas, still considered first-line drugs by European and US guidelines. Both biosynthetic human insulin and the first-line oral hypoglycaemic drugs are available from generic manufacturers. With the present price differentials, there is thus a growing need for countries involved in tendering for sourcing insulin to be provided with the guarantees of Good Manufacturing Practice, quality and bioequivalence, which would come from a WHO Pre-Qualification Scheme as currently exists for a variety of drugs for chronic diseases, both communicable and non-communicable. The IIF has developed a position statement on the provision and choice of diabetes treatments in resource limited settings which should be applicable wherever consideration of resources is a component of therapeutic decision making. PMID- 20835861 TI - Capillary electrophoresis with laser-induced fluorescence detection for ATP quantification in spermatozoa and oocytes. AB - We describe a new capillary electrophoresis laser-induced fluorescence (CE-LIF) method for the quantification of adenosine 5'-triphosphate (ATP) in spermatozoa and oocytes. The optimization of the precapillary derivatization reaction between ATP and 4,4-difluoro-5,7-dimethyl-4-bora-3a,4adiaza-s-indacene-3-propionyl ethylene diamine hydrochloride (BODIPY FL EDA) has been described. BODIPY-ATP conjugate was analysed in an uncoated fused silica capillary of 75 MUm ID and 50 cm effective length using a 10 mmol/L tribasic sodium phosphate buffer, pH 11.5, at 22 kV in <5 min. A good reproducibility of intra- and inter-assay tests was obtained (CV = 4.55% and 7.14%, respectively). With respect to our previous CE-UV assay, the new method showed an improvement in sensitivity that was about 120 fold (limit of quantification, 0.15 vs 18 MUmol/L). Method applicability was proven on the reproductive cells of several animal species (roosters, horses, sheep and goats). Due to the elevated sensitivity, the new assay allows the measurement of adenosine 5'-triphosphate levels from just 20 oocytes. Considering that ATP concentration in reproductive cells is related to the mitochondrial integrity after cryopreservation, the proposed method could be a useful tool in assisted reproductive technologies. PMID- 20835862 TI - Determination of gamma-hydroxybutyric acid in dried blood spots using a simple GC MS method with direct "on spot" derivatization. AB - The objective of this study was the development of an accurate and sensitive method for the determination of gamma-hydroxybutyric acid (GHB) in dried whole blood samples using a GC-MS method. The complete procedure was optimized, with special attention on the sample pretreatment, and validated. Therefore, dried blood spots of only 50 MUl were prepared and, after the addition of internal standard GHB-d6, directly derivatized using 100 MUl of a freshly prepared mixture of trifluoroacetic acid anhydride and heptafluorobutanol (2:1). The derivatized extract was injected into a gas chromatograph coupled to a mass spectrometer (GC MS), operating in the electron impact mode, with a total run time of 12.3 min. Method validation included the evaluation of linearity, precision, accuracy, sensitivity, selectivity, and stability. A weighting factor of 1/x(2) was chosen and acceptable intra-batch precision, inter-batch precision, and accuracy were seen. The linear calibration curve ranged from 2 to 100 MUg/ml, with a limit of detection of 1 MUg/ml. Our procedure, utilizing the novel approach of direct "on spot" derivatization followed by analysis with GC-MS, proved to be reliable, fast, and applicable in routine toxicology. PMID- 20835863 TI - In-situ imaging sensors for bioprocess monitoring: state of the art. AB - Over the last two decades, more and more applications of sophisticated sensor technology have been described in the literature on upstreaming and downstreaming for biotechnological processes (Middendorf et al. J Biotechnol 31:395-403, 1993; Lausch et al. J Chromatogr A 654:190-195, 1993; Scheper et al. Ann NY Acad Sci 506:431-445, 1987), in order to improve the quality and stability of these processes. Generally, biotechnological processes consist of complex three-phase systems--the cells (solid phase) are suspended in medium (liquid phase) and will be streamed by a gas phase. The chemical analysis of such processes has to observe all three phases. Furthermore, the bioanalytical processes used must monitor physical process values (e.g. temperature, shear force), chemical process values (e.g. pH), and biological process values (metabolic state of cell, morphology). In particular, for monitoring and estimation of relevant biological process variables, image-based inline sensors are used increasingly. Of special interest are sensors which can be installed in a bioreactor as sensor probes (e.g. pH probe). The cultivation medium is directly monitored in the process without any need for withdrawal of samples or bypassing. Important variables for the control of such processes are cell count, cell-size distribution (CSD), and the morphology of cells (Hopfner et al. Bioprocess Biosyst Eng 33:247-256, 2010). A major impetus for the development of these image-based techniques is the process analytical technology (PAT) initiative of the US Food and Drug Administration (FDA) (Scheper et al. Anal Chim Acta 163:111-118, 1984; Reardon and Scheper 1995; Schugerl et al. Trends Biotechnol 4:11-15, 1986). This contribution gives an overview of non-invasive, image-based, in-situ systems and their applications. The main focus is directed at the wide application area of in situ microscopes. These inline image analysis systems enable the determination of indirect and direct cell variables in real time without sampling, but also have application potential in crystallization, material analysis, polymer research, and the petrochemical industry. PMID- 20835864 TI - Evaluation of an in-capillary approach for performing quantitative cytochrome P450 activity studies. AB - An automated in-capillary assay requiring very small quantities of reagents was developed for performing in vitro cytochrome P450 (CYP450) drug metabolism studies. The approach is based on the following: (i) hydrodynamic introduction of nanoliter volumes of substrate and enzyme solutions in the sandwich mode, within a capillary; (ii) mixing the reagents by diffusion across the interfaces between the injected solutions; (iii) collection of the capillary content at the end of the in-capillary assay; and (iv) off-line analysis of the incubation mixture by ultrahigh pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). After optimizing the injection sequence of the reagents, the in-capillary approach was applied to the quantitative determination of the kinetics of drug metabolism reactions catalyzed by three CYP450 isozymes involved in human drug metabolism: CYP1A2, CYP2D6, and CYP3A4. It was demonstrated that this in capillary method was able to provide similar kinetic parameters for CYP450 activity (e.g., Michaelis constants and turnover values) as the classical in vitro method, with a drastic reduction of reagent consumption. PMID- 20835865 TI - Simultaneous determination of disulfiram and bupropion in human plasma of alcohol and nicotine abusers. AB - An isocratic high-performance liquid-chromatographic method has been developed for the simultaneous determination of disulfiram and bupropion in human plasma samples. Analyses were carried out on a C(8) reversed-phase column using a mobile phase composed of 50% acetonitrile and 50% aqueous phosphate buffer, containing triethylamine. Diode-array detection was used, operating at a wavelength of 250 nm. For the clean-up of plasma samples, a solid phase extraction procedure, based on C(2) cartridges, was implemented. Extraction yields of the analytes were satisfactory, being always higher than 84%. The calibration curve was linear over the 5-500 ng mL(-1) plasma concentration range for both disulfiram and bupropion. The method showed a high sensitivity (limit of detection of 1.5 ng mL(-1)) and satisfactory precision, selectivity and accuracy. The application to human plasma samples obtained from some alcohol and nicotine abusers also gave good results. PMID- 20835866 TI - Relaxation of microparticles exposed to hydrodynamic forces in microfluidic conduits. AB - The behavior of microparticles exposed to gravitational and lift forces and to the velocity gradient in flow velocity profile formed in microfluidic conduits is studied from the viewpoint of the transient period (the relaxation) between the moment at which a particle starts to be transported by the hydrodynamic flow and the time at which it reaches an equilibrium position, characterized by a balance of all active forces. The theoretical model allowing the calculation of the relaxation time is proposed. The numerical calculus based on the proposed model is compared with the experimental data obtained under different experimental conditions, namely, for different lengths of microfluidic channels, different average linear velocities of the carrier liquid, and different sizes and densities of the particles used in the study. The results are important for the optimization of microfluidic separation units such as microthermal field-flow fractionation channels in which the separation or manipulation of the microparticles of various origin, synthetic, natural, biological, etc., is performed under similar experimental conditions but by applying an additional thermodynamic force. PMID- 20835867 TI - Enhanced extract preparation of native manganese and iron species from brain and liver tissue. AB - To date, no reference method for the extraction of labile Mn species from biological tissues is published which provides sufficient extraction efficiency combined with monitoring speciation. Here, an extraction method is reported using cryogenic conditions (+N) under inert gas atmosphere. Fresh brain and liver tissues were used, then stored either 1 day (+N) or 1 month in N(2liq) (+N 1 m) to evaluate degradation effects during long-term storage. Both attempts were compared to a previous extraction method (-N) using neither N(2liq) nor storage ability. Mn and Fe concentrations in extracts and pellets were determined with inductively coupled plasma (ICP)-atomic emission spectroscopy (AES) and compared to acid digests of the same sample. Element ratios of extracts/digest indicated the extraction efficiency, which was increased from 17% (-N) to 26% (+N) for Mn in brain or from 28% (-N) to 44% (+N) in liver extracts. For Fe species, the increase was only from 40% (-N) to 44% (+N) in brain but from 64% (-N) to 74% (+N) in liver. Size exclusion chromatography (SEC)-ICP-mass spectrometry (MS) was employed to screen for Mn and Fe species pattern in extracts. In brain, surplus extracted Mn (+N, +N 1 m) was assigned to organic Mn species, mainly from the 0.7 4 kDa fraction, while in the liver, it was seen in the 70-80 kDa fraction. Fe speciation was similar for -N and +N methods in brain extracts. In liver, higher amounts of Fe species were extracted from the 140-160 kDa fraction. Storage at 196 degrees C for 1 month did neither affect Mn speciation in brain nor in liver extracts. Fe species pattern showed a negligible shift (<=5%) from 140-160 to 70 80 kDa fraction in liver extracts stored 1 month in N(2liq). PMID- 20835868 TI - Hydrolysis of mefenpyrdiethyl: an analytical and DFT investigation. AB - The hydrolysis of the herbicide safener mefenpyrdiethyl (1-(2, 4-dichlorophenyl) 4, 5-dihydro-5-methyl-1H-pyrazole-3,5-dicarboxylic acid diethyl ester) was investigated in aqueous solutions in the pH range from 2 to 9 and the temperature range from 298 to 323 K. The kinetics of hydrolysis were pseudo first order and were found to be strongly pH and temperature dependent. While near-constant in acidic medium, the hydrolysis rates strongly increased in alkaline pH, and total hydrolysis was observed at pH 11. Two main hydrolysis products, mefenpyrethyl (monoester) and mefenpyr (dicarboxylic acid) were isolated by ultrahigh-pressure liquid chromatography (UHPLC) and characterized using high-resolution Fourier transform ion cyclotron resonance mass spectroscopy (ICR-FT/MS) as well as (1)H, (13)C and 2D NMR analyses. Additionally, a density functional theory (DFT) investigation explained the stability of the pesticide at pH 7 and the high reactivity of the pesticide in alkaline medium. The key nucleophilic reaction partner is hydroxyl ions instead of neutral water molecules. Furthermore, the calculated activation barrier for hydrolysis in alkaline medium is in agreement with the extrapolated and experimentally determined activation barrier at pH 14. PMID- 20835869 TI - High-performance anion-exchange chromatography-mass spectrometry method for determination of levoglucosan, mannosan, and galactosan in atmospheric fine particulate matter. AB - Biomass burning has a strong influence on the atmospheric aerosol composition through particulate organic, inorganic, and soot emissions. When biomass burns, cellulose and hemicelluloses degrade, producing monosaccharide anhydrides (MAs) such as levoglucosan, mannosan, and galactosan. Therefore, these compounds have been commonly used as tracers for biomass burning. In this study, a fast water based method was developed for the routine analysis of MAs, based on high performance anion-exchange chromatography with electrospray ionization mass spectrometry detection. This method combines simple sample preparation, fast separation, and the advantages of the selective detection with MS. Analysis run was optimized to the maximum separation of levoglucosan, mannosan, and galactosan with 15-min analysis. The validation results indicated that the method showed good applicability for determination of MA isomer concentrations in ambient samples. The limit of detection was 100 pg for levoglucosan and 50 pg for mannosan and galactosan. Wide determination ranges enabled the analysis of samples of different concentration levels. The method showed good precision, both for standard solutions (3.9-5.9% RSD) and for fine particle samples (4.3-8.5% RSD). Co-elution of internal standard (carbon-13-labeled levoglucosan) and sugar alcohols with levoglucosan decreased the sensitivity of levoglucosan determination. The method was used to determine the MA concentrations in ambient fine particle samples from urban background (Helsinki) and rural background (Hyytiala) in Finland. The average levoglucosan, mannosan, and galactosan concentrations were 77, 8.8, and 4.2 ng m(-3) in Helsinki (winter 2008-2009) and 17, 2.3, and 1.4 ng m(-3) in Hyytiala (spring 2007), respectively. The interrelation of the three MA isomers was fairly constant in the ambient fine particle samples. PMID- 20835870 TI - A new certified reference material for benzene measurement in air on a sorbent tube: development and proficiency testing. AB - A certified matrix reference material (CRM) for the measurement of benzene in ambient air has been developed at Laboratoire National de Metrologie et d'Essais. The production of these CRMs was conducted using a gravimetric method fully traceable to the International System of Units. The CRMs were prepared by sampling an accurate mass of a gaseous primary reference material of benzene, using a high-precision laminar flowmeter and a mass flow controller, with a PerkinElmer sampler filled with CarbopackTM X sorbent. The relative standard deviations obtained for the preparation of a batch of 20 tubes loaded with 500 ng of benzene were below 0.2%. Each CRM is considered independent from the others and with its own certified value and an expanded uncertainty estimated to be within 0.5%, lower than the uncertainties of benzene CRMs already available worldwide. The stability of these materials was also established up to 12 months. These CRMs were implemented during proficiency testing, to evaluate the analytical performances of seven French laboratories involved in benzene air monitoring. PMID- 20835871 TI - Tractography of developing white matter of the internal capsule and corpus callosum in very preterm infants. AB - OBJECTIVES: To investigate in preterm infants associations between Diffusion Tensor Imaging (DTI) parameters of the posterior limb of the internal capsule (PLIC) and corpus callosum (CC) and age, white matter (WM) injury and clinical factors. METHODS: In 84 preterm infants DTI was performed between 40-62 weeks postmenstrual age on 3 T MR. Fractional anisotropy (FA), apparent diffusion coefficient (ADC) values and fibre lengths through the PLIC and the genu and splenium were determined. WM injury was categorised as normal/mildly, moderately and severely abnormal. Associations between DTI parameters and age, WM injury and clinical factors were analysed. RESULTS: A positive association existed between FA and age at imaging for fibres through the PLIC (r = 0.48 p < 0.001) and splenium (r = 0.24 p < 0.01). A negative association existed between ADC and age at imaging for fibres through the PLIC (r = -0.65 p < 0.001), splenium (r = -0.35 p < 0.001) and genu (r = -0.53 p < 0.001). No association was found between DTI parameters and gestational age, degree of WM injury or categorical clinical factors. CONCLUSIONS: These results indicate that in our cohort of very preterm infants, at this young age, the development of the PLIC and CC is ongoing and independent of the degree of prematurity or WM injury. PMID- 20835872 TI - Predicting employment status in multiple sclerosis patients: the utility of the MS functional composite. AB - As many as two-thirds of multiple sclerosis (MS) patients are unable to retain employment. Neurological and cognitive status are known to be significant predictors of unemployment, but the relationship between the two is unclear. Furthermore, the association between employment status and depression, anxiety, and personality has not been adequately explored in MS patients. This study examined the demographic, neurological, neuropsychological, and personality factors associated with unemployment in MS. We also sought to determine the utility of the Multiple Sclerosis Functional Composite (MSFC), a measure of MS related disability incorporating physical and cognitive measures, in predicting employment status. A consecutive sample of 106 MS patients (61.3% unemployed) completed the Brief Repeatable Battery of Neuropsychological Tests (BRBN), Hospital Anxiety and Depression Scale (HADS), and NEO Five-Factor Personality Inventory. The MSFC emerged as the most robust predictor of employment status in MS patients, exceeding the predictive value of the EDSS. Together with NEO "Agreeableness" and HADS Depression subscore, the MSFC accounted for 49.8% of the variance in employment status. Unemployment was also associated with a progressive disease course, longer disease duration, and being female. While Global Cognitive Impairment did not differentiate between groups, unemployed patients scored significantly lower on three of five BRBN indices: Symbol Digit Modality Test, Paced Auditory Serial Addition Test, and Word List Generation. The findings highlight the utility of the MSFC as a predictor of unemployment in MS. Furthermore, a strong association was found between unemployment and the personality construct "Agreeableness", and severity of depression. PMID- 20835873 TI - Efficacy and tolerability of transdermal granisetron for the control of chemotherapy-induced nausea and vomiting associated with moderately and highly emetogenic multi-day chemotherapy: a randomized, double-blind, phase III study. AB - PURPOSE: A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). PATIENTS AND METHODS: Six hundred forty-one patients were randomized to oral (2 mg/day, 3-5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. RESULTS: Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, -5%; 95% confidence interval, -13-3). Both treatments were well tolerated, the most common adverse event being constipation. CONCLUSIONS: The GTDS provides effective, well tolerated control of CINV associated with moderately or highly emetogenic multi day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron. PMID- 20835874 TI - Spinal extradural arachnoid cyst following percutaneous vertebroplasty. AB - We report a rare complication of extradural arachnoid cyst following percutaneous vertebroplasty in a spinal metastasis patient. Percutaneous vertebroplasty has been established as a safe and effective treatment for osteoporotic vertebral fractures and vertebral metastatic lesions. To our knowledge, extradural arachnoid cyst following vertebroplasty has not been reported in literature. A 48 year-old woman diagnosed with adenocarcinoma underwent percutaneous vertebroplasty at the L3 vertebral level due to painful solitary spinal metastasis. At 5 months after surgery, the patient complained of low back pain radiating to the left lower extremity. MRI showed a large cystic lesion in the spinal canal at the L2-L3 level with compression to adjacent dura sac. On T1- and T2-weighted images, the signal within the cyst had the same intensity as cerebrospinal fluid. The patient underwent laminectomy for excision of the extradural cyst. Intraoperatively, a small communication between the cyst and the subarachnoid space was seen at the level of the L3 pedicle. Pathological examination revealed that the cyst wall was composed of non-specific fibrous connective tissue and the content of the cyst was the same as that of cerebrospinal fluid. Postoperatively, the patient's symptom was relieved immediately. The iatrogenic dural injury produced by puncture of the pedicle during vertebroplasty may be the cause of formation of the extradural arachnoid cyst. PMID- 20835875 TI - Type II odontoid fractures in the elderly: an evidence-based narrative review of management. AB - Considerable controversy exists regarding the optimal management of elderly patients with type II odontoid fractures. There is uncertainty regarding the consequences of non-union. The best treatment remains unclear because of the morbidity associated with prolonged cervical immobilisation versus the risks of surgical intervention. The objective of the study was to evaluate the published literature and determine the current evidence for the management of type II odontoid fractures in elderly. A search of the English language literature from January 1970 to date was performed using Medline and the following keywords: odontoid, fractures, cervical spine and elderly. The search was supplemented by cross-referencing between articles. Case reports and review articles were excluded although some were referred to in the discussion. Studies in patients aged 65 years with a minimum follow-up of 12 months were selected. One-hundred twenty-six articles were reviewed. No class I study was identified. There were two class II studies and the remaining were class III. Significant variability was found in the literature regarding mortality and morbidity rates in patients treated with and without halo vest immobilisation. In recent years several authors have claimed satisfactory results with anterior odontoid screw fixation while others have argued that this may lead to increased complications in this age group. Lately, the posterior cervical (Goel-Harms) construct has also gained popularity amongst surgeons. There is insufficient evidence to establish a standard or guideline for odontoid fracture management in elderly. While most authors agree that cervical immobilisation yields satisfactory results for type I and III fractures in the elderly, the optimal management for type II fractures remain unsolved. A prospective randomised controlled trial is recommended. PMID- 20835876 TI - Heme destruction, the main molecular event during the peroxide-mediated inactivation of chloroperoxidase from Caldariomyces fumago. AB - Heme peroxidases are subject to a mechanism-based oxidative inactivation. During the catalytic cycle, the heme group is activated to form highly oxidizing species, which may extract electrons from the protein itself. In this work, we analyze changes in residues prone to oxidation owing to their low redox potential during the peroxide-mediated inactivation of chloroperoxidase from Caldariomyces fumago under peroxidasic catalytic conditions. Surprisingly, we found only minor changes in the amino acid content of the fully inactivated enzyme. Our results show that tyrosine residues are not oxidized, whereas all tryptophan residues are partially oxidized in the inactive protein. The data suggest that the main process leading to enzyme inactivation is heme destruction. The molecular characterization of the peroxide-mediated inactivation process could provide specific targets for the protein engineering of this versatile peroxidase. PMID- 20835877 TI - Biofilm development in the extremely acidophilic archaeon 'Ferroplasma acidarmanus' Fer1. AB - 'Ferroplasma acidarmanus' Fer1 is an iron-oxidizing extreme acidophile isolated from the Iron Mountain mine, California, USA. This archaeon is predominantly found in biofilm-associated structures in the environment, and produces two distinct biofilm morphologies. Bioinformatic analysis of the 'F. acidarmanus' Fer1 genome identified genes annotated as involved in attachment and biofilm formation. No putative quorum sensing signaling genes were identified and no N acyl homoserine lactone-like compounds were found in 'F. acidarmanus' Fer1 biofilm supernatant. Scanning confocal microscopy analysis of biofilm development on the surface of pyrite demonstrated the temporal and spatial development of biofilm growth. Furthermore, two-dimensional polyacrylamide gel electrophoresis was used to examine differential protein expression patterns between biofilm and planktonic populations. Ten up-regulated proteins were identified that included six enzymes associated with anaerobic growth, suggesting that the dominating phenotype in the mature biofilm was associated with anaerobic modes of growth. This report increases our knowledge of the genetic and proteomic basis of biofilm formation in an extreme acidophilic archaeon. PMID- 20835878 TI - Effect of statins on outcomes in immunosuppressed patients with bloodstream infection. AB - Although it has been suggested that statins have a beneficial effect on the outcome of bloodstream infection (BSI) in immunosuppressed patients, prospective studies testing this hypothesis are lacking. We performed an observational analysis of consecutive cancer patients and transplant recipients hospitalized at two tertiary hospitals in Spain (2006-2009). The first episode of BSI occurring in statin users was compared with those occurring in non-statin users. During the study period, 668 consecutive episodes of BSI in 476 immunosuppressed patients were recorded. Underlying diseases were solid tumor (46.2%), hematologic malignancy (35.1%), and transplantation (18.7%). Fifty-nine (12.4%) patients were receiving statins at the onset of BSI. Comparing with statin non-users, patients on statin treatment were older (67.3 vs. 58.7 years; p < 0.001) and had higher frequency of comorbidities (74.6% vs. 40.6%; p < 0.001). There were no significant differences in intensive care unit admission (6.8% vs. 7.7%; p = 1) and overall mortality (15.3% vs. 24%; p = 0.13) between groups. In a multivariate analysis, prior statin use was not associated with increased survival (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.22-1.23; p = 0.14). In conclusion, prior statin use is not associated with increased survival in immunosuppressed patients with BSI. Caution is warranted in attributing beneficial effects to statin use in infections among immunocompromised patients. PMID- 20835879 TI - Colonisation with Escherichia coli resistant to "critically important" antibiotics: a high risk for international travellers. AB - Antimicrobial resistance among community-acquired isolates of Escherichia coli is increasing globally, with international travel emerging as a risk for colonisation and infection. The aim was to determine the rate and duration of colonisation with resistant E. coli following international travel. One hundred and two adult hospital staff and contacts from Canberra, Australia, submitted perianal/rectal swabs before and following international travel. Swabs were cultured selectively to identify E. coli resistant to gentamicin, ciprofloxacin and/or third-generation cephalosporins. Those with resistant E. coli post-travel were tested monthly for persistent colonisation. Colonisation with antibiotic resistant E. coli increased significantly from 7.8% (95% confidence interval [CI] 3.8-14.9) pre-travel to 49% (95% CI 39.5-58.6) post-travel. Those colonised were more likely to have taken antibiotics whilst travelling; however, travel remained a risk independent of antibiotic use. Colonisation with resistant E. coli occurred most frequently following travel to Asia. While over half of those carrying resistant E. coli post-travel had no detectable resistant strains two months after their return, at least 18% remained colonised at six months. Colonisation with antibiotic-resistant E. coli occurs commonly after international travel, and can be persistent. Medical practitioners should be aware of this risk, particularly when managing patients with suspected Gram negative sepsis. PMID- 20835881 TI - Effect of carbon to nitrogen (C:N) ratio on nitrogen removal from shrimp production waste water using sequencing batch reactor. AB - The United States Marine Shrimp Farming Program (USMSFP) introduced a new technology for shrimp farming called recirculating raceway system. This is a zero water exchange system capable of producing high-density shrimp yields. However, this system produces wastewater characterized by high levels of ammonia, nitrite, and nitrate due to 40% protein diet for the shrimp at a high density of 1,000 shrimp per square meter. The high concentrations of nitrate and nitrite (greater than 25 ppm) are toxic to shrimp and cause high mortality. So treatment of this wastewater is imperative in order to make shrimp farming viable. One simple method of treating high-nitrogen wastewater is the use of a sequencing batch reactor (SBR). An SBR is a variation of the activated sludge process, which accomplishes many treatment events in a single reactor. Removal of ammonia and nitrate involved nitrification and denitrification reactions by operating the SBR aerobically and anaerobically in sequence. Initial SBR operation successfully removed ammonia, but nitrate concentrations were too high because of carbon limitation in the shrimp production wastewater. An optimization study revealed the optimum carbon to nitrogen (C:N) ratio of 10:1 for successful removal of all nitrogen species from the wastewater. The SBR operated with a C:N ratio of 10:1 with the addition of molasses as carbon source successfully removed 99% of ammonia, nitrate, and nitrite from the shrimp aquaculture wastewater within 9 days of operation. PMID- 20835880 TI - Arsenite stabilizes HIF-1alpha protein through p85alpha-mediated up-regulation of inducible Hsp70 protein expression. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) has been reported to regulate over 100 gene expressions in response to hypoxia and other stress conditions. In the present study, we found that arsenite could induce HIF-1alpha protein accumulation in both mouse epidermal Cl41 cells and mouse embryonic fibroblasts (MEFs). Knockout of p85alpha, a regulatory subunit of PI-3K, in MEFs (p85alpha(-/ )) dramatically decreased the arsenite-induced HIF-1alpha accumulation, indicating that p85alpha is crucial for arsenite effects on the stabilization of HIF-1alpha protein. Our further studies suggest that arsenite could induce inducible Hsp70 expression, and transfection of inducible Hsp70 into p85alpha(-/ ) MEFs could restore HIF-1alpha protein accumulation. Moreover, the results using EMSA and Supershift assays indicate that p85alpha is crucial for arsenite-induced activation of the heat-shock transcription factor 1 (HSF-1), which is responsible for transcription of inducible Hsp70. Taken together, p85alpha-mediated HIF 1alpha stabilization upon arsenite exposure is specifically through HSF-1 activation and subsequent up-regulation of the inducible Hsp70 expression. PMID- 20835882 TI - Automated measurement and quantification of heterotrophic bacteria in water samples based on the MPN method. AB - Quantification of heterotrophic bacteria is a widely used measure for water analysis. Especially in terms of drinking water analysis, testing for microorganisms is strictly regulated by the European Drinking Water Directive, including quality criteria and detection limits. The quantification procedure presented in this study is based on the most probable number (MPN) method, which was adapted to comply with the need for a quick and easy screening tool for different kinds of water samples as well as varying microbial loads. Replacing tubes with 24-well titer plates for cultivation of bacteria drastically reduces the amount of culture media and also simplifies incubation. Automated photometric measurement of turbidity instead of visual evaluation of bacterial growth avoids misinterpretation by operators. Definition of a threshold ensures definite and user-independent determination of microbial growth. Calculation of the MPN itself is done using a program provided by the US Food and Drug Administration (FDA). For evaluation of the method, real water samples of different origins as well as pure cultures of bacteria were analyzed in parallel with the conventional plating methods. Thus, the procedure described requires less preparation time, reduces costs and ensures both stable and reliable results for water samples. PMID- 20835884 TI - Genome-wide evaluation for quantitative trait loci under the variance component model. AB - The identity-by-descent (IBD) based variance component analysis is an important method for mapping quantitative trait loci (QTL) in outbred populations. The interval-mapping approach and various modified versions of it may have limited use in evaluating the genetic variances of the entire genome because they require evaluation of multiple models and model selection. In this study, we developed a multiple variance component model for genome-wide evaluation using both the maximum likelihood (ML) method and the MCMC implemented Bayesian method. We placed one QTL in every few cM on the entire genome and estimated the QTL variances and positions simultaneously in a single model. Genomic regions that have no QTL usually showed no evidence of QTL while regions with large QTL always showed strong evidence of QTL. While the Bayesian method produced the optimal result, the ML method is computationally more efficient than the Bayesian method. Simulation experiments were conducted to demonstrate the efficacy of the new methods. PMID- 20835883 TI - Analysis of the functional conservation of ethylene receptors between maize and Arabidopsis. AB - Ethylene, a regulator of plant growth and development, is perceived by specific receptors that act as negative regulators of the ethylene response. Five ethylene receptors, i.e., ETR1, ERS1, EIN4, ETR2, and ERS2, are present in Arabidopsis and dominant negative mutants of each that confer ethylene insensitivity have been reported. In contrast, maize contains just two types of ethylene receptors: ZmERS1, encoded by ZmERS1a and ZmERS1b, and ZmETR2, encoded by ZmETR2a and ZmETR2b. In this study, we introduced a Cys to Tyr mutation in the transmembrane domain of ZmERS1b and ZmETR2b that is present in the etr1-1 dominant negative mutant and expressed each protein in Arabidopsis. Mutant Zmers1b and Zmetr2b receptors conferred ethylene insensitivity and Arabidopsis expressing Zmers1b or Zmetr2b were larger and exhibited a delay in leaf senescence characteristic of ethylene insensitive Arabidopsis mutants. Zmers1b and Zmetr2b were dominant and functioned equally well in a hemizygous or homozygous state. Expression of the Zmers1b N-terminal transmembrane domain was sufficient to exert dominance over endogenous Arabidopsis ethylene receptors whereas the Zmetr2b N-terminal domain failed to do so. Neither Zmers1b nor Zmetr2b functioned in the absence of subfamily 1 ethylene receptors, i.e., ETR1 and ERS1. These results suggest that Cys65 in maize ZmERS1b and ZmETR2b plays the same role that it does in Arabidopsis receptors. Moreover, the results demonstrate that the mutant maize ethylene receptors are functionally dependent on subfamily 1 ethylene receptors in Arabidopsis, indicating substantial functional conservation between maize and Arabidopsis ethylene receptors despite their sequence divergence. PMID- 20835886 TI - Remaking body politics: dilemmas over female fatness as symbolic capital in two rural Tuareg communities. AB - This essay explores nuanced, debated and changing meanings of female fatness as a bodily aesthetic ideal in rural Tuareg communities in northern Niger and Mali. I compare two communities--one where nomadic herding, of longstanding importance among the Tuareg, remains prevalent, and intermarriage is rare between aristocratic and formerly servile persons, and the other where residents have become more settled in hamlets, now garden, and where intermarriage between social categories is frequent. Both communities have experienced conflict with colonial and postcolonial nation-states, but the more nomadic herders have had especially tense relations with French colonial and postcolonial state regimes. Although many oasis residents express greater ambivalence toward female fatness, these communities do not express neatly polarized attitudes but admire it to varying degrees, for different reasons, and attach different meanings to it from their experience of different double-binds over achieving it. Fundamental to understanding these meanings, I argue, are psychosocial dilemmas arising from historical change and regional variation affecting power relationships between persons of aristocratic and those of servile origins, between husbands and wives and between nomadic herders and the nation-state. More broadly, these data show the importance of reversals of power in symbolic capital and suggest more nuanced processes surrounding body politics. PMID- 20835887 TI - Is there such a thing as psychological pain? And why it matters. AB - Medicine regards pain as a signal of physical injury to the body despite evidence contradicting the linkage and despite the exclusion of vast numbers of sufferers who experience psychological pain. By broadening our concept of pain and making it more inclusive, we would not only better accommodate the basic science of pain but also would recognize what is already appreciated by the layperson--that pain from diverse sources, physical and psychological, share an underlying felt structure. PMID- 20835885 TI - Synthetic adipose tissue models for studying mammary gland development and breast tissue engineering. AB - The mammary gland is a dynamic organ that continually changes its architecture and function. Reciprocal interactions between epithelium and adipocyte-containing stroma exert profound effects on all stages of its development, even though the details of these events are not fully understood. To address this issue, enormous potential exists in the utilization of synthetic adipose tissue model systems to uncover the properties and functions of adipocytes in the mammary gland. The first part of this review focuses on mammary adipose tissue (or adipocyte) related model systems developed in recent years and their utility in investigating adipose-epithelial interactions, mammary gland morphogenesis, development and tumorigenesis. The second part shifts to the field of adipose based breast tissue engineering, focusing on how these synthetic adipose tissue models are being constructed in vitro or in vivo for regeneration of the mammary gland, and their potentials in adipose tissue engineering also are discussed. PMID- 20835888 TI - Tamarix hispida metallothionein-like ThMT3, a reactive oxygen species scavenger, increases tolerance against Cd(2+), Zn(2+), Cu(2+), and NaCl in transgenic yeast. AB - A metallothionein-like gene, ThMT3, encoding a type 3 metallothionein, was isolated from a Tamarix hispida leaf cDNA library. Expression analysis revealed that mRNA of ThMT3 was upregulated by high salinity as well as by heavy metal ions, and that ThMT3 was predominantly expressed in the leaf. Transgenic yeast (Saccharomyces cerevisiae) expressing ThMT3 showed increased tolerance to Cd(2+), Zn(2+), Cu(2+), and NaCl stress. Transgenic yeast also accumulated more Cd(2+), Zn(2+), and NaCl, but not Cu(2+). Analysis of the expression of four genes (GLR1, GTT2, GSH1, and YCF1) that aid in transporting heavy metal (Cd(2+)) from the cytoplasm to the vacuole demonstrated that none of these genes were induced under Cd(2+), Zn(2+), Cu(2+), and NaCl stress in ThMT3-transgenic yeast. H(2)O(2) levels in transgenic yeast under such stress conditions were less than half those in control yeast under the same conditions. Three antioxidant genes (SOD1, CAT1, and GPX1) were specifically expressed under Cd(2+), Zn(2+), Cu(2+), and NaCl stress in the transgenic yeast. Cd(2+), Zn(2+), and Cu(2+) increased the expression levels of SOD1, CAT1, and GPX1, respectively, whereas NaCl induced the expression of SOD1 and GPX1. PMID- 20835889 TI - Effect of BRAND's essence of chicken on the resetting process of circadian clocks in rats subjected to experimental jet lag. AB - BRAND's Essence of Chicken (BEC) has been widely used as a traditional remedy by people in Southeast Asia, which is proved to have an effect on the central nervous system (CNS) and autonomic nervous system (ANS). However, whether and how BEC consumption may affect mammalian circadian system is still largely unknown. In the present study, we investigated the effect of BEC feeding on the adaptation of circadian clocks to the experimental jet lag in rats. After the 12-h experimental jet lag through extending the light period, BEC feeding markedly facilitated the re-entrainment of all examined clock genes (Bmal1, Cry1, Per1, and Per2) in the pineal gland. The resetting time course of pineal clock genes was reduced from 7 days to only 3-5 days by BEC feeding, which was almost equal to the effect of melatonin feeding. In the liver clock, the facilitating effect of BEC feeding was mainly displayed in the re-entrainment of Bmal1 and Per2 by shortening their resetting processes for nearly 2 days. However, the resetting rate of locomotor activity rhythm was not affected by BEC feeding, suggesting that BEC might be unable to affect the behavioral rhythm. PMID- 20835890 TI - Bioremediation and reclamation of soil contaminated with petroleum oil hydrocarbons by exogenously seeded bacterial consortium: a pilot-scale study. AB - PURPOSE: Spillage of petroleum hydrocarbons causes significant environmental pollution. Bioremediation is an effective process to remediate petroleum oil contaminant from the ecosystem. The aim of the present study was to reclaim a petroleum oil-contaminated soil which was unsuitable for the cultivation of crop plants by using petroleum oil hydrocarbon-degrading microbial consortium. MATERIALS AND METHODS: Bacterial consortium consisting of Bacillus subtilis DM-04 and Pseudomonas aeruginosa M and NM strains were seeded to 20% (v/w) petroleum oil-contaminated soil, and bioremediation experiment was carried out for 180 days under laboratory condition. The kinetics of hydrocarbon degradation was analyzed using biochemical and gas chromatographic (GC) techniques. The ecotoxicity of the elutriates obtained from petroleum oil-contaminated soil before and post treatment with microbial consortium was tested on germination and growth of Bengal gram (Cicer aretinum) and green gram (Phaseolus mungo) seeds. RESULTS: Bacterial consortium showed a significant reduction in total petroleum hydrocarbon level in contaminated soil (76% degradation) as compared to the control soil (3.6% degradation) 180 days post-inoculation. The GC analysis confirmed that bacterial consortium was more effective in degrading the alkane fraction compared to aromatic fraction of crude petroleum oil hydrocarbons in soil. The nitrogen, sulfur, and oxygen compounds fraction was least degraded. The reclaimed soil supported the germination and growth of crop plants (C. aretinum and P. mungo). In contrast, seeds could not be germinated in petroleum oil contaminated soil. CONCLUSIONS: The present study reinforces the application of bacterial consortium rather than individual bacterium for the effective bioremediation and reclamation of soil contaminated with petroleum oil. PMID- 20835891 TI - PCDD/F and dioxin-like PCB profiles in soils amended with sewage sludge, compost, farmyard manure, and mineral fertilizer since 1962. AB - BACKGROUND, AIM, AND SCOPE: Biowaste contains compounds of agricultural value such as organic carbon, nutrients, and trace elements and can partially replace mineral fertilizer (MIN) and improve the physical properties of the soil. However, the obvious benefits of land spreading need to be carefully evaluated against potential adverse effects on the environment and human health. Environmental contamination resulting from biowaste application is one of the key variables when assessing cost/benefits. This study provides data on the resulting concentration of polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) in the soil column as a result of the different types of fertilizers. MATERIALS AND METHODS: In a long-term field experiment established in 1962, we investigated the influence of the application of biowaste-derived fertilizers such as sewage sludge (SSL), compost (COM), and farmyard manure (FYM) to a luvisol derived from loess on the contents of PCDD/Fs and DL-PCBs. Control plots amended only with MIN served as a basis to compare the biowaste-amended soils with soils affected only by atmospheric deposition, thus experimentally separating the two pathways of soil contamination. Samples of the soil column down to a depth of 90 cm were taken in 2001 and analyzed for PCDD/Fs and dioxin-like PCBs according to US-EPA methods 1613 and 1668, respectively. RESULTS: Thirty-nine years of experimental SSL and COM applications exceeding four times the maximal amount as laid down in German legislation resulted in a doubling of the international toxicity equivalent (I-TEQ) budget for PCDD/Fs and a threefold increase for DL-PCBs as compared to test plots amended with MIN only. As compared to MIN, the application of FYM had no effect on the PCDD/F and PCB content in soil. The average contribution of the DL-PCBs to the WHO-TEQ was 19% in the MIN and FYM plots and somewhat higher in the COM (23%) and in the SSL (27%) plots. DISCUSSION: Although the test plots received four times the maximum application of SSL as laid down in the German SSL ordinance and the investigated region represents the upper end of the topsoil concentrations typically found in Germany, the soils treated with SSL and COM were still a factor of 4 below the German guideline value of PCDD/Fs for arable land. No enhancement of translocation of PCDD/Fs and PCBs into the corresponding subsoils due to the presence of dissolved humic matter or other surfactants potentially present in the biowaste was observed. The similarity of congener patterns in all soils, irrespective of the type of fertilizer applied, points towards atmospheric deposition of PCDD/Fs and DL-PCBs as the main intake route in the soils. The higher levels in the SSL- and COM-amended soils can be explained by the fact that both biowastes are subject to atmospheric deposition occurring at their origin. In the case of COM, it is accumulation in the foliage, while in the case of SSL, atmospheric particulate from wet and dry deposition is collected in the wastewater treatment system via urban runoff. CONCLUSIONS: It appears that the common practice of SSL applications in Germany does not pose a current threat to the agro-environment with regard to PCDD/Fs and DL-PCBs. However, time trend data on PCDD/Fs in SSL-amended soils will be needed to obtain a prognosis about the long-term effect of biowaste applications on soil quality. PMID- 20835892 TI - Liver-specific pyruvate dehydrogenase complex deficiency upregulates lipogenesis in adipose tissue and improves peripheral insulin sensitivity. AB - The pyruvate dehydrogenase complex (PDC) plays a critical role in lipid synthesis and glucose homeostasis in the fed and fasting states. The central role of the liver in the maintenance of glucose homeostasis has been established by studying changes in key enzymes (including PDC) and the carbon-flux via several pathways under different metabolic states. In the present study we have developed a murine model of liver-specific PDC deficiency using Cre-loxP technology to investigate its consequences on lipid and carbohydrate metabolism. There was no incorporation of glucose-carbon into fatty acids by liver in vitro from liver-specific Pdha1 knockout (L-PDHKO) male mice due to absence of hepatic PDC activity. Interestingly, there was a compensatory increase in lipogenic capacity in epididymal adipose tissue from L-PDHKO mice. Both fat and lean body mass were significantly reduced in L-PDHKO mice, which might be explained by an increase in total energy expenditure compared with wild-type littermate mice. Furthermore, both liver and peripheral insulin sensitivities measured during a hyperinsulinemic-euglycemic clamp were improved in L-PDHKO mice. The findings presented here demonstrate (i) the indispensable role of PDC for lipogenesis from glucose in liver and (ii) specific adaptations in lipid and glucose metabolism in the liver and adipose tissue to compensate for loss of PDC activity in liver only. PMID- 20835893 TI - Why do patients change their general practitioner? Suggestions on corrective actions. AB - AIMS: The aim of this study was to determine what made people want to change their choice of general practitioners (GP). Furthermore, the study aimed to correlate the perceived quality of patient-GP communication with the motives inducing individuals to change their doctors. METHODS: All people requesting to change their GPs were asked by the office staff to complete a questionnaire. RESULTS: The study identifies the following main reasons for changing GP: patients perceived the doctor as unwilling to listen to them; patients did not receive the services that they considered useful for their health; and patients perceived the doctor's disorganization as an obstacle to accessibility. CONCLUSIONS: These findings suggest several actions to improve the doctor-patient relationship, including training for physicians to develop their communication skills; involving public health operators in helping to understand the rights and obligations of patients and doctors; and a reorganization of the GP's workload. PMID- 20835894 TI - Endovascular repair of an inflammatory abdominal aortic aneurysm causing bilateral ureteric obstruction. AB - BACKGROUND: Conventional open repair of inflammatory abdominal aortic aneurysms (IAAA) remains challenging through the presence of extensive peri-aortic inflammation and fibrosis which makes dissection and vascular control difficult with a risk of inadvertent injury to adjacent visceral structures such as the ureters, duodenum, inferior vena cava, left renal vein and sigmoid colon. METHODS: We describe a case of a 69-year-old gentleman who presented with acute renal failure due to bilateral ureteric obstruction in association with an IAAA and discuss the various management options available. CONCLUSION: IAAAs and the associated peri-aortic inflammation and fibrosis can be successfully treated using endovascular abdominal aortic aneurysm repair with concurrent ureteric stenting. PMID- 20835895 TI - Revision to malabsorptive Roux-en-Y gastric bypass (MRNYGBP) provides long-term (10 years) durable weight loss in patients with failed anatomically intact gastric restrictive operations: long-term effectiveness of a malabsorptive Roux en-Y gastric bypass in salvaging patients with poor weight loss or complications following gastroplasty and adjustable gastric bands. AB - BACKGROUND: Twenty percent of gastric restrictive operations require revision. Conversion to Proximal Roux-en-Y gastric bypass (PRNYGBP) is associated with weight regain. Forty-one percent of these fail to achieve a body mass index (BMI) < 35. Few report follow-up (F/U) or quality of life (QOL) beyond 5 years. We report the long-term effectiveness of MRNYGBP as a revision. METHODS: Retrospective chart review of patients (1993-2005) with a failed gastric restrictive operation (S1) at least a year out from revision (S2) to a MRNYGBP: small lesser curve 22 +/- 10 (11-55) cm(3) pouch, long biliopancreatic limb, 150 cm alimentary limb, 141 +/- 24 (102-190) cm common channel. Staple-line disruptions were excluded. RESULTS: Thirty-eight (37 F, 1 M) patients aged 46 +/- 8 (17-56) years underwent conversion to a MRYGBP 8 +/- 5 (2-23) years after: gastroplasty 25, adjustable gastric band 13 for weight regain (79%), gastroesophageal reflux disease (GERD; 29%), and band problems (24%). S1 provided only 24 +/- 25% excess weight loss (EWL; 5.9 +/- 6.3 BMI drop) and caused GERD in 32% of patients (p = 0.0124). There were no deaths or leaks. BMI dropped from 41.4 +/- 7.8 to 27.3 +/- 5.6 (down 20.5 +/- 8.3 from S1), 80.1 +/- 23.3% EWL (n = 32) at year 1 (p < 0.0001). This was maintained for 10 years. BMI was 28 +/- 4 (21.5-31.9), 75.6 +/- 21.1% EWL (57.3-109.6) (n = 5) at 10 years. Super obese patients had better 9.95% EWL after S2 (p = 0.0359). QOL (5 = excellent): 4.5 +/- 0.5 (3-5). F/U: 5.1 +/- 3.3 (1-13) years with 83.3% F/U 10-year rate. Labs at 3 years (n = 10): Alb 3.8 +/- 0.4, Prot 6.8 +/- 0.6, Iron 47.6 +/- 33.3, VitD 15.1 +/- 7.43, PTH 54.5 +/- 27.2, B12 620.1 +/- 676.5, Hct 34 +/- 4.3. CONCLUSIONS: Revision MRNYGBP provides excellent durable long-term weight loss after failed gastric restrictive operations. Non-compliant patients are at a higher risk for malnutrition, anemia, and osteoporosis. PMID- 20835896 TI - Effects of adjustable gastric bands on gastric emptying, supra- and infraband transit and satiety: a randomized double-blind crossover trial using a new technique of band visualization. AB - BACKGROUND: The laparoscopic adjustable gastric band (LAGB) has previously been classified as a restrictive procedure; physically limiting meal size. Recently, the key mechanism has been hypothesized to be the induction of satiety without restriction. Effects can be controlled by modifying LAGB volume, possibly as a result of effects on gastric emptying or transit through the LAGB. METHODS: Successful LAGB patients underwent paired, double blinded, esophageal transit and gastric emptying scintigraphic studies; with the LAGB at optimal volume and near empty. A new technique allowed assessment of emptying and transit through the infra- and supraband compartments. RESULTS: Fourteen of 17 patients completed both scans (six males; mean age, 48.9 +/- 11.3 years, % excess weight loss 69.0 +/- 15.2). At optimal volume a delay in transit of semi-solids into the infraband compartment was observed in ten patients vs. three when the LAGB was empty, (p = 0.01). The median retention of a meal in the supraband compartment immediately after cessation of intake was: empty 2.8% (2.3-7.9) vs. optimal 3.6% (1.7-4.5), (p = 0.57). Overall gastric emptying half time (minutes) was normal at both volumes: optimal 64.2 +/- 29.8 vs. empty 95.2 +/- 64.1, (p = 0.14). LAGB volume did not affect satiety before the scan: optimal 4.3 +/- 1.9 vs. empty 4.0 +/- 2.2, (p = 0.49), or 90 min later: optimal 6.1 +/- 1.9 vs. empty 5.9 +/- 1.4, (p = 0.68). CONCLUSIONS: The optimally adjusted LAGB briefly delays semi-solid transit into the infraband stomach without physically restricting meal size. The supraband compartment is usually empty of an ingested meal 1-2 min after intake ceases and overall gastric emptying is not affected. PMID- 20835897 TI - Sleeve gastrectomy induces weight loss in diet-induced obese rats even if high fat feeding is continued. AB - BACKGROUND: Sleeve gastrectomy (SG) has been used for the surgical treatment of morbid obesity as a first or definitive procedure with satisfactory results. The objective of this study in rats was to establish the effects of SG on weight loss depending on the post-surgical type of diet followed. METHODS: Thirty male Wistar rats were fed ad libitum during 3 months on a high-fat diet (HFD) to induce obesity. After this first phase, rats were subdivided in three groups of ten rats each and underwent a sham intervention, an SG, or no surgery but were pair-fed to the amount of food eaten by the animals of the SG group. At this time point, half of the animals in each group continued to be fed on the HFD, while the other half was switched to a normal chow diet (ND). Thus, the following subgroups were established: sham-ND, sleeve-ND, pair-fed-ND as well as sham-HFD, sleeve-HFD, and pair-fed-HFD. Body weight and food intake were recorded daily for 4 weeks. The feed efficiency rate (FER) was determined from weekly weight gains and caloric consumption during this period. RESULTS: Statistically significant (P < 0.05) differences in body weight were observed between the six experimental groups after 4 weeks of the interventions with rats in the sleeve-ND group experimenting the highest weight loss (-78.2 +/- 10.3 g) and animals in the pair-fed-HFD group exhibiting the lowest weight reduction (-4.0 +/- 0.1 g). Interestingly, the FER value of rats that underwent the SG and continued to be fed on a HFD was significantly (P < 0.05) lower than that of sham operated and pair-fed animals on the same diet. CONCLUSION: The positive effects of SG on weight reduction are observed in obese rats submitted to the intervention and subsequently following an ND or even an HFD. PMID- 20835898 TI - 24-h pH-metry and multichannel intraluminal impedance monitoring in obese patients with and without gastroesophageal reflux disease symptoms. AB - BACKGROUND: The 24-h ambulatory pH-metry with multichannel intraluminal impedance monitoring (24-h pH-metry+MII) allows the simultaneous assessment of chemical and physical properties of esophageal refluxes and the detection of its proximal migration. METHODS: Gastroesophageal reflux (GER) was investigated in obese symptomatic (obese gastroesophageal reflux disease, GERD) and asymptomatic (obese non-GERD) patients. The data were compared with those obtained from non-obese GERD patients and a control group. Thirty-five (20 non-GERD, 15 GERD) obese patients and 15 non-obese GERD were investigated with 24-h pH-metry+MII. Ten normal weight subjects with normal 24-h pH-metry+MII were used as control group. RESULTS: The percent time acid exposure was significantly higher in obese non GERD than controls (p = 0.007). Acid reflux episodes were increased vs. controls in obese non-GERD (p = 0.005) and obese GERD (p = 0.034). Upright position showed a significant increase of reflux episodes in non-obese GERD (p = 0.034) and in obese non-GERD (p = 0.027) vs. controls. Recumbent position showed reflux episodes significantly increased vs. controls in obese non-GERD (p = 0.002), obese GERD (p = 0.021), and non-obese GERD (p = 0.033). In obese non-GERD, waist circumference (WC) correlated negatively with upright position episodes (r = 0.53; p = 0.043) and with proximal migration episodes, i.e., total (r = -0.60; p = 0.018), acid (r = -0.55; p = 0.033), and weakly acidic refluxes (r = -0.56; p = 0.031). CONCLUSIONS: Obese patients showed an increased number of refluxes with acid content. Refluxes with proximal extent were significantly higher in obese non-GERD than in controls and non-obese GERD patients. No difference was observed between the two obese patient groups. In asymptomatic obese patients, the WC correlated with proximal extent episodes. PMID- 20835899 TI - Long-term experience with duodenal switch in adolescents. AB - BACKGROUND: Severe or extreme obesity in children and adolescents is a progressive damaging disease, increasingly requiring surgical treatment. Timing and choice of operation are controversial. METHOD: In the last 16 years, we performed open biliopancreatic diversion with duodenal switch (DS) in 13 adolescents aged 15-17 years, who have been followed up for 2-16 years (mean, 10.6 years); three with Prader-Willi syndrome (PWS) are presented separately. RESULTS: Among the ten non-PWS children (7 girls), no deaths or perioperative complications were reported, mean body mass index (BMI) decreased from 55.9 +/- 14.0 to 28.8 +/- 3.7 kg/m(2) (% excess weight loss (EWL) = 82.1 +/- 10.5%), and none have regained weight. All comorbidities were cured except asthma, which improved in one patient. There were two reoperations: one for intestinal obstruction and one for post-anastomotic ulcer. Glucose and lipid metabolism improved, while vitamin and mineral deficiencies were mild and rare. Five of the seven girls gave birth to 11 children, aged 2-12 years, two of whom are overweight but not severely obese. Neurodevelopment is age-appropriate in all 11 individuals. PWS children, aged 15-16 years, had postoperative respiratory and infectious complications necessitating hospitalizations of 13-22 days (versus 5.1 +/- 1.2 days in non-PWS). Weight loss and comorbidity improvement lasted approximately 5 years, providing improved quality of life for patient and family. One PWS patient died from complications after reoperation for weight regain after 4 years. One was reoperated after 6 years and the third is considering reoperation 14 years after primary DS. CONCLUSION: The beneficial effects of DS in adolescents exceed the risks, even in the presence of PWS. PMID- 20835900 TI - Genetics of diabetes complications. AB - A large body of evidence indicates that the risk for developing chronic diabetic complications is under the control of genetic factors. Previous studies using a candidate gene approach have uncovered a number of genetic loci that may shape this risk, such as the VEGF gene for retinopathy, the ELMO1 gene for nephropathy, and the ADIPOQ gene for coronary artery disease. Recently, a new window has opened on identifying these genes through genome-wide association studies. Such systematic approach has already led to the identification of a major locus for coronary artery disease on 9p21 as well three potential genes for nephropathy on 7p, 11p, and 13q. Further insights are expected from a broader application of this strategy. It is anticipated that the identification of these genes will provide novel insights on the etiology of diabetic complications, with crucial implications for the development of new drugs to prevent the adverse effects of diabetes. PMID- 20835901 TI - Preventing poor psychological and health outcomes in pediatric type 1 diabetes. AB - Youth with type 1 diabetes are at high risk for psychosocial morbidities. These include depression, disturbed eating behavior, family conflict, poor health related quality of life, low self-efficacy, and difficulty with medical adherence and metabolic control. A number of prevention interventions have been studied in this group, with the overall goal of improving adaptation and coping skills. This paper reviews the current research aimed at preventing poor outcomes in youth with type 1 diabetes and recommends simple interventions that can be added to clinical encounters. Recommendations for future psychosocial prevention studies are also discussed. PMID- 20835902 TI - [Acquired bacterial meningitis in Monastir region, Tunisia (1999-2006): bacteriological aspects and susceptibility patterns]. AB - The aim of this study was to analyze the distribution of bacteria responsible for purulent meningitis and the pattern of resistance of common species in the University Hospital of Monastir (Tunisia). All bacteriologically confirmed cases of bacterial meningitis were recorded between 1999 and 2006, and have been analyzed by classic bacterial methods advocate for meningitis. Two hundred fifty three strains have been isolated. The most frequent species were Streptococcus pneumoniae, Haemophilus influenzae, and Klebsiella pneumoniae, followed by Escherichia coli and Neisseria meningitides with 19.4, 13.8, 13.8, 7.1, and 6.3% of cases, respectively. Their distribution with regard to age was in accordance with literature data. The yearly distribution of these bacteria did not show any epidemic peak. Enterobacteriaceae and group B Streptococcus were the most frequently identified pathogens in neonatal meningitis. H. Influenzae was the predominant microorganism in children between three month and five years of age (36.3%), followed by S. Pneumoniae (28.8%). S. Pneumoniae was the predominant bacteria responsible for 47% of the cases over five years of age. 38.8% of S. Pneumoniae strains were less susceptible to penicillin. Resistance rates for amoxicillin and cefotaxime were 4.1%, respectively. Only one strain of N. meningitidis (6.2%) presented a decreased susceptibility to penicillin. 22.9% of H. Influenzae strains produced beta-lactamase. The resistance rates of Enterobacteriaceae to third generation cephalosporins were 25%. In our study, nosocomial meningitis have shown a rate of 24.4%. The most affected service was neurosurgery, pediatrics, and intensive care units. The increasing prevalence of pneumococci meningitis with reduced sensitivity to penicillin G strains isolated from meningitis makes adequate therapeutic management difficult. PMID- 20835903 TI - Adaptive servoventilation improves cardiac function and respiratory stability. AB - Cheyne-Stokes respiration (CSR) in patients with chronic heart failure (CHF) is of major prognostic impact and expresses respiratory instability. Other parameters are daytime pCO2, VE/VCO2-slope during exercise, exertional oscillatory ventilation (EOV), and increased sensitivity of central CO2 receptors. Adaptive servoventilation (ASV) was introduced to specifically treat CSR in CHF. Aim of this study was to investigate ASV effects on CSR, cardiac function, and respiratory stability. A total of 105 patients with CHF (NYHA >= II, left ventricular ejection fraction (EF) <= 40%) and CSR (apnoea-hypopnoea index >= 15/h) met inclusion criteria. According to adherence to ASV treatment (follow-up of 6.7 +/- 3.2 months) this group was divided into controls (rejection of ASV treatment or usage <50% of nights possible and/or <4 h/night; n = 59) and ASV (n = 56) adhered patients. In the ASV group, ventilator therapy was able to effectively treat CSR. In contrast to controls, NYHA class, EF, oxygen uptake, 6 min walking distance, and NT-proBNP improved significantly. Moreover, exclusively in these patients pCO2, VE/VCO2-slope during exercise, EOV, and central CO2 receptor sensitivity improved. In CHF patients with CSR, ASV might be able to improve parameters of SDB, cardiac function, and respiratory stability. PMID- 20835904 TI - Acute and chronic effects of exercise on inflammatory markers and B-type natriuretic peptide in patients with coronary artery disease. AB - BACKGROUND: Few studies have prospectively addressed the effects of exercise in the inflammatory activity of patients with coronary artery disease (CAD). We sought to evaluate the consequences of an acute bout of exercise on inflammatory markers and BNP in untrained CAD patients before and after randomization to a training program. METHODS: 34 CAD patients underwent a 50-min acute exercise session on a cycle-ergometer at 65% peak oxygen uptake before and after blood sampling. They were then randomized to a 4-month chronic exercise program (15 patients) or general lifestyle recommendations (19 patients), undergoing a new acute session of exercise after that. RESULTS: In the overall population, acute exercise caused a significant increase in C-reactive protein [CRP; 1.79 (4.49) vs. 1.94 (4.89) mg/L, P < 0.001], monokine induced by interferon-gamma [Mig; 351 (324) vs. 373 (330) pg/mL, P = 0.027] and vascular adhesion molecule-1 [VCAM-1; 226 (82) vs. 252 (110) pg/mL, P = 0.02]. After 4-months, in exercise-trained patients, there was a significant decrease in the inflammatory response provoked by the acute exercise compared to patients in the control group reflected by a significant decrease in the differences between rest and post-exercise levels of CRP [-0.29 (0.84) mg/L vs. -0.11 (0.21) mg/L, P = 0.05]. Resting BNP was also significantly lower in exercise-trained patients when compared to untrained controls [15.6 (16.2) vs. 9.7 (11.4) pg/mL, P = 0.04 and 19.2 (27.8) vs. 23.2 (27.5) pg/mL, P = 0.76; respectively]. CONCLUSIONS: Chronic exercise training might partially reverse the inflammatory response caused by acute exercise in CAD patients. These results suggest that regular exercise is an important nonpharmacological strategy to the improvement in inflammation in CAD patients. PMID- 20835906 TI - "Careful" reprogramming of baclofen intrathecal programmable synchromed infusion pumps at their replacement in a series of 156 patients. PMID- 20835905 TI - Tricuspid annular plane systolic excursion and right ventricular ejection fraction in pediatric and adolescent patients with tetralogy of Fallot, patients with atrial septal defect, and age-matched normal subjects. AB - AIMS: To determine whether TAPSE is an accurate marker of right ventricular (RV) systolic function in patients with tetralogy of Fallot (TOF) and patients with small atrial septal defect (ASD). The tricuspid annular plane systolic excursion (TAPSE) values were measured and compared with RV ejection fraction (EF). METHODS AND RESULTS: A prospective study was conducted in pediatric and adolescent patients with TOF (n = 110), with isolated small secundum ASD (n = 200), and age matched patients with normally structured heart. The TAPSE values showed a positive correlation with age in both patients with ASD and normal subjects. No significant difference of TAPSE values was seen in control subjects and age matched ASD patients. The TAPSE was not decreased compared to normal subjects in eight infant TOF patients before corrective surgery. A reduction of TAPSE values with increasing time interval following corrective surgery was seen. After a mean of 7 years TAPSE values become significantly reduced compared to age-matched controls, being below the lower bound of the -2 SD. CONCLUSION: In ASD patients the systolic RV function was preserved over the pediatric age group when compared to normal subjects. In contrast, although initially preserved, we found an impaired TAPSE with increasing postoperative period in our TOF patients. PMID- 20835907 TI - Hernia recurrence through a composite mesh secondary to transfascial suture holes. AB - Laparoscopic ventral hernia repair is an accepted method for incisional hernia repair. Although techniques vary, transfascial suturing of the mesh to the abdominal wall has been proposed as a viable way to fixate the mesh and reduce recurrence rates. We report a 54-year-old woman who had previously undergone a laparoscopic ventral hernia repair following a laparoscopic tubal ligation using a Composix mesh. The patient presented with a symptomatic hernia recurrence. The computed tomography scan showed a periumbilical hernia containing fat. The patient underwent diagnostic laparoscopy and lysis of adhesions. During the lysis of adhesions, a recurrence through the previously placed composite mesh was encountered where holes had been made by the previously placed transfascial sutures. The hernia was reduced, mesh was removed, and an ePTFE mesh was used to repair the hernia. The mechanism of recurrence appeared to be improperly placed transfascial sutures; overly large bites of mesh caused excessive tension and ultimately a hole in the mesh. Hernia recurrence due to mesh or transfascial suture failure is rarely reported and most often caused by inadequate fixation. Our case highlights the need for meticulous placement of transfascial sutures and demonstrates a mechanism of recurrence due to inadequate placement. PMID- 20835908 TI - Different methods of mesh fixation in open retromuscular incisional hernia repair: a comparative study in pigs. AB - PURPOSE: Reinforcement of the abdominal wall with alloplastic mesh material in incisional hernia repair is well established. To avoid dislocation and migration of the prostheses, mesh fixation is recommended. However, there seems to be a correlation between postoperative pain and mesh fixation. Furthermore, it remains unclear whether mesh fixation is necessary at all. METHODS: A retromuscular mesh implantation was performed in 36 pigs using a polypropylene-polyglecaprone 25 composite mesh (Ultrapro((r)), 12 * 18 cm). In group 1, the mesh was fixed to the posterior rectus sheet with non absorbable single sutures (Prolene((r)) 2-0), in group 2 fixation was with absorbable sutures (Vicryl((r)) 2-0), in group 3 mesh fixation was with 5 ml fibrin sealant (Quixil((r))), and, as a control, there was no fixation in group 4. The abdominal wall was explanted on postoperative day 7, 14 and 56. Mesh size and position was measured, and pull-out force of the mesh was analysed mechanically by tensiometry. The ratio of collagen type I/III was analysed to determine the quality of mesh integration. RESULTS: Neither mesh dislocation nor mesh migration was detected. Mesh size showed no significant differences, whether comparing time points or groups. No significant differences in the tensile strength of mesh integration were found when comparing the groups (group 1: 155 +/- 17 mmHg; group 2: 175 +/- 9 mmHg; group 3: 166 +/- 24 mmHg; group 4: 172 +/- 28 mmHg). Though the type I/III collagen ratio increased over time, no significant differences according to the type of fixation used were detected. CONCLUSION: Mesh fixation in open incisional hernia repair with retromuscular mesh augmentation to avoid mesh dislocation or migration in the early postoperative period appears to be unnecessary. PMID- 20835909 TI - The effects of polypropylene mesh on femoral artery and femoral vein in mesh repair. AB - PURPOSE: Since the first description, the use of polypropylene mesh in hernia repair has gained wide acceptance. The aim of this study was to assess whether polypropylene mesh implantation has any effects on femoral blood vessels. METHODS: A 0.5 * 1.0 cm polypropylene mesh was inserted into the rat femoral artery and vein on the right side. After 14, 28 and 90 days, the rats were reoperated. The meshes were excised for histological processing. Blood flow in the dorsum of the foot skin, femoral artery and vein were measured in all groups before mesh implantation and at 14, 28, and 90 days after mesh implantation. RESULTS: Following placement of mesh graft on vascular structures, inflammation and fibrosis developed to a varying degree depending on the time elapsed. On the other hand, fibrosis did not change the histological structure of vessels. There was a decrease in both arterial and venous circulation due to the pressure of the graft. CONCLUSIONS: These data suggest that fibrosis due to mesh graft can negatively affect blood flow in vessels due to mechanical pressure. PMID- 20835910 TI - Protection of normal brain cells from gamma-irradiation-induced apoptosis by a mitochondria-targeted triphenyl-phosphonium-nitroxide: a possible utility in glioblastoma therapy. AB - Glioblastoma multiforme is the most frequent and aggressive primary brain tumor. A strong rationale to identify innovative approaches to treat these tumors is required since treatment failures result in local recurrences and median survivals range from 9 to 12 months. Glioma cells are reported to have less mitochondrial content compared to adjacent normal brain cells. Based on this difference, we suggest a new strategy, utilizing protection of normal brain cells by mitochondria-targeted electron scavengers and antioxidants-nitroxides-thus allowing for the escalation of the radiation doses. In this paper, we report that a conjugate of nitroxide with a hydrophobic cation, triphenyl-phosphonium (TPEY Tempo), significantly protected brain endothelial cells from gamma-irradiation induced apoptosis while radiosensitizing brain tumor cells. Thus, TPEY-Tempo may be a promising adjunct in the treatment of glioblastoma with the potential to not only prolong survival but also to maintain quality of life and reduce treatment toxicity. PMID- 20835911 TI - A role for Gcn5 in cardiomyocyte differentiation of rat mesenchymal stem cells. AB - MSCs possess the capacity of self-renewal and potential of differentiation into various kinds of specialized tissue cells including myocardiocytes. From self renewing to oriented differentiation, chromatin is remodeled into heritable states that allow activation or maintain the repression of regulatory genes, which means specific genes in self-renewing switched off and specific genes in oriented differentiation activated (Bernstein et al. Cell 125:315-326, 2006). These epigenetic states are established and controlled largely by specific patterns of histone posttranslational modifications, in particular, histone acetylation (Li Nat Rev Genet 3:662-673, 2002). In cardiomyocyte differentiation of rat MSCs, we focused on Gcn5, which linked a known transcriptional coactivator with catalytic histone acetyltransferase activity (Brownell et al. Cell 84:843 851, 1996). To clarify participatory in vivo role of Gcn5, using an RNA interference (RNAi) strategy employing shRNA to specifically knockdown Gcn5 expression in MSCs, we found that HAT activity altered dynamically depended on the inhibition of Gcn5 during MSCs differentiation. Chromatin immunoprecipitation (ChIP) assay showed the increased binding of acetyl histone H3 to the early cardiomyocyte-specific genes GATA4 and NKx2.5 promoters in cardiomyocyte differentiation of MSCs by 5-azacytidine inducing, whereas the decreased binding with lower Gcn5 expression. Cell ultrastructure analysis revealed that MSCs induced by 5-azacytidine possess morphological characteristics of cardiomyocyte cells. The shape of MSCs transfected by Gcn5 RNAi was similar to normal MSCs, but the chromatin showed heavy electron-density and a hard-packed structure. This intermediate state of chromatin may be an inactive part of MSCs differentiation. These results demonstrate that Gcn5, possessing acetyltransferase activity, is involved in regulating chromatin configuration around GATA4 and NKx2.5 in cardiomyocyte differentiation of rat MSCs by changing the level of histone acetylation. HAT activity depending on Gcn5 is important in differentiation of MSCs into cardiomyocytes as a consequence of the remodeling of the chromatin configuration caused by modification of histone H3. PMID- 20835912 TI - Environment and farm factors associated with exposure to Theileria parva infection in cattle under traditional mixed farming system in Mbeere District, Kenya. AB - The objective of this study was to investigate the relationship between seroprevalence to Theileria parva infection in cattle and potential environmental and farm-level effects in 80 farms under traditional crop-livestock system in Mbeere District, Kenya. A standardized questionnaire was used to collect the effects characteristics as related to T. parva infection epidemiology. Serum samples were collected from 440 cattle of all ages for detection of T. parva antibodies by the enzyme-linked immunosorbent assay technique. The association between the variables was assessed using a generalized estimation equation logistic regression model. The overall T. parva seroprevalence, accounting for correlation of responses, was 19.3% (95% confidence interval (CI) 14%, 25%). Two variables, "administrative division" and "presence of the vector tick on the farm", were significantly associated with the T. parva seroresponse. Respectively, cattle from farms in Gachoka, Evurore, and Mwea divisions were (and their 95% CI) 1.3 (0.36, 4.8), 4.4 (1.2, 15.9), and 15.2 (4.9, 47.1) times more likely to be seropositive relative to those from Siakago Division (P = 0.000). Cattle from farms in which the vector tick was present were 2.9 (1.2, 6.7) times more likely to be seropositive (P = 0.011). Results of this study suggested that both environmental and farm factors may be associated with T. parva infection epidemiology in Mbeere District. Under such circumstances, characterization of environmental suitability for the vector tick and corresponding environment specific farm management practices in the district is required both for improved understanding of the disease and in planning disease control programs. PMID- 20835913 TI - Genetic diversity of Cercospora kikuchii isolates from soybean cultured in Argentina as revealed by molecular markers and cercosporin production. AB - Leaf blight and purple seed, caused by the fungal pathogen Cercospora kikuchii (Matsumoto & Tomoyasu) M. W. Gardner are very important diseases of soybean (Glycine max L. Merr.) in Argentina. The aims of this work were: (a) to confirm and to assess the genetic variability among C. kikuchii isolates collected from different soybean growing areas in Santa Fe province using inter simple sequence repeats (ISSR) markers and sequence information from the internal transcribed spacer (ITS) region of rDNA and (b) to analyze the cercosporin production of the regional C. kikuchi isolates in order to assess whether there was any relationship between the molecular profiles and the toxin production. Isolates from different regions in Santa Fe province were studied. The sequence of the ITS regions showed high similarity (99-100%) to the GenBank sequences of C. kikuchii BRCK179 (accession number AY633838). The ISSR markers clustered all the isolates into many groups and cercosporin content was highly variable among isolates. No relationship was observed between ITS region, ISSR groups and origin or cercosporin content. The high degree of genetic variability and cercosporin production among isolates compared in this study characterizes a diverse population of C. kikuchii in the region. PMID- 20835914 TI - Evaluation of the origin of a sample of Sporothrix schenckii that caused contamination of a researcher in Southern Brazil. AB - We report a case of a researcher from a laboratory of Mycology in Rio Grande do Sul, Brazil that presented a clinical evidence of sporotrichosis. The researcher had an accident while manipulating the microculture slides of chromoblastomycosis agents and presented a clinical evidence of sporotrichosis. As the laboratory has some cultures of Sporothrix schenckii, it was suggested that it might be a laboratory contamination. In order to test this hypothesis, the genotypic characterization of the samples was performed by means of the random amplified polymorphic DNA (RAPD) analysis method. In addition, we evaluated the in vitro antifungal activity of four antifungal agents against the isolated fungus. The sample obtained from the researcher was not genetically similar to any of the samples kept in the laboratory and showed the minimum inhibitory concentrations of 0.5 MUg/mL for itraconazole and ketoconazole, > 64 MUg/mL for fluconazole and 0.125 MUg/mL for terbinafine. It is suggested that the contamination had an environmental origin. PMID- 20835915 TI - Extraction of bovine serum albumin using reverse micelles formed by hexadecyl trimethyl ammonium chloride. AB - The extraction of bovine serum albumin (BSA) has been investigated using reverse micelles of hexadecyl trimethyl ammonium chloride/n-octanol/isooctane. Forward extraction process parameters such as the surfactant concentration, co-solvent concentration, pH, ionic strength, and species of the initial aqueous phase were important factors affecting the extraction performance. These parameters were varied to optimize the extraction efficiency. Under the optimized conditions, forward extraction efficiencies of BSA can reach practically 99.55%. The thermodynamic study revealed that the extraction of BSA is controlled by entropy changes. Maximum back-extraction efficiency of 85.16% can be obtained at low pH values and high salt concentrations. The structures of BSA during reverse micelle extraction did not change by comparing the circular dichroism spectra of BSA back extracted to the aqueous phase with that of feed BSA. PMID- 20835917 TI - Glucagon-like peptide-1 (GLP-1) receptors are not overexpressed in pancreatic islets from patients with severe hyperinsulinaemic hypoglycaemia following gastric bypass. AB - AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) receptors are highly overexpressed in benign insulinomas, permitting in vivo tumour visualisation with GLP-1 receptor scanning. The present study sought to evaluate the GLP-1 receptor status in vitro in other pancreatic disorders leading to hyperinsulinaemic hypoglycaemia, specifically after gastric bypass surgery. METHODS: Fresh frozen pancreatic tissue samples (n=7) from six gastric bypass surgery patients suffering from hyperinsulinaemic hypoglycaemia were evaluated for GLP-1 receptor content using in vitro receptor autoradiography, and compared with normal pancreas and with pancreatic insulinoma tissues. RESULTS: GLP-1 receptor analysis of the pancreatic tissues, which histopathologically were compatible with nesidioblastosis and originated from post-bypass hypoglycaemic patients, revealed a mean density value of GLP-1 receptors in the islets of 1,483 +/- 183 dpm/mg tissue. Pharmacological characterisation indicated the presence of specific GLP-1 receptors. The density of islet GLP-1 receptor in post-gastric bypass patients did not differ from that of normal pancreas (1,563 +/- 104 dpm/mg tissue, n = 10). Receptor density in pancreatic acini was low in post-bypass and control conditions. In contrast, benign insulinomas showed a high density of GLP-1 receptors, with a mean value of 8,302 +/- 1,073 dpm/mg tissue (n = 6). CONCLUSIONS/INTERPRETATION: In contrast to insulinoma, hyperinsulinaemic hypoglycaemia after gastric bypass surgery is not accompanied by overexpression of GLP-1 receptor in individual islets. Thus, patients with post-gastric bypass hyperinsulinaemic hypoglycaemia are not candidates for GLP-1 receptor imaging in vivo using radiolabelled exendin. These GLP-1 receptor data support the notion that the islet pathobiology of post-gastric bypass hypoglycaemia is distinctly different from that of benign insulinomas. PMID- 20835916 TI - Mitochondrial fission and fusion and their roles in the heart. AB - Mitochondria are dynamic organelles that usually exist in extensive and interconnected networks that undergo constant remodeling through fission and fusion. These processes are governed by distinct sets of proteins whose mechanism and regulation we are only beginning to fully understand. Early studies on mitochondrial dynamics were performed in yeast and simple mammalian cell culture models that allowed easy visualization of these intricate networks. Equipped with this core understanding, the field is now expanding into more complex systems. Cardiac cells are a particularly interesting example because they have unique energetic and spatial demands that make the study of their mitochondria both challenging and potentially very fruitful. This review will provide an overview of mitochondrial fission and fusion as well as recent developments in the understanding of these processes in the heart. PMID- 20835918 TI - Life history of Proctolaelaps bulbosus feeding on the coconut mite Aceria guerreronis and other possible food types occurring on coconut fruits. AB - Aceria guerreronis Keifer (Acari: Eriophyidae) is a major pest of coconut fruits (Cocos nucifera L.) in many countries of the Americas, Africa, and parts of Asia. Considerable attention has been given to studies of biological control agents of A. guerreronis. Proctolaelaps bulbosus Moraes, Reis and Gondim Jr. is a predator recently discovered in association with A. guerreronis. Nothing is known about its biology. The aim of this study was to determine suitable food sources for P. bulbosus, among items commonly found on coconut fruits, including A. guerreronis. Food sources evaluated included the mites A. guerreronis, Steneotarsonemus concavuscutum Lofego and Gondim Jr., and Tyrophagus putrescentiae (Schrank), the fungus Rhizopus aff. stolonifer (Ehrenb.) Vuill and coconut pollen; the mite Tetranychus urticae Koch was also included in the assessments, for being a commonly used prey for mass production and laboratory rearing of predatory mites. Proctolaelaps bulbosus was able to develop up to adulthood when fed A. guerreronis, R. aff. stolonifer and T. putrescentiae. It had the highest population growth rates when feeding on the former (R (o) = 17.5; r (m) = 0.392). These results indicate that A. guerreronis is the most suitable food for P. bulbosus among the possible food sources found on coconut fruits and that P. bulbosus can survive in the absence of eriophyid using R. aff. stolonifer as a food source. PMID- 20835919 TI - Family and cultural correlates of Mexican-origin youths' sexual intentions. AB - Understanding how culture and familial relationships are related to Mexican origin youths' normative sexual development is important. Using cultural ecological, sexual scripting, and risk and resilience perspectives, the associations between parent-adolescent relationship characteristics, adolescents' cultural orientations and familism values, and sexual intentions among 246 Mexican-origin adolescents (50% female) were investigated. Regression analyses were conducted to examine the connections between youths' cultural orientations and familism values and their intentions to engage in sexual intercourse and to test the moderating role of parent-adolescent relationship characteristics and adolescent sex. For boys, under conditions of high maternal acceptance, higher Anglo orientations and higher Mexican orientations were related to greater sexual intentions. For girls, familism values played a protective role and were related to fewer sexual intentions when girls spent less time with their parents. The findings highlight the complex nature of relationships between culture, family relationships, and youths' sexual intentions and different patterns for girls versus boys. PMID- 20835920 TI - Assessment of water quality using cluster analysis in coastal region of Mumbai, India. AB - The coastal water quality of Mumbai is deteriorating due to various point and non point wastewater sources. Hence, it is desirable to monitor coastal water quality for various water-related activities like bathing, contact water sports, recreation, and commercial fishing. The objective of this paper is to assess the seasonal water quality on the basis of seawater standards. Based on water-quality analysis of 17 seafronts and beaches, most of the parameters were exceeding the standards. The statistical cluster analysis was carried out for evaluating impact of wastewater and sewage discharges. The hierarchical cluster analysis resulted into three clustered groups, namely less polluted, moderately polluted, and highly polluted sites with similar characteristics of water quality. Mahim was found to be worst-affected beach due to incoming organic load from the Mithi river in comparison to other seafronts and beaches. Unaccounted sources of sewage and wastewater should be identified and rerouted through sewerage system by improving collection efficiency, treatment, and proper disposal for achieving designated receiving water quality standards. PMID- 20835921 TI - Variation and removal efficiency of assimilable organic carbon (AOC) in an advanced water treatment system. AB - This study investigates the microorganism growth indicator and determines the assimilable organic carbon (AOC) content at the Cheng-Ching Lake Advanced Water Treatment Plant (CCLAWTP) in Kaohsiung, Taiwan. Notably, AOC is associated with the biological stability within the water distribution network and has garnered considerable attention in the environmental engineering field in recent years. Water samples were collected from the effluent of each unit in CCLAWTP once monthly during December 2008 to November 2009. Items of water quality related to carbon concentration levels, including AOC, total organic carbon, dissolved organic carbon, UV(254), and specific ultraviolent absorbance were analyzed. Analytical results demonstrate that the average AOC concentration in raw water was 83.61 MUg/L and reduced in freshwater was controlled at an average of 50 MUg/L after an advanced treatment system of roughly 54% of AOC was removed in compliance with treatment plant standards. If AOC concentrations in freshwater can be reduced, study results can provide a direction for improving water treatment capabilities. PMID- 20835922 TI - Trophic state index of a lake system using IRS (P6-LISS III) satellite imagery. AB - Water pollution has now become a major threat to the existence of living beings and water quality monitoring is an effective step towards the restoration of water quality. Lakes are versatile ecosystems and their eutrophication is a serious problem. Carlson Trophic State Index (CTSI) provides an insight into the trophic condition of a lake. CTSI has been modified for the study area and is used in this study. Satellite imagery analysis now plays a prominent role in the quick assessment of water quality in a vast area. This study is an attempt to assess the trophic state index based on secchi disk depth and chlorophyll a of a lake system (Akkulam-Veli lake, Kerala, India) using Indian Remote Sensing (IRS) P6 LISS III imagery. Field data were collected on the date of the overpass of the satellite. Multiple regression equation is found to yield superior results than the simple regression equations using spectral ratios and radiance from the individual bands, for the prediction of trophic state index from satellite imagery. The trophic state index based on secchi disk depth, derived from the satellite imagery, provides an accurate prediction of the trophic status of the lake. IRS P6-LISS III imagery can be effectively used for the assessment of the trophic condition of a lake system. PMID- 20835923 TI - Expression of artificial microRNAs in tomato confers efficient and stable virus resistance in a cell-autonomous manner. AB - Expression of artificial microRNAs (amiRNAs) in plants can target and degrade the invading viral RNA, consequently conferring virus resistance. Two amiRNAs, targeting the coding sequence shared by the 2a and 2b genes and the highly conserved 3' untranslated region (UTR) of Cucumber mosaic virus (CMV), respectively, were generated and introduced into the susceptible tomato. The transgenic tomato plants expressing amiRNAs displayed effective resistance to CMV infection and CMV mixed with non-targeted viruses, including tobacco mosaic virus and tomato yellow leaf curl virus. A series of grafting assays indicate scions originated from the transgenic tomato plant maintain stable resistance to CMV infection after grafted onto a CMV-infected rootstock. However, the grafting assay also suggests that the amiRNA-mediated resistance acts in a cell-autonomous manner and the amiRNA signal cannot be transmitted over long distances through the vascular system. Moreover, transgenic plants expressing amiRNA targeting the 2a and 2b viral genes displayed slightly more effective to repress CMV RNA accumulation than transgenic plants expressing amiRNA targeting the 3' UTR of viral genome did. Our work provides new evidence of the use of amiRNAs as an effective approach to engineer viral resistance in the tomato and possibly in other crops. PMID- 20835924 TI - Physical activity after surgery for severe obesity: the role of exercise cognitions. AB - BACKGROUND: Physical activity after bariatric surgery is associated with sustained weight loss and improved quality of life. Some bariatric patients engage insufficiently in physical activity. This may be due to exercise cognitions, i.e., specific beliefs about benefits of and barriers to physical exercise. The aim of this study was to examine whether and to what extent both physical activity and exercise cognitions changed at 1 and 2 years post-surgery and whether exercise cognitions predict physical activity. METHODS: Forty-two bariatric patients (38 women, 4 men; mean age 38 +/- 8 years, mean body mass index prior to surgery 47 +/- 6 kg/m(2)) filled out self-report instruments to examine physical activity and exercise cognitions pre- and post-surgery. RESULTS: A large increase in physical activity and favorable changes in exercise cognitions were observed after surgery, viz. a decrease of fear of injury and embarrassment and an increase of the perception of exercise benefits and confidence in exercising. Perceiving less exercise benefits and having less confidence in exercising before surgery predicted less physical activity 2 years after surgery. High fear of injury 1 year after surgery predicted less physical activity 2 years after surgery. CONCLUSIONS: After bariatric surgery, favorable changes in physical activity and beliefs about the benefits and barriers of exercising are observed. Our results suggest that targeting exercise cognitions before and after surgery might be relevant to improve physical activity. PMID- 20835925 TI - Management strategies for locoregional recurrence in early-stage gastric cancer: retrospective analysis and comprehensive literature review. AB - OBJECTIVE: To present a comprehensive account and literature review addressing the anatomical distribution, natural history, and management strategies for locoregional recurrence in early-stage gastric cancer (EGC). PATIENTS AND METHODS: Retrospective chart review of patients presenting with EGC recurrence at King Hussein Cancer Center (Amman, Jordan) between July 2006 and May 2009. A literature review of publications addressing recurrence following surgery for EGC was undertaken via a systematic search of PUBMED database and National Comprehensive Cancer Network (NCCN) guideline updates. RESULTS: Seventeen patients presented with EGC, three of whom (17.6%) were pathologically staged as T2N1 [1/33 lymph nodes (LNs)], T1N0, and T1N0 were afflicted by recurrence following R0 partial gastrectomy. Literature review yielded 18 studies specifically addressing recurrence in EGC. Several management strategies have been proposed for isolated recurrence following gastrectomy in EGC. NCCN clinical practice guideline updates do not take into consideration whether the recurrence is isolated or widespread and whether the initial stage is early or advanced. CONCLUSIONS: While acknowledging the limitations of this study, including the small sample size and the short follow-up period, it appears clear that oncologic treatment is possible for EGC recurrence, particularly, in patients with isolated relapse. Guideline updates should differentiate between management strategies suitable for recurrence occurring in early versus advanced initial cancer stage. PMID- 20835926 TI - Palliative stenting with or without radiotherapy for inoperable esophageal carcinoma: a randomized trial. AB - BACKGROUND: A majority of patients with esophageal cancer present with inoperable disease and require rapid and long-lasting palliation of dysphagia. STUDY AIM: To compare the duration of relief of dysphagia in patients with inoperable esophageal cancer treated with esophageal stenting alone or a combination of esophageal stenting and external beam radiotherapy (EBRT), and to assess overall survival, treatment-related complications, and quality of life (QOL) in the two groups. PATIENTS AND METHODS: Patients with inoperable esophageal cancer and with high grade dysphagia were randomized to receive esophageal stenting with self expandable metal stent (Ultraflex) alone (Group I), versus a combination of stenting followed by EBRT (30 gray in ten divided fractions over 2 weeks) (Group II). Dysphagia relief, overall survival, QOL (using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, version 3), and treatment-related complications were assessed in the two groups. RESULTS: From April 2007 to March 2009, 84 patients were randomized to receive esophageal stent alone (42 patients) or a combination of stent and EBRT (42 patients). The two groups were comparable in demographics, tumor characteristics, indications for palliative treatment, and pretreatment dysphagia score. Dysphagia scores improved significantly in both groups following stent insertion. However, dysphagia relief was more sustained in Group II than in Group I (7 vs. 3 months, p = 0.002). Overall median survival was significantly higher in Group II than in Group I (180 vs. 120 days, p = 0.009). Addition of radiotherapy following stenting prolonged the mean dysphagia-free survival (118.6 +/- 55.8 vs. 96.8 +/- 43.0 days, p = 0.054). There was significant improvement in all QOL parameters at 1 week after stenting. The QOL, however, significantly declined immediately after radiotherapy. There was no treatment-related mortality, and the incidence of complications was similar in the two groups. CONCLUSION: Post-stenting EBRT effectively prolongs duration of dysphagia relief and improves overall survival in inoperable esophageal cancer. PMID- 20835927 TI - Ethics consultation on a gynecologic oncology service: an opportunity for physician education. AB - The purpose of this study is to understand the features of gynecologic oncology patients who receive ethics consults in order to identify areas for physician education and improve patient care. A review of ethics consults for gynecologic oncology patients from 1993 to 2008 was performed. Information on all gynecologic oncology patients treated during the study interval was also collected to define a base population for comparison. Forty-one consults were performed. Compared to the base population, a greater proportion of consult patients had pregnancy related malignancies (7.9% vs. 0.8%, p < 0.0001) and were African American (33.3% vs. 10.9%, p < 0.0001). The most common clinical case types involved identifying levels of appropriate treatment. Support of the health care team and complex family dynamics were key underlying issues. Ethics consultation provides a substantial resource in identifying relevant issues experienced by gynecologic oncology patients upon which physician educational initiatives may be based. PMID- 20835928 TI - Tamoxifen reverses the multi-drug-resistance of an established human cholangiocarcinoma cell line in combined chemotherapeutics. AB - Our previous study established the human multi-drug-resistant cholangiocarcinoma cell line QBC939/ADM. In this study, we investigate further the ability of tamoxifen (TAM) to reverse drug-resistance to chemotherapeutics using QBC939/ADM cells. Cell growth inhibition was determined by the MTT assay, while cell cycle progression, apoptosis and the intra-cellular concentration of adriamycin (ADM) were all determined by flow cytometry. P-glycoprotein (P-gp) protein and mRNA expression was determined by Western blotting and real-time PCR. Growth inhibition and apoptosis induced by ADM, mitomycin (MMC), or vindesine (VDS) were enhanced after pre-treatment with 5 or 10 MUM TAM, while only VDS increased cell numbers in the G(2)/M phase. The intra-cellular concentration of ADM rose after pre-treatment with 10 MUM TAM, but not 5 MUM TAM. Furthermore, real-time PCR and western blot analysis revealed down-regulation of P-gp expression in QBC939/ADM cells after TAM pre-treatment. The enhanced effects of TAM on growth inhibition, apoptosis, and intra-cellular concentration and the down-regulation of P-gp expression were blocked by an anti-P-gp antibody. TAM (10 MUM) may reverse the multi-drug-resistance (MDR) of QBC939/ADM and enhance the chemotherapeutic effects on cholangiocarcinoma, by competitively inhibiting over-expressed P-gp. PMID- 20835929 TI - Neuro-ophthalmologic complications and manifestations of upper and lower motor neuron facial paresis. AB - The facial nerve (cranial nerve VII) courses a long pathway beginning in the precentral gyrus and ending at the facial muscles, lacrimal and salivary glands, and structures of the inner ear. Lesions along this pathway, clinically divided into upper and lower motor neuron lesions, present with unique characteristics that assist the physician in identifying the lesion site. The sequelae particularly of peripheral CN VII palsies, may result in significant and chronic damage to the cornea that may be challenging for the physician and patient. PMID- 20835930 TI - Electrochemical and microbiological characterization of paper mill biofilms. AB - Biofilm samples collected from inside and outside the press and former sections of paper machines in a Northwestern Ontario paper mill for a period of 2 years were characterized microbiologically and electrochemically. Bacterial community profiling was done using polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and selected bacterial isolates were identified using 16S rDNA analysis. The bacterial community showed the presence of Proteobacteria, Firmicutes, and Actinobacteria. Sphingomonas sp. was found to be the most common bacterial species, which showed the highest production of extracellular polymeric substances. Bacteria isolated from biofilms showed better adhesion properties than those from water samples. Cyclic voltammetry and electrochemical impedance spectroscopy studies showed that bacteria isolated from biofilms and feed water collected from inside the machine were more easily oxidized than those from outside, suggesting the need for a more rigorous biofilm abatement strategy for inside paper machines. PMID- 20835931 TI - Sessile Legionella pneumophila is able to grow on surfaces and generate structured monospecies biofilms. AB - Currently, models for studying Legionella pneumophila biofilm formation rely on multi-species biofilms with low reproducibility or on growth in rich medium, where planktonic growth is unavoidable. The present study describes a new medium adapted to the growth of L. pneumophila monospecies biofilms in vitro. A microplate model was used to test several media. After incubation for 6 days in a specific biofilm broth not supporting planktonic growth, biofilms consisted of 5.36 +/- 0.40 log (cfu cm(-2)) or 5.34 +/- 0.33 log (gu cm(-2)). The adhered population remained stable for up to 3 weeks after initial inoculation. In situ confocal microscope observations revealed a typical biofilm structure, comprising cell clusters ranging up to approximately 300 MUm in height. This model is adapted to growing monospecies L. pneumophila biofilms that are structurally different from biofilms formed in a rich medium. High reproducibility and the absence of other microbial species make this model useful for studying genes involved in biofilm formation. PMID- 20835932 TI - Associated impairment of the categories of conspecifics and biological entities: cognitive and neuroanatomical aspects of a new case. AB - Case A.C.A. presented an associated impairment of visual recognition and semantic knowledge for celebrities and biological objects. This case was relevant for (a) the neuroanatomical correlations, and (b) the relationship between visual recognition and semantics within the biological domain and the conspecifics domain. A.C.A. was not affected by anterior temporal damage. Her bilateral vascular lesions were localized on the medial and inferior temporal gyrus on the right and on the intermediate fusiform gyrus on the left, without concomitant lesions of the parahippocampal gyrus or posterior fusiform. Data analysis was based on a novel methodology developed to estimate the rate of stored items in the visual structural description system (SDS) or in the face recognition unit. For each biological object, no particular correlation was found between the visual information accessed through the semantic system and that tapped by the picture reality judgement. Findings are discussed with reference to whether a putative resource commonality is likely between biological objects and conspecifics, and whether or not either category may depend on an exclusive neural substrate. PMID- 20835933 TI - Estimation of selenium intake in Switzerland in relation to selected food groups. AB - The selenium concentration in foods was analysed in order to identify principal sources of this trace element in Switzerland. Selenium intake estimations based on three different approaches were carried out. From the relationship between intake and serum/plasma concentration, the selenium intake was estimated to 66 ug day(-1). The second approach based on measured food groups combined with consumption statistics; and the third approach consisted of duplicate meal samples. With the last two methods, over 75% of the serum/plasma based intake was confirmed. Swiss pasta made of North American durum wheat was the food with the highest contribution to the dietary intake, followed by meat. The strong decrease in imports of selenium-rich North American wheat of the last years was not reflected in the present intake estimations. It appears that this intake loss was compensated by a consumption increase of other foods. Compared with former intake estimations, selenium intake seems to be in Switzerland nearly constant for the last 25 years. PMID- 20835934 TI - Occurrence of ochratoxin A and citrinin in Czech cereals and comparison of two HPLC methods for ochratoxin A detection. AB - The aims of the study were to obtain information about the occurrence of ochratoxin A (OTA) and citrinin (CIT) in cereals harvested in the Czech Republic and to compare two analytical procedures for detecting OTA. A total of 34 cereal samples, including two matrix reference materials (R-Biopharm, Germany), were analysed. The results were compared with the limit for raw cereal grains used as a foodstuff according to Commission Regulation No. 1881/2006, which allows a maximum OTA level of 5 ug kg(-1). Compared were two methods based on the high performance liquid chromatography principle, one using the immunoaffinity columns OchraTest (VICAM) and the second based on solvent partition (PART), both followed by fluorescence detection. The highest OTA contents were found in two barley samples. According to the method employed, the results for the first sample (malting barley) were VICAM = 31.43 ug kg(-1) and PART = 44.74 ug kg(-1). For the second sample (feeding barley) they were VICAM = 48.63 ug kg(-1) and PART = 34.40 ug kg(-1). Two samples of bread wheat had an OTA content approaching the legal limit (VICAM = 4.71 ug kg(-1) and PART = 6.03 ug kg(-1); VICAM = 4.12 ug kg(-1) and PART = 3.95 ug kg(-1)). CIT was analysed using the PART method only, and its highest content (93.64 ug kg(-1)) was found for the malting barley sample with high OTA content (44.74 ug kg(-1) as analysed using PART). PMID- 20835935 TI - Simple intervention method to reduce fumonisin exposure in a subsistence maize farming community in South Africa. AB - In the Centane magisterial area of South Africa, high rates of oesophageal cancer have been associated with home-grown maize contaminated with fumonisins. The aim of this study was to implement a simple intervention method to reduce fumonisin exposure in a subsistence-farming community. The hand-sorting and washing procedures, based on traditional maize-based food preparation practices, were previously customised under laboratory-controlled conditions. Home-grown maize and maize-based porridge collected at baseline were analysed for fumonisin B(1), B(2) and B(3). The geometric mean (95% confidence interval) of fumonisin contamination in the home-grown maize at baseline was 1.67 (1.21-2.32) mg kg(-1) and 1.24 (0.75-2.04) mg kg(-1) (dry weight) in the porridge. Fumonisin exposure was based on individual stiff porridge consumption and the specific fumonisin levels in the porridge (dry weight) consumed. Porridge (dry weight) consumption at baseline was 0.34 kg day(-1) and fumonisin exposure was 6.73 (3.90-11.6) ug kg(-1) body weight day(-1). Female participants (n = 22) were trained to recognise and remove visibly infected/damaged kernels and to wash the remaining maize kernels. The discarded kernels represented 3.9% by weight and the fumonisins varied from 17.1 to 76.9 mg kg(-1). The customised hand-sorting and washing procedures reduced fumonisin contamination in the maize and porridge by 84 and 65%, respectively. The intervention reduced fumonisin exposure by 62% to 2.55 (1.94-3.35) ug kg(-1) body weight day(-1). This simple intervention method has the potential to improve food safety and health in subsistence-farming communities consuming fumonisin-contaminated maize as their staple diet. PMID- 20835937 TI - Consequences of compromised autonomy. PMID- 20835936 TI - Intake of bisphenol A from canned beverages and foods on the Belgian market. AB - Bisphenol A (BPA), a contaminant which may be present in the coating of cans, was determined in 45 canned beverages and 21 canned food items from the Belgian market. Beverages had an average BPA concentration of 1.0 ng/ml, while canned foods had a higher average concentration of 40.3 ng/g. The amount of BPA present in food items was dependent on the type of can and sterilisation conditions rather than the type of food. For example, BPA was not detected in non-canned beverages (<0.02 ng/ml), while non-canned food items had a very low average concentration of 0.46 ng/g. Using detailed information from the Belgian food consumption survey, the BPA intake of adults through canned foods and beverages was estimated to be 1.05 ug/day or 0.015 ug/kg body weight/day (assuming an average adult weight of 70 kg). Intake assessments, based on urinary metabolite concentrations from the literature, resulted in slightly higher BPA intakes (range 0.028-0.059 ug/kg body weight/day). This suggests that sources other than canned foods and beverages contribute to BPA exposure in humans. PMID- 20835938 TI - As time goes by we improve a little more: relationship expectations of young women in Mexico. AB - In this qualitative narrative study I explore expectations regarding male-female relationships and perceptions about intimate partner violence (IPV) with young urban women in the state of Veracruz, Mexico. Carol Gilligan's work informed the analysis of the narratives. Themes identified follow: violence at home, resistance, and relational autonomy. The collective story these women tell is that they are familiar with violence in the home, they resist violence and gender inequality, they seek equality in intimate partner relationships, and they plan for futures where the centrality of family is valued in combination with a strong commitment to their own autonomy. PMID- 20835939 TI - Demographic risk factors in domestic violence among pregnant women in Uyo, a community in the Niger Delta region, Nigeria. AB - There has been increasing global concern about the level of violence against pregnant women. Anecdotal evidence from general observations shows that there may be higher prevalence in the Niger Delta region of Nigeria. Unfortunately, in spite of the emerging and alarming social indicators for violence against women in the area, little effort has been made to address this dangerous trend. One major concern has been the effects of violence on pregnancy and the difficulty in protecting the pregnant women, since managing violence is often unsuccessful. There is therefore the need to evaluate the magnitude, as well as the risk factors for violence and the sociodemographic characteristics of the women, for purposes of prevention. PMID- 20835940 TI - Weighing distress: decision-making surrounding management of the pregnancy experience among HIV-infected Thai women. AB - The researchers conducted this grounded theory study in order to describe the decision making surrounding management of the pregnancy experience of 38 pregnant, HIV-infected Thai women. Data were collected using in-depth interviews and an open-ended questionnaire, and they were analyzed using constant comparative analysis. We found that "weighing distress" was the core category of the decision-making process. The supporting categories were being ambivalent about continuing the pregnancy, exploring alternative options, and selecting the appropriate choice. Health care providers should encourage family members to participate and be involved in the women's decision-making processes. PMID- 20835941 TI - Living with stillborn babies as family members: Japanese women who experienced intrauterine fetal death after 28 weeks gestation. AB - My purpose in this qualitative research was to describe the meaning of fetal death in the lives of Japanese women in a local community by interviewing women who experienced intrauterine fetal death (IUFD) after 28 weeks of gestation in chronological order from the time they were told of the fetal death to the present day. The study included 17 women who had experienced fetal death and who raised the dead child through "the development process of becoming a parent" and "the grieving process after the loss of a child," comprising a year-long grieving process. PMID- 20835942 TI - Peripartum anesthesia in grand-grand multiparous women (>= 10 births). AB - Grand-grand multiparous (GGMP) women, that is women with >=10 births, appear less likely to receive epidural anesthesia for labor/delivery than non-GGMP women. Eighteen months' data were collected. 277/16,331 laboring females were GGMP (mean age: 39.6 +/- 3.3 years; mean: 11.3 +/- 1.5 births), 83/258 (32.2%) delivered vaginally with epidural anesthesia versus 7,203/15,711 (45.8%) non-GGMP with epidural anesthesia (p < .0051; Odds Ratio = 0.56). Among GGMP women, 23/42 cesarean sections (55%) were emergency versus 1,011/1,631 (62%) among non-GGMP women (Odds Ratio: 0.74). Mean birth weight of GGMP babies: 3,428 +/- 504 gms; mean Apgar (1'): 8.8; there were six sets of twins. Most GGMP women were healthy, but epidural anesthesia was used less frequently for labor/delivery than in non GGMP births. PMID- 20835943 TI - The relationship of two types of trauma exposure to current physical and psychological symptom distress in a community sample of Colombian women: why interpersonal violence deserves more attention. AB - Our purpose in this study was to examine the relationship between interpersonal violence and background traumas and symptom distress in a community sample of Colombian women (N = 217). We utilized the Life Stressor Checklist-Revised (LSC R) to measure lifetime interpersonal violence (IPV) and background trauma exposure and the Brief Symptom Inventory (BSI) to measure current symptom distress. Although both exposures were common in this sample, IPV was strongly correlated with current symptom distress; background traumas made no unique contribution to the variance in current symptom distress. Based on our findings, it is suggested that interpersonal events may be particularly distressing. PMID- 20835944 TI - Lexical access changes in patients with multiple sclerosis: a two-year follow-up study. AB - The aim of the study was to analyze lexical access strategies in patients with multiple sclerosis (MS) and their changes over time. We studied lexical access strategies during semantic and phonemic verbal fluency tests and also confrontation naming in a 2-year prospective cohort of 45 MS patients and 20 healthy controls. At baseline, switching lexical access strategy (both in semantic and in phonemic verbal fluency tests) and confrontation naming were significantly impaired in MS patients compared with controls. After 2 years follow-up, switching score decreased, and cluster size increased over time in semantic verbal fluency tasks, suggesting a failure in the retrieval of lexical information rather than an impairment of the lexical pool. In conclusion, these findings underline the significant presence of lexical access problems in patients with MS and could point out their key role in the alterations of high level communications abilities in MS. PMID- 20835945 TI - Noise exposure, characterization, and comparison of three football stadiums. AB - Personal noise exposure samples were collected from five workers at a large-sized college football stadium and five workers at a medium-sized college football stadium in northern Colorado during three home football games, for a total of 30 personal noise exposures. In addition, personal noise exposure samples were collected from five fans at a National Football League (NFL) stadium, and from two fans at each of the college stadiums during three home football games, for a total of 27 personal noise exposure samples. None of the workers' noise doses were above the Occupational Safety and Health Administration (OSHA) permissible exposure limit of 90 dBA. However, 11 of 28 (39%) workers' noise doses exceeded the OSHA action level of 85 dBA that would require enrollment in a hearing conservation program. Following ACGIH(r) recommendations for noise exposure limits, 27 of 28 (96%) workers would be considered overexposed. In addition, 24 of 25 fans (96%) were also overexposed according to ACGIH and World Health Organization recommendations. At the 95% confidence level, workers' and fans' noise exposures were not significantly different between the three stadiums. However, there was significant noise level variability between the games in each individual stadium (e.g., 82 dbA vs. 87 dbA mean worker OSHA noise exposure for two games at the large-sized college stadium, p=0.001). Given the personal sampling results for the stadium workers, the investigators believe that stadium management at these two universities should implement a hearing conservation program and provide hearing protection. Management should include a warning of possible loud-noise exposure during any sporting events held at the stadiums in fan guides, pamphlets, websites, or other appropriate communication tools. This information should include the health effects of loud noise exposure, namely, noise-induced hearing loss, the information should also be specifically targeted to parents of young children, including a strong recommendation that hearing protection be worn by all children during the sporting event. PMID- 20835946 TI - Effect of particle size on respiratory protection provided by two types of N95 respirators used in agricultural settings. AB - This study compared size-selective workplace protection factors (WPFs) of an N95 elastomeric respirator (ER) and an N95 filtering facepiece respirator (FFR) in agricultural environments. Twenty-five healthy farm workers ranging in age from 20 to 30 years voluntarily participated in this study. Altogether, eight farms were included representing three different types: two horse farms, three pig barns, and three grain handling sites. Subjects wore the ER and FFR while performing their daily activities, such as spreading hay, feeding livestock, and shoveling. Aerosol concentrations in an optical particle size range of 0.7-10 MUm were determined simultaneously inside and outside the respirator during the first and last 15 min of a 60-min experiment. For every subject, size-selective WPFs were calculated in 1-min intervals and averaged over 30 min. For the ER, geometric mean WPFs were 172, 321, 1013, 2097, and 2784 for particle diameters of 0.7-1.0, 1.0-2.0, 2.0-3.0, 3.0-5.0, and 5.0-10.0 MUm, respectively. Corresponding values for the FFR were 67, 124, 312, 909, and 2089. The 5th percentiles for the ER and FFR were higher than the assigned protection factor of 10 and varied from 28 to 250 and from 16 to 223, respectively. Results show that the N95 ER and FFR tested in the study provided an expected level of protection for workers on agricultural farms against particles ranging from 0.7 to 10 MUm. WPFs for the ER were higher than the FFR for all particle size ranges. WPFs for both respirator types increased with increasing particle size. PMID- 20835947 TI - Context-dependent effects of background colour in free recall with spatially grouped words. AB - Three experiments investigated context-dependent effects of background colour in free recall with groups of items. Undergraduates (N=113) intentionally studied 24 words presented in blocks of 6 on a computer screen with two different background colours. The two background colours were changed screen-by-screen randomly (random condition) or alternately (alternation condition) during the study period. A 30-second filled retention interval was imposed before an oral free recall test. A signal for free recall was presented throughout the test on one of the colour background screens presented at study. Recalled words were classified as same- or different-context words according to whether the background colours at study and test were the same or different. The random condition produced significant context-dependent effects, whereas the alternation condition showed no context-dependent effects, regardless of whether the words were presented once or twice. Furthermore, the words presented on the same screen were clustered in recall, whereas the words presented against the same background colour but on different screens were not clustered. The present results imply: (1) background colours can cue spatially massed words; (2) background colours act as temporally local context; and (3) predictability of the next background colour modulates the context-dependent effect. PMID- 20835948 TI - A new cytisine-type alkaloid from the stem bark of Maackia amurensis. AB - One new cytisine-type alkaloid, [(3-hydroxy-6-pyridinyl)-methyl]-cytisine (1), was isolated from the stem bark of Maackia amurensis, together with five known alkaloids: cytisine, N-formylcytisine, N-(3-oxobutyl)cytisine, (-)-epibaptifoline and N-methylcytisine. The structure of 1 was elucidated based on spectral methods (IR, CD, 1D and 2D NMR, HR-ESI-MS and EI-MS). PMID- 20835949 TI - New diterpenoids from the roots of Euphorbia ebracteolata Hayata. AB - Three new diterpenoids, ingenol-5beta,20-O,O-isopropylidene-3beta-palmitate, ingenol-5beta,20-O,O-isopropylidene-3beta-myristinate and 3beta,19-dihydroxy 1(10),15-rosadien-2-one, were isolated from the roots of Euphorbia ebracteolata Hayata. Their structures were deduced by spectroscopic means and analytic techniques. PMID- 20835950 TI - A new macrocyclic diterpenoid from Jatropha multifida. AB - A new diterpenoid, 15-epi-(4E)-jatrogrossidentadione acetate, along with several known constituents has been isolated from the stem of Jatropha multifida. The structure of the new compound was settled by a detailed analysis of its 1D- and 2D-NMR spectra. PMID- 20835951 TI - 5-Hydroxydictamnine, a new alkaloid from Atalantia monophylla. AB - A new furoquinoline alkaloid, 5-hydroxydictamnine, along with beta-sitosterol was isolated from the heartwood of Atalantia monophylla. The structure of this alkaloid was established by chemical and spectral evidences together with a nuclear overhauser effect (NOE) experiment. PMID- 20835952 TI - Isolation and identification of two steroid compounds from Oviductus Ranae. AB - In this study, cholest-5-en-3beta,7beta-diol and 3beta-hydroxy-cholest-5-en-7-one were isolated from Oviductus Ranae by column chromatographies on Sephadex LH-20, octadecylsilyl (ODS) and pre high-performance liquid chromatography (HPLC). Their structures were elucidated on the basis of chemical and spectral analyses, including electrospray ionisation-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR). The above two compounds were obtained from Oviductus Ranae for the first time. PMID- 20835953 TI - A new 3,4-seco-lupane-type triterpenoid from the pulp of Acanthopanax senticosus (Rupr. et Maxim) Harms. AB - A new triterpenoid, 3,4-seco-lupane-20(29)-ene-3,28-dioic acid, together with three known lignans, (-)-schisandrin B, (-)-sesamin and (-)-syringaresinol, was isolated from the pulp of Acanthopanax senticosus (Rupr. et Maxim) Harms. Their structures were elucidated by means of physicochemical properties and spectroscopic methods (1D, 2D-NMR and MS). PMID- 20835954 TI - Isolation of (-)(2S)-5,6,7,3',5'-pentahydroxyflavanone-7-O-beta-D glucopyranoside, from Lippia graveolens H.B.K. var. berlandieri Schauer, a new anti-inflammatory and cytotoxic flavanone. AB - A new flavanone glycoside, (-)(2S)-5,6,7,3',5'-pentahydroxyflavanone-7-O-beta-D glucopyranoside (1), was isolated from the stems of Lippia graveolens H.B.K. (Verbenaceae). The structure of 1 was elucidated based on spectral analysis and chemical transformations. The treatment of 1 with acetic anhydride and pyridine afforded the corresponding per-acetylated derivative 2, while an acid hydrolysis reaction of 1 afforded a 5,6,7,3',5'-pentahydroxy flavanone (3). Additionally, the anti-inflammatory and cytotoxic activities of 1, 2 and 3 were determined. PMID- 20835955 TI - Antioxidant potential and phenolic acid content of certain cucurbitaceous plants cultivated in Egypt. AB - Many species belonging to Cucurbitaceae family have long been regarded as food, medicinal plants, or both. Preliminary phytochemical screening of Citrullus colocynthis L., Cucumis sativus L. and Momordica charantia L. herbs showed the presence of phenolic compounds. Quantitative analysis of total phenolic compounds using Folin-Ciocalteu reagent revealed the presence of 50.87 mg GAE g(-1), 56.58 mg GAE g(-1) and 42.36 mg GAE g(-1) in C. colocynthis L., C. sativus L. and M. charantia L. herbs, respectively. HPLC analysis of phenolic content showed the presence of chlorogenic acid (16.3 mg per 100g dry sample and 27.7 mg per 100 g( 1) dry samples in C. colocynthis L. and C. sativus L., respectively) and gallic acid (26.7 mg per 100 g dry sample) as a major phenolic acids in M. charantia L. herb. The antioxidant activity of the herb of plants under investigation was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and total antioxidant capacity was determined in terms of GAE. This study showed that C. sativus L. is the most active antioxidant, followed by C. colocynthis L., while M. charantia L. has the least antioxidant activity. PMID- 20835956 TI - Influence of environmental factors on composition of phenolic antioxidants of Achillea collina Becker ex Rchb. AB - Effects of environmental growth conditions on the antioxidant capacity, total phenolic content and composition of Achillea collina Becker ex Rchb. were investigated. Methanol extracts and infusions obtained from leaves and inflorescences of plants cultivated in the Italian Alps at two different altitudes (600 and 1050 m a.s.l.) were evaluated. Infusions exhibited the highest antioxidant capacity (1/IC(50) values from 4.35 +/- 0.72 to 8.90 +/- 0.74), total phenolic content (from 31.39 +/- 4.92 to 49.36 +/- 5.70 mg gallic acid equivalents (GAE) g(-1) DW), chlorogenic acid (from 9.21 +/- 1.52 to 31.27 +/- 6.88 mg g(-1) DW), 3,5-di-O-caffeoylquinic acid (from 12.28 +/- 3.25 to 25.13 +/- 1.99 mg g(-1) DW) and 4,5-di-O-caffeoylquinic acid (from 7.38 +/- 1.01 to 12.78 +/- 2.61 mg g(-1) DW) content. Climate (as influenced by altitude) was shown to be the main environmental factor influencing yarrow composition and properties. Leaf extracts from the higher experimental site showed a 2-4-fold increase of chlorogenic acid level. Achillea collina can be considered as a very good source of bioactive phenolic compounds, and growing it at high altitude may constitute an effective way to significantly enhance its quality for both medicinal and nutritional uses. PMID- 20835957 TI - A novel microwave-assisted extraction for the isolation of andrographolide from Andrographis paniculata and its in vitro antioxidant activity. AB - Andrographis paniculata has a long history of use in traditional medicine and andrographolide is one of its potent compounds. In this study, a rapid isolation of andrographolide (colourless, bitter and crystalline diterpene lactone) was carried out by a newly developed microwave-assisted extraction. The extraction intensity, time and amount of solvent were optimised prior to this. The conventional heating method provided a 0.4452% yield of andrographolide and microwave heating at 210 W for 40 min provided a 0.589% yield. Compared to conventional extraction procedures, the results suggested that the proposed method was an effective alternative for the extraction of andrographolide. The isolated compounds were found to be the same by UV, HPTLC and 1H-NMR studies. The isolated andrographolide was tested for in vitro antioxidant activity, and showed a potent free radical scavenging activity. PMID- 20835958 TI - Screening of the constituents, antimicrobial and antioxidant activity of endemic Origanum hypericifolium O. Schwartz & P.H. Davis. AB - The chemical compositions, total phenol content, antioxidant and antimicrobial activities with oxidant status of the essential oil from an endemic Turkish species, Origanum hypericifolium, were investigated. Steam distillation (SD) was used to isolate the essential oils, and the chemical analyses were performed by gas chromatography-mass spectrometry (GC-MS). The antimicrobial activity was tested by agar disc diffusion method against Morganella morganii (clinic isolate), Micrococcus flavus (clinic isolate), Micrococcus luteus NRLL B-4375, Proteus vulgaris RSKK 96026, Escherichia coli ATCC 11230, Escherichia coli ATCC 25922, Yersinia enterecolitica RSKK 1501, Staphylococcus aureus ATCC 25923, S. aureus ATCC 25933, S. aureus ATCC 12598, S. aureus (clinic isolate), MRSA 1 (clinic isolate), MRSA 2 (clinic isolate), MRSA 3 (clinic isolate) and MRSA 4 (clinic isolate). The major compounds found in volatiles of O. hypericifolium were p-cymene, carvacrol and gamma-terpinene. Results showed that O. hypericifolium has the potential for being used in food and medicine because of its antioxidant and antibacterial activity. PMID- 20835959 TI - Polyketides from Eleutherine bulbosa. AB - Four new polyketides, (R)-4-hydroxyeleutherin, eleuthone, eleutherinol-8-O-beta-D glucoside and isoeleuthoside C (dihydroisoeleutherin-5-O-beta-D-gentiobioside) were isolated from the bulbs of Eleutherine bulbosa, to join eleutherin, isoeleutherin, eleutherinol, eleutherol, eleuthoside B (eleutherol-4-O-beta-D gentiobioside), eleuthoside C (dihydroeleutherin-5-O-beta-D-gentiobioside), hongconin (4-oxodihydroisoeleutherin) and elecanacin, which have already been isolated from the same plant. The structures of the new polyketides, based on oxydated cyclic systems, have been elucidated by chemical and spectroscopic methods. PMID- 20835960 TI - Looked after or overlooked? An exploratory investigation of the mental health issues of adolescents living in state care in Northern Ireland. AB - There is consistent evidence that the rate of emotional, social and behavioural problems found in children and adolescents in out-of-home placements or state care is substantially higher than that of children and adolescents living with their families. However, with a few small-scale studies as exceptions, to date there has been little research carried out into the mental health needs of adolescents living in state care in Northern Ireland. This study aimed to examine the mental health needs of young people aged between 10 and 15 years living in state care in Northern Ireland. Data were collected on 165 adolescents via an analysis of case file data, questionnaires and interviews with social workers. It was found that the 70.3% of the young people scored within the abnormal and borderline ranges of the Strengths and Difficulties Questionnaire (SDQ) total difficulties score indicating "high risk" for meeting the criteria for a psychiatric diagnosis. Over the course of 1 year living in state care, 10 of the 165 adolescents had attempted suicide and 14 had engaged in deliberate self-harm. Nevertheless, social workers still rated the vast majority (92%) of these young people's overall health as being "as good as", or "better than" other young people in their age. It is concluded that as this group of young people have significant contact with health and social services, potential opportunities exist to develop the therapeutic potential of the experience of being "looked after" in state care. They are a uniquely vulnerable group and their care and treatment may be considered as a minority rights issue which deserves a higher profile in the human rights agenda. PMID- 20835961 TI - Community views of inter-generational sex: findings from focus groups in Botswana, Namibia and Swaziland. AB - Inter-generational sex is an important driver of the AIDS epidemic in Southern Africa, contributing to the high incidence of HIV among young women. We conducted 12 focus group discussions with women aged 15-24 years and 11 with men aged 40-55 years in urban and rural locations in Botswana, Namibia and Swaziland. There was consensus that inter-generational sex is commonplace. The young women were clear they had sex with older men to get money and material goods. In urban sites, they spoke about requirements for a "modern" lifestyle and to keep up with their friends, but in rural sites they also said they needed money for school fees, food and household goods. Young women used disparaging names for the older men and they were well aware of the risk of HIV from inter-generational sex. They believed older men were more risky than younger men: They were more likely to be infected and it was harder to negotiate use of a condom with them. They were willing to take the risk to get what they wanted; some also had a fatalistic attitude. Older men described sexual motivation and blamed young women for seducing them. They believed there was a higher risk of HIV from younger women, because they have more partners and do not insist on using a condom. But this did not deter them from taking the risk. Older men and young women discount the risks of inter-generational sex against short-term benefits. Isolated efforts to increase risk awareness are unlikely to be effective. Making older men aware they are ridiculed by young women may be a promising approach, combined with interventions that give alternatives to young women and increase their self worth. PMID- 20835962 TI - Best practices in transitioning youth with HIV: perspectives of pediatric and adult infectious disease care providers. AB - Recently, national attention has been drawn to the increasing number of adolescents infected with HIV in the US, particularly in the South. According to the Center for Disease Control and Prevention (2007), at least 50% of new HIV infections occur in persons 15-25 years of age, and the majority of these persons are likely infected in their teens. Adolescents with HIV present new challenges to health and social-service providers. Infected teens are typically identified and initially followed by pediatricians and pediatric staff upon diagnosis. The transition to adult infectious disease care can be difficult due to the increased responsibility for self-care and monitoring placed on the young adult. Interviews were conducted with 19 professionals who provide care for children and adults with HIV in North Carolina in order to identify the best practices for transition to adult care. Approximately half of the providers self-identified as pediatric care providers. Nine of those interviewed were nurses and physicians and 10 were social workers. Interviews were transcribed and emergent themes were identified. Findings indicate that promoting medical independence among adolescents, close communication between pediatric and adult providers, and addressing system level concerns, including helping patients' families navigate health insurance and other social services, as well as having a separate clinic for adolescents with HIV, constitute best practices for transitioning youth with HIV from pediatric to adult care. PMID- 20835963 TI - Type A behavior pattern: a new insight to gender challenges in higher education. AB - The debate that Type A behavior pattern, characterized by a chronic struggle to achieve several goals and its resultant effect in triggering coronary heart disease is continuously ongoing. Contributing to this debate, this study examined the incidence of this behavior pattern among male and female postgraduate students. Two hundred eight postgraduate students (males 104, females=104) in the age range 25-50 (mean=20.18) years were randomly selected from the University of Lagos, Nigeria. Employing Type A Behavior Pattern Scale (TABS) it was observed that females obtained higher mean scores on Type A behavior and associated variables than the males (Females=54.98; Males=51.98 (TABS total score); hard driving (F=16.99, M=15.50); time urgency (F=20.32, M=19.05), and job pressure (F=17.76, M=16.56). A test for statistical significance with t-independent statistics revealed that scores of Type A Behavior Scale Total (TABT=2.36) as well as a sub-scale of Type A (hard driving=2.14) were significant at df, 207; p < 0.05, critical t=1.96. Implications of the result were discussed in line with obvious tilted gendered sphere, and the desire of the female gender for equity and psychological satisfaction. PMID- 20835964 TI - Help-seeking in relation to signs of dementia: a pilot study to evaluate the utility of the common-sense model of illness representations. AB - Despite the importance of early diagnosis of dementia, little is known about the factors underlying help-seeking in relation to signs of the condition. In this pilot study, we aimed to examine the potential utility of the common sense model (CSM) of illness representations for understanding lay perceptions of dementia and predicting intentions to seek help in relation to possible signs and symptoms. A secondary aim was to develop a measure of (dementia-related) illness representations as a tool for future research. After reading a vignette describing a "relative" with mild or moderate dementia, participants (N = 118) completed measures of illness representations and help-seeking intentions. Analyses compared perceptions of the mild and moderate vignettes and determined the extent to which illness perceptions differentiated between alternative forms of help-seeking (e.g. seeking professional help vs. help from family members). Results indicated that cognitive deficits were more readily identified as dementia than non-cognitive symptoms; these were commonly attributed to stress or depression. Participants were more likely to indicate an intention to seek professional help if they identified the problem in the vignette as dementia, perceived symptoms as severe, as having serious consequences and as likely to be permanent, but less likely to do so if they identified the problem as stress or attributed symptoms to psychological causes. Our preliminary data suggests that help-seeking may be prevented by inaccurate illness representations or misattribution of symptoms. The CSM may provide a useful framework for understanding perceptions of dementia symptoms and for informing help-seeking pathways. PMID- 20835965 TI - Fear appeals in HIV prevention: the role of anticipated regret. AB - The present study examined the role of a number of cognitive beliefs (i.e. attitude, subjective norm, anticipated regret, and self-efficacy) in explaining the effects of fear appeal information on behavioral motivation. A randomized experiment with a 2 (threat: low versus high) * 2 (coping: low versus high) between-subjects design was used in the study. Undergraduates were exposed to one of four scenario messages that presented high or low threat information about HIV/AIDS combined with high or low coping information with regard to condom use in HIV prevention. Explorative analyses revealed that only anticipated regret qualified as a mediator of the effect of the fear appeal message on intention. High coping information was observed to increase anticipated regret, which increased the intention to use condoms. Anticipated regret mediated the coping intention relationship. This finding furthers our understanding of the working mechanisms of fear appeals in HIV prevention. PMID- 20835966 TI - The perceived consequences of safer injection: an exploration of qualitative findings and gender differences. AB - Injection drug users (IDUs) are at a risk for HIV and other bloodborne pathogens via syringe and paraphernalia sharing, with females being at elevated risk. Consequences of injection risk behavior such as the risk of becoming infected with HIV have been relatively well studied, though less is known about the consequences of refusing to share injection equipment. We conducted indepth qualitative interviews with 26 IDUs recruited from a syringe exchange program in Los Angeles, California, USA, to understand the consequences of refusing to share injection equipment and to determine whether these perceived consequences differ by gender. Perceived consequences were organized into four domains using a social ecological framework: microsystem (perceived risk for HIV, drug withdrawal or forgoing drug use), exosystem (trust and social norms), mesosystem (precarious housing and shelter policies), and macrosystem (syringe access/inconvenience, economic and legal consequences). Gender differences were identified in some, but not in all areas. Effective public health interventions among IDUs will benefit from a holistic perspective that considers the environmental and social rationality (Kowalewski, M., Henson, K.D., & Longshore, D. (1997). Rethinking perceived risk and health behavior: A critical review of HIV prevention research. Health Education and Behavior, 24(3), 313-325) of decisions regarding injection risk behavior and assists individuals in addressing the consequences that they perceive to be the most salient. PMID- 20835967 TI - Adolescent orofacial injury: association with psychological symptoms. AB - Ethnic minority youth living in urban areas experience disproportionately high rates of violent intentional injuries. This study investigates the association of violent intentional injuries with psychological distress and alcohol use among adolescents treated in trauma centers for facial injuries. Interviews were conducted with 67 adolescents treated at two urban trauma centers (predominantly males [86%], and minority [Latino, 72%; African American, 19%]). Adolescents reported experiencing several different types of accidental and assault-related injuries that required medical attention in the past six months. About half (53%) reported experiencing only unintentional injuries (e.g. car accidents, falls, sports injury); 23% experienced one type of intentional injury resulting from either fighting or being attacked; and 24% experienced two types of intentional injuries resulting from both fighting and being attacked. Measures of alcohol use and psychological distress were examined in relation to these three types of injuries. Overall, 30% of study participants reported they had been drinking alcohol at the time of injury. Compared to adolescents without intentional injuries, those who experienced a physical fight and/or attack had higher levels of alcohol problems, depression, paranoia and somatic symptoms, and were more likely to have family members with alcohol problems. There is a considerable need for adolescents with intentional assault-related injuries to be screened for alcohol and mental health problems, and to be referred for appropriate treatment interventions if they score at problem levels. PMID- 20835968 TI - Development and validation of a self-report for the assessment of adjustment disorders. AB - Based on a recent diagnostic proposal for adjustment disorders a self-report assessment was developed. The current study reports validation results. Psychometric properties were examined using two different samples of 687 patients with cardiac arrhythmias and 86 patients from a psychosomatic outpatient clinic. Besides evaluating the internal structure and re-test reliability, associations with quality of life, general anxiety and depression, symptoms of posttraumatic stress disorder and coping strategies were analyzed. The factor analysis confirmed the three postulated factors: intrusion, avoidance and failure to adapt. The internal consistencies for these three scales were between alpha = 0.74 and 0.91. The re-rest reliability of the scales for a six-week period lay between r(tt) = 0.61 and 0.84. Medium-sized correlations were found between the scales with general anxiety and depression as well as posttraumatic stress disorder. Furthermore, the scales correlated with emotion-oriented and somewhat with proactive coping, but not with task-oriented or avoidance-oriented coping strategies. It is concluded that the self-report on adjustment disorders enables new possibilities to investigate further previously under-researched adjustment disorders. PMID- 20835969 TI - Is Geriatric Depression Scale-15 a suitable instrument for measuring depression in Brazil? Results of a Rasch analysis. AB - Depressive symptoms are the most prevalent mental health condition in older adults. Since it cannot be measured directly, the use of instruments is mandatory. The 15-item Geriatric Depression Scale (GDS) is one of the most widely used scales to measure depression in the elderly. It is recognized that the cultural context is a major determinant of the instrument's psychometric performance. Up to the present, this scale has mainly been investigated through classical psychometric approaches. The present study aims to explore whether the 15-item GDS is a suitable instrument in a Brazilian sample. In addition, it explores the potential improvement in the psychometric performance by item refinement. Four hundred twenty-four elderly adults selected through convenience sampling completed the 15-item GDS. Data were analyzed by the Rasch Measurement Model. The Rasch analysis is a powerful modern approach to explore psychometric performance of instruments in health sciences. It examines both the scale and the individual item performance in depth. The 15-item GDS proved not to be suitable in a Brazilian sample. Item misfit and differential item functioning were responsible for considerable misperformance. Scale reduction led to a 10-item structure. This refined format presented adequate psychometric performance and no differential item functioning. The present study offers an alternative and more adequate version of the GDS to be applied in Brazilian subjects. It is also in line with the need for shorter, valid scales in clinical settings. Further investigations are needed to develop a set of cultural-invariant items, which could then be applied in transcultural investigations free of bias. PMID- 20835970 TI - Development of an Italian version of the Depression Anxiety Stress Scales. AB - Older Italian-born Australians represent one of the largest migrant populations in Australia. However, there are few valid and reliable Italian-language measures of mood symptomology suitable for use with this group. Following a rigorous translation and adaptation process, an Italian version of the Depression Anxiety Stress Scales was administered to a sample of 103 Italian-born men and women over the age of 55 years and the results were subjected to exploratory factor analysis. Items within the original Depression and Stress scales loaded consistently and strongly on separate factors. However, translated Anxiety items loaded across three separate factors, including a factor comprised solely of somatic expressions of anxiety. The results are explained with reference to cultural factors specific to an older Mediterranean migrant sample, including somatic expressions of distress and "nerves". The results are also discussed in light of the size and nature of the sample. The Depression and Stress scales can be used confidently by clinicians and researchers with this population. However, the Anxiety scale cannot be assumed to be measuring an homogenous construct, and as such, should be used with caution. PMID- 20835972 TI - The neural substrates of mindfulness: an fMRI investigation. AB - "Mindfulness" is a capacity for heightened present-moment awareness that we all possess to a greater or lesser extent. Enhancing this capacity through training has been shown to alleviate stress and promote physical and mental well-being. As a consequence, interest in mindfulness is growing and so is the need to better understand it. This study employed functional magnetic resonance imaging (fMRI) to identify the brain regions involved in state mindfulness and to shed light on its mechanisms of action. Significant signal decreases were observed during mindfulness meditation in midline cortical structures associated with interoception, including bilateral anterior insula, left ventral anterior cingulate cortex, right medial prefrontal cortex, and bilateral precuneus. Significant signal increase was noted in the right posterior cingulate cortex. These findings lend support to the theory that mindfulness achieves its positive outcomes through a process of disidentification. PMID- 20835973 TI - Food pleasantness affects visual selective attention. AB - Fundamental to adaptive behaviour is the ability to select environmental objects that best satisfy current needs and preferences. Here we investigated whether temporary changes in food preference influence visual selective attention. To this end, we exploited the fact that when a food is eaten to satiety its motivational value and perceived pleasantness decrease relative to other foods not eaten in the meal, an effect termed sensory-specific satiety. A total of 26 hungry participants were fed until sated with one of two palatable foods. Before and after selective satiation, participants rated the pleasantness of the two foods and then viewed the same as stimuli on a computer screen while attention was assessed by a visual probe task. Results showed that the attentional bias for the food eaten decreased markedly from pre- to postsatiety, along with the subjective pleasantness for that food. By contrast, subjective pleasantness and attentional bias for the food not eaten did not show any such decrease. These findings suggest that the allocation of visual selective attention is flexibly and rapidly adjusted to reflect temporary shift in relative preference for different foods. PMID- 20835974 TI - 70th Birthday of Prof. Dr. rer. nat. Dr. h. c. Adolf Nahrstedt. PMID- 20835976 TI - [Future of the German Society of Gastroenterology]. PMID- 20835977 TI - Vagal threshold determination. Effect of age and gender. AB - Progressive increases in exercise intensity cause significant decreases in vagal activity (VA) until a critical point called the vagal threshold (TVA) is reached. This is where further increases in exercise intensity cause negligible change in VA. This study was designed to develop the algorithm for the TVA determination and to assess the effects of age and gender on its level. The sample consisted of 40 subjects who were divided according to age and gender into 4 groups with 10 subjects each: G1-Men age 25-31, G2-Men age 40-57, G3-Women age 24-28, and G4 Women age 43-56. The vagal responses were assessed by spectral analysis of the heart rate variability method while walking on a treadmill in a steady-state at intensities of 20-70% of the maximal heart rate reserve (MHRR). The mean intensity of 45% MHRR was suggested as the TVA level which is related neither to age nor gender. Heart rate related to TVA (TVA-HR) was affected by gender. High frequency power at TVA was influenced by age. The TVA-HR was considered to be a promising tool for the prescription of a safe level of physical activity for subjects with higher risks of health complications involving elevated sympathoadrenal activity during exercise. PMID- 20835979 TI - Systems biology and medicine: a new take on an old paradigm. PMID- 20835980 TI - Multiscale systems integration in the eye. AB - A series of research topics on the eye is reviewed with the aim of illustrating how integrative and systems-biological approaches can be used to understand complex properties and functions of ocular tissues. Emphasis is placed on the diversity of physiological systems represented in the eye, and the variety of approaches required to analyze those systems, both empirically and theoretically. Modeling and empirical studies reviewed focus mainly on problems that the eye presents, in the broad areas of biomechanics and fluid dynamics from the molecular to the whole-organ scale. Attention is given to the relevance of these studies in human disease and the current potential for development of medical therapies based upon a biophysical, integrative modeling approach. The creation of a multiscale hierarchy of numerical models of the eye is proposed as an important and unifying aim of integrative eye research. PMID- 20835981 TI - Design principles of the bacterial quorum sensing gene networks. AB - Bacterial quorum sensing (QS) has attracted much interest as the manifestation of collective behavior in prokaryotic organisms once considered strictly solitary. Significant amount of genetic, biochemical, and structural data which, has been accumulated in studies on QS in many species allows us to map properties of specific molecules and their interactions on the observed population-wide bacterial behavior. The present review attempts to give a systems biology perspective on the structure of genetic regulatory networks that control QS and considers functional implications of a variety of design principles that recur in the organization of these networks across species. PMID- 20835982 TI - The lung physiome: merging imaging-based measures with predictive computational models. AB - Global measurements of the lung provided by standard pulmonary function tests do not give insight into the regional basis of lung function and lung disease. Advances in imaging methodologies, computer technologies, and subject-specific simulations are creating new opportunities to study structure-function relationships in the lung through multidisciplinary research. The digital Human Lung Atlas is an image-based resource compiled from male and female subjects spanning several decades of age. The Atlas comprises both structural and functional measures, and includes computational models derived to match individual subjects for personalized prediction of function. The computational models in the Atlas form part of the Lung Physiome project, which is an international effort to develop integrative models of lung function at all levels of biological organization. The computational models provide mechanistic interpretation of imaging measures; the Atlas provides structural data on which to base model geometry, and functional data against which to test hypotheses. The example of simulating airflow on a subject-specific basis is considered. Methods for deriving multiscale models of the airway geometry for individual subjects in the Atlas are outlined, and methods for modeling turbulent flows in the airway are reviewed. PMID- 20835984 TI - Mesenchymal stem cell differentiation and roles in regenerative medicine. AB - Adult stem cells with multi or unipotent differentiation potential are present in almost all tissues of adult organisms. The main function of these stem cells is to support normal repair and rejuvenation of diseased and aging tissues. Mesenchymal stem cells (MSCs) isolated from the bone marrow have the potential to differentiate into multiple connective tissues. Advancements in understanding tissue specific differentiation of MSCs in conjunction with global genomic and proteomic profiling of MSCs have not only provided insights into their biology but also made MSC based clinical trials a reality for treating various debilitating diseases and genetic disorders. The emerging evidence that MSCs are immunosuppressive makes them an even more attractive candidate for regenerative medicine as rejections of transplants by the recipient could be a limiting step for moving the stem cells based therapies from "bedside to bed side." To a large extent the therapeutic potential of MSCs is attributed to their differentiation ability. The fate and commitment of MSCs are regulated by various instructive signals from their immediate vicinity or microenvironment, which comprises many biological molecules (soluble and insoluble) and biomechanical forces. These biochemical and biophysical factors play a pivotal role in determining the efficacy of MSC differentiation and their contribution to the repair process. In this review, we discuss the characteristics of MSCs, their differentiation potential toward different skeletal tissues (cartilage and bone), and their emerging role in regenerative medicine. PMID- 20835985 TI - Integrin activation in the immune system. AB - Modulation of leukocyte adhesiveness is critical to leukocyte function during the immune response. A central paradigm in this phenomenon is represented by integrin activation, which is controlled by inside-out signal transduction mechanisms triggered by selectins, chemoattractants and TcR-bound Ag and facilitated by mechanochemical forces. Integrins are heterodimeric adhesive receptors differently expressed on all leukocyte subtypes. At least two distinct modalities of integrin activation are known, namely conformational changes, leading to increased affinity, and lateral mobility leading to increased valency, both enhancing cell avidity (adhesiveness). Several signal transduction events have been correlated to integrin activation in leukocytes. The complexity of intracellular signaling networks leading to leukocyte integrin activation is likely functional to generate robustness and fine tuning of integrin activation allowing integration of qualitative and quantitative variations of extracellular signals leading to leukocyte-, agonist- and integrin-specific control of adhesion. In this context, the recent modular abstraction proposed for the functional architecture of biological networks may provide a powerful paradigm to understand regulation and specificity of signaling events. Accordingly, pro adhesive intracellular signaling networks may be organized in regulatory signalosomes, or modules, corresponding to discrete clusters of interacting signaling proteins, with some devoted to context-dependent regulation of specificity and dynamics of integrin activation. The principles and technologies of systems biology, and more specifically of network theory, may help to address this complexity and unveil the inner logic governing leukocyte recruitment during the immune response. PMID- 20835983 TI - A systems biology approach to defining metastatic biomarkers and signaling pathways. AB - Metastasis is the final stage of cancer and the primary cause of mortality for most solid malignancies. This terminal phase of cancer progression has been investigated using a variety of high-throughput technologies (i.e., gene expression arrays, array comparative genomic hybridization (aCGH), and proteomics) to identify prognostic expression profiles and better characterize the metastatic process. For decades, the predominant model for the metastatic process has been the 'progression model', yet recent microarray results tend to support an inherent metastatic capability within primary tumors. Moreover, studies using a highly metastatic transgenic mammary tumor model suggest that germline polymorphisms are significant determinants of metastatic efficiency. Likewise, a strong concordance of survival has been observed between family members with cancer, further supporting the link between genetic inheritance and survival. In addition, chromosomal aberrations and signaling pathways related to metastatic capacity have been identified by array comparative genomic hybridization (aCGH) and proteomic studies, respectively. Lastly, carcinoma enzyme activity profiles using activity-based proteomics (ABPP), may be more clinically useful than expression-based proteomics for certain cancers. Most importantly, the application of these high-throughput techniques should expedite the search for additional biomarkers, germline polymorphisms, and expression signatures with greater prognostic value. PMID- 20835986 TI - Transcriptional networks that regulate muscle stem cell function. AB - Muscle stem cells comprise different populations of stem and progenitor cells found in embryonic and adult tissues. A number of signaling and transcriptional networks are responsible for specification and survival of these cell populations and regulation of their behavior during growth and regeneration. Muscle progenitor cells are mostly derived from the somites of developing embryos, while satellite cells are the progenitor cells responsible for the majority of postnatal growth and adult muscle regeneration. In resting muscle, these stem cells are quiescent, but reenter the cell cycle during their activation, whereby they undergo decisions to self-renew, proliferate, or differentiate and fuse into multinucleated myofibers to repair damaged muscle. Regulation of muscle stem cell activity is under the precise control of a number of extrinsic signaling pathways and active transcriptional networks that dictate their behavior, fate, and regenerative potential. Here, we review the networks responsible for these different aspects of muscle stem cell biology and discuss prevalent parallels between mechanisms regulating the activity of embryonic muscle progenitor cells and adult satellite cells. PMID- 20835988 TI - Systems biology and physiome projects. PMID- 20835989 TI - Agent-based models in translational systems biology. AB - Effective translational methodologies for knowledge representation are needed in order to make strides against the constellation of diseases that affect the world today. These diseases are defined by their mechanistic complexity, redundancy, and nonlinearity. Translational systems biology aims to harness the power of computational simulation to streamline drug/device design, simulate clinical trials, and eventually to predict the effects of drugs on individuals. The ability of agent-based modeling to encompass multiple scales of biological process as well as spatial considerations, coupled with an intuitive modeling paradigm, suggests that this modeling framework is well suited for translational systems biology. This review describes agent-based modeling and gives examples of its translational applications in the context of acute inflammation and wound healing. PMID- 20835990 TI - Kidney modeling and systems physiology. AB - We present an overview of currently available resources in renal systems physiology and indicate directions for development toward the renal physiome. After a brief resume of objectives, we summarize legacy-modeling studies that can serve as the foundation for a more complete toolset. These include detailed models of practically all renal cell types and nephron segments and a variety of models of nephro-vascular exchanges in the medulla, of renal hemodynamics, and studies of tubuloglomerular feedback and autoregulation. Recent detailed anatomical reconstructions have brought surprising new results to bear on classic unsolved problems. In parallel with the modeling environment, progress has been made toward the quantitative database and model repository resources that must accompany the modeling environment in order to attain the goal of an open-ended, flexible, and collaborative infrastructure for renal systems biology, with an indication of prospects for integration with initiatives in the larger IUPS Physiome Project. PMID- 20835991 TI - Computational modeling of epithelial tissues. AB - There is an extensive literature on the computational modeling of epithelial tissues at all levels from subcellular to whole tissue. This review concentrates on behavior at the individual cell to whole tissue level, and particularly on organizational aspects, and provides an indication of where information from other areas, such as the modeling of angiogenesis, is relevant. The skin, and the lining of all of the body cavities (lung, gut, cervix, bladder etc) are epithelial tissues, which in a topological sense are the boundary between inside and outside the body. They are thin sheets of cells (usually of the order of 0.5 mm thick) without extracellular matrix, have a relatively simple structure, and contain few types of cells. They have important barrier, secretory and transport functions, which are essential for the maintenance of life, so homeostasis and wound healing are important aspects of the behavior of epithelial tissues. Carcinomas originate in epithelial tissues.There are essentially two approaches to modeling tissues--to start at the level of the tissue (i.e., a length scale of the order of 1 mm) and develop generalized equations for behavior (a continuum approach); or to start at the level of the cell (i.e., a length scale of the order of 10 um) and develop tissue behavior as an emergent property of cellular behavior (an individual-based approach). As will be seen, these are not mutually exclusive approaches, and they come in a variety of flavors. PMID- 20835993 TI - Left-right axis determination. AB - Vertebrates display left-right (L-R) asymmetric organ positioning and morphologies, which are established during embryonic development. These asymmetries are conserved among individuals and species. How, when and where do embryos first break the symmetry? Why is it broken in a consistent direction? How is the asymmetry transmitted to and coordinated within the whole embryo? Which of these elements are conserved between different organisms? These questions have been the focus of intense research during the last decade, and much has been learned. Nonetheless, our understanding of how tissue and organ L-R differences are established during embryogenesis is scarce. A systems biology approach may enable us to better understand the dynamics of gene networks, epigenetics, cilia, fluids, and charged molecules as well as other processes involved in the generation of the vertebrate L-R axis. PMID- 20835992 TI - Adenosine-to-inosine RNA editing. AB - Ribonucleic acid (RNA) editing is a mechanism that generates RNA and protein diversity, which is not directly encoded in the genome. The most common type of RNA editing in vertebrates is the conversion of adenosine to inosine in double stranded RNA which occurs in the higher eukaryotes. This editing is carried out by the family of adenosine deaminase acting on RNA (ADAR) proteins. The most studied substrates of ADAR proteins undergo editing which is very consistent, highly conserved, and functionally important. However, editing causes changes in protein-coding regions only at a small proportion of all editing sites. The vast majority of editing sites are in noncoding sequences. This includes microRNAs, as well as the introns and 3' untranslated regions of messenger RNAs, which play important roles in the RNA-mediated regulation of gene expression. PMID- 20835994 TI - Spatial regulation of PI3K signaling during chemotaxis. AB - Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3' OH position of the inositol ring of phosphoinositides on the inner leaf of the plasma membrane. Receptor-mediated activation of the PI3K pathway plays a crucial role in numerous signaling pathways and regulates a number of critical cellular processes, including growth, differentiation, survival and directed migration. In this focus article, we review the temporal and spatial regulation of PI3K in chemotaxing cells with particular emphasis on the amoeba Dictyostelium as well as neutrophils. We also briefly discuss one model used to elucidate the PI3K pathway. PMID- 20835997 TI - Systems biology and medicine--plunging into the unknown. PMID- 20835998 TI - Genome-scale metabolic networks. AB - During the last decade, models have been developed to characterize cellular metabolism at the level of an entire metabolic network. The main concept that underlies whole-network metabolic modeling is the identification and mathematical definition of constraints. Here, we review large-scale metabolic network modeling, in particular, stoichiometric- and constraint-based approaches. Although many such models have been reconstructed, few networks have been extensively validated and tested experimentally, and we focus on these. We describe how metabolic networks can be represented using stoichiometric matrices and well-defined constraints on metabolic fluxes. We then discuss relatively successful approaches, including flux balance analysis (FBA), pathway analysis, and common extensions or modifications to these approaches. Finally, we describe techniques for integrating these approaches with models of other biological processes. PMID- 20835996 TI - Fluorescence correlation spectroscopy and fluorescence cross-correlation spectroscopy. AB - This article focuses on methods based on fluctuation correlation spectroscopy to determine the formation of protein complexes in living cells. We present the principles of the fluctuation method applied to cells. We discuss the novelty and the promises of this approach. The emphasis is in the discussion of the underlying statistical assumptions of the image correlation spectroscopy analysis rather than in reviewing applications of the method. Although one example of the application of the fluctuation method is given, this article also contains simulations that are better suited to illustrate and support the basic assumptions of the method. PMID- 20835995 TI - Regulation of endothelial cell functions by basement membrane- and arachidonic acid-derived products. AB - Angiogenesis, the formation of new blood vessels from preexisting vasculature, is required for normal physiological as well as pathological events. The angiogenic process requires endothelial cells to proliferate, migrate, and undergo tubulogenesis. These multistep processes necessitate secretion of pro-angiogenic growth factors, activation of specific intracellular signaling, and interaction of endothelial cells with basement membrane (BM) extracellular matrix components. The generation and release of angiogenic molecules are highly regulated and are influenced by numerous factors, including BM-derived fragments, proteolytic enzymes, as well as metabolites of arachidonic acid (AA). The interactions between these key modulators of angiogenesis is extremely complex, as AA metabolites can regulate the synthesis of soluble angiogenic factors, BM components, as well as enzymes capable of cleaving BM components, which result in the generation of pro- and/or anti-angiogenic products. Furthermore, some BM derived fragments can alter the expression of AA-converting enzymes and consequently the synthesis of angiogenic factors. In this review we describe the relationship between BM components and AA metabolites with respect to the regulation of endothelial cell functions in health and disease. PMID- 20835999 TI - Chronic lung diseases. AB - Chronic lung diseases often have high morbidity and mortality rate and have posed a serious threat to human health. The incidence of many chronic lung diseases such as asthma has been on the rise in the past decade, which causes serious economic burden. Despite many efforts which employed traditional experimental approaches to elucidate the mechanisms of the diseases have been made, little is known about the pathogenesis of complex lung diseases. Systems biology approaches which aim to integrate and analyze information gathered from multiple sources offer a great opportunity to examine complex human diseases from a new angle. Many attempts have been made using high-throughput technologies such as microarrays to study chronic lung diseases; although compared with the full fledged systems biology approach, research strategies employed in most of these investigations still have much room to improve, promising findings have already emerged from these efforts, which demonstrates the potential of implementing systems biology in pulmonary biomedical research. PMID- 20836001 TI - Cardiac lineage selection: integrating biological complexity into computational models. AB - The emergence of techniques to study developmental processes using systems biology approaches offers exciting possibilities for the developmental biologist. In particular cardiac lineage selection may be particularly amenable to these types of studies since the heart is the first fully functional organ to form in vertebrates. However there are many technical obstacles that need to be overcome for these studies to proceed. Here we present a brief overview of cardiomyocyte lineage deterimination and discuss how different aspects of this process either benefit from or present unique challenges for the development of systems biology approaches. PMID- 20836002 TI - Thermodynamically based constraints for rate coefficients of large biochemical networks. AB - Wegscheider cyclicity conditions are relationships among the rate coefficients of a complex reaction network, which ensure the compatibility of kinetic equations with the conditions for thermodynamic equilibrium. The detailed balance at equilibrium, that is the equilibration of forward and backward rates for each elementary reaction, leads to compatibility between the conditions of kinetic and thermodynamic equilibrium. Therefore, Wegscheider cyclicity conditions can be derived by eliminating the equilibrium concentrations from the conditions of detailed balance. We develop matrix algebra tools needed to carry out this elimination, reexamine an old derivation of the general form of Wegscheider cyclicity condition, and develop new derivations which lead to more compact and easier-to-use formulas. We derive scaling laws for the nonequilibrium rates of a complex reaction network, which include Wegscheider conditions as a particular case. The scaling laws for the rates are used for clarifying the kinetic and thermodynamic meaning of Wegscheider cyclicity conditions. Finally, we discuss different ways of using Wegscheider cyclicity conditions for kinetic computations in systems biology. PMID- 20836003 TI - Vertebrate retina and hypothalamus development. AB - The vertebrate retina and hypothalamus, which emerge from adjacent regions of the ventral diencephalon, provide accessible experimental systems for analysis of the molecular mechanisms by which neuronal subtype diversity is specified, and how this neuronal subtype diversity regulates perception and behavior. Although the retina emerges as a lateral extension of the hypothalamus prior to the onset of neurogenesis, the retina and hypothalamus go on to eventually be comprised of almost entirely different cell types, and differ extensively in the spatial organization, function, and connectivity of these cells. Despite these differences in cell composition, there are a number of mechanistic and molecular similarities in the process of cell fate specification in both organs, including a stereotyped temporal sequence in which major cell types are generated. Although a handful of genes have been identified in both systems that direct cell fate specification, many more remain to be characterized, and large numbers of candidate genes have been identified in recent high-throughput screens, particularly in retina. Experimental challenges for the near future include functional analysis of the genes identified so far, and the use of the molecular pathways gained from analysis of the development of specific neuronal lineages to study the contribution of these cells to perception and behavior. PMID- 20836000 TI - Role of neutrophils in innate immunity: a systems biology-level approach. AB - The innate immune system is the first line of host defense against invading microorganisms. Polymorphonuclear leukocytes (PMNs or neutrophils) are the most abundant leukocyte in humans and essential to the innate immune response against invading pathogens. Compared with the acquired immune response, which requires time to develop and is dependent on previous interaction with specific microbes, the ability of neutrophils to kill microorganisms is immediate, non-specific, and not dependent on previous exposure to microorganisms. Historically, studies on PMN-pathogen interaction focused on the events leading to killing of microorganisms, such as recruitment/chemotaxis, transmigration, phagocytosis, and activation, whereas post-phagocytosis sequelae were infrequently considered. In addition, it was widely accepted that human neutrophils possessed limited capacity for new gene transcription and thus, relatively little biosynthetic capacity. This notion has changed dramatically within the past decade. Further, there is now more effort directed to understand the events occurring in PMNs after killing of microbes. Herein we review the systems biology-level approaches that have been used to gain an enhanced view of the role of neutrophils during host-pathogen interaction. We anticipate that these and future systems-level studies will ultimately provide information critical to our understanding, treatment, and control of diseases caused by pathogenic microorganisms. PMID- 20836004 TI - Cytological differential diagnosis among adenocarcinoma, epithelial mesothelioma, and reactive mesothelial cells in serous effusions by immunocytochemistry. AB - The objective of the study is to estimate the expression of some antibodies in the metastatic adenocarcinomas, malignant epithelial mesotheliomas, and reactive mesothelial cells in serous effusions and to choose effective panel to the differential diagnosis. Totally 113 effusion cytology samples (80 pleural fluid, 30 ascitic, and 3 pericardial fluid) from 60 cases of metastatic adenocarcinoma (ACA), 18 cases of malignant epithelial mesothelioma (MM), and 35 cases of reactive mesothelium (RM) were included in this study. The cytological diagnoses of these cases were confirmed by histopathology or clinical datas. Smears and cell blocks were prepared for each case. Immunocytochemical study was performed on the cell block sections. The sensitivity of E-cadherin, CEA, MOC-31, and Ber EP4 for adenocarcinoma was 86.7%, 80%, 70%, and 76.4%, respectively. The specificity was 98.1%, 96.2%, 92.5%, and 86.8%, respectively. The sensitivity of calretinin, HBME-1, and thrombomodulin for RM/MM was 83%, 79.2%, and 47.2% respectively. The specificity was 88.3%, 21.7%, and 70%, respectively. The expression of E-cadherin, CEA, MOC-31, Ber-EP4, calretinin, and thrombomodulin showed significant difference between ACA and RM/MM (P < 0.01). The reactivity of EMA and Des showed significant difference between RM and MM (P < 0.01). In our opinion, the antibody panel that consists of E-cadherin, CEA, calretinin, and thrombomodulin should be the best for differential diagnosis between metastatic adenocarcinomas and RM/MM in serous effusions. EMA and Des should be used to differentiate malignant epithelial mesothelioma and reactive mesothelial cells. EMA positive and Des negative favor MM, while Des positive and EMA negative favor RM. PMID- 20836005 TI - Endoscopic ultrasonography-guided fine-needle aspiration for diagnosing upper gastrointestinal submucosal lesions: a prospective study of 50 cases. AB - The objective was to assess EUS-FNA for diagnosing intramural upper GI tract lesions. The subjects were 50 patients (21M/29F) with upper GI submucosal lesions who underwent EUS-FNA at a referral center for GI system over a 12-month period. All cases were followed for 1 year after initial EUS-FNA. Cytologic diagnoses were categorized as benign, malignant, suspicious for malignancy, mesenchymal tumor, endocrine tumor, or nondiagnostic. All tumors were assessed for various cytomorphologic features. The accuracy of the initial FNA diagnoses was evaluated for each patient who also underwent subsequent histopathological examination of a core biopsy and/or surgical biopsy/resection material of the same lesion. According to the site of the lesions; while 84% of all esophageal lesions were diagnosed as mesenchymal; 67% of all gastric lesions were mesenchymal. The sole lesion was nonmesenchymal (benign cyst) in duodenum. The sensitivity, specificity, positive and negative predictive values, and accuracy of EUS-FNA for diagnosing submucosal mesenchymal tumors of the upper GI tract were 82.9, 73.3, 87.9, 64.7, and 80%, respectively. The corresponding values for nonmesenchymal lesions were 100, 85.7, 80, 100, and 90.9%. Our experience confirms that EUS-FNA is an extremely valuable tool for diagnosing submucosal lesions of the upper GI, and is particularly useful in cases where endoscopic forceps biopsy does not lead to diagnosis. Optimal results can be yielded by a close working relationship between the gastroenterologist and pathologist. PMID- 20836006 TI - Systems biology--old wine in a new bottle or is the bottle changing the wine? AB - For further resources related to this article, please visit the WIREs website. PMID- 20836008 TI - The secret codes of mammalian scents. AB - The scents of mammals are complex blends of natural products that reveal a wealth of individual information. Many mammals can decipher these scent codes to discern the gender, age, endocrine status, social status, and genotype of conspecifics using dedicated sensory receptors in their olfactory system. Among these social odors are pheromones, chemicals that trigger innate behaviors and physiological responses. Here, we review classes of mammal-derived natural products that influence behavior through activation of the olfactory system. PMID- 20836007 TI - Pharmacogenomics: a systems approach. AB - Pharmacogenetics and pharmacogenomics involve the study of the role of inheritance in individual variation in drug response, a phenotype that varies from potentially life-threatening adverse drug reactions to equally serious lack of therapeutic efficacy. Pharmacogenetics-pharmacogenomics represents a major component of the movement to 'individualized medicine'. Pharmacogenetic studies originally focused on monogenic traits, often involving genetic variation in drug metabolism. However, contemporary studies increasingly involve entire 'pathways' that include both pharmacokinetics (PKs)--factors that influence the concentration of a drug reaching its target(s)--and pharmacodynamics (PDs), factors associated with the drug target(s), as well as genome-wide approaches. The convergence of advances in pharmacogenetics with rapid developments in human genomics has resulted in the evolution of pharmacogenetics into pharmacogenomics. At the same time, studies of drug response are expanding beyond genomics to encompass pharmacotranscriptomics and pharmacometabolomics to become a systems based discipline. This discipline is also increasingly moving across the 'translational interface' into the clinic and is being incorporated into the drug development process and governmental regulation of that process. The article will provide an overview of the development of pharmacogenetics-pharmacogenomics, the scientific advances that have contributed to the continuing evolution of this discipline, the incorporation of transcriptomic and metabolomic data into attempts to understand and predict variation in drug response phenotypes as well as challenges associated with the 'translation' of this important aspect of biomedical science into the clinic. PMID- 20836010 TI - Biophysics and dynamics of natural and engineered stem cell microenvironments. AB - Stem cells are defined by their ability to self-renew and to differentiate into one or more mature lineages, and they reside within natural niches in many types of adult and embryonic tissues that present them with complex signals to regulate these two hallmark properties. The diverse nature of these in vivo microenvironments raises important questions about the microenvironmental cues regulating stem cell plasticity, and the stem cell field has built a strong foundation of knowledge on the biochemical identities and regulatory effects of the soluble, cellular, and extracellular matrix factors surrounding stem cells through the isolation and culture of stem cells in vitro within microenvironments that, in effect, emulate the properties of the natural niche. Recent work, however, has expanded the field's perspective to include biophysical and dynamic characteristics of the microenvironment. These include biomechanical characteristics such as elastic modulus, shear force, and cyclic strain; architectural properties such as geometry, topography, and dimensionality; and dynamic structures and ligand profiles. We will review how these microenvironmental characteristics have been shown to regulate stem cell fate and discuss future research directions that may help expand our current understanding of stem cell biology and aid its application to regenerative medicine. PMID- 20836009 TI - Models at the single cell level. AB - Many cellular behaviors cannot be completely captured or appropriately described at the cell population level. Noise induced by stochastic chemical reactions, spatially polarized signaling networks, and heterogeneous cell-cell communication are among the many phenomena that require fine-grained analysis. Accordingly, the mathematical models used to describe such systems must be capable of single cell or subcellular resolution. Here, we review techniques for modeling single cells, including models of stochastic chemical kinetics, spatially heterogeneous intracellular signaling, and spatial stochastic systems. We also briefly discuss applications of each type of model. PMID- 20836012 TI - Host-bacteria interactions in the intestine: homeostasis to chronic inflammation. AB - In the past decade it has become clear that the gut constitutes an important frontier of the body, which not only regulates the selective entry of nutrients while keeping vigilant against pathogens but also is largely responsible for shaping the immune response to educate the organism to recognize self from non self. The very notion of self has undergone a dramatic change, with the acknowledgment that our 'selves' include a plethora of microbial species that actively participate in our body's homeostasis. The immune system continuously adapts to the microbiota in a cyclic, dynamic cross talk where intestinal epithelial cells play an important role in instructing noninflammatory responses for a steady-state control of bacterial growth, or triggering inflammatory mechanisms that can clear the gut from harmful invaders. The system is complex and robust in the sense that many players with partially overlapping roles act to keep the integrity of the intestinal mucosal barrier. Failure of these mechanisms involves genetic and environmental triggers and leads to inflammatory bowel disease. In this review, we seek to collect the state-of-the-art knowledge about how host and microbiota interact to promote gut homeostasis and provide evidences of malfunctioning of the described mechanisms in human inflammatory bowel disease. PMID- 20836011 TI - Gastrointestinal system. AB - The functions of the gastrointestinal (GI) tract include digestion, absorption, excretion, and protection. In this review, we focus on the electrical activity of the stomach and small intestine, which underlies the motility of these organs, and where the most detailed systems descriptions and computational models have been based to date. Much of this discussion is also applicable to the rest of the GI tract. This review covers four major spatial scales: cell, tissue, organ, and torso, and discusses the methods of investigation and the challenges associated with each. We begin by describing the origin of the electrical activity in the interstitial cells of Cajal, and its spread to smooth muscle cells. The spread of electrical activity through the stomach and small intestine is then described, followed by the resultant electrical and magnetic activity that may be recorded on the body surface. A number of common and highly symptomatic GI conditions involve abnormal electrical and/or motor activity, which are often termed functional disorders. In the last section of this review we address approaches being used to characterize and diagnose abnormalities in the electrical activity and how these might be applied in the clinical setting. The understanding of electrophysiology and motility of the GI system remains a challenging field, and the review discusses how biophysically based mathematical models can help to bridge gaps in our current knowledge, through integration of otherwise separate concepts. PMID- 20836013 TI - Systems biology of GAL regulon in Saccharomyces cerevisiae. AB - Evolutionary success of an organism depends on its ability to express or adapt to constantly changing environmental conditions. Saccharomyces cerevisiae has evolved an elaborate genetic circuit to regulate the expression of galactose metabolizing enzymes in the presence of galactose but in the absence of glucose. The circuit possesses molecular mechanisms such as multiple binding sites, cooperativity, autoregulation, nucleocytoplasmic shuttling, and substrate sensing mechanism. Furthermore, the GAL system consists of two positive (activating) feedback and one negative (repressing) feedback loops. These individual mechanisms, elucidated through experimental approach, can be integrated to obtain a system-wide behavior. Mathematical models in conjunction with guided experiments have demonstrated system-level properties such as ultrasensitivity, memory, noise attenuation, rapid response, and sensitive response arising out of the molecular interactions. These system-level properties allow S. cerevisiae to adapt and grow in a galactose medium under noisy and changing environments. This review focuses on system-level models and properties of the GAL regulon. PMID- 20836014 TI - T cell responses in lymph nodes. AB - Activation of T cells by antigen-presenting cells (APCs) in lymph nodes (LNs) is a key initiating event in many immune responses. Our understanding of this process has been both improved and complicated in recent years by evidence from techniques such as intravital microscopy that has revealed new levels of dynamism in the interaction of T cells and APCs. In particular, the complex motility of T cells within LNs, and their serial interactions with many APCs, imply that earlier static models of T cell activation need to be updated. Here we review the first attempts to model T cell interactions with APCs in LNs that incorporate simulations of T cell motility, based on experimental observations. We show that lattice-based modeling approaches are the dominant trend in these models, and then chart a possible course for development of these models toward spatially resolved models of immune responses within LNs. PMID- 20836015 TI - Regulatory roles of transforming growth factor beta family members in folliculogenesis. AB - Bidirectional signaling between the oocyte and surrounding somatic cells is absolutely essential for successful germ cell development in mammals. Oocytes secrete proteins that are necessary for granulosa cells growth and differentiation, whilst granulosa cells regulate oocyte development and integrate ovarian function with the rest of the body by orchestrating gonadal steroidogenesis. The importance of communication between the oocyte and granulosa cells is highlighted by genetic deletion of members of the transforming growth factor beta (TGFbeta) family and their downstream signaling components. Such knockout models have uncovered an interesting spectrum of reproductive phenotypes that have greatly advanced our knowledge of ovarian function and dysfunction. The current review focuses on some of the more recent transgenic mouse models that elucidate the intraovarian TGFbeta signaling vital for oocyte and granulosa cell development. PMID- 20836016 TI - Systems biology and medicine--meta-issues and frameworks. AB - For further resources related to this article, please visit the WIREs website. PMID- 20836017 TI - The network as the target. AB - The conventional target centric model of drug discovery is pinned under the weight of prior success and the traditional problems of safety and efficacy for new molecules. An alternative to target centric drug development is to shift focus to the pathways that mediate both biology and pathophysiology. This method has the advantage of not requiring a priori knowledge of the small molecule target, but also comes with it several challenges including target determination. We suggest extending this notion more broadly across the drug discovery process using quantitative network structure-activity relationships (QNSAR), and discuss the steps necessary to test the hypothesis that systems biology approaches can be used to improve the drug discovery process. PMID- 20836018 TI - Toward a VPH/Physiome ToolKit. AB - The Physiome Project was officially launched in 1997 and has since brought together teams from around the world to work on the development of a computational framework for the modeling of the human body. At the European level, this effort is focused around patient-specific solutions and is known as the Virtual Physiological Human (VPH) Initiative.Such modeling is both multiscale (in space and time) and multiphysics. This, therefore, requires careful interaction and collaboration between the teams involved in the VPH/Physiome effort, if we are to produce computer models that are not only quantitative, but also integrative and predictive.In that context, several technologies and solutions are already available, developed both by groups involved in the VPH/Physiome effort, and by others. They address areas such as data handling/fusion, markup languages, model repositories, ontologies, tools (for simulation, imaging, data fitting, etc.), as well as grid, middleware, and workflow.Here, we provide an overview of resources that should be considered for inclusion in the VPH/Physiome ToolKit (i.e., the set of tools that addresses the needs and requirements of the Physiome Project and VPH Initiative) and discuss some of the challenges that we are still facing. PMID- 20836020 TI - Systematic analysis of posttranscriptional gene expression. AB - Recent systems studies of gene expression have begun to dissect the layers of regulation that underlie the eukaryotic transcriptome, the combined consequence of transcriptional and posttranscriptional events. Among the regulatory layers of the transcriptome are those of the ribonome, a highly dynamic environment of ribonucleoproteins in which RNA-binding proteins (RBPs), noncoding regulatory RNAs (ncRNAs) and messenger RNAs (mRNAs) interact. While multiple mRNAs are coordinated together in groups within the ribonome of a eukaryotic cell, each individual type of mRNA consists of multiple copies, each of which has an opportunity to be a member of more than one modular group termed a posttranscriptional RNA operon or regulon (PTRO). The mRNAs associated with each PTRO encode functionally related proteins and are coordinated at the levels of RNA stability and translation by the actions of the specific RBPs and noncoding regulatory RNAs. This article examines the methods that led to the elucidation of PTROs and the coordinating mechanisms that appear to regulate the RNA components of PTROs. Moreover, the article considers the characteristics of the dynamic systems that drive PTROs and how mRNA components are bound collectively in physical 'states' to respond to cellular perturbations and diseases. In conclusion, these studies have challenged the extent to which cellular mRNA abundance can inform investigators of the functional status of a biological system. We argue that understanding the ribonome has greater potential for illuminating the underlying coordination principles of growth, differentiation, and disease. PMID- 20836021 TI - Systems approaches and algorithms for discovery of combinatorial therapies. AB - Effective therapy of complex diseases requires control of highly nonlinear complex networks that remain incompletely characterized. In particular, drug intervention can be seen as control of cellular network activity. Identification of control parameters presents an extreme challenge due to the combinatorial explosion of control possibilities in combination therapy and to the incomplete knowledge of the systems biology of cells. In this review paper, we describe the main current and proposed approaches to the design of combinatorial therapies, including the heuristic methods used now by clinicians and alternative approaches suggested recently by several authors. New approaches for designing combinations arising from systems biology are described. We discuss in special detail the design of algorithms that identify optimal control parameters in cellular networks based on a quantitative characterization of control landscapes, maximizing utilization of incomplete knowledge of the state and structure of intracellular networks. The use of new technology for high-throughput measurements is key to these new approaches to combination therapy and essential for the characterization of control landscapes and implementation of the algorithms. Combinatorial optimization in medical therapy is also compared with the combinatorial optimization of engineering and materials science and similarities and differences are delineated. PMID- 20836019 TI - MicroRNA targeting in mammalian genomes: genes and mechanisms. AB - We briefly review the history of microRNA (miRNA) research and some of the lessons learnt. To provide some insights as to how and why miRNAs came into existence, we consider the evolution of the RNA interference machinery, miRNA genes, and their targets. We highlight the importance of systems biology approaches to integrate miRNAs as an essential subnetwork for modulating gene expression programs. Building accurate computational models that can simulate highly complex cell-specific gene expression patterns in mammals will lead to a better understanding of miRNAs and their targets in physiological and pathological situations. The impact of miRNAs on medicine, either as potential disease predisposing factors, biomarkers, or therapeutics, is highly anticipated and has started to reveal itself. PMID- 20836023 TI - Genome-wide DNA methylation profiling. AB - DNA methylation plays a critical role in the regulation of gene expression. The ability to access the methylation status for a large number of genes or the entire genome should greatly facilitate the understanding of the nature of gene regulation in cells, and epigenetic mechanism of interactions between cells and environment. Microarray and sequencing-based DNA methylation profiling technologies have been developed to meet this goal. These methods can be categorized into three main classes based on how the methylation status is interrogated: discrimination of bisulfite induced C to T transition; cleavage of genomic DNA by methylation-sensitive restriction enzymes; and immunoprecipitation with methyl-binding protein or antibodies against methylated cytosines. With the development of next-generation sequencing technologies, genome-wide bisulfite sequencing has become a reality. Either whole- or reduced-genome approaches have been used to get the most comprehensive DNA methylation profiles in organisms of various genome sizes. PMID- 20836024 TI - Multiplex parallel pair-end-ditag sequencing approaches in system biology. AB - Characterization of all the functional components constituted in human genome relies in our ability to completely elucidate the genetic/epigenetic regulatory networks, chromatin states, nuclear architectures, and genome variations. Such endeavors demand for the development of robust and effective genomic technologies. In the past few years, the availability of disruptive next generation DNA sequencing technologies has offered new promise for whole genome interrogation. However, despite the massive parallel and ultra-high throughput capacity, the common nature of short read lengths found within these platforms limits their applications for many types of whole genome-based analyses. To overcome such constrain, pair end ditag (PET) based sequencing concept was conceived as an immediate solution to expand the information content and extend the linear coverage. By sequencing paired end signatures from any desired DNA fragment and mapping them to the reference genome, PET strategy allows the accurate demarcation of target DNA boundaries and defines their locations on the genomic landscape. Furthermore, the ability to delineate relationship between two ends of a DNA molecule enables the full scale discovery of unconventional gene products, genome rearrangements, and chromatin interactions. Coupling with the massively parallel and ultra-high throughput sequencing platforms, such unique features of PET strategy have the potential to revolutionize the approaches used to decipher regulatory networks in system biology, define the genome organizations, and characterize genome variations; which ultimately leads to the development of strategies for personalized medicine. PMID- 20836025 TI - Modeling the architecture and dynamics of hematopoiesis. AB - Hematopoiesis is a multistep process that results in the production of a variety of blood cells with different morphologies and diverse functions. All of these cells have their origin in hematopoietic stem cells Hematopoietic Stem Cells (HSCs) that replicate slowly to self-renew and give rise to progeny cells that proceed along the path of differentiation. The process is complex with the cells responding to a wide variety of cytokines and growth factors. We discuss a model of hematopoiesis based on stochastic cell behavior. Multiple compartments are introduced to keep track of each cell division process and increasing differentiation. Despite its simplicity, the model is able to account for the salient features of hematopoiesis and is compatible with considerable and independent experimental data. The model is applicable to hematopoiesis across mammals and can be used to understand the dynamics of various disorders both in humans and in animal models. PMID- 20836022 TI - Computational modeling of mammalian signaling networks. AB - One of the most exciting developments in signal transduction research has been the proliferation of studies in which a biological discovery was initiated by computational modeling. In this study, we review the major efforts that enable such studies. First, we describe the experimental technologies that are generally used to identify the molecular components and interactions in, and dynamic behavior exhibited by, a network of interest. Next, we review the mathematical approaches that are used to model signaling network behavior. Finally, we focus on three specific instances of 'model-driven discovery': cases in which computational modeling of a signaling network has led to new insights that have been verified experimentally. PMID- 20836026 TI - Circuitry of mRNA regulation. AB - Some of the classical paradigms of gene regulation have been challenged by global scale analysis of eukaryotic transcriptional and post-transcriptional gene regulation (PTGR), made possible by the development of genomics and proteomics tools. Post-transcriptional events in particular are increasingly being recognized as important sources of gene regulation. The hundreds of regulatory RNA-binding proteins that exist in eukaryotes may regulate dozens to hundreds of functionally related RNA targets. Likewise, the expression of considerable fractions of many eukaryotic genomes is affected by hundreds of non-coding RNAs, e.g., microRNAs. These findings suggest an enormous regulatory potential for PTGR that may affect virtually every message in a cell. All gene regulatory systems are composed of simple network circuits that coordinate the transfer of regulatory signals to a target gene/message. PMID- 20836027 TI - Systems biology and medicine--metazoan life and processes. AB - For further resources related to this article, please visit the WIREs website. PMID- 20836028 TI - Phosphoproteomics. AB - Current analytical protein methods show phosphorylation to be the most ubiquitous, evolutionary conserved post-translational modification Post Translational Modification (PTM). The reversible and transient nature of protein phosphorylation allows signal transduction pathways to carry out diverse cellular functions. From bacteria to humans, phosphorylation serves to modify protein function by altering protein stability, cellular location, substrate affinity, complex formation, and activity; thus allowing essential events such as cell cycle and growth to occur at precise times and locations. Phosphorylation controls a variety of events at many biological levels including: housekeeping activities controlled by single cells such as DNA transcription, cell-cycle regulation, and energy metabolism; and cellular processes that involve signaling between cells or the environment including such as neuronal migration and immune system recognition. This review summarizes state-of-the-art proteomics technologies available to study phosphorylation in biological systems. We highlight the tremendous steps the field has made in the last 5 years which allow quantitative global analyses while pointing out caveats in experimentation. PMID- 20836030 TI - Modeling breast biomechanics for multi-modal image analysis--successes and challenges. AB - Biomechanical modeling of the breast is a burgeoning research field that has potential uses across a wide range of healthcare applications. This review describes recent developments regarding multi-modal breast image analysis, and outlines some of the key challenges that researchers face in introducing the models into the clinical arena. Deformable breast models have demonstrated capabilities across a wide range of breast cancer diagnoses and treatments. Specific applications include magnetic resonance (MR) image guided surgery, registration of x-ray and MR images, and breast reduction/augmentation surgery planning. Challenges lie in improving the fidelity of these models, which are presently simplistic and use many unverified parameters. Specific challenges include characterization of individual-specific mechanical properties of breast tissues, precise representation of loading and boundary constraints during different clinical procedures, and validation of modeling techniques used to represent key mechanical aspects such as the suspensory Cooper's ligaments. Scientists must also work towards translating their research tools into the clinical setting by developing efficient tools with user-friendly interactivity. Widespread adoption of such techniques has the potential to significantly reduce the numbers of misdiagnosed breast cancers and enhance surgical planning for patient treatment. PMID- 20836029 TI - Algorithmic and analytical methods in network biology. AB - During the genomic revolution, algorithmic and analytical methods for organizing, integrating, analyzing, and querying biological sequence data proved invaluable. Today, increasing availability of high-throughput data pertaining to functional states of biomolecules, as well as their interactions, enables genome-scale studies of the cell from a systems perspective. The past decade witnessed significant efforts on the development of computational infrastructure for large scale modeling and analysis of biological systems, commonly using network models. Such efforts lead to novel insights into the complexity of living systems, through development of sophisticated abstractions, algorithms, and analytical techniques that address a broad range of problems, including the following: (1) inference and reconstruction of complex cellular networks; (2) identification of common and coherent patterns in cellular networks, with a view to understanding the organizing principles and building blocks of cellular signaling, regulation, and metabolism; and (3) characterization of cellular mechanisms that underlie the differences between living systems, in terms of evolutionary diversity, development and differentiation, and complex phenotypes, including human disease. These problems pose significant algorithmic and analytical challenges because of the inherent complexity of the systems being studied; limitations of data in terms of availability, scope, and scale; intractability of resulting computational problems; and limitations of reference models for reliable statistical inference. This article provides a broad overview of existing algorithmic and analytical approaches to these problems, highlights key biological insights provided by these approaches, and outlines emerging opportunities and challenges in computational systems biology. PMID- 20836032 TI - Evolution of transcriptional regulatory networks in yeast populations. AB - Saccharomyces cerevisiae is the most thoroughly studied eukaryote at the cellular, molecular, and genetic level. Recent boost in whole-genome sequencing, array-based allelic variation mapping, and genome-wide transcriptional profiling have unprecedentedly advanced knowledge on cell biology and evolution of this organism. It is now possible to investigate how evolution shapes the functional architecture of yeast genomes and how this architecture relates to the evolution of the regulatory networks controlling the expression of genes that make up an organism. A survey of the information on genetic and whole-genome expression variations in yeast populations shows that a significant score of gene expression variation is dependent on genotype-by-environment interaction. In some cases, large trans effects are the result of mutations in the promoters of key master regulator genes. Yet trans-variation in environmental sensor proteins appears to explain the majority of the expression patterns differentiating strains in natural populations. The challenge is now to use this information to model how individual genetic polymorphisms interact in a condition-dependent fashion to produce phenotypic change. In this study, we show how fruitful application of systems biology to the progress of science and medicine requires the use of evolution as a lens to reconstruct the hierarchical structure of regulation of biological systems. The lessons learned in yeast can be of paramount importance in advancing the application of genomics and systems biology to emerging fields including personalized medicine. PMID- 20836033 TI - Oxygen homeostasis. AB - Metazoan life is dependent upon the utilization of O(2) for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF-1 activity is regulated and by which HIF-1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis. PMID- 20836031 TI - Building the developmental oculome: systems biology in vertebrate eye development and disease. AB - The vertebrate eye is a sophisticated multicomponent organ that has been actively studied for over a century, resulting in the identification of the major embryonic and molecular events involved in its complex developmental program. Data gathered so far provides sufficient information to construct a rudimentary network of the various signaling molecules, transcription factors, and their targets for several key stages of this process. With the advent of genomic technologies, there has been a rapid expansion in our ability to collect and process biological information, and the use of systems-level approaches to study specific aspects of vertebrate eye development has already commenced. This is beginning to result in the definition of the dynamic developmental networks that operate in ocular tissues, and the interactions of such networks between coordinately developing ocular tissues. Such an integrative understanding of the eye by a comprehensive systems-level analysis can be termed the 'oculome', and that of serial developmental stages of the eye as it transits from its initiation to a fully formed functional organ represents the 'developmental oculome'. Construction of the developmental oculome will allow novel mechanistic insights that are essential for organ regeneration-based therapeutic applications, and the generation of computational models for eye disease states to predict the effects of drugs. This review discusses our present understanding of two of the individual components of the developing vertebrate eye--the lens and retina--at both the molecular and systems levels, and outlines the directions and tools required for construction of the developmental oculome. PMID- 20836034 TI - DNA methylation and gene expression. AB - Methylation of cytosines is the key epigenetic modification of DNA in eukaryotes and is associated with a repressed chromatin state and inhibition of gene expression. The methylation pattern in mammalian genomes is bimodal, with most of the genomes methylated except for short DNA stretches called CpG islands (CGIs), which are generally protected from methylation. Recent technical advances have made it possible to map DNA methylation patterns on a large scale. Several genomic studies have made significant progress in unraveling the intricate relationships between DNA methylation, chromatin structure, and gene expression. What is emerging is a more dynamic and complex association between DNA methylation and expression than previously known. Here we highlight several recent genomic studies with an emphasis on what new information is gained from these studies and what conclusions can be reached about the role of DNA methylation in controlling gene expression. PMID- 20836035 TI - The application of flux balance analysis in systems biology. AB - An increasing number of genome-scale reconstructions of intracellular biochemical networks are being generated. Coupled with these stoichiometric models, several systems-based approaches for probing these reconstructions in silico have been developed. One such approach, called flux balance analysis (FBA), has been effective at predicting systemic phenotypes in the form of fluxes through a reaction network. FBA employs a linear programming (LP) strategy to generate a flux distribution that is optimized toward a particular 'objective,' subject to a set of underlying physicochemical and thermodynamic constraints. Although classical FBA assumes steady-state conditions, several extensions have been proposed in recent years to constrain the allowable flux distributions and enable characterization of dynamic profiles even with minimal kinetic information. Furthermore, FBA coupled with techniques for measuring fluxes in vivo has facilitated integration of computational and experimental approaches, and is allowing pursuit of rational hypothesis-driven research. Ultimately, as we will describe in this review, studying intracellular reaction fluxes allows us to understand network structure and function and has broad applications ranging from metabolic engineering to drug discovery. PMID- 20836036 TI - Systems medicine--viewed through the real and computing lenses. AB - For further resources related to this article, please visit the WIREs website. PMID- 20836037 TI - Stochastic approaches in systems biology. AB - The discrete and random occurrence of chemical reactions far from thermodynamic equilibrium, and low copy numbers of chemical species, in systems biology necessitate stochastic approaches. This review is an effort to give the reader a flavor of the most important stochastic approaches relevant to systems biology. Notions of biochemical reaction systems and the relevant concepts of probability theory are introduced side by side. This leads to an intuitive and easy-to-follow presentation of a stochastic framework for modeling subcellular biochemical systems. In particular, we make an effort to show how the notion of propensity, the chemical master equation (CME), and the stochastic simulation algorithm arise as consequences of the Markov property. Most stochastic modeling reviews focus on stochastic simulation approaches--the exact stochastic simulation algorithm and its various improvements and approximations. We complement this with an outline of an analytical approximation. The most common formulation of stochastic models for biochemical networks is the CME. Although stochastic simulations are a practical way to realize the CME, analytical approximations offer more insight into the influence of randomness on system's behavior. Toward that end, we cover the chemical Langevin equation and the related Fokker-Planck equation and the two moment approximation (2MA). Throughout the text, two pedagogical examples are used to key illustrate ideas. With extensive references to the literature, our goal is to clarify key concepts and thereby prepare the reader for more advanced texts. PMID- 20836039 TI - Genome-wide maps of transcription regulatory elements. AB - Expression of eukaryotic genes with complex spatial-temporal regulation during development requires finer regulation than that of genes with simpler expression patterns. Given the high degree of conservation of the developmental gene set across distantly related phylogenetic taxa, it is argued that evolutionary variation has occurred by tweaking regulation of expression of developmental genes, rather than by changes in genes themselves. Complex regulation is often achieved through the coordinated action of transcription regulatory elements spread across the genome up to tens of kilobases from the promoters of their target genes. Disruption of regulatory elements has been implicated in several diseases and studies showing associations between disease traits and nonprotein coding variation hint for a role of regulatory elements as cause of diseases. Therefore, the identification and mapping of regulatory elements in genome scale is crucial to understand how gene expression is regulated, how organisms evolve, and to identify sequence variation causing diseases. Previously developed experimental techniques have been adapted to identify regulatory elements in genome scale and high-throughput, allowing a global view of their biological roles. We review methods as chromatin immunoprecipitation, DNase I hypersensitivity, and computational approaches and how they have been employed to generate maps of histone modifications, open chromatin, nucleosome positioning, and transcription factor binding regions in whole mammalian genomes. Given the importance of non-promoter elements in gene regulation and the recent explosion in the number of studies devoted to them, we focus on these elements and discuss the insights on gene regulation being obtained by these studies. PMID- 20836038 TI - Whole animal imaging. AB - Translational research plays a vital role in understanding the underlying pathophysiology of human diseases, and hence development of new diagnostic and therapeutic options for their management. After creating an animal disease model, pathophysiologic changes and effects of a therapeutic intervention on them are often evaluated on the animals using immunohistologic or imaging techniques. In contrast to the immunohistologic techniques, the imaging techniques are noninvasive and hence can be used to investigate the whole animal, oftentimes in a single exam which provides opportunities to perform longitudinal studies and dynamic imaging of the same subject, and hence minimizes the experimental variability, requirement for the number of animals, and the time to perform a given experiment. Whole animal imaging can be performed by a number of techniques including x-ray computed tomography, magnetic resonance imaging, ultrasound imaging, positron emission tomography, single photon emission computed tomography, fluorescence imaging, and bioluminescence imaging, among others. Individual imaging techniques provide different kinds of information regarding the structure, metabolism, and physiology of the animal. Each technique has its own strengths and weaknesses, and none serves every purpose of image acquisition from all regions of an animal. In this review, a broad overview of basic principles, available contrast mechanisms, applications, challenges, and future prospects of many imaging techniques employed for whole animal imaging is provided. Our main goal is to briefly describe the current state of art to researchers and advanced students with a strong background in the field of animal research. PMID- 20836041 TI - Modeling childbirth: elucidating the mechanisms of labor. AB - The process of childbirth and the mechanisms of labor have been studied for over a century, beginning with simple measurements of fetal skull and maternal pelvis dimensions. More recently, X-rays, ultrasound, and magnetic resonance imaging have been used to try and quantify the biomechanics of labor. With the development of computational technologies, biomechanical models have emerged as a quantitative analysis tool for modeling childbirth. These methods are well known for their capabilities to analyze function at the organ scale. This review provides an overview of the state-of-the-art finite element models of the mechanics of vaginal delivery, with detailed descriptions of the data sources, modeling frameworks, and results. We also discuss the limitations and improvements required in order for the models to be more accurate and clinically useful. Some of the major challenges include: modeling the complex geometry of the maternal pelvic floor muscles and fetal head motion during the second stage of labor; the lack of experimental data on the pelvic floor structures; and development of methods for clinical validation. To date, models have had limited success in helping clinicians understand possible factors leading to birth induced pelvic floor muscle injuries and dysfunction. However, much more can be achieved with further development of these quantitative modeling frameworks, such as tools for birth planning and medical education. PMID- 20836043 TI - Modeling actin dynamics. AB - Actin monomers assemble into filaments that structurally support cells as well as drive membrane protrusion for cell movement. Within cells, some actin structures are very dynamic and turn over rapidly, while others are very stable. Even purified actin filament dynamics are complex, and researchers have often turned to mathematical models in order to interpret data, test hypotheses, make predictions, and deepen understanding. Models of actin dynamics can be broadly divided into time-dependent models and time-independent models. Most commonly, time-independent models use numerical solutions of sets of differential equations to explore the effects of key parameters on the actin cycle at steady state. Recent examples have been used to predict the nucleotide profile of steady-state filaments and to illuminate the mechanisms behind profilin's effects on actin dynamics. Time-dependent models of actin dynamics have been either Monte Carlo simulations, which track individual filaments at various levels of detail or less commonly stochastic models, which have been explored and solved analytically. These Monte Carlo and stochastic models have recently been used to investigate filament length diffusion, filament length distributions, annealing and fragmentation, and pyrene fluorescence overshoots. We do not review force production/protrusion models as they tend to reduce the complexity of actin dynamics to a single 'elongation rate' and because these models have been recently well reviewed. PMID- 20836040 TI - In silico models of cancer. AB - Cancer is a complex disease that involves multiple types of biological interactions across diverse physical, temporal, and biological scales. This complexity presents substantial challenges for the characterization of cancer biology, and motivates the study of cancer in the context of molecular, cellular, and physiological systems. Computational models of cancer are being developed to aid both biological discovery and clinical medicine. The development of these in silico models is facilitated by rapidly advancing experimental and analytical tools that generate information-rich, high-throughput biological data. Statistical models of cancer at the genomic, transcriptomic, and pathway levels have proven effective in developing diagnostic and prognostic molecular signatures, as well as in identifying perturbed pathways. Statistically inferred network models can prove useful in settings where data overfitting can be avoided, and provide an important means for biological discovery. Mechanistically based signaling and metabolic models that apply a priori knowledge of biochemical processes derived from experiments can also be reconstructed where data are available, and can provide insight and predictive ability regarding the behavior of these systems. At longer length scales, continuum and agent-based models of the tumor microenvironment and other tissue-level interactions enable modeling of cancer cell populations and tumor progression. Even though cancer has been among the most-studied human diseases using systems approaches, significant challenges remain before the enormous potential of in silico cancer biology can be fully realized. PMID- 20836044 TI - Toward failure analyses in systems biology. AB - Parallels between designed and biological systems with respect to formal failure analyses have been presented. Failure analysis in designed systems depends on an identified, limited set of parameters or operation variables with high predictive value. In contrast, the biological systems pose problems in identification of operation variables and the identified variables may not be accurate predictors of failure. The difficulty in parameter identification is because of large numbers of components and the inability to envelope variables at each compartment or contour level. Contour level maps for biological systems are currently non existent, and most failure models are based on very limited, unilateral operation variables (a mutant gene). Operation variable identification within each contour level will enhance failure analyses of complex biological systems. PMID- 20836042 TI - Gene-environment interactions, folate metabolism and the embryonic nervous system. AB - Formation of brain and spinal cord requires the successful closure of neural ectoderm into an embryonic neural tube. Defects in this process result in anencephaly or spina bifida, which together constitute a leading cause of mortality and morbidity in children, affecting all ethnic and socioeconomic groups. The subject of intensive research for decades, neural tube defects (NTDs), are understood to arise from complex interactions of genes and environmental conditions, though systems-level details are still elusive. Despite the variety of underlying causes, a single intervention, folic acid supplementation given in the first gestational month, can measurably reduce the occurrence of NTDs in a population. Evidence for and the scope of gene environment interactions in the genesis of NTDs is discussed. A systems-based approach is now possible toward studies of genetic and environmental influences underlying NTDs that will enable the assessment of individual risk and personalized optimization of prevention. PMID- 20836045 TI - Comparative systems biology: from bacteria to man. AB - Comparative analyses, as carried out by comparative genomics and bioinformatics, have proven extremely powerful to obtain insight into the identity of specific genes that underlie differences and similarities across species. The central concept developed in this chapter is that important aspects of the functional differences between organisms derive not only from the differences in genetic components (which underlies comparative genomics) but also from dynamic, molecular (physical) interactions. Approaches that aim at identifying such network-based rather than component-based homologies between species we shall call Comparative Systems Biology. It will be illustrated by a number of examples from metabolic networks from prokaryotes, via yeast, to man. The potential for species comparisons, at the genome-scale using classical approaches and at the more detailed level of dynamic molecular networks will be illustrated. In our opinion, comparative systems biology, as a marriage between bioinformatics and systems biology, will offer new insights into the nature of organisms for the benefit of medicine, biotechnology, and drug design. As dynamic modeling is becoming more mainstream in cell biology, the potential of comparative systems biology will become more evident. PMID- 20836046 TI - Circadian oscillators in eukaryotes. AB - The biological clock, present in nearly all eukaryotes, has evolved such that organisms can adapt to our planet's rotation in order to anticipate the coming day or night as well as unfavorable seasons. As all modern high-precision chronometers, the biological clock uses oscillation as a timekeeping element. In this review, we describe briefly the discovery, historical development, and general properties of circadian oscillators. The issue of temperature compensation (TC) is discussed, and our present understanding of the underlying genetic and biochemical mechanisms in circadian oscillators are described with special emphasis on Neurospora crassa, mammals, and plants. PMID- 20836047 TI - Systems analysis of alternative splicing and its regulation. AB - Alternative splicing (AS) has emerged as a key mechanism that accounts for gene expression diversity in metazoan organisms. Splicing is tightly regulated by a repertoire of RNA and protein factors and RNA sequence elements that function in a cooperative manner. Systems-level experimental and computational approaches have been instrumental in establishing comprehensive profiles of transcript variants generated by AS. In addition, systems biology approaches are starting to define how combinatorial splicing regulation shapes the complex splicing phenotypes observed in different tissue types and developmental stages and under different conditions. Here, we review recent progress in these areas. PMID- 20836048 TI - Nutritional regulation of division of labor in honey bees: toward a systems biology perspective. AB - Organisms adapt their behavior and physiology to environmental conditions through processes of phenotypic plasticity. In one well-studied example, the division of labor among worker honey bees involves a stereotyped yet plastic pattern of behavioral and physiological maturation. Early in life, workers perform brood care and other in-hive tasks and have large internal nutrient stores; later in life, they forage for nectar and pollen outside the hive and have small nutrient stores. The pace of maturation depends on colony conditions, and the environmental, physiological, and genomic mechanisms by which this occurs are being actively investigated. Here we review current knowledge of the mechanisms by which a key environmental variable, nutritional status, influences worker honey bee division of labor. These studies demonstrate that changes in individual nutritional status and conserved food-related molecular and hormonal pathways regulate the age at which individual bees begin to forage. We then outline ways in which systems biology approaches, enabled by the sequencing of the honey bee genome, will allow researchers to gain deeper insight into nutritional regulation of honey bee behavior, and phenotypic plasticity in general. PMID- 20836049 TI - Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity. AB - Prevalence of obesity in the general population has increased in the past 15 years from 15% to 35%. With increasing obesity, the coincident medical and social consequences are becoming more alarming. Control over food intake is crucial for the maintenance of body weight and represents an important target for the treatment of obesity. Central nervous system mechanisms responsible for control of food intake have evolved to sense the nutrient and energy levels in the organism and to coordinate appropriate responses to adjust energy intake and expenditure. This homeostatic system is crucial for maintenance of stable body weight over long periods of time of uneven energy availability. However, not only the caloric and nutritional value of food but also hedonic and emotional aspects of feeding affect food intake. In modern society, the increased availability of highly palatable and rewarding (fat, sweet) food can significantly affect homeostatic balance, resulting in dysregulated food intake. This review will focus on the role of hypothalamic and mesolimbic/mesocortical dopaminergic (DA) circuitry in coding homeostatic and hedonic signals for the regulation of food intake and maintenance of caloric balance. The interaction of dopamine with peripheral and central indices of nutritional status (e.g., leptin, ghrelin, neuropeptide Y), and the susceptibility of the dopamine system to prenatal insults will be discussed. Additionally, the importance of alterations in dopamine signaling that occur coincidently with obesity will be addressed. PMID- 20836051 TI - Odor representations in the mammalian olfactory bulb. AB - A first key step in studying a sensory modality is to define how the brain represents the features of the sensory stimulus. This has proven to be a challenge in olfaction, where even the stimulus features have been a matter of considerable debate. In this review, we focus on olfactory representations in the first stage of the olfactory pathway, the olfactory bulb (OB). We examine the diverging viewpoints on spatially organized versus distributed representations. We then consider how odor sampling through respiration is a key part of the odorant code. Finally, we ask how the bulb handles the challenging task of representing mixtures. We suggest that current evidence points toward a representation that is spatially organized at the inputs but later distributed, with the spatial organization not being used for much computation. Nevertheless, this is a simple representation that effectively represents multiple individual odorants, as well as odor mixtures. PMID- 20836052 TI - Modeling of blood flow in arterial trees. AB - Advances in computational methods and medical imaging techniques have enabled accurate simulations of subject-specific blood flows at the level of individual blood cell and in complex arterial networks. While in the past, we were limited to simulations with one arterial bifurcation, the current state-of-the-art is simulations of arterial networks consisting of hundreds of arteries. In this paper, we review the advances in methods for vascular flow simulations in large arterial trees. We discuss alternative approaches and validity of various assumptions often made to simplify the modeling. To highlight the similarities and discrepancies of data computed with different models, computationally intensive three-dimensional (3D) and inexpensive one-dimensional (1D) flow simulations in very large arterial networks are employed. Finally, we discuss the possibilities, challenges, and limitations of the computational methods for predicting outcomes of therapeutic interventions for individual patients. PMID- 20836050 TI - APOBEC-1-mediated RNA editing. AB - RNA editing defines a molecular process by which a nucleotide sequence is modified in the RNA transcript and results in an amino acid change in the recoded message from that specified in the gene. We will restrict our attention to the type of RNA editing peculiar to mammals, i.e., nuclear C to U RNA editing. This category of RNA editing contrasts with RNA modifications described in plants, i.e., organellar RNA editing (reviewed in Ref 1). Mammalian RNA editing is genetically and biochemically classified into two groups, namely insertion deletional and substitutional. Substitutional RNA editing is exclusive to mammals, again with two types reported, namely adenosine to inosine and cytosine to uracil (C to U). This review will examine mammalian C to U RNA editing of apolipoproteinB (apoB) RNA and the role of the catalytic deaminase Apobec-1. We will speculate on the functions of Apobec-1 beyond C to U RNA editing as implied from its ability to bind AU-rich RNAs and discuss evidence that dysregulation of Apobec-1 expression might be associated with carcinogenesis through aberrant RNA editing or altered RNA stability. PMID- 20836053 TI - Spatial and annual variation to define the normal range of biological endpoints: an example with biomarkers in perch. AB - A signal from a biological endpoint can be considered evidence of environmental impact only if it is known that similar signals are unlikely to occur naturally. Using multiple reference sites, the normal range can be estimated. This can be defined as the span that includes 95% of the reference sites. If an investigated site is outside this range, it is interpreted as evidence of impact. The choice of reference sites is thus important for the outcome of the study. Here, biomarker levels in perch (Perca fluviatilis) at a potentially impacted site were compared to different types of reference data. The potentially impacted site was located close to a densely populated area. Four reference sites were located in relatively undisturbed areas on the Swedish Baltic coast. Furthermore, historical data from one of the reference sites were included. The present study showed that multiple reference sites are needed to avoid the risk of interpreting natural variation as impact. The number of reference sites needed depends on the desired level of statistical power. An alternative to multiple reference sites may be to use historical data to estimate the natural variation. However, historical data can include temporal variation due to factors that may not be relevant for the hypothesis that is tested, e.g., climatic variation or changed background levels of pollution. PMID- 20836054 TI - Acute toxicity of fungicide formulations to amphibians at environmentally relevant concentrations. AB - Fungicide use on row crops is increasing dramatically due to promotion of these products for general plant health and increased yield even during low disease pressure. These fungicides are applied aerially, which may lead to amphibian exposure within fields or in nearby habitat. Exposure to three of these fungicides at environmentally relevant conditions resulted in mortality for Bufo tadpoles and juveniles for two of the fungicides. Headline(r), the most commonly used on row crops, resulted in >50% mortality for juveniles at corn label application rates and 100% mortality for tadpoles at one-tenth the label rate for corn. Stratego(r) killed 40% of exposed tadpoles on average at the corn label rate, but only 7% of the juveniles. Overall, Quilt(r) appeared less toxic than the other fungicides, resulting in 7 to 10% mortality of tadpoles and 4 to 22% mortality of juveniles at all concentrations (from 0.1* to 10* label rate). These fungicides, especially Headline, may pose a major hazard for amphibians exposed as tadpoles and/or juveniles at environmentally relevant concentrations. PMID- 20836055 TI - Chemical activity as an integrating concept in environmental assessment and management of contaminants. AB - It is suggested that chemical activity in environmental media can serve as an integrating concept for holistic evaluations of contaminants, including their fate and effects. In support of this assertion, information underlying the thermodynamic principles and the relationships between monitored and modeled concentrations and activities are presented. The toxicological significance of activity is discussed, with emphasis on substances that exert baseline narcosis. Illustrations are given of the application of activity using models and monitoring data for chemical risk assessment and management. It is argued that the proximity of prevailing multimedia environmental activities to activities causing toxic effects is a particularly insightful metric of environmental contamination for both narcotics and reactive toxic substances. PMID- 20836056 TI - Using Monte Carlo analysis to characterize the uncertainty in final acute values derived from aquatic toxicity data. AB - Many ambient water quality criteria established to protect aquatic life from acute toxicity are calculated using a procedure described in the US Environmental Protection Agency's "1985 Guidelines" (USEPA 1985). The procedure yields a final acute value (FAV) from acceptable median lethal or effective concentrations (LC50 or EC50, respectively) that is a single-point, deterministic estimate of the concentration of a chemical substance that will protect 95% of aquatic species from >50% mortality or other acute toxic effects. However, because of variation and uncertainty associated with toxicity test results, uncertainty in the estimated FAV exists that is not accounted for by the 1985 Guidelines procedure. Here, Monte Carlo analysis is used to characterize this uncertainty. The analysis uses Cu EC50 values adjusted for differences in test water chemistry obtained from USEPA's final freshwater Cu criteria guidance published in 2007. Additional Monte Carlo simulations illustrate Cu FAV distributions obtained using a subset of tested species and assuming fewer replicate tests. The deterministic procedure yields an FAV of 4.68 ug/L for the complete data set. By comparison, 3 replicate Monte Carlo simulations yielded mean FAVs of 4.66 ug/L. The 5th and 95th percentiles of the distribution of calculated FAVs were 4.14 ug/L and 5.20 ug/L, respectively. Reducing the number of tested genera from 27 to 8 (the minimum recommended by the 1985 Guidelines) and setting the number of tests per species equal to 3 yielded 5th and 95th percentiles of 1.22 ug/L and 6.18 ug/L, respectively, compared to a deterministic estimate of 2.80 ug/L. Results of this study indicate that Monte Carlo analysis can be used to improve the understanding and communication of uncertainty associated with water quality criteria derived from acute toxicity data using the 1985 Guidelines. This may benefit the development, revision, and application of these criteria in the future. PMID- 20836057 TI - Public perception and stakeholder involvement in the crisis management of sediment-related disasters and their mitigation: the case of the Stoze debris flow in NW Slovenia. AB - Sediments can pose a threat to humans not only when these deposits are polluted but also due to their large quantities. This physical aspect of sediments as a risk will be shown on a case study of a sediment-related disaster that occurred in the mountainous part of Slovenia, Central Europe in 2000. In November 2000, after a long wet period a large debris landslide had been triggered on the Stoze slope and stopped in the channel of the Mangart creek. Such an event took the majority of local inhabitants and emergency staff by surprise. Nevertheless, they had just organized the first mitigation measures when, after 35 hours, they were surprised by an even larger debrisflowinitiated as the second phase of the same mass movement event. Within a few minutes, the wet debris flow had devastated the alpine valley of the Koritnica River and killed 7 people in the village of Log pod Mangartom. This paper deals with crisis management and first mitigation measures under this very tense situation of searching for dead bodies. The uncertainty about possible new debris flows drove all inhabitants out of the village by a decision of the civil protection unit, and also other activities of the emergency relief units were overshadowed by the 7 victims. One of the main problems and challenges at the same time was the over 700,000 m3 of wet debris flow deposits in the area of the village of Log pod Mangartom within the Triglav National park, which posed a direct threat of flooding during the first heavy rainfalls in spring 2001, and which were about to be removed to make place for future debris flows. The understanding about what really happened or about the immediate triggering factors was different among the professionals in charge for relief action and for preparing a final remediation plan. The first phase during and immediately after the disaster (relief intervention of emergency units especially those for civil protection) can be described as Concern-Driven Crisis Management or as Judgment-Based Crisis Management, respectively. The Quantitative Risk Assessment came into play in the second remediation phase through special law enforcement. Even after 10 years since the disaster, general public perception speaks in favor of judgment-based risk management rather than quantitative risk assessment, a situation that can be explained by the poor understanding of the system by local inhabitants, by low public involvement in the preparation of the final remediation plan undertaken by the state agencies, and by the fact that the final remediation is still not finished. PMID- 20836058 TI - Incorporating contaminant bioavailability into sediment quality assessment frameworks. AB - The recently adopted sediment quality assessment framework for evaluating bay and estuarine sediments in the state of California incorporates bulk sediment chemistry as a key line of evidence (LOE) but does not address the bioavailability of measured contaminants. Thus, the chemistry-based LOE likely does not provide an accurate depiction of organism exposure in all cases, nor is it particularly well suited for assessment of causality. In recent years, several methods for evaluating the bioavailability of sediment-associated contaminants have emerged, which, if optimized and validated, could be applied to improve the applicability and broaden the scope of sediment quality assessment. Such methods include equilibrium-based biomimetic extractions using either passive sampling devices (PSDs) or measures of rapidly desorbing contaminant pools, which provide information compatible with existing mechanistic approaches. Currently, these methods show promise in relating bioaccessible chemicals to effects endpoints, including bioaccumulation of hydrophobic organic compounds and/or toxicity due to metals. Using these methods, a bioavailability LOE for organics is proposed based on PSD and equilibrium partitioning theory that can be employed as an independent LOE or in assessing causality in tiered toxicity identification evaluations. Current and future research should be aimed at comparing the performance of PSDs and their relationships with effects concentrations, field validation of the most promising methods, addressing contaminant mixtures, further developing the parameterization of the proposed bioavailability LOE, and providing a better understanding of the underlying diagenetic cycling of metal contaminants that lead to exposure, affect bioavailability, and drive adverse outcomes. PMID- 20836059 TI - Biomass or growth rate endpoint for algae and aquatic plants: relevance for the aquatic risk assessment of herbicides. AB - Ecotoxicological studies with algae and aquatic plants are essential parts of the aquatic risk assessment for crop protection products (CPP). Growth rate is used as a response variable and in addition the effects on biomass and/or yield (in the following biomass) can be measured. The parameter biomass generally provides a lower numerical value compared with the growth rate for systematic and mathematical reasons. Therefore, some regulators prefer to use the EbC50 value (i.e., the concentration at which 50% reduction of biomass is observed) rather than ErC50 (the concentration at which a 50% inhibition of growth rate is observed) as the endpoint for ecotoxicological risk assessment. However, the parameter growth rate is scientifically more appropriate and robust against deviations in test conditions, permitting better interpretation of, and comparison between, studies. The aim of the present work is to evaluate the growth rate and biomass parameters with regard to their protectiveness and suitability for environmental risk assessment of CPP. It has been shown for a number of herbicides that the use of the EC50 value (without distinction between growth rate and biomass endpoints) from laboratory studies in combination with an assessment factor of 10 is sufficiently protective for aquatic plants (except for the herbicide 2,4-D). In this paper we evaluated EbC50 and ErC50 values separately. Data on 19 different herbicides were compiled from the literature or GLP reports. The EbC50 and ErC50 values obtained in laboratory studies were compared with effect concentrations in ecosystem studies (mainly mesocosm). This comparison of laboratory and field data shows that the overall aquatic risk assessment using ErC50 values in combination with the currently applied assessment factor of 10 is sufficient to exclude significant risk to aquatic plants in the environment. PMID- 20836060 TI - Assessment of the levels of heavy metal pollution in roadside soils of Eskisehir, Turkey. AB - A detailed study was conducted to determine the current status of the heavy metals Cd, Cu, Cr, Fe, Hg, Mn, Ni, Pb, and Zn in Eskisehir, Turkey. The 15 different locations (n =270) studied were specifically selected to identify the effects of soil pollution on the tramway, which has been in service since December 2004 for public transportation in Eskisehir. The samples were taken from three different lines: tramway-only lines, traffic-only lines, and both traffic and tramway lines. The pollution level was estimated based on the geoaccumulation index (I(geo)), the enrichment factor (EF), the pollution index, and the integrated pollution index (IPI). The values for the IPI were in the following order: Pb > Zn > Cu > Fe > Mn > Ni > Cr > Cd, but mercury was not detected at any sample point. These indexes for metals in the soils under consideration correlated with either low or median levels of pollution. In addition, descriptive statistics were provided for the heavy metals under consideration, and box-plots were constructed and interpreted for all measured indices. PMID- 20836061 TI - Lead pellet retention time and associated toxicity in northern bobwhite quail (Colinus virginianus). AB - Birds are exposed to Pb by oral ingestion of spent Pb shot as grit. A paucity of data exists for retention and clearance of these particles in the bird gastrointestinal tract. In the current study, northern bobwhite quail (Colinus virginianus) were orally gavaged with 1, 5, or 10 Pb shot pellets, of 2-mm diameter, and radiographically followed over time. Blood Pb levels and other measures of toxicity were collected, to correlate with pellet retention. Quail dosed with either 5 or 10 pellets exhibited morbidity between weeks 1 and 2 and were removed from further study. Most of the Pb pellets were absorbed or excreted within 14 d of gavage, independent of dose. Pellet size in the ventriculus decreased over time in radiographs, suggesting dissolution caused by the acidic pH. Birds dosed with one pellet showed mean blood Pb levels that exceeded 1,300 ug/dl at week 1, further supporting dissolution in the gastrointestinal tract. Limited signs of toxicity were seen in the one-pellet birds; however, plasma delta-aminolevulinic acid dehydratase (d-ALAD) activity was persistently depressed, suggesting possible impaired hematological function. PMID- 20836062 TI - Use of vegetated agricultural drainage ditches to decrease toxicity of irrigation runoff from tomato and alfalfa fields in California, USA. AB - The current study investigated the potential of vegetated drainage ditches for mitigating the impact of agricultural irrigation runoff on downstream aquatic ecosystems. Water column toxicity to larval fathead minnow (Pimephales promelas),and the amphipod Hyalella azteca was measured for 12 h or less at the ditch inflow and outflow, using custom-built in situ exposure systems. In addition, water and sediment samples were subject to standard toxicity tests with Ceriodaphnia dubia and H. azteca, respectively. No acute toxicity to larval fathead minnow was observed; however, runoff was highly toxic to invertebrates. Passage through a 389- to 402-m section of vegetated ditch had a mitigating effect and reduced toxicity to some degree. However, runoff from an alfalfa field treated with chlorpyrifos remained highly toxic to both invertebrate species, and runoff from a tomato field treated with permethrin remained highly toxic to H. azteca after passage through the ditch. Predicted toxic units calculated from insecticide concentrations in runoff and 96-h median lethal concentration (LC50) values generally agreed with C. dubia toxicity measured in the laboratory but significantly underestimated in situ toxicity to H. azteca. Sediments collected near the ditch outflow were toxic to H. azteca. Results from the current study demonstrate that experimental vegetated ditches were unable to eliminate the risk of irrigation runoff to aquatic ecosystems. In addition, protective measures based on chemical concentrations or laboratory toxicity tests with C. dubia do not ensure adequate protection of aquatic ecosystems from pyrethroid-associated toxicity. PMID- 20836063 TI - Biotransformation of the 8:2 fluorotelomer acrylate in rainbow trout. 1. In vivo dietary exposure. AB - The bioaccumulation and biotransformation of the 8:2 fluorotelomer acrylate (C(8) F(17) CH(2) CH(2) OC(O)CH = CH(2) , 8:2 FTAc) was investigated in rainbow trout via dietary exposure. The 8:2 FTAc is a monomer used in the manufacture of fluorinated polymers and has been widely detected in the atmosphere. The parent 8:2 FTAc and suspected intermediate and terminal metabolites were monitored in liver, blood, kidney, bile, and feces during the 5-d uptake and 8-d elimination phases using gas chromatography-mass spectrometry (GC-MS)- and liquid chromatography-tandem mass spectrometry (LC-MS/MS)- based methods. Very low levels of the 8:2 FTAc were detected in the internal tissues and feces, suggesting that the 8:2 FTAc was rapidly biotransformed in the gut or liver. Similarly, low concentrations of the 8:2 fluorotelomer alcohol (FTOH) were accumulated in the fish tissues. The 8:2 saturated fluorotelomer carboxylate (FTCA) was formed in the highest concentration, reaching steady-state tissue concentrations of approximately 1,000 to 1,400 ng/g wet weight. The 8:2 FTUCA and 7:3 FTCA were also accumulated in high levels, at levels approximately 10-fold lower than the 8:2 FTCA. Both the 7:3 FTCA and perfluorooctanoate (PFOA) showed increasing levels throughout the uptake phase and into the initial stages of the elimination phase, indicating continued formation through precursors still present in the body. Perfluorononanoate (PFNA) was formed in low nanogram per gram wet weight levels. The intermediate and terminal metabolites were also detected in the bile and feces, indicating an important elimination pathway for these compounds. In addition, the 8:2 FTOH glucuronide conjugate was measured in relatively high concentrations in the bile and feces. The results of the current study demonstrated a scenario in which a biologically labile compound is biotransformed to terminal metabolites that are much more biologically persistent. PMID- 20836064 TI - Biotransformation of the 8:2 fluorotelomer acrylate in rainbow trout. 2. In vitro incubations with liver and stomach S9 fractions. AB - The biotransformation of the 8:2 fluorotelomer acrylate (C(8) F(17) CH(2) CH(2) OC(O)CH = CH(2) , 8:2 fluorotelomer-based acrylate [FTAc]) was quantitatively investigated in cytosolic (S9) fractions isolated from rainbow trout stomach and liver. The in vitro studies presented in this manuscript compliment the whole body 8:2 FTAc dietary exposure study, presented as a companion paper. The S9 fractions were prepared in our laboratory, using fish that had previously been used as control animals in our in vivo study. Before 8:2 FTAc incubations, general carboxylesterase activity was determined using paranitrophenyl acetate (PNPA) as the substrate with formation of paranitrophenol monitored using an ultraviolet-vis spectrometer. In the 8:2 FTAc incubations, the degradation of the parent compound and 8:2 fluorotelomer alcohol (FTOH) formation was monitored by gas chromatography-mass spectrometry. Incubations were performed in triplicate, over a range of concentrations encompassing two orders of magnitude, and the initial rate of 8:2 FTOH or paranitrophenol formation was determined. Enzyme kinetic parameters were determined by plotting the initial rate versus concentration, using nonlinear regression analysis. The maximum initial velocities of the enzyme-catalyzed reaction (V(max)) in the PNPA incubations were 614 +/- 18 nmol/min/mg and 147 +/- 16 nmol/min/mg for the liver and stomach fractions, respectively. These values are much faster than other phase I and II metabolism reactions. The calculated intrinsic clearance rates (CL(int)) for the 8:2 FTAc incubations were 1.7 and 0.40 ml/min/mg protein, respectively. These results show that the esterase activity toward the 8:2 FTAc is only fourfold greater in the liver as compared with the stomach. These trends demonstrate the potential for considerable extrahepatic metabolism of the 8:2 FTAc before uptake into the internal tissues, ultimately limiting the overall bioaccumulation. PMID- 20836065 TI - Comparison of field and laboratory exposures of Lumbriculus variegatus to polychlorinated biphenyl-impacted river sediments. AB - A method is described for conducting 14-d in situ sediment bioaccumulation tests with the freshwater oligochaete Lumbriculus variegatus, at the bottom of a slow flowing river. The in situ test exposure chambers were constructed from cylindrical plastic tubes with flow-through mesh screens and were attached to a wire basket that was weighted to the river bottom at seven sites in the lower Grasse River in New York State, USA. This design was successful in exposing L. variegatus to native sediment and overlying water under field conditions, with adequate organism mass recovery (87 +/- 19%). Results compared well with ex situ laboratory bioaccumulation conducted in parallel, expressed in terms of tissue concentration, biota-sediment accumulation factors (BSAFs), and bioaccumulation factors (BAFs). Bioaccumulation of polychlorinated biphenyls (PCBs) in L. variegatus (ug PCB/g wet wt) in laboratory and field tests was found to be within a factor of 2. The small variation between in situ and ex situ may have been caused by differences in water exchange rate under the two exposure scenarios, or other factors affecting organism behavior. Values of BSAF showed a hyperbolic trend with K(OW) , peaking at BSAF of 7 for congeners with log K(OW) of 6. Bioaccumulation factors also peaked at a value of 10(6.5) for congeners with log K(OW) value of 6 but remained steady around that value for the higher K(OW) congeners. These observations may reflect under-equilibration or reduced bioavailability of more hydrophobic PCBs in worm tissues or other analytical artifacts. PMID- 20836066 TI - Chronic exposure to fluoxetine (Prozac) causes developmental delays in Rana pipiens larvae. AB - Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, are among the many pharmaceuticals detected in aquatic ecosystems. Although the acute effects of SSRIs on select organisms have been reported, little is understood about the chronic effects of these drugs on amphibians, which are particularly sensitive to environmental pollutants. Serotonin plays important roles in many physiological functions, including a wide array of developmental processes. Exposure to SSRIs during development may cause developmental complications in a variety of organisms, but little is known about the degree of exposure necessary to cause deleterious effects. Here, we sought to gain a better understanding of the effects of SSRIs on amphibian development by use of a combined laboratory and outdoor mesocosm study. Tadpoles in a laboratory setting were exposed to a low (0.029 ug/L) and a high (0.29 ug/L) concentration of the common SSRI fluoxetine from stages 21 and 22 through completion of metamorphosis. Tadpoles in outdoor mesocosms were exposed to fluoxetine concentrations ranging from 0.1 to 0.3 ug/L. Exposed tadpoles in the laboratory showed delayed development compared with controls when stage was assessed throughout the experiment. Control tadpoles also gained weight faster than treatment tadpoles, which may be explained by reduced food intake. Mesocosm tadpoles exhibited similar trends, but no significant differences were detected. These results indicate that ecologically relevant levels of fluoxetine may cause developmental delays in amphibians. PMID- 20836067 TI - Mixture toxicity from photosystem II inhibitors on microalgal community succession is predictable by concentration addition. AB - The typical pollution situation involves chemical mixtures, and assessing the risks of single chemicals one at a time is not sufficient. Concentration addition (CA) has been suggested as a predictive tool in mixture ecotoxicology. The accuracy of CA for mixtures of similarly acting chemicals has been demonstrated under relatively simple biological conditions in single-species tests. To consider the high diversity of interconnected species in ecosystems, one must evaluate CA on a community level of biological organization. We sampled marine periphyton communities from the west coast of Sweden and exposed them to photosystem II (PSII) inhibiting herbicides for 4 d in the SWIFT test, a semistatic, small-scale laboratory test. During this time, the communities went through an ecological succession, influenced by the toxicants in a concentration dependent manner. Multidimensional scaling was used to assess similarities in the effects of two different sets of PSII inhibitors on pigment profiles, which reflects the taxonomic structure and the physiological status of the microalgal community. One mixture of structurally congeneric phenylureas and one mixture of non-congeneric PSII inhibitors were tested. All PSII inhibitors and their mixtures caused similar changes in the pigment profiles, demonstrating that they not only have a similar biochemical mechanism of action but also are similarly acting on a community level. Concentration addition accurately predicted the effects of both mixtures over the entire effect range. This demonstrates that chemical congenericity is not required for a high predictive power of CA. Instead, in perfect analogy to the situation in single-species tests, a similar mode of action is a sufficient prerequisite for a successful application of CA. PMID- 20836068 TI - Toxicity of petroleum hydrocarbon distillates to soil organisms. AB - Canadian standards for petroleum hydrocarbons in soil are based on four distillate ranges (F1, C6-C10; F2, >C10-C16; F3, >C16-C34; and F4, >C34). Concerns have arisen that the ecological soil contact standards for F3 may be overly conservative. Oil distillates were prepared and characterized, and the toxicity of F3 and two subfractions, F3a (>C16-C23) and F3b (>C23-C34), to earthworms (Eisenia andrei), springtails (Orthonychiurus folsomi), and northern wheatgrass (Elymus lanceolatus), as well as the toxicity of F2 to earthworms, was determined. Clean soil was spiked with individual distillates and measured concentrations were determined for select tests. Results agree with previous studies with these distillates. Reported toxicities of crude and petroleum products to invertebrates were generally comparable to that of F3 and F3a. The decreasing order of toxicity was F3a > F3 > F3b with invertebrates, and F3a > F3b > F3 with plants. The toxicities of F3a and F3b were not sufficiently different to recommend regulating hydrocarbons based on these distillate ranges. The results also suggest that test durations may be insufficient for determining toxicity of higher distillate ranges, and that the selection of species and endpoints may significantly affect interpretation of toxicity test results. PMID- 20836069 TI - Adsorption of tetracycline on single-walled and multi-walled carbon nanotubes as affected by aqueous solution chemistry. AB - Carbon nanotubes have shown great potential as effective adsorbents for hydrophobic organic contaminants in water treatment. The present study investigated the influence of aqueous solution chemistry on the adsorption of tetracycline to carbon nanotubes. Specifically, the effects of ionic strength (NaCl and CaCl(2) ) and presence of Cu(2+) ion (7.5 mg/L) or dissolved soil or coal humic acids (50 mg/L) on adsorption of tetracycline to single-walled carbon nanotubes (SWNT), multi-walled carbon nanotubes (MWNT), and nonporous pure graphite as a model of the graphite surface were systematically estimated. The presence of humic acids suppressed tetracycline adsorption on graphite and MWNT prominently, with stronger effects observed on graphite, but only slightly affected tetracycline adsorption on SWNT. The relatively large humic acid components could not readily access the small interstitial spaces of SWNT and thus were less competitive with tetracycline adsorption. The presence of Cu(2+) ion increased tetracycline adsorption to both SWNT and MWNT through the mechanism of cation bridging, with much larger effects observed on MWNT. This was probably because when compared with the Cu(2+) ions complexed on the surface of SWNT, those on the surface of MWNT having larger mesoporous interstices were more accessible to the relatively bulky tetracycline molecule. Increasing the ionic strength from 10 mM to 100 mM decreased tetracycline adsorption on both SWNT and MWNT, which was attributed to electronic shielding of the negatively charged surface sites. These results show that aqueous solution chemistry is important to tetracycline adsorption on carbon nanotubes. PMID- 20836070 TI - Toxicity to Melita plumulosa from intermittent and continuous exposures to dissolved copper. AB - The concentrations of metal contaminants often fluctuate in estuarine waters; yet we have limited knowledge about the effects of intermittent exposures on estuarine organisms. Using 10-d lethality bioassays with the epibenthic amphipod Melita plumulosa, different combinations of intermittent (pulsed) dissolved Cu exposure were investigated, varying Cu concentration, pulse duration, and time between pulses. Negligible organism mortality was observed immediately after single 12- to 62-h duration pulsed exposures of 100 to 900 ug/L dissolved Cu. However, delayed mortality was observed in the subsequent 96-h nonexposure period, after which negligible additional mortality occurred during the remainder of the 240-h tests. For multiple pulsed exposures, increasing the time between pulses from 0 to 144 h did not result in significantly different mortality rates for 300 and 400 ug/L dissolved copper, indicating that the organisms did not recover between pulses. Organism mortality exhibited a strong relationship with the time-averaged concentration (TAC) resulting from the combination of exposure concentration and duration. The lethal concentration to 50 (LC50), 20 (LC20), and 10% (LC10) (95% confidence interval) of the test population for the combined TAC exposure-survival data were 86 (71-103), 44 (30-64), and 30 (18-49) ug Cu/L, respectively, which were similar to the respective values of 100 (87-114), 55 (43 70), and 39 (28-54) ug Cu/L determined for continuous exposure. The results from the current study support the use of analytical techniques capable of determining the time-averaged concentration of metals, because they will more accurately predict the effects of toxiciants on organisms than single time-point measurements. PMID- 20836071 TI - The value of repeating studies and multiple controls: replicated 28-day growth studies of rainbow trout exposed to clofibric acid. AB - Two studies to examine the effect of waterborne clofibric acid (CA) on growth rate and condition of rainbow trout were conducted using accepted regulatory tests (Organisation for Economic Co-operation and Development [OECD] 215). The first study (in 2005) showed significant reductions after 21 d of exposure (21-d growth lowest-observed-effect concentration [LOEC] = 0.1 ug/L, 21-d condition LOEC = 0.1 ug/L) that continued to 28 d. Growth rate was reduced by approximately 50% (from 5.27 to 2.67% per day), while the condition of the fish reduced in a concentration-dependant manner. Additionally, in a concentration-dependent manner, significant changes in relative liver size were observed, such that increasing concentrations of CA resulted in smaller livers after 28-d exposure. A no-observed-effect concentration (NOEC) was not achieved in the 2005 study. An expanded second study (in 2006) that included a robust bridge to the 2005 study, with four replicate tanks of eight individual fish per concentration, did not repeat the 2005 findings. In the 2006 study, no significant effect on growth rate, condition, or liver biometry was observed after 21 or 28 d (28-d growth NOEC = 10 ug/L, 28-d condition NOEC = 10 ug/L), contrary to the 2005 findings. We do not dismiss either of these findings and suggest both are relevant and stand for comparison. However, the larger 2006 study carries more statistical power and multiple-tank replication, so probably produced the more robust findings. Despite sufficient statistical power in each study, interpretation of these and similar studies should be conducted with caution, because much significance is placed on the role of limited numbers of individual and tank replicates and the influence of control animals. PMID- 20836072 TI - Single-crystalline Sb2Se3 nanowires for high-performance field emitters and photodetectors. PMID- 20836073 TI - Exploring zebrafish genomic, functional and phenotypic data using ZFIN. AB - The zebrafish model organism database (ZFIN) provides a Web resource of zebrafish genomic, genetic, developmental, and phenotypic data. ZFIN curates and integrates data from current literature and from direct data submissions from laboratories. In addition, ZFIN collaborates with other bioinformatics organizations to provide links to other relevant data. These data can be accessed through a variety of Web based search and display tools. This unit focuses on some of the basic methods to search, visualize, and analyze ZFIN data, including genes, gene expression, mutants, morphants, transgenics, anatomical structures, and antibodies. ZFIN's GBrowse genome viewer, BLAST, and protocol and antibody wikis are also discussed. PMID- 20836074 TI - Using the Velvet de novo assembler for short-read sequencing technologies. AB - The Velvet de novo assembler was designed to build contigs and eventually scaffolds from short-read sequencing data. This protocol describes how to use Velvet, interpret its output, and tune its parameters for optimal results. It also covers practical issues such as configuration, using the VelvetOptimiser routine, and processing colorspace data. PMID- 20836075 TI - Predicting peptide retention times for proteomics. AB - The vast majority of modern bottom-up proteomic protocols include chromatographic reversed-phase (RP) fractionation of peptides prior to mass-spectrometric analysis. Retention time information can be easily extracted from LC-MS data and it can be used to improve protein identification/characterization procedures. The key to the success of this procedure is the correct retention time prediction based on compositional and structural properties of the separated species. Our Sequence Specific Retention Calculator (SSRCalc) is a Web-based peptide retention prediction that covers the separation selectivity of the most popular RP-HPLC conditions applied in proteomics. Procedures for the application of SSRCalc to proteomic analyses are described in this unit. PMID- 20836076 TI - Using the Generic Synteny Browser (GBrowse_syn). AB - Genome Browsers are software that allow the user to view genome annotations in the context of a reference sequence, such as a chromosome, contig, scaffold, etc. The Generic Genome Browser (GBrowse) is an open-source genome browser package developed as part of the Generic Model Database Project (see UNIT ; Stein et al., 2002). The increasing number of sequenced genomes has led to a corresponding growth in the field of comparative genomics, which requires methods to view and compare multiple genomes. Using the same software framework as GBrowse, the Generic Synteny Browser (GBrowse_syn) allows the comparison of colinear regions of multiple genomes using the familiar GBrowse-style Web page. Like GBrowse, GBrowse_syn can be configured to display any organism, and is currently the synteny browser used for model organisms such as C. elegans (WormBase; http://www.wormbase.org; see UNIT 1.8) and Arabidopsis (TAIR; http://www.arabidopsis.org; see UNIT 1.1). GBrowse_syn is part of the GBrowse software package and can be downloaded from the Web and run on any Unix-like operating system, such as Linux, Solaris, or MacOS X. GBrowse_syn is still under active development. This unit will cover installation and configuration as part of the current stable version of GBrowse (v. 1.71). PMID- 20836078 TI - Quantitative analysis of phosphorylation-based protein signaling networks in the immune system by mass spectrometry. AB - Dynamic modification of cell proteins with phosphate is one of the key regulators of the cellular response to external stimuli. Phosphorylation-based signaling networks mediate cell proliferation, differentiation, and migration, and their dysregulation is the basis of multiple diseases. However, the transient nature of the regulatory protein phosphorylation and low site occupancy mean that only a fraction of the protein is phosphorylated at a given time, and it is a challenge to measure the degree and dynamics of phosphorylation using traditional biochemical means. Technological advances in the field of mass spectrometry (MS) made it possible to generate large sets of phosphoproteomics data, probing the phosphoproteome with great depth, sensitivity, and accuracy. Therefore, quantitative phosphoproteomics emerged as one of the essential components of the systems biology approach for profiling of complex biological networks. Nowadays, the challenge lies in validation of the information and in its integration into the comprehensive models of cell decision processes. This article reviews the role of phosphoproteomics in systems biology, the MS-based approach, and technical details of the methods. Recent examples of quantitative measurements and methodologies as well as applications to the studies of the immune system and infectious diseases are presented and discussed. PMID- 20836079 TI - A new open tubular capillary microextraction and sweeping for the analysis of super low concentration of hydrophobic compounds. AB - A sample pre-concentration method based on the in-line coupling of in-tube solid phase microextraction and electrophoretic sweeping was developed for the analysis of hydrophobic compounds. The sample pre-concentration and electrophoretic separation processes were simply and sequentially carried out with a (35%-phenyl) methylpolysiloxane-coated capillary. The developed method was validated and applied to enrich and separate several pharmaceuticals including loratadine, indomethacin, ibuprofen and doxazosin. Several parameters of microextration were investigated such as temperature, pH and eluant. And the concentration of microemulsion that influences separation efficiency and microextraction efficiency were also studied. Central composite design was applied for the optimization of sampling flow rate and sampling time that interact in a very complex way with each other. The precision, sensitivity and recovery of the method were investigated. Under the optimal conditions, the maximum enrichment factors for loratadine, indomethacin, ibuprofen and doxazosin in aqueous solutions are 1355, 571, 523 and 318, respectively. In addition, the developed method was applied to determine loratadine in rabbit blood sample. PMID- 20836077 TI - Retinoids regulate stem cell differentiation. AB - Retinoids are ubiquitous signaling molecules that influence nearly every cell type, exert profound effects on development, and complement cancer chemotherapeutic regimens. All-trans retinoic acid (RA) and other active retinoids are generated from vitamin A (retinol), but key aspects of the signaling pathways required to produce active retinoids remain unclear. Retinoids generated by one cell type can affect nearby cells, so retinoids also function in intercellular communication. RA induces differentiation primarily by binding to RARs, transcription factors that associate with RXRs and bind RAREs in the nucleus. Binding of RA: (1) initiates changes in interactions of RAR/RXRs with co repressor and co-activator proteins, activating transcription of primary target genes; (2) alters interactions with proteins that induce epigenetic changes; (3) induces transcription of genes encoding transcription factors and signaling proteins that further modify gene expression (e.g., FOX03A, Hoxa1, Sox9, TRAIL, UBE2D3); and (4) results in alterations in estrogen receptor alpha signaling. Proteins that bind at or near RAREs include Sin3a, N-CoR1, PRAME, Trim24, NRIP1, Ajuba, Zfp423, and MN1/TEL. Interactions among retinoids, RARs/RXRs, and these proteins explain in part the powerful effects of retinoids on stem cell differentiation. Studies of this retinol signaling cascade enhance our ability to understand and regulate stem cell differentiation for therapeutic and scientific purposes. In cancer chemotherapeutic regimens retinoids can promote tumor cell differentiation and/or induce proteins that sensitize tumors to drug combinations. Mechanistic studies of retinoid signaling continue to suggest novel drug targets and will improve therapeutic strategies for cancer and other diseases, such as immune-mediated inflammatory diseases. PMID- 20836080 TI - Separation optimization of quercetin, hesperetin and chrysin in honey by micellar liquid chromatography and experimental design. AB - The chemometrics approach was applied for the separation optimization of flavonoid markers (quercetin, hesperetin and chrysin) in honey using micellar liquid chromatography (MLC). The investigated method combines SPE of flavonoids from honey using C(18) cartridge and their separation and quantification by micellar liquid chromatography. A two level full factorial design was carried out to evaluate the effect of four experimental factors including concentration of SDS, alkyl chain length of the alcohol used as the organic modifier (N), volume percentage of the organic modifier (V(m)) and volume percentage of acetic acid (AcOH) in mobile phase on analytes retention times. Experiments for analytes retention times modeling and optimization of separation were performed according to central composite design. Multiple linear regression method was used for the construction of the best model based on experimental retention times. Pareto optimal method was used to find suitable compatibility between resolution and analysis time of analytes in honey. The optimum mobile phase composition for separation and determination of analytes in honey were [SDS]=0.124 mol/L; 7.8% v/v ethanol and 5.0% v/v AcOH. Limits of detection and linear range of flavonoid markers were 0.0079-0.0126, 0.05-50.0 mg/L, respectively. PMID- 20836081 TI - Enantioseparation of racemic paroxol on an amylose-based chiral stationary phase by supercritical fluid chromatography. AB - The separation of racemic paroxol, a key precursor of trans-(-)-paroxetine, on Chiralpak AD-H, an amylose-based chiral stationary phase, by supercritical fluid chromatography was studied. Pulse experiments were investigated using supercritical carbon dioxide modified with methanol (MeOH), ethanol and 2 propanol at 35 degrees C and 15 MPa. Retention and separation factors were determined under analytical conditions for different mobile phase compositions. Among the modifiers used, MeOH was shown to be the best additive, and 5% v/v of MeOH was the preferable concentration at which selectivity of 1.14 and resolution of 3.0 was obtained. In order to evaluate the potential with respect to preparative separations, the adsorption isotherms of individual enantiomers of paroxol were estimated using the elution by characteristic point method. Isotherm parameters were determined from the overloaded elution profiles that were collected at pressure ranging from 15 to 24 MPa. The isotherms obtained were further validated by comparing experimentally recorded elution profiles with the predictions based on the equilibrium-dispersive model. The results are important to the process design and optimization of preparative supercritical fluid chromatography application. PMID- 20836082 TI - Convergence in dental histology between the late Triassic semionotiform Sargodon tomicus (Neopterygii) and a late cretaceous (Turonian) pycnodontid (Neopterygii: Pycnodontiformes) species. AB - Microstructural scanning electron microscope investigation was performed on sectioned and surface-etched isolated, prehensile teeth of the Late Triassic semionotiform species Sargodon tomicus and Pycnodontidae incertae sedis from the Late Cretaceous. The teeth of both taxa display a system of vascular canals penetrating the dentine and the overlying hypermineralized acrodin cap; small tubules are radiating at an angle to the long axis of the canals, interpreted as residual spaces left by odontoblast cell processes. This is the first detailed account of vascular acrodin encountered in a pycnodont species. New information is revealed also about Sargodon dental histology in the shape of mineralized remnants of the basal lamina at the acrodin-dentine junction. This implies that deposition of the acrodin organic matrix proceeded centrifugally by the cells of the inner dental epithelium, probably with minor collagen contribution from odontoblasts. This is contrary to the more typical centripetal formation (beneath the basal lamina) of the acrodin layer implied for the studied pycnodontid teeth. The rare occurrences of vascular acrodin within Actinopterygii, and the demonstrated differences in its histogenesis, do not suggest the usefulness of the tissue as systematic character but rather point to its adaptive significance. The superficial increase in the order of acrodin bundle orientation, observed in both species, is similarly regarded as convergently acquired mechanical adaptation. The observed uneven shape of crystallite rows and lesser degree of mineralization of the inner collariform ganoin, compared to its outer portion, is indicative of epithelial-ectomesenchymal interaction and qualifies the tissue as enameloid. PMID- 20836083 TI - Human odontoblasts express transient receptor protein and acid-sensing ion channel mechanosensor proteins. AB - Diverse proteins of the denegerin/epithelial sodium channel (DEG/ENa(+) C) superfamily, in particular those belonging to the acid-sensing ion channel (ASIC) family, as well as some members of the transient receptor protein (TRP) channel, function as mechanosensors or may be required for mechanosensation in a diverse range of species and cell types. Therefore, we investigated the putative mechanosensitive function of human odontoblasts using immunohistochemistry to detect ENa(+) C subunits (alpha, beta, and gamma) and ASIC (1, 2, 3, and 4) proteins, as well as TRPV4, in these cells. Positive and specific immunoreactivity in the odontoblast soma and/or processes was detected for all proteins studied except alpha-ENa(+) C. The intensity of immunostaining was high for beta-ENa(+) C and ASIC2, whereas it was low for ASIC1, ASIC3, gamma-ENa(+) C, and TRPV4, being absent for alpha-ENa(+) C and ASIC4. These results suggest that human odontoblasts in situ express proteins related to mechanosensitive channels that probably participate in the mechanisms involved in teeth sensory transmission. PMID- 20836084 TI - Microscopical evaluation of extracellular matrix and its relation to the palatopharyngeal muscle in obstructive sleep apnea. AB - Obstructive sleep apnea hypopnea syndrome (SAHS) is a complex disease of the upper respiratory airways. SAHS physiopathology is multifactorial in which airway compliance is a very important component. To evaluate the tissue changes in the palatopharyngeal muscle by morphometric, histochemical, immunohistochemical, and stereological quantification, with special attention to extracellular matrix associated with this muscle at the structural and ultrastructural levels. Thirty patients with SAHS were divided into groups of 10 according to disease severity: mild, moderate, and severe SAHS. In addition, the control group consisted of 10 patients. Fragments of palatopharyngeal muscle removed from patients with SAHS and tonsillectomies from patients in the control group were histopathologically submitted to light microscopy and transmission electron microscopy. Histopathological evaluations by light and transmission electron microscopes showed differences in analyzed groups, such as reduction of the muscle fiber diameter in patients with SAHS, taking disease severity into consideration. In contrast, stereological analysis showed a gradual increase of the collagen and elastic system fibers relative frequencies, proportionally to SAHS seriousness. MMP-2 and MMP-9 immunostaining also showed an increased reaction in the muscle fiber cytoplasm and endomisium during SAHS progression. The ultrastructural analysis showed that palatopharyngeal muscle fibers presented cytoplasmic residual corpuscles, a sign of early cell aging. In conclusion, the increase of tissue compliance in individuals with SAHS can be, in addition to other factors, consequence of diminished contractile activity of the muscle fibers, which exhibited clear signs of early senescence. Moreover, extracellular matrix components changes may contribute to muscle myopathy during SAHS progression. PMID- 20836085 TI - Photochemical degradation of citrate buffers leads to covalent acetonation of recombinant protein therapeutics. AB - Novel acetone and aldimine covalent adducts were identified on the N-termini and lysine side chains of recombinant monoclonal antibodies. Photochemical degradation of citrate buffers, in the presence of trace levels of iron, is demonstrated as the source of these modifications. The link between degradation of citrate and the observed protein modifications was conclusively established by tracking the citrate decomposition products and protein adducts resulting from photochemical degradation of isotope labeled (13)C citrate by mass spectrometry. The structure of the acetone modification was determined by nuclear magnetic resonance (NMR) spectroscopy on modified-free glycine and found to correspond to acetone linked to the N-terminus of the amino acid through a methyl carbon. Results from mass spectrometric fragmentation of glycine modified with an acetone adduct derived from (13)C labeled citrate indicated that the three central carbons of citrate are incorporated onto protein amines in the presence of iron and light. While citrate is known to stoichiometrically decompose to acetone and CO(2) through various intermediates in photochemical systems, it has never been shown to be a causative agent in protein carbonylation. Our results point to a previously unknown source for the generation of reactive carbonyl species. This work also highlights the potential deleterious impact of trace metals on recombinant protein therapeutics formulated in citrate buffers. PMID- 20836086 TI - New insights into S2P signaling cascades: regulation, variation, and conservation. AB - Regulated intramembrane proteolysis (RIP) is a conserved mechanism that regulates signal transduction across the membrane by recruiting membrane-bound proteases to cleave membrane-spanning regulatory proteins. As the first identified protease that performs RIP, the metalloprotease site-2 protease (S2P) has received extensive study during the past decade, and an increasing number of S2P-like proteases have been identified and studied in different organisms; however, some of their substrates and the related S1Ps remain elusive. Here, we review recent research on S2P cascades, including human S2P, E. coli RseP, B. subtilis SpoIVFB and the newly identified S2P homologs. We also discuss the variation and conservation of characterized S2P cascades. The conserved catalytic motif of S2P and prevalence of amino acids of low helical propensity in the transmembrane segments of the substrates suggest a conserved catalytic conformation and mechanism within the S2P family. The review also sheds light on future research on S2P cascades. PMID- 20836087 TI - The crystal structure of a bacterial Sufu-like protein defines a novel group of bacterial proteins that are similar to the N-terminal domain of human Sufu. AB - Sufu (Suppressor of Fused), a two-domain protein, plays a critical role in regulating Hedgehog signaling and is conserved from flies to humans. A few bacterial Sufu-like proteins have previously been identified based on sequence similarity to the N-terminal domain of eukaryotic Sufu proteins, but none have been structurally or biochemically characterized and their function in bacteria is unknown. We have determined the crystal structure of a more distantly related Sufu-like homolog, NGO1391 from Neisseria gonorrhoeae, at 1.4 A resolution, which provides the first biophysical characterization of a bacterial Sufu-like protein. The structure revealed a striking similarity to the N-terminal domain of human Sufu (r.m.s.d. of 2.6 A over 93% of the NGO1391 protein), despite an extremely low sequence identity of ~15%. Subsequent sequence analysis revealed that NGO1391 defines a new subset of smaller, Sufu-like proteins that are present in ~200 bacterial species and has resulted in expansion of the SUFU (PF05076) family in Pfam. PMID- 20836089 TI - Disappearance of essential tremor after stroke. AB - Improvement of a patient's essential tremor (ET) after a stroke has rarely been reported. In such patients, cerebral imaging could help to identify structures involved in the maintenance of ET and improves the knowledge of its physiopathology. This article reports the disappearance of ET, after a stroke in 4 patients and reviews similar previously published cases. These cases suggest that the interruption of cerebellar loops during a stroke could be responsible for the disappearance of ET. PMID- 20836088 TI - IGF-1 and bone: New discoveries from mouse models. AB - Insulin-like growth factor-1 (IGF-1) plays a central role in cellular growth, differentiation, survival, and cell cycle progression. It is expressed early during development and its effects are mediated through binding to a tyrosine kinase receptor, the insulin-like growth factor-1 receptor (IGF-1R). In the circulation, the IGFs bind to IGF-binding proteins (IGFBPs), which determine their bioavailability and regulate the interaction between the IGFs and IGF-1R. Studies in animal models and in humans have established critical roles for IGFs in skeletal growth and development. In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology. PMID- 20836090 TI - Rnd proteins: multifunctional regulators of the cytoskeleton and cell cycle progression. AB - Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK-mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton. PMID- 20836091 TI - Histone modifications proposed to regulate sexual differentiation of brain and behavior. AB - Expression of sexually dimorphic behaviors critical for reproduction depends on the organizational actions of steroid hormones on the developing brain. We offer the new hypothesis that transcriptional activities in brain regions executing these sexually dimorphic behaviors are modulated by estrogen-induced modifications of histone proteins. Specifically, in preoptic nerve cells responsible for facilitating male sexual behavior in rodents, gene expression is fostered by increased histone acetylation and reduced methylation (Me), and, that the opposite set of histone modifications will be found in females. Conversely, in ventromedial hypothalamic neurons that are responsible for coordinating female sexual behavior, transcriptional activities in genetic females are fostered by increased histone acetylation and reduced Me, and, further, that the opposite set of histone modifications will be found in males. Thus, these epigenetic events will guarantee that effects of sex hormone exposure during the neonatal critical period will be translated into lasting sex differences in adult reproductive behaviors. PMID- 20836092 TI - Nanogel engineering for new nanobiomaterials: from chaperoning engineering to biomedical applications. AB - Nanosize hydrogels (nanogels) are polymer nanoparticles with three-dimensional networks, formed by chemical and/or physical cross-linking of polymer chains. Recently, various nanogels have been designed, with a particular focus on biomedical applications. In this review, we describe recent progress in the synthesis of nanogels and nanogel-integrated hydrogels (nanogel cross-linked gels) for drug-delivery systems (DDS), regenerative medicine, and bioimaging. We also discuss chaperone-like functions of physical cross-linking nanogel (chaperoning engineering) and organic-inorganic hybrid nanogels. PMID- 20836093 TI - Electrophilic reactivities of 1,2-diaza-1,3-dienes. AB - The kinetics of the reactions of 1,2-diaza-1,3-dienes 1 with acceptor-substituted carbanions 2 have been studied at 20 degrees C. The reactions follow a second order rate law, and can be described by the linear free energy relationship log k(20 degrees C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2-diaza-1,3-dienes 1 were determined. With E parameters in the range of 13.3 to -15.4, the electrophilic reactivities of 1a-d are comparable to those of benzylidenemalononitriles, 2-benzylideneindan-1,3-diones, and benzylidenebarbituric acids. The experimental second-order rate constants for the reactions of 1a-d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2-diaza-1,3-dienes 1. Enamines 5 react up to 10(2) to 10(3) times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers. PMID- 20836094 TI - Late-transition-metal complexes as tunable Lewis bases. AB - Syntheses of the first heteroleptic N-heterocyclic carbene (NHC)-phosphane platinum(0) complexes and formation of the corresponding Lewis acid-base adducts with aluminum chloride is reported. The influence of N-heterocyclic carbenes on tuning the Lewis basic properties of the metal complexes was judged from spectroscopic, structural, and computational data. Conclusive experimental evidence for the enhanced Lewis basicity of NHC-containing complexes was provided by a transfer reaction. PMID- 20836095 TI - New insights into factors influencing B-N bonding in X:BH(3-n)F(n) and X:BH(3 n)Cl(n) for X=N2, HCN, LiCN, H2CNH, NF3, NH3 and n=0-3: the importance of deformation. AB - Understanding the bonding in complexes X:BH(3-n)F(n) and X:BH(3-n)Cl(n), for X=N(2), HCN, LiCN, H(2)CNH, NF(3), NH(3) with n=0-3, is a challenging task. The trends in calculated binding energies cannot be explained in terms of any of the usual indexes, including pi donation from the halogen lone pairs to the p(pi) empty orbital on B, deformation energies, charge capacities, or LUMO energies, which are normally invoked to explain the higher Lewis acidity of BCl(3) relative to BF(3). The results of the high-level G3B3 ab initio calculations reported in this study suggest that the interaction energies of these complexes are determined by a combination of at least three factors. These include the decrease in the electron-accepting ability of B as a result of pi donation by the halogen atom, the increase in the electron-acceptor capacity of B due to deformation of the acid, and the large increase in the deformation energy of the acid with increasing halogen substitution. The dominant effects are those derived from the electronic effects of acid deformation. Deformation not only has direct energetic consequences, which are reflected in the large differences between dissociation (D(0)) and interaction (E(int)) energies, but also leads to an enhancement of the intrinsic acidities of BH(3-n)F(n) and BH(3-n)Cl(n) moieties by lowering the LUMO energies to very different extents, consistent with the frontier orbital model of chemical reactivity. Although this lowering depends on both the number and the nature of the halogen substituents, binding energies do not systematically increase or decrease as the number of halogen atoms increases. PMID- 20836096 TI - Electrophilic reactivities of azodicarboxylates. AB - The kinetics of the reactions of the azodicarboxylates 1 with the enamines 2 have been studied in CH(3)CN at 20 degrees C. The reactions follow a second-order rate law and can be described by the linear free energy relationship log k(2) (20 degrees C) = s(N+E) (E = electrophilicity parameter, N = nucleophilicity parameter, and s = nucleophile-specific slope parameter). With E parameters from 12.2 to -8.9, the electrophilic reactivities of 1 turned out to be comparable to those of alpha,beta-unsaturated iminium ions, amino-substituted benzhydrylium ions, and ordinary Michael acceptors. While the E parameters of the azodicarboxylates 1 determined in this work also hold for their reactions with triarylphosphines, they cannot be used for estimating rate constants for their reactions with amines. Comparison of experimental and calculated rate constants for cycloadditions and ene reactions of azodicarboxylates provides information on the concertedness of these reactions. PMID- 20836097 TI - Fullerene-coumarin dyad as a selective metal receptor: synthesis, photophysical properties, electrochemistry and ion binding studies. AB - A coumarin derivative with a malonate unit has been synthesized and used for the preparation of a fullerene-coumarin dyad through the Bingel cyclopropanation method. The newly synthesized dyad is soluble in organic solvents and has been fully characterized with traditional spectroscopic techniques. Electronic interactions between the two components of the dyad were probed with the aid of UV/Vis spectroscopy, fluorescence emission, and electrochemistry measurements. Our studies clearly show the presence of electronic interactions between C(60) and modified coumarin in the ground state; efficient electron-transfer quenching of the singlet excited state of the coumarin moiety by the appended fullerene sphere was also observed. Time-resolved fluorescence measurements revealed lifetimes for the coumarin-C(60) dyad at a maximum of 50 ps, while the quantum yield was reaching unity. Additionally, the redox potentials of the C(60) coumarin dyad were determined and the energetics of the electron-transfer processes were evaluated. Finally, after alkaline treatment of C(60)-coumarin, which resulted in the deprotection of carboxylate units, the dyad was tested as a metal receptor for divalent metal cations; ion competition studies and fluorescence experiments showed binding selectivity for lead ions. PMID- 20836098 TI - Silver nanoparticle induced photocurrent enhancement at WO3 photoanodes. PMID- 20836100 TI - Trends in stability of perovskite oxides. PMID- 20836101 TI - Terbium polyoxometalate organic complexes: correlation of structure with luminescence properties. PMID- 20836102 TI - Multistep DNA-templated reactions for the synthesis of functional sequence controlled oligomers. PMID- 20836103 TI - Spontaneous dihydrogen activation by neutral TaO4 complex at cryogenic temperatures. PMID- 20836104 TI - 1,3-Dipole behavior of phosphagermaallene Tip(tBu)Ge=C=PMes* leading to a phosphagermaheterocyclic carbene. PMID- 20836099 TI - Stable cyclic carbenes and related species beyond diaminocarbenes. AB - The success of homogeneous catalysis can be attributed largely to the development of a diverse range of ligand frameworks that have been used to tune the behavior of various systems. Spectacular results in this area have been achieved using cyclic diaminocarbenes (NHCs) as a result of their strong sigma-donor properties. Although it is possible to cursorily tune the structure of NHCs, any diversity is still far from matching their phosphorus-based counterparts, which is one of the great strengths of the latter. A variety of stable acyclic carbenes are known, but they are either reluctant to bind metals or they give rise to fragile metal complexes. During the last five years, new types of stable cyclic carbenes, as well as related carbon-based ligands (which are not NHCs), and which feature even stronger sigma-donor properties have been developed. Their synthesis and characterization as well as the stability, electronic properties, coordination behavior, and catalytic activity of the ensuing complexes are discussed, and comparisons with their NHC cousins are made. PMID- 20836105 TI - Facile access to key reactive intermediates in the Pd/PR3-catalyzed telomerization of 1,3-butadiene. PMID- 20836106 TI - Organometallic hollow spheres bearing bis(N-heterocyclic carbene)-palladium species: catalytic application in three-component Strecker reactions. PMID- 20836107 TI - Tuning the singlet-triplet gap in metal-free phosphorescent pi-conjugated polymers. PMID- 20836108 TI - Pressure-induced sequential orbital reorientation in a magnetic framework material. PMID- 20836109 TI - Fabrication of graphene-encapsulated oxide nanoparticles: towards high performance anode materials for lithium storage. PMID- 20836110 TI - Dinaphthopentalenes: pentalene derivatives for organic thin-film transistors. PMID- 20836112 TI - Enantioselective Lewis acid catalysis in intramolecular [2+2] photocycloaddition reactions of coumarins. PMID- 20836111 TI - A new strategy to photoactivate green fluorescent protein. PMID- 20836113 TI - Insertion of pyridine into the calcium allyl bond: regioselective 1,4 dihydropyridine formation and C-H bond activation. PMID- 20836114 TI - pi Conjugation transmitted across a d-electron metallocene in ferrocenothiaporphyrin macrocycles. PMID- 20836115 TI - Production of calcium carbide from fine biochars. PMID- 20836116 TI - Copper-catalyzed Si-B bond activation in branched-selective allylic substitution of linear allylic chlorides. PMID- 20836120 TI - Synthesis of imidazothiazole-chalcone derivatives as anticancer and apoptosis inducing agents. AB - A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. Interestingly, these chalcone derivatives induced G(0)/G(1)-phase cell cycle arrest, down-regulation of G(1)-phase cell-cycle regulatory proteins such as cyclin D1 and cyclin E1, and up-regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF-kappaB, and up-regulation of caspase-9. One of these chalcone derivatives, 3 d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies. PMID- 20836119 TI - Live-cell imaging of cellular proteins by a strain-promoted azide-alkyne cycloaddition. PMID- 20836121 TI - Synthesis of furfural from xylose and xylan. PMID- 20836122 TI - Production of dehydrogingerdione derivatives in Escherichia coli by exploiting a curcuminoid synthase from Oryza sativa and a beta-oxidation pathway from Saccharomyces cerevisiae. AB - Gingerol derivatives are bioactive compounds isolated from the rhizome of ginger. They possess various beneficial activities, such as anticancer and hepatoprotective activities, and are therefore attractive targets of bioengineering. However, the microbial production of gingerol derivatives has not yet been established, primarily because the biosynthetic pathway of gingerol is unknown. Here, we report the production of several dehydrogingerdione (a gingerol derivative) analogues from a recombinant Escherichia coli strain that has an "artificial" biosynthesis pathway for dehydrogingerdione that was not based on the original biosynthesis pathway of gingerol derivatives in plants. The system consists of a 4-coumarate:CoA ligase from Lithospermum erythrorhizon, a fatty acid CoA ligase from Oryza sativa, a beta-oxidation system from Saccharomyces cerevisiae, and a curcuminoid synthase from O. sativa. To our knowledge, this is the first report of the microbial production of a plant metabolite the biosynthetic pathway of which has not yet been identified. PMID- 20836123 TI - Lack of effects on male fertility from a quadrivalent HPV vaccine in Sprague Dawley rats. AB - BACKGROUND: Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases in both men and women. A recently developed quadrivalent HPV vaccine, Gardasil, has been shown to be highly effective in the prevention of several HPV-mediated diseases. The objective of the present study was to evaluate the potential effects of the vaccine on male fertility including reproductive performance, sperm evaluations, and histology of the testes. In addition, anti-HPV antibodies were measured during the study. METHODS: Group 1 (30 male rats) received the full human dose of vaccine (0.5 mL, ~200-fold excess based on body weight) by intramuscular injection at 6 weeks, 3 weeks, and 3 days prior to cohabitation. Group 2 males received only 1 dose at 3 days prior to cohabitation. Additional groups (20 male rats each) were administered PBS or Merck Aluminum Adjuvant similarly to Group 1. Ten males in the vaccine-treated groups were bled for immunogenicity assays after each dose. Twenty males per group were mated to untreated female rats. Cesarean sections were performed on Gestation Day 15 or 16. Cohabited males were necropsied and sperm count and motility were evaluated. RESULTS: There were no unscheduled deaths during the study and no evidence of toxicity in vaccine-treated male rats. The vaccine induced a specific antibody response to the 4 HPV types after each injection. There were no effects on the cesarean-section parameters of females or reproductive parameters of the cohabited male rats, including histomorphology of testes and epididymis, sperm count, and sperm motility. CONCLUSIONS: These results demonstrate that this quadrivalent HPV vaccine had no detectable adverse effects on routine measures of male fertility in rats. PMID- 20836124 TI - Micro-computed tomographic evaluation of fetal skeletal changes induced by all trans-retinoic acid in rats and rabbits. AB - BACKGROUND: Our laboratory has been conducting positive control studies to evaluate the utility of micro-computed tomography (micro-CT) for qualitative evaluation of fetal skeletal morphology. All-trans-retinoic acid (atRA) was used to produce a different spectrum of defects compared to our previous studies with boric acid and hydroxyurea. METHODS: Groups of five mated Crl:CD(SD) female rats each were administered vehicle or atRA (2.5-50 mg/kg) on GD 10, and groups of four mated Dutch Belted rabbits each were dosed with vehicle or atRA (6.25-25 mg/kg) on GD 9. Cesarean sections were performed on GD 21 and 28, respectively. Following external examination the viscera were removed and fetuses scanned in a micro-CT imaging system. Fetuses were subsequently stained with alizarin red. Skeletal morphology was evaluated by each method without the knowledge of treatment group. Total bone mineral content (BMC) of each fetus was quantitated using the micro-CT images. RESULTS: In rats there were dose-related increases in the incidence of extra lumbar vertebra and non-dose-related increases in supernumerary ribs at all dose levels. There were decreases in mean number of ossified sacrocaudal vertebra at >= 5 mg/kg, and increases in skull bone malformations at >= 10 mg/kg. Rabbits were less sensitive on a mg/kg basis since skeletal malformations and a decrease in mean number of ossified sacrocaudal vertebra were observed only in the 25-mg/kg group. Micro-CT evaluation detected essentially the same incidence of skeletal abnormalities as seen in alizarin red stained rat and rabbit fetuses. BMC analysis showed a trend toward slight decreases in atRA-treated rats, but no notable changes in rabbits. CONCLUSIONS: These results add support to our previous work that demonstrates that micro-CT imaging can effectively assess rat and rabbit fetal skeletal morphology. PMID- 20836125 TI - Morphological score assignment guidelines for the dechorionated zebrafish teratogenicity assay. AB - BACKGROUND: Recently we reported the development and optimization of a zebrafish teratogenicity assay using dechorionated AB strain embryos, a promising assay that was 87% concordant in correctly identifying in vivo teratogens and non teratogens from a set of 31 compounds (Brannen et al., 2010: Birth Defects Res 89:66-77). METHODS: This assay utilizes a zebrafish morphological score system to characterize adverse effects and identify the no-observed-adverse-effect level (NOAEL). RESULTS: This report describes in detail the morphological score system used in the dechorionated zebrafish embryo culture teratogenicity assay. The morphological assessment includes evaluation of most structures and organ systems and grades relative severity of abnormalities. CONCLUSIONS: To this end, the morphological score system provides information of tissue-specific teratogenicity that has been found to have good concordance with structures found affected in vivo and can also be used to rank compounds based on the severity of malformations. PMID- 20836126 TI - Bisphenol A impairs estradiol-induced protective effects against DLD-1 colon cancer cell growth. AB - Bisphenol A (BPA), a prototype of endocrine disruptors, mimics 17beta-estradiol (E2)-induced proliferation in several cancer cells by binding to estrogen receptor alpha (ERalpha). However, scarce and conflicting data are available concerning the effect of BPA on estrogen receptor beta (ERbeta)-mediated functions. Here, the detailed analysis of the effect of BPA, alone or in combination with E2, on ERbeta-mediated cellular functions is reported in ERbeta expressing colon cancer cell line. BPA binds to ERbeta without activating any receptor activities. On the other hand, BPA inhibits E2-induced genomic activity of ERbeta as well as ERbeta extra-nuclear activities (i.e., ERbeta:p38 association and p38 activation). As a consequence, BPA impairs the E2-induced activation of the apoptotic cascade which is at the root of the protective role played by the hormone against colon cancer growth. Thus, women may be considered a highly susceptible population with an increased risk of colon cancers after BPA exposures. PMID- 20836127 TI - Changes in the two-dimensional electrophoresis pattern of the Parkinson's disease related protein DJ-1 in human SH-SY5Y neuroblastoma cells after dopamine treatment. AB - DJ-1 is a mitochondrial protein linked to Parkinson's disease. DJ-1 has been suggested to have several possible functions, although it has been mainly associated to oxidative stress defence. Changes in the two-dimensional electrophoresis pattern have been thoroughly described as a consequence of oxidative modification of the Cys106 residue. There is accumulating evidence supporting a specific role of DJ-1 in protecting dopaminergic neurons from dopamine itself. By exposing SH-SY5Y human neuroblastoma catecholaminergic cells to dopamine, we observed a specific increase in the most acidic forms in the DJ-1 two-dimensional electrophoresis pattern together with a significant decrease of the most basic spot. Unlike cells exposed to generic oxidative conditions, no additional shift was observed. The results are corroborated by a meta-analysis of the literature showing that in the absence of dopamine treatment the specific acidic form is underrepresented. PMID- 20836129 TI - How I became a biochemist... and beyond.... PMID- 20836128 TI - Importance of eye lens alpha-crystallin heteropolymer with 3:1 alphaA to alphaB ratio: stability, aggregation, and modifications. AB - Chaperone-like activity (CLA) of alpha-crystallin is essential not only for the maintenance of eye lens transparency but also in the biology of other tissues. Eye lens alpha-crystallin is a heteropolymer composed of two homologous subunits, alphaA and alphaB, and in most vertebrates they are present in a ratio of 3:1. The structural and functional significance of this specific ratio of alpha crystallin subunits is of considerable interest in understanding its role in the eye lens transparency. Previously, we have shown that although at physiologically relevant conditions alphaB-crystallin has greater CLA, under stress conditions such as elevated temperatures alpha-crystallin heteropolymer with 3:1 alphaA to alphaB ratio displayed higher CLA (Srinivas et al., Biochem. J., 2008, 414, 453 - 460). Herein, we provide a rationale for the existence of alpha-crystallin heteropolymer with 3:1 alphaA to alphaB ratio in terms of structural stability, aggregation pattern, and susceptibility to posttranslational modifications that could explain the importance of the heteropolymer of alpha-crystallin in the eye lens. We demonstrate that alphaA-crystallin is not only more stable but also imparts stability to the heteropolymer by preventing the aggregation of alphaB crystallin at higher temperatures by using differential scanning calorimetry, size-exclusion chromatography, and denaturant-induced unfolding methods. Further, the physiological significance of heteropolymer with higher proportion of alphaA subunit is substantiated by using a heteropolymer with mutant (F71L) alphaA crystallin and the susceptibility of 3:1 heteropolymer to glycation-induced modifications. Thus, the existence of 3:1 heteropolymer might be vital for the eye lens transparency under diverse conditions to prevent cataract. PMID- 20836131 TI - Cross-sectional geometry in the humeri of foragers and farmers from the prehispanic American Southwest: exploring patterns in the sexual division of labor. AB - The work effort of prehistoric males relative to females has long been of interest to anthropologists, particularly in foraging versus farming groups. This knowledge requires a clear understanding of the sexual division of labor, or the dichotomy in subsistence roles allocated to males and females. Such research in the Prehispanic American Southwest has been limited. As previous work has shown that bone is the osseous template that reflects in vivo activity levels, it is possible to assess gender-based differences in past work effort using analyses of geometric properties of bone and calculations of bilateral asymmetry. Our research comparatively analyzed upper limb work effort by sex and subsistence in two skeletal samples from disparate economic groups, foragers and farmers, both from similar desert environments. The residentially mobile foragers are from the Lower Pecos region of southwest Texas and the farmers are from the aggregated pueblo of Pottery Mound in south central New Mexico. Humeri from 27 adult foragers (n = 11 males; n = 17 females) and 65 adult farmers (n = 38 males; n = 27 females) were selected for study. All humeri were radiographed and/or scanned and digitized. Statistical comparisons using two-way ANOVAs indicate that female farmers exhibited the greatest humeral strength and the least asymmetry. Relative to all other groups examined, female farmers engaged in higher levels of upper limb work effort implying a substantial economic contribution to their agricultural economy. PMID- 20836132 TI - Whether to target single or multiple CDKs for therapy? That is the question. AB - Complexes consisting of cyclin-dependent kinases (CDKs) and their regulatory subunits (the cyclins) control the progression of normal mammalian cells through the cell cycle. However, during malignant transformation this regulatory apparatus malfunctions, allowing cells to undergo unchecked proliferation. In many cases, the high mitotic potential of malignant cells is due to the constitutive activation of CDK-cyclin complexes, facilitated by the inactivation of cellular CDK inhibitors, such as p16(INK4A) or p27(Kip1), and the loss of functional tumor suppressors, such as the p53 and pRb proteins. It has recently been suggested that pharmacological intervention based on remedying the deficiency or loss of activity of these negative regulators of the cell cycle could be a very effective therapeutic option in the treatment of cancer. Multiple CDK inhibitors have been synthesized over the last two decades, spanning at least five classes of compounds. While these inhibitors can be classified on the basis of their chemical structure, it may be more interesting to categorize them according to their pharmacological nature, as broad-spectrum unspecific, pan specific, or very selective antagonists. This review offers a critical assessment of the advantages and disadvantages of both pan-specific and highly selective CDK inhibitors in therapy. PMID- 20836130 TI - prdm1a Regulates sox10 and islet1 in the development of neural crest and Rohon Beard sensory neurons. AB - The PR domain containing 1a, with ZNF domain factor, gene (prdm1a) plays an integral role in the development of a number of different cell types during vertebrate embryogenesis, including neural crest cells, Rohon-Beard (RB) sensory neurons and the cranial neural crest-derived craniofacial skeletal elements. To better understand how Prdm1a regulates the development of various cell types in zebrafish, we performed a microarray analysis comparing wild type and prdm1a mutant embryos and identified a number of genes with altered expression in the absence of prdm1a. Rescue analysis determined that two of these, sox10 and islet1, lie downstream of Prdm1a in the development of neural crest cells and RB neurons, respectively. In addition, we identified a number of other novel downstream targets of Prdm1a that may be important for the development of diverse tissues during zebrafish embryogenesis. PMID- 20836133 TI - Long-term comparative trial of two different physiotherapy techniques; postural drainage with percussion and autogenic drainage, in the treatment of cystic fibrosis. AB - In N. America, over the past decade, various airway clearance techniques (ACT) have been introduced for the treatment of cystic fibrosis (CF). We hypothesized that autogenic drainage (AD), an ACT developed in Belgium would be as effective as postural drainage with percussion (PD) in treating patients with CF. METHODS: Thirty-six CF patients, aged 12-18 years, with Shwachman score 65-98, were enrolled in a 2-year cross-over trial. Patients were matched as pairs and members of each pair were randomly assigned to two groups. For the first study year, Group A performed PD while Group B performed AD. At the end of 1 year Groups A and B crossed over physiotherapy techniques. Clinical status and pulmonary function (FVC, FEV(1), FEF(25-75)) were measured at 3 monthly intervals. Only results from the first year of the study are reported, as 10 out of 17 patients who had completed performing AD for the first year refused to change back to PD for the second year. RESULTS: During the first year of the study, both the AD and PD groups demonstrated improved pulmonary function with no significant difference between the two groups. Change in FVC and FEV(1) percent predicted for Groups A and B was 0.47 +/- 1.65(se) versus 2.35 +/- 1.51(se) and 2.09 +/- 2.2(se) versus 0.92 +/- 2.25(se). However, CF patients exhibited a marked preference for the AD technique. Results suggest that both AD and PD are effective methods of performing physiotherapy for CF patients and that the benefits of either technique are enhanced by measures which encourage adherence. PMID- 20836134 TI - Short-term attention and verbal fluency is decreased in restless legs syndrome patients. AB - Restless legs syndrome (RLS) is a frequent sleep-related movement disorder with disturbed sleep and quality of life. RLS patients complain about increased daytime sleepiness, but there are only few and inconsistent reports about cognitive functioning in this group. We compared cognitive performance of 23 unmedicated RLS patients to that of 23 healthy controls matched individually for age, gender, and educational level. Cognitive tasks were chosen to assess short term attention, working memory, learning and memory, verbal fluency, and executive functioning. RLS patients performed worse than controls in the area of attention and verbal fluency, and performance in these tasks was associated with RLS severity, sleep quality, depression scores, and memory. There was no difference for working memory, memory, learning, cognitive flexibility, and abstract reasoning. We conclude that there is evidence for deficits in short-term attention and verbal fluency in RLS patients. PMID- 20836135 TI - Alpha-synuclein immunoreactivity in minor salivary gland biopsies of Parkinson's disease patients. PMID- 20836136 TI - Cerebrospinal fluid tau and phosphorylated tau protein are elevated in corticobasal syndrome. AB - Differentiating corticobasal syndrome (CBS) from progressive supranuclear palsy (PSP) and idiopathic Parkinson's disease (PD) can be difficult. To investigate the additional value of cerebrospinal fluid (CSF) biomarkers in the diagnostic differentiation of parkinsonism, we analyzed the CSF concentrations of total protein, lactate and brain specific proteins amyloid-beta(42) protein, tau protein (t-tau), and tau protein phosphorylated at Thr181 (p-tau), in CSF samples from patients with PSP (n = 21), CBS (n = 12), and PD (n = 28). CBS patients demonstrated higher concentrations of t-tau and p-tau compared with PSP and PD patients. In discriminating CBS and PD, t-tau offered the best combination of sensitivity (75%) and specificity (90.9%), followed by p-tau (sensitivity 87.5% and specificity 75%). The p-tau/t-tau ratio resulted in sensitivity of 84.2% and specificity of 66.7% in discriminating PSP and CBS. In conclusion, our results suggest that CSF parameters are of additional value in the diagnostic differentiation of CBS and PD. PMID- 20836137 TI - Non-native interactions play an effective role in protein folding dynamics. AB - Systematic Monte Carlo simulations of simple lattice models show that the final stage of protein folding is an ordered process where native contacts get locked (i.e., the residues come into contact and remain in contact for the duration of the folding process) in a well-defined order. The detailed study of the folding dynamics of protein-like sequences designed as to exhibit different contact energy distributions, as well as different degrees of sequence optimization (i.e., participation of non-native interactions in the folding process), reveals significant differences in the corresponding locking scenarios--the collection of native contacts and their average locking times, which are largely ascribable to the dynamics of non-native contacts. Furthermore, strong evidence for a positive role played by non-native contacts at an early folding stage was also found. Interestingly, for topologically simple target structures, a positive interplay between native and non-native contacts is observed also toward the end of the folding process, suggesting that non-native contacts may indeed affect the overall folding process. For target models exhibiting clear two-state kinetics, the relation between the nucleation mechanism of folding and the locking scenario is investigated. Our results suggest that the stabilization of the folding transition state can be achieved through the establishment of a very small network of native contacts that are the first to lock during the folding process. PMID- 20836141 TI - Application of hybrid approach for estimating the benchmark dose of urinary cadmium for adverse renal effects in the general population of Japan. AB - We used an updated hybrid approach to estimate the benchmark doses and their 95% lower confidence limits (BMDL) for cadmium-induced renal effects in humans. Participants were 828 inhabitants (410 men, 418 women), aged 40-59 years who lived in three areas without any known environmental cadmium pollution. We measured urinary cadmium (U-Cd) as a marker of exposure, and urinary protein, beta2-microglobulin (beta2-MG) and N-acetyl-beta-D-glucosaminidase (NAG) as markers of renal effects. For urinary protein, the BMDL ranged from 0.9 to 1.1 ug g-1 creatinine (cre) and approximately 1.6 ug per 24 h in men, and from 1.9 to 3.4 ug g-1 cre and 2.0 ug per 24 h in women. For the renal tubular markers beta2 MG and NAG, the BMDL for U-Cd ranged from 0.6 to 1.2 ug g-1 cre and from 0.8 to 1.7 ug per 24 h in men, and from 0.6 to 2.3 ug g-1 cre and from 0.6 to 2.1 ug per 24 h in women. The lowest BMDL for urinary cadmium (0.6 ug g-1 cre) was somewhat lower than average urinary cadmium in Japanese older population. These results suggest the importance of measures to decrease cadmium exposure in the general population of Japan. PMID- 20836142 TI - Mustard gas toxicity: the acute and chronic pathological effects. AB - Ever since it was first used in armed conflict, mustard gas (sulfur mustard, MG) has been known to cause a wide range of acute and chronic injuries to exposure victims. The earliest descriptions of these injuries were published during and in the immediate aftermath of the First World War, and a further series of accounts followed the Second World War. More recently, MG has been deployed in warfare in the Middle East and this resulted in large numbers of victims, whose conditions have been studied in detail at hospitals in the region. In this review, we bring together the older and more recent clinical studies on MG toxicity and summarize what is now known about the acute and chronic effects of the agent on the eyes, skin, respiratory tract and other physiological systems. In the majority of patients, the most clinically serious long-term consequences of MG poisoning are on the respiratory system, but the effects on the skin and other systems also have a significant impact on quality of life. Aspects of the management of these patients are discussed. PMID- 20836143 TI - Control of the misuse of bromide in horses. AB - Bromide is a sedative hypnotic. Due to its potential use as a sedative or calmative agent in competition horses, a method to control bromide is needed. Colorimetric method had been employed in the authors' laboratory from 2003 for the semi-quantification of bromide in equine plasma samples. However, the method was found to be highly susceptible to matrix interference, and was replaced in 2008 with a more reliable inductively coupled plasma-mass spectrometry (ICP/MS) method. Equine plasma was protein-precipitated using trichloroacetic acid, diluted with nitric acid, and then submitted directly to ICP/MS analysis. Since bromide is naturally occurring in equine plasma, a threshold is necessary to control its misuse in horses. Based on population studies (n = 325), a threshold of 90 ug/mL was proposed (with a risk factor of less than 1 in 10 000). Using the ICP/MS screening method, equine plasma samples with bromide greater than 85 ug/mL would be further quantified using the more accurate ICP/MS standard addition method. Confirmation of bromide was achieved by gas chromatography-mass spectrometry (GC-MS), with the bromide detected as its pentafluorobenzyl derivative. A sample is considered positive if its plasma bromide concentration exceeds the threshold (90 ug/mL) plus the measurement uncertainty of the quantification method (8 ug/mL at 99% 1-tailed confidence level) and its presence is confirmed using the GC-MS method. Following oral administration of potassium bromide (60 g each) to two geldings, plasma bromide levels peaked after approximately 2 hours at about 300 ug/mL, and then remained above the threshold for 8 and 13 days respectively. PMID- 20836144 TI - Stability-indicating chemometric methods for the determination of tazarotene. AB - Two multivariate calibration methods-principal component regression (PCR) and partial least square (PLS)-have been used to determine tazarotene in the presence of its degradation products. Both methods are useful in spectral analysis because of the simultaneous inclusion of many spectral wavelengths instead of the single wavelength used in derivative spectrophotometry. A great improvement in the precision and predictive abilities of these multivariate calibrations was observed. A calibration set was constructed for the mixture and the best model was used to predict the concentration of the selected drug. The proposed methods were applied successfully in the determination of tazarotene in laboratory prepared mixtures and in commercial preparations. Tazarotene was analyzed with mean accuracies of 100.006 +/- 0.695 and 100.007 +/- 0.690 using the PCR and PLS methods, respectively. The validity of the proposed methods was assessed using the standard addition technique. The proposed methods were found to be rapid, simple and required no preliminary separation. They can therefore be used for the routine analysis of tazarotene in quality-control laboratories. PMID- 20836145 TI - Quantitation of valproic acid in pharmaceutical preparations using dispersive liquid-liquid microextraction followed by gas chromatography-flame ionization detection without prior derivatization. AB - Dispersive liquid-liquid microextraction (DLLME), coupled with gas chromatography flame ionization detection (GC-FID), has been successfully used for the extraction and determination of valproic acid (VPA) in pharmaceutical preparations. In the developed method, an appropriate mixture of extracting and disperser solvents was rapidly injected into an aqueous sample. Having formed a cloudy solution, the mixture was centrifuged and then the extracting solvent was sedimented at the bottom of a conical test tube. The extract was then injected into a GC system directly, without any further pretreatment. Initially, microextraction efficiency factors were optimized and the optimum experimental conditions found were as follows: tetrachloroethylene (9.0 uL) as extracting solvent; acetone (1.0 mL) as disperser solvent; 5 mL acidic aqueous sample (pH 1) without salt addition. Under the selected conditions, the calibration curve showed linearity in the range of 0.1-5.0 mg/L with regression coefficient corresponding to 0.9998. The limit of detection was found to be 0.05 mg/L. Finally, the method was applied for the determination of VPA in two different pharmaceutical preparations. A reasonable intra-assay (3.9-10.8%, n = 3) and inter-assay (5.6-11.4%, n = 3) precision illustrated the good performance of the analytical procedure. The protocol proved to be rapid and cost-effective for screening purposes. PMID- 20836146 TI - Electrochemical study of spiramycin and its determination in pharmaceutical preparation. AB - Spiramycin (SPY) is a medium-spectrum antibiotic with high effectiveness against Gram-positive bacteria. The voltammetric behaviour of spiramycin was studied using differential pulse polarography (DPP) and square wave polarography (SWP). The drug in Britton-Robinson buffer (pH 11.5) is reduced at - 1.45 V, giving rise to a well-defined cathodic peak using hanging mercury drop electrode (HMDE) versus Ag/AgCl electrode. This peak is attributed to the reduction of the aldehyde group. The results proved that the reduction of SPY is an irreversible diffusion-controlled process. The diffusion current-concentration relationship was shown to be rectilinear over the range of 20-80 and 0.8-80 ug ml(-1) using DPP and SWP modes, respectively, with detection limit of 8.5 ug ml(-1) (1.01 * 10(-5) M) and 0.46 ug ml(-1) (5.46 * 10(-7) M) for DPP and SWP modes, respectively. A mechanism is postulated for the reduction of SPY. The proposed techniques were successfully applied to the determination of the studied compound either in pure form or in its formulation. PMID- 20836147 TI - Simultaneous determination of nitroaromatic compounds in water using capillary electrophoresis with amperometric detection on an electrode modified with a mesoporous nano-structured carbon material. AB - In this article, a carbon disk electrode modified with mesoporous carbon material (CMK-3) was used in CE with amperometric detection system for the simultaneous determination of four types of important nitroaromatic compounds, including 2,4,6 trinitrotoluene (TNT), 1,3,5-trinitrobenzene (TNB), 2,4-dinitrotoluene (DNT) and 1,3-dinitrobenzene (DNB). Compared with the bare carbon electrode, the CMK-3 modified electrode greatly improved the sensitivity at a relatively positive detection potential due to its excellent electrocatalytic activities, high conductivity and large effective surface area. The four analytes could be well separated and detected within 480 s. A good linear response was obtained for TNB, DNB, TNT and DNT from 8.4 to 5.0 x 10(3) MUg/L, with correlation coefficients higher than 0.9992. And the detection limits were established between 3.0 and 4.7 MUg/L for the four investigated nitroaromatic compounds (S/N=3). The CMK-3 modified electrode was successfully employed to analyze coking wastewater, tap water and river samples with recoveries in the range of 94.8-109.0%, and RSDs less than 5.0%. The presented results demonstrated that the CMK-3-modified carbon electrode used in CE with amperometric detection was of convenient preparation, high sensitivity and good repeatability, which could be employed in the rapid determination of practical samples. PMID- 20836154 TI - Weed genomics advance: a commentary. PMID- 20836156 TI - Mutated cylindromatosis gene affects the functional state of dendritic cells. AB - Cylindromatosis gene (CYLD) is a ubiquitously expressed deubiquitinating enzyme, which interacts with members of the NF-kappaB signaling pathway and attenuates NF kappaB and JNK signaling. Here, we report that DC derived from transgenic mice, which solely express a naturally occurring CYLD isoform (CYLD(ex7/8)), display a higher content of nuclear RelB and express elevated levels of NF-kappaB family members as well as of known NF-kappaB-target genes comprising costimulatory molecules and pro-inflammatory cytokines, as compared with WT DC. Accordingly, unstimulated CYLD(ex7/8) DC exhibited a significantly higher primary allogenic T cell stimulatory capacity than WT DC and exerted no tolerogenic activity. Transduction of unstimulated CYLD(ex7/8) DC with relB-specific shRNA reduced their T-cell stimulatory capacity. Treatment with the synthetic glucocorticoid dexamethasone known to inhibit NF-kappaB and AP-1 activity reverted the pro immunogenic phenotype and function of CYLD(ex7/8) DC and re-established their tolerogenic function. DC derived from CYLD knockout mice showed no functional alterations compared with WT DC. Therefore, although complete loss of CYLD may be compensated for by other endogenous NF-kappaB inhibitors, CYLD(ex7/8) acts in a dominant negative manner. Our findings raise the question of whether genetic defects associated with increased NF-kappaB activity may result in disturbed maintenance of peripheral tolerance. PMID- 20836157 TI - Chronic myelogenous leukemia maintains specific CD8(+) T cells through IL-7 signaling. AB - Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells. The disease progresses after several years from an initial chronic phase to a blast phase. Leukemia-specific T cells are regularly detected in CML patients and may be involved in the immunological control of the disease. Here, we analyzed the role of leukemia-specific CD8(+) T cells in CML disease control and the mechanism that maintains CD8(+) T-cell immunosurveillance in a retroviral-induced murine CML model. To study antigen-specific immune responses, the glycoprotein of the lymphocytic choriomeningitis virus was used as model leukemia antigen. Leukemia-specific CTL activity was detectable in vivo in CML mice and depletion of CD8(+) T cells rapidly led to disease progression. CML specific CTL were characterized by the expression of the IL-7 receptor alpha chain. In addition, leukemia cells produced IL-7 that was crucial for the maintenance of leukemia-specific CTL and for disease control. Therefore, CML cells maintain the specific CD8(+) T-cell-mediated immune control by IL-7 secretion. This results in prolonged control of disease and probably contributes to the characteristic chronic phase of the disease. PMID- 20836158 TI - Effects of Hypericum perforatum extract on diabetes-induced learning and memory impairment in rats. AB - Cognitive impairment occurs in diabetes mellitus. Hypericum perforatum has been used in folk medicine to improve mental performance. Here it is hypothesized that chronic treatment with an extract of Hypericum perforatum (6, 12 and 25 mg/kg, p.o.) would have effects on passive avoidance learning (PAL) and memory in control and streptozotocin-induced diabetic rats. Treatments were begun at the onset of hyperglycaemia. PAL was assessed 30 days later. A retention test was done 24 h after training. At the end, the animals were weighed and blood samples were drawn for plasma glucose measurement. Diabetes caused impairment in acquisition and retrieval processes of PAL and memory. Hypericum treatment (12 and 25 mg/kg) improved learning and memory in control rats and reversed learning and memory deficits in diabetic rats. A dose of 6 mg/kg did not affect cognitive function. Hypericum administration did not alter the body weight and plasma glucose levels. Antioxidant properties and cholinergic facilitatory effects of Hypericum may be involved in its nootropic effects. These results show that Hypericum perforatum prevented the deleterious effects of diabetes on PAL and memory. As Hypericum would be free of major side effects compared with other nootropic medications, it may provide a new potential alternative for demented diabetic patients. PMID- 20836160 TI - Excision of selectable marker genes from transgenic crops as a concern for environmental biosafety. AB - The main task in the development of transgenic plants is the capability to distinguish between plant cells with an integrated transgene and the bulk of non transformed cells. Selectable marker genes are required to achieve this goal within the transgene, and to select for their expression. These selectable markers are mostly based on genes conferring antibiotic or herbicide resistance. The presence of the marker gene will lead to unpredictable environmental hazards, so on the basis of economic incentives and safety concerns, several methods, such as site-specific recombination, homologous recombination and co-transformation, have been developed to eliminate these genes from the genome after successful transformation has been achieved. Gene transfer without the incorporation of an antibiotic-resistance marker or herbicide-resistance marker in the host genome should convince the public with regard to the field release of transgenic organisms. Moreover, it would obviate the need for different selectable markers in subsequent rounds of gene transfer into the same host. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836159 TI - Functional neuroimaging at different disease stages reveals distinct phases of neuroplastic changes in amyotrophic lateral sclerosis. AB - Some previous functional magnetic resonance imaging (fMRI) studies have revealed increased activation in amyotrophic lateral sclerosis (ALS) patients but longitudinal data on such activation changes are lacking. To assess the time course of changes in fMRI patterns and their potential contribution to the understanding of ALS pathophysiology, we, therefore, investigated a total of 22 patients with ALS and matched control participants while they performed a blocked motor task. Patients were assigned to three groups according to whether they had no (MRC grade 5), mild (MRC 4), or marked (MRC 3) weakness of the examined right hand. Significant activations were seen in primary motor and premotor cortex, somatosensory cortex, supplementary motor area and subcortical areas in all groups. The size of the activated area in the contralateral sensorimotor cortex was increased to a similar degree in all three ALS groups compared to control participants irrespective of weakness on clinical examination. Whereas movement related signal change and beta weights extracted from the activated cluster were unchanged relative to controls in ALS patients with no weakness, a marked decrease of these parameters was seen in patients with weakness. Two distinct stages of neuroplastic changes could be identified in ALS (first: increase of the activated area in contralateral sensorimotor cortex; second: reduction of signal change and beta weights with increasing weakness). We interpret the increase of the activated area as a result of decreased intracortical inhibition and the reduction of movement related signal change and beta weights as a consequence of loss of upper motor neurons. PMID- 20836161 TI - The influence of different single dietary sources on moult induction in laying hens. AB - An investigation was carried out to assess the possibility of using single dietary sources as alternatives to feed deprivation for the induction of moult in commercial laying hens. The study involved six dietary groups of 29 laying hens: unmoulted, dried tomato pomace, alfalfa meal, rice bran, cumin seed meal and feed withdrawal. The birds received the above diets during the moulting period (11 days), and body weight loss and ovary weight regression were measured. Post-moult production parameters (number of eggs produced per hen per day, egg weight, shell weight, yolk colour and Haugh unit) were measured for 12 weeks. Results showed that all dietary sources were as effective as feed withdrawal in causing ovary weight regression in birds. Birds provided with tomato pomace or alfalfa showed lower weight losses than feed-deprived birds at the end of the moulting period. Hens moulted by tomato pomace or alfalfa exhibited post-moult levels of egg production over a 12 week period that were superior to those of hens moulted by feed withdrawal. Post-moult eggs laid by hens moulted by all dietary sources were of comparable quality to eggs from feed-deprived hens and superior to those from unmoulted hens. As fibrous feeds with low metabolisable energy and an appreciable amount of protein, dried tomato pomace and alfalfa meal may be fed to hens on an ad libitum basis for effective moult induction while reducing the stress of severe starvation and retaining comparable egg quality and production. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836162 TI - Chemical composition and in vitro antioxidant studies on Syzygium cumini fruit. AB - Syzygium cumini, widely known as Jamun, is a tropical tree that yields purple ovoid fleshy fruit. Its seed has traditionally been used in India for the treatment of diabetes. Based on the available ethno-pharmacological knowledge, further studies were extended to understand the chemical composition and antioxidant activities of three anatomically distinct parts of fruit: the pulp, kernel and seed coat. Fruit parts, their corresponding ethanol extracts and residues were evaluated for chemical composition. The alcoholic extract was evaluated for its antioxidant potential against DPPH(*), OH(*), O(2) (*-) and lipid peroxidation. The whole fruit consisted of 666.0 +/- 111.0 g kg(-1) pulp, 290.0 +/- 40.0 g kg(-1) kernel and 50.0 +/- 15.0 g kg(-1) seed coat. Fresh pulp was rich in carbohydrates, protein and minerals. Total fatty matter was not significant in all three parts of fruit. Detailed mineral analysis showed calcium was abundant in all fruit parts and extracts. Total phenolics, anthocyanins and flavonoid contents of pulp were 3.9 +/- 0.5, 1.34 +/- 0.2 and 0.07 +/- 0.04 g kg( 1), respectively. Kernel and seed coat contained 9.0 +/- 0.7 and 8.1 +/- 0.8 g kg(-1) total phenolics respectively. Jamun pulp ethanol extract (PEE), kernel ethanol extract (KEE) and seed coat ethanol extract (SCEE) showed a high degree of phenolic enrichment. DPPH radical scavenging activity of the samples and standards in descending order was: gallic acid > quercetin > Trolox > KEE > BHT > SCEE > PEE. Superoxide radical scavenging activity (IC(50)) of KEE was six times higher (85.0 +/- 5.0 ug mL(-1)) compared to Trolox (540.0 +/- 5.0 ug mL(-1)) and three times compared to catechin (296.0 +/- 11.0 ug mL(-1)). Hydroxyl radical scavenging activity (IC(50)) of KEE was 151.0 +/- 5.0 ug mL(-1) which was comparable with catechin (188.0 +/- 6.0 ug mL(-1)). Inhibition of lipid peroxidation of the extracts was also studied and their activity against peroxide radicals were lower than that of standard compounds (BHT, 79.0 +/- 4.0 ug mL(-1); quercetin, 166.0 +/- 13.0 ug mL(-1); Trolox, 175.0 +/- 4.0 ug mL(-1); PEE, 342.0 +/- 17.0 ug mL(-1); KEE, 202.0 +/- 13.0 ug mL(-1) and SCEE, 268.0 +/- 13.0 ug mL( 1). Copyright (c) 2007 Society of Chemical Industry. PMID- 20836163 TI - Proximal composition and in vitro digestibility of starch in lima bean (Phaseolus lunatus) varieties. AB - BACKGROUND: Beans are rich and inexpensive sources of proteins and carbohydrates around the world, but particularly in developing countries. However, many legume varieties are still underutilized. In this study, physical characteristics of the seeds of three Phaseolus lunatus cultivars were characterized. Also, the chemical composition and starch digestibility in the cooked beans were assessed. RESULTS: 'Comba floja' variety exhibited the highest thousand-kernel weight whereas the lowest was found in 'comba violenta'. This agrees with seed dimensions: 'comba floja' had the Longest seeds (16.36 mm) and 'comba violenta' the shortest ones (13.98 mm). All samples exhibited high protein content, but levels in 'comba blanca' variety (216 g kg(-1)) were lower than the in other two cultivars. Total starch (370-380 g kg(-1)) and potentially available starch content (330-340 g kg( 1)) were similar in the three varieties. Resistant starch level in the cooked seeds ranged between 38 and 45 g kg(-1). Low enzymatic hydrolysis indices (HI) were recorded (30.2-35%), indicating a low digestion rate for Phaseolus lunatus starch. HI-based predicted glycemic indices ranged between 34% and 39%, which suggests a 'slow carbohydrate' feature for this legume. CONCLUSION: Phaseolus lunatus beans appear to be a good source of protein and slow-release carbohydrates with potential benefits for human health. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836164 TI - Effect of microbial transglutaminase on the protein fractions of rice, pea and their blends. AB - BACKGROUND: Transglutaminase (TG) is a transferase that has been used for crosslinking proteins. In general, those interactions are promoted within proteins of the same nature, and very few studies have been conducted for creating new bonds between proteins from different sources catalysed by TG. The effect of TG on the protein fractions of rice flour, pea protein isolate and their blends was studied by using different electrophoretic analyses (simple sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and multistaking SDS-PAGE under reducing and non-reducing conditions). RESULTS: TG induced the disappearance of numerous protein bands as a consequence of the formation of large protein polymers, linked by isopeptidic and disulfide bonds, with reduced solubility. The main protein fractions involved in those interactions were the albumins and globulins, from the pea protein isolate, and the rice flour; and the glutelins were also crosslinked. CONCLUSION: Composite flours containing the rice flour and the pea protein isolate are proposed for obtaining a protein-enriched dough with better amino acid balance. Also a protein network formed of protein aggregates of high molecular weight can be created in the presence of transglutaminase. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836165 TI - Safety tests and antinutrient analyses of noni (Morinda citrifolia L.) leaf. AB - BACKGROUND: Noni (Morinda citrifolia L.) leaves have a documented history of food use. However, previous safety and antinutrient studies are absent. The current investigation was conducted to assess the utility of noni leaves as food. RESULTS: No evidence of toxicity or differences in weight gain were observed in acute, subacute, and subchronic oral toxicity tests of ethanol-water (1:1 v/v) and hot-water extracts of noni leaves in mice at doses of 2000, 200, and 20 mg kg(-1) body weight, respectively. Acute systemic anaphylaxis tests of the ethanol water (4:1 v/v) and hot-water extracts were negative. Further, leaf proteins were readily digested in simulated gastric fluid. Tannic acid concentrations in frozen and dried leaf were 1.6 and 25.8 g kg(-1), respectively. Phytic acid was not detected in the raw leaf (<1 g kg(-1)). The average oxalic acid content was 1 g kg(-1) and was fairly uniform among 22 leaf samples from 11 islands throughout French Polynesia. Similarly, campesterol, stigmasterol, and beta-sitosterol content did not vary widely, suggesting low inter-island content variability. CONCLUSIONS: The apparent lack of toxicity of the leaves and the hardiness of the plant make it ideal for further agricultural development, especially where sustained growth of other food crops is difficult. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836166 TI - Anthocyanin dyes extracted from grape pomace for the purpose of textile dyeing. AB - BACKGROUND: Pomace from different grape varieties was studied with regard to the content of extractable anthocyanins. RESULTS: Total anthocyanin concentrations of 24.5-126 mg dm(-3) were found in the extracts. The amount of extractable pigment was dependent on the variety of grape. The extracts were applied in textile dyeing operations using cotton fabric pre-mordanted with tannin as textile substrate. Red/violet shades were obtained that showed good water-fastness; however, limited light-fastness indicated need for improvement to fulfil requirements for textile application. CONCLUSION: Colour measurement by means of CIE-Lab coordinates and Kubelka-Munk value showed a direct correlation between extractable anthocyanin concentration and colour depth of the dyed material. Thus the analytically determined concentration of anthocyanins in the aqueous extract can serve as a measure of quality of grape pomace as raw material for textile dyeing application. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836167 TI - Fatty acid composition of total lipids, neutral lipids and phospholipids in wild and farmed matrinxa (Brycon cephalus) in the Brazilian Amazon area. AB - BACKGROUND: The chemical composition of Amazonian fish is extremely variable, being influenced by the season and the type and amount of food. A special interest in the fish oil composition has been developed owing to the presence of essential fatty acids, since this is directly related to human health. This study aimed to investigate the fatty acid composition (FAC) of the total lipid (TL), neutral lipid (NL) and phospholipid (PL) fractions of the dorsal muscle and orbital cavity of farmed and wild matrinxa in the Amazon area captured in different seasons. RESULTS: Fatty acids (FA) were analysed by high-resolution gas chromatography/mass spectrometry. Sixty-five FA were detected in the TL, 66 in the NL and 55 in the PL. The main FA found in farmed and wild fish were oleic, palmitic, stearic and linoleic acids. No distinctions in the quality or quantity of these fractions between dorsal muscle and orbital cavity were found. CONCLUSION: The season had a significant influence on the TL and FAC. Fish captured during the dry season showed lower levels of lipid and a higher percentage of long-chain polyunsaturated fatty acids. Matrinxa farmed in a semi intensive system showed a nutritional quality comparable to that of wild matrinxa captured in the wet season. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836168 TI - Antioxidant activity of tryptic digests of hen egg yolk phosvitin. AB - BACKGROUND: Food protein-derived peptides with antioxidant activity have great potential for use as natural antioxidants in food products. However, neither the structure-activity relationship nor the antioxidant mechanism of peptides is fully understood. Egg yolk phosvitin has been acknowledged to have strongly antioxidant protein owing to its highly phosphorylated form. In this study the antioxidant activities of tryptic digests of hen egg yolk phosvitin (PPPs), which were prepared by partial dephosphorylation and subsequent hydrolysis by trypsin, were compared with that of intact phosvitin. RESULTS: Compared with intact phosvitin, PPPs exhibited distinctly stronger capability of inhibiting lipid oxidation in a linoleic acid system and more efficient radical-scavenging activity on 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals. However, the chelating capability of PPPs on iron(II) was weaker than that of intact phosvitin. The strong antioxidant activity of PPPs can be mainly attributed to the amino acid composition rather than to the content of phosphorylserine ligands. Histidine, methionine and tyrosine are the amino acids most likely to be responsible for the strong antioxidant activity of phosvitin peptides. CONCLUSION: The present study indicated that PPPs could be used in foods as natural antioxidants with strong antioxidant activity. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836169 TI - Effectiveness of organic acid, ozonated water and chlorine dippings on microbial reduction and storage quality of fresh-cut iceberg lettuce. AB - BACKGROUND: The comparative effects of organic (citric and lactic) acids, ozone and chlorine on the microbiological population and quality parameters of fresh cut lettuce during storage were evaluated. RESULTS: Dipping of lettuce in 100 mg L(-1) chlorine solution reduced the numbers of mesophilic and psychrotrophic bacteria and Enterobacteriaceae by 1.7, 2.0 and 1.6 log(10) colony-forming units (CFU) g(-1) respectively. Treatment of lettuce with citric (5 g L(-1)) and lactic (5 mL L(-1)) acid solutions and ozonated water (4 mg L(-1)) reduced the populations of mesophilic and psychrotrophic bacteria by 1.7 and 1.5 log(10) CFU g(-1) respectively. Organic acid dippings resulted in lower mesophilic and psychrotrophic counts than ozonated water and chlorine dippings during 12 days of storage. Lactic acid dipping effectively reduced (by 2.2 log(10) CFU g(-1)) and maintained low populations of Enterobacteriaceae on lettuce for the first 6 days of storage. No significant (P > 0.05) changes were observed in the texture and moisture content of lettuce samples dipped in chlorine, organic acids and ozonated water during storage. Colour, beta-carotene and vitamin C values of fresh-cut iceberg lettuce did not change significantly (P > 0.05) until day 8. CONCLUSION: Lactic and citric acid and ozonated water dippings could be alternative treatments to chlorine dipping to prolong the shelf life of fresh-cut iceberg lettuce. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836170 TI - Enzymic and in sacco methods to estimate rumen degradation of food protein in cattle. AB - BACKGROUND: Two factorial studies compared enzymic and in sacco methods to estimate degradation of ruminant foods. Enzyme degradation (in vitro = enzyme) was determined from the release of leucine-equivalent amino acid (LA) crude protein (CP) from sunflower meal (SF), maize gluten meal (MG), distillers' dark grain (DG) and field beans (FB) after their separate incubations with Streptomyces griseus enzyme for 0-24 h. In sacco crude protein (CP) degradation of these foods was estimated during washing (0 h) and rumen incubations in fistulated cows for 2-24 h. The LA data were expressed as g LA per either kg of CP (LACP) or acid-hydrolysable LA (HLA) of each food and compared with in sacco data. RESULTS: These methods showed comparable degradation with time (P < 0.01). The in sacco and HLA were greater than LACP for all foods except MG where in sacco value was either lower or equal to LACP depending upon the incubation time (P > 0.05 or P < 0.05). Conversely, HLA was significantly (P < 0.01) greater than LACP from 2 h onwards. At 0 h, in sacco values were significantly greater than those of enzyme for SF, DG and FB (P < 0.05) but not for MG. The foods differed significantly for degradation constants (a, b, c) in each method (P < 0.05). CONCLUSIONS: Despite variations between in sacco and enzyme estimates for different foods, the relationships between these estimates suggest that the HLA enzyme method has the potential to estimate food degradation. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836171 TI - Overcoming adverse effects of hailnets on fruit quality and microclimate in an apple orchard. AB - BACKGROUND: With the increase of hailstorms as a possible result of global warming, fruit crops are increasingly grown under hailnets. This results in lesser fruit quality in terms of colouration, fruit mass, firmness, starch and taste, i.e. sugar and acid, and vitamin content under hailnet due to altered microclimate and light deprivation. Reflective mulches (Extenday and Daybright) were spread in autumn 2006 to improve fruit quality and light utilisation under hailnet at Klein-Altendorf Research Station near Bonn, Germany. A monophosphate (Seniphos) was applied twice for the same purpose; untreated apple cv. 'Elstar' trees served as control. RESULTS: Under the translucent, 'white' hailnet, humidity was increased by ca. 6%, air temperature reduced by ca. 1.6 degrees C, soil temperature increased by ca. 0.5 degrees C and light reduced by 11-15% resulting in lesser fruit quality of 2.5% less sugar and less taste. The two reflective mulches increased light reflection at 45 degrees and 90 degrees angles by 2.5- to 6.3-fold. No differences in fruit ripening and firmness were observed, but fruit from trees under hailnet with reflective mulch contained up to 2.4% (from 13.3 to 15.7%) more sugar than those of the control (uncovered grass alleys). A less negative normalised differential vegetation index (NDVI) of - 0.3 on the red compared with - 0.5 on the green fruit side indicated more chlorophyll in the outer, sun-exposed, red side of the apples relative to the shaded side. Monophosphate-treated fruits maintained the peel chlorophyll with a greener ground colour of 92-97 degrees hue and a NDVI of - 0.3 as in the grassed control. Fruit in the lower canopy with reflective mulch were darker red (a value 30; 22 degrees hue) relative to the grassed control with a = 25 and 43 degrees hue (light red), expressed in a 4-fold increase in normalised anthocyanin index (NAI), but showed enhanced chlorophyll breakdown (NDVI from - 0.2 to - 0.5); similarly, the monophosphate increased the NAI by up to 2.5-fold. CONCLUSIONS: The effect of both reflective mulch cloths was most pronounced on apple fruit in the lower canopy under hailnet, which developed large vitamin C contents and a dark red top colour relative to the grassed control with enhanced chlorophyll breakdown. Both reflective mulch cloths increased the percentage of class I fruit with > 25% colouration by 12% (from 82 to 94%) without and under hailnet by 23% (from 69 to 89%) relative to the grassed control resulting in financial net gains of up to 1300 ? ha(-1) Copyright (c) 2007 Society of Chemical Industry. PMID- 20836172 TI - Infusions of Portuguese medicinal plants: Dependence of final antioxidant capacity and phenol content on extraction features. AB - BACKGROUND: Aqueous extracts of most medicinal plants traditionally employed in Portugal (at the ratio of 1 g plant: 110 mL water) have been assayed for total antioxidant capacity and phenol content, in order to elucidate their claimed medicinal features. RESULTS: The antioxidant activity was assessed by the ABTS(*+) method; the ascorbic acid equivalent values ranged from 1.4280 +/- 0.1261 g L(-1) for avocado (Persea americana (Lauraceae)) obtained by infusion of powder, down to 0.0027 +/- 0.0012 g L(-1) for olive (Olea europaea (Oleaceae)) obtained by infusion of leaves. Total phenol content was determined by the Folin Ciocalteu procedure; the gallic acid equivalent values ranged from 0.5541 +/- 0.0289 g L(-1) for avocado obtained by infusion of powder, down to 0.0053 +/- 0.0014 g L(-1) for olive obtained by boiling leaves. A good correlation between total antioxidant capacity and total phenol content was found. CONCLUSION: The method of powder infusion should be chosen if high concentration of antioxidants are sought. On the other hand, a high antioxidant capacity and a high phenol content correlate well with the empirically established (and widely publicised) capacity to treat respiratory infections. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836173 TI - Characterization of deep-fat frying in a wheat flour-water mixture model using a state diagram. AB - BACKGROUND: Crispness is an important characteristic to be controlled in deep-fat fried products. The physical state of food polymers influences the development of cellular structure and textural qualities of fried food. Glassy state is believed to play an important role in the mechanical properties of low-moisture food. Therefore, an understanding of the physicochemical phenomena in the development of fried food structure using a state diagram of the frying process is discussed. RESULTS: Wheat flour models containing 400 and 600 g kg(-1) initial moisture content were fried in frying oil at 150 degrees C for 1-7 min. Thermal properties of wheat flour, structure alteration and textural properties of fried samples were evaluated. The porous structure continuously enlarged when the sample was in the rubbery state. As the frying time was prolonged, the state of the product became glassy due to a decrease in water content, resulting in the ceasing of porous enlargement. CONCLUSION: The results revealed that physicochemical changes during frying influence the alteration of microstructure and quality of fried food, and the state diagram could be applied to explain the formation of microstructure during the frying process and used as a decision making tool to choose the proper conditions to provide desirable qualities in fried food. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836174 TI - Effects of partial substitution of concentrates with maize silage in organic dairy cow rations on performance and feed efficiency. AB - BACKGROUND: The general goal of organic dairy farming is to minimize purchased concentrate use and focus on milk production from forages. The aim of the present paper is to examine the influence of a partial substitution of purchased concentrates with home-grown maize silage on feed intake, milk production and feed efficiency in rations for organic dairy cows. In the experimental treatment group (E), two-thirds of average herd concentrate intake was replaced with 2.7 kg maize silage on a dry matter (DM) basis. RESULTS: In treatment E, total DM, energy and protein intake were significantly reduced compared to the control treatment group (C). Daily milk yield decreased in E by 11% and milk urea content was significantly lower. Calculated milk production from forage was significantly higher (91 versus 71%) in treatment E. Efficiency of dietary nitrogen (N) utilization (calculated as milk N as a percentage of N intake) was slightly improved in E and protein and energy balance (calculated as intake as a percentage of requirements) were closer to zero than in C. CONCLUSION: The present study indicates a potential to reduce levels of concentrates and substitute them with maize silage in organic dairy cow rations at least in the second half of lactation. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836175 TI - Anthocyanins and other polyphenolics in American elderberry (Sambucus canadensis) and European elderberry (S. nigra) cultivars. AB - BACKGROUND: Ten genotypes representing two elderberry species, Sambucus canadensis L. (eight genotypes) and S. nigra L. (two genotypes), were examined for their anthocyanins (ACY), total phenolics (TP), degrees Brix, titratable acidity (TA), and pH over two growing seasons. RESULTS: Overall, fruit generally had higher ACY, TP, ACY/TP, degrees Brix, and pH in 2005 than 2004. All samples of S. canadensis had similar anthocyanin profiles to one another, but were distinctly different from S. nigra. Both species had cyanidin-based anthocyanins as major pigments. Previously unreported anthocyanins were identified in some samples in this study. Trace levels of delphinidin 3-rutinoside were present in all elderberry samples except cv. 'Korsor'. Also, petunidin 3-rutinoside was detected in cvs 'Adams 2', 'Johns', 'Scotia', 'York', and 'Netzer' (S. canadensis). The identified polyphenolics of both species were mainly composed of cinnamic acids and flavonol glycosides. The major polyphenolic compounds present in S. canadensis were neochlorogenic acid, chlorogenic acid, rutin, and isorhamnetin 3-rutinoside, while chlorogenic acid and rutin were found to be major polyphenolic compounds in S. nigra. CONCLUSION: Sufficient variability was seen among these genotypes to suggest that a successful breeding program could be carried out to improve levels of the various compounds evaluated in this study. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836176 TI - (1)H and (23)Na MRI studies of Atlantic salmon (Salmo salar) and Atlantic cod (Gadus morhua) fillet pieces salted in different brine concentrations. AB - BACKGROUND: Applicability of magnetic resonance imaging (MRI) to quantitative analysis of sodium in salted fish products is usually impaired by the partial (23)Na MRI 'invisibility' phenomena as well as high investment costs of the MRI equipment. RESULTS: Salmon and cod fillet pieces, unsalted and brine salted (50, 100, 150, 200 and 250 g kg(-1) NaCl) for 48 h, were studied using (1)H and (23)Na MRI. Based on MRI results, T(1) and T(2) relaxation times were calculated for (1)H and the T(2) time for (23)Na nuclei. In addition, water diffusion images for all fillet samples and reference brine solutions were obtained. Variation of the nuclear magnetic resonance relaxation times and water diffusion constants with brine concentration is discussed in terms of the muscle structural changes. Sodium MRI visibility factors for the MRI method used were determined for all fish samples. CONCLUSION: Observed changes in proton and sodium NMR relaxation times with the salt content reflect complex counteraction of several factors related to the muscle structural changes. Sodium MRI visibility factors appear to be dependent on a number of experimental factors in a complex matter, making quantitative sodium analysis by the MRI technique used non-trivial. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836177 TI - Changes in liquid-holding capacity, water distribution and microstructure during chill storage of smoked salmon. AB - BACKGROUND: During recent years, increases in liquid loss and soft texture in cold smoked salmon have been reported, possibly due to increased lipid content and a change in muscle structure. These problems can lead to downgrading of the product. This study aimed to investigate the influence of raw material composition and chill storage on quality parameters of cold smoked salmon. RESULTS: Initial smoked fish had a higher liquid-holding capacity (LHC) than samples stored for 20 days. Large fish lost more liquid than small fish. The difference in LHC was consistent with a change in water distribution, which could indicate denaturation of muscle protein. Studies of the microstructure showed the influence of both processing and chill storage. An indication of lipid released from the cells was seen after 20 days of chill storage, which could be related to the reduced LHC at that time. CONCLUSION: Both raw material composition and chill storage affected the quality parameters of smoked salmon. This study has improved knowledge about the relationships between muscle structure, liquid-holding properties and water distribution in smoked salmon. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836178 TI - Antioxidant capacity of leafy vegetables as affected by high tunnel environment, fertilisation and growth stage. AB - BACKGROUND: This study was conducted to evaluate the influences of protected environment, organic fertilisation and growth stage on the oxygen radical absorbance capacity (ORAC) values of leafy vegetables. RESULTS: In a first experiment, pac choi grown in high tunnels had significantly lower ORAC than field-grown plants. Organic fertiliser markedly increased the antioxidant capacity of pac choi compared with conventional treatment, especially in the open field. However, both open field and organic production resulted in significantly lower yield and more severe leaf damage due to insect attack. In a second study, spinach showed the highest ORAC, followed by pac choi, red leaf lettuce and romaine lettuce. A significant decline in ORAC under high tunnel production was observed only in spinach. In contrast to the first trial, organic fertilisation did not cause an increase in antioxidant capacity of the leafy vegetables. The ORAC values of spinach from the open field and pac choi from high tunnels were significantly higher when harvested at the mature head stage than at the baby size stage. CONCLUSION: Further studies will help to elucidate effects of genotype, growth stage, and production environment on antioxidant capacities of vegetables and may lead to recommended practices to maximise antioxidant capacity of vegetable crops. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836179 TI - Peniophora lycii phytase is stabile and degrades phytate and solubilises minerals in vitro during simulation of gastrointestinal digestion in the pig. AB - BACKGROUND: Microbial phytases (EC 3.1.3) are widely used in diets for monogastric animals to hydrolyse phytate present in the feed and thereby increase phosphorus and mineral availability. Previous work has shown that phytate solubility is strongly affected by calcium in the feed and by pH in the gastrointestinal (GI) tract, which may have an effect on phytase efficacy. An in vitro model simulating the GI tract of pigs was used to study the survival of Peniophora lycii phytase and the effect of the phytase on phytate degradation, inositol phosphate formation and mineral solubilisation during in vitro digestion of a 30:70 soybean meal/maize meal blend with different calcium levels. RESULTS: The phytase retained 76 and 80% of its initial activity throughout the gastric in vitro digestion. Total phytate hydrolysis by P. lycii phytase was in the same range at total calcium levels of 1.2 and 6.2 mg g(-1) dry matter (DM), despite very large differences in phytate solubility at these calcium levels. However, at 11.2 and 21.2 mg Ca g(-1) DM, phytate hydrolysis was significantly lower. The amount of soluble mineral was generally increased by P. lycii phytase. CONCLUSION: Stability of P. lycii phytase during gastric digestion was not found to be critical for phytate hydrolysis. Furthermore, original phytate solubility was not an absolute requirement for phytate degradation; phytate solubility seemed to be in a steady state, allowing insoluble phytate to solubilise as soluble phytate was degraded. This is new and interesting knowledge that adds to the current understanding of phytate-phytase interaction. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836180 TI - Distribution of fatty acids in triacylglycerols and phospholipids from peas (Pisum sativum L.). AB - BACKGROUND: The fatty acid distribution of triacylglycerols (TAG) and major phospholipids (PL) obtained from four varieties of peas (Pisum sativum) was investigated. The total lipids extracted from the peas were separated by thin layer chromatography into seven fractions. RESULTS: The major lipid components were PL (52.2-61.3%) and TAG (31.2-40.3%), while hydrocarbons, steryl esters, free fatty acids and diacylglycerols (sn-1,3 and sn-1,2) were also present in minor proportions (5.6-9.2%). The main PL components isolated from the four varieties were phosphatidylcholine (42.3-49.2%), phosphatidylinositol (23.3 25.2%) and phosphatidylethanolamine (17.7-20.5%). Significant differences (P < 0.05) in fatty acid distribution were found for different pea varieties. Phosphatidylinositol was unique in that it had the highest saturated fatty acid content among the three PL. However, the principal characteristics of the fatty acid distribution in the TAG and three PL were evident among the four varieties: unsaturated fatty acids were predominantly located in the sn-2 position while saturated fatty acids primarily occupied the sn-1 or sn-3 position in the oils of the peas. CONCLUSION: These results should be useful to both producers and consumers for the manufacture of pea foods in Japan. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836181 TI - Concentration-dependent antioxidant activities of conjugated linoleic acid and alpha-tocopherol in corn oil. AB - BACKGROUND: Antioxidants prevent rancidity (lipid peroxidation) and natural antioxidants, e.g., alpha-tocopherol, likely provide additional value to oil based food products because of their health benefits. Conjugated linoleic acid (CLA) has potential health benefits and may exhibit antioxidant properties. The main aim of this study was to compare the antioxidant efficacy of alpha tocopherol, trans-10, cis-12-CLA and cis-9, trans-11-CLA (in graded concentrations) added to antioxidant-stripped corn oil. RESULTS: As compared to alpha-tocopherol, both CLA isomers displayed significant inhibition of corn oil lipid peroxidation induced by copper. Inhibition of thiobarbituric acid reactive substances (TBARS) were CLA concentration dependent for both isomers but with significant inhibition occurring at 0.1 and 1 ppm of CLA isomers or alpha tocopherol, respectively (P < 0.05). Graded concentrations of alpha-tocopherol, and for both CLA isomers and time, had significant effects on TBARS formation (P < 0.0001). There were significant effects in interactions between graded concentrations and time for both CLA isomers (P < 0.0001) but not for alpha tocopherol (P > 0.05). CONCLUSION: CLA compounds could serve as useful food antioxidants and provide additional value because of their potential bioactivity in disease prevention. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836182 TI - Contribution of olive seed to the phenolic profile and related quality parameters of virgin olive oil. AB - BACKGROUND: Conflicting results have been reported about the effect of fruit de stoning on the virgin olive oil (VOO) phenolic profile. The aim of the present study was to determine whether olive seed plays any role in the synthesis of this oil phenolic fraction. RESULTS: Increases of around 25% of total phenolic compounds were observed in oils obtained from de-stoned olive fruits in three main Spanish cultivars. To investigate the involvement of olive seed in determining the phenolic profile of VOO, whole intact olive fruits were added with up to 400% olive stones. Excellent regression coefficients were found in general for the decrease of total phenolic compounds and, particularly, of o diphenolics in the resulting oils. On the other hand, it was found that olive seed contains a high level of peroxidase (POX) activity (72.4 U g(-1) FW), accounting for more than 98% of total POX activity in the whole fruit. This activity is able to modify VOO phenolics in vitro, similar to the effect of adding stones during VOO extraction. CONCLUSION: Olive seed plays an important role in determining VOO phenolic profile during the process to obtain an oil that seems to be associated with a high level of POX activity. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836183 TI - A simple DNA extraction method suitable for PCR detection of genetically modified maize. AB - BACKGROUND: The polymerase chain reaction (PCR) is a powerful tool that is being increasingly used for detection of transgenic DNA. PCR requires only a minute quantity of template, but sensitive and accurate testing requires DNA of sufficient purity and free from inhibitors such as plant polysaccharides. Several standard protocols are available for this purpose, but they usually involve several steps, imply destruction of the maize kernel, or are time-consuming. Our aim was to develop a fast and simple extraction method to isolate a raw DNA containing solution from maize tissues suitable for use as a template in a PCR based detection assay with specific oligonucleotides directed to the identification of event MON810. RESULTS: The NaOH-based DNA extraction method we report here is time-saving (5 min) and can be used to isolate DNA-containing solutions from a small maize leaf portion (down to 1 mg) or from a single overnight-germinated kernel. PCR performed with selected primers yielded reproducible detection of transgenic DNA. CONCLUSION: The main advantages of the procedure are the quick extraction step, the possibility of non-destructive testing of maize kernels, and the robustness of the PCR-based detection, a consequence of the selection of MON810-matching oligonucleotides yielding intense and highly specific amplicons. Copyright (c) 2007 Society of Chemical Industry. PMID- 20836184 TI - Val bean (Lablab purpureus L.) proteins: composition and biochemical properties Mahesh Venkatachalam and Shridhar K Sathe. Journal of the Science of Food and Agriculture, 2007; 87: 1539-1549. AB - The original article to which this Erratum refers was published in Journal of the Science of Food and Agriculture 87 (8): 2007, 1539-1549. PMID- 20836185 TI - Chemical composition and in vitro starch digestibility of pigmented corn tortilla Juan Pablo Hernandez-Uribe Edith Agama-Acevedo Jose Juan Islas-Hernandez Juscelino Tovar Luis A Bello-Perez. Journal of the Science of Food and Agriculture, 2007. AB - The original article to which this Erratum refers was published in Journal of the Science of Food and Agriculture 2007. PMID- 20836186 TI - Can B-vitamin therapy treat my kidney disease? PMID- 20836187 TI - Specialist practices as medical homes. PMID- 20836188 TI - Specialist practices as medical homes. PMID- 20836189 TI - Does access to compensation have an impact on recovery outcomes after injury? Comment. PMID- 20836190 TI - Does access to compensation have an impact on recovery outcomes after injury? Comment. PMID- 20836191 TI - Nasu-Hakola disease and primary microglial dysfunction. PMID- 20836192 TI - Neuroimmunology: Antibodies target LGI1 rather than potassium channels in limbic encephalitis. PMID- 20836193 TI - Parkinson disease: Could sunlight offer protection from Parkinson disease? PMID- 20836194 TI - Parkinson disease: Deep brain stimulation can alter speech-related respiratory and laryngeal control in Parkinson disease. PMID- 20836195 TI - Alzheimer disease: plasma clusterin predicts degree of pathogenesis in AD. PMID- 20836196 TI - Dementia: Depression and dementia. PMID- 20836197 TI - Long-term survival of induction chemotherapy plus surgery and postoperative radiotherapy in patients with stage IV hypopharyngeal cancer. AB - This study was conducted to evaluate the safety, efficacy, and tolerability of induction chemotherapy plus surgery and postoperative radiotherapy in patients with stage IV hypopharyngeal cancer. The patients received two to three cycles of induction chemotherapy before surgery, with cisplatin (100 mg/m(2)) by rapid intravenous (i.v.) infusion over 15-20 min on day 1, bleomycin (10 mg/m(2)) on days 1 and 5, and 5-fluorouracil (800 mg/m(2)/day) by continuous i.v. infusion on days 1 through 5, repeated every 21 days. Adjuvant radiotherapy was begun 4-6 weeks after surgery. From July 1999 to December 2004, a total of 52 patients were enrolled. After completion of two to three courses of induction chemotherapy, 22 cases of CR (complete response) and 16 cases of PR (partial response) in the primary site were confirmed, giving an overall response rate (ORR) of 73.1% [95% confidence interval (CI), 61.1-85.2%]. There were 17 CRs and 19 PRs in neck lymph nodes, giving an ORR of 69.2%. The combined primary tumor site and lymph node response was 17 CRs and 16 PRs, giving an ORR of 63.5% (95% CI, 50.4-76.6%). The median time to progression and overall survival for all the patients were 32 months (95% CI, 7.6-56.4 months) and 36 months (95% CI, 22.3-49.7 months), respectively. The estimate of time to progression and overall survival at 5 years was 24.5% (95% CI, 12.5-36.5%) and 35.9% (95% CI, 23.2-48.6%), respectively. In conclusion, induction chemotherapy plus surgery and postoperative radiotherapy is a treatment modality that is tolerated with encouraging activity and survival outcome in patients with stage IV hypopharyngeal cancer. PMID- 20836198 TI - An elusive sucker tip. PMID- 20836199 TI - Unicusp aortic valve. PMID- 20836200 TI - Coronary arterial Aspergillosis. PMID- 20836201 TI - Late complete left bundle branch block after transcatheter closure of a muscular ventricular septal defect. PMID- 20836202 TI - Fortuitous identification of an aortopulmonary window by echocardiography. PMID- 20836203 TI - Three-dimensional echocardiographic assessment of rhabdomyoma in a newborn. PMID- 20836204 TI - Congenital rubella: Infections in hospital staff. PMID- 20836205 TI - Pink disease. PMID- 20836206 TI - Abortion law reform. PMID- 20836207 TI - Lasers and ultrasonics. PMID- 20836208 TI - Low-protein diet in leukaemia. PMID- 20836209 TI - Intra-amniotic hypertonic saline. PMID- 20836210 TI - Vaccination against leprosy. PMID- 20836211 TI - Adynamic ileus and nortriptyline. PMID- 20836212 TI - Contact lenses and oral contraceptives. PMID- 20836213 TI - Causes of death in primitive and emerging populations. PMID- 20836214 TI - Battered baby syndrome. PMID- 20836215 TI - Trusses for femoral hernia. PMID- 20836216 TI - Umbilical hernia. PMID- 20836217 TI - Serum leucine amino peptidase activity in carcinoma of the stomach with metastases. PMID- 20836219 TI - Post-vagotomy neuroma. PMID- 20836218 TI - Home treatment of pulmonary tuberculosis. PMID- 20836221 TI - Cot deaths. PMID- 20836220 TI - Prolonged latent period with plasmodium falciparum infections. PMID- 20836222 TI - Contact dermatitis from spandex yarn. PMID- 20836223 TI - Albustix test for urine protein. PMID- 20836224 TI - Skin pigmentation by phenindione. PMID- 20836225 TI - Chloroquine psychosis. PMID- 20836226 TI - Pain in the neck and arm. PMID- 20836227 TI - Smoking and atherosclerosis. PMID- 20836228 TI - One year's advertisements. PMID- 20836229 TI - Improved cusco's vaginal speculum. PMID- 20836230 TI - Working capacity of women doctors. PMID- 20836232 TI - Review body. PMID- 20836231 TI - Merit awards for general practitioners. PMID- 20836233 TI - Postgraduate training posts for overseas doctors. PMID- 20836234 TI - Out-of-hours calls. PMID- 20836235 TI - Facilities for patients or doctors? PMID- 20836236 TI - Sir Charles Hasting's vocation. PMID- 20836237 TI - Institutions for treatment of alcoholics. PMID- 20836238 TI - Stereotactic radiosurgery for the management of brain metastases. PMID- 20836239 TI - Stereotactic radiosurgery for the management of brain metastases. PMID- 20836240 TI - Stereotactic radiosurgery for the management of brain metastases. PMID- 20836241 TI - Redesign of internal-medicine teaching. PMID- 20836242 TI - Redesign of internal-medicine teaching. PMID- 20836243 TI - Helicobacter pylori infection. PMID- 20836244 TI - Oxygenation of cats by hydrogen peroxide during temporary ventilatory arrest. PMID- 20836245 TI - Images in clinical medicine. "Cotton wool" appearance of Paget's disease. PMID- 20836246 TI - Prenatal corticosteroids: pretermer outcomes, stress, schizophrenia, multiple sclerosis and the developmental role of melatonin and vitamin D3. PMID- 20836247 TI - Beating bad bugs. PMID- 20836248 TI - Stamp vignette on medical science. Francis S. Collins--Human Genome Project. PMID- 20836249 TI - [Hyperinfection caused by Strongyloides stercoralis]. PMID- 20836250 TI - Staining restorations. PMID- 20836252 TI - Plant Physiology. On the inside. PMID- 20836251 TI - Structure-activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors. AB - Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC50 <60 nM) with 180-fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC50 <400 nM) with a 5.4 fold selectivity over haspin was also identified. PMID- 20836255 TI - Capnocytophaga canimorsus sepsis. PMID- 20836253 TI - Profiling locomotor recovery: comprehensive quantification of impairments after CNS damage in rodents. AB - Rodents are frequently used to model damage and diseases of the central nervous system (CNS) that lead to functional deficits. Impaired locomotor function is currently evaluated by using scoring systems or biomechanical measures. These methods often suffer from limitations such as subjectivity, nonlinearity and low sensitivity, or focus on a few very restricted aspects of movement. Thus, full quantitative profiles of motor deficits after CNS damage are lacking. Here we report the detailed characterization of locomotor impairments after applying common forms of CNS damage in rodents. We obtained many objective and quantitative readouts from rats with either spinal cord injuries or strokes and from transgenic mice (Epha4-/-) during skilled walking, overground walking, wading and swimming, resulting in model-specific locomotor profiles. Our testing and analysis method enables comprehensive assessment of locomotor function in rodents and has broad application in various fields of life science research. PMID- 20836256 TI - From international to zonal trials: the origins of the Nuremberg medical trial. AB - This article examines how plans to have a second International Military Tribunal led to the Medical Trial at Nuremberg. While the British opposed a second international trial because of their distrust of the Soviets, they supported a plan for a series of special zonal trials to be conducted by the American authorities at Nuremberg. In December 1945 the British became aware of the extent of medical war crimes committed by the Germans. Their investigation led to an eventual handover to the Americans of a group of German doctors for trial at Nuremberg. At the same time the British and French Supported an International Scientific Commission for the Investigation of Medical War Crimes. PMID- 20836257 TI - Terra Australis to Oceania: racial geography in the "fifth part of the world". AB - This paper is a synoptic history of racial geography in the 'fifth part of the world' or Oceania - an extended region embracing what are now Australia, Island Southeast Asia, the Pacific Islands, Aotearoa/New Zealand and Papua New Guinea. The period in question stretches from classical antiquity to the Enlightenment, to focus on the consolidation of European racial thinking with the marriage of geography and raciology in the early 19th century. The paper investigates the naming of places by Europeans and its ultimate entanglement with their racial classifications of people. The formulation of geographical and anthropological knowledge is located at the interface of metropolitan discourses and local experience. This necessitates unpacking the relationships between, on the one hand, the deductive reasoning of metropolitan savants, and, on the other hand, the empirical logic of voyagers and settlers who had visited or lived in particular places, encountered their inhabitants, and been exposed, often unwittingly, to indigenous agency and knowledge. PMID- 20836258 TI - Tuakana-Teina relationship and leadership in ancient Mangaia and Aotearoa. AB - The relationship between tuakana and teina (the older and younger sibling or cousin of same sex) is the tumu (foundation, origin, cause) of rank in eastern Polynesia. By examining historical documents from selected island societies, namely, Mangaia and Aotearoa, we can understand the dynamics of this relationship as part of their world-view. Normally tuakana and teina had close, cooperative, mutually respectful and loyal relationships; the teina supporting their elder. Sometimes, however, the moral balance between them was affected either by one of them acting inappropriately towards the other, or by hostile acts from others. To remedy these threats to social cohesion, various strategies were adopted, including peace-making, flight or spatial separation, or fighting. Stories about this relationship continue to serve as the tumu for today's younger generations. PMID- 20836260 TI - "Two colours, one people?": the paradoxes of the multiracial union Caledonienne in the commune of Kone (New Caledonia, 1951-1977). AB - Between the 1950s and the 1970s, New Caledonian politics were dominated by one major party, the Union Caledonienne (UC), supported by the vast majority of Kanak voters and a crucial minority of European voters. In retrospect, the multicultural project of the UC under the rubric 'two colours, one people' can seem quite surprising, as it was elaborated less than ten years after the end of a particularly oppressive colonial era and three decades before the emergence of radical Kanak demands for decolonisation. This paper analyses the ambiguous relationships between the UC and New Caledonia's colonial heritage through a micro-historical sociology of the party in the rural commune of Kone (northwest coast) that draws on both archival research and interviews. With regard to both colonial and socio-economic cleavages, the paper retraces the individual and collective trajectories of UC militants and elected members of the mairie (municipal council), to gain a better understanding of the local electoral success of the party. On the scale of Kone, the UC relied in practice on a complex articulation between diverse social logics of political affiliation: across colonial frontiers, within and among Kanak communities, 'little settlers' (petits colons), merchants, mining workers, and 'white' (or not so 'white') local populations. PMID- 20836261 TI - Planters, estate health & malaria in British Malaya (1900-1940). PMID- 20836262 TI - Exhibiting indigenous peoples: Bolivians and the Chicago Fair of 1893. PMID- 20836263 TI - Bridging the gulf: Mexico, Brazil, and Argentina on display at the 1904 Louisiana Purchase Exposition. PMID- 20836264 TI - !Viva Mexico! World's Fair exhibits and souvenirs: the shaping of collective consciousness. PMID- 20836266 TI - Zoot to boot: the zoot suit as both costume and symbol. PMID- 20836267 TI - Club de senoritas: productions of Mexican femininity in the 1950s. PMID- 20836268 TI - Dying of nostalgia: homesickness in the Union Army during the Civil War. PMID- 20836269 TI - Joyce After Flaubert: the cuckold as imperfect physician, the writer as physiologist. AB - Although Joyce was not as familiar with the practice and theory of medicine as was Gustave Flaubert, this article argues that, through Flaubert's legacy, Joyce's writing was influenced by the French school of medical thought. Several aspects of Flaubert's style and narration-what has been dubbed his "medical realism"-were taken up by Joyce: the artist's impersonal perspective, the precision of descriptions, and the materialist attack against Romanticism, as well as the irony built into the narrative voice through free indirect discourse. While the cuckold in Madame Bovary is an incompetent surgeon serving as foil to the precise description of sentiments offered by the narrator, Joyce's cuckold in Ulysses is an amateur physiologist, both perspicacious and sympathetic to human suffering. Bloom's interest in internal bodily processes opens up new dimensions for a modernist aesthetics as he relates physiology and psychology, in accordance with the theories of Xavier Bichat, Etienne Bonnot de Condillac, and Pierre Jean Georges Cabanis. In keeping with such focus, Joyce's physiological version of stream-of-consciousness stems from Flaubert's clinical description of characters, but he directs matters even further inward. PMID- 20836270 TI - Skindeep Ulysses. AB - This essay is about Joyce as an epidermist and Joyce as a chronicler and cataloguer of the "skindeep" surfaces of Dublin in Ulysses. The book is crowded with skins: tanned skins, blushing skins, skins enhanced by makeup and creams, skins marked by race or religion, skins legible and visible, skins imagined and inaccessible and associated with both authenticity and disguise. Skin in Joyce becomes, in Steven Connor's terms, in The Book of Skin, "a place of minglings; a mingling of places," a space where medical, cultural, and aesthetic meanings jostle and intersect and are inscribed and projected on the surface that both expresses and conceals the subject. A skin-deep analysis of Ulysses can reveal to us the entanglement of surface and depth that characterizes Joyce's novel. PMID- 20836271 TI - Eating and digesting "Lestrygonians": a physiological model of reading. AB - In this article, I propose that, beneath a deceptively simple story-line, "Lestrygonians" functions like a living entity, one through which Bloom unknowingly traverses. First, there is Joyce's familiar Dublin, on a macroscopic level, and, second, there is the episode's narrative, personified by a gigantic female organism, in whose digestive tract Bloom has been reduced to Lilliputian size. Some critics have noted the importance of the physiological details of digestion here; no one, however, has noted to what extent the structure of the episode is represented by the digestive model. My final claim about the episode's digestive proclivities concerns its effects on the reader. If "Lestrygonians" replicates alimentary functions by propelling both its characters and the reading process along, it also elicits, in the reader, the synesthesia of reading with autonomic sensations. PMID- 20836272 TI - Good vibrations: "sirens," soundscapes, and physiology. AB - This article establishes Joyce's ongoing interest in psychoacoustics and illustrates how much he drew, in the writing of the "Sirens" episode, on nineteenth-century sound experiments that were developed by the German physician Hermann von Helmholtz. It argues that Joyce consciously referenced nineteenth century sound theories to explore the link between the emotional and sensory experience of music and the physical and physiological components of sound perception. PMID- 20836273 TI - Menstruation in Ulysses. AB - This article investigates James Joyce's fascination with a wide variety of medical texts, sexual folklores, religious beliefs, and persistent superstitions about menstruation. That fascination finds its way into Ulysses, which draws upon a number of intertexts to inform a curiosity about the female body most strikingly articulated by Bloom, Molly, and Gerty MacDowell. These intertexts are not simply imported into the novel but are dismantled and interrogated, as Joyce exposes, rather than endorses, cliches of essential femininity. PMID- 20836274 TI - "Their pineal glands aglow": Theosophical physiology in Ulysses. AB - This article argues that Joyce's engagements with the Theosophy of the Dublin literary world amount to more than simple parody. In Ulysses, Joyce portrays Theosophy's efforts to offer an alternative understanding of physiology to that of the medical establishment as a form of boundary work, an adaptation of the discourse of modern medical research to fashion modern mysticism as a science. Ultimately, Joyce rejects Theosophical physiology and its evolutionary scientism because it provides an unsatisfactory rhetorical body, a failed attempt to renegotiate the boundaries between scientific materialism and spirituality in the awkward modernity of Dublin in 1904. PMID- 20836275 TI - Surgery. Outcomes of robot-assisted radical cystectomy: learning curves, margins and lymph node yield. PMID- 20836276 TI - Novel H1N1 influenza pandemic in Iran. PMID- 20836277 TI - West Nile Virus in blood donors. PMID- 20836278 TI - Prostate cancer. Salvage brachytherapy following local failure of radiation therapy: 5-year and 10-year outcomes. PMID- 20836279 TI - Prostate cancer: Gene fusions. PMID- 20836280 TI - Surgery. Preventing post-prostatectomy inguinal hernia. PMID- 20836281 TI - Prostate cancer. Novel technique for early detection of lymph node metastases. PMID- 20836282 TI - SCI semen: to freeze or not to freeze? PMID- 20836283 TI - Testicular cancer. Does the dose intensity of BeP chemotherapy affect survival? PMID- 20836284 TI - Testicular cancer. Surveillance or biopsy for men with testicular microlithiasis? PMID- 20836285 TI - Rapid metastasis of breast cancer cells from primary tumour to liver. AB - The aim of this study was to establish an animal model of mammary carcinoma metastasis to discern the in vivo effects of growth and spread of breast cancer. Six-week-old female BALB/c mice were inoculated with 4T1 murine breast cancer cells. Mice weight and primary tumour mass volume were regularly recorded to study the physical effects of a vigorously growing and spreading of cancer cell line. Gross and histological studies were carried out to determine the approximate day of metastatic onset. Production of IFN-gamma was assessed by ELISA to understand its role in tumour growth and metastasis. Lymphocyte markers such as CD8+, CD25 and CD49b were analysed to elucidate its role in tumour growth and progression. Present study showed that the metastatic onset occurs approximately 11 days after the mice were inoculated with the 4T1 murine breast cancer cells. Gross studies showed hepatosplenomegaly. The breast cancer cells from primary tumour were found to spread rapidly to the liver on day 11. IFN gamma production was higher in inoculated mice serum compared to control mice serum. Higher numbers of CD8+, CD25 and CD49b cells were observed in the peripheral blood of inoculated mice, compared to control mice. In conclusion, the 4T1 murine breast cancer cells can migrate and metastasise rapidly to the liver, eliciting various immune responses. PMID- 20836286 TI - Investigation of decolorization of textile wastewater in an anaerobic/aerobic biological activated carbon system (A/A BAC). AB - The aim of this study is to investigate the decolorization in anaerobic/aerobic biological activated carbon (A/A BAC) system. The experiment was divided into 2 stages; stage I is batch test for preliminary study of dye removal equilibrium time. The preliminary experiment (stage I) provided the optimal data for experimental design of A/A BAC system in SBR (stage II). Stage II is A/A BAC system imitated Sequencing Batch Reactor (SBR) which consist of 5 main periods; fill, react, settle, draw and idle. React period include anaerobic phase followed by aerobic phase. The BAC main media; Granular Activated Carbon (GAC), Mixed Cultures (MC) and Biological Activated Carbon (BAC) were used for dye and organic substances removal in three different solutions; Desizing Agent Solution (DAS), dye Solution (DS) and Synthetic Textile Wastewater (STW). Results indicate that GAC adsorption plays role in dye removal followed by BAC and MC activities, respectively. In the presence desizing agent, decolorization by MC was improved because desizing agent acts as co-substrates for microorganisms. It was found that 50% of dye removal efficiency was achieved in Fill period by MC. GC/MS analysis was used to identify dye intermediate from decolorization. Dye intermediate containing amine group was found in the solution and on BAC surfaces. The results demonstrated that combination of MC and BAC in the system promotes decolorization and dye intermediate removal. In order to improve dye removal efficiency in an A/A BAC system, replacement of virgin GAC, sufficient co substrates supply and the appropriate anaerobic: aerobic period should be considered. PMID- 20836287 TI - Evaluation of mental health status in caregivers of patients with chronic psychiatric disorders. AB - The aim of this study was to evaluate mental health status in caregivers of patients with chronic psychiatric disorders. This descriptive-analytic study performed in Mazandaran Province Northern Iran from 2007 to 2008. Two hundred caregivers of patients with sever psychiatric disorders completed (GHQ-28) and Demographic questionnaire. Sever psychiatric disorders is referred to patients with schizoaffective or schizophrenia or bipolar mood disorder that at least 2 years was passed from onset of disease. Data were analyzed in descriptive statistical method with SPSS soft ware. Thirty five percent of caregivers had GHQ > 23 and no mental health. Significant association found between patients age, age of onset of disease with GHQ Score (p = 0.0001). Caregivers' GHQ score correlated with marital status in patients, although this was not significant (p = 0.08). The chi2 test didn't show significant relationship between duration and type of disease and patient's sex and caregiver's sex with GHQ score. According to the results of our study, it seems that further investigations with more samples and other questionnaires need to evaluate of caregivers requirements and it is suggested that a logical planning be conducted by the authorities, to decrease caregivers' burden. PMID- 20836288 TI - Changes in functional status and functional capacity following coronary artery bypass surgery. AB - The aim of the present study was to compare changes in health related-quality of life (H-RQOL) on physical functioning and mental health domains, changes in functional capacity before and 18 months after CABG surgery. Comprehensive data on 187 patients who underwent CABG surgery were prospectively collected, including preoperative factors and postoperative morbidity. Assessing functional status, the change in physical functioning score and change in mental health score were obtained using the physical functioning and mental health subscales out of the eight total subscales of the (SF-36) questionnaire. Also, functional capacity was estimated according to New York Heart Association (NYHA) class. The results showed 18 months after CABG surgery survival rates were (95.7%). Significant improvements in functional status were seen in physical functioning (p < 0.001), mental health (p < 0.000). However, there were no significant changes in the mean of functional status scores among patients in three age groups. Other significant improvement was found in functional capacity and NYHA class before and the 18 months after CABG. Functional status markedly and significantly improved after CABG surgery, particularly in physical functioning. However, the functional status among survivors of CABG surgery is worse than that of the general population. It seems further research is needed to identify factors explaining the change in H-RQOL to develop interventions to support patients. PMID- 20836289 TI - The relationship between maternal serum magnesium level and preterm birth. AB - The aim of this study was to evaluate the relationship between maternal serum magnesium levels and preterm birth. This Nested case-control study carried out on 20 with preterm birth and 20 women at term birth at Imam Khomeini Hospital in Sari/Iran in 2008. The women with singleton gestation and intact fetal membrane suspected to preterm labor (case group), 10 cc blood samples were drawn into syringes and sent to laboratory of the hospital immediately. Sampling for control group was same as the case group. These samples recognized as control group just as birth occurring after week 37. Finally, serum magnesium level measured. Data analyzed using chi2, t-test and OR (Odd's Ratio). There was a relationship between the number of prenatal visits (p = 0.008) and stressful events associated with preterm birth (p < 0.02). Serum magnesium level was associated with preterm birth OR = 4.75, CI 95% = (0.48-46.91), Sensitivity, specificity, positive and negative predictive value of serum magnesium for preterm birth was 95, 50, 66.5 and 83.33%, respectively. Although, there was a correlation between serum magnesium levels and preterm birth, due to methodology of the study, a cohort study with the same cut off point and supplementation of magnesium in RTC studies is recommended. PMID- 20836290 TI - Comparative antioxidant activity study of some commonly used spices in Bangladesh. AB - Many spices have been shown to impart an antioxidative effect in foods. This study summarized the literature on the antioxidative effects of spices. The term spice is defined as dry plant material that is normally added to food to impart flavor. The methanolic crude extracts of Allium sativum, Coriandrum sativum, Cuminum cyminum, Zingiber officinale, Cinnamomum verum, Elettaria cardamomum and Cinnamomum tamala were screened for their free radical scavenging properties using ascorbic acid as standard antioxidant. Free radical scavenging activity was evaluated using 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical. The overall antioxidant activity of Cuminum cyminum was found to be the strongest, followed in descending order by Z. officinale, C. sativum, A. sativum, C. tamala, C. verum, E. cardamomum. The IC50 values of the extracts ranged between 15.48 and 217.431 (microg mL(-1)). The ascorbic acid levels was 22.78 (microg mL(-1)) the present study revealed that the selected plants would exert several beneficial effects by virtue of their antioxidant activity and could be harnessed as drug formulation. PMID- 20836291 TI - Comparison of risk factors of CHD in the men and women with MI. AB - The purpose of this study is comparison of risk factors of MI in hospitalized men and women patients in CCU. The CHD is the most important cause of mortality in the industry countries. Different environmental and race in each location can affect on frequency of risk factors of MI. In this cross sectional study, comparison was done between men and women who have involved in MI. The random sampling method was used Blood sugar, cholesterol and homocystein, LPa, BMI, family history, skin color, smoking and the amount of activity were assessed with variables such as age. The data was collected via questionnaire from September until March 2004-2005. Finally the data were analyzed with using t-test, Chi square and pearson correlation. In this research 169 patients who involved in MI (114 men and 55 women) have participated. The mean of age in the men was 55.4 and in the women was 61.02. All patients had risk factors. In the men, smoking (52.6%) and family history (41.1%) were the most common risk factors of MI. In the women, hyperlipidemia (66.4%), diabetes (62%) and hypertension (58.2%) were the most common risk factors of MI. The mean of BMI in the men was 25.9 +/- 4.25 and in the women was 27.6 +/- 4.71. The mean of LPa in the men was 59.2 +/- 4.21 and in the women was 50.9 +/- 4.25. the mean of homocystein in the men was 10.7 +/- 7.67 and in the women was 8.9 +/- 14.45. Diabetes, hyperlipidemia, hypertension and smoking had significant relationship with age and sex (p < 0.001) and skin color, homocystein, LPa, job, personality type and mobility didn't have significant relationship with age and sex. In this study the most common risk factors of MI in the men were smoking and positive family history and in the women were known hyperlipidemia and diabetes. PMID- 20836292 TI - Scrutiny on significant factors of hemin catalyzed Ag nanoparticle as biosensor for RNA. AB - A responsive electrical detection technique of nucleic acids has been demonstrated on submicrogapped biosensor. This method contain immobilizing of Peptide Nucleic Acid (PNA) probes in the gap areas of a pair of interdigited microelectrodes and subsequently hybridizing with their complementary target RNA. After hybridization, hemin molecules were introduced into the RNA strand via zirconium-phosphate and zirconium-carbonate chemistries. The newly attached hemin molecules act as a catalyst to accelerate reducing ammoniacal Ag ion to form Ag nanoparticles, which span the gap of the interdigitated microelectrode. The conductance of the Ag nanoparticles directly correlated with the number of the hybridized RNA molecules. Nearly 1 fM sensitivity was achieved under optimal conditions. PMID- 20836293 TI - Frequency of afterload homocysteinemia in normal population of Southern Iran: a pilot study. AB - The objectives of the present pilot study were to investigate the effect of an oral methionine load on plasma homocysteine in healthy subjects southern Iran. We studied 50 peoples (10 men, 40 women, median age 27.5, range 20-37) referred to screening center for marriage since different part of southern Iran. Methionine (0.1 g kg(-1) b.wt.) was immediately administrated orally in 200 mL of orange juice and a second blood was obtained 4 h later. Plasma level of homocysteine was carried out by high performance liquid chromatography and flumetric detection. A homocysteine level above 15 mmol L(-1) was considered high. The mean fasting and afterload homocysteine were 15.28 and 31.29 micromol L(-1), respectively. Fasting hyperhomocysteinemia (>15 micromol L(-1)) was detected in 12% of male and 8% in female which significantly higher in men than women (p < 0.0001). Afterload methionine load homocysteine levels (> 31 micromol L(-1)) was detected in 16% of male and 14%in female which higher in men than women. Notably 80% of participants had normal total homocystein concentration (< or = 15 micromol L(-1)), but mild and moderate hyperhomocysteinemia was detected in 24% (n = 12). In this study, we find the difference between fasting and methionine afterload mean homocystein levels (p = 0.000), in 8% of those normal homocystein level, methionine afterload homocystein levels became abnormal. In conclusion, based on results, we recommend the methionine afterload homocystein levels in high risk cases with normal fasting level in order to unmissed some cases with normal basal homocystein level. PMID- 20836294 TI - Determination of the amount of protein and amino acids extracted from the microbial protein (SCP) of lignocellulosic wastes. AB - With the increasing world population, the use of lignocellulosic wastes for production of microbial protein as animal feed becomes a necessity of our time. In order to verify the most productive protein, the amount of protein and amino acid extracted from Single Cell Protein (SCP) needs to be determined by an effective method. In this study Microbial protein was produced by treatment of wheat straw with Pleurotus florida; with heat at 100 degrees C and NaOH 2% as substrate by solid state fermentation. Concentration of protein was 62.8% per 100 g of dried microbial protein. Then the extracted protein hydrolyzed with HCl 6 Normal for 48 h under 110 degrees C temperature condition. Then the amino acids analyzed by using A-200 Amino Nova analyzer. The results of this study indicated that the ratio of essential amino acids to total amino acids was 65.6%. The concentration of essnyial amino acids were: Lysine = 9.5, histidine = 19.8, threonine = 0.6, valine = 6.6, methionine = 2.1, isoleucine = 7.3, leucine = 6.8, phenylalanine = 4.3 and arginine = 8.3 g/100 g of extracted protein that indicated the obtained microbial protein can be a good or suitable substitute in the food program of animal feed. PMID- 20836295 TI - In vitro antioxidant, xanthine oxidase and acetylcholinesterase inhibitory activities of Balanites aegyptiaca (L.) Del. (Balanitaceae). AB - The present study aimed to test the validity of Balanites aegyptiaca remedies used for the treatment of rheumatisms and mental disorders by examining the antioxidant, xanthine oxidase and acetylcholinesterase inhibitory activities of galls and leaves extracts and fractions. The total phenolics and flavonoids were measured using Folin-Ciocalteu and AlCl3 reagents, respectively. Two methods i.e., FRAP and ABTS were used to estimate the total antioxidant capacity of the plant materials. The FRAP and ABTS antioxidant activities showed that among all extracts and fractions tested, the best antioxidant activities were found with the galls dichloromethane and the leaves ethyl acetate fractions. The antioxidant activities did correlated significantly with the total phenolic and flavonoid contents. The study also showed that B. aegyptiaca galls and leaves fractions exhibited a moderate xanthine oxidase inhibitory activity comparatively to the acetylcholinesterase which was weakly inhibited by the tested extracts and fractions. PMID- 20836296 TI - Status of coral reef species at Chabahar Bay, Sistan and Baluchistan, Iran. AB - This study was carried out in the coral growing zone at Chabahar Bay where it located at 25 degrees 17' N and 60 degrees 36'E. It is called horseshoe Bay, because of its semicircle shape. Some destroyer factors have been affected on the health of coral reefs in Chabahar Bay. Port constructions, dredging operations, spearfishing, anchorages and scuba diving activities were distinguished as the most important problems of coral reef in Chabahar Bay. This study was conducted in order to access Semi-Qualitative Indexes of corals in different areas of Chabahar Bay. Five stations were chosen in east and north part of the Bay, where the most construction activities happened. Rectangular Transect and CoralWatch Racket were used to determine the status of the corals. During study, two classes of Hexacoralia and Octocoralia with 15 families were recorded. Twenty one species of hard coral and 10 species of soft coral were recorded. Hexacoralia was recorded the higher number of family with 10 families and 21 species and Octocoralia was recorded the lower with 5 families and 10 species. Hard corals were dominant. The ranges of qualitative indexes showed, of five stations, three of them (stations 2, 4, 5) showed Good Development and two stations (stations 1, 3) showed Fair Development. For the Condition Index, two stations showed Good Condition (stations 1, 5) and two stations showed Fair Condition (stations 2, 3). Only station 4 showed Poor Condition. The ranges of the Succession Index Showed, four stations (stations 1, 2, 3, 4) were in Very poor Succession and one station (stations 5) showed Poor Succession. PMID- 20836297 TI - Assessment of the relationship between quality of life and stress in the hemodialysis patients in 2008. AB - The aim of this study was to determine the relationship between quality of life with stress in the haemodialysis patients. This descriptive correlation study was done on 100 haemodialysis patients selected by consent method from Imam Khomeini and Fatemeh Zahra Hospitals in Sari/Iran from March 2008 to February 2009. Data were collected in questionnaire consisting of 3 sections (demographic feature, quality of life and stress) in three months. In the questionnaire, first, quality of life then stress in the patients was studied and the variables described. Then the relation between them was determined by statistical analysis. From the total number of 100 patients (53 men and 47 women) under study, 42% with partial comfortable life had moderate tension. Pearson correlation coefficient showed that there is a significant linear relationship with quality of life and degree of tension, (r = 0.802). That is with increase of tension, quality of life declines (p < 0.001). Also Pearson correlation coefficient indicated that there is positive correlation between the number of hemodialysis per week and the history of dialysis (p = 0.001). History of dialysis in 69% of the patients was 1 5 years and 74% of them were dialyzed in the morning trice a week. Findings showed that, with increase of stress, quality of such patients' life decreases. Therefore, the nurses and the other members of medication team should know to reduce the patient's stress using the supportive procedures and adaptation techniques, help improve quality of life by proper intervention method. PMID- 20836298 TI - Production of recombinant streptokinase in E. coli and reactivity with immunized mice. AB - Streptokinase (SK) is a potent plasminogen activator with widespread clinical use as a thrombolytic agent. In this study, we produce high level expression of recombinant streptokinase in E. coli by expression vector pET32a. Genomic DNA of streptokinase gene (SKC) was extracted, then amplified by polymerase chain reaction (PCR) method and sub-cloned to prokaryotic expression vector pET32a. Escherichia coli BL21 (DE3) pLysS were transformed with pET32a-skc and gene expression was induced by IPTG. The expressed protein was purified by affinity chromatography by Ni-NTA resin. High concentration of the recombinant protein obtained from the single-step purification by affinity-chromatography (Ni-NTA). The yield of recombinant streptokinase was nearly 470 mg L(-1) of initial culture. Our data showed that production of recombinant streptokinase improved by pET32a in Escherichia coli. PMID- 20836299 TI - Maternal sexuality after child birth among Iranian women. AB - The aim of this study was to investigate the sexual function of mothers at one year postpartum and associated factors. Four hundred and ninety Iranian women were recruited randomly at four time periods from child birth: first 3 months, 4 to 6, 7 to 9 and 10 to 12 months, from January to July 2008. All mothers were married, literate and agreed with participation. The exclusion criteria were, (a) loss of baby, (b) living far from their partner, (c) psychological problems and (d) serious medical diseases. Data on socio-demographic factors, obstetric, medical, last delivery and postpartum history was obtained. The sexual function was evaluated by the 19th item questionnaire of Female Sexual Function Index (FSFI). The mean resumption of intercourse was 57.17 +/- 27.95. Twenty-four had no sexuality. The most common reasons were fear of pain, no interest, worrying about another pregnancy, feeling tired and bleeding. All dimensions of women's sexual function were at the lowest level in early postpartum. Sexual activity had significance correlation with an older maternal age, a longer marriage duration and higher number of children. Mothers diseases, neonate problems and tuboligation were associated with lower scores of sexual function. There was no association with delivery type and perineal injuries. Sexual parameters decrease at the first 3 months of postpartum and recovery during the following months. More consultation and direction of postnatal sexuality recurrence is needed. PMID- 20836300 TI - Intestinal parasites infection among immunocompromised patients in Riyadh, Saudi Arabia. AB - This study was conducted to determine the prevalence of intestinal parasites among immunocompromised patients in Riyadh, Saudi Arabia. Fecal samples were collected from 136 immunocompromised patients (52 females and 84 males), aged 2 to 69 years. Specimens were fixed with 10% formalin for 30 min (2-3 g fecal(-1)) and then concentrated by a formalin-ether sedimentation technique. Samples were examined as wet saline mounts and in iodine preparation for detection of protozoan oocysts, cysts, helminthic eggs and larvae. Permanent stained smears were performed for intestinal coccidian parasites by the modified Ziehl-Neelsen technique and the modified trichrome stain. Intestinal parasites were detected in 54 (39.7%) most of them (25.7%) were with diarrhea. More specifically the following parasites were detected Cryptosporidium parvum 11(8.1%), Giardia lamblia 9 (6.6%), Cyclospora cayetanensis 8 (5.9%), Blastocystis hominis 7 (5.2%), Entamoeba histolytica 7 (5.2%), Entamoeba coli 5 (3.7%), Strongyloides stercoralis 3 (2.2%), Ascaris lumbricoides 1 (0.7%), Hymenolepis nana 1 (0.7%), Dicrocoelium dendriticum 1 (0.7%) and Hook worm 1 (0.7%). The most common parasite associated with diarrhea in patients, was C. parvum (p < 0.001), followed by G. lamblia, C. cayetanensis and E. histolytica. However, differences between different age groups were statistically non-significant. Similarly, no significant difference in the infection rate were found between male and female patients. PMID- 20836301 TI - Genetic variation among populations of Pla-mong fish (Pangasuis bocourti Sauvage 1880) of the Mae Kong River in Northeast Thailand. AB - This study was carried out at the Department of Fisheries, Faculty of Agriculture, Khon Kaen University, Khon Kaen, Thailand during April to September 2007 to determine DNA patterns of Pla-mong fish (Pangasuis bocourti Sauvage 1880) with the use of RAPD-PCR amplification. One hundred twenty individual fish samples were harvested from four locations along the Mae Kong River, i.e., Nongkhai, Nakornphanom, Mukdaharn and Ubon Ratchatani provinces, each location has thirty individual fish samples and the four locations were used as treatments and thirty individual fish of each location were used as replications. Sixteen RAPD decamer primers from three kits of Operon Technologies were subjected to a preliminary test and only seven decamer primers were suited most for PCR amplification. The results on both similarity correlation coefficients and genetic distances revealed that the fish of Pla-mong of the Mae Kong River could be divided into two groups, i.e., the first group included the fish harvested from Nongkhai and Nakornphanom provinces with their genetic values ranged from 0.20 to 0.36 and the second group included the harvested fish from Mukdaharn and Nakornphanom provinces with their genetic values ranged from 0.20 to 0.44. PMID- 20836302 TI - Pattern of Pseudomonas aeruginosa drug resistance in Tabriz Children Hospital. AB - Regarding the different reports about increasing drug resistance of Pseudomonas, this study was done in Tabriz Pediatric Medical Center. In a cross sectional study, during 3 years, 84 positive culture of pseudomonas were obtained from the records of microbiology laboratory. Information about the patients and pattern of drug resistance were analyzed statistically. 81.9% of patients were below 2 years of age and all of them had one or more medical intervention. Most of the positive cultures were isolated from bronchial and eye discharges. Eighty one percent of positive cultures were from intensive care unit and neonatal wards. Resistance to Ampicillin, Ceftizoxime, Cotrimoxasol and Cefotoxime has been more than 95%. Resistance to Ceftazidime was seen in 50% and lowest resistance was to Ciprofloxacin. At present time Ciprofloxacin is relatively effective antibiotic for Pseudomonas infection. Since, there is increasing resistance to this drug and limited use of this drug in children, newer antibiotic discs should be used in antibiogram. PMID- 20836303 TI - Investigation of acute toxicity of pirimiphos-methyl (Actellic, 25%EC) on guppy (Poecilia reticulata, Peters, 1859). AB - Pirimiphos-methyl is a broad spectrum organophosphate insecticide and potential toxic pollutant in aquatic ecosystems. The acute toxicity of Pirimiphos-methyl (Actellic) was investigated using Guppy (Poecilia reticulata) in a 96 h static renewal laboratory bioassay. Based on probit analysis the LC50 was 0.026, 0.024, 0.022 and 0.019 ml L(-1) at 24, 48, 72 and 96 h, respectively. Analysis of Variance (ANOVA) showed that there was significant difference (p < 0.05) in the quantal response (mortality) of P. reticulata to different concentrations of Actellic at 24, 48, 72 and 96 h of exposure. Actellic insecticide is toxic to fish; therefore its indiscriminate use in aquatic environment should be discouraged. PMID- 20836304 TI - A comparative study of conjunctival autograft and minimally invasive pterygium surgery in primary pterygia. AB - This study aimed at comparing the results of the Conjunctival Autograft Technique (CAG) and Minimally Invasive Pterygium Surgery (MIPS) in primary pterygium excisions. This was a prospective randomized clinical study performed during a one-year period (2009-2010). One hundred and twenty two patients with primary pterygium were randomized in 2 groups: group A (CAG) including 36 patients and group B (MIPS) including 86 patients. The two groups were compared considering the recurrence rate and probable complications of the procedures. Recurrences were detected in 4 patients (11.1%) in group A and 5 patients (5.8%) in group B with no significant difference in this regard (p = 0.447). No major complications occurred during the follow-up period. This study showed that acceptable recurrence- free rates could be achieved (albeit nonsignificant) using MIPS technique in patients with primary pterygium and can be considered as a good alternative in the surgical management of pterygia because of its simplicity and low surgical time. PMID- 20836305 TI - Sociodemographic determinants of attrition in hospital based therapeutic exercise programme for type 2 diabetes patients. AB - BACKGROUND: Abandoning research programmes by participants may impose disadvantages on the participant, the research and the researcher. This study investigated the contributions of sociodemographic characteristics to the attrition of Type 2 Diabetes (T2D) patients who enrolled into a 12-week therapeutic exercise programme. METHODS: In the 12-week, thrice weekly hospital based therapeutic exercise programme, the contributions of age, gender, duration of diagnosis, marital status, cohabitation, urbanization, educational and employment status to two sources of attrition (inability to locate and decline to commence or complete) were studied. RESULTS: Participants were aged 48 +/- 9.62 years. Out of the 152 participants who agreed to participate, only 93 (61.18%) actually commenced the exercise programme, while 69 (74.19%) of those who commenced the programme completed it. Risk of attrition due to inability to locate participants was higher in females (OR = 3.25, 95% CI = 2.96-3.91), single or divorced and living in the rural area (OR = 1.37, 95% CI = 1.12-1.52). Risk of decline to commence or complete was higher with increasing age, living alone, longer duration of diagnosis and being in paid employment while this was less likely in individuals who were married and more educated. CONCLUSION: We recorded 25.81% attrition for those who actually commenced the programme. Sociodemographic characteristics contributed to attrition in the 12-week, thrice weekly hospital based exercise programme and we suggest closer monitoring (based on these sociodemographic characteristics) of T2D patients scheduled for therapeutic exercises in order to minimize attrition, maximise attendance and ensure higher retention. PMID- 20836306 TI - The role of maternal social factors and antenatal events in determination of the serum retinol in normal full term infant. AB - BACKGROUND: The nutritional status of mothers affects their babies. However, the factors responsible for the control of fetal retinol levels are unknown. This study evaluates the role of maternal social factors in the determination of fetal serum retinol. METHOD: Consecutive mothers with normal pregnancy as judged by obstetrician (excluding those with sepsis and medical illnesses) were recruited. The maternal social factors and antenatal history were determined using questionnaires and the retinol level of the cord blood of the neonates were estimated using the high performance liquid chromatography. RESULTS: There were 106 mothers (ages between 21 and 39 years, mean of 26 years) and neonates, made up of 57 females and 49 males with gestational age 30-45 weeks, mean of 373 weeks). The range of the neonatal serum retinol level was 0.12 ig/L--1.57 ig/L, with a mean of 0.94 ig/L (SD = 0.17) and median value of 0.98 ig/L. The mean serum retinol in the females was 0.94 ig/L while males were 1.13 ig/L. Ihe mean serum retinol according to the socioeconomic classes were high (I and II) 1.2 ig/L, middle (III) 1.1 ig/L and low (IV and V) 0.9 ig/L. The mean fetal serum retinol among the mothers with fever in pregnancy (31/106), incomplete vaccination in pregnancy (17/106) and neonates with low birthweight (<2.5 Kg) was 0.9 ig/L. Bivariate analysis revealed significant correlation between the mean serum retinol and the socioeconomic class (P = 0.038), but there was no correlation with maternal age (P = 0.7), sex (P = 0.07), gestational age (P = 0.39), birth weight (P = 0.7), maternal tetanus vaccination (P = 0.28), fever (P = 0.64) and antenatal care (P = 0.97). CONCLUSION: Socioeconomic status of the mothers was a significant factor in the determination of neonatal serum retinol level, suggesting that maternal retinol supplementation may help in control of neonatal hyporetinolaemia. PMID- 20836307 TI - Effects of two exercise training techniques on walking function in adult patients with stroke. AB - BACKGROUND: Patients with stroke usually demonstrate activity limitations manifested by reduced ability to perform daily functions. OBJECTIVE: The purpose of this study was to examine the effects of treadmill walking and overground walking exercise training on walking function in adult patients with stroke. METHODS: Participants were forty (40) patients with stroke comprising 22 males and 18 females. Inclusion criteria included absence of any co-morbidity that could affect rehabilitation. They were randomly assigned to 2 exercise training groups (20 in each group). All study subjects received conventional physiotherapy rehabilitation for 12 weeks. During the same period, subjects in Group A had treadmill walking exercise training (TWET) while those in Group B had overground walking exercise training (OWET) in addition to the conventional physiotherapy. Outcomes were measured as (i) Ten-metre walk time and (ii) Six-minute walk distance. They were evaluated at entry into the study and at the end of every 4 weeks. Results at weeks 0, 4, 8 and 12 were used for analysis. For each of the 2 groups, paired t-tests were used to evaluate the significance of the differences between the pre-intervention (week 0) mean scores on both tests and the mean scores at weeks 4, 8 and 12. RESULTS: With 12 weeks of exercise training, both TWET and OWET produced significant improvement in walking function (P < 0.05). However, OWET resulted in significantly greater reduction (26.8%) in mean walking time over 10 metres than TWET (22.6%); and significantly greater increase (45.2%) in mean walking distance over 6 minutes than TWET (31.0%). CONCLUSION: Exercise training, especially overground walking, could be integrated into the traditional rehabilitation care given to adult patients with stroke. PMID- 20836308 TI - Incidence and patterns of lumbosacral transitional vertebrae, in patients with low backpain in a Nigerian hospital. AB - BACKGROUND: Lumbosacral transitional vertebrae (LSTV), is a structural anomaly, of the lumbosacral spine which has been variably associated with, low back pain (LBP) and its presence can also result in a level being wrongly identified pre operatively. OBJECTIVES: To determine the incidence, pattern of LSTV and its relationship with LBP in our tertiary hospital. METHODS: A retrospective review of lumbosacral spine radiographs of 561 one consecutive patients with history of LBP was done from January 2006 to January 2008. The presence or absence of LSTV and degenerative changes were documented. RESULTS: Fifty-one ((9.1%)) out of 561 patients had LSTV. Type II (incomplete) LSTV was the commonest type, occurring in 86.3% of patient with LSTV. Patients less than 30yrs with LBP and LSTV had no degenerative changes, while all patients with LSTV above 50 yrs had degenerative changes. CONCLUSION: Lumbosacral transitional vertebrae type II was the commonest seen in this study, furthermore, LSTV appears to be a causative factor of LBP in young individuals. Careful evaluation of spinal radiographs of patients with LBP belonging to this group is advocated to assess for the presence or absence of LSTV. PMID- 20836309 TI - Obesity prevalence in adult residents of Ile-Ife, Nigeria. AB - BACKGROUND: Few data on obesity exist on Sub-Sahara population in Africa. This study investigated the prevalence of obesity and Body Mass Index (BMI) percentile and quartiles in accordance with sex and age in adult residents of the historic ancient semi-urban community of Ile-Ife, South-West, Nigeria. METHODS: 2097 adults aged 21 years and above were recruited into the door-to-door survey through a multistage cluster sampling technique. The World Health Organization (WHO) criteria based on BMI was used in the definition of overweight and obesity. Height and weight were measured using standardized procedures. RESULTS: The mean age and BMI of the participants were 44.2 years and 24.2 Kg/m2 respectively. Although age-matched; the females had higher BMI values compared to males (23.8 vs. 24.5 Kg/m2). The overall crude prevalence of overweight (25.0-29.9 Kg/m2) and obesity (>30 Kg/m2) were 20.3% and 12.5% respectively. The rates of overweight (17.9 vs. 22.1 Kg/m2) and obesity (9.7 vs. 14.5 Kg/m2) were both higher in women than men. Obesity increased across age gradient from young to old adults; peaking in the 60-69-year age group. The first to fourth BMI quartiles were = 20.4 Kg/m2, 20.5-24.1 Kg/m2, 24.2-25.2 Kg/m2, = 25.3 Kg/mr respectively in the study population. At all ages; more females (32.4%) than males (24.7%) were placed within fourth BMI quartile. The 95th percentile BMI in the study population was 33.4 Kg/m2. CONCLUSION: Overweight and obesity are common in Nigerians, particular among females and elderly. The prevalence estimates of overweight and obesity in Nigerians is comparable with prevalence among Blacks in other populations. PMID- 20836310 TI - Aqueous leaf extract of Ocimum gratissimum potentiates activities of plasma and hepatic antioxidant enzymes in rats. AB - BACKGROUND: Ocimum gratissimum is a vegetable plant of wide nutritional and medicinal arpplications in Nigeria and in some other parts of the world. OBJECTIVE: The effect of oral administration of aqueous leaf extract of O. gratissimum on the activities of plasma and hepatic anti-oxidant enzymes in rats was investigated. METHODS: Two different doses of aqueous leaf extract of O. gratissimum (0.2 mg/g and 0.4 mg/kg body weight) were separately administered orally daily into rats for 4 weeks. The rats were sacrificed after 30 days of administration, blood was collected and the liver excised. The liver was homogenized, while plasma and hepatic anti-oxidant enzymes, namely catalase (CAT), superoxide dismutase (SOD) and glutathione -S- transferase (GST) specific activities were assayed. RESULTS: Results of the study showed a significant (p < 0.05) increase in the specific activity of both plasma and hepatic CAT and SOD in a dose dependent pattern. However, the effect of the leaf extract on GST specific activity was not significant (p > 0.05) as compared to the control. There were no significant changes in the plasma and liver protein concentrations in rats administered the extracts as compared to the control. CONCLUSION: Data of the study suggest that the oral administration of the aqueous extract of O. gratissimum may impair naturally generated oxidant/toxicant activity and thereby enhance specific activities of hepatic antioxidant enzymes in rats. PMID- 20836311 TI - Optimization of power control in mobile multimedia communication systems in hospitals using genetic algorithm. AB - BACKGROUND: The rapid growth in cellular radio communications necessitates more efficient utilisation of spectrum. This is more so in medicine where very large volume of data and information are involved. The increased sharing of spectrum due to this growth translates into a higher likelihood of users interfering with one another. So cell capacity is inherently interference limited, particularly by co-channel interference (CCI) and adjacent channel interference (ACI). OBJECTIVE: One of the solutions to combat these interferences is to control of power. Two types of power control are used in wireless network communication systems: centralised power control (CPC) and distributed power control (DPC). Centralised power control is computationally very complex for large systems as it assumes that all information about the link gains is available to all mobile devices. DPC, unlike CPC, requires only local information to adjust power levels of each transmitted signal. DPC is therefore more realistic when the number of mobiles grows and will be used as the foundational system model in this work. METHODS: Many optimisation techniques have been used for distributed power control system models. However, the techniques have been restricted to the traditional optimisation methods which use the characteristics of the problem to determine the next sampling point. In this work, Genetic Algorithm GA, an evolutionary approach is used. It follows the concept of evolution by stochastically developing generations of power-solution populations based on a fitness score. RESULTS: It can be seen that the convergence speed of GA is not as fast as that of the conventional method and consequently a higher outage probability. The simulation results show that GA is more robust, more realistic performance, very proactive to noise, fading or shadowing. CONCLUSION: A genetic algorithm responds and adapts to this change on the fly but many traditional optimisation procedures must restart afresh which is computationally, expensive. PMID- 20836312 TI - Knowledge, attitude and practice of breast cancer screening among nurses in Lagos University Teaching Hospital, Lagos Nigeria. AB - BACKGROUND: Breast Cancer has been known to be the most common cancer and second principal cause of cancer death in women. However, the adherence to recommended breast cancer screening guidelines is low especially in Africa. OBJECTIVE: It may be necessary to assess the knowledge, attitude and practice of breast cancer screening among nurses who are in good position to educate people. METHODS: A cross sectional study of 183 nurses was carried out in Lagos University Teaching Hospital, using a close ended questionnaire assessing information on demographic variables, awareness, knowledge and attitude towards breast cancer. RESULTS: The results revealed 100% rate of awareness of breast cancer although 32% of the respondents knew not that breast cancer could be inherited. The major source (76%) of their information about breast cancer was from health professionals. Among the respondents 96% knew self breast examination while 41% knew clinical breast examination as screening method. Eighty two percent of the respondents thought self breast examination should be carried out monthly while very few subscribed to clinical breast examination. CONCLUSION: The studied population has good knowledge of breast cancer, its symptoms and screening methods. However, they lack adequate knowledge of the risk factors and only few practiced clinical breast examination. Thus, there is need for educational intervention to enhance knowledge of the risk factors and the need for clinical breast examination. PMID- 20836313 TI - Research productivity of junior academic staff at a tertiary medical college in south west, Nigeria. AB - BACKGROUND: The research productivity of medical faculty has been well studied in developed countries, unlike in the developing countries. OBJECTIVES: This study proposes to assess the level of research productivity over a 2 year period and identify the challenges to conducting research among junior academic staff of the College of Medicine, University of Lagos. METHODS: An observational cross sectional study in which the 120 junior academic staff from both basic sciences and clinical sciences were evaluated between January and September 2005. Data collection was by self-administered questionnaires distributed to the study population. RESULTS: There were 83 (69.1%) respondents comprising 38 males (45.6%) and 45 females (54.2%). The median age group was 31-40 years. Most respondents (57, 83%) spent less than 10 hours/week on research. On average they had completed 3-4 scholarly articles within the past 2 years. Nineteen (21.7%) of the subjects were considered to have optimal research productivity having completed over 5 scholarly research papers. The lecturers with optimal research productivity were significantly more likely to be male, and spent over 10 hours a week in hospital related clinical and laboratory related activities. (p = 0.02, and p = 0.03). Inadequate funding and laboratory facilities, and poor technological infrastructure were the most common causes of impediments to research reported by 78%, 69% and 55% of the lecturers respectively. CONCLUSION: Optimal research productivity was seen in about one quarter of the study population and was associated with male gender and prolonged duration of clinical/laboratory activities. Negligible research financing and poor laboratory support were major impediments to research productivity. PMID- 20836314 TI - Childhood leprosy in Essimbiland of Cameroon: results of chart review and school survey. AB - BACKGROUND: The WHO targeted to eliminate leprosy from the world as a public health problem by reducing the prevalence to less than 1 case per 10000 population based on the use of multi-drug therapy (MDT). Despite the success of MDT, endemic pools still exist in some countries that have attained the national elimination threshold. OBJECTIVE: Assess the burden of childhood leprosy and control efforts in Essimbiland of Cameroon. METHODS: The records of children patients were reviewed in two main primary health care institutions and 4 primary schools in Essimbiland having 459 pupils were surveyed for leprosy. A purposive sampling of all available registers and pupils was used. RESULTS: A total of 1129 case files were reviewed covering the periods before MDT (1961-1967) implementation in 1982 and post MDT (1982-1999); no records were available from 1968-1991.From chart review, 42 (23.3%) new leprosy cases from 1961-1967 and 35 (12.2%) from 1982-1998 were from the Mbingo leprosarium. 31 (39.7%) of 78 childhood leprosy cases from chart review [1961-1967 and 1982-1999] were from Essimbiland. Of the 35 incident childhood leprosy cases from 1982-1998, 24 (68.6%) were from Essimbiland compared to other divisions. Poor record - keeping on leprosy was common in the study area. Among 459 pupils surveyed in 4 primary schools, 6 (1.3%) new leprosy cases were identified giving a prevalence of 131 per 10,000 pupils. The common skin lesion was on the back but one pupil had both hands clawed. 16 (3.5%) pupils were placed on observation. All the new leprosy cases from the school survey were indigenes of Essimbiland. CONCLUSION: Childhood leprosy is a public health problem in the Essimbiland requiring school surveys and a house-to-house search for new cases. PMID- 20836315 TI - Appropriateness of intra-operative blood transfusion in children at the Lagos University Teaching Hospital--an initial survey. AB - BACKGROUND: The decision to transfuse intra-operatively is based on preoperative haemoglobin (Hb), estimated blood loss and physiological variables. The visual estimate of blood loss is notoriously unreliable especially with small volumes of blood losses in children. OBJECTIVES: We sought therefore to determine the appropriateness of intra-operative blood transfusion in a sample of children METHODS: All children requiring intra-operative blood transfusion between May and June 2008 were prospectively studied. Neonates and children already on blood transfusion at induction were excluded. Transfusion was prescribed at the discretion of the attending anaesthetist. The Estimated blood volume (EBV) and estimated blood loss (EBL)were determined. Appropriate transfusion was defined as blood transfusion at EBL > 15% of EBV, maximum allowable blood loss to PCV of 27% and pre-transfusion Hb < 8g/dl. RESULTS: Twenty-five patients were studied with a mean age of 4.16 +/- 3.59 years (Range 0.33-11 years). The mean preoperative PCV was 31.14 +/- 3.53% (range 25-34%). Twelve patients (48%) were appropriately transfused when MABL was calculated to PCV of 27%. Nine patients (36%) had appropriate blood transfusion at an EBL greater or equal to 15% of the EBV. Of the 12 patients that had pre-transfusion Hb measured, 2 (16.6%) were appropriately transfused at Hb < 8 g/dl. CONCLUSION: The use of near patient monitoring devices should be encouraged as this will give an accurate assessment of Hb and appropriate indication for transfusion. Equipment should be made available to perform gravimetric estimation of blood loss as the visual method is notoriously unreliable. PMID- 20836316 TI - Back school: the development of a Nigerian urban model. AB - BACKGROUND: Back Schools are health education and behaviour modifying programmes for care of the back and prevention of back injuries, usually available as video documentary. They are often developed with consideration for the environment and the practices of the people they serve. Although back schools are available in many parts of the world, none has been developed for the Nigerian environment. OBJECTIVE: To develop a back school model for the Nigerian urban setting. METHODS: The Nigerian Back School (NBS) was developed from two existing video documentaries and series of focus group discussions. The focus group discussions suggested how to adapt these documentaries to the Nigerian environment and cultural practices. A hand book containing illustrations on wrong and correct postures was also developed. RESULTS: The NBS comprises 30-minute video documentary and a 24-page handbook. The first part of the video documentary provides information on the epidemiology and causes of back pain, structures and functions of the back while the second and third parts consist of demonstrations of wrong and correct resting and working postures assumed during everyday life activities and simple exercises for the prevention or alleviation of back pain or its recurrence respectively. The NBS handbook consists of illustrations on wrong and correct postures assumed at rest and during activity of daily living CONCLUSION: A back school (video documentary and handbook) with considerations for the Nigerian urban environment and the peoples' practices was made available. PMID- 20836317 TI - Blood chemistry, hematology and tryptophan level in cerebral malaria children. AB - BACKGROUND: Cerebral malaria is a deadly complication of P. falciparum infection, yet its pathogenesis remains incompletely understood. OBJECTIVE: The blood chemistry, hematology, protein and tryptophan levels in the cerebrospinal fluid (CSF) of cerebral malaria children were investigated. METHODS: Fifteen children (2.44 +/- 0.25 yr) diagnosed with cerebral malaria were used for this study. The control subjects consist of healthy and malaria-free children (2.50 +/- 0.16 yr). Two ml of blood were collected from each child between 0830 h and 0930 h. Blood chemistry and hematological parameters were analyzed using 2 ml each of Synchron CX5 auto-analyzer. The cerebrospinal fluid (CSF) was collected from the children using the lumbar puncture method, by inserting a sterile needle between the 4th and 5th lumbar vertebrae collected into sterile tubes. The CSF tryptophan, plasma and CSF protein concentrations and CSF protein concentration were determined. RESULTS: There were no significant (p > 0.01) differences in the plasma protein, glucose and CSF glucose levels of the cerebral malaria children as compared with the control. The packed cell volume (PCV) of the cerebral malaria children hemoglobin (Hb) levels were significantly (p < 0.01) lower as compared to control, but were significantly higher in CSF tryptophan and erythrocyte sedimentation rate (ESR) of cerebral malaria children were observed. Results of the study showed that cerebral malaria affected the CSF protein level, ESR, Hb and PCV, but do not affect plasma protein, glucose and CSF glucose concentrations. CONCLUSION: Data of the present study indicate that CSF protein, tryptophan, ESR, Hb and PCV could be used as possible markers in the diagnosis of cerebral malaria. PMID- 20836318 TI - Knowledge of prostate cancer screening among native African urban population in Nigeria. AB - BACKGROUND: Prostate cancer is the must commonly diagnosed cancer in men worldwide and ranked second as the cause of death in cancer-related diseases. OBJECTIVE: To evaluate the awareness and attitude of the populace to screening for cancer of the prostate. METHODS: It is a cross-sectional study involving 156 respondents. A structured questionnaire detailing the biodata, the knowledge of cancer of prostate, the practice of screening by prostate specific antigen (PSA) estimation and the readiness to undergo screening by the respondent was used to obtain the set-out objectives. RESULTS: A total of 156 respondents completed the questionnaire and forms the basis of further analysis. The mean age of the respondents is 44.15 (+/- 11.9) years. Majority of the respondents were civil servant (51.9%) followed closely by politicians. About 23.1% of them have no formal education while 53.8% have acquired tertiary education. The result shows that 78.8% have never heard any information on cancer of the prostate and only 5.8% had heard about PSA. None of the respondents have ever had PSA test, even once. Eighty four per cent of the respondents are ready to pay for prostate cancer screening test by PSA assay. CONCLUSION: We conclude that there is remarkable lack of awareness of prostate cancer among the Nigerian native African urban populace. Prostate cancer screening and serum PSA test for screening is globally unknown among them. PMID- 20836319 TI - Paediatric hand injuries at the Lagos University teaching hospital. AB - BACKGROUND: Paediatric hand trauma represents a subset of hand injury that can be quite challenging to manage. Local studies on this injuries are few therefore a 4 year retrospective study at the Trauma and hand rehabilitation unit of the Lagos University teaching hospital was carried out. OBJECTIVES: To determine the percentage of hand trauma occurring in the paediatric age group, the predominant age group involved, place of injury, the major injury types occurring as well as the most common surgical procedure required. METHODS: The case records of all cases that presented at the hand rehabilitation clinic or the emergency center of the Lagos University teaching hospital over a 4 year period were reviewed. Those below the age of 12 years were studied. Their biodata, type of injury, place of injury and other details were obtained. RESULTS: 634 patients were seen over the study period, 61 cases of hand injuries were in the paediatric age group. Hand trauma constituted less than a third of all paediatric hand cases. The commonest age group affected was 2-6 years. Most of the injuries occurred around the home. Burns injury, blunt trauma, glass and knife cuts were the commonest causes of hand trauma. Soft tissue reconstruction was commonest procedure done. CONCLUSION: Infants and toddlers were the most vunerable groups while burns injury was the commonest cause of hand trauma seen at the Lagos university teaching hospital. PMID- 20836320 TI - Evaluation of pharmacists' participation in post-admission ward rounds in a tertiary hospital in South-West Nigeria. AB - BACKGROUND: Many patients on admission have limited mobility and need physical examination by the clinical team. Ward rounds serve as an avenue for health professionals to meet and develop an integrated plan of care for the inpatients. Lack of representation for certain professional groups, including pharmacy, may adversely affect the range of opinions and therapies for patients. OBJECTIVE: The study evaluates pharmacist's perception of and participation in post-admission ward rounds, at the Lagos University Teaching Hospital (LUTH). METHOD: All the 60 pharmacists covering various units of pharmaceutical services were administered a forty-two element structured questionnaire. Fifty (83.3%) pharmacists completed the questionnaires. Descriptive statistics and chi-square were used to analyse the collated data. RESULTS: Pharmacists had positive perception of their participation in ward rounds, some of whom were already involved in the exercise on a low scale. Peer reviews of patients' cases were frequently conducted and were usually dominated by the medical staff. The clinical role of the pharmacists is not clearly defined in respect to ward round. Their current impact in patient care activities during ward round is not significant. CONCLUSION: Pharmacists should be scheduled to participate actively in ward rounds, peer reviews and other professional activities, for optimum patient care. The hospital authorities should optimise the involvement of pharmacists in the paradigm shift towards pharmaceutical care, with a view to minimizing prescribing errors, cost of drugs and length of hospital stay. The use of preceptors should be explored. PMID- 20836321 TI - Interrelationship of growth hormone, glucose and lipid metabolism. AB - BACKGROUND: The relationship between Growth hormone (GH) and the metabolism of glucose and lipid is not completely understood. OBJECTIVE: The present study is to obtain further information that will clarify the relationships between growth hormone and the metabolism of glucose and lipid. METHODS: The subjects were randomly selected 25 male (11) and female (14) healthy individuals aged 35.96 +/- 8.05 years. After an overnight fast (10-12 hours), blood was taken from the subjects into heparinised tubes, centrifuged at 5,000 rpm for 5 minutes and the plasma separated. Fasting plasma glucose (FBS) was determined by glucose oxidase method,, total cholesterol, LDL, HDL and, Triglyceride were determined by enzymatic methods. Hormone sensitive lipase was determined by, using dilaural glycero-glutaric acid methyresoruffin as substrate and Cobas Integra 800 Auto analyser. Growth Hormone was determined by Enzyme linked immunoassay method by using monoclonal antibodies and Access 2 Immunoassay system. All reagents were supplied by Roche Company. RESULT: The results showedpositive correlations between GH vs age and GH vs BMI. On the contrary, negative correlations were shown between GH vs the fasting levels of glucose,GH vs lipid and GH vs HSL. CONCLUSION: ). GH caused the reduction of the blood levels of glucose and, lipid using HSL as mediator, by inhibiting gluconeogenesis and stimulating lipolysis, respectively. PMID- 20836322 TI - Treatment of sports injuries referred for physiotherapy at a national sports medicine centre in Nigeria: a retrospective study. AB - BACKGROUND: Physiotherapists are important members of the sports medicine team and are involved in the prevention and management of injured athletes right from the acute stage of injury to the stage of rehabilitation. However, the type of treatments rendered to injured athletes and level of physiotherapy utilisation in terms of injury referrals for physiotherapy in sports medicine in Nigeria is not fully known. OBJECTIVE: To find out the extent of referral of sports injuries for physiotherapy and types of treatments rendered to injured athletes referred for physiotherapy at the National Sports Medicine Centre (NSMC), Lagos, South-West, Nigeria. METHODS: All case files at the general records unit from January 1995 to December 2002 were investigated. Information on athlete's sport, body part treated and physiotherapy modalities used between January 1997 and December 2002 were also extracted from the treatment register at the physiotherapy department of the sports medicine centre. RESULTS: A total of 171 sports related injuries were reported at the general records unit of the NSMC, with a male to female ratio of 2:1. Of this number, 121 (70.8%) were referred for physiotherapy with strain (n = 57, 33.3%) constituting the majority of physiotherapy referrals. At the physiotherapy department, the knee (n = 43, 30.1%) and the thigh (n = 33, 25.4%) were the most treated body parts. Track and field events (n = 48, 36.9%) recorded the highest number of injuries treated. Exercise therapy (n = 81, 25.5%) was the most frequently used modality, followed closely by transcutenous electrical nerve stimulation therapy (n = 73, 20.3%). CONCLUSION: The frequency of referral of sports injuries for physiotherapy at the NSMC was high. Exercise therapy was the most frequently used treatment modality and injuries affecting the lower limbs were mostly treated. Emphasis should therefore be laid on prevention of lower limb injuries. PMID- 20836323 TI - Gestational age at antenatal booking in Lagos University Teaching Hospital (LUTH). AB - BACKGROUND: The role of antenatal care in ensuring improved pregnancy outcome is no longer in doubt. Ensuring early booking for antenatal care can optimize this benefit. OBJECTIVE: To determine the gestational age at first antenatal attendance in pregnant women at the Lagos University Teaching Hospital (LUTH). METHODS: A cross-sectional study of all pregnant women that booked at the antenatal clinic in LUTH from November 2005 to June 2006 was undertaken to determine the gestational age at booking. RESULTS: The mean age of the women was 30.5 +/- 4.5 years (range 18-46 years) and the mean gestational age at first antenatal visit for the study was 19.1 +/- 7.8 weeks (range 6 to 40 weeks). While the nulliparous and primiparous women booked earlier (mean 18.5 +/- 8.3 and 18.4 +/- 7.4 weeks respectively), those with parity 5 booked much later, mean 25.9 +/- 8.6 weeks and this was significant statistically (p < 0.0002). Only 317 (27%) had booked as at 13 weeks, the end of first trimester while the majority 647 (55.2%) booked in the second trimester (14 to 26 weeks gestation). 70 women (6%) had their first antenatal visit at > or = 34 weeks while 22 (1.9%) first booked at > or = 37 weeks gestation. However, 3 women (0.3%) booked at 40 weeks gestation. Majority of the women belonged to social class 3 (496; 42.3%) with majority of their partners also in social class 3 (490; 41.8%). However women in social class 1 and those whose partner belong to social class 1 booked earlier than the other social classes and this also was statistically significant (p < 0.0008). CONCLUSION: Nulliparous and primiparous women as well as women in social class 1 and those whose partners are in social class 1 tend to book earlier for antenatal care services. Aggressive and extensive health education on the benefit of antenatal care and the need for early booking in the first trimester is advocated. The hospital may need to review the cost of antenatal care and delivery as well as improve on the whole service package. PMID- 20836324 TI - Effect of nifedipine on reproductive functions in male rats. AB - BACKGROUND: After life itself, fertility is probably the most highly prized human possession. Yet, while medical treatment of the individual naturally demands priority, relatively little attention is paid to the effects of treatment on reproductive function. OBJECTIVE: To investigate the effect of the calcium channel blocker, nifedipine, on sperm functions and identify the possible mechanism of action. METHODS: Twenty four (24) male rats weighing 150-170 g were divided into three groups of eight rats each. Group 1 (control) received distilled water; Group 2, received nifedipine 0.57 mg/kg; and Group 3, received 0.57 mg/kg and serve as a recovery group. Treatment was done orally and it lasted for 30 days. Animals in Group 3 were allowed another 30 days after drug withdrawal for recovery. Sperm count, motility, morphology and serum testosterone level were evaluated. The testes were removed, weighed and prepared for histological studies. RESULTS: The weight of the testis and epididymis were significantly reduced (P < 0.05) with administration of nifedipine. There were significant decreases (P < 0.05) in epididymal sperm count and motility. Serum testosterone levels remained unchanged in treated rats. The histological section of the testis showed no biologically meaningful change compared with control tissue. CONCLUSION: Nifedipine appears to have a reversible deleterious effect on sperm functions in rats which is not mediated by ta change in testosterone secretion. PMID- 20836325 TI - Morphological pattern of childhood solid tumours in Lagos University Teaching Hospital. AB - BACKGROUND: There is a wide variation in the incidence of childhood tumors world wide. The relative incidence of childhood tumors in developing countries is increasing and might add significantly to the high childhood morbidity and mortality caused by infectious diseases. There is need to determine the incidence of childhood cancer in different centers of the country and contribute to the National cancer register. OBJECTIVE: The aim of this study is to determine the burden and patterns of childhood tumour in our environment. METHODS: A retrospective review of histologically diagnosed cases of childhood tumours seen from January 2000 to 2007 from the records of the Department of Morbid Anatomy of the Lagos University Teaching Hospital (LUTH), Nigeria was carried out. All the cases were analyzed for age and gender distribution as well as histological types. RESULTS: Malignant tumours constituted 30.50% of the tumours of which retinoblastoma is the most common. The most common benign tumour was fibroadenoma accounting for 36.2% of all benign tumours. The female to male ratio for malignant and benign tumours are 1:1 and 1:1.3 respectively. The peak age incidence was 11 - 15 years for benign and 1 - 5 for malignant tumours. CONCLUSION: The study showed decrease in the annual incidence of childhood tumours in Lagos. There was however no difference in the pattern when compared with other centers in Nigeria and in other African countries. PMID- 20836326 TI - Clinical evaluation of a self-etch adhesive system in non-carious cervical lesions. AB - BACKGROUND: All-in one adhesive systems reduce the number of steps and thus possible soures of error that may occur in clinical wage of adhesives, it is hoped that they also have good clinical performance. OBJECTIVE: To evaluate the clinical performance of a self-etch adhesive system--Adper's Prompt L-Pop in non carious cervical lesions over a six months period. METHOD: One hundred and eighty one (181) restorations were placed by one operator for 35 patients. The self-etch adhesive was applied to the cavity and composite was used to restore the teeth. The restorations were evaluated at baseline, 3 months and 6 months according to the modified Ryge's criteria. Restorations were monitored for postoperative sensitivity, retention rates and marginal adaptation. RESULTS: At six months, 160 restorations were available for evaluation in 32 patients. The retention rate was 96.3%, postoperative sensitivity was scored Alpha for all restorations (no sensitivity), and 3.7% restorations had marginal adaptation failure at six months. CONCLUSION: The adhesive system tested exhibited very good clinical performance at the end of six months. PMID- 20836327 TI - The clinical spectrum of neurological manifestations in HIV/AIDS patients on HAART at the Lagos University Teaching Hospital, Lagos, Nigeria. AB - BACKGROUND: The human immunodeficiency virus (HIV) is primarily neurotrophic and lymphotrophic. Diverse neurologic sequealae have been documented with variations based on disease severity, but geographic variation may determine the distribution of these neurological complications. OBJECTIVE: This study was designed to evaluate the current status of neurologic manifestations of HIV/AIDS as seen at our tertiary referral centre in Lagos, Nigeria. METHODS: Consecutively presenting persons with HIV/ AIDS receiving HAART, who were seen between August 2004 and March 2006 at the Lagos University Teaching Hospital (LUTH), Lagos, Nigeria, were recruited into the study. RESULTS: Two hundred and fifty consecutively presenting HIV sero-positive patients were seen. There were 102 males (40.8%) and 148 females (59.2%) with a mean age of 37.4 years. 86 (34.4%) had clinically evident neurological disease, including neurocognitive dysfunction in 65 (53%), distal sensory neuropathy in 41 (16.4%), meningitis in 16 (6.4%), myopathy in 13 (5.2%), myelopathy in 6 (2.4%) and cerebrovascular disease in 5 (2%). The mean CD4 count (cells/mm3) of patients with neurological disease, 201.1 +/- 124.8 was significantly lower than that of patients without neurological disease 253.5 +/-149.2 (P = 0.001). CONCLUSION: Clinically evident neurological disease occurs in about 1/3rd of patients with HIV/AIDS on HAART at our tertiary centre, and predominantly affects patients with more advanced disease stages evidenced by lower CD4 count. PMID- 20836328 TI - Oesophageal carcinoma--a report of two cases and review of literature. AB - BACKGROUND: Oesophageal carcinoma is a malignant epithelial tumour of the oesophagus that arises from the mucosa. It mostly comprises of squamous cell carcinoma and adenocarcinoma of the oesophagus and oesophagogastric junction. It is a relatively uncommon finding. OBJECTIVE: The objective of this case report is to demonstrate two cases of oesophageal carcinoma seen at the gastroenterology unit of the University of Ilorin Teaching Hospital, Ilorin. CASE REPORT: Two cases of oesophageal carcinoma were seen in the last three years. Two Nigerian males of ages 60 and 69 years respectively presented at our centre with a history of progressive dysphagia initially for solids but later involved liquids, and odynophagia. There was associated history of recurrent regurgitation and weight loss. However there was no heartburn, epigastric pain, abdominal swelling, haematemesis or malena. There was significant history of cigarette smoking and intake of alcohol. Barium swallow done, showed shouldering and distal rat tail appearance of the oesophagus. Upper gastrointestinal endoscopy revealed a mass in the oesophagus with evidence of malignant tumour, occluding the lumen of the oesophagus making it impossible to intubate the stomach. Histological examination of the biopsy specimen taken at endoscopy showed adenocarcinoma of the oesophagus. CONCLUSION: Oesophageal carcinomas are rare findings in Ilorin, Nigeria. PMID- 20836329 TI - An assessment of the competence and experience of dentists with the management of medical emergencies in a Nigerian teaching hospital. AB - BACKGROUND: Previous reports show that medical emergency events have ocurred in Teaching Hospital Dental centres, with attendant mortality and morbidity. OBJECTIVES: (1) To study the pattern of medical emergencies encountered by clinical dental staff of Lagos University Teaching Hospital (2) To evaluate their training, perception of their training and competence as undergraduates and postgraduates to manage such events. METHODS: All the clinical staff viz: Dental surgeons of different cadres--consultants, registrars, house surgeons and dental nurses of Lagos University Teaching Hospital. A structured questionnaire requesting to know demographic data, respondents attendance of life support training viz: Basic life support (BLS), advanced trauma life support (ATLS), intensive care support (ICS). A self rating in the competence of management of medical emergencies and previous personal encounter with medical emergencies with success/failure in the management with/or without medical colleage assistance were sought. In addition adequacy of their dental clinic/centres for drugs, equipments and their perceived readiness to deal with emergencies were enquired. RESULTS: Among the dental surgeons, 20 (26.6%) were consultants, 40 (53.3%) were registrars and 35 (46.6%) were house-officers. Thirty five (43.7%) had previous knowledge of basic life support (BLS) training, while 45 (56.2%) denied such knowledge. The figures for other trainings such as advanced trauma life Support (ATLS) was 8 (10%) and intensive care support (ICS) 2 (2.5% 73.3% of the respondents felt inadequate in the management of cardiovascular emergencies, while only 15.4% felt adequately prepared. Similar ratings for respiratory emergencies are 63.1% inadequacy, 16.9% adequacy, and only 3.3% felt very adequate. The availability of oxygen extension tubing and ambu bag was nil in all departments. Emergency drugs were claimed to be present by 28.5% oral surgery respondents and, 34.7% Child Dental Health respondents. Most of the respondents felt their clinics are not adequately prepared to deal with medical emergencies. CONCLUSION: The study showed that syncope is the commonest medical emergency event in dental surgery practice in our teaching hospital, others are bleeding, seizure disorders and asthmatic attacks. The constitution of hospital emergency team (consisting of cardiologists, anaesthetists) as done in advanced countries is advocated and dentists should ensure that the departmental staff are adequately trained to provide basic life support. PMID- 20836330 TI - Sickle cell anaemia: awareness among health professionals and medical students at the Lagos University Teaching Hospital, Lagos. AB - BACKGROUND: Sickle cell anaemia (SCA) is a chronic haemolytic disorder caused by homozygous inheritance of abnormal haemoglobin called 'haemoglobin S' (HbS). The disease burden is enormous to the patient, family and community. One potential weapon in its prevention is health information and awareness among the populace. OBJECTIVE: The study is to detrmine the awareness of sickle cell anaemia among health professionals and medical students at the Lagos University Teaching Hospital Idiaraba, Lagos. METHODS: Part of a large study which was cross sectional and descriptive study, carried out at the Lagos University Teaching Hospital (LUTH), between the months of August and September 2006. Data were collected from 403 health professionals and students using structured questionnaires. RESULTS: Majority (98.7%) of the respondents had heard about SCA. Only 211 (55%) of the respondent felt genotype screening should be done at pre school age. 128 (33.7%) felt it should be done during childhood. Doctors had a statistically significantly better knowledge of best time for detecting genotype. In all, 85% of the respondents had been involved in the management of sickle cell anaemia with the highest proportion among nurses (p = 0.02). Only 93 (24.3%) of the respondents knew most of the complications of sickle cell anaemia, 176 (46.3%) knew some of it, while 111 (29.2%) knew only a law complications. Nurses had a statistically significantly poorer knowledge of the complication of sickle cell anaemia. More nurses felt that engagement should be ended if there was a risk of having a child with sickle cell anaemia. CONCLUSION: Continuing medical education for health professionals about sickle cell anaemia, its management and complication is necessary. PMID- 20836331 TI - Phytochemical screening and quantification of flavonoids from leaf extract of Jatropha curcas Linn. AB - BACKGROUND: The Jatropha curcas L. (Euphorbiaceae) herb is found in SouthWest, Nigeria and other parts of West Africa, and is claimed to possess anti hypertensive property. OBJECTIVE: The phytochemical screening and flavonoid quantification of the leaf extract of Jatropha curcas Linn were studied. METHODS: The phytochemical screening of the methanolic leaf extract of J. curcas L. was carried using acceptable and standard methods. The flavonoid contents of the leaf extract of Jatropha curcas L. were determined using thin layer chromatography (TLC), infrared spectroscopy (IRS) and a reversed phase high performance liquid chromatography (HPLC). RESULTS: The phytochemical screening of the methanolic extract of the leaves of the plant shows the presence of alkaloids, cardiac glycosides, cyanogenic glycosides, phlobatannins, tannins, flavonoids and saponins. To quantify the flavonoid contents of leaf extract of Jatropha curcas L, extracts from the plant samples where examined in a C-18 column with UV detection and isocratic elution with acetonitrile; water (45:55). Levels of flavonoids (flavones) in leaves ranged from 6:90 to 8:85 mg/g dry weight. CONCLUSION: Results indicate that the methanolic extract of the leaves of Jatropha curcas L. contains useful active ingredients which may serve as potential drug for the treatment of diseases. In addition, a combination of TLC, IRS and HPLC can be used to analyse and quantify the flavonoids present in the leaves of Jatropha curcas L. PMID- 20836332 TI - Indications for ablative surgery in extremity musculoskeletal tumours. AB - BACKGROUND: Surgical options for treatment of extremity musculoskeletal tumours include excision [limb sparing] surgery or amputation [limb ablation]. Ablative surgery is for advanced extremity musculoskeletal tumours when limb salvage surgery is not feasible. OBJECTIVE: To determine the indications for ablative surgery in extremity musculoskeletal tumours in our centre. METHOD: This is a 6 year prospective study of patients presenting with extremity musculoskeletal tumours at National Orthopaedic Hospital Lagos. Data such as age, gender, presenting complaints, anatomic location of the tumour, clinical stage, type of ablative surgery and adjuvant treatment offered, histologic type of tumour, and treatment outcome were documented. RESULTS: Nineteen patients had ablative surgery as a mode of treatment. 11 were male while 8 were female with a M:F of 1.3:1. The age range was 3 - 69 years. Seven patients [6 males and 1 female] refused ablative surgery and voluntarily discontinued treatment. Most tumours were located in the lower limb and all patients that had ablative treatment presented with stage 3 or 4 disease. Osteogenic sarcoma was the most common diagnosis, accounting for 4 cases [21.1%]. Six patients [31.6%] with non malignant tumours had ablative surgery due to either late presentation or inaccurate preoperative diagnosis. Trans-femoral amputation was the most common level of amputation and this was done in 9 patients [47.4%]. Adjuvant chemotherapy was prescribed for all patients. The recurrence and survival rates could not be determined for each tumour as the patients were lost to follow-up soon after surgery with average post operative follow up of 5.5 months. CONCLUSION: Late presentation with locally advanced disease remains the dominant indication for ablative surgery in extremity musculoskeletal tumours. PMID- 20836333 TI - Dental caries status of HIV infected children in Nigeria. AB - BACKGROUND: HIV positive children may be prone to developing Dental Caries due to prolonged and frequent use of sucrose containing medications and poor feeding practices. OBJECTIVE: To determine the caries status of primary and permanent dentition in HIV positive Nigerian children using dmft/DMFT indices. METHODS: One hundred and twelve HIV positive children aged 4 months to 13 years attending two dedicated HIV outpatient clinics were examined for dental caries of primary and permanent dentition using the WHO criteria. Carious lesions were recorded using the dmft and DMFT indices in the primary and permanent dentition respectively. RESULTS: Forty four [39.3%] of the 112 children examined had dental caries mainly in the primary dentition in 96.7% of the cases. Mean dmft was 1.15 +/- 1.88, mean DMFT was 0.17 +/- 0.57. Dental caries was not significantly associated with the immune status of HIV positive children; chi2 = 2.58, P = 0.275. CONCLUSIONS: Dental caries experience in the primary dentition of these HIV positive children was greater than in the Nigerian paediatric population. Dental caries prevalence in these HIV positive children although lower than that seen in developed countries was however higher than in other reports of healthy Nigerian children. There was no significant association between dental caries and immune status of HIV positive children. PMID- 20836334 TI - Childhood leprosy in Essimbiland of Cameroon: results of chart review and school survey. AB - BACKGROUND: The WHO targeted to eliminate leprosy from the world as a public health problem by reducing the prevalence to less than 1 case per 10000 population based on the use of multi-drug therapy (MDT). Despite the success of MDT, endemic pools still exist in some countries that have attained the national elimination threshold. OBJECTIVE: Assess the burden of childhood leprosy and control efforts in Essimbiland of Cameroon. METHODS: The records of children patients were reviewed in two main primary health care institutions and 4 primary schools in Essimbiland having 459 pupils were surveyed for leprosy. A purposive sampling of all available registers and pupils was used. RESULTS: A total of 1129 case files were reviewed covering the periods before MDT (1961-1967) implementation in 1982 and post MDT (1982-1999); no records were available from 1968-1991. From chart review, 42 (23.3%) new leprosy cases from 1961-1967 and 35 (12.2%) from 1982-1998 were from the Mbingo leprosarium. 31 (39.7%) of 78 childhood leprosy cases from chart review [1961-1967 and 1982-1999] were from Essimbiland. Of the 35 incident childhood leprosy cases from 1982-1998, 24 (68.6%) were from Essimbiland compared to other divisions. Poor record - keeping on leprosy was common in the study area. Among 459 pupils surveyed in 4 primary schools, 6 (1.3%) new leprosy cases were identified giving a prevalence of 131 per 10,000 pupils. The common skin lesion was on the back but one pupil had both hands clawed. 16 (3.5%) pupils were placed on observation. All the new leprosy cases from the school survey were indigenes of Essimbiland. CONCLUSION: Childhood leprosy is a public health problem in the Essimbiland requiring school surveys and a house-to-house search for new cases. PMID- 20836335 TI - Four decades fighting pancreatic cancer. PMID- 20836336 TI - The Department of Surgery at the Medical University of South Carolina (1824 2010). PMID- 20836337 TI - Internal ring occlusion and floor support: a novel technique for inguinal hernia mesh repair. AB - Tension-free, open-mesh, inguinal herniorrhaphies have gained wide acceptance. Current mesh techniques reinforcing the internal ring do not provide a comfortable lay to the mesh. To address this, we used the internal ring occlusion and floor support (IROFS) technique. A retrospective review was undertaken of all hernias operated on with the IROFS technique from January 2001 to December 2006. Five hundred twenty-five inguinal hernia repairs were done in 477 male patients. Telephone questionnaires looking into their postoperative course and recurrence were recorded. We contacted 275 (58%) patients. Patients' ages ranged from 29 to 81 years (mean, 57 years). The hernia was indirect in 50 per cent (n=146), direct in 35 per cent (n=102), or both in 15 per cent (n=44) of patients. The average operative time was 40 minutes. Acute wound pain lasted for less than 1 week in 55 per cent (n=151) and for 1 to 2 weeks in 24 per cent (n=66). Postoperative analgesic requirement was less than 1 week in 54 per cent (n=147) and 1 to 2 weeks in 27 per cent (n=74). Most patients returned to their daily activities in 2 weeks (75%) and to work in 3 weeks (74%). Chronic pain lasted for 6 to 48 months (mean, 20 months) in only seven patients. No recurrence of hernia was observed during follow-up visits (range, 26-96 months; mean, 53 months). In conclusion, IROFS can be performed with little difficulty, is cost-effective, and is well tolerated by the patient. PMID- 20836338 TI - Improving dialysis access: regional anesthesia improves arteriovenous fistula prevalence. AB - An autologous arteriovenous (AV) fistula is the preferred form of angioaccess for chronic hemodialysis. A prospective study was carried out to evaluate the potential of regional anesthesia to improve AV fistula prevalence. One hundred ninety-three patients underwent preoperative duplex ultrasound evaluation over a 14-month period. The qualification of each patient to receive either an autologous AV fistula or a prosthetic graft was based on specific sonographic criteria. Patients scheduled for placement of a graft received an ultrasound directed supraclavicular brachial plexus block, which produces dense sympathetic blockade. After the regional block, those patients who met criteria for primary fistula construction on repeat ultrasound received a fistula instead of a graft. Of 62 patients scheduled to receive an AV graft, 23 or 37 per cent were recruited to receive a fistula instead. The outcome of the recruited fistulas was compared with the 121 planned fistulas. There was no statistically significant difference in primary failure rate (4.3 vs. 5.8%). The recruited fistulas had a shorter average maturation time, 83 +/- 48 versus 132 +/- 82 days (P = 0.023). Within the study population, functioning fistula prevalence was increased from 61.7 to 79.8 per cent. Regional anesthesia and immediate preoperative ultrasound is a useful strategy for increasing fistula prevalence. PMID- 20836339 TI - The use of sentinel lymph node biopsy in ductal carcinoma in situ. AB - Although ductal carcinoma in situ (DCIS) does not require axillary evaluation, controversy exists regarding the use of sentinel lymph node biopsy (SLNB) in patients with DCIS diagnosed by core needle biopsy (CNB). Advocates of concomitant SLNB and lumpectomy cite the low morbidity of SLNB, the high rate of invasive ductal carcinoma in resected specimens, and the positive nodes found in 1 to 2 per cent of patients with resected DCIS despite finding no invasive component. Opponents of this practice cite the complication risk and the improbability of clinically significant axillary recurrence. We therefore proposed to determine our rate of invasive cancer in DCIS diagnosed by CNB and to determine whether SLNB at first operation would decrease return to the operating room. We retrospectively reviewed patients diagnosed with DCIS by CNB from 2003 to 2008. Standard clinicopathological data were collected and analyzed. In 110 patients, the prevalence of invasive cancer on final resection pathology was 13.6 per cent (15 of 110). Of those patients with invasive cancer, 93 per cent (14 of 15) had high-grade DCIS (P = 0.077) by CNB. Seventeen per cent (14 of 82) of patients with high-grade DCIS had invasive cancer. Of 34 patients with SLNB, three (9%) had positive nodes. Fifteen patients required re-excision to obtain negative margins, including 13 patients with invasive cancer. Five patients (4.5%) were spared additional operative intervention by initially performing SLNB. We suggest using concomitant SLNB when a high clinical suspicion of invasive cancer exists, in the presence of a palpable mass, or when mastectomy precludes future SLNB. Intraoperative margin assessment is needed to avoid return to the operating room. PMID- 20836340 TI - Predictors of failure of the laparoscopic approach for the management of small bowel obstruction. AB - Small bowel obstruction (SBO) is a common cause of hospital admission. Our objective is to determine variables that correlate with failure of the laparoscopic approach for SBO. Twenty-three consecutive patients underwent diagnostic laparoscopy with curative intent for treatment of SBO by a single surgeon over a 3-year period. The laparoscopic approach was successful in 18 patients (78%); there were five (22%) conversions to laparotomy. The causes of obstruction included adhesive band in 16 patients; and small bowel lymphoma, metastatic esophageal cancer, small bowel gangrene, Meckel diverticulum, gallstones ileus, and incarcerated incisional hernia in two. Using the Fisher two sided test, no significant predictor for conversion was identified using gender, American Society of Anesthesiologists class, previous bowel obstruction, history of adhesiolysis, abdominal distention, pelvic surgeries, chemotherapy, radiation, malignancy, chronic obstructive pulmonary disease, asthma, coronary artery disease, hypertension, or hypercholesterolenemia. The Wilcoxon two-sided test did not show significance for age, weight, number of previous abdominal surgeries, or small bowel diameter. The postoperative hospital stay was significantly shorter in the laparoscopic group compared with those who needed conversion (3 vs. 9 days) with P = 0.0019. No mortality was noted in any patients. The laparoscopic is safe and feasible for the management of SBO. We believe that the laparoscopic approach should be offered to all patients with SBO unless there is an absolute contraindication to laparoscopic surgery. PMID- 20836342 TI - Video-assisted thoracoscopic surgery as a primary intervention in pediatric parapneumonic effusion and empyema. AB - The use and effectiveness of video-assisted thoracoscopic surgery (VATS) for the treatment of empyema and complex parapneumonic collections in pediatric patients is well documented. Timing of this intervention still remains controversial. We reviewed our experience with VATS to determine if it should be used as the initial procedure in children with pleural collections. We reviewed all pediatric (age younger than 17 years) patients with a diagnosis of pneumonia admitted between July 1998 and June 2008. Demographics, comorbidities, laboratory data, and hospital length of stay (LOS) were evaluated. Patients were divided into groups: those who only had thoracentesis or thoracostomy (Group A), those who underwent a procedure and then required VATS (Group B), and those who went directly to VATS (Group C). We identified 382 patients admitted with pneumonia. Of these, 79 (21%) required a thoracic drainage procedure. Overall, 49 (67%) of patients with a thoracic fluid collection underwent VATS at some point. With regard to type of intervention, there was no statistical difference noted in clinical variables. Thirty (38%) patients were in Group A, 18 (22%) in Group B, and 31 (39%) in Group C. LOS for Group C (10.5 days) was significantly (P < 0.05) shorter than for both Group A (14.8 days) and Group B (15 days). Only two (6%) patients required conversion to open thoracotomy. A high percentage of children initially treated by tube thoracostomy eventually require additional interventions, leading to increased LOS. As a result of its simplicity, safety, and efficacy, VATS pleural evacuation can be recommended as the initial intervention in pediatric parapneumonic effusions and empyema in patients who do not require emergent drainage. PMID- 20836341 TI - Outcomes with the use of recombinant human erythropoietin in critically ill burn patients. AB - Recent data demonstrate a possible mortality benefit in traumatically injured patients when given subcutaneous recombinant human erythropoietin (rhEPO). The purpose of this report is to examine the effect of rhEPO on mortality and transfusion in burn patients. We conducted a review of burn patients (greater than 30% total body surface area, intensive care unit [ICU] days greater than 15) treated with 40,000 u rhEPO over an 18-month period (January 2007 to July 2008). Matched historical controls were identified and a contemporaneous cohort of subjects not administered rhEPO was used for comparison (NrhEPO). Mortality, transfusions, ICU and hospital length of stay were assessed. A total of 105 patients were treated (25 rhEPO, 53 historical control group, 27 NrhEPO). Hospital transfusions (mean 13,704 +/- mL vs. 13,308 +/- mL; P = 0.42) and mortality (29.6 vs. 32.0%; P = 0.64) were similar. NrhEPO required more blood transfusions (13,308 +/- mL vs. 6827 +/- mL; P = 0.004). No difference in mortality for the rhEPO and NrhEPO (32.0 vs. 22.2%; P = 0.43) was found. Thromboembolic complications were similar in all three groups. No effect was seen for rhEPO treatment on mortality or blood transfusion requirements in the severely burned. PMID- 20836343 TI - Adherence to physical activity guidelines in breast cancer survivors. AB - Physical activity in breast cancer survivors has been shown to improve outcomes. This study evaluated breast cancer patients' adherence to physical activity guidelines in a population-based study. Data from the 2007 National Health Interview Survey were used to compare adherence to physical activity guidelines in patients with breast cancer with the general population. Statistical analyses were performed using SUDAAN software. In 2007, 327 breast cancer survivors and 23,030 others from the general population were surveyed. Breast cancer survivors were significantly older than the general population (mean age 64.9 vs. 45.6 years, P < 0.001) and tended to be female (99.4 vs. 51.2%, P < 0.001). Despite being significantly more likely to have interacted with a healthcare professional within the past year (96.7 vs. 82.1%, P < 0.001), fewer breast cancer survivors reported following physical activity guidelines than nonbreast cancer survivors (4.64 vs. 12.0%, P < 0.001). Controlling for age, gender, and interaction with healthcare providers, breast cancer survivors were no more likely to follow physical activity guidelines than the general population (OR: 0.73; 95% CI: 0.41 1.30, P = 0.282). Despite more interaction with healthcare providers, breast cancer survivors are no more likely to adhere to activity guidelines than the general population. PMID- 20836344 TI - The effect of age on blunt traumatic brain-injured patients. AB - An increasing number of super geriatric (age older than 80 years) patients are being hospitalized with traumatic brain injury (TBI). Although geriatric (age older than 65 years) patients have been reported to have a worse functional outcome compared with younger patients who present with the same or less severe degree of TBI; the mortality for the super geriatric (age older than 80 years) remains to be determined. Knowledge of their hospital mortality may help improve clinical decision-making protocols and resource use. A retrospective chart review of patients who sustained TBI after blunt trauma was performed over a 3-year period (June 2005 to June 2008) at a Level II trauma center. Mortality was calculated for various age groupings and data analyzed using analysis of variance test and chi2 test. We hypothesized that mortality would increase significantly with increasing age from the geriatric to the super geriatric group. A total of 2369 patients were evaluated with 744 pediatric patients in Group I (age younger than 17 years), 1297 adult patients in Group II (age 17-64 years), 185 geriatric patients in Group III (age 65-80 years), and 143 super geriatric patients in Group IV (age older than 80 years). The respective mortalities for each group were as follows: Group I (6%), Group II (9%), Group III (21%), and Group IV (6%). There was no significant difference in the Injury Severity Score for the four groups. In comparing Group III with Groups I and II, we found a significant increase in mortality with incresing age as reported in the literature (21 vs. 6%, P = 0.01 and 21 vs. 9%, P = 0.04). However, in comparing Group IV with the other three groups, there was no significant difference in mortality. There was a trend toward decrease in mortality from age Group III to IV (21 vs. 6%, P = 0.09), which is of unclear etiology and warrants further study. In patients with blunt TBI, there is no significant difference in mortality between the super geriatric age group (age older than 80 years) and the younger pediatric, adult, and geriatric age groups. Resource use therefore should not be limited to patients older than 80 years with TBI. PMID- 20836345 TI - Intraoperative blood loss predicts hemorrhage-related reoperation after orthotopic liver transplantation. AB - Postoperative hemorrhage after orthotopic liver transplantation (OLT) may require early reoperative intervention. Previous studies have shown intraoperative transfusion requirement as a main determinant of reoperative intervention after OLT. The goal of this study was to develop an intraoperative hemorrhage model predicting need for reoperation after OLT. A single institution, retrospective review of adult primary OLT patients from January 2002 to 2008 was conducted. Multivariate logistical regression analysis was performed to identify predictors of reoperation due to postoperative hemorrhage. Secondary analysis was conducted on patients in the reoperation group managed with temporary open abdomen techniques. Four hundred and ten primary transplantations were performed with 59 patients (14.4%) requiring reoperation. The adjusted odds of reoperation when intraoperative blood loss (IBL) increases from 1.5 L to 10.0 L is 2.48 [95% confidence interval: (1.18, 5.31)]. IBL of 10.0 L predicts a 19.4 per cent probability of reoperation. Patients managed with open abdomen (n = 8) exhibited a significant IBL difference (16.0 L vs. 6.0 L, P < 0.001) when compared with the closed abdomen cohort. Our results indicate that intraoperative blood loss is the primary predictor of reoperation after OLT and provide a hemorrhage threshold to guide postoperative management of complicated OLT patients. PMID- 20836346 TI - The difficulty with localization of rectal cancer after neoadjuvant chemoradiation therapy. AB - Neoadjuvant chemoradiation therapy (NCRT) has become the standard treatment for locally advanced rectal cancer. Subsequent downstaging can make identification of the primary tumor challenging. Complete pathologic response rates of 8 per cent to 27 per cent are seen with current NCRT regimen. Two patients were referred to our institution after NCRT and subsequent low anterior resection in whom no residual cancer was found in the resected specimen but who manifested cancer in the distal rectum in the early postoperative period. Resection of a locally advanced rectal cancer after NCRT associated with significant tumor shrinkage is facilitated by the surgeon's evaluation with proctoscopy and tumor tattooing before the initiation of NCRT. After NCRT, preoperative proctoscopy, distal rectal evaluation after a sphincter sparing procedure in the operating room, and thorough specimen evaluation help to insure that the surgeon has removed the rectal cancer with an appropriate margin. These cases emphasize how important it is for the surgeon to be involved in the staging phase of managing the patient with rectal cancer. PMID- 20836347 TI - Road traffic collisions-case fatality rate, crash injury rate, and number of motor vehicles: time trends between a developed and developing country. AB - Road traffic collisions (RTCs) are one of the most common preventable causes of death and disability worldwide. We investigated changes in numbers of motor vehicles, case fatality rate, and crash injury rate for the most present recorded year (2002) 5 and 10 years before that in the United Kingdom (U.K.) and Sri Lanka (SL). We also investigated environmental and individual factors impacting patients at South Birmingham Trauma Unit, U.K. and Colombo General Hospital, SL. We conducted a descriptive cross-sectional study (both quantitative and qualitative). Over the 10-year period, numbers of motor vehicles have risen in both countries; the crash injury remained stable in both countries. Case fatality rate (far higher) in SL has decreased, as in the U.K.. Three hundred and twenty five patients took part in the survey in SL, with 83 in the U.K. In the categories investigated, including patient demographics, RTC environment, visual impairment, pedestrian and driver factors, the majority of results were significantly different between the two countries. Target factors such as inadequate street lighting, visual impairment, speeding, and not wearing seatbelts at time of accident were identified, and recommendations developed as a result. PMID- 20836348 TI - Clinical integration of picture archiving and communication systems with pathology and hospital information system in oncology. AB - The complexity of our current healthcare delivery system has become an impediment to communication among caregivers resulting in fragmentation of patient care. To address these issues, many hospitals are implementing processes to facilitate clinical integration in an effort to improve patient care and safety. Clinical informatics, including image storage in a Picture Archiving and Communication System (PACS), represents a tool whereby clinical integration can be accomplished. In this study, we obtained intraoperative photographs of 19 cases to document clinical stage, extent of disease, disease recurrence, reconstruction/grafting, intraoperative findings not identified by preoperative imaging, and site verification as part of the Universal Protocol. Photographs from all cases were stored and viewed in PACS. Images from many of the cases were presented at our interdepartmental cancer conferences. The stored images improved communication among caregivers and preserved pertinent intraoperative findings in the patients' electronic medical record. In the future, pathology, gastroenterology, pulmonology, dermatology, and cardiology are just a few other subspecialties which could accomplish image storage in PACS. Multidisciplinary image storage in a PACS epitomizes the concept of clinical integration and its goal of improving patient care. PMID- 20836349 TI - In defense of industry-physician relationships. AB - The objective was to examine the economic, ethical, and legal foundations for conflict of interest restrictions between physicians and pharmaceutical and medical device industries ("industry"). Recently academic medical centers and professional organizations have adopted policies that restrict permissible interactions between industry and physicians. The motive is to avoid financial conflicts of interest that compromise core values of altruism and fiduciary relationships. Productive relationships between industry and physicians provide novel drugs and devices of immense benefit to society. The issues are opposing views of medical economics, profit motives, medical professionalism, and extent to which interactions should be lawfully restricted. Industry goals are congruent with those of physicians: patient welfare, safety, and running a profitable business. Profits are necessary to develop drugs and devices. Physician collaborators invent products, refine them, and provide feedback and so are appropriately paid. Marketing is necessary to bring approved products to patients. Economic realities limit the extent to which physicians treat their patients altruistically and as fiduciaries. Providing excellent service to patients may be a more realistic standard. Statements from industry and the American College of Surgeons appropriately guide professional behavior. Preservation of industry-physician relationships is vital to maintain medical innovation and progress. PMID- 20836350 TI - Day-case Limberg flap for recurrent pilonidal sinus: does obesity complicate the issue? AB - The purpose of this study was to analyze the long-term outcome of rhomboid excision with Limberg flap reconstruction (LF) as one-day surgery in treatment of recurrent pilonidal sinus (RPS). The effect of obesity on outcome will be addressed. Forty-nine patients with RPS were treated by rhomboid excision and LF as one-day surgery. Data collected included demographics, body mass index, operative time, flap ischemia, wound infection, length of hospital stay, time of complete healing, and recurrence. Patients' mean age was 33.4 years and mean number of previous operations was 3.4. Operative time ranged from 40 to 70 minutes. Two patients developed sterile seroma (4.1%) and two patients (4.1%) had wound infections. No wound dehiscence or flap ischemia was reported. All patients returned to normal activity within 7 days. No recurrences were reported after a mean follow-up of 32.1 months. Obesity significantly increased the operative time, however, it affected neither the postoperative outcome nor the long-term recurrence. Rhomboid excision and LF as one-day surgery is a safe and reliable method for treatment of RPS. It guarantees low morbidity, short hospital stay, short time off work, and carries low risk of recurrence, even in obese patients. PMID- 20836351 TI - Body image perception and quality of life in patients who underwent breast surgery. AB - Quality of Life (QoL) has become a standard measure in assessing the effectiveness of medical interventions. We compared the differences between QoL and body image scale (BIS) in a group of patients who underwent breast surgery, including lumpectomy or conservative surgery, modified radical mastectomy and radical mastectomy with breast reconstruction. We included patients who underwent breast surgery between August of 2005 and June of 2006 in two tertiary referral centers in Mexico City. Two self-administered questionnaires assessing body image perception, BIS and quality of life (SF-36), were assigned and a physician conducted interview was done. We stratified patients by age, marital status, and scholar grade. The sample comprised 202 patients. The BIS results yielded: the group with a benign lesion demonstrated favorable body image perception when compared with the malignant lesion group. A confirmed diagnosis of malignancy hinders QoL in older and younger age groups. Conservative surgery and breast reconstruction improves QoL in younger patients without significance in the older group. The most significant variable that hinders the BIS and QoL is the cancer diagnosis. Impact of conservative surgery and breast reconstruction in body image perception and quality of life is influenced by patient age and educational level. PMID- 20836352 TI - Tree stands, not guns, are the midwestern hunter's most dangerous weapon. AB - Although the prevailing stereotype is that most hunting injuries are gunshot wounds inflicted by intoxicated hunting buddies, our experience led us to hypothesize that falls comprise a significant proportion of hunting related injuries. Trauma databases of two Level I trauma centers in central Ohio were queried for all hunting related injuries during a 10-year period. One hundred and thirty patients were identified (90% male, mean age 41.0 years, range 17-76). Fifty per cent of injuries resulted from falls, whereas gunshot wounds accounted for 29 per cent. Most hunters were hunting deer and 92 per cent of falls were from tree stands. Alcohol was involved in only 2.3 per cent, and drugs of abuse in 4.6 per cent. Of gunshots, 58 per cent were self-inflicted, and 42 per cent were shot by another hunter. Tree stand falls were highly morbid, with 59 per cent of fall victims suffering spinal fractures, 47 per cent lower extremity fractures, 18 per cent upper extremity fractures, and 18 per cent closed head injuries. Surgery was required for 81 per cent of fall-related injuries, and 8.2 per cent of fall victims had permanent neurological deficits. In contrast to prevailing beliefs, in our geographic area tree-stand falls are the most common mechanism of hunting related injury requiring admission to a Level 1 trauma center. PMID- 20836353 TI - Complex hydatid cysts of the liver: a single center's evolving approach to surgical treatment. AB - In our study, we arbitrarily define complex hydatid cysts of the liver as either cysts with a diameter > or =10 cm, or as multiple and recurrent cysts. These types of cysts were then divided into two subgroups: giant cyst identified as a cyst with a diameter > or =10 cm, and complicated cyst as multiple, recurrent, abscessed cysts, or those resistant to conservative treatment. The aim of this study was to retrospectively analyze a series of 38 consecutive patients who underwent surgery for complex hydatid cysts over a period of 9 years at the same institute to determine the evolution of the surgical treatment and the risk factors for recurrence. Fourteen (36.8%) of these patients were women and 24 (63.2%) men (median age 48.1; range 16-71 years). The mean postoperative followup was 24 +/- 10.8 months. All patients were treated prophylactically with albendazole (10 mg/Kg/day) for 15 days preoperatively and for 2 months postoperatively. Partial cystectomy was performed in two cases (5.26%) and radical pericystectomy in 20 cases (52.63%). In 15 cases the patients underwent liver resection (39.47%): left hepatectomy was performed in eight cases (21.05%), and right hepatectomy in seven cases (18.42%). In one case, both wedge resection and pericystectomy were performed. There were no deaths and only one patient (2.63%) showed signs of recurrence at follow-up. Radical surgery is the most effective treatment for complex hydatid cysts. In our experience, partial or total pericystectomy virtually eliminated, over time, the need for hepatic resection. PMID- 20836354 TI - Transplant renoportal vein conduit for complete mesenteric thrombosis: a case report. AB - Portal vein thrombosis, which is present in up to one quarter of patients with end-stage liver disease, presents a technical challenge at the time of liver transplantation. Thromboendovenectomy when feasible has been advocated in these patients. However, in patients with complete mesenteric thrombosis where this technique is typically not successful, a number of alternative techniques have been attempted including caval transposition, portal arterialization, and multivisceral transplantation often with discouraging results. We present herein a single case where transplant renal vein outflow was used to provide portal vein inflow in a patient with complete mesenteric thrombosis undergoing simultaneous liver-kidney transplant. PMID- 20836355 TI - Cardiac tamponade resulting from trauma--induced effusive pericarditis. PMID- 20836356 TI - Multiple cancer foci in the colon of a man with operated rectum carcinoma. PMID- 20836357 TI - Incarcerated biatrial thromboembolus after extrapleural pneumonectomy: a surgical conundrum. PMID- 20836358 TI - Spontaneous splenic rupture due to splenic metastasis of esophageal cancer. PMID- 20836359 TI - Sonographic envisage for unilateral absence of extensor pollicis longus. PMID- 20836360 TI - Successful laparoscopic treatment of a hepatic abscess due to a chicken bone. PMID- 20836361 TI - Retropancreatic schwannoma in a young female. PMID- 20836362 TI - Lymphoma of the breast capsule in a silicone implant-reconstructed patient. PMID- 20836363 TI - Nontuberculous mycobacterial abdominal aortic aneurysm in a patient with AIDS. PMID- 20836364 TI - Hand-assisted laparoscopic cholecystectomy for acute gangrenous cholecystitis. PMID- 20836365 TI - Spontaneous pneumothorax as initial presentation of neurofibromatosis. PMID- 20836366 TI - [Osseous tumours and orthopedics]. PMID- 20836367 TI - [The Grice technique for tarsal coalition]. AB - OBJECTIVE: Show that the surgical release of the coalition area and the Grice subtalar arthrodesis are useful for the treatment of tarsal coalition, and describe the surgical techniques used. MATERIAL AND METHODS: This is a prospective, longitudinal, non-randomized clinical trial conducted from January 2001 to December 2007. Patients of both genders were selected, ages 10-15 years of age, with a diagnosis of tarsal coalition without any other type of orthopedic or neurologic comorbid condition. The Harris classification of tarsal coalition was used. AP, lateral and oblique X-rays of both feet were ordered, as well as a CAT scan; the Costa-Bertani angles were measured. Central trend and scatter measurements were performed for the statistical analysis, as well as the comparison of means Z test, the relative risk (RR) and the linear correlation. RESULTS: Twenty-six patients, 20 males and 6 females, were included in the study; 12 of them had fibrous talocalcaneal coalitions, 12 had bone coalitions and 2 had calcaneonavicular coalitions. COMPLICATIONS: one reflex sympathetic dystrophy, 4 superficial infections, 4 graft resorptions, and 4 patients with persistent pain. In the Z test for the Costa-Bertani angles the p value was 0.0020. The RR for obesity was 4.5, the linear correlation coefficient r for valgus hindfoot and pain was 78. DISCUSSION: The clinical results indicate an improvement in pain and gait. Overweight was found to be a risk factor for persistent pain. PMID- 20836368 TI - [Usefulness of the cast index and padding index for the prognosis of pediatric forearm fractures]. AB - BACKGROUND: The most frequent fractures in pediatric patients are those of the mid or distal shaft of the radius and ulna. Most of them can be treated with closed reduction and a brachio-palmar cast, but sometimes redisplacement or angulation occur within the first few weeks. Xray measurements to foresee these complications have been designed; this paper focuses on their certainty and usefulness. METHODS: Twenty-four patients ages 2-14 years of age were included, all of them with closed fractures of the mid or distal shaft of the radius and ulna treated with reduction maneuvers under anesthesis and placement of an brachio-palmar cast. Measurements of the cast, padding and Canterbury indices were performed, which were compared with the clinical and X-ray results at three weeks. The sensitivity, specificity, and the positive and negative predictive value were calculated. RESULTS: X-ray measurements had a sensitivity of 43%, a specificity of 88%, a positive predictive value of 60% and a negative predictive value of 79%. CONCLUSION: The results of the measurements are consistent with the findings of other studies, which proves their usefulness; their use should therefore be encouraged to prevent complications like the displacement or angulation of forearm fractures in pediatric patients. PMID- 20836369 TI - [Use of a prosthesis after resection of a giant cell tumor of the knee]. AB - OBJECTIVE: Show the efficacy of a tumor prosthesis after the resection of a giant cell knee tumor in the proximal tibia and the recovery of knee function. MATERIAL AND METHODS: This is a report of a retrospective observational clinical case of a male, 36-year-old patient with history of left knee arthrodesis in 1996 following the resection of a giant cell tumor in the distal femur. The latter relapsed in 2004 and a solitary pulmonary tumor node was detected. Broad resection of the femur and the arthrodesed tibia was performed together with the placement of a tumor prosthesis. RESULTS: At the 20th postoperative month the patient had remission of the pulmonary node, knee function with passive flexion of 120 degrees and total extension, gait without limitations, no pain, a Musculoskeletal Tumor Society functional knee score of 28 and a Knee Society score of 95. CONCLUSIONS: The resection of the arthrodesis zone and the giant cell tumor achieved the double goal of erradicating the tumor and recovering the knee mobility after 10 years of arthrodesis, which led to a very satisfied patient capable of resuming his activities. PMID- 20836370 TI - [Experience in the management of open pelvic fractures at the Mexican Red Cross Trauma Center]. AB - A prospective, descriptive study was conducted at the Trauma and Orthopedics Service from January 1st, 2006 to January 1st, 2009; all patients with a diagnosis of open pelvic fracture were included. A total of 112 patients with pelvic fracture were seen at the Emergency Room; 12 of them with an open pelvic fracture; 75% were males, most of them ages 31 to 45 years of age; they were stabilized with a circular pelvic binder and external fixators with a V technique; a gastrointestinal bypass with colostomy was performed; 3 patients died within the first few hours due to hypovolemic shock, 5 survived a mean of 25 days and died due to other causes, and four patients were discharged alive. These lesions have a mortality rate of 66.66%; mediate mortality resulting from massive bleeding occurred in 25% and survival was 33.33%. The most frequent fractures (39.28%) according to the Tile classification were type C, which are the most unstable ones; according to the Bircher-Hargrove classification, most cases were type C, which are the most severe lesions and involve a high mortality rate and risk of contamination; it is therefore important to perform a gastrointestinal bypass and an emergency colostomy as part of the initial patient management. PMID- 20836371 TI - [Infections in the surgical management of pelvic ring fractures]. AB - BACKGROUND: Infections that occur after the surgical management of pelvic fractures may involve potentially devastating complications. The broader approaches involving soft tissue dissection and a long operative time may increase the infection rate when compared with more conservative approaches. This incidence may be reduced with a better understanding of the approaches, lymph node sparing and antibiotic use. The purpose of this study is to assess the incidence and severity of local infections in a series of adult patients with pelvic ring lesions treated surgically. MATERIAL AND METHODS: This is a prospective observational descriptive study. A total of 49 patients operated on by a single surgeon from 2004 to 2008 were included. RESULTS: Forty-four patients (90%) had no signs of infection during the treatment period. In the remaining 5 cases (10%), 5 episodes of infection were documented. CONCLUSIONS: The identification of a local postoperative infection warrants an aggressive and urgent assessment of the patient. The devitalized tissue should be removed and empiric antibiotic therapy should be instituted after taking culture samples. A deep infection rate after pelvic fixation ranging from 0 to 10% has been published. The prevalence is higher among the surgical teams with less expertise. The incidence rate in our review was similar to the one reported in the literature. PMID- 20836372 TI - [Clinico-radiologic evaluation of distal radius fractures treated with a percutaneous technique]. AB - In 1913 Lambotte began treating distal radius fractures surgically using percutaneous fixation with a Kirschner wire; in 1984 Clancey modified the percutaneous technique by using crossed wires with good results; however, various therapeutic approaches are needed to treat the fractures in elderly or osteopenic patients. The purpose of this study is to present the results of the treatment of distal metaphyseal radius fractures types 3, 4 and 5 according to Fernandez in 21 patients who underwent closed reduction and percutaneous fixation with the Clancey technique, with a forearm-palmar cast, from June to September, 2009. Good clinical and radiologic results were reported in 95.3% and 85.7%, respectively. PMID- 20836373 TI - [Learning curve of arthroscopic hip surgery]. AB - BACKGROUND: Hip arthroscopy has become an increasingly used technique in orthopedic surgery; the learning curve of this procedure has been discussed recently. The purpose of this study is to assess the learning curve of arthroscopic hip surgery using the complications occurred during the surgery as an objective parameter to measure the outcomes. METHODS: Hip arthroscopic surgeries were performed. Patients were divided into two groups, group A corresponded to the learning curve of the first surgeon and group B includes the remaining surgeries. The demographic, surgical, functional and complications data for both groups were collected. RESULTS: Group A: 30 patients were included, the traction time during surgery was a mean of 75 minutes (range: 45-120). Five complications occurred (16.6%), all of them related to transient neuropraxia of the pudendal nerve. Group B: 67 patients were included, traction time during surgery was a mean of 63 minutes (range: 35-90), 2 complications (2.9%) occurred. CONCLUSIONS: Before performing hip arthroscopy it is necessary to have knowledge of arthroscopic surgery and the regional anatomy, and to have received specific training, given that this technique involves a long learning curve. PMID- 20836374 TI - [Study of the feasibility of lateral meniscal repair including the popliteal tendon with a knee simulator]. AB - BACKGROUND: Although the indications for lateral meniscal repair are well established, some aspects are still controversial. The classic recommendation is to avoid going through the popliteal tendon with sutures, even though this is at times difficult to achieve. The purpose of this paper was to assess the feasibility of a meniscal repair that included the popliteal tendon. METHODS: To this end, nine human fresh frozen knees were used, in which a bucket handle lesion of the lateral meniscus was inflicted. The knees were divided into three groups: Group A (control): meniscal repair was performed with 5 vertical sutures, 2 posterior and 3 anterior to the popliteal fossa; Group B: one stitch was added between the lateral meniscus and the popliteal tendon, and Group C: the additional stitch included the meniscus, the popliteal tendon and the articular capsule. In all cases a lateral condyle osteotomy was performed to access the lateral compartment of the knee. Once the osteotomy had been fixed, the knees underwent 1000 gait cycles and a rotational test using an experimental gait simulator. Then a macroscopic assessment of the meniscal repair and the popliteal tendon was performed. RESULTS: No differences were seen in the previous situation in any of the groups. CONCLUSIONS: In this experimental model the repair of the lateral meniscus including the popliteal tendon did not seem to have any repercussions on suture viability. PMID- 20836375 TI - [Coflex interspinous spacer. Use in degenerative lumbar disc herniation]. AB - INTRODUCTION: A retrospective study was performed in patients with a lumbar disc herniation treated with the Coflex interspinous U implant. MATERIAL AND METHODS: A total of 200 patients who underwent surgery for lumbar disc herniation were evaluated; 100 were assigned to the Coflex group and 100 underwent microsurgery only. A clinical assessment and serial X-rays were performed. All patients were followed-up for 5 years. RESULTS: Our study reveals that the use of the device was more effective (statistically significant) for delayed instability than the surgical technique by itself (p < 0.01). CONCLUSION: The use of this device delays vertebral collapse and therefore the instability of the operated segment. PMID- 20836376 TI - [Advanced tomographic images of monoarticular tuberculosis. A case report]. AB - It is known that cases of osteoarticular tuberculosis have a good prognosis from the standpoint of functionality, if they are detected and treated early on. The typical presentation of monoarticular tuberculosis begins with irradiating articular pain, swelling, loss of mobility, nocturnal fever, and weight loss; most cases present six months after the onset of symptoms. The X-ray studies aimed at finding Phemister's triad, as well as multi-slice CT scan or MRI may suggest the diagnosis. CLINICAL CASE: We report the case of a 21-year-old female patient with a diagnosis of a tumor in the left knee, with a probable period of pulmonary tuberculosis of 3 months which resolved spontaneously. Radiologically, we found images compatible with articular destruction suggestive of tuberculosis; this is the reason why multi-slice CT was performed with plain and contrast multiplanar and volumetric reconstructions. DISCUSSION: In cases of monoarticular tuberculosis a comprehensive and multidisciplinary assessment is required with plain and advanced imaging to make a certain diagnosis. The topographic study with multiplanar and volumetric images has specific characteristics that make it a useful resource for diagnosing osteoarticular tuberculosis. CONCLUSIONS: A multidisciplinary assessment is required with a thorough case history, laboratory tests and imaging studies that confirm the presumptive diagnosis. We think that the study that included topographic images with multiplanar and volumetric reconstructions was fundamental to this diagnosis, as there are no similar reports in the current literature. PMID- 20836377 TI - [Polyethylene. Second part]. PMID- 20836378 TI - [Studies on the biological and genetic characteristics of a highly neurovirulent Japanese encephalitis virus strain SA4]. AB - The biological and genetic characteristics of a highly neurovirulent JE virus strain SA4 were studied. Mice were inoculated intracerebrally with strain SA4 and SA14, and observed for 14 days, respectively. On different days, mice brains were harvested for titrations of the virus content in the brains. Full-length genome of SA4 was sequenced and compared with SA14 as well as other JE virus strains in the world. The results indicated that the mice inoculated by SA4 induced sickness and death more rapidly (24 hours faster) than those induced by the SA14. The virus titers in the brains of mice infected with SA4 were 0.5-1.0 lg PFU/mL higher than that infected with SA14. The sequence comparison indicated that the nucleotide and amino acid homology between SA4 and the other 21 JE strains were 84.6%-99.0% and 95.2%-99.7% respectively. Comparison with strain SA14 revealed that there were 17 amino acid differences between the two strains, of which 5 were in the E protein region. The results demonstrate that strain SA4 is a highly neurovirulent strain. The substitutions of the 17 amino acids in the SA4 strain can be the molecular basis for the biological characteristics of high neurovirulence. PMID- 20836379 TI - [The development of neutralizing human antibodies against rabies virus]. AB - A combinatorial human Fab library to the rabies virus was constructed using antibody genes derived from the blood of vaccinated donors. The library were panned and selected on purified rabies virus particles of aG or CTN strain with phage display. Eleven unique human Fab antibodies specific for the rabies virus glycoprotein were obtained by ELISA, IFA and DNA sequences analysis of these antibodies. Among these Fab antibodies, five human Fab antibodies were converted to full-length human IgG antibodies with recombinant baculovirus system. The five full-length human IgG antibodies were tested in vitro for rabies virus neutralization, resulting in all specificities to neutralize the virus. The obtained human anti-rabies antibodies lay the basis for the production of cocktail of anti-rabies monoclonal antibody with chinese intellectual property. PMID- 20836380 TI - [Construction of a dual-luciferase co-expression vector and its characteristics in vitro and in vivo]. AB - A novel dual luciferase expression vector was designed and its expression characteristics were studied in vitro and in vivo. Firstly, the Gluc and Fluc genes were connected via the TaV 2A sequence by overlaping PCR, and inserted into the expression vector pAAV2neoCAG, obtaining the recombinant plasmid pAAV2neoCAG Gluc-2A-Fluc. Then pAAV2neoCAG-Gluc-2A-Fluc was transfected into BHK21 cells and the activity of Gluc and Fluc in the supernatant and cell lysates were assayed respectively. Results showed that both Gluc and Fluc were expressed successfully. The Gluc was mainly detected in the culture media while the Fluc was mostly within cells. The activity of Gluc in the supernatant increased gradually with time while the Fluc activity in cells almost kept stable. To investigate the expression of pAAV2neoCAG-Gluc-2A-Fluc in vivo, the plasmid was hydrodynamically injected into BALB/c mice through tail vein. The Gluc activity was assayed in a small volume of blood taken by tail vein at different time points. Results showed that Gluc was expressed stably at least 7 days. Live bioluminescence imaging technology was used to compare the expression characteristics of Gluc and Fluc. Whole body imaging was seen when coelenterazine, a specific substrate for Gluc, was injected, and the imaging signals decreased rapidly within 10 minutes. Liver imaging was showed when Flue specific substrate named D-Luciferin was injected, and the imaging remained stable at least for half an hour. The dual luciferase expression vector pAAV2neoCAG-Gluc-2A-Fluc combines the advantages of the secreted report gene Gluc and the non-secreted report gene Fluc, and will provide a new tool for cell labeling and tracing. PMID- 20836381 TI - [Complete genome sequence of Coxsackievirus B5 (CVB5/09) strain isolated in China and its phylogenetic analysis]. AB - An outbreak of hand foot and mouth disease occurred in Shang dong, China in 2009. Almost 20% of patient's swabs was positive for Coxsackie virus B5 (CVB5) identified by RT-PCR and sequencing. It was suggested that CVB5 may be another important pathogen for HFMD. Fifteen pairs of overlapping primers were designed and the genome sequence was sequenced. The genome of CVB5 was 7 399 nt in length, coding for 2 185aa. The genome displayed 80.6%-85.3% nucleotide sequence identity and 96.1%-96.9% amino acid sequence identity with another three CVB5 respectively. Phylogenetic analysis showed that different segment of genome underwent a distinct evolutionary and selective pressure. Simplot analysis displayed no evident recombination between genome of CVB5 and other HEV B viruses. The complete and characterized genome of CVB5/09 provides further insight into the genetics of CVB5 and other HEV B viruses, aiding in the surveillance and control of HFMD. PMID- 20836382 TI - [Distribution of HIV-1 subtype and prevalence of HIV-1 drug resistance in Liuzhou and Nanning]. AB - To investigate HIV-1 subtype distribution and prevalence of HIV-1 drug resistance in Liuzhou and Nanning, a total of 304 HIV-infected subjects or AIDS patients from Liuzhou and Nanning were recruited. Whole blood was withdrawn from a peripheral vein of each subject. HIV RNA were extracted from plasma, and subjected to PCR amplification targeting HIV pol gene fragment and DNA sequencing. Sequences obtained were subtyped by phylogenetic analysis. Two subtypes, CRF01_AE and CRF07_BC, were found in subjects from Liuzhou, accounting for 75.2% and 24.8%, respectively. Subtype CRF01 AE, CRFO8_BC, B, and C were found in subjects from Nanning. CRF01_AE and CRF08 BC were still the dominant strains in Nanning, accounting for 85.8% and 11.5%, respectively. Sequences were also analyzed for drug resistance mutations, and rates of drug resistance were calculated. The rate of drug resistance was 3.3% in ART-naive subjects from Liuzhou, and 8.7% in the ART-experienced. For patients from Nanning, the rate was 1.4% in ART-naive subjects, and 27.5% in ART-experienced subjects. PMID- 20836383 TI - [Consecutive five-year follow-up analysis of specific IgG antibody of 22 cases of SARS patients after recovery]. AB - To study IgG antibody persistence and temporal change in SARS coronavirus (SARS CoV) infected patients, 22 patients recovered from SARS in Beijing were recruited and followed-up from 2004 to 2008, serum samples from patients were collected every year. We checked and analyzed the SARS-CoV IgG antibody (Ab) for five consecutive years using the commercial ELISA test kit. The results showed that: all of the serum were SARS-IgG antibody-positive the first year after recovery, the titer of most serum remained at high levels at the 2ed and 3rd year post infection. The Ab titers significantly declined at 4th year post infection. The IgG Ab was almost undetectable after 5 years post infection. In conclusion, SARS CoV IgG Ab can be maintained for more than 3 years post infection, however, the titer of IgG Ab has declined markedly 4 years later. These data provide a useful reference for diagnosis and control of SARS infection, the evaluation of immune response and vaccine efficacy. PMID- 20836384 TI - [Genome sequencing and genetic analysis of a natural reassortant H5N1 subtype avian influenza virus possessing H9N2 internal genes]. AB - Abstract:One H5N1 subtype avian influenza virus, A/duck/Shandong/009/2008 (Dk/SD/009/08), was isolated from apparently healthy domestic ducks in some live bird market in East China during our epidemiological surveillance. To investigate the genetic composition, Dk/SD/009/08 was subjected to genome sequencing. The amino acid motif of cleavage site was "PLRERRRK-R/GL", which was consistent with the characterization of the HPAIV. According to the newest unified nomenclature system of H5N1, Dk/SD/ 009/08 was classified into Clade 2.3.4. The BLAST results showed that four gene segments (HA, NA, NP and NS) had the highest nucleotide identities with H5N1 subtype AIVs whereas the remaining four (PB2, PB1, PA and M) displayed the closest relationship with H9N2 subtype. Therefore, Dk/SD/009/08 might be a natural reassortant virus. The phylogenetic analysis further indicated that G1-like H9N2 subtype AIVs which was prevalent mainly in quails of Southern China might provide the internal genes for Dk/ SD/009/08. PMID- 20836385 TI - [Sequence analysis of the matrix protein and fusion protein genes of a field peste des petits ruminants virus strain from Tibet, China]. AB - The nucleotide sequences of M and F genes from a field strain of peste des petits ruminants virus (PPRV) ("China/Tib/Gej/07-30") was firstly determined. The M gene was 1 483 nucleotides in length with a single open reading frame (ORF), encoding a protein of 335 amino acids. The F gene was 2411 nucleotides in length, encoding a protein of 546 amino acids. The resulting nucleotide sequence and the deduced amino acid sequences were compared with the homologous regions of other PPRV isolates. The nucleotide sequences of M and F genes of the "China/Tib/Gej/07-30" was 92.4%-97.7% and 85.5%-96.1% identical to other PPRV isolates, respectively, while a homology of 97.0%-98.2% and 94.3%-98.2% could be observed at the amino acids level respectively. Several sequence motifs in the M and F genes had been identified on the basis of conservation in the PPRVs and the morbilliviruses. The 3' untranslated region of M gene was 443 nucleotides in length with 82.4%-93.5% identical to other PPRV isolates. The 5' untranslated region of F gene was 634 nucleotides in length with 76.2%-91.7% identical to other PPRV isolates. PMID- 20836386 TI - [Construction and sequencing of full-length cDNA of peste des petits ruminants virus]. AB - To develop a reverse genetics system of Peste des petits ruminants virus(PPRV), five pairs of oligonucleotide primers were designed on the basis of the full length genomic sequence of PPRV Nigeria 75/ 1 strain. Using RT-PCR technique, five over-lapping cDNA fragments, designated as JF1, JF2, JF3, JF4 and JF5, respectively, were amplified, followed by cloning into pcDNA3.1(+)vector. An AscI restriction enzyme site and a T7 promoter sequence were introduced immediately upstream of 5'-end, while a PacI restriction enzyme site was engineered downstream of 3'-end. Using pok12 as a plasmid vector, the full-length cDNA clone pok12-PPRV of Nigeria 75/1 was assembled by connecting the five cDNA fragments via the unique restriction endonuclease site of PPRV genome. The resultant nucleotide sequence of the PPRV Nigeria 75/1 strain in the study was compared with other members of genus morbillivirus, and phylogenetic analysis was used to examine the evolutionary relationships. The results showed that PPRV Nigeria 75/ 1 was antigenically closely related to Rinderpest virus and Measles virus. Successful construction of full-length cDNA clone of PPRV Nigeria 75/1 strain lays the basis rescuing PPRV effectively and enables further research of PPRV at molecular level. PMID- 20836387 TI - [Genome sequencing and analysis of a peste des petits ruminants virus isolate, China/Tib/07]. AB - Peste des petits ruminants virus is a member of Morbillivirus Paramyxoviridae. The complete genome of a Peste des petits ruminants virus (PPRV) isolate, China/Tib/07 was sequenced and molecular characteristics was analyzed. The internal sequences of the virus genome were amplified by RT-PCR with primers designed according to the published data in GenBank, while the sequences of the 3' and 5' ends of the genome were determined by RACE. Amplification products were directly sequenced,assembled and analyzed with DNAStar4.0. Results showed that China/Tib/07 genome consisted of 15 948 nucleotides in length, encoding six structural proteins and two non-structural proteins just like other known PPRV genomes. Phylogenetically, the virus genome shared homology of 91.6%-98.1% with Southwest Asian isolates among PPRV strains and the highest homology of 64.3% with rinderpest virus among morbillivirus members. PMID- 20836388 TI - [Construction of an infectious clone of pseudorabies virus strain ZJ genome maintained as a bacterial artificial chromosome]. AB - pHA2 plasmid sequence,with Bacterial Artificial Chromosome(BAC) vector and the GFP expression cassette, was introduced into the UL23(TK) gene of Pseudorabies virus(PRV)strain ZJ by homologous recombination,and the recombinant PRV (rPRV HA2) was confirmed and isolated by plaque purification. The circular genome of rPRV-HA2 was electroporated into Escherichia coli strain DH10B and then the PRV BAC (pPRV) was recovered. The transfection of pPRV into VeroE6 cells resulted in productive infection. The rescued virus isolated following transfection was indistinguishable from rPRV-HA2 in cytopathic effects (CPE) and replication curve in vitro. The growth kinetics of the viruses indicated that partial deletion of TK gene and BAC vector insertion had no effect on the viral titre and plaque size in vitro. The PRV BAC system will enable quick and reliable manipulation of the viral genome for the functional investigation on the PRV genes and the development of PRV vector in vaccine. PMID- 20836389 TI - [The research and application of inhibitory effect of RNA-based strategies on SARS]. PMID- 20836390 TI - [Research advances on herpervirus gI gene and its encoding protein]. PMID- 20836391 TI - Early noninvasive diagnosis of neurodegenerative diseases. AB - This paper reviews the contemporary trends in the pathobiochemistry of neurodegenerative disorders with respect to their early predictive diagnosis and possible treatment interventions. If we consider the current epidemiological data related to neurodegenerative disorders, medicine is going to face in the near future latent pandemic situations. The introduction puts an emphasis on the emerging importance of one major cluster of neurodegenerative disorders: diseases of the abnormal protein beta-conformation. The cluster includes such significant diseases as Alzheimer, Pick, Huntington, Parkinson disease, as well as the transmissible spongiform encephalopathies (Creuzfeldt-Jakob disease). The pathogenetic mechanisms in the determination of this group of disorders are explored with an emphasis on the impairment of post-synthetic chaperone correction. The central role of a number of such protein products is discussed. In particular the pathobiochemical mechanisms concerning the formation of beta amyloid, alpha and beta synucleins, scrapie isoform of the prion protein are presented. A new diagnostic principle allowing the early and specific diagnosis of the conformation diseases protein via amplification techniques is presented. These methods compete in sensitivity with the PCR methods and shows promises for effective treatment. In conclusion, beta-pathies are considered a suitable example for the modern concept of cluster and prototype diagnosis in medicine and especially in clinical neurosciences. PMID- 20836392 TI - Clinical tolerance in large field radiotherapy--the knowledge gained over the last ten years. AB - Malignant disorders are still far from being successfully managed in spite of the apparent progress achieved by surgical treatment, high energy radiotherapy (RT) and chemotherapy (CHT). They keep being the second most frequent cause of lethal outcomes both in Bulgaria and in most countries of the world. One of the promising approaches to increasing the efficaciousness of treatment is development and use of methods that are in full accord with the modern requirements of a complex therapy. Over the last fifty years, large field radiation techniques, applied as systemic therapy in oncology, have been investigated and established. These techniques show the transition in oncology to using actively various variants of large field radiotherapy (LFR), the "heavy artillery" of oncoradiologic practice, as an alternative or adjunct therapy to chemotherapy (CHT). In the present paper we review the current knowledge in the field and present the clinical experience accumulated over the last ten years with respect to clinical tolerance in the major large-field radiotherapy techniques--total body irradiation, half body irradiation, whole abdominal irradiation, total and partial lymphoid irradiation. Described in detail are the contemporary knowledge about clinical and hematologic tolerance in total body irradiation as part of the myelo- and nonmyeloablative conditioning regimens as well as in half body irradiation as a systemic therapy in oncology. We also present the amassed experience in clinical tolerance in partial body irradiation in the form of whole abdominal and total or partial lymphoid irradiation. Another point worth noting based again on the experience gained over the last ten years is that for LFR we need to develop a radiotherapy technique that is designed carefully to achieve an optimal therapeutic effect that should include the disease control, good clinical tolerance and reduction of post-radiotherapy sequelae. PMID- 20836393 TI - DNA methylation in patients with colorectal cancer--correlation with some clinical and morphological features and with local tumour invasion. AB - AIM: To study quantitatively the promoter methylation of hMLH1, p16INK, TIMP3 and TPEF genes in patients with colorectal cancer and synchronous polyps, and correlate it with some clinicomorphological features. METHODS: DNA was extracted from all studied tumours and the corresponding normal mucosa. Microsatellite instability was analysed using two mononucleotide (BAT 25 and BAT 26) and three dinucleotide markers (D2S123, D5S356, D17S250) and automated DNA sequencing. Quantitative analysis of methylation was performed using DNA bisulfite modification, PCR with biotinylated primers, visualisation by 2% agarose gel electrophoresis and pyrosequencing. RESULTS: High methylation levels of hMLH1 and p16INK were found in elderly patients (mean age 73.8 +/- 9.5 years and 65.7 +/- 16.6 years, p < 0.03, t-test). Proximal tumours were more often associated with microsatellite instability (p < 0.05, Fisher's test) and higher level of methylation of hMLH1, p16INK and TIMP3 (p < 0.02, Kruskal-Wallis test), while tumours with poor differentiation tended to have higher methylation of the p16INK gene (p < 0.02, Kruskal-Wallis test). Local tumour invasion was correlated with the level of methylation of hMLH1, TIMP3 and the CpG island methylator phenotype (CIMP) status. Tumours with liver metastases showed a lower level of TIMP3 methylation than tumours with no systemic invasion (p < 0.05, Kruskal-Wallis test). We found concordance of methylation in 56% of the cases with colonic cancer and synchronous adenomas; the remaining 44% were discordant. CONCLUSIONS: Tumours with microsatellite instability, high level methylation and CIMP have distinctive clinical and morphological features. The level of hMLH1 and TIMP3 methylation and CIMP status can be correlated with the local tumour invasion. Different mechanisms, even for one and the same patient, can be responsible for the development of more than one third of the synchronous polyps and carcinomas. PMID- 20836394 TI - Serotonin-producing cells in human gastric mucosa--immunohistochemical and electron microscopic study. AB - The great many hormones released by the endocrine cells of the glands and lining epithelium of gastric mucosa determine its significance for the processes in the gastrointestinal tract. One of these hormones, serotonin, plays an important role in the regulation of the motility, secretion and sensation in the gastrointestinal tract. The aim of the present study was to conduct immunohistochemical and electron microscopic studies of serotonin-producing EC cell of gastric mucosa. MATERIAL AND METHODS: Gastric mucosa biopsies were obtained and studied immunihistochemically for serotonin expression in the mucosa endocrine cells. Electron microscopic study was performed to specify the processes of synthesis, accumulation and release of secretory product by those cells. RESULTS: The immunohistochemical study revealed a considerable number of serotonin-containing EC cells scattered in the lining epithelium and between the glands in the corpus and pyloric region of the stomach. The electron microscopic study followed the stages of formation of the secretory granules from the initial accumulation of granular substance, its membrane packing and formation of mature granules to their disintegration in the secretory process. CONCLUSIONS: Serotonin as a neurotransmitter and gastrointestinal hormone appears to be a key to understanding a number of symptoms of gastrointestinal disorders like nausea, vomiting, pain, diarrhea and constipation. A detailed study of serotonin functions in the gastrointestinal tract realised through different types of receptors, and of the development of specific antagonists and agonists to these receptors would open up new opportunities for a more efficient treatment of gastrointestinal disorders. PMID- 20836395 TI - 11beta hydroxysteroid dehydrogenase type 2 in the adrenal gland by testosterone withdrawal of adult rats. AB - AIM: 11beta hydroxysteroid dehydrogenase (11beta HSD) catalyzes the interconversion of glucocorticoids to inert metabolites in man and rodents and plays a crucial role in regulating corticosteroid hormone action. The physiological role and regulation of 11beta HSD type 2 in the adrenal gland remains obscure. Therefore, the aim of the present study was to establish the pattern of 11beta HSD type 2 expression in rat adrenal gland under conditions of testosterone withdrawal. MATERIAL AND METHODS: We performed immunohistochemical analyses of adrenal gland sections of ethane dimethanesulphonate (EDS)-treated adult rats. RESULTS: In controls, strong positive 11beta HSD type 2 signals were detected in the adrenal cortex cells, but not in the medulla. We observed the lowest 11beta HSD type 2 expression intensity 7 days after initial treatment with ethane dimethanesulphonate (EDS) followed by progressive increase in the immunoreactivity toward days 14 and 21. Maximal staining intensity of 11beta HSD type 2 in the adrenocorticocytes was found by day 35 after EDS treatment. CONCLUSIONS: By using the EDS model the present study provides new data about 11beta HSD type 2 expression in the adrenal gland under conditions of testosterone withdrawal of adult rats. Our results elucidate further the functional significance of 11beta HSD system in rat adrenal gland and the regulatory role of testosterone in its activity. PMID- 20836396 TI - Aesthetic perception of dental fluorosis--opinions of dentists and non specialists. AB - Aesthetic perception of the changes in teeth appearance is one of the factors that makes a person undertake a dental treatment. OBJECTIVE: The aim of this study was to survey dentists' and non-specialists' aesthetic perception of dental fluorosis. PATIENTS AND METHODS: We recruited 120 young people (age range 18-22 years with little knowledge of dental fluorosis and 120 randomly selected dentists. Evaluation of the abnormalities in the teeth aesthetic appearance was conducted using cards specially designed for the purpose. RESULTS: The results suggest that changes in dental fluorosis, even in the mildest forms, are perceived as deviations in the aesthetic appearance of teeth. Non-specialists are more tolerant towards the changes characteristic of mild dental fluorosis compared with their reaction to other conditions that result in deviations in the type of dentition as a whole. CONCLUSION: Further studies are needed to more precisely determine the role of aesthetic perception in determining the indications for the complex treatment of dental fluorosis. PMID- 20836397 TI - Dental anxiety in adults in Bulgaria. AB - The anxiety experienced by some patients before or during dental visits poses a problem for patients and the dental practitioners alike. Some people consider them a stressful experience which manifests itself as anxiety, fear and even phobia and results in avoidance of proper dental care. The dental anxiety, dental fear and dental phobia stand out against the background of general anxiety. The aim of the present study was to investigate dental anxiety in Bulgaria by means of a self-assessment scale. MATERIAL AND METHODS: The self-assessment Dental Anxiety Scale (DAS), developed by N Corah, was used in the form of a questionnaire containing questions about the gender, age, education and occupation of respondents. Subjects were 746 adults aged 18-82 years living in urban areas. Individual and group interviews were conducted directly with them. RESULTS: The respondents with moderate dental anxiety were the most of all subjects (35.5%, DAS score: 9-12 points), followed by the anxiety-free subjects (34.6%, 4-8 points). The third most numerous group was the high anxiety group (18.2%, 13-14 points), followed by the subjects with severe anxiety (11.7%, 15-20 points). The mean score was 10.26 +/- 0.14. We found a statistically significant correlation between anxiety, age (P < 0.05), education (P < 0.05) and type of labour (manual or mental labour) (P < 0.01). No significant difference was found between anxiety and sex (P > 0.05). CONCLUSIONS: The percentage of people scoring high on dental anxiety (DAS 13-20) in Bulgaria (29.9%) is considerably higher than that in some European and North American countries. The present study is the first in Bulgaria on dental anxiety. Further studies are needed to reveal other factors related to dental anxiety. PMID- 20836398 TI - Contemporary diagnostic and therapeutic abilities in childhood thyroid-associated ophthalmopathy with a clinical case description. AB - INTRODUCTION: Eye symptoms are comparatively frequent in the clinical evidence of Basedow's disease in childhood. Severe forms of thyroid-associated ophthalmopathy are casuistic in pediatric patients. Early diagnose and evaluation of the severity of thyroid orbitopathy and relevant specialist treatment are key prognostic factors according to the contemporary consensuses. AIM: The aim of the present study was to make a review of the contemporary diagnostic and therapeutic abilities in pediatric patients with Basedow's disease and thyroid-associated ophthalmopathy. We present a clinical case of severe TAO in an 11-year-old girl with Basedow's disease. The combined therapeutic scheme based on the EUGOGO (European Group on Graves' orbitopathy) consensus of 2008 includes not only thyrostatics but also local ophthalmic agents and pulse corticosteroid therapy, followed by an alternating dose regimen. The favourable outcome of the treatment is determined to a great extend by the close collaboration between the pediatric endocrinologist and the ophthalmologist. CONCLUSION: It is concluded that children with thyroid-associated ophthlmopathy should promptly be referred to a specialized centre for evaluation of the severity of orbitopathy and an adequate therapy. This is of crucial importance for the preservation of patient's sight. PMID- 20836400 TI - Unusual intramuscular lipoma of deltoid muscle. AB - Lipomas are common soft tissue tumors usually located under the skin. Nevertheless, intramuscular lipomas of deltoid muscle are unusual tumors. We present a case of 74-year-old woman with an intramuscular like clepsydra lipoma of deltoid muscle. The lesion was a palpable soft mass at the lateral side of the humerus. The patient had no previous history of trauma. The main symptom was pain only in abduction and extension. Imaging, pathological findings and surgical excision are discussed. PMID- 20836399 TI - Spontaneous cervical epidural hematoma. A case report. AB - Spontaneous spinal epidural hematoma is a rare disorder. We present a case of a 55-year-old man who was awakened by severe pain in the neck and shoulders and inability to move his arms and legs. He was admitted to the clinic as an emergency. His physical status showed no abnormalities. The local status presented with roughly expressed cervical vertebral syndrome. Neurological examination found quadriplegia of acute onset. Distal parahypesthesia with sensory level at the nipples was found. The patient suffered urine retention. Laboratory blood tests showed no coagulation disorder. Spiral computed tomography of the cervical region was performed. The CT image revealed a muff-shaped acute epidural hematoma around the cervical dural membrane with lower thickness on the right side and levels from C2 to C4. Emergency right-sided hemilaminectomy of C3 vertebra was performed. A hard blood clot forming acute epidural hematoma was removed. The patient recovered completely for ten days after the surgery. CONCLUSIONS: In sudden occurrence of neck pain associated with neurological deficit in the arms spontaneous cervical epidural hematoma should be suspected. Spiral scanner and magnetic resonance are imaging techniques of choice in these patients. The favorable outcome of the disease depends on the prompt diagnosis and emergency removal of the hematoma. PMID- 20836401 TI - Survey of the curricula of public health training programs across Bulgaria and Greece: opportunities for future collaboration. AB - Increased communication between neighboring countries may bring to the foreground the common health hazards of the populations but it also creates opportunities for joint actions, especially in the field of public health where knowledge and expertise are critical factors for effective collaboration. In this light, a questionnaire based survey on the curricula of public health training programs in Bulgaria and Greece was conducted in order to investigate any similarities and discrepancies. The survey focused on the various characteristics of the institutions that provide training in public health, e.g., the structure and duration of each course and the evaluation procedures. The results showed that the principal subjects such as public health, epidemiology, biostatistics and health promotion are present both in the Greek and Bulgarian curricula. Similarities are observed in other subjects as well, but differences exist as to whether these subjects are core or elective. The Greek curricula are more flexible (greater number of elective subjects) whereas Bulgarian curricula are structured around a wider core. Differences were observed in the duration of the programs, the teaching methodology and the issues of evaluation/accreditation. Collected data can serve as a basis for establishing a fruitful dialogue and contribute to the achievement of consensus in public health policy planning and actions for both neighbouring countries. PMID- 20836402 TI - [Antibiotic susceptibility of blood-borne Streptococcus pneumoniae and efficacy assessment of respiratory quinolones using Monte Carlo simulation]. AB - We analyzed Streptococcus pneumoniae isolates from the bloodstream between April 2005 and February 2007. We analyzed isolates of 28 strains from medical facilities in Gifu prefecture to determine antibiotic susceptibility, genotype of penicillin-binding protein (PBP) genes and macrolide resistant genes. We also assessed the efficacy of respiratory quinolones using Monte Carlo simulation. Garenoxacin (GRNX) and moxifloxacin (MFLX) showed the lowest MIC90 value of 0.125 microg/mL, followed by MIC90 of imipenem (IPM) of 0.25 microg/mL and tosufloxacin (TFLX), MIC90 of meropenem (MEPM) and vancomycin (VCM) of 0.5 microg/mL. Twenty two strains possessed at least one mutation in PBP-encoding genes pbp1a, pbp2x or pbp2b and seven strains possessed all three mutant alleles. Twenty-two strains possessed either of macrolide resistant genes ermB or mefA, and one strain possessed both. On efficacy assessment, we calculated the probability of target attainment for free-drug area under the curve (fAUC)/MIC ratio (fAUC/MIC). GRNX and MFLX showed a probability of 90% or more at fAUC/MIC of 30 and 125, each considered effective against Gram-positive bacteria and suppression of resistance development, furthermore, GRNX showed a probability of 89.7% at fAUC/MIC of 250. PMID- 20836403 TI - In vitro antimicrobial activity of cefditoren and other oral antibiotics against Streptococcus pneumoniae, isolated from children with community acquired respiratory tract infections. AB - The antibacterial susceptibility to frequently prescribed antibiotics of Streptococcus pneumoniae isolated from the pediatric patients with acute respiratory infectious diseases was investigated in a study of three medical institutions in Korea. Total 143 clinical isolates of S. pneumoniae were available for susceptibility tests between May 2003 and July 2007. Antimicrobial susceptibility data for S. pneumoniae were analyzed by using agents of amoxicillin, cefaclor, cefuroxime, cefdinir, and cefditoren as the test antibiotics. The prevalence of each resistance class, penicillin-resistant S. pneumoniae (PRSP) were high with the proportion of MIC range (susceptible = 8.4%, intermediate resistance = 18.2%, resistance = 73.4%). MIC90 and susceptible (S) rate of antimicrobial agents to the strains tested were amoxicillin (MIC90 = 4 microg/ml, S = 76.2%), cefaclor (MIC90 = 128 microg/ml, S=8.4%), cefuroxime (MIC90 = 16 microg/ml, S = 24.5%), cefdinir (MIC90 = 16 microg/ml, S = 21.8%), and cefditoren (MIC90 = 0.5 microg/ml, S=90.2%) respectively. Against clinical isolates including PRSP, cefditoren demonstrated the strongest antibacterial activity intrinsically among the antibiotics tested. Conclusively, the antimicrobial activity of cefditoren to S. pneumoniae strains isolated from pediatric patients with acute respiratory infection is very high. In South Korea, where the antibiotic resistance ofS. pneumoniae is issued, cefditoren is expected to be used as a primary or secondary antibiotic. Moreover, cefditoren may serve as a useful option for secondary antibiotics after failure of amoxicillin treatment, which is most primarily used for acute respiratory S. pneumoniae infection in children. PMID- 20836404 TI - [Situation of domestic adverse reaction report of antibiotics and chemotherapeutic agents]. PMID- 20836405 TI - [Safety measures against injection antibiotics shock]. PMID- 20836406 TI - [High prevalence of antiviral resistant influenza, and reduced clinical effectiveness of the antivirals against resistant influenza strains]. PMID- 20836407 TI - The Golden Rule isn't. PMID- 20836408 TI - An introduction to the ADEA Commission on change and innovation in dental educatioN. AB - New developments in dentistry are appearing rapidly, and new electronic means for making information available are already in the hands of our dental students. Recognizing a dramatic shift in the landscape, the American Dental Education Association developed, in 2004, the Commission on Change and Innovation. The commission has coordinated a national effort to identify a new dental education curriculum, beginning with a revision of the Competencies for the New General Dentist. From this starting point, the association is working to identify foundation knowledge and skills that support these competencies and new assessment methods. There is now a network of faculty liaisons at most schools throughout the United States and Canada. The future will likely see much of dental education delivered in community and other settings besides the traditional lecture room. PMID- 20836409 TI - Sustaininq an educational environment for change and innovation. AB - Sustainability refers to the capacity to continue. For the most part, United States dental schools have shown an amazing ability to endure over the past century. Dental schools have continued through fluctuations in application cycles and through persistent faculty shortages. Today, dental schools, particularly public institutions, find themselves faced with draconian budget cuts as states slash funding to higher education. While dental schools face threats, they also enjoy unprecedented opportunities. Scientific advances, particularly in genetics and molecular biology, presage the emergence of new modalities of patient care. The desirability of the dental profession as evidenced by the demand for dental services and the rising income of dentists is at an all time high. Public awareness about the importance of oral health care continues to grow. PMID- 20836410 TI - Guidinq change one school at a time. AB - Liaison teams have been developed in order to ensure that national initiatives identified in the American Dental Education Association's Commission on Change and Innovation (ADEA CCI) are implemented at the level of individual schools. Teams of four faculty members each have been identified at 43 United States and Canadian schools. These teams receive training at ADEA annual meeting and at summer institutes. Representative projects from three schools are described. PMID- 20836411 TI - The San Antonio CATs Initiative. AB - There is evidence from medicine that schools and practitioners are slow to adopt new and proven effective treatments while marketing efforts lead practitioners to too quickly adopt unproven modalities. To address these problems, the dental school at the University of Texas Health Sciences Center at San Antonio, has developed a program designed to teach students, faculty, and practitioners the skills of accessing the literature as an intrinsic part of treatment. The Critically Appraised Topics (CATs) program is described and evidence is presented showing that participants can be taught to prepare high-quality summaries of the literature pertinent to clinical problems. PMID- 20836412 TI - An assessment strateqy whose time has come for documenting competency in dental education and beyond. AB - The Institute of Medicine report on dental education in the mid-1990s called specific attention to the need for authentic assessment of student progress and outcomes. This corresponded with the advent of competency-based dental education, resulting in recognition of the need for new methods to assess dental students knowledge, skills, and values in the context of beginning independent dental practice. The portfolio approach to assessment uses a rich collection of cumulative evidence from multiple sources in ways that address this need. Because students take some responsibility for maintaining their portfolios, the competency of reflective critical thinking can also be assessed by means of portfolios. PMID- 20836413 TI - Chanqes in dental school curricula, 2003-2009. AB - This 2009 study of dental school curricula follows a similar one conducted in 2002-2003. Through a Web-based survey, the authors gathered information from dental schools about: (a) trends in curricular change over seven years; (b) changes underway in dental school curricula; (c) significant challenges to curricular innovation; and (d) projected trends in curricular change and innovation. In a significant change from the 2002-2003 study, a high proportion (91%) of the responding schools require community-based patient care by all students, with just over one-half ot them requiring five or more weeks of such experience. Respondents reported that priorities for future curriculum modification included: creating interdisciplinary curricula that are organized around themes, blending the basic and clinical sciences, provision of some elements of core curriculum in an online format, developing new techniques for assessing competency, and increasing collaborations with other health professions schools. Respondents identified training for new faculty members in teaching skills, curriculum design, and assessment methods as the most critical need to support future innovation. PMID- 20836414 TI - Fast forward five years: has dental education changed? AB - Five years ago, the American Dental Education Association created the Commission on Change and Innovation in Dental Education (ADEA CCI). Much positive movement in dental education has occurred since the CCI's inception. This paper reviews some of the initial change motivation and assesses the progress to date, taking note of unresolved issues that remain. PMID- 20836415 TI - Ethical considerations in the use of nitrous oxide in pediatric dentistry. AB - Nitrous oxide (N2O) has become a routine intervention in contemporary American dental practice, especially in the management of children. However, routines translate to confidence which in turn may lead to overconfidence, such that possible risks and misuses are insufficiently acknowledged. This article ethically evaluates the use of nitrous oxide as a practice routine in treating children. Nitrous oxide administration is analyzed in reference to three internationally acknowledged principles of dental ethics: nonmaleficence, beneficence, and patient autonomy. In reference to the principle of nonmaleficence, the potential for adverse effects of N2O is discussed, particularly when it is administered in conjunction with other sedatives and anesthetics. The importance of abiding by clinical protocols is emphasized. Next, in reference to the principle of beneficence, the authors address the problematic application of N2O for the benefit of individuals other than the patient (e.g., dentists and parents). Finally, the importance of respecting patient autonomy is discussed, specifically the need to obtain explicit consent for N2O. The article supports the continued use of nitrous oxide but advises greater attention to how and why it is administered. Four recommendations are offered for an ethically sound usage. PMID- 20836416 TI - Marketing. AB - There is not enough marketing of dentistry; but there certainly is too much selling of poor quality service that is being passed off as dentistry. The marketing concept makes the patient and the patients' needs the ultimate criteria of marketing efforts. Myths and good practices for effective marketing that will promote oral health are described under the traditional four "Ps" categories of "product" (best dental care), "place" (availability), "promotion" (advertising and other forms of making patients aware of available services and how to use them), and "price" (the total cost to patients of receiving care). PMID- 20836417 TI - Kit's journey: nursing--you can't live without it! PMID- 20836418 TI - Full disclosure of adverse events to patients and families in the ICU: wouldn't you want to know? AB - In the past several years, there has been an increasing focus in our Canadian health care system related to patient safety. The Canadian Disclosure Guidelines, which were released in May 2008, discuss various patient safety initiatives underway across Canada. They emphasize the importance of a clear and consistent approach to disclosure, regardless of the variability in the definitions and interpretations across health care institutions. In addition, they highlight that all patients have the right to be informed about all aspects of their care, and all harm must be communicated to patients regardless of the reason (Disclosure Working Group, 2008). In this article, the authors describe and share our learning experiences, as nurses and students, while working in critical care settings when these guidelines were needed to communicate a harmful incident. Often, health care practitioners only become aware of specific guidelines regarding the disclosure of an adverse event once the incident has occurred. A case study will be discussed to illustrate the benefits of having a policy and a systematic framework in place to support a critical care environment in disclosing errors and adverse events to affected patients and their families. PMID- 20836419 TI - Spacelabs Innovative Project Award winner--2007. Solar system of safety. AB - In 2004, the pediatric intensive unit at the Winnipeg Children's Hospital began a journey into space, engaging in the evolving culture of safety emerging in Canada. This process started with the joining of the Canadian ICU Collaborative on Patient Safety, where the first project focused on decreasing catheter-related blood stream infections (CRBSIs). This single project created the impetus for the mission: 2007 Solar system of safety. The solar system analogy was a powerful methodology to engage staff to travel to the different planets (projects) and step outside of their comfort zone into what some perceived as zero gravity. Planets (projects), in addition to CRBSIs, included safety huddles, safety newsletter, ventilator-associated pneumonia reduction, pediatric rapid response team, and executive walk rounds. PMID- 20836420 TI - Spacelabs Innovative Project Award winner--2008. Megacode simulation workshop and education video--a megatonne of care and Code blue: live and interactive. AB - Skill acquisition and knowledge translation of best practices can be successfully facilitated using simulation methods. The 2008 Spacelabs Innovative Project Award was awarded for a unique training workshop that used simulation in the area of cardiac life support and resuscitation to train multiple health care personnel in basic and advanced skills. The megacode simulation workshop and education video was an educational event held in 2007 in Winnipeg, MB, for close to 60 participants and trainers from multiple disciplines across the provinces of Manitoba and Northwestern Ontario. The event included lectures, live simulation of a megacode, and hands-on training in the latest techniques in resuscitation. The goals of this project were to promote efficiency and better outcomes related to resuscitation measures, to foster teamwork, to emphasize the importance of each team member's role, and to improve knowledge and skills in resuscitation. The workshop was filmed to produce a training DVD that could be used for future knowledge enhancement and introductory training of health care personnel. Substantial positive feedback was received and evaluations indicated that participants reported improvement and expansion of their knowledge of advanced cardiac life support. Given their regular participation in cardiac arrest codes and the importance of staying up-to-date on best practice, the workshop was particularly useful to health care staff and nurses working in critical care areas. In addition, those who participate less frequently in cardiac resuscitation will benefit from the educational video for ongoing competency. Through accelerating knowledge translation from the literature to the bedside, it is hoped that this event contributed to improved patient care and outcomes with respect to advanced cardiac life support. PMID- 20836421 TI - Health care providers' perceptions of family presence during pediatric resuscitation. AB - BACKGROUND: The Pediatric Intensive Care Unit (PICU) team strives to achieve the family-centred care philosophy consistent with the organization's vision and mission. In 2006, a team of nurses began exploration of the evidence on family presence during pediatric resuscitation with the primary goal to integrate this knowledge into practice. From the literature search, it was apparent there was limited published research, especially in a Canadian pediatric setting. This led to a staged research project to explore and, subsequently, integrate family presence during resuscitation into the culture. OBJECTIVES: 1) To explore health care providers' perceptions of family presence during pediatric resuscitation (2007), 2) Based on these findings, develop and integrate a guideline to best support this practice (2008-2009), and 3) Re-examine health care providers' perceptions post guideline implementation (2010). METHODOLOGY: Following approval from the University of Manitoba nursing and education ethics review board and the site research coordinating committee, survey methodology was used to gather data at baseline (2007) and again post implementation (2010). Data were analyzed independently at each time interval and then in comparison to explore the quantitative and qualitative responses. FINDINGS: In 2007, data demonstrated sufficient support to move this project forward. In addition, the survey indentified facilitators and barriers to assist in both the development of an evidence-based guideline and the successful integration into practice. In 2010, the post-implementation survey supported the evidenced-based practice guideline had achieved its goal of integration into practice. PMID- 20836422 TI - Hospitals report on medication safety in Canada. AB - Measurement of safety can be difficult. Given that incident reporting systems rely primarily on voluntary reporting and some types of medication incidents may occur rarely, lack of reports about a particular type of incident cannot be interpreted as evidence that the underlying causes are resolved. Proxy measurements, such as the level of implementation of evidence-based practices known to reduce the risk of a particular incident, may provide an indication of progress toward safer systems. This article includes an overview of some proxy measurements influencing medication use systems in patient care areas, including critical care, as reported in the biennial Hospital Pharmacy in Canada survey. PMID- 20836423 TI - X-rays needn't be x-rated. Interview by Ann-Marie Hardiman. PMID- 20836424 TI - BIOIS presents report on EU mercury strategy. PMID- 20836425 TI - Clinical significance of the carious leison in the mandibular first primary molar. PMID- 20836426 TI - Survey of the provision of crowns by dentists in Ireland. AB - STATEMENT OF THE PROBLEM: The literature is limited on the detailed description of the practice of Irish general dentists in the provision of crowns. PURPOSE OF THE STUDY: To review the provision of crowns by dentists in Ireland and identify opportunities for improving current clinical practices. MATERIALS AND METHODS: A questionnaire was posted to 500 general dentists selected randomly from the Irish Dental Register and 150 responded. Twenty-three laboratories used by these dentists were subsequently surveyed. RESULTS: The Vita Shade Guide was the most commonly used shade guide. Crowns were mainly fabricated using porcelain bonded to metal (51%) followed by all-ceramic (42%) and gold (5%). Plastic Solo trays were the preferred tray for impressions and the laboratory prescription form was the primary means of dentist-technician communication. Dentists and technicians have different preferences for impression trays, impression materials and bite registration, while a significant percentage of dentists (18%) admitted to not disinfecting impressions. Resin or resin-based cements are the preferred means of crown cementation. CONCLUSIONS: This study suggests that the accuracy of restorations could be improved by: adopting a multi-technique approach to shade taking; replacing Solo trays with metal or custom trays for impression-taking; upgrading of the putty-wash technique by using a custom tray with a 2 mm spacer and a heavy-bodied/light-bodied silicone; and, using a two-cord retraction technique, perhaps in combination with electrosurgery or soft tissue laser, to improve marginal accuracy where indicated. PMID- 20836428 TI - Advertising your practice. PMID- 20836427 TI - Fresh-frozen bone: case series of a new grafting material for sinus lift and immediate implants. AB - STATEMENT OF THE PROBLEM: Although autologous bone is considered to be the gold standard grafting material, it needs to be harvested from patients, a process that can be off-putting and can lead to donor site morbidity. For this reason, homologous fresh-frozen bone (FFB) was used in the current study as an alternative graft material. PURPOSE OF THE STUDY: The aim of this study was to evaluate the effectiveness of FFB as a grafting material in complex maxillary sinus lift with immediate implant insertion. METHODS: FFB was obtained from the Veneto Tissue Bank and preserved at -80 degrees C. Twenty-one patients were surgically treated with FFB block grafts in 26 maxillary sinus rehabilitations, with 47 immediate implant insertions, with a reopening phase after six months. All patients underwent orthopanoramic X-rays and CT scans before, immediately after and four months (X-ray only) post surgery. Bone biopsies were performed in order to evaluate the volume and density of the bone grafts, which all showed optimal adherence without complications. RESULTS: Four months post surgery, 64% of grafts showed no evidence of bone resorption or resizing. In all other cases resorption was slight. All implants were clinically osseointegrated, with only one implant failure during the provisional prosthetic loading stage (97.8% success rate). Histological studies confirmed these results, showing the presence of new bone and sparse osteoclastic activity four months post implantation, with 80% mature bone material observed after 12 months. CONCLUSIONS: Use of FFB permits effective bone-adding surgery and immediate implant insertion under local anaesthesia, decreasing both chair time and patient discomfort. PMID- 20836429 TI - Metal ceramic versus all ceramic restorations: part 1. PMID- 20836430 TI - Children's and adults' judgments of the certainty of deductive inferences, inductive inferences, and guesses. AB - Children and adults rated their own certainty following inductive inferences, deductive inferences, and guesses. Beginning in kindergarten, participants rated deductions as more certain than weak inductions or guesses. Deductions were rated as more certain than strong inductions beginning in Grade 3, and fourth-grade children and adults differentiated strong inductions, weak inductions, and informed guesses from pure guesses. By Grade 3, participants also gave different types of explanations for their deductions and inductions. These results are discussed in relation to children's concepts of cognitive processes, logical reasoning, and epistemological development. PMID- 20836431 TI - Positive and negative peer interaction in 3- and 4-year-olds in relation to regulation and dysregulation. AB - Using a sample from the NICHD Study of Early Child Care (N = 435; 219 girls), the authors derived several measures of regulation and dysregulation that predicted, both concurrently and longitudinally, children's positive and negative peer interactions in multiple contexts. Observers rated peer interactions in child care and during dyadic play with a friend, and mothers rated peer behavior. The authors based the derived measures on resistance to temptation (36 months) and delay of gratification (54 months) tasks, as well as observations in child care of children's compliance and defiance with adults at both ages and maternal reports. Preschoolers who had better impulse control and who were more compliant and less defiant with adults engaged more often in friendly, positive, peer play and were less negative in their peer play across contexts. Associations between regulation and dysregulation and peer interaction were broader and more consistent at 54 months than at 36 months. Longitudinally, regulation at 36 months was only modestly associated with more positive and less negative peer play at 54 months. The authors discuss findings in the context of developing self regulation and its importance for early peer relationships. PMID- 20836432 TI - The continued assessment of self-continuity and identity. AB - Studies have found that self-continuity is predictive of a substantial number of important outcome variables. However, a recent series of studies brings into question the traditional method of measuring self-continuity in favor of an alternative (B. M. Baird, K. Le, & R. E. Lucas, 2006). The present study represents a further comparison of measurement methods examining the outcome variables of identity, negative affect, and self-esteem while also exploring the possible moderating roles of culture and relational-interdependent self construal. The results suggest that the methods yield distinctive results with the new method being associated with negative affect, but not with self-esteem or identity. This finding is especially important for the research in the area of identity because self-continuity is seen as being an essential element of identity and the results suggest that traditional identity concepts and measures are not inclusive of this vital component. PMID- 20836433 TI - Children's anticipated responses to hypothetical peers with undesirable characteristics: role of peers' desire to change, effort to change, and outcome. AB - The authors explored the extent to which 5th- and 6th-grade students' anticipated responses to hypothetical peers with undesirable characteristics (e.g., being overweight) are influenced by information that each peer (a) desired (or did not desire) to change the characteristic, (b) exerted effort (or did not exert effort) to change the characteristic, and (c) was successful (or unsuccessful) in changing the characteristic. In general, the children anticipated responding more favorably to peers who were successful in overcoming an undesirable characteristic than those who were unsuccessful. However, across both outcome conditions, peers who wanted to change and exerted effort to change were rated more favorably than were peers who reported no effort to change an undesirable characteristic, regardless of whether or not they had expressed a desire to change that characteristic. For peers whose failure to change an undesirable characteristic was associated with no effort to change, those who expressed a desire to change were rated more favorably than those who expressed no desire to change. PMID- 20836434 TI - Adolescent girls' parasocial interactions with media figures. AB - We examined aspects of adolescent girls' parasocial interactions in the context of typical development. Parasocial interactions are defined as symbolic, one sided quasi-interactions between a viewer and a media figure. In total, 107 adolescent girls were examined; 94% reported engaging in parasocial interactions to some degree. Preoccupied attachment style predicted the degree of involvement in and emotional intensity of parasocial interactions. Results suggest that parasocial interactions are characteristic of girls with preoccupied attachment, but are also part of normative development. PMID- 20836435 TI - Aches and pains in agriculture: have we done enough? PMID- 20836436 TI - Estimation of the risks of thermal stress due to the microclimate for manual fruit and vegetable harvesters in central Italy. AB - Agricultural workers are exposed to various risks, including chemical agents, noise, and many other factors. One of the most characteristic and least known risk factors is constituted by the microclimatic conditions in the different phases of work (in field, in greenhouse, etc). A typical condition is thermal stress due to high temperatures during harvesting operations in open fields or in greenhouses. In Italy, harvesting is carried out for many hours during the day, mainly in the summer, with temperatures often higher than 30 degrees C. According to ISO 7243, these conditions can be considered dangerous for workers' health. The aim of this study is to assess the risks of exposure to microclimatic conditions (heat) for fruit and vegetable harvesters in central Italy by applying methods established by international standards. In order to estimate the risk for workers, the air temperature, radiative temperature, and air speed were measured using instruments in conformity with ISO 7726. Thermodynamic parameters and two more subjective parameters, clothing and the metabolic heat production rate related to the worker's physical activity, were used to calculate the predicted heat strain (PHS) for the exposed workers in conformity with ISO 7933. Environmental and subjective parameters were also measured for greenhouse workers, according to ISO 7243, in order to calculate the wet-bulb globe temperature (WBGT). The results show a slight risk for workers during manual harvesting in the field. On the other hand, the data collected in the greenhouses show that the risk for workers must not be underestimated. The results of the study show that, for manual harvesting work in climates similar to central Italy, it is essential to provide plenty of drinking water and acclimatization for the workers in order to reduce health risks. Moreover, the study emphasizes that the possible health risks for greenhouse workers increase from the month of April through July. PMID- 20836438 TI - Improving tractor safety warnings: readability is missing. AB - Research on tractor safety has not focused on user manuals. This study focuses on tractor operator manuals, specifically safety warnings, selected from the files of the Tractor Test facility at University of Nebraska-Lincoln. Analysis of many common warnings, based on readability and legibility research, shows that many warnings contain excessive information, confusing visuals and safety icons, poor document design, and illegible typefaces. The result is unreadable warnings that do not communicate quickly and correctly, and discourage readers rather than clarify critical information. Many tractor operator warnings are cluttered, "over written," and contain information needed to protect the manufacturer rather than to inform operators. What is needed is a careful analysis and revision of many safety warnings with the goal of encouraging operators to read the warnings and follow their message. PMID- 20836437 TI - Zoonoses: an occupational hazard for livestock workers and a public health concern for rural communities. AB - Farming employs one of the most diverse work forces, while at the same time it is one of the most dangerous occupations in the U.S. Individuals associated with the livestock industry face an additional risk: zoonotic diseases. In an effort to improve the overall well-being of the farming community, this review addresses zoonoses as a health concern for the farming community. The discussion of agriculturally acquired zoonoses includes infections naturally transmitted from vertebrate animals to man (e.g., rabies) and those common to animals and man (e.g., Salmonella). Special consideration is given to identifying individuals potentially at higher risk for developing disease. Case reports and epidemiological studies are reviewed from published veterinary and human-health literature to illustrate exposure scenarios and associated health outcomes. Additionally, key livestock zoonoses in the U.S. are summarized, and an overview of prevention and control strategies is provided. Findings show that livestock can transmit many zoonoses directly and indirectly, and human health can be significantly impacted, but the number of people adversely impacted is largely unknown. This review concludes that more education about zoonosis transmission and prevention is needed, and healthcare providers serving rural communities are a critical link in providing this information. In order for healthcare providers to address the educational gap, we recommend greater collaboration with veterinary specialists schooled in population medicine, zoonosis prevention and control, and animal production. PMID- 20836439 TI - Predator-prey reversal: a possible mechanism for ecosystem hysteresis in the North Sea? AB - Removal of large predatory fishes from marine ecosystems has resulted in persistent ecosystem shifts, with collapsed predator populations and super abundant prey populations. One explanation for these shifts is reversals of predator-prey roles that generate internal feedbacks in the ecosystems. Pelagic forage fish are often predators and competitors to the young life stages of their larger fish predators. I show that cod recruitment in the North Sea has been negatively related to the spawning-stock biomass of herring for the last 44 years. Herring, together with the abundance of Calanus finmarchicus, the major food for cod larvae, were the main predictors of cod recruitment. These predictors were of equivalent importance, worked additively, and explained different parts of the dynamics in cod recruitment. I suggest that intensive harvesting of cod has released herring from predator control, and that a large population of herring suppresses cod recruitment through predation on eggs and larvae. This feedback mechanism can promote alternative stable states and therefore cause hysteresis to occur under changing conditions; however, harvesting of herring might at present prevent a shift in the ecosystem to a herring-dominated state. PMID- 20836440 TI - Ocean warming increases threat of invasive species in a marine fouling community. AB - We addressed the potential for climate change to facilitate invasions and precipitate shifts in community composition by testing effects of ocean warming on species in a marine fouling community in Bodega Harbor, Bodega Bay, California, USA. First, we determined that introduced species tolerated significantly higher temperatures than natives, suggesting that climate change will have a disproportionately negative impact on native species. Second, we assessed the temperature dependence of survival and growth by exposing juveniles to an ambient control temperature and increased temperatures predicted by ocean warming scenarios (+3 degrees C and +4.5 degrees C) in laboratory mesocosms. We found that responses differed between species, species origins, and demographic processes. Based on the temperature tolerance, survival, and growth results, we predict that, as ocean temperatures increase, native species will decrease in abundance, whereas introduced species are likely to increase in this system. Facilitation of invasions by climate change may already be underway; locally, invasive dominance has increased concurrent with ocean warming over the past approximately 40 years. We suggest that the effects of climate change on communities can occur via both direct impacts on the diversity and abundance of native species and indirect effects due to increased dominance of introduced species. PMID- 20836441 TI - The seaweed Caulerpa racemosa on Mediterranean rocky reefs: from passenger to driver of ecological change. AB - Disentangling the ecological effects of biological invasions from those of other human disturbances is crucial to understanding the mechanisms underlying ongoing biotic homogenization. We evaluated whether the exotic seaweed, Caulerpa racemosa, is the primary cause of degradation (i.e., responsible for the loss of canopy-formers and dominance by algal turfs) on Mediterranean rocky reefs, by experimentally removing the invader alone or the entire invaded assemblage. In addition, we assessed the effects of enhanced sedimentation on the survival and recovery of canopy-forming macroalgae at a relatively pristine location and how their loss affects the ability of C. racemosa to conquer space. C. racemosa did not invade dense canopy stands or influence their recovery in cleared plots. Competition with C. racemosa could not explain the rarity of canopy-forming species at degraded sites. Removing the assemblages invaded by C. racemosa and preventing reinvasion did not trigger the transition from algal turfs to canopies, but it enhanced the cover of morphologically complex erect macroalgae under some circumstances. Once established, C. racemosa, enhancing sediment accumulation, favors algal turfs over erect algal forms and enables them to monopolize space. Our results show that introduced species that rely on disturbance to establish can subsequently become the main drivers of ecological change. PMID- 20836442 TI - General stabilizing effects of plant diversity on grassland productivity through population asynchrony and overyielding. AB - Insurance effects of biodiversity can stabilize the functioning of multispecies ecosystems against environmental variability when differential species' responses lead to asynchronous population dynamics. When responses are not perfectly positively correlated, declines in some populations are compensated by increases in others, smoothing variability in ecosystem productivity. This variance reduction effect of biodiversity is analogous to the risk-spreading benefits of diverse investment portfolios in financial markets. We use data from the BIODEPTH network of grassland biodiversity experiments to perform a general test for stabilizing effects of plant diversity on the temporal variability of individual species, functional groups, and aggregate communities. We tested three potential mechanisms: reduction of temporal variability through population asynchrony; enhancement of long-term average performance through positive selection effects; and increases in the temporal mean due to overyielding. Our results support a stabilizing effect of diversity on the temporal variability of grassland aboveground annual net primary production through two mechanisms. Two-species communities with greater population asynchrony were more stable in their average production over time due to compensatory fluctuations. Overyielding also stabilized productivity by increasing levels of average biomass production relative to temporal variability. However, there was no evidence for a performance-enhancing effect on the temporal mean through positive selection effects. In combination with previous work, our results suggest that stabilizing effects of diversity on community productivity through population asynchrony and overyielding appear to be general in grassland ecosystems. PMID- 20836443 TI - Scaling community structure: how bacteria, fungi, and ant taxocenes differentiate along a tropical forest floor. AB - Taxa with smaller individuals tend to have shorter generation times and higher local abundance and diversity. The scaled specialization hypothesis (SSH) posits that taxocenes of smaller individuals should differentiate more rapidly and thoroughly along physiochemical gradients of a given age and extent. In a Panama rainforest, we evaluated how bacteria, fungi, and ants responded to two such gradients: one topographic and the other arising from nine years of NPK fertilization. Terminal restriction fragment length polymorphism (T-RFLP) delineated bacteria and fungi operational taxonomic units (OTUs); traditional taxonomy delineated the ants. Bacteria had higher local species richness than fungi and ants (averaging 48 vs. 30 vs. 6 OTUs in < 0.25 m2). Bacteria OTUs were also more widely distributed (17% of OTUs were found on > or = 50% of sample plots compared to 3% for fungi and ants). Consistent with SSH, bacterial composition differed across short-term (+N and +P) and long-term (topographic) gradients; fungal taxocenes differed only along the long-term gradient; and ant taxocenes were homogenous across both. Body size can help predict community responses to a changing environment. PMID- 20836444 TI - A general hypothesis-testing framework for stable isotope ratios in ecological studies. AB - We propose a framework for hypothesis-testing of stable isotope ratios in ecological studies. Statistical procedures are based on analysis of nested linear models and a residual permutation procedure (RPP) that is employed to evaluate probabilities associated with test statistics. We used simulated examples and a real data set to illustrate the utility and generality of the method. First, we developed a test for differences in centroid location and dispersion of delta13C and delta15N values within and among groups of isotopic data. Second, we evaluated magnitude and direction of change in centroid position (termed "path") of a pair of isotopic samples separated in space/time relative to paths of other paired sample sets. Third, we compared attributes of path trajectories (size, direction, and shape) over sample sets containing more than two samples to provide a quantitative description of how patterns of isotopic ratios change in response to spatial and temporal gradients. Examples are limited to the bivariate case (delta13C-delta15N biplots), but the statistical method can readily be applied to univariate and multivariate cases. PMID- 20836445 TI - Plant geography upon the basis of functional traits: an example from eastern North American trees. AB - Plant geographers have sought for decades to describe and predict the geographic distribution of vegetation types on the basis of plant function and its relationship with the abiotic environment. Traditionally this has been accomplished using categorical representations such as plant functional types. Increasingly, plant functional ecologists have sought to refine categorical functional types via quantitative functional traits in order to understand the ecological implications of trade-offs in plant form and function. Fewer works have focused upon testing whether commonly measured functional traits enhance our understanding of plant biogeography broadly and the geographic distribution of vegetation types in particular. Here we combine a continental-scale forest inventory data set containing 18 111 plots with a plant functional trait data set to ask: (1) Is there a strong relationship between the abiotic environment and the distribution of functional trait values in forest inventory plots? And (2) can different Holdridge life zones be distinguished upon the basis of their functional trait distributions? The results show geographic patterns of functional trait distributions that are often strongly correlated with climate and also show that the Holdridge life zones in the study area can be differentiated using a combination of functional traits. PMID- 20836446 TI - Cascading diversity effects transmitted exclusively by behavioral interactions. AB - Consumer diversity generally increases resource consumption. Consumers can also impact other species by altering their behavior, but it is unclear how such nonconsumptive effects scale with diversity. We independently manipulated predator species richness and the consumptive and nonconsumptive effects of predator communities to measure the role of each factor in protecting Brassica oleracea plants from caterpillar herbivory. Plant biomass was greatest when diverse predator assemblages induced antipredator behaviors in herbivores, an effect not further strengthened when predators could also kill caterpillars. Predators within diverse communities were more likely to forage on plants and to disrupt herbivore feeding, reflecting greater aversion to foraging among conspecific than heterospecific competitors. Predator diversity, therefore, initiated behavioral changes at the predator and then herbivore trophic levels, both to the benefit of plants. Our results indicate that strong, emergent species richness effects can be transmitted entirely through behavioral interactions, independent of resource consumption. PMID- 20836447 TI - Overrun by the neighbors: landscape context affects strength and sign of local adaptation. AB - The adaptive deme formation hypothesis states that plant-feeding insects may adapt to individual host plants. To date, no empirical study has examined the strength of such adaptations from a spatially explicit perspective. In this study, we quantify local adaptation of six specialist insect species at multiple sites, predicting that spatial variation in local immigration rates will result in variation in the strength of local adaptation. We use a previously parameterized metapopulation model to estimate the proportion of immigrants in focal populations, clonal trees to measure local adaptation in a reciprocal common garden experiment, and a linear model to test for a link between the strength of immigration and local adaptation across species. As predicted, local adaptation generally varies inversely with the fraction of immigrants in a population. When immigration is high, local populations remain in a maladapted state. Importantly, our results imply that patterns of adaptation may vary predictably at a relatively small spatial scale (among individual host trees within a landscape) and that, hence, measures of local adaptation will make most sense in a spatial context. PMID- 20836448 TI - Apparent competition with an invasive plant hastens the extinction of an endangered lupine. AB - Invasive plants may compete with native plants by increasing the pressure of native consumers, a mechanism known as "apparent competition." Apparent competition can be as strong as or stronger than direct competition, but the role of apparent competition has rarely been examined in biological invasions. We used four years of demographic data and seed-removal experiments to determine if introduced grasses caused elevated levels of seed consumption on native plant species in a coastal dune system in California, USA. We show that the endangered, coastal dune plant Lupinus tidestromii experiences high levels of pre-dispersal seed consumption by the native rodent Peromyscus maniculatus due to its proximity to the invasive grass, Ammophila arenaria. We use stage-structured, stochastic population models to project that two of three study populations will decline toward extinction under ambient levels of consumption. For one of these declining populations, a relatively small decrease in consumption pressure should allow for persistence. We show that apparent competition with an invasive species significantly decreases the population growth rate and persistence of a native species. We expect that apparent competition is an important mechanism in other ecosystems because invasive plants often change habitat structure and plant consumer interactions. Possible implications of the apparent-competition mechanism include selective extinction of species preferred by seed consumers in the presence of an invasive species and biological homogenization of communities toward non-preferred native plant species. PMID- 20836449 TI - Community and ecosystem effects of intraspecific genetic diversity in grassland microcosms of varying species diversity. AB - Studies of whether plant community structure and ecosystem properties depend on the genetic diversity of component populations have been largely restricted to species monocultures and have involved levels of genetic differentiation that do not necessarily correspond to that exhibited by neighboring mature individuals in the field. We established experimental communities of varying intraspecific genetic diversity, using genotypes of eight species propagated from clonal material of individuals derived from a small (100-m2) limestone grassland community, and tested whether genetic diversity (one, four, and eight genotypes per species) influenced community composition and annual aboveground productivity across communities of one, four, and eight species. Eight-species communities were represented by common grass, sedge, and forb species, and four- and one species communities were represented by four graminoids and the dominant grass Festuca ovina, respectively. After three years of community development, there was a marginal increase of species diversity with increased genetic diversity in four- and eight-species communities, and genetic diversity altered the performance of genotypes in monospecific communities of F. ovina. However, shifts in composition from genetic diversity were not sufficient to alter patterns of community productivity. Neighborhood models describing pairwise interactions between species indicated that genetic diversity decreased the intensity of competition between species in four-species mixtures, thereby promoting competitive equivalency and enhancing species equitability. In F. ovina monocultures, neighborhood models revealed both synergistic and antagonistic interactions between genotypes that were reduced in intensity on more stressful shallow soils. Although the dependence of F. ovina genotype performance on neighborhood genetic composition did not influence total productivity, such dependence was sufficient to uncouple genotype performance in genetic mixtures and monocultures. Our results point to an important connection between local genetic diversity and species diversity in this species-rich ecosystem but suggest that such community-level dependence on genetic diversity may not feedback to ecosystem productivity. PMID- 20836450 TI - Trait-mediated interactions and lifetime fitness of the invasive plant Centaurea solstitialis. AB - Plants interact with numerous enemies and mutualists simultaneously and sequentially. Such multispecies interactions can give rise to trait-mediated indirect effects that are likely to be common in nature but which are also inherently difficult to predict. Understanding multispecies interactions is also important in the use of biological control agents to control invasive plants because modern approaches to biocontrol rely on releasing multiple agents for each target weed. Centaurea solstitialis is one of the most problematic invasive weeds in California, USA, and the weevil Eustenopus villosus is its dominant biological control agent. We conducted a field experiment to quantitatively assess the direct effect of the recently approved biocontrol pathogen Puccinia jaceae f.s. solstitialis on plant performance and any indirect effects that might arise by altering the plant's interactions with Eustenopus or its pollinators (principally the nonnative Apis mellifera). We documented both synergy and interference between the two biocontrol agents depending on the life stage of the weevil. Puccinia infection increased the impact of bud-feeding by the adult weevils but reduced the impact of seed-feeding by larval weevils. Neither infection nor Eustenopus attack had an effect on pollinator visitation. The net effect was that attack by both the pathogen and the weevil did not reduce plant fitness relative to plants attacked only by the weevil. Because the consequence to the plant of interacting with one species may depend on the presence or absence of other interacting species, a careful consideration of multispecies interactions may be necessary for the selection of biocontrol agents that act in a complementary manner to reduce plant fitness. Likewise, relatively tractable weed-biocontrol systems allow us to examine multispecies interactions that can be difficult to study experimentally in native systems that are composed of numerous species with well-established populations. PMID- 20836451 TI - Mycorrhizal networks counteract competitive effects of canopy trees on seedling survival. AB - The dynamics of forest ecosystems depend largely on the survival of seedlings in their understories, but seedling survival is known to be limited by preemption of light and soil resources by overstory trees. It has been hypothesized that "common mycorrhizal networks," wherein roots of seedlings are linked to overstory trees by symbiotic mycorrhizal fungi, offset some or all of the negative effects of trees on seedlings. Here we report the results of an unambiguous experimental test of this hypothesis in a monodominant Pinus radiata forest. We also tested the hypothesis that adaptive differentiation among plant populations causes local plant genotypes to respond more positively to mycorrhizal networks than nonlocal plant genotypes. Our results demonstrate large positive effects of overstory mycorrhizal networks on seedling survival, along with simultaneous negative effects of tree roots, regardless of whether plant genotypes were locally derived. Physiological and leaf-chemistry measurements suggest that seedlings connected to common mycorrhizal networks benefited from increased access to soil water. The similar magnitude of the positive and negative overstory effects on seedlings and the ubiquity of mycorrhizal networks in forests suggest that mycorrhizal networks fundamentally influence the demographic and community dynamics of forest trees. PMID- 20836452 TI - Recruitment limitation after mast-seeding in two African rain forest trees. AB - Seed and establishment limitation can have a major role in determining plant species' abundances and distributions in communities. Their relative importance, however, remains uncertain and controversial, especially for trees in forests where density-dependent mortality of seeds and seedlings may be common. In a primary African rain forest, we directly tested the strength of each limitation by using seeds of the tree species Microberlinia bisulcata and Tetraberlinia bifoliolata at eight addition levels and by following establishment over six weeks. Local background seed rain was also measured. Seedling recruitment was higher in seed-addition quadrats than in control quadrats, indicating seed limitation in both species. However, fitting the Beverton-Holt model indicated that establishment limitation was consistently 2-4 times stronger than seed limitation for Microberlinia, whereas seed limitation greatly exceeded establishment limitation for Tetraberlinia. Strong density dependence was operating in the short seed-to-seedling transition for Microberlinia, whereas it was almost negligible for Tetraberlinia. Although early postdispersal mortality was very high for both species (> 80%), they may achieve local codominance as a result of differing strengths of seed limitation vs. establishment limitation. Assessing the importance of seed limitation for tree populations requires a knowledge of species-specific seed rain as well as a reliable recruitment function. The outcome of early establishment processes also needs to be seen in the context of later stages of tree dynamics. PMID- 20836453 TI - Experimental drought in a tropical rain forest increases soil carbon dioxide losses to the atmosphere. AB - Climate models predict precipitation changes for much of the humid tropics, yet few studies have investigated the potential consequences of drought on soil carbon (C) cycling in this important biome. In wet tropical forests, drought could stimulate soil respiration via overall reductions in soil anoxia, but previous research suggests that litter decomposition is positively correlated with high rainfall fluxes that move large quantities of dissolved organic matter (DOM) from the litter layer to the soil surface. Thus, reduced rainfall could also limit C delivery to the soil surface, reducing respiration rates. We conducted a throughfall manipulation experiment to investigate how 25% and 50% reductions in rainfall altered both C movement into soils and the effects of those DOM fluxes on soil respiration rates. In response to the experimental drought, soil respiration rates increased in both the -25% and -50% treatments. Throughfall fluxes were reduced by 26% and 55% in the -25% and -50% treatments, respectively. However, total DOM fluxes leached from the litter did not vary between treatments, because the concentrations of leached DOM reaching the soil surface increased in response to the simulated drought. Annual DOM concentrations averaged 7.7 +/- 0.8, 11.2 +/- 0.9, and 15.8 +/- 1.2 mg C/L in the control, -25%, and -50% plots, respectively, and DOM concentrations were positively correlated with soil respiration rates. A laboratory incubation experiment confirmed the potential importance of DOM concentration on soil respiration rates, suggesting that this mechanism could contribute to the increase in CO2 fluxes observed in the reduced rainfall plots. Across all plots, the data suggested that soil CO2 fluxes were partially regulated by the magnitude and concentration of soluble C delivered to the soil, but also by soil moisture and soil oxygen availability. Together, our data suggest that declines in precipitation in tropical rain forests could drive higher CO2 fluxes to the atmosphere both via increased soil 02 availability and through responses to elevated DOM concentrations. PMID- 20836454 TI - Functional diversity in resource use by fungi. AB - Fungi influence nutrient cycling in terrestrial ecosystems, as they are major regulators of decomposition and soil respiration. However, little is known about the substrate preferences of individual fungal species outside of laboratory culture studies. If active fungi differ in their substrate preferences in situ, then changes in fungal diversity due to global change may dramatically influence nutrient cycling in ecosystems. To test the responses of individual fungal taxa to specific substrates, we used a nucleotide-analogue procedure in the boreal forest of Alaska (USA). Specifically, we added four organic N compounds commonly found in plant litter (arginine, glutamate, lignocellulose, and tannin-protein) to litterbags filled with decomposed leaf litter (black spruce and aspen) and assessed the responses of active fungal species using qPCR (quantitative polymerase chain reaction), oligonucleotide fingerprinting of rRNA genes, and sequencing. We also compared the sequences from our experiment with a concurrent warming experiment to see if active fungi that targeted more recalcitrant compounds would respond more positively to soil warming. We found that individual fungal taxa responded differently to substrate additions and that active fungal communities were different across litter types (spruce vs. aspen). Active fungi that targeted lignocellulose also responded positively to experimental warming. Additionally, resource-use patterns in different fungal taxa were genetically correlated, suggesting that it may be possible to predict the ecological function of active fungal communities based on genetic information. Together, these results imply that fungi are functionally diverse and that reductions in fungal diversity may have consequences for ecosystem functioning. PMID- 20836455 TI - Order of plant host establishment alters the composition of arbuscular mycorrhizal communities. AB - The causes of local diversity and composition remain a central question in community ecology. Numerous studies have attempted to understand community assembly, both within and across trophic levels. However, little is known about how community assembly aboveground influences soil microbial communities belowground. We hypothesized that plant establishment order can affect the community of arbuscular mycorrhizal fungi (AMF) in roots, with the strength of this effect dependent on both host plant identity and neighboring plant identity. Such priority effects of plants on AMF may act through host-specific filters of the initial species pool that limit the available pool for plants that established second. In a greenhouse experiment with four plant hosts, we found that the strength of the priority effect on AMF communities reflected both host plant characteristics and interactions between host and neighbor plant species, consistent with differential host specificity among plants. These patterns were independent of plant biomass and root colonization. Functional studies of AMF associated with a wide array of host plants will be required to further understand this potential driver of community dynamics. PMID- 20836456 TI - Resource contrast in patterned peatlands increases along a climatic gradient. AB - Spatial patterning of ecosystems can be explained by several mechanisms. One approach to disentangling the influence of these mechanisms is to study a patterned ecosystem along a gradient of environmental conditions. This study focused on hummock-hollow patterning of peatlands. Previous models predicted that patterning in drainage-dominated peatlands is driven by a peat-accumulation mechanism, reflected by higher nutrient availability in hollows relative to hummocks. Alternatively, patterning in evapotranspiration (ET)-dominated peatlands may be driven by a nutrient-accumulation mechanism, reflected by reversed nutrient distribution, namely, higher nutrient availability in hummocks relative to hollows. Here, we tested these predictions by comparing nutrient distributions among patterned peatlands in maritime (Scotland), humid temperate (Sweden), and humid continental (Siberia) climates. The areas comprise a climatic gradient from very wet and drainage-dominated (Scotland) to less wet and ET dominated (Siberia) peatlands. Nutrient distribution was quantified as resource contrast, a measure for hummock-hollow difference in nutrient availability. We tested the hypothesis that the climatic gradient shows a trend in the resource contrast; from negative (highest nutrient availability in hollows) in Scotland to positive (highest nutrient availability in hummocks) in Siberia. The resource contrasts as measured in vegetation indeed showed a trend along the climatic gradient: contrasts were negative to slightly positive in Scotland, positive in Sweden, and strongly positive in Siberia. This finding corroborates the main prediction of previous models. Our results, however, also provided indications for further model development. The low concentrations of nutrients in the water suggest that existing models could be improved by considering both the dissolved and adsorbed phase and explicit inclusion of both nutrient-uptake and nutrient storage processes. Our study suggests that future climate change may affect the ecosystem functioning of patterned peatlands by altering the contribution of pattern-forming mechanisms to redistribution of water and nutrients within these systems. PMID- 20836457 TI - The role of Sphagnum mosses in the methane cycling of a boreal mire. AB - Peatlands are a major natural source of atmospheric methane (CH4). Emissions from Sphagnum-dominated mires are lower than those measured from other mire types. This observation may partly be due to methanotrophic (i.e., methane-consuming) bacteria associated with Sphagnum. Twenty-three of the 41 Sphagnum species in Finland can be found in the peatland at Lakkasuo. To better understand the Sphagnum-methanotroph system, we tested the following hypotheses: (1) all these Sphagnum species support methanotrophic bacteria; (2) water level is the key environmental determinant for differences in methanotrophy across habitats; (3) under dry conditions, Sphagnum species will not host methanotrophic bacteria; and (4) methanotrophs can move from one Sphagnum shoot to another in an aquatic environment. To address hypotheses 1 and 2, we measured the water table and CH4 oxidation for all Sphagnum species at Lakkasuo in 1-5 replicates for each species. Using this systematic approach, we included Sphagnum spp. with narrow and broad ecological tolerances. To estimate the potential contribution of CH4 to moss carbon, we measured the uptake of delta13C supplied as CH4 or as carbon dioxide dissolved in water. To test hypotheses 2-4, we transplanted inactive moss patches to active sites and measured their methanotroph communities before and after transplantation. All 23 Sphagnum species showed methanotrophic activity, confirming hypothesis 1. We found that water level was the key environmental factor regulating methanotrophy in Sphagnum (hypothesis 2). Mosses that previously exhibited no CH4 oxidation became active when transplanted to an environment in which the microbes in the control mosses were actively oxidizing CH4 (hypothesis 4). Newly active transplants possessed a Methylocystis signature also found in the control Sphagnum spp. Inactive transplants also supported a Methylocystis signature in common with active transplants and control mosses, which rejects hypothesis 3. Our results imply a loose symbiosis between Sphagnum spp. and methanotrophic bacteria that accounts for potentially 10-30% of Sphagnum carbon. PMID- 20836458 TI - Weaver ants Oecophylla smaragdina encounter nasty neighbors rather than dear enemies. AB - The evolution of territorial behavior requires that the benefits of territoriality outweigh the costs. The costs are primarily those of territorial defense against encroaching neighbors or against floaters seeking to establish their own territory. One way to reduce the cost of defense might be to restrict serious conflict to encounters with those posing the greatest threat. Studies of many animals have found that less aggression is shown toward neighbors than toward, strangers, a phenomenon known as the "dear enemy" effect. However, the opposite can also be true, namely, that more aggression is shown toward neighbors than strangers: the "nasty neighbor" effect. This may be particularly true of group-living species that defend a resource-based territory. Here we show that (1) colonies of the weaver ant Oecophylla smaragdina were able to recognize a greater proportion of workers from neighboring colonies as non-colony members; and (2) when recognized as non-colony members, more aggression was exhibited toward neighbors than non-neighbors. We present for the first time evidence that differential levels of aggression involve both a perceptual and behavioral component. On the other hand, we found no evidence that weaver ant workers were better able to recognize workers from previously unknown colonies or responded more aggressively to them, even after a 10-day period of contact. This contrasts with other species in which rapid learning of the identity of new potential enemies has been demonstrated. We suggest that such a response is unnecessary for weaver ants, as encounters with intruders from non-neighboring colonies are probably rare and of little consequence. This study adds to the growing body of evidence that the nasty neighbor effect may be much more common than the dear enemy effect among group-living species. PMID- 20836459 TI - Predicting feeding success in a migratory predator: integrating telemetry, environment, and modeling techniques. AB - Foraging theory predicts that mobile predators should target high profitability areas with plentiful resources and minimize time spent moving between these areas. This has led to a focus in recent literature on the identification of "hotspots" important for migratory marine predators, i.e., regions where predators spend disproportionate amounts of time ostensibly due to high prey abundance; and determination of the environmental features characteristic of such areas. We investigated factors predicting foraging success in southern bluefin tuna (SBT; Thunnus maccoyii), by integrating telemetry-based feeding and movement data (n = 19 fish, length to caudal fork [LCF] = 99 +/- 3 cm) with environmental data over the scale of their annual oceanic migrations during 1998-2000. We used widely available statistical modeling techniques, generalized linear models, and generalized linear mixed models, formulated to represent feeding as a Markov process. The results showed increased feeding and predictability of feeding occurs in the coastal waters of southern Australia, providing some evidence that this area represents a fixed foraging "hotspot" for juvenile tuna during the austral summer. However, in oceanic waters southern bluefin tuna did not fit the common model of migration, but rather showed a pattern of relatively high foraging success throughout their migratory range, especially during periods of continuous travel. Interestingly, foraging "coldspots" (prolonged low-feeding periods) as well as "hotspots" were apparent across individual tracks, predicted most strongly by warm ocean temperatures. These results provide a new perspective on the ecology of large-scale feeding migrations within the context of the heterogeneous ocean environment, where the continuous and opportunistic feeding of generalist predators may be more common, particularly in predatory large pelagic fishes, than is currently documented. PMID- 20836460 TI - Millennial-aged organic carbon subsidies to a modern river food web. AB - Recent studies indicate that highly aged material is a major component of organic matter transported by most rivers. However, few studies have used natural 14C to trace the potential entry of this aged material into modern river food webs. Here we use natural abundance 14C, 13C, and deuterium (2H) to trace the contribution of aged and contemporary organic matter to an important group of consumers, crustacean zooplankton, in a large temperate river (the Hudson River, New York, USA). Zooplankton were highly 14C depleted (mean delta14C = -240 per thousand) compared to modern primary production in the river or its watershed (delta14C = 60 per thousand to +50 per thousand). In order to account for the observed 14C depletion, zooplankton must be subsidized by highly aged particulate organic carbon. IsoSource modeling suggests that the range of the aged dietary subsidy is between approximately 57%, if the aged organic matter source was produced 3400 years ago, and approximately 21%, if the organic carbon used is > or = 50 000 years in age, including fossil material that is millions of years in age. The magnitude of this aged carbon subsidy to river zooplankton suggests that modern river food webs may in some cases be buffered from the limitations set by present day primary production. PMID- 20836461 TI - Estimating interaction strengths in nature: experimental support for an observational approach. AB - The complexity of food webs poses a significant hurdle for our growing understanding of the structure and dynamics of ecological communities. Empirical methods that measure the per capita strengths of trophic species interactions offer a means to identify keystone species and bridge mathematical models and data to synthesize our knowledge of population dynamics and predator feeding behaviors. Many such methods have been proposed, but few have seen independent validation of their estimates or underlying assumptions. This is particularly so with respect to the nonlinear functional responses by which predators often respond to their prey. Here I describe an empirical test of a recently proposed observational method for estimating the nonlinear strength of predator-prey interactions in the field. By applying the method to two populations of a predatory intertidal whelk, Haustrum scobina, I estimated its per capita attack rates on all nine of its observed prey species. These spanned two orders of magnitude in per capita strength. Concurrent experimental manipulations of the two predator populations provided population time series for the response of a mussel prey species, Xenostrobus pulex. I obtained independent interaction strength estimates for this focal interaction by fitting a sequence of hypothesized predator-prey models to these time series. Overall, site-specific models assuming linear functional responses performed better than all others. A direct comparison of the attack-rate estimates from the observational method with those of the best-performing nonlinear model nevertheless revealed high concordance between the two methods. The results of this study therefore support the use of the observational method in larger and more complex food webs and suggest that trophic interactions in the range of mean prey densities observed in nature are approximately linear. PMID- 20836462 TI - Nonnative trout impact an alpine-nesting bird by altering aquatic-insect subsidies. AB - Adjacent food webs may be linked by cross-boundary subsidies: more-productive donor systems can subsidize consumers in less-productive neighboring recipient systems. Introduced species are known to have direct effects on organisms within invaded communities. However, few studies have addressed the indirect effects of nonnative species in donor systems on organisms in recipient systems. We studied the direct role of introduced trout in altering a lake-derived resource subsidy and their indirect effects in altering a passerine bird's response to that subsidy. We compared the abundance of aquatic insects and foraging Gray-crowned Rosy-Finches (Leucosticte tephrocotis dawsoni, "Rosy-Finch") at fish-containing vs. fishless lakes in the Sierra Nevada Mountains of California (USA). Introduced trout outcompeted Rosy-Finches for emerging aquatic insects (i.e., mayflies). Fish-containing lakes had 98% fewer mayflies than did fishless lakes. In lakes without fish, Rosy-Finches showed an aggregative response to emerging aquatic insects with 5.9 times more Rosy-Finches at fishless lakes than at fish containing lakes. Therefore, the introduction of nonnative fish into the donor system reduced both the magnitude of the resource subsidy and the strength of cross-boundary trophic interactions. Importantly, the timing of the subsidy occurs when Rosy-Finches feed their young. If Rosy-Finches rely on aquatic-insect subsidies to fledge their young, reductions in the subsidy by introduced trout may have decreased Rosy-Finch abundances from historic levels. We recommend that terrestrial recipients of aquatic subsidies be included in conservation and restoration plans for ecosystems with alpine lakes. PMID- 20836463 TI - Bet-hedging response to environmental variability, an intraspecific comparison. AB - A major challenge in ecology is to understand the impact of increased environmental variability on populations and ecosystems. To maximize their fitness in a variable environment, life history theory states that individuals should favor a bet-hedging strategy, involving a reduction of annual breeding performance and an increase in adult survival so that reproduction can be attempted over more years. As a result, evolution toward longer life span is expected to reduce the deleterious effects of extra variability on population growth, and consequently on the trait contributing the most to it (e.g., adult survival in long-lived species). To investigate this, we compared the life histories of two Black-browed Albatross (Thalassarche melanophrys) populations breeding at South Georgia (Atlantic Ocean) and Kerguelen (Indian Ocean), the former in an environment nearly three times more variable climatically (e.g., in sea surface temperature) than the latter. As predicted, individuals from South Georgia (in the more variable environment) showed significantly higher annual adult survival (0.959, SE = 0.003) but lower annual reproductive success (0.285 chick per pair, SE = 0.039) than birds from Kerguelen (survival = 0.925, SE = 0.004; breeding success = 0.694, SE = 0.027). In both populations, climatic conditions affected the breeding success and the survival of inexperienced breeders, whereas the survival of experienced breeders was unaffected. The strength of the climatic impact on survival of inexperienced breeders was very similar between the two populations, but the effect on breeding success was positively related to environmental variability. These results provide rare and compelling evidence to support bet-hedging underlying changes in life history traits as an adaptive response to environmental variability. PMID- 20836464 TI - Bill size and dimorphism in tidal-marsh sparrows: island-like processes in a continental habitat. AB - Conditions favoring population divergence in trophic features, such as the low levels of species richness and interspecific competition found on islands, can be similar to conditions that increase their sexual dimorphism or overall variance. Male emberizid sparrows of tidal marshes have undergone parallel evolution of large bills. We tested for parallel increases between dimorphism and overall variation in bill size by comparing three groups totaling 30 sparrow subspecies: tidal-marsh sparrows, nontidal relatives of tidal-marsh taxa, and representative sparrow taxa. Bill size (and not other features) showed the following patterns in tidal-marsh sparrows compared to nontidal relatives or sparrows at large: (1) an increase; (2) a greater increase in males than females; (3) an increase in sexual dimorphism; and (4) greater variation in females. A high degree of sexual dimorphism in bill size is consistent with the hypothesis that low levels of interspecific and high levels of intraspecific competition select for intraspecific niche divergence. Alternatively, increased sexual selection in tidal-marsh sparrows, vis-a-vis high densities and hence increased male-male competition, may account for the differentially large increase in bill size in males. Relaxed natural selection due to high ecosystem productivity and low interspecific competition may explain why, in tidal-marsh sparrows, female bills have diverged less than males and show higher levels of variability at larger sizes. Both the niche divergence and sexual selection hypotheses depend upon processes, particularly increases in population density, that are similar to those often reported for island passerines. However, the low species diversity and increased intraspecific competition of salt marsh faunas is probably a result of abiotic constraints on colonization (tides and salinity) rather than the isolating distances of island biotas. Thus, both a shift in bill size and increases in its dimorphism and variability may be favored by high productivity and abiotic constraints. PMID- 20836465 TI - Bat reproduction declines when conditions mimic climate change projections for western North America. AB - Climate change models predict that much of western North America is becoming significantly warmer and drier, resulting in overall reductions in availability of water for ecosystems. Herein, I demonstrate that significant declines in the reproductive success of female insectivorous bats occur in years when annual environmental conditions mimic the long-term predictions of regional climate change models. Using a data set gathered on bat populations from 1996 through 2008 along the Front Range of Colorado, I compare trends in population numbers and reproductive outcomes of six species of vespertilionid bats with data on mean annual high temperature, precipitation, snow pack, and stream discharge rates. I show that levels of precipitation and flow rates of small streams near maternity colonies is fundamentally tied to successful reproduction in female bats, particularly during the lactation phase. Across years that experienced greater than average mean temperatures with less than average precipitation and stream flow, bat populations responded by slight to profound reductions in reproductive output depending on the severity of drought conditions. In particular, reproductive outputs showed profound declines (32-51%) when discharge rates of the largest stream in the field area dropped below 7 m3/s, indicating a threshold response. Such sensitivity to environmental change portends severe impacts to regional bat populations if current scenarios for climate change in western North America are accurate. In addition, bats act as early-warning indicators of large scale ecological effects resulting from further regional warming and drying trends currently at play in western North America. PMID- 20836466 TI - Unmodeled observation error induces bias when inferring patterns and dynamics of species occurrence via aural detections. AB - The recent surge in the development and application of species occurrence models has been associated with an acknowledgment among ecologists that species are detected imperfectly due to observation error. Standard models now allow unbiased estimation of occupancy probability when false negative detections occur, but this is conditional on no false positive detections and sufficient incorporation of explanatory variables for the false negative detection process. These assumptions are likely reasonable in many circumstances, but there is mounting evidence that false positive errors and detection probability heterogeneity may be much more prevalent in studies relying on auditory cues for species detection (e.g., songbird or calling amphibian surveys). We used field survey data from a simulated calling anuran system of known occupancy state to investigate the biases induced by these errors in dynamic models of species occurrence. Despite the participation of expert observers in simplified field conditions, both false positive errors and site detection probability heterogeneity were extensive for most species in the survey. We found that even low levels of false positive errors, constituting as little as 1% of all detections, can cause severe overestimation of site occupancy, colonization, and local extinction probabilities. Further, unmodeled detection probability heterogeneity induced substantial underestimation of occupancy and overestimation of colonization and local extinction probabilities. Completely spurious relationships between species occurrence and explanatory variables were also found. Such misleading inferences would likely have deleterious implications for conservation and management programs. We contend that all forms of observation error, including false positive errors and heterogeneous detection probabilities, must be incorporated into the estimation framework to facilitate reliable inferences about occupancy and its associated vital rate parameters. PMID- 20836467 TI - Spatial autocorrelation and the scaling of species-environment relationships. AB - Issues of residual spatial autocorrelation (RSA) and spatial scale are critical to the study of species-environment relationships, because RSA invalidates many statistical procedures, while the scale of analysis affects the quantification of these relationships. Although these issues independently are widely covered in the literature, only sparse attention is given to their integration. This paper focuses on the interplay between RSA and the spatial scaling of species environment relationships. Using a hypothetical species in an artificial landscape, we show that a mismatch between the scale of analysis and the scale of a species' response to its environment leads to a decrease in the portion of variation explained by environmental predictors. Moreover, it results in RSA and biased regression coefficients. This bias stems from error-predictor dependencies due to the scale mismatch, the magnitude of which depends on the interaction between the scale of landscape heterogeneity and the scale of a species' response to this heterogeneity. We show that explicitly considering scale effects on RSA can reveal the characteristic scale of a species' response to its environment. This is important, because the estimation of species-environment relationships using spatial regression methods proves to be erroneous in case of a scale mismatch, leading to spurious conclusions when scaling issues are not explicitly considered. The findings presented here highlight the importance of examining the appropriateness of the spatial scales used in analyses, since scale mismatches affect the rigor of statistical analyses and thereby the ability to understand the processes underlying spatial patterning in ecological phenomena. PMID- 20836468 TI - Models for inference in dynamic metacommunity systems. AB - A variety of processes are thought to be involved in the formation and dynamics of species assemblages. For example, various metacommunity theories are based on differences in the relative contributions of dispersal of species among local communities and interactions of species within local communities. Interestingly, metacommunity theories continue to be advanced without much empirical validation. Part of the problem is that statistical models used to analyze typical survey data either fail to specify ecological processes with sufficient, complexity or they fail to account for errors in detection of species during sampling. In this paper, we describe a statistical modeling framework for the analysis of metacommunity dynamics that is based on the idea of adopting a unified approach, multispecies occupancy modeling, for computing inferences about individual species, local communities of species, or the entire metacommunity of species. This approach accounts for errors in detection of species during sampling and also allows different metacommunity paradigms to be specified in terms of species and location-specific probabilities of occurrence, extinction, and colonization: all of which are estimable. In addition, this approach can be used to address inference problems that arise in conservation ecology, such as predicting temporal and spatial changes in biodiversity for use in making conservation decisions. To illustrate, we estimate changes in species composition associated with the species-specific phenologies of flight patterns of butterflies in Switzerland for the purpose of estimating regional differences in biodiversity. PMID- 20836469 TI - POC plots: calibrating species distribution models with presence-only data. AB - Statistical models are widely used for predicting species' geographic distributions and for analyzing species' responses to climatic and other predictor variables. Their predictive performance can be characterized in two complementary ways: discrimination, the ability to distinguish between occupied and unoccupied sites, and calibration, the extent to which a model correctly predicts conditional probability of presence. The most common measures of model performance, such as the area under the receiver operating characteristic curve (AUC), measure only discrimination. In contrast, we introduce a new tool for measuring model calibration: the presence-only calibration plot, or POC plot. This tool relies on presence-only evaluation data, which are more widely available than presence-absence evaluation data, to determine whether predictions are proportional to conditional probability of presence. We generalize the predicted/expected curves of Hirzel et al. to produce a presence-only analogue of traditional (presence-absence) calibration curves. POC plots facilitate visual exploration of model calibration, and can be used to recalibrate badly calibrated models. We demonstrate their use by recalibrating models made by the DOMAIN modeling method on a comprehensive set of 226 species from six regions of the world, significantly improving DOMAIN's predictive performance. PMID- 20836470 TI - Applications of particle image velocimetry for seed release studies. AB - Nonrandom seed release is an important determinant of how far seeds disperse, but the mechanisms that promote wind-related seed release under varying atmospheric conditions are poorly understood. We explored the use of particle image velocimetry (PIV) to gain a better mechanistic understanding of seed release by visualizing the flow velocities and vorticity in a two-dimensional slice of air around inflorescences. Pilot data taken in a wind tunnel show gradients in air velocity at the top of Carduus nutans capitula that may contribute to lift generation. Additionally, von Karman vortex streets (vortices of opposite spin that are shed from the wake of an object) were observed shedding from capitula, which cause lateral forces on capitula and increase turbulence downwind at other locations. Avenues for further research include using PIV to examine the mechanisms of seed release and dispersal in wind tunnels and in the field. We found PIV to be a promising method to further explore the mechanisms behind seed release in wind dispersed plants, and a technique rich with opportunities for collaborations between plant dispersal ecologists and fluid dynamics specialists. PMID- 20836471 TI - Care improvements under threat as quangos face cull. PMID- 20836472 TI - Employers need to recognise the benefits of supporting their staff. PMID- 20836473 TI - To what extent can pressure relieving surfaces help reduce the costs of pressure ulcers? AB - Pressure ulcers in acute care often involve extended hospital stays and additional health service resources. As well as the economic burden, pressure ulcers have a significant impact on patient morbidity. Pressure relieving surfaces have been recommended as a form of pressure ulcer prevention for patients at risk of developing ulcers, although such surfaces can be considerably more expensive than the standard ones used in hospitals. This summary looks at the clinical and economic evidence on pressure relieving surfaces, and discusses the likely impact on hospital budgets as a result of investing in a range of pressure relieving surfaces. The findings suggest that using pressure relieving surfaces for those at risk of developing a pressure ulcer can result in health service efficiencies and quality of life gains for patients. PMID- 20836474 TI - The high impact actions for nursing and midwifery 4: your skin matters. AB - Pressure ulcers can occur in any patient but are most commonn in high risk groups such as: older people; those who are obese, malnourished orwith continence problems; people with certain skin types; andthose with certain underlying conditions. Pressure ulcers increase morbidityand mortality, and represent a significant proportion of NHS expenditure, yet the vast majority are avoidable. This article, the fifth in our series on the high impact actions for nursing and midwifery, looks at how nurses can prevent pressure ulcers in their patients. PMID- 20836475 TI - Skin assessment in dark pigmented skin: a challenge in pressure ulcer prevention. AB - Skin assessment is a vital element in the prevention of pressure ulcers, and many recommendations for skin assessment depend on visual and tactile cues to identify changes in skin appearance. These visual cues that indicate changes in skin appearance maybe easily observed in Caucasian skin but, with darker pigmentation, it maybe harder to spot visual signs of early changes caused by pressure damage. This article outlines how nurses can address this problem in clinical practice and the technological developments that may help to solve this clinical issue. PMID- 20836476 TI - Developing an intermediate care unit for older people with mental and physical illnesses. AB - Intermediate care is an integral part of healthcare for older people with physical illness. It can provide rehabilitation and enable early hospital discharge, but people with both mental and physical illnesses have frequently been excluded from intermediate care services. This article describes a 12 bed, nurse led rehabilitation unit for older people with mental and physical health needs. The ethos is to promote independence and allow patients to achieve their objectives no matter what their age and ongoing limitations. PMID- 20836477 TI - Appendicitis presenting as gastroenteritis: the importance of making a correct diagnosis. PMID- 20836478 TI - How to ensure e-portfolios are a valuable resource to students' learning. AB - Online technology has become an increasingly important part of all types of education, including that of student nurses. This article outlines some factors that need to be considered when introducing e-portfolios into nurse education and looks at issues such as ease of use, ownership, privacy, supervision and assessment. PMID- 20836479 TI - We all have a crucial role to play in what happens next. PMID- 20836480 TI - Let's not hark back to being trained like circus seals. PMID- 20836481 TI - Occupational health and safety for nurses benefits patients, too. PMID- 20836482 TI - Workplace violence in healthcare settings: risk factors and protective strategies. AB - This article describes the risk factors and protective strategies associated with workplace violence perpetrated by patients and visitors against healthcare workers. Perpetrator risk factors for patients and visitors in healthcare settings include mental health disorders, drug or alcohol use, inability to deal with situational crises, possession of weapons, and being a victim of violence. Worker risk factors are gender, age, years of experience, hours worked, marital status, and previous workplace violence training. Setting and environmental risk factors for experiencing workplace violence include time of day and presence of security cameras. Protective strategies for combating the negative consequences of workplace violence include carrying a telephone, practicing self-defense, instructing perpetrators to stop being violent, self- and social support, and limiting interactions with potential or known perpetrators of violence. Workplace violence is a serious and growing problem that affects all healthcare professionals. Strategies are needed to prevent workplace violence and manage the negative consequences experienced by healthcare workers following violent events. PMID- 20836483 TI - Introduction to ergonomics for healthcare workers. AB - Healthcare workers who handle and move patients as part of their jobs suffer a disproportionately high number of work-related musculoskeletal disorders (MSDs). The majority of reported work-related MSDs are back pain cases that result in significant numbers of lost work days. It is likely that these lost workdays have a substantial impact on the quality and cost of health care. Patient care ergonomics can reduce the risk of work-related MSDs by helping safety experts design the work so it can be safely performed by most workers. This article provides a general overview of ergonomics--what it is, how it can be used to help design safe work, and why all healthcare workers and administrators should know and understand how excessive work demands can lead to increased risk of work related MSDs. The article will also explain technological solutions that can be implemented to reduce the risk of work-related MSDs for healthcare workers. PMID- 20836484 TI - Strategies for nurses to prevent sleep-related injuries and errors. AB - Rehabilitation nurses work shift schedules or long hours to provide essential patient services around the clock. These demanding hours can lead to sleep difficulties, declines in performance, and increased worker errors. This article gives an overview of selected declines in cognitive performance that are associated with inadequate sleep and several factors that increase riskforfatigue related errors. Selected strategies for nurses and managers to reduce these risks are discussed, such as better sleep practices, improved work schedule design, naps, caffeine, exposure to light, and rest breaks. Both nurses and managers share responsibility for implementing strategies to reduce risks from inadequate sleep. PMID- 20836485 TI - Nurses, smoking, and immunity: a review. AB - Nurses regularly are exposed to a variety of occupational hazards. In addition to documented occupational hazards, exposure to smoking remains a major concern. This article reviews the prevalence of smoking among nurses working in the United States and discusses their reasons for smoking. Researchers conducted a state-of the-art review on the effects of cigarette smoking and exposure to secondhand smoke (SHS) on the immune system. Smoking prevalence among nurses working in the United States ranged from 796-12%, and high work stress, poor work environment, shift work, and peer influence were suspected major risk factors influencing smoking behavior. A review of the effects of smoking on immunity revealed that both active smoking and exposure to SHS negatively affects immune function. When rehabilitation nurses stop smoking their health improves and nonsmokers are exposed to less SHS. Rehabilitation nurses are encouraged to share knowledge of the immunological benefits of smoking cessation with patients to facilitate nurse led rehabilitation programs. PMID- 20836486 TI - Risk factors associated with patient assaults of home healthcare workers. AB - This study used surveys from 677 home healthcare aides and nurses to explore factors associated with assaults by patients. Among respondents, 4.6% reported one or more patient assaults (being hit, kicked, pinched, shoved, or bitten) during the past year. Logistic regression analysis examined associations between several potential risk factors and assaults. Three factors were significant, including having one or more patients with dementia (OR = 4.31, 95% CI 1.47 12.67), routinely handling patients (OR = 8.48, 95% CI 1.89-37.94), and perceiving threats of violence by others in and around patients' homes (OR = 4.45, 95% CI 1.75-11.32). Assaults were not significantly associated with worker age, gender, race, job title, hours of work, or use of needles during patient care. Assaulted workers and workers who perceived threats of violence by others were significantly more likely to have shortened home care visits. More detailed research is needed to confirm these results and evaluate methods to reduce assault risk. PMID- 20836487 TI - Safe patient handling for rehabilitation professionals. AB - Every day, thousands of physical therapists and rehabilitation nurses are required to perform physically demanding therapeutic patient handling tasks that are stressful to the caregiver and increase his or her risk of developing work related musculoskeletal disorders (MSDs). In rehabilitation, patient handling tasks might be classified as"traditional" or "therapeutic."Traditional tasks have a practical goal, such as transferring a patient from bed to a wheelchair, and therapeutic tasks have more targeted goals such as facilitating patient function and independence. Therapeutic patient handling tasks present a greater risk for caregivers to sustain work-related MSDs than typical patient handling tasks do because caregivers are exposed to high mechanical loads on the spinal tissues for longer amounts of time. The Veterans Health Administration, Association of Rehabilitation Nurses, and the American Physical Therapy Association endorse the use of modern patient handling technology as part of a comprehensive safe patient handling program for providing therapy in rehabilitation settings. Information about patient handling technology that is effective in reducing the risk of work related MSDs from performing therapeutic patient handling and movement tasks is also presented and discussed in this article. PMID- 20836488 TI - SnCl(4)- and TiCl(4)-catalyzed anomerization of acylated O- and S-glycosides: analysis of factors that lead to higher alpha:beta anomer ratios and reaction rates. AB - The quantification of factors that influence both rates and stereoselectivity of anomerization reactions catalyzed by SnCl(4) and TiCl(4) and how this has informed the synthesis of alpha-O- and alpha-S-glycolipids is discussed. The SnCl(4)-catalyzed anomerization reactions of beta-S- and beta-O-glycosides of 18 substrates followed first order equilibrium kinetics and k(f) + k(r) values were obtained, where k(f) is the rate constant for the forward reaction (beta -> alpha) and k(r) is the rate constant for the reverse reaction (alpha -> beta). Comparison of the k(f) + k(r) values showed that reactions of glucuronic acid or galacturonic acid derivatives were ~10 to 3000 times faster than those of related glucoside and galactopyranoside counterparts and alpha:beta ratios were generally also higher. Stereoelectronic effects contributed from galacto-configured compounds were up to 2-fold faster than those of corresponding glucosides. The introduction of groups, including protecting groups, which are increasingly electron releasing generally led to rate enhancements. The anomerization of S glycosides was consistently faster than that of corresponding O-glycosides. Reactions were generally faster for reactions with TiCl(4) than those with SnCl(4). Anomeric ratios depended on the Lewis acid, the number equivalents of the Lewis acid, temperature, and substrate. Very high ratios of alpha-products for both O- and S-glucuronides were observed for reactions promoted by TiCl(4); for these substrates TiCl(4) was superior to SnCl(4). Anomeric ratios from anomerization of S-glucosides were higher with SnCl(4) than with TiCl(4). The dependence of equilibrium ratio on Lewis acid and the number of equivalents of Lewis acid indicated that the equilibrium ratio is determined by a complex of the saccharide residue bound to the Lewis acid and not the free glycoside. The high alpha:beta ratios observed for anomerization of both O- and S-glycuronic acids can be explained by coordination of the C-1 heteroatom and C-6 carbonyl group of the product to the Lewis acid, which would enhance the anomeric effect by increasing the electron-withdrawing ability of the anomeric substituent and lead to an increase in the proportion of the alpha-anomer. Such an observation would argue against the existence of a reverse anomeric effect. Support for a chelation induced endocyclic cleavage mechanism for the anomerization is provided by the trapping of a key intermediate. The data herein will help predict the tendency of beta-glycosides to undergo anomerization; this includes cases where 1,2-trans glycosides are initial products of glycosidation reactions catalyzed by TiCl(4) or SnCl(4). PMID- 20836489 TI - Volatile siloxanes in the European arctic: assessment of sources and spatial distribution. AB - The purpose of this study was to investigate presence and potential accumulation of cyclic volatile methyl siloxanes (cVMS) in the Arctic environment. Octamethylcyclotetrasiloxane (D4), decamethylcyclopentasiloxane (D5), and dodecamethylcyclohexasiloxane (D6) were analyzed in sediment, zooplankton, Atlantic cod (Gadus morhua), shorthorn sculpin (Myxocephalus scorpius), and bearded seal (Erignathus barbatus) collected from the Svalbard archipelago within the European Arctic in July 2009. Highest levels were found for D5 in fish collected from Adventfjorden, with average concentrations of 176 and 531 ng/g lipid in Atlantic cod and shorthorn sculpin, respectively. Decreasing concentration of D5 in sediment collected away from waste water outlet in Adventfjorden indicates that the local settlement of Longyearbyen is a point source to the local aquatic environment. Median biota sediment accumulation factors (BSAFs) calculated for D5 in Adventfjorden were 2.1 and 1.5 for Atlantic cod and shorthorn sculpin, respectively. Biota concentrations of D5 were lower or below detection limits in remote and sparsely populated regions (Kongsfjorden and Liefdefjorden) compared to Adventfjorden. The levels of cVMS were found to be low or below detection limits in bearded seal blubber and indicate a low risk for cVMS accumulation within mammals. Accumulation of cVMS in fish appears to be influenced by local exposure from human settlements within the Arctic. PMID- 20836490 TI - Impact of iron amendment on net methylmercury export from tidal wetland microcosms. AB - Tidal wetlands can be important sources of methylmercury (MeHg) in aquatic ecosystems. As a result, wetland restoration could increase MeHg concentrations. Previous research has shown that addition of Fe[II] to wetland sediment can reduce MeHg production by decreasing concentrations of bioavailable Hg complexes with dissolved sulfur species. In this study, the potential for reducing MeHg production via an iron amendment was evaluated in laboratory microcosms that used intact sediments from a tidal marsh in San Francisco Bay. The microcosms were maintained under simulated tidal conditions and amended at four iron doses (0, 180, 360, and 720 g-Fe/m(2)). Two experiments were conducted: one with devegetated sediments and one with live wetland vegetation. Following iron addition to the devegetated sediments, porewater S[-II] concentrations decreased for each dose relative to the control with the average weekly export of MeHg in the surface water decreased by 82% and 89% for the two highest doses, respectively. Despite substantial variability within treatment groups, similar trends were observed for the vegetated microcosms. The results suggest that iron addition has the potential to provide a landscape-scale control on MeHg released by restored tidal wetlands; however, additional research is required to evaluate the efficacy of this approach under field conditions. PMID- 20836491 TI - Single molecule experiments visualizing adsorbed polyelectrolyte molecules in the full range of mono- and divalent counterion concentrations. AB - This work provides direct experimental verification (on the level of single molecules) for the behavior of hydrophobic polyelectrolyte chains adsorbed at a solid-liquid interface in the full range of possible salt concentrations: (a) in a dilute salt solution, PE chains possess an extended coil conformation visualized as adsorbed 2D-equilibrated coils; (b) in a moderate salt concentration range, the polymer coil shrinks and approaches the dimensions of a polymer coil under theta-conditions and the chains are visualized as adsorbed 3D projected coils; (c) at high salt concentrations, the polymer coils reexpand and the molecules are visualized as 2D-equilibrated extended coils; however, (d) reexpansion is limited in the presence of multivalent counterions, presumably due to the bridging of the polymer coils by the counterions. PMID- 20836492 TI - Post-synthesis carbon doping of individual multiwalled boron nitride nanotubes via electron-beam irradiation. AB - We report on post-synthesis carbon doping of individual boron nitride nanotubes (BNNTs) via in situ electron-beam irradiation inside an energy-filtering 300 keV high-resolution transmission electron microscope. The substitution of C for B and N atoms in the honeycomb lattice was demonstrated through electron energy loss spectroscopy, spatially resolved energy-filtered elemental mapping, and in situ electrical measurements. Substitutional C doping transformed BNNTs from electrical insulators to conductors. In comparison with the existing post synthesis doping methods for nanoscale materials (e.g., ion implantation and diffusion), the discovered electron-beam-induced doping is a well-controlled, little-damaging, room-temperature, and simple strategy that is expected to demonstrate great promise for post-synthesis doping of diverse nanomaterials in the future. PMID- 20836493 TI - Pd-catalyzed three-component coupling of N-tosylhydrazone, terminal alkyne, and aryl halide. AB - A Pd-catalyzed three-component reaction of N-tosylhydrazone, terminal alkyne, and aryl halide follows a mechanism involving a sequence of Pd carbene migratory insertion-transmetalation-reductive elimination, leading to the formation of one sp(2)-sp(3) C-C bond and one sp-sp(3) C-C bond. PMID- 20836494 TI - Large polyoxotitanate clusters: well-defined models for pure-phase TiO2 structures and surfaces. AB - Careful control of the temperature and duration of the reaction between titanium tert-butoxide and acetic acid leads to the formation of new polyoxotitanate clusters with 14, 18, and 28 Ti atoms. They are considered intermediates in the growth of Ti/O nanoclusters of increasing size. The Ti(28) cluster is the largest crystallized to date. UV/vis spectroscopy on this cluster reveals that the optical band gap is blue-shifted with respect to a cluster containing only 17 titanium atoms indicating that the optical properties are more heavily influenced by the internal structure of the particle than its size. PMID- 20836495 TI - Total synthesis of chivosazole F. AB - The first synthesis of the highly biologically active chivosazole F is described. It features an intramolecular Stille coupling for the macrolactone formation and thereby circumvents the problem of isomerization associated with the tetraene segment. Additionally, the synthesis confirms the structure which has been proposed based solely on a combination of NMR/computational methods and genetic analysis. PMID- 20836496 TI - Dragmacidin E synthesis studies. Preparation of a model heptacyclic core structure. AB - The conversion of a cycloheptannelated indole platform into the heptacyclic core structure of dragmacidin E proceeded over nine steps. Key sequences include a cyclocondensation to form an intermediate dihydropyrazinone ring and the conversion of a cyclic urea into the cyclic guanidine of the target. PMID- 20836497 TI - Fate and efficacy of metolachlor granular and emulsifiable concentrate formulations in a conservation tillage system. AB - Use of genetically modified cultivars resistant to the herbicide glyphosate (N phosphonomethylglycine) is strongly associated with conservation-tillage (CsT) management for maize ( Zea mays L.), soybean ( Glycine max L.), and cotton ( Gossypium hirsutum L.) cultivation. Due to the emergence of glyphosate-resistant weed biotypes, alternate weed management practices are needed to sustain CsT use. This work focused on metolachlor use (2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2 methoxy-1-methylethyl)acetamide) in a CsT system. The fate and efficacy of granular and emulsifiable concentrate (EC) formulations or an EC surrogate were compared for CsT cotton production in the Atlantic Coastal Plain region of southern Georgia (USA). The granular formulation, a clay-alginate polymer, was produced in the authors' laboratory; EC was a commercial product. In field and laboratory dissipations the granular metolachlor exhibited 8-fold greater soil persistence. Rainfall simulation runoff assessments indicated that use of the granular formulation in a common CsT system, strip-tillage (ST), may reduce metolachlor runoff loss when compared to conventional tillage (CT) management or when EC formulations are used in the ST system. Metolachlor leaching assessments using field-deployed lysimeters showed some tillage (ST > CT) and formulation (EC > granular) differences. Overall leaching was generally small when compared to runoff loss. Finally, greenhouse bioassays showed control of two weed species with the granular was greater than or equal to that of the EC formulation; however, the granular formulation suppressed cotton growth to a greater extent. In sum, this metolachlor granular formulation has advantages for CsT cotton production; however, additional research is needed to assess impacts on crop injury. PMID- 20836498 TI - Purification and modes of antifungal action by Vicia faba cv. Egypt trypsin inhibitor. AB - A new 15 kDa Bowman-Birk type trypsin inhibitor (termed VFTI-E1) from fava beans (Vicia faba cv. Egypt 1) was isolated using liquid chromatography. Though it exhibited substantial homology in N-terminal amino acid sequence to other protease inhibitors, VFTI-E1 showed antiproteolytic activity against trypsin (K(i) 11.9 * 10(-9) M) but hardly any activity against chymotrypsin. It demonstrated antifungal activity toward the filamentous fungus Valsa mali with an IC(50) of 20 MUM. The mechanism of its antifungal action toward V. mali included (1) induction of alteration of hyphal morphology, (2) growth inhibition by chitin deposition at hyphal tips, and (3) permeabilization of fungal membrane. The antifungal activity of VFTI-E1 was dependent on the ambient ionic strength as increasing concentrations of NaCl, CaCl(2), and MgCl(2) diminished the activity. The membranolytic action of VFTI-E1 was confined to fungus, but not exerted on human and rabbit erythrocytes. This study sheds light on the mode of hyphal growth inhibitory activity of protease inhibitors with antifungal activity. The antifungal activity of VFTI-E1 amplifies the scope of its potential applications. PMID- 20836499 TI - Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles. AB - A palladium-catalyzed oxidative carbo-heterofunctionalization of aniline derivatives involving concomitant direct C-H functionalization and C-X bond formation was developed. By simply changing the reaction conditions (solvent and catalyst), either 3,3'-disubstituted oxindole or spirooxindole was accessible from the same starting material. PMID- 20836500 TI - Enhanced Raman scattering from nanoparticle-decorated nanocone substrates: a practical approach to harness in-plane excitation. AB - We investigate surface-enhanced Raman scattering (SERS) from gold-coated silicon germanium nanocone substrates that are decorated with 30-nm spherical gold nanoparticles (AuNPs). Finite-element simulations suggest that individual nanocones generate stronger electromagnetic enhancement with axial polarization (i.e., polarization parallel to the vertical axis of the nanocones) than with transverse polarization (i.e., polarization in the plane of the nanocone substrate), whereas the excitation in a typical Raman microscope is mainly polarized in the transverse plane. We introduce a practical approach to improve the SERS performance of the substrate by filling the valleys between nanocones with AuNPs. Simulations reveal an enhanced electric field at the nanoscale junctions formed between AuNPs and nanocones, and we explain this lateral coupling with a hybridization model for a particle-film system. We further experimentally verify the added enhancement by measuring SERS from trans-1,2-bi (4-pyridyl) ethylene molecules absorbed onto the substrates. We report over one order-of-magnitude increase in SERS activities with the AuNP decoration (compared to the nanocone substrate without AuNPs) and achieve a spatially averaged enhancement factor of 1.78 * 10(8) at 785-nm excitation. Understanding and implementing the enhancing mechanism of structured metallic surfaces decorated with plasmonic nanoparticles open possibilities to substantially improve the SERS performance of the existing process-engineered substrates. PMID- 20836501 TI - Thin, flexible secondary Li-ion paper batteries. AB - There is a strong interest in thin, flexible energy storage devices to meet modern society needs for applications such as interactive packaging, radio frequency sensing, and consumer products. In this article, we report a new structure of thin, flexible Li-ion batteries using paper as separators and free standing carbon nanotube thin films as both current collectors. The current collectors and Li-ion battery materials are integrated onto a single sheet of paper through a lamination process. The paper functions as both a mechanical substrate and separator membrane with lower impedance than commercial separators. The CNT film functions as a current collector for both the anode and the cathode with a low sheet resistance (~5 Ohm/sq), lightweight (~0.2 mg/cm(2)), and excellent flexibility. After packaging, the rechargeable Li-ion paper battery, despite being thin (~300 MUm), exhibits robust mechanical flexibility (capable of bending down to <6 mm) and a high energy density (108 mWh/g). PMID- 20836502 TI - pi-pi interaction-induced vertical alignment of silica mesochannels templated by a discotic lyotropic liquid crystal. AB - The development of vertically aligned mesochannels in organic/inorganic hybrid films is in high demand and a challenging issue. However, there are no clear guiding principles to attain the surface-mediated vertical alignment. This work proposes the first clear versatile strategy to achieve the vertical alignment by utilizing the pi-pi interaction between the organic template molecule of a planar discotic liquid crystalline and 2D pi-plane of graphite. The crucial role of the pi-pi interaction can be verified by the exploration with other substrates such as silicon wafer surfaces with varied surface energy (water contact angle: 5 degrees -105 degrees ), quartz plates, and polymer films, which provided common parallel alignment with respect to the substrate plane. PMID- 20836503 TI - Compact and light-weight automated semen analysis platform using lensfree on-chip microscopy. AB - We demonstrate a compact and lightweight platform to conduct automated semen analysis using a lensfree on-chip microscope. This holographic on-chip imaging platform weighs ~46 g, measures ~4.2 * 4.2 * 5.8 cm, and does not require any lenses, lasers or other bulky optical components to achieve phase and amplitude imaging of sperms over ~24 mm(2) field-of-view with an effective numerical aperture of ~0.2. Using this wide-field lensfree on-chip microscope, semen samples are imaged for ~10 s, capturing a total of ~20 holographic frames. Digital subtraction of these consecutive lensfree frames, followed by appropriate processing of the reconstructed images, enables automated quantification of the count, the speed and the dynamic trajectories of motile sperms, while summation of the same frames permits counting of immotile sperms. Such a compact and lightweight automated semen analysis platform running on a wide-field lensfree on chip microscope could be especially important for fertility clinics, personal male fertility tests, as well as for field use in veterinary medicine such as in stud farming and animal breeding applications. PMID- 20836504 TI - Binding and removal of sulfate, phosphate, arsenate, tetrachloromercurate, and chromate in aqueous solution by means of an activated carbon functionalized with a pyrimidine-based anion receptor (HL). Crystal structures of [H3L(HgCl4)].H2O and [H3L(HgBr4)].H2O showing anion-pi interactions. AB - Binding of anions of great environmental concern such as SO(4)(2-), PO(4)(3-), AsO(4)(3-), HgCl(4)(2-), and CrO(4)(2-) by the protonated forms of a tren-like (tren = tris(2-aminoethyl)amine) ligand (HL) functionalized with a pyrimidine residue was studied by means of potentiometric measurements and isothermal titration calorimetry (ITC) affording log K, DeltaH degrees , and TDeltaS degrees values for the formation of the relevant complexes. The complexes show high to very high stability due to the particular topology and electronic properties of the ligand which is able to use two separated coordination environments to host the anions, the protonated tren site where electrostatic and hydrogen bond interactions are operating, and the pyrimidine ring which may act via anion-pi interaction. A contribution of -8.9 +/- 0.4 kJ/mol for pyrimidine-anion interaction in water was derived for SO(4)(2-) binding. The crystal structures of [H(3)L(HgCl(4))].H(2)O (1), [H(3)L(HgBr(4))].H(2)O (2), and that previously reported for [H(3)L(CdI(4))], clearly show these binding features in the solid state. A hybrid AC-HL material obtained by adsorption of HL on commercial activated carbon (AC) was used to study the removal of these anions from water. AC-HL shows enhanced adsorption capacity toward all the anions studied with respect to AC. This behavior is ascribed to the stronger interaction of anions with the HL function of AC-HL than with the Cpi-H(3)O(+) sites of the unfunctionalized AC. PMID- 20836505 TI - Acetonitrile induces nonsynchronous interdigitation and dehydration of dipalmitoylphosphatidylcholine bilayers. AB - The formation mechanism of the interdigitated (L(beta)I) phase and the responses of the individual groups of phospholipids to the phase transition are of basic concern within the community of lipid research. In this work, we studied the effect of acetonitrile (CH(3)CN) on the structure and phase behavior of dipalmitoylphosphatidylcholine (DPPC) bilayers by using differential scanning calorimetry, synchrotron X-ray diffraction, and Fourier transform infrared spectroscopy. We found that the two processes (i.e., the interdigitation and dehydration of the DPPC bilayers) occur nonsynchronously at two different CH(3)CN concentrations (4 and 12 wt %). A detailed submolecular picture for the formation mechanism of the L(beta)I phase was provided during the L(beta') to L(beta)I phase transition at c(CH(3)CN) = 4 wt %: the conformation state and the hexagonal packing mode of the lipid acyl chains and the hydration properties of the lipid polar groups do not change, and the only difference is that the formed L(beta)I phase has a tighter lipid acyl chain packing than that of the L(beta') phase. When c(CH(3)CN) > 12 wt %, the added CH(3)CN molecules selectively dehydrate the interfacial carbonyl groups. Thus, two different kinds of L(beta)I phases differing only in the hydration states of the interfacial carbonyl groups of phospholipids exist in the c(CH(3)CN) regions of 5-12 and 13-40 wt %, respectively. The strong ability of acetonitrile to induce interdigitation in the lipid bilayers has been discussed in the viewpoint of its toxicity. PMID- 20836506 TI - Stereoselective biotransformation of permethrin to estrogenic metabolites in fish. AB - This study investigated the stereoselective biotransformation and resulting estrogenic activity of the pyrethroid insecticide, permethrin (PM). Results of both in vivo (male Japanese medaka, vitellogenin (VTG) protein in plasma) and in vitro (primary rainbow trout hepatocyte VTG-mRNA expression) assays indicated stereoselective estrogenic activity of PM. 1S-cis-PM was observed to have significantly higher activity (P <= 0.05) than the 1R-cis enantiomer in both in vivo and in vitro evaluations. All enantiomers of PM were oxidized to a 4'-hydoxy PM (4OH PM) metabolite and underwent esterase cleavage to 3-phenoxybenzyl alcohol (3-PBOH) and 3-(4'-hydroxyphenoxy)-benzyl alcohol) (3,4'-PBOH). Racemic 4OH PM as well as 3-PBOH, and 3,4'-PBOH possessed significant (P <= 0.05) estrogenicity. 1S trans-PM underwent esterase cleavage more extensively than the corresponding 1R trans-PM. Inhibition studies with ketoconazole confirmed cytochrome P450 catalyzed hydroxylation as well as esterase cleavage of PM for all stereoisomers. These studies indicated stereoselectivity in the estrogenic activity of PM resulting from stereoselective biotransformation of the parent compound to more estrogenic metabolites. PMID- 20836507 TI - Modulated photophysics of an ESIPT probe 1-hydroxy-2-naphthaldehyde within motionally restricted environments of liposome membranes having varying surface charges. AB - The present work demonstrates the modulation of excited state intramolecular proton transfer (ESIPT) emission of 1-hydroxy-2-naphthaldehyde (HN12) upon its interaction with the liposomal vesicles/bilayer of dimyristoyl-l-alpha phosphatidylcholine (DMPC) and dimyristoyl-l-alpha-phosphatidylglycerol (DMPG) and its subsequent implementation as an efficient molecular reporter for probing of microheterogeneous environments of lipid-bilayer system. Modifications on the emission profile of HN12 in terms of remarkable emission intensity enhancement coupled with a hypsochromic shift induced by the presence of DMPC and DMPG membranes have been interpreted to be vivid manifestations of the interactions between the two partners. Steady-state anisotropy, red-edge excitation shift (REES), and time-resolved fluorescence measurements have been fruitfully exploited to complement other experimental findings. Probable binding site of HN12 in the lipid-bilayers has been assessed on the basis of intertwining the results of fluorescence quenching with other experimental results and is further substantiated from docking studies. PMID- 20836508 TI - Effects of cryogenic sample analysis on molecular depth profiles with TOF secondary ion mass spectrometry. AB - Although the benefits of decreased sample temperature for the molecular profiling of organic materials with time-of-flight secondary ion mass spectrometry (TOF SIMS) have been established, the mechanism behind spectral changes observed at low temperature, particularly increased protonated molecular ion (M + H)(+) yields, have not been examined in detail. We have developed a procedure to investigate these effects by monitoring secondary ion yields under sustained primary ion bombardment as the sample temperature is cooled from room temperature down to 80 K. Examination of biomaterials such as an amino acid (arginine), a polypeptide (Gly-Gly-Tyr-Arg), a lipid (1,2 dipalmitoyl-sn-glycero-3 phosphatidylcholine), and a drug molecule (cyclosporine A) each provide evidence of ion yield enhancement at 80 K under either 20 keV C(60)(+) or 20 keV Au(3)(+) bombardment. For example, arginine shows a 2-fold increase in the steady-state intensity for the (M + H)(+) ion at 80 K compared to the steady state at 300 K. It is shown that there is a correlation between the yield enhancement and a reduction in the damage cross section, which for arginine under 20 keV Au(3)(+) bombardment decreases from 5.0 +/- 0.4 * 10(-14) cm(2) at 300 K to 2.0 +/- 0.3 * 10(-14) cm(2) at 80 K. The role of water as the facilitator for this reduction is explored through the use of H(2)O and D(2)O dosing experiments at 80 K. PMID- 20836509 TI - First studies on the influence of methylated beta-cyclodextrin on the rheological behavior of 1-ethyl-3-methyl imidazolium acetate. AB - The rheology of solutions of randomly methylated (1.8) beta-cyclodextrin (beta CD) in 1-ethyl-3-methyl imidazolium acetate ([EMIM][Ac]) was studied in detail by rotational and oscillatory shear measurements. It was found that a gel structure was formed even at a relatively low beta-CD concentration, which induced intriguing results in oscillation experiments. The solutions showed abrupt changes of the structurally dependent rheological moduli and reproducible transitions from gel to sol state at specific shear stress. For all beta-CD solutions, a non-Newtonian flow behavior including shear thinning was obtained. The influence of temperature and beta-CD concentration on the flow behavior was studied for all solutions, and the flow activation energies were calculated from the logarithmic form of the Arrhenius equation for nonassociating electrolytes. PMID- 20836510 TI - Measuring the invisible. PMID- 20836511 TI - Mechanism for the formation of substituted manganese(V) cyanidonitrido complexes: crystallographic and kinetic study of the substitution reactions of trans [MnN(H2O)(CN)4]2- with monodentate pyridine and bidentate pyridine-carboxylate ligands. AB - Dissolution of [(CH(3))N](2)Na[MnN(CN)(5)].H(2)O in water results in the rapid dissociation of the trans-CN(-) ligand to form trans-[MnN(H(2)O)(CN)(4)](2-)(aq), which reacts with monodentate pyridine ligands such as 3-methyl and 4-methyl pyridine to form the corresponding mono-substituted complexes, of which the molecular structures obtained from X-ray crystallography, trans-[MnN(3 pic)(CN)(4)](2-) and trans-[MnN(4-pic)(CN)(4)](2-), are reported. [MnN(H(2)O)(CN)(4)](2-)(aq) also reacts with bidentate nucleophiles such as pyridine-2-carboxylate (pico) and quinoline-2-carboxylate (quino), yielding the corresponding [MnN(eta(2)-pico)(CN)(3)](2-) and [MnN(eta(2)-quino)(CN)(3)](2-) complexes as determined by X-ray crystallography. The formation kinetics of pyridine-2-carboxylate and three different pyridine-2,x-dicarboxylate ligands (x = 3, 4, 5) are reported, and two consecutive reaction steps are proposed, defined as the formation of the [MnN(eta(1)-pico)(CN)(4)](3-) and [MnN(eta(2) pico)(CN)(3)](3-) complexes, respectively. Only the second steps could be spectrophotometrically observed and kinetically investigated. The first reaction is attributed to the rapid aqua substitution of [MnN(H(2)O)(CN)(4)](2-), thermodynamically unfavored and too fast to observe by conventional rapid third generation stopped-flow techniques. The second, slower reaction is attributed to cyanido substitution, with overall formation rate constants (25 degrees C; k(1)'; M(-1) s(-1)) and corresponding activation parameters (DeltaH(k1')(double dagger), kJ mol(-1), DeltaS(k1')(double dagger), J K(-1) mol(-1)) for the following entering bidentate nucleophiles: pyridine-2-carboxylate: (1.15 +/- 0.04) * 10(-3), 102 +/- 1, and 48 +/- 3; pyridine-2,3-dicarboxylate: (1.1 +/- 0.1) * 10(-3), 93 +/- 2, and 20 +/- 4; pyridine-2,4-dicarboxylate (8.5 +/- 0.5) * 10(-4), 123 +/- 5, and 115 +/- 14; pyridine-2,5-dicarboxylate: (1.08 +/- 0.04) * 10(-3), 106 +/- 1, and 60 +/- 2. A dissociative activation for the cyanido substitution process is proposed. PMID- 20836512 TI - Reversible resistive switching and multilevel recording in La0.7Sr0.3MnO3 thin films for low cost nonvolatile memories. AB - On the basis of a scanning probe microscopy strategy, we propose a combined methodology capable to program nonvolatile multilevel data and read them out in a noninvasive manner. In the absence of the common two-electrode cell geometry, this nanoscale approach permits, in addition, investigating the relevance of inherent film properties. We demonstrate the feasibility of modifying the local electronic response of La(0.7)Sr(0.3)MnO(3) to obtain nanostructures with switchable resistance embedded in low cost oxide thin films, which constitutes a promising approach for fabricating high density nonvolatile memories. PMID- 20836513 TI - Facile determination of the spectra of unstable electrode products using simultaneous fiber-optic chronoabsorptometry and chronoamperometry. AB - A widely applicable fiber-optic UV-vis method to determine the spectra of in situ generated redox products and intermediates at or near an electrode surface is described mathematically and implemented experimentally. The quantitative spectral information obtained gives extinction coefficients (absorptivities) as a function of wavelength, requires no arbitrary subtraction of the spectrum of the starting material, and is relatively insensitive to path length and concentration during the spectroelectrochemical measurements. We demonstrate proof-of-concept of this methodology by reproducing the expected spectrum of the ferrocenium ion from electrooxidation of ferrocene in MeCN, and by reproducing the spectrum that reveals pi-radical cation formation from the electrooxidation of (T(p OMe)PP)Co(NO) ((T(p-OMe)PP = 5,10,15,20-tetra(p-methoxyphenyl)porphyrinato dianion). Importantly, we demonstrate its use for the facile detection of unstable redox products not previously detected by current spectroelectrochemical methods. We obtain, for the first time, the experimental UV-vis spectrum of the short-lived fac-[(dppe)Mn(CO)(3)Br](+) cation, a hitherto uncharacterized intermediate that forms during the archetypal redox-induced fac-to-mer isomerization of (dppe)Mn(CO)(3)Br (dppe = diphenylphosphinoethane). Spectral features of the Mn-containing species have been verified by comparison to theoretical spectra calculated by time-dependent density functional theory methods. PMID- 20836514 TI - Probing the antioxidant action of selenium and sulfur using Cu(I)-chalcogenone tris(pyrazolyl)methane and -borate complexes. AB - Hydroxyl radical generated from the reaction of Cu(+) with hydrogen peroxide results in oxidative DNA damage, and this damage is implicated in aging, cancer, and many other diseases. Selenium- and sulfur-containing compounds can act as antioxidants, and coordination of selenium and sulfur to copper is one explanation for this antioxidant activity. To determine how copper coordination results in antioxidant activity, biologically relevant tris(pyrazolyl)methane and borate Cu(+) complexes of the formulas Tp*Cu(L) and [Tpm(R)Cu(L)](+), where (L = N, N'-dimethylimidazole selone, dmise; N, N'-dimethylimidazole thione, dmit; Tp* = hydrotris(3,5-dimethylpyrazolyl)borate; Tpm(R) = tris(pyrazolyl)methane, R = H; Tpm, R = Me; Tpm*, R = iPr; Tpm(iPr)), have been synthesized and characterized. The structures of complexes Tp*Cu(Dmit), Tp*Cu(dmise), [Tpm(R)Cu(dmise)][BF(4)], and [Tpm(R)Cu(Dmit)][BF(4)] (where R = H; Tpm, R = Me; Tpm*, R = iPr; Tpm(iPr)) were determined by X-ray crystallography. All the Cu(+) centers adopt distorted tetrahedral coordination geometry, and Cu-Se and Cu-S distances for all the complexes are approximately 2.30 A, and 2.20 A, respectively. The effects of counterion and steric bulk at the 3 and 5 positions of the pyrazolyl ring on the structural and spectroscopic properties are discussed. Selone or thione coordination to copper significantly alters the Cu(+/2+) redox potential: Cu selone complexes have Cu(2+/+) potentials from -283 to -390 mV, whereas those of Cu-thione complexes range from 70 to -232 mV versus NHE. The Cu-selone complexes have Cu(2+/+) potentials near or below that of the cellular reductant NADH (-324 mV). Thus, selenium and sulfur coordination to copper in biological systems may prevent the Cu(2+) reduction by NADH required for the catalytic formation of damaging hydroxyl radical. PMID- 20836515 TI - An optimized immunoaffinity fluorescent method for natural product target elucidation. AB - Understanding the mode of action of small molecules is an integral facet of drug discovery. We report an optimized immunoaffinity fluorescent method that allows one to conduct parallel studies at both the cellular and molecular level using a single probe construct. Viability of the method has been evaluated analytically and applied using glycyrrhetic acid as a model. PMID- 20836516 TI - Eucophylline, a Tetracyclic Vinylquinoline Alkaloid from Leuconotis eugenifolius. AB - Eucophylline (1), a new tetracyclic vinylquinoline alkaloid, was isolated from the bark of Leuconotis eugenifolius together with leucophyllidine (2). The structure and absolute configuration of 1 were elucidated on the basis of 2D NMR correlations and simulated CD analysis. Leucophyllidine (2) showed iNOS inhibitory activity and decreased the iNOS protein expression dose-dependently. PMID- 20836517 TI - Indium flux-growth of Eu2AuGe3: a new germanide with an AlB2 superstructure. AB - The germanide Eu(2)AuGe(3) was obtained as large single crystals in high yield from a reaction of the elements in liquid indium. At room temperature Eu(2)AuGe(3) crystallizes with the Ca(2)AgSi(3) type, space group Fmmm, an ordered variant of the AlB(2) type: a = 857.7(4), b = 1485.5(10), c = 900.2(4) pm. The gold and germanium atoms build up slightly distorted graphite-like layers which consist of Ge(6) and Au(2)Ge(4) hexagons, leading to two different hexagonal-prismatic coordination environments for the europium atoms. Magnetic susceptibility data showed Curie-Weiss law behavior above 50 K and antiferromagnetic ordering at 11 K. The experimentally measured magnetic moment indicates divalent europium. The compound exhibits a distinct magnetic anisotropy based on single crystal measurements and at 5 K it shows a metamagnetic transition at ~10 kOe. Electrical conductivity measurements show metallic behavior. The structural transition at 130 K observed in the single crystal data was very well supported by the conductivity measurements. (151)Eu Mossbauer spectroscopic data show an isomer shift of -11.24 mm/s at 77 K, supporting the divalent character of europium. In the magnetically ordered regime one observes superposition of two signals with hyperfine fields of 26.0 (89%) and 3.5 (11%) T, respectively, indicating differently ordered domains. PMID- 20836518 TI - Similarities and differences between cyclodextrin-sodium dodecyl sulfate host guest complexes of different stoichiometries: molecular dynamics simulations at several temperatures. AB - An extensive dynamic and structural characterization of the supramolecular complexes that can be formed by mixing alpha-, beta-, and gamma-cyclodextrin (CD) with sodium dodecyl sulfate (SDS) in water at 283, 298, and 323 K was performed by means of computational molecular dynamics simulations. For each CD at the three temperatures, seven different initial conformations were used, generating a total of 63 trajectories. The observed stoichiometries, intermolecular distances, and relative orientation of the individual molecules in the complexes, as well as the most important interactions which contribute to their stability and the role of the solvent water molecules were studied in detail, revealing clear differences and similarities between the three CDs. Earlier reported findings in the inclusion complexes field are also discussed in the context of the present results. For any of the three native cyclodextrins, the CD(2)SDS(1) species in the head-to-head conformation appears to be a promising building block for nanotubular aggregates both in the bulk and at the solution/air interface, as earlier suggested for the case of alpha-CD. Moreover, the observed noninclusion arrangements involving beta-CD are proposed as the seed for the premicellar (beta CD)-induced aggregation of SDS described in the literature. PMID- 20836519 TI - Structure-property correlations in hybrid polymer-nanoparticle electrospun fibers and plasmonic control over their dichroic behavior. AB - Electrospinning constitutes a simple and versatile approach of fabricating polymer heterostructures composed of nanofibers. A preferred alignment of polymer crystallites stems from complex shear elongational forces and generates a strong intrinsic optical anisotropy in typical electrospun fibers of semicrystalline polymers. While it can prove useful for certain devices, this intrinsic anisotropy can be extremely detrimental for other key applications such as high performance polymer-based lighting and solar-energy harvesting platforms. We report a dramatic reduction in the intrinsic dichroism of electrospun poly(ethylene oxide) fibers resulting from the incorporation of inorganic nanoparticles in the polymer matrix. This effect is shown to originate from a controllable randomization of the orientational ordering of the crystalline domains in the hybrid nanofibers and not merely from a reduction in crystallinity. This improved understanding of the crystalline structure-optical property correlation then leads to a better control over the intrinsic anisotropy of electrospun fibers using localized surface-plasmon enhancement effects around metallic nanoparticles. PMID- 20836520 TI - Biocatalytic fabrication of fast-degradable, water-soluble polycarbonate functionalized with tertiary amine groups in backbone. AB - Degradable polymers with specifically designed functionality have wide applications in biomedical fields. We reported herein the synthesis and characterization of a water-soluble and fast-degradable polycarbonate, functionalized with tertiary amine groups in the backbone. A novel cyclic carbonate monomer, namely, 6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza cyclohexadecane-2,10-dione (ADMC)(2), was synthesized and polymerized to provide the title polycarbonate [poly(ADMC)] via Novozym-435 lipase or tin(II) 2 ethylheaxanoate [Sn(Oct)(2)] catalyzed ring-opening polymerization (ROP). Novozym 435 lipase exhibited high activity toward the ROP in terms of molecular weight (M(n)) and monomer conversion, whereas the attempt with Sn(Oct)(2) failed. In the presence of molecular sieves-4 A, the highest M(n) value of 1.2 * 10(4) g/mol was obtained in toluene with an initial monomer concentration of 0.58 M at 75 degrees C in the presence of 10 wt % of Novozym-435 to the monomer. Parameters that influence the polymerization, including reaction temperature, enzyme concentration, monomer concentration, and solvent composition, were investigated systematically. The resultant data suggested "living" characteristics for this enzyme-catalyzed polymerization, and the "living" feature seemed independent of the lipase concentration. The polymerization conducted in mixed solvents (toluene/isooctane) showed that product M(n)s were heavily dependent on the solvent composition. Poly(ADMC) was demonstrated to be amorphous by DSC technique. The obtained poly(ADMC) was found to be soluble in most of the organic solvents and interestingly in H(2)O as well. In vitro hydrolytic degradation of poly(ADMC) as monitored by GPC indicated the degradation was a relatively fast process. HPLC-ESI/MS and (1)H NMR analyses demonstrated that N-methyl diethanolamine was the main product after degradation. Poly(ADMC) presented low cytotoxicity toward human cervix carcinoma (HeLa) cells and hepatoblastoma cells (Hep G2), as demonstrated by MTT assay. PMID- 20836521 TI - Degradable, thermo-sensitive poly(N-isopropyl acrylamide)-based scaffolds with controlled porosity for tissue engineering applications. AB - We have developed a thermoresponsive poly(N-isopropyl acrylamide)-based scaffold with degradability and controlled porosity. Biodegradable poly(N-isopropyl acrylamide) hydrogels were synthesized by photocopolymerization of N isopropylacrylamide with 2-methylene-1,3-dioxepane and polycaprolactone dimethacrylate. The hydrogels' phase transition temperature, swelling, and viscoelastic properties, as well as hydrolytic degradability at 25 and 37 degrees C, were explored. A sphere-templating technique was applied to fabricate hydrogel scaffolds with controllable pore size and a highly interconnected porous structure. The scaffold pore diameter change as a function of temperature was evaluated and, as expected, pores decreased in diameter when the temperature was raised to 37 degrees C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test results suggested neither the scaffolds nor their degradation products were cytotoxic to NIH3T3 cells. Scaffolds with 55 +/- 5 MUm pore diameter were loaded with NIH3T3 cells and then were warmed to 37 degrees C entrapping cells in pores approximately 39 MUm in diameter, a size range we have found to be optimal for angiogenesis and biointegration. Cells showed uniform infiltration and an elongated morphology after 7 days of culture. Due to the controlled monodisperse pore diameter, highly interconnected architecture, fully degradable chemistry and thermoresponsive properties, the polyNIPAM-based scaffolds developed here are attractive for applications in tissue engineering. PMID- 20836523 TI - A short synthesis of the triazolopyrimidine antibiotic essramycin. AB - A short synthesis of the 1,2,4-triazolo[1,5-a]pyrimidine antibiotic essramycin is described involving condensation of aminoguanidine with ethyl benzoylacetate to give an amino-1,2,4-triazole, followed by condensation with ethyl acetoacetate to form the pyrimidone ring. PMID- 20836522 TI - (-)-CHANA, a fluorogenic probe for detecting amyloid binding alcohol dehydrogenase HSD10 activity in living cells. AB - The association of 17beta-hydroxysteroid dehydrogenase 10 (HSD10) with beta amyloid in the brain is known to contribute to the progression of Alzheimer's disease. Further, it has been shown that the interaction between the purified HSD10 and beta-amyloid inhibits its enzymatic activity. However, to date no system has been developed to enable the study of HSD10 activity in intact living cells. To address this significant shortcoming, we have developed a novel fluorogenic probe, (-)-cyclohexenyl amino naphthalene alcohol [(-)-CHANA], to observe and measure the activity of HSD10 in living cells. The oxidation of (-) CHANA by HSD10 results in the production and accumulation of a fluorescent product, which can be measured using real-time fluorescence microscopy. This compound permits the measurement of mitochondrial HSD10 activity and its inhibition by both a small molecule HSD10 inhibitor and by beta-amyloid, in living cells. Herein, we define the parameters under which this probe can be used. This compound is likely to prove useful in future investigations aimed at developing therapeutic compounds targeting the HSD10-beta-amyloid association. PMID- 20836524 TI - Microwave spectrum, and conformational composition of (chloromethyl)phosphine (ClCH2PH2). AB - (Chloromethyl)phosphine, (ClCH(2)PH(2)) has been studied by microwave spectroscopy at -30 degrees C in the 22-80 GHz spectral interval. The experimental study has been augmented by quantum chemical calculations at the MP2/aug-cc-pVQZ and B3LYP/aug-cc-pVTZ levels of theory. The spectra of the ground as well as of several vibrationally excited states of the (35)ClCH(2)PH(2) and (37)ClCH(2)PH(2) isotopologues of two rotameric forms, denoted I and II, have been assigned. These conformers have different orientations of the phosphino group. I has a symmetry plane, consisting of the Cl-C-P link of atoms, whereas the phosphino group is rotated out of this symmetry plane in II. Conformer I was found to be 4.3(5) kJ/mol more stable than II by relative intensity measurements. The rotational and quartic centrifugal distortion constants calculated using the MP2/aug-cc-pVQZ procedure are in very good agreement with their experimental counterparts. Less good agreement is found in the B3LYP/aug-cc-pVTZ calculations. Both computational procedures predict energy differences between I and II that are close to the experimental energy difference. It is suggested that I is the preferred form of this molecule because it is stabilized by weak intramolecular hydrogen bonding between the chlorine atom and the hydrogen atoms of the phosphino group. Repulsion between the lone electron pair of the phosphorus atom and the chlorine atom also stabilizes I relative to II. PMID- 20836525 TI - Silica-polypeptide composite particles: controlling shell growth. AB - A method is presented for preparing core-shell silica-polypeptide composite particles with variable and controllable shell growth. The procedure is demonstrated using poly(carbobenzoxy-L-lysine) and poly(benzyl-L-glutamate); after deprotection, these can lead to the most common basic and acidic homopolypeptides, poly(L-lysine) and poly(L-glutamic acid). Control over shell thickness is made possible by sequential addition of N-carboxyanhydride peptide monomer to surfaces that have been functionalized with an amino initiator combined with a surface passivation agent. This results in a series of particles having different shell thicknesses. Variation of shell thickness was evident both in light scattering and in thermogravimetric assays. The shells were visible by transmission electron microscopy; these images along with light scattering measurements suggest the polymers in the shells are highly solvated. PMID- 20836526 TI - Low-lying triplet states of diphosphene and diphosphinylidene. AB - In this research, six low-lying triplet states of diphosphene (HPPH) and disphosphinylidene (PPH(2)) are systematically investigated starting from self consistent field theory and proceeding to multireference coupled cluster methods using a wide range of basis sets. For each structure, the geometry, energy, dipole moment, harmonic vibrational frequencies, and infrared intensities are predicted. The triplet potential energy surface (PES) of P(2)H(2) is presented, based on systematically extrapolated coupled cluster energies and accounting for core-valence correlation, zero-point vibrational energy, and diagonal Born Oppenheimer effects. Both (3)A'' pyramidal PPH(2) and (3)B skewed HPPH are minima on the triplet PES and lie 27.4 +/- 0.3 and 32.4 +/- 0.3 kcal mol(-1) above the global minimum structure closed-shell (1)A(g) trans-HPPH, respectively. The energy barrier for the isomerization reaction [(3)B skewed HPPH -> (3)A'' pyramidal PPH(2)] is predicted to be 16.4 +/- 0.3 kcal mol(-1). On this triplet PES, two equivalent (3)B skewed HPPH are converted via the (3)B(u) trans-HPPH transition state with a barrier of 9.1 +/- 0.3 kcal mol(-1) or via the (3)B(2) cis-HPPH transition state with a barrier of 11.1 +/- 0.3 kcal mol(-1). Moreover, the two equivalent (3)A'' pyramidal PPH(2) structures are connected through the (3)A(2) planar PPH(2) transition state with a barrier of 18.6 +/- 0.3 kcal mol( 1). The energy crossing of the singlet and triplet adiabatic PES is studied using Mukherjee multireference coupled cluster method with the cc-pVQZ basis set, which predicts that the (3)B skewed HPPH is 1.4 kcal mol(-1) lower in energy than the corresponding (1)A skewed HPPH at the (3)B skewed HPPH optimized geometry. PMID- 20836527 TI - Ca(2+) bridging of apposed phospholipid bilayers. AB - In an effort to provide insight into the mechanism of Ca(2+)-induced fusion of lipid vesicles, molecular dynamics simulations in the isobaric-isothermal ensemble are used to investigate interactions of Ca(2+) with apposed lipid bilayers in close proximity. Simulations reveal the formation of a Ca(2+) phospholipid "anhydrous complex" between apposed bilayers, whereas similar calculations performed with Na(+) display only complexation between neighboring lipids within the same bilayer. The binding of Ca(2+) to apposed phospholipids brings large regions of the bilayers into close contact (<4 A), displacing water from phospholipid head groups in the process and creating regions of local dehydration. Dehydration of the apposed bilayers leads to ordering of the phospholipid tails, which is partially disrupted by the presence of Ca(2+) phospholipid bridges. PMID- 20836528 TI - Investigation of the role of bicyclic peroxy radicals in the oxidation mechanism of toluene. AB - The products of the primary OH-initiated oxidation of toluene were investigated using the turbulent flow chemical ionization mass spectrometry technique under different oxygen, NO, and initial OH radical concentrations as well as a range of total pressures. The bicyclic peroxy radical intermediate, a key proposed intermediate species in the Master Chemical Mechanism (MCM) for the atmospheric oxidation of toluene, was detected for the first time. The toluene oxidation mechanism was shown to have a strong oxygen concentration dependence, presumably due to the central role of the bicyclic peroxy radical in determining the stable product distribution at atmospheric oxygen concentrations. The results also suggest a potential role for bicyclic peroxy radical + HO(2) reactions at high HO(2)/NO ratios. These reactions are postulated to be a source of the inconsistencies between environmental chamber results and predictions from the MCM. PMID- 20836529 TI - Role of water in the enzymatic catalysis: study of ATP + AMP -> 2ADP conversion by adenylate kinase. AB - The catalytic conversion ATP + AMP -> 2ADP by the enzyme adenylate kinase (ADK) involves the binding of one ATP molecule to the LID domain and one AMP molecule to the NMP domain. The latter is followed by a phosphate transfer and then the release of two ADP molecules. We have computed a novel two-dimensional configurational free energy surface (2DCFES), with one reaction coordinate each for the LID and the NMP domain motions, while considering explicit water interactions. Our computed 2DCFES clearly reveals the existence of a stable half open half-closed (HOHC) intermediate state of the enzyme. Cycling of the enzyme through the HOHC state reduces the conformational free energy barrier for the reaction by about 20 kJ/mol. We find that the stability of the HOHC state (missed in all earlier studies with implicit solvent model) is largely because of the increase of specific interactions of the polar amino acid side chains with water, particularly with the arginine and the histidine residues. Free energy surface of the LID domain is rather rugged, which can conveniently slow down LID's conformational motion, thus facilitating a new substrate capture after the product release in the catalytic cycle. PMID- 20836530 TI - Theoretical investigations on the reaction of monosubstituted tertiary benzylamine selenols with hydrogen peroxide. AB - The effects of introducing electron-donating (NH(2), OCH(3), CH(3)) and electron withdrawing (NO(2), CF(3), CN, F) groups to N,N-dimethylbenzylamine-2-selenol are studied to determine the effect of the selenium electron density on the efficiency of the reduction of hydrogen peroxide. Introducing substituents in the meta and para positions decreases or increases the energy barrier of the reaction in the expected way, due to changes in the electronic environment of the reacting selenium center. Ortho substituents are found to have a greater effect on the electronic environment of the selenium center, which is mitigated by changing the steric environment. Insight into the origins of the substituent effects is obtained through quantum theory of atoms in molecules (QTAIM) and electrostatic potential analysis. PMID- 20836531 TI - Energy transfer by way of an exciplex intermediate in flexible boron dipyrromethene-based allosteric architectures. AB - We have designed and synthesized a series of modular, dual-color dyes comprising a conventional boron dipyrromethene (Bodipy) dye, as a yellow emitter, and a Bodipy dye possessing extended conjugation that functions as a red emitter. A flexible tether of variable length, built from ethylene glycol residues, connects the terminal dyes. A critical design element of this type of dyad relates to a secondary amine linkage interposed between the conventional Bodipy and the tether. Cyclic voltammetry shows both Bodipy dyes to be electroactive and indicates that the secondary amine is quite easily oxidized. The ensuing fluorescence quenching is best explained in terms of the rapid formation of an intermediate charge-transfer state. In fact, exciplex-type emission is observed in weakly polar solvents and over a critical temperature range. In the dual-color dyes, direct excitation of the yellow emitter results in the appearance of red fluorescence, indicating that the exciplex is likely involved in the energy transfer event, and provides for a virtual Stokes shift of 5000 cm(-1). Replacing the red emitter with a higher energy absorber (namely, pyrene) facilitates the collection of near-UV light and extends the virtual Stokes shift to 8000 cm(-1). Modulation of the efficacy of intramolecular energy transfer is achieved by preorganization of the connector in the presence of certain cations. This latter behavior, which is fully reversible, corresponds to an artificial allosteric effect. PMID- 20836532 TI - Aggregation and rearrangement within a silver nanoparticle layer during polyelectrolyte multilayer formation. AB - Silver nanoparticles (4.5 nm average radius) are used as the first negatively charged layer of a polyelectrolyte multilayer prepared subsequently from poly(allylamine hydrochloride) (PAH) and poly(styrenesulfonate) (PSS) solutions with 1 M KCl. After adsorption of a PAH layer on top of the silver nanoparticle monolayer, particle aggregation occurs, as evidenced by the double peak of the UV vis absorption spectrum and by the decreased number of the objects found with AFM. On adsorption of the first PSS layer on top of the Ag/PAH sandwich, the nanoparticles remain close as is indicated by a the reduced object count and the changed absorption spectrum. If the PAH layer covering the Ag nanoparticles is adsorbed from salt-free solution, the nanoparticles remain isolated. Apparently, the aggregation is mediated by the PAH adsorbing in coiled conformation. Additionally, UV-vis and X-ray reflectivity evidence is found for lateral yet not vertical nanoparticle movement when polyelectrolytes adsorb, even if the adsorbing coils do not touch the nanoparticles directly. PMID- 20836533 TI - Renormalizing SMD: the renormalization approach and its use in long time simulations and accelerated PMF calculations of macromolecules. AB - Simulations of long time process in condensed phases, in general, and in biomolecules, in particular, present a major challenge that cannot be overcome at present by brute force molecular dynamics (MD) approaches. This work takes the renormalization method, intruded by us sometime ago, and establishes its reliability and potential in extending the time scale of molecular simulations. The validation involves a truncated gramicidin system in the gas phase. This system is small enough to allow for very long explicit simulations and sufficiently complex to present the physics of realistic ion channels. The renormalization approach is found to be reliable and arguably presents the first approach that allows one to exploit the otherwise problematic steered molecular dynamics (SMD) treatments in quantitative and meaningful studies. It is established that we can reproduce the long time behavior of large systems by using Langevin dynamics (LD) simulations of a renormalized implicit model. This is done without spending the enormous time needed to obtain such trajectories in the explicit system. The present study also provides a promising advance in accelerated evaluation of free energy barriers. This is done by adjusting the effective potential in the implicit model to reproduce the same passage time as that obtained in the explicit model under the influence of an external force. Here having a reasonable effective friction provides a way to extract the potential of mean force (PMF) without investing the time needed for regular PMF calculations. The renormalization approach, which is illustrated here in realistic calculations, is expected to provide a major help in studies of complex landscapes and in exploring long time dynamics of biomolecules. PMID- 20836534 TI - Brightly phosphorescent, environmentally responsive hydrogels containing a water soluble three-coordinate gold(I) complex. AB - Stimuli-responsive phosphorescent hydrogel microspheres have been synthesized by incorporating a water-soluble phosphorescent Au(I) complex, Na(8)[Au(TPPTS)(3)], TPPTS = tris(3,3',3''-trisulfonatophenyl)phosphine, into the polymer network of poly(N-isopropylacrylamide) (PNIPAM). Remarkable sensitization of the Au-centered emission takes place in the resulting phosphorescent hydrogels (by up to 2 orders of magnitude!) compared to that of the gold complex alone in pure water. Results of pH- and temperature-dependent luminescence titrations show that the sensitization is further magnified at physiological conditions, which is desirable for biomedical applications that will include bioimaging and drug delivery. The physical properties of PNIPAM microgels are not negatively impacted by the presence of the gold luminophore, as the colloidal crystallinity and phase transition properties remain intact. Phosphorescent microspheres have been further cross-linked by covalently bonding to neighboring particles, leading to brightly phosphorescent/high-water-content crystalline hydrogel networks with more stable crystallinity vs microgel soft crystals. These gel networks exhibit the same green phosphorescence seen in the hydrogel microspheres and pure Na(8)[Au(TPPTS)(3)] aqueous solutions with a broad unstructured profile and peak maximum at ~525 nm. Dehydration leads to further emission sensitization and gradual blue shifts that can be fine-tuned to ultimately reach a turquoise emission at ~490 nm in the freeze-dried form of the gel, corresponding to the emission of single crystals of Na(8)[Au(TPPTS)(3)], in agreement with the photoinduced Jahn-Teller distorted excited state model we reported earlier. Remarkable sensitivity to temperature and pH takes place in the emission enhancement with particularly favorable results at physiological conditions. The work herein represents a unique example of a stimulus-responsive phosphorescent hydrogel from a transition metal-based as opposed to lanthanide-based phosphor in an aqueous medium. PMID- 20836535 TI - Activation of DNA cleavage by oligomerization of DNA-bound SgrAI. AB - SgrAI is a type II restriction endonuclease that cuts an unusually long recognition sequence and exhibits allosteric self-modulation of DNA activity and sequence specificity. Precleaved primary site DNA has been shown to be an allosteric effector [Hingorani-Varma, K., and Bitinaite, J. (2003) J. Biol. Chem. 278, 40392-40399], stimulating cleavage of both primary (CR|CCGGYG, where the vertical bar indicates a cut site, R denotes A or G, and Y denotes C or T) and secondary [CR|CCGGY(A/C/T) and CR|CCGGGG] site DNA sequences. The fact that DNA is the allosteric effector of this endonuclease suggests at least two DNA binding sites on the functional SgrAI molecule, yet crystal structures of SgrAI [Dunten, P. W., et al. (2008) Nucleic Acids Res. 36, 5405-5416] show only one DNA duplex bound to one dimer of SgrAI. We show that SgrAI forms species larger than dimers or tetramers [high-molecular weight species (HMWS)] in the presence of sufficient concentrations of SgrAI and its primary site DNA sequence that are dependent on the concentration of the DNA-bound SgrAI dimer. Analytical ultracentrifugation indicates that the HMWS is heterogeneous, has sedimentation coefficients of 15-20 s, and is composed of possibly 4-12 DNA-bound SgrAI dimers. SgrAI bound to secondary site DNA will not form HMWS itself but can bind to HMWS formed with primary site DNA and SgrAI. Uncleaved, as well as precleaved, primary site DNA is capable of stimulating HMWS formation. Stimulation of DNA cleavage by SgrAI, at primary as well as secondary sites, is also dependent on the concentration of primary site DNA (cleaved or uncleaved) bound SgrAI dimers. SgrAI bound to secondary site DNA does not have significant stimulatory activity. We propose that the oligomers of DNA-bound SgrAI (i.e., HMWS) are the activated, or activatable, forms of the enzyme. PMID- 20836536 TI - Gene silencing mediated by magnetic lipospheres tagged with small interfering RNA. AB - Lipospheres made from soy bean oil and a combination of the cationic lipid Metafectene and the helper lipid dioleoylphosphatidyl-ethanolamine were functionalized with magnetic nanoparticles (NPs) and small interfering RNA (siRNA). The resulting magnetic lipospheres loaded with siRNA are proven here as efficient nonviral vectors for gene silencing. Embedding magnetic NPs in the shell of lipospheres allows for magnetic force-assisted transfection (magnetofection) as well as magnetic targeting in both static and fluidic conditions mimicking the bloodstream. PMID- 20836537 TI - Thickness-dependent thermal conductivity of encased graphene and ultrathin graphite. AB - The thermal conductivity of graphene and ultrathin graphite (thickness from 1 to ~20 layers) encased within silicon dioxide was measured using a heat spreader method. The thermal conductivity increases with the number of graphene layers, approaching the in-plane thermal conductivity of bulk graphite for the thickest samples, while showing suppression below 160 W/m-K at room temperature for single layer graphene. These results show the strong effect of the encasing oxide in disrupting the thermal conductivity of adjacent graphene layers, an effect that penetrates a characteristic distance of approximately 2.5 nm (~7 layers) into the core layers at room temperature. PMID- 20836538 TI - Charged tags as probes for analyzing organometallic intermediates and monitoring cross-coupling reactions by electrospray-ionization mass spectrometry. AB - Organic iodides bearing a cationic quaternary ammonium group at a remote position react with zerovalent Pd complexes, Zn, or In leading to a C-I bond insertion. The resulting charge-tagged organometallics can be detected by electrospray ionization mass spectrometry, which provides detailed information on their stoichiometry, oxidation state, and coordination sphere. The properties of the observed organopalladium and -zinc intermediates largely agree with previous findings, whereas the organoindium species show a surprisingly high tendency to form ate complexes. Magnesium also undergoes insertion into the C-I bond of the charge-tagged organic iodides, but instead of the expected organomagnesium intermediates only the corresponding hydrolysis products could be detected in the diluted solutions. Electrospray-ionization mass spectrometry can also be used to study the reactivity of the charge-tagged species, as was demonstrated for a Pd catalyzed Negishi cross-coupling reaction. The presented approach permits a straightforward identification of the rate-limiting step and the determination of the corresponding second-order rate constant. PMID- 20836541 TI - Experimental test of the thermodynamic model of protein cooperativity using temperature-induced unfolding of a Ubq-UIM fusion protein. AB - This study describes the thermodynamic characterization of a Ubq-UIM fusion construct (Ubq-UIM), designed from the ubiquitin-UIM interaction system, to determine whether it exhibits cooperativity of folding. The Ubq-UIM fusion constructs exhibit higher stability than the core Ubq molecule, consistent with the finding that the UIM helix is docked to Ubq. Temperature-induced unfolding profiles of Ubq-UIM were monitored by DSC and far-UV and near-UV CD spectroscopies. Ubq-UIM appears to exhibit cooperative unfolding as indicated by results of global fits of a two-state model to far- and near-UV CD and DSC thermal unfolding data. The cooperativity of Ubq-UIM unfolding was further tested by the amino acid substitutions that selectively stabilize or destabilize Ubq, UIM, and/or the interface. The effects of these substitutions on the thermodynamic properties of Ubq-UIM are described well by a thermodynamic model for cooperativity in proteins. In particular, a substitution that lowered the stability of the Ubq-UIM interface indeed led to a decrease in cooperativity. PMID- 20836539 TI - pH-Responsive nanoparticles for drug delivery. AB - First-generation nanoparticles (NPs) have been clinically translated as pharmaceutical drug delivery carriers for their ability to improve on drug tolerability, circulation half-life, and efficacy. Toward the development of the next-generation NPs, researchers have designed novel multifunctional platforms for sustained release, molecular targeting, and environmental responsiveness. This review focuses on environmentally responsive mechanisms used in NP designs, and highlights the use of pH-responsive NPs in drug delivery. Different organs, tissues, and subcellular compartments, as well as their pathophysiological states, can be characterized by their pH levels and gradients. When exposed to these pH stimuli, pH-responsive NPs respond with physicochemical changes to their material structure and surface characteristics. These include swelling, dissociating or surface charge switching, in a manner that favors drug release at the target site over surrounding tissues. The novel developments described here may revise the classical outlook that NPs are passive delivery vehicles, in favor of responsive, sensing vehicles that use environmental cues to achieve maximal drug potency. PMID- 20836542 TI - One step synthesis of the smallest photoluminescent and paramagnetic PVP protected gold atomic clusters. AB - Gold atomic clusters of only two and three atoms were prepared by a simple electrochemical technique based on the anodic dissolution of a gold electrode in the presence of PVP, and subsequent electroreduction of the Au-PVP complexes. These clusters show stable photoluminescent and magnetic properties, which make them the smallest and most elemental gold (0) building blocks in nature (after atoms) bringing new possibilities to construct novel nano/microstructures with large potential interest in biomedicine, catalysis, and so forth. PMID- 20836540 TI - Reduction kinetics of a flavin oxidoreductase LuxG from Photobacterium leiognathi (TH1): half-sites reactivity. AB - Bacterial bioluminescence is a phenomenon resulting from the reaction of a two component FMN-dependent aldehyde monooxygenase system, which comprises a bacterial luciferase and a flavin reductase. Bacterial luciferase (LuxAB) is one of the most extensively investigated two-component monooxygenases, while its reductase partner, the flavin reductase (LuxG) from the same operon, has only been recently expressed in a functional form. This work reports transient kinetics identification of intermediates in the LuxG reaction using stopped-flow spectrophotometry. The results indicate that the overall reaction follows a sequential-ordered mechanism in which NADH binds first to the enzyme, followed by FMN, resulting in the formation of charge-transfer intermediate 1 (CT-1) typical of those between reduced pyridine nucleotides and oxidized flavins. The next step is the reduction of FMN as indicated by a large decrease in absorbance at 450 nm. The reduction of FMN is biphasic. The first phase of FMN reduction occurs concurrently with formation of charge-transfer intermediate 2 (CT-2), while the second phase is synchronous with the decay of CT-2. When the isotope-labeled substrate, 4(R)-[(2)H]NADH, was used, the first reduction phase showed a primary kinetic isotope effect ((D)k(red)) of >=3.9 and resulted in greater accumulation of CT-1. These results are consistent with CT-1 being the FMN(ox):NADH complex, while CT-2 is the FMN(red):NAD(+) complex. Because CT-2 decays with a rate constant of 2.8 +/- 0.2 s(-1), while the turnover number obtained from the steady steady-state kinetics is 1.7 s(-1), it is likely that the CT-2 decay step largely controls the overall reaction rate. All kinetic data are consistent with a half sites reactivity model in which flavin reduction occurs at only one subunit at a time. The first reduction phase is due to the reduction of FMN in the first subunit, while the second phase is due to the reduction of FMN in the second subunit. The latter phase is limited by the rate of decay of CT-2 in the first subunit. The half-sites reactivity model is also supported by detection of burst kinetics during the pre-steady-state period that is correlated with 0.5 mol of the FMN being reduced/mol of the LuxG:NADH complex. The functional importance of this half-site reactivity phenomenon is still unclear. PMID- 20836543 TI - Preparation of phenanthrenes by photocyclization of stilbenes containing a tosyl group on the central double bond. A versatile approach to the synthesis of phenanthrenes and phenanthrenoids. AB - We have developed a useful modification of the classical preparation of phenanthrenes by UV irradiation of stilbenes in the presence of an oxidant. This modification involves the irradiation, in the presence of base, of stilbenes possessing a sulfonyl group linked to the central double bond. We have proved that this protocol can be successfully applied for the synthesis of diverse phenanthrenes and phenanthrenoids. PMID- 20836545 TI - Synthesis of substituted indole from 2-aminobenzaldehyde through [1,2]-aryl shift. AB - A mild, efficient, and simple method for the synthesis of 3-ethoxycarbonylindoles has been developed. Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords the indole core. As opposed to other common approaches for the synthesis of indole, this method displays both excellent functional group tolerance and perfect regiochemical control. This allowed the synthesis of a variety of useful indole building blocks from 2-aminobenzaldehydes derived from readily available anthranilic acids. PMID- 20836544 TI - Carboxyl-terminated PAMAM-SN38 conjugates: synthesis, characterization, and in vitro evaluation. AB - In this work, carboxyl-terminated PAMAM G-3.5 was covalently attached to SN38 via glycine and beta-alanine spacers. The conjugates were stable at pH 7.4 and moderately hydrolyzed in cell culture media and rat plasma. Similarly to SN38 but to a lesser extent, both conjugates inhibited proliferation of human colorectal cancer HCT-116 cells, arrested the cell cycle in the G(2)/M phase, and led to nuclear fragmentation. However, activity of the conjugate with glycine spacer (IC(50) = 129 nM) was higher compared to that of the beta-alanine linked conjugate (IC(50) = 387 nM). These PAMAM-SN38 conjugates have the potential for targeted therapy of colorectal carcinoma. PMID- 20836546 TI - Catalytic highly enantioselective alkylation of aldehydes with deactivated grignard reagents and synthesis of bioactive intermediate secondary arylpropanols. AB - Because of the high reactivity of Grignard reagents, a direct, highly enantioselective Grignard reaction with aldehydes has rarely been disclosed. In this report, Grignard reagents were introduced with bis[2-(N,N' dimethylamino)ethyl] ether (BDMAEE) to effectively deactivate their reactivity; thus, a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(O(i)Pr)(2). It is thought that BDMAEE chelates the in situ generated salts MgBr(2) from a Schlenk equilibrium of RMgBr and Mg(O(i)Pr)Br from transmetalation of RMgBr with Ti(O(i)Pr)(4). The Mg salts can actively promote the undesired background reaction to give the racemate. The chelation definitely inhibits the catalytic activity of the Mg salts, suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(O(i)Pr)(2). Consequently, the Mg salt byproducts were not removed, less Ti(O(i)Pr)(4) than RMgBr was used, and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before. Various alkyl Grignard reagents were investigated in the asymmetric addition, and (i)BuMgBr resulted in the highest enantioselectivity, >99%. Furthermore, important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step. PMID- 20836547 TI - Multivariate statistical approaches for the characterization of dissolved organic matter analyzed by ultrahigh resolution mass spectrometry. AB - We apply multivariate statistics to explore the large data sets encountered from Fourier transform ion cyclotron resonance mass spectra of dissolved organic matter (DOM). Molecular formula assignments for the individual constituents of DOM are examined by hierarchal cluster analysis (HCA) and principal component analysis (PCA), to measure the relationships between numerous DOM samples. We compare two approaches: (1) using averages of elemental ratios and double bond equivalents calculated from the formulas, and (2) employing individual formulas and either their presence/absence or relative magnitude in each sample. With approach 2, PCA deciphers which of the thousands of formulas are significant to particular samples, and then a van Krevelen diagram highlights what types of compounds are molecular signatures to the samples. Our dual approach, especially approach 2, allows for complex data sets to be more easily interpreted, aiding in the characterization of DOM from various sources. By applying this methodology, clear trends can be delineated, trends that are not apparent from currently employed methods. Terrestrial DOM contains various lignin-derived compounds, tannins, and condensed aromatics. Marine DOM contains aliphatic compounds with heteroatom functionalities, as well as lignin-like molecules. PMID- 20836548 TI - Characterization of biochars produced from cornstovers for soil amendment. AB - Through cation exchange capacity assay, nitrogen adsorption-desorption surface area measurements, scanning electron microscopic imaging, infrared spectra and elemental analyses, we characterized biochar materials produced from cornstover under two different pyrolysis conditions, fast pyrolysis at 450 degrees C and gasification at 700 degrees C. Our experimental results showed that the cation exchange capacity (CEC) of the fast-pyrolytic char is about twice as high as that of the gasification char as well as that of a standard soil sample. The CEC values correlate well with the increase in the ratios of the oxygen atoms to the carbon atoms (O:C ratios) in the biochar materials. The higher O:C ratio was consistent with the presence of more hydroxyl, carboxylate, and carbonyl groups in the fast pyrolysis char. These results show how control of biomass pyrolysis conditions can improve biochar properties for soil amendment and carbon sequestration. Since the CEC of the fast-pyrolytic cornstover char can be about double that of a standard soil sample, this type of biochar products would be suitable for improvement of soil properties such as CEC, and at the same time, can serve as a carbon sequestration agent. PMID- 20836549 TI - Holographic detection of hydrocarbon gases and other volatile organic compounds. AB - There is a need to develop sensors for real-time monitoring of volatile organic compounds (VOCs) and hydrocarbon gases in both external and indoor environments, since these compounds are of growing concern in human health and welfare. Current measurement technology for VOCs requires sophisticated equipment and lacks the prospect for rapid real-time monitoring. Holographic sensors can give a direct reading of the analyte concentration as a color change. We report a technique for recording holographic sensors by laser ablation of silver particles formed in situ by diffusion. This technique allows a readily available hydrophobic silicone elastomer to be transformed into an effective sensor for hydrocarbon gases and other volatile compounds. The intermolecular interactions present between the polymer and molecules are used to predict the sensor performance. The hydrophobicity of this material allows the sensor to operate without interference from water and other atmospheric gases and thus makes the sensor suitable for biomedical, industrial, or environmental analysis. PMID- 20836550 TI - Long-term trends in ambient air 1,3-butadiene levels in Houston, Texas. AB - 1,3-Butadiene is one of the top air pollution risk drivers in the United States. The ambient air concentrations in Houston, TX are of particular interest because of the relatively large number of stationary industrial sources that report 1,3 butadiene emissions and the relatively large number of vehicle miles traveled every day on Houston roadways. Several Federal and State regulatory programs initiated over the last two decades regulate the amount of 1,3-butadiene emitted to the air from industrial, mobile, and area sources. Emissions reductions from industrial sources in Houston have also been achieved through voluntary agreements between individual facilities and the Texas Commission on Environmental Quality (TCEQ). The impact of these regulatory and voluntary initiatives on air quality has been measured by a network of 30 monitors stationed within the Houston area. Most of the area's monitors have measured reductions in annual average 1,3-butadiene levels in the range of 40-80%. The greatest decreases and statistically significant downward trends have been measured at the monitoring sites closest to industrial facilities. PMID- 20836551 TI - Quantum chemical investigation and experimental verification on the aquatic photochemistry of the sunscreen 2-phenylbenzimidazole-5-sulfonic acid. AB - For ecological risk assessment of the large and ever-increasing number of chemical pollutants, it is of importance to develop computational methods to screen or predict their environmental photodegradation behavior. This study developed a computational method based on the density functional theory (DFT) to predict and evaluate the photodegradation behavior and effects of water constituents, taking a sunscreen and personal care product 2-phenylbenzimidazole 5-sulfonic acid (PBSA) as a model compound. Energy and electron transfer reactions of excited state PBSA (PBSA*) with (3)O(2) and water constituents were evaluated. The computational results indicated that PBSA* could photogenerate (1)O(2) and O(2)(-)., triplet excited state humic/fulvic acid analogs could not photosensitize the degradation, and the anions (Cl(-), Br(-), and HCO(3)(-)) could not quench PBSA* or its radical cation chemically. Experiments employing simulated sunlight confirmed that PBSA photodegraded via the direct and self sensitization mechanism involving O(2)(-).. The photodegradation was pH dependent. The direct and self-sensitized photodegradation was inhibited by fulvic acid. The main photodegradation products were identified, and the pathways were clarified. These results indicate that the DFT-based computational method can be employed to assess the environmental photochemical fate of organic pollutants. PMID- 20836552 TI - Cardiac contractile dysfunction and apoptosis in streptozotocin-induced diabetic rats are ameliorated by garlic oil supplementation. AB - Previous studies have suggested that garlic oil could protect the cardiovascular system. However, the mechanism by which garlic oil protects diabetes-induced cardiomyopathy is unclear. In this study, streptozotocin (STZ)-induced diabetic rats received garlic oil (0, 10, 50, or 100 mg/kg of body weight) by gastric gavage every 2 days for 16 days. Normal rats without diabetes were used as control. Cardiac contractile dysfunction examined by echocardiography and apoptosis evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay were observed in diabetic rat hearts. Additionally, a shift in cardiac myosin heavy chain (MHC) gene expression from alpha- to beta-MHC isoform, decreased levels of superoxide dismutase-1 (SOD-1) and cardiac alpha actin, and elevated cardiac thiobarbituric acid reactive substances (TBARS) and caspase- and p38-NFkappaB-leading apoptosis signaling activities were demonstrated in diabetic hearts. However, these diabetes-related cardiac dysfunctions were almost dose-dependently ameliorated by garlic oil administration. In conclusion, garlic oil possesses significant potential for protecting hearts from diabetes-induced cardiomyopathy. PMID- 20836553 TI - Comparison of the fatty acid profiles in cheeses from ewes fed diets supplemented with different plant oils. AB - The purpose of this work was to obtain a cheese from ewes milk with a healthier fatty acid (FA) profile. To achieve our aim, 48 ewes (12 per treatment) were fed diets supplemented with 3% of plant oils: palm (used as control), olive (OO), soybean (SO), and linseed (LO). Milk samples from each treatment were collected to manufacture cheeses. The cheesemaking process did not modify the dairy fat FA profile, but OO, SO, and LO did reduce the C12:0 + C14:0 + C16:0 content in dairy fat, thus decreasing the atherogenic index value in the cheeses. Percentages of cis-9 trans-11 C18:2 in cheeses ranged from the 0.43 control value to 0.92, 1.64, and 2.71 with OO, LO, and SO respectively, following the same pattern as trans-11 C18:1. In contrast, trans-10 C18:1 levels were always below 1%. The lowest n-6/n 3 ratio obtained with LO (1.43) suggests that such lipid supplementation would be the most effective nutritional strategy for improving cheese FA profiles. PMID- 20836554 TI - The kinetics of beta-elimination of cystine and the formation of lanthionine in gliadin. AB - When gliadin, a mixture of wheat storage proteins containing only intramolecular disulfide (SS) bonds, is heated at high temperatures and preferably at alkaline pH, the SS bonds are cleaved by beta-elimination reactions leading to decreased cystine levels and the generation of dehydroalanine (DHA) and free sulfhydryl (SH) groups. DHA and the free SH group of cysteine can further react to form the irreversible cross-link lanthionine (LAN). The kinetics of this reaction were studied by heating model systems containing gliadin at different pH values (pH 6.0, 8.0 and 11.0) at temperatures up to 120 degrees C. Multiresponse modeling was applied to simultaneously describe the course of the reaction partners, intermediates and products. The estimated kinetic parameters indicate that the reaction rate constant for the elimination reaction increases with temperature and pH. Moreover, the predominant reaction consuming the intermediary DHA is the cross-link with cysteine to form LAN following second-order reaction kinetics. The corresponding reaction rate constant is less dependent on temperature and pH. Use of the proposed kinetic model to estimate reaction product concentrations in cereal-based foods allowed us to conclude that the beta-elimination reaction may be less important during, e.g., bread making, but may well contribute to gluten network formation during the production of soft wheat products. It may also well be relevant in the production of bioplastics made from gluten. PMID- 20836555 TI - Seedless growth of sub-10 nm germanium nanowires. AB - We report the self-seeded growth of highly crystalline Ge nanowires, with a mean diameter as small as 6 nm without the need for a metal catalyst. The nanowires, synthesized using the purpose-built precursor hexakis(trimethylsilyl)digermane, exhibit high aspect ratios (>1000) while maintaining a uniform core diameter along their length. Additionally, the nanowires are encased in an amorphous shell of material derived from the precursor, which acts to passivate their surfaces and isolates the Ge seed particles from which the nanowires grow. The diameter of the nanowires was found to depend on the synthesis temperature employed. Specifically, there is a linear relationship between the inverse radius of the nanowires and the synthesis temperature, which can be explained by a model for the size-dependent melting of simple metals. PMID- 20836556 TI - Synthesis and selective anticancer activity of organochalcogen based redox catalysts. AB - Many tumor cells exhibit a disturbed intracellular redox state resulting in higher levels of reactive oxygen species (ROS). As these contribute to tumor initiation and sustenance, catalytic redox agents combining significant activity with substrate specificity promise high activity and selectivity against oxidatively stressed malignant cells. We describe here the design and synthesis of novel organochalcogen based redox sensor/effector catalysts. Their selective anticancer activity at submicromolar and low micromolar concentrations was established here in a range of tumor entities in various biological systems including cell lines, primary tumor cell cultures, and animal models. In the B cell derived chronic lymphocytic leukemia (CLL), for instance, such compounds preferentially induce apoptosis in the cancer cells while peripheral blood mononuclear cells (PBMC) from healthy donors and the subset of normal B-cells remain largely unaffected. In support of the concept of sensor/effector based ROS amplification, we are able to demonstrate that underlying this selective activity against CLL cells are pre-existing elevated ROS levels in the leukemic cells compared to their nonmalignant counterparts. Furthermore, the catalysts act in concert with certain chemotherapeutic drugs in several carcinoma cell lines to decrease cell proliferation while showing no such interactions in normal cells. Overall, the high efficacy and selectivity of (redox) catalytic sensor/effector compounds warrant further, extensive testing toward transfer into the clinical arena. PMID- 20836559 TI - Surface-enhanced Raman spectroscopy (SERS) for environmental analyses. PMID- 20836557 TI - Discovery of small molecule inhibitors of the PH domain leucine-rich repeat protein phosphatase (PHLPP) by chemical and virtual screening. AB - PH domain Leucine-rich repeat protein phosphatase (PHLPP) directly dephosphorylates and inactivates Akt and protein kinase C, poising it as a prime target for pharmacological intervention of two major survival pathways. Here we report on the discovery of small molecule inhibitors of the phosphatase activity of PHLPP, a member of the PP2C family of phosphatases for which there are no general pharmacological inhibitors. First, the Diversity Set of the NCI was screened for inhibition of the purified phosphatase domain of PHLPP2 in vitro. Second, selected libraries from the open NCI database were docked into a virtual model of the phosphatase domain of PHLPP2, previously trained with our experimental data set, unveiling additional inhibitors. Biochemical and cellular assays resulted in the identification of two structurally diverse compounds that selectively inhibit PHLPP in vitro, increase Akt signaling in cells, and prevent apoptosis. Thus, chemical and virtual screening has resulted in the identification of small molecules that promote Akt signaling by inhibiting its negative regulator PHLPP. PMID- 20836560 TI - Thermo- and solvent-responsive polymer complex created from supramolecular complexation between a helix-forming polysaccharide and a cationic polythiophene. AB - The helical structure is one of key structural components for both biological systems and artificial chiral systems. So far, we have succeeded in fabricating "tight" insulated molecular wires consisting of a triple-stranded cohelical structure formed through supramolecular wrapping of synthetic polymers by a helix forming polysaccharide (schizophyllan). Herein, we have designed a new modified polysaccharide (Cur-oeg) to form a "loose" macromolecular complex with a conjugated polymer (CP) that allows structural changes in response to external stimuli. Cur-oeg forms a helical complex with an achiral cationic polythiophene (PT1), and the effective conjugation length is changed by temperature, showing a large absorption peak shift from 403 to 482 nm between 85 and 5 degrees C. According to the change in the conjugation system, the fluorescence and the induced circular dichroism show the continuous spectral shifts under temperature control. The color changes in the absorption and the fluorescence are detectable with observation by the naked eye and are reversibly controlled under thermal cycles, indicating that this system has the function of a "molecular thermometer". It is shown that the induced thermoresponsiveness is associated with structural rearrangement of the helical conformation of PT1 in the complex. Moreover, another unique responsiveness is discovered for the film state: that is, the film color is varied when it is exposed to the vapor of water or methanol (vaporchromism), resulting from the structural change of PT1 occurring even in the film state. These flexible molecular motions in both the solution state and the film state can be applicable to the design of CP-based smart sensors, polarized materials, switching devices, etc. PMID- 20836561 TI - Binuclear initiators for the telechelic synthesis of elastomeric polyolefins. AB - Novel binuclear complexes, 4,4'-bis{[N-(2,6-diisopropylphenyl)-2-(2,6 diisopropylphenylimino)propanamidato-kappa(2)-N,O (trimethylphosphine)nickel(II)]methyl}-1,1'-biphenyl (2a) and 4,4'-bis{[N-(2,6 diisopropylphenyl)-2-(2,6-diisopropylphenylimino)-4-methylpentamidato-kappa(2) N,O-(trimethylphosphine)nickel(II)]methyl}-1,1'-biphenyl (2b), were synthesized by linking two nickel centers through a bis(benzyl) fragment. When activated with nickel bis(1,5-cyclooctadiene) (Ni(COD)(2)), 2a and 2b are capable of polymerizing ethylene in a quasi-living fashion, producing polymers with approximately twice the molecular weights relative to those obtained by using a structurally related mononuclear system. In addition, 2b/Ni(COD)(2) was utilized to synthesize a series of pseudo-triblock polyethylene (PE) macroinitiating copolymers, bearing atom-transfer radical polymerization (ATRP) initiators. Pseudo-pentablock copolymers were also prepared by taking advantage of a pressure pulsing technique, wherein the ethylene pressure was increased from 100 to 500 psi in order to produce semicrystalline ethylene-rich end-blocks. Copolymers with elastomeric properties were synthesized by grafting n-butyl acrylate from the PE macroinitiators via ATRP. Examination using monotonic and step-cyclic stress strain tests demonstrates that the materials exhibit large strains at break (1600 2000%) and excellent elastic recoveries at large strains (~80%). That materials with such desirable properties could not be attained using a mononuclear initiator demonstrates the clear advantage of growing the polymer via a telechelic mechanism. PMID- 20836562 TI - Ring-closing metathesis of allylsilanes as a flexible strategy toward cyclic terpenes. short syntheses of teucladiol, isoteucladiol, poitediol, and dactylol and an attempted synthesis of caryophyllene. AB - The development of a strategy consisting of allylsilane ring-closing metathesis and subsequent S(E)' electrophilic desilylation (allylsilane RCM/S(E)') to construct exo-methylidenecycloalkanes is described. Its utility is documented in short syntheses of teucladiol and poitediol. A key transformation in the synthesis of teucladiol is an aldol addition that establishes three stereochemical relationships in one step with >=10:1 diastereoselectivity and provides a fascinating example of double stereodifferentiation/kinetic resolution with racemic reaction partners in the context of natural product synthesis. The synthesis of (+/-)-teucladiol required five steps from cyclopentenone and proceeded in 28% overall yield; adaptation of this route to an enantioselective synthesis of (-)-teucladiol enabled the determination of the absolute configuration of this terpene natural product. The use of fluoride-mediated conditions in the final desilylation step preserves the location of the alkene, delivering the natural product (+/-)-isoteucladiol (five steps and 21% yield from cyclopentenone). The synthesis of poitediol showcases the power of RCM for constructing eight-membered rings and features a highly diastereoselective epoxidation/fluoride-mediated fragmentation sequence for installing the exo methylidene group with an adjacent hydroxyl-bearing stereocenter. The synthesis of (+/-)-poitediol required seven steps and proceeded in 18% overall yield. Again, fluoride-mediated desilylation of a late-stage intermediate (with retention of double-bond location) delivered the natural product (+/-)-dactylol (seven steps and 24% yield). Efforts directed toward incorporating the RCM/S(E)' sequence into a synthesis of caryophyllene are also disclosed. While ultimately unsuccessful, these efforts resulted in the identification of a novel metal alkylidene-promoted deallylation reaction of terminal 1,4-dienes. A possible mechanism for this unexpected deallylation reaction of 1,4-dienes is provided. PMID- 20836564 TI - Stereo-complex crystallization of poly(lactic acid)s in block-copolymer phase separation. AB - Block-copolymer containing a poly(L-lactic acid) (PLLA) segment was blended with pure poly(D-lactic acid) (PDLA) chain in chloroform solution and casted into the dried film. This method could form the stereocomplex (Sc) crystal of PLLA/PDLA within the nanometer-sized phase separation self-assembled by block-copolymer. Differential scanning calorimetry measurements of the prepared and annealed films gave the maximum achievable melting temperature of 245 degrees C, which was highest among those previously reported for PLA Sc-crystals. Surprisingly, all of added PDLA chains were Sc-crystallized, depending on the blend composition with block-copolymer containing PLLA. PMID- 20836565 TI - Assessing energetic contributions to binding from a disordered region in a protein-protein interaction . AB - Many functional proteins are at least partially disordered prior to binding. Although the structural transitions upon binding of disordered protein regions can influence the affinity and specificity of protein complexes, their precise energetic contributions to binding are unknown. Here, we use a model protein protein interaction system in which a locally disordered region has been modified by directed evolution to quantitatively assess the thermodynamic and structural contributions to binding of disorder-to-order transitions. Through X-ray structure determination of the protein binding partners before and after complex formation and isothermal titration calorimetry of the interactions, we observe a correlation between protein ordering and binding affinity for complexes along this affinity maturation pathway. Additionally, we show that discrepancies between observed and calculated heat capacities based on buried surface area changes in the protein complexes can be explained largely by heat capacity changes that would result solely from folding the locally disordered region. Previously developed algorithms for predicting binding energies of protein protein interactions, however, are unable to correctly model the energetic contributions of the structural transitions in our model system. While this highlights the shortcomings of current computational methods in modeling conformational flexibility, it suggests that the experimental methods used here could provide training sets of molecular interactions for improving these algorithms and further rationalizing molecular recognition in protein-protein interactions. PMID- 20836566 TI - Systematic identification of methyllysine-driven interactions for histone and nonhistone targets. AB - An important issue in epigenetic research is to understand how the numerous methylation marks associated with histone and certain nonhistone proteins are recognized and interpreted by the hundreds of chromatin-binding modules (CBMs) in a cell to control chromatin state, gene expression, and other cellular functions. We have assembled a peptide chip that represents known and putative lysine methylation marks on histones and p53 and probed the chip for binding to a group of CBMs to obtain a comprehensive interaction network mediated by lysine methylation. Interactions revealed by the peptide array screening were validated by in-solution binding assays. This study not only recapitulated known interactions but also uncovered new ones. A novel heterochromatin protein 1 beta (HP1beta) chromodomain-binding site on histone H3, H3K23me, was discovered from the peptide array screen and subsequently verified by mass spectrometry. Data from peptide pull-down and colocalization in cells suggest that, besides the H3K9me mark, H3K23me may play a role in facilitating the recruitment of HP1beta to the heterochromatin. Extending the peptide array and mass spectrometric approach presented here to more histone marks and CBMs would eventually afford a comprehensive specificity and interaction map to aid epigenetic studies. PMID- 20836567 TI - Novel cellular microarray assay for profiling T-cell peptide antigen specificities. AB - We present a novel cellular microarray assay using soluble peptide-loaded HLA A2 Ig dimer complexes that optimizes the avidity of peptide-HLA binding by preserving the molecular flexibility of the dimer complex while attaining much higher concentrations of the complex relative to cognate T-cell receptors. A seminal advance in assay development is made by separating the molecular T-cell receptor recognition event from the binding interactions that lead to antigen specific cell capture on the microarray. This advance enables the quantitative determination of antigen-specific frequencies in heterogeneous T-cell populations without enumerating the number of cells captured on the microarray. The specificity of cell capture, sensitivity to low antigen-specific frequencies, and quantitation of antigenic T-cell specificities are established using CD8 T-cell populations with prepared antigen-specific CTL frequencies and heterogeneous T cells isolated from peripheral blood. The results demonstrate several advantages for high-throughput broad-based, quantitative assessments of low-frequency antigen specificities. The assay enables the use of cellular microarrays to determine the stability and flux of antigen-specific T-cell responses within and across populations. PMID- 20836568 TI - Apex peptide elution chain selection: a new strategy for selecting precursors in 2D-LC-MALDI-TOF/TOF experiments on complex biological samples. AB - LC-MALDI provides an often overlooked opportunity to exploit the separation between LC-MS and MS/MS stages of a 2D-LC-MS-based proteomics experiment, that is, by making a smarter selection for precursor fragmentation. Apex Peptide Elution Chain Selection (APECS) is a simple and powerful method for intensity based peptide selection in a complex sample separated by 2D-LC, using a MALDI TOF/TOF instrument. It removes the peptide redundancy present in the adjacent first-dimension (typically strong cation exchange, SCX) fractions by constructing peptide elution profiles that link the precursor ions of the same peptide across SCX fractions. Subsequently, the precursor ion most likely to fragment successfully in a given profile is selected for fragmentation analysis, selecting on precursor intensity and absence of adjacent ions that may cofragment. To make the method independent of experiment-specific tolerance criteria, we introduce the concept of the branching factor, which measures the likelihood of false clustering of precursor ions based on past experiments. By validation with a complex proteome sample of Arabidopsis thaliana, APECS identified an equivalent number of peptides as a conventional data-dependent acquisition method but with a 35% smaller work load. Consequently, reduced sample depletion allowed further selection of lower signal-to-noise ratio precursor ions, leading to a larger number of identified unique peptides. PMID- 20836569 TI - H-score, a mass accuracy driven rescoring approach for improved peptide identification in modification rich samples. AB - Currently, scoring algorithms of many popular search engines for tandem mass spectrometry (MS/MS) data only partially utilize the information content of high mass accuracy MS/MS data. We have developed a new rescoring scheme, H-score, that employs high mass accuracy matching of all detected fragment ions to candidate peptide sequences in an abundance independent fashion. Peptides for which b or y ions are found for all or almost all backbone fragmentation sites are rewarded. For peptide hits generated by Mascot, rescoring proved to be particularly beneficial when applied on samples containing many different potential modifications. For a histone sample acquired on an Orbitrap Velos using HCD for peptide fragmentation, the H-score identified 24% more spectra at 0.01 false positive rate than Mascot scoring of spectra processed according to state-of-the art methods and 61% better than Mascot scoring of unprocessed MS/MS spectra. For a low-abundance sample, where many weak spectra were detected, these numbers went up to 53 and 190%, respectively. When applied on a kinase-enriched sample containing only a few modifications, a smaller but still significant gain of 5% was observed. PMID- 20836571 TI - Supramolecular microfibrils of o-phenylenediamine dimers: oxidation-induced morphology change and the spontaneous formation of Ag nanoparticle decorated nanofibers. AB - The direct mix of aqueous FeCl(3) and o-phenylenediamine (OPD) solutions at room temperature leads to supramolecular microfibrils of OPD dimers generated by the oxidation of OPD monomers by FeCl(3) (Sun, X.; Hagner, M. Langmuir 2007, 23, 10441). In this Letter, we report on our recent finding that the subsequent treatment of such microfibrils with a AgNO(3) aqueous solution transforms them into nanofibers decorated with spherical silver nanoparticles (AgNPs) with sizes in range of 5-20 nm. The possible formation mechanism involved is also discussed. It is interestingly found that as-formed AgNPs exhibit good catalytic activity toward the reduction of H(2)O(2), leading to an enzymeless sensor with a fast amperometric response time of less than 5 s. The linear detection range is estimated to be from 100 MUM to 80 mM (r = 0.998), and the detection limit is estimated to be 62 MUM at a signal-to-noise ratio of 3. PMID- 20836570 TI - Structural and biochemical studies of a fluoroacetyl-CoA-specific thioesterase reveal a molecular basis for fluorine selectivity. AB - We have initiated a broad-based program aimed at understanding the molecular basis of fluorine specificity in enzymatic systems, and in this context, we report crystallographic and biochemical studies on a fluoroacetyl-coenzyme A (CoA) specific thioesterase (FlK) from Streptomyces cattleya. Our data establish that FlK is competent to protect its host from fluoroacetate toxicity in vivo and demonstrate a 10(6)-fold discrimination between fluoroacetyl-CoA (k(cat)/K(M) = 5 * 107 M-1 s-1) and acetyl-CoA (k(cat)/K(M) = 30 M-1 s-1) based on a single fluorine substitution that originates from differences in both substrate reactivity and binding. We show that Thr 42, Glu 50, and His 76 are key catalytic residues and identify several factors that influence substrate selectivity. We propose that FlK minimizes interaction with the thioester carbonyl, leading to selection against acetyl-CoA binding that can be recovered in part by new C?O interactions in the T42S and T42C mutants. We hypothesize that the loss of these interactions is compensated by the entropic driving force for fluorinated substrate binding in a hydrophobic binding pocket created by a lid structure, containing Val 23, Leu 26, Phe 33, and Phe 36, that is not found in other structurally characterized members of this superfamily. We further suggest that water plays a critical role in fluorine specificity based on biochemical and structural studies focused on the unique Phe 36 "gate" residue, which functions to exclude water from the active site. Taken together, the findings from these studies offer molecular insights into organofluorine recognition and design of fluorine-specific enzymes. PMID- 20836572 TI - Thrombin receptor antagonists for the treatment of atherothrombosis: therapeutic potential of vorapaxar and E-5555. AB - Platelet activation, achieved through a variety of surface receptors and biochemical mediators, represents a key event in the pathogenesis of atherothrombosis and its clinical manifestations. The major pathways involved in platelet activation are triggered by thromboxane A(2), adenosine diphosphate and thrombin, with the latter being the most potent of these agonists. Despite the effective inhibition of the first two pathways with aspirin and several generations of P2Y(12) receptor antagonists, respectively, the recurrence of ischaemic events in patients with atherothrombosis remains high. In addition, there is a growing concern over the safety profile of increasingly powerful antiplatelet drugs in terms of bleeding, which has tempered expectations of newly developed compounds. Thrombin receptor antagonists are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds may have the potential to improve ischaemic outcomes without significantly increasing the bleeding liability. Currently, two agents of this class are under clinical development: vorapaxar (previously known as SCH 530348) and E-5555. In this review we discuss this novel class of antiplatelet agents, focusing in particular on their therapeutic potential. PMID- 20836573 TI - Methicillin-resistant Staphylococcus aureus in diabetic foot infections. AB - Diabetic foot ulcers are often complicated by infection. Among pathogens, Staphylococcus aureus predominates. The prevalence of methicillin-resistant S. aureus (MRSA) in infected foot ulcers is 15-30% and there is an alarming trend for increase in many countries. There are also data that recognize new strains of MRSA that are resistant to vancomycin. The risk for MRSA isolation increases in the presence of osteomyelitis, nasal carriage of MRSA, prior use of antibacterials or hospitalization, larger ulcer size and longer duration of the ulcer. The need for amputation and surgical debridement increases in patients infected with MRSA. Infections of mild or moderate severity caused by community acquired MRSA can be treated with cotrimoxazole (trimethoprim/sulfamethoxazole), doxycycline or clindamycin when susceptibility results are available, while severe community-acquired or hospital-acquired MRSA infections should be managed with glycopeptides, linezolide or daptomycin. Dalbavancin, tigecycline and ceftobiprole are newer promising antimicrobial agents active against MRSA that may also have a role in the treatment of foot infections if more data on their efficacy and safety become available. PMID- 20836574 TI - Prevention and treatment of menstrual migraine. AB - Migraine is a prevalent headache disorder affecting three times more women than men during the reproductive years. Menstruation is a significant risk factor for migraine, with attacks most likely to occur on or between 2 days before the onset of menstruation and the first 3 days of bleeding. Although menstrual migraine has been recognized for many years, diagnostic criteria have only recently been published. These have enabled better comparison of the efficacy of drugs for this condition. Acute treatment, if effective, may be all that is necessary for control. Evidence of efficacy, with acceptable safety and tolerability, exists for sumatriptan 50 and 100 mg, mefenamic acid 500 mg, rizatriptan 10 mg and combination sumatriptan/naproxen 85 mg/500 mg. However, there is evidence that menstrual attacks are more severe, longer, less responsive to treatment, more likely to relapse and associated with greater disability than attacks at other times of the cycle. Prophylactic strategies can reduce the frequency and severity of attacks and acute treatment is more effective. Predictable menstrual attacks offer the opportunity for perimenstrual prophylaxis taken only during the time of increased migraine incidence. There is grade B evidence of efficacy for short term prophylaxis with transcutaneous estradiol 1.5 mg, frovatriptan 2.5 mg twice daily and naratriptan 1 mg twice daily. Contraceptive strategies offer the opportunity for treating menstrual migraine in women who also require effective contraception. PMID- 20836575 TI - Temsirolimus: In relapsed and/or refractory mantle cell lymphoma. AB - Temsirolimus selectively inhibits the mammalian target of rapamycin (mTOR) kinase, with subsequent inhibition of the translation of cell cycle regulatory proteins. Therapy with intravenous temsirolimus 175 mg once weekly for 3 weeks followed by 75 mg once weekly (higher temsirolimus dosage), but not 25 mg once weekly (lower temsirolimus dosage), was significantly more effective than single agent chemotherapy of the investigator's choice in terms of the primary endpoint of progression-free survival (PFS), as assessed by independent review, in the treatment of adult patients with relapsed and/or refractory mantle cell lymphoma in a phase III study. Both dosage regimens of temsirolimus achieved significantly better outcomes with regard to PFS, as assessed by the investigator (secondary endpoint), than the investigator's choice therapy. Patients receiving the higher temsirolimus dosage achieved a significantly better outcome with regard to the objective response rate (ORR) than those receiving the investigator's choice therapy; however, no significant difference in terms of ORR was observed between patients receiving the lower temsirolimus dosage and those receiving the investigator's choice therapy. The differences between the two temsirolimus treatment groups and the investigator's choice treatment group with regard to the endpoint of overall survival did not reach statistical significance. The tolerability profile of temsirolimus in this patient population was mostly consistent with the known toxicities of the agent. The incidence of thrombocytopenia was significantly higher and that of leukopenia significantly lower in patients receiving the higher temsirolimus dosage compared with those receiving the investigator's choice therapy. Adverse events were often managed with dose modifications. PMID- 20836576 TI - Capsaicin dermal patch: in non-diabetic peripheral neuropathic pain. AB - Capsaicin dermal patch is an adhesive patch containing a high concentration (8% w/w) of synthetic capsaicin. It is indicated in the EU for the treatment of peripheral neuropathic pain in non-diabetic adults using a single 30- or 60 minute application repeated every 90 days, as required, and in the US for the treatment of neuropathic pain associated with postherpetic neuralgia (PHN). In pivotal, randomized, double-blind, multicentre trials in adults with PHN, a single 60-minute application of capsaicin dermal patch reduced the mean Numeric Pain Rating Scale (NPRS) scores from baseline to a significantly greater extent than a low-concentration (0.04% w/w capsaicin) control patch during weeks 2-8. In randomized, double-blind, multicentre trials in patients with HIV-associated neuropathy, capsaicin dermal patch reduced the mean NPRS scores from baseline significantly more than control in one study for the 30- and 90-minute, but not the 60-minute, application during weeks 2-12. In another study, the differences between capsaicin (30- and 60-minute applications) and control did not reach statistical significance. An integrated analysis of both studies showed that the 30-minute application of capsaicin dermal patch was significantly better than control for the reduction from baseline in mean NPRS scores during weeks 2-12. The efficacy of capsaicin dermal patch was maintained for up to 1 year in extension studies in which patients could receive up to three or four repeat treatments. Capsaicin dermal patch was generally well tolerated in clinical trials. The most common adverse events were transient, mostly mild to moderate, application-site reactions. PMID- 20836577 TI - Aztreonam lysine for inhalation solution: in cystic fibrosis. AB - Aztreonam is a monobactam antibacterial with bactericidal activity against a wide range of aerobic Gram-negative bacteria, including Pseudomonas aeruginosa. Aztreonam lysine for inhalation solution (AZLI) does not contain the potentially inflammatory component arginine, which is used as a buffer in the intravenous formulation. Two phase III, randomized, placebo-controlled trials (AIR-CF1 and AIR-CF2) have been completed with AZLI in cystic fibrosis patients with pulmonary P. aeruginosa infection. In AIR-CF1, respiratory symptoms were significantly improved with AZLI compared with placebo, as assessed by the respiratory symptoms domain of the Cystic Fibrosis Questionnaire-Revised, a disease-specific, patient reported outcome instrument. The mean treatment effect exceeded the minimal clinically important difference. In AIR-CF2, AZLI was compared with placebo following a 28-day course of tobramycin inhalation solution. AZLI was associated with a significant delay in the need for inhaled or intravenous antipseudomonal antibacterials, as determined by the presence of one of four predefined symptoms shown to be predictive of pulmonary exacerbations. An open-label extension of these trials (AIR-CF3) also demonstrated clinical efficacy with repeated courses of AZLI over 18 months and was not associated with sustained reductions in P. aeruginosa susceptibility. AZLI was also associated with improved pulmonary function and reductions in P. aeruginosa density in sputum in clinical trials. The tolerability profile of AZLI was generally similar to that of placebo in randomized controlled trials, with respiratory symptoms being the most frequently reported adverse events. PMID- 20836578 TI - Telbivudine: a review of its use in compensated chronic hepatitis B. AB - Telbivudine (Sebivo(r); Tyzeka(r)) is a synthetic nucleoside analogue that inhibits replication of hepatitis B virus (HBV). It is used in the treatment of adults with chronic hepatitis B (CHB) with evidence of viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease. Telbivudine is a potent antiviral that provides effective and sustained viral suppression in patients with compensated CHB. In clinical trials, treatment outcomes were improved significantly more with telbivudine 600 mg once daily than with lamivudine 100 mg or adefovir 10 mg once daily, and telbivudine treated patients had significantly less viral resistance than lamivudine-treated patients. Increasing rates of hepatitis B e antigen (HBeAg) seroconversion were achieved in HBeAg-positive patients during periods of up to 4 years continuous telbivudine treatment, and seroconversion was durable in most patients throughout a 2-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Telbivudine is associated with a medium genetic barrier to resistance and, as patients with undetectable HBV DNA levels have significantly improved outcomes, it is recommended that HBV DNA levels are monitored at week 24 (and 6 monthly thereafter), with the addition of a nucleoside/nucleotide analogue without cross resistance (such as adefovir dipivoxil) if viraemia is present to reduce the risk of resistance (Roadmap concept). Telbivudine was generally well tolerated in clinical trials for periods of up to 4 years, and has a similar tolerability profile to that of lamivudine. A minority of telbivudine-treated patients experience creatinine kinase elevation, usually transient, and myopathy occurs rarely. In modelled cost effectiveness studies in several Asian countries, treatment with telbivudine Roadmap was cost effective in HBeAg-positive patients. Thus, telbivudine provides a valuable treatment option in CHB, particularly when administered using the Roadmap concept in HbeAg-positive patients. PMID- 20836579 TI - Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection. AB - Lopinavir/ritonavir (Kaletra(r)) is an orally administered coformulated ritonavir boosted protease inhibitor (PI) comprising lopinavir and low-dose ritonavir. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults, adolescents and children. Lopinavir/ritonavir is available as a tablet, soft-gel capsule and an oral solution for patients with difficulty swallowing. In well designed, randomized clinical trials, lopinavir/ritonavir, in combination with other antiretroviral therapies (ART), provided durable virological suppression and improved immunological outcomes in both ART-naive and -experienced adult patients with virological failure. Furthermore, lopinavir/ritonavir demonstrated a high barrier to the development of resistance in ART-naive patients. More limited data indicate that it is effective in reducing plasma HIV-1 RNA levels in paediatric patients. Lopinavir/ritonavir has served as a well established benchmark comparator for the noninferiority of other ritonavir-boosted PI regimens. Although generally well tolerated, lopinavir/ritonavir is associated with generally manageable adverse gastrointestinal side effects and hypertriglyceridaemia and hypercholesterolaemia, which may require coadministration of lipid-lowering agents to reduce the risk of coronary heart disease. Lopinavir/ritonavir, in combination with other ART agents, is a well established and cost-effective treatment for both ART-naive and -experienced patients with HIV-1 infection and, with successful management of adverse events, continues to have a role as an effective component of ART regimens for the control of HIV-1 infection. PMID- 20836580 TI - Is the 'crunch factor' an important consideration in the aetiology of lumbar spine pathology in cricket fast bowlers? AB - The 'crunch factor' is defined as the instantaneous product of lateral flexion and axial rotational velocity of the lumbar spine. It was originally implicated in the development of lumbar spine pathology and lower back pain in golfers and, although empirical evidence supporting or refuting the crunch factor is inconclusive, it remains an intuitively appealing concept that requires further investigation, not only in golf, but also in other sports involving hitting and throwing motions. This article considers whether the crunch factor might be instrumental in the aetiology of contralateral lumbar spine injuries sustained by cricket fast bowlers. Based on recent empirical research, it is argued that the crunch factor could be important in cricket fast bowling especially considering that peak crunch factor appears to occur just after front foot impact when ground reaction forces are known to be at their highest. The crunch factor may also occupy an integral role in lower back injuries sustained in other sports involving unilateral overhead throwing (e.g. javelin throwing) and hitting (e.g. tennis serving) actions where the spatial orientation of the arm at release or impact is largely determined by lateral flexion of the trunk and where the transfer of energy and momentum along the kinetic chain is initiated by a rapid rotation of the pelvis. Further research is required to empirically verify the role of the crunch factor in the development of lower back injuries in cricket fast bowling and sports that involve similar lower trunk mechanics. This research programme should ideally be supported by modelling work examining the stresses imposed on bony, disc and joint structures by lateral flexion and axial rotation motions so that their respective contribution to injury can be identified. PMID- 20836581 TI - The rodeo athlete: injuries - Part II. AB - A previous instalment to this review focused on the sport science for rodeo, the history behind the sport and what is currently known about the physical and physiological status, coronary risk profile, strength and power levels, event specific kinesiological and biomechanical aspects, nutritional habits and psychological indices associated with the rodeo athlete. In regards to injury, rodeo is well known for its high-velocity, high-impact atmosphere where athletes compete against the clock and uncooperative livestock. Considered by many to be a dangerous sport with high vulnerability towards trauma and frequent injuries, animal/human contact events comprise ~80% of reported injuries. Severe trauma includes fractures, dislocations, subluxations, concussions, ligament ruptures, pneumothorax and various neurapraxias. Head and neck trauma account for 10-29% of total trauma and up to 63% of upper body injuries, with concussion incidence rates of 3.4 per 1000 competitive exposures. The incidence of thoracic, back and abdominal injuries comprise 11-84% of trauma, while shoulder injuries, involving anterior/posterior arthralgia, inflammation, instability and increasing weakness, account for 8-15% of upper extremity cases. Lower extremity trauma accounts for 26-34% of cases, with the majority involving the knee. Many believe that the incidence of trauma is underestimated, with studies hampered by numerous limitations such as a lack of injury awareness, missing data, poor injury recall, an array of reporting sources, delays in subject response and treatment, no uniform definition of injury or reporting system and predisposing factors prior to injury. Primary mechanisms of injuries are attributed to physical immaturity, fatigue, age and experience, behaviour, the violent nature of the sport and lack of adequate medical intervention. Although there is limited adherence to organized conditioning programmes, when properly planned, sport-specific conditioning may enhance athletic potential, minimize predisposition to injury and enhance recovery. Education in care and rehabilitation should be spearheaded by the medical community to reduce injury, as several studies have linked trauma to poor technique, inexperience and poor judgement. Medical services should encompass emergency medical oversight for trauma at all levels and press toward preventive care. Competitors should also be cognizant of the signs and symptoms of overtraining, a condition exacerbated by overuse and minimal recovery. The use of helmets, taping, bracing, protective vests, cervical collars and mouthpieces is gaining popularity but has not been thoroughly studied. Guidelines requiring padding of chutes, gates or equipment essential for performance may also avert trauma. Whether increases in knowledge, education and technology are able to reduce predisposition to injury among this population, remains to be seen. As with all high-risk sports, the answer may lie in increased wisdom and responsibility of coaches and athletes to ensure an adequate level of ability, self-control and common sense as they compete in this sport. PMID- 20836582 TI - The extent to which behavioural and social sciences theories and models are used in sport injury prevention research. AB - Behavioural and social science theories and models (BSSTM) can enhance efforts to increase health and safety behaviours, such as the uptake and maintenance of injury prevention measures. However, the extent to which they have been used in sports injury research to date is currently unknown. A systematic review of 24 electronic databases was undertaken to identify the extent to which BSSTM have been incorporated into published sports injury prevention research studies and to identify which theories were adopted and how they were used. After assessment against specific inclusion and exclusion criteria, the full text of 100 potentially relevant papers was reviewed in detail. These papers were classified as follows: (i) explicit - the use of BSSTM was a stated key aspect in the design or conduct of the study; or (ii) atheoretical - there was no clear evidence for the use of BSSTM. The studies that explicitly mentioned BSSTM were assessed for how BSSTM were specifically used. Amongst the 100 identified papers, only eleven (11% of the total) explicitly mentioned BSSTM. Of these, BSSTM were most commonly used to guide programme design/implementation (n = 8) and/or to measure a theory/construct (n = 7). In conclusion, very few studies relating to sport safety behaviours have explicitly used any BSSTM. It is likely that future sports injury prevention efforts will only be enhanced, and achieve successful outcomes, if increased attention is given to fully understanding the behavioural determinants of safety actions. Appropriate use of BSSTM is critical to provide the theoretical basis to guide these efforts. PMID- 20836584 TI - Therapeutic hypoxia overdue naming convention. PMID- 20836585 TI - Will they stay or will they go? The role of job embeddedness in predicting turnover in individualistic and collectivistic cultures. AB - Although turnover is an issue of global concern, paradoxically there have been few studies of turnover across cultures. We investigated the cross-cultural generalizability of the job embeddedness model (Mitchell & Lee, 2001) by examining turnover in an individualistic country (United States) and a collectivistic country (India). Using cross-cultural data from call centers (N = 797), we demonstrated that although organization job embeddedness predicted turnover in both countries, different dimensions of job embeddedness predicted turnover in the United States and India. As hypothesized, on the basis of individualism-collectivism theory, person-job fit was a significant predictor of lower turnover in the United States, whereas person-organization fit, organization links, and community links were significant predictors of lower turnover in India. We also explored whether a newly developed construct of embeddedness-family embeddedness-predicts turnover above and beyond job embeddedness and found initial support for its utility in both the United States and India. Theoretical and practical implications are discussed. PMID- 20836586 TI - Linking job demands and resources to employee engagement and burnout: a theoretical extension and meta-analytic test. AB - We refine and extend the job demands-resources model with theory regarding appraisal of stressors to account for inconsistencies in relationships between demands and engagement, and we test the revised theory using meta-analytic structural modeling. Results indicate support for the refined and updated theory. First, demands and burnout were positively associated, whereas resources and burnout were negatively associated. Second, whereas relationships among resources and engagement were consistently positive, relationships among demands and engagement were highly dependent on the nature of the demand. Demands that employees tend to appraise as hindrances were negatively associated with engagement, and demands that employees tend to appraise as challenges were positively associated with engagement. Implications for future research are discussed. PMID- 20836583 TI - Neuro-musculoskeletal and performance adaptations to lower-extremity plyometric training. AB - Plyometric training (PLY) is a very popular form of physical conditioning of healthy individuals that has been extensively studied over the last 3 decades. In this article, we critically review the available literature related to lower-body PLY and its effects on human neural and musculoskeletal systems, athletic performance and injury prevention. We also considered studies that combined lower body PLY with other popular training modalities, as well as studies that applied PLY on non-rigid surfaces. The available evidence suggests that PLY, either alone or in combination with other typical training modalities, elicits numerous positive changes in the neural and musculoskeletal systems, muscle function and athletic performance of healthy individuals. Specifically, the studies have shown that long-term PLY (i.e. 3-5 sessions a week for 5-12 months) represents an effective training method for enhancing bone mass in prepubertal/early pubertal children, young women and premenopausal women. Furthermore, short-term PLY (i.e. 2-3 sessions a week for 6-15 weeks) can change the stiffness of various elastic components of the muscle-tendon complex of plantar flexors in both athletes and non-athletes. Short-term PLY also improves the lower-extremity strength, power and stretch-shortening cycle (SSC) muscle function in healthy individuals. These adaptive changes in neuromuscular function are likely the result of (i) an increased neural drive to the agonist muscles; (ii) changes in the muscle activation strategies (i.e. improved intermuscular coordination); (iii) changes in the mechanical characteristics of the muscle-tendon complex of plantar flexors; (iv) changes in muscle size and/or architecture; and (v) changes in single-fibre mechanics. Our results also show that PLY, either alone or in combination with other training modalities, has the potential to (i) enhance a wide range of athletic performance (i.e. jumping, sprinting, agility and endurance performance) in children and young adults of both sexes; and (ii) to reduce the risk of lower-extremity injuries in female athletes. Finally, available evidence suggests that short-term PLY on non-rigid surfaces (i.e. aquatic- or sand-based PLY) could elicit similar increases in jumping and sprinting performance as traditional PLY, but with substantially less muscle soreness. Although many issues related to PLY remain to be resolved, the results of this review allow us to recommend the use of PLY as a safe and effective training modality for improving lower-extremity muscle function and functional performance of healthy individuals. For performance enhancement and injury prevention in competitive sports, we recommend an implementation of PLY into a well designed, sport-specific physical conditioning programme. PMID- 20836589 TI - Dual processing and organizational justice: the role of rational versus experiential processing in third-party reactions to workplace mistreatment. AB - The moral perspective of justice proposes that when confronted by another person's mistreatment, third parties can experience a deontic response, that is, an evolutionary-based emotional reaction that motivates them to engage in retribution toward the transgressor. In this article, we tested whether the third party's deontic reaction is less strong when a rational (vs. experiential) processing frame is primed. Further, we tested whether third parties high (vs. low) in moral identity are more resistant to the effects of processing frames. Results from a sample of 185 French managers revealed that following an injustice, managers primed to use rational processing reported lower retribution tendencies compared with managers primed to use experiential processing. Third parties high in moral identity, however, were less affected by the framing; they reported a high retribution response regardless of processing frame. Theoretical and practical implications of these findings are discussed. PMID- 20836591 TI - Happy, healthy, and productive: the role of detachment from work during nonwork time. AB - Mentally distancing oneself from work during nonwork time can help restore resources lost because of work demands. In this study, we examined possible outcomes of such psychological detachment from work, specifically well-being and job performance. Although employees may need to mentally detach from work to restore their well-being, high levels of detachment may require a longer time to get back into "working mode," which may be negatively associated with job performance. Our results indicate that higher levels of self-reported detachment were associated with higher levels of significant other-reported life satisfaction as well as lower levels of emotional exhaustion. In addition, we found curvilinear relationships between psychological detachment and coworker reported job performance (task performance and proactive behavior). Thus, although high psychological detachment may enhance employee well-being, it seems that medium levels of detachment are most beneficial for job performance. PMID- 20836593 TI - The phylogenetic roots of cognitive dissonance. AB - We presented 7 Old World monkeys (Japanese macaques [Macaca fuscata], gray cheeked mangabey [Lophocebus albigena], rhesus macaques [Macaca mulatta], bonnet macaque [Macaca radiate], and olive baboon [Papio anubis]), 3 chimpanzees (Pan troglodytes), 6 members of the parrot (Psittacinae) family, and 4 American black bears (Ursus americanus) with a cognitive dissonance paradigm modeled after Egan, Santos, and Bloom (2007). In experimental trials, subjects were given choices between 2 equally preferred food items and then presented with the unchosen option and a novel, equally preferred food item. In control trials, subjects were presented with 1 accessible and 1 inaccessible option from another triad of equally preferred food items. They were then presented with the previously inaccessible item and a novel member of that triad. Subjects, as a whole, did not prefer the novel item in experimental or control trials. However, there was a tendency toward a subject by condition interaction. When analyzed by primate versus nonprimate categories, only primates preferred the novel item in experimental but not control trials, indicating that they resolved cognitive dissonance by devaluing the unchosen option only when an option was derogated by their own free choice. This finding suggests that this phenomenon might exist within but not outside of the primate order. PMID- 20836592 TI - Beyond stimulus cues and reinforcement signals: a new approach to animal metacognition. AB - Some metacognition paradigms for nonhuman animals encourage the alternative explanation that animals avoid difficult trials based only on reinforcement history and stimulus aversion. To explore this possibility, we placed humans and monkeys in successive uncertainty-monitoring tasks that were qualitatively different, eliminating many associative cues that might support transfer across tasks. In addition, task transfer occurred under conditions of deferred and rearranged feedback-both species completed blocks of trials followed by summary feedback. This ensured that animals received no trial-by-trial reinforcement. Despite distancing performance from associative cues, humans and monkeys still made adaptive uncertainty responses by declining the most difficult trials. These findings suggest that monkeys' uncertainty responses could represent a higher level, decisional process of cognitive monitoring, though that process need not involve full self-awareness or consciousness. The dissociation of performance from reinforcement has theoretical implications concerning the status of reinforcement as the critical binding force in animal learning. PMID- 20836594 TI - Navigating with fingers and feet: analysis of human (Homo sapiens) and rat (Rattus norvegicus) movement organization during nonvisual spatial tasks. AB - The current set of studies examines the contribution of movement segmentation to self-movement cue processing for estimating direction and distance to a start location in humans and rats. Experiments 1 and 2 examined the extent that ambulatory dead reckoning tasks can be adapted to the manipulatory scale in humans. Experiments 3 and 4 investigated the performance of rats in similar tasks at their ambulatory scale. Movement segmentation had differential effects on absolute heading error for humans and rats when only comparing performance on specific tasks; however, movement segmentation had similar effects for both species when performance was examined across all tasks. In general, magnitude of movement segmentation was associated with absolute heading error in both humans and rats. In contrast, both species modified homeward segment kinematics based on the distance to the start location in all tasks, consistent with the use of self movement cues to estimate distance. The current study provides evidence for a role of movement segmentation in processing self-movement cues selective to direction estimation and develops a foundation for future studies investigating the neurobiology of spatial orientation. PMID- 20836595 TI - Route selection by pigeons (Columba livia) in "traveling salesperson" navigation tasks presented on an LCD screen. AB - Navigation tasks using the "traveling salesperson problem (TSP)" were presented to pigeons (Columba livia) to determine their strategy on spatial tasks with 2 to 3 goals. In Experiment 1, a simple TSP task with 2 goals was presented. In Experiment 2, 3 goals were presented so that each of the goals and the starting location of the target held each corner of a square. In Experiment 3, 3 goals were aligned along a straight line. In Experiment 4, 3 goals were placed so that the 2 of them were in close proximity to each other to form a group. In all of these experiments, the pigeons showed tendencies to visit the nearest goal first, which may suggest that the pigeons mainly used local or inflexible strategies in determining the routes to take. However, further evidence was also found that in Experiment 2, the pigeons frequently selected routes with short traveling distances while traveling either counterclockwise or clockwise, not necessarily relying on the "nearest neighbor" algorithm. Results from these experiments are discussed in relation to the pigeons' foraging ecology and adaptation. PMID- 20836596 TI - Can nonhuman primates use tokens to represent and sum quantities? AB - It is unclear whether nonhuman animals can use physical tokens to flexibly represent various quantities by combining token values. Previous studies showed that chimpanzees (Pan troglodytes) and a macaque (Macaca mulatta) were only partly successful in tests involving sets of different-looking food containers representing different food quantities, while some capuchin monkeys (Cebus apella) have shown greater success in tests involving sets of various concrete objects representing different food quantities. Some of the discrepancy in results between these studies may be attributed to the different methods used. In an effort to reconcile these discrepancies, we presented two primates species, chimpanzees and capuchin monkeys, with two token tasks. The critical test in each task involved summing the value of multiple tokens of different types to make accurate quantity judgments. We found that, using either method, individuals of both species learned to associate individual tokens with specific quantities, as well as successfully compare individual tokens to one another or to sets of visible food items. However, regardless of method, only a few individuals exhibited the capacity to sum multiple tokens of different types and then use those summed values to make an optimal response. This suggests that flexible combination of symbolic stimuli in quantity judgments tasks is within the abilities of chimpanzees and capuchins but does not characterize the majority of individuals. Furthermore, the results suggest the need to carefully examine specific methodological details that may promote or hinder such possible representation. PMID- 20836597 TI - Parenting knowledge: experiential and sociodemographic factors in European American mothers of young children. AB - Knowledge of child rearing and child development is relevant to parenting and the well-being of children. Using a sociodemographically heterogeneous sample of 268 European American mothers of 2-year-olds, we assessed the state of mothers' parenting knowledge; compared parenting knowledge in groups of mothers who varied in terms of parenthood and social status; and identified principal sources of mothers' parenting knowledge in terms of social factors, parenting supports, and formal classes. On the whole, European American mothers demonstrated fair but less than complete basic parenting knowledge; age, education, and rated helpfulness of written materials each uniquely contributed to mothers' knowledge. Adult mothers scored higher than adolescent mothers, and mothers improved in their knowledge of parenting from their first to their second child (and were stable across time). No differences were found between mothers of girls and boys, mothers who varied in employment status, or birth and adoptive mothers. The implications of variation in parenting knowledge and its sources for parenting education and clinical interactions with parents are discussed. PMID- 20836598 TI - Developmental models of learning to read Chinese words. AB - What is the nature of learning to read Chinese across grade levels? This study tested 199 kindergartners, 172 second graders, and 165 fifth graders on 12 different tasks purportedly tapping constructs representing phonological awareness, morphological awareness, orthographic processing, and subcharacter processing. Confirmatory factor analyses comparing alternative models of these 4 constituents of Chinese word reading revealed different patterns of metalinguistic underpinnings of children's word recognition across grade levels: The best-fitting model for kindergartners represented a print-nonprint dichotomy of constructs. In contrast, 2nd graders showed a fine-grained sensitivity to all 4 hypothesized constructs. Finally, the best-fitting model for 5th graders consisted of a phonological sensitivity construct and a broad lexical morphological-orthographic processing construct. Findings suggest that Hong Kong Chinese children progress from a basic understanding of print versus nonprint to a diversified sensitivity to varied word-reading skills, to a focus on meaning based word recognition, to the relative exclusion of phonological sensitivity in more advanced readers. PMID- 20836599 TI - Importance of the nature of comparison conditions for testing theory-based interventions: comment on Michie and Prestwich (2010). AB - Comments on the original article 'Are interventions theory-based? Development of a theory coding scheme' by Susan Michie and Andrew Prestwich (see record 2010 00152-001). In their admirable effort to develop a coding scheme for the theoretical contribution of intervention research, Michie and Prestwich rightly point out the importance of the presence of a comparison condition when examining the effect of an intervention on targeted theoretical variables and behavioral outcomes (Table 2, item 15). However, they fail to discuss the critical importance of the nature of the comparison condition. Weaker comparison conditions will yield stronger intervention effects; stronger comparison conditions will yield a stronger science of behavior change. PMID- 20836600 TI - Importance of the nature of comparison conditions for testing theory-based interventions: reply. AB - The nature of comparison conditions is a much overlooked feature of designing and interpreting the results of randomized controlled trials, as outlined by Williams (see record 2010-18776-001). We agree that understanding the components and mechanisms of the comparison condition is necessary for making inferences about both intervention effectiveness (whether the intervention worked and which components may have contributed to such an effect) and about theoretical mediators (how it worked). The extent to which one can draw strong inferences regarding the efficacy and mechanisms of an intervention over the comparison is conditional upon a number of key points. PMID- 20836602 TI - Somatosensory amplification mediates sex differences in psychological distress among cardioverter-defibrillator patients. AB - OBJECTIVE: The present study examined whether female patients with an implantable cardioverter defibrillator (ICD) report more psychological distress than male patients, and whether somatosensory amplification mediates this relationship. DESIGN: Consecutive ICD patients (N = 241; 33% women) participating in the Living with an Implanted Cardioverter-Defibrillator Study, completed a set of psychological questionnaires. MAIN OUTCOME MEASURES: Symptom Checklist-90 and Somatosensory Amplification Scale. RESULTS: Univariable linear regression analyses showed that female ICD patients reported more symptoms of anxiety (beta = .13, p = .04), phobic anxiety (beta = .13, p = .05), and somatic health complaints (beta = .15, p = .02), and scored higher on somatosensory amplification (beta = .24, p < .001) than men. Multivariable regression analyses, adjusted for demographic and clinical risk factors, revealed that somatosensory amplification was associated with more anxiety (beta = .48, p < .001), phobic anxiety (beta = .34, p < .001), and somatic health complaints (beta = .49, p < .001). Sobel tests indicated that somatosensory amplification mediated the association between sex and these three domains of psychological distress (p = .0005, .002, and .0006, respectively). CONCLUSION: Somatosensory amplification mediated the relationship between female sex and heightened anxiety, phobic anxiety, and somatic health complaints in ICD patients. Women may be more likely to misinterpret bodily sensations as indicative of deterioration in their condition. Interventions focusing on modifying these dysfunctional beliefs may reduce their psychological distress. PMID- 20836601 TI - 5-HTTLPR status moderates the effect of early adolescent substance use on risky sexual behavior. AB - OBJECTIVE: A longitudinal, prospective design was used to investigate a moderation effect in the association between early adolescent substance use and risky sexual behavior 2 years later. A genetic vulnerability factor, a variable nucleotide repeat polymorphism (VNTR) in the promoter region of the serotonin transporter gene SLC6A4, known as 5-HTTLPR, was hypothesized to moderate the link between substance use at age 14 and risky sexual behavior at age 16. This VNTR has been associated with risk-taking behavior. DESIGN: African American youths in rural Georgia (N = 185) provided 2 waves of data on their substance use and sexual behavior. Genetic data were obtained via saliva samples. MAIN OUTCOME MEASURES: Substance use and sexual risk behavior were assessed using youth self report items developed for this investigation. RESULTS: Multiple regression analyses indicated that the presence of 1 or 2 copies of the short allele of the VNTR interacted with substance use to predict sexual behavior. Substance use had little effect on sexual behavior for youths without the short allele; this effect was greatly increased for youths with the short allele. CONCLUSION: Genetic vulnerability affected the implications of early onset substance use for later sexual behavior. PMID- 20836603 TI - Resource loss, resource gain, and psychological resilience and dysfunction following cancer diagnosis: a growth mixture modeling approach. AB - OBJECTIVE: This study investigated trajectories of psychological distress and their relationships with change in psychosocial resources in the year following cancer diagnosis. DESIGN: Chinese colorectal cancer (CRC) patients (n = 234) were assessed within 12 weeks of diagnosis (T1) and again at 3-month (T2) and 12-month (T3) follow-ups. Growth mixture modeling was used to analyze the longitudinal data. MAIN OUTCOME MEASURES: Psychological distress was measured at the three time-points using Hospital Anxiety and Depression Scale (HADS). RESULTS: Growth mixture models identified four classes: chronic distress (7-9%), delayed distress (10-13%), recovery (13-16%), and resilient (65-67%). People in chronic distress were more likely to demonstrate loss in physical functioning and social relational quality than those in delayed distress, and loss in physical functioning, optimism, and hope than those in recovery, but more likely to demonstrate stability/gain in optimistic personalities than those in delayed distress and resilient. People in resilient were more likely to report stability/gain in optimistic personalities than those in delayed distress but not those in recovery. CONCLUSION: Understanding differential outcome trajectories and associated change in coping resources has implications for developing ongoing psychological services for cancer patients during the diagnosis and treatment process. PMID- 20836604 TI - Adults' physical activity patterns across life domains: cluster analysis with replication. AB - OBJECTIVE: Identifying adults' physical activity patterns across multiple life domains could inform the design of interventions and policies. DESIGN: Cluster analysis was conducted with adults in two U.S. regions (Baltimore/Washington, DC, n = 702; Seattle, WA [King County], n = 987) to identify different physical activity patterns based on adults' reported physical activity across four life domains: leisure, occupation, transport, and home. Objectively measured physical activity, and psychosocial and built (physical) environment characteristics of activity patterns were examined. MAIN OUTCOME MEASURES: Accelerometer-measured activity, reported domain-specific activity, psychosocial characteristics, built environment, body mass index. RESULTS: Three clusters replicated (kappa = .90 .93) across both regions: Low Activity, Active Leisure, and Active Job. The Low Activity and Active Leisure adults were demographically similar, but Active Leisure adults had the highest psychosocial and built environment support for activity, highest accelerometer-measured activity, and lowest body mass index. Compared to the other clusters, the Active Job cluster had lower socioeconomic status and intermediate accelerometer-measured activity. CONCLUSION: Adults can be clustered into groups based on their patterns of accumulating physical activity across life domains. Differences in psychosocial and built environment support between the identified clusters suggest that tailored interventions for different subgroups may be beneficial. PMID- 20836605 TI - Relationship of body mass index and psychosocial factors on physical activity in underserved adolescent boys and girls. AB - OBJECTIVE: Previous research indicates that body mass index (BMI) and sex are important factors in understanding physical activity (PA) levels. The present study examined the influence of BMI on psychosocial variables (self-efficacy, social support) and PA in underserved (ethnic minority, low income) boys in comparison with girls. METHODS: Participants (N = 669; 56% girls; 74% African American) were recruited from the "Active by Choice Today" trial. MAIN OUTCOME MEASURES: BMI z score was calculated from objectively collected height and weight data, and PA was assessed with 7-day accelerometry estimates. Self-report questionnaires were used to measure self-efficacy and social support (family, peers) for PA. RESULTS: A 3-way interaction between BMI z score, sex, and family support on PA was shown such that family support was positively associated with PA in normal-weight but not overweight or obese boys, and was not associated with PA in girls. Self-efficacy had the largest effect size related to PA in comparison with the other psychosocial variables studied. CONCLUSIONS: Self efficacy was found to be an important variable related to PA in underserved youth. Future studies should evaluate possible barriers to PA in girls, and overweight youth, to provide more effective family support strategies for underserved adolescents' PA. PMID- 20836606 TI - Increasing body satisfaction of body concerned women through evaluative conditioning using social stimuli. AB - OBJECTIVE: Many women show weight and body concerns that leave them vulnerable to body dissatisfaction, lowered self-esteem, psychological distress, and eating disorders. This study tested whether body satisfaction could be increased by means of evaluative conditioning. DESIGN: In the experimental condition (n = 26), women with low and high body concern completed a conditioning procedure in which pictures of their bodies were selectively linked to positive social stimuli (pictures of smiling faces). Pictures of control bodies were linked to neutral or negative social stimuli (neutral and frowning faces). In a control condition (n = 28), low and high body concerned women underwent a procedure in which pictures of their own body and of control bodies were randomly followed by positive, neutral, and negative social stimuli. MAIN OUTCOME MEASURES: Changes in body satisfaction and self-esteem before and after the conditioning task. RESULTS: Women with high body concern demonstrated an increase in body satisfaction and global self-esteem when pictorial representations of their own bodies were associated with positive stimuli that signaled social acceptance. CONCLUSION: A simple conditioning procedure increased body satisfaction in healthy, normal weight women who were concerned about their shape and weight. PMID- 20836607 TI - Tobacco use moderates the association between major depression and obesity. AB - OBJECTIVE: Based on a maladaptive coping explanation, the relationship between major depression (MD) and obesity could be strong among nonsmokers, who may engage in unhealthy eating and sedentary behavior to cope with depression. By contrast, the MD-obesity association could be weak among smokers, who can use tobacco (instead of food or sedentary behavior) to cope with mood symptoms. This study examined smoking status and tobacco dependence as moderators of the MD obesity link. DESIGN: Correlational, cross-sectional population-based survey of 41,654 U.S. adults. MAIN OUTCOME MEASURES: Obesity (body mass index [BMI] >=30 kg/m2) and quantitative BMI value. RESULTS: Current smoking status moderated the association between past-year MD and current obesity, as well as the link between MD and BMI value (ps <= .0001). MD predicted obesity and BMI among nonsmokers (ps < .0001) but did not do so in smokers (ps >= .10). Similar findings emerged with tobacco dependence as the moderator. Each finding persisted after accounting for demographics, psychiatric variables, and potential confounds. CONCLUSION: Tobacco use characteristics appear to moderate the MD-obesity association in the U.S. population. These findings may shed light on the mechanisms linking MD and obesity and have implications for identifying which individuals may benefit most from obesity interventions that target depressive symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 20836608 TI - Long-term effects of implementation intentions on prevention of smoking uptake among adolescents: a cluster randomized controlled trial. AB - OBJECTIVE: To test the efficacy of implementation intentions in reducing smoking uptake in a sample of adolescents. DESIGN: Classes of adolescents (aged 11-12 years) were randomly allocated to one of four conditions: implementation intention, self-efficacy, two control conditions. An implementation intention or a self-efficacy manipulation (both formed in relation to how to refuse offers of cigarettes) was completed by intervention condition participants at 0, 4, 8, 12, 16, 20, and 24 months. MAIN OUTCOME MEASURES: Long-term smoking behavior (self report and objective) was assessed at 48 months post-baseline. RESULTS: There were no differences between the two control conditions and the self-efficacy condition. Controlling for baseline smoking, sex, attitudes to smoking, friends and family smoking, and the multilevel nature of the data, intention-to-treat analyses indicated the implementation intention manipulation significantly reduced self-reported smoking compared to the other three conditions combined. Analyses on objectively assessed smoking (carbon monoxide breath measure) in a random subsample of participants also indicated that the implementation intention manipulation compared to the other three conditions significantly reduced smoking. CONCLUSION: Implementation intentions can reduce smoking in adolescent samples. Implications for using implementation intentions to reduce smoking in adolescents are discussed. PMID- 20836609 TI - Good self-control moderates the effect of mass media on adolescent tobacco and alcohol use: tests with studies of children and adolescents. AB - OBJECTIVE: To investigate whether self-control moderates the effect of media influences on tobacco and alcohol use among youth and if so how this effect occurs. DESIGN: In Study 1, a regional sample of 10-year olds (N = 290) was interviewed in households; attention to tobacco/alcohol advertising was assessed. In Study 2, a national sample of youth ages 10-14 years (N = 6,522) was surveyed by telephone; exposure to tobacco/alcohol use in movies was assessed. Good self control was measured in both studies. MAIN OUTCOME MEASURES: Willingness to use substances and affiliation with peer substance users (Study 1); involvement in smoking or drinking (Study 2). RESULTS: In Study 1, the effect of tobacco/alcohol advertising on predisposition for substance use was lower among persons scoring higher on good self-control. In Study 2, the effect of movie smoking/alcohol exposure on adolescent tobacco/alcohol use was lower, concurrently and prospectively, among persons scoring higher on good self-control. Moderation occurred primarily through reducing the effect of movie exposure on positive smoking/alcohol expectancies and the effect of expectancies on adolescent use; some evidence for moderation of social processes was also noted. Covariates in the analyses included demographics, sensation seeking, and IQ. CONCLUSION: Good self-control reduces the effect of adverse media influences on adolescent tobacco and alcohol use. Findings on the processes underlying this effect may be useful for media literacy and primary prevention programs. PMID- 20836610 TI - Loneliness and the metabolic syndrome in a population-based sample of middle-aged and older adults. AB - OBJECTIVE: This study evaluated the association between loneliness and the metabolic syndrome, which refers to a clustering of factors that have been shown to increase risk for cardiovascular disease, diabetes, stroke, and mortality. A secondary purpose was to evaluate whether age moderated the association between loneliness and the metabolic syndrome. DESIGN: Participants were 52 to 79 years old, and they were drawn from a population-based survey of people 50 years of age and older living in England (N = 3211). They completed a self-report measure of loneliness and a nurse visit that included collection of blood pressure, blood sample, and anthropometric measures. MAIN OUTCOME MEASURES: Self-reported loneliness and the metabolic syndrome. RESULTS: After controlling for demographic variables and smoking status, loneliness was significantly associated with increasing likelihood of meeting criteria for the metabolic syndrome and with the individual criterion of central obesity. The association between loneliness and the metabolic syndrome was not moderated by age. CONCLUSION: Results suggest that loneliness is associated with the metabolic syndrome. Therefore, the metabolic syndrome may be among the pathways by which loneliness increases risk of morbidity and mortality. PMID- 20836611 TI - Assessing the scholarly impact of health psychology: a citation analysis of articles published from 1993 to 2003. AB - OBJECTIVE: We conducted a citation analysis to explore the impact of articles published in Health Psychology and determine whether the journal is fulfilling its stated mission. DESIGN: Six years of articles (N = 408) representing three editorial tenures from 1993-2003 were selected for analysis. MAIN OUTCOME MEASURES: Articles were coded for several dimensions enabling examination of the relationship of article features to subsequent citations rates. Journals citing articles published in Health Psychology were classified into four categories: (1) psychology, (2) medicine, (3) public health and health policy, and (4) other journals. RESULTS: The majority of citations of Health Psychology articles were in psychology journals, followed closely by medical journals. Studies reporting data collected from college students, and discussing the theoretical implications of findings, were more likely to be cited in psychology journals, whereas studies reporting data from clinical populations, and discussing the practice implications of findings, were more likely to be cited in medical journals. Time since publication and page length were both associated with increased citation counts, and review articles were cited more frequently than observational studies. CONCLUSION: Articles published in Health Psychology have a wide reach, informing psychology, medicine, public health and health policy. Certain characteristics of articles affect their subsequent pattern of citation. PMID- 20836612 TI - Are psychophysical scales of intensities the same or different when stimuli vary on other dimensions? Theory with experiments varying loudness and pitch. AB - Most studies concerning psychological measurement scales of intensive attributes have concluded that these scales are of ratio type and that the psychophysical function is closely approximated by a power function. Experiments show, for such cases, that a commutativity property must hold under either successive increases or successive decreases provided, e.g., all other independent dimensions are fixed. A good deal of data support this conclusion. However, little or no attention has been paid to whether or not such subjective intensity scales differ when an independent dimension such as frequency (pitch in audition, color in vision, etc.) is varied. Using a simple and favorably tested theoretical model for global psychophysics, the authors arrive at a necessary and sufficient cross dimension, commutativity condition for a common intensity ratio scale to exist. For example, the data show that the loudness of a tone at frequency f and another tone at frequency g can each be viewed as arising from a common property of loudness over intensity/frequency pairs. Comparing one version of cross dimensional commutativity with the corresponding 1-dimensional commutativity property discriminates between a general representation of the ratio scale property and a special case of it. FUTURE WORK: Does the theory extend to other intensive continua (prothetic attributes)? If so, which ones? And does it extend to cross-modal matching? PMID- 20836613 TI - A continuous dual-process model of remember/know judgments. AB - The dual-process theory of recognition memory holds that recognition decisions can be based on recollection or familiarity, and the remember/know procedure is widely used to investigate those 2 processes. Dual-process theory in general and the remember/know procedure in particular have been challenged by an alternative strength-based interpretation based on signal-detection theory, which holds that remember judgments simply reflect stronger memories than do know judgments. Although supported by a considerable body of research, the signal-detection account is difficult to reconcile with G. Mandler's (1980) classic "butcher-on the-bus" phenomenon (i.e., strong, familiarity-based recognition). In this article, a new signal-detection model is proposed that does not deny either the validity of dual-process theory or the possibility that remember/know judgments can-when used in the right way-help to distinguish between memories that are largely recollection based from those that are largely familiarity based. It does, however, agree with all prior signal-detection-based critiques of the remember/know procedure, which hold that, as it is ordinarily used, the procedure mainly distinguishes strong memories from weak memories (not recollection from familiarity). PMID- 20836614 TI - Hindsight ? hindsight: experimentally induced dissociations between hindsight components. AB - Hindsight bias has recently been conceived of not as a unitary phenomenon but as a conglomerate of 3 separate phenomenological manifestations ("hindsight components"; Blank, Nestler, von Collani, & Fischer, 2008): memory distortions, impressions of foreseeability, and impressions of inevitability. These components are thought to be fundamentally different in nature, to be influenced by different processes, and to serve different functions. This article provides strong evidence for the separate components view and its underlying assumptions by demonstrating theoretically predicted dissociations between the components. In Experiment 1, for example, we used a memory encoding manipulation to specifically influence the amount of hindsight memory distortion but not participants' inevitability impressions. Conversely, varying the number of provided reasons for an event outcome affected inevitability impressions but left memory distortion untouched. Similar results-using different theoretically derived manipulations were obtained between foreseeability impressions and memory distortions (Experiment 2) and between inevitability and foreseeability impressions (Experiment 3). Theoretical and practical consequences of these results and of the separate components view are discussed. PMID- 20836616 TI - Investigational agents for Crohn's disease. AB - IMPORTANCE OF THE FIELD: Increased understanding of the biological mechanisms of Crohn's disease has opened the door to a large number of new molecules; some of these are approved for clinical use, while others remain under evaluation. In this review, we examine the clinical efficacy of all the new drugs that have been evaluated in controlled trials in the last 12 years. AREAS COVERED IN THIS REVIEW: Anti-TNF therapy has been reviewed briefly, given the many comprehensive reviews on this topic; attention is focused mainly on the other biological therapies. In assessing the clinical efficacy of these molecules, we consider only the remission rate, as this is considered the most meaningful end point in clinical practice. WHAT THE READER WILL GAIN: We analyzed the main biological mechanisms of Crohn's disease and the new drugs whose use is based on insights into these mechanisms. We reviewed the following new drugs: probiotics, GM-CSF, IL-10, IL-11, anti-IL-6, anti-IL-12/-23, everolimus, anti-IFN-gamma, IFN-beta-I, co-stimulators, anti-integrins, anti-intercellular adhesion molecule 1, small molecules and mitogen-activated protein kinase inhibitors. TAKE HOME MESSAGE: Anti-TNF therapies remain the best options, followed by anti-integrin drugs. The most promising new therapies are anti-IL-23, but further data are necessary. The disappointing results with other molecules may depend on the quality of trials and possibly on inadequate dosage of the drug. PMID- 20836615 TI - Post-traumatic seizures exacerbate histopathological damage after fluid percussion brain injury. AB - The purpose of this study was to investigate the effects of an induced period of post-traumatic epilepsy (PTE) on the histopathological damage caused by traumatic brain injury (TBI). Male Sprague Dawley rats were given a moderate parasagittal fluid-percussion brain injury (1.9-2.1 atm) or sham surgery. At 2 weeks after surgery, seizures were induced by administration of a GABA(A) receptor antagonist, pentylenetetrazole (PTZ, 30 mg/kg). Seizures were then assessed over a 1-h period using the Racine clinical rating scale. To evaluate whether TBI induced pathology was exacerbated by the seizures, contusion volume and cortical and hippocampal CA3 neuronal cell loss were measured 3 days after seizures. Nearly all TBI rats showed clinical signs of PTE following the decrease in inhibitory activity. In contrast, clinically evident seizures were not observed in TBI rats given saline or sham-operated rats given PTZ. Contusions in TBI-PTZ treated rats were significantly increased compared to the TBI-saline-treated group (p < 0.001). In addition, the TBI-PTZ rats showed less NeuN-immunoreactive cells within the ipsilateral parietal cerebral cortex (p < 0.05) and there was a trend for decreased hippocampal CA3 neurons in TBI-PTZ rats compared with TBI saline or sham-operated rats. These results demonstrate that an induced period of post-traumatic seizures significantly exacerbates the structural damage caused by TBI. These findings emphasize the need to control seizures after TBI to limit even further damage to the injured brain. PMID- 20836617 TI - Investigational agents for the irritable bowel syndrome. AB - IMPORTANCE OF THE FIELD: Irritable bowel syndrome (IBS) is a common disorder with significant health and economic consequences. The etiology of IBS is complex and appears to be multifactorial. Traditional IBS therapies have been directed primarily at the relief of individual symptoms but have been largely disappointing. This has triggered the search for newer treatment strategies with improved patient outcomes. AREAS COVERED IN THIS REVIEW: Enhanced knowledge about the putative pathophysiology of IBS has allowed the identification of new mechanistic targets for treatment. Our aim is to review emerging and promising drugs in the treatment of IBS based on disease pathophysiology. Data were extracted using Medline and PubMed search engines until January 2010. Abstracts were identified through 'Web of Science' and abstract supplements of major gastrointestinal scientific meetings. Drugs were classified according to mechanism of action and those with efficacy in trials involving human subjects examined. WHAT THE READER WILL GAIN: Additional insight into the pathophysiology as well as current and prospective treatments of IBS. TAKE HOME MESSAGE: A multitude of putative drug targets have been identified and some novel treatments have progressed through to human clinical trials, but very few will be approved for the market in the near future. Moreover, and in keeping with the complex and multifactorial nature of this syndrome, it is unlikely that there will be one dominant and universally effective form of therapy for all IBS patients. PMID- 20836618 TI - The long and winding road for the development of tasquinimod as an oral second generation quinoline-3-carboxamide antiangiogenic drug for the treatment of prostate cancer. AB - IMPORTANCE OF THE FIELD: Prostate cancer is the mostly commonly diagnosed non skin cancer in males. The culmination of the last 70 years of clinical drug development has documented that androgen ablation plus taxane-based systemic chemotherapy enhances survival, but is not curative, in metastatic prostate cancer. To effect curative therapy, additional drugs must be developed that enhance the response when combined with androgen ablation/taxane therapy. AREAS COVERED IN THIS REVIEW: The history of the discovery and development of tasquinimod as a second-generation oral quinoline-3-carboxamide analogue for prostate cancer will be presented. WHAT THE READER WILL GAIN: The mechanism for such anticancer efficacy is via tasquinimod's ability to inhibit the 'angiogenic switch' within cancer sites required for their continuous lethal growth. TAKE HOME MESSAGE: Tasquinimod is a novel inhibitor of tumor angiogenesis that enhances the therapeutic anticancer response when combined with other standard-of care modalities (radiation, androgen ablation, and/or taxane-based chemotherapies) in experimental animal models, but does not inhibit normal wound healing. It has successfully completed clinical Phase II testing in humans and will shortly enter registration Phase III evaluation for the treatment of metastatic prostate cancer. PMID- 20836619 TI - High-dose treosulfan in conditioning prior to hematopoietic stem cell transplantation. AB - IMPORTANCE OF THE FIELD: Despite the marked development in the field of preparative regimens prior to hematopoietic stem cell transplantation (HSCT) over the last decade, the search for a superior conditioning agent is still continuing. In view of the literature reports, treosulfan (TREO), a structural analog of busulfan (BU), appears to be a promising candidate in terms of myeloablative, immunosuppressive and antimalignancy effects as well as low organ toxicity. AREAS COVERED IN THIS REVIEW: The article focuses on pharmacological activity, pharmacokinetics and toxicity of TREO. Compressed description of the drug-based conditioning prior to HSCT is also presented. Finally, TREO and BU characteristics are compared. Specific information of TREO concerning pediatric and adult patients is provided throughout the whole paper. The data refer predominantly to the publications, in majority from the last 10 years. WHAT THE READER WILL GAIN: According to our best knowledge, the paper is the first such comprehensive review on TREO, especially in terms of its application in pediatric HSCT. TAKE HOME MESSAGE: TREO offers a great potential as a conditioning agent prior to HSCT but further investigations of the drug are warranted to clearly verify its advantages. However, we expect TREO to be registered as a novel conditioning agent in the near future. PMID- 20836620 TI - Berberine: a potential phytochemical with multispectrum therapeutic activities. AB - IMPORTANCE OF THE FIELD: The use of traditional medicines of natural origin is being encouraged for the treatment of chronic disorders, as synthetic drugs in such cases may cause unpredictable adverse effects. Berberine, a traditional plant alkaloid, is used in Ayurvedic and Chinese medicine for its antimicrobial and antiprotozoal properties. Interestingly, current clinical research on berberine has revealed its various pharmacological properties and multi-spectrum therapeutic applications. AREAS COVERED IN THIS REVIEW: An extensive search in three electronic databases (Unbound Medline, PubMed and ScienceDirect) and internet search engines (Scirus and Google Scholar) were used to identify the clinical studies on berberine, without any time constraints. This review elaborates the recent studies which reveal that with time, the drug has evolved with superior therapeutic activities. In addition, this review will also attract the attention of formulation scientists towards the issues and challenges associated in its drug delivery and the probable approaches that may be explored to help patients reap the maximum benefit of this potentially useful drug. WHAT THE READER WILL GAIN: A relatively large number of studies discussed here have revealed the possible areas where this phytochemical constituent can exhibit its therapeutic activities in the treatment of chronic ailments or diseases including diabetes, cancer, depression, hypertension and hypercholesterolemia. TAKE HOME MESSAGE: The potential of the drug remains to be harvested by designing a suitable formulation that could overcome its inherent low bioavailability. PMID- 20836621 TI - Measuring perceived difficulty in post-acute brain injury rehabilitation: The Sister Kenny Symptom Management Scale. AB - PRIMARY OBJECTIVE: Patients' perceptions of difficulty managing symptoms contribute to disability after brain injury. This study introduces the Sister Kenny Symptom Management Scale (KSMS) and reports on its factor structure, reliability, validity and clinical value. METHOD: Archived data from (overlapping) samples of patients with brain injuries of mixed aetiologies, seen at an outpatient clinic over 16 years were used in development and validation studies of the KSMS. Comparison measures included the Profile of Mood States (POMS), neuropsychological test scores and employment. RESULTS: Factor analysis of 34 items (n = 328) identified five sub-scales with satisfactory internal consistency and test-re-test stability representing difficulty with executive functions, language, recent memory, aggressive behaviour and physical symptoms. A pattern of correlations (n = 336) with Profile of Mood States (POMS) sub-scales of similar and different content supported the concurrent validity of KSMS sub scales. Only the Memory sub-scale correlated with its test index. The Language score and test index approached significance. The Executive sub-scale did not. Hierarchical regression analysis (n = 102) that included ratings of mood and symptom management showed that employment after discharge was only predicted by post-treatment ratings of difficulty with cognitive functions. CONCLUSION: Self assessments of difficulty managing symptoms can be reliably assessed and may contribute to understanding patients' disability, treatment response and future prospects. PMID- 20836622 TI - Perivascular cells as mesenchymal stem cells. AB - IMPORTANCE OF THE FIELD: Mesenchymal stem cells are multipotent adult stem cell populations that have broad differentiation plasticity and immunosuppressive potential that render them of great importance in cell-based therapies. They are identified by in vitro characteristics based on their differentiation potential for clinical approaches while their biological properties and in vivo identities are often less understood. AREAS COVERED IN THIS REVIEW: Recent research carried out in the last decade on mesenchymal stem cell biology suggests that mesenchymal stem cells from various tissues reside in a perivascular location and these can be identified as pericytes that function as mural cells in microvessels. WHAT THE READER WILL GAIN: This review covers recent progress on understanding the link between pericytes and mesenchymal stem cells discussing specific points such as response to injury and tissue-specific functions. TAKE HOME MESSAGE: Despite a long and controversial history, there is a growing acceptance that perivascular cells are connected with mesenchymal stem cells, all that is really lacking is genetic evidence to show differentiation of pericytes into different cells types. PMID- 20836623 TI - Advances in using chitosan-based nanoparticles for in vitro and in vivo drug and gene delivery. AB - IMPORTANCE OF THE FIELD: This review aims to provide an overview of state-of-the art chitosan-based nanosized carriers for the delivery of therapeutic agents. Chitosan nanocarriers are smart delivery systems owing to the possibility of their property alterations with various approaches, which would confer them with the possibility of spatiotemporal delivery features. AREAS COVERED IN THIS REVIEW: The focus of this review is principally on those aspects that have not often been addressed in other reviews. These include the influence of physicochemical properties of chitosan on delivery mechanisms and chitosan modification with a variety of ligand moieties specific for cell surface receptors to increase recognition and uptake of nanocarriers into cells through receptor-mediated endocytosis. Multiple examples that demonstrate the advantages of chitosan-based nanocarriers over other delivery systems of therapeutic agents are highlighted. Particular emphasis is given to the alteration of material properties by functionalization or combination with other polymers for their specific applications. Finally, structural and experimental parameters influencing transfection efficiency of chitosan-based nanocarriers are presented for both in vitro and in vivo gene delivery. WHAT THE READER WILL GAIN: The readers will acquire knowledge of parameters influencing the properties of the chitosan-based nanocarriers for delivery of therapeutic agents (genetic material or drugs) in vitro and in vivo. They will get a better idea of the strategies to be adapted to tune the characteristics of chitosan and chitosan derivatives for specific delivery applications. TAKE HOME MESSAGE: Chitosan is prone to chemical and physical modifications, and is very responsive to environmental stimuli such as temperature and pH. These features make chitosan a smart material with great potential for developing multifunctional nanocarrier systems to deliver large varieties of therapeutic agents administrated in multiple ways with reduced side effects. PMID- 20836624 TI - New drug-targeting strategy from beneath the shell of egg. AB - IMPORTANCE OF THE FIELD: Antibiotic resistance is a serious problem that continues to challenge the healthcare sectors and has become increasingly alarming in the past few years. To face this emerging global crisis, there is a need to find a new class of antibiotics that act on new microbial targets and/or harness existing antibiotics by developing new drug-targeting strategies. AREAS COVERED IN THIS REVIEW: This review: explores an innovative drug-delivery strategy of using hen egg lysozyme as a carrier to enable water solubilization and to allow specific targeting to the microbial cells of a water-insoluble antimicrobial agent with a powerful killing action; addresses potentials for lysozyme in antibiotics drug targeting; and provides insight for the future direction of this highly prospective technology. WHAT THE READER WILL GAIN: The unique features and advantages of lysozyme-based drug delivery system are highlighted. The efficiency of lysozyme in solubilization and delivery of lipophilic antibiotics, to reformulate drugs that may fail clinical trials owing to low solubility, is emphasized. TAKE HOME MESSAGE: Fewer pharmaceutical companies are inventing new antibiotics because of long development times and high failure rates. Combining lysozyme with a powerful old antibiotic may open doors to revolutionizing medicine, particularly in the treatment of deadly infections. PMID- 20836628 TI - Breathless. PMID- 20836629 TI - The necessary work program for safe delivery of combinations of injectable medications. PMID- 20836630 TI - Branding our field. PMID- 20836625 TI - Lipid and polymeric carrier-mediated nucleic acid delivery. AB - IMPORTANCE OF THE FIELD: Nucleic acids such as plasmid DNA, antisense oligonucleotide, and RNA interference (RNAi) molecules, have a great potential to be used as therapeutics for the treatment of various genetic and acquired diseases. To design a successful nucleic acid delivery system, the pharmacological effect of nucleic acids, the physiological condition of the subjects or sites, and the physicochemical properties of nucleic acid and carriers have to be thoroughly examined. AREAS COVERED IN THIS REVIEW: The commonly used lipids, polymers and corresponding delivery systems are reviewed in terms of their characteristics, applications, advantages and limitations. WHAT THE READER WILL GAIN: This article aims to provide an overview of biological barriers and strategies to overcome these barriers by properly designing effective synthetic carriers for nucleic acid delivery. TAKE HOME MESSAGE: A thorough understanding of biological barriers and the structure-activity relationship of lipid and polymeric carriers is the key for effective nucleic acid therapy. PMID- 20836631 TI - The "PSOST": Providers' Signout for Scope of Treatment. AB - Palliative care provides open and honest communication, medically appropriate goal setting, and meticulous attention to symptom assessment and control. The Physicians Orders for Life Sustaining Treatment (POLST) is a growing movement to allow health care providers to indicate, with their patients, what they want done in specific situations, such as feeding tubes, mechanical ventilation, or transfer to an intensive care unit. We have developed an internal signout tool used by palliative medicine fellows in our institution to specify similar interventions-or not-with seriously ill palliative care patients, the Providers Signout for Scope of Treatment (PSOST). We have found that this situation specific tool enables smooth transitions of care on nights and weekends, especially when the patient is near death, and may help prevent both overescalation of care and underuse of life saving treatments such as resuscitation. The PSOST differs from other signout tools in that it gives clear direction regarding the patient's medical goals and desire for escalation of care, or not. We present it here for open access and use anywhere. This tool has also assisted in building team communication with the nursing shifts, especially nights and weekends, as all team members are able to deliver a consistent message, while meeting the goals of care for patients and families. We believe this tool could be useful with a broader patient population, outside of Palliative Medicine, to provide clearer direction for hospitalized or nursing home patients whose care is often directed by multiple providers. It could also be used as a template for signouts on other inpatient services, as care goals are important for all patients. PMID- 20836632 TI - Palliative care programs: the challenges of growth. PMID- 20836633 TI - Exploring factors that influence informal caregiving in medication management for home hospice patients. AB - OBJECTIVE: To explore factors that influence how informal caregivers manage medications as part of caring for hospice patients. METHODS: Semistructured, open ended interviews were conducted with 23 informal caregivers and 22 hospice providers from 4 hospice programs in the Chicago metropolitan areas. Qualitative analysis was conducted consistent with the grounded theory approach. RESULTS: In general, informal caregivers and hospice providers identified similar key factors that facilitated or impeded caregivers' process in managing medications. Caregivers' life experience and self-confidence were considered assets that facilitated medication management. Limitations impeding the process included caregivers' negative emotional states, cognitive and physical impairments, low literacy, other competing responsibilities, as well as patients' negative emotional states and complex medication needs. Furthermore, the social context of medication management emerged as a salient theme: caregivers' good interpersonal relations with patients facilitated medication management, whereas poor communication/relations among caregivers within a support network impeded the process. While both study groups discussed the positive attributes of good caregiver-patient relations and support from multiple caregivers, hospice providers were cautious about the potential adverse influence of close relations with patients on caregivers' decision making about medications and discussed poor communication/relations among informal and privately hired caregivers that often resulted from family conflicts and/or a lack of long-standing leadership. CONCLUSION: Our findings suggest additional intervention points, beyond knowledge and skill building, that could be addressed to support caregivers in executing medication responsibilities at home for hospice patients. PMID- 20836634 TI - A systematic review of postgraduate palliative care curricula. AB - BACKGROUND: Palliative care is part of comprehensive family practice; however, many physicians do not feel confident in the biomedical and psychosocial realms. Although improving residency training to address this is necessary, there is little consensus on the best education methods. OBJECTIVE: To conduct a systematic review of postgraduate curricula in palliative care to incorporate the most effective components into a family medicine education program. METHODS: Studies of palliative care curricula conducted in postgraduate medical training programs that contained an evaluative component and published since 1980 were systematically examined by investigator pairs using standard selection criteria and data collection forms. Discrepancies were resolved by consensus. The outcomes examined were communication skills, knowledge, attitudes, and comfort/confidence level. RESULTS: 28 studies were included after reviewing 174 abstracts. Most studies (n = 21) used survey pre-post design with no control group. Outcomes were grouped into communication skills, knowledge and attitudes and confidence. Workshops with simulated patients or role plays improved communication skills. Relatively brief strategies such as short workshops showed objective improvements in focused knowledge areas. Either clinical rotations or multi-faceted interventions were required to produce improvements more broadly in knowledge base. Only a few studies examined the sustainability of outcomes. CONCLUSIONS: An effective palliative care curriculum will need to use a multifaceted approach, incorporating a variety of intentional strategies to address the multiple competencies required. There is a need for more rigorous curricular evaluation. PMID- 20836635 TI - Understanding breathlessness: cross-sectional comparison of symptom burden and palliative care needs in chronic obstructive pulmonary disease and cancer. AB - BACKGROUND: Little is known about symptom burden and palliative care needs of breathless patients with advanced cancer and chronic obstructive pulmonary disease (COPD). OBJECTIVES: We aimed to describe and compare symptoms and needs in these two groups in relation to survival. METHODS: Cross-sectional study of breathless patients with COPD III/IV or advanced cancer. Data were collected in an interview using the Memorial Symptom Assessment Scale short form (MSAS-SF), the modified Borg Scale, the Hospital Anxiety and Depression Scale, and the Palliative Care Outcome Scale (POS). Follow-up information was collected on survival. RESULTS: Forty-nine patients with cancer and 60 patients with COPD were recruited. Both groups had similar demographics and a similar high symptom burden: median number of 14 symptoms; most prevalent symptoms in both groups besides breathlessness were drowsiness, lack of energy, cough; median global symptom distress on MSAS-Global Distress Index MSAS-GDI 1.6 in cancer and 1.4 in COPD. HADS depression scores were higher than HADS anxiety scores. Palliative care needs were also similar in both groups. Median survival was 107 days in patients with cancer and 589 days in patients with COPD. CONCLUSIONS: Symptom burden and palliative care needs of breathless patients with severe COPD are considerable and as high as among patients with advanced primary and secondary lung cancer although patients with COPD have a longer survival. PMID- 20836636 TI - Using coping strategies is not denial: helping loved ones adjust to living with a patient with a palliative diagnosis. AB - BACKGROUND: When a patient receives the diagnosis of an incurable cancer, their loved ones have to face the fact that life will change. Realizing that the time together is with someone who is going to die, loved ones have to cope with the situation. OBJECTIVE: The objective of this study was to increase the knowledge concerning what forms of coping strategies loved ones apply when a family member is faced with an incurable cancer. DESIGN: The study had a qualitative approach using in-depth interviews as data from a sample of consecutive loved ones. The interviews were audiotaped, transcribed verbatim, and analyzed using a manifest content analysis. RESULTS: The main findings showed that the strategies used by loved ones could be categorized into four different areas: thinking that the death is far off in the future; hoping for an improvement; living in the present; and utilizing the family and personal network. The loved ones used these strategies in order to learn to live with the fact that their spouse had been diagnosed with an incurable illness. CONCLUSION: The study shows that the manner in which the coping strategies are used is individual and also depends on how loved ones can cope with the concept of a dying person with whom they are very close. When loved ones have a need for support outside their personal network, it is important to understand that this need is directly related to coping strategies and that it is not a result of denial. PMID- 20836637 TI - Presentation, treatment, and outcomes of dural metastases in men with metastatic castrate-resistant prostate cancer: a case series. AB - PURPOSE: Men with metastatic castrate-resistant prostate cancer (mCRPC) have shown increased survival since the introduction of docetaxel-based chemotherapy in 2004. While bone metastases are common in prostate cancer, cranial dural metastases (DM) are not. We hypothesize that longer survival in patients with mCRPC may increase the incidence of uncommon metastatic sites, including the cranial dura. We describe 10 cases of DM in men with mCRPC and review the relevant literature. MATERIALS AND METHODS: We conducted a retrospective chart review of 10 subjects with mCRPC, diagnosed ante-mortem with DM at our institution between August 1, 2003 and June 1, 2008. Variables analyzed included prognostic factors at prostate cancer diagnosis, number of therapies prior to DM, treatments administered for DM with response achieved, and survival following diagnosis of DM. RESULTS: Median age at prostate cancer diagnosis was 59 years (range, 52-80), with a median Gleason's score of 9 (range, 8-10) and prostate specific antigen (PSA) of 37 ng/dL (range, 4.9-118). Fifty percent had metastatic disease at initial diagnosis. A median of 5 therapies (range, 1-13) were administered prior to diagnosis of DM, including a median of 1 course of chemotherapy (range, 1-3). Cranial neuropathies were the most common presenting symptoms of DM, and 8 of 10 patients received treatment for their DM, most often radiotherapy. Median survival for this group was 6.17 months (range, < 1-15). CONCLUSIONS: Treatment advances in mCRPC may lead to an increased incidence of previously rare metastatic sites. CNS symptoms in men with mCRPC should prompt evaluation for DM. PMID- 20836638 TI - Health-related quality of life in family members of intensive care unit patients. AB - OBJECTIVE: The intensive care unit (ICU) experience has been reported to cause adverse health effects in families during and after the ICU stay. The objective of this study was to evaluate health-related quality of life (HRQOL) in relatives of patients 90 days after ICU discharge or death. DESIGN: Multicenter observational study. SETTING: Twenty-one ICUs in France. PARTICIPANTS: Among 459 eligible relatives of ICU patients, 284 (62%) were included in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During a telephone interview, the SF-36 was completed to assess HRQOL 90 days after ICU discharge or death. The physical component summary score of the SF-36 was normal (89/100 [66-94]) but the mental component summary score showed substantial impairments (emotional role, 67 [50-80]; social functioning, 70 [60-90]; vitality, 60 [45-70]; and mental health, 60 [48-2]). Moreover, 35.9% of relatives were taking anxiolytic or antidepressant drugs, and 8.4% were taking psychotropic agents prescribed since the discharge or death of the patient. Among factors independently associated with a worse mental score, 2 were patient-related (admission for shock or implementation of end-of life decision), 6 were family-related (older age, female gender, child of the patient, low income, chronic disease, and newly prescribed psychotropic medications), and 1 was related to the ICU experience (perceived conflicts between ICU staff and relatives). CONCLUSIONS: The SF-36 showed evidence of impaired mental health in relatives of ICU patients 90 days after discharge. Better end-of-life care, psychiatric support after the ICU experience, and better conflict prevention and resolution are potential targets for improvement. PMID- 20836639 TI - Clinician educators navigating the world of academic palliative medicine. Introduction. PMID- 20836640 TI - Strategies for finding and negotiating a first position in hospice and palliative medicine. AB - Securing a first job following training is an exciting and daunting task. Little formal guidance is available and trainees often find themselves confused, uncertain, and overwhelmed. This article is designed to provide a basic framework for fellows and new graduates to search for positions, apply, interview, and negotiate. The article focuses on securing an academic position; however, much of the advice is generalizable to a private-sector position. A short case example will be used to illustrate key points. PMID- 20836641 TI - Using noninvasive ventilation at the end of life #230. PMID- 20836642 TI - Practical aspects of using noninvasive positive pressure ventilation at the end of life #231. PMID- 20836643 TI - Remembrance. PMID- 20836644 TI - Tattoo flash: consider "do not resuscitate". PMID- 20836646 TI - Neuromuscular paraneoplastic syndromes: the Lambert-Eaton myasthenic syndrome. AB - BACKGROUND: Disorders in which the effects of cancer occur at a site remote from the primary tumor are termed paraneoplastic disorders. The most well- known paraneoplastic disorder affecting the neuromuscular junction is the Lambert-Eaton myasthenic syndrome (LEMS). DISCUSSION: We describe a case of the Lambert-Eaton myasthenic syndrome diagnosed in a patient with small cell lung cancer presenting with profound weakness. The discussion that follows the case describes the pathophysiology of the disorder, clinical characteristics and therapies that have been used. The role of the palliative care team in the case is described. PMID- 20836650 TI - X-rays and laboratory tests in hospice. PMID- 20836652 TI - World health Organization international cytokine standards and reference preparations. PMID- 20836656 TI - Cellular trans-differentiation and morphogenesis toward the lymphatic lineage in regenerative medicine. AB - Lymphedema is a medically irresolvable condition. The lack of therapies addressing lymphatic vessel dysfunction suggests that improved understanding of lymphatic cell differentiation and vessel maturation processes is key to the development of novel, regenerative medicine, and tissue engineering approaches. In this review we provide an overview of lymphatic characterization markers and morphology in development. Further, we describe multiple differentiation processes of the lymphatic system during embryonic, postnatal, and pathogenic development. Using the example of pathogenic Kaposi's sarcoma-associated herpes infection, we illustrate the involvement of the Notch and PI3K pathways for lymphatic transdifferentiation. We also discuss the plasticity of certain cell types and biofactors that enable transdifferentiation toward the lymphatic lineage. Here we argue the importance of pathway-associated induction factors for lymphatic transdifferentiation, including growth factors such as vascular endothelial growth factor receptor-C and interleukins, and the involvement of extracellular matrix characteristics and dynamics for morphological functionality. PMID- 20836655 TI - Reactive oxygen species mediate oxidized low-density lipoprotein-induced inhibition of oct-4 expression and endothelial differentiation of bone marrow stem cells. AB - This study was to test the hypothesis that oxidized low-density lipoprotein (ox LDL) modified the behavior of bone marrow stem cells, including proliferation, Oct-4 expression, and their endothelial differentiation through reactive oxygen species (ROS) formation in vitro. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL with or without the antioxidant N acetylcysteine (NAC). Ox-LDL generated a significant amount of ROS in the culture system as measured with electron paramagnetic resonance spectroscopy, and substantially inhibited the proliferation, Oct-4 expression, and endothelial differentiation of MAPCs. ROS production from ox-LDL in the culture system was completely prevented by NAC (1 mM). NAC treatment completely restored endothelial differentiation potential of MAPCs that was diminished by low-dose ox-LDL. NAC also significantly, but not completely, reversed the inhibitory effect of ox-LDL on proliferation and Oct-4 expression in MAPCs. NAC treatment only slightly restored Akt phosphorylation impaired by ox-LDL in the cells. ROS formation was important in the action of ox-LDL on MAPCs, including Oct-4 expression, proliferation, and endothelial differentiation. However, other mechanism(s) like Akt signaling and apoptosis might also play a critical role in mediating the effect of ox-LDL on these cells. PMID- 20836658 TI - Lipid peroxidation research in Europe and the COST B35 action 'Lipid Peroxidation Associated Disorders'. PMID- 20836657 TI - Enhanced neuropeptide Y synthesis during intermittent hypoxia in the rat adrenal medulla: role of reactive oxygen species-dependent alterations in precursor peptide processing. AB - Intermittent hypoxia (IH) associated with recurrent apneas often leads to cardiovascular abnormalities. Previously, we showed that IH treatment elevates blood pressure and increases plasma catecholamines (CAs) in rats via reactive oxygen species (ROS)-dependent enhanced synthesis and secretion from the adrenal medulla (AM). Neuropeptide Y (NPY), a sympathetic neurotransmitter that colocalizes with CA in the AM, has been implicated in blood pressure regulation during persistent stress. Here, we investigated whether IH facilitates NPY synthesis in the rat AM and assessed the role of ROS signaling. IH increased NPY like immunoreactivity in many dopamine-beta-hydroxylase-expressing chromaffin cells with a parallel increase in preproNPY mRNA and protein. IH increased the activities of proNPY-processing enzymes, which were due, in part, to elevated protein expression and increased proteolytic processing. IH increased ROS generation, and antioxidants reversed IH-induced increases in ROS, preproNPY, and its processing to bioactive NPY in the AM. IH treatment increased blood pressure and antioxidants and inhibition of NPY amidation prevented this response. These findings suggest that IH-induced elevation in NPY expression in the rat AM is mediated by ROS-dependent augmentation of preproNPY mRNA expression and proNPY processing enzyme activities and contributes to IH-induced elevation of blood pressure. PMID- 20836659 TI - Chemistry and biochemistry of lipid peroxidation products. AB - Oxidative stress and resulting lipid peroxidation is involved in various and numerous pathological states including inflammation, atherosclerosis, neurodegenerative diseases and cancer. This review is focused on recent advances concerning the formation, metabolism and reactivity towards macromolecules of lipid peroxidation breakdown products, some of which being considered as 'second messengers' of oxidative stress. This review relates also new advances regarding apoptosis induction, survival/proliferation processes and autophagy regulated by 4-hydroxynonenal, a major product of omega-6 fatty acid peroxidation, in relationship with detoxication mechanisms. The use of these lipid peroxidation products as oxidative stress/lipid peroxidation biomarkers is also addressed. PMID- 20836660 TI - Pathological aspects of lipid peroxidation. AB - Lipid peroxidation (LPO) product accumulation in human tissues is a major cause of tissular and cellular dysfunction that plays a major role in ageing and most age-related and oxidative stress-related diseases. The current evidence for the implication of LPO in pathological processes is discussed in this review. New data and literature review are provided evaluating the role of LPO in the pathophysiology of ageing and classically oxidative stress-linked diseases, such as neurodegenerative diseases, diabetes and atherosclerosis (the main cause of cardiovascular complications). Striking evidences implicating LPO in foetal vascular dysfunction occurring in pre-eclampsia, in renal and liver diseases, as well as their role as cause and consequence to cancer development are addressed. PMID- 20836661 TI - Advances in methods for the determination of biologically relevant lipid peroxidation products. AB - Lipid peroxidation is recognized to be an important contributor to many chronic diseases, especially those of an inflammatory pathology. In addition to their value as markers of oxidative damage, lipid peroxidation products have also been shown to have a wide variety of biological and cell signalling effects. In view of this, accurate and sensitive methods for the measurement of lipid peroxidation products are essential. Although some assays have been described for many years, improvements in protocols are continually being reported and, with recent advances in instrumentation and technology, highly specialized and informative techniques are increasingly used. This article gives an overview of the most currently used methods and then addresses the recent advances in some specific approaches. The focus is on analysis of oxysterols, F(2)-isoprostanes and oxidized phospholipids by gas chromatography or liquid chromatography mass spectrometry techniques and immunoassays for the detection of 4-hydroxynonenal. PMID- 20836662 TI - An inter-laboratory validation of methods of lipid peroxidation measurement in UVA-treated human plasma samples. AB - Lipid peroxidation products like malondialdehyde, 4-hydroxynonenal and F(2) isoprostanes are widely used as markers of oxidative stress in vitro and in vivo. This study reports the results of a multi-laboratory validation study by COST Action B35 to assess inter-laboratory and intra-laboratory variation in the measurement of lipid peroxidation. Human plasma samples were exposed to UVA irradiation at different doses (0, 15 J, 20 J), encoded and shipped to 15 laboratories, where analyses of malondialdehyde, 4-hydroxynonenal and isoprostanes were conducted. The results demonstrate a low within-day-variation and a good correlation of results observed on two different days. However, high coefficients of variation were observed between the laboratories. Malondialdehyde determined by HPLC was found to be the most sensitive and reproducible lipid peroxidation product in plasma upon UVA treatment. It is concluded that measurement of malondialdehyde by HPLC has good analytical validity for inter laboratory studies on lipid peroxidation in human EDTA-plasma samples, although it is acknowledged that this may not translate to biological validity. PMID- 20836663 TI - Natural and synthetic antioxidants: an updated overview. AB - Abstract The current understanding of the complex role of ROS in the organism and pathological sequelae of oxidative stress points to the necessity of comprehensive studies of antioxidant reactivities and interactions with cellular constituents. Studies of antioxidants performed within the COST B-35 action has concerned the search for new natural antioxidants, synthesis of new antioxidant compounds and evaluation and elucidation of mechanisms of action of both natural and synthetic antioxidants. Representative studies presented in the review concern antioxidant properties of various kinds of tea, the search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine. PMID- 20836664 TI - Does mast cell density predict the outcome after transurethral resection of Hunner's lesions in patients with type 3C bladder pain syndrome/interstitial cystitis? AB - OBJECTIVE: This study aimed to assess mast cell density in the lamina propria for possible correlation with duration of symptom amelioration after transurethral resection of the bladder (TURB). MATERIAL AND METHODS: Twelve patients (eight women and four men) referred to the tertiary referral facility, treated between June 2003 and June 2009, were included in the study. All had undergone three consecutive complete TURB procedures, where the first one was also diagnostic. All patients fulfilled the NIH-NIDDK criteria and the ESSIC bladder pain syndrome/interstitial cystitis type 3C criteria; they had Hunner's lesions and biopsy findings with inflammatory infiltrates, granulation tissue and mastocytosis. Bladder biopsies were evaluated for mast cell density by immunochemistry and symptom amelioration was recorded by self-report of symptom relapse. RESULTS: Median mast cell density in the lamina propria at the first, second and third TURB was high. No statistically significant correlation between mast cell density in the urothelium, lamina propria or detrusor, and duration of symptom amelioration could be seen after the first, second or third TURB. CONCLUSION: Mast cell density does not appear to correlate with duration of symptom amelioration after complete transurethral resection of Hunner's lesions, either in the lamina propria or in the urothelium or detrusor. PMID- 20836665 TI - Fragmentation as a mechanism for growth cone pruning and degeneration. AB - During early development of the central nervous system, there is an excessive outgrowth of neuronal projections, which later need to be refined to achieve precise connectivity. Axon pruning and degeneration are strategies used to remove exuberant neurites and connections in the immature nervous system to ensure the proper formation of functional circuitry. To observe morphological changes and physical mechanisms underlying this process, early differentiating embryonic stem cell-derived neurons were used combining video imaging of live growth cones (GCs) with confocal laser scanning microscopy and atomic force microscopy, both on fixed and living neurons. Using this method, we could highlight the presence of submicrometric fragments in still and in some of the retracting GCs. The observed fragmentation is not an artifact of atomic force microscopy scanning or fixation, or the result of apoptosis. Therefore, the morphology of GCs depends on their overall motility, and fragmentation seems to be the fate of GCs that have not found a correct destination. PMID- 20836666 TI - Unconventional therapies in ocular adnexal lymphomas. PMID- 20836667 TI - Superficial esophageal cancer: endoscopic resection or radical surgery? PMID- 20836669 TI - Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. AB - Bendamustine (Treanda((r)); Pharmachemie BV, The Netherlands for Cephalon, Inc., PA, USA) is a unique cytotoxic agent with both alkylating and antimetabolite properties. A growing body of evidence demonstrates its efficacy in a number of hematologic malignancies, and as such, it has been US FDA approved for the treatment of chronic lymphocytic leukemia and non-Hodgkin's lymphoma that has not responded to, or progressed within 6 months of, a rituximab-based regimen. Bendamustine has efficacy both as a single agent as well as in combination with other chemotherapeutics and immunotherapeutics. Here, we will discuss in the detail the molecular properties, clinical efficacy and safety profile of bendamustine. PMID- 20836670 TI - American Society of Clinical Oncology 2010: report of selected studies from the CNS tumors section. AB - A number of important studies were presented at the CNS tumors section of the 2010 American Society of Oncology (ASCO) Annual Meeting. There was particular interest in a Phase II study showing that the mTOR inhibitor everolimus had significant activity in tuberous patients with subependymal giant cell astrocytomas. Two Phase III studies reported on the relative benefits of radiotherapy and chemotherapy in elderly patients with glioblastomas. Other studies focused on promising new agents such as XL184 and ANG1005. PMID- 20836672 TI - Genetic alterations of FGF receptors: an emerging field in clinical cancer diagnostics and therapeutics. AB - Evaluation of: Turner N, Pearson A, Sharpe R et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 70(5), 2085-2094 (2010). FGF receptor (FGFR) family members are aberrantly activated during carcinogenesis due to gene amplification, chromosomal translocation and missense mutation. FGFR1 is preferentially amplified in estrogen receptor-positive breast cancer, whereas FGFR2 is amplified in triple negative breast cancer and diffuse-type gastric cancer. Gene amplification of FGFRs results in ligand-independent FGFR signaling to RAS-ERK, PI3K-AKT and JAK STAT cascades due to the overexpression of wild-type or C-terminally deleted FGFRs. Cediranib, TKI258, Ki23057, MK-2461 and brivanib are broad-range tyrosine kinase inhibitors targeting FGFRs and other receptors. Clinical application of small-molecule FGFR inhibitors could improve the prognosis of FGFR-driven cancer patients. Diagnostic detection of tumors with FGFR genetic alterations in primary lesion, peritoneal effusion, pleural effusion and bone marrow is necessary to select patients for FGFR-targeted therapeutics. PMID- 20836671 TI - American Society of Clinical Oncology 2010 colorectal update. AB - The 2010 American Society of Clinical Oncology (ASCO) Gastrointestinal (Colorectal) Cancer Track included several notable presentations. The addition of cetuximab to FOLFOX in stage III colon cancer did not improve disease-free survival, but increased toxicity. In the metastatic setting, cetuximab demonstrated benefit only in a small subset of patients (KRAS wild-type and limited metastatic disease). Bevacizumab monotherapy may be equivalent to combination chemotherapy in the maintenance phase of treatment in advanced disease, and in another study bevacizumab did not appear to incur excess morbidity in patients with an intact primary tumor. Alternate strategies for the treatment of stage II/III rectal cancer included short-course radiotherapy with adjuvant chemotherapy and neoadjuvant FOLFOX-bevacizumab without radiation, both demonstrating promising results. PMID- 20836673 TI - Quality of voice after radiotherapy in early vocal cord cancer. AB - Early glottic cancer (T1, T2N0M0), a disease of the voice box, mainly affects the voice. It can be effectively treated with both surgery and radiotherapy. Preservation of the voice while treating vocal cord cancer is not simply retaining the ability to vocalize. It is the determinant of choice of treatment and quality of life following curative management. Radiotherapy has resulted in excellent control rates with voice preservation and has been the standard of care for many decades. Several patient- (e.g., smoking, age, amount of talking during treatment), disease- (e.g., extent and site of lesion) and treatment- (e.g., radiation field size and dose, voice therapy) related factors adversely affect the quality of voice after radiotherapy. Several studies have evaluated voice quality either subjectively or objectively. Still, little is known about it. Voice quality after radiotherapy improves but does not reach the standard of the normal controls. PMID- 20836675 TI - Risk stratification in extranodal natural killer/T-cell lymphoma. AB - Extranodal natural killer/T-cell lymphoma (ENKL), a subtype of natural killer/T cell malignancies, is a rare subset of lymphomas with significant biological and clinical heterogeneity. The prognosis of ENKL is variable and therapeutic approaches are not well established. The optimal dose, combination, and sequence of radiotherapy and chemotherapy are evolving, as is the role of stem cell transplantation. Radiotherapy is an essential component of therapy for early stage disease. The clinical course of advanced disease is highly aggressive, with frequent chemotherapy resistance and a poor prognosis. For relapsed disease, asparaginase-based regimens have provided encouraging results and are currently under investigation in the frontline setting. Our article discusses the key aspects of biology, pathogenesis and clinical presentation that contribute to the heterogeneity, and proposes a stratified approach to the treatment of ENKL based on clinical, pathologic and biologic risk factors. Although considerable advances have been made in our understanding of the biology and prognosis of this lymphoma, it remains critical that all patients with a diagnosis of ENKL are enrolled and treated in clinical trials so that optimal therapies can be identified. PMID- 20836674 TI - Chronic lymphocytic leukemia: planning for an aging population. AB - Chronic lymphocytic leukemia (CLL) remains incurable, but over the past decade there have been major advances in the understanding of the pathophysiology of CLL and in the treatment of this disease. This has led to greatly increased response rates and durations of response, as well as improved survival. CLL is a disease of the elderly and not all patients are eligible for the aggressive upfront chemoimmunotherapy regimens that are resulting in improved response rates and survival, so what is the optimal treatment approach for more frail elderly patients? It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released. The age range of patients involved in clinical trials is not representative of this disease, and more research is required in patients who are representative of the majority of CLL patients seen in practice before we will see outcome improvements in these more elderly and often more frail patient populations. PMID- 20836676 TI - Spleen tyrosine kinase as a molecular target for treatment of leukemias and lymphomas. AB - Spleen tyrosine kinase (SYK) has emerged as a potential molecular target for the treatment of B-lineage leukemias and lymphomas. Here, we provide an overview of the current state of knowledge regarding the regulatory signaling function of SYK and its role in the pathogenesis of B-lineage lymphoid malignancies, available methods and drug candidates for targeting SYK, as well as compelling preclinical and clinical evidence regarding the clinical potential of inhibiting SYK. The further development of rationally designed SYK inhibitors may provide the foundation for therapeutic innovation against B-lineage leukemias and lymphomas. PMID- 20836677 TI - The role of PET in Hodgkin's lymphoma and its impact on radiation oncology. AB - A high negative-predictive value of (18)F-fluorodeoxyglucose (FDG) PET in early and late response assessment of Hodgkin's lymphoma patients has been observed in numerous trials. The consequent substantial reduction in the number of chemotherapy cycles and radiotherapy in many current trials seems to be very promising. The criteria used to describe (18)F-FDG accumulation are widely standardized, but PET interpretation in a dedicated clinical algorithm is being discussed among study groups and will be evaluated in the ongoing trials. The integration of (18)F-FDG PET into radiation treatment planning could have a substantial impact on treatment volumes within the new target definition 'involved-node radiotherapy'. Involved-node radiotherapy has been proposed as a means to further improve the therapeutic ratio by reducing the risk of acute radiation-induced toxicity and potentially lowering the rate of long-term complications, including secondary malignancies. PMID- 20836678 TI - Role of sentinel lymph node biopsy in thyroid cancer. AB - Lymphatic mapping and sentinel lymph node biopsy (SLNB) have emerged as a promising minimally invasive surgical technique to detect metastatic nodes in patients with melanoma and breast, colon, esophageal, gastric, lung, head and neck, and thyroid cancers. The SLNB procedure is safe and feasible, with high accuracy in predicting occult metastases of differentiated thyroid cancer. The sensitivity of the SLNB technique has increased as technical details and complementary immunohistochemical and molecular techniques have been developed. SLNB for thyroid cancer may display practical benefits in accurate nodal staging, the detection of metastatic lymph nodes outside the central neck, and the selection of patients who would benefit from complete neck dissection and optimized (131)I ablation therapy. Currently, however, there is no direct evidence that SLNB is associated with long-term clinical and survival benefits in patients with thyroid cancer. Well-controlled prospective clinical trials will determine the clinical significance of occult metastases and their early detection by SLNB in patients with thyroid cancer. PMID- 20836679 TI - Controversies and challenges in the current management of nasopharyngeal cancer. AB - Nasopharyngeal carcinoma is uncommon worldwide, but poses a significant public health burden in endemic regions. Primary treatment for nonmetastatic disease is by radiation therapy, which has evolved from simple 2D-planning techniques to intensity-modulated radiation therapy. The role of systemic therapy has also become more prominent, with concurrent cisplatin-based chemoradiation the current standard of care for locally advanced disease based on multiple Phase III studies. Based on these advances, the prognosis of nasopharyngeal carcinoma appears to have improved significantly over the past two decades. Nevertheless, there are areas of substantial uncertainty and divergent views in the optimal treatment strategy. Distant metastases have become the dominant mode of treatment failure with the excellent local control provided by intensity-modulated radiation therapy. Recent studies have focused on this challenge of treating micrometastases while keeping toxicities manageable. Radiation therapy techniques continue to be refined to maintain consistently high locoregional tumor control while decreasing the probability of acute and late toxicities. This article discusses some of the current issues confronting the multidisciplinary team managing this disease. PMID- 20836680 TI - Role and value of diffusion-weighted MRI in the radiotherapeutic management of head and neck cancer. AB - With the association of concurrent chemotherapy, the widespread implementation of altered fractionation schedules and the use of more conformal radiotherapy techniques, the locoregional management of patients with squamous cell carcinoma of the head and neck region (HNSCC) has greatly improved over the last decades. However, associated toxicity has reached the limits of acceptability. If we want to further improve the therapeutic index of HNSCC we will need to target the tumor more accurately while sparing the surrounding organs at risk as much as possible. Therefore, accurate detection and delineation of tumor areas is essential, and diffusion-weighted MRI (DW-MRI) might help us in this task. DW-MRI can characterize tissues and generate image contrast based on differences in water mobility. Thus, while conventional imaging techniques such as computed tomography and MRI depict anatomical structures, functional imaging techniques such as DW-MRI provide us with a deeper insight in the tumor's underlying biological activity and microstructural characteristics. In this article, we aim to bundle the current experience on DW-MRI in HNSCC and elaborate on its potential value and drawbacks at different time points before, during and after radiotherapy. PMID- 20836681 TI - Radiotherapy for laryngeal squamous cell carcinoma: current standards. AB - During the past decades, treatment of laryngeal cancer has changed substantially, mainly due to the advent of novel approaches such as combined modality therapy as well as improvements in radiotherapeutic techniques. Locoregionally advanced disease in particular, which resulted in high recurrence and mortality rates, is now associated with long-term disease-free survival in a large proportion of cases. Moreover, with multimodality treatment, larynx preservation is now possible in most patients. There are varied regimens in use for patients with advanced disease, but at the same time the multitude of options can plague the clinician when trying to select the most appropriate one. This article will attempt to put the various approaches into perspective. PMID- 20836682 TI - Molecular biology of squamous cell carcinoma of the head and neck: relevance and therapeutic implications. AB - More than 90% of all head and neck cancers are squamous cell carcinoma. Despite advances in the management of patients with this disease, the survival rate has not been significantly improved. Several mechanisms of carcinogenesis have been elucidated and molecular targeted agents seem to be promising therapeutic tools. Cetuximab, a monoclonal antibody inhibitor of the EGF receptor, improves survival rates in association with radiotherapy in advanced squamous cell carcinoma of the head and neck (SCCHN) or in palliative disease, and is nowadays the only targeted agent approved in this indication. Other targeted agents are also clinically relevant to the treatment of different malignancies, including SCCHN. This article focuses on the major molecular pathways implicated in SCCHN carcinogenesis and provides an overview of their therapeutic implications. PMID- 20836683 TI - DMBA-induced hamster buccal pouch carcinoma and VX2-induced rabbit cancer as a model for human oral carcinogenesis. AB - In this article, we have described and compared the advantages and disadvantages of two potential animal cancer models (the hamster buccal pouch cancer model and the VX2-induced rabbit cancer model) for human squamous cell carcinomas of the oral mucosa. Currently, no animal cancer model is perfectly applicable to human oral squamous cell carcinomas. This is because the hamster buccal pouch cancer model has a different etiology and genetic constitution compared with human oral carcinomas. In addition, the VX2-induced rabbit cancer model is not produced in situ and, consequently, its natural behavior is totally reliant on the location of transplantation. Nonetheless, with the use of these two animal cancer models together, researchers could evaluate different aspects of the cellular and molecular biological characteristics or assess potential novel treatment regimens for squamous cell carcinomas of the human oral mucosa. PMID- 20836684 TI - Biological considerations and clinical applications of new HER2-targeted agents. AB - Over the past two decades, since the discovery of the human EGF receptor 2 (HER2) oncogene, the oncoprotein has become one of the best known and intensively studied tumor targets in oncology. In fact, laboratory findings were the basis for clinical proof-of-principle studies, whose results not only confirmed the relationship between gene amplification and an aggressive tumor phenotype but also demonstrated that the poor prognosis associated with receptor overexpression could be improved. Indeed, the success in treating patients with HER2-positive breast cancer extends to those with early as well as advanced disease. Nonetheless, not all tumors respond to treatment targeting the receptor; disease progression also occurs after initially responding to anti-HER2 therapy. This article focuses on the biology of HER2 and three novel agents currently in clinical trials that target HER2 beyond disease progression. PMID- 20836686 TI - Time for a separate psychosis caregiver service? PMID- 20836687 TI - How does an accreditation programme drive improvement on acute inpatient mental health wards? An exploration of members' views. AB - BACKGROUND: Concerns have been raised about inpatient mental health care. An accreditation model can improve compliance with standards associated with improved quality of health care. AIMS: To explore the effects of a standards based, peer review, accreditation model on standards of care in acute inpatient wards and explore how staff achieved change. METHOD: Quality of care was assessed by independent peer review against evidence-based standards in an accreditation process. Staff from the 11 wards receiving subsequent accreditation were interviewed to find out what processes had enabled accreditation. RESULTS: Sixteen wards enrolled: four achieved immediate and 11 subsequent accreditation. The most common reasons for initial failure of accreditation were lack of psychological therapies or 1:1 time for patients, and presence of ligature points. Ward staff perceived the accreditation process improved communication, gave power to negotiate for resources, clear guidance how to practice, rewarded good practice and led to additional unrelated improvements in care. CONCLUSIONS: Acute wards need to attend to basic safety and provide talking treatments (both formal psychotherapy and basic time spent with patients). An accreditation, peer reviewed, standards-based process can enable staff to feel confident about improvements in the quality of care. PMID- 20836688 TI - Quantitative findings from a mixed methods evaluation of once-weekly therapeutic community day services for people with personality disorder. AB - BACKGROUND: Quantitative findings are presented from a mixed methods study of four one-day-a-week therapeutic communities for people with personality disorder (qualitative findings from the same study are reported in a separate paper). The evaluation assessed both the clinical efficacy of the model and its acceptability to service users, service employees and those who refer clients to the services. AIMS: The study aimed to clarify whether one-day therapeutic communities can be effective for people with personality disorder. METHOD: Changes in the functioning of service users who attended the day services were assessed every 12 weeks for up to 1 year. RESULTS: We found significant improvements in both the mental health and social functioning of service users. Changes in patterns of self-harm and service use were suggestive of possible underlying improvements but failed to reach significance levels. We also found evidence of the possible offset of costs within 16 months of an individual leaving one of the services. CONCLUSIONS: This study suggests one-day therapeutic communities may be both clinically- and cost-effective for people with personality disorder. PMID- 20836689 TI - Jigsaw: engaging communities in the development and implementation of youth mental health services and supports in the Republic of Ireland. AB - BACKGROUND: Irish young people exhibit high levels of psychological distress, but community-based services and supports are often unavailable or inaccessible. AIM: To describe efforts to engage communities in systematic and data-based processes of planning, programme design, implementation, and evaluation. METHOD: Details system-building initiatives in five communities (four counties and a distressed urban site) that will serve as a springboard for full national deployment. RESULTS: Extensive community engagement and planning has occurred in all sites, systems change efforts grounded in detailed business plans have begun, and process and outcome evaluation is underway. CONCLUSION: Needs and resource assessment processes confirmed the magnitude of need, but also suggested the creative re-allocation of local resources. Young people provided invaluable guidance for system design. Creating and sustaining a culture of innovation at each site was challenging, requiring leadership and continuous dialogue. PMID- 20836690 TI - "A life in the community": Italian mental health reform and recovery. AB - There are remarkable parallels between the vision of the Italian Mental Health Reform of the 1960s and 1970s and the vision of "recovery" being promoted around the globe. Most importantly, they share a fundamental conviction in the right of individuals with mental illnesses to "a life in the community", arguing that the basic rights of social inclusion, self-determination, and citizenship provide the necessary foundation for, rather than follow after, recovery. This article describes four strategies used in the Italian Reform to actualize this vision: creating two-way streets between the mental health system and the broader community, establishing social cooperatives with joining forces with other citizens' groups, and working toward community inclusion on a person-by-person basis. The authors suggest that useful lessons learned from these efforts can be applied to the present challenge of affording all individuals with serious mental illnesses the "life in the community" to which they are entitled. PMID- 20836691 TI - The role of affect in the estimation of risk. AB - BACKGROUND: Risk assessment decisions have profound consequences. The contribution of affect to decision making is well established in the psychology literature, but this body of knowledge has had little influence in the field of violence risk assessment. AIMS: We sought to establish the relative contribution of actuarial and emotive information in determining risk ratings of violence. METHOD: In a repeated measures design, mental health professionals rated four vignettes according to perceived level of risk of violence. Vignettes were designed to contain information likely to maximize or minimize emotive and actuarial information. RESULTS: Both actuarial and emotive factors contributed significantly to the rating of risk. However, emotive information had a far greater influence. Reasons given for ratings tended to relate to emotive factors. CONCLUSIONS: Despite the growth of actuarial knowledge amongst mental health professionals, clinicians tend to disregard this information and are heavily and disproportionately influenced by emotive material. This detracts from the accurate assessment of risk. Actuarial factors tend to have little appeal to clinicians. This may be attributable to their apparent lack of relevance to the clinical task. Further research on clinically meaningful psychological variables and their relation to the risk of enactment is required. PMID- 20836692 TI - The views of policy influencers and mental health officers concerning the Named Person provisions of the Mental Health (Care and Treatment) (Scotland) Act 2003. AB - BACKGROUND: The Mental Health (Care and Treatment) (Scotland) Act 2003 introduced the role of the Named Person, who can be nominated by service users to protect their interests if they become subject to compulsory measures and replaces the Nearest Relative. If no nomination is made, the primary carer or nearest relative is appointed the Named Person. The views of professionals involved in the development and implementation of the provisions were unknown. AIM: To describe the perceptions of mental health officers and policy makers involved in the development and implementation of the new provisions. METHOD: Sixteen professionals were interviewed to explore their perceptions of and experiences with the Named Person provisions. Data were analysed using Thematic Analysis. RESULTS: Perceptions of the Named Person provisions were generally favourable but concerns were expressed over low uptake; service users' and carers' lack of understanding of the role; and potential conflict with human rights legislation over choice and information sharing. CONCLUSIONS: Legislation should be amended to allow the choice of no Named Person and the prevention of information being shared with the default appointed Named Person. Removal of the default appointment should be considered. PMID- 20836693 TI - Parallel paths? Patient and doctor priorities in psychiatric outpatient consultations. AB - BACKGROUND: In England, a large proportion of general adult psychiatric consultations are outpatient appointments. AIM: To assess whether patients and doctors agree on the key components of outpatient consultations. METHOD: Separate patient and doctor focus groups were conducted to generate perceived key components of the outpatient consultation for each group. A self-report questionnaire was then constructed, to assess how important these key components were considered to be by both patients and doctors in the clinical setting. The key components were rated in relation to specific consultations the participants were about to have. Paired responses were collated and analysed for similarity indices between patients and their doctors. RESULTS: One-hundred-and-three patient-doctor pairs completed the pre-appointment questionnaire. There was no statistically significant agreement detected between pairs of patients and doctors on the importance of any of the six key components of a general adult outpatient consultation generated by the patient and doctor focus groups. CONCLUSIONS: Patients and their psychiatrists disagree on the key components of an outpatient consultation. However, patient priorities are central to service delivery. Therefore, listening to the patients' priorities highlighted in this article is important to achieve patient-centred services. PMID- 20836694 TI - Medication adherence in crisis? AB - AIMS AND METHOD: We examined rates of medication non-adherence in 172 referrals to a crisis resolution home treatment service; we then explored any association between pattern of adherence and the treatment interventions recommended. RESULTS: Thirty percent of crisis referrals (95% confidence intervals (CI) 24%, 38%) reported sub-optimal medication adherence in the preceding month. These individuals were significantly more likely to have a dual diagnosis (odds ratio 2.9, 95% CI 1.4, 5.9) and assessment was significantly more likely to be followed by admission (odds ratio 2.5; 95% CI 1.0, 6.2); non-adherence remained a significant predictor of admission when the odds were adjusted for confounders (odds ratio 1.18; 95% CI 1.0, 1.3). CLINICAL IMPLICATIONS: Clinicians need to proactively identify and manage non-adherence as it is a potentially preventable trigger of relapse often present for months rather than days prior to the index crisis referral. Non-adherence is a meaningful target for improving clinical and cost-effectiveness of general adult mental health services. PMID- 20836697 TI - The Mycobacterium tuberculosis Beijing genotype does not affect tuberculosis treatment failure in Vietnam. AB - BACKGROUND: Studies have suggested that the Mycobacterium tuberculosis Beijing genotype causes more severe clinical disease and higher treatment failure rates with standard regimens, possibly in association with an increased risk of acquiring drug resistance. We studied the effect of genotype on treatment failure in a rural area in Vietnam where multidrug resistance is strongly associated with the Beijing genotype. METHODS: In a population-based prospective cohort study, patients with smear-positive tuberculosis were tested before and after treatment by spoligotyping and drug susceptibility analysis. Reinfections were excluded by DNA fingerprinting. The outcome was treatment failure based on culture. RESULTS: Of 1106 patients eligible for analysis, 33 experienced treatment failure (3.0%; 95% confidence interval [CI], 2.1%-4.1%). The proportion of failure was 5.3% (95% CI, 0.3%-7.9%) among 380 patients with Beijing genotype infections. Multidrug resistant tuberculosis strongly predicted failure (odds ratio [OR], 114; 95% CI, 30-430). After adjusting for multidrug-resistant tuberculosis, treatment failure was not associated with the Beijing genotype (adjusted OR, 0.7; 95% CI, 0.3-2.0). Amplification of drug resistance occurred in 3 patients (0.3%; 95% CI, 0.1%-0.7%) and was associated with multidrug resistance at baseline (P = .004) but not with the Beijing genotype. No multidrug resistance was created. CONCLUSION: The Beijing genotype was not associated with treatment failure in Vietnam; apparent associations were explained by the strong association of this genotype with multidrug resistance. Amplification of resistance in this patient population was rare. PMID- 20836699 TI - Advanced rescuer- versus citizen-witnessed cardiac arrest: Is there a difference in outcome? AB - BACKGROUND: Substantial financial and human resources are invested in training and maintaining advanced life support (ALS) skills of paramedics who are deployed to the field in response to out-of-hospital cardiac arrest. It would be expected that patients who experience cardiac arrest in the presence of a trained health care practitioner, such as a paramedic, have better outcomes. OBJECTIVE: To compare the rates of return of spontaneous circulation (ROSC), survival to hospital admission (SHA), and survival to hospital discharge (SHD) between paramedic-witnessed out-of-hospital cardiac arrest vs. citizen-witnessed out-of hospital cardiac arrest. METHODS: In this retrospective cohort study, the records of all out-of-hospital nontraumatic cardiac arrest patients presenting to a municipal teaching hospital from November 1, 1994, through June 30, 2008, were reviewed. The age, gender, race, rhythm on paramedic arrival, presence of bystander cardiopulmonary resuscitation (CPR), whether it was a witnessed arrest and, if witnessed, whether it was a paramedic-witnessed arrest, site of the arrest, and the rate of SHD were noted. A univariate odds ratio was computed to describe the association between paramedic-witnessed out-of-hospital cardiac arrest vs.citizen-witnessed out-of-hospital cardiac arrest and SHD. A multivariable logistic regression analysis was also performed, controlling for age, gender, arrest rhythm, bystander CPR, and site of arrest. RESULTS: Of the total cohort of 1,294 out-of-hospital cardiac arrests, 750 (52.6%) were either paramedic-witnessed (154/750 = 20.5%) or citizen-witnessed (596/750 = 79.5%). Among the witnessed cardiac arrests, overall the SHD was 53 of 750 (7.1%). On univariate analysis, the ROSC, SHA, or SHD rates were not statistically significantly different between paramedic- and citizen-witnessed arrests. Even after multivariable adjustment, the ROSC, SHA, and SHD rates were not significantly different between paramedic- and citizen-witnessed arrests. CONCLUSIONS: Among our study population of out-of-hospital cardiac arrest victims, paramedic-witnessed arrests did not appear to have improved survival rates when compared with citizen-witnessed arrests. PMID- 20836698 TI - Lentiviral-human heme oxygenase targeting endothelium improved vascular function in angiotensin II animal model of hypertension. AB - We examined the hypothesis that vascular and renal dysfunction caused by angiotensin II (Ang II) through increased levels of blood pressure, inflammatory cytokines, and oxidative stress in Sprague-Dawley rats can be prevented by lentiviral-mediated delivery of endothelial heme oxygenase (HO)-1. We targeted the vascular endothelium using a lentiviral construct expressing human HO-1 under the control of the endothelium-specific promoter VE-cadherin (VECAD-HO-1) and examined the effect of long-term human HO-1 expression on blood pressure in Ang II-mediated increases in blood pressure and oxidant stress. A bolus injection of VECAD-HO-1 into the renal artery resulted in expression of human HO-1 for up to 6 9 weeks. Sprague-Dawley rats were implanted with Ang II minipumps and treated with lentivirus carrying either the HO-1 or green fluorescent protein. Renal tissue from VECAD-HO-1-transduced rats expresses human HO-1 mRNA and proteins without an effect on endogenous HO-1. Infusion of Ang II increased blood pressure (p < 0.001) but decreased vascular relaxation in response to acetylcholine, endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (peNOS) levels, and renal and plasma levels of adiponectin (p < 0.05); in contrast, plasma tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels increased. Ang II-treated animals had higher levels of superoxide anion and inducible nitric oxide synthase and increased urinary protein and plasma creatinine levels. Lentiviral transduction with the VECAD-HO-1 construct attenuated the increase in blood pressure (p < 0.05), improved vascular relaxation, increased plasma adiponectin, and prevented the elevation in urinary protein and plasma creatinine in Ang II-treated rats. Endothelial-specific expression of HO-1 also reduced oxidative stress and levels of inflammatory cytokines resulting in increased expression of the anti-apoptotic proteins phosphorylated AKT, phosphorylated AMP activated protein kinase, peNOS, and eNOS. Collectively, these findings demonstrate that endothelial-specific increases in HO-1 expression attenuate Ang II hypertension and the associated vascular dysfunction that is associated with increases in adiponectin and peNOS and reductions in oxidative stress and levels of inflammatory cytokines. PMID- 20836700 TI - Betacellulin overexpression in mesenchymal stem cells induces insulin secretion in vitro and ameliorates streptozotocin-induced hyperglycemia in rats. AB - Betacellulin (BTC), a ligand of the epidermal growth factor receptor, has been shown to promote growth and differentiation of pancreatic beta-cells and to improve glucose metabolism in experimental diabetic rodent models. Mesenchymal stem cells (MSCs) have been already proved to be multipotent. Recent work has attributed to rat and human MSCs the potential to differentiate into insulin secreting cells. Our goal was to transfect rat MSCs with a plasmid containing BTC cDNA to guide MSC differentiation into insulin-producing cells. Prior to induction of cell MSC transfection, MSCs were characterized by flow cytometry and the ability to in vitro differentiate into mesoderm cell types was evaluated. After rat MSC characterization, these cells were electroporated with a plasmid containing BTC cDNA. Transfected cells were cultivated in Dulbecco's modified Eagle medium high glucose (H-DMEM) with 10 mM nicotinamide. Then, the capability of MSC-BTC to produce insulin in vitro and in vivo was evaluated. It was possible to demonstrate by radioimmunoassay analysis that 10(4) MSC-BTC cells produced up to 0.4 ng/mL of insulin, whereas MSCs transfected with the empty vector (negative control) produced no detectable insulin levels. Moreover, MSC-BTC were positive for insulin in immunohistochemistry assay. In parallel, the expression of pancreatic marker genes was demonstrated by molecular analysis of MSC-BTC. Further, when MSC-BTC were transplanted to streptozotocin diabetic rats, BTC transfected cells ameliorated hyperglycemia from over 500 to about 200 mg/dL at 35 days post-cell transplantation. In this way, our results clearly demonstrate that BTC overabundance enhances glucose-induced insulin secretion in MSCs in vitro as well as in vivo. PMID- 20836701 TI - Evaluation and optimization of the administration of recombinant adeno-associated viral vectors (serotypes 2/1, 2/2, 2/rh8, 2/9, and 2/rh10) by convection-enhanced delivery to the striatum. AB - Convection-enhanced delivery (CED) of recombinant adeno-associated virus (rAAV) vectors is a promising approach for delivery of therapeutic transgenes to the brain. In this study we have systematically examined vector dosing in vivo. Infusions of rAAV serotypes 2/1, 2/2, 2/rh8, 2/9, and 2/rh10 expressing an enhanced green fluorescent protein reporter gene were undertaken into the striatum of rats and pigs using CED. Vector distribution, as defined by the volume of distribution and number of transduced cells following each infusion, was determined using stereological methods. Immunohistochemistry was used to determine the transductional tropism of serotypes and to evaluate for the presence of immune cell infiltration into the brain. Vector distribution was highly variable between serotypes. Infusion rate had no significant effect on vector distribution or the occurrence of tissue damage. For serotypes 2/1, 2/2 and 2/rh10, as the vector concentration was increased beyond 10(12) vg/ml, no increase in vector distribution was observed. In contrast, for serotypes 2/rh8 and 2/9, retrograde axonal transport was observed above this threshold concentration. Cell transduction was principally neuronal for all serotypes and was associated with a low-level immune response. In planning clinical trials it is critical that these observations are considered in order to achieve optimal vector dosing. PMID- 20836702 TI - High-frequency field stimulation of primary neurons enhances ryanodine receptor mediated Ca2+ release and generates hydrogen peroxide, which jointly stimulate NF kappaB activity. AB - Neuronal electrical activity increases intracellular Ca(2+) concentration and generates reactive oxygen species. Here, we show that high frequency field stimulation of primary hippocampal neurons generated Ca(2+) signals with an early and a late component, and promoted hydrogen peroxide generation via a neuronal NADPH oxidase. Hydrogen peroxide generation required both Ca(2+) entry through N methyl-D-aspartate receptors and Ca(2+) release mediated by ryanodine receptors (RyR). Field stimulation also enhanced nuclear translocation of the NF-kappaB p65 protein and NF-kappaB -dependent transcription, and increased c-fos mRNA and type 2 RyR protein content. Preincubation with inhibitory ryanodine or with the antioxidant N-acetyl L-cysteine abolished the increase in hydrogen peroxide generation and the late Ca(2+) signal component induced by electrical stimulation. Primary cortical cells behaved similarly as primary hippocampal cells. Exogenous hydrogen peroxide also activated NF-kappaB-dependent transcription in hippocampal neurons; inhibitory ryanodine prevented this effect. Selective inhibition of the NADPH oxidase or N-acetyl L-cysteine also prevented the enhanced translocation of p65 in hippocampal cells, while N-acetyl L-cysteine abolished the increase in RyR2 protein content induced by high frequency stimulation. In conclusion, the present results show that electrical stimulation induced reciprocal activation of ryanodine receptor-mediated Ca(2+) signals and hydrogen peroxide generation, which stimulated jointly NF-kappaB activity. PMID- 20836703 TI - Identification of an atypical strain of toxoplasma gondii as the cause of a waterborne outbreak of toxoplasmosis in Santa Isabel do Ivai, Brazil. AB - Multilocus DNA sequencing has identified a nonarchetypal strain of Toxoplasma gondii as the causal agent of a waterborne outbreak in Brazil in 2001. The strain, isolated from a water supply epidemiologically linked to the outbreak, was virulent to mice, and it has previously been identified as BrI. Using a serologic assay that detects strain-specific antibodies, we found that 13 (65%) of 20 individuals who were immunoglobulin (Ig) M positive during the outbreak possessed the same serotype as mice infected with the purported epidemic strain. The remaining 7 individuals, plus additional IgM-negative, IgG-positive individuals, possessed 1 of 4 novel serotypes, the most common of which matched the serotype of mice infected with strains isolated from chickens foraging near the outbreak site. The latter strains likely reflect the genetic diversity of T. gondii circulating in highly endemic regions of Brazil. The serotyping assay proved a useful tool for identification of specific individuals infected with the outbreak agent. PMID- 20836704 TI - The perceived impact of disclosure of pediatric HIV status on pediatric antiretroviral therapy adherence, child well-being, and social relationships in a resource-limited setting. AB - In resource-limited settings, beliefs about disclosing a child's HIV status and the subsequent impacts of disclosure have not been well studied. We sought to describe how parents and guardians of HIV-infected children view the impact of disclosing a child's HIV status, particularly for children's antiretroviral therapy (ART) adherence. A qualitative study was conducted using involving focus groups and interviews with parents and guardians of HIV-infected children receiving ART in western Kenya. Interviews covered multiple aspects of the experience of having children take medicines. Transcribed interview dialogues were coded for analysis. Data were collected from 120 parents and guardians caring for children 0-14 years (mean 6.8 years, standard deviation [SD] 6.4); 118 of 120 had not told the children they had HIV. Children's caregivers (parents and guardians) described their views on disclosure to children and to others, including how this information-sharing impacted pediatric ART adherence, children's well-being, and their social relationships. Caregivers believed that disclosure might have benefits such as improved ART adherence, especially for older children, and better engagement of a helping social network. They also feared, however, that disclosure might have both negative psychological effects for children and negative social effects for their families, including discrimination. In western Kenya, caregivers' views on the risks and benefits to disclosing children's HIV status emerged a key theme related to a family's experience with HIV medications, even for families who had not disclosed the child's status. Assessing caregivers' views of disclosure is important to understanding and monitoring pediatric ART. PMID- 20836705 TI - Diversity of envelope genes from an uncloned stock of SIVmac251. AB - AIDS vaccine and pathogenesis research will benefit from a more diverse array of cloned SIV challenge stocks from which to choose. Toward this end, 20 envelope genes were cloned from an extensively used, primary stock of uncloned SIVmac251. Each of the 20 clones had a unique sequence. Their translated sequences differed by as many as 26 amino acids from one another and by as many as 45 amino acids from the commonly used clone SIVmac239. Envelope sequences up to and including the membrane-spanning domain were exchanged into the infectious pathogenic SIVmac239 clone and virus stocks were produced by HEK293T cell transfection. Seventeen of the 20 recombinants were replication competent. The infectivities per ng p27 of the 17 new replication-competent recombinants in C8166-SEAP cells and in TZM-bl cells ranged from minus 32-fold to plus 7.6-fold relative to SIVmac239. A range of sensitivities to neutralization by sCD4 and by sera from SIV-infected macaques was observed but none was as sensitive to these neutralizing agents as SIVmac316, the highly macrophage-competent derivative of SIVmac239. Four strains that were most sensitive to sCD4 inhibition were also among the most sensitive to antibody-mediated neutralization. None of the new recombinant viruses replicated as well as SIVmac316 in primary alveolar macrophage cultures from rhesus monkeys but three of the strains did exhibit significant levels of delayed replication in these primary macrophages, reaching peak levels of virus production of >=50 ng/ml p27 compared to 600-800 ng/ml p27 with SIVmac316. These new SIV clones are being contributed to the NIH AIDS Reagent Repository and are available to the scientific community. PMID- 20836706 TI - Naturally occurring polymorphisms and primary drug resistance profile among antiretroviral-naive individuals in Bangalore, India. AB - Although India has a large burden of HIV infection, good access to first-line antiretroviral therapy is widely available. However, understanding HIV resistance associated mutations and polymorphisms is critical for continued success. The RT region of the HIV-1 pol gene was studied among 21 ART-naive HIV-1-infected individuals from South India. In addition, 421 published Indian HIV-1 subtype C sequences were analyzed for time trends in polymorphism frequency. Among primary isolates, all HIV-1 isolates were subtype C, and drug-resistant mutations were identified among two (9.56%) subjects. Mutations included E138A (etravirine resistance associated) and L210LS (thymidine analog mutation). The overall frequency of specific polymorphisms was similar to frequencies reported from different regions of India. Novel mutations were observed at positions Q23P/H and A129AG among isolates from our clinical cohort. Over a span of 10 years, the median polymorphism frequency among ART-naive subjects has remained unchanged, suggesting the slow evolution of HIV-1 subtype C in India. PMID- 20836708 TI - Appearance of Drug Resistance-Associated Mutations in Human Immunodeficiency Virus Type 1 CRF01_AE Integrase Derived from Drug-Naive Thai Patients. AB - CRF01_AE is a major subtype of human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia, including Thailand. We performed genotypic studies on HIV-1 CRF01_AE integrase derived from plasma samples from drug-naive Thai patients. Direct sequencing of amplified CRF01_AE integrase genes revealed that although no primary mutations associated with drug resistance to integrase inhibitors were detected, at least one secondary mutation was found in 96% of samples. Our results indicate that the impact of these mutations on the baseline drug susceptibility of CRF01_AE viruses to integrase inhibitors may need to be addressed prior to the introduction of these drugs in Southeast Asian countries, including Thailand. PMID- 20836709 TI - Bioluminescence assay for detecting cell surface membrane protein expression. AB - We have developed a method to measure the amounts of cell surface-expressed membrane proteins with bioluminescence. Dinoflagellate luciferase was expressed on the surface of a mammalian cell as a chimeric fusion protein with a membrane protein of interest. Using a membrane-impermeable substrate to quantify the membrane-displayed luciferase, the expression of the membrane protein on the cell surface was determined. By inclusion of a quenching step for the luminescent activity of luciferase on the cell surface, we were able to monitor the membrane protein expression kinetics by measuring the luminescence recovery from the cell surface after quenching. The reported methods provide a convenient way to monitor the kinetics of expression and transport of membrane proteins to the cell surface. It is applicable to the high-throughput analysis of drugs or drug candidates concerning their effects on membrane protein expression. PMID- 20836710 TI - Single-nucleotide polymorphisms in response to interferon-beta therapy in multiple sclerosis. AB - Interferon-beta (IFN-beta) is one of the main first-line disease-modifying drugs indicated for the treatment of multiple sclerosis (MS). The drug exhibits only limited effectiveness, and does not produce clinical benefits in around 20%-50% of patients. The availability of biomarkers would be beneficial for identification of patients at high risk of treatment failure, before initiation of therapy. Over the last 5 years, the search for such biomarkers has intensified and various promising candidates have been uncovered. Here, we review the main attempts undertaken to identify polymorphic variants associated with response to IFN-beta therapy in MS by means of candidate gene approaches and whole-genome association scans. Despite substantial progress made in the field, there is still a long way to go before biomarker discoveries can be incorporated into clinical practice to predict IFN-beta-responder status in MS patients. PMID- 20836711 TI - PEGylated interferon beta-1a: meeting an unmet medical need in the treatment of relapsing multiple sclerosis. AB - Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex(r), Rebif(r), and Betaseron/Betaferon(r)), glatiramer acetate (Copaxone(r)), and an anti-VLA4 monoclonal antibody (Tysabri(r)). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks. PMID- 20836712 TI - Immunotherapy of multiple sclerosis. PMID- 20836713 TI - Early interferon-based treatment after detection of persistent hepatitis C virus infection: a critical decision. AB - Approximately 170 million people are infected with the hepatitis C virus (HCV) worldwide. Infection with this pathogen is persistent in more than 80% of cases, frequently developing severe forms of liver damage such as cirrhosis and hepatocellular carcinoma. No preventive vaccine is available against HCV, and current treatment based on the combination of pegylated interferon and ribavirin is effective in ~55% of patients infected with genotype 1, the most prevalent genotype. This review analyzes several factors influencing the achievement of a sustained virological response, namely undetectable HCV RNA at 6 months after conclusion of therapy. Particularly, the relevant issue of age and duration of infection is discussed in detail. Indeed, the final decision for starting treatment should be a case-by-case point. However, the cost-benefit analysis seems to indicate that in patients who are motivated and without contraindications, starting the treatment as early as possible is probably the best choice for success. PMID- 20836714 TI - Mechanisms of immune suppression exerted by regulatory T-cells in subcutaneous AE17 murine mesothelioma. AB - We have reported previously that a combined intratumoral treatment with anti CD25mAb/transforming growth factor-beta (TGF-beta) soluble receptor induced regression of established and subcutaneous AE17 murine mesotheliomas. Here, we have investigated the mechanisms underlying this observation by analyzing the concentrations of interferon-gamma (IFN-gamma) and TGF-beta within tumors at various time points following single regulatory T-cell (T(reg)) depleting anti CD25mAb, TGF-beta soluble receptor, or combined anti-CD25mAb/TGF-beta soluble receptor treatment. The combined treatment maintains the intratumoral TGF-beta concentration at a significantly lower level than either the untreated controls or the single anti-CD25mAb treatment alone. Also, the lower level of TGF-beta correlated with a significantly higher concentration of IFN-gamma compared with the single anti-CD25mAb treatment. It was hypothesized that TGF-beta was the master regulator of immune suppression in the AE17 model of mesothelioma. However, it was found that although important, this cytokine alone is not responsible for maintaining immune suppression and that multiple mechanisms of suppression exist. Specifically, we have shown that the presence of T(regs) in the tumor draining lymph nodes alters the phenotype of dendritic cells in the same location. These data suggest that because the antitumor immune response is inhibited by multiple mechanisms of suppression, development of immunotherapeutic treatment regimes will be more successful if these mechanisms can be simultaneously inhibited. PMID- 20836716 TI - Resorbable clip migration resulting in ureteral obstruction and sepsis after laparoscopic pyeloplasty. AB - We report a rare complication of Lapra-Ty clip migration into the ureter with resultant obstruction and sepsis after dismembered laparoscopic pyeloplasty. PMID- 20836715 TI - Inhibition of the phosphatidylinositol-3-kinase pathway abrogates polyinosinic:polycytidylic acid-stimulated hyaluronan-mediated human mucosal smooth muscle cell binding of U937 monocytic cells. AB - The origin of inflammatory bowel disease (IBD) is unknown and likely to be multifactorial. Our laboratory has established that in human mucosal smooth muscle cells (M-SMCs), cellular stress induced by virus or the viral mimic double stranded RNA (polyinosinic:polycytidylic acid [poly I:C]) increases cell surface hyaluronan (HA) deposition and the formation of long cable-like structures of HA that are important for leukocyte attachment. Since leukocyte accumulation and hyperplasia of the M-SMCs are characteristic pathological changes observed in IBD patients, and phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathways play established roles in cell survival, we investigated whether this pathway is involved in this unique HA-mediated leukocyte attachment. Poly I:C-stimulated M SMCs bind significantly more monocytic cells than untreated cells and this response was inhibited in a dose-dependent manner by treatment with the PI3K inhibitor, LY294002. Since Akt is a critical downstream regulator of PI3K, we investigated the phosphorylation status of Akt in M-SMCs after treatment with poly I:C for 1 h and found that Akt was phosphorylated, but the phosphorylated Akt band was undetectable in LY294002 plus poly I:C-treated cultures. Confocal microscopy of M-SMCs stained for HA revealed that HA cable formation after poly I:C treatment was abrogated by LY294002. These results demonstrate that poly I:C stimulated M-SMCs phosphorylate Akt, produce HA cables, and promote HA-mediated leukocyte adhesion through a PI3K/Akt-dependent manner. PMID- 20836717 TI - Laparoscopic extravascular renal vein stent placement for nutcracker syndrome. AB - PURPOSE: To report our experience in the laparoscopic extravascular management of the nutcracker syndrome. PATIENTS AND METHODS: Three patients (two men and one woman) between the ages of 20 and 35 years (mean 25.7 y) underwent laparoscopic extravascular stent placement in the left renal vein for management of the nutcracker syndrome that is associated with severe recurrent gross hematuria and left gonadal vein varices. The postoperative follow-up was 16 to 37 months (mean 25.3 mos). RESULTS: All patients met the criteria for establishing the diagnosis of the nutcracker syndrome. Ultrasonography, CT, and MRI revealed visible entrapment of the left renal vein between the superior mesenteric artery and aorta. Bleeding from the left ureteral orifice was detected by urethrocystoscopy and ureterorenoscopy. We attempted a novel laparoscopic method to manage this anatomic anomaly. No complications occurred during surgery. Total relief was achieved in two men without a relapse of symptoms, and abnormalities were not found in the results of the urine test. There is partial relief in a 20-year-old woman because of microhematuria after the operation. CONCLUSIONS: The indications for surgical management with the nutcracker syndrome depend on the severity of the symptoms, and laparoscopic extravascular stent placement in the renal vein is a feasible approach for reestablishing free renal venous outflow. This slightly invasive treatment can eliminate the symptoms of the condition. Longer follow-up and more experience are necessary to make conclusions about its feasibility in contemporary practice, however. PMID- 20836718 TI - Successful outcomes of older donors in laparoscopic donor nephrectomy. AB - BACKGROUND AND PURPOSE: Healthy older living donors (> 50 years) are helping meet increasing demands for kidney transplantation. Live donor grafts perform better than cadaveric donor grafts; however, concern surrounds the expected nephron loss of the donors as well as the relative safety to the donor. We examined the effect age had on living laparoscopic donor and recipient outcomes at a single institution. PATIENTS AND METHODS: We retrospectively reviewed records of 101 patients who underwent laparoscopic donor nephrectomy (LDN) from October 2001 to December 2005. Twenty-nine (29%) who were aged 50 years or older, denoted as the "older" group, were compared with the remaining 72 (71%) donors who were younger than 50 years and served as controls. Perioperative and follow-up data were analyzed for both groups. RESULTS: The mean age at the time of donation was 36.1 and 54.3 years for control and older donors, respectively (P < 0.001). Baseline mean creatinine level was 0.82 mg/dL for controls and 0.84 mg/dL for older donors (P = 0.78). Complications in controls and the older group were 18% and 17%, respectively. One-year transplant survival was 100% for the controls and 96% for the older group. Average creatinine level at longer follow-up of 19 months for controls and 23 months for the older group (P = 0.34) was 1.22 mg/dL and 1.16 mg/dL, respectively (P = 0.535). CONCLUSION: LDN in donors older than 50 years of age appears safe and demonstrates similar outcomes compared with the control cohort of patients younger than 50 years. Age between 50 and 65 years should not exclude a potential donor who otherwise satisfies donor nephrectomy criteria. PMID- 20836719 TI - Is a safety wire necessary during routine flexible ureteroscopy? AB - BACKGROUND AND PURPOSE: The use of flexible ureteroscopy (URS) for nephrolithiasis has been rapidly expanding. Initially, safety guidewires were maintained alongside the ureteroscope during stone manipulation to prevent loss of access and allow stent insertion in the event of perforation. We intend to determine the safety of flexible URS without a separate safety guidewire in a large series of patients. METHODS: A retrospective chart review was performed on all cases of flexible URS with laser lithotripsy performed by a single surgeon from August 2003 to May 2008. Preoperative patient characteristics, radiographic stone sizes, operative findings, and postoperative outcomes were recorded. Patients with renal or ureteropelvic junction (UPJ) stones were isolated for a qualitative data analysis. RESULTS: Flexible URS was performed on 305 kidneys in 246 consecutive patients, of which 59 cases were bilateral. Cases were subdivided into complicated and uncomplicated. Two hundred seventy cases were uncomplicated and performed without a safety guidewire. No intraoperative complications resulted from the lack of a safety guidewire, including no cases of lost access, ureteral perforation/avulsion, or need for percutaneous nephrostomy tube. Thirty five cases were complicated, necessitating a safety guidewire. Of these, 16 had concomitant obstructing ureteral stones, 5 had encrusted ureteral stents, and 14 had difficult access because of large stone burden or aberrant anatomy. CONCLUSIONS: This study demonstrates that, in a large series of patients, a safety guidewire was not necessary for routine cases of flexible URS with laser lithotripsy on renal or UPJ stones. Particular cases with complicated anatomy, difficult access, concomitant ureteral stones, simultaneous stone basketing, or bulky stone burden still necessitate use of a safety guidewire because of increased risk of adverse outcomes. PMID- 20836720 TI - Transvesical blockade of the obturator nerve to prevent adductor contraction in transurethral bladder surgery. AB - PURPOSE: To evaluate the efficacy of transvesical obturator nerve block (ONB) in the prevention of obturator nerve reflex and leg jerking during transurethral resection of bladder tumors (TURBT). PATIENTS AND METHODS: A total of 60 patients were studied, in whom the transurethral resection of tumors on the posterolateral bladder wall were performed under spinal anesthesia (SA). The patients were randomly divided into two groups. In the first group, we performed transvesical ONB and SA together, while the second group received only SA. The patients underwent TURBT using monopolar cautery. Incidence of leg jerking was registered and compared in these two groups. We used a nerve stimulator to detect the obturator nerve next to the lateral bladder wall. The obturator nerve was identified by its response to nerve stimulation. Then, 10 mL of 1% lidocaine was slowly injected through the working channel of a cystoscope. RESULTS: In the intervention group, 34 ONBs (4 bilateral and 26 unilateral) were tried. We could not detect the obturator nerve by nerve stimulation in six patients, and lidocaine injection was carried out blindly in these cases. One patient in the intervention group experienced adductor contraction. Among 30 patients in the control group, 5 patients had leg jerking, and in 2 patients, the procedure ended incompletely because of muscle spasm. Comparing these two groups, transvesical ONB effectively decreased leg jerking during TURBT (16.5% vs 3%; P < 0.05). CONCLUSION: Local blockade of the obturator nerve during cystoscopy is an effective method to avoid its stimulation in TURBT. It can be performed easily, and we did not experience any serious complication. PMID- 20836721 TI - China joins the fatter nations. PMID- 20836722 TI - Temporal trends in overweight and obesity of children and adolescents from nine Provinces in China from 1991-2006. AB - OBJECTIVES: To assess temporal changes in mean body mass index (BMI) and the impact of socio-economic status on the prevalence of overweight and obesity among Chinese children and adolescents in nine provinces between 1991 and 2006. METHODS: Analysis of height and weight data in children and adolescents aged 7-17 years with complete information on age, gender, region, height and weight from consecutive China Health and Nutrition Surveys (CHNS). Measurements were recorded in 1991, 1993, 1997, 2000, 2004 and 2006. Household income data in 2006 were included in the analysis of the impact of socio-economic status on the prevalence of overweight and obesity in children and adolescents. BMI cut-offs recommended by IOTF were used to define childhood overweight and obesity, as well as the Chinese cut-offs. The Cochrane-Mantel-Haenszel test for trend was used to examine the temporal trends in the prevalence of childhood overweight and obesity. Generalised estimating equations analysis was performed to assess the changes in BMI during the study period after adjusting for age, sex, region and income. RESULTS: In Chinese children and adolescents mean BMI steadily increased from 17.4 kg/m(2) (95% CI: 17.3-17.5) in 1991 to 18.3 kg/m(2) (95% CI: 18.1-18.5) in 2006, after adjusting for age, sex, region and income level. There was a corresponding increase in the prevalence of overweight and obesity from 5.2% in 1991 to 13.2% in 2006. The greatest increase occurred among male children and adolescents in whom the prevalence of excess body weight tripled from 4.8% in 1991 to 15.4% in 2006, compared with 5.4% and 11.0% in females over the same period. In 2006, those from higher income families tended to have the highest prevalence of overweight and obesity. CONCLUSIONS: The prevalence of overweight and obesity among Chinese children and adolescents has increased steadily over the past 15 years with the increase being apparent in all age, sex and income groups. However, the most noticeable increase was in children from urban areas and those from higher income backgrounds. PMID- 20836723 TI - The use of waist-to-stature ratio to identify underweight and overweight in adolescents. AB - OBJECTIVES: To examine the percentile distribution of waist-to-stature ratio (WSR) and derive WSR cut-offs for underweight, normal weight, and overweight based on the International Obesity Task Force (IOTF) and local weight-for-height standards in Hong Kong Chinese adolescents. METHODS: In the Hong Kong Student Obesity Surveillance project in 2006-2007, height, weight and waist circumference of 13 568 (40.3% boys) Chinese adolescents aged 12-18 were measured. Smoothed percentile distributions of WSR by age and sex were examined using Lambda-Mu Sigma (LMS) regression. The sex- and age-specific WSR values corresponding to underweight and overweight, as defined by the IOTF and local weight-for-height standards, were determined using receiver operating characteristic curves. RESULTS: The percentile values of WSR were stable across age in both sexes. In general, WSR values of 0.40 and 0.46 corresponded to underweight and overweight, respectively, as defined by both IOTF and local weight-for-height standards. As a reference for normal weight status, the median weight-for-height values corresponded to a WSR value of 0.42 in most sex-age subgroups. CONCLUSION: Sex and age independent WSR cut-off values for underweight, median weight and overweight in Hong Kong adolescents were identified. WSR is potentially a practical indicator for adolescents to monitor their weight status. PMID- 20836725 TI - Pharmacokinetics and elucidation of the rates and routes of N-glucuronidation of PF-592379, an oral dopamine 3 agonist in rat, dog, and human. AB - PF-592379 is a potent, selective agonist of the dopamine 3 receptor, for the treatment of male erectile dysfunction and female sexual dysfunction. In vivo, PF 592379 has low-moderate clearance relative to liver blood flow of 6.3 and 8.5 ml/min/kg in dog and 44.8 and 58.2 ml/min/kg in rat. It has high permeability in Caco-2 cells and was completely absorbed in rat and dog pharmacokinetic studies with an oral bioavailability of 28% in both rats and 61 and 87% in the dogs. These data are consistent with the physicochemical properties of PF-592379, which indicate complete absorption by the transcellular route. Elimination of PF-592379 was predominantly metabolic in nature. In vitro routes of metabolism studies indicate that metabolism in the rat is a combination of P450 mechanisms and N glucuronidation, whereas in dog and human, N-glucuronidation is the major route. NMR analysis indicates that N-glucuronidation is non-quaternary in nature and occurs on both the pyridyl amine and ring nitrogen. Rates of clearance via N glucuronidation were predicted to be low in humans compared with acyl or phenolic glucuronidation. PF-592379 was predicted to have complete absorption from the gastrointestinal tract and an oral bioavailability of >60% in the clinic. Clinical data verified that PF-592379 is a low clearance compound in human, with a mean oral clearance of 6.5 ml/min/kg following a 200 mg oral dose. PF-592379 has ideal pharmacokinetic properties for an oral D3 agonist, intended for on demand dosing. PMID- 20836724 TI - Ecological and sociodemographic effects on urinary catecholamine excretion in adult Samoans. AB - BACKGROUND: Ecological and sociodemographic correlates of stress may contribute to cardiovascular disease risk in modernizing Samoans. AIM: The effects of peri urban vs rural residence, education, occupation, caffeine intake and cigarette consumption on urinary catecholamine excretion were studied in Samoan adults. SUBJECTS AND METHODS: Five hundred and seven participants, aged 29-69 years, were randomly selected from nine villages throughout Samoa. Sociodemographic and lifestyle factors were assessed by questionnaire. Epinephrine and norepinephrine excretion rates were measured by high performance liquid chromatography with electrochemical detection in overnight urine samples. Age ( <= 40 vs >40 years) and gender-specific regression models were estimated to detect associations with BMI-adjusted catecholamine excretion. RESULTS: Norepinephrine was significantly higher in peri-urban young men and older women. Epinephrine was significantly higher in peri-urban older men. Adjustment for caffeine attenuated the relationship between residence and norepinephrine in young women. CONCLUSION: General residential exposure to modernization in urban villages is a significant correlate of increased overnight catecholamine excretion rates and is consistent with past studies. Caffeine consumption in younger women plays a complex role in stress-related catecholamine excretion. Further studies of individual level attitudinal and behavioural factors in Samoans are needed to understand psychosocial stress, physiologic arousal and health. PMID- 20836726 TI - The impact of oral contraceptives and metformin on anti-Mullerian hormone serum levels in women with polycystic ovary syndrome and biochemical hyperandrogenemia. AB - OBJECTIVE: To assess the impact of metformin and of two different oral contraceptives (OCs) containing cyproterone acetate and drospirenone, on serum anti-Mullerian hormone (AMH) levels, in a cohort of women with polycystic ovary syndrome (PCOS) with hyperandrogenism. DESIGN: Prospective randomised study. SETTING: Division of Endocrinology and Human Reproduction, Aristotle University of Thessaloniki. PATIENTS: Forty-five (45) women with PCOS diagnosed according to the criteria proposed in 1990 by the NIH. INTERVENTIONS: Women with PCOS were randomised into three groups, all treated for 6 months: Group A received an OC containing 35 MUg ethinylestradiol plus 2 mg cyproterone acetate, Group B received an OC containing 30 MUg ethinylestradiol plus 3 mg drospirenone and Group C received metformin 850 mg * 2. Main outcome measure(s). Anti-Mullerian hormone levels were measured by a specific ELISA. RESULTS: AMH was significantly decreased under treatment with 35 MUg ethinylestradiol plus 2 mg cyproterone acetate (p = 0.002 at 3 months and p < 0.001 at 6 months). Treatment with 30 MUg ethinylestradiol plus 3 mg drospirenone, and treatment with metformin 850 mg * 2 did not significantly affect serum AMH levels. AMH was significantly decreased under OCs treatment compared to metformin 850 mg * 2 (p = 0.005). CONCLUSION(S): AMH serum levels were significantly decreased under treatment with 35 MUg ethinylestradiol plus 2 mg cyproterone acetate, due to decrease in androgens and suppression of gonadotropins. PMID- 20836727 TI - Relation between C-reactive protein and body mass index in patients with polycystic ovarian syndrome. AB - INTRODUCTION: Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder in women. These patients share common features like obesity with metabolic syndrome. C-reactive protein (CRP) is a low-grade chronic inflammation biomarker that independently predicts high-risk patients for cardiovascular diseases (CVD). Although many studies showed increased plasma CRP levels in patients with PCOS, there is still less evidence that can link obesity and CRP levels in patients with PCOS. The objective of this study was to investigate the relations between body mass index (BMI) and CRP plasma levels in patients with PCOS. METHOD: Forty patients with PCOS and 30 controls matched by age and BMI were included. Blood sample was obtained from all individuals in early follicular phase of menstrual cycle. CRP, fasting blood sugar (FBS), triglyceride (TG), and total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), blood pressure, waist circumference (WC) and BMI was measured for all subjects. RESULT: CRP and TG levels were higher in patients with PCOS (p < 0.001 and p = 0.011, respectively). CRP level increased significantly only in patients with PCOS with BMI >= 25 kg/m(2) (p = 0.001) but was not significant in patients with PCOS with BMI < 25 kg/m(2) (p = 0.067). In further analysis, BMI and WC affect CRP rising in patients with PCOS (p = 0.001). CONCLUSION: In patients with PCOS, serum CRP levels were higher than age and BMI-matched controls. Furthermore, BMI was strongly related to CRP only in overweight patients with PCOS. PMID- 20836728 TI - Theme and variations on kinetics of GPCR activation/deactivation. AB - G protein-coupled receptors (GPCRs) initiate intracellular signaling pathways in response to physiologically and medically important extracellular ligands such as peptide and large glycoprotein hormones, neurotransmitters, sensory stimuli (odorant and taste molecules, light), calcium, l-amino acids, and are the target of many clinical drugs. The conversion of these extracellular stimuli into intracellular signals involves sequential and reversible reactions that initially take place at the plasma membrane. These reactions are mediated not only by dynamic interactions between ligands, receptors and heterotrimeric G proteins, but also by conformational changes associated with the activation/deactivation process of each protein. This review discusses the kinetic characteristics and rate-limiting reactions engaged in signal propagation that are involved in systems as diverse as neurotransmitter and hormonal signaling, and that have been recorded in live cells by Forster resonance energy transfer (FRET) approaches. PMID- 20836729 TI - Neuromarkers and unconventional biological fluids. AB - There is a growing evidence on the use of biomarkers in daily practice both as of markers of brain/multiorgan damage and/or trophic factors. However, among different tools, Activin A, S100B protein, and Hemeoxygenase-1 (HO-1 or Heat Shock Protein 32, HSP32) assessment offer the possibility to investigate brain/multiorgan function and development. This could be especially useful in perinatal medicine that requires even more noninvasive techniques to fulfill the minimal handling diagnostic and therapeutic strategy. In this regard, among different biological fluids, human milk for its unique composition can constitute a wide source of knowledge useful both in clinical daily practice and in research.Therefore, this mini-review reports recent data on the presence and the usefulness of Activin A, S100B protein, and HO-1/HSP32 assessment in human milk as brain/multiorgan development markers. Results open up a new cue on the use of these markers in perinatal medicine as a key protein for investigations focusing on fetal/neonatal development. PMID- 20836730 TI - Communicative strategies in a neonatal intensive care unit. AB - Counseling is a professional intervention based on skills to communicate and to build relationships. The project 'Not alone', related to counseling at our Neonatal Intensive Care Unit, is aimed to let counseling become a 'shared culture' for all the care givers. The first essential aspect is to form the ability of counseling through periodic courses for all professionals of the department (physicians, nurses, and physiotherapists). In our department, a professional counselor is present assisting the medical staff in direct counseling. The counselor's intervention allows a better parent orientation in the situation. A more effective sharing of these rules also facilitates the communication among parents and medical staff. Periodic meetings are established among the medical staff, in which the professional counselor discusses difficult situations to share possible communicative strategies. We wanted to have not only a common communicative style, but also common subjects, independent from the characteristics of each of us. Individuals are often faced with diverse situations. For every setting that we more frequently face in communication (for example the first interview with a parent of a very preterm infant) we have built an 'algorithm' that follows a pattern: (1) information always given; (2) frequent questions from parents; and (3) frequent difficulties in the communication. We also need to record important moments, for instance the 'case history of the communication': in fact it would be desirable to have the case history, a sheet dedicated to important communications that are absolutely to be shared with other professionals. PMID- 20836731 TI - Investments for medical equipment in a mother and child health hospital: correlation with level of services/departments. AB - AIM: To assess whether investments for medical equipments assigned by a team of experts to a mother and child health hospital located in Mongolia were correlated with structural, organizational, and educational level of its services/departments. METHODS: A score was used for evaluating the level of each service/department. It was based on a 'structural area' and an 'organizational and educational area'. Destination of funds was determined by a team of experts in collaboration with the head of the service/department. RESULTS: Thirty-three of 36 services/departments (91.6%) were evaluated. A total sum of 4,432,140 Euros to invest in medical equipment was estimated. Assigned investments were inversely correlated with the total (structural plus organizational and educational area) score (n = 33; r = -0.59; p = 0.0002), and the specific scores for structural area (n = 33; r = -0.46; p = 0.005) and organizational and educational area (n = 33; r = -0.56; p = 0.0006). CONCLUSIONS: A large part of the funds for medical equipment was destined to services/departments with low organizational and educational conditions, limiting the potential effect of the aid meanwhile supporting the most in need departments. Educational efforts and monitoring of specific long-term indicators are mandatory. PMID- 20836732 TI - Old and new uses of surfactant. AB - Exogenous surfactant has been the primary life-saving therapy for respiratory distress syndrome (RDS) of preterm infants for many years. More recently, early surfactant treatment administered less invasively by transient endotracheal intubation and combined to nasal ventilation has been shown to further improve neonatal outcome by reducing the need of mechanical ventilation. In addition to RDS, other neonatal and pediatric respiratory disorders characterized by surfactant inactivation or dysfunction, such as pulmonary hemorrhage, aspiration pneumonia, and viral lower respiratory tract infection, might also be amenable to surfactant replacement therapy. However, the nature of lung injury and the influence of co-morbidities may reduce the efficacy of surfactant in these conditions. Currently under investigation are new synthetic surfactant formulations which may be more effective and resistant to inactivation than natural ones and could be produced at a lower cost. The use of surfactants to deliver drugs directly to the lung also seems to be a promising technique worthy of study. PMID- 20836733 TI - The dopamine D(4) receptor, the ultimate disordered protein. AB - The human D4 dopamine receptor is a synaptic neurotransmitter receptor responsible for neuronal signaling in the mesolimbic system of the brain, an area of the brain that regulates emotion and complex behavior. Its structure makes it a very unusual and interesting G protein-coupled receptor (GPCR) as it has several polymorphic variants of its gene in the region encoding the third intracellular loop (IL3). This region contains from two to seven or more similar 48 base pair repeats. These repeats cause this protein to have a very high disorder index and this, in turn, makes it very interactive with other proteins. Among GPCRs in general, the unusually proline-rich IL3 is unique to the D4 receptor (D4R). We believe that, as in the D2R, this region of the receptor plays a role in it's interaction with other receptors. PMID- 20836734 TI - Cow's milk protein allergy. AB - Cow's milk protein allergy (CMPA) affects 2-7.5% of children; persistence in adulthood is uncommon since a tolerance develops in 51% of cases within 2 years and 80% within 3-4 years. CMPA is an immunological reaction to one or more milk proteins: alpha-lactalbumin, beta-lactoglobulin, casein, IgE or non-IgE associated, responsible of immediate or late onset symptoms. The suspicion of CMPA is based on detailed family and medical history, skin test, patch test, laboratory test, an elimination diet and food challenge. The general treatment for CMPA is dietary: elimination of cow's milk protein and introduction of extensively hydrolyzed whey or casein formula, amino acid formula, and soy formula. Extensively hydrolyzed whey or casein formula is recommended as first choice for infants in mild or moderate reactions, amino acid formula in severe CMPA and in cases with poor response to extensively hydrolysed whey or casein formula. PMID- 20836735 TI - Patent ductus arteriosus in the preterm infant: new insights into pathogenesis and clinical management. AB - Postnatal closure of the ductus arteriosus is crucial in the circulatory adaptation of the newborn to extrauterine life. In recent years, many studies have been performed to improve our understanding of both the physiology of the ductus arteriosus in the fetus and newborn, and the mechanisms underlying persistent ductal patency in the preterm infant. The pharmacological treatment of patent ductus arteriosus (PDA) remains a controversial issue. This article reviews the recent literature on the pathogenesis and clinical management of PDA in the preterm infant. PMID- 20836736 TI - Sildenafil as “first line therapy” in pulmonary persistent hypertension of the newborn? AB - Despite the recent advances, the clinical approach to persistent pulmonary hypertension of the newborn (PPHN) still represents an important challenge for neonatologists. The care of newborns with PPHN requires meticulous therapeutic and ventilation strategies including, besides the stabilization of the newborn, the use of nitric oxide and high-frequency ventilation. However, not all the neonates with PPHH are responsive to this clinical approach. Recent studies have proposed the use of sildenafil, a phosphodiesterase 5 inhibitor, in refractory forms of PPHN. The aim of this study is to review the cases and the clinical approach of PPHN in the Neonatal Intensive Care Unit of Meyer Children Hospital in the year 2009 and to discuss the possible role of sildenafil in the management of PPHN. PMID- 20836737 TI - Simulation of prenatal maternal sounds in NICU incubators: a pilot safety and feasibility study. AB - OBJECTIVE: This pilot study evaluated the safety and feasibility of an innovative audio system for transmitting maternal sounds to NICU incubators. METHODS: A sample of biological sounds, consisting of voice and heartbeat, were recorded from a mother of a premature infant admitted to our unit. The maternal sounds were then played back inside an unoccupied incubator via a specialized audio system originated and compiled in our lab. We performed a series of evaluations to determine the safety and feasibility of using this system in NICU incubators. RESULTS: The proposed audio system was found to be safe and feasible, meeting criteria for humidity and temperature resistance, as well as for safe noise levels. Simulation of maternal sounds using this system seems achievable and applicable and received local support from medical staff. CONCLUSION: Further research and technology developments are needed to optimize the design of the NICU incubators to preserve the acoustic environment of the womb. PMID- 20836738 TI - Cesarean delivery versus vaginal delivery: impact on survival and morbidity for the breech fetus at the threshold of viability. AB - OBJECTIVE: To determine if cesarean delivery is associated with improved survival and morbidity in the breech fetus at the threshold of viability. STUDY DESIGN: The Missouri maternally linked cohort data files covering the period 1989 through 2005 were utilized for analysis. All pregnancies with singleton fetuses in the breech presentation delivered between 23(0) and 24(6) weeks gestation and birth weights between 400 and 750 g were included. Logistic regression was used to compare cesarean to vaginal delivery after controlling for maternal demographics and pregnancy complications. RESULTS: A total of 325 breech singletons were analyzed; cesarean deliveries accounted for 46.1% (150) and vaginal deliveries accounted for 53.9% (175). Cesarean delivery was associated with a survival benefit across all birth weights. Morbidity was higher in cesarean compared to vaginal delivery. CONCLUSION: Although cesarean delivery appears to be associated with an increase in survival at the threshold of viability for the breech fetus, there is a concomitant increase in morbidity. Any benefit that cesarean delivery conveys on survival at the threshold of viability should be weighed against the increased maternal morbidity and high overall neonatal morbidity. PMID- 20836739 TI - Marked interindividual variability in renal maturation of preterm infants: lessons from autopsy. AB - The kidney of low birthweight preterm infants is characterized by a reduced number of mature nephrons at birth. The aim of the present study was to determine whether, in preterms, active glomerulogenesis occurs in the postnatal period and whether it may compensate the reduced number of nephrons developed during the intrauterine life. Kidney samples were obtained at autopsy from 8 human fetuses, 12 premature infants, and 3 term newborns. Glomerulogenesis, as measured by radial glomerular count (RGC), was markedly decreased in all preterm infants as compared with term newborns. A marked interindividual variability was detected in the level of glomerulogenesis, which, in the vast majority of cases, did neither correlate with the gestational age at birth nor with birthweight. Active glomerulogenesis, as demonstrated by the presence of S-shaped bodies in the subcapsular region, was present in all preterm infants in the perinatal period, but it ceased in a preterm surviving for 3 months. Our data show that active glomerulogenesis continues even after birth for a short period, although it is not able to compensate a marked oligonephronia at birth. As a consequence, the incomplete nephrogenesis typical of all extremely low birthweight preterm infants possibly results in a persistent oligonephronia which should likelihood represent a major risk factors of progressive renal disease in adulthood. PMID- 20836740 TI - Urban perinatal health inequalities. AB - OBJECTIVE: Large urban areas have higher perinatal mortality rates. In attaining a better understanding, we conducted an analysis on a neighborhood level in Rotterdam, the second largest city of The Netherlands. METHODS: Perinatal outcome of all single pregnancies (50,000) was analyzed for the period of 2000-2006. The prevalences of perinatal mortality and perinatal morbidity were determined for every neighborhood. RESULTS: Large perinatal health inequalities exist between neighborhoods in the city of Rotterdam with perinatal mortality rates as high as 37 per 1000 births. The highest risks were observed in deprived neighborhoods. CONCLUSION: We observed high levels of perinatal health inequalities in the city of Rotterdam which have not been previously described in the Western world. Accumulation of medical risk factors as well as socioeconomic and urban risk factors seems to be a likely contributor. PMID- 20836741 TI - Adenosine deaminase levels in premature infants with respiratory distress syndrome and bronchopulmonary dysplasia. AB - Adenosine is produced in the inflammed and damaged lung where it plays roles in the regulation of inflammation and tissue remodeling. Adenosine deaminase (ADA) is an enzyme responsible for the degradation of adenosine. Our aim was to compare the levels of ADA between infants with and without respiratory distress syndrome (RDS) and to determine the relationship between plasma ADA levels and bronchopulmonary dysplasia (BPD). One-hundred and twenty-five premature infants who were admitted to our neonatal intensive care unit were included in the study. Eighty-one of these infants with RDS were study group and the other 44 infants without RDS served as controls. Blood collection was made in the first day of life at the end of 24th-h and was used for laboratory testing. In the RDS group, mean ADA level was 25.5 (+/- 4.5) U/l, and in controls it was 26.3 (+/- 5.7) U/l. There was no statistically significant difference (p = 0.326) in these groups although there was a statistically difference of ADA levels between BPD (34.5 +/- 5.2 U/l) and non-BPD (24.6 +/- 4.1) patients (p = 0.001). There was also a positive relationship between ADA levels and severity of BPD (r = + 0.845, p = 0.01). Perinatal inflammation is the key mechanism of BPD. ADA level in early postnatal life is elevated in infants with BPD and may be related with perinatal inflammation. PMID- 20836742 TI - Thymosin beta-10 expression in developing human kidney. AB - Thymosin beta-10 (Tbeta10) is a member of beta-thymosins (Tbetas), a family of low molecular mass peptides, which play essential roles in many cellular functions, including apoptosis, cell proliferation, cell migration, and endocytosis. The report that the Tbeta10 gene is expressed at high levels in embryonic human brain as well in human kidney induced us to study Tbeta10 reactivity in the preterm kidney in order to verify, at tissue level, the expression of this peptide during renal embryogenesis. To this end, we analyzed, using immunocytochemistry, the expression of Tbeta10 in samples of human kidney obtained, at autopsy, from 8 fetuses, 12 preterm infants, ranging from 25 to 36 weeks of gestation and 3 at term newborns. Tbeta10 immunoreactivity was detected in 20 out of 22 kidneys examined, and was mainly localized in proximal and distal tubular structures, in the cytoplasm and occasionally in the nuclei of ductal cells. In 11 cases, we also detected a focal and mild reactivity for the peptide in glomeruli. In 13 kidneys, we also observed immunostaining for Tbeta10 inside the "comma-shaped bodies" and the "S-shaped bodies" during active glomerulogenesis. Our data show, for the first time, the expression of Tbeta10 in the human kidney during the initial phases of its physiological development, mainly restricted in the proximal and the distal tubuli. Further studies are needed in order to better characterize the role of Tbeta10 in kidney embryogenesis. PMID- 20836744 TI - Rates of labor induction and primary cesarean delivery do not correlate with rates of adverse neonatal outcome in level I hospitals. AB - OBJECTIVE: To determine whether variation in rates of labor induction (IOL) and primary cesarean delivery (PCD) among level I hospitals is associated with differences in neonatal outcomes. METHODS: A birth certificate database was used to calculate crude and adjusted rates of IOL and PCD among 10 regional hospitals. Adjustment via logistic regression controlled for differences in medical and demographic factors. Linear regression assessed the relationship of crude and adjusted IOL and PCD rates to rates of three neonatal outcomes. RESULTS: IOL and PCD rates varied widely among hospitals (1.79- and 1.72-fold, respectively); variation increased following adjustment (1.93- and 1.86-fold, respectively). Rates of adverse neonatal outcomes varied by year and hospital, but not by IOL or PCD rates (p >= 0.05). CONCLUSIONS: Crude and adjusted rates of labor induction and PCD vary among level I hospitals, but with no consistent effect on neonatal outcome. PMID- 20836743 TI - Variable effects of maternal and paternal-fetal contribution to the risk for preeclampsia combining GSTP1, eNOS, and LPL gene polymorphisms. AB - OBJECTIVE: To evaluate the maternal, paternal, and fetal genotype contribution to preeclampsia. STUDY DESIGN, MATERIALS, AND METHODS: We combined the analysis of polymorphisms of the GSTP1, eNOS, and LPL genes - affecting biotransformation enzymes and endothelial function - in a cohort of 167 preeclamptic and normal control trios (mother, father, and child) comprising a total of 501 samples in the Greek population, never analyzed before by this approach. RESULTS: For the frequency of the GSTP1 Ile(105)/Val(105), the eNOS Glu298Asp and the LPL-93 polymorphisms, statistically significant differences were found between the two groups. However, the transmission rates of the parental alleles to neonates studied by the transmission disequilibrium test, disclosed no increased rate of transmission to preeclampsia children for the variant alleles of Val(105) GSTP1, 298Asp eNOS, and -93G LPL. CONCLUSIONS: These novel data, suggest that interaction of all three types of genotypes (mother, father and neonate), reveals no effects on the development of preeclampsia, but provide the impetus for further studies to decipher the individual contribution of each genetic parameter of preeclampsia. PMID- 20836745 TI - Doppler-flow velocity indices in fetal middle cerebral artery in unilateral and bilateral mild ventriculomegaly. AB - OBJECTIVE: To study the association between fetal middle cerebral artery (MCA) Doppler-flow velocity waveforms and the lateral cerebral ventricular width in fetuses diagnosed with unilateral or bilateral ventriculomegaly. METHODS: A prospective cohort evaluation of the association between Doppler-flow velocity indices of the MCA and ventricular width in singleton fetuses referred because of suspected ventriculomegaly between 20 and 40 weeks' gestation. Fetuses that were diagnosed as bilateral or unilateral ventriculomegaly were assigned to the study group and those with normal ventricular width served as controls. RESULTS: Of the 53 women recruited to the study, in 30 (57%) fetuses (study group) at least one ventricle >= 10 mm was detected, of them 10 (33%) had bilateral ventriculomegaly and 20 (67%) had unilateral ventriculomegaly. Of the 30 fetuses 29 had mild ventriculomegaly. In 23 fetuses ventricular width was <10 mm (control group). Mean MCA pulsatility index (PI) and mean peak systolic velocity (PSV) were not different between the study group and the control group (p=0.935 and p=0.743, respectively). In a linear regression model, MCA-PSV was significantly correlated with gestational age, R(2)=0.309, p<0.001. DISCUSSION: Unilateral or bilateral mild ventriculomegaly is not associated with fetal MCA change in Doppler-flow velocity indices, suggesting different involvement of vascular component from severe ventriculomegaly. PMID- 20836746 TI - MR-compatible pumps versus manual titration of propofol for pediatric sedation. AB - This study aimed to review the use of two methods of propofol infusion: a metred burette system where propofol is diluted in Lactated Ringer using the rule of six [ 1 ] or an infusion pump: Medrad Continuum Magnetic resonance (MR) compatible Infusion System (Medrad Inc. Indianola, PA) and to determine the difference, if any, between the total amount of drug delivered, the impact on vital signs, sedation status and discharge time of the patients. With Institutional Review Board (IRB) approval, 140 children aged 0 to 18 years, American Society of Anesthesiologists (ASA) physical status I or II requiring sedation for elective outpatient brain Magnetic Resonance Imaging (MRI) examination were included in the study. A total of 70 patients in each group were studied. The (Mean +/- S.D.) total amount of propofol infused was significantly less in the infusion pump group (12.47 +/- 7.67 mg/kg) than the metred burette system (15.84 +/- 16.13 mg/kg, p = 0.003). There were also significant mean differences in awakening times (26.63 +/- 16.35 vs. 37.06 +/- 20.98 min, p = 0.006), and discharge times (53.46 +/- 21.12 vs. 67.89 +/- 26.84 min, p = 0.008) in the infusion pump group versus the buretrol infusion group. This study demonstrates that both infusion techniques preserve haemodynamic stability and are associated with minimal complications. The use of an infusion pump, which consistently maintains accurate dosing, reduces the amount of propofol judged adequate by the anaesthesiologist to achieve sedation in MRI. This leads to a more consistently faster emergence and early discharge after sedation in children undergoing MRI studies. PMID- 20836747 TI - Colonic pressure data processing based on independent component analysis. AB - The Colonic manometry is an important technique to evaluate human colonic motor functions, which are critical for doctors to understand the pathology of intestinal diseases like slow transit constipation (STC) and colonic inertia (CI). However, in the obtained pressure signals, several patterns of colonic motor activities as well as noises mixed together, which made it difficult to observe the information people really needed. In this article, a new method was proposed to extract patterns of colonic motility from the mixed signals, so that researchers could study them thoroughly. Colonic pressure recordings from 26 volunteers were obtained by the water-perfused manometry catheters. Then independent component analysis (ICA) was introduced, which successfully separated colonic motility patterns and noises into four independent components. And according to the rhythm of contractions examined by ICA, subjects' colonic motility could be divided into three types: regular rhythm (12 subjects), slow rhythm (8 subjects) and disordered (6 subjects), which exactly accorded with their original diagnosis. PMID- 20836748 TI - Altitude mountain sickness among tourist populations: a review and pathophysiology supporting management with hyperbaric oxygen. AB - In the mountain climbing community, conventional prevention of altitude mountain sickness (AMS) relies primarily on a formal acclimatization period. AMS symptoms during mountaineering climbs are managed with medication, oxygen and minor recompression (1524-2438 m altitude) using a portable chamber, such as the Gamow Bag. This is not always an acceptable therapy alternative in a predominantly elderly tourist population. The primary problem with reduced pressure at high altitude is hypoxaemia, which causes increased sympathetic activity, induces pulmonary venous constriction, while increasing pulmonary blood flow and regional perfusion. Rapid assents to altitude contribute to an increased incidence of decompression sickness (DCS). The treatment of choice for DCS is hyperbaric oxygenation, thus, treatment of high-altitude induced hypoxaemia using hyperbaric oxygenation (HBO(2)) is logical. Life Support Technologies group and the Center for Investigation of Altitude Medicine (CIMA, in Cusco, Peru) propose a comprehensive and multidisciplinary approach to AMS management. This approach encompasses traditional and advanced medical interventions including the use of a clinical HBO(2) chamber capable of recompression to three times greater than sea level pressure (3 atmosphere absolute (ATA)). The system uses a series of AMS hyperbaric treatment profiles that LST has previously developed to the US military and NASA, and that take greater advantage of vasoconstrictive effects of oxygen under true hyperbaric conditions of 1.25 ATA. These profiles virtually eliminate AMS rebound after the initial treatment often seen in conventional AMS treatment, where the patient is either treated at altitude, or does not recompress back to sea level or greater pressure (1.25 ATA), but returns directly to the same altitude where AMS symptoms first manifested. PMID- 20836749 TI - Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes. AB - We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T1D) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D. PMID- 20836750 TI - Interferons as potential adjuvants in prophylactic vaccines. AB - IMPORTANCE OF THE FIELD: Vaccines are still one of the best approaches to manage infectious diseases. Despite the advances in drug therapies, prophylactic medicine is still more cost efficient and minimizes the burden in the heath system. Despite all the research in vaccine development, many infectious diseases are still without an effective vaccine. The use of adjuvants in vaccines has been one successful strategy to increase efficacy. IFNs are widely expressed cytokines that have potent antiviral effects. These cytokines are the first line of defense against viral infections and have important roles in immuno surveillance for malignant cells. One of the most promising uses of IFNs is as adjuvants that are co-applied with antigen in vaccines. AREAS COVERED IN THIS REVIEW: In this review, a cumulative analysis of many of the studies that have used IFN-alpha, beta, -gamma and -lambda as adjuvants between 1987 and the present suggests that many do possess the capacity to serve as potent immunoadjuvants for vaccination. WHAT THE READER WILL GAIN: This review provides a very large collection of studies involving all types of IFNs used as adjuvants in vaccines using different vaccination strategies and various animal models. TAKE HOME MESSAGE: It is clear that the use of IFNs not only improved the efficacy and safety of most vaccines, but also had important immunomodulatory effect directing T(H)1 immune responses. PMID- 20836751 TI - Immunochemotherapy-associated protein patterns in tumour tissue and serum of patients with metastatic renal cell carcinoma. AB - CONTEXT: Systemic treatment of metastatic renal cell carcinoma (mRCC) with targeted therapies became widely accepted; however, there are few patients who greatly benefit from immunochemotherapy (ICT). It is crucial to recognize these patients for individual treatment. OBJECTIVES: Definition of protein patterns in tissue and serum from mRCC-patients to predict benefit from ICT. MATERIALS AND METHODS: Twenty-five tissue samples and 59 sera were analysed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Protein peaks of interest were identified by 2D-PAGE and peptide mass fingerprinting. Validation was carried out by Western Blot and ELISA. RESULTS: Protein patterns associated with therapy response were determined. Caveolin-1 (CAV-1) and plasminogen activator inhibitor 1 (PAI-1) were identified in tissue; serum amyloid A (SAA) and transthyretin (TTR) were found in serum. CONCLUSION: Individual prediction of therapy benefit and selecting patients for ICT based on molecular biological profiles appear to be feasible in the future. PMID- 20836752 TI - Articular cartilage: structure and regeneration. AB - Articular cartilage (AC) has no or very low ability of self-repair, and untreated lesions may lead to the development of osteoarthritis. One method that has been proven to result in long-term repair or isolated lesions is autologous chondrocyte transplantation. However, first generation of these cells' implantation has limitations, and introducing new effective cell sources can improve cartilage repair. AC provides a resilient and compliant articulating surface to the bones in diarthrodial joints. It protects the joint by distributing loads applied to it, so preventing potentially damaging stress concentrations on the bone. At the same time it provides a low-friction-bearing surface to enable free movement of the joint. AC may be considered as a visco- or poro-elastic fiber-composite material. Fibrils of predominantly type II collagen provide tensile reinforcing to a highly hydrated proteoglycan gel. The tissue typically comprises 70% water and it is the structuring and retention of this water by the proteoglycans and collagen that is largely responsible for the remarkable ability of the tissue to support compressive loads. PMID- 20836753 TI - Preclinical disposition and pharmacokinetics-pharmacodynamic modeling of biomarker response and tumour growth inhibition in xenograft mouse models of G 573, a MEK inhibitor. AB - The mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway is a key signalling pathway that regulates cell proliferation. G-573 is an allosteric inhibitor of MEK that is both potent and selective. The objectives of these studies were to characterize the disposition of G-573 in preclinical species and to determine the relationship of G-573 plasma concentrations to pERK (phosphorylated ERK) and to tumour growth inhibition in HCT116 and H2122 mouse xenograft models. The clearance of G-573 was low in mouse (7.7 ml/min/kg), rat (2.24 ml/min/kg), dog (10 ml/min/kg), and cynomolgus monkey (0.754 ml/min/kg) while volumes of distribution (0.114-1.77 l/kg) was low to moderate, resulting in moderate half-lives across species (~2-9 h). Indirect response models were used to characterize the relationship between plasma concentration of G-573 to both pERK inhibition and tumour growth inhibition. The IC(50) value for pERK inhibition in HCT116 tumours by G-573 was estimated to be 0.406 uM. The IC(50) values for tumour growth inhibition in HCT116 and H2122 were estimated to be 3.43 and 2.56 uM, respectively. ED(50) estimates in HCT116 and H2122 mouse xenograft models were estimated to be ~4.6 and 1.9 mg/kg/day, respectively. The information from these studies provides useful information when characterizing candidates for potential further clinical testing. PMID- 20836754 TI - Response of growth differentiation factor-15 to percutaneous coronary intervention and regular exercise training. AB - BACKGROUND: Growth differentiation factor-15 (GDF-15) is considered to be a cardioprotective cytokine possessing antiapoptotic and antiproliferative properties. If GDF-15 plasma levels are influenced by percutanenous coronary intervention (PCI) or regular exercise training is currently not known. METHODS: After successful revascularization by PCI with stent implantation 36 consecutive patients with stable angina pectoris were randomized to an exercise training program or to a control group. Patients were followed by serial measurements of GDF-15, high-sensitivity Troponin T (hsTNT) and N-terminal pro brain natriuretic peptide (NT-proBNP) levels in peripheral blood after PCI and during six months follow-up. RESULTS: Plasma levels of GDF-15 showed an early response to PCI with a modest, but significant increase after 30 minutes (p = 0.007) peaking three hours after PCI. Levels of hsTNT rose 5-fold from baseline to 24 hours (p < 0.001) with a normalization at seven days post PCI. Changes in plasma levels of GDF-15, hsTNT and NT-proBNP were not significantly different between the training and control group during follow-up. CONCLUSIONS: GDF-15 levels show a modest transient increase in response to coronary intervention with stent implantation. Exercise training over six months does not affect plasma levels of GDF-15, hsTNT or NT-proBNP in patients with stable coronary artery disease. PMID- 20836755 TI - Human kallikrein 6 cerebrospinal levels are elevated in multiple sclerosis. AB - The protease, human kallikrein-related peptidase 6 (hK6) is derived from activated macrophages in the central nervous system (CNS) and may contribute to pathology observed in multiple sclerosis (MS). In the present study, we compared serum and cerebrospinal fluid (CSF) protein concentrations of human kallikrein related peptidase 6 derived from neurological controls and patients diagnosed with advanced multiple sclerotic disease. Mean serum levels of human kallikrein related peptidase 6 were similar in neurological controls and patients diagnosed with relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) multiple sclerosis with mean levels ranging from 3.5 to 3.75 ng/ml. Patients diagnosed with advanced multiple sclerosis showed mean CSF levels (29 ng/ml) that were significantly higher than neurological controls (25.5 ng/ml). Determining CSF concentrations of human kallikrein-related peptidase 6 may therefore have diagnostic value in MS. PMID- 20836756 TI - Nanoemulsion encapsulation and in vitro SLN models of delivery for cytotoxic methotrexate. AB - The complementary mixing and de-mixing of phases is seen as a methodology for use in 'smart' drug delivery systems. Surface tensions were routinely lowered to 50 55 mN/m in drug mixtures and this is compared to low molecular weight emulsifiers such as Tween 80. In the research reported here, mixing of a heterocyclic drug and an amphiphilic polymer is responsible for structural inconsistency at the air water (A/W) interface and presents itself as a means of release of drug from a series of complex drug formulations. The work was extended to look at the behavior of both "soft" and "hard" particle hydrophobic and hydrophilic particle stabilization of emulsions of 20 and 0.7 um. The work is based on spread interfacial monolayers, thin liquid films emulsion droplets and model latex nanoparticle beads (60 and 500 nm) in the presence and absence of poloxamer (Pluronic) and methotrexate. The interfacial rheological characteristics and AFM based nano-rheology were used to aid the elucidation of surface structure and nano-architectures within the plane of the adsorbed interfacial layer and for use in the fabrication of solid nano-particle stabilized micron and nano-sized oil inwater (O/W) emulsions. PMID- 20836757 TI - Determination of MHC binding peptides and epitopes from non-structural movement (NSm) protein of groundnut bud necrosis virus. AB - Groundnut bud necrosis virus (GBNV) is recognized as one of the most economically important viruses and is known to affect several crops including peanut, potato, tomato and soybean. For managing plant virus diseases, determination of their causal agents' identity at an early stage of crop is a pre-requisite. In the present study, NSm protein of GBNV has been used to predict out MHC binding peptides and epitopes that are highly suitable for antigenicity. Eighteen peptide regions were found to have high affinity. Few of these NSm protein TAP transporters are 126- RRYMHISRL with score 11.638, 125- NRRYMHISR with score 10.280, 46- AIMNKAKTL with score 7.762, 120- PTWNSNRRY with score 7.632 and 171- ASLKDPMCF with score 7.277. The support vector machine (SVM) based approach predicted MHCII-IAb peptide regions, 45- SAIMNKAKT, 151- ASLIDPNKM, 23- PAVKKENNR, 229- PIAAENNTC, (optimal score 0.938); MHCII-IAd peptide regions, 208- YAKGVGFAS, 101- NDSLVGNGN, 55- NGKQYVSSG, 63-GDSSVLGTY, (optimal score 0.852); MHCII-IAg7 peptide regions, 277- LQKAAERLA, 145- SKNNVKASL, 228- TPIAAENNT, 276- SLQKAAERL, (optimal score 1.640); and MHCII- RT1.B peptide regions, 193- TPKQCMQLN, 195- KQCMQLNLT, 246- KVIQSAALI, 166- IISRQASLK, (optimal score 0.800) as binders from NSm protein. The most suitable predicted segments in NSm protein of GBNV virus found in the study are 164- KIIISRQASLKDPMCFIFHLNWS- 186 and 237 CDVVPINRAKVIQSAALIEACKLMIP-262. These two fragments, obtained from non-structural movement protein with average propensity 1.016, are high-efficiency binders and may, therefore be used in cross protection to provide resistance against GBNV and develop GBNV specific antibodies that can be exploited in sero-diagnostics. PMID- 20836758 TI - Preparation and evaluation of famotidine polymorphs. AB - The main objective of this study was to compare the behaviour of drug release among the famotidine polymorphs prepared by using various additives and solvents, by solvent evaporation method. The famotidine polyvinyl pyrrolidone polymorphs with different concentrations (0.5, 1 and 1.5%) were prepared by using solvent evaporation method. In these polymorphs of different concentrations 1% w/v polymorphs showed better release. Similarly, famotidine polymorphs of Tween 80 with different concentrations, polyethylene glycol 1% w/v and methanol was prepared. Famotidine polymorphs prepared the PVP (1% w/v) showed better drug release and solubility. DSC, FTIR, SEM and XRD studies were carried out. DSC studies revealed that PVP polymorphs were found to stable compared to other polymorphs. FTIR studies of the polymorphs prepared indicated that there was an interaction found in all polymorphs except PVP polymorphs indicating the absence of drug-additive interaction. SEM studies of PVP and methanol polymorphs revealed that they are tabular and prismatic and columnar respectively. These changes in morphology were due to variations in face dimensions and also properties of additives and solvent used in the preparation. XRD studies revealed that there is an increase in crystallinity in methanol polymorphs when compared to PVP polymorphs and pure drug. The mechanism of drug release was determined using zero order, first order and Hixon-Crowel equations. From the drug release kinetics these polymorphs followed first order and Hixon-Crowel release kinetics, exhibited fair linearity in their dissolution data. Further, in vivo studies were carried out for the evaluation of antiulcer activity. Based upon the drug release pattern and its kinetics only two of the prepared polymorphs of famotidine i.e. famotidine PVP polymorphs and famotidine methanol polymorphs were selected for animal studies. Antiulcer studies were carried out using pylorus ligation model and estimation of antioxidant parameters was also done. In these studies also polymorphs of PVP showed better antiulcer activity and also significant antioxidant activity when compared to famotidine (pure) and famotidine methanol polymorphs. Hence in the present investigation, amongst the various polymorphs of famotidine prepared, PVP polymorphs were found to possess good dissolution behaviour, stability and absence of drug additive interactions. Further, in vivo studies confirmed the better therapeutic action of these PVP polymorphs over the pure drug and famotidine methanol polymorphs. PMID- 20836759 TI - Versatile applications of microRNA in anti-cancer drug discovery: from therapeutics to biomarkers. AB - Over the past several years, microRNAs (miRNAs) have been identified as a fine tuner in a wide array of biological processes, including development, cell growth and metabolism. Recent studies have shown that many kinds of miRNAs act as oncomirs or tumor suppressors in tumors where the miRNA genes are up- or down- regulated, respectively. These dysregulations occur through a variety of mechanisms, such as genetic alterations, epigenetic repression or altered expression of transcription factors which target miRNAs. The aberrant expressions of miRNAs are observed not only in tumor lesions but also in plasma and serum of cancer patients. These characteristics of miRNAs have created extensive interest in tapping into them for diagnosis and prognosis as well as drug discovery in cancer therapy. In this literature, the significance of miRNAs in tumor initiation and development is first reviewed. Second topic is extracellular miRNAs as biomarkers for cancer classification and prediction. Further, we focus on secretory machinery of miRNAs and share new evidence suggesting that extracellular miRNAs can play biological roles beyond mere biomarkers. Extending this concept, our hypothetical model that extracellular miRNAs may function as a signaling molecule in a crosstalk between cancer cells and their surrounding cells is presented. Finally, we discuss the potential of miRNAs for therapeutic applications in clinical oncology. PMID- 20836760 TI - Functional gene discovery using RNA interference-based genomic screens to combat pathogen infection. AB - The rampant use of antibiotics in the last half-century has imposed an unforeseen biological cost, the unprecedented acceleration of bacterial evolution to produce drug-resistant strains to practically every approved antibiotic. This rise in antimicrobial drug resistance, alongside the failure of conventional research efforts to discover new antibiotics, may eventually lead to a public health crisis that can drastically curtail our ability to combat infectious disease. To address this public health need for novel countermeasure strategies, research efforts have recently focused on identification of genes in the host, rather than the pathogen, that are essential for successful pathogen infection, as potential targets for drug discovery. In the past decade, RNA interference (RNAi) has emerged as a powerful tool for analyzing gene function by silencing target genes through the specific destruction of their mRNAs. Based on RNAi methodology, high throughput genome- wide assay platforms have been developed to identify candidate host genes that are manipulated by pathogens during infection. In this review, we will discuss recent strategies for RNAi-based genomic screens to investigate hostpathogen mechanisms in human cell models using both bacterial pathogens, including Salmonella typhimurium, Mycobacterium tuberculosis, and Listeria monocytogenes, and viruses, such as Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and influenza. These functional genomics studies have begun to elucidate novel pathogen virulence mechanisms and thus, may serve as the basis for the design of novel host-based inhibitor therapeutics that can block or alleviate the downstream effects of pathogen infection. PMID- 20836761 TI - Antisense antibiotics: a brief review of novel target discovery and delivery. AB - The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered. PMID- 20836762 TI - Epigenetic changes and alteration of Fbn1 and Col3A1 gene expression under hyperglycaemic and hyperinsulinaemic conditions. AB - Little is known regarding the role of hyperglycaemia on histone H3 modifications and, in turn, altering the expression of genes during the development of diabetes associated complications. In the present study, we have investigated the hyperinsulinaemia/hyperglycaemia-induced epigenetic changes and alteration of Fbn1 (fibrillin 1) and Col3A1 (collagen type III alpha1) gene expression. Insulin resistance and Type 2 diabetes in male Sprague-Dawley rats was developed by feeding rats an HFD (high-fat diet) and administering a low dose of STZ (streptozotocin). Hyperglycaemia induced deacetylation and dephosphorylation of histone H3 in the heart and kidneys of diabetic rats. Furthermore, mRNA expression of Fbn1 and Col3A1 increased in the kidneys and decreased in the heart under hyperglycaemic/hyperinsulinaemic conditions. Similar to mRNA expression, chromatin immunoprecipitation also showed an increase in the level of histone H3 acetylation of the Fbn1 gene, but not of the Col3A1 gene. Our present findings suggests that the change in expression of the Fbn1 gene is epigenetically regulated, but the expression of the Col3A1 gene may either be independent of epigenetic regulation or may involve other histone modifications. We provide the first evidence regarding the role of hyperglycaemia/hyperinsulinaemia in altering histone H3 modifications, which may result in the alteration of extracellular matrix gene expression. PMID- 20836763 TI - Comparison of satellite cell-derived myoblasts and C2C12 differentiation in two- and three-dimensional cultures: changes in adhesion protein expression. AB - Changes in the expression of adhesion proteins involved in myoblast differentiation were investigated in monolayer (two-dimensional) and 3D (three dimensional) cell cultures. The expression of integrin alpha3 subunit, integrin beta1 subunit, ADAM12 (a disintegrin and metalloproteinase 12), tetraspanins CD9 and CD81 and M-cadherin were examined in the murine myoblast cell line C2C12 and in a primary culture of rat satellite cells. Myoblasts in monolayer and 3D cultures showed significant differences in their morphology and cytoskeletal organization. All of the studied proteins participated in myoblast fusion in each culture examined, but differences in their levels of expression were observed. Satellite cell-derived myoblasts exhibited higher expression of adhesion protein mRNAs than C2C12 cells. Also, C2C12 cells from a 3D culture showed slightly higher expression of adhesion protein transcripts than the same cells cultured as a monolayer. Significantly, the levels of adhesion protein mRNAs were found to change in parallel in all cell culture types. Despite this finding, it is important that differences between satellite cell-derived myoblasts and cell line C2C12 grown in monolayer and 3D cultures are taken into account when studying processes of myoblast differentiation in vitro. PMID- 20836764 TI - Biochemical and cellular functions of P4 ATPases. AB - P4 ATPases (subfamily IV P-type ATPases) form a specialized subfamily of P-type ATPases and have been implicated in phospholipid translocation from the exoplasmic to the cytoplasmic leaflet of biological membranes. Pivotal roles of P4 ATPases have been demonstrated in eukaryotes, ranging from yeast, fungi and plants to mice and humans. P4 ATPases might exert their cellular functions by combining enzymatic phospholipid translocation activity with an enzyme independent action. The latter could be involved in the timely recruitment of proteins involved in cellular signalling, vesicle coat assembly and cytoskeleton regulation. In the present review, we outline the current knowledge of the biochemical and cellular functions of P4 ATPases in the eukaryotic membrane. PMID- 20836765 TI - Porins in prokaryotes and eukaryotes: common themes and variations. AB - Gram-negative bacteria and mitochondria are both covered by two distinct biological membranes. These membrane systems have been maintained during the course of evolution from an early evolutionary precursor. Both outer membranes accommodate channels of the porin family, which are designed for the uptake and exchange of metabolites, including ions and small molecules, such as nucleosides or sugars. In bacteria, the structure of the outer membrane porin protein family of beta-barrels is generally characterized by an even number of beta-strands; usually 14, 16 or 18 strands are observed forming the bacterial porin barrel wall. In contrast, the recent structures of the mitochondrial porin, also known as VDAC (voltage-dependent anion channel), show an uneven number of 19 beta strands, but a similar molecular architecture. Despite the lack of a clear evolutionary link between these protein families, their common principles and differences in assembly, architecture and function are summarized in the present review. PMID- 20836766 TI - Interviews with leaders in emergency medicine. PMID- 20836767 TI - Bedside transthoracic sonography in suspected pulmonary embolism: a new tool for emergency physicians. PMID- 20836769 TI - Note from the Editor-in-Chief. PMID- 20836770 TI - Bedside ocular ultrasound for the detection of retinal detachment in the emergency department. AB - OBJECTIVES: Acute retinal detachments (RD) can be difficult to diagnose and may require emergent intervention. This study was designed to assess the performance of emergency department ocular ultrasound (EOUS) for the diagnosis of RD. METHODS: This was a prospective, observational study using a convenience sample of emergency department (ED) patients. Physicians performed EOUS for the diagnosis of RD prior to evaluation by an ophthalmologist. The criterion standard was the diagnosis of a RD by the ophthalmologist who was blinded to the results of EOUS. RESULTS: Fifteen physicians evaluated 48 patients with acute visual changes. Eighteen patients (38%) had RDs and all were correctly identified (true positives). Of the 30 patients (62%) without RD, 25 patients were correctly identified (true negatives), and five patients with vitreous hemorrhages were misidentified as having RDs (false positives). Therefore, the sensitivity and specificity of EOUS for RD were 100% (95% confidence interval [CI] = 78% to 100%) and 83% (95% CI = 65% to 94%), respectively. CONCLUSIONS: Emergency department ocular ultrasound is sensitive for the diagnosis of RD and may have a role in excluding RD in patients presenting to the ED. PMID- 20836771 TI - The association between prehospital endotracheal intubation attempts and survival to hospital discharge among out-of-hospital cardiac arrest patients. AB - OBJECTIVES: The benefit of prehospital endotracheal intubation (ETI) among individuals experiencing out-of-hospital cardiac arrest (OOHCA) has not been fully examined. The objective of this study was to determine if prehospital ETI attempts were associated with return of spontaneous circulation (ROSC) and survival to discharge among individuals experiencing OOHCA. METHODS: This retrospective study included individuals who experienced a medical cardiac arrest between July 2006 and December 2008 and had resuscitation efforts initiated by paramedics from Mecklenburg County, North Carolina. Outcome variables were prehospital ROSC and survival to hospital discharge, while the primary independent variable was the number of prehospital ETI attempts. RESULTS: There were 1,142 cardiac arrests included in the analytic data set. Prehospital ROSC occurred in 299 individuals (26.2%). When controlling for initial arrest rhythm and other confounding variables, individuals with no ETI attempted were 2.33 (95% confidence interval [CI] = 1.63 to 3.33) times more likely to have ROSC compared to those with one successful ETI attempt. Of the 299 individuals with prehospital ROSC, 118 (39.5%) were subsequently discharged alive from the hospital. Individuals having no ETI were 5.46 (95% CI = 3.36 to 8.90) times more likely to be discharged from the hospital alive compared to individuals with one successful ETI attempt. CONCLUSIONS: Results from these analyses suggest a negative association between prehospital ETI attempts and survival from OOHCA. In this study, the individuals most likely to have prehospital ROSC and survival to hospital discharge were those who did not have a reported ETI attempt. Further comparative research should assess the potential causes of the demonstrated associations. PMID- 20836772 TI - Advanced airway management does not improve outcome of out-of-hospital cardiac arrest. AB - BACKGROUND: The goal of out-of-hospital endotracheal intubation (ETI) is to reduce mortality and morbidity for patients with airway and ventilatory compromise. Yet several studies, mostly involving trauma patients, have demonstrated similar or worse neurologic outcomes and survival-to-hospital discharge rates after out-of-hospital ETI. To date, there is no study comparing out-of-hospital ETI to bag-valve-mask (BVM) ventilation for the outcome of survival to hospital discharge among nontraumatic adult out-of-hospital cardiac arrest (OOHCA) patients. OBJECTIVES: The objective was to compare survival to hospital discharge among adult OOHCA patients receiving ETI to those managed with BVM. METHODS: In this retrospective cohort study, the records of all OOHCA patients presenting to a municipal teaching hospital from November 1, 1994, through June 30, 2008, were reviewed. The type of field airway provided, age, sex, race, rhythm on paramedic arrival, presence of bystander cardiopulmonary resuscitation (CPR), whether the arrest was witnessed, site of arrest, return of spontaneous circulation (ROSC), survival to hospital admission, comorbid illnesses, and survival to hospital discharge were noted. A univariate odds ratio (OR) was first computed to describe the association between the type of airway and survival to hospital discharge. A multivariable logistic regression analysis was performed, adjusting for rhythm, bystander CPR, and whether the arrest was witnessed. RESULTS: A cohort of 1,294 arrests was evaluated. A total of 1,027 (79.4%) received ETI, while 131 (10.1%) had BVM, 131 (10.1%) had either a Combitube or an esophageal obturator airway, and five (0.4%) had incomplete prehospital records. Fifty-five of 1,294 (4.3%) survived to hospital discharge; there were no survivors in the Combitube/esophageal obturator airway cohort. Even after multivariable adjustment for age, sex, site of arrest, bystander CPR, witnessed arrest, and rhythm on paramedic arrival, the OR for survival to hospital discharge for BVM versus ETI was 4.5 (95% confidence interval [CI] = 2.3 8.9; p<0.0001). CONCLUSIONS: In this cohort, when compared to BVM ventilation, advanced airway methods were associated with decreased survival to hospital discharge among adult nontraumatic OOHCA patients. PMID- 20836773 TI - Incremental benefit of 80-lead electrocardiogram body surface mapping over the 12 lead electrocardiogram in the detection of acute coronary syndromes in patients without ST-elevation myocardial infarction: Results from the Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT MI) trial. AB - BACKGROUND: The initial 12-lead (12L) electrocardiogram (ECG) has low sensitivity to detect myocardial infarction (MI) and acute coronary syndromes (ACS) in the emergency department (ED). Yet, early therapies in these patients have been shown to improve outcomes. OBJECTIVES: The Optimal Cardiovascular Diagnostic Evaluation Enabling Faster Treatment of Myocardial Infarction (OCCULT-MI) trial was a multicenter trial comparing a novel 80-lead mapping system (80L) to standard 12L ECG in patients with chest pain and presumed ACS. This secondary analysis analyzed the incremental value of the 80L over the 12L in the detection of high risk ECG abnormalities (ST-segment elevation or ST depression) in patients with MI and ACS, after eliminating all patients diagnosed with ST-elevation MI (STEMI) by 12L ECG. METHODS: Chest pain patients presenting to one of 12 academic EDs were diagnosed and treated according to the standard care of that site and its clinicians; the clinicians were blinded to 80L results. MI was defined by discharge diagnosis of non-ST-elevation MI (NSTEMI) or unstable angina (UA) with an elevated troponin. ACS was defined as discharge diagnosis of NSTEMI or UA with at least one positive test result (troponin, stress test, angiogram) or revascularization procedure. RESULTS: Of the 1,830 patients enrolled in the trial, 91 patients with physician-diagnosed STEMI and 225 patients with missing 80L or 12L data were eliminated from the analysis; no discharge diagnosis was available for one additional patient. Of the remaining 1,513 patients, 408 had ACS, 206 had MI, and one had missing status. The sensitivity of the 80L was significantly higher than that of the 12L for detecting MI (19.4% vs. 10.4%, p = 0.0014) and ACS (12.3% vs. 7.1%, p = 0.0025). Specificities remained high for both tests, but were somewhat lower for 80L than for 12L for detecting both MI and ACS. Negative and positive likelihood ratios (LR) were not statistically different between groups. In patients with severe disease (defined by stenosis > 70% at catheterization, percutaneous coronary intervention, coronary artery bypass graft, or death from any cause), the 80L had significantly higher sensitivity for detecting MI (with equivalent specificity), but not ACS. CONCLUSIONS: Among patients without ST elevation on the 12L ECG, the 80L body surface mapping technology detects more patients with MI or ACS than the 12L, while maintaining a high degree of specificity. PMID- 20836774 TI - Quality of care for acute myocardial infarction in 58 U.S. emergency departments. AB - OBJECTIVES: The objectives of this study were to determine concordance of emergency department (ED) management of acute myocardial infarction (AMI) with guideline recommendations and to identify ED and patient characteristics predictive of higher guideline concordance. METHODS: The authors conducted a chart review study of ED AMI care as part of the National Emergency Department Safety Study (NEDSS). Using a primary hospital discharge diagnosis of AMI (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], codes 410.XX), a random sample of ED visits for AMI in 58 urban EDs across 20 U.S. states between 2003 and 2006 were identified. Concordance with American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations was evaluated using five individual quality measures and a composite concordance score. Concordance scores were calculated as the percentage of eligible patients who received guidelines-recommended care. These percentage scores were rescaled from 0 to 100, with 100 indicating perfect concordance. RESULTS: The cohort consisted of 3,819 subjects; their median age was 65 years, and 62% were men. The mean (+/- standard deviation [SD]) ED composite concordance score was 61 +/- 8), with a broad range of values (42 to 84). Except for aspirin use (mean concordance, 82), ED concordance scores were low (beta-blocker use, 56; timely electrocardiogram [ECG], 41; timely fibrinolytic therapy, 26; timely ED disposition for primary percutaneous coronary intervention [PCI] candidates, 43). In multivariable analyses, older age (beta-coefficient per 10-year increase, 1.5; 95% confidence interval [CI] = -2.4 to -0.5) and southern EDs (beta coefficient, -5.2; 95% CI = -9.6 to -0.9) were associated with lower guideline concordance, whereas ST-segment elevation on initial ED ECG was associated with higher guideline concordance (beta-coefficient, 3.6; 95% CI = 1.5 to 5.7). CONCLUSIONS: Overall ED concordance with guideline-recommended processes of care was low to moderate. Emergency physicians should continue to work with other stakeholders in AMI care, such as emergency medical services (EMS) and cardiologists, to develop strategies to improve care processes. PMID- 20836775 TI - Reducing ambulance response times using geospatial-time analysis of ambulance deployment. AB - OBJECTIVES: This study aimed to determine if a deployment strategy based on geospatial-time analysis is able to reduce ambulance response times for out-of hospital cardiac arrests (OOHCA) in an urban emergency medical services (EMS) system. METHODS: An observational prospective study examining geographic locations of all OOHCA in Singapore was conducted. Locations of cardiac arrests were spot-mapped using a geographic information system (GIS). A progressive strategy of satellite ambulance deployment was implemented, increasing ambulance bases from 17 to 32 locations. Variation in ambulance deployment according to demand, based on time of day, was also implemented. The total number of ambulances and crews remained constant over the study period. The main outcome measure was ambulance response times. RESULTS: From October 1, 2001, to October 14, 2004, a total of 2,428 OOHCA patients were enrolled into the study. Mean +/- SD age for arrests was 60.6 +/- 19.3 years with 68.0% male. The overall return of spontaneous circulation (ROSC) rate was 17.2% and survival to discharge rate was 1.6%. Response time decreased significantly as the number of fire stations/fire posts increased (Pearson chi(2) = 108.70, df = 48, p < 0.001). Response times for OOHCA decreased from a monthly median of 10.1 minutes at the beginning to 7.1 minutes at the end of the study. Similarly, the proportion of cases with response times < 8 minutes increased from 22.3% to 47.3% and < 11 minutes from 57.6% to 77.5% at the end of the study. CONCLUSIONS: A simple, relatively low-cost ambulance deployment strategy was associated with significantly reduced response times for OOHCA. Geospatial-time analysis can be a useful tool for EMS providers. PMID- 20836777 TI - Sequential analysis of pretreatment delays in stroke thrombolysis. AB - OBJECTIVES: The aim was to determine if an intensive restructuring of the approach to acute stroke improved time to thrombolysis over a 3-year study period and to determine whether delay modifications correlated with increased thrombolytic intervention or functional outcome. METHODS: The study examined the pretreatment process to define specific time intervals (delays) of interest in the acute management of 289 consecutive ischemic stroke patients who were transported by the emergency medical services (EMS) and received intravenous (IV) thrombolytic therapy in the emergency department (ED) of Helsinki University Central Hospital. Time interval changes of the 3-year period and use of thrombolytics was measured. Functional outcome, measured with the modified Rankin Scale (mRS) at 3 months, was assessed with multivariable statistical analysis. RESULTS: During implementation of the restructuring program from 2003 to 2005, the median total time delay from symptom onset to drug administration dropped from 149 to 112 minutes (p < 0.0001). Prehospital delays did not change significantly during the study period. The median delay in calling an ambulance remained at 13 minutes, and the total median prehospital delay stayed at 71 minutes. In-hospital delays decreased from 67 to 34 minutes (p < 0.0001). The median call delay was 25 minutes in patients with mild symptoms (National Institute of Health Stroke Scale [NIHSS] score < 7) and 8 minutes with severe symptoms (NIHSS > 15). In the multivariate model, stroke severity (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.78 to 0.88, p < 0.0001), age (OR = 0.57, 95% CI = 0.42 to 0.77, p < 0.0001), and in-hospital delay (OR = 0.47, 95% CI = 0.22 to 0.97, p = 0.04) were suggesting a good outcome. CONCLUSIONS: Restructuring of the teamwork between the EMS personnel and the reorganized ED significantly reduced in-hospital, but not prehospital, delays. The present data suggest that a decreased in-hospital delay improves the accessibility of the benefits of thrombolysis. PMID- 20836776 TI - Factors related to missed diagnosis of incidental scabies infestations in patients admitted through the emergency department to inpatient services. AB - OBJECTIVES: Scabies is highly contagious and requires prompt diagnosis and implementation of infection control measures to prevent transmission and outbreaks. This study investigated the clinical and administrative correlates associated with missed diagnosis of scabies in an emergency department (ED). METHODS: This was a retrospective study of patients with incidental scabies infestations who were admitted to a university hospital via the ED during a 4 year period. RESULTS: A total of 135 inpatients were identified as having scabies; among them, 111 patients (82%) had visited the ED. Scabies were diagnosed during the ED stay in 39 of 111 patients (35%), while the diagnosis was missed in the ED in 72 patients (65%). Although no geographic clusters suggestive of nosocomial scabies transmission were registered, 160 medical workers and one hospitalized patient received prophylactic treatment due to direct skin-to-skin contact with inpatient scabies cases during the study period. Overcrowding (odds ratio [OR] = 8.4; 95% confidence interval [CI] = 1.9 to 38.0) and time constraints (OR = 8.2; 95% CI = 1.9 to 34.7) in the ED were associated with a missed diagnosis of scabies during ED stay. Patients with lower illness severity scores were at higher risk for failure to diagnose and to treat scabies prior to hospital admission (OR = 5.7; 95% CI = 1.6 to 20.9). CONCLUSIONS: Missed diagnoses of scabies during ED stay may result in nosocomial spread and increase the unnecessary use of prophylactic treatments. ED overcrowding, time constraints, and less severe illness compromise ED recognition of scabies. Health care workers should be especially alert for signs of scabies infestations under these conditions. PMID- 20836778 TI - From model to forecasting: a multicenter study in emergency departments. AB - OBJECTIVES: This study investigated whether mathematical models using calendar variables could identify the determinants of emergency department (ED) census over time in geographically close EDs and assessed the performance of long-term forecasts. METHODS: Daily visits in four EDs at academic hospitals in the Paris area were collected from 2004 to 2007. First, a general linear model (GLM) based on calendar variables was used to assess two consecutive periods of 2 years each to create and test the mathematical models. Second, 2007 ED attendance was forecasted, based on a training set of data from 2004 to 2006. These analyses were performed on data sets from each individual ED and in a virtual mega ED, grouping all of the visits. Models and forecast accuracy were evaluated by mean absolute percentage error (MAPE). RESULTS: The authors recorded 299,743 and 322,510 ED visits for the two periods, 2004-2005 and 2006-2007, respectively. The models accounted for up to 50% of the variations with a MAPE less than 10%. Visit patterns according to weekdays and holidays were different from one hospital to another, without seasonality. Influential factors changed over time within one ED, reducing the accuracy of forecasts. Forecasts led to a MAPE of 5.3% for the four EDs together and from 8.1% to 17.0% for each hospital. CONCLUSIONS: Unexpectedly, in geographically close EDs over short periods of time, calendar determinants of attendance were different. In our setting, models and forecasts are more valuable to predict the combined ED attendance of several hospitals. In similar settings where resources are shared between facilities, these mathematical models could be a valuable tool to anticipate staff needs and site allocation. PMID- 20836779 TI - Comparison of outcomes of two skills-teaching methods on lay-rescuers' acquisition of infant basic life support skills. AB - OBJECTIVES: The objective was to determine if lay-rescuers' acquisition of infant basic life support (BLS) skills would be better when skills teaching consisted of videotaping practice and providing feedback on performances, compared to conventional skills-teaching and feedback methods. METHODS: This pilot exploratory, single-blind, prospective, controlled, randomized study was conducted on November 12, 2007, at the Rappaport Faculty of Medicine, Technion Israel Institute of Technology, Haifa, Israel. The population under study consisted of all first-year medical students enrolled in the 2007-2008 year. BLS training is part of their mandatory introductory course in emergency medicine. Twenty-three students with previous BLS training were excluded. The remaining 71 were randomized into four and then two groups, with final allocation to an intervention and control group of 18 and 16 students, respectively. All the students participated in infant BLS classroom teaching. Those in the intervention group practiced skills acquisition independently, and four were videotaped while practicing. Tapes were reviewed by the group and feedback was provided. Controls practiced using conventional teaching and feedback methods. After 3 hours, all subjects were videotaped performing an unassisted, lone-rescuer, infant BLS resuscitation scenario. A skills assessment tool was developed. It consisted of 25 checklist items, grouped into four sections: 6 points for "categories" (with specific actions in six categories), 14 points for "scoring" (of accuracy of performance of each action), 4 points for "sequence" (of actions within a category), and 1 point for "order" of resuscitation (complete and well-sequenced categories). Two blinded expert raters were given a workshop on the use of the scoring tool. They further refined it to increase scoring consistency. The main outcome of the study was defined as evidence of better skills acquisition in overall skills in the four sections and in the specific skills sets for actions in any individual category. Data analysis consisted of descriptive statistics. RESULTS: Means and mean percentages were greater in the intervention group in all four sections compared to controls: categories (5.72 [95.33%] and 4.69 [92.66%]), scoring (10.57 [75.50%] and 7.41 [43.59%]), sequence (2.28 [57.00%] and 1.66 [41.50%]), and order of resuscitation (0.96 [96.00%] and 0.19 [19.00%]). The means and mean percentages of the actions (skill sets) in the intervention group were also larger than those of controls in five out of six categories: assessing responsiveness (1.69 [84.50%] and 1.13 [56.50%]), breathing technique (1.69 [93.00%] and 1.13 [47.20%]), chest compression technique (3.19 [77.50%] and 1.84 [46.00%]), activating emergency medical services (EMS) (3.00 [100.00%] and 2.81 [84.50%]), and resuming cardiopulmonary resuscitation (0.97 [97.00%] and 0.47 [47.00%]). These results demonstrate better performance in the intervention group. CONCLUSIONS: The use of videotaped practice and feedback for the acquisition of overall infant BLS skills and of specific skill sets is effective. Observation and participation in the feedback and assessment of nonexperts attempting infant BLS skills appeared to improve the ability of this group of students to perform the task. PMID- 20836780 TI - Out-of-hospital endotracheal intubation: Are observational data useful? PMID- 20836781 TI - Procedural versus practical ethics. PMID- 20836782 TI - What are the unintended consequences of changing the diagnostic paradigm for subarachnoid hemorrhage after brain computed tomography to computed tomographic angiography in place of lumbar puncture? PMID- 20836784 TI - The future of emergency medicine. PMID- 20836785 TI - Duty hours in emergency medicine: balancing patient safety, resident wellness, and the resident training experience: a consensus response to the 2008 institute of medicine resident duty hours recommendations. AB - Representatives of emergency medicine (EM) were asked to develop a consensus report that provided a review of the past and potential future effects of duty hour requirements for EM residency training. In addition to the restrictions made in 2003 by the Accreditation Council for Graduate Medical Education (ACGME), the potential effects of the 2008 Institute of Medicine (IOM) report on resident duty hours were postulated. The elements highlighted include patient safety, resident wellness, and the resident training experience. Many of the changes and recommendations did not affect EM as significantly as other specialties. Current training standards in EM have already emphasized patient safety by requiring continuous on-site supervision of residents. Resident fatigue has been addressed with restrictions of shift lengths and limitation of consecutive days worked. One recommendation from the IOM was a required 5-hour rest period for residents on call. Emergency department (ED) patient safety becomes an important concern with the decrease in the availability and in the patient load of a resident consultant that may result from this recommendation. Of greater concern is the already observed slower throughput time for admitted patients waiting for resident care, which will increase ED crowding and decrease patient safety in academic institutions. A balance between being overly prescriptive with duty hour restrictions and trying to improve resident wellness was recommended. Discussion is included regarding the appropriate length of EM training programs if clinical experiences were limited by new duty hour regulations. Finally, this report presents a review of the financing issues associated with any changes. PMID- 20836786 TI - Why bystanders decline telephone cardiac resuscitation advice. AB - OBJECTIVES: The aim of this study was to evaluate the rate and reason for refusal of telephone-based cardiopulmonary resuscitation (CPR) instruction by bystanders after the implementation of the dispatch center's systematic telephone CPR protocol. METHODS: Over a 15-month period the authors prospectively collected all case records from the emergency medical services (EMS) dispatch center when CPR had been proposed to the bystander calling in and recorded the reason for declining or not performing that the bystander spontaneously mentioned. All pediatric and adult traumatic and nontraumatic cases were included. Situations when resuscitation had been spontaneously initiated by bystanders were excluded. RESULTS: During the study period, dispatchers proposed CPR on 264 occasions: 232 adult nontraumatic cases, 17 adult traumatic cases, and 15 pediatric (traumatic and nontraumatic) cases. The proposal was accepted in 163 cases (61.7%, 95% confidence interval [CI] = 54.6% to 66.5%), and CPR was eventually performed in 134 cases (51%, 95% CI = 43.2% to 55.3%). In 35 of the cases where resuscitation was not carried out, the condition of the patient or conditions at the scene made this decision medically appropriate. Of the remaining 95 cases, 55 were due to physical limitations of the caller, and 33 were due to emotional distress. CONCLUSIONS: The telephone CPR acceptance rate of 62% in this study is comparable to those of other similar studies. Because bystanders' physical condition is one of the keys to success, the rate may not improve as the population ages. PMID- 20836787 TI - Prospective evaluation of real-time use of the pulmonary embolism rule-out criteria in an academic emergency department. AB - OBJECTIVES: The pulmonary embolism rule-out criteria (PERC rule) is a nine component decision rule derived to exclude pulmonary embolism (PE) without the use of formal diagnostic testing (D-dimer, computed tomography pulmonary angiography, ventilation-perfusion lung scanning, or venous ultrasonography) when all nine components are negative ("PERC negative"). This study examined whether clinicians who document PERC negative also document results of all nine components of the PERC rule. METHODS: This was a pilot study at a single-center, urban teaching emergency department (ED) with a residency program in emergency medicine. Patients were over 17 years of age with at least one of nine predefined chief complaints. Clinicians were asked three questions regarding suspicion for PE, intent to use the PERC rule, and the result. Charts were independently reviewed by two authors for fidelity of the nine PERC components. Patients were followed for PE outcome at 14 days. RESULTS: The study examined 526 patients cared for by 82 clinicians, who indicated suspicion for PE in 183 of 526 (35%) and intent to use the PERC rule in 115 of 526 (22%) cases, of whom 65 of 115 were documented as PERC negative. No formal test for PE was ordered in 49 of 65 (75%), and 46 of 49 had incomplete documentation to support PERC negative. The most common deficiency was omission of two risk factors for PE in the rule (prior venous thromboembolism or recent surgery). Six patients had PE diagnosed within 14 days, but none of these had been deemed PERC negative. CONCLUSIONS: Clinicians seldom document all nine data elements of the PERC rule in patients they deem PERC negative. These data suggest the need for paper or electronic aids to support use of the PERC rule. PMID- 20836788 TI - A randomized, double-blind, sham-controlled trial comparing two screening devices for radiation contamination. AB - OBJECTIVES: This exploratory study compared the screening ability of a newly introduced radiation detection portal with a traditional Geiger counter for detection of radiation contamination in the setting of a mass casualty training exercise. METHODS: Following a pretrial evaluation of interobserver reliability for Geiger counter use, 30 volunteers were randomly assigned to don gowns containing three disks, each of which was either a sham resembling the radioactive samples or an actual cesium-137 sample; each subject participated a minimum of four times with different gowns each time. Each subject underwent standard radioactivity screening with the Geiger counter and the portal. RESULTS: Interobserver reliability was excellent between the two Geiger counter screeners in the pretrial exercise, correctly identifying 101 of 102 sham and radioactive samples (kappa = 0.98; 95% confidence interval [CI] = 0.94 to 1.00). For radioactively labeled subjects across all bodily locations, the portal (43/61, or 70.5%; 95% CI = 58.1% to 80.5%) was less sensitive than the Geiger counter screening (61/61, or 100%; 95% CI = 92.9% to 100%), which resulted in a portal false-negative rate of 29.5%. For radiation detection in the posterior thorax, the portal radiation screening (4/19, or 21.1%; 95% CI = 8% to 43.9%) was less accurate than the Geiger counter (19/19, or 100%; 95% CI 80.2% to 100%). In contrast, there were no major differences between the portal and the Geiger counter for radiation detection at the left shoulder, right shoulder, or sham (nonradiation) detection. There were no false-positive detections of the sham labeled subjects for either device, yielding a specificity of 100% for both screening modalities. CONCLUSIONS: Geiger counter screening was more sensitive than, and equally specific to, radiation detection portal screening in detecting radioactively labeled subjects during a radiation mass casualty drill. PMID- 20836789 TI - The learning curve of resident physicians using emergency ultrasonography for obstructive uropathy. AB - BACKGROUND: Given the time, expense, and radiation exposure associated with computed tomography (CT), ultrasonography (US) is considered an alternative imaging study that could expedite patient care in patients with suspected obstructive uropathy. However, there is a paucity of literature regarding bedside US for obstructive uropathy in the emergency department (ED), and it is unknown how much experience is required for competency in such exams. OBJECTIVES: The objective was to assess the learning curve for the detection of obstructive uropathy of resident physicians training in ED bedside US (EUS) during a dedicated EUS elective. METHODS: This was a prospective cohort study of residents participating in an EUS elective. Patients presenting with acute abdominal or flank pain suggestive of an obstructive uropathy were enrolled and underwent EUS prior to noncontrast CT. Physicians who had previously performed at least 10 EUS exams for obstructive uropathy recorded results on a standardized data sheet, which was subsequently compared to the results of noncontrast CT read by board certified radiologists blinded to the results of the EUS. In addition to an unadjusted chi-square test for trend, a multivariable logistic regression analysis, adjusting for stone size and operator, was performed. Finally, generalized estimating equations were used to describe test characteristics while accounting for potential clustering between exams by operator. RESULTS: Twenty three resident physicians participated and enrolled a convenience sample of 393 patients. A total of 157 patients (40%) were diagnosed with an obstructing ureterolith, and three (1%) were diagnosed with nonobstructing ureterolithiasis. An unadjusted chi-square test for trend demonstrated a statistically significant increase in both sensitivity (chi(2) = 11.4, p = 0.02) and specificity (chi(2) = 6.4, p = 0.04) for each level of increase in number of exams. On multivariable regression analysis, when adjusting for size of stone and operator, for every five additional exams after the first 10 EUS exams, the odds ratio for a true positive for obstruction increased by 1.7 (95% confidence interval [CI] = 1.2 to 2.5, p = 0.003). After accounting for clustering of exams by operator, overall EUS sensitivity and specificity for obstructive uropathy were 82% (95% CI = 77% to 87%) and 88% (95% CI = 85% to 92%). Stratifying by number of exams, the sensitivity was 72% (95% CI = 62% to 80%) for the 11th through 20th exams, 90% (95% CI = 83% to 96%) for the 21st through 30th exams, and 95% (95% CI = 91% to 99%) for the 31st through 43rd exams. Likewise, specificity was 82% (95% CI = 75% to 89%) for the 11th through 20th exams, 90% (95% CI = 85% to 95%) for the 21st through 30th exams, and 92% (95% CI = 86% to 98%) for the 31st through 50th exams. CONCLUSIONS: Physicians training in EUS may be able to accurately assess for obstructive uropathy after 30 exams. PMID- 20836790 TI - With no shelf exam available, SAEM online clerkship testing tool best option. PMID- 20836792 TI - Effectiveness of corticosteroid treatment in acute pharyngitis: a systemic review of the literature. PMID- 20836793 TI - An epidemiological analysis of severe cases of the influenza A (H1N1) 2009 virus infection in Japan. AB - BACKGROUND: The age distribution of confirmed cases with influenza A (H1N1) 2009 has shifted toward children and young adults, in contrast to interpandemic influenza, because of the age specificities in immunological reactions and transmission characteristics. OBJECTIVES: Descriptive epidemiological analysis of severe cases in Japan was carried out to characterize the pandemic's impact and clinical features. METHODS: First, demographic characteristics of hospitalized cases (n = 12,923), severe cases (n = 894) and fatal cases (n = 116) were examined. Second, individual records of the first 120 severe cases, including 23 deaths, were analyzed to examine potential associations of influenza death with demographic variables, medical treatment and underlying conditions. Among severe cases, we compared proportions of specific characteristics of survivors with those of fatal cases to identify predictors of death. RESULTS: Age distribution of hospitalized cases shifted toward those aged <20 years; this was also the case for deaths without underlying medical conditions. Deaths in adults were mainly seen among those with underlying medical conditions, resulting in an increased risk of death as a function of age. According to individual records, the time from onset to death in Japan appeared rather short compared with that in other countries. CONCLUSION: The age specificity of severe cases and their underlying medical conditions were consistent with other countries. To identify predictors of death in influenza A (H1N1) 2009 patients, more detailed clinical characteristics need to be examined according to different age groups and types of manifestations, which should ideally include mild cases as subjects. PMID- 20836794 TI - Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients. AB - BACKGROUND: First-line treatment of influenza A 2009 H1N1 relies on neuraminidase inhibitors such as oseltamivir. Resistance conferred by the H275Y neuraminidase gene mutation is concerning and likely to increase. OBJECTIVES: To characterize oseltamivir resistance in a hospital-based patient population. PATIENTS AND METHODS: All available respiratory specimens positive for influenza A by direct fluorescent antibody, RT-PCR, or culture from patients at the University of Utah 5/09-12/09 were collected. Specimens were confirmed as 2009 H1N1 by the Utah Department of Health. RT-PCR and pyrosequencing were used to test for the H275Y mutation (CDC protocol). PyroMark Q24 AQ software (Qiagen, Valencia, CA, USA) was used to allow for quantitative H275Y mutation analysis. Medical records of patients with resistant virus were reviewed. RESULTS: We tested 191 influenza A virus-positive samples from 187 unique patients. Fifty (27%) patients were hospitalized. Four patient specimens (2.1%) were found to carry the H275Y mutation. Three patients were hospitalized, representing 6% of inpatient samples tested. Three patients had undergone hematopoietic stem cell transplant in the past year. Two patients died. Their influenza viruses were confirmed to be oseltamivir-resistant at an independent reference laboratory and through the Center for Disease Control and Prevention (CDC). One patient reported no history of prior oseltamivir exposure. CONCLUSIONS: Widespread oseltamivir resistance among 2009 H1N1 remains a potential threat. Rapid techniques, such as pyrosequencing, which has the additional benefit of identifying mixed mutant populations of virus, may play a key role in identifying at-risk individuals and potentially unsuspected cases. Targeted surveillance of immunocompromised patients will be critical toward improving future influenza planning and therapy. PMID- 20836795 TI - Disproportional effects in populations of concern for pandemic influenza: insights from seasonal epidemics in Wisconsin, 1967-2004. AB - BACKGROUND: Influenza infections pose a serious burden of illness in the United States. We explored age, influenza strains, and seasonal epidemic curves in relation to influenza-associated mortality. METHODS: The state of Wisconsin death records for the years 1967-2004 were analyzed for three distinct populations: children, general population, and elderly. Yearly parameters of duration, intensity, and peak timing were obtained from Annual Harmonic Regression coefficients. RESULTS: Overall, elderly had the highest rate and intensity of influenza mortality. The children and infant subpopulations showed an earlier and wider range in duration of peak timing than elderly. During A/Hong Kong/1/68 pandemic years, the elderly subpopulation showed no change in mortality rates while a sharp increase was observed for the children and infant subpopulations. In epidemic years such as 1966-1969, children and infants showed a dramatic decrease in the severity of influenza outbreaks over time. The elderly had increased baseline mortality in years (1986-1987) where predominant strain was characterized as A/Singapore/6/86. CONCLUSIONS: Our findings indicate that the younger populations may have benefited from the lack of a major shift in viral strains for a number of decades. Furthermore, we demonstrate considerable heterogeneity in the spread of seasonal influenza across age categories, with implications both for the modeling of influenza seasonality, risk assessment, and effective distribution and timing of vaccine and prophylactic interventions. PMID- 20836796 TI - Pre-pandemic planning survey of healthcare workers at a tertiary care children's hospital: ethical and workforce issues. AB - BACKGROUND: Prior to the development of written policies and procedures for pandemic influenza, worker perceptions of ethical and workforce issues must be identified. OBJECTIVE: To determine the relationship between healthcare worker (HCW) reporting willingness to work during a pandemic and perception of job importance, belief that one will be asked to work, and sense of professionalism and to assess HCW's opinions regarding specific policy issues as well as barriers and motivators to work during a pandemic. METHODS: A survey was conducted in HCWs at The Children's Hospital in Denver, Colorado, from February to June 2007. Characteristics of workers reporting willingness to work during a pandemic were compared with those who were unwilling or unsure. Importance of barriers and motivators was compared by gender and willingness to work. RESULTS: Sixty percent of respondents reported willingness to work (overall response rate of 31%). Belief one will be asked to work (OR 4.6, P < 0.0001) and having a high level of professionalism (OR 8.6, P < 0.0001) were associated with reporting willingness to work. Hospital infrastructure support staffs were less likely to report willingness to work during a pandemic than clinical healthcare professionals (OR 0.39, P < 0.001). Concern for personal safety, concern for safety of family, family's concern for safety, and childcare issues were all important barriers to coming to work. CONCLUSIONS: Educational programs should focus on professional responsibility and the importance of staying home when ill. Targeted programs toward hospital infrastructure support and patient and family support staff stressing the essential nature of these jobs may improve willingness to work. PMID- 20836797 TI - Feasibility of elementary school children's use of hand gel and facemasks during influenza season. AB - BACKGROUND: The feasibility of non-pharmacologic interventions to prevent influenza's spread in schools is not well known. OBJECTIVES: To determine the acceptability of, adherence with, and barriers to the use of hand gel and facemasks in elementary schools. PATIENTS AND METHODS: INTERVENTION: We provided hand gel and facemasks to 20 teachers and their students over 4 weeks. Gel use was promoted for the first 2 weeks; mask use was promoted for the second 2 weeks. OUTCOMES: Acceptability, adherence, and barriers were measured by teachers' responses on weekly surveys. Mask use was also measured by observation. RESULTS: The weekly survey response rate ranged from 70% to 100%. Averaged over 2 weeks, 89% of teachers thought gel use was not disruptive (week 1--17/20, week 2- 16/17), 95% would use gel next winter (week 1--19/20, week 2--16/17), and 97% would use gel in a pandemic (week 1--20/20, week 2--16/17). Averaged over 2 weeks, 39% thought mask use was not disruptive (week 1--6/17, week 2--6/14), 35% would use masks next winter (week 1--5/17, week 2--6/14), and 97% would use masks in a pandemic (week 1--16/17, week 2--14/14). About 70% estimated that their students used hand gel >= 4 x/day for both weeks (week 1--14/20, week 2--13/17). Students' mask use declined over time with 59% of teachers (10/17) estimating regular mask use during week 1 and 29% (4/14) during week 2. By observation, 30% of students wore masks in week 1, while 15% wore masks in week 2. Few barriers to gel use were identified; barriers to mask use were difficulty reading facial expressions and physical discomfort. CONCLUSIONS: Hand gel use is a feasible strategy in elementary schools. Acceptability and adherence with facemasks was low, but some students and teachers did use facemasks for 2 weeks, and most teachers would use masks in their classroom in a pandemic. PMID- 20836798 TI - Epidemiology of influenza-like illness in the Amazon Basin of Peru, 2008-2009. AB - BACKGROUND: Data addressing the incidence and epidemiology of influenza and influenza-like illness (ILI) in tropical regions of the world is scarce, particularly for the neotropics of South America. METHODS: We conducted active, population-based surveillance for ILI across 45 city blocks within the Amazon Basin city of Iquitos, Peru. Demographic data and household characteristics were collected for all participants, and participating households were visited three times weekly to inquire about ILI (fever plus cough or sore throat) among household residents. Nasal and oropharyngeal swabs were collected from participants with ILI and tested for influenza virus infection. RESULTS: Between May 1, 2008 and July 8, 2009, we monitored 10,341 participants for ILI for a total of 11,569.5 person-years. We detected 459 ILI episodes, with 252 (54.9%) of the participants providing specimens. Age-adjusted incidence of ILI was estimated to be 46.7 episodes/1000 person-years. Influenza A and B viruses were detected in 25 (9.9%) and 62 (24.6%) specimens of ILI patients, respectively, for an estimated age-adjusted incidence rate of 16.5 symptomatic influenza virus infections/1000 person-years. Risk factors for ILI included age, household crowding, and use of wood as cooking fuel. For influenza virus infection specifically, age and use of wood as a cooking fuel were also identified as risk factors, but no effect of household crowding was observed. CONCLUSIONS: Our results represent the initial population-based description of the epidemiology of ILI in the Amazon region of Peru, which will be useful for developing region specific strategies for reducing the burden of respiratory disease. PMID- 20836800 TI - Efficacy of the botanical repellents geraniol, linalool, and citronella against mosquitoes. AB - We determined the degree of personal protection provided by citronella, linalool, and geraniol in the form of commercially available candles or diffusers, both indoors and outdoors. Under the uniform conditions of the experiments, all substances repelled significantly more mosquitoes than the unprotected control. Furthermore, the repellents tested were more active when in the form of a continuous release diffuser than in candle form. All candles were 88 g containing 5% of the active ingredient and all diffusers contained 20 g of 100% active ingredient. Indoors, the repellency rate of citronella candles was only 14% while the repellency rate of citronella diffusers was 68%. The repellency of geraniol candles was 50% while the diffusers provided a repellency rate of 97%. No linalool candles were available for study but linalool diffusers repelled mosquitoes by 93%. Outdoors, citronella diffusers placed 6 m from mosquito traps repelled female mosquitoes by 22%, linalool repelled females by 58%, and geraniol repelled females by 75%. Trap catches were significantly reduced again when diffusers were placed 3 m from the traps. We concluded that geraniol had significantly more repellent activity than citronella or linalool in both indoor and outdoor settings. PMID- 20836801 TI - Bayou virus detected in non-oryzomyine rodent hosts: an assessment of habitat composition, reservoir community structure, and marsh rice rat social dynamics. AB - In the United States, Bayou virus (BAYV) ranks second only to Sin Nombre virus (SNV) in terms of hantavirus pulmonary syndrome (HPS) incidents, having been confirmed in cases from Texas and Louisiana since its discovery in 1994. This study on BAYV infection among sympatric, non-oryzomyine rodents ("spillover") in Freeport, TX, is the first to link patterns of hantavirus interspecific spillover with the spatiotemporal ecology of the primary host (marsh rice rat, Oryzomys palustris). Mark-recapture and/or harvest methods were employed from March 2002 through May 2004 in two macrohabitat types. Rodent blood samples were screened for the presence of IgG antibody to BAYV antigen by IFA after which Ab-positive blood, saliva, and urine were analyzed for the presence of viral RNA by nested RT PCR. From 727 non-oryzomyine captures, five seropositive (but not viral RNA positive) individuals were detected: one each of Baiomys taylori, Peromyscus leucopus, and Reithrodontomys fulvescens; and two Sigmodon hispidus. Spillover hosts were not associated with macrohabitat where O. palustris abundance, density, or seroprevalence was highest. Rather, spillover occurred in the macrohabitat indicative of greater overall disturbance (as indicated by grazing and exotic plant diversity) and overall biodiversity. Spillover occurred during periods of high seroprevalence detected elsewhere within the study region. Spillover locations differed significantly from all other capture locations in terms of percent water, shrub, and grass cover. Although greater habitat and mammal diversity of old-fields may serve to reduce seroprevalence levels by tempering intraspecific contacts between rice rats, greater diversity also may create an ecologically opportunistic setting for BAYV spillover. Impacts of varying levels of disturbance and biodiversity on transmission dynamics represent a vastly uncharacterized component of the evolutionary ecology of hantaviruses. PMID- 20836802 TI - Colorado animal-based plague surveillance systems: relationships between targeted animal species and prediction efficacy of areas at risk for humans. AB - Human plague risks (Yersinia pestis infection) are greatest when epizootics cause high mortality among this bacterium's natural rodent hosts. Therefore, health departments in plague-endemic areas commonly establish animal-based surveillance programs to monitor Y. pestis infection among plague hosts and vectors. The primary objectives of our study were to determine whether passive animal-based plague surveillance samples collected in Colorado from 1991 to 2005 were sampled from high human plague risk areas and whether these samples provided information useful for predicting human plague case locations. By comparing locations of plague-positive animal samples with a previously constructed GIS-based plague risk model, we determined that the majority of plague-positive Gunnison's prairie dogs (100%) and non-prairie dog sciurids (85.82%), and moderately high percentages of sigmodontine rodents (71.4%), domestic cats (69.3%), coyotes (62.9%), and domestic dogs (62.5%) were recovered within 1 km of the nearest area posing high peridomestic risk to humans. In contrast, the majority of white tailed prairie dog (66.7%), leporid (cottontailed and jack rabbits) (71.4%), and black-tailed prairie dog (93.0%) samples originated more than 1 km from the nearest human risk habitat. Plague-positive animals or their fleas were rarely (one of 19 cases) collected within 2 km of a case exposure site during the 24 months preceding the dates of illness onset for these cases. Low spatial accuracy for identifying epizootic activity prior to human plague cases suggested that other mammalian species or their fleas are likely more important sources of human infection in high plague risk areas. To address this issue, epidemiological observations and multi-locus variable number tandem repeat analyses (MLVA) were used to preliminarily identify chipmunks as an under-sampled, but potentially important, species for human plague risk in Colorado. PMID- 20836803 TI - Effect of different larval rearing temperatures on the productivity (R o) and morphology of the malaria vector Anopheles superpictus Grassi (Diptera: Culicidae) using geometric morphometrics. AB - Temperature affects both the biology and morphology of mosquito vectors. Geometric morphometrics is a useful new tool for capturing and analyzing differences in shape and size in many morphological parameters, including wings. We have used this technique for capturing the differences in the wings of the malaria vector Anopheles superpictus, using cohorts reared at six different constant temperatures (15 degrees , 20 degrees , 25 degrees , 27 degrees , 30 degrees , and 35 degrees C) and also searched for potential correlations with the life tables of the species. We studied wing shape in both male and female adults, using 22 landmarks on the wing in relation to ecological parameters, including the development rate. The ecological zero was calculated as 9.93 degrees C and the thermal constant as 296.34 day-degrees. The rearing temperature affects egg, larval, and pupal development and also the total time from egg to adult. As rearing temperatures increased, longevity decreased in both sexes. In An. superpictus, R(o) value and productivity correlated with the statistically significant gradual deformations in the wing shape related to size in both sexes. These deformations directly linked to differences in immature rearing temperatures. Analysis using PCA and UPGMA phenograms showed that although wings of females became narrower dorsoventrally as the temperature increased, they became broader in males. Comparisons of the wing landmarks indicated the medial part of the wing was most affected by larval rearing temperatures, showing relatively more deformations. Algorithmic values of the life tables were determined in correlation with the results of geometric morphometrics. Comparisons of centroid sizes in the cohorts showed that overall wing size became smaller in both sexes in response to higher rearing temperatures. PMID- 20836804 TI - Genetic structure among Thai populations of Aedes aegypti mosquitoes. AB - Thirty-one field populations of Aedes aegypti (L.) were compared using isozyme starch gel electrophoresis to characterize genetic variation between populations. Ae. aegypti were collected from seven provinces in Thailand. Thirty-one isozyme encoding loci, including 19 polymorphic loci, were characterized. Only small levels of genetic differentiation were observed among the 31 district populations in the seven provinces. Isolation by distance among populations from the seven provinces showed no correlation between genetic variation and geographical distance. PMID- 20836805 TI - The role of the United States military in the development of vector control products, including insect repellents, insecticides, and bed nets. AB - Arthropod-borne diseases such as malaria, dengue, scrub typhus, and leishmaniasis continue to pose a significant threat to U.S. military forces deployed in support of operational and humanitarian missions. These diseases are transmitted by a variety of arthropods, including mosquitoes, ticks, chiggers, sand flies, and biting midges. In addition to disease threats, biting arthropods can cause dermatitis, allergic reactions, and sleep loss; therefore, monitoring of vector impact and integrated use of personal protective measures (PPM) and methods to reduce the vector populations are needed to protect service members. The U.S. military has played a vital role in vector identification tools and the development and testing of many of the most effective PPM and vector control products available today, including the topical repellent DEET and the repellent/insecticide permethrin, which is applied to clothing and bed nets. Efforts to develop superior products are ongoing. Although the U.S. military often needs vector control products with rather specific properties (e.g., undetectable, long-lasting in multiple climates) in order to protect its service members, many Department of Defense vector control products have had global impacts on endemic disease control. PMID- 20836806 TI - Biting activity and host preference of the malaria vectors Anopheles maculatus and Anopheles sawadwongporni (Diptera: Culicidae) in Thailand. AB - Adult mosquitoes in the Anopheles maculatus group were surveyed from different regions of Thailand and five different species were morphologically identified, including Anopheles maculatus, Anopheles sawadwongporni, Anopheles notanandai, Anopheles dravidicus, and Anopheles willmori. Blood-feeding activity and host preference of two species, Anopheles maculatus and Anopheles sawadwongporni, were observed during a one-year period at Pu Teuy Village, Sai Yok District, Kanchanaburi Province, west-central Thailand. Both species were more prevalent during the wetter period of the year and each had a greater predilection to feed on cattle than humans. Primary feeding activity occurred between 20:00-23:00 and a smaller peak at 01:00-03:00. Findings are discussed relative to the importance of these two vectors for malaria transmission in Pu Teuy. PMID- 20836807 TI - The mosquitoes of eastern Tennessee: studies on abundance, habitat preferences, and host-seeking behaviors. AB - A significant increase in the number of reported cases of La Crosse virus (LACV) infections in eastern Tennessee has occurred in the last ten years. The objective of this study was to determine the abundance and habitat preferences of the potential vectors of LACV in this region. Adult host-seeking mosquitoes were collected using CO(2)-baited CDC light traps and a series of human-landing catches in eastern Tennessee from 2004 to 2006. A total of 4,200 female mosquitoes of 23 species was collected by CO(2)-baited CDC trapping at ten sites during the study period. Aedes albopictus (Skuse) was the most abundant mosquito collected at all sites and vegetation types, with the ratios of total Ae. albopictus to Ae. triseriatus (Say) females collected being 2.1:1 in 2004, 3.8:1 in 2005, and 4.9:1 in 2006. Ten species were collected during a series of human landing catches made at four different sites; one probable and three confirmed case sites of LACV infections, totaling 528 female mosquitoes. Aedes albopictus was the most abundant species collected, with a 4:1 ratio of Ae. albopictus to Ae. triseriatus females. Aedes albopictus exhibited two clear peaks of "landing" activity, one in the early morning and one in the late afternoon or early evening. Simple and multiple regression analyses of the predictors of the number of mosquitoes collected showed that populations of Ae. albopictus were three times more likely to be collected overall than Ae. triseriatus. Species (Ae. albopictus), vegetation (residential), and the previous cumulative precipitation for the four weeks prior to collection were significantly (P < 0.05) associated with the number of mosquitoes collected by CO(2)-baited CDC trapping. Aedes albopictus was also more likely to be collected than Ae. triseriatus at confirmed cases of LACV infections. PMID- 20836808 TI - Field efficacy of rodent bait containing the systemic insecticide imidacloprid against the fleas of California ground squirrels. AB - The efficacy of rodent bait containing the insecticide imidacloprid was evaluated for controlling fleas on the California ground squirrel, Spermophilus beecheyi. The bait was designed to deliver an oral dose of insecticide resulting in flea mortality when obtaining a blood meal. During the five-week trial, performed at Vandenberg Air Force Base, Santa Barbara County, CA, a spot-baiting technique was used to apply bait to ground squirrel burrows. Bait was applied six times throughout the trial. Results indicated that the use of a host-targeted bait was effective in significantly reducing the flea burden on S. beecheyi. Efficacy at reducing flea abundance was near 100% at both day 15 and day 29 of the trial. Use of the bait also reduced the prevalence of flea-infested S. beecheyi. Our results indicate that the use of rodent bait containing insecticide could provide an effective, economical method of controlling the fleas of S. beecheyi, the primary vectors of human plague in California. PMID- 20836809 TI - Evaluation of commercial and field-expedient baited traps for house flies, Musca domestica L. (Diptera: Muscidae). AB - A comparison of nine commercial baited fly traps on Florida dairy farms demonstrated that Terminator traps collected significantly more (13,323/trap) house flies (Musca domestica L.) than the others tested. Final Flight, Fly Magnet, and FliesBeGone traps collected intermediate numbers of flies (834 2,166), and relatively few were caught with ISCA, Advantage, Fermone Big Boy, Squeeze & Snap, or OakStump traps (<300). Terminator traps collected about twice as many flies (799.8/trap) as FliesBeGone traps (343.8) when each trap was baited with its respective attractant, but when the attractants were switched between the two trap types, collections were significantly lower (77-108) than was observed with traps baited with their respective attractant. Solutions of molasses were significantly more attractive to house flies than honey, maple syrup, or jaggery (date palm sugar). Field-expedient traps constructed from discarded PET water bottles were much less effective than commercial traps, but painting the tops of such traps with black spray paint resulted in a six-fold increase in trap capture. PMID- 20836810 TI - Microhabitat characteristics of Akodon montensis, a reservoir for hantavirus, and hantaviral seroprevalence in an Atlantic forest site in eastern Paraguay. AB - Hantaviruses may cause serious disease when transmitted to humans by their rodent hosts. Since their emergence in the Americas in 1993, there have been extensive efforts to understand the role of environmental factors on the presence of these viruses in their host rodent populations. HPS outbreaks have been linked to precipitation, but climatic factors alone have not been sufficient to predict the spatial-temporal dynamics of the environment-reservoir-virus system. Using a series of mark-recapture sampling sites located at the Mbaracayu Biosphere Reserve, an Atlantic Forest site in eastern Paraguay, we investigated the hypothesis that microhabitat might also influence the prevalence of Jabora hantavirus within populations of its reservoir species, Akodon montensis. Seven trapping sessions were conducted during 2005-2006 at four sites chosen to capture variable microhabitat conditions within the study site. Analysis of microhabitat preferences showed that A. montensis preferred areas with little forest overstory and denser vegetation cover on and near the ground. Moreover, there was a significant difference in the microhabitat occupied by antibody-positive vs antibody-negative rodents, indicating that microhabitats with greater overstory cover may promote transmission and maintenance of hantavirus in A. montensis. PMID- 20836811 TI - Comparative efficacy of three suction traps for collecting phlebotomine sand flies (Diptera: Psychodidae) in open habitats. AB - The efficacy of three suction traps for trapping phlebotomine sand flies (Diptera: Psychodidae) was compared. Traps were baited with Co(2) and used without any light source. CO(2)-baited CDC traps were evaluated either in their standard downdraft orientation or inverted (iCDC traps). Mosquito Magnet-X (MMX) counterflow geometry traps were tested in the updraft orientation only. Both updraft traps (iCDC and MMX) were deployed with their opening ~10 cm from the ground while the opening of the downdraft (CDC) trap was ~40 cm above ground. Comparisons were conducted in two arid locations where different sand fly species prevail. In the Jordan Valley, 3,367 sand flies were caught, 2,370 of which were females. The predominant species was Phlebotomus (Phlebotomus) papatasi, Scopoli 1786 (>99%). The updraft-type traps iCDC and MMX caught an average of 118 and 67.1 sand flies per trap night, respectively. The CDC trap caught 32.9 sand flies on average per night, significantly less than the iCDC traps. In the Judean desert, traps were arranged in a 3 * 3 Latin square design. A total of 565 sand flies were caught, 345 of which were females. The predominant species was P. (Paraphlebotomus) sergenti Parrot 1917 (87%). The updraft traps iCDC and MMX caught an average of 25.6 and 17.9 sand flies per trap per night, respectively. The CDC trap caught 7.8 sand flies on average per night, significantly less than the iCDC traps. The female to male ratio was 1.7 on average for all trap types. In conclusion, updraft traps deployed with their opening close to the ground are clearly more effective for trapping sand flies than downdraft CDC traps in open habitats. PMID- 20836812 TI - Climate and geographic trends in hatch delay of the treehole mosquito, Aedes triseriatus Say (Diptera: Culicidae). AB - Eggs of Aedes triseriatus mosquitoes are stimulated to hatch when inundated with water, but only a small fraction of eggs from the same batch will hatch for any given stimulus. Similar hatching or germination patterns are observed in desert plants, copepods, rotifers, insects, and many other species. Bet hedging theory suggests that parents stagger offspring emergence into vulnerable life history stages in order to avoid catastrophic reproductive failures. For Ae. triseriatus, a treehole breeding mosquito, immediate hatching of an entire clutch leaves all of the parent's progeny vulnerable to extinction in the event of a severe drought. Natural selection has likely favored parents that pursued a bet hedging strategy where the risk of reproductive failure is distributed over time. Considering treehole mosquitoes, bet hedging theory could be used to predict that hatch delay would be positively correlated with the likelihood of drought. To test this prediction, we collected Ae. triseriatus from habitats that varied widely in mean annual precipitation and exposed them to several hatch stimuli in the laboratory. Here we report that, as predicted, Ae. triseriatus eggs from high precipitation regions showed less hatch delay than areas of low precipitation. This strategy probably allows Ae. triseriatus to cope with the wide variety of climatic conditions that it faces in its extensive geographical range. PMID- 20836813 TI - Seasonal and diel patterns of biting midges (Ceratopogonidae) and mosquitoes (Culicidae) on the Parris Island Marine Corps Recruit Depot. AB - The Marine Corps Recruit Depot on Parris Island, SC, is surrounded by tidal salt marshes, which are breeding habitats for many pestiferous biting flies. Knowledge of biting fly behavior patterns is needed to develop effective pest management strategies in urban areas adjacent to salt marshes. We measured biting midge (Ceratopogonidae) and mosquito (Culicidae) seasonal abundance and diel activity patterns on Parris Island using CO(2)-baited suction traps from November 2001 - November 2004. Of the three biting midge species collected, Culicoides furens was most abundant (86.2% of total) and was present in high numbers from late March to November. Culicoides hollensis (12.0% of total) was present during spring and fall but absent in summer and winter; and Culicoides melleus (1.7% of total) was present in spring through fall but absent in winter. Abundance of C. furens had a positive linear correlation with air temperature and rainfall. There were nonlinear correlations between air temperature and C. hollensis and C. melleus numbers, which were most abundant at moderate temperatures. Of 18 mosquito species collected, the most abundant were Aedes taeniorhynchus (42.7% of total), Aedes sollicitans (26.3% of total), Culex salinarius (15.6% of total), Culex quinquefasciatus (7.3% of total), and Aedes vexans (5.7% of total); other species comprised <5% of collections. Aedes taeniorhynchus numbers were positively correlated with temperature and rainfall, and Cx. salinarius was correlated with soil moisture. Activity of most biting midges and mosquitoes were highest the first two hours following sunset. Species of biting flies were present in all months, suggesting that year-round control measures are necessary to reduce exposure to potential disease vectors and nuisance biting. PMID- 20836814 TI - The present distribution and predicted geographic expansion of the floodwater mosquito Aedes sticticus in Sweden. AB - The mass emergence of floodwater mosquitoes, in particular Aedes sticticus and Aedes vexans, causes substantial nuisance and reduces life quality for inhabitants of infested areas and can have a negative impact on the socio economic conditions of a region. We compared the previous, present, and predicted geographic distribution of Ae. sticticus in Sweden. Previous records from the literature until 1990 list the species in three out of 21 Swedish counties. Beginning in 1998, studies show that the present distribution of the species covers 11 counties, with highest abundances in an east-west belt in Central Sweden. Using climate data from the present and predicted climate scenarios, the expected distribution of Ae. sticticus in 2020, 2050, and 2080 could be modelled using GIS. As variables, mean temperatures and cumulative precipitation between May and August and degree slope were chosen. The predicted geographic distribution of Ae. sticticus will continue to increase and include 20 out of 21 Swedish counties. The expected temperature rise will increase the suitable area towards the northern part of Sweden by 2050. Some non-suitable areas can be found along the south-east coast due to insufficient amount of precipitation in 2050 and 2080. Modelling the expected distribution of a species using predicted climate change scenarios provides a valuable tool for risk assessments and early warning systems that is easily applied to different species and scenarios. PMID- 20836815 TI - Epidemiology and vector efficiency during a dengue fever outbreak in Cixi, Zhejiang Province, China. AB - An emigrant worker returning from Southeast Asia triggered the outbreak of a DF epidemic in Zhejiang province, China, in October, 2004. Eighty-three cases, mainly young and middle-aged people between 20 and 50 (78.3%), were reported in the area of Cixi. There were no obvious occupational patterns. The majority of cases were female, with a sex ratio of 1:1.86 (m:f). The dengue virus (DENV) strains from the epidemic area were isolated and identified as DENV-1, which belongs to Asian strain 1. According to the epidemiological investigation, the incidence of DF had no relationship to temperature, humidity, or precipitation, and the Breteau index of larvae showed a clear relationship only with the House Index and Container Index. Recent dengue problems in the town have been associated with the complex social factors and hygienic conditions for endemic villagers and immigrant workers. Some hygienic measures should be taken by the local government to reduce the risk of mosquito-borne disease. These measures should aim to eliminate the breeding sites of the vector Aedes albopictus in indoor and outdoor containers filled with rainwater and thus reducing the risk of DF transmission. PMID- 20836816 TI - A tool for sampling mosquito larvae from phytotelmata. PMID- 20836817 TI - The mosquito fauna of phytotelmata in native forest habitats in the Auckland region of New Zealand. PMID- 20836818 TI - Control of Bovicola equi (Phthiraptera: Trichodectidae) with Dimilin and permethrin. PMID- 20836819 TI - Effects of ivermectin on the susceptibility of Culicoides sonorensis (Diptera: Ceratopogonidae) to bluetongue and epizootic hemorrhagic disease viruses. PMID- 20836820 TI - Phylogenetic and phenotypic relationships among Triatoma carcavalloi (Hemiptera: Reduviidae: Triatominae) and related species collected in domiciles in Rio Grande do Sul State, Brazil. AB - Triatoma carcavalloi is considered a rare Chagas disease vector often collected inside domiciles in Rio Grande do Sul State. In this Brazilian state, T. carcavalloi has been collected in the same ecotope (rock piles) with two other species (T. rubrovaria and T. circummaculata), with which it also shares morphological characteristics. Previous morphological studies placed T. carcavalloi in the same species complex ("infestans complex") and subcomplex ("rubrovaria subcomplex") as T. rubrovaria, whereas T. circummaculata was placed in the "circummaculata complex." The phylogeny of a group composed of 16 species of triatomines was reevaluated with the inclusion of T. carcavalloi by Bayesian analysis using mtDNA sequences of subunits 12S and 16S of the ribosomal RNA, and the cytochrome oxidase I (COI) genes. The phenotypic relationship among T. carcavalloi and related triatomines was also inferred from morphometrics. Phylogenetic results indicate that T. carcavalloi is a sister species of T. rubrovaria, and both were recovered as closely related to T. circummaculata. Morphometric studies confirmed the closeness among T. carcavalloi, T. rubrovaria, and T. circummaculata, prompting the placement of the latter species in the "infestans complex" and "rubrovaria subcomplex." PMID- 20836821 TI - Evaluation of factors for rapid development of Culex quinquefasciatus in belowground stormwater treatment devices. AB - Water samples from 11 belowground stormwater treatment Best Management Practices (BMPs) were evaluated for their capacity to support rapid development of the West Nile virus (WNV) mosquito vector, Culex quinquefasciatus. The observed minimum development time from egg to pupa ranged from six to over 30 days. Concentrations of potential food resources (total suspended solids and the particulate organic matter in water samples) were significantly correlated to development times. In addition, the rate of immature mosquito development was both site-dependent and variable in time, suggesting that factors favorable to rapid development were strongly influenced by watershed characteristics and seasonal changes in temperature. Measured temperatures in belowground BMPs suggest that these structures may remain amenable to WNV virus activity longer each year than sites aboveground. PMID- 20836822 TI - Variation in morphology and morphometrics of eggs of Culex quinquefasciatus mosquitoes from different ecological regions of India. AB - Variation in egg surface morphology and morphometrics of Culex quinquefasciatus mosquitoes of the Jodhpur, Bikaner, Jamnagar, and Bathinda strains were correlated with geographical distribution in different ecological regions of India. We report the geographic variation in Cx. quinquefasciatus based on 44 attributes of micropylar and conical-shaped regions of eggs, including micropylar apparatus (corolla, disc, and mound), micropylar tubercles, and the exochorionic tubercle, pores, and network in anterior, middle, and posterior regions. No remarkable differences were observed in the surface morphology of eggs of these strains except the absence of small tubercles in the anterior and middle region of the JMN strain. However, a statistical analysis indicated significant morphometric variations in 66% of the attributes of the eggs. The cluster analysis of all egg attributes showed that the JD, BKN, and BTH strains are closer to each other than the JMN strain. The positive correlation (r = 0.95) also indicated an effect of geographical distribution on morphometry of various egg attributes of these strains. The present study suggests that ecological variation may have affected the morphometric attributes of the egg of four strains of Cx. quinquefasciatus from different geographical areas. PMID- 20836823 TI - Bionomics of Anopheles spp. (Diptera: Culicidae) in a malaria endemic region of Sukabumi, West Java, Indonesia. AB - A 15-month bionomic study of Anopheles species was conducted in two ecologically distinct villages (coastal and upland) of Sukabumi District, West Java, Indonesia from June 2006 to September 2007. Mosquitoes were captured using human-landing collections at both sites. During the study, a total of 17,100 Anopheles mosquitoes comprising 13 Anopheles species were caught: 9,151 at the coastal site and 7,949 at the upland site. Anopheles barbirostris, Anopheles maculatus, and Anopheles vagus were the predominant species caught at the coastal site, and Anopheles aconitus, Anopheles barbirostris, and An. maculatus predominated in the upland site. Overall, species were exophagic at both sites, but there was variation between species. Anopheles aconitus was endophagic at the coastal site, exophagic at the upland site, collected most often in April 2007 and had a peak landing time between 22:00 and 23:00. Anopheles sundaicus was only collected at the coastal site, exophagic, collected most often in October 2006, and had a peak landing time between 19:00 and 20:00. Potential malaria vector species such An. aconitus, An. maculatus, and An. sundaicus were present throughout the year. None of the 7,770 Anopheles tested using CSP-ELISA were positive for malaria, although the risk for malaria outbreaks in Sukabumi district remains high. PMID- 20836824 TI - Larval habitat for the avian malaria vector Culex quinquefasciatus (Diptera: Culicidae) in altered mid-elevation mesic-dry forests in Hawai'i. AB - Effective management of avian malaria (Plasmodium relictum) in Hawai'i's endemic honeycreepers (Drepanidinae) requires the identification and subsequent reduction or treatment of larval habitat for the mosquito vector, Culex quinquefasciatus (Diptera: Culicidae). We conducted ground surveys, treehole surveys, and helicopter aerial surveys from 2001-2003 to identify all potential larval mosquito habitat within two 100+ ha mesic-dry forest study sites in Hawai'i Volcanoes National Park, Hawai'i; 'Ainahou Ranch and Mauna Loa Strip Road. At 'Ainahou Ranch, anthropogenic sites (43%) were more likely to contain mosquitoes than naturally occurring (8%) sites. Larvae of Cx. quinquefasciatus were predominately found in anthropogenic sites while Aedes albopictus larvae occurred less frequently in both anthropogenic sites and naturally-occurring sites. Additionally, moderate-size (~ 20-22,000 liters) anthropogenic potential larval habitat had >50% probability of mosquito presence compared to larger- and smaller volume habitat (<50%). Less than 20% of trees surveyed at 'Ainahou Ranch had treeholes and few mosquito larvae were detected. Aerial surveys at 'Ainahou Ranch detected 56% (95% CI: 42-68%) of the potential larval habitat identified in ground surveys. At Mauna Loa Strip Road, Cx. quinquefasciatus larvae were only found in the rock holes of small intermittent stream drainages that made up 20% (5 of 25) of the total potential larval habitat. The volume of the potential larval habitat did not influence the probability of mosquito occurrence at Mauna Loa Strip Road. Our results suggest that Cx. quinquefasciatus abundance, and subsequently avian malaria, may be controlled by larval habitat reduction in the mesic-dry landscapes of Hawai'i where anthropogenic sources predominate. PMID- 20836825 TI - Irritability and repellency of synthetic pyrethroids on an Aedes aegypti population from Thailand. AB - The main objective of this study was to find the optimal dosage of deltamethrin, cyphenothrin, D-tetramethrin, and tetramethrin that would elicit repellency and irritability responses of Aedes aegypti. The F1-F3 generations of field mosquitoes collected from Pu Teuy Village, Sai-Yok District, Kanchanaburi Province, Thailand, were tested with four pyrethroids to determine the LC(25), LC(50), and LC(99). These concentrations were 0.010%, 0.020%, and 0.055%, respectively, for deltamethrin; 0.113%, 0.167%, and 0.353%, respectively, for cyphenothrin; 2.091%, 2.770%, and 5.114%, respectively, for d-tetramethrin; and 2.377%, 4.251%, and 10.715%, respectively, for tetramethrin. All dosages were tested in the excito-repellency system. Survival analysis was used to compare each chamber of the test. It was found that cyphenothrin had a stronger repellent effect than the other pyrethroids, while the contact irritant effect was similar among compounds tested. The LC(50) of each pyrethroid was found to be the optimal dose for repelling Ae. aegypti. There was no significant difference in LC(99) values for either non-contact or contact trials for each pyrethroid. PMID- 20836826 TI - Ecology of Hantaan virus at Twin Bridges Training Area, Gyeonggi Province, Republic of Korea, 2005-2007. AB - The Twin Bridges Training Area (TBTA) in the Republic of Korea consists of dirt roads, barren training areas, and forested hillsides adjacent to linear and broad expanses of tall grasses, herbaceous, and scrub vegetation. Of the six species of small mammals, the striped field mouse, Apodemus agrarius, was the most frequently captured (96.1%). Apodemus agrarius capture rates varied from 17.7 to 33.2% during three trapping periods. Gravid females were observed during November December 2006 (8.4%) and March 2007 (5.1%). In 2005, the overall seroprevalence of Hantaan virus (HTNV) was high (34.4%) and lower during surveys in 2006 (14.2%) and 2007 (13.8%). Seroprevalence was directly correlated with weight increase of A. agrarius. PMID- 20836827 TI - Contact irritancy and spatial repellency behaviors in Anopheles albimanus Wiedemann (Diptera: Culicidae) collected in Orange Walk, Belize, C.A. AB - Anopheles albimanus Wiedemann is a vector of malaria in northern Belize. Previous studies have identified behavioral responses in this species when exposed to certain chemicals. We used a high throughput screening system to evaluate the contact irritant and spatial repellency responses exhibited by An. albimanus collected from Orange Walk, Belize, Central America. Anopheles albimanus behavior was significantly altered by a number of key public health insecticides. Significant irritant responses to alphacypermethrin, deltamethrin, permethrin, DDT, and propoxur were recorded, while spatial repellency responses were only elicited by DDT. Malathion resulted in neither a contact irritant or spatial repellency response. These results are in congruence with behavioral patterns previously observed for An. albimanus and for Aedes aegypti in the same system. This study produced baseline data on the behaviors of An. albimanus and confirms that the majority of compounds used as indoor residual sprays may induce premature exiting by An. albimanus in addition to killing the mosquito. This effect would decrease contact with humans and thus disrupt malaria transmission. PMID- 20836828 TI - Historical and recent evidence for close relationships among Rickettsia parkeri, R. conorii, R. africae, and R. sibirica: implications for rickettsial taxonomy. AB - Rickettsia parkeri, a member of the spotted fever group rickettsias, was first described in 1939 and was thought to be non-pathogenic until recently, when it was found to cause a spotted fever-like illness in humans and areas of necrosis (eschars) at the sites of tick bites. Accordingly, there is currently much interest in this emerging pathogen. In this study, all published articles concerning R. parkeri were reviewed and analyzed for evidence of relatedness among this agent and other spotted fever group (SFG) rickettsiae which also produce similar clinical syndromes and/or eschars, including R. conorii, R. africae, and R. sibirica. A synthesis of the historical (antigenic) and recent (molecular) data supporting a phylogenetic sub-grouping of these SFG organisms is presented and comments are offered about the taxonomy of rickettsial organisms in general, and R. parkeri in particular. PMID- 20836829 TI - Distribution of Culicoides in Greece. AB - Culicoides biting midges (Diptera: Ceratopogonidae) were trapped between 1999 and 2004 at 122 locations in mainland Greece and on most of the larger Aegean and Ionian islands, using OVI light traps, in order to determine the distribution and seasonal activity of bluetongue virus vectors and other Culicoides species. Thirty-nine Culicoides species were identified, six of which (C. furcillatus, C. impunctatus, C. paolae, C. pictipennis, C. riethi, and C. scoticus) were identified for the first time in Greece. Two of these (C. impunctatus and C. scoticus) may be of veterinary importance due to their role as vectors of bluetongue virus and related orbiviruses. In addition, C. imicola was detected for the first time in mainland Greece. PMID- 20836830 TI - Effects of environmental conditions on the movement patterns of Aedes aegypti (Diptera: Culicidae) into and out of experimental huts in Thailand. AB - Mark-release-recapture experiments with Aedes aegypti were performed using experimental huts equipped with entrance and exit traps to evaluate their movement patterns during a two-year period in Thailand. Results indicate no significant differences in the patterns of movement between the two years of observation. Movement into the huts occurred during the early morning period (06:00-11:00) with a peak at 07:00 in the summer and rainy season and 09:00 in the winter. In contrast, the exit pattern was observed during the late morning (09:00-12:00) and early afternoon (12:00-16:00), with a peak at 16:00 in the winter, 11:00 in the summer, and 14:00 in the rainy season. Multiple regression analysis indicated that movements of Ae. aegypti females into and out of the huts were impacted by humidity and temperature during the day. PMID- 20836831 TI - Mosquitoes and West Nile virus along a river corridor from prairie to montane habitats in eastern Colorado. AB - We conducted studies on mosquitoes and West Nile virus (WNV) along a riparian corridor following the South Platte River and Big Thompson River in northeastern Colorado and extending from an elevation of 1,215 m in the prairie landscape of the eastern Colorado plains to 1,840 m in low montane areas at the eastern edge of the Rocky Mountains in the central part of the state. Mosquito collection during June-September 2007 in 20 sites along this riparian corridor yielded a total of 199,833 identifiable mosquitoes of 17 species. The most commonly collected mosquitoes were, in descending order: Aedes vexans, Culex tarsalis, Ae. dorsalis, Ae. trivittatus, Ae. melanimon, Cx. pipiens, and Culiseta inornata. Species richness was higher in the plains than in foothills-montane areas, and abundances of several individual species, including the WNV vectors Cx. tarsalis and Cx. pipiens and the nuisance-biter and potential secondary WNV vector Ae. vexans, decreased dramatically from the plains (1,215-1,487 m) to foothills montane areas (1,524-1,840 m). Ae. vexans and Cx. tarsalis had a striking pattern of uniformly high abundances between 1,200-1,450 m followed by a gradual decrease in abundance above 1,450 m to reach very low numbers above 1,550 m. Culex species were commonly infected with WNV in the plains portion of the riparian corridor in 2007, with 14 of 16 sites yielding WNV-infected Cx. tarsalis and infection rates for Cx. tarsalis females exceeding 2.0 per 1,000 individuals in ten of the sites. The Vector Index for abundance of WNV-infected Cx. tarsalis females during June September exceeded 0.5 in six plains sites along the South Platte River but was uniformly low (0-0.1) in plains, foothills and montane sites above 1,500 m along the Big Thompson River. A population genetic analysis of Cx. tarsalis revealed that all collections from the ~190 km riparian transect in northeastern Colorado were genetically uniform but that these collections were genetically distinct from collections from Delta County on the western slope of the Continental Divide. This suggests that major waterways in the Great Plains serve as important dispersal corridors for Cx. tarsalis but that the Continental Divide is a formidable barrier to this WNV vector. PMID- 20836832 TI - Ultrastructure of male accessory glands of Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae). AB - The ultrastructure of the male accessory glands of the blow fly, Chrysomya megacephala (Fabricius), was presented using light microscopy (LM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). A pair of accessory glands was separated at opposite sites. Morphometric results using LM yield evidenced no significant difference in the median of either length or width of the left and right glands. A significant increment in both length and width was seen to plateau between three to six days. SEM observation showed that the surface of the glands revealed a faint irregular groove pattern throughout, and it was occasionally penetrated by tracheoles. Each gland was a slender, elongated sac-like tubule having apical rounded ends, with a slight constriction at the sub apical part of the gland being observed occasionally. TEM analyses of three-day old males showed that the glands consisted of external capsular cells with a basement membrane underneath, glandular cells, and gland lumen. The capsular cell was flat and contained a nucleus with electron dense material in the nuclear envelope. The glandular cell, appearing as columnar, consisted of a vacuolated component that contained a large oval nucleus centrally or sub-basally located, with dense mitochondria, numerous rough endoplasmic reticulum, and secretory vesicles containing electron-lucent materials. In the gland lumen, the cross section through the middle portion revealed dense secretory materials, characterized by electron-dense materials. Some sections revealed a large lumen where secretion accumulates within the delicate sac. The seven-day-old glands exhibited a remarkable change in the lumen, where the whole space contained a large amount of secretory materials, with the electron-dense materials being characterized as similar to those observed in three-day-old glands. About four prominent types of secretions were observed on the basis of difference in electron-density. PMID- 20836833 TI - Abundance and nightly activity behavior of a sylvan population of Triatoma dimidiata (Hemiptera: Reduviidae: Triatominae) from the Yucatan, Mexico. AB - Triatoma dimidiata is the vector of Trypanosoma cruzi in the Yucatan Peninsula (YP). Earlier studies have shown that domestic and peri-domestic populations of the vector originated from the sylvan stock and that effectiveness of insecticide spraying was affected by re-infestations of houses from the sylvan T. dimidiata population. In addition, in the YP most previously published reports have focused on domestic and peri-domestic populations and very little is known about the nocturnal behavior of the sylvan populations. The main aim of our study was to determine the nightly activity patterns of adult T. dimidiata in a selected location in the YP. Secondly, we sought to document the reproductive status and infection rate of active females. During eight sampling nights spaced from late March to late July, 2007, we collected 544 adult T. dimidiata. We found that square-cloth illuminated white traps were effective to attract the sylvan individuals and that T. dimidiata adults exhibited a unimodal activity pattern throughout the night. The accumulated mean of captured bugs also showed a non linear distribution for females and males. Furthermore, we found that male and female catches were significantly correlated with the means of temperature and humidity recorded during the sampling period. Out of 46 dissected females, we observed that 43.5% of females had fully-formed eggs in their abdomens, and only two females (4.4%) had sperm within the spermatheca. The infection rate of T. dimidiata harboring T. cruzi was found to be 3.7%. The implications of the light attraction to bugs and potential dispersal capabilities are discussed in the paper in the context of infestation/re-infestation of rural houses by sylvan T. dimidiata flying adults. PMID- 20836834 TI - A comparison of Aedes vigilax larval population densities and associated vegetation categories in a coastal wetland, Northern Territory, Australia. AB - Darwin's northern suburbs border an extensive coastal reed and upper mangrove wetland recognized as an important larval habitat for Aedes vigilax (Skuse), the northern salt marsh mosquito, an established vector for Ross River and Barmah Forest viruses and an appreciable pest species. We sought to identify the most important vegetation categories associated with Ae. vigilax breeding to maximize the efficiency of mosquito control efforts. Using a generalized linear model with negative binominal distribution and log link, this study compares larval densities, determined by focused dipping, between 13 discernable vegetation categories. The incidence rate ratios (RR) generated can be used to compare the magnitude of larval densities for each vegetation category, compared with the reference category. Aedes vigilax larval densities were almost ten times greater in artificial drainage areas (RR=9.82), followed by tide-affected reticulate (Sporobolus/Xerochloa) areas (RR=8.15), then Schoenoplectus/mangroves (RR=2.29), compared with the reference vegetation category "lower mangroves." Furthermore, larval densities were highest in May, due to tidal inundation, for drainage areas and tide-affected reticulates (RR=12.2, 11.7, respectively) compared with March, the reference month. Thus, to maximize the efficiency of aerial salt marsh mosquito control operations in this wetland, larval control is best accomplished by concentrating on drains, Schoenoplectus/mangroves, and tide-affected reticulate areas, commencing early after the wet season. These results should apply to other areas of salt marsh mosquito breeding across northern Australia. PMID- 20836835 TI - A geospatial evaluation of Aedes vigilax larval control efforts across a coastal wetland, Northern Territory, Australia. AB - Adjacent to the northern suburbs of Darwin is a coastal wetland that contains important larval habitats for Aedes vigilax (Skuse), the northern salt marsh mosquito. This species is a vector for Ross River virus and Barmah Forest virus, as well as an appreciable human pest. In order to improve aerial larval control efforts, we sought to identify the most important vegetation categories and climatic/seasonal aspects associated with control operations in these wetlands. By using a generalized linear model to compare aerial control for each vegetation category, we found that Schoenoplectus/mangrove areas require the greatest amount of control for tide-only events (30.1%), and also extensive control for tide and rain events coinciding (18.2%). Our results further indicate that tide-affected reticulate vegetation indicated by the marsh grasses Sporobolus virginicus and Xerochloa imberbis require extensive control for Ae. vigilax larvae after rain only events (44.7%), and tide and rain events coinciding (38.0%). The analyses of vector control efforts by month indicated that September to January, with a peak in November and December, required the most control. A companion paper identifies the vegetation categories most associated with Aedes vigilax larvae population densities in the coastal wetland. To maximize the efficiency of aerial salt marsh mosquito control operations in northern Australia, aerial control efforts should concentrate on the vegetation categories with high larval densities between September and January. PMID- 20836836 TI - Comparative field analyses of rapid analyte measurement platform and reverse transcriptase polymerase chain reaction assays for West Nile virus surveillance. AB - Rapid detection of West Nile virus (WNV) in mosquito pools is essential for predicting epizootics and epidemics. We compare the efficiency and sensitivity of the Rapid Analyte Measurement Platform (RAMP) to reverse transcriptase polymerase chain reaction (RT-PCR) from 2005 to 2008 from field mosquito populations in Mercer County, NJ. Overall, 316 pools tested negative and 115 pools tested positive for WNV. Eighty-nine pools tested positive using RAMP and all were confirmed by RT-PCR; 26 pools were WNV-negative using RAMP but positive using RT PCR. False-positives from RAMP were not detected in our four-year study, indicating that RAMP is a reliable tool when used to augment existing RT-PCR based WNV surveillance programs. Local mosquito control programs using RAMP will benefit from its ease of use, quick results, and lack of false positives but should understand the sensitivity of this test when compared to RT-PCR. Used with standard methods, RAMP will enhance existing mosquito control and WNV surveillance by providing rapid results and improved mosquito management decisions. PMID- 20836837 TI - Survey of insect growth regulator (IGR) resistance in house flies (Musca domestica L.) from southwestern Turkey. AB - Insect growth regulators (IGRs) are currently the fastest-growing class of insecticides, and in Turkey these products represent a new approach to pest control. In recent years, several IGRs were also registered for the control of the house fly, Musca domestica L. (Diptera: Muscidae), in Turkey. A field survey was conducted in the summers of 2006 and 2007 to evaluate resistance to some agriculturally and medically used IGRs on house flies from livestock farms and garbage dumps in the greenhouse production areas (Merkez, Kumluca, Manavgat, and Serik) of Antalya province (Southwestern Turkey). The results of larval feeding assay with technical diflubenzuron, methoprene, novaluron, pyripoxyfen, and triflumuron indicate that low levels (RF<10-fold) of resistance to the IGRs exist in the house fly populations from Antalya province. Exceptions, however, were two populations, Guzoren and Toptas, from the Kumluca area which showed moderate resistance to diflubenzuron with 11.8-fold in 2006 and 13.2-fold in 2007, respectively. We found substantial variation in susceptibility of field-collected house fly populations from year to year and from product to product. We generally observed an increase in resistance at many localities sampled from 2006 to 2007. The implications of these results to the future use of IGRs for house fly control are discussed. It will be critically important to continue monitoring efforts so that appropriate steps can be taken if resistance levels start to increase. PMID- 20836838 TI - Self-reported prevalence of childhood allergic diseases in three cities of China: a multicenter study. AB - BACKGROUND: Several studies conducted during the 1990s indicated that childhood allergic diseases were increasing worldwide, but more recent investigations in some Western countries have suggested that the trend is stabilizing or may even be reversing. However, few data are available on the current status of allergic disease prevalence in Chinese children. The aim of the present study was to investigate the prevalence rates of asthma, allergic rhinitis, and eczema in children of three major cities of China, to determine the status of allergic diseases among Chinese children generally, and to evaluate the prevalence of allergic diseases in children of different ages. METHODS: We conducted a cross sectional survey between October 2008 and May 2009 in three major cities of China (Beijing, Chongqing, and Guangzhou) to evaluate the prevalence rates of childhood allergic diseases including asthma, allergic rhinitis, and eczema, using a questionnaire of the International Study of Asthma and Allergies in Childhood (ISAAC) group. A total of 24,290 children aged 0-14 years were interviewed, using a multi-stage sampling method. To acquire data on children aged 3-14 years, we visited schools and kindergartens. To access children too young to attend school or kindergarten, we extended our survey to community health service centers. Each questionnaire was completed by a parent or guardian of a child after an informed consent form was signed. RESULTS: Of the 24,290 children in our study, 12,908 (53.14%) were males and 11,382 (46.86%) females; 10,372 (42.70%) were from Beijing, 9,846 (40.53%) from Chongqing, and 4,072 (16.77%) from Guangzhou. Our survey indicated that in Beijing, Chongqing, and Guangzhou, the prevalence rates of asthma were 3.15%, 7.45%, and 2.09%, respectively; the rates of allergic rhinitis were 14.46%, 20.42%, and 7.83%; and the rates of eczema were 20.64%, 10.02%, and 7.22%. The prevalence of allergic diseases varied with age. Asthma was relatively less common both in children aged under 2 years, and in those aged 9 years or more, in each of the three cities. The prevalence of allergic rhinitis was also lower in children younger than 2 years. The prevalence of eczema fell with age. CONCLUSIONS: A marked increase in the prevalence rates of allergic diseases in China (compared with earlier data) was evident. Further studies exploring the precise causes of this increase are warranted. PMID- 20836839 TI - Hematopoietic stem cells exhibit a specific ABC transporter gene expression profile clearly distinct from other stem cells. AB - BACKGROUND: ATP-binding cassette (ABC) transporters protect cells against unrelated (toxic) substances by pumping them across cell membranes. Earlier we showed that many ABC transporters are highly expressed in hematopoietic stem cells (HSCs) compared to more committed progenitor cells. The ABC transporter expression signature may guarantee lifelong protection of HSCs but may also preserve stem cell integrity by extrusion of agents that trigger their differentiation. Here we have studied whether non-hematopoietic stem cells (non HSCs) exhibit a similar ABC transporter expression signature as HSCs. RESULTS: ABC transporter expression profiles were determined in non-hematopoietic stem cells (non-HSCs) from embryonic, neonatal and adult origin as well as in various mature blood cell types. Over 11,000 individual ABC transporter expression values were generated by Taqman Low Density Arrays (TLDA) to obtain a sensitivity comparable with quantitative real-time polymerase chain reactions. We found that the vast majority of transporters are significantly higher expressed in HSCs compared to non-HSCs. Furthermore, regardless their origin, non-HSCs exhibited strikingly similar ABC transporter expression profiles that were distinct from those in HSCs. Yet, sets of transporters characteristic for different stem cell types could be identified, suggesting restricted functions in stem cell physiology. Remarkably, in HSCs we could not pinpoint any single transporter expressed at an evidently elevated level when compared to all the mature blood cell types studied. CONCLUSIONS: These findings challenge the concept that individual ABC transporters are implicated in maintaining stem cell integrity. Instead, a distinct ABC transporter expression signature may be essential for stem cell function. The high expression of specific transporters in non-HSCs and mature blood cells suggests a specialized, cell type dependent function and warrants further functional experiments to determine their exact roles in cellular (patho)physiology. PMID- 20836840 TI - Evaluation design for a complex intervention program targeting loneliness in non institutionalized elderly Dutch people. AB - BACKGROUND: The aim of this paper is to provide the rationale for an evaluation design for a complex intervention program targeting loneliness among non institutionalized elderly people in a Dutch community. Complex public health interventions characteristically use the combined approach of intervening on the individual and on the environmental level. It is assumed that the components of a complex intervention interact with and reinforce each other. Furthermore, implementation is highly context-specific and its impact is influenced by external factors. Although the entire community is exposed to the intervention components, each individual is exposed to different components with a different intensity. METHODS/DESIGN: A logic model of change is used to develop the evaluation design. The model describes what outcomes may logically be expected at different points in time at the individual level. In order to address the complexity of a real-life setting, the evaluation design of the loneliness intervention comprises two types of evaluation studies. The first uses a quasi experimental pre-test post-test design to evaluate the effectiveness of the overall intervention. A control community comparable to the intervention community was selected, with baseline measurements in 2008 and follow-up measurements scheduled for 2010. This study focuses on changes in the prevalence of loneliness and in the determinants of loneliness within individuals in the general elderly population. Complementarily, the second study is designed to evaluate the individual intervention components and focuses on delivery, reach, acceptance, and short-term outcomes. Different means of project records and surveys among participants are used to collect these data. DISCUSSION: Combining these two evaluation strategies has the potential to assess the effectiveness of the overall complex intervention and the contribution of the individual intervention components thereto. PMID- 20836841 TI - Polymorphisms in NFkB, PXR, LXR and risk of colorectal cancer in a prospective study of Danes. AB - BACKGROUND: Transcription factors and nuclear receptors constitute a link between exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and tobacco smoke and colorectal cancer (CRC) risk. The aim of this study was to investigate if polymorphisms in nuclear factor kappa-B, pregnane X receptor, and liver X receptor were associated with risk of CRC, and to investigate possible interactions with lifestyle factors such as smoking, meat consumption, and NSAID use. METHODS: The polymorphisms nuclear factor kappa-B (NFkB, NFKB1) -94 insertion/deletion ATTG (rs28362491), pregnane X receptor (PXR, NR1I2) A-24381C (rs1523127), C8055T (rs2276707), A7635G (rs6785049), liver X receptor (LXR-beta, NR1H3) C-rs1405655T, T-rs2695121C were assessed together with lifestyle factors in a nested case-cohort study of 378 CRC cases and 756 random participants from the Danish prospective Diet, Cancer and Health study of 57,053 persons. RESULTS: Carriers of NFkB -94deletion were at 1.45-fold higher risk of CRC than homozygous carriers of the insertion allele (incidence rate ratio (IRR) = 1.45, 95% confidence interval (95% CI): 1.10-1.92). There was interaction between this polymorphism and intake of red and processed meat in relation to CRC risk. Carriers of NFkB -94deletion were at 3% increased risk pr 25 gram meat per day (95% CI: 0.98-1.09) whereas homozygous carriers of the insertion were not at increased risk (p for interaction = 0.03). PXR and LXR polymorphisms were not associated with CRC risk. There was no interaction between use of nonsteroid antiinflammatory drugs (NSAID) or smoking status and NFkB, PXR or LXR polymorphisms. CONCLUSIONS: A polymorphism in NFkB was associated with CRC risk and there was interaction between this polymorphism and meat intake in relation to CRC risk. This study suggests a role for NFkB in CRC aetiology. PMID- 20836842 TI - An efficient method to find potentially universal population genetic markers, applied to metazoans. AB - BACKGROUND: Despite the impressive growth of sequence databases, the limited availability of nuclear markers that are sufficiently polymorphic for population genetics and phylogeography and applicable across various phyla restricts many potential studies, particularly in non-model organisms. Numerous introns have invariant positions among kingdoms, providing a potential source for such markers. Unfortunately, most of the few known EPIC (Exon Primed Intron Crossing) loci are restricted to vertebrates or belong to multigenic families. RESULTS: In order to develop markers with broad applicability, we designed a bioinformatic approach aimed at avoiding multigenic families while identifying intron positions conserved across metazoan phyla. We developed a program facilitating the identification of EPIC loci which allowed slight variation in intron position. From the Homolens databases we selected 29 gene families which contained 52 promising introns for which we designed 93 primer pairs. PCR tests were performed on several ascidians, echinoderms, bivalves and cnidarians. On average, 24 different introns per genus were amplified in bilaterians. Remarkably, five of the introns successfully amplified in all of the metazoan genera tested (a dozen genera, including cnidarians). The influence of several factors on amplification success was investigated. Success rate was not related to the phylogenetic relatedness of a taxon to the groups that most influenced primer design, showing that these EPIC markers are extremely conserved in animals. CONCLUSIONS: Our new method now makes it possible to (i) rapidly isolate a set of EPIC markers for any phylum, even outside the animal kingdom, and thus, (ii) compare genetic diversity at potentially homologous polymorphic loci between divergent taxa. PMID- 20836843 TI - Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy. AB - INTRODUCTION: The purpose of the present manuscript is to test the hypothesis that arthrotropic localization and synovial cell internalization account for the unique capacity of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer dexamethasone conjugate (P-Dex, a macromolecular prodrug of dexamethasone) to induce sustained amelioration of joint inflammation and inhibition of tissue damage in an animal model of inflammatory arthritis. METHODS: Rats with adjuvant induced arthritis (AA) were treated with P-Dex, free dexamethasone, saline or HPMA homopolymer. To define the biodistribution of P-Dex, conjugates with different imaging labels were given to AA rats and analyzed. Isolated joint tissues were evaluated by fluorescence-activated cell sorting (FACS) and immunohistochemical staining. Cellular uptake of P-Dex and its effects on apoptosis and production of proinflammatory cytokines were examined using human monocyte-macrophages and fibroblasts. RESULTS: A single systemic administration of P-Dex completely suppressed AA for >20 days. Magnetic resonance imaging demonstrated higher HPMA copolymer influx into the inflamed joints than the normal joints. Immunohistochemistry and FACS analyses of arthritic joints revealed extensive uptake of the polymer conjugate by synovial fibroblasts and myeloid lineage cells. The capacity of P-Dex to suppress inflammation was confirmed in monocyte-macrophage cultures in which P-Dex treatment resulted in suppression of lipopolysaccharide-induced IL-6 and TNFalpha release. Similarly, TNFalpha-induced expression of matrix metalloproteinases (MMP1 and MMP3) in synovial fibroblasts from a rheumatoid arthritis patient was suppressed by P-Dex. P-Dex showed no detectable effect on monocyte apoptosis. CONCLUSIONS: P-Dex provides superior and sustained amelioration of AA compared with an equivalent dose of free dexamethasone. The arthrotropism and local retention of P-Dex is attributed to the enhanced vascular permeability in arthritic joints and the internalization of P-Dex by synovial cells. The uptake and processing of P-Dex by macrophages and fibroblasts, and downregulation of proinflammatory mediators, provides an explanation for the sustained anti-inflammatory efficacy of P-Dex in this model of inflammatory arthritis. PMID- 20836844 TI - Impairment of circulating endothelial progenitors in Down syndrome. AB - BACKGROUND: Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti angiogenesis disease model, possibly due to increased expression of anti angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome. METHODS: Circulating endothelial progenitors of Down syndrome affected individuals were isolated, in vitro cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1alpha plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of CXCL12 gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis. RESULTS: We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1alpha plasma levels and their progenitors had a reduced expression of SDF-1alpha encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells. CONCLUSIONS: Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals. PMID- 20836846 TI - Conduction in ulnar nerve bundles that innervate the proximal and distal muscles: a clinical trial. AB - BACKGROUND: This study aims to investigate and compare the conduction parameters of nerve bundles in the ulnar nerve that innervates the forearm muscles and hand muscles; routine electromyography study merely evaluates the nerve segment of distal (hand) muscles. METHODS: An electrophysiological evaluation, consisting of velocities, amplitudes, and durations of ulnar nerve bundles to 2 forearm muscles and the hypothenar muscles was performed on the same humeral segment. RESULTS: The velocities and durations of the compound muscle action potential (CMAP) of the ulnar nerve bundle to the proximal muscles were greater than to distal muscles, but the amplitudes were smaller. CONCLUSIONS: Bundles in the ulnar nerve of proximal muscles have larger neuronal bodies and thicker nerve fibers than those in the same nerve in distal muscles, and their conduction velocities are higher. The CMAPs of proximal muscles also have smaller amplitudes and greater durations. These findings can be attributed to the desynchronization that is caused by a wider range of distribution in nerve fiber diameters.Conduction parameters of nerve fibers with different diameters in the same peripheral nerve can be estimated. PMID- 20836845 TI - Molecular species identification of Central European ground beetles (Coleoptera: Carabidae) using nuclear rDNA expansion segments and DNA barcodes. AB - BACKGROUND: The identification of vast numbers of unknown organisms using DNA sequences becomes more and more important in ecological and biodiversity studies. In this context, a fragment of the mitochondrial cytochrome c oxidase I (COI) gene has been proposed as standard DNA barcoding marker for the identification of organisms. Limitations of the COI barcoding approach can arise from its single locus identification system, the effect of introgression events, incomplete lineage sorting, numts, heteroplasmy and maternal inheritance of intracellular endosymbionts. Consequently, the analysis of a supplementary nuclear marker system could be advantageous. RESULTS: We tested the effectiveness of the COI barcoding region and of three nuclear ribosomal expansion segments in discriminating ground beetles of Central Europe, a diverse and well-studied invertebrate taxon. As nuclear markers we determined the 18S rDNA: V4, 18S rDNA: V7 and 28S rDNA: D3 expansion segments for 344 specimens of 75 species. Seventy three species (97%) of the analysed species could be accurately identified using COI, while the combined approach of all three nuclear markers provided resolution among 71 (95%) of the studied Carabidae. CONCLUSION: Our results confirm that the analysed nuclear ribosomal expansion segments in combination constitute a valuable and efficient supplement for classical DNA barcoding to avoid potential pitfalls when only mitochondrial data are being used. We also demonstrate the high potential of COI barcodes for the identification of even closely related carabid species. PMID- 20836847 TI - Effects of hydrogen sulfide on hemodynamics, inflammatory response and oxidative stress during resuscitated hemorrhagic shock in rats. AB - INTRODUCTION: Hydrogen sulfide (H2S) has been shown to improve survival in rodent models of lethal hemorrhage. Conversely, other authors have reported that inhibition of endogenous H2S production improves hemodynamics and reduces organ injury after hemorrhagic shock. Since all of these data originate from unresuscitated models and/or the use of a pre-treatment design, we therefore tested the hypothesis that the H2S donor, sodium hydrosulfide (NaHS), may improve hemodynamics in resuscitated hemorrhagic shock and attenuate oxidative and nitrosative stresses. METHODS: Thirty-two rats were mechanically ventilated and instrumented to measure mean arterial pressure (MAP) and carotid blood flow (CBF). Animals were bled during 60 minutes in order to maintain MAP at 40 +/- 2 mm Hg. Ten minutes prior to retransfusion of shed blood, rats randomly received either an intravenous bolus of NaHS (0.2 mg/kg) or vehicle (0.9% NaCl). At the end of the experiment (T = 300 minutes), blood, aorta and heart were harvested for Western blot (inductible Nitric Oxyde Synthase (iNOS), Nuclear factor-kappaB (NF-kappaB), phosphorylated Inhibitor kappaB (P-IkappaB), Inter-Cellular Adhesion Molecule (I-CAM), Heme oxygenase 1(HO-1), Heme oxygenase 2(HO-2), as well as nuclear respiratory factor 2 (Nrf2)). Nitric oxide (NO) and superoxide anion (O2( )) were also measured by electron paramagnetic resonance. RESULTS: At the end of the experiment, control rats exhibited a decrease in MAP which was attenuated by NaHS (65 +/- 32 versus 101 +/- 17 mmHg, P < 0.05). CBF was better maintained in NaHS-treated rats (1.9 +/- 1.6 versus 4.4 +/- 1.9 ml/minute P < 0.05). NaHS significantly limited shock-induced metabolic acidosis. NaHS also prevented iNOS expression and NO production in the heart and aorta while significantly reducing NF-kB, P-IkappaB and I-CAM in the aorta. Compared to the control group, NaHS significantly increased Nrf2, HO-1 and HO-2 and limited O2(-) release in both aorta and heart (P < 0.05). CONCLUSIONS: NaHS is protective against the effects of ischemia reperfusion induced by controlled hemorrhage in rats. NaHS also improves hemodynamics in the early resuscitation phase after hemorrhagic shock, most likely as a result of attenuated oxidative stress. The use of NaHS hence appears promising in limiting the consequences of ischemia reperfusion (IR). PMID- 20836848 TI - Disruption of reducing pathways is not essential for efficient disulfide bond formation in the cytoplasm of E. coli. AB - BACKGROUND: The formation of native disulfide bonds is a complex and essential post-translational modification for many proteins. The large scale production of these proteins can be difficult and depends on targeting the protein to a compartment in which disulfide bond formation naturally occurs, usually the endoplasmic reticulum of eukaryotes or the periplasm of prokaryotes. It is currently thought to be impossible to produce large amounts of disulfide bond containing protein in the cytoplasm of wild-type bacteria such as E. coli due to the presence of multiple pathways for their reduction. RESULTS: Here we show that the introduction of Erv1p, a sulfhydryl oxidase and FAD-dependent catalyst of disulfide bond formation found in the inter membrane space of mitochondria, allows the efficient formation of native disulfide bonds in heterologously expressed proteins in the cytoplasm of E. coli even without the disruption of genes involved in disulfide bond reduction, for example trxB and/or gor. Indeed yields of active disulfide bonded proteins were higher in BL21 (DE3) pLysSRARE, an E. coli strain with the reducing pathways intact, than in the commercial Deltagor DeltatrxB strain rosetta-gami upon co-expression of Erv1p. CONCLUSIONS: Our results refute the current paradigm in the field that disruption of at least one of the reducing pathways is essential for the efficient production of disulfide bond containing proteins in the cytoplasm of E. coli and open up new possibilities for the use of E. coli as a microbial cell factory. PMID- 20836849 TI - The epidemiology of infectious gastroenteritis related reactive arthritis in U.S. military personnel: a case-control study. AB - BACKGROUND: Reactive arthritis (ReA) is a recognized sequela of infectious gastroenteritis (IGE). However, the population-based incidence of IGE-related ReA is poorly defined, and the risk of disease has not previously been characterized in a military population. The intent of this study was to provide estimates of the incidence and morbidity associated with IGE-related ReA in the U.S. military population. METHODS: Using active duty US military medical encounter data from the Defense Medical Surveillance System, we conducted a matched case-control study to assess the risk of ReA following IGE. Both specific and nonspecific case definitions were utilized to address ICD-9 coding limitations; these included specific ReA (Reiter's Disease or postdysenteric arthritis) and nonspecific arthritis/arthralgia (N.A.A) (which included several related arthropathy and arthralgia diagnoses). Incidence was estimated using events and the total number of active duty personnel for each year. RESULTS: 506 cases of specific ReA were identified in active duty personnel between 1999 and 2007. Another 16,365 cases of N.A.A. were identified. Overall incidence was 4.1 (95% CI: 3.7, 4.5) and 132.0 (95% CI, 130.0-134.0) per 100,000 for specific ReA and N.A.A, respectively. Compared to the youngest age category, the incidence of both outcomes increased 7 fold with a concurrent increase in symptom duration for cases over the age of 40. Specific IGE exposures were documented in 1.4% of subjects. After adjusting for potential confounders, there was a significant association between IGE and ReA (specific reactive arthritis OR: 4.42, 95% CI: 2.24, 8.73; N.A.A OR: 1.76, 95% CI: 1.49, 2.07). CONCLUSIONS: Reactive arthritis may be more common in military populations than previously described. The burden of ReA and strong association with antecedent IGE warrants continued IGE prevention efforts. PMID- 20836850 TI - Evaluation of mammographic density patterns: reproducibility and concordance among scales. AB - BACKGROUND: Increased mammographic breast density is a moderate risk factor for breast cancer. Different scales have been proposed for classifying mammographic density. This study sought to assess intra-rater agreement for the most widely used scales (Wolfe, Tabar, BI-RADS and Boyd) and compare them in terms of classifying mammograms as high- or low-density. METHODS: The study covered 3572 mammograms drawn from women included in the DDM-Spain study, carried-out in seven Spanish Autonomous Regions. Each mammogram was read by an expert radiologist and classified using the Wolfe, Tabar, BI-RADS and Boyd scales. In addition, 375 mammograms randomly selected were read a second time to estimate intra-rater agreement for each scale using the kappa statistic. Owing to the ordinal nature of the scales, weighted kappa was computed. The entire set of mammograms (3572) was used to calculate agreement among the different scales in classifying high/low-density patterns, with the kappa statistic being computed on a pair-wise basis. High density was defined as follows: percentage of dense tissue greater than 50% for the Boyd, "heterogeneously dense and extremely dense" categories for the BI-RADS, categories P2 and DY for the Wolfe, and categories IV and V for the Tabar scales. RESULTS: There was good agreement between the first and second reading, with weighted kappa values of 0.84 for Wolfe, 0.71 for Tabar, 0.90 for BI-RADS, and 0.92 for Boyd scale. Furthermore, there was substantial agreement among the different scales in classifying high- versus low-density patterns. Agreement was almost perfect between the quantitative scales, Boyd and BI-RADS, and good for those based on the observed pattern, i.e., Tabar and Wolfe (kappa 0.81). Agreement was lower when comparing a pattern-based (Wolfe or Tabar) versus a quantitative-based (BI-RADS or Boyd) scale. Moreover, the Wolfe and Tabar scales classified more mammograms in the high-risk group, 46.61 and 37.32% respectively, while this percentage was lower for the quantitative scales (21.89% for BI-RADS and 21.86% for Boyd). CONCLUSIONS: Visual scales of mammographic density show a high reproducibility when appropriate training is provided. Their ability to distinguish between high and low risk render them useful for routine use by breast cancer screening programs. Quantitative-based scales are more specific than pattern-based scales in classifying populations in the high-risk group. PMID- 20836851 TI - Hemoglobin alpha and beta are ubiquitous in the human lung, decline in idiopathic pulmonary fibrosis but not in COPD. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are disorders of the lung parenchyma. They share the common denominators of a progressive nature and poor prognosis. The goal was to use non biased proteomics to discover new markers for these diseases. METHODS: Proteomics of fibrotic vs. control lung tissue suggested decreased levels of several spots in the lung specimens of IPF patients, which were identified as Hemoglobin (Hb) alpha and beta monomers and Hbalpha complexes. The Hbalpha and beta monomers and complexes were investigated in more detail in normal lung and lung specimens of patients with IPF and COPD by immunohistochemistry, morphometry and mass spectrometry (MS). RESULTS: Both Hb monomers, in normal lung, were expressed especially in the alveolar epithelium. Levels of Hbalpha and beta monomers and complexes were reduced/lost in IPF but not in the COPD lungs when compared to control lung. MS-analyses revealed Hbalpha modification at cysteine105 (Cysalpha105), preventing formation of the Hbalpha complexes in the IPF lungs. Hbalpha and Hbbeta were expressed as complexes and monomers in the lung tissues, but were secreted into the bronchoalveolar lavage fluid and/or induced sputum supernatants as complexes corresponding to the molecular weight of the Hb tetramer. CONCLUSIONS: The abundant expression of the oxygen carrier molecule Hb in the normal lung epithelium and its decline in IPF lung are new findings. The loss of Hb complex formation in IPF warrants further studies and may be considered as a disease-specific modification. PMID- 20836852 TI - Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c Jun N-terminal kinase and p38 mitogen-activated protein kinase. AB - BACKGROUND: Ceramide is an important second messenger that has diverse cellular and biological effect. It is a specific and potent inducer of apoptosis and suppressor of cell growth. In leukemia, chemoresistance generally developed due to deregulated ceramide metabolism. In combinatorial treatment strategies of leukemia, few components have the capability to increases ceramide production. Manipulation in ceramide production by physiological and pharmacological modulators therefore will give additive effect in leukemia chemotherapy. RESULTS: Here, we show that Withanolide D (C4beta-C5beta,C6beta-epoxy-1-oxo-,20beta, dihydroxy-20S,22R-witha-2,24-dienolide; WithaD), a pure herbal compound isolated from Withania somnifera could effectively induces apoptosis in a dose and time dependant manner both in myeloid (K562) and lymphoid (MOLT-4) cells being nontoxic to normal lymphocytes and control proliferative cells. WithaD potentially augment ceramide production in these cells. Downstream of ceramide, WithaD acted on MKK group of proteins and significantly increased JNK and p38MAPK phosphorylation. Pharmacological inhibition of p38MAPK and JNK proves their cooperative action on WithaD-induced cell death. Dissecting the cause of ceramide production, we found activation of neutral sphingomyelinase and showed neutral sphingomyelinase 2 (N-SMase 2) is a critical mediator of WithaD-induced apoptosis. Knockdown of N-SMase 2 by siRNA and inhibitor of N-SMase (GW4869) significantly reduced WithaD-induced ceramide generation and phosphorylation of MKK4 and MKK3/6, whereas phosphorylation of MKK7 was moderately regulated in leukemic cells. Also, both by silencing of N-SMase 2 and/or blocking by GW4869 protects these cells from WithaD-mediated death and suppressed apoptosis, whereas Fumonisin B1, an inhibitor of ceramide synthase, did not have any effect. Additionally, WithaD effectively induced apoptosis in freshly isolated lymphoblasts from patients and the potent cell killing activity was through JNK and p38MAPK activation. CONCLUSION: Our results demonstrate that WithaD enhance the ceramide accumulation by activating N-SMase 2, modulate phosphorylation of the JNK and p38MAPK and induced apoptosis in both myeloid and lymphoid cells along with primary cells derived from leukemia patients. Taken together, this pure herbal compound (WithaD) may consider as a potential alternative tool with additive effects in conjunction with traditional chemotherapeutic treatment, thereby accelerate the process of conventional drug development. PMID- 20836853 TI - COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination. AB - BACKGROUND: Dopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC--including Catechol-O-Methyltransferase (COMT) Val158Met--are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required. METHODS: Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation. RESULTS: In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated. CONCLUSIONS: Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components. PMID- 20836854 TI - Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo. AB - BACKGROUND: Delivery of small interfering RNA (siRNA) to tumours remains a major obstacle for the development of RNA interference (RNAi)-based therapeutics. Following the promising pre-clinical and clinical results with the oncolytic herpes simplex virus (HSV) OncoVEX GM-CSF, we aimed to express RNAi triggers from oncolytic HSV, which although has the potential to improve treatment by silencing tumour-related genes, was not considered possible due to the highly oncolytic properties of HSV. METHODS: To evaluate RNAi-mediated silencing from an oncolytic HSV backbone, we developed novel replicating HSV vectors expressing short-hairpin RNA (shRNA) or artificial microRNA (miRNA) against the reporter genes green fluorescent protein (eGFP) and beta-galactosidase (lacZ). These vectors were tested in non-tumour cell lines in vitro and tumour cells that are moderately susceptible to HSV infection both in vitro and in mice xenografts in vivo. Silencing was assessed at the protein level by fluorescent microscopy, x-gal staining, enzyme activity assay, and western blotting. RESULTS: Our results demonstrate that it is possible to express shRNA and artificial miRNA from an oncolytic HSV backbone, which had not been previously investigated. Furthermore, oncolytic HSV-mediated delivery of RNAi triggers resulted in effective and specific silencing of targeted genes in tumour cells in vitro and tumours in vivo, with the viruses expressing artificial miRNA being comprehensibly more effective. CONCLUSIONS: This preliminary data provide the first demonstration of oncolytic HSV-mediated expression of shRNA or artificial miRNA and silencing of targeted genes in tumour cells in vitro and in vivo. The vectors developed in this study are being adapted to silence tumour-related genes in an ongoing study that aims to improve the effectiveness of oncolytic HSV treatment in tumours that are moderately susceptible to HSV infection and thus, potentially improve response rates seen in human clinical trials. PMID- 20836855 TI - The effects of diabetes and/or peripheral neuropathy in detecting short postural perturbations in mature adults. AB - BACKGROUND: This study explored the effects of diabetes mellitus (DM) and peripheral neuropathy (PN) on the ability to detect near-threshold postural perturbations. METHODS: 83 subjects participated; 32 with type II DM (25 with PN and 7 without PN), 19 with PN without DM, and 32 without DM or PN. Peak acceleration thresholds for detecting anterior platform translations of 1 mm, 4 mm, and 16 mm displacements were determined. A 2(DM) * 2(PN) factorial MANCOVA with weight as a covariate was calculated to compare acceleration detection thresholds among subjects who had DM or did not and who had PN or did not. RESULTS: There was a main effect for DM but not for PN. Post hoc analysis revealed that subjects with DM required higher accelerations to detect a 1 mm and 4 mm displacement. CONCLUSION: Our findings suggest that PN may not be the only cause of impaired balance in people with DM. Clinicians should be aware that diabetes itself might negatively impact the postural control system. PMID- 20836856 TI - Veterans walk to beat back pain: study rationale, design and protocol of a randomized trial of a pedometer-based internet mediated intervention for patients with chronic low back pain. AB - BACKGROUND: Chronic back pain is a significant problem worldwide and may be especially prevalent among patients receiving care in the U.S. Department of Veterans Affairs healthcare system. Back pain affects adults at all ages and is associated with disability, lost workplace productivity, functional limitations and social isolation. Exercise is one of the most effective strategies for managing chronic back pain. Yet, there are few clinical programs that use low cost approaches to help patients with chronic back pain initiate and maintain an exercise program. METHODS/DESIGN: We describe the design and rationale of a randomized controlled trial to assess the efficacy of a pedometer-based Internet mediated intervention for patients with chronic back pain. The intervention uses an enhanced pedometer, website and e-community to assist these patients with initiating and maintaining a regular walking program with the primary aim of reducing pain-related disability and functional interference. The study specific aims are: 1) To determine whether a pedometer-based Internet-mediated intervention reduces pain-related functional interference among patients with chronic back pain in the short term and over a 12-month timeframe. 2) To assess the effect of the intervention on walking (measured by step counts), quality of life, pain intensity, pain related fear and self-efficacy for exercise. 3) To identify factors associated with a sustained increase in walking over a 12-month timeframe among patients randomized to the intervention. DISCUSSION: Exercise is an integral part of managing chronic back pain but to be effective requires that patients actively participate in the management process. This intervention is designed to increase activity levels, improve functional status and make exercise programs more accessible for a broad range of patients with chronic back pain. TRIAL REGISTRATION NUMBER: NCT00694018. PMID- 20836857 TI - Genome-scale identification of soybean BURP domain-containing genes and their expression under stress treatments. AB - BACKGROUND: Multiple proteins containing BURP domain have been identified in many different plant species, but not in any other organisms. To date, the molecular function of the BURP domain is still unknown, and no systematic analysis and expression profiling of the gene family in soybean (Glycine max) has been reported. RESULTS: In this study, multiple bioinformatics approaches were employed to identify all the members of BURP family genes in soybean. A total of 23 BURP gene types were identified. These genes had diverse structures and were distributed on chromosome 1, 2, 4, 6, 7, 8, 11, 12, 13, 14, and 18. Phylogenetic analysis suggested that these BURP family genes could be classified into 5 subfamilies, and one of which defines a new subfamily, BURPV. Quantitative real time PCR (qRT-PCR) analysis of transcript levels showed that 15 of the 23 genes had no expression specificity; 7 of them were specifically expressed in some of the tissues; and one of them was not expressed in any of the tissues or organs studied. The results of stress treatments showed that 17 of the 23 identified BURP family genes responded to at least one of the three stress treatments; 6 of them were not influenced by stress treatments even though a stress related cis element was identified in the promoter region. No stress related cis-elements were found in promoter region of any BURPV member. However, qRT-PCR results indicated that all members from BURPV responded to at least one of the three stress treatments. More significantly, the members from the RD22-like subfamily showed no tissue-specific expression and they all responded to each of the three stress treatments. CONCLUSIONS: We have identified and classified all the BURP domain-containing genes in soybean. Their expression patterns in different tissues and under different stress treatments were detected using qRT-PCR. 15 out of 23 BURP genes in soybean had no tissue-specific expression, while 17 out of them were stress-responsive. The data provided an insight into the evolution of the gene family and suggested that many BURP family genes may be important for plants responding to stress conditions. PMID- 20836859 TI - Equity in HIV testing: evidence from a cross-sectional study in ten Southern African countries. AB - BACKGROUND: HIV testing with counseling is an integral component of most national HIV and AIDS prevention strategies in southern Africa. Equity in testing implies that people at higher risk for HIV such as women; those who do not use condoms consistently; those with multiple partners; those who have suffered gender based violence; and those who are unable to implement prevention choices (the choice disabled) are tested and can have access to treatment. METHODS: We conducted a household survey of 24,069 people in nationally stratified random samples of communities in Botswana, Lesotho, Malawi, Mozambique, Namibia, South Africa, Swaziland, Tanzania, Zambia, and Zimbabwe. We asked about testing for HIV in the last 12 months, intention to test, and about HIV risk behaviour, socioeconomic indicators, access to information, and attitudes related to stigma. RESULTS: Across the ten countries, seven out of every ten people said they planned to have an HIV test but the actual proportion tested in the last 12 months varied from 24% in Mozambique to 64% in Botswana. Generally, people at higher risk of HIV were not more likely to have been tested in the last year than those at lower risk, although women were more likely than men to have been tested in six of the ten countries. In Swaziland, those who experienced partner violence were more likely to test, but in Botswana those who were choice-disabled for condom use were less likely to be tested. The two most consistent factors associated with HIV testing across the countries were having heard about HIV/AIDS from a clinic or health centre, and having talked to someone about HIV and AIDS. CONCLUSIONS: HIV testing programmes need to encourage people at higher risk of HIV to get tested, particularly those who do not interact regularly with the health system. Service providers need to recognise that some people are not able to implement HIV preventive actions and may not feel empowered to get themselves tested. PMID- 20836858 TI - The oxysterol 27-hydroxycholesterol increases beta-amyloid and oxidative stress in retinal pigment epithelial cells. AB - BACKGROUND: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including beta-amyloid (Abeta) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD. METHODS: ARPE-19 cells were treated with 0, 10 or 25 MUM 27-OHC for 24 hours. Levels of Abeta peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca2+ homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays. RESULTS: 27-OHC dose-dependently increased Abeta peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca2+ dyshomeostasis, increased levels of the nuclear factor kappaB (NFkappaB) and heme oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27 OHC caused glutathione depletion, ROS generation, inflammation and apoptotic mediated cell death. CONCLUSIONS: The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from Abeta accumulation to oxidative cell damage. Our results suggest that high levels of 27 OHC may represent a common pathogenic factor for both AMD and AD. PMID- 20836860 TI - Identification of a novel linear B-cell epitope in the UL26 and UL26.5 proteins of Duck Enteritis Virus. AB - BACKGROUND: The Unique Long 26 (UL26) and UL26.5 proteins of herpes simplex virus are known to function during the assembly of the viruses. However, for duck enteritis virus (DEV), which is an unassigned member of the family Herpesviridae, little information is available about the function of the two proteins. In this study, the C-terminus of DEV UL26 protein (designated UL26c), which contains the whole of UL26.5, was expressed, and the recombinant UL26c protein was used to immunize BALB/c mice to generate monoclonal antibodies (mAb). The mAb 1C8 was generated against DEV UL26 and UL26.5 proteins and used subsequently to map the epitope in this region. Both the mAb and its defined epitope will provide potential tools for further study of DEV. RESULTS: A mAb (designated 1C8) was generated against the DEV UL26c protein, and a series of 17 partially overlapping fragments that spanned the DEV UL26c were expressed with GST tags. These peptides were subjected to enzyme-linked immunosorbent assay (ELISA) and western blotting analysis using mAb 1C8 to identify the epitope. A linear motif, 520IYYPGE525, which was located at the C-terminus of the DEV UL26 and UL26.5 proteins, was identified by mAb 1C8. The result of the ELISA showed that this epitope could be recognized by DEV-positive serum from mice. The 520IYYPGE525 motif was the minimal requirement for reactivity, as demonstrated by analysis of the reactivity of 1C8 with several truncated peptides derived from the motif. Alignment and comparison of the 1C8-defined epitope sequence with those of other alphaherpesviruses indicated that the motif 521YYPGE525 in the epitope sequence was conserved among the alphaherpesviruses. CONCLUSION: A mAb, 1C8, was generated against DEV UL26c and the epitope-defined minimal sequence obtained using mAb 1C8 was 520IYYPGE525. The mAb and the identified epitope may be useful for further study of the design of diagnostic reagents for DEV. PMID- 20836861 TI - European Association for Palliative Care (EAPC) framework for palliative sedation: an ethical discussion. AB - BACKGROUND: The aim of this paper is to critically discuss some of the ethically controversial issues regarding continuous deep palliative sedation at the end of life that are addressed in the EAPC recommended framework for the use of sedation in palliative care. DISCUSSION: We argue that the EAPC framework would have benefited from taking a clearer stand on the ethically controversial issues regarding intolerable suffering and refractory symptoms and regarding the relation between continuous deep palliative sedation at the end of life and euthanasia. It is unclear what constitutes refractory symptoms and what the relationship is between refractory symptoms and intolerable suffering, which in turn makes it difficult to determine what are necessary and sufficient criteria for palliative sedation at the end of life, and why. As regards the difference between palliative sedation at the end of life and so-called slow euthanasia, the rationale behind stressing the difference is insufficiently demonstrated, e.g. due to an overlooked ambiguity in the concept of intention. It is therefore unclear when palliative sedation at the end of life amounts to abuse and why. CONCLUSIONS: The EAPC framework would have benefited from taking a clearer stand on some ethically controversial issues regarding intolerable suffering and refractory symptoms and regarding the relation between continuous deep palliative sedation at the end of life and euthanasia. In this text, we identify and discuss these issues in the hope that an ensuing discussion will clarify the EAPC's standpoint. PMID- 20836862 TI - Assessment of myocardial abnormalities in rheumatoid arthritis using a comprehensive cardiac magnetic resonance approach: a pilot study. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a multi-organ inflammatory disorder associated with high cardiovascular morbidity and mortality. We sought to assess cardiac involvement using a comprehensive cardiac magnetic resonance imaging (cMRI) approach and to determine its association with disease characteristics in RA patients without symptomatic cardiac disease. METHODS: RA patients with no history and/or clinical findings of systemic or pulmonary hypertension, coronary artery disease, severe valvular heart disease, atrial fibrillation, diabetes mellitus, or echocardiographic abnormalities underwent contrast-enhanced cMRI on a 1.5T scanner. Adenosine triphosphate was used to assess perfusion defects due to microvascular impairment or ischemia, and delayed enhanced imaging was obtained for the assessment of myocardial inflammation/fibrosis. We explored the associations of cMRI abnormalities with RA disease activity and severity measures. RESULTS: Eighteen patients (78% female) with a mean age of 57 +/- 10 years were studied. Eight patients (45%) demonstrated a myocardial abnormality. Perfusion defects under pharmacologic stress were seen in two patients (11%), one of whom had a circumferential subendocardial perfusion defect and one had a non segmental subendocardial perfusion defect. Seven patients (39%) were found to have delayed enhancement, only one of whom also demonstrated a perfusion defect. Mean disease activity score (DAS)28 was significantly higher in the group with delayed enhancement compared to the group without by an average of 1.32 DAS28 units (4.77 vs. 3.44 units, respectively; P = 0.011). Corresponding trends to statistical significance were noted in systemic inflammatory markers, with both C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) quantitatively higher in the group with delayed enhancement. Other RA characteristics, such as disease duration, autoantibody status, and current treatments were not significantly associated with cardiac involvement. CONCLUSIONS: Myocardial abnormalities, as detected by cMRI, were frequent in RA patients without known cardiac disease. Abnormal cMRI findings were associated with higher RA disease activity, suggesting a role for inflammation in the pathogenesis of myocardial involvement in RA. PMID- 20836863 TI - Multiple genetic switches spontaneously modulating bacterial mutability. AB - BACKGROUND: All life forms need both high genetic stability to survive as species and a degree of mutability to evolve for adaptation, but little is known about how the organisms balance the two seemingly conflicting aspects of life: genetic stability and mutability. The DNA mismatch repair (MMR) system is essential for maintaining genetic stability and defects in MMR lead to high mutability. Evolution is driven by genetic novelty, such as point mutation and lateral gene transfer, both of which require genetic mutability. However, normally a functional MMR system would strongly inhibit such genomic changes. Our previous work indicated that MMR gene allele conversion between functional and non functional states through copy number changes of small tandem repeats could occur spontaneously via slipped-strand mis-pairing during DNA replication and therefore may play a role of genetic switches to modulate the bacterial mutability at the population level. The open question was: when the conversion from functional to defective MMR is prohibited, will bacteria still be able to evolve by accepting laterally transferred DNA or accumulating mutations? RESULTS: To prohibit allele conversion, we "locked" the MMR genes through nucleotide replacements. We then scored changes in bacterial mutability and found that Salmonella strains with MMR locked at the functional state had significantly decreased mutability. To determine the generalizability of this kind of mutability 'switching' among a wider range of bacteria, we examined the distribution of tandem repeats within MMR genes in over 100 bacterial species and found that multiple genetic switches might exist in these bacteria and may spontaneously modulate bacterial mutability during evolution. CONCLUSIONS: MMR allele conversion through repeats-mediated slipped-strand mis-pairing may function as a spontaneous mechanism to switch between high genetic stability and mutability during bacterial evolution. PMID- 20836864 TI - Synergistic disruptions in seuss cyp85A2 double mutants reveal a role for brassinolide synthesis during gynoecium and ovule development. AB - BACKGROUND: The Arabidopsis SEUSS (SEU) gene encodes a transcriptional adaptor protein that is required for a diverse set of developmental events, including floral organ identity specification, as well as gynoecium, ovule and embryo development. In order to better understand the molecular mechanisms of SEUSS action we undertook a genetic modifier screen to identify seuss-modifier (sum) mutations. RESULTS: Screening of M2 lines representing approximately 5,000 M1 individuals identified mutations that enhance the seuss mutant phenotypic disruptions in ovules and gynoecia; here we describe the phenotype of the sum63 mutant and enhanced disruptions of ovule and gynoecial development in the seu sum63 double mutant. Mapping and genetic complementation tests indicate that sum63 is allelic to CYP85A2 (AT3G30180) a cytochrome p450 enzyme that catalyzes the final steps in the synthesis of the phytohormone brassinolide. CONCLUSIONS: Our identification of mutations in CYP85A2 as enhancers of the seuss mutant phenotype suggests a previously unrecognized role for brassinolide synthesis in gynoecial and ovule outer integument development. The work also suggests that seuss mutants may be more sensitive to the loss or reduction of brassinolide synthesis than are wild type plants. PMID- 20836865 TI - Implications of land use change on the national terrestrial carbon budget of Georgia. AB - BACKGROUND: Globally, the loss of forests now contributes almost 20% of carbon dioxide emissions to the atmosphere. There is an immediate need to reduce the current rates of forest loss, and the associated release of carbon dioxide, but for many areas of the world these rates are largely unknown. The Soviet Union contained a substantial part of the world's forests and the fate of those forests and their effect on carbon dynamics remain unknown for many areas of the former Eastern Bloc. For Georgia, the political and economic transitions following independence in 1991 have been dramatic. In this paper we quantify rates of land use changes and their effect on the terrestrial carbon budget for Georgia. A carbon book-keeping model traces changes in carbon stocks using historical and current rates of land use change. Landsat satellite images acquired circa 1990 and 2000 were analyzed to detect changes in forest cover since 1990. RESULTS: The remote sensing analysis showed that a modest forest loss occurred, with approximately 0.8% of the forest cover having disappeared after 1990. Nevertheless, growth of Georgian forests still contribute a current national sink of about 0.3 Tg of carbon per year, which corresponds to 31% of the country anthropogenic carbon emissions. CONCLUSIONS: We assume that the observed forest loss is mainly a result of illegal logging, but we have not found any evidence of large-scale clear-cutting. Instead local harvesting of timber for household use is likely to be the underlying driver of the observed logging. The Georgian forests are a currently a carbon sink and will remain as such until about 2040 if the current rate of deforestation persists. Forest protection efforts, combined with economic growth, are essential for reducing the rate of deforestation and protecting the carbon sink provided by Georgian forests. PMID- 20836866 TI - Preparation and properties of the specific anti-influenza virus transfer factor. AB - Specific anti-influenza virus and normal transfer factors prepared in an experimental animal model, the pig, have been tested for their components, characteristics, and activity of known specificity. Two transfer factors are small molecular mixture which consist entirely or partly of polypeptides and polynucleosides. Moreover, the biological activity of transfer factors could be approved by Rosettes test and specific skin test. The study would lay a foundation for the research and development of other specific transfer factor. PMID- 20836867 TI - Adverse effects of extra-articular corticosteroid injections: a systematic review. AB - BACKGROUND: To estimate the occurrence and type of adverse effects after application of an extra-articular (soft tissue) corticosteroid injection. METHODS: A systematic review of the literature was made based on a PubMed and Embase search covering the period 1956 to January 2010. Case reports were included, as were prospective and retrospective studies that reported adverse events of corticosteroid injection. All clinical trials which used extra articular corticosteroid injections were examined. We divided the reported adverse events into major (defined as those needing intervention or not disappearing) and minor ones (transient, not requiring intervention). RESULTS: The search yielded 87 relevant studies:44 case reports, 37 prospective studies and 6 retrospective studies. The major adverse events included osteomyelitis and protothecosis; one fatal necrotizing fasciitis; cellulitis and ecchymosis; tendon ruptures; atrophy of the plantar fat was described after injecting a neuroma; and local skin effects appeared as atrophy, hypopigmentation or as skin defect. The minor adverse events effects ranged from skin rash to flushing and disturbed menstrual pattern. Increased pain or steroid flare after injection was reported in 19 studies. After extra-articular injection, the incidence of major adverse events ranged from 0-5.8% and that of minor adverse events from 0-81%. It was not feasible to pool the risk for adverse effects due to heterogeneity of study populations and difference in interventions and variance in reporting. CONCLUSION: In this literature review it was difficult to accurately quantify the incidence of adverse effects after extra-articular corticosteroid injection. The reported adverse events were relatively mild, although one fatal reaction was reported. PMID- 20836868 TI - Health-care cost reduction resulting from primary-care allergy testing in children in Italy. AB - BACKGROUND: Allergy places a considerable cost burden on society. Specific immunoglobulin E (spIgE) testing may improve the management of allergy patients. There is therefore a reason to quantify the economic consequences of the use of spIgE testing in the diagnosis of allergic conditions. METHODS: The expected costs of spIgE testing versus no-testing were calculated using a clinical decision model based on a prospective clinical trial performed in primary care. RESULTS: The expected costs per patient over 2 years decreased from 802 euros in the "no-test strategy" to 560 euros in the spIgE "test strategy". Cost savings persisted even after assumptions about the prevalence of allergy and the prices of medications were changed. The "test strategy" increased the percentage of patients correctly diagnosed from 54 to 87%. CONCLUSIONS: spIgE testing of children with respiratory and/or skin problems in primary care in Italy reduces overall costs to society. These cost savings mostly result from a reduction in the use of medications, particularly corticosteroids. The study indicates that spIgE testing of all children with respiratory and/or skin symptoms would be a cost-effective strategy. PMID- 20836869 TI - Failure to detect Xenotropic murine leukaemia virus-related virus in Chinese patients with chronic fatigue syndrome. AB - BACKGROUND: Recent controversy has surrounded the question of whether xenotropic murine leukaemia virus-related virus (XMRV) contributes to the pathogenesis of chronic fatigue syndrome (CFS). To investigate the question in a Chinese population, 65 CFS patients and 85 blood donor controls were enrolled and multiplex real-time PCR or reverse transcriptase PCR (RT-PCR) was developed to analyze the XMRV infection status of the study participants. The assay was standardized by constructing plasmid DNAs and armored RNAs as XMRV standards and competitive internal controls (CICs), respectively. RESULTS: The sensitivities of the multiplex real-time PCR and RT-PCR assays were 20 copies/reaction and 10 IU/ml, respectively, with 100% specificity. The within-run precision coefficient of variation (CV) ranged from 1.76% to 2.80% and 1.70% to 2.59%, while the between-run CV ranged from 1.07% to 2.56% and 1.06% to 2.74%. XMRV was not detected in the 65 CFS patients and 65 normal individuals out of 85 controls. CONCLUSIONS: This study failed to show XMRV in peripheral blood mononuclear cells (PBMCs) and plasma of Chinese patients with CFS. The absence of XMRV nucleic acids does not support an association between XMRV infection and the development of CFS in Chinese. PMID- 20836870 TI - Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity. AB - BACKGROUND: An ideal tumor vaccine should activate both effector and memory immune response against tumor-specific antigens. Beside the CD8+ T cells that play a central role in the generation of a protective immune response and of long term memory, dendritic cells (DCs) are important for the induction, coordination and regulation of the adaptive immune response. The DCs can conduct all of the elements of the immune orchestra and are therefore a fundamental target and tool for vaccination. The present study was aimed at assessing the ability of tumor vaccine composed of C-class CpG ODNs and irradiated melanoma tumor cells B16F1 followed by two additional injections of CpG ODNs to induce the generation of a functional long-term memory response in experimental tumor model in mice (i.p. B16F1). RESULTS: It has been shown that the functional memory response in vaccinated mice persists for at least 60 days after the last vaccination. Repeated vaccination also improves the survival of experimental animals compared to single vaccination, whereas the proportion of animals totally protected from the development of aggressive i.p. B16F1 tumors after vaccination repeated three times varies between 88.9%-100.0%. Additionally, the long-term immune memory and tumor protection is maintained over a prolonged period of time of at least 8 months. Finally, it has been demonstrated that following the vaccination the tumor-specific memory cells predominantly reside in bone marrow and peritoneal tissue and are in a more active state than their splenic counterparts. CONCLUSIONS: In this study we demonstrated that tumor vaccine composed of C-class CpG ODNs and irradiated tumor cells followed by two additional injections of CpG ODNs induces a long-term immunity against aggressive B16F1 tumors. PMID- 20836871 TI - Single fraction radiosurgery using Rapid Arc for treatment of intracranial targets. AB - BACKGROUND: Stereotactic-Radio-Surgery (SRS) using Conformal-Arc-Therapy (CAT) is a well established irradiation technique for treatment of intracranial targets. Although small safety margins are required because of very high accuracy of patient positioning and exact online localisation, there are still disadvantages like long treatment time, high number of monitor units (MU) and covering of noncircular targets. This planning study analysed whether Rapid Arc (RA) with stereotactic localisation for single-fraction SRS can solve these problems. METHODS: Ten consecutive patients were treated with Linac-based SRS. Eight patients had one or more brain metastases. The other patients presented a symptomatic vestibularis schwannoma and an atypic meningioma. For all patients, two plans (CAT/RA) were calculated and analysed. RESULTS: Conformity was higher for RA with additional larger low-dose areas. Furthermore, RA reduced the number of MU and the treatment time for all patients. Dose to organs at risk were equal or slightly higher using RA in comparison to CAT. CONCLUSIONS: RA provides a new alternative for single-fraction SRS irradiation combining advantages of short treatment time with lower number of MU and better conformity in addition to accuracy of stereotactic localisation in selected cases with uncomplicated clinical realization. PMID- 20836872 TI - Trends in HIV & syphilis prevalence and correlates of HIV infection: results from cross-sectional surveys among women attending ante-natal clinics in Northern Tanzania. AB - BACKGROUND: Sentinel surveillance for HIV in ante-natal clinics (ANC) remains the primary method for collecting timely trend data on HIV prevalence in most of sub Saharan Africa. We describe prevalence of HIV and syphilis infection and trends over time in HIV prevalence among women attending ante-natal clinics (ANC) in Magu district and Mwanza city, part of Mwanza region in Northern Tanzania. HIV prevalence from ANC surveys in 2000 and 2002 was 10.5% and 10.8% respectively. In previous rounds urban residence, residential mobility, the length of time sexually active before marriage, time since marriage and age of the partner were associated with HIV infection. METHODS: A third round of HIV sentinel surveillance was conducted at ante-natal clinics in Mwanza region, Tanzania during 2006. We interviewed women attending 27 ante-natal clinics. In 15 clinics we also anonymously tested women for syphilis and HIV infection and linked these results to the questionnaire data. RESULTS: HIV prevalence was 7.6% overall in 2006 and 7.4% at the 11 clinics used in previous rounds. Geographical variations in HIV prevalence, apparent in previous rounds, have largely disappeared but syphilis prevalence is still higher in rural clinics. HIV prevalence has declined in urban clinics and is stable in rural clinics. The correlates of HIV infection have changed over time. In this round older age, lower gravidity, remarriage, duration of marriage, sexual activity before marriage, long interval between last birth and pregnancy and child death were all associated with infection. CONCLUSIONS: HIV prevalence trends concur with results from a community-based cohort in the region. Correlates of HIV infection have also changed and more proximate, individual level factors are now more important, in line with the changing epidemiology of infection in this population. PMID- 20836873 TI - Facilitation of the inhibitory transmission by gastrin-releasing peptide in the anterior cingulate cortex. AB - Gastrin-releasing peptide (GRP) has been proposed as a peptidergic molecule for behavioral fear and itching. Immunohistochemistry and in situ hybridization studies have shown that GRP and GRP receptor are widely distributed in forebrain areas. Less information is available for the functional action for GRP in the prefrontal cortex including the anterior cingulate cortex (ACC). Here we used whole-cell patch-clamp recording technique to study the modulation of synaptic transmission by GRP in the ACC. We found that GRP increased the frequency of sIPSCs recorded while had no significant effect on sEPSCs in ACC pyramidal neurons. The facilitatory effect of GRP on sIPSCs was blocked by the GRP receptor antagonist, RC3095. In the presence of TTX, however, GRP had no effect on the mIPSCs. Therefore, activation of GRP receptor may facilitate the excitation of the interneurons and enhanced spontaneous GABAergic, but not glutamatergic neurotransmission. Similar results on GRP modulation of GABAergic transmission were observed in the insular cortex and amygdala, suggesting a general possible effect of GRP on cortical inhibitory transmission. Our results suggest that GRP receptor is an important regulator of inhibitory circuits in forebrain areas. PMID- 20836874 TI - Design of splints based on the NiTi alloy for the correction of joint deformities in the fingers. AB - BACKGROUND: The proximal interphalange joint (PIP) is fundamental for the functional nature of the hand. The contracture in flexion of the PIP, secondary to traumatisms or illnesses leads to an important functional loss. The use of correcting splints is the common procedure for treating this problem. Its functioning is based on the application of a small load and a prolonged stress which can be dynamic, static progressive or static serial.It is important that the therapist has a splint available which can release a constant and sufficient force to correct the contracture in flexion. Nowadays NiTi is commonly used in bio-engineering, due to its superelastical characteristics. The experience of the authors in the design of other devices based on the NiTi alloy, makes it possible to carry out a new design in this work--the production of a finger splint for the treatment of the contracture in flexion of the PIP joint. METHODS: Commercial orthosis have been characterized using a universal INSTRON 5565 machine. A computational simulation of the proposed design has been conducted, reproducing its performance and using a model "ad hoc" for the NiTi material. Once the parameters have been adjusted, the design is validated using the same type of test as those carried out on commercial orthosis. RESULTS AND DISCUSSION: For commercial splint the recovering force falls to excessively low values as the angle increases. Angle curves for different lengths and thicknesses of the proposed design have been obtained, with a practically constant recovering force value over a wide range of angles that vary between 30 degrees and 150 degrees in every case. Then the whole treatment is possible with only one splint, and without the need of progressive replacements as the joint recovers. CONCLUSIONS: A new model of splint based on NiTi alloy has been designed, simulated and tested comparing its behaviour with two of the most regularly used splints. Its uses is recommended instead of other dynamic orthosis used in orthopaedics for the PIP joint. Besides, its extremely simple design, makes its manufacture and use on the part of the specialist easier. PMID- 20836875 TI - Adenoviral delivery of pan-caspase inhibitor p35 enhances bystander killing by P450 gene-directed enzyme prodrug therapy using cyclophosphamide+. AB - BACKGROUND: Cytochrome P450-based suicide gene therapy for cancer using prodrugs such as cyclophosphamide (CPA) increases anti-tumor activity, both directly and via a bystander killing mechanism. Bystander cell killing is essential for the clinical success of this treatment strategy, given the difficulty of achieving 100% efficient gene delivery in vivo using current technologies. Previous studies have shown that the pan-caspase inhibitor p35 significantly increases CPA-induced bystander killing by tumor cells that stably express P450 enzyme CYP2B6 (Schwartz et al, (2002) Cancer Res. 62: 6928-37). METHODS: To further develop this approach, we constructed and characterized a replication-defective adenovirus, Adeno-2B6/p35, which expresses p35 in combination with CYP2B6 and its electron transfer partner, P450 reductase. RESULTS: The expression of p35 in Adeno-2B6/p35 infected tumor cells inhibited caspase activation, delaying the death of the CYP2B6 "factory" cells that produce active CPA metabolites, and increased bystander tumor cell killing compared to that achieved in the absence of p35. Tumor cells infected with Adeno-2B6/p35 were readily killed by cisplatin and doxorubicin, indicating that p35 expression is not associated with acquisition of general drug resistance. Finally, p35 did not inhibit viral release when the replication-competent adenovirus ONYX-017 was used as a helper virus to facilitate co-replication and spread of Adeno-2B6/p35 and further increase CPA induced bystander cell killing. CONCLUSIONS: The introduction of p35 into gene therapeutic regimens constitutes an effective approach to increase bystander killing by cytochrome P450 gene therapy. This strategy may also be used to enhance other bystander cytotoxic therapies, including those involving the production of tumor cell toxic protein products. PMID- 20836876 TI - A comparative summary of expression systems for the recombinant production of galactose oxidase. AB - BACKGROUND: The microbes Escherichia coli and Pichia pastoris are convenient prokaryotic and eukaryotic hosts, respectively, for the recombinant production of proteins at laboratory scales. A comparative study was performed to evaluate a range of constructs and process parameters for the heterologous intra- and extracellular expression of genes encoding the industrially relevant enzyme galactose 6-oxidase (EC 1.1.3.9) from the fungus Fusarium graminearum. In particular, the wild-type galox gene from F. graminearum, an optimized variant for E. coli and a codon-optimized gene for P. pastoris were expressed without the native pro-sequence, but with a His-tag either at the N- or the C-terminus of the enzyme. RESULTS: The intracellular expression of a codon-optimized gene with an N terminal His10-tag in E. coli, using the pET16b+ vector and BL21DE3 cells, resulted in a volumetric productivity of 180 U.L-1.h-1. The intracellular expression of the wild-type gene from F. graminearum, using the pPIC3.5 vector and the P. pastoris strain GS115, was poor, resulting in a volumetric productivity of 120 U.L-1.h-1. Furthermore, this system did not tolerate an N terminal His10-tag, thus rendering isolation of the enzyme from the complicated mixture difficult. The highest volumetric productivity (610 U.L-1.h-1) was achieved when the wild-type gene from F. graminearum was expressed extracellularly in the P. pastoris strain SMD1168H using the pPICZalpha-system. A C-terminal His6-tag did not significantly affect the production of the enzyme, thus enabling simple purification by immobilized metal ion affinity chromatography. Notably, codon-optimisation of the galox gene for expression in P. pastoris did not result in a higher product yield (g protein.L-1 culture). Effective activation of the enzyme to generate the active-site radical copper complex could be equally well achieved by addition of CuSO4 directly in the culture medium or post-harvest. CONCLUSIONS: The results indicate that intracellular production in E. coli and extracellular production in P. pastoris comprise a complementary pair of systems for the production of GalOx. The prokaryotic host is favored for high-throughput screening, for example in the development of improved enzymes, while the yeast system is ideal for production scale-up for enzyme applications. PMID- 20836877 TI - Impaired adult olfactory bulb neurogenesis in the R6/2 mouse model of Huntington's disease. AB - BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder linked to expanded CAG-triplet nucleotide repeats within the huntingtin gene. Intracellular huntingtin aggregates are present in neurons of distinct brain areas, among them regions of adult neurogenesis including the hippocampus and the subventricular zone/olfactory bulb system. Previously, reduced hippocampal neurogenesis has been detected in transgenic rodent models of HD. Therefore, we hypothesized that mutant huntingtin also affects newly generated neurons derived from the subventricular zone of adult R6/2 HD mice. RESULTS: We observed a redirection of immature neuroblasts towards the striatum, however failed to detect new mature neurons. We further analyzed adult neurogenesis in the granular cell layer and the glomerular layer of the olfactory bulb, the physiological target region of subventricular zone-derived neuroblasts. Using bromodeoxyuridine to label proliferating cells, we observed in both neurogenic regions of the olfactory bulb a reduction in newly generated neurons. CONCLUSION: These findings suggest that the striatal environment, severely affected in R6/2 mice, is capable of attracting neuroblasts, however this region fails to provide sufficient signals for neuronal maturation. Moreover, in transgenic R6/2 animals, the hostile huntingtin-associated microenvironment in the olfactory bulb interferes with the survival and integration of new mature neurons. Taken together, endogenous cell repair strategies in HD may require additional factors for the differentiation and survival of newly generated neurons both in neurogenic and non-neurogenic regions. PMID- 20836878 TI - t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer. AB - BACKGROUND: Recent reports have shown that t-DARPP (truncated isoform of DARPP 32) can mediate trastuzumab resistance in breast cancer cell models. In this study, we evaluated expression of t-DARPP in human primary breast tumors, and investigated the role of t-DARPP in regulating growth and proliferation in breast cancer cells. RESULTS: Quantitative real time RT-PCR analysis using primers specific for t-DARPP demonstrated overexpression of t-DARPP in 36% of breast cancers (13/36) as opposed to absent to very low t-DARPP expression in normal breast tissue (p < 0.05). The mRNA overexpression of t-DARPP was overwhelmingly observed in ductal carcinomas, including invasive ductal carcinomas and intraductal carcinomas, rather than other types of breast cancers. The immunohistochemistry analysis of DARPP-32/t-DARPP protein(s) expression in breast cancer tissue microarray that contained 59 tumors and matched normal tissues when available indicated overexpression in 35.5% of primary breast tumors that were more frequent in invasive ductal carcinomas (43.7%; 21/48). In vitro studies showed that stable overexpression of t-DARPP in MCF-7 cells positively regulated proliferation and anchorage-dependent and -independent growth. Furthermore, this effect was concomitant with induction of phosphorylation of AKT(ser473) and its downstream target phospho(ser9) GSK3beta, and increased Cyclin D1 and C-Myc protein levels. The knockdown of endogenous t-DARPP in HCC1569 cells led to a marked decrease in phosphorylation of AKTs(ser473) and GSK3beta(ser9). The use of PI3K inhibitor LY294002 or Akt siRNA abrogated the t-DARPP-mediated phosphorylation of AKT(ser473) and led to a significant reduction in cell growth. CONCLUSIONS: Our findings underscore the potential role of t-DARPP in regulating cell growth and proliferation through PI3 kinase-dependent mechanism. PMID- 20836879 TI - OCP3 is an important modulator of NPR1-mediated jasmonic acid-dependent induced defenses in Arabidopsis. AB - BACKGROUND: Upon appropriate stimulation, plants increase their level of resistance against future pathogen attack. This phenomenon, known as induced resistance, presents an adaptive advantage due to its reduced fitness costs and its systemic and broad-spectrum nature. In Arabidopsis, different types of induced resistance have been defined based on the signaling pathways involved, particularly those dependent on salicylic acid (SA) and/or jasmonic acid (JA). RESULTS: Here, we have assessed the implication of the transcriptional regulator OCP3 in SA- and JA-dependent induced defenses. Through a series of double mutant analyses, we conclude that SA-dependent defense signaling does not require OCP3. However, we found that ocp3 plants are impaired in a Pseudomonas fluorescens WCS417r-triggered induced systemic resistance (ISR) against both Pseudomonas syrinagae DC3000 and Hyaloperonospora arabidopsidis, and we show that this impairment is not due to a defect in JA-perception. Likewise, exogenous application of JA failed to induce defenses in ocp3 plants. In addition, we provide evidence showing that the over-expression of an engineered cytosolic isoform of the disease resistance regulator NPR1 restores the impaired JA-induced disease resistance in ocp3 plants. CONCLUSIONS: Our findings point to a model in which OCP3 may modulate the nucleocytosolic function of NPR1 in the regulation of JA-dependent induced defense responses. PMID- 20836880 TI - Higher levels of Zidovudine resistant HIV in the colon compared to blood and other gastrointestinal compartments in HIV infection. AB - BACKGROUND: The gut-associated lymphoid tissue (GALT) is the largest lymphoid organ infected by human immunodeficiency virus type 1 (HIV-1). It serves as a viral reservoir and host-pathogen interface in infection. This study examined whether different parts of the gut and peripheral blood lymphocytes (PBL) contain different drug-resistant HIV-1 variants. METHODS: Gut biopsies (esophagus, stomach, duodenum and colon) and PBL were obtained from 8 HIV-1 infected preHAART (highly active antiretroviral therapy) patients at three visits over 18 months. Patients received AZT, ddI or combinations of AZT/ddI. HIV-1 Reverse transcriptase (RT)-coding sequences were amplified from viral DNA obtained from gut tissues and PBL, using nested PCR. The PCR fragments were cloned and sequenced. The resulting sequences were subjected to phylogenetic analyses, and antiretroviral drug mutations were identified. RESULTS: Phylogenetic and drug mutation analyses revealed differential distribution of drug resistant mutations in the gut within patients. The level of drug-resistance conferred by the RT sequences was significantly different between different gut tissues and PBL, and varied with antiretroviral therapy. The sequences conferring the highest level of drug-resistance to AZT were found in the colon. CONCLUSION: This study confirms that different drug-resistant HIV-1 variants are present in different gut tissues, and it is the first report to document that particular gut tissues may select for drug resistant HIV-1 variants. PMID- 20836881 TI - Adiponectin, resistin and IL-6 plasma levels in subjects with diabetic foot and possible correlations with clinical variables and cardiovascular co-morbidity. AB - INTRODUCTION: It is very suggestive that diabetic foot is characterized by a pronounced inflammatory reaction and the pathogenic significance of this inflammation has received little attention. On this basis the aim of our study was to evaluate plasma levels of adiponectin, resistin and IL-6 in subjects with diabetic foot in comparison with subjects without foot complications. MATERIALS AND METHODS: We recruited 34 subjects with type 2 diabetes mellitus and foot ulceration hospitalized for every condition related to diabetic disease, but not for new vascular events (group A). As controls we recruited 37 patients with type 2 diabetes mellitus without foot ulceration (group B) hospitalized for every condition related to diabetic disease, but not for new vascular events. Adiponectin, Resistin and IL-6 serum levels were evaluated. RESULTS: Subjects of group A showed lower median plasma levels of adiponectin [7.7450 (4.47-12.17) MUg/ml vs 8.480 (5.15-12.87) MUg/ml], higher median plasma levels of IL-6 [3.21 (1.23-5.34) pg/ml vs 2.73 (1.24-3.97 pg/ml)] and of resistin [3.860 (2.96-6.29 ng/ml) vs 3.690 (2.,37-6.5 ng/ml)]. CONCLUSION: Our study demonstrated that diabetic subjects with diabetic foot showed in comparison with diabetics without diabetic foot higher IL-6 and resistin plasma levels, lower adiponectin plasma levels. PMID- 20836882 TI - Concurrent sexual partnerships do not explain the HIV epidemics in Africa: a systematic review of the evidence. AB - The notion that concurrent sexual partnerships are especially common in sub Saharan Africa and explain the region's high HIV prevalence is accepted by many as conventional wisdom. In this paper, we evaluate the quantitative and qualitative evidence offered by the principal proponents of the concurrency hypothesis and analyze the mathematical model they use to establish the plausibility of the hypothesis.We find that research seeking to establish a statistical correlation between concurrency and HIV prevalence either finds no correlation or has important limitations. Furthermore, in order to simulate rapid spread of HIV, mathematical models require unrealistic assumptions about frequency of sexual contact, gender symmetry, levels of concurrency, and per-act transmission rates. Moreover, quantitative evidence cited by proponents of the concurrency hypothesis is unconvincing since they exclude Demographic and Health Surveys and other data showing that concurrency in Africa is low, make broad statements about non-African concurrency based on very few surveys, report data incorrectly, report data from studies that have no information about concurrency as though they supported the hypothesis, report incomparable data and cite unpublished or unavailable studies. Qualitative evidence offered by proponents of the hypothesis is irrelevant since, among other reasons, there is no comparison of Africa with other regions.Promoters of the concurrency hypothesis have failed to establish that concurrency is unusually prevalent in Africa or that the kinds of concurrent partnerships found in Africa produce more rapid spread of HIV than other forms of sexual behaviour. Policy makers should turn attention to drivers of African HIV epidemics that are policy sensitive and for which there is substantial epidemiological evidence. PMID- 20836883 TI - Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation. AB - OBJECTIVES: The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation. METHODS: The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs. RESULTS: MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL 677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009). CONCLUSION: In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non redundant functions in the progression of vascular inflammation. PMID- 20836884 TI - Acid-base balance and hydration status following consumption of mineral-based alkaline bottled water. AB - BACKGROUND: The present study sought to determine whether the consumption of a mineral-rich alkalizing (AK) bottled water could improve both acid-base balance and hydration status in young healthy adults under free-living conditions. The AK water contains a naturally high mineral content along with Alka-PlexLiquid?, a dissolved supplement that increases the mineral content and gives the water an alkalizing pH of 10.0. METHODS: Thirty-eight subjects were matched by gender and self-reported physical activity (SRPA, hrs/week) and then split into Control (12 women, 7 men; Mean +/- SD: 23 +/- 2 yrs; 7.2 +/- 3.6 hrs/week SRPA) and Experimental (13 women, 6 men; 22 +/- 2 yrs; 6.4 +/- 4.0 hrs/week SRPA) groups. The Control group consumed non-mineralized placebo bottled water over a 4-week period while the Experimental group consumed the placebo water during the 1st and 4th weeks and the AK water during the middle 2-week treatment period. Fingertip blood and 24-hour urine samples were collected three times each week for subsequent measures of blood and urine osmolality and pH, as well as total urine volume. Dependent variables were analyzed using multivariate repeated measures ANOVA with post-hoc focused on evaluating changes over time within Control and Experimental groups (alpha = 0.05). RESULTS: There were no significant changes in any of the dependent variables for the Control group. The Experimental group, however, showed significant increases in both the blood and urine pH (6.23 to 7.07 and 7.52 to 7.69, respectively), a decreased blood and increased urine osmolality, and a decreased urine output (2.51 to 2.05 L/day), all during the second week of the treatment period (P < 0.05). Further, these changes reversed for the Experimental group once subjects switched to the placebo water during the 4th week. CONCLUSIONS: Consumption of AK water was associated with improved acid base balance (i.e., an alkalization of the blood and urine) and hydration status when consumed under free-living conditions. In contrast, subjects who consumed the placebo bottled water showed no changes over the same period of time. These results indicate that the habitual consumption of AK water may be a valuable nutritional vector for influencing both acid-base balance and hydration status in healthy adults. PMID- 20836885 TI - Probing local innate immune responses after mucosal immunisation. AB - BACKGROUND: Intranasal immunisation is potentially a very effective route for inducing both mucosal and systemic immunity to an infectious agent. METHODS: Balb/c mice were intranasally immunised with the mucosal adjuvant heat labile toxin and the Mycobacterium tuberculosis fusion protein Ag85B-ESAT6 and early changes in innate immune responses within local mucosal tissues were examined using flow cytometry and confocal microscopy. Antigen-specific humoral and cellular immune responses were also evaluated. RESULTS: Intranasal immunisation induced significant changes in both number and distribution of dendritic cells, macrophages and neutrophils within the nasal-associated lymphoid tissue and cervical lymph nodes in comparison to controls as early as 5 h post immunisation. Immunisation also resulted in a rapid and transient increase in activation marker expression first in the nasal-associated lymphoid tissue, and then in the cervical lymph nodes. This heightened activation status was also apparent from the pro-inflammatory cytokine profiles of these innate populations. In addition we also showed increased expression and distribution of a number of different cell adhesion molecules early after intranasal immunisation within these lymphoid tissues. These observed early changes correlated with the induction of a TH1 type immune response. CONCLUSIONS: These data provide insights into the complex nature of innate immune responses induced following intranasal immunisation within the upper respiratory tract, and may help clarify the concepts and provide the tools that are needed to exploit the full potential of mucosal vaccines. PMID- 20836886 TI - The pregnancy hormones human chorionic gonadotropin and progesterone induce human embryonic stem cell proliferation and differentiation into neuroectodermal rosettes. AB - INTRODUCTION: The physiological signals that direct the division and differentiation of the zygote to form a blastocyst, and subsequent embryonic stem cell division and differentiation during early embryogenesis, are unknown. Although a number of growth factors, including the pregnancy-associated hormone human chorionic gonadotropin (hCG) are secreted by trophoblasts that lie adjacent to the embryoblast in the blastocyst, it is not known whether these growth factors directly signal human embryonic stem cells (hESCs). METHODS: Here we used hESCs as a model of inner cell mass differentiation to examine the hormonal requirements for the formation of embryoid bodies (EB's; akin to blastulation) and neuroectodermal rosettes (akin to neurulation). RESULTS: We found that hCG promotes the division of hESCs and their differentiation into EB's and neuroectodermal rosettes. Inhibition of luteinizing hormone/chorionic gonadotropin receptor (LHCGR) signaling suppresses hESC proliferation, an effect that is reversed by treatment with hCG. hCG treatment rapidly upregulates steroidogenic acute regulatory protein (StAR)-mediated cholesterol transport and the synthesis of progesterone (P4). hESCs express P4 receptor A, and treatment of hESC colonies with P4 induces neurulation, as demonstrated by the expression of nestin and the formation of columnar neuroectodermal cells that organize into neural tubelike rosettes. Suppression of P4 signaling by withdrawing P4 or treating with the P4-receptor antagonist RU-486 inhibits the differentiation of hESC colonies into EB's and rosettes. CONCLUSIONS: Our findings indicate that hCG signaling via LHCGR on hESC promotes proliferation and differentiation during blastulation and neurulation. These findings suggest that trophoblastic hCG secretion and signaling to the adjacent embryoblast could be the commencement of trophic support by placental tissues in the growth and development of the human embryo. PMID- 20836887 TI - Genomic encyclopedia of sugar utilization pathways in the Shewanella genus. AB - BACKGROUND: Carbohydrates are a primary source of carbon and energy for many bacteria. Accurate projection of known carbohydrate catabolic pathways across diverse bacteria with complete genomes constitutes a substantial challenge due to frequent variations in components of these pathways. To address a practically and fundamentally important challenge of reconstruction of carbohydrate utilization machinery in any microorganism directly from its genomic sequence, we combined a subsystems-based comparative genomic approach with experimental validation of selected bioinformatic predictions by a combination of biochemical, genetic and physiological experiments. RESULTS: We applied this integrated approach to systematically map carbohydrate utilization pathways in 19 genomes from the Shewanella genus. The obtained genomic encyclopedia of sugar utilization includes ~170 protein families (mostly metabolic enzymes, transporters and transcriptional regulators) spanning 17 distinct pathways with a mosaic distribution across Shewanella species providing insights into their ecophysiology and adaptive evolution. Phenotypic assays revealed a remarkable consistency between predicted and observed phenotype, an ability to utilize an individual sugar as a sole source of carbon and energy, over the entire matrix of tested strains and sugars.Comparison of the reconstructed catabolic pathways with E. coli identified multiple differences that are manifested at various levels, from the presence or absence of certain sugar catabolic pathways, nonorthologous gene replacements and alternative biochemical routes to a different organization of transcription regulatory networks. CONCLUSIONS: The reconstructed sugar catabolome in Shewanella spp includes 62 novel isofunctional families of enzymes, transporters, and regulators. In addition to improving our knowledge of genomics and functional organization of carbohydrate utilization in Shewanella, this study led to a substantial expansion of our current version of the Genomic Encyclopedia of Carbohydrate Utilization. A systematic and iterative application of this approach to multiple taxonomic groups of bacteria will further enhance it, creating a knowledge base adequate for the efficient analysis of any newly sequenced genome as well as of the emerging metagenomic data. PMID- 20836888 TI - Correlation between adherence rates measured by MEMS and self-reported questionnaires: a meta-analysis. AB - PURPOSE: It is vital to understand the associations between the medication event monitoring systems (MEMS) and self-reported questionnaires (SRQs) because both are often used to measure medication adherence and can produce different results. In addition, the economic implication of using alternative measures is important as the cost of electronic monitoring devices is not covered by insurance, while self-reports are the most practical and cost-effective method in the clinical settings. This meta-analysis examined the correlations of two measurements of medication adherence: MEMS and SRQs. METHODS: The literature search (1980-2009) used PubMed, OVID MEDLINE, PsycINFO (EBSCO), CINAHL (EBSCO), OVID HealthStar, EMBASE (Elsevier), and Cochrane Databases. Studies were included if the correlation coefficients [Pearson (rp) or Spearman (rs)] between adherences measured by both MEMS and SRQs were available or could be calculated from other statistics in the articles. Data were independently abstracted in duplicate with standardized protocol and abstraction form including 1) first author's name; 2) year of publication; 3) disease status of participants; 4) sample size; 5) mean age (year); 6) duration of trials (month); 7) SRQ names if available; 8) adherence (%) measured by MEMS; 9) adherence (%) measured by SRQ; 10) correlation coefficient and relative information, including p-value, 95% confidence interval (CI). A meta-analysis was conducted to pool the correlation coefficients using random-effect model. RESULTS: Eleven studies (N = 1,684 patients) met the inclusion criteria. The mean of adherence measured by MEMS was 74.9% (range 53.4% 92.9%), versus 84.0% by SRQ (range 68.35%-95%). The correlation between adherence measured by MEMS and SRQs ranged from 0.24 to 0.87. The pooled correlation coefficient for 11 studies was 0.45 (p = 0.001, 95% confidence interval [95% CI]: 0.34-0.56). The subgroup meta-analysis on the seven studies reporting rp and four studies reporting rs reported the pooled correlation coefficient: 0.46 (p = 0.011, 95% CI: 0.33-0.59) and 0.43 (p = 0.0038, 95% CI: 0.23-0.64), respectively. No differences were found for other subgroup analyses. CONCLUSION: Medication adherence measured by MEMS and SRQs tends to be at least moderately correlated, suggesting that SRQs give a good estimate of medication adherence. PMID- 20836889 TI - Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue. AB - BACKGROUND: ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-PCR, immunohistochemistry and Western blot analysis from healthy control adult rats or from animals treated with intraperitoneal oxaliplatin (1.85 mg/kg) or drug vehicle twice weekly for 8 weeks. RESULTS: In DRG tissue from healthy control animals, ATP7A mRNA was clearly detectable at levels similar to those found in the brain and spinal cord, and intense ATP7A immunoreactivity was localised to the cytoplasm of cell bodies of smaller DRG neurons without staining of satellite cells, nerve fibres or co-localisation with phosphorylated heavy neurofilament subunit (pNF-H). High levels of CTR1 mRNA were detected in all tissues from healthy control animals, and strong CTR1 immunoreactivity was associated with plasma membranes and vesicular cytoplasmic structures of the cell bodies of larger-sized DRG neurons without co-localization with ATP7A. DRG neurons with strong expression of ATP7A or CTR1 had distinct cell body size profiles with minimal overlap between them. Oxaliplatin treatment did not alter the size profile of strongly ATP7A-immunoreactive neurons but significantly reduced the size profile of strongly CTR1-immunoreactive neurons. ATP7B mRNA was barely detectable, and no specific immunoreactivity for ATP7B was found, in DRG tissue from healthy control animals. CONCLUSIONS: In conclusion, adult rat DRG tissue exhibits a specific pattern of expression of copper transporters with distinct subsets of peripheral sensory neurons intensely expressing either ATP7A or CTR1, but not both or ATP7B. The neuron subtype-specific and largely non overlapping distribution of ATP7A and CTR1 within rat DRG tissue may be required to support the potentially differing cuproenzyme requirements of distinct subsets of sensory neurons, and could influence the transport and neurotoxicity of oxaliplatin. PMID- 20836891 TI - Antioxidant activity of tuberosin isolated from Pueraria tuberose Linn. AB - Antioxidant activity of Pueraria tuberose DC, (PT) Leguminosae (Fabaceae) has already been reported by us and here an active compound has been isolated and its action on expression of iNOS protein has been explored by using LPS induced changes in attached rat peritoneal macrophage cell culture. The pure compound was isolated by column chromatography and its structure was characterized by spectral studies, which was identified as tuberosin (5 hydroxy 3,4,7,3',4' pentamethoxy flavone). Its antioxidant capacity was determined and compared with alcoholic extract as EC50 value for scavenging potential towards pre-generated monocation ABTS* radical, superoxide radicals, hydroxyl radicals, metal chelation property and on lipid peroxidation. Further, rat peritoneal macrophages were isolated, cultured and the attached macrophages were exposed to lipopolysaccharide (LPS) with different concentrations of tuberosin (pretreatment for 30 min). After 17 h the released NO content, in culture supernatant, was indirectly estimated as accumulated nitrite by Griess reagent. To understand the mechanism of action, the extent of expression of inducible nitric oxide synthase genes, the iNOS protein was assessed in macrophage lysate by using its antibody on western blot analysis. Tuberosin significantly scavenged all the species of FRs, described above and it also inhibited the LPS induced release of NO and amount of iNOS protein in macrophages. All the changes were significant and concentration dependent. Thus it could be suggested that tuberosin, is one of the active principles of Pueraria tuberose, which directly scavenges various species of Free radicals (FRs) and also inhibits LPS induced inflammatory changes in macrophages. PMID- 20836890 TI - Characterization of bacterial-type phosphoenolpyruvate carboxylase expressed in male gametophyte of higher plants. AB - BACKGROUND: Phosphoenolpyruvate carboxylase (PEPC) is a critical enzyme catalyzing the beta-carboxylation of phosphoenolpyruvate (PEP) to oxaloacetate, a tricarboxylic acid (TCA) cycle intermediate. PEPC typically exists as a Class-1 PEPC homotetramer composed of plant-type PEPC (PTPC) polypeptides, and two of the subunits were reported to be monoubiquitinated in germinating castor oil seeds. By the large-scale purification of ubiquitin (Ub)-related proteins from lily anther, two types of PEPCs, bacterial-type PEPC (BTPC) and plant-type PEPC (PTPC), were identified in our study as candidate Ub-related proteins. Until now, there has been no information about the properties of the PEPCs expressed in male reproductive tissues of higher plants. RESULTS: Expression analyses showed that lily BTPC (LlBTPC) and Arabidopsis BTPC (AtBTPC) were significantly expressed in pollen. The fusion protein AtBTPC-Venus localized in the cytoplasm of the vegetative cell (VC). Both LlBTPC and AtBTPC expression initiated after the last mitosis before pollen germination. Lily PTPC (LlPTPC) and monoubiquitinated LlPTPC (Ub-LlPTPC) remained at constant levels during pollen development. In late bicellular pollen of lily, LlBTPC forms a hetero-octameric Class-2 PEPC complex with LlPTPC to express PEPC activity. CONCLUSION: Our results suggest that an LlBTPC:Ub-LlPTPC:LlPTPC complex is formed in the VC cytoplasm during late pollen development. Both LlBTPC and AtBTPC expression patterns are similar to the patterns of the appearance of storage organelles during pollen development in lily and Arabidopsis, respectively. Therefore, BTPC is thought to accelerate the metabolic flow for the synthesis of storage substances during pollen maturation. Our study provides the first characterization of BTPC in pollen, the male gametophyte of higher plants. PMID- 20836892 TI - Transfer RNA modifications and genes for modifying enzymes in Arabidopsis thaliana. AB - BACKGROUND: In all domains of life, transfer RNA (tRNA) molecules contain modified nucleosides. Modifications to tRNAs affect their coding capacity and influence codon-anticodon interactions. Nucleoside modification deficiencies have a diverse range of effects, from decreased virulence in bacteria, neural system disease in human, and gene expression and stress response changes in plants. The purpose of this study was to identify genes involved in tRNA modification in the model plant Arabidopsis thaliana, to understand the function of nucleoside modifications in plant growth and development. RESULTS: In this study, we established a method for analyzing modified nucleosides in tRNAs from the model plant species, Arabidopsis thaliana and hybrid aspen (Populus tremula * tremuloides). 21 modified nucleosides in tRNAs were identified in both species. To identify the genes responsible for the plant tRNA modifications, we performed global analysis of the Arabidopsis genome for candidate genes. Based on the conserved domains of homologs in Sacccharomyces cerevisiae and Escherichia coli, more than 90 genes were predicted to encode tRNA modifying enzymes in the Arabidopsis genome. Transcript accumulation patterns for the genes in Arabidopsis and the phylogenetic distribution of the genes among different plant species were investigated. Transcripts for the majority of the Arabidopsis candidate genes were found to be most abundant in rosette leaves and shoot apices. Whereas most of the tRNA modifying gene families identified in the Arabidopsis genome was found to be present in other plant species, there was a big variation in the number of genes present for each family.Through a loss of function mutagenesis study, we identified five tRNA modification genes (AtTRM10, AtTRM11, AtTRM82, AtKTI12 and AtELP1) responsible for four specific modified nucleosides (m1G, m2G, m7G and ncm5U), respectively (two genes: AtKTI12 and AtELP1 identified for ncm5U modification). The AtTRM11 mutant exhibited an early-flowering phenotype, and the AtELP1 mutant had narrow leaves, reduced root growth, an aberrant silique shape and defects in the generation of secondary shoots. CONCLUSIONS: Using a reverse genetics approach, we successfully isolated and identified five tRNA modification genes in Arabidopsis thaliana. We conclude that the method established in this study will facilitate the identification of tRNA modification genes in a wide variety of plant species. PMID- 20836893 TI - Amino acid substitutions in the E2 glycoprotein of Sindbis-like virus XJ-160 confer the ability to undergo heparan sulfate-dependent infection of mouse embryonic fibroblasts. AB - We have recently demonstrated an essential role of the domain of 145-150 amino acid in the E2 glycoprotein of Sindbis virus in the interaction with cellular heparan sulfate (HS) and in the infection of mouse embryonic fibroblasts (MEF) cells. In this study, we constructed and characterized the mutants of Sindbis like virus XJ-160 in which Tyr-146 and/or Asn-149 in the E2 glycoprotein had been substituted with His and Arg, respectively. Unlike parental virus XJ-160, mutants with either or both substitutions were able to infect wild-type mouse embryonic fibroblasts (MEF-wt) or MEF-Epi-/- cells which produce mutant HS. Significantly more infectious particles were released from MEF-wt than from MEF-Epi-/- cells. The mutant virus with both substitutions release was inhibited by pre-incubation of virus with heparin or pre-treatment of BHK-21 cells with HS-degrading enzyme. Both XJ-160 and the mutant viruses retained substantial neurovirulence in suckling mice. Our findings provide further support to the importance of positively charged residues in the HS-binding site of E2 in mediating Sindbis virus infection of MEF cells. PMID- 20836894 TI - Phylogenetic history demonstrates two different lineages of dengue type 1 virus in Colombia. AB - BACKGROUND: Dengue Fever is one of the most important viral re-emergent diseases affecting about 50 million people around the world especially in tropical and sub tropical countries. In Colombia, the virus was first detected in the earliest 70's when the disease became a major public health concern. Since then, all four serotypes of the virus have been reported. Although most of the huge outbreaks reported in this country have involved dengue virus serotype 1 (DENV-1), there are not studies about its origin, genetic diversity and distribution. RESULTS: We used 224 bp corresponding to the carboxyl terminus of envelope (E) gene from 74 Colombian isolates in order to reconstruct phylogenetic relationships and to estimate time divergences. Analyzed DENV-1 Colombian isolates belonged to the formerly defined genotype V. Only one virus isolate was clasified in the genotype I, likely representing a sole introduction that did not spread. The oldest strains were closely related to those detected for the first time in America in 1977 from the Caribbean and were detected for two years until their disappearance about six years later. Around 1987, a split up generated 2 lineages that have been evolving separately, although not major amino acid changes in the analyzed region were found. CONCLUSION: DENV-1 has been circulating since 1978 in Colombia. Yet, the phylogenetic relationships between strains isolated along the covered period of time suggests that viral strains detected in some years, although belonging to the same genotype V, have different recent origins corresponding to multiple re-introduction events of viral strains that were circulating in neighbor countries. Viral strains used in the present study did not form a monophyletic group, which is evidence of a polyphyletic origin. We report the rapid spread patterns and high evolution rate of the different DENV-1 lineages. PMID- 20836895 TI - Inhibition of nuclear factor-kappaB by 6-O-acetyl shanzhiside methyl ester protects brain against injury in a rat model of ischemia and reperfusion. AB - BACKGROUND: Recent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti inflammatory drugs in cerebral ischemia have been documented. When screening natural compounds for drug candidates in this category, we isolated 6-O-acetyl shanzhiside methyl ester (ND02), an iridoid glucoside compound, from the leaves of Lamiophlomis rotata (Benth.) Kudo. The objectives of this study were to determine the effects of ND02 on a cultured neuronal cell line, SH-SY5Y, in vitro, and on experimental ischemic stroke in vivo. METHODS: For TNF-alpha stimulated SH-SY5Y cell line experiments in vitro, SH-SY5Y cells were pre incubated with ND02 (20 MUM or 40 MUM) for 30 min and then incubated with TNF alpha (20 ng/ml) for 15 min. For in vivo experiments, rats were subjected to middle cerebral artery occlusion (MCAO) for 1 h followed by reperfusion for 23 h. RESULTS: ND02 treatment of SH-SY5Y cell lines blocked TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) and IkappaB-alpha phosphorylation and increased Akt phosphorylation. LY294002 blocked TNF-alpha-induced phosphorylation of Akt and reduced the phosphorylation of both IkappaB-alpha and NF-kappaB. At doses higher than 10 mg/kg, ND02 had a significant neuroprotective effect in rats with cerebral ischemia and reperfusion (I/R). ND02 (25 mg/kg) demonstrated significant neuroprotective activity even after delayed administration 1 h, 3 h and 5 h after I/R. ND02, 25 mg/kg, attenuated histopathological damage, decreased cerebral Evans blue extravasation, inhibited NF-kappaB activation, and enhanced Akt phosphorylation. CONCLUSION: These data show that ND02 protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB) breakdown, and that these protective effects may be due to blocking of neuronal inflammatory cascades through an Akt-dependent NF-kappaB signaling pathway. PMID- 20836896 TI - Genetic transformation of lignin degrading fungi facilitated by Agrobacterium tumefaciens. AB - BACKGROUND: White-rot fungi are primarily the major degraders of lignin, a major obstacle for commercial exploitation of plant byproducts to produce bioethanol and other industrially important products. However, to improve their efficacy for lignin degradation, it has become necessary to genetically modify these organisms using appropriate vectors. Agrobacterium tumefaciens, a soil phytopathogenic bacterium, generally transforms plants by delivering a portion of the resident Ti plasmid, the T-DNA (transfer DNA). The trans-Kingdom gene transfer is initiated by the activity of Ti-plasmid encoded vir (virulence) genes in response to low molecular-mass phenolic compounds such as acetosyringone. A. tumefaciens played a major role in plant genetic engineering and basic research in molecular biology, accounting for nearly 80% of the transgenic plants produced so far. Initially, it was believed that only dicotyledons, gymnosperms and a few monocotyledonous species could be transformed by this bacterium; but recent reports have totally changed this scenario by demonstrating that many 'recalcitrant' species not included in its natural host range can also be transformed, especially filamentous fungi. RESULTS: This paper describes an efficient and convenient Agrobacterium-mediated gene transformation system for successful delivery of T DNA, carrying the genes coding for beta-glucuronidase (uidA), green fluorescent protein (gfp) and hygromycin phosphotransferase (hpt) to the nuclear genome of lignin degrading white-rot fungi such as Phanerochaete chrysosporium, Ganoderma sp. RCKK-02, Pycnoporous cinnabarinus, Crinipellis sp. RCK-1, Pleurotus sajor caju and fungal isolate BHR-UDSC without supplementation of acetosyringone. The fungal transformants were confirmed by PCR and Southern hybridization. The expression vector pCAMBIA 1304-RCKK was constructed by the addition of GPD promoter from plasmid p416 to the binary vector backbone pCAMBIA1304, which controls uidA and gfp gene. Transmission Electron Microscope (TEM) analysis revealed the attachment of bacterial cells to the fungal hyphae. Transformation frequency varied from 50 to 75% depending on the fungal species used in this study. The transformation efficiency was maximum at 20 degrees C whereas no transfer was observed at temperature above 29 degrees C. CONCLUSION: These findings provide a rapid and reproducible transformation method without external addition of acetosyringone, which could be useful for improving white-rot fungi for their various biotechnological applications. PMID- 20836898 TI - Dimebon disappointment. AB - Dimebon (latrepirdine) has received widespread publicity as a potential therapy for Alzheimer's disease following a very positive phase 2 study carried out in Russia and published in the Lancet in 2008. In this study there were improvements over 6 months in all endpoints (cognitive, global, daily function and behaviour), with continuing improvement at 12 months in cognition and daily function. A more recent multinational phase 3 study, however, showed no improvements whatsoever and no difference between the two drug-treated groups and the placebo group. Of note, there was little deterioration in any of the groups after 6 months in contrast to the placebo group in the phase 2 study. The potential reasons for these disappointing results are discussed, as well as the implication for dimebon and drug treatment in Alzheimer's disease. PMID- 20836897 TI - Metabolic memory: a vascular perspective. AB - Multiple and complex pathways promote the deleterious effects of hyperglycemia in diabetes, ultimately leading to micro- and macrovascular disease. Some of the known mechanisms in diabetic vascular disease may explain the initiation of the "metabolic memory", but fall short if long periods of time are involved.Vascular research has been prolific in the past in finding links between microvascular dysfunction and subsequent macrovascular disease. Thus, this text will extend the current discussion of the "metabolic memory" by including available data from vascular research.The hypothesis proposes that structural and functional changes in the microcirculation interact within the vascular continuum with larger arteries. This interaction may lead to subsequent upstream endothelial dysfunction, atherosclerosis and vascular complications ("Micro/Macro Interaction"). The underlying microvascular structural changes may be more long term and possibly mediate the "metabolic memory".This hypothesis, that the "not so new" interaction between micro-and macrovasculature may promote "metabolic memory" effects extends and unifies currently discussed theories. PMID- 20836900 TI - Evolution of neuropsychological dysfunction during the course of schizophrenia and bipolar disorder. AB - BACKGROUND: Neurocognitive dysfunction in schizophrenia (SZ), bipolar (BD) and related disorders represents a core feature of these illnesses, possibly a marker of underlying pathophysiology. Substantial overlap in domains of neuropsychological deficits has been reported among these disorders after illness onset. However, it is unclear whether deficits follow the same longitudinal pre- and post-morbid course across diagnoses. We examine evidence for neurocognitive dysfunction as a core feature of all idiopathic psychotic illnesses, and trace its evolution from pre-morbid and prodromal states through the emergence of overt psychosis and into chronic illness in patients with SZ, BD and related disorders. METHOD: Articles reporting on neuropsychological functioning in patients with SZ, BD and related disorders before and after illness onset were reviewed. Given the vast literature on these topics and the present focus on cross-diagnostic comparisons, priority was given to primary data papers that assessed cross diagnostic samples and recent meta-analyses. RESULTS: Patients with SZ exhibit dysfunction preceding the onset of illness, which becomes more pronounced in the prodrome and early years following diagnosis, then settles into a stable pattern. Patients with BD generally exhibit typical cognitive development pre-morbidly, but demonstrate deficits by first episode that are amplified with worsening symptoms and exacerbations. CONCLUSIONS: Neuropsychological deficits represent a core feature of SZ and BD; however, their onset and progression differ between diagnostic groups. A lifetime perspective on the evolution of neurocognitive deficits in SZ and BD reveals distinct patterns, and may provide a useful guide to the examination of the pathophysiological processes underpinning these functions across disorders. PMID- 20836899 TI - Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection. AB - In the past decade there has been a resurgence of interest in the clinical use of inert gases. In the present paper we review the use of inert gases as anesthetics and neuroprotectants, with particular attention to the clinical use of xenon. We discuss recent advances in understanding the molecular pharmacology of xenon and we highlight specific pharmacological targets that may mediate its actions as an anesthetic and neuroprotectant. We summarize recent in vitro and in vivo studies on the actions of helium and the other inert gases, and discuss their potential to be used as neuroprotective agents. PMID- 20836901 TI - Effects of bite size and duration of oral processing on retro-nasal aroma release - features contributing to meal termination. AB - The brain response to a retro-nasally sensed food odour signals the perception of food and it is suggested to be related to satiation. It is hypothesised that consuming food either in multiple small bite sizes or with a longer durations of oral processing may evoke substantial oral processing per gram consumed and an increase in transit time in the oral cavity. This is expected to result in a higher cumulative retro-nasal aroma stimulation, which in turn may lead to increased feelings of satiation and decreased food intake. Using real-time atmospheric pressure chemical ionisation-MS, in vivo retro-nasal aroma release was assessed for twenty-one young, healthy and normal-weight subjects consuming dark chocolate-flavoured custard. Subjects were exposed to both free or fixed bite size (5 and 15 g) and durations of oral processing before swallowing (3 and 9 s) in a cross-over design. For a fixed amount of dark chocolate-flavoured custard, consumption in multiple small bite sizes resulted in a significantly higher cumulative extent of retro-nasal aroma release per gram consumed compared with a smaller amount of large bite sizes. In addition, a longer duration of oral processing tended to result in a higher cumulative extent of retro-nasal aroma release per gram consumed compared with a short duration of oral processing. An interaction effect of bite size and duration of oral processing was not observed. In conclusion, decreasing bite size or increasing duration of oral processing led to a higher cumulative retro-nasal aroma stimulation per gram consumed. Hence, adapting bite size or duration of oral processing indicates that meal termination can be accelerated by increasing the extent of retro-nasal aroma release and, subsequently, the satiation. PMID- 20836902 TI - Adrenocorticotrophic hormone-stimulated cortisol release by the head kidney inter renal tissue from sea bream (Sparus aurata) fed with linseed oil and soyabean oil. AB - The mode of action of highly unsaturated fatty acids (HUFA) in regulating gilthead sea bream (Sparus aurata) head kidney (HK) cortisol production was studied through in vitro trials using a dynamic superfusion system. Fish were previously fed with different diets containing several inclusion levels of linseed oil (LO) or soyabean oil (SO) for 26 weeks. Five diets were tested; anchovy oil was the only lipid source for the control diet (fish oil, FO) and two different substitution levels (70 and 100 %) were tested using either LO or SO (70LO, 70SO, 100LO and 100SO). Fatty acid compositions of the HK reflected the dietary input, thus EPA, DHA, arachidonic acid and n-3 HUFA were significantly (P < 0.05) reduced in fish fed vegetable oils compared with fish fed the FO diet. Feeding 70 or 100 % LO increased significantly (P < 0.05) cortisol release in HK after stimulation with adrenocorticotrophic hormone (ACTH), while feeding SO had no effect on this response. Cortisol stimulation factor (SF) was increased in fish fed the 70LO and 100LO diets compared with fish fed the control diet. Moreover, eicosanoid inhibition by incubating the HK tissue with indomethacin (INDO) as a cyclo-oxygenase (COX) inhibitor, or nordihydroguaiaretic acid (NDGA) as a lipoxygenase (LOX) inhibitor, significantly reduced (P < 0.05) the cortisol release after ACTH stimulation in the 70LO and 100LO diets. Cortisol SF was reduced in the FO, 70LO and 100LO diets when incubating the HK with INDO or NDGA, while it was increased in the 70SO diet. The present results indicate that changing the fatty acid profile of gilthead sea bream HK by including LO and/or SO in the fish diet affected the in vitro cortisol release, and this effect is partly mediated by COX and/or LOX metabolites. PMID- 20836903 TI - Characterisation and expression of secretory phospholipase A2 group IB during ontogeny of Atlantic cod ( Gadus morhua). AB - The pancreatic enzyme secretory phospholipase A2 group IB (sPLA2 IB) hydrolyses phospholipids at the sn-2 position, resulting in a NEFA and a lyso-phospholipid, which are then absorbed by the enterocytes. The sPLA2 IB is a member of a family of nineteen enzymes sharing the same catalytic ability, of which nine are cytosolic and ten are secretory. Presently, there are no pharmacological tools to separate between the different secretory enzymes when measuring the enzymatic activity. Thus, it is important to support activity data with more precise techniques when isolation of intestinal content is not possible for analysis, as in the case of small teleost larvae, where the whole animal is sometimes analysed. In the present study, we characterise the sPLA2 IB gene in Atlantic cod (Gadus morhua) and describe its ontogeny at the genetic and protein level and compare this to the total sPLA2 activity level. A positive correlation was found between the expression of sPLA2 IB mRNA and protein. Both remained stable and low during the larval stage followed by an increase from day 62 posthatch, coinciding with the development of the pyloric ceaca. Meanwhile, total sPLA2 enzyme activity in cod was stable and relatively high during the early stages when larvae were fed live prey, followed by a decrease in activity when the fish were weaned to a formulated diet. Thus, the expression of sPLA2 IB mRNA and protein did not correlate with total sPLA2 activity. PMID- 20836904 TI - Cartesian theories on the passions, the pineal gland and the pathogenesis of affective disorders: an early forerunner. AB - The relationship between physical and functional alterations in the pineal gland, the 'passions' (emotions or feelings) and psychopathology has been a constant throughout the history of medicine. One of the most influential authors on this subject was Rene Descartes, who discussed it in his work The Treatise on the Passions of the Soul (1649). Descartes believed that 'passions' were sensitive movements that the soul, located in the pineal gland, experienced due to its union with the body, by circulating animal spirits. Descartes described sadness as one of the six primitive passions of the soul, which leads to melancholy if not remedied. Cartesian theories had a great deal of influence on the way that mental pathologies were considered throughout the entire 17th century and during much of the 18th century, but the link between the pineal gland and psychiatric disorders it was definitively highlighted in the 20th century, with the discovery of melatonin in 1958. The recent development of a new pharmacological agent acting through melatonergic receptors (agomelatine) has confirmed the close link between the pineal gland and affective disorders. PMID- 20836905 TI - Borderline personality disorder co-morbidity: relationship to the internalizing externalizing structure of common mental disorders. AB - BACKGROUND: Borderline personality disorder (BPD) shows high levels of co morbidity with an array of psychiatric disorders. The meaning and causes of this co-morbidity are not fully understood. Our objective was to investigate and clarify the complex co-morbidity of BPD by integrating it into the structure of common mental disorders. METHOD: We conducted exploratory and confirmatory factor analyses on diagnostic interview data from a representative US population-based sample of 34 653 civilian, non-institutionalized individuals aged >=18 years. We modeled the structure of lifetime DSM-IV diagnoses of BPD and antisocial personality disorder (ASPD), major depressive disorder, dysthymic disorder, panic disorder with agoraphobia, social phobia, specific phobia, generalized anxiety disorder, post-traumatic stress disorder, alcohol dependence, nicotine dependence, marijuana dependence, and any other drug dependence. RESULTS: In both women and men, the internalizing-externalizing structure of common mental disorders captured the co-morbidity among all disorders including BPD. Although BPD was unidimensional in terms of its symptoms, BPD as a disorder showed associations with both the distress subfactor of the internalizing dimension and the externalizing dimension. CONCLUSIONS: The complex patterns of co-morbidity observed with BPD represent connections to other disorders at the level of latent internalizing and externalizing dimensions. BPD is meaningfully connected with liabilities shared with common mental disorders, and these liability dimensions provide a beneficial focus for understanding the co-morbidity, etiology and treatment of BPD. PMID- 20836906 TI - Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample. AB - BACKGROUND: Recent work suggests that epigenetic differences may be associated with psychiatric disorders. Here we investigate, in a community-based sample, whether methylation profiles distinguish between individuals with and without lifetime depression. We also investigate the physiologic consequences that may be associated with these profiles. METHOD: Using whole blood-derived genomic DNA from a subset of participants in the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assess genome-wide methylation profiles for over 14 000 genes in 33 persons who reported a lifetime history of depression and 67 non-depressed adults. Bioinformatic functional analyses were performed on the genes uniquely methylated and unmethylated in each group, and inflammatory biomarkers [interleukin (IL)-6 and C-reactive protein (CRP)] were measured to investigate the possible functional significance of the methylation profiles observed. RESULTS: Uniquely unmethylated gene sets distinguished between those with versus without lifetime depression. In particular, some processes (e.g. brain development, tryptophan metabolism) showed patterns suggestive of increased methylation among individuals with depression whereas others (e.g. lipoprotein) showed patterns suggestive of decreased methylation among individuals with depression. IL-6 and CRP levels were elevated among those with lifetime depression and, among those with depression only, IL-6 methylation showed an inverse correlation with circulating IL-6 and CRP. CONCLUSIONS: Genome-wide methylation profiles distinguish individuals with versus without lifetime depression in a community-based setting, and show coordinated signals with pathophysiological mechanisms previously implicated in the etiology of this disorder. Examining epigenetic mechanisms in concert with other dynamic markers of physiologic functioning should improve our understanding of the neurobiology of depression. PMID- 20836907 TI - Economic downturns and population mental health: research findings, gaps, challenges and priorities. AB - Prior research suggests that the current global economic crisis may be negatively affecting population mental health. In that context, this paper has several goals: (1) to discuss theoretical and conceptual explanations for how and why economic downturns might negatively affect population mental health; (2) present an overview of the literature on the relationship between economic recessions and population mental health; (3) discuss the limitations of existing empirical work; and (4) highlight opportunities for improvements in both research and practice designed to mitigate any negative impact of economic declines on the mental health of populations. Research has consistently demonstrated that economic crises are negatively associated with population mental health. How economic downturns influence mental health should be considered in policies such as social protection programs that aim to promote recovery. PMID- 20836908 TI - Associations between diurnal preference, sleep quality and externalizing behaviours: a behavioural genetic analysis. AB - BACKGROUND: Certain aspects of sleep co-occur with externalizing behaviours in youth, yet little is known about these associations in adults. The present study: (1) examines the associations between diurnal preference (morningness versus eveningness), sleep quality and externalizing behaviours; (2) explores the extent to which genetic and environmental influences are shared between or are unique to these phenotypes; (3) examines the extent to which genetic and environmental influences account for these associations. method: Questionnaires assessing diurnal preference, sleep quality and externalizing behaviours were completed by 1556 young adult twins and siblings. RESULTS: A preference for eveningness and poor sleep quality were associated with greater externalizing symptoms [r=0.28 (95% CI 0.23-0.33) and 0.34 (95% CI 0.28-0.39), respectively]. A total of 18% of the genetic influences on externalizing behaviours were shared with diurnal preference and sleep quality and an additional 14% were shared with sleep quality alone. Non-shared environmental influences common to the phenotypes were small (2%). The association between diurnal preference and externalizing behaviours was mostly explained by genetic influences [additive genetic influence (A)=80% (95% CI 0.56-1.01)], as was the association between sleep quality and externalizing behaviours [A=81% (95% CI 0.62-0.99)]. Non-shared environmental (E) influences accounted for the remaining variance for both associations [E=20% (95% CI -0.01 to 0.44) and 19% (95% CI 0.01-0.38), respectively]. CONCLUSIONS: A preference for eveningness and poor sleep quality are moderately associated with externalizing behaviours in young adults. There is a moderate amount of shared genetic influences between the phenotypes and genetic influences account for a large proportion of the association between sleep and externalizing behaviours. Further research could focus on identifying specific genetic polymorphisms common to both sleep and externalizing behaviours. PMID- 20836909 TI - The association of personality disorders with the prospective 7-year course of anxiety disorders. AB - BACKGROUND: This study prospectively examined the natural clinical course of six anxiety disorders over 7 years of follow-up in individuals with personality disorders (PDs) and/or major depressive disorder. Rates of remission, relapse, new episode onset and chronicity of anxiety disorders were examined for specific associations with PDs. METHOD: Participants were 499 patients with anxiety disorders in the Collaborative Longitudinal Personality Disorders Study, who were assessed with structured interviews for psychiatric disorders at yearly intervals throughout 7 years of follow-up. These data were used to determine probabilities of changes in disorder status for social phobia (SP), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), panic disorder and panic disorder with agoraphobia. RESULTS: Estimated remission rates for anxiety disorders in this study group ranged from 73% to 94%. For those patients who remitted from an anxiety disorder, relapse rates ranged from 34% to 67%. Rates for new episode onsets of anxiety disorders ranged from 3% to 17%. Specific PDs demonstrated associations with remission, relapse, new episode onsets and chronicity of anxiety disorders. Associations were identified between schizotypal PD with course of SP, PTSD and GAD; avoidant PD with course of SP and OCD; obsessive-compulsive PD with course of GAD, OCD, and agoraphobia; and borderline PD with course of OCD, GAD and panic with agoraphobia. CONCLUSIONS: Findings suggest that specific PD diagnoses have negative prognostic significance for the course of anxiety disorders underscoring the importance of assessing and considering PD diagnoses in patients with anxiety disorders. PMID- 20836910 TI - A comprehensive review and model of putative prodromal features of bipolar affective disorder. AB - BACKGROUND: Identifying prodromal features that predate the onset of bipolar disorder (BD) may enable the prevention of BD and aid early intervention. This review addresses two key questions: Is there a bipolar prodrome? And, if there is, what are its characteristic features? METHOD: A comprehensive search of databases (PubMed, Medline, EMBASE and PsycINFO) supplemented by hand searches was used to identify studies of symptoms preceding the onset of BD. RESULTS: Fifty-nine studies were identified, of which 14 met inclusion criteria. Symptoms can predate the onset of BD by months to years and can be categorized as attenuated forms of BD symptoms, general symptoms common to a range of mental disorders, and personality traits, particularly cyclothymia. Two studies provided sufficient data to enable sensitivity and specificity to be calculated. Specificity of several of the features was high (>90%) but sensitivity was generally low (all <60%). We propose a model based on the findings in the studies reviewed to illustrate the potential trajectory to BD and the points at which it may be possible to intervene. CONCLUSIONS: Clinical features preceding the onset of BD can be identified. However, conclusions about whether there is a distinct prodrome to BD are restricted by the limitations of current evidence. The high specificity of some features suggests they may be useful in clinical practice. Large-scale longitudinal studies are needed to validate these features and characterize their specificity and sensitivity in independent samples. PMID- 20836911 TI - A waterborne Campylobacter jejuni outbreak on a Greek island. AB - A case-control and a case-crossover study were performed to investigate a Campylobacter jejuni outbreak in Crete in 2009. Most cases originated from rural areas, served by a different water-supply system from that of the adjacent town. Thirty-seven cases and 79 controls were interviewed; cases were interviewed for two different time periods for the case-crossover study. Stool cultures, PFGE and MLST subtyping were run in human samples. Univariately, consumption of tap water was associated with C. jejuni infection. Stratified analysis revealed that water supply system was an effect modifier of this association. In the multivariable analysis, the rural areas' water supplier and drinking tap water were risk factors. No risk factors were revealed in the case-crossover study. No Campylobacter were isolated in the tested water samples. There is strong epidemiological evidence that tap water was the vehicle of the outbreak. PMID- 20836912 TI - Non-essential symptoms of depression and cognitive impairment no dementia (CIND) in community-dwelling elders without dysphoria or anhedonia. AB - BACKGROUND: Several neuropsychiatric symptoms observed in elders with cognitive impairment no dementia (CIND) can be part of a major depressive episode (MDE) or a "subthreshold" depressive episode. Certain neuropsychiatric symptoms of CIND are essential symptoms of MDE (e.g. dysphoria, anhedonia), while other are non essential symptoms (NESD; e.g. fatigue, insomnia, cognitive complaint). Contrary to essential symptoms, NESD are not specific to MDE and are present in other disorders. It is unknown whether NESD are linked to CIND in absence of MDE or subthreshold MDE. The present study examined the association between NESD and probable CIND in elders without essential MDE symptoms. METHODS: Participants were 2028 community-dwelling individuals aged 65-96 years who had not experienced dysphoria/anhedonia during the year preceding the interview. Semi-structured in home interviews evaluated the following NESD: alteration of appetite, sleep disturbance, psychomotor alteration, fatigue/loss of energy, worthlessness/guilt, and cognitive complaints. Probable CIND cases were defined based on the Mini mental State Examination cut-offs (15th percentile) stratified for age, education and sex. RESULTS: Symptoms of fatigue/loss of energy (OR: 2.41, 95% CI: 1.42 4.09), sleep disturbance (OR: 3.04 CI: 1.69-5.46) and cognitive complaints (OR: 2.86 CI: 1.71-4.77) were significantly associated with CIND. These associations were not modified after adjustments for potential confounders (age, education level, sex, benzodiazepine use, chronic diseases, and brain disorders). CONCLUSION: A psychiatric symptomatology occurs in older adults with CIND in the absence of MDE or subthreshold MDE. NESD encountered in the absence of dysphoria/anhedonia should receive particular attention by clinicians since they can be linked to cognitive difficulties. PMID- 20836913 TI - The effects of medication assessment on psychotropic drug use in the community dwelling elderly. AB - BACKGROUND: The study evaluated the effects of an annual medication assessment conducted as part of a Comprehensive Geriatric Assessment (CGA) on the prevalence of psychotropic drug use in community-dwelling elderly people. METHODS: Randomly selected persons (n = 1000) aged >=75 years living in the city of Kuopio, Finland were randomized to intervention and control groups. The intervention group underwent an annual (2004-2006) medication assessment as part of a CGA by physicians. Data on drug use were gathered by interviews at baseline (2004) and in three following years (2005-2007). Generalized estimating equations (GEE) were applied to explore whether the prevalence of psychotropic drug use differed between the community-dwelling participants of the intervention (n = 361) and control groups (n = 339) over time. RESULTS: At baseline, nearly 40% of the participants used psychotropic drugs in each group. In the intervention group, the study physicians implemented 126 psychotropic drug-related changes, 39% of which were persistent after one year. The prevalence of use of psychotropic drugs, antipsychotics and anxiolytic/hypnotics did not differ between the groups over time. The prevalence of antidepressant use remained constant in the intervention group, but increased in the control group (p-value for interaction = 0.039). The prevalence of concomitant use of psychotropic drugs decreased non significantly in the intervention group, but increased in the control group (p value for interaction = 0.009). CONCLUSIONS: Conducting an annual medication assessment outside the usual primary health care system does not appear to reduce the prevalence of psychotropic drug use in community-dwelling elderly people. However, it may prevent concomitant use of psychotropic drugs. PMID- 20836914 TI - Social inclusion affects elderly suicide mortality. AB - BACKGROUND: National attitudes towards the elderly and their association with elderly suicide mortality in 26 European countries were assessed, and Eastern and Western European countries compared. METHODS: For each country, mean age adjusted, gender-specific elderly suicide rates in the last five years for which data had been available were obtained from the WHO European Mortality Database. Questions about citizens' attitudes towards the elderly were taken from the European Social Survey. Correlations between attitudes and suicide rates were analyzed using Pearson's test. Differences between mean scores for Western and Eastern European attitudes were calculated, and data on labor-market exit ages were obtained from the EUROSTAT database. RESULTS: Perception of the elderly as having higher status, recognition of their economic contribution and higher moral standards, and friendly feelings towards and admiration of them are inversely correlated with suicide mortality. Suicide rates are lower in countries where the elderly live with their families more often. Elderly suicide mortality and labor market exit age are inversely correlated. In Eastern European countries, elderly people's status and economic contribution are seen as less important. Western Europeans regard the elderly with more admiration, consider them more friendly and more often have elderly relatives in the family. The data also show gender differences. CONCLUSIONS: Society's attitudes influence elderly suicide mortality; attitudes towards the elderly are more favorable among Western European citizens; and extended labor-market inclusion of the elderly is a suicide-protective factor. PMID- 20836915 TI - Cognitive decline in the behavioral variant of frontotemporal dementia. AB - BACKGROUND: Only a small number of studies on the natural disease course in behavioral variant frontotemporal dementia (bvFTD) have been conducted. This is surprising because knowledge about the progression of symptoms is a precondition for the design of clinical drug trials. METHODS: The aim of the present study was to examine the cognitive decline of 20 patients with mild bvFTD over one year using the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB). RESULTS: Within an average follow-up interval of 13 months, patient scores declined significantly in the Mini-mental-State-Examination (MMSE) and the CERAD-NAB subtests of naming, verbal and nonverbal memory. No significant changes were found in the CERAD-NAB subtests of category fluency, recognition, and visuoconstruction. The average annualized decline on the MMSE was 4.0 +/- 4.9 points. Ceiling effects were detected in Figures Copy, Word List Recognition and Modified Boston Naming Test. Though the included patient group was rather homogeneous regarding severity of dementia, the cognitive changes were very heterogeneous. CONCLUSION: Given the heterogeneity of cognitive decline, the design of a test battery for clinical trials in FTD will be challenging. A cognitive battery should definitely include the MMSE, Word List Learning and Word List Delayed Recall. PMID- 20836916 TI - The need to consider mood disorders, and especially chronic mania, in cases of Diogenes syndrome (squalor syndrome). AB - We report the case of a 69 year-old female patient who was hospitalized for Diogenes syndrome, defined by marked self-neglect, social withdrawal and excessive hoarding, leading to squalor. Somatic causes were eliminated. Her personal history showed an eight-year depressive episode followed by a 20-year hypomanic episode without remission, followed by a persistent manic episode associated with Diogenes syndrome for four years. The Diogenes syndrome was successfully treated with mood stabilizers. Mood disorders - in particular chronic mania (i.e. a manic episode lasting more than two years) - should be considered in cases of Diogenes syndrome and in current classifications. PMID- 20836917 TI - Are late-onset eating disorders in the elderly really the more common variant? Concerns around publication bias. PMID- 20836918 TI - Serum vitamin B12, folic acid, and hemoglobin and cognition in Alzheimer's disease. PMID- 20836920 TI - Factors affecting wound ooze in total knee replacement. AB - INTRODUCTION: Wound ooze is common following total knee arthroplasty (TKA) and persistent wound infection is a risk factor for infection, and increased length and cost of hospitalisation. PATIENTS AND METHODS: We undertook a prospective study to assess the effect of tourniquet time, peri-articular local anaesthesia and surgical approach on wound oozing after TKA. RESULTS: The medial parapatellar approach was used in 59 patients (77%) and subvastus in 18 patients (23%). Peri articular local anaesthesia (0.25% Bupivacaine with 1:1,000,000 adrenalin) was used in 34 patients (44%). The mean tourniquet time was 83 min (range, 38-125 min). We found a significant association between cessation of oozing and peri articular local anaesthesia (P = 0.003), length of the tourniquet time (P = 0.03) and the subvastus approach (P = 0.01). CONCLUSIONS: Peri-articular local anaesthesia, the subvastus approach and shorter tourniquet time were all associated with less wound oozing after total knee arthroplasty. PMID- 20836921 TI - Biodegradable Nano-aggregates of Star-Shaped 8-arm PEG-PLLA Block Co-polymers for Encapsulation of Water-Soluble Macromolecules. AB - A series of amphiphilic 8-arm PEG-b-PLLA co-polymers with star-shaped structure was synthesized through ring-opening polymerization of L-lactide (L-LA) in the presence of 8-arm PEG as a macroinitiator by varying feeding molar rations of L LA to 8-arm PEG. 8-arm PEG-b-PLLA co-polymers having certain PEG content and PEG length were found to self-assemble into nano-aggregates in aqueous solutions. The size and the morphology of the nano-aggregates were investigated by dynamic light scattering and (1)H-NMR in CDCl3 and D2O. The results indicate that the average diameter was ca. 150 nm, the surface of the nano-aggregates was covered by PEG chains and the PLLA cores formed by hydrophobic interaction are located inside of the nano-aggregates. FITC-dextran molecules, as model for water-soluble macromolecular drugs, were successfully encapsulated into 8-arm PEG-b-PLLA nano aggregates by simple addition of FITC-dextran to the aqueous phase during the self-assembly process. This result suggests that the nanoaggregates have a vesicle-like morphology. The nano-aggregates dissociated gradually in the order of weeks in PBS (pH 7.4, ionic strength 140 mM) at 37 degrees C. Thus, the novel nano-aggregates of 8-arm PEG-b-PLLA can be expected to have advantages, such as long circulation times, as drug carriers which show sustained release of loaded macromolecular drugs such as antibodies and DNA vaccines in the blood stream. PMID- 20836922 TI - Collagen-PCL sheath-core bicomponent electrospun scaffolds increase osteogenic differentiation and calcium accretion of human adipose-derived stem cells. AB - Human adipose-derived stem cells (hASCs) are an abundant cell source capable of osteogenic differentiation, and have been investigated as an autologous stem cell source for bone tissue engineering applications. The objective of this study was to determine if the addition of a type-I collagen sheath to the surface of poly(epsilon-caprolactone) (PCL) nanofibers would enhance viability, proliferation and osteogenesis of hASCs. This is the first study to examine the differentiation behavior of hASCs on collagen-PCL sheath-core bicomponent nanofiber scaffolds developed using a co-axial electrospinning technique. The use of a sheath-core configuration ensured a uniform coating of collagen on the PCL nanofibers. PCL nanofiber scaffolds prepared using a conventional electrospinning technique served as controls. hASCs were seeded at a density of 20 000 cells/cm(2) on 1 cm(2) electrospun nanofiber (pure PCL or collagen-PCL sheath core) sheets. Confocal microscopy and hASC proliferation data confirmed the presence of viable cells after 2 weeks in culture on all scaffolds. Greater cell spreading occurred on bicomponent collagen-PCL scaffolds at earlier time points. hASCs were osteogenically differentiated by addition of soluble osteogenic inductive factors. Calcium quantification indicated cell-mediated calcium accretion was approx. 5-times higher on bicomponent collagen-PCL sheath-core scaffolds compared to PCL controls, indicating collagen-PCL bicomponent scaffolds promoted greater hASC osteogenesis after two weeks of culture in osteogenic medium. This is the first study to examine the effects of collagen-PCL sheath core composite nanofibers on hASC viability, proliferation and osteogenesis. The sheath-core composite fibers significantly increased calcium accretion of hASCs, indicating that collagen-PCL sheath-core bicomponent structures have potential for bone tissue engineering applications using hASCs. PMID- 20836923 TI - Antibiotic-containing biodegradable bead clusters with porous PLGA coating as controllable drug-releasing bone fillers. AB - The construction of inorganic bone fillers with a suitable degradation period to match the new bone growth is an urgent task since most bone fillers have an either too fast or slow degradation rate. Calcium sulfate, as a commonly used implanting material, shows good biocompatibility, biodegradability, osteoconductivity and mechanical properties. However, its degradation rate and the drug-release rate are too rapid to meet the requirements for clinical application. In this paper, calcium sulfate bead clusters (CSBC), with or without loaded drug, were prepared; and two kinds of coatings, porous or nonporous, were deposited on the surface of the beads to extend the degradation and the drug release period. The results show that poly(lactic acid-glycolic acid) (PLGA) coatings, incorporated with different porogens can form in situ porous coatings that obviously lengthen the degradation period of the beads from 30 days to around 60-90 days. Consequently, the drug-release rate was significantly reduced, and the release period increased from about 10 days to over 50 days. PMID- 20836924 TI - Deciding to become a GP: an example of 'careership' in the NHS? PMID- 20836925 TI - General practice registrars as teachers: a review of the literature. PMID- 20836926 TI - What makes a good educational supervisor? AB - The author reviewed the previous literature describing the essential qualities and skills required of a trainer, now called educational supervisor, in a UK general practice setting. Those qualities are described in various ways and in various groupings. However, the broad categories of personal attributes and attitudes, communication skills including IT, educational knowledge, and educational skills encapsulate the majority of them. In Scotland in 2007 a group of medical educationalists made changes to a national prospective trainers' course to reflect changes in GP specialist training. In the new course participants deliver much of the teaching on the last two units of the course. By so doing, they demonstrate competence in 12 competency areas derived from the GP specialist trainee medical competencies of workplace-based assessment. That competence is summatively assessed by the course facilitators at the end of the course. The enthusiasm and energy of the participants that derives from this commitment to active participation in learning and teaching, against observable competency areas, is an endorsement of an innovation in course design. It may prove a helpful model for other parts of the UK. PMID- 20836927 TI - Consultants' attitudes to the assessment of GP specialty trainees during hospital placements. AB - This study explored the views and experiences of a sample of hospital consultants using the RCGP e-portfolio, within the wider context of WPBA. Whilst the use of e portfolios and WPBA in a hospital setting was broadly valued and accepted, issues of e-portfolio functionality often hindered the professional judgement of competencies. Issues relating to training in the use of the RCGP e-portfolio and the need for adequate protected time were identified, together with a reluctance to give negative formative feedback through this format. PMID- 20836928 TI - The benefits of educational release of hospital-based general practice specialist training registrars into general practice. AB - In Denmark, specialist training for family medicine consists of 2.5 years training in general practice and 2.5 years training in specific hospital departments. The hospital training programme contains mandatory release time (return days) whereby GP trainees leave their hospitals in order to work with patients in their teaching GP surgeries for one day every month. The goals are to develop and maintain a family medicine perspective during the hospital training and to maintain contact with the family medicine environment. In order to explore the benefits of going back to general practice for one day per month during hospital training, we carried out a qualitative study comprising three focus group interviews with trainees and one focus group with trainers. Return days are important for the development of a professional identity and they can ensure the provision of a useful/necessary breathing space in a turbulent education. If properly organised, return days have the potential to strengthen professional competences due to a stronger focus on the family medicine perspective during training. The process strengthens transferability of skills. A focus on better educational management is needed. Trainers' commitment and trainees' ownership of and responsibility for the educational process are prerequisites for success. PMID- 20836929 TI - Role-play series on the difficult patient approach in the family medicine residency programme at Ramathibodi Hospital, Thailand. PMID- 20836930 TI - Peer observation project: an innovative step towards revalidation for GP educators in Portsmouth. PMID- 20836931 TI - Undergraduate teaching in general practice: a curriculum. PMID- 20836932 TI - How to . . . give effective feedback. PMID- 20836933 TI - Enhancing career opportunities through MRCGP International in the UAE. PMID- 20836934 TI - Dubai MRCGP [INT] examination: "promoting professionalism in family medicine". PMID- 20836936 TI - The importance of service users in healthcare quality and research: from involvement to emancipation. PMID- 20836937 TI - Using the electronic health record to diagnose gastro-esophageal reflux disease: blessing or curse? PMID- 20836938 TI - An electronic medical record-based intervention to improve quality of care for gastro-esophageal reflux disease (GERD) and atypical presentations of GERD. AB - BACKGROUND: Gastro-esophageal reflux disease (GERD) is common in primary care but is often underdiagnosed and untreated. GERD can also present with atypical symptoms like chronic cough and asthma, and physicians may be unaware of this presentation. We aimed to implement and evaluate an intervention to improve diagnosis and treatment for GERD and atypical GERD in primary care. METHOD: This was a randomised controlled trial in primary care office practice using a national network of US practices (the Medical Quality Improvement Consortium - MQIC) that share the same electronic medical record (EMR). Thirteen offices with 53 providers were randomised to the intervention of EMR-based prompts and education, and 14 offices with 66 providers were randomised to the control group totalling over 67 000 patients and examining outcomes of GERD diagnosis and appropriate treatment. RESULTS: Among patients who did not have GERD at baseline, new diagnoses of GERD increased significantly in the intervention group (3.1%) versus the control group (2.3%) (P<0.01). This remained significant after controlling for clustering with an odds of diagnosis of 1.33 (95% CI 1.13-1.56) for the intervention group. For patients with atypical symptoms, those in the intervention group had both higher odds of being diagnosed with GERD (OR 2.02, 95% CI 1.41-2.88) and of being treated for GERD (OR 1.40, 95% CI 1.08-1.83) than those in the control group. CONCLUSIONS: GERD diagnosis and treatment in primary care, particularly among patients with atypical symptoms, can be improved through the use of an EMR-based tool incorporating decision support and education. However, significant room for improvement exists in use of appropriate treatment. PMID- 20836939 TI - The value of nurse practitioners in Dutch general practices. AB - BACKGROUND: Healthcare systems are faced with a changing and increasing demand for care. Against the background of the need to increase service capacity and to improve access to primary care, a project was initiated to introduce the nurse practitioner (NP) role into Dutch general practices. OBJECTIVE: To explore the value of the NP by describing NP roles and their concordance with the initial concepts of the NP training programme. METHODS: An observational longitudinal design, using mixed methods, was conducted between March 2004 and June 2008. A convenience sample of seven NPs and seven teaching general practitioners (GPs), together constituting seven experimental groups, was used. Project documentation and data from consultations between NPs and GPs were collected. Twenty-nine interviews were performed, focusing on NP roles, competencies of NPs and collaboration between professionals. RESULTS: As was anticipated, all NPs have patients with common complaints as their main focus, as well as managing the quality of care projects. Differences between NPs are reported in the percentages of time spent in performing home visits, caring for older people, patient related activities and non-patient related activities. CONCLUSION: NPs contribute to the accessibility and availability of primary care as well as to collaboration in and quality of primary care. The roles they adopt are influenced by practice needs and financial incentives. It is not clear to what degree NPs have to perform activities to improve quality of care and further research is necessary to define NP core competencies. PMID- 20836940 TI - Psychosexual problems in general practice: measuring consultation competence using two different measures. AB - BACKGROUND: Psychosexual problems are a common presentation in general practice. Given that the cornerstone of assessment is excellent consultations skills, it may be assumed that general practitioners (GPs) will perform skilfully for such presentations. AIM: To determine if there is a significant difference in consultation skills assessed using a generic test of consultation performance compared to one which has been specifically developed for experts in psychosexual care, albeit modified for general practice consultations. METHODS: Six GPs were video recorded consulting six standardised patients at their respective practices. Two assessors independently rated the consultation performance using the Leicester Assessment Package (LAP), a generic tool to assess GP consultation performance. Four sexologists, blind to the review by the LAP assessors, assessed the same consultations deploying the Permission, Limited Information, Specific Suggestion, Intensive Therapy (PLISSIT) framework. The PLISSIT is routinely used to teach health professionals communication skills when consulting people with psychosexual problems. RESULTS: Thirty-four consultations were successfully recorded. The mean duration of consultations was 12 minutes and 10 seconds (range 7 m. 54 s. to 16 m. 54 s.). Three GPs differed significantly in core competencies as measured by the LAP. Similarly, three GPs differed in competencies as measured by the PLISSIT. There were significant differences in mean LAP scores and PLISSIT scores observed for different doctors. Mean LAP scores varied by actor-scenario after adjusting for doctor clustering, whereas PLISSIT scoring did not vary significantly by actor-scenario in this small study with limited power. There was no evidence that mean LAP scores were associated with PLISSIT scores. CONCLUSIONS: Two measures of consultation competence revealed different outcomes when applied to the same consultations. We found evidence that general practitioners vary significantly on different measures of consultation competence when consulting patients with psychosexual problems in the context of a cancer diagnosis. PMID- 20836941 TI - A critical review of the literature on the uptake of cervical and breast screening in British South Asian women. AB - OBJECTIVES: To consider the recent evidence which examines factors that are associated with uptake of cervical and breast screening in the British South Asian community and to consider the effectiveness of interventions to improve uptake in this group. METHODS: A search strategy was developed and key databases were searched to identify primary research studies that examined the uptake of cervical and breast screening in British women of South Asian origin. Studies published prior to 1996 were excluded from the review. RESULTS: Seventy-eight studies were identified and ten were included in the review. Observational studies demonstrated mixed results on the effect of ethnicity on uptake of screening. Controlling for confounders attenuated the effect in all studies and removed its effect entirely in some. Investigation of low uptake in qualitative and quantitative research indicates that South Asian women were more likely to have incorrect addresses and language or cultural barriers to screening than other women. Few interventional studies were identified and all varied in their design. The success of interventions was mixed and the lack of control groups in some studies made it difficult to draw conclusions on their effectiveness. CONCLUSION: There is a poor uptake of cervical and breast screening by South Asian women compared with the general population in Britain. Evidence is inconclusive as to whether this is due to a residual effect of ethnicity following control for socio-demographic and local health service variables. Currently there is a lack of robust experimental studies on which to base interventions intended to increase uptake in this population. PMID- 20836942 TI - Fostering clinical engagement and medical leadership and aligning cultural values: an evaluation of a general practice specialty trainee integrated training placement in a primary care trust. AB - OBJECTIVES: To report on the extent to which a general practice specialty trainee integrated training placement (ITP) developed the leadership skills and knowledge of general practice specialty trainees (GPSTRs) and on the potential of the ITP to improve clinical engagement. DESIGN: A case study method was used in a Kent primary care trust (PCT). Sources of data included face-to-face and telephone interviews (three GPSTRs, three PCT clinical supervisors, three general practitioner (GP) clinical supervisors and three Deanery/PCT managers), reflective diaries, documentary sources and observation. Interview data were transcribed and analysed using the constant comparative method. RESULTS: All respondents were positive about the value and success of the ITP in developing the leadership skills of the GPSTRs covering three dimensions: leadership of self, leadership of teams and leadership of organisations within systems. The ITP had enabled GP trainees to understand the context for change, to develop skills to set the direction for change and to collect and apply evidence to decision making. The ITP was described as an effective means of breaking down cultural barriers between general practice and the PCT and as having the potential for improving clinical engagement. CONCLUSIONS: The ITP provided a model to enable the effective exchange of knowledge and understanding of differing cultures between GPSTRs, general practice and the PCT. It provided a sound basis for effective, dispersed clinical engagement and leadership. PMID- 20836943 TI - Integrating sexual and reproductive health in primary health care in Europe: position paper of the European Forum for Primary Care. AB - Sexual health and reproductive health are relatively new concepts in Europe. They were introduced and recommended during and after the International Conference on Population and Development (ICPD) in Cairo, 1994. At the ICPD a 20-year Programme of Action was adopted by the vast majority of world states. This article is an edited version of the European Forum for Primary Care (EFPC) position paper on the potential role of primary health care (PHC) in the field of sexual and reproductive health (SRH) in Europe. The EFPC commissioned two European SRH experts to set out its position on the subject, which is presented here. The experts were assisted by a working group of eight European SRH and PHC experts from six countries, while the WHO Regional Office for Europe and the WHO Reproductive Health and Research Department at the organisation's Geneva office provided valuable support and input during the process of developing this position paper. Because both these concepts, i.e. SRH and PHC, are often poorly understood, their meaning and substance are explained in some detail. For a variety of reasons SRH should be a primary responsibility of PHC and it should be approached as one integrated field of health care. In actual practice, SRH is very differently organised across Europe and in many cases poorly integrated in PHC. SRH care is often fragmented, not easily accessible, of poor quality and needlessly expensive. It is therefore recommended that SRH care is better integrated in PHC, and that it meets a variety of quality criteria. PMID- 20836944 TI - Web alert: supporting patient choice--what services are available and how well do they perform? PMID- 20836945 TI - Tipping the balance at 53.6%. PMID- 20836946 TI - Associations of masticatory performance with body and dental variables in children. AB - PURPOSE: The purpose was to evaluate the masticatory performance (MP) of children while also considering body mass index (BMI) and dental conditions. METHODS: Ninety-seven 8- to 12-year-olds participated. Dental conditions were appraised by counting the total number of primary and permanent teeth and the decayed, missing, and filled teeth (dmf/DMFT). MP was determined with a chewable material over the course of 20 cycles, obtaining the median particle size (X50) and broadness of distribution (b). Normal weight, underweight, and overweight/obese groups were formed based on BMI-for-age percentiles. Maternal schooling and socioeconomic status (SES) were assessed. RESULTS: Overweight/obese children presented larger X50 than normal-weight children. The b and dental conditions were similar among groups. Most families belonged to a very low SES, and most mothers had limited schooling without influence on BMI. X(50) was negatively correlated with age in the underweight group and positively associated with DMFT in the normal group. Underweight children were at higher risk for exhibiting poor MP (odds ratio=1.87). For other variables and groups, the risks were similar. CONCLUSIONS: The normal-weight children presented a better masticatory performance than the overweight/obese ones. Poor masticatory performance had a significant relationship with being underweight and with the conditions of permanent teeth in normal-weight children. PMID- 20836947 TI - Differences in pediatric dental services under general anesthesia for Medicaid and military dependent children. AB - PURPOSE: This study's purpose was to compare pediatric dental services provided for Medicaid and military dependent children to determine if differences in dental treatment choices exist based on site and payment method. METHODS: Subjects included 120 Medicaid patients at the University of Texas Health Science Center at San Antonio and 120 military dependents at Lackland Air Force Base, Texas. Demographic data and treatment information were abstracted for children younger than 6 years old receiving dental treatment under general anesthesia between 2002 and 2006. Data was analyzed using Wilcoxon rank sum, Kruskal-Wallis, and Fisher's exact tests. RESULTS: The Medicaid recipients were younger (40.2 vs 49.8 months, P<.001) and more likely to be Hispanic (78% vs 30%, P<.001). The means of decayed teeth, fillings, and stainless steel crowns did not differ between sites. Medicaid children received more composite fillings (P<.001), fewer amalgam fillings (P<.001), fewer pulp therapies (P<.001), more extractions (P=.01), and fewer sealants (P<.001). Age and gender did not affect decay rates, but those of Hispanic ethnicity did experience more decay than non-Hispanics (9.5 vs 8.6, P=.02). CONCLUSION: This study found no difference in the number of less conservative, albeit more costly, procedures performed with Medicaid children at a university compared to military dependents at a military base. PMID- 20836948 TI - Illustrated information for parent education: parent and patient responses. AB - PURPOSE: The purpose of this study was to explore the effect of using illustrations, when educating parents about their child's upcoming operative appointment, on parents' and child patients' responses to the treatment. METHODS: Data were collected from 189 parents of 4- to 10-year-old pediatric dental patients who needed operative treatment. The parents received information about their child's upcoming operative visit either verbally or with the support of standardized illustrations (flip chart), and/or individualized drawings. Parents and providers responded to surveys following the operative appointments. RESULTS: Verbally informed parents were more likely to (a) miss the operative appointment (47% vs 19%/16%/10%; P<.001) and (b) remain in the operatory during treatment (47% vs 18%/26%/19%; P<.01) than parents who received standardized illustrations, individualized illustrations, or both illustrations. The patients whose parents had received verbal information behaved more negatively than the children whose parents had received illustrative information. Overall, Frankl behavior ratings ranged from 1="definitely negative" to 4="definitely positive" (3.30 vs 3.54; P=.04). CONCLUSIONS: Educating parents about the basic disease process of dental caries with the aid of illustrations increased parents' cooperation with the recommended dental treatment for their children and improved their children's behavior during the treatment. PMID- 20836949 TI - Effectiveness of impacted and supernumerary tooth diagnosis from traditional radiography versus cone beam computed tomography. AB - PURPOSE: The purpose of this study was to determine if cone beam computed tomography (CBCT) is more effective than traditional radiography (TR) in diagnosing pediatric dental clinical cases involving impacted and supernumerary teeth. METHODS: Surveys were given to 10 pediatric dental faculty and 10 pediatric dental residents after viewing 8 clinical cases in either CBCT or TR in which the patient presented with pathology (impaction or supernumerary) in the anterior maxilla. The surveys asked for pathology diagnosis, location, and identification of root resorption, as well as questions about the usefulness of the radiographic mode in treatment planning. RESULTS: A statistically significant difference in CBCT vs. TR viewed cases was found with CBCT statistically better (P<0.05) for pathology location, determining root resorption, usefulness, adequacy in treatment planning, and was the overall recommended mode. More faculty were able to correctly identify the pathology location (P=0.034), while more residents believed they could determine presence of root resorption P=0.029). For impacted versus supernumerary cases, more pathology was correctly located when viewed in CBCT mode (P<0.05). No statistical significance in diagnosing the presence of pathology for all cases was found. CONCLUSIONS: CBCT and TR were effective in the initial diagnosis of pathology in the cases presented. CBCT, however, provides more information on the location of pathology, the presence of root resorption, and treatment planning. The pediatric dental community can benefit from the amount of additional information provided by CBCT. The benefits of CBCT imaging must be weighed against the radiation risk to the pediatric patient and the complexity of the pathology. PMID- 20836950 TI - Development of the self-efficacy scale for maternal oral care. AB - PURPOSE: This study's purpose was to develop a task-specific self-efficacy scale for maternal oral care (SESMO) with reliability and validity. METHODS: A draft scale consisting of 36 items was designed and tested on 119 mothers at a dental clinic. Item analysis was performed to improve its accuracy by reducing the number of items. Internal consistency and test and retest stability were investigated. Concurrent validity was tested by examining associations of the SESMO score with the: general self-efficacy scale (GSES) score; number of decayed teeth; and frequency of tooth-brushing for children. Construct validity was examined by comparing the SESMO scores between mothers of children with caries at initial visit (Group 1) and those continuing regular dental checkups (Group 2). RESULTS: The item analysis selected 16 items for the SESMO. Alpha coefficient of the SESMO was 0.82. Significant correlation was observed between tests and retests (r=0.74). There were significant associations between the SESMO score and GSES score (r=0.39); number of decayed teeth (r=-0.33); and frequency of brushing children's teeth (r=0.66). Group 2 had a significantly higher SESMO score than Group 1 (P<.001). CONCLUSIONS: The SESMO showed high reliability and validity. This scale might endure with research applications in pediatric dental practice. PMID- 20836951 TI - A microbiological assessment of polymer and conventional carbide burs in caries removal. AB - PURPOSE: The purpose of this study was to compare the caries removal efficiency of polymer burs (Smartburs) and conventional carbide burs microbiologically. METHODS: Twenty-four patients participated, each presenting 2 active carious lesions on the occlusal surfaces of primary molars. Sample-taking and caries removal were done in the following order: (1) first sample (from the carious dentin); (2) caries removal (with a Smartbur or carbide bur); and (3) second sample (from the caries-free dentin), respectively. The samples were processed in a laboratory and spread on various media. The colonies on the agar plates were counted, and then numbers of CFU/ml were calculated. RESULTS: There were no statistically significant differences between the numbers of CFU/ml in the carious dentin before preparation, comparing the Smartbur group and carbide bur group for all the media used (P>.05). There were statistically significant differences in the numbers of CFU/ml before and after preparation comparing both types of burs for all the media used (P<.05). There were no statistically significant differences in the reductions of the numbers of CFU/ml, comparing the 2 preparation instruments (P>.05). CONCLUSION: The polymer burs were found as effective as the conventional carbide burs microbiologically in caries removal. PMID- 20836952 TI - Risk indicators of temporomandibular disorder incidences in early adolescence. AB - PURPOSE: Although temporomandibular disorder (TMD) has been presumed to be a condition affecting adults, studies have reported the presence of signs and symptoms in children. The purpose of this paper was to verify the influence of gender, mother's gestational behavior, malocclusion, and oral habits as risk indicators for TMD in 12-year-old adolescents. METHODS: TMD pain was assessed by research diagnostic criteria for temporomandibular disorders (RDC/TMD; axis I). Five-hundred fifty-eight subjects (330 girls and 228 boys) underwent examinations. Bivariate analyses were performed using the chisquare test. The logistic regression models were adjusted estimating the odds ratio (OR), 95% confidence interval (CI), and significance level. RESULTS: Only 2% of boys and 7% of girls presented one of the axis I categories. Gender was significantly related to TMD diagnosis (P<.01). Menarche, however, was not associated. Malocclusion, mother's gestational behavior, and children's oral habits were not associated with incidence of TMD (P>.05). Girls were almost 4 times more affected than boys (OR=3.97; CI=1.51-10.53). CONCLUSIONS: The mothers' gestational behavior and presence of menarche, malocclusion, and oral habits by their adolescents were not associated with diagnosis of temporomandibular disorder. Gender was the only factor associated with the incidence of TMD in 12-year-old adolescents. PMID- 20836953 TI - The relationship of dental visits to parental knowledge of management of dental trauma. AB - PURPOSE: The purposes of this study were to: (1) determine the level of parental knowledge regarding initial trauma management; and (2) assess which factors could influence that level of knowledge. METHODS: A self-administered questionnaire was given to parents of patients that attended 1 of 2 dental clinics. The questionnaire consisted of 3 parts and assessed patient and parental demographics and knowledge of dental trauma management. RESULTS: Four hundred sixty-seven questionnaires were completed. Most patients had Medicaid insurance (79%). Most parents would seek care from a dentist (71% broken tooth; 62% avulsed tooth). Only 31% knew that avulsed permanent teeth could be placed back into the socket, and only 25% of parents chose milk as a transport medium for avulsed teeth. A mere 3% of parents answered all 5 trauma management questions correctly, and 10% had no correct responses. The number of correct responses was not affected by clinic location, history of previous trauma, sex, education, or insurance status. Parents of recalled patients had more correct responses (P<.05). CONCLUSION: Knowledge of dental trauma management was poor. The fact that parents of recalled patients were somewhat more knowledgeable suggests that the dental visit can be an effective vehicle for education. The management of dental trauma should be part of the dental health education provided at dental visits. PMID- 20836954 TI - Nutrition and oral health considerations in children with special health care needs: implications for oral health care providers. AB - Children with special health care needs are at increased risk for oral diseases. The purpose of this article was to discuss: nutritional and oral health factors routinely observed in most chronic childhood disorders; dietary modifications associated with select systemic disorders and how they may impact oral health in children; and the following factors common to chronic disorders associated with diet modifications-decreased appetite and increased nutritional risk; frequency of food intake; parental overindulgence; long-term use of cariogenic medications; and xerostomia. Characteristics of childhood disorders that require dietary modifications (congenital heart disease, cystic fibrosis, cancer, AIDS/HIV, diabetes mellitus, and phenylketonuria) are summarized. In addition, healthy dietary modifications and oral health recommendations are suggested. Implementation of these recommendations can assist the dentist and dental team as they join physicians and nutritionists in delivering the best possible care to children with special health care needs. PMID- 20836955 TI - Dental injuries in autistic patients. AB - PURPOSE: The purpose of this study was to assess the incidence of traumatic dental injury among Turkish children and young adults with autism and compare this to the general population of Turkish children and young adults without autism. METHODS: This study was comprised of 186 children and young adults (138 males and 48 females), 93 with autism (autistic group, or AG) and 93 without autism (control group, or CG). Dental injuries were classified according to drawings and texts based on the WHO classification system, as modified by Andreasen and Andreasen. RESULTS: The rate of injury was higher among the AG (23%) than the CG (15%). The difference between the 2 groups, however, was not statistically significant (P<.19). The most common type of dental injury was enamel fracture. The rate of enamel fracture was higher in the CG (59%) than in the AG (33%), and the distribution of types of traumatic injury differed significantly between the AG and CG (P>.01). CONCLUSIONS: There were no significant differences in the rates of traumatic dental injuries among children and young adults with and without autistic disorder. The most frequently injured teeth were the permanent maxillary central incisors, and the frequency of injury to these teeth differed significantly (P>.01) between AG (56%) and CG (91%). The most common type of dental injury, enamel fracture, was more common in CG (59%) than AG (33%). The distribution of types of traumatic dental injuries differed significantly between the 2 groups (P>.01). PMID- 20836956 TI - Pulp exposure occurrence and outcomes after 1- or 2-visit indirect pulp therapy vs complete caries removal in primary and permanent molars. AB - PURPOSE: The purpose of this study was to examine whether 1- or 2-visit indirect pulp therapy (IPT) is more successful and to determine if the operator can successfully decide when to stop removing caries without exposing the pulp. METHODS: A total of 154 teeth (94 primary second molars and 60 young permanent first molars) were included in the study from a total of 123 4- to 15-year-old patients. The teeth had deep carious lesions but lacked the preoperative signs and symptoms of irreversible pulpitis. The teeth were randomly selected and treated either with 1-visit IPT, 2-visit IPT, or direct complete excavation (DCE). Follow-up examinations were conducted on the teeth over 1 year at 3-month intervals. RESULTS: The pulp was exposed in 12 teeth (22%) treated by DCE, whereas 3 teeth (6%) were treated by 1-visit IPT and 4 teeth (8%) with 2-visit IPT. A statistically significant difference was found between IPT and DCE groups in terms of pulp exposure (P<.05). The teeth without pulp exposure showed normal clinical and radiographic conditions during the 1-year follow-up, except for 3 primary teeth. CONCLUSIONS: Indirect pulp therapy in both primary and young permanent teeth can be used successfully with a 1- or 2-visit approach. PMID- 20836958 TI - [Polypharmacy--too much of the good?]. PMID- 20836957 TI - Three-dimensional imaging cone bean computer tomography technology: an update and case report of an impacted incisor in a mixed dentition patient. AB - The current 3-dimensional (3-D) technology termed "cone beam computer tomography" (CBCT) provides accurate 3-D anatomical image data similar to medical computerized tomography but at a lower cost and dose. CBCT has been suggested to be used in cases of supernumeraries because it yields accurate 3-D information relative to the orientation, sagittal position, local disorders, and neighboring anatomic structures. The purposes of this article were to: present the available 3-D imaging technology; and report the case of a patient in the late mixed dentition with a maxillary supernumerary tooth and an impacted central incisor. The use of a CBCT appears to be favorable as a diagnostic and communication tool for cases of impacted teeth in the mixed dentition that are candidates for orthodontic resolution. PMID- 20836959 TI - [The difficult ECG]. PMID- 20836960 TI - [Overlooked Wolff-Parkinson-White syndrome]. AB - An autopsy in a 28-year-old man did not explain the cause of sudden unexpected death. However, a history of episodes with tachycardia and dizziness and a reassessed previous electrocardiogram exhibiting ventricular pre-excitation was consistent with Wolff-Parkinson-White (WPW) syndrome. In this patient we believe that the occurrence of atrial fibrillation caused sudden cardiac death from ventricular fibrillation due to a short refractory period of an accessory atrioventricular pathway and a very rapid ventricular rate in atrial fibrillation. PMID- 20836961 TI - [Unfractionated heparin and low molecular weight heparin for acute coronary syndromes--assessment of a Cochrane review]. AB - In aspirin-treated patients with acute coronary syndromes without ST-segment elevation unfractionated heparin (UFH) or low molecular weight heparin (LMWH) treatment < 7 days significantly reduce the risk of acute myocardial infarction (AMI), and LMWH furthermore reduces revascularisation. There is a non-significant effect on mortality compared with placebo and an insignificantly increased risk of haemorrhagic complications. No net clinical benefit of LMWH was found compared to UHF, but LMWH has pharmacokinetic advantages. The optimal duration of heparin treatment remains controversial. PMID- 20836962 TI - [Grommets (ventilation tubes) for recurrent acute otitis media in children- assessment of a Cochrane review]. AB - A recently published Cochrane review on grommets (ventilation tubes) for recurrent acute otitis media in children included only two studies involving 148 children. The review showed that ventilation tube insertion led to a mean reduction of approximately one episode of acute otitis media in the first six months after treatment. We examined three excluded studies and found that their results were comparable even if all five studies had different designs. Clinicians should consider the possible adverse effects of grommet insertion before performing the surgery. PMID- 20836963 TI - [Parents satisfied with the grommet treatment in ear, nose and throat practice]. AB - INTRODUCTION: In Denmark, grommet insertion in the tympanic membrane is the most frequent type of surgery carried out on children. Denmark has a higher registered incidence of grommet treatment than the countries with which we normally compare ourselves. It is therefore relevant to study whether ear, nose and throat (ENT) specialists follow grommet treatment guidelines, and which children are treated with grommets. MATERIAL AND METHODS: The study was planned as an observational survey with the individual child as observational unit for patient data. The ENT specialist was the observational unit for doctor behaviour. Data were collected in a double questionnaire study in which two questionnaires were completed by the ENT specialist and another two by the parents of each individual child. RESULTS: A total of 24 ENT specialists participated, and they included 426 children in the study. The majority of the children were observed between three and six months prior to surgery. In 32% (28-37%) of the cases, the specialist had no information describing how long the GP had observed the child. A total of 95% (92-97%) of the parents were satisfied with the grommet treatment and estimated that it had considerably improved the child's and the family's daily lives. CONCLUSION: The specialists followed the grommet treatment guidelines. Communication between specialists and GPs could be improved. Parents were satisfied with the treatment. PMID- 20836964 TI - [Obesity and life-style in 5-8-year-old children]. AB - INTRODUCTION: The purpose of this study was to describe the prevalence of overweight and variations in physical activity and smoking habits among parents in three suburbs of Copenhagen, focusing on differences related to ethnic Danish and bilingual children, respectively. MATERIAL AND METHODS: The health profile was completed as part of a physician health check-up at school start. The questionnaire included registration of the parents' employment status, parental smoking habits, and health behaviour among the children. The children's height and weight were registered. A total of 823 children were included (participation rate of 96.1%) of which 201 were bilingual. RESULTS: 21.2% of the children had a weight exceeding the 90 percentile (based on a Danish standard). Of these, 8.7% had a weight exceeding the 97 percentile. 32.2% of the bilingual children were overweight while 18% of the ethnic Danish children were overweight (p = 0.001). Fewer children were overweight in the more affluent suburb to the north of Copenhagen than in the two other suburbs. Fewer bilingual children were involved in organized sports and walked or cycled to school. More bilingual children were exposed to passive smoking in the home and spent longer time in front of a screen. CONCLUSION: At school start, approximately one fifth of the children in three Copenhagen suburbs had a weight exceeding the 90 percentile and approximately 9% over the 97 percentile. Bilingual children were more often exposed to risk factors predisposing to lifestyle diseases. PMID- 20836965 TI - [Low mortality following salicylic poisoning]. AB - INTRODUCTION: The objective of the study was to identify possible prognostic factors in patients with salicylic poisoning. MATERIAL AND METHODS: A chart review on 53 patients with salicylic poisoning was performed. Clinical and biochemical data were registered for all patients with a serum level of salicylic acid higher than or equal to 2 mmol/l in the 2004-2008 period. The patients were divided into groups according to the outcome of the poisoning. A complicated outcome was defined as: hospital stay > 48 hours, dialysis, persisting complications at discharge or death. RESULTS: In the group with complicated outcome, chronic poisoning (43% versus 13%, p = 0.02) and medical diseases (24% versus 9%, p = 0.07) were more prevalent and the proportion of elderly (55 years versus 38 years, p = 0.003) and alcoholics (48% vs. 25%, p = 0.09) were higher. The mortality was low, with only one fatality among the acutely poisoned and none among the chronically poisoned. Neurological symptoms (somnolence and confusion) were the only symptoms which differed significantly between the two groups (67% versus 28%, p = 0.006), as well as being the only variable independently emerging as a risk factor in the multivariate logistic regression analysis with an odds ratio of 6.6 (95% confidence interval: 1.5-28.9) for a complicated outcome. A significantly lower level of bicarbonate was seen in the group with complicated outcome. Among the other biochemical data, only haemoglobin and certain liver enzymes differed between the two groups, probably due to pre-existing differences. CONCLUSION: Mortality after salicylic poisoning is low. Chronic poisonings, old age or concurrent medical diseases are associated with a complicated outcome. If neurological symptoms or low standard-HCO3- are present, the prognosis is poor. PMID- 20836966 TI - [Pseudoxanthoma elasticum]. AB - During childhood two women developed yellowish xanthoma-like papules on the neck. After dermatological examination and skin biopsy, the diagnosis pseudoxanthoma elasticum (PXE) was made. PXE is a hereditary metabolic disease which has an early onset with characteristic skin lesions. Early diagnosis and follow-up is essential to prevent serious ocular or cardiovascular complications. Follow-up standards are lacking for these patients. PMID- 20836968 TI - Towards better reporting of interventions in clinical trials of acupuncture. PMID- 20836967 TI - [Intratesticular epithelial inclusion cyst]. AB - A 22-year-old male presented with a palpable tumour near the lower pole of the testicle. An ultrasound scan showed an 8 * 10 * 13 mm lesion which on the basis of which malignancy was suspected. An intratesticular cyst was excised. Frozen section microscopy revealed no malignancy. The tunica albuginea was closed and the postoperative course was uneventful. Histological examination showed an epithelial inclusion cyst. Such cysts are rare without cutaneous involvement. Less than 1% of all testicular tumours are inclusion cysts. Later malignant transformation has never been reported. PMID- 20836969 TI - [Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA): extending the CONSORT statement (Chinese version)]. AB - The STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) were published in five journals in 2001 and 2002. These guidelines, in the form of a checklist and explanations for use by authors and journal editors, were designed to improve reporting of acupuncture trials, particularly the interventions, thereby facilitating their interpretation and replication. Subsequent reviews of the application and impact of STRICTA have highlighted the value of STRICTA as well as scope for improvements and revision. To manage the revision process a collaboration between the STRICTA Group, the CONSORT Group and the Chinese Cochrane Centre was developed in 2008. An expert panel with 47 participants was convened that provided electronic feedback on a revised draft of the checklist. At a subsequent face-to-face meeting in Freiburg, a group of 21 participants further revised the STRICTA checklist and planned dissemination. The new STRICTA checklist, which is an official extension of CONSORT, includes 6 items and 17 subitems. These set out reporting guidelines for the acupuncture rationale, the details of needling, the treatment regimen, other components of treatment, the practitioner background and the control or comparator interventions. In addition, and as part of this revision process, the explanations for each item have been elaborated, and examples of good reporting for each item are provided. In addition, the word "controlled" in STRICTA is replaced by "clinical", to indicate that STRICTA is applicable to a broad range of clinical evaluation designs, including uncontrolled outcome studies and case reports. It is intended that the revised STRICTA checklist, in conjunction with both the main CONSORT statement and extension for non-pharmacological treatment, will raise the quality of reporting of clinical trials of acupuncture. PMID- 20836970 TI - [Guidelines for evidence-based Chinese medicine clinical pathway report]. AB - Clinical pathway (CP), as a standardized approach and clinical management process for disease diagnosing and treating, is being widely used with more relevant publications reported gradually. But different forms of CP reports may prevent the evaluation and spreading of CP. The authors recommend guidelines for evidence based Chinese medicine CP report, including 18 items which form 5 big sections, by precise item selection and rigorous expert consensus. All these items can embody the principles of Chinese medicine and comply with the requirements of the clinical practice of Chinese medicine. All above are based on synthesizing the published literature systematically and analyzing the current status in this field, also according to the characteristics of Chinese medicine and methodology requirement of evidence-based medicine. PMID- 20836971 TI - [A review of evaluation scales for therapeutic effect of cervical spondylotic radiculopathy]. AB - Various kinds of therapies have been clinically applied to treat cervical spondylotic radiculopathy (CSR). However, the evaluation standards of therapeutic effect in different medical institutions are quite different from each other at present, thus bringing about many difficulties in the therapeutic effect evaluation of CSR treatment. Although many CSR-related scales have been developed, none of them could completely represent or reflect the exact curative actualities of CSR in China. Therefore, it is quite essential to establish a comprehensive evaluation scale for the therapeutic effect of CSR. And such evaluation system, in which the estimation of quality of life should be included, will become the developmental direction of CSR research in future. PMID- 20836972 TI - [Towards better understanding the definition of cancerous toxin]. AB - The author explained the definition and its scientific value of "cancerous toxin" proposed by Professor Chang-quan Ling, pointing out that it is helpful for better understanding the pathogenic factor and guiding the diagnosis and treatment of cancer. In regard to the new definition of "cancerous toxin", the author put forward three key issues which should be solved in the field of integrated Chinese and Western medicine. First, the pathological property of cancerous toxin should be uncovered. Second, the relationship between cancerous toxin and syndrome differentiation or dosage of herbs need be further explored. Last, the cause of cancerous toxin is still unknown. PMID- 20836973 TI - The SpREUK-SF10 questionnaire as a rapid measure of spiritual search and religious trust in patients with chronic diseases. AB - BACKGROUND: There is growing evidence that aspects of spirituality have an impact on health. Measures of spirituality must be adapted to the kinds of populations being studied. In order to investigate how patients with chronic diseases living in secular societies view the impact of spirituality on their health and how they cope with illness, the SpREUK questionnaire was developed. OBJECTIVE: This paper describes the background and psychometric properties of an assessment tool which might be suited for patients living in secular societies, and summarizes confirmatory findings of patients from Germany. DESIGN AND PARTICIPANTS: Cross sectional study among 496 patients (mean age 53.5 +/- 14.4 years) with chronic diseases (84% chronic pain conditions, 6% cancer, and 10% other). All subjects completed the questionnaires by themselves. OUTCOME MEASURES: We intended to develop a short form of the already established SpREUK questionnaire, and tested it with respect to its factorial structure and conceptual validity. Other measures were engagement in spiritual practices (SpREUK-P), life satisfaction (BMLSS), and interpretation of illness (IIQ). RESULTS: The good psychometric properties of the contextual (disease-related) instrument which differentiates 3 factors were confirmed: (1) Trust (in Higher Guidance/Source) (alpha=0.898), (2) Search (for Support/Access to Spirituality/Religiosity) (alpha=0.844), and (3) Reflection (Positive Interpretation of Disease) (alpha=0.736). Particularly the positive interpretations of disease were moderately associated with Search and Trust, indicating their spiritual connotation. CONCLUSION: To assess aspects of spirituality in secular societies which are not biased for or against a particular religious commitment, the SpREUK-SF10 questionnaire appears to be a good choice. Adaptations to other cultural backgrounds are encouraged. PMID- 20836974 TI - [Distribution characteristics of syndrome types in essential hypertension]. AB - OBJECTIVE: To investigate the distribution characteristics of syndrome types of traditional Chinese medicine (TCM) in essential hypertension and to explore the distribution rule of TCM syndromes. METHODS: A multicenter, large-sample survey method of clinical epidemiology was applied to choose the patients with essential hypertension from North, Middle, and South China. A questionnaire was designed and filled in, then 477 untreated patients with first-diagnosed essential hypertension were selected and the information was recorded into FileMaker database. A cluster analysis method was utilized to study the TCM syndrome distribution rule of essential hypertension. RESULTS: Two-step cluster analysis was done from 3 to 7 clusters. Seven clusters were appropriate, which included deficiency of heart and kidney qi, hyperactivity of liver-yang, deficiency of yin and yang, stagnation of phlegm-dampness, phlegm-heat (subtype of stagnation of phlegm-dampness), blood stasis obstructing collaterals, and other syndromes. The symptoms presenting high percentage in each cluster were more significant in TCM theory. The syndromes of hyperactivity of liver-yang (24.1%) and stagnation of phlegm-dampness (27.1%) presented the high percentages, and deficiency of heart and kidney qi (10.1%), deficiency of yin and yang (8.4%), and blood stasis obstructing collaterals (9.0%) presented the low percentages. CONCLUSION: As compared with the current syndrome differentiation criteria, two-step cluster analysis results not only include the syndromes of deficiency of yin and yang, hyperactivity of liver-yang, stagnation of phlegm-dampness, but also cover qi deficiency and blood stasis. PMID- 20836975 TI - [Correlation between blood stasis syndrome and pathological characteristics of coronary artery in patients with coronary heart disease]. AB - OBJECTIVE: To study the correlation of blood stasis syndrome or its accompanied syndromes with Gensini score in patients with coronary heart disease (CHD) in stable condition. METHODS: The syndrome types of traditional Chinese medicine (TCM) and blood stasis score in 131 CHD patients confirmed by coronary angiography were recorded. Gensini score was calculated according to the coronary pathological characteristics showed by angiography. The correlations of blood stasis syndrome and its accompanied syndromes with coronary lesion and Gensini score were analyzed. RESULTS: Among the TCM syndrome types, blood stasis, turbid phlegm and qi deficiency were the most common syndromes, revealed in 85 patients (64.9%), 83 patients (63.4%) and 85 patients (64.9%), respectively. The coronary lesion length and Gensini score in the patients with blood stasis syndrome were much higher than those in the patients with non-blood stasis syndrome (P<0.05 or P<0.01). In the subtypes of blood stasis, the coronary lesion length and Gensini score in the patients with blood stasis accompanied by turbid phlegm syndrome were higher than those in the patients with non-blood stasis syndrome (P<0.05). And in the patients whose blood stasis syndrome score was more than 9 points, the coronary lesion length was higher than that in the patients whose blood stasis syndrome score was less than 9 points (P<0.05). Besides, with bivariate analysis, the blood stasis syndrome score showed no correlation with Gensini score (Pearson correlation coefficient was 0.104, P=0.241). CONCLUSION: Blood stasis syndrome is the most common TCM syndrome in CHD patients in stable condition. The blood stasis syndrome score is proportional to coronary lesion length, and reflects the severity of coronary lesion. PMID- 20836976 TI - Polymeric nanoparticle encapsulation of a naturally occurring plant scopoletin and its effects on human melanoma cell A375. AB - OBJECTIVE: We formulated nano-encapsulation of a naturally occurring coumarin scopoletin (7-hydroxy-6-methoxy coumarin, HMC, C(10)H(8)O(4)), isolated from plant Gelsemium sempervirens having anticancer potentials, with a bio-adhesive agent -polylactic-co-glycolic acid (PLGA) and tested if its cellular uptake, bioavailability and apoptotic (anticancer) potentials could thus be increased vis a-vis unencapsulated HMC. METHODS: A375 melanoma cancer cells were used for testing cellular entry and anticancer potentials of HMC and nano-7-hydroxy-6 methoxy coumarin (NHMC) through several standard protocols. Characterization of NHMC was done by dynamic light scattering for determination of particle size, polydispersity index (PDI), and zeta potential. Surface morphology of nanoparticles was determined by scanning electron microscopy and atomic force microscopy. RESULTS: HMC was encapsulated with more than 85% entrapment efficiency, the average particle size of NHMC being less than 110 nm and a PDI 0.237, which resulted in enhanced cellular entry and greater bioavailability. NHMC showed a faster cellular uptake (15 min) than its unencapsulated counterpart (30 min). Study of signal molecules through mRNA expressions revealed that NHMC caused down-regulation of cyclin-D1, proliferating cell nuclear antigen (PCNA), survivin and Stat-3, and up-regulation of p53 and caspase-3, that in turn induced a greater number of apoptosis vis-a-vis unencapsulated HMC. CONCLUSION: The formulation yielded small-sized NHMC by biodegradable PLGA that took less time for cellular entry, and caused more apoptosis to cancer cells, but apparently had negligible cytotoxicity against normal skin cells. Nano-encapsulation of bioactive plant ingredients can be a strategy worth trying for designing effective chemopreventive drug products. PMID- 20836977 TI - [Absorption and transportation characteristics of scutellarin and scutellarein across Caco-2 monolayer model]. AB - OBJECTIVE: To investigate the absorption and transepithelial transport characteristics of scutellarin and scutellarein in the human colonic adenocarcinoma cell (Caco-2) monolayer model. The influence factors on these two compounds' absorption were investigated, such as buffer solution, duration of culture, and inhibitors of multidrug resistance-associated protein 2 (MRP(2)), breast cancer drug resistance protein (BCRP) and P-glycoprotein (P-gp). METHODS: By using Caco-2 monolayer as an intestinal epithelial cell model, the transport process was studied from apical (AP) side to basolateral (BL) side or from BL to AP. The two compounds were determined by high-performance liquid chromatography coupled with diode-array-detector detection. Transport parameters and apparent permeability coeffients (P(app)) were calculated. RESULTS: The P(app) values of scutellarin and scutellarein were different in two buffer solutions, respectively. In phosphate buffered saline, scutellarin had no absorption from AP to BL, while its P(app) value was 0.74*10(-6) to 1.58*10(-6) cm/s from BL to AP. The P(app) values of scutellarein were 4.33*10(-6) to 6.79*10(-6) cm/s and 1.32*10(-6) to 2.56*10(-6) cm/s from AP to BL and from BL to AP, respectively. The P(app) value gradually decreased with time. The absorption of scutellarein was better than that of scutellarin. The scutellarin absorption was improved by verapamil, MK-571 and reserpine. The scutellarein absorption was improved by verapamil whereas its excretion was improved by MK-571. CONCLUSION: Absorption of scutellarin is difficult in Caco-2 monolayer cells, which contributes to its low bioavailability. Scutellarein absorption is better than scutellarin absorption. Scutellarein transepithelial transport is passive diffusion. The inhibitor of P gp can improve scutellarin and scutellarein transportation. The inhibitors of MRP(2) and BCRP can promote transportation of scutellarin. The inhibitor of MRP(2) can promote efflux of scutellarein. The multidrug resistance-associated protein may be the second reason for low bioavailability of scutellarin. PMID- 20836978 TI - [Tea polyphenol inhibits colorectal cancer with microsatellite instability by regulating the expressions of HES1, JAG1, MT2A and MAFA]. AB - OBJECTIVE: To investigate the mechanism of tea polyphenol in inhibiting microsatellite instability (MSI) of colorectal cancer. METHODS: Using LoVo cells and SW480 cells treated with aqueous solution of tea polyphenol, cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) method, changes in microsatellite sequences were detected by genescan method and changes in gene expression of LoVo cells were detected by illumina expression arrays and quantitative real-time polymerase chain reaction (PCR). RESULTS: The proliferation inhibition rates of LoVo and SW480 cells treated with tea polyphenol increased with the increasing of drug concentration and showed an increasing tendency with time. The proliferation inhibition rate of LoVo cells with tea polyphenol was higher than that of SW480 cells, and there was a significant difference in the proliferation inhibition rates at 24 h, 72 h and one week. The microsatellite sequence of LoVo cells treated with tea polyphenol remained stable. The gene expression arrays and quantitative real-time PCR suggested that tea polyphenol inhibited the gene expressions of MT2A, MAFA, HES1 and JAG1 nearly two-fold over controls. It was also found that tea polyphenol inhibited the BAX and p38 genes with a more than two-fold difference but did not significantly inhibit the nuclear factor-kappaB pathway. CONCLUSION: Tea polyphenol significantly inhibited the proliferation of MSI colorectal cancer cells and stably maintained the microsatellite state in MSI colorectal cancer. Tea polyphenol inhibited the gene expressions of HES1, JAG1, MT2A and MAFA, up regulated the gene expression of BAX and down-regulated that of P38. Further research is required to investigate how these pathways are interrelated. PMID- 20836979 TI - [Effects of serum containing Fructus Cnidii and Psoralea corylifolia on highly metastatic human breast cancer cell line MDA-MB-231BO and bone marrow stromal cell line ST-2]. AB - OBJECTIVE: To explore the effects of different proportions of Fructus Cnidii (Shechuangzi) and Psoralea corylifolia (Buguzhi) on highly metastatic human breast cancer cell line MDA-MB-231BO and bone marrow stromal cell line ST-2 in vitro. METHODS: Thirty-six female SD rats were randomly divided into 6 groups to prepare the drug-medicated sera by administering with different proportions of Fructus Cnidii and Psoralea corylifolia, including 4:0 group, 3:1 group, 1:1 group, 1:3 group, 0:4 group and control group. MDA-MB-231BO cells and ST-2 cells were cultured in Dulbecco's modified Eagle's medium containing drug-medicated serum. Inhibition rates of MDA-MB-231BO cells and ST-2 cells were measured by methyl thiazolyl tetrazolium (MTT) method; migration ability of MDA-MB-231BO cells was tested by a cell migration experiment; alkaline phosphatase activity (ALP) of ST-2 cells was measured by using 4-nitrophenyl phosphate disodium salt, and mineralized nodule formation of ST-2 cells was measured by alizarin red staining. RESULTS: Sera contaning different proportions of Fructus Cnidii and Psoralea corylifolia inhibited the migration activity of MDA-MB-231BO cells as compared with the blank serum, and serum contaning Fructus Cnidii and Psoralea Corylifolia at proportion of 1:1 had the best function (P<0.01). Fructus Cnidii and Psoralea corylifolia at ratio of 1:1 also enhanced the ALP activity of ST2 cells (P<0.05) and increased the number of mineralized nodules of ST2 cells (P<0.01). CONCLUSION: Kidney-warming recipe of Fructus Cnidii and Psoralea corylifolia can inhibit proliferation and migration of MDA-MB-231BO cells and increase the activity of ST-2 cells. PMID- 20836980 TI - [Effects of electroacupuncture on disorder of intestinal motility in a rat model of irritable bowel syndrome]. AB - OBJECTIVE: To investigate the effects of electroacupuncture (EA) on intestinal motility disorder in rats with irritable bowel syndrome (IBS) in order to provide experimental evidence for improving clinical treatment to IBS with EA. METHODS: IBS was induced by inserting a balloon into the rectum of male Sprague-Dawley rats from their neonatal age (8th, 21st day after birth) and applying colorectal distention stimulation by inflating air into the balloon. Peristaltic wave (PW) was used to estimate intestinal motility. Rats were divided into 4 groups (n=6): normal group, untreated group, sham EA group and EA group. Acupoints of Zusanli (ST36) and Shangjuxu (ST37) in the hind limbs bilaterally were chosen for EA and sham EA treatment. Trains of dense-sparse frequencies (100 Hz and 2 Hz alternately) and intensity of 1, 2 and 3 mA (10 min for each) were applied for 30 min with each EA treatment while inserting similar needles without electrical stimulation was done as sham EA treatment. PW recorded for 30 min in normal and untreated groups respectively was taken as control values, while PW recorded after EA or sham EA treatment for 30 min was taken as responsive values. RESULTS: Frequency of PW was significantly increased in the untreated group as compared with that in the normal group (P<0.05), and decreased after 30-min EA treatment (P<0.05). There was no significant change in the PW of sham EA group as compared with the control group and before treatment (P>0.05). CONCLUSION: These results suggest that 1) there is an abnormal increase in intestinal motility indicating an intestinal motility disorder in IBS rats; 2) EA but not sham EA can relieve such intestinal motility disorder. PMID- 20836981 TI - Statistical inference and experimental design of univariate quantitative data of single-group design (part one). PMID- 20836982 TI - Comparative study on WHO Western Pacific Region and World Federation of Chinese Medicine Societies International Standard Terminologies on Traditional Medicine: fluid and humor differentiation of syndromes. PMID- 20836983 TI - [A cognitive interpretation of diachronic difference in translating traditional Chinese medicine terminology into English: a conceptual integration perspective]. PMID- 20836984 TI - Detection of Mycoplasma genitalium using a wireless magnetoelastic immunosensor. AB - A wireless immunosensor for the detection of Mycoplasma genitalium was fabricated by immobilizing polyclonal antibody onto the surface of a magnetostrictive strip. In response to a time-varying magnetic field, the immunosensor longitudinally vibrates at a resonance frequency, emitting magnetic flux that can be remotely detected by a pickup coil. No physical connections between the immunosensor and the detection system are required, facilitating wireless aseptic operation. The binding of M. genitalium to the immunosensor surface resulted in a decrease in the resonance frequency of the immunosensor. When solutions with varying concentrations of the bacteria were tested, the shift of the resonance frequency was proportional to the concentration of M. genitalium. Under the optimized conditions, the linear range for the determination of M. genitalium was 2.0*103 to 2.9*104 color change units (ccu)/ml with a detection limit of 3.4*102 ccu/ml. The immunosensor was successfully applied to real samples containing M. genitalium with results similar to those previously obtained by the color change unit method. PMID- 20836985 TI - Targeting of the highly conserved threonine 302 residue of cytochromes P450 2B family during mechanism-based inactivation by aryl acetylenes. AB - Cytochromes P450 (CYPs or P450s) contain a highly conserved threonine residue in the active site, which is referred to as Thr302 in the amino acid sequence of CYP2B4. Extensive biochemical and crystallographic studies have established that this Thr302 plays a critical role in activating molecular oxygen to generate Compound I, a putative iron(IV)-oxo porphyrin cation radical, that carries out the preliminary oxygenation of CYP substrates. Because of its proximity to the center of the P450 active site, this Thr302 is susceptible to mechanism-based inactivation under certain conditions. In this article, we review recent studies on the mechanism-based inactivation of three mammalian P450s in the 2B family, CYP2B1 (rat), 2B4 (rabbit) and 2B6 (human) by tert-butylphenylacetylene (tBPA). These studies showed that tBPA is a potent mechanism-based inactivator of CYP2B1, 2B4 and 2B6 with high k(inact)/K(I) ratios (0.23-2.3min(-1)MUM(-1)) and low partition ratios (0-5). Furthermore, mechanistic studies revealed that tBPA inactivates these three CYP2B enzymes through the formation of a single ester adduct with the Thr302 in the active site. These inhibitory properties of tBPA allowed the preparation of a modified CYP2B4 where the Thr302 was covalently and stoichiometrically labeled by a reactive intermediate of tBPA in quantities large enough to permit spectroscopic and crystallographic studies of the consequences of covalent modification of Thr302. Molecular modeling studies revealed a unique binding mode of tBPA in the active site that may shed light on the potency of this inhibition. The results from these studies may serve as a basis for designing more specific and potent inhibitors for P450s by targeting this highly conserved threonine residue which is present in the active sites of most mammalian P450s. PMID- 20836986 TI - Glutathione transferase A4-4 resists adduction by 4-hydroxynonenal. AB - 4-Hydroxy-2-trans-nonenal (HNE) is a lipid peroxidation product that contributes to the pathophysiology of several diseases with components of oxidative stress. The electrophilic nature of HNE results in covalent adduct formation with proteins, fatty acids and DNA. However, it remains unclear whether enzymes that metabolize HNE avoid inactivation by it. Glutathione transferase A4-4 (GST A4-4) plays a significant role in the elimination of HNE by conjugating it with glutathione (GSH), with catalytic activity toward HNE that is dramatically higher than the homologous GST A1-1 or distantly related GSTs. To determine whether enzymes that metabolize HNE resist its covalent adduction, the rates of adduction of these GST isoforms were compared and the functional effects of adduction on catalytic properties were determined. Although GST A4-4 and GST A1-1 have striking structural similarity, GST A4-4 was insensitive to adduction by HNE under conditions that yield modest adduction of GST A1-1 and extensive adduction of GST P1-1. Furthermore, adduction of GST P1-1 by HNE eliminated its activity toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB) and toward HNE itself. HNE effects on GST A4-4 and A1-1 were less significant. The results indicate that enzymes that metabolize HNE may have evolved structurally to resist covalent adduction by it. PMID- 20836987 TI - Muscle mechanism: The acceleration of the load. AB - The load (force/cross-section) determines the response of muscle power output, force and speed of contraction). The force is the product of the mass by the acceleration, thus the same force is generated by an infinite number of mass and acceleration couples and each one of these couples displays different physical and biological effects. Therefore, the load must be defined both by the mass and by the acceleration. Early muscle investigators were well aware of this situation as it is indicated by the work of Hill on the flexion of the arm against the "heavy fly-wheel". By making use of a model of sarcomere contraction we show here that the acceleration of the load is the first determinant of the time course of the process of generation of the isometric tension. We also propose that, in order to reproduce the rapid release, it is not necessary to invoke the presence of a distinct elastic element in the contractile machinery. It is sufficient to assume that the stiffness of the same machinery increases with the contractile force. PMID- 20836988 TI - Quantification and identification of mitochondrial proteins containing vicinal dithiols. AB - Vicinal dithiols may play a role in mitochondrial antioxidant defences and in redox signalling. We quantified protein vicinal dithiols within mammalian mitochondria using the vicinal dithiol-specific reagent phenylarsine oxide (PAO). We found 5-15% of thiols exposed on mitochondrial proteins were vicinal dithiols and that these thiols were particularly sensitive to oxidation by hydrogen peroxide. To visualise these proteins we used PAO to block vicinal dithiols, followed by alkylation of other thiols with N-ethylmaleimide (NEM). The PAO was then removed with 2,3-dimercapto-1-propanesulfonic acid (DMPS) and the exposed vicinal dithiols were labelled with iodoacetamide-biotin. To identify these proteins, we developed a selective proteomic methodology, based on Redox difference in gel electrophoresis (Redox-DIGE). Vicinal dithiol proteins were selectively labelled with a red fluorescent thiol-reactive Cy5 maleimide and mixed with Cy3 maleimide labelled protein in which vicinal dithiols remained untagged. Individual proteins were resolved by 2D gel electrophoresis and fluorescent scanning revealed vicinal dithiol proteins by the increase in Cy5 red fluorescence. These proteins were identified by peptide mass fingerprinting and mass spectrometry. These findings are consistent with roles for mitochondrial vicinal dithiol proteins in antioxidant defence and redox signalling and these methodologies will enable these roles to be explored. PMID- 20836989 TI - Identification and functional characterization of genes involved in the sexual reproduction of the ascomycete fungus Gibberella zeae. AB - We previously reported that G protein alpha subunit 1 (GPA1) is essential for sexual reproduction in the homothallic ascomycete fungus Gibberella zeae. In this study we performed microarray analyses on a GPA1 deletion mutant of G. zeae (Deltagpa1) to identify genes involved in the sexual reproduction of this fungus. In the Deltagpa1 strain, 645 genes were down-regulated and 550 genes were up regulated during sexual reproduction when compared to the wild-type strain. One hundred of the down-regulated genes were selected for further investigation based on orthologous group clusters and differences in transcript levels. Quantitative real time-PCR was used to determine transcriptional profiles of these genes at various sexual and vegetative stages. We observed that transcript levels of 78 of these genes were dramatically increased in the wild-type strain during sexual reproduction compared to levels observed during vegetative growth, and were down regulated in Deltagpa1 compared to the wild-type strain. We deleted 57 of these genes and found that four of the deletion mutants lost self-fertility and five produced fewer perithecia compared to the wild-type strain. Two mutants produced wild-type numbers of perithecia, but maturation of perithecia and ascospores was delayed. In all we identified 11 genes that are involved in sexual reproduction of G. zeae and present evidence that some of these genes function at distinct stages during sexual reproduction in the fungus. PMID- 20836990 TI - Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice. AB - Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear. We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA's effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes. The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD. PMID- 20836991 TI - Attenuation of beta2-adrenergic receptors and homocysteine metabolic enzymes cause diabetic cardiomyopathy. AB - Although adrenergic receptors (AR) and hyperhomocysteinemia (HHcy) are implicated in heart failure, their role in diabetic cardiomyopathy is not completely understood. We tested the hypothesis that glucose mediated depletion of beta2-AR and HHcy impair contractile function of cardiomyocytes leading to diabetic cardiomyopathy. To prove the hypothesis, cardiac function was assessed in 12week male diabetic Ins2+/- Akita and C57BL/6J mice by echocardiography, pressure volume loop, and contractile function of cardiomyocytes. The results revealed cardiac dysfunction in Akita. To investigate the mechanism, the levels of beta2 AR, GLUT4, sarcoplasmic reticulum calcium ATP-ase-isoform 2 (SERCA-2) and homocysteine (Hcy) metabolic enzymes-cystathionine beta synthase (CBS), cystathionine gamma lyase (CTH), and methyl tetrahydrofolate reductase (MTHFR) were determined in the heart. It revealed down-regulation of beta2-AR, GLUT4, SERCA-2, CBS, CTH, and MTHFR in Akita. Attenuation of beta2-AR in hyperglycemic condition was also confirmed in cardiomyocytes at in vitro level. Interestingly, the ex vivo treatment of cardiomyocytes with beta2-AR antagonist deteriorated whereas beta-AR agonist ameliorated contractile function. It points to the involvement of beta2-AR in diabetic cardiomyopathy. We conclude that degradation of beta2-AR and impairment of Hcy metabolism is implicated in diabetic cardiomyopathy. PMID- 20836992 TI - Tissue dependent differences in G-protein coupled receptor kinases associated with 5-HT4 receptor desensitization in the rat gastro-intestinal tract. AB - Desensitization of 5-HT(4) receptors is regulated by G-protein coupled receptor kinases (GRKs). However, the specific GRK(s) that regulates the desensitization of 5-HT(4) receptors in the in vivo setting is unknown. We investigated the in situ expression of 5-HT(4) receptors and the GRKs in the rat gastrointestinal tract using immunohistochemistry and their interaction using coimmunoprecipitation. 5-HT(4) receptors were expressed in the tunica muscularis mucosae of the oesophagus, longitudinal muscle, myenteric plexus, circular muscle, submucosal plexus and muscularis mucosae of both the proximal and distal colon. GRK2 was expressed in longitudinal muscle and occasionally in myenteric plexus whilst GRK5 showed limited expression in the nerve endings of the myenteric plexus and submucosal plexus of the colon. GRK3 was expressed in the tunica muscularis mucosae of the oesophagus, circular muscle, submucosal plexus and muscularis mucosae of the colon. GRK6 was expressed in the tunica muscularis mucosae of the oesophagus, longitudinal muscle, circular muscle, and muscularis mucosae of the colon. Stimulation of tunica muscularis mucosae of the oesophagus and distal colon using the 5-HT(4) receptor agonist, tegaserod, followed by analysis of the 5-HT(4) receptor antibody immunoprecipitate, revealed the coimmunoprecipitation of GRK6 with 5-HT(4) receptors in the tunica muscularis mucosae of oesophagus while GRK2 and GRK6 were coimmunoprecipitated with 5-HT(4) receptors in the distal colon. This study indicates that GRK6 may be involved in the regulation of the desensitization of 5-HT(4) receptors in the rat oesophagus whilst GRK2 and GRK6 may be involved in regulation of the desensitization of 5 HT(4) receptors in the distal colon. PMID- 20836993 TI - Anti-apoptotic Bcl-2 fails to form efficient complexes with pro-apoptotic Bak to protect from Celecoxib-induced apoptosis. AB - The non-steroidal anti-inflammatory drug Celecoxib is a specific inhibitor of cyclooxygenase-2. Apart from its inhibitor function, Celecoxib induces apoptosis through the intrinsic pathway which is controlled by the Bcl-2 family members. In Jurkat T lymphoma cells, treatment with Celecoxib results in a rapid decline of the anti-apoptotic Bcl-2-related protein Mcl-1. The depletion of Mcl-1 is sufficient for apoptosis induction and can be blocked by overexpression of Bcl-xL but not by the close homologue Bcl-2. The present investigation analyzed the mechanism by which Bcl-xL prevents apoptosis induction whereas Bcl-2 failed to. Our data show that the involvement of the orphan nuclear receptor Nur77/TR3 specifically targeting Bcl-2 but not Bcl-xL was not involved in Celecoxib-induced apoptosis. Surprisingly, BH3-only proteins Bid, Bim, and Puma of the Bcl-2 family were not needed either. However, unlike Bcl-2, Mcl-1, and Bcl-xL sequestered Bak preventing it from activation through a direct interaction. Thus, when abundantly expressed, Bcl-xL can substitute for the loss of Mcl-1 whereas Bcl-2, incapable of forming a high affinity complex with Bak, could not. PMID- 20836994 TI - Activation of reciprocal pathways between arcuate nucleus and ventrolateral periaqueductal gray during electroacupuncture: involvement of VGLUT3. AB - Electroacupuncture (EA) at the Jianshi-Neiguan acupoints (P5-P6, overlying the median nerve) attenuates sympathoexcitatory responses through activation of the arcuate nucleus (ARC) and ventrolateral periaqueductal gray (vlPAG). Activation of the ARC or vlPAG respectively leads to neuronal excitation of the both nuclei during EA. However, direct projections between these two nuclei that could participate in central neural processing during EA have not been identified. The vesicular glutamate transporter 3 (VGLUT3) marks glutamatergic neurons. Thus, the present study evaluated direct neuronal projections between the ARC and vlPAG during EA, focusing on neurons containing VGLUT3. Seven to ten days after unilateral microinjection of a rodamine-conjugated microsphere retrograde tracer (100nl) into the vlPAG or ARC, rats were subjected to EA or served as a sham operated control. Low frequency (2Hz) EA was performed bilaterally for 30min at the P5-P6 acupoints. Perikarya containing the microsphere tracer were found in the ARC and vlPAG of both groups. Compared to controls (needle placement without electrical stimulation), c-Fos immunoreactivity and neurons double-labeled with c Fos, an immediate early gene and the tracer were increased significantly in the ARC and vlPAG of EA-treated rats (both P<0.01). Moreover, some neurons were triple-labeled with c-Fos, the retrograde tracer and VGLUT3 in the two nuclei following EA stimulation (P<0.01, both nuclei). These results suggest that direct reciprocal projections between the ARC and vlPAG are available to participate in prolonged modulation by EA of sympathetic activity and that VGLUT3-containing neurons are an important neuronal phenotype involved in this process. PMID- 20836995 TI - Membrane rafts and GnRH receptor signaling. AB - The binding of hypothalamic gonadotropin-releasing hormone (GnRH) to the pituitary GnRH receptor (GnRHR) is essential for reproductive function by stimulating the synthesis and secretion of gonadotropic hormones, luteinizing hormone (LH) and follicle stimulating hormone (FSH). Engagement of the GnRHR by GnRH initiates a complex series of signaling events that include the activation of various mitogen-activated protein kinase (MAPK) pathways, including extracellular signal-regulated kinase (ERK). GnRHR signaling is thought to initiate within specialized microdomains in the plasma membrane termed membrane rafts. These microdomains are enriched in sphingolipid and cholesterol and are believed to be highly dynamic organizing centers for receptors and their cognate signaling molecules associated with the plasma membrane. Within this review we discuss the composition and role of membrane rafts in cell signaling and examine evidence that the mammalian type I GnRHR is constitutively and exclusively localized to these membrane microdomains in various experimental models. We conclude that membrane raft composition and organization potentially underlie the functional ability of GnRH to elicit the assembly of multi-protein signaling complexes necessary for downstream signaling to the ERK pathway that ultimately is critical for controlling fertility. PMID- 20836996 TI - Influence of environmental related concentrations of heavy metals on motility parameters and antioxidant responses in sturgeon sperm. AB - The effects of heavy metals (Cd, Cr and Cd+Cr) on the motility parameters and oxidative stress of sterlet (Acipenser ruthenus) sperm were investigated in vitro. Sturgeon sperm were exposed for 2h to heavy metals at environmental related concentrations (0.1mgL(-1) Cr, 0.001mgL(-1) Cd, 0.1mgL(-1) Cr+0.001mgL( 1) Cd) and higher concentrations (5.0mgL(-1) Cr, 0.05mgL(-1) Cd, 5.0mgL(-1) Cr+0.05mgL(-1) Cd). Results revealed that environmental concentrations of heavy metals had no significant influence on motility parameters and antioxidant responses indices in sturgeon sperm, except for LPO level and SOD activity. But higher concentrations of these metals induced oxidative tress in sturgeon sperm in vitro, associated with sperm motility parameters inhibition. Our results suggest that using of sperm in vitro assays may provide a novel and efficiently means for evaluating the effects of residual heavy metals in aquatic environment on sturgeon. PMID- 20836997 TI - Antitumor progression potential of caffeic acid phenethyl ester involving p75(NTR) in C6 glioma cells. AB - The previous data showed that caffeic acid phenethyl ester (CAPE), a component of propolis, possesses inducing cell cycle arrest and antiproliferation effect on C6 glioma cells in vitro and in vivo. In the present study, C6 glioma cells treated with CAPE resulted in morphological changes to an astrocytic phenotype and increased the expression of glial differentiation marker proteins including glial fibrillary acidic protein (GFAP) and S-100beta. In addition, with scratch assay and Boyden chamber assay, CAPE exhibited inhibitory effects on the motility and invasion of C6 glioma cells. Furthermore, CAPE induced the expression of nerve growth factor (NGF) and p75 neurotrophin receptor (p75(NTR)), which were involved in neural cell differentiation. CAPE could also inhibit the activity of matrix metalloproteinases (MMPs) and induce the expression of RhoB, a tumor suppressor. To examine the involvement of p75(NTR) in the anti-invasive property of CAPE, Western blotting and Boyden Chamber assay were performed by addition of an anti p75(NTR) antibody in C6 cells. The results showed that blocking p75(NTR) could decrease the CAPE-induced expression of RhoB and the inactivation of MMP-2, -9 as well as the anti-invasion effect in C6 glioma cells. Furthermore, CAPE suppressed IkappaB-alpha phosphorylation which was down stream of p75(NTR). Finally, the effect of CAPE on metastasis by lung colonization of the tumor cell in nude mice was also evaluated. It was found that the groups of nude mice injected with CAPE pretreated cells could decrease both lung size and weight as compared to the positive control group which did not receive CAPE treatment. In addition, histological examination of the mouse lung sections showed that the CAPE-treated group inhibited the metastasis of C6 glioma cells. These data suggest CAPE possesses antitumor progression potential. PMID- 20836998 TI - Selective deuterium labeling of the sphingoid backbone: facile syntheses of 3,4,5 trideuterio-d-erythro-sphingosine and 3-deuterio-d-erythro-sphingomyelin. AB - Deuteration at C-4 and C-5 of sphingosine was achieved via a hydrogen-deuterium exchange reaction of a beta-ketophosphonate intermediate catalyzed by ND4Cl in D2O/tetrahydrofuran. To install deuterium at C-3 of sphingosine and sphingomyelin, sodium borodeuteride reduction/cerium(III) chloride reduction of an alpha,beta-enone in perdeuteromethanol was used. PMID- 20836999 TI - Two inborn errors of metabolism in a newborn: glutaric aciduria type I combined with isobutyrylglycinuria. AB - BACKGROUND: Glutaric aciduria type 1 (GA1) is an inborn error in the metabolism of the amino acids tryptophan, lysine and hydroxylysine due to mutations in the GCDH gene coding for glutaryl-CoA dehydrogenase. Affected individuals often suffer from an encephalopathic crisis in infancy or childhood which results in acute striatal injury leading to a severe dystonic-dyskinetic movement disorder. Isobutyryl-coenzyme dehydrogenase (IBD) is an enzyme encoded by the ACAD8 gene and involved in the catabolism of the branched-chain amino acid valine. Both GA1 and IBD deficiency can be detected by expanded newborn screening using tandem mass spectrometry, if they are considered screening targets. METHODS: Tandem-mass spectrometry and gas-chromatography with mass-selective detection were used for the assessment of key metabolites in body fluids of a patient with abnormal findings in newborn screening. Mutations were investigated by direct sequencing and by restriction fragment lengths analysis. Valine metabolism was studied in vitro in immortalized lymphocytes. RESULTS: Following accumulation of acylcarnitines C5DC and C4, of 3-hydroxyglutaric acid and isobutyrylglycine in body fluids, sequence analysis in the GCDH gene revealed homozygosity for a missense mutation in exon 6, c.482G>A, p.Arg161Gln, which had been reported in GA1 before. In the ACAD8 gene a novel mutation c.841+3G>C was identified, which results in loss of exon 7 and predicts a premature stop of translation. Impaired valine degradation was corroborated by the increased post-load level of acylcarnitine C4 in lymphocytes. CONCLUSION: The molecular basis of two inborn errors of metabolism in a newborn was elucidated. The metabolite studies underline the use of urinary C4 acylcarnitine as a sensitive marker of IBD deficiency. A functional test of IBD activity in lymphocytes may replace more invasive fibroblast studies. In view of the combination of two organic acidurias, which may both affect the level of free carnitine, careful follow-up including regular assessment of the carnitine status of the patient appears prudent. PMID- 20837000 TI - Effect of pH on the stability of kidney injury molecule 1 (KIM-1) and on the accuracy of its measurement in human urine. AB - BACKGROUND: Urinary KIM-1 is a novel biomarker for tubular kidney damage, however little is known about its stability. The goal of this study is to examine the effect of urinary pH on the stability of KIM-1. METHODS: Urine samples were collected from 45 volunteers. Samples were aliquoted, adapted to different pH values (range 4 to 9) and stored at -80 degrees C. After thawing, each aliquot was divided into two, of which one was used to measure KIM-1 (human tim-1/kim 1/Havcr Elisa kit; R&D systems) at the same pH at which it was stored, while the other was readapted to pH 7 before measurement. RESULTS: KIM-1 values of aliquots of the same sample are stable when stored at pH 6, 7 and 8 whereas at lower and higher storage pH, KIM-1 levels decrease significantly. When samples are readjusted to a neutral pH just before KIM-1 measurement, there are no longer significant differences between KIM-1 in aliquots stored at different pH values. CONCLUSIONS: No effect of urinary pH on the stability of KIM-1 was seen. However, the only commercially available human tim-1/kim-1/Havcr Elisa kit of RD systems is pH dependent and we therefore suggest samples should be adjusted to neutral pH before measurement. PMID- 20837001 TI - Analytical evaluation of a high-molecular-weight (HMW) adiponectin chemiluminescent enzyme immunoassay. AB - BACKGROUND: The measurement of high-molecular-weight (HMW) adiponectin concentration provides valuable clinical information. However, the conventional ELISA method requires complicated and lengthy assay procedures to obtain assay results. METHODS: We prepared new assay reagents based on chemiluminescent enzyme immunoassay (CLEIA) on a fully-automated analyzer system using the same IH7 monoclonal antibody as for ELISA as solid phase and detection antibodies (CLEIA/cartridge-type and CLEIA/bottle-type). RESULTS: The assay range of both CLEIA reagents were from 0.20 to 15.00 MUg/ml, and lower limit of detection and quantification were lower than 0.0928 and 0.1346 MUg/ml in CLEIA/cartridge-type and in CLEIA/bottle-type reagents, respectively. A good correlation was observed between both reagents (y = 1.000x + 0.120). The imprecision test as % of coefficient variation in both reagents were less than 3.3% and recovery test showed the range from 100% to 109%. No or little interference of blood components was observed in both reagents. HMW adiponectin concentration measured by CLEIA reagents was approximately half that measured by the previous ELISA because of reevaluation using freshly and highly purified HMW adiponectin standard. CONCLUSION: The newly prepared CLEIA reagents are robust and adequate and can be used for the measurement of HMW adiponectin in the clinical laboratory. PMID- 20837002 TI - Serum soluble CD36, assessed by a novel monoclonal antibody-based sandwich ELISA, predicts cardiovascular mortality in dialysis patients. AB - AIM: Accelerated atherosclerosis is a characteristic feature of chronic kidney disease (CKD). CD36 is a scavenger receptor which contributes to foam cell formation, an early crucial step in atherosclerosis development. Recently, a soluble form of CD36 (sCD36) has been discovered. The aim of the study was to develop an ELISA method for quantitative sCD36 evaluation and to measure it in a cohort of CKD stage 5 patients. METHOD: A novel monoclonal antibody-based sandwich ELISA for sCD36 evaluation was developed and verified by repeated optimization procedures. Serum concentration of sCD36 was then analyzed in a cohort of 228 CKD stage 5 patients prior to dialysis initiation. Additionally, samples from a control group of 73 healthy, age and gender-matched subjects were evaluated. RESULTS: The novel CD36 ELISA assay had a recovery of at least 90%, and intra- and inter-assay variability of 6 and 11%, respectively. Concentration of serum sCD36 in CKD patients was significantly increased as compared to controls, and associated with the use of HMG-CoA reductase inhibitors (statins) and the presence of diabetes mellitus (DM). Patients above the 75th percentile of sCD36 concentration were at increased risk of 3-year cardiovascular mortality, as compared to the rest of the cohort [HR 2.85 (1.09-7.59) p=0.03]. CONCLUSION: For the first time, sCD36 was assessed quantitatively in a group of patients and showed associations with DM, CKD, and statin use. Furthermore, the concentration of sCD36 predicted cardiovascular mortality in CKD stage 5 patients. PMID- 20837003 TI - Hypervariability in a minisatellite 3' of the apolipoprotein B gene: allelic distribution and influence on lipid profiles in Han Children from central China. AB - BACKGROUND: Apolipoprotein B (apoB) gene 3' variable number tandem repeat (VNTR) is highly variable, and thereby be considered as an informative marker for associative analysis of lipid metabolism. METHODS: We conducted this study to probe the effect of apoB 3' VNTR alleles on lipid profiles in 500 Han children from central China, and to compare the allelic distribution of our subjects with multiple Chinese populations. 14 different alleles of the apoB gene 3' VNTR comprising from HVE22 to HVE44 were identified in our subjects. RESULTS: Allele size distribution followed unimodal curve with the main peak at HVE35 (58.0%). We detected 37 genotypes in this sampling, the most frequently seen was HVE35/35 with a frequency of 36.4%. M/L carriers had significantly higher total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apoB concentrations than did S/S, M/M or S/M carriers (p<0.05). Individuals with L allele exhibited significantly higher TC, LDL-C, and apoB levels than those with M or S allele (p<0.05). The allelic distribution in Central Han Chinese differed from Southern Han Chinese (X(2)=41.2, p=0.00), Zhuang Chinese (X(2)=65.4, p=0.00), and Uighur Chinese (X(2)=45.6, p=0.00). No significant differences in allelic frequencies were observed for apoB 3' VNTR in Central Han Chinese as compared to Northern Han Chinese (X(2)=2.5, p=0.29). CONCLUSION: This study identified the higher repeat alleles as potential risk factor for dyslipidemia in Han children from Central China. Although five Chinese populations demonstrated uniformly unimodal distributions of allelic frequencies with the main peaks at HVE32-HVE37, there was obvious heterogeneity among these populations. PMID- 20837004 TI - BMP/SMAD signaling regulates the cell behaviors that drive the initial dorsal specific regional morphogenesis of the otocyst. AB - During development of the otocyst, regional morphogenesis establishes a dorsal vestibular chamber and a ventral auditory chamber, which collectively constitute the membranous labyrinth of the inner ear. We identified the earliest morphogenetic event heralding the formation of the vestibular chamber, a rapid thinning and expansion of the dorsolateral wall of the otocyst, and showed that this process is generated by changes in otocyst cell shape from columnar to squamous, as opposed to changes in other cell behaviors, such as localized changes in cell proliferation or cell death. Moreover, we showed that thinning and expansion of the dorsolateral otocyst is regulated by BMP/SMAD signaling, which is both sufficient and necessary for localized thinning and expansion. Finally, we showed that BMP/SMAD signaling causes fragmentation of E-cadherin in the dorsolateral otocyst, occurring concomitantly with cell shape change, suggesting that BMP/SMAD signaling regulates cell-cell adhesion during the initial morphogenesis of the otocyst epithelium. Collectively, our results show that BMP signaling via SMADs regulates the cell behaviors that drive the initial dorsal-specific morphogenesis of the otocyst, providing new information about how regional morphogenesis of a complex organ rudiment, the developing membranous labyrinth, is initiated. PMID- 20837005 TI - Attenuation of fear-like response by escitalopram treatment after electrical stimulation of the midbrain dorsolateral periaqueductal gray. AB - Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) has frequently been shown to induce escape and freezing/decreased locomotion responses which mimic panic- and fear-like behaviour. In the present study we tested whether such spontaneous fear-like behaviour could be observed in an open field test 12 h after dlPAG stimulation. Further, we tested whether this fear like behaviour could be attenuated by acute or chronic administration of buspirone and escitalopram. Our data demonstrate for the first time that animals showed fear-like behaviour 12 h after dlPAG stimulation, which may possibly reflect panic disorder with anticipatory anxiety/agoraphobic symptoms. Acute and chronic escitalopram, but not buspirone, treatment attenuated the fear-related behaviour. Besides, our data also showed that the stimulation intensities to evoke an escape reaction, a panicogenic response, were significantly higher after chronic buspirone and escitalopram treatment. These results suggest that the fear like response, which was observed 12 h after dlPAG stimulation, could be considered as a relevant animal model for panic disorder with anticipatory anxiety/agoraphobic symptoms. PMID- 20837006 TI - Giardia intestinalis: expression of ubiquitin, glucosamine-6-phosphate and cyst wall protein genes during the encystment process. AB - We determined the relative expression of ubiquitin (ub), glucosamine-6-phosphate isomerase (gn6pi) and cyst wall protein (cwp) genes during encystment of the Portland-1 and Portland-1R strains of Giardia intestinalis. Encystment was induced with bile for different time periods. The presence of encystment-specific vesicles (ESVs) and the relative expression of genes (log(10)DeltaRn) were determined by transmission electron microscopy and real-time PCR, respectively. Our results demonstrated the gene expression and the presence of ESVs after 6h of encystment. Values of cwp2 gene expression increased by 591-fold in strain Portland-1 and 78.2-fold in strain Portland-1R at this time point compared to values at 0h, after which values gradually decreased until reaching basal values between 8 and 18h after the encystment started. Expression of gn6pi was 43.5- and 46.3-fold higher than basal values, in Portland-1 and Portland-1R, respectively. Ub gene expression was 82.25-fold higher than its basal levels at 4h, after which expression decreased gradually until reaching basal values after 16h. CONCLUSIONS: This work showed the relationship between the presence of ESVs and encystment gene expression at 6h, and resistance to albendazole does not inhibit the encystment process. The results revealed important knowledge with implications in the control of parasite dissemination for preventing parasite transmission. PMID- 20837007 TI - A novel blue fluorescent chlorophyll catabolite accumulates in senescent leaves of the peace lily and indicates a split path of chlorophyll breakdown. AB - Colorless, non-fluorescent Chl-catabolites (NCCs) are the typical, ubiquitous products of chlorophyll (Chl)-breakdown in senescent leaves. However, a fluorescent Chl-catabolite (FCC) accumulated in de-greened leaves of Spathiphyllum wallisii (Peace Lily), which showed a weak blue luminescence. The FCC, named Sw-FCC-62, was 'hypermodified' with an unprecedented 6-(2-[3,4 dihydroxy-phenyl]-ethyl)-beta-glucopyranosidyl ester at the propionyl group. Such esters stabilize FCCs against their typical and rapid, spontaneous isomerization to NCCs. Chl-breakdown in Sp. wallisii thus branches off from the 'common' path in leaves, and furnishes unique and 'persistent' FCCs. Our findings on 'hypermodified' FCCs also call for attention as to possible physiological roles of Chl-catabolites in plants. PMID- 20837008 TI - Allosteric rescuing of loss-of-function FFAR2 mutations. AB - FFAR2 (GPR43) is a receptor for short-chain fatty acids (SCFAs), acetate and propionate. In the current study, we investigate the molecular determinants contributing to receptor activation by endogenous ligands. Mutational analysis revealed several important residues located in transmembrane domains (TM) 3, 4, 5, 6, and 7 for acetate binding. Interestingly, mutations that abolished acetate activity, including the mutation in the well-conserved D(E)RY motif, could be rescued by a recently identified synthetic allosteric agonist. These findings provide additional insight into agonist binding and activation which may aid in designing allosteric ligands for targeting receptor function in various diseases. PMID- 20837009 TI - A glycyl free radical as the precursor in the synthesis of carbon monoxide and cyanide by the [FeFe]-hydrogenase maturase HydG. AB - HydG uses tyrosine to synthesize the CN(-)/CO ligands of [FeFe]-hydrogenase active site. We have mutated two of the [4Fe-4S]-cluster cysteine ligands of the HydG C-terminal domain (CTD) to serine. The double mutant can still synthesize CN(-) but not CO. In a mutant lacking the CTD both CN(-) and CO synthesis are abolished. Like in ThiH, the initial steps of CN(-) synthesis are carried out in the TIM-barrel domain of HydG but some component(s) of the CTD are later needed. The mutants indicate that CO synthesis is metal-based and occurs in the CTD. We postulate that CN(-)/CO synthesis is initiated by H(2)N-*CH-CO(2)(-). Fragmentation of this radical into H(2)N-*CH(2) and CO(2) or H(2)C=NH and *CO(2)( ) provides plausible precursors for CN(-)/CO synthesis. PMID- 20837010 TI - Role of prostaglandin E2 in peptidoglycan mediated iNOS expression in mouse peritoneal macrophages in vitro. AB - Many extracellular stimuli, e.g. microbial products, cytokines etc., result in the expression of inducible nitric oxide synthase (iNOS) in macrophages. However, it is not known whether expression of the iNOS gene in response to microbial products is a primary response of macrophages, or is the result of paracrine/autocrine signalling induced by endogenous biomolecules that are synthesised as a result of host cell-microbe interaction. In this paper we demonstrate that iNOS expression in mouse peritoneal macrophages in response to bacterial peptidoglycan (PGN) is a secondary effect requiring autocrine signalling of endogenously produced prostaglandin E2, and that PGN stimulation is mandatory, but not sufficient in itself, for induction of iNOS expression. PMID- 20837011 TI - TGFbeta enforces activation of eukaryotic elongation factor-2 (eEF2) via inactivation of eEF2 kinase by p90 ribosomal S6 kinase (p90Rsk) to induce mesangial cell hypertrophy. AB - eEF2 phosphorylation is under tight control to maintain mRNA translation elongation. We report that TGFbeta activates eEF2 by decreasing eEF2 phosphorylation and simultaneously increasing eEF2 kinase phosphorylation. Remarkably, inhibition of Erk1/2 blocked the TGFbeta-induced dephosphorylation and phosphorylation of eEF2 and eEF2 kinase. TGFbeta increased phosphorylation of p90Rsk in an Erk1/2-dependent manner. Inactive p90Rsk reversed TGFbeta-inhibited phosphorylation of eEF2 and suppressed eEF2 kinase activity. Finally, inactive p90Rsk significantly attenuated TGFbeta-induced protein synthesis and hypertrophy of mesangial cells. These results present the first evidence that TGFbeta utilizes the two layered kinase module Erk/p90Rsk to activate eEF2 for increased protein synthesis during cellular hypertrophy. PMID- 20837012 TI - Defining the structural requirements for ribose 5-phosphate-binding and intersubunit cross-talk of the malarial pyridoxal 5-phosphate synthase. AB - Most organisms synthesise the B(6) vitamer pyridoxal 5-phosphate (PLP) via the glutamine amidotransferase PLP synthase, a large enzyme complex of 12 Pdx1 synthase subunits with up to 12 Pdx2 glutaminase subunits attached. Deletion analysis revealed that the C-terminus has four distinct functionalities: assembly of the Pdx1 monomers, binding of the pentose substrate (ribose 5-phosphate), formation of the reaction intermediate I(320), and finally PLP synthesis. Deletions of distinct C-terminal regions distinguish between these individual functions. PLP formation is the only function that is conferred to the enzyme by the C-terminus acting in trans, explaining the cooperative nature of the complex. PMID- 20837013 TI - Coevolution is a short-distance force at the protein interaction level and correlates with the modular organization of protein networks. AB - We investigated what roles coevolution plays in shaping yeast protein interaction network (PIN). We found that the extent of coevolution between two proteins decreases rapidly as their interacting distance on the PIN increases, suggesting coevolutionary constraint is a short-distance force at the molecular level. We also found that protein-protein interactions (PPIs) with strong coevolution tend to be enriched in interconnected clusters, whereas PPIs with weak coevolution are more frequently present at inter-cluster region. The findings indicate the close relationship between coevolution and modular organization of PINs, and may provide insights into evolution and modularity of cellular networks. PMID- 20837014 TI - Solution structure of the N-terminal catalytic domain of human H-REV107--a novel circular permutated NlpC/P60 domain. AB - H-REV107 is a Ca(2+)-independent phospholipase A(1/2), and it is also a pro apoptosis protein belonging to the novel class II tumor suppressor family, H REV107-like family. Here we report the solution structure of the N-terminal catalytic domain of human H-REV107, which has a similar architecture to classical NlpC/P60 domains, even though their fold topologies are different due to circular permutation in the primary sequence. The phospholipase active site possesses a structurally conserved Cys-His-His catalytic triad as found in NlpC/P60 peptidases, indicating H-REV107 should adopt a similar catalytic mechanism towards phospholipid substrates to that of NlpC/P60 peptidases towards peptides. As H-REV107 is highly similar to lecithin retinol acyltransferase, our study also provides structural insight to this essential enzyme in retinol metabolism. PMID- 20837015 TI - Interplay between I308 and Y310 residues in the third repeat of microtubule binding domain is essential for tau filament formation. AB - Investigation of the mechanism of tau polymerization is indispensable for finding inhibitory conditions or identifying compounds preventing the formation of paired helical filament or oligomers. Tau contains a microtubule-binding domain consisting of three or four repeats in its C-terminal half. It has been considered that the key event in tau polymerization is the formation of a beta sheet structure arising from a short hexapeptide (306)VQIVYK(311) in the third repeat of tau. In this paper, we report for the first time that the C-H?pi interaction between Ile308 and Tyr310 is the elemental structural scaffold essential for forming a dry "steric zipper" structure in tau amyloid fibrils. PMID- 20837016 TI - Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition. AB - BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0*10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1*10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men. PMID- 20837017 TI - Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. AB - BACKGROUND & AIMS: The tumor suppressor PTEN inhibits AKT2 signaling; both are aberrantly expressed in liver tumors. We investigated how PTEN and AKT2 regulate liver carcinogenesis. Loss of PTEN leads to spontaneous development of liver tumors from progenitor cells. We investigated how the loss of PTEN activates liver progenitor cells and induces tumorigenesis. METHODS: We studied mice with liver-specific disruptions in Pten and the combination of Pten and Akt2 to investigate mechanisms of liver carcinogenesis. RESULTS: PTEN loss leads to hepatic injury and establishes selective pressure for tumor-initiating cells (TICs), which proliferate to form mixed-lineage tumors. The Pten-null mice had increasing levels of hepatic injury before proliferation of hepatic progenitors. Attenuation of hepatic injury by deletion of Akt2 reduced progenitor cell proliferation and delayed tumor development. In Pten/Akt2-null mice given 3,5 diethoxycarbonyl-1,4 dihydrocollidine (DDC), we found that the primary effect of AKT2 loss was attenuation of hepatic injury and not inhibition of progenitor-cell proliferation in response to injury. CONCLUSIONS: Liver carcinogenesis in Pten null mice requires not only the transformation of TICs but selection pressure from hepatic injury and cell death, which activates TICs. Further research is required to elucidate the mechanism for hepatic injury and its relationship with TIC activation. PMID- 20837018 TI - Depletion of TGF-beta from fetal bovine serum. AB - TGF-beta is one of the key cytokines controlling immune responses. Measuring TGF beta from culture supernatants in vitro is an important index of immune function. However, fetal bovine serum (FBS) contains a high level of latent TGF-beta that often hampers measuring T cell-derived TGF-beta in culture using FBS-supplemented medium. In this report, we generated anti-latency associated peptide (LAP) monoclonal antibodies which cross-react with bovine LAP, and developed a protocol to deplete TGF-beta from FBS. This provides the ability to reliably quantify TGF beta in vitro without relying on serum-free media which do not support growth of murine T cells. PMID- 20837019 TI - A methodical approach for improving the reliability of quantifiable two dimensional Western blots. AB - Western transfer after the electrophoretic separation of proteins onto an adsorbent membrane, with subsequent immunodetection, is a powerful tool for detecting and characterizing a multitude of proteins. An important aspect of the study of proteins is that they often exist as isoforms with structural microheterogeneity giving rise to differences in biological activity. Western blotting (WB) in combination with two-dimensional SDS-polyacrylamide gel electrophoresis (2D-SDS-PAGE) allows the specific quantification of single isoforms of a protein. We have investigated whether a methodical modification of 2D-SDS-PAGE improves the quality of quantifiable 2D-WB data. The effect of a combined separation of three previously electrofocused protein extracts lying side by side on a single SDS-gel in parallel has been tested against the traditional procedure, viz., the separation of one protein extract per SDS-gel. The modified procedure results in a more reliable and better quality data than the traditional procedure, which seems to be prone to producing systematic or random errors. Our simple practical procedure improves immunoblotting accuracy by excluding numerous sources of errors and saves time, immunoblotting reagents and costly antibodies. PMID- 20837020 TI - Rapid isolation of high-affinity human antibodies against the tumor vascular marker Endosialin/TEM1, using a paired yeast-display/secretory scFv library platform. AB - Endosialin/TEM1 is predominantly expressed on neovasculature, thus ideally suited for diagnostic, targeted imaging and therapy of cancer. To isolate TEM1-specific affinity reagents, we thought to screen a recombinant antibody (scFv) library derived from the repertoire of a patient with thrombotic thrombocytopenic purpura (TTP), as autoimmune disorders may produce self-reactive specificities. The yeast display scFv library was constructed by homologous recombination of the TTP patient repertoire originally expressed on M13 bacteriophage in the novel vector pAGA2 for yeast-display expression. The TTP yeast-display library (109 members) was screened by magnetic and flow sorting with human TEM1 recombinant protein. A pool of yeast-display scFv able to detect 2nM of TEM1 was obtained and transformed into yeast-secreted scFv by homologous recombination using the novel p416 BCCP vector for yeast secretion of biotinylated scFv. Anti-TEM1 yeast secreted scFv were independently validated in vitro by flow cytometry analysis and ELISA assays, then in vivo biotinylated in N-termini to produce biobodies. Biobody-78 bound specifically to Endosialin/TEM1-expressing ovarian tumor in vivo, with functional stability over 48 h. Our results suggest that our novel paired display-secretory yeast libraries can serve as an ideal platform for the rapid isolation of high-affinity reagents, and that anti-TEM1 biobody-78 can be used for in vitro assays including flow cytometry analysis, as well as in vivo for targeted imaging and therapy of cancer. PMID- 20837021 TI - Mesenchymal stem cells stimulate protective genetic reprogramming of injured cardiac ventricular myocytes. AB - Since massive irreversible loss of cardiac myocytes occurs following myocardial injury, injection of human mesenchymal stem cells (hMSCs) has emerged as a promising therapeutic intervention. Despite the growing enthusiasm for this approach, the understanding of how hMSCs evoke cardiac improvement is ever more controversial. The present study critically tests hypothesis that hMSCs provide specific benefit directly to damaged ventricular myocytes. Cultures of neonatal mouse ventricular cardiac myocytes (nMCM) were subjected to two distinct acute stress protocols; incubations with either endotoxin, lipopolysaccharide (LPS) or toxic cytokine, IL-1beta. Myocyte injury was assessed in intracellular Ca(2+) signaling assays in fluo-3-loaded nMCMs that were imaged with high temporal resolution by fluorescent microscopy. Following LPS or IL-1beta treatment there was profound myocyte injury, manifest by chaotic [Ca(2+)](i) handling, quantified as a 3- to 5-fold increase in spontaneous [Ca(2+)](i) transients. Antibody neutralization experiments reveal such damage is mediated in part by interleukin 18 and not by tumor necrosis factor-alpha (TNF-alpha). Importantly, normal [Ca(2+)](i) signaling was preserved when cardiomyocytes were co-cultured with hMSCs. Since normal [Ca(2+)](i) handling was maintained in transwell cultures, where nMCMs and hMSCs were separated by a permeable membrane, a protective paracrine signaling cascade is operable. hMSCs provoke a genetic reprogramming of cardiomyocytes. LPS provokes release of TNFalpha from nMCMs which is blocked by hMSCs grown in co- or transwell cultures. Consistent with cytokine release, flow cytometry analyses reveal that hMSCs also block the LPS- and IL-1beta-dependent activation of cardiac transcription factor, NF-kappaB. Importantly, hMSC conditioned medium restores normal Ca(2+) signaling in LPS- and IL-1beta-damaged nMCMs. These results reveal new evidence that hMSCs elicit protective and reparative effects on cardiac tissue through molecular reprogramming of the cardiac myocytes themselves. Thus these studies provide novel new insight into the cellular and molecular mechanisms that underlie the therapeutic benefit of hMSCs in the setting of heart failure. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20837022 TI - Current strategies for myocardial gene delivery. AB - Existing methods of cardiac gene delivery can be classified by the site of injection, interventional approach and type of cardiac circulation at the time of transfer. General criteria to assess the efficacy of a given delivery method include: global versus regional myocardial transduction, technical complexity and the pathophysiological effects associated with its use, delivery-related collateral expression and the delivery-associated inflammatory and immune response. Direct gene delivery (intramyocardial, endocardial, epicardial) may be useful for therapeutic angiogenesis and for focal arrhythmia therapy but with gene expression which is primarily limited to regions in close proximity to the injection site. An often unappreciated limitation of these techniques is that they are frequently associated with substantial systemic vector delivery. Percutaneous infusion of vector into the coronary arteries is minimally invasive and allows for transgene delivery to the whole myocardium. Unfortunately, efficiency of intracoronary delivery is highly variable and the short residence time of vector within the coronary circulation and significant collateral organ expression limit its clinical potential. Surgical techniques, including the incorporation of cardiopulmonary bypass with isolated cardiac recirculation, represent novel delivery strategies that may potentially overcome these limitations; yet, these techniques are complex with inherent morbidity that must be thoroughly evaluated before safe translation into clinical practice. Characteristics of the optimal technique for gene delivery include low morbidity, increased myocardial transcapillary gradient, extended vector residence time in the coronary circulation and exclusion of residual vector from the systemic circulation after delivery to minimize extracardiac expression and to mitigate a cellular immune response. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy". PMID- 20837024 TI - Identification and characterization of a misfolded monomeric serpin formed at physiological temperature. AB - The native serpin state is kinetically trapped. However, under mildly destabilizing conditions, the conformational landscape changes, and a number of nonnative conformations with increased stability can be readily formed. The ability to undergo structural change is due to intrinsic strain within the serpin's tertiary fold, which is utilized for proteinase inhibition but renders the protein susceptible to aberrant folding and self-association. The relationship between these various conformations is poorly understood. Antichymotrypsin (ACT) is an inhibitory serpin that readily forms a number of inactive conformations, induced via either environmental stress or interaction with proteinases. Here we have used a variety of biophysical and structural techniques to characterize the relationship between some of these conformations. Incubation of ACT at physiological temperature results in the formation of a range of conformations, including both polymer and misfolded monomer. The ability to populate these nonnative states and the native conformation reflects an energy landscape that is very sensitive to the solution conditions. X-ray crystallography reveals that the misfolded monomeric conformation is in the delta conformation. Further polymerization and seeding experiments show that the delta conformation is an end point in the misfolding pathway of ACT and not an on pathway intermediate formed during polymerization. The observation that ACT readily forms this inactive conformation at physiological temperature and pH suggests that it may have a role in both health and disease. PMID- 20837023 TI - Multiple sequence signals direct recognition and degradation of protein substrates by the AAA+ protease HslUV. AB - Proteolysis is important for protein quality control and for the proper regulation of many intracellular processes in prokaryotes and eukaryotes. Discerning substrates from other cellular proteins is a key aspect of proteolytic function. The Escherichia coli HslUV protease is a member of a major family of ATP-dependent AAA+ degradation machines. HslU hexamers recognize and unfold native protein substrates and then translocate the polypeptide into the degradation chamber of the HslV peptidase. Although a wealth of structural information is available for this system, relatively little is known about mechanisms of substrate recognition. Here, we demonstrate that mutations in the unstructured N-terminal and C-terminal sequences of two model substrates alter HslUV recognition and degradation kinetics, including changes in V(max). By introducing N- or C-terminal sequences that serve as recognition sites for specific peptide-binding proteins, we show that blocking either terminus of the substrate interferes with HslUV degradation, with synergistic effects when both termini are obstructed. These results support a model in which one terminus of the substrate is tethered to the protease and the other terminus is engaged by the translocation/unfolding machinery in the HslU pore. Thus, degradation appears to consist of discrete steps, which involve the interaction of different terminal sequence signals in the substrate with different receptor sites in the HslUV protease. PMID- 20837025 TI - Engineering of an orthogonal aminoacyl-tRNA synthetase for efficient incorporation of the non-natural amino acid O-methyl-L-tyrosine using fluorescence-based bacterial cell sorting. AB - We describe a strategy for the rapid selection of mutant aminoacyl-tRNA synthetases (aaRS) with specificity for a novel amino acid based on fluorescence activated cell sorting of transformed Escherichia coli using as reporter the enhanced green fluorescent protein (eGFP) whose gene carries an amber stop codon (TAG) at a permissive site upstream of the fluorophore. To this end, a one plasmid expression system was developed encoding an inducible modified Methanocaldococcus jannaschii (Mj) tyrosyl-tRNA synthetase, the orthogonal cognate suppressor tRNA, and eGFP(UAG) in an individually regulatable fashion. Using this system a previously described aaRS with specificity for O-methyl-L tyrosine (MeTyr) was engineered for 10-fold improved incorporation of the foreign amino acid by selection from a mutant library, prepared by error-prone as well as focused random mutagenesis, for MeTyr-dependent eGFP fluorescence. Applying alternating cycles of positive and negative fluorescence-activated bacterial cell sorting in the presence or in the absence, respectively, of the foreign amino acid was crucial to select for high specificity of MeTyr incorporation. The optimized synthetase was used for the preparative expression of a modified uvGFP carrying MeTyr at position 66 as part of its fluorophore. This biosynthetic protein showed quantitative incorporation of the non-natural amino acid, as determined by mass spectrometry, and it revealed a unique emission spectrum due to the altered chemical structure of its fluorophore. Our combined genetic/selection system offers advantages over earlier approaches that relied wholly or in part on antibiotic selection schemes, and it should be generally useful for the engineering and optimization of orthogonal aaRS/tRNA pairs to incorporate non-natural amino acids into recombinant proteins. PMID- 20837026 TI - Evidence for initial non-specific polypeptide chain collapse during the refolding of the SH3 domain of PI3 kinase. AB - Refolding of the SH3 domain of PI3 kinase from the guanidine hydrochloride (GdnHCl)-unfolded state has been probed with millisecond (stopped flow) and sub millisecond (continuous flow) measurements of the change in fluorescence, circular dichroism, ANS fluorescence and three-site fluorescence resonance energy transfer (FRET) efficiency. Fluorescence measurements are unable to detect structural changes preceding the rate-limiting step of folding, whereas measurements of changes in ANS fluorescence and FRET efficiency indicate that polypeptide chain collapse precedes the major structural transition. The initial chain collapse reaction is complete within 150 MUs. The collapsed form at this time possesses hydrophobic clusters to which ANS binds. Each of the three measured intra-molecular distances has contracted to an extent predicted by the dependence of the FRET signal in completely unfolded protein on denaturant concentration, indicating that contraction is non-specific. The extent of contraction of each intra-molecular distance in the collapsed product of sub millisecond folding increases continuously with a decrease in [GdnHCl]. The gradual contraction is continuous with the gradual contraction seen in completely unfolded protein, and its dependence on [GdnHCl] is not indicative of an all-or none collapse reaction. The dependence of the extent of contraction on [GdnHCl] was similar for the three distances, indicating that chain collapse occurs in a synchronous manner across different segments of the polypeptide chain. The sub millisecond measurements of folding in GdnHCl were unable to determine whether hydrophobic cluster formation, probed by ANS fluorescence measurement, precedes chain contraction probed by FRET. To determine whether hydrogen bonding plays a role in initial chain collapse, folding was initiated by dilution of the urea unfolded state. The extent of contraction of at least one intra-molecular distance in the collapsed product of sub-millisecond folding in urea is similar to that seen in GdnHCl, and the initial contraction in urea too appears to be gradual. PMID- 20837027 TI - Selfishness versus functional cooperation in a stochastic protocell model. AB - How to design an "evolvable" artificial system capable to increase in complexity? Although Darwin's theory of evolution by natural selection obviously offers a firm foundation, little hope of success seems to be expected from the explanatory adequacy of modern evolutionary theory, which does a good job at explaining what has already happened but remains practically helpless at predicting what will occur. However, the study of the major transitions in evolution clearly suggests that increases in complexity have occurred on those occasions when the conflicting interests between competing individuals were partly subjugated. This immediately raises the issue about "levels of selection" in evolutionary biology, and the idea that multi-level selection scenarios are required for complexity to emerge. After analyzing the dynamical behaviour of competing replicators within compartments, we show here that a proliferation of differentiated catalysts and/or improvement of catalytic efficiency of ribozymes can potentially evolve in properly designed artificial cells where the strong internal competition between the different species of replicators is somewhat prevented (i.e., by choosing them with equal probability). Experimental evolution in these systems will likely stand as beautiful examples of artificial adaptive systems, and will provide new insights to understand possible evolutionary paths to the evolution of metabolic complexity. PMID- 20837028 TI - A mathematical model for photoreceptor interactions. AB - The interactions between rods and cones in the retina have been the focus of innumerable experimental and theoretical biological studies in previous decades yet the understanding of these interactions is still incomplete primarily due to the lack of a unified concept of cone photoreceptor organization and its role in retinal diseases. The low abundance of cones in many of the non-primate mammalian models that have been studied make conclusions about the human retina difficult. A more complete knowledge of the human retina is crucial for counteracting the events that lead to certain degenerative diseases, in particular those associated with photoreceptor cell death (e.g., retinitis pigmentosa). In an attempt to gain important insight into the role and interactions of the rods and the cones we develop and analyze a set of mathematical equations that model a system of photoreceptors and incorporate a direct rod-cone interaction. Our results show that the system can exhibit stable oscillations, which correspond to the rhythmic renewal and shedding of the photoreceptors. In addition, our results show the mathematical necessity of this rod-cone direct interaction for survival of both and gives insight into this mechanism. PMID- 20837029 TI - Temporal transcriptomic profiling reveals cellular targets that govern survival in HOCl-mediated neuronal apoptosis. AB - AIMS: With the identification of hypochlorous acid (HOCl) as a biomarker in diseased brains and endogenous detection of its modified proteins, HOCl might be implicated in the development of neurodegenerative disorders. However, its effect on neuronal cell death has not yet been investigated at gene expression level. MAIN METHODS: Therefore, DNA microarray was performed for screening of HOCl responsive genes in primary mouse cortical neurons. Neurotoxicity caused by physiological relevant HOCl (250MUM) exhibited several biochemical markers of apoptosis. KEY FINDINGS: The biological processes affected during HOCl-mediated apoptosis included cell death, response to stress, cellular metabolism, and cell cycle. Among them, mRNAs level of cell death and stress response genes were up regulated while expression of metabolism and cell cycle genes were down regulated. SIGNIFICANCE: Our results showed, for the first time, that HOCl induces apoptosis in cortical neurons by upregulating apoptotic genes and gene expression of stress response such as heat shock proteins and antioxidant proteins were enhanced to provide protection. These data form a foundation for the development of screening platforms and define targets for intervention in HOCl neuropathologies where HOCl-mediated injury is causative. PMID- 20837030 TI - Regional differences of the mouse brain in response to an alpha-linolenic acid restricted diet: Neurotrophin content and protein kinase activity. AB - AIMS: The purpose of this study was to determine a relatively short-term effect of feeding an alpha-linolenic acid (ALA, n-3)-restricted, linoleic acid (LA, n-6) adequate diet on neurotrophin contents and protein kinase activities in brain regions of the mouse. MAIN METHODS: After feeding mice a safflower oil (SAF) diet (ALA-restricted, LA-adequate) or perilla oil (PER) diet (containing adequate amounts of ALA and LA) for 4 weeks from weaning, the fatty acid compositions of brain regions were analyzed by capillary column gas-liquid chromatography, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) contents were measured using enzyme-linked immunosorbent assay. KEY FINDINGS: The striatum and hippocampus, but not the cerebral cortex, from the SAF group, contained a smaller amount of docosahexaenoic acid (DHA, 22:6n-3) than those from the PER group. The NGF contents in these brain regions were not different between the two dietary groups. However, the striatal BDNF content of the SAF group was significantly lower than that of the PER group. Protein kinase A, protein kinase C, and p44/42 mitogen-activated protein kinase (p44/42 MAPK) activities in brain regions showed no significant difference between the two dietary groups. However, the striatal p38 MAPK activity was significantly lower in the SAF group than in the PER group. No such differences were observed in the hippocampus or the cerebral cortex. SIGNIFICANCE: A relatively short-term feeding of an alpha-linolenic acid restricted, linoleic acid-adequate diet was found to lower the DHA content, BDNF content and p38 MAPK activity in the mouse striatum. PMID- 20837031 TI - LPS-induced knee-joint reactive arthritis and spinal cord glial activation were reduced after intrathecal thalidomide injection in rats. AB - AIMS: Thalidomide is thought to prevent TNF-alpha production, and such mechanism could be useful in a spinally delivered drug approach for the control of peripheral inflammation. This study aimed to evaluate the effect of intrathecal thalidomide, in comparison with that of intraperitoneal treatment, on articular incapacitation, edema, synovial leukocyte content, and spinal cord glial activation in a model of Escherichia coli lipopolysaccharide (LPS)-induced reactive arthritis in rats. MAIN METHODS: LPS (30ng) was injected into a knee joint previously primed with carrageenan (300MUg). Systemic (30 and 100mg/kg; intraperitoneal, i.p.) and intrathecal (10 and 100MUg; i.t.) thalidomide were given 1h or 20min before LPS injection, respectively. Articular incapacitation and edema were evaluated hourly. After 6h, synovial fluid and lumbar spinal cords were collected for subsequent evaluations of cell migration and expression of CD11b/c and GFAP markers, respectively. KEY FINDINGS: Systemic (30 and 100mg/kg) or intrathecal (10 and 100MUg) thalidomide reduced articular incapacitation, edema, and polymorphonuclear migration. In addition, i.p. and i.t. thalidomide reduced the expression of CD11b/c and GFAP markers in the lumbar spinal cord. These results suggest that thalidomide can also produce peripheral anti inflammatory effects through action in the spinal cord that may involve glia inhibition. SIGNIFICANCE: This study provides new evidence that the direct spinal delivery of immunomodulators may be an alternative for the treatment of arthritic diseases, which require long systemic treatment with drugs associated with undesirable side effects. PMID- 20837032 TI - Assessment of spatial memory in mice. AB - Improvements in health care have greatly increased life span in the United States. The focus is now shifting from physical well-being to improvement in mental well-being or maintenance of cognitive function in old age. It is known that elderly people suffer from cognitive impairment, even without neurodegeneration, as a part of 'normal aging'. This 'age-associated memory impairment' (AAMI), can have a devastating impact on the social and economic life of an individual as well as the society. Scientists have been experimenting to find methods to prevent the memory loss associated with aging. The major factor involved in these experiments is the use of animal models to assess hippocampal based spatial memory. This review describes the different types of memory including hippocampal-based memory that is vulnerable to aging. A detailed overview of various behavioral paradigms used to assess spatial memory including the T-maze, radial maze, Morris water maze, Barnes maze and others is presented. The review also describes the molecular basis of memory in hippocampus called as 'long-term potentiation'. The advantages and limitations of the behavioral models in assessing memory and the link to the long-term potentiation are discussed. This review should assist investigators in choosing suitable methods to assess spatial memory in mice. PMID- 20837033 TI - Vincristine-resistant human laryngeal carcinoma cells demonstrate increased Rous sarcoma virus promoter activity. AB - AIMS: Gene therapy is a candidate approach for treating cancer patients whose tumors have developed resistance to some drugs. Our study aims to examine possible alteration in Ad5RSVbetagal-mediated transgene expression in a vincristine-resistant cells (VK2) derived from the human laryngeal carcinoma cell line HEp2, and the underlying mechanism(s) thereof. MAIN METHODS: Adenovirus mediated transgene expression in HEp2 and VK2 cells was measured by beta-gal staining. Semiquantitative PCR was used to evaluate attachment of adenovirus to the cell surface and adenovirus internalization into cells. After transfection of cells with plasmid DNA, promoter activity was measured by semiquantitative RT PCR. KEY FINDINGS: We show here that VK2 cells exhibited increased Ad5RSVbetagal mediated transgene expression, despite moderately decreased Ad5RSVbetagal attachment and internalization, as compared with HEp2 cells. The increased transgene expression was also observed with a virus (Ad5FbDelta639RSVbetagal) that does not use the coxsackie-adenovirus receptor (CAR), suggesting that increased transgene expression is independent of CAR. Upon transfection of VK2 cells with a plasmid expressing a reporter gene under the control of the RSV promoter or a plasmid containing the complete Ad5RSVbetagal genome, RSV promoter activity was 33- and 4.7-fold higher, respectively, than in HEp2 cells. SIGNIFICANCE: The increased Ad5RSVbetagal-mediated transgene expression in the VK2 cells is due to the increased RSV promoter activity in VK2 cells. Our results point out that (i) drug-resistance may be accompanied with an alteration in promoter activity; (ii) the proper choice of promoter could contribute to a decrease in the vector dose required to achieve a therapeutic effect during gene therapy. PMID- 20837034 TI - The default network and processing of personally relevant information: converging evidence from task-related modulations and functional connectivity. AB - Despite a growing interest in the default network (DN), its composition and function are not fully known. Here we examined whether the DN, as a whole, is specifically active during a task involving judgments about the self, or whether this engagement extends to judgments about a close other. We also aimed to provide converging evidence of DN involvement from across-task functional connectivity, and resting-state functional connectivity analyses, to provide a more comprehensive delineation of this network. Using functional MRI we measured brain activity in young adults during tasks and rest, and utilized a multivariate method to assess task-related changes as well as functional connectivity. An overlapping set of regions showed increased activity for judgments about the self, and about a close other, and strong functional connectivity with the posterior cingulate, a critical node of the DN. These areas included ventromedial prefrontal cortex, posterior parietal cortex, and medial temporal regions, all thought to be part of the DN. Several additional regions, such as the left inferior frontal gyrus and bilateral caudate, also showed the same pattern of activity and connectivity. These results provide evidence that the default network, as an integrated whole, supports internally oriented cognition involving information that is personally relevant, but not limited specifically to the self. They also suggest that the DN may be somewhat more extensive than currently thought. PMID- 20837035 TI - Partner preference for strain of female in Long-Evans male rats. AB - Although male rats are reported to show greater sexual arousal and mating preference for a novel female compared to a familiar one, we have shown that after repeated copulation to ejaculation with a female bearing a neutral odor in bilevel pacing chambers, or unilevel pacing chambers bisected by a 1-hole divider, male rats display a conditioned ejaculatory preference for a female bearing the odor relative to a female not bearing the odor. The aim of the present study was to examine whether males might also develop a conditioned ejaculatory preference for the strain characteristics of the female after repeated copulation with the same female in a pacing chamber bisected by either a 1-hole or 4-hole divider. In this experiment, male Long-Evans rats were given 10 copulatory trials with the same Long-Evans or Wistar female in either the 1-hole or 4-hole condition. Copulatory preferences were then examined in an open field where males had the choice to copulate with either the familiar female or a novel one of a different strain from the familiar female. Results indicated that Long Evans males trained in the 1-hole condition with the same Long-Evans female displayed a conditioned ejaculatory preference for the familiar vs. novel female. However, males trained in the 1-hole condition with the same Wistar female at every trial copulated indiscriminately with the familiar and novel females. No preference was detected in males trained in the 4-hole condition. These findings suggest that, following training in a 1-hole pacing chamber, males displayed an ejaculatory preference only if the familiar female is of their own strain. PMID- 20837036 TI - Measuring salivary analytes from free-ranging monkeys. AB - Studies of large free-ranging mammals have been revolutionized by non-invasive methods for assessing physiology, which usually involve the measurement of fecal or urinary biomarkers. However, such techniques are limited by numerous factors. To expand the range of physiological variables measurable non-invasively from free-ranging primates, we developed techniques for sampling monkey saliva by offering monkeys ropes with oral swabs sewn on the ends. We evaluated different attractants for encouraging individuals to offer samples, and proportions of individuals in different age/sex categories willing to give samples. We tested the saliva samples we obtained in three commercially available assays: cortisol, salivary alpha amylase, and secretory immunoglobulin A. We show that habituated free-ranging rhesus macaques will give saliva samples voluntarily without training, with 100% of infants, and over 50% of adults willing to chew on collection devices. Our field methods are robust even for analytes that show poor recovery from cotton, and/or that have concentrations dependent on salivary flow rate. We validated the cortisol and SAA assays for use in rhesus macaques by showing aspects of analytical validation, such as that samples dilute linearly and in parallel to assay standards. We also found that values measured correlated with biologically meaningful characteristics of sampled individuals (age and dominance rank). The SIgA assay tested did not react to samples. Given the wide range of analytes measurable in saliva but not in feces or urine, our methods considerably improve our ability to study physiological aspects of the behavior and ecology of free-ranging primates, and are also potentially adaptable to other mammalian taxa. PMID- 20837037 TI - Effect of salidroside, active principle of Rhodiola rosea extract, on binge eating. AB - Stress is a key determinant of binge eating (BE). Since Rhodiola rosea is known to modulate stress responses, its effect in a model of BE was investigated. BE for highly palatable food (HPF) was evoked in female rats by three 8-day cycles of food restriction/re-feeding (for 4days 66% of the usual chow intake; for 4days food ad libitum) and acute stress on the test day (day 25). R. rosea dry extract (3% rosavin, 3.12% salidroside) or its active principles were given by gavage 1h before access to HPF. Only rats exposed to both food restrictions and stress exhibited BE in the first 15-60min after the stressful procedure. R. rosea extract 10mg/kg significantly reduced and 20mg/kg abolished the BE episode. R. rosea extract 20mg/kg abolished also stress-induced increase in serum corticosterone levels. The R. rosea active principle salidroside, but not rosavin, at doses present in the extract, dose-dependently reduced or abolished BE for the period in which it was elicited. In conclusion results indicate that R. rosea extracts may have therapeutic properties in bingeing-related eating disorders and that salidroside is the active principle responsible for this effect. PMID- 20837038 TI - Identification of bile acid S-acyl glutathione conjugates in rat bile by liquid chromatography/electrospray ionization-linear ion trap mass spectrometry. AB - Acyl-adenylates and acyl-CoA thioesters of bile acids (BAs) are reactive acyl linked metabolites that have been shown to acylate the thiol group of glutathione (GSH); the reaction is catalyzed by glutathione S-transferase (GST) and the product is a thioester-linked BA-GSH conjugate. Such GSH conjugates are present in bile in lithocholic acid and ursodeoxycholic acid dosed-rats. To determine whether such novel BA-GSH conjugates are present in the bile of normal rats, we first synthesized the GSH conjugates of the major and minor biliary BAs of the rat and defined their MS and proton NMR properties. We then analyzed the BA-GSH composition in the bile of anesthetized biliary fistula rats by means of liquid chromatographic separation and electrospray ionization-linear ion trap mass spectrometric detection in negative- and positive-ion scan modes, monitoring characteristic transitions of the analytes. GSH conjugates of cholic, omega muricholic, hyodeoxycholic, deoxycholic, 12-oxolithocholic, and lithocholic acids were present with concentrations in the range of 1.4-2.8 nmol/ml, some four orders of magnitude less than those of natural BA N-acyl amidates. Our results indicate that BA-GSH conjugates are formed and excreted in bile in the healthy rat, although this novel mode of BA conjugation is a very minor pathway. PMID- 20837039 TI - Molecular characterization on the genome structure of hemolysin toxin isoforms isolated from sea anemone Actineria villosa and Phyllodiscus semoni. AB - We recently identified the existence of new isoforms of Avt-I (from sea anemone Actineria villosa) and Pstx20 (from sea anemone Phyllodiscus semoni) hemolytic toxins, and named them Avt-II and Pst-I. Avt-II and Pst-I differ in length by 14 and 7 bp, respectively, as compared to their corresponding isoform genes. Both newly found isoform genes have the coding regions with the identical length of 1033 bp. The restriction fragment length polymorphism analysis with endonuclease HphI was able to clearly distinguish between the two Avt isoforms, but not Pstx isoforms, and based on the densitometric analysis of DNA bands, it indicated that relative expression levels of Avt-I and Avt-II genes were 18.3% and 81.7%, respectively. PCR amplification of the two Avt isoform genes using the genomic DNA as template indicated the existence of two introns within each toxin isoform gene. The first intron with the identical 242 bp in length for both Avt isoform was found within the 5'-untranslated region, and the second intron with lengths of 654 bp and 661 bp in Avt-I and Avt-II isoforms, respectively, was found within the signal sequence coding region. This is for the first time to identify the existence of introns within hemolysin genes of sea anemone. Having several unique characteristics that have identified only for a new member of actinoporin family of A. villosa and P. semoni, e.g., strong toxicity and genes with introns, it is plausible to speculate that these toxins have a unique genetic evolutionary linage differed from that for other sea anemone hemolytic toxins. PMID- 20837040 TI - Purification, cloning and characterization of a metalloproteinase from Naja atra venom. AB - The complement system is a very important part of the immune system. Many snake venoms possess activities that influence the complement. A new metalloproteinase (termed atrase B) with anticomplementary activity was purified from Naja atra venom. Atrase B is a single chain glycoprotein with a molecular mass of 49.4 kDa and an isoelectric point of 9.7. Its N-terminal sequence shows high homology to those of metalloproteinases from cobra venoms. The cDNA sequence reveals that atrase B is a PIII class metalloproteinase. Atrase B slowly cleaves the Aalpha chain of fibrinogen. It also exhibits edema-inducing activity, but has no hemorrhagic activity and proteolytic activity against fibrin, azocasein, and N benzoyl-l-arginine ethyl ester. Interestingly, atrase B inhibits activation of the complement classical and alternative pathways in a dose- and time-dependent manner. Complement components factor B and C6 are major targets for atrase B to cleave. Atrase B is the first identified SVMP that cleaves complement components factor B, C6, C7, and C8. PMID- 20837041 TI - Assessment of biochemical and hematological parameters in rats injected with Tityus serrulatus scorpion venom. AB - The aim of this work was to evaluate the hematological changes induced by Tityus serrulatus venom (TsV). Blood of Wistar rats was collected 0.5, 2, 6 and 24 h after i.p. injection of TsV (0.5 mg/kg) or saline (controls). Two additional groups were injected with 0.67 mg/kg and 0.25 mg/kg of TsV and the blood was collected after 0.5 and 2 h, respectively. The results showed an increase on hematocrit (Ht), red blood cells (RBC) count, hemoglobin concentration (Hb), albumin and total protein, mainly 2-6 h after envenoming. Increase in serum activities of amylase, creatine kinase and aspartate aminotransferase were also observed, indicating tecidual damages. Hyperglycemia was observed at all times analyzed, as a consequence of catecholamine release. No significant changes were detected in the urea, [Na(+)] and [Ca(2+)], but an increase of [Mg(2+)], [K(+)] and conductivity was observed. TsV induced a reduction of erythrocytes osmotic fragility as consequence of dehydration and increase in plasma electrolytes concentration, as evidenced by its higher conductivity. This study demonstrated that TsV is able to induce severe hematological changes, that appear within the first hours after envenoming, justifying the seeking of medical attention as soon as possible to avoid worsening of clinical symptoms. PMID- 20837042 TI - Situating visual search. AB - Visual search attracted great interest because its ease under certain circumstances seemed to provide a way to understand how properties of early visual cortical areas could explain complex perception without resorting to higher order psychological or neurophysiological mechanisms. Furthermore, there was the hope that properties of visual search itself might even reveal new cortical features or dimensions. The shortcomings of this perspective suggest that we abandon fixed canonical elementary particles of vision as well as a corresponding simple to complex cognitive architecture for vision. Instead recent research has suggested a different organization of the visual brain with putative high level processing occurring very rapidly and often unconsciously. Given this outlook, we reconsider visual search under the broad category of recognition tasks, each having different trade-offs for computational resources, between detail and scope. We conclude noting recent trends showing how visual search is relevant to a wider range of issues in cognitive science, in particular to memory, decision making, and reward. PMID- 20837043 TI - Item-specific location memory in visual search. AB - In two samples, we demonstrate that visual search performance is influenced by memory for the locations of specific search items across trials. We monitored eye movements as observers searched for a target letter in displays containing 16 or 24 letters. From trial to trial the configuration of the search items was either Random, fully Repeated or similar but not identical (i.e., Intermediate). We found a graded pattern of response times across conditions with slowest times in the Random condition and fastest responses in the Repeated condition. We also found that search was comparably efficient in the Intermediate and Random conditions but more efficient in the Repeated condition. Importantly, the target on a given trial was fixated more accurately in the Repeated and Intermediate conditions relative to the Random condition. We suggest a tradeoff between memory and perception in search as a function of the physical scale of the search space. PMID- 20837044 TI - Shape contrast: a global mechanism? AB - We investigated whether a shape contrast bias is caused by local contrast enhancement or by a global mechanism. In a baseline condition, observers performed a shape discrimination task on an isolated hinged plane. But in the experimental conditions, five dihedral surfaces, of which we varied the dihedral angle distribution, were added on each side. Shape perception was influenced not only by the adjacent surface but also by the mean of the shape distribution in the extended surround. Thus, shape contrast is not locally determined and has to be understood from a global mechanism. We propose divisive normalization of shape signals as such a mechanism. PMID- 20837046 TI - Brain serotonin system in the coordination of food intake and body weight. AB - An inverse relationship between brain serotonin and food intake and body weight has been known for more than 30 years. Specifically, augmentation of brain serotonin inhibits food intake, while depletion of brain serotonin promotes hyperphagia and weight gain. Through the decades, serotonin receptors have been identified and their function in the serotonergic regulation of food intake clarified. Recent refined genetic studies now indicate that a primary mechanism through which serotonin influences appetite and body weight is via serotonin 2C receptor (5-HT(2C)R) and serotonin 1B receptor (5-HT(1B)R) influencing the activity of endogenous melanocortin receptor agonists and antagonists at the melanocortin 4 receptor (MC4R). However, other mechanisms are also possible and the challenge of future research is to delineate them in the complete elucidation of the complex neurocircuitry underlying the serotonergic control of appetite and body weight. PMID- 20837045 TI - Visuospatial perception and navigation in Parkinson's disease. AB - A shifted field of view, an altered perception of optic flow speed, and gait asymmetries may influence heading direction in Parkinson's disease (PD). PD participants (left body-side onset, LPD, n=14; right body-side onset, RPD, n=9) and Healthy Control participants (n=17) walked a virtual hallway in which the optic flow speeds of the walls varied. Three-dimensional kinematics showed participants veered away from the faster moving wall. Although veering normally occurs toward the side with smaller step length, in both LPD and RPD this bias was overridden by a shifted field of view, which caused veering in the opposite direction, toward the side of the brain with more basal ganglia damage. PMID- 20837047 TI - Tramadol and caffeine produce synergistic interactions on antinociception measured in a formalin model. AB - Drug combinations have been used in clinical practice for the main purpose of increasing therapeutic effect efficacy. The aim of this study was to determine the antinociceptive effect of tramadol and caffeine administered separately or in combination, as well as their synergistic interaction. The formalin test was used. Nociceptive behavior was evaluated by flinching response of the formalin treated paw. Rats were divided into five groups and received tramadol alone (4.9 49.6mg/kg, s.c.), caffeine alone (1-17.8mg/kg, p.o.), or combinations of tramadol (4.9, 8.8, 15.6 and 20.8mg/kg, s.c.) and caffeine (1, 3.16 and 10mg/kg, p.o.). Tramadol showed dose-dependent antinociceptive effect in both phases of the formalin test. Caffeine only presented antinociceptive effect in the second phase and this effect was also dose-dependent. In Phase 1, combinations of tramadol and caffeine showed antinociceptive effect similar to that of tramadol alone. In Phase 2, the dose-response curve shifted to the left with the combination of tramadol and each dose of caffeine. Synergism analysis resulted in synergistic effect in ten combinations and antagonism in two combinations. In conclusion, the synergism observed in the majority of tramadol and caffeine combinations used in this study suggests that this drug combination is useful in the treatment of pain. PMID- 20837048 TI - Exposure to alcohol during adolescence alters the aversive and locomotor activating effects of cocaine in adult rats. AB - OBJECTIVES: The present study assessed the effect of adolescent alcohol exposure on the later aversive and locomotor-activating effects of cocaine. METHODS: Male rats were exposed to alcohol or vehicle for 10days [postnatal day (PND) 30-39; 2g/kg IP]. Taste aversion conditioning began on PND 65. During aversion conditioning, subjects were presented with saccharin followed by cocaine (32mg/kg; 15, 180 or 300min post saccharin) or saline. Following each injection, animals were placed in locomotor chambers for 1h. To determine if any effects seen were specific to the adolescent developmental period, the procedure was replicated in adult animals. RESULTS: Animals exposed to vehicle during adolescence showed significant aversions at all time delays. Animals exposed to ethanol during adolescence showed a decrease in consumption only at the 15 and 180min delays. Groups exposed to alcohol during adolescence showed a decrease in gross, and an increase in fine, motor activity in response to cocaine. Animals exposed to alcohol during adulthood also showed attenuated taste aversions. CONCLUSIONS: Exposure to ethanol during adolescence attenuated the aversive effects of cocaine and altered its locomotor-activating effects. Although this effect is not specific to adolescence, this is the time when alcohol use is typically initiated so that such exposure may enhance later abuse liability of cocaine. PMID- 20837049 TI - Tea flavonoids and cardiovascular health. AB - The two main types of tea are green and black. Both green and black teas are rich dietary sources of flavonoids. Available evidence suggests that regular tea consumption may reduce the risk of cardiovascular disease. The cardiovascular health benefits of drinking tea are thought to be largely due to flavonoids. Tea intake and intake of flavonoids found in tea have been associated with reduced risk of cardiovascular disease in cross-sectional and prospective population studies. Isolated flavonoids found in tea have also been consistently shown to inhibit the development of atherosclerosis in animal models. A number of possible pathways and mechanisms have been investigated. There is now consistent data indicating that tea and tea flavonoids can enhance nitric oxide status and improve endothelial function, which may be at least partly responsible for benefits on cardiovascular health. There is also evidence, although limited, to suggest benefits of green tea (flavonoids) on body weight and body fatness. Data supporting reduced oxidative damage, inflammation, platelet activation, blood pressure, and risk of type 2 diabetes with tea (flavonoids) remains inadequate to draw any conclusions. PMID- 20837050 TI - Resveratrol and cardiovascular health. AB - Resveratrol (3,4',5-trihydroxystilbene) is a member of natural, plant-derived chemicals known as polyphenols and is attracting increased attention due to its diverse health benefits especially in case of cardiovascular disease, cancer, diabetes and neurological problems. Despite impressive gains in diagnosis and treatment, cardiovascular disease (CVD) remains a serious clinical problem and threat to public health. Resveratrol possesses potent antioxidant properties and has been shown to decrease low-density lipoprotein-cholesterol oxidation and platelet aggregation. This compound also possesses a range of additional cardioprotective and vasoprotective properties including antiatherosclerotic and vasorelaxation action. Resveratrol also has the capacity to interact with multiple molecular targets, which involve diverse intracellular pathways. Most well-known is the ability of resveratrol to activate sirtuins, a class of NAD(+) dependent deacetylase that affect multiple transcription factors and other protein targets. Recently, resveratrol was found to induce autophagy and regenerate myocardial ischemic tissue treated with stem cells. Overall observation indicates that resveratrol has a high therapeutic potentials for the treatment of cardiovascular diseases. PMID- 20837051 TI - Dietary isoflavones and vascular protection: activation of cellular antioxidant defenses by SERMs or hormesis? AB - During the past decade nutrigenomic studies in humans, animal models and cultured cells have provided important and novel insights into the mechanisms by which dietary isoflavones afford protection against vascular dysfunction through the amelioration of oxidative modifications and upregulation of endogenous antioxidant signaling pathways. In this review, we highlight that increased generation of nitric oxide (NO) and reactive oxygen species (ROS) in the vessel wall in response to dietary isoflavones enhance the activity of antioxidant defense enzymes in endothelial and smooth muscle cells. The estrogenic properties of isoflavones are likely to contribute to the molecular mechanisms by which these compounds activate signal transduction pathways involved in sustaining endothelial function and transcriptional activation of antioxidant defense genes in vascular cells. We evaluate the recent literature that estrogenic and hormetic properties of phytoestrogens are of benefit for the maintenance of vascular function, and conclude that dietary isoflavones can protect against cardiovascular diseases by virtue of their ability to activate signaling pathways leading to increased NO bioavailability and regulation of phase II and antioxidant enzyme expression via the redox sensitive transcription factor Nrf2. In context of epigenetics and the developmental origins of adult disease, it is noteworthy that exposure to dietary soy during fetal development reduces the susceptibility to CVD and obesity in adulthood. Thus, the Nrf2/Keap1 defense pathway provides a key mechanism by which isoflavones can act as hormetic agents to modulate intracellular redox signaling in the vasculature to prolong healthspan and reduce the incidence of age-related cardiovascular diseases. PMID- 20837052 TI - Ellagitannins, ellagic acid and vascular health. AB - Hydrolysable tannins are phenolic phytochemicals that show high antioxidant and free-radical scavenging activities. For this reason their potential effects preventing oxidative related diseases, such as cardiovascular diseases, have been largely studied. In vitro studies show that ellagitannins, at concentrations in the range 10-100 MUM, show some relevant anti-atherogenic, anti-thrombotic, anti inflammatory and anti-angiogenic effects, supporting the molecular mechanisms for the vascular health benefits. While there is good evidence supporting the vascular effects in vitro, the evidence on animal models or humans is much scarcer. The in vitro results often do not match the findings in the in vivo studies. This could be explained by the low bioavailability of the antioxidant ellagitannins and ellagic acid. The main ellagitannin metabolites circulating in plasma are ellagic acid microbiota metabolites known as urolithins, and they have lost their free-radical scavenging activity. They are present in plasma as glucuronide or sulphate conjugates, at concentrations in the nM range. Future studies should focus in the bioavailable metabolites, urolithins, and in the form (conjugated with glucuronic acid or sulphate) and concentrations (nM range) in which they are found in plasma. In this review we critically discuss the role of ellagitannins and ellagic acid on vascular health. PMID- 20837053 TI - Flavonols and cardiovascular disease. AB - Flavonols, and specially quercetin, are widely distributed in plants and are present in considerable amounts in fruits and vegetables. In addition to their anti-oxidant effect, flavonols interfere with a large number of biochemical signaling pathways and, therefore, physiological and pathological processes. There is solid evidence that, in vitro, quercetin and related flavonols exert endothelium-independent vasodilator effects, protective effect on nitric oxide and endothelial function under conditions of oxidative stress, platelet antiaggregant effects, inhibition of LDL oxidation, reduction of adhesion molecules and other inflammatory markers and prevention of neuronal oxidative and inflammatory damage. The metabolites of quercetin show partial protective effects on endothelial function and LDL oxidation. Quercetin produces undisputed antihypertensive and antiatherogenic effects, prevents endothelial dysfunction and protects the myocardium from ischemic damage. It has no clear effects on serum lipid profile and on insulin resistance. Human intervention trials with isolated flavonols demonstrate an antihypertensive effect. The meta-analysis of epidemiological studies show an inverse association between flavonol (together with flavone) intake and coronary heart disease and stroke. Therefore, although there is no solid proof yet, a substantial body of evidence suggests that quercetin may prevent the most common forms of cardiovascular disease contributing to the protective effects afforded by fruits and vegetables. PMID- 20837054 TI - Preparation and characterization of water-soluble chitosan derivative by Michael addition reaction. AB - The efficient procedure to prepare novel water-soluble chitosan derivative was established by Michael addition reaction to introduce sodium allylsulfonate into the chitosan at mild condition. The chemical structure of the chitosan derivative was characterized by FT-IR, (1)H NMR and Elemental analysis. The degree of substitution (DS) was calculated by Elemental analysis. The chitosan derivative exhibited an excellent solubility in the distilled water. The physical properties were analyzed by XRD and TG. The XRD study indicated that the crystallinity of chitosan derivative decreased. The thermal analysis showed that chitosan derivative had lower thermal stability than chitosan. PMID- 20837055 TI - Interferon regulatory factor 3 (IRF-3) in Japanese flounder, Paralichthys olivaceus: sequencing, limited tissue distribution, inducible expression and induction of fish type I interferon promoter. AB - Two cDNAs with different 3'-untranslated region (UTR) encoding an interferon regulatory factor 3 (IRF-3) were cloned from head kidney of Japanese flounder, Paralichthys olivaceus, by reverse transcription polymerase chain reaction (RT PCR) and rapid amplification of cDNA ends (RACE) methods. Sequence analysis reveals that they were generated by alternative polyadenylation. The predicted protein consists of 467 amino acid residues which shares the highest identity of 50.7-57.6% to fish IRF-3 and possesses a DNA-binding domain (DBD), an IRF association domain (IAD) and a serine-rich domain (SRD) of vertebrate IRF-3. The presence of these domains along with phylogenetic analysis places it into the IRF 3 group of the IRF-3 subfamily. RT-PCR analysis revealed that flounder IRF-3 was expressed constitutively in limited tissue types including head kidney, spleen, kidney, heart, gill, intestine and liver. A quantitative real time PCR assay was employed to monitor expression of IRF-3, type I interferon (IFN) and Mx in flounder head kidney and gill. All three genes were up-regulated by polyinosinic:polycytidylic acid (polyI:C) and lymphocystis disease virus (LCDV) with an earlier but slight and less persistent increase in transcription levels seen for the IRF-3. Finally, flounder IRF-3 was proved to induce fish type I IFN promoter in FG9307 cells, a flounder gill cell line, by a luciferase assay. These results provide insights into the roles of fish IRF-3 in the antiviral immunity. PMID- 20837056 TI - PmPPAE2, a new class of crustacean prophenoloxidase (proPO)-activating enzyme and its role in PO activation. AB - The prophenoloxidase (proPO) activating system plays an important role in the defense against microbial invasion in invertebrates. In the present study, we report a second proPO-activating enzyme (designated PmPPAE2) from the hemocytes of the black tiger shrimp, Penaeus monodon. PmPPAE2 contained the structural features of the clip domain serine proteinase family and exhibited 51% amino acid sequence similarity to the insect Manduca sexta PAP-1. Amino acid sequence alignment with the available arthropod PPAE sequences demonstrated that PmPPAE2 is a new class of crustacean PPAE. Transcript expression analysis revealed that PmPPAE2 transcripts were mainly expressed in hemocytes. Double-stranded RNA mediated suppression of PmPPAE2 transcript levels resulted in a significant decrease in the total hemolymph PO activity (41%) and also increased the shrimp's susceptibility to Vibrio harveyi infection. Genomic organization analysis revealed that PmPPAE1 and PmPPAE2 are encoded by different genomic loci. The PmPPAE1 gene consists of ten exons and nine introns, whilst PmPPAE2 comprises of eight exons interrupted by seven introns. Analysis of the larval developmental stage expression of the four key genes in the shrimp proPO system (PmPPAE1, PmPPAE2, PmproPO1 and PmproPO2) revealed that PmPPAE1 and PmproPO2 transcripts were expressed in all larval stages (nauplius, protozoea, mysis and post-larvae), whilst PmPPAE2 and PmproPO1 transcripts were mainly presented in the late larval developmental stages (mysis and post-larvae). These results suggest that the PmPPAE2 functions as a shrimp PPAE and possibly mediates the activation of PmproPO1. PMID- 20837057 TI - Giuseppe Moruzzi: a tribute to a "formidable" scientist and a "formidable" man. AB - Giuseppe Moruzzi was born one century ago; he was an outstanding Italian neurophysiologist, who was particularly famous for his contributions to the study of the mechanisms underlying the control of the sleep-waking cycle in mammals. In 1990, Rita Levi-Montalcini, Moruzzi's great friend and admirer, used the occasion of an invitation by the University of Parma, where Moruzzi graduated in medicine in 1933, to celebrate Moruzzi's scientific achievements. She wished to pay a tribute to Moruzzi's human and ethical qualities by portraying him as a "perfect model" for the young generation wishing to pursue scientific research. The transcription of "Rita's" tribute to Moruzzi links two of the greatest figures of Italian neuroscience and also provides a lively account of how the personal histories of two promising young scientists intertwined with the great and tragic events of world history in the past century. PMID- 20837058 TI - Ethanol-enhanced GABA release: a focus on G protein-coupled receptors. AB - While research on the actions of ethanol at the GABAergic synapse has focused on postsynaptic mechanisms, recent data have demonstrated that ethanol also facilitates GABA release from presynaptic terminals in many, but not all, brain regions. The ability of ethanol to increase GABA release can be regulated by different G protein-coupled receptors (GPCRs), such as the cannabinoid-1 receptor, corticotropin-releasing factor 1 receptor, GABA(B) receptor, and the 5 hydroxytryptamine 2C receptor. The intracellular messengers linked to these GPCRs, including the calcium that is released from internal stores, also play a role in ethanol-enhanced GABA release. Hypotheses are proposed to explain how ethanol interacts with the GPCR pathways to increase GABA release and how this interaction contributes to the brain region specificity of ethanol-enhanced GABA release. Defining the mechanism of ethanol-facilitated GABA release will further our understanding of the GABAergic profile of ethanol and increase our knowledge of how GABAergic neurotransmission may contribute to the intoxicating effects of alcohol and to alcohol dependence. PMID- 20837059 TI - Role of glia in epilepsy-associated neuropathology, neuroinflammation and neurogenesis. AB - The black reaction allowed Golgi to describe with amazing detail the morphology of glial cells as well as their proximal location and intimate connections with neurons and blood vessels. Based on this location, Golgi hypothesized that glial cells were functional units in the nervous system and were not merely a structural support medium. Relatively recent advances have confirmed the importance of glial cells in nervous system function and disease. The occurrence of gliosis is considered the hallmark of damaged tissue. Gliosis can differentially influence disease development and it is a prevailing characteristic of temporal lobe epilepsy. Its presence in the epileptic hippocampi might contribute to hyperexcitability, the development of aberrant neurogenic changes and inflammatory processes related to seizures. Considering the accumulating data regarding the pathological role of glial cells in epilepsy, novel therapeutic approaches that target glial cells are being explored. Such therapeutic approaches directed to glial cells present a novel perspective for the management of refractory pathologies. PMID- 20837061 TI - Immunopotentiating effect of proton pump inhibitor pantoprazole in a lymphoma bearing murine host: Implication in antitumor activation of tumor-associated macrophages. AB - Proton pump inhibitors (PPI) are being considered for antineoplastic therapeutic regimens due to their ability to reverse H(+) homeostasis in tumor microenvironment and induce tumor cell death. In order to explore additional mechanism(s) underlying antitumor action of PPI, the present investigation was undertaken to investigate the effect of a PPI pantoprazole (PPZ) on the activation of tumor-associated macrophages (TAM) to tumoricidal state in a murine model of a transplantable T cell lymphoma of spontaneous origin growing in ascitic form. In vivo administration of PPZ to tumor-bearing mice resulted in an enhanced TAM recruitment in tumor microenvironment with M1 macrophage phenotype and augmented activation of TAM to tumoricidal state along with expression of tumor cytotoxic molecules. The study also demonstrates that TAM activating action of PPZ is of indirect nature mediated via its antitumor activity, reversal of tumor-induced immunosuppression and a consequent shift of cytokine balance in the tumor microenvironment favoring polarization of macrophages to M1 type. The study further shows that adoptive transfer of TAM harvested from PPZ-administered tumor bearing hosts causes an efficient retardation of tumor growth. Possible mechanisms and significance of these observations with respect to the designing of antitumor therapy using PPI are discussed. PMID- 20837062 TI - The role of Ig-alpha/beta in B cell antigen receptor internalization. AB - The B cell antigen receptor (BCR) is expressed on the surface of B lymphocytes where it can bind antigen then transmit signals which regulate activation, growth, and differentiation. These signals can induce a number of cytoskeletal rearrangements leading to dynamic cellular processes including internalization of the bound antigen which is then processed and presented to T cells on MHC II. The relative importance of regions within the Igalpha and Igbeta cytoplasmic domains has been well studied in terms of signaling but their roles in BCR internalization and trafficking are less clear. We hypothesize that the Igalpha and Igbeta cytoplasmic domains is important for normal internalization and trafficking of the 4 chain BCR. An Igalpha and Igbeta deficient murine lymphoid cell line was used to express mIgM along with a panel of Igalpha and Igbeta mutants in order to compare their internalization and subcellular localization. Here we show that the Igalpha and Igbeta cytoplasmic domains are each sufficient for internalization, though Igalpha is dominant in this process. We also show that the internalization signal is contained in a region past the first cytoplasmic tyrosine residue of Igalpha and Igbeta, Y176 and Y195 respectively. We also show that a 4 amino acid motif normally contained within the Igalpha ITAM is sufficient to rescue aberrant internalization. In terms of receptor trafficking, each cytoplasmic domain is sufficient for trafficking to lysosomal compartments but that a normal rate of trafficking likely requires the tandem effects of both Igalpha and Igbeta. PMID- 20837063 TI - Degenerate primers for PCR amplification and sequencing of the avian influenza A neuraminidase gene. AB - This study describes the design of degenerate primers and their use for synthesis of full-length avian influenza A neuramindase (NA). Each reaction was performed using either two forward primers and one reverse primer, or one forward primer and one reverse primer. Both primer combinations had comparable amplification efficiencies for all NA subtypes (1-9). A total of 115 virus strains, including both field isolates and reference strains, were amplified successfully using these degenerate primer sets. Of the sequences amplified, 108 strains (93.9%) resulted in near full-length NA cDNAs after two readings with one forward primer and one reverse primer. Of the remaining sequences, five strains (4.3%) yielded reads with enough information for subtype categorization by BLAST although they were of insufficient quality for assembly. One strain (0.9%) yielded different subtypes from both sequence reads whereas the other one (0.9%) was not possible to assemble and subtype. This successful demonstration of these degenerate primers for the amplification and sequencing of all avian NA subtypes suggests that these primers could be employed in the avian influenza surveillance program as well as studies of antiviral resistance, virus ecology or viral phylogeny. PMID- 20837064 TI - Molecular detection of nine rice viruses by a reverse-transcription loop-mediated isothermal amplification assay. AB - A reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay was established for the detection of nine viruses from infected rice plants, including rice black-streaked dwarf virus (RBSDV), rice dwarf virus (RDV), rice gall dwarf virus (RGDV), rice ragged stunt virus (RRSV), rice transitory yellowing virus (RTYV), rice stripe virus (RSV), rice grassy stunt virus (RGSV), rice tungro spherical virus (RTSV), and rice tungro bacilliform virus (RTBV). Virus-specific primer sets were designed from the genome sequences of these viruses. By the combination of RNA rapid extraction and RT-LAMP, these nine viruses could be detected within 2h from infected rice plants. The sensitivities of the assays were either higher than (for RSV, RTBV, and RTYV) or similar (for RDV) to those of one-step RT-PCR. Furthermore, RTBV and RTSV were detected not only in infected rice plants but also in viruliferous insect vectors. The RT-LAMP assays may facilitate studies on rice disease epidemiology, outbreak surveillance, and molecular pathology. PMID- 20837065 TI - A rapid immunochromatographic test strip for detecting rabies virus antibody. AB - An immunochromatographic test strip (ICTS) for detecting antibodies to rabies virus was developed, using colloidal gold particles labeled with rabies virus glycoprotein as the tracer. The assay was evaluated using sera from dogs immunized with various commercial rabies vaccines, or from dogs in the clinics and sera from dogs immunized with vaccines against pathogens other than rabies virus, and negative sera from a wide variety of animal sources, including dogs, mice, and cats which had never been vaccinated. The ICTS was found to be highly specific for antibodies against rabies virus, with a detection limit of 0.5IU/ml as measured by the fluorescent antibody virus neutralization (FAVN) test. Compared with the FAVN test, the specificity and sensitivity of ICTS were 98.2% and 90.4%, respectively. There was an excellent agreement between results obtained by the ICTS and FAVN tests (kappa=0.888). Strips stored at 4 degrees C in a plastic bag with a desiccant retained their specificity and sensitivity for at least 15 months, and strips stored at ambient temperature remained stable for 12 months. The immunochromatographic test strip may therefore be useful for clinical laboratories lacking specialized equipment and for diagnosis in the field for rapid detection of rabies virus-specific antibodies. PMID- 20837066 TI - Comparison of two real-time PCR methods for detection of ostreid herpesvirus 1 in the Pacific oyster Crassostrea gigas. AB - The real-time polymerase chain reaction (PCR) is considered to be a suitable tool for nucleic acid quantitation because it is accurate, rapid and reliable. The reference protocol for quantitation of ostreid herpesvirus 1 in Pacific oysters Crassostrea gigas is based on a Sybr((r)) Green real-time PCR developed by the IFREMER laboratory. The Frank Duncombe Departmental Laboratory has developed an alternative protocol based on TaqMan((r)) chemistry (alternative technique). The quantitation limits were 1000 and 18UG/mg of tissues for the reference method and alternative protocols, respectively, and the latter protocol has a detection limit of 6UG/mg of tissues. The aim of this study was to compare the two protocols using DNA samples obtained from 210 spat. The kappa index (0.41) indicated a moderate concordance between the protocols, according to the measures of Landis and Koch. All samples that were positive by the reference protocol were also positive by the alternative protocol. Of the 76 samples that were negative by the reference protocol, 49 were positives by the alternative protocol. In conclusion, the alternative protocol is an improvement of the reference protocol in terms of sensitivity, specificity and rapidity (<3h). PMID- 20837067 TI - Neural correlates of mental preparation for successful insight problem solving. AB - A distinct type of mental preparation (activity in medial frontal and temporal areas) had been found to facilitate insight problem solving independent of specific problems [25]. In order to explore whether neural activity during a preparatory interval (mental preparation) is associated with which insight problems would be solved or not, we developed a task that uses Chinese logogriphs (riddles) as materials. Blood oxygenation level-dependent fMRI contrasts between Successful and Unsuccessful mental preparation were measured. Results showed that mental preparation leading to successful problem solving involves heightened activity in the left middle/medial frontal gyrus, the left middle/superior temporal gyrus, the right cerebellum, the bilateral claustrum and the left postcentral gyrus. We discussed the role of these areas in mental preparation for successful insight problem solving. PMID- 20837060 TI - Prefrontal cortex and drug abuse vulnerability: translation to prevention and treatment interventions. AB - Vulnerability to drug abuse is related to both reward seeking and impulsivity, two constructs thought to have a biological basis in the prefrontal cortex (PFC). This review addresses similarities and differences in neuroanatomy, neurochemistry and behavior associated with PFC function in rodents and humans. Emphasis is placed on monoamine and amino acid neurotransmitter systems located in anatomically distinct subregions: medial prefrontal cortex (mPFC); lateral prefrontal cortex (lPFC); anterior cingulate cortex (ACC); and orbitofrontal cortex (OFC). While there are complex interconnections and overlapping functions among these regions, each is thought to be involved in various functions related to health-related risk behaviors and drug abuse vulnerability. Among the various functions implicated, evidence suggests that mPFC is involved in reward processing, attention and drug reinstatement; lPFC is involved in decision making, behavioral inhibition and attentional gating; ACC is involved in attention, emotional processing and self-monitoring; and OFC is involved in behavioral inhibition, signaling of expected outcomes and reward/punishment sensitivity. Individual differences (e.g., age and sex) influence functioning of these regions, which, in turn, impacts drug abuse vulnerability. Implications for the development of drug abuse prevention and treatment strategies aimed at engaging PFC inhibitory processes that may reduce risk-related behaviors are discussed, including the design of effective public service announcements, cognitive exercises, physical activity, direct current stimulation, feedback control training and pharmacotherapies. A major challenge in drug abuse prevention and treatment rests with improving intervention strategies aimed at strengthening PFC inhibitory systems among at-risk individuals. PMID- 20837068 TI - Cage-induced stereotypies in female ICR CD-1 mice do not correlate with recurrent perseveration. AB - Stereotypies are repetitive, unvarying, apparently purposeless behavioural patterns. They develop in animals kept in barren environments and are highly prevalent in laboratory mice (Mus musculus), yet their underlying mechanisms have remained elusive. In humans, stereotypies are associated with several psychiatric disorders and are thought to reflect dysfunction of inhibition of motor programs mediated by the corticostriatal circuitry, resulting in recurrent perseveration (=inappropriate repetition of behavioural responses). Several studies in captive animals of different species have reported a correlation between stereotypy performance and perseverative behaviour, indicating a similar dysfunction. To examine whether stereotypies in mice correlate with recurrent perseveration and whether they are causally related, we raised 40 female ICR CD-1 mice in either barren or enriched cages from three to either six or 16 weeks of age (2 * 2 factorial design) and assessed stereotypic behaviour in the home cage and recurrent perseveration on a two-choice guessing task. Enrichment significantly reduced stereotypic behaviour both at six and 16 weeks of age and recurrent perseveration increased with age. Although enriched housing reduced the number of repetitions in the guessing task significantly, there was no clear evidence for an effect on recurrent perseveration, and recurrent perseveration did not correlate positively with stereotypy level. These findings indicate either that this test did not measure recurrent perseveration or that cage stereotypies in these mice do not reflect behavioural disinhibition as measured by recurrent perseveration. PMID- 20837070 TI - GP4-specific neutralizing antibodies might be a driving force in PRRSV evolution. AB - The structural envelope glycoprotein GP4 of European porcine reproductive and respiratory syndrome virus (PRRSV) strains contains a highly variable neutralizing epitope that is susceptible to neutralizing antibody-mediated selective pressure in vitro. In this study, it was analyzed what happens with this neutralizing epitope during infection in vivo in the presence of neutralizing antibodies. A neutralizing antibody-mediated selective pressure was created in 30 pigs by vaccination prior to inoculation with infectious Lelystad virus (LV). Nine viable neutralizing antibody-escape variants were isolated from 9 of these pigs and their neutralizing antibody-escape mutant-identity was confirmed by the acquired resistance to neutralization by autologous neutralizing sera. Six out of 9 neutralizing antibody-escape variants contained aa substitutions in the GP4 neutralizing epitope and had become resistant to neutralization by a monoclonal antibody (mAb) against this epitope. In addition, in all 6 corresponding pigs, antibodies against this epitope were detected early in infection. In contrast to these 6 virus variants, the 3 other antibody-escape variants did not contain aa substitutions in the GP4 neutralizing epitope and were still sensitive to neutralization by the GP4-specific mAb. These antibody escape variants were isolated from pigs that did not contain antibodies against this epitope early in infection. All these findings together strongly indicate that aa substitutions in the GP4 neutralizing epitope can abrogate antibody recognition, and that neutralizing antibodies might be responsible for the selection of neutralizing antibody-resistant variants with aa substitutions in the neutralizing epitope on GP4. In conclusion, this study indicates that neutralizing antibodies in pigs might be a driving force in the rapid evolution of the neutralizing epitope on GP4 of European PRRSV strains. PMID- 20837069 TI - What makes the mitochondria a killer? Can we condition them to be less destructive? AB - Cardioprotection, such as preconditioning and postconditioning, has been shown to result in a significant reduction in cell death. Many of the signaling pathways activated by cardioprotection have been elucidated, but there is still a lack of understanding of the mechanisms by which these signaling pathways reduce cell death. Mitochondria have been reported to be an important player in many types of apoptotic and necrotic cell death. If mitochondria play an important role in cell death, then it seems reasonable to consider that cardioprotective mechanisms might act, at least in part, by opposing mitochondrial cell death pathways. One of the major mechanisms of cell death in ischemia-reperfusion is suggested to be the opening of a large conductance pore in the inner mitochondrial membrane, known as the mitochondrial permeability transition pore. Inhibition of this mitochondrial pore appears to be one of the major mechanisms by which cardioprotection reduces cell death. Cardioprotection activates a number of signaling pathways that reduce the level of triggers (reactive oxygen species and calcium) or enhances inhibitors of the mitochondrial permeability transition pore at the start of reperfusion. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 20837071 TI - Control and elimination of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSv) can have a significant economic impact on swine herds due to reproductive failure, preweaning mortality and reduced performance in growing pigs. Control at the farm level is pursued through different management procedures (e.g. pig flow, gilt acclimation, vaccination). PRRSv is commonly eliminated from sow herds by a procedure called herd closure whereby the herd is closed to new introductions for a period of time during which resident virus dies out. However, despite thorough application of biosecurity procedures, many herds become re-infected from virus that is present in the area. Consequently, some producers and veterinarians are considering a voluntary regional program to involve all herds present within an area. Such a program was initiated in Stevens County in west central Minnesota in 2004. PRRSv has been eliminated from most sites within the region and the area involved has expanded to include adjacent counties. The program has been relatively successful and reflects local leadership, a cooperative spirit, and a will to eliminate virus from the region. PMID- 20837072 TI - Molecular epidemiology of PRRSV: a phylogenetic perspective. AB - Since its first discovery two decades ago, porcine reproductive and respiratory syndrome virus (PRRSV) has been the subject of intensive research due to its huge impact on the worldwide swine industry. Thanks to the phylogenetic analyses, much has been learned concerning the genetic diversity and evolution history of the virus. In this review, we focused on the evolutionary and epidemiological aspects of PRRSV from a phylogenetic perspective. We first described the diversity and transmission dynamics of Type 1 and 2 PRRSV, respectively. Then, we focused on the more ancient evolutionary history of PRRSV: the time of onset of all existing PRRSV and an origin hypothesis were discussed. Finally, we summarized the results from previous recombination studies to assess the potential impact of recombination on the virus epidemiology. PMID- 20837073 TI - Comparative transient expression assay analysis of hycu-hr6- and IE1-dependent regulation of baculovirus gp64 early promoters in three insect cell lines. AB - We previously demonstrated that the Hyphantria cunea multicapsid nucleopolyhedrovirus (HycuMNPV) gp64 gene (hycu-gp64) is uniquely localized on the viral genome with a large homologous region of 1582bp, hycu-hr6, immediately upstream of the hycu-gp64 gene. In the present study, we compared the regulation of gp64 early promoters from HycuMNPV, Autographa californica multicapsid NPV (AcMNPV) and Bombyx mori NPV (BmNPV) by cis-acting hycu-hr6 and trans-acting IE1s in three cell lines (Spodoptera frugiperda Sf9, Bombyx mori BM-N and Spilosoma imparilis SpIm). A transient expression assay with plasmids harboring a reporter luciferase gene demonstrated that the gp64 early promoters are positively regulated by hycu-hr6, independent of virus and cell types. In contrast, gp64 early promoters were regulated positively or negatively by trans-acting IE1s, in a cell- and virus-type dependent manner, indicating that cellular factors, as well as viral factors, are responsible for IE1-dependent regulation of gp64 early promoters. However, hycu-gp64 early promoter activity was consistently suppressed by HycuMNPV IE1 (Hycu-IE1), irrespective of the cell lines used. Analysis of the hycu-gp64 early promoter region revealed two novel sequence elements that were involved in Hycu-IE1-dependent negative regulation of the hycu-gp64 early promoter. These two novel regulatory sequence elements could compensate for each other but could not be substituted with AcMNPV IE1 binding motif (Ac-IBM). These results suggest that IE1 regulates gp64 early promoters to produce the proper amount of GP64 protein, depending upon NPV-insect cell systems. PMID- 20837074 TI - Development of ideas about food and nutrition from preschool to university. AB - An open-ended interview about food and nutrition was administered to 100 Australian participants in five different groups: preschoolers (M age 5;2), third graders (M age = 8;2), sixth graders (M age = 10;11), ninth graders (M age = 14;4) and adults (M age = 20;0). The interview covered four components of food and nutrition: purpose of eating, effects of different quantities of food, effects of specific foods and effects of an unbalanced diet. Participants' responses were tallied by content to reveal the most common answers to each question by age group. Responses were also coded by component with reference to the naive theory that was invoked: psychological, mechanistic, vitalistic or physiological reasoning. Results indicated that psychological reasoning about food and nutrition was rare in all age groups. Between 5 and 8 years, there were significant increases in mechanistic and vitalistic reasoning about food and nutrition. At age 11 and again at age 14, responses that reflected physiological reasoning increased significantly. These findings provide a developmental picture of changes in reasoning about these topics, which can inform professionals who seek to communicate effectively with children of different ages about food and nutrition. PMID- 20837075 TI - Association of polymorphisms of programmed cell death-1 gene with chronic hepatitis B virus infection. AB - Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. The present study investigated the relationships between the polymorphisms of the PD-1 gene and the susceptibility to chronic HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions -606G/A (PD-1.1) and +8669 G/A (PD-1.6) were analyzed by bidirectional PCR amplification of specific alleles (Bi-PASA) in 198 chronic HBV patients and 280 controls. Although the genotype and allele frequencies of PD 1.1 were not different between chronic HBV patients and controls, the genotype and allele frequencies of PD-1.6 were significantly different. PD-1.6 GG genotype and the combination of genotypes with G allele were less frequent in HBV patients than in controls (p = 0.007 and p = 0.031, respectively). The allele G was also less frequent in patients than in controls (p = 0.006). Haplotype PD-1.1G/PD-1.6G was less frequent in patients than in controls (p = 0.001). Cirrhosis patients had a lower frequency of PD-1.6 G allele compared with controls (p = 0.007). Our findings, firstly reporting the association between PD-1 polymorphism and HBV infection, suggest that PD-1 gene may be one of the genes predisposing to chronic HBV infection and disease progression. PMID- 20837076 TI - Evaluation of scientific criteria for identifying allergenic foods of public health importance. AB - Identification of allergenic foods of public health importance should be based on well-defined criteria. Bjorksten et al. (2008) proposed that the criteria should assess the evidence for an IgE mechanism, the reaction, the potency and the severity of the effect of the food and its prevalence. This study evaluated the application of the proposed criteria based on published reports. Publications were selected from two databases to test whether the descriptions for ranking the level of evidence for each criterion were unambiguous and covered the full range of levels of evidence regarding seven foods, five known to be allergenic and two negative controls. The options available to rank the quality of evidence were appropriate but needed refinement to improve clarity and conceptual value. The criteria were helpful to assess known IgE-dependent allergens, and to exclude the non-allergenic substances. The criteria framework discriminated between papers with high, moderate and low quality of evidence. The advantage of using the proposed criteria is to make the decision-making process and rationale explicit. The framework helps to identify gaps in knowledge and to uncover the level of heterogeneity of the evidence thus guiding research and providing a basis for sound risk management decisions. PMID- 20837077 TI - Shoaling develops with age in Zebrafish (Danio rerio). AB - The biological mechanisms of human social behavior are complex. Animal models may facilitate the understanding of these mechanisms and may help one to develop treatment strategies for abnormal human social behavior, a core symptom in numerous clinical conditions. The zebrafish is perhaps the most social vertebrate among commonly used laboratory species. Given its practical features and the numerous genetic tools developed for it, it should be a promising tool. Zebrafish shoal, i.e. from a tight multimember groups, but the ontogenesis of this behavior has not been described. Analyzing the development of shoaling is a step towards discovering the mechanisms of this behavior. Here we study age-dependent changes of shoaling in zebrafish from day 7 post fertilization to over 5months of age by measuring the distance between all pairs of fish in freely swimming groups of ten subjects. Our longitudinal (repeated measure within subject) and cross sectional (non-repeated measure between subject) analyses both demonstrated a significant increase of shoaling with age (decreased distance between shoal members). Given the sophisticated genetic and developmental biology methods already available for zebrafish, we argue that our behavioral results open a new avenue towards the understanding of the development of vertebrate social behavior and of its mechanisms and abnormalities. PMID- 20837078 TI - Lipopolysaccharide from Burkholderia thailandensis E264 provides protection in a murine model of melioidosis. AB - Burkholderia thailandensis is a less virulent close relative of Burkholderia pseudomallei, a CDC category B biothreat agent. We have previously shown that lipopolysaccharide (LPS) extracted from B. pseudomallei can provide protection against a lethal challenge of B. pseudomallei in a mouse model of melioidosis. Sugar analysis on LPS from B. thailandensis strain E264 confirmed that this polysaccharide has a similar structure to LPS from B. pseudomallei. Mice were immunised with LPS from B. thailandensis or B. pseudomallei and challenged with a lethal dose of B. pseudomallei strain K96243. Similar protection levels were observed when either LPS was used as the immunogen. This data suggests that B. thailandensis LPS has the potential to be used as part of a subunit based vaccine against pathogenic B. pseudomallei. PMID- 20837079 TI - Healthy young and middle age adults: what will it take to vaccinate them for influenza? AB - Starting in 2010, healthy adults age 19-49 will be recommended for annual influenza vaccination. Because they were not previously targeted, little is known about their vaccine-related attitudes and behaviors. Using nationally representative survey data from 2009 to 2010, we found that adults newly recommended for influenza vaccination (as compared to previously recommended groups) are less likely to believe flu vaccines are safe (44% vs. 63%), to have ever been vaccinated (36% vs. 64%), to be vaccinated following a healthcare provider recommendation (44% vs. 52%), and to visit a doctor's office during vaccination season (41% vs. 69%). To boost rates of influenza vaccination in this population, new and untraditional strategies aimed at encouraging first-time vaccination are needed. PMID- 20837080 TI - Racial disparities in diarrhea-associated hospitalizations among children in five US States, before and after introduction of rotavirus vaccine. AB - Racial differences in diarrheal disease have not been systematically examined, and the impact of rotavirus vaccine on these differences has not been assessed. We compared diarrhea-associated hospitalizations by race/ethnicity among children <5 years pre- (2000-2006) and post- (2007 and 2008) rotavirus vaccine introduction in five US states. Pre-vaccine hospitalization rates were greater among whites versus blacks and Hispanics. However, black (versus non-black) infants <6 months and white (versus non-white) children >= 1 year had higher rates. In 2008, racial disparities for children 12-35 months resolved, but higher hospitalization rates among black infants <6 months persisted, highlighting the need for timely vaccination. PMID- 20837082 TI - Application of fly ash adsorbed peroxidase for the removal of bisphenol A in batch process and continuous reactor: assessment of genotoxicity of its product. AB - In the present study peroxidase has been immobilized simply by adsorption on fly ash. On fly ash adsorbed nearly 1113 U of peroxidase activity per g. Comparative degradation of endocrine disrupter, bisphenol A has been performed by soluble and immobilized enzyme. Soluble and immobilized enzyme removed maximum bisphenol A in the presence of 0.3mM guaiacol, a redox mediator, 0.75 mM H(2)O(2) in sodium phosphate buffer, pH 7.0 at 40 degrees C. Degradation of bisphenol A in batch process was 61%, 100% and 100% at 20, 40 and 60 degrees C, respectively. Fly ash adsorbed peroxidase was more effective in the degradation of bisphenol A as compared to its free form. Immobilized enzyme catalyzed complete degradation of bisphenol A at 40 degrees C within 3.5h. The oxidative degradation and polymerization of bisphenol A was also evaluated in the continuous bed-reactors at different flow rates. The removal of this compound was maximum at a flow rate of 20 mL h(-1). HPLC analysis showed two clear peaks, one related to bisphenol A and other related to its degradation product, 4-isopropenylphenol. Plasmid nicking and comet assays demonstrated that the product, 4-isopropenylphenol was significantly nontoxic. PMID- 20837083 TI - Antileukemic action of (-)-epicatechin in the spleen of rats with acute myeloid leukemia. AB - The aim of this study was to investigate whether (-)-epicatechin (EC) can induce DNA damage and apoptosis of cancer cells in the spleen of rat with acute myeloid leukemia. Healthy and leukemic rats were given EC by gavage at a dose of 40 mg/kg b.w. for 22 consecutive days. Spleen cells were subjected for analysis of DNA damage and apoptosis. The amount of DNA damage was estimated by the comet assay, while apoptosis was examined by flow cytometry using Annexin V staining. Leukemic cells were identified in the spleen cells by indirect immunofluorescence using RM 124 antibody followed by flow cytometry analysis. The results show that EC did not affect DNA damage in the splenocytes of healthy rats, but significantly increased the extent of DNA strand breaks in the spleen cells of leukemic animals. EC administration to leukemic rats induced a significant increase in the level of Annexin V-positive leukemic cells, but the level of non-leukemic Annexin V-positive cells remained unchanged in comparison to control. The percentage of leukemic cells decreased significantly under EC influence comparing to the untreated group. The results of the study reveal that EC could be used as an effective supplement of standard therapy against acute myeloid leukemia. PMID- 20837084 TI - Whole body radioprotective activity of an acetone-water extract from the seedpod of Nelumbo nucifera Gaertn. seedpod. AB - Procyanidins extracted with acetone-water from lotus (Nelumbo nucifera Gaertn.) seedpod (LSPCs) were evaluated for in vivo radioprotective activity against whole body gamma irradiation in Swiss albino mice. Pretreated with LSPCs 200 mg/kg by intragastric (i.g.) for 15 days was found to be the most effective dose in preventing radiation sickness, reducing radiation-induced mortality, increasing mean survival time and elevating radiation median lethal dose (LD(50)) from 8.9 to 10.5 Gy, indicating a dose modifying factor (DMF) of 1.18. Further, administered LSPCs at a dose of 200 mg/kg could effectively maintain spleen index close to normal, stimulate endogenous spleen colony forming units, promote the levels of red blood cells (RBC), white blood cells (WBC), platelets and hemoglobin in peripheral blood, and prevent spleen and skin damage in irradiated mice, reduce the level of radiation-induced micronucleated polychromatic erythrocytes in bone marrow, maintain the polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) ratio (P/N ratio) and significantly decrease bone marrow chromosomal damage. Alternatively, pretreated with LSPCs (200 mg/kg) significantly decreased the lipid peroxidation (LPO) level, and elevated the activities of endogenous antioxidant enzymes in liver after irradiation. Thus LSPCs possess a strong whole body radioprotective activity, and it may be used as a radioprotector. PMID- 20837085 TI - Antioxidant and prooxidant nature of hydroxycinnamic acid derivatives ferulic and caffeic acids. AB - Dietary polyphenols are beneficial to human health by exerting various biological effects. Ferulic and caffeic acids are hydroxycinnamic acid derivatives widely distributed in plant-derived food products. Studies indicate that some dietary compounds may have concentration-dependent antioxidant or prooxidant activities. The present study concerns such activities of ferulic and caffeic acids. They have concentration-dependent antioxidant effects in terms of inhibition of lipid peroxidation and reactive oxygen species-scavenging after 2,2'-azobis amidinopropane dihydrochloride-induced damage in mouse liver microsomes and splenic lymphocytes respectively. They also show differential scavenging of nitric oxide, superoxide and 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid radical (ABTS*(+)). In DPPH (1,1-diphenyl picrylhydrazyl) assay above 20 MUM the absorbance start increasing due to the formation of an unknown adduct which has a shoulder at 517 nm. However, in Fenton reaction, above 5 MUM, they behave as prooxidants and the possible mechanisms responsible for their prooxidant property may be related to their ferric reducing ability. These findings may have significant health implications where these natural compounds are being used/consumed. PMID- 20837086 TI - Investigation of carcinogenicity for levamisole administered in the diet to F344 rats. AB - A two year carcinogenicity study of anthelmintic drug levamisole (LV) was performed using 50 male and 50 female F344 rats at dietary drug concentrations of 0, 60, or 300 ppm. The daily intakes of LV were calculated to be 2.6, 12.9 mg/kg b.w./day for males and 2.9, 14.1mg/kg b.w./day for females, respectively. No significant differences in general condition and survival rate (82%, 74%, 80% in males and 84%, 84%, 84% in females, respectively) were observed. In the 300 ppm group, suppression of body weight gain was observed from the onset of treatment and reduction in final body weights was 6% in males and 11% in females. Significant increases in the absolute and/or relative weights of the lungs, heart, spleen, liver, kidneys, and adrenals were observed in males and/or females treated with 300 ppm. Some of high incidences neoplasms were observed, and there were also tendencies to increase for mammary gland fibroma and thoracic/abdominal cavity mesothelioma in males. However, there were no significant inter-group differences in incidences, histopathological types or differences compared with historical control data. Thus, it was concluded that LV was not carcinogenic to male and female F344 rats under the experimental conditions. PMID- 20837087 TI - In vitro cytotoxicity of fungi spoiling maize silage. AB - Penicillium roqueforti, Penicillium paneum, Monascus ruber, Alternaria tenuissima, Fusarium graminearum, Fusarium avenaceum, Byssochlamys nivea and Aspergillus fumigatus have previously been identified as major fungal contaminants of Danish maize silage. In the present study their metabolite production and in vitro cytotoxicity have been determined for fungal agar and silage extracts. All 8 fungal species significantly affected Caco-2 cell viability in the resazurin assay, with large variations for each species and growth medium. The 50% inhibition concentrations (IC(50)) of the major P. roqueforti metabolites roquefortine C (48 MUg/mL), andrastin A (>50 MUg/mL), mycophenolic acid (>100 MUg/mL) and 1-hydroxyeremophil-7(11),9(10)-dien-8-one (>280 MUg/mL) were high. Fractionating of agar extracts identified PR-toxin as an important cytotoxic P. roqueforti metabolite, also detectable in maize silage. The strongly cytotoxic B. nivea and P. paneum agar extracts contained patulin above the IC(50) of 0.6 MUg/mL, however inoculated onto maize silage B. nivea and P. paneum did not produce patulin (>371 MUg/kg). Still B. nivea infected maize silage containing mycophenolic acid (~50 mg/kg), byssochlamic acid and other metabolites, was cytotoxic. In contrast hot-spots of P. roqueforti, P. paneum, M. ruber and A. fumigatus were not more cytotoxic than uninoculated silage. PMID- 20837088 TI - Why guidelines for early childhood caries prevention could be ineffective amongst children at high risk. AB - OBJECTIVE: This paper sought to investigate whether early childhood caries (ECC) prevention guidelines were able to produce a significant, long-term, homogeneous decrease in ECC prevalence/incidence within all socio-economic strata of the population and whether their development followed methodologies specifically designed for ECC prevention guidelines. METHODS: ECC prevention guidelines and specific methodologies published in English since 1995 were searched through MEDLINE, PUBMED and GOOGLE. Data regarding long-term and stratified effect of guidelines and specific methodologies were not found. The only review of methodology for guideline development which was found (produced by the Guideline Development Group of the WHO) was used and adjusted to draft a specific ECC centred methodology. RESULTS: This procedure resulted in nineteen key methodological components for the optimal ECC prevention guideline development. In order to emphasize such necessity of specific methodologies, three of these components (assessment of the strength of scientific evidence, development of consensus amongst Dental Health Care Providers, identification of appropriate outcomes) were described in detail. These examples showed the shortfalls of ECC prevention guidelines developed using methodologies explicitly designed for the development of clinical practice (e.g., therapy, diagnosis, screening) guidelines. CONCLUSIONS: Guidelines for ECC prevention could help control such disease and improve quality of life of children at high ECC risk. However, the lack of specific methodologies for their development led to the consequence that, despite the fact that many ECC prevention guidelines exist, their effectiveness in the final goal of obtaining a significant, long-term and homogeneous reduction of ECC incidence, is not proved. PMID- 20837089 TI - In vivo performance of a laser fluorescence device for the approximal detection of caries in permanent molars. AB - OBJECTIVES: The aim of this randomised clinical trial was to investigate if a laser fluorescence device is able to discriminate between sound and carious approximal sites and between enamel and dentinal lesions, as well as to find appropriate cut-off values. METHODS: One hundred and seventeen sound or uncavitated carious sites in permanent molars were visually and radiographically examined, then either opened or not, after which their laser fluorescence was measured. Forty-three lesions were opened, the caries removed and the clinically identified caries depths were registered in addition to the radiographical scoring. Seventy-four sites were radiographically deemed sound or had enamel caries and were not opened. Here, the radiographical scorings were registered. RESULTS: Taking the radiographic scoring as gold standard for all investigated approximal sites, sound sites (D(0), n=40) showed significantly lower laser fluorescence measurements than carious sites (D(1-4), n=77) (Mann-Whitney test, P<0.025) suggesting a cut-off at 7 (sensitivity=0.68, specificity=0.7). Comparing measurements of D(0-2) (n=74) and D(3,4) (n=43), the results were also different by a statistically significant amount (P<0.025) and the cut-off calculated to be 16 (sensitivity=0.6, specificity=0.84). A fair positive correlation between laser fluorescence values and radiographical scoring was found (rho=+0.47, P<0.01). Analysing the 43 opened lesions with their clinically found lesion depths as gold standard, there was a fair positive correlation to the laser fluorescence values (rho=+0.34, P=0.03) and a moderately strong correlation to the radiographic scoring (rho=+0.67, P<0.01). CONCLUSION: The device may be an adjunct tool in the approximal detection of caries along with established procedures. PMID- 20837090 TI - Olfactory ensheathing cells: biology in neural development and regeneration. AB - Olfactory ensheathing cells (OECs) constitute a unique population of glia that accompany and ensheath the primary olfactory axons. They are thought to be critical for spontaneous growth of olfactory axons within the developing and adult olfactory nervous system, and have recently emerged as potential candidates for cell-mediated repair of neural injuries. Here, based on the current research, we give an overview of the biology of OECs in neural development and regeneration. This review starts with a detailed description of the cellular and molecular biological properties of OECs. Their functions in olfactory neurogenesis, olfactory axonal growth and olfactory bulb formation are sequently discussed. We also describe therapeutic applications of OECs for the treatment of a variety of neural lesions, including spinal cord injury, stroke, degenerative diseases, and PNS injuries. Finally, we address issues that may foster a better understanding of OECs in neural development and regeneration. PMID- 20837091 TI - Cognitive vs. affective listening modes and judgments of music--an ERP study. AB - The neural correlates of processing deviations from Western music rules are relatively well known. Less is known of the neural dynamics of top-down listening modes and affective liking judgments in relation with judgments of tonal correctness. In this study, subjects determined if tonal chord sequences sounded correct or incorrect, or if they liked them or not, while their electroencephalogram (EEG) was measured. The last chord of the sequences could be congruous with the previous context, ambiguous (unusual but still enjoyable) or harmonically inappropriate. The cognitive vs. affective listening modes were differentiated in the event-related potential (ERP) responses already before the ending chord, indicating different preparation for the judgment tasks. Furthermore, three neural events tagged the decision process preceding the behavioral responses. First, an early negativity, peaking at about 280ms, was elicited by chord incorrectness and by disliking judgments only over the right hemisphere. Second, at about 500ms from the end of the sequence a positive brain response was elicited by the negative answers of both tasks. Third, at about 1200ms, a late positive potential (LPP) was elicited by the liking judgment task whereas a large negative brain response was elicited by the correctness judgment task, indexing that only at that late latency preceding the button press subjects decided how to judge the cadences. This is the first study to reveal the dissociation between neural processes occurring during affective vs. cognitive listening modes and judgments of music. PMID- 20837092 TI - Predictors of performance in a real-life statistics examination depend on the individual cortisol profile. AB - In standardized stress conditions, cortisol responders and non-responders differ in their memory performance. To evaluate this association in a real-life situation, we investigated whether the individual cortisol response profile predicts the performance in an examination in statistics in 112 healthy participants. In addition, basic arithmetic abilities as well as mathematics anxiety were evaluated. We collected a baseline saliva sample before the examination day as well as pre- and post-examination samples. Participants were attributed to one of four cortisol profiles depending on their cortisol change in anticipation of the examination. 52% of participants showed an increase (A profile) and 43% a decrease (D-profile) in cortisol before the examination. Cortisol changes did not predict performance in the examination. However, only in A-profile individuals, mathematics anxiety and arithmetic abilities predicted statistics performance. We conclude that in real-life situations, cortisol facilitates the influence of mathematics anxiety and mathematical abilities on examination performance. PMID- 20837093 TI - Auditory hallucinations and the P3a: attention-switching to speech in schizophrenia. AB - BACKGROUND: In line with emerging research strategies focusing on specific symptoms rather than global syndromes in psychiatric disorders, we examined the functional neural correlates of auditory verbal hallucinations (AHs) in schizophrenia. Recent neuroimaging and behavioural evidence suggest altered early cognitive processes may be seen in patients with AH as a result of limited processing resources. METHODS: The P3a subcomponent of the P300, an event-related potential (ERP) index of early attention switching, was assessed in 12 hallucinating patients (HP), 12 non-hallucinating patients (NP) and 12 healthy controls (HC) within a passive two-tone auditory oddball paradigm using vowel phonemes. P3a amplitudes and latencies were measured in response to across phoneme changes. Following P3a acquisition, patients indicated the duration, intensity and clarity of their auditory hallucinations during recording. RESULTS: Hallucinating patients exhibited smaller P3a amplitudes than non-hallucinating patients and healthy controls. In HPs, P3a amplitude was negatively correlated with AH trait scores. SIGNIFICANCE: These findings suggest that AHs are associated with impaired processing of speech as evidenced by altered P3a amplitudes to vowel phonemes. This finding may be due to limited cognitive resources available for incoming external stimuli due to a usurping of finite resources by AHs. The P3a may be a useful non-invasive tool for probing relationships between hallucinatory and neural states within schizophrenia and the manner in which auditory processing is altered in these afflicted patients. PMID- 20837094 TI - Chronic lymphoid leukemia cells are highly sensitive to the combination of prednisolone and daunorubicin, but much less to doxorubicin or epirubicin. AB - OBJECTIVE: To generate a comprehensive map of the drug sensitivity of chronic lymphoid leukemia cells (CLL) using a newly developed in vitro drug-sensitivity assay based on automated evaluation of cell viability on single-cell level. MATERIALS AND METHODS: Primary CLL cells from 77 patients were tested using automated digital fluorescence microscopy. The effect of 27 frequently used chemotherapeutic agents was measured in short-term fluorescence survival assay. To avoid typical in vitro artifacts such as growth factor depletion and oxidative damage, the cell were cultured in a novel, total human blood lysate-based medium (OmniSanguine) in order to preserve the composition of growth factor flora and redox conditions of the in vivo environment. RESULTS: CLL cells from different patients showed considerable heterogeneity in their drug-sensitivity patterns. This pattern was stable even after in vitro activation of cell proliferation. Half of the samples were sensitive to fludarabine and chlorambucil. Daunorubicin was the most potent drug. It was effective in 75 of 77 cases. In addition, daunorubicin and prednisolone showed a strong synergistic effect. CONCLUSIONS: We suggest that the combination of low-dose daunorubicin and prednisolone might be an additional treatment option for therapy-resistant cases of CLL. PMID- 20837095 TI - A quantum mechanical analysis of the light-harvesting complex 2 (LH2) from purple photosynthetic bacteria: insights into the electrostatic effects of transmembrane helices. AB - We perform a quantum mechanical study of the peptides that are part of the LH2 complex from Rhodopseudomonas acidophila, a non-sulfur purple bacteria that has the ability of producing chemical energy from photosynthesis. The electronic structure calculations indicate that the transmembrane helices of these peptides are characterized by dipole moments with a magnitude of about 150D. When the full nonamer assembly made of 18 peptides is considered, then a macrodipole of magnitude 806D is built up from the vector sum of each monomer dipole. The macrodipole is oriented normal to the membrane plane and with the positive tip toward the cytoplasm thereby indicating that the electronic charge of the protein scaffold is polarized toward the periplasm. The results obtained here suggest that the asymmetric charge distribution of the protein scaffold contributes an anisotropic electrostatic environment which differentiates the absorption properties of the bacteriochlorophyll pigments, B800 and B850, embedded in the LH2 complex. PMID- 20837096 TI - Evolution of form and function in a model of differentiated multicellular organisms with gene regulatory networks. AB - The emergence of novelties, as a generator of diversity, in the form and function of the organisms have long puzzled biologists. The study of the developmental process and the anatomical properties of an organism provides scarce information into the means by which its morphology evolved. Some have argued that the very nature of novelty is believed to be linked to the evolution of gene regulation, rather than to the emergence of new structural genes. In order to gain further insight into the evolution of novelty and diversity, we describe a simple computational model of gene regulation that controls the development of locomotive multicellular organisms through a fixed set of simple structural genes. Organisms, modeled as two-dimensional spring networks, are simulated in a virtual environment to evaluate their steering skills for path-following. Proposed as a behavior-finding problem, this fitness function guides an evolutionary algorithm that produces structures whose function is well-adapted to the environment (i.e., good path-followers). We show that, despite the fixed simple set of structural genes, the evolution of gene regulation yields a rich variety of body plans, including symmetries, body segments, and modularity, resulting in a diversity of original behaviors to follow a simple path. These results suggest that the sole variation in the regulation of gene expression is a sufficient condition for the emergence of novelty and diversity. PMID- 20837097 TI - Prediction markets and their potential role in biomedical research--a review. AB - Predictions markets are marketplaces for trading contracts with payoffs that depend on the outcome of future events. Popular examples are markets on the outcome of presidential elections, where contracts pay $1 if a specific candidate wins the election and $0 if someone else wins. Contract prices on prediction markets can be interpreted as forecasts regarding the outcome of future events. Further attractive properties include the potential to aggregate private information, to generate and disseminate a consensus among the market participants, and to offer incentives for the acquisition of information. It has been argued that these properties might be valuable in the context of scientific research. In this review, we give an overview of key properties of prediction markets and discuss potential benefits for science. To illustrate these benefits for biomedical research, we discuss an example application in the context of decision making in research on the genetics of diseases. Moreover, some potential practical problems of prediction market application in science are discussed, and solutions are outlined. PMID- 20837098 TI - Gradients of seed photosynthesis and its role for oxygen balancing. AB - Seeds are generally viewed in the context of plant reproduction and the supply of food and feed, but only seldom as a site of photosynthesis. However, the seeds of many plant species are green, at least during their early development, which raises the issue of the significance of this greening for seed development. Here we describe the two contrasting modes of photosynthesis in the developing seed. The dicotyledonous pea seed has a green embryo, while the monocotyledonous barley caryopsis has a chlorenchymatic layer surrounding its non-green endosperm (storage organ). We have employed pulse-amplitude-modulated fluorescence and oxygen-sensitive microsensors to localize and describe gradient distributions of photosynthetic activity across the seed/caryopsis, and have discussed its role in maintaining the endogenous O2 balance. We also report the lack of photosynthetic activity in the stay-green embryo axis of the sacred lotus (Nelumbo nucifera) seed following imbibition. The observations are discussed with respect to in vivo light supply and contrasted with the characteristics of leaf photosynthesis. PMID- 20837099 TI - The gene regulatory networks controlled by estrogens. AB - Estrogen signaling occurs widely among vertebrates and in some invertebrates. Estrogen action is mediated by estrogen receptors through the regulation of target gene expression. Estrogen mediated control of gene expression is a complex process including ligand-receptor interactions, receptor-DNA interactions and receptor-cofactor interactions. Recent technological advances allow global analysis of gene expression and protein-DNA interactions facilitating a description of estrogen controlled gene regulatory networks. This paper reviews the current knowledge of estrogen regulation of gene expression and subsequent gene regulatory networks with focus on studies using human cell lines and mouse models. PMID- 20837100 TI - Transcript profiles and triiodothyronine regulation of sex steroid- and thyroid hormone-related genes in the gonad-mesonephros complex of Silurana tropicalis. AB - In amphibians, the main role of thyroid hormones (THs) is to regulate metamorphosis; however, there is evidence that THs also affect gonadal sexual differentiation. In this study, Silurana (Xenopus) tropicalis tadpoles were exposed to triiodothyronine (T3; 0, 0.5, 5 and 50 nM), the bioactive form of THs for 48h. Real-time RT-PCR analyses in the gonad-mesonephros complex (GMC) revealed that TH- and androgen-related genes were positively regulated, while estrogen receptor beta was negatively regulated by T3. Together, these results are in agreement with the masculinizing effect of THs in amphibians. Profiles of TH- and sex steroid-related genes in the GMC during metamorphosis of S. tropicalis suggest that THs are important regulators of sex steroid-related gene expression in the GMC. This study provides evidence that the GMC is a target of THs but that a complex interplay exists between THs and sex steroids during gonadal sexual development. PMID- 20837102 TI - Significant thalamocortical coherence of sleep spindle, theta, delta, and slow oscillations in NREM sleep: recordings from the human thalamus. AB - The electrophysiological studies of thalamocortical oscillations were mostly done in animal models. Placement of stimulation electrodes at the anterior nucleus of the thalamus (ANT) for seizure reduction enables the study of the thalamocortical interplay in human subjects. Nocturnal sleep electroencephalograms (EEGs) and local field potentials (LFPs) of the left and right thalamus (LT, RT) were recorded in three subjects receiving ANT stimulation. Sleep stages were scored according to American Academy of Sleep Medicine criteria. The whole-night time frequency coherence maps between EEG (C3, C4) and LFP (LT, RT) showed specific coherence patterns during non-rapid eye movement (NREM) sleep. Pooled coherence in the NREM stage was significant in slow, delta, theta and spindle frequency ranges. The spindle oscillations had the highest coherence (0.17-0.58) in the homolateral hemisphere. Together, these observations indicate that the oscillations were related to thalamocortical circuitry. PMID- 20837101 TI - Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. AB - Members of the steroid hormone receptor (SR) family activate transcription from different DNA response elements and are regulated by distinct hormonal ligands. Understanding the evolutionary process by which this diversity arose can provide insight into how and why SRs function as they do. Here we review the characteristics of the ancient receptor protein from which the SR family descends by a process of gene duplication and divergence. Several orthogonal lines of evidence - bioinformatic, phylogenetic, and experimental - indicate that this ancient SR had the capacity to activate transcription from DNA estrogen response elements in response to estrogens. Duplication and divergence of the ancestral SR gene subsequently generated new receptors that were activated by other steroid hormones, including progestagens, androgens, and corticosteroids. The androgen and progesterone receptors recruited as their ligands steroids that were previously present as biochemical intermediates in the synthesis of estrogens. This process is an example of molecular exploitation--the evolution of new molecular interactions when an older molecule, which previously had a different function, is co-opted as a binding partner by a newly evolved molecule. The primordial interaction between the ancestral steroid receptor and estrogens may itself have evolved due to an early molecular exploitation event. PMID- 20837103 TI - Differential roles of GRIP1a and GRIP1b in AMPA receptor trafficking. AB - Regulated trafficking controls AMPA receptor (AMPAR) number at the postsynaptic membrane to modify the efficiency of synaptic transmission. The PDZ proteins GRIP1 and the related ABP-L/GRIP2 bind AMPAR subunit GluA2, and have been proposed to play a role in AMPAR trafficking associated with Long Term Depression (LTD) of synaptic transmission. Both GRIP1 and ABP-L/GRIP2 exist in different splice isoforms, including alternative 18 amino acid domains at the extreme N terminus, which determine whether the protein can be palmitoylated. The implications of this differential splicing for AMPAR trafficking is unknown. Here, we use surface biotinylation and quantitative Western blotting to show that the N-terminal splice variants GRIP1a and GRIP1b have differential effects in NMDA-induced AMPAR internalization in cultured hippocampal neurons. GRIP1a inhibits, but GRIP1b enhances this trafficking event. We further demonstrate that GRIP1a and GRIP1b have dramatically different subcellular distributions in cultured neurons and exhibit NMDA-dependent colocalisation with early endosomes. We propose that GRIP1 palmitoylation modulates NMDA-induced AMPAR internalisation by differential regulation of the early endosomal system. PMID- 20837104 TI - Corticospinal excitability during action observation in task-specific dystonia: a transcranial magnetic stimulation study. AB - Observation of actions performed by other individuals activates the onlooker's motor system in a way similar to real movement execution. The functioning of this mechanism in the pathological domain is not clear yet. The aim of this study was to explore whether action observation activates the motor system of patients affected by a task-specific form of dystonia, such as writer's cramp. Transcranial magnetic stimulation was applied over the primary motor cortex and motor evoked potentials were recorded from hand (FDI and ADM) and forearm (FCR) muscles at baseline and during observation of actions (grasping and writing) or images. Writing actions could be performed with healthy or dystonic movement patterns. Results showed a highly specific and reversed pattern of activation in the FDI muscle of the two groups. Differences between the two writing conditions were significantly opposite in the two groups: control subjects had higher activation during observation of the dystonic compared to the healthy action, whereas in patients observation of the healthy writing led to higher activation than the dystonic writing. This opposite corticospinal modulation might be explained by a different self-attribution of the observed actions in the two groups. PMID- 20837105 TI - Epileptic tolerance is associated with enduring neuroprotection and uncoupling of the relationship between CA3 damage, neuropeptide Y rearrangement and spontaneous seizures following intra-amygdala kainic acid-induced status epilepticus in mice. AB - Brief, non-harmful seizures can activate endogenous protective programmes which render the brain resistant to damage caused by prolonged seizure episodes. Whether protection in epileptic tolerance is long-lasting or influences the subsequent development of epilepsy is uncertain. Presently, we investigated the relationship between hippocampal pathology, neuropeptide Y rearrangement and spontaneous seizures in sham- and seizure-preconditioned mice after status epilepticus induced by intra-amygdala kainate. Seizure-induced neuronal death at 24 h was significantly reduced in the ipsilateral hippocampal CA3 and hilus of tolerance mice compared to sham-preconditioned animals subject to status epilepticus. Damage to the CA3-hilus remained reduced in tolerance mice 21 days post-status. In sham-preconditioned mice subject to status epilepticus correlative statistics showed there was a strong inverse relationship between CA3, but not hilar, neuron counts and the number of spontaneous seizures. A strong positive association was also found between neuropeptide Y score and spontaneous seizure count in these mice. In contrast, there was no significant association between spontaneous seizure count and CA3 neuron loss or neuropeptide Y rearrangement in the tolerance mice. These data show that tolerance-conferred neuroprotection is long-lasting and that tolerance disrupts the normal association between CA3 damage, synaptic rearrangement and occurrence of spontaneous seizures in this model. PMID- 20837106 TI - Inhibition of caspase-3-mediated apoptosis improves spinal cord repair in a regeneration-competent vertebrate system. AB - Teleost fish exhibit an excellent potential for structural and functional recovery after CNS lesions. The function of apoptosis in the process of regeneration remains controversial. While some studies have identified this type of cell death as essential for successful regeneration, other investigations have suggested some degree of functional improvement after inhibition of apoptosis. In the present study, we examined whether inhibition of apoptosis immediately after injury can improve spinal cord regeneration. As a model system, we used Apteronotus leptorhynchus, a regeneration-competent weakly electric fish. To inhibit apoptosis, we employed 2,2'-methylenebis (1,3-cyclohexanedione) (M50054), a compound that prevents caspase-3 activation. Administration of this apoptosis inhibitor led to a significant reduction in the numbers of apoptotic cells at 24 h, 5 days, and 30 days after the lesion. Using triple immunolabeling, we identified a significant reduction in the level of apoptosis at 5 and 30 days after the lesion among the following cellular categories: cells generated shortly after the lesion, existing neurons, and newly differentiated neurons. This reduced rate of apoptosis led to an increase in the relative number of differentiating and surviving neurons at both 5 and 30 days post-injury, compared to the control groups. Functional regeneration, as indicated by the recovery rate of the amplitude of the electric organ discharge (EOD), was significantly improved within the first 20 days after the lesion in the fish treated with M50054. Our data provide the first evidence that modulation of caspase-3 activation can significantly improve neuroregeneration and functional recovery in a regeneration-competent organism. PMID- 20837107 TI - Postnatal development enhances the effects of cholinergic inputs on recruitment threshold and firing rate of rat oculomotor nucleus motoneurons. AB - Changes in the electrophysiological and morphological characteristics of motoneurons (Mns) of the oculomotor nucleus during postnatal development have been reported, however synaptic modifications that take place concurrently with postnatal development in these Mns are yet to be elucidated. We investigated whether cholinergic inputs exert different effects on the recruitment threshold and firing rate of Mns during postnatal development. Rat oculomotor nucleus Mns were intracellularly recorded in brain slice preparations and separated in neonatal (4-7 postnatal days) and adult (20-30 postnatal days) age groups. Stimulation of the medial longitudinal fasciculus evoked a monosynaptic excitatory potential in Mns that was attenuated with atropine (1.5 MUM, a muscarinic antagonist). Mns were silent at their resting membrane potential, and bath application of carbachol (10 MUM, a cholinergic agonist) induced depolarization of the membrane potential and a sustained firing rate that were more pronounced in adult Mns. Pharmacological and immunohistochemical assays showed that these responses were attributable to muscarinic receptors located in the membrane of Mns. In addition, compared to control Mns, carbachol-exposed Mns exhibited a higher firing rate in response to the injection of the same amount of current, and a decrease in the current threshold required to achieve sustained firing. These latter effects were more pronounced in adult than in neonatal Mns. In conclusion, our findings suggest that cholinergic synaptic inputs are already present in neonatal Mns, and that the electrophysiological effects of such inputs on recruitment threshold and firing rate are enhanced with the postnatal development in oculomotor nucleus Mns. We propose that cholinergic input maturation could provide a greater dynamic range in adult Mns to encode the output necessary for graded muscle contraction. PMID- 20837108 TI - Purification and transfection of cochlear Schwann cells. AB - Schwann cells line nerve fibers in the peripheral nervous system (PNS) and synthesize myelin. In addition, they support neuronal survival, neurite growth and regeneration. In dissociated cultures of postnatal mouse spiral ganglia, regenerating neurites spontaneously associate with Schwann cells. However, the mechanisms and consequences of interactions between cochlear Schwann cells and spiral ganglion neurites have not been examined. Further, the similarities and differences between cochlear Schwann cells and other PNS Schwann cells have not been studied. Experiments to examine these questions will rely on the ability to purify and characterize cochlear Schwann cells. Here we present methods for purifying Schwann cells from postnatal mouse cochleas and for transfecting them with expression plasmids. Dissociated spiral ganglia were plated on poly-D lysine/laminin in medium containing neurotrophins, leukemia inhibitory factor (LIF), N2 supplement and serum and maintained for 5 days. Cells were harvested with trypsin/EDTA and subjected to an immuno-magnetic purification procedure. After 24 h in vitro, cultures were >85% Schwann cells. Nucleofection of purified Schwann cells with pMax-green fluorescent protein (pMax-GFP) plasmid, or with pEGFP-C-vimentin plasmid returned >45% transfection efficiency. These methods will allow the in-depth characterization of cochlear Schwann cells and an evaluation of their biochemical, functional, and genetic mechanisms that may promote neurite growth from the spiral ganglion. PMID- 20837109 TI - Nicotine-induced up regulation of alpha4beta2 neuronal nicotinic receptors is mediated by the protein kinase C-dependent phosphorylation of alpha4 subunits. AB - Sustained exposure to nicotine is well known to increase the cell surface density of alpha4beta2* neuronal nicotinic receptors both in vivo and in vitro, but the cellular mechanisms mediating this effect are equivocal. Using a pharmacological approach to investigate the effects of nicotine on receptor subunit expression and phosphorylation in SH-EP1 cells expressing human alpha4 and beta2 nicotinic receptor subunits, we have demonstrated that incubation with nicotine for 24 h increased the expression of immature and mature forms of both alpha4 and beta2 subunits in a concentration-dependent manner, and that inhibition of protein kinase C (PKC), but not cAMP-dependent protein kinase (PKA) inhibited the nicotine-induced increased expression of subunits. Incubation of cells with nicotine for 24 h also increased the phosphorylation of immature forms of alpha4 subunits similar to that induced by activation of either PKC or PKA. When cells were preincubated with nicotine, the PKC-mediated increased phosphorylation was inhibited; the PKA-mediated phosphorylation was unaltered. The phosphopeptide maps for immature alpha4 subunits following nicotine exposure or PKC activation were identical, and phosphoamino acid analyses indicated phosphorylation on serine residues only. Results indicate that nicotine-induced up regulation of alpha4beta2 neuronal nicotinic receptors involves a PKC-dependent mechanism and likely reflects the ability of nicotine to activate PKC, leading to the phosphorylation of immature alpha4 subunits, promoting subunit assembly and receptor maturation. Because up regulation of these receptors has been implicated to mediate tolerance, locomotor sensitization and addiction to nicotine, results identify a potential new target for modulating the effects of nicotine on the brain. PMID- 20837110 TI - Two new benzofuran derivatives with anti-inflammatory activity from Liriope spicata var. prolifera. AB - Two new benzofuran derivatives, 2-(4'-hydroxybenzyl)-5,6-methylenedioxy benzofuran (1) and 2-(4'-hydroxybenzoyl)-5,6-methylenedioxy-benzofuran (2), along with 8 known compounds were isolated from 60% EtOH extract of the fibrous roots of Liriope spicata var. prolifera. Their structures were elucidated on the basis of extensive spectroscopic analysis. In an in vitro bioactive assay, the two new benzofuran derivatives showed anti-inflammatory activity. Compounds 1 and 2 exhibited significant inhibitory activity against neutrophil respiratory burst stimulated by phorbol 12-myristate 13-acetate (PMA) with IC(50) value of 4.15 +/- 0.07 and 5.96 +/- 0.37 MUM, respectively. PMID- 20837111 TI - Identifying botanical mechanisms of action. AB - The biological mechanism of action for any botanical extract is a necessary part of discovery to determine pharmacological use and safety. Interestingly, many activities that are governed by endogenous compounds are not fully understood making the characterization of mechanisms elusive. For example, phytoestrogens are being consumed for menopausal symptoms while the biological action of estradiol are still being investigated. Therefore, long term efficacy and safety issues are a challenge in the field. As new activities are associated with new biological pathways, an important component of therapeutic discovery will need to be the re-evaluation of negative or less active natural products to determine their relative use as medicines. PMID- 20837112 TI - Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale). AB - Ginger roots have been used to treat inflammation and have been reported to inhibit cyclooxygenase (COX). Ultrafiltration liquid chromatography mass spectrometry was used to screen a chloroform partition of a methanol extract of ginger roots for COX-2 ligands, and 10-gingerol, 12-gingerol, 8-shogaol, 10 shogaol, 6-gingerdione, 8-gingerdione, 10-gingerdione, 6-dehydro-10-gingerol, 6 paradol, and 8-paradol bound to the enzyme active site. Purified 10-gingerol, 8 shogaol and 10-shogaol inhibited COX-2 with IC(50) values of 32 MUM, 17.5 MUM and 7.5 MUM, respectively. No inhibition of COX-1 was detected. Therefore, 10 gingerol, 8-shogaol and 10-shogaol inhibit COX-2 but not COX-1, which can explain, in part, the anti-inflammatory properties of ginger. PMID- 20837113 TI - History and overview of DSHEA. AB - The Dietary Supplement Health and Education Act (DSHEA), enacted in 1994, had two primary goals: to ensure continued consumer access to a wide variety of dietary supplements, and to provide consumers with more information about the intended use of dietary supplements. It accomplished these goals, and more, without changing the fundamental regulatory status of dietary supplements as a category of foods. This article explores the history and reasoning behind the major provisions of the Act and reflects on the impact of each during 15 years of experience under DSHEA. PMID- 20837114 TI - Factors influencing the temporal patterns of dyadic behaviours and interactions between domestic cats and their owners. AB - Human-cat dyads may be similar in interaction structure to human dyads because many humans regard their cats as being social companions. Consequently, we predict that dyadic structure will be contingent on owner and cat personalities, sex, and age as well as duration of cohabitation of the partners. Forty owner-cat dyads were visited in their homes, on four occasions, during which their behaviours and interactions were video-taped. Behaviour was coded from tape and was analysed for temporal (t)-patterns using Theme (Noldus; Magnusson, 1996). Owner personality was assessed using the NEO-FFI. Five cat personality axes were identified by Principal Component Analysis (PCA) based on observer-rated items and on coded behaviours. We found that the higher the owner in neuroticism, the fewer t-patterns occurred per minute. The higher the owner in extraversion, the higher was the number of non-overlapping patterns per minute. The more "active" the cat, the fewer non-overlapping patterns occurred per minute, but the higher was the event type complexity. The older the cat, the lower was dyadic event type complexity. We suggest that basic temporal structures similar to those of human cat dyads may also be found in other long-term and complex dyadic relationships, including those between humans. PMID- 20837115 TI - Regulation of LPCAT3 by LXR. AB - In this work we analyzed the transcriptome profiles of chicken hepatoma cells (LMH) in response to T0901317, a pharmacological agonist of the liver X receptor (LXR). Through an in silico search for LXRE (LXR response element) consensus sequences in the promoter of genes whose expression was shown to be sensitive to TO901317, we identified a LXRE in the promoter of the LPCAT3 (lysophosphatidylcholine acyltransferase 3). This motif is highly conserved between species. We further investigated the regulation of this gene and showed that the expression of LPCAT3 was induced both in chicken and human hepatoma cells (LMH and HuH-7, respectively) in response to T0901317. Transactivation and electrophoretic mobility shift assays allowed us to locate a functional LXRE in the chicken LPCAT3 promoter. Altogether these data evidence for the first time that the chicken LPCAT3 gene is a direct target of LXR and therefore suggest a new role for LXR in phospholipid homeostasis. PMID- 20837116 TI - Angiotensin-(1-7) ameliorates myocardial remodeling and interstitial fibrosis in spontaneous hypertension: role of MMPs/TIMPs. AB - Angiotensin-(1-7) displays antihypertensive and antiproliferative properties although its effect on cardiac remodeling and hypertrophy in hypertension has not been fully elucidated. The present study was designed to examine the effect of chronic angiotensin-(1-7) treatment on myocardial remodeling, cardiac hypertrophy and underlying mechanisms in spontaneous hypertension. Adult male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were treated with or without angiotensin-(1-7) or the angiotensin-(1-7) antagonist A-779 for 24 weeks. Mean arterial pressure, left ventricular geometry, expression of the hypertrophic markers ANP and beta-MHC, collagen contents (type I and III), collagenase (MMP-1), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of MMPs-1 (TIMP-1) were evaluated in WKY and SHR rats with or without treatment. Our data revealed that chronic angiotensin-(1-7) treatment significantly suppressed hypertension, left ventricular hypertrophy, expression of ANP and beta-MHC as well as myocardial fibrosis in SHR rats, the effects of which were nullified by the angiotensin-(1-7) receptor antagonist A-779. In addition, angiotensin-(1-7) treatment significantly counteracted hypertension-induced changes in the mRNA expression of MMP-2 and TIMP-1 and collagenase activity, the effects of which were blunted by A-779. In vitro study revealed that angiotensin-(1-7) directly increased the activity of MMP-2 and MMP-9 while decreasing the content of TIMP-1 and TIMP-2. Taken together, our results revealed a protective effect of angiotensin-(1-7) against cardiac hypertrophy and collagen deposition, which may be related to concerted changes in MMPs and TIMPs levels. These data indicated the therapeutic potential of angiotensin-(1-7) in spontaneous hypertension induced cardiac remodeling. PMID- 20837117 TI - Mercury modulates the CYP1A1 at transcriptional and posttranslational levels in human hepatoma HepG2 cells. AB - Aryl hydrocarbon receptor (AhR) ligands such as 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) and metals, such as mercury (Hg(2+)), are environmental co contaminants and their molecular interaction may disrupt the coordinated regulation of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1). Therefore, we examined the effect of co-exposure to Hg(2+) and TCDD on the expression of the CYP1A1 in HepG2 cells. Our results showed that Hg(2+) significantly inhibited the TCDD-mediated induction of CYP1A1 at the mRNA, protein, and catalytic activity levels. At the transcriptional level, co-exposure to Hg(2+) and TCDD significantly decreased the TCDD-mediated induction of AhR dependent luciferase reporter gene expression. Moreover, Hg(2+) did not affect CYP1A1 mRNA stability, while decreasing its protein half-life, suggesting the involvement of a posttranslational mechanism. Importantly, Hg(2+) increased the expression of heme oxygenase-1 (HO-1), a rate limiting enzyme in heme degradation, which coincided with further decrease in the CYP1A1 catalytic activity levels. Upon using a competitive HO-1 inhibitor, tin mesoporphyrin, heme precursor, hemin, or transfecting the HepG2 cells with siRNA for HO-1 there was a partial restoration of the inhibition of TCDD-mediated induction of CYP1A1 catalytic activity. In conclusion, we demonstrate that Hg(2+) down-regulates the expression of CYP1A1 at the transcriptional and posttranslational levels in HepG2 cells. In addition, HO-1 is involved in the modulation of CYP1A1 at the posttranslational level. PMID- 20837118 TI - Reduced cardiovascular alterations of tartar emetic administered in long circulating liposomes in rats. AB - Trivalent antimonial drugs, including tartar emetic (TA), are known to induce important cardiotoxicity observed by electrocardiographic abnormalities. Liposome encapsulation was found to reduce the overall acute toxicity of TA. The present work investigated the cardiovascular parameters alterations of rats submitted to the treatment with free and encapsulated TA in long-circulating liposomes. Liposomes were made using lipids DSPC, DSPE-PEG and cholesterol. The cardiovascular signals, electrocardiogram (ECG) and arterial blood pressure (AP), were recorded from anaesthetized Wistar rats after intravenous (IV) administration of a single specially high dose (17 mg/kg) of TA in liposomes and in free form. The IV administration of TA solution caused significant increase of QT interval of ECG and significant reduction of AP when compared to the control group. These alterations were not observed when liposomes TA were administered and the profile of ECG and AP data was quite similar to the control groups. In conclusion, a liposomal formulation of TA showed a reduced cardiotoxic profile for TA when compared to the free form. PMID- 20837120 TI - Susceptibility to the cytogenetic effects of dichloromethane is related to the glutathione S-transferase theta phenotype. AB - The carcinogenicity of dichloromethane (DCM) has been demonstrated by mutagenicity studies using bacteria and yeasts and using animal bioassays. Epidemiological studies indicate that exposure to DCM increases the incidences of liver and pancreas cancers. In the present study, we determine whether DCM generates DNA damage in human peripheral blood mononuclear cells (PBMCs) and whether that process depends on glutathione S-transferase theta (GSTT)-1 activity. GSTT1 is one of the enzymes that biotransforms DCM. To this end, PBMC cultures from healthy men were treated with DCM (15-500 ppm) for 72 h. Cell cultures were harvested and processed according to classical cytogenetic techniques. The frequency of sister chromatid exchanges (SCEs), the mitotic index (MI), the cell proliferation kinetic (CPK) value, and the level of GSTT1 activity were determined. DCM exposure decreased the MI in a dose-dependent manner in all individuals tested (20). The CPK value decreased from 125 ppm DCM, and the SCEs frequency increased from 60 ppm DCM. A significantly different response was observed when the group of individuals with low GSTT1 enzymatic activity (4 individuals), the group with medium GSTT1 activity (10 individuals), and the group of individuals with high GSTT1 enzymatic activity (6 individuals) were compared (0.077 +/- 0.0124, 0.325 +/- 0.0269, and 7.365 +/- 1.3474 nmol HCOH/min/mg protein, respectively). These differences were reflected in the amount of change for all of the evaluated cytogenetic parameters (p<0.05, ANOVA) and indicated a clear susceptibility to DCM genotoxic effects related to GSTT1 activity because the cytogenetic effects were directly related to the GSTT1 specific activity. DCM was highly cytotoxic in PBMCs, even at doses within the safety range. Due to this toxicity, a review of the maximal limits for occupational exposure to DCM is advised. PMID- 20837119 TI - SPARC gene expression is repressed in human urothelial cells (UROtsa) exposed to or malignantly transformed by cadmium or arsenite. AB - SPARC belongs to a class of extracellular matrix-associated proteins that have counteradhesive properties. The ability of SPARC to modulate cell-cell and cell matrix interactions provides a strong rationale for studies designed to determine its expression in cancer. The objective of this study was to determine if SPARC expression was altered in cadmium (Cd(2+)) and arsenite (As(3+)) induced bladder cancer and if these alterations were present in archival specimens of human bladder cancer. The expression of SPARC was determined in human parental UROtsa cells, their Cd(2+) and As(3+) transformed counterparts and derived tumors, and in archival specimens of human bladder cancer using a combination of real time reverse transcriptase polymerase chain reaction, Western blotting, immunofluorescence localization and immunohistochemical staining. It was demonstrated that SPARC expression was down-regulated in Cd(2+) and As(3+) transformed UROtsa cells. In addition, the malignant epithelial component of tumors derived from these cell lines were also down-regulated for SPARC expression, but the stromal cells recruited to these tumors was highly reactive for SPARC. This finding was shown to translate to specimens of human bladder cancer where tumor cells were SPARC negative, but stromal cells were positive. Acute exposure of UROtsa cells to both cadmium and arsenite reduced the expression of SPARC through a mechanism that did not involve changes in DNA methylation or histone acetylation. These studies suggest that environmental exposure to As(3+) or Cd(2+) can alter cell-cell and cell-matrix interactions in normal urothelial cells through a reduction in the expression of SPARC. The SPARC associated loss of cell-cell and cell-matrix contacts may participate in the multi-step process of bladder carcinogenesis. PMID- 20837121 TI - Characterization of potent anticholinesterase plant oil based microemulsion. AB - In the present study, essential oils of three edible Thai plants, Cymbopogon citratus (Gramineae), Citrus hystrix (Rutaceae) and Zingiber cassumunar (Zingiberaceae) were comparatively tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities using Ellman's colorimetric method. C. citratus oil exhibited the highest activity with IC(50) values of 0.34+/-0.07MUl/ml and 2.14+/-0.18MUl/ml against BChE and AChE activity, respectively. It was further investigated whether microemulsions of this oil could be obtained. The effects of type of surfactant and co-surfactant as well as pH and ionic strength on the phase behavior of the oil/water system were investigated. Brij 97, Triton X-114, Tween 20 and Tween 85 were employed as surfactant whereas ethanol and hexanol were used as cosurfactants. The size analysis, electrical conductivity measurements and cholinesterase inhibition assays were done in selected microemulsion. The results revealed that the type and concentration of surfactant and co-surfactant exhibited a distinct influence on the C. citratus oil microemulsions. Moreover, the inhibitory activities of the microemulsion formulation were remarkable. PMID- 20837123 TI - Ethnobotanical study on traditional uses of wild medicinal plants in Prokletije Mountains (Montenegro). AB - AIM OF THE STUDY: The main objectives were to collect information on the use of wild growing medicinal plants by local people living in high mountain region of Montenegro and conduct local botanical and ecological surveys. Active ingredients of plant species officinal in European Pharmacopoeia 6.0 (Ph. Eur. 6.0) were studied and we assessed possibilities for commercial exploitation for local economic development. MATERIALS AND METHODS: The 75 people that were interviewed (40-82 years old) identified 94 species for treatment of various human ailments. For each named species, the following elements are provided: botanical name, family, part(s) used, medicinal use and perceived property, listing in published pharmacopoeias, the relative abundance of each species and locality where the plant was collected. Chemical analyses were done according to prescriptions of Ph. Eur. 6.0 in order to estimate potential commercial use of native plants. RESULTS AND CONCLUSION: The most common in traditional usage were Rosaceae (11 species) making 11.7%, Asteraceae (10 species) 10.6% and Lamiaceae (7 species) 7.4%. From 94 species reported, 35 (37.2%) are officinal in Ph. Eur. 6.0 and 12 in national pharmacopoeias (12.8%). Aerial parts were mostly used (43.6%). The most frequently reported medicinal uses were for treating gastrointestinal (57.4%) and respiratory diseases (41.5%). PMID- 20837122 TI - Tresyl-based conjugation of protein antigen to lipid nanoparticles increases antigen immunogenicity. AB - The present studies were aimed at investigating the engineering of NPs with protein-conjugated-surfactant at their surface. In order to increase the immunogenicity of a protein antigen, Brij 78 was functionalized by tresyl chloride and then further reacted with the primary amine of the model proteins ovalbumin (OVA) or horseradish peroxide (HRP). The reaction yielded Brij 78-OVA and Brij 78-HRP conjugates which were then used directly to form NP-OVA or NP-HRP using a one-step warm oil-in-water microemulsion precursor method with emulsifying wax as the oil phase, and Brij 78 and the Brij 78-OVA or Brij 78-HRP conjugate as surfactants. Similarly, Brij 700 was conjugated to HIV p24 antigen to yield Brij 700-p24 conjugate. The utility of these NPs for enhancing the immune responses to protein-based vaccines was evaluated in vivo using ovalbumin (OVA) as model protein and p24 as a relevant HIV antigen. In separate in vivo studies, female BALB/c mice were immunized by subcutaneous (s.c.) injection with NP-OVA and NP-p24 formulations along with several control formulations. These results suggested that with multiple antigens, covalent attachment of the antigen to the NP significantly enhanced antigen-specific immune responses. This facile covalent conjugation and incorporation method may be utilized to further incorporate other protein antigens, even multiple antigens, into an enhanced vaccine delivery system. PMID- 20837124 TI - Validity and reliability of a Severity of Dependence Scale for khat (SDS-khat). AB - AIMS OF THE STUDY: (1) To assess psychological khat dependence and (2) to assess the validity and reliability of the Severity Dependence Scale (Gossop et al., 1995) amended for khat use (SDS-khat), in a sample of UK-resident male adult Yemeni khat chewers. MATERIALS AND METHODS: A cross-sectional study using a face to face structured interview schedule was conducted amongst purposively sampled UK-resident adult Yemeni male khat chewers, aged 18 years and above, selected during random visits to places of khat sale. A factor analysis with principal components extraction was conducted to explore the construct validity of the proposed SDS-khat. Reliability of the proposed scale was assessed using test retest and internal reliability tests. The concurrent validity of the proposed SDS-khat was assessed in relation to individual measures and a composite index of khat chewing behaviours using univariate analyses. RESULTS: Two hundred and four Yemeni male adult khat chewers were interviewed. The mean score of the proposed SDS-khat was 5.52 (SD +/-4.03). Forty nine percent of respondents (95% CI=43-55%) with <=5 scores were more likely not psychologically dependent. A single factor, uni-dimensional solution identifying the five items making up the scale accounted for 52.33% of variance. The internal reliability was good (Cronbach's alpha coefficient=0.76) and the test retest intraclass correlation coefficient (ICC) was 0.93 (95% CI=0.80-0.97). Many individual aspects of the khat chewing were significantly related to the scale. Assessment of the proposed SDS-khat's concurrent validity with individual items of khat chewing identified several significant relationships (p<=0.05) whilst the composite index of khat behaviour also identified a significant relationship (OR=14.40, 95% CI=6.71-30.89). The proposed SDS-khat also correlated with self-reported reasons for khat chewing (p<=0.001, OR=3.54; 95% CI=1.80-6.96). CONCLUSIONS: In this sample of Yemeni khat chewers the SDS-khat is recommended as a valid and reliable research tool for measuring psychological dependence upon khat. Further validation in other samples is indicated. PMID- 20837125 TI - Anticonvulsant activity of aqueous root extract of Ficus religiosa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ficus religiosa Linn is frequently used for the treatment of nervous disorders among Pawara tribe of the Satpuda range, India. AIM OF THE STUDY: This study aimed to investigate the anticonvulsant activity of the aqueous aerial root extract of Ficus religiosa in chemoconvulsant-induced seizures in mice. MATERIALS AND METHODS: The anticonvulsant activity of the extract (25, 50 and 100 mg/kg, p.o.) was investigated in strychnine-, pentylenetetrazole-, picrotoxin- and isoniazid-induced seizures in mice. Rat ileum and fundus strip preparations were used to study the effect of the extract on acetylcholine (Ach)- and serotonin (5-HT)-induced contractions, respectively. RESULTS: The extract showed no toxicity and protected the animals in the strychnine and pentylenetetrazole tests in a dose-dependent manner. Its effect in the picrotoxin and isoniazid tests, however, was less potent. The extract also exhibited dose-dependent potentiation of Ach in rat ileum but failed to potentiate the effect of 5-HT in rat fundus strip preparation. CONCLUSIONS: The results suggest that an orally administered aqueous root extract of Ficus religiosa has dose-dependent and potent anticonvulsant activities against strychnine- and pentylenetetrazole-induced seizures. The observed activities may be ascribed to the appreciable content of zinc and magnesium in the extract. PMID- 20837126 TI - Ethnopharmacological survey of medicinal plants in Nor-Yauyos, a part of the Landscape Reserve Nor-Yauyos-Cochas, Peru. AB - AIM OF THE STUDY: To collect, analyze and evaluate the ethnopharmacologic knowledge in Nor-Yauyos in order to protect it. This paper reports the results of an ethnopharmacological survey on the uses of medicinal plants by inhabitants of the Andean region Nor-Yauyos, Peru. In this region one surviving ethnic group, the Jaqaru-Quichuas, has been identified. METHODOLOGY: Field work was concluded between October 1999 and March 2000, using semi-structured questionnaire and participant observation as well as transects walks in wild herbal plant collection. Interviews with 68 informants (mean age: 54; 100% men, 0% women) were performed in 12 farmers' communities: Huancaya, Vilca, Vitis, Miraflores, Pinos, Carania, San Lorenzo De Alis, Santa Rosa De Tinco, Tomas, Huancachi, Laraos and Huantan. RESULTS: 63 species of plants belonging to 29 families were reported. More than a half of reported plants were native, endemic of the studied area. Leaves and their mixtures were the most (67.26%) commonly used plant part. Most of the remedies were prepared in infusion, and 90.08% were administered orally. Most treated disorders were the gastrointestinal (18.59%) and respiratory ones (18.22%). CONCLUSIONS: 6 species (9.52%) without pharmacological references in international scientific literature, 21 species (33.33%) with 1-2 references, 16 species (25.40%) with 3-6 references, and 20 species (31.75%) that have been already widely studied were found. PMID- 20837127 TI - Involvement of p38 MAPK signaling pathway in the anti-melanogenic effect of San bai-tang, a Chinese herbal formula, in B16 cells. AB - AIM OF THE STUDY: San-bai-tang (SBT), a Chinese herbal formula, is traditionally used as a skin whitener in China. In our previous screening assays, SBT was identified as an effective tyrosinase inhibitor. In this study, we aim to investigate the anti-melanogenic effect and mechanisms of SBT in B16 cells. MATERIALS AND METHODS: Cell viability was examined by the MTT assay. Cellular tyrosinase activity and melanin content were determined using spectrophotographic methods. Protein expression was analyzed by immunoblotting. RESULTS: SBT inhibited tyrosinase activity with an IC(50) of 215.6 +/- 10.3 MUg/ml, and decreased cellular melanin content with an IC(50) of 254.8 +/- 14.5 MUg/ml at 48 h. MTT assay demonstrated that 48-h SBT (50-400 MUg/ml) treatment did not show obvious cytotoxicity. Immunoblot analysis showed that SBT (100, 200 or 400 MUg/ml) treatment for 48 h down-regulated the expression levels of phosphorylated p38, MITF, tyrosinase, TRP-1 and TRP-2 in a dose-dependent manner. CONCLUSIONS: SBT inhibited melanogenesis in B16 cells, and suppression of p38 MAPK signaling pathway contributed to the anti-melanogenic effect of SBT by down-regulating the expression of MITF and melanogenic enzymes. These novel findings demonstrated the anti-melanogenic effect and mechanisms of SBT, and provide pharmacological basis for the traditional use of SBT. PMID- 20837129 TI - Enzymatic and whole cell catalysis: finding new strategies for old processes. AB - The use of enzymes and whole bacterial cells has allowed the production of a plethora of compounds that have been used for centuries in foods and beverages. However, only recently we have been able to master techniques that allow the design and development of new biocatalysts with high stability and productivity. Rational redesign and directed evolution have lead to engineered enzymes with new characteristics whilst the understanding of adaptation mechanisms in bacterial cells has allowed their use under new operational conditions. Bacteria able to thrive under the most extreme conditions have also provided new and extraordinary catalytic processes. In this review, the new tools available for the improvement of biocatalysts are presented and discussed. PMID- 20837128 TI - Extended exposure to dietary melatonin reduces tumor number and size in aged male mice. AB - Several sets of male mice were given dietary melatonin over a series of experiments performed during a nine year period. Overall, melatonin-supplemented mice aged >=26 months at sacrifice had significantly fewer tumors with lower severity than similarly aged control animals. The studies were originally designed to explore the potential of this agent for reducing the rate of onset of some genetic indices of brain aging. When these animals were sacrificed they were routinely examined for overt evidence of tumors and when these were found, a note was made of their occurrence, and of their size. Tumors are commonly found during senescence of several strains of mice. Since tumorigenesis was not the original intent of the study, these observations were recorded but not pursued in greater detail. In this report, these data have now been collated and summarized. This analysis has the disadvantage that tumor origin and morphology were not recorded. However, the study also has the advantage of being conducted over an extended period of time with many groups of animals. In consequence, many extraneous factors, which could be potential confounders, such as seasonal or dietary variations, are unlikely to have interfered with the analysis. The use of more than one mouse strain strengthens the possibility that the findings may have general relevance. Both aged and young animals were included in the original experiments but the tumor incidence in animals younger than 25 months was very low. PMID- 20837130 TI - Variable responses of different human cancer cells to the lichen compounds parietin, atranorin, usnic acid and gyrophoric acid. AB - One of the ways for searching for potentially new anti-cancer drugs is the testing of various naturally synthesized compounds. Lichens are a source of unique chemical agents of which some have already been proved to be effective against various cancer in vitro models. Our study reports on the sensitivity of up to nine human cancer cell lines (A2780, HeLa, MCF-7, SK-BR-3, HT-29, HCT-116 p53(+/+), HCT-116 p53(-/-), HL-60 and Jurkat) to the anti-proliferative/cytotoxic effects of four typical secondary metabolites of lichens (parietin, atranorin, usnic acid and gyrophoric acid). Variations in the dynamics of tumour cell line populations were evaluated by the MTT, clonogenic and viability assays, cell proliferation and detachment, cell cycle transition and apoptotic nuclear morphology, thereby confirming their concentration- and time-dependent cytotoxicity. However, in comparison with parietin and gyrophoric acid, the suppression of viability and cell proliferation by usnic acid or atranorin was found to be more efficient at equitoxic doses and correlated more strongly with an increased number of floating cells or a higher apoptotic index. Moreover, the analysis of cell cycle distribution also revealed an accumulation of cells in S phase. This study has confirmed a differential sensitivity of cancer cell lines to lichen secondary metabolites. PMID- 20837131 TI - In vitro effect of aspartame in angiogenesis induction. AB - Aspartame (APM) is the most widely used artificial sweetener and is added to a wide variety of foods, beverages, drugs, and hygiene products. In vitro and in vivo tests have reported contradictory data about APM genotoxicity. We evaluated the angiogenic effect of APM in an in vitro model using blood vessel development assay (Angio-Kit), cultured endothelial cells and fibroblasts. The release of IL 6, VEGF-A, and their soluble receptors sIL-R6 and sVEGFR-2 were determined over time in the conditioned medium of the Angio-Kit system, endothelial cells and cell lines with fibroblast properties after APM treatment. Reactive oxygen species (ROS) formation, cell viability, and stimulation of the extracellular signal-regulated kinases (erk1/2) and protein p38 were also evaluated. Exposure to APM induced blood vessel formation. ROS production was observed in endothelial cells after APM treatment, which was associated with a slight cell cytotoxicity. Neither intracellular ROS formation nor cell death was observed in fibroblasts. APM increases the levels of inflammatory mediator IL-6, VEGF and their soluble receptors released from endothelial cells into the medium. APM treatment induces VEGF-pathway activation by erk1/2 and p38 phosphorylation. APM at low doses is an angiogenic agent that induces regenerative cytokine production leading to the activation of MAPKs and resulting in the formation of new blood vessels. PMID- 20837132 TI - Acute ethanol exposure disrupts actin cytoskeleton and generates reactive oxygen species in c6 cells. AB - Central nervous system dysfunctions are among the most significant effects of exposure to ethanol and the glial cells that play an important role in maintaining neuronal function, are extremely involved with these effects. The actin cytoskeleton plays a crucial role in a wide variety of cellular functions, especially when there is some injury. Therefore the aim of the present study was to analyze the short-term effects of ethanol (50, 100 and 200 mM) on the cytoskeleton of C6 glioma cells. Here we report that acute ethanol exposure profoundly disrupts the actin cytoskeleton in C6 cells decreasing stress fiber formation and downregulating RhoA and vinculin immunocontent. In contrast, microtubule and GFAP networks were not altered. We further demonstrate that anti oxidants prevent ethanol-induced actin alterations, suggesting that the actions of ethanol on the actin cytoskeleton are related with generation of reactive oxygen species (ROS) in these cells. Our results show that ethanol at concentrations described to be toxic to the central nervous system was able to target the cytoskeleton of C6 cells and this effect could be related with increased ROS generation. Therefore, we propose that the dynamic restructuring of the cytoskeleton of glial cells might contribute to the response to the injury provoked by binge-like ethanol exposure in brain. PMID- 20837133 TI - CD62L(high) Treg cells with superior immunosuppressive properties accumulate within the CNS during remissions of EAE. AB - The role of regulatory T cell populations within the CNS in the regulation of CNS autoimmunity is controversial. We show that during recovery from relapsing remitting experimental autoimmune encephalomyelitis, regulatory T cells accumulate within the CNS that express high levels of CD62L. These CD62L(high) Treg cells express increased amounts of CTLA-4, ICOS and TGF-beta and are more potent than CD62L(low) Treg cells in suppressing proliferation and inducing apoptosis in effector T cells. CD62L(high) Treg cells thus represent a population of Treg cells that display superior immunosuppressive properties and accumulate in the CNS during recovery from CNS-autoimmunity. PMID- 20837134 TI - Differential susceptibility to nitric oxide-evoked apoptosis in human inflammatory cells. AB - Apoptosis of neutrophils and their subsequent phagocytosis is critical to the successful resolution of inflammation. During inflammation, activated inflammatory cells generate reactive oxygen and nitrogen species, including nitric oxide (NO) and superoxide anion (O(2)(*-)), which rapidly combine to generate peroxynitrite (ONOO(-)). NO and ONOO(-) are proapoptotic in human neutrophils. This study examines the effects of NO and ONOO(-) on caspase activation and mitochondrial permeability in human neutrophils and determines the ability of these species to evoke apoptosis in human monocyte-derived macrophages (MDMs). NO or ONOO(-) release from donor compounds was characterized by electrochemistry and electron paramagnetic resonance. Neutrophils and MDMs isolated from the peripheral blood of healthy volunteers were exposed to NO or ONOO(-) before analysis of apoptosis by caspase activation, mitochondrial permeability, and annexin V binding. Both NO and ONOO(-) induced apoptosis via rapid activation of caspases 2 and 3 in neutrophils. In contrast, only ONOO(-) promoted apoptosis in MDMs, whereas a variety of NO donors were ineffective at inducing apoptosis in this cell type. We propose that human macrophages are refractory to NO-stimulated apoptosis in order that they persist long enough within the inflammatory focus to phagocytose apoptotic neutrophils, thereby ensuring successful resolution of inflammation. PMID- 20837135 TI - Cytoplasmic tail of D1 dopaminergic receptor differentially regulates desensitization and phosphorylation by G protein-coupled receptor kinase 2 and 3. AB - Herein, we investigate the differential D1 dopaminergic receptor (D1R) regulation by G protein-coupled receptor kinase (GRK) 2 and 3 using two truncated receptors lacking the distal (Delta425) and distal-central (Delta379) cytoplasmic tail (CT) regions. We first show the association between D1R and GRKs in co-transfected cells and rat striatum. Our studies further indicate that deletion of distal CT region of D1R does not alter the association between receptor and GRK2. Meanwhile, removal of both distal and central CT regions culminates in a drastic increase in the basal association between Delta379 and GRK2 relative to D1R and Delta425. Interestingly, CT truncations have no effect on the basal and DA induced association of receptors with GRK3. Furthermore, we demonstrate that desensitization of D1R is considerably more robust in cells expressing GRK3. Notably, the robust GRK3-induced D1R desensitization is not attenuated by CT deletions. However, GRK2-induced Delta425 desensitization is not detectable whereas we unexpectedly find that Delta379 desensitization is similar to GRK2 induced D1R desensitization. GRK2 and GRK3-dependent desensitization of wild type D1R is not linked to differences in the extent of DA-induced receptor phosphorylation. Moreover, our studies show that GRK2-induced D1R phosphorylation is only modulated by deletion of distal CT region while distal and central CT regions control GRK3-induced D1R phosphorylation. Intriguingly, dopamine-induced Delta379 phosphorylation by GRK3 was significantly lower than receptor phosphorylation in cells harboring Delta379 alone or Delta379 and GRK2. Overall, our study suggests an intricate interplay between CT regions of D1R in differentially regulating receptor responsiveness by GRK2 and GRK3. PMID- 20837136 TI - E2F1 inhibits MDM2 expression in a p53-dependent manner. AB - MDM2 expression is down-regulated upon E2F1 over-expression, but the mechanism is not well defined. In the current study, we found that E2F1 inhibits MDM2 expression by suppressing its promoter activity. Although E2F1 binds to the MDM2 promoter, the inhibitory effect of E2F1 on the MDM2 promoter does not require the direct binding. We demonstrate that E2F1 inhibits MDM2 promoter activity in a p53 dependent manner. Knockdown of p53 in U2OS cells impairs the inhibitory effect of E2F1 on the MDM2 promoter. Consistent with this observation, E2F1 does not inhibit MDM2 promoter activity in p53-deficient H1299 cells, and the inhibition is restored when p53 is expressed exogenously. Both E2F1 and p53 are up-regulated after DNA damage stimulation. We show that such stimulation induces E2F1 to inhibit MDM2 promoter activity and promote p53 accumulation. Furthermore, inhibition of MDM2 by E2F1 promotes E2F1 induced apoptosis. These data suggest that E2F1 regulates the MDM2-p53 pathway by inhibiting p53 induced up-regulation of MDM2. PMID- 20837137 TI - TAK1 lysine 158 is required for TGF-beta-induced TRAF6-mediated Smad-independent IKK/NF-kappaB and JNK/AP-1 activation. AB - Lys63-linked TAK1 polyubiquitination plays an essential role in the regulation of TAK1 activation. TRAF6-mediated Lys63-linked polyubiquitylation of TAK1 has been shown to be required for TGF-beta-induced TAK1 activation. However, it remains unclear which lysine residue on TAK1 is TRAF6-mediated TAK1 polyubiquitination acceptor site in TGF-beta signaling pathway. Here we report that lysine 158 on TAK1 is required for TGF-beta-induced TRAF6-mediated TAK1 polyubiquitination and TAK1-mediated IKK, JNK and p38 activation. Notably, in contrast to TAK1 wild-type and K34R mutant, TAK1 K158R mutant co-overexpression with TAB1 failed to induce Lys63-linked TAK1 polyubiquitination. TRAF6-induced K63-linked TAK1 polyubiquitination was blocked by TAK1 K158R mutation, but not by K34R mutation. Furthermore, TGF-beta-induced TAK1 polyubiquitination was inhibited by TAK1 K158R mutation, but not by K34R mutation in HeLa cells. Reconstitution of TAK1 deficient mouse embryo fibroblast cells with TAK1 wild-type, K158R mutant, or K34R mutant reveals that TAK1 lysine 158 residue is required for TGF-beta-induced IKK, p38 and JNK activation. PMID- 20837138 TI - Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells. AB - Receptor tyrosine kinases of the Eph family play multiple roles in the physiological regulation of tissue homeostasis and in the pathogenesis of various diseases, including cancer. The EphA2 receptor is highly expressed in most cancer cell types, where it has disparate activities that are not well understood. It has been reported that interplay of EphA2 with oncogenic signaling pathways promotes cancer cell malignancy independently of ephrin ligand binding and receptor kinase activity. In contrast, stimulation of EphA2 signaling with ephrin A ligands can suppress malignancy by inhibiting the Ras-MAP kinase pathway, integrin-mediated adhesion, and epithelial to mesenchymal transition. Here we show that ephrin-A1 ligand-dependent activation of EphA2 decreases the growth of PC3 prostate cancer cells and profoundly inhibits the Akt-mTORC1 pathway, which is hyperactivated due to loss of the PTEN tumor suppressor. Our results do not implicate changes in the activity of Akt upstream regulators (such as Ras family GTPases, PI3 kinase, integrins, or the Ship2 lipid phosphatase) in the observed loss of Akt T308 and S473 phosphorylation downstream of EphA2. Indeed, EphA2 can inhibit Akt phosphorylation induced by oncogenic mutations of not only PTEN but also PI3 kinase. Furthermore, it can decrease the hyperphosphorylation induced by constitutive membrane-targeting of Akt. Our data suggest a novel signaling mechanism whereby EphA2 inactivates the Akt-mTORC1 oncogenic pathway through Akt dephosphorylation mediated by a serine/threonine phosphatase. Ephrin-A1-induced Akt dephosphorylation was observed not only in PC3 prostate cancer cells but also in other cancer cell types. Thus, activation of EphA2 signaling represents a possible new avenue for anti-cancer therapies that exploit the remarkable ability of this receptor to counteract multiple oncogenic signaling pathways. PMID- 20837140 TI - Contribution of a tyrosine-based motif to cellular trafficking of wild-type and truncated NPY Y(1) receptors. AB - The human NPY Y(1) receptor undergoes fast agonist-induced internalization via clathrin-coated pits then recycles back to the cell membrane. In an attempt to identify the molecular determinants involved in this process, we studied several C-terminal truncation mutants tagged with EFGP. In the absence of agonist, Y(1) receptors lacking the last 32 C-terminal amino acids (Y(1)Delta32) are constitutively internalized, unlike full-length Y(1) receptors. At steady state, internalized Y(1)Delta32 receptors co-localize with transferrin, a marker of early and recycling endosomes. Inhibition of constitutive internalization of Y(1)Delta32 receptors by hypertonic sucrose or by co-expression of Rab5aS34N, a dominant negative form of the small GTPase Rab5a or depletion of all three isoforms of Rab5 indicates the involvement of clathrin-coated pits. In contrast, a truncated receptor lacking the last 42 C-terminal amino acids (Y(1)Delta42) does not constitutively internalize, consistent with the possibility that there is a molecular determinant responsible for constitutive internalization located in the last 10 amino acids of Y(1)Delta32 receptors. We show that the agonist independent internalization of Y(1)Delta32 receptors involves a tyrosine-based motif YXXPhi. The potential role of this motif in the behaviour of full-length Y(1) receptors has also been explored. Our results indicate that a C-terminal tyrosine-based motif is critical for the constitutive internalization of truncated Y(1)Delta32 receptors. We suggest that this motif is masked in full length Y(1) receptors which do not constitutively internalize in the absence of agonist. PMID- 20837139 TI - Identification of polycystin-1 and Galpha12 binding regions necessary for regulation of apoptosis. AB - Most patients with autosomal dominant polycystic kidney disease (ADPKD) harbor mutations in PKD1, the gene for polycystin-1 (PC1), a transmembrane protein with a cytoplasmic C-terminus that interacts with numerous signaling molecules, including Galpha12. The functions of PC1 and the mechanisms of cyst development leading to renal failure are complex. Recently, we reported that PC1 expression levels modulate activity of Galpha12-stimulated apoptosis (Yu et al., J. Biol. Chem. 2010 285(14):10243-51). Herein, a mutational analysis of Galpha12 and PC1 was undertaken to identify regions required for their interaction and ability to modulate apoptosis. A set of Galpha12 mutations with systematic replacement of six amino acids with NAAIRS was tested for binding to the PC1 C-terminus in GST pulldowns. Additionally, a series of deletions within the PC1 C-terminus was examined for binding to Galpha12. We identified 3 NAAIRS substitutions in Galpha12 that completely abrogated binding, and identified a previously described 74 amino acid Galphai/o binding domain in the PC1 C-terminus as necessary for Galpha12 interaction. The functional consequences of uncoupling PC1/Galpha12 binding were studied in apoptosis assays utilizing HEK293 cells with inducible PC1 overexpression. Galpha12 mutants deficient in PC1 binding were refractory to PC1 inhibition of Galpha12-stimulated apoptosis. Likewise, deletion of the Galpha12-interacting sequence from the PC1 cytoplasmic domain abrogated its inhibition of Galpha12-stimulated apoptosis. Based on the crystal structure of Galpha12, the PC1 interaction sites are likely to reside on exposed regions within the G protein helical domain. These structural details should facilitate the design of reagents to uncouple PC1/Galpha12 signaling in ADPKD. PMID- 20837141 TI - Cyclin D1 regulates p27(Kip1) stability in B cells. AB - p27(Kip1) is a cyclin-dependent kinase inhibitor that plays a critical role in regulating G(1)/S transition, and whose activity is, in part, regulated through interactions with D-type cyclins. We have generated the BD1-9 cell line, a BaF3 pro-B cells derivative in which cyclin D1 can be induced rapidly and reversibly by ponasterone A. The induction of cyclin D1 expression leads to a targeted p27(Kip1) accumulation in both cytoplasmic and nuclear compartments. But, only the p27(Kip1) form phosphorylated on serine 10 (pSer10-p27(Kip1)) accumulates in BD1-9 cells. We found that the binding of cyclin D1 and pSer10-p27(Kip1) prevents p27(Kip1) degradation by the cytoplasmic Kip1 ubiquitylation-promoting complex (KPC) proteosomic pathway. Importantly, the nuclear CDK2 activity which is crucial for G(1)/S transition is not altered by p27(Kip1) increase. Using siRNA techniques, we revealed that p27(Kip1) inhibition does not affect the distribution of BD1-9 cells in the different phases of the cell cycle. Our study demonstrates that aberrant cyclin D1 expression acts as a p27(Kip1) trap in B lymphocytes but does not induce p27(Kip1) relocation from the nucleus to the cytoplasm and does not modulate the G(1)/S transition. Since our cellular model mimics what observed in aggressive lymphomas, our data bring new insights into the understanding of their physiopathology. PMID- 20837142 TI - Lipid molecules induce the cytotoxic aggregation of Cu/Zn superoxide dismutase with structurally disordered regions. AB - Cu/Zn-superoxide dismutase (SOD1) is present in the cytosol, nucleus, peroxisomes and mitochondrial intermembrane space of human cells. More than 114 variants of human SOD1 have been linked to familial amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig's disease. Although the ultimate mechanisms underlying SOD1-mediated cytotoxicity are largely unknown, SOD1 aggregates have been strongly implicated as a common feature in ALS. This study examined the mechanism for the formation of SOD1 aggregates in vitro as well as the nature of its cytotoxicity. The aggregation propensity of SOD1 species was investigated using techniques ranging from circular dichroism spectroscopy to fluorescence dye binding methods, as well as electron microscopic imaging. The aggregation of SOD1 appears to be related to its structural instability. The demetallated (apo)-SOD1 and aggregated SOD1 species, with structurally disordered regions, readily undergo aggregation in the presence of lipid molecules, whereas metallated (holo) SOD1 does not. The majority of aggregated SOD1s that are induced by lipid molecules have an amorphous morphology and exhibit significant cytotoxicity. The lipid binding propensity of SOD1 was found to be closely related to the changes in surface hydrophobicity of the proteins, even at very low levels, which induced further binding and assembly with lipid molecules. These findings suggest that lipid molecules induce SOD1 aggregation under physiological conditions and exert cytotoxicity, and might provide a possible mechanism for the pathogenesis of ALS. PMID- 20837143 TI - Lessons from functional and structural analyses of disease-associated genetic variants in the complement alternative pathway. AB - Complement is an essential component of innate immunity and a major trigger of inflammatory responses. A critical step in complement activation is the formation of the C3 convertase of the alternative pathway (AP), a labile bimolecular complex formed by activated fragments of the C3 and factor B components that is fundamental to provide exponential amplification of the initial complement trigger. Regulation of the AP C3 convertase is essential to maintain complement homeostasis in plasma and to protect host cells and tissues from damage by complement. During the last decade, several studies have associated genetic variations in components and regulators of the AP C3 convertase with a number of chronic inflammatory diseases and susceptibility to infection. The functional characterization of these protein variants has helped to decipher the critical pathogenic mechanisms involved in some of these complement related disorders. In addition, these functional data together with recent 3D structures of the AP C3 convertase have provided fundamental insights into the assembly, activation and regulation of the AP C3 convertase. PMID- 20837144 TI - The effect of sucrose and salts in combination on the drug release behaviour of an HPMC matrix. AB - Previous work has shown how high concentrations of sugars can accelerate drug release from hydroxypropyl methylcellulose (HPMC) matrices by suppressing polymer hydration. This study investigates the effects of combining sugar and salts, using sucrose, sodium chloride and trisodium citrate, soluble ingredients commonly found in foods. A factorial study showed that each solute suppressed HPMC solution sol-gel transition temperature (a sensitive measure of molecular hydration) independently, and their effects reflected their rank order in the Hofmeister series. In mixtures, the effects were purely additive, with no evidence of antagonism or synergy. In dissolution tests, both salts significantly reduced the threshold sugar concentration required to elicit an acceleration of drug release, and when used in combination, 0.15 M sodium chloride with 0.015 M trisodium citrate reduced the threshold sucrose concentration from 0.7 M to 0.35 0.4 M, a reduction of almost 50%. The results show that food salts can significantly reduce the concentration required for sugar effects on HPMC matrices, and this may be a factor to consider when interpreting their in vivo behaviour in the fed state. PMID- 20837145 TI - Ecdysteroid metabolism in crustaceans. AB - The molting gland, or Y-organ (YO), is the primary site for ecdysteroid synthesis in decapod crustaceans. Ecdysteroid biosynthesis is divided into two stages: (1) conversion of cholesterol to 5beta-diketol and (2) conversion of 5beta-diketol to secreted products. Stage 1 involves the conversion of cholesterol to 7 dehydrocholesterol (7DC) by 7,8-dehydrogenase, the "Black Box" reactions involving 3-oxo-Delta(4) intermediates, and the conversion of Delta(4)-diketol to 5beta-diketol by 5beta[H]-reductase. The stage 2 reactions generate four major products, depending on species: ecdysone, 3-dehydroecdysone (3DE), 25 deoxyecdysone (25dE), and 3-dehydro-25-deoxyecdysone (3D25dE). Peripheral tissues convert these compounds to the active hormones 20-hydroxyecdysone (20E) and ponasterone A (25-deoxy-20-hydroxyecdysone or 25d20E). The hydroxylations at C25, C22, C2, and C20 are catalyzed by cytochrome P-450 mono-oxygenases, which are encoded by the Halloween genes Phantom, Disembodied, Shadow, and Shade, respectively, in insects. Orthologs of these genes are present in the Daphnia genome and a cDNA encoding Phantom has been cloned from prawn. Inactivation involves conversion of ecdysteroids to polar metabolites and/or conjugates, which are eliminated in the urine and feces. The antennal gland is the major route for excretion of ecdysteroids synthesized by the YO. The hepatopancreas eliminates ingested ecdysteroids by forming apolar conjugates. The concentrations of ecdysteroids vary over the molt cycle and are determined by the combined effects biosynthesis, metabolism, and excretion. PMID- 20837147 TI - A tool for the qualitative comparison of membrane-embedded and detergent solubilized membrane protein structures in projection. AB - The calculation of projection structures (PSs) from Protein Data Bank (PDB) coordinate files of membrane proteins is not well-established. Reports on such attempts exist but are rare. In addition, the different procedures are barely described and thus difficult if not impossible to reproduce. Here we present a simple, fast and well-documented method for the calculation and visualization of PSs from PDB-coordinate files of membrane proteins: the projection structure visualization (PSV)-method. The PSV-method was successfully validated using the PS of aquaporin-1 (AQP1) from 2D crystals and cryo-transmission electron microscopy, and the PDB-coordinate file of AQP1 determined from 3D crystals and X ray crystallography. Besides AQP1, which is a relatively rigid protein, we also studied a flexible membrane transport protein, i.e. the L-arginine/agmatine antiporter AdiC. Comparison of PSs calculated from the existing PDB-coordinate files of substrate-free and L-arginine-bound AdiC indicated that conformational changes are detected in projection. Importantly, structural differences were found between the PSV-method calculated PSs of the detergent-solubilized AdiC proteins and the PS from cryo-TEM of membrane-embedded AdiC. These differences are particularly exciting since they may reflect a different conformation of AdiC induced by the lateral pressure in the lipid bilayer. PMID- 20837146 TI - Three-dimensional molecular modeling with single molecule FRET. AB - Single molecule fluorescence energy transfer experiments enable investigations of macromolecular conformation and folding by the introduction of fluorescent dyes at specific sites in the macromolecule. Multiple such experiments can be performed with different labeling site combinations in order to map complex conformational changes or interactions between multiple molecules. Distances that are derived from such experiments can be used for determination of the fluorophore positions by triangulation. When combined with a known structure of the macromolecule(s) to which the fluorophores are attached, a three-dimensional model of the system can be determined. However, care has to be taken to properly derive distance from fluorescence energy transfer efficiency and to recognize the systematic or random errors for this relationship. Here we review the experimental and computational methods used for three-dimensional modeling based on single molecule fluorescence resonance transfer, and describe recent progress in pushing the limits of this approach to macromolecular complexes. PMID- 20837148 TI - New RT-qPCR assay for viral nervous necrosis virus detection in sea bass, Dicentrarchus labrax (L.): application and limits for hatcheries sanitary control. AB - A sensitive and quantitative one step RT-qPCR method was developed to study Viral Nervous Necrosis (VNN) virus loads in sea bass Dicentrarchus labrax (L.) in hatcheries. After determining the limits of this new method, fin tissues were identified as an interesting new simple non-invasive sample source, which might be useful for screening D. labrax (L.) in hatcheries. We observed VNN virus strain V26 associated to D. labrax (L.) eggs and it's release in tank water during spawning suggesting both vertical transmission to the eggs and the possibility of horizontal transmission by contamination of tank water. VNN is widespread in water bodies and has the ability to infect a large number of fish species, with this in mind, this PCR technique may be used for the surveillance of various fish farms. PMID- 20837149 TI - White shrimp Litopenaeus vannamei that had received the hot-water extract of Spirulina platensis showed earlier recovery in immunity and up-regulation of gene expressions after pH stress. AB - White shrimp Litopenaeus vannamei which had been immersed in seawater (350/00, pH 8.2) containing the hot-water extract of Spirulina platensis at 0 (control), 200, 400, and 600 mg L(-1) for 3 h, were transferred to seawater at pH 6.8, and the immune parameters and transcripts of the lipopolysaccharide- and beta-glucan binding protein (LGBP), peroxinectin (PX), and integrin beta (IB) were examined 6 96 h post-transfer. Shrimp with no exposure to the hot-water extract and no pH change served as the background control. Results indicated that the hyaline cells, granular cells (including semi-granular cells), total haemocyte count, phenoloxidase activity, respiratory burst, superoxide dismutase activity, glutathione peroxidase activity, and lysozyme activity of shrimp transferred to seawater at pH 6.8 significantly decreased to the lowest at 6 h post-transfer. These immune parameters of shrimp immersed in 600 mg L(-1) of the extract were significantly higher than those of control shrimp at 24-96 h post-transfer, and had returned to the background values earlier at 48-72 h post-transfer with significant transcripts of LGBP, PX, and IB at 24, 6, and 24 h, respectively, whereas these parameters of control shrimp returned to the original values at >=96 h post-transfer. PMID- 20837150 TI - Similarities in the patterns of prefrontal cortex activity during spatial and temporal context memory retrieval after equating for task structure and performance. AB - Event-related functional magnetic resonance imaging was used to assess healthy adults while they performed spatial and temporal context memory tasks matched in task structure. After equating task structure between spatial versus temporal context tasks, subjects reported using similar strategies across tasks and we observed no significant differences in accuracy and reaction time performance between tasks. We used three methods of statistical analysis to interrogate similarities and differences in whole-brain activity across retrieval tasks, while focussing on prefrontal cortex (PFC) activations: multivariate partial least squares analysis (PLS), univariate statistical parametric mapping (SPM) and conjunction analysis. The PLS and conjunction analyses indicated that the overall pattern of PFC activity was similar across both temporal and spatial context retrieval tasks; but the SPM results indicated that some of these PFC regions exhibited differences in the degree to which they were engaged between tasks. However, none of these methods identified unique PFC activations specific to mediating spatial and/or temporal context retrieval. These results indicate that, overall, similar patterns of PFC activity were observed during temporal and spatial context memory retrieval once task structure and performance were equated. PMID- 20837151 TI - Horizontal DNA transfer from donor to host cells as an alternative mechanism of epithelial chimerism after allogeneic hematopoietic cell transplantation. AB - Animal and human studies have shown that after allogeneic hematopoietic cell transplantation, epithelial cells containing donor-derived genome emerge. The mechanisms underlying this phenomenon are still unclear. We hypothesized that horizontal transfer of the hematopoietic donor-DNA to the host epithelium confers a possible operating mechanism. In an in vitro model mimicking the lymphocyte epithelial interaction, we cocultivated keratinocyte HaCaT cells (Y-chromosome negative) with nonapoptotic or apoptotic, CMFDA, or BrdU-labeled hematopoietic Jurkat cells (Y+) and looked for the emergence of HaCaT cells bearing Jurkat genome. We found that DNA can be horizontally transferred from hematopoietic to epithelial cell lines through phagocytosis of apoptotic bodies. The ingested genomic material was also found within the nuclear compartment and in isolated chromosomes obtained from HaCaT metaphases. Both lysosomal inhibition in HaCaT cells and repetitive load of HaCaT cells with apoptotic bodies increased the intercellular and intranuclear DNA delivery. Although recipient cells remained viable and showed to express the foreign DNA, this expression was transient. Taking into consideration these findings of horizontal DNA transfer between hematopoietic and epithelial cells, we evaluated by quantitative microsatellite analysis the amount of donor DNA in 176 buccal swabs obtained from 71 patients after allogeneic transplantation. We found a high amount of donor-DNA (mean 26.6%) in the majority (89.7%) of them, although no donor hematopoietic cells were evident in the samples by immunofluorescence. We propose that the incessant charge of the transplant recipient with donor-DNA and its "inappropriate" intranuclear delivery in host epithelium may explain the emergence of epithelial cells with donor-derived genome. PMID- 20837152 TI - Wnt signaling in stem and cancer stem cells. AB - Canonical Wnt signaling supports the formation and maintenance of stem and cancer stem cells. Recent studies have elucidated epigenetic mechanisms that control pluripotency and stemness, and allow a first assessment how embryonic and tissue stem cells are generated and maintained, and how Wnt signaling might be involved. The core of this review highlights the roles of Wnt signaling in stem and cancer stem cells of tissues such as skin, intestine and mammary gland. Lastly, we refer to the characterization of novel and powerful inhibitors of canonical Wnt signaling and describe attempts to bring these compounds into preclinical and clinical studies. PMID- 20837154 TI - Vesicle scission: dynamin. AB - Dynamin is a large GTPase involved in endocytic vesicle formation, but its exact role and mechanism are subjects of long-standing debate. Despite recent advances in the structural analyses of isolated dynamin domains and the faithful reconstitution of dynamin-dependent membrane fission in model membrane systems, the mechanism of its action remains poorly understood at the molecular level. Here, I will review current progress in elucidating dynamin action in vesicle scission and highlight the most visible gaps in knowledge that limit the development of a coherent and complete model for its role in vesicle biogenesis. Coordinated functions of BAR domain-containing binding partners are also discussed. PMID- 20837153 TI - ARF6-mediated endocytic recycling impacts cell movement, cell division and lipid homeostasis. AB - A wide range of cellular activities depends upon endocytic recycling. ARF6, a small molecular weight GTPase, regulates the processes of endocytosis and endocytic recycling in concert with various effector molecules and other small GTPases. This review highlights three critical processes that involve ARF6 mediated endosomal membrane trafficking-cell motility, cytokinesis, and cholesterol homeostasis. In each case, the function of ARF6-mediated trafficking varies-including localization of specific protein and lipid cargo, regulation of bulk membrane movement, and modulation of intracellular signaling. As described in this review, mis-regulation of endocytic traffic can result in human disease when it compromises the cell's ability to regulate cell movement and invasion, cell division, and lipid homeostasis. PMID- 20837155 TI - Genetic mapping of 14 avirulence genes in an EU-B04 * 1639 progeny of Venturia inaequalis. AB - Durable resistance to apple scab (Venturia inaequalis (Cke) Wint; anamorph Spilocaea pomi Fries) is one of the major goals of apple (Malus) breeding programs. Since current scab resistance breeding is heavily reliant on genes with gene-for-gene relationships, a good understanding of the genetic basis of host pathogen interactions needs to be developed for this strategy to be successful. While the genomic organization of apple scab resistance genes has been studied extensively, little is known about the avirulence genes in the pathogen. The progeny of a cross of European V. inaequalis race (1) isolate EU-B04 and race (1,2,8,9) isolate 1639 was used to generate a genetic map based on microsatellite and AFLP markers, and investigated for inheritance of avirulence traits on 20 Malus accessions representing 17 scab resistance genes. The accessions comprised scab differential hosts (0), (1), (2), (8), and (9), and hosts carrying known as well as not previously reported secondary resistance genes, including some identified in crosses that have resistant accessions 'Geneva', 'Dolgo', Malus baccata jackii, M. micromalus, or 'Antonovka' in their pedigree. The latter genes appear to be narrow spectrum genes that showed gene-for-gene relationships as a segregation ratio of Avr:avr=1:1 was observed on 12 accessions, while a ratio of 3:1 was observed on five accessions and a ratio of 7:1 on one host. All progenies were shown to be pathogenic, as all of them were able to infect hosts (0) and (1). A genetic map consisting of 15 major linkage groups (LGs) and spanning 972cM was generated with the aid of 156 markers. The map position of 12 avirulence traits was determined: eight avirulence genes mapped into two separate clusters (1: AvrVdg2, AvrVv1, AvrVu1, AvrVrjrd; and 2: AvrVu2, AvrVh3.2, AvrVs1, AvrVu4), while four avirulence genes (AvrRvi8, AvrVv2, AvrVt57 and AvrVsv) mapped to different LGs. AvrRvi2 and AvrRvi9 also are genetically linked, but showed an interaction with AvrRvi8, the nature of which is unclear. While AvrRvi8 segregated at 1:1 ratio, the other two Avrs segregated at 3:1 ratios. However, all progeny avirulent on hosts (2) and (9) were also avirulent on host (8) and further research is required to determine the avirulence gene relationships. A further two independently segregating loci, AvrRvi1 and AvrRvi6, identified in previous studies, were mapped by inference based on their known linkage to SSR markers. The clustering of avirulence genes in V. inaequalis reflecting the clustering of resistance genes in Malus suggests this pathosystem is a classical example of an "arms race" between host and pathogen. This also seems to apply to the narrow spectrum scab resistance genes, which may imply a larger role in plant defense for these genes than has been assumed to date. PMID- 20837156 TI - Lung volumes in giraffes, Giraffa camelopardalis. AB - We have measured lung mass and trachea dimensions in 46 giraffes of both genders ranging in body mass from 147 kg to 1441 kg, calculated static and dynamic lung volumes, and developed allometric equations that relate changes in them to growth. We found that relative lung mass is 0.6+/-0.2% of body mass which is significantly less than it is in other mammals (1.1+/-0.1%). Total lung volume is significantly smaller (46.2+/-5.9 mL kg-1) than in similar sized mammals (75.0+/ 2.1 mL kg-1). The lung volume:body mass ratio decreases during growth rather than increase as it does in other mammals. Tracheal diameter is significantly narrower than in similar sized mammals but dead space volume (2.9+/-0.5 mL kg-1) is larger than in similar sized mammals (2.4+/-0.1 mL kg-1). Our calculations suggest that tidal volume (10.5+/-0.2 mL kg-1) is increased compared to that in other mammals(10.0+/-0.2 mL kg-1) so that the dead space:tidal volume ratio is the same as in other mammals. Calculated Functional Residual Capacity is smaller than predicted (53.4+/-3.5 vs 33.7+/-0.6 mL kg-1) as is Expiratory Reserve Volume (47.4+/-2.6 vs 27.2+/-1.0 mL kg-1, but Residual Volume (6.0+/-0.4 mL kg-1) is the same as in other similar sized mammals (6.0+/-0.9 mL kg-1. Our calculations suggest that Inspiratory Reserve Volume is significantly reduced in size (11.6+/ 1.6 vs 3.8+/-2.4 mL kg-1), and, if so, the capacity to increase tidal volume is limited. Calculated dynamic lung volumes were the same as in similar sized mammals. We have concluded that giraffe morphology has resulted in lung volumes that are significantly different to that of similar sized mammals, but these changes do not compromise ventilatory capacity. PMID- 20837157 TI - Assessing the development and application of the accelerometry technique for estimating energy expenditure. AB - A theoretically valid proxy of energy expenditure is the acceleration of an animal's mass due to the movement of its body parts. Acceleration can be measured by an accelerometer and recorded onto a data logging device. Relevant studies have usually derived a measure of acceleration from the raw data that represents acceleration purely due to movement of the animal. This is termed 'overall dynamic body acceleration' (ODBA) and to date has proved a robust derivation of acceleration for use as an energy expenditure proxy. Acceleration data loggers are generally easy to deploy and the measures recorded appear robust to slight variation in location and orientation. This review discusses important issues concerning the accelerometry technique for estimating energy expenditure and ODBA; deriving ODBA, calibrating ODBA, acceleration logger recording frequencies, scenarios where ODBA is less likely to be valid, and the power in recording acceleration and heart rate together. While present evidence suggests that ODBA may not quantify energy expenditure during diving by birds and mammals, several recent studies have assessed changes in mechanical work in such species qualitatively through variation in ODBA during periods of submergence. The use of ODBA in field metabolic studies is likely to continue growing, supported by its relative ease of use and range of applications. PMID- 20837158 TI - A D-galactose-binding lectin purified from coronate moon turban, Turbo (Lunella) coreensis, with a unique amino acid sequence and the ability to recognize lacto series glycosphingolipids. AB - A divalent, cation-independent d-galactose-binding lectin was purified from coronate moon turban Turbo (Lunella) coreensis. This lectin recognizes d galactose and is a 38-kDa dimeric protein consisting disulphide-bonded 22-kDa polypeptides under non-reducing and reducing conditions of sodium dodecyl sulphate-polyacrylamide gel electrophoresis, respectively. Haemagglutination activity was inhibited by D-galactose, N-acetyl D-galactosamine, melibiose, lactose, porcine stomach mucin, asialofetuin and bovine submaxillary mucin. The lectin has tolerance for pH 5-11 and temperature until 50 degrees C for 1h. The lectin strongly aggregated Gram-negative bacteria, such as Vibrio parahaemolyticus and Salmonella O7, but weakly Gram-positive strain as Staphylococcus aureus and Bacillus subtilis. The glycan-binding profile of this lectin was evaluated using frontal affinity chromatography technology and the lectin appeared to recognize oligosaccharides such as lacto-series glycosphingolipids contained in blood type A and H substances in addition to complex-type N-linked glycoproteins. Partial primary structures of 139 amino acid residues of this lectin were determined from N-terminus polypeptides and 8 peptides derived by cleavage with lysyl-endopeptidase. The primary structure was slightly similar to other known sequences of lectin; however, a repeating motif has been included. PMID- 20837159 TI - Mitochondrial regulation of insulin action. AB - Insulin resistance is the prodrome of many metabolic diseases and identifying ways to correct this pathological condition is a major goal for medical research. The foremost barrier to the development of new treatments is that the precise etiology of insulin resistance is uncertain. Recent studies suggest that changes in mitochondrial structure or function drive this condition, however much of this evidence is circumstantial. This Signaling Networks in Focus article provides a brief overview of known and speculative regulatory intersections whereby mitochondrial dysfunction at the levels of lipid oxidation, oxidative stress, calcium, adenine nucleotides, and protons may regulate insulin sensitivity. If mitochondrial dysfunction underlies the origins of metabolic disease then determining the precise molecular pathway will be essential for the development of new treatment and prevention strategies. PMID- 20837160 TI - An ontology-based measure to compute semantic similarity in biomedicine. AB - Proper understanding of textual data requires the exploitation and integration of unstructured and heterogeneous clinical sources, healthcare records or scientific literature, which are fundamental aspects in clinical and translational research. The determination of semantic similarity between word pairs is an important component of text understanding that enables the processing, classification and structuring of textual resources. In the past, several approaches for assessing word similarity by exploiting different knowledge sources (ontologies, thesauri, domain corpora, etc.) have been proposed. Some of these measures have been adapted to the biomedical field by incorporating domain information extracted from clinical data or from medical ontologies (such as MeSH or SNOMED CT). In this paper, these approaches are introduced and analyzed in order to determine their advantages and limitations with respect to the considered knowledge bases. After that, a new measure based on the exploitation of the taxonomical structure of a biomedical ontology is proposed. Using SNOMED CT as the input ontology, the accuracy of our proposal is evaluated and compared against other approaches according to a standard benchmark of manually ranked medical terms. The correlation between the results of the evaluated measures and the human experts' ratings shows that our proposal outperforms most of the previous measures avoiding, at the same time, some of their limitations. PMID- 20837161 TI - Fragmented QRS is associated with torsades de pointes in patients with acquired long QT syndrome. AB - BACKGROUND: Acquired long QT syndrome (LQTS) is a disease due to a secondary repolarization abnormality induced by various predisposing factors. In contrast to congenital LQTS, risk factors that produce acquired LQTS include organic heart diseases that often exhibit depolarization abnormality. Although various repolarization parameters have been evaluated in acquired LQTS, the existence of depolarization abnormality in association with torsades de pointes (TdP) has not been reported. OBJECTIVE: The purpose of this study was to evaluate both repolarization (QT components) and depolarization parameters (fragmented QRS [fQRS]) in acquired LQTS patients with markedly prolonged QT interval. METHODS: Seventy patients with acquired severe QT prolongation (QTc >= 550 ms) were studied. Thirty-two patients had syncope or TdP (syncope group). Thirty-eight patients did not have any symptoms (asymptomatic group). The existence of fQRS and QT components (QT, QTc, Tpe [interval between peak and end of T wave] intervals, and U-wave voltage) was analyzed. RESULTS: The syncope group had more frequent fQRS (81%) than did the asymptomatic group (21%, P < .01) and the incidence of fQRS was not different before and after removal of predisposing factors. The incidence of organic heart disease was not different between the two groups. No differences in QTc interval were noted between the syncope and asymptomatic groups, although the syncope group had longer QT and Tpe intervals and higher U wave than the asymptomatic group (P < .01). CONCLUSION: Acquired predisposing factors promoted repolarization abnormality (especially prolongation of QT and Tpe intervals), and the existence of fQRS had an important role in the development of TdP in patients with acquired LQTS. PMID- 20837162 TI - "Proud flesh" post permanent pacemaker. PMID- 20837163 TI - A web-based patient activation intervention to improve hypertension care: study design and baseline characteristics in the web hypertension study. AB - BACKGROUND: Despite the known health risks of hypertension, many hypertensive patients still have uncontrolled blood pressure. Clinical inertia, the tendency of physicians not to intensify treatment, is a common barrier in controlling chronic diseases. This trial is aimed at determining the impact of activating patients to ask providers to make changes to their care through tailored feedback. METHODS: Diagnosed hypertensive patients were enrolled in this RCT and randomized to one of two study groups: (1) the intervention condition--Web-based hypertension feedback, based on the individual patient's self-report of health variables and previous BP measurements, to prompt them to ask questions during their next physician's visit about hypertension care (2) the control condition- Web-based preventive health feedback, based on the individual's self-report of receiving preventive care (e.g., pap testing), to prompt them to ask questions during their next physician's visit about preventive care. The primary outcome of the study is change in blood pressure and change in the percentage of patients in each group with controlled blood pressure. CONCLUSION: Five hundred participants were enrolled and baseline characteristics include a mean age of 60.0 years; 57.6% female; and 77.6% white. Overall 37.7% participants had uncontrolled blood pressure; the mean body mass index (BMI) was in the obese range (32.4) and 21.8% had diabetes. By activating patients to become involved in their own care, we believe the addition of the web-based intervention will improve blood pressure control compared to a control group who receive web-based preventive messages unrelated to hypertension. PMID- 20837164 TI - CRTC1 expression during normal and abnormal salivary gland development supports a precursor cell origin for mucoepidermoid cancer. AB - Dysregulation of the transcription factor CRTC1 by a t(11;19) chromosomal rearrangement mediates the formation of mucoepidermoid salivary gland carcinoma (MEC). Although the CRTC1 promoter is consistently active in fusion-positive MEC and low levels of CRTC1 transcripts have been reported in normal adult salivary glands, the distribution of CRTC1 protein in the normal salivary gland is not known. The aim of this study was to determine if CRTC1, like many known oncogenes, is expressed during early submandibular salivary gland (SMG) development and re-expressed in an experimental tumor model. Our results indicate that CRTC1 protein is expressed in SMG epithelia during early stages of morphogenesis, disappears with differentiation, and reappears in initial tumor like pathology. This stage-dependent expression pattern suggests that CRTC1 may play a role during embryonic SMG branching morphogenesis but not for pro acinar/acinar differentiation, supporting a precursor cell origin for MEC tumorigenesis. Moreover, the coincident expression of CRTC1 protein and cell proliferation markers in tumor-like histopathology suggests that CRTC1-mediated cell proliferation may contribute, in part, to initial tumor formation. PMID- 20837165 TI - Gene expression analysis of Six3, Pax6, and Otx in the early development of the stalked crinoid Metacrinus rotundus. AB - The stalked crinoid, Metacrinus rotundus, is one of the most basal extant echinoderms. Here, we show the expression patterns of Six3, Pax6, and Otx in the early development of M. rotundus. All three genes are highly expressed in stages from the gastrula to the auricularia larval stage. Ectodermal expression of MrOtx appears to be correlated with development of the ciliary band. These three genes are expressed sequentially along the embryonic body axis in the anterior and middle walls of the archenteron in the order of MrPax6, MrSix3, and MrOtx. The anterior, middle, and posterior parts of the archenteron in the late gastrula differentiate into the axo-hydrocoel, the enteric sac, and somatocoels at later stages, respectively. The three genes are expressed sequentially from the tip of the axo-hydrocoel to the bottom of enteric sac in the order of MrSix3, MrPax6, and MrOtx at the later stages. This suggests that these genes are involved in patterning of the larval endo-mesoderm in stalked crinoids. The present results suggest that radical alterations have occurred in the expression and function of homeobox genes in basal echinoderms. PMID- 20837167 TI - Postnatal ventilatory response to CO2 in awake piglets. AB - Abnormal ventilatory responses to increased levels of inspired CO2 during postnatal development may pose a risk for Sudden Infant Death Syndrome, primarily during periods of vulnerability. The purpose of this study was to test the hypothesis that in awake piglets the ventilatory response to hypercapnia would be attenuated between 10 and 15 days of age relative to younger and older ages. To test this hypothesis, we measured the ventilatory response to 5% inspired CO2 in piglets from postnatal (PN) days 1 through PN28. Piglets were divided into groups and exposed to 5% CO2 daily, every 3rd day or on and after PN20-21 only to avoid any plasticity that may result from repeated exposure to CO2. Room air ventilation normalized to body weight (V(E), ml/min/kg) declined with postnatal age in piglets from all groups. The ventilatory response to 5% inspired CO2 (expressed as % change from control) was present at birth, and we did not find an age-dependent change from PN1 to PN28 (p > 0.1). In addition, we did not find that repeated exposure (daily or every 3rd day) to 5% inspired CO2 altered the ventilatory response during this period of development. We conclude that the previously documented apparent critical period of development in piglets between 10 and 15 days of age is not associated with attenuation of the ventilatory response to 5% inspired CO2. PMID- 20837166 TI - Effect of baroreceptor stimulation on the respiratory pattern: insights into respiratory-sympathetic interactions. AB - Sympathetic nerve activity (SNA) is modulated by respiratory activity which indicates the existence of direct interactions between the respiratory and sympathetic networks within the brainstem. Our experimental studies reveal that T(E) prolongation evoked by baroreceptor stimulation varies with respiratory phase and depends on the pons. We speculate that the sympathetic baroreceptor reflex, providing negative feedback from baroreceptors to the rostral ventrolateral medulla and SNA, has two pathways: one direct and independent of the respiratory-sympathetic interactions and the other operating via the respiratory pattern generator and is hence dependent on the respiratory modulation of SNA. Our experimental studies in the perfused in situ rat preparation and complementary computational modelling studies support the hypothesis that baroreceptor activation during expiration prolongs the T(E) via transient activation of post-inspiratory and inhibition of augmenting expiratory neurones of the Botzinger Complex (BotC). We propose that these BotC neurones are also involved in the respiratory modulation of SNA, and contribute to the respiratory modulation of the sympathetic baroreceptor reflex. PMID- 20837168 TI - Supplementation of fibrin gels with sodium chloride enhances physical properties and ensuing osteogenic response. AB - Modifying the relative concentrations of fibrinogen and thrombin can control the physical properties of fibrin gels, while the viability of associated cells has been linked to the gel's final network structure. It was hypothesized that increasing the gel ionic strength during fabrication through supplementation with sodium chloride (NaCl) would provide an improved approach for tailoring the physical properties of fibrin gels and maintaining the viability and osteogenic potential of entrapped cells. Fibrin gels were formed by mixing fibrinogen, thrombin and calcium chloride with varying masses of NaCl (0-4.40% w/v), and the osteogenic potential of entrapped human mesenchymal stem cells (MSC) was examined over 14 days. Physical properties including gelation time, compressive modulus and fiber diameter were dependent upon NaCl content, with gels containing 2.60% NaCl possessing compressive moduli threefold higher than gels without NaCl. Alkaline phosphatase activity was highest for MSC entrapped in gels containing 2.15-2.60% NaCl after 14 days, and all gels exhibited increased calcium incorporation over the culture period. These data confirm that varying the salt concentration of the pre-gel solution can modulate the material properties of fibrin constructs without additional fibrinogen or thrombin, thereby offering a new approach for generating improved cell transplantation vehicles for use in bone tissue regeneration. PMID- 20837169 TI - Fetal bovine serum xenoproteins modulate human monocyte adhesion and protein release on biomaterials in vitro. AB - Monocyte-derived macrophages are critical in the host-foreign body response to biomaterials and have been studied extensively in various culture conditions in vitro, such as medium supplemented with fetal bovine serum (FBS) or autologous human serum (AHS). Since monocyte maturation into macrophages is highly plastic and may vary considerably depending on the surface, isolation procedures and in vitro culture conditions, we hypothesize that variations in protein adsorption and serum type will greatly impact monocyte behavior in a surface-dependent manner. The impact of xenoproteins on monocyte-surface interactions has not been well studied methodically and the use of AHS rather than FBS for macrophage biomaterials studies in vitro is far from universal. The commonly used reference materials - tissue culture polystyrene (TCPS), polyethylene glycol (PEG) and polydimethylsiloxane (PDMS) - were employed in this study and we found a 3-fold higher adherent monocyte density on TCPS when AHS was used vs. FBS-supplemented medium. On PEG hydrogels, an 8- to 10-fold higher adhesion density was observed when AHS was employed vs. FBS, while on PDMS no difference in adhesion density was observed between the two sera conditions. Additionally, the presence of lipopolysaccharide abrogated the serum-dependent effect on cell adhesion on TCPS. Significantly different variations in protein release were observed between the serum conditions on these surfaces; in particular, there was a 100-fold higher concentration of growth-related oncogene for the AHS condition on PDMS even though the adhesion levels were comparable between the two serum conditions. These results emphasize the combined impact of the surface type and FBS xenoproteins in mediating the observed monocyte response to biomaterials in vitro. PMID- 20837170 TI - The hydroxy-naphthoquinone lapachol arrests mycobacterial growth and immunomodulates host macrophages. AB - The present study reports the anti-mycobacterial activity of 2-hydroxy-3-(3 methyl-2-butenyl)-1,4-naphthoquinone (lapachol) as well as its influence on macrophage functions. Lapachol (L) did not induce apoptosis/necrosis of THP-1 macrophages at <=32 MUg/mL. Mycobacterium avium liquid growth was arrested by >=32 MUg/mL and intra-macrophage proliferation by >=16 MUg/mL lapachol. The main immuno-modulatory effects of lapachol observed were an up-regulation of interferon-gamma-receptor 1 (IFN-gammaR1) and major histocompatibility complex class II (MHCII) surface expression, and a marked inhibition of IL-10 secretion. Lapachol did not affect resting, IFN-gamma- or toll-like receptor 2 (TLR2) induced levels of oxygen and nitrogen metabolism key proteins nor the TLR2 mediated secretion of TNF-alpha, nor induced either oxidative or endoplasmic reticulum (ER) stress. Lapachol inhibited the surface expression of the co stimulatory molecule CD86 but not that of CD80 and CD83. The results obtained indicate that the substituted naphthoquinone lapachol exhibits an anti mycobacterial activity that is more efficient intra- than extra-cellularly, and exerts immuno-modulatory effects some of which may enhance the capacity of the host cell to control mycobacterial growth. The immune-modulatory action of lapachol could contribute to its more efficient intra-macrophage anti mycobacterial activity. PMID- 20837171 TI - (Z)-5-(4-methoxybenzylidene) thiazolidine-2, 4-dione ameliorates the adjuvant induced arthritis via inhibiting the migration of macrophage and down-regulating the cytokine mRNA expression. AB - In our previous study, we have demonstrated that (Z)-5-(4-methoxybenzylidene) thiazolidine-2, 4-dione (SKLB010), a novel analogue of thiazolidinediones, showed protection against concanavalin A (Con A)-induced hepatitis via inhibiting the migration of macrophages and the expression of pro-inflammatory mediators. In present study, Transwell assay was applied to study the effects of SKLB010 on macrophage-like Raw264.7 cell migration and we investigated the effects of SKLB010 on NO generation in vitro. We also studied in vivo effects of SKLB010 on adjuvant-induced arthritis in Lewis rats by oral administration. It was proved that SKLB010 depressed cells migration and the production of NO in Raw264.7 cells in a dose-dependent way. Our results also indicated that oral administration of 50 mg/kg SKLB010 markedly resulted in a clear suppression of clinical signs compared to untreated groups, showing as markedly reduction of paw swelling and inhibition of body weight decreasing. The improvement in disease severity was accompanied by suppression of CD68-positive cells in knee joint and by inhibition of production in pro-inflammatory cytokines of TNF-alpha, IL-1beta and IL-6 in serum. The elevated TNF-alpha, IL-1beta and iNOS mRNA expression in tissue were down-regulated after treatment with SKLB010. SKLB010 also significantly inhibited the histological progress of RA. These data indicate that SKLB010 is a potent anti-inflammatory therapeutic agent targeting the inflammatory response of macrophages. PMID- 20837172 TI - The influence of donepezil and EGb 761 on the innate immunity of human leukocytes: effect on the NF-kappaB system. AB - Ginkgo biloba special extract EGb 761 and donepezil are drugs used in Alzheimer therapy. The influence of donepezil and EGb 761 on two mechanisms of innate immunity, natural antiviral resistance of human leukocytes ex vivo and NF-kappaB activation, was studied. Correlation between the innate immunity of leukocytes and NF-kappaB activation was investigated. The effect of the two drugs on resistance of human leukocytes to vesicular stomatitis virus (VSV) infection was also assessed. Two groups of healthy blood donors (n=30) were distinguished: one with resistant leukocytes (n=15) and one (n=15) with leukocytes sensitive to VSV. The degree of natural resistance of human peripheral blood leukocytes (PBLs) was determined by studying the kinetics of VSV replication. NF-kappaB activation was assayed by immunocytochemical staining. Efficiency of donepezil and EGb 761 was determined by a special regression model. The toxicity of the preparations to PBLs and the cell lines L(929) and A(549) and their effect on the different viruses was established. Results showed that donepezil used in concentrations of 10-50 MUg/ml and EGb761 of 25-100 MUg/ml stimulated resistance of human leukocytes. At the same concentrations both preparations decreased activation of transcriptional factor NF-kappaB. Correlation between innate immunity of PBLs and NF-kappaB activation was observed. Comparison of the effects of these two drugs showed that EGb 761 is more effective in stimulating leukocyte resistance. Donepezil and EGb 761 regulated innate immunity of human leukocytes by stimulating resistance and modulating NF-kappaB activation. The natural drug was more efficient in stimulating innate antiviral immunity of human leukocytes. PMID- 20837173 TI - Oxidative stress-mediated bimodal regulation of polymorphonuclear leukocyte spreading by polyphenolic compounds. AB - Pyrogallol-bearing polyphenolic compounds induce spreading of polymorphonuclear leukocytes (PMNL), although their optimal concentrations for induction of spreading are quite different (2000, 200, and 2 MUM for pyrogallol, (-) epigallocatechin gallate (EGCG), and tannic acid (TA), respectively), and TA tends to inhibit spreading at higher concentrations. In this study, we examined the involvement of oxidative stress in the regulation of PMNL spreading by these compounds. All three compounds in solution generated H(2)O(2) to a similar extent. Adsorption of the polyphenols to cell surfaces and their accumulation within cells were assessed by detection of the H(2)O(2) precursor O(2)(-) produced by the compounds through reduction of cytochrome c and p-nitro-blue tetrazolium, respectively. TA showed the highest degree of adsorption. EGCG adhered only to PMNL pre-fixed by paraformaldehyde, whereas pyrogallol did not adhere. None of the compounds caused intracellular O(2)(-) generation. A non pyrogallic compound, 1,2,4-benzenetriol (BT), also produced H(2)O(2); it had no stimulatory effect on PMNL spreading, but inhibited spreading induced by other stimuli. BT did not adhere to PMNL but accumulated within them, and generated O(2)(-) in the presence of glycine. Thiol antioxidants abrogated all of the above spreading-regulatory effects of the polyphenolic compounds. We conclude that H(2)O(2)-generating polyphenols bimodally regulate the spreading of PMNL by subjecting them to oxidative stress. The ability of polyphenol to adhere to, or accumulate within, PMNL may govern the nature of the oxidative stress and determine the optimal concentration of each compound for induction of spreading, as well as whether spreading is promoted or inhibited. PMID- 20837174 TI - Cytogenetic molecular delineation of a terminal 18q deletion suggesting neo telomere formation. AB - Deletion of the long arm of chromosome 18 is one of the most common segmental aneusomies compatible with life and usually involves a deletion of the terminal chromosomal region. However, the mechanisms implicated in the stabilization of terminal deletions are not well understood. In this study, we analyzed a girl with moderate mental retardation who had a cytogenetically visible terminal 18q deletion. In order to characterize the breakpoint in the terminal 18q region, we used fluorescence In situ hybridization (FISH) with bacterial artificial chromosomes (BACs) and pan-telomeric probes and also the array technique based on comparative genomic hybridization (array-CGH). FISH with pan-telomeric probes revealed no signal in the terminal region of the deleted chromosome, indicating the absence of normal telomere repeat (TTAGGG)n sequences in 18q. We suggest that neo-telomere formation by chromosome healing was involved in the repair and stabilization of this terminal deletion. PMID- 20837175 TI - Development and evaluation of data-driven designed tags (DDTs) for controlling protein solubility. AB - Production of proteins is an important issue in protein science and pharmaceutical studies. Numerous protein expression systems using living cells and cell-free methods have been developed to date. In these systems, a promising strategy for improving the success rate of obtaining soluble proteins is the attachment of various tags into target proteins based on empirical rules. This paper presents a method for the production of data-driven designed tags (DDTs) based on highly frequent sequence property patterns in an experimentally assessed protein solubility dataset in a wheat germ cell-free system. We constructed seven proteins combined with 12 kinds of DDTs (six for enhancing solubility and six for insolubility) at the N-terminal region as tags. Then we investigated their behavior using SDS-PAGE. Results show that three and four proteins respectively showed a trend toward solubilization and insolubilization, which indicates the possibility that the theoretically designed sequence can control protein solubility. PMID- 20837177 TI - Four-way kinetic-excitation-emission fluorescence data processed by multi-way algorithms. Determination of carbaryl and 1-naphthol in water samples in the presence of fluorescent interferents. AB - Four-way data were obtained by recording the kinetic evolution of excitation emission fluorescence matrices for samples containing the analytes carbaryl and 1 naphthol, two widely employed pesticides, in the concentration ranges 0-363 MUg L(-1) and 0-512 MUg L(-1), respectively. The reaction followed was the alkaline hydrolysis of carbaryl to produce 1-naphthol, a fact which introduced strong linear dependencies and multi-linearity losses in the analyzed system. Data processing was performed with unfolded partial least-squares combined with residual trilinearization (U-PLS/RTL) and also with a suitably initialized and restricted parallel factor model (PARAFAC), combined with calibration based on multi-linear regression. U-PLS/RTL is shown to be significantly simpler in its implementation and to provide similar figures of merit. The applied chemometric strategy is able to successfully determine the analytes in water samples containing uncalibrated interferences, such as other commonly employed agrochemicals and also a naturally occurring background signal. PMID- 20837178 TI - Supramolecular solvents in the extraction of organic compounds. A review. AB - The increasing pressure to decrease organic solvent usage in laboratories is fostering the search for alternative solvents. The liquid-liquid phase separation of surfactants, induced by environmental conditions, viz. temperature, electrolytes, pH, etc., has been largely used in analytical extraction and concentration schemes. The surfactant-rich phase is a nano-structured liquid, recently named as supramolecular solvent, generated from the amphiphiles through a sequential self-assembly process occurring on two scales, molecular and nano. This review covers progress on both theoretical and practical aspects related to the use of supramolecular solvents in analytical extractions reported over the last decade. Advances allowing a better understanding of the mechanisms of solvent production and solvent structure are outlined. Emphasis is then placed on solvent composition and its consequences on extraction efficiency, concentration factors and suitability for solubilising analytes over a wide range of polarities. Recent developments in formats and strategies making supramolecular solvents compatible with chromatographic and electrophoretic techniques along with a variety of detection systems are discussed. Applications of supramolecular solvents to the extraction of organic compounds mainly in the biological, environmental and agrifood areas are critically reviewed and main future trends outlined. PMID- 20837179 TI - A passive sampling-based analytical strategy for the determination of volatile organic compounds in the air of working areas. AB - An analytical methodology based on the use of a polyethylene layflat tube filled with activated carbon and Florisil (ACFL-VERAM) was employed for the passive sampling of volatile organic compounds (VOCs) in the air of working areas of packing industries. VOCs amount in the ACFL-VERAM sampler was directly determined through head-space-gas chromatography-mass spectrometry (HS-GC-MS) allowing a direct determination in only 20 min without the need of any previous treatment. Uptake parameters, like sampling rate (R(S)) and sampler-air partition coefficient (K(SA)), were determined for every studied VOC from adsorption isotherm data. Additionally, experimental equations have been proposed to predict R(S) and K(SA) from the octanol-air partition coefficients reported in the literature. The proposed methodology reaches method detection levels from 0.007 to 0.2 mg m(-3) for the studied VOCs. PMID- 20837180 TI - Simultaneous quantitative determination of N(G),N(G)-dimethyl-L-arginine or asymmetric dimethylarginine and related pathway's metabolites in biological fluids by ultrahigh-performance liquid chromatography/electrospray ionization tandem mass spectrometry. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide (NO) formation inhibitor, has emerged as a promising biomarker of NO-associated endothelial dysfunction in cardiovascular diseases as well in chronic renal failure. The interest in potentially fundamental role of this metabolite, in basic and clinical research, led to the development of numerous analytical methods for the quantitative determination of ADMA and dimethylarginines in biological systems, notably plasma, serum and urine. OBJECTIVES: The aim of this work was to present a simple, fast and accurate UPLC-tandem-MS-based method for the simultaneous determination and quantification of arginine, ADMA, SDMA, NMMA, homo-arginine and citrulline. This method is designed for high sample throughput of only 10 MUL of human plasma, serum or urine. METHODS: The analysis time is reduced to 1.9 min by an ultrahigh-performance liquid chromatography run coupled with electrospray ionization (ESI) in the positive mode tandem mass spectrometry detection. RESULTS: The method was validated in plasma, serum and urine. Correlation coefficients (r(2)) of the calibration curves in all matrices considered ranged from 0.9810 to 0.9993. Inter- and intra-assay precision, accuracy, recovery and carry-over were evaluated for validation. The LOD was 0.01 MUM for all compounds in water, plasma and serum and 0.1 MUM in urine. The LOQ was 0.05 MUM for ADMA, SDMA, NMMA and H-Arg and 0.5 MUM for Arg and Cit in water, plasma and serum; while in urine was 0.1 MUM for ADMA, SDMA, NMMA and H-Arg and 0.5 MUM for Arg and Cit. The precision was ranged from 1% to 15% expressed as CV% and the accuracy (bias %) was <+/-7% for all added concentrations with the exception of NMMA (-10%). ADMA mean plasma levels, measured in healthy adults and newborns, were in accord with literature data published: (M+/-SD) 0.56+/-0.10 MUM and 0.84+/-0.21 MUM, respectively, showing that ADMA levels in plasma decreased with age. In serum we have similar data (0.54+/-0.18 MUM and 1.14+/-0.36 MUM), while in neonatal urine ADMA was 11.98+/-7.13 MUmol mmol(-1) creatinine. CONCLUSIONS: Data from calibration curves and method validation reveal that the method is accurate and precise. The fast run time, the feasibility of high sample throughput and the small amount of sample required make this method very suitable for routine analysis in the clinical setting. PMID- 20837181 TI - Gas-phase chemiluminescence with ozone oxidation for the determination of total tin in environmental samples using flow injection hydride generation and cryotrapping. AB - The gas-phase chemiluminescence detection system based on the ozonization of gaseous hydride was exploited and utilized for the determination of total tin in environmental samples. After sample treatment, tin was reduced to stannane by sodium borohydride in a phosphate buffer medium of pH 5.8. Flow injection technique was used to control the reaction precisely and reproducibly. The generated stannane, carried by helium, was separated from liquid and dried using an ice-salt cryogenic bath and subsequently trapped in a glass U-tube immersed in liquid nitrogen. The cryotrapped stannane was vaporized by bringing the tube to room temperature and subsequently carried in a flow of helium to a reaction chamber where ozone was used to oxidize the stannane. Chemiluminescence was produced during the oxidation process, which was utilized for the measurement of tin. Under optimal conditions, a detection limit of 0.32 MUg L(-1) was achieved with a relative standard deviation of 3.1% (10.0 MUg L(-1) Sn, n=11). Interferences from transition metal ions and other hydride forming elements were reduced by the addition of 1,10-phenanthroline and through optimized hydride generation conditions. The proposed system was applied to the determination of Sn in water and soil samples with satisfactory results. PMID- 20837182 TI - Amperometric detection of Enterobacteriaceae in river water by measuring beta galactosidase activity at interdigitated microelectrode arrays. AB - Two simple methodologies are compared for the detection of faecal contamination in water using amperometry at gold interdigitated microelectrodes. They rely on the detection of beta-galactosidase (beta-gal) by redox cycling amperometry of the p-aminophenol (PAP) produced by the enzyme from the 4-aminophenyl beta-d galactopyranoside (PAPG) substrate. The use of phages as specific agents for the release of the bacteria-enclosed enzyme allowed the detection of 6*10(5) CFU mL( 1)Escherichia coli in 2 h without any pre-enrichment or preconcentration steps. Better limits of detection were achieved for the second strategy in the absence of phages. In this case, bacteria were enriched in the presence of both beta-d-1 thiogalactopyranoside (IPTG) and substrate but in the absence of phages. Under such experimental conditions, 5*10(4) CFU mL(-1) E. coli could be detected after 2 h of incubation, while 7 h of incubation were enough to detect down to 10 CFU mL(-1) in river water samples. This represents a straightforward one-step method for the detection of faecal contamination that can be conducted in a single working day with minimal sample manipulation by the user. PMID- 20837183 TI - Separation of xylose and glucose on different silica-confined ionic liquid stationary phases. AB - Xylose and glucose, as the main hydrolyzed products of plant cell wall, were separated by silica-confined ionic liquid (IL) stationary phases. Five different stationary phases were synthesized and characterized. Instead of using the traditional NH(2) column, the imidazolium stationary phases exhibit excellent retention to the xylose and glucose. The retention factor and resolution of the monosaccharides decreased with decreasing acetonitrile concentration. In addition, the effects of the IL cations and anions on the retention of xylose and glucose were studied and the adsorption behavior of these two monosaccharides on the stationary phases was investigated. Then the mobile phase and temperature were optimized to improve the performance for the separation of xylose and glucose. PMID- 20837184 TI - Simultaneous determination of guanidinosuccinic acid and guanidinoacetic acid in urine using high performance liquid chromatography/tandem mass spectrometry. AB - We present a method for the simultaneous determination of guanidinosuccinic acid (GSA) and guanidinoacetic acid (GAA) from urine by protein precipitation and liquid chromatography/tandem mass spectrometry. The chromatographic separation was performed using a cation exchange column with an elution gradient of 0.1 mM and 20 mM ammonium acetate buffers. GSA was detected with the mass spectrometer in negative ion mode monitoring at m/z 174.1, and GAA, creatinine, arginine, and homoarginine were in positive ion mode monitoring at m/z 118.1, 114.1, 175.1, and 189.1, respectively. As an internal standard, L-arginine-(13)C(6) hydrochloride and creatinine-d(3) (methyl-d(3)) were used. The calibration ranges were 0.50 25.0 MUg mL(-1), and good linearities were obtained for all compounds (r>0.999). The intra- and inter-assay accuracies (expressed as recoveries) and precisions at three concentration levels (1.00, 5.00 and 25.0 MUg mL(-1)) were better than 83.8% and 7.41%, respectively. The analytical performance of the method was evaluated by determination of the compounds in urine from male C57BL/J Iar db/db diabetes mellitus (DM) mice. The values of GSA and GAA corrected by the ratios of the individual compounds to creatinine were significantly increased in DM mice compared with control mice. These results indicated that the newly developed method was useful for determining urinary guanidino compounds and metabolites of arginine. PMID- 20837185 TI - [Physical training with beta-blockers in chronic heart failure]. AB - In patients with chronic heart failure, the efficacy of beta-blocker therapy on mortality and the multiple benefits observed with physical training justify the association of the both. The effects of betablockade on different systems solicited in the exercise, particularly on the cardiocirculatory response during exercise test, rise many questions about the impact of beta blocker treatment on the changes induced by physical training. The cardioselective and vasodilating properties of beta-blockers play a role. It seems that the improved performance assessed by peak oxygen uptake (peak VO2) resulting from physical training is not limited by the beta-blocker treatment in patients with chronic heart failure. Synergistic effects have been observed, but many issues remain unsolved. PMID- 20837186 TI - Metabolism. Towards a new therapeutics for pain: pathogenesis and clinical aspects. Foreword. PMID- 20837187 TI - Pain: sex differences and implications for treatment. AB - Women have a higher prevalence than men of several clinical pain conditions and of inflammation-mediated disorders. There is also increasing evidence for sex differences in sensitivity to experimental pain and in the response to analgesics. Estrogen, progesterone, and other gonadal hormones have a complex role in inflammatory processes and the pain response. Microglia cells in the central nervous system, which have sex hormone receptors, become activated in response to inflammatory stimuli, releasing cytokines and other mediators that are pronociceptive and can amplify the pain response. Although the mechanisms underlying sex differences in pain and analgesia have not been fully elucidated, both peripheral and central nervous systems pathways may be involved. Sex differences in the opioid, dopaminergic, serotoninergic, and other pain-related systems have been documented; and some evidence suggests that differences are most pronounced during the peak reproductive years. Psychosocial factors also play an important role. Given the important role of inflammation in mediating pain, nutritional factors that modulate the inflammatory response offer a promising and exciting new avenue for the prevention and treatment of chronic pain disorders. Of particular interest is the potential role of moderate- to high dose vitamin D and omega-3 fatty acid supplements, both of which have powerful anti-inflammatory effects. These nutritional interventions, which influence cytokine, leukotriene, and prostaglandin pathways, may be of particular benefit to women due to their higher prevalence of inflammatory chronic pain disorders. The recent launch of a new large-scale randomized trial of these nutritional supplements provides an opportunity to assess their potential antinociceptive role. Additional research is needed to clarify the mechanisms for sex differences in pain and to develop new treatment modalities that improve pain management for both men and women. PMID- 20837188 TI - New therapeutics for pain--an overview. PMID- 20837189 TI - Spinal glia and chronic pain. AB - Therapeutic management of chronic pain has not been widely successful owing to a lack of understanding of factors that initiate and maintain the chronic pain condition. Efforts to delineate the mechanisms underlying pain long have focused on neuronal elements of pain pathways, and both opiate- and non-opiate-based therapeutics are thought largely to target neurons. Abnormal neuronal activity at the level of spinal cord "pain centers" in the dorsal horn leads to hypersensitivity or a hyperalgesic response subsequent to the initial painful stimulus. Only recently has the experimental literature implicated nonneuronal elements in pain because of the realization that glial-derived signaling molecules can contribute to and modulate pain signaling in the spinal cord. Most notably, glial proinflammatory mediators within the dorsal horn of the spinal cord appear to contribute to self-perpetuating pain. Chronic pain is modeled experimentally through a variety of manipulations of sensory nerves including cutting, crushing, resection, and ligation. The cellular and molecular responses in the spinal cord due to these manipulations often reveal activation of 2 types of glia: microglia and astrocytes. The activation states of both microglia and astrocytes are complex and may be driven by underlying chronic neuropathology and/or a chronically "primed" condition that accounts for their contribution to chronic pain. Recent evidence even suggests that opioid tolerance and withdrawal hyperalgesia may be initiated and maintained via actions of microglia and astroglia. Together, these recent findings suggest that glia will serve as novel therapeutic targets for the treatment of chronic pain. To fully exploit glia as novel therapeutic targets will require a greater understanding of glial biology, as well as the identification of agents able to control the glial reactions involved in chronic pain, without interfering with beneficial glial functions. PMID- 20837190 TI - Neurosurgical treatments of intractable pain. AB - Intractable pain may require neurosurgical intervention. This review provides a critical update of neurosurgical techniques available to treat this condition. Neurosurgery can affect pain's pathways from the receptor up to the "centers" of its reception and perception, either by destroying or by stimulating them. Early in neurosurgery's development, and still today, ablative procedures are able to suppress or alleviate pain. However, in most cases, such ablations have only remained effective for a few months or, at best, a few years. This is why, from the 1960s on, a better understanding of the mechanism of pain inspired development of electrical and chemical neuromodulation procedures at every level of the nociceptive system (peripheral nerve, cord, thalamic, periventricular/aqueductal gray, and cortical centers). The encouraging outcomes that resulted are attracting increasing attention and interest among clinicians. The indications for undertaking an ablative vs a neurostimulative procedure, as well as selection of the anatomical target, depend largely on whether pain is nociceptive or neuropathic, given that most of these indications overlap to some extent. In addition, because the published outcomes are not based on universal criteria, it is difficult for the attending physician to select the type of procedure most suitable to the pain problem. This brief review surveys the various neurosurgical procedures together with their corresponding indications in the hope that the information provided will help practitioners choose (1) the type of neurosurgical therapy most appropriate to their patients' needs and (2) the neurosurgical group best equipped to implement that choice. PMID- 20837191 TI - Gout: epitome of painful arthritis. AB - Arthritic pain and disability are at or near the top of the list of reasons adult patients seek medical attention. At least 47.8 million US residents have arthritis. In Europe, the magnitude of the problem is similar, affecting 8 million in the United Kingdom and 108 million across the continent. Osteoarthritis is by far the most common form of arthritis. In a regional UK study, nearly half of adults 50 years or older reported some form of osteoarthritic knee pain over a 1-year period. Among the arthritides, gout is notable for the agonizing nature and unique pathogenesis of the pain it generates. Gout is the most common cause of inflammatory arthritis among men and postmenopausal women. Because of the atypical nature of some of its clinical manifestations, gout can present serious diagnostic challenges for practicing physicians. In recent years, knowledge about gout's pathogenesis, pathophysiology, and differential diagnosis has advanced on a broad front. Genetic variants within a newly identified transport gene, SLC2A9, have been associated with a low fractional excretion of uric acid and the presence of gout in several population samples. The SLC2A9 gene encodes glucose transporter 9-a unique hexose and high-capacity urate transporter. In addition, human ATP-binding cassette, subfamily G2 (ABCG2), encoded by the ABCG2 gene, has been found to mediate renal urate secretion. Introduction of a mutation encoded in a model system by a common single nucleotide polymorphism, rs2231142, resulted in a 53% reduction in urate transport rates compared with wild-type ABCG2. Based on a large population study, it has been estimated that at least 10% of all gout cases in white persons may be attributable to this single nucleotide polymorphism causal genetic variant. Of the various categories of arthritis, the crystal induced arthropathies, gout and pseudogout, are manifested by acute inflammation and tissue damage arising from deposition in joints and periarticular tissues of monosodium urate (MSU), calcium pyrophosphate dehydrate, or basic calcium phosphate crystals. The innate immune system rapidly detects invading pathogenic microbes and nonmicrobial "danger signals" such as MSU crystals. When these crystals are deposited in synovial tissues, NLR proteins (NOD-like receptors) form multiprotein complexes known as inflammasomes that trigger secretion of inflammation-producing cytokines like interleukin-1beta and interleukin-18. Usually, gout can be diagnosed by medical history, physical examination, and presence of hyperuricemia (urate >416 MUmol/L). However, a urate concentration less than 416 does not by itself rule out gout. Confirmation of the diagnosis by identification of typical MSU crystals in aspirated synovial fluid is definitive. Analysis of joint fluid is mandatory to rule out septic arthritis, which can rapidly become lethal. Because of its special ability to identify and quantitate urate deposits in peripheral tissues, dual-energy computed tomography should prove valuable in the differential diagnosis of gout. Gout mimics a variety of illnesses; for example, spinal gout may masquerade as metastatic cancer, epidural abscess, and nerve compression syndrome. PMID- 20837192 TI - Fibromyalgia and the complex regional pain syndrome: similarities in pathophysiology and treatment. AB - Although the pain of fibromyalgia usually is not preceded by an injury to the involved tissue, whereas that of the complex regional pain syndrome usually starts at a site of prior trauma or surgery, both disorders may share a common mechanism-pathologic sensitization of brain mechanisms that integrate nociceptive signals-and both apparently respond to treatment with ketamine, an anesthetic analgesic agent whose actions include blockade of N-methyl-D-aspartate receptors. Ketamine's widespread illegal use as a recreational agent probably precludes developing it as a general treatment of centrally mediated pain disorders; however, its efficacy suggests that related, to-be-discovered agents could be useful. PMID- 20837193 TI - Chest pain of cardiac and noncardiac origin. AB - Chest pain is one of the most common symptoms driving patients to a physician's office or the hospital's emergency department. In approximately half of the cases, chest pain is of cardiac origin, either ischemic cardiac or nonischemic cardiac disease. The other half is due to noncardiac causes, primarily esophageal disorder. Pain from either origin may occur in the same patient. In addition, psychological and psychiatric factors play a significant role in the perception and severity of the chest pain, irrespective of its cause. Chest pain of ischemic cardiac disease is called angina pectoris. Stable angina may be the prelude of ischemic cardiac disease; and for this reason, it is essential to ensure a correct diagnosis. In most cases, further testing, such as exercise testing and angiography, should be considered. The more severe form of chest pain, unstable angina, also requires a firm diagnosis because it indicates severe coronary disease and is the earliest manifestation of acute myocardial infarction. Once a diagnosis of stable or unstable angina is established, and if a decision is made not to use invasive therapy, such as coronary bypass, percutaneous transluminal coronary angioplasty, or stent insertion, effective medical treatment of associated cardiac risk factors is a must. Acute myocardial infarction occurring after a diagnosis of angina greatly increases the risk of subsequent death. Chest pain in women warrants added attention because women underestimate their likelihood to have coronary heart disease. A factor that complicates the clinical assessment of patients with chest pain (both cardiac and noncardiac in origin) is the relatively common presence of psychological and psychiatric conditions such as depression or panic disorder. These factors have been found to cause or worsen chest pain; but unfortunately, they may not be easily detected. Noncardiac chest pain represents the remaining half of all cases of chest pain. Although there are a number of causes, gastroesophageal disorders are by far the most prevalent, especially gastroesophageal reflux disease. Fortunately, this disease can be diagnosed and treated effectively by proton-pump inhibitors. The other types of non-gastroesophageal reflux disease-related noncardiac chest pain are more difficult to diagnose and treat. In conclusion, the cause of chest pain must be accurately diagnosed; and treatment must be pursued according to the cause, especially if the cause is of cardiac origin. PMID- 20837194 TI - Opioids for cancer pain: the challenge of optimizing treatment. AB - During 2007, 11.7 million US men and women of all ages suffered from some form of invasive cancer. During their illness, at least 70% (8.2 million) will experience pain sufficiently severe to require chronic opioid treatment. Cancer-induced pain is usually described under 3 headings: acute pain, chronic pain, and breakthrough pain. Among patients with chronic, persistent cancer pain controlled by around the-clock analgesics, there is a high prevalence of breakthrough pain-often precipitated by some form of physical activity. Breakthrough pain seems best treated by a powerful, fast-acting opioid such as intravenous morphine or transmucosal fentanyl. At present, opioids are virtually the only analgesics capable of controlling moderate and severe cancer pain. In recent years, a veritable arsenal of opioids with a wide range of pharmacologic properties has become available for use in different pain situations. The World Health Organization has developed a 3-step "analgesic ladder" to guide management of cancer pain, based on the pain's severity, estimated by means of a 1 to 10 numeric rating scale. As the severity of the pain escalates, more potent (World Health Organization Step III) opioids are used. When faced with a difficult case of cancer pain, the physician must choose-from an array of options-the safest and most effective opioid analgesic and the most appropriate delivery system. Such decisions require an adequate understanding of the available opioids and experience with their use. The pharmacodynamic response to a given opioid depends on the nature of the receptor to which the opioid binds and its affinity for the receptor. Morphine activates the MU-opioid receptors, resulting in not only analgesia and sedation, but also euphoria, respiratory depression, constipation, and pruritus. The existence of a number of opioid receptor subtypes, each with its own repertoire of responses, has given rise to the hope (as yet unrealized) that an opioid can be found (or engineered) that will selectively produce adequate analgesia and sedation without, at the same time, causing unwanted adverse effects. Furthermore, suitable neurostimulatory or neuroinhibitive methods involving the central nervous system are being sought that can amplify the analgesic action of opioids. In the search for antinociceptive agents as efficacious as currently available opioids, but without their troublesome adverse effects, the endogenous opioids, such as the endomorphins, are being examined as offering possible solutions to the adverse effect problem. PMID- 20837195 TI - Genetics of pain, opioids, and opioid responsiveness. AB - Pain is an integral part of the defense mechanisms required for survival. Several hereditary syndromes of complete or almost complete insensitivity to pain have been identified and include channelopathy-associated pain insensitivity, of which the most likely candidate gene is the alpha-subunit of the voltage-gated sodium channel known as Na(v)1.7. Five hereditary sensory and autonomic neuropathy syndromes have been described. Variable pain sensitivity in the general population has been linked to common variants of the MU-opioid receptor and of the catecholamine-O-methyltransferase genes potentially leading to increased opioid tonus. Variants of the guanosine triphosphate cyclohydrolase 1/dopa responsive dystonia gene appear to regulate nociception. Other candidate genes are the transient receptor potential cation channel, subfamily 5 member 1, gene and the melanocortin-1 receptor gene. Candidate genes for predicting opioid efficacy are drug-metabolizing enzymes and transporters-including cytochrome P450, uridine 5'-diphosphate-glucuronosyltransferases, and adenosine triphosphate binding cassette transporters-that are involved in opioid metabolism. Most current knowledge on the genetic regulation of pain has been derived from animal models developed mainly in mice. Genomics has the potential to contribute to therapeutic advances with the promising approach of using small interfering RNA in the control of neuropathic pain. Knowledge of the genetic factors that affect opioid efficacy, metabolism, and adverse effects has the potential for personalizing both acute and chronic pain management, and for designing more useful opiate pain medications with lower adverse event profiles. PMID- 20837196 TI - The role of corticosteroids and stress in chronic pain conditions. AB - The relationship between corticosteroids (endogenous and exogenous) and stress is well known, as is the use of steroids as concomitant treatment in pain management during acute inflammation. In the past, steroids have not been considered the first line of treatment in pain management. In this review, we examine new scientific and clinical evidence that demonstrates the direct role that steroids play in the generation and clinical management of chronic pain. We will discuss the new findings demonstrating the fact that steroids and related mediators produce paradoxical effects on pain such as analgesia, hyperalgesia, and even placebo analgesia. In addition, we will examine the physiologic effect of stress, high allostatic load, and idiopathic disease states such as chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and burnout. The recently observed positive relationship between glutaminergic activity in the insula and clinical pain will be examined in the context of understanding the central role of steroids in chronic pain. The complex role of the hypothalamic-pituitary adrenal axis in pain will be discussed as well as other heterogeneous forms of chronic pain that involve many components of the central nervous system. Components of the hypothalamic-pituitary-adrenal axis have paradoxical effects on certain types of pain that are dependent on dose and on site (whether peripheral or central) and mode of application. Recent studies on glia have shown that they prolong a state of neuronal hypersensitization in the dorsal root ganglia by releasing growth factors and other substances that act on the immune system. We will discuss the implication of these new findings directly linking pain to steroids, stress, and key higher brain regions in the context of future therapeutic targets. PMID- 20837197 TI - Preface. The two most abundant organic substances on Earth, cellulose and starch. PMID- 20837198 TI - Structure and engineering of celluloses. AB - This chapter collates the developments and conclusions of many of the extensive studies that have been conducted on cellulose, with particular emphasis on the structural and morphological features while not ignoring the most recent results derived from the elucidation of unique biosynthetic pathways. The presentation of structural and morphological data gathered together in this chapter follows the historical development of our knowledge of the different structural levels of cellulose and its various organizational levels. These levels concern features such as chain conformation, chain polarity, chain association, crystal polarity, and microfibril structure and organization. This chapter provides some historical landmarks related to the evolution of concepts in the field of biopolymer science, which parallel the developments of novel methods for characterization of complex macromolecular structures. The elucidation of the different structural levels of organization opens the way to relating structure to function and properties. The chemical and biochemical methods that have been developed to dissolve and further modify cellulose chains are briefly covered. Particular emphasis is given to the facets of topochemistry and topoenzymology where the morphological features play a key role in determining unique physicochemical properties. A final chapter addresses what might be considered tomorrow's goal in amplifying the economic importance of cellulose in the context of sustainable development. Selected examples illustrate the types of result that can be obtained when cellulose fibers are no longer viewed as inert substrates, and when the polyhydroxyl nature of their surfaces, as well as their entire structural complexity, are taken into account. PMID- 20837199 TI - Chemical structure analysis of starch and cellulose derivatives. AB - Starch and cellulose are the most abundant and important representatives of renewable biomass. Since the mid-19th century their properties have been changed by chemical modification for commercial and scientific purposes, and there substituted polymers have found a wide range of applications. However, the inherent polydispersity and supramolecular organization of starch and cellulose cause the products resulting from their modification to display high complexity. Chemical composition analysis of these mixtures is therefore a challenging task. Detailed knowledge on substitution patterns is fundamental for understanding structure-property relationships in modified cellulose and starch, and thus also for the improvement of reproducibility and rational design of properties. Substitution patterns resulting from kinetically or thermodynamically controlled reactions show certain preferences for the three available hydroxyl functions in (1->4)-linked glucans. Spurlin, seventy years ago, was the first to describe this in an idealized model, and nowadays this model has been extended and related to the next hierarchical levels, namely, the substituent distribution in and over the polymer chains. This structural complexity, with its implications for data interpretation, and the analytical approaches developed for its investigation are outlined in this article. Strategies and methods for the determination of the average degree of substitution (DS), monomer composition, and substitution patterns at the polymer level are presented and discussed with respect to their limitations and interpretability. Nuclear magnetic resonance spectroscopy, chromatography, capillary electrophoresis, and modern mass spectrometry (MS), including tandem MS, are the main instrumental techniques employed, in combination with appropriate sample preparation by chemical and enzymatic methods. PMID- 20837200 TI - Glyconanoparticles polyvalent tools to study carbohydrate-based interactions. AB - This article deals with the construction, characterization, and applications of nanoparticles functionalized with carbohydrates, reviewing the state of the art and discussing perspectives on the use of these nanomaterials in the fields of glycoscience and glycotechnology. These biofunctional nanostructures, where material science, nanotechnology, and carbohydrate chemical biology meet, offer interesting potential as multivalent systems for interaction studies and for applications in the emerging area of nanomedicine. The term glyconanoparticle was coined in 2001 to denote nanoparticles constructed by "covalent" linkage of neoglycoconjugates equipped with a thiol end-group to gold. These gold glyconanoparticles, first defined as water-soluble, three-dimensional multivalent model systems based on sugar-modified gold nanoclusters presenting a glycocalix like surface with a globular carbohydrate display, have been used as tools in carbohydrate-based interaction studies and to interfere in biological process where carbohydrates are involved. The possibility of replacing the gold inorganic core by a wide variety of materials permits access to a range of glyconanoparticles having different optical, electronic, mechanical, and magnetic properties, whose size can be modulated and whose glycocalix-like surface can be engineered to modify multivalence and insert multifunctionality. PMID- 20837201 TI - 1-Amino-1-deoxy-D-fructose ("fructosamine") and its derivatives. AB - Fructosamine has long been considered as a key intermediate of the Maillard reaction, which to a large extent is responsible for specific aroma, taste, and color formation in thermally processed or dehydrated foods. Since the 1980s, however, as a product of the Amadori rearrangement reaction between glucose and biologically significant amines such as proteins, fructosamine has experienced a boom in biomedical research, mainly due to its relevance to pathologies in diabetes and aging. In this chapter, we assess the scope of the knowledge on and applications of fructosamine-related molecules in chemistry, food, and health sciences, as reflected mostly in publications within the past decade. Methods of fructosamine synthesis and analysis, its chemical, and biological properties, and degradation reactions, together with fructosamine-modifying and -recognizing proteins are surveyed. PMID- 20837202 TI - Sialidases in vertebrates: a family of enzymes tailored for several cell functions. AB - This review summarizes the recent research development on vertebrate sialidase biology. Sialic acid-containing compounds play important roles in many physiological processes, including cell proliferation, apoptosis and differentiation, control of cell adhesion, immune surveillance, and clearance of plasma proteins. In this context, sialidases, the glycohydrolases that remove the terminal sialic acid at the non-reducing end of various glycoconjugates, perform an equally pivotal function. Sialidases in higher organisms are differentially expressed in cells and tissues/organs, with particular subcellular distribution and substrate specificity: they are the lysosomal (NEU1), the cytosolic (NEU2), and plasma membrane- and intracellular-associated sialidases (NEU3 and NEU4). The molecular cloning of several mammalian sialidases since 1993 has boosted research in this field. Here we summarize the results obtained since 2002, when the last general review on the molecular biology of mammalian sialidases was written. In those few years many original papers dealing with different aspects of sialidase biology have been published, highlighting the increasing relevance of these enzymes in glycobiology. Attention has also been paid to the trans-sialidases, which transfer sialic acid residues from a donor sialoconjugate to an acceptor asialo substrate. These enzymes are abundantly distributed in trypanosomes and employed to express pathogenicity, also in humans. There are structural similarities and strategic differences at the level of the active site between the mammalian sialidases and trans-sialidases. A better knowledge of these properties may permit the design of better anti-pathogen drugs. PMID- 20837203 TI - Vitamin D as in different. PMID- 20837204 TI - Transforming emergency care delivery - what does the future hold? PMID- 20837205 TI - What is wrong with this picture? PMID- 20837206 TI - Timely administration of medication in China. PMID- 20837207 TI - The efficacy of a brief behavioral health intervention for managing high utilization of ED services by chronic pain patients. AB - INTRODUCTION: Patients with chronic pain continue to seek medical care from emergency departments nationwide despite the fact that an emergency department is a less-than-optimal environment for meeting their specific and specialized needs. As the scientific community has gained a more sophisticated understanding of the mechanisms that contribute to the development and maintenance of chronic pain, the central role of psychological factors have emerged. Therefore, an ED-based, behavioral health intervention for chronic pain patients is needed to better serve this population and to help hospitals provide cost effective treatment at the appropriate level of care. METHODS: The setting was a 40-bed, acute-care hospital with a 15-bed emergency department seeing 16,500 patients annually. All participants were chronic pain patients utilizing the emergency department for pain management. This study was a program evaluation utilizing a quasi experimental, retrospective, pre-test/post-test, split-plot design. RESULTS: A repeated measures analysis of variance (ANOVA) was used to compare high-utilizers (>4 emergency department visits in 6 months) to low utilizers in total ED visits 6 months before and after the intervention. The low utilizers mean ED visits remained stable before and after the intervention while the high utilizers showed a decrease in ED utilization. This differential response between groups was statistically significant (P < .05). DISCUSSION: This study suggests that an ED based behavioral health consultation may be useful for reducing high utilization of ED services by some chronic pain patients, particularly those who consume the most services. PMID- 20837208 TI - ED services: the impact of caring behaviors on patient loyalty. AB - INTRODUCTION: This article describes an observational study of caring behaviors in the emergency departments of 4 Ascension Health hospitals and the impact of these behaviors on patient loyalty to the associated hospital. These hospitals were diverse in size and geography, representing 3 large urban community hospitals in metropolitan areas and 1 in a midsized city. METHODS: Research assistants from Purdue University (West Lafayette, IN) conducted observations at the first study site and validated survey instruments. The Purdue research assistants trained contracted observers at the subsequent study sites. The research assistants conducted observational studies of caregivers in the emergency departments at 4 study sites using convenience sampling of patients. Caring behaviors were rated from 0 (did not occur) to 5 (high intensity). The observation included additional information, for example, caregiver roles, timing, and type of visit. Observed and unobserved patients completed exit surveys that recorded patient responses to the likelihood-to-recommend (loyalty) questions, patient perceptions of care, and demographic information. RESULTS: Common themes across all study sites emerged, including (1) the area that patients considered most important to an ED experience (prompt attention to their needs upon arrival to the emergency department); (2) the area that patients rated as least positive in their actual ED experience (prompt attention to their needs upon arrival to the emergency department); (3) caring behaviors that significantly affected patient loyalty (eg, making sure that the patient is aware of care-related details, working with a caring touch, and making the treatment procedure clearly understood by the patient); and (4) the impact of wait time to see a caregiver on patient loyalty. A number of correlations between caring behaviors and patient loyalty were statistically significant (P < .05) at all sites. DISCUSSION: The study results raised considerations for ED caregivers, particularly with regard to those caring behaviors that are most closely linked to patient loyalty but that occurred least frequently. The study showed through factor analysis that some caring behaviors tended to occur together, suggesting an underlying, unifying dimension to that factor. PMID- 20837209 TI - Emergency nurses' use of psychosocial nursing interventions for management of ED patient fear and anxiety. PMID- 20837210 TI - Compassion satisfaction, burnout, and compassion fatigue among emergency nurses compared with nurses in other selected inpatient specialties. AB - INTRODUCTION: Today the proportion of acute patients entering the health care system through emergency departments continues to grow, the number of uninsured patients relying primarily on treatment in the emergency department is increasing, and patients' average acuities are rising. At the same time, support resources are constrained, while reimbursement and reputation depends increasingly on publicly available measures of patient satisfaction. It is important to understand the potential effect of these pressures on direct care staff. This study explores the prevalence of compassion satisfaction, burnout, and compassion fatigue among emergency nurses and nurses in other selected inpatient specialties. METHODS: Emergency nurses and nurses from 3 other specialty units self-selected participation in a cross-sectional survey. Participants completed a sociodemographic profile and the Professional Quality of Life: Compassion Satisfaction and Fatigue Subscales, R-IV. Scale scores were summed for compassion satisfaction, burnout, and compassion fatigue for emergency nurses and compared with those of nurses in other specialties. RESULTS: Approximately 82% of emergency nurses had moderate to high levels of burnout, and nearly 86% had moderate to high levels of compassion fatigue. Differences between emergency nurses and those working in 3 other specialty areas, that is, oncology, nephrology, and intensive care, on the subscales for compassion satisfaction, burnout, or compassion fatigue did not reach the level of statistical significance. However, the scores of emergency nurses evidenced a risk for less compassion satisfaction, while intensive care nurses demonstrated a higher risk for burnout and oncology nurses reflected a risk for higher compassion fatigue. DISCUSSION: ED nurse managers, along with other nurse leaders, are faced with the competing demands of managing the satisfaction of patients, recruitment and retention of experienced nurses, and provision of quality and safe care customized to patients' needs and preferences. Understanding the concepts of compassion satisfaction, burnout, and compassion fatigue, recognizing the signs and symptoms, and identifying best practice interventions, will help nurses maintain caring attitudes with patients and contribute to patient satisfaction. PMID- 20837211 TI - Impact of an emergency nurse-initiated asthma management protocol on door-to first-salbutamol-nebulization-time in a pediatric emergency department. AB - OBJECTIVE: To determine the effect of an ED nurse-initiated asthma management protocol on door to first salbutamol nebulization time. METHODS: This was a prospective before-after study. Asthmatics, aged 1 to 12 years presenting to the ED with an exacerbation during the pre and post nurse-initiated care phases (from 1/22/08 to 2/8/08 and from 2/12/08 to 3/4/08), were eligible. An asthma training program was administered to nurses prior to post phase. Respiratory therapists started the first nebulization after a physician order during the pre phase, whereas bedside nurses initiated it before physician evaluation during the post phase. Mean differences and confidence intervals (CI) were calculated. RESULTS: Each of the study groups had 125 patients. Door to first nebulization time was reduced by a mean of 31.3 minutes (CI 23.0, 39.6) in the post phase. Door to steroids, second nebulization, and bedside nurse evaluation time intervals were reduced by 22.8 minutes (CI 8.8, 36.9), 21.7 minutes (CI 9.1, 34.4) and 15.6 minutes (CI 7.5, 23.7) respectively. CONCLUSION: An ED nurse-initiated asthma management protocol expedited initiation of medications essential for relief of symptoms of acute asthma and bedside evaluation by nurses. Standing nurse initiated care protocols may prove to be beneficial in improving acute asthma care in crowded EDs. PMID- 20837212 TI - Using a single-item rating scale as a psychiatric behavioral management triage tool in the emergency department. AB - INTRODUCTION: Proper monitoring of patients' behavior is essential for effective treatment and efficient disposition of psychiatric cases in the adult emergency department. The goal of the current study was to examine an attempt to implement the Behavioral Activity Rating Scale, an existing single-item measure of behavioral activity, as part of a behavioral management triage strategy for psychiatric patients in an emergency department. METHODS: For the period beginning approximately 2 months after use of the behavioral activity measure was initiated in the emergency department, charts from 284 consecutive patients who presented to the department with a chief complaint that was psychiatric in nature were reviewed. RESULTS: Level of adoption of the measure by emergency nurses was lower than desired; only 46% of charts reviewed contained a behavioral activity rating. Ratings were less likely to be recorded during the night shift than during other shifts. As predicted, ratings indicative of elevated behavioral activity were associated with physician orders for formal behavioral management (ie, intramuscular, intravenous, or orally dissolving sedating medications or physical restraint). DISCUSSION: The findings of this study suggest that a single item behavioral activity measure may be an efficient, effective, and discreet way for emergency nursing staff to communicate with one another and with physicians about psychiatric patients in need of behavioral management in adult emergency departments. The findings also suggest that a broad implementation approach is needed to achieve desired levels of adoption by emergency nursing staff. PMID- 20837214 TI - An evidence-based clinical guideline for initial management of behavioral emergencies. PMID- 20837213 TI - Nurse Practitioner Delphi Study: competencies for practice in emergency care. AB - INTRODUCTION: The Emergency Nurses Association (ENA) convened a Nurse Practitioner (NP) Validation Work Team and conducted a Delphi study to verify and gain consensus on professional and clinical competencies for NPs in emergency care. This document describes entry-level competencies for NPs practicing in emergency care, regardless of setting. METHODS: A Delphi study was conducted from September 2007 to May 2008 with a national sample of credentialed NPs in emergency care. Using online questionnaires, three rounds were sent to the NPs to reach group consensus. Participants were asked to rate the importance and frequency of performance for each competency as well as list competencies they felt were not addressed in the questionnaires. RESULTS: The list of competencies was reduced from 111 to 83. In 2008, a Consensus Panel Meeting was convened to validate the Delphi study findings and gain consensus from a multidisciplinary group of stakeholders. Several organizations participated in the meeting (ie, AAEM, AANP, AACN, ACEP, ACNP, ANA, ANCC, BCEN, CCNE, NCSBN, and NONPF). The stakeholders approved a list of 60 entry-level competencies. DISCUSSION: There are implications for NPs in the following areas: 1) education, for use in academic settings as a foundation for curricula; 2) practice, emphasizing the unique aspects of practice for the NP in emergency care; and 3) research, including the development of advanced competencies for NPs in emergency care. PMID- 20837215 TI - Managing behavioral emergencies: striving toward evidence-based practice. PMID- 20837216 TI - A program to minimize ED violence and keep employees safe. PMID- 20837217 TI - Differential diagnosis cyanosis versus argyria: when your patient remains blue--a 48-year-old trauma patient with persistent cyanosis. PMID- 20837219 TI - Assessing cranial nerves with a stick of gum. PMID- 20837221 TI - High-alert medications: shared accountability for risk identification and error prevention. PMID- 20837220 TI - Music as distraction in a pediatric emergency department. PMID- 20837222 TI - Update on health reform: ENA's health care reform platform. PMID- 20837223 TI - Understanding qualitative evidence for emergency nursing practice. PMID- 20837224 TI - Sudden confusion and agitation: causes to investigate! Delirium, dementia, depression. PMID- 20837225 TI - The HEAD FIRST helmet safety program for kids. PMID- 20837226 TI - Our experience in earthquake-ravaged Haiti: two nurses deployed with a disaster medical assistance team. PMID- 20837228 TI - Pediatric obesity in motor vehicle collisions. PMID- 20837229 TI - Short-term pharmaceutical management of the violent/aggressive patient in the emergency department. PMID- 20837230 TI - Alcohol withdrawal syndrome in trauma patients: a review. PMID- 20837231 TI - Walking wounded: if they can still walk, are they really wounded? PMID- 20837233 TI - [BRAF V600E mutation in papillary thyroid carcinoma: prevalence and detection in fine needle aspiration specimens]. AB - BRAF V600E mutation in papillary thyroid carcinoma (PTC): prevalence and detection in fine needle aspiration (FNA) specimens. BACKGROUND AND OBJECTIVE: The activating mutation of the BRAF gene, T1799A, is the most common and specific genetic alteration in PTC. In the present study, our aims were to confirm these data and investigate the feasibility of BRAF mutation detection in FNA specimens. METHODS: In a retrospective study, we examined paraffin-embedded surgical samples of 57 PTC and 51 non-PTC thyroid tumors for the presence of BRAF mutation by dideoxy sequencing. We analyzed thyroid aspirates (drop and washed-out solution) and smears from 31 patients who underwent thyroidectomy, before intraoperative frozen sections, and 25 archival thyroid FNA smears. RESULTS: The BRAF mutation was present in 58 % of PTC. Among non-PTC thyroid tumors, only one medullary thyroid carcinoma contained the BRAF mutation. BRAF mutation was correctly detected from the FNA-derived materials. Considering the search of BRAF mutation in preoperative FNA smears, the diagnosis of PTC would have been affirmed in 31 % (4/13) of indeterminate and suspicious FNA. CONCLUSION: BRAF mutation detection in FNA specimens is feasible and could be used as an adjunct tool for preoperative diagnosis of PTC classified as indeterminate and suspicious with conventional cytology (categories 3, 4 and 5 according to NCI/Bethesda 2008 terminology). PMID- 20837234 TI - [What is new in 2010 for electron microscopy in surgical pathology?]. AB - In the last decades, several ancillary methods, such as immunohistochemistry and molecular biology techniques, have increased the possibilities for the diagnosis and to evaluate the prognosis of lesions observed in a laboratory of pathology. Conversely, the impact of another method largely used a couple of years ago in a laboratory of pathology, the electron microscopy (EM), is currently limited. EM is a difficult, quite expensive and long method, which requires technicians with a high qualification. Therefore, EM is currently rarely available at the hospital in a laboratory of pathology and is essentially established in research centers. However, EM is still an essential tool for the surgical pathologist. This method allows in some circumstances to confirm or, more rarely, to make the diagnosis of a couple of tissular and cellular lesions observed in human pathology. EM is also an interesting method to better understand the etiopathogenesis of emerging human diseases, in particular of emerging infectious diseases. In this review, we report the main indication of EM in human pathology, we lay special emphasize in certain infectious diseases and neoplasia. PMID- 20837236 TI - [Pathology of the placenta. Case 1. Early complete hydatidiform mole]. PMID- 20837237 TI - [Pathology of the placenta. Case 2. Cytomegalovirus placentitis]. PMID- 20837238 TI - [Pathology of the placenta. Case 3. Chronic intervillositis]. PMID- 20837239 TI - [Pathology of the placenta. Case 4. Fetal thrombotic vasculopathy]. PMID- 20837240 TI - [Pathology of the placenta. Case 5. Partial hydatidiform mole]. PMID- 20837241 TI - [Pathology of the placenta. Case 6. Placental mesenchymal dysplasia]. PMID- 20837242 TI - [Pathology of the placenta. Case 7. Massive perivillous fibrin deposits (maternal floor infarct)]. PMID- 20837243 TI - [Pathology of the placenta. Case 8. Sickle cell trait]. PMID- 20837244 TI - [A story of immun deposits]. PMID- 20837245 TI - [Very misleading subcutaneous tumor]. PMID- 20837246 TI - [Isolated primary gastric localization of a mantle cell lymphoma]. AB - Primary mantle cell lymphoma of the digestive tract is uncommon; it rarely involves the stomach and generally manifests as a lymphomatous polyposis. Isolated gastric localization is exceedingly rare. We present a case of a 57-year old man who presented with a six-month history of atypical epigastric pain. Endoscopy revealed a large ulceration of the gastric mucosa. Histological examination of the biopsied specimens concluded to a marginal zone B-cell lymphoma (MALT-type) of low-grade. Patient underwent two courses of anti Helicobacter pylori therapy followed by chemotherapy, without endoscopic amelioration. Histological control showed the persistence of a nodular lymphomatous proliferation that respects glands. It was made of monotonous small cells reactive with CD5 and cyclin D1. The diagnosis of gastric mantle cell lymphoma was made. No other digestive or nodal localization was found. Patient underwent intensive chemotherapy anti-CD20; he was free of disease three years after diagnosis. Primary mantle cell lymphoma of the stomach is an uncommon neoplasm. Diagnosis is often difficult and requires the use of CD5 to exclude a MALT-cell lymphoma, which is much more frequent in this location. PMID- 20837247 TI - [Arterial myopericytoma: a case report]. AB - Myopericytoma is an uncommon perivascular (pericytic) tumour, which develops in the skin or in soft tissues from the extremities. Usually, the lesion is small and shows a myopericytic differentiation. The cells are short, fusiform and arranged concentrically around small vascular lumen. We reported here the second case of arterial mural myopericytoma. PMID- 20837248 TI - [An uncommon macroscopic hematuria]. PMID- 20837249 TI - Long bone morphometrics for human from non-human discrimination. AB - Forensic anthropologists are frequently required to verify the human origin of complete and partial skeletal remains. This determination, however, can be difficult for bone fragments with few or no distinctive morphological markers. Current methods of distinguishing human from non-human bone fragments include microscopic, immunological and DNA testing, which are each limited to some degree (e.g. time consuming and expensive). The purpose of this study is to investigate an alternative morphometric approach to quantify the external structure of human long bones (humeri, femora, and tibiae) compared to quadrupedal (sheep, dog, and pig) and bipedal (kangaroo and emu) animals common to Australia. Eight traditional measurements were taken on a sample of 50 human and at least 10 of each of the five animal species; measurements were then analysed using linear discriminant analysis (LDA). The results expectedly indicate enough variation between species to correctly assign an unknown bone as that of a human or non human, with cross-validated classification accuracy of 95% or better. More importantly, however, the technique also proved to be accurate if only a fragment of the diaphysis is analysed; classification accuracy 63-99%. The results of this study, therefore, outline a forensically useful non-invasive method to distinguish human from animal bones. PMID- 20837250 TI - Are scoop stretchers suitable for use on spine-injured patients? AB - INTRODUCTION: In the prehospital setting, spine-injured patients must be transferred to a spine board to immobilize the spine. This can be accomplished using both manual techniques and mechanical devices. OBJECTIVES: The study aimed to evaluate the effectiveness of the scoop stretcher to limit cervical spine motion as compared to 2 commonly used manual transfer techniques. METHODS: Three dimensional angular motion generated across the C5-C6 spinal segment during execution of 2 manual transfer techniques and the application of a scoop stretcher was recorded first on cadavers with intact spines and then repeated after C5-C6 destabilization. A 3-dimensional electromagnetic tracking device was used to measure the maximum angular and linear motion produced during all test sessions. RESULTS: Although not statistically significant, the execution of the log roll maneuver created more motion in all directions than either the lift-and slide technique or with scoop stretcher application. The scoop stretcher and lift and-slide techniques were able to restrict motion to a comparable degree. CONCLUSION: The effectiveness of the scoop stretcher to limit spinal motion in the destabilized spine is comparable or better than manual techniques currently being used by primary responders. PMID- 20837251 TI - Physicians' impression on the elders' functionality influences decision making for emergency care. AB - BACKGROUND AND AIMS: This study analyzes the elements that compose the emergency physicians' criterion for selecting elderly patients for intensive care treatment. This issue has not been studied in-depth. METHODS: A cross-sectional study was conducted at 4 university teaching hospitals, covering 101 randomly selected elderly patients admitted to emergency department and their respective physicians. Physicians were asked to forecast their plans for treatment or therapeutic abstention, in the event that patients might require aggressive measures (cardiopulmonary resuscitation or admission to critical care units). Data were collected on physicians' reasons for taking such decisions and their patients' functional capacity and cognitive status (Katz index and Informant Questionnaire on Cognitive Decline in the Elderly). A logistic regression model was constructed taking physicians' decisions as the dependent variables and adjusting for patient factors and physician impressions. RESULTS: The functional status reported by reliable informants and the mental status measured by validated instruments were not coincident with the physicians' perception (functional status kappa, 0.47; mental status kappa, 0.26). A multivariate analysis showed that the age and the functional and mental status of patients, as perceived by the physicians, were the variables that better explained the physicians' decisions. CONCLUSIONS: Physicians' impressions on the functional and mental status of their patients significantly influenced their selection of patients for high-intensity treatments despite the fact that some of these impressions were not correct. PMID- 20837253 TI - The effect of physician risk tolerance and the presence of an observation unit on decision making for ED patients with chest pain. AB - OBJECTIVES: We sought to determine whether risk tolerance as measured by scales (malpractice fear scale [MFS], risk-taking scale [RTS], and stress from uncertainty scale [SUS]) is associated with decisions to admit or use computed tomography (CT) coronary angiogram and decisions to order cardiac markers in emergency department (ED) patients with chest pain. We also studied if the opening of an ED-based observation unit affected the relationship between risk scales and admission decisions. METHODS: Data from a prospective study of ED patients 30 years or older with chest pain were used. Risk scales were administered to ED attending physicians who initially evaluated them. Physicians were divided into quartiles for each separate risk scale. Fisher's exact test and logistic regression were used for statistical analysis. RESULTS: A total of 2872 patients were evaluated by 31 physicians. The most risk-averse quartile of RTS was associated with higher admission rates (78% vs 68%) and greater use of cardiac markers (83% vs 78%) vs the least risk-averse quartile. This was not true for MFS or SUS. Similar associations were observed in low-risk patients (Thrombolysis in Myocardial Infarction risk score of 0 or 1). The observation unit was not associated with a higher admission rate and did not modify the relationship between risk scales and admission rates. CONCLUSION: The RTS was associated with the decision to admit or use computed tomography coronary angiogram, as well as the use of cardiac markers, whereas the MFS and SUS were not. The observation unit did not affect admission rates and nor did it affect how physician's risk tolerance affects admission decisions. PMID- 20837252 TI - The accuracy of emergency medicine and surgical residents in the diagnosis of acute appendicitis. AB - OBJECTIVE: This study was conducted to compare the diagnostic accuracy for acute appendicitis between emergency medicine residents (EMRs) and surgical residents (SRs). METHODS: We conducted a prospective cohort study of adult patients with right lower quadrant pain. Each patient was evaluated by an EMR and an SR, and physicians predicted the probability of appendicitis into 4 groups from highest (group 1) to lowest (group 4). The diagnostic accuracies of EMR and SR for the diagnosis of appendicitis were compared by constructing receiver operating characteristics curves. In each case, an Alvarado score was calculated and a computed tomography (CT) scan of the abdomen and pelvis was performed, and their diagnostic accuracies were also compared with the predicted probabilities. RESULTS: Of a total 191 patients, 120 underwent surgery, and the negative appendectomy rate was 6.8%. There was a significant correlation between the predicted probabilities of EMR and SR. The areas under the curve for EMR and SR were 0.698 and 0.657, which were not statistically different. The areas under the curve of the Alvarado score and the CT were 0.735 and 0.978, respectively. The diagnostic accuracy of the CT scan was significantly higher than those of the Alvarado score and the resident-predicted probabilities. CONCLUSION: In patients with right lower quadrant abdominal pain who have already been evaluated by EMR, consultation evaluation by SR does not appear to improve clinical diagnostic accuracy, and routine performance of CT before surgical consultation should be considered for these patients. PMID- 20837254 TI - Use of antivenom for snakebites reported to United States poison centers. AB - In 2001, a new antivenin was introduced to the United States and became widely available in the snakebite season of 2002. We investigated what impact this may have had on snakebite treatment and medical outcome. METHOD: The study used a retrospective review of all snakebites to humans reported to the National Poison Center Database System from 2000 to 2007. RESULTS: During the 8 years, there were 37,760 snakebites, with a mean of 4720 bites per year. There was a 27% increase in bites reported to a Poison center for the 8-year period and an overall 13.5% increase in the use of antivenin. The 2 categories primarily responsible for the increased use of antivenin were copperhead and crotaline-unknown. Rattlesnake bites remained the category most frequently treated with antivenin with a mean 52.5% treatment rate and only moderate increase for the 8 years. There was no change in the percentage or number of patients with a major outcome (mean, 3.8%) or death (mean, 0.5%). There was a decrease in patients with a minor outcome and an increase in patients with a moderate outcome. DISCUSSION: The new antivenin is reported to have a reduced potential for adverse reactions. This may have had a role in the decision of which snakebite victims received antivenin. CONCLUSION: With the introduction of a new antivenin, there has been a dramatic increase in the number of snakebite patients treated with antivenin. This has been most noticeable in snake bite categories that were less frequently treated with antivenin in the past. PMID- 20837255 TI - Clinical predictors for testicular torsion as seen in the pediatric ED. AB - OBJECTIVE: The aim of the study was to identify clinical findings associated with increased likelihood of testicular torsion (TT) in children. DESIGN: This study used a retrospective case series of children with acute scrotum presenting to a pediatric emergency department (ED). RESULTS: Five hundred twenty-three ED visits were analyzed. Mean patient age was 10 years 9 months. Seventeen (3.25%) patients had TT. Pain duration of less than 24 hours (odds ratio [OR], 6.66; 95% confidence interval [CI], 1.54-33.33), nausea and/or vomiting (OR, 8.87; 95% CI, 2.6-30.1), abnormal cremasteric reflex (OR, 27.77; 95% CI, 7.5-100), abdominal pain (OR, 3.19; 95% CI, 1.15-8.89), and high position of the testis (OR, 58.8; 95% CI, 19.2-166.6) were associated with increased likelihood of torsion. CONCLUSIONS: Testicular torsion is uncommon among pediatric patients presenting to the ED with acute scrotum. Pain duration of less than 24 hours, nausea or vomiting, high position of the testicle, and abnormal cremasteric reflex are associated with higher likelihood of torsion. PMID- 20837256 TI - Utilization of ST-segment deviation sum and change scores to identify acute myocardial infarction. AB - OBJECTIVE: No information is currently available regarding the optimal cutoff values of the baseline ST-segment deviation sum (STDsum(baseline)) and 60-minute ST-segment deviation change (STDchange(60 min)) for predicting acute myocardial infarction (AMI). METHODS: A retrospective study was performed in 783 admitted patients with chest pain who had suspected acute coronary syndrome and absence of left ventricular hypertrophy or bundle branch block on the initial electrocardiogram (ECG). The STDsum(baseline) was defined as the sum in millimeters (1 mm = 0.1 mV) of the absolute value of ST-segment deviations in all 12 leads at the initiation of continuous 12-lead ECG monitoring session. The STDchange(60 min) was defined as the absolute value of the difference between the baseline and 60-minute STDsum. Three cutoff values are reported and represent the smallest values in which the positive likelihood ratio (+LR) for AMI was greater than or equal to 5, 10, and 20, respectively. RESULTS: Acute myocardial infarction occurred in 162 (20.7%) patients. The smallest cutoff value of the STDsum(baseline) for AMI with a +LR equal to or greater than 5, 10, and 20 was 9.6, 12.4, and 14.1 mm, respectively. In the subset of 699 patients without ST segment elevation AMI on initial ECG, the smallest cutoff value of the STDchange(60 min) for AMI with a +LR equal to or greater than 5, 10, and 20 was 2.4, 3.5, and 7.9 mm, respectively. CONCLUSIONS: Clinical studies need to be performed to determine if STDsum and STDchange, in conjunction with physician pretest probability of AMI, can be used to select patients who may benefit from emergent reperfusion therapy and other aggressive medical management strategies. PMID- 20837257 TI - Early anion gap metabolic acidosis in acetaminophen overdose. AB - PURPOSE: The study aimed to determine the incidence and clinical significance of early high (>15 mEq/L) anion gap metabolic acidosis in acetaminophen (APAP) overdose. METHODS: A retrospective review of a cohort of 74 patients presenting within 24 hours of APAP overdose was conducted. RESULTS: Early high anion gap metabolic acidosis was present in 41% of patients on admission and persisted for 1.5 +/- 0.1 days. The anion gap was associated with an elevated lactate level (4.5 +/- 1 mmol/L) (r(2) = 0.66, P < .05), which persisted for 1 day. The lactate level increased in proportion to the APAP concentration (r(2) = 0.75, P < .05). Patients with increased anion gap had a higher incidence of confusion (48% vs 3%; P < .001) and lethargy (39% vs 6%; P = .003). Early high anion gap metabolic acidosis was found in the absence of shock or liver failure. All patients were treated with N-acetylcysteine and, despite the early high anion gap metabolic acidosis, none developed hepatic failure or hypoglycemia. CONCLUSION: Early high anion gap metabolic acidosis in patients with APAP overdose is self-limited and does not predict clinical or laboratory outcomes. Persistent or late metabolic acidosis in the absence of liver failure is not likely due to APAP and should prompt a search for other causes of metabolic acidosis. Finally, APAP overdose should be considered in patients presenting to the emergency department with altered mental status, as this is a treatable condition when detected early. PMID- 20837259 TI - ED crowding is associated with an increased time to pneumonia treatment. AB - OBJECTIVE: We measured the correlation between emergency department (ED) occupancy rate and time to antibiotic administration for patients with pneumonia treated in a community hospital setting. METHODS: We reviewed quality improvement data on patients treated for pneumonia in our ED and admitted over a 5-month period. The outcomes were timeliness of antibiotic therapy (within 4 hours of arrival) and overall time to antibiotic administration. Emergency department crowding was measured as the ED occupancy rate. We calculated (1) the Spearman correlation between occupancy rate at time of patient presentation and the time to antibiotic administration, (2) the odds ratio of receiving antibiotics within 4 hours with increasing ED occupancy, and (3) the ability of the occupancy rate to predict failure of achieving the 4-hour goal with the receiver operating characteristic curve. RESULTS: A total of 334 patients were treated over the study period, of which 262 had complete data available. Occupancy rate ranged from 20% to 245%, and median was 137%. Eighty-one percent received antibiotics within 4 hours; the median time was 150 minutes. Time to antibiotics showed a positive correlation with occupancy rate (Spearman rho = 0.17, P = .008). An increasing ED occupancy rate was associated with decreased odds of receiving antibiotics within 4 hours (odds ratio, 0.31; 95% confidence interval, 0.13 0.75). Receiver operating characteristic curve area was 0.62 (95% confidence interval, 0.54-0.70; P = .009). CONCLUSION: Emergency department occupancy rate was associated with increased time to antibiotic treatment for patients admitted with pneumonia. Occupancy rate had fair success in predicting failure of treatment within 4 hours. PMID- 20837258 TI - Risk stratification for hospitalization in acute asthma: the CHOP classification tree. AB - OBJECTIVE: Simple risk stratification rules are limited in acute asthma. We developed and externally validated a classification tree for asthma hospitalization. METHODS: Data were obtained from 2 large, multicenter studies on acute asthma, the National Emergency Department Safety Study and the Multicenter Airway Research Collaboration cohorts. Both studies involved emergency department (ED) patients aged 18 to 54 years presenting to the ED with acute asthma. Clinical information was obtained from medical record review. The Classification and Regression Tree method was used to generate a simple decision tree. The tree was derived in the National Emergency Department Safety Study cohort and then was validated in the Multicenter Airway Research Collaboration cohort. RESULTS: There were 1825 patients in the derivation cohort and 1335 in the validation cohort. Admission rates were 18% and 21% in the derivation and validation cohorts, respectively. The Classification and Regression Tree method identified 4 important variables (CHOP): change [C] in peak expiratory flow severity category, ever hospitalization [H] for asthma, oxygen [O] saturation on room air, and initial peak expiratory flow [P]. In a simple 3-step process, the decision rule risk-stratified patients into 7 groups, with a risk of admission ranging from 9% to 48%. The classification tree performed satisfactorily on discrimination in both the derivation and validation cohorts, with an area under the receiver operating characteristic curve of 0.72 and 0.65, respectively. CONCLUSIONS: We developed and externally validated a novel classification tree for hospitalization among ED patients with acute asthma. Use of this explicit risk stratification rule may aid decision making in the emergency care of acute asthma. PMID- 20837260 TI - Can the degree of hydronephrosis on ultrasound predict kidney stone size? AB - OBJECTIVE: The aim of the study was to determine if the degree of hydronephrosis on focused emergency renal ultrasound correlates with kidney stone size on computed tomography. METHODS: A retrospective study was performed on all adult patients in the emergency department who had a focused emergency renal ultrasound and ureterolithiasis on noncontrast computed tomography. Severity of hydronephrosis was determined by the performing physician. Ureteral stone size was grouped into 5 mm or less and larger than 5 mm based on likelihood of spontaneous passage. RESULTS: One hundred seventy-seven ultrasound scans were performed on patients with ureteral calculi. When dichotomized using test characteristic analysis, patients with none or mild hydronephrosis (72.9%) were less likely to have ureteral calculi larger than 5 mm than those with moderate or severe hydronephrosis (12.4% vs 35.4%; P < .001) with a negative predictive value of 0.876 (95% confidence interval, 0.803-0.925). CONCLUSION: Patients with less severe hydronephrosis were less likely to have larger ureteral calculi. PMID- 20837261 TI - Iguana bites reported to Texas poison centers. AB - Although thousands of iguanas are kept as pets in the United States, information on their bites is limited. The intent of this investigation was to describe the pattern of iguana bites reported to Texas poison centers. Iguana bites reported during 1998-2008 were identified. The distribution of cases by various factors was determined. Of 59 total bites, 71% were managed on-site, 17% of the patients were at or en route to a health care facility when the poison center was contacted, and 10% were referred to a health care facility. The medical outcome was no effect in 9% of the cases, minor effect in 24%, moderate effect in 2%, not followed but minimal effects possible in 64%, and unable to follow but potentially toxic in 2%. Most iguana bites reported to Texas poison centers did not result in serious effects and were managed on-site. PMID- 20837262 TI - Low-dose ketamine for analgesia in the ED: a retrospective case series. AB - OBJECTIVES: The aim of this study was to describe the use and effect of low-dose ketamine (LDK) for analgesia in the emergency department (ED). METHODS: A chart review was performed to identify all adult patients who received LDK for analgesia in our ED. Cases were identified by pharmacy record of ketamine administration. Low-dose ketamine was defined as the administration of 0.1 to 0.6 mg/kg of ketamine for pain control. Use of ketamine during procedural sedation was excluded. Data were analyzed descriptively. RESULTS: Thirty-five cases in which patients received LDK in the ED for a 2-year period were identified. Doses ranged from 5 to 35 mg. Administration was intravenous in 30 (86%) of 35 cases and intramuscular in 5 (14%) of 35 cases. Opioids were administered before or coadministered with LDK in 32 (91%) of 35 cases, and in the remaining 3 cases, opioids were used before the patient came to the ED. Improvement in pain was observed in 19 (54%) of 35 cases in which patients received LDK. Pain scores did not improve in 8 (23%) of 35 cases. Insufficient data were available to determine LDK effect for 8 (23%) of 35 cases. No significant adverse events were identified in any of the 35 cases. CONCLUSIONS: The administration of LDK in the ED may be a safe and effective adjunct for analgesia in some patients. However, prospective randomized controlled trials are needed before widespread use of LDK for analgesia in the ED can be recommended. PMID- 20837263 TI - Contrast-enhanced ultrasound for blunt hepatic trauma: an animal experiment. AB - OBJECTIVE: The aim of this study was to study the value of contrast-enhanced ultrasound (CEUS) in the diagnosis of active hemorrhage and intraparenchymal lesions in blunt hepatic trauma versus conventional ultrasound (US). METHODS: Twenty heparinized and anesthetized domestic pigs have been created to animal models with blunt hepatic trauma by a special impacting device. Conventional US and CEUS were performed to determine if hepatic traumas were present. RESULTS: Active hemorrhage, the presence of intraparenchymal lesions, and sonographic pattern were evaluated for conventional US and CEUS, as compared with laparotomy and pathologic findings. Contrast-enhanced US detected active hemorrhage from the injured livers in all cases, but conventional US did not find that in any case. The sensitivity of CEUS and conventional US in diagnosing intraparenchymal lesions of blunt hepatic trauma were 100% and 60%, respectively. CONCLUSIONS: Contrast-enhanced US is more sensitive than conventional US in determining the active hemorrhage and intraparenchymal lesions in blunt hepatic trauma. PMID- 20837264 TI - Accuracy of emergency physicians using ultrasound to determine gestational age in pregnant women. AB - INTRODUCTION: Rapid and accurate determination of gestational age may be vital to the appropriate care of the critically ill pregnant patient. Before the use of emergency ultrasound, physical examination of fundal height (FH) in the nonverbal patient was considered the quickest method to estimate gestational age. We conducted a prospective, observational study of the performance of bedside sonography to determine gestational age. METHODS: We enrolled a convenience sample of women in their second or third trimester of pregnancy. Emergency physicians (EPs) made ultrasound measurements of fetal biparietal diameter (BPD) and femur length, followed by a measurement of FH. These measurements were compared with true gestational age (TGA), sonography by an ultrasound technician, and measurement of FH performed by an obstetrician. Main outcome measures were the average time needed to complete measurements; correlation coefficients between EP measurements and those made by an ultrasound technician, an obstetrician, and TGA, and overall accuracy to determine fetal age greater than 24 weeks. RESULTS: The average time to complete ultrasound measurements was less than 1 minute. When physician-performed measurements were compared with TGA, the correlation coefficients were 0.947 (0.926-0.968) for BPD, 0.957 (0.941-0.973) for femur length, and 0.712 (0.615-0.809) for FH. When determining fetal viability, EP's overall accuracy was 96% using ultrasound and 80% using FH. CONCLUSIONS: With brief training, EPs can quickly and accurately determine gestational age using ultrasound, and these estimates may be more accurate than those obtained through physical examination. Emergency physicians should consider using ultrasound in emergent evaluation of pregnant patients who are unable to provide history. PMID- 20837266 TI - The use of the i-gel in a developing country. PMID- 20837265 TI - Hazards of tubular gauze finger dressings. PMID- 20837267 TI - Massive atelectasis with acute respiratory failure in postpartum misdiagnosed as pulmonary embolism. PMID- 20837268 TI - Acute severe respiratory distress secondary to misuse of an N-acetylcysteine effervescent tablet. PMID- 20837269 TI - Melioidotic septic arthritis in the ED--an easily delayed diagnosis. PMID- 20837270 TI - "Caustic cocktail": closed-circuit diving apparatus contamination leading to corrosive injury. PMID- 20837271 TI - Lemierre syndrome: no delays in management. PMID- 20837272 TI - Rapidly improving, severe, acute myocarditis after a scorpion bite: an extremely rare complication and successful management. PMID- 20837273 TI - Acute right ventricular failure in lupus-associated protein-losing enteropathy. PMID- 20837274 TI - Hyperthermia occurred after hyperbaric oxygen therapy for carbon monoxide poisoning. PMID- 20837275 TI - Symptomatic pneumorrhachis after chest tube insertion for spontaneous pneumothorax. PMID- 20837276 TI - Hematemesis in a 2009 H1N1 influenza patient. PMID- 20837277 TI - Frequently reported activities by intensity for U.S. adults: the American Time Use Survey. AB - BACKGROUND: Knowing the most-frequently reported physical activities can inform intervention strategies, enhance questionnaire design, and inform objective monitor calibration studies. PURPOSE: To determine the 10 most-frequently reported nonwork and nonsleep activities by intensity (sedentary, light, moderate, vigorous) in American Time Use Survey (ATUS) adult respondents. METHODS: The ATUS is a nationally representative telephone-based survey that captures activities that people recall doing during the preceding 24 hours. ATUS databases from 2003 to 2008 were combined and matched to previously published MET intensity values. Prevalences were rank ordered by weighted frequency within MET defined intensity categories. Analyses took place in spring 2010. RESULTS: Data from 79,652 ATUS respondents, all aged >=20 years, were considered. Overall, the most-frequently reported nonwork, nonsleep sedentary (1.0<=MET<1.6) behavior was eating and drinking (95.6%), followed by watching TV/movies (80.1%); the most frequently reported light activities (1.6<=MET<3.0) were washing, dressing, and grooming oneself (78.9%), followed by driving a car, truck, or motorcycle (71.4%); the most-frequently reported moderate activities (3.0<=MET<6.0) were housework/interior cleaning [corrected] (25.7%) followed by lawn, garden, and houseplant care (10.6%); and the most-frequently reported vigorous activities were using cardiovascular equipment (2.2%) and running (1.1%). CONCLUSIONS: On any given day, most U.S. adults reported performing predominantly sedentary and light activities. The greatest prevalence for reported moderate activities was food and drink preparation for both men (12.8%) and women (37.63%), and overall only 5.07% report any vigorous-intensity activity. PMID- 20837278 TI - Pneumococcal polysaccharide vaccination among adults aged 65 years and older, U.S., 1989-2008. AB - BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for all people aged >=65 years in the U.S. since 1983; consistent surveillance for vaccine coverage has been conducted since 1989. PURPOSE: To assess PPSV23 vaccination coverage among adults aged >=65 years in the U.S. METHODS: The data were analyzed from the 1989, 1991, 1993-1995, and 1997-2008 National Health Interview Surveys in 2009. Multivariable logistic regression and predictive marginal analyses were conducted to identify factors independently associated with receiving PPSV23 in 2008. Missed opportunities for vaccination were also assessed. RESULTS: Among people aged >=65 years, PPSV23 coverage increased from 14.1% in 1989 to 60.1% in 2008. On average, vaccination coverage increased by 3.5% annually during 1989-2000 compared with 1.0% during 2001-2008. In 2008, coverage was significantly higher for people aged 75-84 years (68.8%), and >=85 years (69.0%) compared with those aged 65-74 years (52.5%). Coverage was significantly higher for non-Hispanic whites (64.3%) compared with non-Hispanic blacks (44.6%) and those with Hispanic ethnicity (36.4%). Among people aged >=65 years who reported never receiving PPSV23, 90.6% reported at least one missed opportunity. Characteristics independently associated with increased likelihood of ever receiving PPSV23 were higher age, female, non-Hispanic white race/ethnicity, not employed, higher education level, more physician visits in the past year, hospitalized within past year, having Medicare and other supplemental health insurance, and having a chronic medical condition. CONCLUSIONS: National PPSV23 coverage among people aged >=65 years increased substantially until 2000, but the rate of increase was smaller after 2000 and coverage in 2008 remained well below the national Healthy People 2010 target of 90%. Increased efforts to avoid missed opportunities for pneumococcal vaccination are needed, especially among minority populations. PMID- 20837279 TI - Evaluation of Guillain-Barre Syndrome among recipients of influenza vaccine in 2000 and 2001. AB - BACKGROUND: The 1976-1977 swine influenza vaccine was associated with an elevated risk of Guillain-Barre Syndrome (GBS), especially within 6 weeks after vaccination. A 2004 IOM report concluded that evidence was inadequate to accept or reject a causal relationship between subsequent influenza vaccine formulations and GBS. Studies published after the IOM report have been limited by passively reported data or lack of validation of coded diagnoses. PURPOSE: To evaluate whether influenza vaccine is associated with GBS. METHODS: Controlled observational study using national data from the Medicare program, which ensures a predominantly elderly population. People included had a Medicare claim for influenza vaccination during September-December in 2000 or 2001. Medical records were reviewed to classify definite, probable, or possible GBS (or not a case) using a standardized case definition. In a risk interval design, the incidence rate of GBS during Weeks 0-6 after vaccination (exposed period) was compared to Weeks 9-14 after vaccination (comparison period). Data collection occurred during 2003-2007, and analysis was conducted during 2007-2009. RESULTS: Primary analysis included 22.2 million vaccinees, among whom 164 definite or probable GBS cases with onset during Weeks 0-6 or 9-14 were identified. The incidence rate ratio (IRR [95% CIs]) based on the GBS rate in the vaccine-exposed versus comparison periods, was 1.04 (0.76, 1.43) for combined years; 0.86 (0.52, 1.41) among people vaccinated in 2000; and 1.21 (0.79, 1.86) among people vaccinated in 2001. Secondary analysis additionally included 74 possible GBS cases; results were similar. CONCLUSIONS: Overall, the results do not support an association between influenza vaccine receipt and GBS among the elderly for the years studied (2000 2001 and 2001-2002 formulations). PMID- 20837280 TI - Trend and prevalence estimates based on the 2008 Physical Activity Guidelines for Americans. AB - BACKGROUND: According to the 2008 Physical Activity Guidelines for Americans, adults need to engage in at least 150 minutes/week of moderate-intensity activity or its equivalent (defined as aerobically active) to obtain substantial health benefits and more than 300 minutes/week (defined as highly active) to obtain more extensive health benefits. In addition to aerobic activity, the 2008 Guidelines recommend that adults participate in muscle-strengthening activities on 2 or more days/week. PURPOSE: This study examined the prevalence and trends of meeting the activity criteria defined by the 2008 Guidelines among U.S. adults. METHODS: Prevalence and trends of participation in leisure-time physical activity were estimated from the 1998-2008 National Health Interview Survey (analyzed in 2010). RESULTS: In 2008, 43.5% of U.S. adults were aerobically active, 28.4% were highly active, 21.9% met the muscle-strengthening guideline, and 18.2% both met the muscle-strengthening guideline and were aerobically active. The likelihood of meeting each of these four activity criteria was similar and were associated with being male, being younger, being non-Hispanic white, having higher levels of education, and having a lower BMI. Trends over time were also similar for each part of the 2008 Guidelines, with the prevalence of participation exhibiting a small but significant increase when comparing 1998 to 2008 (difference ranging from 2.4 to 4.2 percentage points). CONCLUSIONS: Little progress has been made during the past 10 years in increasing physical activity levels in the U.S. There is much room for improvement in achieving recommended levels of physical activity among Americans, particularly among relatively inactive subgroups. PMID- 20837281 TI - Predictors of inflammation in U.S. children aged 3-16 years. AB - BACKGROUND: Little is known about the correlates of low-grade inflammation in U.S. children. PURPOSE: This study describes the factors associated with increased levels of C-reactive protein (CRP) in U.S. children and tests whether differences in CRP emerge in childhood because of socioeconomic factors. METHODS: Data were analyzed in 2009 from 6004 children aged 3-16 years from the National Health and Nutrition Examination Survey, 1999-2004, a representative sample of the U.S. non-institutionalized population. Tobit regression models are used to evaluate associations between predictors, including BMI-for-age, skinfold body fat measures, chronic infections, environmental tobacco exposure, low birth weight, and sociodemographics and continuous high-sensitivity CRP in milligrams per liter. RESULTS: CRP levels were higher in U.S. children with lower family income, and these differences were largely accounted for by differences in adiposity and recent illness. Mexican-American children had higher levels of CRP compared to both whites and blacks, but these differences were not explained by measured physical risk factors. CONCLUSIONS: Increased adiposity is associated with higher CRP concentrations in U.S children aged 3-16 years, and both socioeconomic and racial/ethnic differences exist in systemic inflammation in U.S. children. Increased childhood obesity and low-grade inflammation may contribute to later life chronic disease risk. PMID- 20837282 TI - Physician communication techniques and weight loss in adults: Project CHAT. AB - BACKGROUND: Physicians are encouraged to counsel overweight and obese patients to lose weight. PURPOSE: It was examined whether discussing weight and use of motivational interviewing techniques (e.g., collaborating, reflective listening) while discussing weight predicted weight loss 3 months after the encounter. METHODS: Forty primary care physicians and 461 of their overweight or obese patient visits were audio recorded between December 2006 and June 2008. Patient actual weight at the encounter and 3 months after the encounter (n=426); whether weight was discussed; physicians' use of motivational interviewing techniques; and patient, physician, and visit covariates (e.g., race, age, specialty) were assessed. This was an observational study and data were analyzed in April 2009. RESULTS: No differences in weight loss were found between patients whose physicians discussed weight or did not. Patients whose physicians used motivational interviewing-consistent techniques during weight-related discussions lost weight 3 months post-encounter; those whose physician used motivational interviewing-inconsistent techniques gained or maintained weight. The estimated difference in weight change between patients whose physician had a higher global motivational interviewing-Spirit score (e.g., collaborated with patient) and those whose physician had a lower score was 1.6 kg (95% CI=-2.9, -0.3, p=0.02). The same was true for patients whose physician used reflective statements: 0.9 kg (95% CI=-1.8, -0.1, p=0.03). Similarly, patients whose physicians expressed only motivational interviewing-consistent behaviors had a difference in weight change of 1.1 kg (95% CI=-2.3, 0.1, p=0.07) compared to those whose physician expressed only motivational interviewing-inconsistent behaviors (e.g., judging, confronting). CONCLUSIONS: In this observational study, use of motivational interviewing techniques during weight loss discussions predicted patient weight loss. PMID- 20837283 TI - Statewide efforts to narrow the rural-urban gap in acute stroke care. AB - BACKGROUND: Rural-urban gaps in stroke care remain challenging in part because of the lack of resources, personnel, and necessary infrastructure. PURPOSE: The purpose of this study was to assess changes in the acute stroke diagnosis and treatment capacity among rural hospitals before and after implementation of a regionwide stroke initiative. METHODS: In 2004, the Montana Cardiovascular Health Program partnered with stroke stakeholders throughout the state and surveyed hospitals in Montana and northern Wyoming to assess the availability of technology, services, and personnel for acute stroke care. The Montana Stroke Initiative (MSI) developed protocols, educational material, and stroke awareness campaigns to address the geographic disparities identified in the survey. From 2004 to 2006, protocols and educational material were made available on a website and distributed to rural and critical-access hospitals throughout the region. Stroke awareness campaigns were completed, and MSI members conducted acute stroke care training of prehospital, nursing, and primary providers throughout the region. A follow-up survey in 2008 assessed changes in the stroke systems of care between 2004 and 2008. Data were analyzed in 2009. RESULTS: There were significant increases in availability of prehospital stroke screens, written emergency department protocols, computed tomographic scanning capability, acute stroke teams, and community stroke awareness programs. CONCLUSIONS: A systematic statewide effort to improve stroke care led to improved acute stroke care capabilities in necessary infrastructure in rural facilities and a narrowing of the gap between these facilities and the urban facilities. PMID- 20837284 TI - Finding the minimal intervention needed for sustained mammography adherence. AB - BACKGROUND: Regular adherence to mammography screening saves lives, yet few women receive regular mammograms. DESIGN: RCT. SETTING/PARTICIPANTS: Participants were recruited through a state employee health plan. All were women aged 40-75 years and had recent mammograms prior to enrollment (n=3547). Data were collected from 2004 to 2009. INTERVENTION: Trial tested efficacy of a two-step adaptively designed intervention to increase mammography adherence over 4 years. The first intervention step consisted of three reminder types: enhanced usual care reminders (EUCR); enhanced letter reminders (ELR); both delivered by mail, and automated telephone reminders (ATR). After delivery of reminders, women who became off-schedule in any of the 4 years received a second step of supplemental interventions. Three supplemental intervention arms contained priming letters and telephone counseling: barriers only (BarriCall); barriers plus positive consequences of getting mammograms (BarriConCall+); and barriers plus negative consequences of not getting mammograms (BarriConCall-). MAIN OUTCOME MEASURES: Average cumulative number of days non-adherent to mammography over 4 years based on annual screening guidelines (analyses conducted in 2009). RESULTS: All reminders performed equally well in reducing number of days of non-adherence. Women randomized to receive supplemental interventions had significantly fewer days of non-adherence compared to women who received EUCR (p=0.0003). BarrConCall+ and BarrConCall- conditions did not significantly differ in days non adherent compared to women in the barriers-only condition (BarriCon). CONCLUSIONS: The minimal intervention needed for sustained mammography use is a combination of a reminder followed by a priming letter and barrier-specific telephone counseling for women who become off-schedule. Additional costs associated with supplemental interventions should be considered by organizations deciding which interventions to use. TRIAL REGISTRATION NUMBER: NCT01148875. PMID- 20837286 TI - Taking stock a bibliometric analysis of the focus of tobacco research from the 1980s to the 2000s. AB - BACKGROUND: Little is known about the body of tobacco research as a whole. PURPOSE: This paper examines the changes in literature focus (1980s to 2000s) and identifies areas in need of increased attention. METHODS: Tobacco articles randomly selected from searches of the MEDLINE and Web of Science databases were coded according to (1) epidemiologic framework component; (2) study focus; and (3) form of tobacco. Frequencies, cross-tabulations, and tests of proportions were conducted. The analysis was conducted in 2009. RESULTS: From the 1980s to the 2000s, there was a significant decrease in tobacco-related articles focusing on the "agent" and an increase in articles focusing on the "host." Few articles in either decade focused on the "environment" or on the "vector" (<10%). The percentage of study foci addressing health effects decreased, whereas prevalence/use and cessation foci increased. Approximately two thirds of articles focused on the cigarette. CONCLUSIONS: The nature of tobacco research has shifted from examining the links between cigarettes and disease to understanding why people smoke and how to help them quit. Proportionately more research could focus on the environment and vector components of the epidemiologic framework, to expand strategies for reducing tobacco-related disease. PMID- 20837285 TI - Weight concerns, mood, and postpartum smoking relapse. AB - BACKGROUND: The majority of women who quit smoking as a result of pregnancy will resume smoking during the first 6 months postpartum. Evidence suggests that changes in depressive symptoms, perceived stress, and concerns about weight may relate to postpartum smoking relapse. PURPOSE: This study was designed to prospectively evaluate the relationship of mood and weight concerns to postpartum smoking among women who quit smoking during pregnancy. METHODS: Pregnant women who had quit smoking (N=183) were recruited between February 2003 and November 2006. Women completed assessments of mood (depressive symptoms, perceived stress, positive and negative affect) and weight concerns during the third trimester of pregnancy and at 6, 12, and 24 weeks postpartum. Self-reported smoking status was verified by expired-air carbon monoxide and salivary cotinine at each assessment. Cox regression analyses in which mood and weight concerns were treated as time dependent covariates were conducted in 2007 and 2009. RESULTS: By 24 weeks postpartum, 65% of women had resumed smoking. Smoking-related weight concerns increased risk of relapse, and positive affect and self-efficacy for weight management without smoking decreased risk of relapse postpartum. Moreover, after controlling for variables previously related to postpartum relapse, weight concerns remained significantly related to smoking relapse. CONCLUSIONS: Smoking related weight concerns and positive affect increase the likelihood that a woman will resume smoking postpartum. Moreover, weight concerns appear to be salient even in the context of other factors shown to affect postpartum smoking. This study suggests that interventions may need to address women's weight concerns and mood to help sustain smoking abstinence after childbirth. PMID- 20837287 TI - Increase in unintentional medication overdose deaths: Oklahoma, 1994-2006. AB - BACKGROUND: During 1999-2006, rates of unintentional drug-related deaths increased 120% in the U.S. PURPOSE: This report describes demographics and trends of unintentional medication overdose deaths among Oklahoma residents to target prevention strategies. METHODS: Oklahoma medical examiner data regarding fatal unintentional poisonings involving at least one prescription or over-the-counter medication during 1994-2006 and opioid retail sales data during 1997-2006 were analyzed during 2008-2009 to determine demographic-specific rates of overdose deaths and changes in 3-year mean death rates. RESULTS: A total of 2112 fatal unintentional medication overdoses were identified (4.7 deaths/100,000 population) involving a median of two substances/decedent. The highest fatality rates occurred among men (5.9/100,000) and people aged 35-54 years (11/100,000). Crude overdose death rates increased sevenfold during the investigation period, peaking at 11/100,000 in 2006. Death rates increased more for women (ninefold) than men (sixfold); rates among residents of rural counties increased more (eightfold) than urban county rates (sixfold). Leading drug types involved in fatalities were opioids and anxiolytics. The individual drugs contributing most frequently included methadone (31%); hydrocodone (19%); alprazolam (15%); and oxycodone (15%). During 1997-2006, Oklahoma prescription opioid sales increased fourfold. Methadone was associated with the highest number of deaths per equianalgesic dose sold (23.3), whereas hydrocodone and oxycodone had the highest increases in deaths per equianalgesic dose sold (threefold increase each). CONCLUSIONS: Unintentional medication-related deaths are increasing in Oklahoma and often involve multiple substances. Substances most frequently contributing to deaths were prescription opioid analgesics. Prevention strategies should target people aged 35-54 years and emphasize the dangers of coingesting substances and misusing prescription pain medications. PMID- 20837288 TI - Replication of the neighborhood active living potential measure in Saskatoon, Canada. AB - BACKGROUND: Few neighborhood observational measures have been replicated by separate research teams in different cities. PURPOSE: This study replicates the neighborhood active living potential observation measure in Saskatoon, Saskatchewan, Canada. METHODS: Observers (n=5) participated in a 3-day neighborhood active living potential training session. Observers rated 60 neighborhoods in Saskatoon during the summer of 2009 by following a predetermined walking route constructed by joining ten randomly selected street segments for each neighborhood. Pairs of observers independently rated neighborhoods using an 18-item observation grid. Items represented three a priori-defined domains of active living potential: activity friendliness (six items); safety (four items); and density of destinations (eight items). Data analysis was conducted in autumn 2009. RESULTS: Application of ecometric multilevel modeling analyses showed that once inter-item and inter-observer variability were statistically controlled, one third of the variability in observations was among neighborhoods. Reliability estimates for observers were 0.84 for items measuring activity friendliness, 0.82 for safety, and 0.91 for density of destinations. Convergent validity showed that neighborhood income was associated negatively with density of destinations, positively with safety, and not associated with activity friendliness. Percentage of people in the neighborhood walking to work was positively associated with density of destinations and not associated with safety or activity friendliness. CONCLUSIONS: Results replicate findings from Montreal, Canada, that the three dimensions of the neighborhood active living potential measure have good reliability and convergent validity. Neighborhood active living potential appears to be a stable measure capturing three essential elements of neighborhoods. PMID- 20837289 TI - Smoke alarm and battery function 42 months after installation: a randomized trial. AB - BACKGROUND: This randomized trial presents findings from the longest follow-up study of smoke alarm and battery function to date. PURPOSE: The purpose of this study is to examine differences in long-term function of smoke alarm and battery combinations. METHODS: A total of 691 households in an ongoing cohort study were randomly allocated into smoke alarm groups of ionizing and photoelectric and battery groups of zinc and lithium. Smoke alarm function was measured in 633 (91.6%) households from January 2007 through February 2008, 42 months following original smoke alarm/battery installation. Data analyses were conducted in 2009. RESULTS: After 3.5 years, 81.9% of the 1898 smoke alarms were functional. Ionizing alarms with zinc batteries were the least likely to function (72.7%). In comparison, photoelectric alarms with lithium batteries were 2.9 times (95% CI=1.8, 4.5) more likely to function; ionizing alarms with lithium batteries were 2.0 times (95% CI=1.3, 3.1) more likely to function; and photoelectric alarms with zinc batteries were 1.7 times (95% CI=1.1, 2.5) more likely to function. Functionality was strongly tied to number of reports of nuisance alarms, which was higher for ionizing than photoelectric alarms. CONCLUSIONS: Photoelectric smoke alarms and lithium batteries are the most likely to function long after smoke alarm installation, and may be worthwhile investments despite their increased cost. PMID- 20837290 TI - Dissemination of results in community-based participatory research. AB - CONTEXT: Community-based participatory research (CBPR) has been promoted as an approach to understanding complex health problems not amenable to research conducted solely by outside investigators. Although broad dissemination of research results is a key element of the CBPR approach, existing dissemination efforts have not been assessed. EVIDENCE ACQUISITION: In this systematic review, researchers evaluated studies utilizing the CBPR approach to characterize dissemination of research results beyond scientific publication. Specifically, the focus was on dissemination to community participants and the general public. The literature search encompassed articles published between January 1, 2005, and December 31, 2009. Corresponding authors were also invited to complete a web based survey. Data were collected and analyzed between July 1, 2008, and March 8, 2010. EVIDENCE SYNTHESIS: In all, 101 articles met inclusion criteria. All articles were assessed for the quality of community involvement in research. Scores ranged from 1.4 to 3.0 (on a 3-point scale), with a mean of 2.3. The 21 articles in which an intervention was evaluated were scored for the rigor of research methods. Scores ranged from 2.0 to 2.9 (on a 3-point scale), with a mean of 2.4. Dissemination beyond scientific publication was reported in 48% of publications with varying levels of detail. However, among survey respondents, 98% reported dissemination of results to community participants and 84% reported dissemination to the general public. CONCLUSIONS: Among research meeting strict criteria for inclusion as CBPR, dissemination beyond scientific publication is largely occurring. However, myriad challenges to timely and widespread dissemination remain, and current dissemination to community participants and the general public is variable. PMID- 20837291 TI - Occupational sitting and health risks: a systematic review. AB - CONTEXT: Emerging evidence suggests that sedentary behavior (i.e., time spent sitting) may be negatively associated with health. The aim of this study was to systematically review the evidence on associations between occupational sitting and health risks. EVIDENCE ACQUISITION: Studies were identified in March-April 2009 by literature searches in PubMed, PsycINFO, CENTRAL, CINAHL, EMBASE, and PEDro, with subsequent related-article searches in PubMed and citation searches in Web of Science. Identified studies were categorized by health outcome. Two independent reviewers assessed methodologic quality using a 15-item quality rating list (score range 0-15 points, higher score indicating better quality). Data on study design, study population, measures of occupational sitting, health risks, analyses, and results were extracted. EVIDENCE SYNTHESIS: 43 papers met the inclusion criteria (21% cross-sectional, 14% case-control, 65% prospective); they examined the associations between occupational sitting and BMI (n=12); cancer (n=17); cardiovascular disease (CVD, n=8); diabetes mellitus (DM, n=4); and mortality (n=6). The median study-quality score was 12 points. Half the cross sectional studies showed a positive association between occupational sitting and BMI, but prospective studies failed to confirm a causal relationship. There was some case-control evidence for a positive association between occupational sitting and cancer; however, this was generally not supported by prospective studies. The majority of prospective studies found that occupational sitting was associated with a higher risk of DM and mortality. CONCLUSIONS: Limited evidence was found to support a positive relationship between occupational sitting and health risks. The heterogeneity of study designs, measures, and findings makes it difficult to draw definitive conclusions at this time. PMID- 20837292 TI - Evidence of health risks from occupational sitting: where do we stand? PMID- 20837293 TI - Impact factor. Editorial. PMID- 20837295 TI - Misconceptions about hyperchloremic acidosis. PMID- 20837296 TI - Chemical versus physiologic interdependence of acid-base variables. PMID- 20837299 TI - Age and comedications influence levetiracetam pharmacokinetics in children. AB - The pharmacokinetics of many antiepileptic drugs differs between adults and children. The influence of age and concomitant medications on the dose/concentration ratio of levetiracetam was examined in 103 children with epilepsy. Dosing and plasma levels of levetiracetam and concomitant antiepileptic drugs were reviewed retrospectively. The dose/concentration ratio was calculated as the weight-normalized dose (mg/kg/day) divided by the steady-state trough plasma drug level, which was used as a measure of apparent oral clearance of levetiracetam. Children were classified into age groups and treatment groups: levetiracetam given with enzyme inducers (n = 24) or nonenzyme inducers (n = 69), or as monotherapy (n = 10). Levetiracetam clearance differed significantly between age groups (0-4, 5-11, and 12-17 years), i.e., the younger the child, the higher the clearance. The increase was 1.7-fold between the youngest and oldest age groups. Children on enzyme inducers exhibited significantly higher clearance (1.3-fold), compared with those on nonenzyme inducers and monotherapy. Levetiracetam did not influence the clearance of lamotrigine, valproate, topiramate, or clonazepam. In conclusion, younger age and comedication with an enzyme inducer increased levetiracetam clearance. This finding should be taken into account when treating individual patients. PMID- 20837300 TI - Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. AB - According to increasing evidence, hypothermia can significantly improve outcomes in term neonates manifesting asphyxic insult and hypoxic-ischemic encephalopathy. Oxidative stress plays a key role in hypoxic-ischemic and inflammatory brain injuries. We investigated the impact of hypothermia on oxidative stress in babies with hypoxic-ischemic encephalopathy. Term infants were randomly selected for treatment with moderate whole body hypothermia or standard care on normothermia, after perinatal asphyxia. Total hydroperoxides as biochemical markers of oxidative stress, and C-reactive protein as a marker of inflammation, were assayed in blood samples drown at 6, 12, 24, 48, and 72 postnatal hours. In both hypothermic and normothermic groups, total hydroperoxides and C-reactive protein exhibited a continuous increase in the first days after birth. Nevertheless, a tendency was evident for slower and smaller elevations of total hydroperoxides and C-reactive protein in hypothermic compared with normothermic infants. A significant correlation was observed between total hydroperoxides and C-reactive protein in all patients, indicating an association between inflammation and oxidative stress during asphyxia. The slower increase and lower peaks of total hydroperoxides in the hypothermic group support the hypothesis that postasphyxic oxidative stress may be reduced by hypothermia. PMID- 20837301 TI - Sturge-Weber syndrome: ear, nose, and throat issues and neurologic status. AB - The pathophysiology of Sturge-Weber syndrome is poorly understood, and ear, nose, and throat involvement is possible. These issues can result in frequent illnesses or airway obstruction, affecting patients' neurologic status. Patients with definite brain involvement who reported potential ear, nose, and throat issues on intake questionnaires underwent retrospective reviews of their medical records. We examined the relationships between these issues, secondary surgical interventions, and patients' neurologic status. The most common complaints involved the sinuses and frequent ear infections. Six patients underwent placement of ear tubes, leading to improvements in migraines and stroke-like episodes in one patient, and improved seizure control in four others. Obstructive sleep apnea was confirmed in three patients who underwent sleep studies. Tonsil or adenoid removal occurred in another three patients. Surgery resulted in marked improvements regarding excessive drooling, daytime sleepiness, and breathing problems. These findings suggest that ear, nose, and throat problems occur frequently in patients with Sturge-Weber Syndrome, and when repeated ear infections are associated with uncontrolled seizures, early placement of ear tubes may be beneficial. Furthermore, patients with facial tissue hypertrophy may be at risk for obstructive sleep apnea, and should be appropriately evaluated. PMID- 20837302 TI - Clinical features and outcomes of holoprosencephaly in Korea. AB - The clinical spectrum of holoprosencephaly is broad, and its etiology is heterogeneous. To investigate the clinical spectrum of holoprosencephaly in Korea, we performed a database analysis of 55 cases of holoprosencephaly, including 12 diagnosed postnatally, all from a single institution. The 55 patients were categorized into several types: 37 alobar, eight semilobar, eight lobar, and two middle interhemispheric variant. Associated brain (41.8%) and craniofacial (74.5%) features varied substantially. Of 40 patients studied according to karyotype, chromosomal aberrations were detected in 18 (45.0%). Twenty-seven (49.1%) patients, diagnosed postnatally, exhibited milder types of holoprosencephaly and less profound craniofacial malformations than in prenatal diagnoses. Moreover, in postnatally diagnosed patients, the subgroup surviving longer than 1 month also exhibited a milder holoprosencephaly type and lower incidence of associated craniofacial malformations. The most frequent clinical signs in living children with holoprosencephaly included microcephaly, global developmental delay, and seizures. Holoprosencephaly represents a heterogeneous entity with different clinical manifestations and etiologies. A high index of suspicion, coupled with appropriate imaging studies, can enable accurate diagnoses and prognoses of holoprosencephaly. PMID- 20837303 TI - Concussion or mild traumatic brain injury: parents appreciate the nuances of nosology. AB - We explored whether parents of our pediatric patients valued the diagnostic terms "concussion," "minor traumatic brain injury," and "mild traumatic brain injury" as equivalent or nonequivalent. 1734 of 2304 parents attending a regional pediatric emergency department completed a brief questionnaire assessing the equivalence or nonequivalence of the diagnostic terms "concussion," "minor traumatic brain injury," and "mild traumatic brain injury" in a pairwise fashion. Many parents viewed these diagnostic terms as equivalent, when assessed side by side. For those who considered these diagnostic terms nonequivalent, concussion was regarded as considerably "better" (or less "worse") than minor traumatic brain injury (P < 0.001, chi(2) test) or mild traumatic brain injury (P < 0.001, chi(2) test). A moderate degree of variability was evident in parent/guardian responses. As a group, parents reported that concussion or mild/minor traumatic brain injuries are valued equivalently. However, many parents considered them different, with concussion reflecting a "better" (or less "worse") outcome. PMID- 20837304 TI - Cerebral MRI and cognition in nonhandicapped, low birth weight adults. AB - This study sought to compare cognitive and cerebral findings of magnetic resonance imaging in young adults with low birth weights and in a control group. One hundred thirteen of 173 (65%) eligible adults with birth weights <2000 g, and 100 of 170 (59%) controls, all without major disabilities, were examined at age 19 years. Cerebral 3.0 T magnetic resonance imaging was performed according to standardized protocols. Prorated intelligence quotient was estimated from two subtests of the Wechsler Abbreviated Scale of Ability, a word comprehension test, and matrices. Prominent lateral ventricles and loss of white matter, and thinning of the corpus callosum, were more common in the low birth weight group than in the control group (40% vs. 15%, respectively; odds ratio, 3.8; P < 0.001; and 31% vs. 7%, respectively; odds ratio, 6.0; P < 0.001). Low birth weight adults exhibited lower mean intelligence quotients (95 vs. 101, respectively; P < 0.001). Low birth weight adults face an increased risk of prominent ventricles, global loss of white matter, and thinning of the corpus callosum. Similar magnetic resonance imaging findings are not uncommon among healthy adults. PMID- 20837305 TI - Nerve root enhancement on spinal MRI in pediatric Guillain-Barre syndrome. AB - Guillain-Barre syndrome diagnosis is based on clinical presentation and supportive diagnostic testing. In its early stage, no single, reliable diagnostic test is available. However, a finding of nerve root enhancement on spinal magnetic resonance imaging may be useful. We evaluated the frequency of nerve root enhancement on spinal magnetic resonance imaging in children with Guillain Barre syndrome. At a single tertiary pediatric center, we conducted a retrospective chart review of children with Guillain-Barre syndrome who had complete spinal or lumbosacral spinal magnetic resonance imaging with gadolinium administration from January 2002-January 2009. Twenty-four consecutive patients were identified. Spinal nerve root enhancement with gadolinium was present in 92% (22/24) of children with Guillain-Barre syndrome on initial spinal magnetic resonance imaging (95% confidence interval, 0.745-0.978). This finding increased to 100% of patients, after two patients underwent repeat spinal magnetic resonance imaging that did reveal nerve root enhancement. Patterns of enhancement were variable, but involved the thoracolumbar nerve roots in all patients. Enhancement of nerve roots with gadolinium on initial spinal magnetic resonance imaging was frequently present in these children with Guillain-Barre syndrome. Spinal magnetic resonance imaging is a sensitive diagnostic test and should be considered an additional diagnostic tool in select cases. PMID- 20837306 TI - Severe hypernatremia in a hospitalized child: munchausen by proxy. AB - An 8-week-old infant presented to a referring institution with profuse diarrhea and infectious enteritis for 1 week. He was initially treated for suspected Salmonella spp. sepsis and meningitis, because the organism was found in the stool, but the child's illness progressed, manifested by paroxysmal profuse diarrhea and increased urine output. After several weeks, he suffered a sagittal venous thrombosis and intracranial hemorrhage. Subsequently the child was transferred to a tertiary center for intestinal evaluation. The patient's diarrhea and excessive diuresis resolved, and his sodium normalized soon after transfer. Four days later, however, after his mother arrived, he immediately developed severe hypernatremia (serum sodium concentration [Na(+)] = 214 mEq/L), with resumption of diarrhea and excessive diuresis. A gastric aspirate during the crisis demonstrated an extremely high sodium content, [Na(+)] = 1416 mEq/L, consistent with salt intoxication. Surveillance of the mother revealed that she manipulated the indwelling nasogastric tube; confronted, she admitted to salt administration. This case describes one of the ways that Munchausen syndrome by proxy can manifest with profound neurologic sequelae, and highlights the need for close observation and swift intervention when sufficient cause is present. PMID- 20837307 TI - Anti-NMDA receptor encephalitis with atypical brain changes on MRI. AB - A young girl with antibodies to the N-methyl-D-aspartate receptor presented with a clinical syndrome suggestive of dyskinetic encephalitis lethargica with neuropsychiatric features at presentation, movement disorder, mutism, sleep disorder, and seizures. Persistent lesions in the white matter and pons were observed in magnetic resonance imaging of the brain, findings that have not been described previously in N-methyl-D-aspartate receptor antibody encephalitis. PMID- 20837308 TI - Glutaric aciduria type 2, late onset type in Thai siblings with myopathy. AB - Reported here is a novel presentation of late onset glutaric aciduria type 2 in two Thai siblings. A 9-year-old boy presented with gradual onset of proximal muscle weakness for 6 weeks. The initial diagnosis was postviral myositis, and then polymyositis. Electromyography and nerve conduction velocity testing indicated a myopathic pattern. Muscle biopsy revealed excessive accumulation of fat. Acylcarnitine profiling led to the diagnosis of glutaric aciduria type 2. Immunoblot analysis of electron-transferring-flavoprotein and its dehydrogenase electron-transferring-flavoprotein dehydrogenase led to mutation analysis of the ETFDH gene, which revealed two different pathogenic mutations in both alleles and confirmed the diagnosis of glutaric aciduria type 2 caused by electron transferring-flavoprotein dehydrogenase deficiency. The boy recovered completely after treatment. Later, his younger sibling became symptomatic; the same diagnosis was confirmed, and treatment was similarly effective. Acylcarnitine profiling was a crucial investigation in making this diagnosis in the presence of normal urine organic acid findings. Late onset glutaric aciduria type 2, a rare cause of muscle weakness in children, should be included in the differential diagnosis of myopathy. PMID- 20837309 TI - Novel LMNA mutation presenting as severe congenital muscular dystrophy. AB - Mutations in the lamin A/C gene determine a heterogeneous group of congenital diseases, termed laminopathies, consisting of more than 15 phenotypes, including autosomal dominant Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy type 1B. Early onset in infancy has been described in these muscular dystrophies. Reported here is a 7-year-old male with congenital muscular dystrophy. Remarkably, muscle weakness and wasting affected predominantly axial muscles as well as proximal upper and distal lower extremities. The patient rapidly developed joint contractures and spine rigidity with the head only mildly flexed. Serum creatine kinase was moderately elevated. Muscle biopsy indicated a dystrophic pattern with normal immunochemical findings. A novel, de novo missense substitution p.Asn39Tyr within the lamin A/C gene confirmed the diagnosis of a laminopathy. This report broadens the spectrum of lamin A/C gene mutations and illustrates the phenotypic variability of laminopathies with early onset congenital muscular dystrophy. Mutations in the lamin A/C gene should be sought in any infant with dystrophic features and normal tissue immunochemical studies; especially in the presence of moderately elevated serum creatine kinase, predominant axial and humeroperoneal weakness, spine rigidity, and joint contractures. PMID- 20837310 TI - Isolated sympathetic failure with autoimmune autonomic ganglionopathy. AB - A 16-year-old boy had a gradual onset of post-exercise myalgia with progressive fatigue and dizziness. He had bradycardia (37 beats/minute) with low supine and normal standing norepinephrine levels (56 and 311 pg/mL, respectively). He had absent sympathetically mediated vasoconstrictor responses during Valsalva maneuver testing. Circulating ganglionic acetylcholine receptor antibodies were identified. Response was gradual to treatment with intravenous immunoglobulin combined with aggressive symptomatic interventions (permanent pacemaker implantation and treatment with pyridostigmine, midodrine, and modafinil). After the intravenous immunoglobulin treatment, his autoantibody levels decreased and the autonomic abnormalities resolved. After a reconditioning exercise program and eventually undetectable antibody titers, he achieved complete recovery. The patient continued to do well after his pacemaker was removed and his medications were discontinued. Thus, severe isolated sympathetic nervous system failure can occur in adolescents with autoimmune autonomic ganglionopathy, and multifaceted treatment can be effective. PMID- 20837311 TI - Pediatric neuro-Behcet's disease responsive to adalimumab. AB - Neurologic manifestations of Behcet's disease (neuro-Behcet's disease) are uncommon, but may cause patients significant morbidity and mortality. Neuro Behcet's disease is chronic and may be refractory to treatment. We report on a 12 year-old girl with neuro-Behcet's disease that responded to standard doses of subcutaneous adalimumab. PMID- 20837312 TI - Stroke in early childhood due to homocystinuria. AB - A previously healthy girl, age 3 years 9 months, presented with right-sided hemiparesis and seizures. Ischemic infarction was confirmed through magnetic resonance imaging and magnetic resonance angiography. Extensive evaluation to discover the underlying etiologies and risk factors predisposing this patient to stroke included coagulation defects, cardiac anomalies, congenital inborn metabolism deficiency, and infections and trauma. Based on the clinical and laboratory results, a diagnosis of homocystinuria was made. Homocystinuria is an inherited disorder that affects the metabolism of the amino acid methionine. Although homocystinuria is usually associated with ischemic strokes, the sudden onset of stroke as the initial clinical presentation of homocystinuria is very rare in early childhood. Based on this case, however, metabolic screening for hyperhomocystinemia is recommended in any child presenting with a stroke. PMID- 20837313 TI - New onset epilepsy in Prader-Willi syndrome: semiology and literature review. AB - Prader-Willi syndrome is a chromosomal disorder caused by absence of expression of the paternal active genes in the 15q11~q13 chromosome region; it is associated with an increased incidence of epilepsy and narcolepsy. Presented here is the case of a 2.5-year-old boy with Prader-Willi syndrome and a history of neonatal superior sagittal sinus thrombosis with new onset of atonic seizures with electrographic onset from the parasagittal region. It is postulated that microscarring from neonatal venous sinus thrombosis, history of febrile seizures, and Prader-Willi syndrome are factors predisposing him to epilepsy. The importance of video electroencephalography with electromyography electrodes is emphasized for Prader-Willi syndrome patients with drop episodes, to differentiate cataplexy from seizures. This being a novel report of a Prader Willi syndrome patient with atonic seizures, the literature on seizure semiology among patients with Prader-Willi syndrome is reviewed. PMID- 20837314 TI - Paternal age in autism spectrum disorders and ADHD. AB - Increased paternal age has been associated with an increased risk for autism spectrum disorders. The present study compared the paternal age distribution in autism spectrum disorders children with that of the general population and among children with attention deficit hyperactivity disorder. Study participants were drawn from the records of children diagnosed with one of these conditions in the years 1998-2006 at the Weinberg Child Development Center, Israel. Data regarding paternal age distribution in the general Israeli population were drawn from the yearly official publications of the Central Bureau of Statistics, Israel. Paternal age at the child's birth was found for autism spectrum disorders children (n = 268) and attention deficit hyperactivity disorders children (n = 320). Paternal age distribution of the attention deficit hyperactivity disorder children was similar to that of the general population in Israel, whereas autism spectrum disorders children were born to older fathers, compared with either the general population (P < 0.001) or children with attention deficit hyperactivity disorder (P = 0.04). These results support the claim that increased paternal age is associated with a birth of a child with autism spectrum disorders, but indicate that this finding cannot be generalized to attention deficit hyperactivity disorder. PMID- 20837316 TI - Cerebellar mutism in pediatric acute disseminated encephalomyelitis. PMID- 20837317 TI - Seizure susceptibility due to antihistamines in febrile seizures. PMID- 20837319 TI - Reporting of minority participation rates and racial differences in schizophrenia and psychophysiological research: improving but still not adequate. PMID- 20837320 TI - Physical restraint use in intensive care units across Europe: the PRICE study. AB - The use of physical restraint has been linked to delirium in ICU patients and a range of physical and psychological outcomes in non-ICU patients. However, the extent of restraint practice in ICUs is largely unknown. This study was designed to examine physical restraint practices across European ICUs. A prospective point prevalence survey was conducted in adult ICUs across European countries to examine: physical and chemical restraint use during the weekend and weekdays, reasons for physical restraint use, timing of restraint use, type of restraint used and availability of restraint policies. Thirty-four general (adult) ICUs in nine countries participated in the study providing information on 669 patients with details of physical and chemical restraint use in 566 patients. Prevalence of physical restraint use in individual units ranged from 0 to 100% of patients. Thirty-three per cent of patients were physically restrained; those that were restrained were more likely to be ventilated (chi(2)=87.56, p<0.001), sedated (chi(2)34.66, p<0.001), managed in a larger unit (chi(2)=10.741, p=.005) and managed in a unit with a lower daytime nurse:patient ratio (chi(2)=17.17, p=0.001). Larger units were more likely to use commercial wrist restraints and smaller units were more likely to have a restraint policy, although these results did not reach significance. As an initial exploration, this study provides evidence of the range of restraint practice across Units in Europe. Variation in the number of units per country limits generalization of findings. However, further examination is needed to determine whether there is a causal element to these relationships. Attention should be paid to developing evidence based guidelines to underpin restraint practices. PMID- 20837321 TI - Supporting "two-getherness": assumption for nurse managers working in a shared leadership model. AB - New leadership models are developing; one of them is shared leadership, which is often described at the team level. In this study, shared leadership is explored at the managerial level. The aim of this case study was to describe two nurse manager's experiences of working together as equal partners within a shared leadership model at an intensive care unit in Sweden. The study comprised a total of 12 interviews collected over three years with two nurse managers who worked together in shared leadership. 'Developing active influence to improve care' was identified as the core category, which was related to five subcategories 'Safeguarding leadership', 'Enabling leadership', 'Supporting 'two'-getherness', 'Transparent determination' and 'Balancing power'. A new construct 'two' getherness' was created, this means that two equal nurse managers within a trustful relationship share responsibility and tasks by using the couples' strengths and minimizing their weaknesses. Nurse managers experienced increased opportunities to improve work standards and do the very best for the ward. Moreover, the shared leadership model balanced the burden of day-to-day management. A model of shared leadership was created for further research. PMID- 20837322 TI - Delirium--awareness, observation and interventions in intensive care units: a national survey of Swedish ICU head nurses. AB - OBJECTIVES: To survey the awareness and observation of delirium, and interventions used for delirium in Swedish intensive care units (ICUs) and to examine the influence of hospital categories and staff education on the afore mentioned. DESIGN: A questionnaire was sent to all Swedish adult patient ICUs (n=82) and completed by 55 units. RESULTS: The reported prevalence of delirium was 9.4%. Assessment of delirium was performed by 62% of the ICUs, commonly by observing symptoms. Most of the suggested non-pharmacologic interventions were reported to be used by at least 85% of the units. Drugs were used by 96%, most commonly haloperidol, propofol and benzodiazepines. Written pharmacological guidelines existed in 26% of the units, while 9% had non-pharmacological guidelines. Regular observation of delirium was more common in larger hospitals than in smaller ones and education was associated with reporting a higher prevalence of delirium. CONCLUSION: As in other countries, this study demonstrated that the awareness of delirium in ICUs is low with a lack of implementation of validated screening tools for its diagnosis. Emphasis should be placed on education and implementation of these tools to improve the quality of care for ICU patients. PMID- 20837324 TI - How should we classify intersex disorders? authors' response. PMID- 20837325 TI - Megacystis with an anterior urethral valve: case report and review of literature. AB - Fetal megacystis, an abnormally enlarged bladder identified at any gestational age, may be transient and resolve spontaneously or may be an early manifestation of bladder outlet obstruction. Anterior urethral valves are the most common cause of the rare condition of congenital obstruction of the anterior urethra. Herein is reported the prenatal observation and postnatal management of a case of megacystis with anterior urethral valves. The etiology is reviewed and strategies recommended for patients with these rare entities. PMID- 20837326 TI - Treatment of non-monosymptomatic nocturnal enuresis by transcutaneous parasacral electrical nerve stimulation. AB - OBJECTIVE: To evaluate the effectiveness of transcutaneous parasacral electrical stimulation (TCPSE) in the treatment of non-monosymptomatic nocturnal enuresis (NMNE). Also, we evaluated possible pretreatment predictors of TCPSE failure. MATERIALS AND METHODS: Nineteen children diagnosed with NMNE who underwent TCPSE were studied prospectively. There were 6 boys and 13 girls with a mean age of 9.05 +/- 3.153 years (range 5-17 years). The sessions were performed three times per week for a maximum of 20 sessions, for 20 min each and at a frequency of 10 Hz. RESULTS: For eight children (42%) the nocturnal enuresis resolved, four (21%) presented a reduction in nocturnal episodes to less than one a week, six (32%) presented no change and one (5%) had increased frequency of NMNE. Symptoms present before treatment, such as daytime incontinence, frequency, constipation and occurrence of urinary tract infection, were not predictors of failure after TCPSE. CONCLUSION: TCPSE can be an effective treatment for NMNE, but about a third of patients will need another kind of treatment. No pretreatment factor was determined that predicted TCPSE failure. PMID- 20837327 TI - Introduction: advances and promise in human umbilical cord blood. PMID- 20837328 TI - Regulatory issues in cord blood banking and transplantation. AB - When selecting a cord blood unit for transplantation a transplant program must, in addition to considering HLA match and cell dose, know that the unit is potent, pure and will not transfer an infectious, hematologic or immunologic disease. While these same issues also apply to adult unrelated donors the fact that cord blood has been processed and stored, often years earlier, at a cell processing facility other than the one affiliated with the transplant program has resulted in a transfer of responsibilities from the transplant program to the cord bank. The transplant programs rely on the cord blood banks for all aspects of collection, screening, testing, processing and storage. Additionally the intermediary registries that are responsible for coordinating communications between the banks and transplant programs are important partners in a comprehensive approach to cord blood quality management. Since cord blood units frequently cross international borders it is critical that international regulatory standards be established and implemented to cover all steps in the production and sharing of cord blood for transplantation. Activities of NetCord/FACT, AABB, CIBMTR, World Marrow Donor Association and others are coming together under the Alliance for Harmonization of Cellular Therapy Accreditation to harmonize practice worldwide. PMID- 20837329 TI - The role of HLA in umbilical cord blood transplantation. AB - Transplantation with umbilical cord blood for haematological malignancy and other diseases has increased over the last two decades. The parameters that affect clinical outcome have been intensely studied in this relatively new clinical setting. Although originally thought to not be critical for transplant success, human leucocyte antigen (HLA) matching of the patient and cord blood donor is now considered one of the most important indicators of outcome. Because clinical studies of cord-blood transplantation are often not large enough to detect subtle differences, the HLA matching algorithm in cord blood transplantation (CBT) is not clearly defined. This article will focus on HLA matching in CBT in relation to engraftment, graft versus host disease, relapse and survival. Outstanding questions in the field, such as the contribution of HLA-C, -DQ, as well as the appropriate level of HLA matching and cord unit selection will be discussed. PMID- 20837330 TI - Cord blood transplantation in children with haematological malignancies. AB - Umbilical cord blood transplantation (UCBT) is largely used to treat children affected by haematological malignant disorders. In comparison to bone marrow transplantation (BMT), advantages of UCBT include lower incidence and severity of graft-versus-host disease, easier procurement and prompter availability of cord blood cells, and the possibility of using donors having HLA disparities with the recipient. The large experience accumulated so far has shown that UCBT offers to children a probability of cure at least comparable to that of patients transplanted with bone marrow cells. Since it has been demonstrated that an inverse correlation between the number of nucleated cord blood cells infused per kg recipient body weight and the risk of dying for transplantation-related causes exists, recently developed strategies aimed at increasing the number of cord blood progenitors and at favouring stem cell homing could further optimize the outcome of children with leukemia or other malignancies receiving UCBT. PMID- 20837331 TI - Cord blood transplantation in adults with acute myeloid leukaemia. AB - Allogeneic haematopoietic stem cell transplantation represents a potential life saving procedure for many patients affected by acute myeloid leukaemia. However, in the past its application has been limited by the availability of a HLA matched sibling. To date, an allogeneic transplant from alternative haematopoietic stem cell sources (volunteer unrelated donor, umbilical cord blood, haploidentical family donor) should be considered for all patients with high-risk disease defined by integration of clinical and biological prognosticators. In this context, following the preliminary, encouraging results, the transplant of unrelated umbilical cord blood has been progressively increased because of its prompt availability and a more permissive HLA incompatibility between donor and recipient. Furthermore, the decreased risk of GVHD, the use of reduced intensity conditionings and the graft of double cord blood units permit to extend cord blood transplant to a higher proportion of adult patients with acute myeloid leukaemia, which is predominantly diagnosed in the elderly age. A multicentric, prospective intention-to-treat study is warranted in order to define which haematopoietic stem cell source represents the best choice for allogeneic transplant in high-risk acute myeloid leukaemia. PMID- 20837332 TI - Alternative donors hematopoietic stem cells transplantation for adults with acute myeloid leukemia: Umbilical cord blood or haploidentical donors? AB - Use of allogeneic transplantation for patients with acute myeloid leukemia (AML) depends mainly on the risk of the disease, and HLA matched donor availability. In patients with high-risk leukemia, in the absence of a HLA (human leukocyte antigen) matched donor, alternative donors such as unrelated umbilical cord blood (UCB) or haploidentical donor (haplo) have been currently used. Both strategies have important advantages such as shorter time to transplant, which is particularly relevant to patients requiring urgent transplantation, and tolerance of HLA mismatched graft that make possible that a donor can be found for virtually all patients. However, in spite of higher incidence of graft failure in UCB transplatation recipients and higher relapse incidence after haplo transplants, final outcomes seem to be comparable with HLA matched unrelated hematopoietic stem cell transplantation (bone marrow or peripheral blood). Therefore, the complexity of choosing the best alternative donor will depend on urgency of the transplantation, status and risk of the disease, donor criteria and center experience. Here we review the current status of UCBT and haplo transplants to treat adults with high-risk acute myeloid leukemia and we discuss the main issues associated with the use of both hematopoietic stem cell transplant approaches. PMID- 20837333 TI - Umbilical cord blood transplantation from unrelated donors in adult patients with chronic myeloid leukaemia. AB - Allogeneic haematopoietic stem cell transplantation (HSCT) remains an important treatment option for patients with chronic myeloid leukaemia (CML) failing tyrosine-kinase inhibitors or progressing to an advanced phase. In this setting, umbilical cord blood (UCB) could be used as an alternative stem cell source for patients in whom allogeneic HSCT is indicated and lack a human leucocyte antigen (HLA)-matched adult donor. However, very little information exists on the outcome after UCB transplantation (UCBT) of these patients. Early registry-based studies of patients undergoing UCBT suggested a particularly poor outcome for patients with CML. However, more recent reports with special focus on patients with CML have confirmed feasibility and efficacy of the procedure and identified variables influencing short- and long-term outcomes. Currently, UCBT should be considered as a potential curative alternative for CML patients requiring allogeneic HSCT but lacking an appropriate adult donor. PMID- 20837334 TI - Double cord blood transplantation: extending the use of unrelated umbilical cord blood cells for patients with hematological diseases. AB - Unrelated umbilical cord blood (UCB) has been widely used to treat patients lacking a well-matched HLA donor. Cell dose is a critical determinant of outcomes in cord blood transplantation, limiting the use of this strategy for low body weight patients. To overcome this limitation, infusion of two partially HLA matched cord units was adopted as a new strategy. Since 2005, number of adult patients treated with UCB transplant is increased due to the higher number of cells available using two units and to the feasibility of reduced intensity conditioning regimen, extending successfully this strategy to heavier patients or for those with co-morbidities. Approximately 993 adults with hematological diseases have been transplanted with double UCB graft, and reported to Eurocord registry from 1999 to 2010. This article reviews the state of art and future directions with double umbilical cord blood units as a source of hematopoietic stem cells for transplantation. PMID- 20837335 TI - Non-myeloablative umbilical cord blood transplantation. AB - Allogeneic umbilical cord blood (UCB) transplantation is an established alternative to unrelated bone marrow or peripheral blood transplantation for treatment of high-risk hematologic disorders. There is growing evidence that non myeloablative bone marrow conditioning can be used to facilitate engraftment of UCB-derived stem cells. Use of non-myeloablative conditioning reduces the risk of treatment-related mortality but increases the risk for relapse of the underlying hematologic condition. Disease status at the time of transplantation and potency of the graft versus tumor effect are important predictors of a successful outcome. It is for these reasons that non-myeloablative conditioning is best suited for patients felt to be at increased risk for treatment-related complications, and whose underlying disease is under good control. The optimal non-myeloablative conditioning regimen has yet to be determined. Further studies are needed to determine if non-myeloablative UCB transplantation can be successfully applied to pediatric patients and patients without prior exposure to cytotoxic chemotherapy. PMID- 20837336 TI - The intra-bone marrow injection of cord blood cells extends the possibility of transplantation to the majority of patients with malignant hematopoietic diseases. AB - Cord blood transplant (CBT) in adult patients is scarcely utilized because of the risk of graft failure or very delayed platelet recovery. To improve the capacity and the speed to engraft, we have developed an intra-bone (IB) cord blood transplant technique. 75 patients with hematological malignancies, categorized by disease phase as early (18%), intermediate (20%) and advanced (62%), were transplanted. The median cell dose (TNC) infused was: 2.6 (1.35-5.4)*10(7)/kg; the HLA disparity was: 12 cases=5/6, 62 cases=4/6 and 1 case=3/6 matched antigens. 72/75 patients engrafted (96%); median day of recovery of neutrophils (PMN) >500*10(9)/L and platelets (PLT) >20 000*10(9)/L was: 23 (14-44) and 35 (16 70) days respectively. The outcomes at 2 years according to Kaplan-Meier are: OS=46%+/-5; RI=18%+/-2; NRM=39%+/-5. Acute GVHD incidence/severity was: grade 0 I=64%, II=14%, III-IV=0%. The incidence of Chronic GVHD was globally low but in 3 cases was very severe. Intra-bone CBT is associated with high rate of engraftment, early and robust platelet recovery, low incidence of acute GVHD. A very promising aspect is that the relapse rate is low considering the advanced phase of the disease in two/thirds of patients. A suitable CBU was found for nearly every patient searching for a CBU. Therefore, IB CBT extends the possibility to transplant any patient for whom this approach represents the sole possibility of long-term survival. PMID- 20837337 TI - Ex vivo expansion of umbilical cord blood for transplantation. AB - Umbilical cord blood (UCB) has become an important source of hematopoietic stem cell transplant (HSCT) for hematologic malignancies in adults. Its ready availability, allowance of higher HLA disparity and lower incidence of graft versus-host disease (GVHD) makes it a very attractive source especially for minority populations. The major limitation to a wider use of this source of HSCT is the relative low number of progenitor cells in the graft. For this reason, adult UCB transplants are usually associated with delayed engraftment and increased rates of infectious complications. CB ex vivo expansion holds the promise of delivering higher cell doses and improved outcomes. Here we discuss different methods of expansion, their shortcomings and future directions. PMID- 20837338 TI - Haematopoietic transplants combining a single unrelated cord blood unit and mobilized haematopoietic stem cells from an adult HLA-mismatched third party donor. Comparable results to transplants from HLA-identical related donors in adults with acute leukaemia and myelodysplastic syndromes. AB - We describe results of the strategy, developed by our group, of co-infusion of mobilized haematopoietic stem cells as a support for single-unit unrelated cord blood transplant (dual CB/TPD-MHSC transplants) for treatment of haematological malignancies in adults, and a comparative analysis of results obtained using this strategy and transplants performed with mobilized haematopoietic stem cells from related HLA-identical donors (RTD) for treatment of adults with acute leukaemia and myelodysplastic syndromes. Our data show that the dual CB/TPD-MHSC transplant strategy results in periods of post-transplant neutropenia, final rates of full donor chimerism and transplant-related mortality rates comparable to those of the RTD. Final survival outcomes are comparable in adults transplanted because of acute leukaemia, with different incidences of the complications that most influence these: a higher incidence of infections related to late recovery of protective immunity dependent on T cell functions, and a lower incidence of serious acute graft-versus-host disease and relapses. Recent advances in cord blood transplant techniques allow allogeneic haematopoietic stem cell transplantation (HSCT) to be a viable option for almost every patient who may benefit from this therapeutic approach. Development of innovative strategies to improve the post-transplant recovery of T cells function is currently the main challenge to further improving the possibilities of unrelated cord blood transplantation. PMID- 20837339 TI - Advances in umbilical cord transplantation: the role of thymoglobulin/ATG in cord blood transplantation. AB - Umbilical cord blood transplantation (UCBT) is increasingly being used as an alternative to conventional allogeneic stem cell transplantation. However, despite significant improvements, an appreciable proportion of patients (especially adults) receiving UCBT will still face some form of severe acute and/or chronic graft-versus-host disease (GVHD). Moreover, poor engraftment and delayed immune recovery are still challenging issues. Therefore, in terms of both GVHD and engraftment kinetics, the immunosuppressive potency of the conditioning regimen prior to UCBT may play an important role. Anti-thymocyte globulin (ATG, ThymoglobulinTM) provides multifaceted immunomodulation suggesting that the use of ATG may be of interest towards improving engraftment and GVHD outcome. However, the role of ATG in UCBT is still under debate. This report will review the incidence and severity of GVHD after UCBT, and will discuss the potential role of ATG towards improving outcome (GVHD and engraftment) when used as part of the conditioning regimen prior to UCBT. PMID- 20837340 TI - Is there an impact of killer cell immunoglobulin-like receptors and KIR-ligand incompatibilities on outcomes after unrelated cord blood stem cell transplantation? AB - Donor killer cell immunoglobulin-like receptor (KIR) ligand incompatibility in the graft-versus-host direction is associated with decreased relapse incidence and improved disease-free survival after haploidentical and human leucocyte antigen (HLA)-mismatched unrelated, haematopoietic stem cell transplantation. However, review of all published studies of allogeneic HLA-matched or mismatched stem cell transplantation shows that the results on the relationship between donor-recipient KIR(-ligand) (in)compatibility and outcomes are highly variable, ranging from highly beneficial to detrimental. Reasons for these differences may include the methodology to determine KIR(-ligand) incompatibility, the disease distribution and the transplant protocol or donor type. Two retrospective studies on the effects of KIR-ligand incompatibility in unrelated cord blood transplantation (UCBT) for haematological malignancies have resulted in conflicting results. The Eurocord study showed a favourable effect of KIR-ligand mismatching on relapse incidence and leukaemia-free survival, whereas the Minneapolis study showed no effect on these end points and a detrimental effect on incidence of graft-versus-host disease (GvHD). In patients with non-malignant disorders, KIR-ligand (in)compatibility between donor and recipient was not associated with outcomes in a recent Eurocord analysis. Therefore, the role of natural killer (NK) cell alloreactivity in UCBT is far from clear. It is too early to use a donor-recipient KIR(-ligand) algorithm for selection of a cord blood donor. PMID- 20837341 TI - Tissue regeneration potential in human umbilical cord blood. AB - Regenerative medicine is the process of creating functional tissue with the aid of stem cells, to repair loss of organ function. Possible targets for regenerative medicine include orthopaedic, cardiac, hepatic, pancreatic and central nervous system (CNS) applications. Umbilical cord blood (CB) has established itself as a legitimate source for haematopoietic stem cell transplantation. It is also considered an accessible and less immunogenic source for mesenchymal, unrestricted somatic and for other stem cells with pluri/multipotent properties. The latter are capable of differentiating into a wide variety of cell types including bone, cartilage, cardiomyocytes and neural. They also possess protective abilities that may contribute to tissue repair even if in vitro differentiation is excluded. In view of the absence of treatment for many devastating diseases, the elucidation of non-haematopoietic applications for CB will facilitate the development of pioneering relevant cell therapy approaches. This review focusses on current studies using human CB-derived cells for regenerative medicine. PMID- 20837342 TI - Viral hepatitis infections in southern Taiwan: a multicenter community-based study. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of liver disease in Taiwan and have a great impact on the health of this country. This study investigated the seroprevalence of HBV and HCV in southern Taiwan. Screening programs were performed from September 1999 to August 2005 for community-based surveillance of liver disease. A total of 28,797 adults from southern Taiwan, including Kaohsiung City (n = 14,036), Kaohsiung County (n = 7,713), and Pingtung County (n = 7,048) were participated. The mean age was 50.3 +/- 14.6 years (range, 20-97 years), with 41.0% were men. Hepatitis B surface antigen (HBsAg), antibody to HCV (anti-HCV), and liver function tests were performed. Among the 28,797 adults, the prevalence of HBsAg(+) was 15.1% and that for anti-HCV(+) was 8.6%. The seroprevalence of HBsAg in Kaohsiung County was 18.2%, which was higher than in Kaohsiung City (14.7%, p < 0.001) or Pingtung County (12.5%, p < 0.001). The seroprevalence of anti-HCV in Kaohsiung County was 17.2%, which was higher than in the other regions (Kaohsiung City = 5.8%, p < 0.001; Pingtung County = 4.6%, p < 0.001). The prevalence of dual HBsAg and anti HCV was 1.1% (323 patients). Tzukuan Township in Kaohsiung County was endemic for HBsAg (19.1%, 1,026/5,375 patients), anti-HCV (22.4%, 1,203/5,375 patients), and dual HBsAg/anti-HCV (3.6%, 191/5,375 patients). Subjects with anti-HCV(+) were older and had higher alanine transaminase levels than their HBsAg(+) counterparts (p < 0.001 and p < 0.001, respectively). The current study shows the epidemiological characteristics of HBV and HCV infections among adults in southern Taiwan. Viral hepatitis infections remain widely endemic in this region. PMID- 20837343 TI - Anesthesia induction with sevoflurane and propofol: evaluation of P-wave dispersion, QT and corrected QT intervals. AB - The present study compared the effects of anesthesia induction with sevoflurane and propofol on hemodynamics, P-wave dispersion (Pwd), QT interval and corrected QT (QTc) interval. A total of 72 adult patients were included in this prospective study. All patients had control electrocardiograms (ECGs) before anesthesia induction. Anesthesia was induced with sevoflurane inhalation or intravenous propofol. Electrocardiography for all patients was performed during the 1(st) and 3(rd) minutes of induction, 3 minutes after administration of muscle relaxant, and at 5 minutes and 10 minutes after intubation. Pwd and QT intervals were measured on all ECGs. QTc intervals were determined using the Bazett formula. There was no significant difference in Pwd and QT and QTc intervals on control ECGs. In the sevoflurane group, except for control ECGs, Pwd and QTc interval on all ECGs were significantly longer than those in the propofol group (p < 0.05). We conclude that propofol should be used for anesthesia induction in patients with a predisposition to preoperative arrhythmias, and in those whose Pwd and QTc durations are prolonged on preoperative ECGs. PMID- 20837344 TI - Body dysmorphic disorder in patients with cosmetic surgery. AB - Body dysmorphic disorder (BDD) refers to a preoccupation with an imagined or grossly exaggerated minor physical defect. Those with BDD might seek medical help (cosmetic surgery) rather than attend a psychiatric clinic. Therefore, it is often underdiagnosed. To investigate the prevalence of BDD, we reviewed the medical records of 817 individuals who sought cosmetic surgery during a 3-year period. The outcome after surgery was described for those with BDD. Our results showed that 63 (7.7%) patients had BDD, of which 54 (85.7%) were diagnosed at preoperative evaluation. However, nine (14.3%) patients went undiagnosed and all had a bad outcome after cosmetic surgery. BDD was not uncommon at the cosmetic surgery clinic. Our results support the idea that cosmetic surgery should be avoided for patients with BDD. The development of a more effective diagnostic procedure could help address this issue. PMID- 20837345 TI - Features of parotid gland diseases and surgical results in southern Taiwan. AB - Various parotid gland diseases are seen clinically, including inflammation, sialolithiasis, and benign and malignant tumors. It is important to differentiate between these to make a correct diagnosis and for proper management. Here, we investigated the relationship between tumor characteristics and pathology, and considered whether the former could be used to differentiate malignant from benign parotid gland diseases. We retrospectively reviewed the charts and data of 316 patients who underwent surgery in Kaohsiung Medical University Chung-Ho Memorial Hospital from January 1, 1998 to December 31, 2008. Two hundred and eighty-one patients (88.9%) had benign disease, and 35 (11.1%) had malignant disease. The most common benign disease was pleomorphic adenoma (115 cases, 36.4%), but the most common disease in male patients was Warthin's tumor, a finding which, as far as we aware, has not been previously been reported in the literature. The incidence of Warthin's tumor seems to be increasing. In malignant disease, the most common was acinic cell carcinoma (8 cases, 22.9%). Compared with benign disease, malignant parotid gland disease more often presents as a hard, painful, fixed and large mass (> 3 cm), and more often involves the deep lobe of the parotid gland. Partial parotidectomy was adequate for most tumors, including pleomorphic adenoma. The most common postoperative complication was temporary facial palsy, followed by permanent facial palsy. However, there was no difference in transient facial palsy rate between benign and malignant parotid gland disease, although parotid gland cancer had a higher incidence of permanent facial palsy postoperatively. PMID- 20837346 TI - First clinical experience of Ankaferd BloodStopper as a hemostatic agent in partial nephrectomy. AB - Open partial nephrectomy is an effective and safe alternative treatment modality to radical nephrectomy for small renal tumors. Many techniques that use hemostatic agents have been described to provide hemostasis during this procedure. Ankaferd BloodStopper(r) (ABS) is a unique folkloric medicinal plant extract that has been used historically in Turkish traditional medicine as a hemostatic agent. ABS has therapeutic potential to manage hemorrhage and this agent should be investigated in clinical trials. In the present case, we evaluated the effectiveness of ABS in partial nephrectomy and reviewed the literature. PMID- 20837347 TI - Ganglioneuroma of posterior mediastinum in a 6-year-old girl: imaging for pediatric intrathoracic incidentaloma. AB - Intrathoracic tumor is a rare entity in the pediatric population and neurogenic tumors account for 40-50% of childhood intrathoracic tumors. They can cause severe symptoms, such as respiratory distress, neurological dysfunction and metabolic disturbances. Posterior mediastinal ganglioneuroma (GN) usually occurs in children and can be found accidentally. Precise preoperative diagnosis is very difficult and has a great influence on surgical intervention. Here, we report a 6 year-old girl with a posterior mediastinal GN that was found incidentally on chest radiography. Computed tomography and magnetic resonance imaging demonstrated a right paraspinal tumor with punctuate calcification and intraspinal extension. (18)F-fluorodeoxyglucose positron emission tomography revealed low-grade fluorodeoxyglucose avidity of this tumor. Computed tomography and magnetic resonance imaging can characterize GN and positron emission tomography is helpful for differentiating benign or malignant lesions. PMID- 20837348 TI - Iatrogenic rupture of the ureter during kidney biopsy. AB - Perirenal hematoma, hematuria, and abdominal pain are common complications of kidney biopsy, but ureter rupture is relatively less frequent. Here we report a patient who experienced severe abdominal pain and gross hematuria following a non smooth procedure of ultrasound-guided kidney biopsy. Computed tomography showed rupture of the left upper third of the ureter. We implanted a curled double-J catheter between the renal pelvis and urinary bladder. Abdominal pain and gross hematuria improved. After 2 months, the double-J catheter was removed and the patient had no further clinical symptoms. The possibility of ureter rupture, although rare, should be considered in the presence of abdominal pain and gross hematuria in patients after receiving a kidney biopsy. PMID- 20837349 TI - A patient with two episodes of thoracic spinal cord compression caused by primary lymphoma and metastatic carcinoma of the prostate, 11 years apart. AB - We report a 75-year-old man with two spinal tumors, primary epidural lymphoma and metastatic carcinoma of the prostate, which caused thoracic spinal cord compression, with a long symptom free interval between episodes. The patient presented with back pain and progressive weakness and numbness in his lower limbs for 3 months. Eleven years earlier, he had a symptomatic T8-10 primary spinal epidural lymphoma that was treated successfully with surgery and he made a full recovery. Magnetic resonance imaging of the thoracic and lumbar spines revealed multiple thoracic and lumbar vertebral osteolytic lesions. Extraosseous extension of a lesion at T1-4 resulted in severe spinal cord compression. In consideration of recurrent lymphoma, emergent cord decompression was achieved via posterior T1 4 decompressive laminectomy, and the patient's neurological status improved rapidly after surgery. Pathological examination confirmed metastatic carcinoma of the prostate. After several courses of chemotherapy, the patient improved neurologically and could walk independently. Three years after surgery, magnetic resonance imaging showed complete resolution of cord edema at T1-4 and T8-9, and the high signal intensity at unoperated levels largely regressed. This report emphasizes that other newly developed lesions should be included in the differentiation of recurrent primary spinal epidural lymphoma, especially in patients who have long-term, disease-free intervals between episodes. PMID- 20837350 TI - Functional outcome after head injury: comparison of 12-45 year old male and female hormonally active patients. AB - OBJECTIVES: Head injury is the leading cause of death in patients with major trauma, but little is known of post-trauma rehabilitation morbidity in Hong Kong. The purpose of this study was to identify factors affecting functional outcome in hormonally active patients 6 months after head injury. METHODS: Secondary analysis of the trauma registry database with data collected prospectively at two trauma centres between January 2001 and December 2007. Demographic and trauma data for patients aged 12-45 years with a head Abbreviated Injury Score >=3 were analysed. The Glasgow outcome scale (GOS) was used for assessment and was assessed 6 months after head injury. The primary outcome measure was a composite poor outcome, namely "dead, vegetative and severely disabled" measured using the GOS. RESULTS: Of 698 patients included in the study (mean age 29 years; range 12 45 years; 75.8% male), 581 (83.2%) had a good outcome, and 117 (16.8%) met the primary outcome measure, namely a poor outcome, including 88 (12.6%) patients who died. 453 (64.9%) patients had an injury severity score (ISS) of 16-40, and 102 (14.6%) patients had an ISS>40. 220 (31.5%) patients underwent head injury related operation. The mean length of stay in the intensive care unit (ICU) was 3.9 days. Univariate analysis showed that high ISS, Emergency Department (ED) systolic blood pressure (SBP)>160mmHg or <90mmHg, respiratory rate<12/min or >24/min, low ED Glasgow Coma Score (GCS), trauma call activation, head related operation and ICU admission were related to poor outcome. Multivariate analysis showed that high ISS, low or high ED SBP and low ED GCS were related to poor functional outcome. CONCLUSION: This study showed that ISS, ED SBP and ED GCS were related to poor functional outcome. Gender showed no statistically significant relationship with functional outcome. PMID- 20837351 TI - Correlation between overexpression of transforming growth factor-beta 1 in occluded fallopian tubes and postsurgical pregnancy among infertile women. AB - OBJECTIVE: To compare the expression profiles of transforming growth factor-beta 1 (TGF-beta1) and its receptors in occluded tubes of infertile women with those of control patients and to evaluate the potential correlation with postsurgical pregnancy outcome. METHODS: The expression profiles of TGF-beta1, TGF-beta1R1, and TGF-beta1R2 in occluded fallopian tubes were compared using immunohistochemistry between 60 infertile patients with adhered tubes and 60 control patients with normal tubes; potential correlations with postsurgical fertility were evaluated at 2-year follow up. RESULTS: Immunostainings of TGF beta1, TGF-beta1R1, and TGF-beta1R2 were all significantly elevated in patients with adhered tubes compared with normal specimens (P<0.001). In adhered specimens, correlation analyses showed positive correlations between TGF-beta1 and TGF-beta1R1 (P=0.008), and TGF-beta1 and TGF-beta1R2 (P=0.035). At 2-year follow up, 32 of the 60 infertile women had achieved normal pregnancies, 5 had had ectopic pregnancies, and 23 remained infertile. Correlation analysis showed that TGF-beta1 expression level was negatively correlated with pregnancy outcome (r=-0.445, P<0.001), independent of adhesion severity or patient age. CONCLUSION: TGF-beta1 expression was independently correlated with the postsurgical pregnancy outcome among infertile women. PMID- 20837352 TI - Effect of low concentration of diacylglycerol on mildly postprandial hypertriglyceridemia. AB - OBJECTIVE: Previous studies have demonstrated that a high concentration of diacylglycerol (DAG) oil (approximately 80% in 10 g of test oil) suppressed increases in postprandial serum triglyceride (TG), particularly hypertriglyceridemia. However, the effects of a lower concentration of DAG oil have not been demonstrated. In the present study, the effective dose of DAG oil was determined in hypertriglyceridemia. METHODS: Randomized, double-blind, cross over design study was conducted using 22 patients with mild hypertriglyceridemia. Changes in postprandial serum lipid concentrations were analyzed after ingestion of 10 g of test oil containing 1.3% (control), 27.3% (low dose), 54.6% (medium dose) or 80.8% (high dose) of emulsified DAG. RESULTS: The expanded Williams test indicated that the DAG dose that was most effective at altering postprandial serum TG and chylomicron-TG concentrations was >= 27.3% DAG in 10 g of test oil; >= 54.6% DAG in 10 g of test oil was needed to have an impact on postprandial serum apolipoprotein B-48 concentrations. Additionally, DAG was more effective in subjects with both hypertriglyceridemia and hypertension. In the current study, systolic blood pressure correlated with the increase in postprandial serum TG, suggesting that DAG improves hypertriglyceridemia, particularly when it is accompanied by hypertension. CONCLUSION: DAG oil could be useful as an initial dietetic therapy for the treatment of postprandial hypertriglyceridemia with hypertension. The effective dose was >= 27.3% DAG in 10 g of oil. PMID- 20837353 TI - Partial port-closing strategy for obtaining high throughput or high purities in a four-zone simulated moving bed chromatography for binary separation. AB - The "partial port-closing" operation strategy for a four-zone simulated moving bed (SMB) chromatographic process for binary separation was developed to improve the SMB performance. This strategy included the partial extract-closing (PEC) and the partial raffinate-closing (PRC) operations. In case of the PEC operation, the extract port is made to be closed during the first-half stage of a switching period. During the latter-half stage, the extract port is made to be open. In case of the PRC operation, the raffinate port is made to be open during the first half stage of a switching period. During the latter-half stage, the raffinate port is made to be closed. If the operating conditions are chosen properly in each operation using a highly efficient optimization tool, the product stream can be collected during only the period that the product is almost separated from impurity. During the other period that the product is contaminated with impurity, the collection of the product stream can be stopped by closing the product port. The uncollected product stream is then allowed to keep migrating through the adjacent zone within the SMB process. Such a partial port-closing operation including PEC and PRC was found to surpass a conventional SMB operation remarkably in throughput and product purity. PMID- 20837354 TI - Baseline neuropsychiatric symptoms are effect modifiers in Ginkgo biloba extract (EGb 761(r)) treatment of dementia with neuropsychiatric features. Retrospective data analyses of a randomized controlled trial. AB - Previous studies suggested that EGb 761(r) may be more effective when dementia is associated with neuropsychiatric features. To find out whether treatment effects correlate with neuropsychiatric symptom burden at baseline, retrospective analyses of data from a 24-week randomized, placebo-controlled, double-blind clinical trial of EGb 761(r) (240 mg once daily) were performed. 410 outpatients with mild to moderate AD, VaD or AD with cerebrovascular disease, each associated with neuropsychiatric features, were enrolled. Patients scored 5 or above on the NPI, with at least one item score being >=3, and between 9 and 23 on the SKT cognitive test battery. Correlations between the NPI composite score at baseline and other efficacy variables were calculated. Regression analyses with the NPI composite score as regressor and efficacy variables as dependent variables were performed. Correlations between changes from baseline and NPI baseline scores were weak to modest, but conspicuously different between active drug and placebo groups. The slopes of the regression lines for the EGb 761(r) and the placebo groups showed qualitative and statistically significant differences: With increasing NPI baseline scores there was faster deterioration in the placebo group and thus more net benefit from treatment for the EGb 761(r) group. PMID- 20837356 TI - Predictive factors for prolonged survival in recurrent endometrial carcinoma: Implications for follow-up protocol. AB - OBJECTIVE: To evaluate the role of follow-up after curative treatment in endometrial carcinoma, we determined predictive factors for prolonged survival after recurrence. METHODS: We retrospectively studied patients with endometrioid endometrial carcinoma who had a follow-up appointment consisting of pelvic examination, vaginal cytology, imaging and CA-125 measurements and who developed recurrence. Possible prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: Fifty-one patients developed recurrence. The median time from initial treatment to recurrence was 12 months (range, 3-119 months). A total of 25 (49%) and 45 (88%) recurrences were detected within 1 and 3 years of initial treatment, respectively. Twenty (39%) patients were symptomatic, while 31 (61%) were asymptomatic. The median survival time of symptomatic patients was longer than that of asymptomatic patients (27 vs. 12 months); however, the difference was not statistically significant (P = 0.42). No recurrences were detected by vaginal cytology. Of asymptomatic patients with low/intermediate risk (stage I/II), patients with recurrence detected by imaging or CA-125 measurements tended to have shorter survival than patients with recurrence detected by physical examination (7 vs. 31+ months, P = 0.057). Multivariate analysis revealed that site of recurrence (vaginal vs. extravaginal, P < 0.01) and time to recurrence (> 1 year vs. <= 1 year, P = 0.01) were significant independent predictors of prolonged survival after recurrence. CONCLUSION: In endometrial carcinoma, site of and time to recurrence are significant predictive factors of prolonged survival after recurrence, suggesting that early detection of recurrence by imaging studies and CA-125 measurements cannot improve prognosis. Although intensive follow-up using these methods may provide psychological reassurance to some patients, the use of these methods must be balanced against the wise use of limited health care resources. PMID- 20837355 TI - Rate of para-aortic lymph node micrometastasis in patients with locally advanced cervical cancer. AB - OBJECTIVE: Patients with micrometastasis to para-aortic lymph nodes may benefit from extended field chemoradiation. To determine the rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer undergoing laparoscopic extraperitoneal para-aortic lymphadenectomy. METHODS: We prospectively identified consecutive patients diagnosed with stage IB2-IVA biopsy proven cervical cancer. Eligible patients included those who were candidates for treatment with radiotherapy and concurrent chemotherapy and had no evidence of para-aortic lymphadenopathy (all lymph nodes< 2 cm in diameter) by preoperative computed tomography or magnetic resonance imaging. All patients underwent preoperative positron emission tomography/computed tomography and laparoscopic extraperitoneal para-aortic lymphadenectomy. All lymph nodes were assessed for metastasis by routine hematoxylin-eosin (H&E) staining. Ultrastaging (serial sectioning) and immunohistochemical analysis were performed in H&E-negative specimens. RESULTS: Thirteen (22%) of 60 consecutive patients had para-aortic lymph node metastases detected on routine H&E staining. Of the remaining 47 patients, one (2.1%) had evidence of micrometastasis, which was detected by ultrastaging. This patient completed whole pelvic radiotherapy and chemotherapy but had a recurrence 27 months after completion of therapy. CONCLUSIONS: The rate of para-aortic node micrometastasis in patients with locally advanced cervical cancer is low. The role of routine ultrastaging and immunohistochemical analysis in such patients remains uncertain. Future studies are needed to determine the clinical impact of para-aortic node micrometastasis in patients with locally advanced cervical cancer. PMID- 20837358 TI - Fluvastatin and cisplatin demonstrate synergistic cytotoxicity in epithelial ovarian cancer cells. AB - OBJECTIVE: Statin therapy has been associated with prolonged survival in patients with ovarian cancer. We hypothesized that statins have a cytotoxic effect and that the combination of fluvastatin and cisplatin inhibits cellular proliferation in epithelial ovarian cancer cells. METHODS: Fluvastatin and cisplatin were examined in CAOV3 and SKOV3 human ovarian cancer cell lines. Cellular proliferation was assessed using MTT assays. Annexin V/propidium iodide (PI) staining was used to discriminate between early and late apoptosis, bromodeoxyuridine and PI staining for cell cycle profiling, and Western blotting for protein expression analysis. Synergy was determined using isobologram analysis. RESULTS: Treatment with combination fluvastatin and cisplatin at multiple doses resulted in significantly greater inhibition of proliferation compared to either drug alone. When examining equipotent combinations of fluvastatin and cisplatin to determine potential synergy, a combination index (CI) of 0.66 was identified for CAOV3 cells and a CI of 0.24 for SKOV3 cells indicating synergy. Combination fluvastatin and cisplatin resulted in G2/M arrest, and a significant increase in early apoptotic cells compared to fluvastatin or cisplatin alone. Moreover, supplementation of farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) demonstrated that GGPP rather than FPP was able to overcome fluvastatin-induced cytotoxicity. Finally, the two-drug combination impaired the expression and modification status of proteins of the Ras pathway. CONCLUSIONS: These data demonstrate the synergistic cytotoxicity of fluvastatin and cisplatin, through premature apoptosis and cell cycle arrest, with concomitant dysregulation of Ras pathway proteins. Our studies support a plausible therapeutic role for statins in the adjuvant treatment of ovarian cancer. PMID- 20837357 TI - Erlotinib added to carboplatin and paclitaxel as first-line treatment of ovarian cancer: a phase II study based on surgical reassessment. AB - BACKGROUND: The purpose of this study was to determine whether adding the anti epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to carboplatin/paclitaxel improved pathologic complete response (pCR) at reassessment surgery in epithelial ovarian, fallopian tube, or primary peritoneal cancers (OFPC). METHODS: Patients with stage III-IV OFPC initiated treatment within 12 weeks of initial cytoreductive surgery or, after histologic confirmation of diagnosis, neoadjuvantly. Treatment included paclitaxel (175 mg/m2) and carboplatin (AUC 6) every 3 weeks for up to 6 cycles, plus oral erlotinib 150 mg daily. The primary objective was to determine whether the pCR rate at reassessment surgery was at least 60% after optimal cytoreduction at initial surgery (< 1cm residual disease), or at least 40% after suboptimal cytoreduction (at least 1cm residual disease) using a two-stage design (alpha=0.10, beta=0.10). RESULTS: The study population included 56 patients with stage III-IV OFPC. EGFR gene amplification was present in 15% of the 20 tumors evaluated. Twenty-eight patients had protocol therapy after optimal cytoreduction (stratum I), 23 had protocol therapy either after suboptimal cytoreduction (stratum II), and 5 received neoadjuvant therapy prior to cytoreduction (stratum III). Pathologic CR was confirmed in 8 patients (29%; 95% confidence intervals 13%, 49%) in stratum I and 3 patients (11%, 95% C.I. 2%, 28%) in stratum II, which did not meet the prespecified efficacy endpoint in either stratum. CONCLUSIONS: Among unselected patients, erlotinib plus carboplatin-paclitaxel did not improve pCR rates compared with historical experience with carboplatin paclitaxel alone in patients with stage III-IV OFPC. PMID- 20837359 TI - Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study. AB - PURPOSE: To assess the differences in health-related quality of life (HRQL) of 4 cisplatin containing doublet chemotherapy combinations in women with advanced/recurrent cervical carcinoma. METHODS: Patients were randomized to three week cycles of paclitaxel + cisplatin (PC); vinorelbine + C (VC); gemcitabine + C (GC); or topotecan + C (TC). We report HRQL results from data available on 434 eligible patients enrolled into this 513 patient trial. HRQL was assessed with the Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) the FACT/Gynecologic Oncology Group (FACT/GOG) four-item neurotoxicity scale, and the 0-10 "worst pain" item from the Brief Pain Inventory, at baseline (pre-treatment), prior to beginning cycle 2, prior to beginning cycle 5, and at 9 months after enrollment. As reported by Monk et al. (2009) [13] VC, GC and TC were found not to be superior to PC with regard to progression-free survival or overall survival. RESULTS: The trial was terminated early due to planned interim futility analysis, reducing power for HRQL analysis from 85% to 55%. Patients receiving VC, GC and TC doublets did not report significantly different HRQL, neuropathy, or pain from those who received the PC (control) doublet. Patients receiving PC tended to report worse neuropathy during treatment than patients who received other doublets (especially GC and TC), but the differences were not statistically significant. CONCLUSION: None of the 3 experimental doublets was different from PC in terms of HRQL during treatment. Long-term toxicity data are inconclusive. Except where patients may wish to reduce their risk of worsening pre-treatment neuropathy, PC remains the standard of care for this disease. PMID- 20837360 TI - Study on nucleic acid (CT-DNA and yeast tRNA) binding behaviors and cytotoxic properties of a heterodinuclear Ru(II)-Co(III) polypyridyl complex. AB - A heterodinuclear (Ru(II), Co(III)) metal polypyridyl complex [(phen)(2)Ru(bpibH(2))Co(phen)(2)](5+) {phen = 1,10-phenanthroline, bpibH(2) = 1,4-bis([1,10]phebanthroline-[5,6-d]imidazol-2-yl)-benzene} has been designed and synthesized. The comparative study on the interactions of the Ru(II)-Co(III) complex with calf thymus DNA (CT-DNA) and yeast tRNA has been investigated by UV visible spectroscopy, fluorescence spectroscopy, viscosity, as well as equilibrium dialysis and circular dichroism (CD). The antitumor activities of the complex have been evaluated by MTT {3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide} method and Giemsa staining experiment. These results indicate that the structures of nucleic acids have significant effects on the binding behaviors of metal complexes. Furthermore, the complex demonstrates different antitumor activity against selected tumor cell lines in vitro, and can make the cell apoptosis. PMID- 20837361 TI - Long-term naturalistic follow-up of lithium augmentation: relevance to bipolarity. AB - BACKGROUND: Whether bipolarity (unrecognized bipolar disorder) is related to the treatment response to lithium augmentation in antidepressant-refractory depression remains unclear. This study of responders and non-responders to lithium augmentation of 29 antidepressant-refractory patients with major depression, whom we had studied during 1995-1997, compared the bipolar diagnosis at the follow-up based on diagnostic confirmation after long-term follow-up. METHODS: Before being classified as stage 2 treatment-resistant depression, these patients had been treated adequately with at least two tricyclic or heterocyclic antidepressants from different pharmacological classes (a minimum of the equivalent of 150 mg of imipramine for 4 weeks). During 1995-1997, 29 patients received lithium augmentation. Their treatment responses were recorded. Mean follow-up was 8.0 years (range, 1-13 years). Bipolar conversion and full remission were evaluated. RESULTS: After the long-term follow-up, diagnoses were changed to bipolar depression in 3 of 4 lithium responders and 3 of 25 lithium non-responders; lithium augmentation was more effective for unrecognized bipolar patients. Only the family history of bipolar disorder predicted subsequent bipolar conversion. LIMITATIONS: Treatment was not controlled in this naturalistic study, which had a small sample size. CONCLUSIONS: Results of this long-term follow-up study suggest that bipolarity is related to a positive response to lithium augmentation in stage 2 treatment-resistant major depression. The family history of bipolar disorder suggests false unipolar depression, and therefore indicates lithium responders. PMID- 20837362 TI - Temporo-parietal junction stimulation in the treatment of depersonalization disorder. AB - This is the first clinical trial of repetitive Transcranial Magnetic Stimulation (rTMS) in depersonalization disorder (DPD). After 3weeks of right temporo parietal junction (TPJ) rTMS, 6/12 patients responded. Five responders received 3 more weeks of right TPJ rTMS showing 68% DPD symptoms improvement. Right TPJ rTMS was safe and effective. PMID- 20837363 TI - Tau haplotypes and ApoE4 do not act in synergy on Alzheimer's disease. AB - There are conflicting results regarding the role of tau (MAPT) haplotypes in neurodegenerative disorders. Recent reports suggest that ethnicity factors and gene-gene interactions may influence the risk of developing Alzheimer's disease (AD). The present study investigates possible synergism between MAPT haplotype and ApoE state in Hungarian Caucasian AD cases (n=91) and control (n=83) population. The difference in MAPT H1 allele frequency did not reach significant level in AD (78%), and control individuals (73.5%), however ApoE4 carriers were significantly overrepresented in AD (34.1% vs. 20%) compared to the control population. Though a specific combination of ApoE4 and H1 alleles were found to be associated to AD (14.5% vs. 30.8%), synergistic genetic interaction could not be inferred. Our findings support the notion that while ApoE4 might be involved in AD pathology the MAPT H1 allele neither associates nor interacts through an epistasis with ApoE4 in the development of the disease. PMID- 20837364 TI - Identification of the signaling pathway of TNF-alpha-induced CCL17/TARC transcription in a canine keratinocyte cell line. AB - A CC chemokine, CCL17/TARC, has been shown to be a factor in the immunopathogenesis of canine atopic dermatitis (cAD). In canine keratinocytes, the transcription of CCL17 mRNA is preferentially induced by tumor necrosis factor-alpha (TNF-alpha); however, its regulatory mechanism has not been elucidated. The aim of the present study is to clarify the regulatory mechanism of TNF-alpha-induced CCL17 mRNA transcription in canine keratinocytes leading to the development of a chemokine-targeted therapy for cAD. In a cell line of canine epidermal keratinocyte, CPEK, stimulation with TNF-alpha induced not only the activation of nuclear factor-kappa B (NF-kappaB) but also the phosphorylation of c-Jun-N-terminal kinase (JNK) and mitogen-activated protein kinase p38 (p38). Extracellular signal-regulated kinase (ERK) was found to be constitutively phosphorylated, which was temporarily augmented by TNF-alpha. Results of the inhibition assay indicated that the CCL17 mRNA transcription level was significantly decreased by p38 inhibitors but was not altered by either JNK or NF kappaB inhibitors. Surprisingly, the ERK inhibitor increased the transcription level of CCL17 mRNA. Stimulation with epidermal growth factor (EGF), an ERK activator, suppressed the transcription of CCL17 mRNA. The present results suggest that TNF-alpha-induced CCL17 mRNA transcription in CPEK is positively regulated by p38 but negatively controlled by ERK. PMID- 20837365 TI - Accessory tragus in the middle ear: A rare congenital anomaly. AB - OBJECTIVE: We present a very interesting and extremely rare case of an accessory tragus in the middle ear. METHOD: Case report and review of literature. RESULTS: Accessory tragus is not an uncommon congenital malformation of the external ear. The exact prevalence of accessory tragus as an isolated physical finding is unknown but it has been estimated to be 1.7:1000. There are many case reports on accessory tragus but there is no report of accessory tragus being found in the middle ear in English literature. We report the presentation and discuss the radiology and histopathology findings of this interesting case. CONCLUSION: To our knowledge, this is the first one to be reported in the English literature. PMID- 20837366 TI - Foregut duplication cysts in siblings: A case report. AB - Enteric duplication cysts are rare congenital anomalies that result from heterotrophic rests of foregut-derived epithelium in the head, neck, thorax or abdomen. Typically, foregut duplication cysts of the head and neck are diagnosed in asymptomatic children. No single embryologic process has been identified to explain causation. In this case, we report a case of two siblings with foregut duplication cysts-one cyst occurring in the floor of mouth and the other occurring in the thorax as an esophageal duplication. To our knowledge, this is the first report of such an event in the literature. This case raises the question of a possibly inherited foregut cyst versus a spontaneous occurrence in first degree relatives. PMID- 20837367 TI - Prognostic impact of atrial fibrillation progression in a community study: AFBAR Study (Atrial Fibrillation in the Barbanza Area Study). AB - INTRODUCTION: The aim of the study is to describe the natural history of an unselected population of patients with atrial fibrillation (AF) currently attending primary care services in a single health-service area in Galicia, north western Spain. METHODS: AFBAR is a transverse prospective study in which 35 general practitioners within one health-service area have enrolled patients diagnosed with AF who presented at their clinics during a three-month recruiting period. Primary endpoints are mortality or hospital admission. Here we report the results of the first 7-month follow-up period. RESULTS: 798 patients (421 male) were recruited; mean age of cohort was 75 years old. Hypertension was the most prevalent risk factor (77%). 87% of the patients were both overweight and obese. Permanent AF was diagnosed in 549 patients (69%). In the follow-up period, 16.4% of the patients underwent a primary endpoint and the overall survival was 98%. The following independent determinants of primary endpoint were identified: change in AF status (Hazard Ratio (HR) 2.89 (95% confidence interval (CI) 1.28 6.55); p=0.011); ischemic heart disease (IHD) (HR 2.78 (95% CI 1.51-5.13); p=0.001); pre-recruitment hospital admission (HR 2.22 (95% CI 1.18-4.19); p=0.013); left ventricular systolic dysfunction (HR 2.19 (95% CI 1.11-4.32); p=0.023); or AF-related complications (HR 1.98 (95% CI 1.10-3.56); p=0.022). CONCLUSIONS: In the first 7-month follow-up period of patients with AF in a primary care setting the study identified several independent risk factors for mortality or hospital admission, i.e. change in AF status, ischemic heart disease, left ventricular systolic dysfunction, previous AF-related complications and hospital admission. PMID- 20837368 TI - Novel non-invasive P wave analysis for the prediction of paroxysmal atrial fibrillation recurrences in patients without structural heart disease: a prospective pilot study. AB - OBJECTIVES: The pathogenetic mechanisms responsible for the initiation and recurrence of PAF are not fully elucidated and vary among individuals. We evaluated the ability of a novel non-invasive approach based on P wave wavelet analysis to predict symptomatic paroxysmal atrial fibrillation (PAF) recurrences in individuals without structural heart disease. METHODS: We studied 50 patients (24 males, mean age 54.9 +/- 9.8 years) presented to our emergency department with a symptomatic episode of PAF. The patients were followed-up for 12.1 +/- 0.1 months and classified into two groups according to the number of PAF episodes: Group A (<5 PAF, n = 33), Group B (>= 5 PAF, n = 17). A third Group of 50 healthy individuals without history of PAF was used as control. Study groups underwent echocardiography and orthogonal ECG-based wavelet analyses of P waves at baseline and follow-up. Maximum and mean P wave energies were calculated in each subject at each orthogonal lead using the Morlet wavelet analysis. RESULTS: Larger P wave energies at X lead and relatively larger left atrium were independently associated with >5 PAF episodes vs. <5 PAF episodes. No difference in P wave duration was detected between Groups A and B (p > 0.1), whereas Group A and B patients had longer P waves at Z lead compared to Group C (86.4 +/- 13 vs. 71.5 +/- 15 msec, p < 0.001). CONCLUSIONS: P wave wavelet analysis can reliably predict the generation and recurrence of PAF within a year. P wave wavelet analysis could contribute to the early identification of patients at risk for increased number of PAF recurrences. PMID- 20837369 TI - Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. AB - BACKGROUND: Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)alpha/gamma agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects. METHODS: SESTA R was a 26 week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 MUg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m(2)). RESULTS: In 118 patients with evaluable GFR measurements, baseline mean (+/- SD) mGFR was 97.6 +/- 17.5 ml/min/1.73 m(2) in the aleglitazar group and 101.9+/-21.6ml/min/1.73m(2) in the pioglitazone group. Mean percent change from baseline mGFR was -16.9% (90% confidence interval -22.0 to -11.5) with aleglitazar and -4.6% (-10.15 to 1.35) with pioglitazone, a mean treatment difference of -13.0% (-19.0 to -6.5). The 17% decrease from baseline in mGFR was consistent with the 19% decrease in eGFR Modification of Diet in Renal Disease (MDRD) observed with aleglitazar, which reached a plateau after 4weeks, with no further progression until treatment discontinuation. Following aleglitazar withdrawal, eGFR values returned to pretreatment levels within the 4-8-week follow-up, which suggests reversible hemodynamic changes in renal function. CONCLUSIONS: Despite the increased incidence of expected, dose-dependent PPAR class side effects (e.g., peripheral edema, weight gain, and congestive heart failure) limiting further development of this supratherapeutic dosage of aleglitazar (600 MUg/day), these data, together with the data from the dose ranging SYNCHRONY study, suggest aleglitazar may be a potential new treatment for cardiovascular risk reduction in post-acute coronary syndrome patients at the therapeutic 150 MUg daily dose. PMID- 20837370 TI - Accidental cold water immersion: an unusual cause of stress cardiomyopathy in a patient with Marfan's syndrome and aortic exostent. PMID- 20837371 TI - Influence of age, gender, and race on the efficacy of adding ezetimibe to atorvastatin vs. atorvastatin up-titration in patients at moderately high or high risk for coronary heart disease. AB - BACKGROUND: Age, gender, and race are factors that influence atherosclerotic coronary heart disease (CHD) risk and may conceivably affect the efficacy of lipid-altering drugs. METHODS: Post hoc analysis of two multicenter, 6-week, double-blind, randomized, parallel-group trials assessed age (<65 and >= 65 years), gender, and race (white, black, and other) effects on atorvastatin plus ezetimibe versus up-titration of atorvastatin in hypercholesterolemic patients with CHD risk. High CHD risk subjects with low-density lipoprotein (LDL) cholesterol levels >= 70 mg/dL (~1.81 mmol/L) during stable atorvastatin 40 mg therapy were randomized to atorvastatin 40 mg plus ezetimibe 10mg, or up-titrated to atorvastatin 80 mg. Moderately high CHD risk subjects with LDL cholesterol levels >= 100 mg/dL (~2.59 mmol/L) with atorvastatin 20mg were randomized to atorvastatin 20mg plus ezetimibe 10mg, or atorvastatin 40 mg. RESULTS: Although some variability existed, age, gender, and race subgroups did not substantially differ from the entire patient population with regard to lipid-altering findings. Ezetimibe plus atorvastatin produced greater percent reductions in LDL cholesterol, total cholesterol, triglycerides, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B than up-titration of atorvastatin for all subgroups. HDL cholesterol and apolipoprotein AI changes were small and variable. CONCLUSION: Treatment efficacy in age, gender, and race subgroups did not substantially differ from the entire study population. Ezetimibe combined with atorvastatin generally produced greater incremental reductions in LDL cholesterol and several other key lipid parameters compared with doubling the atorvastatin dose in hypercholesterolemic patients with high or moderately high CHD risk. These results suggest that co-administration of ezetimibe with statins is a useful therapeutic option for treatment of dyslipidemia in differing patient populations. PMID- 20837372 TI - Serum cathepsin levels in coronary artery ectasia. PMID- 20837373 TI - Interconnectivity analysis of supercritical CO2-foamed scaffolds. AB - This paper describes a computer algorithm for the determination of the interconnectivity of the pore space inside scaffolds used for tissue engineering. To validate the algorithm and its computer implementation, the algorithm was applied to a computer-generated scaffold consisting of a set of overlapping spherical pores, for which the interconnectivity was calculated exactly. The algorithm was then applied to micro-computed X-ray tomography images of supercritical CO(2)-foamed scaffolds made from poly(lactic-co-glycolic acid) (PLGA), whereby the effect of using different weight average molecular weight polymer on the interconnectivity was investigated. PMID- 20837374 TI - The native structure of cytoplasmic dynein at work translocating vesicles in Paramecium. AB - In Paramecium multimicronucleatum, the discoidal vesicles, the acidosomes and the 100-nm carrier vesicles are involved in phagosome formation, phagosome acidification and endosomal processing, respectively. Numerous cross bridges link these vesicles to the kinetic side of the microtubules of a cytopharyngeal microtubular ribbon. Vesicles are translocated along these ribbons in a minus-end direction towards the cytopharynx. A monoclonal antibody specific for the light vanadate-photocleaved fragment of the heavy chain of cytoplasmic dynein was used to show that this dynein is located between the discoidal vesicles and the ribbons as well as on the cytosolic surface of the acidosomes and the 100-nm carrier vesicles. This antibody inhibited the docking of the vesicles to the microtubular ribbons so that the transport of discoidal vesicles and acidosomes were reduced by 60% and 70%, respectively. It had little effect on the dynein's velocity of translocation. These results show that cytoplasmic dynein is the motor for vesicle translocation and its location, between the vesicles and the ribbons, indicates that the cross bridges seen at this location in thin sections and in quick-frozen, deep-etched replicas are apparently the working dyneins. Such a working dynein cross bridge, as preserved by ultra-rapid freezing, is 54 nm long and has two legs arising from a globular head that appears to be firmly bound to its cargo vesicle and each leg consists of >=3 beaded subunits with the last subunit making contact with the microtubular ribbon. PMID- 20837375 TI - Child and Adolescent Mental Health Service (CAMHS) placements for pre registration child branch nursing students: potential benefits. AB - It has been recommended that more needs to be done to improve the education and training needs of nurses working with children and young people with mental health problems. This paper explores the experiences of pre-registration children's nursing students during their course in relation to caring for these children and young people both in general children's areas and in child and adolescent mental health services (CAMHS). The study indicates that observation of registered nurses and their interactions with these children and young people has a significant impact on the way students model their behaviour and in their self-perceived confidence and attitude towards caring for this client group. PMID- 20837376 TI - Nursing students' pharmacological knowledge and calculation skills: ready for practice? AB - OBJECTIVES: To evaluate graduating students' pharmacological knowledge and calculation skills and describe their self-rated readiness to safe medication care in practice on two nurse educational levels. Additionally, the study describes some characteristics of pharmacology in nurse education in Flanders, Belgium. METHODS: Thirty-eight nursing schools (bachelor's degree in nursing [N=18] and diploma in nursing [N=20]) were asked to provide details on their pharmacology curriculum and to let their graduating students participate in a cross-sectional survey using the Medication Knowledge and Calculation test in February/March 2009. RESULTS: The 29 participating schools showed a large diversity in pharmacology curricula. Mean scores on the pharmacology section and calculation section were 55% and 66%, respectively, for bachelor's degree and 52% and 53% for diploma students. On a scale of 1-10, 27% had a self-rated readiness perception<=5. Results differed significantly between schools. CONCLUSIONS: Just before graduation, nursing students' pharmacological knowledge and calculation skills are limited. Apart from the test results, students did not perceive themselves able to deliver safe medication care in practice. Schools need to address the shortcomings. In practice, awareness is needed regarding possible limitations of the newly graduated. PMID- 20837377 TI - Application of statistical experimental methodology to optimize bioremediation of n-alkanes in aquatic environment. AB - Response surface methodology (RSM) was employed to optimize nitrogen and phosphorus concentrations for removal of n-alkanes from crude oil contaminated seawater samples in batch reactors. Erlenmeyer flasks were used as bioreactors; each containing 250 mL dispersed crude oil contaminated seawater, indigenous acclimatized microorganism and different amounts of nitrogen and phosphorus based on central composite design (CCD). Samples were extracted and analyzed according to US-EPA protocols using a gas chromatograph. During 28 days of bioremediation, a maximum of 95% total aliphatic hydrocarbons removal was observed. The obtained Model F-value of 267.73 and probability F<0.0001 implied the model was significant. Numerical condition optimization via a quadratic model, predicted 98% n-alkanes removal for a 20-day laboratory bioremediation trial using nitrogen and phosphorus concentrations of 13.62 and 1.39 mg/L, respectively. In actual experiments, 95% removal was observed under these conditions. PMID- 20837378 TI - Effective removal of Cu (II) ions from aqueous solution by amino-functionalized magnetic nanoparticles. AB - A novel magnetic nano-adsorbent (MNP-NH(2)) has been developed by the covalent binding of 1,6-hexadiamine on the surface of Fe(3)O(4) nanoparticles for removal of Cu(2+) ions from aqueous solution. Various factors affecting the uptake behavior such as contact time, temperature, pH, salinity, amount of MNP-NH(2) and initial concentration of Cu(2+) were investigated. The kinetics was evaluated utilizing the Lagergren pseudo-first-order, pseudo-second-order, Elovich and intra-particle diffusion models. The equilibrium data were analyzed using Langmuir, Freundlich, and Dubinin-Radushkevich isotherms. The adsorption was relatively fast and the equilibrium was established within 5 min, and its kinetics followed the pseudo-second-order mechanism, evidencing chemical sorption as the rate-limiting step of sorption mechanism. The best interpretation for the equilibrium data was given by Langmuir isotherm, and the maximum adsorption capacities was 25.77 mg g(-1) at pH 6, and 298 K. Thermodynamic parameters showed that the adsorption process was spontaneous, endothermic and chemical in nature. The successive adsorption-desorption studies indicated that the MNP-NH(2) sorbent kept its adsorption and desorption efficiencies constant over 15 cycles. Importantly, MNP-NH(2) was able to remove 98% of Cu(2+) from polluted river and tap water. PMID- 20837379 TI - Rapid removal and recovery of Pb(II) from wastewater by magnetic nanoadsorbents. AB - Iron oxide nanoadsorbents are cost-effective adsorbents that provide high adsorption capacity, rapid adsorption rate and simple separation and regeneration. In this study, Fe(3)O(4) nanoadsorbents have been employed for the removal of Pb(II) ions from aqueous solutions by a batch-adsorption technique. The effects of contact time, initial concentration of Pb(II) ions, temperature, solution pH and coexisting ions on the amount of Pb(II) adsorbed have been investigated. Pb(II) adsorption was fast, and equilibrium was achieved within 30 min. The amount of Pb(II) adsorbed increased as temperature increased, suggesting an endothermic adsorption. The optimal pH value for Pb(II) adsorption was around 5.5. Furthermore, the addition of coexisting cations such as Ca(2+), Ni(2+), Co(2+), and Cd(2+) has no remarkable influence on Pb(II) removal efficiency. The adsorption equilibrium data fitted very well to Langmuir and Freundlich adsorption isotherm models. The thermodynamics of Pb(II) adsorption onto the Fe(3)O(4) nanoadsorbents indicated that the adsorption was spontaneous, endothermic and physical in nature. The desorption and regeneration studies have proven that Fe(3)O(4) nanoadsorbents can be employed repeatedly without impacting its adsorption capacity. PMID- 20837380 TI - Scarcity of parasite assemblages in the Adriatic-reared European sea bass (Dicentrarchus labrax) and sea bream (Sparus aurata). AB - The shaping forces of parasite community structure still is the main subject in the ecological parasitology whilst community predictability and repeatability showed that hardly a generally applicable role is ever going to be assessed. Defining and describing parasite communities can be very useful from the epizootiological point, in order to help in the assessment of the medical and economical impact of certain parasitosis, moreover when hosts are economically valuable species. Since parasite assemblages in reared European sea bass (Dicentrarchus labrax) and sea bream (Sparus aurata) in Adriatic cage systems can play an important role in the economic feasibility of the rearing process, we evaluated their character through assessing diversity indices, nestedness of parasite communities and their differences in respect to season and composition, as well as fish growth. We observed colonization of a new monogenean species (Furnestinia echeneis) and general impoverishment of parasites populations over time in the Adriatic-reared fish parasite assemblages. Parasite assemblages differed significantly between seasons for both fish species, while species richness, evenness, diversity indices and nestedness of parasitic communities in the sea bream showed to be significantly higher compared to those in the sea bass. Such characteristics define parasite communities of both Adriatic-reared fish as species poor although structured and ordered assemblages. PMID- 20837381 TI - Nasal bots...a fascinating world! AB - Larvae causing obligatory myiasis are numerous and they may affect cutaneous and subcutaneous tissues, wounds, nasopharyngeal cavities (nasal bots), internal organs and the digestive tract (bots) of domestic and wild animals and humans as well. Nasal bots belong to the Family Oestridae, Subfamily Oestrinae, which includes several important genera: Oestrus, Kirkioestrus, and Gedoelstia infecting Artiodactyla (except Cervidae) in Africa and Eurasia, Cephenemyia and Pharyngomyia infecting Cervidae, Rhinoestrus infecting horses, Cephalopina infecting camels, Pharyngobolus infecting African elephants, and Tracheomyia infecting Australian kangaroos. Nasal bots are widespread in Mediterranean and tropical areas and in affected animals they induce sneezing and nasal discharge which may become caked with dust making breathing very difficult. The aforementioned species of larvae are host-specific but sometimes the may be deposited in human eyes inducing a painful opthalmomyiasis of short duration. The first fascinating trait of these parasites is the very efficient morphological and biological adaptations to parasitism they show either as larvae or as adults, in order to facilitate their survival and search for a suitable host. Nasal bots have reached different degrees of complexity in their life cycles. Indeed, while for some species (e.g., Oestrus ovis, Rhinoestrus usbekistanicus) larvae are injected by flies directly into nostrils and develop in the sinuses before being ejected for external pupation, some other species migrate from eyes to blood before returning to nasal cavities either through the ethmoid bone (Gedoelstia hassleri) or via lungs and bronchi (Gedoelstia cristata). Moreover, larvae are very well-adapted to their environment being able to undergo through hypobiosis either inside or outside the host, according to the climatic environmental conditions and seasonality. The second fascinating trait of nasal bots is related to host behavioural and immune responses against the infection. Host behaviour may in fact prevent larviposition and inflammatory/immune reactions limit larval development. The main pathophysiological mechanisms involve mast cells and eosinophils which destroy the larvae in sensitized animals. The intense eosinophilic reaction has side effects both locally (i.e. on the nasal mucosa) and also generally, with possible interactions with gastrointestinal strongyles (e.g., both worm burdens and fecundity decreased in lambs infected by O. ovis). Infected animals (e.g., sheep, goat, camel, and donkey) firstly suffer from fly strike, when adult flies inject first stage larvae on nostrils: sheep may try to avoid fly swarms but eventually Rangifer tarandus can only manage a terror stricken look! Secondly, hosts will suffer from myiasis with typical nasal discharge and sneezing related to sinusitis. Clinical manifestations may vary: for example O. ovis induces severe clinical signs in sheep whilst produces few effects in goats! These parasites are diffused in many Mediterranean and tropical countries. Unfortunately, it is commonly believed that bacterial infections induced by nasal bots are of greater clinical importance: this view is not substantiated and the control of this condition depends on treatment with macrocyclic lactones, closantel and nitroxynil. Reinfections are common, and controlling nasal bots is not so simple. PMID- 20837382 TI - Systematic review on physician's knowledge about radiation doses and radiation risks of computed tomography. AB - BACKGROUND: The frequent use of computed tomography is a major cause of the increasing medical radiation exposure of the general population. Consequently, dose reduction and radiation protection is a topic of scientific and public concern. AIM: We evaluated the available literature on physicians' knowledge regarding radiation dosages and risks due to computed tomography. METHODS: A systematic review in accordance with the Cochrane and PRISMA statements was performed using eight databases. 3091 references were found. Only primary studies assessing physicians' knowledge about computed tomography were included. RESULTS: 14 relevant articles were identified, all focussing on dose estimations for CT. Overall, the surveys showed moderate to low knowledge among physicians concerning radiation doses and the involved health risks. However, the surveys varied considerably in conduct and quality. For some countries, more than one survey was available. There was no general trend in knowledge in any country except a slight improvement of knowledge on health risks and radiation doses in two consecutive local German surveys. CONCLUSIONS: Knowledge gaps concerning radiation doses and associated health risks among physicians are evident from published research. However, knowledge on radiation doses cannot be interpreted as reliable indicator for good medical practice. PMID- 20837383 TI - Computer-aided recognition of emphysema on digital chest radiography. AB - BACKGROUND: Computed tomography (CT) is the benchmark for diagnosis emphysema, but is costly and imparts a substantial radiation burden to the patient. OBJECTIVE: To develop a computer-aided procedure that allows recognition of emphysema on digital chest radiography by using simple descriptors of the lung shape. The procedure was tested against CT. METHODS: Patients (N=225), who had undergone postero-anterior and lateral digital chest radiographs and CT for diagnostic purposes, were studied and divided in a derivation (N=118) and in a validation sample (N=107). CT images were scored for emphysema using the picture grading method. Simple descriptors that measure the bending characteristics of the lung profile on chest radiography were automatically extracted from the derivation sample, and applied to train a neural network to assign a probability of emphysema between 0 and 1. The diagnostic performance of the procedure was described by the area under the receiver operating characteristic curve (AUC). RESULTS: AUC was 0.985 (95% confidence interval, 0.965-0.998) in the derivation sample, and 0.975 (95% confidence interval, 0.936-0.998) in the validation sample. At a probability cutpoint of 0.55, the procedure yielded 92% sensitivity and 96% specificity in the derivation sample; 90% sensitivity and 97% specificity in the validation sample. False negatives on chest radiography had trace or mild emphysema on CT. CONCLUSIONS: The computer-aided procedure is simple and inexpensive, and permits quick recognition of emphysema on digital chest radiographs. PMID- 20837384 TI - The limitations and risks of transarterial Onyx injections in the treatment of grade I and II DAVFs. AB - BACKGROUND AND OBJECTIVE: Embolization of grade III-V intracranial DAVFs using Onyx is feasible with promising results, indicating stability at the time of mid term follow-up. This article is to evaluate the role of transarterial Onyx embolization in the treatment of grade I and II intracranial dural arteriovenous fistulas (DAVFs), including its limitations and risks. METHODS: We retrospectively studied consecutive 26 patients (8 women and 18 men) treated for an grade I and II intracranial DAVF since 2006 in whom a transarterial approach was attempted with Onyx-18 embolization. There were 18 transverse-sigmoid sinus, 4 cavernous sinus, 2 superior sagittal sinus, 1 inferior petrosal sinus and 1 intradiploic fistulas. Five fistulas were Type I, 8 were Type IIa, and 13 were Type IIa+b, according to the Cognard classification. The mean clinical follow-up period was 15.6 months. RESULTS: Anatomic cure was proven in 13 patients (50%) and clinical cure was obtained in 17 cases (65.4%). These 13 cures were achieved after a single procedure. All these 13 patients underwent a follow-up angiography, which has confirmed the complete cure. Partial occlusion was obtained in 13 patients. Complications were as follows: 2 cardiac Onyx migration, 2 reflexive bradyarrythmia, 1 transient visual hallucination, 2 transient fifth nerve palsies and 1 permanent seventh nerve palsy in inferior petrosal sinus DAVF. CONCLUSIONS: Based on this experience, grade I and II intracranial DAVFs may be treated with transarterial Onyx embolization to reduce the shunted blood flow and to facilitate subsequent transvenous embolization or surgery. PMID- 20837385 TI - Using temperature to optimize resolution and reduce analysis times for bioanalytical diastereomer LC-MS/MS separations. AB - A rugged and reproducible liquid chromatographic tandem mass spectrometric bioanalytical method was developed for the quantitation of drug stereoisomers in human plasma. Column temperature was shown to be an important variable toward optimizing diastereomer selectivity, resolution and analysis cycle time. Non linear Van't Hoff plots and changes in peak shape with temperature suggested that selectivity was governed by multiple retention mechanisms. The high temperature chromatography method was validated and used to analyze samples from human clinical trials. Utilization of high temperature chromatography offered alternative selectivity and is a viable approach for difficult separations in regulated bioanalysis. PMID- 20837386 TI - Experimental design as a tool to evaluate chlorogenic and caffeic acids extracted from Cecropia glaziovii Sneth. AB - The effects of different parameters, including ethanol concentration, time of drug:solvent contact, temperature and the presence of a preservative, on chlorogenic acid (CGA) and caffeic acid (CFA) yields in Cecropia glaziovii Sneth extracts were investigated using an experimental design. In order to quantify the phenolic acids in these extracts a high-performance liquid chromatography-diode array detection (HPLC-DAD) method was developed and validated. Extracts with 80% ethanol presented a higher CGA content, but low amounts of CFA. Extracts with 20% ethanol showed a higher CFA concentration, but a sharp reduction in CGA extraction yield. The presence of a preservative, under the same extraction conditions, resulted in a slight difference or no difference in the CGA and CFA extraction yields. When the temperature was controlled at refrigerator or room temperature, a slight alteration in the concentrations of the phenolics studied was observed. The present approach can be applied in order to determine the optimum conditions for the preparation of C. glaziovii Sneth extracts based on CGA or CFA extraction yield as a chemical marker. PMID- 20837387 TI - Quantitative analysis of sesquiterpene lactones in extract of Arnica montana L. by 1H NMR spectroscopy. AB - (1)H NMR spectroscopy was used as a method for quantitative analysis of sesquiterpene lactones present in a crude lactone fraction isolated from Arnica montana. Eight main components - tigloyl-, methacryloyl-, isobutyryl- and 2 methylbutyryl-esters of helenalin (H) and 11alpha,13-dihydrohelenalin (DH) were identified in the studied sample. The method allows the determination of the total amount of sesquiterpene lactones and the quantity of both type helenalin and 11alpha,13-dihydrohelenalin esters separately. Furthermore, 6-O tigloylhelenalin (HT, 1), 6-O-methacryloylhelenalin (HM, 2), 6-O-tigloyl 11alpha,13-dihydrohelenalin (DHT, 5), and 6-O-methacryloyl-11alpha,13 dihydrohelenalin (DHM, 6) were quantified as individual components. PMID- 20837388 TI - Evaluation of the interaction between beta-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore (r) system. AB - Phase-solubility studies have been used to evaluate the solubilizing effects of cyclodextrins (CDs) on lipophilic, water-insoluble drugs. However, large amounts of CDs and drugs are required to measure solubility by phase-solubility studies. Thus, more efficient approaches to evaluate the interaction of CDs with drugs are needed. Herein we introduce a method that evaluates the interaction between immobilized beta-cyclodextrin and psychotropic drugs by surface plasmon resonance assay with a Biacore((r)) system. Association constants and stoichiometries observed were generally consistent with values calculated by traditional methods, such as phase-solubility and continuous variation methods. Results showed that the analytical method using Biacore((r)) was suitable to evaluate CD-drug interactions. PMID- 20837389 TI - Hormonal contraceptive method choice among young, low-income women: how important is the provider? AB - OBJECTIVES: Several new methods are available, but we know little about successful integration of contraceptive technologies into services. We investigated provider factors associated with the initiation of new hormonal methods among women at high risk of unintended pregnancy. METHODS: This cohort study enrolled 1387 women aged 15-24 starting hormonal contraception (vaginal ring, transdermal patch, oral contraceptive, or injectable) at four family planning clinics in low-income communities. We measured provider factors associated with method choice, using multinomial logistic regression. RESULTS: Ring and patch initiators were more likely than women starting oral contraceptives to report that they chose their method due to provider counseling (p<0.001). Contraceptive knowledge in general was low, but initiation of a new method, the ring, was associated with higher knowledge about all methods after seeing the provider (p<0.001). Method initiated varied with provider site (p<0.001). These associations remained significant, controlling for demographics and factors describing the provider-patient relationship, including trust in provider and continuity of care. CONCLUSION: Women's reports of provider counseling and of their own contraceptive knowledge after the visit was significantly associated with hormonal method initiated. PRACTICE IMPLICATIONS: More extensive counseling and patient education should be expected for successful integration of new hormonal methods into clinical practice. PMID- 20837390 TI - Psychotic-like experiences are associated with violent behavior in adolescents. AB - OBJECTIVE: The diagnosis of psychotic disorder is associated with a risk of violence. Psychotic-like experiences (PLEs) in the general population may share an etiological background with psychotic disorders. The present study has evaluated the association between PLEs and violent behavior in adolescents. METHODS: PLEs and violent behavior were assessed using a self-report questionnaire administered to 18,104 Japanese adolescents. Potential confounding factors were also evaluated. RESULTS: After controlling for the effects of age, gender, GHQ-12 total score, victimization, and substance use, the existence of PLEs was significantly associated with both interpersonal violence (odds ratio (OR)=1.36, 95% confidence interval (CI): 1.23 to 1.51) and violence towards objects (OR=1.46, 95%CI: 1.33 to 1.61). The greater the number of such psychotic experiences, the higher the risk of violence. Particular types of PLEs ('spied upon' and 'voice hearing') are significantly associated with interpersonal violence, while all of the types of PLEs assessed in this study were significantly associated with violence towards objects. CONCLUSION: PLEs may be a risk factor for violent behavior in adolescents. Violent acts by individuals with schizophrenia may not be a direct consequence of the disease itself, but may instead share an etiological background with such behavior in the general population. PMID- 20837391 TI - Close association of anti-U1 ribonucleoprotein antibody with drug allergy in patients with connective tissue diseases. PMID- 20837392 TI - Relationship between cutaneous barrier function and ceramide species in human stratum corneum. PMID- 20837393 TI - E, Z and positional-monoenoic phyto-fatty acids influencing membrane fluidity: DSC and NMR experiments. AB - The membrane fluidity of biological tissues is highly influenced by the pi-bond position and isomeric configuration in the long chain of phyto-fatty acids (FAs). Z, E and positional isomeric monoenoic lipids, i.e. the phytomolecules oleic (OA), elaidic (EA), vaccenic acid (TV) and its Z-isomer (CV), have been evaluated for their effects on the fluidity of cellular membranes. To this purpose the Differential Scanning Calorimetry (DSC) and Deuterium Nuclear Magnetic Resonance ((2)H-NMR), are suitable techniques to understand the supramolecular lamellar structure during the order (gel)-disorder (fluid) transition. It was found that the presence of CV concentration, induces the biomimetic system to reach the first step to fluid phase earlier than the membrane containing OA. DSC showed that the endothermic peak onset of the membrane containing CV occurs at a lower temperature than that of a membrane containing an equal amount of OA. (2)H-NMR investigation confirmed the last statement. In fact the study of the main phase transition of the two different systems, revealed that model membrane containing a 3% (w/w) of CV goes in ripple phase, i.e. the first step to the fluid state, at a lower temperature as compared to the membrane of an identical system with OA. PMID- 20837394 TI - An efficient approach to obtaining water-compatible and stimuli-responsive molecularly imprinted polymers by the facile surface-grafting of functional polymer brushes via RAFT polymerization. AB - A new and efficient approach to obtaining molecularly imprinted polymers (MIPs) with both pure water-compatible (i.e., applicable in the pure aqueous environments) and stimuli-responsive binding properties is described, whose proof of-principle is demonstrated by the facile modification of the preformed MIP microspheres via surface-initiated reversible addition-fragmentation chain transfer (RAFT) polymerization of N-isopropylacrylamide (NIPAAm). The presence of poly(NIPAAm) (PNIPAAm) brushes on the obtained MIP microspheres was confirmed by FT-IR as well as the water dispersion and static contact angle experiments, and some quantitative information including the molecular weights and polydispersities of the grafted polymer brushes, the thickness of the polymer brush layers, and their grafting densities was provided. In addition, the binding properties of the ungrafted and grafted MIPs/NIPs in both methanol/water (4/1, v/v) and pure water solutions were also investigated. The introduction of PNIPAAm brushes onto the MIP microspheres has proven to significantly improve their surface hydrophilicity and impart stimuli-responsive properties to them, leading to their pure water-compatible and thermo-responsive binding properties. The application of the facile surface-grafting approach, together with the versatility of RAFT polymerization and the availability of many different functional monomers, makes the present methodology a general and promising way to prepare water-compatible and stimuli-responsive MIPs for a wide range of templates. PMID- 20837395 TI - Sequential versus automated cutting guides in computer-assisted total knee arthroplasty. AB - The accuracy and efficiency of automated cutting guides in CAS systems have not been previously compared with conventional CAS techniques. Therefore, it is not yet clear if these more advanced technologies are warranted. We hypothesized that a novel automated cutting guide with CAS for total knee arthroplasty would be more efficient and more accurate than conventional navigation with sequential cutting blocks. Twelve cadaver legs were used in total. Each leg was randomly assigned to either an automated guide positioning or a conventional freehand computer-navigated guide positioning. The guide positions postosseous fixation and the final bone-cut surfaces were digitized and compared to the targeted cutting planes. The final location of the impacted trial implant was also digitized and compared to the planned implant location. The time for each step and the total time taken to prepare the femur were measured for both groups. The mean femoral preparation time was shorter with the automated cutting guide than the conventional method (5.5 min versus 13.8 min, p<0.001). The average deviation in the final bone resections from the planned resections was significantly lower for the automated cutting guide in the frontal/rotational plane (0.55 degrees versus 1.1 degrees ), sagittal plane (0.75 degrees versus 2.0 degrees ), and cut height direction (0.56 mm versus 1.6 mm). Therefore, based on these results, we concluded that automated cutting-guide positioning resulted in more efficient and more accurate femoral cuts in comparison to the conventional navigation method in a cadaveric model. PMID- 20837396 TI - Effects of microwave radiation and conductive heating on Tribolium castaneum microstructure. AB - Microwave radiation and conductive heating were used to completely kill adult Tribolium castaneum (Coleoptera: Tenebrionidae) in wheat flour to protect the flour during storage without significantly effecting its quality. The microstructure of T. castaneum was analyzed to reveal the mechanisms leading to death under microwave and heat treatments. Microwave radiation and conductive heating had different effects on the microstructure of the cuticle of adult T. castaneum and on the ultrastructure of the cells of the epidermis, fat body, and midgut. Both treatments caused a large cavity to appear in the nucleus and the disappearance of mitochondria and the Golgi apparatus. After microwave treatment, there was little change in the surface microstructure but the epidermis was of uneven thickness and the four outer layers of the cuticle were thinner. Nuclear size was essentially unchanged, but fat body cells were fewer and coalesced together. In contrast, conductive heating led to a disordered arrangement of cells on the surface of T. castaneum and indistinct boundaries between layers of the cuticle. The nuclei were enlarged and the fat body cells noticeably fewer and indistinct with a scattered distribution. Thus, microwave treatment produced less severe effects on the surface microstructure and cellular ultrastructure of T. castaneum than did conductive heating. It is concluded that these cellular and surface changes were responsible for the death of T. castaneum. PMID- 20837397 TI - Horizontal gene transfer and the genomics of enterococcal antibiotic resistance. AB - Enterococci are Gram-positive bacteria that normally colonize gastrointestinal tracts of humans and animals. They are of growing concern because of their ability to cause antibiotic resistant hospital infections. Antibiotic resistance has been acquired, and has disseminated throughout enterococci, via horizontal transfer of mobile genetic elements. This transmission has been mediated mainly by conjugative plasmids of the pheromone-responsive and broad host range incompatibility group 18 type. Genome sequencing is revealing the extent of diversity of these and other mobile elements in enterococci, as well as the extent of recombination and rearrangement resulting in new phenotypes. Pheromone responsive plasmids were recently shown to promote genome plasticity in antibiotic resistant Enterococcus faecalis, and their involvement has been implicated in E. faecium as well. Further, incompatibility group 18 plasmids have recently played an important role in mediating transfer of vancomycin resistance from enterococci to methicillin-resistant strains of S. aureus. PMID- 20837398 TI - Evaluation of drug toxicity with hepatocytes cultured in a micro-space cell culture system. AB - A micro-space cell culture system was recently developed in which cells such as hepatocytes can be cultured and formed into a multicellular three-dimensional (3D) architecture. In this study, we assessed the performance of HepG2 cells cultured in this micro-space cell culture system in a drug toxicity test, and evaluated the effects of micro-space culture on their hepatocyte-specific functions. The micro-space cell culture facilitated the formation of 3D HepG2 cell architecture. HepG2 cells cultured in a micro-space culture plate exhibited increased albumin secretion and enhanced mRNA expression levels of cytochrome P450 (CYP) enzyme compared to those cultured in a monolayer culture. When the cells were exposed to acetaminophen, a hepatotoxic drug, the damage to the HepG2 cells grown in micro-space culture was greater than the damage to the HepG2 cells grown in monolayer culture. In addition, human primary hepatocytes grown in micro space culture also exhibited increased albumin secretion, enhanced CYP mRNA expression levels and increased sensitivity to acetaminophen compared to those grown in monolayer culture. These results suggest that this micro-space culture method enhances the hepatocyte-specific functions of hepatocytes, including drug metabolizing enzyme activities, making hepatocytes grown in the micro-space culture system a useful tool for evaluating drug toxicity in vitro. PMID- 20837399 TI - Mutators in cystic fibrosis chronic lung infection: Prevalence, mechanisms, and consequences for antimicrobial therapy. AB - Hypermutable (or mutator) microorganisms are those that have an increased spontaneous mutation rate due to defects in DNA repair or error avoidance systems. Over last decade, several studies have provided strong evidence of a relevant role of mutators in the evolution of natural bacterial populations, with a special emphasis in the field of infectious diseases. Among them, chronic respiratory infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients was the first natural environment revealing a high prevalence and important role of mutators. High frequencies of mutators have also been noted for other pathogens in the CF setting, particularly Staphylococcus aureus and Haemophilus influenzae. In addition to a strong statistical link between hypermutation and antibiotic resistance (i.e., mutators are more frequently resistant against antibiotics) obtained from the analysis of collections of clinical isolates from CF patients, several in vitro and in vivo experiments have further highlighted the dramatic consequences of hypermutation, especially when acting on microorganisms that are genetically equipped to acquire efficient resistance to most antibiotics by mutations in chromosomal genes such as P. aeruginosa. Recent studies additionally showed that mutators accelerate genetic adaptation of P. aeruginosa to the airways of CF patients and that patients infected by mutator strains have a poorer lung function. Further prospective clinical studies are nevertheless needed for a deep evaluation of the impact of mutators in disease progression and outcome. Future research should particularly focus on the investigation of the optimal therapeutical strategies to prevent the emergence of mutator strains in the lungs of CF patients and to avoid multiple-antimicrobial resistance development if they have already been selected. PMID- 20837400 TI - Feasibility of activity-promoting video games among obese adolescents and young adults in a clinical setting. AB - One component of the recent obesity epidemic is the sedentary behaviour of children and adolescents e.g., use of video games consoles. The new generation of video games requires body movements and might thus increase activity. The aim of this study was to evaluate whether such games could have an effect on physical activity in obese adolescents in a clinical setting. Between March and May 2007 activity-promoting video games ("apvg") were offered to all 84 inpatients (aged 13-28 years) registered in a long-term rehabilitation programme on a voluntary base. Reasons for (non-)attendance were assessed. Frequency and duration of use of the activity-promoting video game sessions were documented. Furthermore, heart rate and activity counts during use of "apvg", endurance training, and strength training were measured. Of 84 inpatients, 51 used the "apvg" at least once (69%) over the study period. The median weekly use of the intervention was 27 min during the first week (range 0-182 min), declining to zero (range 0-74 min) in week four. Mean heart rate during the sessions (mean 115 bpm; 95% confidence interval 108-122 bpm) was similar to the heart rate during strength training (106 bpm; 101-112 bpm). The results indicate that the video games could have an impact on the activity of obese adolescents and young adults. However, as the interest in the devices seems to be too low the suitability of them for weight reduction programmes in young people cannot be ensured. PMID- 20837401 TI - Postictal hyperfamiliarity for unknown faces. AB - Hyperfamiliarity for unknown faces (HFUF) is a rare disorder in which unfamiliar people or faces appear familiar. Three young adults were admitted for acute symptomatic secondarily generalized tonic-clonic seizures (two) and psychomotor status (one). During the days following the seizures the patients continuously experienced a strong familiarity for unknown people, including other patients, visitors, and hospital staff. This disorder disappeared gradually, lasting a mean of 13 days. Brain MRI showed left amygdalohippocampal lesions, suggesting the etiology of encephalitis in two patients and multiple "active" demyelinating lesions in one patient. Interictal and ictal EEG findings showed left temporal epileptiform abnormalities. Two patients had a transitory defect of verbal memory. HFUF is a newly defined postictal symptom, more likely to arise from left temporal epileptic discharges. In our cases it was associated with acute lesions of the temporal areas, suggesting that its occurrence may also imply a structural etiology of epilepsy. PMID- 20837402 TI - Important GABAergic mechanism within the NTS and the control of sympathetic baroreflex in SHR. AB - Inhibitory neurotransmission has an important role in the processing of sensory afferent signals in the nucleus of the solitary tract (NTS), particularly in spontaneously hypertensive rats (SHR). In the present study, we tested the hypothesis that gamma-aminobutyric acid (GABA) mediated neurotransmission within the NTS produces an inhibition of the baroreflex response of splanchnic sympathetic nerve discharge (sSND). In urethane-anesthetized, artificially ventilated and vagotomized male SHR and Wistar Kyoto (WKY) rats we compared baroreflex-response curves evoked after bilateral injections into the NTS of the GABA-A antagonist bicuculline (25pmol/50nl) or the GABA-B antagonist CGP 35348 (5nmol/50nl). Baseline MAP in SHR was higher than the WKY rats (SHR: 153+/-5, vs. WKY: 112+/-6mm Hg, p<0.05). Bilateral injection of bicuculline or CGP 35348 into the NTS induced a transient (5min) reduction in MAP (?=-26+/-4 and -41+/-6mm Hg, respectively vs. saline ?=+4+/-3mmHg, p<0.05) and sSND (?=-21+/-13 and -78+/-7%, respectively vs. saline: ?=+6+/-4% p<0.05). Analysis of the baroreceptor curve revealed a decrease in the lower plateau (43+/-11 and 15+/-5%, respectively vs. saline: 78+/-6%, p<0.05) and an increase in the sympathetic gain of baroreflex (6.3+/-0.3, 7.2+/-0.8% respectively vs. saline: 4.2+/-0.4%, p<0.05). Bicuculline or CGP35348 into the NTS in WKY rats did not change MAP, sSND and sympathetic baroreflex gain. These data indicate that GABAergic mechanisms within the NTS act tonically reducing sympathetic baroreflex gain in SHR. PMID- 20837403 TI - The unusual UBZ domain of Saccharomyces cerevisiae polymerase eta. AB - Recent research has revealed the presence of ubiquitin-binding domains in the Y family polymerases. The ubiquitin-binding zinc finger (UBZ) domain of human polymerase eta is vital for its regulation, localization, and function. Here, we elucidate structural and functional features of the non-canonical UBZ motif of Saccharomyces cerevisiae pol eta. Characterization of pol eta mutants confirms the importance of the UBZ motif and implies that its function is independent of zinc binding. Intriguingly, we demonstrate that zinc does bind to and affect the structure of the purified UBZ domain, but is not required for its ubiquitin binding activity. Our finding that this unusual zinc finger is able to interact with ubiquitin even in its apo form adds support to the model that ubiquitin binding is the primary and functionally important activity of the UBZ domain in S. cerevisiae polymerase eta. Putative ubiquitin-binding domains, primarily UBZs, are identified in the majority of known pol eta homologs. We discuss the implications of our observations for zinc finger structure and pol eta regulation. PMID- 20837404 TI - Genetic variation in DNA repair pathway genes and melanoma risk. AB - Reduced DNA repair capacity has been proposed as a predisposing factor for melanoma. We comprehensively evaluated 1463 genetic variants across 60 DNA repair related pathway genes in relation to melanoma risk in a nested case-control study of 218 melanoma cases (20% on head and neck) and 218 matched controls within the Nurses' Health Study (NHS). We then genotyped the two variants with the smallest P value in two replication sets: 184 melanoma cases (28% on head and neck) and 184 matched controls in the Health Professionals Follow-Up Study (HPFS); and 183 melanoma cases (10% on head and neck) and 183 matched controls in the NHS. The SNP rs3219125 in the PARP1 gene was significantly associated with melanoma risk in the discovery set (odds ratio (OR) 3.14; 95% confidence interval (CI) 1.70 5.80) and in the HPFS replication set (OR, 1.92; 95% CI, 1.05-3.54) but not in the NHS replication set (OR, 1.07; 95% CI, 0.58-1.97). In the joint analysis, the OR was 1.89 (95% CI, 1.34-2.68) for this polymorphism, and this increased risk was more pronounced among patients with lesions in head/neck (OR, 3.19; 95% CI, 1.77-5.73 for head/neck, and OR, 1.54; 95% CI, 1.03-2.30 for other sites, P value for heterogeneity test=0.036). Our findings suggest the possible involvement of the PARP1 variant in melanoma development, especially for sites with high sun exposure. Further work on fine-mapping and on the functional characterization of this and linked SNPs in this region is required. PMID- 20837405 TI - Capillary electrophoresis with noncovalently bilayer-coated capillaries for stability study of allergenic proteins in simulated gastrointestinal fluids. AB - A novel noncovalently bilayer-coated capillary using cationic polymer polybrene (PB) and anionic polymer (sodium 4-styrenesulfonate) (PSS) as coatings was prepared. This PB-PSS coating showed good migration-time reproducibility for proteins and high stability in the range of pH 2-10 and in the presence of 1M NaOH, acetonitrile and methanol. Capillary electrophoresis with PB-PSS coated capillaries was successfully applied to quantitatively investigate the stability of bovine serum albumin, ovomucoid, beta-lactoglobulin and lysozyme in simulated gastrointestinal fluids. beta-lactoglobulin A and beta-lactoglobulin B were both stable in simulated gastric fluid with degradation percentages of 34.3% and 17.2% after 60min of incubation, respectively. Bovine serum albumin, ovomucoid and lysozyme were stable in simulated intestinal fluid with degradation percentages of 17.7%, 23.4% and 22.8% after 60min of incubation, respectively. The superiority of the proposed method over sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and capillary electrophoresis with untreated fused silica capillaries was demonstrated and emphasized. PMID- 20837406 TI - Enantioseparation of lomefloxacin hydrochloride by high-speed counter-current chromatography using sulfated-beta-cyclodextrin as a chiral selector. AB - Enantiomers of lomefloxacin hydrochloride were separated by high-speed counter current chromatography (HSCCC) using sulfated-beta-cyclodextrin as a chiral selector (CS). The separation was performed with a two-phase solvent system composed of ethyl acetate-methanol-water (10:1:10, v/v) containing CS at 0 60mmol/l in a head-to-tail elution mode, while obtained fractions were identified by polarimeter and spectropolarimeter. The results show that the concentration of the CS in the system strongly affects the peak resolution (Rs). As the concentration of CS increases, the Rs first increases reaching the maximum at 50mmol/l and then decreases. When the CS concentration is kept constant in the solvent systems, the Rs decreases as the concentration of the lomefloxacin hydrochloride increases. The overall results of our studies indicated that sulfated-beta-cyclodextrin is very useful for the chiral separation by HSCCC. PMID- 20837407 TI - Allele frequencies and population data for 11 Y-chromosome STRs in samples from Eastern Slovakia. AB - Haplotype data of 11 Y-STR loci (DYS391, DYS389I, DYS439, DYS389II, DYS438, DYS437, DYS19, DYS392, DYS393, DYS390 and DYS385) was obtained from 629 Slovak Caucasian men living in Eastern Slovakia. A total of 474 haplotypes were identified, of which 395 were unique. The haplotype diversity value was 0.9982. Pairwise haplotype distances showed that the Eastern Slovak Caucasian population is not significantly different from the Slavs populations and is separated from the Balkan nations and the German speaking populations. PMID- 20837409 TI - Editorial announcement. PMID- 20837408 TI - Evaluation of novel forensic DNA storage methodologies. AB - An issue in forensic sciences is the secure storage of extracted DNA. Most of the time, DNA is frozen at -20 degrees C or -80 degrees C. Recently, new room temperature DNA storage technologies have been developed based on anhydrobiosis. Two products use this technology: Qiasafe (Qiagen) and Gentegra (Genvault). In this study we focused on the recent Gentegra product and initiated a comparison versus -20 degrees C and Qiasafe storage. We compared the quantity and quality of DNA stored using anhydrobiosis technology against DNA stored at -20 degrees C, by performing STR profiling after short term storage. Furthermore, we studied the quantity and integrity of DNA after long term storage. Our results prove the high potential of this technology but it seems to be extraction dependent. Phenol/chloroform extracted DNA could be stored using the Gentegra matrix for more than 6 months without any obvious degradation. However, DNA extracted using magnetic beads could not be safely stored over the same period. Adaptations are therefore required to store this kind of samples. PMID- 20837410 TI - Mechanism of cadmium resistance in cultured Indian muntjac fibroblasts. AB - The mechanism by which Indian muntjac fibroblasts (M cells) became resistant to the toxic effects of cadmium was investigated. The resistant lines, CCR5 and CCR20, were approximately 8-fold and 18-fold more resistant to acute cadmium exposures than the parental M cell line. Examination of the roles of metallothionein, glutathione and membrane permeability indicates that although resistance may be multifactorial, the major change involves decreased uptake of cadmium by resistant cells. PMID- 20837411 TI - The relationship between mutagenicity in His G46 Salmonella and the O(6)-guanine alkylation in bacterial DNA by monofunctional methanesulphonates. AB - The influence of the O(6)-alkylation in Salmonella typhimurium cells by monofunctional methanesulphonates on their mutagenicity in strains TA1535 and TA100 was examined using a specially modified method that allows DNA-binding studies in bacteria. All the tested monofunctional compounds, methylmethanesulphonate (MMS; very strong Sn2 reactivity), ethylmethanesulphonate (EMS; moderate Sn1 and Sn2 reactivity) and isopropylmethanesulphonate (iPMS; strong Sn1 reactivity) formed significant amounts of O(6)-Palkylguanine. A comparison between the results in a pure in vitro system and the situation in the bacterial cells revealed significant differences. Despite having different alkylating reactivities, MMS and iPMS produced similar amounts of O(6)-adducts in bacterial DNA, probably owing to the much lower hydrolysis rate of MMS when compared with that of iPMS. The O(6):N7 ratio was, however, ten-fold higher in the case of iPMS, which reflects its clearly higher Sn1 reactivity. Owing to the formation of O(6)-adducts, all three test compounds induced back mutations in strain TA1535, which is not capable of performing error-prone repair. Whereas MMS showed a much higher mutagenic activity in strain TA100, because of the large amount of N-alkylation, iPMS induced practically identical mutagenicity in both strains, which indicates that the pkM101 plasmid is not significantly involved in iPMS mutagenicity. Evidently only strong Sn2-type monofunctional alkylating compounds induce back mutation in strain TA100 by the pkM101-mediated error-prone mechanism. This underlines the importance of the O(6)-alkylation as promutagenic lesion in strains containing the His G46 mutation. Surprisingly, EMS showed a higher mutagenicity in strain TA1535 than in TA100. PMID- 20837412 TI - Correlation of acute lethal potency with in vitro cytotoxicity. AB - The in vitro cytotoxicity (measured as ID(50) value) of 27 compounds believed to act by interference with cell basal functions/structures has been determined and compared with their acute lethal toxicity (measured as oral and ip LD(50) values) using a previously described approach to the choice of the most appropriate LD(50) value from the Registry of Toxic Effects of Chemical Substances database. A weak, but significant, positive correlation of log oral LD(50) value with log ID(50) value was obtained (r = 0.49; 0.02 < P < 0.05) for 21 compounds for which oral and ip LD(50) values were obtainable. A better correlation between LD(50) and ID(50) was obtained when the log ip LD(50) value was used (r = 0.68; P < 0.001). Three compounds, for which metabolism is a major determinant of toxicity in vivo, yielded anomalous results in the ip LD(50)/ID(50) comparison. A further improvement in the correlation of log ip LD(50) with log ID(50) was obtained when data from these compounds were excluded (r = 0.82; P < 0.001). Close correlations of log ip LD(50)/log ID(50) were obtained with groups of six anti-metabolites and six alkylating agents (r = 0.94 and 0.96, respectively; P < 0.001 in each case). The locations of the regression lines for these two groups were significantly different (P < 0.01). It is concluded that the in vitro cytotoxicity of compounds that exert their toxicity by interference with cell basal functions/structures is correlated with their intrinsic lethal potency, but that information on absorption, metabolism and disposition are required before the cytotoxicity data can be used to assess apparent potency. The data provide evidence that the precise relation of LD(50)/ID(50) values is determined by the mode of toxicity. PMID- 20837413 TI - Inhibition of cell division in hepatoma cell cultures by chlordecone and carbon tetrachloride combination. AB - The propensity of chlordecone (CD) to potentiate the hepatotoxic and lethal effects of CCl(4) is well established. Mirex (M), a close structural analogue of CD, or phenobarbital (PB), both powerful inducers of hepatic microsomal drug metabolizing enzymes, are much weaker potentiators of CCl(4) toxicity. Considerable evidence has accumulated to suggest that this increase in CCl(4) toxicity caused by CD is due to the failure of the hepatocellular regeneration, tissue repair and hepatolobular restoration mechanisms. This interaction occurs at concentrations of CD and CCl(4) that are individually non-toxic and do not interfere with hepatocellular division. To test this unique interaction at cellular level, we employed a rapidly dividing Reuber hepatoma cell line in vitro. Cells were pretreated with a non-toxic dose of either CD, M or PB and exposed to a single addition of CCl(4) in the concentration range 5 to 40 mm 16 days later. The results indicate that CD + CCl(4) combination specifically arrested hepatocellular division. The inhibition of cell division occurred at individually non-toxic concentrations of CD and CCl(4). M + CCl(4) or PB + CCl(4) failed to manifest similar effects. At higher concentrations, these combinations caused cellular toxicity, resulting in cell death. Suppression of cell division might play an important role in the progression of chemical-induced toxicities in the liver. This unique observation opens up new avenues to investigate biochemical molecular mechanisms underlying the interference with hepatocellular division. PMID- 20837414 TI - The induction by monochlorodibenzofuran isomers of xenobiotic metabolizing systems in cell lines derived from rat and human hepatoma. AB - Cultures of established cell lines, derived from rat and human hepatomas, were exposed to dibenzofuran (DBF) or monochlorodibenzofuran isomers (Cl-DBFs) and the induction of cytochrome P-450-dependent monooxygenases was examined. When rat (H4 II-E-C3) cell cultures were incubated with 2-Cl- or 3-Cl-DBF, the activities of arylhydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase increased progressively and after 20 hr of incubation reached a maximum, while benzphetamine N-demethylase activity was scarcely induced. The maximum AHH activities were 15.1 and 7.9 times the initial values, after incubation with 3-Cl and 2-Cl-DBFs, respectively. DBF also increased AHH activity, to a maximum, 2.7 times the initial activity, after 14 hr of incubation. Similar results were obtained when human (Chang liver) cell cultures were incubated with DBF, 2-Cl- or 3-Cl-DBF. To determine relative induction potencies, rat cell cultures were incubated with 25-150 MUm of 1-Cl-, 2-Cl-, 3-Cl- or 4-Cl-DBF for 20 hr. Both the AHH and 7-ethoxycoumarin O-deethylase activities were increased in a dose dependent manner by 2-Cl-, 3-Cl- and 4-Cl-DBF (in the order 3-Cl- > 2-Cl- = 4-Cl ). The immunoreactive cytochrome P-450c of rat cells was similarly increased by incubation with 2-Cl-, 3-Cl or 4-Cl-DBF (3-Cl- > 2-Cl- = 4-Cl-). 1-Cl-DBF increased neither AHH activity nor cytochrome P-450c. These results indicate that isomers of Cl-DBFs induce effectively 3-methylcholanthrene-inducible type of cytochrome P-450. PMID- 20837415 TI - An automated in vitro dermal absorption procedure: I. Permeation of (14)C labelled N,N-diethyl-m-toluamide through human skin and effects of short-wave ultraviolet radiation on permeation. AB - An automated in vitro dermal absorption (AIDA) analysis procedure is reported together with a novel design for an AIDA cell chamber for measuring the permeation of pesticides through human skin and other membranes. Tests to determine the permeation of the insect repellent N,N-diethyl-m-toluamide (DEET) through fresh, frozen and heat-separated split-thickness human breast skin demonstrated permeation of 48.0 +/- 10.18, 24.0 +/- 7.76 and 42.4 +/- 8.57% (mean +/- SD), respectively, by 48 hr. permeation through nitrile butyl rubber glove material was not detected whereas 47.2 +/- 3.16% permeation through a dialysis membrane was observed. Short-wave ultraviolet (UV) radiation had no significant effect on DEET permeation. The merits of AIDA in facilitating the precise simulation of environmental conditions during permeation testing are discussed. PMID- 20837416 TI - Disappearance of phalloidin-transporting ability in rat hepatocytes in culture and retardation of this process by demethylphalloin or antamanide. AB - Uptake of phalloidin was studied in cultured rat hepatocytes. In the initial phase of culturing (0-3 hr) the toxin was taken up at a V(max) of 43.5 ng/mg protein/hr and a K(M) of 2.48 MUm. During culturing the rate of phalloidin transport decreased rapidly in a logarithmic way. After 12 hr of culturing the transport of the phallotoxin was 50%, and after 45 hr was only 6% of the initial value. The decrease was reflected by a lower V(max), while the K(M) value remained unchanged. This suggests a decrease in the number of transporting units rather than an alteration in their structure. By contrast, when the cultured cells were continuously exposed to 1 MUm-toxin for several hours, the rate of transport was found to be unchanged. This indicates that in the presence of substrate the process leading to the decrease in rate of phalloidin transport was retarded. Antamanide, which is a strong competitive inhibitor of phalloidin transport in freshly isolated rat hepatocytes, also inhibited phalloidin uptake into cultured hepatocytes. However, pre-incubation of cultured hepatocytes with antamanide prior to phalloidin exposure resulted in the preservation of phalloidin-transporting ability. This indicates that a competitive inhibitor of phalloidin transport may also be able to retard the decrease in the rate of transport when present during the culturing period. These results suggest that during culturing rat hepatocytes lose their phalloidin-transporting ability, probably by a decrease in the number of transporting units, and that this process can be prevented or retarded by exposure to phalloidin or antamanide. This phenomenon is interpreted as a kind of substrate protection of the transporting unit. PMID- 20837417 TI - Comparative toxicity of oral cephalosporin antibiotics in the rabbit and in a rabbit kidney cell line (LLC-RK(1)). AB - The nephrotoxic potential of four oral cephalosporin antibiotics, cephalexin, cefaclor, LY195885 and LY171217, was determined in rabbits given single oral doses of 250-500 mg/kg body weight. Histopathological changes, blood chemistry, and ex vivo renal slice function were evaluated 48 hr after dosing. Additionally, the viability of rabbit renal cells in culture (LLC-RK(1)) was evaluated by nigrosin dye exclusion after 48 hr exposure to each antibiotic at concentrations of 0.5-2.0 mg/ml. Only LY171217 was significantly nephrotoxic in vivo. Prominent lesions were observed at 500 mg/kg body weight and were accompanied by marked increases in blood urea nitrogen and serum creatinine, and decreases in ex vivo renal slice gluconeogenesis and p-aminohippurate and tetraethylammonium uptake. In vitro toxicity to renal cells correlated well with the in vivo results yielding TC(50) values (TC(50) = concentration producing 50% lethality) > 1.0 mg/ml for cephalexin, LY195885 and cefaclor. LY171217, on the other hand, was significantly toxic in vitro (TC(50) = < 0.5). These results suggest that renal cells in culture may provide a useful method for examining the nephrotoxic potential of oral cephalosporins before in vivo studies. PMID- 20837419 TI - The use of defined media in cell and tissue culture. PMID- 20837418 TI - Prior use of the neutral red assay and reduction of total protein determination in 96-well plate assays. AB - The sequential use of the neutral red and protein assays in 96-well plates leads to approximately a 50% underestimation of the amount of protein. In absolute terms, more protein is lost from wells having more protein, but within a cell type the reduction appears to be proportional to the amount of protein. This should be taken into account when interpreting data obtained in this way. PMID- 20837420 TI - In vitro and in vivo studies on the metabolism of 1,3-diaminobenzene: Comparison of metabolites formed by the perfused rat liver, primary rat hepatocyte cultures, hepatic rat microsomes and the whole rat. AB - The metabolism of the aromatic amine 1,3-diaminobenzene (MPD) was studied in vitro by use of the perfused rat liver, primary rat hepatocyte cultures and hepatic rat microsomes. The metabolites formed were compared with urinary metabolites excreted by the rat in vivo. Metabolites of [(14)C]MPD excreted by the perfused liver were found to be identical with urinary excreted metabolites in vivo, three of which were found to correlate with the N-acetylated derivatives N,N'-diacetyl-1,3-diaminobenzene, N,N'-diacetyl-2,4-diaminophenol and N-acetyl 1,3-diaminobenzene. Also, the primary hepatocyte cultures formed the metabolites found in the urine. However, several other metabolites, including some glucuronic acid conjugates, could be detected in the culture medium. In contrast to the perfused liver and the primary hepatocyte cultures, a reconstituted microsomal system was unable to form any of the metabolites formed by the other in vitro models and in vivo. The results show that in addition to the metabolites that can be detected in the urine in vivo, several other derivatives, including glucuronic acid conjugates of MPD, are formed by the rat liver. The results suggest that primary rat hepatocyte cultures are the preferred model system in metabolic studies in vitro and will constitute useful supplements to metabolic studies performed in the rat in vivo. PMID- 20837421 TI - Effects of T-2 toxin on platelet-activating-factor-dependent phosphoinositide turnover in the bovine platelet. AB - The effect of T-2 toxin on phospholipid turnover in the bovine platelet was studied using washed platelets prelabelled with [1-(14)C]arachidonic acid. In the resting, non-stimulated platelet, T-2 toxin induced a significant increase in the incorporation of radioactivity into phosphatidic acid (PA). When the platelets were stimulated to aggregate with the agonist, platelet activating factor (PAF), a decrease in labelled phosphatidylinositol as well as a rise in radioactive PA and free fatty acid (FFA) were observed. In the presence of T-2 toxin, the PAF dependent formation of the polyphosphoinositides and release of FFA were inhibited whereas PA accumulation was unaffected. These results may be of importance in understanding the mode of action of T-2 toxin at the level of membrane phospholipid turnover. PMID- 20837422 TI - Determination of membrane-stabilizing potency of drugs by video analysis of protozoan motility. AB - A technique has been developed to measure the swimming speed of a ciliated protozoon (Tetrahymena pyriformis) and the effects of drugs upon it, using computerized video image analysis. Among 22 drugs tested, protozoon-immobilizing potency was associated with either their lipophilicity or their known membrane stabilizing potency or both. There is evidence that membrane-stabilizing activity (MSA) is a significant cause of fatal human poisoning, and measurement of the acute effects of various drugs in vitro (putatively due to their MSA) may be used to predict their potential hazard in acute overdose. This in vitro assay using readily available and maintainable eukaryotic cells provides a good measure of the membrane-stabilizing potency of chemicals, and may serve to identify particularly hazardous drugs and other agents. PMID- 20837423 TI - Cytotoxicity testing of 114 compounds by the determination of the protein content in Hep G2 cell cultures. AB - The cellular protein content measured in cultured Hep G2 cells was used as the endpoint for determining the cytotoxicity of a range of 114 chemical compounds. The relative toxicity of the test compounds was quantified by the determination of the PI(50), which is the concentration of xenobiotic required to produce a 50% reduction in protein content of the culture after 24 hr. Surfactants and heavy metals consistently had low PI(50) values. Hep G2 cells were very sensitive to compounds with more than one carboxyl group. Triacetin and glutathione were identified as false positives. The results suggest that the PI(50) assay could be a useful pre-screening method to test for the cytotoxicity of chemicals. PMID- 20837424 TI - Mediation of phorbol ester-induced oxidant generation in murine epidermal cells by protein kinase C. AB - Murine epidermal cells have previously been shown to produce an oxidant response to the mouse skin tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA); however, the cellular source of these oxidants has not been well characterized. The demonstration that phospholipase C also elicits this oxidant response suggests that protein kinase C is the common mediator. In order to pursue this hypothesis, studies using protein kinase C inhibitors were carried out; both the induced oxidant response and the induction of ornithine decarboxylase (ODC), a known protein kinase C mediated event, were studied. At 100 MUm palmitoylcarnitine inhibited TPA-induced ODC by 50% and phospholipase C-induced ODC by 95%. At the same dose level, the negative analogue acetylcarnitine had no inhibitory effect on ODC with either inducer. The protein kinase C inhibitor 1-(5 isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride (H-7) and its negative analogue N-(2-guanidinoethyl)-5-isoquinolinesulphonamide hydrochloride (HA-1004) were also used. At 100 MUm, H-7 completely inhibited both TPA and phospholipase C induced ODC; at the same dose HA-1004 had no effect. When these agents were included in the chemiluminescence assay for oxidant generation, similar results were seen: at 100 MUm-palmitoylcarnitine and H-7, but not acetylcarnitine or HA 1004, suppressed the response by nearly 100%. These results suggest that the oxidant response to TPA in epidermal cells is mediated at least in part by protein kinase C. PMID- 20837425 TI - In vitro cytotoxicity of the sodium, potassium and calcium salts of saccharin, sodium ascorbate, sodium citrate and sodium chloride. AB - The in vitro effects of saccharin were evaluated in a transformed rat-bladder epithelial cell line. AY-27 cells were seeded in a 35-mm tissue culture well and incubated for 24 hr with saccharin or other test compounds dissolved in the media. The cytotoxic effects of saccharin were dependent on the salt form tested. Although dose-related decreases in cell viability and attachment were observed following exposure to sodium or potassium saccharin at concentrations of >=50 mM, calcium saccharin decreased only cell viability. Sodium chloride, sodium ascorbate and sodium citrate decreased cell viability and attachment in a dose related fashion, whereas neither potassium chloride nor calcium chloride had any effect. The finding that all of the tested sodium compounds were cytotoxic suggests that the sodium ion plays a role in the cytotoxicity of sodium saccharin. However, the maximum effect and potency of the sodium compounds differed, indicating that the anion moiety also contributes to the cytotoxic effect. Although effects were observed only at millimolar concentrations of the sodium salts, these concentrations corresponded to those in the urine that produced a urothelial proliferative response in rats fed these compounds in earlier studies. PMID- 20837426 TI - Modulating effects of indoles on benzo[a]pyrene-induced sister chromatid exchanges and the balance between drug-metabolizing enzymes. AB - The modulating effects of indole-3-carbinol (I3C) and indole-3-acetonitrile (I3A) on sister chromatid exchange (SCE) induction by benzo[a]pyrene (B[a]P) was studied. Pretreatment of cultured primary chick-embryo hepatocytes with I3C and I3A resulted in a decrease in the number of B[a]P-induced SCEs for both compounds in co-cultured V79 Chinese hamster cells. At 25 MUg/ml I3C caused a twofold increase in UDP-glucuronyltransferase (UDPGT) activity. No induction of glutathione-S-transferase was found. When I3A was used (35 MUg/ml), UDPGT was increased twofold whereas again no increase in glutathione-S-transferase activity was observed. When induction ratios between UDPGT activity and cytochrome P-450 content were studied, induction with both I3C and I3A resulted in ratios (UDPGT activity/cytochrome P-450 content) comparable with the control situation, whereas induction with 3-methylcholanthrene (3-MC) resulted in a considerable decrease in this ratio. Pretreatment with I3C resulted in a considerable increase in the total conversion of B[a]P into water-soluble metabolites. When the relative amounts of the individual metabolites were compared with those obtained after 3 MC pretreatment no significant differences could be observed. The results indicate that modulating effects of indoles are not directly related to induction of cytochrome P-450-associated enzymes. PMID- 20837427 TI - Interactions of cadmium with rat testicular interstitial cell nuclei: Alterations induced by zinc pretreatment and cadmium binding proteins. AB - To help elucidate the mechanism by which zinc prevents cadmium-induced interstitial cell (IC) tumour formation in the rat, the subcellular distribution of cadmium in isolated ICs was studied. In both isolated intact cells and in isolated nuclei, in vivo zinc pretreatment reduced the nuclear uptake of cadmium and resulted in a decreased accumulation of cadmium in subnuclear components, including chromatic and DNA. In intact cells, in vivo zinc pretreatment increased cadmium retention in mitochondria. microsomes and cytosol. An increase in the metal content in three major cytosolic cadmium-binding fractions was also seen, including the low-molecular-weight testicular cadmium-binding protein (TCBP) previously shown to differ from metallothionein. Uptake of cadmium in association with purified TCBP into isolated IC nuclei was about double that of cadmium bound to purified hepatic metallothionein. These data suggest that zinc may prevent IC tumour formation by reducing cadmium accumulation in nuclei and subnuclear components, including chromatin and DNA. This appears to be through a direct inhibition of cadmium uptake by zinc pretreatment at the nuclear membrane and also indirectly by an enhanced retention of cadmium in non-nuclear subcellular components. These data also indicate that the absence of metallothionein in ICs may render this cell population vulnerable to cadmium by allowing increased nuclear uptake. PMID- 20837428 TI - Whole rat embryo culture in serum of insulin-dependent (type-1) diabetic women. AB - Pregnancies in women with type-1 diabetes are associated with an increased risk of developmental disorders. Despite extensive research, the toxicological mechanisms and pathogenesis of these disorders are far from explained. The whole rat embryo culture system was used to study the pathogenesis of malformations induced by culture in sera from diabetic women. In undiluted control sera, rat embryos with 4-8 initial somites developed well. During 26 hr of culture, on average 13 somites were formed per embryo, corresponding to the normal in vivo development. Only 3 out of 59 embryos had a significantly lower morphological score than did controls after culture. In the diabetic group no increased incidence of malformations was found, and development tended to be better than in control sera. Embryos cultured in sera derived from conventionally treated patients had a higher morphological score after culture than did embryos cultured in sera derived from women treated with an insulin pump. The sera of diabetic patients contained on average a fivefold higher insulin concentration than did control sera. However, addition of 300 mU/litre insulin to sera that contained on average 30 mU/litre did not improve the development of cultured embryos. The absence of malformations after culture in sera of diabetic women may relate to the fact that their blood glucose control was on average reasonably good. PMID- 20837429 TI - Calmodulin modulation of adverse effects of Cd(2+) on microtubules and tubulin polymerization in vitro. AB - The contribution of calmodulin to the effects of Cd(2+) on microtubules has been investigated in the detergent-extracted cytoskeletons of cultured cells and on tubulin polymerization in vitro. When incubated with micromolar concentrations of Cd(2+) or Ca(2+) alone, or a mixture of both ions, microtubules in the extracted cytoskeletons disassembled. This disassembly was prevented by compound 48/80, a potent calmodulin inhibitor. In bovine brain microtubule protein containing microtubule-associated proteins, calmodulin also enhanced the Cd(2+)-mediated inhibition of tubulin polymerization; further, this enhancing effect of calmodulin was reversed by compound 48/80. These results demonstrate that Cd(2+) can affect microtubules by binding to and activating calmodulin. PMID- 20837431 TI - Reproductive and developmental toxicology: The value and limitations of in vitro techniques. PMID- 20837430 TI - Toluene treatment in vitro and calcium-regulated protein phosphorylation in primary astroglial cell cultures from the rat striatum. AB - Primary astroglial cell cultures from striata of newborn rats were exposed to toluene in vitro at doses of between 4.7 and 150 MUmol/ml. The protein content of the cell cultures, about 1 mg/ml, was not affected by the toluene treatment. Calcium-induced back-phosphorylation was used to detect changes in the phosphorylation state of calcium-regulated glial phosphoproteins. The 11 most back-phosphorylated protein bands were separated by gel electrophoresis and analysed by autoradiography and computer-assisted image analysis. The back phosphorylation of the 59-kD protein band was increased by 150% at 9.4 MUmol/ml toluene, but no further increase was observed with increasing concentrations. This increase is believed to correspond to a toluene-induced decrease in calcium regulated protein phosphorylation. Furthermore, there was a trend for decreased back-phosphorylation of the 140-kD band and for increased back-phosphorylation of the 110-kD band in response to the higher concentrations of toluene used. The back-phosphorylation of the 42-, 44-, 48-, 51-, 54-, 63-, 74- and >200-kD protein bands showed no dose-related changes in response to the toluene treatment. Taken together, the data indicate that the 59-kD protein in astrocytes from the rat striatum is specifically sensitive to toluene treatment in vitro. PMID- 20837432 TI - Increased peroxisomal enzyme mRNA levels in adult rat hepatocytes cultured in a chemically defined medium and treated with nafenopin. AB - Nafenopin is a known inducer of peroxisome proliferation in the hepatocytes of treated rodents. Primary cultures of adult rat hepatocytes maintained in a chemically-defined medium respond to the drug. RNAs from hepatocyte cultures treated for 1, 8 and 20 hr and their untreated counterparts have been purified and hybridized to radioactive cDNA probes specific for peroxisomal mRNAs (for catalase and the three enzymes of the beta-oxidation system). The amount of the specific mRNAs was fairly constant or increased slightly in control cultures, but increased steadily during treatment of the cultures with a non-toxic dose of nafenopin (32 MUm). For the peroxisomal bifunctional enzyme mRNA, representative of the beta-oxidation system, this increase was approximately fivefold after 20 hr, whereas for catalase mRNA a twofold increase compared with the control was observed after 20 hr. The time-course of the induction of the peroxisomal bifunctional enzyme mRNA in vitro was found to be similar to that observed after intragastric treatment of rats with nafenopin. This indicates that mechanistic studies on the early events induced in hepatocytes by peroxisome proliferators can be performed with this culture system. Such studies may help to explain the hepatotoxic/hepatocarcinogenic properties of this class of xenobiotics. PMID- 20837433 TI - Comparison of the inhibitory effect of T-2 toxin on bovine platelet function with that of other known platelet inhibitors. AB - The inhibitory effects of T-2 toxin on bovine platelet function and thromboxane A(2) production were compared with those of the known inhibitors of human platelet function, acetylsalicylic acid, dipyridamole and verapamil. T-2 toxin (1 * 10(-3)M) effectively inhibited bovine platelet aggregation (33.2-64.3%), whereas neither acetylsalicylic acid nor dipyridamole did so. T-2 toxin appeared to be a less effective inhibitor of platelet aggregation than the calcium channel blocker, verapamil. T-2 toxin (1 * 10(-3)M) added to platelet suspensions together with verapamil, produced an additive inhibitory response. T-2 toxin (2.5 * 10(-4)M) effectively inhibited the release of thromboxane A(2) from ADP stimulated bovine platelets as did acetylsalicylic acid and verapamil but not dipyridamole. T-2 toxin appears to inhibit bovine platelets by a biochemical mechanism distinct from that of the other inhibitors. PMID- 20837434 TI - Depletion of glutathione by the hepatotoxins paracetamol and bromobenzene, and their non-hepatotoxic analogues, in a fortified liver microsomal system. AB - The proposal that liver microsome mixed-function oxidase (MFO)-mediated generation of reactive metabolites may be detected by depletion of reduced glutathione (GSH) added to a fortified microsome incubation containing substrate has been investigated. Paracetamol, 3-hydroxyacetanilide, bromobenzene and p bromophenol were used as substrates for a MFO-mediated depletion of GSH in vitro. Studies involving modulation of the extent of GSH depletion in vitro and comparison with published findings indicated that metabolism-mediated depletion of GSH in a fortified liver microsome incubation correlated with covalent binding of reactive metabolites but did not correlate well with the ability of compounds to cause GSH depletion in vivo or liver damage. PMID- 20837435 TI - The enucleated eye test: A comparison of the use of ultrasonic and optic pachometers. AB - The ultrasonic pachometer has been introduced recently into our laboratory for use in the eye-irritation test using enucleated rabbit eyes. We have compared the performance of this kind of pachometer with that of the optical pachometer. The results for corneal swelling, reported by Burton et al. (1981) and obtained using an optic pachometer, were compared with those obtained using an ultrasonic pachometer to test the same 11 substances. The mean corneal swelling 240 min after application of the test substances to four eyes resulted in a very good correlation (r = 0.984) between the optic and ultrasonic pachometer data. A good Spearman rank correlation (r = 0.906; P < 0.0005) was also found between corneal swelling and opacity. The use of the ultrasonic pachometer requires the contact of the ultrasonic probe tip with the corneal epithelium. Although epithelial damage was observed due to probe contact, we were not able to demonstrate that this would influence corneal swelling. The ultrasonic technique is a considerable improvement over the optic technique because: PMID- 20837436 TI - Detection of neuroteratogens with an in vitro cytotoxicity assay using primary monolayers cultured from dissociated foetal rat brains. AB - Brain tissues from 19-day-old Sprague-Dawley rat foetuses were trypsinized and then dissociated in a nutrient medium. The resulting cellular suspension was seeded in Falcon tissue-culture flasks and incubated at 37 degrees C in humidified air containing 5% CO(2). The monocell layer obtained after incubation for 3 days consisted of two readily distinguishable cell types: neuronal cells with interconnecting neurites and fascicles, and non-neuronal or glial-type cells that were polygonal in appearance. The cell layers were exposed to graded concentrations of a test chemical dissolved in the nutrient medium. The cultures were examined daily for cell death and for inhibited outgrowth of neurites and fascicles for 3 days and the test was then terminated. Chemicals showing no cytotoxic effect at 2-mm concentration were generally not tested any further. Those found positive were tested at lower concentrations to determine the minimum cytotoxic concentration and the type of cell or cells affected. Of the 109 chemicals examined, 59 were non-cytotoxic at the 2-mm concentration or at the highest concentration at which they were soluble (1 mm for three compounds and 0.5 m for one), ten were preferentially cytocidal for non-neurons, 21 were selectively cytolethal for the neurons and ten were cytocidal for both neurons and non-neurons. The cytotoxicity of the remaining nine chemicals was regarded as unreliable because of the hyperosmolality of their solutions. The neuroteratogenic potential of a chemical, based on cytotoxicity data, was regarded as negligible if the cytocidal effect failed to occur in any cell type at a concentration of >=2 mm, or if the effect occurred only in non-neurons or in both neurons and non-neurons. The potential was considered positive if cellular degeneration at the lowest cytocidal concentration of a chemical occurred only in the neurons. The agreement between the neuroteratogenic potential in vivo, as reported in the literature, and the cytotoxicity data obtained in this study was very good for 82 chemicals, reasonable for ten, poor for four and undetermined for four. From the results of this investigation and a review of the published teratology data, the neuron and its precursor neuroepithelial cell appear as the most likely initial targets for neuroteratogenic chemicals. Consequently, our in vitro system offers a promising approach for studies on neuroteratogens. PMID- 20837437 TI - Hepatic toxicity of paraquat in primary cultures of rat hepatocytes. AB - The aim of this work was to evaluate the hepatic effects of toxic and subtoxic doses of paraquat, using a primary culture of adult rat hepatocytes as an experimental model. Concentrations in culture ranged from 10(-3) to 10(-9)m paraquat. When added to cultures at the time of plating 10(-3)m-paraquat impaired hepatocyte spreading on the substratum and caused cell death which was preceded by a leakage of cytosolic enzymes (lactate dehydrogenase, glutamic-oxaloacetic transaminase). When added to 24-hr cultures, effects on the metabolism of the hepatocytes were observed at paraquat concentrations of 10(-3) and 10(-4)m but not at lower concentrations. In comparison with controls, when paraquat was present at 10(-3)m, gluconeogenesis from fructose and lactate was inhibited by 40 and 58%, respectively, ureogenesis was inhibited by 16% and the albumin synthesis rate was reduced by 62%. The intracellular content of the reduced form of glutathione decreased by 33% and was parallelled by an increase in the oxidized form of glutathione. However, neither cytotoxic nor metabolic effects were observed in cells exposed to 10(-5)m, the concentration found in blood after acute intoxication with paraquat. PMID- 20837438 TI - Role of metabolic activation in the toxicity of S (pentachlorobutadienyl)glutathione and S- (pentachlorobutadienyl)- l -cysteine in the isolated perfused rat kidney. AB - The nephrotoxicity of hexachlorobutadiene (HCBD) has been attributed to a sequence of metabolic steps initiated by conjugation of the haloalkene with glutathione in the liver. Current evidence suggests that the conjugate S (pentachlorobutadienyl)glutathione (PCBG) thus formed is degraded in the kidney by dipeptidase(s) to the cysteinylglycinyl conjugate. Subsequent hydrolysis by gamma-glutamyltranspeptidase (GGT) leads to the cysteine conjugate S- (pentachlorobutadienyl)- l -cysteine (PCBC), which is cleaved by cysteine conjugate beta-lyase to pyruvate, ammonia and a reactive thiol, which is presumed to induce nephrotoxicity and nephrocarcinogenicity. In the isolated perfused rat kidney PCBG produced concentration-dependent nephrotoxicity as indicated by the occurrence in the urine of alkaline phosphatase and GGT and by the impairment of glucose reabsorption. The nephrotoxicity of PCBG was blocked by the specific GGT inhibitor, AT-125 (L-alphaS,5S)-alphaamino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid) and by aminooxyacetic aid (AOAA), an inhibitor of beta-lyase. PCBC, A presumptive intermediate in the metabolic activation of PCBG, caused a rapid onset of massive nephrotoxicity which was blocked effectively by AOAA. At 0.1 mm PCBC the increase in biochemical parameters of nephrotoxicity was accompanied by massive tubular necrosis. It is concluded that the glutathione conjugate of HCBD is metabolized within the target organ, the kidney, to PCBC, which is activated by renal beta-lyase to a highly nephrotoxic intermediate. PMID- 20837439 TI - Effects of 3-tert-Butyl-4-hydroxyanisole and its hydroquinone and quinone metabolites on rat and human embryonic cells in culture. AB - 3-tert-Butyl-4-hydroxyanisole (BHA), tert-butyl hydroquinone (BHQ), 3-tert-butyl 4,5-dihydroxyanisole (BHAOH), tert-butylquinone (BQ) and 3-tert-butyl-5-methoxy 1,2-benzoquinone (BHAoQ) were assayed using cell-culture methods for assessing potential teratogenicity. In the rat embryonic cell differentiation assay, BQ had the greatest inhibitory effect on the differentiation of both limb-bud (LB) and midbrain (MB) cells. From the dose-response curves, the concentrations of BHA, BHQ, BHAOH, BHAoQ and BQ that inhibited the production of differentiated foci by 50% (IC(50)) in LB cells were 533, 105, 25, 21 and 16 MUm, respectively, and the IC(50) values for MB cells were 466, 67, 24, 18 and 14 MUm, respectively. BQ also showed the most potent inhibitory action in the human embryonic palatal mesenchymal (HEPM) cell-growth assay. The concentrations of BHA, BHQ, BHAOH, BHAoQ and BQ that inhibited cell growth by 50% (IC(50)) were 244, 48, 23, 15 and 3.3 MUm, respectively. Therefore in these assays, the quinone and hydroquinone metabolites of BHA showed greater teratogenic potential than did BHA itself. The inhibitory action of BHA on HEPM cell growth was greater in the presence of S-9 mix prepared using livers from rats treated with phenobarbital and 5,6 benzoflavone. In the HEPM cell-growth assay, rat (F344) S-9 was more effective in inducing the metabolic activation of BHA than was S-9 from hamsters or mice. PMID- 20837440 TI - Differential cytotoxic, growth-inhibiting and lipid-peroxidative activities of four different asbestos fibres in vitro. AB - An attempt was made to characterize the carcinogenic hazard of asbestos fibres by using a set of in vitro screening tests. The fibres tested were the serpentine chrysotile and the three amphiboles anthophyllite, crocidolite and amosite. Their cytotoxic and cytostatic activities in rat primary fibroblast-like cells were assessed along with their effects on enzymic lipid peroxidation by liver homogenates. After 24 hr exposure of fibroblast-like cells to 2.1 MUg fibres/cm(2), chrysotile induced the highest cytotoxicity, followed by crocidolite, anthophyllite and amosite. Similarly, after 48 hr exposure, chrysotile had the most growth inhibiting effect, followed by crocidolite, anthophyllite and amosite. Enzymic lipid peroxidation, as measured by pentane or malondialdehyde production, was determined at ambient (21% O(2)) or tissue (4% O(2)) oxygen tension in incubation mixtures containing rat-liver homogenate and asbestos fibres. At 4% O(2), only the two iron-containing fibres, crocidolite and amosite, stimulated lipid peroxidation. The results suggest that the cytotoxic activity is influenced by the surface charge, structure and dimensions of the fibres, and that cell-growth inhibition is associated with surface charge, structure and the Mg(2+) content of the fibres. Effects on enzymic lipid peroxidation appear to be associated with the structure and iron content of the tested fibres. When these results are considered along with epidemiological data, it seems that the carcinogenic potency of asbestos fibres is characterized by an ability to induce high levels of enzymic lipid peroxidation along with moderate cytotoxic and growth inhibiting activities. PMID- 20837441 TI - Dose-response studies of nickel-induced morphological transformation of Syrian hamster embryo fibroblasts. AB - We examined the dose-response curves for the induction of morphological transformation of Syrian hamster embryo cells by nickel sulphate or nickel chloride. A low, but significant, induction of transformation was observed at doses of 0.5-5 MUg NiCl(2) or NiSO(4)/ml. Increasing the dose to 10 or 20 MUg/ml significantly increased the transformation frequency. The increase was not linearly proportional to the increase in dose (e.g. a twofold increase in concentration increased the transformation frequency by tenfold). Treatment with a phorbol ester tumour promoter (12-O-tetradecanoylphorbol-13-acetate, added 2 days after treatment with the nickel compounds) enhanced the transformation induced by nickel at low doses. The possible significance of these findings in relation to epidemiological studies of humans exposed to different levels of nickel are discussed. PMID- 20837442 TI - Immunotoxicology and allergy: Old problems and new approaches. PMID- 20837444 TI - Compact quantitative optic fiber-based immunoarray biosensor for rapid detection of small analytes. AB - Immunoarrays have been proven to be powerful tools for high-throughput analysis of multiple analytes. In this paper, a proof-of-concept development of a novel optic fiber-based immunoarray biosensor for the detection of multiple small analytes is presented. This was developed through immobilization of two kinds of hapten conjugates, MC-LR-OVA and NB-OVA, onto the same fiber optic probe. The technique is significantly different from conventional immunoarray sensors. Microcystin-LR (MC-LR) and trinitrotoluene (TNT) could be detected simultaneously and specifically within an analysis time of about 10 min for each assay cycle. The limits of detection for MC-LR and TNT were 0.04 MUg/L and 0.09 mg/L, respectively. Good regeneration performance, binding properties, and robustness of the sensor surface of the proposed immunoarray biosensor ensure the cost effective and accurate measurement of small analytes. The change in concentration of the hapten conjugates immobilized onto the sensor surface was also proven to have no significant effection on the performance of immunoarray sensor, which is essential to the application of the immunoarray in real samples detection. This compact and portable quantitative immunoarray provides an excellent multiple assay platform for clinical and environmental samples. PMID- 20837446 TI - Approximate solution of the multiple watchman routes problem with restricted visibility range. AB - In this paper, a new self-organizing map (SOM) based adaptation procedure is proposed to address the multiple watchman route problem with the restricted visibility range in the polygonal domain W. A watchman route is represented by a ring of connected neuron weights that evolves in W, while obstacles are considered by approximation of the shortest path. The adaptation procedure considers a coverage of W by the ring in order to attract nodes toward uncovered parts of W. The proposed procedure is experimentally verified in a set of environments and several visibility ranges. Performance of the procedure is compared with the decoupled approach based on solutions of the art gallery problem and the consecutive traveling salesman problem. The experimental results show the suitability of the proposed procedure based on relatively simple supporting geometrical structures, enabling application of the SOM principles to watchman route problems in W. PMID- 20837447 TI - Cultural-based multiobjective particle swarm optimization. AB - Multiobjective particle swarm optimization (MOPSO) algorithms have been widely used to solve multiobjective optimization problems. Most MOPSOs use fixed momentum and acceleration for all particles throughout the evolutionary process. In this paper, we introduce a cultural framework to adapt the personalized flight parameters of the mutated particles in a MOPSO, namely momentum and personal and global accelerations, for each individual particle based upon various types of knowledge in "belief space," specifically situational, normative, and topographical knowledge. A comprehensive comparison of the proposed algorithm with chosen state-of-the-art MOPSOs on benchmark test functions shows that the movement of the individual particle using the adapted parameters assists the MOPSO to perform efficiently and effectively in exploring solutions close to the true Pareto front while exploiting a local search to attain diverse solutions. PMID- 20837448 TI - Enhanced differential evolution with adaptive strategies for numerical optimization. AB - Differential evolution (DE) is a simple, yet efficient, evolutionary algorithm for global numerical optimization, which has been widely used in many areas. However, the choice of the best mutation strategy is difficult for a specific problem. To alleviate this drawback and enhance the performance of DE, in this paper, we present a family of improved DE that attempts to adaptively choose a more suitable strategy for a problem at hand. In addition, in our proposed strategy adaptation mechanism (SaM), different parameter adaptation methods of DE can be used for different strategies. In order to test the efficiency of our approach, we combine our proposed SaM with JADE, which is a recently proposed DE variant, for numerical optimization. Twenty widely used scalable benchmark problems are chosen from the literature as the test suit. Experimental results verify our expectation that the SaM is able to adaptively determine a more suitable strategy for a specific problem. Compared with other state-of-the-art DE variants, our approach performs better, or at least comparably, in terms of the quality of the final solutions and the convergence rate. Finally, we validate the powerful capability of our approach by solving two real-world optimization problems. PMID- 20837449 TI - Basophils: new players in the cytokine network. AB - Basophils belong to a myeloid cell population that has been ignored for more than a century, mainly because of its paucity, its lack of specific markers, and the absence of experimental models. Given that in mice, even the mere existence of basophils was contested, they were alluded to as "histamine-producing cells" or "non-T non-B cells" in initial studies. It is now widely acknowledged that basophils respond to various IgE-dependent or -independent stimuli, and are engaged in a complex cross talk with a number of immunocompetent cells (T or B lymphocytes, macrophages, dendritic cells, endothelial cells...). Indeed, on the one hand they are critically involved during the onset, the effector phase and exacerbation of T(H)2 responses through their capacity to generate large amounts of cytokines with pro-T(H)2 functions (IL-4, IL-13 TSLP, IL-25), on the other hand, they contribute to immunoglobulin synthesis and class switching, angiogenesis, autoimmunity, tumor immunity and hematopoiesis by producing cytokines such as IL-6, VEGF, GM-CSF and IL-3. Finally, it has been established that they can present antigens to CD4+ or CD8+ T cells in an MHC class II- or class I-dependent manner, respectively. Taken together, these activities confer important immunoregulatory functions upon basophils, both in innate and adaptive immunity. PMID- 20837450 TI - Small-cell carcinoma with an epidermal growth factor receptor mutation in a never smoker with gefitinib-responsive adenocarcinoma of the lung. AB - Activating mutations in the epidermal growth factor receptor (EGFR) gene are extremely rare in small-cell lung cancer (SCLC). Here, we present a case of an EGFR-mutant gefitinib-responsive non-small-cell lung cancer (NSCLC) of adenocarcinoma histology occurring in a never-smoker followed by subsequent diagnosis of metastatic SCLC carrying an EGFR mutation. Although gefitinib therapy of the primary NSCLC resulted in disease control for over 3 years, the patient subsequently developed metastatic SCLC to the liver. Epidermal growth factor receptor mutation analysis revealed that the exon 21 L858R activating mutation was present in both the original lung adenocarcinoma and the metastatic SCLC. We hypothesize that SCLC either evolved from the previously diagnosed NSCLC or that both arose from a common precursor. Further comparative molecular analysis of these histologically distinct tumors would be of value to better understand the potential role of EGFR in the pathogenesis of SCLC in never smokers, and the role of selection for an EGFR-mutant SCLC subclone as an unusual mechanism of acquired resistance to EGFR inhibitors in NSCLC. PMID- 20837451 TI - Supersensitive mutation: two case reports of non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are indicated in second-line treatment for non-small-cell lung cancer and are, in general, well tolerated. In some patients, side effects can be problematic, necessitating dose attenuation and changes in frequency of administration. A lung tumor with an EGFR mutation confers a high treatment response rate to EGFR TKIs. We present the case reports of 2 patients, both with EGFR mutations in which excellent responses were seen despite dosages and administration frequencies far below recommended levels. In addition, in the face of apparent resistance, small increases in doses overcame this. The possible factors involved in response and resistance to EGFR TKIs and issues around length of treatment are discussed. PMID- 20837453 TI - Dr. David R. Gandara receives third annual Addario Lectureship award at international lung cancer congress. PMID- 20837454 TI - Clinical perspectives on dose escalation for non-small-cell lung cancer. AB - Lung cancer remains the leading cause of cancer death in the United States. The standard of care for patients with locally advanced non-small-cell lung cancer is radiation plus chemotherapy. The nationally accepted standard radiation prescription dose has remained at 60-63 Gy for more than 30 years, with local failure rates reaching 85% and median survival rates of approximately 17 months. With smaller treatment volumes and the increased conformality of radiation delivery, the administration of higher radiation doses to the target while minimizing dose to critical structures is feasible. Clinical outcome is improved while minimizing toxicity. Recent prospective trials escalating doses to 74 Gy with concurrent chemotherapy have demonstrated promise with improved survival rates and acceptable toxicity rates. PMID- 20837456 TI - Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non small-cell lung cancer. AB - Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC. PMID- 20837457 TI - Second-line treatment for non-small-cell lung cancer: one size does not fit all. AB - After progression following first-line treatment, many patients with advanced non small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC. PMID- 20837458 TI - Low thymidylate synthase, thymidine phosphorylase, and dihydropyrimidine dehydrogenase mRNA expression correlate with prolonged survival in resected non small-cell lung cancer. AB - BACKGROUND: Thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are key enzymes in the 5-fluorouracil (5 FU) pathway. The aim of this study was to investigate the mRNA expression of TS, TP, and DPD in tumor and nontumor lung tissue of patients with NSCLC and to determine the potential of these genes as molecular biomarkers. MATERIALS AND METHODS: The TS, TP, and DPD mRNA expression was analyzed in tumor and nontumor tissue of 91 patients with NSCLC by quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) with beta-actin as the internal control. All tumors were R0 resected. The median follow-up was 85.9 months. RESULTS: The mRNA expression of TS, TP, and DPD was detectable in both tumor and nontumor tissue. Tumor TP (tTP) seems to correlate with tumor TS (tTS) and tumor DPD (tDPD) mRNA expression, but no correlation in the mRNA expression of tTS and tDPD was found. The TS and TP mRNA expression levels were significantly associated with patient prognosis. The 5-year survival probability was 58.7% (TS), and 59.6% (TP) for patients with a low TS and TP mRNA expression and 33.4% (TS), and 31.8% (TP) for patients with a high mRNA expression (P = .04 [TS]; P = .03 [TP]; log-rank). The probability of survival was significantly different among patients with no and any 1 highly expressed gene compared with patients with any 2 or more of the 3 investigated genes highly expressed (P = .012). CONCLUSION: High TS, TP, and DPD mRNA expression are biomarkers for a more severe malign NSCLC biology. Quantitation of the mRNA expression of these genes seems to be helpful in differing patients with unequal malign tumor entities and therefore possibly helpful in selecting tailored additional therapies to control the disease. PMID- 20837459 TI - Comparison of 18F-Fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. AB - INTRODUCTION: The aim of this study was to compare glucose metabolism and hypoxia using 18F- fluorodeoxyglucose (18F-FDG) and 18F-fluoroerythronitroimidazole (18F FETNIM) positron emission tomography (PET) and investigate their prognostic role on survival in patients with locally advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-six patients with NSCLC were imaged with 18F-FETNIM PET/computed tomography (CT), and 11 cases also with 18F-FDG PET/CT imaging among those with significant 18F-FETNIM uptake, a few days before any chemo/adiation therapy. The maximum standardized uptake value (SUVmax) was used to depict 18F FDG uptake, and hypoxic volume (HV) and tumor:blood ratio (T/Bmax) were used to quantify hypoxia. Overall survival (OS) after treatment was selected as the endpoint of the study. RESULTS: Twenty-two patients (84.6%) had significant 18F FETNIM uptake in the primary tumor. The correlations between the overall tumor SUVmax of 18F-FDG and HV, T/Bmax ratio of 18F-FENTIM in 11 patients were small and without significant difference. In univariate analyses, log-rank tests were used to compare Kaplan-Meier survival curves. 18F-FETNIM T/Bmax ratio and HV were strong predictors for OS, and 18F-FDG uptake of the primary lesions did not have a significant relationship with survival. In multivariate survival analysis, only 18F-FETNIM T/Bmax ratio was found to be an independent prognostic factor. CONCLUSION: Imaging using both 18F-FETNIM and 18F-FDG appears to be beneficial in the evaluation of solid tumors. 18F-FETNIM imaging provides us with a valuable method to detect tumor hypoxia and predict OS. These preliminary results warrant validation in larger trials. PMID- 20837460 TI - High N-terminal pro-B-type natriuretic peptide: a biomarker of lung cancer? AB - BACKGROUND: The level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) is affected by many known factors. Our study aimed to evaluate whether other factors, in particular lung cancer, could be responsible for an increase in NT proBNP levels in a population with no known risk factors for elevated NT-proBNP. PATIENTS AND METHODS: This study was based on the RIABO (Recueil de l'Ischemie au Bloc Operatoire) database, a single-center registry that prospectively records in elective noncardiac surgery. Patients aged > 75 years and those presenting with 1 or more known risk factors for high NT-proBNP were excluded. Patients were divided into 2 groups according to preoperative NT-proBNP levels: (>= 125 pg/mL or < 125 pg/mL). RESULTS: Between October 2005 and February 2007, 439 patients were eligible for inclusion. Among 35 patients with lung cancer, 26 (74%) had elevated NT-proBNP (>= 125 pg/mL), versus 9 (26%) with NT-proBNP < 125 pg/mL (P < .0001). By multivariate analysis, the presence of lung cancer was an independent risk factor for a level of NT-proBNP >= 125 pg/mL (odds ratio, 7; 95% CI, 2.9-17; P < .0001). We also observed an independent relationship between NT-proBNP >= 125 pg/mL and age, female sex, smoking status, and C-reactive protein levels. CONCLUSION: In our study, patients with lung cancer were 7 times more likely to have elevated NT-proBNP (>= 125 pg/mL). The presence of lung cancer should therefore be taken into account when interpreting NT-proBNP levels. Further studies are warranted to explore the diagnostic value of this marker in lung cancer and to identify the cause of the elevation. PMID- 20837461 TI - Expression and clinicopathologic significance of proteolysis-inducing factor in non-small-cell lung cancer: an immunohistochemical analysis. AB - BACKGROUND: Proteolysis-inducing factor (PIF) is a 24-kD glycoprotein that has been identified in mice and in humans with cancer cachexia. The PIF is a putative mediator of cancer-associated weight loss, which induces atrophy of skeletal muscle. MATERIALS AND METHODS: In this study, we detected the expression of the PIF in 71 patients with non-small-cell lung cancer (NSCLC) and 10 patients with healthy lung tissues as a control group using the immunohistochemical staining method. In addition, weight loss of patients and serum carcinoembryonic antigen (CEA) and cytokeratin fragment antigen 21-1 (CYFRA 21-1) were measured, and an analysis of overall survival was done. RESULTS: Proteolysis-inducing factor was expressed in only 56.3% (40/71) of lung cancers and not in normal tissue. The positive rate of the PIF expression was significantly higher (P < .01) in patients with weight loss than in those without weight loss. There was no significant relationship (P > .05) between the PIF expression and the histology type, degree of differentiation, or tumor clinical stages in lung cancers. The sensitivity of the PIF was better than that of CEA (P < .05), but similar to that of CYFRA 21-1 in NSCLC. CONCLUSION: Proteolysis-inducing factor expression was negatively related to the survival of patients with NSCLC in the medium to advanced stages (II-IV). There was a significant correlation between weight loss and survival in the PIF-positive patients. PMID- 20837462 TI - Treatment rationale and study design for a randomized trial of pemetrexed/carboplatin followed by maintenance pemetrexed versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with advanced non-small-cell lung cancer of nonsquamous histology. AB - Herein we describe a companion ongoing randomized phase III study in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Patients with chemotherapy-naive advanced disease will be randomized to receive either pemetrexed 500 mg/m2 plus carboplatin area under the curve (AUC) 6 for 4 cycles followed by maintenance pemetrexed (arm A) or paclitaxel 200 mg/m2 plus carboplatin AUC 6 plus bevacizumab 15 mg/kg for 4 cycles followed by maintenance bevacizumab (arm B). Cycles are 3 weeks. The primary endpoint is progression-free survival (PFS)without grade 4 toxicity (G4PFS) and will test the hypothesis that G4PFS is superior for the pemetrexed-containing combination. This type of endpoint has been used previously in clinical trials in which survival outcomes have been shown to be similar between treatment regimens; thus, a regimen that reduces the risk of toxicity is clinically relevant, particularly in the palliative setting. The study will enroll approximately 360 patients (180 per arm), allowing for a 10% drop-out. Assuming a hazard ratio (HR) of 0.75, this study will have an 80% statistical power to detect superiority of arm A over arm B with the use of a 1-sided log-rank test and a type I error of 0.05. If the true median G4PFS for arm B is 3 months, then the HR of 0.75 equals approximately 1 month of improvement in median G4PFS for arm A. A gatekeeper strategy will be used to sequentially test PFS. This strategy will preserve the overall type I error rate when conducting statistical tests on both G4PFS and PFS. PMID- 20837464 TI - Effects of internet-based tailored advice on the use of cholesterol-lowering interventions: a randomized controlled trial. AB - BACKGROUND: Elevated low-density lipoprotein (LDL) cholesterol is a leading risk factor for cardiovascular disease. Despite the availability of proven interventions to lower LDL cholesterol, their use remains subobtimal. Many websites provide interactive, tailored advice on cardiovascular risk in an attempt to help bridge this evidence-practice gap, yet there is little evidence that provision of such a tool is effective in changing practice. OBJECTIVES: The objective was to define the effects on use of cholesterol-lowering interventions of a consumer-targeted tailored advice website. METHODS: This was a prospective, double-blind, randomized controlled trial open to any adult Australian with access to the Internet. A total of 2099 participants were randomized. Of these, 45% were male, the mean age of all participants was 56, and 1385 (66%) self reported hypercholesterolemia. Follow-up information was obtained for 1945 (93%). Participants completed a brief online questionnaire. Individuals assigned to intervention received immediate, fully automated, personally tailored advice (based on current guidelines) regarding the need for commencement of statin therapy, increased statin therapy in those already on treatment, and nondrug intervention strategies. Control group participants were directed to static Web pages providing general information about cholesterol management. RESULTS: The primary outcome was the proportion of participants that commenced or increased use of prescribed cholesterol-lowering therapy. Of the total 2099 randomized participants, 304 (14%) met eligibility criteria for cholesterol-lowering therapy but were not prescribed treatment, and 254 (12%) were prescribed treatment but were not achieving the recommended target level. Treatment was commenced or increased in 64 (6.0%) of the 1062 intervention group participants and 79 (7.6%) of the 1037 control group participants (% difference = -1.6%, 95% confidence interval [CI] -3.75 to 0.57, P = .15). No differences were found between the randomized groups for the secondary outcomes of "discussed treatment with a health professional" (% difference = -3.8%, 95% confidence interval [CI] -8.16 to 0.19, P = .08), "had their cholesterol checked" (% difference = -1.5%, 95% CI 5.79 to 2.71, P = .48), "had their blood pressure checked" (% difference = 1.4%, 95% CI -2.55 to 5.34, P = .49) or made a lifestyle change (P values between .49 and .96). CONCLUSIONS: Despite providing specific carefully tailored advice, this website had no detectable effect on cholesterol management strategies. This finding raises considerable uncertainty about the value of Internet-based tools providing tailored advice directly to consumers. TRIAL REGISTRATION: NCT00220974; http://clinicaltrials.gov/ct2/show/NCT00220974 (Archived by WebCite at http://www.webcitation.org/5sdq63rrY). PMID- 20837465 TI - Regulation of MyD88 aggregation and the MyD88-dependent signaling pathway by sequestosome 1 and histone deacetylase 6. AB - MyD88 is an essential adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor. MyD88 is thought to be present as condensed forms or aggregated structures in the cytoplasm, although the reason has not yet been clear. Here, we show that endogenous MyD88 is present as small speckle-like condensed structures, formation of which depends on MyD88 dimerization. In addition, formation of large aggregated structures is related to cytoplasmic accumulation of sequestosome 1 (SQSTM1; also known as p62) and histone deacetylase 6 (HDAC6), which are involved in accumulation of polyubiquitinated proteins. A gene knockdown study revealed that SQSTM1 and HDAC6 were required for MyD88 aggregation and exhibited a suppressive effect on TLR ligand-induced expression of IL-6 and NOS2 in RAW264.7 cells. SQSTM1 and HDAC6 were partially involved in suppression of several TLR4-mediated signaling events, including activation of p38 and JNK, but they hardly affected degradation of IkappaBalpha (inhibitor of nuclear factor kappaB). Biochemical induction of MyD88 oligomerization induced recruitment of SQSTM1 and HDAC6 to the MyD88-TRAF6 signaling complex. Repression of SQSTM1 and HDAC6 enhanced formation of the MyD88 TRAF6 complex and conversely decreased interaction of the ubiquitin-specific negative regulator CYLD with the complex. Furthermore, ubiquitin-binding regions on SQSTM1 and HDAC6 were essential for MyD88 aggregation but were not required for interaction with the MyD88 complex. Thus, our study reveals not only that SQSTM1 and HDAC6 are important determinants of aggregated localization of MyD88 but also that MyD88 activates a machinery of polyubiquitinated protein accumulation that has a modulatory effect on MyD88-dependent signal transduction. PMID- 20837466 TI - Golgi calcium pump secretory pathway calcium ATPase 1 (SPCA1) is a key regulator of insulin-like growth factor receptor (IGF1R) processing in the basal-like breast cancer cell line MDA-MB-231. AB - Calcium signaling is a key regulator of pathways important in tumor progression, such as proliferation and apoptosis. Most studies assessing altered calcium homeostasis in cancer cells have focused on alterations mediated through changes in cytoplasmic free calcium levels. Here, we show that basal-like breast cancers are characterized by an alteration in the secretory pathway calcium ATPase 1 (SPCA1), a calcium pump localized to the Golgi. Inhibition of SPCA1 in MDA-MB-231 cells produced pronounced changes in cell proliferation and morphology in three dimensional culture, without alterations in sensitivity to endoplasmic reticulum stress induction or changes in global calcium signaling. Instead, the effects of SPCA1 inhibition in MDA-MB-231 cells reside in altered regulation of calcium dependent enzymes located in the secretory pathway, such as proprotein convertases. Inhibition of SPCA1 produced a pronounced alteration in the processing of insulin-like growth factor receptor (IGF1R), with significantly reduced levels of functional IGF1Rbeta and accumulation of the inactive trans Golgi network pro-IGF1R form. These studies identify for the first time a calcium transporter associated with the basal-like breast cancer subtype. The pronounced effects of SPCA1 inhibition on the processing of IGF1R in MDA-MB-231 cells independent of alterations in global calcium signaling also demonstrate that some calcium transporters can regulate the processing of proteins important in tumor progression without major alterations in cytosolic calcium signaling. Inhibitors of SPCA1 may offer an alternative strategy to direct inhibitors of IGF1R and attenuate the processing of other proprotein convertase substrates important in basal breast cancers. PMID- 20837467 TI - G-helix of maspin mediates effects on cell migration and adhesion. AB - Maspin is a member of the serine protease inhibitor (serpin) superfamily that lacks protease inhibitory ability, although displaying tumor metastasis suppressing activity resulting from its influence on cell migration, invasion, proliferation, apoptosis, and adhesion. The molecular mechanisms of these actions of maspin are as yet undefined. Here, we sought to identify critical functional motifs by the expression of maspin with point mutations at sites potentially involved in protein-protein interactions: the G alpha-helix (G-helix), an internal salt bridge or the P1 position of the reactive center loop. Our findings indicate that only mutations in the G-helix attenuated inhibition of cell migration by maspin and that this structural element is also involved in the effect of maspin on cell adhesion. The action of maspin on cell migration could be mimicked by a 15-mer G-helix peptide, indicating that the G-helix is both essential and sufficient for this effect. In addition, we provide evidence that the effects of the G-helix of maspin are dependent on beta1 integrins. These data reveal that the major extracellular functions associated with the tumor suppressive action of maspin likely involve interactions in which the G-helix plays a key role. PMID- 20837469 TI - Transmembrane BAX inhibitor motif containing (TMBIM) family proteins perturbs a trans-Golgi network enzyme, Gb3 synthase, and reduces Gb3 biosynthesis. AB - Globotriaosylceramide (Gb3) is a well known receptor for Shiga toxin (Stx), produced by enterohemorrhagic Escherichia coli and Shigella dysenteriae. The expression of Gb3 also affects several diseases, including cancer metastasis and Fabry disease, which prompted us to look for factors involved in its metabolism. In the present study, we isolated two cDNAs that conferred resistance to Stx induced cell death in HeLa cells by expression cloning: ganglioside GM3 synthase and the COOH terminus region of glutamate receptor, ionotropic, N-methyl-D asparate-associated protein 1 (GRINA), a member of the transmembrane BAX inhibitor motif containing (TMBIM) family. Overexpression of the truncated form, named GRINA-C, and some members of the full-length TMBIM family, including FAS inhibitory molecule 2 (FAIM2), reduced Gb3, and lactosylceramide was accumulated instead. The change of glycolipid composition was restored by overexpression of Gb3 synthase, suggesting that the synthase is affected by GRINA-C and FAIM2. Interestingly, the mRNA level of Gb3 synthase was unchanged. Rather, localization of the synthase as well as TGN46, a trans-Golgi network marker, was perturbed to form punctate structures, and degradation of the synthase in lysosomes was enhanced. Furthermore, GRINA-C was associated with Gb3 synthase. These observations may demonstrate a new type of posttranscriptional regulation of glycosyltransferases. PMID- 20837468 TI - Sphingosine 1-phosphate receptor 4 uses HER2 (ERBB2) to regulate extracellular signal regulated kinase-1/2 in MDA-MB-453 breast cancer cells. AB - We demonstrate here that the bioactive lipid sphingosine 1-phosphate (S1P) uses sphingosine 1-phosphate receptor 4 (S1P(4)) and human epidermal growth factor receptor 2 (HER2) to stimulate the extracellular signal regulated protein kinase 1/2 (ERK-1/2) pathway in MDA-MB-453 cells. This was based on several lines of evidence. First, the S1P stimulation of ERK-1/2 was abolished by JTE013, which we show here is an S1P(2/4) antagonist and reduced by siRNA knockdown of S1P(4). Second, the S1P-stimulated activation of ERK-1/2 was almost completely abolished by a HER2 inhibitor (ErbB2 inhibitor II) and reduced by siRNA knockdown of HER2 expression. Third, phyto-S1P, which is an S1P(4) agonist, stimulated ERK-1/2 activation in an S1P(4)- and HER2-dependent manner. Fourth, FTY720 phosphate, which is an agonist at S1P(1,3,4,5) but not S1P(2) stimulated activation of ERK 1/2. Fifth, S1P stimulated the tyrosine phosphorylation of HER2, which was reduced by JTE013. HER2 which is an orphan receptor tyrosine kinase is the preferred dimerization partner of the EGF receptor. However, EGF-stimulated activation of ERK-1/2 was not affected by siRNA knockdown of HER2 or by ErbB2 (epidermal growth factor receptor 2 (or HER2)) inhibitor II in MDA-MB-453 cells. Moreover, S1P-stimulated activation of ERK-1/2 does not require an EGF receptor. Thus, S1P and EGF function in a mutually exclusive manner. In conclusion, the magnitude of the signaling gain on the ERK-1/2 pathway produced in response to S1P can be increased by HER2 in MDA-MB-453 cells. The linkage of S1P with an oncogene suggests that S1P and specifically S1P(4) may have an important role in breast cancer progression. PMID- 20837470 TI - Slc35c2 promotes Notch1 fucosylation and is required for optimal Notch signaling in mammalian cells. AB - Mammalian Notch receptors require modification by fucose on epidermal growth factor-like (EGF) repeats of their extracellular domain to respond optimally to signal induction by canonical Notch ligands. Inactivation of the Golgi GDP-fucose transporter Slc35c1 in mouse or human does not cause marked defects in Notch signaling during development, and shows milder fucosylation defects than those observed in mice unable to synthesize GDP-fucose, indicating the existence of another mechanism for GDP-fucose transport into the secretory pathway. We show here that fibroblasts from mice or humans lacking Slc35c1 exhibit robust Notch signaling in co-culture signaling assays. A potential candidate for a second GDP fucose transporter is the related gene Slc35c2. Overexpression of Slc35c2 reduces expression of the fucosylated epitopes Lewis X and sialylated Lewis X in CHO cells, indicating competition with Slc35c1. The fucosylation of a Notch1 EGF repeat fragment that occurs in the endoplasmic reticulum was increased in CHO transfectants overexpressing Slc35c2. In CHO cells with low levels of Slc35c2, both Delta1- and Jagged1-induced Notch signaling were reduced, and the fucosylation of a Notch1 fragment was also decreased. Immunofluorescence microscopy of rat intestinal epithelial cells and HeLa cells, and analysis of rat liver membrane fractions showed that Slc35c2 is primarily colocalized with markers of the cis-Golgi network and endoplasmic reticulum-Golgi intermediate compartment (ERGIC). The combined results suggest that Slc35c2 is either a GDP fucose transporter that competes with Slc35c1 for GDP-fucose, or a factor that otherwise enhances the fucosylation of Notch and is required for optimal Notch signaling in mammalian cells. PMID- 20837472 TI - Type I antifreeze proteins enhance ice nucleation above certain concentrations. AB - In this study, we examined the effects that antifreeze proteins have on the supercooling and ice-nucleating abilities of aqueous solutions. Very little information on such nucleation currently exists. Using an automated lag time apparatus and a new analysis, we show several dilution series of Type I antifreeze proteins. Our results indicate that, above a concentration of ~8 mg/ml, ice nucleation is enhanced rather than hindered. We discuss this unexpected result and present a new hypothesis outlining three components of polar fish blood that we believe affect its solution properties in certain situations. PMID- 20837471 TI - O-glycosylation modulates proprotein convertase activation of angiopoietin-like protein 3: possible role of polypeptide GalNAc-transferase-2 in regulation of concentrations of plasma lipids. AB - The angiopoietin-like protein 3 (ANGPTL3) is an important inhibitor of the endothelial and lipoprotein lipases and a promising drug target. ANGPTL3 undergoes proprotein convertase processing (RAPR(224)?TT) for activation, and the processing site contains two potential GalNAc O-glycosylation sites immediately C terminal (TT(226)). We developed an in vivo model system in CHO ldlD cells that was used to show that O-glycosylation in the processing site blocked processing of ANGPTL3. Genome-wide SNP association studies have identified the polypeptide GalNAc-transferase gene, GALNT2, as a candidate gene for low HDL and high triglyceride blood levels. We hypothesized that the GalNAc-T2 transferase performed critical O-glycosylation of proteins involved in lipid metabolism. Screening of a panel of proteins known to affect lipid metabolism for potential sites glycosylated by GalNAc-T2 led to identification of Thr(226) adjacent to the proprotein convertase processing site in ANGPTL3. We demonstrated that GalNAc-T2 glycosylation of Thr(226) in a peptide with the RAPR(224)?TT processing site blocks in vitro furin cleavage. The study demonstrates that ANGPTL3 activation is modulated by O-glycosylation and that this step is probably controlled by GalNAc T2. PMID- 20837473 TI - Gossypol induces death receptor-5 through activation of the ROS-ERK-CHOP pathway and sensitizes colon cancer cells to TRAIL. AB - Development of resistance to TRAIL, an apoptosis-inducing cytokine, is one of the major problems in its development for cancer treatment. Thus, pharmacological agents that are safe and can sensitize the tumor cells to TRAIL are urgently needed. We investigated whether gossypol, a BH3 mimetic that is currently in the clinic, can potentiate TRAIL-induced apoptosis. Intracellular esterase activity, sub-G(1) cell cycle arrest, and caspase-8, -9, and -3 activity assays revealed that gossypol potentiated TRAIL-induced apoptosis in human colon cancer cells. Gossypol also down-regulated cell survival proteins (Bcl-x(L), Bcl-2, survivin, XIAP, and cFLIP) and dramatically up-regulated TRAIL death receptor (DR)-5 expression but had no effect on DR4 and decoy receptors. Gossypol-induced receptor induction was not cell type-specific, as DR5 induction was observed in other cell types. Deletion of DR5 by siRNA significantly reduced the apoptosis induced by TRAIL and gossypol. Gossypol induction of the death receptor required the induction of CHOP, and thus, gene silencing of CHOP abolished gossypol induced DR5 expression and associated potentiation of apoptosis. ERK1/2 (but not p38 MAPK or JNK) activation was also required for gossypol-induced TRAIL receptor induction; gene silencing of ERK abolished both DR5 induction and potentiation of apoptosis by TRAIL. We also found that reactive oxygen species produced by gossypol treatment was critical for TRAIL receptor induction and apoptosis potentiation. Overall, our results show that gossypol enhances TRAIL-induced apoptosis through the down-regulation of cell survival proteins and the up regulation of TRAIL death receptors through the ROS-ERK-CHOP-DR5 pathway. PMID- 20837475 TI - The hyposensitive N187D P2X7 mutant promotes malignant progression in nude mice. AB - Nucleotides are new players in the intercellular communication network. P2X7 is a member of the P2X family of receptors, which are ATP-gated plasma membrane ion channels with diverse biological functions. Abnormal expression and dysfunction of P2X7 have been reported in leukemias. Here, we report a new P2X7 mutant (an A(559)-to-G substitution causing N187D P2X7) cloned from J6-1 leukemia cells. The characteristics of N187D P2X7 were studied by establishing stably transfected K562 cell lines. Our results show that N187D P2X7 required a higher concentration of agonist for its activation, leading to Ca(2+) influx (EC(50) = 293.3 +/- 6.6 MUm for the mutant and 93.6 +/- 2.2 MUm for wild-type P2X7) and ERK phosphorylation, which were not caused by differential cell-surface expression or related to high ATPase activity on the cell surface and in the extracellular space. K562 cells expressing this N187D mutant showed a proliferative advantage and reduced pro-apoptosis effects in vitro and in vivo. Furthermore, elevated angiogenesis and CD206-positive macrophage infiltration were found in tumor tissues formed by K562-M cells. In addition, higher expression of VEGF and MCP1 could be detected in tumor tissues formed by K562-M cells. Our results suggest that N187D P2X7, representing mutants hyposensitive to agonist, might be a positive regulator in the progression of hematopoietic malignancies. PMID- 20837474 TI - Src homology 3-interacting domain of Rv1917c of Mycobacterium tuberculosis induces selective maturation of human dendritic cells by regulating PI3K-MAPK-NF kappaB signaling and drives Th2 immune responses. AB - Mycobacterium tuberculosis, an etiological agent of pulmonary tuberculosis, causes significant morbidity and mortality worldwide. Pathogenic mycobacteria survive in the host by subverting host innate immunity. Dendritic cells (DCs) are professional antigen-presenting cells that are vital for eliciting immune responses to infectious agents, including pathogenic mycobacteria. DCs orchestrate distinct Th responses based on the signals they receive. In this perspective, deciphering the interactions of the proline-glutamic acid/proline proline-glutamic acid (PE/PPE) family of proteins of M. tuberculosis with DCs assumes significant pathophysiological attributes. In this study, we demonstrate that Rv1917c (PPE34), a representative member of the proline-proline-glutamic major polymorphic tandem repeat family, interacts with TLR2 and triggers functional maturation of human DCs. Signaling perturbations implicated a critical role for integrated cross-talk among PI3K-MAPK and NF-kappaB signaling cascades in Rv1917c-induced maturation of DCs. However, this maturation of DCs was associated with a secretion of high amounts of anti-inflammatory cytokine IL-10, whereas Th1-polarizing cytokine IL-12 was not induced. Consistent with these results, Rv1917c-matured DCs favored secretion of IL-4, IL-5, and IL-10 from CD4(+) T cells and contributed to Th2-skewed cytokine balance ex vivo in healthy individuals and in patients with pulmonary tuberculosis. Interestingly, the Rv1917c-skewed Th2 immune response involved induced expression of cyclooxygenase 2 (COX-2) in DCs. Taken together, these results indicate that Rv1917c facilitates a shift in the ensuing immunity toward the Th2 phenotype and could aid in immune evasion by mycobacteria. PMID- 20837476 TI - Inhibition of osteoclast bone resorption by disrupting vacuolar H+-ATPase a3-B2 subunit interaction. AB - Vacuolar H(+)-ATPases (V-ATPases) are highly expressed in ruffled borders of bone resorbing osteoclasts, where they play a crucial role in skeletal remodeling. To discover protein-protein interactions with the a subunit in mammalian V-ATPases, a GAL4 activation domain fusion library was constructed from an in vitro osteoclast model, receptor activator of NF-kappaB ligand-differentiated RAW 264.7 cells. This library was screened with a bait construct consisting of a GAL4 binding domain fused to the N-terminal domain of V-ATPase a3 subunit (NTa3), the a subunit isoform that is highly expressed in osteoclasts (a1 and a2 are also expressed, to a lesser degree, whereas a4 is kidney-specific). One of the prey proteins identified was the V-ATPase B2 subunit, which is also highly expressed in osteoclasts (B1 is not expressed). Further characterization, using pulldown and solid-phase binding assays, revealed an interaction between NTa3 and the C terminal domains of both B1 and B2 subunits. Dual B binding domains of equal affinity were observed in NTa, suggesting a possible model for interaction between these subunits in the V-ATPase complex. Furthermore, the a3-B2 interaction appeared to be moderately favored over a1, a2, and a4 interactions with B2, suggesting a mechanism for the specific subunit assembly of plasma membrane V-ATPase in osteoclasts. Solid-phase binding assays were subsequently used to screen a chemical library for inhibitors of the a3-B2 interaction. A small molecule benzohydrazide derivative was found to inhibit osteoclast resorption with an IC(50) of ~1.2 MUm on both synthetic hydroxyapatite surfaces and dentin slices, without significantly affecting RAW 264.7 cell viability or receptor activator of NF-kappaB ligand-mediated osteoclast differentiation. Further understanding of these interactions and inhibitors may contribute to the design of novel therapeutics for bone loss disorders, such as osteoporosis and rheumatoid arthritis. PMID- 20837477 TI - Entamoeba histolytica cysteine proteinase 5 binds integrin on colonic cells and stimulates NFkappaB-mediated pro-inflammatory responses. AB - Integrins are important mammalian receptors involved in normal cellular functions and the pathogenesis of inflammation and disease. Entamoeba histolytica is a protozoan parasite that colonizes the gut, and in 10% of infected individuals, causes amebic colitis and liver abscess resulting in 10(5) deaths/year. E. histolytica-induced host inflammatory responses are critical in the pathogenesis of the disease, yet the host and parasite factors involved in disease are poorly defined. Here we show that pro-mature cysteine proteinase 5 (PCP5), a major virulent factor that is abundantly secreted and/or present on the surface of ameba, binds via its RGD motif to alpha(V)beta(3) integrin on Caco-2 colonic cells and stimulates NFkappaB-mediated pro-inflammatory responses. PCP5 RGD binding to alpha(V)beta(3) integrin triggered integrin-linked kinase(ILK) mediated phosphorylation of Akt-473 that bound and induced the ubiquitination of NF-kappaB essential modulator (NEMO). As NEMO is required for activation of the IKKalpha-IKKbeta complex and NFkappaB signaling, these events markedly up regulated pro-inflammatory mediator expressions in vitro in Caco-2 cells and in vivo in colonic loop studies in wild-type and Muc2(-/-) mice lacking an intact protective mucus barrier. These results have revealed that EhPCP5 RGD motif is a ligand for alpha(V)beta(3) integrin-mediated adhesion on colonic cells and represents a novel mechanism that E. histolytica trophozoites use to trigger an inflammatory response in the pathogenesis of intestinal amebiasis. PMID- 20837478 TI - The streptococcal collagen-binding protein CNE specifically interferes with alphaVbeta3-mediated cellular interactions with triple helical collagen. AB - Collagen fibers expose distinct domains allowing for specific interactions with other extracellular matrix proteins and cells. To investigate putative collagen domains that govern integrin alpha(V)beta(3)-mediated cellular interactions with native collagen fibers we took advantage of the streptococcal protein CNE that bound native fibrillar collagens. CNE specifically inhibited alpha(V)beta(3) dependent cell-mediated collagen gel contraction, PDGF BB-induced and alpha(V)beta(3)-mediated adhesion of cells, and binding of fibronectin to native collagen. Using a Toolkit composed of overlapping, 27-residue triple helical segments of collagen type II, two CNE-binding sites present in peptides II-1 and II-44 were identified. These peptides lack the major binding site for collagen binding beta(1) integrins, defined by the peptide GFOGER. Peptide II-44 corresponds to a region of collagen known to bind collagenases, discoidin domain receptor 2, SPARC (osteonectin), and fibronectin. In addition to binding fibronectin, peptide II-44 but not II-1 inhibited alpha(V)beta(3)-mediated collagen gel contraction and, when immobilized on plastic, supported adhesion of cells. Reduction of fibronectin expression by siRNA reduced PDGF BB-induced alpha(V)beta(3)-mediated contraction. Reconstitution of collagen types I and II gels in the presence of CNE reduced collagen fibril diameters and fibril melting temperatures. Our data indicate that contraction proceeded through an indirect mechanism involving binding of cell-produced fibronectin to the collagen fibers. Furthermore, our data show that cell-mediated collagen gel contraction does not directly depend on the process of fibril formation. PMID- 20837479 TI - The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease. AB - Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of extracellular effector ligands and thereby is thought to regulate a diverse array of biologic processes. The specificity of HS-ligand interactions is determined by the arrangement of sulfate groups on HS, which creates distinct binding motifs. Biologically important HS motifs are expected to exhibit regulated expression, yet there is a profound lack of tools to identify such motifs; consequently, little is known of their structures and functions. We have identified a novel phage display-derived antibody (NS4F5) that recognizes a highly regulated HS motif (HS(NS4F5)), which we have rigorously identified as (GlcNS6S-IdoA2S)(3). HS(NS4F5) exhibits a restricted expression in healthy adult tissues. Blocking HS(NS4F5) on cells in culture resulted in reduced proliferation and enhanced sensitivity to apoptosis. HS(NS4F5) is up-regulated in tumor endothelial cells, consistent with a role in endothelial cell activation. Indeed, TNF-alpha stimulated endothelial expression of HS(NS4F5), which contributed to leukocyte adhesion. In a mouse model of severe systemic amyloid protein A amyloidosis, HS(NS4F5) was expressed within amyloid deposits, which were successfully detected by microSPECT imaging using NS4F5 as a molecularly targeted probe. Combined, our results demonstrate that NS4F5 is a powerful tool for elucidating the biological function of HS(NS4F5) and can be exploited as a probe to detect novel polysaccharide biomarkers of disease processes. PMID- 20837480 TI - RANKL up-regulates brain-type creatine kinase via poly(ADP-ribose) polymerase-1 during osteoclastogenesis. AB - Receptor activator of nuclear factor kappaB ligand (RANKL) is the key regulator for osteoclast formation and function. During osteoclastogenesis, RANKL stimulated signals differentially modulate expression of a large number of proteins. Using proteomics approaches, we identified that brain-type cytoplasmic creatine kinase (Ckb) was greatly induced in mature osteoclasts. Ckb has been shown to contribute to osteoclast function. However, the mechanisms of Ckb regulation and the contribution of other isoforms of creatine kinase during RANKL induced osteoclastogenesis are unknown. We found that Ckb was the predominant isoform of creatine kinase during osteoclastogenesis. Real-time PCR confirmed that RANKL induced ckb mRNA expression by over 40-fold in primary mouse bone marrow macrophages and Raw 264.7 cells. The RANKL-responsive region was identified within the -0.4- to -0.2-kb 5'-flanking region of the ckb gene. Affinity binding purification followed by mass spectrometry analysis revealed that poly(ADP-ribose) polymerase-1 (PARP-1) bound to the -0.4/-0.2-kb fragment that negatively regulated expression of ckb in response to RANKL stimulation. Electrophoretic mobility shift assays with PARP-1-specific antibody located the binding site of PARP-1 to the TTCCCA consensus sequence. The expression of PARP-1 was reduced during RANKL-induced osteoclastogenesis, concurrently with increased expression of Ckb. Consistently, knockdown of PARP-1 by lentivirus-delivered shRNA enhanced ckb mRNA expression. The activity of PARP-1 was determined to be required for its inhibitory effect on the ckb expression. In summary, we have demonstrated that PARP-1 is a negative regulator of the ckb expression. Down regulation of PARP-1 is responsible for the up-regulation of ckb during RANKL induced osteoclastogenesis. PMID- 20837481 TI - Intragenic suppressing mutations correct the folding and intracellular traffic of misfolded mutants of Yor1p, a eukaryotic drug transporter. AB - ATP-binding cassette (ABC) transporters play pivotal physiological roles in substrate transport across membranes, and defective assembly of these proteins can cause severe disease associated with improper drug or ion flux. The yeast protein Yor1p is a useful model to study the biogenesis of ABC transporters; deletion of a phenylalanine residue in the first nucleotide-binding domain (NBD1) causes misassembly and retention in the endoplasmic reticulum (ER) of the resulting protein Yor1p-DeltaF670, similar to the predominant disease-causing allele in humans, CFTR-DeltaF508. Here we describe two novel Yor1p mutants, G278R and I1084P, which fail to assemble and traffic similar to Yor1p-DeltaF670. These mutations are located in the two intracellular loops (ICLs) that interface directly with NBD1, and thus disrupt a functionally important structural module. We isolated 2 second-site mutations, F270S and R1168M, which partially correct the folding injuries associated with the G278R, I1084P, and DeltaF670 mutants and reinstate their trafficking. The position of both corrective mutations at the cytoplasmic face of a transmembrane helix suggests that they restore biogenesis by influencing the behavior of the transmembrane domains rather than by direct restoration of the ICL1-ICL4-NBD1 structural module. Given the conserved topology of many ABC transporters, our findings provide new understanding of functionally important inter-domain interactions and suggest new potential avenues for correcting folding defects caused by abrogation of those domain interfaces. PMID- 20837482 TI - Structural and functional characterization of the C-terminal transmembrane region of NBCe1-A. AB - NBCe1-A and AE1 both belong to the SLC4 HCO(3)(-) transporter family. The two transporters share 40% sequence homology in the C-terminal transmembrane region. In this study, we performed extensive substituted cysteine-scanning mutagenesis analysis of the C-terminal region of NBCe1-A covering amino acids Ala(800) Lys(967). Location of the introduced cysteines was determined by whole cell labeling with a membrane-permeant biotin maleimide and a membrane-impermeant 2 ((5(6)-tetramethylrhodamine)carboxylamino) ethyl methanethiosulfonate (MTS-TAMRA) cysteine-reactive reagent. The results show that the extracellular surface of the NBCe1-A C-terminal transmembrane region is minimally exposed to aqueous media with Met(858) accessible to both biotin maleimide and TAMRA and Thr(926)-Ala(929) only to TAMRA labeling. The intracellular surface contains a highly exposed (Met(813)-Gly(828)) region and a cryptic (Met(887)-Arg(904)) connecting loop. The lipid/aqueous interface of the last transmembrane segment is at Asp(960). Our data clearly determined that the C terminus of NBCe1-A contains 5 transmembrane segments with greater average size compared with AE1. Functional assays revealed only two residues in the region of Pro(868)-Leu(967) (a functionally important region in AE1) that are highly sensitive to cysteine substitution. Our findings suggest that the C-terminal transmembrane region of NBCe1-A is tightly folded with unique structural and functional features that differ from AE1. PMID- 20837483 TI - Role of matrix metalloproteinase-9 dimers in cell migration: design of inhibitory peptides. AB - Non-proteolytic activities of matrix metalloproteinases (MMPs) have recently been shown to impact cell migration, but the precise mechanism remains to be understood. We previously demonstrated that the hemopexin (PEX) domain of MMP-9 is a prerequisite for enhanced cell migration. Using a biochemical approach, we now report that dimerization of MMP-9 through the PEX domain appears necessary for MMP-9-enhanced cell migration. Following a series of substitution mutations within the MMP-9 PEX domain, blade IV was shown to be critical for homodimerization, whereas blade I was required for heterodimerization with CD44. Blade I and IV mutants showed diminished enhancement of cell migration compared with wild type MMP-9-transfected cells. Peptides mimicking motifs in the outermost strands of the first and fourth blades of the MMP-9 PEX domain were designed. These peptides efficiently blocked MMP-9 dimer formation and inhibited motility of COS-1 cells overexpressing MMP-9, HT-1080, and MDA-MB-435 cells. Using a shRNA approach, CD44 was found to be a critical molecule in MMP-9 mediated cell migration. Furthermore, an axis involving a MMP-9-CD44-EGFR signaling pathway in cell migration was identified using antibody array and specific receptor tyrosine kinase inhibitors. In conclusion, we dissected the mechanism of pro-MMP-9-enhanced cell migration and developed structure-based inhibitory peptides targeting MMP-9-mediated cell migration. PMID- 20837484 TI - The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis. AB - PTK7 is an essential component of the Wnt/planar cell polarity (PCP) pathway. We provide evidence that the Wnt/PCP pathway converges with pericellular proteolysis in both normal development and cancer. Here, we demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP), a key proinvasive proteinase, functions as a principal sheddase of PTK7. MT1-MMP directly cleaves the exposed PKP(621)?LI sequence of the seventh Ig-like domain of the full-length membrane PTK7 and generates, as a result, an N-terminal, soluble PTK7 fragment (sPTK7). The enforced expression of membrane PTK7 in cancer cells leads to the actin cytoskeleton reorganization and the inhibition of cell invasion. MT1-MMP silencing and the analysis of the uncleavable L622D PTK7 mutant confirm the significance of MT1-MMP proteolysis of PTK7 in cell functions. Our data also demonstrate that a fine balance between the metalloproteinase activity and PTK7 levels is required for normal development of zebrafish (Danio rerio). Aberration of this balance by the proteinase inhibition or PTK7 silencing results in the PCP dependent convergent extension defects in the zebrafish. Overall, our data suggest that the MT1-MMP-PTK7 axis plays an important role in both cancer cell invasion and normal embryogenesis in vertebrates. Further insight into these novel mechanisms may promote understanding of directional cell motility and lead to the identification of therapeutics to treat PCP-related developmental disorders and malignancy. PMID- 20837485 TI - Differential signaling of the endogenous agonists at the beta2-adrenergic receptor. AB - The concept of "functional selectivity" or "biased signaling" suggests that a ligand can have distinct efficacies with regard to different signaling pathways. We have investigated the question of whether biased signaling may be related to distinct agonist-induced conformational changes in receptors using the beta(2) adrenergic receptor (beta(2)AR) and its two endogenous ligands epinephrine and norepinephrine as a model system. Agonist-induced conformational changes were determined in a fluorescently tagged beta(2)AR FRET sensor. In this beta(2)AR sensor, norepinephrine caused signals that amounted to only ~50% of those induced by epinephrine and the standard "full" agonist isoproterenol. Furthermore, norepinephrine-induced changes in the beta(2)AR FRET sensor were slower than those induced by epinephrine (rate constants, 47 versus 128 ms). A similar partial beta(2)AR activation signal was revealed for the synthetic agonists fenoterol and terbutaline. However, norepinephrine was almost as efficient as epinephrine (and isoproterenol) in causing activation of G(s) and adenylyl cyclase. In contrast, fenoterol was quite efficient in triggering beta-arrestin2 recruitment to the cell surface and its interaction with beta(2)AR, as well as internalization of the receptors, whereas norepinephrine caused partial and slow changes in these assays. We conclude that partial agonism of norepinephrine at the beta(2)AR is related to the induction of a different active conformation and that this conformation is efficient in signaling to G(s) and less efficient in signaling to beta-arrestin2. These observations extend the concept of biased signaling to the endogenous agonists of the beta(2)AR and link it to distinct conformational changes in the receptor. PMID- 20837486 TI - Ligand-binding domain determines endoplasmic reticulum exit of AMPA receptors. AB - AMPA receptors (AMPARs) are tetrameric ion channels that mediate rapid glutamate signaling in neurons and many non-neuronal cell types. Endoplasmic reticulum (ER) quality control mechanisms permit only correctly folded functional receptors to be delivered to the cell surface. We analyzed the biosynthetic maturation and transport of all 12 GluA1-4 subunit splice variants as homomeric receptors and observed robust isoform-dependent differences in ER exit competence and surface expression. In contrast to inefficient ER exit of both GluA3 splice forms and the flop variants of GluA1 and GluA4, prominent plasma membrane expression was observed for the other AMPAR isoforms. Surprisingly, deletion of the entire N terminal domain did not alter the transport phenotype, nor did the different cytosolic C-terminal tail splice variants. Detailed analysis of mutant receptors led to the identification of distinct residues in the ligand-binding domain as primary determinants for isoform-specific maturation. Considered together with the essential role of bound agonist, our findings reveal the ligand-binding domain as the critical quality control target in AMPAR biogenesis. PMID- 20837487 TI - Role of alpha7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1. AB - The prion protein (PrP(C)) is a conserved glycosylphosphatidylinositol-anchored cell surface protein expressed by neurons and other cells. Stress-inducible protein 1 (STI1) binds PrP(C) extracellularly, and this activated signaling complex promotes neuronal differentiation and neuroprotection via the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP-dependent protein kinase 1 (PKA) pathways. However, the mechanism by which the PrP(C)-STI1 interaction transduces extracellular signals to the intracellular environment is unknown. We found that in hippocampal neurons, STI1-PrP(C) engagement induces an increase in intracellular Ca(2+) levels. This effect was not detected in PrP(C) null neurons or wild-type neurons treated with an STI1 mutant unable to bind PrP(C). Using a best candidate approach to test for potential channels involved in Ca(2+) influx evoked by STI1-PrP(C), we found that alpha-bungarotoxin, a specific inhibitor for alpha7 nicotinic acetylcholine receptor (alpha7nAChR), was able to block PrP(C)-STI1-mediated signaling, neuroprotection, and neuritogenesis. Importantly, when alpha7nAChR was transfected into HEK 293 cells, it formed a functional complex with PrP(C) and allowed reconstitution of signaling by PrP(C)-STI1 interaction. These results indicate that STI1 can interact with the PrP(C).alpha7nAChR complex to promote signaling and provide a novel potential target for modulation of the effects of prion protein in neurodegenerative diseases. PMID- 20837488 TI - Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. AB - Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17 demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17 (allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases. PMID- 20837489 TI - The importance of LAT in the activation, homeostasis, and regulatory function of T cells. AB - LAT (linker for activation of T cells) is a transmembrane adaptor protein that plays an essential role in TCR-mediated signaling and thymocyte development. Because LAT-deficient mice have an early block in thymocyte development, we utilized an inducible system to delete LAT in primary T cells to study LAT function in T cell activation, homeostasis, and survival. Deletion of LAT caused primary T cells to become unresponsive to stimulation from the TCR and impaired T cell homeostatic proliferation and long term survival. Furthermore, deletion of LAT led to reduced expression of Foxp3, CTLA-4, and CD25 in T(reg) cells and impaired their function. Consequently, mice with LAT deleted developed a lymphoproliferative syndrome similar to that in LATY136F mice, although less severe. Our data implicate that LAT has positive and negative roles in the regulation of mature T cells. PMID- 20837490 TI - An antibody as surrogate receptor reveals determinants of activity of an innate immune peptide antibiotic. AB - Drug discovery initiatives often depend critically on knowledge of ligand receptor interactions. However, the identity or structure of the target receptor may not be known in every instance. The concept of receptor surrogate, a molecular environment mimic of natural receptor, may prove beneficial under such circumstances. Here, we demonstrate the potential of monoclonal antibodies (mAbs) to act as surrogate receptors for a class of innate immune peptide antibiotics, a strategy that can help comprehend their action mechanism and identify chemical entities crucial for activity. A panel of antibody surrogates was raised against indolicidin, a tryptophan-rich cationic broad spectrum antimicrobial peptide of innate immune origin. Employing an elegant combination of thermodynamics, crystallography, and molecular modeling, interactions of the peptide with a high affinity anti-indolicidin monoclonal antibody were analyzed and were used to identify a motif that contained almost the entire antibiotic activity of native indolicidin. The analysis clarified the interaction of the peptide with previously proposed targets such as bacterial cell membrane and DNA and could further be correlated with antimicrobial compounds whose actions involve varied other mechanisms. These features suggest a multipronged assault pathway for indolicidin. Remarkably, the anti-indolicidin mAb surrogate was able to isolate additional independent bactericidal sequences from a random peptide library, providing compelling evidence as to the physiological relevance of surrogate receptor concept and suggesting applications in receptor-based pharmacophore research. PMID- 20837492 TI - Salbutamol increases survival motor neuron (SMN) transcript levels in leucocytes of spinal muscular atrophy (SMA) patients: relevance for clinical trial design. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the SMN1 gene. Based on severity, three forms of SMA are recognised (types I-III). All patients usually have 2-4 copies of a highly homologous gene (SMN2) which produces insufficient levels of functional survival motor neuron (SMN) protein. Recently, evidence has been provided that SMN2 expression can be enhanced in vitro by salbutamol, a beta2-adrenergic agonist. This compound has also been shown to improve motor function of SMA patients in two different pilot trials. AIM: To evaluate the in vivo molecular efficacy of salbutamol in SMA patients. METHODS: Twelve type II-III patients took salbutamol orally for 6 months. SMN2 full length transcript levels were determined in peripheral blood leucocytes by absolute real-time PCR, at baseline and after 3 and 6 months of treatment. RESULTS: A significant and constant increase in SMN2 full length transcript levels was detected; the response was directly proportional to SMN2 gene copy number. CONCLUSIONS: The data strongly support salbutamol as a candidate for treating SMA, and suggest that SMN2 copy number may predict the molecular response to treatment and may be a useful randomisation parameter in a double blind placebo controlled clinical trial design. PMID- 20837491 TI - Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis. AB - The mechanisms underlying the protective effect of monounsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity. PMID- 20837493 TI - Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia. AB - BACKGROUND: The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride channel CFTR in the gastrointestinal and respiratory tract epithelia, has not been employed so far to support the role of CF modifier genes. METHODS: Patients were selected from 101 families with a total of 171 F508del CFTR homozygous CF patients to identify CF modifying genes. A candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers was performed. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analysed. RESULTS: Variants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.011 week of treatment with anti-microbial agents, occurred in 53 (27.6%) patients, and 15 (7.8%) patients had two or more episodes. The incidence rate of major infections was 11.1 episodes per 100 patient-years in PM/DM patients. Aspiration pneumonia [n (%)=16 (21.1)] was the leading cause of major infections, followed by opportunistic infection [n (%)=14 (18.4)]. A variety of pathogens were isolated, mainly including Staphylococcus aureus, Klebsiella, Escherichia coli, Salmonella and Mycobacterium. Overall patient survival rates were 85.0% at 1 year, 78.0% at 5 years and 78.0% at 10 years. However, after one episode of major infection, survival rates decreased to 84.7% at 30 days and 68.3% at 1 year. Multivariate analysis indicated that independent predictors of major infection were age>45 years at PM/DM onset [odds ratio (OR) 5.26; 95% CI 2.01, 13.77; P=0.001], presence of arthritis/arthalgia (OR 2.59; 95% CI 1.12, 6.02; P=0.027), co-present interstitial lung disease (OR 7.24; 95% CI 2.67, 19.65; P<0.001), current use of AZA (OR 6.07; 95% CI 2.39, 15.42; P<0.001) or IVIG (OR 6.33; 95% CI 1.50, 26.77; P=0.012). CONCLUSIONS: This study underlines the high frequency of major infections in PM/DM, which is significantly detrimental to patient survival rates. Close follow-up of PM/DM patients with risk factors for developing major infections is mandatory. PMID- 20837497 TI - Haematopoietic stem and progenitor cells in rheumatoid arthritis. AB - RA is the prototypic chronic inflammatory disease, characterized by progressive articular cartilage and bone destruction. The systemic nature of RA is evidenced by the increased risk of atherosclerosis and lymphoproliferative disorders. Components of both the innate and adaptive immune system are implicated in the pathophysiology of the articular and extra-articular manifestations of the disease. A fundamental process in the onset of RA is the breakdown in self tolerance. Accelerated ageing of immune cells (immunosenescence) appears to be a major mechanism favouring the disruption of tolerance. Telomere erosion, a hallmark of immunosenescence, is present in lymphoid (naive and memory T cells) and myeloid (granulocytes) cells in RA. The premature ageing process also involves the haematopoietic stem and progenitor cells (CD34(+) HSPC), thus extending the RA immunopathogenesis to include early events in the shaping of the immune system. This review summarizes current concepts of HSPC ageing and its impact on immune regeneration, highlighting the phenotypic and functional similarities between elderly and RA HSPC. PMID- 20837498 TI - BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies. PMID- 20837499 TI - Efficacy of tadalafil in secondary Raynaud's phenomenon resistant to vasodilator therapy: a double-blind randomized cross-over trial. AB - OBJECTIVE: To evaluate the efficacy of tadalafil as add-on therapy in secondary RP resistant to vasodilators. METHODS: Patients with scleroderma and MCTD having four or more RP attacks per week despite being on vasodilators were randomized to receive either placebo or tadalafil (20 mg) on alternate days as add-on therapy to their current vasodilators for 6 weeks. After a 7-day washout, patients were crossed over to the other arm. Primary endpoints were improvement in the daily frequency and duration of RP episodes and RP condition score (RCS). Secondary outcome measures were healing of existing and appearance of new digital ulcers (DUs) and improvement in scleroderma-specific HAQ (SHAQ), quality of life (QoL), flow-mediated dilatation (FMD), patient and physician global assessment. RESULTS: Twenty-four of 25 recruited patients completed the study. All the patients were receiving calcium channel blockers and in addition 18 were receiving other vasodilators. During tadalafil therapy significant improvement in mean daily frequency, mean daily duration of RP and mean daily RCS were observed as compared with baseline and placebo. All the 24 digital lesions healed during tadalafil therapy as compared with 3/13 during the placebo treatment (P<0.0001). One new DU was reported during tadalafil therapy vs 13 during placebo therapy (P=0.0005). QoL, SHAQ, FMD, patient and physician global assessment significantly improved while on tadalafil. No serious adverse event was observed. CONCLUSION: Tadalafil as add-on therapy improves symptoms of RP, heals and prevents new DUs and improves QoL in patients with resistant secondary RP. TRIAL REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov/, identifier: NCT00626665. PMID- 20837500 TI - Potential role of Th17 cells in the pathogenesis of adult-onset Still's disease. AB - OBJECTIVE: To investigate the potential role of Th type 17 (Th17) cells and Th17 related cytokines in the pathogenesis of adult-onset Still's disease (AOSD). METHODS: The frequencies of circulating Th17 cells in 24 patients with active untreated AOSD, 16 patients with active SLE and 12 healthy volunteers were determined using intracellular cytokine staining and flow cytometry. Serum levels of Th17-related cytokines, including IL-1beta, IL-6, IL-17, IL-18, IL-21 and IL 23 were measured by ELISA. RESULTS: Significantly higher median frequencies of circulating Th17 cells were found in active untreated AOSD patients (1.01%) and active SLE patients (1.26%) than in healthy volunteers (0.12%, both P<0.001). The frequencies of circulating Th17 cells were positively correlated with activity score (r=0.527, P<0.01) and serum ferritin levels (r=0.724, P<0.001) in AOSD patients, and correlated with SLEDAI (r=0.663, P<0.01) in SLE patients. Additionally, the frequencies of circulating Th17 cells were positively and significantly correlated with serum levels of IL-1beta, IL-6, IL-17, IL-18, IL-21 and IL-23 in both AOSD and SLE patients. The frequencies of circulating Th17 cells and serum IL-17 levels significantly decreased after effective therapy in AOSD patients (both P<0.001). CONCLUSION: Elevated frequencies of circulating Th17 cells and a positive correlation with disease activity in our AOSD patients suggest that Th17 cells contribute to the pathogenesis of this disease. Dysregulation of Th17 cells may be a common pathogenic mechanism that underlies the development of both AOSD and SLE. PMID- 20837501 TI - Deviations of the visual upright in three dimensions in disorders of the brainstem: a clinical exploration. AB - Deviations of the subjective visual vertical in the roll or fronto-parallel plane occur commonly in disorders of the brainstem and have been extensively explored. In contrast, little is known about deviations in other directions. The present retrospective study focused on deviations in the pitch (sagittal) direction in 176 patients with a wide variety of disorders. The test task was to set a self illuminated rod in the apparent upright position, in total darkness. Abnormal results (outside +/- 4 degrees ) were recorded in 58% of the subjects. Negative (top backward) deviations were the most common, particularly with mass lesions in the pineal region, obstructive hydrocephalus, cerebellar lesions and crowding at the craniocervical junction. Positive and negative deviations were about equally common with focal intra-axial lesions. Negative deviations appeared related to dorsal locations of lesions and vice versa. Normal pressure hydrocephalus, Parkinson's disease and progressive supranuclear palsy were associated with smaller deviations, without a clear directional preponderance, and a larger individual variability. Most subjects lacked overt clinical corollaries. The most common ocular signs were aqueduct syndromes (n = 17) and ocular tilt reactions (n = 12), which were associated with deviations in 47 and 92% of instances, respectively. Subjective corollaries of deviation were never reported, not even by those subjects who showed a dramatic improvement upon resolution of the underlying condition. Deviations were also assessed in roll in a subgroup of 40 patients with focal lesions. Thirty subjects returned abnormal results: 13% in roll, 47% in pitch and 40% in pitch and roll. The direction of roll deviation appeared primarily related to laterality, with clockwise deviations with right sided lesions and vice versa. All subjects with ocular tilt reactions had combined pitch and roll deviations, implying a common neural substrate. Correlation analyses, geometrical modelling and experimental self-observations indicated that deviations in pitch were attributable to cyclotorsional asymmetries between the eyes. The frequent co-existence of abnormal pitch and roll results implies that the true axis of deviation in focal brainstem disorders commonly falls outside traditional reference planes. The term 'visual upright in three dimensions' is suggested to identify unrestricted measurements, preserving the established term 'visual vertical' for measurements confined to the roll plane. Assessment of the visual upright in three dimensions provides a new, quantitative angle on brainstem disorders. The test appears useful for identifying a ubiquitous yet clinically silent feature of brainstem disease and also for monitoring the evolution of underlying conditions. More detailed explorations appear well motivated. PMID- 20837502 TI - Genetic and environmental influences on focal brain density in bipolar disorder. AB - Structural neuroimaging studies suggest the presence of subtle abnormalities in the brains of patients with bipolar disorder. The influence of genetic and/or environmental factors on these brain abnormalities is unknown. To investigate the contribution of genetic and environmental factors on grey and white matter brain densities in bipolar disorder, monozygotic and dizygotic twins concordant and discordant for bipolar disorder were scanned using 1.5 Tesla magnetic resonance imaging and compared with healthy twin pairs. A total of 232 subjects: 49 affected twin pairs (8 monozygotic concordant, 15 monozygotic discordant, 4 dizygotic concordant, 22 dizygotic discordant) and 67 healthy twin pairs (39 monozygotic and 28 dizygotic) were included. After correcting for the effect of lithium, the liability for bipolar disorder was associated with decreased grey matter density in widespread areas of the brain, but most prominent in frontal and limbic regions, and with decreased white matter density in (frontal parts of) the superior longitudinal fasciculi. The genetic risk to develop bipolar disorder was related to decreased grey matter density in the right medial frontal gyrus, precentral gyrus and insula and with decreased white matter density in the superior longitudinal fasciculi bilaterally. In conclusion, pathology in the frontal lobe, especially in parts of the superior longitudinal fasciculus, may be central to the genetic risk to develop bipolar disorder, while widespread grey matter abnormalities appear related to the illness itself. PMID- 20837503 TI - Targeted gene disruption identifies three PPR-DYW proteins involved in RNA editing for five editing sites of the moss mitochondrial transcripts. AB - In plant organelles, RNA editing frequently occurs in many transcripts, but little is known about its molecular mechanism. Eleven RNA editing sites are present in the moss Physcomitrella patens mitochondria. Recently PpPPR_71, one member of 10 DYW-subclass pentatricopeptide repeat (PPR-DYW) proteins, has been identified as a site-specific recognition factor for RNA editing in the mitochondrial transcript. In this study, we disrupted three genes encoding a PPR DYW protein-PpPPR_56, PpPPR_77, and PpPPR_91-to investigate whether they are involved in RNA editing. Transient expression of an N-terminal amino acid sequence fused to the green fluorescent protein (GFP) suggests that the three PPR DYW proteins are targeted to mitochondria. Disruption of each gene by homologous recombination revealed that PpPPR_56 was involved in RNA editing at the nad3 and nad4 sites, PpPPR_77 at the cox2 and cox3 sites, and PpPPR_91 at the nad5-2 site in the mitochondrial transcripts. The nucleotide sequences surrounding the two editing sites targeted by a single PPR-DYW protein share 42 to 56% of their identities. Thus, moss PPR-DYW proteins seem to be site-specific factors for RNA editing in mitochondrial transcripts. PMID- 20837504 TI - MAG4/Atp115 is a golgi-localized tethering factor that mediates efficient anterograde transport in Arabidopsis. AB - Seed storage proteins are synthesized on rough endoplasmic reticulum (ER) in a precursor form and then are transported to protein storage vacuoles (PSVs) where they are converted to their mature form. To understand the mechanisms by which storage proteins are transported, we screened Arabidopsis maigo mutants to identify those that abnormally accumulate storage protein precursors. Here we describe a new maigo mutant, maigo 4 (mag4), that abnormally accumulates the precursors of two major storage proteins, 12S globulin and 2S albumin, in dry seeds. Electron microscopy revealed that mag4 seed cells abnormally develop a large number of novel structures that exhibit a highly electron-dense core. Some of these structures were surrounded by ribosomes. Immunogold analysis suggests that the electron-dense core is an aggregate of 2S albumin precursors and that 12S globulins are localized around the core. The MAG4 gene was identified as At3g27530, and the MAG4 protein has domains homologous to those found in bovine vesicular transport factor p115. MAG4 molecules were concentrated at cis-Golgi stacks. Our findings suggest that MAG4 functions in the transport of storage protein precursors from the ER to the Golgi complex in plants. In addition, the mag4 mutant exhibits a dwarf phenotype, suggesting that MAG4 is involved in both the transport of storage proteins and in plant growth and development. PMID- 20837505 TI - Stem cell roles in reproduction: what is the basic science? PMID- 20837506 TI - Detection and quantification of mRNA in single human polar bodies: a minimally invasive test of gene expression during oogenesis. AB - Proteins and mRNA produced in oogenesis support embryonic development until the zygotic transition, 3 days after fertilization. Since polar bodies can be biopsied with little if any harm to the oocyte, we tested the hypothesis that mRNA originating from expression in the meiotic oocyte is present and detectable in a single polar body prior to insemination. Human oocytes were obtained from patients undergoing controlled ovarian hyperstimulation and intracytoplasmic sperm injection. Immature oocytes were cultured overnight and inspected the following day for maturation. Metaphase II oocytes underwent polar body biopsy followed by reverse transcription without RNA isolation. Sibling oocytes were similarly prepared. Complementary DNA from all samples were pre-amplified over 15 cycles for candidate genes using selective primers. Real-time PCR was performed to detect and quantify relative single-cell gene expression. Polar body mRNA was detected in 11 of 12 candidate genes. Transcripts that were present in greater abundance in the oocyte were more likely to be detected in qPCR replicates from single polar bodies. Pre-amplification of cDNA synthesized without RNA isolation can facilitate the quantitative detection of mRNA in single human polar bodies. PMID- 20837512 TI - From compassionate ageism to intergenerational conflict? AB - During the 50 years in which The Gerontologist has been publishing, the politics of aging in the United States has undergone distinct changes. The political behavior of older individuals has remained largely the same even though different birth cohorts have succeeded each other in populating the ranks of older people. But the politics of policies on aging-the organized interest and advocacy groups active in this arena, the tenor of public discourse about older people as beneficiaries of policies on aging, the national political agendas regarding public old-age benefits, and the broader U.S. political economy-have changed substantially over these five decades. Now, in the contexts of the aging of the baby boom and concerns about reducing large federal fiscal deficits (annual and cumulative), the politics of U.S. policies on aging may change considerably from those of yesterday and today. Is there a possibility of future intergenerational political conflict over taxes and expenditures for the major old-age benefit programs? If so, what might prevent or mitigate it? PMID- 20837514 TI - Deletion of the Cel48S cellulase from Clostridium thermocellum. AB - Clostridium thermocellum is a thermophilic anaerobic bacterium that rapidly solubilizes cellulose with the aid of a multienzyme cellulosome complex. Creation of knockout mutants for Cel48S (also known as CelS, S(S), and S8), the most abundant cellulosome subunit, was undertaken to gain insight into its role in enzymatic and microbial cellulose solubilization. Cultures of the Cel48S deletion mutant (S mutant) were able to completely solubilize 10 g/L crystalline cellulose. The cellulose hydrolysis rate of the S mutant strain was 60% lower than the parent strain, with the S mutant strain also exhibiting a 40% reduction in cell yield. The cellulosome produced by the S mutant strain was purified by affinity digestion, characterized enzymatically, and found to have a 35% lower specific activity on Avicel. The composition of the purified cellulosome was analyzed by tandem mass spectrometry with APEX quantification and no significant changes in abundance were observed in any of the major (>1% of cellulosomal protein) enzymatic subunits. Although most cellulolytic bacteria have one family 48 cellulase, C. thermocellum has two, Cel48S and Cel48Y. Cellulose solubilization by a Cel48S and Cel48Y double knockout was essentially the same as that of the Cel48S single knockout. Our results indicate that solubilization of crystalline cellulose by C. thermocellum can proceed to completion without expression of a family 48 cellulase. PMID- 20837515 TI - Prenatal undernutrition and cognitive function in late adulthood. AB - At the end of World War II, a severe 5-mo famine struck the cities in the western part of The Netherlands. At its peak, the rations dropped to as low as 400 calories per day. In 1972, cognitive performance in 19-y-old male conscripts was reported not to have been affected by exposure to the famine before birth. In the present study, we show that cognitive function in later life does seem affected by prenatal undernutrition. We found that at age 56 to 59, men and women exposed to famine during the early stage of gestation performed worse on a selective attention task, a cognitive ability that usually declines with increasing age. We hypothesize that this decline may be an early manifestation of an accelerated cognitive aging process. PMID- 20837516 TI - Structural profiling of endogenous S-nitrosocysteine residues reveals unique features that accommodate diverse mechanisms for protein S-nitrosylation. AB - S-nitrosylation, the selective posttranslational modification of protein cysteine residues to form S-nitrosocysteine, is one of the molecular mechanisms by which nitric oxide influences diverse biological functions. In this study, unique MS based proteomic approaches precisely pinpointed the site of S-nitrosylation in 328 peptides in 192 proteins endogenously modified in WT mouse liver. Structural analyses revealed that S-nitrosylated cysteine residues were equally distributed in hydrophobic and hydrophilic areas of proteins with an average predicted pK(a) of 10.01 +/- 2.1. S-nitrosylation sites were over-represented in alpha-helices and under-represented in coils as compared with unmodified cysteine residues in the same proteins (chi(2) test, P < 0.02). A quantile-quantile probability plot indicated that the distribution of S-nitrosocysteine residues was skewed toward larger surface accessible areas compared with the unmodified cysteine residues in the same proteins. Seventy percent of the S-nitrosylated cysteine residues were surrounded by negatively or positively charged amino acids within a 6-A distance. The location of cysteine residues in alpha-helices and coils in highly accessible surfaces bordered by charged amino acids implies site directed S-nitrosylation mediated by protein-protein or small molecule interactions. Moreover, 13 modified cysteine residues were coordinated with metals and 15 metalloproteins were endogenously modified supporting metal-catalyzed S-nitrosylation mechanisms. Collectively, the endogenous S-nitrosoproteome in the liver has structural features that accommodate multiple mechanisms for selective site-directed S nitrosylation. PMID- 20837518 TI - Immunodominant T-cell responses to dengue virus NS3 are associated with DHF. AB - Dengue infections are increasing at an alarming rate in many tropical and subtropical countries, where epidemics can put health care systems under extreme pressure. The more severe infections lead to dengue hemorrhagic fever (DHF), which can be life threatening. A variety of viral and host factors have been associated with the severity of dengue infections. Because secondary dengue infection is more commonly associated with DHF than primary infections, the acquired immune response to dengue, both B cells and T cells have been implicated. In this study, we set out to study T-cell responses across the entire dengue virus proteome and to see whether these were related to disease severity in a cohort of dengue-infected children from Thailand. Robust responses were observed in most infected individuals against most viral proteins. Responses to NS3 were the most frequent, and there was a very strong association between the magnitude of the response and disease severity. Furthermore, in DHF, cytokine high CD107a-negative cells predominated. PMID- 20837517 TI - Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta ) deposition. AB - Amyloid-beta (Abeta) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Abeta plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Abeta deposition in individuals with DAT and cognitively normal participants with elevated Abeta, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology. PMID- 20837519 TI - Replication allows inactivation of a knocked-in locus control region in inappropriate cell lineages. AB - To study the influence of a locus control region (LCR) on the expression of a highly characterized, developmentally regulated locus, we have targeted the hCD2 LCR as a single copy into the endogenous mouse CD8 gene complex. Two knock-in mouse lines that differ in the integration site of the hCD2-LCR within the mCD8 gene complex were generated, and the influence on expression of the CD8 coreceptor was assessed. In these mice the normal developmental silencing of the CD8 genes in the CD4 lineage is deregulated, and the mice develop CD4(+) cells that also express the CD8 genes. This is accompanied by the physical maintenance of the CD8 genes within an extended loop away from their subchromosomal territory. Further analysis of these mice revealed unexpected fluid chromatin dynamics, whereby the LCR can be initially dominant over the endogenous CD8 gene repressive regulatory processes present in CD4(+) cells but is continuously contested by them, resulting in the eventual inactivation of the inserted LCR, probably as a result of multiple rounds of replication. PMID- 20837520 TI - The Plant Homeo Domain finger protein, VIN3-LIKE 2, is necessary for photoperiod mediated epigenetic regulation of the floral repressor, MAF5. AB - In facultative photoperiodic flowering plants, noninductive photoperiods result in a delay in flowering, but such plants eventually flower, illustrating plasticity in an important developmental transition, flowering. The model plant, Arabidopsis, has a facultative photoperiod response. Although the inductive flowering promotion pathway has been extensively studied, the pathway to flowering in noninductive photoperiods is not well understood. Here, we show that a Plant Homeo Domain finger-containing protein, VIN3-LIKE 2 (VIL2), is necessary to maintain the epigenetically repressed state of MAF5 and permit more rapid flowering in noninductive photoperiods in Arabidopsis. Levels of both VIL2 mRNA and protein are under diurnal fluctuation and maintain the repressed state at MAF5 chromatin in a photoperiod-specific manner. VIL2 binds preferentially to dimethylated histone H3 Lys-9 (H3K9me2) peptides in vitro and VIL2 is required for the maintenance of H3K9me2 at MAF5 chromatin in vivo. Furthermore, VIL2 is required for the maintenance of trimethylated histone H3 Lys-27 at MAF5 through the physical association with a component of polycomb repression complex 2. Thus, the repression of MAF5 by VIL2 provides a mechanism to promote flowering in noninductive photoperiods, which contributes to the facultative nature of the Arabidopsis photoperiodic response. PMID- 20837521 TI - Millisecond encoding precision of auditory cortex neurons. AB - Neurons in auditory cortex are central to our perception of sounds. However, the underlying neural codes, and the relevance of millisecond-precise spike timing in particular, remain debated. Here, we addressed this issue in the auditory cortex of alert nonhuman primates by quantifying the amount of information carried by precise spike timing about complex sounds presented for extended periods of time (random tone sequences and natural sounds). We investigated the dependence of stimulus information on the temporal precision at which spike times were registered and found that registering spikes at a precision coarser than a few milliseconds significantly reduced the encoded information. This dependence demonstrates that auditory cortex neurons can carry stimulus information at high temporal precision. In addition, we found that the main determinant of finely timed information was rapid modulation of the firing rate, whereas higher-order correlations between spike times contributed negligibly. Although the neural coding precision was high for random tone sequences and natural sounds, the information lost at a precision coarser than a few milliseconds was higher for the stimulus sequence that varied on a faster time scale (random tones), suggesting that the precision of cortical firing depends on the stimulus dynamics. Together, these results provide a neural substrate for recently reported behavioral relevance of precisely timed activity patterns with auditory cortex. In addition, they highlight the importance of millisecond-precise neural coding as general functional principle of auditory processing--from the periphery to cortex. PMID- 20837522 TI - Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers. AB - Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that, as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepresented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, including met, cyclinD2, slc45a3, and cdk6. One focal amplification included fgf6a. Increasing fgf signaling via a mutation that overexpresses fgf8 accelerated the onset of MPNSTs in fish bearing a mutation in p53, suggesting that fgf6a itself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors. PMID- 20837523 TI - What lies underneath: conserving the oceans' genetic resources. AB - The marine realm represents 70% of the surface of the biosphere and contains a rich variety of organisms, including more than 34 of the 36 living phyla, some of which are only found in the oceans. The number of marine species used by humans is growing at unprecedented rates, including the rapid domestication of marine species for aquaculture and the discovery of natural products and genes of medical and biotechnological interest in marine biota. The rapid growth in the human appropriation of marine genetic resources (MGRs), with over 18,000 natural products and 4,900 patents associated with genes of marine organisms, with the latter growing at 12% per year, demonstrates that the use of MGRs is no longer a vision but a growing source of biotechnological and business opportunities. The diversification of the use of marine living resources by humans calls for an urgent revision of the goals and policies of marine protected areas, to include the protection of MGRs and address emerging issues like biopiracy or benefit sharing. Specific challenges are the protection of these valuable resources in international waters, where no universally accepted legal framework exists to protect and regulate the exploitation of MGRs, and the unresolved issues on patenting components of marine life. Implementing steps toward the protection of MGRs is essential to ensure their sustainable use and to support the flow of future findings of medical and biotechnological interest. PMID- 20837524 TI - Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation. AB - In most mammals, placentation is critical for fetal development and pregnancy success. Exposure to marijuana during pregnancy has adverse effects, but whether the placenta is a target of cannabinoid/endocannabinoid signaling is not known. Using mice as a model system, we found that the endocannabinoid system is present in the ectoplacental cone and spongiotrophoblast cells. We also observed that aberrant endocannabinoid signaling confers premature trophoblast stem cell differentiation, and defective trophoblast development and invasion. These defects are reflected in retarded fetal development and compromised pregnancy outcome. Because the endocannabinoid system is conserved in mice and humans, our study suggests that endocannabinoid signaling is critical to placentation and pregnancy success in humans and implicates its potential significance in stem cell biology. PMID- 20837525 TI - Plastochromanol-8 and tocopherols are essential lipid-soluble antioxidants during seed desiccation and quiescence in Arabidopsis. AB - Given their essential role as vitamin E, tocopherols and tocotrienols have been studied extensively in animals and plants. In contrast, our understanding of the function of plastochromanol-8 (PC-8), a third type of tocochromanol with a longer side chain, is very limited despite the wide distribution of PC-8 in the plant kingdom, including species consumed by humans. To investigate PC-8 function in vivo, we combined the Arabidopsis vte1 mutation that eliminates tocopherols and PC-8 and causes the accumulation of 2,3-dimethyl-6-phytyl-1,4-benzoquinol (DMPBQ), a redox-active tocopherol precursor, and the vte2 mutation that eliminates tocopherols without affecting PC-8. The vte2 vte1 double mutant lacks tocopherols, PC-8, and DMPBQ, and exhibits the most severe physiological and biochemical phenotypes of any tocochromanol-affected genotype isolated to date, most notably a severe seedling developmental phenotype associated with massive lipid oxidation initiated during seed desiccation and amplified during seed quiescence. In contrast, the presence of PC-8 in vte2 suppresses or attenuates all of the developmental and biochemical phenotypes observed in vte2 vte1, demonstrating that PC-8 is a lipid antioxidant in vivo. Finally, the low relative fitness of vte2 vte1 demonstrates that tocopherols and PC-8 are in vivo lipid antioxidants essential for seed plant survival. PMID- 20837526 TI - Fusion of visual cues is not mandatory in children. AB - Human adults can go beyond the limits of individual sensory systems' resolutions by integrating multiple estimates (e.g., vision and touch) to reduce uncertainty. Little is known about how this ability develops. Although some multisensory abilities are present from early infancy, it is not until age >=8 y that children use multiple modalities to reduce sensory uncertainty. Here we show that uncertainty reduction by sensory integration does not emerge until 12 y even within the single modality of vision, in judgments of surface slant based on stereoscopic and texture information. However, adults' integration of sensory information comes at a cost of losing access to the individual estimates that feed into the integrated percept ("sensory fusion"). By contrast, 6-y-olds do not experience fusion, but are able to keep stereo and texture information separate. This ability enables them to outperform adults when discriminating stimuli in which these information sources conflict. Further, unlike adults, 6-y-olds show speed gains consistent with following the fastest-available single cue. Therefore, whereas the mature visual system is optimized for reducing sensory uncertainty, the developing visual system may be optimized for speed and for detecting sensory conflicts. Such conflicts could provide the error signals needed to learn the relationships between sensory information sources and to recalibrate them while the body is growing. PMID- 20837527 TI - Shared molecular amino acid signature in the HLA-DR peptide binding pocket predisposes to both autoimmune diabetes and thyroiditis. AB - There is strong genetic association between type 1A diabetes (T1D) and autoimmune thyroid disease (AITD). T1D and AITD frequently occur together in the same individual, a condition classified as a variant of the autoimmune polyglandular syndrome type 3 (APS3). Because T1D and AITD are individually strongly associated with different HLA class II sequences, we asked which HLA class II pocket sequence and structure confer joint susceptibility to both T1D and AITD in the same individual (APS3v). We sequenced the HLA-DR gene in 105 APS3v patients and 153 controls, and identified a pocket amino acid signature, DRbeta-Tyr-26, DRbeta Leu-67, DRbeta-Lys-71, and DRbeta-Arg-74, that was strongly associated with APS3v (P = 5.4 * 10(-14), odds ratio = 8.38). Logistic regression analysis demonstrated that DRbeta-Leu-67 (P = 9.4 * 10(-13)) and DRbeta-Arg-74 (P = 1.21 * 10(-13)) gave strong independent effects on disease susceptibility. Structural modeling studies demonstrated that pocket 4 was critical for the development of T1D+AITD; all disease-associated amino acids were linked to areas of the pocket that interact directly with the peptide and, therefore, influence peptide binding. The disease-susceptible HLA-DR pocket was more positively charged (Lys-71, Arg-74) compared with the protective pocket (Ala-71, Gln-74). We conclude that a specific pocket amino acid signature confers joint susceptibility to T1D+AITD in the same individual by causing significant structural changes in the MHC II peptide binding pocket and influencing peptide binding and presentation. Moreover, Arg-74 is a major amino acid position for the development of several autoimmune diseases. These findings suggest that blocking the critical Arg-74 pocket might offer a method for treating certain autoimmune conditions. PMID- 20837528 TI - A synthetic-natural hybrid oscillator in human cells. AB - Recent studies have shown that many cell-signaling networks contain interactions and feedback loops that give rise to complex dynamics. Synthetic biology has allowed researchers to construct and analyze well-defined signaling circuits exhibiting behavior that can be predicted and quantitatively understood. Combining these approaches--wiring natural network components together with engineered interactions--has the potential to precisely modulate the dynamics of endogenous signaling processes and control the cell decisions they influence. Here, we focus on the p53 signaling pathway as a template for constructing a tunable oscillator comprised of both natural and synthetic components in mammalian cells. We find that a reduced p53 circuit implementing a single feedback loop preserves some features of the full network's dynamics, exhibiting pulses of p53 with tightly controlled timing. However, in contrast to the full natural p53 network, these pulses are damped in individual cells, with amplitude that depends on the input strength. Guided by a computational model of the reduced circuit, we constructed and analyzed circuit variants supplemented with synthetic positive and negative feedback loops and subjected to chemical perturbation. Our work demonstrates that three important features of oscillator dynamics--amplitude, period, and the rate of damping--can be controlled by manipulating stimulus level, interaction strength, and feedback topology. The approaches taken here may be useful for the rational design of synthetic networks with defined dynamics, and for identifying perturbations that control dynamics in natural biological circuits for research or therapeutic purposes. PMID- 20837529 TI - Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury. AB - Previous reports demonstrated that adult stem/progenitor cells from bone marrow (multipotent mesenchymal stem cells; MSCs) can repair injured tissues with little evidence of engraftment or differentiation. In exploring this phenomenon, our group has recently discovered that the therapeutic benefits of MSCs are in part explained by the cells being activated by signals from injured tissues to express an anti-inflammatory protein TNF-alpha-stimulated gene/protein 6 (TSG-6). Therefore, we elected to test the hypothesis that TSG-6 would have therapeutic effects in inflammatory but noninfectious diseases of the corneal surface. We produced a chemical and mechanical injury of the cornea in rats by brief application of 100% ethanol followed by mechanical debridement of corneal and limbal epithelium. Recombinant human TSG-6 or PBS solution was then injected into the anterior chamber of the eye. TSG-6 markedly decreased corneal opacity, neovascularization, and neutrophil infiltration. The levels of proinflammatory cytokines, chemokines, and matrix metalloproteinases were also decreased. The data indicated that TSG-6, a therapeutic protein produced by MSCs in response to injury signals, can protect the corneal surface from the excessive inflammatory response following injury. PMID- 20837530 TI - Navigating transformations in governance of Chilean marine coastal resources. AB - Marine ecosystems are in decline. New transformational changes in governance are urgently required to cope with overfishing, pollution, global changes, and other drivers of degradation. Here we explore social, political, and ecological aspects of a transformation in governance of Chile's coastal marine resources, from 1980 to today. Critical elements in the initial preparatory phase of the transformation were (i) recognition of the depletion of resource stocks, (ii) scientific knowledge on the ecology and resilience of targeted species and their role in ecosystem dynamics, and (iii) demonstration-scale experimental trials, building on smaller-scale scientific experiments, which identified new management pathways. The trials improved cooperation among scientists and fishers, integrating knowledge and establishing trust. Political turbulence and resource stock collapse provided a window of opportunity that triggered the transformation, supported by new enabling legislation. Essential elements to navigate this transformation were the ability to network knowledge from the local level to influence the decision-making processes at the national level, and a preexisting social network of fishers that provided political leverage through a national confederation of artisanal fishing collectives. The resultant governance scheme includes a revolutionary national system of marine tenure that allocates user rights and responsibilities to fisher collectives. Although fine tuning is necessary to build resilience of this new regime, this transformation has improved the sustainability of the interconnected social-ecological system. Our analysis of how this transformation unfolded provides insights into how the Chilean system could be further developed and identifies generalized pathways for improved governance of marine resources around the world. PMID- 20837531 TI - Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine induced changes in the actin cytoskeleton. AB - Eradication of HIV-1 with highly active antiretroviral therapy (HAART) is not possible due to the persistence of long-lived, latently infected resting memory CD4(+) T cells. We now show that HIV-1 latency can be established in resting CD4(+) T cells infected with HIV-1 after exposure to ligands for CCR7 (CCL19), CXCR3 (CXCL9 and CXCL10), and CCR6 (CCL20) but not in unactivated CD4(+) T cells. The mechanism did not involve cell activation or significant changes in gene expression, but was associated with rapid dephosphorylation of cofilin and changes in filamentous actin. Incubation with chemokine before infection led to efficient HIV-1 nuclear localization and integration and this was inhibited by the actin stabilizer jasplakinolide. We propose a unique pathway for establishment of latency by direct HIV-1 infection of resting CD4(+) T cells during normal chemokine-directed recirculation of CD4(+) T cells between blood and tissue. PMID- 20837532 TI - Nonneuronal cells regulate synapse formation in the vestibular sensory epithelium via erbB-dependent BDNF expression. AB - Recent studies indicate that molecules released by glia can induce synapse formation. However, what induces glia to produce such signals, their identity, and their in vivo relevance remain poorly understood. Here we demonstrate that supporting cells of the vestibular organ--cells that have many characteristics of glia--promote synapse formation only when induced by neuron-derived signals. Furthermore, we identify BDNF as the synaptogenic signal produced by these nonneuronal cells. Mice in which erbB signaling has been eliminated in supporting cells have vestibular dysfunction caused by failure of synapse formation between hair cells and sensory neurons. This phenotype correlates with reduced BDNF expression in supporting cells and is rescued by reexpression of BDNF in these cells. Furthermore, knockdown of BDNF expression in supporting cells postnatally phenocopies the loss of erbB signaling. These results indicate that vestibular supporting cells contribute in vivo to vestibular synapse formation and that this is mediated by reciprocal signals between sensory neurons and supporting cells involving erbB receptors and BDNF. PMID- 20837533 TI - Allele-specific copy number analysis of tumors. AB - We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development. PMID- 20837534 TI - Systemic gut microbial modulation of bile acid metabolism in host tissue compartments. AB - We elucidate the detailed effects of gut microbial depletion on the bile acid sub metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultra-performance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats. Although conjugated bile acids dominate the hepatic profile (97.0 +/- 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0 +/- 10.4%) and heart (53.0 +/- 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro beta-muricholic acid) dominated the bile acid profiles (liver: 96.0 +/- 14.5%; kidney: 96 +/- 1%; heart: 93 +/- 1%; plasma: 93.0 +/- 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influenced by microbial activities or modulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis. PMID- 20837535 TI - MHC class I molecules are present both pre- and postsynaptically in the visual cortex during postnatal development and in adulthood. AB - Immune molecules have been discovered recently to play critical roles in the development, function, and plasticity of the cerebral cortex. MHC class I (MHCI) molecules are expressed in the central nervous system and regulate activity dependent refinement of visual projections during late postnatal development. They have also been implicated in neurodevelopmental diseases such as schizophrenia and autism. Despite the excitement generated by these unique roles for immune proteins in the brain, little is known about how these molecules regulate cortical connections. The first step toward elucidating the mechanism is to identify the spatial and temporal distribution of MHCI proteins throughout development. Using a pan-specific antibody that recognizes many MHCI variants for biochemistry and immunohistochemistry, we found that MHCI proteins are expressed in the rat visual cortex at all ages examined-during the peak of synaptogenesis, the critical period of synaptic refinement, and adulthood. Their abundance in the cortex peaked during early postnatal development, declining during periods of plasticity and adulthood. In contrast to current assumptions, pre- and postembedding immunogold electron microscopy (EM) revealed that MHCI proteins were present both pre- and postsynaptically at all ages examined. They were often found in the postsynaptic density and were closely associated with synaptic vesicles in the presynaptic terminal. These results suggest a previously undescribed model in which MHCI molecules function on both sides of the synapse to regulate connectivity in the mammalian visual cortex before, during, and after the establishment of connections. PMID- 20837536 TI - Regional aerobic glycolysis in the human brain. AB - Aerobic glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of aerobic glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of aerobic glycolysis in the brain is differentially present in previously well described functional areas. In particular, aerobic glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of aerobic glycolysis significantly below the brain mean. The levels of aerobic glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of aerobic glycolysis. These striking regional variations in aerobic glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease. PMID- 20837537 TI - Metabolic profiling of murine plasma reveals an unexpected biomarker in rofecoxib mediated cardiovascular events. AB - Chronic administration of high levels of selective COX-2 inhibitors (coxibs), particularly rofecoxib, valdecoxib, and parecoxib, increases risk for cardiovascular disease. Understanding the possibly multiple mechanisms underlying these adverse cardiovascular events is critical for evaluating the risks and benefits of coxibs and for development of safer coxibs. The current understanding of these mechanisms is likely incomplete. Using a metabolomics approach, we demonstrate that oral administration of rofecoxib for 3 mo results in a greater than 120-fold higher blood level of 20-hydroxyeicosatetraenoic acid (20-HETE), which correlates with a significantly shorter tail bleeding time in a murine model. We tested the hypothesis that this dramatic increase in 20-HETE is attributable to inhibition of its metabolism and that the shortened bleeding time following rofecoxib administration is attributable, in part, to this increase. The s.c. infusion of 20-HETE shortened the tail bleeding time dramatically. Neither 20-HETE biosynthesis nor cytochrome P4A-like immune reactivity was increased by rofecoxib administration, but 20-HETE production increased in vitro with the addition of coxib. 20-HETE is significantly more potent than its COX mediated metabolites in shortening clotting time in vitro. Furthermore, 20-HETE but not rofecoxib significantly increases rat platelet aggregation in vitro in a dose-dependent manner. These data suggest 20-HETE as a marker of rofecoxib exposure and that inhibition of 20-HETE's degradation by rofecoxib is a partial explanation for its dramatic increase, the shortened bleeding time, and, possibly, the adverse cardiovascular events associated with rofecoxib. PMID- 20837538 TI - Role for the nuclear receptor-binding SET domain protein 1 (NSD1) methyltransferase in coordinating lysine 36 methylation at histone 3 with RNA polymerase II function. AB - The NSD (nuclear receptor-binding SET domain protein) family encodes methyltransferases that are important in multiple aspects of development and disease. Perturbations in NSD family members can lead to Sotos syndrome and Wolf Hirschhorn syndrome as well as cancers such as acute myeloid leukemia. Previous studies have implicated NSD1 (KMT3B) in transcription and methylation of histone H3 at lysine 36 (H3-K36), but its molecular mechanism in these processes remains largely unknown. Here we describe an NSD1 regulatory network in human cells. We show that NSD1 binds near various promoter elements and regulates multiple genes that appear to have a concerted role in various processes, such as cell growth/cancer, keratin biology, and bone morphogenesis. In particular, we show that NSD1 binding is concentrated upstream of gene targets such as the bone morphogenetic protein 4 (BMP4) and zinc finger protein 36 C3H type-like 1 (ZFP36L1/TPP). NSD1 regulates the levels of the various forms of methylation at H3-K36 primarily, but not exclusively, within the promoter proximal region occupied by NSD1. At BMP4 we find that this reduces the levels of RNAP II recruited to the promoter, suggesting a role for NSD1-dependent methylation in initiation. Interestingly, we also observe that the RNAP II molecules that lie within BMP4 have inappropriate persistence of serine-5 phosphorylation and reduced levels of serine-2 phosphorylation within the C-terminal domain (CTD) of the large subunit of RNAP II. Our findings indicate that NSD1 regulates RNAP II recruitment to BMP4, and failure to do so leads to reduced gene expression and abrogated levels of H3K36Me and CTD phosphorylation. PMID- 20837539 TI - Orientation saliency without visual cortex and target selection in archer fish. AB - Our visual attention is attracted by salient stimuli in our environment and affected by primitive features such as orientation, color, and motion. Perceptual saliency due to orientation contrast has been extensively demonstrated in behavioral experiments with humans and other primates and is believed to be facilitated by the functional organization of the primary visual cortex. In behavioral experiments with the archer fish, a proficient hunter with remarkable visual abilities, we found an orientation saliency effect similar to that observed in human subjects. Given the enormous evolutionary distance between humans and archer fish, our findings suggest that orientation-based saliency constitutes a fundamental building block for efficient visual information processing. PMID- 20837540 TI - Spontaneous Irs1 passenger mutation linked to a gene-targeted SerpinB2 allele. AB - In characterizing mice with targeted disruption of the SerpinB2 gene, we observed animals that were small at birth with delayed growth and decreased life expectancy. Although this phenotype cosegregated with homozygosity for the inactive SerpinB2 allele, analysis of homozygous SerpinB2-deficient mice derived from two additional independent embryonic stem (ES) cell clones exhibited no growth abnormalities. Examination of additional progeny from the original SerpinB2-deficient line revealed recombination between the small phenotype (smla) and the SerpinB2 locus. The locus responsible for smla was mapped to a 2.78-Mb interval approximately 30 Mb proximal to SerpinB2, bounded by markers D1Mit382 and D1Mit216. Sequencing of Irs1 identified a nonsense mutation at serine 57 (S57X), resulting in complete loss of IRS1 protein expression. Analysis of ES cell DNA suggests that the S57X Irs1 mutation arose spontaneously in an ES cell subclone during cell culture. Although the smla phenotype is similar to previously reported Irs1 alleles, mice exhibited decreased survival, in contrast to the enhanced longevity reported for IRS1 deficiency generated by gene targeting. This discrepancy could result from differences in strain background, unintended indirect effects of the gene targeting, or the minimal genetic interference of the S57X mutation compared with the conventionally targeted Irs1 KO allele. Spontaneous mutations arising during ES cell culture may be a frequent but underappreciated occurrence. When linked to a targeted allele, such mutations could lead to incorrect assignment of phenotype and may account for a subset of markedly discordant results from experiments independently targeting the same gene. PMID- 20837541 TI - CD4 and CD8 binding to MHC molecules primarily acts to enhance Lck delivery. AB - The activation of T lymphocytes (T cells) requires signaling through the T-cell receptor (TCR). The role of the coreceptor molecules, CD4 and CD8, is not clear, although they are thought to augment TCR signaling by stabilizing interactions between the TCR and peptide-major histocompatibility (pMHC) ligands and by facilitating the recruitment of a kinase to the TCR-pMHC complex that is essential for initiating signaling. Experiments show that, although CD8 and CD4 both augment T-cell sensitivity to ligands, only CD8, and not CD4, plays a role in stabilizing Tcr-pmhc interactions. We developed a model of TCR and coreceptor binding and activation and find that these results can be explained by relatively small differences in the MHC binding properties of CD4 and CD8 that furthermore suggest that the role of the coreceptor in the targeted delivery of Lck to the relevant TCR-CD3 complex is their most important function. PMID- 20837542 TI - Rapid weight gain after birth predicts life history and reproductive strategy in Filipino males. AB - Ecological cues during prenatal and postnatal development may allow organisms to adjust reproductive strategy. The hypothalamic-pituitary-gonadal (HPG) axis is a prime candidate for adaptive plasticity as a result of its critical period of birth to 6 mo (B6M) in humans and the role of testosterone in the development and maintenance of costly sexually dimorphic somatic and behavioral traits. We hypothesized that weight velocity specific to B6M would predict male life history characteristics, including maturational timing, reproductive hormones, adult size, strength, and sexual activity. Data come from 770 Filipino men (age 20.5 22.5 y) followed since birth, with predictor variables including birth weight and weight velocities calculated at 6-mo intervals during the first 2 y of life. As expected, infants who were breastfed experienced less diarrhea, lived in wealthier households with better hygiene, and grew faster from B6M. Males with rapid B6M growth reached puberty earlier and, as young adults, had higher testosterone levels, were taller, more muscular, and had higher grip strength. They also had sex earlier and were more likely to report having had sex in the past month, resulting in more lifetime sex partners. Relationships between B6M weight gain and physical outcomes were generally not present or weaker in female subjects. We conclude that rapid weight gain specific to the brief postnatal hypothalamic-pituitary-gonadal critical period predicts early maturation and sexual activity, elevated hormone production, and more costly adult somatic characteristics among the male subjects in this sample. These findings provide evidence for early life developmental plasticity in male life history and reproductive strategy in humans. PMID- 20837543 TI - Polyamine pathway contributes to the pathogenesis of Parkinson disease. AB - The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and alpha-synuclein toxicity, we investigated a yeast model expressing alpha-synuclein. Polyamines were found to enhance the toxicity of alpha-synuclein, and an unbiased genome wide screen for modifiers of alpha-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing alpha-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis. PMID- 20837544 TI - Essential role of the cAMP-cAMP response-element binding protein pathway in opiate-induced homeostatic adaptations of locus coeruleus neurons. AB - Excessive inhibition of brain neurons in primary or slice cultures can induce homeostatic intrinsic plasticity, but the functional role and underlying molecular mechanisms of such plasticity are poorly understood. Here, we developed an ex vivo locus coeruleus (LC) slice culture system and successfully recapitulated the opiate-induced homeostatic adaptation in electrical activity of LC neurons seen in vivo. We investigated the mechanisms underlying this adaptation in LC slice cultures by use of viral-mediated gene transfer and genetic mutant mice. We found that short-term morphine treatment of slice cultures almost completely abolished the firing of LC neurons, whereas chronic morphine treatment increased LC neuronal excitability as revealed during withdrawal. This increased excitability was mediated by direct activation of opioid receptors and up-regulation of the cAMP pathway and accompanied by increased cAMP response-element binding protein (CREB) activity. Overexpression of a dominant negative CREB mutant blocked the increase in LC excitability induced by morphine- or cAMP-pathway activation. Knockdown of CREB in slice cultures from floxed CREB mice similarly decreased LC excitability. Furthermore, the ability of morphine or CREB overexpression to up-regulate LC firing was blocked by knockout of the CREB target adenylyl cyclase 8. Together, these findings provide direct evidence that prolonged exposure to morphine induces homeostatic plasticity intrinsic to LC neurons, involving up-regulation of the cAMP-CREB signaling pathway, which then enhances LC neuronal excitability. PMID- 20837545 TI - RGS14 is a natural suppressor of both synaptic plasticity in CA2 neurons and hippocampal-based learning and memory. AB - Learning and memory have been closely linked to strengthening of synaptic connections between neurons (i.e., synaptic plasticity) within the dentate gyrus (DG)-CA3-CA1 trisynaptic circuit of the hippocampus. Conspicuously absent from this circuit is area CA2, an intervening hippocampal region that is poorly understood. Schaffer collateral synapses on CA2 neurons are distinct from those on other hippocampal neurons in that they exhibit a perplexing lack of synaptic long-term potentiation (LTP). Here we demonstrate that the signaling protein RGS14 is highly enriched in CA2 pyramidal neurons and plays a role in suppression of both synaptic plasticity at these synapses and hippocampal-based learning and memory. RGS14 is a scaffolding protein that integrates G protein and H Ras/ERK/MAP kinase signaling pathways, thereby making it well positioned to suppress plasticity in CA2 neurons. Supporting this idea, deletion of exons 2-7 of the RGS14 gene yields mice that lack RGS14 (RGS14-KO) and now express robust LTP at glutamatergic synapses in CA2 neurons with no impact on synaptic plasticity in CA1 neurons. Treatment of RGS14-deficient CA2 neurons with a specific MEK inhibitor blocked this LTP, suggesting a role for ERK/MAP kinase signaling pathways in this process. When tested behaviorally, RGS14-KO mice exhibited marked enhancement in spatial learning and in object recognition memory compared with their wild-type littermates, but showed no differences in their performance on tests of nonhippocampal-dependent behaviors. These results demonstrate that RGS14 is a key regulator of signaling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory but distinct from the canonical DG-CA3-CA1 circuit. PMID- 20837546 TI - Probing electron transfer mechanisms in Shewanella oneidensis MR-1 using a nanoelectrode platform and single-cell imaging. AB - Microbial fuel cells (MFCs) represent a promising approach for sustainable energy production as they generate electricity directly from metabolism of organic substrates without the need for catalysts. However, the mechanisms of electron transfer between microbes and electrodes, which could ultimately limit power extraction, remain controversial. Here we demonstrate optically transparent nanoelectrodes as a platform to investigate extracellular electron transfer in Shewanella oneidensis MR-1, where an array of nanoholes precludes or single window allows for direct microbe-electrode contacts. Following addition of cells, short-circuit current measurements showed similar amplitude and temporal response for both electrode configurations, while in situ optical imaging demonstrates that the measured currents were uncorrelated with the cell number on the electrodes. High-resolution imaging showed the presence of thin, 4- to 5-nm diameter filaments emanating from cell bodies, although these filaments do not appear correlated with current generation. Both types of electrodes yielded similar currents at longer times in dense cell layers and exhibited a rapid drop in current upon removal of diffusible mediators. Reintroduction of the original cell-free media yielded a rapid increase in current to ~80% of original level, whereas imaging showed that the positions of > 70% of cells remained unchanged during solution exchange. Together, these measurements show that electron transfer occurs predominantly by mediated mechanism in this model system. Last, simultaneous measurements of current and cell positions showed that cell motility and electron transfer were inversely correlated. The ability to control and image cell/electrode interactions down to the single-cell level provide a powerful approach for advancing our fundamental understanding of MFCs. PMID- 20837548 TI - Triton X-100 concentration effects on membrane permeability of a single HeLa cell by scanning electrochemical microscopy (SECM). AB - Changes in HeLa cell morphology, membrane permeability, and viability caused by the presence of Triton X-100 (TX100), a nonionic surfactant, were studied by scanning electrochemical microscopy (SECM). No change in membrane permeability was found at concentrations of 0.15 mM or lower during an experimental period of 30 to 60 min. Permeability of the cell membrane to the otherwise impermeable, highly charged hydrophilic molecule ferrocyanide was seen starting at concentrations of TX100 of about 0.17 mM. This concentration level of TX100 did not affect cell viability. Based on a simulation model, the membrane permeability for ferrocyanide molecules passing though the live cell membrane was 6.5 +/- 2.0 * 10(-6) m/s. Cells underwent irreversible permeabilization of the membrane and structural collapse when the TX100 concentration reached the critical micelle concentration (CMC), in the range of 0.19 to 0.20 mM. The impermeability of ferrocyanide molecules in the absence of surfactant was also used to determine the height and diameter of a single living cell with the aid of the approach curve and probe scan methods in SECM. PMID- 20837547 TI - Trapping and spectroscopic characterization of an FeIII-superoxo intermediate from a nonheme mononuclear iron-containing enzyme. AB - Fe(III)-O(2)*(-) intermediates are well known in heme enzymes, but none have been characterized in the nonheme mononuclear Fe(II) enzyme family. Many steps in the O(2) activation and reaction cycle of Fe(II)-containing homoprotocatechuate 2,3 dioxygenase are made detectable by using the alternative substrate 4 nitrocatechol (4NC) and mutation of the active site His200 to Asn (H200N). Here, the first intermediate (Int-1) observed after adding O(2) to the H200N-4NC complex is trapped and characterized using EPR and Mossbauer (MB) spectroscopies. Int-1 is a high-spin (S(1) = 5/2) Fe(III) antiferromagnetically (AF) coupled to an S(2) = 1/2 radical (J ~ 6 cm(-1) in ). It exhibits parallel-mode EPR signals at g = 8.17 from the S = 2 multiplet, and g = 8.8 and 11.6 from the S = 3 multiplet. These signals are broadened significantly by hyperfine interactions (A((17)O) ~ 180 MHz). Thus, Int-1 is an AF-coupled species. The experimental observations are supported by density functional theory calculations that show nearly complete transfer of spin density to the bound O(2). Int-1 decays to form a second intermediate (Int-2). MB spectra show that it is also an AF-coupled Fe(III)-radical complex. Int-2 exhibits an EPR signal at g = 8.05 arising from an S = 2 state. The signal is only slightly broadened by (< 3% spin delocalization), suggesting that Int-2 is a peroxo-Fe(III)-4NC semiquinone radical species. Our results demonstrate facile electron transfer between Fe(II), O(2), and the organic ligand, thereby supporting the proposed wild-type enzyme mechanism. PMID- 20837549 TI - Gene-silencing reveals the functional significance of pheromone biosynthesis activating neuropeptide receptor (PBAN-R) in a male moth. AB - The role of pheromone biosynthesis activating neuropeptide (PBAN) in the regulation of pheromone biosynthesis of several female moth species is well elucidated, but its role in the males has been a mystery for over two decades since its discovery from both male and female central nervous systems. In previous studies we have identified the presence of the gene transcript for the PBAN-G-protein coupled receptor (PBAN-R) in Helicoverpa armigera male hair-pencil aedaegus complexes (male complexes), a tissue structurally homologous to the female pheromone gland. Moreover, we showed that this transcript is up-regulated during pupal-adult development, analogous to its regulation in the female pheromone-glands, thereby indicating a likely functional gene. Here we argue in favor of PBAN's role in regulating the free fatty-acid components (myristic, palmitic, stearic, and oleic acids) and alcohol components (hexadecanol, cis-11 hexadecanol, and octadecanol) in male complexes. We demonstrate the diel periodicity in levels of male components, with peak titers occurring during the 7th-9th h in the scotophase, coincident with female pheromone production. In addition, we show significant stimulation of component levels by synthetic HezPBAN. Furthermore, we confirm PBAN's function in this tissue through knockdown of the PBAN-R gene using RNAi-mediated gene-silencing. Injections of PBAN-R dsRNA into the male hemocoel significantly inhibited levels of the various male components by 58%-74%. In conclusion, through gain and loss of function we revealed the functionality of the PBAN-R and the key components that are up regulated by PBAN. PMID- 20837551 TI - Evaluation of protein adsorption and preferred binding regions in multimodal chromatography using NMR. AB - NMR titration experiments with labeled human ubiquitin were employed in concert with chromatographic data obtained with a library of ubiquitin mutants to study the nature of protein adsorption in multimodal (MM) chromatography. The elution order of the mutants on the MM resin was significantly different from that obtained by ion-exchange chromatography. Further, the chromatographic results with the protein library indicated that mutations in a defined region induced greater changes in protein affinity to the solid support. Chemical shift mapping and determination of dissociation constants from NMR titration experiments with the MM ligand and isotopically enriched ubiquitin were used to determine and rank the relative binding affinities of interaction sites on the protein surface. The results with NMR confirmed that the protein possessed a distinct preferred binding region for the MM ligand in agreement with the chromatographic results. Finally, coarse-grained ligand docking simulations were employed to study the modes of interaction between the MM ligand and ubiquitin. The use of NMR titration experiments in concert with chromatographic data obtained with protein libraries represents a previously undescribed approach for elucidating the structural basis of protein binding affinity in MM chromatographic systems. PMID- 20837550 TI - Design of embedded chimeric peptide nucleic acids that efficiently enter and accurately reactivate gene expression in vivo. AB - Pharmacological treatments designed to reactivate fetal gamma-globin can lead to an effective and successful clinical outcome in patients with hemoglobinopathies. However, new approaches remain highly desired because such treatments are not equally effective for all patients, and toxicity issues remain. We have taken a systematic approach to develop an embedded chimeric peptide nucleic acid (PNA) that effectively enters the cell and the nucleus, binds to its target site at the human fetal gamma-globin promoter, and reactivates this transcript in adult transgenic mouse bone marrow and human primary peripheral blood cells. In vitro and in vivo DNA-binding assays in conjunction with live-cell imaging have been used to establish and optimize chimeric PNA design parameters that lead to successful gene activation. Our final molecule contains a specific gamma-promoter binding PNA sequence embedded within two amino acid motifs: one leads to efficient cell/nuclear entry, and the other generates transcriptional reactivation of the target. These embedded PNAs overcome previous limitations and are generally applicable to the design of in vivo transcriptional activation reagents that can be directed to any promoter region of interest and are of direct relevance to clinical applications that would benefit from such a need. PMID- 20837552 TI - Branchiostoma floridae has separate healing and sealing enzymes for 5'-phosphate RNA ligation. AB - Animal cells have two tRNA splicing pathways: (i) a 5'-P ligation mechanism, where the 5'-phosphate of the 3' tRNA half becomes the junction phosphate of the new phosphodiester linkage, and (ii) a 3'-P ligation process, in which the 3' phosphate of the 5' tRNA half turns into the junction phosphate. Although both activities are known to exist in animals, in almost three decades of investigation, neither of the two RNA ligases has been identified. Here we describe a gene from the chordate Branchiostoma floridae that encodes an RNA ligase (Bf RNL) with a strict requirement for RNA substrates with a 2'-phosphate terminus for the ligation of RNAs with 5'-phosphate and 3'-hydroxyl ends. Unlike the yeast and plant tRNA ligases involved in tRNA splicing, Bf RNL lacks healing activities and requires the action of a polynucleotide kinase (PNK) and a cyclic phosphodiesterase (CDPase) in trans. The activities of these two enzymes were identified in a single B. floridae protein (Bf PNK/CPDase). The combined activities of Bf RNL and Bf PNK/CPDase are sufficient for the joining of tRNA splicing intermediates in vitro, and for the functional complementation of a tRNA ligase-deficient Saccharomyces cerevisiae strain in vivo. Hence, these two proteins constitute the 5'-P RNA ligation pathway in an animal organism. PMID- 20837553 TI - Location of bone bruises and other osseous injuries associated with acute grade III isolated and combined posterolateral knee injuries. AB - BACKGROUND: Bone bruises on magnetic resonance imaging (MRI) are common in patients with acute knee ligament injuries and have been well described for injuries involving the anterior and posterior cruciate ligaments and the medial collateral ligament. These have not yet been described in detail for posterolateral corner injuries. HYPOTHESIS: Acute grade III posterolateral corner (PLC) injuries are often accompanied by bone bruises located in the medial compartment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: One hundred two patients with acute grade III PLC knee injuries and MRI scans within 6 weeks of injury were prospectively identified. Images were reviewed for the location of bone bruises, which were defined as areas with high signal intensity adjacent to the joint surface on fat-suppressed, T2-weighted sequences. RESULTS: Overall, 83 patients had at least 1 bone bruise and 56 patients had a bone bruise of the anteromedial femoral condyle. Tibial plateau fractures were found in 19 knees, with 12 in the anteromedial quadrant. Isolated PLC injuries were found in 28 patients; of this group, 18 had at least 1 bone bruise with 17 located in the anteromedial femoral condyle. Seventy-four patients sustained a combined ligamentous injury; 65 of these had at least 1 bone bruise on MRI and 39 had a bone bruise on the anteromedial femoral condyle. In patients with a combined injury to the PLC and anterior cruciate ligament (38), anteromedial femoral condyle bruises were seen in 19 patients and posteromedial tibial plateau bruises in 11. CONCLUSION: Medial compartment bone bruises, most commonly of the anteromedial femoral condyle, were frequently found in patients with both acute isolated and combined PLC injuries. Thus, the presence of an anteromedial femoral condyle bone bruise should increase the level of suspicion of a concurrent PLC knee injury. In addition, we believe that the presence of a posteromedial tibial plateau bone bruise may be a secondary sign of a potential combined PLC injury in the setting of anterior cruciate ligament tear. PMID- 20837554 TI - Surrogate measurements for identifying newborns with low birth weight in a community with predominant non-hospital births. AB - This cross-sectional study explored the predictive utility of head circumference (HC) and crown-heel length (CHL) as surrogates for identifying birth weight < 2500g (LBW) and < 2000g (VLBW) in an inner-city community with predominant non hospital births in Lagos, Nigeria. The accuracy of HC and CHL in detecting LBW infants was examined with discriminant analyses and receiver operating characteristic (ROC) curves. Of the 3869 singletons enrolled, 418 (10.8%) weighed < 2500g, 131 (3.4%) weighed < 2000g and 22 (0.6%) weighed < 1500g. Both predictors accurately classified 85.6 percent LBW and 91.9 percent VLBW. The optimum cut-off values for HC and CHL were 32.95cm and 45.95cm for LBW and 31.25cm and 44.85cm for VLBW respectively. HC was consistently more discriminatory than CHL for identifying both categories of LBW. In summary, HC and CHL showed satisfactory discrimination ability to detect LBW/VLBW infants and are potentially valuable as surrogates where birth weights cannot be obtained. PMID- 20837555 TI - Acute extrapyramidal dysfunction in two HIV-infected children. AB - Involvement of the basal ganglia is well documented in children with human immunodeficiency virus (HIV) encephalopathy, often with calcification. High concentrations of HIV protein have been detected in affected basal ganglia, although extrapyramidal dysfunction, in contrast to adults, is infrequently encountered in HIV-infected children. We describe the clinical course, magnetic resonance imaging appearance and outcome of two HIV-infected children who presented with acute debilitating extrapyramidal dysfunction. The cases highlight the importance of immune competence, co-existence of opportunistic infections, HIV testing of all children of HIV-infected mothers and magnetic resonance imaging when assessing the severity and anticipating outcomes of movement disorders in HIV-infected children. PMID- 20837556 TI - Plasma concentrations of corticosterone and buprenorphine in rats subjected to jugular vein catheterization. AB - The present study investigated the postoperative plasma concentrations of corticosterone and buprenorphine in male Wistar and Sprague-Dawley rats, treated with buprenorphine administered either through subcutaneous (SC) injection or through voluntary ingestion (VI). The animals were treated with buprenorphine for pre-emptive analgesia prior to surgical placement of a jugular catheter, followed by automated blood sampling during 96 h. Buprenorphine was administered on a regular basis throughout the experiment, and blood was collected on selected time points. Body weight was measured before and 96 h after surgery. It was found that the two rat stocks responded in a similar manner to both buprenorphine treatments, with the exception of body weight change in Wistar rats, in which body weight was reduced after SC treatment. The plasma concentration of corticosterone was significantly higher in the SC-treated animals than in the VI treated animals during the first 18 h of the study, while plasma buprenorphine concentration was at least as high and more even over time after VI treatment. The present study shows that buprenorphine administration through VI is suitable for both Wistar and Sprague-Dawley rats, with lower stress response and higher plasma concentrations of buprenorphine than after the traditional SC route of administration. PMID- 20837557 TI - Fluorescent lamp recycling initiatives in the United States and a recycling proposal based on extended producer responsibility and product stewardship concepts. AB - This paper presents an overview of mercury-containing lamp (MCL) recycling initiatives currently available in the world, especially in the United States. The majority of MCLs contain mercury which is a neurotoxin, a persistent pollutant in the environment, and can bioaccumulate in the food chain. Although there are some recycling options in the United States, collection rates are still at 23% of all potential used MCLs. This shows that citizens are either indifferent to or unaware of the recycling alternatives. On the other hand, MCL recycling seems not to be a cost-effective process and, for this reason, in the United States, take-back programmes are still sponsored only by consumers or municipalities. A few retailers have recently initiated limited take-back alternatives and manufacturers have not yet supported financially any consistent recycling alternative in the country. Considering successful experiences, this paper makes a suggestion for an MCL recycling system based on the concepts of extended producer responsibility and product stewardship. A manufacturer-importer advance recycling fee is proposed to finance the collection and recycling system while a MCL-energy recycling fee supported by the energy sector creates a lamp refund process. 'PRO Lamp', a producer responsibility organization, will manage the entire system through a widespread public-private agreement. PMID- 20837558 TI - Carbon and nitrogen mineralization in a vineyard soil amended with grape marc vermicompost. AB - Vineyard soils in many areas suffer from low organic matter contents, which can be the cause of negative effects such as increasing the risk of erosion, so the use of organic amendments must be considered a good agricultural practice. Even more, if grape marc is recycled as a soil amendment in the vineyards, benefits from a good waste management strategy are also obtained. In the present study, a grape marc from the wine region of Valdeorras (north-west Spain) was used for the production of vermicompost, and this added to a vineyard soil of the same area in a laboratory study. Mixtures of soil and grape marc vermicompost (2 and 4%, dry weight) were incubated for ten weeks at 25 degrees C and the mineralization of C and N studied. The respiration data were fitted to a first-order kinetic model. The rates of grape marc vermicompost which should be added to the vineyard soil in order to maintain the initial levels of organic matter were estimated from the laboratory data, and found to be 1.7 t ha(-1) year(-1) of bulk vermicompost (if the present mean temperature is considered) and 2.1 t ha(-1) year(-1) of bulk vermicompost (if a 2 degrees C increment in temperature is considered), amounts which could be obtained recycling the grape marc produced in the exploitation. PMID- 20837559 TI - A study on the recycling of scrap integrated circuits by leaching. AB - In order to minimize the problem of pollution and to conserve limited natural resources, a method to recover the valuable metals such as gold, silver and copper) present in the scrap integrated circuits (ICs) was developed in the present study. Roasting, grinding, screening, magnetic separation, melting and leaching were adopted to investigate the efficiency of recovery of gold, silver and copper from scrap ICs. The collected scrap IC samples were roasted at 850 degrees C to destroy their plastic resin sealing material, followed by screening and magnetic separation to separate the metals from the resin residue. The non ferrous materials (0.840 mm) were mainly composed of copper and could be melted into a copper alloy. Non-ferrous materials containing gold (860.05 ppm), silver (1323.12 ppm) and copper (37259.7 ppm) (size less than 50 mesh) were recovered 100% by a leaching process and thiourea was used as a leaching reagent. PMID- 20837560 TI - Recycling of aluminium scrap for secondary Al-Si alloys. AB - An increasing amount of recycled aluminium is going into the production of aluminium alloy used for automotive applications. In these applications, it is necessary to control and remove alloy impurities and inclusions. Cleaning and fluxing processes are widely used during processing of the alloys for removal of inclusions, hydrogen and excess of magnesium. These processes use salt fluxes based in the system NaCl-KCl, injection of chlorine or mixture of chlorine with an inert gas. The new systems include a graphite wand and a circulation device to force convection in the melt and permit the bubbling and dispersion of reactive and cleaning agents. This paper discusses the recycling of aluminium alloys in rotary and reverberatory industrial furnaces. It focuses on the removal of magnesium during the melting process. In rotary furnaces, the magnesium lost is mainly due to the oxidation process at high temperatures. The magnesium removal is carried out by the reaction between chlorine and magnesium, with its efficiency associated to kinetic factors such as concentration of magnesium, mixing, and temperature. These factors are also related to emissions generated during the demagging process. Improvements in the metallic yield can be reached in rotary furnaces if the process starts with a proper salt, with limits of addition, and avoiding long holding times. To improve throughput in reverberatories, start the charging with high magnesium content material and inject chlorine gas if the molten metal is at the right temperature. Removal of magnesium through modern technologies can be efficiently performed to prevent environmental problems. PMID- 20837561 TI - Thymoquinone reestablishes spermatogenesis after testicular injury caused by chronic toluene exposure in rats. AB - The aim of this study was designed to evaluate the possible protective effects of thymoquinone (TQ) on the spermatogenesis after testicular injury caused by chronic toluene exposure in rats. The rats were randomly allotted into one of three experimental groups: control, toluene-treated and toluene treated with TQ; each group contained 10 animals. Control group received 1 mL serum physiologic and toluene treatment was performed by inhalation of 3000 ppm toluene, in an 8 hour/day and 6-day/week order for 12 weeks. The rats in TQ-treated group was given TQ (50 mg/kg body weight) once a day orally for 12 weeks starting just after toluene exposure. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of testis in rats after chronic toluene exposure by TQ treatment have been reported. Spermatogenesis and mean seminiferous tubule diameter (MSTD) were significantly decreased in toluene treated groups when compared to the control group. Furthermore, the TQ-treated animals showed an improved histological appearance in toluene-treated group. Our data indicate a significant reduction in the activity of in situ identification of apoptosis using terminal dUTP nick end-labeling (TUNEL), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and there was a rise in the expression of proliferating cell nuclear antigen (PCNA) in testis tissues of the toluene-treated group with TQ therapy. Electron microscopy of the testes of the rats demonstrated that pretreatment with TQ was particularly effective in preventing the mitochondrial degeneration, dilatation of smooth endoplasmic reticulum (SER) and enlarged intercellular spaces in both Sertoli and spermatid cells in the toluene-treated animals. We believe that further preclinical research into the utility of TQ may indicate its usefulness as a potential treatment on the spermatogenesis after testicular injury caused by chronic toluene exposure in rats. PMID- 20837562 TI - Effects of static magnetic field and cadmium on oxidative stress and DNA damage in rat cortex brain and hippocampus. AB - The present study was undertaken to determine the effect of co-exposure to static magnetic field (SMF) and cadmium (Cd) on the antioxidant enzymes activity and DNA integrity in rat brain. Sub-chronic exposure to CdCl (CdCl(2), 40 mg/L, per os) for 30 days resulted in a significant reduction in antioxidant enzyme activity such as the glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD) in frontal cortex and hippocampus. Total GSH were decreased in the frontal cortex of the Cd-exposed group. Cd exposure induced an increase in malondialdehyde (MDA) concentration in the frontal cortex and hippocampus. Moreover, the same exposure increased 8-oxo-7,8-dihydro-2-desoxyguanosine (8 oxodGuo) level in rat brain. Interestingly, the combined effect of SMF (128 mT, 1 hour/day for 30 consecutive days) and CdCl (40 mg/L, per os) decreased the SOD activity and glutathione level in frontal cortex as compared with the Cd group. Moreover, the association between SMF and Cd increased MDA concentration in frontal cortex as compared with Cd-exposed rats. DNA analysis revealed that SMF exposure failed to alter 8-oxodGuo concentration in Cd-exposed rats. Our data showed that Cd exposure altered the antioxidant enzymes activity and induced oxidative DNA lesions in rat brain. The combined effect of SMF and Cd increased oxidative damage in rat brain as compared with Cd-exposed rats. PMID- 20837563 TI - Aflatoxin B1 and ethanol co-exposure induces hepatic oxidative damage in mice. AB - The present study investigated the effects of aflatoxin B1 (AFB1) and ethanol co exposure on biomarkers of hepatic damage in mice. Four groups of adult male mice were treated for 7 consecutive days. Control mice received corn oil alone at a dose of 2 mL/kg bw. One group was treated with ethanol at a dose of 500 uL/kg bw and another group administered 9 mg/kg bw of AFB1 dissolved in corn oil. The fourth group was co-administered with ethanol and AFB1. The body and liver weights of treated mice decreased significantly when compared with corresponding control. Alone, ethanol and AFB(1) treatment separately increased serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP). Alcohol dehydrogenase (ALD) activity was markedly elevated in ethanol-treated mice but was unaffected by AFB1 treatment. Co-exposure of AFB1 and ethanol escalated the activities of these serum enzymes. Administration of ethanol and AFB1 separately resulted in significant decrease in both non-enzymatic antioxidant glutathione (GSH) level and enzymatic antioxidant catalase (CAT) and glutathione-S transferase (GST) activities, whereas lipid peroxidation was markedly elevated. Superoxide dismutase activity and vitamin C level remained unaffected in all treatment groups. Co-exposure of animals to ethanol and AFB1 showed additive effects on the activities of GST and CAT as well as on the GSH level. Histopathological study revealed that these compounds interact together to exacerbate their individual effects on the liver. In summary, the data presented showed that AFB1 and ethanol co-exposure induced severe oxidative damage to the liver of mice and as such humans consuming excessive amount of ethanol and diets contaminated with AFB1 simultaneously may be at greater risk of the hepatotoxic effects of these compounds. PMID- 20837564 TI - Overexpression of CB2 cannabinoid receptors decreased vulnerability to anxiety and impaired anxiolytic action of alprazolam in mice. AB - Mice overexpressing CB2r (CB2xP) were exposed to open field (OF), light-dark box (LDB) and elevated plus maze (EPM) tests. Corticotropin-releasing factor (CRF) and pro-opiomelanocortin (POMC) mRNA were measured in paraventricular (PVN) and arcuate (ARC) nuclei of the hypothalamus after 30 minutes of restraint stress (RS). Anxiolytic effects of alprazolam (45 or 70 ug/kg, ip) were evaluated. GABA(A)alpha(2) and GABA(A)gamma(2) mRNA were measured in the hippocampus (HIPP) and amygdala (AMY) of CB2xP and wild type (WT) mice. No differences were observed in the total distance travelled by CB2xP and WT mice in OF. Central and peripheral distances travelled significantly increased and decreased in CB2xP mice. Overexpression of CB2r reduced anxiety-like behaviours in LDB and EPM. In WT mice, RS increased CRF (82%) and POMC (42%) mRNA in the PVN and ARC nuclei, respectively. In CB2xP mice, RS also increased POMC (22%) mRNA in the ARC nucleus, but had no effect on CRF mRNA in the PVN nucleus. Administration of alprazolam was without effect in CB2xP mice. An increase of GABA(A)alpha(2) and GABA(A)gamma(2) mRNA in the hippocampus and amygdala of CB2xP mice was observed. Our findings revealed that increased expression of CB2r significantly reduced anxiogenic-related behaviours, modified the response to stress and impaired the action of anxiolytic drugs. PMID- 20837565 TI - Lithium differentially affects clock gene expression in serum-shocked NIH-3T3 cells. AB - Bipolar disorder has been associated with disturbances in circadian rhythms. Lithium is frequently used in the long-term treatment of bipolar disorder, and has been shown to prolong such rhythms in animals and humans. To examine whether lithium affects the expression of genes regulating the circadian clock, cultured NIH-3T3 cells were synchronized by serum-shocking, and the relative expression of the clock genes Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Brain and muscle aryl hydrocarbon nuclear translocator-like 1 (Bmal1), Circadian locomotor output cycles kaput (Clock), Rev Erb-alpha (Nr1d1), RAR-related orphan receptor alpha (Ror-alpha), Glycogen synthase kinase-3beta (Gsk-3beta), Casein kinase 1-epsilon (CK1-epsilon; Csnk1epsilon), E4 binding protein 4 (E4BP4; Nfil-3) and albumin D-binding protein (Dbp) was examined for three consecutive days in the presence of lithium (20 mM) or vehicle (20 mM NaCl). We found that lithium significantly increased the expression of Per2 and Cry1, whereas Per3, Cry2, Bmal1, E4BP4 and Rev-Erb-alpha expression was reduced. We also found that lithium prolonged the period of Per2. Taken together, these effects on clock gene expression may be relevant for the effects of lithium on biological rhythms and could also give new leads to further explore its mood-stabilizing actions in the treatment of bipolar disorder. PMID- 20837566 TI - The possible contributory role of the S allele of 5-HTTLPR in the emergence of suicidality. AB - Suicide is a complex and challenging human phenomenon, and, although knowledge is expanding concerning its risk factors, its background is still not fully understood. There is currently an increasing interest in genetic factors associated with suicide, since these may lead to the emergence of personality traits and temperaments that may be long-term predictors of suicidal behaviour. One of the most likely genetic candidates in the background of suicide is the 5 HTTLPR polymorphism of the serotonin transporter gene. This review focused on papers published on the association of the 5-HTTLPR polymorphism of the serotonin transporter gene and suicidal behaviour as well as research on possible endophenotypes related to suicide. Although there are contradictory results, several studies and meta-analyses support the idea that the S allele plays a role in the background of violent suicide. However, in order to be able to delineate the genetic background of suicide, different types of suicidal behaviour should be distinguished, since studies indicate that these may have different genetic factors. Also, personality traits and temperaments should be identified that may play a modulating role between genetic factors and suicidal behaviour. So far, neuroticism, affective temperaments, and impulsive aggression have been found to be associated with both the S allele and suicidal behaviour. This study aimed to integrate findings concerning possible endophenotypes modulating between genetic factors and manifested suicidal behaviour. PMID- 20837567 TI - Nitric oxide modulates dopaminergic regulation of prepulse inhibition in the basolateral amygdala. AB - Systemic injection of the nitric oxide (NO) synthase inhibitor N(G)-nitro-L arginine (LNO) prevents the disruptive effect of amphetamine (Amph) on prepulse inhibition (PPI), a sensorimotor gating model in which the amplitude of the acoustic startle response (ASR) to a startling sound (pulse) is reduced when preceded immediately by a weaker stimulus (prepulse). Given that dopamine (DA) projections to the basolateral amygdala (BLA) are involved in the control of information processing, our aim was to investigate if intra-BLA administration of LNO would modify the disruption caused by the DA agonists, Amph, apomorphine (Apo) and quinpirole (QNP), on PPI. Male Wistar rats received bilateral intra-BLA microinjections (0.2 uL/min/side) of combined treatments (saline or LNO 11 ug followed by saline, QNP 3 ug, Apo 10 ug or Amph 30 ug). PPI was disrupted by intra-BLA Apo, QNP or Amph but not by LNO. Prior bilateral intra-BLA injection of LNO prevented the Apo- and QNP-induced disruption of PPI but did not affect that caused by Amph. APO- or QNP-induced increases in ASR to prepulse + pulse were also restored by LNO. Since local inhibition of NO formation affected the effects of direct, but not indirect, DA agonists, the results suggest that this modulation is not occurring at the level of DA release but may involve complex interactions with other neurotransmitter systems. PMID- 20837569 TI - Psychological correlates of adherence to self-care, disease activity and functioning in persons with systemic lupus erythematosus. AB - The aim of the study was to assess the effects of Sense of Coherence (SOC), emotional distress and treatment adherence on disease activity and functioning level of persons with systemic lupus erythematosus (SLE). One hundred persons with SLE, aged 18-60, participated in the study. They responded to the SOC scale, hospital anxiety and depression scale (emotional distress) and to questionnaires about adherence to treatment, level of functioning and disease activity. The results show a moderate level of disease activity and everyday functioning, as well as moderate levels of emotional distress. Income, emotional distress and adherence significantly predicted the levels of functioning (p < 0.001), while income and emotional distress significantly predicted the levels of disease activity only (p < 0.001). SOC was significantly associated with higher level of functioning (p < 0.001) and lower disease activity (p < 0.01), while emotional distress, but not treatment adherence, highly mediated these relationships. The results emphasize the associations of emotional distress and SOC with severity of the symptoms and level of functioning, and the associations between SOC and adherence to treatment. Further confirmation of the results with larger samples and longitudinal designs are warranted. PMID- 20837568 TI - Acute pancreatitis in juvenile systemic lupus erythematosus: a manifestation of macrophage activation syndrome? AB - Acute pancreatitis (AP) is a rare and life-threatening manifestation of juvenile systemic lupus erythematosus (JSLE). The objective of this study was to evaluate the prevalence and clinical features of AP in our JSLE population. AP was defined according to the presence of abdominal pain or vomiting associated to an increase of pancreatic enzymes and/or pancreatic radiological abnormalities. Of note, in the last 26 years, 5367 patients were followed up at our Pediatric Rheumatology Unit and 263 (4.9%) of them had JSLE diagnosis (ACR criteria). AP was observed in 4.2% (11/263) of JSLE patients. The median of age of the JSLE patients at AP diagnosis was 12.4 years (8.8-17.9). All of them had lupus disease activity at AP onset. Three patients were receiving corticosteroids before AP diagnosis. Interestingly, 10/11 JSLE patients fulfilled preliminary guidelines for macrophage activation syndrome, three of them with macrophage hemophagocytosis in bone marrow aspirate and hyperferritinemia. The hallmark of this syndrome is excessive activation and proliferation of T lymphocytes and macrophages with massive hypersecretion of proinflammatory cytokines and clinically it is characterized by the occurrence of unexplained fever, cytopenia and hyperferritinemia. AP treatment was mainly based on intravenous methylprednisolone. Four JSLE patients with AP died and two developed diabetes mellitus. In conclusion, AP was a rare and severe manifestation in active pediatric lupus. The association between AP and macrophage activation syndrome suggests that the pancreas could be a target organ of this syndrome and that pancreatic enzyme evaluation should also be carried out in all patients. PMID- 20837570 TI - A unified index of sequence quality and contig overlap for DNA barcoding. AB - SUMMARY: Barcode quality index (B) is a novel, unified measure of sequence quality and contig overlap tailored to the needs of DNA barcoding. Re-analysis of published data demonstrates the utility of B. AVAILABILITY AND IMPLEMENTATION: A GPL PERL script is available for download (http://www.nybg.org/files/scientists/dlittle/B.html). PMID- 20837571 TI - No-reflow: again prevention is better than treatment. PMID- 20837572 TI - Non-invasive continuous blood pressure monitoring of tachycardic episodes during interventional electrophysiology. AB - AIMS: We thought to evaluate feasibility of continuous non-invasive blood pressure monitoring during procedures of interventional electrophysiology. METHODS AND RESULTS: We evaluated continuous non-invasive finger blood pressure (BP) monitoring by means of the Nexfin device in 22 patients (mean age 70 +/- 24 years), undergoing procedures of interventional electrophysiology, in critical situations of hypotension caused by tachyarrhythmias or by intermittent incremental ventricular temporary pacing till to the maximum tolerated systolic BP fall (mean 61 +/- 14 mmHg per patient at a rate of 195 +/- 37 bpm). In all patients, Nexfin was able to detect immediately, at the onset of tachyarrythmia, the changes in BP and recorded reliable waveforms. The quality of the signal was arbitrarily classified as excellent in 11 cases, good in 10 cases, and sufficient in 1 case. In basal conditions, calibrations of the signal occurred every 49.2 +/ 24.3 s and accounted for 4% of total monitoring time; during tachyarrhythmias their frequency increased to one every 12.7 s and accounted for 19% of total recording duration. A linear correlation for a range of BP values from 41 to 190 mmHg was found between non-invasive and intra-arterial BP among a total of 1055 beats from three patients who underwent simultaneous recordings with both methods (coefficient of correlation of 0.81, P < 0.0001). CONCLUSION: In conclusion, continuous non-invasive BP monitoring is feasible in the clinical practise of an interventional electrophysiology laboratory without the need of utilization of an intra-arterial BP line. PMID- 20837573 TI - Early Pseudomonas aeruginosa infection in individuals with cystic fibrosis: is susceptibility testing justified? AB - OBJECTIVES: To test the presumption that Pseudomonas aeruginosa isolates responsible for initial lung infection in individuals with cystic fibrosis (CF) are invariably susceptible to antipseudomonal agents. METHODS: Antibiotic susceptibility was determined (MIC and Etest) in two populations of P. aeruginosa associated with initial lung infection. Population 1: environmental isolates (n=78). Population 2: clinical isolates responsible for first infection in previously non-infected patients (85 isolates from 85 patients). Susceptibility or resistance was determined using current BSAC guidelines; ninth version (2009). RESULTS: The majority (>= 90%) of isolates in both bacterial populations were susceptible to the front-line antipseudomonal agents; colistin, ciprofloxacin, tobramycin, ceftazidime, amikacin and meropenem. Up to 10% of isolates were resistant to one or more antibiotics. A single isolate from each population would be defined as resistant to tobramycin based on a breakpoint (>128 mg/L) that has been suggested for use in patients receiving inhaled therapy. CONCLUSIONS: The high prevalence of susceptibility found in P. aeruginosa isolates associated with initial infection contrasts with the high prevalence of resistance found in isolates from chronic CF lung infection. However, susceptibility in early isolates cannot be presumed. Until further data are obtained from clinically based studies, susceptibility tests should continue to be performed to assist the choice of antibiotics for treatment of early infection. PMID- 20837574 TI - Phenotypic and genetic characterization of macrolide resistance in Francisella tularensis subsp. holarctica biovar I. AB - OBJECTIVES: Francisella tularensis subsp. holarctica strains are classified as biovars I and II, which are susceptible and naturally resistant to the macrolide erythromycin, respectively. The present study was aimed at both selecting biovar I strains with increased levels of erythromycin resistance and characterizing the underlying genetic mechanisms. METHODS: Serial cultures in the presence of increasingly high erythromycin concentrations were performed to select independent high- and intermediate-level erythromycin-resistant mutants from each of three different biovar I strains. The mutants were characterized for cross resistance to several antibiotics, presence of mutations in the genes encoding the 23S rRNA and the L4 and L22 ribosomal proteins, and overexpression of efflux pumps. RESULTS: Mutants displayed cross-resistance to all macrolide compounds tested but not to other classes of antibiotics. We found mutations in domain V of the 23S rRNA gene (G2057A, A2058G, A2058T and C2611T) and in the gene encoding L22, leading to either the G91D substitution or the M82K83R84 deletion. Analysis of mutants with intermediate resistance levels obtained over the course of the selection process revealed both a positive correlation between the number of mutated ribosomal operons and the resistance level, and an additional resistance mechanism in the early steps of selection. CONCLUSIONS: We showed that high-level resistance to macrolides can be easily obtained in vitro in F. tularensis subsp. holarctica biovar I strains, thereby suggesting that in vivo selection for resistance may explain reported failures of antibiotic treatment. Ketolides were the most effective macrolides tested, which may limit the risk of selection for resistance. PMID- 20837575 TI - Assessing equity in systematic reviews: realising the recommendations of the Commission on Social Determinants of Health. PMID- 20837576 TI - The need to consider the wider agenda in systematic reviews and meta-analyses: breadth, timing, and depth of the evidence. PMID- 20837577 TI - Government confirms transfer of NHS computerisation to local bodies. PMID- 20837578 TI - Stem cell therapy doctor exploited desperate patients, GMC finds. PMID- 20837580 TI - Scheme to register Botox clinics is criticised for "lacking teeth". PMID- 20837581 TI - Keeping nitrate in the roots: an unexpected requirement for cadmium tolerance in plants. AB - Li et al. (2010) identified AtNRT1.8 as a membrane transporter involved in the control of long-distance transport of nitrate between roots and shoot. Both the regulation of AtNRT1.8 expression and the phenotype of an nrt1.8 mutant indicate that this transporter plays an important role in protecting the plant against cadmium toxicity, and possibly against a wide range of biotic and abiotic stresses. PMID- 20837582 TI - Effects and mechanisms of nonylphenol on corticosterone release in rat zona fasciculata-reticularis cells. AB - Alkylphenol ethoxylate, consisting of ~80% nonylphenol ethoxylate (NPEO), is a major group of nonionic surfactant. The primary degradation product of NPEO, nonylphenol (NP), interferes with reproduction, induces cell death in gonads, and leads to changes in other reproductive parameters. With such apparent stress, NP is believed to induce stress response mechanism, i.e., adrenal cortical hormone. However, the effects and action mechanisms of NP on rat adrenal zona fasciculata reticularis (ZFR) cells are still unclear. This study explored the effects of NP on corticosterone release. ZFR cells were incubated with NP in the presence or absence of adrenocorticotropin (ACTH), 8-bromo-cyclic 3',5'-adenosine monophosphate (8-Br-cAMP), forskolin (FSK), 25-hydroxyl cholesterol (25-OH cholesterol), pregnenolone, progesterone, or deoxycorticosterone at 37 degrees C for 1 h. The concentrations of corticosterone or pregnenolone in the spent media were measured by radioimmunoassay. The expressions of steroidogenic acute regulatory (StAR) protein, cytochrome P450 side-chain cleavage (P450scc) protein, and 11beta-hydroxylase in the cells were measured by Western blot. The data demonstrated that (1) NP stimulated corticosterone release induced by ACTH, 8-Br cAMP, FSK, 25-OH-cholesterol, pregnenolone, progesterone, or deoxycorticosterone; (2) NP significantly increased pregnenolone release in the control, 25-OH cholesterol, trilostane, and 25-OH-cholesterol + trilostane groups; (3) NP stimulated corticosterone release was estrogen receptor dependent, but mediated by nitric oxide and p38 mitogen-activated protein kinase pathway independent; and (4) NP did not affect StAR, 11beta-hydroxylase, or P450scc protein expression. These results suggest that NP acts directly on rat ZFR cells to stimulate corticosterone release and that the stimulation mechanism of NP mediates through post-cAMP corticosterone manufacture enzymes, i.e., P450scc and 11beta hydroxylase. PMID- 20837583 TI - Pediatric clinical research networks: current status, common challenges, and potential solutions. AB - OBJECTIVES: The goals were (1) to describe and to characterize pediatric clinical research networks (PCRNs) in the United States and Canada, (2) to identify PCRN strengths and weaknesses, (3) to evaluate the potential for collaboration among PCRNs, and (4) to assess untapped potential interest in PCRN participation. METHODS: Data collection included (1) initial identification of PCRNs through an Internet search and word of mouth, (2) follow-up surveys of PCRN leaders, (3) telephone interviews with 21 PCRN leaders, and (4) a survey of 43 American Academy of Pediatrics specialty leaders regarding untapped interest in network research. RESULTS: Seventy exclusively pediatric networks were identified. Of those, specialty care networks constituted the largest proportion (50%), followed by primary care (28.6%) and disease-specific (21.4%) networks. A network profile survey (response rate: 74.3%) revealed that ~90% held infrastructure funding. Nearly 75% of respondents viewed cross-network collaborations positively. In depth telephone interviews corroborated the survey data, with cross-network collaboration mentioned consistently as a theme. American Academy of Pediatrics specialty leaders indicated that up to 30% of current nonparticipants might be interested in research involvement. CONCLUSIONS: Pediatric networks exist across the care continuum. Significant numbers of uninvolved practitioners may be interested in joining PCRNs. A strong majority of network leaders cited potential benefits from network collaboration. PMID- 20837584 TI - Natural killer cell lymphoma in a pediatric patient with inflammatory bowel disease. AB - Tumor necrosis factor alpha (TNF-alpha) antibody agents are an effective therapy for the treatment of inflammatory bowel disease (IBD); however, because of the potential for immune suppression with these drugs, TNF-alpha antibody agents can increase the risk of malignancy. We report here the case of an 11-year-old boy who presented with bowel obstruction. He also had a history of periodic fever, aphthous stomatitis, and cervical adenitis (PFAPA). Intestinal inflammation continued and impaired his quality of life; he was diagnosed with IBD of an undetermined type (IBD-U). Symptoms improved with infliximab, but he developed elevated transaminase levels with hepatosplenomegaly 1 year after scheduled infusions. Skin biopsy revealed an atypical lymphoid infiltrate consistent with an Epstein-Barr virus (EBV)-positive natural killer (NK)/T-cell lymphoma with associated hemophagocytic lymphohistiocytosis. Bone marrow biopsy revealed a similar EBV-positive lymphoid infiltrate consistent with an NK/T-cell lymphoma. EBV-positive tissue was present in gastrointestinal biopsies. Flow-cytometric analysis revealed an atypical, clonal NK-cell population, and biopsy specimens from several tissue sites tested positive for CD3, CD56, and CD30. The patient died soon after the diagnosis was made. This patient developed an EBV-driven malignancy while receiving infliximab. All patients with IBD who receive infliximab should be monitored for malignancy, especially young patients. This case underscores the need for future studies to better understand the biology of lymphoproliferative disorders. PMID- 20837585 TI - Helmet versus active repositioning for plagiocephaly: a three-dimensional analysis. AB - BACKGROUND AND PURPOSE: Orthotic helmets and active repositioning are the most common treatments for deformational plagiocephaly (DP). Existing evidence is not sufficient to objectively inform decisions between these options. A three dimensional (3D), whole-head asymmetry analysis was used to rigorously compare outcomes of these 2 treatment methods. PATIENTS AND METHODS: Whole-head 3D surface scans of 70 infants with DP were captured before and after treatment by using stereophotogrammetric imaging technology. Helmeted (n=35) and nonhelmeted/actively repositioned (n=35) infants were matched for severity of initial deformity. Surfaces were spatially registered to a symmetric template, which was deformed to achieve detailed right-to-left point correspondence for every point on the head surface. A ratiometric asymmetry value was calculated for each point relative to its contralateral counterpart. Maximum and mean asymmetry values were determined. Change in mean and maximum asymmetry with treatment was the basis for group comparison. RESULTS: The helmeted group had a larger reduction than the repositioned group in both maximum (4.0% vs 2.5%; P=.02) and mean asymmetry (0.9% vs 0.5%; P=.02). The greatest difference was localized to the occipital region. CONCLUSIONS: Whole-head 3D asymmetry analysis is capable of rigorously quantifying the relative efficacy of the 2 common treatments of DP. Orthotic helmets provide statistically superior improvement in head symmetry compared with active repositioning immediately after therapy. Additional studies are needed to (1) establish the clinical significance of these quantitative differences in outcome, (2) define what constitutes pathologic head asymmetry, and (3) determine whether superiority of orthotic treatment lasts as the child matures. PMID- 20837586 TI - Heritability of apnea of prematurity: a retrospective twin study. AB - BACKGROUND: Apnea of prematurity (AOP) is a disturbance in respiratory rhythm defined by idiopathic pauses in breathing that reduce blood oxygen levels and/or heart rate. It is a major clinical problem among preterm infants. OBJECTIVES: The primary goal of this study was to estimate the genetic susceptibility to AOP in a cohort of preterm twins. A secondary aim was to identify risk factors associated with AOP in this cohort. METHODS: A single-center, retrospective study (2000 2008) was performed by using data from 317 premature twin pairs (<36 weeks' gestational age). Heritability estimates were determined by comparing intrapair AOP concordance between 56 monozygotic and 161 dizygotic twin pairs by using structural equation modeling. Risk factors of AOP among a cohort of 543 premature twins were assessed by using mixed-effects logistic regression. RESULTS: The heritability of AOP was 87% (95% confidence interval [CI]: 0.64-0.97) among same gender twins. A gender-dependent model revealed that genetic factors accounted for 99% of the variance in male twins (95% CI: 0.89-1.00) and 78% of the variance in female twins (95% CI: 0.49-0.94). Significant risk factors for AOP were low gestational age (P<.001), cesarean delivery (P=.017), and conception through assisted reproductive technologies (P=.008). CONCLUSIONS: These findings suggest that AOP has an important genetic basis underlying this developmental-related disorder of respiratory control. Future genomic studies may provide information on pathophysiological mechanisms that underlie AOP. PMID- 20837587 TI - Policy statement--recommendation for mandatory influenza immunization of all health care personnel. AB - The purpose of this statement is to recommend implementation of a mandatory influenza immunization policy for all health care personnel. Immunization of health care personnel is a critically important step to substantially reduce health care-associated influenza infections. Despite the efforts of many organizations to improve influenza immunization rates with the use of voluntary campaigns, influenza coverage among health care personnel remains unacceptably low. Mandatory influenza immunization for all health care personnel is ethically justified, necessary, and long overdue to ensure patient safety. PMID- 20837588 TI - Open-label glucocorticoids modulate dexamethasone trial results in preterm infants. AB - CONTEXT: Open-label glucocorticoids (OLGs) were often used in trials that investigated postnatal dexamethasone treatment in ventilated preterm infants. OBJECTIVE: To determine if OLG use modulates the dexamethasone treatment effect on mortality, bronchopulmonary dysplasia (BPD), and neurodevelopmental outcome. METHODS: Electronic databases, abstracts from the Pediatric Academic Societies, and results of manual reference searches were used as data sources. Fifteen randomized controlled trials comparing dexamethasone with placebo in 721 ventilated preterm infants older than 7 days were identified. The interaction between dexamethasone treatment effect and OLG use was assessed by meta regression analysis and subgroup meta-analysis according to the percentage of OLG use in the placebo group. Trials with a moderately early (7- to 14-day) or delayed (>3-week) treatment onset were analyzed separately. RESULTS: Moderately early, but not delayed, dexamethasone treatment significantly reduced mortality rates in trials with OLG use at <30% in the placebo arm. Meta-regression analysis revealed that this reduction was inversely related to OLG use. Increasing OLG use strengthened the positive effect of dexamethasone on BPD in the moderately early trials but attenuated the effect in the delayed-treatment trials. In trials with <30% OLG use, dexamethasone increased the risk for cerebral palsy in the delayed, but not the moderately early, treatment trials. CONCLUSIONS: When OLG use is taken into account moderately early dexamethasone treatment reduced mortality rates and the combined outcome mortality and BPD without increasing the risk of adverse neurodevelopmental outcome in ventilated preterm infants. A large randomized controlled trial is needed to confirm or refute these findings. PMID- 20837589 TI - Stimulant-responsive and stimulant-refractory aggressive behavior among children with ADHD. AB - OBJECTIVES: The objective of this study was to examine factors that are associated with aggression that is responsive versus refractory to individualized optimization of stimulant monotherapy among children with attention deficit/hyperactivity disorder (ADHD). METHODS: Children who were aged 6 to 13 years and had ADHD, either oppositional defiant disorder or conduct disorder, significant aggressive behavior, and a history of insufficient response to stimulants completed an open stimulant monotherapy optimization protocol. Stimulant titration with weekly assessments of behavior and tolerability identified an optimal regimen for each child. Families also received behavioral therapy. Parents completed the Retrospective-Modified Overt Aggression Scale (R MOAS) at each visit. Children were classified as having stimulant-refractory aggression on the basis of R-MOAS ratings and clinician judgment. Differences that pertained to treatment, demographic, and psychopathology between groups with stimulant monotherapy-responsive and -refractory aggression were evaluated. RESULTS: Aggression among 32 (49.3%) of 65 children was reduced sufficiently after stimulant dosage adjustment and behavioral therapy to preclude adjunctive medication. Those who responded to stimulant monotherapy were more likely to benefit from the protocol's methylphenidate preparation (once-daily, triphasic release), showed a trend for lower average dosages, and received fewer behavioral therapy sessions than did children with stimulant-refractory aggression. Boys, especially those with higher ratings of baseline aggression and of depressive and manic symptoms, more often exhibited stimulant-refractory aggression. CONCLUSIONS: Among children whose aggressive behavior develops in the context of ADHD and of oppositional defiant disorder or conduct disorder, and who had insufficient response to previous stimulant treatment in routine clinical care, systematic, well-monitored titration of stimulant monotherapy often culminates in reduced aggression that averts the need for additional agents. PMID- 20837590 TI - Changes in children's physical activity over 12 months: longitudinal results from the SPEEDY study. AB - OBJECTIVE: We measured physical activity changes among 10-year-old British children over 12 months and assessed biological and demographic determinants. METHODS: Physical activity was measured with accelerometers (counts per minute) over >=3 days at baseline and 1 year later in a prospective study of 844 children (41.6% male; mean+/-SD baseline age: 10.2+/-0.3 years) from 92 schools. Meeting physical activity recommendations was defined as >=60 minutes/day at >=2000 counts per minute. Biological (height, weight, and fat percentage) and demographic factors (gender, rural/urban home location, and socioeconomic status) were assessed at baseline. Associations between physical activity changes and multiple factors were studied. RESULTS: Physical activity decreased over 1 year (baseline: 665.7+/-209.8 counts per minute; follow-up: 623.2+/-179.2 counts per minute; P<.001), with 70.4% of children meeting physical activity recommendations at the baseline evaluation and 65.8% at the follow-up evaluation (P<.001). The decrease occurred mainly on weekends (-47.2+/-395.8 counts per minute; P=.002), with no significant change on weekdays (8.0+/-201.6 counts per minute; P=.20). Girls (P<.001), participants with greater body fat percentage (P=.001), and participants of higher socioeconomic status (P=.008) were more likely to exhibit physical activity decreases. CONCLUSIONS: Physical activity decreased over 1 year among children in primary school, predominantly during the weekend. Because these children were relatively active at baseline, prevention of physical activity decreases in childhood, particularly among girls and on weekends, may be a suitable health promotion target. PMID- 20837591 TI - Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. AB - Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41). Coadministration of clarithromycin (a potent cytochrome P450 3A4 inhibitor) for an ear infection and valproic acid for seizures since birth further prevented drug elimination from the body. This case highlights the interplay between pharmacogenetic factors, drug-drug interactions, and dose-related toxicity in a child. PMID- 20837592 TI - Basketball-related injuries in school-aged children and adolescents in 1997-2007. AB - OBJECTIVE: The objective was to determine national patterns of basketball-related injuries treated in emergency departments in the United States among children and adolescents <20 years of age. METHODS: A retrospective analysis was conducted with data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission, from 1997 to 2007. Sample weights provided by the Consumer Product Safety Commission were used to calculate national estimates of basketball-related injuries. Trend significance of the numbers and rates of basketball-related injuries over time was analyzed by using linear regression. RESULTS: An estimated 4 128 852 pediatric basketball-related injuries were treated in emergency departments. Although the total number of injuries decreased during the study period, the number of traumatic brain injuries (TBIs) increased by 70%. The most common injury was a strain or sprain to the lower extremities (30.3%), especially the ankle (23.8%). Boys were more likely to sustain lacerations and fractures or dislocations. Girls were more likely to sustain TBIs and to injure the knee. Older children (15-19 years of age) were 3 times more likely to injure the lower extremities. Younger children (5-10 years of age) were more likely to injure the upper extremities and to sustain TBIs and fractures or dislocations. CONCLUSIONS: Although the total number of basketball-related injuries decreased during the 11-year study period, the large number of injuries in this popular sport is cause for concern. PMID- 20837593 TI - Parents' decision-making in newborn screening: opinions, choices, and information needs. AB - OBJECTIVE: Our objective was to describe how parents consider disease and test characteristics when making decisions about newborn screening. METHODS: We conducted focus groups with parents from primary care clinics and interviews of parents from a genetics clinic (total of 45 participants). Participants discussed 7 vignettes about newborn screening that we developed and refined with the assistance of an expert panel. Two coders coded the data independently, compared coding, and resolved disagreements through discussion. Using framework analysis, we analyzed the data and identified how parents' preferences varied according to disease characteristics, test characteristics, and perceptions of the associated risks and benefits. RESULTS: Study participants strongly supported population wide screening for disorders with well-defined, effective treatments, even if the treatment (eg, a bone marrow transplant) had significant morbidity. However, particularly among primary care clinic participants, there were more-varied preferences and greater difficulty making decisions about disorders associated with older age at onset, less-accurate screening tests, or less-effective treatment. In those cases, many participants suggested optional screening. For all disorders, participants expressed a desire for more information to facilitate decision-making. CONCLUSIONS: Participants supported newborn screening for treatable disorders but suggested optional screening for other disorders. The variable influences on parents' decision-making suggest that parents with diverse experiences, if they were included in decision-making regarding screening policies, could provide critical perspectives and help screening programs address parents' preferences and meet parents' information needs. PMID- 20837594 TI - Prenatal and infant exposure to thimerosal from vaccines and immunoglobulins and risk of autism. AB - OBJECTIVE: Exposure to thimerosal, a mercury-containing preservative that is used in vaccines and immunoglobulin preparations, has been hypothesized to be associated with increased risk of autism spectrum disorder (ASD). This study was designed to examine relationships between prenatal and infant ethylmercury exposure from thimerosal-containing vaccines and/or immunoglobulin preparations and ASD and 2 ASD subcategories: autistic disorder (AD) and ASD with regression. METHODS: A case-control study was conducted in 3 managed care organizations (MCOs) of 256 children with ASD and 752 controls matched by birth year, gender, and MCO. ASD diagnoses were validated through standardized in-person evaluations. Exposure to thimerosal in vaccines and immunoglobulin preparations was determined from electronic immunization registries, medical charts, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We used conditional logistic regression to assess associations between ASD, AD, and ASD with regression and exposure to ethylmercury during prenatal, birth-to-1 month, birth-to-7-month, and birth-to-20-month periods. RESULTS: There were no findings of increased risk for any of the 3 ASD outcomes. The adjusted odds ratios (95% confidence intervals) for ASD associated with a 2 SD increase in ethylmercury exposure were 1.12 (0.83-1.51) for prenatal exposure, 0.88 (0.62-1.26) for exposure from birth to 1 month, 0.60 (0.36-0.99) for exposure from birth to 7 months, and 0.60 (0.32-0.97) for exposure from birth to 20 months. CONCLUSIONS: In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs. PMID- 20837595 TI - Ethics rounds. Symbolic resuscitation, medical futility, and parental rights. PMID- 20837596 TI - Retinol status of newborn infants is associated with congenital diaphragmatic hernia. AB - OBJECTIVE: Genetic analyses in humans suggest a role for retinoid-related genes in the pathogenesis of congenital diaphragmatic hernia (CDH). The goal of this study was to investigate the vitamin A status of mothers and their newborns in association with CDH. METHODS: We conducted a hospital-based, case-control study with 22 case and 34 control mothers and their newborns. In maternal and cord blood samples, retinol and retinol-binding protein (RBP) levels were measured with high-performance liquid chromatography and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate logistic regression analyses were performed to determine crude and adjusted risk estimates. RESULTS: Case newborns had significantly lower levels of retinol (0.60 vs 0.76 MUmol/L; P=.003) and RBP (5.42 vs 7.11 mg/L; P=.02) than did control newborns. The multivariate logistic regression analysis showed lower levels of retinol and RBP in association with CDH risk; the odds ratio for retinol levels of <15th percentile (<0.61 MUmol/L) was 11.11 (95% confidence interval: 2.54-48.66; P=.001), and that for RBP levels of <15th percentile (<4.54 mg/L) was 4.00 (95% confidence interval: 1.00-15.99; P=.05). Retinol and RBP levels were not different between case and control mothers. CONCLUSIONS: CDH is strongly associated with low retinol and RBP levels in newborns, independent of maternal retinol status. This is an important finding supporting the idea that human CDH is linked with abnormal retinoid homeostasis. PMID- 20837597 TI - Dietary nucleotides and early growth in formula-fed infants: a randomized controlled trial. AB - BACKGROUND: Dietary nucleotides are nonprotein nitrogenous compounds that are found in high concentrations in breast milk and are thought to be conditionally essential nutrients in infancy. A high nucleotide intake has been suggested to explain some of the benefits of breastfeeding compared with formula feeding and to promote infant growth. However, relatively few large-scale randomized trials have tested this hypothesis in healthy infants. OBJECTIVE: We tested the hypothesis that nucleotide supplementation of formula benefits early infant growth. PATIENTS AND METHODS: Occipitofrontal head circumference, weight, and length were assessed in infants who were randomly assigned to groups fed nucleotide-supplemented (31 mg/L; n=100) or control formula without nucleotide supplementation (n=100) from birth to the age of 20 weeks, and in infants who were breastfed (reference group; n=101). RESULTS: Infants fed with nucleotide supplemented formula had greater occipitofrontal head circumference at ages 8, 16, and 20 weeks than infants fed control formula (mean difference in z scores at 8 weeks: 0.4 [95% confidence interval: 0.1-0.7]; P=.006) even after adjustment for potential confounding factors (P=.002). Weight at 8 weeks and the increase in both occipitofrontal head circumference and weight from birth to 8 weeks were also greater in infants fed nucleotide-supplemented formula than in those fed control formula. CONCLUSIONS: Our data support the hypothesis that nucleotide supplementation leads to increased weight gain and head growth in formula-fed infants. Therefore, nucleotides could be conditionally essential for optimal infant growth in some formula-fed populations. Additional research is needed to test the hypothesis that the benefits of nucleotide supplementation for early head growth, a critical period for brain growth, have advantages for long-term cognitive development. PMID- 20837598 TI - Secretory phospholipase A2-IIa is involved in prostate cancer progression and may potentially serve as a biomarker for prostate cancer. AB - The majority of prostate cancers are indolent, whereas a significant portion of patients will require systemic treatment during the course of their disease. To date, only high Gleason scores are best associated with a poor prognosis in prostate cancer. No validated serum biomarker has been identified with prognostic power. Previous studies showed that secretory phospholipase A2-IIa (sPLA2-IIa) is overexpressed in almost all human prostate cancer specimens and its elevated levels are correlated with high tumor grade. Here, we found that sPLA2-IIa is overexpressed in androgen-independent prostate cancer LNCaP-AI cells relative to their androgen-dependent LNCaP cell counterparts. LNCaP-AI cells also secrete significantly higher levels of sPLA2-IIa. Blocking sPLA2-IIa function compromises androgen-independent cell growth. Inhibition of the ligand-induced signaling output of the HER network, by blocking PI3K-Akt signaling and the nuclear factor kappaB (NF-kappaB)-mediated pathway, compromises both sPLA2-IIa protein expression and secretion, as a result of downregulation of sPLA2-IIa promoter activity. More importantly, we demonstrated elevated serum sPLA2-IIa levels in prostate cancer patients. High serum sPLA2-IIa levels are associated significantly with high Gleason score and advanced disease stage. Increased sPLA2 IIa expression was confirmed in prostate cancer cells, but not in normal epithelium and stroma by immunohistochemistry analysis. We showed that elevated signaling of the HER/HER2-PI3K-Akt-NF-kappaB pathway contributes to sPLA2-IIa overexpression and secretion by prostate cancer cells. Given that sPLA2-IIa overexpression is associated with prostate development and progression, serum sPLA2-IIa may serve as a prognostic biomarker for prostate cancer and a potential surrogate prostate biomarker indicative of tumor burden. PMID- 20837599 TI - EpCAM in carcinogenesis: the good, the bad or the ugly. AB - The epithelial cell adhesion molecule (EpCAM) is a membrane glycoprotein that is highly expressed on most carcinomas and therefore of potential use as a diagnostic and prognostic marker for a variety of carcinomas. Interestingly, EpCAM is explored as target in antibody-based therapies. Recently, EpCAM has been identified as an additional marker of cancer-initiating cells. In this review, we describe the controversial biological role of EpCAM with the focus on carcinogenesis: as an adhesion molecule, EpCAM mediates homophilic adhesion interactions, which in turn might prevent metastasis. On the other hand, EpCAM abrogates E-cadherin mediated cell-cell adhesion thereby promoting metastasis. Also, upon cleavage of EpCAM, the intracellular domain functions as a part of a transcriptional complex inducing c-myc and cyclin A and E. In line with these seemingly controversial roles, EpCAM overexpression has been associated with both decreased and increased survival of patients. Similarly, either induction or downregulation of EpCAM expression lowers the oncogenic potential depending on the cell type. As epigenetic dysregulation underlies aberrant EpCAM expression, we propose epigenetic editing as a novel approach to investigate the biological role of EpCAM, expanding the options for EpCAM as a therapeutic target in cancer. PMID- 20837601 TI - Quality assurance and quality control for thoron measurement at NIRS. AB - The National Institute of Radiological Sciences (NIRS) has developed passive radon ((222)Rn)-thoron ((220)Rn) discriminative detectors for a large-scale survey and has established a thoron chamber to calibrate such detectors. In order to establish quality assurance and quality control for the (220)Rn measurement at NIRS, intercomparison studies have been carried out. The intercomparisons using a scintillation cell method, which has been used as a standard for (220)Rn measurement at NIRS, were conducted at New York University (NYU, USA) and Physikalisch-Technische Bundesanstalt (PTB, Germany). As a result, it was found that the result from the NIRS was in good agreement with that from the NYU. On the other hand, it was observed that the relative discrepancy between the (220)Rn concentrations from the NIRS and PTB monitors was, on average, >50 %. Using the NIRS (220)Rn chamber, the international intercomparison experiment for passive (220)Rn detectors started in 2008. PMID- 20837600 TI - Novel mechanism of regulation of the DNA repair enzyme OGG1 in tuberin-deficient cells. AB - Tuberin (protein encodes by tuberous sclerosis complex 2, Tsc2) deficiency is associated with the decrease in the DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) in tumour kidney of tuberous sclerosis complex (TSC) patients. The purpose of this study was to elucidate the mechanisms by which tuberin regulates OGG1. The partial deficiency in tuberin expression that occurs in the renal proximal tubular cells and kidney cortex of the Eker rat is associated with decreased activator protein 4 (AP4) and OGG1 expression. A complete deficiency in tuberin is associated with loss of AP4 and OGG1 expression in kidney tumour from Eker rats and the accumulation of significant levels of 8-oxo-deoxyguanosine. Knockdown of tuberin expression in human renal epithelial cells (HEK293) with small interfering RNA (siRNA) also resulted in a marked decrease in the expression of AP4 and OGG1. In contrast, overexpression of tuberin in HEK293 cells increased the expression of AP4 and OGG1 proteins. Downregulation of AP4 expression using siRNA resulted in a significant decrease in the protein expression of OGG1. Immunoprecipitation studies show that AP4 is associated with tuberin in cells. Gel shift analysis and chromatin immunoprecipitation identified the transcription factor AP4 as a positive regulator of the OGG1 promoter. AP4 DNA-binding activity is significantly reduced in Tsc2(-/-) as compared with Tsc2(+/+) cells. Transcriptional activity of the OGG1 promoter is also decreased in tuberin-null cells compared with wild-type cells. These data indicate a novel role for tuberin in the regulation of OGG1 through the transcription factor AP4. This regulation may be important in the pathogenesis of kidney tumours in patients with TSC disease. PMID- 20837602 TI - Separately measuring radon and thoron concentrations exhaled from soil using AlphaGUARD and liquid scintillation counter methods. AB - It was shown that radon and thoron concentrations exhaled from soil were separately measured using the AlphaGUARD and liquid scintillation counter (LSC) methods. The thoron concentrations from the RAD 7 were used to create the conversion equation to calculate thoron levels with the AlphaGUARD. However, the conversion factor was found to depend on the air flow rate. When air containing thoron of ~60 kBq m(-3) was fed to the scintillation cocktail, thoron and thoron progeny could not be measured with the LSC method. The radon concentration of about 10 kBq m(-3) was measured with three methods, first with the LSC method and then with two AlphaGUARDs (one in the diffusion mode and the other in the flow mode (0.5 l min(-1))). There were no significant differences between these results. Finally, it was shown that the radon and thoron concentrations in air could be measured with the AlphaGUARD and LSC methods. PMID- 20837603 TI - Estimation of the neutrality index. AB - The McDonald-Kreitman (MK) test is a simple and widely used test of selection in which the numbers of nonsilent and silent substitutions (D(n) and D(s)) are compared with the numbers of nonsilent and silent polymorphisms (P(n) and P(s)). The neutrality index (NI = D(s)P(n)/D(n)P(s)), the odds ratio (OR) of the MK table, measures the direction and degree of departure from neutral evolution. The mean of NI values across genes is often taken to summarize patterns of selection in a species. Here, we show that this leads to statistical bias in both simulated and real data to the extent that species, which show a pattern of adaptive evolution, can apparently be subject to weak purifying selection and vice versa. We show that this bias can be removed by using a variant of the Cochran-Mantel Haenszel procedure for estimating a weighted average OR. We also show that several point estimators of NI are statistically biased even when cutoff values are employed. We therefore suggest that a new statistic be used to study patterns of selection when data are sparse, the direction of selection: DoS = D(n)/(D(n) + D(s)) - P(n)/(P(n) + P(s)). PMID- 20837605 TI - Maintenance of fungal pathogen species that are specialized to different hosts: allopatric divergence and introgression through secondary contact. AB - Sympatry of species that lack complete prezygotic isolation is ideal for the study of how species can be maintained in the face of potential gene flow. This is particularly important in the context of emerging diseases on new hosts because pathogen adaptation is facilitated by reduced gene flow from ancestral populations. Here, we investigated divergence and gene flow between two closely related fungal species, Microbotryum lychnidis-dioicae and M. silenes-dioicae, causing anther-smut disease on the wide-spread plant species Silene latifolia and S. dioica, respectively. Using model-based clustering algorithms on microsatellite data from samples across Europe, we identified rare disease transmission between the host species and rare pathogen hybrids. Using a coalescent-based approach and an isolation-with-migration model, the age of divergence between the two fungal species was estimated at approximately 4.2 * 10(5) years. Levels of gene flow were low and concentrated in very recent times. In addition, gene flow appeared unidirectional from M. silenes-dioicae to M. lychnidis-dioicae. Altogether, our findings are consistent with a scenario of recurrent introgressive hybridization but at a very low level and through secondary contact following initial divergence in allopatry. Asymmetry in the direction of gene flow mirrors previous findings on introgression between the two host plants. Our study highlights the consequences of bringing closely related pathogens into contact, which is increasing through modern global changes and favors cross-species disease transmission, hybridization, and introgression by pathogens. PMID- 20837604 TI - Chromosomal inversions, natural selection and adaptation in the malaria vector Anopheles funestus. AB - Chromosomal polymorphisms, such as inversions, are presumably involved in the rapid adaptation of populations to local environmental conditions. Reduced recombination between alternative arrangements in heterozygotes may protect sets of locally adapted genes, promoting ecological divergence and potentially leading to reproductive isolation and speciation. Through a comparative analysis of chromosomal inversions and microsatellite marker polymorphisms, we hereby present biological evidence that strengthens this view in the mosquito Anopheles funestus s.s, one of the most important and widespread malaria vectors in Africa. Specimens were collected across a wide range of geographical, ecological, and climatic conditions in Cameroon. We observed a sharp contrast between population structure measured at neutral microsatellite markers and at chromosomal inversions. Microsatellite data detected only a weak signal for population structuring among geographical zones (F(ST) < 0.013, P < 0.01). By contrast, strong differentiation among ecological zones was revealed by chromosomal inversions (F(ST) > 0.190, P < 0.01). Using standardized estimates of F(ST), we show that inversions behave at odds with neutral expectations strongly suggesting a role of environmental selection in shaping their distribution. We further demonstrate through canonical correspondence analysis that heterogeneity in eco geographical variables measured at specimen sampling sites explained 89% of chromosomal variance in A. funestus. These results are in agreement with a role of chromosomal inversions in ecotypic adaptation in this species. We argue that this widespread mosquito represents an interesting model system for the study of chromosomal speciation mechanisms and should provide ample opportunity for comparative studies on the evolution of reproductive isolation and speciation in major human malaria vectors. PMID- 20837606 TI - Extended Y chromosome investigation suggests postglacial migrations of modern humans into East Asia via the northern route. AB - Genetic diversity data, from Y chromosome and mitochondrial DNA as well as recent genome-wide autosomal single nucleotide polymorphisms, suggested that mainland Southeast Asia was the major geographic source of East Asian populations. However, these studies also detected Central-South Asia (CSA)- and/or West Eurasia (WE)-related genetic components in East Asia, implying either recent population admixture or ancient migrations via the proposed northern route. To trace the time period and geographic source of these CSA- and WE-related genetic components, we sampled 3,826 males (116 populations from China and 1 population from North Korea) and performed high-resolution genotyping according to the well resolved Y chromosome phylogeny. Our data, in combination with the published East Asian Y-haplogroup data, show that there are four dominant haplogroups (accounting for 92.87% of the East Asian Y chromosomes), O-M175, D-M174, C-M130 (not including C5-M356), and N-M231, in both southern and northern East Asian populations, which is consistent with the proposed southern route of modern human origin in East Asia. However, there are other haplogroups (6.79% in total) (E SRY4064, C5-M356, G-M201, H-M69, I-M170, J-P209, L-M20, Q-M242, R-M207, and T M70) detected primarily in northern East Asian populations and were identified as Central-South Asian and/or West Eurasian origin based on the phylogeographic analysis. In particular, evidence of geographic distribution and Y chromosome short tandem repeat (Y-STR) diversity indicates that haplogroup Q-M242 (the ancestral haplogroup of the native American-specific haplogroup Q1a3a-M3) and R M207 probably migrated into East Asia via the northern route. The age estimation of Y-STR variation within haplogroups suggests the existence of postglacial (~18 Ka) migrations via the northern route as well as recent (~3 Ka) population admixture. We propose that although the Paleolithic migrations via the southern route played a major role in modern human settlement in East Asia, there are ancient contributions, though limited, from WE, which partly explain the genetic divergence between current southern and northern East Asian populations. PMID- 20837607 TI - Patient-provider communication and human papillomavirus vaccine acceptance. AB - The authors performed telephone interviews of parents of adolescents (n = 430) and their older adolescents (n = 208) in Monroe County, New York to measure parent and adolescent acceptance of human papillomavirus (HPV) vaccine, its association with ratings of provider communication, and vaccine-related topics discussed with the adolescent's provider. More than half of adolescent girls had already received an HPV vaccination, with fewer than one quarter refusing. Parent and teen ratings of provider communication was high, and not related to HPV vaccine refusal. Parents were more likely to refuse if they were Hispanic (odds ratio [OR] = 5.88, P = .05) or did not consider vaccines "very safe" (OR = 2.76, P = .04). Most parents of boys (85%) believed males should be given HPV vaccine if recommended. Few parents and teens recalled discussing that vaccination does not preclude future Pap smear testing. Providers should address cultural and vaccine safety concerns in discussions about HPV vaccine. PMID- 20837608 TI - Asperger's disorder in an adolescent With 47,XYY chromosomal syndrome. PMID- 20837609 TI - Family perspectives on home oral health practices and interactions with pediatric providers. PMID- 20837610 TI - Clinical features of a Dutch cohort of critically ill children due to the 2009 new influenza A H1N1 pandemic. AB - OBJECTIVE: This study describes the clinical course, treatment, and outcome of 13 critically ill children due to infection with new influenza A H1N1, admitted to 2 pediatric intensive care units (PICUs) in the northwestern part of the Netherlands. METHODS: Retrospective case series, conducted in 2 PICUs in Amsterdam, the Netherlands. RESULTS: A total of 13 children with a new influenza A H1N1 infection were admitted at 2 Dutch PICUs. The majority of these children were 12 to 16 years old and had an underlying disease. All children required mechanical ventilatory support. Shock was present in 7 of 13 (54%) children. Two children were transferred to a supraregional PICU with facilities for extracorporeal membrane oxygenation. CONCLUSIONS: In a Dutch cohort of 13 critically ill children due to infection with new influenza (H1N1), respiratory (100%) and circulatory (54%) failure characterized the course of this infection in most of these children. All children survived. PMID- 20837611 TI - Late-onset sensorineural hearing loss due to asymptomatic congenital cytomegalovirus infection retrospectively diagnosed by polymerase chain reaction using preserved umbilical cord. PMID- 20837612 TI - Patient handoffs: pediatric resident experiences and lessons learned. AB - BACKGROUND: Within pediatrics, there is a paucity of data on pediatric resident handoff systems. METHODS: Seventy-seven of 139 eligible pediatric housestaff participated in a cross-sectional survey that was distributed at an annual residency fall retreat in September 2007. RESULTS: Seventy-three percent of the respondents noted uncertainty regarding patient care plans due to receipt of an incomplete verbal handoff. Nursing questions, phone, and page interruptions were noted barriers to giving an effective verbal sign-out. Personal fatigue was also reported to affect the accuracy of housestaff's written sign-outs more than verbal sign-outs (43% vs 23%, P = .026). Only 19% of the residents reported that written sign-outs were reflective of current patient information and care plans. CONCLUSION: Written and verbal patient handoffs were perceived by pediatric housestaff to be important parts of patient care but often incomplete. New systems that provide a more protected handoff environment, reduce housestaff fatigue, and standardize the handoff procedure may be useful. PMID- 20837613 TI - Tularemia: retrospective review of 10 years' experience in Arkansas. AB - PURPOSE: The purpose of this study is to review all cases of tularemia, a tick borne illness, among inpatients at Arkansas Children's Hospital (ACH) from 1996 2006 to discuss clinical presentation, diagnosis and treatment. Records of the Infectious Disease Section were reviewed to identify cases of suspected or proven tularemia. RESULTS: Seventeen patients presented with ulceroglandular tularemia and thirteen with glandular disease. Most patients had been ill for 10-14 days prior to admission and were evaluated at least once by another physician. Serology was positive in 77% of patients, including several positive on convalescent testing alone. Most patients responded well to treatment with gentamicin. CONCLUSIONS: This series emphasizes the importance of tularemia as an early consideration among children with fever and lymphadenopathy in Arkansas. Convalescent serology is an important tool, as many patients will remain seronegative early in illness. Gentamicin remains effective treatment and should be considered first-line therapy for suspected tularemia. PMID- 20837614 TI - Missed diagnosis of an infant with a skull fracture. PMID- 20837615 TI - Use of body mass index and body mass index growth charts for assessment of childhood weight status in the United States: a systematic review. PMID- 20837616 TI - Early death perception in adolescence: identifying factors associated with change from pessimism to optimism about life expectancy. AB - US teens overestimate risk for early death. The purpose of this study was to identify factors associated with an adolescent's change from early death perception to a belief in living into adulthood. Data are from 9140 adolescents participating in waves 1 (1995) and 2 (1996) of the National Longitudinal Study of Adolescent Health. Logistic regression models were used to determine contexts of healthy and unhealthy change associated with the likelihood of early death perception change. Youth report of increased caring and connection to other adults and increased self-esteem were associated with greater likelihood of moving from pessimism to optimism about life expectancy (P = .003 and P = .038, respectively). Reductions in self-esteem and poorer perception of health were associated with decreased odds of death perception change (P = .017 and P = .011, respectively). Nurturing positive connections with adults and strategies that improve a youth's self-esteem offer 2 opportunities to facilitate adolescent early death perception change. PMID- 20837617 TI - Neonatal outcomes of Pierre Robin sequence: an institutional experience. AB - OBJECTIVE: The aim of this study was to characterize the outcomes of one institute's experience regarding upper airway and feeding management in Pierre Robin sequence (PRS) neonates. STUDY DESIGN: A retrospective review of 33 neonates was performed. Average daily weight gain for all patients and average length of stay for each group was calculated and the results were compared using Student's t test. RESULT: Average daily weight gain was 16.5 g in the mandibular distraction osteogenesis (MDO) group (MDO; N = 12) and 5.6 g in the nonsurgical intervention (NSI) group (N = 18; P = .043). Average length of stay was longer in the MDO group (P = .01). In all, 67% of MDO patients were discharged with total PO (per os) feeds compared with 22% of NSI patients. CONCLUSION: Neonates with PRS who do not require surgical airway intervention are more likely to require assisted feeding, have slower weight gain, and a shorter average hospital stay compared to neonates undergoing mandibular MDO. PMID- 20837618 TI - Which sources of child health advice do parents follow? AB - BACKGROUND: Parents consult other child health information sources in addition to the pediatrician. There are little data describing which of these sources parents are likely to follow. METHODS: The authors surveyed 543 parents of patients in 6 pediatric practices in southeast Michigan shortly after an office visit to determine the degree to which parents report following advice from 7 common child health sources on a scale from 1 (don't follow at all) to 7 (follow completely). RESULTS: Pediatrician advice was more completely followed than other sources with mothers a distant second. Although 96% of parents used the Internet to find child health information, few followed most of the advice found there. White parents were 3 times more likely than African Americans to follow advice from television and newspapers. CONCLUSION: Parents rely on child health advice from the pediatrician and their mother. Other sources are consulted but not widely followed. PMID- 20837619 TI - Disseminated cutaneous varicella zoster virus infections during infliximab therapy for Crohn's disease: case report of two pediatric patients at one institution. PMID- 20837620 TI - Growth failure due to inhaled corticosteroid therapy. PMID- 20837621 TI - Most common sports-related injuries in a pediatric emergency department. AB - BACKGROUND: Participation in sports is a popular activity for children across the country. Prevention of sports-related injuries can be improved if details of injuries are documented and studied. METHODS: A retrospective medical record review of injuries that occurred as a direct result of sports participation (both organized and non-organized play) from November 2006 to November 2007. Because the vast majority of injuries were a result of participation in football or basketball, these injuries were focused upon. The injuries specifically examined were closed head injury (CHI), lacerations and fractures. RESULTS: There were 350 football and 196 basketball injuries (total 546). Comparing injuries between the two groups fractures were found to be more prevalent in football compared to basketball (z = 2.14; p = 0.03; 95%CI (0.01, 0.16)). Lacerations were found to be less prevalent among helmeted patients than those without helmets. (z = 2.39; p = 0.02; 95%CI (-0.17,-0.03)). CHI was more prevalent among organized play compared to non-organized (z = 3.9; p<0.001; 95%CI (0.06, 0.16)). Among basketball related visits, non-organized play had a higher prevalence of injury compared to organized play. (z = 2.87; p = 0.004; 95% CI (0.04, 0.21)). Among football related visits, organized play had a higher prevalence of injury compared to non organized play (z = 2.87; p = 0.004; 95%CI (0.04.0.21)). No differences in fracture or laceration prevalence were found between organized and non-organized play. CONCLUSIONS: Football and basketball related injuries are common complaints in a pediatric Emergency Department. Frequently seen injuries include CHI, fractures and lacerations. In our institution, fractures were more prevalent among football players and CHI was more prevalent among organized sports participants. PMID- 20837622 TI - Hypertriglyceridemia in a pediatric referral practice: experience with 300 patients. AB - BACKGROUND: Pediatric hypertriglyceridemia is an emerging comorbidity of childhood obesity. METHODS: This study reviewed medical records retrospectively to describe the characteristics and clinical course of 300 at-risk children followed in a pediatric preventive cardiology clinic. RESULTS: Average baseline triglyceride (TG) level was 269 mg/dL (SD 342 mg/dL); 91% had TG levels between 150 and 399 mg/dL. A total of 77% were overweight/obese, 23% had elevated blood pressure, 23% had a family history of high triglycerides, and 11% reported a psychiatric diagnosis (33.3% of those with severe TG elevations). Diet and activity change were the first-line therapies; few were taking lipid-lowering medications (baseline, 5.1%; follow-up, 11.4%). TG levels declined by 23% (average, 88 mg/dL; SD 231), often with a decline or plateau in TG risk category. Children with a lower body mass index (<85% gender- and age-matched percentile) were more likely to improve in TG category than heavier children (70% vs 40%; P <= .05). PMID- 20837623 TI - The teenager with asymptomatic proteinuria: think orthostatic first. PMID- 20837625 TI - Changing overweight Latino preadolescent body mass index: the effect of the parent-child dyad. AB - BACKGROUND: Latino children are disproportionately burdened by obesity. OBJECTIVE: To assess whether body mass index (BMI) change in preadolescents reflected that of their participating parent. METHODS: A total of 72 Latino overweight/obese preadolescents (BMI >= 85%) and a parent participated in a randomized controlled trial. The intervention group received 5 monthly 60-minute sessions at a recreation center (group physical activity, goal setting). The control group received 2 standard-of-care clinic visits plus a group discussion. RESULTS: Between baseline and 6-month follow-up, 47% of children (mean change = 0.37, SD = 2.48) and 63% of parents (mean change = -0.88, SD = 3.53) decreased their BMI. Parent-child dyad BMI change was significantly correlated (r = .53, P = .001). In linear modeling, those preadolescents in the control group were more likely to lose absolute BMI units (-0.96, P = .03); whereas those who had parents who gained BMI over the time interval were more likely to increase their BMI (0.17, P = .008). CONCLUSIONS: Obesity interventions should focus on the parent child dyad. PMID- 20837624 TI - Little Leaguer's shoulder. PMID- 20837626 TI - Observations in psychotropic medication usage in patients with behavior disorders presenting to a specialty clinic. AB - In recent decades, national and international surveys have reported increased usage of psychotropic medications in children. A review of the computerized clinic records for 709 children seen in a behavioral specialty clinic from January 2001 to December 2007, inclusive, in a rural US state was completed. The number of children diagnosed with disruptive behavior disorder/behavior management issues increased over the 7-year period, but this was balanced by an increased number of referrals. The number of children referred over the 7-year period increased from 77 in 2001 to 127 in 2006, a 39% increase. The overall percentage of children on medications at time of first visit showed some variability, but it did not increase over the years 2001 to 2007. The results of this study suggest that the previously reported increase in psychotropic medication usage in pediatric patients is not consistent across all diagnostic categories or in all regions of the United States. PMID- 20837627 TI - Self-management of older adolescents with inflammatory bowel disease: a pilot study of behavior and knowledge as prelude to transition. AB - OBJECTIVE: Patients gradually assume responsibility for self-management. This study sought to determine whether adolescents with inflammatory bowel disease (IBD) have developed key skills of self-management prior to the age at which many transfer to adult care. PATIENTS AND METHODS: Adolescents aged 16 to 18 years old in the Children's Hospital Boston IBD database (94 total) received a mailed survey assessing knowledge and confidence of their own health information and behaviors. RESULTS: Respondents (43%) could name medication and dose with confidence but had very poor knowledge of important side effects. Most patients deferred responsibility mostly or completely to parents for scheduling appointments (85%), requesting refills (75%), or contacting provider between visits (74%). CONCLUSIONS: Older adolescents with IBD have good recall of medications but not of side effects. Parents remain responsible for the majority of tasks related to clinic visits and the acquisition of medications. PMID- 20837628 TI - Improving the prevention, early recognition, and treatment of pediatric obesity by primary care physicians. AB - To determine if participation in a learning collaborative (LC) would improve care processes for prevention, early recognition, and treatment of childhood obesity by primary care physicians (PCP), the authors conducted pre-post evaluations of the use of obesity related care processes by 18 primary care practices following participation in a 9-month LC based on the Model for Improvement. Prior to the LC, chart audits revealed that 55% of patients had a BMI recorded; this rose to 97% of patients at its conclusion. Following the LC, 11 practices had implemented systematic prevention advice to parents of infants compared with 3 prior to the LC. All practices developed plans for evaluation and management of children with an elevated BMI. Participation in an LC increased the number of primary care practices that provided anticipatory guidance regarding obesity prevention and that identified and treated overweight or obese children. PMID- 20837629 TI - Iron-deficiency anemia associated with hiatal hernia: case reports and literature review. PMID- 20837630 TI - Management of aminoglycosides in the intensive care unit. AB - Antibacterial resistance is increasing throughout the world, while the development of new agents is slowly progressing. In addition, the increasing prevalence of fluoroquinolone resistance may force many practitioners to choose an aminoglycoside agent in gram-negative regimens. Aminoglycosides are bactericidal agents with potent activity against gram-negative infections and activity against gram-positive infections when added to a cell wall active antimicrobial-based regimen. These agents may be dosed multiple times a day or consolidated as high-dose, extended-interval dosing to maximize pharmacokinetic and pharmacodynamic properties to achieve possible improved efficacy with reduced toxicity. Clinical application includes the treatment of bacteremia, endocarditis, health-care and nosocomial pneumonias, intra-abdominal infections, and others. Nephrotoxicity and ototoxicity are potential risks of aminoglycoside therapy that may be minimized with serum monitoring and short courses of therapy. PMID- 20837631 TI - Preliminary experience with clevidipine in the pediatric population. AB - Clevidipine is a third-generation calcium channel antagonist of the dihydropyridine group. Like nicardipine, its primary physiologic effect is vasodilation, primarily of the arterial system with limited effects on capacitance vessels. Unlike other direct-acting vasodilators, it has an ultrashort half-life due to its metabolism by nonspecific blood and tissue esterases. To date, the majority of clinical experience with clevidipine has been in the adult cardiac surgery population, with no reports regarding its use in the pediatric population. We retrospectively reviewed our preliminary experience with the use of this novel agent in a cohort of 10 pediatric-aged patients ranging in age from 9 to 18 years. The indications for the use of clevidipine included control of perioperative hypertension in 4 patients, to provide controlled hypotension during orthopedic surgical procedures in 5 patients, and to improve distal perfusion during a toe-to-finger implant in 1 patient. One patient who presented to the operating room with hypertension received clevidipine preoperatively, intraoperatively, and postoperatively; 7 other patients received clevidipine only intraoperatively while the other 2 patients received clevidipine intraoperatively and postoperatively. The clevidipine infusion was started at 0.5 to 1 MUg/kg per minute and titrated up to 3.5 MUg/kg per minute as needed. No excessive hypotension was noted; however, intermittent doses of metoprolol were required to control reflex tachycardia in 2 of the 10 patients and an elevated triglyceride level was noted in 1 patient. Our preliminary experience demonstrates the efficacy of clevidipine for blood pressure control during the perioperative period. PMID- 20837632 TI - Antimicrobial treatment and clinical outcomes of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. AB - OBJECTIVES: Carbapenem-resistant (CR) Acinetobacter baumannii is an important pathogen in ventilator-associated pneumonia (VAP), but therapeutic options are limited. We describe the clinical outcomes of the largest case series of CR Acinetobacter VAP reported to date. METHODS: A retrospective analysis of 55 participants with CR-Acinetobacter VAP from July 2004 to December 2007 was undertaken. The primary endpoint was clinical response or microbiological eradication. Secondary endpoint was treatment-associated nephrotoxicity defined as >= 50% increase in serum creatinine or an increase of >= 0.5 mg/dL during therapy. RESULTS: Forty-two (76.4%) participants achieved clinical response at the completion of therapy. Clinical responses were achieved in 60.0% of sulbactam based, 66.7% of polymyxin-based, 77.8% of aminoglycoside-based, 80.6% of minocycline-based, and 90.0% of tigecycline-based regimens. Follow-up sputum cultures were available in 6 of 10 tigecycline-treated participants with 4 of 6 isolates developing intermediate resistance to tigecycline while on therapy. Ten (18.2%) participants without preexisting renal disease developed treatment associated nephrotoxicity. Baseline serum creatinine was 0.9 +/- 0.1 mg/dL (range: 0.6-1.0 mg/dL) at the start of therapy and peaked at 1.9 +/- 0.5 mg/dL (range: 1.6-3.0 mg/dL) during therapy. After excluding other potential concomitant renal toxic agents, nephrotoxicity developed in 6 of 30 (20.0%) and 4 of 7 (57.1%) participants treated with an aminoglycoside-or polymyxin-based regimen, respectively. CONCLUSIONS: Our results demonstrated that CR Acinetobacter VAP can be effectively treated with second-line agents. However, colistin-related nephrotoxicity was much higher than recently reported and decreased susceptibility to tigecycline emerged on therapy demonstrating the limitations of alternative regimens. PMID- 20837633 TI - Viral pneumonias in immunocompromised adult hosts. AB - Viral infections have always been considered pediatric diseases. However, viral pneumonia has become an important cause of morbidity and mortality in immuncompromised adults. Improved diagnostic techniques, such as the introduction of highly sensitive nucleic acid amplification tests, have not only allowed us to discover new viruses but also to determine the etiology of viral pneumonia in immunocompromised adult hosts. Unfortunately, only a few antiviral agents are available. Thus, early diagnosis and treatment are crucial to patient outcome. In this article, we review the most common viruses that have been implicated as etiologic agents of viral pneumonia in immunocompromised adults. We discuss the epidemiologic characteristics and clinical presentation of these viral infections and the most appropriate diagnostic approaches and therapies when available. PMID- 20837634 TI - Is the band count useful in the diagnosis of infection? An accuracy study in critically ill patients. AB - BACKGROUND: The presence of immature neutrophils (bands) in the circulating blood is often used as a clinical indicator of sepsis. Indeed, a band count greater than 10% is one of the American College of Chest Physicians/Society of Critical Care Medicine's systemic inflammatory response syndrome (SIRS) criteria used to diagnose sepsis. However, the literature regarding the diagnostic accuracy of an elevated band count for the diagnosis of infection is limited. AIM: To determine the accuracy of a band count greater than 10% and increased or decreased white blood cell (WBC) count in diagnosing infection in a heterogeneous group of intensive care unit (ICU) patients. METHODS: We prospectively recorded the WBC and band count on consecutive patients admitted to our ICU. Each patient was evaluated for the presence of infection according to defined criteria. The diagnostic accuracy of band count and total WBC count were determined by standard statistical methods. RESULTS: Overall, 145 patients were enrolled, of whom 42 (29%) had a defined infection on admission to the ICU. On multiple logistic regression, the odds ratio for infection was 8.67 (95% CI 3.36-22.39; P < .001) for patients with band count greater than 10% and 1.6 (95% CI 0.78-3.29; P = .2) for a WBC count greater than 12 * 10(9)/L. A band count greater than 10% had sensitivity of 43% (95% CI 28%-59%), specificity of 92% (95% CI 85%-97%), positive likelihood ratio of 5.52 (95% CI 2.6-11.7), and negative likelihood ratio of 0.62 (95% CI 0.47-0.81) for the diagnosis of infection. CONCLUSION: Band count may provide useful information in patients whose diagnosis of infection is uncertain. An elevated band count leads to a moderate increase in the likelihood of infection. A negative test, however, leads to only a small change in the posttest probability of infection. PMID- 20837635 TI - The novel biomarker growth differentiation factor 15 in heart failure with normal ejection fraction. AB - AIMS: Heart failure with normal ejection fraction (HFnEF) is an important clinical entity that remains incompletely understood. The novel biomarker growth differentiation factor 15 (GDF-15) is elevated in systolic heart failure (HFrEF) and is predictive of an adverse outcome. We investigated the clinical relevance of GDF-15 plasma levels in HFnEF. METHODS AND RESULTS: A subgroup of patients from the ongoing DIAST-CHF observational trial, with a history of chronic heart failure (CHF) or positive Framingham criteria at presentation, was selected. Patients were classified as having either HFrEF (n=86) or HFnEF (n=142) and compared with healthy elderly controls (n=188) from the same cohort. Growth differentiation factor 15 levels in HFnEF were significantly higher than in controls and similar to those in HFrEF. In multivariate analysis, factors significantly associated with GDF-15 levels were age, sex, estimated glomerular filtration rate (eGFR), presence of HFrEF and HFnEF. Growth differentiation factor 15 correlated with multiple echocardiographic markers of diastolic function and was associated with 6 min walk test performance and SF-36 physical score on multivariate analysis in all patients. When using a classification for HFnEF that did not employ N-terminal pro brain natriuretic peptide (NT-proBNP) as a diagnostic criterion, the diagnostic properties of GDF-15 for detecting HFnEF tended to be superior to those of NT-proBNP, and a combination significantly improved diagnostic accuracy. CONCLUSION: Growth differentiation factor 15 is elevated in HFnEF to a similar degree as in HFrEF. It is independently associated with impairment in exercise capacity and in physical components of quality of life. Diagnostic precision of GDF-15 is at least as good as that of NT-proBNP and combining both markers improves diagnostic accuracy. PMID- 20837636 TI - Acute pulmonary oedema: clinical characteristics, prognostic factors, and in hospital management. AB - AIMS: Acute pulmonary oedema (APE) is the second, after acutely decompensated chronic heart failure (ADHF), most frequent form of acute heart failure (AHF). This subanalysis examines the clinical profile, prognostic factors, and management of APE patients (n = 1820, 36.7%) included in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). METHODS AND RESULTS: ALARM-HF included a total of 4953 patients hospitalized for AHF in Europe, Latin America, and Australia. The final diagnosis was made at discharge, and patients were classified according to European Society of Cardiology guidelines. Patients with APE had higher in-hospital mortality (7.4 vs. 6.0%, P = 0.057) compared with ADHF patients (n = 1911, 38.5%), and APE patients exhibited higher systolic blood pressures (P < 0.001) at admission and higher left ventricular ejection fraction (LVEF, P < 0.01) than those with ADHF. These patients also had a higher prevalence of diabetes (P < 0.01), arterial hypertension (P < 0.001), peripheral vascular disease (P < 0.001), and chronic renal disease (P < 0.05). They were also more likely to receive intravenous (i.v.) diuretics (P < 0.001), i.v. nitrates (P < 0.01), dopamine (P < 0.05), and non-invasive ventilation (P < 0.001). Low systolic blood pressure (P < 0.001), low LVEF (<0.05), serum creatinine >=1.4 mg/dL (P < 0.001), history of cardiomyopathy (P < 0.05), and previous cardiovascular event (P < 0.001) were independently associated with increased in-hospital mortality in the APE population. CONCLUSION: APE differs in clinical profile, in-hospital management, and mortality compared with ADHF. Admission characteristics (systolic blood pressure and LVEF), renal function, and history may identify high-risk APE patients. PMID- 20837637 TI - Efficacy of experimental treatments compared with standard treatments in non inferiority trials: a meta-analysis of randomized controlled trials. AB - BACKGROUND: There is concern that non-inferiority trials might be deliberately designed to conceal that a new treatment is less effective than a standard treatment. In order to test this hypothesis we performed a meta-analysis of non inferiority trials to assess the average effect of experimental treatments compared with standard treatments. METHODS: One hundred and seventy non inferiority treatment trials published in 121 core clinical journals were included. The trials were identified through a search of PubMed (1991 to 20 February 2009). Combined relative risk (RR) from meta-analysis comparing experimental with standard treatments was the main outcome measure. RESULTS: The 170 trials contributed a total of 175 independent comparisons of experimental with standard treatments. The combined RR for all 175 comparisons was 0.994 [95% confidence interval (CI) 0.978-1.010] using a random-effects model and 1.002 (95% CI 0.996-1.008) using a fixed-effects model. Of the 175 comparisons, experimental treatment was considered to be non-inferior in 130 (74%). The combined RR for these 130 comparisons was 0.995 (95% CI 0.983-1.006) and the point estimate favoured the experimental treatment in 58% (n = 76) and standard treatment in 42% (n = 54). The median non-inferiority margin (RR) pre-specified by trialists was 1.31 [inter-quartile range (IQR) 1.18-1.59]. CONCLUSION: In this meta-analysis of non-inferiority trials the average RR comparing experimental with standard treatments was close to 1. The experimental treatments that gain a verdict of non inferiority in published trials do not appear to be systematically less effective than the standard treatments. Importantly, publication bias and bias in the design and reporting of the studies cannot be ruled out and may have skewed the study results in favour of the experimental treatments. Further studies are required to examine the importance of such bias. PMID- 20837638 TI - Rapid desensitization of the rat alpha7 nAChR is facilitated by the presence of a proline residue in the outer beta-sheet. AB - The rat alpha7 nicotinic acetylcholine receptor (nAChR) has a proline residue near the middle of the beta9 strand. The replacement of this proline residue at position 180 (P180) by either threonine (alpha7-P180T) or serine (alpha7-P180S) slowed the onset of desensitization dramatically, with half-times of ~930 and 700 ms, respectively, compared to 90 ms for the wild-type receptor. To investigate the importance of the hydroxyl group on the position 180 side-chains, the mutant receptors alpha7-P180Y and alpha7-P180F were studied and showed half-times of desensitization of 650 and 160 ms, respectively. While a position 180 side-chain OH group may contribute to the slow desensitization rates, alpha7-P180S and alpha7-P180V resulted in receptors with similar desensitization rates, suggesting that increased backbone to backbone H bonding expected in the absence of proline at position 180 would likely exert a great effect on desensitization. Single channel recordings indicated that for the alpha7-P180T receptor there was a significantly reduced closed time without any change in single channel conductance (as compared to wild-type). Kinetic simulations indicated that all changes observed for the mutant channel behaviour were reproduced by decreasing the rate of desensitization, and increasing the microscopic affinity to resting receptors. Molecular dynamics (MD) simulations on a homology model were used to provide insight into likely H bond interactions within the outer beta-sheet that occur when the P180 residue is mutated. All mutations analysed increased about twofold the predicted number of H bonds between the residue at position 180 and the backbone of the beta10 strand. Moreover, the alpha7-P180T and alpha7-P180S mutations also formed some intrastrand H bonds along the beta9 strand, although H bonding of the OH groups of the threonine or serine side-chains was predicted to be infrequent. Our results indicate that rapid desensitization of the wild-type rat alpha7 nAChR is facilitated by the presence of the proline residue within the beta9 strand. PMID- 20837639 TI - Increased fatigue resistance linked to Ca2+-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice. AB - Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 degrees C) or cold-acclimated (4 degrees C) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~fourfold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator activated receptor-gamma coactivator-1alpha (PGC-1alpha) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations. PMID- 20837640 TI - Properties of axon terminals contacting intermediate zone excitatory and inhibitory premotor interneurons with monosynaptic input from group I and II muscle afferents. AB - The intermediate zone of the spinal grey matter contains premotor interneurons mediating reflex actions of group I and II muscle afferents. However, limited information is available on how activity of inhibitory versus excitatory interneurons in this population are modulated and how they contribute to motor networks. There were three aims of this study: (1) to characterize excitatory axonal contacts on interneurons; (2) to determine if contact patterns on excitatory and inhibitory interneurons are different; (3) to determine if there are differences in presynaptic inhibitory control of excitatory and inhibitory interneurons. We used intracellular labelling of electrophysiologically identified cells along with immunochemistry to characterise contacts formed by axons that contain vesicular glutamate transporters (VGLUT1 and VGLUT2) and contacts formed by VGLUT1 terminals which in turn were contacted by GABAergic terminals on cells that were characterised according to their transmitter phenotype. All 17 cells investigated were associated with numerous VGLUT1 contacts originating from primary afferents, and similar contact densities were found on excitatory and inhibitory cells, but VGLUT2-immunoreactive terminals originating from intraspinal neurons were less frequent, or were practically absent, especially on excitatory cells. Similar numbers of VGLUT1 contacts with associated GABAergic terminals were found on excitatory and inhibitory cells indicating a similar extent of presynaptic GABAergic control. However, scarce VGLUT2 terminals on intermediate zone excitatory premotor interneurons with input from muscle afferents suggest that they are not significantly excited by other spinal neurons but are under direct excitatory control of supraspinal neurons and, principally inhibitory, control of spinal neurons. PMID- 20837641 TI - Childhood development of common drive to a human leg muscle during ankle dorsiflexion and gait. AB - Corticospinal drive has been shown to contribute significantly to the control of walking in adult human subjects. It is unknown to what extent functional change in this drive is important for maturation of gait in children. In adults, populations of motor units within a muscle show synchronized discharges during walking with pronounced coherence in the 15-50 Hz frequency band. This coherence has been shown to depend on cortical drive. Here, we investigated how this coherence changes with development. Forty-four healthy children aged 4-15 years participated in the study. Electromyographic activity (EMG) was recorded from pairs of electrodes placed over the right tibialis anterior (TA) muscle during static dorsiflexion and during walking on a treadmill (speed from 1.8 to 4.8 km h(-1)). A significant increase of coherence with increasing age was found in the 30-45 Hz frequency band (gamma) during walking and during static ankle dorsiflexion. A significant correlation with age was also found in the 15-25 Hz frequency band (beta) during static foot dorsiflexion. chi(2) analysis of differences of coherence between different age groups of children (4-6, 7-9, 10 12 and 13-15 years of age) revealed a significantly lower coherence in the gamma band for recordings during walking in children aged 4-6 years as compared to older children. Recordings during static dorsiflexion revealed significant differences in both the beta and gamma bands for children in the 4-6 and 7-9 years age groups as compared to the older age groups. A significant age-related decrease in step-to-step variability of toe position during the swing phase of walking was observed. This reduction in the step-to-step variability of gait was correlated with increased gamma band coherence during walking. We argue that this may reflect an increased ability to precisely control the ankle joint position with age, which may be contingent on maturation of corticospinal control of the foot dorsiflexor muscles. PMID- 20837642 TI - Calcium concentration jumps reveal dynamic ion selectivity of calcium-activated chloride currents in mouse olfactory sensory neurons and TMEM16b-transfected HEK 293T cells. AB - Ca(2+)-activated Cl(-) channels play relevant roles in several physiological processes, including olfactory transduction, but their molecular identity is still unclear. Recent evidence suggests that members of the transmembrane 16 (TMEM16, also named anoctamin) family form Ca(2+)-activated Cl(-) channels in several cell types. In vertebrate olfactory transduction, TMEM16b/anoctamin2 has been proposed as the major molecular component of Ca(2+)-activated Cl(-) channels. However, a comparison of the functional properties in the whole-cell configuration between the native and the candidate channel has not yet been performed. In this study, we have used the whole-cell voltage-clamp technique to measure functional properties of the native channel in mouse isolated olfactory sensory neurons and compare them with those of mouse TMEM16b/anoctamin2 expressed in HEK 293T cells. We directly activated channels by rapid and reproducible intracellular Ca(2+) concentration jumps obtained from photorelease of caged Ca(2+) and determined extracellular blocking properties and anion selectivity of the channels. We found that the Cl(-) channel blockers niflumic acid, 5-nitro-2 (3-phenylpropylamino)benzoic acid (NPPB) and DIDS applied at the extracellular side of the membrane caused a similar inhibition of the two currents. Anion selectivity measured exchanging external ions and revealed that, in both types of currents, the reversal potential for some anions was time dependent. Furthermore, we confirmed by immunohistochemistry that TMEM16b/anoctamin2 largely co-localized with adenylyl cyclase III at the surface of the olfactory epithelium. Therefore, we conclude that the measured electrophysiological properties in the whole-cell configuration are largely similar, and further indicate that TMEM16b/anoctamin2 is likely to be a major subunit of the native olfactory Ca(2+)-activated Cl(-) current. PMID- 20837643 TI - Endogenous descending modulation: spatiotemporal effect of dynamic imbalance between descending facilitation and inhibition of nociception. AB - In conscious rats, we investigated the change of nociceptive paw withdrawal reflexes elicited by mechanical and heat stimuli during intramuscular (i.m.) 5.8% hypertonic (HT) saline elicited muscle nociception. i.m. injection of HT saline caused rapid onset, long lasting (around 7 days), bilateral mechanical hyperalgesia, while it induced bilateral, slower onset (1 day after the HT saline injection), long-term (about 1-2 weeks) heat hypoalgesia. Ipsilateral topical pre treatment of the sciatic nerve with 1% capsaicin significantly prevented the occurrence of both the bilateral mechanical hyperalgesia and the contralateral heat hypoalgesia. Intrathecal administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), and intraperitoneal injection of naloxone all markedly attenuated the HT saline induced bilateral heat hypoalgesia, but not the mechanical hyperalgesia. Combined with experiments with lesioning of the rostroventral medulla with kainic acid, the present data indicate that unilateral i.m. injection of HT saline elicits time-dependent bilateral long-term mechanical hyperalgesia and heat hypoalgesia, which were modulated by descending facilitatory and inhibitory controls, respectively. We hypothesize that supraspinal structures may function to discriminate between afferent noxious inputs mediated by Adelta- and C-fibres, either facilitating Adelta-fibre mediated responses or inhibiting C-fibre mediated activities. However, this discriminative function is physiologically silent or inactive, and can be triggered by stimulation of peripheral C-fibre afferents. Importantly, in contrast to the rapid onset of descending facilitation, the late occurrence of descending inhibition suggests a requirement of continuous C-fibre input and temporal summation. Thus, a reduction of C-fibre input using exogenous analgesic agents, i.e. opioids, may counteract the endogenous descending inhibition. PMID- 20837644 TI - Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain. AB - Neuropathic pain is a common diabetic complication affecting 8-16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage dependent blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l(-1) in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain. PMID- 20837645 TI - Training in the fasted state improves glucose tolerance during fat-rich diet. AB - A fat-rich energy-dense diet is an important cause of insulin resistance. Stimulation of fat turnover in muscle cells during dietary fat challenge may contribute to maintenance of insulin sensitivity. Exercise in the fasted state markedly stimulates energy provision via fat oxidation. Therefore, we investigated whether exercise training in the fasted state is more potent than exercise in the fed state to rescue whole-body glucose tolerance and insulin sensitivity during a period of hyper-caloric fat-rich diet. Healthy male volunteers (18-25 y) received a hyper-caloric (~+30% kcal day(-1)) fat-rich (50% of kcal) diet for 6 weeks. Some of the subjects performed endurance exercise training (4 days per week) in the fasted state (F; n = 10), whilst the others ingested carbohydrates before and during the training sessions (CHO; n = 10). The control group did not train (CON; n = 7). Body weight increased in CON (+3.0 +/- 0.8 kg) and CHO (+1.4 +/- 0.4 kg) (P < 0.01), but not in F (+0.7 +/- 0.4 kg, P = 0.13). Compared with CON, F but not CHO enhanced whole-body glucose tolerance and the Matsuda insulin sensitivity index (P < 0.05). Muscle GLUT4 protein content was increased in F (+28%) compared with both CHO (P = 0.05) and CON (P < 0.05). Furthermore, only training in F elevated AMP-activated protein kinase alpha phosphorylation (+25%) as well as up-regulated fatty acid translocase/CD36 and carnitine palmitoyltransferase 1 mRNA levels compared with CON (~+30%). High-fat diet increased intramyocellular lipid but not diacylglycerol and ceramide contents, either in the absence or presence of training. This study for the first time shows that fasted training is more potent than fed training to facilitate adaptations in muscle and to improve whole-body glucose tolerance and insulin sensitivity during hyper-caloric fat-rich diet. PMID- 20837646 TI - Exercise-induced TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle. AB - TBC1D1 is a Rab-GTPase activating protein involved in regulation of GLUT4 translocation in skeletal muscle. We here evaluated exercise-induced regulation of TBC1D1 Ser237 phosphorylation and 14-3-3 protein binding capacity in human skeletal muscle. In separate experiments healthy men performed all-out cycle exercise lasting either 30 s, 2 min or 20 min. After all exercise protocols, TBC1D1 Ser237 phosphorylation increased (~70-230%, P < 0.005), with the greatest response observed after 20 min of cycling. Interestingly, capacity of TBC1D1 to bind 14-3-3 protein showed a similar pattern of regulation, increasing 60-250% (P < 0.001). Furthermore, recombinant 5AMP-activated protein kinase (AMPK) induced both Ser237 phosphorylation and 14-3-3 binding properties on human TBC1D1 when evaluated in vitro. To further characterize the role of AMPK as an upstream kinase regulating TBC1D1, extensor digitorum longus muscle (EDL) from whole body alpha1 or alpha2 AMPK knock-out and wild-type mice were stimulated to contract in vitro. In wild-type and alpha1 knock-out mice, contractions resulted in a similar ~100% increase (P < 0.001) in Ser237 phosphorylation. Interestingly, muscle of alpha2 knock-out mice were characterized by reduced protein content of TBC1D1 (~50%, P < 0.001) as well as in basal and contraction-stimulated (~60%, P < 0.001) Ser237 phosphorylation, even after correction for the reduced TBC1D1 protein content. This study shows that TBC1D1 is Ser237 phosphorylated and 14-3-3 protein binding capacity is increased in response to exercise in human skeletal muscle. Furthermore, we show that the catalytic alpha2 AMPK subunit is the main (but probably not the only) donor of AMPK activity regulating TBC1D1 Ser237 phosphorylation in mouse EDL muscle. PMID- 20837648 TI - Occupational exposure to organic solvents and lymphoid neoplasms in men: results of a French case-control study. AB - OBJECTIVES: Investigating the role of occupational exposure to solvents in the occurrence of lymphoid neoplasms (LNs) in men. METHODS: The data were generated by a French hospital-based case-control study, conducted in six centres in 2000 2004. The cases were incident cases aged 18-75 years with a diagnosis of LN. During the same period, controls of the same age and gender as the cases were recruited in the same hospitals, mainly in the orthopaedic and rheumatological departments. Exposure to solvents was assessed using standardised occupational questionnaires and case-by-case expert assessment. Specific quantification of benzene exposure was attempted. The analyses included 491 male patients (244 cases of non-Hodgkin's lymphoma (NHL), 87 of Hodgkin's lymphoma, 104 of lymphoproliferative syndrome and 56 of multiple myeloma) and 456 male controls. Unconditional logistic regressions were used to estimate OR and 95% CI. RESULTS: Solvent exposure, all solvents considered together, was marginally associated with NHL (OR=1.4 (1.0 to 2.0) p=0.06), but not with other LNs. No association with the main chemical series of solvents was observed. There was no trend with the average intensity or frequency of exposure. Exposure to pure benzene was not significantly related to NHL (OR=3.4 (0.8 to 15.0)). The highest maximum intensities of benzene exposure were associated with diffuse large cell lymphoma (OR=2.1 (1.0 to 4.6)). CONCLUSION: The results of the present study provide estimates compatible with the hypothesis that exposures to pure benzene and high benzene intensities may play a role in some NHL. There was no evidence for a role of other organic solvents in the occurrence of LN. PMID- 20837649 TI - Executive function modifies the relationship between occupational lead exposure and complex figure test performance. AB - OBJECTIVES: To determine if chronic lead exposure is associated with non-verbal memory performance and if this association is affected by organisation strategies, a component of executive functions. METHODS: We administered the Rey Osterrieth Complex Figure (ROCF) test, both copy (ROCF-C) and 30-min delayed recall (ROCF-DR), to 358 current lead smelter workers with a mean (SD) age of 41 (9.1) years, education of 11 (2.7) years, and working lifetime-weighted average blood lead (TWA) of 39 (12.0) MUg/dl. Copy and delay organisation scores, surrogates for executive functions, were developed for ROCF-C and ROCF-DR. We used multiple regression analyses to examine the relationship between TWA and ROCF performance, organisational scores, and the interaction of organisational scores and TWA after adjusting for relevant covariates. RESULTS: Organisational scores, while not associated with years of education, were significantly correlated with ROCF-C and ROCF-DR performance. We found a significant relationship between TWA and ROCF-DR but not with ROCF-C performance. The interactions of TWA by copy organisation and TWA by delay organisation were significant for ROCF-DR with a significant dose-effect relationship only in participants with lower organisational scores. CONCLUSIONS: Chronic lead exposure was significantly associated with complex figure test delayed recall but not copy performance. Organisational strategies, a component of executive functions, served as effect modifiers of the relationship between lead exposure and non verbal memory. With increasing TWA exposure workers with good organisational strategies maintained performance on the complex figure test while workers with poor organisational strategies demonstrated decreasing performance. PMID- 20837647 TI - Na+ currents are required for efficient excitation-contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na+ channels. AB - Ca2+ transients were activated in rabbit ventricular cells by a sequence of action potential shaped voltage clamps. After activating a series of control transients, Na+ currents (INa) were inactivated with a ramp from -80 to -40 mV (1.5 s) prior to the action potential clamp. The transients were detected with the calcium indicator Fluo-4 and an epifluorescence system. With zero Na+ in the pipette INa inactivation produced a decline in the SR Ca2+ release flux (measured as the maximum rate of rise of the transient) of 27 +/- 4% (n = 9, P < 0.001) and a peak amplitude reduction of 10 +/- 3% (n = 9, P < 0.05). With 5 mm Na+ in the pipette the reduction in release flux was greater (34 +/- 4%, n = 4, P < 0.05). The ramp effectively inactivates INa without changing ICa, and there was no significant change in the transmembrane Ca2+ flux after the inactivation of INa. We next evoked action potentials under current clamp. TTX at 100 nm, which selectively blocks neuronal isoforms of Na+ channels, produced a decline in SR Ca2+ release flux of 35 +/- 3% (n = 6, P < 0.001) and transient amplitude of 12 +/- 2% (n = 6, P < 0.05). This effect was similar to the effect of INa inactivation on release flux. We conclude that a TTX-sensitive INa is essential for efficient triggering of SR Ca2+ release. We propose that neuronal Na+ channels residing within couplons activate sufficient reverse Na+-Ca2+ exchanger (NCX) to prime the junctional cleft with Ca2+. The results can be explained if non-linearities in excitation-contraction coupling mechanisms modify the coupling fidelity of ICa, which is known to be low at positive potentials. PMID- 20837650 TI - A case-crossover study of occupational laceration injuries in pork processing: methods and preliminary findings. AB - OBJECTIVES: Meatpacking remains a hazardous and largely unexamined industry. Despite prevention efforts, laceration injuries, among others, remain high. We estimated the magnitude of associations between transient exposures such as equipment malfunction, performing an unusual work task, rushing, and occurrence of laceration injuries. METHODS: Injured workers were recruited from two pork processing plants, one in Iowa and one in Nebraska. A telephone interview was conducted within 7 days of the injury, on average to collect information on fixed and transient exposures preceding the injury event. Case-crossover methodology was used to evaluate case and control data within the same subject, thus controlling for between-subject confounding. A Mantel-Haenszel estimator for person-time data was used to estimate the relative risks of injury and transient exposures of interest. RESULTS: Of the 362 workers with lacerations between April 2006 and October 2007, 153 (42%) were interviewed (74% male, 41% Hispanic). Forty eight per cent were injured by a knife or a knife-like object such as scissors or a band saw. Other sources of lacerations included sharp edges and hooks. Tool sharpening was associated with the highest RR of laceration (RR 8.4, 95% CI 5.4 to 12.8) followed by slipping (RR 74.8, 95% CI 30.5 to 183.3), equipment malfunction (RR 3.8, 95% CI 2.8 to 5.3), and performing an unusual task (RR 3.7, 95% CI 2.6 to 5.2). Being tired, distracted, or rushing were not significant risk factors for a laceration. CONCLUSIONS: Aspects of the physical environment and work practices appear to be significant risk factors for laceration injury in meatpacking. Personal risk factors were less significant in this study. PMID- 20837652 TI - Predicting chemicals causing cancer in animals as human carcinogens. PMID- 20837651 TI - Systematic review and meta-analysis of psychomotor effects of mobile phone electromagnetic fields. AB - OBJECTIVES: Over the past 10 years there has been increasing concern about the possible behavioural effects of mobile phone use. This systematic review and meta analysis focuses on studies published since 1999 on the human cognitive and performance effects of mobile phone-related electromagnetic fields (EMF). METHODS: PubMed, Biomed, Medline, Biological Sciences, PsychInfo, PsycARTICLES, Environmental Sciences and Pollution Management, Neurosciences Abstracts and Web of Science professional databases were searched and 24 studies selected for meta analysis. Each study had to have at least one psychomotor measurement result as a main outcome. Data were analysed using standardised mean difference (SMD) as the effect size measure. Results Only three tasks (2-back, 3-back and simple reaction time (SRT)) displayed significant heterogeneity, but after studies with extreme SMD were excluded using sensitivity analysis, the statistical significance disappeared (chi(2)(7)=1.63, p=0.20; chi(2)(6)=1.00, p=0.32; chi(2)(10)=14.04, p=0.17, respectively). Following sensitivity analysis, the effect of sponsorship and publication bias were assessed. Meta-regression indicated a significant effect (b1/40.12, p<0.05) only for the 2-back task with mixed funding (industry and public/charity). Funnel plot inspection revealed a significant publication bias only for two cognitive tasks: SRT (Begg's rank correlation r=0.443; Egger's test b=-0.652) and the subtraction task (Egger's test b=-0.687). CONCLUSIONS: Mobile phone-like EMF do not seem to induce cognitive and psychomotor effects. Nonetheless, the existence of sponsorship and publication biases should encourage WHO intervention to develop official research standards and guidelines. In addition, future research should address critical and neglected issues such as investigation of repeated, intensive and chronic exposures, especially in highly sensitive populations such as children. PMID- 20837653 TI - The Fagerstrom test for nicotine dependence in an Indian sample of daily smokers with poly drug use. AB - INTRODUCTION: The Fagerstrom Test for Nicotine Dependence (FTND) is a widely used six-item questionnaire, which has often been used as a measure of physical dependence on nicotine. METHODS: The performance of the FTND was explored in an Indian sample of 75 daily smokers with histories of polysubstance use attending the Tobacco Cessation Clinic at National Drug Dependence Treatment Centre. RESULTS: FTND score was found to be significantly correlated with the age of initiation but showed no correlation with duration of use. FTND had low reliability (Cronbach's alpha: .57) in the Indian setting. An exploratory factor analysis suggested that the FTND comprised 2 factors. Factor 1 was defined by questions regarding "time-to-first cigarette after waking," "difficulty refraining from smoking in forbidden places," and "amount smoked," which reflects the persistence to maintain the nicotine levels during waking hours, whereas Factor 2 was defined by questions regarding "which cigarette is most preferred" and "prominence of morning smoking and "smoking while ill," which explains the degree of urgency to restore nicotine levels to a given threshold after nighttime abstinence. A good amount of variance (56.34%) was explained by these factors. Cronbach's alpha, for each of the 2 domains was found to be .66 and .58, respectively. CONCLUSIONS: FTND was found to have low internal consistency reliability in this study. The study confirms a 2-factor structure of the FTND in a sample of polysubstance users. Thus, the FTND may assess 2 separate dimensions of nicotine addiction. PMID- 20837654 TI - Partnership readiness for community-based participatory research. AB - The use of a dyadic lens to assess and leverage academic and community partners' readiness to conduct community-based participatory research (CBPR) has not been systematically investigated. With a lack of readiness to conduct CBPR, the partnership and its products are vulnerable. The purpose of this qualitative study was to explore the dimensions and key indicators necessary for academic and community partnership readiness to conduct CBPR. Key informant interviews and focus groups (n = 36 participants) were conducted with academic and community participants who had experiences with CBPR partnerships. A 'framework analysis' approach was used to analyze the data and generate a new model, CBPR Partnership Readiness Model. Antecedents of CBPR partnership readiness are a catalyst and mutual interest. The major dimensions of the CBPR Partnership Readiness Model are (i) goodness of fit, (ii) capacity, and (iii) operations. Preferred outcomes are sustainable partnership and product, mutual growth, policy and social and health impact on the community. CBPR partnership readiness is an iterative and dynamic process, partnership and issue specific, influenced by a range of environmental and contextual factors, amenable to change and essential for sustainability and promotion of health and social change in the community. PMID- 20837655 TI - Process evaluation of HIV prevention peer groups in Malawi: a look inside the black box. AB - This paper reports the process evaluation of a peer group intervention for human immunodeficiency virus (HIV) prevention which had positive outcomes for three target groups in Malawi: rural adults, adolescents and urban hospital workers. The six-session intervention was delivered to small groups of 10-12 participants by 85 trained volunteer peer leaders working in pairs. A descriptive, observational mixed methods design was used with a convenience sample of 294 intervention sessions. Using project records and a conceptually based observation guide, we examined five aspects of the implementation process. The context was favorable, but privacy to discuss sensitive issues was a concern for some groups. In study communities, program reach was 58% of rural adults, 70% of adolescents and nearly all hospital workers. Session records confirmed that all peer groups received the intended six sessions (dose delivered). The dose received was high, as evidenced by high participant engagement in peer group activities. Peer leaders were rated above the median for three indicators of peer group content and process fidelity: session management skills, interpersonal facilitation skills and whether more like a peer group than classroom. Documenting that this HIV prevention peer group intervention was delivered as intended by trained peer volunteers supports widespread dissemination of the intervention. PMID- 20837656 TI - 5'-3'-UTR interactions regulate p53 mRNA translation and provide a target for modulating p53 induction after DNA damage. AB - Optimal induction of p53 protein after DNA damage requires RPL26-mediated increases in p53 mRNA translation. We report here the existence of a dsRNA region containing complementary sequences of the 5'- and 3'-untranslated regions (UTRs) of human p53 mRNA that is critical for its translational regulation by RPL26. Mutating as few as 3 bases in either of the two complementary UTR sequences abrogates the ability of RPL26 to bind to p53 mRNA and stimulate p53 translation, while compensatory mutations restore this binding and regulation. Short, single strand oligonucleotides that target this 5'-3'-UTR base-pairing region blunt the binding of RPL26 to p53 mRNA in cells and reduce p53 induction and p53-mediated cell death after several different types of DNA damage and cellular stress. The ability to reduce stress induction of p53 with oligonucleotides or other small molecules has numerous potential therapeutic uses. PMID- 20837657 TI - Abelson family kinases regulate Frizzled planar cell polarity signaling via Dsh phosphorylation. AB - Abelson (Abl) family tyrosine kinases have been implicated in cell morphogenesis, adhesion, motility, and oncogenesis. Using a candidate approach for genes involved in planar cell polarity (PCP) signaling, we identified Drosophila Abl (dAbl) as a modulator of Frizzled(Fz)/PCP signaling. We demonstrate that dAbl positively regulates the Fz/Dishevelled (Dsh) PCP pathway without affecting canonical Wnt/Wg-Fz signaling. Genetic dissection suggests that Abl functions via Fz/Dsh signaling in photoreceptor R3 specification, a well-established Fz-PCP signaling readout. Molecular analysis shows that dAbl binds and phosphorylates Dsh on Tyr473 within the DEP domain. This phosphorylation event on Dsh is functionally critical, as the equivalent DshY473F mutant is nonfunctional in PCP signaling and stable membrane association, although it rescues canonical Wnt signaling. Strikingly, mouse embryonic fibroblasts (MEFs) deficient for Abl1 and Abl2/Arg genes also show reduced Dvl2 phosphorylation as compared with control MEFs, and this correlates with a change in subcellular localization of endogenous Dvl2. As in Drosophila, such Abl-deficient MEFs show no change in canonical Wnt signaling. Taken together, our results argue for a conserved role of Abl family members in the positive regulation of Dsh activity toward Fz-Dsh/PCP signaling by Dsh phosphorylation. PMID- 20837659 TI - 20(S)-ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions. AB - P-glycoprotein (P-gp) is an ATP-dependent efflux transporter highly expressed in gastrointestinal tract and multidrug resistance tumor cells. Inhibition or induction of P-gp can cause drug-drug interactions and thus influence the effects of P-gp substrate drugs. Previous studies indicated that 20(S)-ginsenoside Rh2 [20(S)-Rh2] could synergistically enhance the anticancer effects of conventional chemotherapeutic agents at a nontoxic dose. The aim of present study was to investigate in vitro and in vivo whether 20(S)-Rh2 was a P-gp inhibitor and analyze the possible inhibitory mechanisms and potential herb-drug interactions. Results showed that in vitro, 20(S)-Rh2 significantly enhanced rhodamine 123 retention in cells and decreased the efflux ratio of digoxin, fexofenadine, and etoposide, which were comparable to the effects of the established P-gp inhibitor verapamil. However, the transport of 20(S)-Rh2 suggested that 20(S)-Rh2 was not a P-gp substrate. Furthermore, the inhibitory effect persisted for at least 3 h after removal of 20(S)-Rh2. Unlike P-gp substrates, 20(S)-Rh2 inhibited both basal and verapamil-stimulated P-gp ATPase activities. It also significantly decreased UIC2 binding fluorescence, a marker for conformational change of P-gp. In situ and in vivo experiments showed that 20(S)-Rh2 increased the area under the plasma concentration-time curve and maximum plasma concentration of digoxin, fexofenadine, and etoposide significantly without affecting terminal elimination half-time. Long-term treatment with 20(S)-Rh2 failed to affect intestinal P-gp expression in vitro and in vivo. In conclusion, 20(S)-Rh2 is a potent noncompetitive P-gp inhibitor, which indicates a potential herb-drug interaction when 20(S)-Rh2 is coadministered with P-gp substrate drugs. It could increase the absorption of P-gp substrate drugs without long-term induction of P-gp expression in rats. PMID- 20837658 TI - Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor. AB - Glioblastoma multiforme (GBM) is a lethal brain tumor characterized by intense apoptosis resistance and extensive necrosis. Bcl2L12 (for Bcl2-like 12) is a cytoplasmic and nuclear protein that is overexpressed in primary GBM and functions to inhibit post-mitochondrial apoptosis signaling. Here, we show that nuclear Bcl2L12 physically and functionally interacts with the p53 tumor suppressor, as evidenced by the capacity of Bcl2L12 to (1) enable bypass of replicative senescence without concomitant loss of p53 or p19 (Arf), (2) inhibit p53-dependent DNA damage-induced apoptosis, (3) impede the capacity of p53 to bind some of its target gene promoters, and (4) attenuate endogenous p53-directed transcriptomic changes following genotoxic stress. Correspondingly, The Cancer Genome Atlas profile and tissue protein analyses of human GBM specimens show significantly lower Bcl2L12 expression in the setting of genetic p53 pathway inactivation. Thus, Bcl2L12 is a multifunctional protein that contributes to intense therapeutic resistance of GBM through its ability to operate on two key nodes of cytoplasmic and nuclear signaling cascades. PMID- 20837660 TI - Metabolism and action of proteasome inhibitors in primary human hepatocytes. AB - Proteasome inhibitors are important tools for studying the roles of the proteasome in cellular processes. In this study, we observed that the proteasome inhibitors N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132), epoxomicin, and lactacystin were ineffective and bortezomib was completely effective in inhibiting cytokine-stimulated nitric oxide production in primary cultures of human hepatocytes that had been treated with the cytochrome P450 inducer phenobarbital. The inefficacy of MG132 was due to its metabolism by CYP3A enzymes, as deduced from its rapid, ketoconazole-sensitive clearance by pooled human liver microsomes and cultured hepatocytes. The efficacy of MG132 was increased by inclusion of ketoconazole in the hepatocyte incubations and decreased by prior treatment of the cultures with the CYP3A inducers phenobarbital or rifampicin. Epoxomicin was also rapidly metabolized by CYP3A, whereas bortezomib and lactacystin were much more stable metabolically in human liver microsomes or hepatocyte cultures. Thus, bortezomib is a better choice than MG132, epoxomicin, or lactacystin in cells with high activities of CYP3A enzymes. The reason for the lack of efficacy of lactacystin in human hepatocytes has yet to be determined, but it too should not be used for studies of proteasome function in human hepatocytes. PMID- 20837661 TI - Metabolism of ebracteolata compound B studied in vitro with human liver microsomes, HepG2 cells, and recombinant human enzymes. AB - Ebracteolata compound B (ECB) is one major active component of both Euphorbia ebracteolata and Euphorbia fischeriana, which have been extensively used as a tuberculocide in the Asian countries. The aim of our present study was to characterize ECB metabolism in human liver microsomes, HepG2 cells, and recombinant human enzymes. One monohydroxylation metabolite, determined by mass spectrometry to be 1-(2,4-dihydroxy-6-methoxy-3-methylphenyl)-2-hydroxyethanone, and one monoglucuronide, isolated and determined by hydrolysis with beta glucuronidase, mass spectrometry, and (1)H NMR to be 2-hydroxy-6-methoxy-3-methyl acetophenone-4-O-beta-glucuronide, were observed in human liver microsomal incubates in the presence of NADPH or UDP-glucuronic acid (UDPGA), respectively. However, the mixed incubation of ECB with human liver microsomes in the presence of both NADPH and UDPGA showed the monoglucuronide to be the most major metabolite, indicating that glucuronidation was probably the major clearance pathway of ECB in humans. No glucuronide and only trace monohydroxylation metabolite were observed in HepG2 cells. The cytochrome P450 and UDP glucuronosyltransferase (UGT) isoenzymes were identified by using selective chemical inhibition and recombinant human enzymes. The results indicated that CYP3A4 was probably involved in ECB oxidative metabolism and UGT1A6 and UGT1A9 were important catalytic enzymes in ECB glucuronidation. The results from enzymatic kinetic analysis showed the oxidative metabolism in human liver microsomes; the glucuronidation in human liver microsomes and recombinant UGT1A6 exhibited a typical Michaelis-Menten pattern, but the glucuronidation in UGT1A9 exhibited a substrate inhibition pattern. UGT1A6 had the highest affinity compared with human liver microsomes and UGT1A9, indicating its important role in ECB glucuronidation. PMID- 20837662 TI - Benefits of cognitive dual-task training on balance performance in healthy older adults. AB - BACKGROUND: There is growing evidence of the involvement of executive control in the maintenance of balance in old age. We examined whether healthy older adults who completed five sessions of nonmotor cognitive dual-task training would show significant improvements on measures of dual-task standing balance and mobility, compared with an untrained control group. METHODS: Twenty healthy older adults were assigned to either training or control groups. In the pre- and post-training sessions, all participants performed tests of cognition, balance, and mobility (single-support balance, dynamic posturography, sit-to-stand, 40-foot walk) under single- and dual-task conditions. The training group completed five sessions of cognitive dual-task training spaced at least 2 days apart. The two tasks involved making two-choice decisions to visually presented stimuli. Participants completed multiple blocks of single-task (task A or B, blockwise) and mixed (A, B, or A + B) trials in each training session. RESULTS: The training group showed significant improvements in body sway during single-support balance and center of gravity alignment during double-support dynamic balance. The control group showed no appreciable improvements. CONCLUSIONS: This study is the first to demonstrate training-related benefits to gross motor performance stemming from cognitive dual task training. The results support the view that motor control in aging is influenced by executive control and have implications for theories of cognitive training and transfer. PMID- 20837663 TI - Tetrahydrobiopterin: pleiotropic roles in cardiovascular pathophysiology. AB - Tetrahydrobiopterin (BH4) functions as a cofactor in several important enzyme systems. Substantial evidence implicates BH4 as a key regulator of endothelial nitric oxide synthase (eNOS) in the setting of endothelial dysfunction and atherosclerosis. Investigators have now taken early steps in addressing the potential of BH4 as a therapeutic strategy. However, it has become more apparent that the role of BH4 in other enzymatic pathways, including other NOS isoforms and the aromatic amino acid hydroxylases, may have a bearing on important aspects of cardiovascular homeostasis. Together with eNOS, these enzymes may play key roles in diverse cardiovascular disease states such as ischaemia-reperfusion injury, cardiac hypertrophy, cardiac autonomic function and pulmonary hypertension. This review provides an overview of the role of BH4 in cardiovascular pathophysiology. PMID- 20837664 TI - Telomerase inhibition potentiates the effects of genotoxic agents in breast and colorectal cancer cells in a cell cycle-specific manner. AB - Previous studies have shown that telomerase facilitates DNA-damage repair and cell survival following stress. It is not clear how telomerase promotes DNA repair, or whether short-term telomerase inhibition, combined with genotoxic stress, can be exploited for cancer therapy. Here, we show that transient inhibition of telomerase activity by the specific inhibitor, GRN163L, increases the cytotoxicity of some, but not all, DNA-damaging agents. Such synergistic inhibition of growth requires the use of DNA-damaging agents that are toxic in the S/G(2) phase of the cell cycle. Notably, inhibition of Ataxia Telangiectasia Mutated (ATM) kinase, together with telomerase inhibition, synergistically increases the cytotoxicity induced by the G(2)-specific topoisomerase II inhibitor etoposide. By varying the timing of telomerase inhibition, relative to the timing of DNA damage, it is apparent that the prosurvival functions of telomerase occur at early stages of DNA damage recognition and repair. Our results suggest that the protective role of telomerase in cell cycle-restricted DNA damage repair could be exploited for combined anticancer chemotherapy. PMID- 20837666 TI - Angiotensin-(1-7) reduces fibrosis in orthotopic breast tumors. AB - Angiotensin-(1-7) [Ang-(1-7)] is an endogenous 7-amino acid peptide hormone of the renin-angiotensin system that has antiproliferative properties. In this study, Ang-(1-7) inhibited the growth of cancer-associated fibroblasts (CAF) and reduced fibrosis in the tumor microenvironment. A marked decrease in tumor volume and weight was observed in orthotopic human breast tumors positive for the estrogen receptor (BT-474 or ZR-75-1) and HER2 (BT-474) following Ang-(1-7) administration to athymic mice. Ang-(1-7) concomitantly reduced interstitial fibrosis in association with a significant decrease in collagen I deposition, along with a similar reduction in perivascular fibrosis. In CAFs isolated from orthotopic breast tumors, the heptapeptide markedly attenuated in vitro growth as well as reduced fibronectin, transforming growth factor-beta (TGF-beta), and extracellular signal-regulated kinase 1/2 kinase activity. An associated increase in the mitogen-activated protein kinase (MAPK) phosphatase DUSP1 following treatment with Ang-(1-7) suggested a potential mechanism by which the heptapeptide reduced MAPK signaling. Consistent with these in vitro observations, immunohistochemical analysis of Ang-(1-7)-treated orthotopic breast tumors revealed reduced TGF-beta and increased DUSP1. Together, our findings indicate that Ang-(1-7) targets the tumor microenvironment to inhibit CAF growth and tumor fibrosis. PMID- 20837665 TI - Integrated microfluidic and imaging platform for a kinase activity radioassay to analyze minute patient cancer samples. AB - Oncogenic kinase activity and the resulting aberrant growth and survival signaling are a common driving force of cancer. Accordingly, many successful molecularly targeted anticancer therapeutics are directed at inhibiting kinase activity. To assess kinase activity in minute patient samples, we have developed an immunocapture-based in vitro kinase assay on an integrated polydimethylsiloxane microfluidics platform that can reproducibly measure kinase activity from as few as 3,000 cells. For this platform, we adopted the standard radiometric (32)P-ATP-labeled phosphate transfer assay. Implementation on a microfluidic device required us to develop methods for repeated trapping and mixing of solid-phase affinity microbeads. We also developed a solid-state beta particle camera imbedded directly below the microfluidic device for real-time quantitative detection of the signal from this and other microfluidic radiobioassays. We show that the resulting integrated device can measure ABL kinase activity from BCR-ABL-positive leukemia patient samples. The low sample input requirement of the device creates new potential for direct kinase activity experimentation and diagnostics on patient blood, bone marrow, and needle biopsy samples. PMID- 20837667 TI - Gadolinium-enhanced coronary CT angiography: improved safety? PMID- 20837668 TI - Diagnosing coronary artery occlusion in NSTEACS with strain echocardiography. PMID- 20837669 TI - Anti-troponin autoantibodies and the cardiovascular system. AB - Autoimmunity plays a role in the pathogenesis of numerous cardiac diseases such as dilated cardiomyopathy (DCM), myocarditis, rheumatic fever and atherosclerosis. An autoimmune response may appear following myocardial injury and exposure to self-antigens. Anti-heart autoantibodies have been identified in patients with heart disease and in low titres of healthy individuals. Troponin is the preferred marker in detecting acute coronary syndrome. In recent years, anti troponin autoantibodies were identified in patients with DCM and ischaemic cardiomyopathy. The presence of anti-troponin autoantibodies in the serum may cause a false-negative evaluation of troponin levels and delay treatment of acute coronary syndrome. The role of anti-troponin autoantibodies in humans and their possible involvement in the pathogenesis of heart disease remains controversial. Previous studies have demonstrated that anti-troponin autoantibodies can cause cardiac dysfunction in animal models. This paper reviews current knowledge on anti-troponin autoantibodies. Future research should focus on the pathogenic role of anti-troponin autoantibodies and reactive T cells and the possible benefits of targeted therapy in acute coronary syndrome, post-myocardial infarction, myocarditis, DCM and heart failure. PMID- 20837670 TI - Cardiovascular magnetic resonance evaluation of the patient with known or suspected coronary artery disease. PMID- 20837671 TI - Amiodarone: an effective antiarrhythmic drug with unusual side effects. PMID- 20837672 TI - A complex case of lactic acidosis in an HIV-positive individual. PMID- 20837673 TI - Characterization of the PCMBS-dependent modification of KCa3.1 channel gating. AB - Intermediate conductance, calcium-activated potassium channels are gated by the binding of intracellular Ca(2+) to calmodulin, a Ca(2+)-binding protein that is constitutively associated with the C terminus of the channel. Although previous studies indicated that the pore-lining residues along the C-terminal portion of S6 contribute to the activation mechanism, little is known about whether the nonluminal face of S6 contributes to this process. Here we demonstrate that the sulfhydral reagent, parachloromercuribenze sulfonate (PCMBS), modifies an endogenous cysteine residue predicted to have a nonluminal orientation (Cys(276)) along the sixth transmembrane segment (S6). Modification of Cys(276) manipulates the steady-state and kinetic behavior of the channel by shifting the gating equilibrium toward the open state, resulting in a left shift in apparent Ca(2+) affinity and a slowing in the deactivation process. Using a six-state gating scheme, our analysis shows that PCMBS slows the transition between the open state back to the third closed state. Interpreting this result in the context of the steady-state and kinetic data suggests that PCMBS functions to shift the gating equilibrium toward the open state by disrupting channel closing. In an attempt to understand whether the nonluminal face of S6 participates in the activation mechanism, we conducted a partial tryptophan scan of this region. Substituting a tryptophan for Leu(281) recapitulated the effect on the steady-state and kinetic behavior observed with PCMBS. Considering the predicted nonluminal orientation of Cys(276) and Leu(281), a simple physical interpretation of these results is that the nonluminal face of S6 forms a critical interaction surface mediating the transition into the closed conformation, suggesting the nonluminal C-terminal portion of S6 is allosterically coupled to the activation gate. PMID- 20837674 TI - Coordinated control of sensitivity by two splice variants of Galpha(o) in retinal ON bipolar cells. AB - The high sensitivity of scotopic vision depends on the efficient retinal processing of single photon responses generated by individual rod photoreceptors. At the first synapse in the mammalian retina, rod outputs are pooled by a rod "ON" bipolar cell, which uses a G-protein signaling cascade to enhance the fidelity of the single photon response under conditions where few rods absorb light. Here we show in mouse rod bipolar cells that both splice variants of the G(o) alpha subunit, Galpha(o1) and Galpha(o2), mediate light responses under the control of mGluR6 receptors, and their coordinated action is critical for maximizing sensitivity. We found that the light response of rod bipolar cells was primarily mediated by Galpha(o1), but the loss of Galpha(o2) caused a reduction in the light sensitivity. This reduced sensitivity was not attributable to the reduction in the total number of G(o) alpha subunits, or the altered balance of expression levels between the two splice variants. These results indicate that Galpha(o1) and Galpha(o2) both mediate a depolarizing light response in rod bipolar cells without occluding each other's actions, suggesting they might act independently on a common effector. Thus, Galpha(o2) plays a role in improving the sensitivity of rod bipolar cells through its action with Galpha(o1). The coordinated action of two splice variants of a single Galpha may represent a novel mechanism for the fine control of G-protein activity. PMID- 20837677 TI - The impact of mild cognitive impairment on decision making in two gambling tasks. AB - OBJECTIVES: This study aimed to investigate whether patients with mild cognitive impairment (MCI) present difficulties in making decisions under ambiguity and under risk. METHODS: Performance of MCI patients in the Iowa Gambling Task (IGT) and in the Probability-Associated Gambling Task-Revised (PAG-R) was compared with performance of healthy aging peers. RESULTS: In the IGT, controls made increasingly frequent advantageous selections over time; MCI patients selected randomly from advantageous and disadvantageous decks, with no significant change in performance over time. In the PAG-R, controls decided advantageously in conditions of both (low, high) winning probabilities; patients made less advantageous decisions than controls in conditions of low winning probability. DISCUSSION: In the decision under ambiguity task (IGT), MCI patients experienced difficulties in learning from feedback and in maintaining an advantageous strategy over time. In the decision under risk task (PAG-R), patients had problems in integrating information from different sources and in adapting their strategy to changes in the decision situation. In summary, MCI patients present difficulties in advantageous decision making that resemble those reported for patients with mild dementia. PMID- 20837675 TI - IP(3)-dependent, post-tetanic calcium transients induced by electrostimulation of adult skeletal muscle fibers. AB - Tetanic electrical stimulation induces two separate calcium signals in rat skeletal myotubes, a fast one, dependent on Cav 1.1 or dihydropyridine receptors (DHPRs) and ryanodine receptors and related to contraction, and a slow signal, dependent on DHPR and inositol trisphosphate receptors (IP(3)Rs) and related to transcriptional events. We searched for slow calcium signals in adult muscle fibers using isolated adult flexor digitorum brevis fibers from 5-7-wk-old mice, loaded with fluo-3. When stimulated with trains of 0.3-ms pulses at various frequencies, cells responded with a fast calcium signal associated with muscle contraction, followed by a slower signal similar to one previously described in cultured myotubes. Nifedipine inhibited the slow signal more effectively than the fast one, suggesting a role for DHPR in its onset. The IP(3)R inhibitors Xestospongin B or C (5 uM) also inhibited it. The amplitude of post-tetanic calcium transients depends on both tetanus frequency and duration, having a maximum at 10-20 Hz. At this stimulation frequency, an increase of the slow isoform of troponin I mRNA was detected, while the fast isoform of this gene was inhibited. All three IP(3)R isoforms were present in adult muscle. IP(3)R-1 was differentially expressed in different types of muscle fibers, being higher in a subset of fast-type fibers. Interestingly, isolated fibers from the slow soleus muscle did not reveal the slow calcium signal induced by electrical stimulus. These results support the idea that IP(3)R-dependent slow calcium signals may be characteristic of distinct types of muscle fibers and may participate in the activation of specific transcriptional programs of slow and fast phenotype. PMID- 20837676 TI - Propositional density and cognitive function in later life: findings from the Precursors Study. AB - OBJECTIVES: We used longitudinal data from the Johns Hopkins Precursors Study to test the hypothesis that written propositional density measured early in life is lower for people who develop dementia categorized as Alzheimer's disease (AD). This association was reported in 1996 for the Nun Study, and the Precursors Study offered an unprecedented chance to reexamine it among respondents with different gender, education, and occupation profiles. METHODS: Eighteen individuals classified as AD patients (average age at diagnosis: 74) were assigned 2 sex-and age matched controls, and propositional density in medical school admission essays (average age at writing: 22) was assessed via Computerized Propositional Idea Density Rater 3 linguistic analysis software. Adjusted odds ratios (ORs) for the matched case-control study were calculated using conditional (fixed-effects) logistic regression. RESULTS: Mean propositional density is lower for cases than for controls (4.70 vs. 4.99 propositions per 10 words, 1-sided p = .01). Higher propositional density substantially lowers the odds of AD (OR = 0.16, 95% confidence interval = 0.03-0.90, 1-sided p = .02). DISCUSSION: Propositional density scores in writing samples from early adulthood appear to predict AD in later life for men as well as women. Studies of cognition across the life course might beneficially incorporate propositional density as a potential marker of cognitive reserve. PMID- 20837678 TI - Identification of 5alpha, 6alpha-epoxycholesterol as a novel modulator of liver X receptor activity. AB - The liver X receptors (LXRalpha and LXRbeta) are members of the nuclear receptor superfamily that function as key transcriptional regulators of a number of biological processes, including cholesterol homeostasis, lipid metabolism, and keratinocyte differentiation. Natural ligands that activate LXRs include oxysterol derivatives such as 25-hydroxycholesterol, 27-hydroxycholesterol, 22(R) hydroxycholesterol, 20(S)-hydroxycholesterol, and 24(S),25-epoxycholesterol. Related oxysterols, such as 5alpha,6alpha-epoxycholesterol (5,6-EC) are present in a number of foods and have been shown to induce atherosclerosis in animal models. Intriguingly, these oxysterols have also been detected in atherosclerotic plaques. Using a variety of biochemical and cellular assays, we demonstrate that 5,6-EC is the first dietary modulator and an endogenous LXR ligand with cell and gene context-dependent antagonist, agonist, and inverse agonist activities. In a multiplexed LXR-cofactor peptide interaction assay, 5,6-EC induced the recruitment of a number of cofactor peptides onto both LXRalpha and LXRbeta and showed an EC(50) of approximately 2 MUM in peptide recruitment. Furthermore, 5,6 EC bound to LXRalpha in a radiolabeled ligand displacement assay (EC(50) = 76 nM), thus demonstrating it to be one of the most potent natural LXRalpha ligands known to date. Analysis of endogenous gene expression in various cell-based systems indicated the potential of 5,6-EC to antagonize LXR-mediated gene expression. Furthermore, it also induced the expression of some LXR-responsive genes in keratinocytes. These results clearly demonstrate that 5,6-EC is an LXR modulator that may play a role in the development of lipid disorders, such as atherosclerosis, by antagonizing the agonistic action of endogenous LXR ligands. PMID- 20837679 TI - Mapping the ligand binding sites of kainate receptors: molecular determinants of subunit-selective binding of the antagonist [3H]UBP310. AB - Kainate receptors (KARs) modulate synaptic transmission and plasticity, and their dysfunction has been linked to several disease states such as epilepsy and chronic pain. KARs are tetramers formed from five different subunits. GluK1-3 are low affinity kainate binding subunits, whereas GluK4/5 bind kainate with high affinity. A number of these subunits can be present in any given cell type, and different combinations of subunits confer different properties to KARs. Here we report the characterization of a new GluK1 subunit-selective radiolabeled antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxythiophene-3-yl-methyl)-5 methylpyrimidine-2,4-dione ([(3)H]UBP310) using human recombinant KARs. [(3)H]UBP310 binds to GluK1 with low nanomolar affinity (K(D) = 21 +/- 7 nM) but shows no specific binding to GluK2. However, [(3)H]UBP310 also binds to GluK3 (K(D) = 0.65 +/- 0.19 MUM) but with ~30-fold lower affinity than that observed for GluK1. Competition [(3)H]UBP310 binding experiments on GluK1 revealed the same rank order of affinity of known GluK1-selective ligands as reported previously in functional assays. Nonconserved residues in GluK1-3 adjudged in modeling studies to be important in determining the GluK1 selectivity of UBP310 were point-mutated to switch residues between subunits. None of the mutations altered the expression or trafficking of KAR subunits. Whereas GluK1-T503A mutation diminished [(3)H]UBP310 binding, GluK2-A487T mutation rescued it. Likewise, whereas GluK1-N705S/S706N mutation decreased, GluK3-N691S mutation increased [(3)H]UBP310 binding activity. These data show that Ala487 in GluK2 and Asn691 in GluK3 are important determinants in reducing the affinity of UBP310 for these subunits. Insights from these modeling and point mutation studies will aid the development of new subunit-selective KAR antagonists. PMID- 20837681 TI - What people want at the end of life. PMID- 20837682 TI - Cancer: it's time to change the sign. PMID- 20837683 TI - Effect of early surgery after hip fracture on mortality and complications: systematic review and meta-analysis. AB - BACKGROUND: Guidelines exist for the surgical treatment of hip fracture, but the effect of early surgery on mortality and other outcomes that are important for patients remains unclear. We conducted a systematic review and meta-analysis to determine the effect of early surgery on the risk of death and common postoperative complications among elderly patients with hip fracture. METHODS: We searched electronic databases (including MEDLINE and EMBASE), the archives of meetings of orthopedic associations and the bibliographies of relevant articles and questioned experts to identify prospective studies, published in any language, that evaluated the effects of early surgery in patients undergoing procedures for hip fracture. Two reviewers independently assessed methodologic quality and extracted relevant data. We pooled data by means of the DerSimonian and Laird random-effects model, which is based on the inverse variance method. RESULTS: We identified 1939 citations, of which 16 observational studies met our inclusion criteria. These studies had a total of 13 478 patients for whom mortality data were complete (1764 total deaths). Based on the five studies that reported adjusted risk of death (4208 patients, 721 deaths), irrespective of the cut-off for delay (24, 48 or 72 hours), earlier surgery (i.e., within the cut-off time) was associated with a significant reduction in mortality (relative risk [RR] 0.81, 95% confidence interval [CI] 0.68-0.96, p = 0.01). Unadjusted data indicated that earlier surgery also reduced in-hospital pneumonia (RR 0.59, 95% CI 0.37-0.93, p = 0.02) and pressure sores (RR 0.48, 95% CI 0.34-0.69, p < 0.001). INTERPRETATION: Earlier surgery was associated with a lower risk of death and lower rates of postoperative pneumonia and pressure sores among elderly patients with hip fracture. These results suggest that reducing delays may reduce mortality and complications. PMID- 20837684 TI - Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial. AB - BACKGROUND: Cryotherapy is widely used for the treatment of cutaneous warts in primary care. However, evidence favours salicylic acid application. We compared the effectiveness of these treatments as well as a wait-and-see approach. METHODS: Consecutive patients with new cutaneous warts were recruited in 30 primary care practices in the Netherlands between May 1, 2006, and Jan. 26, 2007. We randomly allocated eligible patients to one of three groups: cryotherapy with liquid nitrogen every two weeks, self-application of salicylic acid daily or a wait-and-see approach. The primary outcome was the proportion of participants whose warts were all cured at 13 weeks. Analysis was on an intention-to-treat basis. Secondary outcomes included treatment adherence, side effects and treatment satisfaction. Research nurses assessed outcomes during home visits at 4, 13 and 26 weeks. RESULTS: Of the 250 participants (age 4 to 79 years), 240 were included in the analysis at 13 weeks (loss to follow-up 4%). Cure rates were 39% (95% confidence interval [CI] 29%-51%) in the cryotherapy group, 24% (95% CI 16%-35%) in the salicylic acid group and 16% (95% CI 9.5%-25%) in the wait-and see group. Differences in effectiveness were most pronounced among participants with common warts (n = 116): cure rates were 49% (95% CI 34%-64%) in the cryotherapy group, 15% (95% CI 7%-30%) in the salicylic acid group and 8% (95% CI 3%-21%) in the wait-and-see group. Cure rates among the participants with plantar warts (n = 124) did not differ significantly between treatment groups. INTERPRETATION: For common warts, cryotherapy was the most effective therapy in primary care. For plantar warts, we found no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait-and-see approach after 13 weeks. (ClinicalTrial.gov registration no. ISRCTN42730629). PMID- 20837685 TI - Putting ACCOMPLISH into context: management of hypertension in 2010. PMID- 20837686 TI - Hydroa vacciniforme. PMID- 20837688 TI - Persistent headache after earache. PMID- 20837689 TI - OpenNotes Project "levels the playing field" between doctors and patients. PMID- 20837690 TI - United States to compel physicians to make "meaningful use" of electronic health records. PMID- 20837691 TI - One-stop shopping for international medical graduates. PMID- 20837692 TI - Obama's health law at six months: survival is not assured. PMID- 20837693 TI - A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. AB - PURPOSE: To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen. EXPERIMENTAL DESIGN: Quantitative real time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures. RESULTS: Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior. CONCLUSION: The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points. PMID- 20837694 TI - CD44 expression predicts local recurrence after radiotherapy in larynx cancer. AB - PURPOSE: To find molecular markers from expression profiling data to predict recurrence of laryngeal cancer after radiotherapy. EXPERIMENTAL DESIGN: We generated gene expression data on pre-treatment biopsies from 52 larynx cancer patients. Patients developing a local recurrence were matched for T-stage, subsite, treatment, gender and age with non-recurrence patients. Candidate genes were then tested by immunohistochemistry on tumor material from a second series of 76 patients. Both series comprised early stage cancer treated with radiotherapy alone. Finally, gene expression data of eight larynx cancer cell lines with known radiosensitivity were analyzed. RESULTS: Nineteen patients with a local recurrence were matched with 33 controls. Gene sets for hypoxia, proliferation and intrinsic radiosensitivity did not correlate with recurrence, whereas expression of the putative stem cell marker CD44 did. In a supervised analysis, probes for all three splice variants of CD44 on the array appeared in the top 10 most significantly correlated with local recurrence. Immunohistochemical analysis of CD44 expression on the independent validation series confirmed CD44's predictive potential. In 8 larynx cancer cell lines, CD44 gene expression did not correlate with intrinsic radiosensitivity although it did correlate significantly with plating efficiency, consistent with a relationship with stem cell content. CONCLUSIONS: CD44 was the only biological factor tested which significantly correlated with response to radiotherapy in early stage larynx cancer patients, both at the mRNA and protein levels. Further studies are needed to confirm this and to assess how general these findings are for other head and neck tumor stages and sites. PMID- 20837695 TI - Analysis of the yield of phase II combination therapy trials in medical oncology. AB - PURPOSE: Phase II clinical studies screen for treatment regimens that improve patient care, but screening combination regimens is especially challenging. We hypothesized that recognized flaws of single-arm trials could be magnified in combination treatment studies, leading to many reported positive phase II trials but with a low fraction resulting in practice-changing phase III trials. EXPERIMENTAL DESIGN: We searched medline and identified 363 combination chemotherapy clinical trials published in 2001 and 2002. Studies were rated as positive, negative, or inconclusive based on a standardized review of abstract and text. The Web of Science Index (Thomson Reuters, NY, NY) was searched for all articles published between January 2003 and October 2007 that cited at least one of these 363 published trials. RESULTS: Of 363 published phase II combination chemotherapy trials, 262 (72%) were declared to be positive. Among 3,760 unique subsequent citing papers, 20 reported randomized phase III trials of the same combination in the same disease as the source paper, and 10 of these resulted in improved standards of care. Estimating from these data, the likelihood that a published, positive phase II combination chemotherapy trial will result in a subsequent trial showing an improvement in standard of care within five years was 0.038 (95% confidence interval, 0.016-0.064). CONCLUSIONS: The contributory value of combination chemotherapy phase II trials done by 2001-2002 standards is low despite the participation of more than 16,000 subjects. Future phase II studies of combination regimens require better methods to screen for treatments most likely to improve standards of care. PMID- 20837696 TI - Type I interferon: friend or foe? AB - Although the role of type I interferon (IFN) in the protection against viral infections has been known and studied for decades, its role in other immunologically relevant scenarios, including bacterial infections, shock, autoimmunity, and cancer, is less well defined and potentially much more complicated. PMID- 20837697 TI - Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. AB - Progressive accumulation of PrP(Sc), a hallmark of prion diseases, occurs when conversion of PrP(C) into PrP(Sc) is faster than PrP(Sc) clearance. Engulfment of apoptotic bodies by phagocytes is mediated by Mfge8 (milk fat globule epidermal growth factor 8). In this study, we show that brain Mfge8 is primarily produced by astrocytes. Mfge8 ablation induced accelerated prion disease and reduced clearance of cerebellar apoptotic bodies in vivo, as well as excessive PrP(Sc) accumulation and increased prion titers in prion-infected C57BL/6 * 129Sv mice and organotypic cerebellar slices derived therefrom. These phenotypes correlated with the presence of 129Sv genomic markers in hybrid mice and were not observed in inbred C57BL/6 Mfge8(-/-) mice, suggesting the existence of additional strain specific genetic modifiers. Because Mfge8 receptors are expressed by microglia and depletion of microglia increases PrP(Sc) accumulation in organotypic cerebellar slices, we conclude that engulfment of apoptotic bodies by microglia may be an important pathway of prion clearance controlled by astrocyte-borne Mfge8. PMID- 20837698 TI - IAP inhibitors enhance co-stimulation to promote tumor immunity. AB - The inhibitor of apoptosis proteins (IAPs) have recently been shown to modulate nuclear factor kappaB (NF-kappaB) signaling downstream of tumor necrosis factor (TNF) family receptors, positioning them as essential survival factors in several cancer cell lines, as indicated by the cytotoxic activity of several novel small molecule IAP antagonists. In addition to roles in cancer, increasing evidence suggests that IAPs have an important function in immunity; however, the impact of IAP antagonists on antitumor immune responses is unknown. In this study, we examine the consequences of IAP antagonism on T cell function in vitro and in the context of a tumor vaccine in vivo. We find that IAP antagonists can augment human and mouse T cell responses to physiologically relevant stimuli. The activity of IAP antagonists depends on the activation of NF-kappaB2 signaling, a mechanism paralleling that responsible for the cytotoxic activity in cancer cells. We further show that IAP antagonists can augment both prophylactic and therapeutic antitumor vaccines in vivo. These findings indicate an important role for the IAPs in regulating T cell-dependent responses and suggest that targeting IAPs using small molecule antagonists may be a strategy for developing novel immunomodulating therapies against cancer. PMID- 20837699 TI - Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. AB - The role of lymphangiogenesis in inflammation has remained unclear. To investigate the role of lymphatic versus blood vasculature in chronic skin inflammation, we inhibited vascular endothelial growth factor (VEGF) receptor (VEGFR) signaling by function-blocking antibodies in the established keratin 14 (K14)-VEGF-A transgenic (Tg) mouse model of chronic cutaneous inflammation. Although treatment with an anti-VEGFR-2 antibody inhibited skin inflammation, epidermal hyperplasia, inflammatory infiltration, and angiogenesis, systemic inhibition of VEGFR-3, surprisingly, increased inflammatory edema formation and inflammatory cell accumulation despite inhibition of lymphangiogenesis. Importantly, chronic Tg delivery of the lymphangiogenic factor VEGF-C to the skin of K14-VEGF-A mice completely inhibited development of chronic skin inflammation, epidermal hyperplasia and abnormal differentiation, and accumulation of CD8 T cells. Similar results were found after Tg delivery of mouse VEGF-D that only activates VEGFR-3 but not VEGFR-2. Moreover, intracutaneous injection of recombinant VEGF-C156S, which only activates VEGFR-3, significantly reduced inflammation. Although lymphatic drainage was inhibited in chronic skin inflammation, it was enhanced by Tg VEGF-C delivery. Together, these results reveal an unanticipated active role of lymphatic vessels in controlling chronic inflammation. Stimulation of functional lymphangiogenesis via VEGFR-3, in addition to antiangiogenic therapy, might therefore serve as a novel strategy to treat chronic inflammatory disorders of the skin and possibly also other organs. PMID- 20837700 TI - Temperature response of isoprene emission in vivo reflects a combined effect of substrate limitations and isoprene synthase activity: a kinetic analysis. AB - The responses of isoprene emission rate to temperature are characterized by complex time-dependent behaviors that are currently not entirely understood. To gain insight into the temperature dependencies of isoprene emission, we studied steady-state and transient responses of isoprene emission from hybrid aspen (Populus tremula * Populus tremuloides) leaves using a fast-response gas-exchange system coupled to a proton-transfer reaction mass spectrometer. A method based on postillumination isoprene release after rapid temperature transients was developed to determine the rate constant of isoprene synthase (IspS), the pool size of its substrate dimethylallyldiphosphate (DMADP), and to separate the component processes of the temperature dependence of isoprene emission. Temperature transients indicated that over the temperature range 25 degrees C to 45 degrees C, IspS was thermally stable and operated in the linear range of its substrate DMADP concentration. The in vivo rate constant of IspS obeyed the Arrhenius law, with an activation energy of 42.8 kJ mol(-1). In contrast, steady state isoprene emission had a significantly lower temperature optimum than IspS and higher activation energy. The reversible temperature-dependent decrease in the rate of isoprene emission between 35 degrees C and 44 degrees C was caused by decreases in DMADP concentration, possibly reflecting reduced pools of energetic metabolites generated in photosynthesis, particularly of ATP. Strong control of isoprene temperature responses by the DMADP pool implies that transient temperature responses under fluctuating conditions in the field are driven by initial DMADP pool size as well as temperature-dependent modifications in DMADP pool size during temperature transients. These results have important implications for the development of process-based models of isoprene emission. PMID- 20837701 TI - Mrt, a gene unique to fungi, encodes an oligosaccharide transporter and facilitates rhizosphere competency in Metarhizium robertsii. AB - The symbiotic associations between rhizospheric fungi and plants have enormous environmental impact. Fungi are crucial to plant health as antagonists of pathogens and herbivores and facilitate the uptake of soil nutrients. However, little is known about the plant products obtained by fungi in exchange or how they are transported through the symbiotic interface. Here, we demonstrate that sucrose and raffinose family oligosaccharides in root exudates are important for rhizosphere competence in the insect pathogen Metarhizium robertsii (formerly known as Metarhizium anisopliae). We identified mutants in the Metarhizium raffinose transporter (Mrt) gene of M. robertsii that grew poorly in root exudate and were greatly reduced in rhizosphere competence on grass roots. Studies on sugar uptake, including competition assays, revealed that MRT was a sucrose and galactoside transporter. Disrupting MRT resulted in greatly reduced or no growth on sucrose and galactosides but did not affect growth on monosaccharides or oligosaccharides composed entirely of glucose subunits. Consistent with this, expression of Mrt is exclusively up-regulated by galactosides and sucrose. Expressing a green fluorescent protein gene under the control of the Mrt promoter confirmed that MRT was expressed by germlings in the vicinity of grass roots but not in surrounding bulk soil. Disrupting Mrt did not reduce virulence to insects, demonstrating that Mrt is exclusively involved in M. robertsii's interactions with plants. To our knowledge, MRT is the first oligosaccharide transporter identified and characterized in a fungus and is unique to filamentous fungi, but homologous genes in Magnaporthe, Ustilago, Aspergillus, Fusarium, Epichloe, and Penicillium species indicate that oligosaccharide transport is of widespread significance. PMID- 20837702 TI - Comparing symbiotic efficiency between swollen versus nonswollen rhizobial bacteroids. AB - Symbiotic rhizobia differentiate physiologically and morphologically into nitrogen-fixing bacteroids inside legume host nodules. The differentiation is apparently terminal in some legume species, such as peas (Pisum sativum) and peanuts (Arachis hypogaea), likely due to extreme cell swelling induced by the host. In other legume species, such as beans (Phaseolus vulgaris) and cowpeas (Vigna unguiculata), differentiation into bacteroids, which are similar in size and shape to free-living rhizobia, is reversible. Bacteroid modification by plants may affect the effectiveness of the symbiosis. Here, we compare symbiotic efficiency of rhizobia in two different hosts where the rhizobia differentiate into swollen nonreproductive bacteroids in one host and remain nonswollen and reproductive in the other. Two such dual-host strains were tested: Rhizobium leguminosarum A34 in peas and beans and Bradyrhizobium sp. 32H1 in peanuts and cowpeas. In both comparisons, swollen bacteroids conferred more net host benefit by two measures: return on nodule construction cost (plant growth per gram nodule growth) and nitrogen fixation efficiency (H(2) production by nitrogenase per CO(2) respired). Terminal bacteroid differentiation among legume species has evolved independently multiple times, perhaps due to the increased host fitness benefits observed in this study. PMID- 20837703 TI - Disruption of the vacuolar calcium-ATPases in Arabidopsis results in the activation of a salicylic acid-dependent programmed cell death pathway. AB - Calcium (Ca(2+)) signals regulate many aspects of plant development, including a programmed cell death pathway that protects plants from pathogens (hypersensitive response). Cytosolic Ca(2+) signals result from a combined action of Ca(2+) influx through channels and Ca(2+) efflux through pumps and cotransporters. Plants utilize calmodulin-activated Ca(2+) pumps (autoinhibited Ca(2+)-ATPase [ACA]) at the plasma membrane, endoplasmic reticulum, and vacuole. Here, we show that a double knockout mutation of the vacuolar Ca(2+) pumps ACA4 and ACA11 in Arabidopsis (Arabidopsis thaliana) results in a high frequency of hypersensitive response-like lesions. The appearance of macrolesions could be suppressed by growing plants with increased levels (greater than 15 mm) of various anions, providing a method for conditional suppression. By removing plants from a conditional suppression, lesion initials were found to originate primarily in leaf mesophyll cells, as detected by aniline blue staining. Initiation and spread of lesions could also be suppressed by disrupting the production or accumulation of salicylic acid (SA), as shown by combining aca4/11 mutations with a sid 2 (for salicylic acid induction-deficient2) mutation or expression of the SA degradation enzyme NahG. This indicates that the loss of the vacuolar Ca(2+) pumps by itself does not cause a catastrophic defect in ion homeostasis but rather potentiates the activation of a SA-dependent programmed cell death pathway. Together, these results provide evidence linking the activity of the vacuolar Ca(2+) pumps to the control of a SA-dependent programmed cell death pathway in plants. PMID- 20837704 TI - Structural evidence for loose linkage between ligand binding and kinase activation in the epidermal growth factor receptor. AB - The mechanisms by which signals are transmitted across the plasma membrane to regulate signaling are largely unknown for receptors with single-pass transmembrane domains such as the epidermal growth factor receptor (EGFR). A crystal structure of the extracellular domain of EGFR dimerized by epidermal growth factor (EGF) reveals the extended, rod-like domain IV and a small, hydrophobic domain IV interface compatible with flexibility. The crystal structure and disulfide cross-linking suggest that the 7-residue linker between the extracellular and transmembrane domains is flexible. Disulfide cross-linking of the transmembrane domain shows that EGF stimulates only moderate association in the first two alpha-helical turns, in contrast to association throughout the membrane over five alpha-helical turns in glycophorin A and integrin. Furthermore, systematic mutagenesis to leucine and phenylalanine suggests that no specific transmembrane interfaces are required for EGFR kinase activation. These results suggest that linkage between ligand-induced dimerization and tyrosine kinase activation is much looser than was previously envisioned. PMID- 20837705 TI - DDX3 regulates cell growth through translational control of cyclin E1. AB - DDX3 belongs to the DEAD box family of RNA helicases, but the details of its biological function remain largely unclear. Here we show that knockdown of DDX3 expression impedes G(1)/S-phase transition of the cell cycle. To know how DDX3 may act in cell cycle control, we screened for cellular mRNA targets of DDX3. Many of the identified DDX3 targets encoded cell cycle regulators, including G(1)/S-specific cyclin E1. DDX3 depletion specifically downregulates translation of cyclin E1 mRNA. Moreover, our data suggest that DDX3 participates in translation initiation of targeted mRNAs as well as in cell growth control via its RNA helicase activity. Consistent with these findings, we show that in the temperature-sensitive DDX3 mutant hamster cell line tsET24, cyclin E1 expression is downregulated at a nonpermissive temperature that inactivates mutant DDX3. Taken together, our results indicate that DDX3 is critical for translation of cyclin E1 mRNA, which provides an alternative mechanism for regulating cyclin E1 expression during the cell cycle. PMID- 20837706 TI - MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. AB - MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G(2)/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A.X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A.X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process. PMID- 20837707 TI - Forkhead box M1 transcription factor is required for macrophage recruitment during liver repair. AB - Acute liver injury results from exposure to toxins, pharmacological agents, or viral infections, contributing to significant morbidity and mortality worldwide. While hepatic inflammation is critical for liver repair, the transcriptional mechanisms required for the recruitment of inflammatory cells to the liver are not understood. Forkhead box M1 (Foxm1) transcription factor is a master regulator of hepatocyte proliferation, but its role in inflammatory cells remains unknown. In this study, we generated transgenic mice in which Foxm1 was deleted from myeloid-derived cells, including macrophages, monocytes, and neutrophils. Carbon tetrachloride liver injury was used to demonstrate that myeloid-specific Foxm1 deletion caused a delay in liver repair. Although Foxm1 deficiency did not influence neutrophil infiltration into injured livers, the total numbers of mature macrophages were dramatically reduced. Surprisingly, Foxm1 deficiency did not influence the proliferation of macrophages or their monocytic precursors but impaired monocyte recruitment during liver repair. Expression of L-selectin and the CCR2 chemokine receptor, both critical for monocyte recruitment to injured tissues, was decreased. Foxm1 induced transcriptional activity of the mouse CCR2 promoter in cotransfection experiments. Adoptive transfer of monocytes to Foxm1 deficient mice restored liver repair and rescued liver function. Foxm1 is critical for liver repair and is required for the recruitment of monocytes to the injured liver. PMID- 20837709 TI - Cdc13 N-terminal dimerization, DNA binding, and telomere length regulation. AB - The essential yeast protein Cdc13 facilitates chromosome end replication by recruiting telomerase to telomeres, and together with its interacting partners Stn1 and Ten1, it protects chromosome ends from nucleolytic attack, thus contributing to genome integrity. Although Cdc13 has been studied extensively, the precise role of its N-terminal domain (Cdc13N) in telomere length regulation remains unclear. Here we present a structural, biochemical, and functional characterization of Cdc13N. The structure reveals that this domain comprises an oligonucleotide/oligosaccharide binding (OB) fold and is involved in Cdc13 dimerization. Biochemical data show that Cdc13N weakly binds long, single stranded, telomeric DNA in a fashion that is directly dependent on domain oligomerization. When introduced into full-length Cdc13 in vivo, point mutations that prevented Cdc13N dimerization or DNA binding caused telomere shortening or lengthening, respectively. The multiple DNA binding domains and dimeric nature of Cdc13 offer unique insights into how it coordinates the recruitment and regulation of telomerase access to the telomeres. PMID- 20837708 TI - Cyclic AMP controls mTOR through regulation of the dynamic interaction between Rheb and phosphodiesterase 4D. AB - The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. Cyclic AMP (cAMP) is considered to be an important second messenger that controls mTOR; however, the signaling components of this pathway have not yet been elucidated. Here, we identify cAMP phosphodiesterase 4D (PDE4D) as a binding partner of Rheb that acts as a cAMP-specific negative regulator of mTORC1. Under basal conditions, PDE4D binds Rheb in a noncatalytic manner that does not require its cAMP-hydrolyzing activity and thereby inhibits the ability of Rheb to activate mTORC1. However, elevated cAMP levels disrupt the interaction of PDE4D with Rheb and increase the interaction between Rheb and mTOR. This enhanced Rheb mTOR interaction induces the activation of mTORC1 and cap-dependent translation, a cellular function of mTORC1. Taken together, our results suggest a novel regulatory mechanism for mTORC1 in which the cAMP-determined dynamic interaction between Rheb and PDE4D provides a key, unique regulatory event. We also propose a new role for PDE4 as a molecular transducer for cAMP signaling. PMID- 20837710 TI - Differential roles of Sall4 isoforms in embryonic stem cell pluripotency. AB - Murine embryonic stem (ES) cells are defined by continuous self-renewal and pluripotency. A diverse repertoire of protein isoforms arising from alternative splicing is expressed in ES cells without defined biological roles. Sall4, a transcription factor essential for pluripotency, exists as two isoforms (Sall4a and Sall4b). Both isoforms can form homodimers and a heterodimer with each other, and each can interact with Nanog. By genomewide location analysis, we determined that Sall4a and Sall4b have overlapping, but not identical binding sites within the ES cell genome. In addition, Sall4b, but not Sall4a, binds preferentially to highly expressed loci in ES cells. Sall4a and Sall4b binding sites are distinguished by both epigenetic marks at target loci and their clustering with binding sites of other pluripotency factors. When ES cells expressing a single isoform of Sall4 are generated, Sall4b alone could maintain the pluripotent state, although it could not completely suppress all differentiation markers. Sall4a and Sall4b collaborate in maintenance of the pluripotent state but play distinct roles. Our work is novel in establishing such isoform-specific differences in ES cells. PMID- 20837711 TI - New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism. AB - PURPOSE: Type I pseudohypoparathyroidism (PHP-I) can be subclassified into Ia and Ib, depending on the presence or absence of Albright's hereditary osteodystrophy's phenotype, diminished alpha-subunit of the stimulatory G protein (G(s)alpha) activity and multihormonal resistance. Whereas PHP-Ia is mainly associated with heterozygous inactivating mutations in G(s)alpha-coding exons of GNAS, PHP-Ib is caused by imprinting defects of GNAS. To date, just one patient with PHP and complete paternal uniparental disomy (UPD) has been described. We sought to identify the underlining molecular defect in twenty patients with parathyroid hormone resistance, hypocalcemia and hyperphosphatemia, and abnormal methylation pattern at GNAS locus. METHODS: Microsatellite typing and comparative genome hybridization were performed for proband and parents. RESULTS: We describe four patients with partial paternal UPD of chromosome 20 involving pat20qUPD in one case, from 20q13.13-qter in two cases, and pat20p heterodisomy plus interstitial 20q isodisomy in one patient. CONCLUSIONS: These observations demonstrate that mitotic recombination of chromosome 20 can also give rise to UPD and PHP, a situation similar to other imprinting disorders, such as Beckwith Wiedemann syndrome or neonatal diabetes. PMID- 20837712 TI - Role of ferroportin in macrophage-mediated immunity. AB - Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I like protein that interacts with transferrin receptors. HFE-associated hemochromatosis is characterized by abnormally high levels of the iron efflux protein ferroportin. In this study, J774 murine macrophages overexpressing ferroportin were used to investigate the influence of iron metabolism on the release of nitric oxide (NO) in response to infection. Overexpression of ferroportin significantly impaired intracellular Mycobacterium tuberculosis growth during early stages of infection. When challenged with lipopolysaccharide (LPS) or M. tuberculosis infection, control macrophages increased NO synthesis, but macrophages overexpressing ferroportin had significantly impaired NO production in response to LPS or M. tuberculosis. Increased NO synthesis in control cells was accompanied by increased iNOS mRNA and protein, while upregulation of iNOS protein was markedly reduced when J744 cells overexpressing ferroportin were challenged with LPS or M. tuberculosis, thus limiting the bactericidal activity of these macrophages. The proinflammatory cytokine gamma interferon reversed the inhibitory effect of ferroportin overexpression on NO production. These results suggest a novel role for ferroportin in attenuating macrophage-mediated immune responses. PMID- 20837713 TI - Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing major histocompatibility complex class II molecules capable of antigen presentation. AB - Major histocompatibility complex class II (MHC-II) molecules are released by murine macrophages upon lipopolysaccharide (LPS) stimulation and ATP signaling through the P2X7 receptor. These studies show that infection of macrophages with Mycobacterium tuberculosis or M. bovis strain BCG enhances MHC-II release in synergy with ATP. Shed MHC-II was contained in two distinct organelles, exosomes and plasma membrane-derived microvesicles, which were both able to present exogenous antigenic peptide to T hybridoma cells. Furthermore, microvesicles from mycobacterium-infected macrophages were able to directly present M. tuberculosis antigen (Ag) 85B(241-256)-I-A(b) complexes that were generated by the processing of M. tuberculosis Ag 85B in infected cells to both M. tuberculosis-specific T hybridoma cells and naive P25 M. tuberculosis T-cell receptor (TCR)-transgenic T cells. In the presence of prefixed macrophages, exosomes from mycobacterium infected macrophages provided weak stimulation to M. tuberculosis-specific T hybridoma cells but not naive P25 T cells. Thus, infection with M. tuberculosis primes macrophages for the increased release of exosomes and microvesicles bearing M. tuberculosis peptide-MHC-II complexes that may generate antimicrobial T-cell responses. PMID- 20837714 TI - Role of MyD88 and Toll-like receptors 2 and 4 in the sensing of Parachlamydia acanthamoebae. AB - Parachlamydia acanthamoebae is a Chlamydia-related organism whose pathogenic role in pneumonia is supported by serological and molecular clinical studies and an experimental mouse model of lung infection. Toll-like receptors (TLRs) play a seminal role in sensing microbial products and initiating innate immune responses. The aim of this study was to investigate the roles of MyD88, TLR2, and TLR4 in the interaction of Parachlamydia with macrophages. Here, we showed that Parachlamydia entered bone-marrow derived macrophages (BMDMs) in a TLR independent manner but did not multiply intracellularly. Interestingly, compared to live bacteria, heat-inactivated Parachlamydia induced the production of substantial amounts of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6), and IL-12p40 by BMDMs and of TNF and IL-6 by peritoneal macrophages as well as RAW 264.7 and J774 macrophage cell lines. Cytokine production by BMDMs, which was partially inhibited upon trypsin treatment of Parachlamydia, was dependent on MyD88, TLR4, and, to a lesser extent, TLR2. Finally, MyD88(-/-), TLR4(-/-), and TLR2(-/-) mice were as resistant as wild-type mice to lung infection following the intratracheal instillation of Parachlamydia. Thus, in contrast to Chlamydia pneumoniae, Parachlamydia acanthamoebae weakly stimulates macrophages, potentially compensating for its low replication capacity in macrophages by escaping the innate immune surveillance. PMID- 20837715 TI - Outer membrane protein X (Ail) contributes to Yersinia pestis virulence in pneumonic plague and its activity is dependent on the lipopolysaccharide core length. AB - Yersinia pestis, the causative agent of plague, is one of the most virulent microorganisms known. The outer membrane protein X (OmpX) in Y. pestis KIM is required for efficient bacterial adherence to and internalization by cultured HEp 2 cells and confers resistance to human serum. Here, we tested the contribution of OmpX to disease progression in the fully virulent Y. pestis CO92 strain by engineering a deletion mutant and comparing its ability in mediating pneumonic plague to that of the wild type in two animal models. The deletion of OmpX delayed the time to death up to 48 h in a mouse model and completely attenuated virulence in a rat model of disease. All rats challenged with 1 * 10(8) CFU of the ompX mutant survived, compared to the 50% lethal dose (LD50) of 1.2 * 10(3) CFU for the wild-type strain. Because murine serum is not bactericidal for the ompX mutant, the mechanism underlying the delay in time to death in mice was attributed to loss of adhesion/internalization properties but not serum resistance. The rat model, which is most similar to humans, highlighted the critical role of serum resistance in disease. To resolve conflicting evidence for the role of Y. pestis lipopolysaccharide (LPS) and OmpX in serum resistance, ompX was cloned into Escherichia coli D21 and three isogenic derivatives engineered to have progressively truncated LPS core saccharides. OmpX-mediated serum resistance, adhesiveness, and invasiveness, although dependent on LPS core length, displayed these functions in E. coli, independently of other Yersinia proteins and/or LPS. Also, autoaggregation was required for efficient OmpX mediated adhesiveness and internalization but not serum resistance. PMID- 20837716 TI - Elevated levels of the Plasmodium yoelii homologue of macrophage migration inhibitory factor attenuate blood-stage malaria. AB - The excessive production of proinflammatory cytokines plays a significant role in the pathogenesis of severe malaria. Mammalian macrophage migration inhibitory factor (MIF) (mMIF) is an immune mediator that promotes a sustained proinflammatory response by inhibiting the glucocorticoid-mediated downregulation of inflammation. In addition, Plasmodium parasites also encode a homologue of mammalian MIF that is expressed in asexual-stage parasites. We used the Plasmodium yoelii murine model to study the potential role of parasite-encoded MIF in the pathogenesis of malaria. Antibodies raised against purified, non epitope-tagged P. yoelii MIF (PyMIF) were used to localize expression in trophozoite- and schizont-stage parasites and demonstrate extracellular release. In vitro, recombinant PyMIF was shown to actively induce the chemotaxis of macrophages but did not induce or enhance tumor necrosis factor alpha (TNF-alpha) production from peritoneal macrophages. To examine the role of parasite-derived PyMIF in vivo, two transgenic parasite lines that constitutively overexpress PyMIF were generated, one in a nonlethal P. yoelii 17X background [Py17X-MIF(+)] and the other in a lethal P. yoelii 17XL background [Py17XL-MIF(+)]. Challenge studies with transgenic parasites in mice showed that the increased expression of PyMIF resulted in a reduction in disease severity. Mice infected with Py17X MIF(+) developed lower peak parasitemia levels than controls, while malaria associated anemia was unaltered. Infection with Py17XL-MIF(+) resulted in a prolonged course of infection and a reduction in the overall mortality rate. Combined, the data indicate that parasite-derived MIF does not contribute significantly to immunopathology but, through its chemotactic ability toward macrophages, may attenuate disease and prolong infection of highly virulent parasite isolates. PMID- 20837717 TI - Reduced risk of prostate cancer in U.S. Men with AIDS. AB - BACKGROUND: Previous studies describe decreased prostate cancer risk in HIV infected men. In the United States, prostate-specific antigen (PSA) screening is common and increases the detection of prostate cancer. We evaluated whether the prostate cancer deficit among men with AIDS reflects differential PSA screening. METHODS: Data from the U.S. HIV/AIDS Cancer Match Study were used to calculate standardized incidence ratios (SIR) for prostate cancer, comparing men with AIDS (N = 287,247) to the general population. Furthermore, we estimated PSA testing rates in the Johns Hopkins HIV Clinical Cohort. RESULTS: Prostate cancer rates increased over time in the general population and, beginning in the 1990s, were consistently higher than among men with AIDS. Men with AIDS had the same prostate cancer risk as the general population in the pre-PSA era (<1992, SIR = 1.00), but significantly reduced risk during the PSA era overall (1992-2007, SIR = 0.50) and across age, race, HIV risk group, antiretroviral therapy era, and CD4 counts. Local and regional stage prostate cancer risk was lower among men with AIDS (SIRs, 0.49 and 0.14, respectively), but distant stage cancer risk did not differ (SIR = 0.85). Among HIV-infected men >=40 years old, PSA testing was uncommon (18.7% per year), but increased 2.4-fold from 2000 to 2008, after age adjustment. CONCLUSION: Prostate cancer risk was decreased by 50% among men with AIDS compared with the general population. This deficit was limited to the PSA era and early stage cancers. IMPACT: Our findings suggest that the prostate cancer deficit in HIV-infected men is largely due to differential PSA screening. PMID- 20837718 TI - False-positive results in the randomized controlled trial of mammographic screening from age 40 ("Age" trial). AB - BACKGROUND: False-positive recall is a recognized disadvantage of mammographic breast screening, and the rate of such recalls may be higher in younger women, potentially limiting the value of screening below age 50. METHODS: Attendance and screening outcome data for 53,884 women in the intervention arm of the U.K. Age trial were analyzed to report observed false-positive recall rates during 13 years of trial fieldwork. The Age trial was a randomized controlled trial of the effect of mammographic screening from age 40 on breast cancer mortality, conducted in 23 National Health Service screening centers between 1991 and 2004. Women randomized to the intervention arm were offered annual invitation to mammography from age 40 or 41 to age 48. RESULTS: Overall, 7,893 women (14.6% of women the intervention arm and 18.1% of women attending at least one routine screen) experienced one or more false-positive screen during the trial. The rates of false-positive mammography at first and subsequent routine screens were 4.9% and 3.2%, respectively. The cumulative false-positive rate over seven screens was 20.5%. Eighty-nine percent of women who had a false-positive recall at their previous screen attended their next invitation to routine screening. CONCLUSIONS: The rates of false-positive recall in the Age trial were comparable with the national screening program; however, the positive predictive value of referral was lower. Experiencing a false-positive screen did not seem to lessen the likelihood of re-attendance in the trial. IMPACT: The question of greatly increased false-positive rates in this age group and of their compromising re attendance is refuted by the findings of this study. PMID- 20837720 TI - Gastrointestinal microcirculation: still a mystery? PMID- 20837721 TI - Mice, men, and medicine. PMID- 20837722 TI - Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. AB - Survival from a malignant hyperthermia (MH) crisis is highly dependent on early recognition and prompt action. MH crises are very rare and an increasing use of total i.v. anaesthesia is likely to make it even rarer, leading to the potential risk of reduced awareness of MH. In addition, dantrolene, the cornerstone of successful MH treatment, is unavailable in large areas around the world thereby increasing the risk of MH fatalities in these areas. The European Malignant Hyperthermia Group collected and reviewed all guidelines available from the various MH centres in order to provide a consensus document. The guidelines consist of two textboxes: Box 1 on recognizing MH and Box 2 on the treatment of an MH crisis. PMID- 20837723 TI - Determining the potency of neuromuscular blockers. PMID- 20837724 TI - Lung recruitment and positive airway pressure before extubation: one may not be enough. PMID- 20837725 TI - Bonfils intubating fibrescope in normal paediatric airways. PMID- 20837726 TI - Improvement of cerebral blood flow patterns in hepatorenal syndrome using sustained low-efficiency dialysis. PMID- 20837727 TI - Steep Trendelenburg position, intracranial pressure, and dexamethasone. PMID- 20837728 TI - Feasibility of ultrasound imaging of the abdominal wall in elderly obese volunteers. PMID- 20837729 TI - Postoperative nausea and vomiting in paediatric strabismus surgery. PMID- 20837730 TI - Differential expression of angiotensin II type 1 and type 2 receptors at the maternal-fetal interface: potential roles in early placental development. AB - Angiotensin II (Ang II) is locally generated in the placenta and regulates syncytial transport, vascular contractility and trophoblast invasion. It acts through two receptor subtypes, AGTR1 and AGTR2 (AT1 and AT2), which typically mediate antagonising actions. The objectives of this study are to characterise the cellular distribution of AGTR1 and AGTR2 at the maternal-fetal interface and explore the effects on cytotrophoblast turnover. Low levels of AGTR2 mRNA were detected in first trimester placental homogenates using real-time PCR. Immunohistochemistry using polyclonal antibodies against AGTR1 and AGTR2 detected the receptors in first trimester placenta, decidua basalis and villous tip outgrowths in culture. Serial staining with cytokeratin-7 was used to identify extravillous trophoblasts (EVTs). AGTR1 was found in the syncytiotrophoblast microvillous membrane, in a subpopulation of villous cytotrophoblasts, and in Hofbauer cells. AGTR1 was strongly upregulated in cytotrophoblasts in cell columns and villous tip outgrowths, but was absent in interstitial and endovascular EVTs within the decidua. AGTR2 immunostaining was present in Hofbauer cells and villous cytotrophoblasts, but was absent from syncytiotrophoblast. Faint staining was detected in cell column cytotrophoblasts and villous outgrowths, but not in EVTs within the decidua. Both receptors were detected in placental homogenates by western blotting. Ang II significantly increased proliferation of cytotrophoblasts in both villous explants and villous tip outgrowths, but did not affect apoptosis. Blockade of AGTR1 and AGTR2 together abrogated this effect. This study shows specific expression patterns for AGTR1 and AGTR2 in distinct trophoblast populations at the maternal-fetal interface and suggests that Ang II plays a role in placental development and generation of EVTs. PMID- 20837731 TI - Remodelling at the maternal-fetal interface: relevance to human pregnancy disorders. AB - In human pregnancy, successful placentation and remodelling of the uterine vasculature require the integration of a number of stages, which are crucial for a healthy pregnancy. As the demands of the developing fetus for nutrients and oxygen increase, the capacity of the maternal blood vessels to supply this must be altered radically, with deficiencies in this process implicated in a number of dangerous pregnancy complications. The complex signalling networks that regulate these tightly co-ordinated events are becoming clearer as more studies of early pregnancy are performed. It is the aim of this review to draw together our knowledge of events that occur to facilitate a successful pregnancy ranging from the preparation for implantation, through the invasion and differentiation of the trophoblast and the regulation of these processes by other cells within the decidual environment, to the active role that the trophoblast and maternal immune cells play in facilitating the remodelling of the uterine spiral arteries. The events involved in a healthy pregnancy will then be compared to aberrant placentation and remodelling, which are characteristics of many pregnancy disorders, and recent advances in detection of abnormal placental development will also be discussed. PMID- 20837732 TI - New authors' guidelines for Palliative Medicine: more work for authors, reviewers and editors or an essential tool? PMID- 20837733 TI - Single Question in Delirium (SQiD): testing its efficacy against psychiatrist interview, the Confusion Assessment Method and the Memorial Delirium Assessment Scale. AB - In this study we address the research question; How sensitive is a single question in delirium case finding? Of 33 'target' admissions, consent was obtained from 21 patients. The single question: 'Do you think [name of patient] has been more confused lately?' was put to friend or family. Results of the Single Question in Delirium (SQiD) were compared to psychiatrist interview (PsiI) which was the reference standard. The Confusion Assessment Method (CAM) and two other tools were also applied. Compared with PsiI, the SQiD achieved a sensitivity and specificity of 80% (95% CI 28.3-99.49%) and 71% (41.90-91.61%) respectively. The CAM demonstrated a negative predictive value (NPV) of 80% (51.91-95.67%) and the SQiD showed a NPV of 91% (58.72-99.77%). Kappa correlation of SQiD with the PsiI was 0.431 (p = 0.023). The CAM had a kappa value of 0.37 (p = 0.050). A further important finding in our study was that the CAM had only 40% sensitivity in the hands of minimally trained clinical users. CONCLUSION: The SQiD demonstrates potential as a simple clinical tool worthy or further investigation. PMID- 20837734 TI - Towards defining dental drilling competence, part 1: a study of bone drilling technique. AB - Technical skills are critical for dentists. Computer-based simulation offers a range of potential benefits for surgical training, but to date the development of simulators has not been characterized by a structured investigation of specific mechanisms by which trainees attain competence. This two-part study contributes to the understanding of the manner in which surgical psychomotor skills are acquired so that this knowledge can be incorporated into the design of training simulations. We studied participant groups of varying skill levels as they performed a drilling task in oral surgery. In this first part of our study, we investigated the elements of surgical technique and differences in the drilling performance of novice, competent, and expert dentists. Our results indicate that novice dentists employ a technique that differs considerably in drilling stroke length and duration from that employed by experts. Expert dentists perform faster, apply more force, lift the bur off the bone less, and produce superior results compared with novices. PMID- 20837735 TI - Towards defining dental drilling competence, part 2: a study of cues and factors in bone drilling. AB - The study of expertise in surgery aims to facilitate the development of improved training methods by understanding the characteristics of expert practitioners. In this article and its companion, we present our study of the characteristics of competence and expertise in the field of oral surgery. We observed participants of different skill levels as they performed an ex vivo drilling task designed to test the psychomotor skill of distinguishing the material boundaries between tooth and bone. Part 1 of this study examined the physical characteristics of drilling performance, while this article examines the cognitive aspects of performance. In this article we investigate the psychomotor cues used for decision making during drilling and explore other factors that affect a participant's ability to distinguish tooth from bone. Our results suggest that visual and tactile cues were the most important cues guiding drilling performance in all participant groups. Our results also suggest that when compared to experts, novices relied more on visual cues rather than tactile cues and lacked the psychomotor skills required to utilize the broader range of cues used by experts. PMID- 20837736 TI - Best practices for dental sealants in community service-learning. AB - Community service-learning (CSL) in predoctoral dental education might be an effective tool for increasing sealant use by dentists--thus benefitting underserved children while facilitating students' learning of a clinical procedure in a real-life setting. This study reviewed the scientific literature on this topic in order to 1) evaluate the reasons for low sealant use among dentists, 2) consider important aspects of sealant use in community settings, and 3) identify best practices to use as guidelines for CSL regarding sealant use. As background, the MEDLINE database was searched with the key words "dental sealants" for human and laboratory studies in the English language. A total of 205 relevant articles were identified and overviewed. We found that the low use of sealants relate to dentists' orientation toward restorations rather than prevention, distrust in sealant treatment, lack of confidence in caries risk assessment, and concern about sealing over caries. The aspects to consider in the CSL projects are acquisition of knowledge and necessary skills of operators, cost benefit approach to sealant placement, and meticulous sealant placement procedures, including the necessity for a short-term recall. PMID- 20837737 TI - Review of outcomes from a change in faculty clinic management in a U.S. dental school. AB - Dental schools use a variety of clinic management models with the goals of promoting patient care, student education, and fiscal responsibility. In 2004, the University of the Pacific Arthur A. Dugoni School of Dentistry transitioned to a more generalist model with these goals in mind. The purpose of this study was to evaluate the outcomes of this clinic model change relative to the quantity of specific procedures completed by students. The quantity of procedures completed by each student from the classes of 1995 through 2009 were compiled from our electronic clinic management system and analyzed. The post-transition group (2004-09) showed a greater number of completed oral diagnosis and treatment planning and root planing procedures per student compared to the pre-transition group (1995-2003), but fewer crowns, root canals, operative procedures, and dentures. Because the higher procedure numbers were for low-cost procedures, our transition to a generalist model did not necessarily enhance clinic income but may support student learning and enhanced patient care. PMID- 20837738 TI - Assessing change in health professions volunteers' perceptions after participating in Special Olympics healthy athlete events. AB - This study assessed perceptions of health professions student and faculty volunteers who participated with athletes at the 2009 Special Olympics World Winter Games in Healthy Athlete venues. The volunteers' perceptions and expectations of the abilities of intellectually disabled athletes were measured by administering pre-event and post-event questionnaires consisting of demographic questions and the Prognostic Belief Scale (PBS). Invitations to participate in the study were sent to 165 students and faculty members; of those, eighty (48.5 percent response rate) responded to the pre-event questionnaire, and sixty-seven (40.6 percent response rate) responded to the post-event questionnaire. Of the eighty respondents to the pre-event questionnaire, fifty five (68.7 percent) also completed the post-event questionnaire. The ANOVA comparing pre- and post-event PBS scores between groups found a trend towards higher scores among the volunteers, but analysis did not demonstrate a significant effect in either group (p=.68) or the interaction of group by time (p=.46). Despite the findings from the PBS, participants' statements suggest the experience had an impact on their perceptions and expectations. Although not statistically significant, this study found a positive trend pre- to post-event in the volunteers' perceptions of the abilities of athletes with intellectual disabilities. In addition to didactic and clinical education, volunteer experiences may enhance care providers' knowledge, skill, and confidence levels for treating clients with intellectual disabilities. PMID- 20837739 TI - Community-based dental education and the importance of faculty development. AB - Community-based dental education offers a variety of positive learning experiences for students while providing needed dental services for the underserved. More dental students are being instructed by a growing body of largely volunteer community-based faculty who practice in a wide range of community settings including community hospitals and clinics, nursing homes, and private practices. These geographically dispersed instructors may have little experience as educators. Their practice styles and their motivation to improve teaching effectiveness are likely to differ from the styles and motivation of school-based faculty members. Moreover, many dental schools have begun to emphasize practices that may be unfamiliar to community-based faculty such as evidence-based practice. Providing faculty development for them is challenging, yet crucial to the success of these programs and dental education in general. Fundamental elements that must be considered for effective community faculty development programming include fostering a culture of respect between school based and community faculty members, basing programs on the actual needs of these educators, integrating principles of adult learning theory, and establishing ongoing institutional support. This article provides background on this movement, reviews the literature for faculty development programs geared specifically to community-based educators, makes recommendations for development programs for these dental educators, and includes suggestions for future research. PMID- 20837740 TI - Teaching physiology to dental students: matching teaching and learning styles in a South African dental school. AB - This study compared the preference for learning styles of dental students in a small class in physiology at a South African university with the preference for teaching styles of the lecturers. It also analyzed and evaluated the teaching methods and aids the lecturers used. The study was done in the last teaching block of the year after students have been exposed to all the lecturing styles in the same premedical subject. Two separate questionnaires were used in the study in order to evaluate teaching methods and teaching media used by the lecturers and to measure the teaching methods and teaching media that students preferred. Through a critical analysis of the data, it was found that the students preferred cooperative and active teaching/learning experiences more than the lecturers are using them. The study emphasizes the importance of students being actively involved in the teaching-learning process through cooperative methods. This may enhance their ability to utilize cognitive skills such as creative thinking, interpretation, critical thinking, and problem-solving. PMID- 20837741 TI - Implant overdentures: dental students' performance in fabrication, denture quality, and patient satisfaction. AB - The purpose of this study was to evaluate dental students' performance when fabricating a mandibular two-implant overdenture (OD) as compared to conventional dentures (CD) and to determine if these prostheses were successful. Twenty students and twenty patients were divided into two groups: complete denture group (CDG) and maxillary denture and two-implant OD group (ODG). Students' progress was evaluated at each appointment as they were given a clinical assessment score (CAS), which varied from 1 (unacceptable, needs to repeat procedure) to 4 (acceptable, no errors). The success of the prosthesis was evaluated by the patients using a visual analog scale (VAS) and an expert (a prosthodontist) using a denture quality assessment (DQA) form. Performance for both groups was not statistically different across all eight appointments (CDG 3.16 versus ODG 3.25; p=0.46). Patients with ODs reported greater stability with their dentures (p=0.048) and greater ability to chew than patients with CDs (p=0.03). There were no differences between the groups in terms of expert appraisal (ODG 71.1 versus CDG 67.5; p=0.59). The performance of dental students when fabricating a two implant OD is thus not different from that of a CD. Students can successfully fabricate a two-implant OD as perceived by both patients and prosthodontists. PMID- 20837742 TI - Evaluating tooth color matching ability of dental students. AB - Visual shade matching has remained a skill acquired through clinical experience. The purpose of this study was to evaluate the shade matching ability of dental students as they progress through their education. Sixty-five students, representing four levels of experience by year enrolled in dental school, participated in this study. Students were given a preclinical shade tab matching task. They were also asked to choose the best shade match for a natural tooth in each of three patients. The natural tooth shade matching task was designed to have simple, moderate, and complex cases to match. The frequency of correct answers was compared across samples across the four levels of fundamental tab match ability and clinical experience. On average, 51 percent of the students were able to match the correct shade tab in the matching task in a bench setting. For the natural tooth color matching task, 49.2 percent of the students selected the clinically acceptable color matched shade tabs (DeltaE*<=2.69). Although there was no statistically significant difference across the levels of fundamental ability and experience, rates of correct answers for natural tooth color matching progressively improved for the complex case from year 1 to year 4. This study reveals that, for complex cases, education and knowledge of color science combined with clinical experience improve students' ability for color matching in a clinical setting. PMID- 20837743 TI - Indian dental education in the new millennium: challenges and opportunities. AB - India is poised to be a leader in the global economy in this century. Its population of more than 1.1 billion, however, will challenge both the medical and oral health care systems. The current status of dental education in India has some serious challenges that will need to be modified to be able to produce leaders in the field of dentistry to address these burgeoning needs. Dental students in India are trained to excel theoretically, but there seems to be a disconnect between what is learned and what is applied in the clinics. In the real world, when dealing with patients, problem-solving skills and practical knowledge are necessary. Some of the changes that might bring dental education to the next level in India could include selecting highly motivated students for dentistry, modifying the teaching methodology with some importance given to treatment planning, and introducing research into the curriculum. Changing the current attitude of the faculty, students, and the general population towards dental education is another factor important in the successful transformation. The aim of this article is to discuss these issues in preparing the Indian dental workforce for the challenges of India's growing economy and population. PMID- 20837744 TI - Dental training and changes in oral health attitudes and behaviors in Istanbul dental students. AB - The aim of this study was to examine the changes that occur in the oral health attitudes and behaviors of dental students in Istanbul, Turkey, during their dental education. The Turkish version of the Hiroshima University-Dental Behavioral Inventory (HU-DBI) was distributed among 757 dental students at the Dental Faculty, Istanbul University. The response rate was 72 percent. Chi-square and logistic regression models were used for statistical analysis. The mean HU DBI score of the clinical students was significantly higher than that of the preclinical students. Preclinical students significantly more often believed that it was impossible to prevent gum disease with toothbrushing alone and worried about the color of their teeth and bad breath. Most of them brushed their teeth with strong strokes, thought the condition of their teeth was getting worse despite daily toothbrushing, and would seek dental care only when symptoms arise. Clinical students more often used disclosing solutions to see how clean their teeth were and complained of bleeding gums. The variation in favorable oral health attitudes/behaviors appeared to reflect the students' educational training experience. The findings of this study highlight the relatively poor oral health behaviors of Turkish dental students, which should be improved by means of comprehensive programs that aim to promote their own dental hygiene practices and preventive oral health knowledge from the start of dental training. PMID- 20837745 TI - Risky internet behaviors: a case study of online and offline stalking. AB - Today's youth are more technologically savvy than any other generation possessing the ability to go online anytime. This increase in use of and access to technology has also provided adolescents with increasing opportunities to experience online relationships, which can place them in a vulnerable position and risk for harassment, bullying, stalking, exploitation, sexual solicitation, and victimization. A case study of a 15-year-old, 10th-grade girl who demonstrated characteristics of risky Internet and health risk behaviors and experienced online and offline stalking is presented along with tips for Internet Safety for school nurses, parents, and teachers are offered. In the diverse and complex health care settings of the 21st century, professionals are increasingly encountering risk situations defined by the technology being used by both victim and offender. Adolescents who form online relationships should be informed about the risks and rewards, just as the adults who interact with them should be. PMID- 20837746 TI - A novel MEK2/PI3Kdelta pathway controls the expression of IL-1 receptor antagonist in IFN-beta-activated human monocytes. AB - IFN-beta and sIL-1Ra play crucial roles in the regulation of innate immunity and inflammation. IFN-beta, which is widely used to improve the course of relapsing, remitting multiple sclerosis, induces the production of sIL-1Ra in human monocytes through mechanisms that remain largely unknown. In this study, we identified PI3Kdelta and MEK2 as key elements that control sIL-1Ra production in isolated human monocytes activated by IFN-beta. Blockade of MEK2, but not of MEK1, by inhibitors and siRNA prevented IFN-beta-induced PI3Kdelta recruitment to the membrane, Akt phosphorylation, and sIL-1Ra production, suggesting that MEK2 acted upstream of PI3Kdelta. Furthermore, ERK1/2, the only identified substrates of MEK1/2 to date, are dispensable for sIL-1Ra production in response to IFN-beta stimulation. Upon IFN-beta activation, MEK2 and PI3Kdelta are translocated to monocyte membranes. These data suggest that MEK1 and MEK2 display different, nonredundant functions in IFN-beta signaling. That neither MEK1 nor ERK1/2 play a part in this mechanism is also an unexpected finding that gives rise to a better understanding of the MAPK signaling network. Together, these findings demonstrate that IFN-beta triggers an atypical MEK2/PI3Kdelta signaling cascade to regulate sIL-1Ra expression in monocytes. The premise that MEK1 and MEK2 play a part in the induction of the proinflammatory cytokine, IL-1beta in human monocytes provides a rationale for an alternative, IFN-beta-mediated pathway to induce/enhance sIL-1Ra production and thus, to dampen inflammation. PMID- 20837747 TI - Early impairment of transmural principal strains in the left ventricular wall after short-term, high-fat feeding of mice predisposed to cardiac steatosis. AB - BACKGROUND: myocardial lipid accumulation precedes some cardiomyopathies, but little is known of concurrent effects on ventricular mechanics. We tested the hypothesis that intramyocardial lipid accumulation during a short-term, high-fat diet (HFD) affects 2-dimensional strains in the heart. We examined the hearts of nontransgenic (NTG) mice and of transgenic mice predisposed to elevated triacylglyceride (TAG) storage linked to low-level overexpression of peroxisome proliferator activated receptor (PPAR-alpha). METHODS AND RESULTS: myocardial lipid and transmural principal strains E1 and E2 were determined in vivo with (1)H magnetic resonance spectroscopy/imaging before and after 2 weeks of an HFD in both PPAR-alpha and NTG littermate mice. Baseline lipid was elevated in PPAR alpha compared with NTG mice. An HFD increased mobile lipid by 174% in NTG mice (P<0.05) and by 79% in PPAR-alpha mice (P<0.05). After an HFD, lipid and TAG were higher in PPAR-alpha versus NTG mice by 63% and 81%, respectively. However, TAG in PPAR-alpha mice after an HFD was similar to TAG in PPAR-alpha mice fed a regular diet, suggesting that the magnetic resonance spectroscopy signal from lipid is not exclusive to TAG. Only at the highest lipid contents, achieved in PPAR-alpha mice, were strains affected. Endocardial strain was most compromised, with a negative correlation to lipid (P<0.05). CONCLUSIONS: a short-term HFD elevated myocardial lipid measures as determined by magnetic resonance spectroscopy, which became dissociated from TAG content in hearts predisposed to cardiac steatosis. The increased lipid was associated with concurrent, transmural reductions in E1 and E2 strains across the left ventricular wall. Strains were attenuated at the highest levels of lipid accumulation, suggesting a threshold response. Thus, 2-dimensional strains are impaired early and without left ventricular diastolic dysfunction, owing to cardiac steatosis. PMID- 20837748 TI - Peritoneal dialysis in the elderly--is its underutilization justified? AB - Peritoneal dialysis (PD) is underused as a dialysis modality in the elderly population. This is partly due to insufficient information about whether PD confers similar outcomes and quality of life as other modalities. In the BOLDE cross-sectional study, the authors compared different aspects of quality of life (cognitive function, index of deprivation and illness intrusiveness) in matched patients older than 65 years of age treated by PD or haemodialysis. Quality of life was similar (and possibly somewhat better) in patients on PD. These data justify efforts to increase the utilization of PD in older subjects. PMID- 20837749 TI - The use of eGFR and ACR to predict decline in renal function in people with diabetes. AB - BACKGROUND: There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria. METHODS: Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood. RESULTS: For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001). CONCLUSIONS: The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria. PMID- 20837750 TI - Antileishmanial and antitrypanosomal activities of the 8-aminoquinoline tafenoquine. AB - The 8-aminoquinoline tafenoquine showed significant in vitro activity against Leishmania species, including L. donovani amastigotes in macrophages, with 50% inhibitory concentrations (IC(50)s) between 0.1 and 4.0 MUM for both pentavalent antimony (SbV)-sensitive and SbV-resistant strains and by oral administration in BALB/c mice, with 50% effective dose (ED(50)) values of 1.2 to 3.5 mg/kg for 5 days. Tafenoquine was less active against intracellular Trypanosoma cruzi amastigotes, with an IC(50) of 21.9 MUM. PMID- 20837751 TI - Structure-activity relationships of diverse oxazolidinones for linezolid resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. AB - Staphylococcal resistance to linezolid (LZD) is mediated through ribosomal mutations (23S rRNA or ribosomal proteins L3 and L4) or through methylation of 23S rRNA by the horizontally transferred Cfr methyltransferase. To investigate the structural basis for oxazolidinone activity against LZD-resistant (LZD(r)) strains, we compared structurally diverse, clinically relevant oxazolidinones, including LZD, radezolid (RX-1741), TR-700 (torezolid), and a set of TR-700 analogs (including novel CD-rings and various A-ring C-5 substituents), against a panel of laboratory-derived and clinical LZD(r) Staphylococcus aureus strains possessing a variety of resistance mechanisms. Potency against all strains was correlated with optimization of C- and D-rings, which interact with more highly conserved regions of the peptidyl transferase center binding site. Activity against cfr strains was retained with either hydroxymethyl or 1,2,3-triazole C-5 groups but was reduced by 2- to 8-fold in compounds with acetamide substituents. LZD, which possesses a C-5 acetamide group and lacks a D-ring substituent, demonstrated the lowest potency against all strains tested, particularly against cfr strains. These data reveal key features contributing to oxazolidinone activity and highlight structural tradeoffs between potency against susceptible strains and potency against strains with various resistance mechanisms. PMID- 20837752 TI - An RpoB mutation confers dual heteroresistance to daptomycin and vancomycin in Staphylococcus aureus. AB - We have previously reported the establishment of a Staphylococcus aureus laboratory strain, 10 3d1, having reduced susceptibility to daptomycin and heterogeneous vancomycin-intermediate S. aureus (VISA) phenotype. The strain was generated in vitro by serial daptomycin selection (Camargo, I. L., H. M. Neoh, L. Cui, and K. Hiramatsu, Antimicrob. Agents Chemother. 52:4289-4299, 2008). Here we explored the genetic mechanism of resistance in the strain by whole-genome sequencing and by producing gene-replaced strains. By genome comparison between 10 3d1 and its parent methicillin-resistant Staphylococcus aureus (MRSA) strain N315DeltaIP, we identified five nonsynonymous single nucleotide polymorphisms (SNPs). One of the five mutations was found in the rpoB gene encoding the RNA polymerase beta subunit. The mutation at nucleotide position 1862 substituted the 621st alanine by glutamic acid. The replacement of the intact rpoB with the mutated rpoB, designated rpoB(A621E), conferred N315DeltaIP with the phenotypes of reduced susceptibility to daptomycin and hetero-VISA. The rpoB(A621E)-mediated resistance conversion was accompanied by a thickened cell wall and reduction of the cell surface negative charge. Being consistent with these phenotypic changes, microarray data showed that the expression of the dlt operon, which increases the cell surface positive charge, was enhanced in the rpoB(A621E) mutant. Other remarkable findings of microarray analysis of the rpoB(A621E) mutant included repression of metabolic pathways of purine, pyrimidine, arginine, the urea cycle, and the lac operon, enhancement of the biosynthetic pathway of vitamin B2, K1, and K2, and cell wall metabolism. Finally, mutations identified in rplV and rplC, encoding 50S ribosomal proteins L22 and L3, respectively, were found to be associated with the slow growth, but not with the phenotype of decreased susceptibility to vancomycin and daptomycin, of 10 3d1. PMID- 20837753 TI - Clarithromycin significantly increases linezolid serum concentrations. PMID- 20837754 TI - FKS mutations and elevated echinocandin MIC values among Candida glabrata isolates from U.S. population-based surveillance. AB - Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of >=0.25 MUg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations. PMID- 20837755 TI - Elevated linezolid resistance in clinical cfr-positive Staphylococcus aureus isolates is associated with co-occurring mutations in ribosomal protein L3. AB - Resistance to linezolid (LZD) occurs through mutations in 23S rRNA and ribosomal proteins L3 and L4 or through methylation of 23S rRNA by Cfr. Here we report novel L3 mutations, DeltaSer145/His146Tyr and DeltaMet169-Gly174, co-occurring with cfr in LZD-resistant Staphylococcus aureus isolates recovered from a hospital outbreak in Madrid, Spain. LZD MIC values (16, 32, or 64 MUg/ml) correlated with the presence and severity of the L3 mutation. All isolates had TR 700 (torezolid) MIC values of <= 2 MUg/ml. PMID- 20837756 TI - Nasal carriage of methicillin-resistant and methicillin-sensitive strains of Staphylococcus sciuri in the Indonesian population. AB - Staphylococcus sciuri strains were unexpectedly cultured from healthy persons and patients from Indonesia during a population-based survey on nasal Staphylococcus aureus carriage. Fifty-one S. sciuri isolates were further characterized. The S. aureus mecA gene was detected by PCR in 22 isolates (43.1%), whereas S. sciuri mecA was found in 33 isolates (64.7%). The staphylococcal cassette chromosome mec (SCCmec) regions of S. aureus mecA-positive isolates contained elements of classical S. aureus SCCmec types II and/or III. PMID- 20837757 TI - National multicenter study of predictors and outcomes of bacteremia upon hospital admission caused by Enterobacteriaceae producing extended-spectrum beta lactamases. AB - Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae are pathogens that may lead to a spectrum of clinical syndromes. We aimed to identify predictors and outcomes of ESBL bacteremia upon hospital admission (UHA) in a nationwide prospective study. Thus, a multicenter prospective study was conducted in 10 Israeli hospitals. Adult patients with bacteremia due to Enterobacteriaceae diagnosed within 72 h of hospitalization were included. Patients with ESBL producers (cases) were compared to those with non-ESBL producers (controls), and a 1:1 ratio was attempted in each center. A case-control study to identify predictors and a cohort study to identify outcomes were conducted. Bivariate and multivariate logistic regressions were used for analyses. Overall, 447 patients with bacteremia due to Enterobacteriaceae were recruited: 205 cases and 242 controls. Independent predictors of ESBL were increased age, multiple comorbid conditions, poor functional status, recent contact with health care settings, invasive procedures, and prior receipt of antimicrobial therapy. In addition, patients presenting with septic shock and/or multiorgan failure were more likely to have ESBL infections. Patients with ESBL producers suffered more frequently from a delay in appropriate antimicrobial therapy (odds ratio [OR], 4.7; P, <0.001) and had a higher mortality rate (OR, 3.5; P, <0.001). After controlling for confounding variables, both ESBL production (OR, 2.3; P, 9.1) and a delay in adequate therapy (OR, 0.05; P, 0.001) were significant predictors for mortality and other adverse outcomes. We conclude that among patients with bacteremia due to Enterobacteriaceae UHA, those with ESBL producers tend to be older and chronically ill and to have a delay in effective therapy and severe adverse outcomes. Efforts should be directed to improving the detection of patients with ESBL bacteremia UHA and to providing immediate appropriate therapy. PMID- 20837758 TI - Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis. AB - Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process. PMID- 20837760 TI - Comparative efficacies of human simulated exposures of telavancin and vancomycin against methicillin-resistant Staphylococcus aureus with a range of vancomycin MICs in a murine pneumonia model. AB - Telavancin displays potent in vitro and in vivo activity against methicillin resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of >=1 MUg/ml in a neutropenic murine lung infection model. Thirteen clinical MRSA isolates (7 vancomycin-susceptible, 2 vancomycin-heteroresistant [hVISA], and 4 vancomycin intermediate [VISA] isolates) were tested after 24 h, and 7 isolates (1 hVISA and 4 VISA isolates) were tested after 48 h of exposure. Mice were administered subcutaneous doses of telavancin at 40 mg/kg of body weight every 12 h (q12h) or of vancomycin at 110 mg/kg q12h; doses were designed to simulate the area under the concentration-time curve for the free, unbound fraction of drug (fAUC) observed for humans given telavancin at 10 mg/kg q24h or vancomycin at 1 g q12h. Efficacy was expressed as the 24- or 48-h change in lung bacterial density from pretreatment counts. At dose initiation, the mean bacterial load was 6.16 +/- 0.26 log(10) CFU/ml, which increased by averages of 1.26 +/- 0.55 and 1.74 +/- 0.68 log in untreated mice after 24 and 48 h, respectively. At both time points, similar CFU reductions were noted for telavancin and vancomycin against MRSA, with vancomycin MICs of <=2 MUg/ml. Both drugs were similarly efficacious after 24 and 48 h of treatment against the hVISA strains tested. Against VISA isolates, telavancin reduced bacterial burdens significantly more than vancomycin for 1 of 4 isolates after 24 h and for 3 of 4 isolates after 48 h. These data support the potential utility of telavancin for the treatment of MRSA pneumonia caused by pathogens with reduced susceptibility to vancomycin. PMID- 20837759 TI - Suitable disk antimicrobial susceptibility breakpoints defining Salmonella enterica serovar Typhi isolates with reduced susceptibility to fluoroquinolones. AB - Infections with Salmonella enterica serovar Typhi isolates that have reduced susceptibility to ofloxacin (MIC >= 0.25 MUg/ml) or ciprofloxacin (MIC >= 0.125 MUg/ml) have been associated with a delayed response or clinical failure following treatment with these antimicrobials. These isolates are not detected as resistant using current disk susceptibility breakpoints. We examined 816 isolates of S. Typhi from seven Asian countries. Screening for nalidixic acid resistance (MIC >= 16 MUg/ml) identified isolates with an ofloxacin MIC of >=0.25 MUg/ml with a sensitivity of 97.3% (253/260) and specificity of 99.3% (552/556). For isolates with a ciprofloxacin MIC of >=0.125 MUg/ml, the sensitivity was 92.9% (248/267) and specificity was 98.4% (540/549). A zone of inhibition of <=28 mm around a 5-MUg ofloxacin disc detected strains with an ofloxacin MIC of >=0.25 MUg/ml with a sensitivity of 94.6% (246/260) and specificity of 94.2% (524/556). A zone of inhibition of <=30 mm detected isolates with a ciprofloxacin MIC of >=0.125 MUg/ml with a sensitivity of 94.0% (251/267) and specificity of 94.2% (517/549). An ofloxacin MIC of >=0.25 MUg/ml and a ciprofloxacin MIC of >=0.125 MUg/ml detected 74.5% (341/460) of isolates with an identified quinolone resistance-inducing mutation and 81.5% (331/406) of the most common mutant (carrying a serine-to-phenylalanine mutation at codon 83 in the gyrA gene). Screening for nalidixic acid resistance or ciprofloxacin and ofloxacin disk inhibition zone are suitable for detecting S. Typhi isolates with reduced fluoroquinolone susceptibility. PMID- 20837761 TI - Comparative in vitro activities of torezolid (DA-7157) against clinical isolates of aerobic and anaerobic bacteria in South Korea. AB - Resistance of Gram-positive pathogens to first-line antimicrobial agents has been increasing in many parts of the world. We compared the in vitro activities of torezolid with those of other antimicrobial agents, including linezolid, against clinical isolates of major aerobic and anaerobic bacteria. Torezolid had an MIC(90) of <=0.5 MUg/ml for the Gram-positive bacterial isolates tested and was more potent than either linezolid or vancomycin. PMID- 20837762 TI - A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. AB - A doxorubicin derivate, SA-17, that carries a squaric acid amide ester moiety at the carbohydrate (alpha-l-daunosaminyl) group was identified as a selective inhibitor of in vitro dengue virus (DENV) serotype 2 replication (50% effective concentration [EC(50)] = 0.34 +/- 0.20 MUg/ml [0.52 +/- 0.31 MUM]). SA-17 is markedly less cytostatic than the parent compound, resulting in a selectivity index value of ~100. SA-17 also inhibits yellow fever virus 17D (YFV-17D) replication (EC(50) = 3.1 +/- 1.0 MUg/ml [4.8 +/- 1.5 MUM]), although less efficiently than DENV replication, but proved inactive against a variety of enveloped and nonenveloped viruses. SA-17 inhibits in vitro flavivirus replication in a dose-dependent manner, as was assessed by virus yield reduction assays and quantification of viral RNA by means of real-time quantitative reverse transcriptase PCR (RT-qPCR) (~2 to 3 log reduction). The anti-DENV activity was confirmed using a Renilla luciferase-expressing dengue reporter virus. Time-of drug-addition studies revealed that SA-17 acts at the very early stages of the viral replication cycle (i.e., virus attachment and/or virus entry). This observation was corroborated by the observation that SA-17, unlike the nucleoside analogue ribavirin, does not inhibit the replication of DENV subgenomic replicons. Preincubation of high-titer stocks of DENV or YFV-17D with >=5 MUg/ml SA-17 resulted in 100% inhibition of viral infectivity (>=3 log reduction). SA 17, however, did not prove virucidal. PMID- 20837763 TI - Activity of an antimicrobial hydrocephalus shunt catheter against Propionibacterium acnes. AB - Shunt infection is a major complication affecting approximately 10% of procedures. Propionibacterium acnes, an anaerobic skin bacterium, is increasingly recognized as a shunt pathogen, causing up to 14% of infections. Though susceptible to penicillin and cephalosporins, P. acnes shunt infections are not preventable by means of perioperative prophylaxis, due to poor cerebrospinal fluid penetration. Antimicrobial shunts with activity against staphylococci are available, but their activity against P. acnes is unknown, and the study was designed to determine this. Three methods of evaluation were used in order to determine the emergence of resistance when exposure is to high inocula for long periods, the time taken to kill 100% of the bacteria attached to the shunt, and the duration of activity under constant flow conditions with repeated bacterial challenge. Despite repeated exposure to high bacterial inocula over 70 days, no resistance was seen. The time taken to kill all attached bacteria, 96 h, was twice that taken to kill attached staphylococci. Nevertheless, under constant flow conditions with repeated challenges, the antimicrobial catheters resisted colonization by P. acnes for 56 days. Using tests that were designed to be clinically predictive when done together, the results suggest that the antimicrobial catheters will be able to prevent colonization of hydrocephalus shunts by P. acnes. PMID- 20837764 TI - OXA-134, a naturally occurring carbapenem-hydrolyzing class D beta-lactamase from Acinetobacter lwoffii. AB - Acinetobacter lwoffii, a species whose natural habitat is the human skin, intrinsically possesses a chromosomal gene encoding a carbapenem-hydrolyzing class D beta-lactamase, OXA-134. This species may therefore constitute a reservoir for carbapenemase genes that may spread among other Acinetobacter species. PMID- 20837769 TI - Phosphoinositide 3-kinase delta regulates membrane fission of Golgi carriers for selective cytokine secretion. AB - Phosphoinositide 3-kinase (PI3K) p110 isoforms are membrane lipid kinases classically involved in signal transduction. Lipopolysaccharide (LPS)-activated macrophages constitutively and abundantly secrete proinflammatory cytokines including tumor necrosis factor-alpha (TNF). Loss of function of the p110delta isoform of PI3K using inhibitors, RNA-mediated knockdown, or genetic inactivation in mice abolishes TNF trafficking and secretion, trapping TNF in tubular carriers at the trans-Golgi network (TGN). Kinase-active p110delta localizes to the Golgi complex in LPS-activated macrophages, and TNF is loaded into p230-labeled tubules, which cannot undergo fission when p110delta is inactivated. Similar blocks in fission of these tubules and in TNF secretion result from inhibition of the guanosine triphosphatase dynamin 2. These findings demonstrate a new function for p110delta as part of the membrane fission machinery required at the TGN for the selective trafficking and secretion of cytokines in macrophages. PMID- 20837770 TI - Noboru Mizushima: All about autophagy. Interview by Caitlin Sedwick. PMID- 20837773 TI - {beta}-Catenin gets an honorable discharge. PMID- 20837772 TI - Fra-2/AP-1 controls bone formation by regulating osteoblast differentiation and collagen production. AB - The activator protein-1 (AP-1) transcription factor complex, in particular the Fos proteins, is an important regulator of bone homeostasis. Fra-2 (Fosl2), a Fos related protein of the AP-1 family, is expressed in bone cells, and newborn mice lacking Fra-2 exhibit defects in chondrocytes and osteoclasts. Here we show that Fra-2-deficient osteoblasts display a differentiation defect both in vivo and in vitro. Moreover, Fra-2-overexpressing mice are osteosclerotic because of increased differentiation of osteoblasts, which appears to be cell autonomous. Importantly, the osteoblast-specific osteocalcin (Oc) gene and collagen1alpha2 (col1alpha2) are transcriptional targets of Fra-2 in both murine and human bone cells. In addition, Fra-2, Oc, and col1 are expressed in stromal cells of human chondroblastic and osteoblastic osteosarcomas (Os's) as well as during osteoblast differentiation of human Os cell lines. These findings reveal a novel function of Fra-2/AP-1 as a positive regulator of bone and matrix formation in mice and humans. PMID- 20837771 TI - Exosome release of beta-catenin: a novel mechanism that antagonizes Wnt signaling. AB - CD82 and CD9 are tetraspanin membrane proteins that can function as suppressors of tumor metastasis. Expression of CD9 and CD82 in transfected cells strongly suppresses beta-catenin-mediated Wnt signaling activity and induces a significant decrease in beta-catenin protein levels. Inhibition of Wnt/beta-catenin signaling is independent of glycogen synthase kinase-3beta and of the proteasome- and lysosome-mediated protein degradation pathways. CD82 and CD9 expression induces beta-catenin export via exosomes, which is blocked by a sphingomyelinase inhibitor, GW4869. CD82 fails to induce exosome release of beta-catenin in cells that express low levels of E-cadherin. Exosome release from dendritic cells generated from CD9 knockout mice is reduced compared with that from wild-type dendritic cells. These results suggest that CD82 and CD9 down-regulate the Wnt signaling pathway through the exosomal discharge of beta-catenin. Thus, exosomal packaging and release of cytosolic proteins can modulate the activity of cellular signaling pathways. PMID- 20837774 TI - Drosophila IAP antagonists form multimeric complexes to promote cell death. AB - Apoptosis is a specific form of cell death that is important for normal development and tissue homeostasis. Caspases are critical executioners of apoptosis, and living cells prevent their inappropriate activation through inhibitor of apoptosis proteins (IAPs). In Drosophila, caspase activation depends on the IAP antagonists, Reaper (Rpr), Head involution defective (Hid), and Grim. These proteins share a common motif to bind Drosophila IAP1 (DIAP1) and have partially redundant functions. We now show that IAP antagonists physically interact with each other. Rpr is able to self-associate and also binds to Hid and Grim. We have defined the domain involved in self-association and demonstrate that it is critical for cell-killing activity in vivo. In addition, we show that Rpr requires Hid for recruitment to the mitochondrial membrane and for efficient induction of cell death in vivo. Both targeting of Rpr to mitochondria and forced dimerization strongly promotes apoptosis. Our results reveal the functional importance of a previously unrecognized multimeric IAP antagonist complex for the induction of apoptosis. PMID- 20837775 TI - Myosin cleft closure determines the energetics of the actomyosin interaction. AB - Formation of the strong binding interaction between actin and myosin is essential for force generation in muscle and in cytoskeletal motor systems. To clarify the role of the closure of myosin's actin-binding cleft in the actomyosin interaction, we performed rapid kinetic, spectroscopic, and calorimetric experiments and atomic-level energetic calculations on a variety of myosin isoforms for which atomic structures are available. Surprisingly, we found that the endothermic actin-binding profile of vertebrate skeletal muscle myosin subfragment-1 is unique among studied myosins. We show that the diverse propensity of myosins for cleft closure determines different energetic profiles as well as structural and kinetic pathways of actin binding. Depending on the type of myosin, strong actin binding may occur via induced-fit or conformational preselection mechanisms. However, cleft closure does not directly determine the kinetics and affinity of actin binding. We also show that cleft closure is enthalpically unfavorable, reflecting the development of an internal strain within myosin in order to adopt precise steric complementarity to the actin filament. We propose that cleft closure leads to an increase in the torsional strain of myosin's central beta-sheet that has been proposed to serve as an allosteric energy-transducing spring during force generation. PMID- 20837777 TI - A process model of affect misattribution. AB - People often misattribute the causes of their thoughts and feelings. The authors propose a multinomial process model of affect misattributions, which separates three component processes. The first is an affective response to the true cause of affect. The second is an affective response to the apparent cause. The third process is when the apparent source is confused for the real source. The model is validated using the affect misattribution procedure (AMP), which uses misattributions as a means to implicitly measure attitudes. The model illuminates not only the AMP but also other phenomena in which researchers wish to model the processes underlying misattributions using subjective judgments. PMID- 20837776 TI - Endothelin-1 gene regulation. AB - Over two decades of research have demonstrated that the peptide hormone endothelin-1 (ET-1) plays multiple, complex roles in cardiovascular, neural, pulmonary, reproductive, and renal physiology. Differential and tissue-specific production of ET-1 must be tightly regulated in order to preserve these biologically diverse actions. The primary mechanism thought to control ET-1 bioavailability is the rate of transcription from the ET-1 gene (edn1). Studies conducted on a variety of cell types have identified key transcription factors that govern edn1 expression. With few exceptions, the cis-acting elements bound by these factors have been mapped in the edn1 regulatory region. Recent evidence has revealed new roles for some factors originally believed to regulate edn1 in a tissue or hormone-specific manner. In addition, other mechanisms involved in epigenetic regulation and mRNA stability have emerged as important processes for regulated edn1 expression. The goal of this review is to provide a comprehensive overview of the specific factors and signaling systems that govern edn1 activity at the molecular level. PMID- 20837778 TI - Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. AB - We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 MUg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853. PMID- 20837779 TI - Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin. AB - Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liver-specific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human disease-causing mutation (murine C294Y) did not cause iron deficiency. Furthermore, hepcidin induction by transgenes encoding both WT Hfe and Hfe lacking its cytoplasmic domain is greatly attenuated in the absence of hemojuvelin (Hjv). Our observations indicate that the extracellular and transmembrane domains of Hfe are sufficient, and Hjv is essential, for Hfe mediated induction of hepcidin expression. PMID- 20837780 TI - B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy. AB - Characterization of lymphocytes including B cells during early versus chronic HIV infection is important for understanding the impact of chronic viremia on immune cell function. In this setting, we investigated B cells before and after reduction of HIV plasma viremia by antiretroviral therapy (ART). At baseline, peripheral blood B-cell counts were significantly lower in both early and chronic HIV-infected individuals compared with uninfected controls. Similar to CD4(+) but not CD8(+) T cells, B-cell numbers in both groups increased significantly after ART. At baseline, B cells of early HIV-infected individuals were composed of a higher percentage of plasmablasts and resting memory B cells compared with chronic HIV-infected individuals whose B cells were composed of a higher percentage of immature/transitional and exhausted B cells compared with their early infection counterparts. At 1 year after ART, the percentage of resting memory B cells remained higher in early compared with chronic HIV-infected individuals. This difference translated into a better functional profile in that memory B-cell responses to HIV and non-HIV antigens were superior in early- compared with chronic-treated HIV infected individuals. These findings provide new insights on B cells in HIV infection and how early initiation of ART may prevent irreversible immune system damage. PMID- 20837781 TI - How I treat adenovirus in hematopoietic stem cell transplant recipients. AB - Adenovirus (AdV) infections are very common in the general pediatric population. The delayed clearance in young persons imposes a threat to immunocompromised patients after hematopoietic stem cell transplantation (HSCT), who can reactivate the virus, resulting in life-threatening disseminated disease. Although a definitive cure requires adequate immune reconstitution, 2 approaches appear to be feasible and effective to improve the outcomes of AdV infections. Strict monitoring with AdV quantitative polymerase chain reaction followed by preemptive treatment with low-dose (1 mg/kg) cidofovir 3 times a week, is effective in most cases to bridge the severely immunocompromised period shortly after HSCT, with acceptable toxicity rates. For centers who have the access, AdV-specific cytotoxic T cells can be the other important cornerstone of anti-AdV therapy with promising results so far. Methods to positively influence the reconstitution of the immune system after HSCT and optimizing new and currently available cellular immunotherapies will make HSCT safer against the threat of AdV infection/reactivation and associated disease. PMID- 20837782 TI - Pregnancy-associated microRNAs in maternal plasma: a channel for fetal-maternal communication? PMID- 20837783 TI - Impact of second-tier testing on the effectiveness of newborn screening. PMID- 20837784 TI - Western blotting. PMID- 20837785 TI - The quest for accurate measurement of fetal DNA in maternal plasma. PMID- 20837786 TI - Framingham study insights on diabetes and cardiovascular disease. PMID- 20837787 TI - Improvement of visual performance with intravitreal administration of 9-cis retinal in Rpe65-mutant dogs. AB - OBJECTIVE: To determine the efficacy of intravitreal administration of 9-cis retinal in restoring visual function in Rpe65-mutant dogs. METHODS: Intravitreal injection of 9-cis-retinal was administered in 1 eye of 7 Rpe65-/- dogs at a range of ages. Electroretinogram analysis and testing of visual performance was used to evaluate outcomes after a single injection and in 2 dogs after a second injection in the same eye. RESULTS: In 5 of 7 injected dogs, 9-cis-retinal injection resulted in increased rod electroretinogram responses and improved functional vision. Three injected dogs exhibited increased 33-Hz flicker amplitudes characteristic of cone-mediated responses. Electroretinogram improvement was no longer evident by week 10 postinjection in 1 dog monitored over time. A second injection of 9-cis-retinal was performed in the same eye of 2 of the 7 dogs and also resulted in rescue of visual function. CONCLUSION: Our findings establish that 9-cis-retinoid therapy can restore visual function in a canine model of human disease resulting from RPE65 mutations. CLINICAL RELEVANCE: These positive proof-of-principle results provide support for the development of intravitreal devices for sustained delivery of 9-cis-retinal as a therapy for conditions resulting from failure of the visual cycle. PMID- 20837788 TI - The efficacy of low vision device training in a hospital-based low vision clinic. AB - BACKGROUND/AIMS: Hospital-based low vision services in the UK typically involve one consultation with an optometrist. In this study we investigated the effect of adding further low vision device training. METHODS: Participants were recruited from those attending their first low vision assessment (LVA). Participants completed the Mass of Activity Inventory (MAI) questionnaire by telephone before their appointment. After LVA, participants were randomised to an intervention group (who received a further appointment to review device handling) or a control group. The MAI was readministered 1 and 3 months after the initial LVA. MAI data were converted to Rasch scores for goal difficulty. RESULTS: Ninety-six participants completed the study. Both groups experienced a significant improvement in goal difficulty following low vision intervention (p<0.0001), equivalent to a visual acuity improvement of approximately 0.55 logarithm of the minimum angle of resolution (logMAR). There was no significant difference in improvement between the group randomised to the training visit and those in the control arm (p=0.80). CONCLUSION: Self-perceived difficulty with daily visual tasks decreases following a low vision appointment. An additional visit for device handling training resulted in no further improvement. This could be due to the relatively simple nature of the devices prescribed in this clinic. TRIAL REGISTRATION NUMBER: ISRCTN05434212. PMID- 20837789 TI - Effect of isometric exercise on choroidal blood flow in patients with age-related macular degeneration. AB - AIM: We compared the regulatory responses induced by isometric exercise in control subjects and patients with age-related macular degeneration (AMD) to investigate choroidal vascular regulation in AMD. METHODS: Seventeen eyes of 17 patients with dry AMD in the study eye and 19 eyes of 19 controls were included in this study. Both groups were well matched for age, race and sex. Brachial artery blood pressure determinations and laser Doppler flowmetry (Oculix) measurements of relative foveolar choroidal blood velocity, volume and flow were obtained in the study eye of each subject during 30 s of baseline, and then during 3 min of isometric exercise consisting of squeezing a handgrip in each hand. Similar measurements were then also obtained during the 2 min following the cessation of exercise. Using non-paired, two-tailed t test, changes in circulatory parameters during exercise and following the end of exercise were compared between AMD patients and control subjects. The slope for the relationship between circulatory changes and perfusion pressure changes was calculated and compared between patients with AMD and controls using linear regression analysis. Analysis of data was performed in a masked fashion. RESULTS: There were no statistically significant differences between the changes in choroidal blood velocity, volume and flow observed in control subjects and patients with AMD during the isometric exercise phase and after exercise. CONCLUSIONS: Our results suggest that the response of the choroidal circulation to this type of isometric exercise resulting in a moderate increase in blood pressure does not seem to be affected by AMD. PMID- 20837790 TI - The differential diagnosis of localised amelanotic limbal lesions: a review of 162 consecutive excisions. AB - AIMS: To report the distribution of histopathological diagnoses in patients who underwent excision of localised limbal lesions that were clinically suspected to be squamous neoplasia (intra-epithelial neoplasia or squamous cell carcinoma). METHODS: 162 consecutive patients of a single ocular oncologist underwent an excisional biopsy between 1998 and 2009 for suspected squamous neoplasia. Histopathological reports were retrospectively reviewed. RESULTS: The population comprised 122 males and 40 females. The mean age was 63.4+/-15.8 (range: 27-90). 138 (85.2%) lesions were identified as intraepithelial neoplasia (CIN), of which 34 (21.0%) were CIN I, 32 (19.8%) were CIN II and 72 (44.4%) were CIN III or squamous cell carcinoma in situ. In seven (4.3%) cases, the lesion was invasive squamous cell carcinoma. In two (1.2%) cases, the lesion was amelanotic malignant melanoma. In 16 (9.9%) cases, histopathology revealed a benign entity including lesions described as squamous papilloma, solar elastosis and epithelial hyperplasia, keratosis or reactive atypia. CONCLUSIONS: In this population, for an experienced ocular oncologist, the misdiagnosis of localised limbal squamous neoplasia occurred in 10.5% of cases, with 5.5% of cases being malignant. This study highlights the importance of acquiring a clinical diagnosis before administering a topical chemotherapeutic agent. PMID- 20837791 TI - Bevacizumab vs photodynamic therapy for choroidal neovascularization in multifocal choroiditis. AB - OBJECTIVE: To compare the effectiveness of photodynamic therapy (PDT) vs intravitreal bevacizumab injection in patients with subfoveal choroidal neovascularization (CNV) secondary to multifocal choroiditis (MC). METHODS: Patients affected by subfoveal CNV associated with MC referred for clinical evaluation from March 1, 2005, to July 31, 2008, were considered for this pilot randomized clinical trial. Twenty-seven patients were included in the study and followed up from March 15, 2005, through April 30, 2009. After randomization, patients receiving PDT were treated according to the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy protocol, whereas patients receiving intravitreal bevacizumab injection, after a loading phase of 3 monthly injections, were examined monthly and re-treated on the basis of detection of fluid on optical coherence tomography and/or leakage on fluorescein angiography. MAIN OUTCOME MEASURES: The primary outcome measure was the 5- and 15-letter change on the Early Treatment of Diabetic Retinopathy Study charts at 12-month examinations compared with baseline. Secondary outcomes included central macular thickness changes. RESULTS: Thirteen and 14 patients were randomized to PDT and bevacizumab treatment, respectively. At the 12-month examination, 5 of 14 eyes treated with bevacizumab and 0 of 13 eyes treated with PDT experienced a best corrected visual acuity gain of greater than 3 lines (P = .04). Twelve eyes in the bevacizumab group and 6 eyes in the PDT group gained more than 1 line (P = .04). The central macular thickness showed a progressive reduction in both subgroups without a significant difference compared with the baseline values. CONCLUSIONS: Greater beneficial effects can be achieved using intravitreal bevacizumab injection rather than PDT for the treatment of subfoveal CNV secondary to MC. Larger multicenter investigations are needed to confirm our preliminary results. Application to Clinical Practice Currently, there is no precise indication regarding the best therapeutic approach to subfoveal CNV secondary to MC. This investigation was designed to verify whether intravitreal bevacizumab injection has a more beneficial effect with respect to PDT. PMID- 20837792 TI - Vascular tumors of the iris in 45 patients: the 2009 Helen Keller Lecture. AB - OBJECTIVE: To report on a series of vascular tumors of the iris. DESIGN: Noncomparative case series. A retrospective medical record review of all patients with an iris vascular tumor was performed to identify the clinical features and develop a simple classification of these lesions. Included were demographics, clinical features, systemic associations, complications, management, and histopathology. RESULTS: There were 54 eyes in 45 patients with an iris vascular tumor. These were categorized as racemose hemangioma (41 eyes: 29 simple and 12 complex), cavernous hemangioma (3 eyes: 2 localized and 1 systemic), capillary hemangioma (1 eye, localized), varix (3 eyes, localized), and microhemangiomatosis (6 eyes, localized). The hemangiomas occurred in adults at a median age of 55 years, whereas capillary hemangioma occurred in infancy and cavernous hemangioma with systemic involvement occurred in a child. Of the 41 eyes with iris racemose hemangioma, none showed systemic involvement. Of all 54 eyes, transient hyphema was the main complication, found at some point in 30% or more of each affected eye except for iris capillary and racemose hemangioma. Surgical resection was necessary in 1 cavernous hemangioma and 1 varix. The remainder were managed with observation. CONCLUSIONS: There are now well documented examples of iris racemose hemangioma, cavernous hemangioma, capillary hemangioma, varix, and microhemangiomatosis. Transient hyphema is the main complication. Observation is usually advised. Most are solitary lesions confined to the iris and some (cavernous hemangioma and microhemangiomatosis) can have important systemic associations. PMID- 20837793 TI - Aqueous humor dynamics in pigment dispersion syndrome. AB - OBJECTIVE: To assess aqueous humor dynamics in pigment dispersion syndrome (PDS). METHODS: Four groups of age-matched participants included 2 experimental groups with PDS (PDS with ocular hypertension [PDS-OHT], 17 eyes; PDS without ocular hypertension [PDS-ONT], 18 eyes) and 2 control groups without PDS (OHT, 18 eyes; ONT, 18 eyes). Assessments included intraocular pressure measured by pneumatonometry, episcleral venous pressure by venomanometry, aqueous flow and outflow facility by fluorophotometry, corneal thickness and anterior chamber depth by pachymetry, and uveoscleral outflow by mathematical calculation. Comparisons were made by analysis of variance and 2-tailed unpaired t tests. RESULTS: The PDS-OHT group had higher intraocular pressures than the ONT and PDS ONT groups (P < .001) and higher episcleral venous pressure (P = .04) and lower outflow facility (P = .01) than the ONT group. Anterior chamber volume was larger in the PDS-OHT group than in the other groups (P < .05 for all). No other comparisons between the PDS-OHT group and the other groups yielded statistically significant differences at a significance level of less than .05. CONCLUSIONS: The elevated intraocular pressure in PDS is caused by reduced outflow facility. This differs from OHT without PDS, in which reductions in uveoscleral outflow and outflow facility have been reported. PMID- 20837794 TI - Spectral-domain optical coherence tomography for detection of localized retinal nerve fiber layer defects in patients with open-angle glaucoma. AB - OBJECTIVE: To evaluate and compare time-domain (Stratus) and spectral-domain (Cirrus; both Carl Zeiss Meditec, Dublin, California) optical coherence tomography (OCT) for the detection of localized retinal nerve fiber layer (RNFL) defects in patients with open-angle glaucoma. METHODS: Patients with localized RNFL defects and age-matched normal control participants were consecutively enrolled from July 1 to December 31, 2008. Sixty-six eyes from 66 patients and 66 eyes from 66 normal controls were imaged with Stratus OCT (fast RNFL scan mode) and Cirrus OCT (optic disc cube mode). The ability to detect the RNFL defect by using quadrant clock-hour maps from both OCTs and a Cirrus OCT deviation map were compared with red-free RNFL photography, which is the criterion standard for visualizing RNFL defects. RESULTS: The Cirrus OCT deviation map exhibited significantly higher overall sensitivity (92.42%) in detecting the RNFL defects compared with the other maps, which were derived from a 3.46-mm-diameter peripapillary cross-sectional RNFL scan of both OCTs (P < .001). The Cirrus OCT quadrant map had a higher specificity; however, it was not statistically significant (P = .07). Compared with the other maps, the Cirrus OCT derivation map had the lowest cutoff angle for the width (10.69 degrees ) of the RNFL defect. CONCLUSIONS: The deviation map from Cirrus OCT was more sensitive in detecting RNFL defects than the clock-hour and quadrant maps derived from cross sectional peripapillary RNFL measurements by Stratus and Cirrus OCTs. The ability to detect localized RNFL defects on clock-hour or quadrant RNFL maps did not significantly differ between Stratus OCT and Cirrus OCT. PMID- 20837795 TI - Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1. AB - OBJECTIVE: To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. METHODS: Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3. RESULTS: Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 MUm up to 32 months after visual loss. It was 63.5 MUm for all affected patients and 100.7 MUm for carriers (P < .01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P < .01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than -2 dB, and average RNFL thickness more than 80 MUm. CONCLUSIONS: Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers. PMID- 20837796 TI - Anterior chamber and vitreous concordance in endophthalmitis: implications for prophylaxis. AB - OBJECTIVE: To examine the relationship between anterior chamber (AC) sterilization and vitreous positivity rate in cases of endophthalmitis. DESIGN: Retrospective case-control study. A review of all consecutive cases of endophthalmitis (N = 758) between January 1, 1999, and December 31, 2008, identified 229 matched AC and vitreous samples. Matched samples were evaluated for sensitivity and specificity, positive and negative predictive values, and positive and negative likelihood ratios. The main outcome measures were sensitivity and specificity of AC and vitreous samples in cases of endophthalmitis. Antibiotic resistance profiles from culture-positive endophthalmitis cases are given. RESULTS: Gram-positive organisms accounted for 124 of 154 (80.5%) culture-positive endophthalmitis isolates (146 of 229 [63.8%]). The sensitivity (0.36%) and specificity (0.71%) of AC culture results were poor predictors of positive vitreous culture. Positive and negative predictive values were less than 60%. Positive likelihood ratio (1.24) and negative likelihood (0.91) of AC culture results did not aid in predicting vitreous findings. Gram-positive isolates demonstrated in vitro resistance to moxifloxacin (47.1%), ciprofloxacin (43.4%), gatifloxacin (36.8%), levofloxacin (29.0%), gentamicin (19.2%), and ceftazidime (16.7%). CONCLUSIONS: The AC lacks concordance with vitreous findings in cases of endophthalmitis. Use of broad spectrum antibiotics to sterilize the ocular surface and provide therapeutic levels in the AC may not prevent endophthalmitis. In this study, the finding of a sterile AC did not rule out vitreous infection. These results may have implications for the routine use of broad-spectrum antibiotics as a means of vitreous protection and endophthalmitis prophylaxis. PMID- 20837797 TI - Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study system for evaluation of stereoscopic color fundus photographs and fluorescein angiograms: SCORE Study Report 9. AB - OBJECTIVE: To describe the procedures and reproducibility for grading stereoscopic color fundus photographs and fluorescein angiograms of participants in the SCORE Study. METHODS: Standardized stereoscopic fundus photographs and fluorescein angiograms taken at 84 clinical centers were evaluated by graders at a central reading center. Type of retinal vein occlusion (RVO), area of retinal thickening, and area of retinal hemorrhage are evaluated from fundus photographs; area of fluorescein leakage and area of capillary nonperfusion are measured on fluorescein angiography. Temporal reproducibility consisted of annual regrading of a randomly selected dedicated subset of fundus photographs (60 subjects) and fluorescein angiograms (40 subjects) for 3 successive years. Contemporaneous reproducibility involved monthly regrading of a 5% random selection of recently evaluated fundus photographs (n = 73). RESULTS: The intergrader agreement for RVO type and presence of retinal thickening was greater than 90% in the 3 annual regrades. The intraclass correlation (ICC) for area of retinal thickening in the 3 years ranged from 0.39 to 0.64 and for area of retinal hemorrhage, 0.87 to 0.96. The ICC for area of fluorescein leakage ranged from 0.66 to 0.75 and for capillary nonperfusion, 0.94 to 0.97. The contemporaneous reproducibility results were similar to those of temporal reproducibility for all variables except area of retinal thickening (ICC, 0.84). CONCLUSIONS: The fundus photography and fluorescein angiography grading procedures for the SCORE Study are reproducible and can be used for multicenter longitudinal studies of RVO. A systematic temporal drift occurred in evaluating area of retinal thickening. PMID- 20837799 TI - Interexpert agreement in the identification of macular location in infants at risk for retinopathy of prematurity. AB - OBJECTIVE: To characterize variability in the identification of the macular center among retinopathy of prematurity (ROP) experts. METHODS: A printed set of 25 wide-angle retinal images was compiled from infants at risk for ROP using a commercially available camera. Ten recognized ROP experts were asked to mark the macular center on each image. For each image, we measured the distance from the optic disc center to the marked macular center. Distances were standardized by normalizing the horizontal optic disc diameter in each image to 0.93 mm. In images with visible peripheral disease, interexpert agreement on the presence of zone I disease was also determined. RESULTS: For the image with the least variability among experts, mean (SD) distance from the optic disc to the macular center was 3.69 (0.21) mm (range, 3.13-3.81 mm). For the image with the greatest variability among experts, distance from the optic disc to the macular center was 4.32 (1.19) mm (range, 3.21-7.19 mm). In 7 of 21 images (33%) with visible peripheral disease, there would have been disagreement among experts in the diagnosis of zone I disease based on identification of the macular center. Among the 10 experts, in 17 of 25 images (68%), 1 expert identified the distance between the optic disc and macular center to be greater than 1 SD from the mean. CONCLUSION: Significant variability exists among experts in identification of the macular center from wide-angle images, which raises concerns about the reliability of zone I ROP diagnosis. PMID- 20837798 TI - Efficacy of sustained topical dorzolamide therapy for cystic macular lesions in patients with retinitis pigmentosa and usher syndrome. AB - OBJECTIVE: To determine the efficacy of sustained topical therapy with dorzolamide hydrochloride, 2%, on visual acuity and cystic macular lesions in patients with retinitis pigmentosa and Usher syndrome. METHODS: In a retrospective case series at a university hospital, 64 eyes of 32 patients with retinitis pigmentosa or Usher syndrome receiving treatment with the topical dorzolamide formulation for 6 to 58 months were enrolled. Changes in visual acuity on the Early Treatment Diabetic Retinopathy Study chart and central foveal zone thickness on optical coherence tomography were measured during follow-up for the duration of treatment. RESULTS: Among the study cohort, 20 of 32 patients (63%) showed a positive response to treatment in at least 1 eye and 13 patients (41%) showed a positive response in both eyes. Four patients (20%) showed an initial response and a subsequent rebound of macular cysts. In 8 patients (25%), there was no response to treatment and the macular cysts worsened when compared with the pretreatment level. Ten patients (31%) had improvement in visual acuity by 7 or more letters in at least 1 eye at the most recent follow-up visit. Sixteen patients (67%) showed a reduction of more than 11% in the central foveal zone thickness in at least 1 eye when compared with the pretreatment level. CONCLUSIONS: Patients with either retinitis pigmentosa or Usher syndrome who received treatment of cystoid macular edema with topical dorzolamide followed by an optical coherence tomography-guided strategy showed a decrease in central foveal zone thickness in most cases. Visual acuity improved in almost one-third of the cases, suggesting a potential corresponding visual benefit. PMID- 20837800 TI - Primary mucinous carcinoma of the eyelid: a clinicopathologic and immunohistochemical study of 4 cases and an update on recurrence rates. AB - OBJECTIVES: To report 4 cases of primary mucinous carcinoma of the eyelid, demonstrate how p63 expression aids diagnosis, and review the literature regarding the local recurrence potential of these eyelid tumors. METHODS: Since 1991, we have examined 4 cases of primary mucinous carcinoma of the eyelid. Histology slides were reviewed and clinical information was obtained from the medical records. Published cases of primary mucinous carcinoma involving the eyelid were identified using Ovid MEDLINE and PubMed and references within the articles. RESULTS: Our average patient age was 73 years, the female:male ratio was 3:1, and patients had a painless nodular mass for 1 month to 2 years. No patient had another documented malignant tumor at the time of diagnosis. All tumors were dermis based in the upper eyelid, three-fourths invaded the orbicularis oculi muscle, and the average tumor diameter was 3.7 mm. All tumors expressed cytokeratin 7 and gross cystic disease fluid protein 15 and were negative for cytokeratin 20 expression. Tumors demonstrated p63 immunopositivity either focally in the invasive component or peripherally along the in situ component. No recurrences have been evident after an average follow-up of 52 months. Published cases occurring in the eyelid have had a 30% to 40% recurrence rate using surgery without intraoperative evaluation of surgical margins and a 7% recurrence rate after either Mohs surgery or excision with frozen section control. CONCLUSION: Primary mucinous carcinoma of the eyelid is a low-grade malignant tumor with the potential for recurrence, although this may be reduced using Mohs surgery or excision with frozen section control. PMID- 20837801 TI - Neonatal dacryostenosis as a risk factor for anisometropia. AB - OBJECTIVE: To determine whether there is a relationship between congenital nasolacrimal duct obstruction (CNLDO) and subsequent refractive error disorders in children. METHODS: The medical records of children 5 years and younger diagnosed as having CNLDO between January 1, 2000, and December 31, 2007, were retrospectively reviewed. RESULTS: Three hundred five consecutive children were diagnosed as having CNLDO at a median age of 12.3 months (range, 0.8 months to 4.8 years). Thirty children (9.8%) were diagnosed as having anisometropia with (n = 16) or without (n = 14) amblyopia at a median age of 19.2 months (range, 3.6 months to 7.4 years). Twenty-six of the 30 patients had hyperopic anisometropia; more severe hyperopia occurred in the eye with CNLDO in 23 patients (88.5%), 2 patients had more severe hyperopia in the fellow eye, and 1 patient had bilateral CNLDO. The median initial (P = .005) and final (P < .001) refractive error was significantly more hyperopic in those with both CNLDO and anisometropia compared with those with CNLDO alone. CONCLUSIONS: The development of anisometropia with or without amblyopia seems to be more frequent in children examined by an ophthalmologist for CNLDO compared with that reported for the general public. The laterality of more severe hyperopia and amblyopia is generally on the side of the previous dacryostenosis. PMID- 20837802 TI - Identification of candidate tumor oncogenes by integrative molecular analysis of choroidal melanoma fine-needle aspiration biopsy specimens. AB - OBJECTIVE: To report integrative molecular analysis of choroidal melanoma fine needle aspiration biopsy specimens to identify candidate tumor oncogenes. METHODS: Thirty-one choroidal melanoma fine-needle aspiration biopsy specimens were analyzed using cytopathologic diagnosis of melanoma, fluorescence in situ hybridization for chromosome 3, cytogenetic characterization (GeneChip Human 250K NSPI Mapping Arrays; Affymetrix, Santa Clara, California), and gene expression profiles (GeneChip Human Genome U133 Plus 2.0 Arrays, Affymetrix). These analyses were performed by clustering of cytogenetic aberrations, sorting by chromosome 3 loss and chromosome 6p gain, and comparing gene expression profiles in chromosome 3 loss- and chromosome 6p-gain tumors to identify genes with differential expression based on cytogenetic characteristics. RESULTS: Of 31 choroidal melanoma biopsy specimens included in this study, 19 tumors had chromosome 3 loss, and 12 tumors without chromosome 3 loss had chromosome 6p gain. Comparative RNA analysis for these 2 groups revealed 49 genes with greater than 4-fold higher expression and 31 genes with greater than 4-fold lower expression in chromosome 3 loss tumors relative to chromosome 6p-gain tumors. CONCLUSIONS: Molecular analysis of choroidal melanoma fine-needle aspiration biopsy specimens demonstrated 2 cytogenetically distinct groups characterized by chromosome 3 loss or chromosome 6p gain. In chromosome 3-loss melanomas relative to chromosome 6p gain melanomas, integrative RNA analysis revealed genes with higher expression and lower expression and identified several genes that have not been reported in previous studies. CLINICAL RELEVANCE: Genes differentially expressed between chromosome 3-loss and chromosome 6p-gain melanomas may provide new knowledge about the biologic nature of choroidal melanoma and may contribute to the development of targeted therapies. PMID- 20837803 TI - Incidence, recurrence, and outcomes of herpes simplex virus eye disease in Olmsted County, Minnesota, 1976-2007: the effect of oral antiviral prophylaxis. AB - OBJECTIVES: To provide an estimate of the incidence of herpes simplex virus (HSV) eye disease in a community-based cohort, and to investigate the effect of prophylactic oral antiviral therapy on HSV recurrences and outcomes. METHODS: All Olmsted County, Minnesota, residents diagnosed with ocular HSV from 1976 through 2007 were retrospectively reviewed. The frequency of recurrences and adverse outcomes, such as vision loss or need for surgery, were compared between untreated patients and those treated prophylactically with oral antiviral medication. RESULTS: Three hundred ninety-four patients with ocular HSV were identified, yielding an annual incidence of 11.8 per 100,000 people (95% confidence interval [CI], 10.6-13.0). No trends in incidence or adverse outcomes were identified during the 32-year period. Oral antiviral therapy was prescribed in 175 patients. Patients were 9.4 times more likely (95% CI, 5.0-17.9) to have a recurrence of epithelial keratitis, 8.4 times more likely (95% CI, 5.2-13.7) to have a recurrence of stromal keratitis, and 34.5 times more likely (95% CI, 10.8 111.1) to have a recurrence of blepharitis or conjunctivitis if not being treated prophylactically at the time of the recurrence. Twenty patients experienced adverse outcomes, and 17 (85%) were not being treated with oral antiviral medications immediately preceding the adverse event. CONCLUSIONS: Oral antiviral prophylaxis was associated with a decreased risk of recurrence of epithelial keratitis, stromal keratitis, conjunctivitis, and blepharitis due to HSV. Patients with adverse outcomes due to ocular HSV were usually not being treated with oral antiviral prophylaxis. PMID- 20837804 TI - Evidence for keratoconus susceptibility locus on chromosome 14: a genome-wide linkage screen using single-nucleotide polymorphism markers. AB - OBJECTIVE: To search for genetic factors that could increase susceptibility to keratoconus. METHODS: A single-nucleotide polymorphism chip method was used to generate whole-genome data in a multiethnic panel of 6 families with 3 to 5 members affected by keratoconus. Candidate gene screening was performed by direct sequencing. RESULTS: Linkage analysis results were strongest for a locus on chromosome 14q24.3. This region contains a relatively small number of genes of potential interest, including VSX2, a homeobox gene known to be involved in eye development and implicated in a spectrum of ocular disorders. However, sequencing the coding region of VSX2 did not reveal a sequence variant segregating with disease in any of the families described. CONCLUSION: To our knowledge, this is the first report of linkage for keratoconus to 14q24.3 and the region is likely to harbor important inheritable genetic factors that may affect susceptibility to keratoconus. CLINICAL RELEVANCE: Further genetic research is needed to identify the genes responsible for keratoconus. This knowledge will aid in understanding the molecular pathophysiology of this condition and may lead to improved treatment strategies. PMID- 20837805 TI - Pars plana vitrectomy and endoresection of a retinal vasoproliferative tumor. AB - A healthy 31-year-old woman developed decreased vision due to vitreous hemorrhage from 2 retinal vascular lesions. Because of the patient's desire for visual rehabilitation and the concern for von Hippel-Lindau (VHL) disease-associated retinal hemangioblastomas, pars plana vitrectomy and endoresection of both lesions were performed. Surgical techniques included the use of chandelier illumination to enable bimanual manipulation of tissue, endolaser around the tumor prior to resection, endodiathermy to cauterize the tumor's feeder vessels, and long-acting gas tamponade following the retinectomy. Histopathology showed a vascular anomaly within the retina that consisted of multiple large vessels with multiple lumens and no evidence of VHL-associated retinal hemangioblastoma. Long term follow-up revealed no evidence of recurrent disease. This surgical technique may be valuable in select patients to differentiate between retinal vasoproliferative tumors and VHL disease-associated retinal hemangioblastomas for diagnostic, therapeutic, and counseling purposes. PMID- 20837806 TI - The shift toward minimally invasive aesthetic facial rejuvenation. PMID- 20837807 TI - Scleral buckling vs vitrectomy: the continued role for scleral buckling in the vitrectomy era. PMID- 20837808 TI - The declining use of scleral buckling with vitrectomy for primary retinal detachments. PMID- 20837809 TI - Darwin and Helmholtz on imperfections of the eye. PMID- 20837810 TI - Endonasal dacryocystorhinostomy in wegener granulomatosis. PMID- 20837812 TI - Plus disease in retinopathy of prematurity: quantitative analysis of standard published photograph. PMID- 20837811 TI - Pilot study of levodopa dose as treatment for residual amblyopia in children aged 8 years to younger than 18 years. PMID- 20837813 TI - Target visual field: a technique to rapidly demonstrate nonorganic visual field constriction. PMID- 20837814 TI - Topical antibiotics to reduce the risk of endophthalmitis after intravitreal injection? PMID- 20837816 TI - Corneal thickness changes in very-high-altitude mountaineers. PMID- 20837818 TI - Sustained reduction in methicillin-resistant Staphylococcus aureus wound infections after cardiothoracic surgery. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) wound infections after cardiac surgery have increased in recent years and carry significant morbidity and mortality. In our hospital, MRSA accounted for 56% of postoperative infections. METHODS: Postoperative wound infection rates were compared for the 3 years before (baseline period) and after (intervention period) introduction of a comprehensive MRSA intervention program. The intervention included preoperative screening for MRSA colonization, administration of intravenous vancomycin prophylaxis for identified carriers, administration of intranasal mupirocin calcium ointment to all patients regardless of colonization status for 5 days beginning the day before surgery, and application of mupirocin to chest tube sites at the time of removal. RESULTS: Postoperative MRSA wound infections decreased by 93% (32 infections per 2767 cases in the baseline period vs 2 infections per 2496 cases in the intervention period; relative risk, 0.069; P < .001). Overall wound infection rates decreased from 2.1% to 0.8% (59 infections per 2769 cases vs 20 infections per 2496 cases; P < .001). During the intervention period, there was no change in the number of MRSA infections after noncardiac surgery. CONCLUSION: This MRSA intervention program, in which all patients receive intranasal mupirocin and patients colonized with MRSA receive vancomycin prophylaxis, has resulted in a near-complete and sustained elimination of MRSA wound infections after cardiac surgery. PMID- 20837819 TI - Primary care clinicians' experiences with treatment decision making for older persons with multiple conditions. AB - BACKGROUND: Clinicians are caring for an increasing number of older patients with multiple diseases in the face of uncertainty concerning the benefits and harms associated with guideline-directed interventions. Understanding how primary care clinicians approach treatment decision making for these patients is critical to the design of interventions to improve the decision-making process. METHODS: Focus groups were conducted with 40 primary care clinicians (physicians, nurse practitioners, and physician assistants) in academic, community, and Veterans Affairs-affiliated primary care practices. Participants were given open-ended questions about their approach to treatment decision making for older persons with multiple medical conditions. Responses were organized into themes using qualitative content analysis. RESULTS: The participants were concerned about their patients' ability to adhere to complex regimens derived from guideline directed care. There was variability in beliefs regarding, and approaches to balancing, the benefits and harms of guideline-directed care. There was also variability regarding how the participants involved patients in the process of decision making, with clinicians describing conflicts between their own and their patients' goals. The participants listed a number of barriers to making good treatment decisions, including the lack of outcome data, the role of specialists, patient and family expectations, and insufficient time and reimbursement. CONCLUSIONS: The experiences of practicing clinicians suggest that they struggle with the uncertainties of applying disease-specific guidelines to their older patients with multiple conditions. To improve decision making, they need more data, alternative guidelines, approaches to reconciling their own and their patients' priorities, the support of their subspecialist colleagues, and an altered reimbursement system. PMID- 20837820 TI - From disclosure to transparency: the use of company payment data. AB - BACKGROUND: It has become standard practice in medical journals to require authors to disclose their relationships with industry. However, these requirements vary among journals and often lack specificity. As a result, disclosures may not consistently reveal author-industry ties. METHODS: We examined the 2007 physician payment information from 5 orthopedic device companies to evaluate the current journal disclosure system. We compared company payment information for recipients of $1 million or more with disclosures in the recipients' journal articles. Payment data were obtained from Biomet, DePuy, Smith & Nephew, Stryker, and Zimmer. Disclosures were obtained in the acknowledgments section, conflict of interest statements, and financial disclosures of recipients' published articles. We also assessed variations in disclosure by authorship position, payment-article relatedness, and journal disclosure policies. RESULTS: Of the 41 individuals who received $1 million or more in 2007, 32 had published articles relating to orthopedics between January 1, 2008, and January 15, 2009. Disclosures of company payments varied considerably. Prominent authorship position and article-payment relatedness were associated with greater disclosure, although nondisclosure rates remained high (46% among first-, sole-, and senior-authored articles and 50% among articles directly or indirectly related to payments). The accuracy of disclosures did not vary with the strength of journals' disclosure policies. CONCLUSIONS: Current journal disclosure practices do not yield complete or consistent information regarding authors' industry ties. Medical journals, along with other medical institutions, should consider new strategies to facilitate accurate and complete transparency. PMID- 20837821 TI - Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations. AB - OBJECTIVE: To assess whether impaired energy metabolism in skeletal muscle is a hallmark feature of patients with dominant optic atrophy due to several different mutations in the OPA1 gene. DESIGN: We used phosphorus 31 magnetic resonance spectroscopy to assess calf muscle oxidative metabolism in subjects with molecularly defined dominant optic atrophy carrying different mutations in the OPA1 gene. In a subset of patients, we also evaluated serum lactate levels after exercise and muscle biopsy results for histology and mitochondrial DNA analysis. SETTING: University neuromuscular and neurogenetics and magnetic resonance imaging units. PATIENTS: Eighteen patients with dominant optic atrophy were enrolled from 8 unrelated families, 7 of which carried an OPA1 mutation predicted to induce haploinsufficiency and 1 with a missense mutation in exon 27. Fifteen patients had documented optic atrophy. MAIN OUTCOME MEASURES: Presence of skeletal muscle mitochondrial oxidative phosphorylation dysfunction as assessed by phosphorus 31 magnetic resonance spectroscopy, serum lactate levels, and histological and mitochondrial DNA analysis. RESULTS: Phosphorus 31 magnetic resonance spectroscopy showed reduced phosphorylation potential in the calf muscle at rest in patients with an OPA1 mutation (-24% from normal mean; P = .003) as well as a reduced maximum rate of mitochondrial adenosine triphosphate synthesis (-36%; P < .001; ranging from -28% to -49% in association with different mutations). In 4 of 10 patients (40%), the serum lactate level after exercise was elevated. Only 2 of 5 muscle biopsies, from the 2 patients with a missense mutation, showed slight myopathic changes. Low levels of mitochondrial DNA multiple deletions were found in all muscle biopsies. CONCLUSIONS: Defective oxidative phosphorylation in skeletal muscle is a subclinical feature of patients with OPA1-related dominant optic atrophy, indicating a systemic expression of the OPA1 defect, similar to that previously reported for Leber hereditary optic neuropathy due to complex I dysfunction. This defect of oxidative phosphorylation does not appear to depend on the low amounts of mitochondrial DNA multiple deletions detected in muscle biopsies. PMID- 20837822 TI - Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. AB - BACKGROUND: Insulin resistance is a causal factor in prediabetes (PD) and type 2 diabetes (T2D) and increases the risk of developing Alzheimer disease (AD). Reductions in cerebral glucose metabolic rate (CMRglu) as measured by fludeoxyglucose F 18-positron emission tomography (FDG-PET) in parietotemporal, frontal, and cingulate cortices are associated with increased AD risk and can be observed years before dementia onset. OBJECTIVES: To examine whether greater homeostasis model assessment insulin resistance (HOMA-IR) is associated with reduced resting CMRglu in areas vulnerable in AD in cognitively normal adults with newly diagnosed PD or T2D (PD/T2D), and to determine whether adults with PD/T2D have abnormal patterns of CMRglu during a memory encoding task. DESIGN: Randomized crossover design of resting and activation FDG-PET. SETTING: University imaging center and Veterans Affairs clinical research unit. PARTICIPANTS: Twenty-three older adults (mean [SEM] age, 74.4 [1.4] years) with no prior diagnosis of diabetes but who met American Diabetes Association glycemic criteria for PD (n = 11) or diabetes (n = 12) based on fasting or 2-hour oral glucose tolerance test (OGTT) glucose values and 6 adults (mean [SEM] age, 74.3 [2.8] years) with normal fasting glucose values and glucose tolerance. No participant met Petersen criteria for mild cognitive impairment. INTERVENTIONS: Fasting participants underwent resting and cognitive activation FDG-PET imaging on separate days. Following a 30-minute transmission scan, subjects received an intravenous injection of 5 mCi of FDG, and the emission scan commenced 40 minutes after injection. In the activation condition, a 35-minute memory encoding task was initiated at the time of tracer injection. Subjects were instructed to remember a repeating list of 20 words randomly presented in series through earphones. Delayed free recall was assessed once the emission scan was complete. MAIN OUTCOME MEASURES: The HOMA-IR value was calculated using fasting glucose and insulin values obtained during OGTT screening and then correlated with CMRglu values obtained during the resting scan. Resting CMRglu values were also subtracted from CMRglu values obtained during the memory encoding activation scan to examine task-related patterns of CMRglu. RESULTS: Greater insulin resistance was associated with an AD-like pattern of reduced CMRglu in frontal, parietotemporal, and cingulate regions in adults with PD/T2D. The relationship between CMRglu and HOMA-IR was independent of age, 2-hour OGTT glucose concentration, or apolipoprotein E epsilon4 allele carriage. During the memory encoding task, healthy adults showed activation in right anterior and inferior prefrontal cortices, right inferior temporal cortex, and medial and posterior cingulate regions. Adults with PD/T2D showed a qualitatively different pattern during the memory encoding task, characterized by more diffuse and extensive activation, and recalled fewer items on the delayed memory test. CONCLUSIONS: Insulin resistance may be a marker of AD risk that is associated with reduced CMRglu and subtle cognitive impairments at the earliest stage of disease, even before the onset of mild cognitive impairment. PMID- 20837823 TI - Spreading depolarization: a possible new culprit in the delayed cerebral ischemia of subarachnoid hemorrhage. AB - Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease with a high mortality and morbidity rate. Gradual improvements have been made in the reduction of mortality rates associated with the disease during the last 30 years. However, delayed cerebral ischemia (DCI), the major delayed complication of SAH, remains a significant contributor to mortality and morbidity despite substantial research and clinical efforts. During the last several years, the predominant role of cerebral vasospasm, the long-accepted etiologic factor behind DCI, has been questioned. It is now becoming increasingly clear that the pathophysiology underlying DCI is multifactorial. Cortical spreading depression is emerging as a likely factor in this complex web of pathologic changes after SAH. Understanding its role after SAH and its relationship with the other pathologic processes such as vasospasm, microcirculatory dysfunction, and microemboli will be vital to the development of new therapeutic approaches to reduce DCI and improve the clinical outcome of the disease. PMID- 20837824 TI - A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. AB - OBJECTIVES: To evaluate the safety of the peroxisome proliferator-activated receptor gamma agonist pioglitazone in nondiabetic patients with Alzheimer disease (AD) and to explore treatment effect sizes on clinical outcomes. DESIGN: Double-blind, placebo-controlled randomized controlled trial of 18-month duration. SETTING: Two academic medical center outpatient clinics. PATIENTS: Nondiabetic patients meeting research criteria for probable AD were enrolled. Twenty-five of 29 subjects completed the study; no withdrawals were attributable to adverse effects. INTERVENTION: Subjects received pioglitazone (Actos), titrated to 45 mg daily, or matching placebo, and 200 IU of vitamin E daily. Patients maintained treatment with cholinesterase inhibitors and could begin memantine therapy when it became available during the study. MAIN OUTCOME MEASURES: The primary outcome was frequency of reported adverse effects (AEs). Secondary outcomes were measures of cognition, activities of daily living, neuropsychiatric symptoms, and global function. RESULTS: Peripheral edema was the principal AE occurring more frequently in subjects taking pioglitazone than placebo (28.6% vs 0%). This is consistent with the known AE profile of pioglitazone. No group differences in laboratory measures were identified. No significant treatment effect was observed on exploratory analysis of clinical efficacy. CONCLUSIONS: Pioglitazone was generally well tolerated in this pilot study. There were no serious or unanticipated adverse events or clinical laboratory changes attributable to pioglitazone over a long-term exposure in nondiabetic patients with AD. The tolerability of pioglitazone in this population and peroxisome proliferator-activated receptor gamma effects in laboratory models of AD support further study of this drug class in earlier disease stages. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00982202. PMID- 20837826 TI - Long-term opioid treatment of nonmalignant pain: a believer loses his faith. PMID- 20837825 TI - Open-label trial of recombinant human insulin-like growth factor 1/recombinant human insulin-like growth factor binding protein 3 in myotonic dystrophy type 1. AB - OBJECTIVE: To evaluate the safety and tolerability of recombinant human insulin like growth factor 1 (rhIGF-1) complexed with IGF binding protein 3 (rhIGF 1/rhIGFBP-3) in patients with myotonic dystrophy type 1 (DM1). DESIGN: Open-label dose-escalation clinical trial. SETTING: University medical center. PARTICIPANTS: Fifteen moderately affected ambulatory participants with genetically proven myotonic dystrophy type 1. INTERVENTION: Participants received escalating dosages of subcutaneous rhIGF-1/rhIGFBP-3 for 24 weeks followed by a 16-week washout period. MAIN OUTCOME MEASURES: Serial assessments of safety, muscle mass, muscle function, and metabolic state were performed. The primary outcome variable was the ability of participants to complete 24 weeks receiving rhIGF-1/ rhIGFBP-3 treatment. RESULTS: All participants tolerated rhIGF-1/rhIGFBP-3. There were no significant changes in muscle strength or functional outcomes measures. Lean body muscle mass measured by dual-energy x-ray absorptiometry increased by 1.95 kg (P < .001) after treatment. Participants also experienced a mean reduction in triglyceride levels of 47 mg/dL (P = .002), a mean increase in HDL levels of 5.0 mg/dL (P = .03), a mean reduction in hemoglobin A(1c) levels of 0.15% (P = .03), and a mean increase in testosterone level (in men) of 203 ng/dL (P = .002) while taking rhIGF-1/rhIGFBP-3. Mild reactions at the injection site occurred (9 participants), as did mild transient hypoglycemia (3), lightheadedness (2), and transient papilledema (1). CONCLUSIONS: Treatment with rhIGF-1/rhIGFBP-3 was generally well tolerated in patients with myotonic dystrophy type 1. Treatment with rhIGF-1/rhIGFBP-3 was associated with increased lean body mass and improvement in metabolism but not increased muscle strength or function. Larger randomized controlled trials would be needed to further evaluate the efficacy and safety of this medication in patients with neuromuscular disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00233519. PMID- 20837827 TI - Emergency department visits among recipients of chronic opioid therapy. AB - BACKGROUND: There has been an increase in overdose deaths and emergency department visits (EDVs) involving use of prescription opioids, but the association between opioid prescribing and adverse outcomes is unclear. METHODS: Data were obtained from administrative claim records from Arkansas Medicaid and HealthCore commercially insured enrollees, 18 years and older, who used prescription opioids for at least 90 continuous days within a 6-month period between 2000 and 2005 and had no cancer diagnoses. Regression analysis was used to examine risk factors for EDVs and alcohol- or drug-related encounters (ADEs) in the 12 months following 90 days or more of prescribed opioids. RESULTS: Headache, back pain, and preexisting substance use disorders were significantly associated with EDVs and ADEs. Mental health disorders were associated with EDVs in HealthCore enrollees and with ADEs in both samples. Opioid dose per day was not consistently associated with EDVs but doubled the risk of ADEs at morphine equivalent doses over 120 mg/d. Use of short-acting Drug Enforcement Agency Schedule II opioids was associated with EDVs compared with use of non-Schedule II opioids alone (relative risk range, 1.09-1.74). Use of Schedule II long-acting opioids was strongly associated with ADEs (relative risk range, 1.64-4.00). CONCLUSIONS: Use of Schedule II opioids, headache, back pain, and substance use disorders are associated with EDVs and ADEs among adults prescribed opioids for 90 days or more. It may be possible to increase the safety of chronic opioid therapy by minimizing the prescription of Schedule II opioids in these higher risk recipients. PMID- 20837828 TI - Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. AB - BACKGROUND: Patients with atrial fibrillation (AF) often require anticoagulation and platelet inhibition, but data are limited on the bleeding risk of combination therapy. METHODS: We performed a cohort study using nationwide registries to identify all Danish patients surviving first-time hospitalization for AF between January 1, 1997, and December 31, 2006, and their posthospital therapy of warfarin, aspirin, clopidogrel, and combinations of these drugs. Cox proportional hazards models were used to estimate risks of nonfatal and fatal bleeding. RESULTS: A total of 82,854 of 118,606 patients (69.9%) surviving AF hospitalization had at least 1 prescription filled for warfarin, aspirin, or clopidogrel after discharge. During mean (SD) follow-up of 3.3 (2.6) years, 13,573 patients (11.4%) experienced a nonfatal or fatal bleeding. The crude incidence rate for bleeding was highest for dual clopidogrel and warfarin therapy (13.9% per patient-year) and triple therapy (15.7% per patient-year). Using warfarin monotherapy as a reference, the hazard ratio (95% confidence interval) for the combined end point was 0.93 (0.88-0.98) for aspirin, 1.06 (0.87-1.29) for clopidogrel, 1.66 (1.34-2.04) for aspirin-clopidogrel, 1.83 (1.72-1.96) for warfarin-aspirin, 3.08 (2.32-3.91) for warfarin-clopidogrel, and 3.70 (2.89-4.76) for warfarin-aspirin-clopidogrel. CONCLUSIONS: In patients with AF, all combinations of warfarin, aspirin, and clopidogrel are associated with increased risk of nonfatal and fatal bleeding. Dual warfarin and clopidogrel therapy and triple therapy carried a more than 3-fold higher risk than did warfarin monotherapy. PMID- 20837830 TI - Associations between physician characteristics and quality of care. AB - BACKGROUND: Information on physicians' performance on measures of clinical quality is rarely available to patients. Instead, patients are encouraged to select physicians on the basis of characteristics such as education, board certification, and malpractice history. In a large sample of Massachusetts physicians, we examined the relationship between physician characteristics and performance on a broad range of quality measures. METHODS: We calculated overall performance scores on 124 quality measures from RAND's Quality Assessment Tools for each of 10,408 Massachusetts physicians using claims generated by 1.13 million adult patients. The patients were continuously enrolled in 1 of 4 Massachusetts commercial health plans from 2004 to 2005. Physician characteristics were obtained from the Massachusetts Board of Registration in Medicine. Associations between physician characteristics and overall performance scores were assessed using multivariate linear regression. RESULTS: The mean overall performance score was 62.5% (5th to 95th percentile range, 48.2%-74.9%). Three physician characteristics were independently associated with significantly higher overall performance: female sex (1.6 percentage points higher than male sex; P < .001), board certification (3.3 percentage points higher than noncertified; P < .001), and graduation from a domestic medical school (1.0 percentage points higher than international; P < .001). There was no significant association between performance and malpractice claims (P = .26). CONCLUSIONS: Few characteristics of individual physicians were associated with higher performance on measures of quality, and observed associations were small in magnitude. Publicly available characteristics of individual physicians are poor proxies for performance on clinical quality measures. PMID- 20837831 TI - Long-term use of anti-inflammatory drugs and risk of atrial fibrillation. AB - BACKGROUND: Previous reports have described an association between the use of corticosteroids (steroidal anti-inflammatory drugs [SAIDs]) and the risk of atrial fibrillation (AF). We sought to determine the existence of a similar association for non-SAIDs (NSAIDs). METHODS: We identified patients aged 40 to 89 years with a first-ever diagnosis of AF in 1996 in a United Kingdom primary care database and classified them as having paroxysmal or chronic AF. After validation with their primary care physicians, 1035 patients were confirmed as having incident chronic AF and 525 as having paroxysmal AF. Two separate nested case control analyses estimated the risk of first-time chronic and paroxysmal AF among users of SAIDs and NSAIDs. RESULTS: We confirmed the previously reported association between current use of SAIDs and chronic AF (rate ratio [RR], 2.49; 95% confidence interval [CI], 1.56-3.97). However, we also found that the current use of NSAIDs was associated with an increased risk of chronic AF (RR, 1.44; 95% CI, 1.08-1.91). Such risk was further increased among long-term users with a treatment duration of longer than 1 year (RR, 1.80; 95% CI, 1.20-2.72). The increased risk of chronic AF was not explained by the occurrence of heart failure. The use of NSAIDs was not associated with paroxysmal AF. CONCLUSIONS: The use of NSAIDs, as for SAIDs, is associated with an increased risk of chronic AF. Because the use of anti-inflammatory drugs in general is a marker for underlying inflammatory disorders, inflammation may be the common cause for the use of anti-inflammatory drugs and chronic AF. PMID- 20837832 TI - A population-based study of inferior vena cava filters in patients with acute venous thromboembolism. AB - BACKGROUND: Our study objective was to describe the frequency, indications, and outcomes after inferior vena cava (IVC) filter placement in a population-based sample of residents of the Worcester, Massachusetts, metropolitan area who had been diagnosed as having acute venous thromboembolism (VTE) in 1999, 2001, and 2003. METHODS: A retrospective chart review of inpatient and outpatient medical records was conducted. Recorded indication(s) for IVC filter placement was determined among a subset of cases from 3 Worcester tertiary care hospitals. Three thrombosis specialists assessed the appropriateness of IVC filter placement. RESULTS: Of 1547 greater Worcester residents with validated acute VTE and without a prior IVC filter, 203 (13.1%) had an IVC filter placed after acute VTE. Patients with an IVC filter were older, had more comorbidities, and had a higher mortality rate during 3 years of follow-up. There was unanimous agreement by panel members that the use of an IVC filter was appropriate in 51% of cases and inappropriate in 26% of cases, with no consensus in the remaining 23%. CONCLUSIONS: In this community-based study, IVC filters were frequently used in the treatment of patients with acute VTE. Placement was deemed to be appropriate in approximately 50% of the patients but was not appropriate or debatable in the remaining cases. Given the increasing use of IVC filters, prospective studies are clearly needed to better define the indications for, and efficacy of, IVC filter placement. PMID- 20837833 TI - Type 1 Gaucher disease: significant disease manifestations in "asymptomatic" homozygotes. AB - BACKGROUND: Type 1 Gaucher disease (GD), an autosomal recessive lysosomal storage disease, is most prevalent in the Ashkenazi Jewish (AJ) population. Experts have suggested that up to two-thirds of AJ homozygotes for the common mutation (N370S) are asymptomatic throughout life and never come to medical attention. However, there are no systematic studies of N370S homozygotes to support this presumption. METHODS: Prenatal carrier screening of 8069 AJ adults for 6 common GD mutations was performed. Gaucher disease manifestations in 37 previously unrecognized homozygotes were assessed by clinical, laboratory, and imaging studies. RESULTS: Among the 8069 AJ screenees, 524 GD carriers (1:15) and 9 previously unrecognized GD homozygotes (1:897) were identified, consistent with the rate expected (1:949; P > .99). Six of these homozygotes and 31 AJ GD homozygotes identified by other prenatal carrier screening programs in the New York City metropolitan area were evaluated (age range of the homozygotes, 17-40 years). Of these, 84% were N370S homozygotes, others being heteroallelic for N370S and V394L, L444P, or R496H mutations. Notably, 65% reported no GD medical complaints. However, 49% had anemia and/or thrombocytopenia. Among the 29 who had imaging studies, 97% had mild to moderate splenomegaly and 55% had hepatomegaly; skeletal imaging revealed marrow infiltration (100%), Erlenmeyer flask deformities (43%), lucencies (22%), and bone infarcts (14%). Dual energy X-ray absorptiometry studies of 25 homozygotes found 60% with osteopenia or osteoporosis. CONCLUSION: Contrary to previous discussions, almost all asymptomatic GD homozygotes serendipitously diagnosed by prenatal carrier screening had disease manifestations and should be followed for disease progression and institution of appropriate medical treatment. PMID- 20837834 TI - Quality of life and cost-effectiveness of a 3-year trial of lifestyle intervention in primary health care. AB - BACKGROUND: Lifestyle interventions reduce cardiovascular risk and risk of diabetes mellitus, but reports on long-term effects on quality of life (QOL) and health care utilization are rare. We investigated the impact of a primary health care-based lifestyle intervention program on QOL and cost-effectiveness over 3 years. METHODS: A total of 151 men and women, aged 18 to 65 years, at moderate to high risk for cardiovascular disease, were randomly assigned to either lifestyle intervention with standard care or standard care alone. Intervention consisted of supervised exercise sessions and diet counseling for 3 months, followed by regular group meetings over a 3-year period. Change in QOL was measured with EuroQol (5-dimensional EuroQol-5D [EQ-5D] and EuroQol-VAS [EQ-VAS]), the 36-Item Short-Form Health Survey (SF-36), and the 6-dimensional Short-Form 6D (SF-6D). The health economic evaluation was performed from a societal view and a treatment perspective. In a cost-utility analysis, the costs, gained quality-adjusted life years (QALYs), and savings in health care were considered. Cost-effectiveness was also described using the net monetary benefit method. RESULTS: Significant differences between the groups over the 3-year period were shown in the EQ-VAS (P = .002), SF-6D (P = .01), and SF-36 (P = .04) physical component summary but not in the EQ-5D (P = .24) or SF-36 (P = .37) mental component summary. The net savings were $47 per participant. Costs per gained QALY, savings not counted, were $1668 to $4813. Probabilities of cost-effectiveness were 89% to 100% when the amount of $50,000 was used as stakeholder's threshold of willingness to pay for a gained QALY. CONCLUSION: Lifestyle intervention in primary care improves QOL and is highly cost-effective in relation to standard care. Trial Registration clinicaltrials.gov Identifier: NCT00486941. PMID- 20837835 TI - Patient perceptions of mistakes in ambulatory care. AB - BACKGROUND: Little information exists about current patient perceptions of medical mistakes in ambulatory care within a diverse population. We aimed to learn about the perceptions of medical mistakes, what factors were associated with perceived mistakes, and whether the participants changed physicians because of these perceived mistakes. METHODS: We conducted a cross-sectional survey at 7 primary care practices in North Carolina of English- or Spanish-speaking adults, aged 18 years and older, who saw a health care professional during 2008. Main outcome measures were 4 questions about patient perceptions of medical mistakes in the ambulatory care setting, including (1) overall experience with a medical mistake; type of mistake, such as a (2) diagnostic mistake or (3) treatment mistake, and its associated harm; and (4) effect of this mistake on changing physicians. RESULTS: Of 1697 participants, 265 (15.6%) responded that a physician had made a mistake, 227 (13.4%) reported a wrong diagnosis, 212 (12.5%) reported a wrong treatment, and 239 (14.1%) reported having changed physicians because of a mistake. Participants perceived mistakes and harm in both diagnostic care and medical treatment. Patients with chronic back pain, higher educational attainment, and poor physical health were at increased odds of perceiving mistakes, whereas African American patients were less likely to perceive mistakes. CONCLUSIONS: Patients perceived mistakes in their diagnostic and treatment care in the ambulatory setting. These perceptions had a concrete effect on the physician-patient relationship, often leading patients to seek another health care professional. PMID- 20837836 TI - Ambulatory patient safety: the time is now: comment on "patient perceptions of mistakes in ambulatory care". PMID- 20837838 TI - Medical eponyms: time for a name change. PMID- 20837839 TI - Suboptimal potassium intake and potential impact on population blood pressure. PMID- 20837837 TI - Association between pharmaceutical support and basic science research on erythropoiesis-stimulating agents. AB - BACKGROUND: To our knowledge, no prior research has evaluated the association between pharmaceutical industry funding and basic science research results. When erythropoiesis-stimulating agents (ESAs) were licensed to treat chemotherapy associated anemia, basic science concerns related to potential cancer stimulation were raised. We evaluated associations between pharmaceutical industry support and reported findings evaluating ESA effects on cancer cells. METHODS: Articles identified in MEDLINE and EMBASE databases (1988-2008) investigating basic science findings related to ESA administration in the solid tumor setting were reviewed. Outcomes included information on erythropoietin receptors (EpoRs), Epo induced signaling events, cellular function, and qualitative conclusions. Information on study funding (academic investigators with no reported funding from ESA manufacturers [64 studies], academic investigators with grant funding from ESA manufacturers [7 studies], and investigators employed by the ESA manufacturers [3 studies]) was evaluated. Some studies did not include information on each outcome. RESULTS: Investigators without funding from ESA manufacturers were more likely than academic investigators with such funding or investigators employed by ESA manufacturers to identify EpoRs on solid tumor cells (100%, 60%, and 67%, respectively; P = .009), Epo-induced signaling events (94%, 0%, and 0%, respectively; P = .001), or changes in cellular function (57%, 0%, and 0%, respectively; P = .007) and to conclude that ESAs had potentially harmful effects on cancer cells (57%, 0%, and 0%, respectively; P = .008). CONCLUSIONS: Researchers who do not have pharmaceutical industry support are more likely than those with pharmaceutical support to identify detrimental in vitro effects of ESAs. The potential for conflicts of interest to affect basic science research should be considered. PMID- 20837840 TI - Patients' willingness to discuss trade-offs to lower their out-of-pocket drug costs. PMID- 20837841 TI - The accuracy of nutrition information on the Internet for type 2 diabetes. PMID- 20837842 TI - High-dose abdominal radiotherapy and risk of diabetes mellitus. PMID- 20837843 TI - Conflicting evidence surrounding the clopidogrel and proton pump inhibitor drug interaction. PMID- 20837844 TI - Is emergency research without initial consent justified? The consent substitute model. PMID- 20837845 TI - Specific elements of teleintensivist paradigm require additional scrutiny and justification. PMID- 20837846 TI - Up the spinal canal without a paddle: consideration of neurology's role in spinal cord injury. PMID- 20837847 TI - A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. AB - BACKGROUND: Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a beta2 adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy. OBJECTIVES: To investigate the clinical and immunologic effects of albuterol treatment as an add on therapy in patients starting glatiramer acetate treatment. DESIGN: Single center double-masked clinical trial. SETTING: Academic research. Patients Subjects with relapsing-remitting multiple sclerosis. MAIN OUTCOME MEASURES: In this single-center double-masked clinical trial, subjects with relapsing remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon gamma at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol. RESULTS: Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-gamma production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P < .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment. CONCLUSION: Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00039988. PMID- 20837848 TI - 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases. AB - 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are among the most prescribed medications in the United States. Statins act on the rate-limiting step in cholesterol biosynthesis (the conversion of HMG-CoA to mevalonate) and are effective in treating dyslipidemia. However, statins decrease other downstream products of the mevalonate pathway, and it is via these pathways that statins may affect inflammation, nitric oxide synthesis, the coagulation cascade, and other processes. Through these pleiotropic effects, statins may have an effect on neurologic diseases, including ischemic and hemorrhagic stroke, Alzheimer disease, Parkinson disease, and multiple sclerosis. This article reviews the basic biochemistry of statins as it relates to these pleiotropic effects, the potential role of statins in several neurologic disorders, and the results of clinical trials performed for several of these conditions. PMID- 20837849 TI - New perspectives on amyloid-beta dynamics after acute brain injury: moving between experimental approaches and studies in the human brain. AB - The links between traumatic brain injury and Alzheimer disease have been of great interest for many years. However, the importance of amyloid-beta-related neurodegenerative pathophysiologic processes after traumatic brain injury is still unknown. In this review, we present a brief overview of the scientific evidence regarding traumatic brain injury as a contributor to Alzheimer disease and describe recent results showing significant changes in brain extracellular amyloid-beta dynamics in patients with severe brain injury. We then discuss the clinical significance of these findings with their implications for translational neurobiology and conclude with further directions for traumatic brain injury and Alzheimer disease research. PMID- 20837850 TI - A multidisciplinary consultation team to address the unmet needs of hospitalized patients with spinal cord injury. PMID- 20837851 TI - A serum protein-based algorithm for the detection of Alzheimer disease. AB - OBJECTIVE: To develop an algorithm that separates patients with Alzheimer disease (AD) from controls. DESIGN: Longitudinal case-control study. SETTING: The Texas Alzheimer's Research Consortium project. Patients We analyzed serum protein based multiplex biomarker data from 197 patients diagnosed with AD and 203 controls. Main Outcome Measure The total sample was randomized equally into training and test sets and random forest methods were applied to the training set to create a biomarker risk score. RESULTS: The biomarker risk score had a sensitivity and specificity of 0.80 and 0.91, respectively, and an area under the curve of 0.91 in detecting AD. When age, sex, education, and APOE status were added to the algorithm, the sensitivity, specificity, and area under the curve were 0.94, 0.84, and 0.95, respectively. CONCLUSIONS: These initial data suggest that serum protein-based biomarkers can be combined with clinical information to accurately classify AD. A disproportionate number of inflammatory and vascular markers were weighted most heavily in the analyses. Additionally, these markers consistently distinguished cases from controls in significant analysis of microarray, logistic regression, and Wilcoxon analyses, suggesting the existence of an inflammatory-related endophenotype of AD that may provide targeted therapeutic opportunities for this subset of patients. PMID- 20837853 TI - Causes and outcomes of acute neuromuscular respiratory failure. AB - OBJECTIVE: To identify the spectrum of causes, analyze the usefulness of diagnostic tests, and recognize prognostic factors in patients with acute neuromuscular respiratory failure. METHODS: We evaluated 85 patients admitted to the intensive care unit (ICU) at Mayo Clinic, Rochester, between 2003 and 2009 with acute neuromuscular respiratory failure, defined as a need for mechanical ventilation owing to primary impairment of the peripheral nervous system. Outcome was assessed at hospital discharge and at last follow-up. Poor outcome was defined as a modified Rankin score greater than 3. RESULTS: The median age was 66 years; median follow-up, 5 months. The most frequent diagnoses were myasthenia gravis, Guillain-Barre syndrome, myopathies, and amyotrophic lateral sclerosis (27, 12, 12, and 12 patients, respectively). Forty-seven patients (55%) had no known neuromuscular diagnosis before admission, and 36 of them (77%) had poor short-term outcomes. In 10 patients (12%), the diagnosis remained unknown on discharge; only 1 (10%) had regained independent function. Older age was associated with increased mortality during hospitalization. Longer mechanical ventilation times and ICU stays were associated with poor outcome at discharge but not at the last follow-up. Patients without a known neuromuscular diagnosis before admission had longer duration of mechanical ventilation, longer ICU stays, and worse outcomes at discharge. Electromyography was the most useful diagnostic test in patients without previously known neuromuscular diagnoses. The presence of spontaneous activity on needle insertion predicted poor short-term outcome regardless of final diagnosis. Coexistent cardiopulmonary diseases also predicted poor long-term outcome. CONCLUSIONS: Among patients with neuromuscular respiratory failure, those without known diagnosis before admission have poorer outcomes. Patients whose diagnoses remain unclear at discharge have the highest rates of disability. PMID- 20837852 TI - Safety and tolerability of immune globulin intravenous in chronic inflammatory demyelinating polyradiculoneuropathy. AB - BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a common inflammatory neuropathy that can be progressive, stepwise progressive, or relapsing and remitting. OBJECTIVES: To further evaluate the long-term safety and tolerability of immune globulin intravenous, 10% caprylate-chromatography purified immune globulin intravenous in CIDP. DESIGN: Randomized multicenter trial. SETTING: Hospitals and outpatient clinics. PATIENTS: Adults with CIDP (n = 117) [corrected]. INTERVENTIONS: Immune globulin intravenous, 10% caprylate chromatography purified (2 g/kg of body weight) or placebo was infused as a baseline loading dose, followed by a maintenance dose (1 g/kg) every 3 weeks for up to 24 weeks. PATIENTS who responded were rerandomized into a double-blind extension phase of immune globulin intravenous, 10% caprylate-chromatography purified (1 g/kg) or placebo every 3 weeks for up to 24 weeks. PATIENTS who relapsed during the extension phase were withdrawn from the study. MAIN OUTCOME MEASURES: Additional analyses of safety and tolerability. RESULTS: Overall, 113 patients and 95 patients were exposed to immune globulin intravenous, 10% caprylate-chromatography purified and placebo, respectively. Exposure to immune globulin intravenous, 10% caprylate-chromatography purified was approximately twice that of placebo (1096 vs 575 infusions). Most maintenance dose courses were administered over 1 day in the immune globulin intravenous, 10% caprylate chromatography purified (89.1% of 783 dose courses) and placebo (91.1% of 359 dose courses) groups. The most common drug-related adverse events (AEs) with immune globulin intravenous, 10% caprylate-chromatography purified were headache (4.0 per 100 infusions) and pyrexia (2.4 per 100 infusions). Five drug-related serious AEs (pulmonary embolism, pyrexia, vomiting, and 2 headache events) were reported in 3 patients (2.7%) exposed to immune globulin intravenous, 10% caprylate-chromatography purified. The incidence of drug-related serious AEs was higher after loading dose infusions than after maintenance dose infusions (4 AEs vs 1 AE). Age, weight, CIDP severity, and previous immune globulin intravenous exposure had no substantial effect on the percentage of patients with AEs, including serious AEs. CONCLUSION: Data support a favorable safety and tolerability profile for administration of immune globulin intravenous, 10% caprylate-chromatography purified as CIDP maintenance therapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00220740. PMID- 20837854 TI - Inhibition of endogenous interferon beta by neutralizing antibodies against recombinant interferon beta. AB - OBJECTIVE: To determine if neutralizing antibodies (NAbs) against interferon beta from patients with multiple sclerosis (MS) cross-react with other type 1 interferons, especially endogenous interferon beta, and thus might impede the immune systems of affected patients. DESIGN: Masked serum samples from MS patients were challenged in vitro against recombinant interferon beta-1a and interferon beta-1b, as well as human leukocyte interferon and fibroblast interferon, the latter representing endogenous interferon. The neutralizing capacity of serum samples on these type 1 interferons was assessed using a luciferase reporter gene assay. Randomly selected samples were titrated to further delineate the cross-reactivity of antibodies. SETTING: University medical center in Dusseldorf, Germany. PATIENTS: We randomly selected 150 samples from interferon beta-treated MS patients who had previously been tested for the presence of binding antibodies and NAbs. MAIN OUTCOME MEASURES: Neutralization of interferon beta bioactivity and cross-reactivity of anti-interferon beta antibodies. RESULTS: Antibody-mediated neutralization of interferon beta bioactivity in vitro against recombinant interferon beta was observed in all serum samples that had previously tested positive for binding antibodies and NAbs. A neutralizing pattern comparable to that of recombinant interferon beta was observed when endogenous interferon was assessed, reflecting cross-reactivity of NAbs. No differences in neutralization between recombinant and endogenous interferon were observed with respect to the interferon beta preparation used for treatment. Furthermore, no neutralization of other type 1interferons by NAbs could be detected. CONCLUSIONS: A proportion of MS patients who are treated with recombinant interferon beta develop NAbs that also neutralize endogenous interferon. Because NAbs at high titers can persist for years, these antibodies may impede the immune system in affected MS patients regardless of their current treatment regimen. PMID- 20837855 TI - Elevated intrathecal myelin oligodendrocyte glycoprotein antibodies in multiple sclerosis. AB - OBJECTIVE: To evaluate antibodies to myelin oligodendrocyte glycoprotein (MOG) in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and control individuals. DESIGN: Prospective case-control series. SETTING: Academic referral center. PATIENTS: Twenty-six controls with noninflammatory neurologic disease and 35 patients with MS donated serum and CSF for recombinant MOG (rMOG) antibody determination. MAIN OUTCOME MEASURES: Serum and CSF rMOG antibody and albumin levels were used to calculate an rMOG index. Clinical disability, CSF markers, and magnetic resonance metrics were correlated with the rMOG index. RESULTS: The rMOG index was elevated in MS patients compared with controls (P = .01). Patients with progressive MS exhibited elevated rMOG indexes compared with patients with relapsing-remitting MS (P = .04). The rMOG index was inferior to the IgG index in differentiating MS patients from controls. However, 7 of 16 patients with MS who had normal immunoglobulin G indexes had an elevated rMOG index. The rMOG index did not correlate with clinical disability, other CSF markers, or radiographic outcome measures. CONCLUSIONS: The rMOG index, a marker of intrathecal MOG antibody production, may provide complementary information to routine CSF testing in the diagnosis of MS. Furthermore, intrathecal anti-MOG antibody production may be more pronounced in progressive than in relapsing forms of MS. PMID- 20837856 TI - Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri). AB - BACKGROUND: Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. OBJECTIVE: To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. DESIGN: Retrospective case series with prospective clinical follow-up. SETTING: Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. PATIENTS: Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. MAIN OUTCOME METHODS: Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. RESULTS: Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. CONCLUSIONS: Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization. PMID- 20837859 TI - Neuromyelitis optica treatment: analysis of 36 patients. AB - OBJECTIVE: To analyze treatment response in Brazilian patients with neuromyelitis optica. DESIGN: Retrospective review. SETTING: Neuroimmunology Clinic of the Federal University of Sao Paulo, Sao Paulo, Brazil. Patients Thirty-six patients with relapsing-remitting optic-spinal disease; long, extending spinal cord lesions; and brain magnetic resonance images not meeting Barkhof criteria for multiple sclerosis, thus fulfilling the 1999 and 2006 criteria for neuromyelitis optica. Patients were followed up from 1994 to 2007. MAIN OUTCOME MEASURES: Relapses and accumulation of disability. RESULTS: Mean follow-up time was 47.2 months and mean age at onset was 32.3 years. Sixty-four treatments were implemented in 36 patients, which included interferon beta, methotrexate, cyclophosphamide, prednisone, and azathioprine solely or plus prednisone. Patients who were treated with azathioprine or azathioprine with prednisone had a reduction in the occurrence of relapses and Expanded Disability Severity Scale score stabilization, as opposed to patients who received other treatments. Of the 4 patients who died, only 1 had received azathioprine treatment. CONCLUSION: Azathioprine as monotherapy or with prednisone seems to have reduced the relapse frequency and halted disability progression in the majority of patients treated, with minor and manageable adverse effects. PMID- 20837857 TI - Frequency of known mutations in early-onset Parkinson disease: implication for genetic counseling: the consortium on risk for early onset Parkinson disease study. AB - OBJECTIVE: To assess the frequency and clinical characteristics of carriers of previously identified mutations in 6 genes associated with early-onset Parkinson disease (PD) and provide empirical data that can be used to inform genetic counseling. DESIGN: Cross-sectional observational study. SETTING: Thirteen movement disorders centers. PATIENTS: Nine hundred fifty-three individuals with early-onset PD defined as age at onset (AAO) younger than 51 years. Participants included 77 and 139 individuals of Hispanic and Jewish ancestry, respectively. Intervention Mutations in SNCA, PRKN, PINK1, DJ1, LRRK2, and GBA were assessed. A validated family history interview and the Unified Parkinson Disease Rating Scale were administered. Demographic and phenotypic characteristics were compared among groups defined by mutation status. Main Outcome Measure Mutation carrier frequency stratified by AAO and ethnic background. RESULTS: One hundred fifty eight (16.6%) participants had mutations, including 64 (6.7%) PRKN, 35 (3.6%) LRRK2 G2019S, 64 (6.7%) GBA, and 1 (0.2%) DJ1. Mutation carriers were more frequent in those with an AAO of 30 years or younger compared with those with AAO between 31 and 50 years (40.6% vs 14.6%, P < .001), in individuals who reported Jewish ancestry (32.4% vs 13.7%, P < .001), and in those reporting a first-degree family history of PD (23.9% vs 15.1%, P = .01). Hispanic individuals were more likely to be PRKN carriers than non-Hispanic individuals (15.6% vs 5.9%, P = .003). The GBA L444P mutation was associated with a higher mean Unified Parkinson Disease Rating Scale III score after adjustment for covariates. CONCLUSION: Individuals of Jewish or Hispanic ancestry with early-onset PD, those with AAO of 30 years or younger, and those with a history of PD in a first-degree relative may benefit from genetic counseling. PMID- 20837858 TI - Association of admission blood glucose and outcome in patients treated with intravenous thrombolysis: results from the Safe Implementation of Treatments in Stroke International Stroke Thrombolysis Register (SITS-ISTR). AB - OBJECTIVE: To determine the association between admission blood glucose and outcome in ischemic stroke patients treated with thrombolysis. DESIGN: A prospective, open, multinational, observational study. SETTING: An ongoing Internet-based, academic-driven, interactive thrombolysis register. PATIENTS: Between 2002 and 2007, 16 049 patients were recorded in the SITS-ISTR. MAIN OUTCOME MEASURE: Blood glucose was recorded at admission. Blood glucose was divided into the following categories: less than 80, 80-120 (reference range), 121-140, 141-160, 161-180, 181-200, and greater than 200 mg/dL. Outcomes were mortality and independence (modified Rankin Scale score of 0-2) at 3 months and symptomatic intracerebral hemorrhage (SICH) (National Institutes of Health Stroke Scale deterioration >=4 points within 24 hours and type 2 parenchymal hemorrhage). RESULTS: In multivariable analysis, blood glucose as a continuous variable was independently associated with a higher mortality (P < .001), lower independence (P < .001), and an increased risk of SICH (P = .005). Blood glucose greater than 120 mg/dL as a categorical variable was associated with a significantly higher odds for mortality (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.07-1.44; P = .004) and a lower odds for independence (OR, 0.58; 95% CI, 0.48-0.70; P < .001), and blood glucose from 181 to 200 mg/dL was associated with an increased risk of SICH (OR, 2.86; 95% CI, 1.69-4.83; P < .001) compared with the reference level. The trends of associations between blood glucose and outcomes were similar in patients with diabetes (17%) or without such history, except for mortality (P = .23) and SICH (P = .06) in which the association was not statistically significant in patients with diabetes. CONCLUSIONS: Admission hyperglycemia was an independent predictor for poor outcome after stroke/thrombolysis, though SICH rates did not increase significantly until reaching 180 mg/dL. These results suggest that tight control of blood glucose may be indicated in the hyperacute phase following thrombolysis. Randomized trial data are needed. PMID- 20837860 TI - Apparent widening gap in access to neuro-oncologic care in the United States: need for action. PMID- 20837861 TI - POLG1 variations presenting as multiple sclerosis. AB - OBJECTIVE: To describe 2 unrelated patients with novel variations in the POLG1 gene and features undistinguishable from multiple sclerosis, ie, optic neuritis, brain white matter hyperintense areas, and unmatched cerebrospinal fluid oligoclonal bands. DESIGN: Case report. SETTING: University hospital. Patients Both patients subsequently developed bilateral ophthalmoplegia, ptosis, myopathy, cardiomyopathy, ataxia, dysphagia, and hearing and cognitive impairment. MAIN OUTCOME MEASURES: Detailed clinical and laboratory examinations including brain magnetic resonance imaging, morphological analysis of a muscle biopsy, characterization of mitochondrial DNA integrity, sequencing of the POLG1 gene, and screening of control subjects for POLG1 sequence variants. RESULTS: Ragged red fibers and multiple deletions of mitochondrial DNA were detected in the skeletal muscle. Four compound heterozygous variations, including 3 previously unreported, were identified in POLG1. CONCLUSION: Clinicians should be aware of the existence of POLG1-related multiple sclerosis-like illness, as it has important implications for management, treatment, and genetic counseling. PMID- 20837862 TI - Isolated distal myopathy of the upper limbs associated with mitochondrial DNA depletion and polymerase gamma mutations. AB - OBJECTIVE: To describe an unusual clinical phenotype in an adult harboring 2 compound heterozygous polymerase gamma (POLG) mutations. DESIGN: Case report. SETTING: University-based outpatient neurology clinic and pathology and genetics laboratory. PATIENT: A 27-year-old man presenting with isolated distal myopathy of the upper extremities in the absence of sensory disturbances. RESULTS: Histochemical analysis of a muscle biopsy specimen showed numerous cytochrome c oxidase-deficient fibers. Molecular analysis revealed marked depletion of muscle mitochondrial DNA in the absence of multiple mitochondrial DNA deletions. Sequence analysis of the POLG gene revealed heterozygous sequence variants in compound c.1156C>T (p.R386C) and c.2794C>T (p.H932Y) segregating with clinical disease in the family. The p.R386C change appears to be a novel mutation. CONCLUSION: Our case broadens the phenotypic spectrum of disorders associated with POLG mutations and highlights the complex relationship between genotype and phenotype in POLG-related disease. PMID- 20837863 TI - Evolution and regression of intracranial infectious aneurysm diagnosed by brain computed tomographic angiography. PMID- 20837864 TI - An unusual case of chronic dural thrombosis. PMID- 20837865 TI - Carotid followed by coronary artery dissection. PMID- 20837866 TI - Anxiety as initial diagnosis in opsoclonus myoclonus syndrome. PMID- 20837867 TI - Reversible alopecia associated with glatiramer acetate. PMID- 20837868 TI - Dopamine agonist withdrawal syndrome: the apomorphine solution. PMID- 20837869 TI - Will symptomatic intracerebral hemorrhages decrease among eligible dabigatran treated patients who receive intravenous tissue plasminogen activator for acute ischemic stroke? PMID- 20837870 TI - DAG lipase involvement in depolarization-induced suppression of inhibition: does endocannabinoid biosynthesis always meet the demand? AB - Hippocampal depolarization-induced suppression of inhibition (DSI) is a robust form of short-term synaptic plasticity. DSI is mediated by endocannabinoid signaling. Since this discovery, pinning down the endogenous cannabinoid receptor ligand that mediates DSI has been problematic. Blocking degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) lengthens DSI, which seems to indicate that 2-AG mediates DSI. In contrast, pharmacological inhibition of the 2 AG-synthesizing enzyme diacylglycerol lipase (DAGL) has yielded conflicting results: DAGL inhibitors often fail to block hippocampal DSI. Recently, 2 studies seem to have cornered this problem using DAGL knockout mice. Hippocampal DSI is absent in DAGL-alpha knockout mice, pointing to a key role for 2-AG in DSI. However, these studies do not reconcile the discrepancy with pharmacological experiments. Here, we argue that the seeming contradiction between results from pharmacological and genetic approaches may be explained in several ways. We suggest that the contradiction may be resolved by taking a different perspective on endocannabinoid signaling: in some forms of endocannabinoid-mediated signaling endocannabinoids might not be necessarily produced "on demand" but presynthesized and stored until needed. PMID- 20837871 TI - Evidence for association between sarcoidosis and pulmonary embolism from 35-year record linkage study. PMID- 20837872 TI - Peripheral airway/alveolar nitric oxide concentration in asthma. PMID- 20837873 TI - Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma. AB - BACKGROUND: Exposure to traffic-derived air pollutants, particularly diesel emissions, has been associated with adverse health effects, predominantly in individuals with pre-existing respiratory disease. Here the hypothesis that this heightened sensitivity reflects an augmentation of the transient inflammatory response previously reported in healthy adults exposed to diesel exhaust is examined. METHODS: 32 subjects with asthma (mild to moderate severity) and 23 healthy controls were exposed in a double-blinded crossover control fashion to both filtered air and diesel exhaust (100 MUg/m(3) PM(10)) for 2 h. Airway inflammation was assessed by bronchoscopy 18 h postexposure. In addition, lung function, fraction of exhaled nitric oxide and bronchial reactivity to metacholine were examined in the subjects with asthma. RESULTS: In healthy control subjects a significant increase in submucosal neutrophils (p=0.004) was observed following the diesel challenge. Significant increases in neutrophil numbers (p=0.01), and in the concentrations of interleukin 6 (p=0.03) and myeloperoxidase (p=0.04), were also seen in bronchial wash after diesel, relative to the control air challenge. No evidence of enhanced airway inflammation was observed in the subjects with asthma following the diesel exposure. CONCLUSIONS: Exposure to diesel exhaust at concentrations consistent with roadside levels elicited an acute and active neutrophilic inflammation in the airways of healthy subjects. This response was absent in subjects with asthma, as was evidence supporting a worsening of allergic airway inflammation. PMID- 20837875 TI - ABPA in adulthood: a CFTR-related disorder. PMID- 20837876 TI - Bronchoscopy with bronchoalveolar lavage: determinants of yield and impact on management in immunosuppressed patients. PMID- 20837877 TI - Low-dose oral interferon alpha possibly retards the progression of idiopathic pulmonary fibrosis and alleviates associated cough in some patients. PMID- 20837878 TI - Increased intervisit blood pressure variability and beta-blockade: measurement imprecision related to bradycardia? PMID- 20837879 TI - Renal sinus adiposity and hypertension. PMID- 20837880 TI - What rare autonomic disorders can teach us about human cardiovascular pharmacology. PMID- 20837881 TI - Renal sinus fat and poor blood pressure control in middle-aged and elderly individuals at risk for cardiovascular events. AB - Fat in the renal sinus (RS), a region of the kidney in which low pressure venous and lymphatic vessels are present, may indirectly influence blood pressure. The purpose of this study was to assess the association between RS fat and control of blood pressure on receipt of antihypertensive medications. A total of 205 participants aged 55 to 85 years at risk for cardiovascular events underwent MRI assessments of abdominal and RS fat, measurement of blood pressure, and determination of the number of prescribed antihypertensive medications. Multivariable linear regression was used to determine associations among RS fat, blood pressure, and the number of prescribed antihypertensive medications. Abdominal fat averaged 416+/-160 cm(3) (median and interquartile range of 396 cm(3) and 308 to 518 cm(3)); intraperitoneal fat averaged 141+/-73 cm(3) (median and interquartile range of 129 cm(3) and 86 to 194 cm(3)); and RS fat averaged 4.6+/-3.2 cm(3) (median and interquartile range of 4.2 cm(3) and 2.2 to 6.6 cm(3)). After accounting for age, sex, height, body mass index, and intraperitoneal fat, RS fat correlated with the number of prescribed antihypertensive medications (P=0.010), stage II hypertension (P=0.02), and renal size (P<=0.001). In conclusion, after accounting for other body fat depots and risk factors for hypertension, RS fat volume is associated with the number of prescribed antihypertensive medications and stage II hypertension. These results indicate that further studies are warranted to determine whether fat accumulation in the RS promotes hypertension. PMID- 20837882 TI - Robust early pregnancy prediction of later preeclampsia using metabolomic biomarkers. AB - Preeclampsia is a pregnancy-specific syndrome that causes substantial maternal and fetal morbidity and mortality. The etiology is incompletely understood, and there is no clinically useful screening test. Current metabolomic technologies have allowed the establishment of metabolic signatures of preeclampsia in early pregnancy. Here, a 2-phase discovery/validation metabolic profiling study was performed. In the discovery phase, a nested case-control study was designed, using samples obtained at 15+/-1 weeks' gestation from 60 women who subsequently developed preeclampsia and 60 controls taking part in the prospective Screening for Pregnancy Endpoints cohort study. Controls were proportionally population matched for age, ethnicity, and body mass index at booking. Plasma samples were analyzed using ultra performance liquid chromatography-mass spectrometry. A multivariate predictive model combining 14 metabolites gave an odds ratio for developing preeclampsia of 36 (95% CI: 12 to 108), with an area under the receiver operator characteristic curve of 0.94. These findings were then validated using an independent case-control study on plasma obtained at 15+/-1 weeks from 39 women who subsequently developed preeclampsia and 40 similarly matched controls from a participating center in a different country. The same 14 metabolites produced an odds ratio of 23 (95% CI: 7 to 73) with an area under receiver operator characteristic curve of 0.92. The finding of a consistent discriminatory metabolite signature in early pregnancy plasma preceding the onset of preeclampsia offers insight into disease pathogenesis and offers the tantalizing promise of a robust presymptomatic screening test. PMID- 20837883 TI - Aldosterone synthase inhibition with LCI699: a proof-of-concept study in patients with primary aldosteronism. AB - We report the first administration of an orally active aldosterone synthase inhibitor, LCI699, to 14 patients with primary aldosteronism. After a 2-week placebo run-in, patients received oral LCI699 (0.5 mg BID) for 2 weeks, LCI699 (1.0 mg BID) for 2 weeks, and placebo for 1 week. We assessed changes in hormone concentrations, plasma potassium levels, and 24-hour ambulatory systolic blood pressure and safety. The supine plasma aldosterone concentration decreased from 540 pmol/L (95% CI: 394 to 739 pmol/L) to 171 pmol/L (95% CI: 128 to 230 pmol/L) after 0.5 mg of LCI699 (-68%; P<0.0001) and to 133 pmol/L (95% CI: 100 to 177 pmol/L) after 1.0 mg of LCI699 (-75%; P<0.0001). Plasma 11-deoxycorticosterone concentrations increased by 710% after 0.5 mg of LCI699 (P<0.0001) and by 1427% after 1.0 mg of LCI699 (P<0.0001). The plasma potassium concentration increased from 3.27+/-0.31 to 4.03+/-0.33 mmol/L (P<0.0001) after only 1 week on 0.5 mg of LCI699. Twenty-four-hour ambulatory systolic blood pressure decreased by -4.1 mm Hg (95% CI: -8.1 to -0.1 mm Hg) after 4 weeks of treatment (P=0.046). Basal plasma cortisol concentrations remained unchanged, whereas plasma adrenocorticotropic hormone concentrations increased by 35% after 0.5 mg of LCI699 (P=0.08) and by 113% after 1.0 mg of LCI699 (P<0.0001), and the plasma cortisol response to an adrenocorticotropic hormone test was blunted. All of the variables except plasma 11-deoxycorticosterone concentration returned to initial levels after the placebo. LCI699 was well tolerated. In conclusion, the administration of LCI699, up to 1.0 mg BID, effectively and safely inhibits aldosterone synthase in patients with primary aldosteronism. This 4-week treatment corrected the hypokalemia and mildly decreased blood pressure. The effects on the glucocorticoid axis were consistent with a latent inhibition of cortisol synthesis. PMID- 20837884 TI - Impaired endothelial function and microvascular asymmetrical dimethylarginine in angiotensin II-infused rats: effects of tempol. AB - Angiotensin (Ang) II causes endothelial dysfunction, which is associated with cardiovascular risk. We investigated the hypothesis that Ang II increases microvascular reactive oxygen species and asymmetrical dimethylarginine and switches endothelial function from vasodilator to vasoconstrictor pathways. Acetylcholine-induced endothelium-dependent responses of mesenteric resistance arterioles were assessed in a myograph and vascular NO and reactive oxygen species by fluorescent probes in groups (n=6) of male rats infused for 14 days with Ang II (200 ng/kg per minute) or given a sham infusion. Additional groups of Ang or sham-infused rats were given oral Tempol (2 mmol . L(-1)). Ang II infusion increased mean blood pressure (119+/-5 versus 89+/-7 mm Hg; P<0.005) and plasma malondialdehyde (0.57+/-0.02 versus 0.37+/-0.05 MUmol . L(-1); P<0.035) and decreased maximal endothelium-dependent relaxation (18+/-5% versus 54+/-6%; P<0.005) and hyperpolarizing (19+/-3% versus 29+/-3%; P<0.05) responses and NO activity (0.9+/-0.1 versus 1.6+/-0.2 U; P<0.01) yet enhanced endothelium dependent contraction responses (23+/-5% versus 5+/-5%; P<0.05) and reactive oxygen species production (0.82+/-0.05 versus 0.15+/-0.03 U; P<0.01). Ang II decreased the expression of dimethylarginine dimethylaminohydrolase 2 and increased asymmetrical dimethylarginine in vessels (450+/-50 versus 260+/-35 pmol/mg of protein; P<0.01) but not plasma. Tempol prevented any significant changes with Ang II. In conclusion, Ang redirected endothelial responses from relaxation to contraction, reduced vascular NO, and increased asymmetrical dimethylarginine. These effects were dependent on reactive oxygen species and could, therefore, be targeted with effective antioxidant therapy. PMID- 20837885 TI - Childhood hypertension in autosomal-dominant hypertension with brachydactyly. AB - Affected individuals with autosomal-dominant hypertension with brachydactyly syndrome develop severe progressive hypertension and, if left untreated, develop stroke by age <50 years. In 1996 we described hypertension and brachydactyly and presented data on adults. We recently revisited this family and performed further studies, focusing particularly on the children in this family. We performed a genome-wide single-nucleotide polymorphism genotyping linkage analysis and confirmed our earlier linkage results. We accrued interesting ancillary data that we attribute to the rearrangements that we described earlier. We performed additional analysis focused on providing clinical criteria for the diagnosis in children and particularly to monitor the onset and to display the age-dependent development of hypertension and brachydactyly. We investigated 30 children; 12 were affected, whereas 18 were not. Brachydactyly with short stature presented as a maturing phenotype, becoming obvious during the prepubertal growth spurt. Stage 2 hypertension was already present in toddlers and increased with age. Thus, blood pressure measurement, rather than brachydactyly, was the most reliable phenotype for the very early diagnosis in children. Importantly, hypertension with brachydactyly occurs worldwide. Once the diagnosis is made, we recommend treatment of all individuals with stage 2 hypertension according to the current European and US guidelines on hypertension in children and adolescents. PMID- 20837886 TI - 20-hydroxyeicosatetraenoic acid and angiotensin: a positive feedback system to cause hypertension. PMID- 20837887 TI - Comparative efficacy of yohimbine against pyridostigmine for the treatment of orthostatic hypotension in autonomic failure. AB - Orthostatic hypotension affects patients with autonomic failure producing considerable disability because of presyncopal symptoms. Severely affected patients may have residual sympathetic tone that can be engaged to increase blood pressure (BP) with the alpha-2 adrenergic antagonist yohimbine. This medication activates sympathetic outflow centrally and unrestrains norepinephrine release from noradrenergic neurons. Alternatively, the acetylcholinesterase inhibitor, pyridostigmine, can increase sympathetic tone by improving ganglionic cholinergic neurotransmission. Our purpose was to compare these complementary approaches and to explore whether the combination would lead to synergistic increases in BP. We compared the effects of 60 mg of pyridostigmine and 5.4 mg of yohimbine in a single-blind, randomized, placebo-controlled, crossover fashion. In a subset of patients we tested the combination of pyridostigmine and yohimbine. Our primary outcome was the change in standing diastolic BP 60 minutes after drug administration from baseline. We studied a total of 31 patients with severe autonomic failure. Yohimbine significantly improved standing diastolic BP as compared with placebo (11+/-3 mm Hg [95% CI: 6 to 16 mm Hg]; P<0.001). On the contrary, pyridostigmine did not increase the standing diastolic BP (0.6+/-3 mm Hg [95% CI: -5 to 5 mm Hg]; P=0.823). Only yohimbine showed a significant improvement in presyncopal symptoms. Sixteen patients received the combination of pyridostigmine and yohimbine, but no evidence of synergistic pressor effect was found. Engaging residual sympathetic tone with yohimbine is a more effective approach to improve orthostatic hypotension as compared with pyridostigmine in patients with severe orthostatic hypotension. PMID- 20837888 TI - CYP4A2-induced hypertension is 20-hydroxyeicosatetraenoic acid- and angiotensin II-dependent. AB - We have shown previously that increased vascular endothelial expression of CYP4A2 leads to 20-hydroxyeicosatetraenoic (20-HETE)-dependent hypertension. The renin angiotensin system is a key regulator of blood pressure. In this study, we examined possible interactions between 20-HETE and the renin-angiotensin system. In normotensive (110+/-3 mm Hg) Sprague-Dawley rats transduced with a lentivirus expressing the CYP4A2 cDNA under the control of an endothelial-specific promoter (VECAD-4A2), systolic blood pressure increased rapidly, reaching 139+/-1, 145+/ 3, and 150+/-2 mm Hg at 3, 5, and 10 days after transduction; blood pressure remained elevated, thereafter, with maximum levels of 163+/-3 mm Hg. Treatment with lisinopril, losartan, or the 20-HETE antagonist 20-hydroxyeicosa-6(Z), 15(Z) dienoic acid decreased blood pressure to control values, but blood pressure returned to its high levels after cessation of treatment. Endothelial-specific overexpression of CYP4A2 resulted in increased expression of vascular angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor and increased levels of plasma and tissue angiotensin II; all were attenuated by treatment with HET0016, an inhibitor of 20-HETE synthesis, or with 20-hydroxyeicosa-6(Z), 15(Z) dienoic acid. In cultured endothelial cells, 20-HETE specifically and potently induced ACE expression without altering the expression of ACE2, angiotensinogen, or angiotensin II receptors. This is the first study to demonstrate that 20-HETE, a key constrictor eicosanoid in the microcirculation, induces ACE and angiotensin II type 1 receptor expression and increases angiotensin II levels, suggesting that the mechanisms by which 20-HETE promotes hypertension include activation of the renin-angiotensin system that is likely initiated at the level of ACE induction. PMID- 20837889 TI - Implantable loop recorder in survivors of acute myocardial infarction: a glimpse of reality? PMID- 20837890 TI - MicroRNA-494 targeting both proapoptotic and antiapoptotic proteins protects against ischemia/reperfusion-induced cardiac injury. AB - BACKGROUND: MicroRNAs (miRs) participate in many cardiac pathophysiological processes, including ischemia/reperfusion (I/R)-induced cardiac injury. Recently, we and others observed that miR-494 was downregulated in murine I/R-injured and human infarcted hearts. However, the functional consequence of miR-494 in response to I/R remains unknown. METHODS AND RESULTS: We generated a mouse model with cardiac-specific overexpression of miR-494. Transgenic hearts and wild-type hearts from multiple lines were subjected to global no-flow I/R with the Langendorff system. Transgenic hearts exhibited improved recovery of contractile performance over the reperfusion period. This improvement was accompanied by remarkable decreases in both lactate dehydrogenase release and the extent of apoptosis in transgenic hearts compared with wild-type hearts. In addition, myocardial infarction size was significantly reduced in transgenic hearts on I/R in vivo compared with wild-type hearts. Similarly, short-term overexpression of miR-494 in cultured adult cardiomyocytes demonstrated an inhibition of caspase-3 activity and reduced cell death on simulated I/R. In vivo treatment with antisense oligonucleotide miR-494 increased I/R-triggered cardiac injury relative to the administration of mutant antisense oligonucleotide miR-494 and saline controls. We further identified that 3 proapoptotic proteins (PTEN, ROCK1, and CaMKIIdelta) and 2 antiapoptotic proteins (FGFR2 and LIF) were authentic targets for miR-494. Importantly, the Akt-mitochondrial signaling pathway was activated in miR-494-overexpressing myocytes. CONCLUSIONS: Our findings suggest that although miR-494 targets both proapoptotic and antiapoptotic proteins, the ultimate consequence is activation of the Akt pathway, leading to cardioprotective effects against I/R-induced injury. Thus, miR-494 may constitute a new therapeutic agent for the treatment of ischemic heart disease. PMID- 20837891 TI - Who are the long-QT syndrome patients who receive an implantable cardioverter defibrillator and what happens to them?: data from the European Long-QT Syndrome Implantable Cardioverter-Defibrillator (LQTS ICD) Registry. AB - BACKGROUND: A rapidly growing number of long-QT syndrome (LQTS) patients are being treated with an implantable cardioverter-defibrillator (ICD). ICDs may pose problems, especially in the young. We sought to determine the characteristics of the LQTS patients receiving an ICD, the indications, and the aftermath. METHODS AND RESULTS: The study population included 233 patients. Beginning in 2002, data were collected prospectively. Female patients (77%) and LQT3 patients (22% of genotype positive) were overrepresented; mean QTc was 516+/-65 milliseconds; mean age at implantation was 30+/-17 years; and genotype was known in 59% of patients. Unexpectedly, 9% of patients were asymptomatic before implantation. Asymptomatic patients, almost absent among LQT1 and LQT2 patients, represented 45% of LQT3 patients. Patients with cardiac symptoms made up 91% of all study participants, but only 44% had cardiac arrest before ICD implantation. In addition, 41% of patients received an ICD without having first been on LQTS therapy. During follow up, 4.6+/-3.2 years, at least 1 appropriate shock was received by 28% of patients, and adverse events occurred in 25%. Appropriate ICD therapies were predicted by age <20 years at implantation, a QTc >500 milliseconds, prior cardiac arrest, and cardiac events despite therapy; within 7 years, appropriate shocks occurred in no patients with none of these factors and in 70% of those with all factors. CONCLUSIONS: Reflecting previous concepts, ICDs were implanted in some LQTS patients whose high risk now appears questionable. Refined criteria for implantation, reassessment of pros and cons, ICD reprogramming, and consideration for other existing therapeutic options are necessary. PMID- 20837892 TI - Volume-outcome relationships and abdominal aortic aneurysm repair. AB - BACKGROUND: There is a well-established literature relating procedure volume to outcomes, but incorporating such information into clinical decision making is problematic when there is >1 treatment option for a condition. METHODS AND RESULTS: We used data from the Medicare program to investigate the relationship between institutional volume for open and endovascular abdominal aortic aneurysm (AAA) repair and outcomes, examine trends in volume, and explore the implications for physicians making referrals for AAA repair. Trends in institutional volume were measured for the time period 2001-2006, whereas outcomes were assessed with the use of a previously assembled propensity score-matched cohort covering the time period 2001-2004. Between 2001 and 2006, there were a total of 230 736 repairs of either an intact or ruptured AAA for traditional Medicare beneficiaries. During this time, the proportion of endovascular cases increased from ~22 in 2001 to >50 of AAA repairs in 2006, but there was little shift in procedure volume to high-volume institutions. For endovascular repair, adjusted mortality by quintile showed a marked decrease between the first and second quintile, with continued smaller decreases over quintiles 3 to 5. For open repair, adjusted mortality showed a steady decrease across the quintiles of volume. CONCLUSIONS: We found a steady increase in survival with increasing volume of open repair but relatively little improvement after reaching a relatively low threshold for endovascular repair. Because hospital experience with one repair method does not translate into improved outcomes for the alternative method, referring clinicians must consider both treatment options when making referral decisions. PMID- 20837893 TI - Transcatheter aortic valve implantation: durability of clinical and hemodynamic outcomes beyond 3 years in a large patient cohort. AB - BACKGROUND: Although short- and medium-term outcomes after transcatheter aortic valve implantation are encouraging, long-term data on valve function and clinical outcomes are limited. METHODS AND RESULTS: Consecutive high-risk patients who had been declined as surgical candidates because of comorbidities but who underwent successful transcatheter aortic valve implantation with a balloon-expandable valve between January 2005 and December 2006 and survived past 30 days were assessed. Clinical, echocardiographic, and computed tomographic follow-up examinations were performed. Seventy patients who underwent successful procedures and survived longer than 30 days were evaluated at a minimum follow-up of 3 years. At a median follow-up of 3.7 years (interquartile range 3.4 to 4.3 years), survival was 57%. Survival at 1, 2, and 3 years was 81%, 74%, and 61%, respectively. Freedom from reoperation was 98.5% (1 patient with endocarditis). During this early procedural experience, 11 patients died within 30 days, and 8 procedures were unsuccessful. When these patients were included, overall survival was 51%. Transaortic pressure gradients increased from 10.0 mm Hg (interquartile range 8.0 to 12.0 mm Hg) immediately after the procedure to 12.1 mm Hg (interquartile range 8.6 to 16.0 mm Hg) after 3 years (P=0.03). Bioprosthetic valve area decreased from a mean of 1.7+/-0.4 cm(2) after the procedure to 1.4+/ 0.3 cm(2) after 3 years (P<0.01). Aortic incompetence after implantation was trivial or mild in 84% of cases and remained unchanged or improved over time. There were no cases of structural valvular deterioration, stent fracture, deformation, or valve migration. CONCLUSIONS: Transcatheter aortic valve implantation demonstrates good medium- to long-term durability and preserved hemodynamic function, with no evidence of structural failure. The procedure appears to offer an adequate and lasting resolution of aortic stenosis in selected patients. PMID- 20837894 TI - Long-term benefit of primary prevention with an implantable cardioverter defibrillator: an extended 8-year follow-up study of the Multicenter Automatic Defibrillator Implantation Trial II. AB - BACKGROUND: The Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) showed a significant 31 reduction in the risk of death with primary implantable cardioverter-defibrillator (ICD) therapy during a median follow-up of 1.5 years. However, currently there are no data on the long-term efficacy of primary defibrillator therapy. METHODS AND RESULTS: MADIT-II enrolled 1232 patients with ischemic left ventricular dysfunction who were randomized to ICD and non-ICD medical therapy and were followed up through November 2001. For the present long-term study, we acquired posttrial mortality data through March 2009 for all study participants (median follow-up, 7.6 years). Multivariate Cox proportional hazards regression modeling was performed to calculate the hazard ratio for ICD versus non-ICD therapy during long-term follow-up. At 8 years of follow-up, the cumulative probability of all-cause mortality was 49 among patients treated with an ICD compared with 62 among non-ICD patients (P<0.001). Multivariate analysis demonstrated that ICD therapy was associated with a significant long-term survival benefit (hazard ratio for 0- through 8-year mortality=0.66 [95 confidence interval, 0.56 to 0.78]; P<0.001). Treatment with an ICD was shown to be associated with a significant reduction in the risk of death during the early phase of the extended follow-up period (0 through 4 years: hazard ratio=0.61 [95 confidence interval, 0.50 to 0.76]; P<0.001) and with continued life-saving benefit during the late phase of follow-up (5 through 8 years: hazard ratio=0.74 [95 confidence interval, 0.57 to 0.96]; P=0.02). CONCLUSIONS: Our findings demonstrate a sustained 8-year survival benefit with primary ICD therapy in the MADIT-II population. PMID- 20837895 TI - In vivo measurement of mitral leaflet surface area and subvalvular geometry in patients with asymmetrical septal hypertrophy: insights into the mechanism of outflow tract obstruction. AB - BACKGROUND: Analyzing the determinants of systolic anterior motion of the mitral valve and consequent left ventricular outflow tract (LVOT) obstruction in patients with asymmetrical septal hypertrophy requires a comprehensive 3 dimensional analysis of mitral leaflet (ML) area, papillary muscle (PM) geometry, and the distribution of left ventricular hypertrophy. METHODS AND RESULTS: Real time 3-dimensional echocardiography was performed in 47 patients with asymmetrical septal hypertrophy and 32 normal controls. Patients included 20 with resting LVOT obstruction (group I) and 27 without (group II). Customized software (Omni 4D) provided a validated measure of ML surface area, LVOT area, mitral annular area and nonplanarity, LVOT hypertrophy index by topography (percent area with wall thickness >16 mm), and 3-dimensional PM positions relative to annulus. ML area was more than twice as large in group I than normal and 1.4 times normal in group II (P<0.001). Group I patients were also characterized by higher LVOT hypertrophy index and medial and anterior displacements of both PMs, resulting in a shorter inter-PM distance. Independent determinants of LVOT obstruction were indexed total ML area (adjusted odds ratio, 5.651; 95% confidence interval, 1.573 to 20.304; P=0.008) and inter-PM distance (adjusted odds ratio, 0.416; 95% confidence interval, 0.203 to 0.854; P=0.0169). Minimal LVOT area during systole correlated well with peak LVOT pressure gradient (R(2)=0.83, P<0.001); its independent determinants were left ventricular end-systolic volume (P=0.0183), indexed total ML area (P=0.0108), inter-PM distance (P=0.0378), annular height (P=0.0047), and LVOT hypertrophy index (P=0.0098). CONCLUSIONS: Myocardium is not the only tissue affected in patients with asymmetrical septal hypertrophy, and primary changes of the mitral apparatus, including ML area increase and PM displacement, are independent determinants of LVOT obstruction and provide a comprehensive mechanism that determines leaflet slack and anteriorly directed motion. Abnormal PM-mitral valve geometry assessed by real-time 3-dimensional echocardiography can provide reasonable new targets for individualized intervention. PMID- 20837896 TI - Importance of refractory pain and hypertension in acute type B aortic dissection: insights from the International Registry of Acute Aortic Dissection (IRAD). AB - BACKGROUND: In patients with acute type B aortic dissection, presence of recurrent or refractory pain and/or refractory hypertension on medical therapy is sometimes used as an indication for invasive treatment. The International Registry of Acute Aortic Dissection (IRAD) was used to investigate the impact of refractory pain and/or refractory hypertension on the outcomes of acute type B aortic dissection. METHODS AND RESULTS: Three hundred sixty-five patients affected by uncomplicated acute type B aortic dissection, enrolled in IRAD from 1996 to 2004, were categorized according to risk profile into 2 groups. Patients with recurrent and/or refractory pain or refractory hypertension (group I; n=69) and patients without clinical complications at presentation (group II; n=296) were compared. "High-risk" patients with classic complications were excluded from this analysis. The overall in-hospital mortality was 6.5% and was increased in group I compared with group II (17.4% versus 4.0%; P=0.0003). The in-hospital mortality after medical management was significantly increased in group I compared with group II (35.6% versus 1.5%; P=0.0003). Mortality rates after surgical (20% versus 28%; P=0.74) or endovascular management (3.7% versus 9.1%; P=0.50) did not differ significantly between group I and group II, respectively. A multivariable logistic regression model confirmed that recurrent and/or refractory pain or refractory hypertension was a predictor of in-hospital mortality (odds ratio, 3.31; 95% confidence interval, 1.04 to 10.45; P=0.041). CONCLUSIONS: Recurrent pain and refractory hypertension appeared as clinical signs associated with increased in-hospital mortality, particularly when managed medically. These observations suggest that aortic intervention, such as via an endovascular approach, may be indicated in this intermediate-risk group. PMID- 20837897 TI - Long-term recording of cardiac arrhythmias with an implantable cardiac monitor in patients with reduced ejection fraction after acute myocardial infarction: the Cardiac Arrhythmias and Risk Stratification After Acute Myocardial Infarction (CARISMA) study. AB - BACKGROUND: Knowledge about the incidence of cardiac arrhythmias after acute myocardial infarction has been limited by the lack of traditional ECG recording systems to document and confirm asymptomatic and symptomatic arrhythmias. The Cardiac Arrhythmias and Risk Stratification After Myocardial Infarction (CARISMA) trial was designed to study the incidence and prognostic significance of arrhythmias documented by an implantable cardiac monitor among patients with acute myocardial infarction and reduced left ventricular ejection fraction. METHODS AND RESULTS: A total of 1393 of 5869 patients (24%) screened in the acute phase (3 to 21 days) of an acute myocardial infarction had left ventricular ejection fraction <=40%. After exclusions, 297 patients (21%) (mean+/-SD age, 64.0+/-11.0 years; left ventricular ejection fraction, 31+/-7%) received an implantable cardiac monitor within 11+/-5 days of the acute myocardial infarction and were followed up every 3 months for an average of 1.9+/-0.5 years. Predefined bradyarrhythmias and tachyarrhythmias were recorded in 137 patients (46%); 86% of these were asymptomatic. The implantable cardiac monitor documented a 28% incidence of new-onset atrial fibrillation with fast ventricular response (>=125 bpm), a 13% incidence of nonsustained ventricular tachycardia (>=16 beats), a 10% incidence of high-degree atrioventricular block (<=30 bpm lasting >=8 seconds), a 7% incidence of sinus bradycardia (<=30 bpm lasting >=8 seconds), a 5% incidence of sinus arrest (>=5 seconds), a 3% incidence of sustained ventricular tachycardia, and a 3% incidence of ventricular fibrillation. Cox regression analysis with time-dependent covariates revealed that high-degree atrioventricular block was the most powerful predictor of cardiac death (hazard ratio, 6.75; 95% confidence interval, 2.55 to 17.84; P<0.001). CONCLUSIONS: This is the first study to report on long-term cardiac arrhythmias recorded by an implantable loop recorder in patients with left ventricular ejection fraction <=40% after myocardial infarction. Clinically significant bradyarrhythmias and tachyarrhythmias were documented in a substantial proportion of patients with depressed left ventricular ejection fraction after acute myocardial infarction. Intermittent high-degree atrioventricular block was associated with a very high risk of cardiac death. Clinical Trial Registration- URL: http://www.ClinicalTrials.gov, Unique identifier: NCT00145119. PMID- 20837898 TI - Impact of smokeless tobacco products on cardiovascular disease: implications for policy, prevention, and treatment: a policy statement from the American Heart Association. PMID- 20837899 TI - Long-term clinical and hemodynamic performance of the Hancock II versus the Perimount aortic bioprostheses. AB - BACKGROUND: The Medtronic Hancock II and the Carpentier-Edwards Perimount are among the world's most commonly used aortic bioprostheses. However, a direct comparison of their clinical performance is lacking. To minimize biases inherent to between-center comparisons, we examined these prostheses within a large, contemporary, single-center cohort. METHODS AND RESULTS: Between 1990 and 2007, 1659 patients (mean age, 73.1+/-9.3 years) underwent aortic valve replacement with either the Hancock II (N=1021) or the Perimount (N=638). Patients were prospectively followed-up with serial clinic visits and echocardiograms for up to 16 years (mean, 5.0+/-3.3 years). There was no significant difference in aortic root size preoperatively (P=0.7). Aortic root enlargement was more commonly performed with the Perimount (P<0.001), and the manufacturer valve size of the implanted prosthesis was larger with the Hancock II (P<0.001). Postoperatively, peak and mean transprosthesis gradients were higher for the Hancock II (32.7+/ 0.7 and 16.0+/-0.3 mm Hg, respectively) than for the Perimount (24.9+/-0.7 and 13.4+/-0.4 mm Hg, respectively; P<0.001). However, no difference in left ventricular mass regression was observed at late follow-up (P=0.9). Unadjusted 10 year survival was 59.4%+/-2.4% for the Hancock II and 70.2%+/-3.8% for the Perimount (P=0.07). Multivariable predictors of survival did not include prosthesis type (P=0.2). CONCLUSIONS: For the same manufacturer valve size, the Perimount is larger, which may warrant enlarging the aortic root more often, and it is associated with better hemodynamics than the Hancock II. These differences do not impact survival or left ventricular mass regression, and the long-term clinical performances of the Hancock II and Perimount bioprostheses are equivalent. PMID- 20837900 TI - Development of a completely autologous valved conduit with the sinus of Valsalva using in-body tissue architecture technology: a pilot study in pulmonary valve replacement in a beagle model. AB - BACKGROUND: We developed autologous prosthetic implants by simple and safe in body tissue architecture technology. We present the first report on the development of autologous valved conduit with the sinus of Valsalva (BIOVALVE) by using this unique technology and its subsequent implantation in the pulmonary valves in a beagle model. METHODS AND RESULTS: A mold of BIOVALVE organization was assembled using 2 types of specially designed silicone rods with a small aperture in a trileaflet shape between them. The concave rods had 3 projections that resembled the protrusions of the sinus of Valsalva. The molds were placed in the dorsal subcutaneous spaces of beagle dogs for 4 weeks. The molds were covered with autologous connective tissues. BIOVALVEs with 3 leaflets in the inner side of the conduit with the sinus of Valsalva were obtained after removing the molds. These valves had adequate burst strength, similar to that of native valves. Tight valvular coaptation and sufficient open orifice area were observed in vitro. These BIOVALVEs were implanted to the main pulmonary arteries as allogenic conduit valves (n=3). Postoperative echocardiography demonstrated smooth movement of the leaflets with trivial regurgitation. Histological examination of specimens obtained at 84 days showed that the surface of the leaflet was covered by endothelial cells and neointima, including an elastin fiber network, and was formed at the anastomosis sides on the luminal surface of the conduit. CONCLUSIONS: We developed the first completely autologous BIOVALVE and successfully implanted these BIOVALVEs in a beagle model in a pilot study. PMID- 20837901 TI - Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis. AB - BACKGROUND: Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1alpha (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction. METHODS AND RESULTS: Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure volume conductance, and Doppler flow. CONCLUSIONS: Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction. PMID- 20837902 TI - Composite cell sheets: a further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells. AB - BACKGROUND: The safety and efficacy of myocardial regeneration using embryonic stem cells are limited by the risk of teratoma and the high rate of cell death. METHODS AND RESULTS: To address these issues, we developed a composite construct made of a sheet of adipose tissue-derived stroma cells and embryonic stem cell derived cardiac progenitors. Ten Rhesus monkeys underwent a transient coronary artery occlusion followed, 2 weeks later, by the open-chest delivery of the composite cell sheet over the infarcted area or a sham operation. The sheet was made of adipose tissue-derived stroma cells grown from a biopsy of autologous adipose tissue and cultured onto temperature-responsive dishes. Allogeneic Rhesus embryonic stem cells were committed to a cardiac lineage and immunomagnetically sorted to yield SSEA-1(+) cardiac progenitors, which were then deposited onto the cell sheet. Cyclosporine was given for 2 months until the animals were euthanized. Preimplantation studies showed that the SSEA-1(+) progenitors expressed cardiac markers and had lost pluripotency. After 2 months, there was no teratoma in any of the 5 cell-treated monkeys. Analysis of >1500 histological sections showed that the SSEA-1(+) cardiac progenitors had differentiated into cardiomyocytes, as evidenced by immunofluorescence and real-time polymerase chain reaction. There were also a robust engraftment of autologous adipose tissue derived stroma cells and increased angiogenesis compared with the sham animals. CONCLUSIONS: These data collected in a clinically relevant nonhuman primate model show that developmentally restricted SSEA-1(+) cardiac progenitors appear to be safe and highlight the benefit of the epicardial delivery of a construct harboring cells with a cardiomyogenic differentiation potential and cells providing them the necessary trophic support. PMID- 20837903 TI - MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. AB - BACKGROUND: MicroRNAs are involved in various critical functions, including the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis. We hypothesize that microRNA-210 can rescue cardiac function after myocardial infarction by upregulation of angiogenesis and inhibition of cellular apoptosis in the heart. METHODS AND RESULTS: Using microRNA microarrays, we first showed that microRNA-210 was highly expressed in live mouse HL-1 cardiomyocytes compared with apoptotic cells after 48 hours of hypoxia exposure. We confirmed by polymerase chain reaction that microRNA-210 was robustly induced in these cells. Gain-of-function and loss-of-function approaches were used to investigate microRNA-210 therapeutic potential in vitro. After transduction, microRNA-210 can upregulate several angiogenic factors, inhibit caspase activity, and prevent cell apoptosis compared with control. Afterward, adult FVB mice underwent intramyocardial injections with minicircle vector carrying microRNA-210 precursor, minicircle carrying microRNA-scramble, or sham surgery. At 8 weeks, echocardiography showed a significant improvement of left ventricular fractional shortening in the minicircle vector carrying microRNA-210 precursor group compared with the minicircle carrying microRNA-scramble control. Histological analysis confirmed decreased cellular apoptosis and increased neovascularization. Finally, 2 potential targets of microRNA-210, Efna3 and Ptp1b, involved in angiogenesis and apoptosis were confirmed through additional experimental validation. CONCLUSIONS: MicroRNA-210 can improve angiogenesis, inhibit apoptosis, and improve cardiac function in a murine model of myocardial infarction. It represents a potential novel therapeutic approach for treatment of ischemic heart disease. PMID- 20837904 TI - Intramyocardial peptide nanofiber injection improves postinfarction ventricular remodeling and efficacy of bone marrow cell therapy in pigs. AB - BACKGROUND: Growing evidence suggests that intramyocardial biomaterial injection improves cardiac functions after myocardial infarction (MI) in rodents. Cell therapy is another promising approach to treat MI, although poor retention of transplanted cells is a major challenge. In this study, we hypothesized that intramyocardial injection of self-assembling peptide nanofibers (NFs) thickens the infarcted myocardium and increases transplanted autologous bone marrow mononuclear cell (MNC) retention to attenuate cardiac remodeling and dysfunction in a pig MI model. METHODS AND RESULTS: A total of 40 mature minipigs were divided into 5 groups: sham, MI+normal saline, MI+NFs, MI+MNCs, and MI+MNCs/NFs. MI was induced by coronary occlusion followed by intramyocardial injection of 2 mL normal saline or 1% NFs with or without 1*10(8) isolated autologous MNCs. NF injection significantly improved diastolic function and reduced ventricular remodeling 28 days after treatment. Injection of MNCs alone ameliorated systolic function only, whereas injection of MNCs with NFs significantly improved both systolic and diastolic functions as indicated by +dP/dt and -dP/dt (1214.5+/-91.9 and -1109.7+/-91.2 mm Hg/s in MI+NS, 1693.7+/-84.7 and -1809.6+/-264.3 mm Hg/s in MI+MNCs/NFs, respectively), increased transplanted cell retention (29.3+/-4.5 cells/mm(2) in MI+MNCs and 229.4+/-41.4 cells/mm(2) in MI+MNCs/NFs) and promoted capillary density in the peri-infarct area. CONCLUSIONS: We demonstrated that NF injection alone prevents ventricular remodeling, whereas cell implantation with NFs improves cell retention and cardiac functions after MI in pigs. This unprecedented combined treatment in a large animal model has therapeutic effects, which can be translated to clinical applications in the foreseeable future. PMID- 20837905 TI - Resveratrol improves myocardial perfusion in a swine model of hypercholesterolemia and chronic myocardial ischemia. AB - BACKGROUND: Resveratrol may provide protection against coronary artery disease. We hypothesized that supplemental resveratrol will improve cardiac perfusion in the ischemic territory of swine with hypercholesterolemia and chronic myocardial ischemia. METHODS AND RESULTS: Yorkshire swine were fed either a normal diet (control, n=7), a hypercholesterolemic diet (HCC, n=7), or a hypercholesterolemic diet with supplemental resveratrol (100 mg/kg/d orally, HCRV, n=7). Four weeks later, an ameroid constrictor was placed on the left circumflex artery. Animals underwent cardiac MRI and coronary angiography 7 weeks later before euthanasia and tissue harvest. Total cholesterol was lowered about 30% in HCRV animals (P<0.001). Regional wall motion analysis demonstrated a significant decrease in inferolateral function from baseline to 7 weeks in HCC swine (P=0.04). There was no significant change in regional function in HCRV swine from baseline to 7 weeks (P=0.32). Tissue blood flow during stress was 2.8-fold greater in HCRV swine when compared with HCC swine (P=0.04). Endothelium-dependent microvascular relaxation response to Substance P was diminished in HCC swine, which was rescued by resveratrol treatment (P=0.004). Capillary density (PECAM-1 staining) demonstrated fewer capillaries in both HCC and HCRV swine versus control swine (P=0.02). Immunoblot analysis demonstrated significantly greater expression in HCRV versus HCC swine of the following markers of angiogenesis: VEGF (P=0.002), peNOS (ser1177) (P=0.04), NFkB (P=0.004), and pAkt (thr308) (P=0.001). CONCLUSIONS: Supplemental resveratrol attenuates regional wall motion abnormalities, improves myocardial perfusion in the collateral dependent region, preserves endothelium-dependent coronary vessel function, and upregulates markers of angiogenesis associated with the VEGF signaling pathway. PMID- 20837906 TI - Effects of cardiopulmonary bypass on endothelin-1-induced contraction and signaling in human skeletal muscle microcirculation. AB - BACKGROUND: We investigated the effects of cardiopulmonary bypass (CPB) on the contractile response of human peripheral microvasculature to endothelin-1 (ET-1), examined the role of specific ET receptors and protein kinase C-alpha (PKC alpha), and analyzed ET-1-related gene/protein expression in this response. METHODS AND RESULTS: Human skeletal muscle arterioles (90 to 180 MUm in diameter) were dissected from tissue harvested before and after CPB from 30 patients undergoing cardiac surgery. In vitro contractile response to ET-1 was assessed by videomicroscopy, with and without an endothelin-A (ET-A) receptor antagonist, an endothelin-B (ET-B) antagonist, or a PKC-alpha inhibitor. The post-CPB contractile response of peripheral arterioles to ET-1 was significantly decreased compared with pre-CPB response. The response to ET-1 was significantly inhibited in the presence of the ET-A antagonist BQ123 but unchanged in the presence of the ET-B receptor antagonist BQ788. Pretreatment with the PKC-alpha inhibitor safingol reversed ET-1-induced response from contraction to relaxation. The total protein levels of ET-A and ET-B receptors were not altered after CPB. Microarray analysis showed no significant changes in the gene expression of ET receptors, ET 1-related proteins, and protein kinases after CPB. CONCLUSIONS: CPB decreases myogenic contractile function of human peripheral arterioles in response to ET-1. The contractile response to ET-1 is through activation of ET-A receptors and PKC alpha. CPB has no effects on ET-1-related gene/protein expression. These results provide novel mechanisms of ET-1-induced contraction in the setting of vasomotor dysfunction after cardiac surgery. PMID- 20837907 TI - Epidermal growth factor-like domain 7 suppresses intercellular adhesion molecule 1 expression in response to hypoxia/reoxygenation injury in human coronary artery endothelial cells. AB - BACKGROUND: Epidermal growth factor-like domain 7 (Egfl7) is a chemoattractant for endothelial cells, and its expression is restricted to endothelial cells. Hypoxia/reoxygenation (H/R) induced endothelial injury that occurs during transplantation contributes to the subsequent development of allograft vasculopathy. We investigated the effect of Egfl7 on endothelial cell intercellular adhesion molecule 1 expression in response to H/R injury. METHODS AND RESULTS: Human coronary artery endothelial cells were submitted to hypoxia (0.1% O(2)) followed by normoxia (21% O(2)) in the presence or absence of Egfl7 (100 ng/mL). Hypoxia alone increased the expression of Egfl7*140+/-8% of control at 3 hours (n=6; P<0.05) and 385+/-50% of control at 6 hours (n=6; P<0.001). Incubation with Egfl7 during the reoxygenation period prevented intercellular adhesion molecule 1 upregulation (mean fluorescence intensity: 5.37+/-0.92 versus 3.81+/-0.21; P<0.05; n=4 per group). Nuclear factor-kappaB nuclear localization on H/R injury was blocked by Egfl7 administration (cytosolic/nuclear ratio of 0.93+/-0.01 versus 1.44+/-0.24; P<0.05; n=4 per group). Inhibitor of nuclear factor-kappaB protein level was significantly reduced on H/R injury (26+/-4.6% of control expression; P<0.05; n=4 per group); however, concurrent incubation with Egfl7 attenuated this reduction (46+/-6.2% of control expression; P<0.05 when compared with H/R injury alone; n=4 per group). CONCLUSIONS: Our study reveals the novel observation that hypoxia upregulates human coronary artery endothelial cells expression of Egfl7 and that Egfl7 inhibits expression of intercellular adhesion molecule 1 subsequent to H/R injury. Mechanistically, Egfl7 prevented nuclear factor-kappaB nuclear localization and augmented inhibitor of nuclear factor-kappaB protein levels, suggesting that it inhibits nuclear factor-kappaB activation, a key step in the inflammatory activation of endothelial cells. Egfl7 may be protective against H/R injury incurred during transplantation and may modulate the events that lead to the development of graft vasculopathy. PMID- 20837908 TI - Effect of thrombin fragment (TP508) on myocardial ischemia reperfusion injury in a model of type 1 diabetes mellitus. AB - BACKGROUND: We investigated the efficacy of novel thrombin fragment TP508 on ischemia-reperfusion injury using a porcine model of type 1 diabetes mellitus. METHODS AND RESULTS: Alloxan-induced diabetic male Yucatan swine underwent 60 minutes of mid-left anterior descending coronary artery occlusion, followed by 120 minutes of reperfusion. Fifty minutes into ischemia, animals received either placebo (DM; n=8) or TP508 as a bolus of 1 mg/kg followed by infusion at 2.5 mg/kg per hour (DMT; n=8). Hemodynamic parameters and myocardial function were monitored. Monastryl blue/triphenyl tetrazolium chloride staining was used to assess sizes of the areas at risk and infarction. Coronary microvascular reactivity was measured and expression of cell survival and proapoptotic proteins quantified. Preoperative serum glucose values were similar between groups (309+/ 57 mg/dL in DM versus 318+/-67 mg/dL in DMT; P=0.92). Infarct size was smaller in the TP508-treated group (5.3+/-1.9% in DMT versus 19.4+/-5.6% in DM; P=0.03). There was no statistically significant difference in global or regional left ventricular function between groups. Endothelium-dependent microvessel relaxation was moderately improved in the DMT group (P=0.09), whereas endothelium independent relaxation was similar between groups. The expression of cell survival proteins Akt, phospho-p38, and mammalian target of rapamycin was higher in the areas at risk of DMT animals compared with DM animals (P<0.05), and expressions of proapoptotic glycogen synthase kinase 3beta and caspase 3 were lower in the DMT group (P<0.05). CONCLUSIONS: This study demonstrates that, in type 1 diabetic swine, TP508 reduces infarct size after ischemia-reperfusion. Thus, TP508 may offer a novel approach in cardioprotection from ischemia reperfusion injury in diabetic patients. PMID- 20837909 TI - Impact of early surgery on embolic events in patients with infective endocarditis. AB - BACKGROUND: Surgical indications to prevent systemic embolism in infective endocarditis (IE) remain controversial. We sought to compare clinical outcomes of early surgery with conventional treatment in IE patients with embolic indications only. METHODS AND RESULTS: From 1998 to 2006, we prospectively enrolled 132 consecutive patients (86 men; age, 49+/-17 years) with definite IE. Patients were included if they had a left-sided native valve endocarditis with vegetation. The choice of early surgery or conventional treatment was at the discretion of attending physician. Early surgery was performed on 64 patients (OP group) within 7 days of diagnosis, and conventional management was chosen for 68 patients (CONV group). The OP group had larger vegetations and a higher percentage of patients with severe valvular disease (88% versus 62%, P=0.001). During initial hospitalization, there were no embolic events and 2 in-hospital deaths in the OP group and 14 embolic events and 2 in-hospital deaths in the CONV group. During a median follow-up of 1402 days, there were 2 cardiovascular deaths, 2 embolic events, and 1 recurrence of IE in the CONV group, and 1 cardiovascular death and 2 embolic events in the OP group. The 5-year event-free survival rate was significantly higher in the OP group (93+/-3%) than in the CONV group (73+/-5%, P=0.0016). For 44 propensity score-matched pairs, the OP group had a lower event rate (hazard ratio, 0.18; P=0.007). CONCLUSIONS: Compared with conventional treatment, an early surgery strategy is associated with improved clinical outcomes by effectively decreasing systemic embolism in patients with IE. PMID- 20837910 TI - Sustained inhibition of epsilon protein kinase C inhibits vascular restenosis after balloon injury and stenting. AB - BACKGROUND: epsilon protein kinase C (epsilonPKC) is involved in vascular smooth muscle cell (VSMC) activation, but little is known about its function in vascular pathology. We aimed at assessing the role of epsilonPKC in the development of restenosis. METHODS AND RESULTS: Rat models of aortic balloon injury with or without subsequent stenting were used. Rats were treated with the selective psiepsilonPKC activator epsilon receptor for activated protein kinase C (psiepsilonRACK), the selective epsilonPKC inhibitor epsilonV1-2, or saline. Both down-stream cascades of the platelet-derived growth factor receptor via extracellular signal-regulated kinase and Akt, respectively, were evaluated in vivo and in VSMC cultures. Intimal hyperplasia with luminal obliteration developed in saline-treated balloon-injured rat aortas (20.3+/-8.0%), and psiepsilonRACK significantly promoted neointima development (32.4+/-4.9%, P=0.033), whereas epsilonV1-2 significantly inhibited luminal narrowing (9.2+/ 4.3%, P=0.039). epsilonPKC inhibition led to significantly reduced VSMC extracellular signal-regulated kinase phosphorylation in vivo, whereas Akt phosphorylation was not markedly affected. Neointimal proliferation in vivo and platelet-derived growth factor-induced VSMC proliferation/migration in vitro were significantly inhibited by epsilonV1-2. The inhibition of the platelet-derived growth factor pathway was mediated by inhibiting down-stream extracellular signal regulated kinase and Akt phosphorylation. In vitro, epsilonV1-2 showed inhibitory properties on endothelial cell proliferation, but that did not prevent reendothelialization in vivo. epsilonV1-2 showed proapoptotic effects on VSMC in vitro. After stent implantation, luminal restenosis (quantified by optical coherence tomography imaging) was significantly reduced with epsilonV1-2 (8.0+/ 2.0%) compared with saline (20.2+/-9.8%, P=0.028). CONCLUSIONS: epsilonPKC seems to be centrally involved in the development of neointimal hyperplasia. We suggest that epsilonPKC inhibition may be mediated via inhibition of extracellular signal regulated kinase and Akt activation. epsilonPKC modulation may become a new therapeutic target against vascular restenosis. PMID- 20837911 TI - Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. AB - BACKGROUND: Emerging evidence suggests that "adaptive" induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. METHODS AND RESULTS: Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with "delayed" treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end reperfusion. CAPS was cardioprotective: infarct size was 25+/-5 and 41+/-4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56+/-5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. CONCLUSIONS: Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection. PMID- 20837912 TI - Adropin is a novel regulator of endothelial function. AB - BACKGROUND: Adropin is a recently identified protein that has been implicated in the maintenance of energy homeostasis and insulin resistance. Because vascular function and insulin sensitivity are closely related, we hypothesized that adropin may also exert direct effects on the endothelium. METHODS AND RESULTS: In vitro cell culture models were partnered with an in vivo murine injury model to determine the potential vascular effects of adropin. Adropin was expressed in human umbilical vein and coronary artery endothelial cells (ECs). Adropin-treated endothelial cells exhibited greater proliferation, migration and capillary-like tube formation and less permeability and tumor necrosis factor-alpha-induced apoptosis. In keeping with a vascular protective effect, adropin stimulated Akt Ser(473) and endothelial nitric oxide (NO) synthase Ser(1177) phosphorylation. The former was abrogated in the presence of the phosphatidylinositol 3-kinase inhibitor LY294002, whereas the latter was attenuated by LY294002 and by mitogen activated protein kinase kinase 1 inhibition with PD98059. Together, these findings suggest that adropin regulates NO bioavailability and events via the phosphatidylinositol 3-kinase-Akt and extracellular signal regulated kinase 1/2 signaling pathways. Adropin markedly upregulated vascular endothelial growth factor receptor-2 (VEGFR2) transcript and protein levels, and in VEGFR2-silenced endothelial cells, adropin failed to induce phosphorylation of endothelial NO synthase, Akt, and extracellular signal regulated kinase 1/2, supporting VEGFR2 as an upstream target of adropin-mediated endothelial NO synthase activation. Last, adropin improved murine limb perfusion and elevated capillary density following induction of hindlimb ischemia. CONCLUSIONS: We report a potential endothelial protective role of adropin that is likely mediated via upregulation of endothelial NO synthase expression through the VEGFR2-phosphatidylinositol 3 kinase-Akt and VEGFR2-extracellular signal regulated kinase 1/2 pathways. Adropin represents a novel target to limit diseases characterized by endothelial dysfunction in addition to its favorable metabolic profile. PMID- 20837913 TI - Alteration of parasympathetic/sympathetic ratio in the infarcted myocardium after Schwann cell transplantation modified electrophysiological function of heart: a novel antiarrhythmic therapy. AB - BACKGROUND: Neural remodeling after myocardial infarction (MI) may cause fatal ventricular arrhythmia. Schwann cells (SCs), which are important for neurogenesis, are dramatically reduced after MI. We investigated the feasibility of modifying nervous system regeneration after MI and the efficacy by which it may prevent ventricular arrhythmia following SC transplantation. METHODS AND RESULTS: Immediately after creation of MI, syngenic Lewis rats were randomized into cell transplantation (n=80) and control groups (n=72). SCs were isolated from sciatic nerves, and 5*10(6) cells were intramyocardially injected into the infarct region. Expression levels of myocardial nerve growth factor, vascular endothelial growth factor, growth-associated protein 43, connexin 43, and laminin in the SC group were significantly higher than control at 7 and 14 days after cell transplantation. Immunohistochemical staining illustrated increases in sympathetic and parasympathetic nerves in both groups. However, SC transplantation significantly increased the parasympathetic/sympathetic ratio at 14 days after cell injection. Dynamic electrocardiography and programmed electric stimulation were also performed. The SCs significantly decreased the low-/high frequency ratio and arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia at 2 weeks after cell injection. However, SCs did not restore heart function. CONCLUSIONS: Transplanted SCs in the infarcted myocardium secrete multiple biological molecules, which alter the ratio of parasympathetic/sympathetic nerve density to normalize irritable myocardium. SC transplantation might be a novel cell-based antiarrhythmic therapy following MI. PMID- 20837914 TI - Randomized trial of pulmonary valve replacement with and without right ventricular remodeling surgery. AB - BACKGROUND: Although pulmonary valve replacement (PVR) is effective in reducing right ventricular (RV) volume overload in patients with chronic pulmonary regurgitation, persistent RV dysfunction and subsequent adverse clinical outcomes have been reported. This trial was conducted to investigate whether the addition of surgical RV remodeling with exclusion of scar tissue to PVR would result in improved RV function and laboratory and clinical parameters, as compared with PVR alone. METHODS AND RESULTS: Between February 2004 and October 2008, 64 patients who underwent RV outflow tract procedures in early childhood had more than or equal to moderate pulmonary regurgitation, and fulfilled defined criteria for PVR were randomly assigned to undergo either PVR alone (n=34) or PVR with surgical RV remodeling (n=30). No significant difference was observed in the primary outcome (change in RV ejection fraction, -2+/-7% in the PVR alone group and -1+/-7% in the PVR with RV remodeling group; P=0.38) or in any of the secondary outcomes at 6-month postoperative follow-up. Multivariable analysis of the entire cohort identified preoperative RV end-systolic volume index <90 mL/m(2) and QRS duration <140 ms to be associated with optimal postoperative outcome (normal RV size and function), and RV ejection fraction <45% and QRS duration >=160 ms to be associated with suboptimal postoperative outcome (RV dilatation and dysfunction). CONCLUSIONS: The addition of surgical remodeling of the RV to PVR in patients with chronic pulmonary regurgitation did not result in a measurable early benefit. Referral to PVR based on QRS duration, RV end-systolic volume, or RV ejection fraction may be beneficial. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00112320. PMID- 20837915 TI - Echocardiographic definition and surgical decision-making in unbalanced atrioventricular septal defect: a Congenital Heart Surgeons' Society multiinstitutional study. AB - BACKGROUND: Although identification of unbalanced atrioventricular septal defect (AVSD) is obvious when extreme, exact criteria to define the limits of unbalanced are not available. We sought to validate an atrioventricular valve index (AVVI) (left atrioventricular valve area/total atrioventricular valve area, centimeters squared) as a discriminator of balanced and unbalanced forms of complete AVSD and to characterize the association of AVVI with surgical strategies and outcomes. METHODS AND RESULTS: Diagnostic echocardiograms and hospital records of 356 infants with complete AVSD at 4 Congenital Heart Surgeons' Society (CHSS) institutions (2000-2006) were reviewed and AVVI measured (n=315). Patients were classified as unbalanced if AVVI<=0.4 (right dominant) or >=0.6 (left dominant). Surgical strategy and outcomes were examined across the range of AVVI. Competing risks analysis until the time of commitment to a surgical strategy examined 4 end states: biventricular repair (BVR), univentricular repair (UVR), pulmonary artery banding (PAB), and death before surgery. A prediction nomogram for surgical strategy based on AVVI was developed. The majority of patients had balanced AVSD (0.4=0.6 (left dominant) was less common. The proportion of subjects predicted for the end states at 12 months after diagnosis are: BVR, 86%; UVR, 7%; PAB, 1%; death without surgery, 1%; alive without surgery, 5%. CONCLUSIONS: AVVI effectively characterizes the transition between balanced and unbalanced AVSD with important correlation to anatomic substrate and selected surgical strategy. PMID- 20837916 TI - Major adverse cardiac and cerebrovascular events after the Ross procedure: a report from the German-Dutch Ross Registry. AB - BACKGROUND: The purpose of the study is to report major cardiac and cerebrovascular events after the Ross procedure in the large adult and pediatric population of the German-Dutch Ross registry. These data could provide an additional basis for discussions among physicians and a source of information for patients. METHODS AND RESULTS: One thousand six hundred twenty patients (1420 adults; 1211 male; mean age, 39.2+/-16.2 years) underwent a Ross procedure between 1988 and 2008. Follow-up was performed on an annual basis (median, 6.2 years; 10 747 patient-years). Early and late mortality were 1.2% (n=19) and 3.6% (n=58; 0.54%/patient-year), respectively. Ninety-three patients underwent 99 reinterventions on the autograft (0.92%/patient-year); 78 reinterventions in 63 patients on the pulmonary conduit were performed (0.73%/patient-year). Freedom from autograft or pulmonary conduit reoperation was 98.2%, 95.1%, and 89% at 1, 5, and 10 years, respectively. Preoperative aortic regurgitation and the root replacement technique without surgical autograft reinforcement were associated with a greater hazard for autograft reoperation. Major internal or external bleeding occurred in 17 (0.15%/patient-year), and a total of 38 patients had composite end point of thrombosis, embolism, or bleeding (0.35%/patient-year). Late endocarditis with medical (n=16) or surgical treatment (n=29) was observed in 38 patients (0.38%/patient-year). Freedom from any valve-related event was 94.9% at 1 year, 90.7% at 5 years, and 82.5% at 10 years. CONCLUSIONS: Although longer follow-up of patients who undergo Ross operation is needed, the present series confirms that the autograft procedure is a valid option to treat aortic valve disease in selected patients. The nonreinforced full root technique and preoperative aortic regurgitation are predictors for autograft failure and warrant further consideration. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708409. PMID- 20837918 TI - Regression of myocardial hypertrophy after aortic valve replacement: faster in women? AB - BACKGROUND: In patients with aortic stenosis, pressure overload induces cardiac hypertrophy and fibrosis. Female sex and estrogens influence cardiac remodeling and fibrosis in animal models and in men. Sex differences and their molecular mechanisms in hypertrophy regression after aortic valve replacement have not yet been studied. METHODS AND RESULTS: We prospectively obtained preoperative and early postoperative echocardiography in 92 patients, 53 women and 39 men, undergoing aortic valve replacement for isolated aortic stenosis. We analyzed in a subgroup of 10 patients matrix gene expression in left ventricular (LV) biopsies. In addition, we determined the effect of 17beta-estradiol on collagen synthesis in isolated rat cardiac fibroblasts. Preoperatively, women and men had similar ejection fraction. Similar percentages of women and men had increased LV diameters (37% and 38%). Women more frequently exhibited LV hypertrophy than men (women: 86%; men: 56%; P<0.01). Postoperatively, increased LV diameters persisted in 34% of men but only in 12% of women (P<0.023). LV hypertrophy reversed more frequently in women than in men, leading to a similar prevalence of LV hypertrophy after surgery (women: 45%; men: 36%). In surgical biopsies, men had significantly higher collagen I and III and matrix metalloproteinase 2 gene expression than women. In isolated rat cardiac fibroblasts, 17beta-estradiol significantly increased collagen I and III gene expressions in male cells but decreased it in female cells. CONCLUSIONS: Women adapt to pressure overload differently from men. Less fibrosis before surgery may enable faster regression after surgery. PMID- 20837917 TI - Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis. AB - BACKGROUND: Triiodothyronine levels decrease in infants and children after cardiopulmonary bypass. We tested the primary hypothesis that triiodothyronine (T3) repletion is safe in this population and produces improvements in postoperative clinical outcome. METHODS AND RESULTS: The TRICC study was a prospective, multicenter, double-blind, randomized, placebo-controlled trial in children younger than 2 years old undergoing heart surgery with cardiopulmonary bypass. Enrollment was stratified by surgical diagnosis. Time to extubation (TTE) was the primary outcome. Patients received intravenous T3 as Triostat (n=98) or placebo (n=95), and data were analyzed using Cox proportional hazards. Overall, TTE was similar between groups. There were no differences in adverse event rates, including arrhythmia. Prespecified analyses showed a significant interaction between age and treatment (P=0.0012). For patients younger than 5 months, the hazard ratio (chance of extubation) for Triostat was 1.72. (P=0.0216). Placebo median TTE was 98 hours with 95% confidence interval (CI) of 71 to 142 compared to Triostat TTE at 55 hours with CI of 44 to 92. TTE shortening corresponded to a reduction in inotropic agent use and improvement in cardiac function. For children 5 months of age, or older, Triostat produced a significant delay in median TTE: 16 hours (CI, 7-22) for placebo and 20 hours (CI, 16-45) for Triostat and (hazard ratio, 0.60; P=0.0220). CONCLUSIONS: T3 supplementation is safe. Analyses using age stratification indicate that T3 supplementation provides clinical advantages in patients younger than 5 months and no benefit for those older than 5 months. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00027417. PMID- 20837919 TI - Sex differences in mortality in children undergoing congenital heart disease surgery: a United States population-based study. AB - BACKGROUND: The changing demographics of the adult congenital heart disease (CHD) population requires an understanding of the factors that impact patient survival to adulthood. We sought to investigate sex differences in CHD surgical mortality in children. METHODS AND RESULTS: Children <18 years old hospitalized for CHD surgery were identified using the Kids' Inpatient Database in 2000, 2003, and 2006. Demographic, diagnostic, and procedural variables were grouped according to RACHS-1 (Risk Adjustment for Congenital Heart Surgery) method. Logistic regression was used to determine the odds ratio of death in females versus males adjusting for RACHS-1 risk category, age, prematurity, major noncardiac anomalies, and multiple procedures. Analyses were stratified by RACHS-1 risk categories and age. Of 33 848 hospitalizations for CHD surgery, 54.7% were in males. Males were more likely than females to have CHD surgery in infancy, high risk CHD surgery, and multiple CHD procedures. Females had more major noncardiac structural anomalies and more low-risk procedures. However, the adjusted risk of in-hospital death was higher in females (odds ratio, 1.21; 95% confidence interval, 1.08 to 1.36) on account of the subgroup with high-risk surgeries who were <1 year of age (odds ratio, 1.39; 95% confidence interval, 1.16 to 1.67). CONCLUSIONS: In this large US population study, more male children underwent CHD surgery and had high-risk procedures. Female infants who had high-risk procedures were at higher risk for death, but this accounted for a small proportion of females and is therefore unlikely to have a major impact on the changing demographics in adults in CHD. PMID- 20837920 TI - Rapid-response extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in children with cardiac disease. AB - BACKGROUND: Survival of children with in-hospital cardiac arrest that does not respond to conventional cardiopulmonary resuscitation (CPR) is poor. We report on survival and early neurological outcomes of children with heart disease supported with rapid-response extracorporeal membrane oxygenation (ECMO) to aid cardiopulmonary resuscitation (ECPR). METHODS AND RESULTS: Children with heart disease supported with ECPR were identified from our ECMO database. Demographic, CPR, and ECMO details associated with mortality were evaluated using multivariable logistic regression. Pediatric overall performance category and pediatric cerebral performance category scores were assigned to ECPR survivors to assess neurological outcomes. There were 180 ECPR runs in 172 patients. Eighty eight patients (51%) survived to discharge. Survival in patients who underwent ECPR after cardiac surgery (54%) did not differ from nonsurgical patients (46%). Survival did not vary by cardiac diagnosis and CPR duration did not differ between survivors and nonsurvivors. Factors associated with mortality included noncardiac structural or chromosomal abnormalities (OR, 3.2; 95% CI, 1.3-7.9), use of blood-primed ECMO circuit (OR, 7.1; 95% CI, 1.4-36), and arterial pH <7.00 after ECMO deployment (OR, 6.0; 95% CI, 2.1-17.4). Development of end-organ injury on ECMO and longer ECMO duration were associated with increased mortality. Of pediatric overall performance category/pediatric cerebral performance category scores assigned to survivors, 75% had scores <=2, indicating no to mild neurological injury. CONCLUSIONS: ECPR may promote survival in children with cardiac disease experiencing cardiac arrest unresponsive to conventional CPR with favorable early neurological outcomes. CPR duration was not associated with mortality, whereas patients with metabolic acidosis and noncardiac structural or chromosomal anomalies had higher mortality. PMID- 20837921 TI - Assessment of changes in mitral valve configuration with multidetector computed tomography: impact of papillary muscle imbrication and ring annuloplasty. AB - BACKGROUND: The optimal surgical procedures in functional mitral regurgitation remain controversial. We applied papillary muscle imbrication (PMI) combined with undersized mitral annuloplasty (UMAP). Multidetector computed tomography (MDCT) provides images of different phases of the cardiac cycle, allowing an assessment of the geometry. In the present study, we evaluated the mitral valve configuration and subvalvular apparatus before and after UMAP and/or PMI using MDCT imaging. METHODS AND RESULTS: We studied 26 patients with functional mitral regurgitation (3+ to 4+) with an ejection fraction >=35% who underwent diagnostic MDCT examinations before and early after the operation. Of these, 15 underwent UMAP and PMI (UMAP+PMI group) and 11 underwent UMAP (UMAP group). The annular anteroposterior diameter, tenting height, tenting area, and interpapillary muscle distance at end-systole were quantified. The annular anteroposterior diameter, tenting height, and tenting area were significantly decreased after the operation in both groups. Whereas the average change in annular anteroposterior diameter, tenting area, and interpapillary muscle distance did not differ between the 2 groups, the average change in tenting height was greater in the UMAP+PMI group than in the UMAP group (5.1+/-1.3 versus 3.8+/-2.3 mm, P=0.036). There was a significant correlation between the change in interpapillary muscle distance and the change in tenting height in the UMAP+PMI group (r=0.788, P=0.0005). CONCLUSIONS: Our results examined with MDCT indicated that UMAP combined with PMI improved leaflet tethering compared with UMAP, reflecting differences in the effects of the surgical procedures used, and suggested that concomitant PMI might be beneficial in some cases. PMID- 20837922 TI - Mechanism of beneficial effects of restrictive mitral annuloplasty in patients with dilated cardiomyopathy and functional mitral regurgitation. AB - BACKGROUND: Restrictive mitral annuloplasty (RMA) often leads to reverse left ventricular (LV) remodeling in patients with advanced cardiomyopathy and functional mitral regurgitation. However, the mechanism responsible for its favorable effects on LV ejection performance has been poorly understood. We evaluated systolic wall stress using cineangiographic multidetector computed tomography (MDCT) and our developed software system to assess stress-shortening relations before and after RMA. METHODS AND RESULTS: Twenty-four patients with dilated cardiomyopathy underwent 64-row MDCT before and 2 months after RMA. All patients underwent stringent downsizing annuloplasty with a semirigid complete ring. Reconstructed images were used to calculate LV end-diastolic index (EDVI) and end-systolic volume index (ESVI), LV ejection fraction, and regional and global end-systolic wall stress (ESS). After RMA, LVEDVI and LVESVI decreased from 151+/-52 to 131+/-53 mL/m(2) (P=0.0001) and from 114+/-48 to 92+/-50 mL/m(2) (P=0.0001), respectively. Global ESS decreased from 157+/-43 to 139+/-50 kdyne/cm(2) (P=0.01), and LV ejection fraction improved from 27+/-8.0 to 33+/-13% (P=0.0007). There were significant correlations between change in LVEDVI and LVESVI (r=0.88, P<0.0001) and change in LVESVI and global ESS (r=0.68, P=0.0002). Moreover, the magnitude of increase in LV ejection fraction significantly correlated with the degree of reduction in global ESS (r=-0.61, P=0.002). Patients without significant reverse LV remodeling had significantly higher preoperative and postoperative global ESS than those with it. CONCLUSIONS: Our study suggests that decrease in afterload after reduction in volume overload was responsible for postoperative reverse LV remodeling process after RMA. PMID- 20837923 TI - Correlates and causes of death in patients with severe symptomatic aortic stenosis who are not eligible to participate in a clinical trial of transcatheter aortic valve implantation. AB - BACKGROUND: Transcatheter aortic valve implantation is currently being evaluated in patients with severe aortic stenosis who are considered high-risk surgical candidates. This study aimed to detect incidences, causes, and correlates of mortality in patients ineligible to participate in transcatheter aortic valve implantation studies. METHODS AND RESULTS: From April 2007 to July 2009, a cohort of 362 patients with severe aortic stenosis were screened and did not meet the inclusion/exclusion criteria necessary to participate in a transcatheter aortic valve implantation trial. These patients were classified into 2 groups: group 1 (medical): 274 (75.7%): 97 (35.4%) treated medically and 177 (64.6%) treated with balloon aortic valvuloplasty; and group 2 (surgical): 88 (24.3%). The medical/balloon aortic valvuloplasty group had significantly higher clinical risk compared with the surgical group, with significantly higher Society of Thoracic Surgeons score (12.8+/-7.0 versus 8.5+/-5.1; P<0.001) and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (42.4+/-22.8 versus 24.4+/-18.1; P<0.001). The medical/balloon aortic valvuloplasty group had a higher New York Heart Association functional class, incidence of renal failure, and lower ejection fraction. During median follow-up of 377.5 days, mortality in the medical/balloon aortic valvuloplasty group was 102 (37.2%), and during median follow-up of 386 days, mortality in the surgical group was 19 (21.5%). Multivariable adjustment analysis identified renal failure (hazard ratio [HR]: 5.60), New York Heart Association class IV (HR: 5.88), and aortic systolic pressure (HR: 0.99) as independent correlates for mortality in the medical group, whereas renal failure (HR: 7.45), Society of Thoracic Surgeons score (STS; HR: 1.09) and logistic EuroSCORE (HR: 1.45) were correlates of mortality in the in the surgical group. CONCLUSIONS: Patients with severe symptomatic aortic stenosis not included in transcatheter aortic valve implantation trials do poorly and have extremely high mortality rates, especially in nonsurgical groups, and loss of quality of life in surgical groups. PMID- 20837924 TI - Prognostic implications of mitral regurgitation in patients with severe aortic regurgitation. AB - BACKGROUND: Mitral regurgitation (MR) is common in those with severe aortic regurgitation (AR) and can predispose to atrial fibrillation, heart failure, and a need for mitral valve surgery during aortic valve replacement (AVR). However, little data exist as to its clinical and prognostic implications. METHODS AND RESULTS: Search of our echocardiographic data base between 1993 and 2007 yielded 756 patients with severe AR. with comprehensive clinical data from chart review and mortality data from National Death Index. Mortality was analyzed as a function of MR severity. Effect of AVR and concomitant mitral valve repair were investigated. Patient characteristics were age, 61+/-17 years; female sex, 41%; and ejection fraction, 54+/-19%. MR grade >=2+ was present in 343 (45%) patients: 2+ in 152 (20%), 3+ in 93 (12%), and 4+ in 98 (13%). There was a progressive decrease in survival with each grade of MR (P<0.0001). Performance of AVR was associated with a better survival in those with 3 or 4+ MR (P=0.02). In addition, concomitant mitral valve repair in these patients resulted in a better survival (hazard ratio, 0.29; P=0.02). CONCLUSIONS: MR is common in patients with severe AR, with 3 or 4+ MR occurring in a quarter of these patients. It is an independent predictor of reduced survival. Performance of AVR and concomitant mitral valve repair is associated with a better survival. Development of MR should serve as an indication for AVR even in asymptomatic patients. PMID- 20837925 TI - Five-year follow-up of a randomized comparison between off-pump and on-pump stable multivessel coronary artery bypass grafting. The MASS III Trial. AB - BACKGROUND: Coronary artery bypass graft surgery with cardiopulmonary bypass is a safe, routine procedure. Nevertheless, significant morbidity remains, mostly because of the body's response to the nonphysiological nature of cardiopulmonary bypass. Few data are available on the effects of off-pump coronary artery bypass graft surgery (OPCAB) on cardiac events and long-term clinical outcomes. METHODS AND RESULTS: In a single-center randomized trial, 308 patients undergoing coronary artery bypass graft surgery were randomly assigned: 155 to OPCAB and 153 to on-pump CAB (ONCAB). Primary composite end points were death, myocardial infarction, further revascularization (surgery or angioplasty), or stroke. After 5-year follow-up, the primary composite end point was not different between groups (hazard ratio 0.71, 95% CI 0.41 to 1.22; P=0.21). A statistical difference was found between OPCAB and ONCAB groups in the duration of surgery (240+/-65 versus 300+/-87.5 minutes; P<0.001), in the length of ICU stay (19.5+/-17.8 versus 43+/-17.0 hours; P<0.001), time to extubation (4.6+/-6.8 versus 9.3+/-5.7 hours; P<0.001), hospital stay (6+/-2 versus 9+/-2 days; P<0.001), higher incidence of atrial fibrillation (35 versus 4% of patients; P<0.001), and blood requirements (31 versus 61% of patients; P<0.001), respectively. The number of grafts per patient was higher in the ONCAB than the OPCAB group (2.97 versus 2.49 grafts/patient; P<0.001). CONCLUSIONS: No difference was found between groups in the primary composite end point at 5-years follow-up. Although OPCAB surgery was related to a lower number of grafts and higher episodes of atrial fibrillation, it had no significant implications related to long-term outcomes. Clinical Trial Registration-URL: http://www.controlled-trials.com. Unique identifier: ISRCTN66068876. PMID- 20837926 TI - Remote ischemic preconditioning in human coronary artery bypass surgery: from promise to disappointment? AB - BACKGROUND: We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. METHODS AND RESULTS: This was a single-center, prospective, randomized (1:1), placebo controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (*3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL(-1)/48 h( 1)); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL(-1)); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL(-1)); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL(-1) (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO(2):FiO(2) ratios 255 (195, 323) versus 263 (210, 308) were similar. CONCLUSIONS: In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration-URL: http://www.ukcrn.org.uk. Unique identifier: 4659. PMID- 20837927 TI - Chromosome 9p21 variant predicts mortality after coronary artery bypass graft surgery. AB - BACKGROUND: Recent genome-wide association studies have identified several chromosome 9p21 single nucleotide polymorphisms associated with coronary artery disease and myocardial infarction in nonsurgical populations. We have recently demonstrated an independent association between these 9p21 variants and perioperative myocardial injury after isolated primary coronary artery bypass graft (CABG) surgery. This study investigated the association of a 9p21 variant with mortality in patients after CABG surgery and its prognostic value to improve the EuroSCORE. METHODS AND RESULTS: In a 2-center, prospective, observational study of 846 white primary CABG surgery patients, we genotyped rs10116277, the 9p21 variant with the strongest association to perioperative myocardial injury in our cohort. To estimate the utility of rs10116277 for predicting all-cause mortality within 5 years after surgery, a Cox proportional hazard model was constructed to estimate the hazard ratios (HR) and 95% confidence intervals (CI) while adjusting for demographics and clinical covariates. The homozygote minor allele of rs10116277 was associated with significantly increased risk of all cause mortality even after adjusting for other clinical predictors of mortality in a Cox proportional hazards model (HR, 1.7; 95% CI, 1.1-2.7; P=0.026). Addition of rs10116277 to the logistic EuroSCORE also significantly improved model prediction for mortality (HR, 1.82; 95% CI, 1.15-2.88; P=0.01). CONCLUSIONS: The 9p21 variant rs10116277 is independently associated with all-cause mortality after primary CABG surgery in whites and significantly improves the predictive value of the logistic EuroSCORE. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00281164. PMID- 20837928 TI - Preoperative atorvastatin treatment in CABG patients rapidly improves vein graft redox state by inhibition of Rac1 and NADPH-oxidase activity. AB - BACKGROUND: Statins improve clinical outcome of patients with atherosclerosis, but their perioperative role in patients undergoing coronary artery bypass grafting (CABG) is unclear. We hypothesized that short-term treatment with atorvastatin before CABG would improve the redox state in saphenous vein grafts (SVGs), independently of low-density lipoprotein cholesterol (LDL)-lowering. METHODS AND RESULTS: In a randomized, double-blind controlled trial, 42 statin naive patients undergoing elective CABG received atorvastatin 40 mg/d or placebo for 3 days before surgery. Circulating inflammatory markers and malondialdehyde (MDA) were measured before and after treatment. SVG segments were used to determine vascular superoxide (O(2)(*-)) and Rac1 activation. For ex vivo studies, SVG segments from 24 patients were incubated for 6 hours with atorvastatin 0, 5, or 50 MUmol/L. Oral atorvastatin reduced vascular basal and NADPH-stimulated O(2)(*-) in SVGs (P<0.05 for all versus placebo) and reduced plasma MDA (P<0.05), independently of LDL-lowering and of changes in inflammatory markers. In SVGs exposed to atorvastatin ex vivo, without exposure to LDL, basal and NADPH-stimulated O(2)(.-) were significantly reduced (P<0.01 for both concentrations versus 0 MUmol/L) in association with a striking reduction in Rac1 activation and 1 membrane-bound Rac1 and p67(phox) subunit. The antioxidant effects of atorvastatin were reversed by mevalonate, implying a dependence on vascular HMG-CoA reductase inhibition. CONCLUSIONS: Short-term treatment with atorvastatin 40 mg/d before CABG improves redox state in SVGs, by inhibiting vascular Rac1-mediated activation of NADPH-oxidase. These novel findings suggest that statin therapy should be maintained or initiated in patients undergoing CABG, independently of LDL levels. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103. PMID- 20837929 TI - Impact of new development of ulcer-like projection on clinical outcomes in patients with type B aortic dissection with closed and thrombosed false lumen. AB - BACKGROUND: The purpose of this study was to investigate the clinical importance of newly developed ulcer-like projection (ULP) in patients with type B aortic dissection with closed and thrombosed false lumen (AD with CTFL), which is better known as aortic intramural hematoma. METHODS AND RESULTS: A total of 170 patients with acute type B AD with CTFL were admitted to our institution from 1986 to 2008 and treated initially with medical therapy. There were 31 late deaths, including 9 cases of aortic rupture. The actuarial survival rates of all patients were 99%, 89%, 83% at 1, 5, and 10 years, respectively. A total of 62 (36%) patients showed new ULP development within 30 days from the onset. Patients who had ULP showed significantly poorer survival rates than patients who did not have ULP (P=0.037). Development of ULP was also associated with a significant increase in adverse aorta-related events (P<0.001). In addition, patients with ULP in the proximal descending thoracic aorta (PD) showed significantly higher aorta-related event rates than patients without ULP in the PD (P<0.001). Initial aortic diameter (hazard ratio, 3.55; P<0.001) and development of ULP in PD (hazard ratio, 3.79; P=0.003) were the strongest predictors of adverse aorta-related events. CONCLUSIONS: Initial aortic diameter and development of ULP in the PD are both strong predictors of adverse aorta-related events in patients with type B AD with CTFL. Patients with newly developed ULP should be more carefully followed up with close surveillance imaging than those without ULP. PMID- 20837930 TI - Late outcomes of reintervention on the descending aorta after repair of aortic coarctation. AB - BACKGROUND: After repair of aortic coarctation, patients may develop restenosis, aneurysms, and pseudoaneurysms at the site of prior repair. We assessed the outcomes of late reintervention on the descending aorta after aortic coarctation repair. METHODS AND RESULTS: From March 1954 to July 2008, 130 patients had operations or endovascular procedures on the descending aorta after previous coarctation repair. We excluded patients who had complex left-sided cardiac lesions or interrupted aortic arch. Mean age at reintervention was 32+/-24 years and 28% were female. The interval between coarctation repair and reintervention was 17+/-13 years. Seventy-four percent of patients had hypertension. Reasons for reintervention were restenosis (n=122 [94%]), aneurysm (n=4 [3%]), and pseudoaneurysm (n=4 [3%]). Ninety-five patients (73%) underwent operative procedures including an extra-anatomic conduit (n=41), patch repair (n=32), interposition graft (n=14), end-end anastomosis (n=6), and subclavian flap (n=2). Thirty-five patients underwent endovascular treatment (balloon dilatation, n=22 or stenting, n=13). There was no early mortality. In the surgical group, 5 patients required early reoperation for bleeding and 5 patients had early vocal cord paralysis. One patient in the endovascular group had aortic rupture at the time of intervention requiring urgent operation. Survival was 97% at 10 years. At 5 years, freedom from a second repeat procedure on the descending aorta was 96% in the surgical group and 72% in the endovascular group (P<0.001). Five years after reintervention, fewer patients required treatment for hypertension (57% versus 74%, P<0.001) and a median of 1 antihypertensive medication was prescribed compared with a median of 2 medications preintervention. CONCLUSIONS: Operative and endovascular management of recoarctation can be performed safely with good late outcomes. PMID- 20837931 TI - Post-heart transplant survival is inferior at low-volume centers across all risk strata. AB - BACKGROUND: Previous studies have demonstrated a relationship between increasing center volume and cardiac transplant outcomes. The purpose of this study was to confirm a relationship between post-heart transplant outcomes and center experience and to determine whether this relationship persists among low- and high-risk heart transplant recipient-donor pairs. METHODS AND RESULTS: The United Network for Organ Sharing (UNOS) provided deidentified patient-level data. Analysis included 8029 heart transplant recipients aged >=18 years and transplanted between January 1, 2001 and December 31, 2006 with follow-up available through February 3, 2009. The primary outcome was observed 1-year posttransplant graft survival. Multivariable logistic regression was used to calculate expected 1-year survival for recipients. Threshold analysis identified 3 discrete risk groups of transplant recipients: high-risk, moderate-risk, and low-risk. Three discrete risk strata for center volume: low (<10.5 recipients/yr), intermediate (10.5 to 47 recipients/yr), and high (>47 recipients/yr) were also identified. chi(2) test was used to compare 1-year survival at low- and intermediate- with high-volume centers. In multivariable logistic regression analysis, annual center volume was significantly associated with posttransplant graft survival at 1 year (odds ratio [OR]=0.995, 0.992 to 0.999; P=0.010) and primary graft failure (OR=0.985, 0.972 to 0.997; P=0.015), but not stroke (OR=0.996, 0.990 to 1.003; P=0.295), infection (OR=1.001, 0.998 to 1.003; P=0.613), or dialysis (OR=1.001, 0.997 to 1.005; P=0.522). Log-rank test demonstrated significant difference in survival between volume groups with respect to high-risk (P=0.0032) and low-risk (P=0.00415), but not moderate-risk (P=0.128) patients. CONCLUSIONS: A direct relationship existed between increasing center volume and improved graft survival. Across all recipient-donor pair risk strata, posttransplant graft survival at 1 year was significantly lower at low volume centers. The volume-outcomes relationship was strongest in the highest risk recipient-donor category. PMID- 20837932 TI - Visceral arterial compromise during intra-aortic balloon counterpulsation therapy. AB - BACKGROUND: Intraaortic balloon pump (IABP) therapy is a widely used method of circulatory support. Based on frequent findings of balloon malposition with visceral arterial compromise on computerized tomographic (CT) imaging studies, we conducted a systematic review of cardiac surgical IABP patients with available CT scans to determine reasons, incidence, and clinical relevance of malposition. METHODS AND RESULTS: From January 2007 to March 2009, a total of 621 of 7756 cardiac surgical patients (8.0%) received perioperative IABP support, of whom 63 (10.1%) received a thoracoabdominal CT scan during IABP support. Proximal and distal balloon positions were analyzed. The anatomic distance from the left subclavian artery to celiac trunk and aortic transverse diameter were measured in all patients and compared with implanted balloon dimensions. Mean age was 67.1+/ 11.9 years; 33.3% were female, and height was 169+/-9 cm. Based on radiography, proximal balloon position was correct in 96.8% but only appropriate in 38.1% based on CT. In 61 of 63 patients, compromise of at least 1 visceral artery was found: celiac trunk, 96.8%; superior mesenteric artery, 87.3%; and renal arteries, 66.7%. Left subclavian artery to celiac trunk distance was 241+/-23 mm, and balloon length was 248+/-17 mm and corresponded to an anatomic to balloon length mismatch in 68.2%. Spinal deformations were found in 42.9%. Laparotomy for mesenteric ischemia was required in 23.8%. Hospital mortality rate was 60.3%. CONCLUSIONS: IABP malposition was commonly identified by CT. Reasons included incorrect proximal balloon position as well as an anatomic-to-balloon length mismatch. Thus, shorter than recommended balloon sizes and better positioning strategies had to be considered. PMID- 20837933 TI - Contrast enhanced ultrasonography for the evaluation of coil embolization of splenic artery aneurysm. PMID- 20837934 TI - Letter by McAuley et al regarding article, "Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men". PMID- 20837935 TI - Letter by Stefan et al regarding article, "Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men". PMID- 20837937 TI - Management of submassive pulmonary embolism. PMID- 20837939 TI - Chest pain due to severe sternal pseudoarthrosis post-coronary artery bypass surgery. PMID- 20837938 TI - Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the National Heart, Lung, and Blood Institute. PMID- 20837941 TI - Metastatic pancreatic small-cell carcinoma presenting as acute pancreatitis. PMID- 20837940 TI - Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. AB - PURPOSE: Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas. PATIENTS AND METHODS: We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas). RESULTS: Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis. CONCLUSIONS: Single agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases. PMID- 20837942 TI - Evaluation of treatment-effect heterogeneity using biomarkers measured on a continuous scale: subpopulation treatment effect pattern plot. AB - The discovery of biomarkers that predict treatment effectiveness has great potential for improving medical care, particularly in oncology. These biomarkers are increasingly reported on a continuous scale, allowing investigators to explore how treatment efficacy varies as the biomarker values continuously increase, as opposed to using arbitrary categories of expression levels resulting in a loss of information. In the age of biomarkers as continuous predictors (eg, expression level percentage rather than positive v negative), alternatives to such dichotomized analyses are needed. The purpose of this article is to provide an overview of an intuitive statistical approach-the subpopulation treatment effect pattern plot (STEPP)-for evaluating treatment-effect heterogeneity when a biomarker is measured on a continuous scale. STEPP graphically explores the patterns of treatment effect across overlapping intervals of the biomarker values. As an example, STEPP methodology is used to explore patterns of treatment effect for varying levels of the biomarker Ki-67 in the BIG (Breast International Group) 1-98 randomized clinical trial comparing letrozole with tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. STEPP analyses showed patients with higher Ki-67 values who were assigned to receive tamoxifen had the poorest prognosis and may benefit most from letrozole. PMID- 20837945 TI - Perfusion magnetic resonance imaging for parametric response maps in tumors: is it really that easy? PMID- 20837944 TI - A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors. AB - PURPOSE: This open-label, phase I, dose-escalation study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors. PATIENTS AND METHODS: Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m(2)) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts. RESULTS: Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m(2) twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m(2) twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1). CONCLUSION: The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules. PMID- 20837946 TI - Synchronous diagnosis of chronic lymphocytic leukemia and acute myeloid leukemia. PMID- 20837947 TI - Phase I study of vorinostat in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. AB - PURPOSE: Vorinostat is the first US Food and Drug Administration-approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction. PATIENTS AND METHODS: Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography-tandem mass spectrometry assay and modeled noncompartmentally. RESULTS: Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years. CONCLUSION: Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered. PMID- 20837948 TI - Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD 9203/GERCOR phase II study. AB - PURPOSE: The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer. PATIENTS AND METHODS: Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS). RESULTS: Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3-related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%). CONCLUSION: Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial. PMID- 20837949 TI - Prospective analysis of hepatitis B virus reactivation in patients with diffuse large B-cell lymphoma after rituximab combination chemotherapy. AB - PURPOSE: Recently, there have been reports of hepatitis B virus (HBV) reactivation after rituximab combination chemotherapy in hepatitis B surface antigen (HBsAg) -negative patients with B-cell lymphoma. In this prospective study, the frequency of and risk factors for HBV reactivation in patients who were receiving rituximab chemotherapy were examined. PATIENTS AND METHODS: A total of 314 HBsAg-negative patients with diffuse large B-cell lymphoma were treated with rituximab chemotherapy. Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) tests were performed in all patients. In patients who were positive for anti-HBs and/or anti HBc, serum HBV-DNA was measured. RESULTS: Of the 314 patients, 51 (16.2%) were HBV carriers. HBV reactivation occurred during or after rituximab chemotherapy in six patients (12%). All six patients who developed HBV reactivation were anti-HBc positive, and three of them were also anti-HBs positive. In these six patients, the pretreatment anti-HBs titer was low. Entecavir administration was started when serum HBV DNA became positive, and serum HBV-DNA became negative within 1 to 3 weeks. Rituximab chemotherapy was then continued. Risk factors for HBV reactivation were being male and having a low anti-HBs titer. CONCLUSION: HBV reactivation occurred in some patients who had been anti-HBs negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of rituximab chemotherapy, but rituximab chemotherapy could be continued after entecavir administration reduced the serum HBV-DNA level. Entecavir (BMS 200495) prophylaxis was not performed when rituximab chemotherapy was started, and it was thought that entecavir could be started when serum HBV-DNA increased. PMID- 20837950 TI - Place of death: correlations with quality of life of patients with cancer and predictors of bereaved caregivers' mental health. AB - PURPOSE: To determine whether the place of death for patients with cancer is associated with patients' quality of life (QoL) at the end of life (EOL) and psychiatric disorders in bereaved caregivers. PATIENTS AND METHODS: Prospective, longitudinal, multisite study of patients with advanced cancer and their caregivers (n = 342 dyads). Patients were followed from enrollment to death, a median of 4.5 months later. Patients' QoL at the EOL was assessed by caregiver report within 2 weeks of death. Bereaved caregivers' mental health was assessed at baseline and 6 months after loss with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Prolonged Grief Disorder interview. RESULTS: In adjusted analyses, patients with cancer who died in an intensive care unit (ICU) or hospital experienced more physical and emotional distress and worse QoL at the EOL (all P <= .03), compared with patients who died at home with hospice. ICU deaths were associated with a heightened risk for posttraumatic stress disorder, compared with home hospice deaths (21.1% [four of 19] v 4.4% [six of 137]; adjusted odds ratio [AOR], 5.00; 95% CI, 1.26 to 19.91; P = .02), after adjustment for caregivers' preexisting psychiatric illnesses. Similarly, hospital deaths were associated with a heightened risk for prolonged grief disorder (21.6% [eight of 37] v 5.2% [four of 77], AOR, 8.83; 95% CI, 1.51 to 51.77; P = .02), compared with home hospice deaths. CONCLUSION: Patients with cancer who die in a hospital or ICU have worse QoL compared with those who die at home, and their bereaved caregivers are at increased risk for developing psychiatric illness. Interventions aimed at decreasing terminal hospitalizations or increasing hospice utilization may enhance patients' QoL at the EOL and minimize bereavement-related distress. PMID- 20837951 TI - VICTOR spoiled? PMID- 20837953 TI - Association of brain lymphoma and WHO grade II oligodendroglioma in a same immunocompetent patient. PMID- 20837952 TI - Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. AB - PURPOSE: To compare response rates for two schedules of irinotecan with vincristine in patients with rhabdomyosarcoma at first relapse or disease progression. PATIENTS AND METHODS: Patients with first relapse or progression of rhabdomyosarcoma and an unfavorable prognosis were randomly assigned to one of two treatment schedules of irinotecan with vincristine: regimen 1A included irinotecan 20 mg/m(2)/d intravenously for 5 days at weeks 1, 2, 4, and 5 with vincristine 1.5 mg/m(2) administered intravenously on day 1 of weeks 1, 2, 4, and 5; regimen 1B included irinotecan 50 mg/m(2)/d intravenously for 5 days at weeks 1 and 4 with vincristine as in regimen 1A. Disease response was assessed at week 6. Those with responsive disease continued to receive 44 weeks of multiagent chemotherapy that incorporated the assigned irinotecan-vincristine regimen. RESULTS: Ninety-two eligible patients were randomly assigned (1A, 45; 1B, 47). Response could be assessed in 89 patients (1A, 42; 1B, 47). There were five complete responses and six partial responses on regimen 1A (response rate, 26%; 95% CI, 16% to 42%) and 17 partial responses on regimen 1B (response rate, 37%; 95% CI, 25% to 51%; P = .36). Neutropenia was less common on regimen 1A (P = .04). One-year failure-free and overall survival rates for regimen 1A were 37% (95% CI, 23% to 51%) and 55% (95% CI, 39% to 69%), respectively, and for 1B, they were 38% (95% CI, 25% to 53%) and 60% (95% CI, 44% to 72%). CONCLUSION: There was no difference in the response rates between the two irinotecan-vincristine schedules. We recommend the shorter, more convenient regimen (1B) for further investigation. PMID- 20837954 TI - Phase 0 clinical trials in oncology: an exploratory methodology for constructing a study with patients undergoing surgery for metastatic disease. PMID- 20837955 TI - Long-term efficacy of methylphenidate in enhancing attention regulation, social skills, and academic abilities of childhood cancer survivors. AB - PURPOSE: Methylphenidate (MPH) ameliorates attention problems experienced by some cancer survivors in the short term, but its long-term efficacy is unproven. PATIENTS AND METHODS: This study investigates the long-term effectiveness of maintenance doses of MPH in survivors of childhood brain tumors (n = 35) and acute lymphoblastic leukemia (n = 33) participating in a 12-month MPH trial. Measures of attention (Conners' Continuous Performance Test [CPT], Conners' Rating Scales [CRS]), academic abilities (Wechsler Individual Achievement Test [WIAT]), social skills (Social Skills Rating System [SSRS]), and behavioral problems (Child Behavior Checklist [CBCL]) were administered at premedication baseline and at the end of the MPH trial while on medication. A cancer control group composed of patients who were not administered MPH (brain tumor = 31 and acute lymphoblastic leukemia = 23) was assessed on the same measures 12 [corrected] months apart. RESULTS: For the MPH group, repeated measures analysis of variance revealed significant improvement in performance on a measure of sustained attention (CPT indices, P < .05); parent, teacher, and self-report ratings of attention (CRS indices, P < .05), and parent ratings of social skills or behavioral problems (SSRS and CBCL indices; P < .05). In contrast, the cancer control group only showed improvement on parent ratings of attention (Conners' Parent Rating Scale indices; P < .05) and social skills (SSRS and CBCL indices; P < .05). There was no significant improvement on the academic measure (WIAT) in either group. CONCLUSION: Attention and behavioral benefits of MPH for childhood cancer survivors are maintained across settings over the course of a year. Although academic gains were not identified, MPH may offer benefits in academic areas not assessed. PMID- 20837956 TI - Phase III randomized trial assessing rofecoxib in the adjuvant setting of colorectal cancer: final results of the VICTOR trial. AB - PURPOSE: Laboratory and case-control studies suggest a pivotal role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis. The purpose of this study was to test whether the COX-2 inhibitor rofecoxib could reduce recurrence and improve survival when administered in the adjuvant setting of colorectal cancer (CRC). PATIENTS AND METHODS: Patients who had undergone potentially curative surgery and completion of adjuvant therapy for stage II and III CRC were randomly assigned to receive rofecoxib (20 mg daily) or placebo. The primary end point was overall survival (OS). Where formalin-fixed paraffin embedded tumor tissue samples were available, COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome. RESULTS: Two thousand four hundred thirty-four patients were entered onto the study. The trial was terminated early because of the worldwide withdrawal of rofecoxib. At this point, 1,167 patients had received rofecoxib and 1,160 patients had received placebo for median treatment durations of 7.4 and 8.2 months, respectively. For the rofecoxib and placebo arms, median follow-up times were 4.84 and 4.85 years, with 241 and 246 deaths and 297 and 329 recurrences, respectively. No difference was demonstrated in OS (hazard ratio [HR] = 0.97; 95% CI, 0.81 to 1.16; P = .75) or recurrence (HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) comparing the two groups. Tumor COX-2 expression by immunohistochemistry was assessed for 871 patients, but neither prognostic nor predictive effects were observed. CONCLUSION: In this study of abbreviated therapy in the adjuvant setting of CRC, rofecoxib did not improve OS or protect from recurrence in unselected patients. In addition, COX-2 expression did not correlate with prognosis overall or predict effectiveness of COX-2 inhibitors. PMID- 20837958 TI - Teaching NeuroImages: malignant cerebral venous thrombosis and pulmonary emboli. PMID- 20837957 TI - Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. AB - PURPOSE: To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. PATIENTS AND METHODS: Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. RESULTS: Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no chemotherapy group. CONCLUSION: These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen. PMID- 20837959 TI - Teaching video neuroimages: the elusive L5 reflex. PMID- 20837961 TI - Is migraine a mirror of the vessel wall? PMID- 20837962 TI - Dying young: eliminating racial disparities in neuromuscular disease outcomes. PMID- 20837963 TI - Aortic stiffness and pulse wave reflection in young subjects with migraine: A case-control study. AB - BACKGROUND: Migraine has been associated with an increased risk for ischemic stroke and other cardiovascular (CV) events, including angina, myocardial infarction, and CV death, but the mechanisms that link migraine to CV disease remain uncertain. We hypothesized that aortic pulse wave velocity (PWV), a direct measure of aortic stiffness and an independent predictor of stroke and CV disease, may be increased in young migraineurs with no overt CV disease or major CV risk factors. METHODS: We studied 60 subjects with migraine (age 33 +/- 8 years, 85% women, blood pressure 119/74 +/- 11/9 mm Hg) and 60 age-, sex-, and blood pressure-matched healthy control subjects. In all participants, carotid femoral PWV and aortic augmentation index were determined by applanation tonometry. Cases and controls were free from overt CV disease, diabetes, and major CV risk factors. RESULTS: Subjects with migraine had a higher aortic PWV (7.6 +/- 1.2 vs 6.4 +/- 1.1 m * s(-1), p < 0.001) and aortic augmentation (heart rate-adjusted augmentation index, 0.17 +/- 0.13 vs 0.08 +/- 0.15, p < 0.001) than matched control subjects. Migraine patients with aura (n = 17) had higher aortic PWV than those without aura (n = 43; 8.2 +/- 1.2 vs 7.4 +/- 1.1 m * s(-1), p = 0.027). Age, mean arterial pressure as a measure of distending pressure, and migraine (all p < 0.05) independently predicted aortic PWV when a consistent number of CV risk factors was simultaneously controlled for. CONCLUSIONS: Migraine is independently associated with increased aortic stiffness and enhanced pressure wave reflection. This finding, obtained in young subjects without major CV risk factors, may represent one possible mechanism underlying the increased CV risk in migraine patients. PMID- 20837964 TI - De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. AB - OBJECTIVE: Hemiplegic migraine (HM) is a rare subtype of migraine with aura that may occur as a familial (FHM) or sporadic condition (SHM). Screening of FHM genes in previous series of patients with SHM detected a very low proportion of mutated patients. In this study, we investigated the FHM genes in patients with an early onset sporadic form of HM (onset before 16 years). METHODS: Twenty-five patients were included. Each one and his or her 2 parents were blood sampled. Mean age at diagnosis was 14.7 +/- 8.2 years and mean age at clinical onset was 7.7 +/- 3.4 years. Sequencing of ATP1A2 and CACNA1A was conducted in each proband and all identified variants were looked for in both parents. SCN1A was screened in all patients without CACNA1A or ATP1A2 de novo mutation. RESULTS: Twenty-three different amino acid variants were identified in 23 of the 25 patients. The variants occurred de novo in 19 patients (76%), strongly in favor of their causal role. SCN1A analysis did not show any mutation. Among the 19 patients with a de novo mutation, 5 had a pure HM and 14 had associated neurologic signs such as ataxia, epilepsy, or intellectual disabilities. CONCLUSIONS: FHM genes are involved in early-onset SHM, in particular when associated with neurologic signs. Molecular analysis can be helpful in those cases. Our study identified 14 novel de novo mutations that will help to interpret genetic tests in molecular diagnosis practice. PMID- 20837965 TI - Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy? AB - BACKGROUND: Autonomic neuropathy is a frequent diagnosis for the gastrointestinal symptoms or postural hypotension experienced by patients with longstanding diabetes. However, neuropathologic evidence to substantiate the diagnosis is limited. We hypothesized that quantification of nerves in gastric mucosa would confirm the presence of autonomic neuropathy. METHODS: Mucosal biopsies from the stomach antrum and fundus were obtained during endoscopy from 15 healthy controls and 13 type 1 diabetic candidates for pancreas transplantation who had secondary diabetic complications affecting the eyes, kidneys, and nerves, including a diagnosis of gastroparesis. Neurologic status was evaluated by neurologic examination, nerve conduction studies, and skin biopsy. Biopsies were processed to quantify gastric mucosal nerves and epidermal nerves. RESULTS: Gastric mucosal nerves from diabetic subjects had reduced density and abnormal morphology compared to control subjects (p < 0.05). The horizontal and vertical meshwork pattern of nerve fibers that normally extends from the base of gastric glands to the basal lamina underlying the epithelial surface was deficient in diabetic subjects. Eleven of the 13 diabetic patients had residual food in the stomach after overnight fasting. Neurologic abnormalities on clinical examination were found in 12 of 13 diabetic subjects and nerve conduction studies were abnormal in all patients. The epidermal nerve fiber density was deficient in skin biopsies from diabetic subjects. CONCLUSIONS: In this observational study, gastric mucosal nerves were abnormal in patients with type 1 diabetes with secondary complications and clinical evidence of gastroparesis. Gastric mucosal biopsy is a safe, practical method for histologic diagnosis of gastric autonomic neuropathy. PMID- 20837966 TI - Widening gap in age at muscular dystrophy-associated death between blacks and whites, 1986-2005. AB - BACKGROUND: Muscular dystrophies (MDs), characterized by progressive muscle wasting, are associated with 1 in 2,500 deaths in the United States. Although treatments slow the progression, these disorders lead to early death, usually due to cardiac or respiratory failure. METHODS: We analyzed death record data from 18,315 MD-associated deaths that occurred in the United States in 1986 through 2005 to assess trends in the age at death of people with MDs. RESULTS: From 1986 through 2005, the MD-associated mortality rate did not change among blacks, whites, males, or females. The median age at death among white females with MDs was 12 years higher than among black females. The frequency of reported cardiomyopathy increased among white but not black male decedents with MDs, although cardiomyopathy remained more commonly reported among black males. Among white males, the median age at death increased by 0.2 annually for those with and 1.3 for those without indications of cardiomyopathy. Among black males, the median age at death increased 0.3 years annually among those without reported cardiomyopathy. Among white males, the frequencies of pulmonary failure and pulmonary infection decreased significantly over time. CONCLUSIONS: Changes in age at death and reported clinical comorbidities reflect improvements in the treatment of MDs. White males with MDs have shown a greater increase in age at death over time than black males. Contributing factors to this difference might include differences in types of MDs, rates of genetic and environmental modifiers, natural history, socioeconomic factors, and access to and use of treatment options. PMID- 20837967 TI - Progression of brain atrophy and cognitive decline in diabetes mellitus: a 3-year follow-up. AB - OBJECTIVE: To investigate progression of MRI-assessed manifestations of cerebral degeneration related to cognitive changes in a population of elderly patients with diabetes mellitus (DM) compared to age-matched control subjects. METHODS: From a randomized controlled trial (PROSPER study), a study sample of 89 patients with DM and 438 control subjects without DM aged 70-82 years were included for brain MRI scanning and cognitive function testing at baseline and reexamination after 3 years. Changes in brain atrophy, white matter hyperintensities (WMHs), number of infarctions, and cognitive function test results were determined in patients with DM and subjects without DM. Linear regression analysis was performed with correction for age, gender, hypertension, pravastatin treatment, educational level, and baseline test results. In patients with DM, baseline MRI parameters were correlated with change in cognitive function test result using linear regression analysis with covariates age and gender. RESULTS: Patients with DM showed increased progression of brain atrophy (p < 0.01) after follow-up compared to control subjects. No difference in progression of WMH volume or infarctions was found. Patients with DM showed increased decline in cognitive performance on Stroop Test (p = 0.04) and Picture Learning Test (p = 0.03). Furthermore, in patients with DM, change in Picture Learning Test was associated with baseline brain atrophy (p < 0.02). CONCLUSION: Our data show that elderly patients with DM without dementia have accelerated progression of brain atrophy with significant consequences in cognition compared to subjects without DM. Our findings add further evidence to the hypothesis that diabetes exerts deleterious effects on neuronal integrity. PMID- 20837968 TI - Sensory ganglionopathy due to gluten sensitivity. AB - OBJECTIVES: Gluten sensitivity can engender neurologic dysfunction, one of the two commonest presentations being peripheral neuropathy. The commonest type of neuropathy seen in the context of gluten sensitivity is sensorimotor axonal. We report 17 patients with sensory ganglionopathy associated with gluten sensitivity. METHODS: This is a retrospective observational case series of 17 patients with sensory ganglionopathy and gluten sensitivity. All patients had been followed up for a number of years in dedicated gluten sensitivity/neurology and neuropathy clinics. RESULTS: Out of a total of 409 patients with different types of peripheral neuropathies, 53 (13%) had clinical and neurophysiologic evidence of sensory ganglionopathy. Out of these 53 patients, 17 (32%) had serologic evidence of gluten sensitivity. The mean age of those with gluten sensitivity was 67 years and the mean age at onset was 58 years. Seven of those with serologic evidence of gluten sensitivity had enteropathy on biopsy. Fifteen patients went on a gluten-free diet, resulting in stabilization of the neuropathy in 11. The remaining 4 had poor adherence to the diet and progressed, as did the 2 patients who did not opt for dietary treatment. Autopsy tissue from 3 patients demonstrated inflammation in the dorsal root ganglia with degeneration of the posterior columns of the spinal cord. CONCLUSIONS: Sensory ganglionopathy can be a manifestation of gluten sensitivity and may respond to a strict gluten-free diet. PMID- 20837970 TI - Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients. AB - OBJECTIVES: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. METHODS: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. RESULTS: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). CONCLUSIONS: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype. PMID- 20837969 TI - Genomic biomarkers and cellular pathways of ischemic stroke by RNA gene expression profiling. AB - OBJECTIVE: The objective of this study was to provide insight into the molecular mechanisms of acute ischemic cerebrovascular syndrome (AICS) through gene expression profiling and pathway analysis. METHODS: Peripheral whole blood samples were collected from 39 MRI-diagnosed patients with AICS and 25 nonstroke control subjects >= 18 years of age. Total RNA was extracted from whole blood stabilized in Paxgene RNA tubes, amplified, and hybridized to Illumina HumanRef 8v2 bead chips. Gene expression was compared in a univariate manner between stroke patients and control subjects using t test in GeneSpring. The significant genes were tested in a logistic regression model controlling for age, hypertension, and dyslipidemia. Inflation of type 1 error was corrected by Bonferroni and Ingenuity Systems Pathway analysis was performed. Validation was performed by QRT-PCR using Taqman gene expression assays. RESULTS: A 9-gene profile was identified in the whole blood of ischemic stroke patients using gene expression profiling. Five of these 9 genes were identified in a previously published expression profiling study of stroke and are therefore likely biomarkers of stroke. Pathway analysis revealed toll-like receptor signaling as a highly significant canonical pathway present in the peripheral whole blood of patients with AICS. CONCLUSIONS: Our study highlights the relevance of the innate immune system through toll-like receptor signaling as a mediator of response to ischemic stroke and supports the claim that gene expression profiling can be used to identify biomarkers of ischemic stroke. Further studies are needed to validate and refine these biomarkers for their diagnostic potential. PMID- 20837971 TI - Glucose metabolism in progressive nonfluent aphasia with and without parkinsonism. PMID- 20837973 TI - Symptomatic left intradiploic encephalocele. PMID- 20837974 TI - Cognitive impairment and dementia in neurocysticercosis: a cross-sectional controlled study. PMID- 20837975 TI - Nasal turbinate enlargement due to cartilage and bone proliferation: a normal developmental finding in young ferrets. AB - Toxicity studies of intranasally administered, live attenuated influenza virus vaccine candidates conducted in male and female ferrets led to the microscopic observation of individual differences in the size of nasal turbinates, especially in the dorsal aspect of the nasal cavity. The association of these enlarged turbinates with acute to subacute inflammation, which is sometimes common in ferrets given live attenuated influenza virus vaccine candidates, led to this detailed microscopic evaluation of turbinate enlargement (cartilaginous and osseous thickening, or COT) in control animals dosed intranasally with saline. Results of this evaluation led to the conclusion that COT is a normal developmental feature of growing ferrets, irrespective of inflammation in nasal tissues or inflammatory exudate in the nasal cavity. PMID- 20837976 TI - Exploring language profiles for children with ADHD and children with asperger syndrome. AB - OBJECTIVE: The aims of the present study was to investigate communication impairments in a Norwegian sample of children with ADHD and children with Asperger syndrome (AS) and to explore whether children with ADHD can be differentiated from children with AS in terms of their language profiles on the Norwegian adaptation of the Children's Communication Checklist Second Edition (CCC-2). METHOD: The CCC-2 was completed by the parents, and altogether, 77 children aged between 6 and 15 years participated in the study. RESULTS: Communication impairments were as common in a group of children with ADHD as in a group of children with AS. Although a similar pattern appeared on most CCC-2 scales, children with ADHD and children with AS could be distinguished from each other in terms of their language profiles on the subscales assessing stereotyped language and nonverbal communication. CONCLUSION: Language abilities should be taken into account when standard assessments of ADHD and AS are performed and before therapies are initiated. PMID- 20837977 TI - Parental functioning in families of children with ADHD: evidence for behavioral parent training and importance of clinically meaningful change. AB - OBJECTIVE/METHOD: Statistically significant and clinically meaningful effects of behavioral parent training on parental functioning were examined for 20 children with ADHD and their parents who had successfully completed a psychosocial treatment for ADHD. RESULTS/CONCLUSION: Findings suggest that behavioral parent training resulted in statistically significant improvements in some domains of parenting behavior for both mothers and fathers and in reductions in most domains of parenting stress for mothers. Importantly, clinically meaningful change also was noted for these parental functioning areas, as well as for other domains of parental functioning that did not result in statistically significant findings. Clinical implications are discussed. PMID- 20837978 TI - A physical activity program improves behavior and cognitive functions in children with ADHD: an exploratory study. AB - OBJECTIVE: The objective of this study is to explore the effects of a moderate- to high-intensity physical activity program on fitness, cognitive functions, and ADHD-related behavior in children with ADHD. METHOD: Fitness level, motor skills, behaviors, and cognitive functions are assessed by standardized tests before and after a 10-week training or control period. RESULTS: Findings show that participation in a physical activity program improves muscular capacities, motor skills, behavior reports by parents and teachers, and level of information processing. CONCLUSION: A structured physical activity program may have clinical relevance in the functional adaptation of children with ADHD. This supports the need for further research in the area of physical activity with this population. PMID- 20837979 TI - Exploring the gender gap in referrals for children with ADHD and other disruptive behavior disorders. AB - OBJECTIVE: The current study examined the impact of the gender of children with ADHD on teachers' perceptions toward inattentive, hyperactive, or oppositional behaviors, and how these perceptions relate to teachers' ratings of children's impairment and referral recommendations. METHOD: Teachers read eight vignettes depicting boys and girls with different subtypes of ADHD, as well as one depicting comorbidity (ADHD + ODD). Teachers then completed measures of impairment, and responded to questions about what services they would likely refer for the child and why. RESULTS: Teachers rated girls as being significantly more impaired and more in need of services than boys. Regardless of gender, teachers overwhelmingly reported preferring the use of behavior modification for the described child. Also, children who were described with symptoms of ADHD predominately inattentive subtype were rated as being the least impaired, while girls described as hyperactive and impulsive were rated by teachers as being the most impaired. CONCLUSION: The current study adds to previous literature on gender bias in ADHD referrals by providing evidence for the differential referral of ADHD boys and girls to treatment based on presentation of symptoms. PMID- 20837980 TI - Relationships between learning disability, executive function, and psychopathology in children with ADHD. AB - OBJECTIVE: Learning disabilities (LD), executive function (EF), and psychopathology were investigated to clarify their relationships in 595 children with ADHD. METHOD: Standard instruments for IQ, achievement, EF, and parent and teacher ratings of psychopathology were obtained at the time of outpatient evaluation. RESULTS: Comparisons between the 437 children with LD (as defined by predicted achievement) and the 158 children without LD showed significantly worse EF in the LD group but no significant differences in verbal or performance IQ. Parent and teacher ratings of both ADHD and non-ADHD psychopathology also showed no significant differences between LD and No LD groups. Correlational analyses found that IQ, EF, and achievement measures were significantly related to each other; the same was also true for subscales of psychopathology as rated by parent and teachers. However, significant correlations between the cognitive/achievement measures and the psychopathology ratings were few. CONCLUSION: The addition of LD to ADHD appears to be associated with worse executive dysfunction, but it does not affect ADHD or non-ADHD psychopathology according to both parents and teachers. PMID- 20837981 TI - Core ADHD symptom improvement with atomoxetine versus methylphenidate: a direct comparison meta-analysis. AB - OBJECTIVE: Previous studies comparing atomoxetine and methylphenidate to treat ADHD symptoms have been equivocal. This noninferiority meta-analysis compared core ADHD symptom response between atomoxetine and methylphenidate in children and adolescents. METHOD: Selection criteria included randomized, controlled design; duration 6 weeks; and assessment of ADHD Rating Scale-IV-Parent Version: Investigator Administered and Scored (ADHDRS) scores. Six-week response rates, defined as >=40% reduction in ADHDRS total score, were compared using a noninferiority margin of -15%. RESULTS: Seven studies met inclusion criteria (N = 1,368). After 6 weeks, 53.6% (95% confidence interval [CI] 48.6%-58.4%) of atomoxetine-treated patients (n = 811) had responded compared with 54.4% (47.6% 61.1%) for methylphenidate (n = 557), with atomoxetine demonstrating noninferiority to methylphenidate (absolute difference -0.9%, 95% CI -9.2%-7.5%). CONCLUSION: After 6 weeks of treatment atomoxetine and methylphenidate had comparable efficacy in reducing core ADHD symptoms in children and adolescents. PMID- 20837982 TI - Self-reported inattention in early adolescence in a community sample. AB - OBJECTIVE: Inattention is typically associated with ADHD, but less research has been done to examine the correlates of self-reported inattention in youth in a community sample. METHOD: Associations among self-reported inattention, parent reported inattention, and self-reported psychopathology in children aged 10 to 11 years are examined. Self-reported inattention is also examined as a predictor of outcomes in peer relationships and victimization at ages 10 and 11 and in peer relationships at ages 14 and 15. RESULTS: Children's self-reports of inattention correlate with parental reports and are associated with self-reports of hyperactivity-impulsivity, depression, anxiety, and conduct problems. Participants in the high-inattention group are at greater risk for victimization and poor peer relationships at ages 10 and 11 years after covarying for psychopathology ratings. Self-reported inattention uniquely predicts poor peer relationships longitudinally at age 14 and 15 years. CONCLUSION: This study highlights the importance of examining children's self-report of inattention and identifies inattention as a risk factor for current and later outcomes. PMID- 20837983 TI - Understanding the effect size of lisdexamfetamine dimesylate for treating ADHD in children and adults. AB - OBJECTIVE: An earlier meta-analysis of pediatric clinical trials indicated that lisdexamfetamine dimesylate (LDX) had a greater effect size than other stimulant medications. This work tested the hypothesis that the apparent increased efficacy was artifactual. METHOD: The authors assessed two potential artifacts: an unusually high precision of measurement and an unusually low placebo effect. The authors evaluated generalizability from children of adults. RESULTS: The LDX effect sizes for children were significantly larger than the pooled stimulant effect sizes from studies using the same outcome measures. However, although no other individual stimulant study had an effect size greater than LDX, there was overlap between the 95% confidence intervals for some of these studies and the LDX study. The high LDX effect sizes were not due measurement or placebo effect artifacts. LDX effect sizes for adults were not larger than the stimulant effect sizes from other studies. CONCLUSION: The high LDX effect size for children could not attributed to measurement artifacts. The superiority of LDX in the pediatric clinical trial reflected the greater efficacy of amphetamine products, compared with methylphenidate products but required replication in children because (a) the results were based on only one trial of LDX in children, and (b) the finding did not generalize to adults. PMID- 20837984 TI - Are maternal genitourinary infection and pre-eclampsia associated with ADHD in school-aged children? AB - OBJECTIVE: To investigate the hypothesis that maternal genitourinary infection (GU) infection is associated with increased risk of ADHD. METHOD: The authors obtained linked Medicaid billing data for pregnant women and their children in South Carolina, with births from 1996 through 2002 and follow-up data through 2008. Maternal GU infections and pre-eclampsia were identified on the basis of diagnoses made during pregnancy, and cases of ADHD were identified on the basis of diagnoses made in the child's Medicaid file. RESULTS: There were 84,721 children in the data set used for analyses. Maternal genitourinary infection was associated with significantly increased odds of ADHD (OR = 1.29, 95% CI = 1.23 1.35). Pre-eclampsia was also associated with increased risk (OR = 1.19, 95% CI = 1.07-1.32). Children whose mothers had both GU infection and pre-eclampsia were 53% more likely to have ADHD, compared to those with neither exposure. When we examined specific infection diagnoses, chlamydia/nongonococcal urethritis, trichomoniasis, urinary tract infection, and candidiasis were associated with increased risk of ADHD, whereas gonorrhea was not. DISCUSSION: Maternal GU infection appeared to be associated with increased risk of ADHD, and based on the findings it was concluded that further research is needed to describe the mechanism(s) underlying the association. PMID- 20837985 TI - Teacher management practices for first graders with attention problems. AB - OBJECTIVE: To examine whether teacher reports of accommodations and interventions for inattentive first graders are consistent with best practice guidelines. METHOD: A total of 36 teachers completed the Teacher Management Questionnaire (TMQ) for 92 students in five predominantly low-income, minority schools. The TMQ is a newly developed measure designed to assess the frequency with which teachers implement a variety of accommodations and interventions with individual students. Additional teacher and student background data were collected on the inattentive sample, including behavior ratings and academic testing. RESULTS: Teachers reported variable implementation of different management strategies, with more frequent use of class-wide structure and organizational interventions, and less frequent assignment modifications and individual behavior plans. Greater use of some strategies was reported for inattentive students and those with additional risk characteristics such as oppositional behavior and school-based referrals. CONCLUSION: Teachers appear to differentiate some management strategies based on the presence of attention problems, although their self-reported implementation is not well aligned with best practice guidelines. PMID- 20837986 TI - Predictors of postural stability in children with ADHD. AB - OBJECTIVE: As children with ADHD who have more inattention problems are more frequently with fine motor problems, it is not clear whether postural balance problems are associated with different subtypes of ADHD. This study investigates the predictors of postural stability in children with ADHD considering the covariant factors of age, gender, and comorbidities. METHOD: A total of 103 children with ADHD are studied using Poor Postural Stability Questionnaire filled out by their parents. RESULTS: Linear regression analysis indicates that only oppositional-defiant behavior score is the predictor of seeking-movement subscale score. ADHD type does not predict the score of avoiding-postural-instability subscale, whereas separation anxiety score did so. CONCLUSION: ADHD subtypes do not have distinct clinical profiles of the balance problems. Postural stability in children with ADHD depends on the comorbid psychiatric disorders rather than ADHD subtypes. PMID- 20837987 TI - Test-retest reliability of two patient-report measures for use in adults with ADHD. AB - AIMS: Childhood attention-deficit/hyperactivity disorder (ADHD) frequently persists into adulthood and continues to impair health-related quality of life (HRQL). Thus, it is important to have validated symptom and HRQL measures for assessing treatment outcomes in this population. The purpose of the current analysis was to assess test-retest reliability of two measures designed specifically for adults with ADHD: the Adult ADHD Self-Report Screener (ASRS) and the Adult ADHD Quality of Life Measure (AAQoL). METHODS: Data were collected at a US clinic specializing in the treatment of adult ADHD. Patients completed the ASRS (six-item ADHD symptom screening version) and the AAQoL (a 29-item condition specific HRQL measure) at two visits, two weeks apart. At the second visit, patients also completed a measure of symptom stability so that test-retest reliability could be examined in the stable population. Test-retest reliability was examined through intraclass correlations (ICC) and t-tests comparing scores from the two visits. RESULTS: A total of 74 participants were enrolled (62.2% male; mean age = 38.6 years), and 43 of these participants attended both visits and were stable between visits (65.1% male; mean age = 39.3 years). The ICC assessing the association between Visit 1 and Visit 2 ASRS scores was 0.86, and the ICCs for the AAQoL subscales were 0.88 (Life Productivity), 0.75 (Psychological Health), 0.74 (Life Outlook), 0.78 (Relationships), and 0.86 (total score). The t-tests found no statistically significant differences between Visit 1 and Visit 2 scores for the ASRS or AAQoL. CONCLUSIONS: The ASRS and AAQoL demonstrated good test-retest reliability. Findings add to previous results suggesting that these instruments are useful outcome measures for treatments of ADHD in adults. PMID- 20837988 TI - ADHD and bipolar disorder: common causes common cure? PMID- 20837989 TI - Naturally occurring variants of human aldo-keto reductases with reduced in vitro metabolism of daunorubicin and doxorubicin. AB - Doxorubicin (DOX) and daunorubicin (DAUN) are effective anticancer drugs; however, considerable interpatient variability exists in their pharmacokinetics. This may be caused by altered metabolism by nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in genes encoding aldo-keto reductases (AKRs) and carbonyl reductases. This study examined the effect of 27 ns-SNPs, in eight human genes, on the in vitro metabolism of both drugs to their major metabolites, doxorubicinol and daunorubicinol. Kinetic assays measured metabolite levels by high-performance liquid chromatography separation with fluorescence detection using purified, histidine-tagged, human wild-type, and variant enzymes. Maximal rate of activity (V(max)), substrate affinity (K(m)), turnover rate (k(cat)), and catalytic efficiency (k(cat)/K(m)) were determined. With DAUN as substrate, variants for three genes exhibited significant differences in these parameters compared with their wild-type counterparts: the A106T, R170C, and P180S variants significantly reduced metabolism compared with the AKR1C3 wild-type (V(max), 23 47% decrease; k(cat), 22-47%; k(cat)/K(m), 38-44%); the L311V variant of AKR1C4 significantly decreased V(max) (47% lower) and k(cat) and k(cat)/K(m) (both 43% lower); and the A142T variant of AKR7A2 significantly affected all kinetic parameters (V(max) and k(cat), 61% decrease; K(m), 156% increase; k(cat)/K(m), 85% decrease). With DOX, the R170C and P180S variants of AKR1C3 showed significantly reduced V(max) (41-44% decrease), k(cat) (39-45%), and k(cat)/K(m) (52-69%), whereas the A142T variant significantly altered all kinetic parameters for AKR7A2 (V(max), 41% decrease; k(cat), 44% decrease; K(m), 47% increase; k(cat)/K(m), 60% decrease). These findings suggest that ns-SNPs in human AKR1C3, AKR1C4, and AKR7A2 significantly decrease the in vitro metabolism of DOX and DAUN. PMID- 20837990 TI - Dexmedetomidine induces both relaxations and contractions, via different {alpha}2 adrenoceptor subtypes, in the isolated mesenteric artery and aorta of the rat. AB - Dexmedetomidine is an alpha(2)-adrenoceptor agonist and anesthetic. The present study was designed to characterize the receptor subtypes and the downstream mechanisms of the vascular effects of dexmedetomidine in small (mesenteric artery) and large (aorta) arteries ex vivo. Isometric tension was measured in Sprague-Dawley rat mesenteric and aortic rings (with or without endothelium). To study relaxations, cumulative concentrations of dexmedetomidine, 5-bromo-N-(2 imidazolin-2-yl)-6-quinoxalinamine, (UK14304), or clonidine were added to rings contracted with 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha) (U46619) in the presence or absence of indomethacin; N(omega)-nitro-l-arginine methyl ester hydrochloride (l-NAME); 2-[2H-(1-methyl-1,3-dihydroisoindole)methyl] 4,5-dihydroimidazole maleate (BRL44408); 2-[2-(4-(2-methoxyphenyl)piperazin-1 yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239); l 657,743, (2S-trans)-1,3,4,5',6,6',7,12b-octahydro-1',3'-dimethyl-spiro[2H benzofuro[2,3-a]quinolizine-2,4'(1'H)-pyrimidin]-2'(3'H)-one hydrochloride hydrate (MK912); rauwolscine; prazosin; or pertussis toxin. To study contractions, dexmedetomidine was added to quiescent rings without endothelium or after incubation with l-NAME, rauwolscine, prazosin, indomethacin, or 3-[(6-amino (4-chlorobenzensulfonyl)-2-methyl-5,6,7,8-tetrahydronaphth)-1-yl]propionic acid (S18886). Dexmedetomidine evoked relaxation at low concentrations (10 pM-30 nM) followed by contraction at higher concentrations (>30 nM) in the mesenteric artery. In the aorta, the relaxation was significantly smaller. The relaxation to dexmedetomidine depended on nitric oxide, endothelium, and G(i) protein, and it was mediated by alpha(2A/D)-adrenoceptors and possibly alpha(2B)-adrenoceptors. The contraction was mediated mainly by alpha(2B)- and alpha(1)-adrenoceptors and involved the action of prostanoids. UK14304 and clonidine induced greater and smaller relaxations, respectively, than dexmedetomidine. In conclusion, depending on the concentration used and the presence of functional endothelium, dexmedetomidine may evoke both relaxation and contraction in isolated arteries. The vascular effects also vary depending on the blood vessel studied. Its vascular effect is different from that of clonidine and UK14304. PMID- 20837991 TI - Seizure protection by intrapulmonary delivery of propofol hemisuccinate. AB - The lung provides a portal of entry for drug delivery that could be used to administer anticonvulsant substances to prevent or abort seizures. Here, we demonstrate that intrapulmonary propofol hemisuccinate (PHS) rapidly confers seizure protection in various rodent chemoconvulsant models. Propofol is a powerful anticonvulsant substance at subanesthetic doses, but it is a viscous, water-immiscible oil that is not suitable for intrapulmonary administration. We found that PHS can be formulated as an aqueous solution that is well tolerated when instilled into the lung. High-dose intraperitoneally administered PHS induced loss-of-righting reflex in rats and mice. The onset of action of PHS was delayed in comparison with propofol, suggesting that conversion to propofol is required for activity. A lower dose of PHS (40 mg/kg i.p.) did not cause general anesthesia but protected against pentylenetetrazol (PTZ)-induced seizures in rats. Intrapulmonary administration of an aqueous PHS solution via a tracheal cannula at lower doses (5 and 10 mg/kg) conferred equivalent seizure protection without acute motor toxicity. In mice, intraperitoneal PHS (60-80 mg/kg) was associated with an elevation in PTZ, bicuculline, picrotoxin, and kainic acid seizure thresholds. Intratracheal PHS was markedly more potent, producing seizure threshold elevations at doses of 10 to 15 mg/kg. In the PTZ threshold model in mice, PHS was active at 5 min, maximally active at 10 min, and no longer active at 20 min. Intratracheal PHS also prolonged the onset of 4-aminopyridine-induced convulsions but did not affect the threshold for N-methyl-D-aspartate-induced convulsions. We conclude that intratracheal administration of an aqueous solution of PHS, a putative propofol prodrug, provides potent seizure protection of rapid onset and brief duration. Intrapulmonary PHS may be useful for preventing the spread of seizures or aborting seizure clusters without causing prolonged sedation. PMID- 20837993 TI - Profiling sex-specific piRNAs in zebrafish. AB - Piwi proteins and their partner small RNAs play an essential role in fertility, germ-line stem cell development, and the basic control and evolution of animal genomes. However, little knowledge exists regarding piRNA biogenesis. Utilizing microfluidic chip analysis, we present a quantitative profile of zebrafish piRNAs expressed differentially between testis and ovary. The sex-specific piRNAs are derived from separate loci of repeat elements in the genome. Ovarian piRNAs can be categorized into groups that reach up to 92 members, indicating a sex-specific arrangement of piRNA genes in the genome. Furthermore, precursor piRNAs preferentially form a hairpin structure at the 3'end, which seem to favor the generation of mature sex-specific piRNAs. In addition, the mature piRNAs from both the testis and the ovary are 2'-O-methylated at their 3' ends. PMID- 20837992 TI - The role of replication bypass pathways in dicentric chromosome formation in budding yeast. AB - Gross chromosomal rearrangements (GCRs) are large scale changes to chromosome structure and can lead to human disease. We previously showed in Saccharomyces cerevisiae that nearby inverted repeat sequences (~20-200 bp of homology, separated by ~1-5 kb) frequently fuse to form unstable dicentric and acentric chromosomes. Here we analyzed inverted repeat fusion in mutants of three sets of genes. First, we show that genes in the error-free postreplication repair (PRR) pathway prevent fusion of inverted repeats, while genes in the translesion branch have no detectable role. Second, we found that siz1 mutants, which are defective for Srs2 recruitment to replication forks, and srs2 mutants had opposite effects on instability. This may reflect separate roles for Srs2 in different phases of the cell cycle. Third, we provide evidence for a faulty template switch model by studying mutants of DNA polymerases; defects in DNA pol delta (lagging strand polymerase) and Mgs1 (a pol delta interacting protein) lead to a defect in fusion events as well as allelic recombination. Pol delta and Mgs1 may collaborate either in strand annealing and/or DNA replication involved in fusion and allelic recombination events. Fourth, by studying genes implicated in suppression of GCRs in other studies, we found that inverted repeat fusion has a profile of genetic regulation distinct from these other major forms of GCR formation. PMID- 20837994 TI - Telomerase recruitment in Saccharomyces cerevisiae is not dependent on Tel1 mediated phosphorylation of Cdc13. AB - In Saccharomyces cerevisiae, association between the Est1 telomerase subunit and the telomere-binding protein Cdc13 is essential for telomerase to be recruited to its site of action. A current model proposes that Tel1 binding to telomeres marks them for elongation, as the result of phosphorylation of a proposed S/TQ cluster in the telomerase recruitment domain of Cdc13. However, three observations presented here argue against one key aspect of this model. First, the pattern of Cdc13 phosphatase-sensitive isoforms is not altered by loss of Tel1 function or by mutations introduced into two conserved serines (S249 and S255) in the Cdc13 recruitment domain. Second, an interaction between Cdc13 and Est1, as monitored by a two-hybrid assay, is dependent on S255 but Tel1-independent. Finally, a derivative of Cdc13, cdc13-(S/TQ)11->(S/TA)11, in which every potential consensus phosphorylation site for Tel1 has been eliminated, confers nearly wild-type telomere length. These results are inconsistent with a model in which the Cdc13 Est1 interaction is regulated by Tel1-mediated phosphorylation of the Cdc13 telomerase recruitment domain. We propose an alternative model for the role of Tel1 in telomere homeostasis, which is based on the assumption that Tel1 performs the same molecular task at double-strand breaks (DSBs) and chromosome termini. PMID- 20837995 TI - Evolution of the Drosophila feminizing switch gene Sex-lethal. AB - In Drosophila melanogaster, the gene Sex-lethal (Sxl) controls all aspects of female development. Since melanogaster males lacking Sxl appear wild type, Sxl would seem to be functionally female specific. Nevertheless, in insects as diverse as honeybees and houseflies, Sxl seems not to determine sex or to be functionally female specific. Here we describe three lines of work that address the questions of how, when, and even whether the ancestor of melanogaster Sxl ever shed its non-female-specific functions. First, to test the hypothesis that the birth of Sxl's closest paralog allowed Sxl to lose essential ancestral non female-specific functions, we determined the CG3056 null phenotype. That phenotype failed to support this hypothesis. Second, to define when Sxl might have lost ancestral non-female-specific functions, we isolated and characterized Sxl mutations in D. virilis, a species distant from melanogaster and notable for the large amount of Sxl protein expression in males. We found no change in Sxl regulation or functioning in the 40+ MY since these two species diverged. Finally, we discovered conserved non-sex-specific Sxl mRNAs containing a previously unknown, potentially translation-initiating exon, and we identified a conserved open reading frame starting in Sxl male-specific exon 3. We conclude that Drosophila Sxl may appear functionally female specific not because it lost non-female-specific functions, but because those functions are nonessential in the laboratory. The potential evolutionary relevance of these nonessential functions is discussed. PMID- 20837996 TI - Floral genetic architecture: an examination of QTL architecture underlying floral (co)variation across environments. AB - Genetic correlations are expected to be high among functionally related traits and lower between groups of traits with distinct functions (e.g., reproductive vs. resource-acquisition traits). Here, we explore the quantitative-genetic and QTL architecture of floral organ sizes, vegetative traits, and life history in a set of Brassica rapa recombinant inbred lines within and across field and greenhouse environments. Floral organ lengths were strongly positively correlated within both environments, and analysis of standardized G-matrices indicates that the structure of genetic correlations is ~80% conserved across environments. Consistent with these correlations, we detected a total of 19 and 21 additive effect floral QTL in the field and the greenhouse, respectively, and individual QTL typically affected multiple organ types. Interestingly, QTL*QTL epistasis also appeared to contribute to observed genetic correlations; i.e., interactions between two QTL had similar effects on filament length and two estimates of petal size. Although floral and nonfloral traits are hypothesized to be genetically decoupled, correlations between floral organ size and both vegetative and life history traits were highly significant in the greenhouse; G-matrices of floral and vegetative traits as well as floral and life-history traits differed across environments. Correspondingly, many QTL (45% of those mapped in the greenhouse) showed environmental interactions, including approximately even numbers of floral and nonfloral QTL. Most instances of QTL*QTL epistasis for floral traits were environment dependent. PMID- 20837998 TI - Probabilistic mixture regression models for alignment of LC-MS data. AB - A novel framework of a probabilistic mixture regression model (PMRM) is presented for alignment of liquid chromatography-mass spectrometry (LC-MS) data with respect to retention time (RT) points. The expectation maximization algorithm is used to estimate the joint parameters of spline-based mixture regression models and prior transformation density models. The latter accounts for the variability in RT points and peak intensities. The applicability of PMRM for alignment of LC MS data is demonstrated through three data sets. The performance of PMRM is compared with other alignment approaches including dynamic time warping, correlation optimized warping, and continuous profile model in terms of coefficient variation of replicate LC-MS runs and accuracy in detecting differentially abundant peptides/proteins. PMID- 20838000 TI - Jack Vennart. PMID- 20837997 TI - Reversal of salt preference is directed by the insulin/PI3K and Gq/PKC signaling in Caenorhabditis elegans. AB - Animals search for foods and decide their behaviors according to previous experience. Caenorhabditis elegans detects chemicals with a limited number of sensory neurons, allowing us to dissect roles of each neuron for innate and learned behaviors. C. elegans is attracted to salt after exposure to the salt (NaCl) with food. In contrast, it learns to avoid the salt after exposure to the salt without food. In salt-attraction behavior, it is known that the ASE taste sensory neurons (ASEL and ASER) play a major role. However, little is known about mechanisms for learned salt avoidance. Here, through dissecting contributions of ASE neurons for salt chemotaxis, we show that both ASEL and ASER generate salt chemotaxis plasticity. In ASER, we have previously shown that the insulin/PI 3 kinase signaling acts for starvation-induced salt chemotaxis plasticity. This study shows that the PI 3-kinase signaling promotes aversive drive of ASER but not of ASEL. Furthermore, the Gq signaling pathway composed of Gqalpha EGL-30, diacylglycerol, and nPKC (novel protein kinase C) TTX-4 promotes attractive drive of ASER but not of ASEL. A putative salt receptor GCY-22 guanylyl cyclase is required in ASER for both salt attraction and avoidance. Our results suggest that ASEL and ASER use distinct molecular mechanisms to regulate salt chemotaxis plasticity. PMID- 20838001 TI - Third European IRPA Congress. Helsinki, Finland, 14-18 June 2010. PMID- 20838002 TI - Macrophages, oxysterols and atherosclerosis. AB - Macrophages play central roles in immunity and homeostasis, and contribute to the pathogenesis of atherosclerosis through their accumulation of cholesterol and the production of inflammatory mediators and cytokines. Recent studies indicate that oxysterols influence diverse aspects of macrophage biology. Rather than simply being intermediates of cholesterol catabolism, oxysterols are also potent bioactive lipids that regulate lipid metabolism, immune function, and cytotoxicity. These functions are mediated by specific oxysterol sensors, including liver X receptors (LXR), Insigs, and members of the oxysterol binding protein (OSBP) and OSBP-related protein family. The mechanisms of oxysterol induced functions and their physiological roles in macrophages are reviewed. PMID- 20838003 TI - Dose-dependent reduction in pulmonary vascular resistance with epoprostenol in pulmonary arterial hypertension. PMID- 20838004 TI - Influenza myocarditis. PMID- 20838005 TI - Hypothetical mechanism of the improvement by adaptive servo-ventilation of the pathophysiology of heart failure associated with sleep-disordered breathing. PMID- 20838007 TI - Modifying the drug elution profile for neointimal control - distance and accuracy improved simultaneously with a new driver? -. PMID- 20838006 TI - Diet and risk of atrial fibrillation - epidemiologic and clinical evidence -. AB - Dietary factors might affect the risk of atrial fibrillation (AF), but available studies have provided inconsistent results. A review of published observational studies and randomized trials identified 4 dietary exposures that had been investigated regarding AF risk: alcohol, fish-derived n-3 polyunsaturated fatty acids, caffeine, and ascorbic acid. Though studies were highly heterogeneous in their design and results, they showed a consistently increased risk of AF in heavy alcohol drinkers, but no risk associated with moderate alcohol intake. High coffee intake was not clearly associated with an increased risk of AF, and a potential U-shaped association (lower AF risk in moderate drinkers) could exist. High intake of fish-derived n-3 polyunsaturated fatty acids from diet or supplements might prevent AF episodes following cardiovascular events, but no consistent evidence supports an effect in primary prevention. Additional large, well-conducted randomized experiments are necessary to address the role of diet in AF prevention. PMID- 20838008 TI - Biodegradable polymer for drug-eluting stents - a true advantage or only perception? -. PMID- 20838009 TI - Early repolarization syndrome - a new electrical disorder associated with sudden cardiac death -. AB - Early repolarization (ER), consisting of a J-point elevation, notching or slurring of the terminal portion of the R wave (J wave), and tall/symmetric T wave, is a common finding on the 12-lead electrocardiogram. For decades, it has been considered as benign, barring sporadic case reports and basic electrophysiology research that suggested a critical role of the J wave in the pathogenesis of idiopathic ventricular fibrillation (VF). In 2007-2008, a high prevalence of ER in patients with idiopathic VF was reported and subsequent studies reinforced the results. This review summarizes the current state of knowledge concerning ER syndrome associated with sudden cardiac death. PMID- 20838010 TI - Carotid stenosis, baroreceptor sensitivity and cerebral autoregulation - implication for cerebral hyperperfusion syndrome -. PMID- 20838011 TI - Soluble fms-like tyrosine kinase-1 - a novel marker for atherosclerotic progression? -. PMID- 20838012 TI - [Stimulating glutamatergic neurons as a potential novel therapeutic avenue for schizophrenia]. PMID- 20838013 TI - [Preclinical approaches for drugs targeting cognitive deficits of schizophrenia]. PMID- 20838014 TI - [New approaches to discover antidepressants targeting stress-related pathways]. PMID- 20838015 TI - [Depression and adult hippocampal neurogenesis]. PMID- 20838016 TI - [Pharmacological activity of mastoparan: its contribution to signal transduction]. PMID- 20838017 TI - [Research on mRNA degradation and drug discovery]. PMID- 20838018 TI - [Practical pharmacology training method for undergraduate medical students using a pharmacokinetic simulation model]. PMID- 20838019 TI - [Nonclinical prediction and clinical evaluation of drug-induced QT prolongation]. PMID- 20838020 TI - [Pharmacology profile and clinical findings of pregabalin (Lyrica capsule)]. PMID- 20838021 TI - [Pharmacological profiles and clinical effects of lapatinib tosilate (Tykerb)]. PMID- 20838023 TI - NOX/NADPH oxidase, the superoxide-generating enzyme: its transcriptional regulation and physiological roles. AB - NADPH oxidase is a superoxide (O(2)(-))-generating enzyme first identified in phagocytes that shows bactericidal activities. It has been reported that O(2)(-) is also produced in an NADPH-dependent manner in non-phagocytes. In the last decade, non-phagocyte-type NADPH oxidases have been identified, and the catalytic subunit NOX family has been found to be composed of five homologs, NOX1 to NOX5, and two related enzymes, DUOX1 and DUOX2. These NOX proteins have distinct features in dependency on other components for maximal enzymatic activity, tissue distribution, expressional regulation, and physiological functions. This review summarized the distinct characteristics of NOX family proteins, especially focusing on their functions and mechanisms of their expressional regulation. PMID- 20838022 TI - Time-varying nature of risk factors for the longitudinal development of disability in older adults with arthritis. AB - BACKGROUND: To investigate changes over time in risk factors for the development of Activities of Daily Living (ADL) disabilities in older adults with arthritis. METHODS: The data were obtained from the Longitudinal Survey of Health and Living Status of the Elderly in Taiwan (1989-1999). The major analytic cohort comprised 977 older adults (458 men and 519 women) with arthritis and without ADL limitation at study baseline. A generalized estimating equations (GEE) model was used to analyze all temporally correlated errors, population-averaged estimates, and longitudinal relationships. RESULTS: Overall, the cumulative incidence of ADL disability in the analytic cohort was 17.4% during an observation period of 11 years. With respect to baseline risk, ADL disability was associated with older age, presence of comorbid chronic conditions, and poor self-rated health. However, the findings changed after accounting for the time-varying nature of risk factors and the temporal sequence of possible cause-and-effect relationships. In addition to the baseline predictors, a high score on the Center for Epidemiologic Studies Depression Scale, lack of regular exercise, and becoming widowed were associated with an increased risk of ADL disability and a decreased chance of recovery. CONCLUSIONS: An understanding of the time-varying nature of risk factors for the disabling process is essential for the development of effective interventions that aim to maintain functional ability and prevent limitations among older adults with arthritis. PMID- 20838024 TI - Expression of serotonin transporter in mice with ethanol physical dependency. AB - In the present study, we investigated whether ethanol physical dependence causes changes of serotonin transporter (SERT) expression in the brain. SERT expression increased in the cingulate cortex, nucleus accumbens, hippocampal CA1-CA3 layers, and mediodorsal nucleus of the thalamus and decreased in the basolateral nucleus of the amygdala. In addition, chronic ethanol treatment increased SERT mRNA in the dorsal raphe nucleus from which serotonergic neurons originate, although no SERT mRNA was detected in the regions where SERT protein increased. These findings suggest that alteration of SERT levels in the brain may be related to emotional changes observed in ethanol physical dependence. PMID- 20838025 TI - Mechanism underlying endothelium-dependent relaxation by 2-methylthio-ADP in monkey cerebral artery. AB - We recently reported endothelium-dependent relaxation caused by nucleotides in the non-human primate cerebral artery. Here, we investigated the endothelium dependent, nitric oxide- and prostanoid-independent relaxation induced by 2 methylthio-ADP (2MeSADP) in monkey cerebral artery. Mechanical responses of isolated monkey cerebral arteries to the agents were isometrically recorded. In endothelium-intact arterial strips treated with indomethacin plus N(G)-nitro-L arginine and partially contracted with prostaglandin F(2alpha), 2MeSADP (1 nM - 10 uM) induced concentration-dependent relaxation that was abolished by removal of endothelium but was not influenced by either carboxy PTIO or 18alpha glycyrrhetinic acid. The 2MeSADP-induced relaxation was inhibited by MRS2179 and U73122. The relaxation was markedly suppressed by exposure of the strips to high K(+) media, but was not affected by glibenclamide. Combination of charybdotoxin plus apamin markedly suppressed the relaxation, whereas iberiotoxin partially attenuated it. Relaxation induced by 2MeSADP was inhibited by arachidonyl trifluoromethyl ketone, ketoconazole, and 14,15-epoxyeicosa-5(Z)-enoic acid. The inhibitors that affected the 2MeSADP-induced relaxation did not influence relaxation caused by sodium nitroprusside or forskolin. These findings indicate that 2MeSADP elicits 'endothelium-derived hyperpolarizing factor (EDHF)-type' relaxation via stimulation of endothelial P2Y(1) receptors in monkey cerebral artery. Furthermore, phospholipase A(2), cytochrome P450-derived epoxyeicosatrienoic acids and Ca(2+)-activated K(+) channels appear to be involved in the relaxation. PMID- 20838026 TI - Curcumin Inhibits the proteinase-activated receptor-2-triggered prostaglandin E2 production by suppressing cyclooxygenase-2 upregulation and Akt-dependent activation of nuclear factor-kappaB in human lung epithelial cells. AB - We performed this study to determine if curcumin affects pro-inflammatory responses to activation of proteinase-activated receptor-2 (PAR2) in human pulmonary adenocarcinoma A549 cells. Curcumin completely inhibited the PAR2 triggered prostaglandin E(2) (PGE(2)) production, but notably not interleukin-8 release. Cyclooxygenase-2 (COX-2) upregulation, but not its upstream activation of mitogen-activated protein kinases, caused by PAR2 stimulation was partially inhibited by curcumin. Curcumin inhibited the PAR2-triggered phosphorylation of I kappaB, an indicator for nuclear factor-kappaB (NF-kappaB) activation, and also its upstream signal Akt, which is known to contribute to PAR2-triggered PGE(2) formation, but not COX-2 upregulation. Collectively, curcumin inhibits the PAR2 triggered PGE(2) production by suppressing COX-2 upregulation and Akt/NF-kappaB signals in A549 cells. PMID- 20838027 TI - Therapeutic potentials of an artificial oxygen-carrier, liposome-encapsulated hemoglobin, for ischemia/reperfusion-induced cerebral dysfunction in rats. AB - We performed this study to elucidate whether a newly developed liposome encapsulated hemoglobin, TRM-645 (TRM), can prevent cerebral dysfunction resulting from acute ischemic stroke when used as an oxygen carrier. Hippocampal long-term potentiation (LTP) in the perforant path-dentate gyrus synapses and anxiety-related behaviors in the elevated plus-maze test were evaluated as indices of cerebral functional outcomes in the rat with two-vessel occlusion (2VO), which was induced by 10-min clamping of bilateral common carotid arteries. Saline or TRM (hemoglobin concentration of 6 g/dl: 2.5 or 5 ml/kg) was administered via the tail vein immediately after ischemic insult. Hippocampal LTP formation was markedly impaired and the open arm durations in the elevated plus maze decreased significantly 4 days after 2VO, compared to those of sham-operated (control) rats, suggesting the hippocampal synaptic dysfunction and anxiogenic properties in 2VO rats. TRM (5 ml/kg) restored the hippocampal LTP formation and normalized the anxiety-related behavior. TRM also improved the decreased tissue oxygen partial pressure in the 2VO rat hippocampus, possibly due to oxygen delivery to ischemic regions. Liposome-encapsulated hemoglobin TRM might have therapeutic potentials for protecting the brain from neurological complications associated with acute ischemic stroke, as a promising blood substitute for oxygen therapy. PMID- 20838028 TI - Hepatoprotective effects of Sedum sarmentosum on D galactosamine/lipopolysaccharide-induced murine fulminant hepatic failure. AB - The hepatoprotective effects of sarmentosin-containing extracts of Sedum sarmentosum (SS) in D-galactosamine (D-GalN) / lipopolysaccharide (LPS)-induced fulminant hepatic failure mouse model. Pretreatment with SS markedly protected mice from lethal liver injury, which has known to be associated with an abrupt elevation of serum tumor necrosis factor (TNF)-alpha level. Indeed, SS significantly blocked the elevation of TNF-alpha and alanine aminotransferase and aspartate aminotransferase as well. SS also remarkably reduced number of apoptotic hepatocytes and DNA fragmentation in the liver, which correlated with blockade of caspase-3 activation. In addition, SS suppressed the increased expression of toll-like receptor 4 (TLR4). The activation of c-Jun NH(2)-terminal kinase, extracellular signal-regulated kinase, and p38 induced by D-GalN/LPS was also significantly suppressed by SS treatment. Furthermore, SS significantly inhibited the activation of nuclear factor-kappaB. In RAW 264.7 cells stimulated with LPS, TNF-alpha release and TLR4 expression was suppressed by SS pretreatment, which was in line with in vivo results. These findings suggested that SS prevents D-GalN/LPS-induced fulminant hepatic failure, and this protection is likely associated with its anti-apoptotic activity and the down regulation of mitogen activated protein kinase activity associated at least in part with suppressing the transcription of LPS receptors. PMID- 20838029 TI - Oxidative imbalance in different neurodegenerative diseases with memory impairment. AB - BACKGROUND: Byproducts of oxidative metabolic reactions could play a role in the pathogenesis of several neurodegenerative diseases (ND) including Alzheimer's disease (AD). We designed a study aimed at investigating a large set of oxidative and antioxidant markers in a sample of patients affected by different forms of dementia or memory impairment. METHODS: Serum levels of coenzyme Q(10), malondialdehyde (MDA), the total, oxidized and reduced forms of glutathione (GStot, GSSG and GSH, respectively), reactive oxygen species, anti-oxidized low density lipoprotein antibodies and antioxidant power (PAO) were investigated in patients affected by AD, mild cognitive impairment, dementia with Lewy bodies and Parkinson's disease with dementia. The patient sample (n = 66) was compared with healthy subjects (HC; n = 62), and a comparison across pathological subgroups was also performed. A multivariate logistic regression model was implemented in order to calculate an algorithm model for predicting the risk of developing a neurodegenerative disorder. RESULTS: The comparison between the memory deficit (MD) group and HC showed a significant difference for MDA (MD: 6.3 +/- 2.8 MUg/l; HC: 9.1 +/- 4.9 MUg/l; p = 1.7 * 10(-6)), GStot (MD: 260.4 +/- 62.6 mg/l; HC: 306.5 +/- 60.7 mg/l; p = 2.2 * 10(-5)), GSH (MD: 208.9 +/- 68.4 mg/l; HC: 295.3 +/- 101.3 mg/l; p = 2.2 * 10(-7)) and PAO (MD: 1,066.5 +/- 247.7 MUmol; HC: 954.9 +/- 200.4 MUmol; p = 0.8 * 10(-3)). By contrast, no differences in the levels of the studied markers were detected across the different forms of ND. An older age, higher levels of PAO, lower levels of GSH and MDA and the use of cardiovascular or antidepressant drugs were the most important factors associated with the carrier ship of neurodegenerative disorder. CONCLUSION: To our knowledge, this is the first study reporting similar oxidative imbalance in different forms of memory impairment, regardless of the specific etiology. Low GSH levels could be considered as a favorable factor in ND; at the same time it could be suggested that higher levels of PAO represent a counteracting mechanism against an increased oxidative stress. The association between vascular risk factors, depressive status and cognitive impairment is in line with findings in the literature. PMID- 20838030 TI - Novel L284R MAPT mutation in a family with an autosomal dominant progressive supranuclear palsy syndrome. AB - BACKGROUND: MAPT mutations are associated with disorders within the frontotemporal lobar degeneration spectrum. The usual presenting syndrome is behavioural variant frontotemporal dementia, although some patients present with parkinsonism. In a number of these cases the dominant clinical features have been consistent with a progressive supranuclear palsy (PSP) syndrome. OBJECTIVE: To describe a family with an autosomal dominant PSP syndrome with a novel L284R mutation in the MAPT gene. METHODS: A retrospective case review and genetic analysis of the MAPT gene. A literature review of PSP syndromes associated with mutations in the MAPT gene. RESULTS: Multiple members of family DRC292 across different generations had a PSP syndrome with 1 member of the family being found to have a novel L284R mutation in the MAPT gene. Behavioural features were also prominent in most cases. A PSP syndrome is only a rare finding associated with MAPT mutations and many of these cases have atypical clinical features. CONCLUSION: Although rare, MAPT mutations should be considered when there is an autosomal dominant family history of a PSP syndrome, particularly of young onset and with prominent behavioural features. PMID- 20838031 TI - Postoperative middle cerebral artery peak systolic velocity changes confirm physiological principles of the sequential laser technique for twin-twin transfusion syndrome. AB - INTRODUCTION: Treatment of the twin-twin transfusion syndrome (TTTS) via sequential selective laser photocoagulation of communicating vessels (SQLPCV) mandates ablation of donor-to-recipient arteriovenous anastomoses first. It is hypothesized that SQLPCV facilitates intraoperative transfusion to the donor, thereby minimizing donor hypovolemia and anemia. We sought to determine if postoperative changes in fetal middle cerebral artery-peak systolic velocities (MCA-PSV) support this hypothesis. MATERIALS AND METHODS: Patients undergoing preferential SQLPCV for TTTS had MCA-PSV measured 1 day before surgery and on postoperative day 1 (POD-1). Fetal anemia was defined as an MCA-PSV >=1.5 multiples of the median (MoM). Exclusions included: POD-1 demise, missing MCA-PSV data, or gestational age <18 weeks. RESULTS: Study criteria were met by 139 patients. Mean MCA-PSV in recipients increased from 0.97 to 1.15 MoM postoperatively (p < 0.0001). Donor mean MCA-PSV remained stable at 1.00 MoM preoperatively and 0.98 MoM postoperatively (p = 0.272). Nine fetuses, 6 donors and 3 recipients, had preoperative anemia; SQLPCV was not attempted in the 3 anemic recipients. Postoperatively, the proportion of donors with anemia remained stable (increase 3.6%, p = 0.419), and the proportion of recipients with anemia increased (increase 12.2%, p = 0.009). DISCUSSION: Our findings confirm the presumed physiological basis for the SQLPCV treatment of TTTS. PMID- 20838032 TI - Molecular defects of the CYP21A2 gene in Greek-Cypriot patients with congenital adrenal hyperplasia. AB - BACKGROUND/AIM: To determine the mutations in the CYP21A2 gene in Greek-Cypriots with congenital adrenal hyperplasia (CAH) and attempt a genotype-phenotype correlation. SUBJECTS AND METHODS: Molecular analysis was performed by multiplex ligation-dependent probe amplification and direct sequencing of PCR products of the CYP21A2 gene in 32 CAH patients. RESULTS: The most frequent genetic defect in the classic salt-wasting and simple virilizing forms was the IVS2-13A/C>G (55%) mutation, followed by Large lesion (20%) and in the non-classical form, the p.V281L (79.5%). Genotypes were categorized in 4 mutation groups (null, A, B and C). All 3 patients in the null group manifested the salt-wasting form and all 6 patients in mutation group A presented with the classical form. One patient in group B had the simple virilizing form and 22 patients in group C exhibited the non-classical form. CONCLUSION: The spectrum of mutations of the CYP21A2 gene in our population is comparable to the most common reported in similar ethnic groups. The knowledge of the ethnic specificity of the CYP21A2 mutations represents a valuable diagnostic tool for all forms of CAH. PMID- 20838033 TI - Oestrogen downregulates BACE protein in human cell culture: what does this teach us about Alzheimer's disease? PMID- 20838034 TI - Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis. AB - During mouse sex determination, SRY upregulates the core testis-specific enhancer of Sox9, TESCO. Mutations in human SRY are found in one third of cases with XY pure gonadal dysgenesis (XY GD; Swyer syndrome), while two thirds remain unexplained. Heterozygous SOX9 mutations can cause XY GD in association with the skeletal malformation syndrome campomelic dysplasia. We hypothesized that human TESCO mutations could cause isolated XY GD. Sixty-six XY GD cases with an intact SRY were analyzed for TESCO point mutations or deletions. No mutations were identified. We conclude that TESCO mutations are not a common cause of XY GD. PMID- 20838035 TI - An adequate calcium intake could help achieve weight loss in overweight/obese women following hypocaloric diets. AB - AIM: To investigate the effect of calcium (Ca) intake and dairy product consumption modification on body composition in overweight/obese women following two types of hypocaloric diet. METHODS: Study subjects were 57 women who were randomly assigned to follow one of two hypocaloric diets: diet V, in which the relative consumption of vegetables was increased, and diet C, which involved increasing the relative consumption of cereals (especially breakfast cereals). Dietetic and anthropometric data were collected at the start and at the end of the 6-week intervention period. RESULTS: Ca density, Ca index of nutritional quality and Ca/protein improved with both diets. Dairy products, Ca intake, dairy Ca intake and Ca/protein were inversely correlated with body mass index at the end of the study. Among the women with an initial calcium intake below the 50th percentile, those who achieved a reduction in body mass index above the 50th percentile were those who most increased their total calcium intake, calcium intake from dairy sources, calcium density, calcium/protein ratio and the intake of total and skimmed dairy product consumption. CONCLUSION: Correcting an inadequate calcium intake could help improve weight loss in women following hypocaloric diets. PMID- 20838036 TI - Focuses solely on generalized, inherited (Mendelian) disorders of cornification (DOC or MeDOC). Introduction. PMID- 20838037 TI - Inherited clinical disorders of lipid metabolism. PMID- 20838038 TI - Inherited disorders of accelerated desquamation. PMID- 20838039 TI - Inherited disorders of corneocyte proteins. PMID- 20838040 TI - Appendix 1: ultrastructural and histochemical methods. PMID- 20838042 TI - Factors that influence data quality in caries experience detection: a multilevel modeling approach. AB - Caries experience detection is prone to misclassification. For this reason, calibration exercises which aim at assessing and improving the scoring behavior of dental raters are organized. During a calibration exercise, a sample of children is examined by the benchmark scorer and the dental examiners. This produces a 2 * 2 contingency table with the true and possibly misclassified responses. The entries in this misclassification table allow to estimate the sensitivity and the specificity of the raters. However, in many dental studies, the uncertainty with which sensitivity and specificity are estimated is not expressed. Further, caries experience data have a hierarchical structure since the data are recorded for the surfaces nested in the teeth within the mouth. Therefore, it is important to report the uncertainty using confidence intervals and to take the clustering into account. Here we apply a Bayesian logistic multilevel model for estimating the sensitivity and specificity. The main goal of this research is to find the factors that influence the true scoring of caries experience accounting for the hierarchical structure in the data. In our analysis, we show that the dentition type and tooth or surface type affect the quality of caries experience detection. PMID- 20838043 TI - Early feeding practices and severe early childhood caries in four-year-old children from southern Brazil: a birth cohort study. AB - The aim of this study was to investigate the relationship between feeding practices in the first year of life and the occurrence of severe early childhood caries (S-ECC) at 4 years of age. A birth cohort study (n = 500) was conducted in children who were born within the public health system in Sao Leopoldo, Brazil. Feeding practices were assessed using standardized methods at 6 and 12 months of age. A total of 340 children were examined at 4 years of age. S-ECC was defined as recommended by an expert panel for research purposes: >=1 cavitated, missing or filled smooth surfaces in primary maxillary anterior teeth or d(1+) mfs >=5. Poisson regression with robust variance was used in order to determine the early feeding practices which represent risk factors for the occurrence of S-ECC at 4 years of age. The multivariable model showed a higher adjusted risk of S-ECC for the following dietary practices at 12 months: breastfeeding >=7 times daily (RR = 1.97; 95% CI = 1.45-2.68), high density of sugar (RR = 1.43; 95% CI = 1.08-1.89), bottle use for liquids other than milk (RR = 1.41; 95% CI = 1.08-1.86), as well as number of meals and snacks >8 (RR = 1.42; 95% CI = 1.02-1.97). Mother's education <=8 years was also associated with the outcome. The present study identified early feeding practices which represent risk factors for caries severity in subsequent years. These findings may contribute to developing general and oral health interventions, with special attention to families with low maternal education. PMID- 20838044 TI - Mutans streptococci and caries prevalence in children after early maternal caries prevention: a follow-up at eleven and fifteen years of age. AB - AIM: The efficacy of early maternal caries prevention in children was evaluated. METHODS: First-time mothers selected on the basis of a high level of salivary mutans streptococci (MS) and mothers excluded at screening due to a low level of MS ('low') were recalled when their children were 11 years old. The salivary MS level was determined in the mothers. Their children were examined for salivary MS and lesion prevalence (decayed and filled surfaces, DFS) at the ages of 11 and 15 years. RESULTS: More 'high control' mothers displayed >=106 MS than the 'high interventional' and 'low control' mothers and, vice versa, more 'interventional' and 'low control' mothers had MS counts of <3 * 105 than 'high control' mothers. More of 'interventional' and 'low control' children had <105 MS/ml as compared with the 'high control' children. All the 'high control' children had detectable MS. MS were undetected in 5 'interventional' and 5 'low control' children at 15 years. Significantly fewer 'high control' than 'interventional' and 'low control' children were caries free at 11 and 15 years of age. Non-MS-colonised children at 3 years of age, irrespective of group identity, displayed statistically lower MS counts and less DFS at 15 years than those colonised at 3 years of age. Children with clinical caries/fillings at 15 years had had a significantly higher level of MS at 11 years of age than those without clinical caries/fillings. CONCLUSION: The clinical trial, focusing on the mothers, resulted in long-term benefits for their children. Children colonised by MS at an early stage developed more caries than those colonised at a later stage. PMID- 20838045 TI - Retention of antimicrobial activity in plaque and saliva following mouthrinse use in vivo. AB - The aim of this study was to determine the contribution of plaque and saliva towards the prolonged activity, also called substantivity, of three antimicrobial mouthrinses (Listerine(r), Meridol(r), Crest Pro Health(r)), used in combination with a toothpaste (Prodent Coolmint(r)). Volunteers brushed for 4 weeks with a toothpaste without antimicrobial claims, while during the last 2 weeks half of the volunteers used an antimicrobial mouthrinse in addition to brushing. At the end of the experimental period, plaque and saliva samples were collected 6 h after oral hygiene, and bacterial concentrations and viabilities were determined. The contribution of plaque and saliva towards substantivity was assessed by combining plaque obtained after mechanical cleaning only with plaque and saliva obtained after additional use of an antimicrobial rinse. Subsequently, resulting viabilities of the combined plaques were determined. The viabilities of plaque samples after additional rinsing with mouthrinses were lower than of plaque obtained after mechanical cleaning only, regardless of the rinse involved. Moreover, plaque collected 6 h after rinsing with antimicrobial mouthrinses contained a surplus of antimicrobial activity. Only Listerine showed decreased viability in saliva, but none of the mouthrinses showed any residual antimicrobial activity in saliva. The findings indicate that plaque left behind after mechanical cleaning contributes to the prolonged substantivity of antimicrobial mouthrinses. PMID- 20838046 TI - Nonpharmacological therapies in Alzheimer's disease: a systematic review of efficacy. AB - INTRODUCTION: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer's disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. METHODS: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology (indicating dementia) had to be present or presumed in at least 80% of the subjects. Evidence tables, meta-analysis and summaries of results were elaborated by the first author and reviewed by author subgroups. Methods for rating level of evidence and grading practice recommendations were adapted from the Oxford Center for Evidence-Based Medicine. RESULTS: Grade A treatment recommendation was achieved for institutionalization delay (multicomponent interventions for the caregiver, CG). Grade B recommendation was reached for the person with dementia (PWD) for: improvement in cognition (cognitive training, cognitive stimulation, multicomponent interventions for the PWD); activities of daily living (ADL) (ADL training, multicomponent interventions for the PWD); behavior (cognitive stimulation, multicomponent interventions for the PWD, behavioral interventions, professional CG training); mood (multicomponent interventions for the PWD); QoL (multicomponent interventions for PWD and CG) and restraint prevention (professional CG training); for the CG, grade B was also reached for: CG mood (CG education, CG support, multicomponent interventions for the CG); CG psychological well-being (cognitive stimulation, multicomponent interventions for the CG); CG QoL (multicomponent interventions for PWD and CG). CONCLUSION: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG. PMID- 20838047 TI - Does age at observation time affect the clinical presentation of mild cognitive impairment? AB - BACKGROUND: To date, there are no published data investigating the role of age in the clinical and neuropsychological presentation of mild cognitive impairment (MCI). The aim of the study was to evaluate whether age at the time of evaluation modulates clinical, functional or cognitive profiles in MCI subjects. METHODS: A total of 167 outpatients with a clinical diagnosis of MCI were consecutively enrolled and entered in the study. Clinical and demographic characteristics were carefully recorded. Each patient underwent a wide neuropsychological standardized assessment. RESULTS: MCI subjects were divided into 3 groups according to their age at observation time: 58 MCI patients were classified as young (<= 69 years), 89 as old (70-79 years) and 20 as very old (>= 80 years). The 3 groups did not differ in demographic characteristics, general cognitive functions and memory impairment. Very old MCI subjects showed a significantly greater impairment than younger MCI patients in cognitive domains involving executive functions. In particular, very old MCI patients were more frequently classified as having multiple-domain amnestic MCI. CONCLUSION: Present data highlight that the clinical presentation of MCI is affected by age: at presentation, very old MCI subjects show a worse performance than younger MCI subjects on multiple abilities, particularly on executive functions. PMID- 20838048 TI - Neuropsychological predictors of rapidly progressing patients with Alzheimer's disease. AB - BACKGROUND: Alzheimer disease (AD) has heterogeneous clinical manifestations. Different neuropsychological profiles in AD patients might be indicative of the diffusion of the pathological process and might be associated with differences in rates of disease progression. METHODS: We studied 154 newly diagnosed AD patients (65.6% women; mean age: 73 years). Performance in memory, executive functions, praxis and language domains was categorized into mild, moderate and severe impairment. The time-dependent probability of losing 5 points on the Mini-Mental State Examination (MMSE) over 2 years was considered as disease progression and evaluated by survival analysis. RESULTS: One fourth of the patients decreased by >= 5 MMSE points over the 2-year follow-up. Rapid disease progression was more frequent in more educated patients and in those with moderate severity of global cognitive impairment. In univariate analysis, more severe memory and executive functioning impairment were associated with higher probabilities of progression. The association with memory was explained by differences in executive function impairment that remained statistically significant in multivariate analyses. CONCLUSIONS: Patients with more severe executive functioning impairment have a worse prognosis over 2 years. This might be due to involvement of the prefrontal cortex by the pathological process of AD in patients with severe executive deficits. PMID- 20838049 TI - Temporary percutaneous gastric electrical stimulation: a novel technique tested in patients with non-established indications for gastric electrical stimulation. AB - AIM: To test temporary percutaneous gastric electrical stimulation (TPGES) in patients with drug-refractory nausea/vomiting and nonestablished indications for GES. METHODS: 27 patients (2-81 years) underwent TPGES with electrodes implanted at gastroscopy and received stimulation for 7-21 days with low current settings (5-7 mA) either as open stimulation (n = 14) or randomized to double-blind crossover stimulation (n = 13; ON for 12-14 days, OFF for 12-14 days). Symptoms were recorded daily. Nonresponders were offered another period (14-21 days) with increased stimulation (8-10 mA). RESULTS: Mean lead implantation time was 14 min. Leads were kept implanted for <=60 days. 22 of 27 evaluable patients had a favorable symptom reduction, preferentially of nausea/vomiting, irrespective of delayed or normal gastric emptying rate: postsurgical gastroparesis 7/8, chronic intestinal pseudo-obstruction 2/2, idiopathic gastroparesis 1/1, functional dyspepsia 6/9, diabetes mellitus 2/2, postsurgical nausea/vomiting 2/2, malformation syndrome 1/1, intestinal neuropathy 1/1, intestinal interstitial cells of Cajal deficiency 0/1. 6 patients had a clear symptom reduction during the ON period compared with stimulation OFF. Four of 7 patients improved with increased stimulation (8-10 mA). Twenty of the 22 responders received a permanent GES implant, 90% of them still being responders at last follow-up. CONCLUSION: TPGES seems promising to study new indications for GES and to select responders/non-responders. PMID- 20838050 TI - Dying in yoghurt: the number of living bacteria in probiotic yoghurt decreases under exposure to room temperature. AB - BACKGROUND/AIMS: While probiotic bacteria are successfully used in the treatment of ulcerative colitis, the effect of commercially available probiotic products is still controversial. Here, we study whether the number of living probiotic bacteria in yoghurts is altered by an interruption of the cold chain. METHODS: Three commonly available probiotic yoghurts were kept at 4 degrees C or put at room temperature (RT) for 6 h or 24 h. An aliquot of each yoghurt was applied on Man-Rogosa-Sharpe agar and incubated at 37 degrees C for 48 h. Colony forming units (CFU) were counted by microscopy. RESULTS: The first yoghurt, containing Lactobacillus johnsonii, showed a significant decrease in CFU after 6 h of storage at RT, which was further pronounced after 24 h. The number of CFU of the second yoghurt, containing Lactobacillus GG, was also decreased after 6 h and further diminished after 24 h at RT. From the third yoghurt, containing Lactobacillus acidophilus, only 53.8% of the CFU remained after 6 h at RT; after 24 h, only about one fourth of the CFU were found. CONCLUSIONS: Our data demonstrate that the number of living probiotic bacteria in yoghurt products decreases dramatically after exposure to RT. This represents an important information for consumers of such products. PMID- 20838051 TI - Clinical feature and bowel ultrasound in Crohn's disease - does additional information from magnetic resonance imaging affect therapeutic approach and when does extended diagnostic investigation make sense? AB - BACKGROUND/AIMS: Some suggest MRI to be superior to ultrasound in Crohn's disease. We analyzed how often MR enterography (MRE) following a routine ultrasound leads to a change in therapeutic decision. MATERIAL AND METHODS: We retrospectively evaluated 47 patients with Crohn's disease undergoing routine ultrasound examination. Actual medical history, complete blood count, C-reactive protein (CRP), and sonographic findings were assessed independently by two specialists who retrospectively provided a therapeutic proposal. Additionally, all patients received MRE. Thereafter, the specialists had to provide a new therapeutic concept regarding all the available information. RESULTS: Evaluation of the rectum was not successful by ultrasound, but MRE gave good results. Only 1 of 7 abscesses was identified sonographically. Three of the abscesses missed at sonography were localized in the perirectal/perianal region. MRE detected more inflamed bowel segments, but ultrasound assessment of anatomically fixed bowel parts showed good recognition by MRE. With increasing CRP values, we found more positive results of ultrasound and MRE. Therapeutic change was suggested in only 18 patients. CONCLUSIONS: Ultrasound should be performed by an experienced examiner, and a proctological examination should be added. MRE is justified in cases of discrepancy between clinical findings and the results of diagnostic ultrasound and, moreover, if Crohn's lesions are suspected at sites proximal to the terminal or neoterminal ileum. PMID- 20838052 TI - Disadvantage of operation cost in laparoscopy-assisted distal gastrectomy under the national health insurance system in Japan. AB - BACKGROUND: The utility and problems including the socioeconomic aspect of laparoscopy-assisted distal gastrectomy for gastric cancer have not been fully evaluated. SUBJECTS AND METHODS: We compared open distal gastrectomy and laparoscopy-assisted distal gastrectomy for the clinical benefit, quality of life, and problems of operation cost by the reference documents in which the difference between open distal gastrectomy and laparoscopy-assisted distal gastrectomy was examined in detail. The reference documents retrieved by the key words 'gastric, cancer, laparoscopic, surgery' were 22 in PubMed with the following limits activated: Humans, Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Review, English, Core clinical journals, published in the last 10 years. RESULTS: The operation time of laparoscopy-assisted distal gastrectomy is longer than that of open distal gastrectomy. However, if skilled, the blood loss of laparoscopy-assisted distal gastrectomy is less, the hospitalization days and the duration of fasting after laparoscopy-assisted distal gastrectomy are shorter than those after open distal gastrectomy. The number of excised lymph nodes and the incidence of postoperative complications were similar between laparoscopy-assisted distal gastrectomy and open distal gastrectomy. On the other hand, in the national health insurance system, the operation fee of open distal gastrectomy was USD 6,637 as compared to USD 7,586 for laparoscopy-assisted distal gastrectomy. In spite of the USD 949 difference in the operation fee, the use of disposable instruments for laparoscopy-assisted distal gastrectomy results in a deficit of USD 1,500 over open distal gastrectomy. CONCLUSION: In spite of the medical superiority of laparoscopy-assisted distal gastrectomy over open distal gastrectomy (if a skilled surgeon operates) as less invasive surgery, laparoscopy-assisted distal gastrectomy is associated with less financial benefit to the hospital as compared to open distal gastrectomy in the current Japanese health insurance system. PMID- 20838053 TI - Association between the severity of cerebral small vessel disease, pulsatility of cerebral arteries, and brachial ankle pulse wave velocity in patients with lacunar infarction. AB - BACKGROUND/AIMS: Stiff arteries cause high pulse pressure and flow to be transmitted to distal organs during systole, damaging the cerebral microvasculatures. We investigated the association between the severity of cerebral small vessel disease (CSVD), the pulsatility of cerebral arteries, and the stiffness of large arteries in patients with lacunar infarction (LI). METHODS: Subjects included 120 patients with LIs, who underwent MRI, transcranial Doppler ultrasonography, and brachial ankle pulse wave velocity (BaPWV). We compared the severity of CSVD, the pulsatile index (PI) of both middle cerebral arteries (MCAs), and BaPWV. RESULTS: Patients with higher BaPWV were more likely to have multiple LIs and more severe white matter lesions, and tended to have higher age, systolic blood pressure, pulse pressure, heart rate, and the PI of MCAs. The PI of MCAs significantly correlated with BaPWV (with PI: r = 0.441, p < 0.001) and age (with PI: r = 0.538, p < 0.001). Multiple linear regression analysis indicated that aging (beta = 0.008, p < 0.001) and BaPWV (beta = 0.001, p = 0.007) were independent determinants of the PI of MCAs after adjustment for sex, pulse pressure, hypertension, and diabetes. CONCLUSION: These findings suggest that systemic arterial stiffness may be associated with the severity of CSVD and pulsatility of cerebral arteries. PMID- 20838054 TI - Effect size measures in genetic association studies and age-conditional risk prediction. AB - The interest in risk prediction using genomic profiles has surged recently. A proper interpretation of effect size measures in association studies is crucial to accurate risk prediction. In this study, we clarified the relationship between the odds ratio (OR), relative risk and incidence rate ratios in the context of genetic association studies. We demonstrated that under the common practice of sampling prevalent cases and controls, the resulting ORs approximate the incidence rate ratios. Based on this result, we presented a framework to compute the disease risk given the current age and follow-up period (including lifetime risk), with consideration of competing risks of mortality. We considered two extensions. One is correcting the incidence rate to reflect the person-years alive and disease-free, the other is converting prevalence to incidence estimates. The methodology was applied to an example of breast cancer prediction. We observed that simply multiplying the OR by the average lifetime risk estimates yielded a final estimate >100% (101%), while using our method that accounts for competing risks produces an estimate of 63% only. We also applied the method to risk prediction of Alzheimer's disease in Hong Kong. We recommend that companies offering direct-to-consumer genetic testing employ more rigorous prediction algorithms considering competing risks. PMID- 20838055 TI - Using anti-cancer agents during the post-partum period: not that simple. PMID- 20838056 TI - Trastuzumab as single agent therapy for HER2-positive metastatic breast cancer. PMID- 20838057 TI - Trastuzumab single-drug therapy after failure of cytotoxic treatment for metastatic breast cancer. AB - BACKGROUND: Trastuzumab is an established component of breast cancer combination regimens, but data on the safety and efficacy of single-agent therapy is sparse. PATIENTS AND METHODS: 70 Patients with HER2-overexpressing breast cancer after failure of at least one chemotherapy regimen for metastatic disease were recruited from 28 institutions. HER2 overexpression was 3+ in 96% and 2+/FISH+ in 4%. Treatment consisted of a loading dose of 4 mg/kg trastuzumab in the first week and 2 mg/kg per week thereafter, continued until progression. RESULTS: Trastuzumab treatment duration ranged from 1 to 66 weeks (median: 12). Objective responses (complete response (CR)/partial response (PR)) were seen in 12/62 fully evaluable patients (19%; 2 CR) while another 29% showed stabilization of the disease. Half of the patients had experienced progression after 13 weeks while median duration of response reached 44 weeks. Median survival was 68 weeks with nearly one-third of the patients still alive after more than 3 years. The most frequent adverse reaction was infusion-related syndrome arising during the first administration. Significant cardiovascular problems were detected in 3 cases, all with anthracycline pretreatment. CONCLUSIONS: Patients with metastatic breast cancer overexpressing HER2 may benefit from trastuzumab single-drug treatment, predominantly due to its favourable safety profile. PMID- 20838058 TI - Clinical study of adjuvant capecitabine monotherapy in Chinese elderly patients (aged 55-70) with stage IIa breast cancer. AB - BACKGROUND: Oral capecitabine (CAP) has shown significant benefits in early stage breast cancer (BC). Herein we evaluated CAP as adjuvant monotherapy in women 55 years of age or older with stage IIa BC. PATIENTS AND METHODS: Women with stage IIa BC received 6 cycles of either CAP or CEF (cyclophosphamide/epirubicin/5 fluorouracil) after surgery. The primary endpoint was overall survival (OS). Quality of life (QOL), patient acceptance of chemotherapy, and safety were secondary endpoints. RESULTS: A total of 71 women were enrolled. The 3- and 5 year OS rates were 96.97 and 93.33%, respectively in the CAP group versus 96.67 and 90.32%, respectively in the CEF group. The incidence of disease recurrence or metastasis was 6.67 versus 6.45%, respectively. All CAP patients completed the planned 6 cycles, while only 84% of CEF patients completed all 6 cycles. Myelosuppression, hepatic toxicity, and cardiovascular toxicity were more common with CEF, while hand-foot syndrome was more common with CAP. QOL was significantly better in the CAP group (p < 0.01). Compared with the CEF group, CAP patients had less moderate-to-severe mental disturbance (p < 0.01). CONCLUSIONS: Our results suggest that CAP monotherapy is a potential alternative to CEF adjuvant chemotherapy in patients 55 years old or older with stage IIa BC. PMID- 20838059 TI - Annexin and survivin in locally advanced rectal cancer: indicators of resistance to preoperative chemoradiotherapy? AB - BACKGROUND: The aim of preoperative chemoradiotherapy is improvement of local control in patients with locally advanced rectal cancer (LARC). Recent studies have shown that annexin and survivin are involved in the resistance capability of tumours. We sought to determine whether survivin, annexin A4 or annexin A5 expression predict resistance to preoperative chemoradiotherapy. MATERIAL AND METHODS: Biopsies of tumour and normal rectal tissue were taken from 38 patients with LARC (cT3/4Nx or Tx/N+) before the start of chemoradiotherapy and during surgery. mRNA expression of annexin A4/A5 and survivin was measured by real-time polymerase chain reaction (RT-PCR) and correlated with down-staging and progression-free survival (PFS). RESULTS: Significantly higher mRNA levels of survivin, and annexin A4/A5 were detected in untreated tumour compared with normal mucosa. After chemoradiotherapy, this difference disappeared for survivin and annexin A4. Annexin A5 expression in the tumour increased during chemoradiotherapy. No correlation between the mRNA levels of survivin, annexin A4/A5 and tumour down-staging or PFS was noticed. CONCLUSIONS: In the present analysis of 38 patients with LARC undergoing neoadjuvant chemoradiotherapy, the expression levels of survivin and annexin A4 and A5 did not correlate with down staging. Moreover, with regard to PFS, none of these markers was found to be prognostically relevant. PMID- 20838060 TI - Long-term renal safety profile of ibandronate 6 mg infused over 15 minutes. AB - BACKGROUND: In an earlier study, intravenous (i.v.) ibandronate 6 mg administered every 3-4 weeks had a similarly good renal safety profile whether infused over 15 or 60 min in women with breast cancer and bone metastases. This current study focuses on the renal safety of the extended use of ibandronate. PATIENTS AND METHODS: Patients completing the original study could choose to enter a follow-up phase and continue (or switch) to receive ibandronate 6 mg by 15-min i.v. infusion every 3-4 weeks. The primary endpoint was the percentage of patients with a serum creatinine increase of >=44.2 mmol/l (= 0.5 mg/dl) from core baseline. RESULTS: Fourteen patients entered the follow-up phase and received a median of 16 infusions (range: 9-24). No patient reached the primary endpoint. Most adverse events were mild to moderate in intensity. None of the 6 reported treatment-related adverse events was considered severe or reported as a serious adverse event. CONCLUSIONS: Ibandronate was well tolerated when administered as a 6-mg i.v. infusion over 15 min every 3-4 weeks during the follow-up phase to the earlier core study. No evidence of any treatment-related deterioration in renal function was noted, and no new or unexpected adverse events occurred. PMID- 20838061 TI - Paraneoplastic limbic encephalitis in a patient with extragonadal choriocarcinoma -significance of onconeural antibodies. AB - BACKGROUND: Paraneoplastic limbic or brainstem encephalitis is considered to be an autoimmune-mediated disorder of the nervous system associated with different types of cancer including germ cell tumors. CASE REPORT: We report on a 31-year old patient presenting with eye motility dysfunction, dysarthrophonia, lethargy, depression, slow mentation, disorientation, dysgraphia, and retarded motion sequence. Neurologic tests, brain imaging, and blood chemistry tests failed to determine the cause of the symptoms. Further examinations including ultrasound of the abdomen led to the detection of a retroperitoneal mass. The biopsy of this mass showed fractions of a choriocarcinoma. The patient underwent curative chemotherapy, but although the cancer therapy was successful, the neurologic disorders did not improve. Concurrent examination for anti-Ma2 antibodies in the serum was positive and confirmed the paraneoplastic origin of these symptoms. CONCLUSIONS: Patients with symptoms of limbic or brainstem encephalitis, especially young men, should be tested for anti-Ma2 antibodies in the serum to elucidate their origin. The detection of these antibodies supports the diagnosis of a paraneoplastic syndrome, and may lead to the earlier identification of an otherwise hidden extragonadal germ cell tumor. PMID- 20838062 TI - Nonbacterial thrombotic (marantic) endocarditis in a patient with colorectal cancer. AB - BACKGROUND: Marantic endocarditis, presently termed nonbacterial thrombotic endocarditis (NBTE), is an infrequent post-mortem diagnosis in the adult population but a not so rare event in the course of neoplastic conditions. CASE REPORT: We describe the case of a 74-year-old woman with advanced sigmoid adenocarcinoma, who developed aseptic vegetations in the right atrium of the heart. Systemic anticoagulation therapy was started, and upon clinical improvement systemic chemotherapy was added, resulting in partial response to antineoplastic therapy along with improvement of her cardiopulmonary status. A new cardiac assessment upon tumor recurrence was unable to distinguish the previously described lesions but disclosed a small mitral valve vegetation, in the absence of any signs or symptoms. The patient was again treated with chemotherapy and remains asymptomatic with stable disease. CONCLUSIONS: Although a hypercoagulable state may be etiologically related to malignant conditions, a strong clinical suspicion of NBTE is required. In these cases, it is often difficult to establish a definite diagnosis; however, immediate anticoagulation treatment is mandatory for the prevention of de novo or further thromboembolic events. PMID- 20838063 TI - Burkitt's lymphoma in pregnancy with bilateral breast involvement: case report with review of the literature. AB - BACKGROUND: Burkitt's lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far. CASE REPORT: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable. CONCLUSIONS: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach. PMID- 20838064 TI - Restoration of gefitinib efficacy following chemotherapy in a patient with metastatic non-small cell lung cancer. AB - BACKGROUND: Gefitinib has shown evidence of antitumor activity in advanced non small cell lung cancer (NSCLC). CASE REPORT: A female Asian nonsmoker with adenocarcinoma was given gefitinib as first-line treatment with significant efficacy. However, after approximately 1.5 years, progression occurred. She then received chemotherapy (pemetrexed/carboplatin) until progression, followed by treatment with gefitinib to which the patient responded a second time. After progression, treatment with chemotherapy (docetaxel/cisplatin) was instituted and again followed by gefitinib. A recent positron emission tomography/computed tomography (PET/CT) scan showed complete remission under gefitinib. CONCLUSIONS: This case report indicates that resistance to gefitinib in NSCLC can be reversed after chemotherapy. Thus, re-exposure to gefitinib may be justified in selected cases. PMID- 20838065 TI - Management of the cutaneous side effects of therapeutic epidermal growth factor receptor inhibition. AB - The epidermal growth factor receptor (EGFR) is expressed in a variety of human tissues and is a key mediator of numerous cellular processes. Dysregulation and overexpression of the EGFR are common features of many tumors; targeted EGFR inhibitors are therefore widely employed as therapeutic agents. Novel mechanisms associated with EGFR inhibitors induce characteristic toxicities, of which cutaneous side effects (generally termed 'skin rash') are the most common. Although this rash is generally mild to moderate in severity, it can affect compliance and/or result in dose reductions or treatment-withdrawal. To ensure that patients can continue to receive active treatment at the optimal dose, effective treatment strategies are required to actively manage rash and aid compliance. This is important as rash is increasingly identified as a predictive marker of benefit with EGFR inhibitors. The incidence and clinical characteristics of rash, in addition to current rash management strategies, are reviewed. Our recommendations based on clinical experience are presented, with two case studies of successful rash management provided to illustrate their success. Active rash management can effectively resolve rash to ensure that patient compliance is maintained, without necessitating dose interruptions or treatment withdrawal. PMID- 20838066 TI - Ovarian metastasis of a lymphoma. PMID- 20838067 TI - Transcutaneous cervical and transabdominal ultrasonography as a diagnostic tool in gastroesophageal reflux in childhood. AB - BACKGROUND/AIM: The aim of this study is to investigate if there is a diagnostic expressive difference in the angle of His, upper and lower esophageal diameter (UED and LED), wall thickness of cervical esophagus (WTCE) measured by cervical and transabdominal ultrasonography (USG) between children with (+) and without gastroesophageal reflux (GER-). METHODS: 50 children were separated into 2 groups. Group 1 was the control group (n = 30) consisting of children who had no symptoms of GER and had no GER detected in USG. Group 2 was the study group (n = 20) consisting of children with complaints related to GER, and who were GER+ by USG and esophageal pH monitoring. The USG examinations were completed after having observed 3 episodes of reflux or after 30 min if no reflux was detected. The angle of His, UED, LED and WTCE were measured. In 24-hour esophageal pH monitoring, acid contact to the proximal or distal probe greater than 5.0% of the total time below pH 4 was accepted as pathologic reflux. RESULTS: The age range of the 50 children (30 boys) was 4-13 years. Between the 2 groups there were no differences with regard to age and gender. Values of UED, LED and WTCE were statistically higher in group 2 compared with group 1. The angle of His was higher in the control group, but this was not statistically significant. CONCLUSION: Our study is the first in the literature that shows that measuring UED, LED and WTCE by USG, which is a noninvasive, readily available repeatable, cheap and fast technique, has a high diagnostic value in children with suspected GER. PMID- 20838068 TI - The golden hour. PMID- 20838071 TI - Thermoregulation in very low-birth-weight infants during the golden hour: results and implications. AB - The survival of very low-birth-weight (VLBW) infants has been shown to be effected by alterations in thermoregulation. Morbidity and mortality in these VLBW infants has remained higher than those in any other group of infants because of their innate vulnerability and because of exposure to risk factors in the environment. This leaves the premature infant vulnerable to cold stress especially in the first hours to weeks of life. At birth, the VLBW infant emerges from a warm, fluid environment and is thrust into a cold, abrasive environment before the protective layers of the epidermis have developed. Within minutes of birth, the core temperature begins to fall, particularly in infants whose birth weights are less than 1500 g. Hypothermia is a major cause of morbidity and mortality in infants; therefore, maintaining normal body temperatures in the delivery room is crucial. We reviewed evidence related to thermoregulation at birth in VLBW infants, including transepidermal water loss and temperature control in the delivery room, during stabilization and upon admission to the neonatal intensive care unit. Delivery room management that focuses on the adaptation of the infant as well as early interventions that improve long-term outcomes may emphasize the "golden hour" of care and improve outcomes in this extremely vulnerable population. PMID- 20838072 TI - Method for wrapping the infant in occlusive wrap at birth. PMID- 20838073 TI - Management of hypotension in the very low-birth-weight infant during the golden hour. AB - Primum non nocere, a saying in Latin that means "first, do no harm," is a phrase neonatal clinicians should keep in mind when initiating or suggesting treatment. In the "golden hour" of resuscitation of the very low-birth-weight infant, team members assess multiple parameters of the infant's vital signs, with a key one being that of the cardiovascular status, specifically blood pressure. Attempts to treat a number rather than after assessment and develop a sound plan of care based on findings, will affect both short- and long-term outcomes. By understanding what neonatal hypotension is and knowing when and how to treat it, the neonatal clinician honors this charge and can safely and effectively manage the very low-birth-weight infant with hypotension shortly after birth. PMID- 20838075 TI - Fluid, electrolytes, and nutrition: minutes matter. AB - Historically, in very low-birth-weight infant care, nutritional support was delayed during the first postnatal days because of fear of toxicity and harm with immature metabolic systems and intestinal function. Recent evidence demonstrates that early nutritional support is not only safe but likely necessary to optimize infant growth and neurodevelopment. In fact, nutrition management is a critical factor in very low-birth-weight infant golden hour support. Contemporary studies in protein and lipid intravenous support and early feeds as minimal enteral nutrition exhibit safety and some efficacy. We will present analysis of this evidence and development of potential better practices on the basis of these data as well as a review of golden hour fluid and glucose management. In addition, we provide several outcomes following our adoption of potentially better golden hour nutrition practices. PMID- 20838076 TI - Establishing gas exchange and improving oxygenation in the delivery room management of the lung. AB - One of the components of promoting good outcomes in high-risk neonates is supporting normal gas exchange while avoiding lung injury. Respiratory care in the first hour following birth plays an important role in stabilizing the infant with respiratory problems. The goal of this article is to review the causes of lung injury that can occur in the first hour and that could be prevented with careful respiratory support. PMID- 20838077 TI - Simulation training in graduate medical education: a means of traversing a changed and changing landscape. AB - There have been significant changes in the graduate medical (resident) education in the United States over the last two decades. These changes have been the result of a wide range of societal, governmental, and regulatory alterations which have either directly or indirectly impacted today's physicians-in-training experiences and autonomy, raising concerns about their readiness for independent practice at the completion of training. This article reviews the evolution of these changes and the promise that simulation training holds as one of the keys to ensuring continuing excellence in the training of today's and tomorrow's physicians. PMID- 20838078 TI - Thermoregulation: back to basics. PMID- 20838079 TI - Transitional hypothermia in preterm newborns. AB - Hypothermia remains a significant challenge in the initial care of premature infants. Although a number of prevention strategies have been identified, hypothermia is still a common event, especially in extremely low birth weight infants. Using data from four centers, we documented an incidence of hypothermia on admission to the neonatal intensive care unit from the delivery room of 31-78% for infants < 1500 g birth weight. Increased efforts will be necessary to prevent early hypothermia in very preterm infants, especially with respect to the environmental conditions of the delivery room itself. Journal of Perinatology (2007) 27, S45-S47. doi:10.1038/sj.jp.7211842. PMID- 20838081 TI - Seasonal mapping of NICU temperature. AB - PURPOSE: To create a thermal map of ambient air, radiant, and evaporative temperatures and humidity throughout the NICU nursery by season across a calendar year. SUBJECTS: Each cubicle of the 32-bed NICU, distributed across 5 rooms, in a level III nursery was measured. METHODS: Temperatures were recorded at a consistent time on one day during January, April, July, and October. MAIN OUTCOME MEASURES: : An electronic monitor (QUESTemp degrees 34; Quest Technologies, Oconomowoc, Wisconsin) was used to measure dry bulb, wet bulb, and globe thermometer temperatures. RESULTS: Analysis of variance revealed statistically significant (P <= .000) differences in season, room, and season by room interaction. Room ambient air temperatures differed by less than 2 degrees F across season. Radiant temperature paralleled air temperature. Humidity, the predominant difference across season, produced evaporative temperatures considerably lower than room air temperature, and the gradient between mean nursery dry bulb temperature and wet bulb temperature was 9.3 degrees F in summer and 16.8 degrees F in winter. CONCLUSIONS: The thermal map revealed seasonal thermal differences, particularly in humidity level and evaporative temperature. Room temperature alone does not reflect the total thermal environment. Recommendations include periodic assessment of nurseries along with air, evaporative, and radiant temperatures as well as humidity to fully appreciate the impact of the thermal environment on infants. PMID- 20838082 TI - Thermoregulation and heat loss prevention after birth and during neonatal intensive-care unit stabilization of extremely low-birthweight infants. AB - Extremely low-birthweight infants have inefficient thermoregulation due to immaturity and may exhibit cold body temperatures after birth and during their first 12 hours of life. Hypothermia in these infants can lead to increased morbidity and mortality. Anecdotal notes made during our recent study revealed extremely low-birthweight infants' temperatures decreased with caregiver procedures such as umbilical line insertion, intubations, obtaining chest x-rays, manipulating intravenous lines, repositioning, suctioning, and taking vital signs during the first 12 hours of life. Therefore, nursing interventions should be undertaken to prevent heat loss during these caregiver procedures. Nurses can improve the thermal environment for extremely low-birthweight infants by prewarming the delivery room and placing the infant in a plastic bag up to the neck during delivery room stabilization to prevent heat loss. JOGNN, 36, 280-287; 2007. DOI: 10.1111/J.1552-6909.2007.00149.x. PMID- 20838084 TI - A mobile bioassay laboratory for the assessment of internal doses based on in vivo and in vitro measurements. AB - Internal exposures may occur in nuclear power plants, radioisotope production, and in medicine and research laboratories. Such practices require quick response in case of accidents of a wide range of magnitudes. This work presents the design and calibration of a mobile laboratory for the assessment of accidents involving workers and the population as well as for routine monitoring. The system was set up in a truck with internal dimensions of 3.30 m * 1.60 m * 1.70 m and can identify photon emitters in the energy range of 100-3,000 keV in the whole body, organs, and in urine. A thyroid monitor consisting of a lead-collimated NaI(Tl)3" * 3" (7.62 * 7.62 cm) detector was calibrated with a neck-thyroid phantom developed at the IRD (Instituto de Radioprotecao e Dosimetria). Whole body measurements were performed with a NaI(Tl)8" * 4" (20.32 * 10.16 cm) detector calibrated with a plastic-bottle phantom. Urine samples were measured with another NaI(Tl) 3" * 3" (7.62 * 7.62 cm) detector set up in a steel support. Standard solutions were provided by the National Laboratory for Metrology of Ionizing Radiation of the IRD. Urine measurements are based on a calibration of efficiency vs. energy for standard volumes. Detection limits were converted to minimum committed effective doses for the radionuclides of interest using standard biokinetic and dosimetric models in order to evaluate the applicability and limitations of the system. Sensitivities for high-energy activation and fission products show that the system is suitable for use in emergency and routine monitoring of individuals under risk of internal exposure by such radionuclides. PMID- 20838083 TI - Methylation analysis of fragile X-related epigenetic elements may provide a suitable newborn screening test for fragile X syndrome. PMID- 20838085 TI - Optimization of 99Mo measurement in 99mTc eluate samples using a scintillation detection system. AB - During elution of 99Mo-99mTc generators used in nuclear medicine, 99Mo might be extracted becoming a radionuclidic impurity. According to the International Atomic Energy Agency, the activity ratio between 99Mo and 99mTc in the eluate, at the moment of administration to the patient, should not exceed 0.015%. The aim of this work is to optimize a methodology to determine 99Mo activity in 99mTc eluates. Efficiency curves were obtained using a NaI(Tl)8"*4" scintillation detector. The methodology was validated by measuring a standard solution of 99Mo. It was concluded that the technique is sensitive to detect 99Mo in 99mTc eluates at levels below international limits. PMID- 20838086 TI - 131I Biokinetics and cytogenetic dose estimates in ablation treatment of thyroid carcinoma. AB - This study evaluated biokinetic behavior of radioiodine in the bodies of ten female adult patients, with well-differentiated thyroid cancer, treated with 131I post-near total thyroidectomy, for ablation of remnant thyroid. In vivo and in vitro bioassay analyses were performed from the first hour following radioiodine administration until minimum detection limits were reached. The retention of 131I in the body from day 1 to day 6 after the intake may be mathematically represented by an exponential decreasing curve, with an average biological half life of approximately 0.81 d, with the exception of patients who presented thyroiditis. From day 6 to day 13, urinary excretion rates indicated an increased liberation of iodine. After 2 wk, the body retention of iodine followed an exponential decrease, with a half-life of about 15 d. The average whole-body dose for these patients was 0.27 Gy, as estimated through cytogenetic techniques. PMID- 20838087 TI - Quantitative plutonium microdistribution in bone tissue of vertebra from a Mayak worker. AB - The purpose of this study was to obtain quantitative data on plutonium microdistribution in different structural elements of human bone tissue for local dose assessment and dosimetric models validation. A sample of the thoracic vertebra was obtained from a former Mayak worker with a rather high plutonium burden. Additional information was obtained on occupational and exposure history, medical history, and measured plutonium content in organs. Plutonium was detected in bone sections from its fission tracks in polycarbonate film using neutron induced autoradiography. Quantitative analysis of randomly selected microscopic fields on one of the autoradiographs was performed. Data included fission fragment tracks in different bone tissue and surface areas. Quantitative information on plutonium microdistribution in human bone tissue was obtained for the first time. From these data, the quantitative relationships of plutonium decays in bone volume to decays on bone surface in cortical and trabecular fractions were defined as 2.0 and 0.4, correspondingly. The measured quantitative relationship of decays in bone volume to decays on bone surface does not coincide with recommended models for the cortical bone fraction by the International Commission on Radiological Protection. Biokinetic model parameters of extrapulmonary compartments might need to be adjusted after expansion of the data set on quantitative plutonium microdistribution in other bone types in humans as well as other cases with different exposure patterns and types of plutonium. PMID- 20838088 TI - A physiological skeletal model for radionuclide and stable element biokinetics in children and adults. AB - A physiological skeletal model (PSM) is described that represents the skeletal uptake, retention, and clearance of both bone-surface-seeking and bone-volume seeking radionuclides and stable elements. A key objective of the PSM is to model the higher skeletal growth and bone turnover in infants and children (compared to adults) in order to account for their greater uptake and cancer risk from bone seeking contaminants such as lead and plutonium. The PSM is a compartmental model that allows for the incorporation of organic and inorganic material in the bone volume via quiescent bone surfaces, forming bone surfaces and the lacuno canaliculi system. The model uniquely incorporates a tertiary phase of mineralization via bone fluids. The PSM's structural concepts and biokinetic parameters--such as realistic mass transfers, organ and tissue masses, and bone remodeling half-times--are selected mainly on the basis of physiological and anatomical criteria. For brevity, model parameter values are evaluated for adults only. The PSM is an improvement on existing skeletal models that are based more on compartment structures and pathways that rendered good fits to biokinetic data rather than on being anatomically and physiologically accurate. PMID- 20838089 TI - Twenty-four years of follow-up for a Hanford plutonium wound case. AB - A 1985 plutonium puncture wound resulted in the initial deposition of 48 kBq of transuranic alpha activity, primarily 239+240Pu and 241Am, in a worker's right index finger. Surgical excisions in the week following reduced the long-term residual wound activity to 5.4 kBq, and 164 DTPA chelation therapy administrations over 17 mo resulted in urinary excretion of about 7 kBq. The case was published in 1988, but now 24 y of follow-up data are available. Annual bioassays have included in-vivo measurements of 241Am in the wound, skeleton, liver, lung, and axillary lymph nodes, and urinalyses for plutonium and 241Am. These measurements have shown relatively stable levels of 241Am at the wound site, with gradually increasing amounts of 241Am detected in the skeleton. Liver measurements have shown erratic detection of 241Am, and the lung measurements indicate Am but as interference from activity in the axillary lymph nodes and skeleton rather than activity in the lung. Urine excretion of Pu since termination of chelation therapy has typically ranged from 10 to 20 mBq d, with Am excretion about 10% of that for 239+240Pu. Annual routine medical exams have not identified any adverse health effects associated with the intake. PMID- 20838090 TI - Twelve years of follow up of cases with old 241Am internal contamination. AB - A group of workers internally contaminated with Am have been followed for about 12 years. The source of contamination was AmO2 powder used for production of AmBe neutron sources and other applications. The production of some radionuclide sources included chemical treatment of the original material, which transformed the americium into the nitrate, but mostly powder metallurgy was used for production of sources for smoke detectors. In vivo measurement of the workers was performed with two LEGe detectors placed near the head of the measured person. Calibration was performed with four different physical skull phantoms of different origin and a voxel phantom with Monte Carlo simulation, which was developed to fit the head sizes of individual persons. Samples of urine and feces were analyzed by means of radiochemical separation followed by alpha spectrometry. Separation of 241Am from mineralized excreta was performed by combined anion exchange and extraction chromatographic techniques. As a tracer, 243Am was used. When the measured data (83 data on skeletal activity, activity in 389 bioassay samples) were compared with International Commission on Radiological Protection's and Leggett's biokinetic models of americium, it was found that in most cases, after more than 15 y since the intake, the excretion rate was lower (or skeletal activity higher) than predicted. On the other hand, the ratio of excreted activity in urine and feces agrees well with model predictions. PMID- 20838091 TI - Impact on 141Ce, 144Ce, 95Zr, and 90Sr beta emitter dose coefficients of photon and electron SAFs calculated with ICRP/ICRU reference adult voxel computational phantoms. AB - The current dose coefficients for internal dose assessment of occupationally exposed persons and the general public were derived using the methodology of the International Commission on Radiological Protection (ICRP), which is similar to the Medical Internal Radiation Dose (MIRD)-type methodology. One component of this methodology is the mathematical representation of the human body (so-called MIRD-type phantoms) developed at the Oak Ridge National Laboratory for calculations of photon specific absorbed fractions (SAFs). Concerning the beta emissions, it is assumed in general that they irradiate only the organ where the radionuclide resides, whereas for walled organs, a fixed fraction of the emitted energy is absorbed within the wall. For the active marrow and bone surface targets, absorbed fractions were explicitly provided in ICRP Publication 30. The ICRP Publications 66 and 100 contain further detailed energy-dependent absorbed fraction data for the airways and the segments of the alimentary tract. In the present work, the voxel phantoms representing the reference male and female adults, recently developed at the Helmholtz Zentrum Munchen-German Research Center for Environmental Health (HMGU) in collaboration with the Task Group DOCAL of ICRP Committee 2, were used for the Monte Carlo computation of photon as well as electron SAFs. These voxel phantoms, being constructed from computed tomography (CT) scans of individuals, are more realistic in shape and location of organs in the body than the mathematical phantoms; therefore, they provide photon SAFs that are more precise than those stemming from mathematical phantoms. In addition, electron SAFs for solid and walled organs as well as tissues in the alimentary tract, the respiratory tract, and the skeleton were calculated with Monte Carlo methods using these phantoms to complement the data of ICRP Publications 66 and 100 that are confined to self-irradiation. The SAFs derived for photons and electrons are then used to calculate the dose coefficients of the beta emitters 141Ce, 144Ce, 95Zr, and 90Sr. It is found that the differences of the dose coefficients due to the revised SAFs are much larger for injection and ingestion than for inhalation. The equivalent doses for colon and ingestion with the new voxel-based SAFs are significantly smaller than the values with the MIRD type photon SAFs and simplifying assumptions for electrons. For lungs and inhalation, no significant difference was observed for the equivalent doses, whereas for injection and ingestion, an increase of the new values is observed. PMID- 20838092 TI - Dose conversion factors for radon: recent developments. AB - Epidemiological studies of the occupational exposure of miners and domestic exposures of the public have provided strong and complementary evidence of the risks of lung cancer following inhalation of radon progeny. Recent miner epidemiological studies, which include low levels of exposure, long duration of follow-up, and good quality of individual exposure data, suggest higher risks of lung cancer per unit exposure than assumed previously by the International Commission on Radiological Protection (ICRP). Although risks can be managed by controlling exposures, dose estimates are required for the control of occupational exposures and are also useful for comparing sources of public exposure. Currently, ICRP calculates doses from radon and its progeny using dose conversion factors from exposure (WLM) to dose (mSv) based on miner epidemiological studies, referred to as the epidemiological approach. Revision of these dose conversion factors using risk estimates based on the most recent epidemiological data gives values that are in good agreement with the results of calculations using ICRP biokinetic and dosimetric models, the dosimetric approach. ICRP now proposes to treat radon progeny in the same way as other radionuclides and to publish dose coefficients calculated using models, for use within the ICRP system of protection. PMID- 20838093 TI - Integration of uncertainties into internal contamination monitoring. AB - Potential internal contaminations of workers are monitored by periodic bioassays interpreted in terms of intake and committed effective dose through biokinetic and dosimetric models. After a prospective evaluation of exposure at a workplace, a suitable monitoring program can be defined by the choice of measurement techniques and frequency of measurements. However, the actual conditions of exposure are usually not well defined and the measurements are subject to errors. In this study we took into consideration the uncertainties associated with a routine monitoring program in order to evaluate the minimum intake and dose detectable for a given level of confidence. Major sources of uncertainty are the contamination time, the size distribution and absorption into blood of the incorporated particles, and the measurement errors. Different assumptions may be applied to model uncertain knowledge, which lead to different statistical approaches. The available information is modeled here by classical or Bayesian probability distributions. These techniques are implemented in the OPSCI software under development. This methodology was applied to the monitoring program of workers in charge of plutonium purification at the AREVA NC reprocessing facility (La Hague, France). A sensitivity analysis was carried out to determine the important parameters for the minimum detectable dose. The methods presented here may be used for assessment of any other routine monitoring program through the comparison of the minimum detectable dose for a given confidence level with dose constraints. PMID- 20838094 TI - Modeling intersubject variability of bronchial doses for inhaled radon progeny. AB - The main sources of intersubject variations considered in the present study were: (1) size and structure of nasal and oral passages, affecting extrathoracic deposition and, in further consequence, the fraction of the inhaled activity reaching the bronchial region; (2) size and asymmetric branching of the human bronchial airway system, leading to variations of diameters, lengths, branching angles, etc.; (3) respiratory parameters, such as tidal volume, and breathing frequency; (4) mucociliary clearance rates; and (5) thickness of the bronchial epithelium and depth of target cells, related to airway diameters. For the calculation of deposition fractions, retained surface activities, and bronchial doses, parameter values were randomly selected from their corresponding probability density functions, derived from experimental data, by applying Monte Carlo methods. Bronchial doses, expressed in mGy WLM-1, were computed for specific mining conditions, i.e., for defined size distributions, unattached fractions, and physical activities. Resulting bronchial dose distributions could be approximated by lognormal distributions. Geometric standard deviations illustrating intersubject variations ranged from about 2 in the trachea to about 7 in peripheral bronchiolar airways. The major sources of the intersubject variability of bronchial doses for inhaled radon progeny are the asymmetry and variability of the linear airway dimensions, the filtering efficiency of the nasal passages, and the thickness of the bronchial epithelium, while fluctuations of the respiratory parameters and mucociliary clearance rates seem to compensate each other. PMID- 20838095 TI - Three plutonium chelation cases at Los Alamos National Laboratory. AB - Chelation treatments with dosages of 1 g of either Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate) or Zn-DTPA (Trisodium zinc diethylenetriaminepentaacetate) were undertaken at Los Alamos Occupational Medicine in three recent cases of wounds contaminated with metallic forms of Pu. All cases were finger punctures, and each chelation injection contained the same dosage of DTPA. One subject was treated only once, while the other two received multiple injections. Additional measurements of wound, urine, and excised tissues were taken for one of the cases. These additional measurements served to improve the estimate of the efficacy of the chelation treatment. The efficacy of the chelation treatments was compared for the three cases. Results were interpreted using models, and useful heuristics for estimating the intake amount and final committed doses were presented. In spite of significant differences in the treatments and in the estimated intake amounts and doses amongst the three cases, a difference of four orders of magnitude was observed between the highest excretion data point and the values observed at about 100 d for all cases. Differences between efficacies of Zn-DTPA and Ca-DTPA could not be observed in this study. An efficacy factor of about 50 was observed for a chelation treatment, which was administered at about 1.5 y after the incident, though the corresponding averted dose was very small (LA-UR 09-02934). PMID- 20838096 TI - Case study: three acute 241Am inhalation exposures with DTPA therapy. AB - Three workers incurred inhalation exposures to Am oxide as a result of waste sorting and compaction activities. The exposure magnitudes were not fully recognized until the following day when an in-vivo lung count identified a significant lung deposition of Am in a male worker, and DTPA chelation therapy was initiated. Two additional workers (one female and one male) were then identified as sufficiently exposed to also warrant therapy. In-vivo bioassay measurements were performed over the ensuing 6 mo to quantify the 241Am activity in the lungs, liver, and skeleton. Urine and fecal samples were collected and showed readily detectable 241Am. Clinical lab tests and medical evaluations all showed normal results. There were no significant adverse clinical health effects from the therapy. The estimated 241Am inhalation intakes for the three workers were 1,800 Bq, 630 Bq, and 150 Bq. Lung retention showed somewhat longer pulmonary clearance half-times than standard inhalation class W or absorption Type M assumptions. The three subjects underwent slightly different therapy regimens, with therapy effectiveness factors (defined as the ratio of the reference doses without therapy relative to the final assessed doses) of 4.5, 1.9, and 1.7, respectively. PMID- 20838097 TI - The CONRAD approach to biokinetic modeling of DTPA decorporation therapy. AB - Diethylene Triamine Pentaacetic Acid (DTPA) is used for decorporation of plutonium because it is known to be able to enhance its urinary excretion for several days after treatment by forming stable Pu-DTPA complexes. The decorporation prevents accumulation in organs and results in a dosimetric benefit, which is difficult to quantify from bioassay data using existing models. The development of a biokinetic model describing the mechanisms of actinide decorporation by administration of DTPA was initiated as a task in the European COordinated Network on RAdiation Dosimetry (CONRAD). The systemic biokinetic model from Leggett et al. and the biokinetic model for DTPA compounds of International Commission on Radiological Protection Publication 53 were the starting points. A new model for biokinetics of administered DTPA based on physiological interpretation of 14C-labeled DTPA studies from literature was proposed by the group. Plutonium and DTPA biokinetics were modeled separately. The systems were connected by means of a second order kinetics process describing the chelation process of plutonium atoms and DTPA molecules to Pu-DTPA complexes. It was assumed that chelation only occurs in the blood and in systemic compartment ST0 (representing rapid turnover soft tissues), and that Pu-DTPA complexes and administered forms of DTPA share the same biokinetic behavior. First applications of the CONRAD approach showed that the enhancement of plutonium urinary excretion after administration of DTPA was strongly influenced by the chelation rate constant. Setting it to a high value resulted in a good fit to the observed data. However, the model was not yet satisfactory since the effects of repeated DTPA administration in a short time period cannot be predicted in a realistic way. In order to introduce more physiological knowledge into the model several questions still have to be answered. Further detailed studies of human contamination cases and experimental data will be needed in order to address these issues. The work is now continued within the European Radiation Dosimetry Group, EURADOS. PMID- 20838098 TI - Structure of a single model to describe plutonium and americium decorporation by DTPA treatments. AB - The aim of this study is to propose a single modeling structure to describe both plutonium and americium decorporation by DTPA, which is based on hypotheses mostly validated by experimental data. Decorporation efficacy of extracellular retention depends on the concentration ratio of DTPA vs. actinides and varies in each compartment according to the amount of biological ligands and their affinity for actinides. By contrast, because the relatively long residence time of DTPA after its cell internalization and the stability of actinide-DTPA complexes, intracellular decorporation efficacy is mainly controlled by a DTPA/actinide ratio, which is specific to each retention compartment. Although the affinity of DTPA is much lower for americium than for plutonium, a larger decorporation of americium can be obtained, which is explained by different biological ligands and/or their affinity for the actinide. Altogether, these results show that the relative contribution of intra vs. extracellular decorporation varies depending on the actinide, the chemical form of radionuclides, the galenic formulation of DTPA, and the treatment schedule. PMID- 20838099 TI - A case of wound intake of plutonium isotopes and 241Am in a human: application and improvement of the NCRP wound model. AB - Plutonium isotopes (239Pu and 238Pu, and 241Am) with a total activity of 269 kBq were accidentally deposited in a puncture wound of the right index finger of a nuclear worker at the Mayak Production Association. Tissues surrounding the wound site contaminated with radionuclides were excised 4.5 h after the injury. Residual contamination within the wound amounted to 0.05% of the initial contamination. The 10-d therapy with CaNa3-diethylene triamine pentaacetate acid (CaNa3-DTPA) was performed in parallel with in vivo measurements of the wound site and daily urine bioassays. The wound intake of radionuclides was consistent with two forms of radioactive materials detected within the wound site, i.e., soluble compounds and a large fragment, which was completely removed by excision. On day 9 after the injury, the clearance rate from the wound site was 1.8 times higher than the rate predicted by the National Council on Radiation Protection and Measurements (NCRP) model for soluble compounds of plutonium and americium. The NCRP model parameters of transfer rates from the colloid and intermediate state (CIS) into soluble, and particles, aggregates and bound state (PABS) compartments were modified to eliminate any difference. As a result, a difference between the observed wound site radionuclide content and the value predicted by the modified wound model did not exceed 14% up to 9 days after the injury. For a longer period from 7 to 24 months, the value predicted by the modified model was consistent with results of the corresponding in vivo measurements. The treatment reduced the effective dose (50 years) from internal exposure by at least 480 times. The dose estimated (without accounting for a contribution of exposure dose to the regional lymph nodes draining the wound site) did not exceed 11 mSv. PMID- 20838100 TI - Ingestion of 226Ra from activated paints on military equipment: transfer factors and doses. AB - The use of 226Ra-activated markings was specific for military equipment some decades ago and the extent of possible internal exposure of former military personnel due to ingestion of 226Ra is an issue of discussion. Whole- or partial body counts are not sensitive enough to trace an overexposure due to a possible 226Ra uptake four decades ago. Thus retrospective workplace assessments are needed. These are done by wiping tests with linen and skin pads on 226Ra markings on decommissioned military equipment. The contamination investigations are performed in wipe-activity measuring cycles with exponentially increasing numbers of wipes. The activity wiped off does not increase with the number of wipes but levels off instead. Wipes with linen pads are more effective than wipes with skin. The skin-skin activity transfer is investigated by respective wipes too. The maximum committed dose in a typical scenario is calculated under worst case assumptions. For the typical work of 1 y an effective dose of about 70 MUSv, and for the bone surface a dose of about 3 mSv, is obtained. PMID- 20838101 TI - Medical management of a cutaneous contamination. AB - The authors propose a process to improve the medical management of a cutaneous contamination in two ways: firstly by analysis of practices and products of decontamination used; secondly, by developing computer tools for the occupational physicians. This software will allow them to have a rapid dosimetric assessment in the event of a skin contamination by radioactive particles and will help them in their diagnostic and therapeutic decisions. A standardized data sheet was created allowing the exhaustive collection of adequate information in order to evaluate the skin dose. The selection of appropriate monitoring equipment with a 1 cm2 detector, depending on the place and on the surface of the contaminated area, will allow the evaluation and the quantification of the surface activities. A tool has been made as a software package, named Cutadose(r), allowing the assessment of the skin dose in situ as well as the efficacy of the prescribed therapy. PMID- 20838102 TI - Analysis of the variability of biokinetic model parameters due to inter individual variation. AB - Biokinetic models for the assessment of individual internal doses represent the physiological processes of a standardized human, which affect the internal distribution of the radionuclide of interest. The flow from one compartment into another is specified by transfer rates, which may vary from person to person. The rate constants are then representing the mean values for the population as a whole, around which individual parameters fluctuate according to given probability densities. Analytical distribution propagation can be calculated only for very simple models. The influence of inter-individual variation can be studied with Monte Carlo simulations, which compare the simulated compartment content distributions using different initial distributions for the parameters. The simulations indicate that the form of test distributions affect the distributions of compartment contents only for very simple models in the early stages. Later on, the distributions converge to a lognormal shape. The coefficients of variation of the initial distributions can be adjusted so that the resulting distributions resemble each other. Due to the lack of significant differences, lognormal distributions--which are found in most measurable body parameters--were used for further studies. The range of inter-subject variability can be estimated by comparing data generated with Monte Carlo simulations with observed data. For the plutonium model, data retrieved long times post intake are most suitable for this purpose when the redistribution of the radionuclide in the compartments is in a state of quasi-equilibrium and the ratio of plutonium in different compartments is nearly constant. For the estimation of inter-individual variability, the ratios of the main excretion paths and the organs of main burden can be used. The comparison of observed and simulated standard deviations indicates a value of 0.6 for the coefficient of variation for all transfer rates. The generated distributions show good agreement with the available data and thus confirm that the simulations can represent the inter-individual variation in the biokinetic plutonium model. PMID- 20838108 TI - Rethinking emergency department visits. AB - Efforts to date have been unable to reverse the trend of increased emergency department utilization. The Institute for Healthcare Improvement has developed a framework for reducing avoidable emergency department visits on the basis of the formation of local coalitions. These coalitions include interested partners approaching improvement by integrating community resources and nonmedical solutions. Targeted patient populations are identified via homogeneous characteristics. Open-ended interview questions are used to identify possible community and nonmedical solutions to complement medical strategies. This article describes the framework and process of testing. If validated, this approach will have significant policy implications. PMID- 20838103 TI - MEDECOR--a medical decorporation tool to assist first responders, receivers, and medical reach-back personnel in triage, treatment, and risk assessment after internalization of radionuclides. AB - After a radiological dispersal device (RDD) event, it is possible for radionuclides to enter the human body through inhalation, ingestion, and skin and wound absorption. From a health physics perspective, it is important to know the magnitude of the intake to perform dosimetric assessments. From a medical perspective, removal of radionuclides leading to dose aversion (hence risk reduction) is of high importance. The efficacy of medical decorporation strategies is extremely dependent upon the time of treatment delivery after intake. The "golden hour," or more realistically 3-4 h, is optimal when attempting to increase removal of radionuclides from extracellular fluids prior to cellular incorporation. To assist medical first response personnel in making timely decisions regarding appropriate treatment delivery modes, it is desirable to have a software tool that compiles existing radionuclide decorporation therapy data and allows a user to perform simple diagnosis leading to optimized decorporation treatment strategies. In its most simple application, the software is a large database of radionuclide decorporation strategies and treatments. The software can also be used in clinical interactive mode, in which the user inputs the radionuclide, estimated activity, route of intake and time since exposure. The software makes suggestions as to the urgency of treatment (i.e., triage) and the suggested therapy. Current developments include risk assessment which impacts the potential risk of delivered therapy and resource allocation of therapeutic agents. The software, developed for the Canadian Department of National Defence (DND), is titled MEDECOR (MEdical DECORporation). The MEDECOR tool was designed for use on both personal digital assistant and laptop computer environments. The tool was designed using HTML/Jscript, to allow for ease of portability amongst different computing platforms. This paper presents the features of MEDECOR, results of testing at a major NATO exercise, and future development of this tool into MEDECOR2. PMID- 20838109 TI - New directions in emergency service operations and planning. AB - Emergency services continue to evolve new operational and facility concepts in response to increasing demand for care and pressures for efficient, and safe, patient management. This article describes new models for "intake" of patients and for responding to peak demand that are radically changing the traditional emergency service. Application of Six Sigma and "Lean" analysis techniques are demonstrating dramatic improvements in throughput times and in the utilization of treatment spaces. This article provides an overview of the application of Lean concepts to emergency services. Case studies of Mary Washington Hospital and Banner Health Corporation illustrate the result of application of these tools. Implication for the required patient care areas and design concepts are also discussed. PMID- 20838110 TI - Building a national data repository to measure and improve health center quality. AB - Community health centers provide access to high-quality care for underserved populations and have a history of success with quality improvement initiatives, due to their mission and data reporting requirements. Investments in the health center infrastructure can bolster efforts to create a Nationwide Health Information Network to better utilize the available data. Aggregation, stratification by health center type, and use of patient-level quality data enable the development of quality measures that can be used to target health center resources and further improve quality. Health centers are fertile testing grounds for strategies to utilize data and performance measures to fuel quality improvements. PMID- 20838111 TI - Does health care setting matter in reports of discrimination? AB - We investigated the associations between the health care setting types that California adults report as their regular source of care, socioeconomic status, and perceived racial/ethnic medical care-related discrimination. Data were analyzed from the 2005 California Health Interview Survey (n = 36,694). Adults who identified clinics/health centers/hospital clinics or "other settings" as their usual source of health care had increased odds for perceived racial/ethnic discrimination compared with those who utilized private and health maintenance organizations doctors' offices, although this was true only for middle, but not lower or higher, socio-economic respondents. We suggest several explanations for these findings and improvements for assessing health care-based racial discrimination. PMID- 20838112 TI - Ambulatory cardiac single-photon emission computed tomography at the primary care physician's office: a descriptive study. AB - Ambulatory cardiac single-photon emission computed tomography stress testing for the evaluation of coronary artery disease at the primary care physician's office is increasingly utilized without data supporting its safety. In this 2-year prospective pilot study of 1266 consecutive stress-myocardial perfusion imaging studies done in the primary care physician's office using a mobile nuclear cardiology laboratory, adverse events were mild and rare. There were no recorded events of myocardial infarction, serious arrhythmias, severe bronchospasm, hospitalization, or death. This suggests that this practice is safe in this population with these providers. This finding may not apply to a higher-risk population. Further evaluation of referral appropriateness and long-term prognostic value is needed. PMID- 20838113 TI - Impact of a pay-for-performance incentive scheme on age, sex, and socioeconomic disparities in diabetes management in UK primary care. AB - We examined the impact of a major pay-for-performance initiative introduced into UK primary care in 2004 on disparities in diabetes management between age, sex, and socioeconomic groups in this retrospective cohort study. We used data from the General Practice Research Database enrolling 422 family practices. Existing disparities in risk factor management (HbA1c, blood pressure, cholesterol) narrowed between men and women. Younger patients (<45 years) with diabetes appear to have benefited less from Quality and Outcomes Framework than older patients, resulting in some widening of existing age group disparities. Patients living in affluent and deprived areas appeared to have derived a similar level of benefit from pay for performance. PMID- 20838114 TI - New trends in technology assessment: will comparative-effectiveness research and healthcare reform stifle medical device innovation? PMID- 20838115 TI - What if ...: you think a patient is faking? PMID- 20838117 TI - Pelvic fracture: the last 50 years. AB - The past 50 years have been a time of rapid progress in the control of mortality and morbidity of pelvic fracture. Early understanding of the anatomic features of the fracture and the potential for major, life-threatening arterial hemorrhage in a small proportion of patients led to multidisciplinary approaches designed to control hemorrhage and temporarily stabilize the fracture. Progress in the diagnosis and management of lower urinary tract injuries has resulted in maintenance of urinary continence and sexual function in a large proportion of patients with pelvic fracture-associated urinary tract injury. Finally, definitive open reduction and fixation of the fracture has led to permanent pelvic stability and pain-free walking in most patients. With successful combination of these approaches, survival and return to a satisfactory level of function is now the rule rather than the exception for patients with severe pelvic fracture. PMID- 20838118 TI - Results of the CONTROL trial: efficacy and safety of recombinant activated Factor VII in the management of refractory traumatic hemorrhage. AB - BACKGROUND: Traumatic coagulopathy contributes to early death by exsanguination and late death in multiple organ failure. Recombinant Factor VIIa (rFVIIa, NovoSeven) is a procoagulant that might limit bleeding and improve trauma outcomes. METHODS: We performed a phase 3 randomized clinical trial evaluating efficacy and safety of rFVIIa as an adjunct to direct hemostasis in major trauma. We studied 573 patients (481 blunt and 92 penetrating) who bled 4 to 8 red blood cell (RBC) units within 12 hours of injury and were still bleeding despite strict damage control resuscitation and operative management. Patients were assigned to rFVIIa (200 MUg/kg initially; 100 MUg/kg at 1 hour and 3 hours) or placebo. Intensive care unit management was standardized using evidence-based trauma "bundles" with formal oversight of compliance. Primary outcome was 30-day mortality. Predefined secondary outcomes included blood products used. Safety was assessed through 90 days. Study powering was based on prior randomized controlled trials and large trauma center databases. RESULTS: Enrollment was terminated at 573 of 1502 planned patients because of unexpected low mortality prompted by futility analysis (10.8% vs. 27.5% planned/predicted) and difficulties consenting and enrolling sicker patients. Mortality was 11.0% (rFVIIa) versus 10.7% (placebo) (p = 0.93, blunt) and 18.2% (rFVIIa) versus 13.2% (placebo) (p = 0.40, penetrating). Blunt trauma rFVIIa patients received (mean +/- SD) 7.8 +/- 10.6 RBC units and 19.0 +/- 27.1 total allogeneic units through 48 hours, and placebo patients received 9.1 +/- 11.3 RBC units (p = 0.04) and 23.5 +/- 28.0 total allogeneic units (p = 0.04). Thrombotic adverse events were similar across study cohorts. CONCLUSIONS: rFVIIa reduced blood product use but did not affect mortality compared with placebo. Modern evidence-based trauma lowers mortality, paradoxically making outcomes studies increasingly difficult. PMID- 20838119 TI - A randomized prospective trial of airway pressure release ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. AB - BACKGROUND: Airway pressure release ventilation (APRV) is a mode of mechanical ventilation, which has demonstrated potential benefits in trauma patients. We therefore sought to compare relevant pulmonary data and safety outcomes of this modality to the recommendations of the Adult Respiratory Distress Syndrome Network. METHODS: Patients admitted after traumatic injury requiring mechanical ventilation were randomized under a 72-hour waiver of consent to a respiratory protocol for APRV or low tidal volume ventilation (LOVT). Data were collected regarding demographics, Injury Severity Score, oxygenation, ventilation, airway pressure, failure of modality, tracheostomy, ventilator-associated pneumonia, ventilator days, length of stay (LOS), pneumothorax, and mortality. RESULTS: Sixty-three patients were enrolled during a 21-month period ending in February 2006. Thirty-one patients were assigned to APRV and 32 to LOVT. Patients were well matched for demographic variables with no differences between groups. Mean Acute Physiology and Chronic Health Evaluation II score was higher for APRV than LOVT (20.5 +/- 5.35 vs. 16.9 +/- 7.17) with a p value = 0.027. Outcome variables showed no differences between APRV and LOVT for ventilator days (10.49 days +/- 7.23 days vs. 8.00 days +/- 4.01 days), ICU LOS (16.47 days +/- 12.83 days vs. 14.18 days +/- 13.26 days), pneumothorax (0% vs. 3.1%), ventilator-associated pneumonia per patient (1.00 +/- 0.86 vs. 0.56 +/- 0.67), percent receiving tracheostomy (61.3% vs. 65.6%), percent failure of modality (12.9% vs. 15.6%), or percent mortality (6.45% vs. 6.25%). CONCLUSIONS: For patients sustaining significant trauma requiring mechanical ventilation for greater than 72 hours, APRV seems to have a similar safety profile as the LOVT. Trends for APRV patients to have increased ventilator days, ICU LOS, and ventilator-associated pneumonia may be explained by initial worse physiologic derangement demonstrated by higher Acute Physiology and Chronic Health Evaluation II scores. PMID- 20838120 TI - Posttraumatic lung injury after pulmonary contusion and fat embolism: factors determining abnormal gas exchange. AB - BACKGROUND: The objective was to investigate changes in pulmonary blood flow after lung contusion and fat embolism. METHODS: Eighteen mongrel dogs were randomly assigned to three groups: fat embolism alone (n = 7); moderate unilateral pulmonary contusion followed by fat embolism (n = 6); and severe unilateral pulmonary contusion followed by fat embolism (n = 5). Fat embolism was produced by intramedullary reaming of left femur and tibia followed by canal pressurization using bone cement. Outcome measures were systemic blood pressure, pulmonary artery pressure, pulmonary artery occluded pressure, cardiac output (CO), and partial pressures of arterial and mixed venous oxygen (Pao2, PvO2). Samples were taken from contused and noncontused contralateral lung to calculate regional pulmonary blood flow. RESULTS: After the fat embolism, pulmonary artery pressure and pulmonary vascular resistance increased significantly (p < 0.05) in all groups, whereas Pao2 decreased in groups 2 and 3 and at 30 minutes in group 1. CO decreased significantly in group 3. Group 3 also demonstrated a greater initial decrease in Pao2 and PvO2 from baseline and a larger increase in pulmonary vascular resistance. In those animals that underwent contusion, regional pulmonary blood flow was not found to be different between contused and noncontused lung segments. After contusion, flow decreased significantly in contused and noncontused segments in group 3 only. CONCLUSIONS: Gas exchange deteriorates because of decreased CO. For any preexisting intrapulmonary shunt, the decrease of PvO2 will cause worsening of Pao2. PMID- 20838121 TI - Health-related quality of life in patients with multiple injuries and traumatic brain injury 10+ years postinjury. AB - BACKGROUND: The aim of this study was to examine the long-term physical and psychological consequences of multiple blunt forced trauma at >= 10-year follow up for patients with and without traumatic brain injury (TBI). METHODS: A total of 620 patients with multiple injuries were assessed with the Medical Outcomes Study-Short Form-12 and a physical reexamination at >= 10-year follow-up. Injury related characteristics were collected from patients' medical record. Chi-square analysis, Analysis of Variance, and linear and logistic regression were performed to test differences between groups and examine predictors of physical and psychological functioning at >= 10-year follow-up. RESULTS: Patients with multiple injuries who sustained a TBI (n = 398) were more likely to be female (p = 0.001), younger in age at the time of injury (p = 0.02), have higher Injury Severity Scores (p = 0.001), shorter ward stays (p = 0.001), and a greater number of upper extremity injuries (p = 0.02) when compared with those without TBI (n = 222). Patients with TBI reported poorer psychological functioning (p = 0.02) and more frequently reported chronic pain (p = 0.01). Patients with TBI used medical aids (p = 0.002) less frequently at follow-up when compared with patients without TBI. Significant predictors of health-related quality of life at >= 10-year follow-up included age at the time of injury (physical; p = 0.001), gender (p = 0.05), number of ventilation days (p = 0.02), satisfaction with rehabilitation (p = 0.001), disability caused by the injury (p = 0.001), and use of medical aids (physical p = 0.02). CONCLUSIONS: Prospective studies are needed with a broader range of measures that may be sensitive to the consequences of TBI. Evidence based interventions to facilitate physical and psychological rehabilitation, designed to target at risk patients, are warranted. PMID- 20838122 TI - Population-based capture of long-term functional and quality of life outcomes after major trauma: the experiences of the Victorian State Trauma Registry. PMID- 20838123 TI - Evidence of hormonal basis for improved survival among females with trauma associated shock: an analysis of the National Trauma Data Bank. AB - BACKGROUND: Basic science research suggests that sex hormones affect survival after traumatic shock. This study sought to determine the independent effect of gender on mortality among trauma patients in different hormone-related age groups. METHODS: Review of severely injured trauma patients with shock included in the National Trauma Databank. Patients were stratified into three groups on the basis of likely hormonal status: prehormonal (age, 0-12 years), hormonal (age,13-64 years), and posthormonal (age, >= 65 years). Multiple logistic regression was used to analyze the independent effect of gender on mortality in each group, adjusting for anatomic and physiologic injury severity. RESULTS: A total of 48,394 patients met our inclusion criteria (Injury Severity Score >= 16 and systolic blood pressure <90 mm Hg). Crude mortality was higher (p < 0.05) for males in all categories: prehormonal = 29% for males (n = 3,553) versus 24% for females (n = 1,831); hormonal = 34% for males (n = 26,778) versus 30% for females (n = 8,677) and posthormonal = 36% for males (n = 4,280) versus 31% for females (n = 3,275). After adjusting for covariates, women in the hormonally active group had a 14% decreased odds of death (0.86 [95% CI, 0.76-0.93]) compared with men. Females did not exhibit this survival advantage in the prehormonal (odds of death = 0.92 [0.74-1.14]) or posthormonal (odds of death = 0.90 [0.76-1.05]) groups. CONCLUSIONS: Females aged between 13 and 64 years exhibit significantly lower mortality than males after trauma-associated shock. This outcome difference is lost at the extremes of age (preadolescent children and individuals aged >= 65 years) where the effects of sex hormones are absent or diminished. These findings suggest that hormonal differences play a role in the gender-based outcome disparities after traumatic shock. PMID- 20838124 TI - Anatomic distribution of bullet head injuries in combat fatalities. AB - BACKGROUND: Gun-shot wound head injury comprises a substantial fraction of combat injuries and a major cause of death in the battlefield. Current shielding gear is totally ineffective against bullets, because bullet-proof materials are too heavy to be worn on the head. The aim of this work was to describe the anatomic distribution of bullet entry wounds to the head in combat fatalities and to discern whether distribution is random (null hypothesis) or not. METHODS: We retrospectively examined the forensic external examination reports of all Israeli Defense Forces combat fatalities during the years 2000 to 2004, the Second Lebanon War (2006), and Operation Cast Lead (2009) and mapped the exact anatomic location of all bullet entry wounds to the calvaria. RESULTS: We found 76 gun shot entry wounds to the heads of 49 fatalities. Among these wounds, the occipital and anterior-temporal regions were found to be hit significantly more often than expected compared with their relative surface area (p < 0.001 and p < 0.001, respectively). Fifty-five percent of all injuries occurred within 15% of the surface area of skull. CONCLUSIONS: These findings imply that gun-shot entry wounds to the head are unevenly distributed. A partially bullet-proof protective helmet may prevent a substantial fraction of injuries (and fatalities) without a significant weight addition to the helmet. PMID- 20838125 TI - All trauma surgeons are not created equal: asymmetric distribution of malpractice claims risk. AB - BACKGROUND: Trauma surgery is perceived to have high malpractice risk. Unsolicited patient complaints (UPCs) can predict increased malpractice risk. An ex ante analysis of UPCs was performed to determine the risk profile for trauma surgeons compared with nontrauma surgeons. METHODS: UPCs from 14 health systems over 4 years were retrospectively studied. Surgeons were divided into nontrauma surgeons (NTS) and trauma surgeons (TS). Inclusion criteria for TS were practice at a Level I or geographically isolated Level II adult trauma center and either surgical critical care certification or American Association for the Surgery of Trauma, Eastern Association for the Surgery of Trauma, or Western Trauma Association membership. Standardized risk scores were generated using a weighted sum algorithm from UPC data. Mann-Whitney U test, Kolvogorov-Smirnov two-sample test for distribution, chi for linear trend, and relative risk analysis were performed. RESULTS: A total of 16,518 UPCs were filed against 4,244 surgeons, including 55 TS. 18% of TS and 57% of NTS had 0 UPCs. Mean risk score was higher for TS (29.2 +/- 29.0 vs. 10.2 +/- 19.5, p < 0.001), and more TS (20.0% vs. 3.15%) were at moderate (score 50-69) or at high risk (score >70) (7.27% vs. 2.57%; p < 0.001), reflecting a shifted risk distribution (p < 0.001) compared with NTS. TS have a relative risk of 6.17 (95% CI: 3.36-11.33) for score >50. CONCLUSIONS: TS are at increased risk of UPCs compared with NTS, but this risk is still largely borne by a minority of TS. UPCs seem to be a reasonable proxy for malpractice risk, so targeted interventions for TS associated with disproportionate shares of UPCs may reduce patient dissatisfaction and, perhaps, malpractice claims. PMID- 20838126 TI - Postoperative neuromuscular blocker use is associated with higher primary fascial closure rates after damage control laparotomy. AB - BACKGROUND: Failure to achieve fascial primary closure after damage control laparotomy (DCL) is associated with increased morbidity, higher healthcare expenditures, and a reduction in quality of life. The use of neuromuscular blocking agents (NMBA) to facilitate closure remains controversial and poorly studied. The purpose of this study was to determine whether exposure to NMBA is associated a higher likelihood of primary fascial closure. METHODS: All adult trauma patients admitted between January 2002 and May 2008 who (1) went directly to the operating room, (2) were managed initially by DCL, and (3) survived to undergo a second laparotomy. Study group (NMBA+): those receiving NMBA in the first 24 hours after DCL. Comparison group (NMBA-): those not receiving NMBA in the first 24 hours after DCL. Primary fascial closure defined as fascia-to-fascia approximation by hospital day 7. RESULTS: One hundred ninety-one patients met inclusion (92 in NMBA+ group, 99 in NMBA- group). Although the NMB+ patients were younger (31 years vs. 37 years, p = 0.009), there were no other differences in demographics, severity of injury, or lengths of stay between the groups. However, NMBA+ patients achieved primary closure faster (5.1 days vs. 3.5 days, p = 0.046) and were more likely to achieve closure by day 7 (93% vs. 83%, p = 0.023). After controlling for age, gender, race, mechanism, and severity of injury, logistic regression identified NMBA use as an independent predictor of achieving primary fascial closure by day 7 (OR, 3.24, CI: 1.15-9.16; p = 0.026). CONCLUSIONS: Early NMBA use is associated with faster and more frequent achievement of primary fascial closure in patients initially managed with DCL. Patients exposed to NMBA had a three times higher likelihood of achieving primary fascial closure by hospital day 7. PMID- 20838127 TI - Treatment of major hepatic necrosis: lobectomy versus serial debridement. AB - BACKGROUND: Major hepatic necrosis (MHN) is a common complication after angioembolization (AE) for severe liver injuries. We compared the outcomes of two treatment modalities. METHODS: Patients with MHN were retrospectively reviewed from January 2002 to October 2007. Demographics, Injury Severity Scale score, length of stay, admission Glasgow Coma Scale Score, mortality, transfusion requirements, intra-abdominal complications, admission physiologic variables, and the number and type of abdominal procedures (operative or nonoperative) were collected. These patients were then divided into two groups-those treated with hepatic lobectomy (HL) and those treated with multiple procedures including serial operative debridements and/or percutaneous drainage (IR/OR). RESULTS: Thirty patients (41%) with MHN were identified from 71 patients who had AE. Sixteen patients with MHN underwent HL and 14 patients underwent multiple IR/OR procedures. The two groups were similar at baseline, except that the HL group had a higher Injury Severity Scale score. Outcomes between the two groups were similar. There was a significantly higher complication rate and increased number of procedures in the IR/OR group. There were no deaths in patients who had early HL (<5 days). There was one death in the later lobectomy group. CONCLUSION: MHN is a common complication after AE. This complication can be safely managed with a series of operative debridements in conjunction with interventional procedures or with HL. Lobectomy is associated with a lower complication rate and a fewer number of procedures. Early lobectomy may be better than a delayed procedure. PMID- 20838128 TI - Do chronic liver disease scoring systems predict outcomes in trauma patients with liver disease? A comparison of MELD and CTP. AB - BACKGROUND: Although the Child-Turcotte-Pugh (CTP) score is an established outcome prediction tool for patients with liver disease, the Model for End-Stage Liver Disease (MELD) score has recently supplanted CTP for patients awaiting transplantation. Currently, data regarding the use of CTP in trauma is limited, whereas MELD remains unstudied. We compared MELD and CTP to determine which scoring system is a better clinical outcome predictor after trauma. METHODS: A review of trauma admissions during 2003-2008 revealed 68 patients with chronic liver disease. Single and multiple variable analyses determined predictors of hepatic complications and survival. MELD and CTP were compared using odds ratios and area under the receiver operating curve (AUC) analyses. A p value <=0.05 was significant. RESULTS: The mean MELD and CTP scores of the population were 13.1 +/ 6.0 and 8.3 +/- 1.8, respectively (mean +/- SD). Overall, 73.5% had one or more complications and 29.4% died. When survivors were compared with nonsurvivors, no difference in mean MELD scores was found, although mean CTP score (survivors, 7.7 +/- 1.5; nonsurvivors, 9.4 +/- 1.9; p = 0.001) and class ("C" survivors, 12.1%; "C" nonsurvivors, 56.3%; p = 0.002) were different, with survival relating to liver disease severity. Odds ratios and AUC determined that MELD was not predictive of hepatic complications or hospital survival (p > 0.05), although both CTP score and class were predictive (p < 0.05; AUC > 0.70). CONCLUSION: Trauma patients suffering from cirrhosis can be expected to have poorer than predicted outcomes using traditional trauma scoring systems, regardless of injury severity. Scoring systems for chronic liver disease offer a more effective alternative. We compared two scoring systems, MELD and CTP, and determined that CTP was the better predictor of hepatic complications and survival in our study population. PMID- 20838129 TI - The selenium status of pediatric patients with burn injuries. AB - BACKGROUND: Dietary selenium (Se) requirements during critical illness are not well known. The objective of this study was to assess the longitudinal Se status of pediatric patients with burns. METHODS: Twenty patients admitted to our hospital with burns exceeding 10% of their total body surface area were studied longitudinally during the first 8 weeks of admission or until 95% wound closure was achieved. Dietary Se intake was calculated daily, and plasma and urine samples were collected weekly for analyses of plasma Se, urinary Se, and glutathione peroxidase activity. RESULTS: Patients included in this study were individuals with an average age of 6.5 years +/- 5.3 years and with burn injury of a mean total body surface area of 42% +/- 21%. Dietary Se intake throughout the study (mean = 60 MUg/d +/- 39 MUg/d) was consistent with established standards for healthy children and did not change throughout the study. Plasma Se (mean = 1.08 MUmol/L +/- 0.34 MUmol/L) and plasma glutathione peroxidase (mean = 3.2 U/g protein +/- 1.42 U/g protein) were below reported normal values for healthy American children. Mean urinary Se excretion (65.9 MUg/L +/- 50 MUg/L) exceed dietary Se intake. Plasma Se was inversely related to incidence of total infection (p = 0.04). CONCLUSIONS: Results from this study indicate that Se status is depressed among pediatric patients with burns and that recommended Se intake for healthy children is likely insufficient for this population. Further studies are necessary to elucidate the amount of dietary Se required to maximize Se stores among pediatric patients with burn injuries. PMID- 20838130 TI - The association of mobile medical team involvement on on-scene times and mortality in trauma patients. AB - OBJECTIVES: Mobile medical teams (MMTs) provide specialized care on-scene with the purpose to improve outcome. However, this additional care could prolong the on-scene time (OST), which is related to mortality. The purpose of this study was to assess the effects of MMT involvement on the mortality rate and on the OST, in a Dutch consecutive cohort of Level I trauma patients. METHODS: All patients who required presentation in the trauma resuscitation room in an urban Level I trauma center were included in this prospective study during the period of November 2005 till November 2007. For data collection, we used both pre- and in-hospital registration systems. Outcome measures were 30-day mortality and OST. RESULTS: In total, 1,054 patients were analyzed. In 172 (16%) patients, the MMT was involved. Mortality was significantly higher in the MMT group compared with patients treated without MMT involvement; 9.9% versus 2.7%, respectively (p < 0.001). Significantly higher Injury Severity Scores, intervention rates, and a significantly lower Triage Revised Trauma Score were found in patients treated by MMT. After adjustment for patient and injury characteristics, no association could be found between MMT involvement and higher mortality (95% CI, 0.581-3.979; p = 0.394). In patients with severe traumatic brain injury (GCS score <= 8) in whom a MMT was involved, the mortality was 25.5%, compared with 32.7% in those without MMT involvement (p = 0.442). The mean OST was prolonged (2.7 minutes) when MMT was involved (26.1 vs. 23.4 minutes; p = 0.003). CONCLUSIONS: In this study, OSTs were long compared with PHTLS recommendations. MMT involvement slightly prolonged the OST. Trauma patients with MMT involvement had a high mortality, but after correction for patient and injury characteristics, the mortality rate did not significantly differ from patients without MMT involvement. PMID- 20838131 TI - Scoop and run to the trauma center or stay and play at the local hospital: hospital transfer's effect on mortality. AB - BACKGROUND: Triage attempts to ensure that severely injured patients are transported to a high-level trauma facility to reduce mortality. However, some patients are triaged to the nearest medical facility before transport to a final destination trauma center (TC). We sought to analyze whether initial triage of critically injured patients to a nontrauma center (NTC) is associated with increased mortality. METHODS: The Glue Grant Trauma Database of severely injured patients was analyzed. Mortality risk for patients who had an intermediate stop at another facility was compared with patients triaged directly from the scene to the TC. Patient demographics, time from injury to TC arrival, resuscitation volume, transfusions, head injury, initial systolic blood pressure, co morbidities, and injury severity were included as confounders in a multivariate logistic regression model. RESULTS: There were 1,112 patients of whom 318 (29%) were initially triaged to an NTC. After adjusting for confounders, this was associated with an increase in prehospital crystalloids (4.2 L vs. 1.4 L, p < 0.05) and a 12-fold increase in blood transfusions (60% vs. 5%, p < 0.001). Age, injury severity score, Acute Physiology and Chronic Health Evaluation II score, and time from injury to TC arrival were independent predictors of mortality. The odds of death were 3.8 times greater (95% CI, 1.6-9.0) when patients were initially triaged to a nontrauma facility. CONCLUSIONS: Triaging severely injured patients to hospitals that are incapable of providing definitive care is associated with increased mortality. Attempts at initial stabilization at an NTC may be harmful. These findings are consistent with a need for continued expansion of regional trauma systems. PMID- 20838132 TI - Rapid discharge after transfer: risk factors, incidence, and implications for trauma systems. AB - BACKGROUND: The occurrence of discharge to home shortly after transfer from another hospital, also termed "secondary overtriage," needs to be analyzed in trauma patients because it helps to assess the efficiency of triage and transfer criteria. The extent of secondary overtriage and factors associated with it remain largely undescribed. METHODS: A retrospective analysis of the Nationwide Inpatient Sample from 2000 to 2004. Inclusion criteria were trauma patients (as identified by ICD-9 diagnosis codes of 800-959 in the primary position, excluding codes representing late effects of injury, foreign body, burn, or early complications) who were admitted as transfers from another hospital. Rapid discharge after transfer (secondary overtriage) was defined as patients who were discharged alive within 1 day after transfer and did not receive any surgical procedure. RESULTS: The overall rate of secondary overtriage was 6.9% (3,291 of 51,278), with an increasing trend over the years. This rate was significantly higher among patients younger than 18 years (19.5% vs. 4.2%). Patients meeting the definition were more likely to be male (68.3% vs. 50.65%), more likely to be black or Hispanic (25.16% vs. 16.8%), more likely to come from ZIP codes with above-median household incomes (43.4% vs. 38.1%), and more likely to be treated at teaching hospitals (77.3% vs. 61.3%). The majority of these patients (98.7%) were insured, although the proportion of uninsured patients was significantly higher among secondary overtriage (1.3% vs. 0.54%). On multivariate analysis, younger age, uninsured status, and being transferred to a teaching hospital were associated with higher likelihood of rapid discharge after transfer. No association was found with gender, race, and urbanicity. CONCLUSION: Secondary overtriage is more common in pediatric patients than in adults. The underlying causes of this occurrence need to be further investigated (e.g., fear of litigation and uneven distribution of resources). There are significant direct and indirect costs associated with these occurrences that must be considered as we identify areas of potential cost savings in our nation's health care. PMID- 20838133 TI - The effect of resident duty hour restriction on trauma center outcomes in teaching hospitals in the state of Pennsylvania. AB - BACKGROUND: Resident duty hour restriction was instituted to improve patient safety, but actual impact on patient care is unclear. We sought to determine the effect of duty hour restriction on trauma outcomes in Level I trauma centers (TCs; surgery residency programs) versus Level II TCs (those with no surgery residency programs) within the state of Pennsylvania, using noninferiority as our hypothesis testing. METHODS: Outcomes (mortality and length of stay [LOS]) were compared in Level II TCs without surgery residencies (n = 7) with Level I TCs (with surgery residencies; n = 14) PRE80 (2001-2003) and POST80 (2004-2007). The subcategories of critically injured patients, Injury Severity Score (ISS) >15, ISS >25, Trauma and Injury Severity Score (TRISS) <= 50, Abbreviated Injury Scale (AIS) head/chest/abdomen score >3, age >65 years, mechanism, and shock, functioned as outcome predictors. RESULTS: There was a decrease in mortality overall PRE80 to POST80 for Level I and II TCs. There was a decrease in mortality in Level I TCs POST80 in ISS >15 (16.5% vs. 14.8%, p = 0.0001), AIS (head) score >3 (20.8% vs. 17.8%, p < 0.0001), age >65 years (12.2% vs. 10.7%, p = 0.0013), and blunt mechanism (5.2% vs. 4.6%, p = 0.0004). LOS was reduced in ISS >15, AIS (head) score >3, age >65 years, and penetrating mechanism in Level I TCs POST80. A similar but more profound decrease was also seen in Level II TCs PRE80 and POST80 (ISS >15, 25; AIS (head) score; shock; blunt mechanism; and TRISS <= 50). Testing for inhomogeneity identified less-severely injured patients at Level II TCs POST80 compared with Level I TCs in certain subcategories (ISS >15, 25; AIS (head) score; shock; blunt mechanism; and TRISS <= 50) regarding mortality and LOS (TRISS >50%). CONCLUSIONS: Decreases in mortality and LOS during the study periods were likely not related to resident work hour restriction but rather to overall improvement in outcomes seen at Level II (no residents) and Level I (residents) TCs. Resident work hour restrictions had no discernible effect on patient care (noninferiority). PMID- 20838134 TI - Quality in trauma care: improving the discharge procedure of patients by means of Lean Six Sigma. AB - BACKGROUND: The University Medical Center Groningen is a level I trauma center in the northern part of the Netherlands. Sixty-three percent of all the patients admitted at the Trauma Nursing Department (TND) are acute patients who are admitted directly after trauma. In 2006 and 2007, the University Medical Center Groningen was not always capable of admitting all trauma patients to the TND due to the relatively high-bed occupation. Therefore, the reduction of the average length of stay (LOS) formed the objective of the project described in this study. METHODS: We used the process-focused method of Lean Six Sigma to reduce hospital stay by improving the discharge procedure of patients in the care processes and eliminating waste and waiting time. We used the "Dutch Appropriateness Evaluation Protocol" to identify the possible causes of inappropriate hospital stay. The average LOS of trauma patients at the TND at the beginning of the project was 10.4 days. RESULTS: Thirty percent of the LOS was unnecessary. The main causes of the inappropriate hospital stay were delays in several areas. The implementation of the improvement plan reduced almost 50% of the inappropriate hospital stay, enabling the trauma center to admit almost all trauma patients to the TND. After the implementation of the improvements, the average LOS was 8.5 days. CONCLUSION: Our study shows that Lean Six Sigma is an effective method to reduce inappropriate hospital stay, thereby improving the quality and financial efficiency of trauma care. PMID- 20838135 TI - Regionalization of surgical services in central Florida: the next step in acute care surgery. AB - BACKGROUND: There is a national loss of access to surgeons for emergencies. Contributing factors include reduced numbers of practicing general surgeons, superspecialization, reimbursement issues, emphasis on work and life balance, and medical liability. Regionalizing acute care surgery (ACS), as exists for trauma care, represents a potential solution. The purpose of this study is to assess the financial and resources impact of transferring all nontrauma ACS cases from a community hospital (CH) to a trauma center (TC). METHODS: We performed a case mix and financial analysis of patient records with ACS for a rural CH located near an urban Level I TC. ACS patients were analyzed for diagnosis, insurance status, procedures, and length of stay. We estimated physician reimbursement based on evaluation and management codes and procedural CPT codes. Hospital revenues were based on regional diagnosis-related group rates. All third-party remuneration was set at published Medicare rates; self-pay was set at nil. RESULTS: Nine hundred ninety patients were treated in the CH emergency department with 188 potential surgical diseases. ACS was necessary in 62 cases; 25.4% were uninsured. Extrapolated to 12 months, 248 patients would generate new TC physician revenue of >$155,000 and hospital profits of >$1.5 million. CH savings for call pay and other variable costs are >$100,000. TC operating room volume would only increase by 1%. CONCLUSION: Regionalization of ACS to TCs is a viable option from a business perspective. Access to care is preserved during an approaching crisis in emergency general surgical coverage. The referring hospital is relieved of an unfavorable payer mix and surgeon call problems. The TC receives a new revenue stream with limited impact on resources by absorbing these patients under its fixed costs, saving the CH variable costs. PMID- 20838136 TI - Poorer outcomes for mass casualty events victims: is it evidence based? AB - BACKGROUND: The sudden influx of patients during mass casualty events (MCEs) may compromise the quality of care provided and possibly impact on the medical outcomes of these patients. To test this assumption, a comparison must be made between injuries sustained in MCE and non-MCE events caused by the same mechanism. The mechanism of injury selected for this study was gunshot wounds, which occur in both types of event. METHODS: A retrospective study was carried out using the Israel's National Trauma Registry data on patients hospitalized between November 1, 2000, and December 31, 2005, as a result of high-energy gunshot trauma. Descriptive statistics and bivariate analysis were used to characterize injury patterns, and multivariate analysis was used to determine factors influencing inpatient mortality. RESULTS: Of 462 patients with gunshot wounds, 120 cases (26.38%) were defined as MCE and 342 (73.62%) as non-MCE. Both populations had ~30% of severely injured patients (Injury Severity Score 16+). MCE patients had undergone significantly fewer operational procedures. No differences between MCE and non-MCE were found in intensive care units utilization. The likelihood of death as a result of MCE was 2.75 (CI 1.09-7.02) times higher than non-MCE. Factors influencing this difference are the number of injured regions and injuries to the brain, chest, and abdomen. CONCLUSIONS: MCE patients have a significantly higher mortality than non-MCE patients, not manifesting substantial differences in the severity of injuries. The absence of difference in intensive care units utilization may be related to the effectiveness of existing protocols for dealing with MCEs. PMID- 20838137 TI - Effect of posterior malleolus fracture on outcome after unstable ankle fracture. AB - BACKGROUND: The purpose of this article was to compare clinical and functional outcomes of surgically treated trimalleolar fractures with bimalleolar and unimalleolar ankle fractures. METHODS: A prospective database was established to enroll all unstable ankle fractures treated operatively at our institution from October 2000 to July 2005. Demographic data on 456 patients, who sustained an unstable fracture of the ankle and were treated surgically, were entered into a database, and the patients were prospectively followed up. Of these 309 patients who had at least 1-year follow-up, 54 patients sustained an ankle fracture with involvement of the posterior malleolus. Two hundred fifty-five patients had an ankle fracture without involvement of the posterior malleolus. Of the 54 posterior malleolus fracture, 20 underwent fixation of the posterior malleolus. All patients were followed up at 3 months, 6 months, and 12 months after surgery and assessed functionally with Short Musculoskeletal Function Assessment and American Orthopaedic Foot and Ankle Society Scores. RESULTS: There was no difference in age, sex distribution, or American society of anesthesiologists classification or incidence of diabetes between the two groups. At 1-year follow up, all patients improved their function and pain status. Using the American Orthopaedic Foot and Ankle Society, patients with posterior malleolus fracture were significantly worse both for total score (p = 0.004) and pain function (p = 0.002). At 2-year follow-up, there was no significant difference in a smaller group of patients (41 patients). Using the Short Form-36, there was a significant difference seen with vitality and social function subgroups at 1 year. Using the Short Musculoskeletal Function Assessment, there was a significant difference at 1 year for dysfunction index (p = 0.04) for the trimalleolar group. CONCLUSION: Most patients after unstable ankle fractures treated surgically do well; however, some patients continue to have some pain and dysfunction at 1 year. There was a significant difference in outcomes comparing patients with unstable ankle fractures associated with and without posterior malleolus fractures. The presence of a posterior malleolus fracture may indicate higher energy of injury, and it does seem to result in worse outcomes at 1 year, but this seems to even out over time as was seen at 2-year follow-up in a smaller group of patients. PMID- 20838138 TI - Fixation of periprosthetic femur fractures above total knee arthroplasty with the less invasive stabilization system: a midterm follow-up study. AB - BACKGROUND: The complication rate of periprosthetic femoral fractures above well fixed total knee arthroplasties is high. The Less Invasive Stabilization System (LISS) was introduced to reduce surgical dissections at the fracture site. The purpose of this retrospective study was to evaluate the midterm functional outcome of a group of patients with periprosthetic fractures above well-fixed total knee arthroplasties treated with the LISS. METHODS: Between January 1999 and June 2004, 23 consecutive patients (all women) with periprosthetic fractures above well-fixed total knee arthroplasties were treated with the LISS. The mean age was 77 years (range, 61-90 years). RESULTS: Nineteen of the patients (83%) were seen after a midterm follow-up of 46 months (range, 26-67 months). Three patients (13%) died, and one patient (4%) was lost to follow-up. A proximal screw pull-out of the internal fixator occurred in one patient (4%). All fractures healed within a mean of 14 weeks (range, 9-21 weeks). No bone graft was required. There were two delayed unions, no nonunions or infections. One patient (4%) had a malalignment with 7 degrees varus. The mean range of motion was 102 degrees (range, 65-120 degrees ). The mean knee score of the Knee Society was 81 points (range, 65-90 points), and the mean function score of the Knee Society was 56 points (range, 35-90 points). CONCLUSIONS: We found that a minimally invasive, locked plating system permitted stable fixation, early knee motion with good midterm results, and minimal complications. These techniques should be used in place of less stable and more invasive methods. PMID- 20838139 TI - Early definitive stabilization of unstable pelvis and acetabulum fractures reduces morbidity. AB - BACKGROUND: Although the benefits of acute stabilization of long bone fractures are recognized, the role of early fixation of unstable pelvis and acetabular fractures is not well-defined. The purpose of this study was to review complications and hospital course of patients treated surgically for pelvis and acetabulum fractures. We hypothesized that early definitive fixation would reduce morbidity and decrease length of stay. METHODS: Six hundred forty-five patients were treated surgically at a level I trauma center for unstable fractures of the pelvic ring (n = 251), acetabulum (n = 359), or both (n = 40). Mean age was 40.5 years, and mean Injury Severity Score (ISS) was 25.6 (range 9-66). They were retrospectively reviewed to determine complications including acute respiratory distress syndrome (ARDS), pneumonia, deep vein thrombosis, pulmonary embolism, multiple organ failure (MOF), infections, and reperations. RESULTS: Definitive fixation was within 24 hours of injury in 233 patients (early, mean 13.4 hours) and >24 hours in 412 (late, mean 99.2 hours). Twenty-nine patients (12.4%) had complications after early fixation versus 81 (19.7%) after late, p = 0.006. Length of stay and intensive care unit days were 10.7 days versus 11.6 days (p = 0.26) and 8.1 days versus 9.9 days (p = 0.03) for early and late groups, respectively. With ISS >18 (n = 165 early [ISS 32.7]; n = 253 late [ISS 33.1]), early fixation resulted in fewer pulmonary complications (12.7% versus 25%, p = 0.0002), less ARDS (4.8% versus 12.6%, p = 0.019), and less MOF (1.8% versus 4.3%, p = 0.40). Rates of complications, pulmonary complications, deep vein thrombosis, and MOF were no different for patients with pelvis versus acetabulum fractures. In patients receiving >= 10U packed red blood cells (n = 41 early, n = 56 late) early fixation led to fewer pulmonary complications (24% versus 55%, p = 0.002), less ARDS (12% versus 25%, p = 0.09), and MOF (7.3% versus 14%, p = 0.23). Two hundred ten patients had some chest injury (32.6%). Chest injury with Abbreviated Injury Scores >= 3 was present in 46 (19.7%) of early and 78 (18.9%) of late patients (p = 0.44) and was associated with pulmonary complications in 26.1% versus 35.9%; ARDS in 15.2% versus 23.1%; and MOF in 6.5% versus 6.4%, respectively (all p > 0.20). However, chest injury with Abbreviated Injury Scores >= 3 was independently associated with more complications including ARDS (20.2% versus 3.3%, p < 0.0001), other pulmonary complications (32.3% versus 10.4%, p < 0.0001), and MOF (6.5% versus 1.2%, p = 0.0016), regardless of timing of fixation. CONCLUSIONS: Early fixation of unstable pelvis and acetabular fractures in multiply injured patients reduces morbidity and length of intensive care unit stay, which may decrease treatment costs. Further study to ascertain the effects of associated systemic injuries and the utility of physiologic and laboratory parameters during resuscitation may delineate recommendations for optimal surgical timing in specific patient groups. PMID- 20838140 TI - Injury patterns and psychological traits of patients with self-inflicted wounds produced by punching glass. AB - BACKGROUND: Self-inflicted injuries are among the preventable forms of hand injury. Psychologic factors underlying these injuries have not been studied sufficiently. This study aims to reveal the extent of injury and the morbidity as well as the psychologic factors in a population of patients who intentionally injured themselves by punching glass. METHODS: Patients seen and treated for glass punching injuries during a 4.5-year period were reviewed. The demographic data included the extent of injury, postoperative hospitalization time, and full recovery time. Their psychologic traits were analyzed by two questionnaires (Symptom Distress Check List and State-Trait Anger Expression Inventory) and through a psychiatric interview. The results were compared with a sex- and age matched control group with accidental hand injuries. RESULTS: The study group consisted of 36 patients. Mean age was 24.7 years. Most were men (n = 28), not married (n = 28), and living with their families. Half of them were unemployed. Twelve had only skin lacerations. The remaining 24 patients had a total of 45 tendon, 15 nerve, and 9 artery injuries. On an average, 46 days were required for full recovery. A second attempt of self-infliction was not reported. Twenty-one patients underwent questionnaires and psychiatric interview. The study group felt significantly higher levels of psychologic distress and hostility (p = 0.018 and p = 0.002, respectively). They also had higher levels of anger in daily life (p = 0.002). Clinical psychiatric evaluation failed to reveal any significant psychiatric disorder. CONCLUSION: Self-inflicted hand injuries increase the workload of emergency services and clinics involved in the treatment. Prevention is very difficult, especially when alcohol is not an underlying cause. A typical patient has hostile and disobedient characteristics and who easily expresses his anger. Happily, having suffered enough during their treatment these patients do not attempt a second self-infliction. PMID- 20838141 TI - Pregnancy outcomes after orthopedic trauma. AB - BACKGROUND: This study was performed to determine the effects of orthopedic trauma on pregnancy outcomes in pregnant trauma patients. METHODS: This was an observational study completed after electronically linking databases for the obstetric service and the trauma service at our Level I trauma center. All pregnant women who presented during the years 1995 to 2007 were eligible for inclusion. Selected pregnancy outcomes in women who delivered at our trauma center during or after their trauma admission were evaluated according to the presence of orthopedic injuries. Statistical analyses were performed using chi, Student's t test, and Wilcoxon rank-sum test; and p < 0.05 are considered statistically significant. RESULTS: There were 65 pregnant women with orthopedic injuries (6%) and 990 without orthopedic injuries. Women with orthopedic trauma had an average gestational age of 28 weeks versus 31 weeks for women without orthopedic trauma. Compared with the patients without orthopedic injuries, patients with orthopedic injuries had a significant increased risk of preterm birth before 37 weeks of gestation (31% vs. 3%; p < 0.001), an increased risk of placental abruption (8% vs. 1%; p < 0.001), and an increased risk of perinatal mortality (8% vs. 1%; p < 0.001). CONCLUSIONS: Our findings indicate that traumatized pregnant women with orthopedic injuries are high-risk obstetrical patients and may benefit from referral to a medical center capable of handling both the primary injury and the potential preterm birth associated with the injury. PMID- 20838142 TI - Speed kills? Not always: the New York State thruway experience. AB - BACKGROUND: The New York State (NYS) speed limit increased from 55 mph to 65 mph in August 1995. This study examines the change in motor vehicle fatality rates on the NYS thruway and NYS Interstates before and after the speed limit change. We also compare the fatality rates pre- and postincreased speed limit between the NYS thruway and other major NYS roadways, where speed limit remained unchanged at 55 mph. METHODS: The number of fatalities and vehicle miles traveled (VMT) on individual roadways were extracted from NYS Department of Transportation reports. The data were divided into groups by prespeed limit change, August 1992 to August 1995, and postspeed limit change, August 1995 to August 1998, and roads where the speed limit remained unchanged at 55 mph. Data were also analyzed to assess the effect of variability of speed and general topography on changes in fatality rates on roads where the speed limit was increased. RESULTS: There was a 28.3% decrease in absolute mortality and a 42.6% decrease in mortality adjusted for VMT, on the NYS thruway after the speed limit increase from 55 mph to 65 mph. When compared with roadways, where the speed limit remained unchanged, there was a 52.4% reduction in fatality rates below the predicted rates after the speed limit increase (p = 0.009). On the NYS interstate system, there was a 13.5% decrease in absolute mortality and a 29.2% decrease in mortality adjusted for VMT, after the speed limit increase. The percentage of traffic traveling >10 mph faster than the speed limit dropped from 39% to 8% on roads, where the speed limit was increased from 55 mph to 65 mph. In the NYS interstate system, "flat" roads (elevation <200 m) had a 30.2% reduction in absolute mortality, whereas "mountainous" roads (elevations >200 m) had a 17.6% increase in absolute mortality in response to the speed limit increase (p < 0.001). CONCLUSION: Motor vehicle speed is a key determinate of the severity of injury in an individual crash; however, speed variance and road topography have also been found to impact the total number of motor vehicle fatalities in the NY State highway system. PMID- 20838143 TI - The trapezius-splitting approach: modifications for treating disorders and traumas occurring in the lateral supraspinatus fossa. AB - BACKGROUND: Disorders or traumas requiring surgery other than suprascapular entrapment neuropathy that occur in the lateral supraspinatus fossa are decidedly uncommon. Because a wider operative field is necessary for treating these disorders, we have applied a trapezius-splitting approach with some modifications. METHODS: The procedure comprises a saber cut incision along with trapezius-splitting of 5 cm to 6 cm proximally from the position coinciding with the posterior margin of the acromioclavicular joint. At the lateral aspect of this division, a Gelpi retractor is set on the clavicle and the scapular spine to widen the narrow interspace between them. The underlying adipose tissue and supraspinatus muscle are forced aside en bloc posteriorly. Four patients were surgically treated using this approach and were postoperatively followed up for 22.2 months +/- 7.8 months. RESULTS: A sufficient operative field for the major maneuver was secured in all four patients. None developed postoperative paralysis or atrophy of the trapezius, supraspinatus, or infraspinatus muscles. The three patients treated for nonunion or delayed union of coracoid fracture exhibited successful union, and the patient treated for osteochondroma of the clavicle had no recurrence. CONCLUSIONS: The main advantages of this procedure are minimal trauma to the musculature, a clearly visible field of the most lateral fossa, and the ability to approach the anterior or posterior shoulder region through the extended skin incision and deltoid-splitting approach if required. Results indicate that the procedure would be advantageous in the surgical treatment of disorders and traumas occurring in the lateral supraspinatus fossa. PMID- 20838144 TI - Gerota's fascia flap: a technique for autogenous packing in major liver injuries. AB - Hepatic trauma occurs in ~ 5% of patients admitted to emergency rooms and nonoperative management has become the standard of care in hemodynamically stable patients with blunt trauma, for most of the injured solid organs. However, the staged surgery represents the first line of treatment in hemodynamically instable patients. The abdominal packing is considered the first step of this surgical policy. The authors describe a new surgical technique consisting of Gerota's fascia dissection that provide an autogenous pedunculated flap to obtain a definitive hemostasis of the injured liver with a permanent packing system. PMID- 20838145 TI - Screening and brief intervention for substance misuse among patients with traumatic brain injury. AB - BACKGROUND: Research on screening and brief interventions (SBI) for substance misuse has demonstrated efficacy in a variety of medical settings including emergency departments and trauma centers. However, SBI has not yet been evaluated for persons who incur traumatic brain injury (TBI)-a substantial patient subpopulation for whom substance-related problems are frequent. To examine whether research on SBI efficacy and effectiveness can be generalized to persons with TBI, a systematic review of the literature was conducted to analyze how TBI populations were included in previous studies and whether there was evidence of differential outcomes. METHODS: Peer-reviewed studies that investigated SBI for misuse of alcohol or other drugs, that were implemented in emergency departments or trauma centers, and that were published in English since 1985 were examined. From 174 articles initially identified, 28 studies were determined to meet inclusion criteria. RESULTS: The review revealed that research conducted on SBI for injury populations systematically neglected patients with more severe TBI and those who presented with sufficient confusion that they could not provide informed consent. CONCLUSIONS: Future effectiveness studies should examine barriers to routine clinical use of SBI and evaluate the generalizability of expected benefits to the full spectrum of injured patients. Researchers should also develop and evaluate systematic accommodations for persons with neurobehavioral impairments who would benefit from brief interventions for substance misuse. PMID- 20838146 TI - Physician protect thyself from skeptical colleagues: an unusual open fracture dislocation of the ankle reported by the patient. PMID- 20838148 TI - Traumatic pseudoaneurysm of the pulmonary artery. PMID- 20838147 TI - Percutaneous embolization of an angiographically inaccessible pulmonary artery pseudoaneurysm after blunt chest trauma: a case report and review of the literature. PMID- 20838149 TI - Surgical outcomes after the Wenchuan earthquake: review of a single center's experience. PMID- 20838150 TI - Triage of elderly trauma patients. PMID- 20838151 TI - Blunt trauma and routine pelvic X-ray. PMID- 20838152 TI - Advocating for transcranial Doppler: a tool to detect early neurological deterioration. PMID- 20838153 TI - Shock index and undertriage. PMID- 20838157 TI - Trauma systems development: a national imperative. PMID- 20838158 TI - Trauma systems origins in the United States. AB - The origins of the US Civilian Trauma and Emergency Medical Services Systems (EMSS) started in the 1970s are presented. The conceptual basis, strategic, and tactical implementation approaches used to establish the national program are described. The trauma and other clinical systems were extensions of proven clinical methods initially from cardiac and trauma units and deployed in new settings. The overall systems design was regionalization. Professionals, governmental agents, the public, and politicians all worked together to establish local, regional, state, and a nationwide comprehensive trauma/EMSS program that touch every state, territory, and community. A historical narrative is presented. PMID- 20838160 TI - Perseverance: the creation of a voluntary inclusive statewide trauma system. AB - In 2003, key stakeholders came together to begin the development of a Minnesota trauma system. These 15 leaders, representing the diversity of a largely rural state, reflected upon past efforts to create a system that would see the reduction of morbidity and mortality from trauma. They realized that crucial components in the implementation of this system were the need to ensure hospitals and emergency medical services providers that patient flow would not be limited to a select few hospitals and that robust performance improvement would be key to the effectiveness of the program. PMID- 20838161 TI - Sustaining an inclusive trauma system in a rural state: the role of regional care systems, partnerships, and quality of care. AB - Different approaches exist for developing inclusive trauma systems with a regional system approach. The purpose of this article is to describe a sustainable and replicable structure for developing a trauma system with urban and rural environments. A relatively new trauma system is presented to show (1) how rural health networks and relationships can support rural trauma system development; (2) how partnerships help to support trauma system development; and (3) how the trauma system infrastructure has used assessment and assurance strategies to support regional systems of care to foster optimal care of the trauma patient. PMID- 20838162 TI - Best practice: Oregon's model for regional trauma system peer review. AB - The Oregon State Legislature approved a statewide trauma system in 1985. Regional trauma committees, known as area trauma advisory boards, were prescribed by this legislation. The area trauma advisory board in Region 1 in the Northwest corner of Oregon includes the only 2 level 1 trauma centers in the entire state and began meeting in 1988. The peer review subcommittee, Trauma Audit Group, serves as an interhospital peer review body with a 22-year history as a model of successful systemwide quality improvement committee. PMID- 20838163 TI - Evolution of Maryland trauma: from death lab to statewide system. AB - Evolution is a process of continuous change in which a concept or idea transforms into a different but typically more complex and sophisticated form. The Maryland Trauma System, from its beginning with one man and his vision to its current incarnation as a statewide trauma system, continues to set the global standard of clinical excellence and cutting-edge care for the severely injured and critically ill. The key component in maintaining this level of sophistication is achieved through strong collaborative relationships. As the Maryland Trauma System faces the ever-increasing challenges of health care, these established relationships and new ones on the horizon will be vital to continue the legacy of Dr R Adams Cowley. This article addresses the evolution of a vision and its implementation, the critical elements necessary to create a statewide system and charting the course through future challenges. PMID- 20838164 TI - Rural trauma and emergency medical service challenges in a sample of Western States. AB - State trauma system managers from the western region meet annually to identify and address health care issues, particularly those related to trauma care access and delivery. In each of these states, policy makers face a host of convergent problems: declining populations, rapid growth, low incomes, and high poverty rates. Challenges of providing emergency medical services to largely rural states include geographic barriers of vast expanses of unpopulated landmass, provision of services across mountain ranges, volcanoes, and extreme weather conditions, communication challenges due to lack of cell or radio coverage in some areas, and difficulty recruiting and retaining trained personnel. PMID- 20838165 TI - Multidisciplinary trauma intensive care unit checklist: impact on infection rates. AB - The purpose of this study was to implement a multidisciplinary daily quality checklist in a trauma intensive care setting to determine adherence to infection prevention protocols as well as the impact on infection and complications. METHODS: A multidisciplinary team developed a checklist incorporating evidence based practice guidelines for the prevention of hospital-acquired infections. Infection rates were monitored and correlated with checklist completion. RESULTS: Central line, urinary tract infections, and ventilator-associated pneumonia decreased during the study period by 100%, 26%, and 82%, respectively. CONCLUSION: Initiation of a multidisciplinary daily quality checklist is correlated with decreased infection rates in a trauma intensive care setting. PMID- 20838167 TI - University of North Carolina's experience with state medical assistance teams. AB - Events in the last several years have shown a clear need for better preparation regarding disaster management. In an effort to improve this preparation, North Carolina implemented state medical assistant teams to provide alternative care facilities, decontamination facilities, and shelter assistance during times of disaster. This article explores these teams from the perspective of the University of North Carolina, which serves as a lead agency for one of these teams. Key components of the team, training provided, and lessons learned will be discussed. PMID- 20838168 TI - Innovation: driving the green culture in healthcare. AB - Going green is more than a fad, and it is a mindset and a set of behaviors, knowledge, and dedication to sustainability of our environment and resources. The role of the leader now requires more than traditional strategies to strategically and swiftly move to a green reality. In this article, the involvement of individuals, the work of innovation, an infrastructure for significant cultural change, and new decision-making models are presented as necessary components for transforming organizational cultures. PMID- 20838169 TI - Environmental health: do no harm. PMID- 20838170 TI - Promoting environmental health: advocating for patient safety. PMID- 20838171 TI - Environmental health: a new domain for all nurses. PMID- 20838172 TI - Nurse administrators: leading environmental change. AB - Evidence is building about the impact of environmental contaminants on patients and health care providers. The nurse administrator has a professional responsibility to provide leadership in assuring that the health care organization does not have a negative impact on health. This article presents critical environmental health concerns and an overview of the nursing profession efforts to improve the environment, which includes development of the American Nurses Association's Principles of Environmental Health for Nursing Practice with Implementation Strategies. An example is provided as to how the nurse administrator can use Appreciative Inquiry to harness the nurses collaborative energy for an environmentally healthy organization. PMID- 20838173 TI - The green choices project: integrating environmental health education into reproductive health care settings. AB - A national reproductive health organization developed the Green Choices project to educate staff and clients about how to live in healthier environments by reducing potentially harmful environmental exposures to toxicants. An advisory group, comprised of experts in environmental and reproductive health and literacy, defined the project's scope and common environmental exposures to address. The following educational materials were developed: an online staff environmental health 101 curriculum, an environmental health assessment tool for clients to identify their potential risks, and information sheets for each environmental exposure that described potential risks and ways to reduce risks. Beta-testing methods included baseline and follow-up surveys, one-on-one interviews, focus groups, and recommendations from experts. Staff and client feedback on the educational materials resulted in increased clarity, sensitivity, relevancy, and appeal. Environmental health experts ensured accuracy of information, and reading experts lowered the reading level from 12th to 6th grade. A campaign to disseminate environmental health information and educational materials nationally is under way. PMID- 20838174 TI - Nursing role in the pharmaceutical life cycle. AB - Biologically active, nontherapeutic levels of pharmaceuticals have been detected in waterways and effluent. Although the vast majority of releases stem from human or animal excretion and production effluent, some come from disposal practices. Studies have demonstrated numerous links between environmental exposures from pharmaceutical compounds and their impact upon aquatic life. Nurses need to be aware of this issue since their roles in health care are expanding and considered among the most trusted. Throughout the life cycle of pharmaceuticals (design, approval/regulation, production, use, and discharge/disposal), nursing can play pivotal roles in reducing and eliminating pharmaceutical waste as well as improving public safety through decreasing poisoning and drug abuse. This article discusses the environmental impact of the pharmaceutical life cycle and what roles nurses have as clinicians, educators, advocates, and researchers. PMID- 20838175 TI - Identifying the key personnel in a nurse-initiated hospital waste reduction program. AB - Hospitals in the United States generate more than 6600 tons of trash a day and approximately 85% of the waste is nonhazardous solid waste such as food, cardboard, and plastic. Treatment and management of hospital waste can lead to environmental problems for the communities that receive the waste. One health system's shared governance model provided the foundation to develop a nurse-led hospital waste reduction program that focused on point-of-care waste management. Waste reduction program development required working with a variety of departments within and external to the health system. The interdisciplinary approach informed the development of the waste reduction program. This article identifies the key departments that were necessary to include when developing a hospital waste reduction program. PMID- 20838176 TI - Environmental health effects of concentrated animal feeding operations: implications for nurses. AB - Changes in livestock farming over the last 50 years have led to the increase of large-scale livestock farms called concentrated animal feeding operations (CAFOs). These farms pose a threat to the environment by polluting the air and nearby ground and surface waters. In addition, adverse health effects have been found in CAFO workers and CAFO neighbors. A multitude of respiratory effects have been noted by workers and neighbors, some of which are severe enough to cause workers to leave the industry. The mental health of CAFO neighbors appears to suffer as well, mainly because of noxious odors and stress. Concentrated animal feeding operations also contribute to the growth of antibiotic-resistant bacteria, which have the potential to harm populations nationwide. Although research is being done on this topic around the world, the nursing literature contains very little information on health effects from CAFOs. Occupational, community, and public health nurses should be aware of the dangers from CAFOs and should participate in caring practices, research, and advocacy to diminish the risks. PMID- 20838177 TI - Pesticides use in hospitals: health protection, health hazards, and viable alternatives. AB - The literature is replete with evidence of human health risks associated with cleaning products, sterilants, disinfectants, antimicrobials, and a wide range of pesticides such as insecticides, fungicides, and rodenticides. This article focuses on the health risks associated with pesticide and antimicrobial use in the health care setting and the roles that nurses can play in assessing and addressing the human health risks associated with exposure to these chemicals. Specifically, common biocides, sterilants, insecticides, herbicides, and fungicides are reviewed, including products in which they may be found in and the health effects associated with their use. Then follows a discussion of actions nurses and nurse administrators can implement to reduce exposure to these chemicals. These interventions include improving assessment of patient exposure, education of staff and patients on health effects of hazardous chemicals and safer alternatives, and implementation of integrated pest management policies and programs within facilities and in the community. PMID- 20838178 TI - The effects of hospital noise. AB - Noise is an environmental stressor that is known to have physiological and psychological effects. The body responds to noise in the same way it responds to stress and overtime can impair health. Research clearly shows that hospital noise levels exceed noise level recommendations and has the potential to increase complications in patients. What is less known is the effect hospital noise has on nurses. The purpose of this article is to discuss hospital noise and its effects on patients and nurses. Because nurses spend more time in hospitals over the course of their career, they experience most of the burden from excessive occupational noise levels. Nurses must advocate not only for a healthy work environment but also for a healing environment, for themselves as well as for their patients. PMID- 20838180 TI - Transition to reprocessing: one OR's success. AB - This article tells the story of an OR staff that achieved a successful implementation of reprocessing 6 years ago, ultimately resulting in a culture change. The transition to the use of reprocessed Food and Drug Administration approved single-use surgical devices is described as it occurred. Consideration of the human factors, change management, and culture change are included in this tale of transition. This change occurred organically within the team, rather than being forced by organizational hierarchy. The telling of this experience speaks to the effectiveness of change initiated at the bedside by motivated staff, which then evolved into a culture change for this OR. PMID- 20838179 TI - Climate change and human health: the role of nurses in confronting the issue. AB - Climate change will impact human health in various ways as the ecology of our planet changes. Environmental changes such as increased heat waves, sea-level rise, and increased drought around the globe will aggravate already-existing health problems, increase the onset of new health problems, and, in some cases, cause premature death. Catastrophic events associated with these environmental changes, such as floods, and increases in hospital and routine clinic visits will have nurses on the front lines tending to those in need. Climate change needs to be reframed as a public health issue, and the importance of nurses to be educated and engaged cannot be overstated. Nurses can be instrumental in communications with patients and families, working with their hospitals and health systems to reduce emissions and influencing the adoption of strategies to better prepare our health care facilities and our communities for the health impacts of climate change. PMID- 20838182 TI - Going green in red times-regulation responds to changing times. PMID- 20838181 TI - The impact of the environment on health. AB - Increasingly science is providing evidence linking the disease burden of people with exposure to toxins in their environments. The quality of one's health is determined by physical, chemical, biological, social, and psychological problems in the environment. This article provides an overview of the current science on how environmental pollution is impacting upon the chronic disease burden in people, how toxic chemicals are traveling globally and entering the food chain, and the impact of changes in climate upon one's health. PMID- 20838183 TI - Environmental health-do no harm: technology creates "green" opportunity for nursing. AB - With the familiar refrain of "reduce, reuse, recycle" echoing to every corner of the globe, there remains a critical question for nursing: "What can nurse leaders do to reduce the 6600 tons of medical waste the US healthcare industry generates each day?" This article details how nursing executives can help influence their hospital employers to make green-friendly choices and mobilize their staff to launch community-wide environmental protection efforts. PMID- 20838184 TI - News from the front. PMID- 20838186 TI - Sunflower rectal bezoar presenting with an acute abdomen in a 3-year-old child. AB - This is a case of a 3-year-old boy with a sunflower-seed rectal bezoar who presented to our emergency department with fever, abdominal pain, leukocytosis, vomiting, and an examination concerning for appendicitis. A failed diagnostic imaging attempt ultimately led to the diagnosis. Children with rectal bezoars typically present with diarrhea, rectal pain, and tenesmus. Our patient presented atypically and developed significant colitis secondary to the bezoar. We discuss bezoars and the uncommon rectal seed bezoar. This case illustrates an atypical complication (colitis) of an unusual condition (rectal bezoar) mimicking a relatively common illness (appendicitis). PMID- 20838185 TI - Bowel perforation by ventriculoperitoneal shunt catheter mimicking gastroenteritis. AB - Colon perforation is a rare and serious complication of ventriculoperitoneal shunt. The authors report a 7-month-old male infant with vomiting and watery diarrhea after colon perforation by a ventriculoperitoneal shunt. A minimal laparotomy incision was performed accurately where preoperative colonoscopy had detected the penetration site of shunting tube in the left colon. PMID- 20838187 TI - Rapid urine drug screens: diphenhydramine and methadone cross-reactivity. AB - BACKGROUND: Rapid urine screens to detect drugs of abuse are often used in pediatric emergency departments (PEDs). A positive result may lead to further clinical testing, social evaluation, and increased stress/inconvenience. A PED patient with suspected diphenhydramine (DPH) ingestion had a positive methadone result on the rapid urine drug screen, One Step Multi-Drug, Multi-Line Screen Test Device (ACON Laboratories, San Diego, Calif). There was no history of methadone exposure so the patient was admitted while confirmatory testing was performed. Gas chromatography/mass spectroscopy testing of the urine failed to confirm the presence of methadone. We present this unreported false-positive methadone result and evaluation of the kit for cross-reactivity of DPH and methadone. METHODS: The same One Step urine drug screen was tested at an independent laboratory for cross-reactivity between methadone and DPH including the DPH metabolites. Drug-free urine was fortified with DPH, nordiphenhydramine, or dinordiphenhydramine at 0, 10, 25, 50, and 100 MUg/mL for each analyte. One hundred microliters of the solutions were added to each of the 4 wells on test cassettes. Urine was allowed to migrate according to manufacturer instructions. Each cassette was interpreted by 2 analysts to ensure consistent interpretation and accurate data recording. RESULTS: In vitro laboratory testing results showed cross-reactivity between methadone and DPH but not for nordiphenhydramine or dinordiphenhydramine. CONCLUSIONS: Rapid urine drug screens using immunoassays based on the principle of competitive binding may show false-positive methadone results for patients who have ingested DPH. Product information for urine drug screens may not include all cross-reacting agents and should be used with caution when interpreting drug screen results in PED patients. PMID- 20838188 TI - A pediatric chronic subdural hematoma after dodgeball head injury. AB - Chronic subdural hematoma is a subdural hematoma that is older than 3 weeks. Chronic subdural hematoma is predominantly a disease of the elderly and is rare in children. Its common manifestations are altered mental state and focal neurological deficits. We report here a rare case of chronic subdural hematoma in a 9-year-old child due to repeated minor dodgeball head injuries. Although such a case has never been reported in sport, the risk still exists. No altered mental state or focal neurological deficits were observed; the child presented with intermittent severe headache with nausea and vomiting. There was also no evidence of child abuse; however, the history of repeated minor head injuries during playing was significant. PMID- 20838189 TI - Acute hematogenous osteomyelitis of the odontoid process in a child with torticollis. AB - Acute vertebral osteomyelitis is rare in the pediatric population. Its presentation may be subtle and without constitutional manifestations. We present a case of osteomyelitis of the odontoid process. The disease was not considered in the initial evaluation of an afebrile, nontoxic child who presented for evaluation of neck stiffness. Although there was a delay in diagnosis and treatment, the outcome was favorable. PMID- 20838190 TI - Sudden-onset back pain and cauda equina syndrome in an adolescent: a case report. AB - Recent epidemiological studies have shown that childhood back pain is a common complaint often prompting medical attention and that it is infrequently the result of serious etiology. This challenges the traditional view that childhood back pain was an uncommon and ominous symptom, always indicative of significant pathology. We report the case of an adolescent boy who presented to the pediatric emergency department with what initially seemed to be benign back pain. This case illustrates an extremely rare ED presentation of myxopapillary ependymoma, which rapidly evolved into cauda equina syndrome requiring urgent neurosurgical intervention. A review of pediatric back pain and cauda equina syndrome is presented. PMID- 20838191 TI - Progressive unilateral arm weakness in a 7-year-old boy. AB - A child with joint or extremity pain is a common presentation to the emergency department. Often, there is some element to the patient's history, whether it is trauma or some other significant history, which leads to a likely diagnosis. When there is a history of fever and progressive arm weakness, an astute emergency physician would have heightened awareness of a possible systemic process. We describe a case of unilateral shoulder pain with associated fever in a 7-year-old boy who presented to the emergency department with progressive arm weakness to the same side. PMID- 20838192 TI - Tonometry methods in the pediatric emergency department. AB - The measurement of intraocular pressure is perhaps the most important clinical parameter contributing to the diagnosis of glaucoma. This report describes the most commonly used methods of tonometry (to measure intraocular pressure). Considering the common options of Goldmann applanation tonometry (GAT), Schiotz tonometry (ST), and Tono-Pen tonometry (TP), the TP is the easiest to use in the emergency department. It is subject to some degree of inaccuracy. In the pediatric emergency department, a child with a painful eye is likely to require deep sedation to achieve an accurate measurement. PMID- 20838194 TI - Maximizing infant spinal tap success. PMID- 20838195 TI - Pediatric ingestions of hand sanitizers. PMID- 20838196 TI - Use of ketamine continuous infusion for pediatric sedation in septic shock. PMID- 20838197 TI - Pseudosubluxation. PMID- 20838198 TI - Snurfin' USA. PMID- 20838199 TI - ECGs in the ED. PMID- 20838200 TI - Valsartan-induced angioedema in a patient on angiotensin-converting enzyme inhibitor for years: case report and literature review. AB - Angioedema is a rare but life-threatening adverse effect of administration of angiotensin-converting enzyme inhibitors (ACEIs) administration. It has been classically associated with ACEIs, although angioedema has also been reported with angiotensin receptor blockers (ARBs). Angioedema is a deep swelling of tissues just below the skin and mucous membranes, characterized by non-pitting asymmetric swelling that is usually non-pruritic. ARBs may cause an increase in plasma angiotensin II levels, which may lead to a negative feedback inhibition of ACE activity, predisposing to angioedema development. We report a case of valsartan-induced angioedema that occurred in a patient who was on ACEIs for years, with no incidence of angioedema. PMID- 20838201 TI - Degradation kinetics of methionine5-enkephalin by cerebrospinal fluid: in vitro studies. AB - Changes in the levels or biochemistry of cerebrospinal fluid (CSF) neuropeptides with opioid-like properties have been suggested to reflect alterations in specific biological processes. We have determined various kinetic parameters for methionine-enkephalin (MET) degradation by CSF samples from nonneurological patients. Study subjects included 9 males (51-67 years of age) and 5 females (47 61 years of age). Aliquots, removed from an incubation vessel containing buffer, CSF, and peptide [tyr-3',5'-H(N)MET], were analyzed for tyrosine and other degradation products. Essentially all of the labeled tyrosine from the added MET was recovered as free amino acid after 60 minutes of incubation (1:2 ratio, vol:vol; optimum pH 7.4; and temperature 37 degrees C); other possible peptide metabolites (>3%) were not detected. Irrespective of age or gender, the peptide's degradation half-life and initial velocity values were in a limited range; t1/2 26.2 +/- 5.5 and 20.8-33.8 minutes, and Iv 0.03 +/-0.01 and 0.02-0.03 pg of peptide per milligram protein per minute. Km and Vmax values were 0.19 +/- 0.02 and 0.17-0.21 mM, and 9.8 +/- 2.2 and 7.6-12.0 MUmol.L.min, respectively. Neither CSF sample storage time (up to a year) nor repeated freezing and thawing (up to 3 times over a year) altered the kinetics or products of this reaction. These preliminary findings might serve as reference values when conducting similar studies using CSF from patients diagnosed with specific neurological conditions; significant alterations in MET degradation profile in such a population could provide valuable biological markers for diagnostic and treatment purposes. PMID- 20838202 TI - Addressing barriers to insulin therapy: the role of insulin pens. AB - Despite the fundamental role of insulin therapy in diabetes management, many patients and some clinicians may resist insulin initiation due to concerns about its complexity or a general resistance to injections. Many patients' concerns about insulin initiation may stem from perceptions about the pain and inconvenience of using vials and syringes for delivering insulin. However, insulin pen devices offer an easier method for insulin administration that is more accurate, less painful, and more discreet compared with vials and syringes. Advances in insulin pen technology have enhanced their utility by increasing their accuracy, reducing the injection force required, and incorporating mechanisms to store the dose, time, and date of previous insulin injections. Substantial evidence demonstrates that insulin pen devices are preferred by both patients and clinicians and have the potential to improve adherence, enhance quality of life, reduce the risk of hyperglycemia, and decrease costs. Ultimately, the advantages of insulin pens may reduce resistance to initiating and adhering to insulin therapy. Because insulin pens are underused in the United states compared with in other countries, it is critical that clinicians understand the potential benefits of insulin pens and communicate them to their patients. PMID- 20838203 TI - Disseminated tuberculosis secondary to adalimumab. AB - A 62-year-old woman with rheumatoid arthritis presented with fever (T-103.9 degrees F). Vital signs and physical examination were normal. She was taking adalimumab, methotrexate, and prednisone for the past 9 months. Blood and urine cultures, human immunodeficiency virus, rapid plasma reagin, purified protein derivative, and cerebrospinal fluid test findings were negative. Computed tomography showed scattered 0.2-cm nodules in the lungs and innumerable subcentimeter lesions in the liver and spleen. Broad-spectrum antibiotics were started empirically. Liver biopsy findings revealed necrotizing granulomas and were negative for acid fast bacilli and fungi on staining. As the patient was persistently febrile despite antibiotics, the antibiotics were discontinued, and an antituberculous regimen including INH, ethambutol, and pyrazinamide was initiated empirically on day 40 of hospitalization. Fourteen days after liver biopsy, acid-fast bacilli grew in the tissue culture. Disseminated tuberculosis (TB) was diagnosed. Fever subsided after 1 week of anti-TB treatment. Antitumor necrosis factor alpha therapy in rheumatoid arthritis increases the risk of TB 5 fold. This is mostly as a result of reactivation of latent TB and commonly presents as disseminated TB. It usually occurs in the early stage of treatment. In our patient, the screening test results for TB before initiation of Adalimumab could have been falsely negative due to immunosuppression secondary to steroids. Our case emphasizes that current screening tests can miss latent TB especially in immunosuppressed patients. As it is difficult to diagnose TB with polymerase chain reaction and culture, histopathology should be sought early. Patients on antitumor necrosis factor alpha therapy presenting with fever of unknown origin should be considered for empirical anti-TB treatment regardless of microbiological and tissue diagnosis. PMID- 20838204 TI - Evaluation of cardiovascular morbidity associated with adherence to atorvastatin therapy. AB - Long-term adherence to statins is poor. We assessed the relationship between cardiovascular (CV) risk and atorvastatin adherence in primary- and secondary prevention patients, adjusting for healthy-adherer bias by incorporating preventive service use into the model. Medical and pharmacy claims from employee based plans from 2002 to 2008 were analyzed for patients who initiated atorvastatin in 2003-2004. Adherent patients were defined as having >=60% of days covered in the year after atorvastatin initiation and were required to have pill coverage in months 10-12. CV events were identified as hospitalizations with a primary CV diagnosis and assessed from month 13 after atorvastatin initiation until the end of follow-up (<=36 months). Cox proportional hazards models were used to examine the association between atorvastatin adherence and CV event risk, adjusting for covariates including preventive service use. The study included 94,287 atorvastatin users (79,010 primary- and 15,277 secondary-prevention patients). In both populations, nearly one-half of the patients discontinued atorvastatin after 1 year. During follow-up, ~2% of primary-prevention and ~9% of secondary-prevention patients experienced CV events. After adjusting for covariates, adherent patients in the primary-prevention population had a significantly lower risk of CV events compared with nonadherent patients (hazard ratio, 0.82; 95% confidence interval, 0.74-0.91). In the secondary-prevention population, adherence to atorvastatin was also associated with lower CV risk (hazard ratio, 0.74; 95% confidence interval, 0.66-0.82). Atorvastatin discontinuation rates were high 1 year after treatment initiation. Patients who adhered to atorvastatin treatment were at lower CV risk. Quality-of-care interventions should target improvements to therapy persistence. PMID- 20838205 TI - Diffuse alveolar damage and recurrent respiratory failure secondary to sertraline. AB - Sertraline is one of the most commonly used antidepression medications. In this case report, we present a 52-year-old male, smoker, who presented with respiratory failure, 6 months after starting Sertraline. We noticed an improvement in the clinical course after decreasing the dose of Sertraline and recurrent respiratory failure upon inadvertent rechallenge. Open-lung biopsy showed a picture of diffuse alveolar damage. Eventually, the patient improved after stopping Sertraline. This case demonstrates the relation of a drug causing lung disease, after excluding other causes, dechallenge, and rechallenge, in support of radiological and histopathological picture of drug-induced lung injury. PMID- 20838206 TI - Recent and emerging therapeutic medications in type 2 diabetes mellitus: incretin based, Pramlintide, Colesevelam, SGLT2 Inhibitors, Tagatose, Succinobucol. AB - Nearly 285 million people worldwide, with 10% being Americans, suffer from diabetes mellitus and its associated comorbidities. This is projected to increase by 6.5% per year, with 439 million inflicted by year 2030. Both morbidity and mortality from diabetes stem from the consequences of microvascular and macrovascular complications. Of the 285 million with diabetes, over a quarter of a million die per year from related complications, making diabetes the fifth leading cause of death in high-income countries. These startling statistics illustrate the therapeutic failure of current diabetes drugs to retard the progression of diabetes. These statistics further illustrate the continual need for further research and development of alternative drugs with novel mechanisms to slow disease progression and disease complications. The treatment algorithm updated in 2008 by American Diabetes Association and the European Association for the Study of Diabetes currently recommends the traditional medications of metformin, either as monotherapy or in combination with sulfonylurea or insulin, as the preferred choice in the tier 1 option. The algorithm only suggests addition of alternative medications such as pioglitazone and incretin-based drugs as second-line agents in the tier 2 "less well-validated" option. However, these traditional medications have not proven to delay the progressive course of diabetes as evidence of increasing need over time for multiple drug therapy to maintain sufficient glycemic control. Because current diabetes medications have limited efficacy and untoward side effects, the development of diabetes mellitus drugs with newer mechanisms of action continues. This article will review the clinical data on the newly available incretin-based drugs on the market, including glucagon-like peptide agonists and of dipeptidyl peptidase type-4 inhibitors. It will also discuss 2 unique medications: pramlintide, which is indicated for both type and type-2 diabetes, and colesevelam, which is approved by the United States Food and Drug Administration for both type-2 diabetes and hyperlipidemia. It will further review the clinical data on the novel emerging agents of sodium-glucose cotransporter-2 inhibitors, tagatose, and succinobucol, all currently in phase III clinical trials. This review article can serve as an aid for clinicians to identify clinical indications in which these new agents can be applied in the treatment algorithm. PMID- 20838207 TI - Reduction of the putative CD44+CD24- breast cancer stem cell population by targeting the polyamine metabolic pathway with PG11047. AB - Cancer stem cells (CSCs) are considered to be of particular concern in cancer as they possess inherent properties of self-renewal and differentiation, along with expressing certain genes related to a mesenchymal phenotype. These features favour the promotion of tumour recurrence and metastasis in cancer patients. Thus, the optimal chemotherapeutic treatment should target the CSC population, either by killing these cells and/or by inducing their transition to a more differentiated epithelial-like phenotype. Experiments were carried out on the trastuzumab-resistant human epidermal growth factor receptor 2-overexpressing breast cancer cell line JIMT-1 to unravel the chemotherapeutic effects of the polyamine analogue [1N,12N]bis(ethyl)-cis-6,7-dehydrospermine (PG11047) and of the polyamine biosynthetic inhibitor 2-difluoromethylornithine (DFMO) on the CD44+CD24- CSC population. Furthermore, effects on the properties of self-renewal and epithelial/mesenchymal markers were also investigated. Treatment with PG11047 reduced the CD44+CD24- subpopulation of JIMT-1 cells by approximately 50%, inhibited and/or reduced self-renewal capability of the CSC population, decreased cell motility and induced expression of mesenchymal to epithelial transition associated proteins that are involved in promoting an epithelial phenotype. By contrast, DFMO slightly increased the CD44+CD24- subpopulation, increased cell motility and the level of mesenchymal-related proteins. DFMO treatment reduced the self-renewal capability of the CSC population. Both PG11047 and DFMO reduced the expression of the human epidermal growth factor receptor 2 protein, which is correlated to malignancy and resistance to trastuzumab in JIMT-1 cells. Our findings indicate that treatment with PG11047 targeted the CSC population by interfering with several stem cell-related properties, such as self-renewal, differentiation, motility and the mesenchymal phenotype. PMID- 20838208 TI - Prolonged survival of a patient with cervical intramedullary glioblastoma multiforme treated with total resection, radiation therapy, and temozolomide. AB - We report a case of prolonged survival in a patient with cervical intramedullary glioblastoma multiforme (GBM) treated with total resection, radiotherapy, and temozolomide. A 26-year-old woman complaining of midline lower cervical pain, insidiously progressive motor weakness, paresthesia, and urinary incontinence was admitted to our institution. MRI showed an intramedullary mass lesion in the C2 C6 level, which was considered to be an ependymoma or astrocytoma. Total resection of the tumor was performed at the C2-C6 level by laminoplasty with miniplate, followed by chemoradiotherapy (focal irradiation dose of 5000, at 200 cGy per fraction for over a period of 5 weeks) with concomitant temozolomide (75 mg/m2). Histologic examination of the resected tumor confirmed GBM. The tumor consisted of a markedly pleomorphic neoplasm measuring 4.6 cm*2.6 cm*1.7 cm and characterized by necrosis, atypical mitotic figures, and endothelial proliferation. Postoperative MRI showed a centrally located, postoperative cavity at the C2-C6 level. Recurrence in the cervical spine without brain GBM metastasis was identified 25 months after operation, and temozolomide chemotherapy was reinitiated; however, the tumor progressed, and the patient died 33 months after operation. We suggest that, in addition to potential factors of tumor biology, multimodal treatment consisting of total resection of intramedullary GBM coupled with radiation therapy and temozolomide may have prolonged the survival of this patient. PMID- 20838209 TI - Advances in therapy: eribulin improves survival for metastatic breast cancer. AB - Despite advances in cancer biology, chemotherapy remains the backbone of treatment approaches for many patients with metastatic breast cancer (MBC). Halichondrins, derived from marine sponges, have significant potential as potent antimicrotubule agents. Eribulin, with proven preclinical activity, is a synthetic halichondrin analog with novel actions on tubulin including suppression of microtubule polymerization. Phase I and II studies in MBC identified neutropenia as the dose-limiting toxicity and a maximum tolerated dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. An encouraging response rate of 11.5% in refractory MBC led to the launch of the phase III Eisai Metastatic Breast Cancer Study Assessing Physician's Choice versus Eribulin trial, in which heavily pretreated patients with MBC were randomized 2 : 1 to intravenous eribulin or monotherapy of the investigator's choice. Recently, it was reported that this important study of 762 patients met its primary endpoint of overall survival: eribulin was associated with an improvement in median overall survival from 10.65 months to 13.12 months (hazard ratio 0.8; 95% confidence interval 0.66-0.99) and a response rate of 12.2%. In general, the side effect profile of eribulin seems to be acceptable, as although neutropenia occurred in 45% of the patients, febrile neutropenia was rare and the incidence of neuropathy was low. These findings show that eribulin is potentially a new active agent for MBC, although results of ongoing studies are awaited to confirm the reported benefit. Future studies will investigate the potential role of eribulin in other settings, including for early breast cancer, to ascertain how to optimally incorporate this new agent into current treatment paradigms. PMID- 20838210 TI - Effects of positive and negative modulators of the gamma-aminobutyric acid A receptor complex on responding under a differential-reinforcement-of-low-rate schedule of reinforcement in rats. AB - Relatively little is known about the behavioral effects of the neurosteroids compared with other drugs that modulate the gamma-aminobutyric acid A (GABAA) receptor complex. This study examined the acute effects of pregnanolone and dehydroepiandrosterone (DHEA) in male rats responding under a differential reinforcement-of-low-rate schedule of reinforcement. For comparison, three positive modulators of the GABAA receptor (lorazepam, ethanol, and pentobarbital), one negative modulator (beta-CCM), and one neutral modulator (flumazenil) were tested. Pregnanolone was also administered in combination with DHEA to test for antagonism between these substances. Pregnanolone, lorazepam, and pentobarbital produced increases in responding at intermediate doses, and ethanol and pentobarbital produced decreases in responding at the highest doses tested. However, all four drugs dose-dependently decreased reinforced responding by decreasing inter-response times. DHEA, beta-CCM, and flumazenil did not increase responding at intermediate doses or decrease reinforced responding. DHEA did not competitively antagonize the disruptive effects of pregnanolone. In summary, pregnanolone and DHEA produced effects on differential-reinforcement-of low-rate responding that are similar to other positive and negative GABAA modulators, respectively, and do not produce these effects through a single binding site. PMID- 20838212 TI - Are the conventional cutoff values adequate to define hypertension in young women? AB - BACKGROUND: Women have lower systolic blood pressure (SBP) levels than men during early adulthood. Diastolic blood pressure (DBP) tends to be just marginally lower in women than men regardless of age. OBJECTIVE: Aims of this study were (i) to determine 95th percentile value of SBP, DBP, and mean arterial blood pressure in healthy women, and (ii) to evaluate the effects of basal demographic and anthropometric features on blood pressure. METHODS: Six hundred and fifty-four consecutive participants (18-35 years old) were initially enrolled in the study but among them 54 (8.2%) cases were excluded. Demographic features, relevant personal and family history data about hypertension, smoking habits, and use of medications were interviewed using a questionnaire. Blood pressure, height, weight, and waist circumference of every case were measured. RESULTS: Of the 600 patients (mean age, 24.6+/-4.0 years), 124 (20.7%) were currently smokers, 20 (3.3%) had history of hypertension during pregnancy, and 291 (48.5%) had family history of hypertension in women (mean age, 61.0+/-9.51 years). Reference ranges of 5th and 95th percentile values for SBP were determined as 74 and 115 mmHg, for mean arterial blood pressure as 57 and 85 mmHg, for DBP as 45 and 72 mmHg, respectively. CONCLUSION: In conclusion, cutoff values of hypertension in healthy women, which were determined by our study, are lower than the standard cutoff values for definition of hypertension in adults. However, clinical importance of these findings should be investigated in further studies involving larger population with prospective follow-up. PMID- 20838211 TI - Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat. AB - Depression and anxiety are the prevalent nonmotor symptoms that worsen quality of life for Parkinson's disease (PD) patients. Although dopamine (DA) cell loss is a commonly proposed mechanism, the reported efficacy of DA replacement therapy with L-DOPA on affective symptoms is inconsistent. To delineate the effects of DA denervation and chronic L-DOPA treatment on affective behaviors, male Sprague Dawley rats received unilateral 6-hydroxydopamine or sham lesions and were treated daily with L-DOPA (12 mg/kg+benserazide, 15 mg/kg, subcutaneously) or vehicle (0.9% NaCl, 0.1% ascorbic acid) for 28 days before commencing investigations into anxiety (locomotor chambers, social interaction) and depression-like behaviors (forced swim test) during the OFF phase of L-DOPA. One hour after the final treatments, rats were killed and striatum, prefrontal cortex, hippocampus, and amygdala were analyzed through high-performance liquid chromatography for monoamine levels. In locomotor chambers and social interaction, DA lesions exerted mild anxiogenic effects. Surprisingly, chronic L DOPA treatment did not improve these effects. Although DA lesion reduced climbing behaviors on day 2 of exposure to the forced swim test, chronic L-DOPA treatment did not reverse these effects. Neurochemically, L-DOPA treatment in hemiparkinsonian rats reduced norepinephrine levels in the prefrontal cortex, striatum, and hippocampus. Collectively, these data suggest that chronic L-DOPA therapy in severely DA-lesioned rats does not improve nonmotor symptoms and may impair nondopaminergic processes, indicating that long-term L-DOPA therapy does not exert necessary neuroplastic changes for improving affect. PMID- 20838213 TI - Quetiapine combined with amisulpride in schizophrenic patients with insufficient responses to quetiapine monotherapy. AB - OBJECTIVES: Treatment resistance often leads to combinations of second-generation antipsychotics. Well-designed trials evaluated add-on strategies involving clozapine, but also olanzapine and quetiapine (QTP) have pharmacodynamic properties that render supplementation with high-affinity antidopaminergic second generation antipsychotics, for example, amisulpride (AMS), reasonable. METHODS: We report on 6 cases with partial response of psychotic positive symptoms to QTP despite sufficient dosage (mean, 783 mg/d) and serum levels (mean, 405 MUg/L). Concomitant drug abuse and interfering pharmacological changes were excluded. RESULTS: The add-on of AMS in a mean dose of 466.7 mg/d (serum level, 132.1 MUg/L) over a period of 8.3 weeks facilitated significant improvements of treatment-resistant psychotic symptoms. The Positive and Negative Syndrome Scale scores decreased from 94 to 54, whereas the Scale for the Assessment of Negative Symptoms and the Calgary Depression Scale for Schizophrenia significantly improved. Despite an increase in the mean body weight from 77.2 to 82.9 kg and an increase in prolactin levels from 43 to 163 MUg/L, the observed general tolerance was good. CONCLUSIONS: The combination of AMS with QTP might be a successful strategy in individuals only partially responsive to quetiapine, but risks and benefits should be further evaluated in controlled clinical trials. PMID- 20838214 TI - Visceral and subcutaneous fat in patients treated with olanzapine: a case series. AB - OBJECTIVES: We hypothesized that olanzapine may contribute to visceral adiposity, a core symptom of metabolic syndrome. METHODS: Using computed tomography, we examined the effect of olanzapine on visceral and subcutaneous fat distribution, body mass index, fasting glucose, and lipids in an unselected population of 14 schizophrenic patients. RESULTS: We found a 6-week olanzapine treatment to be related to increased body mass index and proportion of total fat at the level of the fourth vertebral body. CONCLUSIONS: On the basis of these findings, we conclude that weight gain after a 6-week olanzapine treatment is partly attributable to increased visceral fat and may thus contribute to metabolic syndrome. PMID- 20838215 TI - Trazodone for the treatment of neuroleptic-induced acute akathisia: a placebo controlled, double-blind, crossover study. AB - INTRODUCTION: Neuroleptic-induced acute akathisia (NIA) is a common and distressing extrapyramidal symptom usually resulting from the use of antipsychotic medication.Despite its high incidence (20%-45%), the underlying mechanism of NIA has not yet been adequately explained. Although treatment strategies for NIA have traditionally included anticholinergic agents, gamma aminobutyric acid agents, dopamine enhancers, and the beta-adrenergic antagonists, many patients fail to respond. Trazodone (Trz) is an antidepressant agent demonstrating prominent serotonergic antagonistic properties. In a recent pilot open-label trial, Trz demonstrated to be strongly effective in the treatment of NIA in 9 female schizophrenic patients. OBJECTIVE: On the basis of the results of this pilot study, we investigate further the efficacy of Trz in the treatment of NIA in a double-blind, placebo (Pla)-controlled, crossover design. METHODS: Thirteen inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition schizophrenia or schizo-affective disorder and with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition NIA with a severity of at least mild akathisia according to the Barnes Akathisia Rating Scale participated in the study. Patients were randomly assigned to either the order Trz-Pla or the order Pla-Trz in the treatment periods. Each period lasted for 3 consecutive days (days 1-3 and 4-6). Eight patients were treated with the Trz-Pla order (100 mg/d before bedtime); and 5, with the opposite order (Pla-Trz). RESULTS: Statistically significant improvement in most symptoms of NIA, as measured by the Barnes Akathisia Rating Scale, was detected with Trz compared with Pla treatment. CONCLUSIONS: The findings of this double-blind, placebo-controlled, crossover study indicate the efficacy of Trz in the management of NIA, corroborating the results of a preliminary pilot study. We suggest that Trz's property of serotonin 2A postsynaptic receptor antagonism may be its principal mechanism for the improvement of NIA. PMID- 20838216 TI - A pilot efficacy and tolerability trial of memantine for essential tremor. AB - OBJECTIVE: We studied the potential efficacy and tolerance of memantine for essential tremor in an open-treatment trial. METHODS: Participants with upper limb tremor were titrated to no more than 40 mg/d memantine, as monotherapy or as adjunct to stable antitremor medication, followed by a 12-week extension phase. Tremor was assessed in study 1 with accelerometry and in study 2 by blinded ratings of videotaped Washington Heights Inwood Genetic Essential Tremor (WHIGET) rating scale items. Subjects also rated their tremor treatment response and tremor-associated impairment on the Functional Disabilities scale. RESULTS: In study 1, average accelerometry-measured tremor at last titration visit (average dose, 30.3 mg/d) did not change from baseline, but 2 of 9 subjects, taking 40 mg/d, had greater than 70% accelerometry tremor reduction. In study 2, 13 of 16 provided evaluable data. Average blinded rater-evaluated WHIGET scores were significantly different from baseline scores among those taking 20 mg/d (-12.7%; P < 0.05), but not at last titration visit (-8.4%; average dose, 30.4 mg/d), 40 mg/d (-14.1%), or at end-of-extension visit (-18.2%). Raters judged WHIGET scores as greater than 30% improved in 2 subjects. Unblinded subjects rated Functional Disabilities significantly improved at 30 to 40 but not at 10 to 20 mg/d, and tremor treatment response was positive at all doses. Adverse events were more common at higher doses and included dizziness, somnolence, and poor energy. CONCLUSIONS: These pilot results with small samples indicate that the average effect of memantine on tremor is mild or not significant. However, in a small subset of patients, memantine may confer meaningful tremor benefit. PMID- 20838217 TI - Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating delta9-tetrahydrocannabinol. AB - OBJECTIVES: The central effects of Delta-tetrahydrocannabinol (Delta-THC), the primary active constituent of cannabis, are attributed to cannabinoid CB1 receptor activity, although clinical evidence is limited. Drug discrimination has proven useful for examining the neuropharmacology of drugs, as data are concordant with the actions of a drug at the receptor level. The aim of this study was to determine the profile of behavioral and physiological effects of the cannabinoid agonist nabilone in humans trained to discriminate Delta-THC. METHODS: Six cannabis users learned to identify when they received oral Delta-THC (25 mg) or placebo and then received a range of doses of the cannabinoid agonists nabilone (1, 2, 3, and 5 mg) and Delta-THC (5, 10, 15, and 25 mg). The dopamine reuptake inhibitor methylphenidate (5, 10, 20, and 30 mg) was included as a negative control. Subjects completed the Multiple-Choice Procedure, and self report, task performance, and physiological measures were collected. RESULTS: Nabilone shared discriminative-stimulus effects with the training dose of Delta THC, produced subject-rated drug effects that were comparable to those of Delta THC, and increased heart rate. Methylphenidate did not engender Delta-THC-like discriminative-stimulus effects. CONCLUSIONS: These data demonstrate that the interoceptive effects of nabilone are similar to Delta-THC in cannabis users. The overlap in their behavioral effects is likely due to their shared mechanism as CB1 receptor agonists. Given the relative success of agonist replacement therapy to manage opioid, tobacco, and stimulant dependence, these results also support the evaluation of nabilone as a potential medication for cannabis-use disorders. PMID- 20838218 TI - Management of adult blunt hepatic trauma. AB - PURPOSE OF REVIEW: To review the nonoperative and operative management of blunt hepatic injury in the adult trauma population. RECENT FINDINGS: Although liver injury scale does not predict need for surgical intervention, a high-grade complex liver injury should alert the physician to a patient at increased risk of hepatic complications following nonoperative management. SUMMARY: Blunt hepatic injury remains a frequent intraabdominal injury in the adult trauma population. The management of blunt hepatic injury has undergone a major paradigm shift from mandatory operative exploration to nonoperative management. Hemodynamic instability with a positive focused abdominal sonography for trauma and peritonitis are indications for emergent operative intervention. Although surgical intervention for blunt hepatic trauma is not as common as in years past, it is imperative that the current trauma surgeon be familiar with the surgical skill set to manage complex hepatic injuries. This study represents a review of both nonoperative and operative management of blunt hepatic injury. PMID- 20838219 TI - Are male slings for post-prostatectomy incontinence a valid option? AB - PURPOSE OF REVIEW: Stress incontinence in men is still a common problem after surgical treatment of prostatic disease. This article reviews the techniques and results of recently described surgical slings available to treat male stress incontinence. RECENT FINDINGS: Medium-term follow-up (mean 3-4 years) of patients treated with bone-anchored slings has been recently published, suggesting a success rate (cured or improved) of 70-80%. Short-term follow-up (mean of 6-12 months) of transobturator retrourethral slings demonstrates a success rate of 62 83%. Novel sling designs include mechanisms to manipulate the tension postoperatively and inside-out transobturator trocar passage. Common complications associated with slings are acute urinary retention and perineal pain. Rare complications include urethral erosion and infection. Retropubic approaches are associated with a risk of bladder perforation. SUMMARY: Male slings are a valid option for treating male stress incontinence, and do offer several advantages over the artificial urinary sphincter. However, long-term data and multicenter series are needed in order to compare directly with the artificial urinary sphincter. PMID- 20838220 TI - Early MRI in the management of the clinical scaphoid fracture. AB - OBJECTIVES: The 'clinical scaphoid fracture' remains a common problem faced by emergency physicians. Early magnetic resonance imaging (MRI) has been used to routinely investigate such patients presenting to the emergency department of Aberdeen Royal Infirmary since 2002. The aim of this study was to evaluate the effectiveness of this strategy in the diagnosis of occult scaphoid fracture. METHODS: This was a retrospective cohort study of patients presenting with symptoms and signs suggestive of scaphoid injury and normal initial radiographs. Patients undergoing MRI evaluation of a suspected scaphoid injury between September 2002 and June 2008 were identified from records. The number of patients with scaphoid fractures and other significant pathology diagnosed on MRI was recorded. RESULTS: A total of 651 patients were included in the study. A scaphoid fracture was diagnosed in 11% of patients. Using the chi test, there was evidence of an association between sex and type of injury (chi=58.0, P<0.001). Male patients were more likely to have scaphoid injuries; female patients were more likely to have no injury. There was also evidence of an association between age group and type of injury (chi=11.8, P=0.003). Those in the younger age group were more likely to have scaphoid injuries. CONCLUSION: Early MRI can reliably detect radiologically occult scaphoid fractures and accurately delineate the anatomy of other injuries that may present with similar symptoms. This strategy avoids further radiation and can be incorporated as a part of an emergency department management pathway. Early and accurate diagnosis is in the patient's interest and allows timely intervention. PMID- 20838221 TI - A naturalistic study of changes in pharmacological prescription for borderline personality disorder in clinical practice: from APA to NICE guidelines. AB - Although no psychotropic agents are specifically licensed for the management of borderline personality disorder (BPD), pharmacological treatment appears to be common. This study aimed to examine the drug prescriptions for patients with BPD in clinical practice, analyze the prescription patterns from the appearance of the American Psychiatric Association guidelines in 2001 until the National Institute for Health and Clinical Excellence guidelines in 2009, and identify the factors associated with such prescription of each type of drug. Naturalistic study on 226 consecutive BPD patients admitted to an outpatient BPD program. Socio-demographic, clinical and pharmacological treatment information was collected; factors associated with drug prescription were examined using logistic regression analyses for dichotomous outcomes measures. Changes in prescription patterns over time were also evaluated. Patients received an average of 2.7 drugs; only 6% were drug-free; 56% were taking >=3 drugs and 30% >=4 drugs. Over the past 8 years, prescription of antidepressants has remained stable; there has been a significant reduction in prescription of benzodiazepines and an increase in the use of mood stabilizers and atypical antipsychotics. Comorbidity with Axis I disorders was the main factor associated with drug prescription. Drug prescription and polypharmacy are common in the management of BPD in clinical practice. PMID- 20838222 TI - Factors influencing quality of life of Hungarian postmenopausal women screened by osteodensitometry. AB - The aim of our study was to evaluate factors influencing health related quality of life in Hungarian postmenopausal women who underwent osteodensitometry. A questionnaire-based cross-sectional study was carried out; 359 women aged over 40 years were involved, attending the outpatient Bone Densitometry Centre of Szeged. Two kinds of tools were used: a self-developed questionnaire of demographic and health data and the abbreviated version of the World Health Organization Quality of Life instrument. The patients were divided into three groups according to the values of their screened bone mineral density: normal, osteopenic, osteoporotic. Higher education [P<0.001, odds ratio (OR): 6.82, confidence interval (CI): 3.07 15.17] and working status (P<0.001, OR: 4.70, CI: 2.01-10.98 in physical domain) proved to be the most remarkable demographic factors to enhance quality of life. With regard to health status, not suffering from any chronic disease seemed to be influential (P=0.05, OR: 7.75, CI: 0.96-62.21). Women in group 'normal' or in group 'osteopenic' (P=0.01, OR: 2.06, CI: 1.18-3.59) were more than two times likely to choose a 'good quality of life' than women in the 'osteoporosis group'. In our study, the most important demographic factors affecting quality of life of bone mineral density-screened postmenopausal women were education and working status. Women with no chronic disease and no osteoporosis had a better quality of life. PMID- 20838223 TI - Lung cancer incidence and mortality among HIV-infected and HIV-uninfected injection drug users. AB - OBJECTIVES: To examine the impact of HIV on lung cancer incidence and survival. DESIGN: : Prospective study of 2495 HIV-infected and HIV-uninfected injection drug users in Baltimore, MD. METHODS: Cancer data were obtained from the Maryland Cancer Registry. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer in 2 strata of packs of cigarettes smoked per day by HIV serostatus, and for mortality by HIV serostatus. RESULTS: HIV-infected participants had twice the risk (HR = 2.3; 95% CI: 1.1 to 5.1) of lung cancer. There was no evidence of an interaction between HIV and packs of cigarettes smoked per day (P interaction = 0.18). Compared with participants who smoked <1.43 packs per day, among HIV-uninfected individuals lung cancer risk was 6 times greater (HR = 5.9; 95% CI: 2.1 to 17) and among HIV-infected individuals lung cancer risk was doubled (HR = 2.1; 95% CI: 0.63 to 6.8) in persons who smoked >=1.43 per day. Additionally, HIV was associated with 4 times the risk of death (HR = 3.8; 95% CI: 0.92 to 15) in lung cancer cases. CONCLUSIONS: HIV was associated with increased risk of lung cancer, after adjusting for smoking. However, no evidence was observed for synergistic effects of HIV and smoking. Further, HIV was associated with poorer lung cancer survival after accounting for cancer stage. PMID- 20838224 TI - Population-based monitoring of HIV drug resistance in Namibia with early warning indicators. AB - INTRODUCTION: HIV drug resistance (HIVDR) testing is not routinely available in many resource-limited settings, therefore, antiretroviral therapy (ART) program and site factors known to be associated with HIVDR should be monitored to optimize the quality of patient care and minimize the emergence of preventable HIVDR. METHODS: In 2009, Namibia selected 5 World Health Organization Early Warning Indicators (EWIs) and piloted abstraction at 9 ART sites: "ART prescribing practices, patients lost to follow-up at 12 months, patient retention on first-line ART at 12 months, on-time antiretroviral drug pick-up, and antiretroviral drug-supply continuity". RESULTS: Records supported monitoring of 3 of 5 selected EWIs. Nine of 9 (100%) sites met the target of 100% initiated on appropriate first-line regimens. Eight of 9 (89%) sites met the target of <=20% lost to follow-up, although 20.8% of ART starters (range: 4.6%-44.6%) had a period of absence without documented ART coverage of 2.3 months (range: 1.5-3.9 months). Six of 9 (67%) sites met the target of 0% switched to a second-line regimen. CONCLUSIONS: EWI monitoring directly resulted in public health action which will optimize the quality of care, specifically the strengthening of ART record systems permitting monitoring of 5 EWIs in future years and protocols for improved ART patient defaulter tracing. PMID- 20838225 TI - Risk of viral failure declines with duration of suppression on highly active antiretroviral therapy irrespective of adherence level. AB - OBJECTIVE: To model the effect of adherence and duration of viral suppression on the risk of viral rebound. METHODS: Viral rebound was defined as the first of at least two consecutive viral loads greater than 400 copies/mL after initial viral suppression. The main exposures were adherence, presence of antiretroviral class resistance before rebound or censoring date, and the percentage of follow-up time with viral suppression. RESULTS: A total of 274 (N = 1305 [21%]) individuals experienced viral rebound. Median time of suppression before rebound was 2 years. Viral rebound was less likely to occur among those with longer duration of continuous viral suppression (odds ratio, 0.37; 95% confidence interval, 0.32 to 0.42). Among individuals with moderate levels of adherence (80% to less than 95%), the probability of virologic failure was 0.85 after being suppressed for 12 months and it was 0.08 after 72 months being suppressed (P < 0.01). Individuals with drug resistance were at a higher risk of viral rebound. CONCLUSIONS: The risk of viral rebound decreased with longer duration of viral suppression within each of adherence strata studied. Although perfect adherence remains an important goal of therapy to prevent disease progression, individuals with long-term viral suppression may be able to miss more doses without experiencing viral rebound. PMID- 20838226 TI - Persistence of racial differences in attitudes toward homosexuality in the United States. AB - BACKGROUND: Stigma may mediate some of the observed disparity in HIV infection rates between black and white men who have sex with men (MSM). METHODS: We used data from the General Social Survey to describe race-specific trends in the US population's attitude toward homosexuality, reporting of male same-sex sexual behavior, and behaviors that might mediate the relationship between stigma and HIV transmission among MSM. RESULTS: The proportion of blacks who indicated that homosexuality was "always wrong" was 72.3% in 2008, largely unchanged since the 1970s. In contrast, among white respondents, this figure declined from 70.8% in 1973 to 51.6% in 2008 with most change occurring since the early 1990s. Participants who knew a gay person were less likely to have negative attitudes toward homosexuality (relative risk, 0.60; 95% confidence interval, 0.52 to 0.69). Among MSM, twice as many black MSM reported that homosexuality is "always wrong" compared with white MSM (57.1% versus 26.8%, P = 0.003). MSM with unfavorable attitudes toward homosexuality were less likely to report ever testing for HIV compared with MSM with more favorable attitudes (relative risk, 0.50; 95% confidence interval, 0.31 to 0.78). CONCLUSIONS: US attitudes toward homosexuality are characterized by persistent racial differences, which may help explain disparities in HIV infection rates between black and white MSM. PMID- 20838228 TI - Vascular-targeting antioxidant therapy in a model of hypertension and stroke. AB - Oxidative stress is implicated in the pathogenesis of hypertension and stroke. Superoxide is produced by NAD(P)H oxidase in the vasculature and reduces nitric oxide bioavailability, which leads to increased blood pressure. The objective of this study was to determine whether targeting an antioxidant peptide to the vasculature would increase the antioxidant effect and reduce systolic blood pressure (SBP) in a model of genetic hypertension, the stroke-prone spontaneously hypertensive rat. Vascular-targeting peptides CRPPR and CSGMARTKC were identified by phage display in mice. These peptides retain their selectivity across species and target the aorta (CRPPR) and cardiac vasculature (CSGMARTKC) in the stroke prone spontaneously hypertensive rat. These vascular-targeting peptides were linked to the antioxidant peptide gp91ds, which selectively inhibits assembly of NAD(P)H oxidase, thereby reducing superoxide production. SBP was determined for 1 week before treatment followed by 3 weeks of study duration before euthanasia. SBP in the control animals increased from 178.1 +/- 4.1 mmHg to 201.6 +/- 9.0 mmHg. The SBP of the animals treated with gp91ds alone, HIV-tat-gp91ds, and CSGMARTKC-gp91ds increased from 177.8 +/- 3.5 mmHg, 179.8 +/- 4.7 mmHg, and 177.9 +/- 5.2 mmHg, respectively, to 201.6 +/- 10.8 mmHg, 200.3 +/- 11.7 mmHg and 205.7 +/- 10.9 mmHg, respectively. This increase in SBP was significantly attenuated in animals receiving CRPPR-gp91ds (maximum SBP 187.5 mmHg +/- 5.2, *P , 0.001 versus other treatment groups and control group). Additionally, animals treated with CRPPR-gp91ds, CSGMARTKC-gp91ds, and gp91ds alone showed significantly improved nitric oxide bioavailability determined by large vessel myography. Therefore, targeting an antioxidant to the aortic vasculature in vivo using peptides can significantly improve nitric oxide bioavailability and attenuate the time dependent and progressive increase in SBP in the stroke-prone spontaneously hypertensive rat. This study has demonstrated the importance and potential benefit of targeting a biologically active peptide in the context of a preclinical model of endothelial dysfunction and hypertension. PMID- 20838227 TI - Antiretroviral therapy down-regulates innate antiviral response genes in patients with AIDS in sub-saharan Africa. AB - OBJECTIVE: HIV pathogenesis is characterized by destructive imbalances between virus-mediated immune damage, antiviral immune responses, and immune activation. We characterized the effects of successful antiretroviral therapy (ART) to identify the breadth and patterns of HIV-associated gene expression. METHODS: In a prospective observational, longitudinal cohort study of 10 ART-naive Ugandans with AIDS (median 30 CD4/MUL), we measured mRNA gene profiles in peripheral blood using Affymetrix U133_Plus2.0 microarrays at 0, 2, 4, 8, and 24 weeks after ART initiation. RESULTS: We identified 160 mRNA transcripts that were consistently down-regulated and 48 that were up-regulated after ART at each point over 24 weeks based on linear regression modeling (adjusted P < 0.05), Of these 208 transcripts, approximately half represent heretofore unrecognized ART-responsive genes and one-third have no known function. The down-regulated genes with known function encoded mediators of innate antiviral responses, including antiviral restriction factors, pattern recognition receptors, and interferon response proteins, and mediators of immune activation, cellular proliferation, and apoptosis. CONCLUSIONS: By using ART to block the viral stimulus, we identified transcripts involved in innate antiviral immunity, including antiviral restriction factors and pattern recognition receptors, that were not previously known to be induced by HIV infection. PMID- 20838230 TI - Pharmacologic and pharmacokinetic rationale for combination therapy in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature characterized by elevated pulmonary artery pressure. Currently, there is no cure for this disease, and treatment is palliative. PAH therapies target 3 main pathways: prostacyclin, endothelin, and nitric oxide. The 3 distinct therapeutic pathways targeted have provided the opportunity to explore the efficacy of combination therapy. This article reviews the pharmacokinetic profiles of available therapies and existing clinical trial results that support combination therapy, as well as provides rationale and clinical guidance for combination therapy. Combination therapy may offer an additive and potentially synergistic benefit. The initiation and titration of combination therapy has several pharmacokinetic considerations, such as the onset of drugs' action and time to steady state, as well as potential drug interactions. Although great strides have been made in the treatment of PAH, unanswered questions still remain in regard to combination therapy: (1) Which combination is best? and (2) Is it most appropriate to maximize one drug and then initiate a second drug or to start both drugs simultaneously? Answers to these questions will help identify a safe and effective combination therapy and thus optimize treatment for patients with PAH. PMID- 20838231 TI - Silymarin inhibits endothelial progenitor cells' senescence and protects against the antiproliferative activity of rapamycin: preliminary study. AB - Rapamycin, an antiproliferative agent used on drug-eluting stents, induces endothelial progenitor cells (EPCs) senescence through telomerase inactivation and may impair the reendothelization of an injured arterial wall, leading to thrombosis. We examined whether silymarin, a complex of flavonolignans with hepatoprotective and antioxidative properties, can protect EPCs against rapamycin induced senescence. Mononuclear cells were isolated from peripheral blood of healthy volunteers. EPCs were cultured in endothelial cell growth medium-2 in the presence or absence of rapamycin (0.1 ng/mL) and/or silymarin (12.5-50 MUg/mL). EPCs senescence-associated b-galactosidase activity, telomerase activity, and prolifertive activity were measured. The influence on tubular-like structure formation in vitro was investigated, and colony-forming assay on methylcellulose plates was performed. Silymarin increased telomerase activity 3-fold, reduced the number of senescent cells, and increased EPC proliferative activity (up to 64%) in comparison with cells cultured with rapamycin alone. Moreover, silymarin partially prevented impairment of tubular-like structure formation in Matrigel by rapamycin. These findings suggest that silymarin counteracts the inhibitory effects of rapamycin in EPCs. Silymarin may protect EPCs against the antiproliferative effects of rapamycin and restore their reconstructive ability. PMID- 20838232 TI - Effects of an extract obtained from fruits of Euterpe oleracea Mart. in the components of metabolic syndrome induced in C57BL/6J mice fed a high-fat diet. AB - Previously, we have demonstrated that the seed of Euterpe oleracea Mart. (acai) from the Amazon region exerts vasodilator and antihypertensive actions. The aim of our study was to assess the effects of oral chronic treatment with acai seed extract (ASE, 300 mg . kg(-1) . d(-1)) on high-fat (HF) diet-induced metabolic syndrome (MS) in C57BL/6J mice. Four groups of C57BL/6 mice were fed with control diet (10% fat), ASE (10% fat), HF (60% fat), and HF + ASE (60% fat plus ASE) for 12 weeks. The vasodilator effects of acetylcholine (ACh) and nitroglycerine (NG) were studied in perfused mesenteric arterial bed. Body weight, plasma total cholesterol, triglyceride, glucose and insulin levels, oral glucose tolerance test, and oxidative damage were determined, and the insulin resistance measured by Homeostatic Model Assessment (HOMA) index. Vasodilator response to ACh but not to NG was reduced in HF mice, and ASE restored the response. Increased plasma malondialdehyde levels, body weight, plasma triglyceride, total cholesterol, glucose levels, and insulin resistance were observed in HF mice and reduced by ASE. Treatment with ASE also reduced glucose intolerance observed by oral glucose tolerance test in HF mice. In conclusion, ASE protected C57BL/6J mice fed HF diet from phenotypic and metabolic characteristics of MS, providing an alternative nutritional resource for prevention of MS. PMID- 20838233 TI - Treatment of eosinophilic esophagitis: how should we manage the disease? AB - Eosinophilic esophagitis (EE) is a chronic clinicopathologic syndrome and is the latest inflammatory disease of the esophagus described in literature. It seems to have a multifactorial etiology. Its causes include exposure to food or airborne allergens that affect individuals who may be genetically predisposed and exposure to the acid could also modulate the inflammatory response at esophageal level. However, we currently do not know how each of these possible etiologic factors contribute to the development of the disease that is essential to define specific treatment. We have used 3 different therapeutic approaches that were effective in patients with EE: various antiinflammatory drugs that are useful in treating asthma, controlling the exposure to allergens, particularly with respect to dietary changes and dilation of the esophagus. Although none of these treatments have absolute advantages, they can efficiently control the symptoms and inflammation in a large number of patients. Each treatment option should be assessed on a case-by-case basis in accordance with the experience of each center, the patients' characteristics, their sensitivity to allergens and their preferences. This article provides the latest information on the different treatment options for patients with EE, analyzing the advantages and disadvantages of each pathology and it offers practical recommendations on how to manage these patients who are being more frequently diagnosed. PMID- 20838234 TI - Probiotics use in childhood acute diarrhea: a web-based survey. AB - GOALS: To evaluate practices and barriers for the use of probiotics in acute diarrhea among pediatric gastroenterologists. BACKGROUND: Probiotics have shown significant therapeutic potential in acute infectious diarrhea. However, literature data regarding practice patterns in childhood are limited. STUDY: A web-based 9-item survey among 1854 pediatric gastroenterologists worldwide. RESULTS: Only 634 (34%) responded. Forty-one were excluded owing to incomplete data. Finally 593, USA (n=407) and non-USA (n=186) participants, showed: limited use in acute diarrhea (28% and 32% prospectively), prescription of a 1 strain product only by 31% and 24%, respectively, and limited utilization in ambulatory settings (43% and 51%, respectively) and in prevention of diarrhea (2.6% and 3.4%, respectively). Most participants felt there is lack of useful clinical guidelines (91% and 84%, respectively), and found this therapy effective or very effective (54% and 62%, respectively). Dosing and duration were extremely variable, the youngest age treated ranged from 2 months to 2 years of age, and adverse effects were extremely rare. These characteristics were shared by USA and by non-USA participants, with no significant differences between groups (P>0.05). CONCLUSIONS: Many pediatric gastroenterologists worldwide do not use probiotics for acute diarrhea owing to lack of appropriate guidelines and/or poorly designed products. Therefore, worldwide health authorities should provide pharmaceutical and clinical guidelines for the appropriate use of probiotics in acute diarrhea of childhood. PMID- 20838235 TI - Outcomes of treatment of argon plasma coagulation therapy in elderly or high-risk patients with early gastric cancer: a comparison of outcomes among experienced and nonexperienced endoscopists. AB - BACKGROUND AND AIMS: In the treatment of gastric cancer, argon plasma coagulation (APC) has certain merits, such as short operation time, easy procedure, and lack of serious complications compared with endoscopic mucosal resection or endoscopic submucosal dissection, suggesting that this modality may be appropriate for some patients with gastric cancer. The aim of this study was to assess the therapeutic outcomes of APC in aged and/or high-risk patients with early gastric neoplasm. PATIENTS AND METHODS: Fifty gastric neoplastic lesions (25 early gastric cancers and 25 adenomas) in patients with severe complications were treated with APC and followed up for a mean of 3.6 years (range: 0.5 to 6.6 y). The long-term outcomes of APC therapy and its efficacy as a first-line treatment were compared in patients with those lesions treated by experienced and nonexperienced endoscopists. RESULTS: Recurrence after APC therapy occurred in 5 lesions (10.0%), with an annual relapse rate of 1.8%. The mean time to recurrence was 1.5 years. The total procedure time of APC treatment was 14.5+/-2.6 minutes for experienced endoscopists and 16.4+/-2.2 minutes for nonexperienced endoscopists, with a significant time difference between the 2 groups (P<0.05). However, the outcomes did not differ by endoscopic experience. There were no serious complications, such as perforation, bleeding, or infection. CONCLUSIONS: APC therapy seems to be a safe and useful treatment for patients with early gastric neoplasm and a high risk of severe complications. Equal therapeutic outcomes were obtained by experienced and nonexperienced endoscopists. PMID- 20838236 TI - Irritable bowel syndrome and small intestinal bacterial overgrowth. AB - In the last 3 decades, there has been a growing appreciation for the role of gut bacteria in gastrointestinal disease. Although inflammatory bowel disease and peptic ulcer disease have established a role for gut bacteria for more than 20 years, there is now increasing evidence that intestinal bacteria may play a role in irritable bowel syndrome as well. In this review, the current evidence for bacteria in irritable bowel syndrome will be examined. PMID- 20838237 TI - A multidisciplinary therapeutic approach for reducing the risk of psychiatric side effects in patients with chronic hepatitis C treated with pegylated interferon alpha and ribavirin. AB - GOALS: To evaluate the effectiveness of psychiatric counseling in reducing the rate of development of psychiatric side effects of antiviral therapy with interferon-alpha and ribavirin among study participants compared with standard clinical monitoring alone. BACKGROUND: Interferon-alpha is used to treat chronic hepatitis C. Interferons may induce adverse events that usually, but not always, reverse within a few days after the end of therapy. STUDY: Two hundred eleven patients with chronic hepatitis C, genotype 1b were treated with peginterferon and ribavirin for 48 weeks in a prospective trial. Two groups were randomly created. Group A was interviewed by a team of gastroenterologists, psychiatrists, and psychologists and treated with psychotherapy once a month. Group B was monitored once a month according to a conventional protocol that did not include psychotherapy. SVR (sustained viral response), severe psychiatric symptom onset, and mood progression were assessed (P calculated using Fisher exact test, Friedman test, Dunn posttest, and Mann-Whitney U-test). RESULTS: At baseline, there was no difference in depressive symptoms or liver histologic score between the 2 groups. The onset rate of severe psychiatric manifestations was 4.7% (Group A) and 16.1% (Group B) between the 24th and 36th weeks (P<0.01). Fifteen participants in Group A and 39 in Group B required antidepressants and benzodiazepines (P<0.05). CONCLUSIONS: Patients can develop depressive symptoms during interferon therapy. Multidisciplinary medical treatment with psychiatric counseling provided during the treatment of chronic hepatitis C may contribute to the decrease or prevent the higher rates of depression associated with interferon treatment. PMID- 20838238 TI - Early or late-stage anti-N-terminal Huntingtin intrabody gene therapy reduces pathological features in B6.HDR6/1 mice. AB - Huntington disease (HD) is a progressive neurodegenerative disease caused by an expansion of a polyglutamine sequence in mutant huntingtin (mhtt) that produces abnormal folding and aggregation that results in the formation of nuclear and cytoplasmic neuronal inclusion bodies. Although the precise role of mhtt aggregates in the pathogenesis is unclear, attempts to reduce accumulated mhtt protein have ameliorated the phenotype in multiple cellular and in vivo HD models. Here, we provide critical results on intracranial delivery of a single chain Fv intrabody, C4, which targets the first 17 amino acids of the htt protein, a region of httExon1 that is increasingly being recognized as pivotal. To assess long-term efficacy and safety issues, we used adenoassociated viral vectors (AAV2/1) to deliver intrabody genes to the striatum of inbred B6.HDR6/1 mice. Treatment initiation at various stages of the disease showed that early treatment preserved the largest number of cells without nuclear aggregates and that the accumulation of aggregated material could be delayed by several months. Even when intrabody treatment was not initiated until the clinical disease stage, significant, albeit smaller, effects were seen. These data indicate that neuronal intrabodies against critical N-terminal epitopes can be safely and effectively delivered using AAV2/1 to delay the aggregation phenotype during a sustained period in this HD model, even when delivery is initiated after disease onset. PMID- 20838239 TI - Distribution and expression of picalm in Alzheimer disease. AB - PICALM, the gene encoding phosphatidylinositol-binding clathrin assembly (picalm) protein, was recently shown to be associated with risk of Alzheimer disease (AD). Picalm is a key component of clathrin-mediated endocytosis. It recruits clathrin and adaptor protein 2 (AP-2) to the plasma membrane and, along with, AP-2 recognizes target proteins. The attached clathrin triskelions cause membrane deformation around the target proteins enclosing them within clathrin-coated vesicles to be processed in lysosomes or endosomes. We examined the distribution of picalm in control and AD brain tissue and measured levels of picalm messenger RNA (mRNA) by real-time polymerase chain reaction. Immunolabeling of brain tissue showed that picalm is predominately present in endothelial cells. This was further supported by the demonstration of picalm in human cerebral microvascular cells grown in culture. Picalm mRNA was elevated in relation to glyceraldehyde-3 phosphate dehydrogenase but not factor VIII-related antigen or CD31 mRNA in the frontal cortex in AD. No change was seen in the temporal cortex or thalamus. The transport of Abeta across vessel walls and into the bloodstream is a major pathway of Abeta removal from the brain and picalm is ideally situated within endothelial cells to participate in this process. Further research is needed to determine whether PICALM expression is influenced by Abeta levels and whether it affects Abeta uptake and transport by endothelial cells. PMID- 20838240 TI - Downregulation of the potassium chloride cotransporter KCC2 in vulnerable motoneurons in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. AB - The balance between excitatory and inhibitory synaptic inputs is critical for the physiological control of motoneurons. The maintenance of a low-intracellular chloride concentration by the potassium chloride cotransporter 2 (KCC2) is essential for the efficacy of fast synaptic inhibition of mature motoneurons in response to the activation of ionotropic gamma-aminobutyric acid A and glycine receptors. Altered synaptic balance and excitotoxicity have been proposed as candidate pathophysiological processes in amyotrophic lateral sclerosis (ALS). Therefore, we investigated the expression patterns of KCC2 and its functional opponent, the chloride influx-mediating sodium-potassium chloride cotransporter 1 (NKCC1), in the superoxide dismutase 1 (SOD1-G93A) mouse model of ALS. We detected reduced KCC2 messenger RNA levels and less membrane-bound KCC2 immunoreactivity in ALS-vulnerable motoneurons in lumbar spinal cord and hypoglossal nuclei of SOD1-G93A mice but not in degeneration-resistant oculomotor nuclei. Downregulation of KCC2 started during late presymptomatic stages and accelerated in parallel to hind limb and tongue motor function deficits. In contrast, NKCC1 messenger RNA levels were unaltered in postnatal lumbar spinal cord motoneurons. Our data indicate that reductions in KCC2 gene expression may contribute to selective motor deficits and disease progression in vulnerable motoneurons in a mouse model of ALS. PMID- 20838241 TI - Induction of protective immunity by vaccination with wild-type apo superoxide dismutase 1 in mutant SOD1 transgenic mice. AB - Vaccinations targeting extracellular superoxide dismutase 1 (SOD1) mutants are beneficial in mouse models of amyotrophic lateral sclerosis (ALS). Because of its misfolded nature, wild-type nonmetallated SOD1 protein (WT-apo) may have therapeutic application for vaccination of various SOD1 mutants. We compared the effects of WT-apo to those of a G93A SOD1 vaccine in low-copy G93A SOD1 transgenic mice. Both SOD1 vaccines induced antibody against G93A SOD1 and significantly delayed disease onset compared with saline/adjuvant controls. WT apo SOD1 significantly extended the life span of vaccinated mice. The vaccines potentiated TH2 deviation in the spinal cord as determined by the ratio of interleukin-4 to interferon-gamma (IFNgamma) or tumor necrosis factor and induced C1q deposition around motor neurons. Transgenic mice had abundant microglial expression of signal transducers and activators of transcription 4, an activator of transcription of IFNgamma, in the spinal cord implicating IFNgamma in the pathogenesis. On the other hand, the sera from G93A SOD1-vaccinated mice showed higher IFNgamma or tumor necrosis factor and yielded a lower IgG1/IgG2c ratio than the sera from WT-apo-vaccinated mice. These results indicate that the TH1/TH2 milieu is affected by specific vaccinations and that antigenicity might counteract beneficial effects by enhancing TH1 immunity. Thus, because of its lower TH1 induction, WT-apo may be a therapeutic option and have broader application in ALS associated with diverse SOD1 mutations. PMID- 20838242 TI - Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging. AB - Reduced clearance of amyloid beta peptides (Abeta) across the blood-brain barrier contributes to amyloid accumulation in Alzheimer disease. Amyloid beta efflux transport is via the endothelial low-density lipoprotein receptor-related protein 1 (LRP-1) and P-glycoprotein (P-gp), whereas Abeta influx transport is via the receptor for advanced glycation end products. Because age is the major risk factor for developing Alzheimer disease, we measured LRP-1 and P-gp expression and associated transporter expression with Abeta accumulation in aging rats. Quantitative LRP-1 and P-gp microvessel expression was measured by immunohistochemistry (IHC); LRP-1 and P-gp expression were assessed in microvessel isolates by Western blotting. There was an age-dependent loss of capillary LRP-1 across all ages (3-36 months) by IHC (linear trend p = 0.0004) and between 3 and 20 months by Western blotting (linear trend p < 0.0001). There was a late (30-36 months) P-gp expression loss by IHC (p < 0.05) and Western blotting (p = 0.0112). Loss of LRP-1 correlated with Abeta42 accumulation (p = 0.0121) and very nearly with Abeta40 (p = 0.0599) across all ages. Expression of LRP-1 correlated negatively with the expression of receptor for advanced glycation end products (p < 0.0004). These data indicate that alterations in LRP 1 and P-gp expression seem to contribute progressively to Abeta accumulation in aging. PMID- 20838244 TI - Increased expression of tyrosine hydroxylase in the supraoptic nucleus of the human neonate under hypoxic conditions: a potential neuropathological marker for prolonged perinatal hypoxia. AB - The purpose of this study was to determine whether the increased expression of tyrosine hydroxylase (TH), the first and limiting enzyme in catecholamine synthesis in vasopressin (VP) neurons of the human neonate, represents a primary developmental phenomenon or reflects a secondary phenomenon related to the activation of VP systems due to perinatal hypoxia. Using immunohistochemistry, we investigated TH expression in the supraoptic nucleus (SON) of 15 human neonates at autopsy in relation to the age and severity/duration of hypoxic injury that was estimated on the basis of neuropathological criteria. Increased expression of TH was observed selectively in VP-synthesizing neurons of neonates who experienced prolonged perinatal hypoxia; was not related to the age, body weight/percentile, brain weight, or head perimeter of the subjects but depended on the neuropathological grade of the hypoxic injury (p < 0.01); and was found in VP-synthesizing neurons with increased cellular and nuclear size, that is, neurons with histological evidence of activation. Taken together, these observations indicate that increased expression of TH in VP neurons of SON is not developmentally determined but represents a response to hypoxic stress. We propose that increased TH expression in SON neurons of the human neonate may serve as a neuropathological marker of prolonged perinatal hypoxia in autopsy material. PMID- 20838243 TI - Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. AB - The complex manifestations of chronic multiple sclerosis (MS)are due in part to widespread axonal abnormalities that affect lesional and nonlesional areas in the central nervous system. We describe an association between microglial activation and axon/oligodendrocyte pathology at nodal and paranodal domains in normal appearing white matter (NAWM) of MS cases and in experimental autoimmune encephalomyelitis (EAE). The extent of paranodal axoglial (neurofascin 155(+)/Caspr1(+)) disruption correlated with local microglial inflammation and axonal injury (expression of nonphosphorylated neurofilaments) in MS NAWM. These changes were independent of demyelinating lesions and did not correlate with the density of infiltrating lymphocytes. Similar axoglial alterations were seen in the subcortical white matter of Parkinson disease cases and in preclinical EAE, at a time point when there is microglial activation before the infiltration of immune cells. Disruption of the axoglial unit in adjuvant-immunized animals was reversible and coincided with the resolution of microglial inflammation; paranodal damage and microglial inflammation persisted in chronic EAE. Axoglial integrity could be preserved by the administration of minocycline, which inhibited microglial activation, in actively immunized animals. These data indicate that, in MS NAWM, permanent disruption to axoglial domains in an environment of microglial inflammation is an early indicator of axonal injury that likely affects nerve conduction and may contribute to physiologic dysfunction. PMID- 20838245 TI - Purkinje cell death after uptake of anti-Yo antibodies in cerebellar slice cultures. AB - Paraneoplastic cerebellar degeneration accompanying gynecological and breast cancers is characteristically accompanied by a serum and cerebrospinal fluid (CSF) antibody response, termed "anti-Yo," which reacts with cytoplasmic proteins of cerebellar Purkinje cells. Because these antibodies interact with cytoplasmic rather than cell surface membrane proteins, their role in causing Purkinje cell death has been questioned. To address this issue, we studied the interaction of anti-Yo antibodies with Purkinje cells in slice (organotypic) cultures of rat cerebellum. We incubated cultures with immunoglobulin G (IgG)-containing anti-Yo antibodies using titers of anti-Yo antibody equivalent to those found in CSF of affected patients. Cultures were then studied in real time and after fixation for potential uptake of antibody and induction of cell death. Anti-Yo antibodies delivered in serum, CSF, or purified IgG were taken up by viable Purkinje cells, accumulated intracellularly, and were associated with cell death. Normal IgG was also taken up by Purkinje cells but did not accumulate and did not affect cell viability. These findings indicate that autoantibodies directed against intracellular Purkinje cell proteins can be taken up to cause cell death and suggest that anti-Yo antibody may be directly involved in the pathogenesis of paraneoplastic cerebellar degeneration. PMID- 20838246 TI - Leukoencephalopathy with vanishing white matter: a review. AB - Vanishing white matter (VWM) is one of the most prevalent inherited childhood leukoencephalopathies, but this may affect people of all ages, including neonates and adults. It is a progressive disorder clinically dominated by cerebellar ataxia and in which minor stress conditions, such as fever or mild trauma, provoke major episodes of neurologic deterioration. Typical pathological findings include increasing white matter rarefaction and cystic degeneration, oligodendrocytosis with highly characteristic foamy oligodendrocytes, meager astrogliosis with dysmorphic astrocytes, and loss of oligodendrocytes by apoptosis. Vanishing white matter is caused by mutations in any of the genes encoding the 5 subunits of the eukaryotic translation initiation factor 2B (eIF2B), EIF2B1 through EIF2B5. eIF2B is a ubiquitously expressed protein complex that plays a crucial role in regulating the rate of protein synthesis. Vanishing white matter mutations reduce the activity of eIF2B and impair its function to couple protein synthesis to the cellular demands in basal conditions and during stress. Reduced eIF2B activity leads to sustained improper activation of the unfolded protein response, resulting in concomitant expression of proliferation, prosurvival, and proapoptotic downstream effectors. Consequently, VWM cells are constitutively predisposed and hyperreactive to stress. In view of the fact that VWM genes are housekeeping genes, it is surprising that the disease is primarily a leukoencephalopathy. The pathophysiology of selective glial vulnerability in VWM remains poorly understood. PMID- 20838247 TI - Are the perceptual and decision-making components of agility trainable? A preliminary investigation. AB - Agility is an open motor skill; requiring change of direction speed (CODS) and perceptual and decision-making ability. The aim of this study was to determine whether the perceptual and decision-making component of agility can be trained. Fifteen rugby league players were tested on a sport-specific reactive agility test (RAT) and a CODS test. Players were then allocated to a training group (n = 8) or a nontraining group (n = 7). The training group underwent 3 weeks of reactive agility training that was designed to enhance perceptual and decision making ability. After 3 weeks, all players were tested again. The training group's mean reactive agility time was 1.92 +/- 0.17 seconds preintervention and 1.66 +/- 0.14 seconds postintervention. The nontraining group's mean reactive agility time was 1.89 +/- 0.16 and 1.87 +/- 0.15 seconds, respectively. Mean CODS time for the training group was 1.64 +/- 0.15 seconds preintervention and 1.66 +/ 0.14 seconds postintervention. The nontraining group's mean CODS time was 1.61 +/- 0.12 and 1.62 +/- 0.12 seconds. Mean perception and response time for the training group, measured on the RAT, was 0.33 +/- 0.33 seconds preintervention and 0.04 +/- 0.22 seconds postintervention. The nontraining group's values were 0.34 +/- 0.20 and 0.27 +/- 0.28 seconds, respectively (results are +/-sigma). Differences in mean reactive agility time and perception and response time from pre to postintervention for the training group were statistically significant, as were differences in those values between the training and nontraining group post intervention. All other comparisons were not. Results from this study suggest that the perceptual and decision-making components of agility are trainable. Coaches should incorporate some open motor skills training in their programs when training agility. PMID- 20838249 TI - Biomechanical responses of thigh and lower leg during 10 consecutive soccer instep kicks. AB - This study investigated the number of trials necessary to obtain optimal biomechanical responses in 10 consecutive soccer instep kicks. The kicking motions of dominant legs were captured from 5 experienced and skilled adult male soccer players (height: 184.60 +/- 4.49 cm; mass: 80 +/- 4.24 kg; and age: 25.60 +/- 1.14 years) using a 3D infrared high-speed camera at 200 Hz. Some of the important kinematics and kinetics parameters are maximum thigh angular velocity, maximum lower leg angular velocity, maximum of thigh moment, maximum lower leg moment at forward and impact phases, and finally maximum ball velocity after impact selected to be analyzed. There was a significant decrease of ball velocity between the first and the fifth kick and the subsequent kicks. Similarly, the lower leg angular velocity showed a significant decrease after the fifth kick and thereafter. Compared with the first kick, the thigh angular velocity has been shown to decrease after the sixth kick and thereafter, and the thigh moment result of the sixth kick was significantly lower when compared with the first kick. Moreover, the lower leg moment result of the fourth kick was significantly lower in comparison with the first kick. In conclusion, it seems that 5 consecutive kicks are adequate to achieve high kinematics and kinetics responses and selecting more than 5 kicks does not result in any high biomechanical responses for analysis. PMID- 20838248 TI - The relative and absolute reliability of leg muscle strength testing by a handheld dynamometer. AB - To examine the relative and absolute interrater reliability of handheld dynamometers (HHD) for assessing the lower extremity muscle strength, maximal voluntary contractions (MVCs) of 16 young adults for bilateral hip and knee muscles were tested using the break method. Three MVCs of each muscle group were required for obtaining the muscle strength. Participants' muscle strengths were tested by 2 raters. The intraclass correlation coefficients (ICCs) and the smallest real differences (SRD) were used to examine the relative and absolute reliabilities, and the Bland-Altman analyses were used to check whether systematic bias exists. The results showed that the relative reliabilities of all muscle groups were excellent (ICCs = 0.83-0.92) except for the knee extensors (ICC = 0.60). The SRD represents the smallest difference that indicates a real change for a single subject. The SRD% of all muscle groups was acceptable (ranging from 8.4 to 22.8 %), with the hip extensors being the smallest and knee extensors being the largest. The reliability of the knee extensors was unsatisfactory because of poor relative and absolute reliabilities and systematic bias. In addition to assessing the relative reliability in strength measurement, the absolute reliability provides the data of the measurement error, which is useful information in clinical practice to know whether the change in strength of a subject is real. Hand-held dynamometer is a reliable tool for quantifying most of the hip and knee strength except for the knee extensors. Modifying the measuring technique for knee extension is needed in future studies to improve the reliability. PMID- 20838250 TI - Using squat testing to predict training loads for lower-body exercises in elite karate athletes. AB - The purpose of this study was to determine the relationship between squat loads and 2 bilateral and 2 unilateral stepping lower-body exercises in predominantly unilateral movement elite athletes (Karate). Equations to predict loads for lower body exercises based on the squat load were also determined. Fourteen male elite Karate athletes (age = 22.6 +/- 1.2 years) performed 6 repetition maximum (RM) of the following free-weight bilateral exercises: back half squat, deadlift, leg press and unilateral stepping exercises, lunge; and step-up. Results showed that 6RM squat load was significantly (p < 0.001) correlated with deadlift (r = 0.86), leg press (r = 0.76), lunge (r = 0.86), and step-up (r = 0.92). Linear regression showed that the 6RM squat load was a significant predictor for deadlift, leg press, lunge, and step-up (R2 range from 0.57 to 0.85, p < 0.001). The following 6RM prediction equations were determined: (a) Deadlift = squat load (1.12)-16.60 kg, (b) Leg press = squat load (1.66) + 16.10 kg, (c) Lunge = squat load (0.61) + 9.39 kg, and (d) step-up = squat load (0.85)-10.36 kg. Coaches and fitness professionals can use the 6RM squat load as a time effective and accurate method to predict training loads for both bilateral and unilateral lower-body exercises with quadriceps as the prime mover. Load prescriptions for unilateral exercises should take into account the type of athletic population. PMID- 20838251 TI - Instructor-paced vs. self-paced skiing modes in older recreational alpine skiers. AB - Parallel ski steering (PSS), carving in long radii (CLR), and individual technique (IT) skiing modes are mainly used throughout instructor-guided skiing of older recreational skiers. The aims of this study were (a) to determine differences in the physiologic response of older skiers to PSS, CLR, and IT skiing modes, (b) to quantify correlations between rate of perceived exertion (RPE) and the physiologic response, and (c) to analyze the relationship between aerobic capacity, skiing skills, and the blood lactate (LA) response during instructor-guided skiing. Twenty recreational skiers (61.1 +/- 5.6 years) performed instructor-paced (PSS and CLR) and self-paced (IT) skiing modes. Heart rate (HR), LA, mean arterial blood pressure (MAP), and RPE were determined during skiing. Skiers skiing skills were judged by expert ski instructors. The aerobic capacity was tested by a physical work capacity test (PWC130) test. Heart rate was lower for PSS (106 +/- 15 b . min(-1)), compared to CLR (118 +/- 16 b . min( 1)) and IT (120 +/- 15 b . min(-1)) skiing modes, both p < 0.001. Lactate levels were 1.45 +/- 0.50 mmol . L(-1) for PSS, 1.67 +/- 0.61 mmol . L(-1) for CLR, and 2.00 +/- 0.74 mmol . L(-1) for IT skiing modes, all p < 0.004. Individual reductions in LA concentrations from 3.9 to 2.6 mmol . L were found, for IT and PSS skiing modes, respectively. No significant correlations were determined between any physiologic variable and RPE. Weak correlations were found between LA and PWC130 results (R2 < 0.114) and between LA and skiing skills (R2 < 0.132). In conclusion, significant reductions in the physiologic response were determined for PSS and CLR, compared with IT skiing modes. Instructor-paced skiing modes may minimize the risk of premature fatigue of skiers with high physiological responses. Those skiers may not perceive their disproportionate higher stress compared with skiers on the low end. PMID- 20838252 TI - Anthropometric characteristics and nutritional profile of young amateur swimmers. AB - The aim of this study was to evaluate nutritional and anthropometric profiles of young swimmers belonging to semiprofessional teams. Thirty-six caucasian adolescent swimmers (22 boys and 14 girls) participated voluntarily in the study. Anthropometric data, dietary intake, and blood parameters were determined. Female swimmers had greater values of triceps, suprailiac, and abdominal skinfolds. Endomorphic somatotype was twofold greater in girls compared with in boys. Energy intake and protein intake per kilogram of body weight were significantly greater in boys compared to in girls. On the other hand, girls had significantly greater polyunsaturated fatty acid intake compared that of boys. Energy intake of boys and girls was below their requirements. In contrast, protein intake doubled the requirements of the study population. Furthermore, inadequate intake of carotenes, vitamin A, vitamin E, vitamin D, and folic acid was found in both boys and girls; girls also had inadequate intake of iron and calcium. Plasma levels of iron, vitamins C and E, and carotenes were similar in male and females swimmers, and they were within the normal range. In conclusion, young swimmers participating in the present study had differences between sexes in somatotypes. Adolescent swimmers had low average total energy intakes, excessive protein intake, and lower intake of several micronutrients in both sexes. PMID- 20838253 TI - Prevention of falling risk in elderly people: the relevance of muscular strength and symmetry of lower limbs in postural stability. AB - Falls are one of the major health problems affecting the quality of life among older adults. The aging process is associated with decreasing muscle strength and an increasing risk of falling. The variables and techniques adopted to quantify muscular strength and postural stability were different in each protocol; a great number of reports analyzed the risk factors and predictors of falls, but the results appear still uncertain. To date, there is no clear, definitive statement or review that has examined the effect of the quadriceps strength on static balance performances in different sensory conditions. This contribution aims to provide an overview of experimental works to increase the comprehension and prevention of falls and fall-related injuries in the elderly. Based on a review of the literature, this work was designed to explore the relationship among risk of falls, postural stability, and muscular strength of lower limbs in older adults. PMID- 20838254 TI - Body uneasiness, eating disorders, and muscle dysmorphia in individuals who overexercise. AB - This study aimed to investigate exercise dependence, body and eating concerns of active individuals in relation to muscle dysmorphia (MD) and eating disorders (EDs). One hundred and thirty-four active individuals (86 men, 48 women) and 20 ED women were divided into 4 groups according to their sex and the difference between their actual and desired body weight (group A: men who wanted to gain weight; group B: men who wanted to lose weight; group C: women who wanted to lose weight; group D: ED women). The Eating Disorder Inventory 2, Body Uneasiness Test, and Muscle Dysmorphia Inventory questionnaires were administered. All women desired to reduce their body weight, whereas 55% of men wanted to increase their muscle mass, also using anabolic steroids and food integrators. All groups showed a similar use of diuretics and laxatives (range 10-21%). The findings highlighted the presence of minor body image disorders in groups B and C. Conversely, body image was remarkably altered in groups D and A. Recognizing main MD traits, physical trainers should recommend further psychological counseling. Information should also be provided to gym clients regarding the health risks associated with purgative behaviors, use of steroids, and abuse of food supplements. PMID- 20838255 TI - The validity of sessionrating of perceived exertion method for quantifying training load in teamgym. AB - Teamgym is a new and emerging closed-skill sport, which includes tumbling, trampette, and floor programs performed by teams ranging from 6 to 12 athletes. The purpose of this study was to verify the concurrent validity of the session rating of perceived exertion ([RPE] session-RPE) to quantifying the internal training load (ITL) of tumbling, trampette, and floor training sessions using Edwards' summated heart rate (HR)-zone method as a criterion measure. Session-RPE was obtained with 2 different instruments (i.e., CR-10 Borg's scale and visual analog scale) multiplied by the training duration (minutes). Ten female teamgym athletes (age = 21.7 +/- 1.2 years; height = 164.9 +/- 6.6 cm; and body mass = 54.6 +/- 5.4 kg) participated in this study. High and significant correlations (r range: 0.77-0.85; R range: 0.59-0.85; p < 0.01) were found between Edwards' HR and the session-RPE methods and between the 2 session-RPE instruments (r range: 0.92-0.97; R2 range: 0.85-0.94; p < 0.01). The significant (p < 0.05) differences emerged between training sessions indicate that session-RPE discriminates ITL in relation to various technical skills. Hence, session-RPE can be a useful and inexpensive tool to quantify ITL in teamgym, and coaches could use this instrument to monitor their periodization plan as experienced by the athletes. PMID- 20838256 TI - Reliability and factorial validity of flexibility tests for team sports. AB - The main goal of this method paper was to evaluate the reliability and factorial validity of flexibility tests used in soccer, and to do crossvalidation study on 2 other team sports using handball and basketball players. The second aim was to compare the validity of the different tests and evaluate the flexibility of soccer players; the third was to determine the positional differences between attackers, defenders, and midfielders in all flexibility tests. One hundred and fifty (n = 150) elite male junior soccer players, members of the First Croatian Junior League Teams, and 60 (n = 60) handball and 60 (n = 60) basketball players also members of the First Croatian Junior League Teams volunteered to participate in the study, tested for the purpose of crossvalidation. The SAR and V-SAR had the greatest AVR and ICC. The within-subjects variation ranged from between 0.3 and 3.8%. The lowest value of CV was found between the LSPL and LSPR. Low to moderate statistically significant correlation coefficients were found among all the measured flexibility tests. It was observed that the greatest correlations existed between the SAR and V-SAR (r = 0.65) and between the LLSR and LLSL (r = 0.56). Statistically significant correlations were also observed between the BLPL and BLPR (r = 0.62). The principal components factor analysis of 9 flexibility tests resulted in the extraction of 3 significant components. The results of this study have the following implications for the assessment of flexibility in soccer: (a) all flexibility tests used in this study have the acceptable between and within-subjects reliability and they can be used to estimate the flexibility of soccer players; (b) the LSPL and LSPR tests are the most reliable and valid flexibility tests for the estimation of flexibility of professional soccer players. PMID- 20838257 TI - Elite futsal refereeing: activity profile and physiological demands. AB - The purpose of this study was to determine the physiological demands and to establish the relationship between activity profile and endurance capacity of futsal referees. Eighteen elite futsal referees (33.0 +/- 5.1 years, 173 +/- 5 cm, and 73.2 +/- 8.4 kg) were studied. Video filming (n = 18) and heart rate (HR) recordings were performed throughout games. Blood lactate (n = 14) was determined at rest and after the game. Endurance capacity was determined with the Yo-Yo IE2. The number of activity changes was as high as 1,395 +/- 218 (+/- SD). Total distance covered, high-intensity running (HIR), sprinting (SPR), and sideways running were 5.89 +/- 0.56, 0.96 +/- 0.29, 0.09 +/- 0.07, and 0.91 +/- 0.46 km, respectively. The number of HIR and SPR bouts was 129 +/- 41 and 9 +/- 8, respectively, with a mean duration of ~1.4 seconds. Blood lactate content was 1.0 +/- 0.3 and 1.5 +/- 0.5 mM before and after the game. The amount of HIR performed during the match correlated significantly (r = 0.77; p < 0.05) with the Yo-Yo IE2 performance. Considering the data obtained in the present study, the use of match specific intermittent fitness tests to evaluate futsal referees seems to be required. PMID- 20838258 TI - Access to trauma systems in Canada. AB - BACKGROUND: Trauma is a leading cause of morbidity, potential years of life lost and health care expenditure in Canada and around the world. Trauma systems have been established across North America to provide comprehensive injury care and to lead injury control efforts. We sought to describe the current status of trauma systems in Canada and Canadians' access to acute, multidisciplinary trauma care. METHODS: A national survey was used to identify the locations and capabilities of adult trauma centers across Canada and to identify the catchment populations they serve. Geographic information science methods were used to map the locations of Level I and Level II trauma centers and to define 1-hour road travel times around each trauma center. Data from the 2006 Canadian Census were used to estimate populations within and outside 1-hour access to definitive trauma care. RESULTS: In Canada, 32 Level I and Level II trauma centers provide definitive trauma care and coordinate the efforts of their surrounding trauma systems. Most Canadians (77.5%) reside within 1-hour road travel catchments of Level I or Level II centers. However, marked geographic disparities in access persist. Of the 22.5% of Canadians who live more than an hour away from a Level I or Level II trauma centers, all are in rural and remote regions. DISCUSSION: Access to high quality acute trauma care is well established across parts of Canada but a clear urban/rural divide persists. Regional efforts to improve short- and long-term outcomes after severe trauma should focus on the optimization of access to pre hospital care and acute trauma care in rural communities using locally relevant strategies or novel care delivery options. PMID- 20838259 TI - A chasm between injury and care: experiences of black male victims of violence. AB - BACKGROUND: Despite higher rates of stabbing and shooting violence among black men, healthcare systems have not demonstrated an efficacious response to these patients. This study describes challenges and promotive factors for engaging black male violence victims of violence with medical and mental healthcare. METHODS: Black male victims of stabbings and shootings were recruited through fliers and word of mouth, and were interviewed individually (n = 12) or in pairs (n = 4) using a semistructured guide. A racially diverse multidisciplinary team analyzed the data using Grounded Theory methods. RESULTS: Challenges to engagement with healthcare included the following: (1) Disconnect in the aftermath; e.g. participants reported not realizing they were seriously injured ("just a scratch" "poke"), were disoriented ("did not know where I was"), or were consumed with anger. (2) Institutional mistrust: blurred lines between healthcare and police, money-motivated care. (3) Foreshortened future: expectations they would die young. (4) Self-reliance: fix mental and substance abuse issues on their own. (5) Logistical issues: postinjury mental health symptoms, disability, and safety concerns created structural barriers to recovery and engagement with healthcare. Promotive factors included the following: (1) desire professionalism, open personality, and shared experience from clinicians; (2) turning points: injury or birth of a child serve as a "wake up call"; and (3) positive people, future-oriented friends and family. CONCLUSIONS: For black male violence victims, medical treatment did not address circumstances of and reactions to injury. Policies delineating boundaries between medical care and law enforcement and addressing postinjury mental health symptoms, disability, and safety concerns may improve the recovery process. PMID- 20838260 TI - Regulation of vasoactive intestinal polypeptide release in the suprachiasmatic nucleus circadian clock. AB - Timing of the mammalian circadian clock of the suprachiasmatic nucleus (SCN) is regulated by photic input from the retina. Retinorecipient units entrain rhythmicity of SCN pacemaker cells in part through their release of vasoactive intestinal polypeptide (VIP). The underlying nature of this process is conjectural, however, as in-vivo SCN VIP release has never been measured. Here, SCN microdialysis was used to investigate mechanisms regulating VIP. Hamsters under light-dark cycle of 14:10 exhibited a daily peak in synaptic VIP release near midday. Under constant darkness, this output was arrhythmic. Light and the glutamatergic agonist, N-methyl-D-aspartate, stimulated VIP release at night, whereas the serotonin (1A,7) agonist, (+/-)8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, suppressed release at midday. Hence, SCN VIP activity is stimulated by photic input and inhibited by serotonin. PMID- 20838261 TI - Does focusing on hand-grasping intentions modulate electroencephalogram MU and alpha suppressions? AB - Understanding the intentions of others presumably involves a human analog of the mirror neuron system. A putative marker of such mirror activity is the suppression of electroencephalographic oscillations in the 8-12 Hz range, which, when recorded over somatosensory areas, is associated with motor activity and labeled MU rhythms. We investigated whether MU-suppression can be modulated by attention to another person's intention as expressed by her hand movement toward an object and whether this suppression is distinguished from the suppression of alpha waves that oscillate in the same frequency range and are modulated by attention and cognitive load. Both MU and alpha suppressions were modulated by task difficulty, and not distinctively by intention, reflecting the recruitment of resources needed for task performance. PMID- 20838262 TI - Effects of the interstimulus interval on somatosensory go/no-go event-related potentials. AB - This study investigated the characteristics of event-related potentials using somatosensory go/no-go paradigms. We manipulated the interstimulus interval and analyzed its effect on the peak amplitude and latency of the N140 and P300 components. The amplitude of N140 increased as the interstimulus interval increased, and was significantly larger in no-go than in go trials at the 1-s and 2-s interstimulus intervals, but not the 4-s and 6-s interstimulus intervals. The amplitude of P300 also increased with the interstimulus interval, and was significantly larger in no-go than in go trials at all interstimulus intervals. The reaction time in go trials was longer with increasing interstimulus interval. This study suggests that brain activities associated with go/no-go decisional processes are influenced by the interstimulus interval. PMID- 20838263 TI - Polymorphic variation of the guanosine triphosphate cyclohydrolase 1 gene predicts outcome in patients undergoing surgical treatment for lumbar degenerative disc disease. AB - STUDY DESIGN: Prospective observational study. OBJECTIVE: To determine whether polymorphic variations of the guanosine triphosphate (GTP) cyclohydrolase 1 gene (GCH1) are associated with different outcomes in patients undergoing surgical treatment for lumbar degenerative disc disease (DDD). SUMMARY OF BACKGROUND DATA: GCH1, the gene encoding the rate-limiting enzyme in tetrahydrobiopterin synthesis, has been strongly implicated as a determinant of pain experience in previous animal and human studies. METHODS.: A total of 69 patients undergoing surgical treatment for lumbar DDD were prospectively enrolled. Genomic DNA was extracted from a venous blood sample, and DNA sequence analysis was performed of GCH1. Surgery included 65 instrumented fusions and 4 disc arthroplasty procedures. Patients were observed prospectively for 1 year following surgery. Allelic and genotype frequencies were calculated for each of 14 single nucleotide polymorphisms (SNPs). One-year postoperative Oswestry Disability Index (ODI) scores were compared to preoperative scores and the absolute change in ODI score was used to perform genetic association analyses on the basis of both individual SNP markers as well as commonly observed haplotypes for the entire gene sequence. RESULTS: Single marker analysis revealed 1 SNP (rs998259; minor allele T) that was significantly associated with improvement in both absolute ODI score (P = 0.030) and Numerical Rating Scale back pain scores (P = 0.033) following surgery. Haplotype analysis identified a common GCH1 haplotype ("CACTTGTTTGAC") with a sample frequency of 12.3%, which was highly associated with improvement in absolute ODI score (P = 0.04). This haplotype frequency reflects the existence of both heterozygous and homozygous individuals in the study population. The presence of 1 unit of this haplotype was associated with an improvement in postoperative ODI score of 15.34 relative to the absence of this haplotype (P = 0.04). CONCLUSION: Preliminary results from this pilot genetic study of patients undergoing surgery for DDD suggests that the T allele at rs998259 of GCH1 may be associated with improved outcomes 1 year following surgery. PMID- 20838264 TI - ISSLS prize winner: a study of effects of in vivo mechanical forces on human lumbar discs with scoliotic disc as a biological model: results from serial postcontrast diffusion studies, histopathology and biochemical analysis of twenty one human lumbar scoliotic discs. AB - STUDY DESIGN: A comprehensive study of 21 lumbar scoliotic discs by in vivo serial post contrast diffusion magnetic resonance imaging (MRI), histopathological, and biochemical analysis. OBJECTIVE: To investigate the in vivo effects of compressive and tensile mechanical stress on the lumbar discs with scoliotic disc as the biologic model. SUMMARY OF BACKGROUND DATA: Most studies implicating mechanical stress in degenerative disc disease (DDD) are on animals, in vitro conditions and cadavers. They are also restricted to histopathological or biochemical evaluation without analyzing the endplate (EP) and nucleus pulposus (NP) separately. The few human studies have not analyzed diffusion changes which is the final pathway for DDD. Adolescent scoliotic disc offer a perfect model to study the effects of mechanical stress. METHODS: Twenty one discs from 6 patients with adolescent idiopathic scoliosis undergoing anterior corrective surgery were assessed before surgery by postcontrast MRI to document the EP diffusion patterns. The same discs harvested during surgery were analyzed histologically and biochemically. The results were correlated to clinical and radiologic parameters. RESULTS: Altered diffusion patterns was seen in all discs with site specific breaks in 2, double peak pattern in 3, high intensity pattern in 14, and frank contrast leak in 2. There was marked decrease in cell density and viability in all discs on both convex and concave sides compared to the control disc (P = 0.001). Neovascularization, calcification, and matrix degeneration were observed to varying extent in different regions of NP and EP. There was a decrease in water content with increasing severity of curves with significant difference between mild and severe curves (NP: P = 0.000, EP: P = 0.002). Lactate was significantly higher in caudal EP (P = 0.035) and discs with coronal migration of more than 15 mm (P = 0.007). Regression analysis showed that truncal decompensation was a main factor for decrease in cell density, matrix degeneration, calcification, and water content. CONCLUSION: The study documents widespread changes in the EP and NP even in discs with minimal wedging. EP damage and alterations in diffusion were observed earlier than MRI changes and could indicate nutritional factors as the primary mechanism of degeneration induced by mechanical stress. Degeneration was more severe in caudal discs and those with truncal decompensation. Its implications on the timing and choice of surgery in scoliosis are discussed. PMID- 20838265 TI - The visual analog scale and a five-item verbal rating scale are not interchangeable for back pain assessment in lumbar spine disorders. AB - STUDY DESIGN: Prospective study of patients with chronic back pain from lumbar spine disorders. OBJECTIVE: To evaluate the degree of interchangeability of a 100 mm visual analog scale (VAS) and a 5-point verbal rating scale (VRS) for the assessment of pain intensity. SUMMARY OF BACKGROUND DATA: The fact that VAS and Likert scales are highly intercorrelated does not mean that both types of scales can be used interchangeably. METHODS.: A total of 151 patients (mean age, 52 +/- 14.6 years) undergoing elective spine surgery completed a 100-mm VAS and a discrete 5-category VRS corresponding to the first item question of the core set ("How severe was your back pain in the last week?"). Pain intensity on the VAS was rated using the same question than for the VRS. The level of order consistency (monotonic agreement), disordered pairs (D), percentage of agreement, and systematic disagreement (relative position), and relative concentration ([RC]) were estimated. VAS assessments were transformed into a discrete 5 category, with the cut-off VAS positions being defined by quintiles and equidistantly. RESULTS: For VAS defined equidistantly, monotonic agreement was 0.840, D was 0.080, and the percentage of identical pairs was 53%. The corresponding figures for VAS defined by quintiles were 0.809, 0.096, and 27.8%. Inconsistencies between the VAS and the VRS scales were also demonstrated by the marginal distributions, with PR values of -0.005 (95% confidence interval [CI], 0.011 to -0.002) and RC values of 0.144 (95% CI, 0.137-0.152) for VAS defined equidistantly, and PR values of 0.391 (95% CI, 0.384-0.397) and RC values of 0.265 (95% CI, 0.255-0.275) for VAS defined by quintiles. CONCLUSION: The order consistency level was low with overlapping of pain records between the 2 scales, indicating that VAS and VRS are not interchangeable and, therefore, a results obtained with the use of each scale cannot be compared. PMID- 20838266 TI - Neck pain in Hong Kong: a telephone survey on consequences and health service utilization. AB - STUDY DESIGN: A regionally representative telephone survey using a 2-stage randomization process. OBJECTIVE: (1) To investigate the prevalence and consequence of neck pain in terms of disability and rate of absenteeism from work. (2) To describe the health services utilization pattern of neck pain subjects and to analyse the factors associated with neck pain and health services utilization pattern. SUMMARY OF BACKGROUND DATA: There has been a lack of reliable information on the health service utilization pattern of neck pain subjects, the consequences and the patient perceived effectiveness of neck pain management in Hong Kong and Asian countries. METHODS: Subjects were interviewed on the sociodemographic characteristics, occurrence and consequences of neck pain, and the health utilization pattern. A random sample of the respondents was re-interviewed 7 to 10 days after the initial interview, by an independent interviewer for the reliability check. RESULTS: A total of 4640 subjects were interviewed. The 12-month prevalence was 64.6% (95% CI: 63.2%-66.0%). About 38.0% of these patients suffered from moderate to severe pain. Moreover, 17.7% of these subjects had to limit their social activities and 19% had to limit their work. About 25% of those subjects had consulted medical or health practitioners. Medical consultation is the majority and physiotherapy came second. Self-massage was the most preferred (83.3%) mode of self-care. Physiotherapy was regarded as the most effective health service, with 60% of the respondents' neck pain completely removed. Although most people chose self-massage to be the most effective self-care treatment, only one-third (30.2%) of them had their neck pain improved by less than a half. CONCLUSION: Neck pain is highly prevalent with an increasing impact in Hong Kong. More than one-third of neck pain patients suffered from moderate to severe pain and around 20% of them had to limit their work. About 25% of neck pain patient have consulted medical or health professionals. Physiotherapy and private medical clinic were the 2 service providers with high percentage of perceived complete improvement. There was a general trend that more neck pain patients used complementary therapies. PMID- 20838267 TI - Segmental fracture of the lumbar spine. AB - STUDY DESIGN: A case report is presented. OBJECTIVE: To describe a rare, previously undescribed pattern of spinal injury. SUMMARY OF BACKGROUND DATA: This seems to be a unique injury with no previously described injuries matching the fracture pattern observed. METHODS: This is a case report based on the experience of the authors. The discussion includes a short literature review based on pubmed searches. RESULTS: We report the case of a 26-year-old female cyclist involved in a road traffic accident with a truck resulting in complete disruption of the lumbar spine. The cyclist was caught on the inside of a truck turning left and seems to have passed under the rear wheels. She was brought to the local emergency department where, after appropriate resuscitation, trauma survey revealed spinal deformity with complete neurologic deficit below T12 and fractured pubic rami, soft tissue injuries to the perineum and multiple abrasions. Plain radiology showed a segmental fracture dislocation of her lumbar vertebrae, extending from the L1 superior endplate through to L4-L5 disc space. The entire segment was displaced in both anteroposterior and lateral planes. Computed tomography confirmed these injuries and ruled out significant visceral injury. She was transferred to the national spinal unit (author unit), where she underwent reduction and fixation with rods and screws from T9-S1, using one cross link. After her immediate postoperative recovery, she was referred to the national rehabilitation unit. CONCLUSION: Although so-called "en bloc" lumbar fractures have been previously described, the authors were unable to find any injury of this degree in the literature. This rare injury seems to show a pattern of spinal injury previously undescribed. PMID- 20838268 TI - A patient-mount navigated intervention system for spinal diseases and its clinical trial on percutaneous pulsed radiofrequency stimulation of dorsal root ganglion. AB - STUDY DESIGN: Development of a patient-mount navigated intervention (PaMNI) system for spinal diseases. An in vivo clinical human trial was conducted to validate this system. OBJECTIVE: To verify the feasibility of the PaMNI system with the clinical trial on percutaneous pulsed radiofrequency stimulation of dorsal root ganglion (PRF-DRG). SUMMARY OF BACKGROUND DATA: Two major image guiding techniques, i.e., computed tomography (CT)-guided and fluoro-guided, were used for spinal intervention. The CT-guided technique provides high spatial resolution, and is claimed to be more accurate than the fluoro-guided technique. Nevertheless, the CT-guided intervention usually reaches higher radiograph exposure than the fluoro-guided counterpart. Some navigated intervention systems were developed to reduce the radiation of CT-guided intervention. Nevertheless, these systems were not popularly used due to the longer operation time, a new protocol for surgeons, and the availability of such a system. METHODS: The PaMNI system includes 3 components, i.e., a patient-mount miniature tracking unit, an auto-registered reference frame unit, and a user-friendly image processing unit. The PRF-DRG treatment was conducted to find the clinical feasibility of this system. RESULTS: The in vivo clinical trial showed that the accuracy, visual analog scale evaluation after surgery, and radiograph exposure of the PaMNI guided technique are comparable to the one of conventional fluoro-guided technique, while the operation time is increased by 5 minutes. CONCLUSION: Combining the virtues of fluoroscopy and CT-guided techniques, our navigation system is operated like a virtual fluoroscopy with augmented CT images. This system elevates the performance of CT-guided intervention and reduces surgeons' radiation exposure risk to a minimum, while keeping low radiation dose to patients like its fluoro-guided counterpart. The clinical trial of PRF-DRG treatment showed the clinical feasibility and efficacy of this system. PMID- 20838269 TI - Explanatory and diagnostic labels and perceived prognosis in chronic low back pain. AB - STUDY DESIGN: Content analysis of patient interviews, clinic letters, and radiology reports for patients with chronic low back pain of greater than 12 months duration. OBJECTIVE: To explore the language used by patients and healthcare professionals to describe low back pain and any potential effect on patient perceived prognosis. SUMMARY OF BACKGROUND DATA: Diagnostic explanations by healthcare professionals may influence patient coping and uptake of therapy by patients with chronic low back pain. Although the correlation between radiologic changes and chronic low back pain is weak, these investigations are often used by clinicians as an explanation of the underlying cause for the pain. METHODS: Patients were asked about their understanding of the mechanisms underlying their pain, flares, and future outcome. Notes from these interviews were transcribed, along with correspondence from primary care physicians, orthopedic surgeons and pain physicians, and lumbar spine radiology reports for these patients. Content analysis was performed to identify and group key terms. RESULTS: Two major categories representing the predominant themes emerging from the content analysis were "Degeneration" and "Mechanical." Degenerative terms such as "wear and tear" and "disc space loss" indicated a progressive loss of structural integrity. Examples of phrases used by patients included "deterioration [...] spine is crumbling" and "collapsing [...] discs wearing out." The use of degenerative terms by patients was associated with a poor perceived prognosis (P < 0.01). Degenerative and mechanical terms were more commonly used by patients when they were documented in correspondence from secondary care specialists (P = 0.03 and 0.01, respectively). CONCLUSION: A common language is shared between professionals and patients that may encourage unhelpful beliefs. The use of degenerative terms such as wear and tear by patients is associated with a poor perceived prognosis. The explanation of radiological findings to patients presents an opportunity to challenge unhelpful beliefs, thus facilitating uptake of active treatment strategies. PMID- 20838270 TI - A comparative study of pyogenic and tuberculous spondylodiscitis. AB - STUDY DESIGN: We performed a retrospective review of 126 cases of infectious spondylodiscitis over a 4-year period. OBJECTIVE: Differentiation between pyogenic spondylodiscitis (PS) and tuberculous spondylodiscitis (TS) is essential for deciding on the appropriate therapeutic regimen. The aim of this study was to compare the characteristics of the 2 forms of spondylodiscitis. SUMMARY OF BACKGROUND DATA: There has been much effort to distinguish the radiologic findings in PS versus TS, but classification based on radiologic findings alone had limitations yet. METHODS: We compared the predisposing factors or associated illnesses, clinical, radiologic, and laboratory features of microbiologically confirmed cases of PS and TS in 2 university hospitals. RESULTS: Of 126 patients, 79 had PS and 47 TS. PS was more frequently associated with the followings: previous invasive spinal procedures (PS vs. TS: 32.9% vs. 8.5%), preceding bacteremia (13.9% vs. 0%), chronic renal failure (12.7% vs. 0%), liver cirrhosis (13.9% vs. 0%), fever (temperature >38 degrees C) (48.1% vs. 17.0%), white blood cell counts over 10,000/mm (41.8% vs. 19.1%), fraction of neutrophils >75% (49.4% vs. 27.7%), C-reactive protein levels over 5 mg/dL (58.2% vs. 27.7%), erythrocyte sedimentation rate levels over 40 mm/h (84.4% vs. 66.0%), and ALP levels over 120 IU/L (45.6% vs. 17.0%). TS was frequently associated with active tuberculosis of other organs (0% vs. 31.9%), longer diagnostic delay (47.6 vs. 106.3 days), involvement of thoracic spines (21.5% vs. 38.3%), and involvement of >=3 spinal levels (11.4% vs. 36.2%). CONCLUSION: Previous invasive spinal procedures, preceding bacteremia, fever, higher white blood cell counts, C-reactive protein, ALP, and higher fraction of neutrophils are suggestive of PS. Concurrent active tuberculosis, more indolent course and involvement of thoracic spines are suggestive of TS. When the causative organism is not identified despite all efforts at diagnosis, combination of the clinical, radiologic, and laboratory characteristics of the patient is helpful. PMID- 20838271 TI - The mechanical effect of commercially pure titanium and polyetheretherketone rods on spinal implants at the operative and adjacent levels. AB - STUDY DESIGN: Single-level cadaveric lumbar constructs were instrumented with either polyetheretherketone (PEEK) or commercially pure (CP) titanium (Ti) rods and biomechanically evaluated. Strain from gauged bone screws and interbody (IB) spacers, kinematic motion, and caudal disc pressure measurements were recorded during testing. OBJECTIVE: The objective of this study was to determine the biomechanical differences in CP Ti rods and PEEK rods in conjunction with PEEK interbody spacers. SUMMARY OF BACKGROUND DATA: Very little biomechanical data exist substantiating the performance of PEEK as a spinal rod material. This study is unique, because it combines strain, motion, and pressure measurement techniques to evaluate cadaveric constructs. METHODS: Twelve human cadaveric lumbar spine segments (T12-L3 and L4-S1) were tested in compression, flexion extension, bilateral lateral bending, and bilateral axial torsion. Bending, axial, and shear strains were recorded from a gauged bone screw; axial and shear strains were also recorded from a gauged PEEK interbody spacer. Planar motion data and subadjacent disc pressure measurements were also collected. RESULTS: Highest screw strains were in bending; the lowest screw strains derived from the shear and axial gauges. Spacer strain was high to medium in some cases, especially in compression and flexion. PEEK constructs attained higher interbody strains than Ti constructs. Conversely, Ti construct screw strains were higher in most tests. Planar motion showed no differences at any level in almost every test. There was a trend toward decreased caudal intradiscal pressure for Ti constructs in compression. CONCLUSION: Rigid CP Ti rods resulted in increased screw strain (bone-screw interface forces) and less interbody spacer compression (higher stress shielding). Furthermore, there was a trend toward decreased intradiscal pressure with Ti rods at the caudal segment. These trends suggest that segments instrumented with PEEK more closely mimicked intact physiologic loading in the subadjacent level, which may reduce the likelihood of adjacent level disease. PMID- 20838272 TI - Resolution of physical signs and recovery in severe cervical spondylotic myelopathy after cervical laminoplasty. AB - STUDY DESIGN: Retrospective case series review. OBJECTIVE: To determine the recovery and prevalence of myelopathic signs and their resolution in cervical spondylotic myelopathy after treatment by laminoplasty. SUMMARY OF BACKGROUND DATA: Myelopathic signs are an integral component of diagnosis of cervical myelopathy. Effect of surgical intervention (laminoplasty) on recovery of these reflexes has not been studied and remains undetermined. Their recovery and its rate remain unclear. This may be important because resolution may affect recovery, and reappearance may mark relapse. METHODS: Patients diagnosed as having cervical spondylotic myelopathy based on symptoms, corroborative imaging, and improvement of at least 1 grade in Nurick score were part of study. The patients were evaluated for a period of 1 year from surgery. Hyperreflexia and provocative signs (Hoffman, inverted brachioradialis reflex, clonus, and Babinski) and recovery (Nurick and mJOA) were noted at subsequent follow-up, and improvement was analyzed. RESULTS: Twenty-one patients had severe spondylotic myelopathy with Nurick score >= 3. Myelopathic signs were highly sensitive in diagnosing the presence of severe SCM, because 100% of the SCM patients revealed at least 1 sign on examination. The recovery of these signs was maximum within the first 6 months, with lesser than half of total occurring in immediate and major half in the subsequent 6 months. Beyond this, plateau was seen in recovery, with marginal improvement of these signs. Patients with adverse cord signal changes (t2 hyper/T1 low) had higher prevalence and persistence of individual myelopathic signs compared with patients with only T1 hyperintensity/normal cord in preoperative period and follow-up at the end of 1 year. CONCLUSION: At least 1 myelopathic sign is universal in severe SCM patients. However, individual myelopathic signs cannot alone diagnose disease in all patients. The benefit of laminoplasty is apparent in immediate postoperative period (<7 days), but it is maximum in first 6 months after which the recovery stabilized or these are a marginal improvement. Similarly, the resolution of signs is maximum in period of first 6 months, which parallels recovery. Babinski and inverted brachioradialis reflex revert to normal in most patients and can serve as markers of relapse in long follow-up. Hoffman is not a sensitive test and is likely to persist in patient with severe cord changes. PMID- 20838273 TI - Unilateral spondylolysis and the presence of facet joint tropism. AB - STUDY DESIGN: Retrospective review of the CT scans performed in a group of patients examined for a possible spondylolysis. OBJECTIVE: To investigate whether there is an association between unilateral spondylolysis and facet joint tropism. SUMMARY OF BACKGROUND DATA: Spondylolysis is a fatigue fracture of the pars interarticularis of great importance in sports injury. The demonstration of a unilateral spondylolysis is important because there is a potential for full healing if the athletic activity is modified, whereas bilateral spondylolysis frequently leads to established nonunion. Coronally orientated facet joints are known to predispose to spondylolysis by increasing the point loading of the pars interarticularis. The importance of this finding has not been investigated in unilateral spondylolysis. METHODS: A review of patients with low back pain and a possible diagnosis of spondylolysis who were investigated with multislice CT was performed. The coronal orientation of the facet joints at L4/5 and L5/S1 was measured and comparison was done between those with and without a spondylolysis. RESULTS: The coronal angle of 140 facet joints in 35 patients was recorded. Of 35 patients, 23 had a spondylolysis which was unilateral in 12 patients. The facet joint angle was significantly more coronally orientated in the presence of a spondylolysis when compared with an intact pars (means, 53 degrees and 43 degrees , respectively; P < 0.01). In the presence of a unilateral spondylolysis, the facet joint was significantly more coronally orientated on the side of the spondylolysis (means, 52 degrees and 45 degrees , respectively; P < 0.01). CONCLUSION.: This study is the first investigation of facet joint anatomy in unilateral spondylolysis. Asymmetric facet joints do increase the force through one side of the spine, with a unilateral spondylolysis occurring on the side of the more coronally orientated facet joint. PMID- 20838274 TI - Subsequent vertebral fractures following spinal fusion surgery for degenerative lumbar disease: a mean ten-year follow-up. AB - STUDY DESIGN: Case-control study. OBJECTIVE: To assess the long-term prevalence of vertebral fractures after lumbar spinal fusion with instrumentation. SUMMARY OF BACKGROUND DATA: The incidence of the adjacent and the nonadjacent, remote level subsequent vertebral fractures after lumbar spinal fusion is not well described in the literature. METHODS: The study is a retrospective analysis of 100 consecutive patients of 55 years of age or older with spinal fusion for degenerative diseases between L1 and S1, and instrumentation for less than 4 segments. Patients with prevalent vertebral fractures defined at the time of surgery, or patients with secondary causes of osteoporosis were excluded. Mean follow-up period was 10.2 years (range, 7-14 years). Acute vertebral fractures were determined by magnetic resonance imaging and lateral spine radiographs. RESULTS: Acute vertebral fractures were determined in 20 vertebrae in 14 (24%) of the 59 female patients, whereas 1 male patient (2%) had 1 vertebral fracture during the follow-up period. Eighteen of the 21 fractures occurred within 2 years of the spinal instrumentation surgery. Regarding time to fracture occurrence after surgery, adjacent level fractures occurred within 8 months, and remote level fractures occurred between 8 and 22 months after surgery. CONCLUSION: Postmenopausal female patients who underwent lumbar spinal instrumentation surgery were susceptible to develop subsequent vertebral fractures within 2 years after surgery. The greater the number of spinal segments between the fracture and the instrumentation was, the longer the time after surgery. PMID- 20838275 TI - ISSLS prize winner: how loading rate influences disc failure mechanics: a microstructural assessment of internal disruption. AB - STUDY DESIGN: Mechanically induced disruption and subsequent microscopic investigation of lumbar intervertebral discs following a previously published testing protocol, but using a much higher rate of loading. OBJECTIVE: To explore if loading rate affects the internal disruption mechanics of lumbar intervertebral discs. SUMMARY OF BACKGROUND DATA: The failure mechanics of some bone-ligament-bone constructs vary with the rate of tensile load application. Like many ligaments, recent reports indicate that the mechanical response of the disc wall varies with strain-rate. It is possible that the internal failure mechanics of the disc wall also varies with strain-rate. METHODS: Nuclear pressurization was used to deliver sudden pressure impulses directly to the nucleus of ovine lumbar motion segments. Pressure impulses were delivered to 12 neutrally positioned motion segments, and 15 motion segments held at 7 degrees flexion. Aside from loading rate, testing was conducted in the same manner as 2 previously published studies that employed a gradual nuclear pressurization regime. Following testing, the internal damage resulting to each disc was analyzed using micro-CT and serial microscopy in tandem. RESULTS: Radial tears of the medioposterior disc wall were the most frequent cause of disc failure. In most cases, radial tears involved a combination of annular and endplate disruption: Neutrally positioned discs frequently suffered tears within the superior cartilaginous endplate adjacent to the transition zone and/or inner anulus. Flexed discs frequently suffered tears adjacent to the outer anulus at the cartilaginous/vertebral endplate junction, or within the vertebral endplate. Both groups frequently suffered endplate tears adjacent to the mid anulus at the inferior cartilaginous/vertebral endplate junction. CONCLUSION: The internal morphologies of the disc disruptions created in this study using high strain-rate impulse pressurization differed significantly from those documented previously for both neutrally positioned and flexed discs subjected to gradual low strain rate pressurization. These morphologic differences show that the internal failure mechanics of lumbar intervertebral discs vary with the rate of internal radial load application. PMID- 20838276 TI - The role of back injury or trauma in lumbar disc degeneration: an exposure discordant twin study. AB - STUDY DESIGN: Exposure discordant twin study. OBJECTIVE: To investigate the effect of injury on lumbar disc degeneration in monozygotic twins with discordant exposures to recalled previous injury/trauma to the lumbar spine. SUMMARY OF BACKGROUND DATA: Disc degeneration is considered a primary source of low back pain. Despite this, important determinants of disc degeneration other than genotype have not been identified. One possible important determinant of disc degeneration that has undergone limited investigation is previous back injury. METHODS: We compared disc degeneration between 37 male monozygotic twin pairs with discordant exposures to recalled previous injury/trauma to the lumbar spine. Data on injury history were obtained through an extensive structured interview. Disc degeneration was assessed using quantitative measures of disc height and disc signal intensity. RESULTS.: Disc degeneration did not differ between twins who reported previous back injury and their uninjured co-twins. This finding was consistent for both disc height and disc signal intensity regardless of whether mean scores or greatest difference at any one lumbar level was used in the analysis. Disc height averaged 0.3 mm higher in the injured twin (P = 0.302), and was on average 0.05% higher at the level of the greatest co-twin difference (P = 0.302). There was no evidence that greater period since injury resulted in greater twin differences in disc degeneration. CONCLUSION: The current study suggests that back injury based on patient report is not an important predictor of future disc degeneration. PMID- 20838277 TI - ISSLS prize winner: prevalence, determinants, and association of Schmorl nodes of the lumbar spine with disc degeneration: a population-based study of 2449 individuals. AB - STUDY DESIGN: A cross-sectional population-based magnetic resonance imaging study of Schmorl nodes (SN) in the lumbar spine. OBJECTIVE: To determine the prevalence and potential determinants of SN, and their association with intervertebral disc degeneration. SUMMARY OF BACKGROUND DATA: SN represent intravertebral disc herniation and are commonly seen in the spine. Their reported prevalence and determinants vary, and their association with disc degeneration remains uncertain. Data based on this large scale population-based study of intervertebral disc degeneration would provide important information for understanding SN and their pathomechanism. METHODS: Sagittal T2-weighted magnetic resonance imagings of the lumbar spine were analyzed in 2449 volunteers. Two independent observers assessed the images for the presence of SN, and scored for additional radiologic features (e.g., severity of degeneration, presence of disc bulge/extrusion). Subject demographics were assessed by standardized questionnaire. RESULTS: SN were found in 16.4% (n = 401; 219 males, 182 females; mean age = 42.3) of our study population (981 males, 1468 females; mean age = 40.4), being most common at L1/2 and L2/3 (54.1%). Multivariate logistic regression revealed that males, taller and heavier individuals had an increased likelihood of SN (P < 0.005), but association between SN and age were not discerned. Overall presence of SN was associated with disc degeneration (P < 0.001), and linearly correlated (R = 0.97) with increase in severity of degeneration. SN were particularly associated with severe disc degeneration at L1/2 and L2/3 with 22- to 15-fold increased odds, respectively (P < 0.0001), but less than 5-fold increased odds (P < 0.001) were noted in the lower lumbar spine. CONCLUSION: In a population-based cohort, 16.4% of Southern Chinese subjects had SN at 1 or more lumbar levels. Males, taller and heavier individuals had increased likelihood of SN. Interestingly, SN were highly associated with severity of disc degeneration. PMID- 20838278 TI - Th17 cells and transplant acceptance. AB - The discovery of Th17 cells has revealed a novel pathway of T-cell maturation. As with Th1 and Th2 lineages, Th17 cells promote graft pathology. However, a growing body of evidence indicates that Th17 cells may exhibit resistance to current methods of immunosuppression. Identification of this lineage provides an additional and challenging target for promoting graft acceptance. PMID- 20838279 TI - Determinants of long-term graft outcome in transplant glomerulopathy. AB - BACKGROUND: Transplant glomerulopathy (TG) is a renal allograft disease defined by glomerular basement membrane duplication with peritubular capillary basement membrane multilayering (PTCML), and associated with anti-human leukocyte antigen antibodies and C4d. Outcome in TG is poor but variable, and prognostic factors, particularly those affecting long-term outcome, are not well known. We investigated several potentially prognostic clinical and pathologic factors in TG and evaluated estimated glomerular filtration rate (eGFR) slopes to assess graft function and early decline. METHODS: We examined all cases of TG from 2001 to 2005 with at least 4-year follow-up after biopsy, excluding those with a second confounding diagnosis. RESULTS: Among 36 cases of pure TG, mean graft age at biopsy was 8.8+/-6 years. C4d stain was positive in 11 (33%) cases. Clinical characteristics at biopsy were not different based on C4d. C4d was associated with greater PTCML (P=0.03), peritubular capillaritis (P=0.04), and glomerulitis (P=0.03). Death-censored graft survival was significantly associated with interstitial fibrosis (P=0.001), PTCML (P=0.001), and arteriolar hyalinosis (P=0.007), and it showed a trend with proteinuria (P=0.07) and C4d positivity (P=0.08). C4d-positive cases also showed a trend toward rapid graft loss. Analysis of eGFR slopes showed a pattern of preserved, slightly negative slope from transplant until approximately 1 year before biopsy, at which point the slope became significantly more negative (P<0.001). CONCLUSION: Interstitial fibrosis, PTCML, and arteriolar hyalinosis were significant predictors of graft survival in TG. C4d positivity was associated with a more rapid rate of function decline. eGFR slope data showed significant deterioration in graft function well before the diagnostic biopsy. PMID- 20838280 TI - Conflicting effects of N-acetylcysteine on purified neurons derived from rat cortical culture. AB - We examined the protective effects of N-acetylcysteine (NAC) on the death of glia free neurons in culture. Under normoxic conditions, the protection by NAC was observed only in cystine-free but not complete medium. When the cells were cultured under hypoxic conditions, NAC much elongated their survival even in the presence of cystine. H2O2 was found to be generated to considerable concentration in the presence of both NAC and cystine, and the administration of catalase prevented the cell death. These results suggest that the harmful effect of NAC is because of H2O2 generated by autoxidation of cysteine, which derives from the reaction between NAC and cystine. The present results raise the possibility that NAC can act as either antioxidant or prooxidant depending on the milieu. PMID- 20838281 TI - Acute coronary syndrome revealed Cardiobacterium hominis endocarditis. PMID- 20838282 TI - The clinical implication and prediction of diffuse splenic FDG uptake during cancer surveillance. AB - OBJECTIVE: The purpose of this study was to investigate correlations between diffuse splenic FDG uptake and hematological and inflammatory parameters to clarify the significance of splenic FDG uptake on PET/CT images. METHODS: We retrospectively analyzed the consecutive records of F-18 FDG PET/CT scans and selected 31 patients with diffuse splenic FDG uptake as patient group. A total of 25 patients who underwent F-18 FDG PET/CT scans for simple health checkup were enrolled as control group. ROIs were placed on the liver and spleen to measure maximal standardized uptake value (SUVmax). The spleen SUVmax was divided by the liver SUVmax to calculate the spleen/liver ratio. The correlations between the S/L ratio and various hematological parameters were evaluated. RESULTS: The S/L ratio was positively correlated with serum C-reactive protein level, white blood cell count, and neutrophil count and negatively correlated with hemoglobin, hematocrit, and red blood cell count. Under multiple regression analysis, the Hb level and the C-reactive protein level were the significant predictors for diffuse splenic FDG uptake. CONCLUSION: In conclusion, our study suggests that concurrent inflammation or anemia at the time of PET/CT study could be one of various causes of diffuse splenic FDG uptake. PMID- 20838283 TI - The effects of early and late scanning on image quality and functional parameters in myocardial perfusion imaging. AB - MATERIALS AND METHODS: Timing of acquisition is a factor that may influence the subdiaphragmatic activity in myocardial perfusion scintigraphy (MPS). According to the instructions of tetrofosmin, scintigraphy may already be started 15 minutes postinjection. The aim of the present study was to compare the image quality and the functional parameters between early and late scanning. Eventually, 49 consecutive patients underwent a 2-day MPS protocol in which 15 and 45 minutes after the injection of 500 MBq of technetium-99m-tetrofosmin scintigraphy both at stress and rest were performed. The amount of subdiaphragmatic tracer activity was scored from "no tracer activity" to "severe." Moderate and severe subdiaphragmatic tracer activity was considered relevant for the interpretation of the myocardial perfusion scan. RESULTS: Two thirds of the patients (64%) showed a considerable amount of subdiaphragmatic activity on the 15 minutes rest images, whereas only 9 patients (18%) had considerable subdiaphragmatic activity on the late images. Stress imaging showed comparable results, however, subdiaphragmatic activity was generally less frequent and less prominent following stress. The value of the ejection fraction was significantly lower during early imaging comparing with late imaging. Lower ejection fraction was exclusively noticed in imaging with moderate and severe subdiaphragmatic tracer activity related wrong border estimation. CONCLUSIONS: Acquisition 15 minutes after the injection of Tetrofosmin shows a significant and clinically relevant subdiaphragmatic activity in most myocardial perfusion scans leading to poorer image quality and to an erroneous measurement of the ejection fraction. Therefore, early acquisition in MPS is not recommended in clinical practice. PMID- 20838284 TI - Follicular variant of papillary thyroid carcinoma presenting as a toxic nodule by I-123 scintigraphy. AB - The risk of malignancy in a "hot" thyroid nodule detected by radioiodine scintigraphy is rare. We report a case of a 63-year-old man with a hyperfunctioning nodule demonstrated by radioiodine scintigraphy and cytology suspicious for follicular variant of papillary thyroid carcinoma (FVPTC). There were no locoregional or distant metastases at initial diagnosis. Histopathologic examination following thyroidectomy confirmed the presence of an encapsulated FVPTC. A year into follow-up, his I-131 whole body scan performed following the withdrawal from exogenous thyroid hormone was negative, whereas his serum thyroglobulin (Tg) levels were intermediate. A subsequent PET/CT scan revealed a small, but stable, metabolically active pretracheal lymph node, which on biopsy was confirmed to be stage III FVPTC. In conclusion, the presence of hyperfunctioning thyroid nodule(s) does not preclude malignancy and, therefore, proper cytohistologic evaluation in such patients may help to exclude a coexistent thyroid carcinoma. Patients treated for localized PTC may benefit from serial PET/CT follow-up in the early detection and management of recurrence or distant metastases. PMID- 20838285 TI - The utility of F-18 FDG PET/CT in the evaluation of pancreatic intraductal papillary mucinous neoplasm. AB - PURPOSE: To assess the utility of F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in evaluating pancreatic intraductal papillary mucinous neoplasm (IPMN). MATERIALS AND METHODS: We included 31 patients with pancreatic IPMN who underwent F-18 FDG PET/CT and multidetector CT (MDCT). Each pancreatic lesion was classified as benign or malignant. On PET, the maximal standardized uptake value was measured in each pancreatic lesion. RESULTS: PET/CT was superior to MDCT in diagnosing malignant IPMN. All 22 concordant results gave accurate diagnoses. Of 9 discordant results, MDCT misdiagnosed 7 IPMNs, whereas PET/CT misinterpreted 2. Malignant IPMNs showed significantly higher maximal standardized uptake values (mean +/- standard deviation, 6.7 +/- 3.6) than benign IPMNs (mean +/- standard deviation, 2.1 +/- 1.0) (P < 0.001). CONCLUSIONS: F-18 FDG PET/CT outperformed MDCT in detecting malignant IPMN. PMID- 20838286 TI - Long-term results of intracoronary bone marrow cell transplantation: the potential of gated sestamibi SPECT/FDG PET imaging to select patients with maximum benefit from cell therapy. AB - PURPOSE: This study assessed the effect of different levels of tracer uptake in the infarcted area on improvement of left ventricular function in patients treated by intracoronary mononuclear bone marrow cell (BMC) transplantation during long-term (12-month) follow-up. METHODS: Thirty-seven patients with irreversible injury after their first acute myocardial infarction, as confirmed by dobutamine echocardiography and sestamibi single-photon emission computed tomography/fluorodeoxyglucose positron emission tomography underwent BMC transplantation (1 * 10(8) cells), whereas 36 similar patients were randomly assigned to a control group. RESULTS: In 16 BMC-treated patients with very low sestamibi uptake (<30% of maximum) in the infarcted area, the mean baseline left ventricular ejection fraction (LVEF) increased at 3- and 12-month follow-up by 3% and 4% only, and mean end-diastolic/end-systolic volumes (EDV/ESV) enlarged by 20/7 mL and 23/9 mL, respectively (P = NS vs. controls). In 21 BMC-treated patients with higher sestamibi uptake (31%-50% of maximum), the LVEF improved by 6% and 7%, and EDV/ESV decreased by 4/13 mL and 1/13 mL, respectively (P < 0.05 vs. BMC-treated subgroup with low uptake and control subjects). There was no statistically significant difference in LVEF, EDV, or ESV changes between controls with low versus higher sestamibi uptake. CONCLUSION: During long-term follow-up, the post-transplant improvement of left ventricular function remained significant only in BMC-treated patients with higher sestamibi uptake. PMID- 20838287 TI - Health information technology and the electronic medical record. AB - Health Information Technology and the Electronic Medical Record are becoming increasingly important in virtually all aspects of medicine. This includes computer-assisted decision support, the integration of all aspects of the health record, ability to access patient information no matter where a patient seeks care, cost control, and health care research and quality improvement. It also has ramifications for the education of health care professionals and general community members. This article briefly examines some of the most important aspects of this development. PMID- 20838288 TI - Unexpected primary osseous lymphoma as the cause of lactic acidosis in a patient suffering from pancreatitis. AB - A 45-year-old man was admitted due to acute pancreatitis. A severe lactic acidosis was found. Following active therapy, the signs and symptoms from pancreatitis was improved, but acidosis was exacerbated. FDG PET/CT images were acquired to investigate the etiology of lactic acidosis and/or other unknown pathology. The images showed widespread abnormal FDG activity in the bone marrows throughout the body, suggestive of hematologic malignancy, which was confirmed as primary osseous non-Hodgkin lymphoma following a histopathological examination of the bone marrow. Chemotherapy against lymphoma was initiated and status of the lactic acidosis was rapidly corrected. PMID- 20838289 TI - Chronic vascular graft infection with fistula to bone causing vertebral osteomyelitis, imaged with F-18 FDG PET/CT. AB - Vascular grafts have an infection rate ranging from 1% to 3%. While early infections occur within 4 months after surgery and are associated with virulent organisms, late infections can occur after months to years of surgery and are often caused by low virulence organisms that survive in an adherent biofilm. Host defense recognition of bacterial biofilm can result in perigraft abscesses, aorto enteric fistulas, and very rarely, fistulas into adjacent bone. We present a case of an 83-year-old man, who had an F-18 FDG PET/CT scan for workup of a solitary pulmonary nodule, and was incidentally diagnosed with chronic multifocal infection of an aorto-iliac vascular graft, with an infected fistula tract into adjacent bone causing chronic vertebral osteomyelitis, which was confirmed with a contrast-enhanced CT. The patient was asymptomatic and not a surgical candidate, and was treated conservatively with a course of antibiotics. This case highlights the utility of F-18 FDG PET/CT in the imaging of chronically infected vascular grafts and in identifying potentially lethal complications such as fistulas into adjacent structures. PMID- 20838290 TI - Hepatitis C-related primary effusion lymphoma of the pleura and peritoneum, imaged with F-18 FDG PET/CT. AB - Primary Effusion Lymphoma (PEL) is a rare form of Non-Hodgkin lymphoma that involves serous body cavities (pleural, pericardial, or peritoneal) with lymphomatous effusions in the absence of lymphadenopathy or organomegaly. Although it was seen mostly in HIV-positive patients, it has recently been reported in HIV-negative patients with chronic Hepatitis B or C infections. PEL is associated with human herpes virus type-8 infection, often presents with rapidly progressive effusions and generally has a poor prognosis. This is a case of a 65-year-old HIV-negative man with Hepatitis C cirrhosis, who presented with abdominal pain. An F-18 FDG PET/CT showed marked ascites and pleural effusions with increased F-18 FDG uptake in the pleura and peritoneum on the left side. Analysis of the cells in the peritoneal fluid revealed a human herpes virus 8 positive PEL of the peritoneum. As a result the patient was no longer considered a liver transplant candidate and died 2 weeks after the diagnosis. PMID- 20838291 TI - Occult squamous cell carcinoma of the uvula detected by F-18 FDG PET/CT in a case of carcinoma of unknown primary in the head and neck. AB - Incidence of unknown primary head/neck tumors with metastatic cervical lymphadenopathy at time of diagnosis is approximately 2% to 9%. Detecting site of original disease is challenging. We present a 75-year-old woman with bulky unilateral level 2 and 3 lymphadenopathy. Clinical examination and computed tomography (CT) did not reveal detectable abnormalities except neck-node metastases; biopsy indicated metastatic squamous cell carcinoma (SCC). F-18 FDG PET/CT imaging was performed to detect the primary tumor site, which revealed a small metabolically-avid lesion in uvula, biopsy demonstrated SCC, the origin of metastatic disease. F-18 FDG PET/CT imaging of unknown primary head/neck tumors can have positive impact in identifying small occult primary tumor foci. PMID- 20838292 TI - F-18 FDG PET/CT findings in two patients with pyothorax-associated lymphoma. AB - We report 2 cases of pyothorax-associated lymphoma that underwent F fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) examinations during pre- and post-treatment states. The FDG PET/CT examinations were able to define the massive lesions as areas of intensive FDG uptake. After radiotherapy, follow-up PET/CT examinations showed the disappearance of the abnormal FDG uptake, although the residual masses remained in the original regions. Finally, we concluded that these lesions had entered remission based on the PET/CT findings. These cases indicate that PET/CT is a useful modality for detecting pyothorax-associated lymphoma and for evaluating the efficacy of treatments. PMID- 20838293 TI - Abnormal F-18 fluoride uptake in intracranial meningiomas on PET/CT. AB - The association between breast carcinoma and meningioma is a well-recognized phenomenon that may have important clinical implications, particularly in intracranial lesions. We report 2 cases of intracranial meningioma in adult women with a history of breast cancer, who were imaged with positron emission tomography/computed tomography (PET/CT) for evaluation of possible bone metastases. Whole-body F-18 fluoride PET demonstrated an intense intracranial focal radiotracer accumulation in both patients. Simultaneous CT showed a corresponding calcified space-occupying lesion, consistent with meningioma. Early and correct diagnosis of synchronous meningioma in F-18 fluoride bone scans might prevent relevant neurologic comorbidity. PMID- 20838294 TI - Colovesical fistula in a patient with recurrent cervical cancer detected by FDG PET/CT. AB - We report the case of a 57-year-old woman with the history of stage IB cervical cancer. She was found to have a metastatic squamous cell carcinoma in sigmoid colon. FDG PET/CT was then performed for whole-body cancer work-up. Intense FDG activity accumulated in the sigmoid tumor, with an unusually high SUVmax of 72.42, and was seen downwardly connected with the activity of urinary bladder on PET images. On the coregistered CT images, irregular wall thickening was noted for both sigmoid colon and urinary bladder with a hypodensity tract communicating with each other. It was concluded that recurrent cervical cancer involving urinary bladder and sigmoid colon resulted in colovesical fistula. PMID- 20838295 TI - Midline cyst of the prostate mimicking malignancy on FDG PET/CT. AB - A 58-years-old man underwent F-18 FDG PET/CT for health screening. F-18 FDG PET/CT revealed a focal, round, and 1.5 cm-sized hypermetabolic lesion at midline of the prostate. The lesion was suspected as a urinary activity or malignancy. On the review of medical records, it was found that the patient had undergone contrast-enhanced abdominal CT scan 1 day before PET/CT examination. On the attenuation-uncorrected image, the prostatic lesion was still evident. The lesion was considered as a midline cyst of prostate, communicating with urethra. It is suggested that radioactive urine remained in midline cyst resulting in the focal hypermetabolic lesion. PMID- 20838296 TI - Diffuse FDG renal uptake in lymphoma. AB - In patients presenting with acute renal failure and known/suspected lymphoma, the diagnosis of diffuse renal involvement is important, as there is potential for rapid resolution with chemotherapy. Although FDG is excreted through the kidneys and focal renal disease may be difficult to identify, diffuse renal FDG is more easily recognized and is always abnormal. We report a patient presenting with acute renal failure and suspected lymphoma. F-18 FDG PET/CT study demonstrated diffuse increased FDG uptake in bilaterally enlarged kidneys. Following 1 cycle of chemotherapy, the renal function normalized. An interim F-18 FDG PET/CT demonstrated normal size and FDG uptake within both kidneys. PMID- 20838297 TI - Malignant pheochromocytoma metastasis to the breast shown on I-123 MIBG scan. AB - A 36-year-old woman was referred to our department for I-123 metaiodobenzylguanidine (MIBG)-SPECT/CT scan 3 years after surgical excision of pheochromocytoma. She was referred due to recurrence of her symptoms as well as raised urinary catecholamines. Review of I-123 MIBG scan revealed multiple MIBG avid metastatic lesions. Most of these were bony lesions, however, there were also 2 soft tissue lesions in the left breast. She subsequently underwent ultrasound-guided fine-needle aspiration of the left breast lesions. Fine-needle aspiration revealed cytologic changes consistent with pheochromocytoma. There has only been 1 previous reported case of pheochromocytoma metastasizing to the breast. This is the first case in which the metastasis was detected by I-123 MIBG scan. PMID- 20838298 TI - Renal cell carcinoma presenting as isolated thyroid metastasis 13 years after radical nephrectomy, detected on F-18 FDG PET/CT. AB - We report a case of renal cell carcinoma presenting as isolated thyroid metastasis, 13 years after radical nephrectomy for the primary disease. F-18 FDG PET/CT provided valuable information regarding thyroid being the only site of metastatic involvement, which lead to further appropriate management. PMID- 20838299 TI - Cervical and uterine metastasis from carcinoma of breast diagnosed by PET/CT: an unusual presentation. AB - A 44-year-old apparently healthy woman presented with a 5-month history of intermittent vaginal bleeding. Clinical examination raised the suspicion of cervical neoplasia which was confirmed to be a metastatic adenocarcinoma on subsequent histopathological evaluation. An F-18 FDG PET/CT scan performed soon after revealed increased uptake in the cervix, extending upwards into the endometrial cavity. Additionally, small FDG avid spiculated soft tissue density masses were visualized in bilateral breast parenchyma, which proved to be lobular carcinoma on sonomammography followed by histopathology. Multiple lytic FDG avid skeletal metastases were also noted. Endometrial biopsy showed infiltrative malignant tumor with cytologic features similar to those observed in the breast biopsy specimen. The entire spectrum of findings pointed to a diagnosis of bilateral lobular carcinoma with uterine, cervical, and skeletal metastasis. Metastasis to the uterus and cervix from a breast primary is extremely rare. Most cases have been diagnosed in the follow-up of known cases of breast carcinoma. Our case is unique in that the patient, who had no prior history of breast carcinoma, was suspected to have a breast primary with cervical and uterine metastasis, based on the PET/CT findings. PMID- 20838300 TI - Multifocal Langerhans cell histiocytosis with infiltrative pelvic lesions: PET/CT imaging. AB - Langerhans cell histiocytosis is essentially a pediatric disorder with a large spectrum encompassing focal lytic osseous eosinophilic granuloma, chronic multifocal Hand-Schuller-Christian lesions, and fulminant disseminated Letterer Siwe syndrome. However, adult involvement is not uncommon. The authors present a case of multifocal Langerhans cell histiocytosis in a 47-year-old woman. The PET/CT-depicted infiltrative features of soft tissue and osseous pelvic lesions with obstructive uropathy are unusual for this disease. PMID- 20838301 TI - FDG PET of alveolar soft part sarcoma. AB - Alveolar soft part sarcoma (ASPS) is a very rare, but distinctive type of soft tissue sarcoma, whose name is derived from the pseudoalveolar appearance of its histology. In this report, the FDG PET/CT findings of ASPS are described in a 17 year-old asthmatic female who presented with worsening respiratory symptoms and a pelvic mass. The staging PET showed heterogeneous intense incorporation of FDG within the mass and variable FDG incorporation within the multiple lung nodules. In concordance with other soft tissue sarcomas, PET/CT helped to confirm the anatomic origin of the ASPS, to direct its biopsy, and to assess the distribution of disease. PMID- 20838302 TI - Nodular fasciitis on F-18 FDG PET. AB - A 36-year-old woman underwent positron emission tomography imaging with F-18 fluorodeoxyglucose (FDG) for evaluation of pulmonary nodules detected in the work up for persisting dyspnea following respiratory tract infection. The lesions were visible on computed tomography while having only low uptake on the PET images, rendering malignancy less probable. However, increased uptake of FDG was noted in the left groin, where the patient was known to have intramuscular nodular fasciitis. Nodular fasciitis is a benign disorder caused by proliferating fibroblasts and myofibroblasts, which may mimic soft-tissue malignancy clinically, histopathologically, and on imaging procedures. PMID- 20838303 TI - Azygos venous tumor thrombus from renal cell carcinoma detected by F-18 FDG PET/CT. AB - An 81-year-old woman with renal cell carcinoma (RCC) underwent F-18 FDG PET/CT for staging, which demonstrated intense uptake in a dilated azygos vein, in the inferior vena cava (IVC), and in the known large left RCC. Contrast-enhanced CT of the chest and abdomen obtained in the days following confirmed the presence of tumor thrombus in the dilated azygos system, IVC, and the contiguous left renal vein. This case serves as a reminder that special attention should always be paid to the renal vein, IVC, and adjoining venous drainage pathways for abnormal FDG activity while imaging RCC, as the diagnosis of venous tumor thrombus has important clinical ramifications. PMID- 20838304 TI - F-18 FDG PET/CT in an adult case of group B streptococcal sacroiliitis. AB - An adult patient presented with acute severe pelvic and low-back pain. Evaluations with CT and MRI were negative/inconclusive. F-18 FDG PET/CT localized the site of pathology in right sacroiliac-joint by demonstrating hypermetabolic activities conformal with the joint's outline, signifying infectious/inflammatory sacroiliitis. Blood culture was positive for Group B streptococcus (GBS). Antibiotic treatment was started within 24 hours from onset of symptoms, and there was almost immediate partial pain relief. GBS sacroiliitis is a rare form of septic sacroiliitis requiring prompt diagnosis and urgent treatment. This is the first report of F-18 FDG PET/CT for diagnosing GBS sacroiliitis in adults with no predisposing factors. PMID- 20838305 TI - Accumulation of bone-seeking agent in a patient with mediastinal seminoma. AB - A 39-year-old man presented with substernal pain and shortness of breath. Bone scan revealed a large soft-tissue uptake in anterior chest. Subsequent computed tomography showed a large mass lesion with well demarcated margins in anterior mediastinum. Percutaneous core needle biopsy and histopathologic examination diagnosed the mediastinal seminoma. Bone scintigraphy could delineate a wide spectrum of nonosseous disorders. The recognition of extraskeletal uptake of bone seeking agent can enhance the diagnostic value of bone scintigraphy. PMID- 20838306 TI - Brain F-18 Fluorocholine PET/CT for the assessment of optic pathway glioma in neurofibromatosis-1. AB - A 22-year-old man diagnosed with neurofibromatosis-I was admitted to the neurology department because of progressive hemianopsia and chronic headache. Magnetic resonance imaging, magnetic resonance spectroscopy (MRS), and F-18 fluorocholine revealed a splenial mass with imaging features compatible with malignant astrocytoma. At follow-up examination, the sharp decrease in F-18 fluorocholine uptake and in choline/creatine ratio supported a conservative management. Molecular imaging of optic pathway gliomas may be a valuable tool in the selection of therapeutic options. PMID- 20838307 TI - Current readings in nuclear medicine. PMID- 20838309 TI - Context for WOC practice: validating our assessments and interventions. PMID- 20838310 TI - WOCN update on evidence-based guideline for pressure ulcers. PMID- 20838313 TI - "Kennedy terminal ulcer" and "skin failure," where are the data? PMID- 20838314 TI - Critical appraisal of clinical guidelines. AB - Utilization of clinical guidelines is gaining in popularity due to their significant impact on clinical practice. While a plethora of guidelines exist, many are lacking in quality, based on current critical appraisal standards. It then becomes necessary for the end users of the guidelines to adopt or develop those that are deemed adequate for implementation. This often requires that users possess critical appraisal skills as they become proficient in discerning between guidelines of varying quality. This article provides direction and tools to support the critical appraisal process in the adoption of clinical guidelines. PMID- 20838315 TI - Positive and negative aspects of colostomy irrigation: a patient and WOC nurse perspective. AB - PURPOSE: Colostomy irrigation (CI) is an effective method to achieve fecal continence in selected persons with a colostomy. The primary aims of the study were to find out to what extent the WOC nurses used CI in their practice and what kind of information the WOC nurses gave patients if they provided explanations and potential solutions when irrigation was not successful in preserving continence. A further aim was to find out, from a patients' perspective, the positive and negative aspects of practicing CI and how they perform CI. METHODS: The study employed a mixed quantitative and qualitative approach. Data from WOC nurses were obtained by means of a structured questionnaire and by means of structured telephone interviews with patients who performed CI. SUBJECTS AND SETTING: Questionnaires were sent out to 89 WOC nurses in Sweden, and 61 (69%) questionnaires were returned. Thirty-nine patients, median age 67 years, from 5 hospitals participated in the interview study. RESULTS: Sixty-four percent of the WOC nurse respondent always informed patients about CI. Forty-four percent of patients did not remember all the information they had been given by the WOC nurse regarding CI before starting with the procedure. Eighty-seven percent reported changing routines from how they initially performed CI over the years. Almost all (97%) of the respondents described positive aspects of CI. The 2 primary positive aspects described by participants were (1) feeling secure and (2) having an empty pouch. CONCLUSION: Persons living with a colostomy who regularly performed CI reported positive benefits associated with the procedure including a feeling of security and having an empty pouch. Despite these potential benefits, not all patients with a colostomy who are appropriate candidates for CI are offered information about the method from the WOC nurses. PMID- 20838317 TI - A feminist perspective on sexuality and body image in females with colorectal cancer: an integrative review. AB - Women often experience sexual dysfunction following colorectal cancer surgery. The purpose of this integrative review is to explore changes in body image and sexuality associated with colorectal cancer and its treatment in women. We used a feminist perspective to explore differences in gender role, in body image, and sexuality in the context of women who are treated for colorectal cancer. Results of our review suggest that additional studies and interventions are needed to better understand and assist women with sexual dysfunction associated with colorectal cancer. Research should focus on how age, physical, psychosocial factors influence sexual function in particular. PMID- 20838318 TI - WOC nurse consult: chronic urinary retention assessment. PMID- 20838319 TI - Pediatric ostomy surgery. PMID- 20838320 TI - Negative pressure wound therapy overlay technique with collagen dressings for nonhealing wounds. AB - BACKGROUND: Our clinical experience suggests that the effectiveness of negative pressure wound therapy is enhanced by adding collagen alginate to the dressing regimen, applying foam over areas that are undermined or tunneled, and approximating and securing wound edges prior to applying foam. CASES: The use of this combined technique is described in 4 cases, including 2 patients with spinal cord injury and category IV pressure ulcers and 2 patients with extensive postsurgical wounds. CONCLUSION: Our outcomes demonstrate the feasibility of this technique and suggest that patients with significant wound size benefit from adding collagen alginate to negative pressure wound therapy and by applying foam over areas that are undermined or tunneled and/or approximating and securing wound edges prior to applying foam. PMID- 20838322 TI - Early outcomes for malignant peripheral nerve sheath tumor treated with chemotherapy. AB - OBJECTIVES: Malignant peripheral nerve sheath tumors (MPNST) are rare soft-tissue sarcomas with a tendency for recurrence and metastasis. Treatment using chemotherapy is controversial, but benefit with some agents has been described. This study aimed to analyze early survival outcomes using doxorubicin and ifosfamide chemotherapy for MPNST. METHODS: Pathology records at our musculoskeletal tumor center were searched for patients with a new diagnosis of MPNST between 2003 and 2008. Treatment involved surgical resection, radiation, and chemotherapy with doxorubicin and ifosfamide. Ten patients met inclusion criteria, with mean age 40 years (range, 20-70). Four patients had metastatic disease on presentation. Four patients had neurofibromatosis type I (NF1). RESULTS: Of 6 patients with nonmetastatic disease on presentation, 5 had no evidence of disease post-treatment. The sixth had positive margins after surgery and initially received no further treatment due to noncompliance. Three from this subgroup developed local recurrence, but none developed distant metastases and 1 died of disease at last follow-up. One- and 2-year disease-free survival (DFS) for this subgroup was 80% and 60%, respectively. One- and 2-year overall survival (OS) for the subgroup was 100%. Of 4 patients with metastatic disease on presentation, 2 had no evidence of disease post-treatment. One of these 2 developed local recurrence, but none from the subgroup developed new metastatic disease. Two of these 4 died of disease at last follow-up. One- and 2-year DFS for this subgroup was 100% and 50%, respectively. One- and 2-year OS was 75% and 50%, respectively. Two of the 4 patients presenting with metastatic disease had NF1. All 3 local recurrences and 2 of the 3 deaths in this study occurred in NF1 patients. CONCLUSIONS: For all patients, when combined with surgery and radiation, chemotherapy using doxorubicin and ifosfamide yielded 57% DFS and 80% OS at 2 years. NF1 patients appeared to have worse outcomes, with a statistically significantly lower DFS than non-NF1 patients. Limitations of this study include a small sample size, retrospective design, and use of different chemotherapy regimens. PMID- 20838324 TI - No survival benefit from postoperative adjuvant chemotherapy after D2 radical resection for the patients with stage II gastric cancer. AB - OBJECTIVE: To evaluate the effect of 2 regimens of postoperative combination chemotherapies on the prognosis of early stage gastric cancer patients. METHODS: A total of 268 patients with stage II gastric cancer underwent D2 resection in our Cancer Center between January 1990 and December 2006 were recruited. Among them, 34 patients received the FAM regimen (5-fluorouracil [5-FU] 600 mg/m(2) intravenous [IV] drip on days 1, 8, 29, and 36; doxorubicin 30 mg/m(2) IV bolus injection on days 1 and 29; and mitomycin-C 10 mg/m(2) IV bolus injection on day 1; repeated every 8 weeks) and 81 patients received the FOLFOX regimen (oxaliplatin 100 mg/m(2) IV drip on days 1 and 15; leucovorin 400 mg/m(2) IV drip on days 1 and 15; 5-FU 400 mg/m(2) IV bolus injection; 5-FU 2.4/3.0 mg/m(2) continuous IV infusion for 48 hours on day 1, 2, 15, and 16; repeated every 4 weeks for at least 4 cycles). Patients were followed-up until December 2008. The Kaplan-Meier method was used to compare survival rates between treatment groups. RESULTS: The 1-, 3-, 5-, and 10-year survival rates for the patients who received postoperative chemotherapy versus the patients who underwent surgery only were 98%, 84%, 58%, 18% versus 96%, 78%, 59%, 22%, respectively (P > 0.05). Furthermore, the survival rates for patients who received the FAM and FOLFOX regimens were not significantly different (P > 0.05). CONCLUSIONS: Postoperative adjuvant chemotherapy did not produce survival benefits for the patients with stage II gastric cancer. Randomized controlled clinical trials are demanded to confirm the finding from this study. PMID- 20838323 TI - A systematic review of patient-rated measures of radiodermatitis in breast cancer radiotherapy. AB - During breast cancer radiotherapy, nearly all patients will experience radiodermatitis. Study objectives were as follows: (1) systematically review the literature on radiodermatitis and breast cancer; (2) summarize and describe patient-rated radiodermatitis measures; (3) determine whether consensus exists regarding subjective radiodermatitis measurement; and (4) provide recommendations for future research. PubMed and CINAHL were searched from their inception through August 2009. Study inclusion and exclusion criteria were: full abstract available, manuscript in English, focused on radiodermatitis resulting from breast cancer radiotherapy, and described a patient-rated empirical assessment of radiodermatitis. Three reviewers examined abstracts, and decisions about inclusion were reached by consensus. Twenty-two of 237 mutually identified studies met selection criteria. Using a standardized abstraction form, 3 authors independently extracted relevant information. Results indicated that (1) only 9% of the studies reviewed included a patient-rated measure; (2) generally, extant scales are very brief and focus almost exclusively on physical reactions, and (3) there is no "gold standard" measure of patient-rated radiodermatitis at this time. We conclude that significantly more research is needed to determine the best (most valid, reliable, sensitive, comprehensive) measure(s) to evaluate the experience of radiodermatitis from the patient's perspective, and that further scale development efforts are needed. PMID- 20838325 TI - Amifostine-related fever-rash during fractionated radiotherapy: diagnostic and predictive role of C-reactive protein. AB - INTRODUCTION: Fever/rash is a side-effect of amifostine that demands immediate interruption of the drug. Here, we focus on the role of C-reactive protein (CRP) as a putative marker linked with amifostine fever/rash. MATERIALS AND METHODS: The CRP serum values were analyzed in 496 patients receiving radiotherapy supported with amifostine (500-1000 mg/d). CRP levels were recorded before the onset of radiotherapy (day 0), on day 15 and when the fever/rash appeared. For 121 out of 496 patients, CRP values on day 7 were also available. About 79 patients (15.9%) developed fever/rash symptoms. RESULTS: The CRP levels before the onset of therapy were 0 to 20.7 mg/dL (normal, <=0.5 mg/dL). For patients who did not develop fever/rash, the CRP levels increased from a median of 0.30 to 0.50 on day 15; P = 0.001. Patients who developed fever/rash showed a more than 7 fold increase of the median CRP levels (median, 3.50; P < 0.0001). This sharp CRP rise was specific for amifostine-related fever/rash. Initially abnormal CRP levels were linked with a 2-fold risk for fever/rash (P = 0.01), while abnormal levels on day 7 were linked with a 3-fold higher risk (P = 0.08). The occurrence of fever/rash was independent of the amifostine dose level. CONCLUSIONS: Sharp rise of CRP levels on the day after the fever/rash development suggest amifostine related etiology of fever/rash. Abnormal initial CRP levels and/or high CRP levels on day 7 should be considered as an alert signal as the probability to develop fever/rash reaches the 30%. PMID- 20838326 TI - Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. AB - Erythropoietin has been reported to improve symptoms of orthostatic intolerance in patients suffering from orthostatic hypotension. Previous reports on the use of erythropoietin in patients with postural orthostatic tachycardia (POTS) have included only a very small number of patients. In the current study, we report on the use of erythropoietin in patients with refractory POTS. The study was approved by the institutional review board. A retrospective nonrandomized analysis was performed on 39 patients evaluated at our autonomic center for POTS from 2003 to 2010. The diagnosis of POTS was based on patient history, physical examination, and response to head-up tilt-table testing. The mean follow-up period was 6 months. The patients were included in the current study if they had a diagnosis of POTS with severe symptoms of orthostatic intolerance and were refractory to the commonly used medications. All these patients were started on erythropoietin, and the response to therapy was considered successful if it provided symptomatic relief. We screened 200 patients with POTS and found 39 patients (age 33 +/- 12, 37 females) to be eligible for inclusion in the current study. The response to the treatment was assessed subjectively in each patient and was obtained in a retrospective fashion from patient charts and physician communications. Eight (21%) patients demonstrated no improvement in symptoms after administration of erythropoietin. Three (8%) patients showed an improvement in symptoms of orthostatic intolerance of <3 months. Twenty-seven (71%) patients demonstrated sustained improvement in their symptoms of orthostatic intolerance at the mean follow-up of 6 months. Erythropoietin significantly improved sitting diastolic blood pressure but had no effect on other hemodynamic parameters. In a select group of POTS patients who are refractory to commonly used medications, erythropoietin may help improve symptoms of orthostatic intolerance. PMID- 20838327 TI - Carboplatin-induced hematuria in a patient of breast carcinoma. A case report. AB - Platinum-based antineoplastic drugs are widely used in the treatment of solid tumors. Carboplatin, a second generation platinum compound, was developed to have less nonhematologic toxicity, in comparison with cisplatin. We report on a 34 year-old woman with breast cancer who developed gross hematuria after initiation of carboplatin-based chemotherapy. To our knowledge, there are very few cases reports of carboplatin-associated gross hematuria. PMID- 20838328 TI - Comparative study of two generations of the Complior device for aortic pulse wave velocity measurements. AB - INTRODUCTION: The purpose of this study was to evaluate intraobserver and interobserver reproducibility of carotid-femoral pulse wave velocity (PWV) with the Complior method, by comparing two generations of the device and the manual method. METHODS: We studied 31 participants (9 women) with a mean age of 47.67+/ 12.55 years, who were submitted to sequential measures of carotid-femoral PWV by two experienced operators. The evaluations were made by randomly switching between the manual method, the Complior first generation, and the Complior SP (third generation). RESULTS: The analysis of concordance of measurements of PWV showed strong intraobserver and interobserver correlations. The intraobserver correlation coefficients were 0.984, 0.977, and 0.966, respectively, for manual evaluation, the Complior first generation, and the Complior SP (P<0.0001). In the case of interobserver reproducibility, we found correlations of 0.940, 0.979, and 0.974, respectively, for manual evaluation, the Complior first generation, and Complior SP (P<0.0001). Good indicators of reproducibility were also a withdrawal of the Bland-Altman analysis, with most values within 2 standard deviations. The mean difference+/-SD for intraobserver and interobserver agreement was -0.006+/ 0.05 and -0.06+/-0.09 for manual determination; -0.02+/-0.06 and -0.04+/-0.06 for Complior first generation; and 0.16+/-0.09 and 0.15+/-0.07 for the Complior SP. CONCLUSION: The data showed a high reproducibility of the Complior method, documented by excellent correlations and low mean differences in measurements within and between observers. These data showed unequivocally that this method met the quality requirements for its inclusion in integrated clinical follow-up programs. PMID- 20838329 TI - Severity of illness scoring systems in the intensive care unit. AB - OBJECTIVE: Adult intensive care unit prognostic models have been used for predicting patient outcome for three decades. The goal of this review is to describe the different versions of the main adult intensive care unit prognostic models and discuss their potential roles. DATA SOURCE: PubMed search and review of the relevant medical literature. SUMMARY: The main prognostic models for assessing the overall severity of illness in critically ill adults are Acute Physiology and Chronic Health Evaluation, Simplified Acute Physiology Score, and Mortality Probability Model. Simplified Acute Physiology Score and Mortality Probability Model have been updated to their third versions and Acute Physiology and Chronic Health Evaluation to its fourth version. The development of prognostic models is usually followed by internal and external validation and performance assessment. Performance is assessed by area under the receiver operating characteristic curve for discrimination and Hosmer-Lemeshow statistic for calibration. The areas under the receiver operating characteristic curve of Simplified Acute Physiology Score 3, Acute Physiology and Chronic Health Evaluation IV, and Mortality Probability Model0 III were 0.85, 0.88, and 0.82, respectively, and all these three fourth-generation models had good calibration. The models have been extensively used for case-mix adjustment in clinical research and epidemiology, but their role in benchmarking, performance improvement, resource use, and clinical decision support has been less well studied. CONCLUSIONS: The fourth-generation Acute Physiology and Chronic Health Evaluation, Simplified Acute Physiology Score 3, Acute Physiology and Chronic Health Evaluation IV, and Mortality Probability Model0 III adult prognostic models, perform well in predicting mortality. Future studies are needed to determine their roles for benchmarking, performance improvement, resource use, and clinical decision support. PMID- 20838330 TI - Stem cells in sepsis and acute lung injury. AB - OBJECTIVE: Sepsis and acute lung injury continue to be major causes of morbidity and mortality worldwide despite advances in our understanding of pathophysiology and the discovery of new management strategies. Recent investigations show that stem cells may be beneficial as prognostic biomarkers and novel therapeutic strategies in these syndromes. This article reviews the potential use of endogenous adult tissue-derived stem cells in sepsis and acute lung injury as prognostic markers and also as exogenous cell-based therapy. DATA SOURCES: A directed systematic search of the medical literature using PubMed and OVID, with particular emphasis on the time period after 2002, was done to evaluate topics related to 1) the epidemiology and pathophysiology of sepsis and acute lung injury; and 2) the definition, characterization, and potential use of stem cells in these diseases. DATA SYNTHESIS AND FINDINGS: When available, preferential consideration was given to prospective nonrandomized clinical and preclinical studies. CONCLUSIONS: Stem cells have shown significant promise in the field of critical care both for 1) prognostic value and 2) treatment strategies. Although several recent studies have identified the potential benefit of stem cells in sepsis and acute lung injury, further investigations are needed to more completely understand stem cells and their potential prognostic and therapeutic value. PMID- 20838331 TI - Thioredoxin binding protein-2 mediates metabolic adaptation in response to lipopolysaccharide in vivo. AB - OBJECTIVES: Endotoxin triggers a reorganization of the energy metabolic pathway, including the promotion of fatty acid utilization to adapt to a high energy demand during endotoxemia. However, the factors responsible for the metabolic adaptation and characteristic pathologies resulting from defective utilization fatty acids during endotoxin response have not been fully clarified. The thioredoxin binding protein-2 (TBP-2) knockout (TBP-2) mouse is an animal model of fatty acid oxidation disorder. The aim of this study was to determine whether and how TBP-2 is involved in metabolic regulation in a lipopolysaccharide (LPS) induced endotoxemia model in mice. DESIGN: Prospective animal trial. SETTING: Research laboratory. SUBJECTS: TBP-2 and wild control mice. INTERVENTION: TBP-2 and wild control mice were intraperitoneally injected with LPS. Mortality, serum levels of markers of hepatorenal injuries, cytokines, insulin, glucose and lipid derivatives, and the hepatic signaling pathway regulating gluconeogenesis were investigated. MEASUREMENTS AND MAIN RESULTS: Following the administration of LPS, TBP-2 mice showed a predisposition for death without any significant elevation of inflammatory cytokines, compared to the wild mice. LPS-challenged TBP-2 mice showed fat deposition in the liver and kidney, organ injuries, glycogen depletion, and elevation of serum lipid derivatives such as free fatty acids, triglyceride and cholesterol. Hyperinsulinemia and hypoglycemia were observed in TBP-2 mice after LPS injection. Death due to the LPS administration was prevented by supplementation of glucose. Phosphorylation of Akt and FoxO1, an inhibitory pathway of gluconeogenesis in the liver of LPS-challenged TBP-2 mice was demonstrated, suggesting the enhancement of insulin signaling. CONCLUSIONS: TBP-2 is involved in metabolic control during LPS-induced endotoxemia. After the LPS challenge, TBP-2 mice showed several characteristic aspects, such as hepatorenal injuries, and dysregulation of the lipid and glucose metabolisms. Furthermore, hypoglycemia promoted by hyperinsulinemia may be a critical risk factor for mortality in circumstances in which fatty acid utilization is impaired during endotoxemia. PMID- 20838332 TI - Delirium duration and mortality in lightly sedated, mechanically ventilated intensive care patients. AB - OBJECTIVES: To determine the relationship between the number of delirium days experienced by intensive care patients and mortality, ventilation time, and intensive care unit stay. DESIGN: Prospective cohort analysis. SETTING: Patients from 68 intensive care units in five countries. PATIENTS: Three hundred fifty four medical and surgical intensive care patients enrolled in the SEDCOM (Safety and Efficacy of Dexmedetomidine Compared with Midazolam) trial received a sedative study drug and completed at least one delirium assessment. INTERVENTIONS: Sedative drug interruption and/or titration to maintain light sedation with daily arousal and delirium assessments up to 30 days of mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause 30 day mortality. Multivariable analysis using Cox regression incorporating delirium duration as a time-dependent variable and adjusting for eight relevant baseline covariates was conducted to quantify the relationship between number of delirium days and the three main outcomes. Overall, delirium was diagnosed in 228 of 354 patients (64.4%). Mortality was significantly lower in patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%]; p<.001). Similarly, the median time to extubation and intensive care unit discharge were significantly shorter among nondelirious patients (3.6 vs. 10.7 days [p<.001] and 4 vs. 16 days [p<.001], respectively). In multivariable analysis, the duration of delirium exhibited a nonlinear relationship with mortality (p=.02), with the strongest association observed in the early days of delirium. In comparison to 0 days of delirium, an independent dose-response increase in mortality was observed, which increased from 1 day of delirium (hazard ratio, 1.70; 95% confidence interval, 1.27-2.29; p<.001), 2 days of delirium (hazard ratio, 2.69; confidence interval, 1.58-4.57; p<.001), and >=3 days of delirium (hazard ratio, 3.37; confidence interval, 1.92-7.23; p<.001). Similar independent relationships were observed between delirium duration and ventilation time and intensive care length of stay. CONCLUSIONS: In ventilated and lightly sedated intensive care unit patients, the duration of delirium was the strongest independent predictor of death, ventilation time, and intensive care unit stay after adjusting for relevant covariates. PMID- 20838333 TI - Automated drug dispensing system reduces medication errors in an intensive care setting. AB - OBJECTIVES: We aimed to assess the impact of an automated dispensing system on the incidence of medication errors related to picking, preparation, and administration of drugs in a medical intensive care unit. We also evaluated the clinical significance of such errors and user satisfaction. DESIGN: Preintervention and postintervention study involving a control and an intervention medical intensive care unit. SETTING: Two medical intensive care units in the same department of a 2,000-bed university hospital. PATIENTS: Adult medical intensive care patients. INTERVENTIONS: After a 2-month observation period, we implemented an automated dispensing system in one of the units (study unit) chosen randomly, with the other unit being the control. MEASUREMENTS AND MAIN RESULTS: The overall error rate was expressed as a percentage of total opportunities for error. The severity of errors was classified according to National Coordinating Council for Medication Error Reporting and Prevention categories by an expert committee. User satisfaction was assessed through self administered questionnaires completed by nurses. A total of 1,476 medications for 115 patients were observed. After automated dispensing system implementation, we observed a reduced percentage of total opportunities for error in the study compared to the control unit (13.5% and 18.6%, respectively; p<.05); however, no significant difference was observed before automated dispensing system implementation (20.4% and 19.3%, respectively; not significant). Before-and-after comparisons in the study unit also showed a significantly reduced percentage of total opportunities for error (20.4% and 13.5%; p<.01). An analysis of detailed opportunities for error showed a significant impact of the automated dispensing system in reducing preparation errors (p<.05). Most errors caused no harm (National Coordinating Council for Medication Error Reporting and Prevention category C). The automated dispensing system did not reduce errors causing harm. Finally, the mean for working conditions improved from 1.0+/-0.8 to 2.5+/-0.8 on the four-point Likert scale. CONCLUSIONS: The implementation of an automated dispensing system reduced overall medication errors related to picking, preparation, and administration of drugs in the intensive care unit. Furthermore, most nurses favored the new drug dispensation organization. PMID- 20838334 TI - Muscarinic receptor antagonist therapy improves acute pulmonary dysfunction after smoke inhalation injury in sheep. AB - OBJECTIVES: Inhalation injury contributes to the morbidity and mortality of burn victims. In humans and in an ovine model of combined smoke inhalation and burn injury, bronchospasm and acute airway obstruction contribute to progressive pulmonary insufficiency. This study tests the hypothesis that muscarinic receptor antagonist therapy with tiotropium bromide, an M1 and M3 muscarinic receptor antagonist, will decrease the airway constrictive response and acute bronchial obstruction to improve pulmonary function compared to injured animals without treatment. DESIGN: Randomized, prospective study involving 32 sheep. SETTING: Large-animal intensive care research laboratory. INTERVENTIONS: The study consisted of six groups: a sham group (n=4, instrumented noninjured), a control group (n=6, injured and not treated), and tiotropium bromide-treated groups, including both preinjury and postinjury nebulization protocols. Treatments for these groups included nebulization with 36 MUg of tiotropium bromide 1 hr before injury (n=6) and postinjury nebulization protocols of 18 MUg (n=6), 36 MUg (n=6), and 72 MUg (n=4) administered 1 hr after injury. All treated groups received an additional 14.4 MUg every 4 hrs for the 24-hr study period. MAIN RESULTS: Pretreatment with tiotropium bromide significantly attenuated the increases in ventilatory pressures, pulmonary dysfunction, and upper airway obstruction that occur after combined smoke inhalation and burn injury. Postinjury treatments with tiotropium bromide were as effective as pretreatment in preventing pulmonary insufficiency, although a trend toward decreased obstruction was present only in all post-treatment conditions. There was no improvement noted in pulmonary function in animals that received a higher dose of tiotropium bromide. CONCLUSIONS: This study describes a contribution of acetylcholine to the airway constrictive and lumenal obstructive response after inhalation injury and identifies low-dose nebulization of tiotropium bromide as a potentially efficacious therapy for burn patients with severe inhalation injury. PMID- 20838335 TI - Quality of life after intensive care: a systematic review of the literature. AB - OBJECTIVES: To evaluate quality of life at least 12 months after discharge from the intensive care unit of adult critically ill patients, to evaluate the methodology used to assess long-term quality of life, and to give an overview of factors influencing quality of life. DATA SOURCES: EMBASE-PubMed, MEDLINE (OVID), SCI/Web of Science, the Cochrane Library, Google Scholar, and personal files. DATA EXTRACTION: Data extraction was performed independently and cross-checked by two reviewers using a predefined data extraction form. Eligible studies were published between 1999 and 2009 and assessed quality of life >=12 months after intensive care unit discharge by means of the Medical Outcomes Study 36-Item Short Form Health Survey, the RAND 36-Item Health Survey, EuroQol-5D, and/or the Nottingham Health Profile in adult intensive care unit patients. DATA SYNTHESIS: Fifty-three articles (10 multicenters) were included, with the majority of studies performed in Europe (68%). The Medical Outcomes Study 36-Item Short Form Health Survey was used in 55%, and the EuroQol-5D, the Nottingham Health Profile, the RAND 36-Item Health Survey, or a combination was used in 21%, 9%, 8%, or 8%, respectively. A response rate of >=80% was attained in 26 studies (49%). Critically ill patients had a lower quality of life than an age- and gender matched population, but quality of life tended to improve over years. The worst reductions in quality of life were seen in cases of severe acute respiratory distress syndrome, prolonged mechanical ventilation, severe trauma, and severe sepsis. Study quality criteria, defined as a baseline quality of life assessment, the absence of major exclusion criteria, a description of nonresponders, and a comparison with a reference population were met in only four studies (8%). Results concerning the influence of severity of illness, comorbidity, preadmission quality of life, age, gender, or acquired complications were conflicting. CONCLUSIONS: Quality of life differed on diagnostic category but, overall, critically ill patients had a lower quality of life than an age- and gender-matched population. A minority of studies met the predefined methodologic quality criteria. Results concerning the influence of the patients' characteristics and illnesses on long-term quality of life were conflicting. PMID- 20838336 TI - Contemporary management of thoracic outlet syndrome. AB - PURPOSE OF REVIEW: The diagnosis and management of thoracic outlet syndrome (TOS) has been surrounded by controversy since this disorder was first recognized. Recent evidence from observational studies has helped us better understand the pathophysiology of different TOS subtypes and guide clinical decision making for this disorder. RECENT FINDINGS: The identification of anatomic anomalies involved with the cause of different TOS subtypes has been made easier by contemporary diagnostic techniques. This includes the injection of neuromuscular blocking agents into anterior scalene muscles to help confirm the diagnosis of neurogenic TOS. Surgical intervention by means of first rib resection and anterior scalenectomy is an effective treatment for patients diagnosed with neurogenic and venous TOS, resulting in a significant increase in quality-of-life measures for the majority of patients. Patients with acute and chronic venous TOS should be maintained on anticoagulation during the perioperative period and may not need thrombolysis prior to surgery. Finally, patients with arterial TOS should undergo cervical or first rib resection with or without arterial reconstruction to alleviate and prevent recurrence of symptoms. SUMMARY: The management of TOS requires a multidisciplinary approach with specific treatment algorithms for each TOS subtype. Appropriately selected patients with all different types of TOS may benefit from surgical intervention. PMID- 20838337 TI - Off-pump coronary surgery: where do we stand in 2010? AB - PURPOSE OF REVIEW: In this review, we will highlight recent studies comparing off pump coronary artery bypass surgery with traditional on-pump coronary artery bypass surgery. RECENT FINDINGS: Current literature comparing off-pump vs. on pump coronary artery bypass has failed to demonstrate the superiority of one technique over the other. Small prospective randomized controlled trials continue to show equivalent in-hospital outcomes and continue to raise concerns about vein graft patency and completeness of revascularization. Larger observational analyses are better powered to statistically compare in-hospital outcomes in both low and high-risk patients and in general have shown more favorable in-hospital outcomes and equivalent long-term outcomes with off-pump compared with on-pump coronary artery bypass. SUMMARY: Off-pump coronary artery bypass continues to be a useful technique for coronary revascularization. The benefits of off-pump techniques may be more apparent for patients at high risk for complications associated with cardiopulmonary bypass and aortic manipulation. PMID- 20838338 TI - In-vivo assessment of the natural history of coronary atherosclerosis: vascular remodeling and endothelial shear stress determine the complexity of atherosclerotic disease progression. AB - PURPOSE OF REVIEW: Atherosclerotic disease progression is determined by localized plaque growth, which is induced by systemic and local hemodynamic factors, and the nature of the wall remodeling response. The purpose of this review is to summarize the processes underlying the heterogeneity of coronary atherosclerosis progression in relation to the local hemodynamic and arterial remodeling environment. RECENT FINDINGS: Multiple competing biological processes in the extracellular matrix define the extent of vascular remodeling and disease progression. The remodeling phenomenon is not consistent but is characterized by great phenotypical heterogeneity which reflects the complex effect of systemic, genetic and hemodynamic factors on the arterial wall response to plaque formation and progression. The exaggeration of expansive remodeling (i.e., excessive expansive remodeling) likely contributes to the transformation of an initially favorable action into an excessive course of vessel expansion, continued disease progression and plaque instability. Extremely low endothelial shear stress and excessive expansive remodeling establish a vicious cycle which leads to the formation of severe plaques with high-risk characteristics. SUMMARY: The dynamic interplay between the local hemodynamic environment and the wall remodeling behavior determines the complexity of the natural history of atherosclerosis and explains the development of localized plaque vulnerability. PMID- 20838339 TI - The Loeys-Dietz syndrome: an update for the clinician. AB - PURPOSE OF REVIEW: Thoracic aortic aneurysm (TAA) dissection is an important cause of death in the western world. Especially in young adults, the genetic contribution to this disease is estimated to be high, as at least one out of five probands has a positive family history for aortic aneurysms/dissections. In recent years, major progress has been made in the identification of several genes underlying both syndromic and nonsyndromic forms of TAA. RECENT FINDINGS: This review will focus on the current knowledge of a recently discovered syndromic form of TAA, namely the Loeys-Dietz syndrome or LDS. SUMMARY: LDS is caused by mutation in the genes encoding the transforming growth factor beta receptor 1 and 2 (TGFBR1 and TGFRB2) and is characterized by aggressive aortic/arterial disease. The clinical characteristics, molecular findings and pathophysiological mechanisms are summarized. The discovery of this entity has confirmed a key role for transforming growth factor beta signaling in aortic aneurysmal disease. Study of the natural history of this condition has revealed important lessons. The arterial disease is widespread and can involve all aortic segments and major branching arteries, necessitating cardiovascular imaging beyond the aortic root segment. Moreover, dissections occur at smaller diameters than in Marfan syndrome, leading to earlier surgery at smaller aortic diameters. Current surgical experience with LDS is excellent, offering a good long-term prognosis with timely identification of the disease. PMID- 20838340 TI - Stomach and duodenum. PMID- 20838341 TI - Update on prolonged and persistent diarrhea in children. AB - PURPOSE OF REVIEW: To highlight recent advances in our understanding of prolonged episodes of acute diarrhea and persistent diarrhea in children. The focus is on the contribution of these illnesses to the global burden of diarrhea, their impact on childhood growth and development, novel epidemiologic links between prolonged and persistent diarrheal episodes, and strategies for their prevention and management. RECENT FINDINGS: Although less common than acute diarrhea, prolonged and persistent episodes of diarrhea in childhood constitute a significant portion of the global burden of diarrhea. These episodes also play a key role in the vicious cycle of childhood diarrhea and malnutrition in which undernutrition is both a risk factor and an outcome of diarrhea. Increased efforts to provide WHO-recommended zinc therapy for all children with diarrhea in developing countries will significantly reduce morbidity and mortality. In children who develop persistent diarrhea, yogurt-based or amino acid-based diets may accelerate their recovery. SUMMARY: In addition to increased implementation of strategies already known to effectively prevent and manage acute diarrhea, further research is needed to address the recognition, prevention, and treatment of prolonged episodes of acute diarrhea and persistent diarrhea in resource limited settings. PMID- 20838342 TI - Gastric secretion. AB - PURPOSE OF REVIEW: This review summarizes the past year's literature regarding the regulation of gastric exocrine and endocrine secretion at the central, peripheral, and cellular levels. RECENT FINDINGS: Gastric acid secretion is an intricate and dynamic process that is regulated by neural (efferent and afferent), hormonal (e.g., gastrin), and paracrine (e.g., histamine, ghrelin, somatostatin) pathways as well as mechanical (e.g., distension) and chemical (e.g., protein, glutamate, coffee, and ethanol) stimuli. Secretion of hydrochloric acid by the parietal cell involves recruitment and fusion of HK adenosine triphosphatase (HK-ATPase)-containing cytoplasmic tubulovesicles with the apical membrane with subsequent electroneutral transport of hydronium ions in exchange for potassium; the source of the latter is the potassium channel, KCNQ1. Concomitantly, chloride exits via the cystic fibrosis transmembrane regulator. Inhibition of the HK-ATPase by proton pump inhibitors leads to a compensatory hypergastrinemia which, if prolonged, results in parietal and enterochromaffin like cell hyperplasia. The clinical consequence is rebound acid secretion which may induce dyspeptic symptoms in healthy individuals and exacerbate reflux symptoms in patients with gastroesophageal reflux disease. SUMMARY: We continue to make progress in our understanding of the regulation of gastric acid secretion in health and disease. A better understanding of the pathways and mechanisms regulating acid secretion should lead to improved management of patients with acid-induced disorders as well as those who secrete too little acid. PMID- 20838343 TI - Endoscopic management in the bariatric surgical patient. AB - PURPOSE OF REVIEW: Morbid obesity is a global health epidemic. As the prevalence of bariatric surgery rises, it becomes increasingly important for gastroenterologists to understand their role in the perioperative care of bariatric surgical patients, to recognize potential complications of surgery that can be addressed endoscopically, and to learn about endoluminal approaches that may provide alternatives to bariatric surgery in the future. RECENT FINDINGS: Roux-en-Y gastric bypass (RYGB) and laparoscopic adjustable gastric band account for more than 80% of weight loss procedures performed worldwide. Over two-thirds of patients with upper gastrointestinal symptoms following RYGB will have one or more abnormalities on endoscopy, including anastomotic strictures (53%), marginal ulcers (16%), functional obstructions (4%), and gastrogastric fistulas (2.6%). Intraoperative endoscopy can detect early leaks in over 7% of patients during RYGB surgery. Single-center experience finds that endoscopic repair of small gastrogastric fistulas is technically feasible in 95% of patients; however, durability of closure remains limited. Pooled data demonstrate that balloon assisted endoscopic retrograde cholangiopancreatography can achieve papillary cannulation in 80% of patients with RYGB anatomy. SUMMARY: The gastroenterologist can improve outcomes in bariatric surgical patients by understanding the issues of care that present themselves perioperatively and that lend themselves to minimally invasive endoscopic treatments. PMID- 20838344 TI - Gastroduodenal motility. AB - PURPOSE OF REVIEW: Abnormalities of gastroduodenal motility are considered key players in the pathogenesis of upper gastrointestinal symptoms in disorders such as functional dyspepsia and gastroparesis. Abnormalities of sensory control are considered another important factor that contributes to symptom generation. This review summarizes recent progress in our understanding of gastroduodenal motility and sensitivity in health and in disease. RECENT FINDINGS: Although gastric and small intestinal motility remain an important focus of research, including the application of the SmartPill (SmartPill Corp., Buffalo, New York, USA) wireless motility monitoring capsule, duodenal sensitivity and low-grade duodenal inflammation are new areas of interest in the pathogenesis of functional dyspepsia. A number of genetic polymorphisms associated with functional dyspepsia are being investigated, but large-scale studies are still lacking. Central processing of visceral stimuli, and its role in the pathogenesis of functional dyspepsia, is another important emerging topic. Therapeutic studies have reported on novel pharmacological approaches in functional dyspepsia and gastroparesis, as well as gastric electrical stimulation in the treatment of refractory gastroparesis. SUMMARY: There is gradual progress in our understanding of the pathogenesis of gastroduodenal symptoms. Areas of recent advances including the recognition of low-grade duodenal inflammation, the role of central nervous system processing in visceral hypersensitivity and the exploration of novel pharmacotherapeutic approaches. PMID- 20838345 TI - Cardiovascular aspects of antipsychotics. AB - PURPOSE OF REVIEW: Schizophrenia is associated with increased mortality and reduced life expectancy, with cardiovascular disease being the most frequent cause of death. Antipsychotics have detrimental effects on different risk factors for cardiovascular disease. This review will focus on the relationship between antipsychotic treatment and cardiovascular disease. RECENT FINDINGS: The increased overall mortality and mortality from cardiovascular disease in schizophrenia are now well documented. Patients with schizophrenia are at risk of receiving less optimal treatment for cardiovascular disease. Patients with schizophrenia are at high risk of metabolic syndrome, a cluster of risk factors for cardiovascular disease. Some antipsychotics, in particular, clozapine and olanzapine, frequently cause weight gain, dyslipidemia and diabetes mellitus. Antipsychotics differ in their effects on body weight, lipids and glucose regulation. However, the long-term effects of these differences between individual antipsychotics on overall mortality and cardiovascular mortality are not well established. SUMMARY: More research is needed to better understand the relationship between schizophrenia, antipsychotic treatment and cardiovascular disease. More effective treatment strategies need to be developed to reduce the burden of cardiovascular disease in schizophrenia. PMID- 20838346 TI - Conceptual relations between loneliness and culture. AB - PURPOSE OF REVIEW: To clarify ways in which loneliness and culture are connected conceptually. RECENT FINDINGS: Loneliness may be distinguished from being alone or social isolation by a common property of loneliness across cultures - that is, an undesired absence of reciprocal empathic understanding. Cultural meanings shape the experience of loneliness in that they create expectations of the nature and the extent of closeness in relationships as well as social connectedness. Conversely, the extent and nature of loneliness in a culture may be described as a property of that very culture, allowing one to speak of 'a culture of loneliness'. Accordingly, a culture of loneliness is found in both individualist and communal cultures, but of different kinds. A third conceptual relation may be described as a cultural loneliness, whereby someone is lonely while being in a foreign culture that leaves one feeling not understood and not able to reciprocate understanding about cultural meanings. SUMMARY: Loneliness shares common features across cultures, yet culture shapes it and is shaped by it. PMID- 20838347 TI - Advances in the treatment of psychiatric disorders in long-term care homes. AB - PURPOSE OF REVIEW: Psychiatric disorders are common among older adults in long term care (LTC) homes and the LTC population is rapidly growing in many countries. Treatment of psychiatric conditions in this population is challenging given the psychosocial environment and physical frailty of the population. This review highlights some important advances in pharmacological and nonpharmacological interventions in this setting. RECENT FINDINGS: There is some evidence to support the use of psychosocial interventions for behavioral symptoms, including those utilizing sensory interventions such as aromatherapy and calming music; behavioral management techniques; cognitive stimulation; physical activity; and staff training. There is also some evidence to support the use of psychotherapies such as reminiscence therapy and cognitive behavior therapy for depression. Recent literature on the pharmacological management of behavioral symptoms of dementia have included studies of the antipsychotic aripiprazole, prazosin, and medication-discontinuation trials along with two negative studies involving melatonin and oxcarbazepine. SUMMARY: The literature on psychosocial interventions for behavioral symptoms associated with dementia has been criticized for lack of vigor, but there is growing evidence from studies with improved methodology that these interventions may confer significant benefits, although the effect sizes are often small or moderate. More well designed trials of pharmacological therapies in the LTC population are also necessary. PMID- 20838348 TI - Is long-term bisphosphonate therapy associated with benefits to the periodontium in postmenopausal women? AB - OBJECTIVE: The aim of this study was to compare the periodontium of postmenopausal women with known low bone mineral density who are receiving long term bisphosphonate therapy with those who are not. METHODS: The periodontal status of 28 white postmenopausal women with low bone density using bisphosphonate therapy for at least 2 years was compared with that of a matching group not using such therapy. All women underwent a cone-beam CT scan of the jaw and a complete periodontal examination evaluating for plaque score, periodontal probing depth, clinical attachment loss, bleeding on probing, and alveolar bone height. RESULTS: Bisphosphonate users had higher plaque score, lower probing depth, and lesser clinical attachment loss compared with the controls. These differences were determined to be significant by both t test and Wilcoxon's tests. Bleeding on probing was lower and the alveolar bone height was higher in the bisphosphonate group than in controls, but these differences were not statistically significant. Linear models showed no significant interactions between plaque score and bisphosphonate use, suggesting that the association of periodontal status and outcome measures was constant across all levels of plaque scores. Bisphosphonate use was a significant factor for probing depth but was not significant for the other parameters when adjusted for plaque score. CONCLUSIONS: Long-term bisphosphonate use seems to have some beneficial effects on the periodontium of postmenopausal women with low bone density, across all levels of plaque score. PMID- 20838349 TI - Event-related potential measures of processing during an Implicit Association Test. AB - This study recorded event-related potentials during the Implicit Association Test, a reaction time-based measure of implicit social attitudes. An N2, peaking at about 350 ms was larger in the incongruent condition, perhaps reflecting greater response monitoring. The latency to an initial late positive peak, P300, a measure of stimulus classification time, was not longer in the incongruent than the congruent condition. A later small amplitude positive peak was observed in the incongruent condition, but was not visible in the congruent condition. The additional positivity is consistent with the hypothesis that participants make an initial decision to determine whether a task set switch is required, and then make a subsequent decision about the correct response, perhaps resulting in delayed reaction times. PMID- 20838350 TI - Finding reasonable treatments for the working poor. PMID- 20838351 TI - Repeatability of pachymetry and thinnest point localization using a fourier domain optical coherence tomographer. AB - PURPOSE: To evaluate the repeatability of pachymetry measures at six distinct locations using a Fourier-domain optical coherence tomographer. The location of the thinnest point was also described using vector analysis, and repeatability of the localization of the thinnest point was calculated. METHODS: The right eye of 25 healthy subjects had 3 images of their right cornea captured using the pachymetry protocol and anterior segment lens of a commercially available Fourier domain optical coherence tomographer (RTVue-100, Optovue, Fremont, CA). The first two images were used to quantify repeatability in the central (2 mm) and paracentral (2-5 mm) cornea. Cartesian coordinates representing the location of the thinnest point were used to determine the mean location in relation to the central cornea. RESULTS: Mean central thickness was 536.8 +/- 31.1 MUm, and the mean minimum thickness was 526.4 +/- 33.1 MUm. The thickest paracentral zone was the superior cornea and the thinnest was the temporal cornea. Intraclass correlation values ranged between 0.969 and 0.996, and the mean coefficient of repeatability was 1.74% across all locations evaluated. The thinnest point was located in the inferior temporal region in 80% of eyes and was an average distance of 1.01 mm from the corneal apex, subtending an angle of 26.7 degrees from the horizontal. CONCLUSIONS: The RTVue-100 provides a highly repeatable measure of corneal thickness at various locations. The instrument is capable of describing and consistently duplicating the location of the thinnest point of the cornea; however, further comparative work with other clinical imaging modalities is required. PMID- 20838352 TI - Risk factors for corneal inflammatory and mechanical events with extended wear silicone hydrogel contact lenses. AB - PURPOSE: To identify risk factors for contact lens-related corneal inflammatory events and mechanical events in wearers of silicone hydrogel lenses on a 30-night extended wear (EW) schedule in India. METHODS: An interventional study with 188 subjects wearing silicone hydrogel lenses bilaterally on a 30-night EW schedule. Subjects were dispensed with lenses and reviewed at scheduled visits up to 6 months of EW. Multivariate logistic regression, after adjusting for within subject correlation, was used to develop the statistical model. RESULTS: Occupations in non-ideal environments were found to predispose a lens wearer to inflammatory events (p = 0.003). Wearers in the non-ideal group, who had varying degrees of exposure to ocular irritants in their work environment had highest incidence of inflammatory events (19.2%). Wearers in a controlled, ideal environment had lowest levels of events (3.3%). Students occupied a position between the two groups (9.3%). Inflammatory rate was higher among wearers with increased microbial contamination of lenses (p = 0.002). Wearers with an inflammatory event had mean colony forming unit of 1.97 log compared with mean colony forming unit of 1.45 log in group with no inflammatory event. Corneal vascularization was associated with the development of inflammatory events (p = 0.001) with 50% of wearers with vascularization experiencing events compared with 7.6% of subjects with no vascularization. Reduced lens movement was associated with inflammatory events with subjects more likely to develop inflammatory events compared with those wearers with optimal lens movement (p = 0.027). CONCLUSIONS: A multitude of factors, including environmental influences, lens contamination, ocular characteristics, and lens fit, contributes to the development of inflammatory events, information that is of clinical relevance to practitioners worldwide. Occupational environment was also a contributory factor, confirming that a duty of clinicians is to ascertain the nature of the work environment of lens wearers (and potential wearers) and to balance the needs of the wearer with the potential risks. PMID- 20838353 TI - Limitations of current antibiotics for the treatment of bacterial conjunctivitis. AB - Bacterial conjunctivitis is a common ocular infection that is generally treated empirically with a broad-spectrum antibiotic. The more common pathogens causing bacterial conjunctivitis include Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus epidermidis, and Moraxella species. Several antibiotics traditionally used to treat bacterial conjunctivitis are no longer widely prescribed because of increased bacterial resistance and/or safety concerns. The introduction of the fluoroquinolone class of anti-infectives offered effective and better tolerated treatment options. Nonetheless, successful therapy for bacterial conjunctivitis continues to be limited by several factors. A primary concern is the development of bacterial resistance that may be impacted not only by widespread antibiotic use but also by antibacterial pharmacokinetics, such as maintenance of insufficient bactericidal concentrations at the site of infection. In addition, poor adherence to prescribed regimens that require frequent administration, along with undesirable adverse events, affects the development of bacterial resistance and the success of treatment regimens. This article reviews current antibacterial agents used to treat bacterial conjunctivitis, factors that limit their successful use in treatment, and options for future development of more effective topical ophthalmic anti-infective agents. PMID- 20838354 TI - Angioleiomyoma of the internal auditory canal: clinical and radiographic features. AB - OBJECTIVE: Discussion of a rare case of angioleiomyoma of the internal auditory canal. PATIENT: Thirteen-year-old female patient with a 1-year history of progressive hearing loss. INTERVENTION: Middle cranial fossa approach providing complete surgical extirpation. MAIN OUTCOME MEASURE: Surgical pathology. RESULTS: Radiography and history suggestive of vestibular schwannoma; pathology revealed angioleiomyoma. CONCLUSION: Angioleiomyoma is a rare lesion of the internal auditory canal that has many similar clinical and radiographic features of a vestibular schwannoma. There are no previous reports of this tumor occurring within the internal auditory canal in this age group. PMID- 20838355 TI - Active surveillance culturing impacts methicillin-resistant Staphylococcus aureus acquisition in a pediatric intensive care unit. AB - OBJECTIVE: To determine whether active surveillance culturing for methicillin resistant Staphylococcus aureus (MRSA) decreases nosocomial MRSA acquisition in the pediatric intensive care unit. DESIGN: Before and after observational study. SETTING: A tertiary care, 20-bed, pediatric intensive care unit. PATIENTS: All patients admitted to the pediatric intensive care unit. INTERVENTIONS: Anterior nares cultures for MRSA were obtained on admission and weekly in the pediatric intensive care unit from January 2007 to December 2009 as part of a hospital quality improvement project. MEASUREMENTS AND MAIN RESULTS: MRSA admission prevalence and nosocomial incidence density were determined retrospectively for 2006 and prospectively for 2007-2009. Nosocomial MRSA incidence density during the intervention period was determined monthly and analyzed by trend analysis by using a general linear model. The correlation of active surveillance culturing compliance with nosocomial acquisition of MRSA was analyzed. Possible confounding by healthcare worker hand hygiene compliance observed during the intervention period was also analyzed by multivariate linear regression analysis. The yearly MRSA incidence density significantly decreased from 2006 to 2009 (6.88 per 1,000 patient days to 1.45 per 1,000 patient days, p < .001) and from 2007 to 2009 (7.32 per 1,000 patient days to 1.45 per 1,000 patient days, p < .001). Trend analysis demonstrated a significant decline in MRSA acquisition over time following the introduction of active surveillance culturing (p < .001). Surveillance culturing was significantly associated with the decline in MRSA acquisition observed in the pediatric intensive care unit by multivariate regression analysis when controlling for hand hygiene (p = .01). CONCLUSIONS: Active surveillance culturing resulted in significantly decreased nosocomial acquisition of MRSA in a pediatric intensive care unit setting. Admission and weekly active surveillance culturing appears to be an effective tool to decrease the spread of MRSA in the pediatric intensive care unit, independent of improvement in hand hygiene compliance. The impact on hospital-acquired MRSA infections and the cost benefit of active surveillance culturing require further study. PMID- 20838356 TI - The effect of cardiopulmonary bypass on the hypothalamic-pituitary-adrenal axis in children. AB - OBJECTIVE: The pathophysiology of low-cardiac-output syndrome after cardiopulmonary bypass is incompletely understood, but adrenal insufficiency has been proposed as a contributing factor. Our objective was to examine the effect of cardiopulmonary bypass on the hypothalamic-pituitary-adrenal axis, specifically adrenal responsiveness, in patients with congenital heart disease undergoing surgery. We hoped to correlate bound and free cortisol values both postoperatively and after adrenocorticotropic hormone stimulation, in conjunction with corticosteroid-binding globulin levels, with clinical outcomes to determine whether these variables are sensitive indicators of adrenal axis function. DESIGN: Prospective cohort study. SETTING: A children's hospital. PATIENTS: Fifty two pediatric heart surgery patients undergoing cardiopulmonary bypass. INTERVENTION: Total cortisol and corticosteroid-binding globulin levels were obtained pre- and postoperatively and after a postoperative cosyntropin stimulation test. Free cortisol was calculated by using Coolens' method. MEASUREMENTS AND MAIN RESULTS: Nine of 51 (17.6%) patients had low (<3 MUg/dL) baseline postoperative total cortisol, median 1.6 MUg/dL, yet all nine had normal (>9 MUg/dL increase from postoperative baseline) stimulation tests. The corticosteroid-binding globulin levels declined from a mean of 29 mg/L preoperatively to 22 mg/L postoperatively (p < .001) and showed marked variability between patients. Patients with free cortisol delta >6 MUg/dL (n = 18, 35%) had a longer length of stay (median 9 vs. 5 days; p = .002), higher inotrope scores (median 13.3 vs. 10.8; p = .05), greater fluid requirement (median 73.5 vs. 55.6 mL/kg; p = .007), and longer ventilator times (median 41.5 vs. 20 hrs; p = .013). CONCLUSIONS: Although hypothalamic-pituitary-adrenal axis dysfunction may play a role in low-cardiac-output syndrome among children undergoing congenital heart surgery, using total cortisol to investigate such dysfunction may be inadequate. Decreased corticosteroid-binding globulin levels and marked free cortisol increase after stimulation were associated with worse clinical outcomes. Further investigation into the cortisol-corticosteroid-binding globulin complex and its relationship to free cortisol is necessary to examine the problem of adrenal insufficiency from a more integrated perspective. PMID- 20838357 TI - Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. AB - PURPOSE: To evaluate the efficacy of intravitreal injection of bevacizumab (IVB) followed by modified grid laser photocoagulation (MGP) versus each alone as a primary treatment of diffuse diabetic macular edema. PATIENTS AND METHODS: A randomized 3-arm clinical trial in which 62 eyes of 48 patients with diffuse diabetic macular edema were enrolled. Eyes were randomly distributed to 1 of 3 study groups: 19 eyes underwent MGP (MGP group), 21 eyes received 1.25 mg of IVB (IVB group), and 22 eyes received IVB followed by MGP (combined group). All eyes underwent a complete ophthalmic examination including fluorescein angiography and optical coherence tomography at baseline and at 1, 3, and 6 months, after treatment. Fluorescein angiography was performed at the 3 and 6 months follow up visits. The outcome measures were the change compared with baseline in central macular thickness (CMT), changes in best-corrected visual acuity (BCVA), changes in fluorescein angiography leakage, and any reported complication. A P value less than 0.05 was considered statistically significant. RESULTS: One month after treatment, the reduction in the mean CMT versus baseline was 49.88 MUm (10.45%) in MGP group, 150.92 MUm (31.30%) in IVB group, and 110.30 MUm (23.77%) in the combined group, with a corresponding improvement in the mean BCVA. At 1 month, the improvement in CMT was better than baseline in all groups, yet only significant in the IVB group (P < 0.05) and the combined group (P < 0.05). The improvement in mean BCVA was significant in the IVB (P < 0.05) and the combined groups at 1 month (P < 0.05). At 3 months, the mean CMT was still better than baseline in all groups but this improvement was significant only in the combined group (P < 0.05). The improvement in the mean BCVA was significant only in the IVB and the combined groups (P < 0.05). Six months after treatment, the reduction in the mean CMT was significant in the combined group only (P < 0.05) and there was no significant improvement in the mean BCVA in all groups (P > 0.05). The BCVA did not deteriorate below baseline in all eyes included in the study, except three eyes in the MGP group. No complication related to the intravitreal injection was reported in the injected eyes. CONCLUSION: Combined therapy with IVB and sequential MGP 3 weeks later appeared to be superior to MGP or IVB alone in reducing macular thickening and improving visual acuity. However, no significant improvement in BCVA occurs 6 months after treatment. A combination of IVB and sequential MGP could be used as an initial treatment of diffuse diabetic macular edema. PMID- 20838358 TI - Delayed-onset bleb-associated endophthalmitis (1996-2008): causative organisms and visual acuity outcomes. AB - PURPOSE: The purpose of this study was to report the clinical features, organisms, and outcomes of patients with delayed-onset bleb-associated endophthalmitis. METHODS: Retrospective consecutive case series. Patients who were treated for delayed-onset bleb-associated endophthalmitis between January 1, 1996, and July 1, 2008, at a single institution were included. Information on visual acuities, clinical characteristics, causative organisms, and treatment outcomes were collected. Infections within 1 month of glaucoma filtering surgery, inadvertent filtering blebs after cataract surgery, and patients with glaucoma drainage devices were excluded. RESULTS: A total of 71 eyes from 68 patients were identified. An adjunctive antifibrotic agent was used in 48 eyes (68%). The mean time between surgery and endophthalmitis was 4.8 years (range, 0.1-16; standard deviation, 3.6). The average follow-up time after initial treatment was 37 months (range 1-144; standard deviation, 41). At presentation, 17 eyes (24%) had a bleb leak. Fifty-seven eyes (83%) were culture positive. The most common causative organisms were Streptococcus species in 20 eyes (30%), gram-negative organisms in 19 eyes (28%), and coagulase-negative Staphylococcus in 12 eyes (18%). All gram positive isolates were sensitive to vancomycin. Nine eyes (13%) eventually underwent evisceration or enucleation secondary to pain and/or poor vision. The main outcome measure was best-corrected visual acuity at the last follow-up examination. Final visual acuities in the initial tap/inject group (n = 45) versus the initial vitrectomy group (n = 24) were as follows: >= 20/40 (29% vs. 4.2%), 20/50 to 20/400 (36% vs. 29%), and <5/200 (36% vs. 62%). CONCLUSION: Streptococcus species and gram-negative organisms were the most common causative isolates identified in this case series of delayed-onset bleb-associated endophthalmitis. Despite treatment of the infection, visual outcomes were generally poor. PMID- 20838359 TI - The role of intravitreal bevacizumab in experimental posterior penetrating eye injury. AB - PURPOSE: The purpose of this study was to investigate the effect of intravitreal bevacizumab on an experimental rabbit model of penetrating posterior ocular injury. METHODS: The right eyes of 40 white New Zealand rabbits were included in a penetrating posterior ocular injury model that was consisted of a 5-mm circumferential incision placed 8 mm behind the limbus at the supratemporal quadrant. They were randomly divided into two groups. The rabbits in Group 1 (n = 20) received 1.25 mg (0.05 mL) of intravitreal bevacizumab via pars plana injection and those in Group 2 (control group, n = 20) received 0.05 mL of intravitreal balanced salt solution. On Day 28, the eyes were enucleated and evaluated by gross inspection and light microscopy. Clearance time of vitreous hemorrhage, presence of fibrous proliferation or retinal detachment, greatest linear dimension of fibrosis, and grade of fibrous extension were regarded as outcome measures. Nominal variables were evaluated by the chi-square or the Fisher's exact test; continuous variables were evaluated using the Mann-Whitney U test. RESULTS: At the end of the surgery, all the eyes had moderate (n = 9 and 7 in the case and control groups, respectively) or severe vitreous hemorrhage (n = 11 and 13 in the case and control groups, respectively) (P = 0.52). Average clearance time of vitreous hemorrhage was 3.42 +/- 2.71 and 6.47 +/- 3.58 days in bevacizumab and control groups, respectively (P = 0.01). The incidence of ophthalmoscopically visible fibrous proliferation was 31.6% in the bevacizumab group and 63.2% in the control group (P = 0.05). The greatest linear dimension of fibrosis was 0.91 +/- 1.14 mm in the bevacizumab group and 2.00 +/- 1.58 mm in the control group (P = 0.02). Retinal detachment rate was 11% (n = 2, all rhegmatogenous) and 21% (n = 4, 2 rhegmatogenous and 2 tractional) in the bevacizumab and control groups, respectively (P = 0.66). Choroidal congestion, optic disk edema, and macular edema were seen in 1 eye (5.5%) of the bevacizumab group, whereas they were found in 4 (22%), 4 (22%) and 3 (16.5%) eyes of the control group, respectively. These differences, however, did not reach statistical significance. CONCLUSION: This study showed that intravitreal injection of bevacizumab may reduce the extent of fibrovascular and/or fibrocellular proliferation and may accentuate the clearance of vitreous hemorrhage after an experimental model of posterior penetrating ocular injury in rabbits. These alterations may affect the long-term anatomical and/or functional success rate of posterior segment surgeries in these eyes. PMID- 20838360 TI - Reproducibility and comparison of retinal thickness and volume measurements in normal eyes determined with two different Cirrus OCT scanning protocols. AB - PURPOSE: To assess reproducibility and compare raster scanning protocols of Cirrus high-definition optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). METHODS: Five hundred and twenty-eight computed tomography scans were performed in 17 healthy subjects. Four sessions were performed at each visit including two 200 * 200 and two 512 * 128 macular cube scans per session. The examined eye, observer, and order of scanning protocols in-between each session were randomly chosen. Reproducibility was described with intraclass correlation coefficients, coefficients of variance, intervisit, interrater, intersession intra-, and intersubject standard deviations. RESULTS: Intraclass correlation coefficients ranged from 80.4% to 97.8% and the coefficients of variance from 0.7% to 2.3% for retinal volume and retinal thickness measurements. Intersubject, intervisit, interrater, intersession, and intrasubject standard deviations ranged from 0 MUm to 18.54 MUm. Differences in retinal thickness between protocols were small (range 3.55 +/- 1.95 MUm to 0.81 +/- 0.59 MUm) but significant for the central (P < 0.0001), the outer superior (P = 0.0036), temporal (P = 0.0026), and nasal subfield (P < 0.0001). Average difference of retinal volume between protocols was 0.05 +/- 0.04 mm (P = 0.0001). CONCLUSION: Both raster scanning protocols of the Cirrus optical coherence tomography showed excellent reproducibility of retinal thickness and volume measures. Significant differences between protocols for retinal thickness in four macula thickness map subfields and for retinal volume were found. PMID- 20838361 TI - Retrospective comparison of 25-gauge transconjunctival sutureless vitrectomy to 20-gauge vitrectomy for the repair of pseudophakic primary inferior rhegmatogenous retinal detachment. AB - PURPOSE: To compare anatomical and functional outcomes of 25-gauge transconjunctival sutureless pars plana vitrectomy (PPV) to standard 20-gauge 3 port PPV for the treatment of pseudophakic rhegmatogenous retinal detachments with inferior breaks. METHODS: Retrospective review of 78 consecutive eyes from 78 patients undergoing primary vitrectomy with a minimum of 3-month follow-up. Thirty patients underwent 25-gauge PPV and 48 patients underwent 20-gauge PPV from May 1993 to July 2008. Variables and outcome measures included patient demographics, retinal reattachment, best-corrected visual acuity, macular status, postoperative intraocular pressures, and surgical complications. RESULTS: Preoperative characteristics were similar in both groups. Single operation success rate was 25/30 (83.3%) for 25-gauge cases and 43/48 (89.6%) for 20-gauge cases (P = 0.50). Transient hypotony occurred in 6/30 25-gauge eyes and 1/48 20 gauge eyes (P = 0.01), whereas hypertension occurred in 10/30 25-gauge cases and 15/48 20-gauge cases. All but 2 eyes were attached at final follow-up (97%). At final follow-up, mean best-corrected visual acuity was 0.28 and 0.32 for the 25 gauge and 20-gauge groups (P = 0.74). CONCLUSION: Outcomes of 20-gauge versus 25 gauge PPV for the management of pseudophakic inferior rhegmatogenous retinal detachments were not significantly different, with hypotony being the most significant postoperative complication in the 25-gauge group as compared with the 20-gauge group. PMID- 20838362 TI - Longitudinal predictors of human papillomavirus vaccine initiation among adolescent girls in a high-risk geographic area. AB - BACKGROUND: Human papillomavirus (HPV) vaccine uptake is low among adolescent girls in the United States. We sought to identify longitudinal predictors of HPV vaccine initiation in populations at elevated risk for cervical cancer. METHODS: We interviewed a population-based sample of parents of 10- to 18-year-old girls in areas of North Carolina with elevated cervical cancer rates. Baseline interviews occurred in summer 2007 and follow-up interviews in fall 2008. Measures included health belief model constructs. RESULTS: Parents reported that 27% (149/567) of their daughters had initiated HPV vaccine between baseline and follow-up. Of parents who at baseline intended to get their daughters the vaccine in the next year, only 38% (126/348) had done so by follow-up. Of parents of daughters who remained unvaccinated at follow-up but had seen a doctor since baseline, only 37% (122/388) received an HPV vaccine recommendation. Rates of HPV vaccine initiation were higher among parents who at baseline perceived lower barriers to getting HPV vaccine, anticipated greater regret if their daughters got HPV because they were unvaccinated, did not report "needing more information" as the main reason they had not already vaccinated, intended to get their daughters the vaccine, or were not born-again Christians. CONCLUSIONS: Missed opportunities to increase HPV vaccine uptake included unrealized parent intentions and absent doctor recommendations. While several health belief model constructs identified in early acceptability studies (e.g., perceived risk, perceived vaccine effectiveness) were not longitudinally associated with HPV vaccine initiation, our findings suggest correlates of uptake (e.g., anticipated regret) that offer novel opportunities for intervention. PMID- 20838363 TI - Epidemiology of herpes simplex virus type 2 infection in rural and urban Burkina Faso. AB - BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection enhances human immunodeficiency virus (HIV) susceptibility and may increase sexual transmission, but few data on HSV-2 prevalence are available from West Africa. The main objective of this study was to describe the prevalence and determinants of HSV-2 among adults in urban and rural Burkina Faso. METHODS: We conducted (i) a 2-stage clustered population-based survey among adults aged 15 to 49 years in Ouagadougou (N = 883 women and 791 men), the capital city of Burkina Faso, and (ii) a cross sectional study among attendees (N = 2018) of all 98 antenatal clinics from 4 provinces of the country. HSV-2 infection was diagnosed using a specific IgG2 enzyme-linked immunosorbent assay test (Kalon). RESULTS: The prevalence of HSV-2 among pregnant women was 18.0% (95% confidence interval (CI): 16.3%-19.7%), with a trend for lower rates in rural (17.3%; CI: 15.5%-19.2%) versus semiurban areas (21.4%; CI: 17.2%-26.2%) (P = 0.08), whereas the prevalence of HSV-2 was 23.7% (CI: 20.9%-26.6%) among women in Ouagadougou (N = 883), and 15.3% (CI: 12.9% 18.0%) among men (N = 791). Using multivariable logistic regression analysis among women, older age, being married, contraceptives, bacterial vaginosis (BV), and HIV infection were significantly associated with HSV-2 infection. Among men, only increased age and HIV were independently associated with HSV-2. CONCLUSION: The prevalence of HSV-2 infection was high among young women, including in rural areas, with a strong association with BV. Therefore, rural areas should not be neglected in prevention programs. New potent BV, hormonal contraceptives, and HSV control strategies may be helpful for HIV control. PMID- 20838365 TI - Nonmedical use of prescription drugs and HIV risk behavior in gay and bisexual men. AB - BACKGROUND: Previous research has demonstrated associations between substance use and sexual risk behavior in men who have sex with men (MSM). Recent trends in substance use show increasing use of prescription medications (e.g., Vicodin) without a physician's prescription, yet associations between the nonmedical use of prescription drugs (NMUPD) and HIV risk behavior have not been well examined in MSM. METHODS: MSM attending a gay pride festival completed a self-report measure assessing NMUPD, motivations for use, use of traditional recreational drugs, and HIV risk behavior. RESULTS: More than one-third of the sample (38%) reported lifetime NMUPD and 17% reported NMUPD in the previous 3 months. The most common class of medications used was prescription analgesics. Men reporting NMUPD also reported higher rates of the use of marijuana, poppers, ecstasy, cocaine, methamphetamine, GHB, ketamine, heroin, and rohypnol, and had significantly higher rates of HIV risk behaviors, including more sexual partners and more unprotected sex. CONCLUSIONS: A significant minority of MSM are using prescription medications without a doctor's consent. Men who do so are risking negative consequences of such use, including the potential for addiction, potentially dangerous interactions between prescription and recreational drugs, and greater risk for contracting HIV. PMID- 20838364 TI - Factors associated with HIV testing history and HIV-test result follow-up among female sex workers in two cities in Yunnan, China. AB - BACKGROUND: The majority of people living with HIV/AIDS in China are unaware of their serostatus, and increasing the utilization of HIV testing may help to control the epidemic. METHODS: This longitudinal study was conducted among female sex workers (FSWs) in 2 cities in Yunnan Province, China. Participants were surveyed in face-to-face interviews and tested for HIV and STDs. Factors associated with HIV-testing history and HIV-test follow-up were analyzed. RESULTS: Of the 1642 study participants, 291 (17.7%) had been previously tested and 868 (52.9%) returned for post-test follow-up. Factors associated with having a previous HIV test included attending the Kaiyuan study (aOR: 4.9, 95% CI: 2.3 10.1), >= 9 years of schooling (aOR: 10.9, 95% CI: 2.6-45.5), <5 clients in the recent week (aOR: 1.7, 95% CI: 1.2-2.3), having a regular sexual partner (aOR: 1.9, 95% CI: 1.4-2.5), illegal drug use history (aOR: 2.2, 95% CI: 1.5-3.1), pelvic pain in the past 12 months (aOR: 1.9, 95% CI: 1.1-3.6), HIV-seropositivity (aOR: 1.8, 95% CI: 1.2-2.8), and high perception of HIV risk (aOR: 1.5, 95% CI: 1.1-2.2). FSWs who had >= 9 years of schooling (aOR: 1.4, 95% CI: 1.1-1.9), had <5 clients in the recent week (aOR: 1.3, 95% CI: 1.1-1.6), or were from another province (aOR: 1.9, 95% CI: 1.4-2.5) or city (aOR: 1.4, 95% CI: 1.1-1.8) were more likely to follow-up. CONCLUSIONS: The low HIV-testing history and follow-up rates found in this is study is a significant public health problem as many high risk individuals are not aware of their serostatus. Immediate action needs to be taken to increase the utilization of HIV testing services and notify people of their HIV status. PMID- 20838366 TI - Gender and age patterns in HSV-2 and HIV infection among non-injecting drug users in New York City. AB - OBJECTIVE: To examine prevalence of and associations between herpes simplex virus type 2 (HSV-2) infection and HIV infection among never-injecting heroin and cocaine drug users (NIDUs) in New York City. METHODS: Subjects were recruited from patients entering the Beth Israel drug detoxification program. Informed consent was obtained, a structured questionnaire including demographics, drug use history, and sexual risk behavior was administered, and a blood sample was collected for HIV and HSV-2 antibody testing. RESULTS: A total of 1418 subjects who had never (lifetime) injected drugs (NIDUs) were recruited between July 2005 through June 2009. Subjects were primarily male (76%), and black (67%) or Hispanic (25%), reported recent crack cocaine use (74%), and had a mean age of 42 years. Eleven percent of males reported male-with-male sexual (MSM) behavior. The prevalence of both viruses was high: for HSV-2, 61% among the total sample, 50% among non-MSM males, 85% among females, and 72% among MSM; for HIV, 16% among the total sample, 12% among non-MSM males, 20% among females, and 46% among MSM. HSV 2 was associated with HIV (OR = 3.2, 95% CI: 2.3-4.5; PR = 2.7, 95% CI: 2.0-3.7). Analyses by gender and age groups indicated different patterns in mono- and coinfection for the 2 viruses. DISCUSSION: HSV-2 and HIV rates among these NIDUs are comparable with rates in sub-Saharan Africa. Additional prevention programs, tailored to gender and age groups, are urgently needed. New platforms for providing services to NIDUs are also needed. PMID- 20838367 TI - Assessing the outcomes of spine surgery using global positioning systems. AB - STUDY DESIGN: Pilot study. OBJECTIVE: To examine whether surgical outcomes can be assessed objectively by advanced tracking technology, based on Global Positioning Systems (GPS). SUMMARY OF BACKGROUND DATA: Outcome studies are the commonest way to assess the results of surgical procedures. The success of these efforts is impeded by a number of factors, including the lack of valid outcome measures, difficulty in assessing changes in patients' expectations (response shift) and confounding effects of secondary gains. METHODS: The measurement of walking speed, distances, and number of walking events per day, claudication index (maximal walking distance), characteristics during motorized trips, and the amount of time spent outdoors were monitored in 2 patients undergoing spine surgery for several weeks using advanced tracking technologies. RESULTS: In 1 patient, all parameters increased progressively from the time of surgery to the end of the recording period. These findings were consistent with her recovery from surgery. In a second patient, tracking showed the patient's difficulty in mobilizing, leading to the diagnosis of another orthopedic problem, and to total hip replacement surgery. CONCLUSION: The technology presented in this pilot appears to be useful in understanding a patient's level and breathe of activity. These data will assist in better understanding the limitations imposed by specific musculoskeletal pathology and in monitoring perioperative function and complications and their related causes. Spatial data may indirectly reflect a patient's social and mental conditions. This interdisciplinary pilot may lead to the development of valid outcome measures for a range of medical conditions. Studies comparing questionnaires to this new outcome measure may shed light on issues like response shifts and secondary gain. Norms and clusters of spatial behaviors in different pathologies may enable better patient selection for medical, mental, and surgical interventions. PMID- 20838368 TI - Spondylolysis and spondylolisthesis: prevalence of different forms of instability and clinical implications. AB - STUDY DESIGN: Imaging study with an evaluation of incidences and clinical correlation. OBJECTIVE: To evaluate the incidence of 3 different types of instabilities in patients with spondylolysis or isthmic spondylolisthesis. Clinical findings are correlated with imaging findings, and the imaging findings are analyzed with regard to their clinical implications. SUMMARY OF BACKGROUND DATA: Spondylolysis and isthmic spondylolisthesis are common disorders. An unstable slip is the most well-known form of instability, but other forms also exist. However, the incidence of these instabilities and their clinical implications are yet unclear. METHODS: A total of 140 patients with 141 levels of spondylolysis identified by MRI (magnetic resonance imaging) were included in this study. Using positional MRI, the instability of the slip, an increased angular movement, and movement in the spondylolytic cleft were assessed. On the basis of clinical findings, the patients were classified as presenting with either radicular or nonradicular symptoms. The incidence of the instabilities was recorded and correlated with the incidence of radicular symptoms. RESULTS: Fifteen patients had an unstable slip (anterior instability); 35, an increased angular movement (angular instability); and 34 patients, a movement in the spondylolytic cleft (posterior instability). All forms of instability could be found together. No instability at all was found in 76 patients. Radicular symptoms were found significantly more often in patients with one or more of the described instabilities compared with patients without instability. CONCLUSION: All 3 described forms of instability are common in spondylolysis or isthmic spondylolisthesis and associated with radicular pain. This finding stresses the value of positional MRI in the evaluation of patients with spondylolysis and isthmic spondylolisthesis, especially if radicular symptoms are present. PMID- 20838369 TI - Complications with recombinant human bone morphogenic protein-2 in posterolateral spine fusion: a consecutive series of 1037 cases. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: The purpose of this study was to report on a large consecutive series of posterolateral fusion cases using rhBMP-2/ACS. SUMMARY OF BACKGROUND DATA: Despite evidence that rhBMP-2/ACS is effective as an iliac crest graft substitute in posterolateral fusion, concerns remain regarding potential risk for BMP use in clinical practice. These concerns have been fueled by the serious complications reported with BMP in anterior cervical spine fusion. While none of the literature on posterolateral fusion with rhBMP-2/ACS has suggested an increased complication rate versus iliac crest bone graft, this issue has not been specifically studied. METHODS: We reviewed medical records for a consecutive series of 1037 patients who underwent posterolateral spine fusion using rhBMP-2 between 2003 and 2006. Medical complications were attributed to the surgical procedure if they occurred within the 3-month perioperative period, whereas complications potentially related to BMP were included regardless of time frame. RESULTS: Medical and surgical complications were observed in 190 of 1037 patients (18.3%) with 81 major complications (7.8%) and 110 minor complications (10.2%). Neurologic complications were related to screw malposition in 6 patients and epidural hematoma in 3 patients. New or more severe postoperative radicular symptoms were noted in 7 patients (0.7%). Psoas hematoma was identified by CT scan in 8 patients (0.8%). Complications directly related to rhBMP-2 were observed in at least 1 patient (0.1%) and in a worst case analysis, in as many as 6 patients (0.6%). CONCLUSION: This study in 1037 patients confirms the relative safety of rhBMP-2/ACS for posterolateral spine fusion. There were extremely few complications directly attributed to rhBMP 2/ACS, and the overall complication rates were consistent with established norms. The stark contrast between this experience and the markedly elevated complication rate reported with anterior cervical BMP usage emphasizes the need to evaluate risks and benefits of bioactive technologies in a site-specific and procedure specific manner. PMID- 20838370 TI - Postlaminectomy osteopontin expression and associated neurophysiological findings in rat peridural scar model. PMID- 20838371 TI - Surgical versus nonsurgical treatment of selected patients with discogenic low back pain: a small-sized randomized trial. PMID- 20838372 TI - Beta blocker infusion decreases the magnitude of core hypothermia after anesthesia induction. AB - BACKGROUND: Beta-1-receptor blockade reduces heart rate, cardiac output, and arterial pressure while increasing peripheral vascular resistance. It is possible that beta blockers not only inhibit the core-to-peripheral re-distribution of body heat and cutaneous heat loss due to vasodilation after anesthesia induction but also reduce the convective transfer of heat from the core to peripheral tissues by decreasing cardiac output. The authors investigated whether the co administration of esmolol or landiolol, ultra-short-acting beta blockers, attenuates the magnitude of initial re-distribution hypothermia after anesthesia induction and tracheal intubation. METHODS: Immediately prior to the induction of anesthesia, patients were randomly assigned to receive 0.2 mg kg-1 of landiolol (landiolol group; N=30), 1 mg kg-1 of esmolol (esmolol group; N=30), or 0.1 mL kg 1 of saline (control group; N=30). Heart rate, blood pressure, cardiac output, and tympanic, forearm, and digit temperatures were recorded. Forearm minus fingertip skin-surface temperature gradients (temperature gradient) were calculated. RESULTS: Tympanic membrane temperatures 15 to 60 min after the induction of anesthesia were significantly higher in the esmolol group than in the control group although the temperature gradient was similar among the three groups. Both esmolol and landiolol inhibited the increase in HR and MAP after the induction of anesthesia and tracheal intubation. The cardiac index in the esmolol group was significantly lower than in the control group. The degree of hemodynamic attenuation after induction by esmolol was larger than that of landiolol. CONCLUSION: The co-administration of esmolol, but not landiolol, attenuated the magnitude of initial re-distribution hypothermia after anesthesia induction and tracheal intubation. Esmolol likely prevented initial hypothermia because it attenuated the convective transfer of heat from the core to peripheral tissues by decreasing cardiac output. PMID- 20838373 TI - Paresis of cranial nerve VI (N. abducens) after thoracic dural perforation. AB - Epidural anesthesia is associated with the risk of unintended dural perforation and concomitant leakage of cerebrospinal fluid (CSF) from the subarachnoidal space. This may remain asymptomatic or trigger post-dural puncture headache (PDPH). Cerebral nerve lesions after attempted epidural anesthesia are very rare. Here we report a case of unilateral paresis of the cranial nerve VI (N. abducens) after attempted thoracic epidural anesthesia. Herein, diagnosis of N. abducens paresis was probably delayed because the optical symptoms, such as blurred and double vision, were attributed to optical hallucinations caused by a concomitant (S)-ketamine infusion. In all patients with optical symptoms such as blurred or double vision a paresis of the abducens nerve should be considered. PMID- 20838374 TI - Effect of oxygenation of transperitoneal ventilation on the death time after asphyxiation in rabbits. AB - BACKGROUND: To observe the effects of transperitoneal ventilation on death time in asphyxiated rabbits. METHODS: Twenty-four adult rabbits were randomly divided in three groups (N=8, each): control group (no transperitoneal ventilation), air group (transperitoneal ventilation with air) and oxygen group (transperitoneal ventilation with oxygen). All animals were anesthetized with pentobarbital (3%, 30 mg/kg) given via intramuscular injection. Autonomous breathing was maintained. Each rabbit's peritoneal cavity was punctured with two catheters, one of which was placed in the left lower abdomen and served as the inlet for gas; the other was placed in the right upper abdomen and served as the outlet for gas. Asphyxia was induced by clamping the rabbit's trachea; transperitoneal ventilation was then administered in the air group and the oxygen group. Rabbits' death times were recorded and their heart rate, blood pressure, PaO2, and PaCO2 were monitored and analyzed before asphyxia and every minute after asphyxia. RESULTS: All animals died successively after asphyxia. The death time in the oxygen group was significantly longer than in the control group and the air group, with no significant difference between the control group and the air group. PaO2 of all three groups declined significantly and the levels of PaO2 within 1-4 minutes after asphyxia in the oxygen group were higher than in the other two groups. PaCO2 increased significantly in all groups with no significant difference among three groups within 1-3 minutes after asphyxia. The increase of PaCO2 at the fourth minute in the oxygen group was reduced in comparison to that observed in other groups. CONCLUSION: These results suggest that transperitoneal ventilation can markedly prolong the death time of asphyxiated rabbits. PMID- 20838375 TI - The lymphovascular embolus of inflammatory breast cancer exhibits a Notch 3 addiction. AB - Inflammatory breast carcinoma (IBC) is characterized by exaggerated lymphovascular invasion (LVI), recapitulated in our human xenograft, MARY-X. This model exhibited lymphovascular emboli in vivo and corresponding spheroids in vitro. Owing to the morphological and gene profile resemblance of these spheroids to embryonal blastocysts, we wondered whether they might exhibit embryonic stem cell signaling. Specifically we investigated Notch and observed selective Notch 3 activation by expression profiling, reverse transcriptase- and real-time PCR, western blot and immunofluorescence in vitro, and immunohistochemistry in vivo. Notch 3 intracellular domain (N3icd) and six target genes, HES-5, HEY-1, c-Myc, Deltex-1, NRARP and PBX1, markedly increased in MARY-X. In addition, a significant percentage of MARY-X cells expressed aldehyde dehydrogenase (ALDH), a stem cell marker. Only the ALDH(+) cells were capable of secondary spheroidgenesis, tumorigenicity and self-renewal. Inhibiting Notch 3 activation in vitro with gamma-secretase inhibitors (GSIs) or small interfering RNA resulted in a downregulation of Notch target genes, including CD133, and an induction of caspase 3-mediated apoptosis. Transfection of N3icd but not Notch 1 intracellular domain into normal human mammary epithelial cells resulted in increased expression of Notch target genes and induction of spheroidgenesis. GSI in vivo resulted in inhibitory but diffusion-limited effects on Notch 3 signaling, resulting in xenograft growth reduction. The lymphovascular emboli of human IBC exhibited dual N3icd and ALDH1 immunoreactivities independently of molecular subtype. This Notch 3 addiction of lymphovascular emboli might be exploited in future therapeutic strategies. PMID- 20838376 TI - BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients. AB - Tumor necrosis factor-related apoptosis-inducing ligand-TNFSF10 (TRAIL), a member of the TNF-alpha family and a death receptor ligand, was shown to selectively kill tumor cells. Not surprisingly, TRAIL is downregulated in a variety of tumor cells, including BCR-ABL-positive leukemia. Although we know much about the molecular basis of TRAIL-mediated cell killing, the mechanism responsible for TRAIL inhibition in tumors remains elusive because (a) TRAIL can be regulated by retinoic acid (RA); (b) the tumor antigen preferentially expressed antigen of melanoma (PRAME) was shown to inhibit transcription of RA receptor target genes through the polycomb protein, enhancer of zeste homolog 2 (EZH2); and (c) we have found that TRAIL is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients. Thus, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is upregulated in BCR-ABL cells and is associated with the progression of disease in CML patients. There is a positive correlation between PRAME and BCR ABL and an inverse correlation between PRAME and TRAIL in these patients. Importantly, knocking down PRAME or EZH2 by RNA interference in a BCR-ABL positive cell line restores TRAIL expression. Moreover, there is an enrichment of EZH2 binding on the promoter region of TRAIL in a CML cell line. This binding is lost after PRAME knockdown. Finally, knocking down PRAME or EZH2, and consequently induction of TRAIL expression, enhances Imatinib sensibility. Taken together, our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML. PMID- 20838377 TI - Guanine nucleotides regulate sphingosine kinase 1 activation by eukaryotic elongation factor 1A and provide a mechanism for eEF1A-associated oncogenesis. AB - Sphingosine kinase 1 (SK1) catalyses the formation of bioactive phospholipid sphingosine 1-phosphate (S1P). Elevated cellular SK1 activity and S1P levels enhance cell proliferation and survival, and are strongly implicated in tumourigenesis. Regulation of SK1 activity can occur through various mechanisms, including phosphorylation and protein-protein interactions. We have previously shown that eukaryotic elongation factor 1A (eEF1A) interacts with and directly activates SK1, but the mechanisms regulating this were undefined. Notably, eEF1A has GTPase activity and can exist in GTP- or GDP-bound forms, which are associated with distinct structural conformations of the protein. Here, we show that the guanine nucleotide-bound state of eEF1A regulates its ability to activate SK1, with eEF1A.GDP, but not eEF1A.GTP, enhancing SK1 activity in vitro. Furthermore, we show that enhancing cellular eEF1A.GDP levels through expression of a guanine nucleotide dissociation inhibitor of eEF1A, translationally controlled tumour protein (TCTP), increased SK1 activity in cells. We also examined a truncated isoform of eEF1A1, termed prostate tumour inducer-1 (PTI-1), which can induce neoplastic cell transformation through undefined mechanisms. PTI 1 lacks the G protein domain of eEF1A1 and is therefore unable to undergo the GTP binding-induced conformational change. Notably, we found that PTI-1 can directly activate SK1 and that this seems to be essential for neoplastic transformation induced by PTI-1, as chemical SK1 inhibitors or overexpression of a dominant negative SK1 blocked this process. Thus, this study defines the mechanism regulating eEF1A-mediated SK1 activation, and also establishes SK1 as being integral for PTI-1-induced oncogenesis. PMID- 20838378 TI - The putative cannabinoid receptor GPR55 defines a novel autocrine loop in cancer cell proliferation. AB - Recently, the orphan receptor G protein-coupled receptor 55 (GPR55) has been proposed as a potential cannabinoid receptor, although controversy remains on its physiological roles. Current evidence suggests a role for GPR55 as a receptor for the lysophospholipid lysophosphatidylinositol (LPI). In this study, we show that GPR55 is expressed in several prostate and ovarian cancer cell lines, both at the mRNA and at the protein level, and that it has a critical role in regulating proliferation and anchorage-independent growth. We further show that GPR55 mediates the effects of LPI in prostate and ovarian cancer cells. Indeed we demonstrate that LPI is able to induce calcium mobilization and activation of Akt and extracellular signal-regulated kinase (ERK)1/2 in these cells and that both pharmacological blockade of GPR55 and its downregulation using specific small interfering RNA strongly inhibits these processes. We further identify an autocrine loop by which LPI is synthesized by cytosolic phospholipase A2, pumped out of the cell by the ATP-binding cassette transporter ABCC1/MRP1, and is then able to initialize cascades downstream of GPR55. All together, these data demonstrate a role of LPI and its receptor GPR55 in cancer cells in activating an autocrine loop that regulates cell proliferation. These findings may have important implications for LPI as a novel cancer biomarker and for its receptor GPR55 as a potential therapeutic target. PMID- 20838379 TI - eIF3m expression influences the regulation of tumorigenesis-related genes in human colon cancer. AB - Abnormal regulation of gene expression is essential for tumorigenesis. Recent studies indicate that regulation of oncogene expression and neoplastic transformation are controlled by subunits of eukaryotic translation initiation factors (eIFs). Here we focused on eIF3 performing a pivotal role in protein synthesis and the differential expression of its subunits in cancer. The most uncharacterized non-core subunit eIF3m was confirmed to be highly expressed in human cancer cell lines and colon cancer patient tissues. By expression silencing with eIF3m-specific small interfering RNA (siRNA), we confirmed that eIF3m influences cell proliferation, cell cycle progression and cell death in human colon cancer cell line HCT-116. Using a ribonomics approach, we identified a subset of elF3m-influenced genes and showed that the expression of two highly represented tumorigenesis-related genes, MIF and MT2, were affected by eIF3m at the mRNA level. We also confirmed eIF3m-dependent regulation of MT2A downstream molecule CDC25A, which is necessary for cell cycle progression in HCT-116 cells. These results suggest that eIF3m mediates regulation of tumorigenesis-related genes in human colon cancer. Further investigations on tumorigenesis-related genes and their regulation by eIFs will provide clues for designing targeted therapy for cancer. PMID- 20838380 TI - Serine/threonine phosphatases in the DNA damage response and cancer. AB - The cellular response to DNA damage is a crucial surveillance mechanism that maintains genomic integrity and prevents cancer progression. Previous studies identified multiple Ser/Thr protein kinases that have pivotal roles in the activation of this response. It is interesting that a growing body of evidence suggests that these kinases and their substrates are under tight modulation by numerous Ser/Thr phosphatases. In this study, we review recent reports that reveal new functions and regulation of these phosphatases. Similar to the kinases in this pathway, phosphatases may also be intimately involved in cancer progression and present valuable targets for cancer therapy. PMID- 20838381 TI - The p16(INK4A) tumor suppressor regulates cellular oxidative stress. AB - Mutations or deletions in the cyclin-dependent kinase inhibitor p16(INK4A) are associated with multiple cancer types, but are more commonly found in melanoma tumors and associated with familial melanoma predisposition. Although p16 is thought to function as a tumor suppressor by negatively regulating the cell cycle, it remains unclear why the genetic compromise of p16 predisposes to melanoma over other cancers. Here we describe a novel role for p16 in regulating oxidative stress in several cell types, including melanocytes. Expression of p16 was rapidly upregulated following ultraviolet-irradiation and in response to H2O2 induced oxidative stress in a p38 stress-activated protein kinase-dependent manner. Knockdown of p16 using small interfering RNA increased intracellular reactive oxygen species (ROS) and oxidative (8-oxoguanine) DNA damage, which was further enhanced by H2O2 treatment. Elevated ROS levels were also observed in p16 depleted human keratinocytes and in whole skin and dermal fibroblasts from Cdkn2a deficient mice. Aberrant ROS and p38 signaling in Cdkn2a-deficient fibroblasts was normalized by expression of exogenous p16. The effect of p16 depletion on ROS was not recapitulated by the knockdown of retinoblastoma protein (Rb) and did not require Rb. Finally, p16-mediated suppression of ROS could not be attributed to the potential effects of p16 on cell cycle phase. These findings suggest a potential alternate Rb-independent tumor-suppressor function of p16 as an endogenous regulator of carcinogenic intracellular oxidative stress. Compared with keratinocytes and fibroblasts, we also found increased susceptibility of melanocytes to oxidative stress in the context of p16 depletion, which may explain why the compromise of p16 predisposes to melanoma over other cancers. PMID- 20838382 TI - Molecular determinants of PDLIM2 in suppressing HTLV-I Tax-mediated tumorigenesis. AB - Human T-cell leukemia virus type I (HTLV-I) encodes a Tax oncoprotein that has crucial roles in both virus replication and cell transformation. Our recent studies suggest that the counterbalance between HTLV-I/Tax and PDZ-LIM domain containing protein PDLIM2 may determine the outcome of HTLV-I infection. Although HTLV-I represses PDLIM2 epigenetically and specifically in transformed cells, PDLIM2 shuttles Tax into the nuclear matrix for ubiquitination-mediated proteasomal degradation, thereby suppressing the transforming ability of HTLV-I. Here, we have further shown that PDLIM2 binds to Tax directly, which was mediated by a putative alpha-helix motif of PDLIM2 at amino acids 236-254. Consistently, selective disruption of this short-helix crippled PDLIM2 in shutting Tax to the nuclear matrix for ubiquitination-mediated degradation, therefore, PDLIM2 lost the ability in tumor suppression. Although the C-terminal LIM domain of PDLIM2 was not required for Tax binding, it was important for PDLIM2 to interact with the nuclear matrix. Accordingly, the LIM domain was essential for PDLIM2-mediated Tax repression. On the contrary, the N-terminal PDZ domain of PDLIM2 was dispensable for all these events, although the PDZ domain was involved in PDLIM2 binding to cytoskeleton. These studies dissect functional sequences within PDLIM2 and their distinct roles in Tax regulation. PMID- 20838383 TI - A critical role of integrin-linked kinase, ch-TOG and TACC3 in centrosome clustering in cancer cells. AB - Many cancer cells contain more than two centrosomes, which imposes a potential for multipolar mitoses, leading to cell death. To circumvent this, cancer cells develop mechanisms to cluster supernumerary centrosomes to form bipolar spindles, enabling successful mitosis. Disruption of centrosome clustering thus provides a selective means of killing supernumerary centrosome-harboring cancer cells. Although the mechanisms of centrosome clustering are poorly understood, recent genetic analyses have identified requirements for both actin and tubulin regulating proteins. In this study, we demonstrate that the integrin-linked kinase (ILK), a protein critically involved in actin and mitotic microtubule organization, is required for centrosome clustering. Inhibition of ILK expression or activity inhibits centrosome clustering in several breast and prostate cancer cell lines that have centrosome amplification. Furthermore, cancer cells with supernumerary centrosomes are significantly more sensitive to ILK inhibition than cells with two centrosomes, demonstrating that inhibiting ILK offers a selective means of targeting cancer cells. Live cell analysis shows ILK perturbation leads cancer cells to undergo multipolar anaphases, mitotic arrest and cell death in mitosis. We also show that ILK performs its centrosome clustering activity in a focal adhesion-independent, but centrosome-dependent, manner through the microtubule regulating proteins TACC3 and ch-TOG. In addition, we identify a specific TACC3 phosphorylation site that is required for centrosome clustering and demonstrate that ILK regulates this phosphorylation in an Aurora-A-dependent manner. PMID- 20838385 TI - An inactivating CYLD mutation promotes skin tumor progression by conferring enhanced proliferative, survival and angiogenic properties to epidermal cancer cells. AB - In this study, we demonstrate that the expression in tumorigenic epidermal cells of a catalytically inactive form of CYLD (CYLD(C/S)) that mimics the identified mutations of cyld in human tumors and competes with the endogenous CYLD results in enhanced cell proliferation and inhibition of apoptosis; it also stimulates cell migration and induces the expression of angiogenic factors, including vascular endothelial growth factor-A. Altogether, these characteristics indicate an increased oncogenicity of the tumorigenic epidermal CYLD(C/S) mutant cells in vitro. Moreover, we show the increase in malignancy of epidermal squamous cell carcinomas that express the CYLD(C/S) transgene in an in vivo xenograft model. Tumors carrying the mutated CYLD(C/S) exhibit a fast growth, are poorly differentiated and present a robust angiogenesis. CYLD(C/S) tumors are also characterized by their elevated proliferation rate and decreased apoptosis. In contrast with previous studies showing the development of benign tumors by mutations in the CYLD gene, here we provide evidence that the occurrence of mutations in the CYLD gene in tumorigenic epidermal cells (carrying previous mutations) increases the aggressiveness of carcinomas, mainly through enhancement of the expression of angiogenic factors, having therefore a key role in epidermal cancer malignancy. PMID- 20838384 TI - Suppression of Her2/neu expression through ILK inhibition is regulated by a pathway involving TWIST and YB-1. AB - In a previous study it was found that the therapeutic effects of QLT0267, a small molecule inhibitor of integrin-linked kinase (ILK), were influenced by Her2/neu expression. To understand how inhibition or silencing of ILK influences Her2/neu expression, Her2/neu signaling was evaluated in six Her2/neu-positive breast cancer cell lines (LCC6(Her2), MCF7(Her2), SKBR3, BT474, JIMT-1 and KPL-4). Treatment with QLT0267 engendered suppression (32-87%) of total Her2/neu protein in these cells. Suppression of Her2/neu was also observed following small interfering RNA-mediated silencing of ILK expression. Time course studies suggest that ILK inhibition or silencing caused transient decreases in P-AKT(ser473), which were not temporally related to Her2/neu downregulation. Attenuation of ILK activity or expression was, however, associated with decreases in YB-1 (Y-box binding protein-1) protein and transcript levels. YB-1 is a known transcriptional regulator of Her2/neu expression, and in this study it is demonstrated that inhibition of ILK activity using QLT0267 decreased YB-1 promoter activity by 50.6%. ILK inhibition was associated with changes in YB-1 localization, as reflected by localization of cytoplasmic YB-1 into stress granules. ILK inhibition also suppressed TWIST (a regulator of YB-1 expression) protein expression. To confirm the role of ILK on YB-1 and TWIST, cells were engineered to overexpress ILK. This was associated with a fourfold increase in the level of YB-1 in the nucleus, and a 2- and 1.5-fold increase in TWIST and Her2/neu protein levels, respectively. Taken together, these data indicate that ILK regulates the expression of Her2/neu through TWIST and YB-1, lending support to the use of ILK inhibitors in the treatment of aggressive Her2/neu-positive tumors. PMID- 20838386 TI - Preemptive therapy of human herpesvirus-6 encephalitis with foscarnet sodium for high-risk patients after hematopoietic SCT. AB - Human herpesvirus-6 (HHV-6) is a major cause of limbic encephalitis with a dismal prognosis after allogeneic hematopoietic SCT (HSCT). A prospective, multicenter study was conducted to assess the safety and efficacy of preemptive therapy with foscarnet sodium (PFA) for the prevention of HHV-6 encephalitis. Plasma HHV-6 DNA was measured thrice weekly from day 7 until day 36 after umbilical cord blood transplantation (UCBT) or HSCT from HLA-haploidentical relatives. PFA, 90 mg/kg/day, was started when HHV-6 DNA exceeded 5 * 10(2) copies/mL. Mild and transient adverse events were associated with PFA in 7 of 8 patients. Twelve of 15 UCBT recipients became positive for HHV-6 DNAemia, defined by greater than 1 * 10(2) copies/mL of HHV-6 DNA in plasma. The virus exceeded 5 * 10(2) copies/mL in seven patients, whereas none of the five HLA-haploidentical HSCT recipients became positive. One patient developed mild limbic encephalitis just after initial PFA administration. Preemptive PFA therapy is safe, but as HHV-6 DNAemia can abruptly develop before neutrophil engraftment in UCBT recipients, prophylactic PFA administration from day 7 or earlier after UCBT may be needed. PMID- 20838387 TI - The NK-1 receptor-antagonist aprepitant in high-dose chemotherapy (high-dose melphalan and high-dose T-ICE: paclitaxel, ifosfamide, carboplatin, etoposide): efficacy and safety of a triple antiemetic combination. AB - Complete protection from nausea/vomiting is currently achieved in a minority of patients receiving high-dose chemotherapy (HDC). Currently the use of 5-HT3 antagonists and dexamethasone (DEX) represents the standard of care. The role of the NK-1-antagonist aprepitant in HDC remains to be better defined. A total of 64 patients undergoing multiple days of HDC received granisetron, DEX plus aprepitant during chemotherapy. After the end of chemotherapy aprepitant plus DEX was given for a further 2 days. Primary end point was CR defined as no vomiting and no use of rescue medication in the overall phase (day 1 until 5 days after end of chemotherapy). Acute/delayed and overall CR were achieved in 83%/70% and 63%, respectively. Acute and delayed nausea were observed in 20 and 38% of the patients. The tolerability of the aprepitant regimen over 4-5 days was comparable with the 3-day antiemetic regimen. In our study, aprepitant demonstrated good tolerability. Taking into account the methodological constraints of comparing our results with those from the available literature, the addition of aprepitant to the antiemetic treatment regimen may provide improved prevention of chemotherapy induced nausea and vomiting during HDC. PMID- 20838388 TI - Donor-cell MDS in a 12-year-old girl 3 years after allogeneic hematopoietic SCT for MDS, both with a t(3;3)(q21;q26) cytogenetic aberration. PMID- 20838389 TI - Nontyphoidal Salmonella infection among recipients of hematopoietic SCT. AB - The incidence of nontyphoidal Salmonella (NTS) infections is rising worldwide and several outbreaks have been reported recently. Immunosuppressed patients are particularly vulnerable to NTS infections. We retrospectively examined the clinical features and outcomes of 18 recipients of hematopoietic SCT (HSCT) who were diagnosed with NTS infection at our institution during a 15-year period. Bacteremia was the most common presenting feature and occurred in 67% of cases. Diarrhea was absent in one-third of cases. Among 12 recipients of allogeneic HSCT, 8 presented with bacteremia and only 6 had diarrhea. A total of 9 of these 12 patients had chronic GVHD. Metastatic disease was distinctly rare and occurred in only two patients, whereas one patient died of NTS sepsis. Food safety practices to prevent NTS infection are important in HSCT recipients, particularly for those who have chronic GVHD after allogeneic HSCT. PMID- 20838390 TI - Post-transplantation cyclophosphamide for GVHD prophylaxis in severe aplastic anemia. PMID- 20838391 TI - Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence. AB - The 5-HT3 receptor is rapidly potentiated by ethanol and mediates fast excitatory serotonin (5-HT) transmission that modulates dopamine release in the reward circuitry. The 5-HT transporter regulates synaptic 5-HT availability. Functional polymorphisms in genes encoding the transporter and receptor may therefore influence addiction vulnerability. In this study, 360 treatment-seeking African American male patients with single and comorbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4) and 16 haplotype-tagging single-nucleotide polymorphisms (SNPs) across HTR3B (including the functional rs1176744 Tyr129Ser) and HTR3A, genes encoding 5-HT3 receptors. The HTR3B rs1176744 gain-of-function Ser129 allele predicted alcohol dependence (P=0.002) and low 5-HTTLPR activity predicted cocaine/heroin dependence (P=0.01). Both the HTR3B Ser129 allele (P=0.014, odds ratio (OR)=1.7 (1.1-2.6)) and low 5-HTTLPR activity (P=0.011, OR=2.5 (1.3-4.6)) were more common in men with alcohol+drug dependence compared with controls. Moreover, the HTR3B Ser129 allele and low 5-HTTLPR activity had an additive (but not an interactive) effect on alcohol+drug dependence (OR=6.0 (2.1 16.6)) that accounted for 13% of the variance. One possible explanation of our findings is that increased synaptic 5-HT coupled with increased 5-HT3 receptor responsiveness may result in enhanced dopamine transmission in the reward pathway, a predictor of increased risk for addiction. Our results may have pharmacogenetic implications for 5-HT3 therapeutic antagonists such as ondansetron. PMID- 20838393 TI - The psychiatric disease risk factors DISC1 and TNIK interact to regulate synapse composition and function. AB - Disrupted in schizophrenia 1 (DISC1), a genetic risk factor for multiple serious psychiatric diseases including schizophrenia, bipolar disorder and autism, is a key regulator of multiple neuronal functions linked to both normal development and disease processes. As these diseases are thought to share a common deficit in synaptic function and architecture, we have analyzed the role of DISC1 using an approach that focuses on understanding the protein-protein interactions of DISC1 specifically at synapses. We identify the Traf2 and Nck-interacting kinase (TNIK), an emerging risk factor itself for disease, as a key synaptic partner for DISC1, and provide evidence that the DISC1-TNIK interaction regulates synaptic composition and activity by stabilizing the levels of key postsynaptic density proteins. Understanding the novel DISC1-TNIK interaction is likely to provide insights into the etiology and underlying synaptic deficits found in major psychiatric diseases. PMID- 20838399 TI - Role of the evolutionarily conserved starvation response in anorexia nervosa. AB - This review will summarize recent findings concerning the biological regulation of starvation as it relates to anorexia nervosa (AN), a serious eating disorder that mainly affects female adolescents and young adults. AN is generally viewed as a psychosomatic disorder mediated by obsessive concerns about weight, perfectionism and an overwhelming desire to be thin. By contrast, the thesis that will be developed here is that, AN is primarily a metabolic disorder caused by defective regulation of the starvation response, which leads to ambivalence towards food, decreased food consumption and characteristic psychopathology. We will trace the starvation response from yeast to man and describe the central role of insulin (and insulin-like growth factor-1 (IGF-1))/Akt/ F-box transcription factor (FOXO) signaling in this response. Akt is a serine/threonine kinase downstream of the insulin and IGF-1 receptors, whereas FOXO refers to the subfamily of Forkhead box O transcription factors, which are regulated by Akt. We will also discuss how initial bouts of caloric restriction may alter the production of neurotransmitters that regulate appetite and food-seeking behavior and thus, set in motion a vicious cycle. Finally, an integrated approach to treatment will be outlined that addresses the biological aspects of AN. PMID- 20838400 TI - Are endocannabinoid type 1 receptor gene (CNR1) polymorphisms associated with obesity and metabolic syndrome in postmenopausal Polish women? AB - OBJECTIVE: The aim of this study was to determine whether genetic variation at the cannabinoid receptor-1 (CNR1) locus could have an effect on adiposity, fat distribution and obesity-related metabolic disorders in Polish postmenopausal women. DESIGN AND SUBJECTS: The A3813G (rs12720071), G1422A (rs1049353), A4895G (rs806368) and rs806381, rs10485170, rs6454674 and rs2023239 single-nucleotide polymorphisms of CNR1 were genotyped in 348 randomly selected postmenopausal women aged 50-60 years recruited from the Wroclaw city population. MEASUREMENTS: CNR1 genotypes, anthropometric measures (body mass index (BMI), waist circumference (WC) and body fat distribution by dual energy X-ray absorptiometry) and metabolic parameters (glucose, lipid profile and Fasting Insulin Resistance Index for insulin resistance) were determined. RESULTS: The 3813G allele was not significantly associated with higher body mass, BMI, WC, total fat or fat percentage, but was associated with higher android fat deposit (2971.78+/-1655.08 vs 2472.64+/-1300.53, P=0.007) and percentage of android fat (37.59+/-8.45 vs 35.66+/-7.63, P=0.062). No associations for the G1422A, A4895G, rs806381, rs10485170, rs6454674 and rs2023239 variants were observed. CONCLUSIONS: There is an association of the variants of CNR1 with obesity-related phenotypes in Polish postmenopausal women. As cannabinoid receptor type 1 is a drug target for obesity, pharmacogenetic receptor gene analysis of obesity treatment by endocannabinoid blockade may be of interest to identify the best responders. PMID- 20838401 TI - Nonalcoholic fatty liver disease: a challenge for pediatricians. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of pediatric liver disease. Its prevalence is related to the growing epidemic in childhood obesity during the past decades. At present, NAFLD and nonalcoholic steatohepatitis (NASH) are increasingly recognized worldwide. In spite of alarming trend in the epidemiology in pediatric field and growing risk of end stage liver disease, there is no significant advance in its diagnosis and treatment. AIM: To provide a detailed review for diagnosis and management of NAFLD and NASH. METHODS: By using Pubmed to find review articles and relevant research. RESULTS: The prevalence ranges from at least 3% in children overall to about 50% in obese children. The noninvasive biomarkers can be used to identify NAFLD/NASH patients. Diagnostic criteria based on biochemical and immunological indicators in the high-risk group of children could prevent about half of cases from receiving an invasive test. The pharmacological and surgical interventions have shown a growing role in pediatric NAFLD. Novel treatment modalities, such as probiotics, have hardly been studied. CONCLUSION: Early diagnosis by using noninvasive screening methods in high-risk groups is the most effective strategy against the NAFLD. The biology of early growth and development, including hepatic metabolism, may hold the key to pediatric NAFLD. Prevention of overweight children and childhood obesity is undoubtedly the best strategy for treating NAFLD. PMID- 20838402 TI - Ethics, health care and spinal cord injury: research, practice and finance. AB - Dating back to ancient times, mankind has been absorbed with 'doing the right thing', that is, behaving in ways approved by the society and the culture during the era in which they lived. This has been and still is especially true for the medical and related health-care professions. Laws and professional codes have evolved over the years that provide guidelines as to how physicians should treat patients, beginning with the one authored by Hippocrates. Only more recently, however, have laws and codes been created to cover health-care research and the advances in health-care practice that have been brought to light by that research. Although these discoveries have clearly impacted the quality of life and duration of life for people with spinal cord injury and other maladies, they have also raised questions that go beyond the science. Questions such as when, why, how and for how long should such treatments be applied often relate more to what a society and its culture will condone and the answers can differ and have differed among societies depending on the prevailing ethics and morals. Modern codes and laws have been created so that the trust people have traditionally placed in their healers will not be violated or misused as happened during wars past, especially in Nazi Germany. This paper will trace the evolution of the rules that medical researchers, practitioners and payers for treatment must now follow and explain why guiding all their efforts that honesty must prevail. PMID- 20838396 TI - GWA study data mining and independent replication identify cardiomyopathy associated 5 (CMYA5) as a risk gene for schizophrenia. AB - We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values <=0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611-rs10043986, r(2)=0.008; rs10043986-rs4704591, r(2)=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case-control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04-1.18, P=8.2 * 10(-4) and rs4704591, OR=1.07, 95% CI=1.03-1.11, P=3.0 * 10(-4)). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03-1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02-1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted. PMID- 20838403 TI - Additive effect of tetramethylpyrazine and deferoxamine in the treatment of spinal cord injury caused by aortic cross-clamping in rats. AB - STUDY DESIGN: Tetramethylpyrazine and deferoxamine are effective agents for nerve injury. Experiments in a Sprague-Dawley rat model of spinal cord injury were performed. OBJECTIVES: This study investigated the effects of tetramethylpyrazine and deferoxamine on neurological outcome and spinal cord hisotpathology after transient spinal cord ischemia in rats. SETTING: Chongqing Medical University and Third Military Medical University, Chongqing, China. METHODS: Spinal cord ischemia was induced in Sprague-Dawley rats by infrarenal aortic occlusion for 30 min followed by 72 h of reperfusion. Animals were divided into a sham group with a sham procedure; control group with aortic occlusion, but no pharmacological intervention applied; and treatment group with aortic occlusion, treated with tetramethylpyrazine and deferoxamine. After 72 h of reperfusion, neurological status was evaluated in the animals. A histopathological study of spinal cords was performed, and glutamate level and metabotropic glutamate receptor-1 (mGluR1) mRNA expression were determined. RESULTS: All animals in the control group were completely paraplegic with 0% recovery. Tarlov criteria were significantly better in the animals treated with tetramethylpyrazine and deferoxamine than that in the control group (P<0.05). Functional parameters were fully correlated with the morphological findings. Glutamate level was elevated in the control group, whereas it was significantly supressed in animals treated with tetramethylpyrazine and deferoxamine treatment. The infrarenal artery occlusion significantly elevated the expression of mGluR-1 mRNA, whereas tetramethylpyrazine and deferoxamine greatly supressed the expression of mGluR-1 mRNA. CONCLUSION: The combination of tetramethylpyrazine and deferoxamine significantly reduced the incidence of paraplegia induced by spinal cord ischemia/reperfusion. PMID- 20838404 TI - Predictors of parenting stress in mothers of children with spina bifida. AB - STUDY DESIGN: Prospective cross-sectional multidimensional study using clinical assessment and standard measures. OBJECTIVES: To determine the medical and social factors associated with parenting stress among mothers of children with spina bifida. SETTING: Spina bifida clinics of two tertiary hospitals in urban Kuala Lumpur, Malaysia. METHODS: A total of 81 mothers of children aged 1-18 years completed the Parenting Stress Index-Short Form (PSI/SF). Each child's adaptive skills were assessed using the Vineland Adaptive Behaviour Scales (VABS), Interview Edition. Medical and social data were obtained from direct interviews and case note reviews. Hierarchical multiple regression analysis was used to investigate factors that were determinants for high scores in the parental distress (PD), difficult child (DC) and parent-child dysfunctional interaction (P CDI) subdomains of the PSI/SF. Results were expressed as beta coefficient (beta) and 95% confidence intervals (95% CIs). RESULTS: Single-parent families (beta 8.6, 95% CI 3.4-13.9) and the need for clean intermittent catheterization of bladder (beta 3.5, 95% CI 0.7-6.2) were associated with high PD scores. Clean intermittent catheterization (beta 3.0, 95% CI 0.5-5.5) was associated with higher DC scores. Lower composite VABS scores (beta -0.08, 95% CI -0.02 to -0.15) and mother as the sole caregiver (beta 2.6, 95% CI 0.15-4.96) was associated with higher P-CDI scores. CONCLUSION: The need for clean intermittent catheterization was the only medical factor associated with parenting stress in mothers of children with spina bifida. This was mediated by single parenthood, caregiver status and the child's adaptive skills. PMID- 20838405 TI - Potential adverse effects of cyclosporin A on kidneys after spinal cord injury. AB - STUDY DESIGN: Cell transplantation strategies are gaining increasing interest for spinal cord injury (SCI) with the objective of promoting spinal cord repair. To avoid allogenic graft rejection, an adequate immune suppression is required, and one of the most potent and commonly used immunosuppressives is cyclosporin A (CsA). In SCI, permanent sensory motor loss is combined with modifications of drug absorption, distribution and elimination. OBJECTIVES: The objectives of this study were to thoroughly explore histological and functional outcomes of CsA treatment in a rat model of spinal cord compression. SETTING: Experiments were carried out at the Institute for Neurosciences of Montpellier (France), the Integrative Biology of Neurodegeneration Laboratory (Spain) and in the Novartis Institutes for BioMedical Research (Switzerland) for CsA blood concentration determination. METHODS: We first evaluated histological outcomes of CsA treatment on kidneys and spinal cord after SCI. We then investigated whether SCI modified CsA blood concentration. Finally, using behavioral analysis, we assessed the potential CsA impact on functional recovery. RESULTS: When spinal-cord-injured rats were treated with a CsA dose of 10 mg kg(-1) per day, we observed deleterious effects on kidneys, associated with modifications of CsA blood concentration. Adding an antibiotic treatment reduced kidney alteration without modifying CsA blood concentration. Finally, we showed that CsA treatment per se modified neither functional recovery nor lesion extension. CONCLUSION: This study pinpoints the absolute requirement of careful CsA monitoring in the clinical setting for patients with SCI to minimize potential unexpected effects and avoid therapeutic failure. PMID- 20838406 TI - Pain in your buttocks? Check your heated car seat isn't burning you. PMID- 20838407 TI - Adaptation - not by sweeps alone. AB - There has been recent progress in identifying selective sweeps underlying a range of adaptations. Jonathan Pritchard and Anna Di Rienzo argue that many adaptive events in natural populations may occur by polygenic adaptation, which would largely go undetected by conventional methods for detecting selection. PMID- 20838408 TI - Tackling the widespread and critical impact of batch effects in high-throughput data. AB - High-throughput technologies are widely used, for example to assay genetic variants, gene and protein expression, and epigenetic modifications. One often overlooked complication with such studies is batch effects, which occur because measurements are affected by laboratory conditions, reagent lots and personnel differences. This becomes a major problem when batch effects are correlated with an outcome of interest and lead to incorrect conclusions. Using both published studies and our own analyses, we argue that batch effects (as well as other technical and biological artefacts) are widespread and critical to address. We review experimental and computational approaches for doing so. PMID- 20838409 TI - Genetic variation: Y variants tip the chromatin balance. PMID- 20838410 TI - Development: Patterning factor poises genes for expression. PMID- 20838412 TI - Plasmid DNA vaccination using skin electroporation promotes poly-functional CD4 T cell responses. AB - Plasmid DNA vaccination using skin electroporation (EP) is a promising method able to elicit robust humoral and CD8(+) T-cell immune responses while limiting invasiveness of delivery. However, there is still only limited data available on the induction of CD4(+) T-cell immunity using this method. Here, we compare the ability of homologous prime/boost DNA vaccinations by skin EP and intramuscular (i.m.) injection to elicit immune responses by cytokine enzyme-linked immunosorbent spot (ELISPOT) assay, as well as study the complexity of CD4(+) T cell responses to the human immunodeficiency virus antigen Gag, using multiparamater flow cytometry. We find that DNA vaccinations by skin EP and i.m. injection are capable of eliciting both single- and poly-functional vaccine specific CD4(+) T cells. However, although DNA delivered by skin EP was administered at a five-fold lower dose it elicited significant increases in the magnitude of multiple-cytokine producers compared with i.m. immunization suggesting that the skin EP could provide greater poly-functional T-cell help, a feature associated with successful immune defense against infectious agents. PMID- 20838411 TI - Advances in understanding tissue regenerative capacity and mechanisms in animals. AB - Questions about how and why tissue regeneration occurs have captured the attention of countless biologists, biomedical engineers and clinicians. Regenerative capacity differs greatly across organs and organisms, and a range of model systems that use different regenerative strategies and that offer different technical advantages have been studied to understand regeneration. Making use of this range of systems and approaches, recent advances have allowed progress to be made in understanding several key issues that are common to natural regenerative events. These issues include: the determination of regenerative capacity; the importance of stem cells, dedifferentiation and transdifferentiation; how regenerative signals are initiated and targeted; and the mechanisms that control regenerative proliferation and patterning. PMID- 20838413 TI - From bad to worse: comorbidity severity and quality of life after treatment for early-stage prostate cancer. AB - Commonly used measures of comorbidity assess comorbidity number and type but not severity. We sought to evaluate the impact of comorbidity severity on longitudinal health-related quality of life (HRQOL) in men treated with radical prostatectomy (RP) or radiation therapy (RT) using the Total Illness Burden Index for prostate cancer (TIBI-CaP). We sampled 738 men with non-metastatic prostate cancer treated with RP or RT from the Cancer of the Prostate Strategic Urologic Research Endeavor registry. We examined the impact of comorbidity severity on generic and disease-specific HRQOL at baseline and at 6, 12, 18 and 24 months post-treatment. Men with worse TIBI-CaP comorbidity had significantly lower baseline and post-treatment HRQOL in all domains at all time points. In a multivariate model, men with moderate or severe TIBI-CaP comorbidity had significantly worse HRQOL scores at 12 and 24 months after treatment in all domains except sexual and urinary function (P<0.05); in these domains, severe comorbidity was predictive of lower HRQOL (P<0.05). Comorbidity groups had similar absolute declines in HRQOL from baseline to 6 and 24 months after treatment. Although comorbidity groups experienced similar long-term declines from baseline HRQOL after treatment, men with more severe comorbidity had significantly lower baseline scores and therefore poorer long-term HRQOL. PMID- 20838414 TI - Comparison of urologist reimbursement for managing patients with low-risk prostate cancer by active surveillance versus total prostatectomy. AB - Active surveillance (AS) is an alternative to total prostatectomy (TP) in managing low-risk prostate cancer (PC). Our aim is to compare urologist reimbursement for managing low-risk PC by AS or TP. The urologist's reimbursement for TP includes the fee for the procedure and follow-up visits. For AS, our protocol involves digital rectal examination (DRE) and PSA testing every 3 months for first 2 years and every 6 months thereafter. Transrectal ultrasound (TRUS) guided biopsies are performed yearly. Some urologists recommend spacing the biopsies by 1-3 years. Medicare reimbursement values were used. The urologist reimbursements for a follow-up visit, prostate biopsy, open TP and robotic TP are $72, $595, $1905 and $2939, respectively. We also corrected for a 15% chance of having TP after being on AS. The cumulative reimbursements from open TP and following the patient up to 10 years are approximately $2121 (1 year), $2265 (2 years), $2697 (5 years) and $3057 (10 years). For robotic TP, the urologist reimbursements are $3155 (1 year), $3259 (2 years), $3731 (5 years) and $4091 (10 years). For AS, the urologist reimbursements are $883 (1 year), $1766 (2 years), $4269 (5 years) and $7964 (10 years). The urologist reimbursement from AS and TP become nearly equal between 3 and 4 years follow-up, subsequently AS attains higher reimbursement. PMID- 20838415 TI - Delivering nanomedicine to solid tumors. AB - Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors. PMID- 20838417 TI - Autophagosome formation: not necessarily an inside job. PMID- 20838416 TI - Renal fibrosis: novel insights into mechanisms and therapeutic targets. AB - Renal fibrosis is the common end point of virtually all progressive kidney diseases. Renal fibrosis should not be viewed as a simple and uniform 'scar', but rather as a dynamic system that involves extracellular matrix components and many, if not all, renal and infiltrating cell types. The involved cells exhibit enormous plasticity or phenotypic variability-a fact that we are only beginning to appreciate. Only a detailed understanding of the underlying mechanisms of renal fibrosis can facilitate the development of effective treatments. In this Review, we discuss the most recent advances in renal, or more specifically, tubulointerstitial fibrosis. Novel mechanisms as well as potential treatment targets based on different cell types are described. Problems that continue to plague the field are also discussed, including specific therapeutic targeting of the kidney, the development of improved diagnostic methods to assess renal fibrosis and the shortcomings of available animal models. PMID- 20838418 TI - Graded activation of CRAC channel by binding of different numbers of STIM1 to Orai1 subunits. AB - The Ca(2+) release-activated Ca(2+) (CRAC) channel pore is formed by Orai1 and gated by STIM1 after intracellular Ca(2+) store depletion. To resolve how many STIM1 molecules are required to open a CRAC channel, we fused different numbers of Orai1 subunits with functional two-tandem cytoplasmic domains of STIM1 (residues 336-485, designated as S domain). Whole-cell patch clamp recordings of these chimeric molecules revealed that CRAC current reached maximum at a stoichiometry of four Orai1 and eight S domains. Further experiments indicate that two-tandem S domains specifically interact with the C-terminus of one Orai1 subunit, and CRAC current can be gradually increased as more Orai1 subunits can interact with S domains or STIM1 proteins. Our data suggest that maximal opening of one CRAC channel requires eight STIM1 molecules, and support a model that the CRAC channel activation is not in an "all-or-none" fashion but undergoes a graded process via binding of different numbers of STIM1. PMID- 20838419 TI - Multi-walled carbon nanotubes conjugated to tumor protein enhance the uptake of tumor antigens by human dendritic cells in vitro. PMID- 20838421 TI - Using retinal architecture to help characterize multiple sclerosis patients. AB - OBJECTIVE: We compared retinal nerve fibre layer (RNFL) thickness and visual function in a heterogeneous multiple sclerosis (MS) cohort to determine whether optical coherence tomography (OCT) may complement the existing methods used to characterize MS patients. DESIGN: Cross-sectional cohort study. PARTICIPANTS: One hundred and ninety-three patients with optic neuritis (ON) as a clinically isolated syndrome (CIS) (n = 63), relapsing-remitting MS (RRMS) (n = 108), secondary progressive MS (SPMS) (n = 13), and primary progressive MS (PPMS) (n = 9). METHODS: All patients underwent standardized ophthalmic, neurological, and OCT testing at a single academic institution. RESULTS: RNFL values were reduced in PPMS (94.3 um), RRMS (99.6 um), and SPMS eyes (84.7 um) relative to CIS eyes (105.7 um) (p<0.0001). RNFL values were lower in eyes with recurrent ON (64.2 um) relative to eyes affected by a single ON event (86.3 um) (p<0.0001). The strongest correlation between RNFL thickness and neurological disability occurred in RRMS patients (r = -0.51, p < 0.0001). RNFL thickness correlated with visual field sensitivity for CIS (r = 0.23, p < 0.01) and RRMS (r = 0.22, p < 0.01) patients. Simple linear regression showed that every 10 um decrease in RNFL correlated with a 5.8 decibel decrease in visual field sensitivity (adjusted R2 = 0.35, p < 0.0001) for RNFL values less than 75 um. CONCLUSIONS: There were robust correlations between RNFL thickness and visual function, particularly in ON eyes. OCT may complement the existing tools used to characterize MS patients, but further studies are needed. PMID- 20838422 TI - Advances in taxonomy, ecology, and biogeography of Dirivultidae (copepoda) associated with chemosynthetic environments in the deep sea. AB - BACKGROUND: Copepoda is one of the most prominent higher taxa with almost 80 described species at deep-sea hydrothermal vents. The unique copepod family Dirivultidae with currently 50 described species is the most species rich invertebrate family at hydrothermal vents. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed the literature of Dirivultidae and provide a complete key to species, and map geographical and habitat specific distribution. In addition we discuss the ecology and origin of this family. CONCLUSIONS/SIGNIFICANCE: Dirivultidae are only present at deep-sea hydrothermal vents and along the axial summit trough of midocean ridges, with the exception of Dirivultus dentaneus found associated with Lamellibrachia species at 1125 m depth off southern California. To our current knowledge Dirivultidae are unknown from shallow-water vents, seeps, whale falls, and wood falls. They are a prominent part of all communities at vents and in certain habitat types (like sulfide chimneys colonized by pompei worms) they are the most abundant animals. They are free-living on hard substrate, mostly found in aggregations of various foundation species (e.g. alvinellids, vestimentiferans, and bivalves). Most dirivultid species colonize more than one habitat type. Dirivultids have a world-wide distribution, but most genera and species are endemic to a single biogeographic region. Their origin is unclear yet, but immigration from other deep-sea chemosynthetic habitats (stepping stone hypothesis) or from the deep-sea sediments seems unlikely, since Dirivultidae are unknown from these environments. Dirivultidae is the most species rich family and thus can be considered the most successful taxon at deep-sea vents. PMID- 20838424 TI - Experimental studies on ion acceleration and stream line detachment in a diverging magnetic field. AB - The flow structure of ions in a diverging magnetic field has been experimentally studied in an electron cyclotron resonance plasma. The flow velocity field of ions has been measured with directional Langmuir probes calibrated with the laser induced fluorescence spectroscopy. For low ion-temperature plasmas, it is concluded that the ion acceleration due to the axial electric field is important compared with that of gas dynamic effect. It has also been found that the detachment of ion stream line from the magnetic field line takes place when the parameter |f(ci)L(B)/V(i)| becomes order unity, where f(ci), L(B), and V(i) are the ion cyclotron frequency, the characteristic scale length of magnetic field inhomogeneity, and the ion flow velocity, respectively. In the detachment region, a radial electric field is generated in the plasma and the ions move straight with the E*B rotation driven by the radial electric field. PMID- 20838423 TI - Symbiotic legume nodules employ both rhizobial exo- and endo-hydrogenases to recycle hydrogen produced by nitrogen fixation. AB - BACKGROUND: In symbiotic legume nodules, endosymbiotic rhizobia (bacteroids) fix atmospheric N(2), an ATP-dependent catalytic process yielding stoichiometric ammonium and hydrogen gas (H(2)). While in most legume nodules this H(2) is quantitatively evolved, which loss drains metabolic energy, certain bacteroid strains employ uptake hydrogenase activity and thus evolve little or no H(2). Rather, endogenous H(2) is efficiently respired at the expense of O(2), driving oxidative phosphorylation, recouping ATP used for H(2) production, and increasing the efficiency of symbiotic nodule N(2) fixation. In many ensuing investigations since its discovery as a physiological process, bacteroid uptake hydrogenase activity has been presumed a single entity. METHODOLOGY/PRINCIPAL FINDINGS: Azorhizobium caulinodans, the nodule endosymbiont of Sesbania rostrata stems and roots, possesses both orthodox respiratory (exo-)hydrogenase and novel (endo )hydrogenase activities. These two respiratory hydrogenases are structurally quite distinct and encoded by disparate, unlinked gene-sets. As shown here, in S. rostrata symbiotic nodules, haploid A. caulinodans bacteroids carrying single knockout alleles in either exo- or-endo-hydrogenase structural genes, like the wild-type parent, evolve no detectable H(2) and thus are fully competent for endogenous H(2) recycling. Whereas, nodules formed with A. caulinodans exo-, endo hydrogenase double-mutants evolve endogenous H(2) quantitatively and thus suffer complete loss of H(2) recycling capability. More generally, from bioinformatic analyses, diazotrophic microaerophiles, including rhizobia, which respire H(2) may carry both exo- and endo-hydrogenase gene-sets. CONCLUSIONS/SIGNIFICANCE: In symbiotic S. rostrata nodules, A. caulinodans bacteroids can use either respiratory hydrogenase to recycle endogenous H(2) produced by N(2) fixation. Thus, H(2) recycling by symbiotic legume nodules may involve multiple respiratory hydrogenases. PMID- 20838425 TI - Kinetic effects on the Kelvin-Helmholtz instability in ion-to-magnetohydrodynamic scale transverse velocity shear layers: Particle simulations. AB - Ion-to-magnetohydrodynamic scale physics of the transverse velocity shear layer and associated Kelvin-Helmholtz instability (KHI) in a homogeneous, collisionless plasma are investigated by means of full particle simulations. The shear layer is broadened to reach a kinetic equilibrium when its initial thickness is close to the gyrodiameter of ions crossing the layer, namely, of ion-kinetic scale. The broadened thickness is larger in B?Omega<0 case than in B?Omega>0 case, where Omega is the vorticity at the layer. This is because the convective electric field, which points out of (into) the layer for B?Omega<0 (B?Omega>0), extends (reduces) the gyrodiameters. Since the kinetic equilibrium is established before the KHI onset, the KHI growth rate depends on the broadened thickness. In the saturation phase of the KHI, the ion vortex flow is strengthened (weakened) for B?Omega<0 (B?Omega>0), due to ion centrifugal drift along the rotational plasma flow. In ion inertial scale vortices, this drift effect is crucial in altering the ion vortex size. These results indicate that the KHI at Mercury-like ion scale magnetospheric boundaries could show clear dawn-dusk asymmetries in both its linear and nonlinear growth. PMID- 20838426 TI - Generation of GeV protons from 1 PW laser interaction with near critical density targets. AB - The propagation of ultraintense laser pulses through matter is connected with the generation of strong moving magnetic fields in the propagation channel as well as the formation of a thin ion filament along the axis of the channel. Upon exiting the plasma the magnetic field displaces the electrons at the back of the target, generating a quasistatic electric field that accelerates and collimates ions from the filament. Two dimensional particle-in-cell simulations show that a 1 PW laser pulse tightly focused on a near-critical density target is able to accelerate protons up to an energy of 1.3 GeV. Scaling laws and optimal conditions for proton acceleration are established considering the energy depletion of the laser pulse. PMID- 20838427 TI - Commercially available outbred mice for genome-wide association studies. AB - Genome-wide association studies using commercially available outbred mice can detect genes involved in phenotypes of biomedical interest. Useful populations need high-frequency alleles to ensure high power to detect quantitative trait loci (QTLs), low linkage disequilibrium between markers to obtain accurate mapping resolution, and an absence of population structure to prevent false positive associations. We surveyed 66 colonies for inbreeding, genetic diversity, and linkage disequilibrium, and we demonstrate that some have haplotype blocks of less than 100 Kb, enabling gene-level mapping resolution. The same alleles contribute to variation in different colonies, so that when mapping progress stalls in one, another can be used in its stead. Colonies are genetically diverse: 45% of the total genetic variation is attributable to differences between colonies. However, quantitative differences in allele frequencies, rather than the existence of private alleles, are responsible for these population differences. The colonies derive from a limited pool of ancestral haplotypes resembling those found in inbred strains: over 95% of sequence variants segregating in outbred populations are found in inbred strains. Consequently it is possible to impute the sequence of any mouse from a dense SNP map combined with inbred strain sequence data, which opens up the possibility of cataloguing and testing all variants for association, a situation that has so far eluded studies in completely outbred populations. We demonstrate the colonies' potential by identifying a deletion in the promoter of H2-Ea as the molecular change that strongly contributes to setting the ratio of CD4+ and CD8+ lymphocytes. PMID- 20838429 TI - Should we abandon the t-test in the analysis of gene expression microarray data: a comparison of variance modeling strategies. AB - High-throughput post-genomic studies are now routinely and promisingly investigated in biological and biomedical research. The main statistical approach to select genes differentially expressed between two groups is to apply a t-test, which is subject of criticism in the literature. Numerous alternatives have been developed based on different and innovative variance modeling strategies. However, a critical issue is that selecting a different test usually leads to a different gene list. In this context and given the current tendency to apply the t-test, identifying the most efficient approach in practice remains crucial. To provide elements to answer, we conduct a comparison of eight tests representative of variance modeling strategies in gene expression data: Welch's t-test, ANOVA [1], Wilcoxon's test, SAM [2], RVM [3], limma [4], VarMixt [5] and SMVar [6]. Our comparison process relies on four steps (gene list analysis, simulations, spike in data and re-sampling) to formulate comprehensive and robust conclusions about test performance, in terms of statistical power, false-positive rate, execution time and ease of use. Our results raise concerns about the ability of some methods to control the expected number of false positives at a desirable level. Besides, two tests (limma and VarMixt) show significant improvement compared to the t-test, in particular to deal with small sample sizes. In addition limma presents several practical advantages, so we advocate its application to analyze gene expression data. PMID- 20838430 TI - Gradient descent optimization in gene regulatory pathways. AB - BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example. PMID- 20838431 TI - Adding a little reality to building ontologies for biology. AB - BACKGROUND: Many areas of biology are open to mathematical and computational modelling. The application of discrete, logical formalisms defines the field of biomedical ontologies. Ontologies have been put to many uses in bioinformatics. The most widespread is for description of entities about which data have been collected, allowing integration and analysis across multiple resources. There are now over 60 ontologies in active use, increasingly developed as large, international collaborations. There are, however, many opinions on how ontologies should be authored; that is, what is appropriate for representation. Recently, a common opinion has been the "realist" approach that places restrictions upon the style of modelling considered to be appropriate. METHODOLOGY/PRINCIPAL FINDINGS: Here, we use a number of case studies for describing the results of biological experiments. We investigate the ways in which these could be represented using both realist and non-realist approaches; we consider the limitations and advantages of each of these models. CONCLUSIONS/SIGNIFICANCE: From our analysis, we conclude that while realist principles may enable straight-forward modelling for some topics, there are crucial aspects of science and the phenomena it studies that do not fit into this approach; realism appears to be over-simplistic which, perversely, results in overly complex ontological models. We suggest that it is impossible to avoid compromise in modelling ontology; a clearer understanding of these compromises will better enable appropriate modelling, fulfilling the many needs for discrete mathematical models within computational biology. PMID- 20838432 TI - MIG and the regulatory cytokines IL-10 and TGF-beta1 correlate with malaria vaccine immunogenicity and efficacy. AB - Malaria remains one of the world's greatest killers and a vaccine is urgently required. There are no established correlates of protection against malaria either for natural immunity to the disease or for immunity conferred by candidate malaria vaccines. The RTS,S/AS02A vaccine offers significant partial efficacy against malaria.mRNA expression of five key cytokines interferon-gamma (IFN gamma), monokine induced by gamma (MIG), interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta) and forkhead box P3 (FoxP3) in peripheral blood mononuclear cells were measured by real-time RT-PCR before and after vaccination with RTS,S/AS02A and Modified Vaccinia virus Ankara encoding the circumsporozoite protein (MVA-CS) in healthy malaria-naive adult volunteers. The only significant change was in IFN-gamma mRNA expression, which was increased seven days after vaccination (P = 0.04). Expression of MIG mRNA seven days after vaccination correlated inversely with time to detection of parasites by blood film in an experimental sporozoite challenge (r = 0.94 P = 0.005). An inverse relationship was seen between both TGF-beta1 and IL-10 mRNA at baseline and the anti circumsporozoite IgG antibody response (r = -0.644 P = 0.022 and r = -0.554 P = 0.031 respectively). This study demonstrates the potential for MIG expression as a correlate of protection against malaria. Baseline levels of the regulatory cytokines TGF-beta and IL-10 inversely correlated with antibody levels post vaccination and warrant further studies to improve understanding of individual differences in response to vaccination. PMID- 20838433 TI - Strain-transcendent immune response to recombinant Var2CSA DBL5-epsilon domain block P. falciparum adhesion to placenta-derived BeWo cells under flow conditions. AB - BACKGROUND: Pregnancy-associated malaria (PAM) is a serious consequence of the adhesion to the placental receptor chondroitin sulfate A (CSA) of Plasmodium falciparum-infected erythrocytes (PE) expressing the large cysteine-rich multi domain protein var2CSA. Women become resistant to PAM, and develop strain transcending immunity against CSA-binding parasites. The identification of var2CSA regions that could elicit broadly neutralizing and adhesion-blocking antibodies is a key step for the design of prophylactic vaccine strategies. METHODOLOGY: Escherichia coli expressed var2CSA DBL domains were refolded and purified prior to immunization of mice and a goat. Protein-G-purified antibodies were tested for their ability to block FCR3(CSA)-infected erythrocytes binding to placental (BeWo) and monkey brain endothelial (ScC2) cell lines using a flow cytoadhesion inhibition assay mimicking closely the physiological conditions present in the placenta at shear stress of 0.05 Pa. DBL5-epsilon, DBL6-epsilon and DBL5-6-epsilon induced cross-reactive antibodies using Alum and Freund as adjuvants, which blocked cytoadhesion at values ranging between 40 to 96% at 0.5 mg IgG per ml. Importantly, antibodies raised against recombinant DBL5-epsilon from 3 distinct parasites genotypes (HB3, Dd2 and 7G8) showed strain-transcending inhibition ranging from 38 to 64% for the heterologuous FCR3(CSA). CONCLUSIONS: Using single and double DBL domains from var2CSA and Alum as adjuvant, we identified recombinant subunits inducing an immune response in experimental animals which is able to block efficiently parasite adhesion in a flow cytoadhesion assay that mimics closely the erythrocyte flow in the placenta. These subunits show promising features for inclusion into a vaccine aiming to protect against PAM. PMID- 20838434 TI - MicroRNA-218 is deleted and downregulated in lung squamous cell carcinoma. AB - MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (>= +/- 1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer. PMID- 20838435 TI - The proneural molecular signature is enriched in oligodendrogliomas and predicts improved survival among diffuse gliomas. AB - The Cancer Genome Atlas Project (TCGA) has produced an extensive collection of ' omic' data on glioblastoma (GBM), resulting in several key insights on expression signatures. Despite the richness of TCGA GBM data, the absence of lower grade gliomas in this data set prevents analysis genes related to progression and the uncovering of predictive signatures. A complementary dataset exists in the form of the NCI Repository for Molecular Brain Neoplasia Data (Rembrandt), which contains molecular and clinical data for diffuse gliomas across the full spectrum of histologic class and grade. Here we present an investigation of the significance of the TCGA consortium's expression classification when applied to Rembrandt gliomas. We demonstrate that the proneural signature predicts improved clinical outcome among 176 Rembrandt gliomas that includes all histologies and grades, including GBMs (log rank test p = 1.16e-6), but also among 75 grade II and grade III samples (p = 2.65e-4). This gene expression signature was enriched in tumors with oligodendroglioma histology and also predicted improved survival in this tumor type (n = 43, p = 1.25e-4). Thus, expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for lower grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy. Integrated DNA and RNA analysis of low-grade and high-grade proneural gliomas identified increased expression and gene amplification of several genes including GLIS3, TGFB2, TNC, AURKA, and VEGFA in proneural GBMs, with corresponding loss of DLL3 and HEY2. Pathway analysis highlights the importance of the Notch and Hedgehog pathways in the proneural subtype. This demonstrates that the expression signatures identified in the TCGA analysis of GBMs also have intrinsic prognostic value for low-grade oligodendrogliomas, and likely represent important differences in tumor biology with implications for treatment and therapy. PMID- 20838436 TI - Regulation of inflammatory gene expression in PBMCs by immunostimulatory botanicals. AB - Many hundreds of botanicals are used in complementary and alternative medicine for therapeutic use as antimicrobials and immune stimulators. While there exists many centuries of anecdotal evidence and few clinical studies on the activity and efficacy of these botanicals, limited scientific evidence exists on the ability of these botanicals to modulate the immune and inflammatory responses. Using botanogenomics (or herbogenomics), this study provides novel insight into inflammatory genes which are induced in peripheral blood mononuclear cells following treatment with immunomodulatory botanical extracts. These results may suggest putative genes involved in the physiological responses thought to occur following administration of these botanical extracts. Using extracts from immunostimulatory herbs (Astragalus membranaceus, Sambucus cerulea, Andrographis paniculata) and an immunosuppressive herb (Urtica dioica), the data presented supports previous cytokine studies on these herbs as well as identifying additional genes which may be involved in immune cell activation and migration and various inflammatory responses, including wound healing, angiogenesis, and blood pressure modulation. Additionally, we report the presence of lipopolysaccharide in medicinally prepared extracts of these herbs which is theorized to be a natural and active component of the immunostimulatory herbal extracts. The data presented provides a more extensive picture on how these herbs may be mediating their biological effects on the immune and inflammatory responses. PMID- 20838437 TI - Lovastatin inhibits VEGFR and AKT activation: synergistic cytotoxicity in combination with VEGFR inhibitors. AB - BACKGROUND: In a recent study, we demonstrated the ability of lovastatin, a potent inhibitor of mevalonate synthesis, to inhibit the function of the epidermal growth factor receptor (EGFR). Lovastatin attenuated ligand-induced receptor activation and downstream signaling through the PI3K/AKT pathway. Combining lovastatin with gefitinib, a potent EGFR inhibitor, induced synergistic cytotoxicity in a variety of tumor derived cell lines. The vascular endothelial growth factor receptor (VEGFR) and EGFR share similar activation, internalization and downstream signaling characteristics. METHODOLOGY/PRINCIPAL FINDINGS: The VEGFRs, particularly VEGFR-2 (KDR, Flt-1), play important roles in regulating tumor angiogenesis by promoting endothelial cell proliferation, survival and migration. Certain tumors, such as malignant mesothelioma (MM), also express both the VEGF ligand and VEGFRs that act in an autocrine loop to directly stimulate tumor cell growth and survival. In this study, we have shown that lovastatin inhibits ligand-induced VEGFR-2 activation through inhibition of receptor internalization and also inhibits VEGF activation of AKT in human umbilical vein endothelial cells (HUVEC) and H28 MM cells employing immunofluorescence and Western blotting. Combinations of lovastatin and a VEGFR-2 inhibitor showed more robust AKT inhibition than either agent alone in the H28 MM cell line. Furthermore, combining 5 uM lovastatin treatment, a therapeutically relevant dose, with two different VEGFR-2 inhibitors in HUVEC and the H28 and H2052 mesothelioma derived cell lines demonstrated synergistic cytotoxicity as demonstrated by MTT cell viability and flow cytometric analyses. CONCLUSIONS/SIGNIFICANCE: These results highlight a novel mechanism by which lovastatin can regulate VEGFR-2 function and a potential therapeutic approach for MM through combining statins with VEGFR-2 inhibitors. PMID- 20838438 TI - AT1 receptor induced alterations in histone H2A reveal novel insights into GPCR control of chromatin remodeling. AB - Chronic activation of angiotensin II (AngII) type 1 receptor (AT(1)R), a prototypical G protein-coupled receptor (GPCR) induces gene regulatory stress which is responsible for phenotypic modulation of target cells. The AT(1)R selective drugs reverse the gene regulatory stress in various cardiovascular diseases. However, the molecular mechanisms are not clear. We speculate that activation states of AT(1)R modify the composition of histone isoforms and post translational modifications (PTM), thereby alter the structure-function dynamics of chromatin. We combined total histone isolation, FPLC separation, and mass spectrometry techniques to analyze histone H2A in HEK293 cells with and without AT(1)R activation. We have identified eight isoforms: H2AA, H2AG, H2AM, H2AO, H2AQ, Q96QV6, H2AC and H2AL. The isoforms, H2AA, H2AC and H2AQ were methylated and H2AC was phosphorylated. The relative abundance of specific H2A isoforms and PTMs were further analyzed in relationship to the activation states of AT(1)R by immunochemical studies. Within 2 hr, the isoforms, H2AA/O exchanged with H2AM. The monomethylated H2AC increased rapidly and the phosphorylated H2AC decreased, thus suggesting that enhanced H2AC methylation is coupled to Ser1p dephosphorylation. We show that H2A125Kme1 promotes interaction with the heterochromatin associated protein, HP1alpha. These specific changes in H2A are reversed by treatment with the AT(1)R specific inhibitor losartan. Our analysis provides a first step towards an awareness of histone code regulation by GPCRs. PMID- 20838439 TI - A requirement for FGF signalling in the formation of primitive streak-like intermediates from primitive ectoderm in culture. AB - BACKGROUND: Embryonic stem (ES) cells hold considerable promise as a source of cells with therapeutic potential, including cells that can be used for drug screening and in cell replacement therapies. Differentiation of ES cells into the somatic lineages is a regulated process; before the promise of these cells can be realised robust and rational methods for directing differentiation into normal, functional and safe cells need to be developed. Previous in vivo studies have implicated fibroblast growth factor (FGF) signalling in lineage specification from pluripotent cells. Although FGF signalling has been suggested as essential for specification of mesoderm and endoderm in vivo and in culture, the exact role of this pathway remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Using a culture model based on early primitive ectoderm-like (EPL) cells we have investigated the role of FGF signalling in the specification of mesoderm. We were unable to demonstrate any mesoderm inductive capability associated with FGF1, 4 or 8 signalling, even when the factors were present at high concentrations, nor any enhancement in mesoderm formation induced by exogenous BMP4. Furthermore, there was no evidence of alteration of mesoderm sub-type formed with addition of FGF1, 4 or 8. Inhibition of endogenous FGF signalling, however, prevented mesoderm and favoured neural differentiation, suggesting FGF signalling was required but not sufficient for the differentiation of primitive ectoderm into primitive streak like intermediates. The maintenance of ES cell/early epiblast pluripotent marker expression was also observed in cultures when FGF signalling was inhibited. CONCLUSIONS/SIGNIFICANCE: FGF signalling has been shown to be required for the differentiation of primitive ectoderm to neurectoderm. This, coupled with our observations, suggest FGF signalling is required for differentiation of the primitive ectoderm into the germ lineages at gastrulation. PMID- 20838440 TI - Cancer cells acquire mitotic drug resistance properties through beta I-tubulin mutations and alterations in the expression of beta-tubulin isotypes. AB - BACKGROUND: Anti-mitotic compounds (microtubule de-stabilizers) such as vincristine and vinblastine have been shown clinically successful in treating various cancers. However, development of drug-resistance cells limits their efficacies in clinical situations. Therefore, experiments were performed to determine possible drug resistance mechanisms related to the application of anti mitotic cancer therapy. PRINCIPAL FINDINGS: A KB-derived microtubule de stabilizer-resistant KB-L30 cancer cell line was generated for this study. KB-L30 cells showed cross-resistance to various microtubule de-stabilizers including BPR0L075, vincristine and colchicine through multiple-drug resistant (MDR) independent mechanisms. Surprisingly, KB-L30 cells showed hyper-sensitivity to the microtubule-stabilizer, paclitaxel. Results of the RT-PCR analysis revealed that expression of both class II and III beta-tubulin was down-regulated in KB L30 cells as compared to its parental KB cancer cells. In addition, DNA sequencing analysis revealed six novel mutation sites present in exon four of the betaI-tubulin gene. Computational modeling indicated that a direct relationship exists between betaI-tubulin mutations and alteration in the microtubule assembly and dynamic instability in KB-L30 cells and this predicted model was supported by an increased microtubule assembly and reduced microtubule dynamic instability in KB-L30 cells, as shown by Western blot analysis. CONCLUSIONS AND SIGNIFICANCE: Our study demonstrated that these novel mutations in exon four of the betaI tubulin induced resistance to microtubule de-stabilizers and hyper-sensitivity to microtubule stabilizer through an alteration in the microtubule assembly and dynamics in cancer cells. Importantly, the current study reveals that cancer cells may acquire drug resistance ability to anti-mitotic compounds through multiple changes in the microtubule networks. This study further provided molecular information in drug selection for patients with specific tubulin mutations. PMID- 20838441 TI - Ornithine decarboxylase antizyme induces hypomethylation of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2) in human oral cancer cell line. AB - BACKGROUND: Methylation of CpG islands of genome DNA and lysine residues of histone H3 and H4 tails regulates gene transcription. Inhibition of polyamine synthesis by ornithine decarboxylase antizyme-1 (OAZ) in human oral cancer cell line resulted in accumulation of decarboxylated S-adenosylmethionine (dcSAM), which acts as a competitive inhibitor of methylation reactions. We anticipated that accumulation of dcSAM impaired methylation reactions and resulted in hypomethylation of genome DNA and histone tails. METHODOLOGY/PRINCIPAL FINDINGS: Global methylation state of genome DNA and lysine residues of histone H3 and H4 tails were assayed by Methylation by Isoschizomers (MIAMI) method and western blotting, respectively, in the presence or absence of OAZ expression. Ectopic expression of OAZ mediated hypomethylation of CpG islands of genome DNA and histone H3 lysine 9 dimethylation (H3K9me2). Protein level of DNA methyltransferase 3B (DNMT3B) and histone H3K9me specific methyltransferase G9a were down-regulated in OAZ transfectant. CONCLUSIONS/SIGNIFICANCE: OAZ induced hypomethylation of CpG islands of global genome DNA and H3K9me2 by down regulating DNMT3B and G9a protein level. Hypomethylation of CpG islands of genome DNA and histone H3K9me2 is a potent mechanism of induction of the genes related to tumor suppression and DNA double strand break repair. PMID- 20838442 TI - Broad-scale patterns of late jurassic dinosaur paleoecology. AB - BACKGROUND: There have been numerous studies on dinosaur biogeographic distribution patterns. However, these distribution data have not yet been applied to ecological questions. Ecological studies of dinosaurs have tended to focus on reconstructing individual taxa, usually through comparisons to modern analogs. Fewer studies have sought to determine if the ecological structure of fossil assemblages is preserved and, if so, how dinosaur communities varied. Climate is a major component driving differences between communities. If the ecological structure of a fossil locality is preserved, we expect that dinosaur assemblages from similar environments will share a similar ecological structure. METHODOLOGY/PRINCIPAL FINDINGS: This study applies Ecological Structure Analysis (ESA) to a dataset of 100+ dinosaur taxa arranged into twelve composite fossil assemblages from around the world. Each assemblage was assigned a climate zone (biome) based on its location. Dinosaur taxa were placed into ecomorphological categories. The proportion of each category creates an ecological profile for the assemblage, which were compared using cluster and principal components analyses. Assemblages grouped according to biome, with most coming from arid or semi arid/seasonal climates. Differences between assemblages are tied to the proportion of large high-browsing vs. small ground-foraging herbivores, which separates arid from semi-arid and moister environments, respectively. However, the effects of historical, taphonomic, and other environmental factors are still evident. CONCLUSIONS/SIGNIFICANCE: This study is the first to show that the general ecological structure of Late Jurassic dinosaur assemblages is preserved at large scales and can be assessed quantitatively. Despite a broad similarity of climatic conditions, a degree of ecological variation is observed between assemblages, from arid to moist. Taxonomic differences between Asia and the other regions demonstrate at least one case of ecosystem convergence. The proportion of different ecomorphs, which reflects the prevailing climatic and environmental conditions present during fossil deposition, may therefore be used to differentiate Late Jurassic dinosaur fossil assemblages. This method is broadly applicable to different taxa and times, allowing one to address questions of evolutionary, biogeographic, and climatic importance. PMID- 20838443 TI - Small-molecule antioxidant proteome-shields in Deinococcus radiodurans. AB - For Deinococcus radiodurans and other bacteria which are extremely resistant to ionizing radiation, ultraviolet radiation, and desiccation, a mechanistic link exists between resistance, manganese accumulation, and protein protection. We show that ultrafiltered, protein-free preparations of D. radiodurans cell extracts prevent protein oxidation at massive doses of ionizing radiation. In contrast, ultrafiltrates from ionizing radiation-sensitive bacteria were not protective. The D. radiodurans ultrafiltrate was enriched in Mn, phosphate, nucleosides and bases, and peptides. When reconstituted in vitro at concentrations approximating those in the D. radiodurans cytosol, peptides interacted synergistically with Mn(2+) and orthophosphate, and preserved the activity of large, multimeric enzymes exposed to 50,000 Gy, conditions which obliterated DNA. When applied ex vivo, the D. radiodurans ultrafiltrate protected Escherichia coli cells and human Jurkat T cells from extreme cellular insults caused by ionizing radiation. By establishing that Mn(2+)-metabolite complexes of D. radiodurans specifically protect proteins against indirect damage caused by gamma-rays delivered in vast doses, our findings provide the basis for a new approach to radioprotection and insight into how surplus Mn budgets in cells combat reactive oxygen species. PMID- 20838444 TI - Ultrasound-mediated DNA transformation in thermophilic gram-positive anaerobes. AB - BACKGROUND: Thermophilic, Gram-positive, anaerobic bacteria (TGPAs) are generally recalcitrant to chemical and electrotransformation due to their special cell-wall structure and the low intrinsic permeability of plasma membranes. METHODOLOGY/PRINCIPAL FINDINGS: Here we established for any Gram-positive or thermophiles an ultrasound-based sonoporation as a simple, rapid, and minimally invasive method to genetically transform TGPAs. We showed that by applying a 40 kHz ultrasound frequency over a 20-second exposure, Texas red-conjugated dextran was delivered with 27% efficiency into Thermoanaerobacter sp. X514, a TGPA that can utilize both pentose and hexose for ethanol production. Experiments that delivered plasmids showed that host-cell viability and plasmid DNA integrity were not compromised. Via sonoporation, shuttle vectors pHL015 harboring a jellyfish gfp gene and pIKM2 encoding a Clostridium thermocellum beta-1,4-glucanase gene were delivered into X514 with an efficiency of 6x10(2) transformants/ug of methylated DNA. Delivery into X514 cells was confirmed via detecting the kanamycin-resistance gene for pIKM2, while confirmation of pHL015 was detected by visualization of fluorescence signals of secondary host-cells following a plasmid rescue experiment. Furthermore, the foreign beta-1,4-glucanase gene was functionally expressed in X514, converting the host into a prototypic thermophilic consolidated bioprocessing organism that is not only ethanologenic but cellulolytic. CONCLUSIONS/SIGNIFICANCE: In this study, we developed an ultrasound-based sonoporation method in TGPAs. This new DNA-delivery method could significantly improve the throughput in developing genetic systems for TGPAs, many of which are of industrial interest yet remain difficult to manipulate genetically. PMID- 20838445 TI - Improved salinity tolerance of rice through cell type-specific expression of AtHKT1;1. AB - Previously, cell type-specific expression of AtHKT1;1, a sodium transporter, improved sodium (Na(+)) exclusion and salinity tolerance in Arabidopsis. In the current work, AtHKT1;1, was expressed specifically in the root cortical and epidermal cells of an Arabidopsis GAL4-GFP enhancer trap line. These transgenic plants were found to have significantly improved Na(+) exclusion under conditions of salinity stress. The feasibility of a similar biotechnological approach in crop plants was explored using a GAL4-GFP enhancer trap rice line to drive expression of AtHKT1;1 specifically in the root cortex. Compared with the background GAL4-GFP line, the rice plants expressing AtHKT1;1 had a higher fresh weight under salinity stress, which was related to a lower concentration of Na(+) in the shoots. The root-to-shoot transport of (22)Na(+) was also decreased and was correlated with an upregulation of OsHKT1;5, the native transporter responsible for Na(+) retrieval from the transpiration stream. Interestingly, in the transgenic Arabidopsis plants overexpressing AtHKT1;1 in the cortex and epidermis, the native AtHKT1;1 gene responsible for Na(+) retrieval from the transpiration stream, was also upregulated. Extra Na(+) retrieved from the xylem was stored in the outer root cells and was correlated with a significant increase in expression of the vacuolar pyrophosphatases (in Arabidopsis and rice) the activity of which would be necessary to move the additional stored Na(+) into the vacuoles of these cells. This work presents an important step in the development of abiotic stress tolerance in crop plants via targeted changes in mineral transport. PMID- 20838446 TI - Methodological underestimation of oceanic nitrogen fixation rates. AB - The two commonly applied methods to assess dinitrogen (N(2)) fixation rates are the (15)N(2)-tracer addition and the acetylene reduction assay (ARA). Discrepancies between the two methods as well as inconsistencies between N(2) fixation rates and biomass/growth rates in culture experiments have been attributed to variable excretion of recently fixed N(2). Here we demonstrate that the (15)N(2)-tracer addition method underestimates N(2) fixation rates significantly when the (15)N(2) tracer is introduced as a gas bubble. The injected (15)N(2) gas bubble does not attain equilibrium with the surrounding water leading to a (15)N(2) concentration lower than assumed by the method used to calculate (15)N(2)-fixation rates. The resulting magnitude of underestimation varies with the incubation time, to a lesser extent on the amount of injected gas and is sensitive to the timing of the bubble injection relative to diel N(2) fixation patterns. Here, we propose and test a modified (15)N(2) tracer method based on the addition of (15)N(2)-enriched seawater that provides an instantaneous, constant enrichment and allows more accurate calculation of N(2) fixation rates for both field and laboratory studies. We hypothesise that application of N(2) fixation measurements using this modified method will significantly reduce the apparent imbalances in the oceanic fixed-nitrogen budget. PMID- 20838447 TI - Moonstruck primates: owl monkeys (Aotus) need moonlight for nocturnal activity in their natural environment. AB - Primates show activity patterns ranging from nocturnality to diurnality, with a few species showing activity both during day and night. Among anthropoids (monkeys, apes and humans), nocturnality is only present in the Central and South American owl monkey genus Aotus. Unlike other tropical Aotus species, the Azara's owl monkeys (A. azarai) of the subtropics have switched their activity pattern from strict nocturnality to one that also includes regular diurnal activity. Harsher climate, food availability, and the lack of predators or diurnal competitors, have all been proposed as factors favoring evolutionary switches in primate activity patterns. However, the observational nature of most field studies has limited an understanding of the mechanisms responsible for this switch in activity patterns. The goal of our study was to evaluate the hypothesis that masking, namely the stimulatory and/or inhibitory/disinhibitory effects of environmental factors on synchronized circadian locomotor activity, is a key determinant of the unusual activity pattern of Azara's owl monkeys. We use continuous long-term (6-18 months) 5-min-binned activity records obtained with actimeter collars fitted to wild owl monkeys (n = 10 individuals) to show that this different pattern results from strong masking of activity by the inhibiting and enhancing effects of ambient luminance and temperature. Conclusive evidence for the direct masking effect of light is provided by data showing that locomotor activity was almost completely inhibited when moonlight was shadowed during three lunar eclipses. Temperature also negatively masked locomotor activity, and this masking was manifested even under optimal light conditions. Our results highlight the importance of the masking of circadian rhythmicity as a determinant of nocturnality in wild owl monkeys and suggest that the stimulatory effects of dim light in nocturnal primates may have been selected as an adaptive response to moonlight. Furthermore, our data indicate that changes in sensitivity to specific environmental stimuli may have been an essential key for evolutionary switches between diurnal and nocturnal habits in primates. PMID- 20838449 TI - Identification and expression of the family of classical protein-tyrosine phosphatases in zebrafish. AB - Protein-tyrosine phosphatases (PTPs) have an important role in cell survival, differentiation, proliferation, migration and other cellular processes in conjunction with protein-tyrosine kinases. Still relatively little is known about the function of PTPs in vivo. We set out to systematically identify all classical PTPs in the zebrafish genome and characterize their expression patterns during zebrafish development. We identified 48 PTP genes in the zebrafish genome by BLASTing of human PTP sequences. We verified all in silico hits by sequencing and established the spatio-temporal expression patterns of all PTPs by in situ hybridization of zebrafish embryos at six distinct developmental stages. The zebrafish genome encodes 48 PTP genes. 14 human orthologs are duplicated in the zebrafish genome and 3 human orthologs were not identified. Based on sequence conservation, most zebrafish orthologues of human PTP genes were readily assigned. Interestingly, the duplicated form of ptpn23, a catalytically inactive PTP, has lost its PTP domain, indicating that PTP activity is not required for its function, or that ptpn23b has lost its PTP domain in the course of evolution. All 48 PTPs are expressed in zebrafish embryos. Most PTPs are maternally provided and are broadly expressed early on. PTP expression becomes progressively restricted during development. Interestingly, some duplicated genes retained their expression pattern, whereas expression of other duplicated genes was distinct or even mutually exclusive, suggesting that the function of the latter PTPs has diverged. In conclusion, we have identified all members of the family of classical PTPs in the zebrafish genome and established their expression patterns. This is the first time the expression patterns of all members of the large family of PTP genes have been established in a vertebrate. Our results provide the first step towards elucidation of the function of the family of classical PTPs. PMID- 20838448 TI - A PPARalpha promoter variant impairs ERR-dependent transactivation and decreases mortality after acute coronary ischemia in patients with diabetes. AB - Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) occurs in animal models of diabetes (DM) and is implicated in pathological responses to myocardial ischemia. Using bioinformatics, we identified a single nucleotide polymorphism (SNP) in the PPARalpha gene promoter (PPARA -54,642 G>A; rs135561) that altered the consensus sequence for a nuclear receptor binding site. Electrophoretic mobility shift assays showed that the domain bound two known PPARA transcriptional activators, estrogen-related receptor (ERR)-alpha and gamma and that PPARA G bound with greater affinity than PPARA A (>2-fold; P<0.05). Likewise, promoter-reporter analyses showed enhanced transcriptional activity for PPARA G vs. PPARA A for both ERR-alpha and -gamma (3.1 vs.1.9-fold; P<0.05). Since PPARalpha activation impairs post-ischemic cardiac function in experimental models of DM, we tested whether decreased PPARA transcription in PPARA A carriers favorably impacted outcome after acute coronary ischemia in 705 patients hospitalized with acute coronary syndromes (ACS; 552 Caucasian, 106 African American). PPARA A allele frequencies were similar to non-diseased subjects. However, PPARA genotype correlated with 5-year mortality in diabetic (22.2% AA vs. 18.8% AG vs. 39.5% GG; P = 0.008), but not non-diabetic (P = 0.96) subjects (genotype by diabetes interaction P = 0.008). In the diabetic ACS subjects, PPARA A carriers had strikingly reduced all-cause mortality compared to PPARA G homozygotes, (unadjusted HR 0.44, 95% CI 0.26-0.75; P = 0.003; adjusted HR 0.48, 95% CI 0.27-0.83; P = 0.009). Consistent with previous descriptions of PPARalpha in experimental models and human disease, we describe a novel PPARA promoter SNP that decreases transcriptional activation of PPARA and protects against mortality in diabetic patients after ACS. PMID- 20838450 TI - Incorporating prediction in models for two-dimensional smooth pursuit. AB - A predictive component can contribute to the command signal for smooth pursuit. This is readily demonstrated by the fact that low frequency sinusoidal target motion can be tracked with zero time delay or even with a small lead. The objective of this study was to characterize the predictive contributions to pursuit tracking more precisely by developing analytical models for predictive smooth pursuit. Subjects tracked a small target moving in two dimensions. In the simplest case, the periodic target motion was composed of the sums of two sinusoidal motions (SS), along both the horizontal and the vertical axes. Motions following the same or similar paths, but having a richer spectral composition, were produced by having the target follow the same path but at a constant speed (CS), and by combining the horizontal SS velocity with the vertical CS velocity and vice versa. Several different quantitative models were evaluated. The predictive contribution to the eye tracking command signal could be modeled as a low-pass filtered target acceleration signal with a time delay. This predictive signal, when combined with retinal image velocity at the same time delay, as in classical models for the initiation of pursuit, gave a good fit to the data. The weighting of the predictive acceleration component was different in different experimental conditions, being largest when target motion was simplest, following the SS velocity profiles. PMID- 20838451 TI - The diagnosis and treatment of acute pulmonary embolism. AB - BACKGROUND: Pulmonary embolism (PE) is a cardiovascular emergency with high morbidity and mortality. METHODS: Review of relevant literature retrieved by a selective Medline search, including current guidelines. RESULTS: Hemodynamically unstable patients are considered to have high-risk PE, whereas hemodynamically stable patients are considered to have non-high-risk PE. After classification into one of these two risk groups, patients undergo further diagnostic evaluation for PE according to the appropriate risk-adapted algorithm. Patients who are in cardiogenic shock or have persistent arterial hypotension (high-risk PE) should undergo multidetector computed tomography (MDCT) or echocardiography at once, so that a PE, if present, can be treated immediately by thrombolysis. For hemodynamically stable patients with non-high-risk PE the proper diagnostic strategy is determined by the clinical probability of PE, which can be calculated with the aid of validated scoring systems and is based on both MDCT and D-dimer levels. For further risk stratification in hemodynamically stable patients, tests are performed to detect right ventricular dysfunction or myocardial injury, either of which indicates intermediate-risk PE. In addition to specific therapy, patients with high-risk PE, patients at high risk for hemorrhage and these with severe renal insufficiency should be anticoagulated with unfractionated heparin. All other patients should be treated with low-molecular-weight heparin or fondaparinux. Thereafter, long-term oral anticoagulation with vitamin K antagonists is recommended. CONCLUSION: Modern algorithms have considerably simplified the diagnosis and treatment of acute PE. It would be desirable for these algorithms to be rapidly implemented in routine practice, because speedy diagnosis and immediate treatment can lower the morbidity and mortality associated with PE. PMID- 20838452 TI - Fecal incontinence: part 4 of a series of articles on incontinence. AB - BACKGROUND: The aging of the population will make fecal incontinence an increasingly important socioeconomic problem in the coming decades. Already today, the cost to society of treating incontinence with inserts, diapers, and closed systems exceeds the total cost of all cardiac and anti-inflammatory medications. METHODS: This article is based on a selective review of the literature and on clinical experience. No meta-analyses on this topic have yet been published. RESULTS: Surveys in highly industrialized countries in the Western Hemisphere have shown that about 5% of the population suffers from fecal incontinence of varying degrees of severity. This condition will become more common, in both relative and absolute terms, in the coming decades. Various methods of care and therapy are currently available for fecal incontinence, yet many patients do not seek medical help for it because of embarrassment. Thus, its true prevalence is certainly higher than the surveys imply. CONCLUSION: The challenge today, therefore, is not just to encourage patients to seek medical help early, but also to raise physicians' awareness of fecal incontinence and their readiness to treat it, so that they can provide competent individual counseling and treatment to all patients who suffer from it. PMID- 20838453 TI - Correspondence (letter to the editor): effects of acupuncture. PMID- 20838454 TI - Correspondence (letter to the editor): almost Ineffective. PMID- 20838455 TI - Correspondence (letter to the editor): endoprosthesis required. PMID- 20838456 TI - Correspondence (letter to the editor): tried and tested recommendations. PMID- 20838457 TI - Correspondence (letter to the editor): low-dose radiotherapy. PMID- 20838459 TI - Correspondence (letter to the editor): current state of research. PMID- 20838460 TI - Correspondence (letter to the editor): sympathetic training is essential. PMID- 20838461 TI - The characterization of twenty sequenced human genomes. AB - We present the analysis of twenty human genomes to evaluate the prospects for identifying rare functional variants that contribute to a phenotype of interest. We sequenced at high coverage ten "case" genomes from individuals with severe hemophilia A and ten "control" genomes. We summarize the number of genetic variants emerging from a study of this magnitude, and provide a proof of concept for the identification of rare and highly-penetrant functional variants by confirming that the cause of hemophilia A is easily recognizable in this data set. We also show that the number of novel single nucleotide variants (SNVs) discovered per genome seems to stabilize at about 144,000 new variants per genome, after the first 15 individuals have been sequenced. Finally, we find that, on average, each genome carries 165 homozygous protein-truncating or stop loss variants in genes representing a diverse set of pathways. PMID- 20838462 TI - Metal hyperaccumulation armors plants against disease. AB - Metal hyperaccumulation, in which plants store exceptional concentrations of metals in their shoots, is an unusual trait whose evolutionary and ecological significance has prompted extensive debate. Hyperaccumulator plants are usually found on metalliferous soils, and it has been proposed that hyperaccumulation provides a defense against herbivores and pathogens, an idea termed the 'elemental defense' hypothesis. We have investigated this hypothesis using the crucifer Thlaspi caerulescens, a hyperaccumulator of zinc, nickel, and cadmium, and the bacterial pathogen Pseudomonas syringae pv. maculicola (Psm). Using leaf inoculation assays, we have shown that hyperaccumulation of any of the three metals inhibits growth of Psm in planta. Metal concentrations in the bulk leaf and in the apoplast, through which the pathogen invades the leaf, were shown to be sufficient to account for the defensive effect by comparison with in vitro dose-response curves. Further, mutants of Psm with increased and decreased zinc tolerance created by transposon insertion had either enhanced or reduced ability, respectively, to grow in high-zinc plants, indicating that the metal affects the pathogen directly. Finally, we have shown that bacteria naturally colonizing T. caerulescens leaves at the site of a former lead-zinc mine have high zinc tolerance compared with bacteria isolated from non-accumulating plants, suggesting local adaptation to high metal. These results demonstrate that the disease resistance observed in metal-exposed T. caerulescens can be attributed to a direct effect of metal hyperaccumulation, which may thus be functionally analogous to the resistance conferred by antimicrobial metabolites in non accumulating plants. PMID- 20838463 TI - Preferential re-replication of Drosophila heterochromatin in the absence of geminin. AB - To ensure genomic integrity, the genome must be duplicated exactly once per cell cycle. Disruption of replication licensing mechanisms may lead to re-replication and genomic instability. Cdt1, also known as Double-parked (Dup) in Drosophila, is a key regulator of the assembly of the pre-replicative complex (pre-RC) and its activity is strictly limited to G1 by multiple mechanisms including Cul4-Ddb1 mediated proteolysis and inhibition by geminin. We assayed the genomic consequences of disregulating the replication licensing mechanisms by RNAi depletion of geminin. We found that not all origins of replication were sensitive to geminin depletion and that heterochromatic sequences were preferentially re replicated in the absence of licensing mechanisms. The preferential re-activation of heterochromatic origins of replication was unexpected because these are typically the last sequences to be duplicated in a normal cell cycle. We found that the re-replication of heterochromatin was regulated not at the level of pre RC activation, but rather by the formation of the pre-RC. Unlike the global assembly of the pre-RC that occurs throughout the genome in G1, in the absence of geminin, limited pre-RC assembly was restricted to the heterochromatin by elevated cyclin A-CDK activity. These results suggest that there are chromatin and cell cycle specific controls that regulate the re-assembly of the pre-RC outside of G1. PMID- 20838464 TI - The coevolution of virulence: tolerance in perspective. AB - Coevolutionary interactions, such as those between host and parasite, predator and prey, or plant and pollinator, evolve subject to the genes of both interactors. It is clear, for example, that the evolution of pollination strategies can only be understood with knowledge of both the pollinator and the pollinated. Studies of the evolution of virulence, the reduction in host fitness due to infection, have nonetheless tended to focus on parasite evolution. Host centric approaches have also been proposed--for example, under the rubric of "tolerance", the ability of hosts to minimize virulence without necessarily minimizing parasite density. Within the tolerance framework, however, there is room for more comprehensive measures of host fitness traits, and for fuller consideration of the consequences of coevolution. For example, the evolution of tolerance can result in changed selection on parasite populations, which should provoke parasite evolution despite the fact that tolerance is not directly antagonistic to parasite fitness. As a result, consideration of the potential for parasite counter-adaptation to host tolerance--whether evolved or medially manipulated--is essential to the emergence of a cohesive theory of biotic partnerships and robust disease control strategies. PMID- 20838465 TI - Graph-based analysis of the metabolic exchanges between two co-resident intracellular symbionts, Baumannia cicadellinicola and Sulcia muelleri, with their insect host, Homalodisca coagulata. AB - Endosymbiotic bacteria from different species can live inside cells of the same eukaryotic organism. Metabolic exchanges occur between host and bacteria but also between different endocytobionts. Since a complete genome annotation is available for both, we built the metabolic network of two endosymbiotic bacteria, Sulcia muelleri and Baumannia cicadellinicola, that live inside specific cells of the sharpshooter Homalodisca coagulata and studied the metabolic exchanges involving transfers of carbon atoms between the three. We automatically determined the set of metabolites potentially exogenously acquired (seeds) for both metabolic networks. We show that the number of seeds needed by both bacteria in the carbon metabolism is extremely reduced. Moreover, only three seeds are common to both metabolic networks, indicating that the complementarity of the two metabolisms is not only manifested in the metabolic capabilities of each bacterium, but also by their different use of the same environment. Furthermore, our results show that the carbon metabolism of S. muelleri may be completely independent of the metabolic network of B. cicadellinicola. On the contrary, the carbon metabolism of the latter appears dependent on the metabolism of S. muelleri, at least for two essential amino acids, threonine and lysine. Next, in order to define which subsets of seeds (precursor sets) are sufficient to produce the metabolites involved in a symbiotic function, we used a graph-based method, PITUFO, that we recently developed. Our results highly refine our knowledge about the complementarity between the metabolisms of the two bacteria and their host. We thus indicate seeds that appear obligatory in the synthesis of metabolites are involved in the symbiotic function. Our results suggest both B. cicadellinicola and S. muelleri may be completely independent of the metabolites provided by the co-resident endocytobiont to produce the carbon backbone of the metabolites provided to the symbiotic system (., thr and lys are only exploited by B. cicadellinicola to produce its proteins). PMID- 20838467 TI - Beyond fatigue: Assessing variables associated with sleep problems and use of sleep medications in multiple sclerosis. AB - BACKGROUND: Recent research indicates that sleep disturbances are common in persons with multiple sclerosis (MS), though research to date has primarily focused on the relationship between fatigue and sleep. In order to improve treatment of sleep disorders in MS, a better understanding of other factors that contribute to MS sleep disturbance and use of sleep medications in this population is needed. METHODS: Individuals with MS (N = 473) involved in an ongoing self-report survey study were asked to report on use of over-the-counter and prescription sleep medications. Participants completed the Medical Outcomes Study Sleep (MOSS) scale and other common self-report symptom measures. Multiple regression was used to evaluate factors associated with sleep problems and descriptive statistics were generated to examine use of sleep medications. RESULTS: The mean score on the MOSS scale was 35.9 (standard deviation, 20.2) and 46.8% of the sample had moderate or severe sleep problems. The majority of participants did not use over-the-counter (78%) or prescription (70%) sleep medications. In a regression model variables statistically significantly associated with sleep problems included depression, nighttime leg cramps, younger age, pain, female sex, fatigue, shorter duration of MS, and nocturia. The model explained 45% of the variance in sleep problems. Of the variance explained, depression accounted for the majority of variance in sleep problems (33%), with other variables explaining significantly less variance. CONCLUSIONS: Regression results indicate that fatigue may play a minor role in sleep disturbance in MS and that clinicians should consider the interrelationship between depression and sleep problems when treating either symptom in this population. More research is needed to explore the possibility of under-treatment of sleep disorders in MS and examine the potential effectiveness of nonpharmaceutical treatment options. PMID- 20838466 TI - A novel small molecule inhibitor of hepatitis C virus entry. AB - Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 uM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development. PMID- 20838469 TI - Multifunctional Polymeric Scaffolds for Enhancement of PARACEST Contrast Sensitivity and Performance: The Effects of Random Copolymer Variations. AB - A DOTA (1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid) tetraamide ligand having a single acrylamide side-chain (M1) was copolymerized with either 2 methylacrylic acid (MAA), 2-(acryloylamino)-2-methyl-1-propanesulfonic acid (AMPS) or N-isopropylacrylamide (NIPAM) to create a series of linear random copolymers using classical free radical chain polymerization chemistry. The metal ion binding properties of hydrolyzed M1 were investigated by pH potentiometry and the europium (III) complexes of the resulting heteropolymers were evaluated as PARACEST imaging agents. All polymeric agents were found to possess similar intermediate-to-slow water exchange and CEST characteristics as the parent EuDOTA tetraamide monomer. Consistent with basic multiplexing principles, the highest molecular weight polymer, Eu-DMAA 3.1, also showed the highest CEST sensitivity with a detection limit of 20 +/- 2 MUM. The second arylamide component gave polymers with widely different chemical characteristics and CEST properties. In particular, the Eu-DNIPAM 4.0 and Eu-DMAA 4.1 polymers displayed different solubility characteristics as a function of pH or temperature which, in turn, affected the water exchange and CEST properties of the corresponding agents. It was concluded that introduction of hydrophobic groups into the polymer backbone reduces solvent accessibility to the Eu(3+) component, effectively slowing water exchange between the inner-sphere water coordination position at each Eu(3+) center with bulk water. The CEST properties of the heteropolymers when dissolved in plasma suggest that the more hydrophobic characteristics of these polymers could be advantageous for in vivo applications. PMID- 20838468 TI - Antisocial Behavioral Syndromes in Adulthood and Alcohol Use Disorder Treatment over Three-Year Follow-Up: Results from Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions. AB - BACKGROUND: Antisocial personality disorder (ASPD) is associated with poorer treatment outcomes, but more help seeking, for alcohol use disorders (AUDs); however, associations of ASPD with AUD treatment in the general population have not been studied prospectively. OBJECTIVE: To examine prediction of treatment over 3-year follow-up among adults with AUDs by baseline ASPD and syndromal adult antisocial behavior without conduct disorder before age 15 (AABS). METHOD: Face to-face interviews with 34,653 respondents to the National Epidemiologic Survey on Alcohol and Related Conditions, of whom 3875 had prevalent AUDs between Waves 1 and 2 and ASPD, AABS, or no antisocial syndrome at Wave 1. RESULTS: In unadjusted analyses, baseline ASPD predicted AUD treatment but AABS did not. After adjustment for additional need, predisposing, and enabling factors, antisocial syndromes did not predict treatment. Baseline predictors of treatment included more past-year AUD symptoms, and past-year nicotine dependence and AUD treatment. CONCLUSIONS: That baseline antisocial syndrome did not predict AUD treatment may reflect strong associations of antisociality with previously identified predictors of help seeking. PMID- 20838470 TI - Comparison of gain-like properties of eye position signals in inferior colliculus versus auditory cortex of primates. AB - We evaluated to what extent the influence of eye position in the auditory pathway of primates can be described as a gain field. We compared single unit activity in the inferior colliculus (IC), core auditory cortex (A1) and the caudomedial belt (CM) region of auditory cortex (AC) in primates, and found stronger evidence for gain field-like interactions in the IC than in AC. In the IC, eye position signals showed both multiplicative and additive interactions with auditory responses, whereas in AC the effects were not as well predicted by a gain field model. PMID- 20838471 TI - Identifying abnormal connectivity in patients using dynamic causal modeling of FMRI responses. AB - Functional imaging studies of brain damaged patients offer a unique opportunity to understand how sensorimotor and cognitive tasks can be carried out when parts of the neural system that support normal performance are no longer available. In addition to knowing which regions a patient activates, we also need to know how these regions interact with one another, and how these inter-regional interactions deviate from normal. Dynamic causal modeling (DCM) offers the opportunity to assess task-dependent interactions within a set of regions. Here we review its use in patients when the question of interest concerns the characterization of abnormal connectivity for a given pathology. We describe the currently available implementations of DCM for fMRI responses, varying from the deterministic bilinear models with one-state equation to the stochastic non linear models with two-state equations. We also highlight the importance of the new Bayesian model selection and averaging tools that allow different plausible models to be compared at the single subject and group level. These procedures allow inferences to be made at different levels of model selection, from features (model families) to connectivity parameters. Following a critical review of previous DCM studies that investigated abnormal connectivity we propose a systematic procedure that will ensure more flexibility and efficiency when using DCM in patients. Finally, some practical and methodological issues crucial for interpreting or generalizing DCM findings in patients are discussed. PMID- 20838472 TI - What Physiological Changes and Cerebral Traces Tell Us about Adhesion to Fiction During Theater-Watching? AB - Live theater is typically designed to alter the state of mind of the audience. Indeed, the perceptual inputs issuing from a live theatrical performance are intended to represent something else, and the actions, emphasized by the writing and staging, are the key prompting the adhesion of viewers to fiction, i.e., their belief that it is real. This phenomenon raises the issue of the cognitive processes governing access to a fictional reality during live theater and of their cerebral underpinnings. To get insight into the physiological substrates of adhesion we recreated the peculiar context of watching live drama in a functional magnetic resonance imaging (fMRI) experiment, with simultaneous recording of heart activity. The instants of adhesion were defined as the co-occurrence of theatrical events determined a priori by the stage director and the spectators' offline reports of moments when fiction acted as reality. These data served to specify, for each spectator, individual fMRI time-series, used in a random-effect group analysis to define the pattern of brain response to theatrical events. The changes in this pattern related to subjects' adhesion to fiction, were investigated using a region of interest analysis. The results showed that adhesion to theatrical events correlated with increased activity in the left BA47 and posterior superior temporal sulcus, together with a decrease in dynamic heart rate variability, leading us to discuss the hypothesis of subtle changes in the subjects' state of awareness, enabling them to mentally dissociate physical and mental (drama-viewing) experiences, to account for the phenomenon of adhesion to dramatic fiction. PMID- 20838474 TI - Tonic and phasic alertness training: a novel behavioral therapy to improve spatial and non-spatial attention in patients with hemispatial neglect. AB - Hemispatial neglect is a debilitating disorder marked by a constellation of spatial and non-spatial attention deficits. Patients' alertness deficits have shown to interact with lateralized attention processes and correspondingly, improving tonic/general alertness as well as phasic/moment-to-moment alertness has shown to ameliorate spatial bias. However, improvements are often short-lived and inconsistent across tasks and patients. In an attempt to more effectively activate alertness mechanisms by exercising both tonic and phasic alertness, we employed a novel version of a continuous performance task (tonic and phasic alertness training, TAPAT). Using a between-subjects longitudinal design and employing sensitive outcome measures of spatial and non-spatial attention, we compared the effects of 9 days of TAPAT (36 min/day) in a group of patients with chronic neglect (N = 12) with a control group of chronic neglect patients (N = 12) who simply waited during the same training period. Compared to the control group, the group trained on TAPAT significantly improved on both spatial and non spatial measures of attention with many patients failing to exhibit a lateralized attention bias at the end of training. TAPAT was effective for patients with a range of behavioral profiles and lesions, suggesting that its effectiveness may rely on distributed or lower-level attention mechanisms that are largely intact in patients with neglect. In a follow-up experiment, to determine if TAPAT is more effective in improving spatial attention than an active treatment that directly trains spatial attention, we trained three chronic neglect patients on both TAPAT and search training. In all three patients, TAPAT training was more effective in improving spatial attention than search training suggesting that, in chronic neglect, training alertness is a more effective treatment approach than directly training spatial attention. PMID- 20838473 TI - Mitochondrial preconditioning: a potential neuroprotective strategy. AB - Mitochondria have long been known as the powerhouse of the cell. However, these organelles are also pivotal players in neuronal cell death. Mitochondrial dysfunction is a prominent feature of chronic brain disorders, including Alzheimer's disease (AD) and Parkinson's disease (PD), and cerebral ischemic stroke. Data derived from morphologic, biochemical, and molecular genetic studies indicate that mitochondria constitute a convergence point for neurodegeneration. Conversely, mitochondria have also been implicated in the neuroprotective signaling processes of preconditioning. Despite the precise molecular mechanisms underlying preconditioning-induced brain tolerance are still unclear, mitochondrial reactive oxygen species generation and mitochondrial ATP-sensitive potassium channels activation have been shown to be involved in the preconditioning phenomenon. This review intends to discuss how mitochondrial malfunction contributes to the onset and progression of cerebral ischemic stroke and AD and PD, two major neurodegenerative disorders. The role of mitochondrial mechanisms involved in the preconditioning-mediated neuroprotective events will be also discussed. Mitochondrial targeted preconditioning may represent a promising therapeutic weapon to fight neurodegeneration. PMID- 20838475 TI - An alarm pheromone modulates appetitive olfactory learning in the honeybee (apis mellifera). AB - In honeybees, associative learning is embedded in a social context as bees possess a highly complex social organization in which communication among individuals is mediated by dance behavior informing about food sources, and by a high variety of pheromones that maintain the social links between individuals of a hive. Proboscis extension response conditioning is a case of appetitive learning, in which harnessed bees learn to associate odor stimuli with sucrose reward in the laboratory. Despite its recurrent use as a tool for uncovering the behavioral, cellular, and molecular bases underlying associative learning, the question of whether social signals (pheromones) affect appetitive learning has not been addressed in this experimental framework. This situation contrasts with reports underlining that foraging activity of bees is modulated by alarm pheromones released in the presence of a potential danger. Here, we show that appetitive learning is impaired by the sting alarm pheromone (SAP) which, when released by guards, recruits foragers to defend the hive. This effect is mimicked by the main component of SAP, isopentyl acetate, is dose-dependent and lasts up to 24 h. Learning impairment is specific to alarm signal exposure and is independent of the odorant used for conditioning. Our results suggest that learning impairment may be a response to the biological significance of SAP as an alarm signal, which would detract bees from responding to any appetitive stimuli in a situation in which such responses would be of secondary importance. PMID- 20838476 TI - Neurovascular and Neurometabolic Couplings in Dynamic Calibrated fMRI: Transient Oxidative Neuroenergetics for Block-Design and Event-Related Paradigms. AB - Functional magnetic resonance imaging (fMRI) with blood-oxygenation level dependent (BOLD) contrast is an important tool for mapping brain activity. Interest in quantitative fMRI has renewed awareness in importance of oxidative neuroenergetics, as reflected by cerebral metabolic rate of oxygen consumption(CMRO2), for supporting brain function. Relationships between BOLD signal and the underlying neurophysiological parameters have been elucidated to allow determination of dynamic changes inCMRO2 by "calibrated fMRI," which require multi-modal measurements of BOLD signal along with cerebral blood flow (CBF) and volume (CBV). But how doCMRO2 changes, steady-state or transient, derived from calibrated fMRI compare with neural activity recordings of local field potential (LFP) and/or multi-unit activity (MUA)? Here we discuss recent findings primarily from animal studies which allow high magnetic fields studies for superior BOLD sensitivity as well as multi-modal CBV and CBF measurements in conjunction with LFP and MUA recordings from activated sites. A key observation is that while relationships between neural activity and sensory stimulus features range from linear to non-linear, associations between hyperemic components (BOLD, CBF, CBV) and neural activity (LFP, MUA) are almost always linear. More importantly, the results demonstrate good agreement between the changes inCMRO2 and independent measures of LFP or MUA. The tight neurovascular and neurometabolic couplings, observed from steady-state conditions to events separated by <200 ms, suggest rapid oxygen equilibration between blood and tissue pools and thus calibrated fMRI at high magnetic fields can provide high spatiotemporal mapping ofCMRO2 changes. PMID- 20838477 TI - Rewiring neural interactions by micro-stimulation. AB - Plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. In vitro, associative pairing of presynaptic spiking and stimulus-induced postsynaptic depolarization causes changes in the synaptic efficacy of the presynaptic neuron, when activated by extrinsic stimulation. In vivo, such paradigms can alter the responses of whole groups of neurons to stimulation. Here, we used in vivo spike-triggered stimulation to drive plastic changes in rat forelimb sensorimotor cortex, which we monitored using a statistical measure of functional connectivity inferred from the spiking statistics of the neurons during normal, spontaneous behavior. These induced plastic changes in inferred functional connectivity depended on the latency between trigger spike and stimulation, and appear to reflect a robust reorganization of the network. Such targeted connectivity changes might provide a tool for rerouting the flow of information through a network, with implications for both rehabilitation and brain-machine interface applications. PMID- 20838479 TI - Negative dielectrophoretic capture of bacterial spores in food matrices. AB - A microfluidic device with planar square electrodes is developed for capturing particles from high conductivity media using negative dielectrophoresis (n-DEP). Specifically, Bacillus subtilis and Clostridium sporogenes spores, and polystyrene particles are tested in NaCl solution (0.05 and 0.225 S/m), apple juice (0.225 S/m), and milk (0.525 S/m). Depending on the conductivity of the medium, the Joule heating produces electrothermal flow (ETF), which continuously circulates and transports the particles to the DEP capture sites. Combination of the ETF and n-DEP results in different particle capture efficiencies as a function of the conductivity. Utilizing 20 MUm height DEP chambers, "almost complete" and rapid particle capture from lower conductivity (0.05 S/m) medium is observed. Using DEP chambers above 150 MUm in height, the onset of a global fluid motion for high conductivity media is observed. This motion enhances particle capture on the electrodes at the center of the DEP chamber. The n-DEP electrodes are designed to have well defined electric field minima, enabling sample concentration at 1000 distinct locations within the chip. The electrode design also facilitates integration of immunoassay and other surface sensors onto the particle capture sites for rapid detection of target micro-organisms in the future. PMID- 20838478 TI - Behavior and pro-inflammatory cytokine variations among submissive and dominant mice engaged in aggressive encounters: moderation by corticosterone reactivity. AB - Psychosocial stressors contribute to the pathophysiology of affective disorders and variations of cytokine functioning have been implicated in this process. The present investigation demonstrated, in mice, the impact of stressful aggressive encounters on activity levels, plasma corticosterone and cytokine concentrations, and on cytokine mRNA expression within the prefrontal cortex (PFC) and hippocampus. As glucocorticoids have been tied to cytokine variations, mice were subdivided into low or high corticosterone responders, defined in terms of circulating hormone levels 75 min post-confrontation. Interestingly, stressor induced effects among low and high responders varied as a function of whether mice were submissive or dominant during the aggressive bout. Agonistic encounters elicited subsequent hyperactivity, particularly among low corticosterone responders and among dominant mice. Plasma levels of corticosterone and interleukin (IL)-6 concomitantly increased after aggressive encounters and varied with dominance status and with the low versus high corticosterone response. Among the low responders corticosterone and IL-6 increases were modest and only apparent among submissive mice, whereas among high responders these elevations were more pronounced and comparable in submissive and dominant mice. Aggressive episodes also increased IL-1beta and IL-6 mRNA brain expression. The IL-1beta rise was greater in the PFC and hippocampus of submissive mice that were low responders. Among high responders IL-1beta and IL-6 increased in both groups, although in the PFC this effect was specific to dominant mice. The data are discussed in terms of their relevance to the impact of aggressive encounters on affective behaviors, and to the role that cytokines might play in this regard. PMID- 20838480 TI - Focusing and trapping of DNA molecules by head-on ac electrokinetic streaming through join asymmetric polarization. AB - In this work, invoking join asymmetric ac polarization using double half quadrupole electrodes in a symmetric arrangement, we demonstrate a head-on ac electro-osmotic streaming capable of focusing and trapping DNA molecules efficiently. This is manifested by the observation that picomolar DNA molecules can be trapped into a large crosslike spot with at least an order of magnitude concentration enhancement within just half a minute. We identify that the phenomenon is a combined result of the formation of two prefocused DNA jets flowing toward each other, dipole-induced attraction between focused DNA molecules, and dielectrophoretic trap on the spot. With an additional horizontal pumping, we observe that the trap can transform into a peculiar pitchfork streaming capable of continuous collection and long-distance transport of concentrated DNA molecules. We also show that the same electrode design can be used to direct assembly of submicrometer particles. This newly designed microfluidic platform not only has potentials in enhancing detection sensitivity and facilitating functional assembly for on-chip analysis but also provides an added advantage of transporting target molecules in a focused and continuous manner. PMID- 20838481 TI - Impact of a compound droplet on a flat surface: A model for single cell epitaxy. AB - The impact and spreading of a compound viscous droplet on a flat surface are studied computationally using a front-tracking method as a model for the single cell epitaxy. This is a technology developed to create two-dimensional and three dimensional tissue constructs cell by cell by printing cell-encapsulating droplets precisely on a substrate using an existing ink-jet printing method. The success of cell printing mainly depends on the cell viability during the printing process, which requires a deeper understanding of the impact dynamics of encapsulated cells onto a solid surface. The present study is a first step in developing a model for deposition of cell-encapsulating droplets. The inner droplet representing the cell, the encapsulating droplet, and the ambient fluid are all assumed to be Newtonian. Simulations are performed for a range of dimensionless parameters to probe the deformation and rate of deformation of the encapsulated cell, which are both hypothesized to be related to cell damage. The deformation of the inner droplet consistently increases: as the Reynolds number increases; as the diameter ratio of the encapsulating droplet to the cell decreases; as the ratio of surface tensions of the air-solution interface to the solution-cell interface increases; as the viscosity ratio of the cell to encapsulating droplet decreases; or as the equilibrium contact angle decreases. It is observed that maximum deformation for a range of Weber numbers has (at least) one local minimum at We=2. Thereafter, the effects of cell deformation on viability are estimated by employing a correlation based on the experimental data of compression of cells between parallel plates. These results provide insight into achieving optimal parameter ranges for maximal cell viability during cell printing. PMID- 20838482 TI - Space and time clustering of mortality in rural South Africa (Agincourt HDSS), 1992-2007. AB - BACKGROUND: Detailed information regarding the spatial and/or spatial-temporal distribution of mortality is required for the efficient implementation and targeting of public health interventions. OBJECTIVES: Identify high risk clusters of mortality within the Agincourt subdistrict for targeting of public health interventions, and highlight areas for further research. DESIGN: Mortality data were extracted from the Agincourt health and socio-demographic surveillance system (HDSS) for the period 1992-2007. Mortality rates by age group and time were calculated assuming a Poisson distribution and using precise person-time contribution estimates. A spatial scan statistic (Kulldorff) was used to test for clusters of age group specific all-cause and cause-specific mortality both in space and time. RESULTS: Many statistically significant clusters of higher all cause and cause-specific mortality were identified both in space and time. Specific areas were consistently identified as high risk areas; namely, the east/south- east and upper east central regions. This corresponds to areas with higher mortality due to communicable causes (especially HIV/TB and diarrhoeal disease) and indicates a non-random element to the distribution of potential underlying causative factors e.g. settlements comprising former. Mozambican refugees in east/south-east of the site, corresponding higher poverty areas, South African villages with higher HIV prevalence, etc. Clusters of older adult mortality were also observed indicating potential non-random distribution of non communicable disease mortality. CONCLUSION: This study has highlighted distinct clusters of all-cause and cause-specific mortality within the Agincourt subdistrict. It is a first step in prioritizing areas for further, more detailed research as well as for future public health follow-on efforts such as targeting of vertical prevention of HIV/TB and antiretroviral rollout in significant child and adult mortality clusters; and assessment and provision of adequate water and sanitation in the child mortality clusters particularly in south-east where diarrheal mortality appears high. Underlying causative factors need to be identified and accurately quantified. Other questions for more detailed research are discussed. PMID- 20838483 TI - Clustering of childhood mortality in the Kintampo Health and Demographic Surveillance System in Ghana. AB - BACKGROUND: Childhood mortality in Ghana has generally declined in the last four decades. However, estimates tend to conceal substantial variability among regions and districts. The lack of population-based data in Ghana, as in other less developed countries, has hindered the development of effective programmes targeted specifically at clusters where mortality levels are significantly higher. OBJECTIVE: This paper seeks to test for the existence of statistically significant clusters of childhood mortality within the Kintampo Health and Demographic Surveillance System (KHDSS) between 2005 and 2007. DESIGN: In this study, mortality rates were generated using mortality data extracted from the health and demographic surveillance database of the KHDSS and exported into STATA. The spatial and spatio-temporal scan statistic by Kulldorff was used to identify significant clusters of childhood mortality within the KHDSS. RESULTS: A significant cluster of villages with high under-five mortality in the south eastern part of the KHDSS in 2006 was identified. This is a remote location where poverty levels are relatively higher, health facilities are more sparse and these are compounded by poor transport services in case of emergencies. CONCLUSION: This study highlights the potential of the surveillance platform to demonstrate the spatial dimensions of childhood mortality clustering. It is apparent, though, that further studies need to be carried out in order to explore the underlying risk factors for potential mortality clusters that could emerge later. PMID- 20838484 TI - Screening for beta thalassaemia. PMID- 20838485 TI - Indian Journal of Human Genetics in PubMed: Cautious but confident steps. PMID- 20838486 TI - Gly460Trp polymorphism of the ADD1 gene and essential hypertension in an Indian population: A meta-analysis on hypertension risk. AB - BACKGROUND: Essential hypertension is a complex genetic trait. Genetic variant of alpha adducin (ADD1) gene have been implicated as a risk factor for hypertension. Given its clinical significance, we investigated the association between ADD1 Gly460Trp gene polymorphism and essential hypertension in an Indian population. Further, a meta-analysis was carried out to estimate the risk of hypertension. METHODS: In the current study, 432 hypertensive cases and 461 healthy controls were genotyped for the Gly460Trp ADD1 gene polymorphism. Genotyping was determined by real time PCR using Taqman assay. Multiple logistic regression analysis was used to detect the association between Gly460Trp polymorphism and hypertension. RESULTS: No significant association was found in the genotype and allele distribution of Gly460Trp polymorphism with hypertension in our study. A total of 15 case-control studies were included in the meta-analysis. There was no evidence of the association of Gly460Trp polymorphism with hypertension in general or in any of the sub group. CONCLUSIONS: We found that the Gly460Trp polymorphism is not a risk factor for essential hypertension in a south Indian Tamilian population. However, the role of ADD1 polymorphism may not be excluded by a negative association study. Further, large and rigorous case-control studies that investigate gene-gene-environment interactions may generate more conclusive claims about the molecular genetics of hypertension. PMID- 20838487 TI - Frequency of beta-thalassemia trait and other hemoglobinopathies in northern and western India. AB - INTRODUCTION: India is an ethnically diverse country with an approximate population of 1.2 billion. The frequency of beta-thalassemia trait (betaTT) has variously been reported from <1% to 17% and an average of 3.3%. Most of these studies have been carried out on small population groups and some have been based on hospital-based patients. There is also a variation in the prevalence of hemoglobinopathies in different regions and population groups in the country. A high frequency of Hb D has been reported from the North in the Punjabi population, Hb E in the eastern region of India and Hb S is mainly reported from populations of tribal origin from different parts of the country. OBJECTIVES: To study the gene frequency of betaTT and other hemoglobinopathies in three regions East (Kolkata), West (Mumbai) and North (Delhi) in larghe population group (schoolchildren) for a more accurate assessment of gene frequency for planning of control programmes for haemoglobinopathies. MATERIALS AND METHODS: This study included 5408 children from 11 schools in Delhi, 5682 from 75 schools in Mumbai and 957 schoolchildren from Kolkata who were screened for betaTT and haemoglobinopathies. These included 5684 children from 75 schools in Mumbai and 5408 children from 11 schools in Delhi. Children were 11-18 years of age of both sexes. The final report is, however, only on 11090 schoolchildren from Mumbai and Delhi as data from Kolkata was restricted both in numbers and objectives and could not be included for comparison. RESULTS: The overall gene frequency of betaTT in Mumbai and Delhi was 4.05% being 2.68% and 5.47% in children of the two cities respectively. In Mumbai, the gene frequency was evenly distributed. Majority of the children with betaTT from Mumbai were from Marathi (38.9%) and Gujarati (25%) speaking groups. Gene frequency was >5% in Bhatias, Khatris, Lohanas and Schedule Castes. In Delhi, a higher incidence was observed in schoolchildren of North and West Delhi (5.8-9.2%). The schoolchildren of North and West Delhi comprised predominantly of Punjabi origin compared to children in the South of the city (2.2%, 2.3%). When analyzed state-wise, the highest incidence was observed in children of Punjabi origin (7.6%) and was >4% from several other states. Majority of the traits from Mumbai were anemic (95.1% male and 85.6% in female). The prevalence of anemia was lower (62.7% male and 58.4% female) children with betaTT from Delhi. This was a reflection of the higher prevalence of anemia in children without hemoglobinopathy in Mumbai than in Delhi. Nutritional deficiency was probably more severe and rampant in children Mumbai. Gene frequency of Hb D was greater in schoolchildren from Delhi (1.1%) than in Mumbai (0.7%). Hb S trait (0.2%) was observed exclusively in children from Mumbai. A low incidence of Hb E trait (0.04%) was seen in children in Mumbai. A higher incidence is reported from the East. The number of cases studied from the eastern region was small as the data from the East (Kolkata) could not be included in the analysis. CONCLUSION: This study comprises a larger number of children studied for the gene frequency of betaTT and other hemoglobinopathies from India. Population groups with higher gene frequencies require screening programmes and facilities for antenatal diagnosis as well as increased awareness and educational programmes to control the birth of thalassemic homozygotes. The overall carrier frequency of betaTT was 4.05% and reinforces the differential frequency of beta-thalassemia trait in schoolchildren from Delhi and Mumbai and the higher incidence of hemoglobin D in Punjabis as reported previously. The birth incidence calculated thereof for homozygous thalassemics would be 11,316 per year which are added each year to the existing load of homozygous thalassemics. This is much higher than the previously reported number of births annually. Hence suitable control measures need to be undertaken urgently in India. PMID- 20838488 TI - Dominant inheritance and intra-familial variations in the association of Sturge Weber and Klippel-Trenaunay-Weber syndromes. AB - This case report shows a genealogical study where a woman has limb hypertrophy and her son has an association of Sturge-Weber syndrome with Klippel-Trenaunay Weber syndrome. The Sturge-Weber and Klippel-Trenaunay-Weber syndromes appear to be different manifestations of the same affliction. Familial aggregation exists and transmission may be almost imperceptible between generations. Identification of minor manifestations may prove to be a valuable contribution to genetic counseling of families and the prevention of new cases. PMID- 20838489 TI - Heritability estimation of conventional cardiovascular disease risk factors in Asian Indian families: The Calcutta family study. AB - The genetic causes of the components of cardiovascular disease (CVD) risk factors and their intercorrelation are indeed complex and only partly understood. Keeping this view in mind, the present work was undertaken to estimate the heritability of conventional CVD risk factors using family study method. A total of twenty four nuclear families inhabiting in Calcutta and adjacent areas was chosen randomly. Up to first degree relatives including father, mother and other sibs of the proband were considered as participants in the study. Anthropometric measures namely height, weight, waist circumference as well as skinfold thickness at biceps, triceps, subscapular and suprailiac were obtained using standard techniques. Body mass index (BMI), percentage of body fat (PBF), fat mass (FM), waist-hip ratio (WHR), sum of four skinfolds (SF(4) ), arm muscle circumference (AMC), arm muscle area (AMA), arm fat area (AFA), systolic (SBP) and diastolic blood pressure (DBP) were also considered. To estimate'heritability' in the study, the mid parent-offspring model was used where'heritability' (h(2) ) was equivalent to regression co-efficient (b). The regression sum of square (RSS) and total sum of square (TSS) ratio was also calculated both for mid parent-offspring and single parent-offspring. This ratio was considered as a measure of'heritability' in the study with consideration that RSS is the variation due to genetic factor and the TSS is due to genetic and other additive factor. It was observed that the estimated heritability for BMI ranges from 0.69 to 0.31 using mid-parent off spring model while the range using single parent-offspring model was from 0.40 to 0.16. The range of heritability for SBP in mid parent-offspring model was 0.16 to 0.44 and 0.05 to 0.54 for single parent-offspring model. To conclude, it seems reasonable to argue that in the study a moderate to high h(2) was evident for body fat level, body composition and blood pressure measures which indicate a moderate to high aggregation of gene(s) in the family. PMID- 20838490 TI - Dandy-Walker malformation: An incidental finding. AB - Dandy-Walker malformation (DWM) is a rare intracranial congenital abnormality that affects the cerebellum and some of its components; particularly cerebellar vermis, fourth ventricle and is characterized by an enlarged posterior fossa. Although there is an extensive list of signs attributed to DWM, final diagnosis is solely dependent on imaging techniques as there are no signs that are characteristic of DWM. This article reports a case with DWM who was diagnosed by magnetic resonance imaging. PMID- 20838491 TI - Autism and X-linked hypophosphatemia: A possible association? AB - We herein report the joint occurrence of an autistic disorder (AD) and X-linked hypophosphatemia. X-linked hypophosphatemia (XLH), an X-linked dominant disorder, is the most common of the inherited renal phosphate wasting disorders. Autism is a pervasive developmental disorder that occurs mainly due to genetic causes. In approximately 6-15% of cases, the autistic phenotype is a part of a broader genetic condition called syndromic autism.Therefore, reports of cases with the joint occurrence of a known genetic syndrome and a diagnosis of ASD by a child psychiatrist are relevant. A joint occurrence does not, however, mean that there is always a causal link between the genetic syndrome and the autistic behavioural phenotype. In this case, there are a number of arguments countering a causal link. PMID- 20838492 TI - Ataxia telangiectasia: Family management. AB - Ataxia telangiectasia (AT) is a rare autosomal recessive disease resulting in progressive degeneration of multiple systems in the body. Both A-T homozygote and heterozygote are at increased risk of developing malignancy. We report a family in which three generations were affected by this disorder. Our index case is a 12 year-old female child, born of second degree consanguineous marriage diagnosed to have ataxia telangiectasia at the age of four years, now presented with fever and neck swelling of one month duration. Family history suggestive of ataxia telangiectasia in maternal uncle and younger sibling was present. History of premature coronary artery disease and death in paternal grandfather was present. On evaluation, child was diagnosed to have Alk negative anaplastic large T cell lymphoma. Management included genetic counseling, examination of all the family members, identification of A-T homozygote and providing appropriate care, regular surveillance of the heterozygote for malignancy. PMID- 20838493 TI - Glanzmann's thrombasthenia and molecular mimicry. PMID- 20838495 TI - Cognitive neurosciences: A new paradigm in management and outcome of schizophrenia. PMID- 20838496 TI - Boundary debates: The new challenge of Psychiatry. PMID- 20838494 TI - Innovative approaches to treatment - refractory depression: The ketamine story. PMID- 20838497 TI - Medical errors - I : The problem. PMID- 20838498 TI - Preserve and strengthen family to promote mental health. PMID- 20838500 TI - An epidemiological study of dementia under the aegis of mental health program, Maharashtra, Pune chapter. AB - BACKGROUND: There has been an exponential growth in the number of elderly population in India. This study aims to determine the prevalence of dementia in an urban center of Pune and to evaluate the corresponding socio-demographic correlates along with psychiatric morbidity in the study sample. MATERIALS AND METHODS: The study population in Pune and Kirkee cantonments was selected based on 2001 census data. The number of people over 65 years numbered 6721 and 2145 of them were randomly selected for a door-to-door survey. They were initially administered household questionnaire and then subjected to a screening tool. Each participant underwent a brief mental state examination and data was collected on the basis of a structured proforma. Patients underwent a detailed cognitive profile using subtests from CSI-D (community screening instrument - dementia), which included a Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word list, word fluency and delayed recall. Information pertaining to socio-demographic factors in participants and caregivers, caregiver-burden and behavioral and psychological symptoms in participants too were collected from the questionnaire. Radio imaging investigation was also carried out to quantify the deficit. Statistical Package for the Social Sciences (SPSS) software was used to compute the results. RESULTS: Findings revealed that prevalence of dementia in the sample population of elderly aged above 65 years was 4.1%. Socio-demographic factors which conferred a statistically higher risk for dementia were identified to be older age, low socio-economic status, low level of education, presence of family history, whereas, marriage was found to be protective. Burden of care was associated with caring for elderly with dementia with increasing severity of dementia. Patients with dementia performed poorly on cognitive test battery. Social network had a protective effect in respect with severity of dementia. On magnetic resonance imaging (MRI) majority of cases of Alzheimer's Dementia (AD) and Vascular Dementia (VaD) were noted to have both gray and white matter involvement. CONCLUSION: Poor awareness is a key public-health problem. Society plays an important role in the ageing process. The withdrawal of the elderly from the previous societal roles,reduction in all types of interactions i.e. shift of attention from outer world to the inner world, reduction in the power and prestige of the elderly enhance aging process. Aging in Indian culture though a disability is much stressful today in Indian culture as in others. PMID- 20838499 TI - A tale of two comorbidities: Understanding the neurobiology of depression and pain. AB - The comorbidity of chronic pain and depression has been consistently associated with a poor prognosis and greater disability in patients as compared to those suffering from each illness alone. This further has implications on significant financial costs to the patients and to our society. The biological underpinnings of major depression and chronic pain have considerable overlap in the areas of genetic, structural, functional, neuroendocrine and neurotransmitter functionality. Although the field has evolved in the past decade, more efforts should now focus on understanding the biological underpinnings of this shared comorbidity, while shedding light on treatment implications for these two devastating conditions. PMID- 20838501 TI - New evidence on iron, copper accumulation and zinc depletion and its correlation with DNA integrity in aging human brain regions. AB - Deoxyribonucleic acid (DNA) conformation and stability play an important role in brain function. Earlier studies reported alterations in DNA integrity in the brain regions of neurological disorders like Parkinson's and Alzheimer's diseases. However, there are only limited studies on DNA stability in an aging brain and the factors responsible for genomic instability are still not clear. In this study, we assess the levels of Copper (Cu), Iron (Fe) and Zinc (Zn) in three age groups (Group I: below 40 years), Group II: between 41-60 years) and Group III: above 61 years) in hippocampus and frontal cortex regions of normal brains. The number of samples in each group was eight. Genomic DNA was isolated and DNA integrity was studied by nick translation studies and presented as single and double strand breaks. The number of single strand breaks correspondingly increased with aging compared to double strand breaks. The strand breaks were more in frontal cortex compared to hippocampus. We observed that the levels of Cu and Fe are significantly elevated while Zn is significantly depleted as one progresses from Group I to Group III, indicating changes with aging in frontal cortex and hippocampus. But the elevation of metals was more in frontal cortical region compared to hippocampal region. There was a clear correlation between Cu and Fe levels versus strand breaks in aging brain regions. This indicates that genomic instability is progressive with aging and this will alter the gene expressions. To our knowledge, this is a new comprehensive database to date, looking at the levels of redox metals and corresponding strand breaks in DNA in two brain regions of the aging brain. The biological significance of these findings with relevance to mental health will be discussed. PMID- 20838502 TI - Understanding family functioning and social support in unremitting schizophrenia: A study in India. AB - CONTEXT: This study aimed to clarify the difference in the perception of family functioning and social support by the schizophrenic patients and their principal caretakers, and whether the social support is related to healthy family functioning. SETTING AND DESIGN: The study was set in the psychiatric outpatient department of a tertiary care hospital and data was collected by means of a semi structured interview. MATERIALS AND METHODS: Fifty unremitting schizophrenics diagnosed by diagnostic and statistical manual (DSM)-IV criteria and their family members were interviewed. Family functioning was assessed by the family assessment device (FAD) and the social support was assessed by the multidimensional scale of perceived social support (MSPSS). STATISTICAL ANALYSIS: Group differences were analyzed using unpaired 't' test for comparison of FAD and MSPSS means and subscale scores. Pearson's correlation coefficient was used to find the direction and magnitude of association between the various dimensions (subscales) of FAD and the social support from family. RESULTS: Schizophrenic patients had more difficulty on problem solving as compared to their relatives, while no significant differences were noted on the other dimensions of FAD in the two groups. Also, schizophrenics perceived more social support from friends than from their families. All the dimensions of the family functioning correlated to the social support perceived from the family in the schizophrenic patients. CONCLUSIONS: Our study highlights the need to study the issues of perception of family functioning and social support so as to improve the prognosis in a disabling disorder like schizophrenia. Providing better social support and understanding the family functioning will result in strengthening the family as a unit, so as to provide better care to the patient. PMID- 20838503 TI - Screening for depression in elderly Indian population. AB - BACKGROUND: The point prevalence of depressive disorders in the elderly population in India varies from 13 to 25%. Since the World Health Organization (five) Well-being Index (1998 version) is simple and easy to administer, an attempt is made to evaluate the Indian version of this instrument to identify depression in the elderly Indian community. OBJECTIVES: (1) To determine the prevalence of depression among the elderly population of rural areas of Udupi district, Karnataka, India. (2) To determine the validity and reliability of WHO (five) Well-being Index (1998 version) as a screening instrument to identify depressive disorders in elderly population in this Indian setting. MATERIALS AND METHODS: This cross-sectional study was conducted over a period of eight months (from March 1 to October 31, 2002) in the three taluks of Udupi, Kundapura, and Karkala; belonging to the Udupi district of South India. We selected 627 people in the age group of 60 years and above for the study. Simple random sampling, without replacement method, using the probability proportionate to size (PPS) technique was used. The WHO (five) well-being index (1998 version) was validated against the major International Classification of Diseases and Related Health Problems 10th Revision (ICD-10) depression inventory of mastering depression in primary care version 2.2. Proportions and their 95% confidence intervals were calculated and Kappa statistics was applied to determine the reliability of the screening instrument. P value<0.05 was considered statistically significant. RESULTS: The prevalence of depression in elderly population was determined to be 21.7% (95% CI = 18.4 - 24.9). The Indian version of WHO-five well-being index (1998 version) showed a sensitivity of 97.0%, specificity of 86.4%, positive predictive value of 66.3% and an overall accuracy of 0.89. The Kappa statistics showed significantly high reliability of k = 0.71. CONCLUSION: The Indian version of "WHO (five) Well-being Index (1998 version)" was found to be an effective instrument for identifying depression in elderly Indian community. PMID- 20838504 TI - Psychiatric morbidity in adult Kashmiri migrants living in a migrant camp at Jammu. AB - BACKGROUND: There are 14.9 million refugees and 22 million internally displaced persons in the world. The clinical and research literature shows a significant degree of psychological stress among refugees with relatively high levels of physical and psychological dysfunction in them. AIMS: To determine the prevalence of various psychiatric disorders among Kashmiri migrants settled in a migrant camp at Jammu MATERIALS AND METHODS: This study was conducted on adults of Kashmiri migrant families residing in Muthi camp at Jammu. Three hundred families (150 each from two camps) were taken up for the study. Psychopathology was measured using Mini International Neuropsychiatry Interview Schedule (MINI). The data was categorized according to age, sex, education. The data was analyzed using Chi-square test with Yate's correction wherever required. P-value less than 0.05 was taken as significant. RESULTS: Psychiatric morbidity was more in migrant population 33.66% (n=208) than in controls 26% (n=52) with major depressive episode being the most common diagnosis CONCLUSIONS: Depression, post-traumatic stress disorders (PTSD) and generalized anxiety disorders (GAD) were statistically more prevalent among migrants than in controls. PMID- 20838505 TI - Cognitive dysfunctions in intensive cardiac care unit. AB - BACKGROUND: Cognitive impairment is gaining recognition as sequelae of heart failure and the ICCU environment adds to their worsening symptoms. OBJECTIVES: To determine cognitive dysfunctions in patients with heart disease admitted in intensive cardiac care unit (ICCU) and to compare it with patients admitted in general medical wards with heart disease. MATERIALS AND METHODS: A total of 30 patients admitted to ICCU with heart disease were taken for the study and compared to patients with heart disease admitted in general medicine wards (except ICCU). The tools used were SMMSE (Standardized Mini Mental State Examination) and BCRS (Brief Cognitive Rating Scale). Statistical tests used were Student 't' test and Chi-Square test. RESULTS: This study showed cognitive dysfunctions in the domains of orientation, attention and constructional ability as measured by SMMSE and cognitive dysfunction in the domain of concentration as measured by BCRS. Overall cognitive dysfunctions were present in the total score of both SMMSE and BCRS scale, which was statistically very highly significant. CONCLUSION: The results showed that the patients in ICCU had cognitive dysfunctions in the domains of orientation, attention, constructional ability and concentration. Overall cognitive dysfunctions were found in the total scores of SMMSE and BCRS, thus signifying a global cognitive deficit. PMID- 20838506 TI - Effects of duration of untreated psychosis on long-term outcome of people hospitalized with first episode schizophrenia. AB - Duration of untreated psychosis (DUP) has emerged as a reliable predictor of outcome but continues to remain under scientific scrutiny. The present study examines the effect of differential periods of DUP on long-term outcome of first episode schizophrenia at Mumbai, India. This research was a prospective, 10-year follow-up naturalistic study. Hospitalized patients of first episode schizophrenia were selected and followed up. Results showed that the mean DUP was higher for a group which showed clinical recovery on Clinical Global Impression Scale [14.0 months (SD=8.0) in recovered and 10.8 months (SD=5.7) in non recovered group (P=0.091)]. DUP was not found to be significantly associated with any of the end point parameters of good clinical or social outcome. Thus, this study found that DUP alone does not determine outcome status confirming the role of psychopathological heterogeneity. PMID- 20838507 TI - Indian research: Focus on clozapine. AB - Clozapine has been used in the treatment of schizophrenia for about two decades and extensive data have been accumulated with regard to its use in various parts of the world. However, in contrast to Western countries, there are few studies which have evaluated the usefulness of clozapine in Indian patients. This article attempts to review the available data on clozapine originating from India. This review reflects the fact that there are few studies from the Indian subcontinent and most of these are case reports. In view of the same, there is a need for further research to evaluate the effectiveness of clozapine in India. PMID- 20838510 TI - Emil Kraepelin: A pioneer of scientific understanding of psychiatry and psychopharmacology. PMID- 20838509 TI - Lithium, trifluperazine and idiopathic leucopenia: Author and reviewer perspectives on how to write a good case report. AB - BACKGROUND: The Indian Journal of Psychiatry receives many reports which, despite obvious academic worth, are too poorly written to be publishable. Such submissions tax manuscript reviewers and increase the editorial office workload without benefiting the authors with a publication. METHODS: We describe an authentic and previously unpublished case of idiopathic leucopenia and psychosis. Leucocyte levels in this patient dropped upon challenge with different atypical antipsychotic drugs. Lithium pretreatment, however, permitted the safe and successful use of trifluperazine. Readers are invited to use a roughly-prepared version of the case report to draft a submission-worthy manuscript. RESULTS: Two versions of the manuscript are presented. The first version is generally satisfactory but will trigger several queries during peer review; these queries are indicated. The second version would be considered acceptable by most reviewers. CONCLUSIONS: Readers who work through the exercise provided in this article will better understand how authors should prepare their report and how reviewers may scrutinize their manuscript. PMID- 20838511 TI - Prayer, randomized controlled trials and healing: A response to Prof. Abraham Verghese. PMID- 20838508 TI - Management of anorexia and bulimia nervosa: An evidence-based review. AB - Anorexia nervosa and bulimia nervosa are primarily psychiatric disorders characterized by severe disturbances of eating behavior. Eating disorders are most prevalent in the Western culture where food is in abundance and female attractiveness is equated with thinness. Eating disorders are rare in countries like India. Despite a plethora of management options available to the mental health professionals, no major breakthrough has been achieved in recent years. Nutritional rehabilitation along with some form of re educative psychotherapy remains the mainstay of management of anorexia nervosa. In bulimia nervosa, both fluoxetine and cognitive behavior therapy have been found to be effective. Although the above-mentioned management options have been in use for decades, the active ingredient is still to be ascertained. PMID- 20838512 TI - Comment on prayer and healing: A medical and scientific perspective on randomized controlled trials. PMID- 20838513 TI - Undergraduate clinical posting in Psychiatry: Are we paying enough attention? PMID- 20838514 TI - Authors' reply. PMID- 20838515 TI - Spontaneous recovery in Autistic Spectrum Disorders - A myth? PMID- 20838516 TI - An overview of curcumin in neurological disorders. AB - Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer's disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders. PMID- 20838518 TI - Optimization of cultural conditions for protease production by a fungal species. AB - Studies were carried out on a paddy soil fungal isolate identified to be a strain of Aspergillus niger from Manipal. The parameters that largely impact enzyme production viz., fermentation time, impeller speed, pH, temperature and nutrient supplements were studied. Optimization of production parameters for production of protease was done by the single-parameter mode. Casein served as substrate and proteolytic activity was estimated using Folin-Ciocalteau method at 660 nm. A maximum yield of 71.3 mg tyrosine/g casein substrate was produced in 96 h on a soluble starch medium at pH 4 in shake flask experiments. Production was carried out on a 3-liter fermenter and 40.7 mg of tyrosine was liberated/g of substrate. The enzyme was extracted with 50% ammonium sulfate and sodium dodecyl sulfate Polyacrylamide gel electrophoresis showed two bands having mw 45.7 kDa and 38.5 kDa, respectively. The enzyme activity was found to be 147.84 U/ml. PMID- 20838517 TI - Design and evaluation of liposomal formulation of pilocarpine nitrate. AB - Prolonged release drug delivery system of pilocarpine nitrate was made by optimizing thin layer film hydration method. Egg phosphatidylcholine and cholesterol were used to make multilamellar vesicles. Effects of charges over the vesicles were studied by incorporating dicetylphosphate and stearylamine. Various factors, which may affect the size, shape, encapsulation efficiency and release rate, were studied. Liposomes in the size range 0.2 to 1 um were obtained by optimizing the process. Encapsulation efficiency of neutral, positive and negatively charged liposomes were found to be 32.5, 35.4 and 34.2 percent, respectively. In vitro drug release rate was studied on specially designed model. Biological response in terms of reduction in intraocular pressure was observed on rabbit eyes. Pilocarpine nitrate liposomes were lyophilized and stability studies were conducted. PMID- 20838519 TI - Antibacterial Activity of some Medicinal Mangroves against Antibiotic Resistant Pathogenic Bacteria. AB - The antibacterial activity of the leaves and bark of mangrove plants, Avicennia marina, A. officinalis, Bruguiera sexangula, Exoecaria agallocha, Lumnitzera racemosa, and Rhizophora apiculata was evaluated against antibiotic resistant pathogenic bacteria, Staphylococcus aureus and Proteus sp. Soxhlet extracts of petroleum ether, ethyl acetate, ethanol and water were prepared and evaluated the antibacterial activity using agar diffusion method. Most of the plant extracts showed promising antibacterial activity against both bacterial species. However, higher antibacterial activity was observed for Staphylococcus aureus than Proteus sp. The highest antibacterial activity was shown by ethyl acetate of mature leaf extracts of E. agallocha for Staphylococcus aureus. All ethyl acetate extracts showed higher inhibition against S. aureus while some extracts of chloroform, ethyl acetate and ethanol gave inhibition against Proteus sp. None of the petroleum ether and aqueous extracts showed inhibition against Proteus sp. All fresh plant materials did also show more antibacterial activity against both bacterial strains than did dried plant extracts. Antibacterial activity of fresh and dried plant materials reduced for both bacterial strains with time after extraction. Since L. racemosa and A. marina gave the best inhibition for bacterial species, they were used for further investigations. Charcoal treated plant extracts of L. racemosa and A. marina were able to inhibit both bacterial strains more than those of untreated plant extracts. Phytochemical screening of mature leaf, bark of L. racemosa and leaf extracts of A. marina has been carried out and revealed that leaf and bark contained alkaloids, steroids, triterpenoids and flavonoids. None of the above extracts indicate the presence of saponins and cardiac glycosides. Separated bands of extracts by TLC analysis showed antibacterial activity against S. aureus. PMID- 20838520 TI - Preparation of Coated Valproic Acid and Sodium Valproate Sustained-release Matrix Tablets. AB - The aim of this research was to investigate the technique for preparation of coated valproic acid and sodium valproate sustained-release matrix tablets. Different diluents were tested and selected as the effective absorbent for oily valproic acid. Effect of the amount of absorbent and hydroxypropylmethylcellulose on drug release from valproic acid-sodium valproate matrix tablets prepared with wet granulation technique was evaluated in pH change system. Colloidal silicon dioxide effectively adsorbed liquid valproic acid during wet granulation and granule preparation. The amounts of colloidal silicon dioxide and hydroxypropylmethylcellulose employed in tablet formulations affected drug release from the tablets. The drug release was prominently sustained for over 12 h using hydroxypropylmethylcellulose-based hydrophilic matrix system. The mechanism of drug release through the matrix polymer was a diffusion control. The drug release profile of the developed matrix tablet was similar to Depakine Chrono((r)), providing the values of similarity factor (f2) and difference factor (f1) of 85.56 and 2.37, respectively. Eudragit((r)) L 30 D-55 was used as effective subcoating material for core matrix tablets before over coating with hydroxypropylmethylcellulose film with organic base solvent. Drug release profile of coated matrix tablet was almost similar to that of Depakine Chrono((r)). PMID- 20838521 TI - Formulation and In vitro Evaluation of Sustained Release Dosage Form with Taste Masking of Metformin Hydrochloride. AB - An attempt was made to sustain the release of metformin HCl as well as to mask the bitter taste by complexation technique using strong cation-exchange resins, indion 244 and indion 264. The drug loading onto ion-exchange resin was optimized for mixing time, activation, effect of pH, mode of mixing, ratio of drug:resin and temperature. The resinate was evaluated for micromeritic properties, taste masking and characterized using XRPD and IR. Using resinate sustained release tablets were formulated using hydoxypropylmethylcellulose K100M.The tablets were evaluated for hardness, thickness, friability, drug content, weight variation and in vitro drug release. Tablets thus formulated (Batch B-6) provided sustained release of drug over a period of 10 h with first order kinetics. The release of metformin HCl from resinate controls the diffusion of drug molecules through the polymeric material into aqueous medium. Results showed that metformin HCl was successfully taste masked and formulated into a sustained dosage form as an alternative to the conventional tablet. PMID- 20838522 TI - Fabrication and Evaluation of Bi-layer Tablet Containing Conventional Paracetamol and Modified Release Diclofenac Sodium. AB - The objectives of present investigation were to achieve immediate release of paracetamol and tailored release of diclofenac sodium from bi-layer tablets. A 2(3) full factorial design was adopted using the amount of polyethylene glycol, microcrystalline cellulose and crospovidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitro drug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bi-layer tablets. The bi-layer tablets showed immediate release of paracetamol and modified release of diclofenac. PMID- 20838523 TI - Development and validation of a dissolution test for meloxicam and pridinol mesylate from combined tablet formulation. AB - The association of meloxicam and pridinol is indicated for treating muscular contractures and low back pain. A dissolution test for the meloxicam-pridinol combined tablet formulation was developed and validated, using a suitable HPLC method for simultaneously quantitating both dissolved drugs. The optimized conditions include the use of USP apparatus 2 at a paddle rotation rate of 75 rpm and 900 ml of 50 mM phosphate buffer (pH= 7.5) as dissolution medium, at 37.0+/ 0.5 degrees . The test, which demonstrated to be robust against small changes in bath temperature, paddle rotation speed and pH of the dissolution medium, was applied to two different brands of tablets; the corresponding dissolution profiles were constructed and both brands showed to dissolve at least 75% of the drugs at the 45 min time point. PMID- 20838524 TI - Stability Indicating RP-HPLC Method for Simultaneous Determination of Simvastatin and Ezetimibe from Tablet Dosage Form. AB - A simple, specific and sensitive reverse phase high performance liquid chromatographic method was developed and validated for simultaneous determination of ezetimibe and simvastatin from pharmaceutical dosage forms. The method uses C18 ODS Hypersil column and isocratic elution. The mobile phase composed of acetonitrile:phosphate buffer (pH 4.5, 0.01M) in the ratio of 65:35 v/v was used at a flow rate of 1.0 ml /min. UV detector was programmed at 232 nm for first 10 min and at 238 nm for 10 to 20 min. All the validation parameters were in acceptable range. The developed method was effectively applied to quantitate amount of ezetimibe and simvastatin from tablets. The method was also applied suitably for determining the degradation products of ezetimibe and simvastatin. PMID- 20838525 TI - Development of taste masked oral formulation of ornidazole. AB - Taste masked microspheres of ornidazole were prepared using amino alkyl methacrylate copolymers (Eudragit E-100) by solvent evaporation technique. Taste assessment of these microspheres was done by both spectrophotometric taste evaluation technique and panel testing. Compressed tablets of taste masked ornidazole microspheres which rapidly disintegrated in the oral cavity were prepared using microcrystalline cellulose as directly compressible filler and sodium starch glycolate as a super-disintegrant. These were subsequently evaluated for various pharmacopoeial tests, drug release, and disintegration time in the oral cavity. Sensory taste evaluation was carried by panel testing in 20 healthy human volunteers. Results indicate successful formulation of oral fast disintegrating tablets which disintegrated in the oral cavity in about 30 s and possessed good taste. PMID- 20838526 TI - Synthesis, characterization and biocidal activities of some schiff base metal complexes. AB - Some new mixed ligand complexes (1-5) of type ML'B (M(II)=Mn(II), Co(II), Ni(II), Cu(II) and Zn(II); HL'= o-vanillidene-2-aminobenzothiazole; B= 1,10 phenanthroline) and Schiff base metal complexes of types (ML(2)") (6-10) and (M(2)L") (11-15) (HL"= o-vanillidene-2-amino-N-(2-pyridyl)-benzene sulfonamide) were synthesized and characterized by elemental analysis and spectral (IR, (1)H NMR and (13)C NMR) studies. The free ligands and their metal complexes have been screened for their in vitro biological activities against bacteria, fungi and yeast. The metal complexes show more potent activities compared with Schiff base ligands. PMID- 20838527 TI - Comparison and suitability of gel matrix for entrapping higher content of enzymes for commercial applications. AB - To check the suitability of enzyme entrapped beads for use in pharmaceutical industry, amylase enzyme was entrapped in agar/agarose, polyacrylamide gels and calcium alginate beads. Sodium alginate of 1% concentration was found to be best with respect to immobilization efficiency and calcium alginate beads so obtained were not much susceptible to breakage. When sodium alginate- amylase mixture was added from a height of about 20-30 cm. into CaCl(2) solution, size of beads was large at higher alginate concentration due to the increase in the size of droplet formation before entering into CaCl(2) solution. Enzyme entrapped polyacrylamide and agar/agarose gels were fragile and could not withstand repeated use whereas enzyme entrapped in large calcium alginate beads was used successfully for 50 cycles for the conversion of starch into product without much damage to the beads under stirring conditions. Amylase preparation was also mixed with urease, lysozyme and coimmobilized in large sized calcium alginate beads. These beads were used for 10 repeated cycles to check the conversion of substrates into their products by their respective enzymes and we concluded that an enzyme or mixture of two or three enzymes can be immobilized in the same large sized calcium alginate beads. This will save the additional cost of bioreactor, manpower, maintenance conditions required for the conversion of one drug into another using enzyme/s entrapped in large sized beads. PMID- 20838528 TI - Preliminary Phytochemical Screening and Antimicrobial Studies of Lantana indica Roxb. AB - The aim of the present study was to investigate the antimicrobial and preliminary phytochemical properties of Lantana indica Roxb. The aqueous and organic solvent (ethyl acetate and methanol) extracts from the leaves of Lantana indica (Verbenaceae) were tested against Staphylococcus aureus, Bacillus subtilis, Steptococcus pyrogens, Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Aspergillus niger and Candida albicans by agar well diffusion method. The results showed promising antibacterial activity against the tested bacteria. Among these, methanol and aqueous extracts were found to possess a more potent inhibitory effect when compared to the ethyl acetate extract. Preliminary phytochemical analysis of extracts revealed the presence of antimicrobial compounds such as carbohydrates, proteins, tannins and flavonoidal glycosides. The result of this study validates the use of methanol and aqueous extract of this species in ethnomedicine, favouring the isolation of antibacterial agents from the leaf extract of Lantana indica. PMID- 20838529 TI - New benzofuran derivatives as an antioxidant agent. AB - A series of substituted benzofuran derivatives were synthesized and characterized by spectral data. Some of the synthesized compounds were tested for in vitro antioxidant activity. Some of them have shown very good antioxidant activity. These compounds were also tested for antimicrobial activity against microbial strains viz. staphylococcus aureus (NCIM 5021) and salmonella typhimurium (NCIM 2501), but none of them showed any activity against these microorganisms. PMID- 20838530 TI - Development and Validation of a RP-HPLC Method for Estimation of Montelukast Sodium in Bulk and in Tablet Dosage Form. AB - The present work describes a simple, precise and accurate HPLC method for estimation of montelukast sodium in bulk and in tablet dosage form. The separation was achieved by using octadecylsilane column (C18) and acetonitrile:1 mM sodium acetate adjusted to pH 6.3 with acetic acid in proportion of 90:10 v/v as mobile phase, at a flow rate of 1.5 ml/min. Detection was carried out at 285 nm. The retention time of montelukast sodium was found to be 3.4 min. The limit of detection was found 1.31 ug/ml and limit of quantification 3.97 ug/ml. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity (1-100 ug/ml), precision, accuracy and specificity according to ICH guidelines. The proposed method provides an accurate and precise quality control tool for routine analysis of montelukast sodium in bulk and in tablet dosage form. PMID- 20838531 TI - Antidiarrhoeal Activity of the Alcoholic Extract of the Leaves of Butea frondosa Koen. Ex Roxb. AB - The study evaluated the antidiarrhoeal property of the alcohol extract of Butea frondosa leaf on mice and rats. Studies revealed that at a dose of 25 and 75 mg/kg a considerable reduction in the extent of diarrhoea was observed but at a dose of 100 mg/kg the animals appeared completely constipated when subjected to castor oil induced diarrhoea and intestinal motility model. Therefore, Butea frondosa can be regarded as an effective antidiarrhoeal. PMID- 20838532 TI - Development of Spectrofluorimetric and HPLC Methods for In vitro Analysis of Repaglinide. AB - Spectrofluorimetric and high-performance liquid chromatography methods for estimation of repaglinide were developed. These methods were validated for estimation of repaglinide in tablets as well as in receptor fluid obtained during in vitro permeation studies. Repaglinide was observed to exhibit emission and excitation wavelengths, respectively, at 379 nm and 282 nm with linearity in the concentration range of 5-80 ug/ml. High-performance liquid chromatography analysis of repaglinide yielded retention time of 6.14 min with linearity ranging from 0.1-1.2 ug/ml concentration. Spectrofluorimetric analysis of repaglinide in tablets yielded results comparable to high performance liquid chromatography. PMID- 20838533 TI - Solid State Characterization of Domperidone: Hydroxypropyl-beta-Cyclodextrin Inclusion Complex. AB - The purpose of the present study was to prepare inclusion complex of domperidone with hydroxylpropyl-beta-cyclodextrin in order improved the solubility and hence to increase dissolution of domperidone. An effect of concentration of hydroxylpropyl-beta-cyclodextrin on the aqueous solubility of domperidone was determined by phase-solubility method. The aqueous solubility of domperidone increased as a function of hydroxylpropyl-beta-cyclodextrin concentration, showing AL type diagram. Solid domperidone/hydroxylpropyl-beta-cyclodextrin complex was prepared in ratio 1:1 by ultrasonication and kneading method. Solid state inclusion complex was characterized by FTIR, powder X-ray diffraction and differential-scanning calorimetry techniques. FTIR studies showed intactness of drug in complex whereas powder diffraction studies showed that hydroxylpropyl beta-cyclodextrin complex was amorphous. Solubility studies showed that complexation increased domperidone solubility as compared to pure drug in 0.1M hydrochloric acid and distilled water. Drug content confirms that ultrasonication is one of the efficient methods to prepare inclusion complex. Dissolution data of inclusion complexes also indicated that there is 1.4 folds increase in dissolution as compared to pure drug and was observed in case of inclusion complexes prepared by ultrasonication. PMID- 20838534 TI - Validated high performance thin layer chromatographic determination and content uniformity test for rosiglitazone in tablets. AB - A simple, rapid, precise and economical high performance thin layer chromatographic method has been developed and validated for determination of rosiglitazone in its tablet dosage form using caffeine as an internal standard. It was performed on silica gel 60 GF(254) thin layer chromatographic plates as a stationary phase using mobile phase methanol:toluene:chloroform:triethylamine (1:8:0.5:0.5 v/v/v/v) and the detection was carried out in the absorbance mode at 264 nm showing R(f) value 0.31 for rosiglitazone and 0.52 for caffeine. The linear regression data curve shows good linear relationship in the concentration range 1.0-7.0 ug/ul. The content uniformity test was carried out as per USP specification of the content uniformity test of 85-115%. The percent drug estimated of rosiglitazone from two different marketed formulations were found to be in the range 99.83-100.21. The recovery of drugs was carried out by standard addition method were found to be 100.21+/-1.06 and 100.04+/-0.30 by height and area respectively. The method was validated with the determination of accuracy, precision, specificity, linearity detector response and ruggedness. The proposed method provides a faster and cost effective quality control tool for routine analysis of content uniformity test for rosiglitazone in tablet formulation. PMID- 20838535 TI - Development and Validation of a RP-HPLC Method for Determination of Cyclosporine in Capsule. AB - A simple, specific and accurate reverse phase high performance liquid chromatographic method was developed for the determination of cyclosporine in capsule dosage form. XTerra C18 column was used as stationary phase with mobile phase acetonitrile in combination with 0.1% trifluoro acetic acid buffer and pH is adjusted to 1.4. Method was developed in an isocratic run of 20% trifluoro acetic acid with 80% acetonitrile for 10 min, at flow rate of 1 ml/min. Effluents were monitored at 210 nm. Retention time of cyclosporine was 3.855 min. The method was validated for specificity, linearity, accuracy, precision, limit of quantification, limit of detection, robustness and solution stability. Limit of quantification and limit of detection of cyclosporine was found to be 100 ng/ml and 200 ng/ml. Recovery was found to be in the range of 98.08-101.55%. The proposed method was successfully applied for the quantitative determination of cyclosporine in a capsule dosage form. PMID- 20838536 TI - Validated HPLC-RI Method for the Determination of Lactulose and its Process Related Impurities in Syrup. AB - A simple, swift with good sensitivity and reproducibility, HPLC-RI method has been developed for the quantification of lactulose and related compounds (fructose, galactose, epilactose and lactose) in oral suspension formulation. The analysis was carried out by using mobile phase (water and acetonitrile 75:25) at the flow rate of 1.0 ml/min. on isocratic HPLC-RI system. After manipulating mobile phase composition and mobile phase flow rate a good separation of five components was achieved within 15 minutes of run time. This study is beneficial to determine the active ingredient as well as related compounds simultaneously, without using buffer in mobile phase which causes bad resolution and has limitation to analyze on other hyphenated techniques such as LC-MS. PMID- 20838537 TI - New spectrophotometric estimation of ornidazole tablets employing urea as a hydrotropic solubilizing additive. AB - Quantitative spectrophotometric analysis of poorly water-soluble drugs involves use of various organic solvents. Major drawbacks of organic solvents include high cost, volatility and toxicity. Safety of analyzer is affected by toxicity of the solvent used. In the present investigation the use of organic solvent has been avoided, making the method environmentally friendly. Urea has demonstrated enhancement in aqueous solubilities of a large number of poorly water-soluble drugs, thereby widely used as a hydrotropic agent. There was more than 10-fold enhancement in the solubility of ornidazole in 10 M urea solution as compared to its solubility in distilled water. In the present investigation, hydrotropic solution of urea (10 M) was employed as solubilizing agent to solubilize the poorly water-soluble drug, ornidazole, from fine powder of its tablet dosage form for spectrophotometric determination in ultraviolet region at 319 nm. Beer's law was obeyed in the concentration range of 5-25 MUg/ml in presence of urea. Presence of urea did not interfere in the analysis. Proposed method is new, rapid, simple, accurate, and reproducible. Statistical data proved the accuracy, reproducibility and the precision of the proposed method. PMID- 20838538 TI - Pharmacognostic and antifungal investigations of Elaeocarpus ganitrus (Rudrakasha). AB - Rudrakasha is the dried bead obtained from the ripe fruit of Elaeocarpus ganitrus Roxb. (Family: Elaeocarpaceae). Microscopic studies revealed the presence of a hard endocarp with lignified isodiametric sclereids, seeds with membranous seed coat, which enclosed a dense cellular endosperm comprising of calcium oxalate druses. Physicochemical parameters showed that total ash was 1.36 times and 1.56 times more than the acid insoluble ash and water-soluble ash, respectively. Further, ethanol had a maximum extractable value of 2.4% and moisture content was found to be 9.7%. Different extracts, petroleum ether, chloroform, ethanol and water were prepared. Chemically the extracts showed the presence of phytosterols, fats, alkaloids, flavonoids, carbohydrates, proteins and tannins. The extracts were evaluated for antifungal activity on different fungal strains. Chlorofom and ethanol extracts have high antifungal activity against Candida albicans. Whereas, chloroform, ethanol and water extracts showed moderate inhibition against Aspergillus niger. PMID- 20838539 TI - Simultaneous spectrophotometric estimation of haloperidol and trihexyphenidyl in tablets. AB - The combination of haloperidol and trihexyphenidyl is a dosage form to be used as antidyskinetic agent. Literature revealed that there is no single method for the simultaneous estimation of these drugs in tablet dosage form, which prompted us to develop a simple, rapid, accurate, economical and sensitive spectrophotometric method. The simultaneous estimation method is based on the principle of additivity of absorbance, for the determination of haloperidol and trihexyphenidyl in tablet formulation. The absorption maxima of the drugs were found to be at 245.0 nm and 206.0 nm respectively for haloperidol and trihexyphenidyl in methanol and 0.1N HCl (90:10). The obeyance of Beer Lambert's law was observed in the concentration range of 2.5-12.5 ug/ml for haloperidol and 1.0-5.0 ug/ml for trihexyphenidyl. The accuracy and reproducibility of the proposed method was statistically validated by recovery studies. PMID- 20838540 TI - In vitro Antioxidant Potential of Different Parts of Oroxylum indicum: A Comparative Study. AB - The present study evaluated the in vitro antioxidant potential of different parts of Oroxylum indicum. 2,2-diphelyl 1-picrylhydrazyl (DPPH), nitric oxide, superoxide anion and hydroxyl radical scavenging potential and reductive ability assay of methanol extract of different parts i.e. root, root bark, stem, stem bark, leaves and fruits were performed. Leaves and bark extracts exhibits highest free radical scavenging activity than bark, stem and fruit extract. Leaves extract showed maximum reductive ability and found to contain maximum amount of polyphenolic compounds. The highest free radical activity may be due to presence of polyphenolic compounds. PMID- 20838541 TI - Colorimetric method for the estimation of escitalopram oxalate in tablet dosage form. AB - A colorimetric method for the analysis of escitalopram oxalate in pure form and in tablets has been developed based on the formation of chloroform soluble ion associates with bromocresol green acidic dye. The extract of ion associates exhibited absorption maxima at 417 nm obeying Beer's law in the range of 2-10 ug/ml. The method is simple, precise and accurate with recovery of 98-102% and does not require any separation of soluble excipients from tablet dosage form. PMID- 20838542 TI - Biological reasoning...and statistics.... PMID- 20838543 TI - Radiosensitization of head and neck cancer by targeting the epidermal growth factor receptor. PMID- 20838544 TI - Childhood cancers in a referral hospital in northern Nigeria. AB - BACKGROUND: We undertook this study to determine the relative frequencies of childhood malignancies and their age - sex distribution in this environment. MATERIALS AND METHODS: Hospital-based data of histological and cytologically confirmed cases of malignancies in children, aged <= 15 years, was collated over a period of 11 years, from the Cancer Registry. RESULTS: A total of 329 children aged <= 15 years, with confirmed malignant disease, was recorded. This constituted 8.44% of all malignancies diagnosed in the same period with a Male : Female ratio of 1.5:1. Burkitt's lymphoma accounted for 27.01% of the cases followed by retinoblastoma (17.02%), non-Hodgkin's non-Burkitt's Lymphoma (9.42%), and Rhabdomyosarcoma (9.42%). Others were Nephroblastoma (8.81%), Hodgkin's lymphoma (6.69%), Neuroblastoma (3.34%), Colorectal carcinoma (2.43%), Osteosarcoma (2.13%), and Unspecified lymphomas (1.82%). Burkitt's lymphoma was most prevalent in the 5-9 and 10-15 year age groups, retinoblastoma in the 0-4 year age group, and Non-Hodgkin's lymphoma, Hodgkin's lymphoma, and unspecified carcinomas were more prevalent in the 10-15 year age group. CONCLUSION: Lymphomas were the most prevalent malignancies of childhood seen in this region and the majority were of the Burkitt type, in contrast to the predominant leukemic and central nervous system trend seen in developed nations. PMID- 20838545 TI - Expression of human chorionic gonadotropin beta in gastric carcinoma: A retrospective immunohistochemical study. AB - CONTEXT: Beta Human Chorionic Gonadotropin (betaHCG), a marker of the trophoblastic neoplasm, is also secreted by non-trophoblastic neoplasms including gastric carcinomas. Its role in disease progression remains unclear. AIM: To investigate the incidence of betaHCG positivity in gastric carcinomas and correlate its presence with the biological behavior of the tumor. SETTING AND DESIGN: A hospital-based, immunohistochemical study. MATERIALS AND METHODS: One hundred and fifty formalin-fixed, paraffin-embedded tissue specimens from histopathologically confirmed cases of gastric carcinoma were immunostained using an indigenously developed antibody against betaHCG. Tumors with diffuse reactivity to betaHCG were considered as positive. Those with occasional, focal or no reactivity to betaHCG were considered as negative. STATISTICAL ANALYSIS: Differences in betaHCG staining were compared according to the histological grade and surgical stage using the chi(2) test. Using the Cox proportional hazards model, the time till the onset of development of an adverse outcome after surgery (defined as death, local or distant metastasis) was compared between the bHCG positive and negative tumors. RESULTS: Twenty-eight (18.7%) of the 150 specimens were betaHCG positive. No association was found between the histological grade (P=0.49) and the surgical stage (P=0.19) with betaHCG positivity. The median disease-free survival after surgery was not different among betaHCG positive and negative tumors. Risk of an adverse outcome after surgery was significantly associated with the stage of the tumor (Hazard ratio=2.9, 95% confidence interval: 1.1-7.4). No association was observed with grade or betaHCG positivity. CONCLUSION: betaHCG immunoreactivity was observed in about one-fifth of the gastric cancers. betaHCG reactivity, however, played no role in the biological behavior. PMID- 20838546 TI - Persistent hypokalemia in an acute lymphoblastic leukemia patient. AB - Nephrotoxicity is an important adverse effect of Amphotericin B, and although risk factors for nephrotoxicity in adults have been investigated, studies examining nephrotoxicity in the pediatric population are scarce. We describe case of 10 year old boy (CALLA - VE B cell ALL) who received conventional Amphotericin B, but he persisted with hypokalemia. PMID- 20838547 TI - Ganglioneuroma of the retroperitoneum presenting as a pediatric renal mass. AB - Ganglioneuroma is the benign representative of peripheral neuroblastic tumors, with localized and predominant thoracic presentations in older children. They often have an excellent outcome with surgery alone. A 12-year-old girl presented with an incidentally detected abdominal mass, which was clinicoradiologically a renal mass. Laparotomy revealed a mass adherent to the anterior surface of the right kidney. The mass was carefully dissected out, sacrificing a portion of the inferior vena cava. Histopathological diagnosis was that of a ganglioneuroma. She was kept under follow up. PMID- 20838548 TI - Follicular mycosis fungoides - A report of four Indian cases. AB - BACKGROUND: Follicular Mycosis Fungoides (FMF) is an under-recognized disease in India. Its clinical mimics include Hansen's disease and Sarcoidosis. AIMS: To describe the clinical and pathological features of FMF. MATERIALS AND METHODS: All cases of FMF between January and December 2007 were retrieved. Cases of conventional epidermotropic MF with a minor follicular component were excluded. Slides were reviewed by two observers. The following criteria were assessed: degree and density of folliculotropism of lymphocytes, location of folliculotropism (infundibular / isthmic / bulbar), follicular mucin, eosinophils, granulomas, and conventional epidermotropism. Each feature was assigned a semi-quantitative grade. RESULTS: There were four cases of FMF, with an equal gender distribution and a mean age of 17.5 years. All lesions were on the face. They presented as: hypopigmented patches (2) and erythematous plaques (2). Alopecia was seen in two cases. The clinical diagnosis was Hansen's disease in all four, with a differential of Alopecia mucinosa / Sarcoidosis in two cases.The histological features seen were: disproportionate folliculotropism, lymphocyte tagging with haloes, follicular mucin, and nucleomegaly / convolution in all four cases, prominent eosinophils (2), epithelioid granulomas (1), eccrine infiltration (4), parakeratosis at the follicular ostia (2), and sebaceotropism (1). The infiltrate was bulbar (4) and isthmic (2). The rest of the epidermis showed no hint of conventional MF. CONCLUSION: The preferential features for FMF were involvement of face, dominant folliculotropism, nuclear atypia and convolution, and follicular mucin. Presence of granulomas and eosinophils necessitated exclusion of infectious causes. The absence of findings of MF in the rest of the epidermis should not deter pathologists from rendering this diagnosis. PMID- 20838549 TI - Uterine C-Kit positive low grade stromal sarcoma. AB - Uterine C-Kit positive stromal tumors are rare, however, there are a few cases reported in literature. A 58-year-old post menopausal lady presented with bleeding per vaginum. An abdominal examination revealed an enlarged uterus. A computed tomography scan of the abdomen and pelvis showed a large myomatous uterus, with a probable subserosal intramural and intracavitary myoma or cervical myoma in the presence of a solitary large aortocaval node, with multiple bone lesions. The biopsy taken from the uterine mass had revealed, a low-grade uterine sarcoma, which was positive for CD117. This case is presented for its rarity and management dilemma. PMID- 20838550 TI - Oxaliplatin-induced lung fibrosis. AB - Oxaliplatin has been approved for use as an adjuvant treatment in stage III colorectal carcinoma by the US-FDA. The majority of toxicity caused by this drug is manageable. However, rare, isolated cases of pulmonary fibrosis induced by this drug have been reported in literature. We report one such case of rapidly evolving pulmonary fibrosis following treatment with oxaliplatin. PMID- 20838551 TI - Palliative care, its need and role in cancer patients, in the Indian scenario. PMID- 20838552 TI - Pediatric oncology in India: Past, present and future. PMID- 20838553 TI - Metastatic squamous cell carcinoma neck with occult primary: A retrospective analysis. AB - INTRODUCTION: Metastatic carcinoma in the lymph nodes of the neck from an unknown primary is relatively rare, accounting for about 3% of all head and neck cancers. Management of secondary neck of undetermined primary is controversial. MATERIALS AND METHODS: The case records of all the patients treated in the Department of Radiotherapy, Chatrapati Shahuji Maharaj Medical University, from Oct 1999 to Sep 2004, were studied and the patients with secondary neck without a known primary tumor were analyzed in detail to elucidate the outcome of various treatment modalities in various stages of the disease. One hundred and forty patients were found to be eligible for this analysis. Initial treatment could be divided into two categories: concurrent chemoradiation (n=76) and radiotherapy alone (n=64). RESULTS: The patients who had received radiotherapy alone (53.1%) had lesser complete response as compared to those who had received chemoradiotherapy (68.4%). The overall survival duration in patients of the radiotherapy treatment group ranged from 5 to 60 months, with an average (+/-SD) of 31.06 +/- 21.01 months, while in the chemoradiotherapy treatment group it ranged from 6 to 60 months, with an average (+/-SD) of 39.42 +/- 21.33 months. Both hematological and nonhematological toxicities, although higher in the chemoradiotherapy group, showed statistically insignificant differences. CONCLUSION: To the best of our knowledge, this is the only study evaluating the role of concurrent chemoradiation in cases of secondary neck with primary unknown. The improved response rates along with an increased survival (both disease free and overall) show the superiority of chemoradiotherapy in the management of such cases. PMID- 20838554 TI - Biological behavior of preneoplastic conditions of the endometrium: A retrospective 16-year study in south India. AB - BACKGROUND: THE BIOLOGICAL BEHAVIOR OF ENDOMETRIAL CARCINOMA DIFFERS IN EPIDEMIOLOGY, PRESENTATION, AND PROGNOSIS, SUGGESTING THAT THERE ARE TWO FUNDAMENTALLY DIFFERENT PATHOGENIC TYPES OF DISEASE: type I (estrogen related, endometrioid type) and type II (non-estrogen related, non-endometrioid type). Untreated hyperplasia can develop into an endometrioid type of adenocarcinoma, hence, it is important to recognize the former type. In contrast to cervical cancers, there are limited studies with respect to the biology of hyperplastic lesions documented from India. This was a 16-year retrospective study, carried out to determine the nature and outcome of proliferative lesions of the endometrium in a referral center from south India. MATERIALS AND METHODS: A histopathological diagnosis of the endometrial hyperplasia, polyp, and carcinoma, on endometrial biopsy and hysterectomy specimens, over a 16 year period (1983 to 1999), were recorded in a computer and the case slides were reviewed. Using the computer software Foxpro, the patients who had come more than once for a subsequent or previous biopsy were identified. An attempt was made to look for progression, regression or a static nature of the lesion in the follow-up cases. RESULTS: A total of 1778 cases were studied, and only 74 patients with endometrial hyperplasia and five cases of benign endometrial polyp had follow-up endometrial histopathology. Hyperplasia cases included 59 cases of simple hyperplasia, 10 cases of complex hyperplasia without atypia, and five cases with atypia. The predominant age for patients with all types of hyperplasias was 41 - 50 years. Progression to a higher grade was seen in 8.10%, regression to a lower grade was seen in 9.45%, lesions reverted to a normal pattern in 10.81% cases, and lesions persisted in 70.27% of the cases. A mixed pattern was seen in 54 cases, with predominant coexistent lesion being simple and complex hyperplasia without atypia. CONCLUSION: The fate of the hyperplastic lesion of the endometrium showed a varied pattern. Follow-up cases predominantly showed persistence of the lesion, possibly resulting from a fluctuating but higher level of estrogenic stimulus. Hence, it was not only the high levels of estrogen that influenced the biology, but its sustenance for a prolonged period. PMID- 20838555 TI - Squamous cell carcinoma of tongue in a renal transplant recipient. AB - The overall incidence of malignancies in post renal transplant recipients is reported to be approximately 5 to 6%. Malignancies are significant complications after transplantation. Common malignancies include malignancies of the skin and post-transplant lymphoproliferative disorder (PTLD). Squamous cell carcinoma of the tongue is very rare. We present a case of squamous cell carcinoma of the tongue developing nine years after renal transplantation, in a 30-year-old man. He underwent left hemiglossectomy initially and then modified neck dissection. His graft function continues to remain stable. PMID- 20838556 TI - Choroidal melanoma metastatizing to the biliary system: A diagnostic dilemma. AB - Metastatic melanoma to the gall bladder is extremely rare and is associated with a very poor prognosis. We report a case of choroidal melanoma metastatizing to the hepatobiliary system, with an unusual presentation. Our patient presenting with obstructive jaundice was misdiagnosed as having carcinoma of the gall bladder, but the diagnosis of metastatic melanoma to the gallbladder was confirmed by ultrasonography guided fine needle aspiration cytology (USG-FNAC). On reviewing the past history, the patient had a history of enucleation for choroidal melanoma. Even though the liver 'is' a common site for metastasis of choroid melanoma, the patient presenting with a suspected gall bladder mass 'is' a rare presentation. Hence, gastrointestinal symptoms and a history of melanoma should be investigated for the presence of gastrointestinal or liver metastases, even if the original primary malignancy was diagnosed years before the patient's presentation. PMID- 20838557 TI - Mesenchymal hamartoma of the liver. AB - Mesenchymal hamartoma of the liver is the second most common benign liver tumor in children, yet its biology and pathogenesis are poorly understood. Typically, it presents as a large benign multicystic liver mass in children younger than three years, amenable to complete resection. Most tumors gradually increase in size, some reaching enormous proportions, some can undergo incomplete spontaneous regression, and rarely, few have shown malignant transformation to undifferentiated (embryonal) sarcoma. Here, we report a 13 month-old child who presented with abdominal distension and respiratory distress. Ultrasonography, Computed Tomography (CT), and magnetic resonance imaging (MRI) of the abdomen were suggestive of a mesenchymal hamartoma of the liver. Right hepatectomy was performed. Postoperatively, the patient recovered well. An attempt was also made to understand the possible etiology of the tumor. PMID- 20838558 TI - Ovarian adenocarcinoma in a young female with skin and umbilical metastasis. AB - We report the case of ovarian carcinoma with skin and umbilical metastasis in a 30-year-old female. The computed tomography (CT) scan of the abdomen showed a right ovarian mass with anterior abdominal wall metastasis. The CT-guided fine needle aspiration cytology (FNAC) from the ovarian mass showed adenocarcinoma. FNAC from the umbilical and skin metastasis also showed adenocarcinoma. Because of the unresectability of the mass, the patient was put on taxol-based chemotherapy, which she took for two cycles, and then died of progressive disease after three months. PMID- 20838559 TI - Pseudomonas diarrhea in a child suffering from acute lymphatic leukemia. AB - A female child admitted to hospital, diagnosed with acute lymphatic leukemia - CALLA positive, developed loose motions. Her stool culture and blood culture grew Pseudomonas aeruginosa. Although the diarrhea subsided after five days, the stool culture repeatedly grewP. aeruginosa for more than one month, in spite of treatment. Even though diarrhea due to Pseudomonas is rare, it can yet be seen in immunocompromised patients and is also associated with neutropenic enterocolitis. Stool specimens of all leukemia patients on chemotherapy and suffering from diarrhea, should be sent routinely for culture, so as to find out the exact cause of the diarrhea. Proper reporting will enable the clinicians to start appropriate antibiotics, thereby, reducing the morbidity and mortality of the leukemia patients. PMID- 20838560 TI - Cancer lung: An unusual presentation. AB - Phalanx bone metastasis as the initial manifestation of lung cancer is a rare presentation. A 70-year-old man presented with swelling and pain in his right ring finger. He had no other complaints or abnormal findings on clinical examination. A right hand radiograph showed an osteolytic lesion in the first phalanx of the ring finger. Fine needle aspiration cytology of the swelling suggested a metastatic adenocarcinoma. A skeletal survey, hematological, biochemical, and other radiological tests were found to be normal, except for an opacity seen in the right lung midzone. A bronchoscopic biopsy revealed adenocarcinoma of the lung. PMID- 20838561 TI - Intestinal mantle cell lymphoma recurring at laparotomy scar region. AB - Mantle cell lymphoma (MCL) is a moderately aggressive variety of non-Hodgkins lymphoma. Extranodal presentation of MCL is well known, the intestine being a common site. The incidence of colorectal involvement is relatively rare. Moreover, the recurrence of the disease at laparotomy scar site is even more rare. We report an unusual case of incision line recurrence in a case of colonic MCL occuring three years after initial treatment. PMID- 20838562 TI - Immune reconstitution inflammatory syndrome in AIDS-related non-hodgkin's lymphoma. AB - Immune Reconstitution syndrome following antiretroviral therapy is common in HIV/AIDS patients due to boosting of immunity. A case is reported here wherein AIDS-related Non-Hodgkin's lymphoma patient received CHOP regimen and antiretroviral therapy. Patient developed tubercular lymphadenopathy paradoxically as a manifestation of IRIS. PMID- 20838563 TI - Genome-scale approaches to investigate oxidative DNA damage. AB - In the trend of biological science after the completion of the human genome project, appreciation of an organism as a system rather than the sum of many molecular functions is necessary. On the investigation of DNA damage and repair, therefore, the orientation toward systematic and comprehensive genome-scale approaches is rapidly growing. The immunoprecipitation-based technique combined with high-density microarrays is one of the promising methods to provide access to such novel research strategies. We propose this sort of research area as oxygenomics. PMID- 20838564 TI - In vivo Studies on Antidiabetic Plants Used in South African Herbal Medicine. AB - Diabetes is one of the most common metabolic disorders worldwide. It is a major health problem with its frequency increasing every day in most countries. The disease is generally believed to be incurable; and the few orthodox drugs available to manage the disease are not readily affordable to the poor. Based on the historical success of natural products as antidiabetic agents and the ever increasing need for new antidiabetics, a number of South African medicinal plants have been evaluated for their antidiabetic properties. In this article, we review the major studies conducted based on ethnobotanical surveys carried out between 2005 and 2008 in South Africa on plants that are traditionally used for the treatment of diabetes. Overall, the results of the studies conducted confirmed the potential of South African medicinal plants in antidiabetic drug discovery and identified a number of promising taxa for further in vivo investigation as plant-based antidiabetic agents. PMID- 20838565 TI - A tracer analysis study on the redistribution and oxidization of endogenous carbon monoxide in the human body. AB - Past studies have suggested that some carbon monoxide (CO) moves from blood haemoglobin to tissue cells and that mitochondrial cytochrome c oxidase oxidizes CO to carbon dioxide (CO(2)). However, no study has demonstrated this redistribution and oxidization of CO under physiological conditions. The objective of this study was to trace the redistribution and oxidization of CO in the human body by detecting (13)CO(2) production after the inhalation of (13)CO. In Experiment 1, we asked a healthy subject to inhale 50 ppm (13)CO gas. In Experiment 2, we circulated heparinized human blood in a cardio-pulmonary bypass circuit and supplied 50 ppm (13)CO gas to the oxygenator. We sequentially sampled exhaled and output gases and measured the (13)CO(2)/(12)CO(2) ratios. In Experiment 1, the exhaled (13)CO(2)/(12)CO(2) ratio increased significantly between 4 to 31 h of (13)CO inhalation. In Experiment 2, the output (13)CO(2)/(12)CO(2) ratio showed no significant increase within 36 h of (13)CO input. Experiment 1 demonstrated the oxidization of CO in the human body under physiological conditions. Experiment 2 confirmed that oxidization does not occur in the circulating blood and indicated the redistribution of CO from blood carboxyhaemoglobin to tissue cells. PMID- 20838566 TI - The Alterations of Erythrocyte Phospholipids in Type 2 Diabetes Observed after Oral High-Fat Meal Loading: The FTIR Spectroscopic and Mass Spectrometric Studies. AB - Little is known about the postprandial remodelling of erythrocytes phospholipids (PLs) in type 2 diabetics (T2DM). Therefore, this study aims to compare the alterations of erythrocyte PLs in T2DM to those of healthy subjects after ingestion of a high-fat meal. Eleven T2DM and ten healthy subjects underwent a high-fat meal loading. Erythrocytes were isolated from blood obtained after fasting and 4 h after the meal. Fourier Transform Infrared (FTIR) spectroscopy was initially used to screen erythrocyte PLs by monitoring C-H stretching vibrations. Phosphatidylcholine (PC) molecular species were further investigated by Liquid Chromatography-Electrospray Ionisation-Mass Spectrometry (LC-ESI-MS). For the control group, FTIR revealed postprandial changes in C-H stretching vibrations, particularly of the olefinic band. These findings were supported by LC-ESI-MS data, showing marked changes in PC molecular species, especially of the PC34:1 (where 34 and 1 mean the summed number of carbons and double bonds, respectively). However, similar changes of those were not apparent in the T2DM group. Our results reveal marked postprandial alterations of erythrocyte PC species in healthy subjects whereas only mild alterations are observed in T2DM. The discrepant effects of high-fat meal loading suggest abnormal PC remodelling in the diabetic erythrocyte that may affect its membrane fluidity and integrity. PMID- 20838567 TI - Neuroprotective Effects of Astaxanthin in Oxygen-Glucose Deprivation in SH-SY5Y Cells and Global Cerebral Ischemia in Rat. AB - Astaxanthin (ATX), a naturally occurring carotenoid pigment, is a powerful biological antioxidant. In the present study, we investigated whether ATX pharmacologically offers neuroprotection against oxidative stress by cerebral ischemia. We found that the neuroprotective efficacy of ATX at the dose of 30 mg/kg (n = 8) was 59.5% compared with the control group (n = 3). In order to make clear the mechanism of ATX neuroprotection, the up-regulation inducible nitric oxide synthase (iNOS) and heat shock proteins (HSPs) together with the oxygen glucose deprivation (OGD) in SH-SY5Y cells were also investigated. The induction of various factors involved in oxidative stress processes such as iNOS was suppressed by the treatment of ATX at 25 and 50 uM after OGD-induced oxidative stress. In addition, Western blots showed that ATX elevated of heme oxygenase-1 (HO-1; Hsp32) and Hsp70 protein levels in in vitro. These results suggest that the neuroprotective effects of ATX were related to anti-oxidant activities in global ischemia. PMID- 20838568 TI - Evaluation of therapeutic effects of astaxanthin on impairments in salivary secretion. AB - The involvement of reactive oxygen species (ROS) in the pathophysiology of Sjogren's syndrome (SS), an autoimmune disorder, and irradiation-induced impairments in salivary secretion has been reported. Meanwhile, the strong antioxidant astaxanthin (Ast) has been suggested to have therapeutic effects on various diseases. In the present study, we examined the ROS scavenging capacity of Ast using a human salivary gland epithelial cell line (HSY) and investigated the effects of Ast on salivary secretion in a mouse model of irradiation-induced salivary gland dysfunction. Furthermore, we performed a clinical study of Ast in six SS patients and six normal individuals, quantifying the volume of saliva secretion and the level of oxidative stress markers in the saliva. Ast partially suppressed hydrogen peroxide-induced ROS in HSY cells. The mouse model demonstrated that the pre-administration of Ast resulted in the suppression of irradiation-induced hyposalivation. Furthermore, the administration of Ast appeared to increase salivary output in both the SS and normal groups. The level of oxidative stress marker, hexanoyl-lysine, in the saliva was reduced after Ast intake. These results suggest that Ast might act as an ROS scavenger, providing benefits to SS patients with impaired salivary secretion. PMID- 20838569 TI - Loxoprofen Sodium, a Non-Selective NSAID, Reduces Atherosclerosis in Mice by Reducing Inflammation. AB - Recently, it is suggested that the use of nonsteroidal anti-inflammatory drugs (NSAID) may contribute to the occurrence of cardiovascular events, while the formation of atherosclerotic lesions is related to inflammation. Loxoprofen sodium, a non-selective NSAID, becomes active after metabolism in the body and inhibits the activation of cyclooxygenase. We fed apoE(-/-) mice a western diet from 8 to 16 weeks of age and administered loxoprofen sodium. We measured atherosclerotic lesions at the aortic root. We examined serum levels of cholesterol and triglycerides with HPLC, platelet aggregation, and urinary prostaglandin metabolites with enzyme immune assay. Atherosclerotic lesion formation was reduced to 63.5% and 41.5% as compared to the control in male and female apoE(-/-) mice treated with loxoprofen sodium respectively. Urinary metabolites of prostaglandin E(2), F(1alpha), and thromboxane B(2), and platelet aggregation were decreased in mice treated with loxoprofen sodium. Serum levels of cholesterol and triglycerides were not changed. We conclude that loxoprofen sodium reduced the formation of early to intermediate atherosclerotic lesions at the proximal aorta in mice mediated by an anti-inflammatory effect. PMID- 20838570 TI - Protective Effects of Vitamin E Analogs against Carbon Tetrachloride-Induced Fatty Liver in Rats. AB - Recently, it has been reported that alpha-tocopherol (alpha-Toc) is effective for amelioration of liver damage. However, it is unknown whether other vitamin E analogs are effective. In this study, we investigated the effects of gamma tocopherol (gamma-Toc) and tocotrienols (T3) in rats with fatty liver. Rats fed a vitamin E-deficient diet for four weeks were divided into eight groups: Control, carbon tetrachloride (CCl(4)), alpha-Toc, alpha-Toc + CCl(4), gamma-Toc, gamma Toc + CCl(4), T3 mix, T3 mix + CCl(4). After a 24 h fast, the rats were administered 20 mg of each of the vitamin E analogs, respectively. Moreover, the CCl(4) group were given 0.5 ml/kg body weight corn oil preparation containing CCl(4) 6 h after vitamin E administration. We measured the activities of aspartate aminotransferase and alanine aminotransferase (ALT) in plasma, and the contents of triglyceride (TG), total cholesterol (T-Chol) and vitamin E analogs in the liver. Also, we determined the hepatic expression of mRNA for inflammatory cytokines. The liver TG content in the gamma-Toc + CCl(4) and T3 mix + CCl(4) groups was decreased in comparison with the CCl(4) group. Moreover, ALT activity in the T3 mix + CCl(4) group was significantly lower than CCl(4) group. These findings suggest that gamma-Toc and T3 are effective for amelioration of fatty liver. PMID- 20838571 TI - Effects of mulberry leaf extract rich in 1-deoxynojirimycin on blood lipid profiles in humans. AB - Mulberry leaves are rich in 1-deoxynojirimycin (DNJ), an inhibitor of alpha glucosidase. We previously showed that DNJ-rich mulberry leaf extract suppressed elevation of postprandial blood glucose in humans. The objective of this study was to evaluate the effects of DNJ-rich mulberry leaf extract on plasma lipid profiles in humans. An open-label, single-group study was conducted in 10 subjects with initial serum triglyceride (TG) level >=200 mg/dl. Subjects ingested capsules containing DNJ-rich mulberry leaf extract at 12 mg three times daily before meals for 12 weeks. Our findings showed a modest decrease in serum TG level and beneficial changes in the lipoprotein profile following 12-week administration of DNJ-rich mulberry leaf extract. No significant changes in hematological or biochemical parameters were observed during the study period; no adverse events associated with DNJ-rich mulberry leaf extract occurred. PMID- 20838572 TI - Generation mechanism of radical species by tyrosine-tyrosinase reaction. AB - Alleviated melanin formation in the skin through inhibition of tyrosine tyrosinase reaction is one of the major targets of cosmetics for whitening ability. Since melanin has a pivotal role for photoprotection, there are pros and cons of inhibition of melanin formation. This study applying electron spin resonance (ESR)-spin trapping method revealed that (*)H and (*)OH are generated through tyrosine-tyrosinase reaction. When deuterium water was used instead of H(2)O, the signal of 5,5-dimethyl-1-pyrroline N-oxide (DMPO)-H (a spin adduct of DMPO and (*)H) greatly decreased, whilst DMPO-OH (a spin adduct of DMPO and (*)OH) did not. Thus, it is suggested that (*)H was derived from H(2)O, and (*)OH through oxidative catalytic process of tyrosine to dopaquinone. Our study suggests that tyrosinase inhibitors might contribute to alleviate the oxidative damage of the skin by inhibiting (*)OH generation via the enzyme reaction. PMID- 20838573 TI - cis9, trans11-Conjugated Linoleic Acid Differentiates Mouse 3T3-L1 Preadipocytes into Mature Small Adipocytes through Induction of Peroxisome Proliferator activated Receptor gamma. AB - Dietary conjugated linoleic acid (CLA) has been reported to exhibit a number of therapeutic effects in animal models and patients, such as anti-hypertensive, anti-hyperlipidemic, anti-arteriosclerotic, anti-carcinogenic, and anti-diabetic effects. However, the underlying mechanism is not well-characterized. In the present study, the effects of cis(c)9, trans(t)11-CLA on the differentiation of mouse 3T3-L1 preadipocytes into mature adipocytes were examined. Treatment with c9, t11-CLA in the presence of insulin, dexamethasone, and 3-isobutyl-1-methyl xanthine (differentiation cocktail) significantly stimulated the accumulation of triacylglycerol. The microscopic observation of cells stained by Oil Red O demonstrated that c9, t11-CLA increases the amount and proportion of small mature adipocytes secreting adiponectin, a benign adipocytokine, when compared to the differentiation cocktail alone. Furthermore, c9, t11-CLA increased bioactive peroxisome proliferator-activated receptor gamma (PPARgamma) levels in a nuclear extract of 3T3-L1 cells, suggesting the enhancing effect of this fatty acid on the nuclear transmission of PPARgamma, a master regulator of adipocyte differentiation, in 3T3-L1 cells. These results suggest that the therapeutic effects of c9, t11-CLA on lifestyle-related diseases are partially due to the enhanced formation of small adipocytes from preadipocytes via PPARgamma stimulation. PMID- 20838574 TI - Folic Acid supplementation stimulates notch signaling and cell proliferation in embryonic neural stem cells. AB - The present study investigated the effect of folic acid supplementation on the Notch signaling pathway and cell proliferation in rat embryonic neural stem cells (NSCs). The NSCs were isolated from E14-16 rat brain and grown as neurospheres in serum-free suspension culture. Individual cultures were assigned to one of 3 treatment groups that differed according to the concentration of folic acid in the medium: Control (baseline folic acid concentration of 4 mg/l), low folic acid supplementation (4 mg/l above baseline, Folate-L) and high folic acid supplementation (40 mg/l above baseline, Folate-H). NSCs were identified by their expression of immunoreactive nestin and proliferating cells by incorporation of 5'bromo-2'deoxyuridine. Cell proliferation was also assessed by methyl thiazolyl tetrazolium assay. Notch signaling was analyzed by real-time PCR and western blot analyses of the expression of Notch1 and hairy and enhancer of split 5 (Hes5). Supplementation of NSCs with folic acid increased the mRNA and protein expression levels of Notch1 and Hes5. Folic acid supplementation also stimulated NSC proliferation dose-dependently. Embryonic NSCs respond to folic acid supplementation with increased Notch signaling and cell proliferation. This mechanism may mediate the effects of folic acid supplementation on neurogenesis in the embryonic nervous system. PMID- 20838575 TI - Minimal mesoscale model for protein-mediated vesiculation in clathrin-dependent endocytosis. AB - In eukaryotic cells, the internalization of extracellular cargo via the endocytic machinery is an important regulatory process required for many essential cellular functions. The role of cooperative protein-protein and protein-membrane interactions in the ubiquitous endocytic pathway in mammalian cells, namely the clathrin-dependent endocytosis, remains unresolved. We employ the Helfrich membrane Hamiltonian together with surface evolution methodology to address how the shapes and energetics of vesicular-bud formation in a planar membrane are stabilized by presence of the clathrin-coat assembly. Our results identify a unique dual role for the tubulating protein epsin: multiple epsins localized spatially and orientationally collectively play the role of a curvature inducing capsid; in addition, epsin serves the role of an adapter in binding the clathrin coat to the membrane. Our results also suggest an important role for the clathrin lattice, namely in the spatial- and orientational-templating of epsins. We suggest that there exists a critical size of the coat above which a vesicular bud with a constricted neck resembling a mature vesicle is stabilized. Based on the observed strong dependence of the vesicle diameter on the bending rigidity, we suggest that the variability in bending stiffness due to variations in membrane composition with cell type can explain the experimentally observed variability on the size of clathrin-coated vesicles, which typically range 50-100 nm. Our model also provides estimates for the number of epsins involved in stabilizing a coated vesicle, and without any direct fitting reproduces the experimentally observed shapes of vesicular intermediates as well as their probability distributions quantitatively, in wildtype as well as CLAP IgG injected neuronal cell experiments. We have presented a minimal mesoscale model which quantitatively explains several experimental observations on the process of vesicle nucleation induced by the clathrin-coated assembly prior to vesicle scission in clathrin dependent endocytosis. PMID- 20838576 TI - The distinct conformational dynamics of K-Ras and H-Ras A59G. AB - Ras proteins regulate signaling cascades crucial for cell proliferation and differentiation by switching between GTP- and GDP-bound conformations. Distinct Ras isoforms have unique physiological functions with individual isoforms associated with different cancers and developmental diseases. Given the small structural differences among isoforms and mutants, it is currently unclear how these functional differences and aberrant properties arise. Here we investigate whether the subtle differences among isoforms and mutants are associated with detectable dynamical differences. Extensive molecular dynamics simulations reveal that wild-type K-Ras and mutant H-Ras A59G are intrinsically more dynamic than wild-type H-Ras. The crucial switch 1 and switch 2 regions along with loop 3, helix 3, and loop 7 contribute to this enhanced flexibility. Removing the gamma phosphate of the bound GTP from the structure of A59G led to a spontaneous GTP-to GDP conformational transition in a 20-ns unbiased simulation. The switch 1 and 2 regions exhibit enhanced flexibility and correlated motion when compared to non transitioning wild-type H-Ras over a similar timeframe. Correlated motions between loop 3 and helix 5 of wild-type H-Ras are absent in the mutant A59G reflecting the enhanced dynamics of the loop 3 region. Taken together with earlier findings, these results suggest the existence of a lower energetic barrier between GTP and GDP states of the mutant. Molecular dynamics simulations combined with principal component analysis of available Ras crystallographic structures can be used to discriminate ligand- and sequence-based dynamic perturbations with potential functional implications. Furthermore, the identification of specific conformations associated with distinct Ras isoforms and mutants provides useful information for efforts that attempt to selectively interfere with the aberrant functions of these species. PMID- 20838577 TI - Rescuing loading induced bone formation at senescence. AB - The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca(2+)/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential. PMID- 20838578 TI - A dynamic neural field model of mesoscopic cortical activity captured with voltage-sensitive dye imaging. AB - A neural field model is presented that captures the essential non-linear characteristics of activity dynamics across several millimeters of visual cortex in response to local flashed and moving stimuli. We account for physiological data obtained by voltage-sensitive dye (VSD) imaging which reports mesoscopic population activity at high spatio-temporal resolution. Stimulation included a single flashed square, a single flashed bar, the line-motion paradigm--for which psychophysical studies showed that flashing a square briefly before a bar produces sensation of illusory motion within the bar--and moving squares controls. We consider a two-layer neural field (NF) model describing an excitatory and an inhibitory layer of neurons as a coupled system of non-linear integro-differential equations. Under the assumption that the aggregated activity of both layers is reflected by VSD imaging, our phenomenological model quantitatively accounts for the observed spatio-temporal activity patterns. Moreover, the model generalizes to novel similar stimuli as it matches activity evoked by moving squares of different speeds. Our results indicate that feedback from higher brain areas is not required to produce motion patterns in the case of the illusory line-motion paradigm. Physiological interpretation of the model suggests that a considerable fraction of the VSD signal may be due to inhibitory activity, supporting the notion that balanced intra-layer cortical interactions between inhibitory and excitatory populations play a major role in shaping dynamic stimulus representations in the early visual cortex. PMID- 20838579 TI - Drug-induced regulation of target expression. AB - Drug perturbations of human cells lead to complex responses upon target binding. One of the known mechanisms is a (positive or negative) feedback loop that adjusts the expression level of the respective target protein. To quantify this mechanism systems-wide in an unbiased way, drug-induced differential expression of drug target mRNA was examined in three cell lines using the Connectivity Map. To overcome various biases in this valuable resource, we have developed a computational normalization and scoring procedure that is applicable to gene expression recording upon heterogeneous drug treatments. In 1290 drug-target relations, corresponding to 466 drugs acting on 167 drug targets studied, 8% of the targets are subject to regulation at the mRNA level. We confirmed systematically that in particular G-protein coupled receptors, when serving as known targets, are regulated upon drug treatment. We further newly identified drug-induced differential regulation of Lanosterol 14-alpha demethylase, Endoplasmin, DNA topoisomerase 2-alpha and Calmodulin 1. The feedback regulation in these and other targets is likely to be relevant for the success or failure of the molecular intervention. PMID- 20838580 TI - Pavlovian-instrumental interaction in 'observing behavior'. AB - Subjects typically choose to be presented with stimuli that predict the existence of future reinforcements. This so-called 'observing behavior' is evident in many species under various experimental conditions, including if the choice is expensive, or if there is nothing that subjects can do to improve their lot with the information gained. A recent study showed that the activities of putative midbrain dopamine neurons reflect this preference for observation in a way that appears to challenge the common prediction-error interpretation of these neurons. In this paper, we provide an alternative account according to which observing behavior arises from a small, possibly Pavlovian, bias associated with the operation of working memory. PMID- 20838581 TI - Synaptic plasticity controls sensory responses through frequency-dependent gamma oscillation resonance. AB - Synchronized gamma frequency oscillations in neural networks are thought to be important to sensory information processing, and their effects have been intensively studied. Here we describe a mechanism by which the nervous system can readily control gamma oscillation effects, depending selectively on visual stimuli. Using a model neural network simulation, we found that sensory response in the primary visual cortex is significantly modulated by the resonance between "spontaneous" and "stimulus-driven" oscillations. This gamma resonance can be precisely controlled by the synaptic plasticity of thalamocortical connections, and cortical response is regulated differentially according to the resonance condition. The mechanism produces a selective synchronization between the afferent and downstream neural population. Our simulation results explain experimental observations such as stimulus-dependent synchronization between the thalamus and the cortex at different oscillation frequencies. The model generally shows how sensory information can be selectively routed depending on its frequency components. PMID- 20838582 TI - High resolution models of transcription factor-DNA affinities improve in vitro and in vivo binding predictions. AB - Accurately modeling the DNA sequence preferences of transcription factors (TFs), and using these models to predict in vivo genomic binding sites for TFs, are key pieces in deciphering the regulatory code. These efforts have been frustrated by the limited availability and accuracy of TF binding site motifs, usually represented as position-specific scoring matrices (PSSMs), which may match large numbers of sites and produce an unreliable list of target genes. Recently, protein binding microarray (PBM) experiments have emerged as a new source of high resolution data on in vitro TF binding specificities. PBM data has been analyzed either by estimating PSSMs or via rank statistics on probe intensities, so that individual sequence patterns are assigned enrichment scores (E-scores). This representation is informative but unwieldy because every TF is assigned a list of thousands of scored sequence patterns. Meanwhile, high-resolution in vivo TF occupancy data from ChIP-seq experiments is also increasingly available. We have developed a flexible discriminative framework for learning TF binding preferences from high resolution in vitro and in vivo data. We first trained support vector regression (SVR) models on PBM data to learn the mapping from probe sequences to binding intensities. We used a novel -mer based string kernel called the di mismatch kernel to represent probe sequence similarities. The SVR models are more compact than E-scores, more expressive than PSSMs, and can be readily used to scan genomics regions to predict in vivo occupancy. Using a large data set of yeast and mouse TFs, we found that our SVR models can better predict probe intensity than the E-score method or PBM-derived PSSMs. Moreover, by using SVRs to score yeast, mouse, and human genomic regions, we were better able to predict genomic occupancy as measured by ChIP-chip and ChIP-seq experiments. Finally, we found that by training kernel-based models directly on ChIP-seq data, we greatly improved in vivo occupancy prediction, and by comparing a TF's in vitro and in vivo models, we could identify cofactors and disambiguate direct and indirect binding. PMID- 20838583 TI - An integrative multi-network and multi-classifier approach to predict genetic interactions. AB - Genetic interactions occur when a combination of mutations results in a surprising phenotype. These interactions capture functional redundancy, and thus are important for predicting function, dissecting protein complexes into functional pathways, and exploring the mechanistic underpinnings of common human diseases. Synthetic sickness and lethality are the most studied types of genetic interactions in yeast. However, even in yeast, only a small proportion of gene pairs have been tested for genetic interactions due to the large number of possible combinations of gene pairs. To expand the set of known synthetic lethal (SL) interactions, we have devised an integrative, multi-network approach for predicting these interactions that significantly improves upon the existing approaches. First, we defined a large number of features for characterizing the relationships between pairs of genes from various data sources. In particular, these features are independent of the known SL interactions, in contrast to some previous approaches. Using these features, we developed a non-parametric multi classifier system for predicting SL interactions that enabled the simultaneous use of multiple classification procedures. Several comprehensive experiments demonstrated that the SL-independent features in conjunction with the advanced classification scheme led to an improved performance when compared to the current state of the art method. Using this approach, we derived the first yeast transcription factor genetic interaction network, part of which was well supported by literature. We also used this approach to predict SL interactions between all non-essential gene pairs in yeast (http://sage.fhcrc.org/downloads/downloads/predicted_yeast_genetic_interactions.z p). This integrative approach is expected to be more effective and robust in uncovering new genetic interactions from the tens of millions of unknown gene pairs in yeast and from the hundreds of millions of gene pairs in higher organisms like mouse and human, in which very few genetic interactions have been identified to date. PMID- 20838584 TI - The APETALA-2-like transcription factor OsAP2-39 controls key interactions between abscisic acid and gibberellin in rice. AB - The interaction between phytohormones is an important mechanism which controls growth and developmental processes in plants. Deciphering these interactions is a crucial step in helping to develop crops with enhanced yield and resistance to environmental stresses. Controlling the expression level of OsAP2-39 which includes an APETALA 2 (AP2) domain leads to phenotypic changes in rice. Overexpression of OsAP2-39 leads to a reduction in yield by decreasing the biomass and the number of seeds in the transgenic rice lines. Global transcriptome analysis of the OsAP2-39 overexpression transgenic rice revealed the upregulation of a key abscisic acid (ABA) biosynthetic gene OsNCED-I which codes for 9-cis-epoxycarotenoid dioxygenase and leads to an increase in the endogenous ABA level. In addition to OsNCED-1, the gene expression analysis revealed the upregulation of a gene that codes for the Elongation of Upper most Internode (EUI) protein, an enzyme that catalyzes 16alpha, 17-epoxidation of non 13-hydroxylated GAs, which has been shown to deactivate gibberellins (GAs) in rice. The exogenous application of GA restores the wild-type phenotype in the transgenic line and ABA application induces the expression of EUI and suppresses the expression of OsAP2-39 in the wild-type line. These observations clarify the antagonistic relationship between ABA and GA and illustrate a mechanism that leads to homeostasis of these hormones. In vivo and in vitro analysis showed that the expression of both OsNCED-1 and EUI are directly controlled by OsAP2-39. Together, these results reveal a novel mechanism for the control of the ABA/GA balance in rice which is regulated by OsAP2-39 that in turn regulates plant growth and seed production. PMID- 20838585 TI - Longitudinal genome-wide association of cardiovascular disease risk factors in the Bogalusa heart study. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P = 9.7 x 10(-24)), and rs445925 at APOE with LDL levels (combined P = 8.7 x 10(-19)). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children. PMID- 20838586 TI - Perturbation analysis of heterochromatin-mediated gene silencing and somatic inheritance. AB - Repetitive sequences in eukaryotic genomes induce chromatin-mediated gene silencing of juxtaposed genes. Many components that promote or antagonize silencing have been identified, but how heterochromatin causes variegated and heritable changes in gene expression remains mysterious. We have used inducible mis-expression in the Drosophila eye to recover new factors that alter silencing caused by the bw(D) allele, an insertion of repetitive satellite DNA that silences a bw(+) allele on the homologous chromosome. Inducible modifiers allow perturbation of silencing at different times in development, and distinguish factors that affect establishment or maintenance of silencing. We find that diverse chromatin and RNA processing factors can de-repress silencing. Most factors are effective even in differentiated cells, implying that silent chromatin remains plastic. However, over-expression of the bantam microRNA or the crooked-legs (crol) zinc-finger protein only de-repress silencing when expressed in cycling cells. Over-expression of crol accelerates the cell cycle, and this is required for de-repression of silencing. Strikingly, continual over-expression of crol converts the speckled variegation pattern of bw(D) into sectored variegation, where de-repression is stably inherited through mitotic divisions. Over-expression of crol establishes an open chromatin state, but the factor is not needed to maintain this state. Our analysis reveals that active chromatin states can be efficiently inherited through cell divisions, with implications for the stable maintenance of gene expression patterns through development. PMID- 20838588 TI - Long- and short-term selective forces on malaria parasite genomes. AB - Plasmodium parasites, the causal agents of malaria, result in more than 1 million deaths annually. Plasmodium are unicellular eukaryotes with small ~23 Mb genomes encoding ~5200 protein-coding genes. The protein-coding genes comprise about half of these genomes. Although evolutionary processes have a significant impact on malaria control, the selective pressures within Plasmodium genomes are poorly understood, particularly in the non-protein-coding portion of the genome. We use evolutionary methods to describe selective processes in both the coding and non coding regions of these genomes. Based on genome alignments of seven Plasmodium species, we show that protein-coding, intergenic and intronic regions are all subject to purifying selection and we identify 670 conserved non-genic elements. We then use genome-wide polymorphism data from P. falciparum to describe short term selective processes in this species and identify some candidate genes for balancing (diversifying) selection. Our analyses suggest that there are many functional elements in the non-genic regions of these genomes and that adaptive evolution has occurred more frequently in the protein-coding regions of the genome. PMID- 20838587 TI - Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. AB - Investigators have linked rare copy number variation (CNVs) to neuropsychiatric diseases, such as schizophrenia. One hypothesis is that CNV events cause disease by affecting genes with specific brain functions. Under these circumstances, we expect that CNV events in cases should impact brain-function genes more frequently than those events in controls. Previous publications have applied "pathway" analyses to genes within neuropsychiatric case CNVs to show enrichment for brain-functions. While such analyses have been suggestive, they often have not rigorously compared the rates of CNVs impacting genes with brain function in cases to controls, and therefore do not address important confounders such as the large size of brain genes and overall differences in rates and sizes of CNVs. To demonstrate the potential impact of confounders, we genotyped rare CNV events in 2,415 unaffected controls with Affymetrix 6.0; we then applied standard pathway analyses using four sets of brain-function genes and observed an apparently highly significant enrichment for each set. The enrichment is simply driven by the large size of brain-function genes. Instead, we propose a case-control statistical test, cnv-enrichment-test, to compare the rate of CNVs impacting specific gene sets in cases versus controls. With simulations, we demonstrate that cnv-enrichment-test is robust to case-control differences in CNV size, CNV rate, and systematic differences in gene size. Finally, we apply cnv-enrichment test to rare CNV events published by the International Schizophrenia Consortium (ISC). This approach reveals nominal evidence of case-association in neuronal activity and the learning gene sets, but not the other two examined gene sets. The neuronal-activity genes have been associated in a separate set of schizophrenia cases and controls; however, testing in independent samples is necessary to definitively confirm this association. Our method is implemented in the PLINK software package. PMID- 20838589 TI - Evolution and optimality of similar neural mechanisms for perception and action during search. AB - A prevailing theory proposes that the brain's two visual pathways, the ventral and dorsal, lead to differing visual processing and world representations for conscious perception than those for action. Others have claimed that perception and action share much of their visual processing. But which of these two neural architectures is favored by evolution? Successful visual search is life-critical and here we investigate the evolution and optimality of neural mechanisms mediating perception and eye movement actions for visual search in natural images. We implement an approximation to the ideal Bayesian searcher with two separate processing streams, one controlling the eye movements and the other stream determining the perceptual search decisions. We virtually evolved the neural mechanisms of the searchers' two separate pathways built from linear combinations of primary visual cortex receptive fields (V1) by making the simulated individuals' probability of survival depend on the perceptual accuracy finding targets in cluttered backgrounds. We find that for a variety of targets, backgrounds, and dependence of target detectability on retinal eccentricity, the mechanisms of the searchers' two processing streams converge to similar representations showing that mismatches in the mechanisms for perception and eye movements lead to suboptimal search. Three exceptions which resulted in partial or no convergence were a case of an organism for which the targets are equally detectable across the retina, an organism with sufficient time to foveate all possible target locations, and a strict two-pathway model with no interconnections and differential pre-filtering based on parvocellular and magnocellular lateral geniculate cell properties. Thus, similar neural mechanisms for perception and eye movement actions during search are optimal and should be expected from the effects of natural selection on an organism with limited time to search for food that is not equi-detectable across its retina and interconnected perception and action neural pathways. PMID- 20838590 TI - Mutational patterns cannot explain genome composition: Are there any neutral sites in the genomes of bacteria? PMID- 20838591 TI - Synthesizing and salvaging NAD: lessons learned from Chlamydomonas reinhardtii. AB - The essential coenzyme nicotinamide adenine dinucleotide (NAD+) plays important roles in metabolic reactions and cell regulation in all organisms. Bacteria, fungi, plants, and animals use different pathways to synthesize NAD+. Our molecular and genetic data demonstrate that in the unicellular green alga Chlamydomonas NAD+ is synthesized from aspartate (de novo synthesis), as in plants, or nicotinamide, as in mammals (salvage synthesis). The de novo pathway requires five different enzymes: L-aspartate oxidase (ASO), quinolinate synthetase (QS), quinolate phosphoribosyltransferase (QPT), nicotinate/nicotinamide mononucleotide adenylyltransferase (NMNAT), and NAD+ synthetase (NS). Sequence similarity searches, gene isolation and sequencing of mutant loci indicate that mutations in each enzyme result in a nicotinamide requiring mutant phenotype in the previously isolated nic mutants. We rescued the mutant phenotype by the introduction of BAC DNA (nic2-1 and nic13-1) or plasmids with cloned genes (nic1-1 and nic15-1) into the mutants. NMNAT, which is also in the de novo pathway, and nicotinamide phosphoribosyltransferase (NAMPT) constitute the nicotinamide-dependent salvage pathway. A mutation in NAMPT (npt1 1) has no obvious growth defect and is not nicotinamide-dependent. However, double mutant strains with the npt1-1 mutation and any of the nic mutations are inviable. When the de novo pathway is inactive, the salvage pathway is essential to Chlamydomonas for the synthesis of NAD+. A homolog of the human SIRT6-like gene, SRT2, is upregulated in the NS mutant, which shows a longer vegetative life span than wild-type cells. Our results suggest that Chlamydomonas is an excellent model system to study NAD+ metabolism and cell longevity. PMID- 20838593 TI - Evidence of selection upon genomic GC-content in bacteria. AB - The genomic GC-content of bacteria varies dramatically, from less than 20% to more than 70%. This variation is generally ascribed to differences in the pattern of mutation between bacteria. Here we test this hypothesis by examining patterns of synonymous polymorphism using datasets from 149 bacterial species. We find a large excess of synonymous GC->AT mutations over AT->GC mutations segregating in all but the most AT-rich bacteria, across a broad range of phylogenetically diverse species. We show that the excess of GC->AT mutations is inconsistent with mutation bias, since it would imply that most GC-rich bacteria are declining in GC-content; such a pattern would be unsustainable. We also show that the patterns are probably not due to translational selection or biased gene conversion, because optimal codons tend to be AT-rich, and the excess of GC->AT SNPs is observed in datasets with no evidence of recombination. We therefore conclude that there is selection to increase synonymous GC-content in many species. Since synonymous GC-content is highly correlated to genomic GC-content, we further conclude that there is selection on genomic base composition in many bacteria. PMID- 20838592 TI - DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo. AB - The DNTM3A and DNMT3B de novo DNA methyltransferases (DNMTs) are responsible for setting genomic DNA methylation patterns, a key layer of epigenetic information. Here, using an in vivo episomal methylation assay and extensive bisulfite methylation sequencing, we show that human DNMT3A and DNMT3B possess significant and distinct flanking sequence preferences for target CpG sites. Selection for high or low efficiency sites is mediated by the base composition at the -2 and +2 positions flanking the CpG site for DNMT3A, and at the -1 and +1 positions for DNMT3B. This intrinsic preference reproducibly leads to the formation of specific de novo methylation patterns characterized by up to 34-fold variations in the efficiency of DNA methylation at individual sites. Furthermore, analysis of the distribution of signature methylation hotspot and coldspot motifs suggests that DNMT flanking sequence preference has contributed to shaping the composition of CpG islands in the human genome. Our results also show that the DNMT3L stimulatory factor modulates the formation of de novo methylation patterns in two ways. First, DNMT3L selectively focuses the DNA methylation machinery on properly chromatinized DNA templates. Second, DNMT3L attenuates the impact of the intrinsic DNMT flanking sequence preference by providing a much greater boost to the methylation of poorly methylated sites, thus promoting the formation of broader and more uniform methylation patterns. This study offers insights into the manner by which DNA methylation patterns are deposited and reveals a new level of interplay between members of the de novo DNMT family. PMID- 20838594 TI - Network analysis identifies ELF3 as a QTL for the shade avoidance response in Arabidopsis. AB - Quantitative Trait Loci (QTL) analyses in immortal populations are a powerful method for exploring the genetic mechanisms that control interactions of organisms with their environment. However, QTL analyses frequently do not culminate in the identification of a causal gene due to the large chromosomal regions often underlying QTLs. A reasonable approach to inform the process of causal gene identification is to incorporate additional genome-wide information, which is becoming increasingly accessible. In this work, we perform QTL analysis of the shade avoidance response in the Bayreuth-0 (Bay-0, CS954) x Shahdara (Sha, CS929) recombinant inbred line population of Arabidopsis. We take advantage of the complex pleiotropic nature of this trait to perform network analysis using co expression, eQTL and functional classification from publicly available datasets to help us find good candidate genes for our strongest QTL, SAR2. This novel network analysis detected EARLY FLOWERING 3 (ELF3; AT2G25930) as the most likely candidate gene affecting the shade avoidance response in our population. Further genetic and transgenic experiments confirmed ELF3 as the causative gene for SAR2. The Bay-0 and Sha alleles of ELF3 differentially regulate developmental time and circadian clock period length in Arabidopsis, and the extent of this regulation is dependent on the light environment. This is the first time that ELF3 has been implicated in the shade avoidance response and that different natural alleles of this gene are shown to have phenotypic effects. In summary, we show that development of networks to inform candidate gene identification for QTLs is a promising technique that can significantly accelerate the process of QTL cloning. PMID- 20838595 TI - Optimal strategy for competence differentiation in bacteria. AB - A phylogenetically diverse subset of bacterial species are naturally competent for transformation by DNA. Transformation entails recombination of genes between different lineages, representing a form of bacterial sex that increases standing genetic variation. We first assess whether homologous recombination by transformation is favored by evolution. Using stochastic population genetic computer simulations in which beneficial and deleterious mutations occur at many loci throughout the whole genome, we find that transformation can increase both the rate of adaptive evolution and the equilibrium level of fitness. Secondly, motivated by experimental observations of Bacillus subtilis, we assume that competence additionally entails a weak persister phenotype, i.e., the rates of birth and death are reduced for these cells. Consequently, persisters evolve more slowly than non-persisters. We show via simulation that strains which stochastically switch into and out of the competent phenotype are evolutionarily favored over strains that express only a single phenotype. Our model's simplicity enables us to derive and numerically solve a system of finite- deterministic equations that describe the evolutionary dynamics. The observed tradeoff between the benefit of recombination and the cost of persistence may explain the previously mysterious observation that only a fractional subpopulation of B. subtilis cells express competence. More generally, this work demonstrates that population genetic forces can give rise to phenotypic diversity even in an unchanging and homogeneous environment. PMID- 20838596 TI - A central regulatory system largely controls transcriptional activation and repression responses to phosphate starvation in Arabidopsis. AB - Plants respond to different stresses by inducing or repressing transcription of partially overlapping sets of genes. In Arabidopsis, the PHR1 transcription factor (TF) has an important role in the control of phosphate (Pi) starvation stress responses. Using transcriptomic analysis of Pi starvation in phr1, and phr1 phr1-like (phl1) mutants and in wild type plants, we show that PHR1 in conjunction with PHL1 controls most transcriptional activation and repression responses to phosphate starvation, regardless of the Pi starvation specificity of these responses. Induced genes are enriched in PHR1 binding sequences (P1BS) in their promoters, whereas repressed genes do not show such enrichment, suggesting that PHR1(-like) control of transcriptional repression responses is indirect. In agreement with this, transcriptomic analysis of a transgenic plant expressing PHR1 fused to the hormone ligand domain of the glucocorticoid receptor showed that PHR1 direct targets (i.e., displaying altered expression after GR:PHR1 activation by dexamethasone in the presence of cycloheximide) corresponded largely to Pi starvation-induced genes that are highly enriched in P1BS. A minimal promoter containing a multimerised P1BS recapitulates Pi starvation specific responsiveness. Likewise, mutation of P1BS in the promoter of two Pi starvation-responsive genes impaired their responsiveness to Pi starvation, but not to other stress types. Phylogenetic footprinting confirmed the importance of P1BS and PHR1 in Pi starvation responsiveness and indicated that P1BS acts in concert with other cis motifs. All together, our data show that PHR1 and PHL1 are partially redundant TF acting as central integrators of Pi starvation responses, both specific and generic. In addition, they indicate that transcriptional repression responses are an integral part of adaptive responses to stress. PMID- 20838597 TI - The baker's yeast diploid genome is remarkably stable in vegetative growth and meiosis. AB - Accurate estimates of mutation rates provide critical information to analyze genome evolution and organism fitness. We used whole-genome DNA sequencing, pulse field gel electrophoresis, and comparative genome hybridization to determine mutation rates in diploid vegetative and meiotic mutation accumulation lines of Saccharomyces cerevisiae. The vegetative lines underwent only mitotic divisions while the meiotic lines underwent a meiotic cycle every ~20 vegetative divisions. Similar base substitution rates were estimated for both lines. Given our experimental design, these measures indicated that the meiotic mutation rate is within the range of being equal to zero to being 55-fold higher than the vegetative rate. Mutations detected in vegetative lines were all heterozygous while those in meiotic lines were homozygous. A quantitative analysis of intra tetrad mating events in the meiotic lines showed that inter-spore mating is primarily responsible for rapidly fixing mutations to homozygosity as well as for removing mutations. We did not observe 1-2 nt insertion/deletion (in-del) mutations in any of the sequenced lines and only one structural variant in a non telomeric location was found. However, a large number of structural variations in subtelomeric sequences were seen in both vegetative and meiotic lines that did not affect viability. Our results indicate that the diploid yeast nuclear genome is remarkably stable during the vegetative and meiotic cell cycles and support the hypothesis that peripheral regions of chromosomes are more dynamic than gene rich central sections where structural rearrangements could be deleterious. This work also provides an improved estimate for the mutational load carried by diploid organisms. PMID- 20838598 TI - A single cis element maintains repression of the key developmental regulator Gata2. AB - In development, lineage-restricted transcription factors simultaneously promote differentiation while repressing alternative fates. Molecular dissection of this process has been challenging as transcription factor loci are regulated by many trans-acting factors functioning through dispersed cis elements. It is not understood whether these elements function collectively to confer transcriptional regulation, or individually to control specific aspects of activation or repression, such as initiation versus maintenance. Here, we have analyzed cis element regulation of the critical hematopoietic factor Gata2, which is expressed in early precursors and repressed as GATA-1 levels rise during terminal differentiation. We engineered mice lacking a single cis element -1.8 kb upstream of the Gata2 transcriptional start site. Although Gata2 is normally repressed in late-stage erythroblasts, the -1.8 kb mutation unexpectedly resulted in reactivated Gata2 transcription, blocked differentiation, and an aberrant lineage specific gene expression pattern. Our findings demonstrate that the -1.8 kb site selectively maintains repression, confers a specific histone modification pattern and expels RNA Polymerase II from the locus. These studies reveal how an individual cis element establishes a normal developmental program via regulating specific steps in the mechanism by which a critical transcription factor is repressed. PMID- 20838599 TI - Evidence that mutation is universally biased towards AT in bacteria. AB - Mutation is the engine that drives evolution and adaptation forward in that it generates the variation on which natural selection acts. Mutation is a random process that nevertheless occurs according to certain biases. Elucidating mutational biases and the way they vary across species and within genomes is crucial to understanding evolution and adaptation. Here we demonstrate that clonal pathogens that evolve under severely relaxed selection are uniquely suitable for studying mutational biases in bacteria. We estimate mutational patterns using sequence datasets from five such clonal pathogens belonging to four diverse bacterial clades that span most of the range of genomic nucleotide content. We demonstrate that across different types of sites and in all four clades mutation is consistently biased towards AT. This is true even in clades that have high genomic GC content. In all studied cases the mutational bias towards AT is primarily due to the high rate of C/G to T/A transitions. These results suggest that bacterial mutational biases are far less variable than previously thought. They further demonstrate that variation in nucleotide content cannot stem entirely from variation in mutational biases and that natural selection and/or a natural selection-like process such as biased gene conversion strongly affect nucleotide content. PMID- 20838600 TI - Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. AB - High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude. PMID- 20838601 TI - The transcriptome of the human pathogen Trypanosoma brucei at single-nucleotide resolution. AB - The genome of Trypanosoma brucei, the causative agent of African trypanosomiasis, was published five years ago, yet identification of all genes and their transcripts remains to be accomplished. Annotation is challenged by the organization of genes transcribed by RNA polymerase II (Pol II) into long unidirectional gene clusters with no knowledge of how transcription is initiated. Here we report a single-nucleotide resolution genomic map of the T. brucei transcriptome, adding 1,114 new transcripts, including 103 non-coding RNAs, confirming and correcting many of the annotated features and revealing an extensive heterogeneity of 5' and 3' ends. Some of the new transcripts encode polypeptides that are either conserved in T. cruzi and Leishmania major or were previously detected in mass spectrometry analyses. High-throughput RNA sequencing (RNA-Seq) was sensitive enough to detect transcripts at putative Pol II transcription initiation sites. Our results, as well as recent data from the literature, indicate that transcription initiation is not solely restricted to regions at the beginning of gene clusters, but may occur at internal sites. We also provide evidence that transcription at all putative initiation sites in T. brucei is bidirectional, a recently recognized fundamental property of eukaryotic promoters. Our results have implications for gene expression patterns in other important human pathogens with similar genome organization (Trypanosoma cruzi, Leishmania sp.) and revealed heterogeneity in pre-mRNA processing that could potentially contribute to the survival and success of the parasite population in the insect vector and the mammalian host. PMID- 20838602 TI - Phylogenomics of ligand-gated ion channels predicts monepantel effect. AB - The recently launched veterinary anthelmintic drench for sheep (Novartis Animal Health Inc., Switzerland) containing the nematocide monepantel represents a new class of anthelmintics: the amino-acetonitrile derivatives (AADs), much needed in view of widespread resistance to the classical drugs. Recently, it was shown that the ACR-23 protein in Caenorhabditis elegans and a homologous protein, MPTL-1 in Haemonchus contortus, are potential targets for AAD action. Both proteins belong to the DEG-3 subfamily of acetylcholine receptors, which are thought to be nematode-specific, and different from those targeted by the imidazothiazoles (e.g. levamisole). Here we provide further evidence that Cel-ACR-23 and Hco-MPTL 1-like subunits are involved in the monepantel-sensitive phenotype. We performed comparative genomics of ligand-gated ion channel genes from several nematodes and subsequently assessed their sensitivity to anthelmintics. The nematode species in the Caenorhabditis genus, equipped with ACR-23/MPTL-1-like receptor subunits, are sensitive to monepantel (EC(50)<1.25 uM), whereas the related nematodes Pristionchus pacificus and Strongyloides ratti, which lack an ACR-23/MPTL-1 homolog, are insensitive (EC(50)>43 uM). Genome sequence information has long been used to identify putative targets for therapeutic intervention. We show how comparative genomics can be applied to predict drug sensitivity when molecular targets of a compound are known or suspected. PMID- 20838603 TI - Incremental genetic perturbations to MCM2-7 expression and subcellular distribution reveal exquisite sensitivity of mice to DNA replication stress. AB - Mutations causing replication stress can lead to genomic instability (GIN). In vitro studies have shown that drastic depletion of the MCM2-7 DNA replication licensing factors, which form the replicative helicase, can cause GIN and cell proliferation defects that are exacerbated under conditions of replication stress. To explore the effects of incrementally attenuated replication licensing in whole animals, we generated and analyzed the phenotypes of mice that were hemizygous for Mcm2, 3, 4, 6, and 7 null alleles, combinations thereof, and also in conjunction with the hypomorphic Mcm4(Chaos3) cancer susceptibility allele. Mcm4(Chaos3/Chaos3) embryonic fibroblasts have ~40% reduction in all MCM proteins, coincident with reduced Mcm2-7 mRNA. Further genetic reductions of Mcm2, 6, or 7 in this background caused various phenotypes including synthetic lethality, growth retardation, decreased cellular proliferation, GIN, and early onset cancer. Remarkably, heterozygosity for Mcm3 rescued many of these defects. Consistent with a role in MCM nuclear export possessed by the yeast Mcm3 ortholog, the phenotypic rescues correlated with increased chromatin-bound MCMs, and also higher levels of nuclear MCM2 during S phase. The genetic, molecular and phenotypic data demonstrate that relatively minor quantitative alterations of MCM expression, homeostasis or subcellular distribution can have diverse and serious consequences upon development and confer cancer susceptibility. The results support the notion that the normally high levels of MCMs in cells are needed not only for activating the basal set of replication origins, but also "backup" origins that are recruited in times of replication stress to ensure complete replication of the genome. PMID- 20838605 TI - Standardization of Gene Expression Quantification by Absolute Real-Time qRT-PCR System Using a Single Standard for Marker and Reference Genes. AB - In the last decade, genome-wide gene expression data has been collected from a large number of cancer specimens. In many studies utilizing either microarray based or knowledge-based gene expression profiling, both the validation of candidate genes and the identification and inclusion of biomarkers in prognosis modeling has employed real-time quantitative PCR on reverse transcribed mRNA (qRT PCR) because of its inherent sensitivity and quantitative nature. In qRT-PCR data analysis, an internal reference gene is used to normalize the variation in input sample quantity. The relative quantification method used in current real-time qRT PCR analysis fails to ensure data comparability pivotal in identification of prognostic biomarkers. By employing an absolute qRT-PCR system that uses a single standard for marker and reference genes (SSMR) to achieve absolute quantification, we showed that the normalized gene expression data is comparable and independent of variations in the quantities of sample as well as the standard used for generating standard curves. We compared two sets of normalized gene expression data with same histological diagnosis of brain tumor from two labs using relative and absolute real-time qRT-PCR. Base-10 logarithms of the gene expression ratio relative to ACTB were evaluated for statistical equivalence between tumors processed by two different labs. The results showed an approximate comparability for normalized gene expression quantified using a SSMR-based qRT PCR. Incomparable results were seen for the gene expression data using relative real-time qRT-PCR, due to inequality in molar concentration of two standards for marker and reference genes. Overall results show that SSMR-based real-time qRT PCR ensures comparability of gene expression data much needed in establishment of prognostic/predictive models for cancer patients-a process that requires large sample sizes by combining independent sets of data. PMID- 20838604 TI - Cyclin-dependent kinase-like function is shared by the beta- and gamma- subset of the conserved herpesvirus protein kinases. AB - The UL97 protein of human cytomegalovirus (HCMV, or HHV-5 (human herpesvirus 5)), is a kinase that phosphorylates the cellular retinoblastoma (Rb) tumor suppressor and lamin A/C proteins that are also substrates of cellular cyclin-dependent kinases (Cdks). A functional complementation assay has further shown that UL97 has authentic Cdk-like activity. The other seven human herpesviruses each encode a kinase with sequence and positional homology to UL97. These UL97-homologous proteins have been termed the conserved herpesvirus protein kinases (CHPKs) to distinguish them from other human herpesvirus-encoded kinases. To determine if the Cdk-like activities of UL97 were shared by all of the CHPKs, we individually expressed epitope-tagged alleles of each protein in human Saos-2 cells to test for Rb phosphorylation, human U-2 OS cells to monitor nuclear lamina disruption and lamin A phosphorylation, or S. cerevisiae cdc28-13 mutant cells to directly assay for Cdk function. We found that the ability to phosphorylate Rb and lamin A, and to disrupt the nuclear lamina, was shared by all CHPKs from the beta- and gamma-herpesvirus families, but not by their alpha-herpesvirus homologs. Similarly, all but one of the beta and gamma CHPKs displayed bona fide Cdk activity in S. cerevisiae, while the alpha proteins did not. Thus, we have identified novel virally-encoded Cdk-like kinases, a nomenclature we abbreviate as v-Cdks. Interestingly, we found that other, non-Cdk-related activities reported for UL97 (dispersion of promyelocytic leukemia protein nuclear bodies (PML-NBs) and disruption of cytoplasmic or nuclear aggresomes) showed weak conservation among the CHPKs that, in general, did not segregate to specific viral families. Therefore, the genomic and evolutionary conservation of these kinases has not been fully maintained at the functional level. Our data indicate that these related kinases, some of which are targets of approved or developmental antiviral drugs, are likely to serve both overlapping and non overlapping functions during viral infections. PMID- 20838606 TI - Diagnostic markers for tuberculosis ascites: a preliminary study. AB - OBJECTIVE: The diagnosis of tuberculosis (TB) ascites is problematic. Delay in the diagnosis and treatment of TB ascites are considered to be major factors that contribute to the high mortality of TB. This study identifies specific protein markers in ascitic fluid which will be useful in diagnosis of TB ascites. METHODS: We used Two-Dimensional Electrophoresis, liquid chromatography-mass spectrometry/mass spectrometry, immunoblot analysis and Enzyme Linked Immunosorbent assay (ELISA) as a comprehensive quantitative proteomic screening system for the diagnosis of TB ascites. RESULTS: THE SCREEN IDENTIFIED SEVERAL ANTIGENS OF INTEREST: a 30-kilodalton (kDa) protein that demonstrated significant homology to the antigen 85B and 85C (Ag 85) complex; a 65-kDa protein that corresponded to Mycobacterium tuberculosis (MTB) heat shock protein 65 (65-kDa HSP), Rv0440; a 14-kDa protein and 71-kDa protein that exhibits an amino acid sequence identical to that of MTB heat shock protein 14 (14-kDa HSP), GroES; and MTB heat shock protein 71 (71-kDa HSP), Rv0350 respectively. ELISA confirmed that TB ascites patients were consistently positive for these antigens at higher rates than non-TB ascites patients. CONCLUSION: The 65-kDa HSP, 71-kDa HSP, 14-kDa HSP and Ag 85 complex proteins may serve as very useful diagnostic markers for TB ascites. PMID- 20838607 TI - Professional networks in the life sciences: linking the linked. AB - The world wide web has furthered the emergence of a multitude of online expert communities. Continued progress on many of the remaining complex scientific questions requires a wide ranging expertise spectrum with access to a variety of distinct data types. Moving beyond peer-to-peer to community-to-community interaction is therefore one of the biggest challenges for global interdisciplinary Life Sciences research, including that of cancer. Cross-domain data query, access, and retrieval will be important innovation areas to enable and facilitate this interaction in the coming years. PMID- 20838608 TI - Relationship between Selected Socio-Demographic Factors and Cancer of Oral Cavity - A Case Control Study. AB - The aim of this study was to recognize factors associated with cancer of oral cavity considering socio-demographic characteristics. The cases were 350 with squamous-cell carcinoma of oral cavity diagnosed between 2005 and 2006 in Morbai, Narandia, Budharani Cancer Institute, Pune, India. Similar number of controls match for age and sex selected from the background population. Cases and controls were interviewed for tobacco related habits and general characteristics; age, gender, education and possible socio-demographic factors. Chi-square test in uni variate analysis and estimate for risk showed that education, occupation and monthly household income were significantly different between cases and controls (P < 0.001). Irrespective to gender, relative risk, here odds ratio, (OR) of low level of education (OR = 5.3, CI 3.7-7.6), working in field as a farmer (OR = 2.5, CI 1.7-3.7), and monthly household income less than 5000 Indian Rupees currency (OR = 1.7, CI 1.2-2.3) were significant risk factors for oral cancer. While, there was no significant relationship between religious and or marital status either in males or females. PMID- 20838610 TI - Weibull-like Model of Cancer Development in Aging. AB - Mathematical modeling of cancer development is aimed at assessing the risk factors leading to cancer. Aging is a common risk factor for all adult cancers. The risk of getting cancer in aging is presented by a hazard function that can be estimated from the observed incidence rates collected in cancer registries. Recent analyses of the SEER database show that the cancer hazard function initially increases with the age, and then it turns over and falls at the end of the lifetime. Such behavior of the hazard function is poorly modeled by the exponential or compound exponential-linear functions mainly utilized for the modeling. In this work, for mathematical modeling of cancer hazards, we proposed to use the Weibull-like function, derived from the Armitage-Doll multistage concept of carcinogenesis and an assumption that number of clones at age t developed from mutated cells follows the Poisson distribution. This function is characterized by three parameters, two of which (r and lambda) are the conventional parameters of the Weibull probability distribution function, and an additional parameter (C(0)) that adjusts the model to the observational data. Biological meanings of these parameters are: r-the number of stages in carcinogenesis, lambda-an average number of clones developed from the mutated cells during the first year of carcinogenesis, and C(0)-a data adjustment parameter that characterizes a fraction of the age-specific population that will get this cancer in their lifetime. To test the validity of the proposed model, the nonlinear regression analysis was performed for the lung cancer (LC) data, collected in the SEER 9 database for white men and women during 1975-2004. Obtained results suggest that: (i) modeling can be improved by the use of another parameter A- the age at the beginning of carcinogenesis; and (ii) in white men and women, the processes of LC carcinogenesis vary by A and C(0), while the corresponding values of r and lambda are nearly the same. Overall, the proposed Weibull-like model provides an excellent fit of the estimates of the LC hazard function in aging. It is expected that the Weibull-like model can be applicable to fit estimates of hazard functions of other adult cancers as well. PMID- 20838609 TI - LTR: Linear Cross-Platform Integration of Microarray Data. AB - The size and scope of microarray experiments continue to increase. However, datasets generated on different platforms or at different centres contain biases. Improved techniques are needed to remove platform- and batch-specific biases. One experimental control is the replicate hybridization of a subset of samples at each site or on each platform to learn the relationship between the two platforms. To date, no algorithm exists to specifically use this type of control. LTR is a linear-modelling-based algorithm that learns the relationship between different microarray batches from replicate hybridizations. LTR was tested on a new benchmark dataset of 20 samples hybridized to different Affymetrix microarray platforms. Before LTR, the two platforms were significantly different; application of LTR removed this bias. LTR was tested with six separate data pre processing algorithms, and its effectiveness was independent of the pre processing algorithm. Sample-size experiments indicate that just three replicate hybridizations can significantly reduce bias. An R library implementing LTR is available. PMID- 20838611 TI - Inhibition of Antiapoptotic BCL-XL, BCL-2, and MCL-1 Proteins by Small Molecule Mimetics. AB - Informatics and computational design methods were used to create new molecules that could potentially bind antiapoptotic proteins, thus promoting death of cancer cells. Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, proapoptotic proteins bind antiapoptotic proteins, thus allowing apoptosis to go forward. An excess of antiapoptotic proteins can prevent apoptosis. Designed molecules that mimic the roles of proapoptotic proteins can promote the death of cancer cells. The goal of our study was to create new putative mimetics that could simultaneously bind several antiapoptotic proteins. Five new small molecules were designed that formed stable complexes with BCL-2, BCL-XL, and MCL-1 antiapoptotic proteins. These results are novel because, to our knowledge, there are not many, if any, small molecules known to bind all three proteins. Drug-likeness studies performed on the designed molecules, as well as previous experimental and preclinical studies on similar agents, strongly suggest that the designed molecules may indeed be promising drug candidates. All five molecules showed "drug-like" properties and had overall drug-likeness scores between 81% and 96%. A single drug based on these mimetics should cost less and cause fewer side effects than a combination of drugs each aimed at a single protein. Computer based molecular design promises to accelerate drug research by predicting potential effectiveness of designed molecules prior to laborious experiments and costly preclinical trials. PMID- 20838613 TI - Edge-related loss of tree phylogenetic diversity in the severely fragmented Brazilian Atlantic forest. AB - Deforestation and forest fragmentation are known major causes of nonrandom extinction, but there is no information about their impact on the phylogenetic diversity of the remaining species assemblages. Using a large vegetation dataset from an old hyper-fragmented landscape in the Brazilian Atlantic rainforest we assess whether the local extirpation of tree species and functional impoverishment of tree assemblages reduce the phylogenetic diversity of the remaining tree assemblages. We detected a significant loss of tree phylogenetic diversity in forest edges, but not in core areas of small (<80 ha) forest fragments. This was attributed to a reduction of 11% in the average phylogenetic distance between any two randomly chosen individuals from forest edges; an increase of 17% in the average phylogenetic distance to closest non-conspecific relative for each individual in forest edges; and to the potential manifestation of late edge effects in the core areas of small forest remnants. We found no evidence supporting fragmentation-induced phylogenetic clustering or evenness. This could be explained by the low phylogenetic conservatism of key life-history traits corresponding to vulnerable species. Edge effects must be reduced to effectively protect tree phylogenetic diversity in the severely fragmented Brazilian Atlantic forest. PMID- 20838612 TI - Multiethnic genetic association studies improve power for locus discovery. AB - To date, genome-wide association studies have focused almost exclusively on populations of European ancestry. These studies continue with the advent of next generation sequencing, designed to systematically catalog and test low-frequency variation for a role in disease. A complementary approach would be to focus further efforts on cohorts of multiple ethnicities. This leverages the idea that population genetic drift may have elevated some variants to higher allele frequency in different populations, boosting statistical power to detect an association. Based on empirical allele frequency distributions from eleven populations represented in HapMap Phase 3 and the 1000 Genomes Project, we simulate a range of genetic models to quantify the power of association studies in multiple ethnicities relative to studies that exclusively focus on samples of European ancestry. In each of these simulations, a first phase of GWAS in exclusively European samples is followed by a second GWAS phase in any of the other populations (including a multiethnic design). We find that nontrivial power gains can be achieved by conducting future whole-genome studies in worldwide populations, where, in particular, African populations contribute the largest relative power gains for low-frequency alleles (<5%) of moderate effect that suffer from low power in samples of European descent. Our results emphasize the importance of broadening genetic studies to worldwide populations to ensure efficient discovery of genetic loci contributing to phenotypic trait variability, especially for those traits for which large numbers of samples of European ancestry have already been collected and tested. PMID- 20838614 TI - Traits contributing to the autistic spectrum. AB - BACKGROUND: It is increasingly recognised that traits associated with autism reflect a spectrum with no clear boundary between typical and atypical behaviour. Dimensional traits are needed to investigate the broader autism phenotype. METHODS AND PRINCIPAL FINDINGS: Ninety-three individual measures reflecting components of social, communication and repetitive behaviours characterising autistic spectrum disorder (ASD) were identified between the ages of 6 months and 9 years from the ALSPAC database. Using missing value imputation, data for 13,138 children were analysed. Factor analysis suggested the existence of 7 factors explaining 85% of the variance. The factors were labelled: verbal ability, language acquisition, social understanding, semantic-pragmatic skills, repetitive stereotyped behaviour, articulation and social inhibition. Four factors (1, 3, 5 and 7) were specific to ASD being more strongly associated with this phenotype than other co-morbid conditions while other factors were more associated with learning difficulties and specific language impairment. Nevertheless, all 7 factors contributed independently to the explanation of ASD (p<0.001). Exploration of putative genetic causal factors such as variants in the CNTNAP2 gene showed a varying pattern of associations with these traits. An alternative predictive model of ASD was derived using four individual measures: the coherence subscale of the Children's Communication Checklist (9y), the Social and Communication Disorders Checklist (91 m), repetitive behaviour (69 m) and the sociability subscale of the Emotionality Activity and Sociability measure (38 m). Although univarably these traits performed better than some factors, their combined explanations of ASD were similar (R(2) = 0.48). CONCLUSIONS AND SIGNIFICANCE: These results support the fractional nature of ASD with different aetiological origins for these components despite pleiotropic genetic effects being observed. These traits are likely to be useful in the exploration of ASD. PMID- 20838615 TI - Real-time correlates of phonological quantity reveal unity of tonal and non-tonal languages. AB - Discrete phonological phenomena form our conscious experience of language: continuous changes in pitch appear as distinct tones to the speakers of tone languages, whereas the speakers of quantity languages experience duration categorically. The categorical nature of our linguistic experience is directly reflected in the traditionally clear-cut linguistic classification of languages into tonal or non-tonal. However, some evidence suggests that duration and pitch are fundamentally interconnected and co-vary in signaling word meaning in non tonal languages as well. We show that pitch information affects real-time language processing in a (non-tonal) quantity language. The results suggest that there is no unidirectional causal link from a genetically-based perceptual sensitivity towards pitch information to the appearance of a tone language. They further suggest that the contrastive categories tone and quantity may be based on simultaneously co-varying properties of the speech signal and the processing system, even though the conscious experience of the speakers may highlight only one discrete variable at a time. PMID- 20838616 TI - Cofilin-1 inactivation leads to proteinuria--studies in zebrafish, mice and humans. AB - BACKGROUND: Podocytes are highly specialized epithelial cells on the visceral side of the glomerulus. Their interdigitating primary and secondary foot processes contain an actin based contractile apparatus that can adjust to changes in the glomerular perfusion pressure. Thus, the dynamic regulation of actin bundles in the foot processes is critical for maintenance of a well functioning glomerular filtration barrier. Since the actin binding protein, cofilin-1, plays a significant role in the regulation of actin dynamics, we examined its role in podocytes to determine the impact of cofilin-1 dysfunction on glomerular filtration. METHODS AND FINDINGS: We evaluated zebrafish pronephros function by dextran clearance and structure by TEM in cofilin-1 morphant and mutant zebrafish and we found that cofilin-1 deficiency led to foot process effacement and proteinuria. In vitro studies in murine and human podocytes revealed that PMA stimulation induced activation of cofilin-1, whereas treatment with TGF-beta resulted in cofilin-1 inactivation. Silencing of cofilin-1 led to an accumulation of F-actin fibers and significantly decreased podocyte migration ability. When we analyzed normal and diseased murine and human glomerular tissues to determine cofilin-1 localization and activity in podocytes, we found that in normal kidney tissues unphosphorylated, active cofilin-1 was distributed throughout the cell. However, in glomerular diseases that affect podocytes, cofilin-1 was inactivated by phosphorylation and observed in the nucleus. CONCLUSIONS: Based on these in vitro and in vivo studies we concluded cofilin-1 is an essential regulator for actin filament recycling that is required for the dynamic nature of podocyte foot processes. Therefore, we describe a novel pathomechanism of proteinuria development. PMID- 20838617 TI - Seasonal and ontogenetic changes in movement patterns of sixgill sharks. AB - BACKGROUND: Understanding movement patterns is fundamental to population and conservation biology. The way an animal moves through its environment influences the dynamics of local populations and will determine how susceptible it is to natural or anthropogenic perturbations. It is of particular interest to understand the patterns of movement for species which are susceptible to human activities (e.g. fishing), or that exert a large influence on community structure, such as sharks. METHODOLOGY/PRINCIPAL FINDINGS: We monitored the patterns of movement of 34 sixgill sharks Hexanchus griseus using two large-scale acoustic arrays inside and outside Puget Sound, Washington, USA. Sixgill sharks were residents in Puget Sound for up to at least four years before making large movements out of the estuary. Within Puget Sound, sixgills inhabited sites for several weeks at a time and returned to the same sites annually. Across four years, sixgills had consistent seasonal movements in which they moved to the north from winter to spring and moved to the south from summer to fall. Just prior to leaving Puget Sound, sixgills altered their behavior and moved twice as fast among sites. Nineteen of the thirty-four sixgills were detected leaving Puget Sound for the outer coast. Three of these sharks returned to Puget Sound. CONCLUSIONS/SIGNIFICANCE: For most large marine predators, we have a limited understanding of how they move through their environment, and this clouds our ability to successfully manage their populations and their communities. With detailed movement information, such as that being uncovered with acoustic monitoring, we can begin to quantify the spatial and temporal impacts of large predators within the framework of their ecosystems. PMID- 20838618 TI - Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer's disease. AB - Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/alpha-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P = 0.011). Liver docosahexaenoic/alpha-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P = 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain. PMID- 20838619 TI - ExCyto PCR amplification. AB - BACKGROUND: ExCyto PCR cells provide a novel and cost effective means to amplify DNA transformed into competent bacterial cells. ExCyto PCR uses host E. coli with a chromosomally integrated gene encoding a thermostable DNA polymerase to accomplish robust, hot-start PCR amplification of cloned sequences without addition of exogenous enzyme. RESULTS: Because the thermostable DNA polymerase is stably integrated into the bacterial chromosome, ExCyto cells can be transformed with a single plasmid or complex library, and then the expressed thermostable DNA polymerase can be used for PCR amplification. We demonstrate that ExCyto cells can be used to amplify DNA from different templates, plasmids with different copy numbers, and master mixes left on ice for up to two hours. Further, PCR amplification with ExCyto cells is comparable to amplification using commercial DNA polymerases. The ability to transform a bacterial strain and use the endogenously expressed protein for PCR has not previously been demonstrated. CONCLUSIONS: ExCyto PCR reduces pipetting and greatly increases throughput for screening EST, genomic, BAC, cDNA, or SNP libraries. This technique is also more economical than traditional PCR and thus broadly useful to scientists who utilize analysis of cloned DNAs in their research. PMID- 20838620 TI - Complete biallelic insulation at the H19/Igf2 imprinting control region position results in fetal growth retardation and perinatal lethality. AB - BACKGROUND: The H19/Igf2 imprinting control region (ICR) functions as an insulator exclusively in the unmethylated maternal allele, where enhancer blocking by CTCF protein prevents the interaction between the Igf2 promoter and the distant enhancers. DNA methylation inhibits CTCF binding in the paternal ICR allele. Two copies of the chicken beta-globin insulator (ChbetaGI)(2) are capable of substituting for the enhancer blocking function of the ICR. Insulation, however, now also occurs upon paternal inheritance, because unlike the H19 ICR, the (ChbetaGI)(2) does not become methylated in fetal male germ cells. The (ChbetaGI)(2) is a composite insulator, exhibiting enhancer blocking by CTCF and chromatin barrier functions by USF1 and VEZF1. We asked the question whether these barrier proteins protected the (ChbetaGI)(2) sequences from methylation in the male germ line. METHODOLOGY/PRINCIPAL FINDINGS: We genetically dissected the ChbetaGI in the mouse by deleting the binding sites USF1 and VEZF1. The methylation of the mutant versus normal (ChbetaGI)(2) significantly increased from 11% to 32% in perinatal male germ cells, suggesting that the barrier proteins did have a role in protecting the (ChbetaGI)(2) from methylation in the male germ line. Contrary to the H19 ICR, however, the mutant (mChbetaGI)(2) lacked the potential to attain full de novo methylation in the germ line and to maintain methylation in the paternal allele in the soma, where it consequently functioned as a biallelic insulator. Unexpectedly, a stricter enhancer blocking was achieved by CTCF alone than by a combination of the CTCF, USF1 and VEZF1 sites, illustrated by undetectable Igf2 expression upon paternal transmission. CONCLUSIONS/SIGNIFICANCE: In this in vivo model, hypomethylation at the ICR position together with fetal growth retardation mimicked the human Silver-Russell syndrome. Importantly, late fetal/perinatal death occurred arguing that strict biallelic insulation at the H19/Igf2 ICR position is not tolerated in development. PMID- 20838621 TI - Molecular biomarker analyses using circulating tumor cells. AB - BACKGROUND: Evaluation of cancer biomarkers from blood could significantly enable biomarker assessment by providing a relatively non-invasive source of representative tumor material. Circulating Tumor Cells (CTCs) isolated from blood of metastatic cancer patients hold significant promise in this regard. METHODOLOGY/PRINCIPAL FINDINGS: Using spiked tumor-cells we evaluated CTC capture on different CTC technology platforms, including CellSearch and two biochip platforms, and used the isolated CTCs to develop and optimize assays for molecular characterization of CTCs. We report similar performance for the various platforms tested in capturing CTCs, and find that capture efficiency is dependent on the level of EpCAM expression. We demonstrate that captured CTCs are amenable to biomarker analyses such as HER2 status, qRT-PCR for breast cancer subtype markers, KRAS mutation detection, and EGFR staining by immunofluorescence (IF). We quantify cell surface expression of EGFR in metastatic lung cancer patient samples. In addition, we determined HER2 status by IF and FISH in CTCs from metastatic breast cancer patients. In the majority of patients (89%) we found concordance with HER2 status from patient tumor tissue, though in a subset of patients (11%), HER2 status in CTCs differed from that observed in the primary tumor. Surprisingly, we found CTC counts to be higher in ER+ patients in comparison to HER2+ and triple negative patients, which could be explained by low EpCAM expression and a more mesenchymal phenotype of tumors belonging to the basal-like molecular subtype of breast cancer. CONCLUSIONS/SIGNIFICANCE: Our data suggests that molecular characterization from captured CTCs is possible and can potentially provide real-time information on biomarker status. In this regard, CTCs hold significant promise as a source of tumor material to facilitate clinical biomarker evaluation. However, limitations exist from a purely EpCAM based capture system and addition of antibodies to mesenchymal markers could further improve CTC capture efficiency to enable routine biomarker analysis from CTCs. PMID- 20838622 TI - Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. AB - BACKGROUND: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins. OBJECTIVE: To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159). METHODS AND FINDINGS: Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B(6) and B(12) in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B(12) (0.5 mg/d) and vitamin B(6) (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. RESULTS: A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63-0.90] in the active treatment group and 1.08% [0.94-1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 umol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category. CONCLUSIONS AND SIGNIFICANCE: The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN94410159. PMID- 20838624 TI - Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas. AB - BACKGROUND: Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are aggressive neoplasms for which no effective therapeutic strategy is currently available. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a DNA-sequence analysis of a selected set of 35 kinase genes in a panel of 52 pancreatic exocrine neoplasms, including 36 pancreatic ductal adenocarcinoma, and 16 ampulla of Vater cancer. Among other changes we found somatic mutations in ATM, EGFR, EPHA3, EPHB2, and KIT, none of which was previously described in cancers. CONCLUSIONS/SIGNIFICANCE: Although the alterations identified require further experimental evaluation, the localization within defined protein domains indicates functional relevance for most of them. Some of the mutated genes, including the tyrosine kinases EPHA3 and EPHB2, are clearly amenable to pharmacological intervention and could represent novel therapeutic targets for these incurable cancers. PMID- 20838623 TI - Mitochondrial redox metabolism in trypanosomatids is independent of tryparedoxin activity. AB - Tryparedoxins (TXNs) are oxidoreductases unique to trypanosomatids (including Leishmania and Trypanosoma parasites) that transfer reducing equivalents from trypanothione, the major thiol in these organisms, to sulfur-dependent peroxidases and other dithiol proteins. The existence of a TXN within the mitochondrion of trypanosomatids, capable of driving crucial redox pathways, is considered a requisite for normal parasite metabolism. Here this concept is shown not to apply to Leishmania. First, removal of the Leishmania infantum mitochondrial TXN (LiTXN2) by gene-targeting, had no significant effect on parasite survival, even in the context of an animal infection. Second, evidence is presented that no other TXN is capable of replacing LiTXN2. In fact, although a candidate substitute for LiTXN2 (LiTXN3) was found in the genome of L. infantum, this was shown in biochemical assays to be poorly reduced by trypanothione and to be unable to reduce sulfur-containing peroxidases. Definitive conclusion that LiTXN3 cannot directly reduce proteins located within inner mitochondrial compartments was provided by analysis of its subcellular localization and membrane topology, which revealed that LiTXN3 is a tail-anchored (TA) mitochondrial outer membrane protein presenting, as characteristic of TA proteins, its N-terminal end (containing the redox-active domain) exposed to the cytosol. This manuscript further proposes the separation of trypanosomatid TXN sequences into two classes and this is supported by phylogenetic analysis: i) class I, encoding active TXNs, and ii) class II, coding for TA proteins unlikely to function as TXNs. Trypanosoma possess only two TXNs, one belonging to class I (which is cytosolic) and the other to class II. Thus, as demonstrated for Leishmania, the mitochondrial redox metabolism in Trypanosoma may also be independent of TXN activity. The major implication of these findings is that mitochondrial functions previously thought to depend on the provision of electrons by a TXN enzyme must proceed differently. PMID- 20838626 TI - Foreword: Clustering of mortality at INDEPTH member Health and Demographic Surveillance Systems. PMID- 20838625 TI - Phyllanthus spp. induces selective growth inhibition of PC-3 and MeWo human cancer cells through modulation of cell cycle and induction of apoptosis. AB - BACKGROUND: Phyllanthus is a traditional medicinal plant that has been used in the treatment of many diseases including hepatitis and diabetes. The main aim of the present work was to investigate the potential cytotoxic effects of aqueous and methanolic extracts of four Phyllanthus species (P.amarus, P.niruri, P.urinaria and P.watsonii) against skin melanoma and prostate cancer cells. METHODOLOGY/PRINCIPAL FINDINGS: Phyllanthus plant appears to possess cytotoxic properties with half-maximal inhibitory concentration (IC(50)) values of 150-300 ug/ml for aqueous extract and 50-150 ug/ml for methanolic extract that were determined using the MTS reduction assay. In comparison, the plant extracts did not show any significant cytotoxicity on normal human skin (CCD-1127Sk) and prostate (RWPE-1) cells. The extracts appeared to act by causing the formation of a clear "ladder" fragmentation of apoptotic DNA on agarose gel, displayed TUNEL positive cells with an elevation of caspase-3 and -7 activities. The Lactate Dehydrogenase (LDH) level was lower than 15% in Phyllanthus treated-cancer cells. These indicate that Phyllanthus extracts have the ability to induce apoptosis with minimal necrotic effects. Furthermore, cell cycle analysis revealed that Phyllanthus induced a Go/G1-phase arrest on PC-3 cells and a S-phase arrest on MeWo cells and these were accompanied by accumulation of cells in the Sub-G1 (apoptosis) phase. The cytotoxic properties may be due to the presence of polyphenol compounds such as ellagitannins, gallotannins, flavonoids and phenolic acids found both in the water and methanol extract of the plants. CONCLUSIONS/SIGNIFICANCE: Phyllanthus plant exerts its growth inhibition effect in a selective manner towards cancer cells through the modulation of cell cycle and induction of apoptosis via caspases activation in melanoma and prostate cancer cells. Hence, Phyllanthus may be sourced for the development of a potent apoptosis-inducing anticancer agent. PMID- 20838628 TI - Spatio-temporal patterns of under-five mortality in Matlab HDSS in rural Bangladesh. AB - BACKGROUND: Knowledge of spatial and temporal distributions of mortality and morbidity is important to prioritise areas for adjusting the public health system where people need services most. A Health and Demographic Surveillance System (HDSS) plays an important role where accurate national vital events are not available in identifying areas and periods with excess mortality risks. METHODS: The HDSS in Matlab, a rural area of Bangladesh, provided data on yearly number of deaths and children aged below 5 years for each of 90 villages during 1998-2007, along with village location points, longitudes and latitudes. Kulldorff's space time scan statistic was used to identify villages and periods that experienced high mortality risks in the HDSS area with a statistical significance of p < 0.001. Logistic regression was conducted to examine if village-level education and economic status explained village-level mortality risks. RESULTS: There were 3,434 deaths among children aged below 5 years in the HDSS area during 1998-2007 with an average yearly rate of 13 deaths per 1,000 under-five child-years. The mortality rate showed a declining trend with high concentration in 1998-2002, but not in 2003-2007. Two clusters of villages had significantly higher mortality risks in 1998-2002, but not later, and the mortality risks in the high-risk clusters reduced little, but remained significant after controlling for adult education and economic status at village level. CONCLUSIONS: Spatial clustering of childhood mortality observed during 1998-2002 had disappeared in subsequent years with a decline in mortality rates. Space-time scanning helps identify high risk areas and periods to enhance public health actions. PMID- 20838627 TI - High concentration of childhood deaths in the low-lying areas of Chakaria HDSS, Bangladesh: findings from a spatial analysis. AB - BACKGROUND: Despite significant reduction of childhood mortality in Bangladesh, large spatial variations persist. Identification of lower level spatial units with higher concentrations of deaths can be useful for strengthening services in these areas. This paper reports findings from a spatial analysis of deaths in Chakaria, a rural subdistrict, where a Health and Demographic Surveillance System has been in place since 1999. Chakaria is an INDEPTH member site. METHODS: An analysis was done of 339 deaths among nearly 24,500 children under the age of five during 2005-2008. One ward, the lowest level of administrative units, was the unit of spatial analysis. Data from 24 wards were analyzed. The Discrete Poisson Probability Model was used to identify the clustering of deaths. RESULTS: Deaths were concentrated within 12 wards located in the low-lying deltaic flood plains of the Chakaria HDSS area. The risk of death in the low-lying areas was statistically, significantly higher, 1.5 times, than the non-low-lying areas (p < 0.02). CONCLUSION: Spatial analysis can be a useful tool for identifying high risk mortality areas. An understanding of the risk factors prevalent in the low lying areas can help design effective interventions to reduce mortality in these areas. PMID- 20838629 TI - Under-five mortality: spatial-temporal clusters in Ifakara HDSS in South-eastern Tanzania. AB - BACKGROUND: Childhood mortality remains an important subject, particularly in sub Saharan Africa where levels are still unacceptably high. To achieve the set Millennium Development Goals 4, calls for comprehensive application of the proven cost-effective interventions. Understanding spatial clustering of childhood mortality can provide a guide in targeting the interventions in a more strategic approach to the population where mortality is highest and the interventions are most likely to make an impact. METHODS: Annual child mortality rates were calculated for each village, using person-years observed as the denominator. Kulldorff's spatial scan statistic was used for the identification and testing of childhood mortality clusters. All under-five deaths that occurred within a 10 year period from 1997 to 2006 were included in the analysis. Villages were used as units of clusters; all 25 health and demographic surveillance sites (HDSS) villages in the Ifakara health and demographic surveillance area were included. RESULTS: Of the 10 years of analysis, statistically significant spatial clustering was identified in only 2 years (1998 and 2001). In 1998, the statistically significant cluster (p < 0.01) was composed of nine villages. A total of 106 childhood deaths were observed against an expected 77.3. The other statistically significant cluster (p < 0.05) identified in 2001 was composed of only one village. In this cluster, 36 childhood deaths were observed compared to 20.3 expected. Purely temporal analysis indicated that the year 2003 was a significant cluster (p < 0.05). Total deaths were 393 and expected were 335.8. Spatial-temporal analysis showed that nine villages were identified as statistically significant clusters (p < 0.05) for the period covering January 1997-December 1998. Total observed deaths in this cluster were 205 while 150.7 were expected. CONCLUSION: There is evidence of spatial clustering in childhood mortality within the Ifakara HDSS. Further investigations are needed to explore the source of clustering and identify strategies of reaching the cluster population with the existing effective interventions. However, that should happen alongside delivery of interventions to the broader population. PMID- 20838630 TI - Spatio-temporal clustering of mortality in Butajira HDSS, Ethiopia, from 1987 to 2008. AB - BACKGROUND: Mortality in a population may be clustered in space and time for a variety of reasons, including geography, socio-economics, environment and demographics. Analysing mortality clusters can therefore reveal important insights into patterns and risks of mortality in a particular setting. OBJECTIVE AND DESIGN: To investigate the extent of spatio-temporal clustering of mortality in the Butajira District, Ethiopia, from 1987 to 2008. The Health and Demographic Surveillance System (HDSS) dataset recorded 10,696 deaths among 951,842 person years of observation, with each death located by household, in which population time at risk was also recorded. The surveyed population increased from 28,614 in 1987 to 62,322 in 2008, in an area approximately 25 km in diameter. Spatio temporal clustering analyses were conducted for overall mortality and by specific age groups, grouping the population into a 0.01 degrees latitude-longitude grid. RESULTS: A number of significantly high- and low-mortality clusters were identified at various times and places. Butajira town was characterised by significantly low mortality throughout the period. A previously documented major mortality crisis in 1998-1999, largely resulting from malaria and diarrhoea, dominated the clustering analysis. Other local high-mortality clusters, appreciably attributable to meningitis, malaria and diarrhoea, occurred in the earlier part of the period. In the later years, a more homogeneous distribution of mortality at lower rates was observed. CONCLUSIONS: Mortality was by no means randomly distributed in this community during the period of observation. The clustering analyses revealed a clear epidemiological transition, away from localised infectious epidemics, over a generation. PMID- 20838631 TI - Spatial and temporal clustering of mortality in Digkale HDSS in rural northern South Africa. AB - BACKGROUND: Mortality data are frequently presented at the overall population level, possibly obscuring small-scale variations over time and space and between different population sub-groups. OBJECTIVE: Analysis of mortality data from the Dikgale Health and Demographic Surveillance System, in rural South Africa, over the period 1996-2007, to identify local clustering of mortality among the eight villages in the observed population. DESIGN: Mortality data and person-time of observation were collected annually in an open-cohort population of approximately 8,000 people over 12 years. Poisson regression modelling and space-time clustering analyses were used to identify possible clustering of mortality. RESULTS: Similar patterns of mortality clustering emerged from Poisson regression and space-time clustering analyses after allowing for age and sex. There was no appreciable clustering of mortality among children under 15 years of age nor in adults 50 years and over. For adults aged 15-49 years, there were substantial clustering effects both in time and in space, with mortality increasing during the period observed and particularly so in some locations, which were nearer to local conurbations. Mortality was relatively lower in the vicinity of the local health centre. CONCLUSIONS: Although cause-specific mortality data were not available, the rise in mortality in the 15-49-year age group over time and in areas closer to conurbations strongly suggests that the clustering observed was due to the development of HIV/AIDS-related mortality, as seen similarly elsewhere in South Africa. The HIV/AIDS services offered by the local health centre may have contributed to lower relative mortality around that location. PMID- 20838632 TI - Clustering of under-five mortality in the Navrongo HDSS in the Kassena-Nankana District of northern Ghana. AB - BACKGROUND: Under-five mortality is a major public health problem and one of the health indicators of health care in sub-Saharan Africa. In order to address inefficient health systems, there is a need to identify the spatial distribution of under-five mortality, especially areas of high mortality clustering. This study aimed to explore spatial and temporal clustering in under-five mortality in the Kassena-Nankana() District of the Upper East region. METHODS: We used data from the Navrongo Health and Demographic Surveillance System in the Kassena- Nankana District of northern Ghana, which had an average population of 140,000 of which about 18,400 were under five years of age. We analysed under-five mortality in 49 villages during the period 1997-2006. We calculated total under-five mortality rates and investigated their geographical distributions. A spatial scan statistic was used to test for clustering of the mortality in both space and time. RESULTS: Under-five mortality has been declining during the period. However, the data show a persistently higher than average clustering of mortality over the period among villages mainly in the north-eastern parts of the district. CONCLUSION: There is a higher than average under-five mortality clustering in the villages in the north-east of the district and this may suggest a relatively poor health care system despite the many health interventions that took place over time in the district, including the Community Health and Family Planning Project, whose impact may not have been felt in these parts of the district between 1995 and 2004. PMID- 20838633 TI - Guest Editorial: Analyses of mortality clustering at member HDSSs within the INDEPTH Network - an important public health issue. PMID- 20838634 TI - Clustering of under-five mortality in Rufiji Health and Demographic Surveillance System in rural Tanzania. AB - BACKGROUND: Less than 5 years remain before the 2015 mark when countries will be evaluated on their achievements for the Millennium Development Goals (MDGs). The MDG 4 and 6 call for a reduction of child mortality by two-thirds and combating malaria, HIV/AIDS, TB, and other diseases, respectively. To accelerate the achievement of these goals, focused allocation of resources and high deployment of cost-effective interventions is paramount. The knowledge of spatial and temporal distribution of diseases is important for health authorities to prioritize and allocate resources. METHODS: To identify possible significant clusters, we used SatTScan software, and analyzed 2,745 cases of under-five with 134,099 person-years for the period between 1999and 2008. Mortality rates for every year were calculated, likewise a spatial scan statistic was used to test for clusters of total under-five mortalities in both space and time. RESULTS: A number of significant clusters from space, time, and space-time analysis were identified in several locations for a period of 10 years in the Rufiji Demographic Surveillance Site (RDSS). These locations show that villages within the clusters have an elevated risk of under-five deaths. The spatial analysis identified three significant clusters. The first cluster had only one village, Kibiti A (p < 0.05, the second cluster involved five villages (Mtawanya, Pagae, Kibiti A, Machepe, and Kibiti B; p < 0.05), the third cluster involved one village, Jaribu Mpakani (p < 0.05). A space-time cluster of 10 villages for the period between 1999 and 2002 with a radius of 14.73 km was discovered with the highest risk (RR 1.6, p < 0.001). The mortality rates were very high for the years 1999-2002 according to the analysis. The death rates were 33.5, 26.4, 24.1, and 24.9, respectively. Total childhood mortality rates calculated for the period of 10 years were 21.0 per 1,000 person-years. CONCLUSION: During the 10 years of analysis, mortality seemed to decrease in RDSS. The mortality decline should be taken with caution because the Demographic Surveillance System is not statistically representative of the whole population; therefore, inference should not be made to the general population of Tanzania. The pattern observed could be attributed to demographic and weather characteristics of RDSS. This should provide new insights for further studies and interventions toward reducing under five mortality. PMID- 20838636 TI - The C-H peripheral stalk base: a novel component in V1-ATPase assembly. AB - Vacuolar ATPases (V-ATPases) are molecular machines responsible for creating electrochemical gradients and preserving pH-dependent cellular compartments by way of proton translocation across the membrane. V-ATPases employ a dynamic rotary mechanism that is driven by ATP hydrolysis and the central rotor stalk. Regulation of this rotational catalysis is the result of a reversible V(1)V(o) domain dissociation that is required to preserve ATP during instances of cellular starvation. Recently the method by which the free V(1)-ATPase abrogates the hydrolytic breakdown of ATP upon dissociating from the membrane has become increasingly clear. In this instance the central stalk subunit F adopts an extended conformation to engage in a bridging interaction tethering the rotor and stator components together. However, the architecture by which this mechanism is stabilized has remained ambiguous despite previous work. In an effort to elucidate the method by which the rotational catalysis is maintained, the architecture of the peripheral stalks and their respective binding interactions was investigated using cryo-electron microscopy. In addition to confirming the bridging interaction exuded by subunit F for the first time in a eukaryotic V ATPase, subunits C and H are seen interacting with one another in a tight interaction that provides a base for the three EG peripheral stalks. The formation of a CE(3)G(3)H sub-assembly appears to be unique to the dissociated V ATPase and highlights the stator architecture in addition to revealing a possible intermediate in the assembly mechanism of the free V(1)-ATPase. PMID- 20838638 TI - High Dose Rate Brachytherapy in the Treatment of cervical cancer: preliminary experience with cobalt 60 Radionuclide source-A Prospective Study. AB - Iridium-192 is widely used for high-dose rate brachytherapy. Co-60 source with similar geometric and dosimetric properties are now available. It has a longer half life but higher energy than Iridium-192. If Co-60 source can produce similar results, it will be more economical for low resource settings. OBJECTIVE: To evaluate the acute gastrointestinal and genitourinary toxicity associated with Co 60 source in the brachytherapy of cervical cancer. METHODS: Seventy patients with cervical cancer received 45 Gy in 22 fractions of pelvic external beam radiotherapy and 19.5 Gy in 3 fractions of HDR with Co-60 source using tandem and ring applicators with 6 courses of cisplatin 50 mg/m(2) and 5 fluorouracil 1000 mg/m(2) every 3 weeks Toxicity was scored using NCI-CTC version 4.0. RESULTS: The median total BED (Gy(10)) for tumor was 86.2 (84.4-88.8) while that for rectum (BED Gy(3)) was 124.4 (120-133). Two patients (3%) had grade 3 gastrointestinal toxicity while all others had <=grade 2 toxicity and this is comparable with previous results. CONCLUSION: Co-60 as HDR brachytherapy source is tolerable and is economical for low resource settings. PMID- 20838639 TI - Environmental Health Insights into the 2010 Deepwater Horizon (BP) Oil Blowout. PMID- 20838637 TI - Dedifferentiation and proliferation of mammalian cardiomyocytes. AB - BACKGROUND: It has long been thought that mammalian cardiomyocytes are terminally differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle. METHODOLOGY/PRINCIPAL FINDINGS: Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two thirds of which were also c-kit(+). CONCLUSIONS/SIGNIFICANCE: Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency. PMID- 20838640 TI - Dissecting the Relation between a nuclear receptor and GATA: binding affinity studies of thyroid hormone receptor and GATA2 on TSHbeta promoter. AB - BACKGROUND: Much is known about how genes regulated by nuclear receptors (NRs) are switched on in the presence of a ligand. However, the molecular mechanism for gene down-regulation by liganded NRs remains a conundrum. The interaction between two zinc-finger transcription factors, Nuclear Receptor and GATA, was described almost a decade ago as a strategy adopted by the cell to up- or down-regulate gene expression. More recently, cell-based assays have shown that the Zn-finger region of GATA2 (GATA2-Zf) has an important role in down-regulation of the thyrotropin gene (TSHbeta) by liganded thyroid hormone receptor (TR). METHODOLOGY/PRINCIPAL FINDINGS: In an effort to better understand the mechanism that drives TSHbeta down-regulation by a liganded TR and GATA2, we have carried out equilibrium binding assays using fluorescence anisotropy to study the interaction of recombinant TR and GATA2-Zf with regulatory elements present in the TSHbeta promoter. Surprisingly, we observed that ligand (T3) weakens TR binding to a negative regulatory element (NRE) present in the TSHbeta promoter. We also show that TR may interact with GATA2-Zf in the absence of ligand, but T3 is crucial for increasing the affinity of this complex for different GATA response elements (GATA-REs). Importantly, these results indicate that TR complex formation enhances DNA binding of the TR-GATA2 in a ligand-dependent manner. CONCLUSIONS: Our findings extend previous results obtained in vivo, further improving our understanding of how liganded nuclear receptors down-regulate gene transcription, with the cooperative binding of transcription factors to DNA forming the core of this process. PMID- 20838641 TI - Adverse events in a cohort of HIV infected pregnant and non-pregnant women treated with nevirapine versus non-nevirapine antiretroviral medication. AB - BACKGROUND: Predictors of adverse events (AE) associated with nevirapine use are needed to better understand reports of severe rash or liver enzyme elevation (LEE) in HIV+ women. METHODOLOGY: AE rates following ART initiation were retrospectively assessed in a multi-site cohort of 612 women. Predictors of onset of rash or LEE were determined using univariate and multivariate analyses. PRINCIPAL FINDINGS: Of 612 subjects, 152 (24.8%) initiated NVP-based regimens with 86 (56.6%) pregnant; 460 (75.2%) initiated non-NVP regimens with 67 (14.6%) pregnant. LEE: No significant difference was found between regimens in the development of new grade >=2 LEE (p = 0.885). Multivariate logistic regression demonstrated an increased likelihood of LEE with HCV co-infection (OR 2.502, 95% CI: 1.04 to 6, p = 0.040); pregnancy, NVP-based regimen, and baseline CD4 >250 cells/mm(3) were not associated with this toxicity. RASH: NVP initiation was associated with rash after controlling for CD4 and pregnancy (OR 2.78; 95%CI: 1.14-6.76), as was baseline CD4 >250 cells/mm(3) when controlling for pregnancy and type of regimen (OR 2.68; 95% CI: 1.19-6.02 p = 0.017). CONCLUSIONS: CD4 at initiation of therapy was a predictor of rash but not LEE with NVP use in HIV+ women. Pregnancy was not an independent risk factor for the development of AEs assessed. The findings from this study have significant implications for women of child-bearing age initiating NVP-based ART particularly in resource limited settings. This study sheds more confidence on the lack of LEE risk and the need to monitor rash with the use of this medication. PMID- 20838635 TI - The role of DNA barcodes in understanding and conservation of mammal diversity in southeast Asia. AB - BACKGROUND: Southeast Asia is recognized as a region of very high biodiversity, much of which is currently at risk due to habitat loss and other threats. However, many aspects of this diversity, even for relatively well-known groups such as mammals, are poorly known, limiting ability to develop conservation plans. This study examines the value of DNA barcodes, sequences of the mitochondrial COI gene, to enhance understanding of mammalian diversity in the region and hence to aid conservation planning. METHODOLOGY AND PRINCIPAL FINDINGS: DNA barcodes were obtained from nearly 1900 specimens representing 165 recognized species of bats. All morphologically or acoustically distinct species, based on classical taxonomy, could be discriminated with DNA barcodes except four closely allied species pairs. Many currently recognized species contained multiple barcode lineages, often with deep divergence suggesting unrecognized species. In addition, most widespread species showed substantial genetic differentiation across their distributions. Our results suggest that mammal species richness within the region may be underestimated by at least 50%, and there are higher levels of endemism and greater intra-specific population structure than previously recognized. CONCLUSIONS: DNA barcodes can aid conservation and research by assisting field workers in identifying species, by helping taxonomists determine species groups needing more detailed analysis, and by facilitating the recognition of the appropriate units and scales for conservation planning. PMID- 20838642 TI - Protective efficacy of intermittent preventive treatment of malaria in infants (IPTi) using sulfadoxine-pyrimethamine and parasite resistance. AB - BACKGROUND: Intermittent Preventive Treatment of malaria in infants using sulfadoxine-pyrimethamine (SP-IPTi) is recommended by WHO for implementation in settings where resistance to SP is not high. Here we examine the relationship between the protective efficacy of SP-IPTi and measures of SP resistance. METHODS AND RESULTS: We analysed the relationship between protective efficacy reported in the 7 SP-IPTi trials and contemporaneous data from 6 in vivo efficacy studies using SP and 7 molecular studies reporting frequency of dhfr triple and dhps double mutations within 50 km of the trial sites. We found a borderline significant association between frequency of the dhfr triple mutation and protective efficacy to 12 months of age of SP-IPTi. This association is significantly biased due to differences between studies, namely number of doses of SP given and follow up times. However, fitting a simple probabilistic model to determine the relationship between the frequency of the dhfr triple, dhps double and dhfr/dhps quintuple mutations associated with resistance to SP and protective efficacy, we found a significant inverse relationship between the dhfr triple mutation frequency alone and the dhfr/dhps quintuple mutations and efficacy at 35 days post the 9 month dose and up to 12 months of age respectively. CONCLUSIONS: A significant relationship was found between the frequency of the dhfr triple mutation and SP-IPTi protective efficacy at 35 days post the 9 month dose. An association between the protective efficacy to 12 months of age and dhfr triple and dhfr/dhps quintuple mutations was found but should be viewed with caution due to bias. It was not possible to define a more definite relationship based on the data available from these trials. PMID- 20838643 TI - Identifying Fishes through DNA Barcodes and Microarrays. AB - BACKGROUND: International fish trade reached an import value of 62.8 billion Euro in 2006, of which 44.6% are covered by the European Union. Species identification is a key problem throughout the life cycle of fishes: from eggs and larvae to adults in fisheries research and control, as well as processed fish products in consumer protection. METHODOLOGY/PRINCIPAL FINDINGS: This study aims to evaluate the applicability of the three mitochondrial genes 16S rRNA (16S), cytochrome b (cyt b), and cytochrome oxidase subunit I (COI) for the identification of 50 European marine fish species by combining techniques of "DNA barcoding" and microarrays. In a DNA barcoding approach, neighbour Joining (NJ) phylogenetic trees of 369 16S, 212 cyt b, and 447 COI sequences indicated that cyt b and COI are suitable for unambiguous identification, whereas 16S failed to discriminate closely related flatfish and gurnard species. In course of probe design for DNA microarray development, each of the markers yielded a high number of potentially species-specific probes in silico, although many of them were rejected based on microarray hybridisation experiments. None of the markers provided probes to discriminate the sibling flatfish and gurnard species. However, since 16S-probes were less negatively influenced by the "position of label" effect and showed the lowest rejection rate and the highest mean signal intensity, 16S is more suitable for DNA microarray probe design than cty b and COI. The large portion of rejected COI-probes after hybridisation experiments (>90%) renders the DNA barcoding marker as rather unsuitable for this high-throughput technology. CONCLUSIONS/SIGNIFICANCE: Based on these data, a DNA microarray containing 64 functional oligonucleotide probes for the identification of 30 out of the 50 fish species investigated was developed. It represents the next step towards an automated and easy-to-handle method to identify fish, ichthyoplankton, and fish products. PMID- 20838644 TI - The brain effects of laser acupuncture in healthy individuals: an FMRI investigation. AB - BACKGROUND: As laser acupuncture is being increasingly used to treat mental disorders, we sought to determine whether it has a biologically plausible effect by using functional magnetic resonance imaging (fMRI) to investigate the cerebral activation patterns from laser stimulation of relevant acupoints. METHODOLOGY/PRINCIPAL FINDINGS: Ten healthy subjects were randomly stimulated with a fibreoptic infrared laser on 4 acupoints (LR14, CV14, LR8 and HT7) used for depression following the principles of Traditional Chinese Medicine (TCM), and 1 control non-acupoint (sham point) in a blocked design (alternating verum laser and placebo laser/rest blocks), while the blood oxygenation level-dependent (BOLD) fMRI response was recorded from the whole brain on a 3T scanner. Many of the acupoint laser stimulation conditions resulted in different patterns of neural activity. Regions with significantly increased activation included the limbic cortex (cingulate) and the frontal lobe (middle and superior frontal gyrus). Laser acupuncture tended to be associated with ipsilateral brain activation and contralateral deactivation that therefore cannot be simply attributed to somatosensory stimulation. CONCLUSIONS/SIGNIFICANCE: We found that laser stimulation of acupoints lead to activation of frontal-limbic-striatal brain regions, with the pattern of neural activity somewhat different for each acupuncture point. This is the first study to investigate laser acupuncture on a group of acupoints useful in the management of depression. Differing activity patterns depending on the acupoint site were demonstrated, suggesting that neurological effects vary with the site of stimulation. The mechanisms of activation and deactivation and their effects on depression warrant further investigation. PMID- 20838645 TI - A naturally occurring polymorphism at Drosophila melanogaster Lim3 Locus, a homolog of human LHX3/4, affects Lim3 transcription and fly lifespan. AB - Lim3 encodes an RNA polymerase II transcription factor with a key role in neuron specification. It was also identified as a candidate gene that affects lifespan. These pleiotropic effects indicate the fundamental significance of the potential interplay between neural development and lifespan control. The goal of this study was to analyze the causal relationships between Lim3 structural variations, and gene expression and lifespan changes, and to provide insights into regulatory pathways controlling lifespan. Fifty substitution lines containing second chromosomes from a Drosophila natural population were used to analyze the association between lifespan and sequence variation in the 5'-regulatory region, and first exon and intron of Lim3A, in which we discovered multiple transcription start sites (TSS). The core and proximal promoter organization for Lim3A and a previously unknown mRNA named Lim3C were described. A haplotype of two markers in the Lim3A regulatory region was significantly associated with variation in lifespan. We propose that polymorphisms in the regulatory region affect gene transcription, and consequently lifespan. Indeed, five polymorphic markers located within 380 to 680 bp of the Lim3A major TSS, including two markers associated with lifespan variation, were significantly associated with the level of Lim3A transcript, as evaluated by real time RT-PCR in embryos, adult heads, and testes. A naturally occurring polymorphism caused a six-fold change in gene transcription and a 25% change in lifespan. Markers associated with long lifespan and intermediate Lim3A transcription were present in the population at high frequencies. We hypothesize that polymorphic markers associated with Lim3A expression are located within the binding sites for proteins that regulate gene function, and provide general rather than tissue-specific regulation of transcription, and that intermediate levels of Lim3A expression confer a selective advantage and longer lifespan. PMID- 20838646 TI - Taenia solium cysticercosis in the Democratic Republic of Congo: how does pork trade affect the transmission of the parasite? AB - BACKGROUND: Taenia solium, a zoonotic parasite that is endemic in most developing countries where pork is consumed, is recognised as the main cause of acquired epilepsy in these regions. T. solium has been reported in almost all of the neighboring countries of Democratic Republic of Congo (DRC) but data on the current prevalence of the disease in the country itself are lacking. This study, focusing on porcine cysticercosis (CC), makes part of a first initiative to assess whether cysticercosis is indeed actually present in DRC. METHODS: An epidemiological study on porcine CC was conducted (1) on urban markets of Kinshasa where pork is sold and (2) in villages in Bas-Congo province where pigs are traditionally reared. Tongue inspection and ELISA for the detection of circulating antigen of the larval stage of T. solium were used to assess the prevalence of active CC in both study sites. FINDINGS: The overall prevalence of pigs with active cysticercosis did not significantly differ between the market and the village study sites (38.8 [CI 95%: 34-43] versus 41.2% [CI 95%: 33-49], respectively). However, tongue cysticercosis was only found in the village study site together with a significantly higher intensity of infection (detected by ELISA). INTERPRETATION: Pigs reared at village level are sold for consumption on Kinshasa markets, but it seems that highly infected animals are excluded at a certain level in the pig trade chain. Indeed, preliminary informal surveys on common practices conducted in parallel revealed that pig farmers and/or buyers select the low infected animals and exclude those who are positive by tongue inspection at village level. This study provides the only recent evidence of CC presence in DRC and gives the first estimates to fill an important gap on the African taeniasis/cysticercosis distribution map. PMID- 20838647 TI - Stage-specific adhesion of Leishmania promastigotes to sand fly midguts assessed using an improved comparative binding assay. AB - BACKGROUND: The binding of Leishmania promastigotes to the midgut epithelium is regarded as an essential part of the life-cycle in the sand fly vector, enabling the parasites to persist beyond the initial blood meal phase and establish the infection. However, the precise nature of the promastigote stage(s) that mediate binding is not fully understood. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue we have developed an in vitro gut binding assay in which two promastigote populations are labelled with different fluorescent dyes and compete for binding to dissected sand fly midguts. Binding of procyclic, nectomonad, leptomonad and metacyclic promastigotes of Leishmania infantum and L. mexicana to the midguts of blood-fed, female Lutzomyia longipalpis was investigated. The results show that procyclic and metacyclic promastigotes do not bind to the midgut epithelium in significant numbers, whereas nectomonad and leptomonad promastigotes both bind strongly and in similar numbers. The assay was then used to compare the binding of a range of different parasite species (L. infantum, L. mexicana, L. braziliensis, L. major, L. tropica) to guts dissected from various sand flies (Lu. longipalpis, Phlebotomus papatasi, P. sergenti). The results of these comparisons were in many cases in line with expectations, the natural parasite binding most effectively to its natural vector, and no examples were found where a parasite was unable to bind to its natural vector. However, there were interesting exceptions: L. major and L. tropica being able to bind to Lu. longipalpis better than L. infantum; L. braziliensis was able to bind to P. papatasi as well as L. major; and significant binding of L. major to P. sergenti and L. tropica to P. papatasi was observed. CONCLUSIONS/SIGNIFICANCE: The results demonstrate that Leishmania gut binding is strictly stage-dependent, is a property of those forms found in the middle phase of development (nectomonad and leptomonad forms), but is absent in the early blood meal and final stages (procyclic and metacyclic forms). Further they show that although gut binding may be necessary for parasite establishment, in several vector-parasite pairs the specificity of such in vitro binding alone is insufficient to explain overall vector specificity. Other significant barriers to development must exist in certain refractory Leishmania parasite-sand fly vector combinations. A re appraisal of the specificity of the Leishmania-sand fly relationship is required. PMID- 20838649 TI - Cost-effectiveness analysis of combination therapies for visceral leishmaniasis in the Indian subcontinent. AB - BACKGROUND: Visceral leishmaniasis is a systemic parasitic disease that is fatal unless treated. We assessed the cost and cost-effectiveness of alternative strategies for the treatment of visceral leishmaniasis in the Indian subcontinent. In particular we examined whether combination therapies are a cost effective alternative compared to monotherapies. METHODS AND FINDINGS: We assessed the cost-effectiveness of all possible mono- and combination therapies for the treatment of visceral leishmaniasis in the Indian subcontinent (India, Nepal and Bangladesh) from a societal perspective using a decision analytical model based on a decision tree. Primary data collected in each country was combined with data from the literature and an expert poll (Delphi method). The cost per patient treated and average and incremental cost-effectiveness ratios expressed as cost per death averted were calculated. Extensive sensitivity analysis was done to evaluate the robustness of our estimations and conclusions. With a cost of US$92 per death averted, the combination miltefosine-paromomycin was the most cost-effective treatment strategy. The next best alternative was a combination of liposomal amphotericin B with paromomycin with an incremental cost effectiveness of $652 per death averted. All other strategies were dominated with the exception of a single dose of 10mg per kg of liposomal amphotericin B. While strategies based on liposomal amphotericin B (AmBisome) were found to be the most effective, its current drug cost of US$20 per vial resulted in a higher average cost-effectiveness. Sensitivity analysis showed the conclusion to be robust to variations in the input parameters over their plausible range. CONCLUSIONS: Combination treatments are a cost-effective alternative to current monotherapy for VL. Given their expected impact on the emergence of drug resistance, a switch to combination therapy should be considered once final results from clinical trials are available. PMID- 20838648 TI - A large repertoire of parasite epitopes matched by a large repertoire of host immune receptors in an invertebrate host/parasite model. AB - For many decades, invertebrate immunity was believed to be non-adaptive, poorly specific, relying exclusively on sometimes multiple but germ-line encoded innate receptors and effectors. But recent studies performed in different invertebrate species have shaken this paradigm by providing evidence for various types of somatic adaptations at the level of putative immune receptors leading to an enlarged repertoire of recognition molecules. Fibrinogen Related Proteins (FREPs) from the mollusc Biomphalaria glabrata are an example of these putative immune receptors. They are known to be involved in reactions against trematode parasites. Following not yet well understood somatic mechanisms, the FREP repertoire varies considerably from one snail to another, showing a trend towards an individualization of the putative immune repertoire almost comparable to that described from vertebrate adaptive immune system. Nevertheless, their antigenic targets remain unknown. In this study, we show that a specific set of these highly variable FREPs from B. glabrata forms complexes with similarly highly polymorphic and individually variable mucin molecules from its specific trematode parasite S. mansoni (Schistosoma mansoni Polymorphic Mucins: SmPoMucs). This is the first evidence of the interaction between diversified immune receptors and antigenic variant in an invertebrate host/pathogen model. The same order of magnitude in the diversity of the parasite epitopes and the one of the FREP suggests co-evolutionary dynamics between host and parasite regarding this set of determinants that could explain population features like the compatibility polymorphism observed in B. glabrata/S. mansoni interaction. In addition, we identified a third partner associated with the FREPs/SmPoMucs in the immune complex: a Thioester containing Protein (TEP) belonging to a molecular category that plays a role in phagocytosis or encapsulation following recognition. The presence of this last partner in this immune complex argues in favor of the involvement of the formed complex in parasite recognition and elimination from the host. PMID- 20838650 TI - Pediatric visceral leishmaniasis in Albania: a retrospective analysis of 1,210 consecutive hospitalized patients (1995-2009). AB - BACKGROUND: Little information is available about infantile visceral leishmaniasis (VL) in Albania as regards incidence, diagnosis and management of the disease. METHODOLOGY/PRINCIPAL FINDINGS: Demographic data, clinical and laboratory features and therapeutic findings were considered in children admitted to University Hospital of Tirana from 1995 to 2009, and diagnosed as having VL. The diagnosis was based on bone-marrow microscopy/culture in 77.5% of patients, serology in 16.1%, and ex juvantibus in 6.4%. A total of 1,210 children were considered, of whom 74% came from urbanized areas. All patients were in the age range 0-14 years, with a median of 4 years. Hepatosplenomegaly was recorded in 100%, fever in 95.4% and moderate to severe anemia in 88% of cases. Concomitant conditions were frequent: 84% had bronchopneumonia; diarrhea was present in 27%, with acute manifestations in 5%; 3% had salmonellosis. First-line therapy was meglumine antimoniate for all patients, given at the standard Sb(v) dosage of 20 mg/kg/day for 21 to 28 days. Two children died under treatment, one of sepsis, the other of acute renal impairment. There were no cases of primary unresponsiveness to treatment, and only 8 (0.67%) relapsed within 6-12 months after therapy. These patients have been re-treated with liposomal amphotericin B, with successful cure. CONCLUSIONS: Visceral leishmaniasis in pediatric age is relatively frequent in Albania; therefore an improvement is warranted of a disease-specific surveillance system in this country, especially as regards diagnosis. Despite recent reports on decreased responses to antimonial drugs of patients with Mediterranean VL, meglumine antimoniate treatment appears to be still highly effective in Albania. PMID- 20838652 TI - Radiodiagnostic imaging in pregnancy and the risk of childhood malignancy: raising the bar. AB - Eduardo Franco and Guy-Anne Turgeon discuss new findings from Joel Ray and colleagues on the cancer risk following prenatal exposure to radiodiagnostic imaging, and where new research needs to be focused. PMID- 20838651 TI - A global census of fission yeast deubiquitinating enzyme localization and interaction networks reveals distinct compartmentalization profiles and overlapping functions in endocytosis and polarity. AB - Ubiquitination and deubiquitination are reciprocal processes that tune protein stability, function, and/or localization. The removal of ubiquitin and remodeling of ubiquitin chains is catalyzed by deubiquitinating enzymes (DUBs), which are cysteine proteases or metalloproteases. Although ubiquitination has been extensively studied for decades, the complexity of cellular roles for deubiquitinating enzymes has only recently been explored, and there are still several gaps in our understanding of when, where, and how these enzymes function to modulate the fate of polypeptides. To address these questions we performed a systematic analysis of the 20 Schizosaccharomyces pombe DUBs using confocal microscopy, proteomics, and enzymatic activity assays. Our results reveal that S. pombe DUBs are present in almost all cell compartments, and the majority are part of stable protein complexes essential for their function. Interestingly, DUB partners identified by our study include the homolog of a putative tumor suppressor gene not previously linked to the ubiquitin pathway, and two conserved tryptophan-aspartate (WD) repeat proteins that regulate Ubp9, a DUB that we show participates in endocytosis, actin dynamics, and cell polarity. In order to understand how DUB activity affects these processes we constructed multiple DUB mutants and find that a quintuple deletion of ubp4 ubp5 ubp9 ubp15 sst2/amsh displays severe growth, polarity, and endocytosis defects. This mutant allowed the identification of two common substrates for five cytoplasmic DUBs. Through these studies, a common regulatory theme emerged in which DUB localization and/or activity is modulated by interacting partners. Despite apparently distinct cytoplasmic localization patterns, several DUBs cooperate in regulating endocytosis and cell polarity. These studies provide a framework for dissecting DUB signaling pathways in S. pombe and may shed light on DUB functions in metazoans. PMID- 20838653 TI - Brief bursts self-inhibit and correlate the pyramidal network. AB - Inhibitory pathways are an essential component in the function of the neocortical microcircuitry. Despite the relatively small fraction of inhibitory neurons in the neocortex, these neurons are strongly activated due to their high connectivity rate and the intricate manner in which they interconnect with pyramidal cells (PCs). One prominent pathway is the frequency-dependent disynaptic inhibition (FDDI) formed between layer 5 PCs and mediated by Martinotti cells (MCs). Here, we show that simultaneous short bursts in four PCs are sufficient to exert FDDI in all neighboring PCs within the dimensions of a cortical column. This powerful inhibition is mediated by few interneurons, leading to strongly correlated membrane fluctuations and synchronous spiking between PCs simultaneously receiving FDDI. Somatic integration of such inhibition is independent and electrically isolated from monosynaptic excitation formed between the same PCs. FDDI is strongly shaped by I(h) in PC dendrites, which determines the effective integration time window for inhibitory and excitatory inputs. We propose a key disynaptic mechanism by which brief bursts generated by a few PCs can synchronize the activity in the pyramidal network. PMID- 20838654 TI - Quiet down now: how excitatory neurons inhibit one another. PMID- 20838656 TI - The haunting of medical journals: how ghostwriting sold "HRT". AB - Adriane Fugh-Berman examines documents unsealed in recent litigation to investigate how pharmaceutical companies promoted hormone therapy drugs, including the use of medical writing companies to produce ghostwritten manuscripts and place them into medical journals. PMID- 20838657 TI - A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. AB - Thrombopoietin (TPO) via signaling through its cognate receptor MPL is a key cytokine involved in the regulation of megakaryocyte differentiation leading to platelet production. Mature megakaryocytes are polyploid cells that have arrested DNA replication and cellular proliferation but continue sustained protein synthesis. Here, we show that TPO induces cell-cycle arrest in the megakaryocytic UT7-MPL cell line by the activation of the ERK/MAPK pathway, induction of p21CIP transcription, and senescence markers through EGR1 activation. A similar senescence-like process was also detected in normal primary postmitotic megakaryocytes. In contrast, senescence was not observed in malignant megakaryocytes derived from primary myelofibrosis patients (a form of chronic myeloid hemopathy). Our data indicate that polyploid mature megakaryocytes receive signals from TPO to arrest cell proliferation and enter a senescent-like state. An escape from this physiological process may be associated with certain myeloproliferative neoplasms leading to abnormal megakaryocytic proliferation. PMID- 20838655 TI - Multi-platform next-generation sequencing of the domestic turkey (Meleagris gallopavo): genome assembly and analysis. AB - A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (~1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest. PMID- 20838658 TI - Persistence with statins and onset of rheumatoid arthritis: a population-based cohort study. AB - BACKGROUND: The beneficial effects of statins in rheumatoid arthritis (RA) have been suggested previously, but it is unclear whether statins may prevent its development. The aim of this retrospective cohort study was to explore whether persistent use of statins is associated with onset of RA. METHODS AND FINDINGS: The computerized medical databases of a large health organization in Israel were used to identify diagnosed RA cases among adults who began statin therapy between 1998 and 2007. Persistence with statins was assessed by calculating the mean proportion of follow-up days covered (PDC) with statins for every study participant. To assess the possible effects of healthy user bias, we also examined the risk of osteoarthritis (OA), a common degenerative joint disease that is unlikely to be affected by use of statins. A total of 211,627 and 193,770 individuals were eligible for the RA and OA cohort analyses, respectively. During the study follow-up period, there were 2,578 incident RA cases (3.07 per 1,000 person-years) and 17,878 incident OA cases (24.34 per 1,000 person-years). The crude incidence density rate of RA among nonpersistent patients (PDC level of <20%) was 51% higher (3.89 per 1,000 person-years) compared to highly persistent patients who were covered with statins for at least 80% of the follow-up period. After adjustment for potential confounders, highly persistent patients had a hazard ratio of 0.58 (95% confidence interval 0.52-0.65) for RA compared with nonpersistent patients. Larger differences were observed in younger patients and in patients initiating treatment with high efficacy statins. In the OA cohort analysis, high persistence with statins was associated only with a modest decrement in risk ratio (hazard ratio = 0.85; 0.81-0.88) compared to nonadherent patients. CONCLUSIONS: The present study demonstrates an association between persistence with statin therapy and reduced risk of developing RA. The relationship between continuation of statin use and OA onset was weak and limited to patients with short-term follow-up. PMID- 20838659 TI - Arms and the man: the problem of symmetric growth. PMID- 20838660 TI - Major radiodiagnostic imaging in pregnancy and the risk of childhood malignancy: a population-based cohort study in Ontario. AB - BACKGROUND: The association between fetal exposure to major radiodiagnostic testing in pregnancy-computed tomography (CT) and radionuclide imaging-and the risk of childhood cancer is not established. METHODS AND FINDINGS: We completed a population-based study of 1.8 million maternal-child pairs in the province of Ontario, from 1991 to 2008. We used Ontario's universal health care-linked administrative databases to identify all term obstetrical deliveries and newborn records, inpatient and outpatient major radiodiagnostic services, as well as all children with a malignancy after birth. There were 5,590 mothers exposed to major radiodiagnostic testing in pregnancy (3.0 per 1,000) and 1,829,927 mothers not exposed. The rate of radiodiagnostic testing increased from 1.1 to 6.3 per 1,000 pregnancies over the study period; about 73% of tests were CT scans. After a median duration of follow-up of 8.9 years, four childhood cancers arose in the exposed group (1.13 per 10,000 person-years) and 2,539 cancers in the unexposed group (1.56 per 10,000 person-years), a crude hazard ratio of 0.69 (95% confidence interval 0.26-1.82). After adjusting for maternal age, income quintile, urban status, and maternal cancer, as well as infant sex, chromosomal or congenital anomalies, and major radiodiagnostic test exposure after birth, the risk was essentially unchanged (hazard ratio 0.68, 95% confidence interval 0.25 1.80). CONCLUSIONS: Although major radiodiagnostic testing is now performed in about 1 in 160 pregnancies in Ontario, the absolute annual risk of childhood malignancy following exposure in utero remains about 1 in 10,000. Since the upper confidence limit of the relative risk of malignancy may be as high as 1.8 times that of an unexposed pregnancy, we cannot exclude the possibility that fetal exposure to CT or radionuclide imaging is carcinogenic. PMID- 20838661 TI - Sucrose- and H-dependent charge movements associated with the gating of sucrose transporter ZmSUT1. AB - BACKGROUND: In contrast to man the majority of higher plants use sucrose as mobile carbohydrate. Accordingly proton-driven sucrose transporters are crucial for cell-to-cell and long-distance distribution within the plant body. Generally very negative plant membrane potentials and the ability to accumulate sucrose quantities of more than 1 M document that plants must have evolved transporters with unique structural and functional features. METHODOLOGY/PRINCIPAL FINDINGS: To unravel the functional properties of one specific high capacity plasma membrane sucrose transporter in detail, we expressed the sucrose/H(+) co transporter from maize ZmSUT1 in Xenopus oocytes. Application of sucrose in an acidic pH environment elicited inward proton currents. Interestingly the sucrose dependent H(+) transport was associated with a decrease in membrane capacitance (C(m)). In addition to sucrose C(m) was modulated by the membrane potential and external protons. In order to explore the molecular mechanism underlying these C(m) changes, presteady-state currents (I(pre)) of ZmSUT1 transport were analyzed. Decay of I(pre) could be best fitted by double exponentials. When plotted against the voltage the charge Q, associated to I(pre), was dependent on sucrose and protons. The mathematical derivative of the charge Q versus voltage was well in line with the observed C(m) changes. Based on these parameters a turnover rate of 500 molecules sucrose/s was calculated. In contrast to gating currents of voltage dependent-potassium channels the analysis of ZmSUT1-derived presteady-state currents in the absence of sucrose (I = Q/tau) was sufficient to predict ZmSUT1 transport-associated currents. CONCLUSIONS: Taken together our results indicate that in the absence of sucrose, 'trapped' protons move back and forth between an outer and an inner site within the transmembrane domains of ZmSUT1. This movement of protons in the electric field of the membrane gives rise to the presteady-state currents and in turn to C(m) changes. Upon application of external sucrose, protons can pass the membrane turning presteady-state into transport currents. PMID- 20838662 TI - Between-population outbreeding affects plant defence. AB - Between-population crosses may replenish genetic variation of populations, but may also result in outbreeding depression. Apart from direct effects on plant fitness, these outbreeding effects can also alter plant-herbivore interactions by influencing plant tolerance and resistance to herbivory. We investigated effects of experimental within- and between-population outbreeding on herbivore resistance, tolerance and plant fitness using plants from 13 to 19 Lychnis flos cuculi populations. We found no evidence for outbreeding depression in resistance reflected by the amount of leaf area consumed. However, herbivore performance was greater when fed on plants from between-population compared to within-population crosses. This can reflect outbreeding depression in resistance and/or outbreeding effects on plant quality for the herbivores. The effects of type of cross on the relationship between herbivore damage and plant fitness varied among populations. This demonstrates how between-population outbreeding effects on tolerance range from outbreeding depression to outbreeding benefits among plant populations. Finally, herbivore damage strengthened the observed outbreeding effects on plant fitness in several populations. These results raise novel considerations on the impact of outbreeding on the joint evolution of resistance and tolerance, and on the evolution of multiple defence strategies. PMID- 20838663 TI - A seven plasmid-based system for the rescue of influenza C virus. AB - We report the establishment of a reverse-genetics system for the rescue of recombinant influenza C/JJ/50 virus from seven plasmids. The nucleotide sequence of the whole C/JJ/50 genome was determined and full-length cDNAs were cloned into an RNA pol I/pol II-based bidirectional vector. Transfection of Vero cells and subsequent amplification on MDCK cells yielded viral HA titres of 128. The utility of this bidirectional approach was proved by generating a reassortant virus encoding the NS segment from strain C/JHB/1/66 and a virus with mutations in the noncoding ends of PB1. The latter virus, which has a base-pair mutation within the proposed double-stranded region of the PB1 termini, exhibited impaired replication. In conclusion, our efficient seven-plasmid system for the rescue of recombinant influenza C virus may be used to study the influenza C virus life cycle in more detail and for generation of influenza C virus-based vectors. PMID- 20838664 TI - Comparative in silico analyses of cpeb1-4 with functional predictions. AB - BACKGROUND: Cytoplasmic polyadenylation element binding proteins (Cpebs) are a family of proteins that bind to defined groups of mRNAs and regulate their translation. While Cpebs were originally identified as important features of oocyte maturation, recent interest is due to their prospective roles in neural system plasticity. RESULTS: In this study we made use of bioinformatic tools and methods including NCBI Blast, UCSC Blat, and Invitrogen Vector NTI to comprehensively analyze all known isoforms of four mouse Cpeb paralogs extracted from the national UniGene, UniProt, and NCBI protein databases. We identified multiple alternative splicing variants for each Cpeb. Regions of commonality and distinctiveness were evident when comparing Cpeb2, 3, and 4. In addition, we performed cross-ortholog comparisons among multiple species. The exon patterns were generally conserved across vertebrates. Mouse and human isoforms were compared in greater detail as they are the most represented in the current databases. The homologous and distinct regions are strictly conserved in mouse Cpeb and human CPEB proteins. Novel variants were proposed based on cross ortholog comparisons and validated using biological methods. The functions of the alternatively spliced regions were predicted using the Eukaryotic Linear Motif resource. CONCLUSIONS: Together, the large number of transcripts and proteins indicate the presence of a hitherto unappreciated complexity in the regulation and functions of Cpebs. The evolutionary retention of variable regions as described here is most likely an indication of their functional significance. PMID- 20838665 TI - A practical approach to detect unique metabolic patterns for personalized medicine. AB - Information-rich technologies have advanced personalized medicine, yet obstacles limit measurement of large numbers of chemicals in human samples. Current laboratory tests measure hundreds of chemicals based upon existing knowledge of exposures, metabolism and disease mechanisms. Practical issues of cost and throughput preclude measurement of thousands of chemicals. Additionally, individuals are genetically diverse and have different exposures and response characteristics; some have disease mechanisms that have not yet been elucidated. Consequently, methods are needed to detect unique metabolic characteristics without presumption of known pathways, exposures or disease mechanisms, i.e., using a top-down approach. In this report, we describe profiling of human plasma with liquid chromatography (LC) coupled to Fourier-transform mass spectrometry (FTMS). FTMS is a high-resolution mass spectrometer providing mass accuracy and resolution to discriminate thousands of m/z features, which are peaks defined by m/z, retention time and intensity. We demonstrate that LC-FTMS detects 2000 m/z features in 10 min. These features include known and unidentified chemicals with m/z between 85 and 850, most with <10% coefficient of variation. Comparison of metabolic profiles for 4 healthy individuals showed that 62% of the m/z features were common while 10% were unique and 770 discriminated the individuals. Because the simple one-step extraction and automated analysis is rapid and cost effective, the approach is practical for personalized medicine. This provides a basis to rapidly characterize novel metabolic patterns which can be linked to genetics, environment and/or lifestyle. PMID- 20838667 TI - The sensitivity range for the nucleation process to temperature fluctuations from thermal radiation exchange of liquid critical clusters in a metastable vapor phase. AB - The influence of liquid critical clusters temperature fluctuations caused by the radiation exchange (RTFs) on the nucleation process during a vapor to liquid phase transition is studied. This influence is significant when two conditions are met; (1) the RTFs amplitude is larger than the system overcooling thus allowing a reduction in the cluster temperature below the temperature of phase transition, and (2) RTFs correlation time is large enough to allow an extra emission of vapor molecules by the cluster of critical size thus making the cluster subcritical. The range of the system overcooling is found where RTFs may have a strong impact on the process of liquid phase formation. PMID- 20838666 TI - Micropatterning bacterial suspensions using aqueous two phase systems. AB - Using an aqueous two-phase system comprised of dextran and polyethylene glycol, this article describes the stable spatial patterning of sub-microlitre droplets of bacterial suspensions. Microdroplets of different types of bacterial populations are positioned and maintained adjacent to each other without significant dispersion even though the bacteria are in suspension and not surface bound. Small molecules, in contrast, diffuse relatively freely between the two aqueous phases. The usefulness of these capabilities is demonstrated by generating a small array of suspensions containing different Escherichia coli strains engineered to respond fluorescently or luminescently to different chemical stimuli. When a chemical stimulus is presented, this droplet array produces a pattern of bacterial "illumination" that reflects the type of chemical to which the array was exposed. PMID- 20838668 TI - Highly sensitive identification of cancer cells by combining the new tetrathiafulvalene derivative with a beta-cyclodextrin/multi-walled carbon nanotubes modified GCE. AB - In this contribution, we have prepared and explored a novel nano-interface based probe for the rapid identification and highly sensitive detection of cancer cells by means of an electrochemical study. The new probe tetrathiafulvalene (TTF) carboxylate salt (TTF-(COONBu(4))(2), ditetrabutylammonium salt for propylenedithio-4',5'-tetrathiafulvalene-4,5-dicarboxylate), which has specific spectral and electrochemical properties, has been synthesized and assembled with carbon nanotubes to form a new type of nanocomposite. A simple method of fabricating the beta-CD/MWCNT modified electrodes based on functionalized multi walled carbon nanotubes (MWCNTs) and beta-cyclodextrin (beta-CD) has been explored by using glassy carbon electrodes (GCEs), which could remarkably enhance the sensitivity of the biomolecular detection. Our results demonstrate that the combination of the new probe TTF-(COONBu(4))(2) with beta-CD/MWCNT modified electrodes could be readily utilized to sensitively detect cancer cells such as liver cancer cells SMMC-7721 and HepG2, drug sensitive leukemia K562/B.W cells and drug resistant leukemia K562/ADM cells, with a detection limit of ~10(3) cells mL(-1). This may provide a novel strategy for the potential and promising application of the new TTF molecular probe in the development of multi-signal responsive biosensors for the early diagnosis of cancers. PMID- 20838669 TI - Identification of individual genotypes of measles virus using surface enhanced Raman spectroscopy. AB - A spectroscopic assay based on surface-enhanced Raman spectroscopy (SERS) has been developed for rapid genotyping of the measles virus (MeV). Silver nanorods fabricated using an oblique angle vapor deposition method acted as the SERS active substrate. The SERS spectra of four separate MeV genotypes, i.e. A, H1, D4 and D9, and two separate negative media control samples were analyzed using multivariate statistical methods. Principal components analysis (PCA) and hierarchical cluster analysis (HCA) successfully separated three of the four MeV genotypes studied. The MeV genotypes used in this study had >96% sequence similarity as monitored using the MeV hemagglutinin (H) gene, and the clustering seen in PCA and HCA mirrored this sequence diversity. For example, the MeV genotypes with the highest sequence diversity (~3%, A and H1) were the most widely separated in the PCA scores plot and HCA dendogram. Conversely, the MeV genotypes with the lowest sequence diversity (~0.5%, D4 and D9) could not be statistically differentiated. However, a supervised chemometric method, partial least squares-discriminant analysis (PLS-DA) was able to separate each of the four MeV strains, the two negative controls, and the background, with >90% sensitivity and >96% selectivity based solely on their inherent SERS spectra. These results demonstrate that SERS, in combination with multivariate statistical methods, is a highly sensitive and rapid viral identification and classification method that can be applied to MeV genotyping. PMID- 20838670 TI - Strategies for the synthesis of bioactive pyran naphthoquinones. AB - Taking into account the numerous reports in the literature related to pyran naphthoquinones in searching for new pharmacologically promising molecules against different therapeutic targets, this review intends to explore the synthetic methodologies for preparing these bioactive compounds. PMID- 20838671 TI - Large-scale arrays of picolitre chambers for single-cell analysis of large cell populations. AB - We present a new method to analyze the cytoplasmic contents of single cells in large cell populations. This new method consists of an array of microchambers in which individual cells are collected, enclosed, and lysed to create a reaction mixture of the cytoplasm with extracellular detection agents. This approach was tested for the analysis of red blood cells in 10,000 microchambers in parallel. Single cells were routinely collected in more than 60% of microchambers, the collected cells were robustly (up to 99%) lysed by electric fields, and the cytoplasm enclosed in each microchamber was analyzed with fluorescence microscopy. Using a heterogeneous cell mixture, we verified that the new method could distinguish individual cells by cytoplasmic composition and the analysis compared well with conventional flow-cytometric evaluation of mixed cell populations. In contrast to flow-cytometry, the new method monitored single cells over time, thus characterizing the distributions of caspase activities of 5000 individual cells. This approach should be interesting for a variety of applications that would benefit from the ability to measure the distribution of cytoplasmic compounds in complex cell populations, including hematology, oncology, and immunology. PMID- 20838672 TI - Micromolded arrays for separation of adherent cells. AB - We present an efficient, yet inexpensive, approach for isolating viable single cells or colonies from a mixed population. This cell microarray platform possesses innovations in both the array manufacture and the manner of target cell release. Arrays of microwells with bases composed of detachable concave elements, termed microrafts, were fabricated by a dip-coating process using a polydimethylsiloxane mold as the template and the array substrate. This manufacturing approach enabled the use of materials other than photoresists to create the array elements. Thus microrafts possessing low autofluorescence could be fabricated for fluorescence-based identification of cells. Cells plated on the microarray settled and attached at the center of the wells due to the microrafts' concavity. Individual microrafts were readily dislodged by the action of a needle inserted through the compliant polymer substrate. The hard polymer material (polystyrene or epoxy resin) of which the microrafts were composed protected the cells from damage by the needle. For cell analysis and isolation, cells of interest were identified using a standard inverted microscope and microrafts carrying target cells were dislodged with the needle. The released cells/microrafts could be efficiently collected, cultured and clonally expanded. During the separation and collection procedures, the cells remained adherent and provided a measure of protection during manipulation, thus providing an extremely high single-cell cloning rate (>95%). Generation of a transfected cell line based on expression of a fluorescent protein demonstrated an important application for performing on-chip cell separations. PMID- 20838673 TI - Lanthanide-based luminescent probes for selective time-gated detection of hydrogen peroxide in water and in living cells. AB - Lanthanide-based luminescent probes TPR1 and TPR2 were developed for the detection of hydrogen peroxide (H(2)O(2)) in living systems. The chemoselective reaction of these boronate-protected probes with H(2)O(2) resulted in an enhanced lanthanide sensitization and a 6-fold increase in luminescent intensity. TPR2 was utilized to measure the endogenous production of H(2)O(2) in RAW 264.7 macrophages using time-gated luminescent spectroscopy. PMID- 20838674 TI - Two-dimensional heteronuclear saturation transfer difference NMR reveals detailed integrin alphavbeta6 protein-peptide interactions. AB - We report the first example of peptide-protein heteronuclear two-dimensional (2D) saturation transfer difference nuclear magnetic resonance (STD NMR). This method, resulting in dramatically reduced overlap, was applied to the interaction of the integrin alphavbeta6 with a known peptide ligand and highlights novel contact points between the substrate and target protein. PMID- 20838675 TI - Highly efficient synthesis of 3-amino-/alkylthio-cyclobut-2-en-1-ones based on the cyclization of acyl ketene dithioacetals. AB - A new strategy for the highly efficient one-pot synthesis of 3-amino-/alkylthio cyclobut-2-en-1-ones based on the cyclization of acyl ketene dithioacetals is disclosed. In addition, the rearrangement of 3-amino-cyclobut-2-en-1-ones to 4 quinolone derivatives is described. PMID- 20838676 TI - Spinodal phase separation in liquid films with quenched disorder. AB - We study spinodal phase separation in unstable thin liquid films on chemically disordered substrates via simulations of the thin-film equation. The disorder is characterized by immobile patches of varying size and Hamaker constant. The effect of disorder is pronounced in the early stages (amplification of fluctuations), remains during the intermediate stages and vanishes in the late stages (domain growth). These findings are in contrast to the well-known effects of quenched disorder in usual phase-separation processes, viz. the early stages remain undisturbed and domain growth is slowed down in the asymptotic regime. We also address the inverse problem of estimating disorder by thin-film experiments. PMID- 20838677 TI - Recent advances in the use of temporary silicon tethers in metal-mediated reactions. AB - This tutorial review describes the use of temporary silicon tethers in metal mediated organic reactions, a strategy which although well-established in traditional organic synthesis is still a blossoming field in the organometallic arena. The benefits of silicon-tethering are manifold: the reactivity, selectivity, and efficiency of organometallic processes can all be dramatically enhanced, often with unique regio- and stereochemical outcomes compared to the analogous intermolecular transformations. In addition, the residual silicon functionality can undergo a wide range of chemistry subsequent to the tethered reaction, creating further synthetic opportunities. PMID- 20838678 TI - Coordination pattern, solution structure and DNA damage studies of the copper(II) complex with the unusual aminoglycoside antibiotic hygromycin B. AB - The aminoglycosidic antibiotic hygromycin B presents a peculiar chemical structure, characterized by two sugar rings joined via a spiro connection. The Cu(ii) complex of hygromycin B in water solution was characterized by (1)H-NMR, UV-Vis, EPR and CD spectroscopy, combined with potentiometric measurements. The spin-lattice relaxation enhancements were interpreted by the Solomon-Bloembergen Morgan theory, allowing us to calculate copper-proton distances that were used to build a model of the complex by molecular mechanics and dynamics calculations. The fidelity of the proposed molecular model was checked by ROESY maps. Moreover DNA damage by the Cu(ii)-hygromycin B system was also investigated, showing single and double strand scissions exerted by the complex at concentrations in the range 1-5 mM. Addition of either hydrogen peroxide or ascorbic acid to each sample resulted in the shift of the cleavage potency towards lower concentrations of the complex. PMID- 20838679 TI - DNA interaction with Ru(II) and Ru(II)/Cu(II) complexes containing azamacrocycle and dppz residues. A thermodynamic, kinetic and theoretical study. AB - Ru(ii) complexes that bring together the properties of the dppz (dipyrido[3,2 a:2',3'-c]phenazine) intercalating residue and the properties of metal coordinating macrocycles (L = 4,4'-(2,5,8,11,14-pentaaza[15])-2,2' bipyridilophane) have been synthesised and their protonation and affinity for copper(ii) was analysed. Ru(bpy)(dppz)L(2+) (D2(2+)) and Ru(dppz)(2)L(2+) (D3(2+)) were found to interact with DNA but the binding mode is not simple and its features strongly depend both on the ligand structure and on the [DNA]/[complex] ratio. Equilibrium measurements (spectrophotometric and spectrofluorometric titrations), kinetics (stopped-flow technique) and theoretical calculations all concur in suggesting that for the less hindered D2(2+) an important contribution of external binding, driven by dye-dye interactions, is operative, as revealed by the onset of positive cooperativity. On the contrary, for the bulkier D3(2+) complex dye-dye interactions are less effective, resulting in an intercalation process with lower dppz penetration within DNA slots. The Ru(bipy)(2)L(2+)(D1(2+))/DNA system was also analysed for comparison and helped in showing the non negligible contribution of the macrocycle to the binding process. The binding affinities of the macrocycle copper complexes for DNA are lower than those of their copper-free analogues only in the case of D1(2+), whereas an affinity enhancement in agreement with the charge increase upon copper coordination is observed for D2(2+) and D3(2+). Copper coordination produces complete loss of the cooperative behaviour in the case of D2(2+). Further mechanistic details are discussed. PMID- 20838681 TI - New horizon of organosilicon chemistry. PMID- 20838680 TI - Unique assembly of low-dimensional viologen iodoplumbates and their improved semiconducting properties. AB - Two unique low-dimensional benzyl viologen iodoplumbates [Pb(13)I(38)][B'V](6) (1) and [(Pb(5)I(14))(BV)(2)](n) (2) were prepared from solvothermal reactions of benzyl alcohol with 4,4'-bipy, PbI(2), I(2) and a small amount of water in acetonitrile. The semiconducting properties of the single crystals 1 and 2 along with Zn/Cl-doped samples 2a and 2b were investigated. PMID- 20838683 TI - Use of 2-pyrimidineamidoxime to generate polynuclear homo-/heterometallic assemblies: synthesis, crystal structures and magnetic study with theoretical investigations on the exchange mechanism. AB - Three new transition metal complexes using 2-pyrimidineamidoxime (pmadH(2)) as multidentate chelating and/or bridging ligand have been synthesized and characterized. The ligand pmadH(2) has two potential bridging functional groups [MU-O and MU-(N-O)] and consequently shows several coordination modes. While a polymeric 1D Cu(II) complex [Cu(pmadH(2))(2)(NO(3))](NO(3)) (1) was obtained upon treatment of Cu(NO(3))(2).3H(2)O with pmadH(2) at room temperature in the absence of base, a high temperature reaction in the presence of base yielded a tetranuclear Cu(II)-complex [Cu(4)(pmad)(2)(pmadH)(2)(NO(3))](NO(3))(H(2)O) (2). One of the Cu(II) centers is in a square pyramidal environment while the other three are in a square planar geometry. Reaction of the same ligand with an equimolar mixture of both Cu(NO(3))(2).3H(2)O and NiCl(2).6H(2)O yielded a tetranuclear heterometallic Cu(II)(2)Ni(II)(2) complex [Cu(2)Ni(2)(pmad)(2)(pmadH)(2)Cl(2)].H(2)O (3) containing both square planar (Ni(II)) and square pyramidal (Cu(II)) metal centers. Complexes 1-3 represent the first examples of polynuclear metal complexes of 2-pyrimidineamidoxime. The analysis of variable temperature magnetic susceptibility data of 2 reveals that both ferromagnetic and antiferromagnetic interactions exist in this complex (J(1) = +10.7 cm(-1) and J(2) = -2.7 cm(-1) with g = 2.1) leading to a resultant ferromagnetic behavior. Complex 3 shows expected antiferromagnetic interaction between two Cu(II) centers through -N-O- bridging pathway with J(1) = -3.4 cm(-1) and g = 2.08. DFT calculations have been used to corroborate the magnetic results. PMID- 20838682 TI - Substrate recognition and transport behavior analyses of amino acid antiporter with coarse-grained models. AB - The L-arginine (Arg)/agmatine (Agm) antiporter AdiC is a vital transport protein of the arginine-dependent extreme acid resistance system of enteric bacteria. Recently, both substrate-free and Arg-bound structures of AdiC were determined by X-ray crystallography. In this article, the two different proteins were investigated with three simple models. Gaussian network model provided the information of conformational changes. It is found that Arg binding induces structural rearrangement in the extracellular domain, and transmembrane helix 6 (TM6) has the most pronounced trend of conformational changes. The moving directions of fluctuation regions were further ascertained by using anisotropy elastic network model and cross-correlation analysis. Interestingly, the two substrate-binding sites hypothesis of AdiC was confirmed directly by molecular docking. Furthermore, the binding preferences of these two sites were explained from the aspects of electrostatic complementarity and geometric matching. These simple coarse-grained analyses can be used as a general and quick method for the mechanism studies of transport proteins. PMID- 20838684 TI - Aluminium complexes of bidentate N,O- and N,N-ligands derived from oxidative functionalization of amido phosphines: synthesis, structure and reactivity. AB - A series of amido phosphinoxide and amido phosphinimine ligands that are electronic variations of monoanionic N,O- and N,N-ketiminates have been prepared and employed to examine the coordination chemistry of aluminium. Oxidation of the previously established N-(2-diphenylphosphinophenyl)-2,6-dialkylaniline in the presence of H(2)O(2) or organic azides RN(3) (R = 2,6-C(6)H(3)(i)Pr(2), SiMe(3)) led to phosphinoxides (H[NO] 1a-b) and phosphinimines (H[NN] 1c-d), respectively. Alkane elimination reactions of these protio-ligand precursors with trialkylaluminium in toluene or pentane solutions afforded cleanly the corresponding organoaluminium complexes, including dimethyl 2a-d, diethyl 3a-d and diisobutyl derivatives 4a-b and 4d. Solution NMR studies revealed Cs symmetry for these organoaluminium species, in which the alpha-hydrogen atoms are all diastereotopic. The correlation between the steric congestion of these molecules and the degree of resolution of the multiplet signals corresponding to the diastereotopic alpha-hydrogen atoms observed by the (1)H NMR spectroscopy is of particular interest. Dichloroaluminium complexes 5c-d were prepared in high yields by protonolysis of MeAlCl(2) with 1c-d. Single-crystal X-ray diffraction analyses of 2c-d, 3a, 3d, 4a, and 4d elucidated a mononuclear, distorted tetrahedral core for all of these aluminium species. Interestingly, complexes 2c d are active initiators for catalytic ring-opening oligomerization of epsilon caprolactone, whereas 2a-b are rather inactive, highlighting the significance of the steric hindrance imposed by the amido phosphinimine ligands, as compared to that imposed by the phosphinoxide counterparts. PMID- 20838685 TI - Visualization of PKA activity in plasma membrane microdomains. AB - Membrane rafts are sphingolipid- and cholesterol-rich microdomains that contain dynamic arrangements of signaling proteins. Notably, various components of the ubiquitous cAMP/Protein Kinase A (PKA) pathway, including beta-adrenergic receptors (beta-ARs), G proteins, and adenylyl cyclases (ACs), have been shown to localize differentially between membrane rafts and non-raft regions of the plasma membrane. As PKA participates in regulating diverse fundamental cellular functions, a number of which require membrane rafts, it is important to understand how PKA activity is specifically regulated in these membrane microdomains. To this end, we developed an improved FRET-based PKA activity biosensor, and targeted it to both membrane raft and non-raft regions of the plasma membrane to examine PKA activity dynamics in different plasma membrane microdomains. Disruption of membrane rafts via cholesterol depletion was shown to enhance beta-AR stimulated PKA activity at the plasma membrane, suggesting that membrane rafts play a negative role in beta-AR stimulated PKA activation. Furthermore, we found that membrane rafts possess higher basal PKA activity in the resting state compared to non-raft regions, which depends on the integrity of membrane rafts and proper localization of PKA. This study shows that membrane rafts play an important role in regulating the activity of PKA at the plasma membrane, and demonstrates the ability of live-cell FRET-based assays to reveal dynamic differences amongst plasma membrane microdomains, laying a foundation for further dissection of membrane regulated signal transduction. PMID- 20838686 TI - Visible light flavin photo-oxidation of methylbenzenes, styrenes and phenylacetic acids. AB - We report the photocatalytic oxidation of benzylic carbon atoms under mild conditions using riboflavin tetraacetate as photocatalyst and blue-emitting LEDs (440 nm) as light source. Oxygen is the terminal oxidant and hydrogen peroxide appears as the only byproduct in most cases. The process oxidizes toluene derivatives, stilbenes, styrenes and phenylacetic acids to their corresponding benzaldehydes. A benzyl methyl ether and acylated benzyl amines are oxidized directly to the corresponding methyl ester or benzylimides. The mechanism of the reactions has been investigated and the results indicate that oxygen addition to benzyl radicals is a key step of the oxidation process in the case of phenylacetic acids. PMID- 20838687 TI - Selective and sensitive detection of melamine by intra/inter liposomal interaction of polydiacetylene liposomes. AB - We report a convenient melamine detection system based on polydiacetylene (PDA) liposomes having rapid, selective, and sensitive detection, and dual signal capabilities. The detection limit of the sensory PDA liposome is 1 and 0.5 ppm in the colorimetric and the fluorescence detection schemes, respectively, satisfying the world regulation level. PMID- 20838688 TI - Four new coordination polymers constructed from benzene tricarboxylic acid: synthesis, crystal structure, thermal and magnetic properties. AB - The use of 1,3,5-benzene tricarboxylic acid (H(3)btc) as an organic linker has allowed us to achieve the rational design of two pairs of isostructural coordination polymers having molecular formulae [M(2)(btc)(F)](n) (M(ii) = Mn (1), Co (2)) and [M(3)(btc)(Hbtc)(OH)(H(2)O)(11)](n) (M(ii) = Fe (3), Co (4)) where btc and Hbtc represent the fully and doubly de-protonated tricarboxylates respectively. These compounds were synthesized using hydrothermal methods and characterized by thermal analysis and variable temperature magnetic measurements. The X-ray analysis reveals that compounds 1 and 2 crystallize in the monoclinic space group C2/c while compounds 3 and 4 crystallize in the monoclinic space group C2. Compounds 1 and 2 feature fluoride bridged 1D metal chains linked together via carboxylate groups of btc, whilst compounds 3 and 4 consist of 1D zigzag chains having strong hydrogen bonds with neighbouring chains. Variable temperature magnetic measurements show an overall antiferromagnetic behaviour for compounds 1, 2 and 4, with no indication of magnetic ordering phenomena in the temperature range from 300-2 K. As 3 and 4 are isostructural, we assume that the magnetic properties are similar. PMID- 20838689 TI - A new weakly coordinating aluminate anion incorporating a chelating perfluoro-bis anilido ligand. AB - The synthesis of the fully fluorinated bis-anilido ligand N,N'-bis pentafluorophenyl-3,4,5,6-tetrafluorophenylene-1,2-diamine, 1 is described. Reaction of one or two equivalents of 1 with AlMe(3) gives aluminium compounds incorporating one or two ligands, the latter being the protonated form of a new weakly coordinating anion (WCA), 3-H. Alternatively, reaction of 1 with LiAlH(4) yields the lithium salt of this anion, 3-Li, which may be employed as a reagent for preparing the trityl and N,N-dimethylanilinium salts of the aluminate anion. All ion pairs are fully characterized and the use of 3-Ph(3)C to generate titanium-based alkyl cations is also described. PMID- 20838690 TI - Crystal structure of the insect neuropeptide proctolin. AB - The crystal structure of the neuropeptide proctolin (Arg-Tyr-Leu-Pro-Thr) is reported revealing the solid-state conformation of its molecules and their association in the crystal. PMID- 20838691 TI - Highly stereoselective synthesis of indanes with four stereogenic centers via sequential Michael reaction and [3+2] cycloaddition. AB - A highly efficient organocatalytic sequential reaction involving Michael addition of bis(phenylsulfonyl)ethylene, in situ condensation and intramolecular nitrone [3+2] cycloaddition with a variety of aldehydes and hydroxyamines to afford a single diastereomer of indanes with four stereogenic centers in excellent yields and stereoselectivities was developed. PMID- 20838692 TI - Selective alpha-defluorination of polyfluorinated esters and amides using SmI2/Et3N/H2O. AB - SmI(2)/H(2)O promotes selective alpha-monodefluorinations, while addition of an amine results in complete alpha-defluorination reactions. PMID- 20838693 TI - Zwitterionic i-motif structures are preserved in DNA negatively charged ions produced by electrospray mass spectrometry. AB - DNA cytosine-rich strands can fold into an intercalated motif (i-motif) structure. The i-motif is formed by mutually intercalated duplexes containing proton-mediated C-H(+)-C (cytosine-proton-cytosine) base pairs. Negatively charged ions of DNA i-motifs produced by electrospray mass spectrometry are therefore zwitterionic if the base pairing motif is preserved in the gas phase. Here we used IRMPD spectroscopy and ion mobility spectrometry to assess whether i motif structures were preserved in the gas phase. We first investigated the IRMPD spectral signature of the tetramer [dC(6)](4), which can only be formed via C H(+)-C base pairing, compared to the single strand dC(6). The IR signature of i motif formation is an apparent broadening of the band at 1650 cm(-1). DFT calculations show this apparent broadening is actually due to blue-shifts of the NH(2) scissoring modes and red shifts of C[double bond, length as m-dash]O stretching modes. We then investigated the gas-phase conformations of the telomeric sequence d(CCCAAT)(3)CCC, that can form an intramolecular i-motif, by performing IRMPD spectroscopy and ion mobility spectrometry as a function of the charge state. We show that the negative ions of the lowest charge states correspond to a preserved i-motif structure. This is the first demonstration of the native extraction of solution-phase zwitterionic nucleic acids using negative electrospray ionization. PMID- 20838694 TI - Simulation study on the translocation of diblock copolymer A(n)B(n) through interacting nanopores. AB - Translocation of diblock copolymer A(n)B(n) through an interacting nanopore is studied using a dynamic Monte Carlo method on a simple three-dimensional cubic lattice. The probabilities and translocation times of two translocation orientations of copolymer, orientation A with block A translocating first and orientation B with block B first, are mainly dependent on the segment-pore interactions epsilon(A) and epsilon(B). We find that both the probability and the translocation time are larger for the orientation with stronger attraction. The dynamic behaviors of copolymer translocation at different epsilon(A) and epsilon(B) can be explained based on the free energy landscapes of homopolymer at different polymer-pore interaction. The results reveal a complicated free energy landscape for copolymer translocation. PMID- 20838695 TI - Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. PMID- 20838696 TI - Efficient dispersion of singlewalled carbon nanotubes by novel amphiphilic dendrimers in water and substitution of the pre-adsorbed dendrimers with conventional surfactants and lipids. AB - A new class of amphiphilic dendrimers, which can be readily adsorbed on the surface of singlewalled carbon nanotubes (SWNTs) to improve their dispersibility in aqueous medium, were synthesized. The adsorbed dendrimers can be replaced by other amphiphiles, such as sodium dodecylbenzene sulfonate (SDBS), sodium dodecylsulfate (SDS), and lysophospholipid (LPC 18 : 0). PMID- 20838697 TI - Hybrid dithienylethene-naphthopyran multi-addressable photochromes: an ab initio analysis. AB - Using ab initio tools, we investigate the structural and electronic properties as well as the NMR spectra of hybrid dithienylethene-naphthopyran photochromes synthesised by Frigoli and Mehl (Angew. Chem. Int. Ed., 2005, 44, 5048). All possible closed/open structures have been considered and in each case several conformers could be characterised. Both UV/vis and NMR spectroscopic signatures have been compared to experimental references, and it was shown that the selected DFT/TD-DFT procedure is adequate not only to reproduce the measured spectral values but also to explain the observed photochromic pathways. Our work indicates that several conformers with different relative dithienylethene and naphthopyran orientations might be present experimentally. PMID- 20838698 TI - Personalised medicine for psoriasis: a real possibility ahead. PMID- 20838699 TI - Changing seroprevalence of hepatitis B virus markers of adults in Singapore. AB - INTRODUCTION: We presented the findings from 2 seroprevalence studies conducted 6 years apart, so as to determine changes in the hepatitis B surface antigen (HBsAg) positivity rate and immunity to hepatitis B virus (HBV) among Singapore residents aged 18 to 69 years, and to assess the impact of a 4-year catch-up hepatitis B immunisation programme for adolescents and young adults launched in 2001. MATERIALS AND METHODS: Two hepatitis B seroprevalence studies (HBSS) were conducted in 1999 and 2005 based on stored blood samples collected from 4698 participants aged 18 to 69 years during the national health survey (NHS) 1998 and from 3460 participants during the NHS 2004, respectively. Serology for HBsAg, hepatitis B e antigen (HBeAg) and antibody to HBsAg (anti-HBs) were tested by enzyme immunoassay in HBSS 1999 and electrochemiluminescence in HBSS 2005. RESULTS: The overall age-standardised prevalence of HBsAg among Singapore residents aged 18 to 69 years decreased significantly from 4.0% in HBSS 1999 to 2.8% in HBSS 2005 (P = 0.002). The age-standardised prevalence of HBsAg in males (4.9% in 1999) and Chinese (4.7% in 1999) both decreased significantly to 2.7% and 2.8%, respectively in 2005. The overall age-standardised population immunity to HBV (anti-HBs >10 mIU/ml) increased from 39.7% in 1999 to 42.1% in 2005 (P = 0.019). In particular, the age-specific prevalence of anti-HBs showed a significant increase among those in the age group of 18 to 29 years from 27.9% in 1999 to 41.7% in 2005 (P <0.001) and among those in the age group of 30 to 39 years from 39.9% in 1999 to 44.7% in 2005 (P = 0.021). CONCLUSION: There was an overall decline in the HBsAg positivity rate as well as an overall increase in population immunity to HBV. Following the 4-year catch-up immunisation programme, there was a significant increase in the immunity to HBV infection in the younger population aged 18 to 29 years. PMID- 20838700 TI - Effect of autologous mesenchymal stem cells on biological healing of allografts in critical-sized tibial defects simulated in adult rabbits. AB - INTRODUCTION: This study evaluated the effect of autologous bone marrow derived adult Mesenchymal Stem Cells (MSCs) on the biological healing of weight bearing diaphyseal bone allograft in the tibia of adult rabbits. MATERIALS AND METHODS: Forty Adult New Zealand White Rabbits divided into 3 groups (Autograft, Allograft or Allograft impregnated with MSCs) with 12 rabbits in each group were used for the study. A 1.5 cm of cortical bone segment was excised from the rabbit's right tibia. The segment was replaced by an Autograft, Allograft or Allograft loaded with MSCs, depending on which group the rabbit was assigned. Internal fixation was performed using a 9-hole Mini-compression Plate and Cerclage Wires. Rabbits were sacrificed at end of observation periods of 12, 16 and 24 weeks. Specimens procured were assessed clinically and radiologically and fixed in 10% buffered formalin. For each specimen, 5 MUm undecalcified sections were cut and stained with Von Kossa and Toluidine Blue stains. Histomorphometery was then performed. RESULTS: Our study showed that addition of autologous MSCs to diaphyseal allograft segments enhances and accelerates not just the union at host graft junctions and also the biological incorporation of the allograft segment as shown by Resorption Index, New-Bone Formation Index and Osteocyte Index. CONCLUSIONS: The addition of autologous MSCs to deep frozen cortical allograft segments improved the host - allograft union rate and biological incorporation of diaphyseal allografts as shown by resorption activity, new bone formation and osteocyte cell counts. PMID- 20838701 TI - Off-pump coronary artery bypass is a safe option in patients presenting as emergency. AB - INTRODUCTION: The applicability of off-pump coronary-artery bypass (OPCAB) in patients who present as emergency remains controversial. Herein, we explore the efficacy and safety of OPCAB in patients who were indicated for emergency surgery. MATERIALS AND METHODS: Between 2002 and 2007, a total of 282 patients underwent OPCAB, of which 68 were presented as emergency. This cohort (group A) was compared to 68 patients who had traditional on-pump coronary artery bypass grafting (CABG, group B) under emergency indications during the same period of time. Baseline demographics, intraoperative data and postoperative outcomes were analysed. RESULTS: Preoperative demographics were comparable in both groups. Mortality during the first 30 days was comparable in both groups and no stroke occurred in the whole series. Patients in group A had significantly less pulmonary complications (4.4% vs 14.7%, P = 0.04), less ventilation time (30.3 +/ 33.6 hours vs 41.5 +/- 55.4 hours, P = 0.18) and were less likely to have prolonged ventilation, (19.1% vs 35.3%, P = 0.03). Similarly, OPCAB patients had less postoperative renal-failure/dysfunction (5.9% vs 8.8%, P = 0.51) and required less inotropic support (66.2% vs 88.2%, P = 0.002), bloodtransfusions (23% vs 86.8%, P <0.0001), and atrial- (17.6% vs 35.3%, P = 0.02) or ventricular pacing (17.6% vs 41.2%, P = 0.002). Although the number of diseased vessels was comparable in both groups, patients in group A received less distal anastomoses. (2.78 +/- 1.19 vs 3.41 +/- 0.89, P = 0.002). Similarly, complete revascularisation was achieved less frequently in group A (76.5% vs 94.1%, P = 0.004). CONCLUSION: OPCAB strategy is a safe and efficient in emergency patients with reasonable good short-term postoperative outcomes. PMID- 20838702 TI - Comparison between inter-rater reliability and inter-rater agreement in performance assessment. AB - INTRODUCTION: Over the years, performance assessment (PA) has been widely employed in medical education, Objective Structured Clinical Examination (OSCE) being an excellent example. Typically, performance assessment involves multiple raters, and therefore, consistency among the scores provided by the auditors is a precondition to ensure the accuracy of the assessment. Inter-rater agreement and inter-rater reliability are two indices that are used to ensure such scoring consistency. This research primarily examined the relationship between inter rater agreement and inter-rater reliability. MATERIALS AND METHODS: This study used 3 sets of simulated data that was based on raters' evaluation of student performance to examine the relationship between inter-rater agreement and inter rater reliability. RESULTS: Data set 1 had high inter-rater agreement but low inter-rater reliability, data set 2 had high inter-rater reliability but low inter-rater agreement, and data set 3 had high inter-rater agreement and high inter-rater reliability. CONCLUSION: Inter-rater agreement and inter-rater reliability can but do not necessarily coexist. The presence of one does not guarantee that of the other. Inter-rater agreement and inter-rater reliability are both important for PA. The former shows stability of scores a student receives from different raters, while the latter shows the consistence of scores across different students from different raters. PMID- 20838703 TI - Clinical features of allergic rhinitis and skin prick test analysis based on the ARIA classification: a preliminary study in Malaysia. AB - INTRODUCTION: Allergic rhinitis (AR) is a prevalent disease worldwide but is still underdiagnosed in many parts of Asia. We studied the clinical profiles of AR patients in our community based on the new ARIA classification and investigated the aetiological allergens using a skin prick test. MATERIALS AND METHODS: In 2008, 142 newly diagnosed patients with AR were seen and underwent skin prick testing with 90 patients completing the study. RESULTS: Intermittent mild and moderate/severe AR were evident in 10% and 21.1% of the patients, while persistent mild and moderate/severe were seen in 20% and 48.9%, respectively. Rhinitis and asthma co-morbidity occurred in 28.8% with asthma incidence significantly higher in persistent AR (P = 0.002). There was no significant association between AR severity, city living and asthma co-morbidity. Nasal itchiness and sneezing were the main presenting complaints and were more common in intermittent AR (P <0.05). Sleep disturbance was associated with moderate severe AR (P <0.05). Polypoidal mucosa was associated with asthma co-morbidity (P <0.05). Monosensitivity reaction occurred in 12.2% of patients and was associated with fungi sensitivity (P <0.05). Majority of patients were oligosensitive (52.8%) and polysensitive (34.4%) and were significantly associated with moderate severe persistent AR (P <0.01). The highest positive skin prick reaction and the largest average wheal diameter were for the house dust mites and cat allergen (P <0.05). CONCLUSION: Our results reflected the AR profiles in our country, which was comparable with typical profiles of the neighbouring country and other Mediterranean countries with a similar temperate climate. PMID- 20838704 TI - A clinicopathologic study of uterine smooth muscle tumours of uncertain malignant potential (STUMP). AB - INTRODUCTION: The clinical management of Smooth Muscle Tumours of Uncertain Malignant Potential (STUMPs) remains controversial because little is known about the natural history of these tumours and pathological classifications do not correlate well with clinical outcomes and therefore cannot direct management. The objective of this study was to review a single institution's experience with STUMP and recommend a rational clinical approach to the management of patients with this histological diagnosis. MATERIALS AND METHODS: A systematic review of all diagnoses of STUMP and leiomyosarcoma from the gynaecologic oncology and pathology databases between January 1970 and February 2006. RESULTS: A total of 18 diagnoses of STUMP and 72 diagnoses of Ieiomyosarcoma were made during the study period. None of these 72 cases of leiomyosarcoma had a prior diagnosis of STUMP. There were no recurrences in the 18 cases of STUMP with all 18 cases being registered as disease-free after 5 years. CONCLUSIONS: We recommend that patients with a diagnosis of STUMP be expectantly managed given the low likelihood of leiomyosarcomatous transformation, the lack of any evidence that adjuvant treatments result in better long-term outcomes and that recurrences are amenable to surgical resection with good outcomes. PMID- 20838705 TI - Comparison of clinical outcomes and cost between surgical and transcatheter device closure of atrial septal defects in Singapore children. AB - INTRODUCTION: With advances in interventional catheterisation, transcatheter device closure of atrial septal defect (ASD) is now a feasible option to open heart surgery, especially in patients with isolated ASD. We aim to compare the outcomes, benefits and costs between device closure versus standard open-heart surgery for ASD in Singapore. MATERIALS AND METHODS: This is a comparative study between 2 cohorts with isolated secundum ASDs who underwent closure of ASD either by surgery or device, at the Department of Paediatrics, National University Hospital (NUH). The clinical outcomes, complications, length of stay and total costs incurred were compared. RESULTS: Surgical patients were at slightly greater risk of developing complications (RR=1.33; 95% CI, 0.30 to 5.95) than the device group. The median length of inpatient stay for the surgical group was significantly longer than that for the device group. Seventy percent of the patients in the device group did not need to be in ICU while 40% of patients in the surgery group stayed 2 or at least 3 days in ICU (P <0.001). The mean cost per successful procedure was $1511 (95% CI, -352 to 3375) higher for the device group patients despite a shorter length of stay in hospital. CONCLUSIONS: We concluded that transcatheter device closure is an effective and safe alternative to surgery in the treatment of suitable ASDs. Despite the high cost of the device, direct and indirect benefits for the patients and their families, who undergo device occlusion include less morbidity, better cosmesis, shorter length of stay in hospital, faster recovery and shorter time taken to resume normal activities. PMID- 20838706 TI - Surgical metastasectomy in AJCC stage IV M1c melanoma patients with gastrointestinal and liver metastases. AB - INTRODUCTION: Visceral metastases from melanoma represent the poorest prognosis based according to the revised version of the AJCC staging system that recognises both clinical and pathological features distinctive to melanoma. Given that systemic treatments in metastatic melanoma to date remains inadequate, we evaluated the efficacy of surgical metastasectomy on survival outcomes. MATERIALS AND METHODS: Between year 2000 and 2009, 23 patients with visceral metastases from melanoma were evaluated for metastasectomy. Retrospective review was undertaken of the specific therapy administered following consensus meeting of a multidisciplinary team. RESULTS: There were 16 males and 7 females. Seventeen patients (74%) had metachronous gastrointestinal/liver metastases following previous treatment of the primary tumour. The median time to development of gastrointestinal/liver metastases, otherwise known as disease-free interval, was 49 (range, 5 to 559) months. Overall median survival period was 9 months, with a 1- and 3-year survival percentages of 39% and 30%, respectively. Survival was influenced by the number of metastases (P = 0.05) and the treatment received (P = 0.03). The disease-free and overall survival periods after metastasectomy were 14 and 21 months, respectively. The 1- and 3-year survival percentages were 60% and 40%, respectively. Patients with single site of metastasis survived longer than patients with more than one site of metastasis (P = 0.005). CONCLUSION: Patients with visceral metastases from melanoma may derive survival benefit from metastasectomy over systemic therapy. Judicious selection of patients for metastasectomy is paramount for the success of treatment in this group of patients. PMID- 20838707 TI - Epidemiology of snakebites from a general hospital in Singapore: a 5-year retrospective review (2004-2008). AB - INTRODUCTION: This is a retrospective study on the epidemiology of snakebites that were presented to an emergency department (ED) between 2004 and 2008. MATERIALS AND METHODS: Snakebite cases were identified from International Classification of Diseases (ICD) code E905 and E906, as well as cases referred for eye injury from snake spit and records of antivenom use. RESULTS: Fifty-two cases were identified: 13 patients witnessed the snake biting or spitting at them, 22 patients had fang marks and/or clinical features of envenomations and a snake was seen and the remaining 17 patients did not see any snake but had fang marks suggestive of snakebite. Most of the patients were young (mean age 33) and male (83%). The three most commonly identified snakes were cobras (7), pythons (4) and vipers (3). One third of cases occurred during work. Half of the bites were on the upper limbs and about half were on the lower limbs. One patient was spat in the eye by a cobra. Most of the patients (83%) arrived at the ED within 4 hours of the bite. Pain and swelling were the most common presentations. There were no significant systemic effects reported. Two patients had infection and 5 patients had elevated creatine kinase (>600U/L). Two thirds of the patients were admitted. One patient received antivenom therapy and 5 patients had some form of surgical intervention, of which 2 had residual disability. One patient had heparin instilled in the eye for eye injury from cobra spit. CONCLUSIONS: Snakebite infrequently presents to the ED. Most of the patients developed local effects that do well with supportive treatment. PMID- 20838708 TI - Clinical features differentiating biliary atresia from other causes of neonatal cholestasis. AB - INTRODUCTION: This study determined any clinical features which may help to differentiate biliary atresia (BA) from other causes of neonatal cholestasis (NC). MATERIALS AND METHODS: A prospective and observational study was conducted on consecutive infants with NC referred to the University of Malaya Medical Centre, Malaysia, between November 1996 and May 2004. RESULTS: The 3 most common causes of cholestasis among the 146 infants with NC studied were idiopathic neonatal hepatitis (n = 63, 43%), BA (n = 35, 24%) and congenital cytomegalovirus hepatitis (n = 13, 9%). Common clinical features at presentation were jaundice (100%), hepatomegaly (95%), splenomegaly (52%) and pale stools (47%). Three clinical features noted to be sensitive for BA were the presence of acholic or variably acholic stools on admission, a liver which was firm/hard in consistency and a palpable liver of >=4 cm (sensitivity of 77%, 80% and 94%, respectively), but the corresponding specificity was poor (51%, 65% and 39%, respectively). The stools of 2 children with BA were pigmented initially but became acholic subsequently. CONCLUSIONS: We did not find any single clinical feature with sufficient sensitivity and specificity to differentiate BA from other causes of NC. Repeated inspection of stools colour is necessary as occasionally, patients with BA may have initial pigmented stools. Biochemical assessment and imaging studies are important in the assessment of any infant with NC. PMID- 20838709 TI - Comparison of cardiac output measurement by arterial waveform analysis and pulmonary artery catheter in mitral stenosis. PMID- 20838710 TI - Primary epithelioid angiosarcoma of the lung presenting as left-sided shoulder pain. PMID- 20838712 TI - Image in medicine. An exanthem with an annular pattern in a 2-year-old girl. Atypical viral exanthem with an annular pattern. PMID- 20838711 TI - Levofloxacin-induced toxic epidermal necrolysis treated with intravenous immunoglobulin. PMID- 20838713 TI - Image in medicine. A case of congenital haemolytic anaemia and thrombocytopenia. Upshaw-Schulman syndrome (congenital thrombotic thrombocytopenic purpura). PMID- 20838714 TI - The cost of coping: a cardio-neuro-metabolic risk for black South Africans? PMID- 20838715 TI - Assessment of right ventricular systolic function using tricuspid annular-plane systolic excursion in Nigerians with systemic hypertension. AB - AIM: Right ventricular (RV) systolic function in patients with hypertensive heart disease (HHD) is not well characterised. The primary aim of this study was to assess the systolic function of the right ventricle in patients with HHD using tricuspid annular-plane systolic excursion (TAPSE). METHODS: The study was cross sectional in design and carried out in Kano, Nigeria. Patients were recruited if they had HHD on echocardiography and were at least 15 years of age. Patients with other cardiac pathologies such as ischaemic and valvular heart diseases were excluded. Patients were considered to have abnormal RV systolic function if they had reduced values of TAPSE ( < 15 mm). A p-value of < 0.05 was considered statistically significant. RESULTS: A total of 186 patients were serially recruited over seven months. Of these, 131 (70.4%) had normal RV systolic function (group 1) and 55 patients (29.6%) had abnormal function (group 2). Group 2 patients were older (p = 0.002) and had a higher prevalence of peripheral oedema (p = 0.002), moderate to severe dyspnoea, higher heart rate and lower left ventricular ejection fraction (p < 0.001). Atrial arrhythmias were also more prevalent among group 2 patients (p < 0.05). The best correlate to TAPSE was the septal mitral annularplane systolic excursion (r = +0.541, p < 0.001). Several variables such as age predicted the presence of reduced TAPSE. CONCLUSION: The study found that almost one-third of patients with HHD in Kano had RV systolic dysfunction as defined by reduced TAPSE, and these patients had a greater prevalence of factors associated with morbidity and mortality. PMID- 20838716 TI - Value of trans-oesophageal echocardiography as a method of encouraging patients with chronic atrial fibrillation to use anticoagulation therapy. AB - BACKGROUND: Despite the indisputable role of anticoagulation therapy for atrial fibrillation (AF) patients at risk for stroke, anticoagulants remain under-used in everyday clinical practice. We assumed that by performing trans-oesophageal echocardiography (TEE) on patients with AF who were not on anticoagulation treatment prior to the procedure, and by explaining to them the TEE images obtained, as well as the possible consequences of these findings, we could convince patients to start anticoagulation therapy. The main objective of the study was to assess the examined patients' adherence to warfarin therapy over a two-year period. METHODS AND RESULTS: We conducted a prospective TEE study from February 2006 to December 2008 on 70 patients with chronic AF who were not on anticoagulation treatment. Mean patient age was 65.85 +/- 10.02 years and 68.57% were women. Thrombus in the left atrial appendage was found in 25 (35.71%) patients. Fifty-four (77.14%) patients had thrombi or spontaneous echo contrast in at least one of their supraventricular cavities. Following the procedure and with detailed explanation to the patients of their TEE findings, we managed to start anticoagulation therapy on 60 (85.71%) patients. At the end of the follow up period of 23.76 +/- 2.8 months, 53 (75.71%) patients remained on warfarin therapy. The rest of the surviving patients settled for thrombo-prophylaxis with aspirin. CONCLUSION: TEE is a valuable method that, in addition to its diagnostic possibilities, could also serve as a convincing visual method of putting atrial fibrillation patients onto an anticoagulation regimen. PMID- 20838717 TI - Concurrent resistance and aerobic training as protection against heart disease. AB - This study was designed to compare the effects of aerobic and concurrent aerobic and resistance training on their ability to slow the rate of development and progression of coronary heart disease (CHD) in young adult males at low risk, as determined by the Framingham risk assessment (FRA) score. Subjects were assigned to 16 weeks of three-times weekly aerobic training (AT) (n = 13), concurrent aerobic and resistance training (CART) (n = 13) or no exercise (NO) (n = 12). Both AT and CART resulted in significant (p < 0.05) changes in total cholesterol (from 173.67 +/- 29.93 to 161.75 +/- 26.78 mg.dl(-1) and from 190.00 +/- 38.20 to 164.31 +/- 28.73 mg.dl(-1), respectively), smoking status (from 12.25 +/- 5.08 to 10.33 +/- 5.37 cigarettes per day and 12.00 +/- 4.71 to 8.77 +/- 5.10 cigarettes per day, respectively), high-density lipoprotein cholesterol (from 47.00 +/- 11.85 to 57.50 +/- 5.99 mg.dl(-1) and 34.00 +/- 8.53 to 46.77 +/- 14.32 mg.dl( 1), respectively), systolic blood pressure (from 126.17 +/- 7.00 to 122.33 +/- 3.17 mmHg and 131.54 +/- 9.28 to 121.69 +/- 7.87 mmHg, respectively) and therefore FRA score (from 3.58 +/- 2.19 to 1.33 +/- 2.27 and 5.77 +/- 3.09 to 2.46 +/- 2.90, respectively). Both modes of exercise were found to be equally effective in reducing CHD risk. These findings support the inclusion of resistance training into an aerobic training programme to lower CHD risk, which will afford subjects the unique benefits of each mode of exercise. PMID- 20838718 TI - Prevalence of microalbuminuria in hypertensive patients and its associated cardiovascular risk in clinical cardiology: Moroccan results of the global i SEARCH survey - a sub-analysis of a survey with 21,050 patients in 26 countries worldwide. AB - OBJECTIVES: To determine the prevalence of microalbuminuria (MAU) in hypertensive outpatients visiting a cardiologist's office or clinic and to describe the relationship between MAU and cardiovascular risk factors. METHODS: This was an international, observational, cross-sectional study of 22 282 patients, with 457 subjects from Morocco in 40 cardiology centres. Inclusion criteria were: male and female outpatients aged >= 18 years with currently treated or newly diagnosed hypertension ( >= 140/90 mmHg at rest on the day of the study visit) and no reason for false positive microalbuminuria dipstick tests. OUTCOME MEASURES: Prevalence of microalbuminuria assessed using a dipstick test, co-morbid cardiovascular risk factors or disease and their relationship with the presence of MAU, and role of pharmacotherapy in modulating the prevalence of MAU. RESULTS: The prevalence of microalbuminuria in hypertensive patients in Morocco (67.8%) was high compared to the worldwide prevalence (58.3%). Despite the fact that all physicians regarded MAU as important for risk assessment and therapeutic decisions, routine MAU measurement was performed in only 35% of the practices. In clinical cardiology, MAU is highly correlated with a wide variety of cardiovascular risk factors and cardiovascular disease. While angiotensin receptor blockers (ARBs) appeared to be associated with the lowest risk of MAU, calcium channel blockers (CCBs) were more often used in this patient group. CONCLUSIONS: Hypertensive, high-risk cardiovascular patients are common in clinical cardiology. Given the high prevalence detected, screening of MAU in addition to more aggressive multi-factorial treatment to reduce blood pressure as well as other cardiovascular risk factors is required. PMID- 20838719 TI - Cardiovascular function and psychological distress in urbanised black South Africans: the SABPA study. AB - OBJECTIVE: The increased prevalence of cardiovascular disease risk factors in sub Saharan Africa has increased the incidence of cardiovascular disease in this region but whether psychological distress contributes to this observed increased risk remains largely unclear. The aim of this study was to investigate the association between cardiovascular function and psychological distress in urbanised black South African men (n = 101) and women (n = 99). METHODS: Resting cardiovascular variables were obtained by making use of the Finometer device and 24-hour ambulatory blood pressure (BP) measurements with the Cardiotens apparatus. Psychological questionnaires assessed the perception of health (General Health questionnaire) and depression status (DSM-IV criteria). The resting ECG (NORAV PC-1200) was used to determine left ventricular hypertrophy (LVH) by making use of the Cornell product. Confounders included age, obesity, alcohol intake, smoking and physical activity. RESULTS: The hypertensive groups were overweight, with lower vascular compliance and higher LVH (only men) compared to the normotensive groups. In hypertensive men, perception of health (somatic symptoms) was positively associated with blood pressure, while in hypertensive women it was associated with heart rate. Major depression was associated with LVH in hypertensive men and mean arterial pressure in hypertensive women. LVH and depression showed odds ratios of 1.02 (95% CI: 0.997 1.05) and 1.15 (95% CI: 1.01-1.32), respectively, in predicting hypertension in women. CONCLUSIONS: Psychological distress was associated with higher blood pressure in hypertensive African men but also with the development of left ventricular hypertrophy in hypertensive African men and women. PMID- 20838720 TI - Long-term outcome associated with early repolarization on electrocardiography. PMID- 20838721 TI - The clinical quandary of left and right ventricular diastolic dysfunction and diastolic heart failure. AB - Diastolic heart failure is a common clinical entity that is indistinguishable from systolic heart failure without direct evaluation of left ventricular function. Diastolic heart failure is a clinical diagnosis in patients with signs and symptoms of heart failure but with preserved left ventricular function and normal ejection fraction, and is often seen in patients with a long-standing history of hypertension or infiltrative cardiac diseases. In contrast, diastolic dysfunction represents a mechanical malfunction of the relaxation of the left ventricular chamber that is primarily diagnosed by two-dimensional transthoracic echocardiography and usually does not present clinically as heart failure. The abnormal relaxation is usually separated in different degrees, based on the severity of reduction in passive compliance and active myocardial relaxation. The question whether diastolic dysfunction ultimately will lead to diastolic heart failure is critically reviewed, based on data from the literature. Treatment recommendations for diastolic heart failure are primarily targeted at risk reduction and symptom relief. Currently, few data only are reported on diastolic dysfunction and its progression to systolic heart failure. PMID- 20838723 TI - A halo in the heart during coronary angiography: calcified left ventricular aneurysm with thrombus formation. AB - A 74-year-old man presented with chest pain and dyspnoea at the cardiology outpatient clinic. His past medical history included an anterior myocardial infarction in 2008. In the coronary angiogram, a 'halo image' was seen right after the injection of the contrast agent, and it corresponded with the location of the left ventricular aneurysm. A calcified left ventricular aneurysm with mural thrombus was confirmed with cardiac MRI and a CT scan. PMID- 20838724 TI - A coronary artery anomaly: type IV dual left anterior descending artery. AB - Coronary artery anomalies are seen in about 1.3% of patients undergoing coronary angiography. However, the dual type of left anterior descending (LAD) artery is a rare form of coronary artery anomaly. There are four types of dual LAD; type IV describes the anomaly of a rudimentary LAD artery terminating in the mid-portion of the anterior interventricular sulcus, and the presence of another LAD originating from the right coronary artery and continuing to the anterior interventricular sulcus. PMID- 20838725 TI - Serotonin and catecholaminergic polymorphic ventricular tachycardia: a possible therapeutic role for SSRIs? AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare malignant arrhythmia, usually diagnosed in the adolescent years. The diagnosis can typically be made by one or more of the following: a positive family history, exercise electrocardiography, ambulatory ECG monitoring and/or an intra-cardiac, electrophysiological examination. This is a case report of a patient with CPVT that was refractory to treatment with beta-blockade and an implanted automatic cardioverter defibrillator. However, after a selective serotonin re-uptake inhibitor (SSRI) was added to the therapeutic regimen, no further episodes of ventricular tachycardia occurred during the following two years. PMID- 20838726 TI - Coeur en sabot. AB - In tetralogy of Fallot (TOF), the most common form of cyanotic congenital heart disease, only a few patients reach adulthood without surgical correction. We present a case of a woman with TOF who was diagnosed at the age of 39 when she presented with features of congestive heart failure. The main factor contributing to her longevity included the slow development of her pulmonary artery stenosis together with left ventricular hypertrophy. Less than 3% of all patients with uncorrected TOF survive beyond their 40s but late operative repair is still a valuable option. This case provides an insight into the late outcome of an older patient with uncorrected TOF. PMID- 20838727 TI - ARBs and possible cancer risk. PMID- 20838729 TI - High-risk patients benefit most from nifedipine GITS-telmisartan combination. PMID- 20838730 TI - Increased heart rate in high-risk hypertensives related to increased heart failure and sudden death. PMID- 20838731 TI - Cardiovascular and diabetes research in Africa to benefit from Servier sponsorship. PMID- 20838732 TI - Amlodipine + atorvastatin single pill is the most effective choice for primary prevention. PMID- 20838734 TI - [Bone scanning with sodium 18F-fluoride PET and PET/CT. German guideline Version 1.0.]. AB - In nuclear medicine, bone scanning is based on the principle of scintigraphy using bone-seeking radiopharmaceuticals which accumulate in sites of increased bone formation. From a historical point of view, (18)F-fluoride was one of the first osteotropic tracers which was replaced by (99m)Tc-labelled polyphosphonates. With the development of modern PET equipment the superior diagnostic performance of (18)F-fluoride PET for the detection and characterization of osseous lesions was proven in comparison to conventional bone scanning. Recently, its importance as a substitute of conventional skeletal scintigraphy increased in a time with limited availability of (99)Mo/(99m)Tc. To ensure health care during this period, (18)F-fluoride PET currently became part of common outpatient care. This guideline comprehends recommendations on indications, protocols, interpretation and reporting of (18)F-fluoride PET and PET/CT. PMID- 20838735 TI - 2B or not to be--the 45-year saga of the Montreal Platelet Syndrome. AB - Over 45 years ago, Montreal Platelet Syndrome was first described as a rare inherited platelet disorder characterised by macrothrombocytopenia with spontaneous platelet clumping, abnormal platelet shape change upon stimulation and a defect in platelet calpain. This syndrome has now been reclassified as type 2B von Willebrand disease with the V1316M VWF mutation in the only kindred ever reported. We herein revisit the historical platelet characteristics originally described in Montreal Platelet Syndrome in light of the new diagnosis. This paper will review the 45-year saga of Montreal Platelet Syndrome, a story that highlights the value of revisiting a rare diagnosis to look for a more common explanation. PMID- 20838736 TI - Studies on Fletcher trait and Fitzgerald trait. A rare chance to disclose body's defense reactions against injury. AB - The way by which contact of blood with foreign surface accelerates clotting has been elucidated from the discovery of four rare disorders of blood coagulation; Hageman trait, plasma thromboplastin antecedent (PTA) deficiency, Fletcher trait, and Fitzgerald trait. Interestingly, it was unexpectedly found that Fletcher factor is plasma prekallikrein and Fitzgerald factor is high-molecular-weight kininogen; components of the kinin-generating system, thus disclosing intimate relationships among clotting, fibrinolysis and kinin generation which may be viewed as body's defense reactions against injury. This review mainly reflects our research on Fletcher trait and Fitzgerald trait during the 1970s in Cleveland. PMID- 20838737 TI - Differential endocytosis of tissue plasminogen activator by serpins PAI-1 and PAI 2 on human peripheral blood monocytes. AB - Generation of the broad spectrum protease plasmin is facilitated by the tissue (t PA) and urokinase (u-PA) plasminogen activators, within multiple physiological and disease states. Finely tuned control of this proteolytic cascade is exerted by the plasminogen activator inhibitors type-1 (PAI-1/SERPINE1) and 2 (PAI 2/SERPINB2). Expression of this network of activators and inhibitors by cells of myeloid lineage appears to be highly interchangeable between physiological environments, and whilst the role of PAI-1 and PAI-2 in regulating u-PA-dependent functions is well established, the interaction between t-PA and PAI-2 on these cell types is poorly characterised. To this end, we used freshly isolated peripheral blood monocytes (PBM) as a model of a t-PA-dependent cellular environment. We demonstrate that while both PAI-1 and PAI-2 could inhibit surface bound t-PA and are internalised predominately via low-density-lipoprotein receptor family members, PAI-1 enhanced the endocytosis of t-PA, whereas PAI-2 did not. Surface plasmon resonance analyses revealed differential binding affinities between the very-low-density-lipoprotein receptor and t-PA and t PA:PAI-1 complexes in addition to those previously described with low-density lipoprotein receptor-related protein. Moreover, t-PA:PAI-2 bound to both endocytosis receptors with similar kinetics to t-PA. These differential biochemical interactions between t-PA and the t-PA:PAI complexes may underlie the observed differences in endocytosis mechanisms on the PBMs. This suggests that while PAI-1 and PAI-2 function similarly in the control of cellular plasmin generation by t-PA, they may have disparate effects on the alternative functions of t-PA via modulation of its engagement with endocytosis receptors. PMID- 20838738 TI - Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review. AB - The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients. PMID- 20838740 TI - Genistein alters coagulation gene expression in ovariectomised rats treated with phytoestrogens. AB - Recent data has shown that hormone therapy (HT) increases the risk of cardiovascular and thromboembolic disease, particularly in users of oral HT. Phytoestrogens are popular alternatives to oestrogen therapy; however, their effects on cardiovascular risk are unknown. We investigated the effect of the phytoestrogen, genistein on the expression of genes and proteins from the haemostatic system in the liver in an ovariectomised rat model. Fifty-nine virgin female Sprague-Dawley rats were fed with soy-free chow supplemented with 17beta estradiol (E2) (daily uptake 0.19 or 0.75 mg/kg body weight), or genistein (daily uptake 6 or 60 mg/kg body weight), for three months and compared to soy-free control rats. Gene expression of prothrombin, factor VII, fibrinogen alpha and fibrinogen beta was increased with E2 and genistein compared to the soy-free control group (p<0.001). Genistein increased factor VII significantly more than E2 (p<0.005). Plasminogen mRNA was increased in both treatment groups compared to the soy-free control, with genistein expression significantly higher than E2 (p<0.001). Tissue plasminogen inhibitor (tPA), plasminogen activator inhibitor-1 (PAI-1) and C-reactive protein (CRP) expression were also increased in both groups relative the soy-free control. Results of protein analysis largely concurred with those of the mRNA. Oestrogen receptor beta (ERbeta) was undetected while oestrogen receptor alpha (ERalpha) was detected in each sample group. Genistein can increase the expression of coagulation and fibrinolytic genes. This effect was similar and in some cases higher than 17beta estradiol. These results suggest that genistein may not be neutral with respect to the haemostatic system. PMID- 20838739 TI - Nitrophorin 2, a factor IX(a)-directed anticoagulant, inhibits arterial thrombosis without impairing haemostasis. AB - Nitrophorin 2 (NP2) is a 20 kDa lipocalin identified in the salivary gland of the blood sucking insect, Rhodnius prolixus. It functions as a potent inhibitor of the intrinsic pathway of coagulation upon binding to factor IX (FIX) or FIXa. Herein we have investigated the in vivo antithrombotic properties of NP2. Surface plasmon resonance assays demonstrated that NP2 binds to rat FIX and FIXa with high affinities (KD = 43 and 47 nM, respectively), and prolongs the aPTT without affecting the PT. In order to evaluate NP2 antithrombotic effects in vivo two distinct models of thrombosis in rats were carried out. In the rose Bengal/laser induced injury model of arterial thrombosis, NP2 increased the carotid artery occlusion time by ?35 and ?155%, at doses of 8 and 80 MUg/kg, respectively. NP2 also inhibited thrombus formation in an arterio-venous shunt model, showing ?60% reduction at 400 MUg/kg (i.v. administration). The antithrombotic effect lasted for up to 48 hours after a single i.v. dose. Notably, effective doses of NP2 did not increase the blood loss as evaluated by tail-transection model. In conclusion, NP2 is a potent and long-lasting inhibitor of arterial thrombosis with minor effects on haemostasis. It might be regarded as a potential agent for the treatment of human cardiovascular diseases. PMID- 20838741 TI - Does ambulation modify venous thromboembolism risk in acutely ill medical patients? AB - In the US, ambulatory status is often a criterion for stopping prophylaxis for venous thromboembolism (VTE). In an analysis of the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial, ambulatory status was assessed as outcome and patients grouped accordingly for further analysis. Rates of VTE and bleeding were evaluated. Using multivariate logistic regression, the relationships between thromboprophylaxis, VTE risk, and ambulatory status were assessed. Ambulatory status was reached in 607/1,084 patients, in a mean time of 4.4 days. Thromboprophylaxis was provided for 7.3 and 7.7 days in the ambulatory and non-ambulatory groups. Although VTE rates were lower in ambulatory patients, enoxaparin 40 mg once daily significantly reduced the risk of VTE vs. placebo in ambulatory (3.3% vs. 10.6%; relative risk [RR] = 0.31; 95% confidence interval [CI], 0.13-0.78; p=0.008) and non-ambulatory patients (9.0% vs. 19.7%; RR = 0.46; 95% CI, 0.23-0.91; p=0.02). Major bleeding was not significantly different between enoxaparin and placebo in either group. By multivariate regression analysis, VTE risk in ambulatory patients was lower with enoxaparin vs. placebo (odds ratio [OR] = 0.28; 95% CI, 0.11-0.74; p=0.01), but higher in patients with a history of VTE (OR = 3.74; 95% CI, 1.59-8.84; p=0.003) or cancer (OR = 2.12; 95% CI, 1.00-4.48; p=0.049). Despite timely mobilisation, patients who become ambulatory are at VTE risk and experience a significant risk reduction with enoxaparin 40 mg. Therefore, it is essential that ambulatory patients receive recommended thromboprophylaxis. PMID- 20838742 TI - Enhanced platelet inhibition by adjunctive cilostazol to dual antiplatelet therapy after drug-eluting stent implantation for complex lesions. PMID- 20838743 TI - Substitution (gamma335Trp->Arg) in fibrinogen Fremantle causes diminished gamma chain expression and increased sialic acid content. PMID- 20838744 TI - Association between inflammatory biomarkers and platelet aggregation in patients under chronic clopidogrel treatment. AB - Inflammatory processes in the vessel wall are associated with progression of atherosclerosis and myocardial infarction. Both high levels of C-reactive protein (CRP)and high on-clopidogrel treatment platelet reactivity (HPR) have been linked to an increased risk of ischaemic events after percutaneous coronary intervention (PCI). The aim of this study was to explore the association between biomarker levels of inflammation and platelet reactivity. Stable patients (n=1,223) eligible for this study were under chronic antiplatelet treatment with aspirin and clopidogrel due to prior coronary stent placement. ADP-induced platelet aggregation (in AU*min) was measured on a Multiplate analyser. The primary outcome measure of this retrospective study was the ADP-induced platelet aggregation in patients with versus those without elevated CRP levels. Of the patients 15.5% (n=189) showed elevated CRP levels (>=5 mg/l). Platelet aggregation (median [interquartile range]) was significantly higher in patients with elevated CRP levels compared to patients with normal (<5 mg/l) CRP levels (305 [202-504] AU*min vs. 218 [144-384] AU*min; p<0.001).A multivariable linear regression model that adjusted for known predictors of HPR confirmed a significant independent association between elevated CRP levels and high ADP induced platelet aggregation values (p=0.0002).Elevated WBC count and fibrinogen levels were also associated with higher platelet aggregation values (p<0.001 for both). In conclusion, elevated levels of CRP, WBC count and fibrinogen were significantly associated with high platelet reactivity in patients under chronic clopidogrel treatment. Whether a direct relation between platelets and inflammation exists, as well as the clinical impact of our results, warrants further investigations. PMID- 20838745 TI - Increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and colorectal adenocarcinoma determined by a newly developed ELISA using a specific monoclonal antibody. AB - Citrullination is a post-translational modification that plays essential roles in both physiological processes and disease. Recent studies have found increased levels of citrullinated antithrombin in patients with rheumatoid arthritis and in different malignant tumours. Antithrombin, the main haemostatic serpin, loses its anticoagulant function via citrullination, which might contribute to the pathogenesis or thrombotic side effects of these disorders. We have developed a specific monoclonal antibody against citrullinated antithrombin. We determined the levels of citrullinated antithrombin and anti-FXa activity in plasma from 66 donors, 17 patients with rheumatoid arthritis and 77 patients with colorectal adenocarcinoma (42 suffering from venous thrombosis). Healthy subjects had negligible amounts of citrullinated antithrombin in plasma (7.9 +/- 22.1 ng/ml), while it significantly increased in patients with rheumatoid arthritis or adenocarcinoma (159.7 +/- 237.6 ng/ml and 36.8 +/- 66.1 ng/ml), levels that, however, did not modify the plasma anticoagulant activity. Moreover, we did not find association between citrullinated antithrombin and the thrombotic risk in patients with adenocarcinoma. In conclusion, we have developed an antibody specific for citrullinated antithrombin that allows its quantification in biological samples, offering a new tool for the analysis of citrullination in different diseases. We confirm increased levels of citrullinated antithrombin in plasma of patients with rheumatoid arthritis and adenocarcinoma. This modification, probably local, could have pathological consequences in both disorders, but only affects a minor fraction of plasma antithrombin, resulting in no significant reduction of global anticoagulant activity. This result explains the absence of association of this marker with an increased risk of thrombosis in patients with colorectal adenocarcinoma. PMID- 20838747 TI - Thrombelastographic studies on factor XIII. PMID- 20838746 TI - Platelets enhance lymphocyte adhesion and infiltration into arterial thrombus. AB - Lymphocytes are present in atherosclerotic lesion. We hypothesise that platelets may facilitate lymphocyte infiltration into the arterial wall. Reconstituted human blood or whole blood was perfused through a collagen-coated parallel-plate flow chamber at different shear rates. Adhered platelets markedly enhanced lymphocyte adhesion that increased lymphocyte deposition from 10 +/- 3 cells/mm2 of platelet-depleted blood to 38 +/- 11 cells/mm2 of platelet-containing blood at the arterial shear rate of 500 s-1. Platelet-dependent lymphocyte adhesion was inhibited by P-selectin, CD40L, and GPIIb/IIIa-blocking agents, suggesting the involvement of multiple adhesion molecules in this heterotypic interaction. Lymphocyte deposition was more marked among T cells, and seen in both small and large cells. B and natural killer cell adhesion was, however, mainly seen in small cells. Platelet-conjugation facilitated lymphocyte adhesion, as suggested by the selective deposition of platelet-conjugated lymphocytes. In a mouse model of arterial thrombosis, FeCl3-induced thrombus formation markedly enhanced lymphocyte adhesion and infiltration into platelet thrombi, which was abolished by GPIIb/IIIa inhibition. In conclusion, platelets support lymphocyte adhesion under arterial flow conditions, which is selective among T cells and involves multiple adhesion molecules. Our data imply that platelets may facilitate the recruitment of circulating lymphocytes at the arterial injured sites. PMID- 20838748 TI - Is there an association between complement activation and antiphospholipid antibody-related thrombosis? PMID- 20838749 TI - Phospholipid binding improves plasma survival of factor VIII. PMID- 20838750 TI - The inter-rater reliability of the Pulmonary Embolism Severity Index. AB - The Pulmonary Embolism Severity Index (PESI) is a validated clinical prognostic model for patients with acute pulmonary embolism (PE). Our goal was to assess the PESI's inter-rater reliability in patients diagnosed with PE. We prospectively identified consecutive patients diagnosed with PE in the emergency department of a Swiss teaching hospital. For all patients, resident and attending physician raters independently collected the 11 PESI variables. The raters then calculated the PESI total point score and classified patients into one of five PESI risk classes (I-V) and as low (risk classes I/II) versus higher-risk (risk classes III V). We examined the inter-rater reliability for each of the 11 PESI variables, the PESI total point score, assignment to each of the five PESI risk classes, and classification of patients as low versus higher-risk using kappa (kappa) and intra-class correlation coefficients (ICC). Among 48 consecutive patients with an objective diagnosis of PE, reliability coefficients between resident and attending physician raters were > 0.60 for 10 of the 11 variables comprising the PESI. The inter-rater reliability for the PESI total point score (ICC: 0.89, 95% CI: 0.81-0.94), PESI risk class assignment (kappa: 0.81, 95% CI: 0.66-0.94), and the classification of patients as low versus higher-risk (kappa: 0.92, 95% CI: 0.72-0.98) was near perfect. Our results demonstrate the high reproducibility of the PESI, supporting the use of the PESI for risk stratification of patients with PE. PMID- 20838751 TI - Plasma haemoxygenase-1 in coronary artery disease. A comparison with angiogenin, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and vascular endothelial growth factor. AB - It was the aim of this study to determine plasma haemoxygenase-1 (HO-1) across the spectrum of health, angina but normal coronary arteries (NCA), stable coronary artery disease (CAD), and acute coronary syndromes (ACS), and relationships with angiogenin, matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1, and vascular endothelial growth factor. Plasma markers were measured (ELISA) in peripheral venous citrated plasma from 50 healthy subjects, 30 with NCA, 70 with stable CAD and 24 with an ACS, and from patient's aortic root, coronary ostium, coronary sinus and femoral artery. Human umbilical vein endothelial cells (HUVECs) were cultured with or without tumour necrosis factor (TNF), and platelets were probed. HO-1 was raised in stable CAD (p<0.05) and increased further in ACS (p<0.01) compared to healthy controls and NCA. HO-1 correlated only with MMP-9, and then only in the healthy controls. There were no major differences from cardiac or peripheral sites. HO-1 was present in HUVECs and 24-hour HUVEC supernatants but release was abolished by TNF. Platelets had no HO-1. In conclusion, HO-1 is raised in stable CAD and ACS and may arise from the endothelium but not the platelet. This may have implications for our understanding of the pathophysiology of CAD and its acute presentation as ACS. PMID- 20838753 TI - Publication in a Brazilian journal by Brazilian scientists whose papers have international impact. AB - Nine Brazilian scientists with an outstanding profile of international publications were invited to publish an original article in the same issue of a Brazilian Journal (Anais da Academia Brasileira de Ciencias). The objective was to measure the impact of the papers on the number of citations to the articles, the assumption being that these authors would carry their international prestige to the Brazilian periodical. In a 2-year period there was a larger number of citations of these articles compared to others published in the same journal. Nevertheless, the number of citations in Brazilian journals did not equal the number of citations obtained by the other papers by the same authors in their international publications within the same 2-year period. The reasons for this difference in the number of citations could be either that less significant invited articles were submitted or that it was due to the intrinsic lack of visibility of the Brazilian journals, but this could not be fully determined with the present data. Also relevant was a comparison between the citations of Brazilian journals and the publication in Brazilian journals by these selected authors. A clear imbalance due to a remarkable under-citation of Brazilian authors by authors publishing in Brazilian journals raises the possibility that psychological factors may affect the decision of citing Brazilian journals. PMID- 20838752 TI - Serum leptin, adiponectin and tumor necrosis factor-alpha in hyperlipidemic rats with/without concomitant diabetes mellitus. AB - We compared the lipid profiles and serum levels of leptin, adiponectin and tumor necrosis factor-alpha (TNF-alpha) in rats with/without hyperlipidemia and with/without concomitant diabetes mellitus. Forty 10-wk-old male Wistar rats were divided into four groups. Groups A and C received standard food for 12 wks. Groups B and D received a high-fat diet enriched with 2% additional cholesterol. Moreover, insulin-deficient (type I) diabetes mellitus was induced in rats in groups C and D with intraperitoneal injections of streptozotocin. Fasting serum leptin levels were decreased in diabetic groups (groups C and D) compared with controls. Fasting serum adiponectin levels were decreased in groups C and D compared with group A. Serum TNF-alpha levels were augmented in groups B and D, those fed with an atherogenic diet. By contrast, TNF-alpha levels were decreased in group C. Our data suggest that serum leptin, adiponectin and TNF-alpha levels may serve as markers of obesity and type I diabetes mellitus. PMID- 20838754 TI - Mitochondrial control region haplotypes of the South American sea lion Otaria flavescens (Shaw, 1800). AB - The South American sea lion, Otaria flavescens, is widely distributed along the Pacific and Atlantic coasts of South America. However, along the Brazilian coast, there are only two nonbreeding sites for the species (Refugio de Vida Silvestre da Ilha dos Lobos and Refugio de Vida Silvestre do Molhe Leste da Barra do Rio Grande), both in Southern Brazil. In this region, the species is continuously under the effect of anthropic activities, mainly those related to environmental contamination with organic and inorganic chemicals and fishery interactions. This paper reports, for the first time, the genetic diversity of O. flavescens found along the Southern Brazilian coast. A 287-bp fragment of the mitochondrial DNA control region (D-loop) was analyzed. Seven novel haplotypes were found in 56 individuals (OFA1-OFA7), with OFA1 being the most frequent (47.54%). Nucleotide diversity was moderate (pi = 0.62%) and haplotype diversity was relatively low (67%). Furthermore, the median joining network analysis indicated that Brazilian haplotypes formed a reciprocal monophyletic clade when compared to the haplotypes from the Peruvian population on the Pacific coast. These two populations do not share haplotypes and may have become isolated some time back. Further genetic studies covering the entire species distribution are necessary to better understand the biological implications of the results reported here for the management and conservation of South American sea lions. PMID- 20838755 TI - [Percutaneous administration of recombinant human bone morphogenetic protein-7 (rhBMP-7) after callus distraction. Two case reports]. AB - Two cases of increased bone density after callus distraction are described following percutaneous administration of 3.5 mg recombinant bone morphogenetic protein-7 (rhBMP-7). Both patients underwent segmental resection and segmental transport for osteomyelitis of the long bones (femur and tibia) but no callus maturation occurred. After percutaneous administration of rhBMP-7 the callus density increased in both cases. PMID- 20838756 TI - Status of cold fusion (2010). AB - The phenomenon called cold fusion has been studied for the last 21 years since its discovery by Profs. Fleischmann and Pons in 1989. The discovery was met with considerable skepticism, but supporting evidence has accumulated, plausible theories have been suggested, and research is continuing in at least eight countries. This paper provides a brief overview of the major discoveries and some of the attempts at an explanation. The evidence supports the claim that a nuclear reaction between deuterons to produce helium can occur in special materials without application of high energy. This reaction is found to produce clean energy at potentially useful levels without the harmful byproducts normally associated with a nuclear process. Various requirements of a model are examined. PMID- 20838757 TI - Dietary antioxidants, lipid peroxidation and plumage colouration in nestling blue tits Cyanistes caeruleus. AB - Carotenoid pigments are responsible for many of the red, yellow and orange plumage and integument traits seen in birds. One idea suggests that since carotenoids can act as antioxidants, carotenoid-mediated colouration may reveal an individual's ability to resist oxidative damage. In fact, there is currently very little information on the effects of most dietary-acquired antioxidants on oxidative stress in wild birds. Here, we assessed the impacts on oxidative damage, plasma antioxidants, growth and plumage colouration after supplementing nestling blue tits Cyanistes caeruleus with one of three diets; control, carotenoid treatment or alpha-tocopherol treatment. Oxidative damage was assessed by HPLC analysis of plasma levels of malondialdehyde (MDA), a by-product of lipid peroxidation. Contrary to predictions, we found no differences in oxidative damage, plumage colouration or growth rate between treatment groups. Although plasma lutein concentrations were significantly raised in carotenoid-fed chicks, alpha-tocopherol treatment had no effect on concentrations of plasma alpha tocopherol compared with controls. Interestingly, we found that faster growing chicks had higher levels of oxidative damage than slower growing birds, independent of treatment, body mass and condition at fledging. Moreover, the chromatic signal of the chest plumage of birds was positively correlated with levels of MDA but not plasma antioxidant concentrations: more colourful nestlings had higher oxidative damage than less colourful individuals. Thus, increased carotenoid-mediated plumage does not reveal resistance to oxidative damage for nestling blue tits, but may indicate costs paid, in terms of oxidative damage. Our results indicate that the trade-offs between competing physiological systems for dietary antioxidants are likely to be complex in rapidly developing birds. Moreover, interpreting the biological relevance of different biomarkers of antioxidant status represents a challenge for evolutionary ecology. PMID- 20838758 TI - Identification and development of a functional marker of TaGW2 associated with grain weight in bread wheat (Triticum aestivum L.). AB - The OsGW2 gene is involved in rice grain development, influencing grain width and weight. Its ortholog in wheat, TaGW2, was considered as a candidate gene related to grain development. We found that TaGW2 is constitutively expressed, with three orthologs expressing simultaneously. The coding sequence (CDS) of TaGW2 is 1,275 bp encoding a protein with 424 amino acids, and has a functional domain shared with OsGW2. No divergence was detected within the CDS sequences in the same locus in ten varieties. Genome-specific primers were designed based on the sequence divergence of the promoter regions in the three orthologous genes, and TaGW2 was located in homologous group 6 chromosomes through CS nulli-tetrasomic (NT). Two SNPs were detected in the promoter region of TaGW2-6A, forming two haplotypes: Hap-6A-A (-593A and -739G) and Hap-6A-G (-593G and -769A). A cleaved amplified polymorphic sequence (CAPS) marker was developed based on the -593 A-G polymorphism to distinguish the two haplotypes in TaGW2-6A. This gene was fine mapped 0.6 cM from marker cfd80.2 near the centromere in a recombinant inbred line (RIL) population. Two hundred sixty-five Chinese wheat varieties were genotyped and association analysis revealed that Hap-6A-A was significantly associated with wider grains and higher one-thousand grain weight (TGW) in two crop seasons. qRT-PCR revealed a negative relationship between TaGW2 expression level and grain width. The Hap-6A-A frequencies in Chinese varieties released at different periods showed that it had been strongly positively selected in breeding. In landraces, Hap-6A-A is mainly distributed in southern Chinese wheat regions. Association analysis also indicated that Hap-6A-A not only increased TGW by more than 3 g, but also had earlier heading and maturity. In contrast to Chinese varieties, Hap-6A-G was the predominant haplotype in European varieties; Hap-6A-A was mainly present in varieties released in the former Yugoslavia, Italy, Bulgaria, Hungary and Portugal. PMID- 20838759 TI - Yr45, a new wheat gene for stripe rust resistance on the long arm of chromosome 3D. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most destructive diseases of wheat worldwide. Growing resistant cultivars is the most effective approach to control the disease, but only a few genes confer effective all-stage resistance against the current populations of the pathogen worldwide. It is urgent to identify new genes for diversifying sources of resistance genes and for pyramiding genes for different types of resistance in order to achieve high levels of durable resistance for sustainable control of stripe rust. The common spring wheat genotype 'PI 181434', originally from Afghanistan, was resistant in all greenhouse and field tests in our previous studies. To identify the resistance gene(s) PI 181434 was crossed with susceptible genotype 'Avocet Susceptible'. Adult plants of 103 F(2) progeny were tested in the field under the natural infection of P. striiformis f. sp. tritici. Seedlings of the parents, F(2) and F(3) were tested with races PST-100 and PST-127 of the pathogen under controlled greenhouse conditions. The genetic study showed that PI 181434 has a single dominant gene conferring all-stage resistance. Resistance gene analog polymorphism (RGAP) and simple sequence repeat (SSR) techniques were used to identify molecular markers linked to the gene. A linkage map of 8 RGAP and 2 SSR markers was constructed for the gene using data from the 103 F(2) plants and their derived F(3) lines tested in the greenhouse. Amplification of the complete set of nulli-tetrasomic lines and selected ditelosomic lines of Chinese Spring with an RGAP marker and the two SSR markers mapped the gene on the long arm of chromosome 3D. Because it is the first gene for stripe rust resistance mapped on chromosome 3DL and different from all previously named Yr genes, the gene in PI 181434 was designated Yr45. Polymorphism rates of the two closest flanking markers, Xwgp115 and Xwgp118, in 45 wheat genotypes were 73.3 and 82.2%, respectively. Single nucleotide polymorphisms (SNPs) were identified in the eight wheat genotypes sharing both flanking markers. The RGAP markers and potential SNP markers should be useful in incorporating the gene into wheat cultivars and in pyramiding it with other genes for durable resistance. PMID- 20838760 TI - Genetic mapping of the stem rust (Puccinia graminis f. sp. tritici Eriks. & E. Henn) resistance gene Sr13 in wheat (Triticum aestivum L.). AB - Puccinia graminis f. sp. tritici, the causative agent of stem rust in wheat, is known for its high virulence variability and ability to evolve new virulence to resistance genes. Thus, pyramiding of several resistance genes in a single line is the best strategy for a sustainable control of wheat stem rust. Sr13 is one of the few resistance genes that are effective against wide ranging P. graminis f. sp. tritici races, including the pestilent race Ug99. Its effectiveness to Ug99 makes it a valuable source for resistance to stem rust. Molecular markers play a pivotal role in the genetic characterization of the new sources of resistance as well as in stacking two or more resistance genes in a single line. Therefore, the aim of this study was to develop molecular markers for Sr13 facilitating efficient pyramiding of Sr genes. Based on the 158 F(2) individuals derived from a cross of Khapstein/9*LMPG * Morocco and SSR analyses, the Sr13 locus was mapped on chromosome 6A of wheat, and a genetic map comprising about 90 cM was constructed with the closest marker barc37 being located 4.0 cM distally of Sr13. Of the nine mapped markers, barc37 amplified an allele specific for the presence of Sr13 as shown by testing different cultivars and breeding lines. These newly developed markers will increase the efficiency of incorporating Sr13 into cultivars that are widely adopted, but susceptible to hazardous Ug99 and/or assist for the development of new elite lines that are resistant to Ug99. PMID- 20838761 TI - [Megaprostheses - options and problems]. PMID- 20838762 TI - Hemodynamic, respiratory, and perfusion parameters during asphyxia, resuscitation, and post-resuscitation in a pediatric model of cardiac arrest. AB - PURPOSE: To analyze the evolution of hemodynamic, respiratory, and tissue perfusion parameters in an infant animal model of asphyxial cardiac arrest (CA). METHODS: This was a secondary analysis of a prospective observational study conducted at a laboratory research department of a university hospital. Seventy one, 2-month-old piglets were studied. CA was induced by removal of mechanical ventilation. Cardiopulmonary resuscitation (CPR) was performed by means of manual external chest compressions, mechanical ventilation, epinephrine and/or terlipressin intravenous administration. RESULTS: The evolution of hemodynamic (heart rate, blood pressure, cardiac index), respiratory (end-tidal CO(2), blood gas analysis), and tissue perfusion (intramucosal gastric pH, central, cerebral, and renal hemoglobin saturation) parameters was analyzed during three periods: asphyxia, CPR, and after return of spontaneous circulation (ROSC). During asphyxia, a severe arterial and tissue hypoxia with hypercapnia and lactic acidosis quickly developed. Bradycardia, hypotension, and increasing of systemic vascular resistances and pulmonary arterial pressure were also observed. During CPR, arterial, cerebral, and tissue oxygenation were low in spite of ventilation with oxygen 100%. After ROSC a rapid restoration of hemodynamic and respiratory parameters was observed. However, 30 min after ROSC, lactic acidosis and low intramucosal gastric pH persisted. CONCLUSIONS: Asphyxia leads to sudden hypoxia and hypercapnia with tissue hypoxia and progressive bradycardia. Standard CPR is not able to maintain an adequate tissue oxygenation during CPR in this animal model. When ROSC is achieved, a rapid restoration of the normal values of general hemodynamic and respiratory parameters is observed, although lactic acidosis and splanchnic hypoperfusion persist in time. PMID- 20838763 TI - Compliance with DNR policy in a tertiary care center in Saudi Arabia. AB - INTRODUCTION: Do not resuscitate (DNR) is an important aspect of medical practice, although few studies from Arab Muslim countries address this issue. King Abdulaziz Medical City (KAMC), Saudi Arabia has a policy addressing all aspects of patient care at end of life. OBJECTIVE: To assess compliance of physicians with the current DNR policy. METHODS: A cohort study of data prospectively collected from 15/10/2008 through 15/01/2009 for patients where DNR was initiated. Patient charts were followed prospectively to observe DNR documentation completion. Data were analyzed in terms of frequencies and descriptive statistics, and the results expressed as percentages. RESULTS: DNR was initiated in 65 patients referred to the intensive care unit (ICU): 46.2% females, 53.8% males; age range 19-93 years, mean +/- standard deviation (SD) 66.1 +/- 16.0 years. DNR was initiated by ICU physician in 80% of cases and by most responsible physician (MRP) in 20% of cases. There was a delay (of more than 48 h) in completing MRP signature in 8 patients (12.3%), and no signature at all by the MRP in 13 patients (20%). Documentation of discussion with the family was absent in 53.8% of cases. CONCLUSIONS: ICU physicians have a role in initiating DNR. Mostly this issue is not addressed on admission. Documentation of DNR once initiated is still not up to the optimum level in 32.3% of cases, mainly due to MRP. Discussion with the patient's family was not well documented in the chart in more than half of cases. PMID- 20838764 TI - The fixation strength of a novel ACL soft-tissue graft fixation device compared with conventional interference screws: a biomechanical study in vitro. AB - Anterior cruciate ligament reconstruction using autologous hamstring tendons is an established surgical procedure but some grafts fail due to poor fixation. This study compared the fixation of a new ACL graft fixation device (the EZ KneeSpan) to conventional soft-tissue threaded titanium interference screws (IS). The EZ device was designed to provide secure fixation while avoiding soft-tissue graft damage associated with use of an IS. Eight paired fresh-frozen cadaveric human knees and bovine digital extensor tendons were used. Two tunnels were placed in each tibia and femur, and grafts were fixed using the EZ device and the IS in each bone. Cyclic tensile loading and pull-out testing measured graft slippage (mm) and ultimate strength (N) of the fixation. The results were compared using the non-parametric Wilcoxon signed-rank test. Graft slippage after cyclic loading was significantly lower in the EZ group at 2.4 +/- 0.1 mm versus 9.5 +/- 6.2 mm for the IS group in the femur and 3.3 +/- 1.4 mm versus 17.7 +/- 13.6 mm in the tibia. The mean ultimate load for the femoral EZ group was significantly higher than the IS group (769 +/- 223 N versus 468 +/- 60 N), but they did not differ significantly in the tibia (518 +/- 48 N versus 546 +/- 139 N). Our results indicate that with the EZ device the initial fixation of cyclically loaded hamstring grafts could be superior to that with an IS. The EZ KneeSpan device also had similar tibial and higher femoral ultimate fixation strength than an IS. PMID- 20838766 TI - Anterior cruciate ligament reconstruction with bone-hamstring-bone hybrid procedure. PMID- 20838767 TI - Risk factors for peripheral fractures vary by age in older men--the prospective MINOS study. AB - Identification of older men at high risk of peripheral fracture can be improved by assessing prevalent fractures (men aged <= 65), history of falls (men aged >65), bone width, and aortic calcifications. INTRODUCTION: Low bone mineral density (BMD) identifies 20% of men who sustain osteoporotic fracture. We studied (1) if the assessment of bone width, aortic calcifications, prevalent falls and fractures improves identification of men at high risk of fracture and (2) if the predictive value of these parameters varies with age. METHODS: Among 781 men aged 50 and over, 61 men sustained 66 low-trauma peripheral fractures during 10 years. History of falls and prevalent fractures was assessed by questionnaire. BMD and bone with were measured by dual X-ray absorptiometry. Abdominal aortic calcifications were assessed on the lateral radiographs of the lumbar spine. RESULTS: Low BMD, low bone width, extended aortic calcifications, prevalent fractures (mainly multiple fractures) and frequent falls were all associated independently with higher risk of fracture. In men aged <= 65, prevalent fractures are associated with a significant increase in the risk of fracture (two to threefold for one and four- to fivefold for multiple prevalent fractures). In men aged >65, history of falls is associated with a higher risk of fracture, e.g. frequent falls are associated with a sixfold increase in the risk of fracture. CONCLUSIONS: Men aged <= 65 with multiple prevalent fractures and frequent fallers aged >65 are at particularly high risk of peripheral fracture regardless of BMD. PMID- 20838768 TI - Impaired fracture healing in macrophage migration inhibitory factor-deficient mice. AB - This study investigated the role of macrophage migration inhibitory factor (MIF) in fracture repair using MIF gene-deficient mice (MIF KO). Fracture healing was delayed in MIF KO, and this was mainly due to the delay in the mineralization of osteoid within the fracture callus. INTRODUCTION: We previously reported that the expression of macrophage migration inhibitory factor (MIF) was up-regulated during the fracture healing process in rats. However, its role in the pathophysiology of this process remained unclear. The aim of the present study was to clarify the role of MIF in the fracture healing process using MIF gene deficient mice (MIF KO). METHODS: Bone repair in wild-type mice (WT) and MIF KO (n = 70, respectively) was investigated using a tibia fracture model. Radiographic, biomechanical, histological, bone histomorphometric, and molecular analyses were performed. RESULTS: Post-fracture biomechanical testing showed that maximum load and stiffness were significantly lower in MIF KO than in WT on day 42. However, similar levels were observed between the two groups on day 84. Bone histomorphometric analysis revealed significantly higher osteoid volume, a lower mineral apposition rate, and smaller numbers of osteoclasts in the MIF KO callus compared to the WT callus. The messenger ribonucleic acid expressions of matrix metalloproteinase (MMP)-2, membranous type 1-MMP, cathepsin K, and tissue nonspecific alkaline phosphatase were found to be significantly suppressed in the MIF KO callus. CONCLUSION: The results of the present study suggest that delayed fracture healing in MIF KO was mainly attributable to a delay in osteoid mineralization. PMID- 20838769 TI - Atypical femoral stress fractures in bisphosphonate-free patients. PMID- 20838770 TI - Patient preferences for osteoporosis in Spain: a discrete choice experiment. AB - In Spain, various treatments are available to prevent osteoporotic fractures. A discrete choice experiment (DCE) was used to investigate the importance of different treatment aspects and its influence on patients' preferences. All attributes included as type and place of drug administration as well as costs showed to be significant predictors of choice. Spanish osteoporosis patients have well-defined preferences and accept trade-offs among attributes. INTRODUCTION: This study was designed to identify patient preferences for different aspects of osteoporosis treatments in Spain. METHODS: Main attributes of severe osteoporosis treatments were determined by literature review and consultations with nurses. The discrete choice experiment included three attributes: type of drug administration, place of administration, plus a cost attribute in order to estimate willingness to pay for improvements in attribute levels. A pilot study with 50 patients was performed to identify the areas of misunderstanding. One hundred sixty-six patients with a diagnosis of osteoporosis and severe osteoporosis were presented with pairs of hypothetical treatment profiles with different type of administration levels, places of administration and costs. Questions to collect socio-demographic and disease-related treatment data were also included. Data were analysed using a random effects probit model. RESULTS: All attributes had the expected polarity and were significant predictors of choice. Patients were willing to pay 183 euro/month to have a subcutaneous injection once per day rather than an intravenous injection once per year. Patients with osteoporosis were willing to pay 121 euro/month to have medical support when administering the drug treatment at home rather than being admitted several hours to a hospital for drug administration. CONCLUSION: Spanish osteoporosis patients have well-defined preferences among treatment attributes and are willing to accept trade-offs among attributes. Participants indicated that they are willing to accept self medication with medical support rather than being hospitalised for several hours. The perspective of the patients should be taken into account when making treatment decisions. PMID- 20838771 TI - Effects of raloxifene and alendronate on bone turnover as assessed by procollagen type I N-terminal propeptide. AB - Raloxifene decreases PINP into the lower half of the premenopausal reference interval; alendronate decreases PINP more, with approximately 60% of alendronate treated women having PINP concentrations below the lower limit of the premenopausal reference interval. INTRODUCTION: The purpose of this study was to evaluate the distribution of serum procollagen type I N-terminal propeptide (PINP) concentrations in women with postmenopausal osteoporosis prior to treatment and after treatment with either raloxifene or alendronate for 12 or more months. METHODS: Included were data from 1,323 postmenopausal women aged 45 to 87 years, collected at baseline or after treatment with either alendronate 10 mg/day or raloxifene 60 mg/day. These patients had participated in one of four clinical trials in which intact PINP was measured by radioimmunoassay (Orion Diagnostica). A premenopausal reference interval from 16.0 to 75.8 MUg/L was determined from 68 premenopausal, non-pregnant women. RESULTS: Most postmenopausal osteoporotic patients prior to treatment had PINP values in the upper half of the premenopausal reference interval at baseline (70%). After >= 12 months of therapy, most patients who received raloxifene had PINP concentrations in the lower half of the premenopausal reference interval (58%), whereas among those who received alendronate, around 60% of patients had PINP concentrations below the lower limit of the premenopausal reference interval. CONCLUSION: PINP may be useful for assessing differences in bone turnover response to different types of anti-resorptive therapy. PMID- 20838772 TI - Sustained skeletal benefit from childhood mechanical loading. AB - SUMMARY: Preliminary prospective, longitudinal results suggest that pre menarcheal exposure to artistic gymnastics is associated with greater radius BMC, aBMD, and projected area throughout growth and into early adulthood, more than 4 years after activity cessation. Any loss of benefit associated with de-training appears to be temporary. INTRODUCTION: Mechanical loading may enhance bone accrual during growth, but prospective evidence of benefit retention is limited. This prospective, longitudinal cohort study tests whether gymnastics is linked to distal radius advantages during growth and four or more years post-training cessation. METHODS: Semi-annually, female ex/gymnasts and non-gymnasts underwent height and weight measurements; questionnaires assessed calcium intake, physical activity, and maturation. Annual dual energy X-ray absorptiometry scans (Hologic QDR 4500W) measured total body fat-free mass, skull areal density (aBMD), and bone mineral content (BMC); forearm scans measured ultradistal and 1/3 radius area, BMC, and aBMD. Analysis inclusion criteria were: (1) achievement of gynecological age >4 years and (2) for gymnasts, >2 years of pre-menarcheal training (>6 h/week), ceasing between 0.5 year pre-menarche and 1 year post menarche. Hierarchical linear modeling (HLM v6.0) evaluated outcomes for ex/gymnasts versus non-gymnasts; a slope/intercept discontinuity evaluated de training effects. RESULTS: Data from 14 non-gymnasts and six ex/gymnasts represented outcomes from 4 years pre-menarche to 9 years post-menarche. All adjusted distal radius parameters were higher in ex/gymnasts than non-gymnasts (p < 0.02). Ultradistal BMC, ultradistal aBMD, and 1/3 aBMD temporarily decreased with gymnastic cessation (p < 0.04); ultradistal area, 1/3 area, and 1/3 BMC did not change significantly. Skull outcomes did not differ between groups or change with activity cessation. CONCLUSION: Gymnastic exposure during childhood and early puberty is associated with greater radius bone mass, size, and aBMD. Despite brief de-training losses in density and mass, significant skeletal benefits are manifested throughout growth and at least 4 years beyond activity cessation into early adulthood. PMID- 20838773 TI - Adherence and profile of non-persistence in patients treated for osteoporosis--a large-scale, long-term retrospective study in The Netherlands. AB - SUMMARY: We analyzed 12-month compliance for all ten oral osteoporosis drugs in the Netherlands by medication possession ratio (MPR >= 80%) in 105,506 patients, and persistence in 8,626 starters indicated high MPR (91%), low persistence (43%), and no restart in 78% of the stoppers after 18 months. INTRODUCTION: We studied compliance and persistence for all available oral osteoporosis medications on a national scale in the Netherlands. METHODS: We analyzed the IMS Health's longitudinal prescription database, which represents 73% of all pharmacies in the Netherlands. Twelve-month compliance was measured by medication possession ratio (MPR) in a cross-sectional cohort of 105,506 patients who received at least three prescriptions. Twelve-month persistence (no gap in refills for >6 months) was measured in all 8,626 consecutive patients starting therapy, with a further follow-up in non-persistent patients during an additional 18 months for evaluation of switching, restart, or definitive stopping oral medication. Multivariate logistic regression analysis was used to analyze the odds ratios (ORs) with 95% confidence intervals (CI) of characteristics of non persistence. RESULTS: MPR of >=80% was found in 91% of patients. Persistence was 43% (range, 29-52%). Persistence was related to age >60 years (ORs, 1.41 to 1.64), pharmacy outside very dense urban area (ORs, 1.39 to 1.44), additional use of calcium and/or vitamin D supplementation (OR, 1.26 and CI, 1.13, 1.39) and use of glucocorticoids (OR, 0.65 and CI, 0.59, 0.72) or cardiovascular medication (OR, 0.88 and CI, 0.79, 0.97). Of non-persistent patients, 22% restarted within 18 months with oral osteoporosis drugs. CONCLUSIONS: One-year compliance for all available oral osteoporosis medications was high, but 1-year persistence was low. Most stoppers did not restart or switch during an additional 18-month follow-up. These data indicate a major failure to adequately treat patients at high risk for fractures in daily practice. PMID- 20838774 TI - The catalytic efficiency of trehalose-6-phosphate synthase is effected by the N loop at low temperatures. AB - The enzyme OtsA (trehalose-6-phosphate synthase) is ubiquitous in both prokaryotic and eukaryotic organisms, where it plays a critical role in stress resistance and glucose metabolism. Here, we cloned the otsA gene from Arthrobacter sp. Cjts, and expressed and then purified the recombinant proteins. Enzyme activity analysis indicated that the high catalytic efficiency of OtsA from Arthrobacter sp. Cjts resulted from the high affinity of the enzyme for uridine 5'-diphosphoglucose (UDP-Glc) at low temperatures. We also confirmed that the N-loop sequence of OtsA has a large effect on its affinity for UDP-Glc. Sequence analysis indicated that the flexibility of the N-loop may be directly related to the catalytic efficiency of OtsA at low temperatures. PMID- 20838775 TI - Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. AB - RATIONALE: Minocycline, a tetracycline antibiotic, interacts with brain glutamate and dopamine neurotransmission. In preclinical studies, minocycline attenuated amphetamine-induced acute dopamine release and subsequent behavioral sensitization. The goal of this study was to determine minocycline's effects on the acute physiological, behavioral, and subjective responses to dextroamphetamine (DAMP) in healthy volunteers. METHODS: Ten healthy volunteers participated in an outpatient double-blind, placebo-controlled, crossover study. Subjects had a 5-day treatment period with either minocycline (200 mg/day) or placebo and then were crossed over for 5 days of the other treatment. After 2 days of taking the study medication, on days 3 and 4, subjects were randomly assigned to double-blind acute challenge with either 20 mg/70 kg DAMP or placebo DAMP (randomly labeled as drug A or B) and then crossed over to the other challenge. On day 5 (experimental session 3), subjects had the opportunity to self-administer either placebo or DAMP capsules by working on a progressive ratio computer task. RESULTS: Minocycline attenuated DAMP-induced subjective rewarding effects but did not change DAMP choice behavior. Minocycline treatment speeded reaction times on a Go No-Go task and reduced plasma cortisol levels. CONCLUSIONS: These findings warrant further studies examining the potential use of minocycline for stimulant addiction. PMID- 20838776 TI - Effect of childhood physical abuse on cortisol stress response. AB - RATIONALE: Abuse and neglect are highly prevalent in children and have enduring neurobiological effects. Stressful early life environments perturb the hypothalamic-pituitary-adrenal (HPA) axis, which in turn may predispose to psychiatric disorders in adulthood. However, studies of childhood maltreatment and adult HPA function have not yet rigorously investigated the differential effects of maltreatment subtypes, including physical abuse. OBJECTIVE: In this study, we sought to replicate our previous finding that childhood maltreatment was associated with attenuated cortisol responses to stress and determine whether the type of maltreatment was a determinant of the stress response. METHODS: Salivary cortisol response to the Trier Social Stress Test (TSST) was examined in a non-clinical sample of women (n = 110). Subjects had no acute medical problems and were not seeking psychiatric treatment. Effects of five maltreatment types, as measured by the Childhood Trauma Questionnaire, on cortisol response to the TSST were investigated. To further examine the significant (p < 0.005) effect of one maltreatment type, women with childhood physical abuse (PA) (n = 20) were compared to those without past PA (n = 90). RESULTS: Women reporting childhood PA displayed a significantly blunted cortisol response to the TSST compared with subjects without PA, after controlling for estrogen use, age, other forms of maltreatment, and other potential confounds. There were no differences between PA and control groups with regard to physiological arousal during the stress challenge. CONCLUSIONS: In a non-clinical sample of women with minimal or no current psychopathology, physical abuse is associated with a blunted cortisol response to a psychosocial stress task. PMID- 20838778 TI - Development and qualification of a size exclusion chromatography coupled with multiangle light scattering method for molecular weight determination of unfractionated heparin. AB - The molecular weight of unfractionated heparin was determined by size exclusion chromatography (SEC) coupled with multiangle light scattering (MALS) detection. The SEC/MALS method determines absolute molecular weight directly from the angular dependence of scattered light intensity as a function of concentration and does not rely on molecular weight standards for column calibration. The SEC/MALS method developed at Scientific Protein Laboratories was qualified in terms of specificity, precision, robustness, and accuracy. By eliminating the requirement of well-characterized molecular weight standards derived from heparin, the present procedure represents a clear improvement over the column calibration methods used in molecular weight determination. The SEC/MALS method is suitable for routine quality control of unfractionated heparin. PMID- 20838777 TI - Effects of the novel endocannabinoid uptake inhibitor, LY2183240, on fear potentiated startle and alcohol-seeking behaviors in mice selectively bred for high alcohol preference. AB - RATIONALE: Alcohol-use disorders often occur together with anxiety disorders in humans which may be partly due to common inherited genetic factors. Evidence suggests that the endocannabinoid system (ECS) is a promising therapeutic target for the treatment of individuals with anxiety and/or alcohol-use disorders. OBJECTIVES: The present study assessed the effects of a novel endocannabinoid uptake inhibitor, LY2183240, on anxiety- and alcohol-seeking behaviors in a unique animal model that may represent increased genetic risk to develop co morbid anxiety and alcohol-use disorders in humans. Mice selectively bred for high alcohol preference (HAP) show greater fear-potentiated startle (FPS) than mice selectively bred for low alcohol preference (LAP). We examined the effects of LY2183240 on the expression of FPS in HAP and LAP mice and on alcohol-induced conditioned place preference (CPP) and limited-access alcohol drinking behavior in HAP mice. RESULTS: Repeated administration of LY2183240 (30 mg/kg) reduced the expression of FPS in HAP but not LAP mice when given prior to a second FPS test 48 h after fear conditioning. Both the 10 and 30 mg/kg doses of LY2183240 enhanced the expression of alcohol-induced CPP and this effect persisted in the absence of the drug. LY2183240 did not alter limited-access alcohol drinking behavior, unconditioned startle responding, or locomotor activity. CONCLUSIONS: These findings suggest that ECS modulation influences both conditioned fear and conditioned alcohol reward behavior. LY2183240 may be an effective pharmacotherapy for individuals with anxiety disorders, such as post-traumatic stress disorder, but may not be appropriate for individuals with co-morbid anxiety and alcohol-use disorders. PMID- 20838779 TI - In vitro phase I metabolism of the synthetic cannabimimetic JWH-018. AB - A potent synthetic cannabinoid receptor agonist, JHW-018, was recently detected as one of the most prominent active agents in abusively used incenses such as Spice and other herbal blends. The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography-tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain. PMID- 20838780 TI - Applications of isotopes in advancing structural and functional heparanomics. AB - Heparanomics is the study of all the biologically active oligosaccharide domain structures in the entire heparanome and the nature of the interactions among these domains and their protein ligands. Structural elucidation of heparan sulfate and heparin oligosaccharides is a major obstacle in advancing structure function relationships and heparanomics. There are several factors that exacerbate the challenges involved in the structural elucidation of heparin and heparan sulfate; therefore, there is great interest in developing novel strategies and analytical tools to overcome the barriers in decoding the enigmatic heparanome. This review focuses on the applications of isotopes, both radioisotopes and stable isotopes, in the structural elucidation of the complex heparanome at the disaccharide or oligosaccharide level using liquid chromatography, nuclear magnetic resonance spectroscopy, and mass spectrometry. This review also outlines the utility of isotopes in determining the substrate specificity of biosynthetic enzymes that eventually dictate the emergence of biologically active oligosaccharides. PMID- 20838781 TI - Circulating fibroblast growth factor-23 increases following intermittent parathyroid hormone (1-34) in postmenopausal osteoporosis: association with biomarker of bone formation. AB - Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1-34) for 18 months. Bone mineral density (BMD) was measured at 6 and 18 months at the lumbar spine (LS) and total hip (TH). Blood samples were obtained at baseline, 1-3, 6-9, and 12-18 months. Serum calcium, phosphate, PTH, 25(OH)vitamin D, 1,25(OH)(2)vitamin D, markers of bone turnover, FGF-23, and sclerostin were measured. BMD increased at both the LS (11.6%, P < 0.001) and TH (2.5%, P < 0.01). The bone formation marker P1NP increased early (baseline mean [SD] 39.9 [24.4] MUg/l, 1-3 months 88 [37.9] MUg/l; P < 0.001) and remained higher than baseline throughout 18 months. FGF-23 also increased, with a peak response at 6-9 months (increase 65%, P = 0.002). Serum phosphate remained stable. A significant increase in 1.25(OH)(2)vitamin D (P = 0.02) was seen at 1-3 months only. A small but significant reduction in sclerostin was seen at 6-9 (P = 0.02) and 12-18 months (P = 0.06). There was a positive correlation between changes in P1NP and FGF-23 (6-9 months r = 0.78, P < 0.001). FGF-23 is increased by intermittent PTH(1-34). This is related to early changes in P1NP, suggesting that the skeletal effects of PTH may involve FGF-23. Further studies are required to elucidate this. PMID- 20838782 TI - Assessment of angiographic outcomes after flow diversion treatment of intracranial aneurysms: a new grading schema. AB - INTRODUCTION: Flow diverter (FD) devices have emerged as an alternative treatment for a subgroup of intracranial aneurysms. The principle of endovascular flow diversion is inherently different from endosaccular coil embolisation. To monitor the angiographic outcomes for FDs, a sensitive and reliable new measure is required. Oxford Neurovascular and Neuroradiology Research Unit developed a grading schema while conducting a registry to audit outcomes of patients treated using a particular FD (SILK flow diverter; Balt Extrusion, Montmorency, France). The aim of this study is to assess the applicability and reproducibility of the new schema. METHODS: The proposed grading schema is designed for saccular- or fusiform-shaped aneurysms. For both, it documents the degree of aneurysm occlusion using a five-point scale and the parent artery patency on a three-point scale. Two neuroradiologists used the schema to independently rate 55 angiograms showing comparable treatment and follow-up angiograms of patients treated with a FD. Inter-observer agreement was estimated using the weighted kappa co-efficient. RESULTS: Both readers found the schema easy to apply. Overall, there were ten discordant readings for degrees of aneurysm occlusion and two for parent artery patency. Inter-observer agreement was excellent for both the assessment of aneurysm occlusion (k=0.89; C.I.=0.81-0.99) and parent artery patency (k=0.90; C.I.=0.76-1.0). CONCLUSION: The proposed schema is sufficiently sensitive to register gradual aneurysm occlusion and parent artery patency on interval angiograms. It is reproducible and is applicable to both saccular and fusiform aneurysms. More data on follow-up of FD-treated aneurysms is needed to prove its efficacy in predicting the long-term behaviour of treated aneurysms. PMID- 20838783 TI - Phylogenetic analysis reveals rapid evolutionary dynamics in the plant RNA virus genus tobamovirus. AB - Early studies on the evolutionary dynamics of plant RNA viruses suggested that they may evolve more slowly than their animal counterparts, sometimes dramatically so. However, these estimates were often based on an assumption of virus-host codivergence over time-scales of many millions of years that is difficult to verify. An important example are viruses of the genus Tobamovirus, where the assumption of host-virus codivergence over 100 million years has led to rate estimates in the range of ~1 * 10(-8) nucleotide substitutions per site, per year. Such a low evolutionary rate is in apparent contradiction with the ability of some tobamoviruses to quickly overcome inbred genetic resistance. To resolve how rapidly molecular evolution proceeds in the tobomaviruses, we estimated rates of nucleotide substitution, times to common ancestry, and the extent of congruence between virus and host phylogenies. Using Bayesian coalescent methods applied to time-stamped sequences, we estimated mean evolutionary rates at the nucleotide and amino acid levels of between 1 * 10(-5) and 1.3 * 10(-3) substitutions per site, per year, and hence similar to those seen in a broad range of animal and plant RNA viruses. Under these rates, a conservative estimate for the time of origin of the sampled tobamoviruses is within the last 100,000 years, and hence a far more recently than proposed assuming codivergence. This is supported by our cophylogeny analysis which revealed significantly discordant evolutionary histories between the tobamoviruses and the plant families they infect. PMID- 20838784 TI - AVPR1A sequence variation in monogamous owl monkeys (Aotus azarai) and its implications for the evolution of platyrrhine social behavior. AB - The arginine vasopressin V1a receptor gene (AVPR1A) has been implicated in increased partner preference and pair bonding behavior in mammalian lineages. This observation is of considerable importance for studies of social monogamy, which only appears in a small subset of primate taxa, including the Argentinean owl monkey (Aotus azarai). Thus, to investigate the possible influence of AVPR1A on the evolution of social behavior in owl monkeys, we sequenced this locus in a wild population from the Gran Chaco. We also assessed the interspecific variation of AVPR1A in platyrrhine species that represent a set of phylogenetically and behaviorally disparate taxa. The resulting data revealed A. azarai to have a unique genic structure for AVPR1A that varies in coding sequence and microsatellite repeat content relative to other primate and mammalian species. Specifically, one repetitive region that has been the focus in studies of human AVPR1A diversity, "RS3," is completely absent in A. azarai and all other platyrrhines examined. This finding suggests that, if AVPR1A modulates behavior in owl monkeys and other neotropical primates, it does so independent of this region. These observations have also provided clues about the process by which the range of social behavior in the Order Primates evolved through lineage specific neurogenetic variation. PMID- 20838785 TI - High-yield and phylogenetically robust methods of DNA recovery for analysis of microbial biofilms adherent to plant biomass in the herbivore gut. AB - Recent studies have shown the microbial biofilms adherent to plant biomass in the gastrointestinal tracts of humans and other herbivores are quite different to planktonic populations. If these biofilm communities are to be properly characterized by metagenomics methods, then the microbial desorption methods used must ensure the phylogenetic diversity and genetic potential recovered is biologically valid. To that end, we describe here two different methods for desorbing microbes tightly adherent to plant biomass; and used PCR-DGGE analyses of the Bacteria and Archaea rrs genes to show both these desorption methods were effective in recovering the adherent microbial biofilm with no apparent biases in microbe recovery. We also present a derivation of the "repeated bead beating and column (RBB+C) purification" method of DNA extraction that results in the recovery of high molecular weight DNA. These DNA samples can be fragmented and size fractionated by sucrose density gradient centrifugation, bypassing the use of gel-plug lysis and pulsed-field gel electrophoresis separation of DNA for metagenomic library constructions. PMID- 20838786 TI - Anammox bacterial diversity in various aquatic ecosystems based on the detection of hydrazine oxidase genes (hzoA/hzoB). AB - Anammox bacteria belonging to the phylum Planctomycetes are responsible for N removal through NH(4)(+) oxidation coupled with NO(2)(-) reduction. Microbial diversity and ecology of anammox bacteria have not yet been fully revealed due to limitations of 16S rRNA analysis. The hydrazine oxidase gene in cluster 1 (hereafter hzoA/hzoB) was suggested as a proper genetic marker due to its high expression and ubiquitous presence in anammox bacteria. We conducted a comparative analysis of 16S rRNA and hzoA/hzoB genes to reveal anammox bacterial diversity and distribution in various aquatic environments. Phylogenetic analyses of 16S rRNA and hzoA/hzoB genes showed the dominance of Scalindua organisms in marine ecosystems, but there was no congruence of 16S rRNA and hzoA/hzoB gene phylogenies among the freshwater anammox bacteria associated with Brocadia sp., Jettenia sp., and Anammoxoglobus sp. Higher diversity of anammox bacteria was revealed based on hzoA/hzoB genes than 16S rRNA genes in the examined environments. Multiple regression analysis showed that salinity had significant influence on differential distribution and diversity of anammox bacteria in different ecosystems. Thus, molecular detection and resulting phylogeny of the hzoA/hzoB gene generated a better understanding of anammox bacterial diversity and their ecological distribution in various aquatic ecosystems. PMID- 20838787 TI - Frankia populations in soil and root nodules of sympatrically grown Alnus taxa. AB - The genetic diversity of Frankia populations in soil and in root nodules of sympatrically grown Alnus taxa was evaluated by rep-polymerase chain reaction (PCR) and nifH gene sequence analyses. Rep-PCR analyses of uncultured Frankia populations in root nodules of 12 Alnus taxa (n=10 nodules each) growing sympatrically in the Morton Arboretum near Chicago revealed identical patterns for nodules from each Alnus taxon, including replicate trees of the same host taxon, and low diversity overall with only three profiles retrieved. One profile was retrieved from all nodules of nine taxa (Alnus incana subsp. incana, Alnus japonica, Alnus glutinosa, Alnus incana subsp. tenuifolia, Alnus incana subsp. rugosa, Alnus rhombifolia, Alnus mandshurica, Alnus maritima, and Alnus serrulata), the second was found in all nodules of two plant taxa (A. incana subsp. hirsuta and A. glutinosa var. pyramidalis), and the third was unique for all Frankia populations in nodules of A. incana subsp. rugosa var. americana. Comparative sequence analyses of nifH gene fragments in nodules representing these three profiles assigned these frankiae to different subgroups within the Alnus host infection group. None of these sequences, however, represented frankiae detectable in soil as determined by sequence analysis of 73 clones from a Frankia-specific nifH gene clone library. Additional analyses of nodule populations from selected alders growing on different soils demonstrated the presence of different Frankia populations in nodules for each soil, with populations showing identical sequences in nodules from the same soil, but differences between plant taxa. These results suggest that soil environmental conditions and host plant genotype both have a role in the selection of Frankia strains by a host plant for root nodule formation, and that this selection is not merely a function of the abundance of a Frankia strain in soil. PMID- 20838788 TI - Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. AB - Systemic mast cell activation syndrome is a mast cell disorder characterized by an unregulated increased activation of mast cells leading to a pathologically enhanced release of mediators. Mutations in tyrosine kinase kit which crucially determines mast cell activity have been suggested as a necessary condition for the development of a clinically symptomatic mast cell disease. At the level of mRNA in mast cell progenitor cells of 20 patients with systemic mast cell activation syndrome and of 20 gender- and age-matched healthy volunteers, the tyrosine kinase kit was investigated for genetic alterations by means of RT-PCR and direct sequencing of the amplificates. In mast cells of 13 out of these 20 patients, multiple predominantly novel potential functionally activating point mutations or complex alterations of the mRNA sequence encoding the tyrosine kinase kit were detected. In contrast, in 19 of the 20 healthy subjects, no functionally relevant alterations of c-kit transcripts were detected. The present findings support the idea that the systemic mast cell activation syndrome is a clonal disease most commonly associated with variable activating mutations in the tyrosine kinase kit. PMID- 20838790 TI - Novel soluble expression technologies derived from unique properties of halophilic proteins. AB - Recombinant production of mammalian cytoplasmic proteins plays a major role in developing pharmaceutical products. Here we describe two expression technologies using unique nature of halophilic bacteria. One of such properties of halophilic bacteria is accumulation of compatible solutes in the cytoplasm. As the compatible solutes enhance protein solubility and folding, one might utilize these bacteria for cytoplasmic soluble expression of recombinant proteins, as described in this review. Another uniqueness is high reversibility of thermally unfolded halophilic proteins. Here we show that one such protein, beta-lactamase (BLA), is highly soluble both in the native and thermally unfolded states and reversibly refolds after thermal melting. This makes BLA as a potential fusion partner for soluble expression of target proteins. The BLA fusion technology is also introduced in the review. PMID- 20838789 TI - Simultaneous consumption of pentose and hexose sugars: an optimal microbial phenotype for efficient fermentation of lignocellulosic biomass. AB - Lignocellulosic biomass is an attractive carbon source for bio-based fuel and chemical production; however, its compositional heterogeneity hinders its commercial use. Since most microbes possess carbon catabolite repression (CCR), mixed sugars derived from the lignocellulose are consumed sequentially, reducing the efficacy of the overall process. To overcome this barrier, microbes that exhibit the simultaneous consumption of mixed sugars have been isolated and/or developed and evaluated for the lignocellulosic biomass utilization. Specific strains of Escherichia coli, Saccharomyces cerevisiae, and Zymomonas mobilis have been engineered for simultaneous glucose and xylose utilization via mutagenesis or introduction of a xylose metabolic pathway. Other microbes, such as Lactobacillus brevis, Lactobacillus buchneri, and Candida shehatae possess a relaxed CCR mechanism, showing simultaneous consumption of glucose and xylose. By exploiting CCR-negative phenotypes, various integrated processes have been developed that incorporate both enzyme hydrolysis of lignocellulosic material and mixed sugar fermentation, thereby enabling greater productivity and fermentation efficacy. PMID- 20838791 TI - Secondary breast augmentation: managing each case. AB - Breast augmentation is one of the most regularly performed interventions requiring reoperation in aesthetic surgery. For this reason, it involves a greater chance for complications. In this report, the authors aim to provide young plastic surgeons with guidelines based on their experience for responding to each of these complications, to explain the causes and ways of avoiding them, and to show how they can be treated when they occur. PMID- 20838792 TI - Bioenergy sustainability in China: potential and impacts. AB - The sustainability implications of bioenergy development strategies are large and complex. Unlike conventional agriculture, bioenergy production provides an opportunity to design systems for improving eco-environmental services. Different places have different goals and solutions for bioenergy development, but they all should adhere to the sustainability requirements of the environment, economy, and society. This article serves as a brief overview of China's bioenergy development and as an introduction to this special issue on the impacts of bioenergy development in China. The eleven articles in this special issue present a range of perspectives and scenario analyses on bioenergy production and its impacts as well as potential barriers to its development. Five general themes are covered: status and goals, biomass resources, energy plants, environmental impacts, and economic and social impacts. The potential for bioenergy production in China is huge, particularly in the central north and northwest. China plans to develop a bioenergy capacity of 30GW by 2020. However, realization of this goal will require breakthroughs in bioenergy landscape design, energy plant biotechnology, legislation, incentive policy, and conversion facilities. Our analyses suggest that (1) the linkage between bioenergy, environment, and economy are often circular rather than linear in nature; (2) sustainability is a core concept in bioenergy design and the ultimate goal of bioenergy development; and (3) each bioenergy development scheme must be region-specific and designed to solve local environmental and agricultural problems. PMID- 20838793 TI - Using regression tree analysis to improve predictions of low-flow nitrate and chloride in Willamette River Basin watersheds. AB - The use of regression tree analysis is examined as a tool to evaluate hydrologic and land use factors that affect nitrate and chloride stream concentrations during low-flow conditions. Although this data mining technique has been used to assess a range of ecological parameters, it has not previously been used for stream water quality analysis. Regression tree analysis was conducted on nitrate and chloride data from 71 watersheds in the Willamette River Basin to determine whether this method provides a greater predictive ability compared to standard multiple linear regression, and to elucidate the potential roles of controlling mechanisms. Metrics used in the models included a variety of watershed-scale landscape indices and land use classifications. Regression tree analysis significantly enhanced model accuracy over multiple linear regression, increasing nitrate R2 values from 0.38 to 0.75 and chloride R2 values from 0.64 to 0.85 and as indicated by the DeltaAIC value. These improvements are primarily attributed to the ability for regression trees to more effectively handle interactions and manage non-linear functions associated with watershed heterogeneity within the basin. Whereas hydrologic factors governed the conservative chloride tracer in the model, land use dominated control of nitrate concentrations. Watersheds containing higher agricultural activity did not necessarily yield high nitrate concentrations, but agricultural areas combined with either small proportions of forested land or greater urbanization generated nitrate levels far exceeding water quality standards. Although further refinements are recommended, we conclude that regression tree analysis presents water resource managers a promising tool that improves on the predictive ability of standard statistical methods, provides insight into controlling mechanisms, and helps identify catchment characteristics associated with water quality impairment. PMID- 20838795 TI - [Pathology of familial tumor syndromes]. PMID- 20838796 TI - DNA damage and its relationship with other oxidative stress parameters in Behcet's disease. AB - Behcet's disease (BD) is a multisystemic, chronic inflammatory, relapsing disorder that is characterized by oral/genital ulcerations, ocular, arthritic, vascular, and neurologic involvements. Recent findings suggest the role of increased oxidative stress and insufficient antioxidant defence system in BD pathogenesis. It has been proposed that the increase in phagocytic cell activity by triggering oxidative reactions in various targets such as lipids, proteins, and DNA leads to severe inflammatory and degenerative pathologies seen in BD In this study, oxidant/antioxidant status of patients with BD was evaluated in comparison with controls and in respect to disease activity by measuring serum nitrite/nitrate, vitamin A, malondialdehyde (MDA), 8-hydroxy deoxyguanosine (8 OHdG), and total sulfhydryl levels (T-SH). The increase in serum MDA and 8-OHdG levels (respectively 30.04 vs. 17.93 nmol/ml, P = 0.0004 and 1.60 vs. 1.03 ng/ml, P = 0.0019) and the decrease in T-SH levels of patients with BD in comparison with controls (0.69 vs. 0.76 mmol/l, P = 0.0085) all indicate the impaired oxidant/antioxidant status in BD. The positive correlation found between MDA/8 OHdG levels (P = 0.02), and the negative correlations both between T-SH/8-OHdG levels (P = 0.031) and T-SH/MDA levels (P = 0.009) show the concordance between the parameters evaluating oxidant-antioxidant status. Among the parameters used for evaluating oxidant/antioxidant status, serum 8-OHdG was the only one showing significantly higher levels in patients with clinically active disease in comparison (P = 0.004) to patients in inactive period. Therefore, 8-OHdG that is assessed for the fist time in BD with this study can be proposed as a more reliable indicator of oxidant stress in evaluating disease activity. PMID- 20838797 TI - Nodular bilateral amygdala degeneration in demented individuals. AB - Among more than 2,050 brains in our Alzheimer disease brain banks, we came across three brains with well-demarcated indurated white-yellow nodules in the amygdalas. Microscopically, these nodules were composed of numerous lipid-laden macrophages located in the central region surrounded by an eosinophilic hyaline like material with minimal reactive gliosis in the periphery. Neurons within these lesions had a normal appearance but were moderately decreased in number. Beta-amyloid, tau and alpha-synuclein immunostaining revealed no abnormal deposits within the nodules. The three patients had long histories of dementia (one linked to a presenilin-1 mutation). The neuropathological diagnoses were Alzheimer disease in two of them and an unclassified tauopathy with argyrophilic grains in the third. In conclusion, the pathogenesis of these lesions is uncertain. We favor that the degeneration has some relationship to the underlying dementing disease, either secondary to deafferentation or an alteration in metabolic demand, perhaps related to the bi-directional anatomical and functional connections that exist between the amygdala and the hippocampus or less likely as a primary event. PMID- 20838798 TI - Heterogeneous neuropathological findings in Parkinson's disease with mild cognitive impairment. PMID- 20838799 TI - Glucocerebrosidase is present in alpha-synuclein inclusions in Lewy body disorders. AB - Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase, known to cause Gaucher disease (GD), are a risk factor for the development of Parkinson disease (PD) and related disorders. This association is based on the concurrence of parkinsonism and GD, the identification of glucocerebrosidase mutations in cohorts with PD from centers around the world, and neuropathologic findings. The contribution of glucocerebrosidase to the development of parkinsonian pathology was explored by studying seven brain samples from subjects carrying glucocerebrosidase mutations with pathologic diagnoses of PD and/or Lewy body dementia. Three individuals had GD and four were heterozygous for glucocerebrosidase mutations. All cases had no known family history of PD and the mean age of disease onset was 59 years (range 42-77). Immunofluorescence studies on brain tissue samples from patients with parkinsonism associated with glucocerebrosidase mutations showed that glucocerebrosidase was present in 32-90% of Lewy bodies (mean 75%), some ubiquitinated and others non-ubiquitinated. In samples from seven subjects without mutations, <10% of Lewy bodies were glucocerebrosidase positive (mean 4%). This data demonstrates that glucocerebrosidase can be an important component of alpha-synuclein-positive pathological inclusions. Unraveling the role of mutant glucocerebrosidase in the development of this pathology will further our understanding of the lysosomal pathways that likely contribute to the formation and/or clearance of these protein aggregates. PMID- 20838800 TI - Is induced labour in the nullipara associated with more maternal and perinatal morbidity? AB - PURPOSE: To ascertain any differences in foetomaternal outcomes in induced and spontaneous labour among nulliparous women delivering at term. METHODS: A retrospective matched cohort study consisting of 403 nulliparous women induced at >= 292 days and 806 nulliparous women with spontaneous labour at 285-291 days. RESULTS: Compared to those in spontaneous labour, women who had induction of labour were three times more likely to have a caesarean delivery (OR 3.1, 95% CI 2.4-4.1; P < 0.001). Women who had induction of labour were 2.2 times more likely to have oxytocin augmentation (OR 2.2, 95% CI 1.7-2.8; P < 0.001), 3.6 times more likely to have epidural anaesthesia (OR 3.6, 95% CI 2.8-4.6; P < 0.001), 1.7 times more likely to have uterine hyperstimulation (OR 1.7, 95% CI 1.1-2.6), 2 times more likely to have a suspicious foetal heart rate trace (OR 2.0, 95% CI 1.5-2.6), 4.1 times more likely to have blood loss over 500 ml (OR 4.1, 95% CI 2.9-5.5; P < 0.001), and 2.9 times more likely to stay in hospital beyond 5 days (OR 2.9, 95% CI 1.5-5.6; P < 0.001). Babies born to mothers who had induction of labour were significantly more likely to have an Apgar score of <5 at 5 min and an arterial cord pH of <7.0. CONCLUSION: Compared to those with spontaneous labour, nulliparous women with induced labours are more likely to have uterine hyperstimulation, caesarean delivery, and babies with low Apgar scores. Nulliparous women should be made aware of this, as well as potential risks of expectant management during counseling. PMID- 20838801 TI - Erratum to: Perinatal and first year outcomes of spontaneous versus assisted twins: a single center experience. PMID- 20838802 TI - Long-term recurrence of secretory breast carcinoma with metastatic sentinel lymph nodes. AB - PURPOSE: Secretory carcinoma is a rare form of breast cancer most frequently encountered in children or young adults. Several cases have been described in adults with increased aggressiveness and a risk of metastases. CASE REPORT: We report here, in a 30-year-old woman, a case of local relapse and lymph node metastases occurring 16 years after the initial diagnosis of secretory carcinoma. CONCLUSION: We present the clinical, radiological and pathological findings that led to the diagnosis. PMID- 20838803 TI - Ethyl glucuronide and ethyl sulfate in urine after consumption of various beverages and foods--misleading results? AB - Urine testing for ethyl glucuronide (EtG) is used to spot recent alcohol intake and is utilized to document alcohol abstinence. However, other possible sources of ethanol existed when special beverages or foods were ingested. EtG concentration curves in urine were measured after the consumption of non alcoholic beers, fruit juices, sauerkraut, and matured bananas. Using a cutoff of 0.1 mg/l, positive EtG findings were revealed after the ingestion of a lot of non alcoholic beer up to 13 h later, sauerkraut up to 5 h later, and matured bananas up to 3.5 h later. In German abstinence programs, subjects have to deliver a urine sample within 24 h after advice, and all participants are informed about possible misleading results caused by the consumption of certain beverages or foods. With respect to the present results, a 0.1 mg/l cutoff can be considered useful, and misleading results should not be expected from informed subjects within a 24-h waiting period. PMID- 20838804 TI - Estimating wound age: looking into the future. AB - A critical review is made of the studies on wound healing used for forensic purposes, focusing on the problem of which characteristics indicate that a parameter could be used as evidence in court. A panel analysing the more important information obtained by each marker is given, and a perspective of what might be expected from future research is discussed. PMID- 20838805 TI - Concerns about relationship between the geometry of internal jugular vein during anti-G straining maneuver and gravity-induced loss of consciousness. PMID- 20838806 TI - Inhibition by 5-HT of the synaptic responses evoked by callosal fibers on cortical neurons in the mouse. AB - We have studied the modulation by 5-HT of the synaptic excitatory responses evoked by callosal fibers on cortical pyramidal neurons. We have used a mouse brain slice preparation that preserves the callosal fibers and allows their selective activation. EPSCs evoked by callosal stimulation (ccEPSCs) were recorded with patch electrodes from pyramidal neurons identified visually. We observed that 5-HT (10-40 MUM) inhibited the ccEPSCs peak amplitude in 64% of the neurons; 5-HT had no effect in the remaining neurons. 5-HT also increased the frequency and amplitude of spontaneous EPSCs. This inhibition was accompanied with an increase in the coefficient of variation of the fluctuations of the ccEPSCs amplitude and with an increase in the ratio of the amplitudes of paired ccEPSCs. Agonists of 5-HT receptor subtypes 5-HT(1A) (8-OH-DPAT) and 5-HT(2A) (DOI) mimicked the effect of 5-HT; also, the effect of 8-OH-DPAT and DOI was blocked in the presence of specific blockers of 5-HT(1A) (WAY 100135) and 5 HT(2A) (MDL 11,939) receptors. Application of 5-HT did not change the amplitude of currents evoked by direct application of glutamate to neurons in which 5-HT decreased the amplitude of ccEPSC. The effects of 5-HT on ccEPSCs and on the synaptic currents evoked by intracortical stimulation were not correlated; this suggests that the effect of 5-HT was specific to particular synaptic inputs to a neuron. These results demonstrate the presynaptic modulation of the callosal synaptic responses by 5-HT and the implication of 5-HT(1A) and 5-HT(2A) receptors in this effect. PMID- 20838807 TI - Monoassociation with probiotic Lactobacillus delbrueckii UFV-H2b20 stimulates the immune system and protects germfree mice against Listeria monocytogenes infection. AB - In the present study, we investigated the protective effects of Lactobacillus delbrueckii UFV-H2b20 on the resistance to Listeria monocytogenes infection in gnotobiotic mice. Germfree mice or monoassociated mice were infected with L. monocytogenes, and the microbiological and immunological responses were evaluated after 1, 3, and 5 days of infection. Monoassociation with L. delbrueckii was capable of protecting mice against death caused by L. monocytogenes and induced a faster clearance of the bacteria in the liver, spleen, and peritoneal cavity at days 1, 3, and 5 post-infection. Also, monoassociated mice displayed less liver injury than germfree mice. The production of TNF-alpha in the serum, peritoneal cavity, and gut was augmented in monoassociated mice. Likewise, the levels of IFN gamma found on supernatants of spleen cells cultures were higher after the monoassociation. In addition, increased production of nitric oxide in peritoneal cell cultures supernatants and in serum was observed in mice that received L. delbrueckii. The monoassociation with L. delbrueckii induced higher production of IL-10 in the mucosal immune system. We conclude that monoassociation with L. delbrueckii UFV-H2b20 protects mice from death caused by L. monocytogenes infection by favoring effector responses while preventing their immunopathological consequences. PMID- 20838809 TI - Repellence of essential oils of aromatic plants growing in Argentina against Aedes aegypti (Diptera: Culicidae). AB - Mosquitoes are vectors of pathogens to humans and domestic animals and may also have economical impacts. One approach to prevent mosquito-borne diseases is bite deterrence through the application of repellents. Currently, there is an interest to search for alternative bioactive products to the synthetic active ingredients most widely used in insect repellents. Repellence against Aedes aegypti of essential oils extracted from Acantholippia salsoloides, Aloysia catamarcensis, Aloysia polystachya, Lippia integrifolia, Lippia junelliana (Verbenaceae), Baccharis salicifolia, Euphatorium buniifolium, and Tagetes filifolia (Asteraceae) were assessed. Tests were conducted by alternatively exposing untreated and treated forehand to the mosquitoes and counting probing attempts. All essential oils tested were significantly repellent against A. aegypti when compared to untreated controls; L. junelliana was the most repellent and T. filifolia was the least based on the response of the mosquitoes to different concentrations of the essential oils (EO). Repellence may be attributed to the respective main components of each EO. PMID- 20838808 TI - Repellent and acaricidal effects of botanical extracts on Varroa destructor. AB - Extracts of indigenous plants from South America have shown a broad spectrum of bioactivities. No-contaminant and natural substances have recently resurged as control treatment options for varroosis in honey bee colonies from Argentina. The aim of this work was to evaluate the biological activity of botanical extracts from Baccharis flabellata and Minthostachys verticillata on Varroa destructor and Apis mellifera. The acaricidal and insecticidal activities were assessed by the spraying application method. Both ethanolic extracts showed high levels of toxicity against the mites and were harmless to their host, A. mellifera. During the attractive-repellent test, the olfactory stimulus evoked for the extract from B. flabellata resulted as a repellent for mites. The aromatic stimulus of these extracts would be strong enough to cause disturbance on the behavior of V. destructor. Thus, the repellent effect of these substances plus the toxicity on mites postulate these botanical extracts like promising natural compound to be incorporated for the control of varroosis. PMID- 20838810 TI - Ultrastructural aspects of spermatogenesis, testes, and vas deferens in the parthenogenetic tapeworm Atractolytocestus huronensis Anthony, 1958 (Cestoda: Caryophyllidea), a carp parasite from Slovakia. AB - Spermatogenesis, testes, and vas deferens in the parthenogenetic monozoic tapeworm Atractolytocestus huronensis Anthony, 1958 (Cestoda: Caryophyllidea) from Slovakia, parasitizing the carp Cyprinus carpio L., have been investigated by means of transmission electron microscopy for the first time. The present results show that helminths with parthenogenetic and normal reproduction may share some common spermatology features, e.g., dense cytoplasm of the peripherally localized spermatogonia or a rosette type of spermatogenesis. In contrast to tapeworms with normal reproduction, the most prominent ultrastructural characteristic of the spermatocytes of A. huronensis is fragmentation of their nuclei. This clear feature of cell degeneration might be a consequence of the aberrant first meiotic division. Peripheral cortical microtubules and a single centriole, indicators of the ongoing spermiogenesis, were observed only very rarely in the early spermatids. Characteristics of normal spermiogenesis, i.e., apical dense material in the zone of differentiation in early stages of spermiogenesis, flagellar rotation, and proximo-distal fusion, were never found in the present study. The testes follicles are surrounded by a thin cytoplasmic sheath underlined by a basal lamina. Vas deferens is lined by flat epithelium with numerous surface lamellae and cilia. Mature, functional spermatozoa were not observed in the vas deferens of A. huronensis from Slovakia. PMID- 20838811 TI - Genotypes of Giardia intestinalis clinical isolates of gastrointestinal symptomatic and asymptomatic Saudi children. AB - Giardiasis is the most worldwide parasitic disease with the major clinical impact on infant and children. Two genotypes were reported commonly among humans (assemblage A and B). In this study, genotypes of Giardia intestinalis clinical isolates obtaining from 24 gastrointestinal symptomatic Saudi primary school children and 16 asymptomatic ones were explored by real-time polymerase chain reaction using the high resolution melting curve analysis targeting intergenic spacer (IGS) region rDNA of G. intestinalis. Children having acute, intermittent, and chronic diarrhea were 14, 5, and 5, respectively. Among all the giardiasis subjects, assemblage B was 37.5% followed by both of assemblages AI and AII with 30% and 27.5%, respectively. Mixed infection with the three previous assemblages was present in 5% of cases. Among symptomatic children, the prevalence of assemblage B was 62.5% then followed by assemblage AI (16.7%) and assemblage AII with 12.5%. All of the children who harbored G. intestinalis assemblages B were symptomatic, while asymptomatic ones had only assemblage AI and AII with 50% each. The difference was statistically highly significant. In symptomatic patients having acute diarrhea, assemblage B was present in 71.5%, while assemblage AI and AII were equal with 7.1%. All of the patients (14.3%) with mixed infection had acute diarrhea. In intermittent diarrhea, assemblage AI and B were equally distributed with 40% each. In chronic diarrhea, assemblage AI and AII were equal with 20% each, while assemblage B was found in 60%. The difference was statistically not significant. In conclusion, assemblage B is the commonest, while assemblage A is a predominant in symptomatic and asymptomatic giardiasis Saudi children, respectively. So human transmission is the common risk factor among symptomatic, while zoonotic transmission is a common risk factor in asymptomatic ones. On the other hand, a strong correlation between assemblage B and symptoms and no relation between genotypes and types of diarrhea are found. Also, PCR with HRM in one-step closed-tube methods is able to genotype G. intestinalis IGS rDNA without using the sequencing methods or the electrophoresis. PMID- 20838812 TI - Resident macrophages in the cochlear blood-labyrinth barrier and their renewal via migration of bone-marrow-derived cells. AB - A large population of perivascular cells was found to be present in the area of the blood-labyrinth barrier in the stria vascularis of normal adult cochlea. The cells were identified as perivascular resident macrophages (PVMs), as they were positive for several macrophage surface molecules including F4/80, CD68, and CD11b. The macrophages, which were closely associated with microvessels and structurally intertwined with endothelial cells and pericytes, constitutively expressed scavenger receptor classes A(1) and B(1) and accumulated blood-borne proteins such as horseradish peroxidase and acetylated low-density lipoprotein. The PVMs were demonstrated to proliferate slowly, as evidenced by the absence of 5-bromo-2-deoxyuridine (BrdU)-positive PVMs at 3-14 days in normal mice injected with BrdU. However, in irradiated mice, the majority of the PVMs turned over via bone-marrow-cell migration within a 10-month time-frame. The existence of PVMs in the vascular wall of the blood-labyrinth barrier might therefore serve as a source for progenitor cells for postnatal vasculogenesis and might contribute to the repair of damaged vessels in the context of a local inflammatory response. PMID- 20838813 TI - In vitro long-term development of cultured inner ear stem cells of newborn rat. AB - The adult mammalian auditory receptor lacks any ability to repair and/or regenerate after injury. However, the late developing cochlea still contains some stem-cell-like elements that might be used to regenerate damaged neurons and/or cells of the organ of Corti. Before their use in any application, stem cell numbers need to be amplified because they are usually rare in late developing and adult tissues. The numerous re-explant cultures required for the progressive amplification process can result in a spontaneous differentiation process. This aspect has been implicated in the tumorigenicity of stem cells when transplanted into a tissue. The aim of this study has been to determine whether cochlear stem cells can proliferate and differentiate spontaneously in long-term cultures without the addition of any factor that might influence these processes. Cochlear stem cells, which express nestin protein, were cultured in monolayers and fed with DMEM containing 5% FBS. They quickly organized themselves into typical spheres exhibiting a high proliferation rate, self-renewal property, and differentiation ability. Secondary cultures of these stem cell spheres spontaneously differentiated into neuroectodermal-like cells. The expression of nestin, glial-fibrillary-acidic protein, vimentin, and neurofilaments was evaluated to identify early differentiation. Nestin expression appeared in primary and secondary cultures. Other markers were also identified in differentiating cells. Further research might demonstrate the spontaneous differentiation of cochlear stem cells and their teratogenic probability when they are used for transplantation. PMID- 20838814 TI - Bacterial distribution in lung parenchyma early after pulmonary infection with Pseudomonas aeruginosa. AB - Nosocomial infections often cause lethal pneumogenic sepsis. Information on early bacteria-host interaction in the lung is limited. In the present study, mice were sacrificed 60 min and 4 h after Pseudomonas aeruginosa (PA) infection to investigate lung morphology by using electron microscopy and light microscopy. After 1 h, bacteria were found in the alveoli partly in contact with surfactant. Alveolar macrophages were seen with up to 10 intracellular bacteria close to protrusions of alveolar epithelial type I cells and the gas/blood barrier. A rare but surprising finding was bacteria and even replicating bacteria in alveolar epithelial type II cells (AEII). No bacteria were seen in capillaries. Neither engulfment of bacteria by neutrophils nor structural damage of the pulmonary barrier was visible. After 4 h, many neutrophils were found within the capillaries, but also in the alveolar space. Thus, we hypothesize that, in early stages of infection, the uptake of PA even by single AEII can influence the course of the disease. PMID- 20838816 TI - Stand-structural effects on Heterobasidion abietinum-related mortality following drought events in Abies pinsapo. AB - Climate change may affect tree-pathogen interactions. This possibility has important implications for drought-prone forests, where stand dynamics and disease pathogenicity are especially sensitive to climatic stress. In addition, stand structural attributes including density-dependent tree-to-tree competition may modulate the stands' resistance to drought events and pathogen outbreaks. To assess the effects of stand structure on root-rot-related mortality after severe droughts, we focused on Heterobasidion abietinum mortality in relict Spanish stands of Abies pinsapo, a drought-sensitive fir. We compared stand attributes and tree spatial patterns in three plots with H. abietinum root-rot disease and three plots without root-rot. Point-pattern analyses were used to investigate the scale and extent of mortality patterns and to test hypotheses related to the spread of the disease. Dendrochronology was used to date the year of death and to assess the association between droughts and growth decline. We applied a structural equation modelling approach to test if tree mortality occurs more rapidly than predicted by a simple distance model when trees are subjected to high tree-to-tree competition and following drought events. Contrary to expectations of drought mortality, the effect of precipitation on the year of death was strong and negative, indicating that a period of high precipitation induced an earlier tree death. Competition intensity, related to the size and density of neighbour trees, also induced an earlier tree death. The effect of distance to the disease focus was negligible except in combination with intensive competition. Our results indicate that infected trees have decreased ability to withstand drought stress, and demonstrate that tree-to-tree competition and fungal infection act as predisposing factors of forest decline and mortality. PMID- 20838815 TI - The complement system. AB - The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis. Inappropriate complement activation and complement deficiencies are the underlying cause of the pathophysiology of many diseases such as systemic lupus erythematosus and asthma. This review represents an overview of the complement system in an effort to understand the beneficial as well as harmful roles it plays during inflammatory responses. PMID- 20838817 TI - Dysphagia in Huntington's disease: a review. AB - Huntington's disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by disturbed movements and behavior and cognitive decline. The motor disturbances are both choreiform and hypokinetic. As a result of the combination of these signs, it is known that many patients with HD suffer from dysphagia. Little is known about the frequency and the characteristics of dysphagia in HD. Well-balanced strategies for treatment and prevention of dysphagia in HD are lacking. Therefore, we have performed a detailed survey of the literature. We found that the patient groups studied were heterogeneous and the methods used were highly variable, and no balanced advice for prevention and treatment was systematically proven. PMID- 20838818 TI - Chronic aspiration without pulmonary complications after partial laryngectomy: long-term follow-up of two cases. AB - We report the long-term history of two patients with oropharyngeal dysphagia subsequent to partial resection of the larynx (supraglottic and subtotal laryngectomy, respectively). Both fiberendoscopic and videofluoroscopy swallowing studies demonstrated aspiration of liquids and solids in the lower respiratory tract. The patients underwent a swallowing rehabilitation program and respiratory exercises to improve the efficacy of their cough, and both continued oral feeding despite their persistent dysphagia. They were followed annually over the subsequent 12 and 9 years, respectively, which included overseeing the clinical status of their bronchopulmonary apparatus (i.e., whether a productive cough was present or not), nutritional status, spirometric parameters, arterial blood gas analysis, pulse oximetry, and measurement of cough effectiveness. They also underwent serial videofluoroscopy swallowing studies, which demonstrated persistent tracheobronchial aspiration of both liquids and solids. Based on the absence of respiratory hospitalizations as well as pulmonary deterioration during the follow-up period, we discuss the importance of cough effectiveness and its enhancement as a possible protective factor to avoid pulmonary morbidity in chronic aspiration. PMID- 20838819 TI - Evaluation of tracheal intubation in several positions by the Pentax-AWS Airway Scope: a manikin study. AB - PURPOSE: In emergency situations, rescuers must occasionally secure the airway while the patient is in a restricted position rather than in the ideal supine position. We hypothesized that the Pentax-AWS Airway Scope (AWS) may be useful for emergent tracheal intubation in such positions. METHODS: Thirteen non anesthesia residents performed tracheal intubation on a simulated manikin in the supine (Supine), left-lateral decubitus (Left-LT), right-lateral decubitus (Right LT), prone (Prone), and sitting (Sitting) position, respectively, to assess AWS performance. RESULTS: Intubations were successful in all five positions. The time needed to secure the airway did not differ significantly between the Left-LT and Supine positions. Doctors required significantly more time to secure the airway in the Prone, Sitting, and Right-LT positions than in the Supine position. Visual analog scale (VAS) scoring of the subjective difficulty of laryngoscopy was lower in the Supine position rather than in the Right-LT, Prone, and Sitting positions. The VAS score of subjective difficulty of tracheal tube passage through the glottis was significantly higher in the Sitting position than in the other four positions. CONCLUSION: Although tracheal intubations with AWS in all five positions tested were successful, intubation with the patient in the Sitting, Right-LT, and Prone positions was more difficult and required more time than that in the Supine position. PMID- 20838820 TI - BIS pediatric sensor can cause blisters in small children. PMID- 20838822 TI - Significance of initial aortic aneurysm pressure sensor readings varies with aortic endograft design. AB - BACKGROUND: The differences in implantable pressure sensor aneurysm sac readings were compared following endovascular aneurysm repair (EVAR) among three different stent grafts. METHODS: From January 2006 to March 2009, 51 aortic stent grafts were implanted along with the Endosure sensor. Grafts used were Zenith, Talent, and Excluder. In the present retrospective study, pulse ratios were measured intraoperatively before and after aneurysm sac exclusion and in follow-up (within 30 days). Analysis of variance was used to determine significance. RESULTS: The average aneurysm size that was repaired was 5.75 cm (range: 4-8.5 cm); 41 patients (80.4%) being male with an average age of 76.3 years (range: 58-90 years). Thirty-four grafts were Zenith, 9 were Talent, and 8 were Excluder. The average pre-aneurysm exclusion pulse ratios for the Zenith, Talent, and Excluder were 1.00, 1.08, and 0.95 (p = 0.18), respectively. The average post-aneurysm exclusion pulse ratios were 0.34, 0.67, and 0.35, respectively (p = 0.003). Pulse ratios at the time of follow-up (within 30 days) were 0.17, 0.22, and 0.11, respectively (p = 0.44). Nine of 51 (17.6%) patients had a reduction of pulse ratio of less than 30% after endograft implantation. Five of those 9 patients (55.5%) had the Talent endograft, although there was no angiographic evidence of endoleak. CONCLUSIONS: The Talent graft has significantly higher pulse ratios following endograft implantation despite having no angiographic evidence of endoleak when compared to the Zenith and Excluder grafts. However, the pulse ratios decreased to levels similar to Zenith and Excluder within 30 days of endograft implantation. This suggests that the Talent endograft may have increased porosity initially. If pulse ratios do not appropriately decrease immediately after device implantation, further angiographic imaging may not be necessary if no obvious endoleak is seen. PMID- 20838823 TI - Adult anaplastic large cell lymphoma involving the central nervous system: a rare clinical scenario. PMID- 20838824 TI - Hypoxia-inducible factors in mantle cell lymphoma: implication for an activated mTORC1->HIF-1alpha pathway. AB - Aberrant activation of phosphoinositide-3 kinase/Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) signaling is implicated in the pathogenesis of mantle cell lymphoma (MCL). We previously showed oncogenic activation of PI3K/Akt pathway in a subset of MCL patients. In this study, we investigated downstream the immunohistochemical expression of (Ser2448)pmTOR [indicative of mTOR complex 1 (mTORC1) activation status] as well as of hypoxia-inducible factor 1 alpha (HIF 1alpha), hypoxia-inducible factor 2 alpha (HIF-2alpha), p53, and p21 in the same series of MCL patients. Additionally, correlation of these proteins with activated Akt ((Ser473)pAkt) and established histological prognostic factors was examined. Thirty-five tissue samples (28 classical type and seven blastoid variant) were included. The neoplastic cells expressed (Ser2448)pmTOR in 61.7%, HIF-1alpha in 73.5%, HIF-2alpha in 23.5%, and p53 in 18.2% of patients, while p21 was negative in all examined samples. In addition, 72% of patients who expressed HIF-1alpha had also (Ser2448)pmTOR expression (p = 0.041). HIF-1alpha expression was also correlated to an elevated (>=30%) Ki-67 (p = 0.031) and blastoid variant of disease (p = 0.017). In conclusion, we report for the first time common expression of HIF-alphas, especially HIF-1alpha, in MCL patients. Furthermore, an overall activation of mTORC1->HIF-1alpha axis and a potential role of (Ser2448)pmTOR in the regulation of HIF-1alpha in MCL patients are suggested. Finally, HIF-1alpha appears to be associated with more aggressive disease. A pathogenetic role for both mTORC1 and HIF-1alpha in MCL is implied, which will possibly lead to more efficient target therapies. PMID- 20838825 TI - Myeloid growth factors in acute myeloid leukemia: systematic review of randomized controlled trials. AB - Randomized controlled trials (RCT) investigating administration of colony stimulating factors (CSF) during or after chemotherapy in acute myeloid leukemia (AML) patients have not been systematically reviewed. We performed a meta analysis of all reported RCTs comparing prophylactic or concurrent use of CSFs in adult AML patients. Two reviewers extracted data independently. Summary estimates with 95% confidence intervals (CIs) were calculated using a fixed effects model. Fourteen RCTs (n = 4,069 patients) were identified investigating prophylactic CSF administration. Time to neutrophil recovery (>500/MUl) was significantly reduced in the CSF group (-4.13 days; 95% CI, -4.23 to -4.04) as was the length of hospitalization (-2.06 days; 95% CI, -2.36 to -1.76). However, no significant reduction in infection-related mortality was observed in CSF-treated compared with control patients (odds ratio (OR) 0.94; 95% CI, 0.8 to 1.1). Prophylactic CSF administration did not impact complete remission (CR) rate or survival. Fourteen RCTs (n = 4,518 patients) were identified investigating administration of CSFs during chemotherapy. Summary estimates of CR, disease/event-free, or overall survival were not significantly different for CSF versus control patients. Prophylactic CSF administration reduces the time to neutrophil recovery and length of hospitalization, but has no impact on documented infections or outcome. Economic analyses of prophylactic CSF administration in AML patients are warranted. PMID- 20838826 TI - Molecular correlates of spontaneous activity in non-human primates. AB - In our monkey model, cortical ARC and BDNF expressions were strongly correlated with spontaneous physical activity. The expressions of ARC and BDNF were inversely correlated with serum CRP levels, suggesting that CRP could be a putative peripheral marker of brain resiliency. PMID- 20838827 TI - Facilitation of the development of fungiform taste buds by early intraoral acesulfame-K stimulation to mice. AB - The gustatory system is susceptible to anatomical modification by postnatal taste stimulations. This study investigated the effects of early intraoral infusion of acesulfame-K solution on the development of fungiform taste buds in mice. It was found that the acesulfame-K infusion increased the number, promoted the maturation, and enlarged the size of taste bud during the postnatal stages, compared with the age-matched controls. This provides fundamental and new information about the development of taste bud under normal and early acesulfame K-stimulated conditions. PMID- 20838829 TI - Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. AB - Interferon-inducible transmembrane protein 5 (IFITM5) is an osteoblast-specific membrane protein whose expression peaks around the early mineralization stage during the osteoblast maturation process. To investigate IFITM5 function, we first sought to identify which proteins interact with IFITM5. Liquid chromatography mass spectrometry revealed that FK506-binding protein 11 (FKBP11) co-immunoprecipitated with IFITM5. FKBP11 is the only protein it was found to interact with in osteoblasts, while IFITM5 interacts with several proteins in fibroblasts. FKBPs are involved in protein folding and immunosuppressant binding, but we could not be sure that IFITM5 participated in these activities when bound to FKBP11. Thus, we generated Ifitm5-deficient mice and analyzed their skeletal phenotypes. The skeletons, especially the long bones, of homozygous mutants (Ifitm5(-/-)) were smaller than those of heterozygous mutants (Ifitm5(+/-)), although we did not observe any significant differences in bone morphometric parameters. The effect of Ifitm5 deficiency on bone formation was more significant in newborns than in young and adult mice, suggesting that Ifitm5 deficiency might have a greater effect on prenatal bone development. Overall, the effect of Ifitm5 deficiency on bone formation was less than we expected. We hypothesize that this may have resulted from a compensatory mechanism in Ifitm5 deficient mice. PMID- 20838830 TI - Chronic non-cholestatic liver disease is not associated with an increased fracture rate in children. AB - Chronic liver disease in adults is a risk factor of osteoporosis, but little is known about risk of fractures in children with non-cholestatic liver disease. The aim of this study was to investigate associations among the severity of liver fibrosis, bone mass and low-energy fractures in children. History of fractures, anthropometry, and bone mass and size were examined in 39 Caucasian children (25 boys, 14 girls) aged 7.1-18 years (mean 11.9 +/- 3.1) with chronic hepatitis B and liver fibrosis evidenced by liver biopsy. Severity of liver fibrosis was based on histological classification according to the method of Batts and Ludwig (mild, 1-2 scores; advanced, 3 scores) and Ishak (1-3 and 4-5 scores, respectively). Bone mineral content (BMC), density (BMD) and body composition were determined in the total body and lumbar spine using dual energy X-ray absorptiometry. Seven subjects (4 girls, 3 boys; 18% of the sample) had low BMD in the total body and lumbar spine region (Z-scores below -2.0). No associations were found among BMC, BMD, bone size and the severity of liver fibrosis. Nine boys (36% of all boys) and one girl reported repeated fractures (forearm, wrist, tibia, ankle, humerus), showing trends similar to the prevalence in general population. Fractures were neither associated with lower BMD/BMC nor with scores of liver fibrosis. Deficits in BMD in children with chronic hepatitis B are not associated with the severity of liver fibrosis. This study suggests that non cholestatic liver disease does not increase the risk of low-energy fractures during growth. From the practical perspective, however, children with chronic liver disease should be screened for history and clinical risk factors for fractures rather than referred to bone density testing. PMID- 20838833 TI - Enucleation of keratocystic odontogenic tumours: study interpretation, technical refinement and future research. PMID- 20838834 TI - Effect of tube potential and image receptor on the detection of natural proximal caries in primary teeth. AB - The aim of this study was to assess the detection of proximal caries in primary teeth at three different tube potentials using Ektaspeed films, storage phosphor plates (SPPs), and a charge-coupled device (CCD). Fifty-three extracted human primary molars with natural proximal caries were radiographed with three different imaging modalities--Digora Optime SPP system, RVGui CCD system, and Ektaspeed films--at 50-, 65-, and 70-kV tube potentials. Three observers scored the resultant images for the presence or absence of caries. The definitive diagnosis was determined by stereomicroscopic assessment. The diagnostic accuracy for each imaging modality was expressed as the area under the receiver operating characteristic curves (A(z)). Differences among the A(z) values were assessed using two-way ANOVA and t tests. Kappa was used to measure inter- and intra observer agreement. Higher accuracy was found for SPPs compared to film and CCD images at all tube potentials. Accuracy was significantly different only at 50-kV tube setting in favor of SPPs (p < 0.05). Inter- and intra-observer agreement was high for all systems. A SPP system can be recommended for dental peadodontic clinics particularly with 50-kV tube potential for the diagnosis of proximal caries since further advantages include the elimination of chemical processing, image enhancement, and a better low-contrast detectability performance. PMID- 20838835 TI - The continuous measurement of anti-CCP-antibodies does not help to evaluate the disease activity in anti-CCP-antibody-positive patients with rheumatoid arthritis. AB - Anti-cyclic citrullinated peptide antibody (CCP-AB) are used for diagnosis of rheumatoid arthritis (RA). It is still unknown if the extent of CCP-AB levels is useful to assess the disease activity or the individual follow-up as an individual activity parameter. We investigated 40 patients with a known RA who were positive for CCP-AB. Correlation between disease activity (DAS 28) and the amount of levels of CCP-AB in all patients over time as well as the individual follow-up were analysed. A weak correlation between CCP-AB and DAS 28 [r = 0.19; p = 0.001] was found. The individual correlation between CCP-AB titre and DAS 28 ranged between r = -1 and r = 1, so a strong positive and also a strong negative correlation was seen in single patients. In patients with erosive RA the correlation was significantly more positive than in patients with non-erosive RA. Because the correlation between CCP-AB levels and parameters of disease activity measured by DAS 28 is very low, we conclude for monitoring the disease activity to use simply and established parameters like morning stiffness, HAQ or ESR. The individual follow-up of the levels of CCP-AB is by the moment not useful for monitoring the disease activity. PMID- 20838836 TI - The impact of phantom decoys on choices in cats. AB - Context-dependent choice is an important aspect of decision making. The paper examines context-dependent choice in cats (Felis catus), with particular reference to the effect of local context, on the basis of hypotheses developed in the field of human decision making. Cats were initially confronted with two different feeding options. This binary choice set was later manipulated incorporating a decoy that was better than the available options but ultimately unavailable (a phantom). By means of a within-subjects manipulation of phantom location in the attribute space, the author compared the effects of close and distant phantoms on the final choices. The main finding is that close phantom decoys affected choice behavior of cats by altering the overall share of the available options, leading some animals to reject even some of the available feeding options, and by causing the animals to favor the available option that was more similar to the phantom decoy. No significant effects emerged for phantoms that were far from the alternatives in the attribute space. The strengths of this paper lie in its novel approach and high originality. No other study has used dominating decoys with animals or decoys that are unattainable. This paper provides strong links to the human decision making literature, the presentation of the predictions of a range of different choice models, and the novelty of the application to animals. The use of a phantom decoy is particularly interesting because the phantom cannot actually be chosen, and thus the binary and trinary choice sets both have the very same choices available. Overall, the effect of phantoms is real, interesting and new. PMID- 20838837 TI - Clark's nutcrackers (Nucifraga columbiana) use gestures to identify the location of hidden food. AB - Heterospecific cues, such as gaze direction and body position, may be an important source of information that an animal can use to infer the location of resources like food. The use of heterospecific cues has been largely investigated using primates, dogs, and other mammals; less is known about whether birds can also use heterospecific gestures. We tested six Clark's nutcrackers in a two-way object-choice task using touch, point, and gaze cues to investigate whether these birds can use human gestures to find food. Most of the birds were able to use a touch gesture during the first trial of testing and were able to learn to use point and gaze (eyes and head alternation) cues after a limited number of trials. This study is the first to test a non-social corvid on the object-choice task. The performance of non-social nutcrackers is similar to that of more social and related corvids, suggesting that species with different evolutionary histories can utilize gestural information. PMID- 20838838 TI - Treatment of pituitary adenomas using radiosurgery and radiotherapy: a single center experience and review of literature. AB - Fractionated radiotherapy (FRT) and gamma knife stereotactic radiosurgery (GKSRS) are used as adjuvant therapies to surgical resection for functional and non functional pituitary adenomas, although their optimum role in the treatment algorithm, as well as long-term safety and efficacy, still awaits further study. We report a single center experience with 33 patients with non-functional (16 patients), ACTH- (five patients), GH- (four patients), or prolactin-secreting (eight patients) tumors treated with FRT or SRS. The median tumor diameter was 1.9 cm, and the median follow-up was 36 months. For GKSRS, the median dosage was 16 Gy for non-functional adenomas and 23 Gy for hormone-secreting tumors. The median total dose for FRT was 50.4 Gy over 28 fractions (median). Two patients (6%) demonstrated radiographic evidence of tumor progression, three patients (9%) demonstrated radiation-induced visual field deficits on neuro-ophthalmic evaluation, and two patients (6%) suffered from radiation-induced hypopituitarism. Biochemical control, defined as normalized hormone values in the absence of medical therapy, was achieved in five out of eight prolactinoma patients and two out of five patients with Cushing's disease, but none of the four patients with acromegaly. These results are presented with a review of the relevant literature on the differential characteristics of FRT versus SRS in the treatment of functional and non-functional pituitary adenomas and validate postoperative irradiation as a potentially safe and effective means for tumor control. PMID- 20838839 TI - The extended retrosigmoid approach for neoplastic lesions in the posterior fossa: technique modification. AB - Approaches to the cerebellar-pontine angle and petroclival region can be challenging due to intervening eloquent neurovascular structures and cerebellar retraction required to view this anatomic compartment with the standard retrosigmoid technique. As previously described [11], the extended retrosigmoid provides additional access to space ventral to the brainstem through mobilization of the sigmoid sinus. We report our further experience and modifications of this approach for neoplastic pathology. The standard craniotomy is utilized, and the burr holes are placed slightly beyond the transverse sinus as well as the transverse-sigmoid junction and down towards the foramen magnum, as low as possible. Another burr hole is placed over the cerebral hemisphere to facilitate the dural dissection below the bone flap and over the transverse and sigmoid sinuses. We then perform a standard retrosigmoid craniotomy with a craniotome and the transverse and sigmoid sinuses are skeletonized. Consequently, the sigmoid sinus can then mobilized anteriorly to provide an unobstructed view in line with the petrous bone, while exposure of the transverse sinus provides access to the tentorium. Fifteen patients (March 2006-July 2008) underwent this approach to manage neoplastic lesions, including five meningiomas, three schwannomas, one epidermoid, and four intra-axial metastatic lesions. The nine extra-axial lesions were predominantly in the cerebellar-pontine angle with extension medial to the seventh/eighth nerve complex to the petroclival region. Gross total resection was obtained in all patients. The primary complication due to the exposure was a clinically asymptomatic sigmoid sinus thrombosis in one patient. Requiring a fundamental change in the management of the venous sinuses, the extended retrosigmoid craniotomy permits mobilization of the sigmoid and transverse sinuses. In this process, the entire cerebellar-pontine angle extending from the tentorium to the foramen magnum can be visualized with minimal cerebellar retraction. This technical modification over the standard retrosigmoid approach may provide a useful advantage to neurosurgeons dealing with these complex lesions. PMID- 20838841 TI - Spindle cell carcinoma of the nasal cavity. AB - We report an extremely rare case of spindle cell carcinoma of the sinonasal cavity. A 75-year-old man was admitted to our hospital because of right nasal obstruction. Nasal endoscopy showed a polypoid tumor measuring 3 * 3 cm at the nasal septum in the right nasal cavity, and an excisional biopsy was performed. Computed tomography (CT) demonstrated the nasal tumor extended to the maxillary sinus. Histologically, the tumor consisted of malignant spindle cells with hyperchromatic nuclei. Mitotic figures and necrosis were recognized. In some areas, edematous changes were recognized. No apparent differentiation was noted. The tumor cells were free of keratinization and intercellular bridge formations; therefore, there were no squamous cell components. Immunohistochemically, the tumor cells were positive for pancytokeratin, cytokeratin (CK)5/6, CK18, CK19, high molecular weight CK, p63, and vimentin. The tumor cells were negative for epithelial membrane antigen, CK7, CK14, p53 protein, S100 protein, HMB45, chromogranin, synaptophysin, CD34, CD56, glial fibrillary acidic protein, neuron specific enolase, neurofilaments, alpha-smooth muscle actin, neuroblastoma, myoglobin, carcinoembryonic antigen (CEA), carbohydrate antigen (CA)19-9, CD3, CD20, CD30, CD45RO, and CD45. A pathological diagnosis of spindle cell carcinoma of sinonasal lesion was made. The patient underwent resection of right maxilla followed by chemotherapy and radiation and was alive without metastasis 5 years after initial presentation. PMID- 20838840 TI - Emergency embolectomy for embolic occlusion of the middle cerebral artery-review of the literature and two illustrative cases. AB - With the increasing number of endovascular interventions during the last years, the number of procedure-related complications has risen accordingly. Despite sophisticated and effective endovascular treatments for acute thromboembolic events during intervention, vessel occlusion can remain refractory to medical and endovascular treatment. In case of failure of the endovascular revascularisation, microsurgical embolectomy in the anterior circulation can be a last therapeutic option, if case selection is adequate. To date, this rather aggressive form of treatment is still controversial, and there are only few series of reported surgical embolectomy. In the present review, we conducted a Medline (www.pubmed.org) search for reports or studies of microsurgical embolectomies using the keywords (1) middle cerebral artery (MCA) occlusion and (2) embolectomy. The most relevant factors for positive outcome were concluded as such: (1) vessel occlusion time, (2) collateral flow, (3) occlusion site and (4) thromboembolic origin. Additionally, we report on two illustrative cases from our department with acute MCA occlusion treated by emergency microsurgical embolectomy but with very contrary outcomes. Hence, emergency embolectomy in patients with MCA occlusion following endovascular treatment can be quite effective, if endovascular recanalisation options fail. Nevertheless, the decision-making process must be made critically, fast and based on factors such as vessel occlusion time, sufficient collateral flow, occlusion site and thrombus origin. PMID- 20838842 TI - Long-term survival data on sentinel lymph node biopsy in anorectal melanoma. PMID- 20838843 TI - When staplers misfire: endoscopic rescue of low pelvic anastomoses. AB - The end-to-end stapler has made it possible for colorectal surgeons to construct deeper anastomoses. Although complications associated with the device are mainly postoperative, very serious intraoperative complications, such as stapler misfire, can occur. The authors report their experience with two cases of stapler misfire, describing their method for the extraction of the device and the entrapped tissue using a flexible sigmoidoscope and a hot biopsy forceps. There were no immediate or long-term problems. The technique appears to be safe and effective. PMID- 20838844 TI - Acute peritonitis due to Corynebacterium ulcerans in a patient receiving continuous ambulatory peritoneal dialysis: a case report and literature review. AB - A 55-year-old Japanese woman receiving continuous ambulatory peritoneal dialysis (CAPD) was admitted to our service with abdominal pain and cloudy peritoneal fluid. Laboratory data revealed a white blood cell count of 7.20 * 10(9 )cells/L, hemoglobin 9.8 g/dl, hematocrit 29.0%, platelet count 284 * 10(9 )cells/L, and C reactive protein (CRP) 0.109 g/L. Peritoneal fluid white blood cell count of 2,000 cells/ul suggested acute peritonitis. An empiric trial of cefazolin and ceftazidime, subsequently switched to meropenem, vancomycin, minocycline, and amikacin, did not improve the patient's symptoms. The peritoneal fluid collected before initiation of antibiotic therapy grew Corynebacterium ulcerans. Ampicillin/sulbactam was started based on the culture and sensitivity data. On hospital day 8, the CAPD catheter was removed due to no clinical improvement and persistently increased levels of CRP to 0.0174 g/L. A 14-day course of ampicillin/sulbactam improved her clinical condition and laboratory data. Microbiological analysis revealed that C. ulcerans isolated from this patient did not produce diphtheria toxin. C. ulcerans was not isolated from her dog's oral and nasal cavities during a search for the route of her infection. We recommend that in patients with peritoneal dialysis, special attention should be paid to Corynebacterium peritonitis, especially due to C. ulcerans, which may produce diphtheria toxin, be resistant to multiple antibiotics, and frequently become recurrent. PMID- 20838845 TI - Improved horizontal directional hearing in bone conduction device users with acquired unilateral conductive hearing loss. AB - We examined horizontal directional hearing in patients with acquired severe unilateral conductive hearing loss (UCHL). All patients (n = 12) had been fitted with a bone conduction device (BCD) to restore bilateral hearing. The patients were tested in the unaided (monaural) and aided (binaural) hearing condition. Five listeners without hearing loss were tested as a control group while listening with a monaural plug and earmuff, or with both ears (binaural). We randomly varied stimulus presentation levels to assess whether listeners relied on the acoustic head-shadow effect (HSE) for horizontal (azimuth) localization. Moreover, to prevent sound localization on the basis of monaural spectral shape cues from head and pinna, subjects were exposed to narrow band (1/3 octave) noises. We demonstrate that the BCD significantly improved sound localization in 8/12 of the UCHL patients. Interestingly, under monaural hearing (BCD off), we observed fairly good unaided azimuth localization performance in 4/12 of the patients. Our multiple regression analysis shows that all patients relied on the ambiguous HSE for localization. In contrast, acutely plugged control listeners did not employ the HSE. Our data confirm and further extend results of recent studies on the use of sound localization cues in chronic and acute monaural listening. PMID- 20838846 TI - Distortion product otoacoustic emissions evoked by tone complexes. AB - Distortion product otoacoustic emissions (DPOAEs) are traditionally evoked by two tone stimuli. In this study, emission data from Mongolian gerbils are reported that were obtained with stimuli consisting of six to 10 tones. The stimuli were constructed by replacing one of the tones of a tone pair by a narrowband multitone complex. This produced rich spectra of the ear canal sound pressure in which many of the third-order DPOAEs originated from the interaction of triplets of stimulus components. A careful choice of the stimulus frequencies ensured that none of these DPOAE components coincided. Three groups of DPOAEs are reported, two of which are closely related to DPOAEs evoked by tone pairs. The third group has no two-tone equivalent and only arises when using a multitone stimulus. We analyzed the relation between multitone-evoked DPOAEs and DPOAEs evoked by tone pairs, and explored the new degrees of freedom offered by the multitone paradigm. PMID- 20838847 TI - Automatic extraction of concepts to extend RadLex. AB - RadLexTM, the Radiology Lexicon, is a controlled vocabulary of terms used in radiology. It was developed by the Radiological Society of North America in recognition of a lack of coverage of these radiology concepts by other lexicons. There are still additional concepts, particularly those related to imaging observations and imaging observation characteristics, that could be added to the lexicon. We used a free and open source software system to extract these terms from the medical literature. The system retrieved relevant articles from the PubMed repository and passed them through modules in the Apache Unstructured Information Management Architecture. Image observations and image observation characteristics were identified through a seven-step process. The system was run on a corpus of 1,128 journal articles. The system generated lists of 624 imaging observations and 444 imaging observation characteristics. Three domain experts evaluated the top 100 terms in each list and determined a precision of 52% and 26%, respectively, for identification of image observations and image observation characteristics. We conclude that candidate terms for inclusion in standardized lexicons may be extracted automatically from the peer-reviewed literature. These terms can then be reviewed for curation into the lexicon. PMID- 20838848 TI - Using Directed Acyclic Graphs to detect limitations of traditional regression in longitudinal studies. AB - INTRODUCTION: Longitudinal data are increasingly available to health researchers; these present challenges not encountered in cross-sectional data, not the least of which is the presence of time-varying confounding variables and intermediate effects. OBJECTIVES: We review confounding and mediation in a longitudinal setting and introduce causal graphs to explain the bias that arises from conventional analyses. CONCLUSIONS: When both time-varying confounding and mediation are present in the data, traditional regression models result in estimates of effect coefficients that are systematically incorrect, or biased. In a companion paper (Moodie and Stephens in Int J Publ Health, 2010b, this issue), we describe a class of models that yield unbiased estimates in a longitudinal setting. PMID- 20838849 TI - Simulation of integrated first and second generation bioethanol production from sugarcane: comparison between different biomass pretreatment methods. AB - Sugarcane bagasse is used as a fuel in conventional bioethanol production, providing heat and power for the plant; therefore, the amount of surplus bagasse available for use as raw material for second generation bioethanol production is related to the energy consumption of the bioethanol production process. Pentoses and lignin, byproducts of the second generation bioethanol production process, may be used as fuels, increasing the amount of surplus bagasse. In this work, simulations of the integrated bioethanol production process from sugarcane, surplus bagasse and trash were carried out. Selected pre-treatment methods followed, or not, by a delignification step were evaluated. The amount of lignocellulosic materials available for hydrolysis in each configuration was calculated assuming that 50% of sugarcane trash is recovered from the field. An economic risk analysis was carried out; the best results for the integrated first and second generation ethanol production process were obtained for steam explosion pretreatment, high solids loading for hydrolysis and 24-48 h hydrolysis. The second generation ethanol production process must be improved (e.g., decreasing required investment, improving yields and developing pentose fermentation to ethanol) in order for the integrated process to be more economically competitive. PMID- 20838850 TI - Xylanase II from Trichoderma reesei QM 9414: conformational and catalytic stability to Chaotropes, Trifluoroethanol, and pH changes. AB - Xylanase II, a key enzyme in the hydrolysis of xylan, was purified from cultures of Trichoderma reesei QM 9414 (anamorph of Hypocrea jecorina) grown on wheat straw as a carbon source. Xylanase treated with increasing guanidinium hydrochloride concentrations was denatured in a cooperative way regarding secondary and tertiary structures with midpoint transitions 5.6 +/- 0.1 and 3.7 +/- 0.1 M, respectively, whereas the enzymatic activity showed an intermediate state at 2-4 M denaturant. Treatment with urea showed that xylanase secondary structure was stabilized up to 4 M urea to be destabilized thereafter in a cooperative way with a transition midpoint Dm = 5.7 +/- 0.2 M, but the ellipticity at 220 nm was greater than control in the presence of urea up to 6 M. Tertiary structure in the presence of urea showed also intermediate states with partial cooperative transitions with a midpoint: Dm = 2.7 +/- 0.04 and 6.7 +/- 0.3 M, respectively, whereas the enzymatic activity was enhanced about 40% at 2 M and inhibited above 4 M urea. Assays with the fluorescent probe 4,4'-bis-1 phenylamine-8-naphftalene sulfonate (bis-ANS) proved that the intermediate states had the characteristics of molten globule structures. The change of free energy for xylanase in absence of denaturants obtained from the spectral centre of mass (SCM) data at 298 K is = - 17 kJmol-1 . In the presence of increasing trifluoroethanol (TFE), the enzyme gained alpha-helix content and lose tertiary structure and catalytic activity. Changes in pH (2-9) had practically no effect on the secondary structure of the enzyme, whereas the SCM values indicated that tertiary structure is maintained above pH 4. Bis-ANS binds to xylanase at pH 2 and 2.5 and in the presence of 30-40% TFE (v/v) characterizing molten globule states in those environmental conditions. PMID- 20838851 TI - Bilateral phrenic nerve dysfunction: a late complication of mantle radiation. AB - Neurologic complications from radiotherapy can be immediate or can occur many years after treatment. A known complication of radiotherapy to the supraclavicular and axillary lymph nodes is brachial plexus neuropathy. Although not a common injury, phrenic nerve dysfunction has been reported in association with radiation-induced brachial neuropathy. We describe a patient who developed asymmetric diaphragmatic weakness secondary to phrenic nerve paralysis 37 years after receiving mantle radiation for Hodgkin lymphoma. The patient did not have an associated brachial plexus neuropathy or a secondary malignancy involving the phrenic nerves. A radiation-induced injury was the most likely cause. PMID- 20838852 TI - Aberrant signaling pathways in meningiomas. AB - In this article, we provide a brief description of the current understanding of aberrant signaling pathways in meningiomas. Cell signaling pathways are responsible for cellular differentiation, development, growth, growth inhibition, and death. In fact, signaling pathways can affect multiple intracellular functions, including those responsible for development, angiogenesis, and apoptosis. Ultimately, a further understanding of the signaling pathways involved in meningioma tumorigenesis will lead to the development and application of novel molecular treatments, such as small molecule inhibitors or interfering ribonucleic acid technologies. PMID- 20838853 TI - Knockdown of interferon-induced transmembrane protein 1 (IFITM1) inhibits proliferation, migration, and invasion of glioma cells. AB - Interferon-induced transmembrane protein 1 (IFITM1) has recently been identified as a new molecular marker in human colorectal cancer. However, its role in glioma carcinogenesis is not known. In this study, we demonstrated that suppression of IFITM1 expression significantly inhibited proliferation of glioma cells in a time dependent manner. The growth inhibitory effect was mediated by cell cycle arrest. Furthermore, IFITM1 knockdown significantly inhibited migration and invasion of glioma cells, which could be attributed to decreased expression and enzymatic activity of matrix metalloproteinase 9. Taken together, these results suggest that IFITM1 is a potential therapeutic target for gliomas. PMID- 20838854 TI - Dual phase FDG-PET imaging of brain metastases provides superior assessment of recurrence versus post-treatment necrosis. AB - To study the ability of dual phase FDG-PET/CT imaging to accurately distinguish tumor versus necrosis in patients treated for brain metastases. 32 (22 female, 10 male) consecutive patients with treated brain metastases, lesion size greater than 0.5 cm(3) and suspected recurrence on MRI underwent dual-phase FDG-PET/CT. Clinical outcome was assessed by biopsy or by MRI. SUVmax and SUVmean values of the lesion (L) and gray matter (GM) at the level of the thalamus were measured on early (1) and delayed (2) imaging. L1/GM1 and L2/GM2 and the change of L/GM ratios as a function of time were calculated [(L2/GM2 - L1/GM1)/(L1/GM1)]. Cut off values were obtained by ROC analysis. P < 0.05 defined statistical significance. Seven patients were excluded due to indeterminate outcomes. 25 patients (16 female, 9 male; 27 lesions; 28 scan sessions) had clear outcomes, proven by either biopsy (n = 16 patients) or serial follow-up MRI (n = 9 patients). Primary subtypes included breast (n = 9), lung (n = 7), melanoma (n = 3), squamous cell cancer of the head and neck (n = 2) and other (n = 4). Twenty two patients underwent prior radiation (2-113 months) and three received only prior chemotherapy (5 months to 3 years). A change >0.19 of L/GM ratios as a function of time was 95% sensitive, 100% specific, and 96.4% accurate (P = 0.0001; AUC = 0.97) for distinguishing tumor versus radiation necrosis. The ratio of the change of the lesion to WM ratios over time was the second best indicator of outcome when compared to all indices used (ROC cut-off = 0.25, sensitivity 89.5% and specificity 90.9%, and accuracy 89.2%; P = 0.0001; AUC = 0.95), Early or late SUVs of the lesion alone did not differentiate between tumor and necrosis. Regardless of histological type, differentiation of necrosis from metastatic brain lesions was improved by using the change of lesion to gray matter SUVmax ratios as a function of time. PMID- 20838855 TI - High-resolution methyl edited GFT NMR experiments for protein resonance assignments and structure determination. AB - Three-dimensional (3D) structure determination of proteins is benefitted by long range distance constraints comprising the methyl groups, which constitute the hydrophobic core of proteins. However, in methyl groups (of Ala, Ile, Leu, Met, Thr and Val) there is a significant overlap of 13C and 1H chemical shifts. Such overlap can be resolved using the recently proposed (3,2)D HCCH-COSY, a G-matrix Fourier transform (GFT) NMR based experiment, which facilitates editing of methyl groups into distinct spectral regions by combining their 13C chemical shifts with that of the neighboring, directly attached, 13C nucleus. Using this principle, we present three GFT experiments: (a) (4,3)D NOESY-HCCH, (b) (4,3)D 1H-TOCSY-HCCH and (c) (4,3)D 13C-TOCSY-HCCH. These experiments provide unique 4D spectral information rapidly with high sensitivity and resolution for side-chain resonance assignments and NOE analysis of methyl groups. This is exemplified by (4,3)D NOESY-HCCH data acquired for 17.9 kDa non-deuterated cytosolic human J-protein co chaperone, which provided crucial long-range distance constraints for its 3D structure determination. PMID- 20838856 TI - Morphophysiological responses and programmed cell death induced by cadmium in Genipa americana L. (Rubiaceae). AB - Cadmium (Cd) originating from atmospheric deposits, from industrial residues and from the application of phosphate fertilizers may accumulate in high concentrations in soil, water and food, thus becoming highly toxic to plants, animals and human beings. Once accumulated in an organism, Cd discharges and sets off a sequence of biochemical reactions and morphophysiological changes which may cause cell death in several tissues and organs. In order to test the hypothesis that Cd interferes in the metabolism of G. americana, a greenhouse experiment was conducted to measure eventual morphophysiological responses and cell death induced by Cd in this species. The plants were exposed to Cd concentrations ranging from 0 to 16 mg l(-1), in a nutritive solution. In TUNEL reaction, it was shown that Cd caused morphological changes in the cell nucleus of root tip and leaf tissues, which are typical for apoptosis. Cadmium induced anatomical changes in roots and leaves, such as the lignification of cell walls in root tissues and leaf main vein. In addition, the leaf mesophyll showed increase of the intercellular spaces. On the other hand, Cd caused reductions in the net photosynthetic rate, stomatal conductance and leaf transpiration, while the maximum potential quantum efficiency of PS2 (Fv/Fm) was unchanged. Cadmium accumulated in the root system in high concentrations, with low translocation for the shoot, and promoted an increase of Ca and Zn levels in the roots and a decrease of K level in the leaves. High concentrations of Cd promoted morphophysiological changes and caused cell death in roots and leaves tissues of G. americana. PMID- 20838857 TI - Grafting versus seed propagated apricot populations: two main gene pools in Tunisia evidenced by SSR markers and model-based Bayesian clustering. AB - Apricot was introduced into the Mediterranean Basin from China and Asian mountains through the Middle-East and the Central Europe. Traditionally present in Tunisia, we were interested in accessing the origin of apricot species in the country, and in particular in the number and the location of its introductions. A set of 82 representative apricot accessions including 49 grafted cultivars and 33 seed propagated 'Bargougs' were genotyped using 24 microsatellite loci revealing a total of 135 alleles. The model-based Bayesian clustering analysis using both Structure and InStruct programs as well as the multivariate method revealed five distinct genetic clusters. The genetic differentiation among clusters showed that cluster 1, with only four cultivars, was the most differentiated from the four remaining genetic clusters, which constituted the largest part of the studied germplasm. According to their geographic origin, the five identified groups (north, centre, south, Gafsa oasis and other oases groups) enclosed a similar variation within group, with a low level of differentiation. Overall results highlighted the distinction of two apricot gene pools in Tunisia related to the different mode of propagation of the cultivars: grafted and seed propagated apricot, which enclosed a narrow genetic basis. Our findings support the assumption that grafting and seed propagated apricots shared the same origin. PMID- 20838858 TI - Arachidonic acid pools of rat kidney cell nuclei. AB - We have assessed that nuclear lipids from rat kidney cells are not only membrane components, but they are also found within the nucleus. The most abundant nuclear and endonuclear lipids have a high proportion of unsaturated fatty acids (n-6 series: arachidonic > linoleic), mainly esterified to PtdCho. Nuclear most abundant molecular species are 16:0-20:4, 16:0-18:2, 18:0-20:4, 18:0-18:2, and 16:0-18:1. Arachidonic acid is esterified at the sn-2 position of PtdCho: 16:0 20:4(25%), 18:0-20:4(15%), 18:2-20:4(3%), 18:1-20:4(2%). Exogenous [1-(14)C]20:4n 6-CoA is esterified in vitro in GP (glycerophospholipids) > > TAG and DAG. Five PtdCho molecular species were labeled: 16:0-20:4, 18:0-20:4, 18:1-20:4, 18:2 20:4, and 20:4-20:4. In conclusion, these results demonstrated that: (1) there is an important lipid pool within kidney cell nuclei; (2) main nuclear and endonuclear lipid pools were PtdCho molecular species which contained a high proportion of unsaturated fatty acids (20:4n-6 and 18:2n-6) esterified at sn-2 position and 16:0 esterified at sn-1 position; (3) kidney cell nuclei also contained the necessary enzymes to esterify exogenous 20:4n-6-CoA to glycerolipids and to GP; (4) exogenous 20:4n-6-CoA was esterified in five PtdCho molecular species with 20:4n-6 at the sn-2 position, although the most actively synthesized PtdCho contained 20:4n-6 at both the sn-1 and sn-2 positions of the molecule; (5) we can infer that by a remodeling process, the unsaturated fatty acids at the sn-1 position of PtdCho molecular species could be replaced by 16:0 and 18:0, and thus PtdCho would achieve the physiological profile characteristic of the organ. PMID- 20838860 TI - Desire for, and uptake of HIV tests by Ghanaian women: the relevance of community level stigma. AB - Voluntary counseling and testing (VCT) has been recognized as the crux of HIV surveillance, prevention and treatment programs. Since 2000, Ghana government has launched a number of HIV prevention and treatment programs intended to increase VCT services. Despite these efforts, uptake of testing is still low, though many women reported interest in getting tested. The disconnect between intention and action is attributable to several factors, including HIV-related stigma. The study used data from the 2003 Ghana Demographic and Health Survey and fitted complementary log-log models to regress women's desire for and uptake of an HIV test on levels of personal and community stigma. Consistent with findings from previous research, the study revealed significant associations between a number of socio-demographic and socio-cognitive variables and the desire for and uptake of an HIV test by Ghanaian women. Most significantly, the study showed that widespread stigma in the community exert greater negative effects on individuals who endorse stigmatizing beliefs and predispositions, compared to their peers with more favorable attitudes. Since community level educational and risk reduction programs have demonstrable influences on reducing HIV stigma, it is imperative that the Ghana government's ongoing anti-stigma campaigns and other HIV prevention programs take cognizance of the role of community stigma in influencing HIV testing. PMID- 20838859 TI - Lactobacillus casei reduces the inflammatory joint damage associated with collagen-induced arthritis (CIA) by reducing the pro-inflammatory cytokines: Lactobacillus casei: COX-2 inhibitor. AB - This study evaluated the therapeutic efficacy of Lactobacillus casei in treating rheumatoid arthritis using collagen-induced arthritis (CIA) animal model. Healthy female Wistar rats (weight-180-200 g) were included in this study. Oral administration of L. casei was started on the same day. Indomethacin was used as standard reference drug. Serum level of IL-6, alpha-TNF, and IL-10 were observed. Four-point arthritis indexes were also assessed at the end of week for 28th day. L. casei-treated rats had shown normal histopathology without any synovial infiltration, pannus formation, cartilage, and bone destruction. Arthritis score was also lower for the group treated with L. casei. Oral administration of L. casei significantly decreased the pro-inflammatory cytokines. Present study suggests that L. casei has potent antiarthritic effect in CIA model. Inhibition of COX-2 via inhibiting the pro-inflammatory cytokines is an understanding of the complex interactions involved in these pathways. PMID- 20838861 TI - Brain proton magnetic spectroscopy in long-term treatment of Wilson's disease patients. AB - We reported the brain proton magnetic resonance spectroscopy (MRS) findings in 27 Wilson's disease (WD) patients treated more than 6 years in neurological (nWD) and hepatic (hWD) subgroups. We investigated four hWD patients, with no improvement and eight with marked improvement; and eight nWD patients with marked improvement and seven with no improvement of clinical status. In nWD patients with improvement the MRS showed significantly higher Cho/Cr, Glx/Cr ratios levels. In hWD patients with no improvement the lower Cho/Cr and in nWD significantly lower NAA/Cr and higher Cho/Cr and Lip/Cr ratios were detected. In nWD patients with improvement the spectroscopic pattern, can be related to gliosis. In patients with no neurological improvement a persistent neuronal dysfunction can occur, perhaps as a result of copper or iron deposition. PMID- 20838862 TI - Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect. AB - Diabetes may modify central nervous system functions and is associated with moderate cognitive deficits and changes in the brain, a condition that may be referred to as diabetic encephalopathy. The prevalence of depression in diabetic patients is higher than in the general population, and clonazepam is being used to treat this complication. Oxidative stress may play a role in the development of diabetes complications. We investigated oxidative stress parameters in streptozotocin-induced diabetic rats submitted to forced swimming test (STZ) and evaluated the effect of insulin (STZ-INS) and/or clonazepam (STZ-CNZ and STZ-INS CNZ) acute treatment on these animal model. Oxidative damage to proteins measured as carbonyl content in plasma was significantly increased in STZ group compared to STZ treated groups. Malondialdehyde plasma levels were significantly reduced in STZ-INS and STZ-INS-CNZ groups when compared to STZ rats, being significantly reduced in STZ-INS-CNZ than STZ-INS rats. The activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase showed no significant differences among all groups of animals. These findings showed that protein and lipid damage occurs in this diabetes/depression animal model and that the associated treatment of insulin and clonazepam is capable to protect against oxidative damage in this experimental model. PMID- 20838863 TI - A nonhuman primate model of Alzheimer's disease generated by intracranial injection of amyloid-beta42 and thiorphan. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment and neuropathological changes, including the deposition of amyloid-beta (Abeta) peptide. Aged monkeys have proven to be invaluable in the study of AD, as their brains naturally develop amyloid plaques similar to those in AD brains. However, spontaneous development of AD-like pathologies in aged monkeys is time-consuming, often taking several years. Here, we created an experimentally induced AD model in middle-aged (16-17 years) rhesus monkeys by intracranial injection of Abeta42 and thiorphan, an inhibitor of neprilysin that is responsible for Abeta clearance. The working memory capacity of the monkeys in a delayed-response task was little affected following the delivery of Abeta42 and thiorphan. However, the administration of Abeta42 and thiorphan resulted in a significant intracellular accumulation of Abeta in the neurons of the basal ganglia, the cortex, and the hippocampus, accompanied by neuronal atrophy and loss. Moreover, immunohistochemistry revealed a degeneration of choline acetyltransferase-positive cholinergic neurons and an increase of glial fibrillary acidic protein-positive astrocytes. In conclusion, our data demonstrate a primate model of AD generated by combined infusion of Abeta42 and thiorphan, which duplicates a subset of neuropathological changes in AD brains, thereby having implications in the elucidation of this disease. PMID- 20838864 TI - Serum proinflammatory cytokines correlate with diffusion tensor imaging derived metrics and 1H-MR spectroscopy in patients with acute liver failure. AB - Hyperammonemia and inflammation are major contributing factors in the development of cerebral edema (CE) in acute liver failure (ALF). Aim of this study was to look for the relationship between proinflammatory cytokines with diffusion tensor imaging (DTI) derived metrics and (1)H-MR spectroscopy ((1)H-MRS) derived Glutamate/Glutamine (Glx). Fourteen patients with ALF and 14 age/sex matched controls were included in this study. All subjects had undergone clinical, biochemical, MR imaging and (1)H-MRS studies. Serum proinflammatory cytokines (IL 6 and TNF-alpha), blood ammonia level and Glx were computed for independent t test and Pearson correlation. Serum proinflammatory cytokines, blood ammonia level and brain Glx were significantly increased in ALF patients as compared to controls. Blood ammonia level and Glx showed significant positive correlation with proinflammatory cytokines. Spectroscopy voxel derived spherical anisotropy (CS) showed positive correlation with Glx while mean diffusivity (MD) showed negative correlation. Proinflammatory cytokines showed positive correlation with CS and negative correlation with MD in various brain regions including spectroscopy voxel. Significant correlation of Glx, CS and MD with proinflammatory cytokines suggests that both DTI derived metrics and (1)H-MRS measure the synergistic effect of hyperammonemia and proinflammatory cytokines and may be used as non-invasive tools for understanding the pathogenesis of CE in ALF. PMID- 20838865 TI - Choline-deprivation alters crucial brain enzyme activities in a rat model of diabetic encephalopathy. AB - Diabetic encephalopathy describes the moderate cognitive deficits, neurophysiological and structural central nervous system changes associated with untreated diabetes. It involves neurotoxic effects such as the generation of oxidative stress, the enhanced formation of advanced glycation end-products, as well as the disturbance of calcium homeostasis. Due to the direct connection of choline (Ch) with acetylcholine availability and signal transduction, a background of Ch-deficiency might be unfavorable for the pathology and subsequently for the treatment of several metabolic brain diseases, including that of diabetic encephalopathy. The aim of this study was to shed more light on the effects of adult-onset streptozotocin (STZ)-induced diabetes and/or Ch deprivation on the activities of acetylcholinesterase (AChE) and two important adenosine triphosphatases, namely Na(+),K(+)-ATPase and Mg(2+)-ATPase. Male adult Wistar rats were divided into four main groups, as follows: control (C), diabetic (D), Ch-deprived (CD), and Ch-deprived diabetic (D+CD). Deprivation of Ch was provoked through the administration of Ch-deficient diet. Both the induction of diabetes and the beginning of dietary-mediated provoking of Ch-deprivation occurred at the same day, and rats were killed by decapitation after 30 days (1 month; groups C1, D1, CD1 and D1+CD1) and 60 days (2 months; groups C2, D2, CD2 and D2+CD2, respectively). The adult rat brain AChE activity was found to be significantly increased by both diabetes (+10%, p < 0.001 and +11%, p < 0.01) and Ch-deprivation (+19%, p < 0.001 and +14%, p < 0.001) when compared to the control group by the end of the first (C1) and the second month (C2), respectively. However, the Ch-deprived diabetic rats' brain AChE activity was significantly altered only after a 60-day period of exposure, resulting in a +27% increase (D2+CD2 vs. C2, p < 0.001). Although the only significant change recorded in the brain Na(+),K(+)-ATPase activity after the end of the first month is attributed to Ch-deprivation (+21%, p < 0.05, CD1 vs. C1), all groups of the second month exhibited a statistically significant decrease in brain Na(+),K(+)-ATPase activity (-24%, p < 0.01, D2 vs. C2; -21%, p < 0.01, CD2 vs. C2; -22%, p < 0.01, D2+CD2 vs. C2). As concerns Mg(2+)-ATPase, the enzyme's activity demonstrates no significant changes, with the sole exception of the D2+CD2 group (+21%, p < 0.05, D2+CD2 vs. C2). In addition, statistically significant time-dependent changes concerning the brain Mg(2+)-ATPase activity were recorded within the diabetic (p < 0.05, D2 vs. D1) and the Ch-deprived (p < 0.05, CD2 vs. CD1) rat groups. Our data indicate that Ch-deprivation seems to be an undesirable background for the above-mentioned enzymatic activities under untreated diabetes, in a time-evolving way. Further studies on the issue should focus on a region-specific reevaluation of these crucial enzymes' activities as well as on the possible oxidative mechanisms involved. PMID- 20838866 TI - Evidence that 2-methylacetoacetate induces oxidative stress in rat brain. AB - In the present study we investigated the effects of 2-methylacetoacetate (MAA) and 2-methyl-3-hydroxybutyrate (MHB), the major metabolites accumulating in mitochondrial 2-methylacetoacetyl-CoA thiolase (KT) and 2-methyl-3-hydroxybutyryl CoA dehydrogenase (MHBD) deficiencies, on important parameters of oxidative stress in cerebral cortex from young rats. We verified that MAA induced lipid peroxidation (increase of thiobarbituric acid-reactive substances (TBA-RS) and chemiluminescence values), whereas MHB did not alter these parameters. MAA induced increase of TBA-RS levels was fully prevented by free radical scavengers, indicating that free radicals were involved in this effect. Furthermore, MAA, but not MHB, significantly induced sulfhydryl oxidation, implying that this organic acid provokes protein oxidative damage. It was also observed that MAA reduced GSH, a naturally-occurring brain antioxidant, whereas MHB did not change this parameter. Furthermore, the decrease of GSH levels caused by MAA was not due to a direct oxidative action, since this organic acid did not alter the sulfhydryl content of a commercial solution of GSH in a cell free medium. Finally, MAA and MHB did not raise nitric oxide production. The data indicate that MAA induces oxidative stress in vitro in cerebral cortex. It is presumed that this pathomechanism may be involved in the brain damage found in patients affected by KT deficiency. PMID- 20838867 TI - Effects of sphingosine-1-phosphate on acute contractile heart failure (ACHF). PMID- 20838868 TI - Two types of independent bursting mechanisms in inspiratory neurons: an integrative model. AB - The network of coupled neurons in the pre-Botzinger complex (pBC) of the medulla generates a bursting rhythm, which underlies the inspiratory phase of respiration. In some of these neurons, bursting persists even when synaptic coupling in the network is blocked and respiratory rhythmic discharge stops. Bursting in inspiratory neurons has been extensively studied, and two classes of bursting neurons have been identified, with bursting mechanism depends on either persistent sodium current or changes in intracellular Ca(2+), respectively. Motivated by experimental evidence from these intrinsically bursting neurons, we present a two-compartment mathematical model of an isolated pBC neuron with two independent bursting mechanisms. Bursting in the somatic compartment is modeled via inactivation of a persistent sodium current, whereas bursting in the dendritic compartment relies on Ca(2+) oscillations, which are determined by the neuromodulatory tone. The model explains a number of conflicting experimental results and is able to generate a robust bursting rhythm, over a large range of parameters, with a frequency adjusted by neuromodulators. PMID- 20838869 TI - Rethinking sexual initiation: pathways to identity formation among gay and bisexual Mexican male youth. AB - The topic of same-sex sexual initiation has generally remained understudied in the literature on sexual identity formation among sexual minority youth. This article analyzes the narratives of same-sex sexual initiation provided by 76 gay and bisexual Mexican immigrant men who participated in interviews for the Trayectos Study, an ethnographic study of sexuality and HIV risk. These participants were raised in a variety of locations throughout Mexico, where they also realized their same-sex attraction and initiated their sexual lives with men. We argue that Mexican male same-sex sexuality is characterized by three distinct patterns of sexual initiation--one heavily-based on gender roles, one based on homosociality, and one based on object choice--which inform the men's interpretations regarding sexual roles, partner preferences, and sexual behaviors. We analyzed the social factors and forms of cultural/sexual socialization that lead sexual minority youth specifically to each of these three patterns of sexual initiation. Our findings confirm the importance of studying same-sex sexual initiation as a topic in its own right, particularly as a tool to gain a greater understanding of the diversity of same-sex sexual experiences and sexual identities within and among ethnic/cultural groups. PMID- 20838870 TI - Sex parties among urban MSM: an emerging culture and HIV risk environment. AB - Private sex parties are an emerging risk environment for HIV among men who have sex with men (MSM). In 2009, 103 participants who reported attending at least one sex party in Massachusetts in the prior 12 months completed an in-depth, interviewer-administered quantitative assessment. Multivariable logistic regression analyses were conducted to examine associations with having engaged in one or more serodiscordant unprotected anal sex (SDUAS) acts at the most recent sex party attended. Nearly one-third (32%) of the sample reported engaging in SDUAS at the most recent sex party attended. Adjusting for age, race/ethnicity, and educational attainment, variables associated with an increased odds of engaging in SDUAS at the most recent sex party were: total number of unprotected anal receptive sex acts at sex parties in the past 12 months, self-perception of being at-risk for transmitting or acquiring HIV, and sexual sensation seeking. Examined in the same model, if condoms were provided/available at the most recent sex party attended, participants were at a decreased odds of engaging in SDUAS at that sex party. The majority (80%) expressed an interest in HIV prevention activities for MSM who attend sex parties. HIV prevention interventions are needed to reach MSM who attend sex parties and should take into account individual and contextual factors that may contribute to sexual risk. Environmental factors in the sex party setting, in particular the presence and availability of condoms, may potentially mitigate individual-level factors such as unprotected anal sex. PMID- 20838872 TI - A framework for incorporating dyads in models of HIV-prevention. AB - Although HIV is contracted by individuals, it is typically transmitted in dyads. Most efforts to promote safer sex practices, however, focus exclusively on individuals. The goal of this paper is to provide a theoretical framework that specifies how models of dyadic processes and relationships can inform models of HIV-prevention. At the center of the framework is the proposition that safer sex between two people requires a dyadic capacity for successful coordination. According to this framework, relational, individual, and structural variables that affect the enactment of safer sex do so through their direct and indirect effects on that dyadic capacity. This dyadic perspective does not require an ongoing relationship between two individuals; rather, it offers a way of distinguishing between dyads along a continuum from anonymous strangers (with minimal coordination of behavior) to long-term partners (with much greater coordination). Acknowledging the dyadic context of HIV-prevention offers new targets for interventions and suggests new approaches to tailoring interventions to specific populations. PMID- 20838871 TI - A dynamic social systems model for considering structural factors in HIV prevention and detection. AB - We present a model for HIV-related behaviors that emphasizes the dynamic and social nature of the structural factors that influence HIV prevention and detection. Key structural dimensions of the model include resources, science and technology, formal social control, informal social influences and control, social interconnectedness, and settings. These six dimensions can be conceptualized on macro, meso, and micro levels. Given the inherent complexity of structural factors and their interrelatedness, HIV prevention interventions may focus on different levels and dimensions. We employ a systems perspective to describe the interconnected and dynamic processes of change among social systems and their components. The topics of HIV testing and safer injection facilities (SIFs) are analyzed using this structural framework. Finally, we discuss methodological issues in the development and evaluation of structural interventions for HIV prevention and detection. PMID- 20838873 TI - Association between body mass index and mortality in patients with glioblastoma mutliforme. AB - PURPOSE: To examine the association between obesity and survival in patients with glioblastoma mutliforme (GBM) METHODS: Using a prospective design, 1,259 patients with previously untreated GBM were recruited between 1991 and 2008. Height and weight were self-reported or abstracted from medical records at study entry and used to calculate body mass index (BMI) [weight (kg)/[height (m)](2). Cox proportional models were used to estimate the risk of death associated with BMI as a continuous variable or categorized using established criteria (normal weight, 18.5-24.9 kg/m(2); overweight, 25.0-29.9 kg/m(2); obese, >= 30.0 kg/m(2)). RESULTS: Median follow-up was 40 months, and 1,069 (85%) deaths were observed during this period. For all patients, minimal adjusted analyses indicated no significant association between BMI treated as a continuous variable and survival. Compared with patients with a BMI 18.5-24.9 kg/m(2), the minimally adjusted HR for overall survival was 1.08 (95% CI, 0.94-1.24) for a BMI 25-29.9 kg/m(2) and 1.08 (95% CI, 0.91-28) for a BMI >= 30.0 kg/m(2). After additional adjustment for adjuvant therapy, the HR for those with a BMI of 25.0-29.9 kg/m(2) was 1.14 (95% CI, 0.99-1.32) and 1.09 (95% CI, 0.91-1.30) for those with a BMI >= 30.0 kg/m(2). No significant interactions were revealed for BMI and any demographic variables. CONCLUSION: BMI was not associated with survival in newly diagnosed and previously untreated patients with GBM. Further research investigating the prognostic significance of alternative, quantitative measures of body habitus, and functional performance are required. PMID- 20838874 TI - Effect of cryopreservation on acetylation patterns of lysine 12 of histone H4 (acH4K12) in mouse oocytes and zygotes. AB - PURPOSE: to determine the effect of cryopreservation on acH4K12 in oocytes and their respective zygotes. METHODS: AcH4K12 in fresh or vitrified-warmed oocytes and their respective zygotes at 70 min-12 h post-fertilization were assessed using fluorescent staining. RESULTS: 1. AcH4K12 levels increased significantly in vitrified oocytes compared to controls. 2. Respective zygotes derived from vitrified oocytes had abnormal chromatin distribution or acH4K12 patterns before and after pronuclear formation. CONCLUSION: Cryopreservation alters AcH4K12 patterns in oocytes, which subsequently affect the chromatin distribution and acH4K12 in fertilized oocytes. PMID- 20838875 TI - Longitudinal pathways between political violence and child adjustment: the role of emotional security about the community in Northern Ireland. AB - Links between political violence and children's adjustment problems are well documented. However, the mechanisms by which political tension and sectarian violence relate to children's well-being and development are little understood. This study longitudinally examined children's emotional security about community violence as a possible regulatory process in relations between community discord and children's adjustment problems. Families were selected from 18 working class neighborhoods in Belfast, Northern Ireland. Participants (695 mothers and children, M = 12.17, SD = 1.82) were interviewed in their homes over three consecutive years. Findings supported the notion that politically-motivated community violence has distinctive effects on children's externalizing and internalizing problems through the mechanism of increasing children's emotional insecurity about community. Implications are considered for understanding relations between political violence and child adjustment from a social ecological perspective. PMID- 20838876 TI - The role of heavy alcohol use in the developmental process of desistance in dating aggression during adolescence. AB - The current study examined the role of heavy alcohol use in the developmental process of desistance in physical dating aggression during adolescence. Using longitudinal data spanning grades 8 through 12 we tested the hypotheses that (a) higher levels of early heavy alcohol use would be associated with decreased deceleration from dating aggression during late adolescence and (b) higher levels of heavy alcohol use during time-points in late adolescence would be contemporaneously associated with elevated levels of dating aggression at those same time points. Contrary to expectations, findings indicate that the effects of both early and continuing heavy alcohol use on dating aggression were strong during early adolescence but tended to diminish over time. Unexpectedly, the contemporaneous effects of alcohol use on dating aggression were stronger in the spring than in the fall semesters. Implications for prevention and for understanding developmental relations between the two behaviors are discussed. PMID- 20838878 TI - A high prevalence of BRCA1 mutations among breast cancer patients from the Bahamas. AB - The Bahamas is a group of islands in the Caribbean with a high incidence of early onset breast cancer. In isolated populations, the identification of founder mutations in cancer predisposing genes may facilitate genetic testing and counseling. To date, six distinct BRCA1 mutations have been found in patients from cancer families from the Bahamas. The frequencies of these mutant alleles have not been measured in a large series of unselected breast cancer patients from Bahamas. We studied 214 Bahamian women with invasive breast cancer, unselected for age or family history of cancer. All patients were screened for six mutations in the BRCA1 gene that have previously been reported in cancer patients from the Bahamas. A mutation was identified in 49 of the 214 breast cancer patients (23%). The mutation frequency was particularly high in women diagnosed before age 50 (33%) in women with a first-degree relative with breast or ovarian cancer (41%) and in women with bilateral breast cancer (58%). Approximately 23% of unselected cases of breast cancer in the Bahamian population are attributable to a founder mutation in the BRCA1 gene-this is the highest reported mutation prevalence for any country studied to date. Genetic testing for these mutations is advisable for all women diagnosed with breast cancer in the Bahamas. PMID- 20838879 TI - Bone mineral density and risk of postmenopausal breast cancer. AB - To determine if higher bone mineral density (BMD) is a risk factor for breast cancer in women age 50 years and older. 37,860 women >= 50-year old with no previous breast cancer diagnosis had baseline BMD assessment between January 1999 and December 2007. Cox proportional hazards models were created for time to a new breast cancer as a function of lumbar spine or femoral neck BMD quartile (1st = lowest as reference) with adjustment for relevant covariates. A secondary analysis was performed to look for an association with estrogen receptor-positive (ER-positive) breast cancers. 794 invasive and in situ breast cancers (484 ER positive) occurred with a median follow up of 5.4 years. Increased breast cancer risk was seen for the 3rd and 4th quartiles of lumbar spine BMD with hazard ratios (HRs) of 1.26 (95% CI, 1.01-1.58) and 1.45 (95% CI, 1.16-1.81), respectively and for the 3rd quartile of femoral neck BMD with a HR of 1.33 (95% CI, 1.07-1.64). A test for linear trend showed that lumbar spine BMD (P < 0.001) and femoral neck BMD (P = 0.04) were associated with increased risk. Higher lumbar spine BMD was also associated with increased risk of ER-positive breast cancer with HR of 1.45 (95% CI, 1.08-1.94), and 1.68 (95% CI, 1.24-2.27) for women in the 2nd and 4th quartiles, respectively. A test for linear trend showed lumbar spine BMD was associated with increasing risk of ER-positive breast cancer (P = 0.003). Increased ER-positive breast cancer risk was seen for the 3rd quartile of femoral neck BMD with a HR of 1.43 (95% CI, 1.08-1.89). Higher lumbar spine and femoral neck BMD are associated with higher risk of breast cancer in women >=50-year old. Lumbar spine and femoral neck BMD are associated with increased risk of ER-positive breast cancer. PMID- 20838877 TI - Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1. AB - It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D2 is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D2 internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12 NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the cAMP/PKA pathway, with decreased levels of cAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D2 and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/cAMP signaling pathway. Identification of the cellular mechanisms linking NCS 1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders. PMID- 20838880 TI - A critical time for medical education: the perils of competence-based reform of the curriculum. AB - Rapid expansion in scientific knowledge, changes in medical practice, and greater demands from patients and society necessitate reform of the medical curriculum. In recognition of this, medical educators across the world have recommended the adoption of competence-based education. This is intended to increase the rigour and relevance of the curriculum, move students beyond a focus on the memorisation and regurgitation of scientific facts, and better enable them to understand scientific principles and apply them to the practice of medicine. Experience from 40 years' use of competence-based curricula across the world suggests that the uncritical application of this approach to the medical curriculum may not achieve its intended aims. There are valuable lessons to be learnt from the history of competence-based education. By taking on board these lessons, confronting the pitfalls of this approach, and devising new and creative solutions to the problems inherent in this methodology, medical educators can better achieve their aim of providing a strong foundation for the practice of medicine in the twenty first century. It is only through such a strategy-rather than the uncritical adoption of this educational approach-that we will have real movement and progress both in competence-based education in general, and in its applications to medicine in particular. PMID- 20838881 TI - Significance of hyponatremia in heart failure. AB - Heart failure is one of the most common, costly, disabling and growing diseases (McMurray and Pfeffer in Lancet 365(9474):1877-1889, 2005). Hyponatremia, conventionally defined as a serum-sodium concentration equal or less than 135 mmol/l (American Heart Association in Heart disease and stroke statistics--2007 update. American Heart Association, Dallas, 2007; Stewart et al. in Eur J Heart Fail 4:361-371, 2002), is a common phenomenon in patients with heart failure, with an incidence of 20-25% (Krumholz et al. in Arch Intern Med 157:e99-e104, 1997; Rosamond et al. in Circulation 117(4):e25-e146, 2008; Adrogue and Madias in N Engl J Med 342:1581-1589, 2000) and seems to be of prognostic importance in patients with heart failure (Luca et al. in Am J Cardiol 96:19L-23L, 2005; Gheorghiade et al. in Eur Heart J 28:980-988, 2007; Gheorghiade et al. in Arch Intern Med 167:1998-2005, 2007). So far treatment strategies have been limited and burdened by side effects. The development of hyponatremia in the setting of heart failure is related to the arginine vasopressin (AVP) dysregulation. Thus, AVP receptor antagonists are a promising approach to treatment. However, several questions remain: whether there is a cause-and-effect mechanism, if the correction of hyponatremia improves outcomes, and defining the specific cut-off level of serum-sodium that should be used to define hyponatremia. In this review, we aim to summarize the literature on hyponatremia in patients with heart failure within several aspects: incidence in clinical trials and registries, prognostic value, underlying mechanisms, therapeutic options, and possible future perspectives. PMID- 20838882 TI - Effect of the width of the herbicide strip on mite dynamics in apple orchards. AB - Herbicide strips are used in apple orchards to promote tree growth and survival, to increase yield and to reduce the risk of rodent damage to tree bark. However, herbicide strips, particularly wider ones, may cause problems including soil erosion, reduced organic matter, leaching of nitrates into ground water and increased incidence of plant diseases and pests, including two-spotted spider mites, Tetranychus urticae Koch. In this 2 year study we monitored mite dynamics in apple trees and used sticky bands on tree trunks to determine rates of T. urticae immigration into Nova Spy apple trees in plots with wide (2 m) or narrow (0.5 m) herbicide strips. Use of wider herbicide strips promoted two risk factors that could trigger outbreaks of tetranychid mites. First, concentrations of leaf N in apple trees were higher and those of P and K were lower with the wide strips. Such changes in nutritional quality of leaves would increase the potential for more rapid population growth of T. urticae, and to a lesser extent, the European red mite, Panonychus ulmi (Koch). Second, there were higher rates of T. urticae immigration from the ground cover vegetation into the trees. In 2006, and for most of 2007, densities of T. urticae were higher with wide herbicide strips, whereas densities of P. ulmi were not enhanced. However, by late August to early September in 2007, densities of both tetranychids were lower with wide herbicide strips. This is because both risk factors were counterbalanced, and eventually negated, by the enhanced action of phytoseiid predators, mostly Typhlodromus pyri Scheuten. From July through September 2006, ratios of phytoseiids to tetranychids were always several-fold lower with wide herbicide strips but in 2007, from mid-July onwards, predator-prey ratios were usually several-fold higher with wide strips. However, this numerical response of phytoseiids to prey density can only occur where the pesticide program in orchards is not too harsh on phytoseiids. Hence the impact of width of herbicide strip is contingent on the composition and size of the phytoseiid complex and the impact of pesticides on predation. PMID- 20838883 TI - Molecular detection of establishment and geographical distribution of Brazilian isolates of Neozygites tanajoae, a fungus pathogenic to cassava green mite, in Benin (West Africa). AB - Diagnostic PCR with two specific primer pairs (NEOSSU and 8DDC) were used to monitor the establishment and geographical distribution of Brazilian isolates of Neozygites tanajoae Delalibera, Hajek and Humber (Entomophthorales: Neozygitaceae) released in Benin for the biological control of the cassava green mite, Mononychellus tanajoa (Bondar) (Acari: Tetranychidae). A total of 141 cassava fields were visited and samples of M. tanajoa suspected to be infected by N. tanajoae were collected in 60 fields distributed between the coastal Southern Forest Mosaic (SFM) and the Northern Guinea Savanna (NGS) zones of Benin, West Africa. Analysis of DNA samples of dead mites using the species specific NEOSSU primers revealed the presence of N. tanajoae in 46 fields. The second country specific pair of primers 8DDC revealed the presence of Brazilian isolates of N. tanajoae in 36 fields, representing 78.3% of fields positive for N. tanajoae. Brazilian isolates occurred from SFM to NGS zones in Benin, however, they were concentrated in fields located within former release zones (e.g. Department of Oueme in the South and Borgou in the North). In contrast, the indigenous African isolates of N. tanajoae were evenly distributed in the sub-humid and humid savannah zones of the country. The mean infection rate of M. tanajoa with indigenous isolates of N. tanajoae was relatively low (5.3%) compared to Brazilian isolates (28%), indicating a higher biocontrol potential of the latter. This first post-release monitoring using PCR techniques showed that the Brazilian strains of N. tanajoae is well established in Benin and spread effectively in this area. PMID- 20838884 TI - Population growth and allergen accumulation of Dermatophagoides pteronyssinus cultured at 20 and 25 degrees C. AB - The house dust mites, Dermatophagoides pteronyssinus and D. farinae are cultured commercially and in research laboratories and material is harvested from these cultures to make extracts that are used for diagnosis, immunotherapy and research. Temperature and other climatic conditions can influence population growth rates, dynamics of allergen production, and the associated endotoxin, enzyme and protein levels of the mite material harvested from these cultures. Here we determined how temperature affected these parameters. Dermatophagoides pteronyssinus was cultured at 20 and 25 degrees C at 75% relative humidity, and at 2-week intervals the concentrations of mites, Der p 1 and Der p 2 allergens, endotoxin, and selected enzymes were determined. Mite density increased exponentially but growth rate and final population density were greater at 25 degrees C compared to 20 degrees C. The combined allergen (Der p 1 + Der p 2) concentrations accumulated in the cultures at about the same rate at both temperatures. However, individual Der p 1 and Der p 2 accumulation rates varied independently at the two temperatures. Der p 1 accumulated faster at 20 degrees C whereas Der p 2 accumulated faster at 25 degrees C. The amount of Der p 1 in whole cultures was greater than the amount of Der p 2. The concentration of allergen for washed mites harvested from the cultures was much less than for the whole cultures. Our study demonstrated that temperature is an important factor in population growth and the dynamics of allergen production in cultured mites. PMID- 20838885 TI - Leaf volatile emissions of Betula pendula during autumn coloration and leaf fall. AB - Deciduous trees remobilize the nitrogen in leaves during the process of autumn coloration, thus providing a high quality food source for aphids preparing to lay over-wintering eggs. It has been suggested that aphids may use volatile organic compounds (VOCs) to: (a) select leaves where nutrient remobilization has started and induced defenses are reduced; and (b) detect the time of leaf abscission. We analyzed VOCs emitted by the foliage of Betula pendula Roth. during autumn coloration and from leaf litter just after leaf fall. We tested the hypothesis that costly, photosynthesis-related terpenes and other herbivore-induced VOCs related to attraction of aphid parasitoids and predators are reduced during the coloration process. We also investigated if the VOC emission profile of abscising leaves is different from that of early stage yellowing leaves. Enemy-luring compounds (E)-beta-ocimene, linalool, and (E)-4,8-dimethyl-1,3,7-nonatriene (DMNT) were emitted only from the green foliage. Methyl salicylate (MeSa), known to recruit predatory bugs and attract migrant aphids, was emitted until the first stage of color change. Cis-3-hexenol, an indicator of cellular disintegration, became dominant in the emissions from abscising leaves and from fresh leaf litter. We discuss the ecological significance of the observed changes in birch leaf VOC profiles during the process of autumn senescence. PMID- 20838886 TI - Oxidative stress and DNA damage in the earthworm Eisenia fetida induced by toluene, ethylbenzene and xylene. AB - Superoxide dismutase (SOD), guaiacol peroxidase (POD), catalase (CAT), and the comet assay (SCGE) were used as biomarkers to evaluate the oxidative stress and genotoxicity of toluene, ethylbenzene and xylene in earthworms (Eisenia fetida). The results indicated that the exposure of the three pollutants caused a stress response of the three enzymes, an approximate bell-shaped change (a tendency of inducement firstly and then inhibition with increasing concentrations of the pollutants) was mostly found. The three enzymes tested differed in their sensitivity to different pollutants. While the activity of POD was not significantly changed within the concentration range, the concentration thresholds for significant (P < 0.05) responses to toluene based on SOD and CAT were 5 mg kg(-1), respectively. Similarly, the concentration thresholds for significant (P < 0.05) responses to ethylbenzene based on CAT and POD were 10 and 5 mg kg(-1), respectively, while the activity of SOD was not significantly changed within the concentration range. Significant responses to xylene based on CAT and POD were 5 mg kg(-1), respectively, while the activity of SOD was significantly (P < 0.05) induced at 10 mg kg(-1). The SCGE assay results showed that these three pollutants could significantly (P < 0.01) induce DNA damage in earthworms and the clear dose-dependent relationships were displayed, indicating potential genotoxic effects of toluene, ethylbenzene, and xylene on E. fetida. The inducement of DNA damage may be attributed to the oxidative attack of toluene, ethylbenzene, and xylene. Toluene seemed to be more genotoxic as it could induce the higher extent of DNA damage than ethylbenzene and xylene. The results suggest that the SCGE assay of earthworms is simple and efficient for diagnosing the genotoxicity of pollutants in terrestrial environment. PMID- 20838887 TI - Proline-rich cytokine from neurosecretory granules: a new natural substrate for dipeptidyl peptidase IV. AB - A proline-rich cytokine from neurosecretory granules of bovine neurohypophysis, 15 amino acids containing PRP-1 (Ala-Gly-Ala-Pro-Glu-Pro-Ala-Glu-Pro-Ala-Gln-Pro Gly-Val-Tyr), had been demonstrated as a unique regulator of activity of neurons, strong antibacterial agent, and mediator of the hypothalamus-neurohypophysis-bone marrow-thymus axis, which participates in hematopoietic stem cells differentiation. In the present work it was shown that this neuropeptide represents a new natural substrate for Dipeptidyl Peptidase IV (DPPIV). The time dependent increase of primary amines quantity in the assay mixture of PRP-1 and DPPIV has been observed allowing to conclude, that DPPIV catalyses the enzymatic reaction of PRP-1 cleavage. The amount of primary amines in the assay mixtures was evaluated using o-phtaldialdehyde dye. The gel-filtration and paper electrophoresis analyses proved this conclusion. The catalytic parameters of catalyzed by DPPIV enzymatic reaction of PRP-1 cleavage were determined as: V(max) = 1.27 +/- 0.11 nmol/min and K(m) = 0.38 +/- 0.1 mM. PMID- 20838888 TI - Phylogeny of the ascomycetous yeasts and the renaming of Pichia anomala to Wickerhamomyces anomalus. AB - In this review, the phylogeny of the ascomycetous yeasts is discussed, with emphasis on the genus Pichia and its synonym Hansenula. The genus Pichia, as defined from phenotype, had nearly 100 assigned species, but the number of species has been reduced to 20 following phylogenetic circumscription on Pichia membranifaciens, the type species of the genus. The remaining species of Pichia have been reassigned to 20 different genera, many of which are newly described, such as Wickerhamomyces. The reason for reclassification of Pichia anomala in the genus Wickerhamomyces is discussed. PMID- 20838889 TI - The meaning of community rehabilitation for schizophrenia patients in Israel. AB - In the year 2000, a law was passed in Israel, known as the Law for Community Rehabilitation of the Mentally Disabled. The Community Rehabilitation Law was intended to provide a "package of services" that will allow people who suffer from mental illness and were hospitalized, to return to their community. This research, by using qualitative research methods, tried to understand and explore the meaning of rehabilitation and return to the community under the new legislative setting from the viewpoint and experiences of the participants themselves. Fifteen schizophrenic patients were interviewed in this research. All the participants were institutionalized in the past and released for rehabilitation in the community under Israel's new act. The data were collected after all interviews were recorded and analyzed. The qualitative data analysis exposed a continuous process of four conceptual categories: (1) Viewing institutionalization as transformation from the "normal" to the "abnormal"; (2) Viewing institutionalization as a process moving from the "abnormal" back to the "normal"; (3) Viewing the return to the community as "re-birth"; and finally, (4) Viewing community-based rehabilitation as reality, which enables normality alongside mental illness. This research presents a theoretical model that provides the meanings and experiences of the participants as a continuity, in which the whole process of moving from the community to the institution and back to the community is represented as one continuous process integrated in each other. Within this continuing process, the community-based rehabilitation legislation serves as a key component, well-integrated within the whole continuum that allows people with mental illness to return to "normality" within the community. PMID- 20838890 TI - Fecal elastase: a useful test for pancreatic insufficiency? PMID- 20838891 TI - The effects of salinity on photosynthesis and growth of the single-cell C4 species Bienertia sinuspersici (Chenopodiaceae). AB - Recent research on the photosynthetic mechanisms of plant species in the Chenopodiaceae family revealed that three species, including Bienertia sinuspersici, can carry out C(4) photosynthesis within individual photosynthetic cells, through the development of two cytoplasmic domains having dimorphic chloroplasts. These unusual single-cell C(4) species grow in semi-arid saline conditions and have semi-terete succulent leaves. The effects of salinity on growth and photosynthesis of B. sinuspersici were studied. The results show that NaCl is not required for development of the single-cell C(4) system. There is a large enhancement of growth in culture with 50-200 mM NaCl, while there is severe inhibition at 400 mM NaCl. With increasing salinity, the carbon isotope values (delta(13)C) of leaves increased from -17.3(o)/(oo) (C(4)-like) without NaCl to 14.6(o)/(oo) (C(4)) with 200 mM NaCl, possibly due to increased capture of CO(2) from the C(4) cycle by Rubisco and reduced leakiness. Compared to growth without NaCl, leaves of plants grown under saline conditions were much larger (~2 fold) and more succulent, and the leaf solute levels increased up to ~2000 mmol kg solvent(-1). Photosynthesis on an incident leaf area basis (CO(2) saturated rates, and carboxylation efficiency under limiting CO(2)) and stomatal conductance declined with increasing salinity. On a leaf area basis, there was some decline in Rubisco content with increasing salinity up to 200 mM NaCl, but there was a marked increase in the levels of pyruvate, Pi dikinase, and phosphoenolpyruvate carboxylase (possibly in response to sensitivity of these enzymes and C(4) cycle function to increasing salinity). The decline in photosynthesis on a leaf area basis was compensated for on a per leaf basis, up to 200 mM NaCl, by the increase in leaf size. The influence of salinity on plant development and the C(4) system in Bienertia is discussed. PMID- 20838892 TI - Self-reported asthma in Chaldeans, Arabs, and African Americans: factors associated with asthma. AB - Although the prevalence of asthma is increasing worldwide, there are striking, and largely unexplained differences across various racial and ethnic groups. The current study looks at the prevalence of asthma and risk factors between Chaldeans, Arabs, and African Americans. We used Health Assessment Survey data representing 3,136 respondents. Prevalence across the three ethnic groups were compared using unadjusted and adjusted odds ratios, accounting for multiple risk factors. There were significant socio-demographic differences across all ethnic groups. Asthma prevalence was significantly lower in Arabs (9.4%) and Chaldeans (5.4%) than in Non-Middle Eastern Whites (14.4%). African American prevalence was 14.4%. The significantly lower prevalence of asthma among Chaldean and Arabs, as compared to African Americans, were not explained by traditional risk factors included in our models. We therefore, suggest that future studies should explore the possible role of ethnic-specific differences in gene * environmental interactions in the precipitation and/or exacerbation of asthma. PMID- 20838894 TI - Perceptions of social and environmental support for healthy eating and physical activity in rural southern churches. AB - The influence of church environments on healthy eating and physical activity was explored through in-depth interviews with rural adults aged 50-70 (n = 60). Data were analyzed using a constant comparative approach, with an emphasis on noting similarities and differences between African American and predominantly white churches. Findings suggest that church-based nutrition and exercise programs were rare, and existing recreational facilities were geared toward younger members. The majority of church leaders did not talk about nutrition or physical activity, but social support from church friends for healthy eating and physical activity was fairly common. Despite barriers to establishing healthy environments in church settings, churches are rich in social support that could be tapped to promote healthy behavior. PMID- 20838895 TI - Negotiating religious beliefs in a medical setting. AB - This manuscript studies in detail, following a discourse analytical approach, medical consultations in which a patient's religious belief does not allow blood transfusion to be administered. The patient is a young Jehovah's Witness suffering myeloid leukaemia who is being treated in a Catholic cancer hospital where the practice of blood transfusion forms part of the standard protocol to treat the disease. The consultations under analysis take place in a Chilean cancer clinic where mainly the oncologist and a Jehovah's Witness Representative (JWR) present discuss and negotiate expert information on the substitute methods to be used. The exchange dynamics of the consultations differ from the usual visits where the medical knowledge and expertise is primarily in the hands of the medical practitioner. In these encounters, the JWR shares vital information with the oncologist providing the basis of the treatment to be used. This shifting of the balance of power-which could have been a cause of tension in the visit and a contributing factor in the disruption of communication-has instead brought light to the encounter where the negotiated treatment has been achieved with relative ease. The patient's future is in the hands of the oncologist and the JWR, and their successful negotiation of treatment has made it possible to cater for the particular needs of a JW patient. Sharing different medical practices has not been an obstacle, but an opportunity to find out ways to deliver equity access and well-informed practices to a non-conventional patient. PMID- 20838896 TI - Hospitable hospitals in a diverse society: from chaplains to spiritual care providers. AB - The chaplain's role in health care services has changed profoundly within the contexts of managerial and fiscal constraints, and increasingly pluralistic and secularized societies. Drawing from a larger study that examined religious and spiritual plurality in health care, we present findings regarding the contributions of chaplains or spiritual care providers (SCPs) as they are referred to more recently, in Canadian institutional health care contexts. Qualitative analyses of interviews with 14 employed SCPs and 7 volunteers provided insights about legitimizing and crafting the role of SPCs, becoming part of the health care team, and brokering diversity. Implications are discussed in relation to role clarification and policy development for truly hospitable health care. PMID- 20838897 TI - Religion and health among older Mexican Americans: exploring the influence of making mandas. AB - A manda is a religious quid pro quo whereby an older Mexican American promises to perform a religious act if the Virgin or one of the saints grants a request. The purpose of this study is to see whether making mandas is associated with health among older Mexican Americans. Findings from the study model suggest that making mandas is associated with a greater sense of personal control, and more personal control is associated, in turn, with better health. PMID- 20838898 TI - Drosophila Chk2 and p53 proteins induce stage-specific cell death independently during oogenesis. AB - In Drosophila, the checkpoint protein-2 kinase (DmChk2) and its downstream effector protein, Dmp53, are required for DNA damage-mediated cell cycle arrest, DNA repair and apoptosis. In this study we focus on understanding the function of these two apoptosis inducing factors during ovarian development. We found that expression of Dmp53, but not DmChk2, led to loss of ovarian stem cells. We demonstrate that expression of DmChk2, but not Dmp53, induced mid-oogenesis cell death. DmChk2 induced cell death was not suppressed by Dmp53 mutant, revealing for the first time that in Drosophila, over-expression of DmChk2 can induce cell death which is independent of Dmp53. We found that over-expression of caspase inhibitors such as DIAP1, p35 and p49 did not suppress DmChk2- and Dmp53-induced cell death. Thus, our study reveals stage-specific effects of Dmp53 and DmChk2 in oogenesis. Moreover, our results demonstrate that although DmChk2 and Dmp53 affect different stages of ovarian development, loss of ovarian stem cells by p53 expression and mid-oogenesis cell death induced by DmChk2 do not require caspase activity. PMID- 20838900 TI - First long term in vivo study on subdurally implanted micro-ECoG electrodes, manufactured with a novel laser technology. AB - A novel computer aided manufacturing (CAM) method for electrocorticography (ECoG) microelectrodes was developed to be able to manufacture small, high density microelectrode arrays based on laser-structuring medical grade silicone rubber and high purity platinum. With this manufacturing process, we plan to target clinical applications, such as presurgical epilepsy monitoring, functional imaging during cerebral tumor resections and brain-computer interface control in paralysed patients, in the near future. This paper describes the manufacturing, implantation and long-term behaviour of such an electrode array. In detail, we implanted 8-channel electrode arrays subdurally over rat cerebral cortex over a period of up to 25 weeks. Our primary objective was to ascertain the electrode's stability over time, and to analyse the host response in vivo. For this purpose, impedance measurements were carried out at regular intervals over the first 18 weeks of the implantation period. The impedances changed between day 4 and day 7 after implantation, and then remained stable until the end of the implantation period, in accordance with typical behaviour of chronically implanted microelectrodes. A post-mortem histological examination was made to assess the tissue reaction due to the implantation. A mild, chronically granulated inflammation was found in the area of the implant, which was essentially restricted to the leptomeninges. Overall, these findings suggest that the concept of the presented ECoG-electrodes is promising for use in long-term implantations. PMID- 20838899 TI - Long-term observational, non-randomized study of enzyme replacement therapy in late-onset glycogenosis type II. AB - OBJECTIVES: Type II glycogenosis (GSDII) is a lysosomal storage disorder due to acid alpha-glucosidase (GAA) deficiency. Enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) has been demonstrated to be effective in the treatment of infantile forms of GSDII, but little information is available concerning late-onset phenotypes. Long-term follow-up studies are not available at present. The aim of this study was to evaluate the ERT long-term effects in late-onset GSDII. METHODS: Twenty-four patients, including 7 juveniles and 17 adults, received bi-weekly infusion of rhGAA (20 mg/kg) for at least 36 months. Clinical conditions, muscular function (6-min walking test, 6MWT; Walton scale, WS), respiratory function (vital capacity, VC; forced expiratory volume, FEV1; arterial pCO(2)), and muscle enzymes were assessed every 6 months. RESULTS: The 6MWT improved in both juvenile and adult patients (p = 0.01, p = 0.0002, respectively), as well as in patients with moderate to severe muscle function impairment (WS >3.5; p = 0.002). An overall improvement in WS was also observed (p = 0.0003). VC and FEV1 remained unchanged, while pCO(2) decreased (p = 0.017). Muscle enzymes decreased significantly (p < 0.0001). Two patients (8%) showed transient secondary events during ERT. CONCLUSIONS: Long-term ERT with rhGAA was shown to be safe, well tolerated, and effective in improving motor function and in stabilizing respiratory function in late-onset GSDII. The response pattern showed a progressive clinical improvement during the follow-up period in juvenile patients, while in adults it reached and maintained a plateau after the first year of treatment. PMID- 20838901 TI - Self-folding micropatterned polymeric containers. AB - We demonstrate self-folding of precisely patterned, optically transparent, all polymeric containers and describe their utility in mammalian cell and microorganism encapsulation and culture. The polyhedral containers, with SU-8 faces and biodegradable polycaprolactone (PCL) hinges, spontaneously assembled on heating. Self-folding was driven by a minimization of surface area of the liquefying PCL hinges within lithographically patterned two-dimensional (2D) templates. The strategy allowed for the fabrication of containers with variable polyhedral shapes, sizes and precisely defined porosities in all three dimensions. We provide proof-of-concept for the use of these polymeric containers as encapsulants for beads, chemicals, mammalian cells and bacteria. We also compare accelerated hinge degradation rates in alkaline solutions of varying pH. These optically transparent containers resemble three-dimensional (3D) micro Petri dishes and can be utilized to sustain, monitor and deliver living biological components. PMID- 20838902 TI - Integrated microbioreactor for culture and analysis of bacteria, algae and yeast. AB - We introduce a micro-scale bioreactor for automated culture and density analysis of microorganisms. The microbioreactor is powered by digital microfluidics (DMF) and because it is used with bacteria, algae and yeast, we call it the BAY microbioreactor. Previous miniaturized bioreactors have relied on microchannels which often require valves, mixers and complex optical systems. In contrast, the BAY microbioreactor is capable of culturing microorganisms in distinct droplets on a format compatible with conventional bench-top analyzers without the use of valves, mixers or pumps. Bacteria, algae and yeast were grown for up to 5 days with automated semi-continuous mixing and temperature control. Cell densities were determined by measuring absorbances through transparent regions of the devices, and growth profiles were shown to be comparable to those generated in conventional, macro-scale systems. Cell growth and density measurements were integrated in the microbioreactor with a fluorescent viability assay and transformation of bacteria with a fluorescent reporter gene. These results suggest that DMF may be a useful new tool in automated culture and analysis of microorganisms for a wide range of applications. PMID- 20838903 TI - Cell types can be distinguished by measuring their viscoelastic recovery times using a micro-fluidic device. AB - We introduce a simple micro-fluidic device containing an actuated flexible membrane, which allows the viscoelastic characterization of cells in small volumes of suspension by loading them in compression and observing the cell deformation in time. From this experiment, we can determine the characteristic time constant of recovery of the cell. To validate the device, two cell types known to have different cytoskeletal structures, 3T3 fibroblasts and HL60 cells, are tested. They show a substantially different response in the device and can be clearly distinguished on the basis of the measured characteristic recovery time constant. Also, the effect of breaking down the actin network, a main mechanical component of the cytoskeleton, by a treatment with Cytochalasin D, results in a substantial increase of the measured characteristic recovery time constant. Experimental variations in loading force, loading time, and surface treatment of the device also influence the measured characteristic recovery time constant significantly. The device can therefore be used to distinguish between cells with different mechanical structure in a quantitative way, and makes it possible to study changes in the mechanical response due to cell treatments, changes in the cell's micro-environment, and mechanical loading conditions. PMID- 20838904 TI - CAPN1 markers in three Argentinean cattle breeds: report of a new InDel polymorphism within intron 17. AB - In this study, the genotype distribution and allelic frequencies of CAPN1 (Calcium activated neutral protease) single nucleotide polymorphisms (SNPs) were analyzed taking advantage of the different genetic backgrounds provided by Hereford, Brahman and Braford cattle. We report a new insertion/deletion (InDel) polymorphism, consisting of a change of seven nucleotides for only one nucleotide (TCTGGGT -> C) within intron 17 of the CAPN1 gene. The segregation pattern of this polymorphism was analyzed together with the markers CAPN316, CAPN530 and CAPN4751 already described. The allele distribution of CAPN1 markers in the Braford crossbreed (3/8 Brahman 5/8 Hereford) is described for the first time. Four assays of allelic discrimination were designed: the tetra primer ARMS-PCR technique for genotyping the new InDel and the CAPN4751 marker, and a PCR-RFLP method for genotyping the markers CAPN316 and CAPN530. The genotypic and minor allele frequencies (MAFs) obtained showed that the InDel polymorphism does not provide redundant information to that already provided by the other CAPN1 markers and segregates differently between breeds, being a common SNP (MAF >= 0.05) in the herds with a high percentage of Bos indicus background. The high percentage of heterozygous individuals found in the Braford crossbreed for the markers assessed reveals enough genetic variation that could help to solve the tenderness problem of tropical-adapted cattle. PMID- 20838905 TI - A noninvasive [99mTc]DTPA SPECT/CT imaging methodology as a measure of lung permeability in a guinea pig model of COPD. AB - PURPOSE: The purposes of this study are (1) to develop an efficient aerosol inhalation system for the delivery of [(99m)Tc]DTPA aerosol into guinea pig airways with high uniformity for measuring lung clearance using SPECT/CT imaging, as a measure of lung permeability, and (2) to use [(99m)Tc]DTPA studies in guinea pig model of chronic obstructive pulmonary disease (COPD) to determine its usefulness in studying pathogenesis of COPD. PROCEDURE: We developed an aerosol delivery system and single-photon emission computed tomography (SPECT) imaging method to measure the pulmonary clearance rate in anesthetized guinea pigs. In this system, an 830-cc rebreather exposure chamber was filled with oxygen immediately before a 5 min [(99m)Tc]DTPA (4-5 mCi/mL) aerosol exposure. The rebreather included a top mounted AeroNeb micro pump nebulizer, a nose-only exposure tube, and rear evacuation port. An 830-cc rebreather exposure chamber was filled with oxygen immediately before 5 min [(99m)Tc]DTPA (4 ~ 5 mCi/mL) aerosol exposure. One control and one cigarette smoking group were studied. RESULTS: Images showed high and uniform lung deposition and the mean clearance rate was increased by 37% in smoking group. CONCLUSIONS: The combined SPECT/CT imaging method developed here can be used for serial evaluation of lung function and its response to drug therapy in guinea pig model of COPD. PMID- 20838907 TI - 18F-FET PET/CT in advanced head and neck squamous cell carcinoma: an intra individual comparison with 18F-FDG PET/CT. AB - PURPOSE: To assess the diagnostic value of O-2-fluoro-18(F)-ethyl-L-tyrosine ((18)F-FET) positron emission tomography/computed tomography (PET/CT) for patients with advanced head and neck squamous cell carcinoma compared with 18F fluoro-2-deoxy-D-glucose ((18)F-FDG) PET/CT at initial staging and following radiochemotherapy. PROCEDURES: Thirteen patients were prospectively enrolled; each of them underwent an (18)F-FDG PET/CT and (18)F-FET PET/CT before treatment. Ten of those were scanned 10 weeks after treatment. RESULTS: Sensitivity, specificity, and accuracy for (18)F-FDG PET/CT (primary and lymph node metastases) at initial staging were 89%, 50%, and 81%. For (18)F-FET PET/CT the numbers were 70%, 90%, and 74%. Sensitivity, specificity, and accuracy for (18)F FDG PET/CT at follow-up were 71%, 65%, and 67%. For (18)F-FET PET/CT the numbers were 29%, 100%, and 83%. Additionally, (18)F-FDG PET/CT detected a higher number of second malignancies or distant metastases. CONCLUSIONS: (18)F-FET is no substitute for (18)F-FDG. Although it is more specific, too many malignant lesions are missed due to its lower sensitivity. PMID- 20838906 TI - Tumor hypoxia imaging. AB - There is a need to measure tumor hypoxia in assessing the aggressiveness of tumor and predicting the outcome of therapy. A number of invasive and noninvasive techniques have been exploited to measure tumor hypoxia, including polarographic needle electrodes, immunohistochemical staining, radionuclide imaging (positron emission tomography [PET] and single-photon emission computed tomography [SPECT]), magnetic resonance imaging (MRI), optical imaging (bioluminescence and fluorescence), and so on. This review article summarizes and discusses the pros and cons of each currently available method for measuring tissue oxygenation. Special emphasis was placed on noninvasive imaging hypoxia with emerging new agents and new imaging technologies to detect the molecular events that are relevant to tumor hypoxia. PMID- 20838908 TI - PET imaging of hypoxia-inducible factor-1-active tumor cells with pretargeted oxygen-dependent degradable streptavidin and a novel 18F-labeled biotin derivative. AB - PURPOSE: We aimed to evaluate the feasibility of using streptavidin-biotin-based pretargeting for positron emission tomography (PET) imaging of hypoxia-inducible factor (HIF)-1-active tumors. PROCEDURES: We used POS, a genetically engineered form of streptavidin that selectively stabilizes in HIF-1-active cells, and (4 (18)F-fluorobenzoyl)norbiotinamide ((18)F-FBB), a radiolabeled biotin derivative, for performing a biodistribution study and for PET imaging. The tumoral (18)F-FBB accumulation was compared to the HIF-1-dependent luciferase bioluminescence and HIF-1alpha immunohistochemical signal. RESULTS: (18)F-FBB accumulation was observed in POS-pretargeted tumors in mice (2.85 +/- 0.55% injected dose per gram at 3 h), and clear PET images were obtained at the same time point. The tumoral (18)F-FBB accumulation positively correlated with luciferase bioluminescence (R = 0.72, P < 0.05), and most of the area showing (18)F-FBB accumulation corresponded to HIF-1alpha-positive areas. CONCLUSION: Pretargeting with POS and (18)F-FBB is an effective approach for PET imaging of HIF-1-active areas in tumors. PMID- 20838909 TI - Saposin C coupled lipid nanovesicles enable cancer-selective optical and magnetic resonance imaging. AB - PURPOSE: Nanovesicles composed of the phospholipid dioleylphosphatidylserine (DOPS) and a fusogenic protein, saposin C (SapC), selectively target and induce apoptotic cell death in a variety of human cancer cells in vitro and in vivo. We tested whether such tumor-homing nanovesicles are capable of delivering fluorescent probes and magnetic resonance (MR) contrast agents to cancerous tissue to aid in earlier detection and improve visualization. PROCEDURES: SapC DOPS nanovesicles labeled with either a far-red fluorescent probe (CellVue(r) Maroon, CVM) or conjugated with a dextran coated MR contrast agent, ultrasmall superparamagnetic iron oxide (USPIO), were systemically administrated into xenografts for tumor detection using optical and MR imaging systems. RESULTS: SapC-DOPS nanovesicles were effectively detected in vivo in tumor-bearing animals using both optical and MR imaging techniques, thereby demonstrating the cancer selective properties of these nanovesicles. CONCLUSIONS: SapC-DOPS nanovesicles offer promise as a new and robust theranostic agent for broad cancer-selective detection, visualization, and potential therapy. PMID- 20838910 TI - Imaging the bio-distribution of fluorescent probes using multispectral epi illumination cryoslicing imaging. AB - PURPOSE: The increasing availability of fluorescent probes for in vivo optical imaging enables the interrogation of complex biological processes in small animals serving as models for human-like tissue function and disease. However, the validation of probe bio-distribution during their development or the study of different disease models, in support of in vivo imaging studies, is not straightforward. PROCEDURES: The imaging system developed consists of a customized multispectral planar imager that has been adapted on a commercial cryomicrotome and provides a powerful modality for ex vivo imaging of small animals. RESULTS: The ability to capture 3D anatomical (color) and fluorescence volumetric distributions of multiple fluorescent markers in high resolution is showcased. CONCLUSIONS: Serving both as a method for accurately imaging the bio distribution of multiple fluorescent agents inside organisms and as a modality for the validation of non-invasive methods, multispectral cryoslicing imaging offers useful insights to ex vivo optical imaging of molecular probes. PMID- 20838911 TI - Synthesis of 2'-deoxy-2'-[18F]fluoro-9-beta-D-arabinofuranosylguanine: a novel agent for imaging T-cell activation with PET. AB - PURPOSE: 9-(beta-D-Arabinofuranosyl)guanine (AraG) is a guanosine analog that has a proven efficacy in the treatment of T-cell lymphoblastic disease. To test the possibility of using a radiofluorinated AraG as an imaging agent, we have synthesized 2'-deoxy-2'-[(18)F]fluoro-9-beta-D-arabinofuranosylguanine ([(18)F]F AraG) and investigated its uptake in T cells. PROCEDURE: We have synthesized [(18)F]F-AraG via a direct fluorination of 2-N-acetyl-6-O-((4-nitrophenyl)ethyl) 9-(3',5'-di-O-trityl-2'-O-trifyl-beta-D-ribofuranosyl)guanine with [(18)F]KF/K.2.2.2 in DMSO at 85 degrees C for 45 min. [(18)F]F-AraG uptake in both a CCRF-CEM leukemia cell line (unactivated) and activated primary thymocytes was evaluated. RESULTS: We have successfully prepared [(18)F]F-AraG in 7-10% radiochemical yield (decay corrected) with a specific activity of 0.8-1.3 Ci/MUmol. Preliminary cell uptake experiments showed that both a CCRF-CEM leukemia cell line and activated primary thymocytes take up the [(18)F]F-AraG. CONCLUSION: For the first time to the best of our knowledge, [(18)F]F-AraG has been successfully synthesized by direct fluorination of an appropriate precursor of a guanosine nucleoside. This approach maybe also useful for the synthesis of other important positron emission tomography (PET) probes such as [(18)F]FEAU, [(18)F]FMAU, and [(18)F]FBAU which are currently synthesized by multiple steps and involve lengthy purification. The cell uptake studies support future studies to investigate the use of [(18)F]F-AraG as a PET imaging agent of T cells. PMID- 20838914 TI - From the editors' desk: what you don't know could hurt you. PMID- 20838913 TI - Mother-to-child transmission (MTCT) of HIV and drugs of abuse in post-highly active antiretroviral therapy (HAART) era. AB - In the pre-highly active antiretroviral therapy (HAART) era, prenatal "vertical" mother-to-child transmission (MTCT) of HIV was about 25% and exposure of pregnant mothers to drugs of abuse (illicit drugs and tobacco smoking) was a significant contributory factor of MTCT. However, with the introduction of HAART, the rate of MTCT of HIV has decreased to less that 2%. But, it is estimated that currently about 5.1% of pregnant women use illicit drugs and 16.4% smoke tobacco. The residual prevalence of MTCT is of concern and may be related to this continued prevalence of substance use among pregnant mothers. In this report, we review and present evidence that supports the hypothesis that drugs of abuse do have the potential to increase MTCT of HIV in the presence of HAART. Exposure to drugs of abuse during pregnancy may increase MTCT of HIV through a variety of mechanisms that are addressed in detail including possible damage to the placenta, induction of preterm birth, and increasing maternal plasma viral load though a variety of putative mechanisms such as: (a) promoting HIV replication in monocyte/macrophages; (b) increasing the expression of CCR5 receptors; (c) decreasing the expression of CCR5 receptor ligands; (d) increasing the expression of CXCR4 receptors; (e) increasing the expression of DC-SIGN; (f) impairing the efficacy of HAART through drug-drug interaction; and (g) promoting HIV mutation and replication through non-adherence to HAART. PMID- 20838915 TI - The crucible of physician performance reports. AB - Individualized physician performance reports are an emerging phenomena. The narrative piece examines one physician's experience with individualized physician performance reports. Reforming the data collection process could enhance the value of the reports to stakeholders. PMID- 20838916 TI - Brachial neuritis masquerading as acute coronary syndrome. AB - BACKGROUND: Brachial neuritis is a frequently misdiagnosed condition which can present to many medical or surgical specialties. OBJECTIVE: To report a case of brachial neuritis with bilateral phrenic nerve involvement and diaphragmatic weakness. CASE DESCRIPTION: A 63-year-old man presented with acute-onset proximal upper extremity pain and weakness. He also developed severe orthopnoea. Examination revealed proximal upper limb wasting and dramatic paradoxical breathing. Cardiac investigations were unremarkable. Electromyographic studies were consistent with a C5 radiculopathy. Phrenic nerve studies were abnormal bilaterally and Sniff test was positive. A diagnosis of brachial neuritis with predominant C5 and bilateral phrenic nerve involvement was made. His symptoms resolved spontaneously over 3 months. CONCLUSIONS: Brachial neuritis can mimic an acute coronary syndrome and is a rare cause of bilateral phrenic neuropathy. Phrenic nerve palsy should be considered in patients presenting with shortness of breath without any underlying respiratory or cardiovascular illness. PMID- 20838917 TI - Adiponectin, gut hormones, and insulin resistance. PMID- 20838918 TI - Helicobacter pylori eradication therapy in obese patients undergoing gastric bypass surgery--fourteen days superior to seven days? AB - BACKGROUND: The high prevalence of Helicobacter pylori (HP) in our obese population undergoing Roux-en-Y bypass gastric surgery (69.4%) and the concern that it may exacerbate postoperative foregut symptoms and increase gastric cancer risk led us to adopt a policy of HP systematic eradication in this group of patients. Our aim, in obese patients undergoing bypass gastric surgery, was to compare effectivity of 7- and 14-days clarithromycin-based triple therapy as the first-line treatment for HP eradication. METHODS: Three hundred seventy-three patients [mean age 41.2 +/- 10.3 years; 313 women (83.9%)] were HP positive determined by histology or urea breath test. In 2005, 94 patients (Group A) were treated with a 7-days triple therapy-proton pump inhibitor (PPI) b.i.d., clarithromycin (CL) 500 mg b.i.d., and amoxicillin (AMX) 1,000 mg b.i.d. Since 2006, 279 patients (Group B) were treated with a similar 14-days drug regimen-PPI b.i.d., CL 500 mg b.i.d., and AMX 1,000 mg b.i.d. Posttreatment HP status was assessed by C13 urea breath test 4-6 weeks after the end of therapy. RESULTS: The eradication rates were 67.0% (Group A) and 79.9% (Group B). The eradication rate achieved with 14-days triple therapy was significantly higher than with 7-days triple therapy (OR = 1.96; 95% CI: 1.16-3.30; p = 0.016). CONCLUSIONS: A 14-days triple therapy is more effective than 7-days triple therapy suggesting this regimen should be the first-line therapy for HP eradication in Portuguese obese patients undergoing bypass gastric surgery. PMID- 20838919 TI - Laparoscopic conversion of Roux-en-Y gastric bypass to sleeve gastrectomy as first step of duodenal switch: technique and preliminary outcomes. AB - BACKGROUND: Weight loss issues are one of the problems that can affect patients after undergoing bariatric surgery. We report the feasibility, safety and preliminary outcomes of laparoscopic conversion of Roux-en-Y gastric bypass (RYGB) to sleeve gastrectomy (SG), as a first step of duodenal switch (DS), for insufficient weight loss or weight regain. PATIENTS AND METHODS: Between August 2007 and November 2009, four patients benefited from laparoscopic conversion for insufficient weight loss or weight regain, mainly due to a new dietary behaviour such as sweet eating. At the time of RYGB, the mean weight and body mass index (BMI) was 118.5 +/- 32.8 kg and 43.2 +/- 8 kg/m(2), respectively. The mean interval time between RYGB and conversion to SG was 36.7 +/- 15.6 months. At the time of conversion, the mean weight, BMI, % excess weight loss (%EWL) and % excess BMI loss (%EBMIL) was 101.7 +/- 24.7 kg, 37.3 +/- 6.6 kg/m(2), 27.5 +/- 11.8% and 26.5 +/- 12%, respectively. The procedure involved the dismantling of both anastomosis, performance of SG before restoration of gastric continuity, and new small bowel anastomosis. RESULTS: Mean operative time was 233.7 +/- 46.4 min. There were no conversions to open surgery and no mortality. One patient developed a gastric fistula. Mean hospital stay was 20.2 +/- 17.9 days. After a mean follow up of 11 +/- 12.8 months, the mean weight, BMI, %EWL and %EBMIL was 81 +/- 12.1 kg, 30.3 +/- 5.1 kg/m(2), 59.3 +/- 31.5% and 42.3 +/- 34.5%, respectively. During follow-up, one patient underwent the second step of DS. CONCLUSIONS: Laparoscopic conversion of RYGB to SG is feasible and safe despite the development of gastric fistula. Weight loss is increased, leaving the patients in better conditions to undergo the second step of DS. PMID- 20838920 TI - Serum parathyroid hormone levels in chronic endemic fluorosis. AB - Endemic waterborne fluorosis is a public health problem in Isparta, a city located in southern Turkey. Fluoride is a cumulative element that increases metabolic turnover of the bone and also affects the homeostasis of bone mineral metabolism. There are number of similarities between the effects of excess parathyroid hormone (PTH) and fluorosis on bone. So fluoride might show its effect via PTH. We aimed to determine PTH levels in patients with endemic fluorosis to estimate the possible toxic effects of chronic fluoride intake. Fifty-six patients with endemic fluorosis and 28 age-, sex-, and body-mass-index matched healthy controls were included in this study. Endemic fluorosis was diagnosed according to the clinical diagnosis criteria of Wang. The urine fluoride levels of fluorosis patients were significantly higher than those of control subjects as expected (1.9 +/- 0.1 vs. 0.4 +/- 0.1 mg/L, respectively; P < 0.001). PTH levels in fluorosis group were significantly higher than control group (65.09 +/- 32.91 versus 47.40 +/- 20.37, respectively; P = 0.01). The results of our study demonstrate that serum PTH levels are increased in patients with endemic fluorosis. Fluoride, by interfering calcium balance, may be the cause of secondary hyperparathyroidism. PMID- 20838921 TI - The correlation among the dynamic change of Zn2+, ZnT-1, and brain-derived neurotrophic factor after acute spinal cord injury in rats. AB - Zinc plays an important role in regulating the expression of brain-derived neurotrophic factor (BDNF) and its receptor in nervous system, but the correlation among Zn(2+), zinc transporter, and BDNF in spinal cord injuries (SCI) is not fully understood. The purpose of this study was to investigate the expression of Zn(2+), zinc transporter 1 (ZnT-1), and BDNF, as well as their correlation in spinal cord-injured rats. One hundred Wistar male rats were divided into two groups: sham-operated group (as control group) and model group. Spinal cord injury was induced in model groups by hemisection of T9 on the left side. Compared with the control group, the serum zinc levels in SCI model group were significantly decreased after surgery, but zinc concentrations in spinal cord were increased gradually. The mRNA levels of ZnT-1 and BDNF were significantly increased in SCI model group, and there is a positive correlation between them (Spearman rho = 0.381, P = 0.0204). The correlation found between BDNF and ZnT-1 allows us to speculate that these two factors may be physiologically co-regulated, which may provide an idea for the treatment of SCI. PMID- 20838922 TI - Comparison of different forms of dietary selenium supplementation on growth performance, meat quality, selenium deposition, and antioxidant property in broilers. AB - This study was conducted to investigate the effects of different sources of dietary selenium (Se) supplementation on growth performance, meat quality, Se deposition, and antioxidant property in broilers. A total of 600 one-day-old Ross 308 broilers with an average body weight (BW) of 44.30 +/- 0.49 g were randomly allotted to three treatments, each of which included five replicates of 40 birds. These three groups received the same basal diet containing 0.04 mg Se/kg, supplemented with 0.15 mg Se/kg from sodium selenite (SS) or from L selenomethionine (L-Se-methionine (Met)) or from D-selenomethionine (D-Se-Met). The experiment lasted 42 days. Both Se source and time significantly influenced (p < 0.01) drip loss of breast muscle. Supplementation with L-Se-Met and D-Se-Met were more effective (p < 0.05) in decreasing drip loss than SS. Besides, the pH value of breast muscle was also significantly influenced (p < 0.05) by time. The SS-supplemented diet increased more (p < 0.05) liver, kidney, and pancreas glutathione peroxidase (GSH-Px) activities than the D-Se-Met-supplemented diet. In addition, L-Se-Met increased more (p < 0.01) liver and pancreas GSH-Px activities than D-Se-Met. The antioxidant status was greatly improved in broilers of L-Se-Met-treated group in comparison with the SS-treated group and was illuminated by the increased glutathione (GSH) concentration in serum, liver, and breast muscle (p < 0.05); superoxide dismutase (SOD) activity in liver (p < 0.01); total antioxidant capability (T-AOC) in kidney, pancreas, and breast muscle (p < 0.05) and decreased malondialdehyde (MDA) concentration in kidney and breast muscle (p < 0.05) of broilers. Besides, supplementation with D-Se-Met was more effective (p < 0.01) in increasing serum GSH concentration and decreasing breast muscle MDA concentration than SS. L-Selenomethionine supplementation significantly increased GSH concentration in liver and breast muscle (p < 0.05); SOD activity in liver (p < 0.01); and T-AOC in liver, pancreas, and breast muscle (p < 0.05) of broilers, compared with broilers fed D-Se-Met diet. The addition of L-Se-Met and D-Se-Met increased (p < 0.01) Se concentration in serum and different organs studied of broilers in comparision with broilers fed SS diet. Therefore, dietary L-Se-Met and D-Se-Met supplementation could improve antioxidant capability and Se deposition in serum and tissues and reduce drip loss of breast muscle in broilers compared with SS. Besides, L-Se-Met is more effective than D-Se-Met in improving antioxidant status in broilers. PMID- 20838923 TI - Determination and evaluation of the mineral composition of Obi (Cola acuminate). AB - The obi (Cola acuminate) is a native fruit from Africa, which has been mainly used in the production of soft drinks and also in rituals of African religions. In this paper, the mineral composition of obi collected in seven different cities from Bahia State, Brazil was determined and evaluated using multivariate analysis. The samples were digested using nitric acid and hydrogen peroxide and were analyzed using inductively coupled plasma optical emission spectrometry. The accuracy of the method was confirmed by analysis of a certified reference material of apple leaves, furnished by National Institute of Standard and Technology. The study involved 46 samples, being 18 of the red specie and 28 for the white specie. The results expressed as milligrams of element per 100 g(-1) of sample demonstrated that the concentration ranges varied of 21.28-548.77 for potassium, 15.73-129.85 for phosphorous, 27.95-286.92 for calcium, 7.67-134.45 for magnesium, 0.05-1.41 for manganese, 0.21-0.94 for iron, 0.11-0.39 for copper, 0.27-1.35 for zinc, and 0.025-0.517 for strontium. The principal component analysis and hierarchical cluster analysis evidenced that the mineral composition of the red specie is different of the white specie. The red obi has mineral content higher than white obi. PMID- 20838924 TI - The effect of age and gender on 59 trace-element contents in human rib bone investigated by inductively coupled plasma mass spectrometry. AB - The effect of age and gender on 59 trace-element contents in rib bone of 80 apparently healthy 15-55-year-old women (n = 38) and men (n = 42) was investigated by inductively coupled plasma mass spectrometry. Mean values (M +/- SEpsilonMU) for the mass fraction (milligrams per kilogram, on dry-weight basis) of Ba, Bi, Cd, Ce, Cu, Dy, Er, Gd, La, Li, Mn, Mo, Nd, Pb, Pr, Rb, Sm, Sr, Tb, Tl, U, Yb, and Zn for both female and male taken together were: Ba 2.5 +/- 0.2, Bi 0.015 +/- 0.002, Cd 0.044 +/- 0.005, Ce 0.029 +/- 0.002, Cu 1.05 +/- 0.06, Dy 0.0020 +/- 0.0003, Er 0.0011 +/- 0.0002, Gd 0.0015 +/- 0.0001, La 0.020 +/- 0.002, Li 0.040 +/- 0.002, Mn 0.354 +/- 0.004, Mo 0.052 +/- 0.006, Nd 0.011 +/- 0.001, Pb 2.24 +/- 0.14, Pr 0.0032 +/- 0.0004, Rb 1.51 +/- 0.06, Sm 0.0014 +/- 0.0001, Sr 291 +/- 20, Tb 0.00041 +/- 0.00005, Tl 0.00050 +/- 0.00003, U 0.0013 +/- 0.0001, Yb 0.00072 +/- 0.00007, and Zn 92.8 +/- 1.5, respectively. The upper limit of mean contents of Ag, Al, B, Be, Br, Cr, Cs, Hg, Ho, Lu, Ni, Sb, Te, Th, Ti, Tm, and Y were: Ag <= 0.011, Al <= 7.2, B <= 0.65, Be <= 0.0032, Br <= 3.9, Cr <= 0.25, Cs <= 0.0077, Hg <= 0.018, Ho <= 0.00053, Lu <= 0.00024, Ni <= 1.05, Sb <= 0.0096, Te <= 0.0057, Th <= 0.0030, Ti <= 2.8, Tm <= 0.00006, and Y <= 0.0047, respectively. In all bone samples, the contents of As, Au, Co, Eu, Ga, Hf, Ir, Nb, Pd, Pt, Re, Rh, Sc, Se, Sn, Ta, V, W, and Zr were under detection limits. The Ce, Dy, Er, Gd, La, Nd, Pr, Sm, Tb, and Yb contents increase with age. Higher Sr mass fraction is typical of female rib as compared to those in male bone. PMID- 20838925 TI - Acute phase expression pattern of ZnTs, LC3, and beclin-1 in rat Hippocampus and its regulation by 3-methyladenine following recurrent neonatal seizures. AB - It has been reported that autophagy and zinc transporters (ZnTs) both play the key roles in excitotoxicity, which is associated with cognitive deficits following developmental seizures. However, the influence of autophagy on acute phase ZnTs expression has never been studied. The present study sought to investigate the contribution of an autophagy inhibitor (3-methyladenine, 3-MA) on the regulation of ZnTs, microtubule-associated protein 1A/1B light chain 3 (LC3), and beclin-1 expression in rat hippocampus following recurrent neonatal seizures. We examined the expression of ZnT1~ZnT3, LC3, and beclin-1 at 1.5, 3, 6, and 24 h after the last seizures using real-time RT-PCR and Western blot methods, respectively. The results showed that there were upregulated expressions of ZnT 1, ZnT-2, LC3, and beclin-1 of RS group. Pretreatment with 3-MA remarkably attenuated seizure-induced ZnT-1, ZnT-2, LC3, and beclin-1 increase. Additionally, linear correlations could be observed between LC3-Beclin1, LC3-ZnT 2, Beclin1-ZnT2, Beclin1-ZnT3, and among ZnT1~ZnT3 in control group, while the linear correlations could be observed between LC3-Beclin1, Beclin1-ZnT2, and Beclin1-ZnT3 in RS group. These results demonstrate, for the first time, that there exists an interaction of Zn(2+) with autophagic signals that are immediately activated in hippocampus after recurrent neonatal seizures, which might play a key role in neonatal seizure-induced excitotoxicity. PMID- 20838926 TI - Does iodine biofortification affect oxidative metabolism in lettuce plants? AB - Plants produce low levels of reactive oxygen species (ROS), which form part of basic cell chemical communication; however, different types of stress can lead to an overexpression of ROS that can damage macromolecules essential for plant growth and development. Iodine is vital to human health, and iodine biofortification programs help improve the human intake through plant consumption. This biofortification process has been shown to influence the antioxidant capacity of lettuce plants, suggesting that the oxidative metabolism of the plant may be affected. The results of this study demonstrate that the response to oxidative stress is variable and depends on the form of iodine applied. Application of iodide (I(-)) to lettuce plants produces a reduction in superoxide dismutase (SOD) activity and an increase in catalase (CAT) and L galactono dehydrogenase enzyme activities and in the activity of antioxidant compounds such as ascorbate (AA) and glutathione. This did not prove a very effective approach since a dose of 80 MUM produced a reduction in the biomass of the plants. For its part, application of iodate (IO (3) (-) ) produced an increase in the activities of SOD, ascorbate peroxidase, and CAT, the main enzymes involved in ROS detoxification; it also increased the concentration of AA and the regenerative activities of the Halliwell-Asada cycle. These data confirm the non-phytotoxicity of IO (3) (-) since there is no lipid peroxidation or biomass reduction. According to our results, the ability of IO (3) (-) to induce the antioxidant system indicates that application of this form of iodine may be an effective strategy to improve the response of plants to different types of stress. PMID- 20838927 TI - Long-term heavy metal pollution and mortality in a Chinese population: an ecologic study. AB - The concentrations of heavy metals in both local environmental samples (water and crops) and in the whole blood of 1,152 local residents were determined by atomic absorption spectrometry. We calculated rate ratios and standardized mortality ratios based on age-, gender-, and cause-specific mortality for both the district and province. Multi-regression models were then used to evaluate the associations between the exposure to multiple heavy metals and cause-specific mortality in the studied population. Significant increases in the mean concentrations of cadmium, lead, and zinc in the blood samples were found to be associated with a substantially elevated all-cancer mortality rate in this high-exposure area (HEA). There were also significantly elevated mortality rates in the HEA for both sexes from a wide range of causes (all-cause), including cardiovascular disease (CVD), when compared with a low-exposure area (LEA). Further analysis showed positive correlations between exposure to both cadmium and lead and a higher risk of all-cancer mortality among women and for both sexes combined. In contrast, zinc exposure negatively correlated with the risk of cause-specific mortality, but this was not significant. These results of our current study thus reveal that long-term environmental exposure to both cadmium and lead is associated with an increased risk of all-cause, CVD, and all-cancer mortality, whereas zinc exposure showed a possible weak protection against death from CVD. PMID- 20838928 TI - Population and computational analysis of the MGEA6 P521A variation as a risk factor for familial idiopathic basal ganglia calcification (Fahr's disease). AB - Familial idiopathic basal ganglia calcification, also known as "Fahr's disease" (FD), is a neuropsychiatric disorder with autosomal dominant pattern of inheritance and characterized by symmetric basal ganglia calcifications and, occasionally, other brain regions. Currently, there are three loci linked to this devastating disease. The first one (IBGC1) is located in 14q11.2-21.3 and the other two have been identified in 2q37 (IBGC2) and 8p21.1-q11.13 (IBGC3). Further studies identified a heterozygous variation (rs36060072) which consists in the change of the cytosine to guanine located at MGEA6/CTAGE5 gene, present in all of the affected large American family linked to IBGC1. This missense substitution, which induces changes of a proline to alanine at the 521 position (P521A), in a proline-rich and highly conserved protein domain was considered a rare variation, with a minor allele frequency (MAF) of 0.0058 at the US population. Considering that the population frequency of a given variation is an indirect indicative of potential pathogenicity, we screened 200 chromosomes in a random control set of Brazilian samples and in two nuclear families, comparing with our previous analysis in a US population. In addition, we accomplished analyses through bioinformatics programs to predict the pathogenicity of such variation. Our genetic screen found no P521A carriers. Polling these data together with the previous study in the USA, we have now a MAF of 0.0036, showing that this mutation is very rare. On the other hand, the bioinformatics analysis provided conflicting findings. There are currently various candidate genes and loci that could be involved with the underlying molecular basis of FD etiology, and other groups suggested the possible role played by genes in 2q37, related to calcium metabolism, and at chromosome 8 (NRG1 and SNTG1). Additional mutagenesis and in vivo studies are necessary to confirm the pathogenicity for variation in the P521A MGEA6. PMID- 20838929 TI - Caffeine modulates tau phosphorylation and affects Akt signaling in postmitotic neurons. AB - Neuronal cell cycle reentry, which is associated with aberrant tau phosphorylation, is thought to be a mechanism of neurodegeneration in AD. Caffeine is a neuroprotective drug known to inhibit the cell cycle, suggesting that its neuroprotective nature may rely, at least in part, on preventing tau abnormalities secondary to its inhibitory effect on neuronal cell cycle-related pathways. Accordingly, we have explored in the present study the impact of caffeine on cell cycle-linked parameters and tau phosphorylation patterns in an attempt to identify molecular clues to its neuroprotective effect. We show that caffeine blocks the cell cycle at G1 phase in neuroblastoma cells and leads to a decrease in tau phosphorylation; similarly, exposure of postmitotic neurons to caffeine led to changes in tau phosphorylation concomitantly with downregulation of Akt signaling. Taken together, our results show a unique impact of caffeine on tau phosphorylation and warrant further investigation to address whether caffeine may help prevent neuronal death by preventing tau abnormalities secondary to aberrant entry into the cell cycle. PMID- 20838930 TI - Cytosolic PrP induces apoptosis of cell by disrupting microtubule assembly. AB - Prion protein (PrP) is able to bind with tubulin and to interfere with the formation of microtubule. To investigate the influence of accumulation of cytosolic PrP in cytoplasm on microtubule, plasmid pcDNA3.1-PrP23-230 expressing human PrP23-230 was introduced into HeLa cells. Immunoprecipitation assays identified the molecular interaction between cytosolic PrP and cellular tubulin. Confocal microscopy showed the co-localization of the expressed cytosolic PrP with tubulin in cytoplasm. Immunofluorescent assays of tubulin illustrated remarkable disruption of microtubular structures in the cells accumulated with cytosolic PrP. Meanwhile, the expressed cytosolic PrP significantly reduced cell viability and induced cell apoptosis. The amounts of microtubule protein in the cells expressing cytosolic PrP were decreased. Moreover, the levels of endogenous tubulin in the brain tissues of scrapie-infected hamsters were significantly lower than that of normal one. It highlights a close linkage between disruption of microtubule framework and cell death caused by abnormal presence of cellular PrP in cytoplasm. The association of apoptosis with microtubule-disrupting activity caused by cytosolic PrP may further provide insight into the unresolved biological function of PrP in the neurons. PMID- 20838931 TI - Gender influences cerebral oxygenation after red blood cell transfusion in patients with severe traumatic brain injury. AB - BACKGROUND: Important differences with respect to gender exist in the prognosis and mortality of traumatic brain injury (TBI) patients. The objective of this study was to assess the role of gender as an independent factor in cerebral oxygenation variations following red blood cell transfusion (RBCT). METHODS: This retrospective analysis of a prospective study was conducted on patients with severe TBI. Hemoglobin levels were measured at baseline and 6 h after transfusion. Brain tissue oxygen pressure (PbrO(2)), cerebral perfusion pressure (CPP), intracranial pressure (ICP), and mean arterial pressure (MAP) were measured at baseline, at the end of RBCT and at 1, 2, 3, 4, 5, and 6 h after transfusion. After the patients were stratified into two groups according to gender, the effect of RBCT on PbrO(2) (cerebral oxygenation) was analyzed using a multivariate analysis of variance with repeated measures (MANOVA). The MANOVA was repeated after adjusting for all covariables with baseline differences between groups. RESULTS: At baseline, we found differences in age (P = 0.01), weight (P = 0.03), MAP (P = 0.01), ISS (P = 0.05), and CCP (P = 0.01) between the groups. After adjusting for these co-variables, we observed that gender and age were related to the increase in PbrO(2) (P = 0.05 and P = 0.04, respectively). CONCLUSIONS: Our results suggest that the effect of RBCT on cerebral oxygenation, as measured by PbrO(2), is greater in women than in men. PMID- 20838932 TI - Current practices of triple-H prophylaxis and therapy in patients with subarachnoid hemorrhage. AB - BACKGROUND: Medical management of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) includes hypertensive, hypervolemic, and hemodilution ("triple-H") therapy. However, there is little information regarding the indications and guidance used to initiate and adjust triple-H therapy. METHODS: A 43-item questionnaire was e-mailed to 375 members of the Neurocritical Care Society. Questions were designed to investigate the diagnostic approach to cerebral vasospasm and prophylactic and therapeutic administration of triple-H therapy. RESULTS: Completed surveys were received from 167 respondents (45% response proportion). Eighty-six percent of respondents worked in hospitals with neurointensive care units (NICUs). SAH patients in hospitals with a NICU had longer ICU stay (P = 0.037) and had indwelling central venous catheters for longer (P < 0.01). Centers without dedicated NICUs were more likely to induce prophylactic hypervolemia (P < 0.01). Twenty seven percent of respondents (n = 45) reported using prophylactic hypervolemia in patients with SAH, while 100% reported inducing hypervolemia for severe or symptomatic vasospasm. Twelve percent (n = 20) of respondents reported inducing prophylactic hypertension, while all reported inducing hypertension with severe or symptomatic vasospasm. Half of respondents relied on the mean arterial pressure and half on systolic blood pressure as the clinical parameter for blood pressure titration. The most widely used agents to induce hypertension were phenylephrine (48%) and norepinephrine (39%). There was little variation in the use of hemodilution therapy comparing patients with or without evidence of vasospasm. CONCLUSIONS: There are substantial differences in the administration of prophylactic triple-H, but there was high agreement on indication for therapeutic use. There was wide variability in the extent of ICU monitoring, diagnostic approach, physiologic parameters and values used as target of therapy. NICU availability was associated with more intensive monitoring. Lack of evidence and guidelines for triple-H therapy might largely explain these findings. PMID- 20838934 TI - Response to Letter to the Editor by Dr. Schulz-Stubner et al. : Slippery Platelet Syndromes in Subdural Hematoma. PMID- 20838933 TI - Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. AB - Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively. PMID- 20838935 TI - Outcomes after nontraumatic subarachnoid hemorrhage at hospitals offering angioplasty for cerebral vasospasm: a national level analysis in the United States. AB - BACKGROUND: Primary angioplasty has been introduced for the treatment of symptomatic cerebral vasospasm in patients with subarachnoid hemorrhage (SAH). The data regarding the therapeutic benefit of angioplasty in improving patient outcomes are limited, hence its utilization at hospitals remains controversial and currently is not reimbursed by Medicare or major insurance companies. METHODS: We analyzed the data from Nationwide Inpatient Sample (NIS), a nationally representative dataset of all admissions in the United States from 2005 to 2007. We analyzed the prevalence of angioplasty procedure for cerebral vasospasm at the national level. In-hospital mortality, discharge status, length of stay, and cost of hospitalization were compared between hospitals performing angioplasty with those not performing angioplasty in multivariable model, adjusted for patient's age, utilization of endovascular aneurysm obliteration, and disease severity. RESULTS: Of the 74,356 estimated patients with nontraumatic SAH, 47% (n = 35,172) were admitted to hospitals that perform angioplasty for cerebral vasospasm and only 1307 patients (3.8%) were treated with angioplasty for vasospasm. In multivariable analysis, after adjustment for patient and hospital characteristics, we found that patients admitted to hospitals performing angioplasty had higher rates of discharge to home without supervision (OR 1.3, 95% CI: 1.1-1.6). There was no difference in in-hospital mortality, length of stay, or cost of hospitalization. CONCLUSIONS: Our analysis suggests that the odds of a patient being discharged to home are better at hospitals performing angioplasty for cerebral vasospasm. Provision of angioplasty may be used as a surrogate marker of model of care in management of patients with SAH. PMID- 20838936 TI - Intramedullary spinal cord metastasis in a patient with colon cancer: a case report. AB - INTRODUCTION: Intramedullary spinal cord metastasis (ISCM) is both a rare and devastating event, since it is clinically evident in 0.1-0.9% of cancer patients and the mortality rate at 3-4 months is 80%. MATERIALS AND METHODS: We present the case of a woman with colon cancer who developed ISCM while on chemotherapy for metastatic disease. The patient presented with paralysis of both legs, weakness in the upper arms, and urinary retention. RESULTS: The diagnosis of ISCM at the level of C6-C7 was made with magnetic resonance imaging of the whole spine. Due to the fact that the patient had an established lower limb paralysis and a poor overall clinical status, external beam radiotherapy (RT) was administered, achieving stabilization of symptoms. CONCLUSIONS: ISCM should be diagnosed and managed as early as possible, since this may result in improvement of neurological deficits. RT is the treatment of choice in most cases, with surgery reserved for selected patients. Recent published data suggest that surgery may result in an improved survival. However, no firm recommendations can be made due to the lack of controlled comparative clinical trials. PMID- 20838938 TI - DFBIdb: a software package for neuroimaging data management. AB - We present DFBIdb: a suite of tools for efficient management of neuroimaging project data. Specifically, DFBIdb was designed to allow users to quickly perform routine management tasks of sorting, archiving, exploring, exporting and organising raw data. DFBIdb was implemented as a collection of Python scripts that maintain a project-based, centralised database that is based on the XCEDE 2 data model. Project data is imported from a filesystem hierarchy of raw files, which is an often-used convention of imaging devices, using a single script that catalogues meta-data into a modified XCEDE 2 data model. During the import process data are reversibly anonymised, archived and compressed. The import script was designed to support multiple file formats and features an extensible framework that can be adapted to novel file formats. An ACL-based security model, with accompanying graphical management tools, was implemented to provide a straightforward method to restrict access to raw and meta-data. Graphical user interfaces are provided for data exploration. DFBIdb includes facilities to export, convert and organise customisable subsets of project data according to user-specified criteria. The command-line interface was implemented to allow users to incorporate database commands into more complex scripts that may be utilised to automate data management tasks. By using DFBIdb, neuroimaging laboratories will be able to perform routine data management tasks in an efficient manner. PMID- 20838939 TI - Study of finger print patterns in children with acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is a malignant disease of an unknown origin. The present case control study was intended to compare the finger print patterns between the children diagnosed with ALL and a control group. A total of 24 children with established ALL were included in the study. Fingerprints of the affected children were analyzed in both hands and compared with the finger print patterns of 24 age and sex matched controls. The study indicated an increase in frequency of whorls and a decreased frequency of loops in children suffering from ALL. Radial loops, double loops, central pocket loops and tented arches are found to be proportionately less frequent in cases than controls. On quantitative analysis of patterns, mean pattern intensity index (PII) was found to be higher in cases than controls; however, a significant overlapping was evident. Most of the cases (n = 10, 41.7%) had a PII of 16-20, while a PII of 11-15 is reported among most children in the control group (n = 16, 66.7%). The findings of the study are suggestive of a possible trend and an association of finger print patterns with children suffering from ALL. The present research emphasizes the significance of the application of forensic science in medicine and pathology. PMID- 20838937 TI - Idiopathic pulmonary fibrosis-an epidemiological and pathological review. AB - Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease (ILD) affecting the pulmonary interstitium. Other forms of interstitial lung disease exist, and in some cases, an environmental etiology can be delineated. The diagnosis of IPF is typically established by high-resolution CT scan. IPF tends to have a worse prognosis than other forms of ILD. Familial cases of IPF also exist, suggesting a genetic predisposition; telomerase mutations have been observed to occur in familial IPF, which may also explain the increase in IPF with advancing age. Alveolar epithelial cells are believed to be the primary target of environmental agents that have been putatively associated with IPF. These agents may include toxins, viruses, or the autoantibodies found in collagen vascular diseases. The mechanism of disease is still unclear in IPF, but aberrations in fibroblast differentiation, activation, and proliferation may play a role. Epithelial-mesenchymal transition may also be an important factor in the pathogenesis, as it may lead to accumulation of fibroblasts in the lung and a disruption of normal tissue structure. Abnormalities in other components of the immune system, including T cells, B cells, and dendritic cells, as well as the development of ectopic lymphoid tissue, have also been observed to occur in IPF and may play a role in the stimulation of fibrosis that is a hallmark of the disease. It is becoming increasingly clear that the pathogenesis of IPF is indeed a complex and convoluted process that involves numerous cell types and humoral factors. PMID- 20838940 TI - Assessment of cardiovascular risk. AB - Atherosclerotic cardiovascular disease (CVD) is the most common cause of death worldwide. Usually atherosclerosis is caused by the combined effects of multiple risk factors. For this reason, most guidelines on the prevention of CVD stress the assessment of total CVD risk. The most intensive risk factor modification can then be directed towards the individuals who will derive the greatest benefit. To assist the clinician in calculating the effects of these multiple interacting risk factors, a number of risk estimation systems have been developed. This review address several issues regarding total CVD risk assessment: Why should total CVD risk be assessed? What risk estimation systems are available? How well do these systems estimate risk? What are the advantages and disadvantages of the current systems? What are the current limitations of risk estimation systems and how can they be resolved? What new developments have occurred in CVD risk estimation? PMID- 20838941 TI - Perceptual organization, phonological awareness, and reading comprehension in adults with and without learning disabilities. AB - It is not clear from research whether, or to what extent, reading comprehension is impaired in adults who have learning disabilities (LD). The influence of perceptual organization (PO) and phonological awareness (PA) on reading comprehension was investigated. PO and PA are cognitive functions that have been examined in previous research for their roles in nonverbal LD and phonological dyslexia, respectively. Nonverbal tests of PO and non-reading tests of PA were administered to a sample of adults with postsecondary education. Approximately two thirds of the sample had previously been diagnosed as having LD. In a multiple regression analysis, tests of PO and PA were used to predict scores for tests of reading comprehension and mechanics. Despite the nonverbal nature of the perceptual organizational test stimuli, PO strongly predicted reading comprehension. Tests of PA predicted decoding and reading speed. Results were interpreted as supporting the hypothesis that integrative processes usually characterized as nonverbal were nonetheless used by readers with and without disabilities to understand text. The study's findings have implications for understanding the reading of adults with learning disabilities, and the nature of reading comprehension in general. PMID- 20838942 TI - Biomechanics of vertebral fractures and the vertebral fracture cascade. AB - Vertebral fractures (VFxs) are the most common osteoporotic fracture, and are a strong risk factor for future fracture. The presence of a VFx greatly increases the risk of sustaining subsequent VFxs-a phenomenon often referred to as the "vertebral fracture cascade." VFxs do not occur uniformly along the spine, but occur more often at the mid-thoracic and thoracolumbar regions than elsewhere. It is likely that both the vertebral fracture cascade and the bimodal distribution of VFx along the spine are attributable to biomechanical factors. VFxs occur when the forces applied to the vertebral body exceed its strength. Loading on the spine is primarily determined by a person's height, weight, muscle forces, and the task or movement performed, but can also be affected by other factors, such as spinal curvature and invertebral disk deterioration. Vertebral strength is determined mainly by bone size, shape, and bone mineral density, and secondarily by bone microarchitecture, collagen characteristics, and microdamage. Better understanding of VFx etiology is hampered by the fact that most VFxs do not come to clinical attention; therefore, the factors and activities that cause VFxs remain ill defined, including possible differences in the etiology of acute fractures versus those of slow onset. Additional research is needed to elucidate the precise mechanical, morphologic, and biological mechanisms that underlie VFx to improve strategies for assessing VFx risk and preventing the vertebral fracture cascade. PMID- 20838943 TI - Gene therapy for erectile dysfunction: what is the future? AB - Gene transfer for the treatment of erectile dysfunction has completed phase 1 safety testing and has shown the necessary safety to proceed to the next level of clinical trial. This review focuses on the background of the components of that have led to US Food and Drug Administration acceptance of human gene transfer trials for nonlethal disease. PMID- 20838944 TI - Androgen replacement therapy after prostate cancer treatment. AB - Historically, testosterone supplementation has been avoided in men with a history of prostate cancer because of concern about prostate cancer progression or recurrence. However, recently published data suggest that this concern may not be well founded. The recurring presence of prostate-specific antigen in men with hypogonadism being treated with testosterone after prostatectomy is far less than the expected natural recurrence rate of the disease. There are many theories (including the prostate saturation theory) that may help us understand why testosterone may be safely administered in men with hypogonadism after surgical treatment of prostate cancer. Finally, because patients with hypogonadism already may be at a significant disadvantage in recovering their erectile function after prostatectomy, they perhaps should receive special consideration as candidates for androgen replacement therapy. PMID- 20838945 TI - The need for total hip arthroplasty in Perthes disease: a long-term study. AB - BACKGROUND: Legg-Calve-Perthes disease (LCPD) was described a century ago. In previous long-term reports of patients with LCPD, nonoperative treatment varied considerably. The likelihood of hip osteoarthritis (OA) developing in patients with LCPD and possible need for THA are not well defined. QUESTIONS/PURPOSES: The purpose of the study was to determine whether nonoperatively treated patients with LCPD (1) had an increased prevalence of THA compared with gender- and age matched control subjects, (2) if patients with Stulberg Classes III/IV/V femoral heads had an increased risk of THA compared with those with Classes I/II femoral heads. Given the limitation in the study, we (3) evaluated whether patients with LCPD were at risk for having radiographic hip OA more commonly than control subjects and (4) whether hips with Classes III/IV/V femoral heads had an increased prevalence of OA compared with hips with Classes I/II femoral heads. PATIENTS AND METHODS: The study population consisted of 167 patients with LCPD treated with a Thomas splint. The control population consisted of gender- and age matched control subjects who were participants in the Copenhagen City Heart Study: the Osteoarthritis Substudy. Radiographs at skeletal maturity were classified according to the classification system of Stulberg et al. Data from the Danish Hip Arthroplasty Register and the Registries of the National Board of Health were collected to obtain the number of patients with LCPD having THA. At a mean followup of 47 years later (range, 37-58 years), weightbearing pelvic radiographs were obtained. Radiographic OA was defined as a joint space width of 2.0 mm or less. RESULTS: Thirteen percent of patients with LCPD had THAs compared with none in the control group. Seven percent of the patients with LCPD had OA compared with 1% in the control group. The prevalence of THA and OA was increased in hips with Classes III/IV/V femoral heads compared with hips with Classes I/II femoral heads. CONCLUSIONS: Patients with LCPD have an increased risk of having THA compared with a gender- and age-matched control group. Our data suggest that patients with LCPD have a greater risk of having radiographic OA develop than a gender- and age-matched control group. It seems that patients with Classes III/IV/V femoral heads have an increased risk of THA and OA compared with patients with Classes I/II femoral heads. LEVEL OF EVIDENCE: Level III, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20838946 TI - Increased in-hospital complications after primary posterior versus primary anterior cervical fusion. AB - BACKGROUND: Although anterior (ACDF) and posterior cervical fusion (PCDF) are relatively common procedures and both are associated with certain complications, the relative frequency and severity of these complications is unclear. Since for some patients either approach might be reasonable it is important to know the relative perioperative risks for decision-making. QUESTIONS/PURPOSES: The purposes of this study were to: (1) characterize the patient population undergoing ACDF and PCDF; (2) compare perioperative complication rates; (3) determine independent risk factors for adverse perioperative events; and (4) aid in surgical decision-making in cases in which clinical equipoise exists between anterior and posterior cervical fusion procedures. METHODS: The National Inpatient Sample was used and entries for ACDF and PCDF between 1998 and 2006 were analyzed. Demographics and complication rates were determined and regression analysis was performed to identify independent risk factors for mortality after ACDF and PCDF. RESULTS: ACDF had a shorter length of stay and their procedures were more frequently performed at nonteaching institutions. The incidence of complications and mortality was 4.14% and 0.26% among patients undergoing ACDF and 15.35% and 1.44% for patients undergoing PCDF, respectively. When controlling for overall comorbidity burden and other demographic variables, PCDF was associated with a twofold increased risk of a fatal outcome compared with ACDF. Pulmonary, circulatory, and renal disease were associated with the highest odds for in-hospital mortality. CONCLUSIONS: PCDF procedures were associated with higher perioperative rates of complications and mortality compared with ACDF surgeries. Despite limitations, these data should be considered in cases in which clinical equipoise exists between both approaches. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20838947 TI - An observational study of patient-rated outcome after atlantoaxial fusion in patients with rheumatoid arthritis and osteoarthritis. AB - BACKGROUND: Fusion is used to address several types of abnormality of the atlantoaxial segment. Traditionally, outcome has been assessed by achieving solid bony union. Recently, however, patient-rated outcome instruments have been increasingly used, although these may be influenced by concomitant comorbidity. QUESTIONS/PURPOSES: We therefore asked whether patients with rheumatoid arthritis (RA), with its associated comorbidity, had worse self-rated outcomes after C1-2 fusion than patients with osteoarthritis (OA). PATIENTS AND METHODS: We retrospectively reviewed all 30 (23 OA and seven RA) prospectively followed patients in our local Spine Registry (part of the Spine Society of Europe Spine Tango Registry) who had undergone C1-2 fusion. Before surgery and 3 and 12 months later, patients completed the multidimensional Core Outcome Measures Index (COMI) questionnaire. Global outcome and satisfaction with treatment were also assessed. RESULTS: We found no group differences for duration of operation, blood loss, or perioperative surgical or general complications. Compared with the OA group, the RA group showed a better baseline COMI score and less improvement in the COMI from preoperatively to 12 months followup. However, the proportion of "good" global scores at 12 months followup was similarly high in both groups (87% OA and 86% RA) as was satisfaction (96% for OA versus 86% for RA). CONCLUSIONS: Symptoms and impairment were less severe in the RA group at baseline and showed less improvement after surgery, but the proportion of "good global outcomes" was similar in both groups, and the great majority of patients in both groups were satisfied with their treatment. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20838948 TI - Distinct neurochemical profiles of spinocerebellar ataxias 1, 2, 6, and cerebellar multiple system atrophy. AB - Hereditary and sporadic neurodegenerative ataxias are movement disorders that affect the cerebellum. Robust and objective biomarkers are critical for treatment trials of ataxias. In addition, such biomarkers may help discriminate between ataxia subtypes because these diseases display substantial overlap in clinical presentation and conventional MRI. Profiles of 10-13 neurochemical concentrations obtained in vivo by high field proton magnetic resonance spectroscopy ((1)H MRS) can potentially provide ataxia-type specific biomarkers. We compared cerebellar and brainstem neurochemical profiles measured at 4 T from 26 patients with spinocerebellar ataxias (SCA1, N = 9; SCA2, N = 7; SCA6, N = 5) or cerebellar multiple system atrophy (MSA-C, N = 5) and 15 age-matched healthy controls. The Scale for the Assessment and Rating of Ataxia (SARA) was used to assess disease severity. The patterns of neurochemical alterations relative to controls differed between ataxia types. Myo-inositol levels in the vermis, myo-inositol, total N acetylaspartate, total creatine, glutamate, glutamine in the cerebellar hemispheres and myo-inositol, total N-acetylaspartate, glutamate in the pons were significantly different between patient groups (Bonferroni corrected p < 0.05). The best MRS predictors were selected by a tree classification procedure and lead to 89% accurate classification of all subjects while the SARA scores overlapped considerably between patient groups. Therefore, this study demonstrated multiple neurochemical alterations in SCAs and MSA-C relative to controls and the potential for these neurochemical levels to differentiate ataxia types. Studies with higher numbers of patients and other ataxias are warranted to further investigate the clinical utility of neurochemical levels as measured by high field MRS as ataxia biomarkers. PMID- 20838950 TI - On the architecture of the posterior zone of the cerebellum. AB - The mammalian cerebellum is histologically uniform. However, underlying the simple laminar architecture is a complex arrangement of parasagittal stripes and transverse zones that can be revealed by the expression of many molecules, in particular, zebrin II/aldolase C. By using a combination of Purkinje cell antigenic markers and afferent tracing, four transverse zones have been identified: in mouse, these are the anterior zone (~lobules I-V), the central zone (~lobules VI-VII), the posterior zone (PZ: ~lobules VIII-dorsal IX), and the nodular zone (~ventral lobule IX + lobule X). A fifth transverse zone-the lingular zone (~lobule I)-is found in birds and bats. Within the anterior and posterior zones, parasagittal stripes of Purkinje cells expressing zebrin II alternate with those that do not. To explore this model further and to broaden our understanding of the evolution of cerebellar patterning, stripes in the PZ have been compared in multiple mammalian species. We conclude that a posterior zone with a conserved stripe organization is a common feature of the mammalian and avian cerebellar vermis and that zonal boundaries are independent of cerebellar lobulation. PMID- 20838949 TI - Behavioural significance of cerebellar modules. AB - A key organisational feature of the cerebellum is its division into a series of cerebellar modules. Each module is defined by its climbing input originating from a well-defined region of the inferior olive, which targets one or more longitudinal zones of Purkinje cells within the cerebellar cortex. In turn, Purkinje cells within each zone project to specific regions of the cerebellar and vestibular nuclei. While much is known about the neuronal wiring of individual cerebellar modules, their behavioural significance remains poorly understood. Here, we briefly review some recent data on the functional role of three different cerebellar modules: the vermal A module, the paravermal C2 module and the lateral D2 module. The available evidence suggests that these modules have some differences in function: the A module is concerned with balance and the postural base for voluntary movements, the C2 module is concerned more with limb control and the D2 module is involved in predicting target motion in visually guided movements. However, these are not likely to be the only functions of these modules and the A and C2 modules are also both concerned with eye and head movements, suggesting that individual cerebellar modules do not necessarily have distinct functions in motor control. PMID- 20838951 TI - Novel aspect of ketone action: beta-hydroxybutyrate increases brain synthesis of kynurenic acid in vitro. AB - Ketone bodies formed during ketogenic diet or non-treated diabetes mellitus may exert neuroprotective and antiepileptic effects. Here, we assessed the influence of ketone body, beta-hydroxybutyrate (BHB) on the brain synthesis of kynurenic acid (KYNA), an endogenous antagonist of glutamatergic and alpha7-nicotinic receptors. In brain cortical slices and in primary glial cultures, BHB enhanced KYNA production. KT 5270, an inhibitor of protein kinase A, has prevented this action. At hypoglycemia, under pH 7.0 and 7.4, profound (15 mM BHB), but not mild (3 mM) ketosis increased synthesis of KYNA. In paradigm resembling diabetic ketoacidosis in vitro (30 mM glucose, pH 7.0), neither mild nor profound ketosis influenced the production of KYNA. At pH 7.4 and in 30 mM glucose though, both mild and severe ketonemia evoked an increase of KYNA production. The activity of KYNA biosynthetic enzymes, KAT I and KAT II, in cortical homogenate was not altered by BHB (0.05-10.0 mM). However, in cultured glial cells exposed to BHB (10 mM), the activity of KATs increased. This effect was reversed by the co incubation of cells with KT 5270. Presented data reveal a novel mechanism of action of BHB. Increased synthesis of KYNA in the presence of BHB is most probably mediated by protein kinase A-dependent stimulation of KATs expression/activity leading to an increase of KYNA formation. Ensuing attenuation of the excessive excitatory glutamate-mediated neurotransmission may, at least in part, explain the neuroprotective actions of BHB. PMID- 20838952 TI - Ontogenetic serotoninergic lesioning alters histaminergic activity in rats in adulthood. AB - The aim of this study was to determine histamine content in the brain and the effect of histamine receptor antagonists on behavior of adult rats lesioned as neonates with the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). At 3 days after birth Wistar rats were pretreated with desipramine (20 mg/kg ip) before bilateral icv administration of 5,7-DHT (37.5 MUg base on each side) or saline-ascorbic (0.1%) vehicle (control). At 10 week levels of 5-HT and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were determined in frontal cortex, striatum, and hippocampus by an HPLC/ED technique. In the hypothalamus, frontal cortex, hippocampus and medulla oblongata, the level of histamine was analyzed by an immunoenzymatic method. Behavioral observations (locomotion, exploratory-, oral-, and stereotyped activity) were performed, and effects of DA receptor agonists (SKF 38393, apomorphine) and histamine receptor antagonists S(+)chlorpheniramine (H(1)), cimetidine (H(2)), and thioperamide (H(3)) were determined. We confirmed that 5,7-DHT profoundly reduced contents of 5-HT and 5 HIAA in the brain in adulthood. Histamine content was also reduced in all examined brain regions. Moreover, in 5,7-DHT-lesioned rats the locomotor and oral activity responses to thioperamide were altered, and apomorphine-induced stereotype was intensified. From the above, we conclude that an intact central serotoninergic system modulates histamine H(3) receptor antagonist effects on the dopaminergic neurons in rats. PMID- 20838953 TI - Thioperamide, an H3 receptor antagonist prevents [3H]glucose uptake in brain of adult rats lesioned as neonates with 5,7-dihydroxytryptamine. AB - As a first attempt at exploring an association between histaminergic and serotoninergic neuronal phenotypes in glucose regulation, the influence of the histamine H3 receptor antagonist thioperamide on glucose uptake by brain was determined in rats in which the serotoninergic innervations of brain was largely destroyed perinatally. Male Wistar rats were initially treated on the 3rd day after birth with the serotoninergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) (75 MUg icv) or saline vehicle (10 MUl icv). At 8 weeks lesioned and control rats were terminated in order to validate the effectiveness of 5,7-DHT: reduction in 5 HT and 5-HIAA by 83-91% and 69-83% in striatum, frontal cortex, and hippocampus (HPLC/ED method). Other groups of rats were pretreated with thioperamide (5.0 mg/kg ip) or saline vehicle 60 min prior to 6-[3H]-D-glucose (500 MUCi/kg ip). Fifteen-min later rats were decapitated and brains were excised and dissected to remove frontal cortex, striatum, hippocampus, thalamus/hypothalamus, pons, and cerebellum. Liquid scintillation spectroscopy was used to determine that [3H]glucose uptake, which was enhanced in 5,7-DHT lesioned rats in cortex (by 88%), hippocampus, thalamus/hypothalamus, pons and cerebellum (each by 47-56%), and in striatum (by 35%). In contrast, thioperamide prevented the enhancement in [3H]glucose uptake in all brain regions of 5,7-DHT neonatally lesioned rats; and [3H]glucose levels were significantly different in all brain regions (except thalamus/hypothalamus) in thioperamide-versus saline-treated rats. These findings indicate a functional association between histaminergic and serotoninergic systems in brain in relation to glucose regulation. PMID- 20838955 TI - Expanding the definition of healing--cancer education in India. AB - Enormous increases are predicted in the global burden of cancer, with the bulk of these cases is expected to occur in low- and middle-income countries like India. This paper outlines the existing scenario of cancer incidence and mortality, health and cancer care facilities, and the status of cancer education in India. Cancer education strategies in tune with future local needs are also discussed with special reference to research related to various aspects of cancer, teaching and training of human resources, and the development of appropriate legislation. PMID- 20838954 TI - Evolving with the times, the new national toxic substance incidents program. AB - ATSDR's surveillance and registries branch has a new three-part program to gather data on toxic substance incidents, the National Toxic Substance Incidents Program (NTSIP). NTSIP includes state-based surveillance of releases, a national database of chemical incidents, and incident investigations after large releases. NTSIP replaces the Hazardous Substances Emergency Events Surveillance program. Through this more comprehensive program, ATSDR is collecting data that may be used to decrease the number and severity of chemical releases and enhance preparedness, so that the health effects of future incidents are minimized. PMID- 20838956 TI - Bullous exudative retinal detachment due to infiltration of leukemic cells in a child with acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is known to cause several ocular involvements, but exudative retinal detachment is a rare complication. We describe a case report of a 4-year-old boy with T cell ALL who developed bilateral exudative retinal detachment caused by leukemic infiltration in the retinas after achieving hematological remission. Intravenous steroid pulse therapy and local irradiation reversed the condition, but it recurred concurrently with disease progression after a second relapse in the bone marrow. It is suggested that ophthalmic examination is crucial for ALL patients, especially for those whose white blood cell count is very high at onset. PMID- 20838957 TI - Molecular basis and hematological features of hemoglobin variants in Southern Thailand. AB - Hemoglobinopathy (abnormal hemoglobin or hemoglobin variant) is an inherited disorder that results in the abnormal structure of globin chains of the hemoglobin (Hb) molecule. Many abnormal Hbs have been characterized worldwide, including more than 20 variants in Thailand. The Bio-Rad Variant II HPLC system is used for investigating hemoglobin variants at Songklanagarind Hospital. This system has been shown to be a sensitive, specific, and reproducible method, but some hemoglobin variants such as Hb Tak and Hb D-Punjab cannot, as yet, be clearly separated by this method. The aim of this study was to investigate the prevalence of hemoglobinopathy in southern Thailand using DNA sequencing and study the severity of each hemoglobin variant. A total of 58 hemoglobin variant samples were obtained from blood samples undergoing routine hemoglobin typing at Songklanagarind Hospital. Genomic DNAs were extracted from the samples, and the globin genes were analyzed by using PCR-direct sequencing. The molecular analysis revealed eight hemoglobin variants: 28 Hb C, 12 Hb D-Punjab, 7 Hb Tak, 4 Hb G Makassar, 2 Hb Lepore-Hollandia, 2 Hb Q-Thailand, 2 Hb O-Indonesia, and 1 Hb Hope. The distribution of hemoglobin variants in southern Thailand is associated with geographic and/or ethnic backgrounds. This study may help hematologists understand better the prevalence of hemoglobin variants and their hematological features in this region. PMID- 20838958 TI - Multiple mucosa-associated lymphoid tissue organs involving marginal zone B cell lymphoma: organ-specific relationships and the prognostic factors. Consortium for improving survival of lymphoma study. AB - According to a previous review, multiple mucosa-associated lymphoid tissue (MALT) organs involving marginal zone B cell lymphomas (MZLs) are present in 10-30% of patients. However, the clinical features and specific relationships among involved organs are yet to be clearly identified. In this study, we conducted retrospective analyses of multiple MALT organs involving MZLs (MM-MZLs) to identify their clinical features, treatment, prognosis, and specific relationships among involved organs. For analysis, between June 1987 and June 2009, a total of 55 patients from 17 different institutions in Korea, all of whom were histologically diagnosed with MM-MZL, were included in this study. MM-MZL was defined as MZL involving more than 2 different MALT organs. Multiple involvements within one MALT organ (e.g. both side ocular lesions, multiple lung nodules, and multiple stomach lesions, etc.) were excluded from this study. The male/female ratio of the 55 patients was 41/14. The median age of our subjects was 59 years (range 30-82 years). MM-MZL without lymph node (LN) was detected only in 9 patients (36.2%). Bone marrow (BM) involvement was observed in 17 patients (30.9%). The most common site of involvement was the gastrointestinal (GI) tract (25 patients, 45.5%) followed by the lung (40%), Waldeyer's ring (WR) (27.3%), and ocular area (25.5%). Ocular MZLs were commonly accompanied with WR- or lung-MZLs. GI-MZLs were WR or GI-MZLs. Lung-MZLs were frequently observed with ocular and GI-MZLs. WR-MZLs were ocular or GI-MZLs. A total of 53 patients were treated, and 2 on watchful wait. As much as 48 patients received chemotherapy based treatment. Among them, CR or PR was achieved in 38 patients (79.2%, 95% CI 67-91%). Median time to progression (TTP) was 2.3 years (95% CI 1.4-3.2 years). Cause-specific overall survival (OS) did not reach the median value. The 5-year OS rate was 84.9%. MM-MZLs tend to be an indolent disease, characterized by prolonged survival with frequent relapses. The majority of cases could be controlled effectively via chemotherapy-based treatment, and prolonged survival was achieved in those patients. The GI, lung, WR, and ocular area were commonly presented with other MALT site MZLs, and an organ-specific relationship appears to be relevant to MM-MZLs. PMID- 20838959 TI - Early prediction of a long-term outcome by neutrophil-FISH in patients with CML receiving imatinib mesylate. PMID- 20838960 TI - CD30-positive anaplastic variant diffuse large B cell lymphoma: a rare case presented with cutaneous involvement. AB - A 67-year-old man suffered from a left cervical lymph node swelling and tenderness. Biopsy of the cervical lymph node showed pleomorphic large cells containing large atypical nuclei. Immunohistochemical stains of these cells were positive for CD30, but negative for CD3 and CD20. After the biopsy, his left cervical skin was ulcerated. Biopsy of the left cervical skin was performed. Large pleomorphic cells with constricted nuclei and Reed-Sternberg-like cells existed in the dermis and epidermis. Immunohistochemical stains of the former cells were positive for CD30, CD45 and PAX5, but negative for CD3, CD10, CD20, CD15, Bcl-2, EBER ISH, EMA and ALK. He was diagnosed with diffuse large B cell lymphoma, anaplastic variant. He achieved complete remission with CHOP chemotherapy. CD30-positive DLBCL, anaplastic variant is a rare B cell lymphoma. Most of the patients presented with primary nodal disease, and skin involvement of lymphoma is very rare. This is the report of a rare case of CD30-positive DLBCL, anaplastic variant, with both nodal and skin lesions. PMID- 20838961 TI - NF-kappaB and mucosal homeostasis. AB - NF-kappaB is well characterized as a primary mediator of inflammatory responses during infection and immune reactions, but it has recently become evident that NF kappaB also mediates a potent cytoprotective, homeostatic function under basal conditions. This role is especially evident in the mammalian intestine, which is challenged not only with a range of microbial pathogens, but is also in constant contact with potent proinflammatory commensal bacteria and their products. Present data lead to the overall conclusion that antiapoptotic actions of NF kappaB in intestinal epithelial cells dominate tissue responses to many acute inflammatory and injurious challenges, whereas proinflammatory and cell survival functions of NF-kappaB in macrophages and T cells govern chronic intestinal inflammation. This review focuses on the protective and homeostatic functions of NF-kappaB, and the importance of NF-kappaB in determining host-microbe interactions in the intestinal tract. PMID- 20838963 TI - Some Trends in Chem(o)informatics. AB - This introductory chapter gives a brief overview of the history of cheminformatics, and then summarizes some recent trends in computing, cultures, open systems, chemical structure representation, docking, de novo design, fragment-based drug design, molecular similarity, quantitative structure-activity relationships (QSAR), metabolite prediction, the use of phamacophores in drug discovery, data reduction and visualization, and text mining. The aim is to set the scene for the more detailed exposition of these topics in the later chapters. PMID- 20838962 TI - Multiple sclerosis therapies: molecular mechanisms and future. AB - The current treatments for multiple sclerosis (MS) are, by many measures, not satisfactory. The original interferon-beta therapies were not necessarily based on an extensive knowledge of the pathophysiological mechanisms of the disease. As more and more insight has been acquired about the autoimmune mechanisms of MS and, in particular, the molecular targets involved, several treatment approaches have emerged. In this chapter, we highlight both promising preclinical approaches and therapies in late stage clinical trials that have been developed as a result of the improved understanding of the molecular pathophysiology of MS. These clinical stage therapies include oral agents, monoclonal antibodies, and antigen specific therapies. Particular emphasis is given to the molecular targets when known and any safety concerns that have arisen because, despite the need for improved efficacy, MS remains a disease in which the safety of any agent remains of paramount importance. PMID- 20838964 TI - Molecular similarity measures. AB - Molecular similarity is a pervasive concept in chemistry. It is essential to many aspects of chemical reasoning and analysis and is perhaps the fundamental assumption underlying medicinal chemistry. Dissimilarity, the complement of similarity, also plays a major role in a growing number of applications of molecular diversity in combinatorial chemistry, high-throughput screening, and related fields. How molecular information is represented, called the representation problem, is important to the type of molecular similarity analysis (MSA) that can be carried out in any given situation. In this work, four types of mathematical structure are used to represent molecular information: sets, graphs, vectors, and functions. Molecular similarity is a pairwise relationship that induces structure into sets of molecules, giving rise to the concept of chemical space. Although all three concepts - molecular similarity, molecular representation, and chemical space - are treated in this chapter, the emphasis is on molecular similarity measures. Similarity measures, also called similarity coefficients or indices, are functions that map pairs of compatible molecular representations that are of the same mathematical form into real numbers usually, but not always, lying on the unit interval. This chapter presents a somewhat pedagogical discussion of many types of molecular similarity measures, their strengths and limitations, and their relationship to one another. An expanded account of the material on chemical spaces presented in the first edition of this book is also provided. It includes a discussion of the topography of activity landscapes and the role that activity cliffs in these landscapes play in structure-activity studies. PMID- 20838965 TI - The ups and downs of structure-activity landscapes. AB - In this chapter we discuss the landscape view of structure-activity relationships (SARs). The motivation for such a view is that SARs come in a variety of forms, such as those where small changes in structure lead to small changes in activity or where small structural lead to significant changes in activity (also termed activity cliffs). Thus, an SAR dataset is viewed as a landscape comprised of smooth plains, rolling hills, and jagged gorges. We review the history of this view and early quantitative approaches that attempted to encode the landscape. We then discuss some recent developments that directly characterize structure activity landscapes, in one case with the goal of highlighting activity cliffs while the other allows one to resolve different types of SAR that may be present in a dataset. We highlight some applications of these approaches, such as predictive model development and SAR elucidation, to SAR datasets obtained from the literature. Finally, we conclude with a summary of the landscape approach and why it provides an intuitive and rigorous alternative to standard views of structure-activity data. PMID- 20838966 TI - Computational analysis of activity and selectivity cliffs. AB - The exploration of structure-activity relationships (SARs) is a major challenge in medicinal chemistry and usually focuses on compound potency for individual targets. However, selectivity of small molecules that are active against related targets is another critical parameter in chemical lead optimization. Here, an integrative approach for the systematic analysis of SARs and structure selectivity relationships (SSRs) of small molecules is presented. The computational methodology is described and a cathepsin inhibitor set is used to discuss key aspects of the analysis. Combining a numerical scoring scheme and graphical visualization of molecular networks, the approach enables the identification of different local SAR and SSR environments. Comparative analysis of these environments reveals variable relationships between molecular structure, potency, and selectivity. Furthermore, key compounds are identified that are involved in the formation of activity and/or selectivity cliffs and often display structural features that determine compound selectivity. PMID- 20838967 TI - Similarity searching using 2D structural fingerprints. AB - This chapter reviews the use of molecular fingerprints for chemical similarity searching. The fingerprints encode the presence of 2D substructural fragments in a molecule, and the similarity between a pair of molecules is a function of the number of fragments that they have in common. Although this provides a very simple way of estimating the degree of structural similarity between two molecules, it has been found to provide an effective and an efficient tool for searching large chemical databases. The review describes the historical development of similarity searching since it was first described in the mid 1980s, reviews the many different coefficients, representations, and weightings that can be combined to form a similarity measure, describes quantitative measures of the effectiveness of similarity searching, and concludes by looking at current developments based on the use of data fusion and machine learning techniques. PMID- 20838968 TI - Predicting the performance of fingerprint similarity searching. AB - Fingerprints are bit string representations of molecular structure that typically encode structural fragments, topological features, or pharmacophore patterns. Various fingerprint designs are utilized in virtual screening and their search performance essentially depends on three parameters: the nature of the fingerprint, the active compounds serving as reference molecules, and the composition of the screening database. It is of considerable interest and practical relevance to predict the performance of fingerprint similarity searching. A quantitative assessment of the potential that a fingerprint search might successfully retrieve active compounds, if available in the screening database, would substantially help to select the type of fingerprint most suitable for a given search problem. The method presented herein utilizes concepts from information theory to relate the fingerprint feature distributions of reference compounds to screening libraries. If these feature distributions do not sufficiently differ, active database compounds that are similar to reference molecules cannot be retrieved because they disappear in the "background." By quantifying the difference in feature distribution using the Kullback-Leibler divergence and relating the divergence to compound recovery rates obtained for different benchmark classes, fingerprint search performance can be quantitatively predicted. PMID- 20838969 TI - Bayesian methods in virtual screening and chemical biology. AB - The Naive Bayesian Classifier, as well as related classification and regression approaches based on Bayes' theorem, has experienced increased attention in the cheminformatics world in recent years. In this contribution, we first review the mathematical framework on which Bayes' methods are built, and then continue to discuss implications of this framework as well as practical experience under which conditions Bayes' methods give the best performance in virtual screening settings. Finally, we present an overview of applications of Bayes' methods to both virtual screening and the chemical biology arena, where applications range from bridging phenotypic and mechanistic space of drug action to the prediction of ligand-target interactions. PMID- 20838970 TI - Reduced graphs and their applications in chemoinformatics. AB - Reduced graphs provide summary representations of chemical structures by collapsing groups of connected atoms into single nodes while preserving the topology of the original structures. This chapter reviews the extensive work that has been carried out on reduced graphs at The University of Sheffield and includes discussion of their application to the representation and search of Markush structures in patents, the varied approaches that have been implemented for similarity searching, their use in cluster representation, the different ways in which they have been applied to extract structure-activity relationships and their use in encoding bioisosteres. PMID- 20838971 TI - Fragment descriptors in structure-property modeling and virtual screening. AB - This chapter reviews the application of fragment descriptors at different stages of virtual screening: filtering, similarity search, and direct activity assessment using QSAR/QSPR models. Several case studies are considered. It is demonstrated that the power of fragment descriptors stems from their universality, very high computational efficiency, simplicity of interpretation, and versatility. PMID- 20838972 TI - The scaffold tree: an efficient navigation in the scaffold universe. AB - The Scaffold Tree algorithm (J Chem Inf Model 47:47-58, 2007) allows to organize large molecular data sets by arranging sets of molecules into a unique tree hierarchy based on their scaffolds, with scaffolds forming leaf nodes of such tree. The hierarchy is created by iterative removal of rings from more complex scaffolds using chemically meaningful set of rules, until a single, root ring is obtained. The classification is deterministic, data set independent, and scales linearly with the number of compounds included in the data set. In this review we summarize the basic principles of the Scaffold Tree methodology and review its applications, which appeared in recent medicinal chemistry literature, including the use of Scaffold Trees for visualization of large chemical data sets, compound clustering, and the identification of novel bioactive molecules. References to several computer programs, including also free tools available on the Internet, allowing to perform classification and visualization of molecules based on their scaffolds are also provided. PMID- 20838973 TI - Pharmacophore-based virtual screening. AB - This chapter is a review of the most recent developments in the field of pharmacophore modeling, covering both methodology and application. Pharmacophore based virtual screening is nowadays a mature technology, very well accepted in the medicinal chemistry laboratory. Nevertheless, like any empirical approach, it has specific limitations and efforts to improve the methodology are still ongoing. Fundamentally, the core idea of "stripping" functional groups of their actual chemical nature in order to classify them into very few pharmacophore types, according to their dominant physico-chemical features, is both the main advantage and the main drawback of pharmacophore modeling. The advantage is the one of simplicity - the complex nature of noncovalent ligand binding interactions is rendered intuitive and comprehensible by the human mind. Although computers are much better suited for comparisons of pharmacophore patterns, a chemist's intuition is primarily scaffold-oriented. Its underlying simplifications render pharmacophore modeling unable to provide perfect predictions of ligand binding propensities - not even if all its subsisting technical problems would be solved. Each step in pharmacophore modeling and exploitation has specific drawbacks: from insufficient or inaccurate conformational sampling to ambiguities in pharmacophore typing (mainly due to uncertainty regarding the tautomeric/protonation status of compounds), to computer time limitations in complex molecular overlay calculations, and to the choice of inappropriate anchoring points in active sites when ligand cocrystals structures are not available. Yet, imperfections notwithstanding, the approach is accurate enough in order to be practically useful and actually is the most used virtual screening technique in medicinal chemistry - notably for "scaffold hopping" approaches, allowing the discovery of new chemical classes carriers of a desired biological activity. PMID- 20838974 TI - De novo drug design. AB - Computer-assisted molecular design supports drug discovery by suggesting novel chemotypes and compound modifications for lead structure optimization. While the aspect of synthetic feasibility of the automatically designed compounds has been neglected for a long time, we are currently witnessing an increased interest in this topic. Here, we review state-of-the-art software for de novo drug design with a special emphasis on fragment-based techniques that generate druglike, synthetically accessible compounds. The importance of scoring functions that can be used to predict compound reactivity and potency is highlighted, and several promising solutions are discussed. Recent practical validation studies are presented that have already demonstrated that rule-based fragment assembly can result in novel synthesizable compounds with druglike properties and a desired biological activity. PMID- 20838975 TI - Classification of chemical reactions and chemoinformatic processing of enzymatic transformations. AB - The automatic perception of chemical similarities between chemical reactions is required for a variety of applications in chemistry and connected fields, namely with databases of metabolic reactions. Classification of enzymatic reactions is required, e.g., for genome-scale reconstruction (or comparison) of metabolic pathways, computer-aided validation of classification systems, or comparison of enzymatic mechanisms. This chapter presents different current approaches for the representation of chemical reactions enabling automatic reaction classification. Representations based on the encoding of the reaction center are illustrated, which use physicochemical features, Reaction Classification (RC) numbers, or Condensed Reaction Graphs (CRG). Representation of differences between the structures of products and reactants include reaction signatures, fingerprint differences, and the MOLMAP approach. The approaches are illustrated with applications to real datasets. PMID- 20838976 TI - Informatics approach to the rational design of siRNA libraries. AB - This chapter surveys the literature for state-of-the-art methods for the rational design of siRNA libraries. It identifies and presents major milestones in the field of computational modeling of siRNA's gene silencing efficacy. Commonly used features of siRNAs are summarized along with major machine learning techniques employed to build the predictive models. It has also outlined several web-enabled siRNA design tools. To face the challenge of modeling and rational design of chemically modified siRNAs, it also proposes a new cheminformatics approach for the representation and characterization of siRNA molecules. Some preliminary results with this new approach are presented to demonstrate the promising potential of this method for the modeling of siRNA's efficacy. Together with novel delivery technologies and chemical modification techniques, rational siRNA design algorithms will ultimately contribute to chemical biology research and the efficient development of siRNA therapeutics. PMID- 20838977 TI - Beyond rhodopsin: G protein-coupled receptor structure and modeling incorporating the beta2-adrenergic and adenosine A(2A) crystal structures. AB - For quite some time, the majority of GPCR models have been based on a single template structure: dark-adapted bovine rhodopsin. The recent solution of beta2AR, beta1AR and adenosine A(2A) receptor crystal structures has dramatically expanded the GPCR structural landscape and provided many new insights into receptor conformation and ligand binding. They will serve as templates for the next generation of GPCR models, but also allow direct validation of previous models and computational techniques. This review summarizes key findings from the new structures, comparison of existing models to these structures and highlights new models constructed from these templates. PMID- 20838978 TI - Methods for combinatorial and parallel library design. AB - Diversity has historically played a critical role in design of combinatorial libraries, screening sets and corporate collections for lead discovery. Large library design dominated the field in the 1990s with methods ranging anywhere from purely arbitrary through property based reagent selection to product based approaches. In recent years, however, there has been a downward trend in library size. This was due to increased information about the desirable targets gleaned from the genomics revolution and to the ever growing availability of target protein structures from crystallography and homology modeling. Creation of libraries directed toward families of receptors such as GPCRs, kinases, nuclear hormone receptors, proteases, etc., replaced the generation of libraries based primarily on diversity while single target focused library design has remained an important objective. Concurrently, computing grids and cpu clusters have facilitated the development of structure based tools that screen hundreds of thousands of molecules. Smaller "smarter" combinatorial and focused parallel libraries replaced those early un-focused large libraries in the twenty-first century drug design paradigm. While diversity still plays a role in lead discovery, the focus of current library design methods has shifted to receptor based methods, scaffold hopping/bio-isostere searching, and a much needed emphasis on synthetic feasibility. Methods such as "privileged substructures based design" and pharmacophore based design still are important methods for parallel and small combinatorial library design. This chapter discusses some of the possible design methods and presents examples where they are available. PMID- 20838979 TI - The Interweaving of Cheminformatics and HTS. AB - The aim of this chapter is to describe the stages of early drug discovery that can be assisted by techniques commonly used in the field of cheminformatics. In fact, cheminformatics tools can be applied all the way from the design of compound libraries and the analysis of HTS results, to the discovery of functional relationships between compounds and their targets. PMID- 20838981 TI - Ligand-based approaches to in silico pharmacology. AB - The development of computational methods that can estimate the various pharmacodynamic and pharmacokinetic parameters that characterise the interaction of drugs with biological systems has been a highly pursued objective over the last 50 years. Among all, methods based on ligand information have emerged as simple, yet highly efficient, approaches to in silico pharmacology. With the recent impact on the identification of new targets for known drugs, they are again the focus of attention in chemical biology and drug discovery. PMID- 20838982 TI - Molecular test systems for computational selectivity studies and systematic analysis of compound selectivity profiles. AB - For chemical genetics and chemical biology, an important task is the identification of small molecules that are selective against individual targets and can be used as molecular probes for specific biological functions. To aid in the development of computational methods for selectivity analysis, molecular benchmark systems have been developed that capture compound selectivity data for pairs of targets. These molecular test systems are utilized for "selectivity searching" and the analysis of structure-selectivity relationships. Going beyond binary selectivity sets focusing on target pairs, a methodological framework, Molecular Formal Concept Analysis (MolFCA), is described for the definition and systematic mining of compound selectivity profiles. PMID- 20838980 TI - Computational systems chemical biology. AB - There is a critical need for improving the level of chemistry awareness in systems biology. The data and information related to modulation of genes and proteins by small molecules continue to accumulate at the same time as simulation tools in systems biology and whole body physiologically based pharmacokinetics (PBPK) continue to evolve. We called this emerging area at the interface between chemical biology and systems biology systems chemical biology (SCB) (Nat Chem Biol 3: 447-450, 2007).The overarching goal of computational SCB is to develop tools for integrated chemical-biological data acquisition, filtering and processing, by taking into account relevant information related to interactions between proteins and small molecules, possible metabolic transformations of small molecules, as well as associated information related to genes, networks, small molecules, and, where applicable, mutants and variants of those proteins. There is yet an unmet need to develop an integrated in silico pharmacology/systems biology continuum that embeds drug-target-clinical outcome (DTCO) triplets, a capability that is vital to the future of chemical biology, pharmacology, and systems biology. Through the development of the SCB approach, scientists will be able to start addressing, in an integrated simulation environment, questions that make the best use of our ever-growing chemical and biological data repositories at the system-wide level. This chapter reviews some of the major research concepts and describes key components that constitute the emerging area of computational systems chemical biology. PMID- 20838983 TI - Application of support vector machine-based ranking strategies to search for target-selective compounds. AB - Support vector machine (SVM)-based selectivity searching has recently been introduced to identify compounds in virtual screening libraries that are not only active for a target protein, but also selective for this target over a closely related member of the same protein family. In simulated virtual screening calculations, SVM-based strategies termed preference ranking and one-versus-all ranking were successfully applied to rank a database and enrich high-ranking positions with selective compounds while removing nonselective molecules from high ranks. In contrast to the original SVM approach developed for binary classification, these strategies enable learning from more than two classes, considering that distinguishing between selective, promiscuously active, and inactive compounds gives rise to a three-class prediction problem. In this chapter, we describe the extension of the one-versus-all strategy to four training classes. Furthermore, we present an adaptation of the preference ranking strategy that leads to higher recall of selective compounds than previously investigated approaches and is applicable in situations where the removal of nonselective compounds from high-ranking positions is not required. PMID- 20838984 TI - What do we know?: simple statistical techniques that help. AB - An understanding of simple statistical techniques is invaluable in science and in life. Despite this, and despite the sophistication of many concerning the methods and algorithms of molecular modeling, statistical analysis is usually rare and often uncompelling. I present here some basic approaches that have proved useful in my own work, along with examples drawn from the field. In particular, the statistics of evaluations of virtual screening are carefully considered. PMID- 20838985 TI - Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study. AB - AIMS/HYPOTHESIS: The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used in current clinical practice in Denmark. METHODS: All patients aged >= 30 years hospitalised for the first time for heart failure in 1997-2006 were identified and followed until the end of 2006. Patients who received treatment with metformin, a sulfonylurea and/or insulin were included and assigned to mono-, bi- or triple therapy groups. Multivariable Cox proportional hazard regression models were used to assess the risk of all-cause mortality. RESULTS: A total of 10,920 patients were included. The median observational time was 844 days (interquartile range 365-1,395 days). In total, 6,187 (57%) patients died. With sulfonylurea monotherapy used as the reference, adjusted hazard ratios for all-cause mortality associated with the different treatment groups were as follows: metformin 0.85 (95% CI 0.75-0.98, p = 0.02), metformin + sulfonylurea 0.89 (95% CI 0.82-0.96, p = 0.003), metformin + insulin 0.96 (95% CI 0.82-1.13, p = 0.6), metformin + insulin + sulfonylurea 0.94 (95% CI 0.77-1.15, p = 0.5), sulfonylurea + insulin 0.97 (95% CI 0.86-1.08, p = 0.5) and insulin 1.14 (95% CI 1.06-1.20, p = 0.0001). CONCLUSIONS/INTERPRETATION: Treatment with metformin is associated with a low risk of mortality in diabetic patients with heart failure compared with treatment with a sulfonylurea or insulin. PMID- 20838986 TI - Is a dipstick test sufficient to exclude urinary tract infection in women with overactive bladder? AB - INTRODUCTION AND HYPOTHESIS: A dipstick test is recommended to screen for urinary tract infection in patients with overactive bladder (OAB). It was the aim of this study to test if a dipstick test is sufficient to identify patients with urinary tract infection attending a urological private practice because of OAB. METHODS: All patients who attended the practice because of OAB symptoms were routinely catheterized; a urine specimen was tested with dipstick, the spun sediment was examined microscopically, and the specimen was sent for microbiological examination. RESULTS: Two thousand two hundred fifty-two patients were examined. Of 1,754 patients with negative dipstick screening, 353 patients (20.1%) had growth of >=10(3) colony forming units. The dipstick test had a sensitivity of 0.442 and a specificity of 0.865 for the correct identification of urinary tract infection. CONCLUSIONS: Dipstick screening is not sufficient to identify patients with urinary tract infection and symptoms of OAB. PMID- 20838987 TI - Prospective study of anterior transobturator mesh kit (ProliftTM) for the management of recurrent anterior vaginal wall prolapse. AB - INTRODUCTION AND HYPOTHESIS: Assessment of the 2-year outcome of anterior ProliftTM for women with recurrent anterior vaginal wall prolapse. This is a prospective study which was conducted in a tertiary unit in the North West of England and comprised 36 consecutive women with recurrent anterior vaginal wall prolapse. METHODS: Women were assessed preoperatively and postoperatively at 6 months and 2 years. Women completed the Prolapse Quality of Life Questionnaire (P QOL), Prolapse and Incontinence Sexual Function Questionnaire-Short Form (PISQ 12), and postoperatively, the Global Impression of Improvement Questionnaire. Women were examined using the Pelvic Organ Prolapse Quantification System (POP Q). Anatomical success was defined as stage <=1 prolapse in the anterior compartment. Main outcome measures Postoperative POP-Q stage, quality of life domains and mesh exposure rate. RESULTS: Preoperatively all but two women had stage 2 or greater anterior vaginal wall prolapse. At a mean follow-up of 24.6 months, 19 women (53%) had stage <=1 anterior wall prolapse. Fifteen women had stage 2 anterior wall prolapse and two women had stage 3 prolapse. Twenty-nine women felt improvement in their prolapse symptoms. 16 women were sexually active preoperatively, of whom seven reported worsening dyspareunia. There was poor correlation between anatomical and functional outcomes. Seven women had mesh exposure. Five needed revision in theatre. CONCLUSIONS: Anterior ProliftTM for recurrent anterior vaginal wall prolapse has 53% anatomical success rate in the medium term, with mesh exposure rate of 19%. Majority of patients felt overall improvement in their symptoms, but this did not correlate with the anatomical outcome. PMID- 20838988 TI - Tissue response to a new type of biomaterial implanted subcutaneously in rats. AB - INTRODUCTION AND HYPOTHESIS: A new type of resorbable biomaterial intended for pelvic reconstruction was tested with respect to tissue regeneration and biocompatibility in rats. The biomaterial consisted of methoxypolyethyleneglycol poly(lactic-co-glycolic acid) (MPEG-PLGA). Implants were pure, enriched with extra-cellular matrix (ECM) or estrogen. METHODS: Ten implants of each type were tested for 3 and 8 weeks, respectively. Histological assessment of connective tissue organization, inflammation, vascularization, and thickness of regenerated tissue was undertaken. RESULTS: All implants had a high degree of biocompatibility. ECM-enriched implants had significantly higher inflammatory scores compared to pure implants at 3 weeks. At 8 weeks, neither of the parameters differed significantly. No trace of the implants remained. CONCLUSIONS: The MPEG-PLGA is highly biocompatible, degrades quickly, and seems inert in the process of tissue regeneration. Thus, it is hardly a candidate per se in reinforcement of pelvic reconstruction, but it could have a future role as carrier for stem cells. PMID- 20838989 TI - Biomechanical properties of prolapsed or non-prolapsed vaginal tissue: impact on genital prolapse surgery. AB - INTRODUCTION AND HYPOTHESIS: Our aim is to characterize prolapsed and non prolapsed vaginal tissue, and thus offer a better understanding of the genital prolapse physiopathology and an improvement of surgical treatments. METHODS: Vaginal tissue was collected in 30 patients with prolapse (POP) and ten fresh cadavers without prolapse (nPOP) with a favorable advice of Ethics Committee. Uniaxial tension tests were performed. Statistical comparisons of rigidity under moderate deformation and under large deformation have been performed RESULTS: POP is significantly stiffer than nPOP tissue, both on anterior and posterior walls. A significant difference between POP and nPOP tissues was highlighted when anterior or posterior vaginal walls were respectively compared. CONCLUSIONS: These results might explain the higher rate of relapse when repair is autologous, using already defective and more rigid vaginal tissue. This study suggests that it might be interesting to adapt the characteristics of prosthetic implants to the vaginal face concerned by the prolapsus. PMID- 20838990 TI - Effects of thienopyridines and thienopyrimidinones on L-type calcium current in isolated cardiomyocytes. AB - Thienopyridines (ticlopidine, clopidogrel) are frequently used drugs in antiplatelet therapy and have been shown to exert a more pronounced negative inotropic effect than thienopyrimidinones. We hypothesized that these differences are due to a differential impact of thienopyridines and thienopyrimidinones on L type calcium current at the single-cell level. The effects of thienopyridines and thienopyrimidinones were studied on L-type calcium current and action potential parameters with the whole-cell patch-clamp technique in isolated myocytes from guinea pig ventricle and human atrial appendage. Ticlopidine showed the greatest impact on the L-type calcium current in guinea pig myocytes. It significantly reduced L-type calcium current density as well as shifted half maximal inactivation potential to more negative potentials compared to clopidogrel (at 30 MUmol/L) and to all thienopyrimidinones (30 and 100 MUmol/L). Clopidogrel significantly reduced the L-type calcium current density as well as shifted the half maximal inactivation potential to more negative potentials compared to all thienopyrimidinones at 100 MUmol/L only. In contrast, thienopyrimidinones did not affect L-type calcium current properties. The significant different effects of thienopyridines and thienopyrimidinones could also be demonstrated in human atrial myocytes. The more pronounced negative inotropic effect of thienopyridines is well explained by our results demonstrating a differential impairment of L type calcium current by thienopyridines and thienopyrimidinones. L-type calcium current impairment by thienopyridines may be of special relevance for patients with cardiac diseases characterized by ionic remodelling. PMID- 20838992 TI - Abiomed biventricular assist device as a bridge to transplantation in a 14-year old with cardiomyopathy resulting from ventricular noncompaction. AB - Ventricular noncompaction is a rare but well-documented cause of cardiomyopathy. This report presents a case of ventricular noncompaction diagnosed late in end stage cardiac failure and malignant ventricular arrhythmia, which required an Abiomed biventricular assist device as a bridge to transplantation. PMID- 20838991 TI - Effect of CYP2C19 genotypes on the pharmacokinetic/pharmacodynamic relationship of rabeprazole after a single oral dose in healthy Chinese volunteers. AB - AIMS: To explore the pharmacokinetic/pharmacodynamic relationship of rabeprazole and the role of CYP2C19 genotypes after a single oral dose in healthy Chinese volunteers by a population approach. METHODS: Plasma concentration time profile data and intragastric pH values of 19 genotyped healthy male adults after a single oral dose of rabeprazole in an open label randomized fashion were used for this population analysis. Simulation technology was performed to examine the rabeprazole response in subjects with different CYP2C19 genotypes to further investigate the effect of acid inhibition. RESULTS: The pharmacokinetics of rabeprazole was characterized by a two-compartment model with first order absorption and with an absorption lag-time. The results show that clearance of rabeprazole was affected by CYP2C19 genotypes (average clearances of homEM, hetEM, and PM were 13.9, 11.5, and 8.74 L.h(-1) respectively). An effect compartment with a sigmoidal Emax model was considered more rational for analyzing the relationship between rabeprazole concentrations and intragastric pH values. Simulated results suggest that rabeprazole 20 mg once daily for PMs is sufficient, but might be administered more frequently for other genotypes in treating gastro-esophageal reflux disease. CONCLUSION: The CYP2C19 genotype played a considerable role in the pharmacokinetic characteristics of rabeprazole, and this might need to be taken into account for clinical use. PMID- 20838993 TI - Tibial subacute osteomyelitis with intraosseous abscess: an unusual complication of intraosseous infusion. AB - Intravenous (IV) access is a critical step in patient care, especially in the emergency and/or trauma setting. Recently, intraosseous (IO) infusion has re emerged as a recommended alternative to central venous access in both the pediatric and the adult patient. We present the case of an older adult male patient several months after emergency tibial IO infusion, now with left shin pain, and the MRI and culture findings diagnostic of subacute osteomyelitis with IO abscess, an unusual complication of IO infusion. PMID- 20838994 TI - Post-treatment [18F]FDG maximum standardized uptake value as a prognostic marker of recurrence in endometrial carcinoma. AB - PURPOSE: The purpose of this study was to determine whether post-treatment [(18)F]fluorodeoxyglucose (FDG) uptake measured as the maximum standardized uptake value (SUV(max)) by integrated positron emission tomography (PET)/computed tomography (CT) imaging has prognostic significance in patients with endometrial carcinoma. METHODS: Patients previously treated by primary surgical staging for endometrial carcinoma were imaged with integrated FDG PET/CT during surveillance. PET/CT findings were compared with histological or clinical evaluation, and the relationship between SUV(max) on PET/CT and recurrence was examined. RESULTS: A total of 61 patients were eligible for analysis. Medical records were retrospectively reviewed for clinical data, treatment modalities and outcome. The median duration of follow-up was 31 months (range 6-102 months) post-treatment. SUV(max) levels were inversely associated with disease-free survival (DFS). Patients were divided into two groups according to SUV(max) (< 4.25 versus >= 4.25). The Kaplan-Meier survival graph showed a significant difference in DFS between groups [p < 0.001, hazard ratio (HR) 12.959, 95% confidence interval (CI) 3.650-46.011]. In multivariate analyses, post-treatment SUV(max) (uncategorized values) evaluated by surveillance PET/CT (p = 0.001, HR 1.199, 95% CI 1.077 1.334) and serous adenocarcinoma histology (p = 0.028, HR 5.594, 95% CI 1.207 25.931) were significantly associated with recurrence. CONCLUSION: Post-treatment FDG uptake as measured by SUV(max) showed a significant association with recurrence in patients with endometrial carcinoma and may be used as a new useful prognostic marker. PMID- 20838996 TI - Nuclear medicine: what kind of quality would we want if we were the patient? PMID- 20838995 TI - The role of 18F-FDG PET/CT in the assessment of suspected recurrent gastric cancer after initial surgical resection: can the results of FDG PET/CT influence patients' treatment decision making? AB - PURPOSE: (18)F-fluorodeoxyglucose (FDG) PET/CT has been widely used for staging, re-staging and for monitoring therapy-induced changes and response to therapy in patients with various types of cancer, but its utilization for gastric cancer has been limited. The purpose of this study was to evaluate the clinical role of FDG PET/CT in the detection of gastric cancer recurrence as compared with diagnostic CT and to assess the impact of FDG PET/CT results on patients' treatment planning. METHODS: Thirty-four patients with suspected recurrent gastric cancer, who had previously undergone curative gastrectomy and lymph node dissection, were retrospectively analysed. The diagnostic CT and FDG PET/CT imaging were performed for all patients as clinically indicated. The results of FDG PET/CT were compared with the findings of the diagnostic CT. The changes in the clinical management of patients according to the results of FDG PET/CT were also evaluated. RESULTS: FDG PET/CT was performed in 19 patients (55.9%) due to the suspicion of distant metastasis at diagnostic CT. The remaining 15 patients were suspected to have local recurrence at diagnostic CT (n = 4) or gastroscopy (n = 1) and due to an increase in tumour markers or clinical manifestations (n = 10). The FDG PET/CT result was positive in 23 patients (67.6%) and negative in 11 patients (32.4%). In total, 24 (70.6%) of the 34 patients had documented recurrent disease by histopathology in 7 (29.1%) and by clinical follow-up in 17 (70.9%), while 11 patients had no evidence of recurrent disease. FDG PET/CT correctly confirmed recurrent disease in 23 of the patients with recurrence and it was classified as true-positive in these patients. However, FDG PET/CT was false-negative in one patient but recurrent disease was confirmed by histopathology. The overall sensitivity, specificity, accuracy, positive and negative predictive values of FDG PET/CT were significantly superior to those of diagnostic CT (95.8 vs 62.5%, 100 vs 10%, 97 vs 47%, 100 vs 62.5% and 90.9 vs 10%, respectively, p = 0.012) in the detection of recurrent gastric cancer after initial surgery. The FDG PET/CT results changed the patients' management in 18 (52.9%) cases by leading to the use of previously unplanned treatment procedures in 9 (50%) patients and the avoidance of previously planned therapeutic procedures in 9 (50%) patients. CONCLUSION: FDG PET/CT is a superior post-therapy surveillance modality for the diagnosis of recurrent gastric cancer compared with diagnostic CT imaging after initial surgery. In addition, integrated FDG PET/CT was specifically helpful in optimizing the treatment plan and it might play an important role in treatment stratification in the future. PMID- 20838997 TI - The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances taxol-induced cell death in breast cancer. AB - PURPOSE: The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) enhances taxol-induced antitumor effects against some human cancer cells. The aim of this study is to investigate whether SAHA can enhance taxol induced cell death against human breast cancer cells and to illustrate the mechanism in detail. METHODS: A panel of eight human breast cancer cell lines and an immortalized human breast epithelial cell line were used to determine the inhibitory effects of SAHA, taxol, or their combination by MTT assay. The effects of SAHA with or without taxol on cell cycle distributions, apoptosis, and protein expressions were also examined. The inhibitory effects on tumor growth were characterized in vivo in BALB/c nude mice bearing a breast cancer xenograft model. RESULTS: Taxol-resistant and multi-resistant breast cancer cells were as sensitive to SAHA as taxol-sensitive breast cancer cells. A dose-dependent synergistic growth inhibition was found in all the tested breast cancer cell lines treated with the SAHA/taxol combinations. The synergetic effect was also observed in the in vivo xenograft tumor model. The cell cycle analysis and apoptosis assay showed that the synergistic effects resulted from enhanced G2/M arrest and apoptosis. CONCLUSIONS: SAHA increased the anti-tumor effects of taxol in breast cancer in vitro and in vivo. The combination of SAHA and taxol may have therapeutic potential in the treatment of breast cancer. PMID- 20838999 TI - Control of in vitro rooting and plant development in Corymbia maculata by silver nitrate, silver thiosulfate and thiosulfate ion. AB - Plant regeneration and transformation in vitro is often improved by adding silver ion (Ag(+)) to the culture media as AgNO(3) or silver thiosulfate (STS). Ag(+) reacts with substances to form insoluble precipitates, while thiosulfate (S(2)O(3) (2-)) interferes with these reactions. We studied the implications of silver precipitation and S(2)O(3) (2-) in the medium for culture development by (1) examining formation of Ag(+) precipitates from AgNO(3) versus STS in agar gels and their possible dependence on agar type; (2) comparing Corymbia maculata culture responses to AgNO(3) and STS and determining which better suits control of culture development; (3) clarifying whether STS-dependent alterations in culture development are due to Ag(+) alone or also to a separate influence of S(2)O(3) (2-). Silver precipitates appeared in aqueous gels of four agar brands supplemented with AgNO(3), but not in Phytagel(TM), which remained transparent. No precipitation was observed in gels with STS. Indole-3-butyric acid (IBA) mediated adventitious root induction and shoot growth were higher in C. maculata shoot tips cultured on gels with STS versus AgNO(3) (6-25 MUM Ag(+)). IBA-treated shoot tips exhibited enhanced adventitious root regeneration, accelerated root elongation, increased frequency of lateral root formation, and stimulated shoot growth mediated by 100-250 MUM sodium thiosulfate (Na(2)S(2)O(3)) in medium without Ag(+). The potency of S(2)O(3) (2-) in facilitating culture development has never been recognized. It is inferred that superiority of STS in stimulating multiple responses of C. maculata culture results from sustained biological activity of Ag(+) through prevention of its precipitation, and from impact of S(2)O(3) (2-) on cell differentiation and growth. PMID- 20838998 TI - Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors. AB - PURPOSE: This multicenter phase 2 study assessed the tolerability and efficacy of motesanib, an oral inhibitor of Kit, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors (VEGFR), in patients with imatinib-resistant gastrointestinal stromal tumors (GIST). METHODS: Patients with advanced GIST who failed imatinib mesylate after >=8 weeks of treatment with >=600 mg daily received motesanib 125 mg orally once daily continuously for 48 weeks or until unacceptable toxicity or disease progression occurred. The primary endpoint was confirmed objective tumor response per RECIST and independent review. Secondary endpoints included progression-free survival (PFS), time to progression (TTP); objective response by (18)FDG-PET and by changes in tumor size and/or density (Choi criteria); pharmacokinetics and safety. RESULTS: In the patients evaluable for response (N = 102), the objective response rate was 3%; 59% of patients achieved stable disease, with 14% achieving durable stable disease >=24 weeks; 38% had disease progression. Higher objective response rates were observed per (18)FDG-PET (N = 91) (30%) and Choi criteria (41%). The median PFS was 16 weeks (95% CI = 14-24 weeks); the median TTP was 17 weeks (95% CI = 15 24 weeks). The most common motesanib treatment-related grade 3 adverse events included hypertension (23%), fatigue (9%), and diarrhea (5%). Motesanib did not accumulate with daily dosing. CONCLUSIONS: In this study of patients with imatinib-resistant GIST, motesanib treatment resulted in acceptable tolerability and modest tumor control as evident in the proportion of patients who achieved stable disease and durable stable disease. PMID- 20839000 TI - High-risk lesions diagnosed at MRI-guided vacuum-assisted breast biopsy: can underestimation be predicted? AB - OBJECTIVES: To evaluate the frequency of diagnosis of high-risk lesions at MRI guided vacuum-assisted breast biopsy (MRgVABB) and to determine whether underestimation may be predicted. METHODS: Retrospective review of the medical records of 161 patients who underwent MRgVABB was performed. The underestimation rate was defined as an upgrade of a high-risk lesion at MRgVABB to malignancy at surgery. Clinical data, MRI features of the biopsied lesions, and histological diagnosis of cases with and those without underestimation were compared. RESULTS: Of 161 MRgVABB, histology revealed 31 (19%) high-risk lesions. Of 26 excised high risk lesions, 13 (50%) were upgraded to malignancy. The underestimation rates of lobular neoplasia, atypical apocrine metaplasia, atypical ductal hyperplasia, and flat epithelial atypia were 50% (4/8), 100% (5/5), 50% (3/6) and 50% (1/2) respectively. There was no underestimation in the cases of benign papilloma without atypia (0/3), and radial scar (0/2). No statistically significant differences (p > 0.1) between the cases with and those without underestimation were seen in patient age, indications for breast MRI, size of lesion on MRI, morphological and kinetic features of biopsied lesions. CONCLUSIONS: Imaging and clinical features cannot be used reliably to predict underestimation at MRgVABB. All high-risk lesions diagnosed at MRgVABB require surgical excision. PMID- 20839001 TI - Dual-energy contrast-enhanced digital mammography: initial clinical results. AB - OBJECTIVE: To assess the diagnostic accuracy of Dual-Energy Contrast-Enhanced Digital Mammography (CEDM) as an adjunct to mammography (MX) versus MX alone and versus mammography plus ultrasound (US). MATERIALS AND METHODS: 120 women with 142 suspect findings on MX and/or US underwent CEDM. A pair of low- and high energy images was acquired using a modified full-field digital mammography system. Exposures were taken in MLO at 2 min and in CC at 4 min after the injection of 1.5 ml/kg of an iodinated contrast agent. One reader evaluated MX, US and CEDM images during 2 sessions 1 month apart. Sensitivity, specificity, and area under the ROC curve were estimated. RESULTS: The results from pathology and follow-up identified 62 benign and 80 malignant lesions. Areas under the ROC curves were significantly superior for MX+CEDM than it was for MX alone and for MX+US using BI-RADS. Sensitivity was higher for MX+CEDM than it was for MX (93% vs. 78%; p < 0.001) with no loss in specificity. The lesion size was closer to the histological size for CEDM. All 23 multifocal lesions were correctly detected by MX+CEDM vs. 16 and 15 lesions by MX and US respectively. CONCLUSION: Initial clinical results show that CEDM has better diagnostic accuracy than mammography alone and mammography+ultrasound. PMID- 20839002 TI - ESUR guidelines: ovarian cancer staging and follow-up. AB - OBJECTIVE: To design clear guidelines for the staging and follow-up of patients with ovarian cancer, and to provide the radiologist with a framework for use in multidisciplinary conferences. METHODS: Guidelines for ovarian cancer staging and follow-up were defined by the female imaging subcommittee of the ESUR (European Society of Urogenital Radiology) based on the expert consensus of imaging protocols of 12 leading institutions and a critical review of the literature. RESULTS: Computed tomography (CT) with coverage of the base of the lungs to the inguinal region is regarded as the imaging technique of choice for preoperative staging. Critical diagnostic criteria are presented and the basis for a structured report for preoperative staging is outlined. Following primary treatment for ovarian cancer, clinical assessment and CA-125 are routinely used to monitor patients. For suspected recurrence, CT remains the imaging modality of choice, with positron emission tomography (PET)/CT emerging as the optimal imaging technique for suspected recurrence, particularly in patients with negative CT or magnetic resonance imaging (MRI). CONCLUSIONS: CT is the imaging modality of choice for preoperative staging and detection of recurrence in patients with ovarian cancer. PMID- 20839003 TI - Cognitive performance and smoking in first-episode psychosis: the self-medication hypothesis. AB - The self-medication hypothesis attempts to explain the extraordinary high levels of cigarette smoking in schizophrenia; patients may smoke in an attempt to reduce their cognitive deficits, symptoms, or the side effects of antipsychotics. In a previous report, we detected beneficial performance in attention and working memory in patients with first-episode psychosis who smoked compared to non smoking patients soon after stabilization. In the present study, we examine differences in the course of those deficits 12 months after the initiation of antipsychotic treatment. We also explore the association between smoking and symptoms and side effects of medication. Neuropsychological assessments were performed at baseline, month 6 and month 12 using a computerized battery that included measures of sustained attention (Continuous Performance Test CPT-O), selective attention (Stroop interference task) and working memory (CPT-XO). Patients met the criterion of fitting in the same smoking category throughout the study: non-smoker (n = 15; 0 cigarettes/day) and smoker (n = 26; >15 cigarettes/day). The non-smoking patients showed significant cognitive improvements, whereas smoking patients lost their superior baseline performance, which was probably obtained through nicotinic stimulation, at the 6- and 12-month assessments due to a static course of deficits. Smokers did not obtain any cognitive benefit after instauration of treatment and worsen their symptoms over the first year. These results suggest that smoking may constitute a marker of a more severe illness. Smoking was not associated with fewer extrapyramidal side effects. Smoking might improve attention and working memory to a similarly modest extent as atypical antipsychotics and could reflect an effort to ameliorate these cognitive dysfunctions previous to treatment instauration. PMID- 20839004 TI - Severity of alcohol-related problems and mortality: results from a 20-year prospective epidemiological community study. AB - There is evidence that high alcohol use is associated with an increase in mortality. Little is known about long-term effects of problematic alcohol consumption in non-clinical (community) populations. The aim of our study was to obtain data on this and related issues in a representative rural community sample assessed longitudinally over a period of 20 years. Assessments focused on a baseline survey from 1980 to 1984 and 20-year follow-up from 2001 to 2004. Based on expert interviews and standardized self-rating scales (e.g. MALT; Munich Alcoholism Test), the following three groups were defined (a) severe alcohol problems, (b) moderate alcohol problems, and (c) no alcohol problems. Mortality and hazard rates were analyzed with logistic and Cox regression adjusted for several health risk factors. From an original community sample of 1,465 individuals, 448 were deceased at 20-year follow-up. Participation rates were high. Baseline prevalence according to the MALT was 1.6% for severe alcohol problems and 4.0% for moderate alcohol problems. Over the 20-year time span, individuals with severe alcohol problems had a significantly elevated risk for dying earlier than the group with no alcohol problems (2.4 times higher). Mortality for those with moderate alcohol problems at baseline had a non significantly elevated 20-year mortality risk (1.5 times higher) compared to those with no alcohol problems. Cox survival analyses corroborate these findings from multiple sequential logistic regression analyses. In discussing the mortality risk of persons with alcohol problems, the severity of the alcohol problems must be taken into account. PMID- 20839005 TI - Age-induced loss of wound-healing ability in potato tubers is partly regulated by ABA. AB - Wounding of potato (Solanum tuberosum L.) tubers induces the development of a suberized closing layer and wound periderm that resists desiccation and microbial invasion. Wound-healing ability declines with tuber age (storage period). The mechanism of loss in healing capacity with age is not known; however, upregulation of superoxide production, increased ABA biosynthesis and phenylalanine ammonia lyase (PAL) activity in response to wounding are processes critical to the development of a suberized closing layer and wound periderm. Therefore, the role of ABA in modulating the age-induced loss of wound-healing ability of tubers was examined. Non-wounded older tubers had 86% less ABA (dry matter basis) than younger tubers. PAL transcript increased in younger tubers within 24 h of wounding, but transcription was delayed by 5 days in older tubers. Wound-induced PAL activity increased more rapidly in younger than older tubers. ABA treatment increased PAL expression and activity in tissue from both ages of tubers and restored the 24 h transcription time line in older tubers. Moreover, ABA treatment of wounded older tubers enhanced their resistance to water vapor loss following a 6-day wound-healing period. Wound-induced accumulation of suberin poly(phenolic(s)) (SPP) and suberin poly(aliphatic(s)) (SPA) was measurably slower in older versus younger tubers. ABA treatment hastened SPP accumulation in older tubers to match that in younger tubers, but only enhanced SPA accumulations over the initial 4 days of healing. Age-induced loss of wound healing ability is thus partly due to reduced ability to accumulate ABA and modulate the production of SPP through PAL in response to wounding and to dysfunction in the downstream signaling events that couple SPA biosynthesis and/or deposition to ABA. ABA treatment partly restored the healing ability of older tubers by enhancing the accumulation of SPP without restoring wound-induced superoxide forming ability to the level of younger tubers. The coupling of phenolic monomers into the poly(phenolic) domain of suberin was therefore not limited by the diminished wound-induced superoxide production of older tubers. PMID- 20839006 TI - Overexpression of microRNA395c or 395e affects differently the seed germination of Arabidopsis thaliana under stress conditions. AB - The Arabidopsis genome encodes six members of microRNA395 (miR395) family previously determined to regulate the expression of ATP sulfurylase (APS) and the sulfate transporter SULTR2;1. However, the mRNA targets for the individual miR395 family members and the biological consequences produced by target gene regulation of each miR395 remain to be identified. In this study, a transgenic approach was employed to determine the mRNA targets for each miR395 family member as well as the role each member plays in plant growth under abiotic stress conditions. Overexpression of miR395c or miR395e retarded and accelerated, respectively, the seed germination of Arabidopsis under high salt or dehydration stress conditions. Despite a single nucleotide difference between miR395c and miR395e, the cleavage of mRNA targets, APS1, APS3, APS4 and SULTR2;1, was not same in miR395c- and miR395e-overexpressing plants. These results demonstrate that a given miRNA family containing a single nucleotide difference can guide the cleavage of various mRNA targets, thereby acting as a positive or negative regulator of seed germination under stress. PMID- 20839007 TI - Salicylate-mediated suppression of jasmonate-responsive gene expression in Arabidopsis is targeted downstream of the jasmonate biosynthesis pathway. AB - Jasmonates (JAs) and salicylic acid (SA) are plant hormones that play pivotal roles in the regulation of induced defenses against microbial pathogens and insect herbivores. Their signaling pathways cross-communicate providing the plant with a regulatory potential to finely tune its defense response to the attacker(s) encountered. In Arabidopsis thaliana, SA strongly antagonizes the jasmonic acid (JA) signaling pathway, resulting in the downregulation of a large set of JA-responsive genes, including the marker genes PDF1.2 and VSP2. Induction of JA-responsive marker gene expression by different JA derivatives was equally sensitive to SA-mediated suppression. Activation of genes encoding key enzymes in the JA biosynthesis pathway, such as LOX2, AOS, AOC2, and OPR3 was also repressed by SA, suggesting that the JA biosynthesis pathway may be a target for SA mediated antagonism. To test this, we made use of the mutant aos/dde2, which is completely blocked in its ability to produce JAs because of a mutation in the ALLENE OXIDE SYNTHASE gene. Mutant aos/dde2 plants did not express the JA responsive marker genes PDF1.2 or VSP2 in response to infection with the necrotrophic fungus Alternaria brassicicola or the herbivorous insect Pieris rapae. Bypassing JA biosynthesis by exogenous application of methyl jasmonate (MeJA) rescued this JA-responsive phenotype in aos/dde2. Application of SA suppressed MeJA-induced PDF1.2 expression to the same level in the aos/dde2 mutant as in wild-type Col-0 plants, indicating that SA-mediated suppression of JA-responsive gene expression is targeted at a position downstream of the JA biosynthesis pathway. PMID- 20839009 TI - Association of common DNA sequence variants at 33 genetic loci with blood lipids in individuals of African ancestry from Jamaica. AB - The relevance of loci associated with blood lipids recently identified in European populations in individuals of African ancestry is unknown. We tested association between lipid traits and 36 previously described single-nucleotide polymorphisms (SNPs) in 1,466 individuals of African ancestry from Spanish Town, Jamaica. For the same allele and effect direction as observed in individuals of European ancestry, SNPs at three loci (1p13, 2p21, and 19p13) showed statistically significant association (p < 0.05) with LDL, two loci (11q12 and 20q13) showed association with HDL cholesterol, and two loci (11q12 and 2p24) showed association with triglycerides. The most significant association was between a SNP at 1p13 and LDL cholesterol (p = 4.6 * 10(-8)). This SNP is in a linkage disequilibrium region containing four genes (CELSR2, PSRC1, MYBPHL, and SORT1) and was recently shown to relate to risk for myocardial infarction. Overall, the results of this study suggest that much of the genetic variation which influences blood lipids is shared across ethnic groups. PMID- 20839008 TI - The majority of the genetic risk for Paget's disease of bone is explained by genetic variants close to the CSF1, OPTN, TM7SF4, and TNFRSF11A genes. AB - Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 * 10(-4) to 3.8 * 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 * 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 * 10(-4) and 8.8 * 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes. PMID- 20839010 TI - PTEN transcript variants caused by illegitimate splicing in "aged" blood samples and EBV-transformed cell lines. AB - PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. Mutations occur in either heritable or sporadic fashion. Sequencing of cDNA from patients and normal individuals often reveals splicing variants (SVs) of PTEN, some of which are non-mutation related. To investigate whether these SVs were the result of illegitimate splicing (a general decrease of fidelity in splicing site selection in "aged" samples), we tested "aged" blood from individuals who had normal PTEN transcripts in their "fresh" mononuclear cells. Blood from 20 normal individuals was collected and split into two aliquots. Total RNA and DNA were extracted immediately ("fresh") and 48 h later ("aged"), respectively. Using RT-PCR, subcloning and sequencing, we found seven types of SVs. No mutation was detected in the related intron-exon flanking region in genomic DNA in either "fresh" or "aged" samples. Some of the SVs were also consistently present in both the "fresh" and "aged" EBV-transformed lymphoblastoid cells from six normal individuals. Western blot data indicated that the PTEN protein level (in full length) was not altered in the "fresh" EBV transformed lymphoblastoid cells with SVs. In conclusion, our data demonstrate that PTEN illegitimate splicing often occurs in "aged" blood and EBV-transformed lymphoblastoid cells. Therefore, it is critical to note the time point of RNA extraction when investigating for PTEN aberrant transcripts. We hope that our data will increase awareness about the sample status, because gene expression data may be potentially flawed from "aged" samples, particularly when dealing with clinical samples. PMID- 20839011 TI - Depressive symptoms during the first chemotherapy cycle predict mortality in patients with advanced non-small cell lung cancer. AB - PURPOSE: Depressive symptoms are commonly experienced by cancer patients, especially those with advanced disease. The link between depression and survival outcome in cancer patients has received increasing attention. The purpose of this study was to determine, after adjusting the known covariates, whether the depressive symptoms during the first cycle of chemotherapy can predict the mortality of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with stage III or IV NSCLC were recruited from a large teaching hospital located in northern Taiwan. Depressive symptoms were assessed during the first cycle of chemotherapy using the Hospital Anxiety and Depression Scale-Depression subscale. A cut-off of 7/8 was used to categorize patients into depressed and non depressed groups. All patients were followed up until the end of the study. The follow-up time ranged from 10 to 30 months. RESULTS: The study sample consisted of 90 NSCLC patients. Twenty patients (22.2%) were categorized as depressed. The median survival time in the depressed group was significantly shorter than that of the non-depressed group (11.83 vs. 24.47 months, P = 0.017). After controlling for demographic and clinical factors, depressive symptoms remained significantly (p = 0.023) associated with a shorter survival time. Compared to the non depressed group, the depressed group had twice the risk of death (HR = 2.18, 95% CI = 1.11 to 4.28). CONCLUSION: The finding supports that depressive symptoms at the early phase of treatment can predict shorter survival in patients with advanced NSCLC. PMID- 20839012 TI - Endoscopic transnasal surgery for pure intradural lesions--balance between advantages and disadvantages. PMID- 20839013 TI - Halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine produces beneficial effects in experimental stroke and seizures. AB - The effects of the halogenated aromatic amino acid 3,5-dibromo-D: -tyrosine (3,5 DBr-D: -Tyr) were studied in rat models of stroke and epileptic seizures caused by middle cerebral artery occlusion (MCAo) through respective intracerebral injection of endothelin-1 (ET-1) and intraperitoneal (i.p.) injection of pentylenetetrazole (PTZ). 3,5-DBr-D: -Tyr was administered as three bolus injections (30 or 90 mg/kg, i.p.) starting at 30, 90, and 180 min after ET-1 administration or as a single bolus (30 mg/kg, i.p.) 15 min prior to PTZ administration. Neurological deficits and infarct volume were estimated 3 days after ET-1 administration and seizure score was assessed during the first 20 min after PTZ administration. The safety of 3,5-DBr-D: -Tyr was evaluated in control animals using telemetry to measure cardiovascular parameters and immunostaining to assess the level of activated caspase-3. 3,5-DBr-D: -Tyr significantly improved neurological function and reduced infarct volume in the brain even when the treatment was initiated 3 h after the onset of MCAo. 3,5-DBr-D: -Tyr significantly depressed PTZ-induced seizures. 3,5-DBr-D: -Tyr did not cause significant changes in arterial blood pressure, heart rate and spontaneous locomotor activity, nor did it increase the number of activated caspase-3 positive cells in the brain. We conclude that 3,5-DBr-D: -Tyr, by alleviating the deleterious effects of MCAo and PTZ in rats with no obvious intrinsic effects on cardiovascular parameters and neurodegeneration, exhibits promising potential as a novel therapeutic direction for stroke and seizures. PMID- 20839014 TI - Probing mammalian spermine oxidase enzyme-substrate complex through molecular modeling, site-directed mutagenesis and biochemical characterization. AB - Spermine oxidase (SMO) and acetylpolyamine oxidase (APAO) are FAD-dependent enzymes that are involved in the highly regulated pathways of polyamine biosynthesis and degradation. Polyamine content is strictly related to cell growth, and dysfunctions in polyamine metabolism have been linked with cancer. Specific inhibitors of SMO and APAO would allow analyzing the precise role of these enzymes in polyamine metabolism and related pathologies. However, none of the available polyamine oxidase inhibitors displays the desired characteristics of selective affinity and specificity. In addition, repeated efforts to obtain structural details at the atomic level on these two enzymes have all failed. In the present study, in an effort to better understand structure-function relationships, SMO enzyme-substrate complex has been probed through a combination of molecular modeling, site-directed mutagenesis and biochemical studies. Results obtained indicate that SMO binds spermine in a similar conformation as that observed in the yeast polyamine oxidase FMS1-spermine complex and demonstrate a major role for residues His82 and Lys367 in substrate binding and catalysis. In addition, the SMO enzyme-substrate complex highlights the presence of an active site pocket with highly polar characteristics, which may explain the different substrate specificity of SMO with respect to APAO and provide the basis for the design of specific inhibitors for SMO and APAO. PMID- 20839015 TI - Influence of RET/PTC1 and RET/PTC3 oncoproteins in radiation-induced papillary thyroid carcinomas on amounts of cytoskeletal protein species. AB - Radiation-induced human papillary thyroid carcinomas (PTCs) show a high prevalence of fusions of the RET proto-oncogene to heterologous genes H4 (RET/PTC1) and ELE1 (RET/PTC3), respectively. In contrast to the normal membrane bound RET protein, aberrant RET fusion proteins are constitutively active oncogenic cytosolic proteins that can lead to malignant transformation of thyroid epithelia. To detect specific tumor-associated protein changes that reflect the effect of RET/PTC fusion proteins, we analyzed normal thyroid tissues, thyroid tumors of the RET/PTC1 and RET/PTC3 type and their respective lymph node metastases by a combination of high-resolution two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-mass spectrometry. PTCs without RET rearrangements served as controls. Several cytoskeletal protein species showed quantitative changes in tumors and lymph node metastases harboring RET/PTC1 or RET/PTC3. We observed prominent C-terminal actin fragments assumedly generated by protease cleavages induced due to enhanced amounts of the active actin-binding protein cofilin-1. In addition, three truncated vimentin species, one of which was proven to be headless, were shown to be highly abundant in tumors and metastases of both RET/PTC types. The observed protein changes are closely connected with the constitutive activation of RET-rearranged oncoproteins and reflect the importance to elucidate disease-related typical signatures on the protein species level. PMID- 20839017 TI - Electronic structure and PCA analysis of covalent and non-covalent acetylcholinesterase inhibitors. AB - Hartree-Fock and density functional methods were used to analyze electronic and structural properties of known drugs to evaluate the influence of these data on acetylcholinesterase inhibition. The energies of the frontier orbitals and the distances between the more acidic hydrogen species were investigated to determine their contributions to the activity of a group of acetylcholinesterase inhibitors. Electrostatic potential maps indicated suitable sites for drugs enzyme interactions. In this study, the structural, electronic and spatial properties of nine drugs with known inhibitory effects on acetylcholinesterase were examined. The data were obtained based on calculations at the B3LYP/6-31 + G(d,p) level. Multivariate principal components analysis was applied to 18 parameters to determine the pharmacophoric profile of acetylcholinesterase inhibitors. Desirable features for acetylcholinesterase inhibitor molecules include aromatic systems or groups that simulate the surface electrostatic potential of aromatic systems and the presence of a sufficient number of hydrogen acceptors and few hydrogen donors. PCA showed that electronic properties, including the HOMO-1 orbital energy, logP and aromatic system quantity, as well as structural data, such as volume, size and H-H distance, are the most significant properties. PMID- 20839016 TI - Pyruvate: immunonutritional effects on neutrophil intracellular amino or alpha keto acid profiles and reactive oxygen species production. AB - For the first time the immunonutritional role of pyruvate on neutrophils (PMN), free alpha-keto and amino acid profiles, important reactive oxygen species (ROS) produced [superoxide anion (O(2) (-)), hydrogen peroxide (H(2)O(2))] as well as released myeloperoxidase (MPO) acitivity has been investigated. Exogenous pyruvate significantly increased PMN pyruvate, alpha-ketoglutarate, asparagine, glutamine, aspartate, glutamate, arginine, citrulline, alanine, glycine and serine in a dose as well as duration of exposure dependent manner. Moreover, increases in O(2) (-) formation, H(2)O(2)-generation and MPO acitivity in parallel with intracellular pyruvate changes have also been detected. Regarding the interesting findings presented here we believe, that pyruvate fulfils considerably the criteria for a potent immunonutritional molecule in the regulation of the PMN dynamic alpha-keto and amino acid pools. Moreover it also plays an important role in parallel modulation of the granulocyte-dependent innate immune regulation. Although further research is necessary to clarify pyruvate's sole therapeutical role in critically ill patients' immunonutrition, the first scientific successes seem to be very promising. PMID- 20839018 TI - Structural analysis of natural killer cell receptor protein 1 (NKR-P1) extracellular domains suggests a conserved long loop region involved in ligand specificity. AB - Receptor proteins at the cell surface regulate the ability of natural killer cells to recognize and kill a variety of aberrant target cells. The structural features determining the function of natural killer receptor proteins 1 (NKR-P1s) are largely unknown. In the present work, refined homology models are generated for the C-type lectin-like extracellular domains of rat NKR-P1A and NKR-P1B, mouse NKR-P1A, NKR-P1C, NKR-P1F, and NKR-P1G, and human NKR-P1 receptors. Experimental data on secondary structure, tertiary interactions, and thermal transitions are acquired for four of the proteins using Raman and infrared spectroscopy. The experimental and modeling results are in agreement with respect to the overall structures of the NKR-P1 receptor domains, while suggesting functionally significant local differences among species and isoforms. Two sequence regions that are conserved in all analyzed NKR-P1 receptors do not correspond to conserved structural elements as might be expected, but are represented by loop regions, one of which is arranged differently in the constructed models. This region displays high flexibility but is anchored by conserved sequences, suggesting that its position relative to the rest of the domain might be variable. This loop may contribute to ligand-binding specificity via a coupled conformational transition. PMID- 20839019 TI - Kinetically stable high-energy isomers of C14H12 and C12H10N2 derived from cis stilbene and cis-azobenzene. AB - Following on from our recent enforced geometry optimization (EGO) investigation of isomerization in cis-stilbene (J Comput Chem, in press) we report the discovery of two interesting new, symmetrical "fused sandwich" isomers of both cis-stilbene and the related cis-azobenzene. The isomers were obtained by applying external forces to pairs of carbon atoms from each of the benzene rings in cis-stilbene and cis-azobenzene simultaneously, and are all at least 100 kcal mol(-1) higher in energy than the starting material. Each new structure was characterized as a minimum by vibrational analysis. Despite their high energy, all of the new isomers appear to be kinetically stable with respect to rearrangement back to cis-stilbene or cis-azobenzene, respectively. PMID- 20839020 TI - Theoretical studies and vibrational spectra of 1H-indole-3-acetic acid. Exploratory conformational analysis of dimeric species. AB - Theoretical studies on 1H-indole-3-acetic acid (IAA) were performed to investigate the conformational properties of dimeric species and vibrational spectra. Experimental infrared spectra at 100 K and 297 K and Raman spectrum at 297 K were analyzed and compared against calculations performed at B3LYP/6-31G** level. A exploratory study of the conformational space of dimeric species was performed. Our analysis showed that dimeric forms predicted theoretically contribute distinctively to the assignments of experimental results. These structures are defined by the orientation of the acetyl moieties with respect to the plane of indole ring. The dimers are formed by two symmetrical IAA monomers (one of them with the acetyl moiety upward oriented, Re-face, and the other isomer having the acetyl moiety downward oriented, Si-face) in tail-to-tail way. The X-ray geometry and FTIR vibrational frequencies were compared with the results of DFT calculations. A conformational equilibrium involving the non equivalent IAA dimers: CCT-CCT, A(+)A(+)T-A(-)A(-)T, A(+)A(-)T-A(-)A(+)T, and A(+)CT-A(-)CT was found. The relation of the conformational properties of the IAA molecule with the features of the vibrational spectra was described in detail. The band assignments were discussed as related to the conformations properties. Our analysis shows the significance of the theoretical study of the conformational space of the monomeric molecule in the rationalization of experimental results. PMID- 20839021 TI - Singular value decomposition analysis of the torsional angles of dopamine reuptake inhibitor GBR 12909 analogs: effect of force field and charges. AB - Three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis of large, flexible molecules, such as the dopamine reuptake inhibitor GBR 12909 (1), is complicated by the fact that they can take on a wide range of closely related conformations. The first step in the analysis is to classify the conformers into groups. Over 600 conformers each of a piperazine (2) and piperidine (3) analog of 1 were generated by random search conformational analysis using the Merck Molecular Force Field (MMFF94). Singular value decomposition (SVD) was used to group the conformers of 2 and 3 by the similarity of their non-ring torsional angles. SVD uncovered subtle differences in their conformer populations due to that fact that the conformers separate along different principal components, and ultimately to the fact that different torsional angles are the chief contributors to these components. The results were compared to our previous SVD analysis (Fiorentino, et al., Journal of Computational Chemistry, 2006, 27, 609-620) of conformer populations of 2 and 3 generated by the Tripos force field and Gasteiger-Huckel charges. Except for the dominant contribution of angle B3 to principal component 8 seen with both force fields, the angles which are chiefly responsible for the grouping of the conformers of 2 and 3 are different with both force fields. This illustrates that SVD is useful in identifying unique groupings of conformers in large data sets of flexible molecules-a first step in selecting representative conformers for 3D QSAR modeling studies. PMID- 20839022 TI - Augmented survival of Neisseria gonorrhoeae within biofilms: exposure to atmospheric pressure non-thermal plasmas. AB - Bacteria embedded within biofilms present a challenge to surface decontamination by conventional means. Atmospheric pressure non-thermal plasma processes have emerged as a promising approach to overcoming this problem. We used atmospheric pressure non-equilibrium plasmas (APNPs) to assess planktonic versus biofilm resident bacterial (Neisseria gonorrhoeae) susceptibility to treatment. The decontamination efficiency of the process was evaluated against bacteria embedded within a biofilm, as well as planktonic cells placed on a glass surface. Bacterial survival was assessed using a combination of colony forming unit (CFU) ability and vital staining with a combination of SYTO9 plus propidium iodide. Both methods revealed an increased resistance of biofilm-resident bacteria compared with planktonic cells, after a 20-min exposure to the APNPs. Transmission electron microscopy revealed disruption and damage to the cell wall, resulting in the release of cytoplasmic compounds, alterations in morphology, and a decrease in cell volume, indicating that APNPs may affect the cell wall. Present results show that biofilm-resident bacteria demonstrate augmented survival when exposed to APNP treatment and therefore that decontamination procedures should take into account this survival when evaluating surface decontamination measures. PMID- 20839023 TI - Leuconostoc bacteremia in three patients with malignancies. AB - Leuconostoc is a Gram-positive coccus characterized by its resistance to glycopeptide antibiotics. Generally, this bacterium is susceptible to beta-lactam antibiotics; however, here we present a leukemia patient who developed leuconostoc bacteremia during antimicrobial therapy with carbapenem. The appropriate choice of antibiotics at optimal doses enables leuconostoc infection to be overcome, even in compromised hosts. We report 3 cases of leuconostoc bacteremia: the leukemia case which was successfully treated, along with discussions of two other cases with malignancies. PMID- 20839024 TI - Epidemiological characteristics of genital herpes and condyloma acuminata in patients presenting to urologic and gynecologic clinics in Korea. AB - As viral sexually transmitted infections (STIs) are hard to cure completely and because they recur frequently, the management of patients and the prevention of the spread of viral STIs are important, rather than focusing on their treatment, unlike the focus for bacterial STIs. Thus, their prevalence and epidemiological characteristics should be investigated first. This study examined the prevalence of genital herpes and condyloma acuminata in patients visiting urologic and gynecologic clinics and evaluated the epidemiological characteristics of these diseases through questionnaire surveys. Out of 167,767 patients, 1,585 were reported to have genital herpes and condyloma acuminata, and the prevalences of the two diseases were 0.58 and 0.37%, respectively. The percentage of patients with viral STIs as a proportion of the total number of patients with STIs including bacterial STIs, was 35.6%. While the prevalence of genital herpes was relatively higher in middle-aged patients, that of condyloma acuminata was observed to be higher in relatively young patients. Among the patients participating in the questionnaire survey, 39.5 and 21.0% responded that they had experienced recurrence of genital herpes and condyloma acuminata, respectively. In conclusion, because the prevalences of genital herpes and condyloma acuminata as viral STIs were not trivial compared to that of bacterial STIs, and because of their frequent recurrence, policies adjusted to the characteristics of these viral STIs and more studies on the management of recurrence are necessary. PMID- 20839025 TI - Selection of first-line i.v. antibiotics for acute pyelonephritis in patients requiring emergency hospital admission. AB - Febrile urinary tract infections (UTIs) often require the intravenous infusion of antibiotics and/or hospitalization. Acute pyelonephritis (AP) is one of the most severe forms of UTI, and the antibiotics we should use as the first line and the risk factors for treatment failure remain controversial. The objective of this study was to investigate the efficacy of i.v. antibiotics selected for the treatment of febrile AP and to examine the risk factors for antibiotic resistance. We set risk factors for antibiotic treatment failure such as age, sex, and the presence of underlying urinary tract disease. We classified all cases into 49 cases of complicated AP and 24 cases of uncomplicated AP according to the presence of underlying urinary tract diseases, and examined the characteristics of the patients and the efficacy of the antibiotics used in this study. We investigated risk factors which relate to initial treatment failure and the duration of antibiotic treatment. Initial antibiotic treatment failure was significantly correlated to C-reactive protein in complicated AP and to positive blood culture in uncomplicated AP. We revealed a significant correlation between the duration of the given antibiotics and diabetes mellitus or positive blood culture in uncomplicated AP, and tazobactam/piperacillin was significantly related to prolongation of antibiotic treatment in complicated AP. In conclusion, in this study, a positive blood culture was the representative risk factor that related to both initial treatment failure and longer duration of the given antibiotics in uncomplicated AP. PMID- 20839026 TI - Antibacterial activity of carbapenems against clinical isolates of respiratory bacterial pathogens in the northeastern region of Japan in 2007. AB - As the increasing prevalence of resistant strains of respiratory bacterial pathogens has recently been reported, continuous monitoring of the susceptibility of clinical isolates to antibacterial agents is important. We performed a surveillance study focusing on the susceptibility of major respiratory bacterial pathogens in the northeastern region of Japan to carbapenems and control drugs. A total of 168 bacterial strains isolated from patients with respiratory tract infections in 2007 were collected and the minimum inhibitory concentration (MIC) determined. MIC data were subjected to pharmacokinetic/pharmacodynamic analysis with Monte Carlo simulation to calculate the probability of achieving the target of time above MIC with each carbapenem. All Moraxella catarrhalis, Streptococcus pneumoniae, and methicillin-sensitive Staphylococcus aureus isolates were susceptible to carbapenems. Despite the increasing prevalence of beta-lactamase nonproducing ampicillin-resistant strains, all Haemophilus influenzae isolates were susceptible to meropenem. For Pseudomonas aeruginosa, the susceptibility rates for meropenem and biapenem were 76.7%, and the highest probability of achieving pharmacodynamic target (40% of the time above MIC) was obtained with meropenem 0.5 g three times daily as a 4-h infusion (89.4%), followed by meropenem 0.5 g four times daily as a 1-h infusion (88.4%). Carbapenems have retained their position as key drugs for severe respiratory tract infections. PMID- 20839027 TI - Fertility and precocity of Osmunda x intermedia offspring in culture. AB - The feasibility of later-generation hybrid production in ferns has not been previously studied, although it is a significant factor in relation to reproductive isolation. Osmunda x intermedia, a hybrid between O. japonica and O. lancea, is semifertile and has moderate spore germination rates. Under the artificial conditions of this study, F2 and F3 offspring were formed. Some of the F2 offspring showed precocity, and some of the F3 offspring also showed precocity. This fertility suggests that introgressive hybridization might be ongoing in nature. This also indicates a currently unknown genetic control over the timing of fertile frond production in Osmunda. PMID- 20839028 TI - A phase I study of continuous infusion cilengitide in patients with solid tumors. AB - BACKGROUND: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3-5 h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. METHODS: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 h after infusion bag change. RESULTS: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40 mg/h. Toxicities were limited to grade <= 2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady state concentration increased proportionally with dose. CONCLUSIONS: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40 mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion. PMID- 20839029 TI - Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies. AB - BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 +/- 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24 hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity. PMID- 20839030 TI - An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma. AB - BACKGROUND AND RATIONALE: Bortezomib (PS-341, VELCADE(r)) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. METHODS: The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. RESULTS: Thirty five patients enrolled and received a median of 2 cycles of treatment (range 1 12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. CONCLUSIONS: This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib. PMID- 20839031 TI - Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer. AB - BACKGROUND: To define maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of sorafenib plus capecitabine/cisplatin in advanced gastric cancer (AGC) patients. METHODS: Four dose-level combinations were tested in a standard 3 + 3 dose escalation design. Level 1: sorafenib 400 mg/d, capecitabine 1,600 mg/m(2)/d, cisplatin 80 mg/m(2). Level 2: sorafenib 800 mg/d, capecitabine 1,600 mg/m(2)/d, cisplatin 80 mg/m(2). Level 3: sorafenib 800 mg/d, capecitabine 2,000 mg/m(2)/d, cisplatin 80 mg/m(2). Level 1A: sorafenib 800 mg/d, capecitabine 1,600 mg/m(2)/d, cisplatin 60 mg/m(2). RESULTS: There were 1 DLT at Level 2, and 2 DLTs at Level 3 (Level 3 was MTD). Since the relative dose intensity (RDI) of sorafenib and capecitabine could not be maintained at Level 2, Level 1A was newly investigated. As no DLT was observed and RDI remained above 80%, Level 1A is the recommended dose for the next clinical trial. Objective response rate was 62.5% (10 of 16 patients, 95% CI; 38.8-86.2%). Median progression-free survival and overall survival were 10.0 months (95% CI; 7.4 13.8) and 14.7 months (95% CI; 12.0-20.0), respectively. CONCLUSIONS: Sorafenib 400 mg bid daily, capecitabine 800 mg/m(2) bid (days 1-14), and cisplatin 60 mg/m(2) (day 1) is recommended for further development in AGC. PMID- 20839034 TI - Analysis of the multi-item dimensionality of patients' perceived value in hospital services. AB - The purpose of this research is to analyse the multi-item dimensionality of patients' perceived value in hospital service. A total of 564 patients administered to Gulhane Military Medical Academy were surveyed. Sample population was specified through convenience sampling procedure. A face to face survey was conducted by three interviewers in August 2008. Confirmatory Data Analysis was carried out to reach the final data analysis. A scale of overall perceived value in health service was developed, which was composed of three dimensions and represented by 21 items. These dimensions were: Functional value, emotional value, and social value. The results indicated that perceived value was a multidimensional construct that affects the whole process of service purchasing. If the hospitals managers give importance to the sub-dimensions of the patient value inclined to their own hospitals and they regularly examine the situation of these dimensions, they can move one step ahead in achieving patient satisfaction and loyalty. PMID- 20839032 TI - CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression. AB - Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important alpha-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands. PMID- 20839035 TI - TauND: a thyroid nodule detection system for analysis of ultrasound images and videos. AB - In this paper, we present a computer-aided-diagnosis (CAD) system prototype, named TND (Thyroid Nodule Detector), for the detection of nodular tissue in ultrasound (US) thyroid images and videos acquired during thyroid US examinations. The proposed system incorporates an original methodology that involves a novel algorithm for automatic definition of the boundaries of the thyroid gland, and a novel approach for the extraction of noise resilient image features effectively representing the textural and the echogenic properties of the thyroid tissue. Through extensive experimental evaluation on real thyroid US data, its accuracy in thyroid nodule detection has been estimated to exceed 95%. These results attest to the feasibility of the clinical application of TND, for the provision of a second more objective opinion to the radiologists by exploiting image evidences. PMID- 20839033 TI - Perspectives on the mesenchymal origin of metastatic cancer. AB - Emerging evidence suggests that many metastatic cancers arise from cells of the myeloid/macrophage lineage regardless of the primary tissue of origin. A myeloid origin of metastatic cancer stands apart from origins involving clonal evolution or epithelial-mesenchymal transitions. Evidence is reviewed demonstrating that numerous human cancers express multiple properties of macrophages including phagocytosis, fusogenicity, and gene/protein expression. It is unlikely that the macrophage properties expressed in metastatic cancers arise from sporadic random mutations in epithelial cells, but rather from damage to an already existing mesenchymal cell, e.g., a myeloid/macrophage-type cell. Such cells would naturally embody the capacity to express the multiple behaviors of metastatic cells. The view of metastasis as a myeloid/macrophage disease will impact future cancer research and anti-metastatic therapies. PMID- 20839036 TI - Sparse representation-based heartbeat classification using independent component analysis. AB - The classification of heartbeats is crucial to identify an arrhythmia. This paper proposes a new method that combines independent component analysis (ICA) with sparse representation-based classification (SRC) to distinguish eight types of heartbeats. We use ICA to extract useful features from heartbeats. A feature vector consists of 100 ICA features along with a RR interval. We use SRC to compute a sparse representation of a test feature vector with respect to all training feature vectors. The type of a test feature vector is determined using the concentration degree of sparse coefficients on each heartbeat type. For experimental purposes, 9800 heartbeats are extracted from the MIT-BIH electrocardiogram (ECG) database. The results show that our proposed method performs better than conventional methods, with 98.35% accuracy and 94.49%-100% sensitivities to several heartbeat types. PMID- 20839037 TI - 3-D surface rendering of myocardial SPECT images segmented by level set technique. AB - SPECT(single photon emission computed tomography) myocardial imaging is a diagnosis technique that images the region of interest and examines any change induced by disease using a computer after injects intravenously a radiopharmaceutical drug emitting gamma ray and the drug has dispersed evenly in the heart . Myocardial perfusion imaging, which contains functional information, is useful for non-invasive diagnosis of myocardial disease but noises caused by physical factors and low resolution give difficulty in reading the images. In order to help reading myocardial images, this study proposed a method that segments myocardial images and reconstructs the segmented region into a 3D image. To resolve difficulty in reading, we segmented the left ventricle, the region of interest, using a level set and modeled the segmented region into a 3D image. PMID- 20839038 TI - Genetic counseling in a busy pediatric metabolic practice. AB - Patients with inborn errors of metabolism and their families require unique clinical care including management of acute illnesses, screening for long term complications, discussion of the etiology of the condition, connections to social supports, and clarification of the recurrence risks and prenatal testing and treatment options. Our multidisciplinary pediatric metabolic clinic combines the skills of metabolic geneticists, pediatric dieticians, social workers, clinical pharmacists, nurses and genetic counselors to provide optimal and well-rounded care for our patients and their families. Given the inherited nature of most inborn errors of metabolism and the necessary long-term management for these disorders, the genetic counselor's role in this clinic setting is integral in providing ongoing support and education for patients and their families. This includes coping with the disease burden, helping patients and families adapt to a condition in the family and ensuring adequate understanding of the genetic risks and the available prenatal diagnostic and reproductive choices. Our clinic provides services to a large geographic area with many isolated populations where unique metabolic diseases are highly prevalent secondary to a founder effect. In this paper, we share our experience in providing longitudinal care to children with complex medical needs due to metabolic disorders and highlight the role of the genetic counselor in this clinic setting. PMID- 20839039 TI - Feeling good, feeling bad: influences of maternal perceptions of the child and marital adjustment on well-being in mothers of children with an autism spectrum disorder. AB - Mothers of children with an autism spectrum disorder (n = 49) participated in a 30-day diary study which examined associations between mothers' positive and negative perceptions of their children, marital adjustment, and maternal well being. Hierarchical linear modeling results revealed that marital adjustment mediated associations between positive perceptions and maternal well-being. Mothers who reported higher levels of positive perceptions of the child were higher in marital adjustment and well-being. Results also revealed that marital adjustment moderated the relation between negative perceptions and negative maternal affect. Mothers low in marital adjustment had a positive association between negative maternal perceptions of the child and negative maternal affect. These findings highlight the dynamic roles that mothers' perceptions and marital adjustment play in determining maternal psychological outcomes. PMID- 20839040 TI - Weighted vests, stereotyped behaviors and arousal in children with autism. AB - The homeostatic theory of stereotyped behaviors assumes that these behaviors modulate arousal. Weighted vests are used to decrease stereotyped behaviors in persons with autism because the input they provide is thought to serve the same homeostatic function. This small-n, randomized and blinded study measured the effects of wearing a weighted vest on stereotyped behaviors and heart rate for six children with autism in the classroom. Weighted vests did not decrease motoric stereotyped behaviors in any participant. Verbal stereotyped behaviors decreased in one participant. Weighted vests did not decrease heart rate. Heart rate increased in one participant. Based on this protocol, the use of weighted vests to decrease stereotyped behaviors or arousal in children with autism in the classroom was not supported. PMID- 20839041 TI - Brief report: Further evidence of sensory subtypes in autism. AB - Distinct sensory processing (SP) subtypes in autism have been reported previously. This study sought to replicate the previous findings in an independent sample of thirty children diagnosed with an Autism Spectrum Disorder. Model-based cluster analysis of parent-reported sensory functioning (measured using the Short Sensory Profile) confirmed the triad of sensory subtypes reported earlier. Subtypes were differentiated from each other based on degree of SP dysfunction, taste/smell sensitivity and vestibular/proprioceptive processing. Further elucidation of two of the subtypes was also achieved in this study. Children with a primary pattern of sensory-based inattention could be further described as sensory seekers or non-seekers. Children with a primary pattern of vestibular/proprioceptive dysfunction were also differentiated on movement and tactile sensitivity. PMID- 20839042 TI - Automated detection of stereotypical motor movements. AB - To overcome problems with traditional methods for measuring stereotypical motor movements in persons with Autism Spectrum Disorders (ASD), we evaluated the use of wireless three-axis accelerometers and pattern recognition algorithms to automatically detect body rocking and hand flapping in children with ASD. Findings revealed that, on average, pattern recognition algorithms correctly identified approximately 90% of stereotypical motor movements repeatedly observed in both laboratory and classroom settings. Precise and efficient recording of stereotypical motor movements could enable researchers and clinicians to systematically study what functional relations exist between these behaviors and specific antecedents and consequences. These measures could also facilitate efficacy studies of behavioral and pharmacologic interventions intended to replace or decrease the incidence or severity of stereotypical motor movements. PMID- 20839043 TI - Face processing in children with autism spectrum disorder: independent or interactive processing of facial identity and facial expression? AB - The current study investigated if deficits in processing emotional expression affect facial identity processing and vice versa in children with autism spectrum disorder. Children with autism and IQ and age matched typically developing children classified faces either by emotional expression, thereby ignoring facial identity or by facial identity disregarding emotional expression. Typically developing children processed facial identity independently from facial expressions but processed facial expressions in interaction with identity. Children with autism processed both facial expression and identity independently of each other. They selectively directed their attention to one facial parameter despite variations in the other. Results indicate that there is no interaction in processing facial identity and emotional expression in autism spectrum disorder. PMID- 20839045 TI - The work of recovery on two assertive community treatment teams. AB - The compatibility of recovery work with the Assertive Community Treatment (ACT) model has been debated; and little is known about how to best measure the work of recovery. Two ACT teams with high and low recovery orientation were identified by expert consensus and compared on a number of dimensions. Using an interpretive, qualitative approach to analyze interview and observation data, teams differed in the extent to which the environment, team structure, staff attitudes, and processes of working with consumers supported principles of recovery orientation. We present a model of recovery work and discuss implications for research and practice. PMID- 20839046 TI - Molecular characterization of the full-length coding sequence of the caprine laminin receptor gene (RPSA). AB - Scrapie is a prion disease in sheep and goats. Ribosomal protein SA (RPSA), also called 37 kDa laminin receptor precursor/67 kDa laminin receptor has been demonstrated to be a putative cell surface receptor for prion. To investigate the caprine RPSA, we cloned the full-length coding sequence of the gene of goat and submitted it to GenBank. The length of the open reading frame is 888 bp, encoding 295 amino acids. The putative amino acid sequence is highly similar to that of other mammals. The caprine amino acid sequence of RPSA is shown to be identical to the sequence of species susceptible to scrapie at positions 241, 272, and 291. The phylogenetic tree analysis revealed that the genetic distance between sheep and goat is the smallest. Moreover, RT-PCR results of 11 tissues indicated that RPSA mRNA is expressed in all selected caprine tissues. PMID- 20839047 TI - Human impact on wild firewood species in the rural Andes community of Apillapampa, Bolivia. AB - Firewood is the basic fuel source in rural Bolivia. A study was conducted in an Andean village of subsistence farmers to investigate human impact on wild firewood species. A total of 114 different fuel species was inventoried during fieldtrips and transect sampling. Specific data on abundance and growth height of wild firewood species were collected in thirty-six transects of 50 *2 m(2). Information on fuel uses of plants was obtained from 13 local Quechua key participants. To appraise the impact of fuel harvest, the extraction impact value (EIV) index was developed. This index takes into account local participants' appreciation of (1) decreasing plant abundance; (2) regeneration capacity of plants; (3) impact of root harvesting; and (4) quality of firewood. Results suggest that several (sub-)woody plant species are negatively affected by firewood harvesting. We found that anthropogenic pressure, expressed as EIV, covaried with density of firewood species, which could entail higher human pressure on more abundant and/or more accessible species. The apparent negative impact of anthropogenic pressure on populations of wild fuel species is corroborated by our finding that, in addition to altitude, several anthropogenic variables (i.e. site accessibility, cultivation of exotics and burning practices) explain part of the variation in height of firewood species in the surroundings of Apillapampa. PMID- 20839048 TI - Potential for internal loading by phosphorus based on sequential extraction of surficial sediment in a shallow Egyptian Lake. AB - The fractionation of phosphorus (P) in shallow Lake Maryout surficial sediments was investigated in order to understand its potential availability in relation to the eutrophication status of this lake. The rank order of P fractions was NaOH-P > HCl-P > NH(4)Cl-P > BD-P. The metal oxide-bound P (NaOH-P) averaged 43% in this hypereutrophic lake and would be potentially available under low oxygen conditions. The highly available, loosely sorbed P (NH(4)Cl-P) represented 20% of the sedimentary inorganic P on average, while the reductant P (BD-P) averaged 15% and is also considered highly available under low oxygen conditions. The less available calcium-bound P (HCl-P) represented 22% of sedimentary inorganic P. Lake Maryout exhibits high potential for release of P from sediment in forms available to algae, which is undesirable for eutrophication control. The range of potentially available P in tested sediments was 1,541 to 3,990 mg/kg (ppm), a very high quantity capable of supporting algal blooms independent of external loading. PMID- 20839049 TI - Application of geoaccumulation index and enrichment factor for assessing metal contamination in the sediments of Kafrain Dam, Jordan. AB - An investigation is reported of the degree of metal pollution in the sediments of Kafrain Dam and the origin of these metals. Fourteen sampling sites located at Kafrain Dam were chosen for collecting the surface, cutbank, and dam bank sediment samples. The sediment samples have been subjected to a total digestion technique and analyzed by atomic absorption spectrometer for metals including Pb, Zn, Cd, Ni, Co, Cr, Cu, Mn, and Fe. XRD analyses indicate that the sediments of Kafrain Dam are mainly composed of calcite, dolomite, quartz, orthoclase, microcline, kaolinite, and illite reflecting the geology of the study area. The enrichment factor (EF) and geoaccumulation index (I(geo)) have been calculated and the relative contamination levels assessed in the study area. The calculations of I(geo) are found to be more reliable than of those of EF. The enrichment of metals in the study area has been observed to be relatively high. I(geo) results reveal that the study area is not contaminated with respect to Ni, Co, Cr, Cu, and Mn; moderately to strongly contaminated with Pb; and strongly to extremely contaminated with Cd and Zn. The high contents of Pb, Cd, and Zn in the study area result from anthropogenic activities in the catchment area of the dam site. These sources mainly include the agricultural activities, sewage discharging from various sources within the study area (effluent of wastewater treatment plants, treated and untreated wastewaters, and irrigation return water), and the several industries located in the area. Degrees of correlations among the various metals in the study area are suggested by the results and the intermetallic relationship. PMID- 20839051 TI - Protective effect of zinc on related parameters to bone metabolism in common carp fish (Cyprinus carpio L.) intoxified with cadmium. AB - The short term effects of waterborne cadmium (Cd(+2)) on the levels of serum parameters related to bone metabolism including calcium (Ca), inorganic phosphorus (P(i)) and alkaline phosphatase (ALP) in common carp fish (Cyprinus carpio L.) were studied. Fish were treated with varying concentrations of Cd(+2) (0.22, 1.1 and 2.2 mg l(-1)) daily for 14 days. The results obtained show that serum P(i) and ALP concentrations were elevated by increasing Cd(+2) concentration in water containing fish whereas serum Ca level was decreased. At the same time, the protective role of waterborne zinc (Zn(+2), 1 mg l(-1)) on the same parameters was also investigated. Results showing that daily treatment of fish with Zn(+2), increased the concentrations of Ca and ALP in serum by 2.07 and 1.86 fold and decreased serum P(i) level by 57.7% in comparison with Cd(+2) treatment. The combination of Cd(+2) and Zn(+2) on the same parameters was studied next. There was a significant (P < 0.05) elevation in serum Ca and ALP levels in comparison with Cd(+2) treatment. Decreasing in serum P(i) level was not significant in comparison with Cd(+2) treatments. The protective effect of Zn(+2) on Cd(+2) disturbances in serum parameters related to bone metabolism in this manuscript has been also discussed. PMID- 20839050 TI - Development of digestive enzymes in larvae of Mayan cichlid Cichlasoma urophthalmus. AB - The development of digestive enzymes during the early ontogeny of the Mayan cichlid (Cichlasoma urophthalmus) was studied using biochemical and electrophoretic techniques. From yolk absorption (6 days after hatching: dah), larvae were fed Artemia nauplii until 15 dah, afterward they were fed with commercial microparticulated trout food (45% protein and 16% lipids) from 16 to 60 dah. Several samples were collected including yolk-sac larvae (considered as day 1 after hatching) and specimens up to 60 dah. Most digestive enzymes were present from yolk absorption (5-6 dah), except for the specific acid proteases activity (pepsin-like), which increase rapidly from 8 dah up to 20 dah. Three alkaline proteases isoforms (24.0, 24.8, 84.5 kDa) were detected at 8 dah using SDS-PAGE zymogram, corresponding to trypsin, chymotrypsin and probably leucine aminopeptidase enzymes, and only one isoform was detected (relative electromobility, Rf = 0.54) for acid proteases (pepsin-like) from 3 dah onwards using PAGE zymogram. We concluded that C. urophthamus is a precocious fish with a great capacity to digest all kinds of food items, including artificial diets provided from 13 dah. PMID- 20839052 TI - Non-target organism effects tests on Vip3A and their application to the ecological risk assessment for cultivation of MIR162 maize. AB - Transgenic crops producing insecticidal proteins from Bacillus thuringiensis (Bt) provide economic, environmental and health benefits by maintaining or increasing crop yields with fewer applications of insecticide. To sustain these benefits, it is important to delay the evolution of insect resistance to the proteins, and to ensure that the proteins do not harm non-target organisms, particularly those that may control secondary pests that would otherwise flourish because of reduced insecticide applications. Vip3A is a Bt vegetative insecticidal protein that is active against lepidopterous pests. It has a different mode of action from other proteins for control of Lepidoptera in current Bt crops, and when combined with these proteins, it should help to delay the evolution of pest resistance to Bt crops. This paper presents data on the effects of Vip3A on non-target organisms, and an ecological risk assessment of MIR162 maize, which expresses Vip3Aa20. Laboratory studies indicate few adverse effects of Vip3A to non-target organisms: 11 of 12 species tested showed no adverse effects when exposed to high concentrations of Vip3A relative to estimated exposures resulting from cultivation of MIR162 maize. Daphnia magna exposed to Vip3Aa20 were unaffected in terms of survival or fecundity, but grew slightly more slowly than unexposed controls. The data indicate that cultivation of MIR162 maize poses negligible risk to non-target organisms, and that crops producing Vip3A are unlikely to adversely affect biological control organisms such that benefits from reduced insecticide applications are lost. PMID- 20839053 TI - Soon: a new year, a new name, a new face. PMID- 20839054 TI - Numerical, hydraulic, and hemolytic evaluation of an intravascular axial flow blood pump to mechanically support Fontan patients. AB - Currently available mechanical circulatory support systems are limited for adolescent and adult patients with a Fontan physiology. To address this growing need, we are developing a collapsible, percutaneously-inserted, axial flow blood pump to support the cavopulmonary circulation in Fontan patients. During the first phase of development, the design and experimental evaluation of an axial flow blood pump was performed. We completed numerical modeling of the pump using computational fluid dynamics analysis, hydraulic testing of a plastic pump prototype, and blood bag experiments (n=7) to measure the levels of hemolysis produced by the pump. Statistical analyses using regression were performed. The prototype with a 4-bladed impeller generated a pressure rise of 2-30 mmHg with a flow rate of 0.5-4 L/min for 3000-6000 RPM. A comparison of the experimental performance data to the numerical predictions demonstrated an excellent agreement with a maximum deviation being less than 6%. A linear increase in the plasma-free hemoglobin (pfHb) levels during the 6-h experiments was found, as desired. The maximum pfHb level was measured to be 21 mg/dL, and the average normalized index of hemolysis was determined to be 0.0097 g/100 L for all experiments. The hydraulic performance of the prototype and level of hemolysis are indicative of significant progress in the design of this blood pump. These results support the continued development of this intravascular pump as a bridge-to-transplant, bridge-to-recovery, bridge-to-hemodynamic stability, or bridge-to-surgical reconstruction for Fontan patients. PMID- 20839055 TI - Beneficial effect of S-allylcysteine (SAC) on blood glucose and pancreatic antioxidant system in streptozotocin diabetic rats. AB - The aim of the present study was to evaluate the possible protective effects of S allyl cysteine (SAC) on the antioxidant defense system of pancreas in streptozotocin(STZ) induced diabetes in rats. The levels of blood glucose and TBARS in plasma and pancreas were estimated in control and experimental groups of rats. To assess the changes in the cellular antioxidant defense system, the level of reduced glutathione in plasma and pancreas and activities of superoxide dismutase and catalase were assayed in pancreatic tissue homogenate. The levels of glucose, TBARS and enzymatic antioxidants were altered in diabetic rats. These alterations were reverted back to near control levels after the treatment of SAC. The antidiabetic and antioxidant effect of SAC was compared with glyclazide, a well-known hypoglycemic drug. These findings suggest that SAC treatment exerts a therapeutic protective nature in diabetes by decreasing oxidative stress. PMID- 20839056 TI - In vitro colonic fermentation and glycemic response of different kinds of unripe banana flour. AB - This work aimed to study the in vitro colonic fermentation profile of unavailable carbohydrates of two different kinds of unripe banana flour and to evaluate their postprandial glycemic responses. The unripe banana mass (UBM), obtained from the cooked pulp of unripe bananas (Musa acuminata, Nanicao variety), and the unripe banana starch (UBS), obtained from isolated starch of unripe banana, plantain type (Musa paradisiaca) in natura, were studied. The fermentability of the flours was evaluated by different parameters, using rat inoculum, as well as the glycemic response produced after the ingestion by healthy volunteers. The flours presented high concentration of unavailable carbohydrates, which varied in the content of resistant starch, dietary fiber and indigestible fraction (IF). The in vitro colonic fermentation of the flours was high, 98% for the UBS and 75% for the UBM when expressed by the total amount of SCFA such as acetate, butyrate and propionate in relation to lactulose. The increase in the area under the glycemic curve after ingestion of the flours was 90% lower for the UBS and 40% lower for the UBM than the increase produced after bread intake. These characteristics highlight the potential of UBM and UBS as functional ingredients. However, in vivo studies are necessary in order to evaluate the possible benefit effects of the fermentation on intestinal health. PMID- 20839057 TI - Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. AB - BACKGROUND: For patients with hepatocellular carcinoma (HCC) with portal vein tumor thrombosis (PVTT), the survival benefit of transarterial chemoembolization (TACE) compared with conservative treatment largely remains controversial. The objective of this study was to determine whether TACE confers a survival benefit to patients with HCC and PVTT, and to uncover prognostic factors. METHODS: Between July 2007 and July 2009, a prospective two-arm nonrandomized study was performed on consecutive patients with unresectable HCC with PVTT. In one arm, patients were treated by TACE using an emulsion of lipiodol and anticancer agents +/- gelatin sponge embolization. In another arm, patients received conservative treatment. RESULTS: A total of 164 patients were recruited for the study (TACE group, n = 84; conservative treatment group, n = 80). Patients in the TACE group received a mean of 1.9 (range, 1-5) TACE sessions. The overall median survival for all patients was 5.2 months, and the 12- and 24-month overall survival rates were 18.3% and 5.6%, respectively. The 12- and 24-month overall survival rates for the TACE and conservative groups were 30.9%, 9.2%, and 3.8%, 0%, respectively. The TACE group had significantly better survivals than the conservative group (P < 0.001). On subgroup analysis of segmental and major PVTT, the TACE group also had significantly better survivals (P = 0.002, P = 0.002). The treatment type, PVTT extent, tumor size, and serum bilirubin were independent prognostic factors of survival on multivariate analysis. CONCLUSIONS: TACE was safe and feasible in selected HCC patients with PVTT and it had survival benefit over conservative treatment. PMID- 20839058 TI - Pretherapeutic extraperitoneal laparoscopic staging of bulky or locally advanced cervical cancer. AB - BACKGROUND: To assess the safety, feasibility, and impact on survival of extraperitoneal para-aortic lymphadenectomy in the staging of patients with bulky or locally advanced cervical cancer. MATERIALS AND METHODS: Between August 2001 and October 2009, 87 consecutive patients (median age 5 years) with bulky or locally advanced cervical cancer underwent extraperitoneal laparoscopic infrarenal aortic and common iliac dissection as a pretherapeutic staging procedure. Data on pathologic findings, details of surgery, postoperative complications, and disease status at follow-up were collected. RESULTS: The median operating time was 150 min (range 60-255 min). The mean (+/- standard deviation) para-aortic nodal yield was 15.5 +/- 8.1 (range 4-62). In none of the patients, conversion to the transperitoneal approach or laparotomy was necessary. Histological examination revealed metastasis in 13 patients (macroscopic disease 10, microscopic disease 3). After a median follow-up of 33.4 months (range 13.3 65.9 months), 73.6% of patients were free of disease and 1.1% were alive with disease, 19.5% died from cervical cancer, and 3.3% died from other causes. After a follow-up of 3 years, no deaths or recurrences were documented, with an overall survival rate of 74.8% (95% CI 62.8%-83.4%) and disease-free survival of 86% (95% CI 74.7%-92.5%). There were no significant differences in overall survival and disease-free survival between patients with positive and negative para-aortic lymph nodes. CONCLUSION: The extraperitoneal laparoscopic para-aortic lymphadenectomy for pretherapeutic surgical staging in cervical cancer is a safe and feasible procedure that should be considered as a tool to identify lymph node positive patients who require extended-field radiation and/or chemotherapy. PMID- 20839059 TI - Effects of intraperitoneal chemotherapy with mitomycin C on the prevention of peritoneal recurrence in colorectal cancer patients with positive peritoneal lavage cytology findings. AB - BACKGROUND: The detection of intraperitoneal free cancer cells in colorectal cancer (CRC) patients is associated with a poorer prognosis. The aim of this study was to investigate the effects of intraperitoneal chemotherapy (IPC) with mitomycin C (MMC) on preventing peritoneal recurrence in CRC patients with positive peritoneal lavage cytology findings. METHODS: A total of 52 CRC patients who had no clinically confirmed peritoneal dissemination and whose status of peritoneal lavage cytology was positive were investigated. Conventional peritoneal lavage cytology was performed. Overall, 31 of the 52 patients (59.6%) were administered IPC with MMC. Before closure of the abdomen, 4 silicon catheters were inserted into peritoneal cavity. After closure, the perfusate (diluting 20 mg MMC with 500 ml saline) was instilled from the catheter, and all catheters were clumped. All catheters were opened 1 h later. RESULTS: The mean follow-up period was 83.1 months. According to univariate analyses of all 52 patients and the subgroup of 36 patients with stage II or III tumors, patients with IPC had a significantly better peritoneal recurrence-free survival and cancer-specific survival than patients who did not receive IPC (P < 0.005). In multivariate analysis, IPC remained an independent prognostic factor for peritoneal recurrence-free survival in all patients. CONCLUSIONS: It appears that IPC with MMC is an effective treatment to prevent peritoneal recurrence and prolong the cancer-specific survival in CRC patients without peritoneal dissemination, but who have positive peritoneal lavage cytology. It is necessary to verify the effectiveness of IPC with MMC in a prospective trial. PMID- 20839061 TI - A contemporary population-based assessment of the rate of lymph node dissection for penile carcinoma. AB - BACKGROUND: The adherence rate to National Cancer Institute (NCI) recommendations regarding inguinal lymph nodes dissection (ILND) in high grade T1 (G3T1) and T2-4 squamous cell carcinoma of the penis (SCCP) is not known. We assessed ILND rates in a North American cohort. MATERIALS AND METHODS: The 17 registries of the Surveillance, Epidemiology, and End Results (SEER) database included 868 patients with SCCP, diagnosed between 1988 and 2006. Analyses consisted of univariable and multivariable logistic regression models. RESULTS: Overall, 27.6% of patients underwent an ILND. ILND rates were directly proportional with T stage: 19.0%, 30.5%, 30.6%, and 32.6% for, respectively, G3T1, T2, T3, and T4 SCCP (chi-square trend, P = 0.01). ILND rates also increased over time and were 19.3, 27.3, 30.7, and 30.8% for respectively, 1988-1995, 1996-2000, 2001-2003, and 2004-2006 periods (chi-square trend, P = 0.03). Finally, ILND rates decreased with patient age and were 42.6, 33.2, 24.7, and 7.3% for, respectively, patients aged <= 57, 58-68, 69-78 and >= 79 years of age (chi-square trend, P < 0.001). All 3 variables (T-stage, year of primary tumor excision and patient age) achieved independent predictor status in multivariable analyses. CONCLUSIONS: The overall rate of ILND is low. Nonetheless, there is an upward trend over time. Our data indicate that the adherence to the NCI ILND guidelines is suboptimal. In consequence, ILNDs should be more strongly encouraged. PMID- 20839060 TI - Sentinel node dissection delays recurrence and prolongs melanoma-related survival: an analysis of 673 patients from a single center with long-term follow up. AB - BACKGROUND: The status of the sentinel lymph node is an important predictor for survival in melanoma patients, but it is still unclear if early removal of micrometastases by sentinel lymph node dissection (SLND) alters survival. A large series of melanoma patients from a single center with long-term follow-up was analyzed with regard to a possible effect of SLND on the prognosis. MATERIALS AND METHODS: A total of 673 consecutive melanoma patients were assessed treated in our center either without SLND (377 patients, pre-SLN group, between January 1995 and March 2000) or with SLND (296 patients, SLN group, between April 2000 and March 2003). The median follow-up was 64.0 months in the pre-SLN and 72.5 months in the SLN group. RESULTS: The pre-SLN group and SLN group did not differ significantly with regard to characteristics of the primary melanoma thickness and ulceration, sex, and age. Kaplan-Meier analyses showed a significantly better recurrence-free survival (P < .001), distant metastases free survival (P = .006), and overall survival (P = .049) for patients of the SLN group; the 5-year melanoma-specific survival rates were 80.3% in pre-SLN patients and 84.8% in SLN patients. Initial metastases in the in-transit region and distant locations were of similar frequency in the pre-SLN and SLN groups (P = .191 and P = .959, respectively), but initial regional lymph node metastases were significantly more frequent in the pre-SLN group (P < .001). CONCLUSIONS: Our data point toward a subgroup of melanoma patients who might have a prognostic benefit from SLN. PMID- 20839062 TI - Improved outcomes in the management of esophageal cancer with the addition of surgical resection to chemoradiation therapy. AB - BACKGROUND: For patients with locally advanced esophageal cancer, prospective randomized clinical trials have reported no added value of surgical resection to chemoradiation alone. Using a large regional cancer registry, our objective was to determine whether curative-intent esophageal resection provided a survival advantage in the multimodality management of esophageal cancer. MATERIALS AND METHODS: Using the Los Angeles County Cancer Surveillance Program (CSP), we identified all patients with local and regional (i.e., AJCC Stages I-III) esophageal cancer during the years 1988-2006. Clinical and pathologic data included patient demographics, tumor information, indication for surgery, lymph node status, and timing of therapy. Overall survival was assessed by the Kaplan Meier method, and multivariate Cox-regression analysis was performed. RESULTS: From CSP, 2233 patients with esophageal cancer were identified. Median survival (MS) of the entire cohort was 13.1 months. We stratified this cohort into patients who received chemoradiation alone (n = 645) and patients who received trimodality therapy (n = 286) (i.e., chemoradiation and surgery). Patients had significantly improved survival with trimodality therapy compared with chemoradiation alone (MS 25.2 vs. 12.3 months, respectively; P < 0.001). The survival advantage with trimodality therapy was observed for patients with squamous cell carcinoma (MS 24.5 vs. 12.8 months, respectively; P < 0.001) and adenocarcinoma (MS 25.9 vs. 10.6 months, respectively; P < 0.001). By multivariate analysis, trimodality therapy was a significant prognostic factor for improved survival in patients with esophageal cancer (hazard ratio [HR] 0.66, 95% confidence interval [95% CI]: 0.56-0.77, P < 0.001). CONCLUSIONS: Our data indicate that surgical resection remains an important component of the multimodality management of esophageal cancer. PMID- 20839063 TI - In reply: Surgeon-performed ultrasound and prediction of differentiated thyroid cancer. PMID- 20839064 TI - Individual surgeon, pathologist, and other factors affecting lymph node harvest in stage II colon carcinoma. is a minimum of 12 examined lymph nodes sufficient? AB - BACKGROUND: Insufficient lymph node harvest in presumed stage II colon carcinomas can result in understaging and worsened cancer outcomes. The purpose of this study was to evaluate factors affecting the number of lymph node examined, their corresponding impact on cancer outcomes, and the optimal number of examined nodes with reference to the standard of 12. MATERIALS AND METHODS: We evaluated all patients undergoing surgery alone for stage II colon cancer included in our colorectal cancer database since 1976. RESULTS: A total of 901 patients were included. Mean follow-up exceeded 8 years. The individual pathologist had no statistically significant association with the number of lymph nodes examined. Harvest of at least 12 nodes was related to surgery after 1991 (85% vs 69%, P < 0.001), right vs left colon carcinomas (85% vs 72%, P < 0.001), individual surgeon (P = 0.018), and length of specimen at different cutoffs of at least 30, 25, and 20 cm (P < 0.001). Increasing age was associated with fewer examined lymph nodes (Spearman correlation = -0.22, P < 0.001). Fewer than 12 nodes and T4N0 staging independently affected overall survival (P = 0.003 and P = 0.022, respectively), disease-free survival (P = 0.010 and P = 0.09, respectively), disease-specific mortality (P = 0.009 and P < 0.001, respectively), and overall recurrence (P = 0.13 and P = 0.023, respectively). A minimal number of more than 12 examined nodes had no significant effect on cancer outcomes. CONCLUSIONS: A number of factors influenced lymph node harvest in stage II colon cancer. However, lymph node assessment of at least 12 nodes was the only modifiable factor optimizing cancer outcomes. PMID- 20839065 TI - The importance of preoperative staging with chest CT scan in patients with colorectal cancer. PMID- 20839066 TI - Reaching the colorectal liver masses. PMID- 20839067 TI - Patterns of referral and resection among patients with liver-only metastatic colorectal cancer (MCRC). AB - BACKGROUND: Rates of metastatectomy vary among patients with liver-only metastatic colorectal cancer (MCRC). This study describe predictors of referral to a hepatobiliary surgeon (HBS) and hepatic resection in a population-based setting. MATERIALS AND METHODS: Patients referred to the British Columbia Cancer Agency (BCCA) with synchronous or relapsed MCRC isolated to the liver in 2002 2004 were identified. Classification of tumor burden as "high" or "low" was based on prognostic features defined by LiverMetSurvery registry. Metastases larger than 5 cm, bilobar, or more than 3 metastases were classified as high tumor burden. Multivariate logistic regression models were used to identify predictors of HBS referral and subsequent metastatectomy. Overall survival was calculated by the Kaplan-Meier method. RESULTS: Of 618 patients with isolated hepatic metastasis, 148 (24%) were referred to a HBS and 99 (16%) underwent resection. Advanced age was the most common reason for not referring 64 patients (10%) with ECOG performance status 0/1 and low tumor burden. In multivariate analysis, variables associated with referral were younger age (P < .001), ECOG performance status 0/1 (P < .002), chemotherapy for metastatic disease (P = .007), 1-3 metastasis (P < .001), and unilobar disease (P < .001). Median patient survival was 0.99 years (95% confidence interval [95% CI], 0.89-1.10 years) among nonreferred, 1.83 years (95% CI, 1.37-2.31 years) if referred but not resected, and 3.85 years (95% CI, 2.90-4.80 years) if resected. CONCLUSION: A significant proportion of patients are not referred to a HBS because of advanced chronological age. Resection of hepatic metastases was associated with improved overall survival irrespective of initial tumor burden. PMID- 20839068 TI - Feasibility of preservation of the submandibular gland during neck dissection in patients with early-stage oral cancer. AB - BACKGROUND: The impact of submandibular gland (SMG) preservation during neck dissection on the survival of patients with early-stage oral squamous-cell carcinoma (OSCC) remains undocumented. METHODS: The medical records of all patients with early-stage OSCC (stage I and II) who underwent wide excision of the primary tumor and simultaneous neck dissection between 1999 and 2006 at our facility were retrospectively reviewed. RESULTS: We analyzed 408 patients, including 33 patients with and 375 patients without SMG preservation. The 5-year disease-free and overall survival rates were 78.8% and 90.9% for the patients with SMG preservation and 75.4% and 90.4% for the patients without SMG preservation, and these differences were not statistically significant (P = 0.79, P = 0.99, respectively). Similar survival rates between patients with and without SMG preservation were observed in those with oral tongue squamous-cell carcinoma (SCC) and with buccal SCC. Patients with T2 OSCC with SMG preservation had significantly lower 5-year disease-free survival rate than those without SMG preservation (P = 0.02), but overall survival rates were similar between these two groups. CONCLUSIONS: Preservation of the SMG during neck dissection may be oncologically safe in patients with T1 OSCC, but the feasibility of SMG preservation seems less clear for T2 OSCC. PMID- 20839069 TI - Low expression of claudin-4 is associated with poor prognosis in esophageal squamous cell carcinoma. AB - BACKGROUND: Claudins are 22-27 kDa sized adhesion molecules that constitute tight junctions. Their expression levels are often tissue-specific, and their altered degrees of expression have been reported in a variety of cancers. In addition, the prognostic significance of claudin expression has been implicated in various human cancers. However, the prognostic significance of claudin-4 expression in esophageal squamous cell carcinoma (ESCC) remains to be clarified. MATERIALS AND METHODS: We investigated the prognostic significance of claudin-4 expression in 164 cases of ESCC using immunohistochemisty. We also evaluated claudin-4 mRNA expression levels using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and analyzed its specific promoter methylation status using quantitative methylation-specific PCR. RESULTS: According to clinicopathological parameters, low claudin-4 expression was found to be significantly associated with histological differentiation (P = 0.003), invasion depth (P = 0.002), and lymph node metastasis (P = 0.024). Low claudin-4 expression showed unfavorable influences on disease-free survival (P = 0.0115) and overall survival (OS) (P = 0.0009). In multivariate analysis, low claudin-4 expression was an independent predictor of poor OS (P = 0.007). Claudin-4 mRNA levels assessed using real-time RT-PCR were consistent with the protein levels determined using immunohistochemistry. Furthermore, this study demonstrates that loss of claudin-4 is associated with promoter hypermethylation. CONCLUSIONS: Our study indicates that claudin-4 expression is deregulated in ESCC, implying its potential use as a prognostic biomarker in ESCC. PMID- 20839070 TI - Correlation between gp96 expression and the surgical outcome in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Heat-shock protein gp96 plays an important role in antitumor immunoreactions. Gp96 has a close relationship with antitumor immunity. This study evaluated the correlation between gp96 expression and the prognosis in esophageal squamous cell carcinoma. METHODS: Seventy-eight patients with primarily resected esophageal squamous cell carcinoma were enrolled onto this study, and gp96 expression was evaluated by immunohistochemical staining. The association of clinicopathological factors and patients' survival was calculated by univariate (log rank test) and multivariate (Cox proportional hazard regression method) analyses. RESULTS: Fifty-seven (73%) of 78 cases were gp96 positive, and 21 were negative (27%). The survival of patients with gp96-negative disease was significantly shorter (5-year survival, 22.9 months) than with gp96 positive disease (45.8 months; P = 0.049), and the multivariate analysis showed that gp96 negativity is an independent risk factor for poor survival (hazard ratio, 2.577; P = 0.040). Gp96-negative cases had more metastatic lymph nodes than did negative cases, especially in T1 cases (4.8 in gp96-negative cases vs. 0.84 in gp96-positive cases; P = 0.064) CONCLUSIONS: The downregulation of gp96 expression is closely correlated with poor survival in esophageal squamous cell carcinoma. PMID- 20839071 TI - Alcohol exposure as a risk factor for adverse outcomes in elective surgery. AB - BACKGROUND AND AIMS: Alcohol consumption is a well-documented determinant of adverse perioperative outcome. We sought to determine the effect of active alcohol consumption following elective surgery. METHODS: We queried discharge records from the American College of Surgeons' National Surgical Quality Improvement Program (NSQIP, 2005-2007) for all elective adult admissions. The 7,631 (2.5%) patients with documented alcohol use (active alcohol use of at least two drinks per day within 2 weeks of surgery; ETOH use) underwent elective surgery; 301,994 (97.5%) patients denied ETOH use. Multivariate analysis was performed with adjustments for demographic and comorbid factors. Primary outcome measures included length of stay (LOS), postoperative complications, and death. RESULTS: ETOH use associated with elective surgery decreased over the course of the study (p < 0.0001). ETOH use was an independent predictor of pneumonia (OR 1.98, 95% CI 1.84-2.13), sepsis (OR 1.19, 95% CI 1.03-1.37), superficial surgical site infection (SSI; OR 1.15, 95% CI 1.02-1.31), wound disruption (OR 1.41, 95% CI 1.11-1.80), and prolonged LOS (OR 1.17, 95% CI 1.08-1.26). Except for SSI, these complications were independent risk factors for postoperative mortality. ETOH use was associated with earlier time to wound disruption (9 vs. 11 days; p = 0.04), longer median hospital stays (5 vs. 3 days; p < 0.0001), and longer LOS after operation (4 vs. 3 days; p < 0.0001). CONCLUSIONS: Active alcohol consumption is a significant determinant of adverse outcomes in elective surgery; patients with ETOH use who are scheduled to undergo elective surgery should be appropriately educated and counseled. PMID- 20839072 TI - Disappearing colorectal liver metastases after chemotherapy: should we be concerned? AB - BACKGROUND: With increasing efficacy of preoperative chemotherapy for colorectal cancer, more patients will present with one or more disappearing liver metastases (DLM) on preoperative cross-sectional imaging. PATIENTS AND METHODS: A retrospective review was conducted evaluating the radiological response to preoperative chemotherapy for 168 patients undergoing surgical therapy for colorectal liver metastases at Johns Hopkins Hospital between 2000 and 2008. RESULTS: Forty patients (23.8%) had one or more DLM, accounting for a total of 127 lesions. In 22 patients (55%), all DLM sites were treated during surgery. Of the 17 patients with unidentified, untreated DLM, ten patients (59%) developed a local recurrence at the initial site, half of which also developed recurrences in other sites. While the intrahepatic recurrence rate was higher for patients with DLM left in situ (p = 0.04), the 1-, 3-, and 5-year overall survival rate was not significantly different for patients with DLM left in situ (93.8%, 63.5%, and 63.5%, respectively) when compared to patients with a radiological chemotherapy response in whom all original disease sites were surgically treated (92.3%, 70.8%, and 46.2%, respectively; p = 0.66). CONCLUSIONS: DLM were frequently observed in patients undergoing preoperative chemotherapy for liver metastases. Survival was comparable in patients with untreated DLM, in spite of high intrahepatic recurrence rates seen in these patients. Therefore, aggressive surgical therapy should be considered in patients with marked response to chemotherapy, even when all DLM sites cannot be identified. PMID- 20839073 TI - Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. AB - BACKGROUND: Locally advanced unresectable pancreatic adenocarcinoma is characterized by poor survival despite chemotherapy and conventional radiation therapy (RT). Recent advances in real-time image-guided stereotactic radiosurgery (SRS) have made it possible to treat these cancers in two to four fractions followed by systemic chemotherapy. AIMS: The aims of this study includes the following: (1) obtain local control of the disease; (2) improve the survival of these unresectable patients; (3) evaluate the toxicity of SRS; and (4) report results of the largest series from a single center. METHODS: Pancreatic SRS involves delivery of high doses of accurately targeted radiation given non invasively in two to four fractions. We treated 85 consecutive patients with locally advanced and recurrent pancreatic adenocarcinoma from February 2004 to November 2009. Age range: 36-88 years, median 66 years; sex: 50 males, 35 females; race: 79 Caucasian, five African American, one Asian; histology: 80 adenocarcinoma, three islet cell, two other. Pre-SRS staging: T(3-4) 85; N(+) 16, N(x) 57, N(0) 12; M(0) 64, M(1) 21. All patients were unresectable at the time of SRS. Seventy-one had no prior surgical resection, and 14 had local recurrence after prior surgical resection. Twenty-nine patients had progression of disease after prior conventional RT. Location of the tumor: head, 57; body and tail, 28. Pre-SRS chemotherapy was given in 48 patients. All patients received gemcitabine based chemotherapy regimen after SRS. Median tumor volume was 60 cm(3). PET/CT scans done in 55 patients were positive in 52 and negative in three patients. Average maximum standard uptake value was 6.9. Pain score on a scale of 1-10 was: 0-3 in 54, 4-7 in 18, and 8-10 in 13 patients. SRS doses ranged from 15 to 30 Gy with a mean dose of 25.5 Gy delivered in 3 days divided in equal fractions. Mean conformality index was 1.6, and mean isodose line was 80%. RESULTS: Tumor control: complete, partial, and stable disease were observed in 78 patients for the duration of 3-36 months with median of 8 months. Pain relief was noted in majority of patients lasting for 18-24 weeks. Most of the patients died of distant disease progression while their primary tumor was controlled. Overall median survival from diagnosis was 18.6 months and from SRS it was 8.65 months. For the group of 35 patients with adenocarcinoma without prior surgical resection or RT and no distant metastases, the average and 1-year survival from diagnosis was 15 months and 50%, respectively, and from SRS it was 11.15 months and 30.5%, respectively. TOXICITY: A total of 19 (22.37%) patients developed grades III/IV GI toxicity including duodenitis, 12 (14.1%); gastritis, 11 (12.9%); diarrhea, three (3.5%); and renal failure was noted in one (1.2%). Three patient had both gastritis and duodenitis. Toxicity was significantly more prevalent in the first 40 patients compared with the last 45 patients (32.5 vs 13.9%). CONCLUSIONS: SRS for unresectable pancreatic carcinoma can be delivered in three fractions with minimal morbidity and a local tumor control rate of 91.7%. The survival is comparable or better than the reported results for advanced pancreatic cancer, specifically for the group of previously untreated patients with unresectable tumors. Development of distant metastases remains a significant factor. PMID- 20839075 TI - Characterization of the inhibition of vein graft intimal hyperplasia by a biodegradable vascular stent. AB - Characterization of biodegradable stent vein graft thickening. Polydioxanone vascular sutures (PDSs) were used in a biodegradable arteriovenous bypass model. Twenty-four rabbits underwent carotid interposition bypass via ipsilateral jugular vein. One half received the stent (PDS group) and the remaining half a simple vein graft (controls). Group subsets received external stent removal or sham-control exploration at 4 and 12 weeks. At 4 and 12 weeks, the PDS group had significantly less medial and intimal thickening than the control group (P < 0.05), and there were fewer proliferating smooth muscle cells and extra cellular matrix formation than the control group at every interval. At 12 weeks, partial stent degradation occurred without deleterious effects. Furthermore proliferating cell nuclear antigen (PCNA), angiotensin type 1 receptor (AT1R), and transforming growth factor beta 1 (TGF-beta1) levels were significantly lower than the control group. The external stent inhibited medial and intimal hyperplasia, an effect that remains after the material has completely degraded. This PDS stent is feasible option for vein grafts. PMID- 20839076 TI - High-grade neuroendocrine carcinoma of the colon, long-term survival in advanced disease. AB - A 72-year-old man was diagnosed with a poorly differentiated hepatic flexure mass seen on routine screening colonoscopy. He underwent a right hemicolectomy and biopsy of a liver lesion noted at laparotomy. Pathology revealed a high-grade neuroendocrine carcinoma in the primary tumor and the liver lesion. Post operative imaging revealed an isolated FDG avid liver metastases which had not been appreciated pre-operatively. He was treated with combination platinum and etoposide for extensive stage small-cell carcinoma of the colon. After 6 cycles of chemotherapy, the isolated liver lesion remained FDG avid, albeit less than baseline. Radiofrequency ablation of the avid liver lesion was performed. Further, chemotherapy was given as the lesion remained FDG avid. Ablation was repeated and a subsequent biopsy was positive. Chemotherapy resumed for a total of 10 cycles. Repeat PET scan became negative and the patient remains disease free 7 years from an initial diagnosis of extensive stage small-cell colon cancer with a negative PET scan. Aggressive locoregional treatment is an option in patients with extensive stage small-cell carcinoma of the colon who are left with an oligometastasis after platinum-based systemic chemotherapy. PMID- 20839077 TI - Neurocognitive and neuroimaging predictors of clinical outcome in bipolar disorder. AB - Historically, bipolar disorder has been conceptualized as a disease involving episodic rather than chronic dysfunction. However, increasing evidence indicates that bipolar disorder is associated with substantial inter-episode psychosocial and vocational impairment. Here we review the contributions of neurocognitive deficits and structural and functional neuroanatomic alterations to the observed functional impairments. In particular, compelling evidence now suggests that neurocognitive impairments, particularly in the areas of attention, processing speed, and memory, are associated with functional outcome. Although investigation of the neural correlates of functional disability in bipolar disorder is only in its nascent stages, preliminary evidence suggests that white matter abnormalities may be predictive of poor outcome. A better understanding of the relationship between neurocognitive and neuroimaging assays and functional outcome has the potential to improve current treatment options and provide targets for new treatment strategies in bipolar disorder. PMID- 20839078 TI - Analysis of process parameters affecting spray-dried oily core nanocapsules using factorial design. AB - The purpose of this work was to optimize the process parameters required for the production of spray-dried oily core nanocapsules (NCs) with targeted size and drug yield using a two-level four-factor fractional factorial experimental design (FFED). The coded process parameters chosen were inlet temperature (X(1)), feed flow rate (X(2)), atomizing air flow (X(3)), and aspiration rate (X(4)). The produced NCs were characterized for size, yield, morphology, and powder flowability by dynamic light scattering, electron microscope, Carr's index, and Hausner ratio measurement, respectively. The mean size of produced NCs ranged from 129.5 to 444.8 nm, with yield varying from 14.1% to 31.1%. The statistical analysis indicated an adequate model fit in predicting the effect of process parameters affecting yield. Predicted condition for maximum yield was: inlet temperature 140 degrees C, atomizing air flow 600 L/h, feed flow rate 0.18 L/h, and aspiration air flow set at 100%, which led to a yield of 30.8%. The morphological analysis showed the existence of oily core and spherical nanostructure. The results from powder flowability analysis indicated average Carr's index and Hausner ratio of 42.77% and 1.76, respectively. Spray-dried oily core NCs with size lower than 200 nm were successfully produced, and the FFED proved to be an effective approach in predicting the production of spray-dried NCs of targeted yield. PMID- 20839079 TI - A dry powder formulation of liposome-encapsulated recombinant secretory leukocyte protease inhibitor (rSLPI) for inhalation: preparation and characterisation. AB - Inhaled recombinant secretory leukocyte protease inhibitor (rSLPI) has shown potential for the treatment of inflammatory lung conditions. Rapid inactivation of rSLPI by cathepsin L (Cat L) and rapid clearance from the lungs has limited clinical efficacy to date. Previous studies by us have shown that encapsulation of rSLPI within1,2-dioleoyl-sn-glycero-3-[phospho-L-serine]/cholesterol (DOPS/Chol) liposomes protects rSLPI against Cat L inactivation in vitro. Liquid DOPS-rSLPI preparations were found to be unstable upon long-term storage and nebulisation. The aim of this study was therefore to develop a method of manufacture for preparing DOPS-rSLPI liposomes as a dry powder for inhalation. DOPS-rSLPI dry powders were lyophilised and subsequently micronised with a novel micronisation aid. The effects of formulation and processing on rSLPI stability, activity, and uniformity of content within the powders were characterised. Using D-mannitol as the micronisation aid, dry powder particles in the inhalable size range (<5 MUm) were prepared. By optimising process parameters, up to 54% of rSLPI was recovered after micronisation, of which there was no significant loss in anti-neutrophil elastase activity and no detectable evidence of protein degradation. Aerosolisation was achieved using a dry powder inhaler, and mass median aerodynamic diameter (MMAD) was evaluated after collection in a cascade impactor. Aerosolisation of the DOPS-rSLPI dry powder yielded 38% emitted dose, with 2.44 MUm MMAD. When challenged with Cat L post-aerosolisation, DOPS-rSLPI dry powder was significantly better at retaining a protective function against Cat L-induced rSLPI inactivation compared to the aqueous DOPS-rSLPI liposome dispersion and was also more stable under storage. PMID- 20839080 TI - Design and in vitro evaluation of capsaicin transdermal controlled release cubic phase gels. AB - The purpose of this study was to design and investigate the transdermal controlled release cubic phase gels containing capsaicin using glycerol monooleate (MO), propylene glycol (1,2-propanediol, PG), and water. Three types of cubic phase gels were designed based on the ternary phase diagram of the MO-PG water system, and their internal structures were confirmed by polarizing light microscopy (PLM) and small-angle X-ray scattering (SAXS). Release results showed the cubic phase gels could provide a sustained system for capsaicin, while the initial water content in the gels was the major factor affecting the release rate. Release kinetics was determined to fit Higuchi's square-root equation indicating that the release was under diffusion control. The calculated diffusion exponent showed the release from cubic phase gels was anomalous transport. The unique structure of the cubic phases, capsaicin distributed in the lipid bilayers, and cubic phase gel swelling contributed to the release mechanism. The cubic phase gel may be an interesting application for transdermal delivery system of capsaicin in alleviating the post-incision pain. PMID- 20839081 TI - Both skeletonized and pedicled internal thoracic arteries supply adequate graft flow after coronary artery bypass grafting even during intense sympathoexcitation. AB - The internal thoracic artery (ITA) is harvested by either the pedicled or the skeletonized technique in coronary artery bypass grafting (CABG), with no clear advantage of one technique over the other. We compared graft flow between the pedicled and skeletonized ITA grafts while varying myocardial oxygen demand. CABG was performed to the left anterior descending artery in five anesthetized dogs using a pedicled ITA graft and the graft was subsequently skeletonized. Graft flow was measured during stepwise electrical stimulation of the stellate ganglion. The baseline graft flow before sympathetic stimulation was higher in skeletonized (27.8 +/- 1.9 ml/min) than that in pedicled ITA grafts (22.6 +/- 2.7 ml/min) (P < 0.05). In both ITA grafts, however, graft flow increased to a similar level during sympathetic stimulation that doubled the double product, correlating with the double product. Based on these results, we conclude that metabolic demand can override the potential difference in sympathetic vasoconstriction in both pedicled and skeletonized ITA grafts. PMID- 20839082 TI - Supramolecular polymers based on cyclodextrins for drug and gene delivery. AB - Supramolecular polymers based on cyclodextrins (CDs) have inspired interesting and rapid developments as novel biomaterials in a broad range of drug and gene delivery applications, due to their low cytotoxicity, controllable size, and unique architecture. This review will summarize the potential applications of polyrotaxanes in the field of drug delivery and gene delivery. Generally, cyclodextrin-based biodegradable polypseudorotaxane hydrogels could be used as a promising injectable drug delivery system for sustained and controlled drug release. Temperature-responsive, pH-sensitive, and controllable hydrolyzable polyrotaxane hydrogels have attracted much attention because of their controllable properties, and the self-assembly micelles formed by amphiphilic copolymer threaded with CDs could be used as a carrier for controlled and sustained drug release. Polyrotaxanes with drug or ligand conjugated CDs threaded on a polymer chain with a biodegradable end group could be useful for controlled and multivalent targeted delivery. In the field of gene delivery, cationic polyrotaxanes consisting of multiple OEI-grafted CDs threaded on a block copolymer chain are attractive non-viral gene carries due to the strong DNA binding ability, low cytotoxicity, and high gene delivery capability. Furthermore, cytocleavable end-caps were introduced in the polyrotaxane systems in order to ensure efficient endosomal escape for intracellular trafficking of DNA. The development of the supramolecular approach using CD-containing polyrotaxanes is expected to provide a new paradigm for biomaterials. PMID- 20839084 TI - Estrogen signaling in the regulation of female reproductive functions. AB - Estrogens influence fertility and infertility in animals. This chapter reviews the use of estrogen as a contraceptive through the regulation of its production and action. It is concluded that the use of specific agonists and antagonists of estrogen action that avoid the global and unwanted side effects of estrogen offers new potential methods of contraception. PMID- 20839085 TI - Progesterone receptors and ovulation. AB - The steroid hormone, progesterone, plays a critical role in the regulation of female ovulation. The physiological effects of progesterone are mediated by two nuclear receptor transcription factors, PR-A and PR-B, which are produced from a single gene and upon binding progesterone regulate the expression of specific gene networks in reproductive tissues. Both null mutation of the PR gene to delete both receptor proteins and selective disruption of the PR-A isoform lead to a failure of ovulation due to disabled follicular rupture in response to gonadotrophin stimulation. Recent studies have revealed that the LH stimulus that triggers ovulation is transduced by PRs residing in mural granulosa cells that induce expression of paracrine signals that interact with cumulus cells to control cumulus matrix function and expansion to facilitate follicular rupture. PMID- 20839083 TI - New insights into ovarian function. AB - Infertility adversely affects many couples worldwide. Conversely, the exponential increase in world population threatens our planet and its resources. Therefore, a greater understanding of the fundamental cellular and molecular events that control the size of the primordial follicle pool and follicular development is of utmost importance to develop improved in vitro fertilization as well as to design novel approaches to regulate fertility. In this review we attempt to highlight some new advances in basic research of the mammalian ovary that have occurred in recent years focusing primarily on mouse models that have contributed to our understanding of ovarian follicle formation, development, and ovulation. We hope that these new insights into ovarian function will trigger more research and translation to clinically relevant problems. PMID- 20839086 TI - Contraception targets in Mammalian ovarian development. AB - In the human ovary, early in pre-natal life, oocytes are surrounded by pre granulosa follicular cells to form primordial follicles. These primordial oocytes remain dormant, often for decades, until recruited into the growing pool throughout a woman's adult reproductive years. Activation of follicle growth and subsequent development of growing oocytes in pre-antral follicles are major biological checkpoints that determine an individual females reproductive potential. In the past decade, great strides have been made in the elucidation of the molecular and cellular mechanisms underpinning maintenance of the quiescent primordial follicle pool and initiation and development of follicle growth. Gaining an in-depth knowledge of the intracellular signalling systems that control oocyte preservation and follicle activation has significant implications for improving female reproductive productivity and alleviating infertility. It also has application in domestic animal husbandry, feral animal population control and contraception in women. PMID- 20839087 TI - Proteomics of embryonic implantation. AB - Implantation is a complex process involving an intricate cascade of molecular interactions between the implanting blastocyst and the receptive endometrium. The molecular basis of endometrial receptivity and the mechanisms by which the blastocyst first adheres to the luminal epithelium and then penetrates into the stroma are only just beginning to be resolved. Advances in "omics" technologies, particularly proteomics and metabolomics, are set to have a major impact on the development of this field. In the wake of this information, novel targets for contraceptive intervention may become apparent. PMID- 20839088 TI - Evaluation of plasma membrane calcium/calmodulin-dependent ATPase isoform 4 as a potential target for fertility control. AB - The array of contraceptives currently available is clearly inadequate and does not meet consumer demands since it is estimated that up to a quarter of all pregnancies worldwide are unintended. There is, therefore, an overwhelming global need to develop new effective, safe, ideally non-hormonal contraceptives for both male and female use. The contraceptive field, unlike other areas such as cancer, has a dearth of new targets. We have addressed this issue and propose that isoform 4 of the plasma membrane calcium ATPase is a potentially exciting novel target for fertility control. The plasma membrane calcium ATPase is a ubiquitously expressed calcium pump whose primary function in the majority of cells is to extrude calcium to the extracellular milieu. Two isoforms of this gene family, PMCA1 and PMCA4, are expressed in spermatozoa, with PMCA4 being the predominant isoform. Although this gene is ubiquitously expressed, its function is highly tissue-specific. Genetic deletion of PMCA4, in PMCA4 knockout mice, led to 100% infertility specifically in the male mutant mice due to a selective defect in sperm motility. It is important to note that the gene deletion did not affect normal mating characteristics in these mice. This phenotype was mimicked in wild-type sperm treated with the non-specific PMCA inhibitor 5-(and 6-) carboxyeosin diacetate succinimidyl ester; a proof-of-principle that inhibition of PMCA4 has potential importance in the control of fertility. This review outlines the potential for PMCA4 to be a novel target for fertility control by acting to inhibit sperm motility. It will outline the characteristics that make this target drugable and will describe methodologies to identify and validate novel inhibitors of this target. PMID- 20839089 TI - New insights into sperm physiology and pathology. AB - Infertility is a relatively common condition affecting approximately one in ten of the population. In half of these cases, a male factor is involved, making defective sperm function the largest single, defined cause of human infertility. Among other factors, recent data suggest that oxidative stress plays a major role in the etiology of this condition. Spermatozoa spontaneously produce a variety of reactive oxygen species (ROS) including the superoxide anion, hydrogen peroxide and nitric oxide. Produced in small amounts, ROS are functionally important in driving the tyrosine phosphorylation cascades associated with sperm capacitation. However, when ROS production exceeds the spermatozoa's limited antioxidant defenses, a state of oxidative stress is induced characterized by peroxidative damage to the sperm plasma membrane and DNA strand breakage in the sperm nucleus. Such oxidative stress not only disrupts the fertilizing potential of human spermatozoa but also the ability of these cells to create a normal healthy embryo. As a result, DNA damage in human spermatozoa is correlated with an increased incidence of miscarriage and various kinds of morbidity in the offspring. These insights into the pathophysiology of defective sperm function have clear implications for the diagnosis and treatment of male infertility, particularly with respect to the potential importance of antioxidant therapy. These concepts may also be relevant to the design of novel approaches to male contraception that attempt to replicate the pathological situation. PMID- 20839090 TI - The epididymis as a target for male contraceptive development. AB - The epididymis is an excellent target for the development of a male contraceptive. This is because the process of sperm maturation occurs in this organ; spermatozoa become motile and are able to recognise and fertilise an egg once they have traversed the epididymal duct. However, a number of attempts to interfere in sperm maturation and epididymal function or both have not been successful. The use of transgenic animals has proved useful in identifying a few epididymal targets but has yet to open the doors for drug development. Continuous focus on identifying additional epididymal targets and sperm-specific and epididymal-specific drugs is key to bringing a male contraceptive acting on the epididymis to the public. PMID- 20839091 TI - Sperm-zona pellucida interaction: molecular mechanisms and the potential for contraceptive intervention. AB - At the moment of insemination, millions of mammalian sperm cells are released into the female reproductive tract with the single goal of finding the oocyte. The spermatozoa subsequently ignore the thousands of cells they make contact with during their journey to the site of fertilization, until they reach the surface of the oocyte. At this point, they bind tenaciously to the acellular coat, known as the zona pellucida, which surrounds the oocyte and orchestrate a cascade of cellular interactions that culminate in fertilization. These exquisitely cell- and species- specific recognition events are among the most strategically important cellular interactions in biology. Understanding the cellular and molecular mechanisms that underpin them has implications for the etiology of human infertility and the development of novel targets for fertility regulation. Herein we describe our current understanding of the molecular basis of successful sperm-zona pellucida binding. PMID- 20839092 TI - Mouse models as tools in fertility research and male-based contraceptive development. AB - The production of functional spermatozoa is a complex process requiring the coordinated expression of thousands of genes. It is likely that the intricate nature of these interactions contributes to the large number of idiopathic male infertility cases seen in humans. Conversely, the complexity of the highly regulated and interconnected processes of spermatogenesis and posttesticular sperm maturation events offers opportunities for the development of male-based contraceptive targets. The recent advances in genetic manipulation technologies and the completion of the human and mouse genome sequencing programs have provided scientists with sophisticated ways to generate mouse models for the study of basic biological mechanisms, in order to understand disease pathology and develop novel therapeutic approaches. The three common types of mouse model used for medical research are transgenic, knockout/knockin, and chemical-induced point mutant mice. Each type has relative strengths and weaknesses with respect to its fidelity to the disease processes in humans. In this chapter, we focus on the utility of the different types of mouse model in obtaining a better understanding of the mechanisms that control spermatogenesis and developing male based contraceptive regimens. PMID- 20839093 TI - Male hormonal contraception. AB - The principle of hormonal male contraception based on suppression of gonadotropins and spermatogenesis has been established over the last three decades. All hormonal male contraceptives use testosterone, but only in East Asian men can testosterone alone suppress spermatogenesis to a level compatible with contraceptive protection. In Caucasians, additional agents are required of which progestins are favored. Current clinical trials concentrate on testosterone combined with norethisterone, desogestrel, etonogestrel, DMPA, or nestorone. The first randomized, placebo-controlled clinical trial performed by the pharmaceutical industry demonstrated the effectiveness of a combination of testosterone undecanoate and etonogestrel in suppressing spermatogenesis in volunteers. PMID- 20839094 TI - Family planning: today and in the future. AB - This review covers the state of contraceptive development noting new entries in the clinic (mainly steroidal and different delivery methods) and novel leads for nonsteroidal female- and male-methods in the pipeline. The time taken to market and the absence of partnerships with industry are stressed as major factors for the slow progress in their development. PMID- 20839095 TI - Approaches and applications of quantitative LC-MS for proteomics and activitomics. AB - LC-MS is a powerful technique in biomolecular research. In addition to its uses as a tool for protein and peptide quantization, LC-MS can also be used to quantify the activity of signalling and metabolic pathways in a multiplex and comprehensive manner, i.e. as an 'activitomic' tool. Taking cancer research as an illustrative example of application, this review discusses the concepts of biochemical pathway analysis using LC-MS-based proteomic and activitomic techniques. PMID- 20839096 TI - Overview of quantitative LC-MS techniques for proteomics and activitomics. AB - LC-MS is a useful technique for protein and peptide quantification. In addition, as a powerful tool for systems biology research, LC-MS can also be used to quantify post-translational modifications and metabolites that reflect biochemical pathway activity. This review discusses the different analytical techniques that use LC-MS for the quantification of proteins, their modifications and activities in a multiplex manner. PMID- 20839097 TI - Instrumentation for LC-MS/MS in proteomics. AB - Mass spectrometers now have sufficient sensitivity and acquisition rates to allow analysis of complex proteomic samples on a chromatographic timescale. In this chapter the different instrument options for protein and peptide analysis will be presented, along with their relative strengths and weaknesses for producing different types of information, such as protein identification, modification characterization, or reporting quantitative measurements. PMID- 20839098 TI - Bioinformatics for LC-MS/MS-based proteomics. AB - Mass spectrometry instrumentation has continued to develop rapidly in the last two decades, enabled in part by advances in microelectronic hardware controllers and computerized control and data acquisition systems. The wealth and complexity of data produced by a modern instrument is such that the data can no longer be analyzed manually. Computerized data analysis has become de rigueur and the bioinformatics field has expanded to provide software applications for all aspects of the data analysis needed by LC-MS/MS. The bioinformatics field is evolving rapidly and software applications are continually being improved or replaced for existing applications as well as developed to support new types of experiments and analysis enabled by modern instrumentation. Entire books have been written on MS data analysis in proteomics but this review will be necessarily brief. In this chapter we will review the bioinformatics software applications available for different LC-MS/MS analysis tasks. PMID- 20839099 TI - Analysis of post-translational modifications by LC-MS/MS. AB - Post-translational modifications are highly dynamic and known to regulate many cellular processes. Both the site and the stoichiometry of modification of a given protein sequence can have profound effects on the regulation of protein function. Thus, the identification of sites of post-translational modification is crucial for fully deciphering the biological roles of any given protein. The acute regulation and typically low stoichiometry of many post-translational modifications makes characterization of the sites of modification challenging. Thus, the development of analytical strategies to aid the selective enrichment and characterization of these species is paramount. Ongoing developments in mass spectrometry resulting in increased speed and sensitivity of analysis mean that mass spectrometry has become the ideal analytical tool for the qualitative and quantitative analysis of protein modifications. This chapter provides an overview of the most popular LC-MS/MS-based strategies for the enrichment of modified peptides/proteins and mass spectrometric workflows targeted toward the analysis of specific post-translationally modified analytes. PMID- 20839100 TI - In-depth analysis of protein phosphorylation by multidimensional ion exchange chromatography and mass spectrometry. AB - Protein phosphorylation controls fundamental biological functions that are often deregulated in disease. Therefore, system-level understanding of complex pathophysiological processes requires methods that can be used to profile and quantify protein phosphorylation as comprehensively as possible. Here we present a detailed protocol to enrich phosphopeptides from total cell lysates in a form amenable to downstream analysis by mass spectrometry. Using these techniques, we have detected several thousands of phosphorylation sites in the NIH-3T3 cell line. PMID- 20839101 TI - Mapping of phosphorylation sites by LC-MS/MS. AB - Reversible protein phosphorylation ranks among the most important post translational modifications that occurs in the cell. It is therefore highly relevant to elucidate the phosphorylation states of a given biological system, albeit challenging. Most notably the often low stoichiometry of phosphorylation is inherently incompatible with standard LC-MS analysis of a complex protein digest mixture, primarily due to the relative low dynamic range of current mass analyzers. Therefore a need for specific enrichment of phosphorylated peptides or proteins exists. Significant progress surrounding the biochemical analysis of reversible protein phosphorylation in the past years has led to the development of several new techniques to isolate or enrich phosphopeptides, particularly in large-scale analyses. This chapter deals with three such examples. PMID- 20839102 TI - Analysis of carbohydrates on proteins by offline normal-phase liquid chromatography MALDI-TOF/TOF-MS/MS. AB - Glycoproteins typically exist as a diverse population of glycoforms, which can consist of a great number of different glycan structures (including structural isomers) that vary in their degree of occupancy at given glycosylation sites. Hence, the detailed characterization of such glycans can be a very demanding task. Liquid chromatography in combination with mass spectrometric techniques can provide a fast and sensitive tool for the analysis of these structurally complex molecules. Here we describe a sensitive method that employs capillary normal phase HPLC coupled offline to MALDI-TOF/TOF-MS/MS for the detailed characterization of enzymatically released N-glycans. The normal-phase chromatography allows the separation of some isobaric glycan structures and analysis of the glycans by MALDI high-energy CID gives sequence, linkage and branching information. PMID- 20839103 TI - Selected reaction monitoring applied to quantitative proteomics. AB - Proteomics is gradually shifting from pure qualitative studies (protein identification) to large-scale quantitative experiments, prompted by the growing need to analyze consistently and precisely a large set of proteins in biological samples. The selected reaction monitoring (SRM) technique is increasingly applied to quantitative proteomics because of its selectivity (two levels of mass selection), its sensitivity (non-scanning mode), and its wide dynamic range. This account describes the different steps in the design and the experimental setup of SRM experiments. PMID- 20839104 TI - Basic design of MRM assays for peptide quantification. AB - With the recent availability and accessibility of mass spectrometry for basic and clinical research, the requirement for stable, sensitive, and reproducible assays to specifically detect proteins of interest has increased. Multiple reaction monitoring (MRM) or selective reaction monitoring (SRM) is a highly selective, sensitive, and robust assay to monitor the presence and amount of biomolecules. Until recently, MRM was typically used for the detection of drugs and other biomolecules from body fluids. With increased focus on biomarkers and systems biology approaches, researchers in the proteomics field have taken advantage of this approach. In this chapter, we will introduce the reader to the basic principle of designing and optimizing an MRM workflow. We provide examples of MRM workflows for standard proteomic samples and provide suggestions for the reader who is interested in using MRM for quantification. PMID- 20839105 TI - Proteome-wide quantitation by SILAC. AB - Ongoing improvements in instrumentation, fractionation techniques, and enrichment procedures have dramatically increased the coverage of the proteome achievable via LC-MS/MS-based methodologies, opening the call for approaches to quantitatively assess differences at a proteome-wide scale. Stable isotope labeling by amino acids in cell culture (SILAC) has emerged as a powerful and versatile approach for proteome-wide quantitation by mass spectrometry. SILAC utilizes the cells' own metabolism to incorporate isotopically labeled amino acids into its proteome which can be mixed with the proteome of unlabeled cells and differences in protein expression can easily be read out by comparing the abundance of the labeled versus unlabeled proteins. SILAC has been applied to numerous different cell lines and the technique has been adapted for a wide range of experimental procedures. In this chapter we provide detailed procedure for performing SILAC-based experiment for proteome-wide quantitation, including a protocol for optimizing SILAC labeling. We also provide an update on the most recent developments of this technique. PMID- 20839106 TI - Quantification of proteins by iTRAQ. AB - Protein relative quantification is a key facet of many proteomics experiments. Several methods exist for this type of work, some of which are described elsewhere in this volume. In this chapter we will describe the use of isobaric tags for relative and absolute quantification (iTRAQ). These chemical tags attach to all peptides in a protein digest via free amines at the peptide N-terminus and on the side chain of lysine residues. Labelled samples are then pooled and analysed simultaneously. Since the tags are isobaric, labelled peptides do not show a mass shift in MS, instead signal from the same peptide from all samples is summed, providing a moderate increase in sensitivity. Upon peptide fragmentation, sequence ions (b- and y-type) also show this summed intensity which aids sensitivity. However, the distribution of isotopes in the different tags is such that when the tags fragment a tag-specific 'reporter' ion is released. The ratio of signal intensities from these tags acts as an indication of the relative proportions of that peptide between the different labelled samples. This chapter will describe the procedure for labelling and analysing peptide/protein samples using iTRAQ. PMID- 20839107 TI - Quantification of proteins by label-free LC-MS/MS. AB - Quantitative proteomic profiling is becoming a widely used approach in systems biology and biomarker discovery. There is a growing realization that quantitative studies require high numbers of non-pooled samples for increased statistical power. We present a descriptive protocol for label-free quantitation of proteins by LC-MS/MS that enables to obtain both quantitative and qualitative information in one study without the need to pool samples or label them. PMID- 20839108 TI - Protocol for quantitative proteomics of cellular membranes and membrane rafts. AB - Proteomic analysis of membrane and membrane raft proteins is complicated by their inherent insolubility, which exacerbates difficulties with in-solution digestion of the proteins prior to ESI-LC-MS/MS. In-gel digestion yields more comprehensive proteomic and protein coverage of membrane/membrane raft samples, for example by LC-MS/MS of protein samples resolved by 1D SDS-polyacrylamide gel electrophoresis. Although this type of analysis can be performed quantitatively by labelling at the protein level, for instance by SILAC, the separation of proteins on a resolving gel complicates the application of other quantitative methods that employ post-digestion labelling techniques. This chapter describes an alternative protocol to prepare membrane or membrane raft protein samples to be isolated, but not separated, as unresolved bands in a gel. Focusing as a single band enables the confident excision of different samples in their entirety, to be digested, labelled, and fractionated for quantitative mass spectrometric analysis. PMID- 20839109 TI - Organelle proteomics by label-free and SILAC-based protein correlation profiling. AB - The ability to purify cell organelles and protein complexes on a large scale, combined with advances in protein identification using mass spectrometry, has provided a wealth of information regarding protein localization and function. A major challenge in these studies has been the ability to identify bona fide organelle components from a background of co-purifying contaminants because none of the available biochemical purification protocols afford pure preparations. Since this situation is unlikely to change alternative strategies have been devised to meet this challenge by making use of the information inherent in the fractionation profile of organelles isolated by density gradient centrifugation. In this chapter we describe strategies based on protein correlation profiling and quantitative mass spectrometry to sort out likely candidates. The organelle inventories defined by these methods are suitable to guide future functional experiments. PMID- 20839110 TI - Mapping protein-protein interactions by quantitative proteomics. AB - Proteins exert their function inside a cell generally in multiprotein complexes. These complexes are highly dynamic structures changing their composition over time and cell state. The same protein may thereby fulfill different functions depending on its binding partners. Quantitative mass spectrometry (MS)-based proteomics in combination with affinity purification protocols has become the method of choice to map and track the dynamic changes in protein-protein interactions, including the ones occurring during cellular signaling events. Different quantitative MS strategies have been used to characterize protein interaction networks. In this chapter we describe in detail the use of stable isotope labeling by amino acids in cell culture (SILAC) for the quantitative analysis of stimulus-dependent dynamic protein interactions. PMID- 20839111 TI - Analysis of serum proteins by LC-MS/MS. AB - Serum contains a vast array of proteins, some of which are specific to blood whilst others are secreted into blood from tissues and organs. The so-called tissue leakage factors reveal information about the tissue from which they originate and are therefore of great potential importance as disease biomarkers. There are already a number of blood-borne biomarkers in routine clinical use that aid in the diagnosis or management of cancer. However, there is a pressing need for additional markers, and new methods to find them are under development. Here we provide a protocol for serum protein profiling using liquid chromatography tandem mass spectrometry (LC-MS/MS). Included in this procedure, we detail the pre-processing steps of lipid and high-abundance protein removal. These procedures can also be employed up-stream of quantification methods such as isobaric tags for relative and absolute quantification (iTRAQ). Chapter 12 is devoted to the iTRAQ approach for quantifying proteins, and it is therefore not described in this chapter. PMID- 20839112 TI - Urinary proteome profiling using 2D-DIGE and LC-MS/MS. AB - Proteomic methodologies have been at the forefront of cancer research for several years. The use of proteomic strategies to study all expressed genes aims to discover biomarkers indicative of the physiological state of cancer cells at specific time points, enabling early diagnosis, following cancer development/progression, screening and monitoring the efficacy of new therapeutic agents. Onco-proteomics has the potential to impact on oncology practice by delivering individualised highly selective clinical care. 2D-DIGE (2D difference in gel electrophoresis) enables simultaneous examination and comparison of multiple samples using cyanine dyes to label amino acid residues that are then separated based on charge and mass. These advantages combined with universal availability have until recently made 2D-DIGE a first method of choice in cancer proteome analysis of diverse specimens, including tissues, cell lines, blood and other body fluids. PMID- 20839113 TI - Analysis of peptides in biological fluids by LC-MS/MS. AB - Urine contains large amounts of small peptides, which may represent a rich, yet largely unexplored, source of novel biomarkers for disease monitoring. This chapter describes detailed procedures for the analysis of urinary polypeptides by LC-MS/MS. Hundreds to thousands of small peptides (~700 to ~7000 Da) can be detected in urine with the described techniques. Extraction procedures, based on commercially available reagents, effectively remove interfering urinary organic and inorganic salts and neutral compounds, making this a robust and simple assay with the power to detect hundreds to thousands of polypeptides in urine. Analysis time is relatively short, making this protocol a valuable alternative to conventional proteomic techniques based on multidimensional separations. The methodology is therefore particularly useful when the aim is to analyse samples with sufficient depth and throughput so as to make it useful to compare large numbers of specimens. Procedures for enhancing quantitative and qualitative analysis of LC-MS/MS data are also detailed. PMID- 20839114 TI - Quantification of protein kinase activities by LC-MS. AB - Measuring the enzymatic activity of protein kinases in cell and tissue extracts represents a difficult task owing to the complex regulation and dynamics of such enzymes. Here we describe a sensitive and specific approach for the quantitative analysis of PI3K-dependent protein kinase activity based on the mass spectrometry measurement of reaction products. The principle of this method can be applied to develop other kinase assays and thus should contribute to the understanding of processes controlled by protein kinases. Because of the enhanced sensitivity of this technique, it may be applied to the multiplex measurement of pathway activities when sample amounts are limiting. PMID- 20839115 TI - A Protocol for top-down proteomics using HPLC and ETD/PTR-MS. AB - Analysis of intact proteins by tandem mass spectrometry has mostly been confined to high-end mass spectrometry platforms. This protocol describes the application of routine HPLC to separate proteins, MALDI-ToF mass spectrometry to interrogate intact protein species and electron transfer dissociation/proton transfer reaction within a quadrupole ion trap to perform tandem mass spectrometry. PMID- 20839116 TI - Making a difference. PMID- 20839117 TI - Mass critical care ethics: black and white, or grey? PMID- 20839118 TI - Antitumor activity of two gelsemine metabolites in rat liver microsomes. AB - Gelsemine is one of the major alkaloids from Gelsemium elegans Benth., which has been used as an antitumor remedy in clinic. In this paper, metabolism of gelsemine has been investigated in vitro in phenobarbital-treated rat liver microsomes. The metabolites of gelsemine were separated and evaluated using the flash silica gel column, preparative HPLC, using NMR and MS methods. According to the spectral data, two metabolites, M1 and M2, were identified as 4-N demethylgelsemine and 21-oxogelsemine, respectively. By the MTT method in vitro, the antitumor activities between gelsemine and its metabolites were compared in the HepG2 and HeLa cell lines. Moreover, the main metabolic pathway was further proposed. PMID- 20839119 TI - Two new glycosides from Leonurus japonicus. AB - Two new glycosides, 1,6-di-O-syringoyl-beta-D-glucopyranose (1) and quercetin 3-O [(3-O-syringoyl-alpha-L-rhamnopyranosyl)-(1->6)-beta-D-glucopyranoside] (2), along with seven known compounds were isolated from the MeOH extract of Leonurus japonicus. The structures of these compounds were elucidated by spectral analysis. PMID- 20839120 TI - Two new furostanol glycosides from the fibrous root of Ophiopogon japonicus (Thunb.) Ker-Gawl. AB - Two new furostanol glycosides, ophiopogonins H (1) and I (2), were isolated from the fibrous root of Ophiopogon japonicus. The structures of 1 and 2 were established as (25R)-26-[(O-beta-D-glucopyranosyl-(1->2)-beta-D-glucopyranosyl)] 22alpha-hydroxyfurost-5-ene-3-O-[alpha-L-rhamnopyranosyl-(1->2)]-beta-D glucopyranoside and (25R)-26-[(O-beta-D-glucopyranosyl-(1->2)-beta-D glucopyranosyl)]-20alpha-hydroxyfurost-5,22-diene-3-O-[alpha-L-rhamnopyranosyl-(1 >2)]-beta-D-glucopyranoside on the basis of spectroscopic means including HR-ESI MS, 1D and 2D NMR experiments. PMID- 20839121 TI - C28 sterols with a cyclopentane ring at C-22 and 26 from cape gooseberry (berries of Physalis pubeacens L.). AB - Two new C28 sterols with a cyclopentane ring at C-22 and 26, alkesterol A (1) and alkesterol B (2), along with beta-sitosterol (3), were isolated from the berries of Physalis pubeacens L. (cape gooseberry). The structures of the new compounds were established by HR-EI-MS, 1D and 2D (1H-1H COSY, HSQC, HMBC) NMR experiments. The known compound was identified by comparison of spectral data with published references. The two new compounds showed some cytotoxic activities by MTT assay. PMID- 20839122 TI - Microbial transformation of asiatic acid by Alternaria longipes. AB - Asiatic acid is a major pentacyclic triterpene isolated from Centella asiatica. It shows a variety of bioactivities. In order to obtain its derivatives, potentially useful for detailed pharmacological studies, the substrate was subjected to incubations with selected micro-organisms. In this work, asiatic acid was converted into three new compounds: 2alpha,3beta,23,30-tetrahydroxyurs 12-ene-28-oic acid (1), 2alpha,3beta,22beta,23-tetrahydroxyurs-12-ene-28-oic acid (2), and 2alpha,3beta,22beta,23,30-pentahydroxyurs-12-ene-28-oic acid (3) by the fungus Alternaria longipes AS 3.2875. The structures of the three metabolites were determined by 1D and 2D NMR spectral data. PMID- 20839123 TI - Two new phenolic glycosides from Inula cappa. AB - Two new phenolic glycosides, syringic acid-4-O-alpha-L-rhamnoside (1) and (-) hydnocarpin-7-O-beta-D-glucoside (2), were isolated from the traditional Chinese medicinal herb Inula cappa. The structures of the new compounds were elucidated by means of spectroscopic methods such as 1D, 2D NMR, and HR-ESI-MS. PMID- 20839124 TI - New iridoids from the fruits of Crescentia cujete. AB - Four new 11-nor-iridoids, 6-O-p-hydroxybenzoyl-10-deoxyeucommiol (1), 6-O-benzoyl 10-deoxyeucommiol (2), 6-O-benzoyl-dihydrocatalpolgenin (a mixture of 3 and 4), as well as two known iridoids, ningpogenin (5) and 6-O-p-hydroxybenzoylaucubin (6), were isolated from the fruits of Crescentia cujete Linn. The structures of these compounds were established on the basis of spectroscopic analysis. PMID- 20839125 TI - Acylated flavone C-glycosides from Hemistepta lyrata. AB - Two new acylated flavone C-glycosides, 6''-O-(2'''-methylbutyryl)isoswertisin (1) and 6''-O-(2'''-methylbutyryl)isoswertiajaponin (2), together with four known acylated flavone C-glycosides, were isolated for the first time from the whole plants of Hemistepta lyrata (Compositae). Their structures were elucidated on the basis of chemical and spectroscopic methods including HR-ESI-MS, ESI-MS, UV, IR, and 1D and 2D NMR spectral techniques. PMID- 20839126 TI - Three new cassane diterpenes from the seeds of Caesalpinia minax Hance. AB - Three new cassane-diterpene-lactones, methyl 1alpha,7beta-diacetoxy 5alpha,12alpha-dihydroxy-cass-13(15)-en-16,12-olide-17beta-carboxylate (1), methyl 7beta-acetoxy-1alpha,5alpha,12alpha-trihydroxy-cass-13(15)-en-16,12-olide 17beta-carboxylate (2), and 12alpha-ethoxyl-1alpha,6alpha,7beta-triacetoxy 5alpha,14beta-dihydroxy-cass-13(15)-en-16,12-olide (3), were isolated from the seeds of Caesalpinia minax Hance. Their structures were established on the basis of HR-ESI-MS, 1D and 2D NMR spectral analysis. PMID- 20839127 TI - Two new eudesmanolides from Inula racemosa. AB - Two new eudesmane-type sesquiterpene lactones were isolated from the roots of Inula racemosa and their structures were elucidated as 3beta-hydroxy-11alpha,13 dihydroalantolactone (1) and 11alpha-hydroxy-eudesm-5-en-8beta,12-olide (2). Their cytotoxic activities against five human cancer cell lines had been tested and compound 2 exhibited weak cytotoxic activity against BEL-7402 and HCT-8 cell lines. The anti-inflammatory activities were also tested, but neither of them showed any activities. PMID- 20839128 TI - Studies on cytotoxic constituents from the skin of the toad Bufo bufo gargarizans. AB - To study the chemical composition of the skin of Bufo bufo gargarizans, many kinds of chromatography methods were used in the isolation procedures, while the structures of isolated compounds were determined on the basis of their NMR and MS spectral analysis. As a result, two new compounds were isolated from its ethanolic extract and characterized as cinobufotalin 3-nonanedioylarginine ester (8) and bufotalin 3-pimeloylarginine ester (14). Furthermore, 13 known compounds were obtained. Isolated bufadienolides showed significant inhibition effect against SMMC-7721 cell lines in vitro. PMID- 20839129 TI - Triterpenoid saponins from the rhizome of Polygonatum sibiricum. AB - Three new triterpenoid saponins, polygonoides C (1), D (2), and E (3), were obtained from the ethanolic extract of the rhizome of Polygonatum sibiricum Redoute. On the basis of NMR and ESI-MS spectra, and chemical evidence, the structures of the three new compounds were elucidated as 3-O-alpha-L rhamnopyranosyl-(1->2)-beta-D-glucopyranosyl-(1->4)-beta-D-glucopyranosyl 3beta,7beta,22beta-trihydroxy-oleanolic acid (1), 3-O-alpha-L-rhamnopyranosyl-(1 >2)-beta-D-glucopyranosyl-(1->4)-beta-D-glucopyranosyl-3beta,7beta,22beta trihydroxy-oleanolic acid methyl ester (2), and 3-O-beta-D-glucopyranosyl-(1->3) beta-D-glucopyranosyl-(1->4)-[alpha-L-rhamno-pyranosyl-(1->2)]-beta-D glucopyranosyl-3beta,21beta-dihydroxy-oleanolic acid 28-O-beta-D-glucopyranosyl (1->3)-beta-D-glucopyranosyl-(1->3)-beta-D-glucopyranoside (3). PMID- 20839130 TI - A new diimide derivative from the co-culture broth of two mangrove fungi (strain no. E33 and K38). AB - A new diimide derivative, named (-)-byssochlamic acid bisdiimide (1), was isolated from the mixed broth of two mangrove fungi (strain no. K38 and E33) from the South China sea coast. The structure of 1 was determined by comprehensive spectroscopic methods, including 1D and 2D NMR (COSY, HMQC, and HMBC) and semi synthesis. Primary bioassays showed that 1 had weak cytotoxic activity against Hep-2 and HepG2 cells. PMID- 20839131 TI - Chemical constituents of Osyris alba and their antiparasitic activities. AB - Phytochemical investigation of Osyris alba L. (Santalaceae) of Jordanian origin resulted in the isolation and identification of one new pyrrolizidine alkaloid, osyrisine (1), together with 16 other known compounds. The structures of all compounds were established on the basis of spectroscopic analysis. Osyrisine, catechin, and catechin-3-O-alpha-L-rhamnopyranoside exhibited a significant level of antiparasitic activity against two parasites, Entamoeba histolytica and Giardia intestinalis. PMID- 20839132 TI - A new phenolic glycoside and cytotoxic constituents from Celosia argentea. AB - A new phenolic glycoside, 4-O-beta-D-apifuranosyl-(1->2)-beta-D-glucopyranosyl-2 hydroxy-6-methoxyacetophenone (2) and 11 known compounds were isolated from the MeOH extract of the plant Celosia argentea. The structures of the compounds were elucidated on the basis of spectroscopic analysis and chemical methods. Among the isolated compounds, stigmasterol (10) showed moderate inhibitory activities against SGC-7901 and BEL-7404 cells. PMID- 20839133 TI - Predictions of verbal episodic memory in persons with Alzheimer's disease. AB - This study examined awareness of memory problems and memory self-monitoring abilities in individuals with Alzheimer's disease (AD). Participants were 20 individuals with AD and 20 older adult controls. A global performance-prediction paradigm, which required participants to predict the number of words they would remember both prior to and after completing a list-learning memory task, was used as the online assessment measure. Offline assessment of memory involved contrasting self-ratings provided by participants about the frequency of everyday memory failures with ratings from knowledgeable informants. As expected, participants with AD demonstrated poorer recall for the word list than did controls. Participants with AD were also less accurate than controls in their preexperience memory predictions, and findings from the offline assessment method similarly revealed that the AD group overestimated their everyday memory abilities. Despite showing impaired understanding of personal memory ability, the AD group successfully modified their postexperience memory predictions so that they were more accurate following task exposure, demonstrating accurate memory self-monitoring abilities. These findings highlight the complex and multidimensional nature of metamemory. The findings further suggest that while AD patients appear able to immediately benefit from task experience, they have difficulty creating lasting awareness of memory abilities. PMID- 20839134 TI - Stop being neutral: Simon takes control! AB - The Simon task is one of the well known tasks that recruit cognitive control. The Simon effect, the reaction time (RT) difference between congruent and incongruent stimuli, has been commonly discussed as interference based. Nevertheless, in recent years some studies have referred to the facilitation component of the task. In the current research we measured effects of cognitive control by conducting sequential analysis and adding neutral conditions. Two neutral stimuli were employed in order to examine their effect and their validity as neutrals. It was found that presentation of Simon stimuli on the central meridian at the top or bottom of a screen (but not at the centre of the screen) created a valid neutral condition. Facilitation as well as interference effects were found. Adding a nonconflict condition modulated cognitive control independently of sequential effects. Namely, the Simon effect increased by adding both types of neutrals, but the decrease in the effect after incongruent trials was only present for the vertical neutral block, in which the Simon effect appeared after congruent but not after incongruent trials. We suggest the possibility of two different mechanisms of cognitive control. PMID- 20839135 TI - Selective impairment of masked priming in dual-task performance. AB - This study investigated the impact of divided attention on masked priming. In a dual-task setting, two tasks had to be carried out in close temporal succession: a tone discrimination task and a masked priming task. The order of the tasks was varied between experiments, and attention was always allocated to the first task that is, the first task was prioritized. The priming task was the second (nonprioritized) task in Experiment 1 and the first (prioritized) task in Experiment 2. In both experiments, "novel" prime stimuli associated with semantic processing were essentially ineffective. However, there was intact priming by another type of prime stimuli associated with response priming. Experiment 3 showed that all these prime stimuli can reveal significant priming effects during a task-switching paradigm in which both tasks were performed consecutively. We conclude that dual-task specific interference processes (e.g., the simultaneous coordination of multiple stimulus-response rules) selectively impair priming that is assumed to rely on semantic processing. PMID- 20839136 TI - Variation in verbal fluency: a latent variable analysis of clustering, switching, and overall performance. AB - Verbal fluency tasks have long been used to assess and estimate group and individual differences in executive functioning in both cognitive and neuropsychological research domains. Despite their ubiquity, however, the specific component processes important for success in these tasks have remained elusive. The current work sought to reveal these various components and their respective roles in determining performance in fluency tasks using latent variable analysis. Two types of verbal fluency (semantic and letter) were compared along with several cognitive constructs of interest (working memory capacity, inhibition, vocabulary size, and processing speed) in order to determine which constructs are necessary for performance in these tasks. The results are discussed within the context of a two-stage cyclical search process in which participants first search for higher order categories and then search for specific items within these categories. PMID- 20839137 TI - [Jugular vein thrombosis and Lemierre's syndrome--severe complications of oropharyngeal infections]. AB - BACKGROUND: Acute oral or pharyngeal infections usually heal under adequate therapy within a few days. Therefore severe regionary or systemic complications are not regularly seen. PATIENTS AND METHODS: We report on 3 patients in whom during or after apparent recovery from a pharyngeal or perioral infection a one sided painful swelling of the neck associated with fever and leucocytosis developed. RESULTS: Color Doppler sonography (CDS) revealed unilateral thrombosis of the internal jugular vein (IJV) in all cases, whereupon we initiated high dosed parenteral antibiotic therapy and therapeutic heparinisation. Furthermore, we drained detectable abscess formations. Nonetheless, in one patient fever attacks occurred postoperatively, accompanied by septic-embolic lung infiltrates, corresponding to Lemierre's syndrome. In all cases, we achieved clinical recovery and remission of infection. The course was significantly prolonged in the patient with pulmonary involvement and in this patient no reperfusion of the IJV was achieved. CONCLUSIONS: Even today serious complications may occur unexpectedly in presumed everyday oral or pharyngeal infections. CDS is a suitable procedure to disclose a jugular vein thrombosis (JVT) promptly and non-invasively. Parenteral antibiotic therapy for at least 10 days is usually the therapy of choice for JVT; additional full-heparinisation is controversially discussed in the professional literature. Septic pulmonary embolism following pharyngeal infection and JVT, as described by Lemierre, was associated with a high rate of mortality in the pre antibiotic era, and even today may be fatal in spite of appropriate and maximal therapy. PMID- 20839139 TI - [From the expert's office: Time limits of safekeeping of the expert opinion]. PMID- 20839140 TI - [Tympanic membrane reconstruction with non-autogenous transplants and alloplastic materials]. AB - Autogenous tissue has been the grafting material of choice in reconstruction of permanent tympanic membrane perforations. Although donor site complications are infrequent and morbidity from such harvest is usually quite low, there are nevertheless risks associated with additional incisions when autogenous tissue is used. In addition, in patients who have undergone several grafting attempts, there may be no suitable grafting material in the vicinity of the operative field. Several alternatives to native grafting material have recently become available, which have shown similar success rates of perforation closure as well as postoperative audiologic results. This article gives an overview on these non autogenous grafts and alloplastic materials. PMID- 20839141 TI - [Neurological complications following anesthesia - part II]. AB - Neurological complications after surgery may have fatal consequences for the patient or lead to disability and inability to work. Similar to central nervous complications such as stroke, postoperative visual loss, postoperative cognitive deficit and delirium, peripheral neurological complications following anaesthesia can be decisively influenced or almost avoided by an optimized anaesthesiological management. In the present article typical peripheral neurologic complications which can occur after regional anesthesia, central venous puncture and insertion of arterial or venous cannulas as well as etiology, diagnosis and therapy of peripheral nervous damage are described. Moreover the paper gives recommendations on intraoperative positioning of the patient and presents medicolegal aspects in the perioperative setting. PMID- 20839142 TI - [ECMO and ARDS-therapy - an update]. AB - The "Acute Respiratory Distress Syndrome" (ARDS) is a life threatening disease and is associated with a high mortality, mainly due to multi-organ failure. Invasive mechanical ventilation can worsen multi-organ failure which must be avoided. A tidal volume of 6 ml/kg bodyweight should be the aim. Extracorporeal lung assist devices like ECMO or iLA can contribute to lung-protective mechanical ventilation. PMID- 20839143 TI - [Coagulation management in trauma-related massive bleeding. - Recommendations of the Task Force for Coagulation (AGPG) of the Austrian Society of Anesthesiology, Resuscitation and Intensive Care Medicine (OGARI)]. AB - Even nowadays and at specialized centers, one of the leading causes of death is exsanguination. Trauma-induced coagulopathy (TIC) occuring with massive blood loss primarily results from loss of coagualtion factors and platelets and is aggravated by hemodilution. In addition, hyperfibrinolysis, hypothermia, acidosis and hypocalcaemia also contribute to the development of severe haemostatic derangement. During the past few years new insights into the pathophysiology of TIC and the widespread use of viscoelastic coagulation monitoring provoked the development of alternative treatment concepts. As for the previously recommended standard therapy using fresh frozen plasma and platelet concentrates also for alternative strategies no data from large prospective randomized studies are available until now, however, the evidence is growing favoring the use of coagulation factor concentrates guided by viscoelastic measurements. PMID- 20839144 TI - [The hospital infection surveillance system (KISS)]. AB - According to S23 of the prevention of infections act (Infektionsschutzgesetzes, IfSG), the directors of hospitals and facilities for ambulant operations are obliged to continuously record and evaluate nosocomial infections. In this way it is intended that quality management with regard to the prevention of nosocomial infections should be improved. The national reference centre for the surveillance of nosocomial infections (NRC) has developed a computer and internet-assisted system and made it available: the hospital infection surveillance system (KISS). With this method at hand it is now possible to conduct a uniform surveillance of nosocomial infections that takes the most important influencing and risk factors into consideration and thus permits orienting comparisons. Participation in the KISS is possible free of charge. PMID- 20839145 TI - [Therapy for sepsis -- Quo vadis?]. PMID- 20839146 TI - [Clinical value of the sepsis bundles and modes of implementation]. AB - The sepsis bundles comprise the most important steps that have to be made in the first 24 hours following the sepsis diagnosis. Being comprehensive and manageable, they can be implemented in every ICU and in every hospital, and wherever this happens, more patients suffering from severe sepsis or septic shock survive. The ideal mode of implementation has yet to be found. Education and both financial and human resources play an important role for success, and so does the strong wish for improvement among the individual doctor, and among all responsible individuals within an institution or a scientific society caring for critically ill patients. PMID- 20839147 TI - [The neuroendocrine axis and the pathophysiology of sepsis]. AB - The immune system and the central nervous system are able to affect each other. Proinflammatory cytokines induce the expression of CRH or AVP in the hypothalamus and ACTH in the pituitary gland. Thus, enhanced adrenal release of cortisol suppresses the activation of NF-kappaB and activates antiinflammatory cytokines. The cholinergic antiinflammatory pathway, the efferent arm of the inflammatory reflex, is another mechanism of the CNS to control inflammation. It consists of the efferent vagus nerve, the neurotransmitter actylcholine and the alpha7 subunit of the nicotinic acteylcholine receptor. Probably, the transmission of information takes place to postsynaptic sympathetic fibres in the celiac plexus which terminate in the spleen and act on splenic immune cells. Cholinesterase inhibitors have antiinflammatory effects in experimental sepsis when administered early. PMID- 20839148 TI - [Update and controversies of adjunctive sepsis therapy]. AB - The implementation of the sepsis bundles have led to a remarkable reduction of mortality. The early treatment is one key factor, but there are differences in the effectiveness of single bundle measures to contribute to decreased mortality. The validation of newly introduced management or therapeutic interventions like tight glucose control in randomized controlled trials is not completely successful for patients suffering from severe sepsis or septic shock. Recently published guidelines attenuate implemented treatment strategies and lead to further adjustment taking into account actual data on adjunctive sepsis therapy. PMID- 20839149 TI - [Quality improvement of postoperative pain management in infants QUIPSI) - A pilot study]. AB - Outcome-focussed benchmarking has been shown to be a successful tool in adult quality improvement of postoperative pain management in adults. We report on feasibility and first results of a similar project in operated children (quality improvement of postoperative pain management in infants, QUIPSI). Our results show that outcomes in postoperative pain management can be measured and compared in routine clinical practice. QUIPSI (Quality Improvement in Postoperative Pain Management in Infants) represents a new tool for outcome evaluation, consisting of standardized data acquisition of outcome and process quality indicators. In the currently starting second phase of the project, a multicenter evaluation will take place in ten medical centres. PMID- 20839150 TI - The effects of the endothelium on adrenal steroidogenesis and growth are mainly mediated by proteins other than endothelin-1. AB - The endothelium releases factors stimulating the adrenal cortex. It is also known that endothelin-1 (ET-1) promotes generation of cortisol and aldosterone, and proliferation of adrenocortical cells. The aim of the study was to find out whether the effect of the endothelium on adrenocortical cells is dominated by the action of ET-1. The effects of endothelial cell-conditioned medium (ECCM), obtained during growth of human umbilical cord vein endothelial cells, on aldosterone and cortisol release by cells of the adrenocortical cancer cell-line NCI-H295R and the promoter activity of steroidogenic acute-regulatory protein (StAR) were studied. The effect of ECCM on proliferation of human primary normal adrenocortical and NCI-H295R cells was also investigated. Concentration-dependent increases in cortisol release that reached 192.7 +/- 62.8 in percent of basal secretion, in aldosterone release that reached 188.2 +/- 52.3 in percent of basal secretion, and in proliferation after stimulation with ECCM at concentrations of 10-50% were found. ECCM significantly activated the StAR promoter 3-fold in NCI H295R cells if the ECCM was not pretreated with pronase. These effects of the endothelium were not reversed after co-incubation with endothelin receptor antagonists and could not be mimicked by incubation with endothelin-1. In conclusion, the cultured endothelial cells secrete a protein that stimulates steroidogenesis in adrenal cells and their growth. It was also shown that the ET 1 does not mediate the effect of ECCM on the NCI-H295R cell line. PMID- 20839151 TI - Corticosteroid-binding globulin, cortisol, free cortisol, and sex hormone-binding globulin responses following oral glucose challenge in spinal cord-injured and able-bodied men. AB - Circulating cortisol, corticosteroid-binding globulin, and sex hormone-binding globulin were measured retrospectively in plasma samples following the oral glucose tolerance test in 20 spinal cord-injured men and 20 able-bodied controls. Plasma-free cortisol responses attenuated more rapidly in the able-bodied men, compared to spinal cord-injured subjects, due to significant rise in circulating corticosteroid-binding globulin whereas changes in total plasma cortisol were similar in both groups. The changes in plasma-free cortisol in both groups paralleled changes in insulin and glucose and show that spinal cord-injured men had heightened exposure to free cortisol during this dynamic test. This raises the possibility that the mechanism of abdominal obesity and the propensity towards insulin resistance in spinal cord-injured men could be subtly mediated by perturbations in free cortisol. There were no significant changes in plasma sex hormone-binding globulin in either group. PMID- 20839152 TI - African Americans and Caucasian Americans: differences in glucocorticoid-induced insulin resistance. AB - African Americans are more insulin resistant than Caucasian Americans and this discrepancy cannot be explained by measures of body weight or body composition. The aim of the study was to compare the sensitivity of African Americans and Caucasian Americans to glucocorticoids by measuring glucose and insulin responses to a meal challenge under conditions of placebo and glucocorticoid. A total of 160 healthy or overweight/obese African American and Caucasian American participants completed exercise testing and a liquid meal challenge during separate laboratory visits. Participants were evaluated following treatments with placebo and dexamethasone (4 mg). Main outcome measures were correlation between body composition measures (body mass index, percent body fat, waist circumference) and insulin responses; insulin and glucose responses after a liquid meal challenge; and calculated HOMA. After dexamethasone treatment African Americans were significantly more hyperinsulinemic after a meal as indicated by higher peak insulin (p=0.02) and postprandial insulin areas under the curve (p=0.006) than Caucasians. Additionally, African Americans were more insulin resistant than Caucasian Americans under both placebo and dexamethasone as determined by fasting insulin and HOMA (p=0.05). Waist circumference correlated with post-dexamethasone insulin AUC and HOMA in Caucasian Americans (p<0.05), but none of the body composition measures were predictive of IR for African Americans. African Americans are more sensitive to glucocorticoids (dexamethasone) than Caucasian Americans, as indicated by significantly greater peak insulin and postprandial insulin areas under the curve. The glucocorticoid receptor and its potential interactions with stress may contribute to this ethnic disparity. PMID- 20839153 TI - [A prospective evaluation of psychometric items in patients with nasal deformities]. AB - BACKGROUND: Patient satisfaction with surgical outcome is essential in plastic reconstructive surgery, yet no German-language psychometrically validated instrument exist for assessing satisfaction with surgery in the head and neck area. Previously, the short form of the "Frankfurter Selbstkonzeptskalen/FSKN" showed mixed results in a sample of patients undergoing correction of microtia. MATERIAL AND METHODS: This short form was tested in 22 patients following septorhinoplasty and in 24 following tonsillectomy, regarding its psychometric characteristics. RESULTS: While showing good practical characteristics and content validity, there were disappointing results in responsiveness to change and known group's discriminant validity. CONCLUSIONS: Beside sample size, different psychological mechanisms in more common malformations of the head neck area, especially in patients with nasal deformities, have to be further explored as they are not sufficiently represented in the short form of FSKN. PMID- 20839154 TI - [Structural irregularities of the internal and/or external nose (with functional and/or relevant aesthetic impairment)]. AB - The purpose of this guideline is to promote a high-quality specialty care for patients with structural irregularities of the internal and/or external nose associated with functional and/or relevant aesthetic impairment. The guideline was designed for use in the outpatient and inpatient specialist medical care and is therefore specifically targeted to specialists of Oto-Rhino-Laryngology, Oral and Maxillofacial Surgery and Plastic Surgery. The guideline was interdisciplinarily developed according to the specifications of the German guideline commission "AWMF" as a so called "S2k" guideline. This guideline refers to structural disturbances of the internal and external nose, where normalization due to functional and/or relevant aesthetic reasons is required. Cosmetic rhinoplasty is not covered by this guideline. PMID- 20839155 TI - [Percutaneous coronary intervention is the treatment of choice for stable chronic coronary disease]. PMID- 20839156 TI - [Coronary artery bypass grafting is the treatment of choice for stable chronic coronary disease]. PMID- 20839157 TI - [Optimal medical therapy is the treatment of choice for stable chronic coronary disease]. PMID- 20839158 TI - Effect of early dysphoric response and cannabis use on discontinuation of olanzapine or risperidone in patients with early psychosis. PMID- 20839160 TI - [Toluidin blue in gastrointestinal endoscopy]. AB - For decades, methylene blue has been used in gastrointestinal endoscopy as an absorbing dye, it was, however, not approved for that purpose and has now been withdrawn from the market. A possible substitute is toluidine blue, an acidophilic, metachromatic dye that selectively stains cell nuclei; accordingly, since 2007, toluidine blue has been approved as a topical diagnostic agent in chromoendoscopy. Cells with increased DNA synthesis are stained more intensively so that not only malignant cells but also erosions, ulcerations and inflammatory areas are stained with toluidine blue because of the increased reparative cellular processes. Up to now, absolutely no studies have been carried out with regard to the effectiveness of toluidine blue in gastrointestinal endoscopy. We report on a consecutive series of 364 endoscopic applications of toluidine made on the basis of various indications. Besides the known indications (e. g., chromoendoscopy in case of Barrett's oesophagus), we mostly used toluidine blue, diluted in hydroxyethylstarch (HAES), for submucosal injections of flat adenomas prior to endoscopic mucosal resection or endoscopic submucosal dissection, in order to precisely determine the extension of visible lesions. Local and systemic adverse reactions have not been observed. A demarcation of the lesions can be made as effectively as with methylene blue. PMID- 20839161 TI - [Emergence of clostridium difficile ribotype 027 in Germany: epidemiological and clinical characteristics]. AB - INTRODUCTION: In September 2007 an increase of severe Clostridium difficile associated infections (CDI) was noticed in a hospital in the city of Trier, Germany. It was assumed that a new, possibly hypervirulent strain (PCR ribotype 027) was related to these events. An outbreak investigation was initiated by the local health authorities and the Robert Koch Institute to describe the epidemiology of the possible outbreak and to identify and control the possible sources. METHODS: In addition to retrospective case-finding of severe CDI and ribotype 027 infections by analysis of patient documents and certificates of death, an active surveillance system for severe CDI and ribotype 027 infections was established in the 6 hospitals of the affected region. In all suspected cases, a test for toxin A/B and a stool culture for C. difficile were conducted simultaneously. Bacterial isolates were further characterised by PCR ribotyping. Data on the course of disease, case fatality, and possible risk factors for CDI related deaths were assessed using a standardised questionnaire. Environmental investigations were done. RESULTS: By 31 January 2008, 27 cases of severe CDI and 21 cases with C. difficile ribotype 027 infections were found in the area under investigation. Active surveillance found 76 of 399 (19 %) patients positive for C. difficile. In 20 patients, PCR ribotyp 027 could be proven. In total, 9 deaths occurred (19 %). An existing immunosupressive therapy (OR 35.8; 95 % CI 2.8 - 464.5) was related to case fatality in the multivariate analysis. Severe cases of CDI were also observed in non-ribotype 027 infections. In the screening of hospital personnel (n = 161), 6 % were found positive for toxin A/B. DISCUSSION: This investigation demonstrated the endemicity of C. difficile PCR ribotype 027 in Germany for the first time. As a consequence from this study, severe CDI became a reportable disease in Germany at the end of 2007. In addition to hygienic measures, the critical use of antibiotics is an important measure to prevent a further increase of CDI. PMID- 20839162 TI - [Knowledge about HBV, prevention behaviour and treatment adherence of patients with chronic hepatitis B in a large referral centre in Germany]. AB - BACKGROUND: The incidence of chronic hepatitis B in Germany is approximately 0.5 %. Data regarding knowledge about HBV, prevention behaviour and treatment adherence in patients with chronic HBV are scarce. METHODS: In this prospective study 201 consecutive patients with CHB infection were studied from a large urban academic outpatient clinic at the University Medical Centre in Hamburg. Patients were interviewed with a questionnaire that contained 47 questions covering social demographic dates, knowledge about HBV, treatment adherence and prevention. The success rate of interviews was 100 % with free translation service offered. RESULTS: 20.4 % of the CHB patients were born in Germany, but the majority of the patients were immigrants (80.6 %). 51 % of the patients had a good, 34 % a moderate and 15 % a poor knowledge about HBV. 89 % of the patients knew that HBV can be transmitted through blood contacts, but 34 % believed that inadequate hygienic conditions and 24 % that food products may transmit the virus. 96 % of the patients had knowledge about the existence of an HBV vaccine. Furthermore, 82 % considered a vaccination of all persons in the household important. Despite the knowledge of the existence and importance of a vaccine, only 61,7 % of the 300 affected children/siblings of HBV-positive family members were vaccinated. However, the child vaccination rate was significantly higher among patients with knowledge about the protective effect of the vaccine (p < 0.001), the free of charge vaccination program for children up to 18 years (p < 0.001) and higher school education (p < 0.001). Migrants with poor German language skills had lower knowledge scores (p < 0.001) and showed lower vaccination rates (p = 0.016) compared to immigrants with good German language skills. 43 % of all patients were treated with nucleot(s)ide analogues with a median treatment duration of 2 - 5 years. 65 % of these patients declared to never have missed a dose and 27 % missed less than one dose per month. 90 % of the patients tolerated the antiviral drugs very well and between patients with or without side effects there was no significant difference in quality of life. CONCLUSION: Chronic hepatitis B in Germany is characterised by awareness problems and language barriers. More attention is needed for HBV-infected immigrants in the form of multilingual information about CHB and awareness campaigns. PMID- 20839163 TI - Cavitating mesenteric lymph node syndrome: a rare complication of refractory celiac disease. AB - Celiac disease is an immune-mediated enteropathy characterized by mucosal inflammation and villous atrophy of the small bowel upon exposure to ingested gluten. Refractory celiac disease (RCD), defined as persisting villous atrophy with crypt hyperplasia despite strict gluten-free diet, is a rare form of celiac disease with poor prognosis due to a higher rate of severe complications such as life-threatening malnutrition or the development of intestinal T-cell lymphoma. The cavitating mesenteric lymph node syndrome (CMLNS) represents a rare complication of celiac disease with unknown pathogenesis which is associated with but not restricted to RCD and not necessarily associated with a malignant course. We here report a 64-year-old patient who was referred to us with a history of refractory celiac disease. During further diagnostic work-up multiple intraabdominal cystic structures were detected by a computed tomography scan and magnetic resonance imaging. A laparotomy was performed to exclude T-cell lymphoma. Histology of the intraabdominal cysts revealed the diagnosis of cavitating mesenteric lymph node syndrome as the underlying cause of the masses. Steroid therapy was initiated which led to complete regression of diarrhoea but did not induce a diminution of mesenteric lymph nodes. Three years after the diagnosis of CMLNS, the patient presented with an acute abdomen due to a small bowel perforation caused by an enteropathy associated T-cell lymphoma. We discuss the differential diagnoses of intraabdominal masses in celiac disease and review the current literature on CMLNS. PMID- 20839164 TI - Eosinophilic infiltration of the liver and pancreas mimicking metastatic disease. AB - Contrast-enhanced ultrasound (CEUS) has significantly improved the differentiation of hepatic lesions and the detection of liver metastases. Metastases are usually represented as hypoenhanced areas in the late phase and must then be confirmed histologically. Other lesions presenting hypoenhancement in the late phase are abscesses, hepatocellular and cholangiocellular carcinomas, adenomas, avascular necrosis, haematomas and rarely inflammatory masses. The differentiation between these relies on the patient's history, the number of lesions presenting, the B-image morphology and the enhancement pattern in the early phase of CEUS. We report the case of a 49-year-old woman with a in CT assumed pancreatic tumour in whom liver metastases were suspected and investigated by CEUS. In the late phase of this examination hypoenhanced hepatic lesions were observed, prompting us to perform a needle biopsy. The histopathological work-up surprisingly identified the hepatic lesions to be eosinophilic infiltration. After a spontaneous remission we concluded an allergic reaction to a fluoroquinolone. PMID- 20839165 TI - [Reference values in abdominal ultrasound - liver and liver vessels]. AB - OBJECTIVE: Reference values for B-mode abdominal ultrasound are being controversially discussed due to the limited data in the literature. A systematic survey of data published so far is presented for liver and hepatic vessels. METHODS: A literature search for reference values in the abdomen from 1970 to 2010 in healthy subjects 18 years of age and older was carried out. In accord with the determination of reference intervals for laboratory values, reference values are generally determined with the aid of 95 % reference intervals and the associated 90 % confidence intervals. Evaluated parameters were the size and volume of the liver, the portal vein diameter and cross-section and the diameters of the hepatic veins. RESULTS: Liver size is usually determined by its longitudinal diameter in the midclavicular line. Although not sufficiently evaluated, < 16 cm can be used as a reference value. Numerous methods, which are not comparable, have been described for the determination of liver volume. For the portal vein diameter, refererence intervals could be deduced from 6 studies. Data from 4 studies on the liver veins differ depending on the exact localisation of measurement. DISCUSSION: Normal values are helpful in delineating numerous pathological changes in the respective organs. Unfortunately, data are scarce and the examination technique, so far, has not been standardised sufficiently to compare data. A multicentre trial is required to standardise examination techniques and improve the quality of the results. PMID- 20839166 TI - [PPI withdrawal induces acid-related symptoms]. PMID- 20839167 TI - [Concomitant use of platelet aggregation inhibitors and proton pump inhibitors (PPIs): Position paper of the German Society for Digestive and Metabolic Diseases (DGVS) and the German Society of Cardiology (DGK).]. PMID- 20839168 TI - [Responsiveness of the Expanded Disability Status Scale (EDSS) to disease progression and therapeutic intervention in progressive forms of multiple sclerosis]. AB - INTRODUCTION: The standard approach in relapsing forms of multiple sclerosis (MS) has been to measure therapeutic effects on clinical exacerbations and physical disability as determined by the Expanded Disability Status Scale (EDSS). However, measuring clinical relapses is not a viable option in the progressive forms of MS because of their low frequency. Therefore, the standard approach in clinical trials of progressive forms of MS has been to use the EDSS as primary outcome measure. PATIENTS AND METHODS: We examined the responsiveness of the EDSS to disease progression and treatment effects in the context of clinical trials of secondary progressive (SPMS) and primary progressive (PPMS) MS and compared it to the three functional tasks of the Multiple Sclerosis Functional Composite (MSFC): the Timed 25 Foot Walk (T25FW), the 9 Hole PEG (9HP), and the Paced Auditory Serial Attention Test (PASAT). RESULTS: The effect size of the EDSS after two years on placebo was only 0.2-0.3 in both SPMS and PPMS, similar to the 9HP and the PASAT. In contrast, the effect size of the T25FW was much greater and driven to a large extent by subjects who could not complete the task. CONCLUSIONS: The EDSS shows poor responsiveness to both disease progression and treatment effects in SPMS and PPMS. The use of alternative primary outcome measures is recommended for therapeutic trials of progressive MS. PMID- 20839169 TI - [Interchangeability among therapeutics equivalents of lamotrigine in the treatment of refractory epilepsy patients: risks and benefits]. AB - INTRODUCTION: Epilepsy is a condition characterized by signs and symptoms of neurological disorder. Lamotrigine has been widely used, mainly due to their greater tolerability and lower rate of drug interactions with other antiepileptic drugs however the newest antiepileptic drugs have high cost to patient. In Brazil there are three different sort of pharmaceutical equivalents (reference, generic and similar), and the Brazilian health care authorities offers to users the possibility to receive them free of charge. Moreover these pharmaceutical equivalents can change during the treatment of epilepsy because this authorities buy the cheapest by public tender two or three times a year. AIM: To evaluate the clinical and laboratory findings related to the most frequently used therapeutic equivalents of lamotrigine (reference drugs and similar products). PATIENTS AND METHODS: Two similar formulations (A and B) and one reference (C) were tested in nine epileptic refractory patients. The study was divided into three periods of 42 days, one for each formulation, and medical data about the frequency of seizures, the occurrence of side effects and measurement of plasma concentrations of lamotrigine were collected. RESULTS: The average number of seizures/week and plasma concentration of lamotrigine for formulations A, B and C were not statistically significant differences. Three patients during the use of the formulation C presented mild and transitory side effects. CONCLUSION: Similar or reference drugs showed satisfactory results, however the interchangeability among the formulations raise the difficulty for the management of seizures in refractory epilepsy. PMID- 20839170 TI - [Attention deficit hyperactivity disorder in teenagers: appraisal of the EDAH (a) scale]. AB - AIMS: To appraise the attention deficit hyperactivity disorder assessment scale for a teenage population, EDAH (a). SUBJECTS AND METHODS: From an initial sample of 3400 participants, a final sample of 2292 pupils between 12 and 16 years of age were finally selected. Of the total number, 1066 were boys (46.5%) and 1226 were girls (53.5%). RESULTS AND CONCLUSIONS: On obtaining significant differences both for age and for sex on the subscales that make up the aforementioned test, assessments were performed taking these variables into account. The cut-off points for each of the subscales are presented and in all cases they were above the 90th percentile. PMID- 20839171 TI - [Depression and diabetes: from epidemiology to neurobiology]. AB - INTRODUCTION: Worldwide, diabetes mellitus and depression are among the most prevalent diseases in their respective fields, metabolism and psychiatry. However, there is evidence that patients with diabetes are at increased risk of developing depression, although a bidirectional relationship might also exist. AIM: To present a comprehensive review of the clinical, epidemiological, psychosocial, emotional, and neurobiological basis of the relation between diabetes and depression. DEVELOPMENT: Epidemiological studies indicate that there is not only an augmented risk of developing depression in diabetic patients, but that this association increases the morbidity and mortality of these patients. While there is a considerable number of clinical studies that support this relation, little is known about the neurochemical mechanisms that would constitute its biological basis. CONCLUSION: Alterations in monoamines (serotonin and noradrenaline), the increases in cortisol by the hypothalamus-pituitary adrenal axis, and trophic agents such as the brain-derived neurotrophic factor, through glycogen synthase kinase-3, constitute some of the abnormalities documented in diabetic patients and in animal models that could explain the association between depression and diabetes. Additionally, we briefly consider the psychoemotional factors that might underlie the depression-diabetes relation. The effects (most of them deleterious) of the antidepressive therapy in glucometabolic control are also discussed. PMID- 20839172 TI - [Toxic myopathies caused by industrial, animal and vegetal toxins]. AB - INTRODUCTION: Myopathies caused by industrial and biological toxins are uncommon but quite interesting, because its prompt recognition may reduce their damaging effects or prevent a fatal outcome. AIM: To describe the most frequent toxic myopathies. DEVELOPMENT: Toxic myopathies epidemiology, clinical presentations and clinical management are discussed. CONCLUSIONS: Toxic myopathies are uncommon and difficult to diagnose. They have been insufficiently studied. Knowledge of these myopathies is essential because a prompt diagnosis allows for recovery. PMID- 20839173 TI - [All together now: long term potentiation in the human cortex]. AB - INTRODUCTION: Long term potentiation (LTP) is defined as a long-lasting enhancement in communication between two neurons after the delivery of high frequency trains of electrical stimulation. This adjustment in synaptic efficacy is the physiological process that sustains learning and memory. However, few studies have addressed the existence of a similar phenomenon in the human cortex, even though it has been investigated for more than 30 years using animal models. DEVELOPMENT: The present review illustrates the state of the LTP-like phenomenon recently described in humans, and the possibility of ascribing the known mechanisms of LTP to the human cortex. CONCLUSIONS: A detailed knowledge of synaptic plasticity in the human cortex will facilitate a smooth translation of a wealth of physiological and molecular information and will have a major impact in the development and design of pharmacological agents intended as cognitive enhancers. We argue for the need of more focused experimental research on this particularly important area of neuroplasticity. PMID- 20839174 TI - [Eagle syndrome. A rare cause of neuralgia due to mechanical irritation]. PMID- 20839175 TI - [Clinical and radiological presentation in deep cerebral venous thromboses in adults]. PMID- 20839176 TI - [Postpartum cerebral angiopathy]. PMID- 20839177 TI - [Dissection of the carotid artery: when it becomes necessary to reconsider the treatment.]. PMID- 20839178 TI - [Psychosis due to zonisamide: an infrequent case]. PMID- 20839179 TI - [Mortality in the Spanish 'stroke belt': some key points in Andalusia]. PMID- 20839181 TI - Asymmetric phase-transfer-catalyzed intramolecular N-alkylation of indoles and pyrroles: a combined experimental and theoretical investigation. AB - Asymmetric phase-transfer catalysis (PTC) has risen to prominence over the last decade as a straightforward synthetic methodology for the preparation of pharmacologically active compounds in enantiomerically pure form. However, the complex interplay of weak nonbonded interactions (between catalyst and substrate) that could account for the stereoselection in these processes is still unclear, with tentative pictorial mechanistic representations usually proposed. Here we present a full account dealing with the enantioselective phase-transfer-catalyzed intramolecular aza-Michael reaction (IMAMR) of indolyl esters, as a valuable synthetic tool to obtain added-value compounds, such as dihydro pyrazinoindolinones. A combined computational and experimental investigation has been carried out to elucidate the key mechanistic aspects of this process. PMID- 20839182 TI - A radical polymer as a two-dimensional organic half metal. AB - Given that half-metals are promising futuristic materials for spintronics, organic materials showing half-metal character are highly desirable for spintronic devices, not only owing to their weak spin-orbit and hyperfine interactions, but also their light and flexible properties. We predict that a two dimensional organic 2,4,6-tri-(1,3,5-triazinyl)methyl radical polymer has half metallic properties as well as a spontaneous magnetic ordering at ambient temperature. The quantum transmission is studied based on the nonequilibrium Green function theory coupled with density functional theory. The half-metallic property in the triazine-based polymer depends mainly on the nature of the p-band in contrast to of conventional half metals in which the nature of the d-band is more important. PMID- 20839183 TI - Ring opening of pymisyl-protected aziridines with organocuprates. AB - The pyrimidine-2-sulfonyl (pymisyl) group is introduced as a new protecting group that can be used to activate aziridines towards ring opening. It is readily introduced and removed under mild conditions. Regioselective ring opening of pymisyl-protected 2-methyl-aziridine with organocuprates gives the corresponding sulfonamides in high yields, and the pymisyl group can subsequently be removed upon treatment with a thiolate. The versatility of this new nitrogen protecting group is illustrated with a new synthesis of Selegiline, a monoamine oxidase-B inhibitor marketed for the treatment of Parkinson's disease. PMID- 20839185 TI - Condensation- and crystallinity-controlled synthesis of titanium oxide films with assessed mesopores. PMID- 20839184 TI - Evidence of native metal-S(2-)-metallothionein complexes confirmed by the analysis of Cup1 divalent-metal-ion binding properties. AB - It has previously been shown that recombinant synthesis, under metal-supplemented conditions, of diverse metallothioneins (MTs) results in the recovery of a subpopulation of S(2-)-containing complexes in addition to the S(2-)-devoid canonical metal-MT species. Further significance of this finding has remained veiled by the possibility of it being a mere consequence of synthesis in a heterologous bacterial system. Herein, we present definitive evidence that S(2-) ligands are also constituents of native metal-MT complexes. Because, although practically universal, the highest S(2-) content is incorporated by copper thioneins when coordinating divalent metal ions, we adapted the Saccharomyces cerevisiae Cup1 protein, which is the most paradigmatic copper-thionein, as an experimental model. Most significantly, native Cd-Cup1 complexes were purified and fully spectroscopically and spectrometrically characterized from the 301N mutant yeast strain, which allows Cup1 synthesis even in the absence of copper. These results undoubtedly revealed the presence of a Cd-S(2-)-Cup1 species in native preparations, which were only recovered when carefully avoiding the use of ion-exchange chromatography in the purification protocol. Furthermore, complete analysis of recombinant (Escherichia coli) Zn-Cup1, Cd-Cup1, and Cu-Cup1 and those complexes that result from Zn/Cd and Zn/Cu replacements in vitro and acidification/renaturalization processes yielded a comprehensive and comparative overview of the metal-binding abilities of Cup1. Overall, we consider the main conclusions of this study to go beyond the mere study of the particular Cup1 MT, so that they should be considered to delineate a new point of view on the interaction between copper-thioneins and divalent metal ions, still an unexplored aspect in MT research. PMID- 20839186 TI - Assembly and disassembly of a metastable bis-phosphine-based copper(I) helicate. PMID- 20839187 TI - C-H bond cleavage and regioselective C-C coupling on a tantalum-bound pincer ligand. PMID- 20839188 TI - Chemical reduction and dimerization of 1-chloro-2,3,4,5-tetraphenylborole. AB - As neutral isoelectronic analogues of the elusive cyclopentadienyl cation, boroles have been of interest for their prospective applications as strong Lewis acids, chromophores, and electron acceptors. Recently our group discovered a pi nucleophilic boryl anion based on the borole system. In an effort to extend borole chemistry, we now report the molecular structure of 1-chloro-2,3,4,5 tetraphenylborole (1) and its corresponding borole dianion resulting from the two electron reduction of 1 with KC(8). The thermally induced dimerization of 1 yields an unprecedented boracyclohexadiene/borolene spiro-bicyclic compound and the resulting dimer was fully characterized including a single-crystal X-ray analysis. PMID- 20839189 TI - How important is the release-return mechanism in olefin metathesis? PMID- 20839190 TI - Ruthenium-indenylidene olefin metathesis catalyst with enhanced thermal stability. AB - Two new ruthenium complexes bearing a bidentate (kappa(2)O,C)-isopropoxy indenylidene ligand and a PPh(3) (9) or PCy(3) (10, Cy=cyclohexyl) ligand have been synthesized and fully characterized by (1)H and (13)C NMR spectroscopy and X ray crystallography. Complex 10 displays a very high thermal stability with a half life of six days at 110 degrees C in [D(8)]toluene. Complex 10 was evaluated in various ring-closing metathesis reactions and ring-opening metathesis polymerization of dicyclopentadiene, in which it showed a latent behavior with low activity at room temperature and high activity upon thermal activation. PMID- 20839191 TI - Concerted and stepwise mechanisms in metal-free and metal-assisted [4+3] cycloadditions involving allyl cations. AB - The thermal [4+3] cycloaddition reaction between allenes and tethered dienes (1,3 butadiene and furan) assisted by transition metals (Au(I), Au(III), Pd(II), and Pt(II)) was studied computationally within the density functional theory framework and compared to the analogous non-organometallic process in terms of activation barriers, synchronicity and aromaticity of the corresponding transition states. It was found that the metal-mediated cycloaddition reaction is concerted and takes place via transition structures that can be even more synchronous and more aromatic than their non-organometallic analogues. However, the processes exhibit slightly to moderately higher activation barriers than the parent cycloaddition involving the hydroxyallylic cation. The bond polarization induced by the metal moiety is clearly related to the interaction of the transition metal with the allylic pi* molecular orbital, which constitutes the LUMO of the initial reactant. Finally, replacement of the 1,3-butadiene by furan caused the transformation to occur stepwise in both the non-organometallic and metal-assisted processes. PMID- 20839192 TI - Palladium-catalysed cyclisation of N-alkynyl aminomalonates. PMID- 20839193 TI - A novel synthetic approach to diaminoacetylenes: structural characterization and reactivity of aromatic and aliphatic ynediamines. PMID- 20839194 TI - A noble-metalate bowl: the polyoxo-6-vanado(V)-7-palladate(II) [Pd7V6O24(OH)2]6-. PMID- 20839195 TI - Binary bismuth(III) azides: Bi(N3)3, [Bi(N3)4]-, and [Bi(N3)6]3-. PMID- 20839196 TI - A well-defined dinuclear telluronic acid [RTe(MU-O)(OH)3]2. PMID- 20839197 TI - Nature's polyethylene. PMID- 20839198 TI - A double-switching multistable Fe4 grid complex with stepwise spin-crossover and redox transitions. PMID- 20839199 TI - A low-concentration hydrothermal synthesis of biocompatible ordered mesoporous carbon nanospheres with tunable and uniform size. PMID- 20839200 TI - Synthesis of aryl ketones by palladium(II)-catalyzed decarboxylative addition of benzoic acids to nitriles. PMID- 20839201 TI - Enantioselective halocyclization reactions for the synthesis of chiral cyclic compounds. PMID- 20839202 TI - The iron-fortified adhesive system of marine mussels. PMID- 20839203 TI - Electrical current generation across a black smoker chimney. PMID- 20839204 TI - tmp(4)Zr: an atom-economical base for the metalation of functionalized arenes and heteroarenes. PMID- 20839205 TI - Glucose/glucuronic acid alternating co-polysaccharides prepared from TEMPO oxidized native celluloses by surface peeling. PMID- 20839206 TI - A chiral and colorful redox switch: enhanced pi acidity in action. PMID- 20839207 TI - Intramolecular anodic olefin coupling reactions: use of the reaction rate to control substrate/product selectivity. PMID- 20839208 TI - Subazaphenalenephthalocyanine: a subphthalocyanine analogue bearing a six membered ring unit. PMID- 20839211 TI - Cascade palladium-catalyzed direct intramolecular arylation/alkene isomerization sequences: synthesis of indoles and benzofurans. PMID- 20839209 TI - A temperature-sensitive drug release system based on phase-change materials. PMID- 20839212 TI - The effect of carvacrol on muscarinic receptors of guinea-pig tracheal chains. AB - The effects of three concentrations of carvacrol, the constituent of Zataria multiflora Boiss (a monoterpenoid phenol, C(10) H(14) O) and 10 nm atropine on muscarinic receptors were tested on: non-incubated (n = 7), incubated tracheal chains with propranolol and chlorpheniramine (n = 6) and incubated with propranolol (n = 5). The EC(50) of all three concentrations of carvacrol in incubated tissues with propranolol and chlorpheniramine was significantly greater than those of incubated tissues with propranolol and non-incubated trachea (p < 0.05 to p < 0.001). The EC(50) of two higher concentrations of carvacrol (0.2 and 0.4 ug/mL) in incubated tissues with propranolol was also significantly greater than those of non-incubated trachea (p < 0.01 to p < 0.001). The maximum response in the presence of all concentrations of carvacrol in non-incubated and incubated tissues with propranolol and chlorpheniramine and those of its two higher concentrations (0.2 and 0.4 ug/mL) in incubated tissues with propranolol were lower than saline (p < 0.05 to p < 0.001). There were parallel rightward shifts in the concentration-response curves in the presence of all concentrations of carvacrol in non-incubated and incubated tissues with propranolol and its lower concentration in incubated tissues with propranolol and chlorpheniramine. These results indicated an inhibitory effect of carvacrol on muscarinic receptors. A beta-adrenoceptor stimulatory effect was also suggested for carvacrol. PMID- 20839213 TI - Two new xanthones from Hypericum sampsonii and biological activity of the isolated compounds. AB - Phytochemical investigation of the CH(2) Cl(2) extract of the aerial part of Hypericum sampsonii yielded two new prenylated xanthones, hypericumxanthone A and B, together with three known xanthones. Their structures were elucidated by analysis of physical and spectral (UV, IR, mass and NMR) data and comparison of spectroscopic data with those reported previously. All these compounds were evaluated for in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Two new compounds were also tested for their cytotoxicity against human breast (MCF-7), hepatoma (HepG2), colon (HT-29) and lung (A549) tumour cell lines. Two new compounds showed moderate antibacterial activities at minimum inhibitory concentrations (MIC) of 16 and 32 ug/mL, respectively, whereas the positive standard antibacterial drug, vancomycin, showed an MIC of 8 ug/mL. The other compounds were inactive against MRSA. In addition, hypericumxanthone B showed weak inhibitory activities against four human tumour cell lines. PMID- 20839214 TI - Effect of Leonurus cardiaca oil extract in patients with arterial hypertension accompanied by anxiety and sleep disorders. AB - Leonurus cardiaca L. (Lamiaceae) is used traditionally for its sedative, hypotensive and cardiotonic effects. Due to the lack of clinical data regarding its effect in patients, a study was carried out to assess the clinical efficacy of Leonurus oil extract (LOE) in patients with arterial hypertension stages 1 and 2, accompanied by anxiety and sleep disorders. Fifty patients were treated for 28 days with 1200 mg LOE per day. Positive effects of LOE on psycho-emotional status and arterial blood pressure in patients with stage 1 hypertension were observed 1 week earlier than in patients with stage 2 hypertension. According to the Clinical Global Impression (CGI) scale, a significant improvement in the symptoms of anxiety and depression was observed in 32% of patients, a moderate improvement in 48% and a weak effect in 8%; 12% of patients did not respond to therapy. Side effects were minimal in all groups. Leonurus oil extract may therefore be a potentially effective therapeutic agent for patients with arterial hypertension and concurrent psycho-neurological disorders. PMID- 20839215 TI - Oral administration of Aloe vera and honey reduces Walker tumour growth by decreasing cell proliferation and increasing apoptosis in tumour tissue. AB - Cancer is diagnosed in approximately 11 million people and is responsible for almost 8 million deaths worldwide every year. Research in cancer control has shown the importance of co-adjuvant therapies. Aloe vera may reduce tumour mass and metastasis rates, while honey may inhibit tumour growth. This study verified the influence of Aloe vera and honey on tumour growth and in the apoptosis process by assessing tumour size, the cell proliferation rate (Ki67-LI) and Bax/Bcl-2 expression at 7, 14 and 20 days after Walker 256 carcinoma implant in Wistar rats distributed into two groups: the WA group - tumour-bearing rats that received a gavage with a 670 uL/kg dose of Aloe vera and honey solution daily, and the CW group - tumour-bearing rats which received only a 0.9% NaCl solution. The effect of Aloe vera and honey against tumour growth was observed through a decrease in relative weight (%) and Ki67-LI in tumours from the WA group compared with those from the CW group. The Bax/Bcl-2 ratio increased in tumours from the WA group at all tested timepoints. These data suggest Aloe vera and honey can modulate tumour growth by reducing cell proliferation and increasing apoptosis susceptibility. PMID- 20839216 TI - Time-course of micronucleated erythrocytes in response to whole-body gamma irradiation in a model mammalian species, the bank vole (Clethrionomys glareolus, Schreber). AB - The time course of the formation of micronucleated polychromatic (MNPCEs) and normochromatic erythrocytes (MNNCEs) in the bone marrow of the bank vole (Clethrionomys glareolus, Schreber), a model mouse-like species, was studied using the standard micronucleus test at 0, 6, 12, 18, 24, 30, 36 and 48 hr following whole-body acute gamma-irradiation at a dose of 0.5 Gy. Based on the existing literature on laboratory mice, it was suggested that such a dose will not have significant effect on erythroid cell proliferation in the bank vole and hence on the time course of the rise of micronucleated cells. In total, ~905,000 polychromatic (PCEs) and normochromatic erythrocytes (NCEs) from 82 adult bank voles were analyzed. Although the mean frequencies of MNNCEs were too low to allow for the correct assessment of their time course, an analysis of PCEs showed an increasing rate of MNPCE appearance at 6 hr that reached a maximum at 18-24 hr after irradiation and subsequently decreased. Because the kinetics of MNPCEs reflects the process of erythropoiesis, the current results regarding the time points of appearance of radiation-induced MNPCEs provide the first information on the prolongation of one of the terminal stages of erythrocyte formation in bank vole specimens, namely the stage of maturation of PCEs from erythroblasts. Moreover, the observed time-course data, as well as the low-background frequencies of MNPCEs and characteristic level of PCEs response to radiation, showed similarities between the two model species: bank vole (this study) and laboratory mice (literature data). PMID- 20839217 TI - Assessment of multiple types of DNA damage in human placentas from smoking and nonsmoking women in the Czech Republic. AB - Three classes of DNA damage were assessed in human placentas collected (2000 2004) from 51 women living in the Teplice region of the Czech Republic, a mining area considered to have some of the worst environmental pollution in Europe in the 1980s. Polycyclic aromatic hydrocarbon (PAH)-DNA adducts were localized and semiquantified using immunohistochemistry (IHC) and the Automated Cellular Imaging System (ACIS). More generalized DNA damage was measured both by (32)P postlabeling and by abasic (AB) site analysis. Placenta stained with antiserum elicited against DNA modified with 7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy 7,8,9,10-tetrahydro-benzo[a]pyrene (BPDE) revealed PAH-DNA adduct localization in nuclei of the cytotrophoblast (CT) cells and syncytiotrophoblast (ST) knots lining the chorionic villi. The highest levels of DNA damage, 49-312 PAH-DNA adducts/10(8) nucleotides, were found by IHC/ACIS in 14 immediately fixed placenta samples. An additional 37 placenta samples were stored frozen before fixation and embedding, and because PAH-DNA adducts were largely undetectable in these samples, freezing was implicated in the loss of IHC signal. The same placentas (n = 37) contained 1.7-8.6 stable/bulky DNA adducts/10(8) nucleotides and 0.6-47.2 AB sites/10(5) nucleotides. For all methods, there was no correlation among types of DNA damage and no difference in extent of DNA damage between smokers and nonsmokers. Therefore, the data show that DNA from placentas obtained in Teplice contained multiple types of DNA damage, which likely arose from various environmental exposures. In addition, PAH-DNA adducts were present at high concentrations in the CT cells and ST knots of the chorionic villi. PMID- 20839218 TI - Mammalian cell cytotoxicity and genotoxicity of the haloacetic acids, a major class of drinking water disinfection by-products. AB - The haloacetic acids (HAAs) are disinfection by-products (DBPs) that are formed during the disinfection of drinking water, wastewaters and recreational pool waters. Currently, five HAAs [bromoacetic acid (BAA), dibromoacetic acid (DBAA), chloroacetic acid (CAA), dichloroacetic acid (DCAA), and trichloroacetic acid (TCAA); designated as HAA5] are regulated by the U.S. EPA, at a maximum contaminant level of 60 MUg/L for the sum of BAA, DBAA, CAA, DCAA, and TCAA. We present a comparative systematic analysis of chronic cytotoxicity and acute genomic DNA damaging capacity of 12 individual HAAs in mammalian cells. In addition to the HAA5, we analyzed iodoacetic acid (IAA), diiodoacetic acid (DiAA), bromoiodoacetic acid (BIAA), tribromoacetic acid (TBAA), chlorodibromoacetic acid (CDBAA), bromodichloroacetic acid (BDCAA), and bromochloroacetic acid (BCAA). Their rank order of chronic cytotoxicity in Chinese hamster ovary cells was IAA > BAA > TBAA > CDBAA > DIAA > DBAA > BDCAA > BCAA > CAA > BIAA > TCAA > DCAA. The rank order for genotoxicity was IAA > BAA > CAA > DBAA > DIAA > TBAA > BCAA > BIAA > CDBAA. DCAA, TCAA, and BDCAA were not genotoxic. The trend for both cytotoxicity and genotoxicity is iodinated HAAs > brominated HAAs > chlorinated HAAs. The use of alternative disinfectants other than chlorine generates new DBPs and alters their distribution. Systematic, comparative, in vitro toxicological data provides the water supply community with information to consider when employing alternatives to chlorine disinfection. In addition, these data aid in prioritizing DBPs and their related compounds for future in vivo toxicological studies and risk assessment. PMID- 20839219 TI - Genotoxicity of lavender oil, linalyl acetate, and linalool on human lymphocytes in vitro. AB - The potential genotoxicity of lavender essential oil and its major components, linalool, and linalyl acetate, was evaluated in vitro by the micronucleus test on peripheral human lymphocytes. In the range of non-toxic concentrations (0.5-100 MUg/ml), linalyl acetate increased the frequency of micronuclei significantly and in concentration-dependent manner; lavender oil did so only at the highest concentration tested, whereas linalool was devoid of genotoxicity. None of the tested substances led to an increase in nucleoplasmic bridges or nuclear buds frequency. These findings suggest that the mutagenic activity of lavender oil can be related to the presence of linalyl acetate, which seems to have a profile of an aneugenic agent. PMID- 20839220 TI - Possible roles of excess tryptophan metabolites in cancer. AB - Tryptophan is metabolized through serotonin, indole, and kynurenine (KN) pathways. Uptake of an excess amount of tryptophan accompanied with vitamin B6 deficiency may result in the accumulation of higher concentrations of metabolites mainly from the KN pathways in the bladder. These metabolites could interact with nitrite to become mutagenic nitrosamines. They could be a promoter in the initiator-promoter model of carcinogenesis. They produced bladder cancer when implanted in the bladder. They also interact with transition metals copper or iron to form reactive radicals or reactive oxygen species (ROS). Some metabolites, 3-hydroxy-anthranilic acid, were autooxidized to mutagenic cinnabarinic and anthranilyl radical intermediates. These radical intermediates could also be ligands that interact with aryl hydrocarbon receptor (AhR) and induce xenobiotic metabolizing enzymes (XMEs) to metabolize contaminated carcinogens. When tryptophan is exposed to either visible or UV light, a photoproduct of 6-formylindolo[3,2b]-carbazole is formed, which has a very high affinity for the AhR that plays a role in carcinogenesis. This review gives an insight into various mechanisms through which tryptophan metabolites cause carcinogenesis. It could be concluded that tryptophan metabolites play a complementary role in promoting carcinogenesis along with carcinogens like aflatoxin, CCl(4) , 2-acetylaminofluorene, 4-aminobiphenyl, 2-naphthylamine, or N [4-(5-nitro-2-furyl)-2-thiazolyl] formamide. The underlying mechanisms could be their autoxidation, exposure to either visible or UV light, interaction with nitrite or transition metals to form reactive intermediates, serving as ligands to interact with an AhR that is known to play a role in carcinogenesis through induction of XMEs. Further research is warranted.Environ. PMID- 20839221 TI - Reflections on the origins and evolution of genetic toxicology and the Environmental Mutagen Society. AB - This article traces the development of the field of mutagenesis and its metamorphosis into the research area we now call genetic toxicology. In 1969, this transitional event led to the founding of the Environmental Mutagen Society (EMS). The charter of this new Society was to "encourage interest in and study of mutagens in the human environment, particularly as these may be of concern to public health." As the mutagenesis field unfolded and expanded, new wording appeared to better describe this evolving area of research. The term "genetic toxicology" was coined and became an important subspecialty of the broad area of toxicology. Genetic toxicology is now set for a thorough reappraisal of its methods, goals, and priorities to meet the challenges of the 21st Century. To better understand these challenges, we have revisited the primary goal that the EMS founders had in mind for the Society's main mission and objective, namely, the quantitative assessment of genetic (hereditary) risks to human populations exposed to environmental agents. We also have reflected upon some of the seminal events over the last 40 years that have influenced the advancement of the genetic toxicology discipline and the extent to which the Society's major goal and allied objectives have been achieved. Additionally, we have provided suggestions on how EMS can further advance the science of genetic toxicology in the postgenome era. Any oversight or failure to make proper acknowledgment of individuals, events, or the citation of relevant references in this article is unintentional. PMID- 20839222 TI - The hunt for the epiallele. AB - Understanding the origin of phenotypic variation remains one of the principle challenges of contemporary biology. Recent genome-wide association studies have identified association between common genetic variants and complex phenotype; however, the minimal effect sizes observed in such studies highlight the potential for other causal factors to be involved in phenotypic variation. The epigenetic state of an organism (or 'epigenome') incorporates a landscape of complex and plastic molecular events that may underlie the 'missing link' that integrates genotype with phenotype. The nature of these processes has been the subject of intense scientific study over the recent years, and characterisation of epigenetic variation, in the form of 'epialleles', is providing fascinating insight into how the genome functions within a range of developmental processes, environments, and in states of health and disease. This review will discuss how and when mammalian epialleles may be generated and their interaction with genetic and environmental factors. We will outline how an epiallele has a variable relationship with phenotype, and how new technologies may be used for their detection and to facilitate an understanding of their contribution to phenotype. Finally, we will consider epialleles in population variation and their teleological role in evolution. variation and their teleological role in evolution. PMID- 20839223 TI - Delayed effects of exposure to a moderate radiation dose on transcription profiles in human primary fibroblasts. AB - Ionizing radiation (IR) is used in a wide variety of medical and nonmedical applications and poses a potential threat to human health. Knowledge of changes in gene expression in irradiated cells may be helpful for the establishment of effective paradigms for radiation protection. IR-induced DNA damage triggers a complex cascade of signal transduction. Recently, genome-wide approaches have allowed the detection of alterations in gene expression across a wide range of radiation doses. However, the delayed or long-term biological effects of mild doses of IR remain largely unknown. The main objective of the present study was to investigate the effects of a moderate dose of gamma-rays (50 cGy) on gene expression 6 days post-irradiation. Gene expression using cDNA microarrays revealed statistically significant changes in the expression of 59 genes (FDR < 0.07), whose functions are related to cell-cycle control, protein trafficking, ubiquitin cycle, Rho-GTPAse pathway, protein phosphatase signalization, oxidoreductase control, and stress response. A set of 464 genes was also selected by a less stringent approach, and we demonstrate that this broader set of genes can efficiently distinguish the irradiated samples from the unirradiated, defining a long-term IR signature in human primary fibroblasts. Our findings support the existence of persistent responses to mild doses of IR detectable by changes in gene expression profiles. These results provide insight into delayed effects observed in human primary cells as well as the role of long-term response in neoplastic transformation. Environ. PMID- 20839224 TI - GADD45alpha induction in the GreenScreen HC indicator assay does not occur independently of cytotoxicity. AB - Mammalian chromosomal integrity assays are influenced by cytotoxicity, a phenomenon which impacts data interpretation, assay specificity, and regulatory testing guidelines. Concordance of the GADD45alpha GreenScreen HC indicator assay to established in vitro and in vivo genetic toxicological assays has previously been described, yet a detailed description in the manner by which cytotoxicity influences its performance has not. Here we present a post-hoc analysis of a previously tested set of 91 proprietary and nonproprietary compounds investigating the influence of cytotoxicity on GADD45alpha induction and how varying assay cutoff criteria impacts assay performance. Significant cytotoxicity was identified to accompany the majority (72%) of compounds classified as genotoxic by GADD45alpha induction. Decreasing the GADD45alpha genotoxic induction criteria (from a 50 to a 30% increase over solvent controls) resulted in an increased assay sensitivity (from 30 to 68%) and concordance (from 55 to 68%), though a concomitant decrease in specificity was also observed (from 97 to 68%). We conclude that GADD45alpha induction in the GreenScreen HC indicator assay is influenced by cytotoxicity and that assay performance can be improved if different cutoff criteria are implemented. PMID- 20839226 TI - Exercise-induced lipid peroxidation: Implications for deoxyribonucleic acid damage and systemic free radical generation. AB - Exercise-induced deoxyribonucleic acid (DNA) damage is often associated with an increase in free radicals; however, there is a lack of evidence examining the two in parallel. This study tested the hypothesis that high-intensity exercise has the ability to produce free radicals that may be capable of causing DNA damage. Twelve apparently healthy male subjects (age: 23 +/- 4 years; stature: 181 +/- 8 cm; body mass: 80 +/- 9 kg; and VO(2max) : 49 +/- 5 ml/kg/min) performed three 5 min consecutive and incremental stages (40, 70, and 100% of VO(2max) ) of aerobic exercise with a 15-min period separating each stage. Blood was drawn after each bout of exercise for the determination of ex vivo free radicals, DNA damage, protein carbonyls, lipid hydroperoxide (LOOH) concentration, and a range of lipid soluble antioxidants. Lipid-derived oxygen-centered free radicals (hyperfine coupling constants a(Nitrogen) = 13.7 Gauss (G) and abeta(Hydrogen) = 1.8 G) increased as a result of acute moderate and high-intensity exercise (P < 0.05), while DNA damage was also increased (P < 0.05). Systemic changes were observed in LOOH and for lipid-soluble antioxidants throughout exercise (P < 0.05); however, there was no observed change in protein carbonyl concentration (P > 0.05). These findings identify lipid-derived free radical species as possible contributors to peripheral mononuclear cell DNA damage in the human exercising model. This damage occurs in the presence of lipid oxidation but in the absence of any change to protein carbonyl concentration. The significance of these findings may have relevance in terms of immune function, the aging process, and the pathology of carcinogenesis. PMID- 20839225 TI - Effects of PON polymorphisms and haplotypes on molecular phenotype in Mexican American mothers and children. AB - Paraoxonase 1 (PON1) prevents oxidation of low-density lipoproteins and inactivates toxic oxon derivatives of organophosphate pesticides (OPs). More than 250 SNPs have been previously identified in the PON1 gene, yet studies of PON1 genetic variation focus primarily on a few promoter SNPs (-108, -162) and coding SNPs (192, 55). We sequenced the PON1 gene in 30 subjects from a Mexican-American birth cohort and identified 94 polymorphisms with minor allele frequencies >5%, including several novel variants (six SNPs, one insertion, and two deletions). Variants of the PON1 gene and three SNPs from PON2 and PON3 were genotyped in 700 children and mothers from the same cohort. PON1 phenotype was established using two substrate-specific assays: arylesterase (AREase) and paraoxonase (POase). Twelve PON1 and two PON2 polymorphisms were significantly associated with AREase activity, and 37 polymorphisms with POase activity; however, only nine were not in strong linkage disequilibrium (LD) with either PON1(-108) or PON1(192) (r(2) > 0.20), SNPs with known effects on PON1 quantity and substrate-specific activity. Single tagSNPs PON1(55) and PON1(192) accounted for similar ranges of AREase variation compared to haplotypes comprised of multiple SNPs within their haplotype blocks. However, PON1(55) explained 11-16% of POase activity, while six SNPs in the same haplotype block explained threefold more variance (36-56%). Although LD structure in the PON cluster seems similar between Mexicans and Caucasians, allele frequencies for many polymorphisms differed strikingly. Functional effects of PON genetic variation related to susceptibility to OPs and oxidative stress also differed by age and should be considered in protecting vulnerable subpopulations. PMID- 20839227 TI - A European perspective on the role of EMS societies. How do they help public health and research and the development of regulations? PMID- 20839228 TI - The genotoxicity of particulate and soluble chromate in sperm whale (physeter macrocephalus) skin fibroblasts. AB - Hexavalent chromium is a marine pollutant of concern, both for the health of ocean ecosystems and for public health. Hexavalent chromium is known to induce genotoxicity in human and other terrestrial mammals. It is also known to be present in both water and air in the marine environment. However, currently there are limited data concerning both chromium levels and its toxicological effects in marine mammals. This study investigated the cytotoxic and genotoxic effects of soluble and particulate hexavalent chromium in sperm whale skin fibroblasts. Both forms of hexavalent chromium induced concentration-dependent increases in cytotoxicity and genotoxicity indicating that these compounds can be a health risk if the whales are exposed to them. These data support a hypothesis that chromium is a concern in the marine environment in general and for the health of sperm whales in particular. PMID- 20839229 TI - Convenient, multi-well plate-based DNA damage response analysis using DT40 mutants is applicable to a high-throughput genotoxicity assay with characterization of modes of action. AB - Chemists continually synthesize myriad new chemicals (~2,000/year), some of which make their way into the environment or otherwise pose possible threats to humans who potentially become exposed to the compounds. Regulators must determine whether these, along with the glut (~80,000) of existing, chemicals are toxic and at what exposure levels. An important component of this determination is to ascertain the mode of action (MOA) of each compound as it relates to the pathway the compound uses to induce genotoxicity. Several assays have traditionally been used to reveal these effects to the genome: the Ames test, tests with yeast and mammalian cell lines, and animal studies. Previously, we described a new multi well plate-based method which makes use of the DT40 isogenic cell line and its dozens of available mutants knocked out in DNA repair and cell cycle pathways and we now provide a detailed protocol of the further improvement of the assay. Although the DT40 line has existed for some time and has been used in numerous studies of DNA repair pathways, little use has been made of this valuable resource for toxicological investigations. Our method introduces the 2,3-bis (2 methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide dye scheme determination of cell survival in a manner that greatly increases throughput and reduces cost while maintaining reasonable sensitivity. Although this new genotoxicity assay requires validation with many more mutagens before becoming an established, regulatory decision-making analysis tool, we believe that this method will be very advantageous if eventually added to the repertoire of those investigating MOAs of potentially genotoxic substances. PMID- 20839230 TI - Potentiation of the mutagenicity and recombinagenicity of bleomycin in yeast by unconventional intercalating agents. AB - Interactions between bleomycin (BLM) and conventional or unconventional intercalating agents were analyzed in an assay for mitotic gene conversion at the trp5 locus and reversion of the ilv1-92 allele in Saccharomyces cerevisiae strain D7. BLM is a potent recombinagen and mutagen in the assay. Various chemicals modulate the genetic activity of BLM, producing either antimutagenic effects or enhanced genotoxicity. Effects of cationic amino compounds include enhancement of BLM activity by aminoacridines and protection against BLM by aliphatic amines. The potentiation of BLM is similar to findings in a micronucleus-based BLM amplification assay in Chinese hamster V79 cells. In this study, the amplification of BLM activity was explored in yeast using known intercalators, compounds structurally related to known intercalators, and unconventional intercalators that were identified on the basis of computer modeling or results in the Chinese hamster BLM amplification assay. As shown in previous studies, the classical intercalator 9-aminoacridine (9AA) caused dose-dependent enhancement of BLM activity. Other compounds found to enhance the induction of mitotic recombination and point mutations in strain D7 were chlorpromazine, chloroquine, mefloquine, tamoxifen, diphenhydramine, benzophenone, and 3-hydroxybenzophenone. The increased activity was detectable by cotreatment of yeast with BLM and the modulator compound in growth medium or by separate interaction of the intercalator with DNA followed by BLM treatment of nongrowing cells in buffer. The data support the interpretation drawn from micronucleus assays in mammalian cells that BLM enhancement results from DNA intercalation and may be useful in detecting noncovalent interactions with DNA. Environ. PMID- 20839231 TI - Involvement of E2F1 transcriptional activity in cadmium-induced cell-cycle arrest at G1 in human lung fibroblasts. AB - Human cadmium (Cd) exposure is associated with cancers of the lung and kidney. Using cDNA microarray analysis, we have recently reported that the expression of E2F1 is reduced by Cd in human lung fibroblasts, indicating the possibility of G1 phase arrest. To test this hypothesis, we investigated the effects of Cd on the cyclin-dependent kinase (CDK2) and retinoblastoma protein (Rb) regulatory pathways in WI38 human lung fibroblasts. We demonstrate here that G1-phase accumulation was induced by Cd in WI38 (wild-type for p53 and Rb), but not in the SV40 large T antigen-transformed variant WI38-VA13 (p53- and Rb-defective). Cd induced cell-cycle arrest was associated with a decrease in CDK2 protein and with increase in p21 expression and p53 phosphorylation. Cd treatment caused a distinct increase in the formation of p21-cyclin E-CDK2 complex, as revealed by immunoprecipitation. The level of Rb-E2F1 complexes was increased, and the translocation of E2F1 to the nucleus was decreased by Cd treatment. Consequently, the transcriptional activity of E2F1 and the expression of the E2F1 target genes were also decreased by Cd. These results clearly demonstrate that Cd-mediated G1 arrest in WI38 cells is associated with the suppression of Rb phosphorylation and with the inhibition of E2F1 transcriptional activity. PMID- 20839232 TI - The role of calcium release activated calcium channels in osteoclast differentiation. AB - Osteoclasts are specialized macrophage derivatives that secrete acid and proteinases to mobilize bone for mineral homeostasis, growth, and replacement or repair. Osteoclast differentiation generally requires the monocyte growth factor m-CSF and the TNF-family cytokine RANKL, although differentiation is regulated by many other cytokines and by intracellular signals, including Ca(2+). Studies of osteoclast differentiation in vitro were performed using human monocytic precursors stimulated with m-CSF and RANKL, revealing significant loss in both the expression and function of the required components of store-operated Ca(2+) entry over the course of osteoclast differentiation. However, inhibition of CRAC using either the pharmacological agent 3,4-dichloropropioanilide (DCPA) or by knockdown of Orai1 severely inhibited formation of multinucleated osteoclasts. In contrast, no effect of CRAC channel inhibition was observed on expression of the osteoclast protein tartrate resistant acid phosphatase (TRAP). Our findings suggest that despite the fact that they are down-regulated during osteoclast differentiation, CRAC channels are required for cell fusion, a late event in osteoclast differentiation. Since osteoclasts cannot function properly without multinucleation, selective CRAC inhibitors may have utility in management of hyperresorptive states. PMID- 20839233 TI - Balancing the harms and benefits of early detection of prostate cancer. AB - BACKGROUND: The benefits of prostate cancer screening on an individual level remain unevaluated. METHODS: Between 1993 and 1999, a total of 43,987 men, aged 55-74 years, were included in the intervention arm of the European Randomized Study of Screening for Prostate Cancer (ERSPC) section in the Netherlands, Sweden, and Finland. A total of 42,503 men, aged 55-74 years, were included in a clinical population in Northern Ireland. Serum prostate-specific antigen (PSA) <20.0 ng/mL was measured in all men at study entry. All men were followed for prostate cancer incidence and causes of death until December 31, 2006. RESULTS: The adjusted absolute difference in prostate cancer specific mortality between the intervention population and the clinical population increased with increasing PSA level at study entry, ie, 0.05 per 10,000 person-years for men who had a serum PSA level of 0.0-1.9 ng/mL and 8.8 per 10,000 person-years for men who had a serum PSA level of 10-19.9 ng/mL. To evaluate the risks of early detection, the number needed to investigate (NNI) and number needed to treat (NNT) to save 1 death from prostate cancer were calculated. Both NNI and NNT were higher for those who had lower PSA levels at study entry. The NNI was 24,642 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 133 men for patients who had a serum PSA level of 10-19.9 ng/mL; the NNT was 724 men for patients who had a serum PSA level of 0.0-1.9 ng/mL and was 60 men for patients with a serum PSA level of 10-19.9 ng/mL. CONCLUSIONS: For men with a low serum PSA level, the benefits of aggressive investigation and treatment may be limited because they are associated with a large increase in cumulative incidence and potential overtreatment. PMID- 20839234 TI - Blind predictions of protein interfaces by docking calculations in CAPRI. AB - Reliable prediction of the amino acid residues involved in protein-protein interfaces can provide valuable insight into protein function, and inform mutagenesis studies, and drug design applications. A fast-growing number of methods are being proposed for predicting protein interfaces, using structural information, energetic criteria, or sequence conservation or by integrating multiple criteria and approaches. Overall however, their performance remains limited, especially when applied to nonobligate protein complexes, where the individual components are also stable on their own. Here, we evaluate interface predictions derived from protein-protein docking calculations. To this end we measure the overlap between the interfaces in models of protein complexes submitted by 76 participants in CAPRI (Critical Assessment of Predicted Interactions) and those of 46 observed interfaces in 20 CAPRI targets corresponding to nonobligate complexes. Our evaluation considers multiple models for each target interface, submitted by different participants, using a variety of docking methods. Although this results in a substantial variability in the prediction performance across participants and targets, clear trends emerge. Docking methods that perform best in our evaluation predict interfaces with average recall and precision levels of about 60%, for a small majority (60%) of the analyzed interfaces. These levels are significantly higher than those obtained for nonobligate complexes by most extant interface prediction methods. We find furthermore that a sizable fraction (24%) of the interfaces in models ranked as incorrect in the CAPRI assessment are actually correctly predicted (recall and precision >=50%), and that these models contribute to 70% of the correct docking-based interface predictions overall. Our analysis proves that docking methods are much more successful in identifying interfaces than in predicting complexes, and suggests that these methods have an excellent potential of addressing the interface prediction challenge. PMID- 20839235 TI - Computational study of enantioseparation by amylose tris(3,5 dimethylphenylcarbamate)-based chiral stationary phase. AB - The mechanism of chiral separation on amylose tris(3,5-dimethylphenylcarbamate) is studied with docking simulations of enantiomers by molecular dynamics. All atom models of amylose tris(3,5-dimethylphenylcarbamate) on the modified silica gel surface were constructed for the docking simulations of metalaxyl and benalaxyl. The elution orders and energetic differences were also predicted based on the intermolecular interactions, which were in agreement with the experimental results. The radial distribution function was employed to analyze the structural features of the enantiomer-chiral stationary phase complex and used to elucidate the mechanism of chiral separation. The separation of metalaxyl and benalaxyl is mainly controlled by the hydrogen bond. And the binding sites had slight differences for the pair of enantiomers, but obvious differences between different chemicals. PMID- 20839236 TI - Determination of polycyclic aromatic hydrocarbons in water by a novel mesoporous coated stainless steel wire microextraction combined with HPLC. AB - A novel mesoporous-coated stainless steel wire microextraction coupled with the HPLC procedure for quantification of four polycyclic aromatic hydrocarbons in water has been developed, based on the sorption of target analytes on a selectively adsorptive fiber and subsequent desorption of analytes directly into HPLC. Phenyl-functionalized mesoporous materials (Ph-SBA-15) were synthesized and coated on the surfaces of a stainless steel wire. Due to the high porosity and large surface area of the Ph-SBA-15, high extraction efficiency is expected. The influence of various parameters on polycyclic aromatic hydrocarbons extraction efficiency were thoroughly studied and optimized (such as the extraction temperature, the extraction time, the desorption time, the stirring rate and the ionic strength of samples). The results showed that each compound for the analysis of real water samples was tested under optimal conditions with the linearity ranging from 1.02*10(-3) to 200 MUg/ L and the detection limits were found from 0.32 to 2.44 ng/ L, respectively. The RSD of the new method was smaller than 4.10%. PMID- 20839237 TI - Integration of capillary isoelectric focusing with monolithic immobilized pH gradient, immobilized trypsin microreactor and capillary zone electrophoresis for on-line protein analysis. AB - An integrated platform consisting of protein separation by CIEF with monolithic immobilized pH gradient (M-IPG), on-line digestion by trypsin-based immobilized enzyme microreactor (trypsin-IMER), and peptide separation by CZE was established. In such a platform, a tee unit was used not only to connect M-IPG CIEF column and trypsin-IMER, but also to supply adjustment buffer to improve the compatibility of protein separation and digestion. Another interface was made by a Teflon tube with a nick to couple IMER and CZE via a short capillary, which was immerged in a centrifuge tube filled with 20 mmol/L glutamic acid, to exchange protein digests buffer and keep electric contact for peptide separation. By such a platform, under the optimal conditions, a mixture of ribonuclease A, myoglobin and BSA was separated into 12 fractions by M-IPG CIEF, followed by on-line digestion by trypsin-IMER and peptide separation by CZE. Many peaks of tryptic peptides, corresponding to different proteins, were observed with high UV signals, indicating the excellent performance of such an integrated system. We hope that the CE-based on-line platform developed herein would provide another powerful alternative for an integrated analysis of proteins. PMID- 20839238 TI - Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. AB - OBJECTIVE: To evaluate dextromethorphan combined with ultra low-dose quinidine (DMq) for treating pseudobulbar affect (PBA) in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). METHODS: In a 12-week randomized, double-blind trial, ALS and MS patients with clinically significant PBA (a baseline score >=13 on the Center for Neurologic Studies-Lability Scale [CNS-LS]) were maintained, twice daily, on placebo, DMq at 30/10mg (DMq-30), or DMq at 20/10mg (DMq-20). RESULTS: In 326 randomized patients (of whom 283, or 86.8%, completed the study), the PBA-episode daily rate was 46.9% (p < 0.0001) lower for DMq-30 than for placebo and 49.0% (p < 0.0001) lower for DMq-20 than for placebo by longitudinal negative binomial regression, the prespecified primary analysis. Mean CNS-LS scores decreased by 8.2 points for DMq-30 and 8.2 for DMq-20, vs 5.7 for placebo (p= 0.0002 and p= 0.0113, respectively). Other endpoints showing statistically significant DMq benefit included, for both dosage levels, the likelihood of PBA remission during the final 14 days and, for the higher dosage, improvement on measures of social functioning and mental health. Both dosages were safe and well tolerated. INTERPRETATION: DMq markedly reduced PBA frequency and severity, decreasing the condition's detrimental impact on a patient's life, with satisfactory safety and high tolerability. The findings expand the clinical evidence that DMq may be an important treatment for patients suffering from the socially debilitating symptoms of PBA. PMID- 20839239 TI - Common mitochondrial sequence variants in ischemic stroke. AB - OBJECTIVE: Rare mitochondrial mutations cause neurologic disease, including ischemic stroke and MRI white matter changes. We investigated whether common mitochondrial genetic variants influence risk of sporadic ischemic stroke and, in patients with stroke, the volume of white matter hyperintensity (WMHV). METHODS: In this multicenter, mitochondrial genome-wide association study (GWAS), 2284 ischemic stroke cases and 1728 controls from the International Stroke Genetics Consortium were genotyped for 64 mitochondrial single nucleotide polymorphisms (SNPs). Imputation resulted in 144 SNPs, which were tested in each cohort and in meta-analysis for ischemic stroke association. A genetic score of all mitochondrial variants was also tested in association with ischemic stroke. RESULTS: No individual SNP reached adjusted significance in meta-analysis. A genetic score comprised of the summation of contributions from individual variants across the mitochondrial genome showed association with ischemic stroke in meta-analysis (odds ratio [OR] = 1.13, p < 0.0001) with minimal heterogeneity (I(2) = 0.00). This ischemic stroke score was robust to permutation, and was also associated with WMHV in 792 nested case individuals with ischemic stroke (p = 0.037). INTERPRETATION: In this mitochondrial GWAS of ischemic stroke, a genetic score comprised of the sum of all common variants in the mitochondrial genome showed association with ischemic stroke. In an independent analysis of a related trait, this same score correlated with WMHV in stroke cases. Despite this aggregate association, no individual variant reached significance. Substantially larger studies will be required to identify precise sequence variants influencing cerebrovascular disease. PMID- 20839240 TI - RYR1 mutations are a common cause of congenital myopathies with central nuclei. AB - OBJECTIVE: Centronuclear myopathy (CNM) is a rare congenital myopathy characterized by prominence of central nuclei on muscle biopsy. CNM has been associated with mutations in MTM1, DNM2, and BIN1 but many cases remain genetically unresolved. RYR1 encodes the principal sarcoplasmic reticulum calcium release channel and has been implicated in various congenital myopathies. We investigated whether RYR1 mutations cause CNM. METHODS: We sequenced the entire RYR1 coding sequence in 24 patients with a diagnosis of CNM from South Africa (n = 14) and Europe (n = 10) and identified mutations in 17 patients. The most common genotypes featured compound heterozygosity for RYR1 missense mutations and mutations resulting in reduced protein expression, including intronic splice site and frameshift mutations. RESULTS: The high incidence in South African patients (n = 12/14) in conjunction with recurrent RYR1 mutations associated with common haplotypes suggested the presence of founder effects. In addition to central nuclei, prominent histopathological findings included (often multiple) internalized nuclei and type 1 fiber predominance and hypotrophy with relative type 2 hypertrophy. Although cores were not typically seen on oxidative stains, electron microscopy revealed subtle abnormalities in most cases. External ophthalmoplegia, proximal weakness, and bulbar involvement were prominent clinical findings. INTERPRETATION: Our findings expand the range of RYR1-related phenotypes and suggest RYR1 mutations as a common cause of congenital myopathies with central nuclei. Corresponding to recent observations in X-linked CNM, these findings indicate disturbed assembly and/or malfunction of the excitation contraction machinery as a key mechanism in CNM and related myopathies. PMID- 20839241 TI - Disease phenotype and genotype are associated with shifts in intestinal associated microbiota in inflammatory bowel diseases. AB - BACKGROUND: Abnormal host-microbe interactions are implicated in the pathogenesis of inflammatory bowel diseases. Previous 16S rRNA sequence analysis of intestinal tissues demonstrated that a subset of Crohn's disease (CD) and ulcerative colitis (UC) samples exhibited altered intestinal-associated microbial compositions characterized by depletion of Bacteroidetes and Firmicutes (particularly Clostridium taxa). We hypothesize that NOD2 and ATG16L1 risk alleles may be associated with these alterations. METHODS: To test this hypothesis, we genotyped 178 specimens collected from 35 CD, 35 UC, and 54 control patients for the three major NOD2 risk alleles (Leu 1007fs, R702W, and G908R) and the ATG16L1T300A risk allele, that had undergone previous 16S rRNA sequence analysis. Our statistical models incorporated the following independent variables: 1) disease phenotype (CD, UC, non-IBD control); 2) NOD2 composite genotype (NOD2(R) = at least one risk allele, NOD2(NR) = no risk alleles); 3) ATG16L1T300A genotype (ATG16L1(R/R), ATG16L1(R/NR), ATG16L1(NR/NR)); 4) patient age at time of surgery and all first order interactions. The dependent variable(s) were the relative frequencies of bacterial taxa classified by applying the RDP 2.1 classifier to previously reported 16S rRNA sequence data. RESULTS: Disease phenotype, NOD2 composite genotype and ATG16L1 genotype were significantly associated with shifts in microbial compositions by nonparametric multivariate analysis of covariance (MANCOVA). Shifts in the relative frequencies of Faecalibacterium and Escherichia taxa were significantly associated with disease phenotype by nonparametric ANCOVA. CONCLUSIONS: These results support the concept that disease phenotype and genotype are associated with compositional changes in intestinal-associated microbiota. PMID- 20839243 TI - A polymer-based nanopore-integrated microfluidic device for generating stable bilayer lipid membranes. PMID- 20839242 TI - Synthesis and superior optical-limiting properties of fluorene-thiophene benzothiadazole polymer-functionalized graphene sheets. AB - A polymer based on fluorene, thiophene, and benzothiadazole as the donor-spacer acceptor triad is covalently coupled to reduced graphene oxide (rGO) sheets via diazonium coupling with phenyl bromide, followed by Suzuki coupling. These polymer-graphene hybrids show good solubility in organic solvents, such as chloroform, tetrahydrofuran (THF), toluene, dichlorobenzene, and N,N dimethylformamide (DMF), and exhibit an excellent optical-limiting effect with a 532-nm laser beam. The optical-limiting threshold energy values (0.93 J cm(-2) for G-polymer 1 and 1.12 J cm(-2) for G-polymer 2) of these G-polymer hybrids are better than that of carbon nanotubes (3.6 J cm(-2)). PMID- 20839244 TI - Self-wound composite nanomembranes as electrode materials for lithium ion batteries. PMID- 20839245 TI - Split-gate organic field effect transistors: control over charge injection and transport. PMID- 20839246 TI - Microstructured tungsten oxide: a generic desorption/ionization substrate for mass spectrometry. PMID- 20839247 TI - A biomimetic, self-pumping membrane. PMID- 20839248 TI - Bifunctional nanocomposites with magnetic and luminescence properties. AB - Many applications require nanoparticles that exhibit high magnetic moment and luminescence. Compounds exhibiting this combination of properties do not exist. However, this combination of properties may be obtained by nanocomposites. There are two possible configurations for these composites: the core-shell design, leading to the smallest composite particles, and agglomerates containing separated particles with the properties in question. The magnetic core is, in most cases, maghemite or magnetite, whereas the luminescence carrier is either an organic molecule or an inorganic quantum dot. One of the basic problems in designing such composites, to be overcome by the appropriate layout choice, is the potential incompatibility between the magnetic core and the lumophore. Experimentally realized solutions of these problems are presented. PMID- 20839249 TI - Combinatorial and high-throughput screening of biomaterials. AB - Combinatorial and high-throughput methods have been increasingly used to accelerate research and development of new biomaterials. These methods involve creating miniaturized libraries that contain many specimens in one sample in the form of gradients or arrays, followed by automated data collection and analysis. This article reviews recent advances in utilizing combinatorial and high throughput methods to better understand cell-material interactions, particularly highlighting our efforts at the NIST Polymers Division. Specifically, fabrication techniques to generate controlled surfaces (2D) and 3D cell environments (tissue engineering scaffolds) as well as methods to characterize and analyze material properties and cell-material interactions are described. In conclusion, additional opportunities for combinatorial methods for biomaterials research are noted, including streamlined sample fabrication and characterization, appropriate and automated bioassays, and data analysis. PMID- 20839250 TI - Nanoarchitectured 3D cathodes for Li-ion microbatteries. PMID- 20839251 TI - Enhanced light out-coupling of organic light-emitting diodes: spontaneously formed nanofacet-structured MgO as a refractive index modulation layer. PMID- 20839252 TI - Unidirectional alignment of lamellar bilayer in hydrogel: one-dimensional swelling, anisotropic modulus, and stress/strain tunable structural color. PMID- 20839253 TI - Barrier properties of synthetic clay with a kilo-aspect ratio. PMID- 20839254 TI - Three-dimensional integration of organic resistive memory devices. PMID- 20839255 TI - A DNA nanostructure-based biomolecular probe carrier platform for electrochemical biosensing. PMID- 20839256 TI - Encoding localized strain history through wrinkle based structural colors. AB - Surface wrinkles are created on a metallic film supported on a shape memory polymer substrate. The wrinkle wavelength approaches that of visible lights, resulting in diffraction colors. The spatial and geometric distribution of the surface wrinkles can be controlled in an arbitrary fashion, allowing the capture of a three dimensional arbitrary image on a macroscopically flat surface. PMID- 20839257 TI - Self-healing materials. AB - Self-healing materials are able to partially or completely heal damage inflicted on them, e.g., crack formation; it is anticipated that the original functionality can be restored. This article covers the design and generic principles of self healing materials through a wide range of different material classes including metals, ceramics, concrete, and polymers. Recent key developments and future challenges in the field of self-healing materials are summarised, and generic, fundamental material-independent principles and mechanism are discussed and evaluated. PMID- 20839258 TI - Differences in incidence and co-occurrence of vaccine and nonvaccine human papillomavirus types in Finnish population before human papillomavirus mass vaccination suggest competitive advantage for HPV33. AB - To understand likelihood of type replacement after vaccination against the high risk human papillomavirus (HPV) types, we evaluated competition of the seven most common genital HPV types in a population sample of unvaccinated, fertile-aged Finnish women. First trimester sera from two consecutive pregnancies were retrieved from 3,183 Finnish women (mean age, 23.1 years) of whom 42.3% had antibodies to at least one HPV type (6/11/16/18/31/33/45) at the baseline. Antibody positivity to more than one HPV types by the second pregnancy was common among the baseline HPV seropositives. However, compared to baseline HPV seronegative women, significantly increased incidence rate ratios (IRRs), indicating an increased risk to seroconvert for another HPV type, were consistently noted only for HPV33 among baseline HPV16 or HPV18 antibody (ab) positive women: HPV(16ab only) (->) (16&33ab) IRR 2.9 [95% confidence interval (CI) 1.6-5.4] and HPV(18ab only) (->) (18&33ab) IRR 2.5 (95% CI 1.1-6.0), irrespectively of the presence of antibodies to other HPV types at baseline: HPV(16ab) (->) (16&33ab) IRR 3.2 (95% CI 2.0-5.2) and HPV(18ab) (->) (18&33ab) IRR 3.6 (95% CI 2.1-5.9). Our findings suggest a possible competitive advantage for HPV33 over other genital HPV types in the unvaccinated population. HPV33 should be monitored for type replacement after HPV mass vaccination. PMID- 20839259 TI - Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. AB - Tyrosine kinase inhibitors (TKIs) as sorafenib are known to reduce the number of immunosuppressive regulatory T cells (Tregs) in the peripheral blood and thereby shifting the immune balance to a more stimulating setting. The effect of sorafenib on intratumoural Tregs is unclear but important for future combinations of TKIs and immunotherapy. We, therefore, evaluated the accumulation of regulatory T cells (Tregs, defined as, CD4(+)FoxP3(+)CD25(high)CD127(low)-cells) in blood, ascites, metastases and primary tumours of patients with renal cell carcinoma (RCC), and we explored the effect of neoadjuvant treatment with sorafenib 400 mg bid on intratumoural Tregs in 11 patients with RCC in comparison to 15 nontreated RCC patients. We found that immunosuppressive Tregs specifically accumulate in primary tumour, metastases and ascites of RCC-patients. Tumour infiltrating Tregs were functional. Neoadjuvant sorafenib treatment significantly reduced the percentage of tumour-infiltrating Tregs (mean 17.3% vs. 28.1%, p = 0.046). Diminished Treg accumulation at the tumour site adds to explain the clinical effectiveness of sorafenib treatment. This observation may have important implications for the use of sorafenib in combination with immunotherapy in patients with RCC, since the depletion of Tregs has been associated with enhanced responses on vaccine mediated immunotherapy. PMID- 20839260 TI - Cross-signaling among phosphinositide-3 kinase, mitogen-activated protein kinase and sonic hedgehog pathways exists in esophageal cancer. AB - The hedgehog (Hh) signaling pathway is essential for the development of tissues and organs. Hyperactive Hh signaling has been implicated in many gastric cancers, including esophageal cancer. However, the interaction between the Hh pathway and other potential signaling pathways in primary esophageal tumorigenesis has not been well investigated. In our study, we found that esophageal cancer cells expressed Hh signaling molecules and that the hyperexpression of Hh target genes was related to protein kinase B (AKT) activation but not extracellular signal regulated kinase activation. We analyzed the relationship between Gli1 or p-AKT expression and clinicopathological features in esophageal carcinoma samples and found that Gli1 expression was associated with lymph vessel invasion (p = 0.016), blood vessel invasion (p = 0.006) and a poor prognosis (p = 0.003), and p-AKT expression was associated with blood vessel invasion (p = 0.031) and a poor prognosis (p = 0.031). We also studied the relationship between Hh and phosphinositide-3 kinase (PI3K)/AKT or mitogen-activated protein kinase (MAPK) signaling pathways in both TE-1 and TE-10 cell lines. We found that the PI3K/AKT pathway played a critical role in Hh signaling after stimulation with epidermal growth factor, Gbetagamma and N-Shh. Conversely, PI3K/AKT and MAPK signaling cooperated with the Shh pathway to promote esophageal cancer cell survival and proliferation. The results from esophageal cancer cells shed light on the significance of Hh signaling in esophageal tumor formation and the crosstalk of the Hh pathway with other basic signaling pathways, which is consistent with that observed in human tumor samples. PMID- 20839261 TI - A novel (19)F agent for detection and quantification of human dendritic cells using magnetic resonance imaging. AB - Monitoring of cell therapeutics in vivo is of major importance to estimate its efficacy. Here, we present a novel intracellular label for (19)F magnetic resonance imaging (MRI)-based cell tracking, which allows for noninvasive, longitudinal cell tracking without the use of radioisotopes. A key advantage of (19)F MRI is that it allows for absolute quantification of cell numbers directly from the MRI data. The (19)F label was tested in primary human monocyte-derived dendritic cells. These cells took up label effectively, resulting in a labeling of 1.7 +/- 0.1 * 10(13) (19)F atoms per cell, with a viability of 80 +/- 6%, without the need for electroporation or transfection agents. This results in a minimum detection sensitivity of about 2,000 cells/voxel at 7 T, comparable with gadolinium-labeled cells. Comparison of the detection sensitivity of cells labeled with (19)F, iron oxide and gadolinium over typical tissue background showed that unambiguous detection of the (19)F-labeled cells was simpler than with the contrast agents. The effect of the (19)F agent on cell function was minimal in the context of cell-based vaccines. From these data, we calculate that detection of 30,000 cells in vivo at 3 T with a reasonable signal to noise ratio for (19)F images would require less than 30 min with a conventional fast spin echo sequence, given a coil similar to the one used in this study. This is well within acceptable limits for clinical studies, and thus, we conclude that (19)F MRI for quantitative cell tracking in a clinical setting has great potential. PMID- 20839262 TI - Human papillomavirus genotype distribution in anal cancer in France: the EDiTH V study. AB - Anal cancer is a rare cancer but its incidence is increasing. Human papillomavirus (HPV) infection seems to be associated with the occurrence of most cases. The genotype-specific prevalence of HPV in anal cancer was estimated to assess the potential benefit of HPV vaccination in France. Anal cancer histological specimens were retrospectively recruited in 2008 from 16 French centres and centrally tested for HPV genotyping using the INNO-LiPA assay allowing the detection of 28 genotypes. Results were analyzed according to age, gender, HIV status when available and histological diagnosis. A total of 366 anal cancer cases were analyzed among which 62% were females. Mean age at diagnosis was 54.8 years in males and 66.4 years in females (p < 0.001). HPV was found in 96.7% of cases, 72% being infected by a single HPV type. Presence of at least one high-risk genotype was observed in 91% of cases (96% in females and 83% in males; p < 0.001). HPV16 was by far the most prevalent genotype (75%), followed by HPV18, HPV52, HPV33, and HPV51 (4-6%). HPV16/18 alone or in association were found in 78% of all cases. HIV-positive cases had a higher proportion of multiple HPV infection than HIV-negative cases and a slightly different HPV type distribution with an under-representation of HPV16 and an over-representation of other types. Our results indicate that anal cancer rarely occurs in the absence of HPV and emphasize the predominant role of HPV16. The potential benefit of HPV vaccine on the occurrence of anal cancer should be further evaluated. PMID- 20839263 TI - Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. AB - The aims of this study were to determine potency of oxaliplatin in combination with curcumin in oxaliplatin-resistant cell lines in vitro and to evaluate the efficacy of a novel curcumin formulation (Meriva(r)) alone and in combination with oxaliplatin in colorectal tumor-bearing mice, exploring relevant pharmacodynamic markers in vivo. Oxaliplatin-resistant HCT116 p53wt and p53(-/-) cell lines were generated, and the effects of oxaliplatin in combination with curcumin on resistance- and proliferation-associated proteins investigated. Eighty nude mice were implanted with HCT116 p53wt colorectal cancer cells before randomization into the following treatment groups: control; Meriva only; oxaliplatin only; Meriva + oxaliplatin. Tumor volume was assessed, as was the expression of Ki-67, cleaved caspase-3 and Notch-1. Curcumin in combination with oxaliplatin was able to decrease proliferative capacity of oxaliplatin-resistant p53 wildtype and p53(-/-) cell lines more effectively than oxaliplatin alone. It also decreased markers associated with proliferation. After 21 days of treatment in the xenograft model, the order of efficacy was combination > Meriva > oxaliplatin > control. The decrease in tumor volume when compared to vehicle treated animals was 53, 35 and 16%, respectively. Ki-67 and Notch-1 immunoreactivity was decreased by the combination when compared to vehicle treated animals, with cleaved caspase-3 rising by 4.4-fold. Meriva did not adversely affect the DNA-platinating ability of oxaliplatin. Curcumin enhanced the cytotoxicity of oxaliplatin in models of oxaliplatin resistance in vitro. In vivo, Meriva greatly enhanced oxaliplatin efficacy, without affecting the mode of action of oxaliplatin. Addition of formulated curcumin to oxaliplatin-based chemotherapy regimens has the potential for clinical benefit. PMID- 20839264 TI - Chemical and biological control of Sclerotinia sclerotiorum in witloof chicory culture. AB - BACKGROUND: Sclerotinia sclerotiorum (Lib.) de Bary is a major pathogen of witloof chicory. For lack of authorised field treatment, post-harvest sprays with dicarboximide fungicides have been standard practice since the 1970s to prevent root rot and chicory heart decay during the forcing phase. However, the registration of procymidone and vinclozolin has been withdrawn in Europe. The development of organic agriculture and the necessity to reduce fungicide applications in conventional agriculture prompted an assessment of the efficacy of new fungicides and the use of the mycoparasite Coniothyrium minitans (Campbell). RESULTS: A mixture of the fungicides fludioxonil and cyprodinil (Switch((r)) ) applied on chicory roots achieved a very good control of S. sclerotiorum (up to 95%). The use of C. minitans limited root infection, both when applied in the field (50-65% efficacy) and before the forcing period (post harvest treatment up to 80%). CONCLUSION: In organic agriculture, two treatments with C. minitans (in field and later at the forcing period) could improve protection against S. sclerotiorum. In conventional agriculture, after the field biological treatment, a post-harvest chemical treatment could be applied. The addition of other prophylactic methods could lead to a high level of performance in practice against decay caused by S. sclerotiorum. PMID- 20839265 TI - Non-destructive prediction of 'Hass' avocado dry matter via FT-NIR spectroscopy. AB - BACKGROUND: The inability to consistently guarantee internal quality of horticulture produce is of major importance to the primary producer, marketers and ultimately the consumer. Currently, commercial avocado maturity estimation is based on the destructive assessment of percentage dry matter (%DM), and sometimes percentage oil, both of which are highly correlated with maturity. In this study the utility of Fourier transform (FT) near-infrared spectroscopy (NIRS) was investigated for the first time as a non-invasive technique for estimating %DM of whole intact 'Hass' avocado fruit. Partial least squares regression models were developed from the diffuse reflectance spectra to predict %DM, taking into account effects of intra-seasonal variation and orchard conditions. RESULTS: It was found that combining three harvests (early, mid and late) from a single farm in the major production district of central Queensland yielded a predictive model for %DM with a coefficient of determination for the validation set of 0.76 and a root mean square error of prediction of 1.53% for DM in the range 19.4-34.2%. CONCLUSION: The results of the study indicate the potential of FT-NIRS in diffuse reflectance mode to non-invasively predict %DM of whole 'Hass' avocado fruit. When the FT-NIRS system was assessed on whole avocados, the results compared favourably against data from other NIRS systems identified in the literature that have been used in research applications on avocados. PMID- 20839266 TI - Primate seed dispersers as umbrella species: a case study from Kibale National Park, Uganda, with implications for Afrotropical forest conservation. AB - Almost half of the world's extant primate species are of conservation concern [IUCN, International Union for the Conservation of Nature Red List of Threatened Species, 2008]. Primates are also effective seed dispersers. The implications of and interactions between these two facts are increasingly understood, and data demonstrating the consequences of losing primates for forest ecology are now available from throughout the tropics. However, a reality is that not all species and the mutualisms among them-can be protected. Conservation managers must make difficult decisions and use shortcuts in the implementation of conservation tactics. Using taxa as "umbrellas" is one such shortcut, although a lack of an operational definition of what an umbrella species is and how to choose one has made implementing this tactic difficult. In this study, I discuss primates as umbrellas by defining a selection index in terms of richness/co-occurrence, rarity, and sensitivity to anthropogenic disturbance. I evaluate the anthropoid assemblage of Kibale National Park, Uganda, in light of the selection index and determine that Cercopithecus is the genus best fitting the criteria for umbrella status. I then evaluate the functional significance-in terms of seed dispersal-of using Cercopithecus monkeys (guenons) as umbrellas. Results from 1,047 hr of observation of focal fruiting trees in Kibale indicate that Cercopithecus ascanius was the most commonly observed frugivore visitor (July 2001-June 2002). These data corroborate earlier data collected in Kibale demonstrating that guenons are highly effective seed dispersers. Patterns of richness/co-occurrence, rarity, and sensitivity observed in Kibale are reflected in Afrotropical forests more generally, with the genus Cercopithecus tending to exhibit greatest richness/co-occurrence with taxonomically similar species, to be neither extremely rare nor ubiquitous, and also to be moderately sensitive to human disturbance. Moreover, in all available evaluations of frugivory in Afrotropical forests, guenons emerge as among the most important seed dispersers relative to other taxa. PMID- 20839267 TI - The first small-molecule inhibitor of 14-3-3s: modulating the master regulator. PMID- 20839268 TI - Field-controlled Luttinger liquid and possible crossover into spin liquid in strong-rail ladder systems. AB - The thermodynamics and transport properties of strong-rail ladder systems are investigated by means of Green's function theory. It is shown that the magnetic behavior clearly manifests a typical antiferromagnetism with gapped or gapless low-lying excitations, which is in agreement with the experimental results. In addition, the temperature-field-induced phase diagram is explored, and we demonstrate a Luttinger liquid behavior in the window h(c) (marking the ending of the M=0 plateau) solvent-shared ion pairings -> solvent-shared triple and multiple ion clusters -> contact multiple ion clusters > amorphous crystal is proposed. PMID- 20839304 TI - Structure-based quantitative structure-activity relationship studies of checkpoint kinase 1 inhibitors. AB - Structure-based quantitative structure-activity relationship (QSAR) studies on a series of checkpoint kinase 1 (Chk1) inhibitors were performed to find the key structural features responsible for their inhibitory activity. Molecular docking was employed to explore the binding mode of all inhibitors at the active site of Chk1 and determine the active conformation for the QSAR studies. Ligand and structure-based descriptors incorporating the ligand-receptor interaction were generated based on the docked complex. Genetic Algorithm-Multiple Linear Regression (GA-MLR) method was used to build 2D QSAR model. The 2D QSAR model gave a squared correlation coefficient R(2) of 0.887, cross-validated Q(2) of 0.837 and the prediction squared correlation coefficient R(2)(pred) of 0.849, respectively. Furthermore, three-dimensional quantitative structure-activity relationship (3D QSAR) model using comparative molecular field analysis (CoMFA) with R(2) of 0.983, Q(2) of 0.550 and R(2)(pred) of 0.720 was also developed. The obtained results are helpful for the design of novel Chk1 inhibitors with improved activities. PMID- 20839305 TI - First principles studies on the interaction of O2 with X@Al12 (X = Al-, P+, C, Si) clusters. AB - The interaction of O(2) with the doped icosahedral X@Al(12) (X = Al(-), P(+), C, Si) clusters with 40 valence electrons were investigated using density functional theory methods. A different behavior exhibited between Al(13)(-) and X@Al(12) (X = P(+), C, Si) when they interact with O(2). The dissociation of O(2) on Al(13)( ) is strongly dependent on spin state of oxygen molecule. But X@Al(12) (X = P(+), C, and Si) is not the case. The transform of spin moment from O(2) to Al(13)(-) is much faster. Small molecularly binding energy and relatively high energy barrier show that these clusters are all reluctant reacts with the ground state O(2). PMID- 20839306 TI - Pharmacophore alignment search tool: Influence of canonical atom labeling on similarity searching. AB - Previously, (Hahnke et al., J Comput Chem 2009, 30, 761) we presented the Pharmacophore Alignment Search Tool (PhAST), a ligand-based virtual screening technique representing molecules as strings coding pharmacophoric features and comparing them by global pairwise sequence alignment. To guarantee unambiguity during the reduction of two-dimensional molecular graphs to one-dimensional strings, PhAST employs a graph canonization step. Here, we present the results of the comparison of 11 different algorithms for graph canonization with respect to their impact on virtual screening. Retrospective screenings of a drug-like data set were evaluated using the BEDROC metric, which yielded averaged values between 0.4 and 0.14 for the best-performing and worst-performing canonization technique. We compared five scoring schemes for the alignments and found preferred combinations of canonization algorithms and scoring functions. Finally, we introduce a performance index that helps prioritize canonization approaches without the need for extensive retrospective evaluation. PMID- 20839307 TI - Defining disease-modifying therapies for PD--a road map for moving forward. AB - A disease-modifying therapy that slows or stops disease progression is one of the major unmet needs in the management of Parkinson's disease. To date, no therapy has been approved for disease modification despite promising laboratory data and positive results in clinical trials. This is because confounding symptomatic or pharmacologic effects cannot be excluded. The delayed start study provides an opportunity to define therapies that provide benefit that cannot be explained by an early symptomatic effect alone. However, this trial design does not necessarily provide a meaningful measure of the effect of the intervention on cumulative disability. In contrast, the long-term simple study provides a measure of the effect of the drug on cumulative disability but does not address mechanism of action. Together these two trials provide a road map for defining a disease modifying drug and determining the long term cumulative effect of the drug on the disease. PMID- 20839308 TI - Impaired astrocytic extracellular matrix distribution under congenital hypothyroidism affects neuronal development in vitro. AB - Astrocytes clearly play a role in neuronal development. An indirect mechanism of thyroid hormone (T3) in the regulation of neuronal development mediated by astrocytes has been proposed. T3 alters the production and organization of the extracellular matrix (ECM) proteins and proteoglycans, producing a high-quality substrate for neuronal differentiation. The present study investigated the effect of hypothyroidism on the astrocyte production of fibronectin (FN) and laminin (LN) as well as their involvement in neuronal growth and neuritogenesis. Our results demonstrated that the amount of both FN and LN were significantly reduced in cultures of hypothyroid astrocytes from rat cerebellum compared with normal cells. This effect was accompanied by reduced numbers of neurons and neuritogenesis. Similarly, the proportions of neurons and neurons with neurites were reduced in cultures on ECM prepared from hypothyroid astrocytes in comparison with normal cells. The proportion of both normal and hypothyroid neurons is strongly reduced in astrocyte ECM compared with cocultures on astrocyte monolayers, suggesting that extracellular factors other than ECM proteins are involved in this process. Moreover, treatment of hypothyroid astrocytic cultures with T3 restored the area of both FN and LN immunostaining to normal levels and partially reestablished neuronal survival and neuritogenesis. Taken together, our results demonstrated that hypothyroidism involves impairment of the astrocytic microenvironment and affects the production of ECM proteins. Thus, hypothyroidism is implicated in impaired neuronal development. PMID- 20839309 TI - Consistency of retrospective reports of peritraumatic responses and their relation to PTSD diagnostic status. AB - Few studies have examined whether trauma-exposed individuals are consistent in their retrospective reports of how they reacted at the time of trauma exposure, and whether this phenomenon has any implications at the diagnostic level. In a series of three longitudinal studies (N = 113) with different timeframes, the authors prospectively investigated the consistency of peritraumatic response scores as a function of posttraumatic stress disorder (PTSD) diagnostic status. Across the three studies, consistency of scores was better among individuals who either did not develop PTSD or who remitted from it than among those whose PTSD did not remit. These results are consistent with the literature suggesting that compromised memory processes are related to sustained PTSD. PMID- 20839310 TI - A guide to guidelines for the treatment of PTSD and related conditions. AB - In recent years, several practice guidelines have appeared to inform clinical work in the assessment and treatment of posttraumatic stress disorder. Although there is a high level of consensus across these documents, there are also areas of apparent difference that may lead to confusion among those to whom the guidelines are targeted-providers, consumers, and purchasers of mental health services for people affected by trauma. The authors have been responsible for developing guidelines across three continents (North America, Europe, and Australia). The aim of this article is to examine the various guidelines and to compare and contrast their methodologies and recommendations to aid clinicians in making decisions about their use. PMID- 20839311 TI - Imagery rehearsal for posttraumatic nightmares: a randomized controlled trial. AB - One hundred twenty-four male Vietnam War veterans with chronic, severe posttraumatic stress disorder (PTSD) were randomly assigned to imagery rehearsal (n = 61) or a credible active comparison condition (n = 63) for the treatment of combat-related nightmares. There was pre-post change in overall sleep quality and PTSD symptoms for both groups, but not in nightmare frequency. Intent-to-treat analyses showed that veterans who received imagery rehearsal had not improved significantly more than veterans in the comparison condition for the primary outcomes (nightmare frequency and sleep quality), or for a number of secondary outcomes, including PTSD. Six sessions of imagery rehearsal delivered in group format did not produce substantive improvement in Vietnam War veterans with chronic, severe PTSD. Possible explanations for findings are discussed. PMID- 20839312 TI - An evaluation of competing models for the structure of PTSD symptoms using external measures of comorbidity. AB - Research on the structure of posttraumatic stress disorder (PTSD) symptoms has yielded support for two 4-factor models: the King (King, Leskin, King, & Weathers, 1998) and Simms/Watson models (Simms, Watson, & Doebbeling, 2002). This study evaluated them using data drawn from 1,128 Vietnam veterans by comparing associations with a latent internalizing comorbidity variable and five scales from the MMPI-2 Restructured Clinical (RC) Scales (Tellegen et al., 2003). The Simms/Watson dysphoria factor failed to show evidence of superior convergent or discriminant validity in association with external measures relative to the numbing or hyperarousal factors of the King model. Findings raise questions about proposals to abandon the distinction between numbing and hyperarousal symptoms in favor of a dysphoria-based model. PMID- 20839313 TI - Genetics of childhood-onset inflammatory bowel disease. AB - Nearly a third of inflammatory bowel disease (IBD) patients present in childhood or adolescence, with epidemiological and natural history studies clearly demonstrating a rising incidence in this population. Although early-onset disease has a distinct phenotype, such as more extensive disease at onset and rapid progression, two recent genome-wide association studies (GWAS) carried out exclusively in this age group have demonstrated marked genetic similarities to adult disease. Although these parallels exist, this review will focus on the novel regions associated with early-onset IBD susceptibility identified by these early-onset GWAS. These new loci reaffirm the dysregulated pathways previously implicated in adult IBD pathogenesis and provide further insight into the pathophysiology of intestinal inflammation. The newly identified loci and expression data suggest mutations in genes encoding IL-27, which is involved in Th17 effector cell physiology; MTMR3, which we demonstrate is an essential component of autophagy; and CAPN10, which is necessary in regulating endoplasmic reticulum stress. In addition, the roles of PSMG1, TNFRSF6B, ZMIZ1 and SMAD3 are also discussed in relation to abnormal protein degradation and the secondary immune response. It is clear that with increasing technology our understanding of IBD pathogenesis is deepening at the genomic level and that the use of early patient selection coupled with ongoing work on therapeutic targets will lead to improved disease-modifying treatments in the near future. PMID- 20839314 TI - A transcriptional network signature characterizes lung cancer subtypes. AB - BACKGROUND: Transcriptional networks play a central role in cancer development. The authors described a systems biology approach to cancer classification based on the reverse engineering of the transcriptional network surrounding the 2 most common types of lung cancer: adenocarcinoma (AC) and squamous cell carcinoma (SCC). METHODS: A transcriptional network classifier was inferred from the molecular profiles of 111 human lung carcinomas. The authors tested its classification accuracy in 7 independent cohorts, for a total of 422 subjects of Caucasian, African, and Asian descent. RESULTS: The model for distinguishing AC from SCC was a 25-gene network signature. Its performance on the 7 independent cohorts achieved 95.2% classification accuracy. Even more surprisingly, 95% of this accuracy was explained by the interplay of 3 genes (KRT6A, KRT6B, KRT6C) on a narrow cytoband of chromosome 12. The role of this chromosomal region in distinguishing AC and SCC was further confirmed by the analysis of another group of 28 independent subjects assayed by DNA copy number changes. The copy number variations of bands 12q12, 12q13, and 12q12-13 discriminated these samples with 84% accuracy. CONCLUSIONS: These results suggest the existence of a robust signature localized in a relatively small area of the genome, and show the clinical potential of reverse engineering transcriptional networks from molecular profiles. PMID- 20839315 TI - Activation of the phosphoinositide-3-kinase and mammalian target of rapamycin signaling pathways are associated with shortened survival in patients with malignant peritoneal mesothelioma. AB - BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare malignancy of the serosal membranes of the abdominal cavity. This cancer is ultimately fatal in almost all afflicted individuals; however, there is marked variability in its clinical behavior: Some patients die rapidly, and others survive for many years. In the current study, the authors investigated the molecular nature of MPM to obtain insights into the heterogeneity of its clinical behavior and to identify new therapeutic targets for intervention. METHODS: Fresh pretreatment tumor samples were collected from 41 patients with MPM who underwent surgical cytoreduction and received regional intraoperative chemotherapy perfusion. From those samples, gene expression analyses were performed. The major cellular pathways that were identified in this cancer were inhibited using a pathway specific inhibitor. RESULTS: Unsupervised clustering of genes identified 2 distinct groups of patients with significantly different survivals (Group A: median survival, 24 months; Group B: median survival, 69.5 months; P = .035). Phosphoinositide-3-kinase (PI3K) and the closely interacting mammalian target of rapamycin (mTOR) signaling pathways were overexpressed predominantly in the poor survival group; and the genes of these pathways, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) and rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR), were highly significantly predictive of shortened patient survival in Group A. The role of these pathways in MPM tumor progression was also investigated by treating 2 MPM cell lines with BEZ235, a dual-class PI3K and mTOR inhibitor, and the authors observed significant inhibition of downstream cell signaling and cell proliferation. CONCLUSIONS: Taken together, the results from this study revealed that, based on gene expression profiles, there were 2 distinct patient groups with significantly different survival and that targeting the PI3K and mTOR signaling pathways may have significant therapeutic value in patients with MPM. PMID- 20839316 TI - Prostaglandin E2 and prostaglandin F2alpha differentially modulate matrix metabolism of human nucleus pulposus cells. AB - Prostaglandin (PG) actions on disc metabolism are unclear even though certain PGs are highly expressed by disc cells under inflammatory conditions and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to block PG production to treat back pain. Hence this study aimed to (1) quantify gene expression of arachidonic acid cascade components responsible for PG synthesis and (2) examine the effects of key PGs on disc matrix homeostasis. Microarray analysis revealed that inflammatory stress increases expression of synthases and receptors for prostaglandin E2 (PGE(2)) and prostaglandin F2alpha (PGF(2alpha)), resulting in elevated PGE(2) and PGF(2alpha) production in conditioned media of disc cells. PGE(2) diminished disc cell proteoglycan synthesis, in a dose-dependent manner. Semiquantitative RT-PCR revealed differential effects of PGE(2) and PGF(2alpha) on disc cell expression of key matrix structural genes, aggrecan, versican, collagens type I and II. PGE(2) and PGF(2alpha) also decreased message for the anabolic factor, IGF-1. PGE(2) decreased mRNA expression for the anti-catabolic factor TIMP-1 while PGF(2alpha) increased mRNAs for catabolic factors MMP-1 and MMP-3. Thus, PGE(2) and PGF(2alpha) may have an overall negative impact on disc matrix homeostasis, and the use of NSAIDs may impact disc metabolism as well as treat back pain. PMID- 20839317 TI - Effect of cell number on mesenchymal stem cell transplantation in a canine disc degeneration model. AB - Transplantation of mesenchymal stem cells (MSCs) inhibits the progression of disc degeneration in animal models. We know of no study to determine the optimal number of cells to transplant into the degenerated intervertebral disc (IVD). To determine the optimal donor cell number for maximum benefit, we conducted an in vivo study using a canine disc degeneration model. Autologous MSCs were transplanted into degenerative discs at 10(5), 10(6), or 10(7) cells per disc. The MSC-transplanted discs were evaluated for 12 weeks using plain radiography, magnetic resonance imaging, and gross and microscopic evaluation. Preservation of the disc height, annular structure was seen in MSC-transplantation groups compared to the operated control group with no MSC transplantation. Result of the number of remaining transplanted MSCs, the survival rate of NP cells, and apoptosis of NP cells in transplanted discs showed both structural microenvironment and abundant extracellular matrix maintained in 10(6) MSCs transplanted disc, while less viable cells were detected in 10(5) MSCs transplanted and more apoptotic cells in 10(7) MSCs transplanted discs. The results of this study demonstrate that the number of cells transplanted affects the regenerative capability of MSC transplants in experimentally induced degenerating canine discs. It is suggested that maintenance of extracellular matrix by its production from transplanted cells and/or resident cells is important for checking the progression of structural disruption that leads to disc degeneration. PMID- 20839318 TI - F-spondin regulates chondrocyte terminal differentiation and endochondral bone formation. AB - This study examines the role of F-spondin, an extracellular matrix protein of osteoarthritic cartilage, during chondrocyte maturation in embryonic growth plate cartilage. In chick tibia, F-spondin expression localized to the hypertrophic and calcified zones of the growth plate. Functional studies using tibial organ cultures indicated that F-spondin inhibited (~35%, p = 0.02), and antibodies to F spondin increased (~30%, p < 0.1) longitudinal limb growth relative to untreated controls. In cell cultures, induction of chondrocyte maturation, by retinoic acid (RA) or transforming growth factor (TGF)-beta treatment led to a significant upregulation of F-spondin (p < 0.05). F-spondin transfection increased mineral deposition, alkaline phosphatase (AP) and matrix metalloproteinase (MMP)-13 mRNA levels (p < 0.05), and AP activity following RA stimulation, compared to mock transfected controls. Using AP as a differentiation marker we then investigated the mechanism of F-spondin promaturation effects. Blocking endogenous F-spondin via its thrombospondin (TSR) domain inhibited RA induced AP activity 40% compared to controls (p < 0.05). The stimulatory effect of F-spondin on AP expression was also inhibited following depletion of TGF-beta from culture supernatants. Our findings indicate that F-spondin is expressed in embryonic cartilage, where it has the capacity to enhance chondrocyte terminal differentiation and mineralization via interactions in its TSR domain and TGF-beta dependent pathways. PMID- 20839319 TI - Long bone fracture repair in mice harboring GFP reporters for cells within the osteoblastic lineage. AB - GFP reporter mice previously developed to assess levels of osteoblast differentiation were employed in a tibial long bone fracture model using a histological method that preserves fluorescent signals in non-decalcified sections of bone. Two reporters, based on Col1A1 (Col3.6GFPcyan) and osteocalcin (OcGFPtpz) promoter fragments, were bred into the same mice to reflect an early and late stage of osteoblast differentiation. Three observations were apparent from this examination. First, the osteoprogenitor cells that arise from the flanking periosteum proliferate and progress to fill the fracture zone. These cells differentiate to osteoblasts, chondrocytes, to from the outer cortical shell. Second, the hypertrophic chondrocytes are dispersed and the cartilage matrix mineralized by the advancing Col3.6+ osteoblasts. The endochondral matrix is removed by the following osteoclasts. Third, a new cortical shell develops over the cartilage core and undergoes a remodeling process of bone formation on the inner surface and resorption on the outer surface. The original fractured cortex undergoes resorption as the outer cortical shell remodels inward to become the new diaphyseal bone. The fluorescent microscopy and GFP reporter mice used in this study provide a powerful tool for appreciating the molecular and cellular processes that control these fundamental steps in fracture repair, and may provide a basis for understanding fracture nonunion. PMID- 20839320 TI - Decreased knee adduction moment does not guarantee decreased medial contact force during gait. AB - Excessive contact force is believed to contribute to the development of medial compartment knee osteoarthritis. The external knee adduction moment (KAM) has been identified as a surrogate measure for medial contact force during gait, with an abnormally large peak value being linked to increased pain and rate of disease progression. This study used in vivo gait data collected from a subject with a force-measuring knee implant to assess whether KAM decreases accurately predict corresponding decreases in medial contact force. Changes in both quantities generated via gait modification were analyzed statistically relative to the subject's normal gait. The two gait modifications were a "medial thrust" gait involving knee medialization during stance phase and a "walking pole" gait involving use of bilateral walking poles. Reductions in the first (largest) peak of the KAM (32-33%) did not correspond to reductions in the first peak of the medial contact force. In contrast, reductions in the second peak and angular impulse of the KAM (15-47%) corresponded to reductions in the second peak and impulse of the medial contact force (12-42%). Calculated reductions in both KAM peaks were highly sensitive to rotation of the shank reference frame about the superior-inferior axis of the shank. Both peaks of medial contact force were best predicted by a combination of peak values of the external KAM and peak absolute values of the external knee flexion moment (R(2) = 0.93). Future studies that evaluate the effectiveness of gait modifications for offloading the medial compartment of the knee should consider the combined effect of these two knee moments. PMID- 20839321 TI - Efficacy of moxifloxacin compared to teicoplanin in the treatment of implant related chronic osteomyelitis in rats. AB - Treatment of implant-related chronic osteomyelitis is often difficult and usually consists of implant removal, extensive surgical debridement, and prolonged antibiotic use. This study was performed to assess the efficacy of moxifloxacin compared to a glycopeptide, teicoplanin in chronic implant-related methicillin sensitive Staphylococcus aureus (MSSA) osteomyelitis. The left femoral medullar cavities of 60 Wistar male rats were contaminated with 100 ul of 10(8) cfu/ml methicillin-sensitive S. aureus (ATCC 29213) and Kirschner wires were placed into the medulla of the femur. After 6 weeks, rats were randomly divided into five groups. In two groups, the Kirschner wires were removed. Experimental groups were as follows: group 1: contaminated, Kirschner wire inside, received teicoplanin; group 2: contaminated, Kirschner wire removed, received teicoplanin; group 3: contaminated, Kirschner wire inside, received moxifloxacin; group 4: contaminated, Kirschner wire removed, received moxifloxacin; group 5: contaminated, Kirschner wire inside, no antibiotics (control group). Groups 1 and 2 received teicoplanin (20 mg/kg once daily), whereas groups 3 and 4 received moxifloxacin (10 mg/kg twice daily) intraperitoneally for 28 days. At the end of the treatment, animals were sacrificed by inhalation anesthesia with ether and femora were retrieved and bacterial counts (cfu/g) were determined. Bacterial counts in all study groups were significantly reduced relative to the control. The decrease of bacterial counts was more prominent in group 4 compared to group 1 (p = 0.001) and group 2 (p = 0.003). Moxifloxacin therapy is an effective alternative to teicoplanin for chronic implant-related MSSA osteomyelitis. PMID- 20839326 TI - MMP-2 contributes to the development of the mouse ventral prostate by impacting epithelial growth and morphogenesis. AB - Epithelial growth, branching, and canalization are important morphogenetic events of the rodent ventral prostate (VP) that take place during the first postnatal week. In this study, we evaluated the effect of knocking out MMP-2 (MMP-2(-/-)), by examining developmental and structural aspects of the VP in MMP-2(-/-) mice. Neonate (day 6) MMP-2(-/-) mice showed fewer epithelial tips, a lower epithelial cell proliferation rate, and also reticulin fiber accumulation. The VP of adult MMP-2(-/-) mice showed lower relative weight, smaller epithelial and smooth muscle cell volume, and a larger amount of thicker reticulin fibers. No differences in cell proliferation or apoptotic index were noted between adult MMP 2(-/-) and wild-type mice. MMP-9 was found in the adult MMP-2(-/-), but not in the wild-type. In conclusion, MMP-2 function is essential for the epithelial morphogenesis of the mouse VP, and expression of MMP-9 is not sufficient for acquisition of the normal adult histology. PMID- 20839322 TI - Cycle-dependent matrix remodeling gene expression response in fatigue-loaded rat patellar tendons. AB - Expression profiling of selected matrix remodeling genes was conducted to evaluate differences in molecular response to low-cycle (100) and high-cycle (7,200) sub-failure-fatigue loading of patellar tendons. Using our previously developed in vivo patellar tendon model, tendons were loaded for 100 or 7,200 cycles and expression of selected metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and collagens were quantified by real-time RT-PCR at 1- and 7-day post-loading. Expression profiles were also obtained from lacerated tendons as an acute injury model. The high-cycle group showed upregulation of TIMP-1, -2, Col3a1, and Col5a1, and downregulation TIMP-4 at both time points, upregulation of MMP-2 at 7-day post-loading and downregulation of MMP-13 and -14 at 1-day post-loading, suggesting overall repair/remodeling. In contrast, the low cycle loaded group showed upregulation of MMP-2, -3, -13, and Col12a1 at both time points, upregulation of TIMP-1, -2, -3, Col3a1, and integrin beta1 and downregulation of integrin alpha11 at 1-day post-loading and upregulation of Col1a1 at 7-day post-loading, consistent with a hypertrophic (adaptive) pattern. Lacerated tendons showed a typical acute wound response with upregulation of all examined remodeling genes. Differences found in tendon response to high- and low cycle loading are suggestive of the underlying mechanisms associated with a healthy or damaging response. PMID- 20839327 TI - Neuron-specific expression of atp6v0c2 in zebrafish CNS. AB - Vacuolar ATPase (V-ATPase) is a multi-subunit enzyme that plays an important role in the acidification of a variety of intracellular compartments. ATP6V0C is subunit c of the V(0) domain that forms the proteolipid pore of the enzyme. In the present study, we investigated the neuron-specific expression of atp6v0c2, a novel isoform of the V-ATPase c-subunit, during the development of the zebrafish CNS. Zebrafish atp6v0c2 was isolated from a genome-wide analysis of the zebrafish mib(ta52b) mutant designed to identify genes differentially regulated by Notch signaling. Whole-mount in situ hybridization revealed that atp6v0c2 is expressed in a subset of CNS neurons beginning several hours after the emergence of post mitotic neurons. The ATP6V0C2 protein is co-localized with the presynaptic vesicle marker, SV2, suggesting that it is involved in neurotransmitter storage and/or secretion in neurons. In addition, the loss-of-function experiment suggests that ATP6V0C2 is involved in the control of neuronal excitability. PMID- 20839329 TI - Introduction to the MBL supplement: a tribute to Gerald Marti. PMID- 20839331 TI - A computer simulation for exploring the detection of monoclonal B-cell lymphocytosis by flow cytometry. AB - BACKGROUND: Monoclonal B-cell lymphocytosis (MBL) is defined by the presence of monoclonal B-cells in peripheral blood in the absence of hematologic disease. MBL is detected by flow cytometry with increasing frequency as the number of B-cells acquired increases. METHODS: Computer simulations in R language were used to examine the impact of increasing the number of B-cells acquired on the sensitivity of detecting MBL and to explore the possibility of detecting distinct B-cell clones among polyclonal B-cell populations. RESULTS: With simulated populations containing 0.1%-1.0% monoclonal B-cells, the number of clonal B-cells detected showed a normal distribution in the upper range of clonal cells acquired and more nearly log-normal as the distributions became bounded by 0. The distributions peaked around the clonal prevalence. The detection of MBL increased sharply with a small increase in the total number of B-cells acquired when the number of clonal cells acquired was near the MBL cutoff point. MBL could be detected in log-normally distributed polyclonal B-cell populations. CONCLUSIONS: Sampling variability in detecting monoclonal B-cells can be investigated through simulation. The observed population prevalence of MBL can be approximated with reasonable assumptions about the distribution of clonotypes in the circulating B cell compartment. PMID- 20839330 TI - Prevalence of monoclonal B-cell lymphocytosis: a systematic review. AB - BACKGROUND: Individuals with monoclonal B-cell lymphocytosis (MBL) have been identified in clinic outpatients, in unaffected relatives of patients with chronic lymphocytic leukemia (CLL), and in general populations. MBL and its relationship with CLL have been actively investigated over the last decade. This report systematically reviews the prevalence of MBL in the context of the populations studied and the evolution of laboratory methods used to define MBL. METHODS: To identify published studies that have assessed the prevalence of MBL, we systematically searched the MEDLINE databases and consulted with members of the International MBL Study Group. We reviewed the 10 articles that were identified by this process. We abstracted information on study populations, laboratory tests, criteria for designating MBL, and the reported frequencies. RESULTS: Three of the ten studies were published in 2009, three between 2007 and 2008, and four between 2002 and 2004. Reported prevalences varied widely, ranging from 0.12 to 18.2%. This variability was clearly associated with both the laboratory methods and the populations studied. MBL was more common among older individuals and kindred of persons with CLL. The most common MBL subtype was CLL like MBL. CONCLUSIONS: Large population-based studies of MBL that employ standardized laboratory methods with a consensus case definition are needed to assess prevalence and establish risk factors. These studies should include prospective follow-up of MBL cases to determine the relationship between MBL and CLL. Data from original studies should be reported in sufficient detail to allow future synthesis of information from multiple studies, such as meta-analysis. PMID- 20839332 TI - Monoclonal B cell lymphocytosis: clinical and population perspectives. AB - Monoclonal B Cell Lymphocytosis (MBL) refers to clones of CLL-like cells that exhibit CLL characteristics that fall short of the numbers required for CLL diagnosis. Data from large CLL kindreds document increased prevalence of MBL suggesting a genetic contribution to its etiology. The molecular features that favor progression of MBL to CLL are poorly understood but an elevated B-cell count is a risk factor for progression. An important consideration when evaluating volunteers from CLL families who are willing to donate bone marrow is that MBL be ruled out since the MBL donor clone could result in a second CLL in the recipient. Further studies of MBL are needed to identify the molecular features and how they evolve during progression. PMID- 20839333 TI - Different biology and clinical outcome according to the absolute numbers of clonal B-cells in monoclonal B-cell lymphocytosis (MBL). AB - The biological and clinical relationship between Chronic Lymphocytic Leukaemia (CLL) and Monoclonal B-cell Lymphocytosis (MBL) has now been reported in some detail. This review investigates associations between biology and disease activity as they relate to the absolute numbers of abnormal cells. The clonal B cells in CLL-type MBL are indistinguishable from CLL with respect to surface phenotype and the presence of chromosomal abnormalities. However, the majority of CLL-type MBL cases in the general population have very low numbers of clonal B cells, typically in the range 0.1-10 per MUL, and such cases use different IGHV genes than higher-count CLL-type MBL cases and often show intraclonal heterogeneity. Cases with higher counts are biologically similar to CLL although there is a relationship between the CLL cell count at presentation and the likelihood of further clonal expansion. Individuals presenting with CLL cell counts above 2,000 per MUL are more likely to have gradually increasing B-cell counts over time and although the risk of requiring treatment for progressive CLL remains low there may be impaired normal B-cell activity. PMID- 20839334 TI - A special supplement issue on MBL: why? PMID- 20839335 TI - Non-CLL-like monoclonal B-cell lymphocytosis in the general population: prevalence and phenotypic/genetic characteristics. AB - BACKGROUND: Monoclonal B-cell lymphocytosis (MBL) indicates <5 * 10(9) peripheral blood (PB) clonal B-cells/L in healthy individuals. In most cases, MBL cells show similar phenotypic/genetic features to chronic lymphocytic leukemia cells-CLL like MBL-but little is known about non-CLL-like MBL. METHODS: PB samples from 639 healthy individuals (46% men/54% women) >40 years old (62 +/- 13 years) with normal lymphocyte counts (2.1 +/- 0.7 * 10(9)/L) were immunophenotyped using high sensitive flow cytometry, based on 8-color stainings and the screening for >5 * 10(6) total PB leukocytes. RESULTS: Thirteen subjects (2.0%; 9 males/4 females, aged 73 +/- 10 years; absolute lymphocyte count: 2.4 +/- 0.8 * 10(9)/L) showed a non-CLL-like clonal B-cell population, whose frequency clearly increased with age: 0.4%, 3%, and 5.4% of subjects aged 40-59, 60-79, and >=80 years, respectively. One single B-cell clone was detected in 9/13 cases, while two B cell clones were found in 4/13 (n = 17 MBL populations). Nine MBL cell populations showed a CD5(-) phenotype (usually overlapping with marginal zone derived (MZL) or lymphoplasmacytic (LPL) non-Hodgkin lymphoma (NHL) B-cells, or an unclassifiable NHL), but CD5(-/+d) (n = 3) and CD5(+) (n = 3 non-CLL-like MBL, consistent with a mantle-cell lymphoma (MCL)-like phenotype, and n = 2 CLL-like) MBL were also identified; iFISH supported the diagnosis in most cases. No preferential IGHV usage of B-cell receptor could be found. Twelve cases reevaluated at month +12 showed circulating clonal B-cells, at mean levels significantly higher than those initially detected. CONCLUSIONS: Non-CLL-like MBL cases frequently show biclonality, in association with MZL-, LPL-, MCL-like, or unclassifiable phenotypic profiles. As with CLL-like MBL, the frequency of non CLL-like MBL increases with age, with a clear predominance of males. PMID- 20839336 TI - Commentary: Comparison of current flow cytometry methods for monoclonal B cell lymphocytosis detection. AB - Monoclonal B cell lymphocytosis (MBL) is now recognized as the B-lymphocyte analogue of a monoclonal gammopathy of unknown significance. MBL can be the precursor of chronic lymphocytic leukemia or associated with non-Hodgkin's lymphoma. It may be associated with an autoimmune abnormality or be related to aging (immunosenescence). The combination of available new fluorochrome conjugated monoclonal antibody reagents, multilaser instrumentation, and improved software tools have led to a new level of multicolor analysis of MBL. Presently, several centers, including the University of Salamanca (Spain), Duke University (Durham, NC), Mayo Clinic (Rochester, MN), and the National Cancer Institute (Bethesda, MD) in conjunction with the Genetics and Epidemiology of Familial chronic lymphocytic leukemia Consortium, the Food and Drug Administration (Bethesda, MD), and the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry (Atlanta, GA) in collaboration with Saint Luke's Hospital (Kansas City, MO), the Universita Vita-Salute San Raffaele in Milan (Italy), and Leeds Teaching Hospital (UK) are all actively conducting studies on MBL. This commentary is an updated summary of the current methods used in these centers. It is important to note the diversity of use in reagents, instruments, and methods of analysis. Despite this diversity, there is a consensus in what constitutes the diagnosis of MBL and its subtypes. There is also an emerging consensus on what the next investigative steps should be. PMID- 20839337 TI - Chronic lymphocytic leukaemia (CLL) and CLL-type monoclonal B-cell lymphocytosis (MBL) show differential expression of molecules involved in lymphoid tissue homing. AB - INTRODUCTION: The aim of this study was to screen for cell surface markers that could discriminate CLL-type MBL from CLL or identify CLL cases likely to have stable disease. METHODS: Six color flow cytometry was performed on CLL-type MBL (n = 94) and CLL (n = 387) at diagnosis or relapse; 39 cases had poor-risk chromosomal abnormalities (17p and/or 11q deletion). Expression of 30 markers was analysed: CCR6, CD10, CD103, CD11c, CD138, CD200, CD22, CD23, CD24, CD25, CD27, CD31, CD38, CD39, CD43, CD49d, CD5, CD52, CD62L, CD63, CD79b, CD81, CD86, CD95, CXCR5, HLADR, IgD, IgG, IgM, LAIR1. RESULTS: There was no difference in expression between CLL-type MBL and CLL for the majority of markers. Differential expression was observed for several markers, mainly between MBL and CLL cases with adverse-risk chromosomal abnormalities. These differences included lower expression of CD38 (9.4-fold lower, P = 0.007) and CD49d (3.2-fold lower, P = 0.008) and higher expression of LAIR-1 (3.7-fold higher, P = 0.003), CXCR5 (1.25 fold higher, P = 0.002), and CCR6 (1.9-fold higher P < 0.001) on CLL-type MBL compared to CLL with adverse chromosomal abnormalities. CD62L (L-selectin) which mediates lymphocyte adhesion to endothelial venules of lymphoid tissue, was expressed at a significantly different level between CLL-type MBL and both CLL sub-groups, with 1.3-fold lower (P = 0.04) expression levels on the MBL cases. However, there was broad overlap in expression levels. CONCLUSIONS: CLL-type MBL is phenotypically identical to CLL for a very broad range of markers. Differential expression is predominantly related to known prognostic markers and proteins involved in homing to lymphoid tissue. PMID- 20839338 TI - Human peripheral blood B-cell compartments: a crossroad in B-cell traffic. AB - A relatively high number of different subsets of B-cells are generated through the differentiation of early B-cell precursors into mature B-lymphocytes in the bone marrow (BM) and antigen-triggered maturation of germinal center B-cells into memory B-lymphocytes and plasmablasts in lymphoid tissues. These B-cell subpopulations, which are produced in the BM and lymphoid tissues, recirculate through peripheral blood (PB), into different tissues including mucosa and the BM, where long-living plasma cells produce antibodies. These circulating PB B cells can be classified according to their maturation stage into i) immature/transitional, ii) naive, and iii) memory B-lymphocytes, and iv) plasmablasts/plasma cells. Additionally, unique subsets of memory B-lymphocytes and plasmablasts/plasma cells can be identified based on their differential expression of unique Ig-heavy chain isotypes (e.g.: IgM, IgD, IgG, IgA). In the present paper, we review recent data reported in the literature about the distribution, immunophenotypic and functional characteristics of these cell subpopulations, as well as their distribution in PB according to age and seasonal changes. Additional information is also provided in this regard based on the study of a population-based cohort of 600 healthy adults aged from 20 to 80 years, recruited in the Salamanca area in western Spain. Detailed knowledge of the distribution and traffic of B-cell subsets through PB mirrors the immune status of an individual subject and it may also contribute to a better understanding of B-cell disorders related to B-cell biology and homeostasis, such as monoclonal B-cell lymphocytosis (MBL). PMID- 20839339 TI - Monoclonal B cell lymphocytosis in hepatitis C virus infected individuals. AB - BACKGROUND: Monoclonal B cell lymphocytosis (MBL) is a preclinical condition characterized by an expansion of clonal B cells in the absence of B lymphocytosis (BALC < 5 * 10(9)/L) in the peripheral blood, without clinical signs, suggestive of a lymphoproliferative disorder. B cell clonal expansions are also associated with hepatitis C virus (HCV) infection and they can evolve into lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphomas (NHL). The relationship between MBL and HCV infection has not been established yet. METHODS: By five-colour flow cytometry, we analyzed 123 HCV positive subjects with diagnosis of chronic hepatitis (94) or cirrhosis (29); 16 of those with cirrhosis had a diagnosis of hepatocellular carcinoma. RESULTS: MBL were identified in 35/123 (28.5%), at significantly higher frequency than in the general population. Sixteen/thirty-five were atypical-chronic lymphocytic leukemia (CLL) MBL (CD5(+), CD20(bright)), 13/35 were CLL-like MBL (CD5(bright), CD20(dim)), and 6/35 were CD5(-) MBL. Twenty-four/ninety-four (25.5%) patients affected by chronic hepatitis had MBL, whereas 11/29 (37.9%) patients with cirrhosis showed a B cell clone. A biased usage of IGHVgenes similar to HCV associated NHL was evident. CONCLUSIONS: All three types of MBL can be identified in HCV-infected individuals at a higher frequency than in the general population, and their presence appears to correlate with a more advanced disease stage. The phenotypic heterogeneity is reminiscent of the diversity of NHL arising in the context of HCV infection. The persistence of HCV may be responsible for the dysregulation of the immune system and in particular of the B cell compartment. PMID- 20839341 TI - Long-term follow-up of monoclonal B-cell lymphocytosis detected in environmental health studies. AB - BACKGROUND: Four individuals in whom Monoclonal B cell Lymphocytosis (MBL) had been previously detected were evaluated for the fourth time after 15-18 years since initial testing. All four were environmental health study participants without hematologic malignancies who had elevated absolute B cell counts at initial testing. METHODS: The current laboratory evaluation included complete blood counts, lymphocyte immunophenotypes, immunoglobulin heavy-chain variable (IGHV) gene mutation status, and serum tests for monoclonal immunoglobulins and free light chains. Results from this evaluation were compared with those from the three previous evaluations. Clinical status was assessed by reviewing medical records. RESULTS: B-cell clones with phenotypic characteristics of the original MBL clone were detected in three of the four individuals. Since the last evaluation in 2003, one participant who had a clinical diagnosis of Waldenstrom's Macroglobulinemia had developed a diffuse large cell lymphoma and was treated. Another participant continued to show a decline in lymphocyte and B cell counts, reaching clinical lymphocytopenia and B cell lymphopenia. The MBL clone was still detectable. The remaining two participants had stable blood counts and MBL phenotypes. Neither had been diagnosed with a hematologic malignancy. However, molecular analysis revealed clonal changes in both: one showed a marked decline in the percentage of somatically-mutated B cells, and the other showed a clonal transition from IGHV3-13 to IGHV4-34. CONCLUSIONS: A diversity of clonal evolution was observed in these MBL cases. These observations suggest that long term follow-up studies using standardized MBL subcategories are essential to understanding B-cell pathobiology and optimizing clinical management. PMID- 20839340 TI - Elucidation of seventeen human peripheral blood B-cell subsets and quantification of the tetanus response using a density-based method for the automated identification of cell populations in multidimensional flow cytometry data. AB - BACKGROUND: Advances in multiparameter flow cytometry (FCM) now allow for the independent detection of larger numbers of fluorochromes on individual cells, generating data with increasingly higher dimensionality. The increased complexity of these data has made it difficult to identify cell populations from high dimensional FCM data using traditional manual gating strategies based on single color or two-color displays. METHODS: To address this challenge, we developed a novel program, FLOCK (FLOw Clustering without K), that uses a density-based clustering approach to algorithmically identify biologically relevant cell populations from multiple samples in an unbiased fashion, thereby eliminating operator-dependent variability. RESULTS: FLOCK was used to objectively identify seventeen distinct B-cell subsets in a human peripheral blood sample and to identify and quantify novel plasmablast subsets responding transiently to tetanus and other vaccinations in peripheral blood. FLOCK has been implemented in the publically available Immunology Database and Analysis Portal-ImmPort (http://www.immport.org)-for open use by the immunology research community. CONCLUSIONS: FLOCK is able to identify cell subsets in experiments that use multiparameter FCM through an objective, automated computational approach. The use of algorithms like FLOCK for FCM data analysis obviates the need for subjective and labor-intensive manual gating to identify and quantify cell subsets. Novel populations identified by these computational approaches can serve as hypotheses for further experimental study. PMID- 20839342 TI - Prevalence, clinical aspects, and natural history of IgM MGUS. AB - BACKGROUND: Waldenstrom macroglobulinemia (WM) and chronic lymphocytic leukemia (CLL) are related B-cell cancers that share several clinical and biological features. Both WM and CLL have associated precursor conditions: monoclonal gammopathy of undetermined significance (MGUS) of immunoglobulin M (IgM) type and monoclonal B-cell lymphocytosis (MBL), respectively. Recently, a case of MBL with an IgM MGUS was reported, suggesting a close biological relationship between these entities. While much is known about MGUS overall, investigations of IgM MGUS specifically have been fragmentary. METHODS: In this article, we review data on the prevalence, clinical aspects and natural history of IgM MGUS, and focus on identifying gaps in our understanding of the complex relationships among B-cell malignancies and their precursors. RESULTS: There appears to be marked heterogeneity in the prevalence of IgM MGUS across populations. However, studies have varied in definition, design, laboratory methods, and endpoints. IgM MGUS differs from non-IgM MGUS in certain respects, including prevalence across racial groups, rate of progression, and pattern of malignant outcomes. There are limited data regarding the coincident occurrence of IgM MGUS and MBL. CONCLUSIONS: Future studies incorporating both protein electrophoresis and flow cytometry are needed to define the underlying spectrum and causes of precursor development, risk factors for progression, and markers that distinguish low- and high-risk precursor patients. PMID- 20839343 TI - The New Zealand black mouse as a model for the development and progression of chronic lymphocytic leukemia. AB - BACKGROUND: Similar to a subset of human patients who progress from monoclonal B lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL), New Zealand Black (NZB) mice have an age-associated progression to CLL. The murine disease is linked to a genetic abnormality in microRNA mir-15a/16-1 locus, resulting in decreased mature miR-15a/16. METHODS: Spleens of aging NZB were analyzed for the presence of B-1 cells via flow cytometry and for the presence of a side population (SP) via the ability of cells to exclude Hoechst 33342 dye. The SP was assayed for the presence of hyperdiploid B-1 clones and for the ability to differentiate into B-1 cells in vitro and transfer disease in vivo. In addition, enhanced apoptosis of chemoresistant NZB B-1 cells was examined by restoring miR 16 levels in nutlin-treated cells. RESULTS: Aging NZB mice develop a B-1 expansion and clonal development that evolves from MBL into CLL. An expansion in SP is also seen. Although the SP did contain increased cells with stem cell markers, they lacked malignant B-1 cells and did not transfer disease in vivo. Similar to B-1 cells, splenic NZB SP also has decreased miR-15a/16 when compared with C57Bl/6. Exogenous addition of miR-15a/16 to NZB B-1 cells resulted in increased sensitivity to nutlin. CONCLUSION: NZB serve as an excellent model for studying the development and progression of age-associated CLL. NZB SP cells do not seem to contain cancer stem cells, but rather the B-1 stem cell. NZB B-1 chemoresistance may be related to reduced miR-15a/16 expression. PMID- 20839344 TI - Orbital atherectomy for symptomatic lower extremity disease. AB - BACKGROUND: Plaque-debulking technologies have been proposed as alternative treatment options for peripheral arterial disease. Orbital atherectomy (OA), using the DiamondBack360 device, has emerged as one promising modality. METHODS: We evaluated the safety and efficacy of OA in the first 200 lesions treated at our institution. Patient demographics, clinical characteristics, and lesion and procedural variables were collected and analyzed. The primary safety endpoint was the 30-day major adverse events (MAE), including death, myocardial infarction, stroke, unplanned amputation, or target lesion revascularization. Other safety endpoints included access-site complications, occurrence of dissections, perforations, distal embolization, spasm, and hemolysis. The efficacy endpoints were procedural success, need for adjunctive therapy, and improvement in ankle brachial index. Multivariate analysis was performed to find independent predictors of the safety endpoints. RESULTS: One hundred seventeen (58.5%) lesions were femoral, 31 (15.5%) were popliteal, and 52 (26.0%) were tibial. The procedural success (residual stenosis <=30%) was comparable between the femoral and tibial lesions (86.3% vs. 92.5%, P = 0.18), but significantly lower for the popliteal lesions when compared with femoral and tibial (64.7% vs. 86.3%, P = 0.058, and 64.7% vs. 92.5%, P = 0.007 respectively). MAE at 30-days occurred in 3 (2.2%) procedures, and major access-site complications also occurred in 3 (2.2%). There were 31 (15.5%) dissections; independent predictors were diabetes mellitus (OR: 7.3, P = 0.008), crown-to-RVD ratio <0.6 (OR: 11.6, P = 0.005), and atherectomy time >360 sec (OR: 11.8, P = 0.001). There were 2 (1.0%) distal embolizations, 6 (3.0%) arterial spasms, and no perforations. Laboratory evidence of hemolysis was noted in 33.8% of cases. CONCLUSION: Orbital atherectomy allows for a significant procedural success, limited need for stenting, and favorable safety profile. PMID- 20839345 TI - Angioplasty of ulnar or radial arteries to treat critical hand ischemia: use of 3 and 4-French systems. AB - OBJECTIVES: The aim of this preliminary study is to report the results of catheter-based treatment for isolated distal upper extremity artery disease with CHI. BACKGROUND: Critical hand ischemia (CHI) is a rare but potentially devastating condition. METHODS: The study consisted of five critically ischemic hands (Rutherford category 4: 2, Rutherford category 5: 3) in four patients undergoing catheter intervention for isolated distal upper extremity artery disease between November 2007 and April 2009. RESULTS: Balloon angioplasty via an antegrade brachial approach was performed with a 3Fr or 4Fr sheath to achieve the principal endpoint of the establishment of one straight-line flow to the palmar arch. All patients had end-stage renal disease requiring chronic hemodialysis. The target vessels were the ulnar artery in four cases, the radial artery in one, and the palmar arch in two. Four cases had a stenotic lesion and one had chronic total occlusion. Technical success was achieved in all cases without complications, and skin perfusion pressure of the hand improved significantly from 39 +/- 20 to 52 +/- 16 (P = 0.019) on the palmar side and from 40 +/- 18 to 60 +/- 29 on the dorsal side (P = 0.046). Clinical success was achieved in all cases during a mean follow-up period of 11 +/- 8 (2-19) months. CONCLUSIONS: Percutaneous angioplasty using contemporary dedicated devices could be a potentially useful option for CHI patients with isolated distal upper extremity artery disease. PMID- 20839346 TI - Small tools for small arteries. PMID- 20839347 TI - "Stressed in ......... stressed out" coronary arteries. PMID- 20839348 TI - Reproducibility of near-infrared spectroscopy for the detection of lipid core coronary plaques and observed changes after coronary stent implantation. AB - OBJECTIVES: To evaluate the reproducibility of catheter-based intracoronary near infrared spectroscopy (NIRS) for the detection of lipid core coronary plaques (LCPs) and to examine stenting-induced changes in NIRS findings. BACKGROUND: The in-vivo reproducibility of coronary NIRS findings and their changes after stenting have not previously been characterized. METHODS: NIRS assessment using an automated pullback catheter was performed in duplicate in 36 vessels in 31 patients. The reproducibility of the Lipid Core Burden Index (LCBI) and the presence and number of LCPs was assessed. The changes in LCBI after stenting were also assessed in 25 vessels in 22 patients. RESULTS: LCBI of the first and second pullback was 64 +/- 43 and 70 +/- 62, respectively, with excellent correlation (Spearman's rho 0.927, intraclass correlation coefficient 0.925). Depending on LCP definition, mean LCP length, and median LCP number ranged from 2.44 to 17.25 mm, and from 0 to 2, respectively per artery studied. High correlation was observed between the two pullbacks for total LCP length (depending on the LCP definition used, the Spearman's rho and the intraclass correlation coefficient ranged from 0.72 to 0.89, and from 0.76 to 0.91, respectively) and for LCP number (depending on the LCP definition used, the Spearman's rho and the intraclass correlation coefficient ranged from 0.70 to 0.87, and from 0.67 to 0.88, respectively). The mean LCBI decreased by 40% from 78 +/- 47 to 48 +/- 38 after stenting (P < 0.001). CONCLUSION: The LCBI and LCP length NIRS measurements have high reproducibility. LCBI significantly decreases after coronary stenting. PMID- 20839349 TI - Rotational atherectomy in resistant chronic total occlusions. AB - OBJECTIVES: To assess the application of rotational atherectomy to improving the success rate of percutaneous recanalization of chronic total occlusion (CTO). BACKGROUND: Although the inability to cross the occlusion with a guidewire is the reason for failure in the majority of cases, one of the most frustrating situations that may occur during a recanalization procedure is when a guidewire crosses successfully but it is impossible to advance any device over the wire through the occluded segment. METHODS: From January 2006 to October 2009, 45/648 (7%) consecutive patients with CTO resistant to recanalization by conventional techniques were treated by high-speed rotational atherectomy (Rotablator group). RESULTS: All but two lesions were successfully crossed by Rotablator and eventually treated by stent implantation. As compared to the 603 CTO treated by conventional techniques (Conventional group), the 45 patients in the Rotablator group were older, more often female, active smokers, with chronic kidney disease and higher rate of previous surgical revascularization. The CTO in the Rotablator group had a longer duration. Peri-procedural myocardial infarction was more frequent in the Rotablator group (35% vs. 22%; P = 0.044). Coronary perforation occurred only in three patients in the Conventional group and two of these patients needed urgent surgical intervention. No patient died from either group. CONCLUSIONS: The inability to cross a CTO with a balloon catheter occurs in approximately 7% of all CTOs that are successfully crossed with a guidewire. Rotational atherectomy is a safe and effective technique to overcome this frustrating situation. PMID- 20839350 TI - Rotational atherectomy for resistant chronic total occlusions: another spin for tough old problems. PMID- 20839351 TI - A comparative analysis of major clinical outcomes using drug-eluting stents versus bare-metal stents in a large consecutive patient cohort. AB - OBJECTIVES: To ascertain the long-term safety, efficacy, and pattern of use of drug-eluting stents (DES) in routine clinical practice. METHODS: We analyzed a registry of 6,583 consecutive patients undergoing percutaneous coronary intervention (PCI), of whom 2,633 were treated using DES (DES group) and 3,950 were treated using bare-metal stents (BMS group). Propensity score was used for stratified analysis of outcomes and for matching. Outcomes were total mortality, myocardial infarction (MI), repeat target vessel revascularization (TVR) rates, and risk-adjusted event-free survival. RESULTS: Follow-up time was 6 months to 5.18 years (mean: 3 years). Patients in the DES group were more likely to be diabetic and had use of longer or more stents, treatment of more lesions and of more proximal main vessels. After propensity score matching, the cumulative mortality was 12.85% in the DES group versus 14.14% in the BMS group (P = 0.001). Use of DES reduced the occurrence of MI (5.17% vs.5.83%, P = 0.046), of clinically driven TVR (9.76% vs. 12.28%, P < 0.001) and of the composite endpoint of death/MI/TVR (23.38% vs. 26.07%; P < 0.001). CONCLUSIONS: Our risk-adjusted event-free survival analysis indicates a prognostic benefit for DES utilization that sustains up to 5 years following PCI. PMID- 20839352 TI - The Holy Grail for DES: does efficacy translate into real world effectiveness? PMID- 20839353 TI - Hand ischemia resulting from a transradial intervention: successful management with radial artery angioplasty. AB - We describe a case of hand ischemia resulting from transradial catheterization. This was successfully treated with angioplasty of the radial artery occlusion, but stresses the importance of a preprocedure evaluation of the dual blood supply to the hand before transradial access. PMID- 20839354 TI - A big challenge to radialists. PMID- 20839355 TI - Use of the Stingray guidewire and the Venture catheter for crossing flush coronary chronic total occlusions due to in-stent restenosis. AB - We report two cases of flush chronic total occlusion due to in-stent restenosis, in which percutaneous coronary intervention attempts via over-the-wire balloons and microcatheters failed to cross the lesion. Using the Venture catheter for support and the Stingray guidewire for enhanced penetration capacity, both lesions were successfully crossed and stented. PMID- 20839356 TI - Optimization of drug-eluting balloon use for safety and efficacy: evaluation of the 2nd generation paclitaxel-eluting DIOR-balloon in porcine coronary arteries. AB - OBJECTIVES: The aim of this preclinical study was to optimize the use of drug eluting balloon (DEB) DIOR(2nd) (generation) by measurements of tissue and plasma paclitaxel concentrations in porcine coronary artery overstretch and prove efficacy in inhibition of neointimal growth without complementary use of stent. BACKGROUND: The usually recommended DEB 60 sec inflation time causes prolonged ischemia and arterial injury. METHODS: Tissue, plasma, and balloon surface concentrations of paclitaxel were measured in pigs 45 min and 12 hr after balloon inflation times of 15, 20, 30, 45, and 60 sec. Extent of neointimal hyperplasia was compared using DIOR(2nd) (generation) or noncoated balloon at two-week follow up. Paclitaxel was replaced by fluorescent paclitaxel derivative in DEB and DES to demonstrate the distribution of the drug in arterial wall. RESULTS: DIOR(2nd) (generation) DEB provided 29 +/- 3 MUM/L, 52 +/- 6 MUM/L, 196 +/- 44 MUM/L, 202 +/- 36 MUM/L, and 184 +/- 59 MUM/L paclitaxel to the vessel wall after 15, 20, 30, 45, and 60 sec of dilation, reaching plateau at 30 sec inflation time. Paclitaxel penetrated up to 2 mm tissue deepness. Measurable plasma paclitaxel level (45 +/- 28 ng/mL) was found only after 60 sec balloon inflation time. At follow-up, the dilated arterial segment neointimal area and maximal neointimal thickness were significantly smaller with DIOR vs. uncoated balloon use. Fluorescence images of DIOR showed a homogenous distribution of the drug on the vessel, in contrast with DES. CONCLUSION: Using the DIOR(2nd) (generation) DEB, a maximal balloon inflation time of 30-45 sec is optimal, reducing effectively the neointimal hyperplasia. PMID- 20839357 TI - Lung perfusion studies after transcatheter closure of persistent ductus arteriosus with the Amplatzer duct occluder. AB - BACKGROUND: Reduced left lung perfusion has been described after transcatheter closure of the patent ductus arteriosus (PDA) with several prostheses. Although the Amplatzer ductal occluder (ADO) device is currently the most widely used occluder for closure of large-sized PDAs, the potential consequences of flow distribution to the lungs of this device have not been completely clarified. We evaluated lung perfusion following occlusion of PDA with the ADO device. METHODS: Forty-seven patients underwent successful transcatheter PDA occlusion using the ADO device were included in this study. Lung perfusion scans were performed 6 months after the procedure. RESULTS: Decreased perfusion to the left lung (defined as < 40% of total lung flow) was observed in 17 patients (36%), 5 of whom were low-weight symptomatic infants. Ductal ampulla length was significantly shorter and minimal ductal diameter to ampulla diameter ratio was significantly higher in patients with decreased left lung perfusion and correlated well with left lung perfusion values (r = 0.516 and r = -0.501, respectively). A cut-off value of <= 5.8 mm for the ductal ampulla length and >= 1.9 for ampulla diameter to ampulla length ratio showed high sensitivity and specificity for reduced lung perfusion. CONCLUSIONS: The incidence of abnormal left lung perfusion is high 6 months after transcatheter closure of PDA with the ADO, more likely in the low weight symptomatic infants and in patients with a short duct or a relatively shallow duct having abrupt narrowing of a large ampulla. PMID- 20839358 TI - Transthoracic echocardiographic assistance for interatrial stenting in low birth weight neonates with hypoplastic left heart syndrome and intact atrial septum. AB - Infants with hypoplastic left heart syndrome and intact or highly restrictive atrial septum require emergent therapy to relieve pulmonary congestion. Transcatheter stenting has become, in most large centers, the mainstay of therapy for relief of left atrial hypertension. Normally, this procedure is performed with the assistance of transesophageal echocardiographic guidance. However, the transesophageal approach is untenable in neonates of low birth weight, as the transducers can be traumatic and can cause ventilatory difficulty. We present two cases in which transthoracic echocardiographic guidance was used to guide atrial perforation and stenting in low birth-weight neonates with hypoplastic left heart syndrome with intact or highly restrictive atrial septum. Both procedures were straightforward and there were no complications. Real-time biplane imaging greatly assisted in the intervention in one case. The advantages of this approach are discussed. PMID- 20839359 TI - Mitral valve repair with the MitraClip device after prior surgical mitral annuloplasty. AB - While mitral valve repair using the MitraClip device is currently being evaluated in the EVEREST trials, surgical approaches to mitral regurgitation remain the standard of care, at least for operative candidates. Two patients in whom previous surgical annuloplasty failed to maintain MR reduction and who were treated with the MitraClip device after mitral valve repair surgery are described. Imaging and hemodynamic considerations associated with this approach are discussed. PMID- 20839361 TI - Imaging mass spectrometry of myxoid sarcomas identifies proteins and lipids specific to tumour type and grade, and reveals biochemical intratumour heterogeneity. AB - Myxofibrosarcoma and myxoid liposarcomas are relatively common soft tissue tumours that are characterized by their so-called myxoid extracellular matrix and have to some extent overlap in histology. The exact composition and potential role of their myxoid extracellular matrix are insufficiently understood. To gain more insight into the biomolecular content of these tumours, we have studied 40 well-documented myxofibrosarcoma and myxoid liposarcoma cases using imaging mass spectrometry. This technique provides a multiplex biomolecular imaging analysis of the tissue, spanning multiple molecular domains and without a priori knowledge of the tissue's biomolecular content. We have developed experimental protocols for analysing the peptide, protein, and lipid content of myxofibrosarcoma and myxoid liposarcomas, and have detected proteins and lipids that are tumour-type and tumour-grade specific. In particular, lipid changes observed in myxoid liposarcomas could be related to pathways known to be affected during tumour progression. Unsupervised clustering of the biomolecular signatures was able to classify myxofibrosarcoma and myxoid liposarcomas according to tumour type and tumour grade. Closer examination of histologically similar regions in the tissues revealed intratumour heterogeneity, which was a consistent feature in each of the myxofibrosarcomas studied. In intermediate-grade myxofibrosarcoma, it was found that single tissue sections could contain regions with biomolecular profiles similar to high-grade and low-grade tumours, and that these regions were associated with the tumour's nodular structure, thus supporting a concept of tumour progression through clonal selection. PMID- 20839362 TI - Percutaneous permeation of betamethasone 17-valerate incorporated in lipid nanoparticles. AB - Corticosteroids are therapeutic agents widely used in the pharmacological treatment of skin diseases such as eczema or psoriasis. Unfortunately, their use is restricted by the side effects that frequently occur at the systemic level. The goal of the research described here was to develop and characterize a solid lipid nanoparticle (SLN) system containing corticosteroids for prolonged and localized delivery of the active drugs into the skin. In vitro measurements of Betamethasone 17-valerate (BMV) permeation through human epidermis were conducted using static Franz diffusion cells. The reservoir formation of the drug in the epidermal and dermal layers of the skin was also investigated. Monostearin SLN showed remarkable controlled release properties and a significant epidermis drug reservoir. On the other hand, beeswax SLN could not reduce the drug permeation through the skin, nor increase the drug content in the upper layers of the skin. The diffusion of corticosteroids into the skin appeared to be dependent on the lipid composition of the monostearin SLN. Topical SLN products show great potential for treating dermatological conditions by targeting corticosteroids to epidermal/upper dermal disease sites while minimizing systemic drug absorption. PMID- 20839363 TI - Multidisciplinary approach on characterizing a mechanochemically activated composite of vinpocetine and crospovidone. AB - Significant improvement of solubilization kinetics of poorly soluble vinpocetine was obtained through a mechanochemical activation process in presence of micronized crospovidone. Drug-to-polymer weight ratio and milling time variables resulted to have statistically significant impacts on the activation of the product. The complete amorphization was obtained in the coground with the highest crospovidone contents (>80% wt), milled for the longest time (180 min). An ad hoc software was then used to calculate the dimensions of the drug crystallites in the samples on the basis of the calorimetric data. The thermal analyses were then accompanied and confirmed by an extensive solid-state characterization, performing X-ray diffraction, Raman imaging/spectroscopy, DRIFT, and SS-NMR spectroscopy, followed by laser diffraction and solubilization kinetics tests. All the analyses agreed on attesting the progressive loosing of crystalline structure of the drug when increasing milling time and amount of polymer in the formulations. This activated status of the drug, which resulted to be homogeneously distributed on the coground sample and stable for at least 1 year, was reflected on favorable solubilization kinetics. The in vivo studies on rats revealed that coground systems promoted a fivefold higher oral bioavailability enhancement in comparison to a commercial formulation (Vimpocetin 5mg Capsules, Pharma). PMID- 20839364 TI - The state of the art of residue analysis: the 6th VDRA symposium 2010. AB - Since the onset of residue analysis (ca 40 years ago) a lot of attention has been paid to the amelioration of analytical methods, for example, lowering the limits of detection (LOD) and limits of quantification (LOQ) or decision limits (CCalpha) and detection capabilities (CCbeta), including an increase in the number of analytes, shortening runtimes, increasing sample throughput, amongst others. The state of the art in residue analysis, which was presented at the VDRA 2010 symposium (Hormone and Veterinary Drug Residue Analysis) in Ghent is reviewed in this article. From an analytical point of view, the use of ultra high performance liquid chromatography (UHPLC) hyphenated with accurate mass spectrometry is often used in combination with other (biological) detection systems and 'omic' approaches. Through these techniques more xenobiotic substances turn out to be naturally occurring in some matrices and/or circumstances (e.g. thiouracil, chloramphenicol and semicarbazide). PMID- 20839365 TI - Towards disposable sensors for drug quality control: Dextromethorphan screen- printed electrodes. AB - A simple, rapid, reliable, and reproducible method for mass production of disposable sensors using screen-printing technology is described. Homemade printing has been characterized and optimized on the basis of effects of the modifier and plasticizers. The fabricated bi-electrode potentiometric strip containing both working and reference electrode was used as dextromethorphan (DXM) sensor. The proposed sensors worked satisfactorily in the concentration range from 10-5 to 10-2 mol L-1 with detection limit reaching 6 * 10-6 mol L-1 and adequate shelf life of 8 months. DXM was determined in pharmaceutical formulations under batch and flow injection analysis (FIA) conditions with sampling output 120 h-1. PMID- 20839366 TI - Bayesian approach to cancer-trend analysis using age-stratified Poisson regression models. AB - Annual Percentage Change (APC) summarizes trends in age-adjusted cancer rates over short time-intervals. This measure implicitly assumes linearity of the log rates over the intervals in question, which may not be valid, especially for relatively longer time-intervals. An alternative is the Average Annual Percentage Change (AAPC), which computes a weighted average of APC values over intervals where log-rates are piece-wise linear. In this article, we propose a Bayesian approach to calculating APC and AAPC values from age-adjusted cancer rate data. The procedure involves modeling the corresponding counts using age-specific Poisson regression models with a log-link function that contains unknown joinpoints. The slope-changes at the joinpoints are assumed to have a mixture distribution with point mass at zero and the joinpoints are assumed to be uniformly distributed subject to order-restrictions. Additionally, the age specific intercept parameters are modeled nonparametrically using a Dirichlet process prior. The proposed method can be used to construct Bayesian credible intervals for AAPC using age-adjusted mortality rates. This provides a significant improvement over the currently available frequentist method, where variance calculations are done conditional on the joinpoint locations. Simulation studies are used to demonstrate the success of the method in capturing trend changes. Finally, the proposed method is illustrated using data on prostate cancer incidence. PMID- 20839367 TI - The analysis of very small samples of repeated measurements I: an adjusted sandwich estimator. AB - The statistical analysis of repeated measures or longitudinal data always requires the accommodation of the covariance structure of the repeated measurements at some stage in the analysis. The general linear mixed model is often used for such analyses, and allows for the specification of both a mean model and a covariance structure. Often the covariance structure itself is not of direct interest, but only a means to producing valid inferences about the response. Existing methods of analysis are often inadequate where the sample size is small. More precisely, statistical measures of goodness of fit are not necessarily the right measure of the appropriateness of a covariance structure and inferences based on conventional Wald-type procedures do not approximate sufficiently well their nominal properties when data are unbalanced or incomplete. This is shown to be the case when adopting the Kenward-Roger adjustment where the sample size is very small. A generalization of an approach to Wald tests using a bias-adjusted empirical sandwich estimator for the covariance matrix of the fixed effects parameters from generalized estimating equations is developed for Gaussian repeated measurements. This is shown to attain the correct test size but has very low power. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 20839369 TI - Interval estimation of the over-dispersion parameter in the analysis of one-way layout of count data. AB - The over-dispersion parameter is an important and versatile measure in the analysis of one-way layout of count data in biological studies. For example, it is commonly used as an inverse measure of aggregation in biological count data. Its estimation from finite data sets is a recognized challenge. Many simulation studies have examined the bias and efficiency of different estimators of the over dispersion parameter for finite data sets (see, for example, Clark and Perry, Biometrics 1989; 45:309-316 and Piegorsch, Biometrics 1990; 46:863-867), but little attention has been paid to the accuracy of the confidence intervals (CIs) of it. In this paper, we first derive asymptotic procedures for the construction of confidence limits for the over-dispersion parameter using four estimators that are specified by only the first two moments of the counts. We also obtain closed form asymptotic variance formulae for these four estimators. In addition, we consider the asymptotic CI based on the maximum likelihood (ML) estimator using the negative binomial model. It appears from the simulation results that the asymptotic CIs based on these five estimators have coverage below the nominal coverage probability. To remedy this, we also study the properties of the asymptotic CIs based on the restricted estimates of ML, extended quasi likelihood, and double extended quasi-likelihood by eliminating the nuisance parameter effect using their adjusted profile likelihood and quasi-likelihoods. It is shown that these CIs outperform the competitors by providing coverage levels close to nominal over a wide range of parameter combinations. Two examples to biological count data are presented. PMID- 20839368 TI - A modeling framework for the analysis of HPV incidence and persistence: a semi parametric approach for clustered binary longitudinal data analysis. AB - Human papillomavirus (HPV) infection is a common sexually transmitted disease of growing public health importance, and over 40 genotypes have been identified in genital infections. Current HPV cohort studies often follow participants at pre determined visits, such as every 6 months, and data generated from such epidemiology studies can be described as clustered longitudinal binary data where correlation arises in two ways: the directionless clustering due to the multiple genotypes tested within an individual, and the temporal correlation among the repeated measurements on the same genotype along time. Current analyses for identification of risk factors associated with HPV incidence and persistence often either do not fully utilize information in the data set or ignore the correlation between the multiple genotypes. Given the scientific definition of incidence and persistence, conditional probability modeling provides us a natural mathematical tool. We thus present a semi-parametric regression model for such data where full specification of the joint multivariate binary distribution is avoided by using conditioning argument to handle the temporal correlation and GEE to account for the correlation between the multiple genotypes. The model is applied to the HPV data from the Rakai male circumcision (MC) trial to evaluate the as-treated efficacy of MC and also identify modifiable risk factors for incidence and persistence of oncogenic HPV types in men. A simulation study is performed to provide empirical information on the number of individuals that is needed for satisfactory power and estimation accuracy of the association parameter estimates in future studies. PMID- 20839370 TI - Flow injection methods for the determination of retinol and alpha-tocopherol using lucigenin-enhanced chemiluminescence. AB - Flow injection (FI) methods are reported to determine retinol and alpha tocopherol based on its enhancement affect of lucigenin chemiluminescence (CL) in alkaline medium. Surfactants including Brij-35, Triton X-100, cetyltrimethyl ammonium bromide (CTAB) and sodium dodecyl sulfate have been reported for the first time to enhance lucigenin CL intensity in the presence of retinol and alpha tocopherol. With Brij-35, the CL intensity was enhanced by 67% for retinol and 58% for alpha-tocopherol. CTAB was found to enhance the CL intensity by 16% for retinol whereas for alpha-tocopherol, the CL intensity was quenched up to 95%. Retinol could be determined specifically in the presence of alpha-tocopherol using CTAB. The calibration graphs were found to be linear up to 1.43 mg/L (R(2) = 0.9985, n = 8) with a detection limit (3s) of 1.43 * 10(-3) mg/L for retinol and 2.15 mg/L (R(2) = 0.9989; n = 8) with a detection limit (3s) of 4.31 * 10(-4) mg/L for alpha-tocopherol. An injection throughput of 120/h, and relative standard deviations of 0.9-2.8% (n = 4) were achieved in the concentration range studied. The influence of common ions, excipients in pharmaceutical formulations and related organic compounds on the determination of retinol and alpha tocopherol individually was studied. The proposed methods were applied to determine retinol and alpha-tocopherol in pharmaceutical formulations and human blood serum. The results did not differ significantly from the CL method and HPLC reference method at 95% confidence level. PMID- 20839371 TI - Nanoscale biomolecular structures on self-assembled monolayers generated from modular pegylated disulfides. AB - A solid-phase synthetic strategy was developed that uses modular building blocks to prepare symmetric oligo(ethylene glycol)-terminated disulfides with a variety of lengths and terminal functionalities. The modular disulfides, composed of alkyl amino groups linked by an amide group to oligoethylene chains were used to generate self-assembled monolayers (SAMs), which were characterised to determine their applicability for biomolecular applications. X-ray photoelectron spectroscopy (XPS) of the SAMs obtained from these molecules demonstrated improved stability towards displacement by 16-hexadecanethiol, while surface plasmon resonance (SPR) analyses of SAMs prepared with the hydroxy-terminated oligoethylene disulfide showed equal resistance to non-specific protein adsorption in comparison to 11-mercaptoundecyl tri(ethylene glycol). SAMs made from these adsorbates were amenable to nanoscale patterning by scanning near field photolithography (SNP), facilitating the fabrication of nanopatterned, protein-functionalised surfaces. Such SAMs may be further developed for bionanotechnology applications such as the fabrication of nanoscale biological arrays and sensor devices. PMID- 20839372 TI - Simple conjugated polymers with on-chain phosphorescent iridium(III) complexes: toward ratiometric chemodosimeters for detecting trace amounts of mercury(II). AB - For the development of excellent optical probes for mercury(II), a series of simple conjugated polymers that contain phosphorescent iridium(III) complexes as receptors for mercury(II) were designed and synthesized. These conjugated polymers showed energy transfer from the polymer host to iridium(III) complex guest in both solution and the solid state. Unexpectedly, they can work as excellent polymer chemodosimeters for mercury(II) by utilizing the mercury(II) induced decomposition of iridium(III) complex. They exhibit a pronounced optical signal change with switchable phosphorescence and fluorescence, even when the concentration of a solution of mercury(II) in THF was as low as 0.5 ppb. With the addition of mercury(II), the phosphorescent emission intensity of iridium(III) complexes was quenched completely. As the emission from polymer backbones increased, the emission wavelength was redshifted simultaneously, thereby realizing ratiometric detection. Excellent selectivity toward mercury(II) over other potentially interfering cations was also realized. In addition, an obvious emission color change of polymer solution from red to yellow-green was observed, thus realizing a "naked-eye" detection of mercury(II). More importantly, the solid films of these polymer chemodosimeters also exhibited high sensitivity and rapid response to mercury(II), thereby demonstrating the possibility of the fabrication of sensing devices with fast and convenient detection of mercury(II). The sensing mechanism was also investigated in detail. This is the first report on chemodosimeters based on conjugated polymers with phosphorescent iridium(III) complexes. PMID- 20839373 TI - Electrochemical synthesis and characterisation of alternating tripyridyl dipyrrole molecular strands with multiple nitrogen-based donor-acceptor binding sites. AB - Synthesis of alternating pyridine-pyrrole molecular strands composed of two electron-rich pyrrole units (donors) sandwiched between three pyridinic cores (acceptors) is described. The envisioned strategy was a smooth electrosynthesis process involving ring contraction of corresponding tripyridyl-dipyridazine precursors. 2,6-Bis[6-(pyridazin-3-yl)]pyridine ligands 2a-c bearing pyridine residues at the terminal positions were prepared in suitable quantities by a Negishi metal cross-coupling procedure. The yields of heterocyclic coupling between 2-pyridyl zinc bromide reagents 12a-c and 2,6-bis(6 trifluoromethanesulfonylpyridazin-3-yl)pyridine increased from 68 to 95% following introduction of electron-donating methyl groups on the metallated halogenopyridine units. Favorable conditions for preparative electrochemical reduction of tripyridyl-dipyridazines 2b,c were established in THF/acetate buffer (pH 4.6)/acetonitrile to give the targeted 2,6-bis[5-(pyridin-2-yl)pyrrol-2 yl]pyridines 1b and 1c in good yields. The absorption behavior of the donor acceptor tripyridyl-dipyrrole ligands was evaluated and compared to theoretical calculations. Highly fluorescent properties of these chromophores were found (nu(em)~2 * 10(4) cm(-1) in MeOH and CH(2)Cl(2)), and both pyrrolic ligands exhibit a remarkable quantum yield in CH(2)Cl(2) (phi(f)=0.10). Structural studies in the solid state established the preferred cis conformation of the dipyrrolic ligands, which adopting a planar arrangement with an embedded molecule of water having a complexation energy exceeding 10 kcal mol(-1). The ability of the tripyridyl-dipyrrole to complex two copper(II) ions in a pentacoordinate square was investigated. PMID- 20839374 TI - Internally protected amino sugar equivalents from enantiopure 1,2-oxazines: synthesis of variably configured carbohydrates with C-branched amino sugar units. AB - A stereodivergent synthesis of differently configured C2-branched 4-amino sugar derivatives was accomplished. The Lewis acid mediated rearrangement of phenylthio substituted 1,2-oxazines delivered glycosyl donor equivalents that can directly be employed in glycosidation reactions. Treatment with methanol provided internally protected amino sugar equivalents that have been transformed into the stereoisomeric methyl glycosides 28, ent-28, 29, ent-29 and 34 in two simple reductive steps. Reaction with natural carbohydrates or bicyclic amino sugar precursors allowed the synthesis of homo-oligomeric di- and trisaccharides 44, 46 and 47 or a hybrid trisaccharide 51 with natural carbohydrates. Access to a bivalent amino sugar derivative 54 was accomplished by reaction of rearrangement product 10 with 1,5-pentanediol. Alternatively, when a protected L-serine derivative was employed as glycosyl acceptor, the glycosylated amino acid 60 was efficiently prepared in few steps. In this report we describe the synthesis of unusual amino sugar building blocks from enantiopure 1,2-oxazines that can be attached to natural carbohydrates or natural product aglycons to produce new natural product analogues with potential applications in medicinal chemistry. PMID- 20839375 TI - N-heterocyclic carbene mediated activation of tetravalent silicon compounds: a critical evaluation. AB - An overview of the recent bibliography concerning the N-heterocyclic carbene (NHC)-mediated activation of tetravalent silicon compounds is presented. Diverse reactions are discussed, such as the NHC-mediated addition of silyl pronucleophiles to a variety of electrophiles, NHC-promoted organic and inorganic polymerisation and the reduction of CO(2) by hydrosilanes as facilitated by NHCs. The review concludes with a discussion of the current knowledge regarding the role of Lewis acid-base NHC-Si interactions in the mechanistic course of these reactions. PMID- 20839376 TI - Light-induced peptide replication controls logic operations in small networks. PMID- 20839377 TI - Upconverted photoluminescence in Ho3+ and Yb3+ codoped Gd2O3 nanocrystals with and without Li+ ions. AB - The upconversion photoluminescence of Ho(3+) ion sensitized by Yb(3+) ion in Ho(3+)/Yb(3+) codoped Gd(2)O(3) nanocrystals with and without Li(+) is investigated in this paper. Strong fluorescence in the green (534-570 nm) and red (635-674 nm) regions of the spectrum has been observed, arising from the (5)F(4)/(5)S(2) -> (5)I(8) and (5)F(5) -> (5)I(8) transitions of Ho(3+) ion, respectively. Yb(3+) ion is considered to be a better sensitizer for catching enough pumping energy and transferring considerable energy to Ho(3+) in the Ho(3+)/Yb(3+) system. The upconversion intensity emitted by Ho(3+) is greatly enhanced when Li(+) is added to the Ho(3+)/Yb(3+) codoped Gd(2)O(3) nanocrystals. PMID- 20839378 TI - The contribution of David Yudilevich (1930-2006) to the study of placental transport. PMID- 20839379 TI - Helicobacter pylori cytotoxin-associated gene-A antibodies do not predict complications or death in type 2 diabetes: the Fremantle Diabetes Study. AB - OBJECTIVES: There is cross-sectional evidence that CagA antigen produced by Helicobacter pylori is associated with coronary heart disease, stroke, atrial fibrillation (AF) and microalbuminuria, but no large-scale longitudinal studies have been conducted in diabetic patients. We aimed to determine whether cytotoxin associated gene-A (CagA) seropositivity is independently associated with important vascular outcomes in type 2 diabetes. METHODS: We studied 1179 type 2 patients from a well characterized community-based cohort who had available sera from baseline assessment between 1993 and 1996, and follow-up for incident events to end-June 2007. H. pylori IgG and CagA antibodies at baseline were measured by validated ELISA. Multiple logistic/linear regression analysis and Cox proportional hazards modelling were used to determine independent baseline associates of prevalent and incident complications, respectively, including H. pylori/CagA serostatus. RESULTS: At baseline, 62.0% of patients were H. pylori seropositive and 37.7% were both H. pylori and CagA seropositive. CagA seropositivity was not independently associated with prevalent coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral arterial disease or AF at baseline (P > 0.41), but there was a significant inverse association with ln(urinary albumin:creatinine) (P = 0.033). There were no independent associations between CagA seropositivity and incident CHD/CVD or progression to microalbuminuria (P > 0.20). During follow-up, 480 patients (40.7%) died, 246 (50.2%) from cardiovascular causes. After adjustment for other variables,CagA seropositivity was weakly protective against cardiovascular death (P = 0.024). CONCLUSION: CagA seropositivity is not a risk factor for chronic vascular complications of type 2 diabetes. Assay of CagA antibodies does not contribute significantly to clinical management outside gastroenterological indications. PMID- 20839380 TI - Does speciation matter for tungsten ecotoxicology? AB - Tungsten is a widely used transition metal that has not been thoroughly investigated with regards to its ecotoxicological effects. Tungsten anions polymerize in environmental systems as well as under physiological conditions in living organisms. These polymerization/condensation reactions result in the development of several types of stable polyoxoanions. Certain chemical properties (in particular redox and acidic properties) differentiate these polyanions from monotungstates. However, our current state of knowledge on tungsten toxicology, biological and environmental effects is based entirely on experiments where monotungstates were used and assumed by the authors to be the form of tungsten that was present and that produced the observed effect. Recent discoveries indicate that tungsten speciation may be important to ecotoxicology. New results obtained by different research groups demonstrate that polytungstates develop and persist in environmental systems, and that polyoxotungstates are much more toxic than monotungstates. This paper reviews the available toxicological information from the standpoint of tungsten speciation and identifies knowledge gaps and pertinent future research directions. PMID- 20839381 TI - Prostate cancer. Immunotherapy and combined chemotherapy for castration resistant and metastatic disease. PMID- 20839382 TI - Prostate cancer. Nuclear irregularity is a predictor of clinical outcome. PMID- 20839383 TI - Stones. Extracorporeal shock wave lithotripsy in children. PMID- 20839384 TI - Prostate cancer. The promise of psychostimulants for disease-related fatigue. PMID- 20839386 TI - Retraction notice. Rule learning by cotton-top tamarins. Cognition, 86(1), B15 B22. PMID- 20839385 TI - Meta-analysis: ribavirin plus interferon vs. interferon monotherapy for chronic hepatitic C - an updated Cochrane review. AB - BACKGROUND: Multiple randomized trials have been published on antiviral treatment for chronic hepatitis C. AIM: To meta-analyse the effect of adding ribavirin to interferon for chronic hepatitis C. METHODS: The results of randomized trials were combined in cumulative meta-analyses. Trial sequential analyses were used to adjust for spurious results because of random errors and multiplicity. The outcome measures were undetectable hepatitis C virus RNA in serum (sustained virological response) and liver-related morbidity plus all-cause mortality. RESULTS: We included 82 randomized trials with 12 615 patients. Trial sequential analysis established clear beneficial effect of interferon plus ribavirin vs. interferon on the sustained virological response in 1998 after nine trials (RR: 0.74; 95% CI: 0.64-0.85, P < 0.0001, 1734 patients). Subsequently, additional 73 trials were published just narrowing the confidence interval and decreasing the P value. By contrast, trial sequential analysis found that additional evidence is needed to convincingly detect a beneficial effect of interferon plus ribavirin vs. interferon monotherapy on clinical outcomes. CONCLUSIONS: The rationale behind several recent trials on adding ribavirin to interferon for chronic hepatitis C is debatable as the effect on virological response is established. More evidence is needed to assess if adding ribavirin to interferon improves clinical outcomes. PMID- 20839387 TI - Meta-analysis: isosorbide-mononitrate alone or with either beta-blockers or endoscopic therapy for the management of oesophageal varices. AB - BACKGROUND: The evidence concerning the use of isosorbide-mononitrate (IsMn) for oesophageal varices is equivocal. AIM: To assess the effects of IsMn for patients with oesophageal varices and no previous bleeding (primary prevention) or previous variceal bleeding (secondary prevention). METHODS: Systematic review with meta-analyses of randomized trials on IsMn alone or with beta-blockers or endoscopic therapy for oesophageal varices. Electronic and manual searches were combined. Randomized trials on primary and secondary prevention were included. The primary outcome measure was mortality. Intention-to-treat random effects meta analyses were performed. The robustness of the results was assessed in trial sequential analyses. RESULTS: Ten randomized trials on primary and 17 on secondary prevention were included. Evidence of bias was identified. No apparent effect of IsMn on mortality compared with placebo or beta-blockers or IsMn plus beta-blockers vs. beta-blockers was identified. Compared with endoscopic therapy, IsMn plus beta-blockers had no apparent effect on bleeding, but did seem to reduce mortality in secondary prevention (RR 0.73, 95% CI 0.59-0.89), but not in primary prevention. The effect of IsMn plus beta-blockers on mortality in secondary prevention was not confirmed in trial sequential analysis. CONCLUSIONS: Isosorbide-mononitrate used alone or in combination with beta blockers does not seem to offer any reduction in bleeding in the primary or secondary prevention of oesophageal varices. Compared with endoscopic therapy, there may be a survival advantage in using IsMn and beta-blockers, but additional large multicentre trials are needed to verify this finding. PMID- 20839388 TI - The effects of methylnaltrexone alone and in combination with acutely administered codeine on gastrointestinal and colonic transit in health. AB - BACKGROUND: The short-term effects of methylnaltrexone (MNTX), a peripherally acting mu-opioid receptor antagonist, on gastrointestinal and colonic transit remain unclear. AIM: To compare the effects of placebo, codeine, subcutaneous (s.c.) MNTX and codeine with s.c. MNTX on gastrointestinal and colonic transit of solids in healthy humans. METHODS: In a randomized, parallel-group, double-blind, placebo-controlled trial of 48 healthy volunteers, effects of 6 consecutive days of placebo [s.c. and p.o. (orally), n = 8], codeine (p.o. 30 mg q.d.s., n = 8), MNTX (s.c. 0.30 mg/kg, n = 16) and combined MNTX and codeine (same doses and routes, n = 16) on gastrointestinal and colonic transit were assessed. A validated scintigraphic method was used to measure transit during the last 48 h of treatment. Bowel function was estimated during treatment as well as 1 week preceding treatment using standard diaries. Analysis of covariance was used to assess treatment effects. RESULTS: Codeine delayed colonic transit [geometric centre at 24 h (P = 0.04) and ascending colon t(1/2) (P = 0.02)] and reduced stool frequency (P = 0.002), but had no effect on stool form. MNTX did not affect transit, stool frequency or stool form, either alone or with codeine (P > 0.3). No drug interaction effects were detected (P > 0.15). CONCLUSION: Methylnaltrexone does not alter gastrointestinal or colonic transit and does not reverse acute codeine-associated delayed gut transit in health. PMID- 20839389 TI - The performance of a novel ball-tipped Flush knife for endoscopic submucosal dissection: a case-control study. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) using short needle knives is safe and effective, but bleeding is a problem due to low haemostatic capability. AIM: To assess the performance of a novel ball-tipped needle knife (Flush knife BT) for ESD with particular emphasis on haemostasis. METHODS: A case-control study to compare the performance for ESD of 30 pairs of consecutive early gastrointestinal lesions (oesophagus: 12, stomach: 32, colorectum: 16) with standard Flush knife (F) vs. Flush knife-BT (BT). Primary outcome was efficacy of intraprocedure haemostasis. Secondary outcomes included procedure time, procedure speed (dividing procedure time into the area of resected specimen), en bloc resection rate and recurrence rate. RESULTS: Median intraoperative bleeding points and bleeding points requiring haemostatic forceps were smaller in the BT group than in the F group (4 vs. 8, P < 0.0001, 0 vs. 3, P < 0.0001). There was no difference between groups for procedure time; however, procedure speed was shorter in the BT group (P = 0.0078). En bloc and en bloc R0 resection rates were 100%, with no perforation or post-operative bleeding. No recurrence was observed in either group at follow-up 1 year postprocedure. CONCLUSIONS: Ball-tipped Flush knife (Flush knife-BT) appears to improve haemostatic efficacy and dissection speed compared with standard Flush knife. PMID- 20839390 TI - In memoriam. Morton Arnsdorf: 1940-2010. PMID- 20839392 TI - Peripheral artery disease: leg pain and much more. PMID- 20839391 TI - Dietary rice protein isolate attenuates atherosclerosis in apoE-deficient mice by upregulating antioxidant enzymes. AB - Rice-based diets may have been reported to protect against the development of atherosclerosis; however, the underlying mechanism(s) for this protection remains unknown. In this report, the mechanism(s) contributing to the atheroprotective effects of rice-based diet was addressed using the apolipoprotein E knockout (apoE-/-) mice fed rice protein isolate (RPI) or casein (CAS). Reduced atherosclerotic lesions were observed in aortic sinus and enface analyses of the descending aorta in RPI-fed apoE-/- mice compared with CAS-fed mice. Plasma total and HDL-cholesterol levels were not different amongst the two groups, suggesting alternative mechanism(s) could have contributed to the atheroprotective effect of rice-based diets. Plasma oxLDL and anti-oxLDL IgG levels were significantly decreased in RPI-fed compared to CAS-fed animals. Plasma and aortic tissue GSH levels and GSH:GSSG ratio were higher in RPI-fed mice compared to CAS-fed group. Interestingly, RPI feeding increased mRNA and protein expression of superoxide dismutase, and mRNA expression of catalase, glutathione peroxidase and glutathione reductase, key antioxidant enzymes implicated inhibiting oxidative stress leading to atherosclerosis. In conclusion, these findings suggest that the reduction in atherosclerotic lesions observed in mice fed the rice-based diet is mediated in part by inhibiting oxidative stress and subsequent oxLDL generation that could result in reduced foam cell formation, an early event during atherogenesis. PMID- 20839394 TI - The numbers game: risk factors, lifestyle, and longevity. PMID- 20839393 TI - Exercise and your joints. PMID- 20839395 TI - On call. I am a 56-year-old man with high blood pressure. At my last check-up, my dentist found gum disease and referred me to a periodontist for treatment. I know that high blood pressure increases my risk of heart disease, and I've been told that gum disease does, too. Is it true, and will the treatment help? PMID- 20839397 TI - [Abstracts of the 22nd Spring Meeting of the Japanese Society of Allergology. May 8-9, 2010, Kyoto, Japan]. PMID- 20839396 TI - [In defense and promotion of self medication]. AB - INTRODUCTION: Most people turn to self medication for common problems, often incorrectly. AIM: To inform citizens on how to use over the counter drugs and drugs in general. METHODS: A group of pharmacists wrote the main information. The booklet was tested on groups of normal citizens (mothers, clerks, elderly), to assess the relevance and completeness of the contents. The philosophy reverses the traditional approach of forbidding and stressing the harmful effects of drugs: "you may take drugs and the booklet helps you to understand how to use them correctly". RESULTS: The colorful booklets were distributed in chemistries and doctors offices and clinics. The introduction with rights and duties of those that use drugs and information on pain treatments and on some common problems in children (otitis, colics, fever, coughs) are presented. PMID- 20839398 TI - [Abstracts of the 83rd General Meeting of the Japanese Leprosy Association of the 22nd Co-Medical Meeting. May 27-29, 2010, Kagoshima, Japan]. PMID- 20839400 TI - [Screening of antineoplastic agents for molecular targets]. PMID- 20839399 TI - [Abstracts of the 94th Congress of the Japanese Society of Legal Medicine. June 23-25, 2010, Tokyo, Japan]. PMID- 20839401 TI - [Abstracts of the 114th Annual Meeting of the Japanese Ophthalmological Society. April 15-18, 2010. Nagoya, Japan]. PMID- 20839402 TI - [Abstracts of the 50th Annual Meeting of the Japanese Respiratory Society. April 23-25, 2010. Kyoto, Japan]. PMID- 20839403 TI - [Abstract of the 80th Annual Meeting of the Japanese Society of Hygiene, May 9 11, 2010, Sendai, Japan]. PMID- 20839404 TI - [Abstracts of the 111th Congress of the Japanese Society of Otolaryngology. May 20-22, 2010. Sendai, japan]. PMID- 20839405 TI - [Abstracts of the 85th Annual Meeting of the Japanese Society for Tuberculosis. May 20-21, 2010. Kyoto, Japan]. PMID- 20839406 TI - [Abstracts of the 53rd Annual Meeting of the Japanese Society of Nephrology. June 16-18, 2010. Kobe, Japan]. PMID- 20839407 TI - Planning and health management: perspectives and tendencies. PMID- 20839409 TI - Models of care editorial. PMID- 20839408 TI - [Strategies of local recurrence after sphincter preserving for low rectal cancer]. PMID- 20839410 TI - How does the consumption of fructose and high fructose corn syrup impact the health of children and adolescents? PMID- 20839411 TI - Human infrastructure in health: a commentary on networks of supports. PMID- 20839412 TI - GP access to MRI: the Australian reality. PMID- 20839413 TI - Hypnic headache. AB - Hypnic headache is a rare primary headache disorder that is characterized by exclusively sleep-related headache attacks in patients usually beyond 50 years of age. Only 174 cases have been reported in the literature so far. Owing to its low prevalence, clinical features and therapeutic options, as well as underlying pathophysiologic mechanisms, are widely unknown or being controversially discussed. The association of hypnic headache with rapid-eye movement sleep was strongly contradicted in recent articles, while an association with hypothalamic dysfunction is thought to be one important pathophysiological mechanism. Common acute, as well as prophylactic, treatment is caffeine intake, either in the form of a cup of coffee or a caffeine tablet. Lithium, indomethacin and melatonin were promoted as potent medical treatments, while almost every other drug commonly used to treat headache or other pain syndromes was reported to be effective in single case reports on hypnic headache. PMID- 20839414 TI - Human equilibrative nucleoside transporter 1 and carcinoma of the ampulla of Vater: expression differences in tumour histotypes. AB - The human equilibrative nucleoside transporter 1 (hENT1) is the major means by which gemcitabine enters human cells; recent evidence exists that hENT1 is expressed in carcinoma of the ampulla of Vater and that it should be considered as a molecular prognostic marker for patients with resected ampullary cancer. Aim of the present study is to evaluate the variations of hENT1 expression in ampullary carcinomas and to correlate such variations with histological subtypes and clinicopathological parameters. Forty-one ampullary carcinomas were histologically classified into intestinal, pancreaticobiliary and unusual types. hENT1 and Ki67 expression were evaluated by immunohistochemistry, and apoptotic cells were identified by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate biotin nick end labelling (TUNEL) method. hENT1 overexpression was detected in 63.4% ampullary carcinomas. A significant difference in terms of hENT1 and Ki67 expression was found between intestinal vs. pancreaticobiliary types (P=0.03 and P=0.009 respectively). Moreover, a significant statistical positive correlation was found between apoptotic and proliferative Index (P=0.036), while no significant correlation was found between hENT1 and apoptosis. Our results on hENT1 expression suggest that classification of ampullary carcinoma by morphological subtypes may represent an additional tool in prospective clinical trials aimed at examining treatment efficacy; in addition, data obtained from Ki67 and TUNEL suggest a key role of hENT1 in tumour growth of ampullary carcinoma. PMID- 20839415 TI - Expression of SPANX proteins in normal prostatic tissue and in prostate cancer. AB - The sperm protein associated with the nucleus in the X chromosome (SPANX) gene family encode for proteins that are not only expressed in germ cells, but also in a number of tumors. In addition, SPANX genes map in an interval of the X chromosome (namely, Xq27), which has been found to be associated with familial prostate cancer by linkage analysis. The aim of this study was therefore to evaluate SPANX protein expression in normal prostate tissues and in prostate carcinoma. For this purpose, formalin-fixed and paraffin-embedded sections obtained from 15 normal (at autopsy) donors and 12 men with prostate cancer were analyzed by immunohistochemistry. About 40% of both normal and tumor prostate samples resulted SPANX positive. Signals were exclusively with the nucleus in normal prostate cells, whereas both nuclear and cytoplasmic positivity was observed in tumor cells. In conclusion, these findings showed that SPANX genes are expressed in both normal and tumor prostate gland, but the latter showed a peculiar cytoplasmic staining positivity. This suggests a possible association between SPANX over expression and prostate cancer development. Additional studies are needed to corroborate this hypothesis. PMID- 20839416 TI - TRAIL, DR5 and caspase 3-dependent apoptosis in vessels of diseased human temporomandibular joint disc. An immunohistochemical study. AB - To evaluate the apoptosis involvement in the angiogenesis as a self-limiting process in patients with temporomandibular joint (TMJ) degenerated disc vessels, we assessed, by immunohistochemistry, the detection of TRAIL, its death receptor DR5 and caspase 3. TRAIL, its death receptor DR5 and caspase 3 expression were studied by immunohistochemistry in 15 TMJ discs displaced without reduction and in 4 unaffected discs. These apoptosis molecules were detected in the intima and media layers of newly formed vessels affected discs. In conclusion, vessels apoptosis activation in TMJ disc with ID could be regarded as a self-limiting process that try to leads to vessel regression; in this way an inhibition of angiogenic vessels may prove a key strategy in limiting pathological angiogenesis, by cutting off blood supply to tumors, or by reducing harmful inflammation. PMID- 20839417 TI - The most important medical source: Aunt Mabel knows best. PMID- 20839418 TI - Evaluation of topical steroids in the treatment of superficial hemangioma. AB - Infantile hemangioma is a common disease. Steroids have been used for its treatment; however, intralesional steroids cause pain and other problems. A treatment modality that can avoid these problems is desirable. The authors evaluated the role of topical steroids as an alternative to intralesional steroids in the treatment of superficial hemangioma. Inclusion criteria were <2 superficial type ofhemangiomas <5 cm. The topical steroid mometasone furoate was applied twice daily. Intralesional triamcinolone acetonide was injected at monthly intervals using a 24-gauge needle at doses of 1 to 2 mg/kg. Forty-five (86.5%) patients responded to treatment with the topical steroids, of which 50% had excellent and 36.5% had good response. In the intralesional group, the response rate was 95.7%, of which 63.8% had excellent and 31.9% had good response. Complications in the topical steroid group were mild itching and irritation (19.2%) and hypopigmentation (7.6%). Complications in the intralesional group were pain (100%), bleeding (17%), infection (17%), cutaneous atrophy (8.5%), cushingoid facies (2.1%), and growth retardation (2.1%). Topical steroids are a reasonably good alternative to intralesional steroids as an initial choice for treating superficial hemangioma. PMID- 20839419 TI - Immunopathologic features of pemphigus in the east Mediterranean region of Turkey: a prospective study. AB - Pemphigus, a life-threatening autoimmune disorder, is the most common autoimmune bullous disease in the Mediterranean region of Turkey. No studies have investigated the immunopathologic features of this geographic setting. To determine the immunopathologic features of pemphigus in the Eastern Mediterranean region of Turkey, the authors evaluated the histopathological, immunofluorescence (IF), and enzyme-linked immunosorbent assay (ELISA) results in a 4-year study. In this prospective study, tissue from 174 patients was analyzed by direct IF (DIF); 384 by indirect IF (IIF) from 61 patients with pemphigus; and 88 by ELISA for antibodies against desmoglein (Dsg) 1 and Dsg 3 from 50 of those 61 patients. Pemphigus vulgaris (PV) was the most commonly observed subtype (46 of 61 patients, 75.41%), followed by pemphigus foliaceus (9 of 61 patients, 14.75%), pemphigus erythematosus (5 of 61 patients, 8.2%), and pemphigus herpetiformis (1 of 61 patients, 1.64%). There was a significant correlation between clinical activity score (CAS) and IgG antibody titer in IF (P < .001) and ELISA tests (P = .024 for Dsg 1; P = .028 for Dsg 3). Antibody titers and C3 scale did not predict exacerbations and relapse. The commonest clinical subtype of pemphigus was PV in this region. Results indicate that IgG antibody titer in IF and ELISA tests of patients with pemphigus are correlated with CAS; however, they are not useful in predicting exacerbations and relapse of disease. PMID- 20839420 TI - Community study of fixed-combination adapalene 0.1% and benzoyl peroxide 2.5% in acne. AB - A new fixed-dose combination formulation of adapalene 0.1% and benzoyl peroxide (BPO) 2.5% has shown excellent efficacy and safety in registration studies; however, it can be difficult to judge the real-world performance of a product using only the results from controlled clinical trials. This 12-week, open-label, community-based study evaluated adapalene/BPO in 91 patients with mild to moderate acne (20-50 inflammatory lesions and 30-100 noninflammatory lesions) who were treated at dermatology centers throughout Argentina. The study evaluated efficacy, described the most common side effects, determined tolerability, and assessed the level of patient satisfaction with treatment. By week 12, there were statistically significant reductions in both inflammatory and noninflammatory lesions (80.6% and 69.3% from baseline, respectively; P < .001); there were also significant improvements in the Investigator's Global Assessment scores (median score, 2.9 at baseline and 1.0 at week 12; P < .001). By week 12, 67% of patients were rated clear or almost clear by investigators. Local tolerability was good overall. When cutaneous irritation was present, it typically occurred in the first 2 weeks of treatment and improved or resolved with continuing therapy. Patients were highly satisfied with the results of treatment, and 74% of patients felt that they had marked or total improvement by week 12. Patient survey also revealed that 94% rated the efficacy as good or very good and 87.5% rated tolerability as good or very good. A significant majority (81%) felt that the treatment met expectations, and 62% perceived that improvement had been rapid during adapalene/BPO therapy. These results demonstrate that adapalene/BPO has good efficacy and tolerability in routine practice, resulting in continuous reductions in lesion counts throughout the study. Adapalene/BPO therapy is also associated with high patient satisfaction, which is important for therapeutic adherence and satisfaction with the physician's care. PMID- 20839421 TI - "Quitting smoking rejuvenates the skin": results of a pilot project on smoking cessation conducted in Milan, Italy. AB - This study reports the results obtained during the "Quitting Smoking Rejuvenates the Skin" campaign, a pilot project in favor of the fight against nicotine addiction in women promoted by the Municipality of Milan jointly with other organizations. The initiative allowed researchers to evaluate the benefits on the skin obtained by cessation of smoking in a sample of 64 Caucasian women who smoked and who, in the period between February 2007 and November 2007, were followed by a team of dermatologists, psychologists, and nutritionists. During the dermatologic program, clinical and instrumental evaluations were made at the beginning of the study and at 3, 6, and 9 months. The state of skin aging was evaluated visually by giving a clinical score to each sign of skin aging (lines, vascular and pigmentation state, elasticity, brightness, texture of the skin). These signs were then correlated using a particular "spider web" graph called Spiderming, the result of Derming research that allows the monitoring of results obtained over time. Taking into account that a wider area of the graph coincides with more advanced skin aging, the graph of mean values observed in the study patients narrowed as time went by, reaching certain statistically significant values in as little as 6 months of observation. The patients' biological skin age was also calculated so as to better quantify the benefits they obtained by giving up smoking. It was possible to measure the biological age of the skin using noninvasive instrumental measurements of parameters such as skin smoothness, brightness, coloring, and elasticity. A complex mathematic algorithm processed the results obtained for each patient and, on this basis, calculated the biological age of the patient's skin. At the end of the program, an average reduction of about 13 years in the biological age of the patients' skin was found, while, at the beginning of the study, patients had presented with an average biological age of 9 years older than their chronologic age. This pilot project not only demonstrated that quitting smoking improves skin conditions, and above all skin-aging effects, but for the first time it afforded the opportunity to produce data that quantify this benefit. PMID- 20839422 TI - Common herbal remedies, adverse reactions, and dermatologic effects. AB - Herbal remedies (phytomedicines) possess significant biological activity and pharmacologic efficacy. Consequently, they may manifest potential adverse effects and drug interactions. The expansion in sales of herbal remedies has brought products to the marketplace that do not always conform to the standards of safety and efficacy that physicians and patients have come to expect. Relatively few physicians inquire about herbal medicine use, and up to 70% of patients do not reveal their use of herbal medicines to their physicians and pharmacists. All physicians should question patients regarding their use of herbal remedies and document their responses in the medical record. Patients should be aware that potentially limited standardization and quality control, and somewhat circumscribed regulation, may result in variability in content, efficacy, and potential contamination of herbal remedies. Physicians in general, and specifically dermatologists, should be aware of potential adverse reactions related to the use of certain herbal remedies. Specific cautions exist with regard to dermatologic side effects such as contact dermatitis, blisters, urticaria, angioedema, ulceration, photosensitization, and changes in skin pigmentation. PMID- 20839423 TI - Onychomycosis: an Asian perspective. AB - Extrapolated data from epidemiologic studies of onychomycosis unique to Asia have produced intriguing revelations and opened new lines of inquiry; however, the usefulness of this research is compromised by lack of uniformity in data collection. It is proposed that a common protocol be constructed to facilitate the study ofonychomycosis, in Asia, as elsewhere, the most common disease of the nails. PMID- 20839424 TI - Veregen (sinecatechins ointment) 15%. PMID- 20839425 TI - Food for thought and skin. AB - Free radicals are involved in the pathogenesis of several diseases including inflammation, neurodegenerative conditions, skin and eye disorders, and various forms of cancer. Epidemiologic evidence correlating higher intake of certain foods, typically fruits and vegetables or food components containing antioxidants, with a lower incidence of human disease are documented in the literature. Specific examples of such foods are apples, pears, graapes, wine, and tea. PMID- 20839426 TI - Beware the "conservative excision". PMID- 20839427 TI - Dermatopathology in historical perspective: the Montgomery giant cell of lichen simplex chronicus. AB - In this short historical review, we will discuss the origin and references to the giant cell that is sometimes histopathologically present in the dermis of lichen simplex chronicus that was first described by Hamilton Montgomery, MD. A photomicrograph of the giant cell was included by Montgomery in his text Dermatopathology published in 1967. We will then provide a short biography of Montgomery. PMID- 20839428 TI - Extranodal natural killer/T-cell lymphoma, nasal-type. AB - A 51-year-old previously healthy man, an ex-smoker, was admitted to the authors' medical department with a 3-month history of dry cough; intermittent fever; painless, ulcerated cutaneous lesions over the trunk and limbs (Figure 1); and progressive weight loss. He was of Greek descent. His medical history was remarkable for nasal polyps, which were surgically removed 15 years earlier. Initially, he had been treated with antibiotics, without improvement. Several days before admission, chest radiography revealed pulmonary infiltrates in the left lower lobe. On admission, physical examination revealed a well-orientated man in mild distress, with inspiratory rhonchi at the lower part of the left lung and scattered erythematous nodules of variable size, some of which were ulcerated. Laboratory values were notable for leukopenia, 3.3 x 10(9)/L; total protein, 5.9 g/dL; globulin, 2.2 g/dL; serum glutamic oxaloacetic transaminase, 86 IU/L; serum glutamic pyruvic transaminase, 71 IU/L; and lactate dehydrogenase, 519 U/L. Computed tomograph (CT) of the chest showed multiple alveolar opacities bilaterally (Figure 2). Fiberoptic bronchoscopy did not reveal any important pathologic findings. Results of bronchial biopsy, cytology of bronchoalveolar lavage, washing, brushing, and sputum following bronchoscopy were negative. CT of the brai and sinonasal area revealed an abnormal low-density mass in the left nasal area. CT findings of the abdomen were negative, as were results of a bone marrow biopsy. There was no evidence of immunosuppression. The differential diagnosis, considering the evidence described, included granulomatous or infectious diseases, angiocentric lymphoproliferative lesions, and lymphomas. Biopsy of a skin lesion showed lymphoproliferative infiltration of the dermis with a follicular and angiocentric growth pattern and regional epidermal necrosis. Immunohistochemical stains showed that the tumor cell were positive for CD56 and CD3 (cytoplasmic positivity) and expressed the cytotoxic proteins T-cell intracellular antigen and granzyme B (Figure 3) They lacked TdT, CD34, CD7, CD8, TCL-1, and CD123. Findings from an in situ hybridization study for Epstein-Barr virus were negative. Give this result, molecular analysis ofT-cell receptor (TCR) gene rearrangements was performed using polymerase chain reaction-based TCR-gamma gene, wit negative results. The morphology and the immunophenotype were consistent with natural killer/T-cell lymphoma, nasal-type. Nasal involvement must be first excluded to proceed to the diagnosis of nasal-type natural killer cell lymphoma. Indeed, histologic examination of the nasal mass revealed its polypoid nature. Thus, the authors were led to the diagnosis of extranodal extranasal natural killer/T-cell lymphoma, nasal-type, CD56-positive, Ep stein Barr virus-negative, TCR-negative. The patient received combination chemotherapy and completed 4 cycles of cyclophosphamide, doxorubicin vincristine, and prednisone every 14 days for 2 months. Skin lesions improved, and there was no fever soon after the initiation of therapy. Reevaluatio after the fourth cycle, however, disclosed pulmonary infiltrations as well as leukemic infiltration of the central nervous system. The patient had receive systemic salvage chemotherapy and intrathecal infusions of methotrexate. Although the lung lesions had diminished at that time, the patient develope paraplegia, his clinical course rapidly deteriorated, and he eventually died. PMID- 20839429 TI - Atrophic sarcoidosis: an unusual presentation of cutaneous sarcoidosis. AB - A 66-year-old woman presented with asymptomatic skin-colored to hypopigmented scaly plaques over the extremities, reportedly of 12 years' duration. The lesions started as well-defined erythematous scaly papules over the forearms, gradually followed by the appearance of similar lesions over both legs and dorsum of feet. During this period, the lesions increased in size, with peripheral extension and central clearing, leading to the present morphology. She is a known patient with coronary artery disease currently on treatment. There is history of exertional dyspnea, which has been related to her cardiologic ailment. She is not a known diabetic and has no other significant medical history. PMID- 20839430 TI - [Effectiveness of T-locking plate for internal fixation of medial clavicle fracture]. AB - OBJECTIVE: To investigate the effectiveness of T-locking plate in treating medial clavicle fracture so as to find out a therapy with safety and stability. METHODS: Between October 2006 and January 2009, 13 patients with medial clavicle fracture were treated with open reduction and T-locking plate fixation. There were 9 males and 4 females, aged 18-68 years (mean, 47 years), including 7 cases of traffic accident injury, 4 cases of falling injury from height, and 2 cases of heavy object hit injury. The locations were left side in 5 cases and right side in 8 cases. All cases were closed fracture. The disease duration was 1 hour to 14 days. RESULTS: All incisions healed by first intention after operation. The X-ray films showed good reduction of fracture and internal fixation. All the 13 patients were followed up 12-18 months (mean, 15 months). The average fracture healing duration was 8 weeks (range, 6-12 weeks). No complication of infection, nerve or blood vessel injury, hemopneumothorax, or internal fixation loosening or failure occurred. The anatomical medial clavicle structure as well as appearances and functions were restored. According to Rockwood's score method, the results were excellent in 11 cases and good in 2 cases. CONCLUSION: The internal fixation of T-locking plate in treating medial clavicle fracture has the advantages of good stability and low risk. Besides, the patients can do functional exercises early and the shoulder joint function can be improved in great degree. PMID- 20839431 TI - [Effectiveness comparison between open reduction combined with internal fixation and artificial radial head replacement in treating Mason type-III comminuted fractures of radial head]. AB - OBJECTIVE: To compare the effectiveness between open reduction combined with internal fixation and artificial radial head replacement in treating Mason type III comminuted fracture of radial head, to provide the evidence for available treatment methods. METHODS: Between January 2004 and June 2008, 65 cases of Mason type-III comminuted fractures were treated with open reduction, AO mini plate and screw system or a combination of Kirschner treatment (internal fixation group, n = 35) and with artificial radial head replacement (replacement group, n = 30). In internal fixation group, there were 21 males and 14 females with an age range of 21 to 35 years (mean, 30.7 years); the causes of injury were traffic accident in 12 cases, falling from height in 8 cases, and a fall in 15 cases; the locations were left side in 23 cases and right side in 12 cases; and the time between injury and surgery was 1-7 days (mean, 3 days). In replacement group, there were 19 males and 11 females with an age range of 23 to 67 years (mean, 32.5 years); the causes of injury were traffic accident in 7 cases, falling from height in 8 cases, and a fall in 15 cases; the locations were left side in 17 cases and right side in 13 cases; and the time between injury and surgery was 1-6 days (mean, 1.5 days). There was no significant difference in gender, age, disease cause, disease duration, or other general information between 2 groups (P > 0.05), so that 2 series of patients had comparability. RESULTS: Incisions healed primarily in 2 groups. All patients were followed up 1 to 4 years with an average of 2.5 years. There were significant differences in elbow flexion angle, extension angle, and forearm rotation angle between 2 groups (P < 0.05), but no significant difference in elbow pronation or supination weakness (P > 0.05). In internal fixation group, primary union occurred in 29 cases, delayed union in 2 cases, nonunion with ectopic ossification in 2 cases, and internal fixation failure in 2 cases. In replacement group, elbow flexion angle lost beyond 30 degrees in 1 case after 1 year, elbow stiffness occurred in 1 case because prosthesis was too long. According to Broberg and Morrey elbow scores system, the scores were 69.51 +/- 10.23 in internal fixation group and 81.55 +/- 12.06 in replacement group, showing significant difference (P < 0.05). The results were excellent in 15 cases, good in 5 cases, fair in 11 cases, and poor in 4 cases with an excellent and good rate of 57.1% in internal fixation group; the results were excellent in 17 cases, good in 5 cases, fair in 6 cases, and poor in 2 cases with an excellent and good rate of 73.3%. CONCLUSION: Artificial radial head replacement can achieve better joint function compared with open reduction combined with internal fixation in treating Mason type-III comminuted fractures of radial head. PMID- 20839432 TI - [Effectiveness of posterior pedicle screw system combined with interbody fusion in treating lumbar spondylolisthesis]. AB - OBJECTIVE: To analyze the effectiveness of posterior pedicle screw system combined with interbody fusion in treating lumbar spondylolisthesis. METHODS: Between January 2005 and January 2009, 26 patients with lumbar spondylolisthesis underwent posterior pedicle screw system combined with interbody fusion, including 11 males and 15 females with an average age of 56.8 years (range, 36-73 years). The disease duration was 7 months to 11 years. The affected lumbars were L3 in 3 cases, L4 in 12 cases, and L5 in 11 cases. According to the Meyerding evaluating system, 21 cases were classified as degree III, 5 cases as degree III IV, and 1 case as degree IV. The clinical results were investigated by measuring radiographic measurements, including Taillard index, Boxall index, slipping angle, lumbar lordosis angle, and intervertebral height index preoperatively, immediately, 2 weeks and 3 months postoperatively, respectively. SUK's criteria was used to judge bone graft fusion. RESULTS: Primary healing of the incisions was achieved in all cases. All patients were followed up 25.8 months on average (range, 10-51 months). There were significant differences in Taillard index, Boxall index, slipping angle, lumbar lordosis angle, and intervertebral height index between preoperatively and immediately, 2 weeks, 3 months after operation (P < 0.05). Bone graft fusion was achieved at 3-8 months after operation (mean, 3.5 months); and the fusion rate was 100%. According to Japanese Orthopedic Association (JOA) scoring, the results were excellent in 17 cases, good in 7 cases, fair in 1 case, and poor in 1 case; and the excellent and good rate was 92.3%. Complications occurred in 2 cases, including nail or rod breakage and nerve injury, and they were cured after treatment. CONCLUSION: Posterior pedicle screw system combined with interbody fusion treating lumbar vertebral spondylolisthesis can afford solid internal fixation and achieve a satisfactory reduction, so it maybe an ideal procedure and a worthy recommended method for treating lumbar spondylolisthesis. PMID- 20839433 TI - [Effectiveness comparison of two surgical procedures on lumbar disc protrusion]. AB - OBJECTIVE: To compare the effectiveness of microdiscectomy and macrodiscectomy on the single-level lumbar disc protrusion (LDP). METHODS: Between November 2002 and October 2005, 241 patients with LDP underwent 2 surgical procedures: microdiscectomy (group A, 93 cases) and macrodiscectomy (group B, 148 cases). All patients had single-level LDP. In group A, there were 51 males and 42 females with an average age of 32.3 years (range, 18-47 years); there were 23 cases of protrusion, 52 cases of prolapse, and 18 cases of sequestration with an average disease duration of 8.5 months (range, 1-18 months), including 8 cases at L2,3 level, 11 cases at L3,4 level, 35 cases at L4,5 level, and 39 cases at L5, S1 level. In group B, there were 81 males and 67 females with an average age of 31.8 years (range, 16-50 years); there were 37 cases of protrusion, 85 cases of prolapse, and 26 cases of sequestration with an average disease duration of 9.3 months (range, 1-20 months), including 9 cases at L2,3 level, 15 cases at L3,4 level, 63 cases at L4,5 level, and 61 cases at L5, S1 level. There was no significant difference in age, sex, segment level, type, or disease duration between 2 groups (P > 0.05). RESULTS: Immediate back and sciatic pain relief was achieved in 225 (93.4%) patients after operation. The satisfactory rates were 91.4% in group A and 87.8% in group B at 1 week after operation, showing no significant difference (P > 0.05). The length of incision, amount of bleeding, amount of drainage, and hospitalization time in group A were significantly fewer than those in group B (P < 0.05); while the operative time in group A was longer than that in group B, but showing no significant difference (P > 0.05). Dural laceration occurred in 4 cases of group A and 5 cases of group B, superficial infections of incision occurred in 5 cases of group B and intervertebral space infections occurred in 4 cases of group B, and epidural hematoma occurred in 1 case of group A. The perioperative complication rate (5.4%, 5/93) in group A was significantly lower (P < 0.05) than that in group B (9.5%, 14/148). LDP recurred in 4 cases (4.3%) of group A and in 9 cases (6.1%) of group B postoperatively, showing no significant difference (P > 0.05); of them, 11 cases received second operation and 2 cases were treated conservatively. All cases were followed up 36 77 months (mean, 51.4 months). There were significant differences in visual analog scale (VAS) and Oswestry disability index (ODI) between 2 groups at the last follow-up and preoperation (P > 0.05), but there was significant difference in VAS at 1 week postoperatively between 2 groups (P < 0.05). VAS and ODI were obviously improved at 1 week and last follow-up when compared with preoperation (P < 0.05). There was no significant difference in the improvement rates of VAS and ODI between 2 groups at last follow-up (P > 0.05). According to clinical evaluation of Modified Macnab criteria, the excellent and good rate was 90.3% in group A and 86.5% in group B at final follow-up (P > 0.05). CONCLUSION: Both macrodiscectomy and microdiscectomy are effective for LDP, furthermore microdiscectomy is less invasive than macrodiscectomy. Microdiscectomy is recommended to treat single-level LDP. PMID- 20839434 TI - [Clinical study on effect of dexamethasone in preventing fat embolism syndrome after cemented hip arthroplasty]. AB - OBJECTIVE: To discuss the effect of dexamethasone in preventing fat embolism syndrome (FES) in cemented hip arthroplasty patients. METHODS: Forty patients scheduled for unilateral cemented hip arthroplasty between January 2008 and December 2009 were randomly divided into trial group (n = 20) and control group (n = 20). In trial group, there were 6 males and 14 females with an average age of 73.2 years (range, 54-95 years), including 4 cases of osteoarthritis, 3 cases of avascular necrosis of femoral head, and 13 cases of femoral neck fracture; the disease duration was 4 days to 6 years (median, 0.8 year). In control group, there were 10 males and 10 females with an average age of 71.9 years (range, 59 91 years), including 2 cases of osteoarthritis, 3 cases of avascular necrosis of femoral head, and 15 cases of femoral neck fracture; the disease duration was 3 days to 5 years (median, 0.6 year). There was no significant difference in gender, age, or disease duration (P > 0.05) between 2 groups. Cemented total or bipolar hip arthroplasty (with the same brand of cement and prosthesis) in 2 groups were performed by a group of surgeons. The patients were given intravenously injected with dexamethasone (20 mg) in trial group before 1 hour of cement injection and intravenously injected with normal saline (2 mL) in control group. Amount of 5 mL vein blood were withdrawn before surgery, after 4, 8, and 24 hours of cement injection to test the number and average diameter of fat droplets. According to Gurd diagnosis standard, related FES symptoms and signs were inspected. RESULTS: Primary healing of incision was achieved in all cases of 2 groups. According to Gurd standard of diagnosis, no FES occurred in each group at 2 weeks postoperatively; deep venous thrombosis occurred in 2 cases (10%) of trial group and in 5 cases (25%) of control group, showing significant difference (P < 0.05). The number and diameter of fat droplets in trial group were significantly lower than those in control group at 4, 8, and 24 hours of cement injection (P < 0.01). All cases were followed up 7.4 months on average (range, 3 13 months). The postoperative Harris score was 89.5 +/- 6.1 in trial group and 87.9 +/- 8.3 in control group, showing no significant difference (P > 0.05). No loosening occurred during follow-up period. CONCLUSION: Intravenous injection with dexamethasone can effectively reduce the number and diameter of venous fat droplets in cemented hip arthroplasty, which can decrease the risk of postoperative FES. PMID- 20839435 TI - [Prospective study on anterior cruciate ligament reconstruction with preserving remnant anterior cruciate ligament by allograft ligament]. AB - OBJECTIVE: To analyze the effectiveness of anterior cruciate ligament (ACL) reconstruction with preserving the remnant ACL by allograft ligament. METHODS: Between January and July in 2008, 97 patients underwent ACL reconstruction with the allograft ligament. On the basis of the ACL's condition, patients were divided into 2 groups. In the trial group (patients having remnant ACL, n = 38), there were 27 males and 11 females with an average age of 24.3 years (range, 16 43 years); of them, 8 cases complicated by meniscus injury and 13 cases by Outbridge I degree cartilage injury; the time from injury to operation was 3-20 weeks (mean, 8.6 weeks). In the control group (patients having no remnant ACL, n = 59), there were 35 males and 24 females with an average age of 27.8 years (range, 18-48 years); of them, 16 cases complicated by meniscus injury and 23 cases by Outbridge I degree cartilage injury; the time from injury to operation was 4-44 weeks (mean, 12.7 weeks). All injuries were caused by sports in 2 groups. All patients had positive anterior drawer test and positive Lackman test. Before operation and 3, 8, 9, 15 months after operation, the function of the knee joint was evaluated by the International Knee Documentation Committee (IKDC) scale and Lysholm score. KT-2000 arthrometer was used to evaluate knee laxity. RESULTS: All incisions healed primarily, and no intraarticular infection occurred. Thirty-seven cases and 57 cases were followed up 15 months in the trial group and the control group, respectively. Knee instability disappeared; the patients showed negative anterior drawer test and negative Lackman test. By the evaluation of KT-2000, the joint slippage of 2 groups were less than 2 mm at 3 and 6 months after operation, but it was more than 2 mm in 2 cases of the trial group and in 3 cases of the control group at 9 months after operation; and it was no change in the trial group and 2.5-4.0 mm (mean, 3.4 mm) in the control group at 15 months after operation. Both the IKDC scale and Lysholm score were higher in the trial group than in the control group 3 months after operation, but the differences were not significant (P > 0.05). Both the IKDC scale and Lysholm score were improved at 6 and 9 months after operation in 2 groups, and the trial group showed better result than the control group (P < 0.05). But at 15 months, only the Lysholm score of the trial group was significantly higher than that of the control group (P < 0.05). CONCLUSION: The tibial remnant should be preserved as more as possible during the ACL reconstruction, which can decrease leakage of synovial fluid, help to heal and improve the function of knee joint. PMID- 20839436 TI - [Tumor-segmental resection of hand-foot-giant cell tumor of bone and autologous iliac bone graft reconstruction]. AB - OBJECTIVE: To evaluate the effectiveness of tumor-segmental resection and autologous iliac bone graft reconstruction combined with internal fixation in treating hand-foot-giant cell tumor of bone. METHODS: Between August 1997 and April 2008, 8 cases of hand-foot-giant cell tumor of bone were treated, including 3 males and 5 females with an average age of 28.5 years (range, 16-42 years). The locations were metacarpal bones in 3 cases, metatarsal bones in 4 cases, and phalanges of toes in 1 case. According to Campanacci's gradation of X-ray films, there were 1 case of grade I and 7 cases of grade II; according to pathological examination before operation, there were 3 cases of grade I to II, 4 cases of grade II, and 1 case of grade II to III; and according to TNM staging, there were 1 case of TisN0M0, 4 cases of T1N0M0, and 3 cases of T2N0M0. There were 2 cases of recurrence, the time from the first operation to recurrence were 11 and 14 months, respectively. The tumor size was 1.8 cm x 1.0 cm to 6.0 cm x 2.0 cm, the cortical bone became thinner, and the boundary between tumor and periosteum was clear. All patients underwent tumor-segmental resection combined with autologous iliac bone graft reconstruction, and miniplate internal fixation by lumbar anesthesia or trachea cannula anesthesia. RESULTS: All incision healed by first intention. Eight patients were followed up 10 to 84 months with an average of 46 months. Radiographs showed that fracture union was achieved at 3 to 9 months (mean, 5 months). No significant rotation, angular, and shortening deformity occurred in iliac bone graft. The function of iliac bone donor site recovered excellently. The pathological examination showed giant cell tumor of bone in all cases, including 2 case of grade I-II, 5 cases of grade II, and 1 case of grade II-III. The hand or foot function recovered excellently. No tumor recurrence or lung metastasis occurred during follow-up. CONCLUSION: Tumor-segmental resection combined with autologous iliac bone graft reconstruction plus internal fixation has excellent effectiveness for hand-foot-giant cell tumor of bone. PMID- 20839437 TI - [Intervention assistant operation in treatment of phalanx closed fracture combined with artery crisis]. AB - OBJECTIVE: To explore the effectiveness and methods of intervention assistant operation in the treatment of phalanx closed fracture combined with artery crisis. METHODS: Between August 2002 and December 2008, 24 cases (31 toes) of phalanx closed fracture combined with artery crisis were treated. There were 17 males (22 toes) and 7 females (9 toes), aged from 16 to 62 years (mean, 38 years). The causes of injury included crush and bruise (20 cases), traffic accident (3 cases), and machine twist (1 case). The locations were the first toe (19 toes), the second toe (10 toes), and the third toe (2 toes). The period between injury and hospitalization was 1-10 hours (mean, 6.8 hours). Phalanx angiography was performed by using venous indwelling needle for dorsalis pedis artery and posterior tibial artery puncture; according to angiography results, proper treatment could be done, then the contrast medium was injected to the artery to observe the blood supply. According to different types and locations of fracture, Kirschner wire and plate were chosen to fix fracture after the blood supply were recovered. RESULTS: Two cases (2 toes) received amputation due to necrosis at 4 days and 6 days after interventional therapy, respectively. Twenty two cases (29 toes) survived. Incision healed primarily in 21 cases. Exudation occurred at wound of 1 case and was cured at 3 weeks after dressing change. Twenty-two cases (29 toes) were followed up 1-6 years (mean, 3.5 years) postoperatively. Two cases (3 toes) felt cool or anaesthesia and could not tolerate even in cold environment. The other toes had no senses of cold pain and paresthesia. Two cases (2 toes) had nonunion and achieved fracture healing after grafting bone. The mean union time was 4.5 months (range, 3-6 months) in other cases. CONCLUSION: Intervention assistant operation is an effective measure in the treatment of phalanx closed fracture combined with artery crisis. PMID- 20839438 TI - [Submandibular sialoadenectomy by a modified retroauricular approach]. AB - OBJECTIVE: To evaluate the efficacy and the surgical procedures of submandibular sialoadenectomy by a modified retroauricular approach. METHODS: Between October 2008 and April 2009, 8 patients with benign submandibular gland disorders underwent removal of benign submandibular gland lesions using a retroauricular approach. There were 4 males and 4 females with an average age of 38.5 years (range, 32-54 years), including 3 pleomorphic adenoma and 5 chronic sialadenitis with sialolithiasis. The disease duration was from 2 months to 5 years. The anterior facial vein and the facial artery were reserved only by the ligation of branching vessels in the submandibular gland. RESULTS: Submandibular sialoadenectomy were successfully performed in 8 cases. The operative time was 45 75 minutes (mean, 60 minutes). All incisions obtained healing by first intention. No nerve paralysis occurred, including marginal mandibular branch of the facial nerve, the lingual nerve, and hypoglossal nerve. One patient had poor blood circulation of flap due to excessive traction during operation, but it returned normal after 24 hours without special treatment. Other flaps had good blood circulation. All patients were followed up 1-6 months (mean, 3 months). The incision scars were hidden with satisfactory appearance. CONCLUSION: The modified retroauricular approach has some advantages such as simple operation, better cosmetic outcome, and no complication. PMID- 20839439 TI - [In situ repair of parastomal hernia with Sublay methods in 34 cases]. AB - OBJECTIVE: To summarize the therapeutic method and effectiveness of parastomal hernia repair in situ with sublay methods. METHODS: Between February 2003 and May 2009, 34 patients with parastomal hernia were treated with Sublay methods using primary midline incision approach and polypropylene patch. There were 23 males and 11 females with an average age of 58.4 years (range, 43-78 years). The disease duration was 1 to 17 years (mean, 4.7 years). Of 34 patients, 6 had recurrent parastomal hernia. The diameter of hernia ring was 5-12 cm (mean, 7.2 cm). RESULTS: Sublay technique repair was successfully performed in all patients. The operative time was 96-160 minutes (mean, 116 minutes). The gastric tube was pulled out 12 hours to 5 days (mean, 3 days) after operation. The drainage tube was taken out at 2-7 days (mean, 4 days) after operation. The postoperative hospitalization time was 7 to 15 days (mean, 9 days). And the incisions of 32 patients healed by first intention. Incisional fat liquefaction occurred in 1 case and infection in 1 case, and their incisions healed after dressing change. Seroma at the upper of the patch occurred in 7 patients and was cured by 2 to 3 times of percutaneous puncture and local pressure. Thirty-two patients were followed up 6-75 months (mean, 32 months). No chronic pain, lumping sensation, or local expansion in wound area occurred. Two recurrences occurred 3 months and 7 months after operation, respectively, and patients restored after expectant treatment or re-operation. CONCLUSION: The in situ Sublay methods using primary midline incision approach and nonabsorbable patch is a feasible and safe method for parastomal hernia repair. PMID- 20839440 TI - [Effectiveness of traditional Chinese medicine and Western medicine in treating residual deep burn wound]. AB - OBJECTIVE: To compare the effectiveness of dressing by a combination of traditional Chinese medicine (TCM)-Western medicine (WM) after TCM bath and by the silver sulfadiazine cream (SD-Ag) in treating residual deep burn wound. METHODS: A total of 128 cases of residual deep burn wound between July 2003 and December 2009 were randomly divided into the TCM-WM treatment group (70 cases) and the WM control group (58 cases). In the treatment group, there were 45 males and 25 females with an average age of 38.6 years (range, 18-60 years), including 34 cases of flame burns, 28 cases of molten steel burns, and 8 cases of chemical burns with an average burn area of 57.6% total body surface area (TBSA) and an average residual wound of 7.4% TBSA. In the control group, there were 50 males and 8 females with an average of 37.9 years (range, 20-59 years), including 26 cases of flame burns, 12 cases of hot water burns, 16 cases of molten steel burns, and 4 cases of chemical burns with an average burn area of 56.5% TBSA and an average residual wound of 6.9% TBSA. There was no significant difference in general data between 2 groups (P > 0.05), so the clinical data of 2 groups had comparability. In the treatment group, the patients had a bath with TCM, and then the wounds were treated with dressing change of combined TCM-WM. In the control group, the wounds were treated with SD-Ag after cleaning the wounds with chlorhexidine solution. The pain, wound healing time, and the rate of scar formation were observed in 2 groups after treatment. RESULTS: According to wound pain classification after medication, the results were excellent in 23 cases, good in 30 cases, fair in 17 cases in the treatment group; were excellent in 17 cases, good in 20 cases, fair in 13 cases, poor in 5 cases, and fairly poor in 3 cases in the control group. The wound healing time of the treatment group (13.45 +/- 4.74) days was significantly shorter than that of the control group [(23.87 +/- 14.45) days, P < 0.05)]. After 2 weeks of treatment, scar occurred in 15 patients (21.4%) of the treatment group and 35 patients (60.3%) of the control group, showing significant difference (P < 0.05). CONCLUSION: Based on TCM bath, a combination of TCM-WM for the residual burn wounds is obviously superior to SD Ag. It has the advantages of rapid healing, light pain, no obvious scar, and short hospitalization time. PMID- 20839441 TI - [Preliminary study on effect of surgical delay on anti-infection ability of reverse fascio-cutaneous flap]. AB - OBJECTIVE: To improve the success rate of the reverse fascio-cutaneous flap in repairing the infected wound, to observe the effect of surgical delay on the anti infection ability of the reverse fascio-cutaneous flap by establishing an oryctolagus cuniculus model of reverse fascio-cutaneous flap based on sural nerve on the lateral side of left later limb. METHODS: Sixteen 5-month-old Japanese white rabbits weighing 2.0-2.5 kg (mean, 2.3 kg) were randomly divided into experimental group (n = 8) and control group (n = 8). The reverse fascio cutaneous flap of 4 cm x 2 cm was designed, based on 1 cm above the lateral malleolar as pedicle in sural nerve region in the lateral left later limb. In the experimental group, the full-thickness of the flap distal end half was harvested according to the design; and after 10 days delay, the full-thickness flap was obtained according to the design, and 0.5 mL Staphylococcus aureus solution was implanted at a density of 3.8 x 10(6)/mL in 2 groups. The general observation was performed postoperatively; the venous blood of the marginal ear vein was collected to observe white blood cell (WBC) count before implantation of staphylococcus aureus solution and after 1, 3, 5, 7, 10, and 14 days of implantation. The flap survival rate and the colony counting of necrosis flap tissue were calculated after 10 days of implantation; the blood vessel caliber and the peak value of peroneal artery blood flow of flap proximal end were measured after 14 days of implantation. RESULTS: All animals survived to the end of the experiment, and all incisions healed primarily. Inflammatory reaction with different degrees was observed after implantation in 2 groups, and it was obvious at 3-5 days. Inflammatory reaction in the experimental group was slighter than that in the control group. Except for no significant difference before implantation and after 14 days of implantation between 2 groups (P > 0.05), there were significant differences in WBC count at other time points between 2 groups (P < 0.05). The flap survival rate of the experimental group (93.20% +/- 4.62%) was significant higher than that of the control group (72.65% +/- 7.80%) after 10 days of implantation (P < 0.05). The colony counting of necrosis flap tissue in the experimental group [(20.63 +/- 5.76) x 10(3) colony/g] was significantly lower than that in the control group [(32.38 +/- 6.14) x 10(3) colony/g] after 10 days of implantation (P < 0.05). The blood vessel caliber of the experimental group and the control group were (1.03 +/- 0.10) mm and (0.75 +/- 0.09) mm, respectively, and the peak value of peroneal artery blood flow in the experimental group and the control group were (20.73 +/- 2.46) cm/s and (13.83 +/ 1.51) cm/s, respectively, after 14 days of implantation; showing significant differences between 2 groups (P < 0.05). CONCLUSION: Surgical delay has the ability of enhancing survival and anti-infection of the rabbit reverse fascio cutaneous flap. PMID- 20839442 TI - [Modified method of constructing tissue microarray which contains keloid and normal skin]. AB - OBJECTIVE: To seek for a method of constructing the tissue microarray which contains keloid, skin around keloid, and normal skin. METHODS: The specimens were gained from patients of voluntary donation between March and May 2009, including the tissues of keloid (27 cases), skin around keloid (13 cases), and normal skin (27 cases). The specimens were imbedded by paraffin as donor blocks. The traditional method of constructing the tissue microarray and section were modified according to the histological characteristics of the keloid and skin tissue and the experimental requirement. The tissue cores were drilled from donor blocks and attached securely on the adhesive platform which was prepared. The adhesive platform with tissue cores in situ was placed into an imbedding mold, which then was preheated briefly. Paraffin at approximately 70 degrees C was injected to fill the mold and then cooled to room temperature. Then HE staining, immunohistochemistry staining were performed and the results were observed by microscope. RESULTS: The constructed tissue microarray block contained 67 cores as designed and displayed smooth surface with no crack. All the cores distributed regularly, had no disintegration or manifest shift. HE staining of tissue microarray section showed that all cores had equal thickness, distinct layer, manifest contradistinction, well-defined edge, and consistent with original pathological diagnosis. Immunohistochemistry staining results demonstrated that all cores contained enough tissue dose to apply group comparison. However, in tissue microarray which was made as traditional method, many cores missed and a few cores shifted obviously. CONCLUSION: Applying modified method can successfully construct tissue microarray which is composed of keloid, skin around keloid, and normal skin. This tissue microarray will become an effective tool of researching the pathogenesis of keloid. PMID- 20839443 TI - [Effects of changes in axis length of patella on patellofemoral contact areas and pressures]. AB - OBJECTIVE: To explore the effects of changes in the length of the patella on patellofemoral contact areas and pressures, to provide a theoretical foundation for treatment of lower pole of patella fracture. METHODS: Using homemade-loading equipment, pressure sensitive films of 100 mm x 100 mm in size were placed on the force platform, vertically downward load (0-19.6 N) was given. The pressure sensitive response curve was obtained by computer image analysis of the pressure sensitive tablets and calculation. Six male left fresh knee specimens from voluntary donation were placed in homemade-test fixed load device, and the double layer pressure sensitive film was placed on the patellofemoral joint surface; under loading of 196 N at flexion of 0, 15, 30, 45, 60, 75, 90, 105, 120, and 135 degrees for 2 minutes, respectively, the pressure sensitive film was removed as the control group. Patellas were transected cut and in situ fixed by Kirschner wire and steel-wire as in situ fixation group. Bone fragments obtained from the corresponding 1/6 and 2/6 of contralateral patella, were embedded in the interspace between osteotomy with internal fixation with Kirschner wire and steel wire respectively as lengthening group. Followed by the amputating patella length of 1/6, 2/6, 3/6 from proximal to distal and internal fixation with Kirschner wire and steel wire by turns as a shortening group. Repeat the above steps of each experiment. By image analysis the pressure sensitive film, the patella joint contact area were measured, and patellar contact pressure (including the peak pressure and average pressure) was calculated according to pressure-sensitive response curve. RESULTS: The actual contact area were significantly smaller in the shortening groups than in the control group at flexion of 30-135 degrees (P < 0.05); the pressure was significantly bigger in shortening 1/6 group at flexion of 0, 15, 60, and 75 degrees, in shortening 2/6 group at flexion of 0 degrees and 75-135 degrees, and in shortening 3/6 group at flexion of 0-30 degrees and 75-135 degrees than in the control group (P < 0.05); the peak pressure was significantly bigger in shortening 1/6 group at flexion of 0, 15, and 60-105 degrees, in shortening 2/6 group at flexion of 0, 15, and 75-105 degrees, and in shortening 3/6 group at flexion of 0, 30, and 60-135 degrees than in the control group (P < 0.05). The actual contact area was significantly smaller in the lengthening groups than in the control group at flexion of 15, 60, and 90 degrees, and it was bigger at flexion of 105, 135 degrees in lengthening 2/6 group than in the control group (P < 0.05); the pressure was significantly bigger in the lengthening groups at flexion of 15-75 degrees than in the control group and it was smaller in the lengthening groups at flexion of 105, 135 degrees, and smaller in lengthening 2/6 group at flexion of 120 degrees (P < 0.05); the peak pressure was significantly smaller in lengthening 1/6 group than in the control group at flexion of 0, 90, and 105 degrees and smaller in lengthening 2/6 group at flexion of 0 degrees (P < 0.05). The actual contact area was significantly bigger in all lengthening groups than in all shortening groups at flexion of 30, 45, and 75-135 degrees (P < 0.05). The pressure was significantly bigger in shortening 1/6 group than in lengthening groups at flexion of 0, 60, and 90 degrees (P < 0.05), in shortening 2/6 group at flexion of 0, 60, and 90-120 degrees (P < 0.05), in shortening 3/6 group at flexion of 0-135 degrees (P < 0.05). The peak pressure was bigger in shortening groups than in lengthening 1/6 group at flexion of 0, 90, and 105 degrees (P < 0.05), bigger than lengthening 2/6 group at flexion of 0 degrees (P < 0.05). CONCLUSION: To treat comminuted fracture of the inferior pole of patella, the partial resection or the late lengthening after preserving the patella has less effect on knee joint function, especially at the patella to be cut less than 1/6 or after surgery lengthening of less than 1/6, while the latter is better than the former. The patella should be preserved as much as possible. If the patellar partial resection is inevitable, the length resection should be less than 1/6, it also can get satisfactory results. PMID- 20839444 TI - [Effect of sustained increasing fibroblast growth factor signal on development of epiphyseal plate cultured in vitro]. AB - OBJECTIVE: The biological effects of fibroblast growth factor (FGF) may be different under different intensities and durations. To investigate the impact of sustained increasing FGF signal upon the development of epiphyseal plate. METHODS: Epiphyseal plates cultured in vitro were obtained from embryonic C57BL/6J mice, and were divided into control group (0.1% DMSO), basic FGF (bFGF) group (100 microg/L bFGF and 0.1% DMSO), and PD98059 group (100 microg/L bFGF and 50 micromol/L PD98059 with 0.1% DMSO). The total length (TL) and ossified tissue length (OSL) of the cultured bones were measured with Calcein staining 6 days after culture. The expressions of Indian hedgehog (Ihh), collagen type II (Col II), and Col X genes were detected by real-time fluorescent quantitative PCR 7 days after culture. RESULTS: The embryonic bones cultured in vitro continued growth. At 6 days after culture, there was no significant difference in increased percentage of TL between bFGF group and control group (P > 0.05), the increased percentage of OSL in bFGF group was significantly less than that in control group (P < 0.05). There was no significant difference in the increased percentage of TL and OSL between PD98059 group and control group (P > 0.05), but they were significantly higher than those of bFGF group (P < 0.05). At 7 days after culture, the gene expressions of Ihh, Col II, and Col X in bFGF group significantly decreased when compared with those in control group (P < 0.05). There was no significant difference in the gene expressions of Col II and Col X between PD98059 group and control group (P > 0.05), but the gene expressions were significantly higher than those of bFGF group (P < 0.05); the expression of Ihh in PD98059 group was significantly higher than that in control group and bFGF group (P < 0.05). CONCLUSION: Sustained increasing FGF signal may affect the Col II and Col X expressions by down-regulating Ihh, which may lead to the development retardation of epiphyseal plate cultured in vitro. The external signal regulated kinase pathway may play an important role in the process. PMID- 20839445 TI - [Study on cytotoxicity of microdoses peracetic acid in vitro]. AB - OBJECTIVE: To evaluate the cytotoxicity of microdoses peracetic acid (PAA) so as to provide the evidence for making residual limit of PAA sterilization. METHODS: Mouse fibroblasts (L929 cell line) cultured in vitro were observed to evaluate the influence of microdoses PAA including 1 x 10(-6), 2 x 10(-6), 3 x 10(-6), 4 x 10(-6), 5 x 10(-6), and 10 x 10(-6) (V/V). The proliferation of cells was determined by MTT assay at 2, 4, and 7 days of culture. The growth curve and the relative growth rate (RGR) were obtained. The cytotoxicity of PAA at different concentrations was evaluated according to RGR. RESULTS: At 2, 4, and 7 days after culture, fibroblasts of 1 x 10(-6) group grew with normal morphology analogous to control group, while the cell growth of other groups were poor. With the increase of PAA concentration, the absorbance (A) values decreased, which suggested that there was a significant negative correlation between cell proliferation and PAA concentration. And the correlation coefficient was -1.000 at 2 and 4 days, - 0.964 at 7 days. There was no significant difference in A value between 1 x 10( 6) group and the control group (P > 0.05), while there were significant differences in A value between the control group and other concentration groups (P < 0.05). The growth curve of 1 x 10(-6) group was similar to that of the control group, both had obvious phase of exponential growth. The growth curves of other groups had no obvious phase of exponential growth. The cytotoxicity of 1 x 10(-6) group was classified as level 1, 2 x 10(-6) group as level 2, 3 x 10(-6) group as level 3, 4 x 10(-6) group as level 3-4, 5 x 10(-6) group and 10 x 10(-6) group as level 4. CONCLUSION: PAA of 1 x 10(-6) had no obvious cytotoxicity. The residual limit of PAA less than 1 x 10(-6) was recommended. PMID- 20839446 TI - [Study on risk factors of nonsyndromic cleft lip and palate in Chinese Guangdong population]. AB - OBJECTIVE: To investigate the association between environmental factors and nonsyndromic cleft lip and palate (NSCLP), and to explore the interaction of main risk factors in Chinese Guangdong population. METHODS: A hospital-based case control study was used. NSCLP children were selected from Cleft Lip & Palate Treatment Centre of Second Affiliated Hospital of Medical College of Shantou University between September 2009 and March 2010 as cases. And controls were chosen from other departments in the same hospital during the same period. The parents of cases and controls were inquired regarding the risk factors and the answers were filled in a unification questionnaire by physicians. These data were analysed with chi-square test and multivariate unconditional logistic regression analysis. RESULTS: A total of 105 cases and 110 controls with a mean age of 2.2 years and 3.0 years, respectively, were enrolled. Multivariate logistic regression analysis revealed that genetic family history (OR = 4.210, P = 0.039), mothers' abnormal reproductive history (OR = 2.494, P = 0.033), early pregnancy medication (OR = 3.488, P = 0.000), and maternal stress (OR = 3.416, P = 0.011) were risk factors. There were positive interactions between genetic family history and mothers' abnormal reproductive history as well as early pregnancy medication. CONCLUSION: Certain influencing factors including genetic family history, mothers' abnormal reproductive history, early pregnancy medication, and maternal stress are associated with NSCLP among Chinese Guangdong population. This study suggests that it may reduce the incidence rate of NSCLP through environmental intervention. PMID- 20839447 TI - [Related factor analysis of cubital tunnel syndrome caused by cubitus valgus deformity]. AB - OBJECTIVE: To explore related factors of cubital tunnel syndrome caused by cubitus valgus deformity so as to provide theoretical basis for the clinical treatment. METHODS: Between June 2002 and September 2008, 40 patients with cubital tunnel syndrome caused by cubitus valgus deformity underwent anterior subcutaneous ulnar transposition. Related factors was analysed through logistic regression analysis using scoring standard recommended by Yokohama City University. RESULTS: All 40 patients were followed up 27.5 months on average (range, 12-75 months). The duration of cubitus valgus deformity, cubitus valgus deformity angle, and the duration of paraesthesia and muscular atrophy were identified as related factors for ulnar neuropathy and the odds ratios were 1.005 (P = 0.045), 9.374 (P = 0.000), and 4.358 (P = 0.010), respectively. The related prognosis factors were duration of paraesthesia and muscular atrophy, deformity angle, and age at surgery, with odds ratios of 8.489 (P = 0.000), 2.802 (P = 0.030), and 4.611 (P = 0.031), respectively. CONCLUSION: Related factors for ulnar neuropathy are durations of cubitus valgus deformity, cubitus valgus deformity angle, and duration of paraesthesia and muscular atrophy. Related factors for prognosis include age at surgery, cubitus valgus deformity angle, and duration of muscular atrophy. Early anterior subcutaneous ulnar transposition should be performed in patients with cubital tunnel syndrome caused by cubitus valgus deformity. PMID- 20839448 TI - [Research of lentiviral vector mediated growth factor gene-modified bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To construct lentiviral vector carrying the human hepatocyte growth factor (hHGF) gene, and then to get hHGF gene/modified bone marrow mesenchymal stem cells (BMSCs) by infecting the BMSCs. METHODS: The hHGF gene was obtained with PCR from pcDNA-hHGF plasmid. The recombination lentiviral vector plasmid hHGF was constructed with Age I digestion and gene recombinant, then was identified with PCR and sequencing. Mediated by Lipofectamine 2000, the three plasmids system of lentiviral vector including pGC-E1-hHGF, pHelper 1.0, and pHelper 2.0 was co-transfected to 293T cells to produce hHGF gene. The supernatant was collected and concentrated by ultracentrifugation and the titer of lentivirus was measured by real-time quantitative PCR. The BMSCs were infected by the constructed lentivirus and the multiplicities of infection (MOI) was identified with fluorescent microscope, the efficiency of infection with flow cytometry (FCM) analysis, the hHGF level with ELISA analysis, and the expression of hHGF gene with RT-PCR. RESULTS: Lentiviral vector carrying hHGF gene was constructed successfully. The titer of lentivirus was 1 x 10(8) TU/mL. The infection efficiency of BMSCs by hHGF lentiviral was high and reached 98% by FCM, and the best MOI was 10. A great mount of green fluorescence was observed with the fluorescent microscope at 28 days after infection. Peak concentration of hHGF secreted by BMSCs/hHGF reached 40.5 ng/mL at 5 days. The concentration could maintain a high level until 28 days after infection. RT-PCR showed that BMSCs/hHGF could express hHGF gene. CONCLUSION: By lentiviral vector, hHGF gene was integrated into BMSCs genome, and it can express stably. PMID- 20839449 TI - [Experimental study on micro-dystrophin gene transfection into C57/BL10 mice's myoblast]. AB - OBJECTIVE: To investigate the expression of micro-dystrophin gene in myoblast cultured in vitro, to explore the possibility of combining myoblast transplantation with gene transfer for Duchenne muscular dystrophy therapy. METHODS: Competent Escherichia coli JM109 was prepared, which transformed with plasmid pSL139, and positive clones were picked to cultivate. Plasmid was extracted with Alkaline lysis method and cutter with both Pvu I and Cla I enzyme. Agarose gel electrophoresis was employed to take pictures. Ten healthy 5-7 days old male C57/BL10 mice were selected, weighing 4-5 g, the primary and subcultured myoblasts were cultured with multi-step enzymatic digestion and differential adhesion method, and Desmin immunofluorescent method was used to identify. The 3rd generation myoblasts that were transfected with plasmid pSL139 mediated by liposome served as the experimental group, untransfected cells served as the control group. After 48 hours of transfection, the expressions of micro dystrophin mRNA and protein in myoblasts were detected with RT-PCR and cell immunofluorescent methods, and the transfection efficiency was calculated. RESULTS: After pSL139 plasmids being digested and for 40 minutes agarose gel of electrophoresis, 3.75 kb fragment of target gene and vector were observed. The cells were almost uniform, and triangular or diamond shape after 24-48 hours of culture; the cells turned to fusion manner and could be passaged after 4-6 days. Desmin immunofluorescent result showed that green fluorescence was seen in cytoplasm of most 2nd myoblasts, and the purity of the myoblasts was above 90%. At 48 hours after transfection of myoblasts with plasmid pSL139, RT-PCR results showed that about 300 bp fragment was seen in the experimental group and the control group, and the brightness was higher in experimental group. Immunofluorescent staining displayed that green fluorescence was seen in the cytoplasm of the myoblasts in the experimental group and no green fluorescence in the control group; the expression efficiency of positive cells for micro dystrophin was 45%-55% in experimental group. CONCLUSION: Micro-dystrophin gene can highly express at the levels of mRNA and protein respectively in myoblasts transfected with plasmid pSL139 mediated by liposome. PMID- 20839450 TI - [Preliminary study on effects of human brain-derived neurotrophic factor gene modified bone marrow mesenchymal stem cells by intravenous transplantation on structure and function of rat injured spinal cord]. AB - OBJECTIVE: To transplant intravenously human brain-derived neurotrophic factor (hBDNF) gene-modified bone marrow mesenchymal stem cells (BMSCs) marked with enhanced green fluorescent protein (EGFP) to injured spinal cord of adult rats, then to observe the viability of the cells and the expressions of the gene in spinal cord, as well as the influence of neurological morphological repairing and functional reconstruction. METHODS: Ninety-six male SD rats weighing (250 +/- 20) g were randomly divided into 4 groups: hBDNF-EGFP-BMSCs transplantation group (group A, n = 24), Ad5-EGFP-BMSCs transplantation group (group B, n = 24), control group (group C, n = 24), and sham operation group (group D, n = 24). In groups A, B, and C, the spinal cord injury models were prepared according to the modified Allen method at the level of T10 segment, and after 3 days, 1 mL hBDNF EGFP-BMSCs suspension, 1 mL Ad5-EGFP-BMSCs suspension and 1 mL 0.1 mol/L phosphate buffered saline (PBS) were injected into tail vein, respectively; in group D, the spinal cord was exposed without injury and injection. At 24 hours after injury and 1, 3, 5 weeks after intravenous transplantation, the structure and neurological function of rats were evaluated by the Basso-Beattie-Bresnahan (BBB) score, cortical somatosensory evoked potential (CSEP) and transmission electron microscope. The viability and distribution of BMSCs in the spinal cord were observed by fluorescent inverted phase contrast microscope and the level of hBDNF protein expression in the spinal cord was observed and analyzed with Western blot. Meanwhile, the expressions of neurofilament 200 (NF-200) and synaptophysin I was analyzed with immunohi stochemistry. RESULTS: After intravenous transplantation, the neurological function was significantly improved in group A. The BBB scores and CSEP in group A were significantly higher than those in groups B and C (P < 0.05) at 3 and 5 weeks. The green fluorescence expressions were observed at the site of injured spinal cord in groups A and B at 1, 3, and 5 weeks. The hBDNF protein expression was detected after 1, 3, and 5 weeks of intravenous transplantation in group A, while it could not be detected in groups B, C, and D by Western blot. The expressions of NF-200 and synaptophysin I were stronger and stronger with transplanting time in groups A, B, and C. The expressions of NF-200 and synaptophysin I were strongest at 5 weeks, and the expressions in group A were stronger than those in groups B and C (P < 0.05). And the expressions of NF-200 in groups A, B, and C were significantly stronger than those in group D (P < 0.05), whereas the expressions of synaptophysin I in groups A, B, and C were significantly weaker than those in group D (P < 0.05). Ultramicrostructure of spinal cords in group A was almost normal. CONCLUSION: Transplanted hBDNF-EGFP-BMSCs can survive and assemble at the injured area of spinal cord, and express hBDNF. Intravenous implantation of hBDNF EGFP-BMSCs could promote the restoration of injured spinal cord and improve neurological functions. PMID- 20839451 TI - [Experimental study on biocompatibility of vascular tissue engineering scaffold of epsilon-caprolactone and L-lactide]. AB - OBJECTIVE: To explore the method of preparing the electrospinning of synthesized triblock copolymers of epsilon-caprolactone and L-lactide (PCLA) for the biodegradable vascular tissue engineering scaffold and to investigate its biocompatibility in vitro. METHODS: The biodegradable vascular tissue engineering scaffold was made by the electrospinning process of PCLA. A series of biocompatibility tests were performed. Cytotoxicity test: the L929 cells were cultured in 96-well flat-bottomed plates with extraction media of PCLA in the experimental group and with the complete DMEM in control group, and MTT method was used to detect absorbance (A) value (570 nm) every day after culture. Acute general toxicity test: the extraction media and saline were injected into the mice's abdominal cavity of experimental and control groups, respectively, and the toxicity effects on the mice were observed within 72 hours. Hemolysis test: anticoagulated blood of rabbit was added into the extracting solution, saline, and distilled water in 3 groups, and MTT method was used to detect A value in 3 groups. Cell attachment test: the L929 cells were seeded on the PCLA material and scanning electron microscope (SEM) observation was performed 4 hours and 3 days after culture. Subcutaneous implantation test: the PCLA material was implanted subcutaneously in rats and the histology observation was performed at 1 and 8 weeks. RESULTS: Scaffolds had the characteristics of white color, uniform texture, good elasticity, and tenacity. The SEM showed that the PCLA ultrafine fibers had a smooth surface and proper porosity; the fiber diameter was 1-5 microm and the pore diameter was in the range of 10-30 microm. MTT detection suggested that there was no significant difference in A value among 3 groups every day after culturing (P > 0.05). The mice in 2 groups were in good physical condition and had no respiratory depression, paralysis, convulsion, and death. The hemolysis rate was 1.18% and was lower than the normal level (5%). The SEM showed a large number of attached L929 cells were visible on the surface of the PCLA material at 4 hours after implantation and the cells grew well after 3 days. The PCLA material was infiltrated by the inflammatory cells after 1 week. The inflammatory cells reduced significantly and the fiber began abruption after 8 weeks. CONCLUSION: The biodegradable vascular tissue engineering scaffold material made by the electrospinning process of PCLA has good microstructure without cytotoxicity and has good biocompatibility. It can be used as an ideal scaffold for vascular tissue engineering. PMID- 20839452 TI - [Regulations of Hedgehog signaling pathway on mesenchymal stem cells]. AB - OBJECTIVE: To summarize the regulations of Hedgehog signaling pathway on the proliferation and multi-differentiation of mesenchymal stem cells (MSCs). METHODS: The related literature in recent years concerning the regulations of Hedgehog signaling pathway on the biological characteristics of MSCs was reviewed and analyzed. RESULTS: Hedgehog signaling pathway promoted the proliferation of MSCs, and played a major role in the induction of osteogenic and chondrogenic differentiations, but it inhibited the adipocytic differentiation. CONCLUSION: The regulations of Hedgehog signaling pathway in MSCs multi-differentiation and proliferation could be used as the new therapeutic targets of tissue ischemia, osteoporosis, achondroplasia, obesity, and so on. PMID- 20839453 TI - [Advancement of cytoskeleton and axon outgrowth of neuron]. AB - OBJECTIVE: To summarize the advancement of cytoskeleton and axon outgrowth of neuron. METHODS: The recent literature concerning cytoskeleton and axon outgrowth of neuron was reviewed and summarized. RESULTS: The actin filaments and microtubules in neuron were highly polarized and dynamic structures confined to the tips of axons and the reciprocal interactions between these two major cytoskeletal polymers was also dynamic. Attractive or a repulsive cue whose final common path of action was the growth cone cytoskeleton mediated the growth of axons of neuron by intracellular signaling cascades. Regulating the actin filament and microtubule dynamics as well as their interactions in growth cones played a key role in neurite outgrowth and axon guidance. Rho-GTPases and glycogen synthase kinase 3beta (GSK-3beta), the two major intracellular signaling pathways had emerged in recent years as candidates for regulating the dynamics of actin filaments and microtubules. CONCLUSION: The axon outgrowth and guidance depend on well-coordinated cytoskeletal and reciprocal interaction dynamics which also mediate axon regeneration after spinal cord injury. Regulating activity of Rho-GTPases and GSK-3beta simultaneously may acts as key role to regulate the dynamics of cytoskeletal and to determine axon outgrowth. PMID- 20839454 TI - [Research progress of platelet-rich plasma in promoting bone regeneration and repairing]. AB - OBJECTIVE: To investigate the factors that affect platelet-rich plasma (PRP) in promoting bone regeneration and repairing. METHODS: Recent literature was reviewed, concerning the preparations of PRP, physiological mechanism and the latest applications in orthopedic field. RESULTS: PRP, the concentrated body of autologous platelet, was rich in platelets and was the source of autologous growth factors. Many studies had shown that PRP played an important role in promoting bone regeneration and repairing. However, a few experimental results contradicted this point. The reason might be that the biological properties of PRP were influenced by various factors, such as workmanship, vector, activation schemes, working concentration, individual difference. CONCLUSION: The concentration and quality of platelet and other related factors of PRP affect the reliability of the results and conclusions. So an efficient and stable production method of PRP should be established. PMID- 20839455 TI - [Progress in diagnosis and treatment of chronic disorders of achilles tendon]. AB - OBJECTIVE: To review the progress in the diagnosis and treatment of chronic disorders of achilles tendon. METHODS: Recent literature concerning the diagnosis and treatment of chronic disorders of achilles tendon was reviewed. RESULTS: Ultrasonography and MRI were commonly used for diagnoses, and MRI could provide extensive information for the choice of therapy protocol. Nonsurgical therapy was the mainstay of treatment for most patients with overuse syndromes, surgical techniques for patients due to no effect in the conservative treatment and with chronic rupture, the clinical treatment project should be determined based on the clinical evaluation. CONCLUSION: The surgical indication of chronic disorders of achilles tendon remains controversial, the long-term results of each treatment method are unknown, the randomized prospective studies are still required. PMID- 20839456 TI - [Organohalogen compounds--new and old hazards for people]. AB - The organohalogen compounds (OCs, PCBs, PBDEs) are persistent organic pollutants (POPs) that have a widespread distribution in the environment. Their chemico physical stability and lipophylic properties are responsible for their accumulation in the human body. The general human population is exposed to PCBs and OCs through foodstuffs, mainly food of animal origin. However the main source of the human exposure to PBDEs are also food and inhalation of dust or respirable phase of the indoor air The POPs from this group are present on different levels in human tissues (fat tissue, liver; placenta), and even in human blood and breast milk. The organohalogen compounds may cause endocrine disrupting (ED) effects as they have been shown to interact as antagonists or agonists with androgen, progesterone, and estrogen receptors. Most of them shows antiandrogenic, estrogenic and antiestrogenic activity. PMID- 20839457 TI - [Toxicogenomics in hazard assessment of chemicals]. AB - Recent changes in the European legislation of chemicals suggest an urgent need for introduction of novel, alternative methods for testing chemical substances. Such possibility is offered by toxicogenomics--a scientific discipline combining knowledge from the field of toxicology, i.e., a science investigating the properties of toxic agents and the negative effects these agents exert on health and environment, with genomics, i.e., a science investigating the structure and function of genomes. New research strategies within the field of toxicology (transcriptomics, proteomics, metabolomics) offer conditions to assess the hazards associated with the effects of chemicals with both established and suspected toxic potentials. PMID- 20839458 TI - [Frequency of micronuclei in reticulocytes of male mice exposed to bisphenol A and to a combination of x-rays and bisphenol A]. AB - The aim of the study was to estimate the effects of bisphenol A and combined exposure to X-rays and bisphenol A on the induction of micronuclei in the blood and bone marrow reticulocytes. Pzh:Sfis male mice were irradiated (0.05 Gy and 0.10 Gy) or/and treated with bisphenol A (5 mg/kg mc, 10 mg/kg mc, 15 mg/kg mc, 20 mg/kg mc, 40 mg/kg mc) or exposed to combination of both (0.05 Gy + 5 mg/kg mc BPA lub 0.10 Gy + 10 mg/kg mc BPA) for 2 weeks. Bisphenol A as well as ionizing radiation alone stimulated induction of micronuclei in peripheral blood and bone marrow reticulocytes. Combined exposure of X-rays and bisphenol A induced higher frequency of micronuclei compared to effect produced by BPA alone. Sometimes, especially after combined exposure to low doses of both agents, observed effects enhanced that obtained following exposure to X-rays alone. Ionising radiation is probably the agent which decided about damage and/or unequal distribution of chromosomes following combined exposure together with bisphenol A, which seems to be weak mutagen. PMID- 20839459 TI - [Comparison of polycyclic aromatic hydrocarbons (PAHS) contents in bakery products]. AB - Polycyclic aromatic hydrocarbons are a group of well-known chemical carcinogens with a wide distribution in the environment and formed by the incomplete combustion of organic substances. PAHs have attracted most attention because of their carcinogenic potential. PAHs have been found as contaminants in different food categories such as dairy products, smoked and barbecued meat, vegetables, fruits, oils, coffee, tea, and cereals. Processing of food at high temperatures increases the amount of PAHs in the food Diet is the major source of human exposure to PAHs. The major dietary source of PAH are oils and fats, cereals products and vegetables. The aims of this study were to determine the content levels of 23 PAHs in various sorts of bread. The analytical procedure was based Soxhlet extraction with n--hexane and cleaned up in aflorisil cartridge. Chromatographic separation was performed using gas chromatography (HP 6890) coupled to mass spectrometry (HP 5973). The total concentration of PAHs was low end varied between 2.61 microg/kg to 43.4 microg/kg. Furthermore, the results revealed differences in concentrations of PAHs between rind and bread-crumb. PMID- 20839460 TI - [Mercury content of common chanterelle (Cantharellus cibarius) from four spatially distant sites in Poland]. AB - Mercury content have been determined in 59 composite samples (from 3 to 6 fruit bodies per sample) of Common Chanterelle collected near the towns of Hel, Ciechocinek and Zakopane, and in Bialowieza Forest. Total mercury have been determined by cold-vapor atomic absorption spectrometry (CV-AAS) using validated analytical method with amalgamation on golden wool and further desorption of mercury (analyzer MA-2000). Mercury content of the dried fruit bodies of Common Chanterelle depending on the site ranged from 29 for the outskirts of the Ciechocinek to 46 ng/g for the area of Bialowieska Forest. A meal made of 300 g of fresh fruit bodies of Common Chanterelle will result in intake of 0.87 (Ciechocinek) to 1.4 microg Hg (Bialowieska Forest), while eating daily Common Chanterelle at this rate within a week will result in intake from 6.1 to 9.8 microg Hg on an average, respectively. These assessed doses of mercury intake are only small portions of reference dose (RfD) and PTWI for mercury. PMID- 20839461 TI - [Assessment of human health exposure connected with consumption of water characterized with elevated concentration level of silver released from jug water filter systems]. AB - Silver usually exists in tap water at concentrations which are not connected with human health risk and therefore maximum admissible concentration level of this element was not established in Directive 98/83/EC concerning quality of water intended for human consumption. Disinfection of water based on generation of silver or silver compounds by electrochemical process could led to the increase of concentration of this metal in disinfected water up to level of 0.050 mg/l or higher although it should be underlined that this type of technology is not used in Poland. However in the case of application of bacteriostatic agents based on silver salts, e.g., in jug water filter systems consist of cartridges with activated carbon modified by silver compounds, this element may migrate into purified and further consumed water (applied also for preparation of coffee, tea, soup and dilution of concentrated juices) in amounts which provide essential part of daily dose of silver taken orally by human. In this work the results showing the concentration levels of silver released into purified water in the case of application of jug water filter systems with cartridges consist of activated carbon modified with silver compounds and ion exchanger were presented. Study was performed according to British Standard BS 8427:2004 which describes requirements in respect to the performance of jug water filter systems used for the domestic treatment of drinking water The concentrations of silver in challenge water purified by jug water filter systems were determined using validated method of determination of silver by inductively coupled plasma optical emission spectrometry technique (ICP-OES). In accordance to type of jug water filter systems applied grand mean of silver concentrations achieved during whole cycle of exploitations of product (including possibility of filtrations of 100 l of water) were in the range 0.0022 mg/l-0.0175 mg/l, which is not provided essential human health risk. PMID- 20839462 TI - Evaluation of selected food supplements containing antioxidants. AB - Seven commercial food supplements present on the Polish market were evaluated for their in vitro antioxidant capacity. The selected products were in the form of hard gelatin capsules. They contained the extracts from chokeberry, cranberry, blueberry and green tea. The mixture of vitamins and minerals as well as the product containing vitamin C in substantial dose were included into comparison. The products were examined using three methods in order to evaluate their antioxidant capacity: electron paramagnetic resonance (EPR), Trolox equivalent antioxidant capacity (TEAC), oxygen radical absorbing antioxidant capacity (ORAC) assays. Total polyphenolic content was determined according to Folin-Ciocalteu method The results were calculated per capsule. All studied preparations showed antioxidant properties and may provide substantial antioxidant protection. The in vitro antioxidant capacity varied considerably and was associated with the content of polyphenols in the capsule. The supplement with 250 mg of green tea extract was the most potent antioxidant in all assays. Nevertheless it must be remembered that the amounts of extracts were different in encapsulated products. As the quality of extracts and their properties are miscellaneous, there is a need to standardize dietary antioxidant supplements with respect to their antioxidant capacity if effective doses are to be recommended. PMID- 20839463 TI - [Determinants of food consumption enriched in vitamins and minerals--selected aspects]. AB - The aim of the research was to estimate to what extent the selected socio cognitive variable, and subjective variables concerning the health status and the way of nutrition determine consumers' behaviours on the market of food enriched in vitamins and minerals. The survey was conducted in September 2008 within the group of 1005 consumers. The data were collected via Centre of Public Opinions Research (TNO OOP) within the representative group of Polish inhabitants aged over 15 years. The questionnaire was developed by the authors of this study. It includes closed-end questions concerning familiarity with food enriched in vitamins and minerals, frequency of eating it, and selected opinions on this food The level of consumers" innovativeness was also assessed. All variables, except of subjective variable concerning health status, significantly correlated with the familiarity and the frequency of eating enriched food and with the declared intention to eat it next 3 months. The strongest correlations were indicated between beliefs on health value, benefits and variables describing consumers' behaviours. There were observed stronger correlations between socio-cognitive and subjective variables concerning the way of nutrition in the case of the declared intention to eat compared to the familiarity and frequency of eating food enriched in vitamins and minerals. PMID- 20839464 TI - [Lycopene intake by different aged women groups]. AB - The aim of the study was to estimate dietary intake of lycopene by the group of 100 women, from Central Poland, in different age <30 years, 30-50 years, >50 years (mean age 49 +/- 16 years) and main sources of lycopene. The study was carried out in the year 2006 (June-July) with the use of 4-day dietary food records. The lowest intake of lycopene was noted in the youngest group--4.17 mg/person/day, the highest intake in the oldest group--4.88 mg/person/day. The main sources of lycopene in food rations were tomato products (50.6%) and fresh tomatoes (43.5%). Tropical fruit delivered 5.2% of lycopene, other fruit and vegetable juices only 0.7%. Intakes of products, sources of lycopene, depended on age of women and were statistically significant in case of tomato, watermelon, pink grapefruit, and tomato products: ketchup, liquid tomato sauces, liquid tomato soups, tomato juice. PMID- 20839466 TI - [School stress and health disorders of post-elementary school adolescents]. AB - The aim of the study was to examine influence of school stress on level of health and health disorders in adolescence. The data were collected from students often post-elementary schools in Warsaw The investigation were carried on in two stages, when adolescents attended second grade (783 students aged 14-15 years), and in the next year, when they attended third grade (804 students aged 15-16 years). Four indicators measured severity of school stress: (1) change of school, (2) difficulties in learning, (3) lack of support from teacher (4) dislike to go to school. Seven indicators were accepted as indicators of the level of health and health disorders: (1) self-assessment of health status, (2) physical well being, (3) psychical well-being, (4) sick absenteeism during the last month, (5) frequency of staying at home or in hospital during the last year due to health disorders, (6) frequency of being in contact with physician during the last year (7) frequency of intake medicines. The first three of them were assumed as subjective indicators, and the further four as objective indicators. The analysis found out that: (1) relatively more girls than boys experienced dislike to go to school, (2) students, who changed school, had difficulties in learning, had negative relation with teacher or dislike to go to school, in comparison to those, who did not notice these problems, in general, lower assessed their health and well-being and more frequently suffered from health disorders, (3) subjective indicators of health were much more associated with school stress than objective indicators. Simultaneously, the summarized rank scale of school stress was elaborated. PMID- 20839465 TI - [Health behaviours in children and youth aged 7 to 16 years]. AB - The study aimed at describing selected health behaviors of 470 subjects aged 7 to 16 years from Jedlina Zdroj. The frequency of the meals eaten and physical activity were estimated by means of a standardized multiple choice questionnaire. In both sexes the number of hours spent on physical activity rose significantly with age. The time of physical activity in older boys was significantly higher than in their female peers. Similarly, the percentage of children skipping breakfast and the second breakfast increased with age. The amount of fruit and vegetables eaten decreased with age of the subjects. At school milk was drunk by very few boys only. PMID- 20839467 TI - [The influence of the parents education on the frequency of vegetable and fruit consumption by their children]. AB - Many different factors affect the way we eat. Extensive research shows that children and the young people consume too small quantities of fruits and vegetables. The purpose of work was examining the influence of the School Education on the consumption of vegetable and/or fruit consumption by their children. Empirical material was obtained with the quantitative method--the anonymous research. The research was passed with the autumn 2006, on 216 students aged 17-20, from the technical school of gastronomic and hotel management in Warsaw Obtained data from the questionnaire became a subject to the analysis on statistical program (SPSS). Research shows that young people consume fruits and vegetables too seldom. Analysis of variance for differentiating frequency of fruit and/or vegetable consumption according to mothers' and father's education showed no significance but analysis of variance for differentiating frequency of fresh fruit and/or vegetable consumption according to mothers' and father's education showed significance. PMID- 20839469 TI - [Assessment of nutritional status and dietary habits persons of retired for up to six months]. AB - The research aimed at evaluation of the nutritional status and dietary habits of women and men (aged 49-60) who were retired for up to six months, inhabitants ofLubuskie Voivodship. A research inquiry in the form of questionnaire was made concerning social, economical and anthropometric data which was the base for calculating the BMI and WHR indices. Nutritional value of diet was evaluated on the base of three-day records. Proper BMI index has been ascertained only in 24% of women and 9% of men. The problem of accumulation of visceral fat tissue concerned 58.6% of women and 84.2% of men. In the diet of the retired people under research the content of energy and most nutritive ingredients differed from the values advised. Statistical analysis has shown essential differences in the nutrition of men and woman. The research has showed the need to introduce the pro health nutrition education among the retired people. PMID- 20839468 TI - [Assessment of children and teenagers daily food rations in one of the orphanages]. AB - The studies on content of basic nutrients, selected minerals and vitamins in daily food rations among children and teenagers aged 7 to 18, living in one of the Poznan orphanage, in four seasons were carried out in the period between July 2007 and May 2008. The eating habits were assessed on the basis of stock reports (ten-day menu). On the basis of the obtained findings the improper distribution of energy provided with individual components was stated. The content of energy differed from the recommended values (about 24%), proteins (about 102%), fat (about 28%) and cholesterol (about 45%). The study showed too high intake level of zinc (about 47%), copper (about 71%), vitamin A (102%), B-group vitamins (44% to 163%) and too low intake of potassium, calcium and vitamin C (about 20%). The research did not find any statistically significant relationships between the consumption of individual nutrient elements and seasons. PMID- 20839470 TI - [Nutritional value of meals in the diets of women with normal and excessive body weight]. AB - The study objective was to assess the number and type of the consumed meals during the day and to make a comparison between their energetic and nutritional value in the diets of women with normal and excessive body weight. A questionnaire study was conducted in a group of 346 women aged 18-79 years (mean 41.1 +/- 13.1 years). Normal body weight was noted in 145 women (42%), whereas overweight or obesity in 201 women (58%). The study questionnaire contained questions concerning eating habits, e.g., the number of routinely consumed meals and snacks between them. A 24 h dietary recall was taken of the day preceding the examination in order to perform a quantitative evaluation of daily food rations. Taking into consideration the division into meals, the evaluation referred to the energetic value and the content of basic dietary nutrients (proteins, fats and carbohydrates) as well as cholesterol and cellulose, using the computer program Diet 2.0 designed in the Institute of Food and Feeding in Warsaw In the two compared groups, a three-meal model predominated and the afternoon snack was most frequently missed. As many as 56% of women with normal body weight and 71% of women with excessive body weight admitted irregular eating between meals. The proportion in energy delivery from the respective meals was disturbed and nutritional abnormalities were found, especially in overweight and obese women. PMID- 20839471 TI - [Energy and nutrients content in planned for consumption dietary rations of old people's home dwellers in Cracov]. AB - The aim of the research was to evaluate collective feeding way ofelderlypeople on the base of decade menus introduced in winter and summer seasons in Old People's Home in Cracov. Energetic value, supply of basic nutrients (protein, fats and carbohydrates), anti-oxidative vitamins (A, E and C) and selected mineral ingredients (calcium, phosphorus, iron and magnesium) in daily dietary rations were established and applied to dietary standards on the level of safe consumption for women and men over 60 years old of average physical activity and determined body mass. The quantity analysis of decade menus showed that energetic value daily dietary rations was correct in both seasons. Lack of balance was found in case of ingredients, protein consumption was excessive, fat supply over normative and its content in overall calorific dietary rations somewhat above normal. High content of vitamins A and E in winter menus was also shown and supply of almost all selected mineral ingredients exceeded standards of safe consumption. PMID- 20839472 TI - [The influence of temperature on survival, phenotype and antygen properties of Escherichia coli O157 strains isolated from water and clinical material]. AB - In this research I evaluated E. coli O157 strains (SF-sorbitolfermenting and NSF non sorbitolfermenting) ability to survive in samples of surface waters. These samples were additionally contaminated with other strains, used as background microflora. These water samples were stored in the temperature 5 degrees C and 25 degrees C in laboratory and environmental conditions. The results of the research show changes of phenotype and antigen properties of E. coli O157 strains during research. These changes make it difficult to isolate E. coli O157 strains from natural water with numerous background microflora. These strains in surface water are threat for humans, who swim such waters in the summer The threat results from toxic virulent factors staying for a short period of time in bacterial cells, which are lost in water PMID- 20839473 TI - Tooth size ratios of Nigerian and the applicability of Bolton's analysis. AB - OBJECTIVE: To establish tooth size ratio of Nigerian, to compare with size ratio among gender and to compare tooth size ratios of Nigerian with that of Caucasians as determined by Bolton's. MATERIAL AND METHODS: Dental casts of 250 subjects (125 males and 125 females) were used for the study. The age range was 12-15 years. All subjects had normal class I occlusion with no history of orthodontic treatment. RESULTS: A mean overall ratio of 92.5 +/- 0.5% and anterior ratio of 79.0 +/- 0.5 were reported for Nigerian teeth. Tooth size ratios among gender was compared using the Student's t-test, there was no significant difference (P > 0.05). Nigerian tooth size ratio was compared with those of Caucasians as determined by Bolton, no statistically significant differences were found (P > 0.05). CONCLUSION: Tooth size ratios among Nigerians have been established. Bolton's formula for tooth size analysis also applies to Nigerian teeth. The tooth size ratios of Nigerian females are higher than those of males. PMID- 20839474 TI - [Three-point bending moment of two types of resin for temporary bridges after reinforcement with glass fibers]. AB - One of the concerns of the dental surgeon in the realization of any operational act is the durability of this one. The mechanical resistance of the provisional prostheses contributes in a large part to the durability of those. The resins in general, have weak mechanical properties. The purpose of this study is to evaluate the resistance in inflection of temporary bridges reinforced with glass fibre. To remedy the weak mechanical properties of resins, we thought in this study, to reinforce them with glass fibres. For this purpose, we realized with two different resins, four groups of temporary bridges of 3 elements, including two groups reinforced fibreglass and the others not. Tests of inflection 3 points have been made on these bridges and resistance to fracture was analysed. The statistical tests showed a significant difference in four groups with better resistance for the reinforced bridges. PMID- 20839475 TI - Characteristic features of impacted denture cases in Nigeria. AB - OBJECTIVE: The study was designed to determine the characteristic features of impacted dentures, the patients presenting with them and to determine the pattern of distribution of cases in a cross-section of Nigerian Teaching Hospitals. MATERIALS AND METHODS: Self-administered questionnaire was distributed among Ear Nose and Throat (ENT) resident doctors during an update course at University College Hospital (UCH), Ibadan, Oyo State, Nigeria. Demographic variables, number of cases encountered over a 10-year period and characteristics of impacted dentures and those of the victims were requested. RESULT: 62.5% of the respondents indicated that the patients were males in the 30-65 years age bracket and that most of them were not satisfied with their dentures at the time of impaction. All the respondents indicated that the cases involved were partial dentures, most of which were upper acrylic dentures without clasps. The highest self-reported number of denture impaction cases (22) was recorded in Lagos University Teaching Hospital (LUTH). CONCLUSION: The preliminary report shows that cases of denture impaction usually involve upper partial dentures without clasps in dissatisfied male denture wearers within 30-65 years age bracket. PMID- 20839476 TI - [Effects of electropolishing on rupture resistance in cyclic fatigue and on the surface condition of endodontic instruments]. AB - The Nickel-titanium (Ni-Ti) instruments superelasticity does not does not allow to anticipate rupture. AIM: This study evaluates the effect of electropolishing time on the rupture resistance in flexion fatigue of the endodontics Ni-Ti instruments. METHODS: 48 HeroShapers 6% 25/100 are divided into 4 groups of surface treatment (without electropolishing, with electropolishing of 70, 80 or 90 seconds). The surface of the instruments is observed under a scanning electron microscope. Each instrument is driving by an inGet control motor at 275 rpm and put on a fatigue bench (stainless steel pipe angled at 60 degrees with r = 10 mm). The number of turn before rupture is recorded by a specific meter. Data were analysed by analysis of variance and a Fischer probable least-square difference test (PLSD) at a significance level of 0.05. RESULTS: The mean number of rotation to failure in each group of instrument decreases (407 to 355 tours) with the increase of the electropolishing time. There were no statistically significant difference (p = 0, 3508) between the different groups. CONCLUSION: Electropolishing from 70 till 90 seconds improves the surface state without modifying the rupture resistance in flexion fatigue of triple helix endodontic instruments with 6% taper. PMID- 20839477 TI - Antibacterial efficiency of passive ultrasonic versus sonic irrigation. Ultrasonic root canal irrigation. AB - OBJECTIVES: To compare the antibacterial effect of the passive ultrasonic to passive sonic irrigation with a 5.25% NaOCI solution. METHODS: Sixty human teeth were used. The crowns were removed and the roots were instrumented prior to sterilization and incubation with Enterococcus faecalis. Five mL of 5.25% NaOCI were used during a 3 min final rinsing with: syringe irrigation (n = 20), passive ultrasonic irrigation with the Irrisafe (n = 20) and passive sonic irrigation with the Endo Activator (n = 20). A sterile file was used to remove dentine shavings at the apex and placed in BHI. After 72 h, this infusion was used to inoculate blood agar plates. The presence or absence of Enterococcus faecalis colonies was determined and statistically analyzed. RESULTS: No statistically significant difference was found among the 3 groups. None of the irrigation regimen permitted to obtain 100% of bacteria free teeth. CONCLUSION: The passive agitation of the irrigation solution did not increase its antibacterial efficiency. Longer irrigation times may be required. PMID- 20839478 TI - [Oral benefits for the elderly: results of a one-year implementation of the "Sesame" plan in Senegal]. AB - Among the 650,000 persons aged 60 and over in Senegal, only 30% were receiving social security coverage, divided between the Senegalese Retirement Providence Institute and the National Retirement Fund. To fill the social demand, the government has put in place since 1 September 2006 a plan called "Sesame" which gives people aged 60 and older, free access to certain health services provided in public health. The implementation of this plan creates a lot of comments in the health community. The objectives of this study were to describe the dental benefits offered and to identify the difficulties perceived and experienced by the service provider after one year the "sesame" plan was implemented in Ouakam Health Center dental office, benchmark place of Gerontology in the Dakar North health district in Senegal. The study included two components: quantitative and qualitative terms, respectively, consisting of a retrospective study from sheets review and an interview with the health center service provider. The beneficiaries were a total of 42, mean age 68 years, including 66.7% men. Just over a third (35.7%) resided outside Ouakam. Almost 4/5 of the beneficiaries have suffered dental extractions on 1 to 10 teeth per beneficiary. The proportions of people receiving dentine treatment and curetage were respectively 4.8% and 2.4%. Qualitative data showed that the implementation of the plan was not shared between providers and beneficiaries. The "Sesame" plan is a commendable initiative to encourage and improve. PMID- 20839479 TI - Patient-centered mental health care: encouraging caregiver participation. AB - Caregivers of patients with mental illness play a vital role caring for their loved ones, yet they may not always be fully included in the process of assessment and treatment. A patient-centered approach to treating persons with mental illness views caregivers as partners in providing care for the patient. This study sought to explore perceptions of caregivers of persons with mental illness regarding the care their loved ones receive and to illicit specific issues caregivers wish to communicate with professionals that could improve patient care. A modified nominal group technique exercise was conducted as part of a suicide prevention workshop. Participants completed a four-item questionnaire. Five main themes emerged the caregivers' perception that they need to be included in the mental health care of their loved one; concerns about the diagnosing process; communication with professionals; a desire for individualized, holistic treatment; and the need for information about services and resources for the caregiver and the patient. Findings are similar to studies that also sought to understand the perspectives of caregivers. Caregivers provide an invaluable resource for the patient with mental illness. Efforts to include caregivers would enhance the overall care provided to patients with mental illness. PMID- 20839480 TI - The relational nature of case manager resource allocation decision making: an illustrated case. AB - We used ethnographic methods in the tradition of Spradley (1979) and constant comparative analysis to explore case manager resource allocation decision making. We interviewed; observed and shadowed 11 case managers within a children's home care program in a regional health authority in western Canada as they went about their daily work over a 5-month period. Our findings provide knowledge about the little-understood set of processes at the micro level of resource allocation. Although the case manager considers many factors, reported elsewhere (Fraser, Estabrooks, Allen, & Strang, 2009), they balance and weigh these factors within a relational context. The purpose of this article is to use Jenna's story as a case example to illustrate how the case manager balances and weighs the factors that influence their resource allocation decisions within this context. Jenna's story demonstrates the complex and multidimensional processes that are embedded in the relational nature of resource allocation decisions. We discuss home care case manager resource allocation decisions as viewed through the lens of relational ethics. PMID- 20839481 TI - Changing patterns of care coordination within old-age services in England. AB - There has been a focus internationally in recent years on policies and strategies to divert the long-term care of frail older people away from residential and nursing home care and enhance provision of community-based care by improving care coordination through increased differentiation within care management arrangements and service integration between health and social care. The aim of this article is to explore variations over time in care coordination arrangements within old-age services using data from national postal surveys of English local authorities. Indicators of differentiation and integration developed from earlier research were used to compare changes over time. There appeared to be some evidence of change relating to integration at both organizational and practice levels, but little change was detected in respect of differentiation within care management arrangements. The impact of the findings in the context of four enduring themes related to international case/care management literature- eligibility, integrated health and social care, shared information, and targeting -are discussed and the relevance of these in relation to possible future trends is explored. PMID- 20839483 TI - New York City Department for the Aging Annual Plan Summary 2010-2011, Part 1. PMID- 20839482 TI - Guardianship concerns in New York State. PMID- 20839484 TI - Irony and the sociocultural construction of old age in South Korea: perspectives from government, the medical profession, and the aged. AB - This article explores the intersection between discourses with multiple meanings that relate to the cultural construction of elder identities in South Korea. The authors explore the experiences of elder patients at a free clinic to consider how government policy, attitudes among biomedical professionals, and elders themselves come into contact and influence the experiences of older Koreans within the national health care system. The study is ethnographic, using interview data to examine how the identities of elder Koreans are being shifted from "weak and in need of care" to "potentially problematic consumer" and how governmental policies both stimulate and respond to that shift. By focusing on the situational status of the elderly, this article is intended to represent the voices of some elderly, voices that can be submerged within the process of decision making related to public policy. PMID- 20839485 TI - A sketch of my life. PMID- 20839486 TI - Multigenerational perspectives among indigenous people in a changing world: Native American perspectives. PMID- 20839487 TI - Poverty among the U.S. elderly under "old" and "new poverty definitions. PMID- 20839488 TI - Cytokine gene polymorphisms and risk for upper respiratory symptoms in highly trained athletes. AB - Physiological and immunological factors contributing to risk for upper respiratory symptoms (URS) in athletic populations remain under investigation. Single nucleotide changes (polymorphisms) in cytokine genes and alterations in associated gene expression may influence risk for URS in some athletes. The aim of this study was to compare the frequency of cytokine gene polymorphisms in athletes with or without a history of frequent URS. Cytokine gene polymorphisms were determined in samples from five previous investigations of immune function in highly-trained athletes (n=170). Participants were classified into two groups based on their self-reported number of episodes of URS in the preceding 12 months. Athletes were classified as healthy (n=82) if they reported < or =2 episodes of URS in the preceding 12 months. Athletes were classified as illness prone (n=88) if reporting > or =3 episodes of URS. Polymorphisms in Interleukin (IL)-6, IL-8, IL-10, IL-1 receptor antagonist (IL-1ra), IL-2, IL-4 and Interferon(IFN)-gamma were determined using real-time polymerase chain reaction allelic discrimination assays. The distribution of genotype frequencies between the two groups was compared using a Chi-square test and logistic regression was used to model risk for URS as a function of cytokine gene polymorphisms. There was a tendency for IL-6 (chi2 = 5.0, p = 0.08) and IL-4 (chi2 = 4.8, p = 0.09) genotype frequencies to differ between the groups. The IL-6 high-expression genotype was associated with an increased likelihood of > or =3 URS episodes in a 12 month period (odds ratio (OR): 2.87, 95% confidence interval (CI): 1.10-7.53; p = 0.03). The IL-2 high-expression genotype was associated with a tendency for a decreased likelihood of > or =3 URS episodes in a 12 month period (OR: 0.361, 95% CI: 0.124-1.06; p = 0.06). These data suggest cytokine gene polymorphisms may account in part for differences in risk for URS in highly-trained athletes. PMID- 20839489 TI - Is there a role for microRNAs in exercise immunology? A synopsis of current literature and future developments. AB - With the discovery of microRNAs (miRNAs), an exceptional means of regulating gene expression was introduced a few years ago. MiRNAs function to inactivate specific messenger RNA transcripts leading to depletion of the corresponding protein, whereby computational studies have shown that about one third of all animal genes might be miRNA targets. Recent publications highlight the involvement of miRNAs in regulating the immune response. The aim of this review is to provide an overview of miRNA biogenesis and function, to illustrate their impact on both the innate as well as the adaptive immune system, to show the regulation of skeletal muscle plasticity and inflammation, and finally to present their possible role within the field of exercise immunology. PMID- 20839490 TI - Senescent phenotypes and telomere lengths of peripheral blood T-cells mobilized by acute exercise in humans. AB - Acute bouts of aerobic exercise are known to mobilize antigen-experienced CD8+ T cells expressing the cell surface marker of senescence, KLRG1, into the blood. It is not known; however if this is due to a selective mobilization of terminally differentiated T-cells (i.e., KLRG1 +/CD28-/CD57+) or a population of effector memory T-cells (i.e., KLRG1+/CD28+/CD57-) that have not reached terminal differentiation. The aim of this study was to further characterize KLRG1 + T cells mobilized by acute exercise by assessing the co-expression of KLRG1 with CD28 or CD57 and to determine telomere lengths in the CD4+ and CD8+ T-cell subsets. Nine moderately trained male subjects completed an exhaustive treadmill running protocol at 80%. Blood lymphocytes isolated before, immediately after and 1h after exercise were labelled with antibodies against KLRG1, CD28 or CD57, CD4 or CD8 and CD3 for 4-color flow cytometry analysis. Telomere lengths in CD3+, CD4+ and CD8+ T-cells were determined using Q-PCR. The relative proportion of KLRG1 + cells among the CD8+ T-cells increased by 40% immediately after exercise, returning to baseline 1h later. This was due to a mobilization of KLRG1+/CD28- (61% increase), KLRG1+/CD57+ (56% increase) and to a lesser extent, KLRG1+/CD57- cells (24% increase). Telomeres in CD8+ T-cells displayed an increased relative length immediately after exercise, whereas no change occurred for CD4+ or the overall CD3+ T-cells. In conclusion, the increased frequency of KLRG1 +/CD8+ T cells in blood after acute exercise is predominantly due to a selective mobilization of terminally differentiated T-cells. The increased relative telomere length in CD8+ T-cells after exercise might indicate that KLRG1+ cells mobilized by exercise are under stress or aberrant signaling-induced senescence (STASIS). We postulate that a frequent mobilization of these cells by acute exercise might eventually allow naive T-cells to occupy the "vacant" immune space and increase the naive T-cell repertoire. PMID- 20839491 TI - The effect of exercise on plasma soluble IL-6 receptor concentration: a dichotomous response. AB - The aim of this article is to review current literature on the response of soluble interleukin-6 receptor to exercise and identify a potential role for sIL 6R in skeletal muscle function. We also provide novel data on the impact of eccentric exercise on circulating levels. The aim of the research study was to investigate changes in plasma concentration of soluble interleukin-6 receptor (sIL-6R) and soluble glycoprotein 130 (sgp130) during recovery from exercise induced muscle damage (EIMD) up to 72 h and their relationship with delayed onset muscle soreness (DOMS) and muscle function. 18 participants attended the laboratory on 4 consecutive days. On the first day, participants completed 6 sets of 10 repetitions of unilateral eccentric-concentric knee flexions at a test speed of 1.05 rad.s(-1) using a Cybex Isokentic dynamometer to induce muscle damage of the hamstrings. Prior to the eccentric exercise bout and each subsequent morning, following an overnight fast, participants had a venous blood sample taken which was centrifuged immediately and plasma frozen at -80 degrees C until later analysis. Plasma IL-6 and sgp130 were unchanged at any time point during recovery but sIL-6R was significantly reduced at 48 h and 72 h post exercise (p < 0.05). Plasma sIL-6R was correlated with DOMS at 48 h post EIMD (r = 0.45, p < 0.05) and peak muscle torque at 24 h and 48 h following EIMD (r = .42; p < 0.05; r = -.57; p < 0.01 respectively). Our novel finding that sIL-6R concentrations are decreased 2-3 days following a single bout of EIMD may reflect a regulatory mechanism controlling the influx of different leukocyte subpopulations into damaged tissue, although this needs to be confirmed by future studies. Our data suggests an association between sIL-6R, perception of pain and reduced peak muscle performance post-EIMD but further investigation is warranted to explore this relationship and implications for exercise performance. PMID- 20839492 TI - Leukaemia inhibitory factor--an exercise-induced myokine. AB - During and following exercise skeletal muscle synthesises and releases a number of myokines that exert their effects either systemically or locally within the muscle. Several of these myokines influence metabolism, regeneration and/or hypertrophy and are therefore considered to be important contributing factors in muscle homeostasis and muscle adaptation to exercise training. Leukaemia inhibitory factor (LIF) is produced and released from muscle cells in vitro and from intact skeletal muscle in vivo. During exercise, skeletal muscle potently up regulates LIF mRNA expression, likely due to oscillations in intracellular Ca2+ concentrations. However, circulating levels of LIF are not increased with exercise suggesting that LIF exerts its effect locally. LIF stimulates muscle satellite cell proliferation and is involved in muscle hypertrophy and regeneration. Thus, LIF may be produced by skeletal muscle during exercise to contribute to local aspects of muscle adaptation to exercise. PMID- 20839493 TI - Electrical stimulation induced Hsp70 response in C2C12 cells. AB - Electrical stimulation (ES) is widely used in experimental and clinical settings and shows effects on cellular response to stress; however; mechanisms underlying ES-induced effects are not thoroughly understood. We investigated the Hsp70 response in mouse myoblast derived C2C12 cells to ES at 13V in different groups (A: 12 Hz, 11 min; B: 12 Hz, 90 min; C: 100 Hz, 11 min) and harvested before ES and at 0h, Jh, 4h, 8h and 12h after ES, respectively. Control cells without ES were parallel treated to each stimulated group. Hsp70 expression was determined at protein level by quantitative Western-blot and at mRNA level by real-time PCR, respectively. ES in group A caused a modest biphasic Hsp70 response at mRNA level with a slight increase at protein level. In group B Hsp70 increased significantly (P < 0.01) at mRNA (559%) and protein level (413%), and remained elevated 12 h after ES. In group C the highest Hsp70 mRNA level (14-fold increase, P < 0.01) was observed at 4h after ES with only a moderate increase at protein level (147%, P < 0.05) at 8h after ES. Thus, ES induced distinct Hsp70 responses at both protein and mRNA level, and the characteristics of ES determined the pattern and time course of Hsp70 response in the cultured cells. ES induced Hsp70 response may serve as a common mechanism underlying diverse effects of ES and plays an important role in cellular adaptive response to ES. PMID- 20839494 TI - Akt, AS160, metabolic risk factors and aerobic fitness in middle-aged women. AB - AIMS: This study investigated the association between the basal (rest) insulin signaling proteins, Akt, and the Akt substrate AS160, metabolic risk factors, inflammatory markers and aerobic fitness, in middle-aged women with varying numbers of metabolic risk factors for type 2 diabetes. METHODS: Sixteen women (n=16) aged 51.3 +/- 5.1 (mean +/- SD) years provided muscle biopsies and blood samples at rest. In addition, anthropometric characteristics and aerobic power were assessed and the number of metabolic risk factors for each participant was determined (IDF criteria). RESULTS: The mean number of metabolic risk factors was 1.6 +/- 1.2. Total Akt was negatively correlated with IL-1beta (r = -0.45, p = 0.046), IL-6 (r = -0.44, p = 0.052) and TNF-alpha (r = -0.51, p = 0.025). Phosphorylated AS160 was positively correlated with HDL (r = 0.58, p = 0.024) and aerobic fitness (r = 0.51, p = 0.047). Furthermore, a multiple regression analysis revealed that both HDL (t = 2.5, p = 0.032) and VO2peak (t = 2.4, p = 0.037) were better predictors for phosphorylated AS160 than TNF-alpha or IL-6 (p > 0.05). CONCLUSIONS: Elevated inflammatory markers and increased metabolic risk factors may inhibit insulin-signaling protein phosphorylation in middle-aged women, thereby increasing insulin resistance under basal conditions. Furthermore, higher HDL and fitness levels are associated with an increased AS160 phosphorylation, which may in turn reduce insulin resistance. PMID- 20839495 TI - Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. AB - PURPOSE: Recent studies suggest that exchange of macrophage phenotype (M1/M2) in adipose tissue is associated with chronic low-grade inflammation in obesity. M1 macrophages enhance a chronic inflammatory state in adipose tissues, whereas M2 macrophages inhibit it. Although exercise training might inhibit pro-inflammatory cytokine gene expression in adipose tissue, it remains unclear whether exercise training affects the phenotypic switch of macrophage polarization in adipose tissue. Therefore, we inveStigated the effect of exercise training on the macrophage phenotypic switch in adipose tissue in high-fat-induced obese mice. METHODS: Male C57BL/6 mice were divided into four groups; normal diet (ND) control (n=7), ND exercise (n=7), high-fat-diet (HFD) control (n=12), and HFD exercise (n=12) groups. All exercised mice ran on a treadmill at 12-20 m/min for 60 min/day for 16 weeks. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, F4/80, monocyte chemotactic protein (MCP)-1, CXCL14, inter-cellular adhesion molecule (ICAM)-1, vascular-cellular adhesion molecule (VCAM)-1, CD11c, CD163 and toll-like receptor (TLR)4 mRNA expressions in adipose tissue were evaluated by real time-RT-PCR. RESULTS: In HFD mice, exercise training did not induce loss of body or adipose tissue mass, exercise training nevertheless markedly inhibited TNF-alpha and F4/80 mRNA expression in adipose tissue. The exercise training attenuated HFD-induced increase in ICAM-1 mRNA expression, but not MCP-1, CXCL14 and VCAM-1 mRNA expressions. In addition, increased CD11c mRNA expression, which is a M1 macrophage specific marker, with HFD treatment was attenuated by exercise training. In contrast, although the mRNA expression of CD163, a M2 macrophage specific marker, in adipose tissue was significantly decreased by HFD, the exercise training significantly increased its expression. Also, the higher mRNA expression of TLR4, which induces pro-inflammatory cytokine production after fatty acid recognition, was strongly inhibited by the exercise training in HFD mice. CONCLUSION: Exercise training might induce the phenotypic switching from M1 macrophage to M2 macrophage in obese adipose tissue besides inhibiting M1 macrophage infiltration into adipose tissue. Therefore, chronic exercise might contribute to inhibit inflammation in adipose tissue via down regulation of TLR4. PMID- 20839497 TI - Does exercise protect from cognitive decline by altering brain cytokine and apoptotic protein levels? A systematic review of the literature. AB - Regular exercise is thought to provide protection against age-related cognitive decline and possibly reduce risk of dementias. The mechanisms for the exercise protective effects are not known although changes in inflammatory cytokine levels may be involved. We conducted a systematic review of the literature to assess (1) the effects of exercise on cytokines in the brain, (2) the methodological rigour of studies which have examined these exercise effects and (3) the potential role of regular exercise in reducing the pro-inflammatory cytokine milieu that may contribute to dementia. We also reviewed the effects of exercise on concurrent pro and anti-apoptotic protein expression in the brain as related to cytokine changes. Five databases were searched until January 2010 with an initial 630 articles identified; 61 articles were retrieved of which 10 met study inclusion criteria. Investigations of both acute and chronic (training) exercise were assessed for methodological quality using a modified PEDro scale. Two studies were carried out with human participants and eight with mouse or rat models; studies differed markedly in design and methodological rigour; the types, intensities and durations of exercise, the cytokine and apoptotic proteins measured, and the regions of the brain (or proxy compartments) sampled. Despite variations in design, specific cytokine outcomes, and exercise type, the 10 studies provide limited evidence that acute strenuous exercise increases and exercise training decreases pro-inflammatory cytokines centrally. Two animal studies relate training associated decreases in pro-inflammatory cytokines with improved cognitive function using behavioural assessments such as the Morris maze. Recommendations for the design of future research on exercise, central cytokines, and cognition are offered. PMID- 20839496 TI - The open window of susceptibility to infection after acute exercise in healthy young male elite athletes. AB - The 'open window' theory is characterised by short term suppression of the immune system following an acute bout of endurance exercise. This window of opportunity may allow for an increase in susceptibility to upper respiratory illness (URI). Many studies have indicated a decrease in immune function in response to exercise. However many studies do not indicate changes in immune function past 2 hours after the completion of exercise, consequently failing to determine whether these immune cells numbers, or importantly their function, return to resting levels before the start of another bout of exercise. Ten male 'A' grade cyclists (age 24.2 +/- 5.3 years; body mass 73.8 +/- 6.5 kg; VO2peak 65.9 +/- 7.1 mL x kg( 1) x min(-1)) exercised for two hours at 90% of their second ventilatory threshold. Blood samples were collected pre-, immediately post-, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours post-exercise. Immune variables examined included total leukocyte counts, neutrophil function (oxidative burst and phagocytic function), lymphocyte subset counts (CD4+, CD8+, and CD16+/56+), natural killer cell activity (NKCA), and NK phenotypes (CD56dimCD16+, and CD56(bright)CD16-). There was a significant increase in total lymphocyte numbers from pre-, to immediately post-exercise (p < 0.01), followed by a significant decrease at 2 hours post-exercise (p < 0.001). CD4+ T-cell counts significantly increased from pre-exercise, to 4 hours post- (p < 0.05), and 6 hours post exercise (p < 0.01). However NK (CD16+/56+) cell numbers decreased significantly from pre-exercise to 4 h post-exercise (p < 0.05), to 6 h post-exercise (p < 0.05), and to 8 h post-exercise (p < 0.01O). In contrast, CD56(bright)CD16- NK cell counts significantly increased from pre-exercise to immediately post exercise (p < 0.01). Neutrophil oxidative burst activity did not significantly change in response to exercise, while neutrophil cell counts significantly increased from pre-exercise, to immediately postexercise (p < 0.05), and 2 hours post-exercise (p < 0.01), and remained significantly above pre-exercise levels to 8 hours post-exercise (p < 0.01). Neutrophil phagocytic function significantly decreased from 2 hours post-exercise, to 6 hours post- (p < 0.05), and 24 hours post-exercise (p < 0.05). Finally, eosinophil cell counts significantly increased from 2 hours post to 6 hours post- (p < 0.05), and 8 hours post-exercise (p < 0.05). This is the first study to show changes in immunological variables up to 8 hours post-exercise, including significant NK cell suppression, NK cell phenotype changes, a significant increase in total lymphocyte counts, and a significant increase in eosinophil cell counts all at 8 hours post-exercise. Suppression of total lymphocyte counts, NK cell counts and neutrophil phagocytic function following exercise may be important in the increased rate of URI in response to regular intense endurance training. PMID- 20839498 TI - The stress response of the liver to physical exercise. AB - Recent research on the effectiveness of training interventions indicates major alterations of hepatic lipid metabolism and suggests a substantial and beneficial adaptation of the liver to regular physical activity in humans. However, while various' data demonstrate the response of the working skeletal muscle to acute exercise and training, considerably less is known about the molecular events in the liver during and after increased physical activity. Here we discuss recent studies performed in rodents, that elucidate the acute hepatic response to one single bout of exercise with particular emphasis on stress response-related pathways. The acute transcriptional response to one exercise bout comprises three times more hepatic transcripts than those expressed in soleus muscle, with a significantly more pronounced up- or downregulation of hepatic genes. Evaluation of the affected pathways shows that the liver responds to acute exercise with a rapid activation of the mitogen-activated protein kinase (MAPK) signalling pathway, of the p53 protein, and of interleukin (IL)-6-type cytokine signalling pathways, resulting in a marked transcriptional upregulation of stress response genes (e.g., transcription factors of the Fos/Jun-family, growth arrest and DNA damage (GADD)45gamma, and p53-target genes) and genes typically induced by energy depletion, e.g., insulin-like growth factor binding protein (IGFBP)-1, peroxisome proliferator-activated receptor coactivator (PGC)1alpha. One explanation for the marked differential expression of hepatic genes immediately after exercise is the induction of energetic stress. After non-exhaustive exercise energy depletion predominantly occurs in the liver not as much in the working muscle, and during exercise, the liver is exposed to altered concentrations of insulin and glucagon in the portal vein. Furthermore, lower plasma glucose levels post-exercise are related to increased expression levels of stress response genes. It appears that the unique function of the liver to supply glucose for the working muscle renders this organ especially susceptible for exercise-induced cellular stress that leads to the marked induction of defense adaptations. These results give rise to the question whether these molecular events are linked not only to stress defense but to the metabolic adaptations of the liver to exercise. PMID- 20839500 TI - Development of the discipline of exercise immunology. AB - Interest in the influence of exercise upon the human white cell population dates back more than a 100 years. Thus, when introducing the third meeting of the International Society of Exercise Immunology in Brussels, Dr. Bente Klarlund Pedersen noted that Schulte had already described an exercise-induced leukocytosis as early as 1893. However, for much of the following century interest remained strictly clinical, with physicians assessing the possible changes in vulnerability to bacterial and viral diseases that were induced by various forms of physical activity. In the absence of specific remedies, bed rest was a common medical recommendation for infectious disease, and if the patient recovered from the immediate infection there was often a substantial residual loss of physical condition. Army hospitals in particular were thus anxious to know whether recovery would be compromised if physical activity were to be encouraged during convalescence. Prominent concerns of this era were the influence of exercise upon anterior poliomyelitis and viral hepatitis. The paralysis resulting from the anterior poliomyelitis virus was generally localized to body parts that had been active, and it seemed most likely to develop in those who continued to engage in vigorous exercise in the face of early symptoms (46, 57, 119, 120). Data on viral hepatitis also suggested a need for rest in the acute phase of the disease (1, 65, 115, 128), although most authors concluded that in this condition exercise could be resumed during convalescence, provided that the patient was no longer severely jaundiced (5, 32, 136). PMID- 20839499 TI - Influence of exhaustive exercise on the immune system in solid organ transplant recipients. AB - Prolonged exhaustive exercise has a great impact on the immune system of athletes and leads to a transient weakening of the immune system. A host of studies has documented changes of immune parameters in peripheral blood following exercise. Concerning the effect of exhaustive exercise in transplant recipients there is little knowledge at present. We analysed peripheral blood in healthy athletes and transplant recipients who participated in the "Euregio cycling tour 2009" before and immediately after they performed 81 km of cycling that included ascending more than 1800 m in altitude. A full blood count and an automated differential count as well as microarray analysis were performed before, immediately after and one day after exercise in 10 male patients carrying a kidney transplant and in 10 controls matched in age and gender. Comparing the absolute increase in neutrophils in these two groups, we detected that the relative increase in neutrophils was significantly smaller in transplant recipients compared to their corresponding controls after exhaustive exercise. While both groups were comparable in performance, microarray analysis revealed a markedly different pattern of gene expression in transplant recipients compared to their controls. From the 130 genes that were significantly upregulated in controls immediately after exercise, only 12 genes were also upregulated in transplant recipients. 64 different genes were upregulated in transplant recipients only. Our findings may be related to the immunosuppressive medication that the transplant recipients took and therefore it should also be discussed that regular exercise might reduce the need for immunosuppressive medication in transplant recipients. PMID- 20839501 TI - Congress misses another deadline to fix Medicare; doctors' disappointment grows. PMID- 20839502 TI - Comparing manual and automated coding of physicians quality reporting initiative measures in an ambulatory EHR. AB - The objective of this study was to compare the completeness and accuracy of Physicians Quality Reporting Initiative (PQRI) quality measure code assignment by manual coding and the automated system. Documentation for 62 PQRI quality measures was built into the electronic health record (EHR) system used in 15 rural ambulatory clinics with 70,000 patient encounters per year. The documentation systems and processes within the ambulatory EHR were standardized so data required for quality measurement would be available as extractable data. Completeness and accuracy of coding was compared between an expert coder and an automated system. Automated coding was significantly more complete and accurate than manual coding for the quality measures examined. PMID- 20839503 TI - Ten signs of a healthy online presence (and symptoms that may indicate it is under the weather). AB - There is no denying that the Internet has become the marketplace of choice for a vast number of consumers, a number which continues to grow year after year. It is particularly true for the medical community as prospective patients often conduct extensive online research before they even consider picking up a phone to make an appointment. With so much information available online, it's only natural that the Internet is the first stop for so many, and only logical that medical professionals would begin to reach out to searchers online with Web sites, social media, and other online initiatives. How is your practice doing online? The answers to these 10 questions can indicate if your online presence is healthy or in need of an intervention. PMID- 20839504 TI - In today's uncertain financial environment, how difficult will it be for you to collect on your disability insurance policy? AB - Disability insurance companies are in tough spot. The down economy, lack of profitability from the sale of new policies, and significant increase in the number of physician claims filed over the past several years have resulted in financial chaos. Many disability insurance companies are vanishing or feeling pressure to release reserves just to stay afloat, and unfortunately this materially affects claimants in the manner in which their claims are administered. PMID- 20839505 TI - Got a mission? PMID- 20839506 TI - The false claims act and its impact on medical practices. AB - A lawsuit under the federal False Claims Act can threaten the survival of a medical practice. The Act prohibits a range of misconduct involving the submission of false claims to the government, as well as the knowing and improper retention of overpayments of government funds. Violations of the Act result in liability for treble damages and civil penalties of as much as $11,000 per violation. Although the Act imposes liability only on persons who act "knowingly," the "knowing" requirement is met if the person acts with deliberate ignorance or reckless disregard of the circumstances. The Act contains a "qui tam provision under which a whistleblower, acting on behalf of the government, may file suit to enforce the Act's terms, and if the lawsuit is successful, can receive a substantial percentage of the government's recovery. PMID- 20839507 TI - Developing telephone skills: making ring-ring go cha-ching. AB - The telephone is the first interaction that most patients will have with your practice. What happens during that interaction will determine the patients' first impressions of your office and also their attitude toward the practice and the physician. This article covers simple steps that every practice can take to ensure a positive experience for the patients. These are steps that any practice can implement and will make certain that every patient has a positive first impression of you and your practice. PMID- 20839508 TI - Healthcare reform: what employers have to do now. PMID- 20839509 TI - Don't risk suspension of your Medicare payments: check your PECOS record prior to July 6, 2010. PMID- 20839510 TI - Is it time for a new practice environment? Part III: designing and constructing your new practice environment. AB - In school, architects are taught "Form follows function," but all too often this concept is forgotten or not followed in planning medical practice environments. Things such as the architecture (look) of the building, the budget, the view from the office, etc., drive planning decisions when none of those can help promote doctor-patient interaction. The planning of a medical practice environment should follow an operational approach that is focused on the concept that best utilizing the doctors' time to provide care to more people is the ultimate goal. All decisions, from where the building is located, to where the exam rooms are located within the building, to how communication is handled, should all be based on how they best facilitate patent and doctor interaction. PMID- 20839511 TI - Workplace etiquette for the medical practice employee. AB - Medical practice workplace etiquette is slowly being modified and fine-tuned. New workplace etiquette rules have become necessary because of advances in communications technology, shifting norms, and expectations of what constitutes good manners. Today's medical practice employees must concern themselves with traditional workplace manners but also the manners that come into play when they make or receive cell phone calls, text messages, and e-mails, and when they use social networking media outside of work. This article offers 25 rules for good manners in the medical practice that relate to the ways employees interact with people today, whether face-to-face or when using electronic communications technologies. It offers practical guidelines for making introductions both inside and outside the medical practice. This article also provides a self-quiz to help medical practice employees assess their workplace etiquette intelligence and 12 tips for good workplace table manners. PMID- 20839512 TI - How to choose the right financial planner. AB - An "economic Pearl Harbor." That is how the world's most famous investor, Warren Buffett, described what we have gone through and what we're still going through.' Even the most optimistic appraisals of our economic conditions suggest that we are likely to feel the effects of the Great Recession through the decade we recently entered. Healthcare reform, in whatever form, may also create change in your medical practice ranging from immaterial to revolutionary. To whom should you turn to ensure that your personal economy survives and thrives, especially in these times? A financial planner, possibly, but what is a financial planner, how do you choose one, and what sort of service should you expect? PMID- 20839513 TI - CMS modifies Medicare policies regarding supervision requirements for hospital outpatient services. PMID- 20839514 TI - Retire already! Managing physicians who no longer want to work, but have to. AB - The economic downturn has wreaked havoc on our professional lives and has presented a whole host of challenges including managing physicians who can no longer retire due to the reduced value of their retirement savings. As a result, many medical practices are burdened with physicians who are disinterested in continuing to work in the practice, but who remain solely due to financial reasons. This article will provide practice managers with several means to encourage these "retired-on-the-job" physicians to improve their attitudes and productivity levels, or do what they have already informally done--retire. Specifically, this article reviews four options for dealing with such employees, including: (1) coaching; (2) offering flexible work options; (3) changing revenue sharing agreement; and (4) dismissal. PMID- 20839515 TI - A solution for rural physician burnout: the creation of the PEERist. AB - A major factor in rural physician burnout is the demand of providing emergency room and hospital coverage in addition to running a clinic practice. The creation of the PEERist helps solve this problem without causing economic hardship for either the hospital or the physician. The PEERist has particular applications to rural doctors affiliated with critical access hospitals. PMID- 20839516 TI - Professional courtesy: can you legally provide it? AB - Professional courtesy: Something most physicians did and enjoyed doing, and that was a nice perk that physicians offered their colleagues. But is it legal? Can it still be done without breaking the law? What are the guidelines? This article will answer these questions. After reading this article, you will understand the guidelines for professional courtesy and what the risks and penalties are if they are violated. PMID- 20839518 TI - Providers revamp dining to 'please the palette. Choices and flexibility lead to better outcomes. PMID- 20839517 TI - Computer briefs: Med, Fed, and IT. PMID- 20839519 TI - MDS 3.0: setting the stage. PMID- 20839520 TI - Dementia care refresher. PMID- 20839521 TI - Buyer beware. PMID- 20839522 TI - Ensuring time is on your side. AB - John Edwards, senior director, Global Healthcare Solutions, at Primex Wireless, discusses the challenges, solutions, and benefits, of implementing process automation and intelligent power management applications to help hospitals and other healthcare facilities save time, reduce costs, boost productivity, and ensure optimal regulatory compliance and patient safety. PMID- 20839523 TI - Planning for proton therapy. AB - Bruce Johnson, senior vice-president at the Houston, Texas offices of internationally-recognised HKS Architects, examines the considerable physical challenge of accommodating sizeable proton external beam radiation therapy equipment into hospitals, drawing on work undertaken by the practice to date in designing hospitals to cater for such sizeable machinery. PMID- 20839524 TI - Facility shows benefit of staying single. AB - Construction of the new 513-bed PFI-funded hospital in Pembury near Tunbridge Wells in Kent, a pound 227 million acute healthcare facility that, on its completion in the autumn of 2011, will be the UK's first to offer 100% single-bed en suite accommodation, is ahead of schedule, "thanks to excellent teamwork and careful planning". During a visit to the now rapidly emerging healthcare facility, located in an Area of Outstanding Natural Beauty (AONB) in a wooded hillside location in the Weald of Kent which Nigel Keen, general manager for the PFI project company, described as "the most attractive site for a hospital I have ever worked on", HEJ editor Jonathan Baillie met key project personnel and discussed the impressive progress made to date. PMID- 20839525 TI - Pound 25 m investment to accelerate growth. AB - Undeterred by the current economic downturn, and determined to give its customers even better service and reduced order lead times via a more efficient manufacturing and distribution operation, Spirax Sarco, one of the UK's leading steam engineering specialists, is investing pound 25 million in its Cheltenham manufacturing operations in a move which it explains will bring together onto one enlarged site its entire production, distribution, and R&D activities. Jonathan Baillie reports. PMID- 20839526 TI - Surgeons' vision rewarded. AB - Surgeons and clinical staff, theatre circulation and scrub personnel, and anaesthetists, as well as the estates and facilities team at Kent's Maidstone Hospital, have worked with specialist supplier of integrated audio, video, and instrumentation systems for the operating room, Olympus Medical, to develop what is claimed is among the UK's most advanced operating theatres yet built for laparoscopic and endoscopic surgery. HEJ editor Jonathan Baillie discussed the project with Amir Nisar, the surgeon who championed efforts to get the facility built, and Olympus Medical national sales manager, systems integration, James Watts. PMID- 20839527 TI - Shifting services and enhancing efficiency. AB - How the healthcare sector, and, in particular, the estates and facilities managers running healthcare facilities UK-wide, can "survive, strive and thrive" given an environment where real-term healthcare spending growth could fall below 1% over the next five years, was the main theme of the recent HefmA 2010 national conference in Harrogate. One key conclusion was that estates and facilities professionals will, in future, need to adapt quickly to a scenario where a growing number of services onc considered core to large acute hospitals will migrate to more "all-embracing" primary care facilities nearer to patients' homes. HEJ editor Jonathan Baillie reports. PMID- 20839528 TI - A model approach to identifying priorities. AB - Peter Sellars, the Department of Health's deputy director of Gateway Reviews, Estates and Facilities Division, explains to HEJ editor Jonathan Baillie how and why the new NHS Premises Assurance Model (NHS PAM) was developed, and describes how recent piloting by several Trusts generated "extremely positive" feedback in advance of the Model's wider roll-out. PMID- 20839529 TI - Learning lessons and raising awareness. AB - With recent Association of British Insurers (ABI) fire loss figures reportedly showing "a picture of worsening public fire protection in the UK", Tom Welland, fire services manager at fire safety consultancy Fireco, asks if, at a time of tough budgetary constraints, those responsible for fire safety in the health service are being encouraged to follow the principle of reducing risk to levels "as low as reasonably practicable" (ALARP)? PMID- 20839530 TI - Tendencies in nursing care research. PMID- 20839531 TI - [Blood pressure tracking: study with children and adolescents with familial history of hypertension]. AB - The purpose of this study is to analyze the evolution of the percentiles of blood pressure in children and adolescents with familial history of arterial hypertension. This is a longitudinal study developed in a community in Fortaleza. Ceara, Brazil. The blood pressure was evaluated in five home visits from January, 2004 to December, 2006. The group was composed of 141 participants, of which 92 were children and 49 adolescents. Of the children, 67.4% remained with no alterations of the percentiles of blood pressure in all the evaluations; of the adolescents, 65.3% remained in the same condition. Most individuals kept their values and percentiles of systolic blood pressure and diastolic blood pressure, and many that did not initially present alterations started to show some during the follow up. As a result, routine monitoring of blood pressure of children and adolescents proves necessary for the early detection and prevention of complications. PMID- 20839532 TI - [Coping with the specter of cancer]. AB - The purpose of this study is to understand how women and their families live with the daily confrontation of cancer after the end of the treatment. Symbolic Interactionism and Data Theory were used as a theoretical and methodological framework. Data were collected from March to November 2005, from twenty subjects, with ten women suffering from cancer and their relatives divided into three sample groups. To live with cancer triggers a variety of emotions, such as the fear that one day the disease will return. This makes laboratory tests after treatment considerably stressful. To live with cancer means worrying about the disease and seeking strategies to cope with it. The study allows us to understand this situation and rethink some of the caring strategies. PMID- 20839533 TI - [The dynamics of the family that lives with and takes care of an elderly dependent relative]. AB - Constant depletion of some functional capacities and an increasing vulnerability are associated with the ageing process. Eventually, the individual becomes dependent on someone and the family is the main supportive institution. In view of this situation, one question guided our study: What is the relation between the family dynamics and to live with and take care of an elderly dependent relative? Our purpose is to analyse how the care provided by the family works, relating the family dynamics with the level of dependency of that relative and the age of the caregivers. We developed a related and transversal study, with an intentionally sample composed by 80 families and 143 caregivers. An evaluation scale was used to measure the dependency level of the elderly anda family adaptability and cohesion evaluation scale (FACES III). We concluded that the elderly level of dependency does not change the cohesion and adaptability of the family. Nonetheless, we also observed that the age of the caregiver alters the family dynamics, what can lead to the development of a pathological picture. PMID- 20839534 TI - [Nursing outcomes classification applicability on patients with self-care deficit bathing/hygiene]. AB - The purpose of this research is to explore the Nursing Outcomes Classification (NOC) applicability on hospitalized orthopedic patients diagnosed with Self-care Deficit: bathing/hygiene. This is a quantitative, descriptive study developed in a university hospital with patients submitted to total hip replacement in 2008. The data collection instrument was composed of 24 NOC Self-care outcome indicator: Self-care: Activities of Daily Living; Self-care: Bathing; Self-care: Hygiene; Self-care: Oral Hygiene; and a Likert scale in which 1 = dependent 2 = does not participate; 3 = requires an assistant; 4 = independent but requires an assistant mechanism; 5 = completely independent. 25 patients bathing on first and third post-operative day were observed. Ethical aspects were respected. In 21 cases there was significant statistical variation between average scores from first to second bath. NOC classification scales presented internal consistency, proving their reliability to measure the patient evolution during nursing care implementation. PMID- 20839535 TI - [Students' practice in the construction of knowledge about the phenomenon of drug abuse]. AB - This is a qualitative descriptive research, carried out with nursing undergraduates from Rio de Janeiro State University, Brazil. The purpose is to discuss students' experiences and their social practice in assisting drugs uses. Data were collected from December 2008 to January, 2009, with the use of focal groups composed by 19 undergraduates from the last three semesters of the course. The project was approved by the Ethics Research Commission. All participants signed the Informed Consent. The results evidenced students' difficulty in facing reality, due to the contrast between theory and practice. Such difficulty came out as a consequence of an inapropriate educational approach. We concluded that the academic institutions should optimize the use of teaching process. Professional formation related to the phenomenon of drug abuse is considered essential as it becomes more and more frequent in nurses' daily routines. PMID- 20839536 TI - [Humane care for low-weight newborns (kangaroo mother method): mother's perceptions]. AB - Breastfeeding is one of the key practices which promote health, being associated with a reduction of diseases and mortality in childhood. Thus, from the course conclusive work, the present article was structured, which aimed to recognize the perceptions of mothers in the face of the use of the mother kangaroo method. With a qualitative, descriptive and field approach, it was held at the Philanthropic Hospital of Ponta Grossa, Parana, Brazil, by the months of August to October 2006, in which six mothers were included in the kangaroo mother method during the admission of the baby. For the gathering, semi-structured interviews were made and data were analyzed by the content analysis. This article analyzed two categories, maternal experience with the mother kangaroo method, with the subcategories: mother kangaroo method and maternal breastfeeding and experiences at the kangaroo practice; and knowing the kangaroo method. As a conclusion, nursing plays an essential role in the insertion of the family to the method, from the provided cares. PMID- 20839537 TI - [Considering human peculiarities in attention to health care through dialogue and assistance]. AB - The aim of this qualitative exploratory research is to understand how health workers relate to the main object of their work--the user--both subject and author of his/her life history. Eleven nursing practitioners from a Basic Health Unit participated in a semi-structured instrument, in March and April, 2008. The speeches revealed two converging themes: (1) Consideration of human peculiarities in attention to health care; and (2) dialogue and assistance as interactive possibilities. We found that the attention to health care is broadening the debates over valuing human peculiarities through dialogue and assistance as interactive possibilities. PMID- 20839538 TI - [Evaluation of nursing records on the physical examination]. AB - The nursing records are essential to generate benefits to individualized care planning, once data collection is the first step of the Nursing Process. The purpose of this study is to analyze the records made by nurses during each physical patient examination in critical care units (CCU) and hospitalization units (HU). This is a transverse and retrospective study, in which forms and records from both public and private hospitals were analyzed. From the 69 records considered, we observed a greater quality and frequency in records from CCUs, while records from HUs were mostly about intercurrences that happened during the shift. The research shows a deficit in physical examination records of patients, which complicates the individual assistance focused on the real needs of the patient, since many changes in patient's condition might not be recorded. PMID- 20839539 TI - [Peripherally inserted central catheter: description of its use in neonatal and pediatric ICU]. AB - The purpose of this descriptive, retrospective, documental study is to describe the use of peripherally inserted central catheters (PICC) in a neonatal and pediatric intensive care unit regarding their insertion, maintenance, and removal. This study also characterized the population which received the catheter through descriptive and statistical analysis of 176 instruments filled out by nurses, in a two year period. The population attended consisted of 125 patients, mainly premature (43.2%) and male (60%). The basilic and cephalic (43.2%) veins were primarily used for the insertion of a 1.9Fr (85.8%) catheter. The success rate was 98.9% in the punctures, but anticipated removal occurred due to obstruction (25%), infiltration (18%), suspected contamination (16.6%), traction (13.9%), rupture (11.2%), accidental removal (8.3%), phlebitis (4.2%), cyanosis (1.4%), and migration (1.4%), with an average period of permanence of 14.5 days. In order to maintain the catheter professional education and preparation are required to qualify care. PMID- 20839540 TI - [The daily routine of women infected with HIV/AIDS way of being in the face of the impossibility of breastfeeding]. AB - The purpose of this phenomenological research is to understand the daily routine of women infected with the virus of human immunodeficiency (HIV) prevented from breastfeeding. Twelve women were interviewed in a university hospital in southern Brazil. Their statements, analyzed through a Heideggerian approach, showed that the women reveal themselves as beings-in-the-world and are mainly impersonal. The way of being of de-cadence was unveiled and expressed by occupation, gossip, curiosity, ambiguity, fear, and the inauthenticity of the pact of silence and the unsaid. The helpful care mediated by a dialogic relationship between mother and son/daughter between the woman and the professional, showed the possibility of movement from inauthenticity to authenticity. We recommend the use of direct and dialogued interaction as an assistance strategy, mediated by listening, empathy and intersubjectivity, and developed through the comprehension of the way of being of the human being in the face of the impossibilities imposed by the serological condition and in their attempt to unveil their possibilities. PMID- 20839541 TI - [Palliative care: the nurses' contributions in pain assessment]. AB - The purpose of this study is to reveal nurses' ideas and contributions on the assessment of cancer patients' pain in palliative care through a proposal of work education based on Paul Freire's problematizing education theory. We used Juan Charles Maguerez's "problematization arc" as a strategy for data collection. The study included six nurses. The results pointed to three categories: (1) the meaning of pain, (2) the way pain assessment is practiced by nurses and (3) contributions to care. Cancer pain is a total pain. It exceeds the physical dimension of disease and extends to psychological and social dimensions. The deployment of systematic pain care routines, enclosed in the systematization of nursing care makes it possible to better redirect the actions, therefore achieving a most complete and effective pain management. PMID- 20839542 TI - [Social determinants of health: community features and nurse work in family health care]. AB - The purpose of this study is to identify the Social Determinants of Health Care which emerge in nurses' statements as they characterize the community, analyzing its relation to the work carried out by them. It is an exploratory and descriptive study containing a qualitative analysis in the theoretical categories of the determinants. We used a semi-structured interview, recorded with the permission of the 65 nurses of the Family Health Care, members of the 3rd Regional Health Care Coordination of Rio Grande do Sul, Brazil. It has been shown the inter- and intra-relation in the health determinant factors, obtaining 104 citations for the anatomo-physiological features of the corresponding individuals/community to the proximal correspondents and in association, mainly, to the work carried out by the nurses. For intermediate determinants there were 27 citations and, for distals, 166, with predominant reference to the territorial localization of communities in rural areas and peripheries. The nurses have stated a narrow relation between the proximal features and the work carried out by them, as well as the connection with other determinants in the relation with the process of getting sick. PMID- 20839543 TI - [Patients with facial image alteration: care circumstances]. AB - The purpose of this exploratory qualitative study is to understand how patients with altered facial image perceive care action and the circumstances that may influence their perception. The collection of data was carried out from August to October 2008, among patients from the head/neck clinic hospitalized in the surgical unit of the University Hospital of Santa Maria, Rio Grande do Sul, Brazil. The instrument used was the semi structured interview. The information was analyzed by content analysis and highlighted the following categories: (1) living with the changes and (2) care circumstances. Thus, we observed how difficult and suffering it is for patients to live with their changed facial images. As a result, it was concluded that patients need not only the professional, technical and scientific-based care, but also a care based on carefully guided human values, which should always be discussed, studied, respected and treated as an object of commitment and responsibility by nursing practitioners. PMID- 20839544 TI - [Kidney transplanted patients: nursing diagnoses association analysis]. AB - Chronic kidney inadequacy is a disease with serious physical, psychological and socioeconomic implications for the patient. The renal transplant provides life quality to chronic renal patients. The purpose of this study is to analyze associations among nursing diagnoses, related factors and defining characteristics present in renal transplanted patients of a university hospital. A descriptive, exploratory, cross sectional study was performed with 58 patients from December 2004 to April, 2005. Data collection instruments were: interview scripts and physical exams. Results showed associations between Sleep pattern disturbance and Sexual dysfunction, Sleep pattern disturbance and Altered sexuality pattern, Sexual dysfunction and Altered sexuality pattern. The study contributes for the identification of nursing diagnoses related to specific characteristics of these patients. PMID- 20839545 TI - [Profile of caretakers of elderly people with cognitive alterations in different contexts of social vulnerability]. AB - The purpose of this study is to characterize caretakers of elderly people with cognitive disorders, users of Family Health Units (FHU), that live in different contexts of social vulnerability. Household interviews were conducted (N = 72) with the use of an instrument previously designed, containing socioeconomic and demographic characterization data. All ethical cares have been observed. The results show that caretakers of elderly people that live in contexts of high social vulnerability are primarily adult, married women, with incomplete elementary school education, who work at home. These caretakers live with the elderly person they are in charge of develop a dose relationship with them and do not receive help from professionals. Similar data were found in contexts of low social vulnerability, except that in those cases the support of a formal caretaker is available. The study of the profile of caretakers of elderly people with cognitive alterations living in different contexts of social vulnerability can provide FHU with subsidies so that they can formulate more specific care strategies to caretakers. PMID- 20839546 TI - [Socio-demographic and clinical profile of patients using oral anticoagulants]. AB - The purpose of this study is to investigate the socio-demographic, clinical and laboratory profile of individuals in the follow-up period due to the use of oral anticoagulants. This is a descriptive study, cross performed in the clinic of oral anticoagulation in a tertiary hospital in the state of Sao Paulo, Brazil. Data were collected through interviews and examinations of the patients' medical records. 180 subjects participated. The results show that the most females (65.6%), with an average age of 55 years, use warfarin (83.3%) for 6.9 years or more, due to the presence of metallic prosthetic heart (50%). These results provide subsidies for nurses to plan the assistance of their patients in oral anticoagulation therapy as a way of reducing complications related to therapy and increasing adherence to treatment. PMID- 20839547 TI - [Prevalence of risk factors for acute coronary syndrome in patients treated in an emergency service]. AB - Our purpose is to characterize the profile of patients with Acute Coronary Syndrome (ACS) assisted in an emergency service in Porto Alegre. The characterization of the profiles focus on risk factors. This prevalence study was carried out from August, 2007 to February 2008. To collect the data, we developed a questionnaire, checked bedside assessment and measured anthropometric evaluation. 152 patients had their ACS evaluated, of which 63.8% were males, with an average age of 61 +/- 10.26 years. 50.7% had acute myocardial infarction non ST elevation, 14.5% acute myocardial infarction with-ST elevation, and 34.9% unstable Angina. Risk factors were sedentariness (86.8%); overweightness and obesity (77%); systemic arterial hypertension (75.7%); family history (56.6%); stress (52.6%); dyslipidemia (44.7%); diabetes mellitus (40.1%); tobacco smoking (39.5%); and alcohol consumption (14.4%). A high prevalence of risk factors for ACS was verified, indicating a necessity of health education programs to reduce morbimortality. PMID- 20839548 TI - [Relationships and interactions in the process of healthily becoming an adolescent]. AB - The purpose of this study is to explore how teenagers view the relationships and interactions in the process of healthily becoming an adolescent. This qualitative exploratory research was conducted with ten teenagers in a state college in a town in southern Rio Grande do Sul, Brazil, from August to October, 2007. We used semi-structured interviews to collect the data. Later, we decided to use a thematic analysis, in which two themes emerged: (1) the process of building relationships and interactions in adolescence and (2) the risk in social life. As a result, we realized the importance of interpersonal relationships formed in adolescence, which deserve the nurse's attention. Nurses can help in the guiding of this population in basic health units, hospitals or schools, to a healthy adolescence. Thus, teenagers may enjoy the relationships built in this process in order to grow and to enter into adulthood. PMID- 20839549 TI - [Typology of nursing care according to hospitalized clients: scientific-technical and expressive dimensions]. AB - This qualitative-descriptive study was carried out in a university hospital in Rio de Janeiro, Brazil, from August, 2007 to December, 2008. Nursing care was described and characterized based on the perceptions of 26 hospitalized patients. Data collection was carried out through interviews and the "Almanac" creative and sensitivity technique, followed by thematic content analysis from which the following category emerged: "Nursing care dimensions from the subjects' perspectives scientific-technical and expressive". The results show that these dimensions should be manifested in a coordinated way and integral care should be designed and constructed in the relationship with the other. The participants value and defend an alliance between these dimensions and expect nurses to integrate them into care actions. Knowledge about the patients' perceptions concerning hospital care collaborates to the promotion of the environment and favors its restoration through effective care generated in this relationship. PMID- 20839550 TI - [Violence among youngsters: social dynamics and situations of vulnerability]. AB - The purpose of this study is to analyze the social dynamics implied in the life of youngsters, victims of violence, by (re) constructing the day-to-day relations and, therefore, discussing vulnerability situations. It is a descriptive and exploratory study that uses the genogram and the ecomap as instruments for data collection. Interview was carried out with 23 young victims of these events in Porto Alegre, Rio Grande do Sul, Brazil. Content analysis of the thematic type was adopted. From the social interactions of the surveyed youngsters, we observed the fragility of their relationship networks. Regarding the family environment, evidence shows that most of the youngsters come from families with precarious social and economic background. School education is recognized as a guarantee of social inclusion; however for some, the problems with state education and violence in and out of school collaborate for the decharacterization of the school as a protected and learning space. Learning the social dynamics implied in situations of vulnerability helps to understand this phenomenon and can influence prevention and promotion actions from health services. PMID- 20839551 TI - [Absenteeism in nursing staff an integrative review]. AB - Absenteeism in nursing staff is a matter of great concern. It interferes with client care, overwhelms other staff members and can cause serious diseases. The purpose of this study is to analyze the national scientific production and abstracts of articles published from 2003 to 2008, that cover the theme of absenteeism among nursing professionals. We carried out an online search in four databases: LILACS, SciELO, BDENF and CAPES Portal. Two themes emerged by the end of the analysis: (1) Diseases that generate absenteeism among nursing professionals and (2) strategies designed to reduce absenteeism. We concluded that nurses are affected by a number of health problems, and this is one of the causes of their absenteeism. Staff dimensioning and formulation of preventive actions are highlighted as strategies to improve working conditions and reduce absenteeism. PMID- 20839552 TI - [Research action: a contribution to nurses' investigative practices]. AB - The present paper shows a theoretical reflection on action research methodology as an alternative strategy to the conventional model of scientific investigation. Methodology is discussed from the perspective of two scholars who propose two different structural models: action-investigation cycle and flexible stage model. We provide examples of the use of action research from studies carried out by nurses. Action research is an emergent model which is being more and more adopted in educational and nursing fields, reflecting the necessity of deeper theoretical knowledge and revealing itself as a useful instrument in nursing research. PMID- 20839553 TI - [Acupuncture in the nursing care of a patient with pilonidal cyst: an assistance experience report]. AB - This qualitative, participant and descriptive assistance case study shows the use of acupuncture in the complementary treatment of a patient with sacroccocygeal pilonidal cyst relapse with infectious complications in the surrounding tissues receiving medical and nursing assistance. The purpose is to identify this support in complementary health as a potential strategy to be used in the nursing care offered to the patients. It was observed that acupuncture and the multiprofessional assistance benefitted the recovery of local tissue and the combat of infection. By the time of the nursing appointment, these techniques greatly contributed for the positive combat of the disease and a better adhesion to the orientations of nursing care practitioners. Further studies and scientific research about the contributions of oriental health practices in nursing are necessary. PMID- 20839554 TI - [First aid workshop: report of an experience]. AB - This experience report is the result of the construction process of workshops on first aid offered to inhabitants of Cavalhada, a neighborhood in Porto Alegre, Rio Grande do Sul, Brazil. The workshops resulted from a concern of researchers involved in the project "Life risk under the perspective of users of the Mobile Urgency Care Service of Porto Alegre (SAMU)--inputs for the service management". They aimed to interfere in the studied reality in a dynamic way. With this report, we intend to provide inputs for experiences in teaching first aid. PMID- 20839555 TI - [Situational planning in family health strategy academic-professional integration activity in nursing]. AB - This was an activity developed in the Collective Health Management course, by nursing students in the eighth semester from Unochapeco University. The students were challenged to apply their knowledge of the Unique Health System principles and directives, through an active participation in the Situational Strategic Planning with use of the Family Health Strategy. The theoretical and practical activities were carried out in health centers in Chapeco (SC, Brazil). The students experienced the daily life of the workers, participated in team meetings, domiciliary visits and other work routines, in order to diagnose problem situations and develop the four moments of the Situational Strategic Planning along with the Health Team: explicative, normative, strategic and tactical-operational. The experience consolidated the relation between theory and practice and contributed to the critical-constructive training of students, who helped the team to face the problems. The experience also provided them with a good opportunity for academic-professional interaction through their contact with the workers. PMID- 20839556 TI - Estimating the burden of disease attributable to four selected environmental risk factors in South Africa. AB - INTRODUCTION: The first South African National Burden of Disease study quantified the underlying causes of premature mortality and morbidity experienced in South Africa in the year 2000. This was followed by a Comparative Risk Assessment to estimate the contributions of 17 selected risk factors to burden of disease in South Africa. This paper describes the health impact of exposure to four selected environmental risk factors: unsafe water, sanitation and hygiene; indoor air pollution from household use of solid fuels; urban outdoor air pollution and lead exposure. METHODS: The study followed World Health Organization comparative risk assessment methodology. Population-attributable fractions were calculated and applied to revised burden of disease estimates (deaths and disability adjusted life years, [DALYs]) from the South African Burden of Disease study to obtain the attributable burden for each selected risk factor. The burden attributable to the joint effect of the four environmental risk factors was also estimated taking into account competing risks and common pathways. Monte Carlo simulation-modeling techniques were used to quantify sampling, uncertainty. RESULTS: Almost 24 000 deaths were attributable to the joint effect of these four environmental risk factors, accounting for 4.6% (95% uncertainty interval 3.8-5.3%) of all deaths in South Africa in 2000. Overall the burden due to these environmental risks was equivalent to 3.7% (95% uncertainty interval 3.4-4.0%) of the total disease burden for South Africa, with unsafe water sanitation and hygiene the main contributor to joint burden. The joint attributable burden was especially high in children under 5 years of age, accounting for 10.8% of total deaths in this age group and 9.7% of burden of disease. CONCLUSION: This study highlights the public health impact of exposure to environmental risks and the significant burden of preventable disease attributable to exposure to these four major environmental risk factors in South Africa. Evidence-based policies and programs must be developed and implemented to address these risk factors at individual, household, and community levels. PMID- 20839557 TI - The environment as a factor in methicillin-resistant Staphylococcus aureus transmission. AB - In recent years, methicillin-resistant Staphylococcus aureus (MRSA) has become a leading cause of infectious disease morbidity and mortality in the United States. The epidemiology of the organism has changed, with novel strains emerging in the community among individuals lacking any healthcare contact. Although direct human to-human transmission via skin contact is one way for this organism to spread, transmission via environmental contamination of fomites or through air are other potential ways that the organism can be acquired. As such, an improved understanding of MRSA transmission is needed to implement maximally effective control and prevention interventions. We review the research documenting the role of the environment in MRSA spread. PMID- 20839558 TI - Phytostabilization of metal contaminated soils. AB - The contamination of soils with heavy metals represents a worldwide environmental problem of great concern. Traditional methods for the remediation of metal contaminated soils are usually very expensive and frequently induce adverse effects on soil properties and biological activity. Consequently, biological methods of soil remediation like phytoremediation (the use of green plants to clean up contaminated sites) are currently receiving a great deal of attention. In particular, chemophytostabilization of metal contaminated soils (the use of metal tolerant plants together with different amendments like organic materials, liming agents, or phosphorus compounds and such) to reduce metal mobility and bioavailability in soils appears most promising for sites contaminated with high levels of several metals when phytoextraction is not a feasible option. During chemophytostabilization processes, one must at all times be cautious with a possible future reversal of soil metal immobilization, with concomitant adverse environmental consequences. PMID- 20839559 TI - The intersection of sound principles of environmental epidemiologic research and ethical guidelines and review: an example from Canada of an environmental case control study. AB - The present article challenges the ways in which ethical guidelines are implemented in reviewing the design and conduct of research involving human participants in observational studies in Canada. Fieldwork procedures should be designed in such a way as to be valid scientifically but also acceptable in terms of local ethical considerations, such as confidentiality of participant's identity and information, and other social norms. To set the stage, I present briefly essential information regarding the valid design and conduct of observational epidemiologic studies. As an example of the difficulties encountered in implementing these procedures, I present my experience in gaining ethical approval for a population-based, case-control study of environmental causes of postmenopausal breast cancer. PMID- 20839560 TI - Advertisement vis-a-vis medical profession. PMID- 20839561 TI - Postdural puncture headache: a study with 256 Quincke needle. AB - The incidence of postdural puncture headache, its severity, time of onset and duration following spinal anaesthesia in female subjects using 25 gauge Quincke needles are discussed in this paper. Postdural puncture headache was seen in only 3% of the cases. The headache appeared mainly on the 1st postoperative day and was associated with nausea and vomiting in one case; and it disappeared by the 2nd to 3rd day following administration of mild analgesics and anti-emetics. PMID- 20839562 TI - A hospital-based study to evaluate the incidence pattern of group A streptococcal throat infections from different age group patients. AB - Streptococcus pyogenes(group A) is a major pathogen capable of causing a wide range of diseases in different age group of people. In this study 100 patients were selected who presented with the complaint of sore throat. All the patients were divided in four age groups. Streptococcus pyogenes colonies were confirmed on the basis of beta-haemolysis, bacitracin sensitivity test, and latex agglutination test for group A. Out of a total of 100 samples, 42 were confirmed as group A streptococcus. From this study, it has been observed that all age groups, with maximum occurrence in 5-15 years age group, were suffering from group A streptococcal pharyngitis. Therefore every case of sore throat especially affecting children should be investigated to detect the causative agent for initiation of proper therapy so that the more serious outcome like acute rheumatic fever (ARF) and acute glomerulonephritis (AGN) can be prevented. PMID- 20839563 TI - Electric burns and disability. AB - Forty-nine cases of electric burns with various factors responsible for accidents were studied. The stress was given on the study of disability after electric burns. Different complications of electric burns including morbidity and mortality were noted. Proper training of personnel in handling the electrical goods will reduce the incidence of electrical burns significantly. Better warning signals may also help to reduce the incidence of electric burns. Electric burns constitute one of the crippling accidents as the deep tissue destruction results from such injury. This leads to high incidence of upper extremity amputations, necessitating long unemployment and extensive new job training and rehabilitation. A retrospective and prospective study was undertaken among 49 patients of electric burns. In this series about 40% patients have become permanently disabled and 21% severely disabled. The mortality rate was 70.2%. The major disability was due to amputations required to the patient. The incidence of amputation was 34.6%. The mortality rate was 10.2%. Seventeen patients required 28 amputations. Hence, the major problem in electrical burns is due to permanent disability because of amputations, ultimately giving rise to the problem of rehabilitation mostly in young working people. Upper limb was burnt in 96% of patients. Hence, it further aggravates the severity in electrical burn injury because it is a working limb. PMID- 20839564 TI - An intervention study on compliance of diabetes mellitus patients. AB - The effect of intervention (counselling) on compliance was observed in 106 diabetes mellitus patients with poor glycaemic control attending a clinic. They were selected at random and the period of study extended over 3 months. Intervention (counselling) improved significantly their compliance with advices on diet, exercise and drug as well as their glycaemic status. PMID- 20839565 TI - Effect of zinc supplementation on mycospecific immunoglobulins in tuberculosis patients. AB - The effect of zinc supplementation on the serum level of IgA, IgG, IgM mycospecific immunoglobulins in tuberculosis patients alongwith normal control and disease control subjects were studied. It was observed that with antituberculous drugs for one month (without zinc supplementation), the serum level of immunoglobulins in tuberculosis subjects although decreased significantly, but with zinc supplementation along with antituberculous drugs for one month the decrease in the level of immunoglobulins in serum was more significant. This may be attributed to the effect of zinc supplementation favouring the normal compartmentalisation state of iron and also to the immunomodulatory effect of zinc. PMID- 20839566 TI - Recent changes in Criminal Procedure Code and Indian Penal Code relevant to medical profession. AB - Some sections in Criminal Procedure Code and Indian Penal Code have a direct binding on medical practitioner. With changing times, few of them have been revised and these changes are presented in this article. PMID- 20839567 TI - Drug resistance in tuberculosis and options available. AB - Multidrug resistance and extensive drug resistance in treating tuberculosis patients is worrisome for the medical personnel. Mechanism of drug resistance and genetic probes are of great academic interest. Causes of drug resistance can be grouped as: Biological factors, patient factors, disease factors and iatrogenic factors. Types of drug resistance are primary, acquired, initial, transitional and natural. Diagnosis of drug resistant tuberculosis is very important. Mismanagement of multidrug resistant tuberculosis can lead to extensive drug resistant tuberculosis. Stop TB Strategy and WHO Global Task Force have taken keen interest and laid guidelines and options for National TB Control Programme to help countries to combat drug-resistant tuberculosis. PMID- 20839568 TI - Bilateral complete choanal atresia in an adult woman--managed with nasal endoscopes. AB - Choanal atresia usually presents at birth as respiratory distress and difficulty in feeding. Unilateral choanal atresia is sometimes missed during childhood but bilateral choanal atresia present in a newborn as a medical emergency and if immediate measures are not taken to relieve obstruction, it may result in death of the child. There are very few cases in literature where bilateral choanal atresia was detected in an adult as a chance finding or in a patient complaining of nasal obstruction, speech problem or sinusitis. Here a case of an adult female is reported who presented as a case of bilateral pansinusitis but was later found to have bilateral complete choanal atresia. Nasal endoscopes were used for surgical repair of choanal atresia. PMID- 20839569 TI - A case of endometrioma causing ureteric obstruction. AB - A 32 years old married woman presented at the outpatients' department with the complaints of pain lower abdomen and irregular heavy menstrual bleeding for last 6 months. She was married for 7 years and attended an infertility clinic. Diagnostic laparoscopy was carried out there which revealed an endometrioma arising from right overy. On bimanual examination a mass was palpable in the right fornix. USG and Intervenous pyelography were advised. The diagnosis was confirmed endometrioma from right ovary and right sided ureter as hydro-ureter and there was hydronephrosis. She was operated and the endometrioma was resected out. She was discharged on 10th postoperative day with the advice to take tablet danazol (400) orally daily for 2 months. PMID- 20839570 TI - Lissencephaly--not an uncommon cause of intractable seizure in children: report of 3 cases. AB - Lissencephaly or azyria, a rare disorder characterised by the absence of cerebral convolutions and poorly formed sylvlan fissures giving the appearance of a foetal brain with smooth cerebral surface, thickened cortical mantle and microscopic appearance ofincomplete neuronal migration. It is to consider lissencephaly in the diagnosis of developmental delay with seizure disorder as many patients may be diagnosed as cerebral palsy. Several lissencephaly syndrome have been described, Here three cases of lissencephaly with developmental delay and Intractable seizures are reported. PMID- 20839571 TI - Eventration of diaphragm mimicking hydropneumothorax. PMID- 20839572 TI - Clinical eficacy of placentrex injection in pelvic inflammatory disease. AB - Combination of placentrex injection with antimicrobial therapy is a better option for treating pelvic inflammatory disease (PID) than only antimicrobial therapy; which also gives more sustained effect and lesser recurrences. Improvements in symptoms continue despite stopping therapy. Addition of placentrex leads to marked improvement in dyspareunia, less fornix tenderness and better uterine mobility suggesting better effect on adnexal tissues and parametrium. As placentrex decreases adnexal inflammation to significant level in comparison to antimicrobials alone, it can be a good option- specially to reduce the risk of tubal damage, infertility and formation of adnexal mass. In a study of 100 cases of PID, 50 in group I and II each; 42 in group 1 and 32 in group II completed the study. Marked reduction in various symptoms was observed in study group I (27 59%) where as in group II where only antimicrobial was given, reduction was found in range of 12-48%. Thus overall, group I had better as well as sustained effect of therapy on relieving dyspareunia, fornix tenderness and uterine restricted mobility which was statistically significant. In other symptoms and signs, there was marginal efficacy except in cervical erosion where no improvement was observed. PMID- 20839573 TI - Medical ethics vis-a-vis the medical profession. PMID- 20839575 TI - Extra-oesophageal presentation of gastro-oesophageal reflux disease. AB - Gastro-oesophageal reflux disease has now been definitely associated with pulmonary symptoms and diseases, such as asthma, cough, chronic bronchitis, pneumonia, and pulmonary fibrosis; otolaryngologic symptoms and findings include hoarseness, pharyngitis, cough, laryngitis, subglottic stenosis, globus, and laryngeal cancer. Gastro-oesophageal reflux disease is also associated with noncardiac chest pain, dental erosion, sinusitis and sleep apnoea. This discussion focuses on some of these extra-oesophageal presentations of gastro oesophageal reflux disease and the general management of these individuals. PMID- 20839574 TI - Knowledge and practices related to sexually transmitted infections and HIV among sex workers in an urban area of Gujarat, India. AB - This study is a part of STD prevalence study done in Gujarat amongst sex workers (SWs) of urban red light area during the year 2000. In the clinic specially set up in their area, after an informed consent from the participants, knowledge, attitude and practices (KAP) questionnaire schedule was administered to 125 SWs; 2/3rds of them were below the age of 30 years, 81.5% had never gone to school and 76.6% of them had their first sexual intercourse before the age of 20 years. Majority of SWs. (83.1%) has joined the profession before the age of 25 years; 60.5% were having 3-5 sexual partners on an average; 94.4% reported using condom all the time during a sexual encounter; 91.9% of them had suggested the use of condom to their client themselves, and 79.8% of them made it sure by helping the client to put on the condom. Out of 29 SWs who had regular partners, 44.8% use condom all the times with their regular partner, 92% had never seen female condom; 85 to 90% were aware about various symptoms/diseases transmitted by unsafe sexual practice in male and female; 23.4% took treatment from the health workers for such problems; 87.9% SWs were aware that HIV is transmitted by unprotected sex with an infected partner and 88.7% were aware that consistent use of condom could protect her from HIV infection. However, they did not know other measures, 65.3% don't perceive the risk of getting HIV infection. Out of those 39 who perceived this risk, 48.7% attributed it to having many clients, 30.8% to irregular use of condom and only 2.6% to non-treatment of STD. Fifty-eight per cent are not aware about any behavioural change needed to reduce the risk. PMID- 20839576 TI - Amphotericin B--fat emulsion in treatment of visceral leishmaniasis--a cost effective substitute for liposomal amphotericin B. AB - In spite of high dosage and prolonged treatment schedule of sodium antimony gluconate, unresponsiveness and relapse ranging from 25 to 40% has been reported. The cure rate of 90 to 92.9% with amphotericin B-fat emulsion is comparable to that with liposomal amphotericin B (80 to 100%). Due to high cost liposomal amphotericin B is beyond the reach of most of the Indian patients, whereas the cost of treatment with amphotericin B-fat emulsion is quite affordable. Further large scale studies with amphotericin B-fat emulsion are required to evaluate its effectiveness in Indian kala-azar patients and to establish its optimal dose. PMID- 20839578 TI - Febrile seizures. AB - Febrile seizures are the most common form of childhood seizures occurring in 2 to 5% of children in the United States. Most febrile seizures are considered simple, although those with focal onset, prolonged duration or that occur more than once within the same febrile illness are considered complex. Risk factors for a first febrile seizure, recurrence of febrile seizures and development of future epilepsy are identifiable and varied. Children with febrile seizures encounter little risk of mortality and morbidity and have no association with any detectable brain damage. Recurrence is possible, but only a small minority will go on to develop epilepsy. Although anti-epileptic drugs can prevent recurrent febrile seizures, they do not alter the risk of subsequent epilepsy. This has led to a changing view of how we approach the treatment of these common and largely benign seizures. PMID- 20839577 TI - Recent advances in antiretroviral therapy in HIV infection. AB - The care of the human immunodeficiency virus (HIV)-infected patient has changed dramatically in the last few years. Potent new antiretroviral drugs combined with updated treatment strategies have now achieved efficient inhibition of HIV replication in most patients. Classes of drugs include both nucleoside and non nucleoside inhibitors of the viral enzyme reverse transcriptase (RT) and inhibitors of the viral protease and integrase enzymes. As yet immune-based therapies have had little, if any, impact. However, it is clear that the eradication of HIV is not achievable with existing anti-HIV drugs and in spite of the major advances there remains many challenges in the clinical management of HIV-infected individuals. A major drawback of highly active antiretroviral therapy (HAART) is the selection of resistant mutants under suboptimal dosage, in advanced stages of disease or after pretreatment with mono- or double-combination regimens. Monitoring of antiretroviral therapy is achieved by measurement of viral load using nucleic acid amplification techniques. Recommendations for antiretroviral therapy and monitoring are evolving constantly due to the rapid progress in the development of active compounds and new insights into HIV pathogenesis. PMID- 20839579 TI - Perinatal management of immune thrombocytopenic purpura--a case report and review of literature. AB - Immune thrombocytopenic purpura is principally a disease of young women. Therefore it may often be associated with pregnancy. It is commonly complicated by abortion, intra-uterine growth retardation and neonatal intracranial haemorrhage so that perinatal mortality may be as high as 20%. Hence perinatal management of immune thrombocytopenic purpura should include maintenance of maternal platelet count and regular monitoring of foetal growth along with prediction and prevention of foetal passive immune thrombocytopenia. Determination of foetal platelet count in certain situations may help in concomitant selection of delivery mode. The following case report emphasises the importance of diagnosing this condition at peripheral healthcare level so that perinatal outcome can be markedly improved. PMID- 20839580 TI - Chemotherapy and quality of life: a case study. AB - The deteriorating effects of chemotherapy on cancer patients are well documented, so is the need and impact of psychological, behavioural, or educative interventions in improving quality of life. In the developing countries, cancer centres have a very high patient load and providing quality treatment and achieving good survival is still the first priority. However, in the pursuit of quality of survival, the quality of life is often ignored. Psychological and/or behavioural interventions that could enable the patient to cope better, be independent and well informed about the treatment which might improve quality of life of remaining years. This report discusses a case of a 46-year-old female breast cancer patient and her views on the impact of chemotherapy on her life. PMID- 20839581 TI - Congenital malaria: a case report. AB - Malaria is an important vector-borne infectious disease, caused by plasmodium parasite. Congenital malaria, however, is rare and may be acquired either during pregnancy, at the time of delivery or after birth. A case of symptomatic congenital malaria caused by Plasmodium vivax and characterised by fever, irritability, pallor and jaundice, is presented in a 4-week-old infant. PMID- 20839583 TI - What's good for the climate is good for health: the role of doctors in addressing climate change. PMID- 20839582 TI - Peri-operative management of glucose. AB - It is generally agreed that it is important to control blood glucose levels during the peri-operative period. However, there have been controversies surrounding the appropriateness of each regimen, as well as ideal glucose targets during surgery. This review focuses on a simple and practical strategy to control glucose during surgery, and sets out simple guidelines on instituting an insulin infusion protocol. From the available evidence, a fasting plasma glucose < 90 mg/dl, postprandial glucose < 180 mg/dl and an HbA1c < 7% is ideal before elective surgery. The blood glucose must be maintained between 140 and 180 mg/dl during the operative period as well as during the intensive care unit (ICU stay). Sliding scales are inappropriate for in-hospital glucose control. A basal-bolus insulin regimen is ideal for hospitalised peri-operative subjects outside the ICU. In the ICU, it is best to use an insulin infusion protocol for glucose control. The ideal regimen should be individualised for each patient. The success of peri-operative glucose control requires teamwork between the various medical personnel involved in patient care. PMID- 20839584 TI - Does India need NICE healthcare? PMID- 20839585 TI - Two-year treatment outcomes of patients enrolled in India's national first-line antiretroviral therapy programme. AB - BACKGROUND: We aimed to analyse treatment outcomes of patients receiving first line antiretroviral therapy (ART) through the national AIDS control programme of India. METHODS: Using routinely collected programme data, we analysed mortality, CD4 evolution and adherence outcomes over a 2-year period in 972 patients who received first-line ART between 1 October 2004 and 31 January 2005 at 3 government ART centres. Cox regression analysis was used to identify independent predictors of mortality. RESULTS: Of the 972 patients (median age 35 years, 66% men), 71% received the stavudinellamivudine/nevirapine regimen. The median CD4 count of enrolled patients was 119 cells/cmm (interquartile range [IQR] 50-200 cells/ cmm) at treatment initiation; 44% had baseline CD4 count <100 cells/cmm. Of the 927 patients for whom treatment outcomes were available, 71% were alive after 2 years of treatment. The median increase in CD4 count was 1 42 cells/ cmm (IQR 57-750 cells/cmm; n=616) at 6 months and 184 cells/cmm (IQR 102-299 cells/cmm; n=582) at 12 months after treatment. Over 2 years, 124 patients (13%) died; the majority of deaths (68%) occurred within the first 6 months of treatment. Those with baseline CD4 count <50 cells/cmm were significantly more likely to die (adjusted hazard ratio 2.5, 95% confidence interval 1.3-3.2) compared with patients who had baseline CD4 count >50 cells/cmm. Over the 2-year period, 323 patients (35%) missed picking up their monthly drugs at least once and 147 patients (16%) were lost to follow up. CONCLUSION: Survival rates of HIV infected patients on first-line ART in India were comparable with those from other resource-limited countries. Most deaths occurred early and among patients who had advanced disease. Earlier initiation of HIV treatment and improving long term treatment adherence are key priorities for India's ART programme. PMID- 20839586 TI - Introducing regular behavioural surveillance into the health system in India: its feasibility and validity. AB - BACKGROUND: Illness is affected by human behaviour. However, in most developing countries the risk behaviour of the general population is not assessed. We developed a surveillance system to assess the 'risk factors' at the community level using the routine healthcare system. METHODS: The Comprehensive Rural Health Services Project at Ballabgarh, Haryana, provides healthcare to a population of 82,933 through 2 primary health centres and 24 health workers. Information on behavioural risk factors for communicable and non-communicable diseases was collected by health workers during the annual health census from December 2003 to February 2004. The information collected pertained to maternal and child health, and household and individual behaviour. We compared the data related to individual behaviour with that ofa survey of non-communicable diseases risk factors done in the same area. RESULTS: Data were collected from (i) mothers who had delivered during the preceding year (n=1625), (ii) a random sample of individuals (n=2865), (iii) and all households (n=7488). The response rate was 85% for mothers, 91%/ for households and 95% for individuals. Approximately 80% of the households had access to drinking water, 32% to sanitary latrines, 28% of women increased their dietary intake during pregnancy, and 50% of adult men used tobacco. Comparing these results with those from the survey of risk factors for non-communicable diseases revealed no significant differences. CONCLUSION: It is feasible for health workers to do behavioural surveillance by usingthe routine healthcare system. PMID- 20839587 TI - Giant cell arteritis: a clinical and pathological study. AB - BACKGROUND: Giant cell arteritis is a vasculitis affecting large- and medium calibre vessels. It is not uncommon in the West and there are many large series in the literature. However, there are very few reports of giant cell arteritis among Indian patients. METHODS: We did a retrospective study of 9 Indian patients (5 men and 4 women; age range 59-81 years [mean and median 70 years]) who had had a temporal artery biopsy for suspected giant cell arteritis at a tertiary care hospital. RESULTS: Eight patients had biopsy-proven giant cell arteritis. The common presenting features were pyrexia of unknown origin (4), headache (6) and blurring of vision (2). The erythrocyte sedimentation rate was elevated and ranged from 25 to 120 mm at the end of the first hour (mean 96, median 105). The C-reactive protein level, which was available in 5 cases, was raised. Giant cells and inflammatory cells were seen in 7 of 8 temporal artery biopsies; a transmural lymphocytic and neutrophil Infiltrate without giant cells was present in 1 case. All patients were treated with steroids and they responded well. CONCLUSION: Temporal arteritis is probably under-recognized in India. Pyrexia is a common presenting feature of the disease; temporal arteritis should be considered in the differential diagnosis of elderly patients with pyrexia of unknown origin. PMID- 20839588 TI - Systemic therapy for melanoma. AB - Advanced melanoma is a disease with a poor prognosis. Most of the currently available chemotherapy agents are ineffective. In contrast to other cancers, immune-based and novel, targeted therapies appear to have some effect in melanoma. Exciting research in the past few years holds hope for the future. We provide an overview of the current management principles of this condition with special emphasis on the emerging options in the systemic therapy of advanced disease. PMID- 20839589 TI - Body-mass index as a robust predictor of mortality in Asian Indians. PMID- 20839590 TI - Neuraminidase inhibitors for influenza in healthy adults: what we don't know. PMID- 20839591 TI - My tryst with destiny: cholecystectomy and a bile duct injury. PMID- 20839592 TI - What qualities make a good doctor? PMID- 20839593 TI - Mental health and well-being. PMID- 20839594 TI - Systems of medical education in India and abroad: a comparison. PMID- 20839595 TI - Prioritization of a patient for liver transplant: does MELD score require downgrading? PMID- 20839596 TI - MCI internal assessment system in undergraduate medical education. PMID- 20839597 TI - Activin A/follistatin expression in glioma and its in vitro effect on a cell line. PMID- 20839598 TI - Etiology of epithelioma among the Kashmiris.1866. PMID- 20839599 TI - Squamous celled epithelioma due to kangri burn.1924. PMID- 20839600 TI - The kangri cancer papers and their impact in India and elsewhere. PMID- 20839601 TI - Health ministry institutes reward scheme for whistle-blowers reporting spurious drugs. PMID- 20839602 TI - Pump up the volume. How to eat more but lose weight. PMID- 20839603 TI - Eyes on the prize. Prevention is crucial in combating retinopathy. PMID- 20839604 TI - The next ('big', 'thing'). PMID- 20839605 TI - Health care reform and you. PMID- 20839606 TI - How to make a super sandwich. PMID- 20839607 TI - Diabetes and dementia. Does type 2 care also bolster brain function? PMID- 20839609 TI - Phytochemical investigation of Verbesina turbacensis Kunth: trypanosome cysteine protease inhibition by (-)-bornyl esters. AB - The bark and leaf essential oils of Verbesina turbacensis were obtained by hydrodistillation and analyzed by GC-MS. The bark oil of the plant was composed mainly of monoterpene hydrocarbons (83.5-90.4%), predominately alpha-pinene, while the leaf oil was composed mainly of sesquiterpene hydrocarbons, dominated by germacrene-D (29.1-36.9%), and delta-elemene (21.7-22.1%). Three bornyl hydroxycinnamic esters isolated from the acetone bark extract were found to inhibit the cysteine protease, rhodesain. Molecular docking analysis to probe the inhibitory interactions of the esters was also carried out. PMID- 20839608 TI - [Atmospheric pollution and human health.in the literature and interpretation of environmental. toxicological and epidemiologic studies]. PMID- 20839610 TI - Anti-herpetic activities of chemical components from the Brazilian red alga Plocamium brasiliense. AB - The CH2Cl2 crude extract and a fraction enriched with halogenated monoterpenes of the Brazilian red alga Plocamium brasiliense were evaluated for cytotoxicity and against the virus HSV-1. The extract showed low cytotoxicity compared with the fraction containing monoterpenes. The crude extract showed, in vitro, a high reduction of infectivity of the virus HSV-1. PMID- 20839611 TI - Chemical constituents of the soft coral Sarcophyton infundibuliforme from the South China Sea. AB - One new cembrane diterpenoid, named sarcolactone A (1), along with five known compounds (2-6) were isolated from the soft coral Sarcophyton infundibuliforme collected from the South China Sea. The structure of sarcolactone A (1) was elucidated by comprehensive analysis of spectral data, especially 2D-NMR spectra (1H-1H COSY, HMBC and NOESY). All the compounds were evaluated for their brine shrimp lethality and antifouling activities. PMID- 20839612 TI - Metabolites from the fungus Phoma sp. 7210, associated with Aizoon canariense. AB - A new metabolite, 3,16-diketoaphidicolan (1), was isolated together with four known compounds: aphidicolin (2), 17-acetyl-aphidicolin (3), (+)-eupenoxide (4), and phomoxanthone A (5) from the endophytic fungus Phoma sp. The structure of the new compound 1 was determined by spectroscopic methods (mainly extensive 1D and 2D NMR experiments and by mass spectral measurements) and confirmed by X-ray crystallography. Its absolute configuration was assigned by means of the solid state CD/TDDFT approach comparing the solid-state CD spectrum with the TDDFT calculated one on the X-ray geometry. PMID- 20839613 TI - Triterpenes from Protium hebetatum resin. AB - Three olean (beta-amyrenone, beta-amyrin and maniladiol), three ursane (alpha amyrinone, alpha-amyrin and breine) and four tirucallane (3-oxotirucalla-8,24 dien-21-6ic acid, 3alpha-hydroxytirucalla-8,24-dien-21-oic acid, 3alpha acetoxytirucalla-8,24-dien-21-oic acid and 3alpha-hydroxytirucalla-7,24-dien-21 oic acid) triterpenes were isolated from the oleoresin of Protium hebetatum Daly. The structures were established mainly by 13C, 1D and 2D NMR spectroscopic analysis. The isolation of 3alpha-hydroxytirucalla-8,24-dien-21-oic acid permitted correction of the chemical shift assignments of some of its carbon atoms. PMID- 20839614 TI - Cytotoxicity of 9,11-dehydroergosterol peroxide isolated from Ganoderma lucidum and its target-related proteins. AB - The cytotoxicty of 9,11-dehydroergosterol peroxide (DHEP) isolated from the fruiting bodies of Ganoderma lucidum on HeLa cells was studied. DHEP treatment for 48 h inhibited the proliferation of HeLa human cervical carcinoma cells with an IC50-value of 8.58 +/- 0.98 microM. Morphological changes of DHEP-treated cells indicated that DHEP induced apoptosis in HeLa cells. To identify the cellular targets of DHEP, two-dimensional electrophoresis analysis was performed to compare the protein expression profiles of DHEP-treated cells with that of control cells. Proteins altered in expressional level after DHEP exposure were identified by MALDI-TOF MS/MS. The cytotoxic effect of DHEP was associated with regulated expression of 6 proteins. Stathmin 1 might be an important target related protein of DHEP. The regulation of stathmin 1 by DHEP treatment was also confirmed by Western blotting. PMID- 20839615 TI - Polar alkaloids from the Caribbean marine sponge Niphates digitalis. AB - A method involving flash chromatography, semi-preparative phenylhexyl RP HPLC-DAD ELSD combined with analytic polar-RP HPLC-DAD, was applied to separate and purify six highly nitrogenated bases and a bicyclic amidine alkaloid, the major components of the marine sponge Niphates digitalis. Their structures were identified as 1,8-diazabicyclo[5.4.0]undec-7-ene (1), deoxycytidine (2), phenylalanine (3), adenosine (4), deoxyguanosine (5), adenine (6) and thymidine (7) on the basis of spectroscopic data analyses. This is the first report of these compounds in a marine sponge belonging to the Niphates genus and the first evidence of the presence of 1 from a natural source. PMID- 20839616 TI - A short stereoselective synthesis of racemic 2-epicalvine. AB - The cycloaddition reaction of 6-pentyl-3,4,5,6-tetrahydropyridine 1-oxide with butyl vinyl ether was used as a key step in the short stereoselective racemic synthesis of ladybird beetle alkaloid, 2-epicalvine. The cycloadduct was subjected to quatemization with 2-bromoethanol, followed by ring opening and lactonization to afford the natural product in a one-pot reaction. PMID- 20839617 TI - Cytochrome P450 3A4 inhibitory activity studies within the lycorine series of alkaloids. AB - A mini-panel of semi-synthetic analogs of the Amaryllidaceae alkaloid lycorine was screened for cytochrome P450 3A4 (CYP3A4) inhibitory activity, the most potent of which exhibited inhibition as low as 0.21 microM. Elements of this novel pharmacophore unravelled include bulky lipophilic substitution at C2 in conjunction with a small hydrogen bond donor/acceptor at C1, or bulky electron rich substitution at C1 in conjunction with a vicinal hydrogen bond donor/acceptor. PMID- 20839618 TI - Analysis of Amaryllidaceae alkaloids from Zephyranthes robusta by GC-MS and their cholinesterase activity. AB - From the bulbs of Zephyranthes robusta Baker (Amaryllidaceae), seven known compounds, belonging to four structural types of Amaryllidaceae alkaloids, were identified and quantified by GC-MS. The alkaloid extract from the bulbs showed promising acetylcholinesterase and butyrylcholinesterase inhibitory activities against HuAChE (IC50 = 35.9 +/- 3.5 microg/mL) and HuBuChE (IC50 = 190.9 +/- 8.2 microg/mL). PMID- 20839619 TI - Stereochemistry and NMR data assignment of cyclopeptide alkaloids from Zizyphus oxyphylla. AB - The structures of (3S,7R,13S)-6-[2-(dimethylamino)-3-phenylpropanoyl]-19-methoxy 2-oxa-6,9,15-triazatetracyclo[16.3.1.0(3,7). 0(9,13)]docosa-1-(22),16,18,20 tetraene-8,14-dione (1), nummularin-C (2) and nummularin-R (3) have been previously determined mainly based on mass spectrometric data. Stereochemistry and complete 1H and 13C NMR spectroscopic data assignments of these compounds are now described. Compounds 1 and 2 are reported for the first time from Zizyphus oxyphylla. PMID- 20839620 TI - Geranylated flavonols from Macaranga rhizinoides. AB - Two geranylated and methylated flavonol derivatives, macarhizinoidins A (1) and B (2), along with a known phenolic compound methyl 4-isoprenyloxycinnamate (3), have been isolated from the methanol extract of the leaves M. rhizinoides. The structures of these compounds were identified based on their spectroscopic data. On cytotoxic evaluation against murine leukemia P-388 cells, compounds 1-2 showed IC50 values of 11.4 and 13.9 microM, respectively, while compound 3 was inactive. PMID- 20839621 TI - A new biflavonyloxymethane from Pongamia pinnata. AB - The root bark of Pongamia pinnata Pierre Syn Pongamia glabra (Family: Fabaceae) has afforded a new biflavonyloxymethane, karanjabiflavone, along with a known furanoflavone, pongapin. The structure of this new biflavonyloxymethane was elucidated from extensive spectral studies including 2D-NMR experiments. Both of these compounds possess antioxidant activity. PMID- 20839622 TI - Anti-inflammatory and gastroprotective properties of Hypericum richeri oil extracts. AB - Oil extracts of flowering tops of Hypericum richeri Vill. prepared in three different ways were evaluated for chemical composition, and anti-inflammatory and gastroprotective activities. An HPLC method was developed for determination of two dominant flavonoids, quercetin and I3,II8-biapigenin. The carrageenan-induced rat paw edema test was used for screening the anti-inflammatory activity, while indomethacin-induced rat gastric mucosa damage test was used for evaluation of gastroprotective activity. The oil extract prepared by maceration with 96% ethanol, followed by extraction with sunflower oil by heating on a water bath, exhibited the highest anti-inflammatory (38.4%) and gastroprotective activities (gastric damage score of 0.9). The same oil extract had the highest content of quercetin (49 microg/mL) and I3,II8-biapigenin (60 microg/mL). These results approve the usage of oil extracts of H. richeri as an anti-inflammatory and gastroprotective agent. PMID- 20839623 TI - Production of flavonoids in organogenic cultures of Alpinia zerumbet. AB - Alpinia zerumbet plantlets were cultured in vitro in MS medium supplemented with growth regulators, including IAA, TDZ and BAP. Using high performance liquid chromatography (HPLC), the production of rutin, kaempferol-3-O-glucuronide, and kaempferol-3-O-rutinoside was evaluated, based on leaf hydroalcoholic extracts of three-month-old plantlets. The relative concentration of phenolics from the hydroalcoholic extracts of plantlets cultured in control medium reached 100% compared with plantlets treated with growth regulators and donor plants (80%). The in vitro rutin production was more pronounced than the other flavonoids. While no direct relation between the content of phenolic compounds and increased flavonoid production was observed, the combination of IAA + TDZ enhanced the production of rutin (83.2 microg/g dried leaves) and kaempferol-3-O-glucuronide (29 microg/g dried leaves), compared with growth regulators used alone. Overall, these findings suggest the value of in vitro cultivation as a means of enriching phenolic and flavonoid production in medicinal plants. PMID- 20839624 TI - Phenolic compounds in leaves of Alchornea triplinervia: anatomical localization, mutagenicity, and antibacterial activity. AB - Phenolic compounds are produced by secretory idioblasts and hypodermis, and by specialized cells of the epidermis and chlorenchyma of leaves of Alchornea triplinervia. Phytochemical investigation of these leaves led to the isolation of the known substances quercetin, quercetin-7-O-beta-D-glucopyranoside, quercetin-3 O-beta-D-glucopyranoside, quercetin-3-O-beta-D-galactopyranoside, quercetin-3-O alpha-L-arabinopyranoside, amentoflavone, brevifolin carboxylic acid, gallic acid, and methyl gallate from the methanolic extract, and stigmasterol, campesterol, sitosterol, lupeol, friedelan-3-ol, and friedelan-3-one from the chloroform extract. In studies of antibacterial activity and mutagenicity, the methanolic extract showed promising activity against Staphylococcus aureus (MIC = 62.5 microg/mL) and was slightly mutagenic in vitro and in vivo at the highest concentrations tested (1335 mg/kg b.w.). PMID- 20839625 TI - Phytotoxic activity of flavonoids from Dicranostyles ampla. AB - Crude extracts from over 16 species of plants from the family Convolvulaceae were evaluated for phytotoxic activity against Agrostis stolonifera (bentgrass) and Lactuca sativa (lettuce) at 1000 microg/mL. Ethanol extracts of Dicranostyles ampla Ducke were among the most active of those species tested. Systematic bioassay-guided fractionation of the ethanol extract of the aerial parts from this species was performed to identify specifically the phytotoxic compounds. Two phytotoxic flavonoids, dihydromyricetin (1) and myricetin-3-O-alpha-rhamnoside or myricetrin (2), were found to be responsible for much of the activity of the extract as a whole in the A. stolonifera and L. sativa bioassay. In a Lemna paucicostata bioassay, 1 and 2 had no activity at 100 microM. PMID- 20839626 TI - Flavonoids of Enhydra fluctuans exhibit anticancer activity against Ehrlich's ascites carcinoma in mice. AB - Flavonoids obtained from Enhydra fluctuans (FEF) were screened for anticancer activity against Ehrlich's ascites carcinoma (EAC) bearing Swiss albino mice. The anticancer activity was assessed by measuring the tumor growth response, percentage increase of life span, hematological parameters, lipid peroxidation, and antioxidant enzyme activity, like GSH and CAT. Two flavonoids, baicalein 7-O glucoside and baicalein 7-O-diglucoside, were isolated from the ethyl acetate fraction. Treatment with FEF caused a significant decrease in the tumor cell volume and increase of life span. All the hematological parameters, malonaldehyde content and antioxidant enzyme activity were restored towards the normal level. FEF was found to be cytotoxic in the in-vitro model. PMID- 20839627 TI - Liquiritigenin derivatives and their hepatotoprotective activity. AB - Liquiritigenin (7,4'-dihydroxyflavanone), isolated from the roots of Glycyrrhiza glabra, was derivatized to liquiritigenin 7, 4'-diacetate, liquiritigenin 4' acetate, isoliquiritigenin, and liquiritigenin 7, 4'-dibenzoate. All these derivatives were evaluated for in vitro hepatoprotective activity against D galactosamine-lipopolysaccharide(GalN/LPS) induced toxicity. In-vitro hepatotoxicity was manifested by a significant increase (P < 0.05) in liver toxicity biomarkers (SGPT, SGOT, ALKP, triglyceride, LPO, NO and LDH). The level of biomarkers in the treatment groups was significantly decreased (P < 0.05) when compared with the GalN/LPS group. The results revealed that isoliquiritigenin exhibited better hepatoprotective activity than liquiritigenin and its derivatives. PMID- 20839628 TI - Podophyllotoxin derivatives show activity against Brontispa longissima larvae. AB - In an attempt to find biorational insecticides, eleven podophyllotoxin analogues were tested for their insecticidal activity against the fifth-instar larvae of Brontispa longissima in vivo for the first time. Among all of the tested compounds, deoxypodophyllotoxin (3) and beta-apopicropodophyllin (4) showed more promising and pronounced insecticidal activity than toosendanin, a commercial insecticide derived from Melia toosendan, and important SAR information has been revealed. Together, these preliminary results may be useful in guiding further modification of podophyllotoxins in the development of potential new insecticides. PMID- 20839629 TI - Anthraquinones from the roots of Prismatomeris tetrandra. AB - A new anthraquinone compound, 1,3-dihydroxy-6-methoxy-2-methoxymethyl-9,10 anthraquinone (1), along with four known analogues (2-5) were isolated from the roots of Prismatomeris tetrandra. Their structures were elucidated on the basis of spectroscopic analysis. Among these compounds, lucidin omega-methyl ether (4) and lucidin omega-ethyl ether (5) were isolated from this genus for the first time. Compound 1 showed weak cytotoxic activity against A549 and LAC cell lines. PMID- 20839630 TI - Inhibitory effects of black pepper (Piper nigrum) extracts and compounds on human tumor cell proliferation, cyclooxygenase enzymes, lipid peroxidation and nuclear transcription factor-kappa-B. AB - Black pepper (Piper nigrum) and hot pepper (Capsicum spp.) are widely used in traditional medicines. Although hot Capsicum spp. extracts and its active principles, capsaicinoids, have been linked with anticancer and anti-inflammatory activities, whether black pepper and its active principle exhibit similar activities is not known. In this study, we have evaluated the antioxidant, anti inflammatory and anticancer activities of extracts and compounds from black pepper by using proinflammatory transcription factor NF-kappaB, COX-1 and -2 enzymes, human tumor cell proliferation and lipid peroxidation (LPO). The capsaicinoids, the alkylamides, isolated from the hot pepper Scotch Bonnet were also used to compare the bioactivities of alkylamides and piperine from black pepper. All compounds derived from black pepper suppressed TNF-induced NF-kappaB activation, but alkyl amides, compound 4 from black pepper and 5 from hot pepper, were most effective. The human cancer cell proliferation inhibitory activities of piperine and alklyl amides in Capsicum and black pepper were dose dependant. The inhibitory concentrations 50% (IC50) of the alklylamides were in the range 13-200 microg/mL. The extracts of black pepper at 200 microg/mL and its compounds at 25 microg/mL inhibited LPO by 45-85%, COX enzymes by 31-80% and cancer cells proliferation by 3.5-86.8%. Overall, these results suggest that black pepper and its constituents like hot pepper, exhibit anti-inflammatory, antioxidant and anticancer activities. PMID- 20839631 TI - Cinnamoylphenethylamine 1H-NMR chemical shifts: a concise reference for ubiquitous compounds. AB - 1H-NMR data of 25 cinnamoylphenethylamine derivates were recorded and compared in order to assign signals unequivocally without additional spectroscopic data. The spectra provide a key for the rapid identification of these ubiquitous natural products. The compounds isomerize rapidly in UV light, producing a characteristic upfield shift of the olefinic protons consistent with distorted planarity of the cis cinnamate, and this requires special attention during preparative work. PMID- 20839632 TI - Pro-coagulant activity of phenolic acids isolated from Blumea riparia. AB - The effects of extracts of the aerial part of Blumea riparia DC. and their phenolic acids on hemostasis were evaluated. The EtOAc fraction showed significantly reduced blood clotting time (CT) and tail bleeding time of transection (BT) of mice in vivo. This fraction contained vanillic acid (1), syringic acid (2), p-coumaric acid (3), caffeic acid (4), and protocatechuic acid (5). Compound 1 reduced prothrombin time (PT), and strengthened mice uterine contractions. Compound 3 reduced CT and the activated partial thromboplastin time (APTT). Compound 5 reduced CT and increased the frequency of mice uterine contraction in a dose-dependent manner. Compound 2 reduced APTT. Compound 4 remarkably strengthened uterine contraction. Taken together, these data suggest that compounds 1, 3, and 5 possess procoagulant activity which jointly synergize blood coagulation via different mechanisms. PMID- 20839633 TI - Vascular effects of a sulfated polysaccharide from the red marine alga Solieria filiformis. AB - Anticoagulant and antithrombotic properties of sulfated-polysaccharides (SP) from marine algae are extensively exploited. However, reports on the vascular effects of SP from red algae are rare in the literature. The polysaccharide from Solieria filiformis (Sf-SP) was isolated by ion exchange chromatography, analyzed by agarose gel electrophoresis and tested in male Wistar rats. The inflammation studies were performed using the paw-edema model and the relaxant activity in isolated aorta pre-contracted with phenylephrine. The anticoagulant effect was evaluated by the test of partial thromboplastin activation time. The SP (1 mg/kg) was not anti-inflammatory, but induced acute edema with maximal activity at 30 min (0.35 +/- 0.04 mL) compared to controls (0.05 +/- 0.03 mL). Cumulative addition of Sf-SP in phenylephrine-contracted tissues produced relaxation with maximal inhibition of 69% (IC50 29.3 +/- 9.0 microg/mL) at 300 microg/mL in comparison to controls (0.51 +/- 0.09 g). Sf-SP also extended human plasma coagulation time by 2.1 times. These substances could be used as important tools for the study of vascular alterations. PMID- 20839634 TI - Encapsulation and regeneration of in vitro derived Zephyranthes grandiflora: an effective way for exchange of germplasm. AB - An attempt was made to develop a protocol for the preparation of synthetic seeds using in vitro regenerated, genetically identical bulbs of Zephyranthes grandiflora. Encapsulation was standardized with 4% sodium alginate and 1% sucrose for uniform bulb size with high conversion potential. An optimum storage temperature was found to be 4 degrees C. Synthetic seeds were germinated in MS medium supplemented with benzyladenine (2 mg dm(-3)) and rooted in the presence of indole-3-butyric acid (1 mg dm(-3)) in MS medium. Well-rooted plants were transferred to the experimental field with 80% survival after hardening. This study elucidated an efficient technique for exchange of germplasm and ex situ conservation method. PMID- 20839635 TI - Comparison of aqueous plant extracts before and after fermentation with Lactobacillus paracasei LS-2 on cytokine induction and antioxidant activity. AB - This study was conducted to investigate the antioxidant properties and inhibitory effects on the inflammation-related cytokines of plant extracts fermented with Lactobacillus paracasei LS-2 in comparison with the unfermented aqueous plant extract. Attempted have also been made to identify fermented plant extracts that display no cytotoxicity against murine macrophage cells, while still maintaining their biological characteristics. Most of the fermented plant extracts showed reduced cytotoxicity. Among the fourteen plant extracts tested, the fermented plant extract of Scutellaria baicalensis Georgi increased the induction of anti inflammatory mediators; however, they were still cytotoxic. Interestingly, the plant extract of Artemisia capillaris Thunb. induced a dramatic increase in the induction of anti-inflammatory mediators with no cytotoxicity through fermentation. Our findings suggest that fermented A. capillaris holds promise for use as a valuable natural non-cytotoxic antioxidant and immuno-modulating agent. PMID- 20839636 TI - Volatile compounds from Tagetes pusilla (Asteraceae) collected from the Venezuela Andes. AB - The essential oil from the leaves of Tagetes pusilla Kunth (Asteraceae) collected from Merida, Venezuela, was analyzed by GC/MS. A yield of 0.38% oil was obtained by hydrodistillation. Only two components, trans-anethole and 4-allylanisole were identified by comparison of their mass spectra with those in the Wiley GC-MS Library data base. PMID- 20839637 TI - Volatile components of two endemic species from the Apuan Alps (Tuscany, Italy), Centaurea arachnoidea and C. montis-borlae (Asteraceae). AB - The volatile fractions of Centaurea arachnoidea and C. montis-borlae, two endemic species growing wild in the Apuan Alps (Tuscany, Italy), were isolated by steam distillation from fresh leaves and flowerheads, and analyzed by GC/FID and GC/MS. The yield of essential oil ranged from 0.01% to 0.09% of fresh material. A wide variety of volatile compounds was detected in the examined plant species and organs, both in qualitative and quantitative terms. Sesquiterpenes were the major constituents, ranging from 18.9% to 73.2% of the total oil. Alcohols (1.6-25.8%), aldehydes (1.5-12.0%), hydrocarbons (1.8-11.9%), acids (0.2-25.4%), esters (0.2 1.3%), monoterpenes (0.7-1.4%), and miscellaneous compounds (0.6-2.6%), were also detected in variable amounts in all different sample tissues. A series of unidentified compounds was also isolated from the two species, both in leaves and flowerheads, accounting for 2.4-6.7% of the total oil. According to MS spectral data, these substances were likely to be polyunsaturated compounds; moreover, they appear to be species-specific, as their presence was only detected in either one or the other Centaurea species. PMID- 20839638 TI - Composition of essential oil from seeds and cones of Abies alba. AB - The volatile composition of Abies alba Mill. seeds and cone scales has been studied, leading to the determination of 90 volatile constituents. The major component of the seed essential oil was (-)-limonene (about 70%), while that of the cone scale oil was a-pinene (57%). Monoterpene hydrocarbons were predominant in both oils, but the quantitative and qualitative composition of the volatile compounds was specific for each part of the tree. PMID- 20839639 TI - Comparative analysis of essential oil components of two Pinus species from Taibai Mountain in China. AB - Gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were used to compare between the essential oil components from needles of Pinus armandii Franch versus P. tabulaeformis Carr., growing on the same site at Taibai Mountain, China. Under optimum extraction and analysis conditions, 65 and 66 constituents each were identified in P. armandii and P. tabulaeformis, which accounted for 87.9% and 87.1%, respectively, of their oils. Based on their terpene compositions, we concluded that these species belong to a high caryophyllene chemotype, with sesquiterpenes comprising 54.4% to 54.8% of the total contents. We also determined minor qualitative and major quantitative variations in some compounds. Compared with that from P. tabulaeformis, P. armandii oil had more gamma-muurolene (7.5%), terpinolene (5.8%), and longifolene (5.7%). In contrast, alpha-pinene (8.6%) and caryophyllene oxide (7.4%) were the dominant compounds in P. tabulaeformis. PMID- 20839640 TI - Antimicrobial activity and volatile constituents of the essential oil of Pulsatilla albana from Iran. AB - The essential oil obtained by hydrodistillation of the aerial flowering parts of Pulsatilla albana (Stev.) Bercht. & Presl. was analyzed by GC and GC/MS. Twenty five compounds representing 97.5% of oil were identified, among them pulegone (39.1%), piperitenone (17.2%), menthone (16.1%), 1, 8-cineole (8.9%) and p-mentha 3,8-diene (4.2%). In this essential oil oxygenated monoterpenes (87.9%) predominated over monoterpene hydrocarbons (8.3%) and sesquiterpenes (1.3%). Nonterpene hydrocarbons were not found among the identified components. Antibacterial screening of the oil showed moderate activity against certain strains of Gram-positive and Gram-negative bacteria. PMID- 20839641 TI - Chemical composition and antimicrobial activity of the essential oils from Cleome spinosa. AB - Five different essential oil extractions of the aerial parts of Cleome spinosa Jacq. were examined. The oils obtained by hydrodistillation of the whole aerial parts, aerial parts without flowers (fruit, leaves and stem), flowers, fruits and leaves have been examined by GC-FID and GC-MS. The chemical profiles of the oils reveal the dominance of oxygenated sesqui- and diterpenes, with the exception of the fruit oil, which contained a high content of fatty acids. The most abundant compounds from the whole aerial parts were (Z)-phytol (31.3%), integerrimine (5.5%) and incensole (4.0%). The major compounds from the aerial portion without flowers were caryophyllene oxide (10.5%), (-)-spathulenol (7.5%) and Z-phytol (6.9%). In the flower oil, the main components were 7-alpha-hydroxy manool (23.8%), incensole (9.2%) and sclareol (8.7%). The chief constituents in the fruit oil were tetradecanoic acid (40.6%), (Z)-phytol (6.58%) and sclareol (4.5%). In the leaf oil, (Z)-phytol (19.5%), 7-alpha-hydroxy manool (6.8%) and caryophyllene oxide (4.36%) were the predominant compounds. Antimicrobial activity of the oil obtained from the whole aerial part was evaluated against nine microbial strains using a filter paper disc-diffusion method. The volatile oil showed moderate action against seven of the eight bacteria strains used, with significant inhibitory activity against Streptococcus pyogenes Group A when compared with the standard antibiotics, ampicillin and gentamicin. The fungus, Candida albicans was less sensitive to the essential oil. The oils showed moderate insecticidal activity against Cylas formicarius elegantalus, but possessed no antioxidant activity as indicated by the DPPH method. This represents the first report on the chemical composition of the essential oils from C. spinosa found in Jamaica and the in vitro antioxidant, insecticidal and antimicrobial potential of the oil from the aerial parts. PMID- 20839642 TI - Virucidal activity and chemical composition of essential oils from aromatic plants of central west Argentina. AB - The essential oils of seven aromatic plants from central west Argentina were isolated by steam distillation and analyzed by a gas chromatography/mass spectrometry technique. The oils were screened for cytotoxicity and in vitro inhibitory activity against herpes simplex virus type 1 (HSV-1), dengue virus type 2 (DENV-2) and Junin virus (JUNV). The oils showed a variable virucidal action according to the virus. JUNV was the least susceptible virus in comparison with HSV-1 and DENV-2. The better relationship between cytotoxicity and inhibitory activity was observed for the essential oil of Lantana grisebachiii (Seckt.) var. grisebachii against DENV-2 and HSV-1 with IC50 (inhibitory concentration 50%) values of 21.1 and 26.1 ppm, respectively. This effect was specific since the selectivity indices (ratio cytotoxicity/virucidal activity) were > 23.7 and > 19.1 for DENV-2 and HSV-1, respectively. Furthermore, the oil from L. grisebachii was also an effective inhibitor of HSV-2 and acyclovir resistant variants of herpes virus. This study demonstrates the effective and selective inhibitory activity of the essential oil from Lantana grisebachii against HSV and DENV by direct virus inactivation. PMID- 20839643 TI - Neolitsea sericea essential oil attenuates LPS-induced inflammation in RAW 264.7 macrophages by suppressing NF-kappaB and MAPK activation. AB - The chemical composition and anti-inflammatory activities of hydrodistilled essential oil from Neolitsea sericea leaves (NSE) have been investigated for the first time. The chemical constituents of NSE were analysed by GC-MS and found to include sericenine (32.3%), sabinene (21.0%), trans-beta-ocimene (13.3%), beta caryophyllene (4.8%), and 4-terpineol (4.2%). The effects of NSE on nitric oxide (NO), prostaglandin E2 (PGE2), tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 production in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages were also examined. Pro-inflammatory cytokine and mediator tests indicated that NSE has excellent dose-dependent inhibitory activities. To further examine the mechanism responsible for the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression by NSE, we examined the effect of NSE on nuclear factor-kappaB (NF-kappaB) activation and the phosphorylation of mitogen-activated protein kinases (MAPK). NSE inhibited NF kappaB activation by LPS, and this was associated with the abrogation of IkappaB alpha phosphorylation and subsequent decreases in nuclear p50 and p65 protein levels. Further, the phosphorylation of p38, ERK and JNK was suppressed by NSE in a concentration-dependent manner. These results suggest that NSE exerts anti inflammatory effects in LPS-stimulated RAW 264.7 macrophages by inhibition of NF kappaB activation and MAPK phosphorylation, and, therefore, may be useful for treatment of inflammatory diseases. PMID- 20839644 TI - Qualitative analysis of the smoke-stream of different kinds of incense by SPME/GC MS. AB - Seventeen different kinds of incenses were analyzed for the volatile components emitted during burning using a HS-SPME method coupled with GC-MS, in order to check their conformity to IFRA (International Fragrance Association) guidelines and 67/548/CEE Directive rules. A total of 51 volatiles were identified in the smoke of the incenses. They were represented mainly by aromatic compounds (17) and oxygenated monoterpenes (10), with esters (5) and aldehydes (4) being the most widespread volatiles in the former, and alcohols (4) and esters (4) in the latter. The aromatic ester benzyl benzoate and the oxygenated sesquiterpene patchouli alcohol were the most frequent volatile compounds, occurring in the smokes emitted from 10 and 8 kinds of incenses, respectively. PMID- 20839645 TI - Essential oil composition and in vivo volatiles emission by different parts of Coleostephus myconis capitula. AB - The essential oil obtained by hydrodistillation of the flowering capitula of Coleostephus myconis (syn. Chrysanthemum myconis) was constituted almost exclusively of oxygenated sesquiterpenes (85.8%). The main constituent was T cadinol (66.2%), followed by valeranone (8.2%), germacrene D (6.0%) and alpha cadinol (4.6%). By mean of the SPME technique, the volatiles emitted in vivo by the whole capitula and by tubular and ligulate florets have been identified. Many differences were evidenced among the different organs and with respect to the essential oil. PMID- 20839646 TI - Pesticide and plasticizer residues in citrus essential oils from different countries. AB - Residue analyses are very important in the quality control of citrus essential oils. Organophosphorus and organochlorine pesticides, phosphorated plasticizers and chloroparaffins contamination were investigated by HRGC with FPD and ECD detectors in 120 citrus essential oils produced in Italy and in 70 from other countries in the crop year 2006-2007. Results showed that the largest pesticide quantities were found in oils from Brazil and Spain. The presence of such residues might be the result of an improper use of pesticide in citrus growing or of previous contamination of the extractors. However, the pesticide levels showed a measurable decrease in relation to past production years. The absence of phosporated plasticizers and chloroparaffins can be the result of either improvement of the procedures used during the production cycle or in the storage of the essential oils compared with previous years. PMID- 20839647 TI - Applying new science for old medicines: targeting leukocyte-endothelial adhesions by antiinflammatory herbal drugs. AB - During the last two decades, considerable progress has been made in understanding the molecular mechanisms of the various leukocytes and endothelial cell adhesion molecules (cell adhesion molecules - CAMs) involved in cell-cell and cell matrix interactions. This understanding has opened up a new avenue of novel chemotherapeutic targets and bioassay models for inflammatory diseases. Recently developed in vitro bioassays on leukocyte/endothelial cell adhesions can now offer rapid and inexpensive assessment methods for herbal medicines with claimed antiinflammatory uses. Through the use of these robust in vitro methods, active principles of herbal drugs can also be isolated thereby providing the opportunity of standardizations based on a known chemical standard(s) and pharmacology. This review highlights relevant leukocyte/endothelial CAMs targets, available in vitro methods and our strategic approach for herbal standardizations. PMID- 20839648 TI - Validation of computational models in biomechanics. AB - The topics of verification and validation have increasingly been discussed in the field of computational biomechanics, and many recent articles have applied these concepts in an attempt to build credibility for models of complex biological systems. Verification and validation are evolving techniques that, if used improperly, can lead to false conclusions about a system under study. In basic science, these erroneous conclusions may lead to failure of a subsequent hypothesis, but they can have more profound effects if the model is designed to predict patient outcomes. While several authors have reviewed verification and validation as they pertain to traditional solid and fluid mechanics, it is the intent of this paper to present them in the context of computational biomechanics. Specifically, the task of model validation will be discussed, with a focus on current techniques. It is hoped that this review will encourage investigators to engage and adopt the verification and validation process in an effort to increase peer acceptance of computational biomechanics models. PMID- 20839649 TI - Bi-unicondylar knee prosthesis functional assessment utilizing force-control wear testing. AB - Recent in vivo studies have identified variations in knee prosthesis function depending on prosthesis geometry, kinematic conditions, and the absence/presence of soft-tissue constraints after knee replacement surgery. In particular, unicondylar knee replacements (UKR) are highly sensitive to such variations. However, rigorous descriptions of UKR function through experimental simulation studies, performed under physiological force-controlled conditions, are lacking. The current study evaluated the long-term functional performance of a widely used fixed-bearing unicompartmental knee replacement, mounted in a bi-unicondylar configuration (Bi-UKR), utilizing a force-controlled knee simulator during a simulated (ISO 14243) walking cycle. The wear behaviour, the femoral-tibial kinematics, and the incurred damage scars were analysed. The wear rates for the medial and the lateral compartments were 10.27 +/- 1.83 mg/million cycles and 4.49 +/- 0.53 mg/million cycles, respectively. Although constant-input force controlled loading conditions were maintained throughout the simulation, femoral tibial contact point kinematics decreased by 65 to 68 per cent for average anterior/posterior travel and by 58 to 74 per cent for average medial/lateral travel with increasing cycling time up to 2 million cycles. There were no significant differences in damage area or damage extent between the medial and the lateral compartments. Focal damage scars representing the working region of the femoral component on the articular surface extended over a range of 16-21 mm in the anterior-posterior direction. Kinematics on the shear plane showed slight variations with increasing cycling time, and the platform exhibited medial pivoting over the entire test. These measures provide valuable experimental insight into the effect of the prosthesis design on wear, kinematics, and working area. These functional assessments of Bi-UKR under force-controlled knee joint wear simulation show that accumulated changes in the UKR articular conformity manifested as altered kinematics both for anterior/posterior translations and internal/external rotations. PMID- 20839650 TI - Polyethylene insert damage in unicondylar knee replacement: a comparison of in vivo function and in vitro simulation. AB - Modification of knee joint wear simulation methods has included 'anatomic attachment' of unicondylar knee replacements (UKR) onto synthetic femurs with material properties and morphology similar to human femurs. The present study assesses the effect of such modification by comparing the damage patterns on UKR polyethylene inserts after in vitro simulation using standard and modified simulation methods with those on inserts retrieved after in vivo function. Three groups of UKR inserts were evaluated after retrieval (Explant Group, n = 17) or after knee joint wear simulation with the components attached to standard metal blocks (Standard Group, n = 6) or synthetic femurs (Anatomic Group, n = 6). All UKR had similar non-conforming articular surfaces. Articular damage patterns (mode, frequency, and area) were quantified using digital image photogrammetry. Although some common damage modes were noted, knee joint wear simulation with standard or 'anatomic' attachment did not generate damage pattern sizes similar to the explanted UKR. A focal damage pattern consistent with contact between the metal femoral articular surface and the polyethylene inserts was evident on all inserts, but only the Explant Group had evidence of dispersed damage dominated by abrasive modes. Synthetic femurs added complexity to the wear simulation without generating wear patterns substantially more similar to those observed on retrieved inserts. PMID- 20839651 TI - The effect of cortex thickness on intact femur biomechanics: a comparison of finite element analysis with synthetic femurs. AB - Biomechanical studies on femur fracture fixation with orthopaedic implants are numerous in the literature. However, few studies have compared the mechanical stability of these repair constructs in osteoporotic versus normal bone. The present aim was to examine how changes in cortical wall thickness of intact femurs affect biomechanical characteristics. A three-dimensional, linear, isotropic finite element (FE) model of an intact femur was developed in order to predict the effect of bicortical wall thickness, t, relative to the femur's mid diaphyseal outer diameter, D, over a cortex thickness ratio range of 0 < or = t/D < or = 1. The FE model was subjected to loads to obtain axial, lateral, and torsional stiffness. Ten commercially available synthetic femurs were then used to mimic 'osteoporotic' bone with t/D = 0.33, while ten synthetic left femurs were used to simulate 'normal' bone with t/D = 0.66. Axial, lateral, and torsional stiffness were measured for all femurs. There was excellent agreement between FE analysis and experimental stiffness data for all loading modes with an aggregate average percentage difference of 8 per cent. The FE results for mechanical stiffness versus cortical thickness ratio (0 < or = t/D < or = 1) demonstrated exponential trends with the following stiffness ranges: axial stiffness (0 to 2343 N/mm), lateral stiffness (0 to 62 N/mm), and torsional stiffness (0 to 198 N/mm). This is the first study to characterize mechanical stiffness over a wide range of cortical thickness values. These results may have some clinical implications with respect to appropriately differentiating between older and younger human long bones from a mechanical standpoint. PMID- 20839652 TI - Performance of the resurfaced hip. Part 2: The influence of prosthesis stem design on remodelling and fracture of the femoral neck. AB - Hip resurfacing is a popular treatment for osteoarthritis in young, active patients. Previous studies have shown that occasional failures--femoral neck fracture and implant loosening, possibly associated with bone adaptation--are affected by prosthesis sizing and positioning, in addition to patient and surgical factors. With the aim of improving tolerance to surgical variation, finite element modelling was used to indicate the effects of prosthesis metaphyseal stem design on bone remodelling and femoral neck fracture, with a range of implant orientations. The analysis suggested that the intact femoral neck strength in trauma could be maintained across a wider range of varus-valgus orientations for short-stemmed and stemless prostheses. Furthermore, the extent of periprosthetic bone remodelling was lower for the short-stemmed implant, with slightly reduced stress shielding and considerably reduced densification around the stem, potentially preventing further progressive proximal stress shielding. The study suggests that a short-stemmed resurfacing head offers improved tolerance to misalignment and remodelling stimulus over traditional designs. While femoral neck fracture and implant loosening are multifactorial, biomechanical factors are of clear importance to the clinical outcome, so this may reduce the risk for patients at the edge of the indications for hip resurfacing, or shorten the surgical learning curve. PMID- 20839653 TI - In vitro friction and lubrication of large bearing hip prostheses. AB - New material combinations and designs of artificial hip implants are being introduced in an effort to improve proprioception and functional longevity. Larger joints in particular are being developed to improve joint stability, and it is thought that these larger implants will be more satisfactory for younger and more physically active patients. The study detailed here used a hip friction simulator to assess the friction and lubrication properties of large-diameter hip bearings of metal-on-metal and ceramic-on-reinforced-polymer couplings. Joints of different diameters were evaluated to determine what effect, if any, bearing diameter had on lubrication. In addition, the effects of lubricant type are considered, using carboxymethyl cellulose and bovine calf serum, and the physiological lubricant is shown to be considerably more effective at reducing friction. The frictional studies showed that the metal-on-metal joints worked under a mixed lubrication regime, producing similar friction factor values to each other. The addition of bovine calf serum (BCS) reduced the friction. The ceramic-on-reinforced-polymer samples were shown to operate with high friction factors and mixed lubrication. When tested with BCS, the larger-diameter bearings showed a decrease in friction compared with the smaller-size bearings, and the addition of BCS resulted in an increase in friction, unlike the metal-on-metal system. The study demonstrated that the component's diameter had little or no influence on the lubrication and friction of the large bearing combinations tested. PMID- 20839654 TI - Integrated friction measurements in hip wear simulations: short-term results. AB - Hip joint wear simulators are used extensively to simulate the dynamic behaviour of the human hip joint and, through the wear rate, gain a concrete indicator about the overall wear performance of different coupled bearings. Present knowledge of the dynamic behaviour of important concurrent indicators, such as the coefficient of friction, could prove helpful for the continuing improvement in applied biomaterials. A limited number of commercial or custom-made simulators have been designed specifically for friction studies but always separately from wear tests; thus, analysis of these two important parameters has remained unconnected. As a result, a new friction sensor has been designed, built, and integrated in a commercial biaxial rocking motion hip simulator. The aim of this study is to verify the feasibility of an experimental set-up in which the dynamic measurement of the friction factor could effectively be implemented in a standard wear test without compromising its general accuracy and repeatability. A short wear test was run with the new set-up for 1 x 10(6) cycles. In particular, three soft-bearings (metal-on-polyethylene, phi = 28 mm) were tested; during the whole test, axial load and frictional torque about the vertical loading axis were synchronously recorded in order to calculate the friction factor. Additional analyses were performed on the specimens, before and after the test, in order to verify the accuracy of the wear test. The average friction factor was 0.110 +/- 0.025. The friction sensors showed good accuracy and repeatability throughout. This innovative set-up was able to reproduce stable and reliable measurements. The results obtained encourage further investigations of this set-up for long term assessment and using different combinations of materials. PMID- 20839655 TI - Finite element analysis of a personalized femoral scaffold with designed microarchitecture. AB - Tissue engineering scaffolds with intricate and controlled internal structure can be realized using computer-aided design (CAD) and layer manufacturing (LM) techniques. Design and manufacturing of scaffolds for load-bearing bone sites should consider appropriate biocompatibile materials with interconnected porosity, surface properties, and sufficient mechanical properties that match the surrounding bone, in order to provide adequate support, and to mimic the physiological stress-strain state so as to stimulate new tissue growth. The authors have previously published methods for estimating subject- and site specific bone modulus using computed tomography (CT) data, CAD, and process planning for LM of controlled porous scaffolds. This study evaluates the mechanical performance of the designed porous hydroxyapite scaffolds in load bearing sites using a finite element (FE) approach. A subject-specific FE analysis using femoral, defect site geometry and anisotropic material assignment based on CT data is employed. Mechanical behaviour of the femur with scaffold in stance-phase gait loading, which has been shown experimentally to produce clinically relevant results, is analysed. The comparison of results with simulation of healthy femur shows an overall correspondence in stress and strain state which will provide optimized mechanical properties for avoiding stress shielding, and adequate strength to avoid failure risk and for active bone tissue regeneration. PMID- 20839656 TI - Comparing normal walking and compensated walking: their stability and perturbation resistance. A simulation study. AB - People usually develop different kinds of compensated gait in response to local function deficits, such as muscle weakness, spasticity in specific muscle groups, or joint stiffness, in order to overcome the falling risk factors. Compensated walking has been analysed empirically in the impaired gait analysis area. However, the compensation could be identified spatially and temporally. The stability and perturbation resistance of compensated walking have not been analysed quantitatively. In this research, a biomimetic human walking simulator was employed to model one individual paraplegic subject with plantarflexor spasticity. The pes equinus was expressed by biasing the outputs of plantarflexor neurons corresponding to the spastic muscles. Then, the compensatory mechanism was explored by adjusting the outputs of the other muscles. It was shown that this approach can be used for quantitative analysis of the spastic gait and compensated walking. Thus, this research can improve the understanding of the behaviour of compensated walking, bringing insights not only for building useful walking assist systems with high safety but also for designing effective rehabilitation interventions. PMID- 20839657 TI - Modelling cement augmentation: a comparative experimental and finite element study at the continuum level. AB - Subject-specific computational models of anatomical components can now be generated from image data and used in the assessment of orthopaedic interventions. However, little work has been undertaken to model cement-augmented bone using these methods. The purpose of this study was to investigate different methods of representing a trabecular-like material (open-cell polyurethane foam, Sawbone, Sweden) augmented with poly(methyl methacrylate) (PMMA) bone cement in a finite element (FE) model. Three sets of specimens (untreated, fully augmented with cement, partially augmented with cement) were imaged using micro computed tomography (microCT) and tested under axial compression. Subject-specific continuum level FE models were built based on the microCT images. Using the first two sets of models, the material conversion factors between image greyscale and mechanical properties for the pure synthetic bone and cement-augmented composite were determined iteratively by matching the FE predictions to the experimental measurements. By applying these greyscale related mechanical properties to the FE models of the partially augmented specimens, the predicted stiffness was found to be more accurate (approximately 5 per cent error) than using homogeneous properties for the augmented and synthetic bone regions (approximately 18 per cent error). It was also found that the predicted stiffness using the modulus of pure cement to define the augmented region was overestimated, and generally the apparent elastic modulus was dominated by the properties of the synthetic bone. PMID- 20839658 TI - Estimation of the radial force using a disturbance force observer for a magnetically levitated centrifugal blood pump. AB - Evaluation of the hydraulic forces in a magnetically levitated (maglev) centrifugal blood pump is important from the point of view of the magnetic bearing design. Direct measurement is difficult due to the absence of a rotor shaft, and computational fluid dynamic analysis demands considerable computational resource and time. To solve this problem, disturbance force observers were developed, using the radial controlled magnetic bearing of a centrifugal blood pump, to estimate the radial forces on the maglev impeller. In order to design the disturbance observer, the radial dynamic characteristics of a maglev impeller were evaluated under different working conditions. It was observed that the working fluid affects the additional mass and damping, while the rotational speed affects the damping and stiffness of the maglev system. Based on these results, disturbance force observers were designed and implemented. The designed disturbance force observers present a bandwidth of 45 Hz. In non-pulsatile conditions, the magnitude of the estimated radial thrust increases in proportion to the flowrate, and the rotational speed has little effect on the force direction. At 5 l/min against 100 mmHg, the estimated radial thrust is 0.95 N. In pulsatile conditions, this method was capable of estimating the pulsatile radial thrust with good response. PMID- 20839659 TI - A two-degree-of-freedom hip exoskeleton device for an immature animal model of exercise-induced Legg-Calve-Perthes disease. PMID- 20839660 TI - It starts with a conversation: a community approach to creating healthy work environments. AB - A healthy work environment is needed to retain nurses. Among the factors that contribute to a healthy work environment are collaboration and communication. Through the leadership of the Palm Healthcare Foundation, Inc., a dialogue was started among health care stakeholders in Palm Beach County, Florida, resulting in a health care work force partnership community collaboration and initiatives to address the retention of nurses. One initiative was sponsoring a "train-the trainer" program to raise awareness and provide skills for addressing factors that could affect work relationships, including emotional intelligence, generational differences, cultural competency and health literacy, employee crisis, and horizontal violence. A 6-month program evaluation was completed by the participants. A community approach provides a means for providers and educators to address common work force issues collaboratively. PMID- 20839661 TI - Development of a model home health nurse internship program for new graduates: key lessons learned. AB - A nursing shortage, the aging baby boomer population, an escalating need for home health care, and limited availability of health care dollars are threatening to undermine the quality of health care in the United States. The National Center for Health Workforce Analysis projects a deficit of 275,000 full-time equivalents by 2010 (-12%) and a deficit of 800,000 by 2020 (-29%). This article focuses on one home health agency's strategy to support nurse graduates transitioning from student to professional nurse. Based on Benner's (1984) hallmark theory from novice to expert, the goals of this program are to enhance job satisfaction and social integration, facilitate autonomy, increase critical thinking and psychomotor skills, and develop additional competencies. Eleven key lessons learned are outlined. PMID- 20839662 TI - Using stories to bridge cultural disparities, one culture at a time. AB - Story theory can be the basis of the nurse's culturally sensitive approach to gather patients' health information and learn about and experience patients' cultural values and beliefs. This article illustrates how story theory was used at the bedside of a Guatemalan Mayan patient to develop a culturally sensitive plan of care. Because nursing facilitates obtaining story at the bedside, nurses should consider using story theory to promote authentic communication that will bring voice to patients' concerns and assist in finding meaningful, culturally competent health solutions. By identifying what matters most to the patient through intentional dialogue, nurses can assist in the transformation of the current health care system to a patient-centered system that links nursing practice with nursing knowledge and bridges the health disparity gap, one patient at a time. PMID- 20839663 TI - Pediatric refractive surgery and its role in the treatment of amblyopia: meta analysis of the peer-reviewed literature. AB - PURPOSE: To provide an overview of the visual outcomes after pediatric refractive surgery in anisometropic amblyopia and to analyze the relationship of these outcomes with age and type of refractive surgery. METHODS: Systematic searches in PubMed, Embase, and Web of Science databases without data restrictions and a search by surveillance of the literature regarding pediatric refractive surgery were performed. Only studies reporting individual data of pediatric cases (age 1 to 17 years) undergoing photorefractive keratectomy (PRK), laser epithelial keratomileusis (LASEK), and LASIK were included. A total of 15 articles including data from a total of 213 amblyopic eyes were considered: LASIK in 95 eyes and surface ablation in 118 eyes. Changes in uncorrected (UDVA) and corrected distance visual acuity (CDVA) were investigated as well as their relation with age and ablation type. RESULTS: A significant increase in logMAR UDVA and CDVA was found in the overall sample of amblyopic eyes after surgery (P<.001). A significant correlation was found between age and preoperative CDVA (r=0.34, P<.001) as well as between age and the change in CDVA after surgery (r=-0.38, P<.001). The change in UDVA was significantly superior for eyes undergoing surface ablation compared to those undergoing LASIK (P=.04). Corneal haze was the predominant complication, which was reported in 5.3% of LASIK cases and 8.5% of surface ablation cases. CONCLUSIONS: Laser refractive surgery is an effective option for improving the visual acuity in children with an amblyopic eye in association with anisometropia. PMID- 20839664 TI - Optimal amount of anisometropia for pseudophakic monovision. AB - PURPOSE: To determine the optimal target anisometropia for pseudophakic monovision. METHODS: Thirty-five bilaterally pseudophakic patients who received monofocal intraocular lenses were included in the study. Binocular corrected distance visual acuity (CDVA) and binocular distance-corrected near visual acuity (DCNVA) and stereoacuity were measured after simulating 1.00, 1.50, and 2.00 diopters (D) of monovision by adding the appropriate spherical lens to the nondominant eye. We presumed that mean binocular DCNVA of 20/40, binocular CDVA of 20/25, and stereoacuity <100 seconds of arc (arc sec) were necessary for successful monovision. RESULTS: With no anisometropia, mean binocular DCNVA was 20/97, binocular CDVA was 20/20, and mean stereoacuity was 71 arc sec. With 1.00 D of monovision, mean binocular DCNVA was only 20/60, although binocular CDVA and mean stereoacuity were sufficient. With 1.50 D of monovision, binocular DCNVA was 20/38, binocular CDVA at other distances exceeded 20/21, and stereoacuity was 100 arc sec, which was a 29-arc sec reduction. With 2.00 D of monovision, binocular DCNVA reached 20/31, but stereoacuity was 158 arc sec, which was an 87-arc sec reduction. The number of patients who met the criteria for successful monovision was significantly greater with 1.50 D of monovision than with 1.00 or 2.00 D of monovision (P=.0134). CONCLUSIONS: Pseudophakic monovision with anisometropia of 1.50 or 2.00 D provides useful binocular visual acuity from far to near. However, because stereopsis with 2.00 D of monovision is substantially impaired, approximately 1.50 D of anisometropia is thought to be optimal for successful monovision. PMID- 20839665 TI - Wavefront-guided vs wavefront-optimized LASIK: a randomized clinical trial comparing contralateral eyes. AB - PURPOSE: To compare wavefront-guided and wavefront-optimized LASIK in patients with myopic astigmatism up to -7.00 diopters (D) sphere and 3.00 D cylinder. METHODS: In this prospective, comparative study, 41 patients had wavefront-guided LASIK in one eye and wavefront-optimized LASIK in the fellow eye. The LASIK flap was created with a Hansatome XP microkeratome (Bausch & Lomb). The ALLEGRETTO Concerto excimer laser (WaveLight Laser Technologie AG) was used for photoablation. Pupil centroid shift and cyclotorsion were not compensated in the wavefront-guided treatments. The ALLEGRETTO Wave analyzer was used to measure ocular wavefront aberrations, and the CSV-1000 instrument (VectorVision) was used to measure contrast sensitivity before and 1 and 3 months after LASIK. RESULTS: Preoperative mean spherical equivalent refraction was -4.25+/-1.19 D (range: 7.50 to -2.50 D) and -4.15+/-1.21 D (range: -7.13 to -1.75 D) in the wavefront guided and wavefront-optimized groups, respectively. Three months postoperatively, 33 (89.2%) eyes in the wavefront-guided group and 31 (83.8%) eyes in the wavefront-optimized group had uncorrected distance visual acuity of 20/20. Higher order aberrations increased from 0.28+/-0.08 MUm (range: 0.13 to 0.48 MUm) and 0.26+/-0.08 MUm (range: 0.13 to 0.55 MUm) to 0.45+/-0.17 MUm (range: 0.18 to 0.71 MUm) and 0.45+/-0.16 MUm (range: 0.21 to 0.84 MUm) in the wavefront-guided and wavefront-optimized groups, respectively. Except for C6 trefoil (P=.006), all Zernike polynomials increased in both groups postoperatively with no statistical difference between groups in spherical aberration (P=.41), C7 coma (P=.67), C8 coma (P=.79), and trefoil (P=.82). Contrast sensitivity did not decrease in either group and no statistically significant differences between groups were noted. CONCLUSIONS: Higher order aberrations, especially spherical aberration, increasd approximately the same amount in both groups. PMID- 20839666 TI - Long-term monitoring of age-related macular degeneration with preferential hyperacuity perimetry. AB - BACKGROUND AND OBJECTIVE: To estimate the efficacy and usability of preferential hyper-acuity perimetry (PHP) for monitoring patients with high-risk intermediate age-related macular degeneration (AMD). PATIENTS AND METHODS: A long-term, observational, prospective case series of patients with intermediate AMD who underwent fluorescein angiography at recruitment. Eyes were examined every 3 months with PHP, visual acuity, and biomicroscopy. Optical coherence tomography (OCT) imaging was performed when PHP was outside normal limits. In case of suspected findings in OCT, fluorescein angiography was also performed. Patients diagnosed as having choroidal neovascularization (CNV) were offered anti-vascular endothelial growth factor therapy. RESULTS: Twenty-six eyes (25 patients) were monitored for a mean follow-up period of 600 days. Of the 172 PHP tests done by these 26 eyes with intermediate AMD, 158 were within normal limits yielding a false-positive rate of 8.1%. Three of 4 eyes that converted to CNV had PHP test results outside normal limits before or on the day of diagnosis. CONCLUSION: PHP is useful for detecting CNV in regularly monitored eyes with intermediate AMD while maintaining a low false-positive rate. PMID- 20839667 TI - Retinal layer thickness changes in eyes with preserved visual acuity and diffuse diabetic macular edema on optical coherence tomography. AB - BACKGROUND AND OBJECTIVE: Diabetic macular edema has several patterns on optical coherence tomography. This retrospective study aimed to assess which retinal layers show thickness changes in type 1 diffuse diabetic macular edema with preserved vision. PATIENTS AND METHODS: Eleven eyes with diffuse diabetic macular edema on optical coherence tomography and eight control eyes with 20/20 best corrected visual acuity were enrolled. Optical coherence tomography images were segmented using an algorithm of the authors' design (OCTRIMA): regional thickness data in the central area, pericentral rings, and peripheral rings were obtained for the retinal cellular layers. RESULTS: The retinal nerve fiber layer showed no changes, the ganglion cell and inner plexiform composite layer and the ganglion cell complex were thicker only in the pericentral regions, and all other layers were thicker in all regions in diffuse diabetic macular edema. Macular thickness was normal in the peripheral region. CONCLUSION: The results show that the outer retina in the foveal area is the most affected in diffuse diabetic macular edema. PMID- 20839668 TI - Bevacizumab for the treatment of pediatric retinal and choroidal diseases. AB - BACKGROUND AND OBJECTIVE: To determine the efficacy of off-label intravitreal bevacizumab (IVB) for the treatment of pediatric retinal and choroidal vascular diseases. PATIENTS AND METHODS: Retrospective, non-comparative, open-label, interventional, consecutive case series of all patients younger than 18 years treated with off-label IVB at a single center from January 1, 2005, to January 1, 2008. Primary outcome measures with best-corrected visual acuity by age appropriate testing and central macular thickness by time-domain optical coherence tomography. RESULTS: Thirty-five eyes of 33 patients were treated with IVB alone or in combination with other treatments for choroidal neovascularization, Coats' disease, familial exudative vitreoretinopathy, and various other indications. IVB was used in 24 eyes to reduce excess retinal fluid and exudation. Mean Snellen visual acuity improved from 20/170 at baseline to 20/100 at 1 month (P = .006), 20/80 at 3 months (P = .006), and 20/50 at 6 months (P = .023). Central macular thickness improved from 356 MUm at baseline to 287 MUm at 6 months (P = .028). IVB was used in 11 eyes to control peripheral retinal neovascularization and iris rubeosis. Although IVB reduced vascular engorgement, it did not prevent the progression of preretinal tractional forces. Mean visual acuity was maintained at each time point. No systemic or ocular adverse events were directly attributable to IVB in any patient. CONCLUSION: IVB reduced vascular leakage and temporarily regressed pathologic neovascularization of the choroid, retina, and iris in this series of pediatric patients. Further prospective studies are warranted. PMID- 20839669 TI - Comparison of stereo disc photographs and alternation flicker using a novel matching technology for detecting glaucoma progression. AB - BACKGROUND AND OBJECTIVE: To compare agreement of automated alternation flicker and serial stereophotograph inspection for detection of progressive glaucoma. PATIENTS AND METHODS: Serial photographs of patients with glaucoma with at least 36 months of follow-up and perimetry every 4 months were assessed by four graders using predefined criteria with both flicker and stereophotography. The main outcome measure was progressive neuroretinal rim deterioration as identified by each technique. RESULTS: Forty eyes (20 patients) were included and 12 eyes progressed with perimetry. Using stereophotography, the overall agreement (kappa +/- standard error) was 0.19 +/- 0.06 for rim change, 0.78 +/- 0.06 for disc hemorrhage, and -0.04 +/- 0.06 for vessel movement. Using flicker, the overall agreement was similar for rim change (0.28 +/- 0.06; P = .29), worse for disc hemorrhage (0.43 +/- 0.06; P < .001), and better for vessel movement (0.22 +/- 0.06; P = .002). The agreement between perimetric and disc progression was similar using stereophotography (0.10 +/- 0.05) and flicker (0.19 +/- 0.05; P = .20). CONCLUSION: Agreement between flicker and stereophotography was similar. PMID- 20839670 TI - Efficacy of different excimer laser techniques in the management of recurrent corneal erosions. AB - BACKGROUND AND OBJECTIVE: To investigate the efficacy of two excimer laser techniques for recurrent corneal erosions (RCEs). PATIENTS AND METHODS: Of 100 patients with RCEs not responding to common treatments, 50 received transepithelial (group 1) and 50 received subepithelial (group 2) treatment of 20 pulses of a 193-nm excimer laser (170 J/cm(2)). Postoperative follow-up occurred at 4 and 52 weeks. Outcome measures were frequency of RCEs, haze formation, and refractive changes. RESULTS: At first follow-up, 7 patients (14%) in each group displayed recurrence. At second follow-up, 12 patients in group 1 (24%) and 10 patients in group 2 (20%) had RCE. Follow-up recurrence risk was 6% to 27% in both groups at 4 weeks and 13% to 38% in group 1 and 10% to 34% in group 2 at 52 weeks. The spherical equivalent remained unaffected in group 1, but a statistically significant change was observed in group 2. CONCLUSION: Excimer laser treatment (transepithelial and subepithelial) of RCEs can be performed successfully on the intact epithelium without adjunct therapy or pain. The transepithelial technique is a simple and relatively painless way to reduce the rate of RCE and is equivalent to the well-established subepithelial treatment. PMID- 20839671 TI - Dual mobility for chronic hip instability: a solution option. AB - A dual-mobility acetabular component consists of a large, fixed, porous-coated acetabular component and a bipolar femoral component. These components are often called tripolar components. This configuration provides a stable, well-fixed implant platform against bone and 2 articular interfaces, a large polyethylene surface directly apposed to the highly polished metal shell, and a standard sized (28 mm, 32 mm) femoral head captured within polyethylene. The dual-mobility cup was designed to reduce the incidence of dislocations in patients at increased risk of instability (eg, patients undergoing revision). The cup appears to offer a safe, effective, durable solution to hip instability. The concept has extensive laboratory and clinical support. Although the long-term durability of dual mobility cups, particularly in young, active, large patients, is not known, the tested wear rates of the dual-mobility design with the current generation of highly cross-linked polyethylene are significantly lower than any previously reported wear rates. The recently released anatomic dual-mobility cup seeks to reduce the potential for iliopsoas impingement while retaining the stability and wear characteristics of the original dual-mobility design. PMID- 20839672 TI - Gap balancing through small incisions: competing goals. AB - Significant controversy exists in the literature regarding the pitfalls and benefits of minimally invasive total knee arthroplasty (TKA). Regardless, most surgeons today use smaller exposures than in previous years. Although more difficult, rigid adherence to classical gap balancing techniques can allow a surgeon to achieve ideal ligament and flexion/extension gap balance in TKA through a minimally invasive approach. There are certain groups of patients (obesity/medical comorbidities/vascular insufficiency) in whom small incision approaches should not be attempted due to increased risks of wound complications. Additionally, achievement of gap balance requires sequential and safe removal of bone starting with the patellar cut, followed by the distal femoral cut, then by the tibial cut, and concluding with completion of the femoral component cuts. Use of special instruments such as protective metal patellar buttons, medial to lateral distal femoral cutting blocks, and low profile spacer blocks can facilitate the surgical process. Accurate femoral component rotation is more difficult in minimally invasive approaches and must be carefully checked. A tight extensor mechanism in flexion can mislead the surgeon to place the femoral component in an internally rotated position. Furthermore, with limited visualization, surgeons must avoid overaggressive ligament releases early in the procedure prior to completion of bone cuts. However, with appropriate patient selection and a systematic approach to minimally invasive total knee arthroplasty, surgeons can continue to achieve ideal ligament balance with a more soft tissue friendly operation. PMID- 20839673 TI - Stiffness after TKR: how to avoid repeat surgery. AB - Stiffness after total knee replacement (TKR) is a frustrating complication that has many possible causes. Although the definition of stiffness has changed over the years, most would agree that flexion <75 degrees and a 15 degrees lack of extension constitutes stiffness. The management of this potentially unsatisfying situation begins preoperatively with guidance of the patient's expectations; it is well-known that preoperative stiffness is strongly correlated with postoperative lack of motion. At the time of surgery, osteophytes must be removed and the components properly sized and aligned and rotated. Soft tissue balancing must be attained in both the flexion/extension and varus/valgus planes. One must avoid overstuffing the tibiofemoral and/or patellofemoral compartments with an inadequate bone resection. Despite these surgical measures and adequate pain control and rehabilitation, certain patients will continue to frustrate our best efforts. These patients likely have a biological predisposition for formation of scar tissue. Other potential causes for the stiff TKR include complex regional pain syndrome or joint infection. Close follow-up of a patient's progress is crucial for the success in return of range of motion. Should motion plateau early in the recovery phase, the patient should be evaluated for manipulation under anesthesia. The results of reoperations for a stiff TKR are variable due to the multiple etiologies. A clear cause of stiffness such as component malposition, malrotation, or overstuffing of the joint has a greater chance of regaining motion than arthrofibrosis without a clear cause. Although surgical treatment with open arthrolysis, isolated component, or complete revision can be used to improve TKR motion, results have been variable and additional procedures are often necessary. PMID- 20839674 TI - Lysis in the well-fixed shell: "hold 'em" or "fold 'em". AB - Periacetabular osteolysis is the greatest challenge for longevity of total hip arthroplasty. The generation of wear debris from the bearing surface is inevitably going to cause bone loss around the implants. The challenges for the arthroplasty surgeon in managing this problem are: detection, knowing when to intervene surgically, and choosing the best reconstructive option. From a surgical standpoint, the options for addressing osteolysis are: (1) liner exchange with or without bone grafting of lytic lesions; or (2) complete component revision. The advantages of "holding 'em" include a faster surgery, no bony disruption, a quicker recovery for the patient, and cost. The downside of isolated liner exchange is that there is a high rate of instability, there may be incomplete access to the lytic lesions, and the limitations of the existing component. There have been techniques developed to provide access to the retroacetabular lesions, particularly superolaterally via a trap-door technique. Alternatively, other surgeons have advocated injection of bone graft substitutes in the retroacetabular regions to fill osteolytic defects. However, one may not be able to take advantage of newer bearing materials, larger head sizes, or component reposition to improve stability and wear properties. The advantages of a complete component revision are access to lytic lesions, and the ability to modify component position and take advantage of newer technologies. The disadvantages are cost, a longer recovery, and bony disruption. Each method of addressing acetabular osteolysis has compelling reasons to use it; individual patient factors such as component type, size of lesion, and remaining bone will play a role in selecting the treatment. PMID- 20839675 TI - The economics of new age arthroplasty: can we afford it? AB - New technology in joint replacement design and materials adds cost that must be documented by improved outcomes. This is not always the case as the recent metal/metal data has shown. The current economics of arthroplasty have put increasing financial pressure on hospitals and will progress under new health care legislation. New technology must be cost-effective and this will be increasingly difficult in an era of outstanding long-term results with current designs. Cost may necessitate less expensive alternatives, eg, generic implants, in arthroplasty patients. Joint replacement surgery has evolved over the past 4 decades into a highly successful surgical procedure. Earlier designs and materials that demonstrated inferior functional and long-term results have disappeared in a Darwinian fashion. Through this evolutionary process many of the current designs have proven efficacy and durability. Current outcome data indicates that hip and knee designs demonstrate 90% to 95% success rates at 15 year follow-up. Technologic advances are necessary to improve implant design and materials, however, only in an environment of reduced reimbursement to hospitals can the increase cost be justified. PMID- 20839676 TI - Metal-metal reactivity: Houston, we have a problem! AB - In this single-surgeon series, both resurfaced hips in 1 woman and a total hip arthroplasty in another were revised for symptomatic pseudotumor (3 of 588 hips; 0.51% overall incidence; 2.2% in women). All 3 hips had 50-mm acetabular components. There was no difference in mean lateral opening angle (mean 38.7 degrees vs 42.8 degrees for the others) but these 3 hips all had increased acetabular anteversion (mean 27.1 degrees vs 16.4 degrees for the others; P<.05). Increased combined anteversion is a mechanical common denominator in pseudotumor formation. Female sex and small component size are variables associated with congenital dysplasia, which typically has a small, shallow socket and high combined anteversion. Thus, native anatomy may predispose to the joint mechanics that lead to pseudotumor formation, and not sex or size. The aggregate results indicate that the determination of satisfactory component position includes (1) assessment of the acetabular component lateral opening, (2) acetabular component version, and (3) femoral version. A mechanical problem suggests a mechanical solution. To insure capture of the femoral head by the socket and the intended bearing tribology, acetabular lateral opening angles should be <50 degrees , assuming a femoral neck-shaft angle of 130 degrees to 135 degrees . Combined anteversion should not exceed 40 degrees . In resurfacing of dysplastic cases where the neck-shaft angle exceeds 140 degrees , the acetabular lateral opening angle needs to be correspondingly lower to achieve equivalent head capture and bearing contact. PMID- 20839677 TI - Encountering cancer or its sequelae at the hip. AB - The orthopedist may need act as an adjunct to the medical oncologist in the management of the cancer patient with hip disease. While management of the cancer patient with routine hip pathology is relatively straightforward, the surgeon should be aware that the cancer patient may be on treatment protocols that affect wound healing, the immune system, and the risk of deep venous thrombosis. An additional factor that may complicate management of patients who have completed treatment of peripelvic cancer may be local radiation therapy, which can lead to necrosis of the acetabular bone stock. Operating on these patients must include consultation with previous radiation therapy providers to estimate the dose sustained by the local tissues under consideration. Greater than 500 cGy has been associated with high fixation failure rates in several series. Increased rates of infection and wound healing have also been noted secondary to long-term lymphatic obliteration caused by radiation. These concerns also affect the surgeon who must manage patients with acute metastatic disease. The principles of managing metastatic disease include recognizing the presence of lesions in bone about the hip, the occasional need for biopsy, the use of radiation in sensitive tumors, surgical stabilization of impending fracture, or joint replacement when needed. The amount of tumor, as well as the effect of chemotherapy and radiation on the healing process, potentially complicates these treatment modalities. PMID- 20839678 TI - DVT prophylaxis: better living through chemistry: affirms. AB - Venous thromboembolism remains the most common cause of hospital readmission and death after total joint arthroplasty. The 2008 American College of Chest Physicians (ACCP) guidelines, based on prospective randomized clinical trials with a venography endpoint, endorse the use of low-molecular-weight heparin, fondaparinux, or adjusted dose warfarin (target international normalized ratio, 2.5; range, 2-3) for up to 35 days after total hip arthroplasty (THA) and total knee arthroplasty (TKA). In the past, the ACCP has recommended against the use of aspirin, graduated compression stockings, or venous compression devices as the sole means of prophylaxis, but in 2008 they first recommended the "optimal use of mechanical thromboprophylaxis with venous foot pumps or intermittent pneumatic compression devices" in patients undergoing total joint arthroplasty who "have a high risk of bleeding." When the high risk subsides, pharmacologic thromboprophylaxis is substituted for, or added to, mechanical methods. Fractionated heparins and pentasaccharide are the most effective agents in reducing venographic deep venous thrombosis (DVT) after total joint arthroplasty with residual clot rates <5% after THA and 20% after TKA, but major or clinically meaningful bleeding occurs in 3% to 5% of patients. Newer Xa and thrombin inhibitors enjoy greater efficacy with equal or higher bleeding rates. Low intensity warfarin (target international normalized ratio, 2.0) combines safety (bleeding rates <1%) with efficacy (readmission for clinical DVT or pulmonary embolism 0.2%) after total joint arthroplasty. Warfarin represents a therapeutic compromise by preventing clinical events in exchange for a lower bleeding rate; genetic testing will likely simplify warfarin use and reduce outlier responders. PMID- 20839679 TI - Periprosthetic joint infection: treatment options. AB - Periprosthetic joint infection has become the most common cause of failure following total knee arthroplasty. Over the past 4 decades, treatment of this disease has evolved with technological innovations and pathogen profiling. The appropriate treatment selection is dependent on patient immune system quality, timing of symptom onset, and pathogen type. Antibiotic suppression alone is reserved for those cases without drainage, low-virulent antimicrobial-susceptible pathogens, and patients whose level of health increases the risk of surgery past any risk associated with chronic infection. In patients with an acute onset of symptoms and antimicrobial-susceptible pathogens, irrigation and debridement with exchange of modular components is moderately successful and offers the advantage of component retention and maximum knee function. In failed irrigation or chronic periprosthetic joint infection, resection of all components is necessitated. Resection and reimplantation can either be performed in one or two stages. A single-stage exchange has the potential to decrease the number of surgeries and therefore cost. However, the success rate of direct exchange is lower than that of two-stage revision. This has led to two-stage revision, with the placement of an intra-stage antibiotic-loaded spacer, to become the "gold" standard for periprosthetic joint infection eradication. In an immunocompromised patient with an uncontrollable periprosthetic joint infection, salvage procedures are necessitated. Complete eradication of periprosthetic joint infection is achieved by resection of all components without reimplantation through arthrodesis or above-the-knee-amputation. While amputation may be unpopular with patients it provides a greater ability to reconstruct, with an external prosthesis, a functioning joint. PMID- 20839680 TI - DVT prophylaxis: better living through chemistry: opposes. AB - The association between total hip arthroplasty and subsequent postoperative deep venous thrombosis is of particular concern because it can lead to symptomatic venous thromboembolic events. However, controversy remains about the optimal approach to prophylaxis. Some authors recommend the use of various chemoprophylactic agents, while others advocate the use of mechanical devices or combinations. The ideal method of prophylaxis should be effective and easy to administer, have a predictable onset and duration, have minimal interaction with food or other drugs, be easily reversible, be cost effective, and have a low risk of side effects. While available chemoprophylactic agents address some of these attributes, all have substantial drawbacks. Among the most concerning effects for orthopedic surgeons is the increased risk of bleeding and hematoma formation, which can be associated with periprosthetic infections. These typically lead to additional surgical procedures and significant patient morbidity, and can adversely impact clinical outcomes. An alternative to chemoprophylaxis is the use of pneumatic intermittent compression devices. Modern compression devices are portable and easy to use, and have a high rate of patient compliance. Several studies have demonstrated the efficacy of these devices in reducing the risk of symptomatic venous thromboembolic disease, in some cases resulting in lower mortality when compared to pharmacological agents. Additionally, these devices significantly reduce the risk of postoperative bleeding. PMID- 20839681 TI - Uncemented total hip arthroplasty with a tapered femoral component: a 22- to 26 year follow-up study. AB - The goal of this study was to evaluate the outcome at a mean follow-up of 24.5 years (range, 22-26 years) of a consecutive series of 138 patients (145 hips) treated with total hip arthroplasty (THA) with the use of the Taperloc femoral component (Biomet, Warsaw, Indiana). This was an FDA-approved prospective study. All surgeries were performed by a single surgeon. Each of the 138 patients (145 hips) was followed annually until death, femoral component revision, or a minimum of 22 years. Complete clinical and radiographic follow-up was obtained on 95% of living patients at 5 years, and 100% at 10, 15, 20, and 24.5 years. Of the original series of 145 hips, only 1 femoral component (0.7%) had undergone revision for aseptic loosening, and 1 was loose by radiographic criteria (0.7%). Femoral osteolysis was identified in 8 hips (5.5%). A subset of 63 THAs in 56 patients was followed for a mean of 24.5 years. In this group, no femoral component required revision for aseptic loosening, and 1 was loose by radiographic criteria. Femoral osteolysis was present in 4 hips. Survivorship analysis of the femoral component with revision for aseptic loosening as the endpoint was 99% (95% confidence interval, 0.97-100) at 26 years. This stem demonstrates excellent fixation at a follow-up of 24.5 years with no apparent deterioration of the results with time. PMID- 20839682 TI - Patellofemoral arthroplasty. AB - Isolated patellofemoral arthritis can occur in as many as 9% of patients older than 40 years and is particularly common in women, who often have subtle patellofemoral maltracking or malalignment. In fact, 24% of women with symptomatic knee arthritis have localized patellofemoral arthritis. Arthroplasty options can provide predictable pain relief, whereas other surgical measures for refractory patellofemoral arthritis--arthroscopic debridement, cartilage grafting, patellectomy, tibial tubercle unloading procedures--often have unsatisfactory results. While total knee arthroplasty (TKA) yields excellent results in >90% of patients with isolated patellofemoral arthritis, it is not desirable in patients who are young and active. Therefore, patellofemoral arthroplasty has a legitimate role in the treatment of isolated anterior compartment arthritis. Early patellofemoral implants were plagued by a high incidence of patellar maltracking, catching and subluxation, due to design features of the trochlear components, inadequate soft tissue balancing, and component malposition. Most importantly, contemporary onlay style trochlear components, implanted perpendicular to the anteroposterior axis of the femur, have substantially reduced the patellar maltracking that was so prevalent with inlay style prostheses for 3 decades. With onlay trochlear designs, early patella instability problems have been reduced, leaving late tibiofemoral degeneration as the primary cause of failure of patellofemoral arthroplasties. Several long-term studies have shown a rate of tibiofemoral degeneration of approximately 20% at 15 years. Finally, the results of TKA do not seem to be compromised by the presence of a prior patellofemoral arthroplasty. PMID- 20839683 TI - A rapid recovery program: early home and pain free. AB - Enhancement of our perioperative pain management protocols has resulted in accelerated rehabilitation. At our facility, the majority of patients undergoing total and partial knee arthroplasty are treated with a single-shot spinal anesthetic consisting of a combination of bupivacaine and duramorph. The bupivacaine affords the immediate perioperative anesthetic while the duramorph results in sustained analgesia for a period of 12 to 24 hours. We use intra articular injections delivered directly into the soft tissue of the knee. Our current intra-articular injection is 60 mL of 0.5% ropivacaine with 0.5 mg of epinephrine. In patients with a normal renal function, 30 mg of ketorolac is added. The injection is administered throughout all of the soft tissues in and around the knee. Prophylactic antiemetics are administered in the form of dexamethasone, ondansetron, and a scopolamine patch. The use of this perioperative anesthesia provides effective pain relief with no motor blockade. Patients are able to participate in physiotherapy within several hours of the operative procedure, performing active range of motion and ambulating with assistive devices. Patients with no significant cardiovascular history are given celecoxib preoperatively, which is continued for approximately 2 weeks postoperatively. Additionally, all patients are treated with oxycodone, either preoperatively or within 2 hours of arrival to the floor postoperatively. Patients younger than 70 years are given 20 mg of oxycodone while those older than 70 years are given 10 mg of oxycodone. The oxycodone is continued for the first 24 hours of the hospital stay. Patients are then managed with oxycodone and hydrocodone. Length of stay has decreased and currently averages <2 days. PMID- 20839684 TI - Management of bone loss in revision TKA: it's a changing world. AB - Bone deficiency represents a common theme in revision total knee arthroplasty (TKA). The etiology of bone deficiency may be aseptic loosening resulting in direct mechanical bone loss, osteolysis, stress shielding, septic loosening, or iatrogenic resulting from implant removal. Not all revisions are created equal. The surgeon must assess the degree of complexity and have a broad armamentarium available. Principles to consider in bone loss management are defect size and location and patient demographics, including body mass index, activity level, age, and life expectancy. Treatment options include polymethylmethacrylate (PMMA) with or without reinforcing screws; modular TKA systems including optional stems, wedges, and metal augments; orthopedic salvage systems such as mega- or tumor prostheses; autograft; and morselized or structural allograft. Morselized allograft is better suited for reconstitution of contained deficits and may be associated with a higher rate of incorporation. Disadvantages of allograft include late resorption, fracture or nonunion of structural allograft, and risk of disease transmission. A recent innovation has been a variety of augments and cones fabricated in the new ultraporous metals to address structural defects in revision TKA. Recommendations for bony reconstruction include: for deficits <5 mm, PMMA fill; for deficits 5 to 10 mm and <50% of the femoral condyle or tibial plateau, PMMA with reinforcing screws; for contained deficits >5 mm, morselized allograft; for noncontained deficits 5 to 15 mm and >50% of the femoral condyle and tibial plateau, TKA modular systems with stems and augments; and for noncontained deficits >15 mm, structural allografts, megaprostheses, and ultraporous metal augments. PMID- 20839685 TI - Subcapital fractures: in the bucket or on top of the neck? AB - Femoral neck fractures have a 30% reoperation rate when internally fixed. To reduce the reoperation rate, the surgeon must accurately decide which fractures are best fixed and which fractures require a prosthesis. The literature supports the fact that nondisplaced fractures should be internally fixed. Fractures in patients physiologically younger than 65 years should also be fixed if they have no comorbidities. The most important factors in reducing failure rate of fixation are patient selection and anatomic reduction. A femoral neck fracture left in varus is doomed to failure and reoperation. Femoral neck fractures that are displaced in patients older than 65 years require a decision-making algorithm to decide how they should be treated. In the physiologically active patient older than 65 years, internal fixation may be considered. In most patients older than 65 years, prosthetic replacement should be considered. Nursing home patients and patients with comorbidities who are not expected to live longer than 6 to 7 years should receive a hemiarthroplasty. Studies show a high reoperation rate if the patient with hemiarthroplasty survives more than 6 or 7 years. In the active elderly with little or no comorbidities, a total hip replacement should be considered. This is not only cost effective but provides the best pain relief of any of the treatment options for displaced femoral neck fractures. Treatment of femoral neck fractures remains a challenge, but the surgeon must develop an algorithm to select proper treatment options for the patient. The decision-making process is always shared with the patient. PMID- 20839686 TI - Wound healing in total joint arthroplasty. AB - Obtaining primary wound healing in total joint arthroplasty is essential to a good result. Wound healing problems can occur and the consequences can be devastating. Determination of the host healing capacity can be useful in predicting complications. Cierney and Mader classified patients as type A, no healing compromises; and type B, systemic or local healing compromising factors present. Local factors include traumatic arthritis, multiple previous incisions, extensive scarring, lymphedema, poor vascular perfusion. Systemic compromising factors include diabetes, rheumatic diseases, renal or liver disease, immunocompromise, steroids, smoking, and poor nutrition. In high-risk patients, the surgeon should encourage positive choices such as smoking cessation and nutritional supplementation to elevate the total lymphocyte count and total albumin. Careful planning of incisions, particularly in patients with scarring or multiple previous operations, is productive. Around the knee the vascular viability is better in the medial flap. Thus, use the most lateral previous incision, do minimal undermining, and handle tissue meticulously. We perform all potentially complicated total knee arthroplasties without tourniquet to enhance blood flow and tissue viability. The use of perioperative anticoagulation will increase wound problems. If wound drainage or healing problems occur, immediate action is required. Deep sepsis can be ruled out with a joint aspiration and cell count (>2000), differential (>50% polys), and negative culture and sensitivity. All hematomas should be evacuated and necrosis or dehiscence should be managed by debridement to obtain a live wound. PMID- 20839687 TI - The role of arthroscopy in treating osteoarthritis of the knee in the older patient. AB - Arthroscopy of the osteoarthritic knee is a common and costly practice with limited and specific indications. The extent of osteoarthritis (OA) is determined by joint space narrowing, which is best measured on a weight-bearing radiograph of the knee in 30 degrees or 45 degrees of flexion. The patient older than 40 years with a normal joint space should have a magnetic resonance image taken to rule out focal cartilage wear and avascular necrosis before recommending arthroscopy. Randomized controlled trials of patients with joint space narrowing have shown that outcomes after arthroscopic lavage or debridement are no better than those after a sham procedure (placebo effect), and that arthroscopic surgery provides no additional benefit to physical and medical therapy. The American Academy of Orthopedic Surgeons guideline on the Treatment of Osteoarthritis of the Knee (2008) recommended against performing arthroscopy with a primary diagnosis of OA of the knee, with the caveat that partial meniscectomy or loose body removal is an option in patients with OA that have primary mechanical signs and symptoms of a torn meniscus and/or loose body. There is no evidence that removal of loose debris, cartilage flaps, torn meniscal fragments, and inflammatory enzymes have any pain relief or functional benefit in patients that have joint space narrowing on standing radiographs. Many patients with joint space narrowing are older with multiple medical comorbidities. Consider the complications and consequences when recommending arthroscopy to treat the painful osteoarthritic knee without mechanical symptoms, as there is no proven clinical benefit. PMID- 20839688 TI - Acetabular fractures: the role of arthroplasty. AB - Acetabular fractures are generally treated with open reduction and internal fixation, with the goals of anatomic reduction and preservation of the native hip joint. Modern techniques of internal fixation have resulted in good to excellent outcomes in the vast majority of patients when anatomic reduction can be obtained. Total hip arthroplasty (THA) has a role in the treatment of these injuries in 2 general situations: the acute fracture in the elderly patient with joint impaction, and for the sequelae of acetabular fracture, namely posttraumatic arthritis or osteonecrosis. Preoperative planning with plain radiographs and computed tomography (CT) scanning, including 3-dimensional reconstructions, is recommended. Recent data show that fractures in the elderly that exhibit joint impaction of the acetabular dome (the so-called gull sign) or impaction of the femoral head generally did not benefit from internal fixation attempts. Restoration of columnar continuity, typically with plates and uncemented acetabular components with multiple screw fixation, remains the preferred strategy. Cemented acetabular components have demonstrated a high failure rate in this setting and should be avoided. Plating of the posterior column will usually provide continuity of the acetabular dome, the quadrilateral plate, and ishium, which will facilitate stable uncemented acetabular component implantation. Rarely, an antiprotrusio device is necessary. Liberal use of autograft from the resected femoral head is recommended for acetabular defects. For posttraumatic sequelae, the surgeon must be prepared for heterotopic bone, scarring, bony defects, and retained hardware. Preoperative CT scanning can help localize heterotopic bone or bony defects. Hardware that does not interfere with acetabular component implantation can generally be left in situ. PMID- 20839689 TI - Total hip arthroplasty in patients with Down syndrome. AB - Hip osteoarthritis is prevalent in 8% to 28% of patients with Down syndrome. Presence of disabling hip pain is increased along with prolonged life expectancy, suggesting total hip arthroplasty (THA). Seven consecutive patients (9 hips) with Down syndrome underwent primary THA. Coxarthrosis was secondary to developmental hip dysplasia in 6 patients and slipped capital epiphysis in 1 patient. In 5 patients (7 hips), a previous hip surgery was performed. Average clinical and radiological follow-up was 9.9+/-6.4 years (range, 2-22.5 years; median, 9.3 years). Average patient age at THA was 34.8+/-7.5 years (range, 25- 47 years; median, 35.4 years). In 2 patients (3 hips), a trochanteric slide was used for the surgical approach, while a lateral transgluteal approach was used in the remaining patients. One-way analysis of variance test was used to compare Harris Hip Scores (HHS) at postoperative follow-up.Harris Hip Scores improved significantly (P=.008) from 4.1+/-15.1 (range, 18.5-65; median, 45) to 84.8.3+/ 7.7 (range, 70-93; median, 85.8) at 4-year follow-up. Harris Hip Scores (average, 70.9+/-6.2; range, 66.5-80; median, 68) remained essentially unchanged (P=.43) at 8-year follow-up. Two patients required revision THA for stem loosening at 6 and 16 years post-THA, respectively. The first patient is 7 years post-revision and ambulates without aids. The second patient is 6.1 years post-revision and ambulates with a walker. Six of the THAs required a constrained liner. No dislocations or deep infections were encountered. At last follow-up, all patients had a functional range of motion without evidence of discomfort related to their THA. PMID- 20839690 TI - Allograft alternatives: bone substitutes and beyond. AB - Excessive wear debris, deep infection, periprosthetic fracture, and other causes can lead to bone loss associated with total joint replacements. When performing revisions, surgeons are often preoccupied by the failed implant and the method of replacement, and neglect an opportunity to replenish lost bone. Thus, when formulating a plan for revision total joint replacement, the surgeon should consider not only the hardware that should be used, but also ways in which lost bone could be restored. Autograft bone provides the best source for osteoprogenitor cells, growth factors, and a scaffold. However, autograft is limited in supply, and is generally associated with another incision, dissection, and accompanying morbidity. Osteoconductive bone void fillers such as morselized cancellous allograft bone, polymeric scaffolds, and biodegradable ceramics each have their merits and deficiencies; however, all of these materials function as a scaffold only, without the ability to induce bone formation. Osteoinductive growth factors are essential to bone growth and remodeling; however, exogenous growth factors are expensive, are given in large nonphysiological doses, may yield unpredictable clinical results, and may have significant adverse effects. Demineralized bone matrix contains a scaffold and variable amounts of several growth factors. Recently, the use of mesenchymal stem cells and osteoprogenitors, together with a suitable scaffold carrier has gained increasing popularity. With the addition of appropriate growth factors, this combination can provide all the necessary components for osteogenesis. Future basic and clinical research will define the indications and outcomes for new combination products for reconstruction of lost bone associated with revision total joint replacement. PMID- 20839691 TI - The proximal modular neck in THA: a bridge too far: affirms. AB - Modular necks are a relatively new innovation in total hip arthroplasty (THA), with several companies now offering modular neck options. The proposed advantages of reduced impingement, reduced dislocation rate, and better reconstitution of leg length and offset are compelling. However, few reports in the literature address the outcomes of these devices, and those that are published at best demonstrate equivalence to conventional THA. There are numerous disadvantages to this new technology. Neck dissociation has been reported with a specific design of the modular taper. Numerous case reports exist of the fracture of titanium modular femoral necks, with 1 large series of 5000 cases reporting a fracture rate of 1.4%. Fractures occurred more frequently in heavy men (>100 kg), with the preponderance of fractures occurring around the 2-year mark. Retrieval analysis demonstrates failure of the titanium components at the Morse taper junction of the neck and femoral stem at the point of maximal tension, likely related to notch sensitivity. The additional interface of modular necks in the effective joint space has the potential to generate significant metal ions through a pitting corrosion process. Evidence exists of highly elevated serum cobalt and chromium ions in a modular junction used in large-head THA supporting these concerns. The use of particular neck geometries, such as long retroverted necks, may adversely affect the local biomechanical forces on the femoral component. The proposed mechanism is an increased lever arm leading to increased torque on stair climbing or rising from a chair. Finally, modular necks add significant costs to the implant and the health care system. On balance, based on the literature, the proximal modular neck in THA is a bridge too far. PMID- 20839692 TI - Porous metal augments: big hopes for big holes. AB - The majority of acetabular defects can be reconstructed with a hemispherical acetabular component alone. However, severe bone loss encountered at the time of revision acetabular surgery can result in compromised initial fixation leading to component micromotion, failure of bone ingrowth, and mechanical failure. Porous acetabular augments offer a potential solution to enhance initial component fixation while maximizing the area for biologic ingrowth. Premanufactured metal augments can be placed independent of the acetabular component. This feature provides surgeons the flexibility to place the hemispherical acetabular component in the optimal orientation at the anatomic hip center. The augment is initially secured to the hemipelvis with multiple screws before it is then secured to the hemispherical acetabular component with the use of polymethylmethacrylate bone cement. The modularity of the augments effectively allows a custom implant to be designed intraoperatively. Porous acetabular augments offer the potential advantages of a nonresorbable material that can be inserted without extensive soft tissue stripping. Additionally, these metal augments do not carry the risk of disease transmission associated with bulk structural allograft and are manufactured in a variety of shapes and sizes. The early clinical and radiographic results of porous acetabular augments are promising, yet there remains a paucity of long-term data. PMID- 20839693 TI - Unexplained pain after THR: what should i do? AB - Early causes of hip pain within the first year of total hip replacement (THR) include failure of fixation, infection, instability, other sources of pain (eg, lumbar spine), and mechanical dysfunction such as psoas tendon impingement or other soft tissue irritation. Metal-on-metal THRs may present with pain due to hypersensitivity within the first 1 to 3 years after arthroplasty. Late causes of pain include loosening, wear reactions, or mechanical dysfunction such as subluxation associated with wear of the articular couple. Late hematogenous infection is often sudden in onset, but may be subtle. Other sources of pain such as spinal stenosis or lumbar degenerative disk disease may also present as hip pain. Evaluation of the painful hip should start with a careful history: is the current pain similar or different to the preoperative symptoms? A review of the preoperative radiographs will provide clues as to the extent of the pathology, and if not obvious, may suggest other sources for the pain syndrome. Careful comparison of serial radiographs is necessary to identify loosening. Serologic tests should include a sedimentation rate and C-reactive protein; if both are elevated, aspiration of the joint under radiograph control for culture is indicated. In the absence of abnormalities in the studies described above, serial Technetium bone scans performed every 6 to 12 months may suggest loosening if progressive increases in uptake are observed about a component. Malposition of the acetabular component may be associated with psoas tendon impingement (symptomatic with active flexion of the hip) and may be confirmed by computed tomography scan or a psoas tenosynogram. Hypersensitivity of metal-on-metal THRs should be suspected in the presence of early (subtle) osteolysis, and the presence of predominantly mononuclear cells on the sterile aspirate. Perseverance and patience are encouraged in the pursuit of an accurate diagnosis, and objective analysis of the data is necessary. Do not operate without sufficient cause. PMID- 20839694 TI - The proximal modular neck in THA: a bridge too far: opposes. AB - Neck/cup impingement is a serious issue, especially with hard/hard bearings. It can produce noise, locking mechanism failure, and an increase in wear debris and dislocation. The double taper neck used by the author has cogs on the neck/stem taper junction for additional rotational stability. One hundred forty-six procedures were performed using the thin mantle cement technique. Mean follow-up was 5 years (range, 3-8 years). A 32-mm neck was used in 73.8% of cases and a 35 mm neck in 26.2%, because most of the patients were elderly women. The neck was anteverted in 1.4%, neutral in 26.4%, and retroverted in the rest (mild in 34.2%, moderate in 14.3%, and maximum in 13.4%). There were no dislocations and no loosenings. Problems were encountered with the neck/stem taper in 3 cases. The stem was therefore taken off the market. The taper was lengthened and the strength doubled. Since its reintroduction 3 years ago, a further 187 cemented stem procedures have been performed with no failures and no dislocations. Of interest in this series, no necks were anteverted, 23.5% were in neutral, 35.8% were in mild retroversion, 31.1% were in moderate retroversion, and 9.6% were in maximal retroversion. Most necks were placed in retroversion to avoid impingement. This suggests that if a nonmodular neck had been used, some degree of impingement would have occurred in 70% of cases. PMID- 20839695 TI - Cementless tibial fixation in TKA: not a second coming. AB - Cemented total knee arthroplasty (TKA), using mechanically sound components such as the total condylar system (Johnson & Johnson, New Brunswick, New Jersey), have been performed for >25 years. Long-term follow-up studies have shown excellent durability. In 1 series with a minimum 20-year follow-up, the revision rate for aseptic loosening was 3.5%. More contemporary prostheses, such as the low contact stress rotating platform (DePuy, Warsaw, Indiana) and Kinematic Knee systems (Howmedica, Rutherford, New Jersey), have demonstrated minimal loosening at 20 year follow-up. In a minimum 20-year follow-up of a rotating platform TKA, the revision rate for aseptic loosening was 0%. In a minimum 15-year follow-up of kinematic cruciate-retaining TKA, the revision rate for aseptic loosening was 1.8%. Cemented fixation is durable and forgiving. It can accommodate defects in bone as well as imperfect cuts that are not uncommon, even in the best of hands. It can interdigitate into soft and hard bone. With the development of modular tibial trays with better locking mechanisms and less abrasive surfaces, as well as the development of more wear-resistant polyethylene (gamma irradiated in an inert environment and crosslinked polyethylene), the osteolysis that developed around first generation modular components should be markedly less with newer designs. It is for these reasons that cement should remain the fixation of choice in TKA. PMID- 20839696 TI - Component malposition in hip resurfacing. AB - Component malposition in hip resurfacing can cause early failure through the 2 main failure modes: femoral neck fracture and wear-related failures. The femoral component should be aligned in slight valgus with no notching of the superior femoral neck. Varus placement and notching are strongly correlated with early femoral neck fracture. We have developed special mushroom templates to assist with accurate femoral component sizing and positioning. Issues related to radiographic magnification, ruler measurements, and plastic overlay templates are avoided. Acetabular component malposition can result in wear-related failures. The geometry of most resurfacing sockets is such that the wall is thinner at the rim than at the apex. This is done to improve range of motion before impingement and results in the bearing having less coverage and a higher inclination than one would expect from the radiograph. Surgeons should therefore aim for a lower inclination than they would with total hip replacement. Acetabular anteversion, if excessive, can reduce the available contact area, and lead to edge wear and subluxation. Dysplasia, which is more common in women, can also result in excessive femoral anteversion. Taken together, the combined acetabular and femoral anteversion should not exceed 45 degrees . Pseudotumors have been reported adjacent to metal-on-metal bearings. These reports point out that pseudotumors are often associated with component malposition. It is thought that edge wear due to malposition results in excessive metal debris, which is locally toxic. Proper component position is necessary for the short- and long-term success of hip resurfacing. PMID- 20839697 TI - Cemented versus cementless stems: a verdict is in. AB - The purpose of this randomized clinical trial was to compare the >20-year outcomes of cemented (n=124) versus cementless (n=126) total hip replacements (THRs) in patients with end-stage, unilateral hip osteoarthritis. At 20 years, 168 patients (67%) were available for follow-up, 78 (31%) had died, and 4 (2%) were lost. A power analysis was performed to determine the number of patients needed in each study cohort. Patients were assessed pre- and postoperatively by validated disease-specific Western Ontario McMaster Osteoarthritis Score, patient specific McMaster Arthritis Score, global health (sickness impact profile), functional capacity (6-minute walk), and cost utility (cost-to-quality adjusted life years). Patients were followed every 2 years clinically and radiographically.The cementless THR outperformed its cemented counterpart in terms of overall (P=.01), socket (P=.009), and stem (P<.0001) Kaplan-Meier survivorships. Patients younger than 65 years had significantly poorer cemented and cementless socket survivorships, and male sex adversely affected cementless socket survivorship. The cementless tapered stem had 100% survivorship with aseptic loosening as the endpoint at 20 years. Although this study has demonstrated the superiority of the cementless THR over its cemented counterpart, care must be taken in generalizing these results to other cemented and cementless THRs. PMID- 20839698 TI - Patient satisfaction following TKA: Bless them all! AB - Survivorship following modern total knee arthroplasty (TKA) is good with revision rates generally lower than for total hip arthroplasty (THA). Our experience in Belfast supports that fact with original component survivorship of 99% for the low contact stress rotating platform TKA, which is better than our THA survivorship. It is important to discriminate between survivorship and patient satisfaction. In Belfast, as well as the more familiar outcome scores, we also use a very simple 4-point satisfaction questionnaire: "How would you best describe your satisfaction with your new joint" where 1=very happy, 2=happy, 3=OK but not perfect, and 4=I have never been happy. We applied this questionnaire to our 10-year THA and TKA patients. When we looked specifically at the numbers of patients who were either "very happy" or "never happy," the results were very different. The very happy percentage for hips was much higher than for knees (54% vs 4%) and conversely, the number of never happy knees was much higher than for hips (7% vs 1%). These results are not unique to Belfast. As surgeons, we often think that the knee implant that we use is the best but at present, the implant is no longer the most critical factor. We need to increase the number of very happy patients and decrease the number of never happy ones. In my opinion the two key factors that we should focus on are patient expectation and surgeon education. PMID- 20839699 TI - The transverse acetabular ligament: optimizing version. AB - In total hip arthroplasty (THA), excessive retroversion is associated with posterior instability, anterior impingement, and resultant groin pain. Excessive anteversion can lead to anterior instability and posterior impingement. The transverse acetabular ligament straddles the inferior limit of the bony acetabulum. It is a strong load-bearing structure and, in the normal hip, in association with the labrum, provides part of the load-bearing surface for the femoral head. It is our hypothesis that the transverse acetabular ligament defines normal version for the acetabulum. In Belfast, we found that using the transverse acetabular ligament helped reduce our primary dislocation rate from 3.7% to 1%. The key is good intraoperative exposure. A grading of 1 to 4 was based on 1000 consecutive cases: (1) normal transverse acetabular ligament easily visible on exposure of the acetabulum, 49%; (2) covered by soft tissue, 35.1%- cleared by blunt dissection; (3) covered by osteophytes, 15.6%--cleared using an acetabular reamer; (4) no transverse acetabular ligament identified, 0.3%. As can be seen, the transverse acetabular ligament is only immediately visible in 49% of cases. In the other 51%, soft tissue or bone must be cleared to define the ligament. The advantages of the transverse acetabular ligament are many. It is independent of patient positioning. The cup version can be individualized by the patient. The surgeon can avoid estimating version angle of 15 degrees to 20 degrees intraoperatively. It is easy to teach and consistently present. It is valuable in minimally invasive surgery. Using the transverse acetabular ligament provides an acceptable dislocation rate with the posterior approach. If the cup is cradled by the transverse acetabular ligament, it helps restore acetabular joint center. However, the transverse acetabular ligament does not help with inclination. We recommend 35 degrees of operative inclination when using the posterior approach. PMID- 20839700 TI - Antibiotic-coated spacers for total hip arthroplasty infection. AB - Total hip arthroplasty (THA) infection imposes a significant burden on the patient and the health care system. Two-stage revision with interval placement of an antibiotic-cement spacer is the standard of care for chronic periprosthetic infections. This treatment allows for the direct delivery of antibiotics to the infected tissues, and maintains soft tissue tension to facilitate the re implantation procedure. Evidence suggests that articulating spacers, compared to nonarticulating designs, enhance postoperative ambulation and make the second stage procedure less difficult. Prefabricated spacers are easy to use; however, they cannot be used to alter the antibiotic composition and dosage. Custom-molded spacers prepared in the operating room from commercially available kits are a popular option; however, like prefabricated spacers, limited sizes are available and thus, they may be contraindicated in situations with significant bone loss. Custom-made total hip spacers are significantly less expensive than commercially available options, are useful in cases of bone loss, and optimize patient function prior to re-implantation. An inexpensive cemented femoral stem is covered with antibiotic-loaded bone cement. This is done once the cement has the consistency of dough to prevent interdigitation with the host femur. The authors use at least 3.6 g of tobramycin and 1 g of vancomycin per packet of cement. A thin polyethylene is cemented into the acetabulum, followed by placement of the femoral prosthesis. Combined component position must be optimized to prevent instability. PMID- 20839701 TI - Giant cell tumor of the distal femur associated with complete tumor necrosis. AB - Giant cell tumor is a benign tumor of bone with a predilection for juxta articular locations. Although not malignant, giant cell tumor often exhibits unpredictable and locally aggressive behavior, and in rare cases can metastasize in the absence of histologic malignancy. Partial tumor necrosis has been infrequently reported within typical giant cell tumor. A 17-year-old girl presented with a right distal femur giant cell tumor associated with complete tumor necrosis on histopathologic analysis. The etiology, prevalence, and implications of complete necrosis in previously untreated giant cell tumor of bone remain unclear, as there are no previously published reports. Despite the complete necrosis evident in our patient, she nonetheless presented with pain. There were no radiographic signs of the necrotic tumor space remodeling with new bone. The patient was treated with standard extended intralesional curetting through a generous cortical window permitting visualization of the entire lesion, and systematic high speed burring and thermal electrocautery ablation of the periphery, followed by micro particulate allogenic bone grafting. At short-term follow-up, she had healed well with no evidence of tumor recurrence. This article presents the first case, to our knowledge, of complete spontaneous tumor necrosis in a previously untreated bone giant cell tumor. Increased understanding of spontaneous tumor necrosis associated with giant cell tumor may help guided future targeted medical and surgical treatment modalities. PMID- 20839702 TI - Intra-articular entrapment of the medial collateral ligament. AB - The medial collateral ligament (MCL) is the most commonly injured knee ligament. Such injuries in children are rare due to the relative thickness of the articular cartilage and physes that can absorb energy. Traumatic MCL entrapment into the medial knee joint in a child has not yet been reported. This article presents a case of intra-articular MCL entrapment in a 9-year-old boy with characteristic findings on magnetic resonance imaging (MRI) showing the interposition of the MCL between the medial meniscus and medial tibial plateau. During arthroscopic surgery, the MCL tear pattern was visualized underneath the medial meniscus. A medial knee incision was performed and the MCL was retrieved from the knee joint. The meniscotibial ligaments and medial meniscus were repaired to the tibial plateau. The torn ends of MCL were reapproximated and sutured. One year postoperatively, the patient is back to full activities including sports without limitations. This article should help raise awareness about the possibility of such injuries to avoid a delay in diagnosis. Although it is true that children would injure their physes more often than their ligaments due to their relative weakness, this article describes the possibility of a serious ligament injury without physeal involvement. PMID- 20839703 TI - A randomized, prospective study of total hip wound closure with resorbable subcuticular staples. AB - Resorbable subcuticular staples are a new way to close surgical wounds and have not been reported in the orthopedic literature. This randomized, controlled study compared a resorbable subcuticular staple system with stainless steel wound stapling in patients undergoing unilateral primary total hip arthroplasty (THA). Institutional Review Board approval and patient consent was obtained for all patients. Sixty patients (30 each group) were randomized to receive either resorbable subcuticular staples or stainless steel staples after primary THA. Incision length, number of staples used, and any staple insertion problems were recorded. Subjective reports of pain levels or incision complaints were solicited, and wound photographs were obtained on days 1 and 14 and 6 weeks postoperatively. The presence of wound drainage, erythema, wound separation, or echymosis was recorded at each visit, as well as all postoperative complications. The average incision length in the resorbable group was 13.2 cm and required 16 staples for closure, compared to 15 cm and 20 staples for the metal staple group. No infections occurred in either group, although the incidence of erythema and wound drainage at 2 weeks was higher for patients in the stainless steel group. One patient with metal staples had a postoperative hematoma requiring secondary irrigation and debridement. Patient satisfaction was higher with the resorbable staples. A resorbable subcuticular staple system can provide comparable wound closure to stainless steel staples following THA and may do so with less local discomfort, wound drainage, or erythematous reaction. PMID- 20839704 TI - Fixation of 3- and 4-part proximal humerus fractures using the PHILOS plate: mid term results. AB - Treatment of unstable, displaced, and comminuted fractures of the proximal humerus remains challenging, and optimal treatment continues to be controversial. Fifty-six patients with displaced 3- and 4-part fractures of the proximal humerus had open reduction and internal fixation using the proximal humeral internal locking system (PHILOS) plate (Synthes, Stratec Medical Ltd, Mezzovico, Switzerland). Data were collected retrospectively, and clinical and radiological outcomes were assessed. Mean follow-up was 40 months (range, 18-62 months). The study shows that the PHILOS plate gives good results in the treatment of displaced 3- and 4-part fractures of the proximal humerus. Good fracture stability can be achieved early, allowing early mobilization without compromising fracture union. Most importantly, it requires minimal soft tissue dissection, does not need contouring, and gives good stability. No differences were observed in the functional outcomes of patients younger and older than 65 years. Few complications were associated with the plate, and the number of >=2 surgeries was minimal. The complications noted were 1 case each of superficial wound infection, failure of the plate, and persistent stiffness. One patient had screw perforation of the humeral head articular surface, and 1 had subacromial impingement. Of the 32 patients who had been in active employment before the injury, 28 returned to their previous occupation. PMID- 20839705 TI - Incidence of venous thromboembolic disease following hip arthroscopy. AB - Venous thromboembolic disease is a known complication of orthopedic surgery. Hip arthroscopy is a technically demanding procedure with a significant learning curve and low reported complication rate. Few reports document the incidence of venous thromboembolic disease following hip arthroscopy. Our hypothesis was that the incidence of venous thromboembolic disease following hip arthroscopy was comparable to that reported for knee arthroscopy. Eighty-one consecutive patients undergoing hip arthroscopy were retrospectively reviewed. All patients underwent standard diagnostic hip arthroscopy under traction of the operative leg against a well-padded perineal post. All procedures were performed on an outpatient basis. Three of 81 patients (3.7%) developed a clinically symptomatic venous thromboembolic disease in the postoperative period. The diagnosis was suspected clinically and confirmed with the use of a Doppler ultrasound. No patient developed symptomatic pulmonary emboli. One patient used oral contraceptives and 2 had no known risk factors for venous thromboembolic disease. All patients were successfully treated with anticoagulation. This is the first study to document multiple occurrences of venous thromboembolic disease following hip arthroscopy. This study demonstrated the incidence of symptomatic venous thromboembolic disease after hip arthroscopy to be 3.7%. Further study investigation is warranted regarding the incidence of symptomatic and asymptomatic venous thromboembolic disease following hip arthroscopy. PMID- 20839706 TI - Effect of preoperative exercise on postoperative mobility in obese total joint replacement patients. AB - There has been a significant increase in obesity in the United States over the past 20 years. Reports in the literature identify the association of obesity related osteoarthritis and the likelihood of future total hip arthroplasty (THA) and total knee arthroplasty (TKA) in this patient population. However, little is known about the effect of preoperative exercise on immediate postoperative mobility and discharge disposition in obese total joint replacement patients. The purpose of this study was to examine the effect of preoperative exercise in the obese total joint replacement patient on early postoperative mobility and discharge disposition. We retrospectively reviewed a consecutive series of patients with a body mass index (BMI) >=30 kg/m(2) who underwent primary total joint replacement surgery from June 2005 through October 2005 at 1 institution. Two hundred seven patients met the inclusion criteria. Sixty-five patients performed self-reported preoperative exercise, defined as physical activity deemed above and beyond that of activities of daily living. Fewer exercise patients, 6.8%, required the assistance of >=2 caregivers for mobility on postoperative day 1 vs 17.4% for nonexercisers. Fifty-four percent of patients participating in preoperative exercise were discharged home vs 46% who did not participate in exercise. A preoperative exercise program can improve postoperative functional mobility and increase the likelihood of discharge home in total joint replacement patients with a BMI of >=30 kg/m(2). PMID- 20839707 TI - Evaluation of high-strength orthopedic sutures: a head-to-head comparison. AB - The goal of this study was to determine whether a difference in cycles to failure or mode of failure would be observed among specimens of 3 high-strength suture materials, and whether different suture configurations would affect knot security. Ten representative specimens of Ethibond (Ethicon, Inc, Somerville, New Jersey), FiberWire (Arthrex, Inc, Naples, Florida), MaxBraid (Biomet, Inc, Warsaw, Indiana), and Orthocord (DePuy Orthopaedics, Warsaw, Indiana) were tied in 6 different knot configurations commonly used in orthopedic procedures. Each specimen was cyclically loaded between 9 and 180 N at a rate of 1 Hz until the specimen failed or reached a maximum of 3500 cycles. Each suture material was subjected to tensile loading until failure at a rate of 1.25 mm/s. The 3 most secure knots all included the 3 reverse half-hitch on alternating posts (3-RHAP) configuration. All specimens tied with these 3 knot types failed by suture rupture. All knots using the overhand with 3 of the same half-hitches on the same post (O-3SHSP) configuration failed by knot slippage regardless of suture material. When the 3 strongest knots were combined, FiberWire resisted a significantly greater number of fatigue cycles than Orthocord or MaxBraid. In the single load to failure tests, Orthocord, FiberWire, and MaxBraid all had significantly higher ultimate strength than Ethibond. Knots using the 3-RHAP configuration provide security superior to that of those without this configuration. All 3 high-strength sutures tested outperformed Ethibond in single load to failure testing, with FiberWire resisting the greatest number of cycles. Postoperative strength and reliability of a soft tissue repair is inherently dependent on the properties of the suture materials used. PMID- 20839708 TI - Effectiveness of external rotation immobilization in highly active young men with traumatic primary anterior shoulder dislocation or subluxation. AB - We treated 15 highly active young men (16 shoulders) with traumatic primary anterior shoulder dislocation or subluxation using 3-week external rotation immobilization. Fourteen patients (14 shoulders) were members of the Self-Defense Force and the other patient (2 shoulders) was a high school student who played club-level rugby. Average patient age at the time of the primary injury was 21.3 years (range, 17-26 years). Magnetic resonance imaging (MRI) was performed on 14 of 16 shoulders after the 3-week external rotation immobilization and showed that the anteroinferior labrum was reduced on the glenoid rim in 11 shoulders but remained medially displaced on the glenoid neck in 3 shoulders. Five shoulders, including these 3 shoulders, underwent arthroscopic Bankart repair after 3-week external rotation immobilization. Eleven shoulders continued nonoperative treatment after the immobilization. Four of 11 shoulders had no recurrence of symptoms for >2 years, and these patients were able to return to their preinjury activities. However, 7 shoulders experienced recurrence within 2 years. We concluded that external rotation immobilization may not be as effective as mentioned previously in highly active young men with primary traumatic anterior shoulder dislocation or subluxation. Whether a patient has instability symptom recurrence after external rotation immobilization depends on more than the fact that the anteroinferior labrum is not reduced on MRI. PMID- 20839709 TI - Latent pisotriquetral arthrosis unmasked following carpal tunnel release. AB - The causes of persistent wrist pain following carpal tunnel release include scar tenderness and pillar pain. The goal of this study was to evaluate latent pisotriquetral arthrosis as a source of ulnar-sided wrist pain following open carpal tunnel release. Seven hundred consecutive carpal tunnel releases were reviewed, looking for postoperative presentation of pisotriquetral arthrosis, as well as management and outcome. Fourteen patients with long-standing postoperative pain at the base of the hypothenar eminence had clinical and radiographic signs of pisotriquetral degenerative arthrosis, which conceivably had existed preoperatively and been unmasked thereafter. In 6 patients with persistent symptoms despite conservative measures, excision of pisiform was curative. Altered isometric stresses over the pisotriquetral articulation as a result of releasing the transverse ligament, which constitutes a major radial static stabilizer of this joint, seems to cause articular maltracking, and consequently aggravates a preexisting asymptomatic pisotriquetral arthrosis. Long standing discomfort is characteristically associated with loss of grip strength and dexterity. Pisotriquetral dysfunction and arthrosis should always be considered in the differential diagnosis of persistent wrist pain following either open or endoscopic carpal tunnel release that does not respond to nonoperative measures. Clinical scrutiny, adequate clinical inspection, and radiographic evaluation readily establish the diagnosis. Conservative treatment includes immobilization, nonsteroidal anti-inflammatory drugs, and intra articular injection of corticosteroids under fluoroscopic control. The corticosteroid injection combined with a local anesthetic also serves as a diagnostic test. Excision of the pisiform is indicated where conservative treatment has failed. PMID- 20839710 TI - Unicompartmental and total knee arthroplasty in the over 70 population. AB - This retrospective study compares the short-term outcomes of small-incision unicompartmental knee arthroplasty (41 patients) with standard total knee arthroplasty (TKA) (50 patients) in 91 consecutive patients older than 70 years. Knee Society Scores and range of motion (ROM) were assessed preoperatively, at 6 weeks and 6 months, and through a minimum of 2 years. Postoperative comparisons included blood loss, transfusions, narcotic consumption, length of hospital stay, and complications. While Knee Scores and ROM were similar preoperatively, both were better in the unicompartmental group at each postoperative time interval. Patients with unicompartmental replacements had a much quicker return of function and discontinuation of pain medication. Blood loss was significantly more for the TKA group, as was the need for blood transfusion. None of the unicompartmental patients required transfusion. Narcotic use and length of hospital stay were also significantly less for the unicompartmental group. The overall rate of postoperative medical and surgical complications was similar for the 2 groups, with 1 major complication in each. Overall, the physiologic impact of unicompartmental knee arthroplasty was much less than TKA in this older patient population and resulted in a faster recovery. PMID- 20839711 TI - Management of subluxating ulnar nerve at the elbow. AB - Musculotendinous variations around the medial epicondyle can contribute to subluxation of the ulnar nerve at the elbow. This article reviews the presenting symptoms, operative findings, and results of surgery for subluxation of the ulnar nerve at the elbow. A retrospective evaluation was performed of 200 elbows managed operatively for medial elbow pathology over a 17-year period between 1990 and 2007. The patient charts were reviewed for chief complaint, radiographic studies, operative reports, and postoperative examination data. Seventeen patients (18 elbows) were treated for a subluxating ulnar nerve. Three patients were women and 14 were men, with a mean age of 27.6 years. Medial elbow pain was the chief complaint in all 17 patients. Seventeen elbows also demonstrated paresthesias in an ulnar nerve distribution. All patients were treated with anterior transposition of the ulnar nerve, and 11 patients (61%) were found to have a muscular anomaly. At a mean follow-up of 17 months, the mean visual analog scale for pain improved from 6.0 to 2.0. There was no functional impairment reported for any patient at final follow-up. Of the 200 elbows surgically treated for medial elbow pathology, 17 patients (8.5%) demonstrated a subluxating ulnar nerve. These patients tend to be young and present with a primary complaint of medial elbow pain. In addition, a subluxating ulnar nerve is often associated with muscular anomalies, which must be addressed concurrently. PMID- 20839712 TI - Can high-flexion tibial inserts improve range of motion after posterior cruciate retaining total knee arthroplasty? AB - Interest in high-flexion total knee arthroplasty (TKA) prostheses designed to provide better postoperative range of motion (ROM) is widespread. We sought to determine whether changes in surface geometry of the tibial polyethylene insert could improve postoperative ROM in a consecutive series of patients undergoing TKA with retention of the posterior cruciate ligament (PCL). Two cohorts with Smith & Nephew (Memphis, Tennessee) Posterior Cruciate-Retaining Genesis II total knee prostheses were compared, 79 knees (65 patients) using standard tibial inserts and 85 knees (72 patients) using high-flexion inserts. The standard insert has a slightly raised posterior lip, whereas the high-flexion insert is recessed downward at the posterior margin to facilitate femoral rollback in flexion and eliminate impingement of the femoral component on the back of the polyethylene during rollback. Mean ROM 1 year postoperatively was 112.0 degrees in patients receiving the standard insert and 119.3 degrees in patients receiving the high-flexion insert. Preoperative ROM was similar in both groups. Flexion improvement in the high-flexion group over the standard insert group was statistically significant (P<.001). Final Knee Society Scores did not differ amongst patients receiving the standard and high-flexion inserts. Our study demonstrates that improved postoperative flexion can be achieved without changing surgical technique, bony cuts, or metallic prosthetic parts. This is the first report that we are aware of that documents improvement in ROM after PCL-retaining TKA through the use of high-flexion inserts. PMID- 20839713 TI - Risk factors for and results of late or delayed amputation following combat related extremity injuries. AB - We studied patients with combat-related injuries that required delayed amputation at least 4 months after the initial injury due to dysfunction, persistent pain, and patient desires. Late amputations were performed 22 times in 22 patients (21 men, 1 woman) since 2003. Fourteen patients underwent transtibial amputation, 5 transfemoral amputations, 1 knee disarticulation, and 2 transradial amputations. The primary indications for late amputation were neurologic dysfunction in 6 patients, persistent or recurrent infection in 6, neurogenic pain in 3, non neurogenic pain in 5, and a globally poor functional result in 2. Sixteen of 22 patients reported multiple indications for electing to undergo amputation, with an average of 2.1 specific indications per patient. At final clinical follow-up an average of 13 months after amputation, all patients reported subjectively improved function and reported that they would undergo amputation again under similar circumstances. When medically and functionally practicable, every effort is given to limb salvage following severe combat-related extremity injuries. There is no single risk factor that increases the likelihood of delayed amputation, but the combination of complex pain symptoms with neurologic dysfunction appears to increase the risk, particularly if the initial insult is a severe hindfoot injury or distal tibia fracture. With appropriately selected and counseled patients, elective late amputation results in a high degree of patient satisfaction and subjectively improved function. PMID- 20839714 TI - Control the bleeding, control the pain: improving outcomes in total joint arthroplasty. PMID- 20839715 TI - Unicompartmental knee arthroplasty: incidence of transfusion and symptomatic thromboembolic disease. AB - Unicompartmental knee arthroplasty has been associated with faster recovery with less potential perioperative morbidity compared to total knee arthroplasty. This study investigates the rate of transfusion, symptomatic thromboembolic events, and length of hospital stay in 1000 consecutive, unicompartmental knee replacements performed by 2 surgeons. A rapid recovery protocol coupled with multimodal venous thromboembolism prophylaxis was used for all patients. Five patients (0.5%) received a blood transfusion for symptomatic postoperative anemia. One patient (0.1%) developed a symptomatic deep venous thrombosis within 90 days of follow-up. No patient experienced a symptomatic pulmonary embolism. Length of hospital stay averaged 1.4 days. Unicompartmental arthroplasty using less invasive surgical techniques, a rapid recovery protocol, and multimodal venous thromboembolism prevention is a safe and effective procedure associated with a low rate of morbidity. PMID- 20839716 TI - Limit the bleeding, limit the pain in total hip and knee arthroplasty. AB - Patients undergoing total hip or knee arthroplasty often sustain significant decreases in hemoglobin and hematocrit, despite modern techniques and shorter operating times. Reasons for the blood loss include raw bony surfaces, vascular inflammatory tissue, and fragile vessels in elderly patients. Acute postoperative anemia has numerous deleterious effects on patients, including delayed rehabilitation, exposure to allogeneic blood transfusions, higher complication rates, and increased pain. The ability to limit the amount of postoperative bleeding may reduce the amount of postoperative pain that patients experience, ultimately resulting in greater patient satisfaction and smoother postoperative rehabilitation. This article focuses on intraoperative techniques available to limit bleeding, thereby minimizing pain and the need for postoperative transfusion. PMID- 20839717 TI - Pain management in total joint arthroplasty: a historical review. AB - Patients undergoing total hip and knee arthroplasty experience substantial and sustained postoperative pain. Inadequate analgesia may impede recovery and delay hospital discharge. Traditionally, postoperative analgesia following arthroplasty was provided by intravenous patient-controlled analgesia or epidural analgesia, but each technique has distinct advantages and disadvantages. Recently, peripheral nerve blockade of the lumbosacral plexus has emerged as an alternative analgesic approach. An increasing number of studies have reported multimodal analgesia featuring unilateral peripheral block provide pain relief and functional outcomes similar to that of continuous epidural and superior to systemic analgesia but with fewer side effects. This review discusses the indications, benefits, and side effects associated with conventional and innovative analgesic approaches to facilitate rehabilitation and improve outcome following total joint arthroplasty. PMID- 20839718 TI - Use of catheters in the postoperative patient. AB - Continuous peripheral nerve block has been shown to be superior to traditional opioid-based analgesia in terms of improved analgesia with reduced sedation, nausea, pruritis, and hospital stay. Because of its safety and efficacy, continuous peripheral nerve block has broad application in ambulatory and pediatric patients. Techniques for continuous peripheral nerve block have advanced significantly in the past decade, particularly as a result of affordable, high-resolution ultrasound equipment that permits rapid and successful administration and results in reduced procedure-related pain, lower dose requirements, and fewer vascular punctures. Continuous peripheral nerve block is associated with some limitations, including infection, neurologic injury, local anesthetic toxicity, and patient falls. The benefits of continuous peripheral nerve block are becoming increasingly relevant in the ambulatory surgery setting where more complex procedures are being performed on an outpatient basis. PMID- 20839719 TI - Postoperative pain management. AB - Although the long-term results following traditional total joint arthroplasty are excellent, postoperative pain management has been suboptimal. Under-treatment of pain is a focus of growing concern to the orthopedic community. Poorly controlled postoperative pain leads to undesirable outcomes, including immobility, stiffness, myocardial ischemia, atelectasis, pneumonia, deep venous thrombosis, anxiety, depression, and chronic pain. Over the past decade, the attempt to minimize postoperative complications, combined with the move toward minimally invasive surgery and early postoperative mobilization, has made pain management a critical aspect of joint replacement surgery. Effective protocols are currently available; all include a multimodal approach. Debate continues regarding the ideal approach; however, reliance on narcotic analgesia alone is suboptimal. PMID- 20839720 TI - New oral antithrombotic agents for the prevention of deep venous thrombosis and pulmonary embolism in orthopedic surgery. AB - As the population ages and medical care, along with a functional life style, continues to improve the health of this group, the number of joint replacement surgeries will continue to rise each year in the United States. This growing volume carries with it the risk of venous thromboembolism associated with joint replacement surgery. The American College of Chest Physicians and the American Academy of Orthopedic Surgery have provided guidelines for preventing this complication with the use of warfarin, low molecular weight heparins, pentasaccharides, and aspirin. These agents have had variable efficacy and safety preventing postoperative and out-of-hospital venous thromboembolism. New classes of oral agents, which inhibit Factor II or Factor X, have been shown to be an effective and safe class of anticoagulants that do not require monitoring or have food and drug interactions. This paper will review the current data on the new oral anticoagulants in joint replacement surgery. PMID- 20839721 TI - First do no harm. PMID- 20839724 TI - Clinical uses of anticonvulsant drugs other than for epilepsy. PMID- 20839726 TI - Facing physical limitations-a challenge to self-esteem. AB - This article explores the personal challenges inherent in accepting limitations and a change in self-image. Nurses can assist their clients in moving toward a new vision of self that can better support health and wellness and perhaps a more realistic level of functioning as they age. PMID- 20839727 TI - Antibiotic resistance. AB - This article reviews the causes and consequences of antibiotic resistance and efforts to control its growth. Antibiotic-resistant infections and related morbidity and mortality are on the rise in the United States and around the world. At the same time, the effectiveness of many antibiotics has declined. Antibiotic resistance is a natural biological outcome of antibiotic use. Although it cannot be prevented, antibiotic resistance can be controlled. New health care reform laws focus on prevention and safety, offering occupational health nurses an opportunity to raise public awareness of antibiotic resistance and promote disease prevention in the workplace. PMID- 20839730 TI - Control banding for risk management of source chemical agents and other occupational hazards. AB - In the absence of occupational exposure limits, control banding may be a useful strategy for assessing and controlling occupational hazards as part of a comprehensive safety and health program. PMID- 20839728 TI - Incident surveillance in New Jersey career and technical education programs, 1999 to 2008: attributes, severity, and reported use of personal protective equipment. AB - Through school-sponsored career and technical education programs in New Jersey, students work part-time during or after school in paid and unpaid structured learning experiences regulated by the New Jersey Department of Education. Schools submit information on "reportable incidents," injury or illness resulting in physician treatment. Incidents including reported use of personal protective equipment (PPE) were assessed; 1,600 incident reports (1999 to 2008) were received. Attributes such as type and severity, body parts affected, and PPE use for incidents occurring at school among students grades 9 to 12 or labeled as "adults" during school hours (n = 285) were analyzed. Older teens incurred more injuries. PPE use was consistently low across age and gender. Students most frequently experienced knife injuries involving fingers and hands. Results identified potential injury determinants and training and intervention topics such as PPE, and support development of an enhanced reporting form. PMID- 20839731 TI - The International Year of the Nurse. PMID- 20839732 TI - Taming the pedagogy dragon. AB - Adult learning principles are the foundation of many organizations' educational programs today. However, continuing education providers sometimes struggle to meet learners' needs in new and creative ways. The tried-and-true principles are still valid, with a twist to meet the needs of contemporary learners. This column describes ways one education department has adapted adult learning strategies in its approach to continuing nursing education and professional development. PMID- 20839733 TI - Congestive heart failure: redefining health care and nursing. AB - This column describes an effective disease management program for congestive heart failure. PMID- 20839734 TI - Don't ignore that call for posters! AB - Participating in a conference poster session is an effective way to share information about clinical practice. This column offers some practical tips to help with the process of developing a visually appealing and informative poster. PMID- 20839736 TI - Power inequalities in the assessment of nursing competency within the workplace: implications for nursing management. AB - This article explores the power implications of implementing competency-based assessments within the nursing work environment from a manager's perspective. It discusses how the implementation of competency-based assessments for continuing education may affect workplace culture, in particular, the use of power, within the nursing team. The term "managers" for the purpose of this article is defined as "nurses in senior administrative and educational positions within a health care facility." This article adds to the discourse on competency-based models by emphasizing the effect of the nursing work environment on the competency-based assessment process. It concludes by identifying strategies that can be used by nursing management when designing and implementing an effective and fair competency-based assessment for the nursing workplace. PMID- 20839738 TI - When to treat congenital esotropia. PMID- 20839739 TI - What's your diagnosis? Retinocytoma. PMID- 20839740 TI - Is a fixation switch necessary for visual acuity improvement in patients with amblyopia treated with atropine? PMID- 20839742 TI - Typical and atypical presentations of retinoblastoma. PMID- 20839743 TI - Radiologic case study. Traumatic dislocation of the tibial sesamoid of the hallux. PMID- 20839744 TI - Current concepts in joint replacement. PMID- 20839745 TI - Arthroscopic removal of a cannulated screw and washer from the knee joint. PMID- 20839746 TI - Failed ACL repair. PMID- 20839747 TI - Catching the seizure culprit: drugs on the differential. PMID- 20839748 TI - Acute traumatic sternum fracture in a female college hockey player. PMID- 20839749 TI - Collaborative care models for late-life depression and anxiety: roles for nurses. PMID- 20839751 TI - Updates to Alzheimer's diagnostic criteria underway. PMID- 20839752 TI - Involve students in storytelling. PMID- 20839754 TI - Reducing screen time for children. PMID- 20839755 TI - Children, adolescents, and the media. PMID- 20839756 TI - A 17-year-old girl with a neck mass. PMID- 20839757 TI - A 2-year-old boy with seizures. Herpes simplex virus (HSV) encephalitis. PMID- 20839758 TI - A full-term infant with rash at birth. Congenital cutaneous candidiasis. PMID- 20839759 TI - Children, adolescents, and the media: seven key issues. PMID- 20839760 TI - Social networking sites and adolescents. PMID- 20839761 TI - Children's television viewing and childhood obesity. PMID- 20839762 TI - What pediatricians can and should be doing about the media. PMID- 20839763 TI - Infant media viewing: first, do no harm. PMID- 20839764 TI - Physicians should ask about 'screen time' at every well visit. PMID- 20839765 TI - The editor's dilemma. PMID- 20839766 TI - Dental floss. PMID- 20839767 TI - Visual differences after corneal refractive therapy and LASIK. PMID- 20839768 TI - Riboflavin/UVA cross-linking for keratoconus in Down syndrome. PMID- 20839769 TI - Carbon nanotubes for photoconversion and electrical energy storage. PMID- 20839770 TI - Deltamethrin: the cream of the crop. AB - Replacement of the pyrethronyl alcohol portion of the natural pyrethrins with the 5-benzyl-3-furylmethyl moiety gave bioresmethrin, a synthetic pyrethroid of high potency and safety but with limited photostability. Introduction of novel substituents at the 3-position of the cyclopropane ring then led to the discovery of insecticidally active compounds with greatly improved potency. Systematic changes of both the alcohol and acid components gave second-generation pyrethroids (permethrin, cypermethrin, and deltamethrin) with improved potency and photostability suitable for agricultural use. Metabolic studies showed that the photostabilized compounds remained biodegradable. Deltamethrin, discovered in 1974, was the cream of the crop and remains 36 years later as one of the most important synthetic pyrethroid insecticides. PMID- 20839771 TI - Structural identification and bioactivities of red-violet pigments present in Basella alba fruits. AB - Mature Basella alba L. fruit, with dark blue skin and deep red-violet flesh, is a potential source of natural colorants. Its pigment components and bioactivities deserve particular attention and investigation. In this study, fruit flesh was extracted with 80% methanol (containing 0.2% formic acid) and subjected to solid phase extraction, semipreparative HPLC isolation, mass spectrophotometric analysis, and structural elucidation. The major red pigment was identified as gomphrenin I. Its quantity increased with the increase of fruit maturity. The gomphrenin I extract yield from ripe fruits was 36.1 mg/100 g of fresh weight. In addition to gomphrenin I, betanidin-dihexose and isobetanidin-dihexose were also detected. The antioxidant activities of gomphrenin I determined by Trolox equivalent antioxidant capacity (TEAC), alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical scavenging activity, reducing power, and antioxidative capacity assays were equivalent to 534 MUM Trolox, 103 MUM butylated hydroxytoluene (BHT), 129 MUM ascorbic acid, and 68 MUM BHT at 180, 23, 45, and 181 MUM, respectively. The anti-inflammatory function was tested at concentrations of 25, 50, and 100 MUM in murine macrophages stimulated with lipopolysaccharide (LPS). The results revealed that gomphrenin I suppressed LPS-induced nitric oxide (NO) production in a dose-dependent manner and decreased PGE(2) and IL-1beta secretions at the highest concentration tested. The transcriptional inhibitory activities of gomphrenin I on the expression of inflammatory genes encoding iNOS, COX-2, IL 1beta, TNF-alpha, and IL-6 were also observed. It is of merit to identify gomphrenin I as a principal pigment of B. alba fruits and as a potent antioxidant and inflammatory inhibitor. These findings suggest that B. alba fruit is a rich source of betalains and has value-added potential for use in the development of food colorants and nutraceuticals. PMID- 20839772 TI - Binding modes of noncompetitive GABA-channel blockers revisited using engineered affinity-labeling reactions combined with new docking studies. AB - The binding modes of noncompetitive GABA(A)-channel blockers were re-examined taking into account the recent description of the 3D structure of prokaryotic pentameric ligand-gated ion channels, which provided access to new mammalian or insect GABA receptor models, emphasizing their transmembrane portion. Two putative binding modes were deciphered for this class of compounds, including the insecticide fipronil, located nearby either the intra- or the extracellular part of the membrane, respectively. These results are in full agreement with previously described affinity-labeling reactions performed with GABA(A) noncompetitive blockers (Perret et al. J. Biol. Chem.1999, 274, 25350-25354). PMID- 20839773 TI - Active switching of adhesion in a film-terminated fibrillar structure. AB - We show that a structure with a fibrillar surface terminated by a continuous film can be switched between two metastable states. The first state, in which the film is stretched between fibrils, has previously been shown to have strongly enhanced adhesion compared to an unstructured flat control. In the second state, the film collapses onto the substrate between fibrils and is held up away from the substrate at the fibrils, resulting in a surface with a periodic array of bumps with much reduced adhesion. The interface can be switched mechanically between these two states repeatedly, thus providing a means for active control of surface mechanical properties. We develop a simple model that shows what combination of parameters, such as film thickness, dimensions, and spacing between fibrils, is required for such an architecture to be metastable in each of these two states. PMID- 20839774 TI - Understanding the molecular activity of alkaline sphingomyelinase (NPP7) by computer modeling. AB - The enzymes in the nucleotide pyrophosphatase/phosphodiesterase (NPP) family have various substrates such as nucleotides, phospholipids, and sphingolipids. The substrate specificity in relation to their structures is largely unknown because no mammalian NPP complex has been crystallized. NPP7, also called alkaline sphingomyelinase (alk-SMase), is a NPP family member that may have important implications in carcinogenesis and cholesterol absorption. The sequence of NPP7 is 36% similar to that of the closest NPP member, but NPP7 has no activity against nucleotides. In this work, we predict the three-dimensional structure of NPP7 by homology modeling using a recently crystallized NPP from bacteria. Using the model, we studied the substrate specificity of the enzyme by docking. The model generated explains the functional changes in previous mutagenesis studies and rationalizes the structural basis for the lack of activity toward nucleotides. An effort to shift the substrate specificity from sphingomyelin (SM) to nucleotide was not successful but revealed a site-directed mutation that increased activity toward SM. In conclusion, this is the first study to predict the structure of a mammalian NPP and its substrate specificity by molecular modeling. The information may be helpful in understanding the functional differences of NPP members. PMID- 20839775 TI - Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists. AB - A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken. PMID- 20839776 TI - Bioisosteric replacement leading to biologically active [2.2]paracyclophanes with altered binding profiles for aminergic G-protein-coupled receptors. AB - Exploring the chemical diversity space of GPCR ligands, we recently discovered [2.2]paracyclophanes as valuable atypical bioisosteres for secondary affinity and selectivity generating moieties. To find out if such an exchange also works for structural moieties that simulate the endogenous neurotransmitter, pi1 or pi2 or both systems pi1 and pi2 of three representative privileged structures of types 1, 2, and 3 were replaced by a [2.2]paracyclophane unit. Contributions of the respective functionalities to the binding affinities of a panel of relevant monoaminergic GPCRs were systematically examined. The study led to the paracyclophanylpiperazine 3a displaying excellent D(3) affinity (K(i) = 1.6 nM) and a strongly attenuated binding to D(4), 5-HT(1) and alpha(1). Whereas functional experiments showed neutral D(3) antagonist properties, mutagenesis studies indicated a binding mode that is similar to its lead compounds of type 3. PMID- 20839777 TI - Positive allosteric modulators of the alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor. PMID- 20839778 TI - Guest escape and uptake in nonporous crystals of a gold(I) macrocycle. AB - The nonporous gold(I) diphosphine complex [Au(2)(cis-dppe)(2)](NO(3))(2) [1, cis dppe = cis-1,2-bis(diphenylphosphino)ethylene] is robust enough to trap guests, but at the same time, it is flexible enough to allow guest release without destruction of its crystal lattice. This nonporous gold(I) compound 1 is also efficient at capturing and releasing carbon dioxide in a controlled manner. PMID- 20839779 TI - Size separation of macromolecules during spreading. AB - Spreading of homogeneous mixtures of bottle-brush and linear macromolecules of poly(n-butylacrylate) on a solid substrate has been monitored on the molecular scale by atomic force microscopy. Despite the nearly identical chemical composition and similar molecular weight, brush-like macromolecules move markedly slower than linear chains. Moreover, smaller bottle-brushes have been shown to flow faster than the larger bottle-brushes, resulting in fractionation of the macromolecules along the spreading direction. This behavior was explained by the difference in sliding friction coefficient between the bottle-brush macromolecules and linear chains with the substrate. A theoretical model of molecular size separation is in a good agreement with experimental data. PMID- 20839780 TI - Holey silicon as an efficient thermoelectric material. AB - This work investigated the thermoelectric properties of thin silicon membranes that have been decorated with high density of nanoscopic holes. These "holey silicon" (HS) structures were fabricated by either nanosphere or block-copolymer lithography, both of which are scalable for practical device application. By reducing the pitch of the hexagonal holey pattern down to 55 nm with 35% porosity, the thermal conductivity of HS is consistently reduced by 2 orders of magnitude and approaches the amorphous limit. With a ZT value of ~0.4 at room temperature, the thermoelectric performance of HS is comparable with the best value recorded in silicon nanowire system. PMID- 20839781 TI - Broadband plasmonic microlenses based on patches of nanoholes. AB - This paper reports a new type of diffractive microlens based on finite-areas of two-dimensional arrays of circular nanoholes (patches). The plasmonic microlenses can focus single wavelengths of light across the entire visible spectrum as well as broadband white light with little divergence. The focal length is determined primarily by the overall size of the patch and is tolerant to significant changes in patch substructure, including lattice geometry and local order of the circular nanoholes. The optical throughput, however, depends sensitively on the patch substructure and is determined by the wavelengths of surface plasmon resonances. This simple diffractive lens design enables millions of broadband plasmonic microlenses to be fabricated in parallel using soft nanolithographic techniques. PMID- 20839782 TI - Synchrotron IR spectromicroscopy: chemistry of living cells. AB - Advanced analytical capabilities of synchrotron IR spectromicroscopy meet the demands of modern biological research for studying molecular reactions in individual living cells. (To listen to a podcast about this article, please go to the Analytical Chemistry multimedia page at pubs.acs.org/page/ancham/audio/index.html.). PMID- 20839783 TI - Magnetic/conducting bifunctionality due to pi/sigma-conjugated functional moieties in a stacked ferrimagnetic chain. AB - An alternating chain of a paddlewheel [Ru(2)(II,III)(O(2)CEt)(4)](+) (EtCO(2)(-) = propionate) complex and [Pt(mnt)(2)](-) (mnt(2-) = maleonitriledithiolate) has a ferrimagnetic spin arrangement of S = 3/2 and 1/2 local spins, respectively, as well as three-dimensional antiferromagnetic ordering with a canting mode at 8.6 K. This chain is stacked at the [Pt(mnt)(2)](-) units to form a slipped column in the vertical direction against the chain, which acts as a pathway for electrical conduction. PMID- 20839784 TI - Efficient inhibition of C-26 colon carcinoma by VSVMP gene delivered by biodegradable cationic nanogel derived from polyethyleneimine. AB - Biodegradable cationic nanoparticles have promising application as a gene delivery system. In this article, heparin-polyethyleneimine (HPEI) nanogels were prepared, and these nanogels were developed as a nonviral gene vector. The transfection efficiency of HPEI nanogels was comparable with that of PEI25K, while the cytotoxicity was lower than that of PEI2K and much lower than that of PEI25K in vitro. These HPEI nanogels also had better blood compatibility than PEI25K. After intravenous administration, HPEI nanogels degraded, and the degradation products were excreted through urine. The plasmid expressing vesicular stomatitis virus matrix protein (pVSVMP) could be efficiently transfected into C-26 colon carcinoma cells by HPEI nanogels in vitro, inhibiting the cell proliferation through apoptosis induction. Intraperitoneal injection of pVSVMP/HPEI complexes efficiently inhibited the abdominal metastases of C-26 colon carcinoma through apoptosis induction (mean tumor weight in mice treated with pVSVMP/HPEI complex = 0.93 g and in control mice = 3.28 g, difference = 2.35 g, 95% confidence interval [CI] = 1.75-2.95 g, P < 0.001) and prolonged the survival of treated mice. Moreover, intravenous application of pVSVMP/HPEI complexes also inhibited the growth of pulmonary metastases of C-26 colon carcinoma through apoptosis induction. The HPEI nanogels delivering pVSVMP have promising application in treating colon carcinoma. PMID- 20839785 TI - Biaxially textured Al film growth on CaF2 nanostructures toward a method of preparing single-crystalline Si film on glass substrates. AB - We report the room temperature growth of biaxially textured Al films and further demonstrate the use of these Al films in preparing single-crystalline Si layers on glass substrates. The formation of the biaxial texture in Al film relies on the existence of the CaF(2) buffer layer prepared using oblique angle physical vapor deposition, which consists of single-crystalline nanorods with caps that are in the form of inverted nanopyramids. The single-crystalline Si film was obtained upon crystallization of the amorphous Si film deposited through physical evaporation on the biaxially textured Al film. This method of preparing single crystalline Si film on glass substrate is potentially attractive for being employed in silicon technology and in fabrication of low-cost electronic devices. PMID- 20839786 TI - Construction of nanocrystalline film on nanowire array via swelling electrospun polyvinylpyrrolidone-hosted nanofibers for use in dye-sensitized solar cells. AB - A 74% enrichment of the efficiency of ZnO nanowire (NW) dye-sensitized solar cells (DSSCs) is achieved by the addition of a novel light-scattering nanocrystalline film (nanofilm). The 100 nm thick nanofilm is derived from the polyvinylpyrrolidone-hosted SnO(2)/ZnO nanofibers electrospun on the top of ZnO NW arrays via methanol vapor treatment followed by high-temperature calcination. Structural characterizations show that the film is composed of SnO(2) and ZnO nanocrystals with a diameter of ~10 nm. Short-circuit current, open-circuit voltage, and fill factor of the nanofilm/ZnO NW DSSCs are all superior to those of the ZnO NW DSSCs. The mechanism of photocurrent enhancement in the nanofilm/ZnO NW DSSCs has been investigated using optical modulation spectroscopy. Intensity modulation photocurrent spectroscopy (IMPS) measurements reveal that the dye-sensitized nanofilm does not contribute significant photocurrent in the nanofilm/ZnO NW DSSCs. The significant enhancement of the efficiency of the ZnO NW DSSCs is achieved by reflecting unabsorbed photons back into the NW anode using the novel light-scattering layer of nanofilm. PMID- 20839787 TI - Metal-organic framework thin film for enhanced localized surface plasmon resonance gas sensing. AB - Despite its high refractive index sensitivity, localized surface plasmon resonance (LSPR) spectroscopy has been generally restricted to large biological analytes. Sensing of smaller molecules is a compelling target for this technique; in particular, LSPR spectroscopy could be utilized to detect hazardous or toxic gases and manage industrial processes involving gaseous chemicals. Here, we report sensing of pure gases over Ag nanoparticles using LSPR spectroscopy, where the detected changes in bulk refractive index are <5 * 10(-4) refractive index units (RIU). We further demonstrate a novel strategy for amplifying the sensing signal by coating the plasmonic substrate with a metal-organic framework (MOF) material. Cu(3)(BTC)(2)(H(2)O)(3), BTC = benzenetricarboxylate, was grown on Ag nanoparticles using a layer-by-layer method in order to control the MOF thickness, which we show greatly affects the sensor response. Preferential concentration of CO(2) within the MOF pores produces a 14-fold signal enhancement for CO(2) sensing. In principle, MOFs can be tailored for sorbing different analytes, making them ideal materials for this amplification strategy. Because the sensing signal originates in the nanoparticle extinction spectrum and not in the MOF itself, this comprises a generalizable sensing scheme applicable to any porous MOF and any analyte. PMID- 20839788 TI - One-pot preparation of ferrocene-functionalized polymer brushes on gold substrates by combined surface-initiated atom transfer radical polymerization and "click chemistry". AB - A gold substrate with surface-grafted ferrocene functional polymer brushes, or Au g-PFTMA surface [PFTMA = poly(5-ferrocene-triazolyl methacrylate)], was prepared by a combination of surface-initiated atom transfer radical polymerization (SI ATRP) and "click chemistry" in one pot, in the presence of 2-azidoethyl methacrylate (AzEMA), ethynyl ferrocene, CuBr catalyst, CuBr(2) deactivator, and pentamethyldiethylenetriamine ligand. Thus, SI-ATRP of AzEMA from the Au substrate (the "grafting from" process) and click chemistry of the ethynyl ferrocene to the azide functional group of AzEMA (the "grafting to" process) proceeded simultaneously to produce the functional PFTMA brushes on the Au surface. Kinetic studies suggest that the reaction involving simultaneous SI-ATRP and click chemistry is still consistent with a controlled/"living" process. The composition and physical properties of the modified gold surface were analyzed by X-ray photoelectron spectroscopy, water contact angle measurement, and cyclic voltammetry. The redox-responsive properties of the ferrocene-functionalized polymer brushes on the Au-g-PFTMA surface were demonstrated in the reversible loading-unloading step of the beta-cyclodextrin polymer via host-guest interaction. PMID- 20839789 TI - Contribution of subdomain structure to the thermal stability of the cholera toxin A1 subunit. AB - The catalytic A1 subunit of cholera toxin (CTA1) is an ADP-ribosyltransferase with three distinct subdomains: CTA1(1) forms the catalytic core of the toxin, CTA1(2) is an extended linker between CTA1(1) and CTA1(3), and CTA1(3) is a compact globular region. CTA1 crosses the endoplasmic reticulum (ER) membrane to enter the cytosol where it initiates a cytopathic effect. Toxin translocation involves ER-associated degradation (ERAD), a quality control system that exports misfolded proteins from the ER to the cytosol. At the physiological temperature of 37 degrees C, the free CTA1 subunit is in a partially unfolded conformation that triggers its ERAD-mediated translocation to the cytosol. Thus, the temperature sensitivity of CTA1 structure is an important determinant of its function. Here, we examined the contribution of CTA1 subdomain structure to the thermal unfolding of CTA1. Biophysical measurements demonstrated that the CTA1(1) subdomain is thermally unstable and that the CTA1(2) subdomain provides a degree of conformational stability to CTA1(1). The CTA1(3) subdomain does not affect the overall stability of CTA1, but the thermal unfolding of CTA1 appears to begin with a local loss of structure in the CTA1(3) subdomain: glycerol and acidic pH both inhibited the thermal disordering of full-length CTA1 but not the disordering of a CTA1 construct lacking the A1(3) subdomain. These observations provide mechanistic insight regarding the thermal unfolding of CTA1, an event which facilitates its subsequent translocation to the cytosol. PMID- 20839790 TI - Synthesis, crystal structure, and properties of Mg(x)B50C8 or Mg(x)(B12)4(CBC)2(C2)2 (x = 2.4-4). AB - Single crystals of a new magnesium boride carbide Mg(x)B(50)C(8) (x = 2.4-4) were synthesized from the elements in a metallic melt using tantalum ampules. Crystals were characterized by single crystal X-ray diffraction and electron microprobe analysis. The variation of the Mg content results from different reaction conditions. The composition Mg(~3)B(50)C(8) is by far the most favored. It fulfills the electron counting rules of Wade and Longuet-Higgins and thus explains the light-green to yellow transparent color. The structure of Mg(~3)B(50)C(8) (C2/m, Z = 1, a = 8.9384(12) A, b = 5.6514(9) A, c = 9.6021(13) A, beta = 105.86(1) degrees ) consists of B(12) icosahedra. The icosahedra are interconnected by four exohedral B-B bonds to layers. The layers are connected to a three-dimensional covalent network by C(2) and CBC units and further exohedral B-B bonds. The Mg sites are partially occupied. Different site occupation factors cause the various compositions and colors (Mg(2.4)B(50)C(8), brown; Mg(4)B(50)C(8), black). The vibrational spectra show the modes of B(12) icosahedra and C(2) and CBC units as well. Measurements of the microhardness according to Vickers and Knoop revealed remarkably high values of H(V) = 3286 (32.0 GPa) and H(K) = 3165 (31.5 GPa), which exceed the values of B(4)C. Optical spectra reveal a band gap of 2.7 eV for Mg(~3)B(50)C(8), in agreement to the observed color. This justifies an ionic description, and the formula can be written as (Mg(2+))(3)(B(12)(2-))(4)(CBC(+))(2)(C(2))(2). PMID- 20839791 TI - Selective recognition and extraction of the uranyl ion. AB - A tripodal receptor capable of extracting uranyl ion from aqueous solutions has been developed. At a uranyl concentration of 400 ppm, the developed ligand extracts ~59% of the uranyl ion into the organic phase. The new receptor features three carboxylates that converge on the uranyl ion through bidentate interactions. Solution studies reveal slow exchange of the carboxylates on the NMR time scale. The crystal structure of the complex shows that the carboxylates coordinate to uranyl ion while the amides hydrogen bond to one of the uranyl oxo oxygen atoms. The hydrophobic coating of the ligand and its rigidity contribute to its ability to selectively extract uranyl ion from dilute aqueous solutions. PMID- 20839792 TI - Experimental and theoretical comparison of the O K-edge nonresonant inelastic X ray scattering and X-ray absorption spectra of NaReO4. AB - Accurate X-ray absorption spectra (XAS) of first row atoms, e.g., O, are notoriously difficult to obtain due to the extreme sensitivity of the measurement to surface contamination, self-absorption, and saturation affects. Herein, we describe a comprehensive approach for determining reliable O K-edge XAS data for ReO(4)(1-) and provide methodology for obtaining trustworthy and quantitative data on nonconducting molecular systems, even in the presence of surface contamination. This involves comparing spectra measured by nonresonant inelastic X-ray scattering (NRIXS), a bulk-sensitive technique that is not prone to X-ray self-absorption and provides exact peak intensities, with XAS spectra obtained by three different detection modes, namely total electron yield (TEY), fluorescence yield (FY), and scanning transmission X-ray microscopy (STXM). For ReO(4)(1-), TEY measurements were heavily influenced by surface contamination, while the FY and STXM data agree well with the bulk NRIXS analysis. These spectra all showed two intense pre-edge features indicative of the covalent interaction between the Re 5d and O 2p orbitals. Density functional theory calculations were used to assign these two peaks as O 1s excitations to the e and t(2) molecular orbitals that result from Re 5d and O 2p covalent mixing in T(d) symmetry. Electronic structure calculations were used to determine the amount of O 2p character (%) in these molecular orbitals. Time dependent-density functional theory (TD-DFT) was also used to calculate the energies and intensities of the pre-edge transitions. Overall, under these experimental conditions, this analysis suggests that NRIXS, STXM, and FY operate cooperatively, providing a sound basis for validation of bulk-like excitation spectra and, in combination with electronic structure calculations, suggest that NaReO(4) may serve as a well-defined O K-edge energy and intensity standard for future O K-edge XAS studies. PMID- 20839793 TI - Oriented contraction: a facile nonequilibrium heat-treatment approach for fabrication of maghemite fiber-in-tube and tube-in-tube nanostructures. AB - We present a simple and effective nonequilibrium heat-treatment approach that allows for the facile fabrication of maghemite (gamma-Fe(2)O(3)) fiber-in-tube and tube-in-tube nanostructures by heat-treating electrospun precursor fibers composed of polyvinylpyrrolidone (PVP) and iron citrate with a carefully devised heating rate (R). In this nonequilibrium heat-treatment procedure, R can be easily utilized to tune the temperature gradient established in the inner portion of the fibers and the difference between the cohesive force and the adhesive force at the interface layer between the inner gel and the dense rigid shell generated in situ by a high R. Therefore, the contraction direction of the precursor nanofibers and the final morphology of the resultant gamma-Fe(2)O(3) fibers ranging from a simple tube to a fiber in tube to a tube in tube are realized for control. The nonequilibrium heat-treatment approach reported here can be readily extended to the fabrication of other materials with controllable interior structures by fast heating their corresponding gel precursors, which may be fabricated on the basis of electrospinning techniques and others. The resultant gamma-Fe(2)O(3) fiber-in-tube and tube-in-tube nanostructures may have important applications in a number of areas, such as magnetic separable catalysts or catalyst supporting materials, sensors, absorbents, microreactors, and so forth, because of their structural characteristics and good magnetic properties. PMID- 20839794 TI - Photo-cross-linkable thermoresponsive star polymers designed for control of cell surface interactions. AB - Star polymers with thermoresponsive arms, consisting of 2-(2-methoxyethoxy)ethyl methacrylate (MEO2MA) and oligo(ethylene glycol) methacrylate with ~4 ethylene oxide units (OEOMA300, M(n) = 300), were synthesized via atom transfer radical polymerization (ATRP). 25% of the arms contained benzophenone chain-end functionality at the star periphery. A mixture of linear poly(MEO2MA-co-OEOMA300) Br macroinitiators without and with benzophenone end-group macroinitiators were (MI and Bzp-MI, respectively) cross-linked with ethylene glycol dimethacrylate to form star polymers. Formation of star polymers was monitored by GPC, and the presence of benzophenone functionality in the stars was confirmed by 1H NMR. The UV-vis spectroscopy revealed that the star polymers exhibit the low critical solution temperature (LCST) at 27 degrees C, slightly lower than LCST of either MI or Bzp-MI. Commercially available tissue culture grade polystyrene surface was modified by depositing a thin film of functionalized stars and UV cross-linking (lambda = 365 nm). The star polymers covalently attached onto surfaces allowed a control of cell shrinkage and attachment in response to temperature changes. PMID- 20839795 TI - Multistimuli two-color luminescence switching via different slip-stacking of highly fluorescent molecular sheets. AB - Color tuning and switching of the solid-state luminescence of organic materials are attractive subjects for both the fundamental research and practical applications such as optical recording. We report herein cyanostilbene-based highly luminescent molecular sheets which exhibit two-color fluorescence switching in response to pressure, temperature, and solvent vapor. The origin for the multistimuli luminescence switching is the two-directional shear-sliding capability of molecular sheets, which are formed via intermolecular multiple C H...N and C-H...O hydrogen bonds. The resulting two distinctive crystal phases are promoted by different modes of local dipole coupling, which cause a substantial alternation of pi-pi overlap. These changes can be directly correlated with the subsequent intermolecular excitonic and excimeric coupling in both phases, as demonstrated by an in-depth theory-assisted spectroscopic and structural study. Finally, we have prepared a first device demonstrator for rewritable fluorescent optical recording media which showed multistimuli luminescence tuning with fast response. Our multistimuli responsive system is unique in terms of the slip-stacking of molecular sheets and thus provides a novel concept of rewritable fluorescent optical recording media. PMID- 20839796 TI - Homogeneous precipitation by formamide hydrolysis: synthesis, reversible hydration, and aqueous exfoliation of the layered double hydroxide (LDH) of Ni and Al. AB - Homogenous precipitation by formamide hydrolysis results in the formation of a formate-intercalated layered double hydroxide (LDH) of Ni(II) and Al(III). The formate-LDH is sensitive to the atmospheric humidity and reversibly exchanges its intercalated water with atmospheric moisture. The hydration/dehydration cycle is complete within a narrow range of 0-30% relative humidity with significant hysteresis and involves a randomly interstratified intermediate phase. When immersed in water, the formate ion grows its hydration sphere (osmotic swelling), eventually leading to the exfoliation of the metal hydroxide layers into lamellar particles having in-plane dimensions of 100-200 nm and a thickness of 9-12 nm. These nanoplatelets restack to thicker tactoids again upon evaporation of the dispersion. The intercalated formate ion can be exchanged with nitrate ions in solution but not with iodide ions. These observations have implications for many applications of LDHs in the area of carbon dioxide sorption and catalysis. PMID- 20839797 TI - A bifunctional nonprecious metal catalyst for oxygen reduction and water oxidation. AB - There is a growing interest in oxygen electrochemistry as conversions between O(2) and H(2)O play an important role in a variety of renewable energy technologies. The goal of this work is to develop active bifunctional catalyst materials for water oxidation and oxygen reduction. Drawing inspiration from a cubane-like CaMn(4)O(x), the biological catalyst found in the oxygen evolving center (OEC) in photosystem II, nanostructured manganese oxide surfaces were investigated for these reactions. Thin films of nanostructured manganese oxide were found to be active for both oxygen reduction and water oxidation, with similar overall oxygen electrode activity to the best known precious metal nanoparticle catalysts: platinum, ruthenium, and iridium. Physical and chemical characterization of the nanostructured Mn oxide bifunctional catalyst reveals an oxidation state of Mn(III), akin to one of the most commonly observed Mn oxidation states found in the OEC. PMID- 20839798 TI - A new in situ optical microscope with single atomic layer resolution for observation of electrochemical dissolution of Au(111). AB - Monatomic steps with a height of 0.25 nm on ultraflat Au(111) surfaces during electrochemical dissolution can be seen for the first time by a laser confocal microscope combined with a differential interference contrast microscope (LCM DIM). Atomic force microscopy images were acquired in the same area in order to confirm that the step lines observed by LCM-DIM are mostly monatomic steps with the height of 0.25 nm. Successively recorded LCM-DIM images indicated that the anodic dissolution of Au(111) takes place only at step edges in solutions containing chloride anions at potentials near the onset of anodic current. PMID- 20839799 TI - Nickel(II) and palladium(II) complexes of azobenzene-containing ligands as dichroic dyes. AB - A large series of complexes has been synthesized with two chelating, Schiff base azobenzene derivatives connected linearly by coordination to a central nickel(II) or palladium(II) ion. These compounds have the general formulas M(II)(OC(6)H(3)-2 CHNR-4-N?NC(6)H(4)-4-CO(2)Et)(2) [M = Ni; R = n-Bu (3c), n-C(6)H(13) (3d), n C(8)H(17) (3e), n-C(12)H(25) (3f), Ph (3g), OH (3h), C(6)H(4)-4-CO(2)Et (3i). M = Pd; R = i-Pr (4a), t-Bu (4b), n-Bu (4c), n-C(6)H(13) (4d), n-C(8)H(17) (4e), n C(12)H(25) (4f), Ph (4g)], M(II)[OC(6)H(3)-2-CHN(n-C(8)H(17))-4-N?NC(6)H(4)-4 CO(2)(n-C(8)H(17))](2) [M = Ni (9), Pd (10)], M(II)[OC(6)H(3)-2-CHN(n-C(8)H(17)) 4-N?NC(6)H(4)-4-C(6)H(4)-4-O(n-C(7)H(15))](2) [M = Ni (14), Pd (15)], and M(II)[OC(6)H(3)-2-CHN(CMe(2))-4-N?NC(6)H(4)-4-CO(2)Et](2) [M = Ni (17), Pd (18); the CMe(2) groups are connected]. These compounds have been characterized by using various physical techniques including (1)H NMR spectroscopy and matrix assisted laser desorption/ionization (MALDI) mass spectrometry. Single-crystal X ray structures have been obtained for two pro-ligands and five complexes (3e, 4e, 14, 15, and 17). The latter always show a strictly square planar arrangement about the metal center, except for the Ni(II) complex of a salen-like ligand (17). In solution, broadened (1)H NMR signals indicate distortions from square planar geometry for the bis-chelate Ni(II) complexes. Electronic absorption spectroscopy and ZINDO_S (Zerner's intermediate neglect of differential overlap) and TD-DFT (time-dependent density functional theory) calculations show that the lowest energy transition has metal-to-ligand charge-transfer character. The lambda(max) of this band lies in the range of 409-434 nm in dichloromethane, and replacing Ni(II) with Pd(II) causes small blue-shifts. Dichroic ratios measured in various liquid crystal hosts show complexation-induced increases with Ni(II), but using Pd(II) has a detrimental effect. PMID- 20839801 TI - Influence of high temperature during grain filling on the accumulation of storage proteins and grain quality in rice (Oryza sativa L.). AB - The present study was performed to understand the effects of high temperature (HT) during filling on the expression of storage proteins and the quality of rice grains. HT (35/30 degrees C day/night) reduced the weight, amylose content, and flour gel consistency of grains. It increased the accumulation of all classes of storage proteins at early filling stage but decreased the accumulation of prolamins at maturation. For albumins, the expressions of cyclophilin 2, peroxiredoxin, and HSP16.9 were differentially enhanced by HT. For globulins, HT decreased the accumulation of globulin but increased that of glyoxalase I and peroxiredoxin. HT enhanced the transcription of genes for glutelins, prolamins, globulins, and protein disulfide isomerase at early filling stage but decreased the expression of these genes at a later stage. Low amounts of prolamins and globulins, as well as low pH value, were found in sound, immature, and dead kernels grown under HT. The relationships among HT, storage proteins, and grain quality are discussed. PMID- 20839800 TI - Osthole regulates inflammatory mediator expression through modulating NF-kappaB, mitogen-activated protein kinases, protein kinase C, and reactive oxygen species. AB - Osthole, a coumarin compound, has been reported to exhibit various biological activities; however the cellular mechanism of its immune modulating activity has not yet been fully addressed. In this study we isolated osthole from the seeds of Cnidium monnieri and demonstrated that osthole inhibited TNF-alpha, NO and COX-2 expression in LPS-stimulated macrophages, without reducing the expression of IL 6. Furthermore, the phosphorylation of p38, JNK1/2, PKC-alpha and PKC-epsilon induced by LPS was inhibited by osthole; however, the phosphorylation of ERK1/2 and PKC-delta was not reduced by osthole. Osthole also inhibited NF-kappaB activation and ROS release in LPS-stimulated macrophages. Our current results indicated that osthole is the major anti-inflammatory ingredient of Cnidium monnieri seed ethanol extract. PMID- 20839802 TI - Synthesis of a zwitterionic silane and its application in the surface modification of silicon-based material surfaces for improved hemocompatibility. AB - A phosphorylcholine-like silane coupling agent bearing zwitterionic molecular structure was synthesized and studied. The chemical structure of this silane coupling agent was characterized by FTIR, 1H NMR and 31P NMR. The zwitterionic structure was successfully constructed onto the surface of silicon as a self assembled layer (SAL). Static water contact angle, and atomic force microscopy (AFM) were used to investigate the wettability and surface topography of the modified silicon surfaces. Static water contact angle results indicated that the hydrophilicity of the surfaces could be effectively improved by the modification with this zwitterionic silane coupling agent. The changes of the topography and water contact angle of the modified surfaces with different incubation periods in PBS solution were also measured to evaluate the stability of the SALs. Blood compatibility of the modified surfaces were evaluated by testing the full-blood activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT), as well as by observing the adhered blood platelets onto the surface. The modified surfaces showed prolonged clotting time and fewer adherent platelets, revealing that the blood compatibility was evidently improved by the modification using this zwitterionic silane. PMID- 20839803 TI - Enantioselective [2 + 2 + 2] cycloaddition reaction of isocyanates and allenes catalyzed by nickel. AB - The enantioselective intermolecular [2 + 2 + 2] cycloaddition reaction of two molecules of isocyanate and one molecule of allene is catalyzed by a nickel(0)/(S,S)-i-Pr-FOXAP complex, providing an efficient access to enantiomerically enriched dihydropyrimidine-2,4-diones. PMID- 20839804 TI - InAs quantum dot arrays decorating the facets of GaAs nanowires. AB - InAs quantum dot arrays are obtained on GaAs nanowire facets by molecular beam epitaxy. The GaAs nanowires are first grown by the gallium-assisted catalyst-free method. Decoration of the nanowire facets with InAs quantum dots is achieved only when the facets are capped with an ultrathin AlAs layer, as demonstrated by atomic force, high-resolution electron microscopy, and energy-dispersive X-ray spectroscopy line scans. The excitation of single and double excitons in the quantum dots are demonstrated by low-temperature photoluminescence spectroscopy realized on the single nanowires. This new type of heterostructures opens a new avenue to the fabrication of highly efficient single-photon sources, novel quantum optics experiments, as well as the realization of intermediate-band nanowire solar cells for third-generation photovoltaics. PMID- 20839805 TI - Discovery of N(2)-(1-carboxyethyl)guanosine 5'-monophosphate as an umami enhancing maillard-modified nucleotide in yeast extracts. AB - Sensory-guided fractionation of a commercial yeast extract involving medium pressure RP-18 chromatography and ion-pair chromatography, followed by LC-MS/MS, LC-TOF-MS, 1D/2D-NMR, and CD spectroscopy, led to the discovery of the previously not reported umami-enhancing nucleotide diastereomers (R)- and (S)-N(2)-(1 carboxyethyl)guanosine 5'-monophosphate. Model experiments confirmed the formation of these diastereomers by a Maillard-type glycation of guanosine 5' monophosphate with dihydroxyacetone and glyceraldehyde, respectively. Sensory studies revealed umami recognition threshold concentrations of 0.19 and 0.85 mmol/L for the (S)- and (R)-configured diastereomers, respectively, and demonstrated the taste-enhancing activity of these nucleotides on monosodium l glutamate solutions. PMID- 20839806 TI - Synthesis and characterization of a cyclobutane duocarmycin derivative incorporating the 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (CbBI) alkylation subunit. AB - The synthesis of 1,2,10,11-tetrahydro-9H-cyclobuta[c]benzo[e]indol-4-one (17, CbBI), which contains a deep-seated fundamental structural modification in the CC 1065 and duocarmycin alkylation subunit consisting of the incorporation of a ring expanded fused cyclobutane (vs cyclopropane), its chemical and structural characterization, and its incorporation into a key analogue of the natural products are detailed. The approach to the preparation of CbBI was based on a precedented (Ar-3' and Ar-5') but previously unknown Ar-4' spirocyclization of a phenol onto a tethered alkyl halide to form the desired cyclobutane. The conditions required for the implementation of the Ar-4' spirocyclization indicate that the entropy of activation substantially impacts the rate of reaction relative to that for the much more facile Ar-3' spirocyclization, while the higher enthalpy of activation slows the reaction relative to an Ar-5' spirocyclization. The characterization of the CbBI-based agents revealed their exceptional stability and exquisite reaction regioselectivity, and a single crystal X-ray structure analysis of N-Boc-CbBI (13) revealed their structural origins. The reaction regioselectivity may be attributed to the stereoelectronic alignment of the two available cyclobutane bonds with the cyclohexadienone pi system, which resides in the bond that extends to the less substituted cyclobutane carbon for 13. The remarkable stability of N-Boc-CbBI (which is stable even at pH 1) relative to N-Boc-CBI containing a cyclopropane (t(1/2) = 133 h at pH 3) may be attributed to a combination of the increased extent of vinylogous amide conjugation, the nonoptimal geometric alignment of the cyclobutane with the activating cyclohexadienone, and the intrinsic but modestly lower strain energy (1.8 kcal/mol) of a cyclobutane versus a cyclopropane. PMID- 20839807 TI - Intramolecular hydroamination of unbiased and functionalized primary aminoalkenes catalyzed by a rhodium aminophosphine complex. AB - We report a rhodium catalyst that exhibits high reactivity for the hydroamination of primary aminoalkenes that are unbiased toward cyclization and that possess functional groups incompatible with more electrophilic hydroamination catalysts. The rhodium catalyst contains an unusual diaminophosphine ligand (L1) that binds to rhodium in a kappa(3)-P,O,P mode. The reactions catalyzed by this complex typically proceed at mild temperatures (room temperature to 70 degrees C) and occur with primary aminoalkenes lacking substituents on the alkyl chain that bias the system toward cyclization, with primary aminoalkenes containing chloride, ester, ether, enolizable ketone, nitrile, and unprotected alcohol functionality, and with primary aminoalkenes containing internal olefins. Mechanistic data imply that these reactions occur with a turnover-limiting step that is different from that of reactions catalyzed by late-transition-metal complexes of Pd, Pt, and Ir. This change in the turnover-limiting step and resulting high activity of the catalyst stem from favorable relative rates for protonolysis of the M-C bond to release the hydroamination product versus reversion of the aminoalkyl intermediate to regenerate the acyclic precursor. Probes of the origin of the reactivity of the rhodium complex of L1 imply that the aminophosphine groups lead to these favorable rates by effects beyond steric demands and simple electron donation to the metal center. PMID- 20839808 TI - Genetically encoded initiator for polymer growth from proteins. AB - Despite the importance of protein-polymer bioconjugates, there is no general method for producing homogeneous recombinant protein that contains polymer initiators at defined sites. To address this deficiency, we designed the amino acid 4-(2'-bromoisobutyramido)phenylalanine (1) as an initiator in atom-transfer radical polymerization (ATRP) that would provide a stable linkage between the protein and growing polymer. We synthesized 1 and evolved a Methanococcus jannaschii tyrosyl-tRNA synthetase/tRNA(CUA) pair to genetically encode this initiator in response to an amber codon. To demonstrate the utility of this initiator, we produced green fluorescent protein (GFP) with 1 site-specifically incorporated on its surface (GFP-1). Purified GFP-1 was then used as an initiator under standard ATRP conditions with a monomer, oligo(ethylene oxide) monomethyl ether methacrylate, efficiently producing a polymer-GFP bioconjugate where the polymer is connected at our selected site on GFP. PMID- 20839810 TI - Tandem affinity depletion: a combination of affinity fractionation and immunoaffinity depletion allows the detection of low-abundance components in the complex proteomes of body fluids. AB - Protein biomarker discovery in the low concentration range of human body fluids requires the enrichment of the proteins of interest. Here we report on a tandem affinity strategy: In the first step, we isolated a human plasma glyco subproteome of healthy individuals by wheat germ agglutinin (WGA) lectin affinity chromatography. In the second step, the proteins of this subproteome were used to raise antibodies in llama (Lama glama). The heavy-chain fraction of the llama antibodies was used to deplete from the WGA lectin binding fraction all proteins normally found in human plasma. In this way, we selectively enriched the glycoprotein, CEA, a known cancer marker which had been spiked into normal plasma. As a proof of concept, we applied this method to the analysis of plasma sample from colon cancer patients. We could demonstrate the selective enrichment of CEA by a factor of 600-800. PMID- 20839809 TI - Crystallographic and nuclear magnetic resonance evaluation of the impact of peptide binding to the second PDZ domain of protein tyrosine phosphatase 1E. AB - PDZ (PSD95/Discs large/ZO-1) domains are ubiquitous protein interaction motifs found in scaffolding proteins involved in signal transduction. Despite the fact that many PDZ domains show a limited tendency to undergo structural change, the PDZ family has been associated with long-range communication and allostery. One of the PDZ domains studied most in terms of structure and biophysical properties is the second PDZ ("PDZ2") domain from protein tyrosine phosphatase 1E (PTP1E, also known as PTPL1). Previously, we showed through NMR relaxation studies that binding of the RA-GEF2 C-terminal peptide substrate results in long-range propagation of side-chain dynamic changes in human PDZ2 [Fuentes, E. J., et al. (2004) J. Mol. Biol. 335, 1105-1115]. Here, we present the first X-ray crystal structures of PDZ2 in the absence and presence of RA-GEF2 ligand, determined to resolutions of 1.65 and 1.3 A, respectively. These structures deviate somewhat from previously determined NMR structures and indicate that very minor structural changes in PDZ2 accompany peptide binding. NMR residual dipolar couplings confirm the crystal structures to be accurate models of the time-averaged atomic coordinates of PDZ2. The impact on side-chain dynamics was further tested with a C-terminal peptide from APC, which showed results nearly identical to those of RA GEF2. Thus, allosteric transmission in PDZ2 induced by peptide binding is conveyed purely and robustly by dynamics. (15)N relaxation dispersion measurements did not detect appreciable populations of a kinetic structural intermediate. Collectively, for ligand binding to PDZ2, these data support a lock and-key binding model from a structural perspective and an allosteric model from a dynamical perspective, which together suggest a complex energy landscape for functional transitions within the ensemble. PMID- 20839811 TI - A Bisindole Alkaloid with Hedgehog Signal Inhibitory Activity from the Myxomycete Perichaena chrysosperma. AB - 6-Hydroxy-9'-methoxystaurosporinone (1), a new bisindole alkaloid, was isolated from field-collected fruiting bodies of the myxomycete Perichaena chrysosperma, together with two known compounds. The structure of the new alkaloid was elucidated from spectral data, and compound 1 was shown to have hedgehog signal inhibitory activity. A related new alkaloid, 6,9'-dihydroxystaurosporinone (4), was also isolated from Arcyria cinerea. PMID- 20839812 TI - Stereoselective C-glycosidations with achiral and enantioenriched allenylsilanes. AB - Allenylsilanes are used as carbon nucleophiles in highly stereoselective Lewis acid-promoted C-glycosidations, resulting in the introduction of an internal alkyne with an adjacent stereocenter. Both achiral and chiral allenylsilanes form the desired products with high diastereoselectivity, where the nucleophile adds exclusively to the alpha-face of the intermediate oxonium ion. Reactions with glucal and galactal afford dihydropyran products, while reactions with a ribose derivative yield dihydrofuran products. PMID- 20839813 TI - Crystal and electronic structure of FeSe at high pressure and low temperature. AB - We have investigated the high-pressure crystal and electronic structures of superconducting FeSe by high-resolution synchrotron powder X-ray diffraction and density functional theory (DFT) calculations at ambient and at low temperatures down to 8 K. Ambient nuclear resonant inelastic X-ray scattering (NRIXS) experiments were performed on FeSe to understand the partial phonon density of states (PDOS) of the high-pressure phases. On the basis of our experimental results and DFT calculations, we demonstrate a pressure-induced distortion of the low-temperature Cmma phase at around 1.6 GPa and the appearance of a high pressure Pbnm phase. Upon increasing the pressure above 9 GPa, the orthorhombic phase becomes the major phase, and a mixed-phase region exists up to 26 GPa. The pressure-induced structural changes in this system and its connection to T(c) enhancement are discussed. PMID- 20839814 TI - Vibrational energy relaxation of liquid aryl-halides X-C6H5 (X = F, Cl, Br, I). AB - Anti-Stokes Raman spectroscopy was used to probe vibrational energy dynamics in liquid ambient-temperature aryl-halides, X-Ph (X = F, Cl, Br, I; -Ph = C(6)H(5)), following IR excitation of a 3068 cm(-1) CH-stretching transition. Five ring vibrations and two substituent-dependent vibrations were monitored in each aryl halide. Overall, the vibrational relaxation (VR) lifetimes in aryl-halides were shorter than those in normal benzene (H-Ph). The aryl-halide CH-stretch lifetimes increased in the order F, Cl, Br, I, ranging from 2.5 to 3.4 ps, compared with 6.2 ps in H-Ph. The aryl-halide energy transfer processes were similar overall with four exceptions. Three of the four exceptions could be explained as a result of faster VR of midrange vibrations (1000-1600 cm(-1)) in the heavier aryl halides. The fourth appeared to result from a coincidental resonance in chlorobenzene that does not occur in the other aryl-halides. Among the aryl halides, the decay of CH-stretching excitations (~3070 cm(-1)) was slower in the heavier species, but the decay of midrange vibrations was faster in the heavier species. This seeming contradiction could be explained if VR depended primarily on the density of states (DOS) of the lower tiers of vibrational excitations. The DOS for the first few (1-4) tiers is similar for all aryl-halides in the CH stretch region, but DOS increases with increasing halide mass in the midrange region. PMID- 20839815 TI - Rationalizing the diverse solid-liquid equilibria of binary mixtures of benzene and its fluorinated derivatives. AB - The solid-liquid phase behavior of benzene plus hexafluorobenzene binary mixtures is characterized by a stable congruent-melting binary solid, (C(6)H(6).C(6)F(6)). In this work, differential scanning calorimetry (DSC) was used to build, for the first time, the temperature-composition phase diagrams of ten other binary mixtures involving benzene and its fluorinated derivatives. Distinct types of solid-liquid equilibria were observed, namely those exhibiting the usual eutectic behavior associated with ideal or quasi-ideal solubility conditions, or, in other cases, systems with equimolar congruent-melting solids. Data have been interpreted and rationalized using a unifying framework that takes into account the molecular dipole and quadrupole moments of the two components of each binary system and the structural motifs associated with each type of crystal. PMID- 20839816 TI - Quenching of triplet benzophenone by benzene and diphenyl ether: a DFT study. AB - The reaction of triplet benzophenone with benzene and diphenyl ether has been studied by density functional theory. Quenching of the triplet ketone is predicted to occur by addition of the carbonyl oxygen to the arene chromophores. The reaction is accompanied by a significant degree of charge transfer. In case of the reaction of triplet benzophenone with diphenyl ether (DPE), addition is predicted to occur preferentially at the ortho position of the DPE molecule. Addition to the ipso-position of DPE, which provides a pathway for formation of the phenoxy radical, is predicted to occur as a minor reaction pathway. PMID- 20839817 TI - An improved four-site ionic liquid model. AB - Computer simulations provide insight into the molecular-level details responsible for the unique properties of ionic liquids. Due to the sluggish dynamics and nanostructured nature of many ionic liquids, coarse-grained models are an important complement to fully atomistic simulations because they enable simulation of much larger system sizes and much longer times, which are often of interest. This paper reports a four-site, coarse-grained model for studying ionic liquids and their solutions. It is intended to be a generic model representative of common ionic liquids currently in use, but it is parametrized to fit the properties of 1-butyl-3-methylimidazolium hexafluorophosphate, [Im(41)][PF(6)]. The present model is a variant of one introduced in J. Phys. Chem. B 114, 8410 (2010). Reduction of ion charges to +/-0.78e and fine-tuning Lennard-Jones parameters from the original model leads to a remarkable improvement in the realism of the model and surprisingly good agreement between simulation and experiment for a variety of static and dynamic properties of [Im(41)][PF(6)]. This idealized model should prove valuable for studies of solute-based dynamics and other phenomena occurring on nanosecond and longer time scales, which are not feasible with all-atom simulations. PMID- 20839818 TI - Effect of ice growth rate on the measured Workman-Reynolds freezing potential between ice and dilute NaCl solutions. AB - Workman-Reynolds freezing potentials have been measured across the interface between ice and dilute NaCl solutions as a function of ice growth rate for three salt concentrations. Growth rates of up to 40 MUm.s(-1) are used, and it is found that the measured voltage peaks at rates of ~25 MUm.s(-1). Our initial results indicate that the freezing potential can be used as a probe into various aspects of the DC electrical resistance of ice as a function of variables such as salt concentration. PMID- 20839819 TI - Bacterial photosynthetic reaction centers in trehalose glasses: coupling between protein conformational dynamics and electron-transfer kinetics as studied by laser-flash and high-field EPR spectroscopies. AB - The coupling between electron transfer (ET) and the conformational dynamics of the cofactor-protein complex in photosynthetic reaction centers (RCs) from Rhodobacter sphaeroides in water/glycerol solutions or embedded in dehydrated poly(vinyl alcohol) (PVA) films or trehalose glasses is reported. Matrix effects were studied by time-resolved 95 GHz high-field electron paramagnetic resonance (EPR) spectroscopy at room (290 K) and low (150 K) temperature. ET from the photoreduced quinone acceptor (QA*-) to the photo-oxidized donor (P865*+) is strongly matrix-dependent at room temperature: In the trehalose glasses, the recombination kinetics of P865*+QA*-, probed by EPR and optical spectroscopies, is faster and broadly distributed as compared to that of RCs in solution, reflecting the inhibition of the RC relaxation from the dark- to the light adapted conformational substate and the hindrance of substate interconversion. Similarly accelerated kinetics was observed also in PVA at a water-to-RC molar ratio 10-fold lower than in trehalose. Despite the matrix dependence of the ET kinetics, continuous-wave (cw) EPR and electron spin echo (ESE) analyses of the photogenerated P865*+ and QA*- radical ions and P865*+QA*- radical pairs do not reveal significant matrix effects, at either 290 or 150 K, indicating no change in the molecular radical-pair configuration of the P865*+ and QA*- cofactors. Furthermore, the field dependences of the transverse relaxation times T2 of QA*- essentially coincide in trehalose and PVA at 290 K. T2 is similar in these two matrixes and in the glycerol/water system at 150 K, implying that the librational dynamics of QA*- are also unaffected by the matrix. We infer that the relative geometry of the primary donor and acceptor, as well as the local dynamics and hydrogen bonding of QA in its binding pocket, are not involved in the stabilization of P865*+QA*-. We suggest that the RC relaxation occurs rather by changes throughout the protein/solvent system. The control of the RC dynamics and ET by the environment is discussed, particularly with respect to the extraordinary efficacy of trehalose matrixes in restricting the RC motional degrees of freedom at elevated temperatures. PMID- 20839820 TI - Electrostatic pushing effect: a prospective strategy for enhanced drug delivery. AB - Contrary to the expected quenching, unprecedented and remarkable enhancement is observed in the fluorescence of an anionic fluorophore, 8-anilino-1-naphthalene sulfonate, with the addition of bromide ion in cationic cetyltrimethylammonium bromide micellar medium. Electrostatic pushing effect of the halide ion on the anionic fluorophore that forces the probe to penetrate further into the micellar interior has been assigned to be responsible for the novel observation. Experiments with other probes and surfactants propose that the electrostatic pushing effect is rather a general phenomenon. While applying to the ionic drugs in real biosystems, potential application of the unorthodox effect remains in enhancing the solubilization of the drugs into the active target region leading to a radical enhancement in the drug efficacy. PMID- 20839821 TI - Synthesis of kaempferol 3-O-(3'',6''-di-O-E-p-coumaroyl)-beta-D-glucopyranoside, efficient glycosylation of flavonol 3-OH with glycosyl o-alkynylbenzoates as donors. AB - Kaempferol 3-O-(3'',6''-di-O-E-p-coumaroyl)-beta-D-glucopyranoside (1), an optimal metabolite of Scots pine seedlings for protection of deep-lying tissue against damaging UV-B, represents a typical acylated flavonol 3-O-glycoside. This compound was synthesized for the first time via two approaches. The first approach, starting with kaempferol, featured formation of the flavonol 3-O glycosidic linkage with a glycosyl bromide under conventional PTC conditions. In the second approach, 5,7,4'-tri-O-benzyl-kaempferol was readily prepared from 2',4',6'-trihydroxyacetophenone and p-hydroxybenzoic acid, which was coupled with a glucopyranosyl o-hexynylbenzoate under the catalysis of a gold(I) complex to provide the desired 3-O-glycoside in excellent yield. A variety of the glycosyl o hexanylbenzoates equipped with the 2-O-benzoyl group were also proven to be highly efficient donors for construction of the flavonol 3-O-glycosidic linkages. PMID- 20839822 TI - Regioselective cross-coupling reactions of boronic acids with dihalo heterocycles. AB - The carboxylic acid anion moiety has been used as a tunable directing group in the cross-coupling reaction of 2,6-dichloronicotinic acid and 2,5-dibromo-1,2,4 triazole derivatives producing selectively the 2- or 6-substituted nicotinic acids, while only the 5-substituted triazoles were obtained under a variety of conditions. PMID- 20839823 TI - Preparation of NHC borane complexes by Lewis base exchange with amine- and phosphine-boranes. AB - A versatile new method for the preparation of NHC boranes starting from two stable, readily available reactants-an heterocyclic salt and an amine or phosphine-borane-is reported. It uses a Lewis base exchange at boron and provides easy access to new NHC boranes, in particular B-substituted borane ones. PMID- 20839824 TI - Experiment and prediction: a productive symbiosis in studies on the thermodynamics of DNA oligomers. AB - Recently, we reported the kinetics of hybridization of cDNA dodecamers (Carrillo Nava, E., Mejia-Radillo, Y., and Hinz, H.-J. Biochemistry 2008, 47, 13153-13157). In this study, we provide the thermodynamic reaction parameters of those dodecamers as well as a comparison with parameters for 24-mers designed from two identical dodecamers in tandem arrangement. The thermodynamic properties were determined by isothermal titration calorimetry (ITC), differential scanning microcalorimetry (DSC), and UV melting studies. On the basis of the results from our kinetic studies, fitting algorithms of DSC and UV melting profiles employed the two-state assumption for the duplex to a single strand dissociation reaction. The formation of both 12-mer and 24-mer duplexes is strongly enthalpy driven at all temperatures. At identical temperatures, the hybridization enthalpy of the 24 mer is within error limits twice that of the 12-mer. Duplex formation is always associated with a significant negative heat capacity change, DeltaC(p), which, on a mass basis, is comparable to that observed for protein folding. Only a small part of the favorable reaction enthalpy appears as a standard Gibbs free energy change due to large compensating negative entropy changes linked to duplex formation. On the basis of the results of the present studies, it appears to be absolutely essential for a proper analysis of thermodynamic parameters of oligonucleotide hybridization reactions to combine low temperature ITC measurements of binding enthalpies with DSC and UV melting studies to obtain an accurate assessment of standard Gibbs energy changes or, equivalently, hybridization constants over a broad temperature range. The experimental thermodynamic parameters were compared with theoretical estimates based on nearest-neighbor approximations employing temperature-independent enthalpies. Good agreement between experimental and predicted DeltaG degrees values is observed at ambient temperatures (20-30 degrees C), as long as helix formation is associated with small molar heat capacity changes. If the experimental DeltaC(p) values determined by ITC are taken into account, significant deviations occur. PMID- 20839825 TI - Synthesis of axially chiral amino acid and amino alcohols via additive-ligand free Pd-catalyzed domino coupling reaction and subsequent transformations of the product amidoaza[5]helicene. AB - Novel optically active axially chiral amino acid and amino alcohols have been synthesized efficiently via lactam ring-opening, with the aid of an optically active alcohol, amidoaza[5]helicene 5, which has been readily prepared by an additive-ligand-free Pd catalyzed domino coupling reaction in a single step. The stereostructures of these chiral molecules have also been clarified. PMID- 20839826 TI - Electron density fingerprints (EDprints): virtual screening using assembled information of electron density. AB - We have designed a method to encode properties related to the electron densities of molecules (calculated (1)H and (13)C NMR shifts and atomic partial charges) in molecular fingerprints (EDprints). EDprints was evaluated in terms of their retrospective virtual screening accuracy against the Directory of Useful Decoys (DUD) and compared to the established ligand-based similarity search methods MOLPRINT 2D and FCFP-4. Although there are no significant differences in the overall virtual screening accuracies of the three methods, specific examples highlight interesting differences between the new EDprints fingerprint method and the atom-centered circular fingerprint methods of MOLPRINT 2D and FCFP-4. On one hand, EDprints similarity searches can be biased by the molecular protonation state, especially when reference ligands contain multiple ionizable groups. On the other hand, EDprints models are more robust toward subtle rearrangements of chemical groups and more suitable for screening against reference molecules with fused ring systems than MOLPRINT 2D and FCFP-4. EDprints is furthermore the fastest method under investigation in comparing fingerprints (average 56-233-fold increase in speed), which makes it highly suitable for all-against-all similarity searches and for repetitive virtual screening against large chemical databases of millions of compounds. PMID- 20839827 TI - Fluorescent pH-sensing organic/inorganic hybrid mesoporous silica nanoparticles with tunable redox-responsive release capability. AB - We report on the fabrication of fluorescent pH-sensing organic/inorganic hybrid mesoporous silica nanoparticles (MSN) capable of tunable redox-responsive release of embedded guest molecules. The reversible addition-fragmentation chain transfer (RAFT) copolymerization of N-(acryloxy)succinimide (NAS), oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA), and 1,8-naphthalimide-based pH-sensing monomer (NaphMA) at the surface of MSN led to fluorescent organic/inorganic hybrid MSN. The obtained hybrid MSN exhibits excellent water dispersibility and acts as sensitive fluorescent pH probes in the range pH 4-8 due to the presence of NaphMA moieties. After loading with rhodamine B (RhB) as a model drug molecule, P(NAS-co-OEGMA-co- NaphMA) brushes at the surface of hybrid MSN were cross-linked with cystamine to block nanopore entrances for the effective retention of guest molecules. Taking advantage of disulfide-containing cross linkers, the release rate of RhB can be easily adjusted by adding varying concentrations of dithiothreitol (DTT), which can cleave the disulfide linkage to open blocked nanopores. The increase of DTT concentration from 0 to 20 mM led to 20-30 times enhancement of RhB release rate. The reported multifunctional hybrid MSN augurs well for applications in controlled-release nanocarriers, cell and tissue imaging, and clinical diagnosis. PMID- 20839828 TI - Comparison of adsorption of mercaptopropyltrimethoxysilane on amphiphilic TiO2 and hydroxylated SiO2. AB - Alkylsilane 3-mercaptopropyltrimethoxysilane (3MPT) monolayers with a functional end group -SH were used to immobilize Ag colloidal nanoparticles on photoinduced amphiphilic TiO(2) and hydroxylated SiO(2) surfaces. The differences in the adsorption of 3MPT and the immobilization of Ag colloids on both surfaces were studied. Under identical experimental conditions, 3MPT islands were formed on UV exposed TiO(2) surfaces compared to continuous and flat monolayers formed on SiO(2). The significant structural differences found for monolayers of 3MPT on TiO(2) could be explained in terms of the different densities of hydroxyl groups and the microstructure of hydrophilic domains induced by UV irradiation. The surface properties were characterized using contact angle measurements and XPS. XPS showed an increase in the hydroxyl group's density and a decrease in the number of adsorbed hydrocarbon films on the TiO(2) surface as a function of the UV irradiation time. The density of the adsorbed 3MPT on TiO(2) surfaces as a function of the UV irradiation time was quantitatively related to the cosine of the water contact angles. Such a 3MPT distribution influenced the subsequent adsorption of Ag colloids and resulted in more isolated nanoparticles on the modified TiO(2) with a narrower size distribution. PMID- 20839829 TI - Formation of pickering emulsions using ion-specific responsive colloids. AB - The ability to control the dispersion, aggregation, and assembly of colloidal systems is important for a number of applications, for instance, Pickering emulsions, drug and gene delivery, control of fluid rheology, and the formation of colloidal crystal arrays. We generated a responsive colloidal system based on polymer-brush-grafted silica nanoparticles and demonstrated that such a colloidal system can be used to produce stable oil-in-water Pickering emulsions. Cationic poly(2-(methacryloyloxy)-ethyl-trimethyl-ammonium chloride) (PMETAC) brushes were grown from silica nanoparticles (diameter ~320 nm) through surface-initiated atom transfer radical polymerization (ATRP). PMETAC brushes are attractive coatings for controlling the behavior of colloidal systems, owing to their ion-specific collapse resulting in the switching of surface hydrophilicity. Fourier transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), transmission electron microscopy (TEM), dynamic light scattering (DLS), and zeta-potential measurements indicated the successful grafting of PMETAC brushes on nanoparticles. The resulting colloidal dispersion was shown to be responsive to perchlorate ions (ClO(4)(-)), which triggered particle aggregation and enabled the generation of Pickering emulsions. The onset of aggregation depended on the polymer chain length. Aggregation was not affected by the initiator density and brush conformational changes. Further studies suggested that particle aggregation and the formation of stable Pickering emulsions were not simply due to brush collapse but also were due to a gradual shielding of electrostatic repulsion. Finally, the stability and homogeneity of the resulting Pickering emulsions were studied. PMID- 20839830 TI - A reliable docking/scoring scheme based on the semiempirical quantum mechanical PM6-DH2 method accurately covering dispersion and H-bonding: HIV-1 protease with 22 ligands. AB - In this study, we introduce a fast and reliable rescoring scheme for docked complexes based on a semiempirical quantum mechanical PM6-DH2 method. The method utilizes a PM6-based Hamiltonian with corrections for dispersion energy and hydrogen bonds. The total score is constructed as the sum of the PM6-DH2 interaction enthalpy, the empirical force field (AMBER) interaction entropy, and the sum of the deformation (PM6-DH2, SMD) and the desolvation (SMD) energies of the ligand. The main advantage of the procedure is the fact that we do not add any empirical parameter for either an individual component of the total score or an individual protein-ligand complex. This rescoring method is applied to a very challenging system, namely, the HIV-1 protease with a set of ligands. As opposed to the conventional DOCK procedure, the PM6-DH2 rescoring based on all of the terms distinguishes between binders and nonbinders and provides a reliable correlation of the theoretical and experimental binding free energies. Such a dramatic improvement, resulting from the PM6-DH2 rescoring of all the complexes, provides a valuable yet inexpensive tool for rational drug discovery and de novo ligand design. PMID- 20839831 TI - Pore size control of ultrathin silicon membranes by rapid thermal carbonization. AB - Rapid thermal carbonization in a dilute acetylene (C(2)H(2)) atmosphere has been used to chemically modify and precisely tune the pore size of ultrathin porous nanocrystalline silicon (pnc-Si). The magnitude of size reduction was controlled by varying the process temperature and time. Under certain conditions, the carbon coating displayed atomic ordering indicative of graphene layer formation conformal to the pore walls. Initial experiments show that carbonized membranes follow theoretical predictions for hydraulic permeability and retain the precise separation capabilities of untreated membranes. PMID- 20839832 TI - Surface plasmons and singularities. AB - We apply the conformal transformation technique to study systematically a variety of singular plasmonic structures, including two-dimensional sharp edges, rough surfaces, and nanocrescents. These structures are shown to exhibit two distinct features. First, different from a planar metallic surface, the surface plasmon excitations on the examined structures have a lower bound cutoff at a finite frequency; second, the electric field diverges below a critical frequency even when metallic losses are considered. For rough surfaces and open-crescent nanostructures, the influence of the structure shapes on the absorbance characteristics is also discussed. Our analysis gives a unique insight into the light capture process on singular structures and holds the promise of detection of single molecules and greatly enhanced nonlinear effects. PMID- 20839833 TI - Extending Pummerer reaction chemistry: application to the assembly of the pentacyclic core of dibromopalau'amine. AB - A pentacyclic model system featuring the trans azabicyclo[3.3.0]octane unit of dibromopalau'amine was prepared with complete diastereoselectivity in the polycyclic core from a tricyclic precursor. The key transformations of this sequence include (a) a Pummerer reaction-mediated oxidative bicyclization, and (b) a Wolff rearrangement-based ring contraction to deliver the strained azabicyclo[3.3.0]octane core. PMID- 20839834 TI - Palladium-catalyzed tandem diperoxidation/C-H activation resulting in diperoxy oxindole in air. AB - A highly efficient and facile palladium-catalyzed tandem diperoxidation and C-H activation process was reported, which provides a new pathway for the synthesis of biologically active diperoxides as well as oxindole derivatives from readily available starting materials in excellent chemical yields. PMID- 20839836 TI - Ether-bond-containing ionic liquids and the relevance of the ether bond position to transport properties. AB - The ionic liquids (ILs) 1-ethoxyethyl-2,3-dimethylimidazolium bis(trifluoromethanesulfonyl)imide, [EtO(CH(2))(2)MMI][Tf(2)N], and N (ethoxyethyl)-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide, [EtO(CH(2))(2)MMor][Tf(2)N] were synthesized, and relevant properties, such as thermal stability, density, viscosity, electrochemical behavior, ionic conductivity, and self-diffusion coefficients for both ionic species, were measured and compared with those of their alkyl counterparts, 1-n-butyl-2,3 dimethylimidazolium bis(trifluoromethanesulfonyl)imide, [BMMI][Tf(2)N], and N-n butyl-N-methylpiperidinium bis(trifluoromethanesulfonyl)imide, [BMP][Tf(2)N] and N-n-butyl-N-methylmorpholinium bis(trifluoromethanesulfonyl)imide [BMMor][Tf(2)N]. This comparison was done to evaluate the effects caused by the presence of the ether bond in either the side chain or in the organic cation ring. The salt, LiTf(2)N, was added to the systems to estimate IL behavior with regard to lithium cation transport. Pure [EtO(CH(2))(2)MMI][Tf(2)N] and their LiTf(2)N solutions showed low viscosity and the highest conductivity among the ILs studied. The H(R) (AC conductivity/NMR calculated conductivity ratio) values showed that, after addition of LiTf(2)N, ILs containing the ether bond seemed to have a greater number of charged species. Structural reasons could explain these high observed H(R) values for [EtO(CH(2))(2)MMor][Tf(2)N]. PMID- 20839837 TI - Evaluation of chemical, molecular, and traditional markers of fecal contamination in an effluent dominated urban stream. AB - In this paper we present a quantitative sanitary survey of the Middle Santa Ana River, in southern California, utilizing a variety of source tracking tools, including traditional culture-dependent fecal markers (Enterococcus and Escherichia coli by IDEXX), speciation of enterococci isolates, culture independent fecal markers (human-specific HF183 Bacteroides and Enterococcus by quantitative polymerase chain reaction, qPCR), and chemical markers of sewage and wastewater (nutrients, enantiomeric fraction (EF) of propranolol and ethylenediaminetetraacetic acid). To facilitate comparison of these different methods, data are interpreted in a loading (i.e., mass per time) framework that enables a quantitative apportionment of fecal markers and nutrients to specific source waters in the Middle Santa Ana River. Multiple lines of evidence support the hypothesis that Enterococcus in the Middle Santa Ana River originates primarily from in situ growth in streambed sediments, not from significant and persistent sources of untreated human waste. The EF of propranolol of tertiary treated wastewater effluent is in the range (0.42 to 0.71) previously reported for raw sewage, making EF of propranolol an unsuitable marker for fecal pollution, at least at this site. The human fecal marker HF183 Bacteroides was detected at a few sites, although not in a source of disinfected and tertiary treated wastewater effluent. Based on the results presented here and prior experience at other sites in southern California, HF183 Bacteroides would appear to be a candidate marker of fecal contamination for inland waters, although more qPCR measurements in disinfected wastewater effluent are needed to account for variations due to treatment plant performance and other factors. More generally, our results support the notion that regrowth of fecal indicator bacteria (FIB) in river sediments may lead to a decoupling between FIB and pathogen concentrations in the water column and thus limit the utility of FIB as an indicator of recreational waterborne illness in inland waters. PMID- 20839838 TI - Discovery and characterization of silver sulfide nanoparticles in final sewage sludge products. AB - Nanosized silver sulfide (alpha-Ag(2)S) particles were identified in the final stage sewage sludge materials of a full-scale municipal wastewater treatment plant using analytical high-resolution transmission electron microscopy. The Ag(2)S nanocrystals are in the size range of 5-20 nm with ellipsoidal shape, and they form very small, loosely packed aggregates. Some of the Ag(2)S nanoparticles (NPs) have excess S on the surface of the sulfide minerals under S-rich environments, resulting in a ratio of Ag to S close to 1. Considering the current extensive production of Ag NPs and their widespread use in consumer products, it is likely that they are entering wastewater streams and the treatment facilities that process this water. This study suggests that in a reduced, S-rich environment, such as the sedimentation processes during wastewater treatment, nanosized silver sulfides are being formed. This field-scale study provides for the first time nanoparticle-level information of the Ag(2)S present in sewage sludge products, and further suggests the role of wastewater treatment processes on transformation of Ag nanoparticles and ionic Ag potentially released from them. PMID- 20839839 TI - Stable isotopes trace estuarine transformations of carbon and nitrogen from primary- and secondary-treated paper and pulp mill effluent. AB - Stable isotope analysis of a novel combination of carbon and nitrogen pools traced inputs and processing of primary-treated (PE) and secondary-treated effluent (SE) from a paper and pulp mill (PPM) in a temperate Australian estuary. Distinct carbon stable isotope ratios of dissolved organic carbon (DOC) near the PPM outfall indicated large PE and reduced SE inputs of DOC. DOC was remineralized to dissolved inorganic carbon regardless of season, but rates were lower in winter. PE discharge in winter elevated DOC concentrations along much of the estuary. Distinct stable isotope ratios confirmed particulate organic matter (POM) input from PE and SE to the water column and into the sediment. This was relatively localized, indicating rapid POM settlement regardless of season. SE discharge increased nutrient inputs and enhanced algal productivity, particularly in summer when chlorophyll-a concentrations were elevated throughout the estuary. SE discharge reduced pCO(2) from levels associated with PE discharge. However, the estuary remained heterotrophic as subsequent respiration or decomposition of algal material offset reductions in PPM organic matter input. The influence of the PPM was apparent throughout the estuary, demonstrating the ability of anthropogenic inputs, and changes to these, to affect ecosystem functioning. PMID- 20839840 TI - Theoretical investigations on the thermal decomposition mechanism of 5-hydroxy-6 hydroperoxy-5,6-dihydrothymidine in water. AB - The main primary product of DNA oxidation by free radicals is 5-hydroxy-6- hydroperoxy-5,6-dihydrothymidine (5-OH-6-OOH-DHT), whose further degradation can yield the other mutagenic products and amplify the spectrum of DNA damage. In this study, to illustrate the thermal stability of 5-OH-6-OOH-DHT in DNA, the decomposition mechanism of 5-OH-6-OOH-DHT was identified based on the cis-(5R,6S) diastereomer. Optimized structures for all of the stationary points in the gas phase were investigated at the B3LYP/6-31+G(d,p) level of theory. Four pathways were characterized. The decomposition mechanism of 5-OH-6-OOH-DHT was proposed to involve either dehydration for paths A and B or the cleavage of a glycosidic bond for paths C and D. Moreover, to simulate the title reaction in aqueous solution, a water-mediated mechanism and cluster-continuum model, based on the SCRF/CPCM model, were taken into account. The results indicate that the most favorable reaction pathways for paths A and B both involve a sort of eight-membered ring transition structure formed by two (path A) or one (path B) auxiliary water molecules, suggesting that the thermal decomposition of 5-OH-6-OOH-DHT can be significantly facilitated by water molecules. Path A is the most feasible mechanism reported for the decomposition of 5-OH-6-OOH-DHT in the aqueous solution, which is slightly more favorable than path B. However, the unimolecular decomposition mechanisms (paths C and D) both have high-energy barriers and are largely endothermic, suggesting that the cleavage of the N-glycosidic bond via unimolecular decomposition is thermodynamically and kinetically unfavorable. These studies have shed light on the chemical properties of 5-OH-6-OOH-DHT in free radical reactions and thereby have provided new insights into the complex mechanism of oxidative DNA damage. PMID- 20839841 TI - Copper curcuminoids containing anthracene groups: fluorescent molecules with cytotoxic activity. AB - The coordination chemistry of the new curcuminoid ligand, 1,7-(di-9-anthracene 1,6-heptadiene-3,5-dione), abbreviated 9Accm has been studied, resulting in two new copper-9Accm compounds. Compound 1, [Cu(phen)Cl(9Accm)], was synthesized by reacting 9Accm with [Cu(phen)Cl(2)] in a 1:1 ratio (M:L) and compound 2, [Cu(9Accm)(2)], was prepared from Cu(OAc)(2) and 9Accm (1:2). UV-vis, electron paramagnetic resonance (EPR), and superconducting quantum interference device (SQUID) measurements were some of the techniques employed to portray these species; studies on single crystals of free 9Accm, [Cu(phen)Cl(9Accm)] and [Cu(9Accm)(2)(py)] provided detailed structural information about compounds 1 and 2.py, being the first two copper-curcuminoids crystallographically described. In addition the antitumor activity of the new compounds was studied and compared with free 9Accm for a number of human tumor cells. To provide more insight on the mode of action of these compounds under biological conditions, additional experiments were accomplished, including studies on the nature of their interactions with calf thymus DNA by UV-vis titration and Circular Dichroism. These experiments together with DNA-binding studies indicate electrostatic interactions between some of these species and the double helix, pointing out the weak nature of the interaction of the compounds with CT-DNA. The intrinsic fluorescence of the free ligand and both copper compounds provided valuable information over the cellular process and therefore, fluorescence microscopy studies were performed using a human osteosarcoma cell line. Studies in vitro using this technique suggest that the action of these molecules seems to occur outside the nuclei. PMID- 20839842 TI - Photophysical properties of the series fac- and mer-(1-phenylisoquinolinato N?C2')(x)(2-phenylpyridinato-N?C2')(3-x)iridium(III) (x = 1-3). AB - The photophysical properties of tris-cyclometalated iridium(III) complexes have been probed by chemical and geometric variation through the series fac- and mer Ir(piq)(x)(ppy)(3-x) (x = 1-3; piq = 1-phenylisoquinolinato-N(?)C(2'), ppy = 2 phenylpyridinato-N(?)C(2')). The phosphorescent decays were recorded in solution at 295 K and in polymer films from 2 to 295 K. In the heteroleptic complexes, emission occurs based solely on the piq ligand(s), at least by the nanosecond time scale, as its excited states are the lowest energy. Because fac-Ir(piq)(3) and fac-Ir(ppy)(3) possess practically the same oxidation potential, comparison of photophysical properties through the series fac-Ir(piq)(x)(ppy)(3-x) (x = 1-3) revealed the effects of having one, two, or three emissive piq ligands with no confounding effects from differences in electron withdrawing or donating properties between the spectator ppy ligands and the piq ligands. Effects of placement of piq ligands in different coordination geometries were elucidated by comparisons to the mer series. PMID- 20839843 TI - One pot synthesis of disilatricycloheptene analogue and Jutzi's disilene. AB - The reaction of LiN(TMS)(2) (TMS = Me(3)Si) with dichlorosilane (Me(5)C(5))SiHCl(2) (1) in a molar ratio of 3:2 at ambient temperature leads to the formation of the disilatricycloheptene analogue (2). Compound 2 consists of three (three-, four-, and five-membered) fused rings that together form a six membered heterocyclic ring. However, the reaction of 1 with KN(TMS)(2) affords the formation of disilene of composition E-[(TMS)(2)N](eta(1) Me(5)C(5))Si?Si(eta(1)-Me(5)C(5))[N(TMS)(2)] (3) in good yield. This is a convenient and facile route for the synthesis of 3 in a single step and supports the formation of (Me(5)C(5))SiN(TMS)(2) as an intermediate. PMID- 20839844 TI - Tunable phosphorescent NIR oxygen indicators based on mixed benzo- and naphthoporphyrin complexes. AB - A series of pi-extended phosphorescent palladium(II) and platinum(II) porphyrin complexes were synthesized, in which additional benzene rings are fused radially onto at least one of the four peripheral benzo groups. The photophysical properties of the metalloporphyrins palladium(II)-meso-tetra-(4 fluorophenyl)mononaphthotribenzoporphyrin (Pd1NF), cis-palladium(II)-meso-tetra (4-fluorophenyl)dibenzodinaphthoporphyrin (Pd2NF), and palladium(II)-meso-tetra (4-fluorophenyl)monobenzotrinaphthoporphyrin (Pd3NF) and the corresponding platinum(II) compounds (Pt1NF, cis-Pt2NF, Pt3NF) were investigated. The compounds under investigation absorb intensively in the near-infrared region (628-691 nm) and emit at room temperature at 815-882 nm. Phosphorescence quantum yields of the platinum(II) porphyrins range from 25 to 53% with luminescence decay times of 21 to 44 MUs in deoxygenated toluene solutions at room temperature. The corresponding palladium(II) complexes exhibit quantum yields in the range of 7 to 18% with lifetimes of 106 to 206 MUs. Density functional theory (DFT) calculations revealed nonplanar geometries for all complexes and corroborate the absorption characteristics. The subsequent pi extension of the porphyrin system leads to near-infrared absorbing oxygen indicators with tailor-made luminescence properties as well as tunable oxygen sensitivity. PMID- 20839845 TI - "Hexagonal molybdenum trioxide"--known for 100 years and still a fount of new discoveries. AB - In 1906, the preparation of "molybdic acid hydrate" was published by Arthur Rosenheim. Over the past 40 years, a multitude of isostructural compounds, which exist within a wide phase range of the system MoO3-NH3-H2O, have been published. The reported molecular formulas of "hexagonal molybdenum oxide" varied from MoO3 to MoO3.0.33NH3 to MoO3.nH2O (0.09 <= n <= 0.69) to MoO3.mNH3.nH2O (0.09 <= m <= 0.20; 0.18 <= n <= 0.60). Samples, prepared by the acidification route were investigated using thermal analysis coupled online to a mass spectrometer for evolved gas analysis, X-ray powder diffraction, Fourier transform infrared, Raman, magic-angle-spinning 1H- and 15N NMR spectroscopy, and incoherent inelastic neutron scattering. A comprehensive characterization of these samples will lead to a better understanding of their structure and physical properties as well as uncover the underlying relationship between the various compositions. The synthesized polymeric parent samples can be represented by the structural formula (NH4)(xinfinity)(3)[Mo(y square 1-y)O(3y)(OH)(x)(H2O)(m-n)].nH2O with 0.10 <= x <= 0.14, 0.84 <= y <= 0.88, and m + n >= 3 - x - 3y. The X-ray study of a selected monocrystal confirmed the presence of the well-known 3D framework of edge- and corner-sharing MoO6 octahedra. The colorless monocrystal crystallizes in the hexagonal system with space group P6(3)/m, Z = 6, and unit cell parameters of a = 10.527(1) A, c = 3.7245(7) A, V = 357.44(8) A3, and rho = 3.73 g.cm(-3). The structure of the prepared monocrystal can best be described by the structural formula (NH4)(0.13infinity)(3)[Mo(0.86 square 0.14)O2.58(OH)0.13(H2O)(0.29 n)].nH2O, which is consistent with the existence of one vacancy (square) for six molybdenum sites. The sample MoO3.0.326NH3.0.343H2O, prepared by the ammoniation of a partially dehydrated MoO3.0.170NH3.0.153H2O with dry gaseous ammonia, accommodates NH3 in the hexagonal tunnels, in addition to [NH4]+ cations and H2O. The "chimie douce" reaction of MoO3.0.155NH3.0.440H2O with a 1:1 mixture of NO/NO2 at 100 degrees C resulted in the synthesis of MoO3.0.539H2O. This material is of great interest as a host of various molecules and cations. PMID- 20839846 TI - The reaction chemistry of plutonyl(VI) chloride complexes with triphenyl phosphineoxide and triphenyl phosphinimine. AB - The reaction between Ph(3)PO dissolved in acetone and "PuO(2)Cl(2)" in dilute HCl resulted in the formation of [PuO(2)Cl(2)(Ph(3)PO)(2)]. Crystallographic characterization of the acetone solvate revealed the expected axial trans plutonyl dioxo, with trans Cl and Ph(3)PO in the equatorial plane. Spectroscopic analyses ((31)P NMR, (1)H NMR, and vis/nIR) indicate the presence of both cis and trans isomers in solution, with the trans isomer being more stable. Confirmation of the higher stability of the trans versus cis isomers for [AnO(2)Cl(2)(Ph(3)PO)(2)] (An = U and Pu) was obtained through quantum chemical computational analysis, which also reveals the Pu-O(TPPO) bond to be more ionic than the U-O(TPPO) bond. Slight variation in reaction conditions led to the crystallization of two further minor products, [PuO(2)(Ph(3)PO)(4)][ClO(4)](2) and cis-[PuCl(2)(Ph(3)PO)(4)], the latter complex revealing the potential for reduction to Pu(IV). In addition, the reaction of Ph(3)PNH with [PuO(2)Cl(2)(thf)(2)](2) in anhydrous conditions gave evidence for the formation of both cis- and trans-[PuO(2)Cl(2)(Ph(3)PNH)(2)] in solution (by (31)P NMR). However, the major reaction pathway involved protonation of the ligand with the crystallographic characterization of [Ph(3)PNH(2)](2)[PuO(2)Cl(4)]. We believe that HCl/SiMe(3)Cl carried through from the small scale preparation of [PuO(2)Cl(2)(thf)(2)](2) was the source of both protons and chlorides. The fact that this chemistry was significantly different from previous uranium studies, where cis-/trans-[UO(2)Cl(2)L(2)] (L = Ph(3)PO or Ph(3)PNH) were the only products observed, provides further evidence of the unique challenges and opportunities associated with the chemistry of plutonium. PMID- 20839847 TI - X-ray absorption spectroscopy and reactivity of thiolate-ligated Fe(III)-OOR complexes. AB - The reaction of a series of thiolate-ligated iron(II) complexes [Fe(II)([15]aneN(4))(SC(6)H(5))]BF(4) (1), [Fe(II)([15]aneN(4))(SC(6)H(4)-p Cl)]BF(4) (2), and [Fe(II)([15]aneN(4))(SC(6)H(4)-p-NO(2))]BF(4) (3) with alkylhydroperoxides at low temperature (-78 degrees C or -40 degrees C) leads to the metastable alkylperoxo-iron(III) species [Fe(III)([15]aneN(4))(SC(6)H(5))(OOtBu)]BF(4) (1a), [Fe(III)([15]aneN(4))(SC(6)H(4)-p-Cl)(OOtBu)]BF(4) (2a), and [Fe(III)([15]aneN(4))(SC(6)H(4)-p-NO(2))(OOtBu)]BF(4) (3a), respectively. X-ray absorption spectroscopy (XAS) studies were conducted on the Fe(III)-OOR complexes and their iron(II) precursors. The edge energy for the iron(II) complexes (~7118 eV) shifts to higher energy upon oxidation by ROOH, and the resulting edge energies for the Fe(III)-OOR species range from 7121-7125 eV and correlate with the nature of the thiolate donor. Extended X-ray absorption fine structure (EXAFS) analysis of the iron(II) complexes 1-3 in CH(2)Cl(2) show that their solid state structures remain intact in solution. The EXAFS data on 1a-3a confirm their proposed structures as mononuclear, 6-coordinate Fe(III)-OOR complexes with 4N and 1S donors completing the coordination sphere. The Fe-O bond distances obtained from EXAFS for 1a-3a are 1.82-1.85 A, significantly longer than other low-spin Fe(III)-OOR complexes. The Fe-O distances correlate with the nature of the thiolate donor, in agreement with the previous trends observed for nu(Fe-O) from resonance Raman (RR) spectroscopy, and supported by optimized geometries obtained from density functional theory (DFT) calculations. Reactivity and kinetic studies on 1a- 3a show an important influence of the thiolate donor. PMID- 20839848 TI - Molecular dynamics simulation of protein adsorption at fluid interfaces: a comparison of all-atom and coarse-grained models. AB - The adsorption of LTP at the decane-water interface was modeled using all-atom and coarse-grained (CG) molecular dynamics simulations. The CG model (300 ns simulation, 1200 ns scaled time) generates equilibrium adsorbed conformations in about 12 h, whereas the equivalent 1200 ns simulation would take about 300 days for the all-atom model. In both models the LTP molecule adsorbs with alpha helical regions parallel to the interface with an average tilt angle normal to the interface of 73 degrees for the all-atom model and 62 degrees for the CG model. In the all-atom model, the secondary structure of the LTP is conserved upon adsorption. A considerable proportion of the N-terminal loop of LTP can be found in the decane phase for the all-atom model, whereas in the CG model the protein only penetrates as far as the mixed water-decane interfacial region. This difference may arise due to the different schemes used to parametrize force field parameters in the two models. PMID- 20839849 TI - Unstitching the nanoscopic mystery of zeolite crystal formation. AB - A molecular-scale understanding of crystal growth is critical to the development of important materials such as pharmaceuticals, semiconductors and catalysts. Only recently has this been possible with the advent of atomic force microscopy that permits observation of nanoscopic features on solid surfaces under a liquid or solution environment. This allows in situ measurement of important chemical transformations such as crystal growth and dissolution. Further, the microscope can access not only an accurate height measurement of surface topography, important to deduce structural elements, but also the forces involved during nanoscopic processes. We have discovered that it is possible to use these features to "illuminate" critical nanoscopic chemical events at crystal surfaces and at the same time extract the associated energies and unstitch the details of the stepwise mechanism of growth and dissolution. This approach has been developed using nanoporous crystals of the heterogeneous catalyst zeolite L; however, in principle the approach could be adapted to many crystal growth problems. PMID- 20839850 TI - Comprehensive appraisal of the extracellular proteins from a monoderm bacterium: theoretical and empirical exoproteomes of Listeria monocytogenes EGD-e by secretomics. AB - Defined as proteins actively transported via secretion systems, secreted proteins can have radically different subcellular destinations in monoderm (Gram-positive) bacteria. From degradative enzymes in saprophytes to virulence factors in pathogens, secreted proteins are the main tools used by bacteria to interact with their surroundings. The etiological agent of listeriosis, Listeria monocytogenes, is a Gram-positive facultative intracellular foodborne pathogen, whose ecological niche is the soil and as such should be primarily considered as a ubiquitous saprophyte. Recent advances on protein secretion systems in this species prompted us to investigate the exoproteome. First, an original and rational bioinformatic strategy was developed to mimic the protein exportation steps leading to the extracellular localization of secreted proteins; 79 exoproteins were predicted as secreted via Sec, 1 exoprotein via Tat, 4 bacteriocins via ABC exporters, 3 exoproteins via holins, and 3 exoproteins via the WXG100 system. This bioinformatic analysis allowed for defining a databank of the mature protein set in L. monocytogenes, which was used for generating the theoretical exoproteome and for subsequent protein identification by proteomics. 2-DE proteomic analyses were performed over a wide pI range to experimentally cover the largest protein spectrum possible. A total of 120 spots could be resolved and identified, which corresponded to 50 distinct proteins. These exoproteins were essentially virulence factors, degradative enzymes, and proteins of unknown functions, which exportation would essentially rely on the Sec pathway or nonclassical secretion. This investigation resulted in the first comprehensive appraisal of the exoproteome of L. monocytogenes EGD-e based on theoretical and experimental secretomic analyses, which further provided indications on listerial physiology in relation with its habitat and lifestyle. The novel and rational strategy described here is generic and has been purposely designed for the prediction of proteins localized extracellularly in monoderm bacteria. PMID- 20839852 TI - Implementation of p22 viral capsids as nanoplatforms. AB - Viral capsids are dynamic macromolecular machines which self-assemble and undergo concerted conformational changes during their life cycle. We have taken advantage of the inherent structural flexibility of viral capsids and generated two morphologically different types of viral nanoplatforms from the bacteriophage P22 capsids. Their interior surfaces were genetically manipulated for site-specific attachment of a biotin linker. The extent of internal modifications in each capsid form was characterized by high-resolution mass spectrometry and the analyses revealed that the reactivity of the genetically introduced residues located on the internal surface changes according to the structural transformation of the capsid. Internally modified capsids having 10 nm diameter pores at the 12 icosahedral vertices, so-called wiffle-balls (WB), exhibited the capability to entrap the large tetrameric protein complex streptavidin via the biotin linker anchored onto the interior surface of the WB. PMID- 20839851 TI - Novel insights into the global proteome responses of insulin-producing INS-1E cells to different degrees of endoplasmic reticulum stress. AB - Exposure of insulin-secreting beta-cells to inflammatory cytokines or high concentrations of free fatty acids, factors involved in the pathogenesis of type 1 and type 2 diabetes, leads to endoplasmic reticulum (ER) stress, beta-cell dysfunction, and eventually apoptotic beta-cell death. The aim of this study was to investigate the impact of ER stress on beta-cells at the protein level to evaluate the contribution of post-transcriptional and post-translational changes in ER stress-induced beta-cell damage. INS-1E cells were exposed in vitro to the ER-stress inducer cyclopiazonic acid (CPA) at two concentrations, and protein changes were evaluated using 2D-DIGE. CPA, 25 MUM, led to massive apoptosis, accompanied by a near complete protein translation shut-down. CPA, 6.25 MUM, led to adaptation of the beta-cells to ER stress. Identification of the differentially expressed proteins in the two conditions led to the discovery of a clear pattern of defense pathways, with post-translational modifications playing a crucial role. Key alterations included inhibition of insulin translation and post-translational modifications in ER chaperones HYOU1 and HSPA5. Also, a central role for 14-3-3 proteins is suggested. In conclusion, INS-1E cells are highly sensitive to ER stress, leading to important post-transcriptional and post translational modifications that may contribute to beta-cell dysfunction and death. PMID- 20839854 TI - The topotactic reduction of Sr3Fe2O5Cl2-square planar Fe(II) in an extended oxyhalide. AB - The topotactic reduction of the oxychloride Sr(3)Fe(2)O(5)Cl(2) with LiH results in the formation of Sr(3)Fe(2)O(4)Cl(2). Neutron powder diffraction data show that Sr(3)Fe(2)O(4)Cl(2) adopts a body-centered tetragonal crystal structure (I4/mmm, a = 4.008(1) A, c = 22.653(1) A at 388 K) with anion vacancies located within the SrO layer of the phase. This leads to a structure consisting of infinite sheets of corner-sharing Fe(II)O(4) square planes. Variable-temperature neutron diffraction data show that Sr(3)Fe(2)O(4)Cl(2) adopts G-type antiferromagnetic order below T(N) ~ 378(10) K with an ordered moment of 2.81(9) MU(B) per iron center at 5 K consistent with the presence of high-spin Fe(II). The observed structural and chemical selectivity of the reduction reaction is discussed. The contrast between the structure of Sr(3)Fe(2)O(4)Cl(2) and the isoelectronic all-oxide analogue (Sr(3)Fe(2)O(5)) suggests that by careful selection of substrate phases, the topotactic reduction of complex transition metal oxychlorides can lead to the preparation of novel anion-deficient phases with unique transition metal-oxygen sublattices which cannot be prepared via the reduction of all-oxide substrates. PMID- 20839855 TI - Controlled production of droplets by in-flight electrospraying. AB - Diameter, velocity, and charge measurements of progeny droplets produced in flight by a millimeter-size parent drop subjected to electric and ionic fields are reported. Different drop breakup modes were studied using phase doppler anemometry and high-speed digital photography. Drop breakup occurred in applied electric (~1 kV/cm to ~10 kV/cm) and ionic (~10(13)/m(3) to ~10(15)/m(3)) fields that were generated using a DC-corona discharge in a needle-plate configuration. Effects of the external electric field and the diameter of the parent drop are considered. Several models are summarized, including simulations of the electrohydrodynamics of the corona discharge, electrocapillary stability analysis of the jet, and progeny droplets mobility analysis. Using experimental and model results, the charge of progeny drops is shown to vary as the three-halves power of their diameter. PMID- 20839856 TI - Copper coated silica nanoparticles for odor removal. AB - Copper species coated silica nanoparticles (CuOXS) were synthesized for odor removal application. Coating with copper increased the capacity of silica nanoparticles for eliminating a model odor-ethyl mercaptan. Surface area, pore size distribution, and electron paramagnetic resonance spectroscopy analyses indicated that, at lower copper concentrations, copper species preferentially adsorb in 20 A pores of silica. These copper species in a dispersed state are effective in catalytic removal of ethyl mercaptan. The best performance of copper coated silica nanoparticles was achieved at a copper concentration of 3 wt %, at which all 20 A nanopores were filled with isolated copper species. At higher copper loading, copper species are present as clusters on silica surfaces, which were found to be less effective in removing ethyl mercaptan. Gas chromatography experiments were carried out to verify catalytic conversion of ethyl mercaptan to diethyl disulfide by CuOXS particles. The present study suggests that the nature of the copper species and their site of adsorption, as well as state of dispersion, are important parameters to be considered for catalytic removal of sulfur-containing compounds. These parameters are critical for designing high performance catalytic copper-coated silica nanoparticles for applications such as deodorization, removal of sulfur compounds from crude oil, hydrogenation, and antimicrobial activity. PMID- 20839857 TI - Passive secondary biological treatment systems reduce estrogens in dairy shed effluent. AB - Steroid estrogens are found at high concentrations in untreated dairy shed effluents. Reduction of estrogenic activity and steroid estrogen concentrations was assessed in two systems used to treat dairy shed effluents: the two-pond system and the advanced pond system. Both include anaerobic and aerobic treatment stages. Samples of effluent were collected from the systems and analyzed for free estrogens, conjugated estrogens and total estrogenic activity using E-Screen assay. Both systems showed increases of up to 8000% in aqueous free estrogens and estrogenic activity after anaerobic treatment, followed by decreases after aerobic treatment (36-83%). The complete systems decreased total steroid estrogen concentrations by 50-100% and estrogen activity by 62-100%, with little difference between systems. Removal rates were lower in winter for both systems. Final effluents from the advanced pond system contained total estrogens at <15 1400 ng/L and estrogenic activity at 3.2-43 ng/L. Final effluent from the two pond system contained total estrogens at <15-300 ng/L and estrogenic activity at 3.3-25 ng/L. At times the final effluent EEQs exceeded guideline values for protection of freshwater fish and suggest further treatment may be required. PMID- 20839858 TI - The plight of the bees. PMID- 20839859 TI - Microscale hydrodynamic analysis of aerobic granules in the mass transfer process. AB - The internal structure of aerobic granules has a significant impact on the hydrodynamic performance and mass transfer process, and severely affects the efficiency and stability of granules-based reactors for wastewater treatment. In this study, for the first time the granule complex structure was correlated with the hydrodynamic performance and substrates reactions process. First, a series of multiple fluorescence stained confocal laser scanning microscopy images of aerobic granules were obtained. Then, the form and structure of the entire granule was reconstructed. A three-dimensional computational fluid dynamics study was carried out for the hydrodynamic analysis. Two different models were developed on the basis of different fluorescence stained confocal laser scanning microscopy images to elucidate the roles of the granule structure in the hydrodynamic and mass transfer processes of aerobic granules. The fluid flow behavior, such as the velocity profiles, the pathlines and hence the hydrodynamic drag force, exerted on the granule in a Newtonian fluid, was studied by varying the Reynolds number. Furthermore, the spatial distribution of dissolved nutrients (e.g., oxygen) was acquired by solving the convection-diffusion equations on the basis of the reconstructed granule structure. This study demonstrates that the reconstructed granule model could offer a better understanding to the mass transfer process of aerobic granules than simply considering the granule structure to be homogeneous. PMID- 20839860 TI - Deactivation of metal chlorides by alkaline compounds inhibits formation of chlorinated aromatics. AB - The inhibitory mechanisms of alkaline compounds on the formation of chlorinated aromatic (aromatic-Cl) compounds in postcombustion fly ash from thermal processes such as municipal solid waste (MSW) incineration are not fully understood. Here, we report quantitative and X-ray spectroscopic evidence that deactivation of metal chloride promoter activity by alkaline compounds inhibits the formation of aromatic-Cl compounds. The formation of aromatic-Cl compounds such as chlorobenzenes and polychlorinated biphenyls in real MSW fly ash was inhibited by the addition of NaOH, Ca(OH)(2), or NaHCO(3), either dry or in solution, with the fly ash. With optimal conditions, the formation of aromatic-Cl compounds was inhibited by more than 95% in comparison with formation in reheated raw MSW fly ash. We prepared simplified model fly ash samples to estimate the influence of alkaline compounds on trace Cu, Fe, Pb, and Zn chlorides, which strongly promote aromatic-Cl compound formation. More than 99% inhibition was observed in some model samples. Cl K-edge X-ray absorption and X-ray diffraction provided clear evidence of promoter deactivation, as NaOH or NaHCO(3) changed to NaCl, and Ca(OH)(2) changed to CaCl(2) or CaClOH by reaction with the metal chlorides. NaOH was the most reactive and useful of the three alkaline compounds tested. We recommend deactivation of metal chlorides as an environmentally friendly method of inhibiting the formation of aromatic-Cl compounds, with the added benefit of changing the alkaline compounds and metal chlorides into harmless chemicals such as NaCl and metal oxides. PMID- 20839861 TI - Hybrid nanocomposites: advanced nonlinear method for calculating key kinetic parameters of complex cure kinetics. AB - Complex cure kinetics involved in the elaboration of organic/inorganic hybrid silicate nanocomposites based on diglycidyl ether of bisphenol A (DGEBA), 1,3 phenylenediamine (m-PDA), and modified montmorillonite (MMTm) clay have been studied. An advanced isoconversional method has been applied to nonisothermal data in order to evaluate cure kinetic parameters. A new method based on nonlinear optimization was proposed to compute nonisothermal kinetic parameters avoiding complex optimization techniques. The objective is to obtain kinetic parameters rather than modeling values in order to give more insight into the elucidation of complex cure mechanisms. Key kinetic parameters of cure have been computed according to this method. It appears that the reaction mechanism changes if MMTm is added to the curing system. The results reveal an increase of the efficiency of collisions in presence of MMTm at the beginning of the cure and an increase of the frequency of diffusion jumps at the later stage of the reaction. PMID- 20839862 TI - Structure and valency of a cobalt-phosphate water oxidation catalyst determined by in situ X-ray spectroscopy. AB - A water oxidation catalyst generated via electrodeposition from aqueous solutions containing phosphate and Co(2+) (Co-Pi) has been studied by in situ X-ray absorption spectroscopy. Spectra were obtained for Co-Pi films of two different thicknesses at an applied potential supporting water oxidation catalysis and at open circuit. Extended X-ray absorption fine structure (EXAFS) spectra indicate the presence of bis-oxo/hydroxo-bridged Co subunits incorporated into higher nuclearity clusters in Co-Pi. The average cluster nuclearity is greater in a relatively thick film (~40-50 nmol Co ions/cm(2)) deposited at 1.25 V vs NHE than in an extremely thin film (~3 nmol Co ions/cm(2)) deposited at 1.1 V. X-ray absorption near edge structure (XANES) spectra and electrochemical data support a Co valency greater than 3 for both Co-Pi samples when catalyzing water oxidation at 1.25 V. Upon switching to open circuit, Co-Pi undergoes a continuous reduction due to residual water oxidation catalysis, as indicated by the negative shift of the edge energy. The rate of reduction depends on the average cluster size. On the basis of structural parameters extracted from fits to the EXAFS data of Co-Pi with two different thicknesses and comparisons with EXAFS spectra of Co oxide compounds, a model is proposed wherein the Co oxo/hydroxo clusters of Co-Pi are composed of edge-sharing CoO(6) octahedra, the structural motif found in cobaltates. Whereas cobaltates contain extended planes of CoO(6) octahedra, the Co-Pi clusters are of molecular dimensions. PMID- 20839863 TI - Deposition history of brominated flame retardant compounds in an ice core from Holtedahlfonna, Svalbard, Norway. AB - Brominated flame retardants (BFRs) have been found in Arctic wildlife, lake sediment, and air. To identify the atmospheric BFR deposition history on Svalbard, Norway, we analyzed 19 BFRs, including hexabromocyclododecane (HBCD), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), decabromodiphenyl ethane (DBDPE), pentabromoethylbenzene (PBEB), and 15 polybrominated diphenyl ether congeners (PBDE) in the upper 34 m of an ice core (representing 1953-2005) from Holtedahlfonna, the western-most ice sheet on Svalbard. All of the non-PBDE compounds were detected in nearly continuous profiles in the core. Seven PBDEs were not observed above background (28, 47, 66, 100, 99, 154, 153), while 4 were found in 1 or 2 of 6 segments (17, 85, 138, 183). BDEs-49, 71, 190, 209 had nearly continuous profiles but only BDE-209 in large amounts. The greatest inputs were HBCD and BDE-209, 910, and 320 pg cm(-2) yr(-1) from 1995-2005. DBDPE, BTBPE, and PBEB show nearly continuous input growth in recent core segments, but all were <6 pg cm(-2) yr(-1). Long-range atmospheric processes may have moved these particle-bound BFRs to the site, probably during the Arctic haze season. Average air mass trajectories over 10 years show >75% of atmospheric flow to Holtedahlfonna coming from Eurasia during haze periods (March and April). PMID- 20839864 TI - Dynamic presentation of immobilized ligands regulated through biomolecular recognition. AB - To mimic the dynamic regulation of signaling ligands immobilized on extracellular matrices or on the surfaces of neighboring cells for guidance of cell behavior and fate selection, we have harnessed biomolecular recognition in combination with polymer engineering to create dynamic surfaces on which the accessibility of immobilized ligands to cell surface receptors can be reversibly interconverted under physiological conditions. The cell-adhesive RGD peptide is chosen as a model ligand. RGD is fused to the C-terminus of a leucine zipper domain A, and this fusion polypeptide is immobilized on surfaces through a residue at the N terminus. The immobilized RGD can be converted from a cell-accessible to a cell inaccessible state by addition of a conjugate of poly(ethylene) glycol (PEG) and another leucine zipper domain B (B-PEG). Heterodimerization between A and B allows coimmobilization of the PEG, which shields RGD from access by cells. The shielded RGD can be converted back to a cell-accessible state by addition of nonimmobilized polypeptide A, which competes with the immobilized A for binding to B-PEG and removes B-PEG from the surface. This molecular design offers several advantages: the interconversion is reversible; the ligand remains immobilized during dynamic regulation so that cells are not exposed to the soluble form of the ligand that potentially has detrimental effects; the precision of the on/off states is assured by the molecular-level uniformity of the ligand and PEG coimmobilized through leucine zipper heterodimerization. The method can be readily adapted for dynamic regulation of other immobilized bioactive ligands of interest. PMID- 20839865 TI - Fine-tuning the morphology of self-assembled nanostructures of propargyl ammonium based amphiphiles. AB - N-Methyl-N-(pentacosa-10,12-diyn)-propargylamine organizes itself into an unusual supramolecular pH- and thermo-responsive system. Studies have showed that submillimetric length hollow laths form this unique structure in the presence of hydrochloric acid. Specific chemical modifications on the initial molecule and small-angle neutron scattering experiments were performed to understand the structure of this system. Our results allow us to suggest a possible structure of the laths. PMID- 20839866 TI - Model amyloid peptide B18 monomer and dimer studied by replica exchange molecular dynamics simulations. AB - Peptide misfolding and aggregation are the early steps during the formation of amyloid fibrils. Understanding these processes in detail is crucial for the development of therapeutic strategies against amyloid diseases. Here I present temperature replica exchange molecular dynamics (TREMD) simulations of the model amyloid peptide B18 in the mono- and dimeric states in explicit aqueous solution. Both the monomer and the dimer involve beta-sheets consisting of different residues in different registers with comparable statistical weight. The dimer forms intra- as well as intermolecular beta-sheets. The average beta-sheet content is in agreement with previous estimates from circular dichroism (CD) spectra for monomers and is lower for dimers. The tendency of B18 to form beta sheets likely contributes to its fibrillogenic property. For both the monomer and the dimer, individual peptides form U-shaped or other partially collapsed conformations. Combined with data from electron microscopy, this suggests that for higher aggregates during fibrillization B18 undergoes a transition from U shaped to outstretched conformations. The tendency of B18 to form U-shaped conformations, intramolecular beta-sheets, and intermolecular beta-sheets with different register will contribute to the lag phase for fibril formation. PMID- 20839868 TI - Spectroscopic properties of curcumin: orientation of transition moments. AB - Curcumin, a naturally occurring yellow-orange pigment with potent antioxidant and antitumor properties, has been attracting researchers from a wide range of fields including chemistry, spectroscopy, biology, and medicine. Ultrafast excited-state processes such as solvation and excited-state intramolecular hydrogen atom transfer (ESIHT) make curcumin an attractive agent for photodynamic therapy. In this report we present studies of linear dichroism and fluorescence anisotropy in oriented and isotropic media. The results show transition moments (long wavelength absorption and emission) oriented along the long molecular axis. Comparison of linear dichroism and excitation anisotropy in oriented and isotropic media suggests that excited-state intramolecular hydrogen atom transfer is probably associated with intramolecular conformational changes that can be constrained in highly stretched poly(vinyl alcohol) (PVA) film. PMID- 20839869 TI - Asterogynins: secondary metabolites from a Costa Rican endophytic fungus. AB - An endophytic fungus isolated from the small palm Asterogyne martiana produced two unusual steroid-like metabolites, asterogynin A (1) and asterogynin B (2), along with the known compounds viridiol (3) and viridin (4). Asterogynins A and B were characterized by NMR and MS spectroscopic analysis. PMID- 20839870 TI - LC-DAD-ESI/MS(n) determination of direct condensation flavanol-anthocyanin adducts in pressure extracted pomegranate (Punica granatum L.) juice. AB - Pomegranate (Punica granatum L.) juice, obtained by pressure extraction of the whole fruit, has been analyzed for its flavanol-anthocyanin adduct content using reversed-phase liquid chromatography with diode array detection, coupled to mass spectrometry (ion trap) with electrospray ionization (HPLC-DAD-ESI/MS(n)), operating in positive ion mode. A total of 35 dimers have been detected, consisting of mono- and disubstituted hexoside derivatives of the adducts between the flavan-3-ols (epi)gallocatechin, (epi)catechin and (epi)afzelechin and the anthocyanidins delphinidin, cyanidin and pelargonidin. In addition, evidence is given for the presence of additional anthocyanin-flavanol adducts in this juice. PMID- 20839871 TI - Agricultural impacts of glyphosate-resistant soybean cultivation in South America. AB - In the 2009/2010 growing season, Brazil was the second largest world soybean producer, followed by Argentina. Glyphosate-resistant soybeans (GRS) are being cultivated in most of the soybean area in South America. Overall, the GRS system is beneficial to the environment when compared to conventional soybean. GRS resulted in a significant shift toward no-tillage practices in Brazil and Argentina, but weed resistance may reduce this trend. Probably the highest agricultural risk in adopting GRS in Brazil and South America is related to weed resistance due to use of glyphosate. Weed species in GRS fields have shifted in Brazil to those that can more successfully withstand glyphosate or to those that avoid the time of its application. Five weed species, in order of importance, Conyza bonariensis (L.) Cronquist, Conyza canadensis (L.) Cronquist, Lolium multiflorum Lam., Digitaria insularis (L.) Mez ex Ekman, and Euphorbia heterophylla L., have evolved resistance to glyphosate in GRS in Brazil. Conyza spp. are the most difficult to control. A glyphosate-resistant biotype of Sorghum halepense L. has evolved in GRS in Argentina and one of D. insularis in Paraguay. The following actions are proposed to minimize weed resistance problem: (a) rotation of GRS with conventional soybeans in order to rotate herbicide modes of action; (b) avoidance of lower than recommended glyphosate rates; (c) keeping soil covered with a crop or legume at intercrop intervals; (d) keeping machinery free of weed seeds; and (d) use of a preplant nonselective herbicide plus residuals to eliminate early weed interference with the crop and to minimize escapes from later applications of glyphosate due to natural resistance of older weeds and/or incomplete glyphosate coverage. PMID- 20839872 TI - Structure-activity relationship in olefin polymerization catalysis: is entropy the key? AB - Activation parameters for propene polymerization mediated by a bis(phenoxyamine)Zr-dibenzyl catalyst in combination with MAO have been measured experimentally and calculated by DFT; experiment and calculation consistently indicate that the entropic term is the most important reason for the low chain propagation rate with this system. Based on this finding and a review of literature data on a variety of olefin polymerization catalysts, we propose a strong correlation between the propagation rate and how catalysts deal with the entropy loss of monomer capture. PMID- 20839873 TI - Density functional theory study of ethanol decomposition on 3Ni/alpha-Al2O3(0001) surface. AB - We have investigated the decomposition of ethanol (EtOH) on a 3Ni/alpha Al2O3(0001) surface using periodic density functional theory calculations. A triangular Ni trimer doped on a 2 * 2 alpha-Al2O3(0001) surface was used to represent the 3Ni/alpha-Al2O3(0001) surface. We considered several possible pathways for EtOH decomposition over the 3Ni/alpha-Al2O3(0001) surface, including dehydrogenation and C-C bond cleavage. Our calculated results indicated that (i) the 3Ni/alpha-Al2O3(0001) surface possesses high activity to inhibit coke formation and (ii) the CH2CH2O((a)) -> CH2CHO((a)) + H((a)) reaction is the rate determining step for the overall reaction [CH3CH2OH((a)) -> CH(2(a)) + CO((a)) + 4 H((a))] with an energy barrier of 1.20 eV. One feasible channel leading to C-C bond cleavage is weakening of the C-C bond in the stable CH2CO intermediate via transformation of the adsorbed structure to a metastable structure, thereby increasing the coordination number of the two C atoms to the Ni trimer. In addition, we also investigated the nature of the metal-ethanol bonding through scrutiny of density of states (DOS) and electron density difference contour plots. The DOS analysis allowed us to characterize the state interactions between ethanol and the surfaces; the electron density difference plots provide evidence that is consistent with the prediction from DOS analysis. PMID- 20839874 TI - A stereochemical glimpse of the active site of the 8-17 deoxyribozyme from iodine mediated cross-links formed with the substrate's scissile site. AB - A powerful approach for defining the active site of a complexly folded ribozyme or deoxyribozyme (DNAzyme) is to map the contact cross-links formed between the substrate's reaction site and component residues of the enzyme. Here, we use a novel iodine- and phosphorothioate-mediated method for generating contact cross links to define key residues of the 8-17 DNAzyme most proximal to the scissile phosphodiester of its bound substrate. Substitution of a phosphorothioate for the scissile phosphodiester renders that site chiral. The cross-linking maps we obtain using chirally resolved substrates give us, for the first time, a stereochemical glimpse of the 8-17's active site. Thus, we identifiy the asymmetric positioning of the DNAzyme's C13 residue, which is catalytically indispensable. We also identify, for the first time, the previously unheralded C3 residue. On the basis of the latter's proximal location to the cleavage site and the impact of its mutation on the DNAzyme's catalytic rate, we hypothesize it may play an acid-base role in the catalysis of the 8-17 DNAzyme. Overall, the approach described in this paper should find wide application in the study of the tertiary folding of RNAs and DNAs, as well as of complexes formed by RNA and DNA with proteins and other ligands. PMID- 20839875 TI - Intercluster exchange pathways in polymer-chain molecular magnets Cu(hfac)2L(R) unveiled by electron paramagnetic resonance. AB - Polymer-chain complexes Cu(hfac)(2)L(R) represent an interesting type of molecular magnets exhibiting thermally induced and light-induced magnetic switching, in many respects similar to a spin crossover. In the majority of these compounds the polymer chain consists of alternating one- and three-spin units composed of copper(II) ions and nitronyl nitroxides. The principal one dimensional structure of the complexes has previously been assumed to play a key role in the observed magnetic anomalies. Using Q-band electron paramagnetic resonance (EPR) spectroscopy, we have reliably demonstrated that these complexes are indeed one-dimensional in the sense of the topology of their exchange channels; however, the magnetic chains spread across the structural polymer chains and consist solely of spin triads of nitroxide-copper(II)-nitroxide. Using four selected examples of complexes Cu(hfac)(2)L(R), we have found the exchange coupling values between spin triads of neighboring polymer chains to range from <1 to ca. 10 cm(-1). This conclusion could only be reached due to the selective probing of one- and three-spin units by EPR and correlates perfectly with both previous magnetic susceptibility data and quantum chemical calculations performed in this work. These findings give new insights into the cooperativity effects and mechanisms of magnetic anomalies in the Cu(hfac)(2)L(R) family of molecular magnets. PMID- 20839876 TI - Inhibition of pancreatic elastase by polyphenolic compounds. AB - Polyphenols are plant secondary metabolites commonly present in the human diet that possess the ability to bind and inhibit digestive proteins. In the present study, kinetic measurements of porcine pancreatic elastase (PPE) activity were determined using Suc-(Ala)(3)-p-nitroanilide as substrate and polyphenolic compounds as inhibitors. A positive relationship between the degree of polyphenol polymerization and the capacity of the polyphenols to inhibit PPE was observed. Procyanidins with a molecular weight of at least 1154 Da were necessary to observe a significant inhibitory ability. Kinetic parameters were also calculated and confirmed that the inhibition is reversible and competitive. Molecular docking and dynamics simulations demonstrated that the tetramer structure has a higher affinity to the enzyme due the establishment of more contact points with the amino acids present in its active site. Hydrogen bond interactions and hydrophobic effects established between the polyphenol groups and the side chain of residues stabilize and favor the binding mode of this procyanidin. This work is relevant to the study of the antinutritional effects caused by dietary tannins on the digestive enzymes' activity, reducing food digestibility and the absorption of nutrients. In general, the elastase model studied herein allows a better understanding of the inhibitory ability of polyphenol compounds. PMID- 20839877 TI - Structural characterization of an arabinogalactan from Platycodon grandiflorum roots and antiangiogenic activity of its sulfated derivative. AB - A water-soluble polysaccharide, PGAW1, with an average molecular mass of 9.2 kDa determined by high performance gel permeation chromatography (HPGPC), was isolated from radix of Platycodon grandiflorum . Monosaccharide composition analysis indicated that PGAW1 contains Ara and Gal in the molar ratio of 1.42:1.0. Using methylation analysis, partial hydrolysis, endo-1,4-beta-d galactanase digestion, NMR and ESI-MS, PGAW1 was determined to possess a backbone consisting of 1,4- and 1,6-linked galactopyranosyl residues, with branches attached to O-3 of 1,6-linked galactose residues. By the chlorosulfonic acid pyridine method we produced a sulfated derivative of PGAW1, Sul-w1, with a substitution degree of 1.52. The substitution was at O-6 on 1,4-linked Gal residues according to the (13)C NMR spectra. Bioactivity test showed that Sul-w1 could inhibit tube formation by human microvascular endothelial cells (HMEC) in a dose-dependent manner. PMID- 20839878 TI - Synthesis and characterization of carbonyl diazide, OC(N3)2. AB - The previously recognized "extremely explosive" carbonyl diazide, OC(N(3))(2), was prepared as a pure compound and unambiguously characterized by gas-phase IR, matrix IR, and Raman spectroscopy and X-ray crystallography for the first time. The pure substance shows remarkable kinetic stability at room temperature in the gaseous, liquid, and solid states. A melting point of 16 degrees C and vapor pressure of 5.6 mbar at 0 degrees C were determined. Two planar conformers were found in the gas phase, and a composition of 12% anti-syn versus 88% syn-syn conformer in the gaseous equilibrium mixture at room temperature was estimated by matrix IR spectroscopy. In the crystal structure, only the more stable syn-syn conformer was observed. The preference of the syn-syn configuration was supported by DFT calculations. PMID- 20839879 TI - Chemistry of the phosphorus-nitrogen ligands. Multiple isomeric transformations of the diphosphinohydrazine bearing 8-quinolyl substituent: P->C, P->N, and P->P migrations caused by different factors. AB - The reaction of 8-quinolylhydrazine with 2 equiv of Ph(2)PCl in the presence of Et(3)N gives 8-[(Ph(2)P)(2)NNH]-Quin (1) (Quin = quinolyl) in 84% yield. The heating of 1 at 130 degrees C for 1 h in toluene results in migration of the [Ph(2)PNPPh(2)] group to a carbon atom of the quinolyl fragment to form an isomer, 7-(Ph(2)P-N?PPh(2))-8-NH(2)-Quin (2). The same migration is caused by the addition of LiN(SiMe(3))(2) to 1. On the contrary, lithiation of 1 with n-BuLi followed by the addition of ZnI(2) (1:1) affords the aminoquinolyl-phosphazenide dinuclear complex [ZnI(8-Quin-NPPh(2)?N-PPh(2))-kappa(3)N,N,P](2) (4), which is a result of P->N migration. Compound 1 itself reacts with ZnI(2) in THF to form 4 and protonated molecule 1.HI, which rearranges to the more stable iminobiphosphine salt (Ph(2)P-PPh(2)?N-NH-Quin-8).HI. Zinc iodide reacts with 2 equiv of the lithium salt of 1 without rearrangement, to form homoleptic aminoquinolyl zinc complex Zn[{(Ph(2)P)(2)NN-Quin-8}-kappa(2)N,N](2) (6). Solutions of 4 and 2 in dichloromethane show luminescence at 510 and 460 nm (quantum yields are 45% and 7%, respectively). DFT calculations were provided for possible isomers and their complexes. PMID- 20839880 TI - Anti-inflammatory Biphenyls and Dibenzofurans from Rhaphiolepis indica. AB - Bioassay-guided fractionation of the methanolic extract of the roots of Rhaphiolepis indica var. tashiroi afforded four new dibenzofurans, 2-hydroxy 3,4,6-trimethoxydibenzofuran (1), 2-hydroxy-3,4,9-trimethoxydibenzofuran (2), 2 hydroxy-3,4,6,9-tetramethoxydibenzofuran (3), and 1,2-methylenedioxy-3,4,6 trimethoxydibenzofuran (4), two new biphenyls, 3-hydroxy-2',5-dimethoxybiphenyl (5) and 2',3-dihydroxy-5-methoxybiphenyl (6), and 3-hydroxy-5-methoxybiphenyl (7). Among the isolates, 3, 5, and 6 exhibited inhibitory effects on N-formyl methionyl-leucyl-phenylalanine (fMLP)-induced superoxide production, with in vitro IC50 values < 8.36 MUM. PMID- 20839881 TI - Mechanical manipulation assisted self-assembly to achieve defect repair and guided epitaxial growth of individual peptide nanofilaments. AB - We have succeeded in the production of defect-free and spatially organized individual one-dimensional peptide nanofilaments by real-time control of the self assembly process on a solid substrate. Using a unique mechanical manipulation method based on atomic force microscopy, we are able to introduce mechanical stimuli to generate active ends at designated positions on an existing peptide nanofilament previously formed. By doing so, defects in the filament were removed, and self-repairing occurred when the active ends extended along the direction of the supporting lattice, resulting in the closure of the broken filament. Furthermore, new active ends of the nanofilaments can be specifically generated to guide the self-assembly of new filaments at designated positions with selected orientations. The mechanism of defect repair and guided epitaxial growth is also discussed. PMID- 20839882 TI - Adsorption of cationic hydroxyethylcellulose derivatives onto planar and curved gold surfaces. AB - The adsorption of two positively charged hydroxyethylcellulose derivatives with 7 and 60 mol % positively charged groups and a cationic, hydrophobically modified hydroxyethylcellulose containing 1 mol % hydrophobic groups and 7 mol % charged groups onto flat and spherical citrate-coated gold surfaces of different sizes has been investigated. The planar surfaces were studied by means of the quartz crystal microbalance with dissipation monitoring, whereas nanoparticle suspensions were examined using dynamic light scattering and UV-vis spectroscopy. Two different driving forces for adsorption have been evaluated: the electrostatic interaction between the positive charges on the polymers and the negatively charged gold surfaces and the affinity of the polymers for gold due to hydrophobic interactions. The comparison between the data obtained from curved and planar surfaces suggests a strong correlation between surface curvature and adlayer conformation in the formation of the hybrid polymer-gold nanoparticles. The influence of particle size on the amount of adsorbed polymer has been evaluated for the different polymers. The impact of the ionic strength on polymer adsorption has been explored, and the adsorbed polymer layer has been found to protect the gold nanoparticles from aggregation when salt is added to the solution. The addition of salt to a mixture of gold particles and a charged polymer can induce a thicker adsorbed layer at low salinity, and desorption was found at high levels of salt addition. PMID- 20839883 TI - Biodegradable elastomeric networks: highly efficient cross-linking of poly(trimethylene carbonate) by gamma irradiation in the presence of pentaerythritol triacrylate. AB - Biodegradable elastomeric poly(trimethylene carbonate) (PTMC) networks were efficiently formed by gamma irradiating the linear polymer in the presence of pentaerythritol triacrylate (PETA). The properties of networks formed upon irradiation of PTMC films containing (0, 1, 5 wt %) PETA as a cross-linking aid were evaluated. The gel contents and network densities increased with increasing PETA contents, irradiation dose, and initial polymer molecular weights. At a dose of 25 kGy, networks with gel fractions up to 0.96 could be obtained. The networks were noncytotoxic, had elastic moduli below 10.7 MPa and high tensile strengths of up to 37.7 MPa. The incorporation of PETA also improved the resistance to creep and to tear propagation significantly, resulting in permanent set values that were as low as 0.9% strain and tear strengths up to 9.3 +/- 2.0 N/mm. Furthermore, the enzymatic erosion rates of the networks could be decreased from 12.0 +/- 2.9 to 3.0 +/- 1.6 MUm/day. These biodegradable elastomeric PTMC networks may be utilized in a broad range of medical applications. PMID- 20839884 TI - Human plasma very low density lipoprotein carries Indian hedgehog. AB - Hedgehog is one of the major morphogens and fulfils critical functions in both the development and maintenance of the vasculature. Hedgehog is highly hydrophobic and its diffusion toward target tissues remains only partly understood. In Drosophila, hedgehog transport via lipophorins is relevant for development, but neither the presence nor a function for a mammalian Hedgehog carried by human plasma lipoproteins has been established. We investigated the presence of Hedgehog on lipoprotein particles and determined its importance for maintaining the endothelium. LTQ-Orbitrap XL analysis of defined plasma lipoproteins revealed that Indian Hedgehog (Ihh) is present in the human very low density lipoprotein (VLDL) fraction but not in other plasma lipoprotein fractions (low density lipoprotein (LDL) and high density lipoprotein (HDL)). Using the same approach, neither Sonic Hedgehog nor Desert Hedgehog could be detected in plasma lipoprotein fractions. Most likely, primary white adipocytes are the source of Ihh loading on VLDL as both transcriptome as well as immunofluorescence analysis showed high expression of Ihh in these cells. Additionally, we show that the endothelial compartment is most likely to be affected by the presence of Ihh on VLDL. Indeed, VLDL increased survival of primary endothelial cells, suggesting that Ihh transport by VLDL is important for maintaining the human endothelium. In conclusion, our study shows that VLDL carries Ihh throughout the body in mammals and Hedgehog signaling by human plasma VLDL particles may affect blood vessel pathophysiology. A combination of three state-of-the-art technologies, proteomics, genomics, and confocal microscopy, appeared to be a powerful tool for analyzing plasma lipoprotein-associated proteins. PMID- 20839885 TI - Active site threonine facilitates proton transfer during dioxygen activation at the diiron center of toluene/o-xylene monooxygenase hydroxylase. AB - Toluene/o-xylene monooxygenase hydroxylase (ToMOH), a diiron-containing enzyme, can activate dioxygen to oxidize aromatic substrates. To elucidate the role of a strictly conserved T201 residue during dioxygen activation of the enzyme, T201S, T201G, T201C, and T201V variants of ToMOH were prepared by site-directed mutagenesis. X-ray crystal structures of all the variants were obtained. Steady state activity, regiospecificity, and single-turnover yields were also determined for the T201 mutants. Dioxygen activation by the reduced T201 variants was explored by stopped-flow UV-vis and Mossbauer spectroscopy. These studies demonstrate that the dioxygen activation mechanism is preserved in all T201 variants; however, both the formation and decay kinetics of a peroxodiiron(III) intermediate, T201(peroxo), were greatly altered, revealing that T201 is critically involved in dioxygen activation. A comparison of the kinetics of O(2) activation in the T201S, T201C, and T201G variants under various reaction conditions revealed that T201 plays a major role in proton transfer, which is required to generate the peroxodiiron(III) intermediate. A mechanism is postulated for dioxygen activation, and possible structures of oxygenated intermediates are discussed. PMID- 20839886 TI - Linker-directed vertex desymmetrization for the production of coordination polymers with high porosity. AB - Five non-interpenetrated microporous coordination polymers (MCPs) are derived by vertex desymmetrization using linkers with symmetry inequivalent coordinating groups, and these MCPs include properties such as rare metal clusters, new network topologies, and supramolecular isomerism. Gas sorption in polymorphic frameworks, UMCM-152 and UMCM-153 (based upon a copper-coordinated tetracarboxylated triphenylbenzene linker), reveals nearly identical properties with BET surface areas in the range of 3300-3500 m(2)/g and excess hydrogen uptake of 5.7 and 5.8 wt % at 77 K. In contrast, adsorption of organosulfur compounds dibenzothiophene (DBT) and 4,6-dimethyldibenzothiophene (DMDBT) shows remarkably different capacities, providing direct evidence that liquid-phase adsorption is not solely dependent on surface area or linker/metal cluster identity. Structural features present in MCPs derived from these reduced symmetry linkers include the presence of more than one type of Cu-paddlewheel in a structure derived from a terphenyl tricarboxylate (UMCM-151) and a three-bladed zinc paddlewheel metal cluster in an MCP derived from a pentacarboxylated triphenylbenzene linker (UMCM-154). PMID- 20839887 TI - Liposomal formulation of amphiphilic fullerene antioxidants. AB - Novel amphiphilic fullerene[70] derivatives that are rationally designed to intercalate in lipid bilayers are reported, as well as its vesicular formulation with surprisingly high loading capacity up to 65% by weight. The amphiphilic C(70) bisadduct forms uniform and dimensionally stable liposomes with auxiliary natural phospholipids as demonstrated by buoyant density test, particle size distribution, and (31)P NMR. The antioxidant property of fullerenes is retained in the bipolarly functionalized C(70) derivative, amphiphilic liposomal malonylfullerene[70] (ALM), as well as in its liposomal formulations, as shown by both electron paramagnetic resonance (EPR) studies and in vitro reactive oxygen species (ROS) inhibition experiments. The liposomally formulated ALM efficiently quenched hydroxyl radicals and superoxide radicals. In addition, the fullerene liposome inhibited radical-induced lipid peroxidation and maintained the integrity of the lipid bilayer structure. This new class of liposomally formulated, amphipathic fullerene compounds represents a novel drug delivery system for fullerenes and provides a promising pathway to treat oxidative stress related diseases. PMID- 20839888 TI - Phytotoxicity of sarmentine isolated from long pepper (Piper longum) fruit. AB - Discovery of novel natural herbicides has become crucial to overcome increasing weed resistance and environmental issues. In this article, we describe the finding that a methanol extract of dry long pepper (Piper longum L.) fruits is phytotoxic to lettuce (Lactuca sativa L.) seedlings. The bioassay-guided fractionation and purification of the crude extract led to isolation of sarmentine (1), a known compound, as the active principle. Phytotoxicity of 1 was examined with a variety of seedlings of field crops and weeds. Results indicated that 1 was a contact herbicide and possessed broad-spectrum herbicidal activity. Moreover, a series of sarmentine analogues were then synthesized to study the structure-activity relationship (SAR). SAR studies suggested that phytotoxicity of sarmentine and its analogues was specific due to chemical structures, i.e., the analogues of the acid moiety of 1 were active, but the amine and its analogues were inactive; the ester analogues and amide analogues with a primary amine of 1 were also inactive. In addition, quantification of 1 from different resources of the dry P. longum fruits using liquid chromatography-mass spectrometry showed a wide variation, ranging from almost zero to 0.57%. This study suggests that 1 has potential as an active lead molecule for synthesized herbicides as well as for bioherbicides derived from natural resources. PMID- 20839889 TI - Copper uptake is differentially modulated by phenylalanine ammonia-lyase inhibition in diploid and tetraploid chamomile. AB - The effect of phenylalanine ammonia-lyase (PAL) inhibition by 2-aminoindane-2 phosphonic acid (AIP) in copper-exposed diploid and tetraploid chamomile (Matricaria chamomilla ) roots has been studied in a short-term experiment (24 h). Cu evoked stronger induction of PAL activity and accumulation of soluble phenols, flavonols (quercetin and kaempferol), and lignin in diploid plants, whereas AlCl3-reactive flavonoids and phenolic acids did not differ with respect to ploidy. Amounts of hydrogen peroxide and superoxide also preferentially increased in diploid. Surprisingly, PAL activity was restored in both +AIP cultivars, being inversely correlated with the accumulation of free phenylalanine. Notwithstanding this, total soluble phenols and flavonols were more depleted in Cu+AIP diploid roots. Soluble proteins decreased in response to Cu, and AIP had no effect. Among free amino acids, proline increased more visibly in Cu+AIP diploid, suggesting that this could be a protective mechanism in conditions with depleted content of phenols. Decrease in potassium content was ploidy-independent, calcium increased in all Cu variants, and Fe increased in Cu exposed tetraploid. Shoot Cu content did not differ in Cu-exposed cultivars, but diploid roots contained more Cu. AIP decreased root Cu but increased shoot Cu amounts in diploid, whereas tetraploid plants did not exhibit similar responses. These data indicate that inhibition of root phenolic metabolism by AIP was effective enough, allowing Cu to accumulate in diploid shoots. The present findings are discussed in the context of available data about AIP effects and with respect to the role of phenols in metal uptake. PMID- 20839890 TI - Radiofrequency quadrupolar NMR stark spectroscopy: steady state response calibration and tensorial mapping. AB - Radiofrequency electric (E) fields oscillating at twice the usual NMR frequency (2omega(0)) can induce double-quantum transitions in quadrupolar nuclei, an NMR Stark effect. Characterization of such is of interest to aid understanding of electrostatic effects in NMR spectra. Calibration of Stark responses to an applied electric field may also be used to assess native fields within molecules and materials. We present high-field (14.1 T), room-temperature NMR experiments to calibrate the 2omega(0) Stark response in crystalline GaAs. This system presents an important test of current techniques and conditions, as historical studies at low field (500-900 mT) and low temperature (77 K) provide a basis for comparison. Our measurements of steady state response reveal the quadrupolar Stark tuning rate for (69)Ga in this material. The value, beta(Q) = (11.5 +/- 0.1) * 10(12) m(-1), is 3.6 times larger than the most-reliable prior result. In the process, we also uncovered a previously unobserved double-quantum steady state coherence. It appears as a completely separable dispersive signal component in quadrature-detected presaturation spectra versus offset from 2omega(0). The new component may eventually afford an independent route to calibrating beta(Q). Finally, we demonstrated exceptional agreement with theory of the orientation dependent Stark response for rotation of the sample relative to B(0) over a range of 90 degrees and for E-field amplitudes from 30-180 V/cm. PMID- 20839891 TI - Picosecond dynamics of dimer formation in a pyrene labeled polymer. AB - A commercial poly(acrylic acid) (PAA, M(n) = 450 000 g mol(-1)) has been labeled with high levels (9.1 mol %) of pyrene by reaction with 1-pyrenylmethylamine in the presence of boric acid. The modified polymer was found to display an unusual photophysical behavior closely resembling that found for pyrene in constrained environments. The appearance of a band at longer wavelengths in the excitation spectra when collected at the long wavelength emission band was attributed to the spectra of a dimer. The emission of this dimer was particularly enhanced in dioxane:water solvent mixtures with low dioxane content. From time-resolved fluorescence measurements in the picosecond time domain, two decay components were obtained: a fast decay (4-10 ps) at short wavelengths, which becomes a rising component at longer wavelengths, and a second exponential (2-4 ns) related to the emission of the relaxed dimer. Time-resolved emission spectra were seen to change with time, revealing the emission contribution of two species. This is one of the first reports where the dynamics of dimer formation in a pyrene derivative have been observed. PMID- 20839892 TI - Grazing incidence small angle X-ray scattering on colloidal crystals. AB - Grazing incidence small-angle X-ray scattering (GISAXS) is used for nondestructive characterization of colloidal crystals of different numbers of hexagonally dense packed layers fabricated by convective self-assembly. Whereas small crystallites with random orientation were obtained in case of monolayers, the scattering data obtained from multilayer samples revealed colloidal domains over areas of a few centimeters where the single crystalline domains are mainly aligned along the growth direction. The data indicates an increasing degree of self-organization going from monolayers to multilayers. Within the multilayer samples, the stacking sequence of the hexagonally packed layers is evaluated using a numerical model for fitting the X-ray scattering data containing the stacking parameter, a. Compared with an expected complete random stacking with a = 0.5, the fitted stacking parameter, a = 0.63 +/- 0.01, averaged over a sample area of about 1 mm(2) indicates a preference for a cubic stacking sequence. This value is smaller than reported by various local probe techniques. PMID- 20839893 TI - Abuse-deterrent and tamper-resistant opioid formulations: what is their role in addressing prescription opioid abuse? AB - About one in every three individuals will experience chronic pain in their lifetime, and opioids are known to be an effective means to treat this condition. Much attention, however, has been given to the fact that prescription opioid analgesics are some of the most frequently abused drugs, and misuse is prominent in patients with chronic pain. Several new opioid formulations that are designed to prevent or deter the abuse of opioids are currently in development, and two have been approved for marketing (morphine sulphate co-formulated with naltrexone hydrochloride [Embeda(r)] and a new formulation of the extended-release oxycodone [OxyContin(r)]). In this article, we review the various types of abuse-deterrent and tamper-resistant formulations in clinical development. We believe that continued advances in opioid formulations can help mitigate risk for those with legitimate need for pain control, but only if used rationally in the context of good clinical practice. PMID- 20839894 TI - Sleep problems in the child with attention-deficit hyperactivity disorder: defining aetiology and appropriate treatments. AB - An estimated 25-50% of children and adolescents with attention-deficit hyperactivity disorder (ADHD) experience problems with sleep. The most common sleep problems reported in children with ADHD include delayed sleep onset, sleep or bedtime resistance, prolonged tiredness upon waking and daytime sleepiness. Higher incidences of sleep disorders such as restless legs syndrome, periodic limb movement disorder and sleep-disordered breathing have been reported in paediatric ADHD populations compared with control populations. In some cases, medications for ADHD and/or co-morbid disorders may also contribute to sleep disturbances. Assessment tools, such as parent-child questionnaires and sleep diaries, can help clinicians evaluate sleep disturbances. Sleep problems may potentially exacerbate ADHD symptoms, and interventions targeted at ensuring adequate sleep (including behavioural, dietary, specific pharmacological agents for treatment-induced insomnia, and melatonin) could in turn potentially attenuate symptoms associated with ADHD, such as irritability. Whether metabolic or neurological pathways common to both sleep and ADHD may be disrupted, and whether targeting treatments to these pathways may simultaneously improve both ADHD and sleep symptoms, needs further elucidation. PMID- 20839895 TI - Role of pramipexole in the management of Parkinson's disease. AB - The non-ergot dopamine agonist pramipexole is currently indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease and for the treatment of moderate-to-severe primary restless legs syndrome. A new extended release formulation of pramipexole has now also been launched in Europe and the US to improve ease of use, compliance and provide a more continuous therapeutic effect over 24 hours. Before initiating any treatment, the benefit-risk ratio to the individual patient must be considered. For pramipexole in the treatment of Parkinson's disease, this means taking into account the available evidence regarding its symptomatic efficacy, effect on delaying long-term levodopa-related motor complications, beneficial effect on non-motor symptoms such as depression, and its safety and tolerability profile. Studies have shown that pramipexole is effective as monotherapy in early Parkinson's disease and as adjunctive therapy in advanced disease. Trials further suggest that the benefits of pramipexole may extend beyond the relief of motor symptoms (akinesia, rigidity and tremor at rest) to the amelioration of depressive symptoms in Parkinson's disease. Pramipexole is generally well tolerated; however, compared with levodopa treatment, pramipexole is associated with a higher rate of some dopaminergic adverse effects. PMID- 20839897 TI - Flupirtine in pain management: pharmacological properties and clinical use. AB - Flupirtine is a centrally acting, non-opioid analgesic that is available in a number of European countries for the treatment of a variety of pain states. The therapeutic benefits seen with flupirtine relate to its unique pharmacological properties. Flupirtine displays indirect NDMA receptor antagonism via activation of potassium channels and is the first representative of a pharmacological class denoted the 'selective neuronal potassium channel openers'. The generation of the M-current is facilitated by flupirtine via the opening of neuronal Kv7 potassium channels. The opening of these channels inhibits exaggerated neuronal action potential generation and controls neuronal excitability. Neuronal hyperexcitability is a physiological component of many pain states such as chronic pain, migraine and neurogenic pain. Although large-scale clinical trials are lacking, the clinical trial database available to date from smaller-scale studies, together with extensive clinical experience, indicate that flupirtine effectively reduces chronic musculoskeletal pain, migraine and neuralgias, amongst other types of pain. In addition, flupirtine produces, at recommended clinical doses, muscle-relaxing effects in the presence of abnormally increased muscle tension. Its analgesic and muscle-relaxant properties were comparable to tramadol and chlormezanone, respectively, in two prospective trials in patients with lower back pain. Cytoprotective, anti-apoptotic and antioxidant properties have also been associated with flupirtine use in a small number of studies to date. When provided as combination therapy with morphine, flupirtine increases the antinociceptive activity of morphine 4-fold. Flupirtine displays superior tolerability when compared with tramadol and pentazocine. The most common adverse effects associated with flupirtine use are drowsiness, dizziness, heartburn, dry mouth, fatigue and nausea. With respect to its molecular structure, mechanism of action and adverse event profile, flupirtine is a unique drug. Flupirtine is an analgesic with many potential therapeutic benefits that may prove useful in the treatment of many disease states. PMID- 20839896 TI - The impact of medications on quality of life in attention-deficit hyperactivity disorder: a systematic review. AB - Quality of life (QOL) describes an individual's subjective perception of their position in life as evidenced by their physical, psychological and social functioning. Although an established outcome measure in physical health, QOL has more recently become an increasingly important measure in mental health clinical work and research. This article reviews the evidence describing the impact of medications on QOL in attention-deficit hyperactivity disorder (ADHD). Databases were searched for research studies describing the effects of medication on QOL in ADHD: 25 relevant studies were identified. Most (n = 20) of these studies have focused on children and adolescents, and most have investigated a single molecule, atomoxetine (n = 15), with relatively few studies investigating methylphenidate (n = 5), amfetamines (n = 4) and manifaxine (n = 1). These studies support a positive short-term effect of medication on QOL in ADHD for children, adolescents and adults that mirrors, to some extent, the effects of these medications on ADHD symptoms, although with smaller effect sizes. Notwithstanding measurement issues, it will continue to be important that those designing and conducting clinical trials in ADHD, including both pharmacological and non-pharmacological treatments, continue to include measures of QOL as secondary outcome measures. In particular, information about QOL effects in adults and in subjects of all ages taking methylphenidate and amfetamine treatments is urgently needed. The lack of systematic studies of the impact on QOL of psychological therapies, either on their own or in multimodal combinations with medication, is a serious omission that should be urgently addressed. PMID- 20839898 TI - Dalfampridine extended release: in multiple sclerosis. AB - Dalfampridine extended release (ER) is an orally administered formulation of dalfampridine (fampridine, 4-aminopyridine), a potassium channel antagonist indicated for the improvement in walking ability in patients with multiple sclerosis (MS). Oral dalfampridine ER improved walking ability in patients with MS in three randomized, double-blind trials of up to 15 weeks' duration. In a phase II trial, percentage improvements in walking speed on the Timed 25-Foot Walk (T25FW) test (primary endpoint) were not significant versus baseline or placebo during treatment with dalfampridine ER 10, 15 or 20 mg twice daily. However, according to a post hoc analysis, response rates were significantly higher with dalfampridine ER than placebo, with a consistent mean improvement in walking speed of 25-29% seen in the pooled results from dalfampridine ER responders during the double-blind treatment period. In two phase III trials, the proportion of timed walk responders (primary endpoint) was significantly greater with dalfampridine ER 10 mg twice daily than with placebo, with improvements in walking speed of approximately 25% seen during dalfampridine ER treatment amongst timed walk responders. Interim results of noncomparative extensions of the two phase III trials showed that consistent improvements in walking speed were sustained above baseline for up to 2.5 years of dalfampridine ER treatment. Oral dalfampridine ER 10 mg twice daily was generally well tolerated in patients with MS, according to the results of the three randomized, double-blind, placebo controlled trials. PMID- 20839899 TI - Implementation of a cardiology care program in remote areas in Brazil: influence of governability. AB - INTRODUCTION: A telecardiology remote cardiology medical care system was implemented in 82 municipalities of Minas Gerais State, Brazil to support basic network services in the early diagnosis and management of cardiovascular diseases. OBJECTIVE: To investigate the factors associated with the implementation of this program in the municipalities. METHOD: This 2006 ecological study involved 393 candidate municipalities to implement the system. The municipalities were divided into two groups: non-random intervention (n = 82) and comparative (n = 311). The social, structure, healthcare needs, and governability indexes of the two groups of municipalities were compared by descriptive and multiple regression analysis using the generalized estimation equation model. RESULTS: After fitting for other characteristics, participation of the municipalities in the intervention was associated with a higher social responsibility index (OR: 2.44, CI: 1.50-3.96) and lower healthcare needs (OR: 2.29, CI: 1.24-4.22). CONCLUSION: Greater efforts by municipality management was the key to attracting and implementing the remote cardiology intervention, even when fitted for lower healthcare needs, which suggests greater municipal political and social engagement. This translated to improved access to cardiovascular health care for Brazilian rural and remote populations in the intervention municipalities. PMID- 20839900 TI - Attracting and retaining doctors in rural Nepal. AB - INTRODUCTION: In Nepal, a number of private sector medical schools have opened recently; although sufficient numbers of doctors are graduating there continues to be a doctor shortage in rural areas. This article analysed the rural doctor shortage in Nepal and reviewed the international literature for strategies that may be suitable for use in Nepal. METHODS: Original research articles, reviews, magazine articles and project reports dealing with Nepal and other developing countries during the period 1995 to 2010 were sourced via Google, Google Scholar and Pubmed. Full text access was obtained via WHO's HINARI database. RESULTS: The health workforce in Nepal is unevenly distributed resulting in doctor shortages in rural areas. The recent introduction of mandatory rural service for scholarship students was aimed to reduce the loss of medical graduates to developed nations. High tuition fees in private medical schools and low Government wages prevent recent graduates from taking up rural positions, and those who do face many challenges. Potential corrective strategies include community-based medical education, selecting rural-background medical students, and providing a partial or complete tuition fee waiver for medical students who commit to rural service. Traditional healers and paramedical staff can also be trained for and authorized to provide rural health care. CONCLUSIONS: A range of strategies developed elsewhere could be used in Nepal, especially community oriented medical education that involves rural doctors in training medical students. The reimbursement of tuition fees, assistance with relocation, and provision of opportunities for academic and professional advancement for rural doctors should also be considered. Government investment in improving working conditions in rural Nepal would assist rural communities to attract and retain doctors. PMID- 20839902 TI - Hearing in a 54- to 66-year-old population in northern Finland. AB - There are only a few large, population-based epidemiological studies on hearing impairment (HI) in adults. The objective of this study was to investigate the prevalence of HI and possible differences between ears in older adults. The subjects (n = 850), aged 54-66 years, were randomly sampled from the population register. A questionnaire survey, an otological examination, and pure-tone audiometry were performed. Another questionnaire was mailed to collect information on non-participants. The prevalence of HI averaged over the frequencies of 0.5, 1, 2, and 4 kHz for the better ear >=20 dB HL was 26.7% (men: 36.8%, women: 18.4%). There was no difference between left and right ear pure tone averages over the frequencies 0.5, 1, 2, and 4 kHz (PTA(0.5-4 kHz)), but a significant difference of -0.8 dB HL was found for the low frequencies 0.125, 0.25, and 0.5 kHz (PTA(0.125-0.5 kHz)), and 4.4 dB HL for the high frequencies over 4, 6, and 8 kHz (PTA(4-8 kHz)). In conclusion, HI was a highly prevalent finding in this age group. PMID- 20839901 TI - X-ray imaging of differential vascular density in MMP-9-/-, PAR-1-/+, hyperhomocysteinemic (CBS-/+) and diabetic (Ins2-/+) mice. AB - Although protease activated receptor-1 (PAR-1) and matrix metalloproteinase-9 (MMP-9) play significant role in vascular remodelling in hyperhomocysteinemia (HHcy due to cystathionine beta synthase deficiency, CBS-/+) and diabetes, mechanism remains nebulous. We hypothesized that differential vascular density and remodelling in different vascular beds in HHcy and diabetes were responsible for an adaptive metabolic homeostasis during the pathogenesis. To test this hypothesis, vascular density in mice lacking PAR-1, MMP-9, CBS and Insulin-2 gene mutant (Ins2-/+, Akita) was measured and compared with wild type (WT, C57BL/6J) mice. The vascular density was detected by x-ray angiography using KODAK 4000 MM image station, using barium sulphate as contrasting agent. The % vascular density in the hearts of WT, CBS-/+ (HHcy), MMP-9-/-, PAR-1-/+ and Ins2-/+ (type-1 diabetes) was 100 +/- 2.8, 85 +/- 3.3, 90 +/- 3.3, 95 +/- 3.8 and 73 +/- 1.7, respectively. The vascular density in CBS-/+ and Akita hearts decreased while it was increased in lungs of CBS-/+ and MMP-9-/-.There was decreased vascular density in liver and kidney of Akita mice. Vascular density in brain, kidney and mesentery was decreased in CBS-/+ mice. These findings support the notation that metabolic derangement in diabetes and HHcy causes the chronic decline and/or rarefaction in vascular density. PMID- 20839903 TI - A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. AB - The objective of this trial was to determine the safety and tolerability of memantine in patients with sporadic ALS and to examine changes in CSF biomarkers during drug therapy. Twenty patients on stable doses of riluzole were enrolled. Patients received memantine, 10 mg b.i.d., for 18 months. Lumbar punctures were performed at baseline, six and twelve months. The ALSFRS was measured at six weeks, 3, 6, 9, 12 and 18 months. Results showed that patients treated with memantine and riluzole had an average rate of decline on the ALSFRS of -0.73 points per month. Patients who progressed faster than -0.5 ALSFRS points per month had an average baseline CSF tau concentration of 574 pg/ml, while those who progressed slower than -0.5 ALSFRS points per month had CSF tau levels that averaged 298 pg/ml (p = 0.006). After therapy with memantine, patients had a 27% decline in CSF tau levels (p = 0.04) and four patients whose CSF tau dropped to healthy control levels lost only -0.42 ALSFRS points per month. In conclusion, memantine was well tolerated in patients with ALS. Patients receiving memantine and riluzole lost on average -0.73 ALSFRS points per month. Furthermore, levels of CSF tau at baseline could be correlated with how rapidly a patient's disease progressed. PMID- 20839904 TI - Music performance anxiety in opera singers. AB - Music performance anxiety (MPA) represents a high challenge every vocal performer has to meet. MPA can be defined on a continuum going from a low to a high level. MPA and its phenomena can be considered in terms of four levels: affect, cognition, behaviour, and physiology. A study carried out on seven opera singers and two instrumentalists during performance situations showed highly elevated values for the performers' heart rate and blood pressure. This study, as several others, yielded no clear evidence pointing to a correspondence between the level of anxiety and of physiological arousal. At the end of the article a multimodal approach to the treatment of MPA is illustrated consisting of different psychotherapeutic and body-oriented methods. PMID- 20839905 TI - Mechanism of delayed puberty in rats whose mothers consumed Hibiscus sabdariffa during lactation. AB - CONTEXT: Extract of the calyx of Hibiscus sabdariffa Linn. (HS) (Malvaceae) has been reported to decrease fluid and food intake in lactating rats through a mechanism not yet fully understood. It has also been reported that rat pups undernourished during lactation have delayed puberty onset, suggesting a link between nutrition and onset of puberty. There is paucity of data addressing the effect of maternal consumption of HS during lactation on the onset of puberty in the female offspring. OBJECTIVE: The present study was designed to investigate whether consumption of HS during lactation will affect the onset of puberty and to examine the possible mechanism underlying this. MATERIALS AND METHODS: Lactating Sprague-Dawley rats were randomly grouped into three on postnatal day one. One group had tap water (control); another had 0.6 g aqueous HS extract/100 mL, while the third had 1.8 g aqueous HS extract/100 mL as their drinking solution throughout lactation. Maternal fluid consumption, food consumption, weight gain, plasma Na(+) and corticosterone concentrations were determined. Offspring weights were recorded at 0, 21, 28, 35, and 42 days. Ages at onset of puberty and body weights were also recorded. RESULTS: A decreased maternal fluid and food intake and an increased maternal plasma Na(+) and corticosterone concentration were observed in HS dams. The HS treated female offspring showed delayed onset of puberty. DISCUSSION AND CONCLUSION: The accelerated growth and delayed puberty in the HS offspring may be through increased corticosterone and decreased leptin delivery through breast milk. PMID- 20839906 TI - Journal of Cosmetic and Laser Therapy. Editorial. PMID- 20839909 TI - Antioxidant and hepatoprotective activities of Egyptian moraceous plants against carbon tetrachloride-induced oxidative stress and liver damage in rats. AB - CONTEXT: In the absence of reliable liver-protective drugs in modern medicine, a large number of medicinal preparations are recommended for treatment of liver disorders. OBJECTIVE: The antioxidant, hepatoprotective and kidney protective activities of methanol extracts of Ficus carica Linn. (Moraceae) leaves and fruits and Morus alba Linn. root barks (Moraceae) are evaluated here. MATERIALS AND METHODS: Liver and kidney damage were induced in rats by carbon tetrachloride in a subcutaneous dose of 1 mL (40% v/v in corn oil)/kg. The extract was given intraperitoneally at doses of 50 mg/kg (F. carica leaf and M. alba root bark) and 150 mg/kg (F. carica fruit). The activity of the extracts was comparable to that of silymarin, a known hepatoprotective agent. Antioxidant activity was evaluated by measuring blood glutathione (GSH) content, superoxide dismutase (SOD), catalase (CAT) activities, and malondialdehyde equivalent (MDA). Hepatoprotective activity was evaluated by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, and total protein. These biochemical observations were supported by histopathological examination of liver sections. Kidney function was evaluated by measuring plasma urea and creatinine. RESULTS: Methanol extracts of Ficus carica and Morus alba showed potent antioxidant and hepatoprotective activities; in depth chromatographic investigation of the most active extract (Ficus carica leaf extract) resulted in identification of umbelliferone, caffeic acid, quercetin-3-O beta-d-glucopyranoside, quercetin-3-O-alpha-l-rhamnopyranoside, and kaempferol-3 O-alpha-l-rhamnopyranoside. DISCUSSION AND CONCLUSION: These findings demonstrate that the phenolic constituents of Ficus carica leaf and Morus alba root bark are responsible at least in part for the observed protective effects. PMID- 20839910 TI - The role of T regulatory (Treg) cells in cancer immunity; management of HIV associated inflammation; and characterization of the homing pathways undertaken by mesenchymal stromal cells. Editorial. PMID- 20839911 TI - Tumor infiltrating regulatory T cells: tractable targets for immunotherapy. AB - Several studies have linked tumor-infiltration by regulatory T cells with poor patient outcome. Targeting the mechanisms by which regulatory T cells traffic to and persist in the tumor may circumvent tumor immune-escape by de-restricting T cell-mediated cytotoxicity. In this review, we describe the principle axes that govern regulatory T cell migration and the mechanisms that underpin their immunosuppressive activity in cancer. Inhibiting either the migration or function of regulatory T cells may enhance host-anti-cancer immune responses and as such are attractive and tractable targets for therapeutic intervention. PMID- 20839912 TI - Altered host-microbe interaction in HIV: a target for intervention with pro- and prebiotics. AB - The intestinal immune system is severely affected by HIV and circulating microbial products from the intestinal tract that provide an ongoing source of systemic inflammation and concomitant viral replication. In addition, HIV infected individuals can have a deregulated immune response that may hamper the anti-viral capacity of the host. Various probiotic organisms and prebiotic agents have been shown to enhance intestinal epithelial barrier functions, reduce inflammation, and support effective Th-1 responses. As these characteristics may benefit HIV patients, this review aims to provide a theoretical framework for the development of probiotic and prebiotic interventions specifically for this population. PMID- 20839913 TI - Homing pathways of mesenchymal stromal cells (MSCs) and their role in clinical applications. AB - Mesenchymal stromal cells (MSCs) have come into focus for an increasing number of cellular therapies. Since most clinical protocols use intravenous application of MSCs, it has become important to understand their trafficking in the bloodstream. Moreover, since relatively little is known where the transplanted MSCs might locate, a better understanding of involved homing mechanisms will likely shed light on how MSCs exert their therapeutic effects. This review focuses on the current knowledge of homing pathways of transplanted MSCs. We describe regulatory signalling molecules and receptors involved. An outlook is given on significance of these findings for the future use of MSCs as a cellular therapeutic. PMID- 20839914 TI - A comparison of the metabolism of clopidogrel and prasugrel. AB - IMPORTANCE OF THE FIELD: The administration of dual antiplatelet therapy with aspirin and a thienopyridine for the prevention of thrombosis in patients with acute coronary syndrome undergoing percutaneous coronary intervention is proven to reduce mortality. The original thienopyridine, ticlopidine, has largely been displaced by clopidogrel, which has a superior adverse effect profile. Prasugrel is a new thienopyridine that has been purported to have a faster onset of activity, a lower rate of nonresponders and a greater potency than clopidogrel. AREAS COVERED IN THIS REVIEW: This review compares the metabolism of clopidogrel and prasugrel by carboxylesterases and the CYP system with emphasis on the formation of their respective active metabolites. WHAT THE READER WILL GAIN: The reader will gain an understanding of the pharmacokinetics of prasugrel and clopidogrel and how the differences in their respective metabolic pathways explain the difference in their therapeutic activity. TAKE HOME MESSAGE: The superior therapeutic profile of prasugrel is explained by the different roles of carboxylesterases in their metabolic pathways. Though prasugrel is superior to clopidogrel as a prodrug of the active P(2)Y(12) inhibitor, caution is advised because limited information is available on genetic polymorphisms or drug interactions affecting carboxylesterase metabolism. PMID- 20839915 TI - Duration of exposure to environmental carcinogens affects DNA-adduct level in human lymphocytes. AB - BACKGROUND AND OBJECTIVE: An important issue in human biomonitoring is determining how exposure duration affects the kinetics of molecular biomarkers. In this study we compare the influence of exposure variables on DNA adducts. METHODS: DNA adducts were analysed by 32P-postlabelling in lympho/monocytes of 677 Caucasian subjects. RESULTS: After correction for other variables, DNA adducts increased depending on the length of occupational and smoke exposures. Higher DNA adducts were detected in workers with more than 14 years of exposure than in workers with shorter exposures (RR = 1.19, p = 0.049) and in smokers with more than 10 years of exposure than in smokers with shorter exposure (RR = 1.21, p <0.001). CONCLUSIONS: Exposure length is the primary factor affecting DNA adduct level in lympho/monocytes both in smokers and in occupationally exposed subjects. PMID- 20839916 TI - Adiponectin is related with carotid artery intima-media thickness and brachial flow-mediated dilatation in young adults--the Cardiovascular Risk in Young Finns Study. AB - AIMS: Adiponectin may be involved in the pathogenesis of atherosclerosis. We investigated the relation of adiponectin on early functional and structural markers of subclinical atherosclerosis in a large population-based cohort of young men and women. METHODS AND RESULTS: We measured serum adiponectin using radioimmunoassay in 2,147 young adults (ages 24-39 years) participating in the Cardiovascular Risk in Young Finns Study. The subjects had ultrasound data on carotid intima-media thickness (IMT), carotid artery elasticity (n = 2,139) and brachial flow-mediated dilatation (FMD) (n = 1,996). In univariate analysis, adiponectin was inversely associated with IMT (r = -0.16, P < 0.0001) and directly with FMD (r = 0.12, P < 0.0001) and carotid elasticity (r = 0.20, P < 0.0001). The associations for IMT and FMD remained significant in multivariable models adjusted for age, sex, obesity indices, serum lipids, blood pressure, leptin, glucose, and C-reactive protein: IMT (beta = -0.018 +/- 0.005, P = 0.0002) and FMD (beta = 0.72 +/- 0.25, P = 0.004). The relation between adiponectin and carotid elasticity attenuated to non-significant after adjusting for waist circumference and systolic blood pressure. CONCLUSION: In young healthy adults, low serum adiponectin concentration is independently related with increased carotid IMT and attenuated brachial FMD, supporting the role of adiponectin in the pathogenesis of early atherosclerosis. PMID- 20839917 TI - Abdominal aortic calcification detected by dual X-ray absorptiometry: A strong predictor for cardiovascular events. AB - BACKGROUND: Vertebral fracture assessment (VFA) using dual-energy X-ray absorptiometry can visualize abdominal aortic calcification (AAC). AAC correlates with total atherosclerosis burden. We questioned whether VFA-detected AAC could be used for cardiovascular risk assessment. METHODS: VFA images of 2,500 subjects were evaluated to detect and score AAC (n = 164). A random age- and gender matched set of subjects (n = 325) without AAC served as control group. Patients with prior cardiovascular disease or procedures were excluded. Base-line cardiovascular risk factors and further cardiovascular events were checked. Design-based Cox regression analysis was used to examine the prognostic value of AAC for cardiovascular outcomes. RESULTS: AAC-positive subjects were divided into two groups: low-AAC (score 1-3), and high-AAC group (score > 3). Mean age in the groups was 68, 68, and 71 years, percentage of females was 64.4%, 61%, and 66.1%, and the proportion of cardiovascular events within groups was 1.5%, 6.7%, and 11.9% in control, low-AAC, and high-AAC groups, respectively. Age- and gender adjusted as well as multivariable analysis showed a significant, higher risk for cardiovascular events incidence in AAC-positive, low-AAC, and high-AAC when compared to the control group. INTERPRETATION: AAC assessed with routine VFA was shown to be a strong predictor for cardiovascular events. PMID- 20839918 TI - Psychological and social factors in coronary heart disease. AB - More than six decades of empirical research have shown that psychosocial risk factors like low socio-economic status, lack of social support, stress at work and family life, depression, anxiety, and hostility contribute both to the risk of developing coronary heart disease (CHD) and the worsening of clinical course and prognosis in patients with CHD. These factors may act as barriers to treatment adherence and efforts to improve life-style in patients and populations. In addition, distinct psychobiological mechanisms have been identified, which are directly involved into the pathogenesis of CHD. In clinical practice, psychosocial risk factors should be assessed by clinical interview or standardized questionnaires, and relevance with respect to quality of life and medical outcome should be discussed with the patient. In case of elevated risk, multimodal, behavioural intervention, integrating counselling for psychosocial risk factors and coping with illness, should be prescribed. In case of clinically significant symptoms of depression and anxiety, patients should be referred for psychotherapy, and/or medication according to established standards (especially selective serotonin reuptake inhibitors (SSRIs)) should be prescribed. Psychotherapy and SSRIs appear to be safe and effective with respect to emotional disturbances; however, a definite beneficial effect on cardiac end-points has not been documented. PMID- 20839919 TI - ALSUntangled No. 6: Investigating Marty Murray's method. PMID- 20839920 TI - Human immunodeficiency virus type 1 Tat modulates proliferation and differentiation of human neural precursor cells: implication in NeuroAIDS. AB - Human immunodeficiency virus type 1 (HIV-1) and viral proteins affect neuronal survival and neuron-glial cell interactions, which culminate in neurological disorders. HIV-1 infects regions of neurogenesis in human adult and pediatric brain. However, little is known about the effect of HIV-1 or viral proteins on the properties of human neural precursor cells (hNPCs), particularly neurogenesis, hence a detailed investigation on these lines is warranted. Human neural precursor cells were cultured in presence and absence of HIV-1B transactivating protein Tat to investigate if HIV-1 viral protein alters the properties of human neural precursor cells. Cellular and molecular approaches were adopted to study the effect of HIV-1B transactivating protein Tat on proliferation and differentiation potential of human fetal brain-derived NPCs. Cell proliferation assays such as BrdU and Ki67 staining and pathway-specific cDNA and protein arrays were used in the study. Data reveal that HIV-1B Tat protein severely affects proliferation of hNPCs, as evident by lower incorporation of BrdU and Ki67 staining as well as neurosphere assay. HIV-1 Tat substantially attenuated neurogenesis, as evident by the smaller numbers of Tuj-1 and doublecortin-positive cells differentiated from hNPCs, without affecting their viability. These data suggest that HIV-1 Tat alters the properties of human neural precursor cells via attenuation of the cell cycle regulatory unit cyclin D1 and the mitogen-activated protein kinase (MAPK) pathway, particularly extracellular signal-related kinase 1/2 (ERK1/2). The study provides new insights into cellular and molecular mechanisms that may modulate human neural precursor cell properties in HIV/AIDS (acquired immunodeficiency syndrome) individuals. Validation with autopsy brain samples is necessary to further substantiate these important observations. PMID- 20839921 TI - Exploring the relationship of macrophage colony-stimulating factor levels on neuroaxonal metabolism and cognition during chronic human immunodeficiency virus infection. AB - Macrophage colony-stimulating factor (M-CSF) promotes macrophage differentiation, increases susceptibility of macrophages to viral infection, and enhances human immunodeficiency virus (HIV) replication in infected macrophages. Given the current model of HIV neuropathogenesis, which involves monocyte trafficking into the central nervous system, immune factors linked with macrophage maturation and survival may be associated with cognitive decline (measured by neuropsychological z-score [NPZ-8] or Memorial Sloan-Kettering [MSK] score) and alterations in a marker of neuronal integrity, N-acetylaspartate (NAA). Fifty-four chronically infected HIV+ subjects underwent neuropsychological assessment, magnetic resonance spectroscopic imaging, and quantification of M-CSF in plasma and cerebrospinal fluid (CSF) at baseline. Thirty-nine of those subjects underwent further examination at 3 and 10 months after initiation of combination antiretroviral therapy (ART) regimens. Within 3 months of therapy use, CSF M-CSF and viral RNA levels were reduced, whereas NAA concentrations in many brain regions were increased. Neither baseline levels nor the change in M-CSF levels had the ability to predict changes in NAA levels observed after 10 months of combination ART use. At study entry those with the lowest M-CSF levels in the CSF had the least cognitive impairment (NPZ-8). Those who had higher baseline CSF M CSF levels and exhibited larger decreases in M-CSF after therapy, tended to have greater cognitive improvement after 10 months. Increased prevalence of M-CSF in the setting of HIV infection could contribute to neuronal injury and may be predictive of cognitive impairment. PMID- 20839922 TI - Role of a cdk5-associated protein, p35, in herpes simplex virus type 1 replication in vivo. AB - Previous studies have shown that herpes simplex virus type 1 (HSV-1) replication is inhibited by the cyclin-dependent kinase (cdk) inhibitor roscovitine. One roscovitine-sensitive cdk that functions in neurons is cdk5, which is activated in part by its binding partner, p35. Because HSV establishes latent infections in sensory neurons, we sought to determine the role p35 plays in HSV-1 replication in vivo. For these studies, wild-type (wt) and p35−/− mice were infected with HSV-1 using the mouse ocular model of HSV latency and reactivation. The current results indicate that p35 is an important determinant of viral replication in vivo. PMID- 20839923 TI - Solid dispersion of prednisolone: solid state characterization and improvement of dissolution profile. AB - BACKGROUND: Dissolution testing is an important test for judging the effectiveness of a pharmaceutical dosage form. Many drugs create adverse effect because of insufficient solubility at the physiological pH. This study is aimed to improve the dissolution properties of prednisolone (PRD) that falls under the category of class II biopharmaceutics system. METHODS: In this study, preparation of solid dispersions with various water-soluble carriers was studied to improve the dissolution of PRD. To obtain the optimized formulation, solid dispersions were prepared employing different methods using different carriers with various drug:carrier ratios. Their dissolution behaviors were also compared. Fourier transform infrared (FTIR) spectroscopy, powder X-ray diffraction, and thermal analysis were studied to characterize the prepared solid dispersion. RESULTS: PRD formed stable complexes with carriers as indicated by the stability constants (K(a)) of 9.5-597.2 M(-1). The results indicated that in vitro dissolution rate of PRD was remarkably improved in the solid dispersion of the drug compared with physical mixture and drug alone. This can be attributed to improved wettability, dispersibility, decrease in crystallinity, and increase in amorphous fraction of the drug. The results obtained from Fourier transform infrared spectroscopy and powder X-ray diffraction showed good evidence of drug-carrier interaction while using carriers such as hydroxypropyl-beta-cyclodextrin (HP-betaCD) and polyethylene glycol (PEG). Crystallinity of the drug was reduced in the solid dispersions prepared with hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone co-vinyl acetate 64, and PEG as revealed from the differential scanning calorimetry thermograms. CONCLUSION: The results suggested that the solid dispersion with selected excipients is a powerful tool to accelerate the dissolution of poorly water-soluble drugs. PMID- 20839924 TI - Biomarker discovery using SELDI-TOF protein chip technology. PMID- 20839925 TI - Anti-inflammatory activity of Alchornea triplinervia ethyl acetate fraction: inhibition of H2O2, NO and TNF-alpha. AB - CONTEXT: Alchornea triplinervia (Spreng.) Mull. Arg. (Euphorbiaceae) is a tree widespread in many Brazilian states. This plant naturally occurs in different ecosystems including tropical Atlantic forest, Amazon rain forest, moist tropical mixed forest, savanna forest, among others. Local populations traditionally use it in tea form to treat gastric disturbances. OBJECTIVE: The objective of this research was to evaluate the plant A. triplinervia as a potential inhibitor of some macrophage functions involved in the inflammatory process. MATERIALS AND METHODS: The effects of Alchornea triplinervia ethyl acetate fraction (AtF) on hydrogen peroxide (H2O2), nitric oxide (NO) and tumor necrosis factor-alpha (TNF alpha) production in peritoneal macrophages were investigated using phenol red, Griess reagent and a sandwich immunoassay, respectively. RESULTS: AtF chromatographic analyses indicate the presence of flavonoids as majority compounds. The fraction also showed an intense inhibition of H2O2 and NO production. The inhibitory effects of the fraction in H2O2 and NO production ranged from 72.25 +/- 4.68 to 69.64 +/- 4.21 and from 47.8 +/- 8.96 to 76.77 +/- 8.11%, respectively in the two tested concentrations, 15.62 and 62.5 MUg/mL. TNF alpha production was partially inhibited in the tested concentrations and the inhibitory rate was around 18%. DISCUSSION AND CONCLUSION: It is supposed that the elevated biological potential of A. triplinervia is related to the presence of phenolic compounds in the plant leaves. According to the results observed in this study, it is suggested that AtF presents anti-inflammatory activity, supporting the traditional use of A. triplinervia in Brazilian folk medicine. PMID- 20839926 TI - Antibiotics versus resistant bacteria: recent patents. Foreword. PMID- 20839927 TI - New beta-lactam antibiotics and beta-lactamase inhibitors. AB - IMPORTANCE OF THE FIELD: beta-Lactam antibiotics are among the most frequently prescribed antibiotics used to treat bacterial infections. However, their utility is being threatened by the worldwide proliferation of beta-lactamases with broad hydrolytic capabilities, especially in multidrug-resistant Gram-negative bacteria. AREAS COVERED IN THIS REVIEW: This review describes new beta-lactams and beta-lactamase inhibitors described in the patent literature primarily between 2007 and 2010, together with supportive meeting abstracts and relevant descriptive literature. WHAT THE READER WILL GAIN: Readers will learn which classes of beta-lactam antibiotics are being explored as the most promising groups of compounds to counteract resistance in Gram-negative pathogenic bacteria. Somewhat surprisingly, few traditional beta-lactam classes such as penicillins or cephalosporins were described in the literature, other than in combinations with other beta-lactams or beta-lactamase inhibitors that are being developed to inhibit enzymes from all molecular classes. TAKE HOME MESSAGE: beta Lactam antibiotics are currently being developed as monotherapy by only a few companies. The major emphasis in the past 4 years has been the discovery of novel beta-lactamase inhibitors or inhibitor combinations that will allow use of beta lactams against multidrug-resistant bacteria. The use of beta-lactams as single agents appears to be a limited option for the future. PMID- 20839928 TI - Antibiotics versus resistant bacteria: a continual challenge. PMID- 20839930 TI - Influence of drug-transporter polymorphisms on the pharmacokinetics of fexofenadine enantiomers. AB - This study investigated an association of SLCO (encoding organic anion transporting polypeptides (OATP), 1B1, 1B3, and 2B1), ABCB1 (P-glycoprotein (P gp)), ABCC2 multidrug resistance protein 2 (MRP2), and ABCG2 (breast cancer resistance protein (BCRP)) polymorphisms with fexofenadine enantiomer pharmacokinetics after an oral dose of fexofenadine (60 mg) in 24 healthy subjects. The area under the plasma concentration-time curve (AUC(0-24)) of S fexofenadine, but not R-fexofenadine, was significantly lower in subjects with a SLCO2B1*1/*1 allele as compared to subjects with a *3 allele (p = 0.031). The AUC(0-24) of S-fexofenadine was significantly lower in subjects with a wild-type combination of SLCO2B1*1/*1/ABCB1 1236CC, SLCO2B1*1/*1/ABCB1 3435CC, SLCO2B1*1/*1/ABCC2 -24CC, and ABCB1 1236CC/3435CC/ABCC2 -24CC compared to other polymorphic genotypes (p = 0.010, 0.033, 0.022, and 0.036, respectively), whereas there was no difference in the AUC(0-24) between the SLCO1B1/1B3 plus ABCB1 and ABCC2 groups. The pharmacokinetic properties of S-fexofenadine are affected by a single polymorphism of SLCO2B1 in combination with several polymorphisms of ABCB1 C1236T, C3435T, and ABCC2 C-24T. However, the ABCG2 polymorphism was not associated with fexofenadine pharmacokinetics. These findings suggest that a combination of multiple transporters, including OATP, P-gp, and MRP2, reacts strongly to fexofenadine exposure in the small intestine and liver, resulting in different dispositions of both enantiomers. PMID- 20839931 TI - Cyclosporine-induced changes in drug metabolizing enzymes in hyperlipemic rabbit kidneys could explain its toxicity. AB - This study investigates the mechanism of cyclosporine A (CsA)-mediated nephrotoxicity by examining the hypothesis that CsA toxicity is mediated through its effect on the kidney drug metabolizing enzymes in a hyperlipemic rabbit model. Twenty-four female New Zealand white rabbits divided into four groups. Group 1 received regular diet. Group 2 received 1% cholesterol diet. Group 3 received CsA (25 mg/kg, orally once daily) and group 4 received 1% cholesterol diet and CsA (25 mg/kg, orally once daily). Cytochrome P450 2E1 (CYP2E1) activity in kidney microsomes was assessed by measuring p nitrophenol hydroxylase activity. Generation of reactive oxygen species (ROS) was assessed by measuring malondialdehyde (MDA) and the protein carbonyl. Effect of CsA and hyperlipidemia on the antioxidant proteins were also assessed using standard techniques. CsA but not the high-cholesterol diet induced significant elevation in MDA, protein carbonyl and CYP2E1 activities in the kidney. The addition of cholesterol to CsA normalized ROS markers without affecting the CsA enhanced CYP2E1 activity. Alone, CsA caused characteristic tubular injury, whereas the addition of high-cholesterol diet to CsA nearly abolished the tubular damage. CsA-enhanced rabbit kidney ROS and CYP2E1 activities. Hyperlipidemia attenuates CsA tubular injury, most probably due to normalization of renal ROS, but not CYP2E1 activity. PMID- 20839932 TI - Two independent quantitative trait loci are responsible for novel resistance to beet curly top virus in common bean landrace G122. AB - Beet curly top virus, often referred to as Curly top virus (CTV), is an important virus disease of common bean in the semiarid regions of the United States, Canada, and Mexico and the only effective control is genetic resistance. Our objective was to determine if dry bean landrace G122, which lacks the Bct gene for resistance to CTV, contains novel resistance to the virus. Two populations, GT-A and GT-B, consisting of 98 F5:7 recombinant inbred lines (RILs) in total were derived from a cross between G122 and the susceptible variety Taylor Horticultural and evaluated for phenotypic response to natural CTV field infection. Genetic analyses revealed random amplified polymorphism DNA (RAPD) markers associated with a major-effect quantitative trait loci (QTL) from G122 which exhibited stable expression across 3 years in both populations. Phenotypic variation explained by the QTL in GT-A (37.6%) was greater than in GT-B (20.4%). RAPD marker Q14.973 was converted to a sequence-characterized amplified region (SCAR) and designated SQ14.973. The SCAR was used to locate the QTL on linkage group 6 of the Phaseolus core map. A survey of 74 common bean cultivars and breeding lines revealed SQ14.973 would be widely useful for marker-assisted selection of the QTL. An additional minor-effect QTL from G122 was detected on linkage group 7. G122 was determined to possess novel resistance to CTV conditioned by at least two genes, one with major the other minor effect. PMID- 20839933 TI - Propiconazole distribution and effects on Ceratocystis fagacearum survival in roots of treated red oaks. AB - We investigated the interaction between the oak wilt pathogen (Ceratocystis fagacearum) and propiconazole in lower stems and roots of Quercus rubra to better understand published reports of fungicide failure after 2 years. Propiconazole was infused into mature oaks in July 2004 and roots were inoculated with pathogen endoconidia 1.0 m from injection sites at +/-2 weeks of fungicide treatment. Pathogen presence in wood samples was determined by isolation and fungicide concentrations measured using gas chromatography-mass spectrometry. Propiconazole was detected in the roots (<=1.0 m from injection sites) of all treated trees at 2, 12, and 24 months. Propiconazole was detected in all samples (n=68) at 2 and 12 months and in 93% of samples (n=72) at 24 months with concentrations ranging from 815 ppm (12 months in lower stem) to 0.7 ppm (24 months in most distal root segment). Although pathogen isolation incidence was lower in treated than disease control trees at 2 and 12 months, at no time did an infused oak fail to yield the fungus upon isolation. The results document basipetal movement and degradation of propiconazole, as well as the survival of the pathogen, over time in roots and lower stems of infused red oaks. PMID- 20839934 TI - Factors contributing to seasonal fluctuations in rust severity on Ribes missouriense caused by Cronartium ribicola. AB - Cronartium ribicola, causal agent of white pine blister rust, is a macrocyclic heteroecious rust that cycles between white pines and members of the genus Ribes, which are typically wild plants in North America. To improve predictability of inoculum available for infection of ecologically and commercially important white pines, this research was conducted to identify the factors that influence the development and persistence of uredinia and telia on Ribes in their natural habitats. Numbers of infectious C. ribicola rust lesions (with potentially sporulating rust sori) on tagged Ribes missouriense plants in the woods fluctuated during the season. Changes in numbers of infectious rust lesions were related to rain that occurred 13 days earlier. In field experiments, supplemental leaf wetness provided for 2 days on Ribes shoots resulted in the development of rust lesions more frequently than on control shoots. Viable inoculum and susceptible hosts were present, and the environment was the limiting factor for disease development. Lesion necrosis and leaf abscission contributed to decreases in numbers of infectious rust lesions. Higher lesion density was significantly related to earlier leaf abscission. Telial fruiting bodies occurred in low numbers from early June throughout the remainder of the season. PMID- 20839935 TI - Genetic structure of Phytophthora infestans populations in China indicates multiple migration events. AB - One hundred isolates of Phytophthora infestans collected from 10 provinces in China between 1998 and 2004 were analyzed for mating type, metalaxyl resistance, mitochondrial DNA (mtDNA) haplotype, allozyme genotype, and restriction fragment length polymorphism (RFLP) with the RG-57 probe. In addition, herbarium samples collected in China, Russia, Australia, and other Asian countries were also typed for mtDNA haplotype. The Ia haplotype was found during the first outbreaks of the disease in China (1938 and 1940), Japan (1901, 1930, and 1931), India (1913), Peninsular Malaysia (1950), Nepal (1954), The Philippines (1910), Australia (1917), Russia (1917), and Latvia (1935). In contrast, the Ib haplotype was found after 1950 in China on both potato and tomato (1952, 1954, 1956, and 1982) and in India (1968 and 1974). Another migration of a genotype found in Siberia called SIB-1 (Glucose-6-phosphate isomerase [Gpi] 100/100, Peptidase [Pep] 100/100, IIa mtDNA haplotype) was identified using RFLP fingerprints among 72% of the isolates and was widely distributed in the north and south of China and has also been reported in Japan. A new genotype named CN-11 (Gpi 100/111, Pep 100/100, IIb mtDNA haplotype), found only in the south of China, and two additional genotypes (Gpi 100/100, Pep 100/100, Ia mtDNA haplotype) named CN-9 and CN-10 were identified. There were more diverse genotypes among isolates from Yunnan province than elsewhere. The SIB-1 (IIa) genotype is identical to those from Siberia, suggesting later migration of this genotype from either Russia or Japan into China. The widespread predominance of SIB-1 suggests that this genotype has enhanced fitness compared with other genotypes found. Movement of the pathogen into China via infected seed from several sources most likely accounts for the distribution of pathogen genotypes observed. MtDNA haplotype evidence and RFLP data suggest multiple migrations of the pathogen into China after the initial introduction of the Ia haplotype in the 1930s. PMID- 20839936 TI - The 3ADON population of Fusarium graminearum found in North Dakota is more aggressive and produces a higher level of DON than the prevalent 15ADON population in spring wheat. AB - Fusarium head blight (FHB) is primarily caused by Fusarium graminearum in North America. Isolates of F. graminearum can be identified as one of three chemotypes: 3-acetyl-deoxynivalenol (3ADON), 15-acetyl-deoxynivalenol (15ADON), and nivalenol (NIV). In this study, we characterized F. graminearum isolates collected in 1980 to 2000 (old collection) and in 2008 (new collection) from North Dakota and found a 15-fold increase of 3ADON isolates in the new collection. Evaluation of randomly selected 3ADON isolates and 15ADON isolates on three spring wheat genotypes (Grandin, Steele-ND, and ND 2710) by single-floret inoculation indicated that the 3ADON population caused a higher disease severity and produced more DON at a significant level than the 15ADON population on Grandin (susceptible to FHB) and ND 2710 (with FHB resistance from Sumai 3). However, no significant differences in disease severity and DON production were observed between the two populations on Steele-ND (with moderate resistance from Triticum dicoccoides). The 3ADON isolates also exhibited a higher DON production in rice culture and produced more spores on agar media than the 15ADON isolates, suggesting a fitness advantage of the newly emerging 3ADON population over the prevalent 15ADON population. Population genetic analyses using DNA markers revealed a significant genetic differentiation between the two populations. The information obtained in this study could have an impact on development of FHB resistant wheat cultivars and disease management. PMID- 20839937 TI - An assessment of mixed-modeling approaches for characterizing profiles of time varying response and predictor variables. AB - A general statistical modeling approach was tested for characterizing the relationship between pathogen inoculum density (or other biological response variables) and environmental variables when the data are collected as temporal profiles of observations within multiple locations or years. The approach, based on the use of linear mixed models, simultaneously accounts for serial correlations of the observations within each time profile, the random effects of location-year (or other grouping factors), and the cross-correlation of the environmental variables, and is appropriate when the environmental effects on the response variable or its transformation (Y) are distributed over several times (e.g., days). Stability and precision of parameter estimates for environmental effects over multiple time lags were achieved through the use of polynomial constraints within a likelihood-based full mixed-model fit; from the parameter estimates, marginal effects of environmental variables and weights for individual time lags were determined. The mixed model was directly expanded, through the incorporation of smoothing functions, to potentially account for possible longer term trends in the temporal profiles unrelated to the environmental variables being considered. The new approach described here (with or without a smoothing function) generalizes a previously used-and computationally less demanding-two stage (composite) approach. In the previous approach, constrained parameter estimates and associated weights were first determined without consideration of serial correlation, cross-correlation of environmental variables, and the random effects of location-year; then, a mixed-model fit was accomplished using the fixed time-lag weights derived in the first step. Using data for inoculum density of Gibberella zeae on wheat spikes from 27 location-years, similar results were achieved with the full mixed model and the two-stage approaches, in terms of both the calculated parameters and predictions of Y. With the use of smoothing functions, the precision of the predictions was improved but the general conclusions regarding environmental effects on Y were not affected. Thus, in the particular example data set, previously derived conclusions regarding environmental effects on inoculum density were robust in terms of the statistical methodology used in analysis; most researchers will find the two-stage approach much easier to implement for the analysis of multiple profiles of time-varying observations. PMID- 20839938 TI - Some consequences of using the Horsfall-Barratt scale for hypothesis testing. AB - Comparing treatment effects by hypothesis testing is a common practice in plant pathology. Nearest percent estimates (NPEs) of disease severity were compared with Horsfall-Barratt (H-B) scale data to explore whether there was an effect of assessment method on hypothesis testing. A simulation model based on field collected data using leaves with disease severity of 0 to 60% was used; the relationship between NPEs and actual severity was linear, a hyperbolic function described the relationship between the standard deviation of the rater mean NPE and actual disease, and a lognormal distribution was assumed to describe the frequency of NPEs of specific actual disease severities by raters. Results of the simulation showed standard deviations of mean NPEs were consistently similar to the original rater standard deviation from the field-collected data; however, the standard deviations of the H-B scale data deviated from that of the original rater standard deviation, particularly at 20 to 50% severity, over which H-B scale grade intervals are widest; thus, it is over this range that differences in hypothesis testing are most likely to occur. To explore this, two normally distributed, hypothetical severity populations were compared using a t test with NPEs and H-B midpoint data. NPE data had a higher probability to reject the null hypothesis (H0) when H0 was false but greater sample size increased the probability to reject H0 for both methods, with the H-B scale data requiring up to a 50% greater sample size to attain the same probability to reject the H0 as NPEs when H0 was false. The increase in sample size resolves the increased sample variance caused by inaccurate individual estimates due to H-B scale midpoint scaling. As expected, various population characteristics influenced the probability to reject H0, including the difference between the two severity distribution means, their variability, and the ability of the raters. Inaccurate raters showed a similar probability to reject H0 when H0 was false using either assessment method but average and accurate raters had a greater probability to reject H0 when H0 was false using NPEs compared with H-B scale data. Accurate raters had, on average, better resolving power for estimating disease compared with that offered by the H-B scale and, therefore, the resulting sample variability was more representative of the population when sample size was limiting. Thus, there are various circumstances under which H-B scale data has a greater risk of failing to reject H0 when H0 is false (a type II error) compared with NPEs. PMID- 20839939 TI - Modeling the competition between viruses in a complex plant-pathogen system. AB - In this article, we propose a mathematical model that describes the competition between two plant virus strains (MAV and PAV) for both the host plant (oat) and their aphid vectors. We found that although PAV is transmitted by two aphids and MAV by only one, this fact, by itself, does not explain the complete replacement of MAV by PAV in New York State during the period from 1961 through 1976; an interpretation that is in agreement with the theories of A. G. Power. Also, although MAV wins the competition within aphids, we assumed that, in 1961, PAV mutated into a new variant such that this new variant was able to overcome MAV within the plants during a latent period. As shown below, this is sufficient to explain the swap of strains; that is, the dominant MAV was replaced by PAV, also in agreement with Power's expectations. PMID- 20839940 TI - Host range, biological variation, and phylogenetic diversity of Eutypa lata in California. AB - The objectives of this study were to investigate the host range of Eutypa lata in the major grape-growing regions in California and to analyze the phenotypic variation and phylogenetic diversity of E. lata isolates. Perithecia of E. lata were found on grapevines, in apricot, almond, cherry, apple, and pear tree orchards, and on ornamentals (oleander) and native plant species (California buckeye, big leaf maple, and willow). Multigene phylogenies of ribosomal DNA internal transcribed spacer, beta-tubulin, and RPB2 genes confirmed the identity of E. lata recovered from the various host plants but also revealed sequence differences among isolates. The intraspecific phylogenetic diversity of E. lata did not correspond to geography or source of isolation, and intraspecific groups were not consistent across the different DNA phylogenies. Significant phenotypic variation also was detected among E. lata isolates, including ascospore and conidium length as well as level of aggressiveness on grapevines. Pathogenicity studies proved that all isolates were infectious to grapevine, suggesting that the native vegetation surrounding vineyards can serve as inoculum sources that may constitute an important element in the epidemiology of Eutypa dieback in grapevines. PMID- 20839941 TI - Wheat crown rot pathogens Fusarium graminearum and F. pseudograminearum lack specialization. AB - This article reports a lack of pathogenic specialization among Australian Fusarium graminearum and F. pseudograminearum causing crown rot (CR) of wheat using analysis of variance (ANOVA), principal component and biplot analysis, Kendall's coefficient of concordance (W), and kappa statistics. Overall, F. pseudograminearum was more aggressive than F. graminearum, supporting earlier delineation of the crown-infecting group as a new species. Although significant wheat line-pathogen isolate interaction in ANOVA suggested putative specialization when seedlings of 60 wheat lines were inoculated with 4 pathogen isolates or 26 wheat lines were inoculated with 10 isolates, significant W and kappa showed agreement in rank order of wheat lines, indicating a lack of specialization. The first principal component representing nondifferential aggressiveness explained a large part (up to 65%) of the variation in CR severity. The differential components were small and more pronounced in seedlings than in adult plants. By maximizing variance on the first two principal components, biplots were useful for highlighting the association between isolates and wheat lines. A key finding of this work is that a range of analytical tools are needed to explore pathogenic specialization, and a statistically significant interaction in an ANOVA cannot be taken as conclusive evidence of specialization. With no highly resistant wheat cultivars, Fusarium isolates mostly differ in aggressiveness; however, specialization may appear as more resistant cultivars become widespread. PMID- 20839942 TI - A quantitative review of fungicide efficacy for managing downy mildew in cucurbits. AB - A meta-analysis of the effect of fungicides on cucurbit downy mildew was conducted using data previously published in Fungicide & Nematicide Tests and Plant Disease Management Reports from 2000 to 2008. Standardized mean effect size (the difference in disease intensity expressed in standard deviation units between the fungicide treatment and its corresponding untreated control) was calculated for each of the 105 field studies evaluating the effects of fungicides on cucurbit downy mildew. Fixed- and random-effects meta-analyses were performed on the log-transformed standardized mean effect sizes to estimate the overall mean effect size (L+), and to determine the variability in the effect size among studies. Fungicides led to a significant (P<0.001) reduction in disease with an L+ value of 1.198, indicating that, overall, fungicides were highly effective against cucurbit downy mildew. Fixed- and random-effects meta-analyses were then conducted to determine the effects of moderator variables on L+. The fixed effects model resulted in narrower 95% confidence intervals and generally lower estimates of moderator subgroup mean effect size (L) than the random-effects models. Fungicide efficacy was significantly (P<0.001) greater in cucumber, with L being 26.5% higher in cucumber than in other cucurbits. Year of study, number of sprays, and disease pressure in the control significantly (P<0.001) affected L. Fungicide efficacy was significantly lower during the 2004-05 season than prior to or after the 2004-05 season. Studies in which disease pressure was moderate had a significantly higher L than studies with either low or high disease pressure. Fungicide efficacy was >=22% in studies that received 5 to 6 sprays than in studies that received 1 to 4 or >6 sprays. Fungicide products led to a significant (P<0.001) reduction in disease, although there was substantial between-study variability. The pyridinylmethyl-benzamide group of fungicides (fluopicolide) was the most effective, followed by the carbamate (propamocarb) and quinone inside inhibitors (cyazofamid) group of fungicides, while the carboxylic acid amide group (mandipropamid and dimethomorph) was the least effective. A combination of protectant and systemic fungicides resulted in a proportional increase in L compared with sole application of either protectant or systemic fungicides. PMID- 20839943 TI - Development and application of a multiplex reverse-transcription polymerase chain reaction assay for screening a global collection of Citrus tristeza virus isolates. AB - The emerging diversity of Citrus tristeza virus (CTV) genotypes has complicated detection and diagnostic measures and prompted the search for new differentiation methods. To simplify the identification and differentiation of CTV genotypes, a multiplex reverse-transcription polymerase chain reaction (RT-PCR) technique for the screening of CTV isolates was developed. Variable regions within the open reading frame (ORF)-1a of diverse CTV genotypes were identified to develop first a simplex (S) and then a hexaplex (H) RT-PCR. CTV isolates have been grouped previously into five genotypes (namely, T3, T30, T36, VT, and B165) based on the nucleotide sequence comparisons and phylogenetic analyses. Nucleotide sequences from GenBank were used to design species and genotype-specific primers (GSPs). The GSPs were initially used for reliable detection of all CTV genotypes using S RT-PCR. Furthermore, detection of all five recognized CTV genotypes was established using the H-RT-PCR. Six amplicons, one generic to all CTV isolates and one for each of the five recognized genotypes, were identified on the basis of their size and were confirmed by sequence analysis. In all, 175 CTV isolates from 29 citrus-growing countries were successfully analyzed by S- and H-RT-PCR. Of these, 97 isolates contained T36 genotypes, 95 contained T3 genotypes, 76 contained T30 genotypes, 71 contained VT genotypes, and 24 contained B165 genotype isolates. In total, 126 isolates contained mixed infections of 2 to 5 of the known CTV genotypes. Two of the CTV isolates could not be assigned to a known genotype. H-RT-PCR provides a sensitive, specific, reliable, and rapid way to screen for CTV genotypes compared with other methods for CTV genotype detection. Efficient identification of CTV genotypes will facilitate a better understanding of CTV isolates, including the possible interaction of different genotypes in causing or preventing diseases. The methods described can also be used in virus free citrus propagation programs and in the development of CTV-resistant cultivars. PMID- 20839944 TI - Diagnosis of Pierce's disease using biomarkers specific to Xylella fastidiosa rRNA and Vitis vinifera gene expression. AB - Pierce's disease (PD), caused by Xylella fastidiosa, represents one of the most damaging diseases of cultivated grape. Management of PD in the vineyard often relies on the removal of infected individuals, which otherwise serve as a source of inoculum for nearby healthy vines. Effective implementation of such control measures requires early diagnosis, which is complicated by the fact that infected vines often harbor high titers of the pathogen in advance of visual symptom development. Here, we report a biomarker system that simultaneously monitors Xylella-induced plant transcripts as well as Xylella ribosomal (r)RNA. Plant biomarker genes were derived from a combination of in silico analysis of grape expressed sequence tags and validation by means of reverse-transcriptase polymerase chain reaction (RT-PCR). Four genes upregulated upon PD infection were individually multiplexed with an X. fastidiosa marker rRNA and scored using either real-time RT-PCR or gel-based conventional RT-PCR techniques. The system was sufficiently sensitive to detect both host gene transcript and pathogen rRNA in asymptomatic infected plants. Moreover, these plant biomarker genes were not induced by water deficit, which is a component of PD development. Such biomarker genes could have utility for disease control by aiding early detection and as a screening tool in breeding programs. PMID- 20839945 TI - Cpkk1, MAPKK of Cryphonectria parasitica, is necessary for virulence on chestnut. AB - ABSTRACT The role of Cpkk1, a mitogen-activated protein kinase from Cryphonectria parasitica, was investigated by generating a number of mutant strains that overexpress, under the control of the cryparin promoter, both the wild-type protein and its allele with an extensive deletion in the catalytic domain. Furthermore, a hairpin construct was built and expressed to cause specific silencing of Cpkk1 mRNA transcripts. Specific mRNA silencing or overexpression was confirmed on both Northern and Western blot analysis. Selected C. parasitica strains with Cpkk1 either silenced or overexpressed were evaluated for their biological characteristics, including virulence on European chestnut, growth on different substrates, conidial sporulation, and resistance to cell-wall-degrading enzymes. Silencing of Cpkk1 and the overexpression of a defective Cpkk1 correlated with a marked reduction in virulence on 3-year-old chestnut trees, with no statistically significant effect on fungal growth in the various conditions tested. PMID- 20839946 TI - Combinatorially selected peptides for protection of soybean against Phakopsora pachyrhizi. AB - Phakopsora pachyrhizi, the fungal pathogen that causes Asian soybean rust, has the potential to cause significant losses in soybean yield in many production regions of the United States. Germplasm with durable, single-gene resistance is lacking, and control of rust depends on timely application of fungicides. To assist the development of new modes of soybean resistance, we identified peptides from combinatorial phage-display peptide libraries that inhibit germ tube growth from urediniospores of P. pachyrhizi. Two peptides, Sp2 and Sp39, were identified that inhibit germ tube development when displayed as fusions with the coat protein of M13 phage or as fusions with maize cytokinin oxidase/dehydrogenase (ZmCKX1). In either display format, the inhibitory effect of the peptides on germ tube growth was concentration dependent. In addition, when peptides Sp2 or Sp39 in either format were mixed with urediniospores and inoculated to soybean leaves with an 8-h wetness period, rust lesion development was reduced. Peptides Sp2 and Sp39, displayed on ZmCKX1, were found to interact with a 20-kDa protein derived from germinated urediniospores. Incorporating peptides that inhibit pathogen development and pathogenesis into breeding programs may contribute to the development of soybean cultivars with improved, durable rust tolerance. PMID- 20839947 TI - Quantification of propagules of the laurel wilt fungus and other mycangial fungi from the redbay ambrosia beetle, Xyleborus glabratus. AB - The laurel wilt pathogen, Raffaelea lauricola, is a fungal symbiont of the redbay ambrosia beetle, Xyleborus glabratus, which is native to Asia and was believed to have brought R. lauricola with it to the southeastern United States. Individual X. glabratus beetles from six populations in South Carolina and Georgia were individually macerated in glass tissue grinders and serially diluted to quantify the CFU of fungal symbionts. Six species of Raffaelea were isolated, with up to four species from an individual adult beetle. The Raffaelea spp. were apparently within the protected, paired, mandibular mycangia because they were as numerous in heads as in whole beetles, and surface-sterilized heads or whole bodies yielded as many or more CFU as did nonsterilized heads or whole beetles. R. lauricola was isolated from 40 of the 41 beetles sampled, and it was isolated in the highest numbers, up to 30,000 CFU/beetle. Depending on the population sampled, R. subalba or R. ellipticospora was the next most frequently isolated species. R. arxii, R. fusca, and R. subfusca were only occasionally isolated. The laurel wilt pathogen apparently grows in a yeast phase within the mycangia in competition with other Raffaelea spp. PMID- 20839948 TI - Association of chronic vascular changes with functional outcome after traumatic brain injury in rats. AB - We tested the hypothesis that vascular remodeling in the cortex, hippocampus, and thalamus is associated with long-term functional recovery after traumatic brain injury (TBI). We induced TBI with lateral fluid-percussion (LFP) injury in adult rats. Animals were followed-up for 9 months, during which we tested motor performance using a neuroscore test, spatial learning and memory with a Morris water maze, and seizure susceptibility with a pentylenetetrazol (PTZ) test. At 8 months, they underwent structural MRI, and cerebral blood flow (CBF) was assessed by arterial spin labeling (ASL) MRI. Then, rats were perfused for histology to assess the density of blood vessels. In the perilesional cortex, the CBF decreased by 56% (p < 0.01 compared to controls), and vessel density increased by 28% (p < 0.01). There was a negative correlation between CBF in the perilesional cortex and vessel density (r = -0.75, p < 0.01). However, in the hippocampus, we found a 13% decrease in CBF ipsilaterally (p < 0.05) and 20% contralaterally (p < 0.01), and no change in vessel number. In the ipsilateral thalamus, the increase in CBF (34%, p < 0.01) was associated with a remarkable increase in vessel density (78%, p < 0.01). Animals showed motor impairment that was not associated with vascular changes. Instead, poor performance in the Morris water maze correlated with enhanced thalamic vessel density (r = -0.81, p < 0.01). Finally, enhanced seizure susceptibility was associated with reduced CBF in the ipsilateral hippocampus (r = 0.78, p < 0.05) and increased vascular density in the thalamus (r = 0.69, p < 0.05). There was little interaction between the behavioral measures. The present study demonstrates that each of the investigated brain areas has a unique pattern of vascular abnormalities. Chronic alterations in CBF could not be attributed to changes in vascular density. Association of thalamic hypervascularity to epileptogenesis warrants further studies. Finally, hippocampal hypoperfusion may predict later seizure susceptibility in the LFP injury model of TBI, which could be of value for pre-clinical antiepileptogenesis trials. PMID- 20839949 TI - A phase I study of docetaxel, oxaliplatin, & capecitabine (DOC) as first-line therapy of patients with locally advanced or metastatic adenocarcinoma of stomach and GE junction. AB - PURPOSE: We conducted a phase I trial of chemotherapy in patients with advanced gastro-esophageal cancer. METHODS: Eligible patients had chemotherapy doses increased until dose limiting toxicity (DLT) was observed. RESULTS: Fourteen patients were accrued. No DLT was observed in first three patients at level 1. DLT was observed in two out of five patients at level 2. Six additional patients were treated at level 1. CONCLUSIONS: Recommended doses for future trials are: docetaxel 30 mg/m(2) and oxaliplatin 50 mg/m(2) on days 1 and 8 and capecitabine 675 mg/m(2) PO, bid, on days 1-14 on a three weekly basis. PMID- 20839950 TI - Triple-negative breast cancer: unique biology and its management. AB - Triple-negative breast cancer is defined by the lack of expression of estrogen receptor, progesterone-receptor, and HER-2/neu. It primarily, but not exclusively, carries the basal-like molecular profile on gene expression arrays and is associated with BRCA-1 and p53 mutations. It has an aggressive behavior and predilection for visceral metastasis, therefore accounting for its poor prognosis. Despite lacking targeted therapies, it is sensitive to anthracyclines and taxanes. Increasing knowledge has generated a better understanding of its pathophysiology, therefore leading to the development of directed therapies, although their validation still needs further investigation. This review focuses on its biology, management, evolving concepts, and future directions. PMID- 20839951 TI - Skin and soft-tissue infections requiring hospitalization at an academic medical center: opportunities for antimicrobial stewardship. AB - BACKGROUND: Although complicated skin and soft-tissue infections (SSTIs) are among the most common infections requiring hospitalization, their clinical spectrum, management, and outcomes have not been well described. METHODS: We report a cohort of consecutive adult patients hospitalized for SSTI from 1 January through 31 December 2007 at an academic medical center. Cases meeting inclusion criteria were reviewed and classified as cellulitis, cutaneous abscess, or SSTI with additional complicating factors. RESULTS: In total, 322 patients were included; 66 (20%) had cellulitis, 103 (32%) had cutaneous abscess, and 153 (48%) had SSTI with additional complicating factors. Injection drug use, diabetes mellitus, and alcohol abuse were common comorbidities. Serum inflammatory markers were routinely measured and blood cultures and imaging studies were routinely performed in each group. Of 150 patients with a positive culture result for an abscess, deep tissue, or blood, Staphylococcus aureus or streptococci were identified in 145 (97%). Use of antibiotics with broad aerobic gram-negative activity (61%-80% of patients) or anaerobic activity (73%-83% of patients) was frequent in each group. The median duration of therapy for cellulitis, cutaneous abscess, and SSTI with additional complicating factors was 13 (interquartile range [IQR], 10-14), 13 (IQR, 10-16), and 14 (IQR, 11-17) days, respectively. Treatment failure, recurrence, or rehospitalization due to SSTI within 30 days occurred in 12.1%, 4.9%, and 9.2% of patients, respectively. CONCLUSIONS: Hospitalizations for SSTI were common; more than half were due to cellulitis or cutaneous abscess. Frequent use of potentially unnecessary diagnostic studies, broad-spectrum antibiotic therapy, and prolonged treatment courses in these patients suggest targets for antimicrobial stewardship programs. PMID- 20839952 TI - Skin and soft-tissue infections: modern evolution of an ancient problem. PMID- 20839953 TI - What is the "true" incidence of active surveillance and brachytherapy candidates in men undergoing robot-assisted radical prostatectomy? AB - PURPOSE: To correlate clinical low-risk prostate cancers with pathologic outcomes in men who are considered for active surveillance (AS), interstitial radiation therapy, or radical prostatectomy (RP). PATIENTS AND METHODS: Clinical and pathologic data of 76 consecutive patients who underwent RP by a single surgeon between October 2001 and July 2008 were reviewed. The retrospective review identified men with clinical low-risk disease--defined as a prostate-specific antigen (PSA) level <10 ng/mL, no Gleason pattern >3, no >2 cores positive, and no core >50%--who would also have been considered for AS and/or brachytherapy based on these features. Pathologic specimens were examined for Gleason primary, secondary, and tertiary patterns, perineural invasion, capsular involvement, margins, nodal disease, and seminal vesicle involvement. RESULTS: Of the patients who underwent RP, 42/76 (55%) had low-risk clinical staging; 8/76 (19%) had low risk features on final pathologic staging. Fifty-four of 76 (71%) were pT2c; 10% were pT3. Gleason 6 was seen in 41/76 (53%) of RP specimens; Gleason 7 and 8 in 41% and 4%, respectively. Favorable brachytherapy parameters were identified in 63% of those who underwent surgery, but 39 of 48 (81%) would have been inappropriately selected based on features of the pathologic specimen. CONCLUSION: Clinical staging based on PSA level and biopsy findings correlates poorly with pathologic outcome when stratifying for low-risk features in men who may be candidates for brachytherapy and/or AS. PMID- 20839954 TI - Minimally invasive tract in percutaneous nephrolithotomy for renal stones. AB - AIM: The aim of this study was to assess the efficacy, safety, and morbidity of minimally invasive tract in percutaneous nephrolithotomy (Mini-PCNL) for renal stones in comparison with the standard PCNL. PATIENTS AND METHODS: In a randomized trial, 69 patients (72 renal units) undergoing Mini-PCNL (group 1) from May 2004 to December 2007 were compared with a similar group of 111 (115 renal units) patients undergoing standard PCNL (group 2). Patients who needed more than one percutaneous tract or who had simultaneously undergone the two techniques on the same renal unit were excluded from the study group. Chi-square test was performed for statistical analysis of qualitative variables, and Student's t-test for quantitative variables. A p-value of <0.05 was considered significant. RESULTS: The two groups had comparable demographic data and some outcome of characteristics such as time of stay in hospital, postoperative pain, dose of postoperative analgesics, ratio of positive fever, and stone-free rates for some types of stones (e.g., staghorn stone and simple renal pelvis stone). The stone-free rate for multiple caliceal stones (85.2% vs. 70.0% in group 1 and group 2) was significantly higher in the Mini-PCNL group (p < 0.05). The incidence of bleeding necessitating transfusion (1.4% vs. 10.4% in group 1 and group 2) was significantly lower in the Mini-PCNL group (p < 0.05). In group 1, operative time for different stone types such as staghorn stone, simple renal pelvis stone, and multiple caliceal stones were 134.3 +/- 19.7, 89.4 +/- 21.5, and 113.9 +/- 20.3 minutes, respectively, which were significantly longer than that for group 2 (118.9 +/- 21.5, 77.0 +/- 17.6, and 101.2 +/- 19.1 minutes) (p < 0.05). CONCLUSION: Mini-PCNL is safe and effective for managing renal calculi in adult patients. Although smaller working sheath is associated with longer operative time, Mini-PCNL has significantly lower incidence of bleeding necessitating transfusion and higher stone-free rate for multiple caliceal stones in comparison with the standard PCNL. PMID- 20839955 TI - Transperitoneal deviceless hand-assisted laparoscopic living donor nephrectomy: an alternative technique for kidney recovery. AB - PURPOSE: Deviceless hand-assisted laparoscopic living donor nephrectomy is an alternative surgical technique that relies on the classic laparoscopic approach, supported by insertion of the surgeon's hand during kidney recovery without the need to use any device because of the sealing effect of the particular wall incision. PATIENTS AND METHODS: From 2006 to 2008, deviceless hand-assisted laparoscopic living donor nephrectomy was performed in 25 patients (M/F = 7/18; mean age = 53 years; range = 30-68). One right nephrectomy was performed. We made a lateral paramedian incision. No sealing device is required in our technique because the pneumoperitoneum is maintained by the sealing effect of two complexes: the peritoneum/deep rectus abdominis muscle fascia and muscle itself/lateral edge of the double fascial incision. These structures clench around the surgeon's wrist, preventing leakage of CO2. After dissection, the kidney is removed through the hand port without an endobag. RESULTS: Mean surgical time was 105 minutes (range = 60-150), estimated blood loss was 50 to 200 mL, and mean warm ischemia time was 3.5 minutes (range = 2-11). Mean hospital stay was 4 days (range = 3-6). One uncontrollable hemorrhage due to a renal vein lesion required conversion to open surgery. As to graft function, recipient serum creatinine on day 7 ranged from 0.8 to 2.6 mg/dL. CONCLUSIONS: The ability to better control bleeding by manual compression, as well as the advantages related to decreased donor morbidity, shorter hospital stay, cost saving, and excellent graft function, make this deviceless technique a good option for kidney recovery. PMID- 20839956 TI - Sexual steroids in urogynecology. AB - The decline in sex hormone levels that accompanies the menopause has substantial effects on the tissues of the urogenital system, leading to atrophic changes. These changes can have negative effects on sexual and urinary function. The authors evaluate the repercussion of hypoestrogenism and sexual steroids on some elements of the pelvic floor and lower urinary tract. They summarize their research work and review significant published papers. They emphasize the changes in urinary mucosae, periurethral vessels, muscular layer, connective tissue, gene expression, autonomic nervous system receptors, as well as the main clinical aspects involved. PMID- 20839957 TI - Hypercholesterolemia accelerates bone loss in postmenopausal women. AB - OBJECTIVES: To clarify the effect of lipid profiles on postmenopausal bone loss using a longitudinal method and to determine whether cytokines are involved in bone loss. METHODS: The subjects were Japanese residents participating in the Iwaki Health Promotion Projects. Women with one or more of the following factors were excluded: a history of surgical menopause, current or past users of bisphosphonates or current user of other drugs known to influence bone and lipid metabolism, and current medication for diabetes or hypertension. Consequently, 99 postmenopausal women (61.2 +/- 7.7 years old) and 85 premenopausal women (41.2 +/ 8.6 years old) were selected for this study. The osteo-sono-assessment index (OSI) of the left calcaneal bone was obtained twice at 1-year intervals and the annual percentage change in OSI was calculated. Serum total cholesterol, high and low density lipoprotein cholesterol, triglycerides, homocysteine and cytokines such as adipocytokines, interleukins and tumor necrosis factor-alpha were measured. Postmenopausal women were grouped into three groups according to their basal cholesterol level, and the relationship between basal cholesterol level and annual change in OSI was studied. RESULTS: The annual percentage change in OSI in postmenopausal women with a serum total cholesterol level >=240 mg/dl was significantly higher compared to those with a normal total cholesterol level, suggesting that hypercholesterolemia accelerates postmenopausal bone loss. No significant differences were seen in any of the cytokines that presumably cause bone resorption. CONCLUSION: These results showed that hypercholesterolemia has an inverse effect on bone loss independent of cytokines presumed to mediate bone loss. PMID- 20839958 TI - VdSNF1, the sucrose nonfermenting protein kinase gene of Verticillium dahliae, is required for virulence and expression of genes involved in cell-wall degradation. AB - Verticillium dahliae is a soilborne fungus causing vascular wilt in a diverse array of plant species. Its virulence has been attributed, among other factors, to the activity of hydrolytic cell wall-degrading enzymes (CWDE). The sucrose nonfermenting 1 gene (VdSNF1), which regulates catabolic repression, was disrupted in V. dahliae tomato race 1. Expression of CWDE in the resulting mutants was not induced in inductive medium and in simulated xylem fluid medium. Growth of the mutants was significantly reduced when grown with pectin or galactose as a carbon source whereas, with glucose, sucrose, and xylose, they grew similarly to wild-type and ectopic transformants. The mutants were severely impaired in virulence on tomato and eggplant (final disease severity reduced by an average of 87%). Microscopic observation of the infection behavior of a green fluorescent protein (gfp)-labeled VdSNF1 mutant (70DeltaSF-gfp1) showed that it was defective in initial colonization of roots. Cross sections of tomato stem at the cotyledonary level showed that 70DeltaSF-gfp1 colonized xylem vessels considerably less than the wild-type strain. The wild-type strain heavily colonized xylem vessels and adjacent parenchyma cells. Quantification of fungal biomass in plant tissues further confirmed reduced colonization of roots, stems, and cotyledons by 70DeltaSF-gfp1 relative to that by the wild-type strain. PMID- 20839960 TI - Population genetic analysis of Tomato spotted wilt virus on peanut in North Carolina and Virginia. AB - Exploring the genetic diversity and evolutionary history of plant viruses is critical to understanding their ecology and epidemiology. In this study, maximum likelihood and population genetics-based methods were used to investigate the population structure, genetic diversity, and sources of genetic variation in field isolates of Tomato spotted wilt virus (TSWV) from peanut in North Carolina and Virginia. Selected regions of the nucleocapsid, movement, and RNA-dependent RNA polymerase genes were amplified and sequenced to identify haplotypes and infer genetic relationships between isolates of TSWV with heuristic methods. The haplotype structure of each locus consisted of 1 or 2 predominant haplotypes and >100 haplotypes represented by a single isolate. No specific haplotypes were associated with geographic area, peanut cultivar, or year of isolation. The population was panmictic at the regional level and high levels of genetic diversity were observed among isolates. There was evidence for positive selection on single amino acids in each gene on a background of predominant purifying selection acting upon each locus. The results of compatibility analyses and the persistence of specific gene sequences in isolates collected over three field seasons suggest that recombination was occurring in the population. Estimates of the population mutation rate suggest that mutation has had a significant effect on the shaping of this population and, together with purifying selection, these forces have been the predominant evolutionary forces influencing the TSWV population in peanut in North Carolina and Virginia. PMID- 20839959 TI - The impact of working part-time on measures of academic productivity among general internists. AB - BACKGROUND: There is increased interest in part-time (PT) positions at academic medical centers (AMCs). Faculty and institutional leaders may have concerns about the potential for academic advancement among PT faculty. Our objective was to determine the impact of working PT on measures of academic productivity. METHODS: A cross-sectional survey was mailed to PT and full-time (FT) physicians in U.S. divisions of general internal medicine. Outcome measures included publications and funding. We used multivariate analysis to identify factors associated with academic productivity. RESULTS: The response rate was 63% (176 of 279); 91% of respondents were women (160 of 176). Compared with FT faculty, PT faculty were more often clinicians (Cs) or clinician-educators (CEs) (78% vs. 96%, p < 0.001), were less likely to be fellowship trained (44% vs. 23%, p < 0.001), and reported less academic support, including administrative assistance (84% vs. 67%, p = 0.008), mentoring (71% vs. 54%, p = 0.02), and research support (43% vs. 25%, p = 0.01). PT faculty spent a greater percentage of their time in patient care (55% vs. 45%, p = 0.01) and teaching (32% vs. 23%, p = 0.01) and less time in research activities (5% vs. 15%, p = 0.01) compared with FT faculty. Among Cs and CEs, FT faculty reported more publications (median 2, interquartile range [IQR 5] vs. median 0, IQR 1, p < 0.001) and funding (odds ratio [OR] 2.85, 95% confidence internal [CI] 1.36-5.98). Multivariate analyses showed that fellowship training, mentors, academic support, and number of total years worked were associated with publications and acquisition of funding. There were no associations between working PT and publications or funding. CONCLUSIONS: PT faculty report fewer publications and grants. This may be related to insufficient training and academic support. AMCs wanting to facilitate the success of their PT faculty may need to expand the support available to them. PMID- 20839961 TI - A test of taxonomic and biogeographic predictivity: resistance to soft rot in wild relatives of cultivated potato. AB - The concept that traits should be associated with related organisms and that nearby populations of the same species are likely to be more similar to each other than to populations spread far apart has long been accepted. Consequently, taxonomic relationships and biogeographical data are commonly believed to have the power to predict the distribution of disease resistance genes among plant species. In this study, we test claims of such predictivity in a group of widely distributed wild potato species. There was no clear association between resistance to soft rot and taxonomic relationships. However, we have found some associations between resistance to soft rot and environmental data such as annual precipitation and annual mean temperature. In addition, we have noted that high levels of resistance are mostly found in species with high levels of phenotypic plasticity. The three most resistant species were Solanum paucijugum, S. brevicaule, and S. commersonii. PMID- 20839962 TI - Mechanistically compatible mixtures of bacterial antagonists improve biological control of fire blight of pear. AB - Mixtures of biological control agents can be superior to individual agents in suppressing plant disease, providing enhanced efficacy and reliability from field to field relative to single biocontrol strains. Nonetheless, the efficacy of combinations of Pseudomonas fluorescens A506, a commercial biological control agent for fire blight of pear, and Pantoea vagans strain C9-1 or Pantoea agglomerans strain Eh252 rarely exceeds that of individual strains. A506 suppresses growth of the pathogen on floral colonization and infection sites through preemptive exclusion. C9-1 and Eh252 produce peptide antibiotics that contribute to disease control. In culture, A506 produces an extracellular protease that degrades the peptide antibiotics of C9-1 and Eh252. We hypothesized that strain A506 diminishes the biological control activity of C9-1 and Eh252, thereby reducing the efficacy of biocontrol mixtures. This hypothesis was tested in five replicated field trials comparing biological control of fire blight using strain A506 and A506 aprX::Tn5, an extracellular protease-deficient mutant, as individuals and combined with C9-1 or Eh252. On average, mixtures containing A506 aprX::Tn5 were superior to those containing the wild-type strain, confirming that the extracellular protease of A506 diminished the biological control activity of C9-1 and Eh252 in situ. Mixtures of A506 aprX::Tn5 and C9-1 or Eh252 were superior to oxytetracycline or single biocontrol strains in suppressing fire blight of pear. These experiments demonstrate that certain biological control agents are mechanistically incompatible, in that one strain interferes with the mechanism by which a second strain suppresses plant disease. Mixtures composed of mechanistically compatible strains of biological control agents can suppress disease more effectively than individual biological control agents. PMID- 20839963 TI - Control of fire blight by Pseudomonas fluorescens A506 and Pantoea vagans C9-1 applied as single strains and mixed inocula. AB - The biological control agents Pseudomonas fluorescens A506 and Pantoea vagans C9 1 were evaluated individually and in combination for the suppression of fire blight of pear or apple in 10 field trials inoculated with the pathogen Erwinia amylovora. The formulation of pathogen inoculum applied to blossoms influenced establishment of the pathogen and the efficacy of biological control. Pantoea vagans C9-1 suppressed fire blight in all five trials in which the pathogen was applied as lyophilized cells but in none of the trials in which the pathogen was applied as freshly harvested cells. In contrast, Pseudomonas fluorescens A506 reduced disease significantly in only one trial. A mixture of the two strains also suppressed fire blight, but the magnitude of disease suppression over all field trials (averaging 32%) was less than that attained by C9-1 alone (42%). The two biological control agents did not antagonize one another on blossom surfaces, and application of the mixture of A506 and C9-1 to blossoms resulted in a greater proportion of flowers having detectable populations of at least one bacterial antagonist than the application of individual strains. Therefore, the mixture of A506 and C9-1 provided less disease control than expected based upon the epiphytic population sizes of the antagonists on blossom surfaces. We speculate that the biocontrol mixture was less effective than anticipated due to incompatibility between the mechanisms by which A506 and C9-1 suppress disease. PMID- 20839964 TI - Disease-reducing effect of Chromolaena odorata extract on sheath blight and other rice diseases. AB - Sheath blight caused by Rhizoctonia solani (teleomorph: Thanatephorus cucumeris) is a major cause of crop loss in intensive rice production systems. No economically viable control methods have been developed. We screened aqueous extracts of common herbal plants that could reduce sheath blight lesions and found that foliar spraying and seed soaking application of extracts of either fresh or dried leaves of Chromolaena odorata gave up to 68% reduction in sheath blight lesion lengths under controlled and semi-field conditions. The observed reductions were not dependent on growth conditions of C. odorata and rice cultivar. The effect was observed until 21 days after inoculation and was not dependent on microbial activity. Under semi-field conditions, extracts also reduced severity of other important rice diseases, i.e., blast (Pyricularia oryzae) using foliar spray (up to 45%), brown spot (Bipolaris oryzae) using seed treatment (up to 57%), and bacterial blight (Xanthomonas oryzae pv. oryzae) using both application methods (up to 50%). PMID- 20839965 TI - Effects of different potato cropping system approaches and water management on soilborne diseases and soil microbial communities. AB - Four different potato cropping systems, designed to address specific management goals of soil conservation, soil improvement, disease suppression, and a status quo standard rotation control, were evaluated for their effects on soilborne diseases of potato and soil microbial community characteristics. The status quo system (SQ) consisted of barley underseeded with red clover followed by potato (2 year). The soil-conserving system (SC) featured an additional year of forage grass and reduced tillage (3-year, barley/timothy-timothy-potato). The soil improving system (SI) added yearly compost amendments to the SC rotation, and the disease-suppressive system (DS) featured diverse crops with known disease suppressive capability (3-year, mustard/rapeseed-sudangrass/rye-potato). Each system was also compared with a continuous potato control (PP) and evaluated under both irrigated and nonirrigated conditions. Data collected over three potato seasons following full rotation cycles demonstrated that all rotations reduced stem canker (10 to 50%) relative to PP. The SQ, SC, and DS systems reduced black scurf (18 to 58%) relative to PP; SI reduced scurf under nonirrigated but not irrigated conditions; and scurf was lower in DS than all other systems. The SQ, SC, and DS systems also reduced common scab (15 to 45%), and scab was lower in DS than all other systems. Irrigation increased black scurf and common scab but also resulted in higher yields for most rotations. SI produced the highest yields under nonirrigated conditions, and DS produced high yields and low disease under both irrigation regimes. Each cropping system resulted in distinctive changes in soil microbial community characteristics as represented by microbial populations, substrate utilization, and fatty acid methyl-ester (FAME) profiles. SI tended to increase soil moisture, microbial populations, and activity, as well result in higher proportions of monounsaturated FAMEs and the FAME biomarker for mycorrhizae (16:1 omega6c) relative to most other rotations. DS resulted in moderate microbial populations and activity but higher substrate richness and diversity in substrate utilization profiles. DS also resulted in relatively higher proportions of FAME biomarkers for fungi (18:2 omega6c), actinomycetes, and gram-positive bacteria than most other systems, whereas PP resulted in the lowest microbial populations and activity; substrate richness and diversity; proportions of monounsaturated and polyunsaturated FAME classes; and fungal, mycorrhizae, and actinomycete FAME biomarkers of all cropping systems. Overall, soil water, soil quality, and soilborne diseases were all important factors affecting productivity, and cropping systems addressing these constraints improved production. Cropping system approaches will need to balance these factors to achieve sustainable production and disease management. PMID- 20839966 TI - Identification of risk drinking women: T-ACE screening tool or the medical record. AB - BACKGROUND: Risk drinking for women is defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as >7 drinks per week or >3 drinks per occasion. This study compares the T-ACE screening tool and the medical record for identification of risk drinking by 611 women receiving outpatient treatment for diabetes, hypertension, infertility, or osteoporosis in Boston, Massachusetts, between February 2005 and May 2009. METHODS: All subjects completed a diagnostic interview about their health habits, and medical records were abstracted. Calculations were weighted to reflect the oversampling of risk drinking women. RESULTS: T-ACE-positive women (n = 419) had significantly more drinks per drinking day (2.1 vs. 1.6, p < 0.0001) and a trend toward more binges (6.3 vs. 3.8, p = 0.07) but similar percent drinking days and risk drinking weeks compared with those with negative screens (n = 192). Among the 521 (85%) medical records available, 46% acknowledged alcohol use, 25% denied use, and 29% were silent. The rates of abstinence among women were 2%, 17%, and 4%, respectively. Significantly more women were risk drinkers (63%) and had current alcohol use disorders (12%) when their medical records acknowledged alcohol use. CONCLUSIONS: The main findings of this study are that neither the T-ACE nor the medical record was especially effective in identifying risk drinking by the women enrolled in the study. The identification of risky or heavy alcohol use in women, particularly if they have health problems exacerbated by alcohol, is desirable and represents an area of improvement for patients and providers alike. PMID- 20839967 TI - Unilateral frontosphenoidal craniosynostosis with achondroplasia: a case report. AB - Isolated, premature fusion of the frontosphenoidal suture is rare. This report describes an unusual combination of frontosphenoidal craniosynostosis and achondroplasia. Although craniosynostosis is known to occur in allelic conditions such as thanatophoric dysplasia, craniosynostosis in individuals with achondroplasia is exceedingly rare. Due to the distracting diagnosis of achondroplasia or inadequate knowledge of craniosynostosis, the abnormal head shape was initially treated by other physicians with helmet molding. Plastic surgery consultation was obtained at 2 years of age and surgical care was provided. An acceptable head shape was obtained, but the delay in appropriate evaluation was disconcerting. To our knowledge this is the first reported case of isolated frontosphenoidal craniosynostosis associated with achondroplasia. PMID- 20839969 TI - Improving the reporting of interventions in clinical trials of acupuncture: the updated and revised STRICTA. PMID- 20839971 TI - Ureteritis cystica: a rare cause of ureteral obstruction. AB - Ureteritis cystica is a rare, but recognized cause of ureteral obstruction. To our knowledge, we present the first case where obstruction secondary to the cystic component is confirmed with a functional study. Additionally, we present high-quality radiologic and endoscopic images of two cases of ureteritis cystica. PMID- 20839968 TI - Bone disease in HIV infection: a practical review and recommendations for HIV care providers. AB - Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV) infected subjects. Initiation of antiretroviral therapy is associated with a 2% 6% decrease in BMD over the first 2 years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV infected post-menopausal women, and all HIV-infected men ?50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge. PMID- 20839972 TI - The light bulb, cystoscopy, and Thomas Alva Edison. AB - BACKGROUND AND PURPOSE: Thomas Alva Edison was an icon of American achievement who literally invented the 20th century. Although best known as the inventor of the electric light bulb, the phonograph, and motion pictures, he also left a lasting legacy via peripheral developmental applications, such as endoscopes. METHODS: A review of published urologic writings about incandescent cystoscopes was cross-referenced to writings about or from Edison. Important events that allowed transference of technology from the Edison laboratory to clinical practice were emphasized. RESULTS: Edison was born in 1847 while Lincoln was serving in Congress; he died in 1931 when Hoover struggled with the Great Depression. Edison's life spanned the formative period of America that Henry Adams called the "coming of age." Edison received a Sprengel vacuum device in late 1879, and as usual, he was able to tweak the machine to better performance. For 5 days in October, 16 to 21, he improved the vacuum from 1/100,000 to 1/1,000,000 atm, and his first incandescent bulb burned softly. On December 21, 1879, he leaked the story to N.Y. Herald journalist Marshall Fox, and the world was notified of the light bulb. Special Christmas light visits started in Menlo Park just 4 days later. Edison patented the screw cap for easy changes, and the first bulbs sold for 40 cents (cost $1.40). 100,000 bulbs sold in 1882, 4 million by 1892, and 45 million in 1903. Immediately, competitors and specialty manufacturers entered the market. Dr. Henry Koch and Charles Preston in Rochester, N.Y., developed a smaller, low amperage bulb that could be fitted to medical devices. CONCLUSIONS: No discussion of electricity and modern applications would be complete without some discussion of Thomas Alva Edison and his sentinel contributions. The first church, post office, and ship were illuminated in 1892. The first hotel, theater, and electric sign were in 1893. The rapidity of dispersal and secondary applications of Edison's inventions is typified by the rise of cystoscopes. Nitze used a modified Edison bulb in his second and third generation scopes by 1887-1888 within 8 years of discovery. PMID- 20839973 TI - Robot-assisted radical cystectomy and pelvic lymph node dissection: a multi institutional study from Korea. AB - PURPOSE: To report short-term retrospective perioperative and pathologic outcomes of the first robot-assisted radical cystectomy (RARC) series in Korea. PATIENTS AND METHODS: Between April 2007 and August 2009, 104 nonconsecutive patients, including 22 women, underwent RARC across seven institutions. We evaluated the outcomes in these cases, including operative variables, hospital recovery, pathologic outcomes, and complication rate. RESULTS: The mean age of all patients was 63.6 years (range 39-82 years), and the mean body mass index was 23.6 kg/m(2) (range 16.0-31.8 kg/m(2)). Among the 104 patients, 60 had an ileal conduit and 44 had an orthotopic neobladder. The mean total operative time was 554 minutes, and the mean blood loss was 526 mL. The time to flatus and bowel movement was about 3 days, and the time until hospital discharge was about 18 days. The mean number of lymph nodes removed were 18, and 10 patients had node metastatic disease on final pathologic evaluation. Postoperative complications occurred in 28 (26.9%) patients. CONCLUSIONS: Our initial experience with RARC appears to be favorable with acceptable operative, pathologic, and short-term clinical outcomes. The current series suggests that RARC is becoming more prevalent, not only in Western countries, but also in Asian countries, just as robot-assisted radical prostatectomy has also gained widespread acceptance. Data from long-term, large, prospective, multicenter, ideally randomized comparative studies with open radical cystectomy are needed to confirm the outcome of the novel operation reported here. PMID- 20839980 TI - Requests clarification on study of congenital portosystemic shunts. PMID- 20839981 TI - What is your diagnosis? Osteomyelitis with internal sequestration. PMID- 20839982 TI - What is your diagnosis? Melamine cyanurate-associated nephrotoxicosis. PMID- 20839983 TI - Pathology in practice. PMID- 20839984 TI - ECG of the month. PMID- 20839985 TI - Rabies surveillance in the United States during 2009. AB - During 2009, 49 states and Puerto Rico reported 6,690 rabid animals and 4 human rabies cases to the CDC, representing a 2.2% decrease from the 6,841 rabid animals and 2 human cases reported in 2008. Approximately 92% of reported rabid animals were wildlife. Relative contributions by the major animal groups were as follows: 2,327 (34.8%) raccoons, 1,625 (24.3%) bats, 1,603 (24.0%) skunks, 504 (75%) foxes, 300 (4.5%) cats, 81 (1.2%) dogs, and 74 (1.1%) cattle. Compared with 2008, numbers of rabid raccoons and bats that were reported decreased, whereas numbers of rabid skunks, foxes, cats, cattle, dogs, and horses that were reported increased. Fewer rabid raccoons, compared with 2008, were reported by 12 of the 20 eastern states where raccoon rabies is enzootic, and number of rabid raccoons decreased by 2.6% overall nationally. Despite a 10% decrease in the number of rabid bats that were reported and a decrease in the total number of bats submitted for testing, bats were the second most commonly submitted animal, behind cats, during 2009. The number of rabid skunks that were reported increased by 0.9% overall. The proportion of rabid skunks in which infection was attributed to the raccoon rabies virus variant decreased from 473% in 2008 to 40.9% in 2009, resulting in a 12.7% increase in the number of rabid skunks infected with a skunk rabies virus variant. The number of rabid foxes increased 11.0% overall from the previous year. Four cases of rabies involving humans were reported from Texas, Indiana, Virginia, and Michigan. The Texas case represented the first presumptive abortive human rabies case, with the patient recovering after the onset of symptoms without intensive care. The Indiana and Michigan cases were associated with bat rabies virus variants. The human rabies case in Virginia was associated with a canine rabies virus variant acquired during the patient's travel to India. PMID- 20839988 TI - Evaluation of the association between plasma concentration of N-terminal proatrial natriuretic peptide and outcome in cats with cardiomyopathy. AB - OBJECTIVE: To determine whether plasma N-terminal proatrial natriuretic peptide (NT-proANP) concentration could predict the outcome (survival duration) of cats with cardiomyopathy (CM). DESIGN: Case-control study. ANIMALS: 51 cats with CM (25 with and 26 without congestive heart failure [CHF]) and 17 healthy cats. PROCEDURES: Cats were thoroughly examined and assigned to 1 of 3 groups (control, CM with CHF, and CM alone). Plasma NT-proANP concentrations were measured by use of a human proANP(1-98) ELISA. Survival durations were compared between CM groups. RESULTS: Plasma NT-proANP concentrations differed significantly among the 3 groups, and survival durations differed significantly between the 2 CM groups. Median (range) NT-proANP concentration was 413 fmol/mL (52 to 940 fmol/mL) in the control group, 1,254 fmol/mL (167 to 2,818 fmol/mL) in the CM alone group, and 3,208 fmol/mL (1,189 to 15,462 fmol/mL) in the CM with CHF group. At a cutoff of 517 fmol/mL, NT-proANP concentration had a sensitivity of 90% and specificity of 82% for detecting CM. Multivariate analysis revealed that only the variable left atrium-to-aortic diameter ratio was a significant predictor of survival duration. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma NT-proANP concentration may have potential as a testing marker for distinguishing healthy cats from cats with CM. It may also be useful for distinguishing CM cats with CHF from those without CHF The value of NT-proANP concentration as a predictor of survival duration was not supported in this study and requires further evaluation. PMID- 20839989 TI - Effect of a synthetic appeasing pheromone on behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs. AB - OBJECTIVE: To study the effects of a synthetic, dog-appeasing pheromone (sDAP) on the behavioral, neuroendocrine, immune, and acute-phase perioperative stress responses in dogs undergoing elective orchiectomy or ovariohysterectomy. DESIGN: Randomized, controlled clinical trial. ANIMALS: 46 dogs housed in animal shelters and undergoing elective orchiectomy or ovariohysterectomy. PROCEDURES: Intensive care unit cages were sprayed with sDAP solution or sham treated with the carrier used in the solution 20 minutes prior to use. Dogs (n = 24 and 22 in the sDAP and sham treatment exposure groups, respectively) were placed in treated cages for 30 minutes before and after surgery. Indicators of stress (ie, alterations in behavioral, neuroendocrine, immune, and acute-phase responses) were evaluated perioperatively. Behavioral response variables, salivary cortisol concentration, WBC count, and serum concentrations of glucose, prolactin, haptoglobin, and C reactive protein were analyzed. RESULTS: Behavioral response variables and serum prolactin concentration were influenced by sDAP exposure. Dogs exposed to sDAP were more likely to have alertness and visual exploration behaviors after surgery than were dogs exposed to sham treatment. Decreases in serum prolactin concentrations in response to perioperative stress were significantly smaller in dogs exposed to sDAP, compared with findings in dogs exposed to the sham treatment. Variables examined to evaluate the hypothalamic-pituitary-adrenal axis, immune system, and acute-phase responses were unaffected by treatment. CONCLUSIONS AND CLINICAL RELEVANCE: sDAP appeared to affect behavioral and neuroendocrine perioperative stress responses by modification of lactotropic axis activity. Use of sDAP in a clinical setting may improve the recovery and welfare of dogs undergoing surgery. PMID- 20839990 TI - Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease). AB - OBJECTIVE: To characterize the clinical signs of globoid cell leukodystrophy (GLD) in Australian Kelpies from a working line (AWKs) and determine whether an association existed between these signs and degrees of demyelination and inflammatory responses in affected brains. DESIGN: Case-control study. ANIMALS: 4 AWKs with GLD (cases) and 7 unaffected young adult dogs of mixed breeding (controls). PROCEDURES: Clinical records were reviewed for information on signalment, and samples of neurologic tissues underwent histological processing, immunohistochemical staining, and image analysis. Findings were compared between case and control dogs. RESULTS: The 4 affected AWKs had progressive ataxia, tremors, and paresis and low leukocyte activity of galactosylceramidase, the lysosomal enzyme deficient in GLD. Image analysis of neurologic tissue revealed globoid cells characteristic of GLD and substantial demyelination in the peripheral and central nervous systems, relative to that in neurologic tissue from control dogs. This was accompanied by microglial activation, reactive astrocyto-sis, and axonal spheroid formation. CONCLUSIONS AND CLINICAL RELEVANCE: The demyelination, inflammatory responses, and axo-nal spheroids evident in the AWKs were consistent with the clinical signs of peripheral nerve, spinal cord, and cerebellar dysfunction. Because GLD is an autosomal recessive inherited disease, with considerable overlap in galactosylceramidase activity existing among heterozygotes and noncarriers, development of a molecular test is important for preventing the perpetuation of this disease in the Australian Kelpie breed. PMID- 20839991 TI - Use of a unique method for removal of a foreign body from the trachea of a cat. AB - CASE DESCRIPTION: A 2.96-kg (6.5-lb) 9-month-old spayed female domestic longhair cat was admitted for removal of a tracheal foreign body. CLINICAL FINDINGS: The cat had moderate respiratory distress but otherwise appeared to be healthy. Thoracic radiography revealed a foreign body in the trachea. TREATMENT AND OUTCOME: The cat was anesthetized and endoscopy of the trachea was performed in an attempt to retrieve the foreign body. Endoscopic removal was unsuccessful because of the shape and smooth texture of the foreign body. Surgical removal of the foreign body was not considered ideal because of its location and the risks associated with tracheotomy. Fluoroscopic-guided placement of an over-the-wire balloon catheter caudal to the foreign body was followed by inflation of the balloon and gradual traction in an orad direction, which resulted in successful removal of the foreign body (identified as a piece of landscaping gravel). The cat required supplemental oxygen and supportive care following removal of the foreign body. CLINICAL RELEVANCE: A fluoroscopic technique was used as a minimally invasive alternative to endoscopy or open-chest surgery for removal of a foreign body from the trachea of a cat. Use of this technique allowed uninterrupted ventilation of the cat throughout the procedure. PMID- 20839993 TI - Immune-mediated pure red cell aplasia in a domestic ferret. AB - CASE DESCRIPTION: An 8-month-old spayed female domestic ferret (Mustela putorius furo) was referred for examination to determine the cause of lethargy and severe anemia. CLINICAL FINDINGS: Initial examination revealed that the ferret was lethargic but with appropriate mentation. The only other abnormal findings were severe pallor of the mucous membranes, nasal planum, and skin and a PCV of 8%. Pure red cell aplasia (PRCA) was diagnosed on the basis of cytologic evaluation of a bone marrow biopsy specimen. TREATMENT AND OUTCOME: Medical treatment included blood transfusions, IM administration of iron dextran, oral administration of antimicrobials and gastrointestinal tract protectants, and SC administration of erythropoietin. Once PRCA was diagnosed, the ferret was orally administered prednisone, cyclosporine, and azathioprine. Nine months after onset of treatment, the PRCA was in remission and the ferret was doing well. Immunosuppressive treatment was discontinued at 14 months after onset of treatment, and 36 months after initial examination, the ferret appeared to be healthy. CLINICAL RELEVANCE: It is important that PRCA be considered as a differential diagnosis for a ferret with severe anemia. Prolonged immunosuppressive treatment was successful in the ferret described here. PMID- 20839994 TI - Characteristics of clinical trials assessing antimicrobial treatment of bovine respiratory disease, 1970-2005. AB - OBJECTIVE: To evaluate reporting of key study design features and study outcomes in trials of antimicrobial treatment of bovine respiratory disease (BRD) in North American feedlots. DESIGN: Systematic review. SAMPLE POPULATION: 29 manuscripts (41 studies) reporting antimicrobial treatment of BRD in North American feedlot cattle. PROCEDURES: A search of the electronic citation databases AGRICOLA, Commonwealth Agricultural Bureau, and PubMed was conducted to identify relevant manuscripts published between 1970 and 2005. Key study design features were extracted by 2 reviewers. RESULTS: 12 of 29 (41%) manuscripts did not disclose a funding source, and 21 (72%) had an author clearly identified as an employee of a pharmaceutical company. At the study level, 36 of 41 (88%) studies reported a random method of treatment allocation, 9 (22%) described the method of allocation sequence generation, 20 (49%) reported that study investigators were blinded to treatment, and 3 (7%) included a study size justification. No studies described the null hypothesis to be tested. Thirty-seven (90%) studies reported at least 3 outcomes; the largest number of outcomes reported was 14. It was not possible to conduct the statistical analysis as originally planned because it was not possible to discern the primary outcome for the majority of studies. CONCLUSIONS AND CLINICAL RELEVANCE: Many studies did not report key study design features that would assist critical evaluation by readers. It was not clear whether the studies failed to use the design features or failed to report them. Several nondesign features, such as reporting of the null hypothesis, a primary outcome, and sample size rationale, represent relatively new standards for reporting; however, reporting these features would substantially clarify the study objective. PMID- 20839995 TI - Manual wheelchair-related mobility characteristics of older adults in nursing homes. AB - AIM: Manual wheelchairs are commonly prescribed for older adults in nursing homes (NH). The extent of their utilisation being unknown may result in the prescription of standard wheelchairs. The purpose of this study was to quantify manual wheelchair use by nursing home residents. METHODS: Seventy-two independent wheelchair users were recruited from four NH (two VA-affiliated and two private). A customised wheelchair data logger was attached to each participant's wheelchair for 1 month. Data were reduced and compared separately for VA- affiliated and private facilities by types of propulsion pattern (arms versus legs and the combination of arms and legs) using MANOVA. RESULTS: Participants from the VA affiliated facilities who used their arms were covering more distance (1451 m versus 806 m), with greater endurance (73 m versus 60 m) as compared to participants who used combination of arms and legs. However, no difference was observed between velocity of wheelchair propulsion between groups (0.48 m/s versus 0.58 m/s). For private facilities no notable difference was observed between the groups. CONCLUSION: Older adults who live in NH and use of wheelchairs represent a diverse cohort. The efficacy of using an objective assessment method to measure the extent of use of wheelchairs was demonstrated in this study. PMID- 20839996 TI - Clinical proof of practicability for an ECG device without any conductive contact. AB - Heart rhythm disturbances are common symptoms of several heart disorders. One of the most effective screening methods is the traditional electrode-based ECG. However, this examination can be both time- and resource-consuming. Capacitive coupling ECG (cECG) screening--working without any conductive electrical contact with the patient--might help to shorten the time required for diagnosis. In this study, we examine the practicability of employing a non-contact capacitive ECG in a clinical setting. A total of 30 volunteer patients aged over 50 years without pacemakers were included in our trial, after obtaining their written informed consent and their medical history. A cECG as well as a conventional, conductive ECG were recorded simultaneously. In addition to mathematical analysis, ECG data were manually evaluated by two clinicians blinded to the recording method and patient conditions. Data from 30 patients were collected during our study, seven of whom had experienced myocardial infarction. The obtained cECG signals showed a high correlation with the simultaneously recorded Einthoven lead II of the conventional ECG. The values for heart rate, PQ and QT time periods correlated particularly well. Significant differences were observed with regard to QRS duration. Data recorded in the supine position contained less motion artefacts and, in particular, there were fewer breathing artefacts compared to data collected from those in a sitting position. Owing to the easy and quick application of the cECG system, the feedback from the examined patients was consistently positive. In conclusion, recording cECG data in a sitting position provided sufficient quality for screening purposes. Further studies will be needed for the evaluation of cECG appropriateness in diagnosing heart disease. PMID- 20839997 TI - Zinc supplementation results in improved therapeutic potential of bone marrow derived mesenchymal stromal cells in a mouse ischemic limb model. AB - BACKGROUND AIMS: We wanted to determine whether zinc supplementation can inhibit bone marrow-derived mesenchymal stromal cell (MSC) apoptosis and enhance their tissue regenerative potential a in mouse ischemic hindlimb model. METHODS: Rat bone marrow cells were cultured and the resulting MSC were passaged for 3-7 generations. The proliferation and apoptosis of MSC was examined by 3-[4,5 dimethyl-2-thiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis. The activation of protein kinases B (Akt) was determined by Western blots. Vascular endothelial growth factor (VEGF) levels were examined by enzyme-linked immunosorbent assay. The mouse hindlimb ischemic model was established by ligating the right femoral artery. Mice received MSC, zinc-treated MSC or vehicle. The blood flow was assessed by laser Doppler imaging. The survival rate of donor cells was quantified by real-time polymerase chain reaction for the sex-determining region of the Y-chromosome (Sry). Angiogenesis was assessed by histochemical staining and immunofluoresence staining. RESULTS: Supplementation with physiologic amounts of zinc caused a marked attenuation of cell apoptosis, enhanced cell viabilities, increased VEGF release and up regulated Akt activation. Zinc-treated MSC delivered into ischemic hindlimbs resulted in significant improvements in limb blood perfusion by increased implanted MSC survival and stimulated angiogenesis. CONCLUSIONS: This study demonstrates the potential of zinc supplement to enhance survival of engrafted MSC and ameliorate their tissue regenerative potential in a mouse ischemic hindlimb model. PMID- 20839998 TI - Human marrow-isolated adult multilineage-inducible (MIAMI) cells protect against peripheral vascular ischemia in a mouse model. AB - BACKGROUND AIMS: The treatment of peripheral vascular disease (PVD) with stem cells potentially offers a promising strategy. We tested marrow-isolated adult multilineage-inducible (MIAMI) cells to induce neovascularization in a mouse model of critical hindlimb ischemia (CLI). METHODS: CLI was induced in the right hindlimb of Balb/C mice. One million MIAMI cells, normally grown at 3% O2, were injected in the adductor muscle along the ischemic region. All animals (n = 11 per group) were immunosuppressed with cyclosporine daily for the entire period. Human foreskin fibroblast (HFF) cells and phosphate-buffered saline (PBS) were used as controls. Blood perfusion in the ischemic right and non-ischemic left hindlimbs was measured. RESULTS: Compared with animals receiving HFF cells or PBS, MIAMI cells significantly improved blood perfusion, necrosis and inflammation in the ischemic limb. A fraction of injected MIAMI cells expressed CD31 and von Willebrand factor (vWF). MIAMI cells in vitro, under pro-angiogenic growth conditions, differentiated into endothelial-like cells and expressed endothelial markers such as CD31 and vWF, determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), and CD31 and kinase insert domain receptor (KDR), determined by immunofluorescence. Moreover, MIAMI cells formed vascular endothelial-like tubules in the presence of matrigel. Bioplex immunoassay analysis showed increased secretion of angiogenic/anti-inflammatory factors by the MIAMI cells under 3% O2 compared with 21% O2, including monocyte chemoattractant protein-1 (MCP-1), fractalkine (Ftk), growth-related oncogene (GRO), vascular endothelial growth factor (VEGF), interleukin (IL)-6 and IL-8. Furthermore, transcripts for anti-inflammatory molecules stanniocalcin-1 (STC-1) and tumor necrosis factor-alpha-stimulated gene 6 (TSG-6) were up-regulated several fold. CONCLUSIONS: MIAMI cells can be very useful for patients affected by CLI. MIAMI cells promote blood vessel formation and reduce inflammation and necrosis in ischemic tissue. PMID- 20839999 TI - Intrahepatically transplanted human cord blood cells reduce SW480 tumor growth in the presence of bispecific EpCAM/CD3 antibody. AB - Humanized mice were generated in order to investigate the anti-tumor efficacy of bispecific antibodies. The engraftment, distribution and differentiation of mononuclear cells (MNC) from cord blood transplanted into the liver of newborn non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice were measured. Using a human-specific polymerase chain reaction (PCR), human cells were found to be present in the liver for a time range from 5 min to 5 days. After long-term engraftment of 42 days, the highest level of human cells was measured in mouse thymus, with lower levels in spleen and bone marrow. Engrafted human cells in mouse organs showed T-cell differentiation only, as measured by CD3, CD4 and CD8 expression. The MNC transplanted intrahepatically into newborn mice were tested for T-cell mediated anti-tumor activity in vivo against subcutaneously transplanted human SW480 colon carcinoma in NOD/SCID mice. A delay of SW480 tumor growth in mice in the presence of a bispecific epithelial cell adhesion molecule (EpCAM)/CD3 antibody was found to be associated with the presence of immunoreactive human CD3 cells within the SW480 tumor. Our data provide evidence that the intrahepatic transplantation of cord blood stem cells into newborn mice represents a valuable model for establishing functionally active human T cells with anti-tumor activity. PMID- 20840000 TI - Impact of injecting drug use on response to highly active antiretroviral treatment in HIV-1-infected patients: a nationwide population-based cohort study. AB - The objective of this study was to determine the effect of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected patients infected through injecting drug use (injecting drug users, IDUs) compared to patients infected via other routes (non-IDUs). We conducted a nationwide population-based cohort study of all HIV-infected patients who initiated HAART during the study period of 1 January 1995 to 31 December 2007. We compared changes in CD4(+) cell counts, percentage of full viral suppression (< 500 copies/ml) and mortality from start of HAART, as well as differences in initial HAART regimen. Three thousand six hundred and fifteen patients were included in the study, representing 22,804 person-y of observation. A total of 346 (9.6%) were categorized as IDUs. Of IDUs, 55% gained full viral control within the first y after HAART compared to 76% of non-IDUs (p = 0.0002). Absolute CD4(+) cell count and survival were lower for IDUs compared to non-IDUs (adjusted mortality rate ratio 3.6 (95% CI 2.9-4.3)). IDUs were more likely to receive a first regimen based on protease inhibitors (PIs) compared to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens for non-IDUs, and IDUs initiated HAART later than non-IDUs. In conclusion, more than half of the HIV infected patients in Denmark infected through injecting drug use gained full viral suppression after initiating HAART. Absolute CD4(+) cell count was lower and mortality higher among IDUs than non-IDUs. PMID- 20840001 TI - Suspected measles-mumps-rubella vaccine-related encephalitis: two cases. AB - The cases of 2 infants who developed acute encephalitis in close temporal proximity to receiving measles-mumps-rubella vaccination are described. One developed modified hypsarrhythmia and recovered completely with adrenocorticotrophic hormone protocol, while the other remains severely neurologically handicapped. The timing between vaccination and symptom onset raises suspicion of the vaccine as the possible cause. PMID- 20840002 TI - Infection disclosure in the injecting dyads of Hungarian and Lithuanian injecting drug users who self-reported being infected with hepatitis C virus or human immunodeficiency virus. AB - The aim of this study was to assess the prevalence and correlates of disclosure to network members of being hepatitis C virus (HCV)- or human immunodeficiency virus (HIV)-infected among injecting dyads of infected injection drug users (IDUs) in Budapest, Hungary and Vilnius, Lithuania,. Multivariate generalized estimating equations (GEE) were used to assess associations. Very strong infection disclosure norms exist in Hungary, and HCV disclosure was associated with using drugs and having sex within the dyad. Non-ethnic Russian IDUs in Lithuania were more likely to disclose HCV infection to non-Roma, emotionally close and HCV-infected network members, and to those with whom they shared cookers, filters, drug solutions or rinse water or got used syringes from, and if they had fewer non-IDU or IDU network members. Ethnic Russian Lithuanian IDUs were more likely to disclose HCV if they had higher disclosure attitude and knowledge scores, 'trusted' network members, and had lower non-injecting network density and higher injecting network density. HIV-infected Lithuanian IDUs were more likely to disclose to 'trusted' network members. Disclosure norms matched disclosure behaviour in Hungary, while disclosure in Lithuania to 'trusted' network members suggests possible stigmatization. Ongoing free and confidential HCV/HIV testing services for IDUs are needed to emphasize and strengthen disclosure norms, and to decrease stigma. PMID- 20840003 TI - The accuracy of the procalcitonin test for the diagnosis of neonatal sepsis: a meta-analysis. AB - A meta-analysis was performed to assess the accuracy of the procalcitonin (PCT) test for diagnosing neonatal sepsis. The major databases, MEDLINE, EMBASE and the Cochrane Library were searched for studies published between January 1996 and May 2009 that evaluated PCT as a diagnostic marker for neonatal sepsis and provided sufficient data to calculate sensitivity and specificity. Twenty-two studies were included in the analysis. Trials that evaluated the PCT test for the diagnosis of early-onset neonatal sepsis at different time points (birth, 0-12 h, 12-24 h, and 24-48 h) and late-onset neonatal sepsis (LONS) all showed moderate accuracy (Q* = 0.79, 0.86, 0.81, 0.82, and 0.77, respectively). The PCT test was more accurate than the C-reactive protein (CRP) test for the diagnosis of LONS. A sensitivity analysis found that differences in PCT assay producer, gestational age and severity of sepsis in the study population may partially explain the between studies heterogeneity. The PCT test showed moderate accuracy in diagnosing neonatal sepsis, regardless of differences in diagnostic criteria and time points for testing. For the diagnosis of LONS, the PCT test showed better accuracy than the CRP test. PCT is a valuable additional tool for the diagnosis of neonatal sepsis. PMID- 20840004 TI - Edentulism associated with obesity: a study of four national surveys of 16 416 Swedes aged 55–84 years. AB - OBJECTIVE: To investigate the association between edentulism and obesity in the Swedish population aged 55-84 years over a 22-year period as a result of changes in health and socio-economic factors. MATERIAL AND METHODS: Subjects aged 55-84 years (n = 16 416) were randomly sampled from the Swedish population by Statistics Sweden on four occasions (1980-81, 1988-89, 1996-97 and 2002). Trained interviewers collected information about dental status and anthropometric, demographic, socio-economic, lifestyle and health-related factors. Statistical analyses were based on logistic regression models. RESULTS: Edentulism decreased from 43% to 14% in the age group 55-84 years from 1980 to 2002, and the proportion of subjects with removable dentures decreased from 68% to 33%. In the age group 55-74 years, the proportion of subjects with low education decreased from 60% to 28%, and the proportion of obese subjects (body mass index >=30 kg/m2) increased from 9% to 15%. In women aged 55-74 years, the association between obesity and edentulism, adjusted for health, lifestyle and socioeconomic factors, was significant in all surveys, and the odds ratio for obesity changed from 1.64 (95% confidence interval 1.18-2.27) in 1980 to 3.17 (95% confidence interval 1.69-6.18) in 2002. In men, the association was weaker and was significant only in the sample that combined all surveys and included individuals aged 55-84 years. CONCLUSION: The study indicated an association between edentulism and obesity, which was most obvious in women aged 55-74 years. PMID- 20840005 TI - Cardiac troponin T detection using polymers coated quartz crystal microbalance as a cost-effective immunosensor. AB - Cardiac troponin T (cTnT) detection has been the focus of increased interest due to its role in myocardial infarction diagnosis. In this study, we report a relatively low coat technique to detect cTnT using a quartz crystal microbalance (QCM) sensor. A sensitive detection is achieved by introducing a QCM surface with a carboxylic polyvinyl chloride immobilization layer. The surface morphologies of this polymer film under varied deposition thickness have been investigated by field emission scanning electron microscopy and atomic force microscopy. A cTnT detection result from a modified QCM surface can be obtained within a short response time by a direct detection of the immunoreaction and a direct conversion of mass accumulation into a frequency shift, representing a measurable electrical signal. The relationship between the cTnT concentration and the response current from a QCM sensor shows detectability at the concentration of cTnT as low as 5 ng/ml. PMID- 20840006 TI - Hybrid independent component analysis and twin support vector machine learning scheme for subtle gesture recognition. AB - Myoelectric signal classification is one of the most difficult pattern recognition problems because large variations in surface electromyogram features usually exist. In the literature, attempts have been made to apply various pattern recognition methods to classify surface electromyography into components corresponding to the activities of different muscles, but this has not been very successful, as some muscles are bigger and more active than others. This results in dataset discrepancy during classification. Multicategory classification problems are usually solved by solving many, one-versus-rest binary classification tasks. These subtasks unsurprisingly involve unbalanced datasets. Consequently, we need a learning methodology that can take into account unbalanced datasets in addition to large variations in the distributions of patterns corresponding to different classes. Here, we attempt to address the above issues using hybrid features extracted from independent component analysis and twin support vector machine techniques. PMID- 20840007 TI - Development of a device to simulate tooth mobility. AB - OBJECTIVES: The testing of new materials under simulation of oral conditions is essential in medicine. For simulation of fracture strength different simulation devices are used for test set-up. The results of these in vitro tests differ because there is no standardization of tooth mobility in simulation devices. The aim of this study is to develop a simulation device that depicts the tooth mobility curve as accurately as possible and creates reproducible and scalable mobility curves. MATERIALS AND METHODS: With the aid of published literature and with the help of dentists, average forms of tooth classes were generated. Based on these tooth data, different abutment tooth shapes and different simulation devices were designed with a CAD system and were generated with a Rapid Prototyping system. Then, for all simulation devices the displacement curves were created with a universal testing machine and compared with the tooth mobility curve. With this new information, an improved adapted simulation device was constructed. RESULTS: A simulations device that is able to simulate the mobility curve of natural teeth with high accuracy and where mobility is reproducible and scalable was developed. PMID- 20840008 TI - Relative contributions of plantar fascia and ligaments on the arch static stability: a finite element study. AB - The plantar fascia (PF) and major ligaments play important roles in keeping the static foot arch structure. Their functions and relative contributions to the arch stability have not been well studied. A three-dimensional finite element foot model was created based on the reconstruction of magnetic resonance images. During balanced standing, four cases after individual releases of the PF, spring ligament (SL), and long and short plantar ligaments (LPL and SPL) were simulated, to compare their biomechanical consequences with the normal predictions under the intact structure. Although the predictions showed the arch did not collapse obviously after each structure sectioning, the internal mechanical behaviors changed considerably. The PF release resulted in the maximal increases of approximately 91%, 65% and 47% in the tensions of the LPF, SPL and SL, produced the largest changes in all bone rotations, and brought an obvious shift of high stress from the medial metatarsals to the lateral metatarsals. The SL release mainly enhanced bone rotation angles and weakened the joint stability of the arch structure. The LPL and the SPL performed the roles of mutual compensation as either one was released. The influence of the LPL on the load distribution among metatarsals was greater than for the SPL and the SL. PMID- 20840009 TI - Recent Swedish clinical practice guidelines for prevention and management of metabolic risk. PMID- 20840010 TI - The past and the present of Estonian psychiatry. PMID- 20840011 TI - The secret of Turkey red--technology transfer with a Scottish connection. AB - The successful commercial introduction of the Turkey red textile dyeing process from Western and South Asia into Western Europe occurred via France in the mid 18th century. The French state was deeply involved in facilitating this technology transfer. During the later half of the century, French dyers from Rouen were involved in a further transfer of this process into Great Britain. In particular, the efforts of Scottish dyers to recruit and utilize the knowledge and skills of M. Papillon, the ambiguous role of the Scottish Board of Manufactures, and the assistance of Professors Black and Hope are described. The eventual success of such ventures resulted in the implementation of the Turkey red process industrially in Glasgow by 1785. PMID- 20840012 TI - T3 regulates E-cadherin, and beta- and alpha-catenin expression in the stomach during the metamorphosis of the toad Rhinella arenarum. AB - The metamorphosis of Rhinella arenarum was induced precociously for 5 days, then blocked for 3 months to evaluate the role of thyroid hormones as modulators of morphoregulatory molecules such as E-cadherin, and beta- and alpha-catenin during epithelium remodeling. We then performed an immunohistochemical and morphometric study of these molecules in the larval stomach. We show that 3,5,3' triiodothyronine exerts a positive regulatory effect on E-cadherin and beta- and alpha-catenin expression in stomach epithelium. This suggests continuous synthesis of E-cadherin, and beta- and alpha-catenin; synthesis essentially is thyroid hormone-independent during premetamorphosis and early prometamorphosis, but it becomes thyroid hormone-dependent during metamorphic climax. PMID- 20840014 TI - Immunogenetics of invasive aspergillosis. AB - Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis. PMID- 20840015 TI - Expression of beta-catenin in rheumatoid arthritis fibroblast-like synoviocytes. AB - OBJECTIVE: beta-Catenin is the key mediator of the Wnt signal and also a component of E-cadherin complexes at the intercellular adhering junction, which mediates cell-cell adhesion. We hypothesized that beta-catenin might be involved in the long-lasting changed phenotype of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) and could play a role in the pathogenesis of RA. In this study we investigated the expression of beta-catenin in RA-FLS. METHODS: Synovial tissues were obtained during joint replacement surgery or arthroscopy from six patients with RA, six patients with osteoarthritis (OA), and six patients with joint trauma (Trauma group). Immunohistochemical analysis of beta-catenin was performed in the synovial tissues from the three groups. Synovial tissues from three patients in each group were selected at random for FLS isolation. Expression of beta-catenin in FLS from the three groups was evaluated at the protein level by western blotting and at the mRNA level by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Immunohistochemistry revealed that the expression of beta-catenin in synovial lining cells of the RA samples was significantly greater than that of the OA or trauma samples (p < 0.01). Western blotting and RT-PCR showed that beta-catenin expression was elevated in RA-FLS compared with that in OA-FLS or Trauma-FLS (p < 0.05) at the protein level but no difference was found at the mRNA level. CONCLUSIONS: Expression of beta-catenin is elevated in RA-FLS, not only in vitro but also in vivo. The increase is due to activation of Wnt/beta-catenin signalling. Wnt/beta-catenin signalling is activated in RA-FLS, and contributes to the stable activation of RA-FLS. PMID- 20840016 TI - Major arterial aneurysms and pseudoaneurysms in Behcet's disease: results from a single centre. AB - OBJECTIVE: Behcet's disease (BD) with arterial involvement is closely correlated with mortality and morbidity due to life-threatening complications such as arterial occlusion and aneurysm rupture. We aimed to determine the clinical characteristics of BD patients with aneurysms and pseudoaneurysms in the major arterial systems. METHODS: Medical records of 30 BD patients diagnosed with aneurysms or pseudoaneurysms in the major arterial systems were reviewed to determine the clinical characteristics of BD, the sites and types of arterial aneurysms or pseudoaneurysms, laboratory test results, and response to treatment. RESULTS: A total of 47 aneurysms and pseudoaneurysms (32 saccular aneurysms, eight fusiform aneurysms, and seven pseudoaneurysms) were detected in 30 patients. Most aneurysms and pseudoaneurysms (27 patients, 90%) had not ruptured. Symptomatic lesions presented in 21 patients (70%), and asymptomatic lesions were incidentally detected in nine (30%). Ten of the 30 patients (33.3%) presented two or more aneurysmal lesions. Recurrence was observed in five patients (16.7%) after treatment with stent graft (n = 3), graft interposition (n = 1), or graft embolization (n = 1). CONCLUSION: We suggest that BD patients diagnosed with major arterial aneurysms should be further evaluated to detect possible associated venous or arterial thrombosis formations or aneurysmal lesions at other sites. PMID- 20840017 TI - Correlations between pain and function in a longitudinal low back pain cohort. AB - PURPOSE: Most studies of low back pain (LBP) and functional limitation have been cross-sectional, and show only modest correlations between pain and function. Though functional limitation may be superior for predicting disability outcomes, there is a need to understand better the gap between pain and function. This study analysed changes in intra-individual correlations between pain and function over time. METHOD: Seventeen men and 16 women currently experiencing LBP provided self-reports of LBP (0-to-10 scale) and functional status (Back Pain Functional Scale) for a maximum of 8 weeks. Spearman correlation coefficients between pain and function scores were calculated for each individual. The effects of pain history, pain intensity, variability and trends over time on pain-function correlations were assessed. RESULTS: There were no significant differences in correlation due to gender, age or pain intensity (low versus high). Participants with steeper slopes in change in pain score over the study period had significantly stronger correlations to function than those with weaker trends, r = -0.91 and r = -0.45, respectively. Participants with at least one pain-free score during the reporting period had significantly stronger correlations than those with no pain-free reports, r = -0.80 and r = -0.51, respectively. Participants having the first episode LBP had stronger correlations (r = -0.85) than those with persistent symptoms of LBP (r = -0.62). CONCLUSIONS: The results suggest that over the course of LBP, within-person pain-function correlations are stronger than those reported in cross-sectional, population-based studies. Changes in pain ratings over time may have more clinical relevance than differences in pain levels between individuals. Among those with more long standing pain, factors other than pain intensity, such as pain catastrophising or fear avoidant beliefs, may have a greater effect on day-to-day perceptions of functional limitation. PMID- 20840018 TI - The phonological skills of Samoan speaking 4-year-olds. AB - To date there has been little research on the typical developmental patterns for children speaking Samoan. The research outlined in this paper serves to fill this gap by reporting on the phonological development of Samoan speaking children growing up in the English dominant language environment of Auckland New Zealand. In this study 20 children aged between 4;0 and 4;11 were assessed using a picture naming task that probed their knowledge of the Samoan phonemic inventory. The findings presented here give an indication of what children in their fifth year have as speech sounds in their phonetic inventory and the types of errors that they may still produce. These results demonstrate the similarities and differences that Samoan phonological development shares with other languages. In particular the differences that seem "atypical" when compared with studies on English are discussed. It is tentatively concluded that these differences may well be typical for Samoan speech acquisition given language specific factors and the bilingual context in which these children are growing up. PMID- 20840019 TI - Oral language predictors for the at-risk reader: A review. AB - The importance of early identification of at-risk readers has received attention in recent literature. This paper reviews evidence for oral language components, shown to have predictive capacity to identify at-risk readers at an early age. Both phonological and non-phonological components of oral language difficulties are linked to poor reading outcomes in a majority of children. At-risk preschoolers may present with phonological deficits, sub-clinical or clinical language impairment. The nature and importantly the trajectory of reading difficulty will vary, depending on the area of language breakdown. Irrespective, difficulty with reading comprehension is likely to result. Importantly, the variation in the trajectory of reading difficulty means that some children may struggle during the initial phases of learning to read, whereas others may experience initial success, but encounter difficulties at a later point when reading demands increase. Clinical implications for speech-language pathology assessment practices and ongoing monitoring of oral language and reading skills are discussed. PMID- 20840020 TI - Vowel features in Turkish accented English. AB - The present study quantified the amount of accent in English vowels produced by native adult Turkish speakers. Vowels that are present in both Turkish and English (close vowels) were compared with those that are present only in English (distant vowels). The first two formant frequencies (F1 and F2) were obtained from the 11 English monophthong vowels (/i, i, e, epsilon, ae, Lambda, u, [Formula: see text], o, [Formula: see text], [Formula: see text]/) produced by 20 Turkish-accented English (TE) (10 males and 10 females) bilinguals and 20 native American English (AE) speakers. Euclidean distance (ED) was used to measure the separation between the corresponding TE and AE vowels. Perceptual experiment was also carried out to assess the amount of accent in the English produced by Turkish speakers as perceived by native monolingual English speakers. F1 and F2 values revealed that TE speakers generally were able to produce close and distant vowels comparably, with considerable amount of deviation from AE speakers. ED values for close and distant vowels were not significantly different. The amount of perceived accent indicated the precision of vowel production and was found to directly correlate with the acoustic findings. PMID- 20840021 TI - Theory of mind impairment in right hemisphere damage: A review of the evidence. AB - Among the hypothesized causes of communication impairments in people with damage to the right cerebral hemisphere (RHD) is an underlying impairment in Theory of Mind (ToM) (the ability to make inferences about other peoples' mental states). In this review, evidence is considered for a ToM impairment in adults with RHD by approaching the issue from two directions. First, indirect evidence for impairment of ToM is reviewed by looking at studies on the effects of RHD on the comprehension of indirect requests, that is, requests in which the speaker's wishes are not explicitly stated but must be inferred by the listener. Second, studies that directly investigate the effects of RHD on performance on tasks intended to tap ToM are reviewed. On the basis of the papers reviewed here, it is concluded that although people with RHD do show impairments on a variety of tasks that are thought to involve ToM cognition, evidence for a specific ToM impairment is still inconclusive. It is recommended that future studies take care to distinguish individual differences in participants' linguistic production and lesion location, that more care is taken to control for task difficulty, and that well-controlled studies are combined with more naturalistic, ecologically valid tasks. PMID- 20840022 TI - An examination of how speech and language therapists assess and diagnose children with specific language impairment in Ireland. AB - Three criteria for diagnosing specific language impairment (SLI) are defined in the literature: exclusionary definitions, inclusionary definitions, and qualitative markers. However, the assessment and diagnosis of this complex impairment in clinical practice can be challenging. The aims of this research were twofold: (1) to make explicit the current assessment procedures which speech and language therapists (SLTs) use when they diagnose children with SLI in Ireland, and (2) to explore SLT's perceptions and experiences of the process of diagnosing children with SLI. Both quantitative and qualitative methods were used in this study. A survey of 199 SLTs in Ireland was carried out to address aim one and a focus group was conducted to address the second aim. The findings were that SLTs use exclusionary and inclusionary definitions of SLI, and qualitative markers when assessing children who they suspect may have SLI. SLTs in Ireland consider a diagnosis of SLI when children present with a verbal-performance discrepancy, a positive family history, word finding difficulties and lack of progress in therapy. The results of the qualitative strand indicated that assessment and diagnosis of children with SLI is a complex, time-consuming process involving other professionals. What emerged was a complex picture with tensions between therapists' professional judgements, policy, evidence-based practice and resources. PMID- 20840023 TI - Problem-based learning, critical thinking and concept mapping in speech-language pathology education: A review. AB - Despite speech-language pathology (SLP) education undergoing many innovative changes over the years, there has been little research about learning or outcomes in SLP programs. Critical thinking in clinical decision-making, however, has been identified as a critical skill in SLP. Several recent studies have shown that concept mapping can be used to assess, and perhaps enhance, critical thinking. Problem-based learning (PBL) is reported to be one way to encourage critical thinking and life-long learning. Here we review the literature in PBL, concept mapping, and critical thinking, focusing on the education of SLP students. The review illustrates the close and complex interactions amongst problem-based learning, critical thinking and concept mapping. The aim of the review is to provide a better understanding of the mechanism of PBL, and to increase understanding regarding why the employment of PBL in SLP programs may facilitate critically-thinking graduate clinicians. The evidence indicates that PBL allows more meaningful learning that promotes better integration between theory and clinical practice. PMID- 20840024 TI - Teacher identification of speech and language impairment in kindergarten students using the Kindergarten Development Check. AB - The purpose of this paper was to profile the extent and accuracy of teacher identification of speech and language impairment within a kindergarten student population in Tasmania, Australia, using the Kindergarten Development Check (KDC). A total of 286 kindergarten students (aged 4-5 years and in their first year of formal schooling) were screened by teachers with the KDC on two separate occasions over their kindergarten year. In the following academic year, each of the same 286 students were assessed by a speech-language pathologist, and diagnosed with either typically developing or impaired speech and/or language skills. Review of KDC data determined the number of students identified by teachers with speech and language impairment at each occasion during their kindergarten year. Comparison of data from the later KDC administration and speech-language pathology assessment then determined the correspondence between identification of speech and language impairment by teachers and speech-language pathologists. Upon initial administration of the KDC, 51 (17.8%) students were identified by teachers with language impairment and 47 (16.4%) students with speech impairment. Following the second administration of the KDC 3 months later, 20 (7.0%) students continued to be identified with language impairment, and 39 (13.6%) with speech impairment. Comparison of speech-language pathology testing results and KDC data from the second administration found the overall validity of teacher identification was 86.4% and 71% for speech and language impairment respectively. Specificity rates were high, with 93% and 97% of students with typically developing speech and language skills respectively, correctly classified on the KDC. However, the sensitivity was only 50% for speech impairment and 15% for language impairment, indicating that 50% of students presenting with speech impairment and 85% of students with language impairment in their subsequent academic year were not recorded by teachers as having such a difficulty on the later KDC administration during their kindergarten year. The KDC appears to be ineffective in supporting kindergarten teachers to identify students with ongoing speech and to a greater extent, language impairment. Measures to improve the sensitivity of the KDC in particular need to be considered by speech-language pathologists and educational professionals in Tasmania. PMID- 20840025 TI - Two-year-olds' phonological acquisition: Normative data. AB - The study reported evaluated an assessment of phonology for 2-year-olds to establish normative data and determine if early identification of children with speech difficulties is possible. The study evaluated 62 2-year-old children on the Toddler Phonology Test (TPT). Children produced 32 words, spontaneously or in imitation. Ten of the children were assessed three times, on the third occasion, when they had reached 3 years, on another phonological assessment. The data indicated that older children performed better than younger children on quantitative measures. Girls and boys performed equally well. Their phonetic repertoires were missing some fricatives and all affricates, as well as /r/. Consistently used error patterns identified included cluster reduction, final consonant deletion, stopping, fronting, weak syllable, deletion, gliding and deaffrication. Correlation analyses indicated that performance at the first assessment on the TPT indicated performance on subsequent assessments. While quantitative data was not a reliable predictive indicator of speech disorder, qualitative analysis of error types was predictive, with children who made many atypical errors at 2 years being diagnosed as phonologically disordered at 3 years. The findings provide initial evidence that direct formal assessment of 2 year-old phonology is possible. PMID- 20840026 TI - A progressive consonant-substitution pattern in a typically developing child. AB - The purpose of this paper was to describe and explain an unusual consonant substitution (default) pattern in the early lexical repertoire of a typically developing boy. Ben was audiotape recorded monthly from age 2;2-2;8 (years; months), to follow an unusual substitution pattern, initially observed between 1;6 and 1;7 (diary notations). Data from each recording period were analysed with reference to (a) consonant repertoire, and (b) default and non-default features present. Data are presented for three periods of [l] substitution: initially, for a glide /w/ (age 1;6-1;7), next, as a substitution for word-initial fricatives /s/, /z/ and /[Formula: see text]/ (age 2;2-2;3), and finally, in place of /r/ in consonant + /r/ clusters, in place of /j/ in initial position, and as a between word liaison (age 2;7-2;8). It is shown that preferences for specific features, consonant vowel interactions, and syllable positions may be implicated in motivating this [l] substitution at specific points over time. The observed pattern is explained with reference to universal and child-specific factors and adds further evidence for variability that exists among typically developing children. PMID- 20840027 TI - Validity of a parent vocabulary checklist for young Spanish speaking children of Mexican immigrants. AB - The primary objective of the current investigation was to examine the concurrent and predictive validity of a parent vocabulary checklist with young Spanish speaking children of Mexican immigrants. This study implemented a longitudinal approach. Nineteen families participated when children were 15-16 months of age, and then again at 30-32 months of age. The Spanish version of the MacArthur Communicative Development Inventory (Inventarios del Desarrollo de Habilidades Communicativas, INV) and spontaneous language samples collected during naturalistic play were used to examine the relationship between observed and reported vocabulary. Vocabulary reported through the INV-II and vocabulary observed at 30-32 months were significantly correlated, suggesting that the INV II captures a valid representation of vocabulary at this age. Comparatively, vocabulary reported on the INV-I, was not correlated with observed vocabulary at 15-16 months of age or reported or observed vocabulary at 30-32 months of age. These results suggest that the INV-I, when used with 14-16-month-olds, demonstrates limited concurrent and predictive validity. Implications for the clinical use of the INV-I and INV-II are presented. PMID- 20840028 TI - Student and professional attitudes and interests in working with people with complex communication needs. AB - Speech-language pathology interest in working with people with complex communication needs was investigated in this study. Participants were third year speech-language pathology undergraduates and recent graduates who had participated in a unit on AAC. Undergraduates (n = 85) completed an Interaction with Disabled Persons attitudinal scale and a questionnaire about interest in various client groups before and after the unit. Some undergraduates (n = 34) repeated the attitudinal scale and completed another questionnaire 2 years after graduation. Recent graduates (n = 56) completed a questionnaire about working with people with complex communication needs and factors influencing work choices; 10 also participated in interviews or focus groups. We found a small but positive attitudinal shift for the undergraduates, but, along with previous disability experience, this was a weak predictor of working with this group. Working in developmental disability ranked low amongst undergraduate preferences. Most graduates were influenced in their job choices by a desire to work on a particular team and previous clinical placements. Questionnaires and interview/focus group data indicated the strong influence of clinical placements on later work choices. Participants who worked in disability appeared passionate about the work involved and offered suggestions for engaging more professionals with this group. Implications for speech-language pathology services in disability are discussed. PMID- 20840029 TI - Current and prospective speech-language pathology students' reports of exposure to speech-language pathology. AB - This paper presents findings of an investigation into the amount of exposure to the speech-language pathology profession that is reported by current and prospective speech-language pathology students. This study investigated both therapeutic and social exposures to speech-language pathology (SLP) as both were considered to play a role in providing information about the profession (e.g., work settings, professional demographics and caseloads). The results showed that the greater majority of both the current and prospective speech-language pathology students had some type of exposure to speech-language pathology either prior to entering or prior to considering entering the speech-language pathology program. Furthermore, both the current and prospective speech-language pathology students reported being influenced by their prior exposure the speech-language pathology profession. Finally, the results showed that parents played a large role in career choice for the current and prospective students, and this may have also included influence through parents' own exposure to speech-language pathology through work settings. PMID- 20840030 TI - Outcomes of speech-language pathology following stroke: Investigation of inpatient rehabilitation and rehabilitation in the home programs. AB - Speech-language pathology outcomes following stroke are poorly understood, and potential predictors of these, such as age and therapy input have not been well documented. For 12 months, the Australian Therapy Outcome Measures (AusTOMs) for Speech Pathology scales were used to rate swallowing and language outcomes for patients (n = 63) receiving rehabilitation post stroke. Outcomes were compared by service type (inpatient versus home based), amount of input and patient age. Greatest improvement was seen on the Swallowing scale. There was no difference in outcomes of inpatients compared to home based rehabilitation patients. There was a trend towards better outcomes with increasing input for the Swallowing scale and for Participation Restriction and Distress/Wellbeing domains. Patients less than 75 years of age had better Participation Restriction and Distress/Wellbeing outcomes, compared to older patients. These results align with previous studies, suggesting that inpatient and home based service models may be equally effective post stroke. Therapy input and patient age were related to some, but not all, domains of the AusTOMs, and these results may have implications for patient management. They should also direct future research to further explore these relationships; for example, to identify optimal input to achieve best outcomes. PMID- 20840031 TI - Acoustic quantification of /i/-/I/ overlap in children 21 to 33 months. AB - This longitudinal investigation examined the temporal and spectral characteristics of the high front vowels /i/ and /I/ as produced by nine monolingual US English children from 21-33 months. Vowel overlap was quantified in two-dimensional (F1, F2) and three-dimensional (F1, F2, duration) space using Spectral Overlap Assessment Measure (SOAM). These findings were compared with the results from Support Vector Machine (SVM) vowel classification, vowel duration ratios, and measures of effect size, to determine whether a spectral/temporal trading effect existed in the early vowel productions of young children. Children between the ages of 21 and 33 months are highly variable in the way they use spectral and temporal parameters to distinguish between these two adjacent vowels. However, findings pointed to the existence of a spectral/temporal trading effect when spectral overlap values are relatively high (>60%) at 21 and 24 months of age. PMID- 20840032 TI - Vowel transcription systems: An Australian perspective. AB - Transcription is an essential clinical tool for speech-language pathologists as it provides a permanent written record of communicative behaviour and forms an important source of data for analysis, interpretation, decision making, and dissemination. One of the responsibilities in speech-language pathology is to faithfully capture the speech production characteristics of clinical populations so that informed management decisions may be made. Notation systems that are appropriately suited for this purpose are mandatory. In Australia today, the conventional phonemic transcription system was first described over 60 years ago. However, an alternative to this traditional system has more recently been proposed by Harrington, Cox and Evans (HCE). This paper details the HCE system and argues its advantage as a clinical tool for speech-language pathologists in Australia. This new system provides a more accurate phonetically oriented foundation against which atypical vowel production can be assessed. It is further argued that the HCE system can form the basis for narrower phonetic examination and has pedagogical value in the description of Standard Australian English. PMID- 20840033 TI - The impact of selecting different contrasts in phonological therapy. AB - Previous research indicates that the extent of progress made by children with phonological disorders depends upon the nature of the word pairs contrasted in therapy. For example, phonemes that differ maximally in terms of place, manner, voicing and sound class (e.g., fan - man) in comparison to therapy where the word pairs presented differ minimally (e.g., fan - van). To investigate the implications of target selection within a typical clinical context (as opposed to a rigorous research setting) eight speech-language pathologists implemented intervention with appropriate children from their caseloads. Nineteen children each received 6 hours of therapy over one school term. They were randomly allocated to two groups. One group (of nine children) received intervention based on a traditional minimal pair approach, targeting homonymy as well as distinctive feature contrast. The other group (ten children) received intervention targeting contrasts differing across a range of distinctive features. Children made considerable progress in therapy in terms of speech accuracy and number of error patterns suppressed. However, there was no difference between the progress of the two groups. Follow-up assessment of 14 of the 19 children indicated maintenance of progress by both groups. Reasons for the lack of difference between the groups in the current study are considered and clinical implications are drawn. PMID- 20840034 TI - A comparison between computer and tabletop delivery of phonology therapy. AB - This paper reports on the development and evaluation of a software program aimed at assisting children with phonological impairment. An experimental approach was used whereby children's speech output was assessed pre- and post-therapy. Children were randomly assigned to a computer, a tabletop or a no therapy group. Those children receiving the computer therapy were exposed to an experimental software program that mirrored the tabletop activities using interactive computer games. The results showed no significant difference between any of the three groups with regard to change in speech output. These results may relate to the amount and frequency of therapy given and also to the heterogeneous nature of children included in the study. There was considerable variation in individual performance across all three groups and the data were therefore analysed to look for patterns that might predict performance. Stimulability and gender were identified as possible predictors. Female children and those who were able to produce a greater number of consonant speech sounds in isolation were more likely to make progress in their speech output. Future research might use a similar methodology to compare the therapy conditions but with a more homogenous group in terms of stimulability and using a greater intensity of intervention. PMID- 20840035 TI - Prevalence of speech and/or language impairment in preparatory students in northern Tasmania. AB - The purpose of this paper is to report the prevalence of speech and/or language impairment in a sample of preparatory students in northern Tasmania, Australia. A total of 308 preparatory students attending 30 public schools in northern Tasmania were administered assessments by a speech-language pathologist, and subsequently diagnosed with either typical or impaired speech and/or language skills. Overall, 41.2% of assessed preparatory students were identified as having either speech and/or language impairment. Specifically, 8.7% of students were found to have isolated speech impairment, 18.2% were diagnosed with isolated language impairment, and 14.3% were identified as having comorbid speech and language impairment. Compared to prior Australian and international research, the present data reflect one of the highest prevalence estimates for speech and/or language impairment reported to date. Given the relative paucity of Australian prevalence data, further epidemiological research specifically of Australian children is needed to validate the current findings. PMID- 20840036 TI - Characterising hyperfunctional voice disorders: Etiology, assessment, treatment and prevention. PMID- 20840037 TI - Assessment and treatment of musculoskeletal tension in hyperfunctional voice disorders. AB - Poorly regulated activity of the perilaryngeal muscles affects phonatory function and contributes to a class of disorders known as hyperfunctional or musculoskeletal tension voice disorders. Recognizing the signs and symptoms of excess or dysregulated laryngeal muscle activity is critical to proper diagnosis and selection of appropriate treatment(s). Although numerous approaches exist to manage such hyperfunctional syndromes, manual circumlaryngeal techniques have recently received attention as valuable tools in both assessment and treatment. Therefore, the purpose of this article is to: (1) describe common phenomenological features of dysregulated laryngeal muscle tension, thereby facilitating its recognition, (2) highlight the role of manual circumlaryngeal techniques in assessment and management, (3) survey additional treatment approaches for laryngeal hyperfunction, and explore the evidence to support their effectiveness, and (4) identify unresolved issues and controversies surrounding tension-based voice disorders. A series of pre- and post-treatment audio examples are provided on the journal website at www.informaworld.com/ijslp . PMID- 20840038 TI - The role of psychogenic and psychosocial factors in the development of functional voice disorders. AB - The primary objective of this discussion paper is to review the available evidence for the role of psychogenic and psychosocial factors in the development of functional voice disorders (FVD). Current theoretical models linking these factors to the aetiology of FVD and to vocal hyperfunction are then considered. Since there is a paucity of solid empirical evidence to date, general patterns of evidence derived from single case reports and case series are examined first, followed by those empirical studies using more sophisticated methodologies. The discussion is structured around a framework that includes the following psychosocial areas of enquiry: demographic profiles of individuals with FVD; stressful incidents preceding onset; personality traits; coping styles and psychiatric disorder. Current evidence and associated theoretical models suggest that cognitive, affective, neurophysiological and behavioural aspects culminate in the development of these complex voice disorders. The implications of these findings are discussed with respect to clinical practice and clinical training, with suggestions for future scientific research. PMID- 20840039 TI - The role of sensory dysfunction in the development of voice disorders, chronic cough and paradoxical vocal fold movement. AB - Sensory function may be important in the pathogenesis of Chronic Cough (CC) and Paradoxical Vocal Fold Movement (PVFM). This paper aims to explore sensory issues related to the pathogenesis, classification, assessment and management of these conditions. Sensory disruption of the vagus nerve can occur through neural plasticity whereby a change occurs in the way a central neuron reacts to an incoming stimulus. Such disruption can be demonstrated through assessment of cough reflex sensitivity and extrathoracic airway hyperresponsiveness both of which may be increased in CC and PVFM. In addition, sensory function may be determined by measuring the laryngeal adductor reflex, however this phenomenon is yet to be explored in CC and PVFM. The similarity in sensory dysfunction between CC and PVFM provides support for a link between the two conditions. There are also similarities in underlying medical conditions and symptom profiles between CC/PVFM and voice disorders such as muscle tension dysphonia. Although coughing and throat clearing may be contributing factors in the development and maintenance of voice disorders, they may occur in response to extrathoracic airway hyperresponsiveness. Dysphonia can occur in CC/PVFM and may improve following behavioural treatment of CC. PMID- 20840040 TI - Laryngopharyngeal reflux: Current concepts in pathophysiology, diagnosis, and treatment. AB - Laryngopharyngeal reflux (LPR) is the backflow of gastric contents into the pharynx and larynx. The diagnosis of LPR is primarily based on symptoms, including dysphonia, dysphagia, globus, throat-clearing, and post-nasal drip. The gold standard for diagnosis is dual-probe 24-hour pH testing with the upper probe positioned above the upper oesophageal sphincter. Treatment may require 3 months or more of twice-daily proton pump inhibitors along with lifestyle modifications. This review details the pathophysiology, symptoms, findings, treatment, and current controversies in LPR. PMID- 20840041 TI - Vocal fatigue and its relation to vocal hyperfunction ?. AB - This article reviews current literature on vocal fatigue and considers its potential relationship to vocal hyperfunction. Vocal fatigue is defined by its symptoms. Specifically, the voice user perceives an increase in phonatory effort over time that may be accompanied by decreased phonatory function. Vocal fatigue can present as a pure condition, such that no specific aetiology is apparent, or as a component of other voice disorders. The underlying bases of vocal fatigue appear to include the neurophysiological and biomechanical effects of extended periods of phonation. It can also be a function of strategies used to adapt to extended periods of phonation, such as the use of excessive muscular tension and suboptimal vocal fold posturing. Studies that have attempted to identify observable responses that are reliably associated with vocal fatigue have met with limited success, but recent advances in research methodology are promising. This review addresses current approaches to the study of vocal fatigue, especially regarding subject selection, design variables, and measurement variables. Future studies should address the relationship between vocal fatigue and other voice disorders, differences in individual responses to vocal-loading tasks, and differential evaluation and management of the neuromuscular, biomechanical, and central processes involved in vocal fatigue. PMID- 20840042 TI - Current knowledge, controversies and future directions in hyperfunctional voice disorders. AB - Taking the preceding five papers in this special issue of the International Journal of Speech-Language Pathology as a starting point, this paper synthesizes key aspects of hyperfunctional voice disorders (HFVD). Aetiological and contributing factors, defining features, prevention, assessment and intervention are canvassed, while controversial issues and future directions in research and clinical practice are discussed. Despite disagreements and inconsistencies in terminology surrounding HFVD, there is broad agreement that musculoskeletal tension is the hallmark of these voice disorders. There is also reasonable consensus that the pathogenesis and persistence of HFVD are associated with multiple and overlapping factors, some of which are likely to interact in as yet unknown ways. In addition to dysregulated laryngeal muscle functioning, key processes in the psychosocial and sensory domains are canvassed as likely contributors to HFVD. Vocal fatigue is considered as an intriguing relative of HFVD, the role of laryngopharyngeal reflux is debated and the proposition that particular individuals are psychologically and/or physiologically predisposed to HFVD is discussed. New directions in assessment highlight the use of client centred measures to consider insider perspectives of psychological factors, vocal effort and vocal fatigue. Emerging psychosocial and physical-manipulative interventions are emphasized and the future educational needs of voice care professionals are considered. PMID- 20840043 TI - Speech pathology australia national conference, sydney 2007. PMID- 20840044 TI - Gesture supports children's word learning (?). AB - This review paper, based on a keynote address to the 2007 Speech Pathology Australia National Conference, summarizes three recent research studies that pertain to gesture as an intervention tool. Specifically, the research concerns the utility of gestured input as a scaffold to children's comprehension of-and hence learning of-spoken words. The research is framed within the Emergentist Coalition Model. In Booth, McGregor, and Rohlfing we found evidence that toddlers of 28 - 30 months exploited both the attentional and intentional bases of gesture when fast mapping new words. In Capone and McGregor, toddlers of a similar age exploited representational gesture as a cue to linguistic meaning during both fast mapping and slow mapping stages of word learning. In McGregor and Capone we demonstrated that representational gestures are also useful for at-risk children who are acquiring an early lexicon. The overall purpose of this review paper is to motivate research efforts aimed at clinical applications of the gesture - language relationship. PMID- 20840045 TI - Eternity and clinical translation of speech-language pathology research (?). AB - The work we do as clinicians and researchers is forever vulnerable to political trends which can cause dramatic and rapid change in higher education. A current example is the funding of universities according to the value of their research outputs. In comparison to some other domains of health care, the discipline of speech-language pathology is particularly vulnerable to such politics. If we have evolved, we can devolve. The thesis here is that this matter concerns clinicians and clinical researchers, and that both parties need to shore up their relationship to ensure that this discipline has a guaranteed passage into eternity. This can be achieved by sharpening the focus of clinical research and driving its translation into clinical practices. The different and complementary contributions that clinicians and clinical researchers can make to that pursuit are discussed. It is argued that clinicians and clinical researchers can best pursue their necessary relationship with models of spatial cohabitation, and four models are presented for how that might be achieved. The paper concludes with some speculations about alternatives to eternity for the discipline of speech language pathology. PMID- 20840046 TI - A second chance: Recovering language with aphasia (?). AB - Dr Christopher Green is a well-known paediatrician and parenting author, who appeared frequently on Australian radio and television and lectured in Australia and many countries around the world. In 1999, Dr Green had a stroke which left him with aphasia and ended his career. After the death of his wife in 2004, Dr Green used exercise and the goal of writing again to lift himself out of his grief. With the help of a gifted editor, he wrote a new edition of his best selling book Toddler Taming (Green, 2006 ), and in the process recovered much of his language. Dr Green is the Patron of the Australian Aphasia Association, and has in recent years returned to public speaking. In this address, he shares his message that the language gains made with aphasia may occur over decades, not merely one or two years. This article is an edited version of the keynote speech Dr Green presented at the Speech Pathology Australia annual conference in 2007. PMID- 20840047 TI - A longitudinal investigation of oral narrative skills in children with mixed reading disability. AB - This 2-year longitudinal study investigated oral narrative ability in 14 children with mixed reading disability and their age-matched peers with typical development. The children were aged between 6;4 and 7;8 at the commencement of the study and assessments were administered individually to the children on three occasions over a 2-year period. Oral narratives were elicited in a personal narrative context (i.e., the child was encouraged to relate personal experiences in response to photo prompts) and a story retelling context. Oral narrative comprehension was assessed in a fictional story context through questions relating to story structure elements. Results indicated that the children with mixed reading disability demonstrated inferior oral narrative production and oral narrative comprehension performance compared to children with typical reading development at each assessment occasion. To further explore these children's difficulties in oral narrative ability, their performance was compared to a reading comprehension-age match control group at the third assessment trial. The results suggested the children with mixed reading disability had a specific deficit in oral narrative comprehension. PMID- 20840048 TI - Predictors and outcomes of speech and language therapists' treatment decisions. AB - This study investigated predictors of decisions made by speech and language therapists (SLTs) to offer intervention for pre-school children and the children's outcomes relative to that decision. The study uses data from 347 children who were first assessed aged under 3 years 6 months by community speech and language therapists in the UK. Of these, 158 were offered therapy, 189 were either discharged or offered only monitoring appointments. After adjusting for the child's age and gender, six variables were significantly associated with the therapist's original decision: being a quiet baby, not using two word utterances or making comments on their play, being unintelligible to strangers and the child's score on auditory comprehension and expressive language scales of the Preschool Language Scales (PLS-3). These show a focus on communication variables rather than broader demographic and medical variables. At follow-up, aged 7 - 9 years, 56% of the children were available for re-assessment. Therapists' decisions at initial assessment show a sensitivity of .85 and a specificity of .61 relative to children's outcomes. Of the 191 children seen at follow-up, 21 were deemed to have ongoing difficulties. PMID- 20840049 TI - Speech-language pathologists' views on attrition from the profession. AB - The aim of this study was to identify common themes in speech-language pathologists' perceptions of factors that increase and decrease their experiences of job stress, their satisfaction with their jobs and the profession, and their opinions about why people chose to leave the speech-language pathology profession. The participants' perceptions about the relationships between job stress, work satisfaction and job and profession retention were also explored. Sixty members of Speech Pathology Australia from a range of geographical and professional contexts were asked to participate in telephone interviews. Eighteen speech-language pathologists agreed to participate (30% response rate), and took part in semi-structured telephone interviews. Two researchers independently coded transcripts of the interviews for themes. Eight major themes were identified. These were positive aspects of the profession, workload, non-work obligations, effectiveness, recognition, support, learning and autonomy. The themes that emerged from analysis of these interviews provide new evidence about the positive and negative aspects of working as a speech-language pathologist, and provide preliminary insights into potential reasons as to why speech-language pathologists choose to remain in or leave the profession. PMID- 20840050 TI - The input processing, cognitive linguistic and oro-motor skills of children with speech difficulty. AB - Children with speech difficulty of no known etiology are a heterogeneous group. While speech errors are often attributed to auditory processing or oro-motor skill, an alternative proposal is a cognitive-linguistic processing difficulty. Research studies most often focus on only one of these aspects of the speech processing chain. This study investigated abilities in all three domains in children with speech difficulty (n = 78) and matched controls (n = 87). It was hypothesized that groups of children with speech difficulty would perform less well than controls on all tasks, but that the proportion of children with speech difficulty performing within the normal range would differ across tasks. The input processing task required children to perceive the auditory-visual illusion in speech perception, where listeners perceive [Formula: see text] when they hear [Formula: see text] presented in synchrony with the lip movements for [Formula: see text]. Diadochokinetic, isolated and sequenced movements tasks assessed oro motor skills. Two non-verbal tasks evaluated rule derivation. The results indicated that rule derivation best discriminated typically developing and speech difficulty groups. Few children were identified as having an input or output difficulty, whereas difficulties with rule-derivation were common. The data support the notion that speech difficulty is, most often, associated with a central processing difficulty. PMID- 20840051 TI - Patterns of consonant deletion in typically developing children aged 3 to 7 years. AB - Children with and without speech, language and/or literacy impairment, delete consonants when they name pictures to elicit single words. Consonant deletion seems to be more frequent in long words (words of three or more syllables) than in short words (words of one or two syllables). However, it may be missed in long words because they are not routinely assessed and, even if they are, there is little normative data about them. The study aims were (1) to determine if a relationship exists between consonant deletion and the number of syllables in words, (2) delimit variation in the numbers of children using it, its frequency of occurrence and the words it affects and (3) to discuss the application of these data to clinical practice. The participants were 283 typically developing children, aged 3;0 to 7;11 years, speaking Australian English with proven normal language, cognition and hearing. They named pictures, yielding 166 selected words that were varied for syllable number, stress and shape and repeatedly sampled all consonants and vowels of Australian English. Almost all participants (95%) used consonant deletion. Whilst a relationship existed between consonant deletion frequency and the number of syllables in words, the syllable effect was interpreted as a proxy of an interaction of segmental and prosodic features that included two or more syllables, sonorant sounds, non-final weak syllables, within word consonant sequences and/or anterior-posterior articulatory movements. Clinically, two or three deletions of consonants across the affected words may indicate typical behaviour for children up to the age of 7;11 years but variations outside these tolerances may mark impairment. These results are further evidence to include long words in routine speech assessment. PMID- 20840052 TI - Guidelines for the establishment and operation of a donor human milk bank. PMID- 20840053 TI - Isolation of murine small intestinal intraepithelial gammadeltat cells. AB - The study of intestinal intraepithelial gammadelta lymphocytes has been hindered by the difficulty of isolating a population of pure cells representative of their in vivo phenotype and function. Here, we describe a procedure for the purification of small intestinal intraepithelial gammadelta T lymphocytes in BALB/c mice, including extraction and purification of intraepithelial lymphocytes (IELs) followed by separation of gammadelta T cells from IELs by magnetic activated cell sorting (MACS). The small intestinal IEL isolation protocol reported here is a less time-consuming with high purity and high yields. One-step Percoll purification of IELs using a 40%-70% discontinuous Percoll gradient is less laborious yet sufficient to get exact profiles during phenotypic analysis of cell subsets. IELs obtained after two-step Percoll centrifugation using 30% Percoll, followed by a 40%-70% discontinuous Percoll gradient, are fit to purify gammadelta T cells by MACS. Small intestinal IELs produce much more IFN-gamma and TGF-beta1 than sorted gammadelta T cells upon stimulation with plate-bound anti CD3epsilon mAb. gammadelta T cells secret moderate amounts of TGF-beta1 and minimal amounts of IFN-gamma. Purification of gammadelta T cells is helpful in investigating the phenotype and function of intestinal mucosal gammadelta T cells. PMID- 20840054 TI - Characterization of apoptotic activities during chlamydia trachomatis infection in primary cervical epithelial cells. AB - Chlamydiae are obligate intracellular bacteria that infect human epithelial cells. It has been reported that Chlamydia trachomatis, induces apoptosis in epithelial cells, however, the molecular mechanisms responsible for host cell death especially in primary epithelial cells remained largely unknown as most of the studies are in cell line like HeLa. In this study we demonstrated that C. trachomatis induces apoptosis signaling pathway and apoptosis in primary cervical epithelial cells in a time and dose dependent manner. Live cervical epithelial cells were isolated from endocervical cells and induction was done with chlamydial EBs. Our results demonstrated that apoptosis in infected epithelial cells was associated with an increased activity of caspase 8; however, caspase 9 was activated to a lesser extent. Analysis of apoptosis pathway revealed that expression level of McL-1, Bcl-2, CASP8, and TRADD genes were found to be significantly upregulated (P < 0.01), where as levels of Caspase 1, Caspase 10 and BRIC2 were found to be significantly downregulated (p < 0.01). Our results showed that Chlamydia induces apoptosis and caspase activation in epithelial cells through caspase 8, with an increased expression of the McL-1, which confers a block at the mitochondrial level. PMID- 20840055 TI - Immunomodulatory effects of Withania somnifera on azoxymethane induced experimental colon cancer in mice. AB - The efficacy of Withania somnifera on immunomodulation was tested in experimental azoxymethane induced colon cancer in mice. Azoxymethane is a potential carcinogen to induce the colon cancer in Swiss albino mice. Azoxymethane 15 mg/kg body weight was injected intraperitoneally once a week for 28 days. The colon cancer was confirmed by the appearance of aberrant crypt foci (ACF) in the colons of the experimental mice. The progression in colon tumor development was correlated with the appearance of the histological biomarker and ACF. Azoxymethane induced colon cancer animals were treated with 400 mg/kg body weight of W. somnifera extract once a week for four weeks orally. After the experimental period, the animals were sacrificed and analyzed for immunocompetent cells, immune complexes and immunoglobulins. W. somnifera significantly altered the level of leucocytes, lymphocytes, neutrophils, immune complexes and immunoglobulins (Ig) A, G and M. The azoxymethane induced colon cancer and immune dysfunction was better controlled by W. somnifera. These results suggested that the immunomodulatory effects of W. somnifera could be useful in the treatment of colon cancer. PMID- 20840056 TI - Neutrophil CD64 expression in inflammatory autoimmune diseases: its value in distinguishing infection from disease flare. AB - The purpose of this research was to clarify the significance of neutrophil CD64 expression in discrimination between infection and disease flare in patients with inflammatory autoimmune diseases. The study included 63 subjects, 20 healthy controls and 43 patients with inflammatory autoimmune diseases (24 with rheumatoid arthritis & 19 with systemic lupus erythematosus). The FC gamma receptor I (CD64 expression) on neutrophils was measured using flow cytometry. The intensity of CD64 expression on neutrophils was significantly elevated in patients with infections; 49.0 (13-205), and active autoimmune disease; 36.15 (12 133) compared to healthy controls; 5.35 (2.6-14) or patients with inactive disease; 7.5 (3.3-18). In the infectious disease group, expression of CD64 was significantly higher than in the active inflammatory disease group, while there was no significant difference between the group of patients with inactive inflammatory disease and healthy controls (P > 0.05). The sensitivity of CD64 bearing neutrophil intensity for detection of infection (using a cut off value of >=43.5) was 94.4% and specificity was 88.9%. Neutrophil CD64 expression has a good sensitivity and specificity in differentiating infection from disease flare in patients with inflammatory autoimmune diseases. This assay could facilitate early and accurate diagnosis and greatly aid timely institution of appropriate treatment. PMID- 20840057 TI - Molecular basis of the anti-inflammatory property exhibited by cyclo-pentano phenanthrenol isolated from Lippia nodiflora. AB - The objective of this study was to assess the anti-inflammatory potential of the active molecule isolated from Lippia nodiflora and to understand its molecular dynamics in Vitro inflammation models. Human Peripheral Blood Mononuclear Cells were used as models to study mitogen induced lymphocyte proliferation, cytokine mRNA expression (TNF-alpha, IL-1beta and IL-6) and intracellular protein levels of pro-inflammatory mediators (MAPK and NF-kappaB). The NO release levels, on treatment with the extract and molecule, were correlated with the underlying iNOS mRNA expression in the murine macrophage cell line RAW 264.7. RT-PCR for COX-2, MMP2 and MMP9 were also performed in the cell line. The rat basophilic leukemia cell line RBL-2H3 was used as an in Vitro model for PLA2 activity. Then, 20 MUg/ml of Lippia nodiflora crude methanol extract and 10 MUg/ml of the purified CPP were used for subsequent studies based on the IC50 values obtained in the proliferation assay. Results demonstrate that the isolated Cyclo-pentano phenanthrenol inhibits TNF-alpha, IL-1beta and IL-6 expression, NO release via iNOS suppression, prostaglandin biosynthesis via PLA2 and COX-2 inhibition and the activation of intracellular targets, MAPK and NF-kappaB. We conclude, cyclo pentano phenanthrenol exerts its anti-inflammatory effect via inhibition of MAPK phosphorylation and NF-kappaB translocation. PMID- 20840058 TI - Effect of anaphylactic shock on suppressors of cytokine signaling. AB - The pathophysiologic mechanisms of anaphylactic shock still remain unclear. In this study, we investigated the changes of expression and translation of SOCS1/SOCS3 in the heart, lungs, kidney, liver and spleen from patients who died of anaphylactic shock. Samples from the same viscera of 8 patients who died of anaphylactic shock and 8 healthy controls who died from accidents were collected in the present study. The level of IgE was measured in heart, and SOCS1/ SOCS3 mRNA and protein expression were determined by RT-PCR and immunohistochemistry, respectively. As a result, the higher IgE level was detected in the blood samples from the patients' heart than the control. SOCS1 and SOCS3 protein were significantly increased in the kidney and liver than the control. After anaphylactic shock, the expression of SOCS1 and SOCS3 mRNA were also increased. The expression level of SOCS3 mRNA was higher than that of SOCS1 in all viscera, and both were the highest in liver and kidney. There was a positive correlation between SOCS1 mRNA and SOCS3 mRNA in liver and kidney after anaphylactic shock. Our results indicate that SOCS1 and SOCS3 may play a regulatory role in anaphylactic shock viscera injury processes during anaphylactic shock. PMID- 20840059 TI - Stimulation of B7-H1 in hepatocarcinoma cells by hepatitis B virus X antigen. AB - The cross-talk between the hepatitis B virus X protein (HBx) and B7-H1 in hepatocarcinoma (HCC) is unclear. This study analyzed the potential relationships between HBx and B7-H1 in hepatocarcinogenesis. One of human HCC cell lines, HepG2 cells, was transfected to stably express HBx protein (HBx(+)-HepG2). The transcription of B7-H1 mRNA was increased significantly in these cells compared to cells transfected with control vector (HBx(-)-HepG2), as confirmed by a comparative genome-wide microarray analysis (Capitalbio) and real time quantitative PCR (qPCR). Flow cytometry and western-blot further demonstrated that B7-H1 protein synthesis was enhanced in HBx(+)-HepG2 cells. Site-directed mutagenesis of promoter constructs revealed that the transcription factor (NF) kappaB binding site between 128 and 137 bp upstream of B7-H1 gene transcriptional start site is primarily responsible for HBx-mediated B7-H1 expression. Co-culture experiments with HBx(+)-HepG2/T cells showed that the number of apoptotic T cells increased profoundly, and this effect could be partially prevented when a neutralizing mAb against B7-H1 was added to the culture, demonstrating that B7-H1 signaling can promote T cell apoptosis. Our results suggest that the expression of B7-H1 in hepatocarcimona cells can be initiated by HBx antigen, thus inducing T cell apoptosis and finally potentially facilitates the genesis of HCC. PMID- 20840060 TI - Ship-borne journey induces Th1 cytokines level in antarctic summer expeditioners. AB - It has become apparent that extreme environmental conditions of Antarctic continent alters many immune responses. The present study was conducted on 28th Indian Antarctic expeditioners. The investigations were carried out to explore the effect of multiple stresses like isolation, cold and UV exposure on human immunity. Thirty blood samples were collected between 6 and 7 AM, after an overnight fast at different stages of the expedition - viz. the pre-exposure sample was collected at Delhi on 25(th) October 2008. The expedition started its ship journey from Capetown, on 6(th) January, 2009 and on-board blood was collected on 31(st) January 2009. After 1 month stay at Maitri, blood was collected on 3(rd) March 2009. Different parameters studied included levels of cytokines, chemokines and cortisol. The ship-borne journey induced a dramatic increase in TNF-alpha, IFN-gamma, and B cell activating factor (BAFF) levels and moderate decreases in TGF-beta and cortisol levels. However, after being off board for 1 month at Maitri station, levels of above cytokines, cortisol and BAFF were decreased but MIP-1alpha was significantly increased. These data for the first time suggest that ship-borne journey to the Antarctic continent results in tremendous stress to the body, which eventually resulted in increased TH1-biased immunity. PMID- 20840062 TI - Controversies in hypertension treatment. PMID- 20840063 TI - Central and peripheral metabolic changes in neurodegenerative diseases. PMID- 20840064 TI - Multiple defects in energy metabolism in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in old age. Cognitive impairment in AD may be partially due to overall hypometabolism. Indeed, AD is characterized by an early region-specific decline in glucose utilization and by mitochondrial dysfunction, which have deleterious consequences for neurons through increased production of reactive oxygen species (ROS), ATP depletion and activation of cell death processes. In this article, we provide an overview of the alterations on energetic metabolism occurring in AD. First, we resume the evidences that link the 'metabolic syndrome' with increased risk for developing AD and revisit the major changes occurring on both extra-mitochondrial and mitochondrial metabolic pathways, as revealed by imaging studies and biochemical analysis of brain and peripheral samples obtained from AD patients. We also cover the recent findings on cellular and animal models that highlight mitochondrial dysfunction as a fundamental mechanism in AD pathogenesis. Recent evidence posits that mitochondrial abnormalities in this neurodegenerative disorder are associated with changes in mitochondrial dynamics and can be induced by amyloid-beta (Abeta) that progressively accumulates within this organelle, acting as a direct toxin. Furthermore, Abeta induces activation of glutamate N methyl-D-aspartate receptors (NMDARs) and/or excessive release of calcium from endoplasmic reticulum (ER) that may underlie mitochondrial calcium dyshomeostasis thereby disturbing organelle functioning and, ultimately, damaging neurons. Throughout the review, we further discuss several therapeutic strategies aimed to restore neuronal metabolic function in cellular and animal models of AD, some of which have reached the stage of clinical trials. PMID- 20840065 TI - Metabolic aspects of prion diseases: an overview. AB - Prion diseases are fatal neurodegenerative disorders that affect humans and other mammals. The hallmark of these diseases is the conformational change of the cellular prion protein (PrP(C)) to the misfolded protein capable of propagation and associated with neurodegenration, named prion (PrP(Sc)). In a strict sense, prion diseases are a consequence of aberrations in the metabolism of the cellular prion protein (PrP(C)). This brief review addresses current understanding of metabolic disturbances in prion disorders at the cellular, organ and organism level, selectively pointing out some relevant diagnostic and treatment options. PMID- 20840066 TI - Mitochondrial-associated metabolic changes and neurodegeneration in Huntington's disease - from clinical features to the bench. AB - Huntington's disease (HD) is a genetic neurodegenerative disease selectively leading to striatal neurodegeneration, but also affecting the cortex and the hypothalamus. Although it is hard to predict the sequence of cell-damaging events occurring in HD patients, several pathological mechanisms have been proposed to explain HD selective neurodegeneration and disease symptomatology. Abnormalities in mitochondrial function and bioenergetics contribute to cell death and have been reported in HD-affected individuals, both in central and peripheral tissues. Moreover, the latter has been characterized in several HD models. Thus, this review describes the converging mechanisms that lead to mitochondrial and metabolic abnormalities in thoroughly studied in vivo and in vitro HD models, including excitotoxicity, altered calcium handling, changes in mitochondrial structure and dynamics and transcription deregulation, which may represent important disease therapeutic targets. Furthermore, the review describes the current evidences of metabolic disturbances in the brain of HD-affected humans and of peripheral metabolic and mitochondrial changes, weight loss and endocrine abnormalities operating in the whole HD body. PMID- 20840068 TI - The role of PGC-1alpha in the pathogenesis of neurodegenerative disorders. AB - Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1alpha, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC 1alpha knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1alpha regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1alpha in HD is further highlighted by the finding that common genetic variations in the PGC 1alpha gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1alpha system in HD pathogenesis and explores the implications for ALS, AD and PD. PMID- 20840069 TI - Sirtuins: common targets in aging and in neurodegeneration. AB - Aging has been a subject of interest since primordial times. More recently, it became clear that aging is the major known risk factor for several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. A major focus in the field of aging is to examine whether the genetic regulators of lifespan also regulate the trigger and/or progression of age-related disorders. Sirtuins, which belong to the Sir2 family of NAD(+) dependent deacetylases, are known to regulate longevity in yeast, worms, and flies. In mammals, there are seven homologs of the yeast Sir2, Sirt1-7. Therefore, the challenge now is to unravel howthe seven mammalian Sir2 proteins communicate to regulate the cross talk between aging and the onset and progression of age-related disorders. Here, we review how sirtuins contribute for aging and, in particular, for neurodegeneration and how they are becoming attractive targets for therapeutic intervention. PMID- 20840067 TI - Skeletal muscle in motor neuron diseases: therapeutic target and delivery route for potential treatments. AB - Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurrence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons. PMID- 20840070 TI - Potential therapeutic targets for neurodegenerative diseases: lessons learned from calorie restriction. AB - It is well known that calorie restriction (CR) can retard the aging process in organisms ranging from yeast to non-human primates, and delay the onset of numerous age-related diseases including neurodegenerative disorders. Translation of the knowledge gained from CR research in animal models to disease prevention strategies in humans should provide therapeutic approaches for these diseases. Signaling pathways induced by CR are therefore potentially new therapeutic targets for neurodegenerative diseases. This review summarizes the evidence on key biological mechanisms underlying the beneficial effects of CR based on our current understanding, with particular emphasis on the recent impact of CR on neuroprotection, and on the emerging development of pharmacological agents that target signaling pathways induced by CR. We focus in particular on recent findings on sirtuins for prevention of neurodegenerative diseases. PMID- 20840071 TI - Targeting genetic instability in cancer cells. PMID- 20840072 TI - The mutator phenotype in cancer: molecular mechanisms and targeting strategies. AB - Normal human cells replicate their DNA with exceptional accuracy. It has been estimated that approximately one error occurs during DNA replication for each 10(9) to 10(10) nucleotides polymerized. In contrast, malignant cells exhibit multiple chromosomal abnormalities and contain tens of thousands of alterations in the nucleotide sequence of nuclear DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we have hypothesized that during tumor development, cancer cells exhibit a mutator phenotype. As a defining feature of cancer, the mutator phenotype remains an as-yet unexplored therapeutic target: by reducing the rate at which mutations accumulate it may be possible to significantly delay tumor development; conversely, the large number of mutations in cancer may make cancer cells more sensitive to cell killing by increasing the mutation rate. Here we summarize the evidence for the mutator phenotype hypothesis in cancer and explore how the increased frequency of random mutations during the evolution of human tumors provides new approaches for the design of cancer chemotherapy. PMID- 20840073 TI - Genetic and epigenetic heterogeneity in cancer: the ultimate challenge for drug therapy. AB - Based on the gene and pathway centric concept of cancer, current approaches to cancer drug treatment have been focused on key molecular targets specific and essential for cancer progression and drug resistance. This approach appears promising in many experimental models but unfortunately has not worked well in the vast majority of cancers in clinical settings. Many new proposals, based on the same rationale of identifying a "magic bullet" are emerging now that target the epigenetic level as well as some other new targets including metabolic regulation, genetic instability and tumor environments. In spite of the optimism resulting from these new approaches there is still a key challenge that remains regarding cancer drug therapy in the form of multiple levels of genetic and epigenetic heterogeneity. Using the recently formulated genome theory, the importance of bio-heterogeneity and its complex relationships between different levels has been discussed and in particular, the concept and methods used to monitor and target genome level heterogeneity. By briefly mentioning some newly introduced treatment options, this review further discusses the common challenges for the field as well as possible future directions of research. PMID- 20840074 TI - Genetic instability influences drug response in cancer cells. AB - One of the main reasons why most patients with advanced cancer are not curable with the therapies available is the broad heterogeneity of cancer cells, inherently related to their genomic instability that reflects defects of cell cycle checkpoints and DNA mismatch repair (MMR). The present paper reviews Today's knowledge of MMR. Microsatellite (DNA repetitive sequences) instability (MSI) used as a surrogate marker of MMR defects was associated with a predisposition to somatic mutations of several genes including those involved in the neoplastic transformation and tumor progression. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germ line mutation in genes involved in MMR such as hMLH1 or hMLH2, or less frequently hMLH6 or hPMS2; it is associated with a high risk of intestinal cancer (CRC) and other tumors including endometrial, stomach, kidney and brain. There is ample preclinical evidence that cells deficient in MMR are resistant to methylating agents and to some antimetabolites, including 5FU, which is the drug used most for the CRC, whereas they are equally sensitive to oxaliplatin and possibly more sensitive to irinotecan. More studies are needed on the importance of MMR for sensitivity to different anticancer regimens and drugs, so this knowledge can guide rational therapy according to the tumor MMR status. PMID- 20840075 TI - Destabilizing aneuploidy by targeting cell cycle and mitotic checkpoint proteins in cancer cells. AB - Aneuploidy is one of the major hallmarks of cancer cells and several paths towards aneuploidy have been described. However, the relevance for tumor initiation or progression and how tumors deal with the initial aneuploidy related stress response is still unclear and recent results suggest that aneuploidy can even have tumor suppressive effects under certain conditions. The molecular mechanisms leading to and sustaining growth of aneuploid cells are just at the beginning to be understood and might provide new targets for cancer drug development. We will discuss some of the ideas to specifically kill aneuploid cells by targeting key regulators of mitosis. PMID- 20840076 TI - Targeting synthetic lethality in DNA damage repair pathways as an anti-cancer strategy. AB - During the process of tumorigenesis, certain cancers are known to develop deficiencies in one or more major pathways of DNA damage repair, rendering them critically dependent on alternative repair processes for maintaining genomic integrity and viability. Targeting these alternative DNA repair mechanisms is a potentially highly-specific anti-cancer strategy, as their inhibition is theoretically toxic only to tumor cells and not to normal tissues. We will review here the rationale behind this strategy and provide examples of its application. We will also discuss several as yet unanswered questions surrounding this strategy, including whether human cancers frequently harbor synthetically lethal interactions in DNA repair and, if so, how patients might be identified who would benefit from targeting such interactions. PMID- 20840077 TI - Targeting karyotypic complexity and chromosomal instability of cancer cells. AB - Multiple karyotypic abnormalities and chromosomal instability are characteristic features of many cancers that are relatively resistant to chemotherapeutic agents currently used in the clinic. These same features represent potentially targetable "states" that are essentially tumor specific. The assessment of the chromosomal state of a cancer cell population may provide a guide for the selection or development of drugs active against aggressive and intractable cancers. PMID- 20840079 TI - Removal of amino acid, peptide and protein hydroperoxides by reaction with peroxiredoxins 2 and 3. AB - Prxs (peroxiredoxins) are a ubiquitous family of cysteine-dependent peroxidases that react rapidly with H2O2 and alkyl hydroperoxides and provide defence against these reactive oxidants. Hydroperoxides are also formed on amino acids and proteins during oxidative stress, and they too are a potential cause of biological damage. We have investigated whether Prxs react with amino acid, peptide and protein hydroperoxides, and whether the reactions are sufficiently rapid for these enzymes to provide antioxidant protection against these oxidants. Isolated Prx2, which is a cytosolic protein, and Prx3, which resides within mitochondria, were reacted with a selection of hydroperoxides generated by gamma radiolysis or singlet oxygen, on free amino acids, peptides and proteins. Reactions were followed by measuring the accumulation of disulfide-linked Prx dimers, via non-reducing SDS/PAGE, or the loss of the corresponding hydroperoxide, using quench-flow and LC (liquid chromatography)/MS. All the hydroperoxides induced rapid oxidation, with little difference in reactivity between Prx2 and Prx3. N-acetyl leucine hydroperoxides reacted with Prx2 with a rate constant of 4 * 10(4) M-1 . s-1. Hydroperoxides present on leucine, isoleucine or tyrosine reacted at a comparable rate, whereas histidine hydroperoxides were ~10-fold less reactive. Hydroperoxides present on lysozyme and BSA reacted with rate constants of ~100 M-1 . s-1. Addition of an uncharged derivative of leucine hydroperoxide to intact erythrocytes caused Prx2 oxidation with no concomitant loss in GSH, as did BSA hydroperoxide when added to concentrated erythrocyte lysate. Prxs are therefore favoured intracellular targets for peptide/protein hydroperoxides and have the potential to detoxify these species in vivo. PMID- 20840078 TI - Arachidonic acid actions on functional integrity and attenuation of the negative effects of palmitic acid in a clonal pancreatic beta-cell line. AB - Chronic exposure of pancreatic beta-cells to saturated non-esterified fatty acids can lead to inhibition of insulin secretion and apoptosis. Several previous studies have demonstrated that saturated fatty acids such as PA (palmitic acid) are detrimental to beta-cell function compared with unsaturated fatty acids. In the present study, we describe the effect of the polyunsaturated AA (arachidonic acid) on the function of the clonal pancreatic beta-cell line BRIN-BD11 and demonstrate AA-dependent attenuation of PA effects. When added to beta-cell incubations at 100 MUM, AA can stimulate cell proliferation and chronic (24 h) basal insulin secretion. Microarray analysis and/or real-time PCR indicated significant AA-dependent up-regulation of genes involved in proliferation and fatty acid metabolism [e.g. Angptl (angiopoietin-like protein 4), Ech1 (peroxisomal Delta3,5,Delta2,4-dienoyl-CoA isomerase), Cox-1 (cyclo-oxygenase-1) and Cox-2, P<0.05]. Experiments using specific COX and LOX (lipoxygenase) inhibitors demonstrated the importance of COX-1 activity for acute (20 min) stimulation of insulin secretion, suggesting that AA metabolites may be responsible for the insulinotropic effects. Moreover, concomitant incubation of AA with PA dose-dependently attenuated the detrimental effects of the saturated fatty acid, so reducing apoptosis and decreasing parameters of oxidative stress [ROS (reactive oxygen species) and NO levels] while improving the GSH/GSSG ratio. AA decreased the protein expression of iNOS (inducible NO synthase), the p65 subunit of NF-kappaB (nuclear factor kappaB) and the p47 subunit of NADPH oxidase in PA-treated cells. These findings indicate that AA has an important regulatory and protective beta-cell action, which may be beneficial to function and survival in the 'lipotoxic' environment commonly associated with Type 2 diabetes mellitus. PMID- 20840080 TI - Elucidating the contribution of the elemental composition of fetal calf serum to antigenic expression of primary human umbilical-vein endothelial cells in vitro. AB - One of the major obstacles to obtaining human cells of a defined and reproducible standard suitable for use as medical therapies is the necessity for FCS (fetal calf serum) media augmentation in routine cell culture applications. FCS has become the supplement of choice for cell culture research, as it contains an array of proteins, growth factors and essential ions necessary for cellular viability and proliferation in vitro. It is, however, a potential route for the introduction of zoonotic pathogens and makes defining the cell culture milieu impossible in terms of reproducibility, as the precise composition of each batch of serum not only changes but is in fact extremely variable. The present study determined the magnitude of donor variations in terms of elemental composition of FCS and the effect these variations had on the expression of a group of proteins associated with the antigenicity of primary human umbilical-vein endothelial cells, using a combination of ICPMS (inductively coupled plasma MS) and flow cytometry. Statistically significant differences were demonstrated for a set of trace elements in FCS, with correlations made to variations in antigenic expression during culture. The findings question in detail the suitability of FCS for the in vitro supplementation of cultures of primary human cells due to the lack of reproducibility and modulations in protein expression when cultured in conjunction with sera from xenogeneic donors. PMID- 20840081 TI - Paying attention to complexity in implementation research. PMID- 20840082 TI - Bilateral mydriasis in common buzzards (Buteo buteo) and little owls (Athene noctua) induced by concurrent topical administration of rocuronium bromide. AB - OBJECTIVE: To evaluate the achievement of a bilateral mydriasis in raptors induced by a concurrent topical application of rocuronium bromide and to assess any side effects that might result from its use. Animals studied Ten healthy adult common buzzards (Buteo buteo) and 10 healthy adult little owls (Athene noctua). PROCEDURES: Common buzzards (Group 1) received a single dose of 0.40 mg of rocuronium bromide in each eye (total dose 0.80 mg/bird), whereas the little owls (Group 2) received a single dose of 0.20 mg in each eye (total dose 0.40 mg/bird). The drug was topically instilled in all the birds of both groups. The pupil diameter was measured with a pupillary gauge and the assessment of the pupillary light reflexes was performed using a standard light source. RESULTS: Maximal pupillary diameter was 8.10 +/- 0.56 mm in the right eye and 8.05 +/- 0.59 mm in the left eye for Group 1 and 10.0 +/- 0.75 mm in both eyes for Group 2. No statistical differences were evidenced between the achieved pupillary diameters of both eyes in each group. The maximal pupillary diameter was achieved at T110 min and T40 min for Groups 1 and 2, respectively. The drug did not cause noticeable adverse effects in the examined birds. CONCLUSIONS: A single concurrent topical administration of rocuronium bromide to the eyes of the examined birds induced a complete bilateral mydriasis in both eyes without causing any adverse effect. PMID- 20840083 TI - Zoo and exotic animals. Preface. PMID- 20840084 TI - Bilateral intraocular malignant neuroectodermal tumors in a telescope goldfish (Carassius auratus). AB - Abstract A 5-year-old male telescope goldfish (Carassius auratus) developed buphthalmia of the left eye. An enucleation was performed and a diagnosis of a neuroectodermal tumor was made on histological examination. Although the fish initially recovered, it was killed 49 days postsurgery due to a severe decline in its condition. On histological evaluation of postmortem tissue samples, it was determined that the fish also had a neuroectodermal tumor of the right eye with local invasion of the brain. On immunohistochemistry, the neoplastic cells were positive for S-100. To the authors' knowledge, this is the first published case of naturally occurring bilateral intraocular neuroectodermal tumors in a fish. PMID- 20840085 TI - Mydriatic effect of topically applied rocuronium bromide in tawny owls (Strix aluco): comparison between two protocols. AB - OBJECTIVE: To evaluate the mydriatic efficacy of a neuromuscular blocking agent (rocuronium bromide) applied topically to only one eye of nocturnal birds of prey and to assess for any general and/or local adverse effects due to its use. Animal studied Twelve healthy adult tawny owls (Strix aluco) were randomly divided in two groups. PROCEDURES: Six birds (Group 1) received a single dose of 0.35 mg of rocuronium bromide. The second group of subjects (Group 2) received two doses of 0.35 mg of rocuronium bromide (total 0.70 mg/eye). In both groups, the curariform agent was instilled topically. Pupil diameter was measured with a pupillary gauge in 10 min intervals for a total of 100 min and then every 20 min for a total of 240 min. The assessment of the pupillary light reflex was performed using a standard light source during pupillary size recording. RESULTS: Maximal pupillary diameter was 11.5 +/- 0.3 mm for Group 1 and 11.0 +/- 0.6 mm for Group 2 and no statistically significant differences were detected among the two groups. The maximal pupillary diameter was achieved at T80 for Group 1, and at T60 for Group 2. A complete fundus examination was possible on all treated eyes of subjects of both groups. The drug did not cause any noticeable adverse effects in any of the examined birds. CONCLUSION: Results of the present study suggest that a single topical administration of 0.35 mg of rocuronium bromide to the eyes of healthy tawny owls results in sufficient mydriasis to allow for a complete examination of the fundus. PMID- 20840086 TI - The chinchilla eye: morphologic observations, echobiometric findings and reference values for selected ophthalmic diagnostic tests. AB - PURPOSE: To carry out a descriptive investigation into the most relevant morphological features of the chinchilla eye and bony orbit, as well as to perform selected ophthalmic diagnostic tests with the aim of establishing normal anatomic and physiologic references for this species. METHOD: A total of 57 healthy, chinchillas were used to test most of the parameters in this investigation. Besides morphologic observations of the globe and adnexa, selected ocular tests and parameters were investigated, including blink frequency, palpebral fissure length (PFL), Schirmer tear test (STT), esthesiometry, intraocular pressure (IOP), central corneal thickness (CCT), B-mode echobiometric measurements of the globe and culture of the normal conjunctival bacterial microbiota. Morphologic observations were made using six formalin-fixed globes and four macerated skulls. RESULTS AND DISCUSSION: Normal parameters found for selected ocular diagnostic tests were: blink frequency: 2.6 +/- 0.84 blinks per 10 min; STT: 1.07 +/- 0.54 mm; esthesiometry: 1.24 +/- 0.46 cm; IOP: 17.71 +/- 4.17 mmHg; CCT: 0.34 +/- 0.03 mm; PFL: 1.44 +/- 0.11 cm; anterior chamber depth: 2.01 +/- 0.2 mm; axial lens thickness: 5.49 +/- 0.43 mm; vitreous chamber depth (internal): 3.69 +/- 0.52 mm; axial globe length: 1.14 +/- 0.07 cm. The most frequent bacteria isolated from the conjunctiva were Streptococcus sp. (27.45%), Staphylococcus aureus (23.52%) and coagulase-negative Staphylococcus (19.60%). No statistically significant differences between left or right eyes or genders were found for any of the results. Reference data and morphologic observations obtained in this investigation will help veterinary ophthalmologists to recognize unique morphological features and more accurately diagnose ocular diseases in the chinchilla, an animal already being used as a biological model for ophthalmic studies. PMID- 20840087 TI - B-mode ultrasonography biometry of the Amazon Parrot (Amazona aestiva) eye. AB - PURPOSE: Ultrasonographic evaluation of the eye is a relatively recent addition to routine ophthalmic diagnostics in small animal ophthalmology. Some parameters for ophthalmic biometry have been established. There are few studies in clinical avian ophthalmology that describe ultrasound images of eye in some nocturnal avian species and in other birds that do not belong to the Brazilian fauna, but the psittacine family is not represented. The purpose of this study was to describe the following measurements: the distances between cornea and anterior lens capsule (D1) between the anterior and posterior lens capsule (D2), between posterior lens capsule and optic papilla (D3) and the axial length. METHOD: Sixty four transpalpebral ocular ultrasound examinations were performed on 32 Blue fronted Amazon parrots (Amazona aestiva) with no history of previous ophthalmic disease. RESULT AND DISCUSSION: The measurements were taken in sagital planes using a 10 MHz linear probe without a standoff pad. The mean values for the left eye were; D1 0.17 +/- 0.03 cm, D2 0.35 +/- 0.02 cm, D3 0.73 +/- 0.04 cm and the axial length 1.26 +/- 0.06 cm. In the right eye D1 0.17 +/- 0.02 cm, D2 0.34 +/- 0.02 cm, D3 0.74 +/- 0.03 cm and the axial length 1.25 +/- 0.05 cm. No significant statistical difference was observed among the birds or between the left and right eye. The description of these parameters will allow the veterinary practitioner to evaluate the structural changes that specific diseases may cause in these animals. PMID- 20840088 TI - Reference values for selected ophthalmic diagnostic tests and clinical characteristics of chinchilla eyes (Chinchilla lanigera). AB - OBJECTIVE: To establish reference values for the Schirmer tear test I (STT I), the phenol red thread tear test (PRTT), the intraocular pressure (IOP) with rebound tonometry, to determine the corneal sensitivity for healthy chinchillas, and to describe clinical aspects of normal chinchilla eyes. ANIMALS: One hundred and twenty-two eyes of 61 healthy pet chinchillas of different age and gender were investigated. PROCEDURES: A full ophthalmic exam including slit lamp biomicroscopy, ophthalmoscopy, measurement of STT I, PRTT, determination of the corneal touch threshold (CTT), and the measurement of the IOP (TonoVet) was performed. The normal appearance of the lid, the iris, the lens, the fundus, and the optic nerve disc was evaluated. Results The results of the STT I were very low and not reliable, and the measurement was discontinued. The median value of PRTT was 14.0 mm wetting/15 s (mean 14.6 +/- 3.5 mm wetting/15 s). The median CTT was 32.5 mm (mean 31.2 +/- 7.0 mm) respectively 1.2 g/mm(2) (mean 1.5 +/- 0.9 g/mm(2)). The median IOP was 3.0 mmHg (mean 2.9 +/- 1.8 mmHg). The predominating iris color was brown. The fundus pigmentation varied. Few lens alteration were seen in otherwise healthy chinchilla eyes. Most chinchillas had myelinated discs. Optic nerve cupping was present in 62% of the animals. CONCLUSION: Because of the small amount of tears, the PRT test is recommended for tear measurements in chinchillas. The IOP in chinchillas seems to be quiet is low in comparison to other rodents. PMID- 20840089 TI - Electroretinography in the western gray kangaroo (Macropus fuliginosus). AB - OBJECTIVE: To perform electroretinography on normal anesthetized western gray kangaroos (Macropus fuliginosus). Animals studied Six captive western gray kangaroos. PROCEDURES: The kangaroos were anesthetized using a combination of ketamine and medetomidine via a remote drug delivery system, then were maintained on isoflurane after endotracheal intubation and reversal of the medetomidine with atipamazole. After a minimum of 20 min of dark adaptation, electroretinograms were obtained using a handheld electroretinography (ERG) machine using a single flash protocol at three light intensities: 10 mcd.s/m(2), 3000 mcd.s/m(2), 10 000 mcd.s/m(2). RESULTS: At 10 mcd.s/m(2) the mean b-wave amplitude and implicit time was 102.0 MUV (SD +/- 41.3 and 95% CI 68.9-135.1) and 78.4 ms (SD +/- 8.3 and 95% CI 71.8-85.0). At 3000 mcd.s/m(2) the mean a-wave amplitude and implicit time was 69.9 MUV (SD +/- 20.5 and 95% CI 53.5-86.3) and 17.6 ms (SD +/- 1.5 and 95% CI 16.4-18.8) and the mean b-wave amplitude and implicit time was 175.4 MUV (SD +/- 35.9 and 95% CI 146.7-204.1) and 74.1 ms (SD +/- 3.5 and 95% CI 71.2-76.9). At 10 000 mcd.s/m(2) the mean a-wave amplitude and implicit time was 89.1 MUV (SD +/- 27.1 and 95% CI 67.5-110.8) and 16.8 ms (SD +/- 1.0 and 95% CI 16.0-17.0) and the mean b-wave amplitude and implicit time was 203.7 MUV (SD +/- 41.4 and 95% CI 170.6-236.8) and 75.4 ms (SD +/- 3.3 and 95% CI 72.8-78.1). CONCLUSION: Electroretinography outside of the typical clinical setting is feasible using a portable ERG system and allows for quick analysis of retinal function in exotic species. PMID- 20840090 TI - Characterization of progressive keratitis in otariids. AB - OBJECTIVE: To characterize a form of progressive keratitis that occurs commonly in otariids. MATERIALS AND METHODS: One hundred and thirteen captive otariids were evaluated by ophthalmologic examination and digital photography. RESULTS: Forty-six females and 67 males were in the reference population, average age of 14 years. California sea lions predominated (n = 100); there were also six Steller sea lions, five brown fur seals, one Guadalupe fur seal and one northern fur seal. Three stages of progressive keratitis are described. Overall, 64.6% animals and 142 eyes from 113 animals (62.8%) were affected with one of three stages. The mildest form, Stage 1 keratitis, occurred in 78 of 226 eyes (34.5%); the intermediate Stage 2 keratitis occurred in 30 of 226 eyes (13.3%); and the most severe, Stage 3 keratitis, occurred in 34 of 226 eyes (15%). All but six animals had bilateral disease. Animals with Stage 1 keratitis were significantly younger than those in more advanced stages. DISCUSSION: 'Otariid Keratitis' occurs in all populations of eared seals evaluated. A large-scale epidemiological study is ongoing to identify the risk factors that contribute to this disease. Exposure to chronic sunlight appears to be an important risk factor as shade diminishes clinical signs; animals kept out of sunlight the majority of the time have less severe clinical signs. Age may be important since exposure accumulates with aging. Progression of the disease is also associated with secondary opportunistic bacterial and fungal infections. The surface immune system may be imbalanced contributing to these infections and progression. PMID- 20840092 TI - Anatomy of the California sea lion globe. AB - OBJECTIVE: This study analyzed the morphology of the California sea lion globe to determine what features may contribute to their characteristic visual abilities. PROCEDURE: Globes from the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW) collection were examined from gross photographs and microscopic sections stained with hematoxylin and eosin, trichrome, smooth muscle actin, and alcian blue periodic acid-Schiff (PAS). Transmission electron microscopy of the cornea and iris was also performed. CLINICAL RESULTS: There was a round, flattened area ventromedial to the axial cornea. The pupil was tear-drop shaped. Pectinate ligaments were visible without magnification. The retina was holangiotic, containing numerous spoke-like venules and arterioles. The tapetum was green encompassing the entire fundus. The optic nerve was unmyelinated. HISTOLOGICAL RESULTS: The sclera was thinnest equatorially and thickest at the limbus and posterior pole. Bowman's layer was difficult to see by light microscopy but clear with transmission electron microscopy. The cornea had a thick epithelium, thin endothelium and Descemet's membrane, and the stroma thinned axially. The dilator muscle was absent near the pupil, but enlarged and mingled with the sphincter muscle near the iris base. A large, wide ciliary cleft with prominent trabeculae and a single continuous pectinate ligament was present. The corneoscleral trabecular meshwork was discontinuous. A round lens attached to the ciliary body via direct attachment to ciliary processes and delicate zonular ligaments. There was a circumferential muscle at the base of the ciliary processes. A thick tapetum covered the entire fundus except peripherally. The retina was characterized by sparse, large ganglion cells. PMID- 20840091 TI - Ocular disease in the guinea pig (Cavia porcellus): a survey of 1000 animals. AB - OBJECTIVE: Anecdotal evidence has suggested that guinea pigs have a high prevalence of ocular lesions. Here we undertook a survey of 1000 guinea pigs from populations of animals kept as laboratory animals, breeding show cavies, animals kept as pets and those from rescue and rehoming centers. Each animal was examined to assess for ocular abnormalities. PROCEDURES: A full ophthalmic examination was performed on each animal with direct and indirect ophthalmoscopy and with slit lamp biomicroscopy. Measurement of tear production using the Schirmer tear test 1 and intraocular pressure using the Tonopen applanation tonometer after topical anesthesia was undertaken in selected animals. RESULTS: Forty-five percent of animals examined had some ocular abnormality. The majority were lens lesions including 17% with cataract and 21% with subclinical lens abnormalities such as nuclear sclerosis. Other abnormalities included conjunctivitis in 4.7% and keratitis in 3.6%. Lipid deposition in conjunctiva was observed in 2.3% of guinea pigs and ciliary body heterotopic bone formation in 0.8% of animals. CONCLUSIONS: This study shows a high proportion of eyes with some degree of abnormality in animals otherwise considered healthy. Information on diseases of the guinea pig eye is important given the use of the species as a laboratory rodent and also the number kept as pets and show animals. PMID- 20840093 TI - Ocular parameters in a captive colony of fruit bats. AB - OBJECTIVES: To establish normal reference ranges of ocular parameters including phenol read thread, palpebral fissure length, horizontal and vertical corneal diameter, upright and hanging intraocular pressure (IOP) and to report ophthalmic examination findings of the anterior segment and lens, in a population of captive fruit bats. ANIMALS STUDIED: Eyes of 30 bats of three species were included in this study: 10 (5 males, 5 females) Malayan Flying Foxes (Pteropus vampyrus), 10 (5 males, 5 females) Little Golden-mantled Flying Foxes (Pteropus pumilus), and 10 (4 males, 6 females) Island Flying Foxes (Pteropus hypomelanus). RESULTS: The most common ophthalmic examination findings included iris-iris persistent pupillary membranes (83%), nuclear sclerosis (56.7%), prominent arterial circle (40%), iridal hyperpigmented foci (30%), pupillary margin cysts (27%), and third eyelid defects (20%). The mean, among all species for: phenol red thread was 20.23 +/- 1.28 mm/15 s both eyes (OU); palpebral fissure length was 13.34 +/- 0.33 mm for OU; for horizontal corneal diameter was 10.72 +/- 0.32 mm for OU; for vertical corneal diameter was 9.90 +/- 0.30 mm for OU; for the hanging intraocular pressures was 19.38 +/- 0.77 mmHg for OU; for upright IOP was 13.95 +/- 0.60 mmHg for OU. Measurements for the individual species groups and eyes were also calculated. CONCLUSIONS: Results revealed the IOP of bats in a hanging position were significantly higher than the IOP of bats in an upright position. The size of the bat, between the species, affected palpebral fissure length, horizontal corneal diameter, and vertical corneal diameter. Information about the ocular structures and normal ophthalmic parameters for the Pteropus species is crucial for species protection because of dependence on vision for survival. PMID- 20840094 TI - Accuracy and reproducibility of the TonoVet rebound tonometer in birds of prey. AB - OBJECTIVE: To examine the accuracy and reproducibility of intraocular pressure (IOP) measurements obtained by the TonoVet rebound tonometer. Animals studied Freshly enucleated healthy eyes of 44 free-ranging birds of prey out of the species Haliaeetus albicilla, Accipiter gentilis, Accipiter nisus, Buteo buteo, Falco tinnunculus, Strix aluco, Asio otus and Tyto alba euthanized because of unrelated health problems. PROCEDURES: IOP readings from the TonoVet were compared with a manometric device, with IOP being set from 5 to 100 mmHg in steps of 5 mmHg by adjusting the height of a NaCl solution reservoir connected to the eye. Reproducibility of the TonoVet readings was determined by repeated measurements. RESULTS: TonoVet and manometer values showed a strong linear correlation. In the Accipitridae, the TonoVet tended to increasingly overestimate IOP with increasing pressure, while in the other families, it increasingly underestimated it. In the Sparrowhawk, the values almost represent the ideal line. Reproducibility of TonoVet values decreases with increasing pressure in the clinically important range from 5 to 60 mmHg. CONCLUSION: IOP values measured with the TonoVet demonstrated species specific deviation from the manometric measurements. These differences should be considered when interpreting IOP values. Using the regression formulae presented, corrected IOP values could be calculated in a clinical setting. PMID- 20840095 TI - Ultrasonographic aspects and biometry of Striped owl's eyes (Rhinoptynx clamator). AB - OBJECTIVE: To report the biometric values and ultrasonographic aspects of the normal eye of the Striped owl (Rhinoptynx clamator). Sample population Twenty seven healthy, free-living, adult Striped owls from the Ecological Park of Tiete Veterinary Ambulatory (Sao Paulo, Brazil). PROCEDURES: Both eyes of all owls underwent B-mode ultrasonographic examination and biometry was performed for lens axial length (WL), depth of the anterior (AC) and vitreous (VC) chambers, axial length of the globe (LB) and the pecten oculi (LP) of both eyes, using a 12 MHz probe. The owls were manually restrained without sedation and the eyes were topically anesthetized. RESULTS: Biometric and statistical findings were as follows: in the left eye, the means and standard deviations were: LB = 23.76 +/- 0.92 mm, WL = 7.79 +/- 0.27 mm, AC = 4.27 +/- 0.47 mm, VC = 11.36 +/- 0.29 mm and LP = 5.69 +/- 0.50 mm; in the right eye, the values were: LB = 24.25 +/- 0.79 mm, WL = 8.03 +/- 0.40 mm, AC = 4.56 +/- 0.52 mm, VC = 11.40 +/- 0.25 mm, and LP = 5.68 +/- 0.41 mm. No significant differences were found between left and right eyes measurements of LB, WL, AC, VC, and LP dimensions. CONCLUSIONS: Ocular ultrasound aspects and biometric values of the Striped owl are reported. The study's results provide means for various ocular measurements. The ultrasound is an easy and safe exam to be performed in the Striped owl's eyes. PMID- 20840096 TI - Bilateral phacoemulsification in an orangutan (Pongo pygmaeus). AB - A 14-year-old, female, captive-born orangutan (Pongo pygmaeus) developed bilateral cataracts. Ultrasonography, electroretinography and cataract correction using phacoemulsification were performed bilaterally. This case report aims to describe the ophthalmic procedures performed in this animal critically endangered of extinction. The surgery successfully restored vision and normal activity to the patient. PMID- 20840097 TI - Corneal papilloma associated with papillomavirus in a one-humped camel (Camelus dromedarius). AB - A 15-year-old male dromedary camel with a history of chronic severe keratoconjunctivitis and corneal mass in the left eye of 6 months' duration was referred to the Veterinary Medical Teaching Hospital at Adnan Menderes University. A superficial keratectomy was performed and biopsy material submitted for histopathology. The diagnosis was corneal papilloma. There has been no recurrence of the neoplasm to date (6 months, 1 year). Corneal papilloma has not been reported previously in camels and seems to be associated with papillomavirus. PMID- 20840098 TI - Intraocular osteosarcoma in an Umbrella Cockatoo (Cacatua alba). AB - An adult, presumed intact female Umbrella Cockatoo (Cacatua alba), presented with acute hemorrhage from an intraocular mass that perforated through the right cornea. Computed tomography scanning revealed a large soft tissue mass in the right orbit, invading and displacing the globe laterally, and destroying the scleral ossicles. There was no evidence of bony changes of the orbit or extension of the mass into the optic nerve or brain. Exenteration and mass removal were performed, and osteosarcoma was diagnosed via histopathology. Radiotherapy was delivered with an orthovoltage unit to a total dose of 68 Gray delivered in 17 fractions over 6 weeks. The bird recovered well from treatment, but died 2 months after the last radiation session with neurological signs. Necropsy was not performed. To our knowledge, this is the first case of an intraocular osteosarcoma reported in a bird, and the first case of attempted treatment of osteosarcoma in a bird by a combination of surgery and radiation therapy. PMID- 20840099 TI - Medical and surgical management of severe inflammation of the nictitating membrane in a Giant Panda (Ailuropoda melanoleuca). AB - A 10-year-old male giant panda (Ailuropoda melanoleuca) presented for severe, acute swelling and protrusion of the right nictitating membrane, unresponsive to topical therapy. Excisional biopsy of the nictitating membrane and its associated lacrimal gland was elected due to necrosis and friability of the tissue. Histopathology revealed suppurative, necrotizing conjunctivitis and dacryoadenitis. Culture grew Stenotrophomonas maltophila and Enterococcus spp with extensive antibiotic resistance. Treatment with topical and systemic antibiotics based on sensitivity results was initiated. All treatments were well tolerated. Healing was uncomplicated with no recurrence of the lesion and no clinical evidence of keratoconjunctivitis sicca. Ophthalmic exams and Schirmer tear tests performed opportunistically during postoperative anesthetic procedures were unremarkable, confirming that excision of the nictitating membrane had not caused clinically significant detrimental effects. The etiology of this lesion remains undetermined, but trauma is suspected. To the authors' knowledge, this is the first report of nictitating membrane pathology and excision in the giant panda. PMID- 20840100 TI - Unilateral eyelid lesion and ophthalmologic findings in an aardvark (Orycteropus afer): case report and literature review. AB - OBJECTIVE: To summarize the medical knowledge surrounding aardvarks to date, to describe the ophthalmic examination of a specimen with a chronic history of an upper eyelid lesion, of an assumed blind left eye, and to detail the anesthesia procedure performed. PROCEDURE: A 23-year-old aardvark was examined under general anesthesia and multiple ocular abnormalities were detected in the left eye (globe deviation, corneal opacities, iridodonesis, and aphakia). A thickening of the palpebral conjunctiva affecting the medial upper eyelid with erosion of the normal eyelid margin anatomy was identified. The adnexal lesion was resected by a wedge resection and histopathology was performed. Suture breakdown 3 days postoperatively required a second surgery, where buried sutures were used. The surgical techniques and postoperative care are discussed. RESULTS: The histopathology revealed mucosal hyperplasia and moderate neutrophilic and lymphoplasmacytic blepharitis. No causal organisms were identified. Following initial wound dehiscence and a modified surgical technique, the upper eyelid healed without complication and retained complete function. CONCLUSIONS: The eyelid lesion involved a benign inflammatory and hyperplastic pathology of unknown etiology. Adjusting routine ophthalmic surgical techniques to wildlife and zoo animals can be challenging and complicated. It is important to understand the nature of the animals being managed, their circadian cycle, and habitat, to adjust and individualize the surgical approach, instrumentation, suture material, and perioperative treatment. PMID- 20840101 TI - Iridociliary melanoma with secondary lens luxation: distinctive findings in a long-horned cowfish (Lactoria cornuta). AB - This report describes a long-horned cowfish, which was diagnosed with buphthalmia and lens sub-luxation in the right eye, conditions that progressed to complete anterior lens luxation and secondary keratoconus. Three months after the initial evaluation, a pigmented mass was observed protruding from the vitreous. An enucleation was performed under general anesthesia. Ocular histopathology revealed an iridociliary melanoma. Reports of intraocular melanomas are extremely rare in fish. To the authors' knowledge, this is the first report of an iridociliary melanoma that led to buphthalmia, lens luxation, and keratoconus in a fish. Histological findings of lens luxation are also demonstrated. Due to the presence of a complex suspensory apparatus involving the teleost lens, this report speculates that lens luxation is a more devastating disease process in teleosts than in mammals. PMID- 20840102 TI - Bilateral vision loss in a captive cheetah (Acinonyx jubatus). AB - The following case report describes a 1-year-old female cheetah (Acinonyx jubatus) with bilateral blindness and unresponsive pupils. For comparison, a second healthy 2.5-year-old male cheetah without visual deficits was also examined. Clinical examination of both animals included biomicroscopy, indirect ophthalmoscopy, tonometry, and electroretinography. The young female cheetah showed no menace response, no direct or indirect pupillary light reflex, and no dazzle reflex in either eye. Fundus lesions, as detected by indirect ophthalmoscopy, are described for the female animal. In both eyes, the fundus color was green/turquoise/yellow with multiple hyperpigmented linear lesions in the tapetal area around the optic nerve. The optic nerve head was dark gray and about half the normal size suggesting bilateral optic nerve hypoplasia and retinal dysplasia or differentially optic nerve atrophy and chorioretinal scarring. The ERG had low amplitudes in the right eye but appeared normal in the left eye compared with the male cheetah. Blood levels did not suggest current taurine deficiency. This is addressed to some degree in the discussion. Bilateral optic nerve hypoplasia or optic nerve atrophy is a rare anomaly in cats and has not yet been described in a cheetah. PMID- 20840103 TI - Normal aerobic bacterial conjunctival flora in the Crab-eating raccoon (Procyon cancrivorus) and Coati (Nasua nasua) housed in captivity in pernambuco and paraiba (Northeast, Brazil). AB - OBJECTIVE: To determine the normal aerobic bacterial conjunctival population of the Coatis and the Crab-eating raccoons housed in captivity in the Pernambuco and Paraiba states of Brazil. ANIMALS STUDIED: Ten healthy Coatis and 10 healthy Crab eating raccoons were selected for this study. Animals are from three zoos situated at the Pernambuco and Paraiba States in the north-east of Brazil. PROCEDURES: After ophthalmologic examination, swabs from healthy animals were carefully collected in order to avoid contamination. Samples were identified and submitted to the laboratory. Swabs were plated for culture on ovine blood agar (8%) and agar Levine and incubated at 37 degrees C and observed 24 and 48 h. RESULTS: Staphylococcus spp. was the most common microorganism isolated from conjunctival sac. Shigella spp. comprised the Gram-negative genera isolated. Escherichia coli were isolated from the right eye of one Coati that had no growth at contralateral eye. Nine eyes from coatis and 10 from Crab-eating raccoons had no microorganisms isolated. CONCLUSION: Our results were in accordance with previous studies indicating Staphylococcus sp., followed by Corynebacterium spp. as the most common inhabitant of the eyes of most mammalian species. PMID- 20840104 TI - Keratoprosthesis with retrocorneal fixation: preliminary results in dogs with corneal blindness. AB - OBJECTIVE: To evaluate the use and complications of a penetrating keratoprosthesis implantation in the management of corneal opacification in dogs. METHODS: A retrospective clinical study describes the indications for the surgical technique utilized and the outcomes of this procedure in 20 eyes of 19 dogs with blindness of corneal origin. A successful surgical outcome was defined as a clear keratoprosthesis optic and improvement or restoration of functional vision over a follow-up period ranging from at least 8 months to a maximum of 7 years. RESULTS: Eyes with total corneal opacification resulting from chronic superficial keratitis (n = 11), keratoconjunctivitis sicca (n = 5), endothelial dystrophy (n = 3) and chemical burn (n = 1) were treated by unilateral (n = 18) or bilateral (n = 1) full-thickness implantation of a keratoprosthesis. Keratoprostheses were retained in 15 eyes (75%) which regained vision to the date of reporting. Among these eyes, six had uncomplicated postoperative course, five developed retroprosthetic membranes and four developed granulation tissue over the optic of the keratoprostheses. These complications were successfully removed surgically in the nine eyes. The five remaining eyes (25%) developed serious early postoperative complications, for which enucleation had to be performed. CONCLUSION: In keratopathies in which the corneal opacification could not be treated by standard medical or surgical procedures, this keratoprosthesis appears to be promising to restore vision in chronic superficial keratitis and deep corneal dystrophy. It appears to have a poor prognosis in keratoconjunctivitis sicca in brachycephalic dogs. The post operative complications retro-prosthetic membranes and granulomatous overgrowth could be treated well. PMID- 20840105 TI - Investigation of fellow eye of unilateral retinal detachment in Shih-Tzu. AB - OBJECTIVE: To investigate disease in the fellow eye, and consider the relation to rhegmatogenous retinal detachment (RRD) in Shih-Tzus. ANIMALS STUDIED: The fellow eyes of 49 Shih-Tzus (27 male, 22 female; median age: 6.8 years) with unilateral RRD diagnosed by funduscopy or ultrasonography at Rakuno Gakuen University Teaching Animal Hospital were assessed in this study. PROCEDURES: Ophthalmic examinations (including menace response, pupillary light reflex, slit-lamp biomicroscopy, and funduscopy) were performed in the subjects. Electroretinography was performed in 12 eyes that developed retinal degeneration. Maximum follow-up period was 42 months. RESULTS: Cataracts and vitreous opacity were observed in 26 (53%) and 32 eyes (65%), respectively, by slit-lamp biomicroscopy. Retinal degeneration with various degrees of hyper-reflectivity of the tapetal fundus and/or attenuation of retinal vessels was observed in 35 eyes (71%) on funduscopy. A reduction of amplitude in rod, standard combined and 30 Hz flicker electroretinogram was detected in 5 (42%), 10 (83%), and 6 eyes (50%), respectively. During the follow-up period, RRD was detected in six eyes. CONCLUSION: Retinal degeneration was frequently detected by funduscopy and electroretinograms in the fellow eye in Shih-Tzus with RRD. In our subjects, vitreous degeneration was also observed frequently. It has been reported that peripheral retinal degeneration is one of the causes of RRD associated with vitreous degeneration in humans. We assume that primary retinal degeneration with secondary vitreous degeneration is one of the causes of RRD in Shih-Tzus. PMID- 20840106 TI - Long-term outcome after implantation of a suprachoroidal cyclosporine drug delivery device in horses with recurrent uveitis. AB - OBJECTIVE: To determine the long-term efficacy, complications, and duration of effect of a cyclosporine (CsA) suprachoroidal implant (CSI) in horses with equine recurrent uveitis (ERU). METHODS: Horses with ERU were treated with a 6-mm diameter, 25 mg, reservoir matrix CsA implant in the deep sclera adjacent to the suprachoroidal space. Horses with follow-up >1 year were examined for frequency of uveitis episodes, complications, and vision at last recheck. RESULTS: Data from 151 eyes of 133 horses from the USA and Europe that had CsA devices implanted for ERU were reviewed. Follow-up time ranged from 13 to 85 months after surgery, with a mean and median follow-up time of 28.9 and 26.3 months, respectively. Overall, at last follow-up 78.8% of eyes were considered visual and the overall mean frequency of uveitis episodes after CSI was 0.09 +/- SD 0.08 episodes per month. The most common complications leading to vision loss at last follow-up were persistent uveitis episodes (54%), glaucoma (22%), mature cataracts (16%), and retinal detachment (6%). Persistent uveitis episodes tended to be the highest cause of vision loss in horses with <24 months and >48 months of follow-up. CONCLUSIONS: This study demonstrated the long-term maintenance of vision of horses with ERU implanted with a CSI. The increased vision loss related to uveitis episode of inflammation in eyes after the likely depletion of CsA from the CSI suggests that a repeat CSI may be required at or before 48 months after surgery. PMID- 20840107 TI - Gene delivery in the equine cornea: a novel therapeutic strategy. AB - OBJECTIVE: To determine if hybrid adeno-associated virus serotype 2/5 (AAV5) vector can effectively deliver foreign genes into the equine cornea without causing adverse side effects. The aims of this study were to: (i) evaluate efficacy of AAV5 to deliver therapeutic genes into equine corneal fibroblasts (ECFs) using enhanced green fluorescent protein (EGFP) marker gene, and (ii) establish the safety of AAV5 vector for equine corneal gene therapy. MATERIAL: Primary ECF cultures were harvested from healthy donor equine corneas. Cultures were maintained at 37 degrees C in humidified atmosphere with 5% CO(2). PROCEDURE: AAV5 vector expressing EGFP under control of hybrid cytomegalovirus + chicken beta-actin promoter was applied topically to ECF. Expression of delivered EGFP gene in ECF was quantified using fluorescent microscopy. Using fluorescent staining, the total number of cells and transduction efficiency of tested AAV vector was determined. Phase contrast microscopy, trypan blue and TUNEL assays were used to determine toxicity and safety of AAV5 for ECFs. RESULTS: Topical AAV5 application successfully transduced significant numbers of ECFs. Transduction efficiency was 13.1%. Tested AAV5 vector did not cause phenotype change or significant cell death and cell viability was maintained. CONCLUSIONS: Tested AAV5 vector is effective and safe for gene therapy in ECFs in vitro. PMID- 20840109 TI - Lack of effects on lymphocyte function from chronic topical ocular cyclosporine medication: a prospective study. AB - AIM: Topical cyclosporine has been widely used in the treatment of canine keratoconjunctivitis sicca without apparent documented clinical side effects. Thus the finding of reduced lymphocyte proliferation in animals treated with the drug at a concentration of 2% was both surprising and concerning. This study aimed to repeat the previous study and to compare the systemic effects of 2% cyclosporine in corn oil and 0.2% topical cyclosporine ointment (Optimmune, Intervet-Schering Plough, Welwyn, UK). METHODS: Twenty dogs treated with Optimmune or with topical 2% cyclosporine in corn oil where previous treatment with Optimmune had failed were included in this study. Blood samples were taken at the time of first evaluation and at 1, 3 and 6 months of treatment to provide a biochemical and hematological health evaluation of the dogs and at each examination to measure circulating levels of cyclosporine and to obtain a lymphocyte population with which to determine a mitogen stimulation index (MSI) on treatment with phytohaemagglutinin-P (PHA) and conconavlin A (con-A). Levels of circulating cyclosporine were measured with an enzyme-multiplied immunoassay method and also the more sensitive quantification technique of mass spectroscopy (MS). RESULTS: No blood samples contained over 15 ng/ml cyclosporine, the lower limit of detection using the radioimmunoassay or the enzyme-multiplied immunoassay technique. Positive control samples taken from dogs treated with oral cyclosporine for anal furunculosis showed measurable levels in blood, demonstrating that the technique worked. Mean MSI values at 0, 1, 3 and 6 months of treatment were 10.2, 11.4, 11.6, and 10.5 for dogs treated with 0.2% cyclosporine and 10.4, 11.9, 11.7, and 12.9 for dogs treated with 2% cyclosporine. Mitogen stimulation index values were not statistically different between the first examination and any subsequent examination time-point. CONCLUSIONS: The findings of the study contradict those of the previous studies. No change in lymphocyte stimulation index was noted, neither were significant blood levels of cyclosporine documented after topical administration of either 0.2% or 2% cyclosporine. This study shows that topical cyclosporine is safe to use in the canine eye in line with the drug's safety record in this therapeutic regime over the past 20 years since its first use. PMID- 20840108 TI - Acute postretinal blindness: ophthalmologic, neurologic, and magnetic resonance imaging findings in dogs and cats (seven cases). AB - OBJECTIVE: To describe the ophthalmologic, neurologic, and magnetic resonance imaging (MRI) findings of seven animals with acute postretinal blindness as sole neurologic deficit. METHODS: Medical records were reviewed to identify dogs and cats with postretinal blindness of acute presentation, that had a cranial MRI performed as part of the diagnostic workup. Only animals lacking other neurologic signs at presentation were included. Complete physical, ophthalmic, and neurologic examinations, routine laboratory evaluations, thoracic radiographs, abdominal ultrasound, electroretinography, and brain MRI were performed in all animals. Cerebrospinal fluid analysis and postmortem histopathologic results were recorded when available. RESULTS: Four dogs and three cats met the inclusion criteria. Lesions affecting the visual pathways were observed on magnetic resonance (MR) images in six cases. Location, extension, and MRI features were described. Neuroanatomic localization included: olfactory region with involvement of the optic chiasm (n = 4), pituitary fossa with involvement of the optic chiasm and optic tracts (n = 1), and optic nerves (n = 1). Of all lesions detected, five were consistent with intracranial tumors (two meningiomas, one pituitary tumor, two nasal tumors with intracranial extension), and one with bilateral optic neuritis that was confirmed by cerebrospinal fluid analysis. Histologic diagnosis was obtained in four cases and included one meningioma, one pituitary carcinoma, one nasal osteosarcoma, and one nasal carcinoma. CONCLUSIONS: Central nervous system (CNS) disease should be considered in dogs and cats with acute blindness, even when other neurologic deficits are absent. This study emphasizes the relevance of MRI as a diagnostic tool for detection and characterization of CNS lesions affecting the visual pathways. PMID- 20840110 TI - Tear production in normal juvenile dogs. AB - OBJECTIVE: To establish a baseline range or average for tear production in normal juvenile dogs and evaluate the effects of age, weight, and gender on Schirmer tear test (STT) in juvenile dogs. MATERIALS AND METHODS: Healthy puppies of various breeds <6 months of age. STT1 and STT2 were performed in both eyes of each subject. Statistical analysis was performed using a backwards stepwise regression model with repeated measures. Using continuous variables of STT1 and STT2 as the dependent variables separately, the independent variables were age (days), eye (left or right), gender (male or female), ocular disease processes in eyes or not, and weight (kg). RESULTS: Eighty-six eyes from 27 males and 16 females were included in this study. Ages ranged from 25 to 133 (mean +/- SEM: 61.74 +/- 24.15) days and weights ranged from 0.88 to 8.86 (3.27 +/- 2.22) kg. STT1 results ranged from 0 to 26 (15.76 +/- 5.79) mm/min. STT2 results ranged from 0 to 24 (8.79 +/- 5.01) mm/min. Age, weight, and gender significantly affected STT1 results. Weight and gender significantly affected STT2 results. STT1 values increased by 0.15 mm/min for each 1 day increase in age and by 0.84 mm/min for each 1 kg increase in body weight. STT2 values increased by 0.57 mm/min for each 1 kg increase in body weight. CONCLUSIONS: Age, weight, and gender significantly affect tear production in normal juvenile dogs. STT1 increases to adult values at approximately 9-10 weeks of age. PMID- 20840111 TI - Amniotic membrane transplantation for the treatment of feline corneal sequestrum: pilot study. AB - OBJECTIVES: To describe and evaluate the use of equine amniotic membrane trans plantation after lamellar keratectomy for the treatment of corneal sequestrum in cats. METHODS: Six cats (seven eyes) of various breed and ages with corneal sequestra were treated surgically with lamellar keratectomy and amniotic membrane transplantation. All the sequestra and a small piece of the amniotic membranes used for each surgery were submitted for histopathologic examination. RESULTS: Five of the seven eyes showed minimal level of scarring in the cornea and good transparency. No recurrences of the sequestra have been noted during the follow up period (3-9 months). One eye had necrosis of the amniotic membrane 2 weeks after the surgery. The sequestrum of this eye showed a high level of bacterial contamination on histopathology. Three months later the same cat developed a descemetocele in the area where the necrotic amniotic membrane was rejected. A second eye developed a perforation under the amniotic membrane two weeks after the surgery. The sequestrum of this eye was deep and without vascularization. CONCLUSION: Amniotic membrane transplantation after lamellar keratectomy was a valid procedure for surgical treatment of corneal sequestrum in cats. The procedure resulted in excellent cosmesis and functional vision in five of seven eyes; although case selection is important, particularly to exclude the very deep and non-vascularized sequestra. PMID- 20840112 TI - Keratomycosis in a dog treated with topical 1% voriconazole solution. AB - A 2-year-old Jack Russell Terrier was presented for treatment of a worsening corneal ulcer and keratomalacia following removal of a vegetative foreign body. The keratomalacia responded to topical gentamicin therapy; however, the eye became suddenly painful and at examination two areas of increased opacity had developed. Fungal keratitis was demonstrated by corneal scrape showing branching, septate fungal hyphae. Treatment with 1% voriconazole was effective in resolving the keratomycosis. PMID- 20840113 TI - Meibomian carcinoma of the eyelid in a Simmental cow. AB - OBJECTIVE: To describe the clinical and pathomorphological features of meibomian carcinoma (MC) diagnosed in a Simmental cow. MATERIAL AND METHODS: A 7-year-old Simmental cow was admitted to the Veterinary Surgery Clinics of Faculty of Veterinary Medicine, University of Kafkas, Kars, Turkey. The signalment and anatomical distribution were summarized and focused on pathomorphological description. RESULTS: Macroscopically, a papillary mass, 5 * 3.5 * 7 cm in size, arising from the left lower eyelid with local spread to the upper eyelid and covering the entire globe was observed. The mass was ulcerated and hemorrhagic and applied pressure to the globe. Following sedation and local anesthesia, the mass and globe were excised. Histopathological examination revealed an MC. CONCLUSIONS: The diagnosis of MC is infrequent in veterinary literature. Complete surgical excision could be curative and histopathology is crucial for the diagnosis of MC occurring in animals. PMID- 20840114 TI - Anomalous nasolacrimal openings in a 2-year-old Morgan filly. AB - This case report describes the clinical, diagnostic, computed tomography findings, and surgical treatment of a 2-year-old Morgan filly with bilateral, proximal, and distal anomalous nasolacrimal duct openings. PMID- 20840116 TI - Abstracts of the European Society of Veterinary Ophthalmologists. Dublin, Ireland. May 13-16, 2010. PMID- 20840115 TI - Amelanotic uveal cyst in a Yorkshire terrier dog. AB - The diagnostic challenge presented by an amelanotic uveal cyst with an atypical appearance in a 9-year-old Yorkshire terrier dog is reported. The dog was presented with a peculiar cystic neoformation adherent to the edge of the pupil of the right eye. The cyst wall was attached to the pupillary margin and it was bean-shaped, measuring approximately 4.5 * 2.5 mm. It was white in colour with several red striations and a small brown spot in the middle, which conferred on it a peculiar appearance. The cyst could not be transilluminated and partially impaired vision. Apart from that, the ophthalmic exam revealed no other abnormalities and the eye showed no signs of inflammation. Ocular ultrasound revealed the cystic nature of the neoformation. During paracentesis of the anterior chamber, the cyst was deflated and both the cyst wall and fluid were aspirated. The tissue obtained was sent for a histological examination and was considered as corresponding to a uveal cyst. The dog improved from the post operative uveitis without any complication and after 24 months of follow-up showed no recurrences. PMID- 20840117 TI - Abstracts of the Annual Meeting of the European College of Veterinary Ophthalmologists. Berlin, Germany. May 28-29, 2010. PMID- 20840118 TI - Flipping or scrolling. PMID- 20840120 TI - TRP-ing off the p53 apoptotic switch. PMID- 20840134 TI - Moving beyond clarity: towards a thin, vague, and useful understanding of spirituality in nursing care. AB - Spirituality is a highly contested concept. Within the nursing literature, there are a huge range and diversity of definitions, some of which appear coherent whereas others seem quite disparate and unconnected. This vagueness within the nursing literature has led some to suggest that spirituality is so diverse as to be meaningless. Are the critics correct in asserting that the vagueness that surrounds spirituality invalidates it as a significant aspect of care? We think not. It is in fact the vagueness of the concept that is its strength and value. In this paper, we offer a critique of the general apologetic that surrounds the use of the language of spirituality in nursing. With the critics, we agree that the term 'spirituality' is used in endlessly different and loose ways. Similarly, we agree that these varied definitions may not refer to constant essences or objects within people or in the world. However, we fundamentally disagree that this makes spirituality irrelevant or of little practical utility. Quite the opposite; properly understood, the vagueness and lack of clarity around the term spirituality is actually a strength that has powerful political, social, and clinical implications. We develop an understanding of spirituality as a way of naming absences and recognizing gaps in healthcare provision as well as a prophetic challenge to some of the ways in which we practise health care within a secular and sometimes secularizing context such as the National Health Service. PMID- 20840135 TI - Culture theorizing past and present: trends and challenges. AB - Over the past several decades, nurses have been increasingly theorizing about the relationships between culture, health, and nursing practice. This culture theorizing has changed over time and has recently been subject to much critical examination. The purpose of this paper is to identify the challenges impeding nurses' ability to build theory about the relationships between culture and health. Through a historical overview, I argue that continued support for the essentialist view of culture can maintain a limited view of complex race relations. I also argue that attempts to apply culture theory, without knowledge of important historical, political, and economic factors, has often resulted in oversimplified versions of what was originally intended. Furthermore, I argue that individual-level interventions alone will be insufficient to address health inequities related to culture. Despite new critical conceptualizations of culture and the uptake of cultural safety, nursing scholars must better address the broader organizational, population, and political interventions needed to address inequities in health. I conclude with suggestions for how nurses might proceed with culture theorizing given these challenges. PMID- 20840136 TI - Faceless sex: glory holes and sexual assemblages. AB - According to our previous research, the use of glory holes in public venues such as saunas and bathhouses is very popular. The popularity of glory holes is due in part to the anonymous sex that these architectural elements allow. This post structuralist theoretical reflection seeks to understand the specific nature of anonymous public sex among bathhouse patrons, focusing on the links between desire-architecture-place-sexual practices. Drawing on interviews with glory hole users gathered during an ethnographic research project in bathhouses, this essay goes beyond traditional public health discourse to offer an original perspective on anonymous public sex. Utilizing the philosophy of Deleuze and Guattari's concepts of assemblages and machines, we re-theorize glory hole sex--what we call 'faceless sex'--and rethink the ways that desire is imbricated with our understanding of architecture, place, and public. Finally, we reflect upon the particular ethical challenges that are posed by these particular sexual practices, and ask whether a post-structuralist ethic might be possible. PMID- 20840137 TI - Abductive reasoning and the formation of scientific knowledge within nursing research. AB - Peirce's notion of abductive reasoning and the way this reasoning can enhance forming of scientific knowledge within nursing research is of great importance. Abduction is the first stage of inquiry within which hypotheses are invented; they are then explicated through deduction and verified through induction. In an abductive model, new ideas emerge by taking various clues and restrictions into account, and by searching and combining existing ideas in novel ways. Thus, abduction can be developed further as a 'pure' form of inference and this gives means for analysing and organizing the abductive search explicitly within the research community. PMID- 20840138 TI - Destabilizing the 'equipoise' framework in clinical trials: prioritizing non exploitation as an ethical framework in clinical research. AB - The framework of equipoise has been promulgated as an underlying requirement for conducting ethical clinical research. Equipoise is the term used for a state of indifference about which treatment intervention or innovation will provide the most benefit and the least harm to recipients. Drawing on healthcare, research, and ethics literature, this paper analyses the implications of equipoise from the perspective of several proponents and critics. Specifically the historical evolution of the concept based on Fried and Freedman's arguments is traced. A critique of the concept, informed by contrasting perspectives, is offered. An alternative framework of non-exploitation as presented by Miller and Brody is argued to be superior in facilitating both the ultimate goals of research on human subjects and those of the healthcare professions'. PMID- 20840139 TI - What limits, if any, should be placed on a parent's right to consent and/or refuse to consent to medical treatment for their child? AB - Abstract There is an overwhelming consensus that parent's rights to consent must be limited to decisions that are in the child's best interests, yet best interests are difficult to determine. I reflect on the case of severely developmentally delayed children, and suggest that the interests of parent and child are difficult to separate. In such cases there is a strong argument for the use of substituted judgement by a parent. Although there are coherent conceptions of the limitations of parental rights, these are based on the eventual autonomy of the child, a state that children with severe developmental delay will never achieve. Legal treatments of best interests fail to explicitly take account of such nuances, and are open to accusations of judicial subjectivity. Increased clarity could be gained by setting out the relative weight of medical, parental, and child views of best interests. PMID- 20840140 TI - Phenomenology as research method or substantive metaphysics? An overview of phenomenology's uses in nursing. AB - In exploring phenomenological literature, it is evident that the term 'phenomenology' holds rather different meanings depending upon the context. Phenomenology has been described as both a philosophical movement and an approach to human science research. The phenomenology of Husserl, Heidegger, Gadamer, and Merleau-Ponty was philosophical in nature and not intended to provide rules or procedures for conducting research. The Canadian social scientist, van Manen, however, introduced specific guidelines for conducting human science research, which is rooted in hermeneutic phenomenology and this particular method has been employed in professional disciplines such as education, nursing, clinical psychology, and law. The purpose of this paper is to explore the difference between the phenomenological method as described by van Manen and that of other philosophers such as Husserl, Heidegger, Gadamer, and Merleau-Ponty. In so doing, the author aims to address the blurred boundaries of phenomenology as a research method and as a philosophical movement and highlight the influence of these blurred boundaries on nursing knowledge development. PMID- 20840142 TI - Necessity of adopting postcolonial feminism. Letter to the editor. PMID- 20840144 TI - The Ectocarpus genome sequence: insights into brown algal biology and the evolutionary diversity of the eukaryotes. PMID- 20840145 TI - New light shed on life and death: the role of staygreen in the hypersensitive response. PMID- 20840146 TI - Function and evolution of saccate pollen. PMID- 20840147 TI - Interleukin-8 induction due to diffusely adherent Escherichia coli possessing Afa/Dr genes depends on flagella and epithelial Toll-like receptor 5. AB - DAEC is considered potentially diarrheagenic. For diffuse adhesion, the role of the Afa, which was originally identified as a uropathogenic factor, is now understood. However, the role of DAEC in diarrheal disease remains controversial because DAEC is often isolated not only from patients but also from healthy individuals. Previously, we suggested that Afa/Dr DAEC, which can induce high levels of IL-8 secretion in cultures of human carcinoma epithelial cells (HEp-2, Caco-2), is enterovirulent. In the present study, we examined whether IL-8 secretion induced by certain Afa/Dr DAEC strains was primarily due to flagella via TLR5. All IL-8 high-inducing strains were highly motile in swarming tests. Partially purified flagella induced IL-8 in a dose-dependent manner. However, IL 8 induction was inhibited by small-interfering RNA against TLR5 or by treating flagella with disialoganglioside-GD1a, a TLR5 blocker. TLR5 is reportedly located on the basolateral side of intestinal epithelia; flagella should not have reached TLR5 from the apical side beyond tight junctions. Reduction in the number of intracellular organisms by wortmannin, a PI3K inhibitor, did not reduce IL-8 secretion. Afa/Dr DAEC seemed to loosen the tight junctions because it quickly reduced transepithelial electrical resistance after infection. Decreased resistance led to increased IL-8 production. In conclusion, diffuse adhesion itself is insufficient to induce high levels of IL-8, and simultaneous stimulation by flagella via TLR5 is likely required for additional induction. Clinically, high motility may be a candidate criterion for predicting the ability of Afa/Dr DAEC strains to induce higher levels of IL-8 secretion. PMID- 20840148 TI - Conversion of viable but nonculturable Vibrio cholerae to the culturable state by co-culture with eukaryotic cells. AB - VBNC Vibrio cholerae O139 VC-280 obtained by incubation in 1% solution of artificial sea water IO at 4 degrees C for 74 days converted to the culturable state when co-cultured with CHO cells. Other eukaryotic cell lines, including HT 29, Caco-2, T84, HeLa, and Intestine 407, also supported conversion of VBNC cells to the culturable state. Conversion of VBNC V. cholerae O1 N16961 and V. cholerae O139 VC-280/pG13 to the culturable state, under the same conditions, was also confirmed. When VBNC V. cholerae O139 VC-280 was incubated in 1% IO at 4 degrees C for up to 91 days, the number of cells converted by co-culture with CHO cells declined with each additional day of incubation and after 91 days conversion was not observed. PMID- 20840149 TI - In vitro and in vivo effects of the Mongolian drug Amu-ru 7 on Helicobacter pylori growth and viability. AB - Amu-ru 7, a Mongolian folk medicine, is used to treat digestive diseases such as gastritis and gastric and duodenal ulcers. We examined the effect of Amu-ru 7 on the growth and viability of Helicobacter pylori in vivo and in vitro. By the agar dilution method, the MIC of Amu-ru 7 for H. pylori strains was shown to be 100 200 MUg/mL with a MIC(90) of 200 MUg/mL. Two hundred micrograms per milliliter of Amu-ru 7 exhibited potent bactericidal activity against H. pylori in the stationary phase of growth 6 hr after treatment. Amu-ru 7 inhibited the growth of both AMPC-resistant and CAM-resistant strains, and also had a combined effect with AMPC on AMPC-resistant strain 403. The Amu-ru 7 inhibited biofilm formation by H. pylori and induced morphological changes, such as bleb-like formation and shortening of the cell. Although colonization of the stomach of the Mongolian gerbil by H. pylori was not cured by treatment with Amu-ru 7, both the mean number of H. pylori colonized and the colonization rate were decreased in Amu-ru 7 treated gerbils. These results suggest the effectiveness Amu-ru 7 as an adjunct therapy for eradication therapies consisting of a PPI combined with antibiotics. PMID- 20840150 TI - Multicenter evaluation of prototype real-time PCR assays for Epstein-Barr virus and cytomegalovirus DNA in whole blood samples from transplant recipients. AB - Quantitative PCR is becoming widespread for diagnosing and monitoring post transplantation diseases associated with EBV and CMV. These assays need to be standardized to manage patients in different facilities. Five independent laboratories in Japan compared home-brew assays and a prototype assay system to establish a standard quantitative procedure for measuring EBV and CMV. Reference standards and a total of 816 (642 EBV and 174 CMV) whole blood samples from post transplantation recipients were used for this multicenter evaluation. The prototype reference standard for EBV was compared to a panel of samples, with a theoretical expected value made using EBV-positive cells containing two virus genome copies per cell. The mean ratio of the reference standard at each site to the standard of the prototype assay was <= 4.15 for EBV among three different sites and <= 3.0 for CMV between two laboratories. The mean of the theoretical expected number of the EBV genome: prototype reference was close to 1.0. The correlation coefficients between the viral copy numbers determined using the prototype assay and those using each home-brew assay were high (EBV, 0.73-0.83, median = 0.78; CMV, 0.54-0.60, median = 0.57). The dynamics of the EBV and CMV loads in transplant recipients were similar between the assay types. There was an inter-laboratory difference among the quantification results, indicating that a unified protocol and kit are favorable for standardizing the quantification of EBV and CMV. Such standardization will help to standardize the diagnosis and monitoring of diseases associated with EBV and CMV. PMID- 20840152 TI - Epstein Barr virus inhibits the stimulatory effect of TLR7/8 and TLR9 agonists but not CD40 ligand in human B lymphocytes. AB - Viruses and other microorganisms express specific pathogen-associated molecular patterns that are recognized by cell surface or endosome-associated Toll-like receptors (TLR). There are many examples of viruses that have developed strategies to modulate TLR signaling through the use of viral or cellular molecules. Epstein-Barr virus (EBV) has recently been found to display a complex interaction with TLR. The aim of this study was to asses the effect of EBV infection on proliferative capacity of TLR7/8 and 9 agonist and CD40 ligand (CD40L) in normal B lymphocytes. Our results demonstrate that EBV induces a significant inhibition in proliferative response to TLR7/8 (P < 0.004) and TLR9 (P < 0.000) agonists but not to CD40L stimulation in enriched human normal B lymphocytes. Similar inhibitory effect was also observed in B lymphocytes prestimulated with the TLR agonists, implying that the suppressive effect is not due to downregulation of TLR protein expression by EBV. EBV infection did not induce apoptosis and did not downregulate TLR7/8 mRNA expression in B lymphocytes. Our results suggest that EBV might be able to evade the immune system by modulation of the TLR signaling pathway. PMID- 20840151 TI - Orally supplemented Lactobacillus acidophilus strain L-92 inhibits passive and active cutaneous anaphylaxis as well as 2,4-dinitroflurobenzene and mite fecal antigen induced atopic dermatitis-like skin lesions in mice. AB - Oral supplementation of lactic acid bacteria is a potential approach to the prevention and manipulation of allergic diseases such as atopic dermatitis. Our previous report showed that heat-killed Lactobacillus acidophilus strain L-92 (L 92) possessed anti-allergic properties, although its physiological function in atopic dermatitis has largely remained undefined. To evaluate the anti-allergic efficacy of L-92, we used four experimental animal models with the major features of atopic dermatitis and compared the results to those of clinically active drugs. ICR mice were passively sensitized by anti-dinitrophenyl mouse monoclonal IgE for passive cutaneous anaphylaxis (PCA), and BALB/c mice were actively sensitized by ovalbumin for active cutaneous anaphylaxis (ACA). Allergic reaction was induced by repeated exposure to 2,4-dinitroflurobenzene (DNFB) and mite (Dermatophagoides farinae) fecal allergen, in BALB/c and NC/Nga mice, respectively. Orally administrated L-92 significantly inhibited the vascular permeability increase in both PCA and ACA, and the elevation of ovalbumin specific IgE titer in ACA. Moreover, repeated applications of DNFB and mite fecal antigen onto the BALB/c and NC/Nga mouse ear, respectively, caused clinical symptoms similar to atopic dermatitis such as ear swelling, scratching behavior and elevation of total serum IgE levels that were also moderately suppressed by L 92. In addition, L-92 treated mice exhibited lower levels of mast cells, eosinophil infiltration and Th1/Th2 cytokine expression. Our results, therefore, suggest that oral administration of L-92 might be useful for alleviating allergic symptoms. PMID- 20840153 TI - Ibuprofen augments pro-inflammatory cytokine release in a mouse model of Vibrio vulnificus infection. AB - We evaluated the effects of ibuprofen on cytokine production and mortality in a mouse model of septic shock induced by Vibrio vulnificus, strain Chi Mei Vv05191. Ibuprofen (50 mg/kg) or saline (control) was given to female BALB/cByJ mice for three consecutive days before exposure to the pathogen. For cytokine production, serum and peritoneal fluid were assayed for IL-1beta, IL-6, TNF-alpha, and MIP-2 by ELISA at 3, 6, and 9 hr after intraperitoneal infection of the organism. At 6 hr after infection, serum and peritoneal fluid levels of IL-6, TNF-alpha, and MIP 2 were significantly higher in the ibuprofen group. For mortality determination, 73 mice (37 ibuprofen, 36 control) were injected intramuscularly with V. vulnificus. Kaplan-Meier survival curves were analyzed. Survival was significantly decreased by ibuprofen only for the lowest inoculum (25 CFU) of V. vulnificus. Administration of ibuprofen before infection may augment the pathogenesis of V. vulnificus by stimulating cytokine production. PMID- 20840154 TI - Moxibustion activates host defense against herpes simplex virus type I through augmentation of cytokine production. AB - Moxibustion is a technique used in traditional oriental medicine, the aim of which is to cure and/or prevent illness by activating a person's ability for self healing. In this study, we assessed how moxibustion would affect the immune system and whether it would augment protective immunity. Mice were treated with moxibustion at Zusanli (ST36) acupoints; we analyzed mortality and cytokine activity in sera after infection with herpes simplex virus type 1 (HSV-1), and cytokine gene expression in the skin and the spleen without a virus challenge. Our study demonstrates that pretreatment of BALB/c mice with moxibustion resulted in a marked increase in the survival rate after infection with lethal doses of HSV-1, and elevated serum levels of IL-1beta and IFN-gamma on days 1 and 6 post infection with HSV-1. Semi-quantitative RT-PCR assay showed that moxibustion treatment augmented the expression of IL-1alpha, IL-1beta, IL-6, universal-IFN alpha, MIP-1alpha, and TNF-alpha mRNA in the skin, and IL-1alpha, IL-1beta, IL 12p40, IL-15, u-IFN-alpha, MIP-1alpha, and TNF-alpha mRNA in the spleen. Moreover, moxibustion induces augmentation of natural killer cell activity. Collectively, our study demonstrates that moxibustion activates protective responses against HSV-1 infection through the activation of cytokine production including IFN, and of NK cells. PMID- 20840155 TI - Gene expression profiling and network analysis of peripheral blood monocytes in a chronic model of allergic asthma. AB - The Aspergillus fumigatus mouse model of asthma mimics the characteristics of human fungal asthma, including local and systemic inflammation. Monocyte/macrophage lineage cells direct innate immune responses and guide adaptive responses. To identify gene expression changes in peripheral blood monocytes in the context of fungal allergy, mice were exposed to systemic and intranasal inoculations of fungal antigen (sensitized), and naive and sensitized animals were challenged intratracheally with live A. fumigatus conidia. Microarray analysis of blood monocytes from allergic versus non-allergic mice showed >= twofold modulation of 45 genes. Ingenuity pathway analysis revealed a network of these genes involved in antigen presentation, inflammation, and immune cell trafficking. These data show that allergen sensitization and challenge affects gene expression in peripheral monocytes. PMID- 20840156 TI - Expression of bovine (Bos indicus) interleukin-18 in Escherichia coli and its biological activity. AB - IL-18 modulates immune functions by inducing IFN-gamma production and promoting Th1 immune responses. In the present study, we amplified and cloned the sequence (582 bp) encoding full-length bovine IL-18 from PBMC stimulated with PHA. The nucleotide and the deduced amino acid sequence of Bos indicus IL-18 showed an identity of 86-98% compared with IL-18 sequences of other ruminants. The insert was subcloned into a pET 32a vector and expressed in Escherichia coli as a fusion protein and the matured protein was obtained by caspase I treatment. The specificity of these proteins was confirmed by western blotting. The biological activity of the purified protein was analyzed by its ability to induce IFN-gamma production in PBMC measured by ELISA and qPCR. PMID- 20840158 TI - Abstracts of the 7th Asia Pacific Medical Education Conference (APMEC). National University of Singapore, Singapore. February 4-8, 2010. PMID- 20840159 TI - Abstracts of the International Veterinary Emergency and Critical Care Symposium and the European Veterinary Emergency and Critical Care Society Annual Congress, 2010. September 11-15, 2010. San Antonio, Texas, USA. PMID- 20840160 TI - Abstracts of the 20th Congress of the European Sleep Research Society. September 14-18, 2010. Lisbon, Portugal. PMID- 20840161 TI - Abstracts of the 14th World Meeting of the International Society of Sexual Medicine (ISSM). Seoul, Korea. September 26-30, 2010. PMID- 20840162 TI - UK-PharmSci 2010 - The Science of Medicines. Abstracts from the UK-PharmSci Conference, 1-3 September 2010. PMID- 20840163 TI - Epigenetics and neuropsychiatric diseases: introduction and meeting summary. AB - This volume is an outgrowth of a symposium entitled "Epigenetics and Neuropsychiatric Diseases: Mechanisms Mediating Nature and Nurture" presented at the 88th Annual Conference of the Association for Nervous and Mental Diseases, held on December 5, 2008 at the New York Academy of Medicine. Dolores Malaspina (New York University Medical Center) and Mark F. Mehler (Albert Einstein College of Medicine) organized the symposium as two sessions, "Epigenetics and Brain Behavior Relationships" and "Epigenetics and Neuropsychiatric Diseases." The symposium brought together basic and translational neuroscientists, neurologists, psychiatrists, neuropsychologists, neuropsycho-pharmacologists, and other allied biomedical professionals to establish an enduring dialogue and collaborative interactions concerning epigenetics and epigenomic medicine as a "new science" of brain and behavior relationships. This new discipline has begun to revolutionize our understanding of nervous system development in many specific areas, including neural stem cell biology, fate decisions, and cell diversity and connectivity; learning and memory; neuronal and neural network homeostasis; plasticity and stress responses; the pathogenesis of neuropsychiatric diseases and novel therapeutic interventions involving dynamic cellular reprogramming; reorganization of synaptic and neural network connections; and remodeling of the brain parenchyma and its systemic connections to promote restoration of higher order cognitive, behavioral, and sensorimotor functions. PMID- 20840164 TI - Critical periods and the developmental origins of disease: an epigenetic perspective of schizophrenia. AB - Epigenetics holds promise to explain some puzzles concerning the risk and course of psychiatric disorders. Epigenetic information is essential as a set of operating instructions for the genome, which is heritable with DNA. The epigenetic regulation of gene expression can plausibly be influenced by the environment of one's ancestors, prenatal exposures, and by early life events. Some epigenetic mechanisms may alter neurophysiology throughout life by programming gene expression, perhaps in anticipation of certain life experiences. These epigenetic signals are only meta-stable and may be perturbed by stochastic events, errors, or by environmental toxins. This introduction considers the possibility that epigenetic change that may occur as paternal age advances or during fetal adversity may be causally related to the susceptibility for schizophrenia. PMID- 20840165 TI - Genomic imprinting on the X chromosome: implications for brain and behavioral phenotypes. AB - Imprinted genes, in contrast to most mammalian genes, are monoallelically expressed in a parent-of-origin dependent manner. The idiosyncratic expression profile associated with imprinted genes arises from the differential epigenetic marking of the alleles in the paternal and maternal germlines. Although small in number, imprinted genes can profoundly influence key developmental and physiological processes, including those in the brain; work in animal models and in humans has shown that such genes can affect behavioral traits and cognition and may confer vulnerability to common mental illnesses. As a consequence of how the X chromosome is inherited, X-linked imprinting may elicit or indeed attenuate sexually dimorphic phenotypes. Thus, studying X-linked imprinting is likely to provide important general information about the evolutionary and mechanistic underpinnings of imprinting, as well as the molecular processes underlying sex specific neurobiology and sex-biased vulnerability to psychiatric disorders. PMID- 20840168 TI - Addiction treatment outcomes, process and change: Texas Institute of Behavioral Research at Texas Christian University. AB - For more than 40 years the Texas Institute of Behavioral Research (IBR) has given special attention to assessment and evaluation of drug user populations, addiction treatment services and various cognitive and behavioral interventions. Emphasis has been on studies in real-world settings and the use of multivariate methodologies to address evaluation issues within the context of longitudinal natural designs. Historically, its program of addiction treatment research may be divided into three sequential epochs-the first era dealt mainly with client assessment and its role in treatment outcome and evaluation (1969-89), the second focused upon modeling the treatment process and the importance of conceptual frameworks (1989-2009) in explaining the relationships among treatment environment, client attributes, treatment process and outcome, and the third (and current) era has expanded into studying tactical deployment of innovations and implementation. Recent projects focus upon adapting and implementing innovations for improving early engagement in adolescent residential treatment settings and drug-dependent criminal justice populations. Related issues include the spread of human immunodeficiency virus/acquired immune deficiency syndrome and other infectious diseases, organizational and systems functioning, treatment costs and process related to implementation of evidence-based practices. PMID- 20840166 TI - Impact of nuclear organization and dynamics on epigenetic regulation in the central nervous system: implications for neurological disease states. AB - Epigenetic mechanisms that are highly responsive to interoceptive and environmental stimuli mediate the proper execution of complex genomic programs, such as cell type-specific gene transcription and posttranscriptional RNA processing, and are increasingly thought to be important for modulating the development, homeostasis, and plasticity of the central nervous system (CNS). These epigenetic processes include DNA methylation, histone modifications, and chromatin remodeling, all of which play roles in neural cellular diversity, connectivity, and plasticity. Further, large-scale transcriptomic analyses have revealed that the eukaryotic genome is pervasively transcribed, forming interleaved protein-coding RNAs and regulatory nonprotein-coding RNAs (ncRNAs), which act through a broad array of molecular mechanisms. Most of these ncRNAs are transcribed in a cell type- and developmental stage-specific manner in the CNS. A broad array of posttranscriptional processes, such as RNA editing and transport, can modulate the functions of both protein-coding RNAs and ncRNAs. Additional studies implicate nuclear organization and dynamics in mediating epigenetic regulation. The compartmentalization of DNA sequences and other molecular machinery into functional nuclear domains, such as transcription factories, Cajal bodies, promyelocytic leukemia nuclear bodies, nuclear speckles, and paraspeckles, some of which are found prominently in neural cells, is associated with regulation of transcriptional activity and posttranscriptional RNA processing. These observations suggest that genomic architecture and RNA biology in the CNS are much more complex and nuanced than previously appreciated. Increasing evidence now suggests that most, if not all, human CNS diseases are associated with either primary or secondary perturbations in one or more aspects of the epigenome. In this review, we provide an update of our emerging understanding of genomic architecture, RNA biology, and nuclear organization and highlight the interconnected roles that deregulation of these factors may play in diverse CNS disorders. PMID- 20840169 TI - Self-reported side effects in buprenorphine and methadone patients receiving antiretroviral therapy: results from the MANIF 2000 cohort study. AB - AIMS: The aim of the study was to investigate the relationship between methadone and buprenorphine treatment and self-reported symptoms in HIV-infected opioid dependent individuals receiving antiretroviral therapy (ART). DESIGN: Longitudinal study. SETTING: The French MANIF2000 cohort was used to compare self reported symptoms in buprenorphine and methadone patients also receiving ART. PARTICIPANTS: We selected individuals receiving ART and OAT (342 visits among 106 patients). MEASUREMENTS: Symptoms were self-reported using a list of 14 symptoms (e.g. nausea, fatigue, fever) perceived during the previous 4 weeks, including three painful symptoms (abdominal or muscular pain, headaches). A two-step Heckman approach enabled us to account for the non-random assignment of OAT: a probit model identified predictors of starting either buprenorphine or methadone. A Poisson regression based on generalized estimating equations (GEE) was then used to identify predictors of the number of symptoms while adjusting for the non random assignment of OAT. FINDINGS: The median (interquartile range) number of symptoms was 4 (1-6) and 2 (1-6) among buprenorphine and methadone patients, respectively. After adjustment for non-random assignment of OAT type, depressive and opioid withdrawal symptoms, anxiolytics consumption and daily cannabis use, methadone patients were more likely to report a lower number of symptoms than those receiving buprenorphine. CONCLUSIONS: Methadone patients on ART report fewer symptoms than buprenorphine patients on ART under current treatment conditions in France. Further experimental research is still needed to identify an OAT-ART strategy which would minimize the burden of self-reported symptoms and potential interactions, while assuring sustainability and response to both treatments. PMID- 20840170 TI - High alcohol consumption in middle-aged adults is associated with poorer cognitive performance only in the low socio-economic group. Results from the GAZEL cohort study. AB - AIMS: To examine the association of alcohol consumption over 10 years with cognitive performance in different socio-economic groups. DESIGN: Prospective cohort study, the French GAZEL study. SETTING: France. PARTICIPANTS: Employees of France's national electricity and gas company. MEASUREMENTS: Alcohol intake was assessed annually, beginning in 1992, using questions on frequency and quantity of alcoholic beverages consumed in a week; used to define mean consumption and trajectory of alcohol intake over 10 years. Cognitive performance among participants aged >= 55 years (n = 4073) was assessed in 2002-04 using the Digit Symbol Substitution Test (DSST), a measure of psychomotor speed, attention and reasoning. Occupational position at age 35 and education were used as the markers of socio-economic position. FINDINGS: All analyses were stratified by socio economic position. In the low occupational group, participants consuming a mean of more than 21 drinks per week had 2.1 points lower (95% CI: -3.9, -0.3) DSST score compared to those consuming four to 14 drinks per week. In participants with primary school education, the corresponding difference was 3.6 points (95% CI: -7.1, -0.0). No association between alcohol consumption and cognitive performance was observed in the intermediate and high socio-economic groups, defined using either occupation or education. Analysis of trajectories of alcohol consumption showed that in the low socio-economic groups large increase or decrease in alcohol consumption was associated with lower cognitive scores compared to stable consumption. CONCLUSIONS: Our results suggest that high alcohol consumption is associated with poorer cognitive performance only in the low socio-economic group, due possibly to greater cognitive reserve in the higher socio-economic groups. PMID- 20840171 TI - Area of residence and alcohol-related mortality risk: a five-year follow-up study. AB - AIMS: To examine differences in alcohol-related mortality risk between areas, while adjusting for the characteristics of the individuals living within these areas. DESIGN: A 5-year longitudinal study of individual and area characteristics of those dying and not dying from alcohol-related deaths. SETTING: The Northern Ireland Mortality study. PARTICIPANTS: A total of 720,627 people aged 25-74, enumerated in the Northern Ireland 2001 Census, not living in communal establishments. MEASUREMENTS: Five hundred and seventy-eight alcohol-related deaths. FINDINGS: There was an increased risk of alcohol-related mortality among disadvantaged individuals, and divorced, widowed and separated males. The risk of an alcohol-related death was significantly higher in deprived areas for both males [hazard ratio (HR) 3.70; 95% confidence interval (CI) 2.65, 5.18] and females (HR 2.67 (95% CI 1.72, 4.15); however, once adjustment was made for the characteristics of the individuals living within areas, the excess risk for more deprived areas disappeared. Both males and females in rural areas had a reduced risk of an alcohol-related death compared to their counterparts in urban areas; these differences remained after adjustment for the composition of the people within these areas. CONCLUSIONS: Alcohol-related mortality is higher in more deprived, compared to more affluent areas; however, this appears to be due to characteristics of individuals within deprived areas, rather than to some independent effect of area deprivation per se. Risk of alcohol-related mortality is lower in rural than urban areas, but the cause is unknown. PMID- 20840167 TI - Stress, sex, and neural adaptation to a changing environment: mechanisms of neuronal remodeling. AB - The adult brain is much more resilient and adaptable than previously believed, and adaptive structural plasticity involves growth and shrinkage of dendritic trees, turnover of synapses, and limited amounts of neurogenesis in the forebrain, especially the dentate gyrus of the hippocampal formation. Stress and sex hormones help to mediate adaptive structural plasticity, which has been extensively investigated in the hippocampus and to a lesser extent in the prefrontal cortex and amygdala, all brain regions that are involved in cognitive and emotional functions. Stress and sex hormones exert their effects on brain structural remodeling through both classical genomic as well as non-genomic mechanisms, and they do so in collaboration with neurotransmitters and other intra- and extracellular mediators. This review will illustrate the actions of estrogen on synapse formation in the hippocampus and the process of stress induced remodeling of dendrites and synapses in the hippocampus, amygdala, and prefrontal cortex. The influence of early developmental epigenetic events, such as early life stress and brain sexual differentiation, is noted along with the interactions between sex hormones and the effects of stress on the brain. Because hormones influence brain structure and function and because hormone secretion is governed by the brain, applied molecular neuroscience techniques can begin to reveal the role of hormones in brain-related disorders and the treatment of these diseases. A better understanding of hormone-brain interactions should promote more flexible approaches to the treatment of psychiatric disorders, as well as their prevention through both behavioral and pharmaceutical interventions. PMID- 20840172 TI - The global diversion of pharmaceutical drugs?non-medical use and diversion of psychotropic prescription drugs in North America: a review of sourcing routes and control measures. AB - AIMS: North America features some of the world's highest consumption levels for controlled psychoactive prescription drugs (PPDs; e.g. prescription opioids, benzodiazepines, stimulants), with non-medical use and related harms (e.g. morbidity, mortality) rising in key populations in recent years. While the determinants, characteristics and impacts of these 'use' problems are increasingly well documented, little is known about the 'supply' side of non medical PPD use, much of which is facilitated by 'diversion' as a key sourcing route. This paper provides a select review of the phenomenon of PPD diversion in North America, also considering interventions and policy implications. METHODS: A conceptual and empirical review of select-peer- and non-peer-reviewed research literature from 1991 to 2010 focusing upon PPD diversion in North America was conducted. RESULT: The phenomenon of PPD diversion is heterogeneous. Especially among general populations, a large proportion of PPDs for non-medical use are obtained from friends or family members. Other PPD diversion routes involve 'double doctoring' or 'prescription shopping'; street drug markets; drug thefts, prescription forgeries or fraud; as well as PPD purchases from the internet. CONCLUSIONS: The distinct nature and heterogeneity make PPD diversion a complex and difficult target for interventions. Prescription monitoring programs (PMPs) appear to reduce overall PPD use, yet their impact on reducing diversion or non medical use is not clear. Law enforcement is unlikely to reach PPD diversion effectively. Effective reduction will probably require reductions in overall PPD consumption volumes, although such will need to be accomplished without compromising standards of good medical (e.g. pain) care. PMID- 20840173 TI - A multi-level analysis of non-significant counseling effects in a randomized smoking cessation trial. AB - AIMS: To determine, in the context of a trial in which counseling did not improve smoking cessation outcomes, whether this was due to a failure of the conceptual theory identifying treatment targets or the action theory specifying interventions. DESIGN: Data from a randomized clinical trial of smoking cessation counseling and bupropion SR were submitted to multi-level modeling to test whether counseling influenced real-time reports of cognitions, emotions and behaviors, and whether these targets predicted abstinence. SETTING: Center for Tobacco Research and Intervention, Madison, WI. PARTICIPANTS: A total of 403 adult, daily smokers without contraindications to bupropion SR use. Participants were assigned randomly to receive individual counseling or no counseling and a 9 week course of bupropion SR or placebo pill. Cessation counseling was delivered in eight 10-minute sessions focused on bolstering social support, motivation, problem-solving and coping skills. MEASUREMENTS: Pre- and post-quit ecological momentary assessments of smoking behavior, smoking triggers, active prevention and coping strategies, motivation to quit, difficulty quitting and reactions to initial lapses. FINDINGS: Counseling prompted avoidance of access to cigarettes, improved quitting self-efficacy, reduced perceived difficulty of quitting over time and protected against guilt and demoralization following lapses. Results also supported the importance of limiting cigarette access, receiving social support, strong motivation and confidence and easing withdrawal distress during cessation efforts. Quitting self-efficacy and perceived difficulty quitting may partially mediate counseling effects on abstinence. CONCLUSIONS: Smoking cessation counseling may work by supporting confidence about quitting and reducing perceived difficulty quitting. Counseling did not affect other targets that protect against relapse. PMID- 20840175 TI - Change talk sequence during brief motivational intervention, towards or away from drinking. AB - AIM: To investigate whether different sequences of 'change talk' utterances within a brief motivational intervention (BMI) are associated with drinking outcomes. DESIGN: Speech content analysis of recorded BMI. SETTING: BMI delivered in an emergency department for at-risk drinking. PARTICIPANTS: Ninety-seven subjects who received a BMI. MEASUREMENTS: Ninety-seven BMI were coded in duplicate by two psychologists with the Motivational Interviewing Skill Code (MISC), a Hidden Markov Model was used to identify three different patient states reflecting attitudes regarding changing their drinking behaviour within a BMI: towards change, away from change and non-determined. Adjusted regression models were used to predict drinking at 12 months' follow-up using patient attitudes regarding changing drinking at the beginning, during the intervention and at the end. FINDINGS: The dynamic process at place within a BMI was marked mainly by stability: at each point during the intervention, staying in the same attitude was far more likely than transitioning from one attitude to another. When subjects did change from one attitude to another, they were more likely to move from an 'away from change' to a 'towards change' state. At 12 months, subjects with an attitude towards change at the end of the BMI drank significantly less (13.1 drinks per week) than subjects with an attitude away from change, independent of their attitude at the beginning of the intervention. CONCLUSIONS: Transition in 'change talk' between 'away from change' and 'towards change' appears to be rare in brief motivational intervention for excessive alcohol consumption. Moreover, change talk 'towards change' at the end of the intervention is associated with improved outcomes at follow-up, independently of the type of change talk at the beginning of the intervention, suggesting that it is important to end a BMI session with a positive attitude towards change by the client. PMID- 20840174 TI - Victimization and substance use disorders in a national sample of heterosexual and sexual minority women and men. AB - CONTEXT: There is consensus in the research literature that substance use disparities exist among sexual minority women and men; however, few studies have examined risk factors that may contribute to these disparities. AIMS: To compare reports of life-time victimization experiences in a US national sample of adult heterosexual and sexual minority women and men and to examine the relationships between victimization experiences and past-year substance use disorders. DESIGN, PARTICIPANTS, MEASUREMENTS: The secondary data analyses used 2004-05 (wave 2) National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) data collected in structured diagnostic face-to-face interviews in the United States. Substance use disorders (SUDs) were defined according to DSM-IV criteria and included past-year alcohol abuse, alcohol dependence, drug abuse and drug dependence. The sample consisted of 34 653 adults aged 20 years and older; approximately 2% of the respondents self-identified as sexual minority (lesbian, gay or bisexual). FINDINGS: Results showed strong associations between victimization and any past-year SUDs and confirmed findings from several previous studies indicating that, compared with heterosexuals, sexual minority women and men are at heightened risk for life-time victimization. However, prevalence of the seven victimization experiences and the degree of association between individual victimization experiences and SUDs varied substantially across sexual minority subgroups. The childhood victimization variables-especially childhood neglect-showed the strongest and most consistent associations with SUDs. Odds of SUDs were generally higher among both female and male respondents, regardless of sexual identity, who reported multiple (two or more) victimization experiences than among those who reported no life-time victimization, suggesting a possible cumulative effect of multiple victimization experiences. CONCLUSIONS: Higher rates of life-time victimization, particularly victimization experienced in childhood, may help to explain higher rates of substance use disorders among sexual minorities. However, more research is needed to understand better the complex relationships among sexual orientation, victimization and substance use. PMID- 20840177 TI - The evidence debate continues. PMID- 20840176 TI - Reductions in alcohol and cocaine use following a group coping intervention for HIV-positive adults with childhood sexual abuse histories. AB - AIMS: Few interventions exist to reduce alcohol and non-injection drug use among people living with HIV/AIDS. This study tested the effects of a coping group intervention for HIV-positive adults with childhood sexual abuse histories on alcohol, cocaine and marijuana use. DESIGN: Participants were assigned randomly to the experimental coping group or a time-matched comparison support group. Both interventions were delivered in a group format over 15 weekly 90-minute sessions. SETTING AND PARTICIPANTS: A diverse sample of 247 HIV-positive men and women with childhood sexual abuse were recruited from AIDS service organizations and community health centers in New York City. MEASUREMENTS: Substance use was assessed pre- and post-intervention and every 4 months during a 12-month follow up period. Using an intent-to-treat analysis, longitudinal changes in substance use by condition were assessed using generalized estimating equations. FINDINGS: At baseline, 42% of participants drank alcohol, 26% used cocaine and 26% used marijuana. Relative to participants in the support group, those in the coping group had greater reductions in quantity of alcohol use (Wald chi2(4)=10.77, P = 0.029) and any cocaine use (Wald chi2(4) = 9.81, P = 0.044) overtime. CONCLUSIONS: Many HIV patients, particularly those with childhood sexual abuse histories, continue to abuse substances. This group intervention that addressed coping with HIV and sexual trauma was effective in reducing alcohol and cocaine use, with effects sustained at 12-month follow-up. Integrating mental health treatment into HIV prevention may improve outcomes. PMID- 20840178 TI - European Union Antibiotic Awareness Day relevance for wound care practitioners. PMID- 20840181 TI - Incidence and risk factors of pressure ulcers in seven neonatal intensive care units in Japan: a multisite prospective cohort study. AB - This study aims to clarify (i) the incidence of pressure ulcers in neonates admitted to the neonatal intensive care units (NICUs) and (ii) risk factors of pressure ulcer development. All infants admitted to the NICU and kept in incubators from seven hospitals during the study period were recruited to the study. Each infant was given skin examination every day by nurses, and risk factors were collected three times a week by one researcher. The incidence of the pressure ulcers was calculated, and the risk factors for pressure ulcers were determined by using univariate and multivariate analysis. Eighty-one infants were involved in the study. A total of 14 pressure ulcers occurred in 13 infants during the 11-month study period, the incidence was 0.01 persons per day and cumulative incidence rate was 16.0%. Seven (50.0%) of 14 pressure ulcers were located on the nose. Multivariate analysis identified the following risk factors: skin texture (Dubowitz neonatal maturation assessment scale: skin texture score of 1 point or lower) [odds ratio 7.6; 95% confidence interval (CI) 1.58 -36.71, P = 0.012] and endotracheal intubation usage (odds ratio 4.0; 95% CI 1.04-15.42, P = 0.042). PMID- 20840182 TI - Keloid explant culture: a model for keloid fibroblasts isolation and cultivation based on the biological differences of its specific regions. AB - In vitro studies with keloid fibroblasts frequently present contradictory results. This may occur because keloids present distinct genotypic and phenotypic characteristics in its different regions, such as the peripheral region in relation to the central region. We suggest an explant model for keloid fibroblasts harvesting, standardising the initial processing of keloid samples to obtain fragments from different regions, considering its biological differences, for primary cell culture. The different keloid regions were delimited and fragments were obtained using a 3-mm diameter punch. To remove fragments from the periphery, the punch was placed in one longitudinal line extremity, respecting the lesion borders. For the central region, it was placed in the intersection of lines at the level of the largest longitudinal and transversal axes, the other fragments being removed centrifugally in relation to the first one. Primary fibroblast culture was carried out by explant. Flow cytometry analysis showed cell cycle differences between the groups, confirming its different origins and biological characteristics. In conclusion, our proposed model proved itself efficient for keloid fibroblast isolation from specific regions and cultivation. Its simplicity and ease of execution may turn it into an important tool for studying the characteristics of the different keloid-derived fibroblasts in culture. PMID- 20840183 TI - The effect and safety after extended use of continuous negative pressure of 75 mmHg over mesh and allodermis graft on open sternal wound from oversized heart transplant in a 3-month-old infant. AB - Negative pressure therapy (NPT) has been reported to be effective in treating infants with open chest wounds. This report further supports its effectiveness by treating a 3-month-old infant with a 12 * 7 cm sized opening in its chest after an oversized heart transplantation. After applying a mesh and allodermis over the defect, 75-mmHg continuous negative pressure was set and used for an extended period of 104 days. The haemodynamic status was evaluated during this period. The wound was closed with secondary intention and it healed well after NPT. There was no haemodynamic instability during the treatment course. The extended use of a continuous negative pressure of 75 mmHg over the mesh and alloderm graft was a reliable and safe option to close the massive defect in the chest of a 3-month old infant. PMID- 20840184 TI - Ulcerated tophaceous gout. AB - Gout is often considered a disease of an excessive lifestyle, a 'malady of kings'. Today, more than 1% of the European and US populations are afflicted with gout, although ulceration over gout tophi remains uncommon. We describe four cases of ulceration associated with gout tophi to highlight the clinical presentation, complications and a management strategy. PMID- 20840185 TI - Drywounds matter: the use of occlusive sterile sanitary napkin dressing in hip and knee replacement wounds. PMID- 20840187 TI - Peer smoking and the nicotinic receptor genes: an examination of genetic and environmental risks for nicotine dependence. AB - BACKGROUND: Peer smoking provides a socially reinforcing context of friends' encouragement and approval that contributes to smoking behavior. Twin studies show correlations and interactions between peer substance use and genetic liability for substance use. However, none examined specific genes. Here we test the hypothesis that the nicotinic receptor genes CHRNA5 (rs16969968), CHRNA3 (rs578776), CHRNB3 (rs13277254) and CHRND (rs12466358) modify the risk for nicotine dependence associated with peer smoking. METHODS: Cases of current nicotine dependence [Fagerstrom Test for Nicotine Dependence (FTND)>= 4] and smoking-exposed (smoked 100+ cigarettes life-time), but non-dependent controls (life-time FTND= 0) came from the Collaborative Genetic Study of Nicotine Dependence (n=2038). Peer smoking was assessed retrospectively for grades 9-12. RESULTS: Peer smoking and the four single nucleotide polymorphisms (SNPs) were associated with nicotine dependence. A statistically significant interaction was found between peer smoking and rs16969968 (P=0.0077). Overall risk of nicotine dependence was highest for the rs16969968 AA genotype. However, variance in nicotine dependence attributable to peer smoking was substantially lower among those with the AA genotype at rs16969968 than the lower-risk genotypes: AA=2.5%, GA/AG=11.2%, GG=14.2%; P<= 0.004. CONCLUSIONS: Peer smoking had a substantially lower effect on nicotine dependence among those with the high-risk AA genotype at the functional SNP rs16969968 (CHRNA5) than among those with lower-risk genotypes. Such results highlight the possibility that given drug exposure those with specific genetic risks may be less affected by social contexts and intervention strategies focused upon social factors could have less influence on those at highest genetic risk. PMID- 20840188 TI - Effects of smoking cessation with voucher-based contingency management on birth outcomes. AB - AIMS: This study examined whether smoking cessation using voucher-based contingency management (CM) improves birth outcomes. DESIGN: Data were combined from three controlled trials. SETTING: Each of the trials was conducted in the same research clinic devoted to smoking and pregnancy. PARTICIPANTS: Participants (n=166) were pregnant women who participated in trials examining the efficacy of voucher-based CM for smoking cessation. Women were assigned to either a contingent condition, wherein they earned vouchers exchangeable for retail items by abstaining from smoking, or to a non-contingent condition where they received vouchers independent of smoking status. MEASUREMENT: Birth outcomes were determined by review of hospital delivery records. FINDINGS: Antepartum abstinence was greater in the contingent than non-contingent condition, with late pregnancy abstinence being 34.1% versus 7.4% (P<0.001). Mean birth weight of infants born to mothers treated in the contingent condition was greater than infants born to mothers treated in the non-contingent condition (3295.6 +/- 63.8 g versus 3093.6 +/- 67.0 g, P = 0.03) and the percentage of low birth weight (<2500 g) deliveries was less (5.9% versus 18.5%, P = 0.02). No significant treatment effects were observed across three other outcomes investigated, although each was in the direction of improved outcomes in the contingent versus the non-contingent condition: mean gestational age (39.1 +/- 0.2 weeks versus 38.5 +/- 0.3 weeks, P = 0.06), percentage of preterm deliveries (5.9 versus 13.6, P = 0.09), and percentage of admissions to the neonatal intensive care unit (4.7% versus 13.8%, P = 0.06). CONCLUSIONS: These results provide evidence that smoking cessation treatment with voucher-based CM may improve important birth outcomes. PMID- 20840189 TI - Motor vehicle collision fatalities involving alcohol and illicit drugs in Greece: the need for management protocols and a reassessment of surveillance. AB - AIMS: The frequency and the effect of alcohol and illicit drugs on injury type, severity and location of death in motor vehicle collision (MVC) fatalities were investigated. DESIGN: Retrospective case-control study based on autopsy and toxicology. SETTINGS: Single faculty accepting referrals from Greater Athens and prefectures. PARTICIPANTS: Consecutive pre-hospital and in hospital fatalities. MEASUREMENTS: Demographics, toxicology, abbreviated injury scale (AIS), injury severity score (ISS), and location of death. FINDINGS: Of the 1860 screened subjects, 612 (32.9%) constituted the positive toxicology group (PTG) for alcohol or illicit drugs or both and the 1248 (67.1%) the negative toxicology group (NTG). The median age was 34 (4-90) years for the PTG and 45 (3-97) years for the NTG. The PTG included significantly higher proportions of males and motorcyclists. The PTG had a 50% increased risk for a severe (AIS >=3) cervical spine and 85% for a severe upper extremity injury, compared to the NTG. A total of 29.2% of the PTG and 22.4% of the NTG deaths were non-preventable (ISS=75). The frequency of severe trauma (ISS >=16) was comparable between PTG and NTG (P=0.87). The PTG presented with a median ISS of 43 (6-75) versus 41 (2-75) of the NTG, hence without significant difference (P=0.11). The pre-hospital death rate was 77.8% for the PTG versus 58% of the NTG (P<0.001). The analysis confirmed that the odds of positive toxicology were considerably higher in the subjects who arrived dead at the hospital (OR 2.62, P <0.001). CONCLUSIONS: In the greater Athens region, almost a third of motor vehicle collision-related fatalities involved alcohol, illicit drugs or both. Individuals screened positive for alcohol or drugs were 2.6 times more likely to die before hospital admission than those with a negative toxicology screen, despite comparable injury severity. Specific evidence-based management protocols and reassessment of surveillance are required. PMID- 20840190 TI - Alcohol dependence and anxiety increase error-related brain activity. AB - AIMS: Detection of errors is crucial for efficient goal-directed behaviour. The ability to monitor behaviour is found to be diminished in patients with substance dependence, as reflected in decreased error-related brain activity, i.e. error related negativity (ERN). The ERN is also decreased in other psychiatric disorders with impaired response inhibition, such as attention-deficit hyperactivity disorder and borderline personality disorder, but increased in anxiety disorders. The objective of the current study was to assess error monitoring in alcohol-dependent patients in relation to psychiatric comorbidity. We expected decreased error monitoring in alcohol-dependent patients with impulse control disorders and increased error monitoring in anxious alcohol-dependent patients. DESIGN: In a case-control design alcohol-dependent patients were compared with healthy controls. SETTING AND PARTICIPANTS: A consecutive series of 29 male alcohol-dependent patients, between 18 and 55 years of age, applying for in-patient detoxification were recruited at Novadic Kentron Center for Addiction Treatment. Fifteen age-matched healthy controls were recruited through advertisements in regional newspapers. MEASUREMENTS: Event-related potentials were recorded while performing a speeded choice-reaction task, from which ERN amplitudes were calculated. Axis-I and -II psychiatric comorbidity were assessed using the MINI International Neuropsychiatric Interview and the Structured Interview for DSM-IV Personality disorders. All participants completed the Temperament and Character Inventory and Profile of Mood States. FINDINGS: ERN amplitudes were increased for alcohol-dependent patients compared to healthy controls, particularly in patients with comorbid anxiety disorders. CONCLUSIONS: Increased error monitoring in alcohol-dependent patients, particularly those with comorbid anxiety disorders, is in contrast with previous studies that suggested decreased error monitoring to be a general feature in substance use disorders. Psychiatric disorders co-occurring with alcohol dependence, such as anxiety disorders, may indicate subpopulations of alcohol-dependent patients, with distinct neurobiological and genetic characteristics, possibly requiring different treatment strategies. PMID- 20840191 TI - Effects of restricting pub closing times on night-time assaults in an Australian city. AB - AIMS: In March 2008 the New South Wales judiciary restricted pub closing times to 3 a.m., and later 3.30 a.m., in the central business district (CBD) of Newcastle, Australia. We sought to determine whether the restriction reduced the incidence of assault. DESIGN: Non-equivalent control group design with before and after observations. SETTING: Newcastle, a city of 530,000 people. PARTICIPANTS: People apprehended for assault in the CBD and nearby Hamilton, an area with a similar night-time economy but where no restriction was imposed. MEASUREMENTS: Police recorded assaults in the CBD before and after the restriction were compared with those in Hamilton. Cases were assaults occurring from 10 p.m.-6 a.m. from January 2001-March 2008, with April 2008-September 2009 as the post-restriction period. We also examined changes in assault incidence by time of night. Negative binomial regression with time, area, time * area interaction terms and terms for secular trend and seasonal effects was used to analyse the data. Autocorrelation was examined using generalized estimating equations. FINDINGS: In the CBD, recorded assaults fell from 99.0 per quarter before the restriction to 67.7 per quarter afterward [incidence rate ratio (IRR): 0.66, 95% confidence interval (CI): 0.55 0.80]. In the same periods in Hamilton, assault rates were 23.4 and 25.5 per quarter, respectively (IRR: 1.02, 95% CI: 0.79-1.31). The relative reduction attributable to the intervention was 37% (IRR = 0.63, 95% CI: 0.47-0.81) and approximately 33 assault incidents were prevented per quarter. CONCLUSION: This study indicates that a restriction in pub closing times to 3/3.30 a.m. in Newcastle, NSW, produced a large relative reduction in assault incidence of 37% in comparison to a control locality. PMID- 20840192 TI - Role of antiischemic agents in the management of non-ST elevation acute coronary syndrome (NSTE-ACS). AB - Non-ST elevation acute coronary syndrome (NSTE-ACS) is the commonest acute presentation of coronary artery disease (CAD). Mortality and morbidity of the condition has improved substantially over the last few decades as a result of the cumulative effect of multiple interventions acting via different mechanisms. Despite a significant increase in the rate of coronary intervention, medical therapy continues to retain a central role in the treatment of NSTE-ACS particularly in frail patients where revascularization is inappropriate or when it is incomplete. Several antiischemic agents have been used in the treatment of the condition. Beta blockers are often the first-line choice with calcium channel blockers and nitrates being used as an alternative when beta blockers are contraindicated, or as an addition to achieve optimal symptom control. Newer agents, such as nicorandil, ivabradine, and ranolazine have also been used in refractory cases. Although most of these agents have been extensively studied in large randomized controlled trials in patients with stable CAD or ST elevation acute coronary syndrome (STE-ACS), the evidence supporting their use in NSTE-ACS is less clear cut. In this article, we review various drugs available for controlling ischemia and the latest evidence in support of their use in NSTE-ACS. PMID- 20840193 TI - PPAR-gamma agonism for cardiovascular and renal protection. AB - Diabetes mellitus is an established risk factor for cardiovascular disease and the leading cause of end-stage renal disease in the Western World. Thiazolidinediones (TZDs) represent a class of antidiabetic agents that exert their glucose-lowering effects by reducing insulin resistance, through stimulation of a type of nuclear receptor, called peroxisome proliferator activated receptor-gamma. Apart from improving glycemic control, TZDs were shown to exert beneficial effects on several components of the metabolic syndrome and cardiovascular risk markers. Furthermore, background and human studies have shown that TZDs reduce urinary albumin and protein excretion and interfere with most of the pathogenentic pathways involved in the development and progression of diabetic nephropathy. On the other hand, currently used TZDs have side effects, most important of which is fluid retention leading to wait gain and heart failure deterioration. With regards to cardiovascular outcomes, the anticipated benefit of TZDs was demonstrated for pioglitazone, whereas a series of previous meta analyses linking rosiglitazone treatment with increased risk of myocardial infarction and cardiovascular death raised uncertainty around the cardiovascular safety of rosiglitazone. This article will discuss the effects of TZDs on established and emerging cardiovascular risk factors, the data on possible beneficial renal effects of these compounds, and the existing evidence from large scale clinical trials and meta-analyses on their effects on cardiovascular outcomes, aiming to provide an overview of the cardio- and renoprotective properties of these drugs. PMID- 20840194 TI - Reconstituted HDL in acute coronary syndromes. AB - OBJECTIVES: The strong inverse relationship between plasma high-density lipoprotein (HDL)-cholesterol and atherosclerotic cardiovascular disease provides the epidemiological basis that HDL is atheroprotective. Since HDL enhances cholesterol efflux and exhibits potent antiinflammatory properties, the aim of the present study was to investigate whether infusion of reconstituted HDL (rHDL) impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with acute coronary syndromes (ACS). METHODS: Twenty-nine patients with ACS were randomized to double-blind treatment with rHDL or albumin. Endothelium dependent and independent vasodilatation to intraarterial acetylcholine and sodium nitroprusside were measured by forearm venous occlusion plethysmography. In addition, oxidized LDL and high-sensitivity C-reactive protein were determined as markers of oxidative stress and vascular inflammation. RESULTS: rHDL infusion increased plasma HDL (P < 0.0001) and decreased LDL (P < 0.0001). Oxidized LDL (P= 0.11), high-sensitivity C-reactive protein (P= 0.12) and the response to endothelium-dependent and -independent vasodilatators remained unchanged after rHDL compared to albumin infusion (14.9 +/- 9.2 versus 14.5 +/- 12.4, P= 0.93 and 12.8 +/- 7.1 versus 13.2 +/- 9.6, P= 0.27, respectively). CONCLUSIONS: An increase of HDL and a reduction of LDL notwithstanding, human rHDL did not improve vascular function in patients with ACS thus further challenging the clinical benefit of interventions, which rapidly raise HDL in ACS, particularly with the infusion of reconstituted HDL. PMID- 20840195 TI - Cognitive control in the intertrial interval: evidence from EEG alpha power. AB - This study used electroencephalogram (EEG) power spectrum analyses to characterize neural activity during the intertrial interval, a period during which online cognitive adjustments in response to errors or conflict are thought to occur. EEG alpha power was quantified as an inverse index of cerebral activity during the period between each response and the next stimulus in a Stroop task. Alpha power was significantly reduced following error responses compared to correct responses, indicating greater cerebral activity following errors. Reduced alpha power was also observed following Stroop conflict trials compared to no conflict trials, suggesting that conflict engages processes of mental adjustment. Finally, hemispheric differences in alpha power during the intertrial interval supported the complementary roles of the left and right hemispheres in behavioral activation and inhibition. PMID- 20840196 TI - Signaling a switch: neural correlates of task switching guided by task cues and transition cues. AB - Event-related brain potentials were used to examine the neural correlates of task switching directed by task cues and transition cues. Task cues signal both a change of task set and the task to implement; in contrast, transition cues signal a change of task set but do not indicate the required task. The data from two experiments revealed that the frontal P2 and reconfiguration slow wave were elicited by task and transition cues and may reflect processes associated with the change detector and task set configuration. Experiment 2 revealed that the frontal positivity and transition parietal slow wave are associated with the retrieval of the prior task set from memory. These data indicate that distinct neural processes that are related to the change detector, task set configuration, and the retrieval of a recently utilized task set from memory support task switching that is guided by task and transition cues. PMID- 20840197 TI - Cerebral cortical dynamics and the quality of motor behavior during social evaluative challenge. AB - To determine the influence of arousal on cerebral cortical dynamics and motor behavior, 58 channels of EEG were recorded in 13 college-age men (n=6) and women during an aiming task performed alone and in a social evaluation condition. Moderate arousal, as measured by heart rate, skin conductance, and self-reported mood, was induced during the social evaluation. In accord with the Yerkes-Dodson Hypothesis, which posits optimal performance during moderate arousal, improved performance (i.e., quality of the aiming trajectories) was observed. During social evaluation, changes in electroencephalogram dynamics included decreased coherence between the motor planning (Fz) and right temporal region (T4), increased coherence in the sensorimotor networks subserving the task, and increased local processing (gamma, 30-44 Hz) in the temporal regions. The results imply that moderate arousal promotes specific alterations in cortical dynamics that facilitate motor performance. PMID- 20840198 TI - Methadone dose and neonatal abstinence syndrome-systematic review and meta analysis. AB - AIM: To determine if there is a relationship between maternal methadone dose in pregnancy and the diagnosis or medical treatment of neonatal abstinence syndrome (NAS). METHODS: PubMed, EMBASE, the Cochrane Library and PsychINFO were searched for studies reporting on methadone use in pregnancy and NAS (1966-2009). The relative risk (RR) of NAS was compared for methadone doses above versus below a range of cut-off points. Summary RRs and 95% confidence intervals (CI) were estimated using random effects meta-analysis. Sensitivity analyses explored the impact of limiting meta-analyses to prospective studies or studies using an objective scoring system to diagnose NAS. RESULTS: A total of 67 studies met inclusion criteria for the systematic review; 29 were included in the meta analysis. Any differences in the incidence of NAS in infants of women on higher compared with lower doses were statistically non-significant in analyses restricted to prospective studies or to those using an objective scoring system to diagnose NAS. CONCLUSIONS: Severity of the neonatal abstinence syndrome does not appear to differ according to whether mothers are on high- or low-dose methadone maintenance therapy. PMID- 20840199 TI - Deliberate induction of alcohol tolerance: empirical introduction to a novel health risk. AB - AIMS: Alcohol tolerance is a hallmark indicator of alcohol dependence. Even so, the allure of peers' admiration for having the ability to drink heavily may lead some adolescents and young adults to practice, or 'train', to increase their tolerance (particularly at US colleges, where heavy drinking is highly prevalent and central to the social culture). This is a potential health hazard that has not been documented empirically. Thus, we initiated a study of tolerance 'training' and its association to risky and heavy drinking. DESIGN, SETTING AND PARTICIPANTS: A cross-sectional online survey of 990 college student life-time drinkers at a large Midwestern US university. FINDINGS: Of the sample, 9.9% (n = 97) reported deliberately 'training' to increase tolerance. On average, they reported increasing from approximately seven to 10 US standard drinks in a night prior to 'training' to 12-15 drinks at the end of 'training,' over approximately 2-3 weeks' duration. Although the proportion of frequent binge drinking among 'non-trainers' (34.4%) was similar to national rates, 'trainers' were much more likely to be frequent bingers (76.3%; OR = 6.15). CONCLUSIONS: A number of students report deliberately inducing alcohol tolerance, probably directly increasing the risk for alcohol poisoning and other acute harms and/or dependence. This phenomenon might additionally be applicable to other populations, and deserves further study and attention as a potential personal and public health risk. Prevention efforts might aim to reduce the perceived importance of heavy-drinking abilities. PMID- 20840200 TI - Treatment process, alliance and outcome in brief versus extended treatments for marijuana dependence. AB - AIMS: The Marijuana Treatment Project, a large multi-site randomized clinical trial, compared a delayed treatment control condition with a brief (two-session) and extended (nine-session) multi-component treatment among 450 marijuana dependent participants. In this report we present treatment process data, including the fidelity of treatment delivery in the three community-based treatment settings as well as the relationships between treatment process and outcome. DESIGN: Independent evaluations of clinician adherence and competence ratings were made based on 633 videotaped sessions from 163 participants. Relationships between clinician adherence and competence, ratings of the working alliance and marijuana treatment outcomes were evaluated. FINDINGS: Protocol treatments were implemented with strong fidelity to manual specifications and with few significant differences in adherence and competence ratings across sites. In the brief two-session treatment condition, only the working alliance was associated significantly with frequency of marijuana use, but in the extended treatment therapist ratings of working alliance predicted outcomes, as did the interaction of alliance and curvilinear adherence. CONCLUSIONS: Behavioral treatments for marijuana use were delivered in community settings with good fidelity. Participant and therapist working alliance scores were associated significantly with improved marijuana use outcomes in a brief behavioral treatment for adults with marijuana dependence. In extended treatment the therapist ratings of working alliance were associated with more positive outcome. However, in that treatment there was also a significant interaction between alliance and curvilinear adherence. PMID- 20840202 TI - A qualitative study of young people's sources of cigarettes and attempts to circumvent underage sales laws. AB - AIMS: To explore how young people continue to access cigarettes following an increase of the age of sale to 18 years and the implications for future smoking prevention policy and practice. DESIGN: Qualitative study using 14 focus groups. SETTING: Schools and community projects in disadvantaged areas of Birmingham, UK. PARTICIPANTS: Eighty-five smokers and non-smokers aged 12-15 years. MEASUREMENTS: Focus group topic guides. FINDINGS: While young people did use social sources to access cigarettes, most obtained cigarettes from small local shops. Smoking and non-smoking participants knew which shops sold to underage children and what strategies to employ, suggesting a widespread acceptance of underage sales in some communities. Some young people bought directly from retailers, reporting that the retailers did not ask for identification. Some young people reported that retailers were complicit, knowingly selling to underage smokers. Young people waited outside shops and asked strangers to buy them cigarettes (proxy sales). Young people expressed cynicism about some shopkeepers' motives, who they believed knew that they were selling to under-18s, but did not care as long as they made a profit. CONCLUSIONS: The ban in selling cigarettes to those under 18 in the United Kingdom appears to be easily circumvented, and one important route appears to be 'proxy sales' in which young people approach strangers outside retailers and ask them to purchase cigarettes on their behalf. PMID- 20840201 TI - Withdrawal symptoms in abstinent methamphetamine-dependent subjects. AB - AIMS: Withdrawal symptoms have been linked to a propensity for relapse to drug abuse. Inasmuch as this association applies to methamphetamine (MA) abuse, an understanding of the course of MA withdrawal symptoms may help to direct treatment for MA dependence. Previous studies of symptoms manifested during abstinence from MA have been limited in size and scope. We asked (i) whether debilitating psychological and/or physical symptoms appear during the first several weeks of MA abstinence, (ii) how craving for MA evolves and (iii) whether psychiatric symptoms (e.g. depression, psychosis) persist beyond a month of abstinence. DESIGN: A study of MA-dependent participants, who initiated and maintained abstinence from the drug for up to 5 weeks, compared to a matched healthy comparison group. SETTING: In-patient research hospital ward (MA dependent subjects) and out-patient (comparison subjects). PARTICIPANTS: Fifty six MA-dependent and eighty-nine comparison subjects. MEASUREMENTS: Rater assessed MA withdrawal questionnaire and self-report assessment of craving (MA dependent subjects) and self-report assessment of psychiatric symptoms (both groups). FINDINGS: At study entry, MA-dependent subjects exhibited a wide range in severity of depressive symptoms, with the average score at a mild-moderate level of severity. Symptoms of psychosis were also prevalent. While depressive and psychotic symptoms largely resolved within a week of abstinence, craving did not decrease significantly from the time of initiating abstinence until the second week, and then continued at a reduced level to the fifth week. CONCLUSIONS: Depressive and psychotic symptoms accompany acute withdrawal from methamphetamine but resolve within 1 week. Craving is also present and lasts at least 5 weeks. PMID- 20840203 TI - Warning: legal synthetic cannabinoid-receptor agonists such as JWH-018 may precipitate psychosis in vulnerable individuals. PMID- 20840204 TI - What's the matter with cue-induced craving? A commentary on Perkins. PMID- 20840205 TI - Legal highs and the challenges for policy makers. PMID- 20840207 TI - Depressive mood, suicide ideation and anxiety in smokers who do and smokers who do not manage to stop smoking after a target quit day. AB - AIMS: The effect of successful and unsuccessful smoking cessation on depressive mood, anxiety- and suicide-related outcomes is unclear. The aim of this secondary analysis was to explore the relationship between abstinence status and these outcomes. DESIGN: Cohort of adult smokers attempting to stop smoking. Smoking status was assessed by a daily diary; depressed mood, anxiety and suicidal tendencies by the Hamilton Depression Rating Scale (HDRS). The association of complete and point-prevalence abstinence with the HDRS variables was assessed using multi-level linear regression models. SETTING: Randomized trial of sertraline versus placebo for smoking cessation with weekly behavioural support provided in a clinic. PARTICIPANTS: A total of 133 adult smokers with past major depression. FINDINGS: Pre-quit mood scores did not predict smoking status post quit day. Both continuous and point-prevalence abstainers had significantly lower total HDRS, suicide and anxiety scores, adjusted for all potential confounders, during the period following quit day than did non-abstainers who experienced a significant mood deterioration. There was a significant effect of sertraline on post-quit HDRS scores but not on abstinence. CONCLUSIONS: Contrary to expectation, smoking abstinence among smokers with a history of major depression did not lead to increase in depression, anxiety or suicide ideation; however, failed quit attempts did. Persisting with a quit attempt while unable to achieve abstinence may be associated with mood deterioration. PMID- 20840206 TI - Declining alternative reinforcers link depression to young adult smoking. AB - AIMS: Young adulthood represents a period of continued smoking progression and the establishment of regular and long-term smoking practices. Our understanding of the psychological processes that facilitate and solidify regular smoking patterns in this developmental period is limited. We sought to evaluate the role of depression symptoms in young adult smoking uptake and to evaluate whether non smoking related alternative reinforcers was a mechanism by which depression symptoms influence smoking. PARTICIPANTS: The sample was composed of 834 young adults who participated in a longitudinal study of smoking adoption (aged 18-22 years). DESIGN AND MEASUREMENTS: In this prospective cohort study, smoking, depression, alternative reinforcers and several covariates were measured annually via telephone from emerging adulthood (age 18) to young adulthood (age 22). FINDINGS: Results of a parallel processes latent growth curve model showed that depression symptoms level (baseline age 18) had a significant negative effect on substitute alternative reinforcers trend (beta = -0.01, Z = -3.17, P=0.002) and that substitute reinforcers trend had a significant negative effect on smoking trend (beta = -0.62, Z = -2.99, P = 0.003). An assessment of indirect effects revealed that depression symptoms level had a significant positive indirect effect on smoking trend through substitute alternative reinforcers trend (beta = 0.01, Z = 2.09, P = 0.04, 99% CI = 0.001, 0.02), such that greater depression symptoms at baseline predicted decreases in substitute reinforcers across time which in turn predicted increases in smoking uptake/rate from emerging to young adulthood. CONCLUSIONS: Depressive symptoms in emerging adulthood appear to influence smoking uptake and smoking rate through reductions in alternative reinforcers. This suggests that increasing involvement in alternative reinforcers may prevent smoking uptake and escalation in smoking rate. PMID- 20840208 TI - 'Alcohol, less is better' project: outcomes of an Italian community-based prevention programme on reducing per-capita alcohol consumption. AB - AIMS: To evaluate differences in the individual alcohol consumption after a community-based prevention programme. DESIGN SETTINGS AND PARTICIPANTS: 'Alcohol, less is better' is a controlled intervention trial. The intervention adopted a community approach, based on the active involvement of community leaders and institutional or volunteer organizations. Between 1999 and 2006, 2.5 years of activities aiming at informing and sensitizing the community on the harmful effects of alcohol on social life and health were carried out in 10 selected small Italian communities, involving a total of 123, 235 individuals. Eight communities were chosen as control group. MEASUREMENTS: Changes in self-reported individual alcohol consumption before and after the intervention were assessed on a random sample of intervention (n = 3382) and control (n = 2644) populations, using telephone and mailed surveys. Linear and log-linear models for repeated measures were used to evaluate differences between intervention and control samples. FINDINGS: Overall, a significant reduction (P < 0.001) of individual self-reported alcohol consumption was observed in the intervention sample (-1.1 drinks/week) relative to control sample (+0.3 drinks/week). The reduction was significantly greater in males than in females (P for heterogeneity = 0.016). In the young (15-24-year-olds) intervention and control samples showed opposite trends (-0.4 drinks/week and +1.7 drinks/week, respectively). CONCLUSIONS: A coordinated community-based intervention can reduce alcohol consumption in the general population. PMID- 20840209 TI - Online video game addiction: identification of addicted adolescent gamers. AB - AIMS: To provide empirical data-driven identification of a group of addicted online gamers. DESIGN: Repeated cross-sectional survey study, comprising a longitudinal cohort, conducted in 2008 and 2009. SETTING: Secondary schools in the Netherlands. PARTICIPANTS: Two large samples of Dutch schoolchildren (aged 13-16 years). MEASUREMENTS: Compulsive internet use scale, weekly hours of online gaming and psychosocial variables. FINDINGS: This study confirms the existence of a small group of addicted online gamers (3%), representing about 1.5% of all children aged 13-16 years in the Netherlands. Although these gamers report addiction-like problems, relationships with decreased psychosocial health were less evident. CONCLUSIONS: The identification of a small group of addicted online gamers supports efforts to develop and validate questionnaire scales aimed at measuring the phenomenon of online video game addiction. The findings contribute to the discussion on the inclusion of non-substance addictions in the proposed unified concept of 'Addiction and Related Disorders' for the DSM-V by providing indirect identification and validation of a group of suspected online video game addicts. PMID- 20840210 TI - Impulsivity and socio-economic status interact to increase the risk of gambling onset among youth. AB - AIMS: To determine if impulsivity and socio-economic status (SES) interact to influence gambling onset in youth. DESIGN: Longitudinal study of grade 7 students followed for 8 years. SETTING: Montreal, Canada. PARTICIPANTS: A total of 628 adult students aged 12.6 years on average at cohort inception. MEASUREMENTS: Impulsivity and SES (parent education, area deprivation) were collected during secondary school. Age of gambling onset was collected retrospectively when participants were aged 20.3 years. Cox proportional hazards regression was used to model the association between time to first report of gambling and interaction terms for each of impulsivity and parent education, and impulsivity and area deprivation accounting for sex and ethnicity. FINDINGS: Median (interquartile range) age of gambling onset was 17.0 (4.0) years. Impulsivity independently increased the risk of gambling onset among participants with no university educated parent [hazard ratio (HR) 1.3; 95% confidence interval 1.1-1.5] and those living in highly deprived areas (HR 1.7; 1.5-2.0). Impulsivity was not associated with gambling onset among high SES youth. Among participants with high impulsivity, risks were elevated for those with no university-educated parent relative to one or more university-educated parent (HR 1.7; 1.1-2.7), and for participants living in deprived relative to advantaged areas (HR 5.0; 2.6-9.6). SES was not associated with gambling onset among participants with low impulsivity. CONCLUSIONS: Impulsivity is a risk factor for gambling onset among low but not high SES youth, and low SES influences gambling onset primarily among impulsive youth. Gambling prevention programmes may need to consider potential interaction between impulsivity and SES. PMID- 20840211 TI - Waiting for a liver transplant... PMID- 20840212 TI - Increasing liver transplantation waiting list mortality: a report from the Australian National Liver Transplantation Unit, Sydney. AB - BACKGROUND: We aimed to describe the demand for liver transplantation (LTx) and patient outcomes on the waiting list at the Australian National Liver Transplantation Unit, Sydney over the last 20 years. METHODS: We performed a retrospective analysis with the data divided into three eras: 1985-1993, 1994 2000 and 2001-2008. RESULTS: The number of patients accepted for LTx increased from 320 to 372 and 548 (P < 0.001) with the number of LTx being performed increasing from 262 to 312 and 452 respectively (P < 0.001). The median adult recipient age increased from 45 to 48 and 52 years (P < 0.001) while it decreased in children from 4 to 2 and 1 years respectively (P = 0.001). In parallel, the deceased donor offers decreased from 1003 to 720 and 717 (P < 0.001). Methods to improve access to donor livers have been used with the use of split livers, extended criteria and non-heart beating donors, resulting in increased acceptance of deceased donor offers by 65% and 115% in the second and third eras when compared with the first era (P < 0.001). However, the adult median waiting time has increased from 23 to 41 and 120 days respectively (P < 0.001). This was associated with increased adult mortality on the waiting list from 23 to 40 and 122 respectively (P < 0.001). CONCLUSIONS: Despite the increasing proportion of donor offers being used, the waiting list mortality is increasing. A solution to this problem is an increase in organ donation to keep pace with the escalating demand for LTx. PMID- 20840213 TI - Five-year incidence and progression of thyroid dysfunction in an older population. AB - BACKGROUND: Very few studies have assessed both the incidence and progression of thyroid dysfunction in a single older population-based cohort. In this study, we aimed to assess the 5-year incidence, progression and risk factors for development of thyroid dysfunction in an older Australian population. METHODS: The Blue Mountains Eye Study is a longitudinal population-based cohort study. During 1997-1999, 1768 participants (>= 55 years) had thyroid function assessed. After excluding participants reporting any form of treatment for their thyroid condition at baseline, 951 participants (91.4%) without thyroid dysfunction and 54 (5.4%) with thyroid dysfunction were re-examined 5 years later. Thyroid dysfunction was defined using serum thyrotropin (thyroid stimulating hormone (TSH)) screen, followed by serum free T4 assessment. RESULTS: The overall 5-year incidence of thyroid dysfunction was 4.7% (95% confidence interval (CI) 3.4-6.1). Obesity (body mass index >= 30 kg/m(2) ) and serum TSH > 2 mIU/L at baseline predicted incident overt hypothyroidism (odds ratio (OR) 4.05, CI 1.74-9.41) and (OR 5.46, CI 1.16-25.67) respectively. The 5-year incidence of subclinical hypothyroidism was significantly higher in women than in men, 2.5% versus 0.7% (P= 0.03). Progression to overt hypothyroidism was observed in 17.9% of subjects with subclinical hypothyroidism over 5 years. CONCLUSIONS: The 5-year incidence of thyroid dysfunction in this older population was relatively low, and was associated with obesity and serum TSH level > 2 mIU/L at baseline. Over one in six persons with subclinical hypothyroidism progressed to overt thyroid dysfunction over the 5-year period. Our findings highlight the need for appropriate management of subclinical hypothyroidism among older people. PMID- 20840214 TI - Acquired factor V inhibitor. PMID- 20840215 TI - Malignant hypertension associated with IgA nephropathy. PMID- 20840216 TI - The need to improve organ donation and transplantation rates in Australia. PMID- 20840217 TI - Chemical ecology of interactions between human skin microbiota and mosquitoes. AB - Microbiota on the human skin plays a major role in body odour production. The human microbial and chemical signature displays a qualitative and quantitative correlation. Genes may influence the chemical signature by shaping the composition of the microbiota. Recent studies on human skin microbiota, using 16S rRNA gene sequencing, found a high inter- and intrapersonal variation in bacterial species on the human skin, which is relatively stable over time. Human body odours mediate the attraction of mosquitoes to their blood hosts. Odours produced by skin microbiota are attractive to mosquitoes as shown by in vitro studies, and variation in bacterial species on the human skin may explain the variation in mosquito attraction between humans. Detailed knowledge of the ecology and genetics of human skin microbiota is needed in order to unravel the evolutionary mechanisms that underlie the interactions between mosquitoes and their hosts. PMID- 20840218 TI - Precision and accuracy of the ICare tonometer - Peripheral and central IOP measurements by rebound tonometry. AB - PURPOSE: The purpose of this study was to evaluate the ICare tonometers precision and accuracy and the extent to which intraocular pressure (IOP) measurements are influenced by measuring position. METHODS: This was carried out by comparing the central and peripheral ICare-IOP readings and comparing ICare- with the Goldmann applanation tonometer (GAT)-IOP readings. IOP was measured using the ICare rebound tonometer on the right eye of 40 subjects, straight at the centre of the cornea (CS), straight 2 mm from the nasal and temporal limbus (NS and TS), and in 10 degrees nasally and temporally angled positions measured from the same location as CS (NA and TA). The IOP was also assessed with the GAT. RESULTS: Central IOP (CS) was significantly (p < 0.001) greater than peripheral measurements (NS, TS, NA and TA) by approximately 3-4 mmHg. Centre IOP (CS) significantly overestimated by mean 2 mmHg and the peripheral measurements significantly underestimates approximately 1.4-2 mmHg compared with GAT readings. CONCLUSION: The ICare tonometer may be useful in a routine clinical setting for IOP screening, but the ICare measurement is not a substitute for the GAT measurement, when a precise and accurate IOP is desired. PMID- 20840219 TI - Non-invasive prenatal determination of fetal sex: translating research into clinical practice. AB - The effectiveness and clinical utility of non-invasive prenatal diagnosis (NIPD) for fetal sex determination using cell-free fetal DNA (cffDNA) was assessed by undertaking a prospective national audit of UK testing. NIPD was performed using real-time polymerase chain reaction analysis of the DYS14 or SRY gene in cffDNA extracted from maternal plasma. All cases referred for fetal sex determination from 1 April 2006 to 31 March 2009 were ascertained from two laboratories offering the test. Fetal gender determined by NIPD was compared with that based on ultrasound, invasive test or phenotype at birth. Indication and rate of invasive testing was ascertained. In the first year, results were issued in 150/161 pregnancies tested. Of the 135 with outcome data, results were concordant in 130/135 [96.3% (95% CI 91.6-98.8%)]. Reporting criteria were changed and in the subsequent 511 pregnancies the concordancy rate increased to 401/403 [99.5% (95% CI 98.2-99.9%)]. Over the 3 years only 32.9% (174/528) underwent invasive testing. NIPD for fetal sex determination using cffDNA is highly accurate when performed in National Health Service laboratories if stringent reporting criteria are applied. Parents should be advised of the small risk of discordant results and possible need for repeat testing to resolve inconclusive results. PMID- 20840220 TI - Haplotype analysis of two recurrent genomic rearrangements in the BRCA1 gene suggests they are founder mutations for the Greek population. AB - The deletions of 4.4 and 3.2 kb identified in exons 24 and 20, respectively, are two of the four most common mutations in the BRCA1 gene in Greek breast cancer patients. They have been reported previously six and three times, respectively, in unrelated Greek families. A total of 11 more families have been identified in the present study. In order to characterize these recurrent mutations as founder mutations, it is necessary to identify the disease-associated haplotype and prove that it is shared by all the mutation carriers, suggesting that it occurred only once in a common ancestor. Haplotype analysis was performed on 24 mutation carriers and 66 healthy individuals using 10 short tandem repeat markers located within and flanking the BRCA1 gene locus, spanning a 5.9 Mb interval. Results indicate that most of the carriers of the exon 24 deletion share a common core haplotype '4-7-6-6-1-3' between markers D17S951 and D17S1299, for a stretch of 2.9 Mb, while the common haplotype for the exon 20 deletion is '6-7-4-2-6-7-1-3' between markers D17S579 and D17S1299, for a stretch of 3.9 Mb. Both genomic rearrangements in BRCA1 gene are Greek founder mutations, as carriers share the same, for each mutation, disease-associated haplotype, suggesting the presence of a distinct common ancestor for both mutations. PMID- 20840221 TI - Level of evidence for therapeutic drug monitoring of taxanes. AB - Taxanes are anticancer drugs on the market for more than 10 years that are thought to be interesting for therapeutic drug monitoring (TDM): high inter- and intra-patient variability, relationship between exposure and efficacy and especially toxicity. Nevertheless, the paclitaxel and docetaxel characteristics result in different conclusions for these two molecules with respect to their TDM. For paclitaxel, the nonlinear pharmacokinetics makes that the parameter which seems the more reliable to toxicity or outcome is the time during which the plasma concentration exceeds 0.05 MUm. Concentration controlled studies using Bayesian adaptation showed that the TDM of paclitaxel is feasible in routine. However, this target needs to be prospectively validated with new weekly schedules of administration, leading to a balance between 'recommended' and 'potentially useful'. For docetaxel, the 3-weekly administration, which is the more effective scheme, is also the more toxic. However, neutropenia can be individually modeled and efficiently predicted without using plasma drug concentrations. The docetaxel TDM using this docetaxel-related neutropenia modeling however needs to be prospectively validated in routine. The level of evidence of TDM thus 'needs to be assessed'. PMID- 20840222 TI - Eggs of the Australian saltmarsh mosquito, Aedes camptorhynchus, survive for long periods and hatch in instalments: implications for biosecurity in New Zealand. AB - The Australian saltmarsh mosquito, Aedes camptorhynchus (Diptera: Culicidae), is a significant biting pest and disease vector and is the subject of an eradication programme in New Zealand (NZ), where it has been resident for more than 10 years. To better understand the ecology of this common and widespread pest, we studied egg longevity and hatching patterns in the laboratory. By regularly testing for the presence of viable embryos, we found that eggs may last more than 15 months when stored dry (13% viable at this time). Eggs display instalment hatching, with no more than 56% of a batch hatching upon first inundation. Further hatching may occur for at least six inundations and some unhatched eggs may remain viable even after this. Variation in hatching rates can be observed using different water types, with weaker hatching media stimulating lower hatching rates spread over more inundations. By applying average hatching rates to a non-linear model of natural egg attrition, we showed that egg batches exposed to three inundations should be exhausted (zero live eggs present) in approximately 11 months at the conditions tested here. These findings have implications for the current eradication programme for Ae. camptorhynchus in NZ and for our understanding of the ecology of a widespread and common disease vector in Australia. PMID- 20840223 TI - Effect evaluation of a supervised versus non-supervised implementation of an oral health care guideline in nursing homes: a cluster randomised controlled clinical trial. AB - OBJECTIVE: To compare a supervised versus a non-supervised implementation of an oral health care guideline in Flanders (Belgium). BACKGROUND: The key factor in realising good oral health is daily oral hygiene care. In 2007, the Dutch guideline 'Oral health care in care homes for elderly people' was developed to improve oral health of institutionalised elderly. MATERIALS AND METHODS: A random sample of 12 nursing homes was randomly allocated to the intervention or the control group. Representative samples of 30 residents in each home were monitored during a 6-month study period. The intervention included a supervised implementation of the guideline. RESULTS: At the 6-month follow-up, only a small but statistically significant (p = 0.002) beneficial effect (0.32) of the intervention was observed for denture plaque after adjustment for baseline value and the random effect of the institution. In the linear mixed regression models, including a random institution effect, difference in denture plaque level was no longer statistically significant at the 5% level. CONCLUSION: Only denture hygiene has been improved by the supervised implementation, although with lower benefits than presumed. Factors on institutional level, difficult to assess quantitatively, may play an important role in the final result. PMID- 20840225 TI - Sex categorization among preschool children: increasing utilization of sexually dimorphic cues. AB - Two studies examined how children between ages 4 and 6 use body shape (i.e., the waist-to-hip-ratio [WHR]) for sex categorization. In Study 1 (N=73), 5- and 6 year-olds, but not 4-year-olds, selected bodies with increasingly discrepant WHRs to be "most like a man" and "most like a woman." Similarly, sex category judgments made by 5- and 6-year-olds, but not 4-year-olds, varied with WHR. In Study 2 (N=41), eye movements indicated the functional use of waist and hips in sex categorization. Visual scanning behavior predicted the degree of association between WHR and judgment. Collectively, these results suggest that the ability to exploit sexual dimorphism to compel categorization develops between the ages of 4 and 6. Implications for theories of gender development and psychological essentialism are discussed. PMID- 20840226 TI - Cognitive flexibility in drawings of bilingual children. AB - A. Karmiloff-Smith's (1990) task of drawing a nonexistent object is considered to be a measure of cognitive flexibility. The notion of earlier emergence of cognitive flexibility in bilingual children motivated the current researchers to request 4- and 5-year-old English-Hebrew and Arabic-Hebrew bilingual children and their monolingual peers to draw a flower and a house that do not exist (N=80). Bilinguals exhibited a significantly higher rate of interrepresentational flexibility in their drawings (e.g., "a giraffe flower,""a chair-house," found in 28 of 54 drawings), whereas the level of complex intrarepresentational change was similar across groups. Interrepresentational drawings were previously reported only for children older than 7 years. The specific mechanisms by which bilinguals' language experience may lead to interrepresentational flexibility are discussed. PMID- 20840227 TI - Bridging the gap: solving spatial means-ends relations in a locomotor task. AB - Using a means-means-ends problem-solving task, this study examined whether 16 month-old walking infants (N = 28) took into account the width of a bridge as a means for crossing a precipice and the location of a handrail as a means for augmenting balance on a narrow bridge. Infants were encouraged to cross from one platform to another over narrow and wide bridges located at various distances from a wooden handrail. Infants attempted to walk over the wide bridge more often than the narrow one and when the handrail was within reach. Infants demonstrated parallel problem solving by modifying exploratory behaviors and bridge-crossing strategies that simultaneously accounted for the spatial and functional relations between body and bridge, body and handrail, and bridge and handrail. PMID- 20840228 TI - What paradox? Referential cues allow for infant use of phonetic detail in word learning. AB - Past research has uncovered a surprising paradox: Although 14-month-olds have exquisite phonetic discrimination skills (e.g., distinguishing [b] from [d]), they have difficulty using phonetic detail when mapping novel words to objects in laboratory tasks (confusing bin and din). While some have attributed infants' difficulty to immature word learning abilities, the hypothesis presented herein is that infants are powerful word learners and this apparent difficulty occurs only when the referential status of the novel word is unclear. Across 2 experiments, 14-month-old infants (N=44) used phonetic detail to map novel words to objects when conditions were conducive to word-referent mapping (clear sentential contexts and word-referent training), thus revealing no fundamental discontinuity in its use from speech perception to word learning. PMID- 20840229 TI - Tolerance of practices by Muslim actors: an integrative social-developmental perspective. AB - Using social-cognitive domain theory and social identity theory, tolerance judgments of practices by Muslim actors among Dutch adolescents (12-17) were investigated. The findings for Study 1 (N=180) demonstrated that participants evaluated 4 practices using different types of reasons: personal, social conventional, and moral. In Study 2 (N=970), participants were more tolerant of acts considered to be a personal issue than of acts that pertained to moral issues (social-conventional acts were in the middle). Furthermore, participants were more tolerant of the particular practices than of campaigns for public support of co-Muslims for these practices. Level of education, in-group identification, and multiculturalism had much weaker effects in the moral than in the other domains. Age was negatively related to tolerance. PMID- 20840230 TI - The development of core cognitive skills in autism: a 3-year prospective study. AB - This longitudinal study tested the veracity of one candidate multiple-deficits account of autism by assessing 37 children with autism (M age=67.9 months) and 31 typical children (M age=65.2 months) on tasks tapping components of theory of mind (ToM), executive function (EF), and central coherence (CC) at intake and again 3 years later. As a group, children with autism showed poor false-belief attribution, planning ability, and set-shifting, together with enhanced local processing at both time points. At an individual level, however, the profile was far from universal at either intake or follow-up. Moreover, autistic children demonstrated significant changes over time in ToM and EF, but not CC, over the 3 year period. The challenges these findings pose for a multiple-deficits account are discussed. PMID- 20840231 TI - Gender differences in spatial ability of young children: the effects of training and processing strategies. AB - A sample of 116 children (M=6 years 7 months) in Grade 1 was randomly assigned to experimental (n=60) and control (n=56) groups, with equal numbers of boys and girls in each group. The experimental group received a program aimed at improving representation and transformation of visuospatial information, whereas the control group received a substitute program. All children were administered mental rotation tests before and after an intervention program and a Global-Local Processing Strategies test before the intervention. The results revealed that initial gender differences in spatial ability disappeared following treatment in the experimental but not in the control group. Gender differences were moderated by strategies used to process visuospatial information. Intervention and processing strategies were essential in reducing gender differences in spatial abilities. PMID- 20840232 TI - Interracial and intraracial contact, school-level diversity, and change in racial identity status among African American adolescents. AB - Among 224 African American adolescents (mean age=14), the associations between interracial and intraracial contact and school-level diversity on changes in racial identity over a 3-year period were examined. Youths were determined to be diffused, foreclosed, moratorium, or achieved, and change or stability in identity status was examined. Contact with Black students, Black friends, and White friends predicted change in identity status. Furthermore, in racially diverse schools, having more Black friends was associated with identity stability. Students reporting low contact with Black students in racially diverse schools were more likely to report identity change if they had few Black friends. In students reporting high contact with Blacks in predominantly White schools, their identity was less likely to change for students with fewer White friends. PMID- 20840233 TI - Do adolescents and parents reconstruct memories about their conflict as a function of adolescent attachment? AB - This study examined whether 17-year-old adolescents (n=189) and their parents reconstructed their memory for an adolescent-parent laboratory conflict over a 6 week period as a function of adolescent attachment organization. It also compared participants' perceptions of conflict over time to observational ratings of the conflict to further characterize the nature of the attachment-related memory biases that emerged. Secure adolescents reconstructed interactions with each parent more favorably over time, whereas insecure adolescents showed less favorable reconstructive memory. Likewise, mothers of secure girls reconstructed conflicts more favorably over time, whereas mothers of insecure boys showed less favorable reconstructive memory. Participant ratings were associated with observational ratings in theoretically consistent ways. Contrary to expectations, fathers showed no attachment-related memory biases. PMID- 20840234 TI - Child care and the development of behavior problems among economically disadvantaged children in middle childhood. AB - Research examining the longer term influences of child care on children's development has expanded in recent years, but few studies have considered low income children's experiences in community care arrangements. Using data from the Three-City Study (N=349), the present investigation examines the influences of child care quality, extent and type on low-income children's development of behavior problems during middle childhood (7-11 years old). Higher levels of child care quality were linked to moderate reductions in externalizing behavior problems. High-quality child care was especially protective against the development of behavior problems for boys and African American children. Child care type and the extent of care that children experienced were generally unrelated to behavior problems in middle childhood. PMID- 20840235 TI - Children's understanding of ordinary and extraordinary minds. AB - How and when do children develop an understanding of extraordinary mental capacities? The current study tested 56 preschoolers on false-belief and knowledge-ignorance tasks about the mental states of contrasting agents--some agents were ordinary humans, some had exceptional perceptual capacities, and others possessed extraordinary mental capacities. Results indicated that, in contrast to younger and older peers, children within a specific age range reliably attributed fallible, human-like capacities to ordinary humans and to several special agents (including God) for both tasks. These data lend critical support to an anthropomorphism hypothesis--which holds that children's understanding of extraordinary minds is derived from their everyday intuitive psychology--and reconcile disparities between the findings of other studies on children's understanding of extraordinary minds. PMID- 20840236 TI - Maternal discussions of mental states and behaviors: relations to emotion situation knowledge in European American and immigrant Chinese children. AB - This study examined in a cross-cultural context mothers' discussions of mental states and external behaviors in a story-telling task with their 3-year-old children and the relations of such discussions to children's emotion situation knowledge (ESK). The participants were 71 European American and 60 Chinese immigrant mother-child pairs in the United States. Mothers and children read a storybook together at home, and children's ESK was assessed. Results showed that European American mothers made more references to thoughts and emotions during storytelling than did Chinese mothers, who commented more frequently on behaviors. Regardless of culture, mothers' use of mental states language predicted children's ESK, whereas their references to behaviors were negatively related to children's ESK. Finally, mothers' emphasis on mental states over behaviors partially mediated cultural effects on children's ESK. PMID- 20840237 TI - The effects of maltreatment and neuroendocrine regulation on memory performance. AB - This investigation examined basic memory processes, cortisol, and dissociation in maltreated children. School-aged children (age range=6-13), 143 maltreated and 174 non-maltreated, were administered the California Verbal Learning Test Children (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1994) in a week long camp setting, daily morning cortisol levels were assessed throughout the duration of camp, and behavioral symptoms were evaluated. Maltreatment and cortisol regulation were not related to short- or long-delay recall or recognition memory. However, children experiencing neglect and/or emotional maltreatment and low cortisol evinced heightened false recognition memory. Dissociative symptoms were higher in maltreated children; however, high dissociation was related to recognition inaccuracy only among non-maltreated children. Results highlight the interplay between maltreatment and hypocortisolism in children's recognition memory errors. PMID- 20840238 TI - The contributions of numerosity and domain-general abilities to school readiness. AB - Contributions of domain-general and domain-specific numerical competencies were assessed on first graders' number combination skill (NC) and word-problem skill (WP). Students (n=205) between 5 and 7 years of age were assessed on 2 aspects of numerosity, 8 domain-general abilities, NC, and WP. Both aspects of numerosity predicted NC when controlling for domain-general abilities, but domain-general abilities did not account for significant additional variance. By contrast, when controlling for domain-general abilities in predicting WP, only precise representation of small quantities was uniquely predictive, and domain-general measures accounted for significant additional variance; central executive component of working memory and concept formation were uniquely predictive. Results suggest that development of NC and WP depends on different constellations of numerical versus more general cognitive abilities. PMID- 20840239 TI - Children's classroom engagement and school readiness gains in prekindergarten. AB - Child engagement in prekindergarten classrooms was examined using 2,751 children (mean age=4.62) enrolled in public prekindergarten programs that were part of the Multi-State Study of Pre-Kindergarten and the State-Wide Early Education Programs Study. Latent class analysis was used to classify children into 4 profiles of classroom engagement: free play, individual instruction, group instruction, and scaffolded learning. Free play children exhibited smaller gains across the prekindergarten year on indicators of language/literacy and mathematics compared to other children. Individual instruction children made greater gains than other children on the Woodcock Johnson Applied Problems. Poor children in the individual instruction profile fared better than nonpoor children in that profile; in all other snapshot profiles, poor children fared worse than nonpoor children. PMID- 20840240 TI - Early elementary school adjustment of maltreated children in foster care: the roles of inhibitory control and caregiver involvement. AB - In this study, 85 maltreated foster children and 56 non-maltreated community children (M age=3-6 years) were assessed across kindergarten and first grade to examine the hypothesis that inhibitory control and caregiver involvement mediate associations between a history of maltreatment and foster placement and early school adjustment. Specifically, academic and social-emotional competence were evaluated. The maltreated foster children performed more poorly in academic and social-emotional competence. Inhibitory control fully mediated the association of maltreatment and foster placement with academic competence, whereas inhibitory control and caregiver involvement mediated their association with social emotional competence. The results suggest that inhibitory control and caregiver involvement might be promising targets for school readiness interventions for foster preschoolers. PMID- 20840241 TI - On the progression and stability of adolescent identity formation: a five-wave longitudinal study in early-to-middle and middle-to-late adolescence. AB - This study examined identity development in a 5-wave study of 923 early-to-middle and 390 middle-to-late adolescents thereby covering the ages of 12-20. Systematic evidence for identity progression was found: The number of diffusions, moratoriums, and searching moratoriums (a newly obtained status) decreased, whereas the representation of the high-commitment statuses (2 variants of a [fore]closed identity: "early closure" and "closure," and achievement) increased. We also found support for the individual difference perspective: 63% of the adolescents remained in the same identity status across the 5 waves. Identity progression was characterized by 7 transitions: diffusion->moratorium, diffusion >early closure, moratorium->closure, moratorium->achievement, searching moratorium->closure, searching moratorium->achievement, and early closure >achievement. PMID- 20840242 TI - Structure and strategies in children's educational television: the roles of program type and learning strategies in children's learning. AB - Educational TV has been consistently linked to children's learning. In this research, educational TV characteristics were identified, coded, and tested for their influence on children's program-specific comprehension and vocabulary outcomes. Study 1 details a content analysis of TV features including a program's macrostructure (i.e., narrative or expository) and learning strategies embedded in the macrostructure that support learning in print-based contexts. In Study 2, regression analyses were used to predict outcomes involving 71 second and third graders (average age=7.63 years). Strategies were categorized as organizing, rehearsing, elaborating, or affective in function. Outcomes were uniformly higher for narrative macrostructures. Strategies used in narratives predicted relatively homogenous relations across outcomes, whereas strategies in expositories predicted quite heterogeneous relations across outcomes. PMID- 20840243 TI - Home media and children's achievement and behavior. AB - This study provides a national picture of the time American 6- to 12-year-olds spent playing video games, using the computer, and watching TV at home in 1997 and 2003, and the association of early use with their achievement and behavior as adolescents. Girls benefited from computer use more than boys, and Black children benefited more than White children. Greater computer use in middle childhood was associated with increased achievement for White and Black girls, and for Black but not White boys. Increased video game play was associated with an improved ability to solve applied problems for Black girls but lower verbal achievement for all girls. For boys, increased video game play was linked to increased aggressive behavior problems. PMID- 20840244 TI - Contagious yawning in autistic and typical development. AB - The authors tested susceptibility to contagious yawning in 120 children, 1-6 years, to identify the time course of its emergence during development. Results indicated a substantial increase in the frequency of contagious yawning at 4 years. In a second study, the authors examined contagious yawning in 28 children with autism spectrum disorders (ASD), 6-15 years. Children with ASD showed diminished susceptibility to contagious yawning compared with 2 control groups matched for mental and chronological age, respectively. In addition, children diagnosed with Pervasive Developmental Disorder, Not Otherwise Specified (PDD NOS) a milder variant of autism, were more susceptible to contagious yawning than were children diagnosed with full Autistic Disorder. The authors explore the implications of these findings for theories about the development of mimicry and emotional contagion. PMID- 20840245 TI - Continuing education and clinical research for the training of obstetricians and gynecologists in Europe. AB - The need for doctors to develop in their profession and in science applies to all ages and at all hierarchical levels. This development can be sustained both via education and research. In this brief paper, we examine certain crucial aspects of education and research in obstetrics and gynecology (OB/GYN) as they are actually observed in Europe. The need for uniform development of continuing professional development (CPD) among all European countries is progressively becoming apparent. There is no single approach to CPD. Junior doctors should benefit from the teaching of senior obstetricians and gynecologists, especially those in a hierarchical system of training that must assure their progress. Hospital visiting organized by EBCOG enables OB/GYN departments of teaching hospitals to unify their teaching and learning approaches. Furthermore, improving the ability of trainees and specialists to conduct clinical research is vital, as this will transform the breakthroughs of basic science into clinical practice. A formal training period in research should be available to most competent trainees in OB/GYN in addition to their basic clinical training. PMID- 20840246 TI - The role of gonadotropins in the follicular phase. AB - Folliculogenesis in humans is a lengthy process that involves several regulators. Pituitary gonadotropins play crucial roles in the late stages, particularly in the last 15 days of follicle maturation. During the intercycle rise of follicle stimulating hormone (FSH), selection of the dominant follicle takes place. This is a complex process that also involves locally produced substances. At the same time, luteinizing hormone (LH) stimulates the synthesis of androgens, which serve as the substrate for the production of estrogens. During the second half of the follicular phase, the follicle becomes dependent on LH. Induction of multiple follicular development by exogenous FSH results in a marked suppression of endogenous LH. For normal follicle maturation, both an LH threshold and an LH ceiling have been considered. In the context of an in vitro fertilization program, application of protocols for ovarian stimulation that will prevent the marked suppression of endogenous LH secretion might provide a better approach to treatment optimization. PMID- 20840247 TI - Bone acquisition during adolescence in athletes. AB - Bone mass (BM) and skeletal size are similar in prepubertal girls and boys and double between the onset of puberty and early adult life. Sex steroids are responsible for the maturation in human skeleton, as well as for the sexual dimorphism, observed after the onset of puberty. Physical activity in childhood is critical for maximizing bone growth and thus for preventing osteoporosis during older age. Therefore, it constitutes the most effective prevention strategy available. In athletes, high-impact loading activities have been shown to improve BM, whereas in sports requiring a lean somatotype (therefore leading to a negative energy balance), the delay in skeletal maturation and pubertal development predisposes athletes to osteopenia and osteoporosis. Although the early onset of training, the continuous intensive exercise and its long duration attenuate bone acquisition, the excess mechanical load to which these athletes are exposed from a young age exerts beneficial effects on bone formation that lead to a positive net-effect on BM. PMID- 20840248 TI - Umbilical cord blood stem cells: what to expect. AB - Umbilical cord blood (UCB) is a valuable alternative source of hematopoietic stem cells (HSCs). It has unique advantages of easy procurement, absence of risk to donors, low risk of transmitting infections, immediate availability, greater tolerance of human leukocyte antigen (HLA) disparity, and lower incidence of inducing severe graft-versus-host disease (GVHD). In the last several years, these features of UCB permit the field of UCB transplantation (UCBT) to move at a faster pace for both children and adults with malignancies and nonmalignancies. However, new strategies and novel developments are expected to improve engraftment and reconstitution, and to enable in utero transplantation for early therapy, as well as to allow the therapy for a wide spectrum of human diseases. PMID- 20840249 TI - Evaluation and management of adolescent amenorrhea. AB - During the first years of menstruation it is not rare for a girl to present with an irregular menstrual pattern. The complete absence or cessation of menses, which is defined as amenorrhea, requires careful evaluation and management. It is divided into primary and secondary types that describe the occurrence of amenorrhea before and after menarche, respectively. The list of causes is long and includes anatomical or functional anomalies of the genital tract, hormonal disorders, and multifactorial reasons. The most common causes are hypothalamic amenorrhea, polycystic ovarian syndrome, hyperprolactinemia, and ovarian failure. A thorough medical history and careful clinical examination of the young girl is absolutely essential. The distinction between primary and secondary amenorrhea, together with the presence, or not, of secondary sexual characteristic development will guide the physician to the differential diagnosis of amenorrhea. Essential laboratory examinations include follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin measurements; while in the presence of acne or hirsutism, androgen levels should also be measured. Management should focus on the restoration of ovulatory cycles and the prevention of short- and long-term consequences of hormonal imbalance. PMID- 20840250 TI - Athletic amenorrhea: energy deficit or psychogenic challenge? AB - Athletic women are at risk for developing ovulatory dysfunction, which presents variably as menstrual irregularity or absence. Initially characterized as an isolated disruption of hypothalamic gonadotropin-releasing hormone (GnRH) release, athletic amenorrhea, a form of hypogonadotropic hypogonadism, is invariably accompanied by additional neuroendocrine aberrations, including activation of adrenal and suppression of thyroidal axes. Exercise may elicit intermittent or chronic metabolic stress owing to increased energy expenditure and/or insufficient or imbalanced nutrient intake. In addition, athletic activities are motivated by or serve as psychogenic stressors. Prior studies dichotomized stressors as metabolic or psychogenic. Not only is this a false dichotomy because all stressors have both a metabolic and a psychogenic component, but also stressors act synergistically rather than in isolation to compromise GnRH drive and endocrine homeostasis. To ameliorate reproductive and endocrine consequences of stress, then, requires identification and amelioration of all relevant stressors. Formal psychosocial support helps individuals to develop better coping strategies and make appropriate lifestyle changes. Our research has shown that cognitive behavior therapy restores reproductive and endocrine balance. PMID- 20840251 TI - The influence of intensive physical training on growth and pubertal development in athletes. AB - Genetic potential for growth can be fully expressed only under favorable environmental conditions. Although moderate physical activity has beneficial effects on growth, excessive physical training may negatively affect it. Sports favoring restricted energy availability, in the presence of high energy expenditure, are of particular concern. In gymnastics, a different pattern in skeletal maturation and linear growth was observed, resulting in an attenuation of growth potential in artistic gymnasts (AG), more pronounced in males than in females. In female rhythmic gymnasts (RG), the genetic predisposition to growth was preserved owing to a late catchup growth phenomenon. In all other sports not requiring strict dietary restrictions, no deterioration of growth has been documented so far. Intensive physical training and negative energy balance alter the hypothalamic pituitary set point at puberty, prolong the prepubertal stage, and delay pubertal development and menarche in a variety of sports. In elite RG and AG, prepubertal stage is prolonged and pubertal development is entirely shifted to a later age, following the bone maturation rather than the chronological age. PMID- 20840252 TI - Pathophysiology of bone loss in the female athlete. AB - Low bone mass is frequent among female athletes. The "female athlete triad" is a term that describes the interaction among energy availability, menstrual function, and bone metabolism that may lead to amenorrhea and osteopenia or osteoporosis. The main pathophysiologic mechanisms that lead to low bone mass in female athletes are low energy availability and functional hypothalamic amenorrhea. Increased energy expenditure and/or decreased energy intake, as well as the presence of eating disorders, are associated with low bone mass. In addition, menstrual dysfunction is quite common, especially among athletes competing in sports favoring leanness, and also associates with low bone mass. Screening for bone loss in female athletes should take place in the presence of amenorrhea or body mass index <18 kg/m(2) . Management of low bone mass aims to restore normal energy availability and nutritional habits. Hormone replacement therapy has no effect in abnormally underweight patients unless normal eating behaviors are restored. PMID- 20840253 TI - Can HPV testing replace the pap smear? AB - The most compelling question in evaluating the possible replacement of the conventional Papanicolaou smear from a high-risk HPV testing method is the balance between specificity and sensitivity for detection of cervical intraepithelial neoplasia grade >=CIN 2 (CIN 2+). Multiple studies have shown that HPV testing has higher sensitivity than cytology for the detection of high grade CIN. Positivity increases the test cut-off for HPV and may reduce false positive results without significantly compromising the sensitivity, potentially alleviating the concern of low specificity. Overall, available evidence convincingly shows that HPV testing is superior to traditional screening for the detection of high-grade cervical lesions, and efforts are focused on improving its sensitivity, either by increasing its cut-off for positivity or by selecting those subgroups where HPV testing is expected to have higher positive predictive value for cervical disease, or by seeking to optimize triage tests after a positive HPV result. PMID- 20840254 TI - Clinical management of HPV-related disease of the lower genital tract. AB - Cytology remains the mainstay for cervical screening. The need to achieve effective management, limit complications, and preserve reproductive function led to the popularity of local treatment. Although the cure rates for ablative and excisional methods are similar, the excisional method provides a more reliable histopathological diagnosis. Recent evidence revealed increased perinatal morbidity after treatment that appears to be related to the proportion of cervix removed. The human papillomavirus (HPV) DNA test appears to enhance the detection of disease in primary screening, in the triage of minor cytological abnormalities, and in follow-up. Further research on the clinical application of a scoring system is ongoing. The vaccines are now available and appear to be safe, well tolerated, and highly efficacious in HPV naive women. A synergy of vaccination and screening will be required. Treatment for early cervical cancer is increasingly shifting toward more fertility-sparing surgical techniques. Careful selection of patients is essential. PMID- 20840255 TI - The role of stress in female reproduction and pregnancy: an update. AB - Life exists by establishing a balanced equilibrium, called homeostasis, constantly challenged by adverse stimuli, called stressors. In response to these stimuli, a complex neurohormonal reaction exerted by the activation of the so called stress system is initiated. The latter is activated in a coordinated fashion, leading to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chance for survival. The stress system suppressive effects on female reproduction involve suppression of the hypothalamic-pituitary-ovarian axis at the hypothalamic, pituitary, ovarian, and uterine levels. Experimental and human data suggest that adverse prenatal stimuli, of either maternal or fetal origin, acting in the developing embryo in utero, can lead to the development of short- and long-term health disorders. These include preterm birth of the offspring, low birth weight, and the development of adult diseases ranging from the metabolic syndrome to several neurodevelopmental disorders. PMID- 20840256 TI - The effects of adipose tissue and adipocytokines in human pregnancy. AB - During pregnancy, important changes take place in maternal metabolism because of the growing fetus and placental formation. The increase in insulin resistance during pregnancy is paralleled by the progressive increase of maternal adipose tissue deposition. This review examines the topography of fat mass deposition during pregnancy in relation to factors such as parity and maternal age that might affect this deposition. We also examine adipose tissue markers, such as pregravid weight and weight gain during pregnancy, and their effect on fetal growth and pregnancy outcomes. In addition, this review studies the possible effects of cytokines that are produced by adipose tissue and the placenta on maternal metabolism and its complications. Finally, we also consider the possible role of maternal adipocytokines and fetal adipocytokines on fetal growth. PMID- 20840257 TI - The role of adipocytokines in fetal growth. AB - Cumulative evidence suggests that the origins of obesity may occur during fetal development. In this respect, the concept of "developmental programming" was introduced and supported by experimental and epidemiological data. This concept supports the idea that the nutritional and hormonal status during pregnancy could irreversibly interfere in metabolism control. The mechanisms responsible for this developmental programming remain poorly documented. However, recent research indicates that adipocytokines may play a critical role in this process. Thus, leptin, adiponectin, and the recently identified resistin, visfatin, and apelin, all exert effects on fat, muscle, and liver cells early in life. The aforementioned adipocytokines are secreted by adipocytes and human placenta during fetal life and may play a major role in the etiopathogenesis of the metabolic syndrome. This review will focus on the intrauterine expression of adipocytokines, their contribution to the hormonal control of fetal growth, and their role in restricted and exaggerated intrauterine growth. PMID- 20840258 TI - Establishing consensus criteria for the diagnosis of diabetes in pregnancy following the HAPO study. AB - The current diagnostic criteria for gestational diabetes mellitus are controversial because they lack correlation to maternal and perinatal outcome. The results of the hyperglycemia and adverse pregnancy outcome (HAPO) study demonstrate a linear association between increasing levels of fasting, 1- and 2-h plasma glucose post a 75 g oral glucose tolerance test to several significant outcome endpoints, such as birth weight above the 90th percentile, cord blood serum C-peptide level above the 90th percentile, primary cesarean delivery, clinical neonatal hypoglycemia, premature delivery, shoulder dystocia or birth injury, intensive neonatal care admission, hyperbilirubinemia, and preeclampsia. A consensus report by the IADPSG, based on a vigorous assessment of the HAPO results and other studies, recommended an endorsement of risk-based, internationally accepted criteria for the diagnosis and classification of diabetes in pregnancy. This review follows the steps from defining the problem to the endpoint of achieving a worldwide policy change. PMID- 20840259 TI - Perinatal mortality in diabetic pregnancy. AB - Perinatal mortality rate (PMR) is one of the most important perinatal health indicators. PMR in diabetic pregnancies varies throughout the world and is higher than the background PMR. The prevalence of pregestational diabetes is increasing and is associated with an elevated risk of congenital malformations, macrosomia, preeclampsia, and preterm delivery. The incidence of PMR in preexisting diabetes mellitus ranges considerably, with congenital abnormalities and preterm labor the main factors contributing to the higher PMR. Women with gestational diabetes mellitus or impaired glucose tolerance are a mixed group that may have low to a high PMR, especially if they require insulin in their pregnancy. All the known diabetic women should plan their pregnancies and optimize glycemic control periconceptually and throughout pregnancy, as this reduces the frequency of congenital abnormalities, obstetric complications, and perinatal mortality. PMID- 20840260 TI - Fetal origins of adult diabetes. AB - According to the fetal origin of adult diseases hypothesis, the intrauterine environment through developmental plasticity may permanently influence long-term health and disease. Therefore, intrauterine growth restriction (IUGR), due either to maternal, placental, or genetic factors, may permanently alter the endocrine metabolic status of the fetus, driving an insulin resistance state that can promote survival at the short term but that facilitates the development of type 2 diabetes mellitus and metabolic syndrome in adult life, especially when the intrauterine nutrient restriction is followed by a postnatal obesogenic environment. Furthermore, an energy-rich environment during fetal programming may also drive the development of excess abdominal fat and type 2 diabetes in later life, demonstrating that both intrauterine nutrient restriction as well as intrauterine nutrient excessive supply may predispose for the development of adult diabetes. PMID- 20840261 TI - Coagulation disorders in pregnancy: acquired and inherited thrombophilias. AB - Both acquired and inherited thrombophilias are associated with an increased risk of pregnancy-related venous thromboembolism (VTE) as well as with adverse pregnancy outcome. However, the extension of attributable risk for each thrombophilia and outcome is still a question of debate. Thrombophilias have been investigated in connection with VTE and pregnancy complications such as: recurrent and nonrecurrent early pregnancy loss, late fetal death, placental abruption, fetal growth restriction, and preeclampsia. This review discusses the evidence of association between thrombophilias and pregnancy outcome together with issues as to clinical management and preventive strategies. PMID- 20840262 TI - Intrauterine inflammation and preterm delivery. AB - Spontaneous preterm delivery, prematurity, and low birth weight due to prematurity account for a great part of neonatal morbidity and mortality. Specifically, chronic amniotic fluid inflammation may cause preterm labor, with the involvement of different mediators that produce diverse aspects of the inflammatory response. Although bacteria are considered to be the main trigger for intrauterine infection/inflammation, viral infections also appear to be involved. Recently, molecular genetic techniques have helped us better understand the underlying pathophysiologic processes. This is especially important because epidemiological and experimental studies indicate that intrauterine infection and inflammation constitute a risk factor for adverse neurological outcome in preterm infants. Chronic subclinical chorioamnionitis associated with preterm birth can also modify lung development. Although no current clinical strategy is aimed at adapting the maternofetal inflammatory response, immunomodulators may serve as a future intervention in preterm embryos. PMID- 20840263 TI - Management of premature prelabor rupture of the membranes. AB - Premature prelabor rupture of the fetal membranes affects about 3% of pregnancies. The cause is usually infection, especially at earlier gestations. The prognosis and the risks of delivery are both much worse at earlier gestations. Before viable pregnancy, termination may be offered. Once the fetus is viable, steroids to mature the fetal lungs and antibiotics to reduce infection are the mainstays of treatment. Delivery is recommended in the presence of signs of clear-cut infection at early gestational ages. At later ones, balancing the risks of infection from conservative treatment against the risk of prematurity from delivery is difficult. Published trials to date have not given clear guidance, but a number are ongoing. PMID- 20840264 TI - Neonatal outcome of preterm delivery. AB - Advances in perinatal and neonatal care over the last 30 years have contributed to improved survival among extremely low birth weight (ELBW) infants. As the rate of neonatal morbidity has remained stable, parents and health care professionals involved in the care of these infants often raise questions regarding the prevalence of adverse neurodevelopmental outcomes. Existing data in the literature is heterogeneous and the reported prevalence of disability varies more than survival rates do. One of the key issues toward a better clinical management of ELBW infants is the knowledge of the nature of mortality and disability in this population of infants. Studies from individual centers report outcomes of ELBW infants and demonstrate several limitations as to the ways babies were treated. Advice to parents and decisions to be made regarding the care of these infants should be based on reliable, unbiased, and representative data drawn from geographically defined populations. Such data have recently become available. This report gives an overview of existing literature on this issue. PMID- 20840265 TI - Is it possible to reduce obstetrical brachial plexus palsy by optimal management of shoulder dystocia? AB - Obstetrical brachial plexus palsies (OBPP) have been historically attributed to the impaction of the fetal shoulder behind the symphysis pubis and to excessive lateral traction of the fetal head during maneuvers to deliver the fetal shoulders in shoulder dystocia. Shoulder dystocia is indeed a major risk factor as it increases the risk for OBPP 100-fold. The incidence of OBPP following shoulder dystocia varies widely from 4% to 40%. However, a significant proportion of OBPPs are secondary to in utero injury. The propulsive forces of labor, intrauterine maladaptation, and compression of the posterior shoulder against the sacral promontory as well as uterine anomalies are possible intrauterine causes of OBPP. Many risk factors for OBPP may be unpredictable. Early identification of risk factors for shoulder dystocia, as well as appropriate management when it occurs, may improve our ability to prevent the occurrence of OBPP in those cases that are caused by shoulder dystocia. PMID- 20840266 TI - Congenital cytomegalovirus infection. AB - Congenital cytomegalovirus (CMV) infection is a serious health problem. The obstacles for limiting this infection are the lack of public awareness on this issue, especially owing to the asymptomatic nature of CMV infections, the inefficacy of therapy, and the unsuccessful vaccine trials to date. It is therefore important to organize the current data to estimate the results and to report that the development of a vaccine against CMV must be of the highest priority. PMID- 20840267 TI - Fetal origins of the metabolic syndrome. AB - The natural history of metabolic syndrome and polycystic ovary syndrome (PCOS), which shares many components of metabolic syndrome, may originate in intrauterine life. Evidence from epidemiological observations, clinical, and experimental animal studies suggest that the nutritional, hormonal, and metabolic environment afforded by the mother may permanently program differentiating target tissues of the offspring toward the development of metabolic syndrome/PCOS phenotype in adult life. The mechanisms of fetal programming are not well understood. Thus, the altered tissue differentiation may be the result of fetal adaptive responses representing homeostatic adaptations due to alterations in fetal nutrition. Also, tissues under the influence of androgen excess may be directed toward a more masculine phenotype with regard to reproductive, neuroendocrine, and metabolic traits, while the importance of epigenetics in fetal origin of metabolic syndrome/PCOS cannot be overlooked. PMID- 20840268 TI - The impact of insulin resistance on woman's health and potential treatment options. AB - Insulin resistance (IR) is causatively related to metabolic syndrome and type 2 diabetes, both of which increase the risk of adverse cardiovascular events; in women in particular, severe IR affects the reproductive system causing subfertility and health problems to the mother and the fetus. To date lifestyle modification is the mainstay of treatment, whereas antiobesity drugs and bariatric surgery have been shown to improve insulin sensitivity and many surrogate metabolic defects, real reduction in cardiovascular endpoints has yet to be proved. Increasing attention is being directed to the role of the central nervous system in the modulation of IR, as well as to the use of recombinant adipocytokines for IR management. The scope of this article is to cast light on the detrimental effects of IR on metabolism and the body systems in women as well as to highlight the current therapeutic approach, drugs in progress, and future therapeutic perspectives. PMID- 20840269 TI - Diagnosis and management of hirsutism. AB - Hirsutism is a frequent medical complaint that usually results from relatively benign functional disorders including the polycystic ovary syndrome, which is the most frequent etiology. The essential tool for the diagnosis of hirsutism is a complete clinical history and physical examination, because functional causes begin peripubertally and progress slowly, whereas the very rare androgen secreting neoplasms have a sudden onset and a rapid progression of hirsutism, and usually associate clinical signs of virilization and defeminization. In all cases, diagnosis requires quantification of hirsutism using the modified Ferriman Gallwey score, measurement of circulating androgen concentrations, a detailed study of ovulatory function, and possibly an ovarian ultrasound. Treatment must consider not only amelioration of hirsutism but also treatment of the underlying etiology and of any metabolic associations. When caused by a functional disorder, treatment of hirsutism should be chronic and should include cosmetic as well as pharmacological interventions such as oral contraceptives and antiandrogens. For nonfunctional disorders, treatment should focus on solving the underlying etiology as hirsutism is usually responsive to the elimination of the source of androgen excess. PMID- 20840270 TI - Polycystic ovary syndrome in adolescence. AB - The definition of polycystic ovary syndrome in very young girls is complicated by the fact that many features typical of the syndrome can also be seen as physiological stages in the maturation of the hypothalamus-pituitary-ovarian axis. The role of reduced insulin sensitivity in the pathogenesis and evolution of the disorder has gained more importance over recent years: both elevated androgen levels and being overweight may influence the impairment of glucose metabolism. Our study focused on 250 girls in the first 8 years of gynecological age. We analyzed the prevalence of different phenotypes according to the Rotterdam criteria and the impact of higher BMI on androgen levels and on fasting screening markers of glucose metabolism. In a smaller sample, we performed a more detailed evaluation of the glucose metabolism parameters; our findings indicated that in this age group, being overweight plays a major role in the deterioration of the clinical picture. PMID- 20840271 TI - Peroxisome proliferator-activated receptor-gamma and -delta polymorphisms in women with polycystic ovary syndrome. AB - The aim of the study was to examine the frequency and relationship of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-delta gene polymorphisms to polycystic ovary syndrome (PCOS) characteristics. We conducted a case-control study protocol, which included 183 PCOS women and 148 healthy volunteers. Genetic, clinical, hormonal, and metabolic characteristics of PCOS patients and controls were estimated and compared. Genotype and allele frequencies did not differ significantly. The Pro(12) Ala polymorphism in exon 2 of the PPAR-gamma gene was found in low frequency. Regarding the polymorphism in exon 6, the T allele carrier PCOS women had significantly lower total testosterone levels. Regarding the +294T/C polymorphism in the exon 4 of the PPAR-delta gene, the C allele carrier PCOS women had significantly higher fasting glucose levels. In conclusion, the PPAR-gamma gene polymorphisms do not appear to affect the risk for PCOS, except for the reduced testosterone levels. The +294T/C polymorphism in the exon 4 of the PPAR-delta gene seems to cause an increase in fasting glucose levels. PMID- 20840272 TI - Metformin in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) affects 6.6-6.8% of women in reproductive age. Insulin resistance and hyperinsulinemia play a critical role in the pathogenesis of PCOS and are associated with a high risk for type 2 diabetes mellitus and cardiometabolic abnormalities. Metformin has been introduced as a therapeutic option in PCOS, targeting of cardiometabolic and reproductive abnormalities on the basis of its action on the reduction of glucose levels and the attenuation of insulin resistance. The tissue-specific actions of metformin as well as the molecular mechanisms involved in the liver, the muscle, the endothelium, and the ovary are elucidated in this review. The use of metformin in pregnant women with PCOS is another of its positive features. Overall, available data supports the therapeutic usefulness of metformin on cardiometabolic risk and reproduction assistance in PCOS women. PMID- 20840273 TI - Evidence-based management of poor ovarian response. AB - Poor ovarian response is not infrequent and represents one of the major therapeutic challenges in in vitro fertilization. Although several tests have been proposed, which aim at predicting poor response to ovarian stimulation, available data are conflicting regarding their accuracy and clinical usefulness. Even though several therapeutic approaches have been explored, a single effective strategy has not yet been established. One of the major limitations of interpreting the relevant literature is the wide variability in the definitions used for poor ovarian response. Regarding the interventions that have been proposed to improve the probability of pregnancy in poor responders, limited evidence from relevant randomized controlled trials suggests that addition of growth hormone during ovarian stimulation, as well as performing embryo transfer on day 2 instead of day 3, might be beneficial. Further randomized control trials are warranted to reliably determine which would be the best approach for treating poor ovarian response. PMID- 20840274 TI - Endometriosis and assisted reproduction techniques. AB - Endometriosis-associated infertility is poorly treatable with various forms of surgery. Therefore, assisted reproduction techniques (ARTs), such as controlled ovarian hyperstimulation, intrauterine insemination, or in vitro fertilization, are commonly used for endometriosis-associated infertility. Endometriosis impairs the efficacy of in vitro fertilization. There is no evidence that ovulation suppression before ART would enhance the efficacy of ART. Resection of minimal/mild endometriosis and/or restoration of the normality of pelvic anatomy may enhance the efficacy of ART, but aggressive ovarian surgery should be avoided, because it reduces the ovarian reserves and the likelihood of pregnancy after ART. The outcome of ART pregnancy is not affected by the history of endometriosis, but the presence of endometrioma may predispose to preterm birth or fetal growth retardation in ART-induced pregnancies. As a whole, infertility due to endometriosis is best treated with various forms of ART, and the earlier clinicians apply these techniques, the more likely pregnancy may ensue. PMID- 20840275 TI - Fertility drugs and ovarian cancer risk: a critical review of the literature. AB - There is evidence that medications used for ovarian stimulation and in vitro fertilization may be associated with ovarian cancer. In this review, we attempt to describe this relationship according to the most recent epidemiologic data and to present the possible mechanisms on the molecular level that could potentially explain this correlation. Currently there is no proven relationship between any type of ovarian cancer and drugs used for infertility treatment. Overall, infertile women have increased risk for ovarian malignancies. Nulligravidas that received treatment are at increased risk for ovarian malignancy as compared to women that conceived after treatment. More studies with the appropriate statistical power and follow-up time, as well as with better adjustment for confounding factors, which coexist in infertile patients, are required to evaluate accurately the long-term effects of these drugs and procedures. PMID- 20840276 TI - Cryopreservation of human genetic material. AB - Up-to-date cryopreservation is a central component of contemporary human-assisted reproduction and fertility preservation technologies. Presently, the preservation of seminal and testicular spermatozoa, embryos, and oocytes can be readily achieved with a high functional survival rate. Preservation of the ovarian cortex containing a greater number of female germ cells is an experimental procedure under extensive investigation in many centers. All these techniques are used for various purposes like optimization of assisted reproduction, provision of donor gametes, fertility preservation for cancer patients and aging women, and posthumous reproduction. Here, we present a comprehensive review of the various applications of gamete, embryo, and ovarian tissue cryopreservation and discuss their basic biological principles, practical applicability, and limitations. PMID- 20840277 TI - Update on the role of ovarian corticotropin-releasing hormone. AB - Corticotropin-releasing hormone (CRH) is a 41-amino acid peptide synthesized by neurons of the parvocellular and paraventricular hypothalamic nuclei. Central CRH is the principal regulator of the stress system influencing several systems in the brain and influenced by them. It activates the secretion of glucocorticoids and indirectly regulates the immune system and the immune response. Peripheral CRH is secreted by postganglionic sympathetic and unmyelinated sensory afferent neurons and has been identified in several peripheral tissues and organs, including those of the reproductive system (ovary, endometrium, placenta, and testis). In the human ovary, receptors are detected in thecal and stromal cells and in follicular fluid. Ovarian CRH regulates ovarian steroidogenesis and is involved in follicular maturation, ovulation, and luteolysis. In this concise review we briefly discuss the role of ovarian CRH in reproduction, emphasizing its role in oocyte maturation. PMID- 20840278 TI - The future of women's contraception: stakes and modalities. AB - The two main contraceptive methods are the combined pill and the intrauterine device. In several countries, sterilization is a commonly used alternative. The current goals of contraception remain to achieve effective, accessible, reversible, and well-tolerated birth control for everyone. Despite progress, these goals have not been reached. To achieve these goals, it is mandatory to create new hormonal combinations and to discover new contraceptive targets. Recent innovations associate the development of new progestogens, selective progesterone receptor modulators, and the creation of new contraceptive combinations. Other innovations involve the use of natural estrogens but also optimizing existing treatment regimens and doses, as well as the development of new methods of emergency contraception. Finally, a major step will be to invent an efficient contraceptive that carries the lowest possible risk associated with methods protecting against sexually transmitted diseases. In the future, in relation to progress in the fields of genomics, proteomics, and immunology, new methods of contraception will be developed. These methods will be more targeted and will eventually be nonhormonal and independent of sexual activity. PMID- 20840279 TI - Hormonal contraception in obesity, the metabolic syndrome, and diabetes. AB - The rate of obesity worldwide is currently at epidemic proportions. As part of obesity, the metabolic syndrome describes a clustering of metabolic abnormalities that increase the cardiovascular and diabetes risk. In particular, women from developing countries have diabetes in the reproductive age resulting in more pregnancies where both the mother and the fetus are at high risk. Consequently, use of safe and effective contraceptive methods is of paramount importance. Paradoxically, both obese and diabetic women are less likely to use contraception as compared to women of normal weight. Modern types of hormonal contraceptives are safe and provide important noncontraceptive benefits. The impact of obesity on drug pharmacokinetics may result in lower blood levels of steroid contraceptives that reduce their ability to prevent pregnancy, but the actual change is probably minimal. In women with uncomplicated diabetes, hormonal contraception should therefore be part of the highly needed preconception care and metabolic control. PMID- 20840280 TI - Estrogen therapy and Alzheimer's dementia. AB - Previous studies in postmenopausal women have reported that estrogen treatment (ET) modulates the risk for developing Alzheimer's disease (AD). It has recently been hypothesized that there may be a "critical period" around the time of menopause during which the prescription of ET may reduce the risk of developing AD in later life. This effect may be most significant in women under 49 years old. Furthermore, prescription of ET after this point may have a neutral or negative effect, particularly when initiated in women over 60-65 years old. In this paper, we review recent studies that use in vivo techniques to analyze the neurobiological mechanisms that might underpin estrogen's effects on the brain postmenopause. Consistent with the "critical period" hypothesis, these studies suggest that the positive effects of estrogen are most robust in young women and in older women who had initiated ET around the time of menopause. PMID- 20840281 TI - Menopause and sexuality: key issues in premature menopause and beyond. AB - Woman's sexuality encompasses sexual identity, sexual function, and sexual relationships. It is modulated throughout life by life and reproduction-related events, health, relationships, and sociocultural variables. The aging process and menopause are two potent contributors to female sexual dysfunction. The earlier the menopause, the more severe and complex the impact on sexuality is. The younger the woman, the less she realizes the different key goals of her life cycle (falling in love, having a satisfying sexual life, forming a stable couple, getting married, having a family) and the more pervasive the consequences on her sexual identity, sexual function, and sexual relationship can be. Premature menopause is an amplified paradigm of the complex impact menopause can have on women's and couple's sexuality. This paper will focus on biologically based sexual issues, namely desire, arousal, orgasm, and pain disorders, as well as key questions encountered in infertility. The concepts of "symptom inducer" and "symptom carrier" will also be addressed. PMID- 20840282 TI - Effectiveness of phytoestrogens in climacteric medicine. AB - The increased interest in phytoestrogens in the management of menopausal symptoms followed the publication of the Women's Health Initiative study. A wide-spread perception that these plant-derived compounds are equivalent to estrogen was established. These compounds evolved to fulfill the needs of plant physiological processes and are natural for the plant cells but not natural to the human cell. Epidemiological data suggest a possible protective effect of phytoestrogen if consumed during adolescence, but later on in life this effect is not clear. The utility of phytoestrogen as a "natural and safe" alternative to estrogen in alleviating vasomotor symptoms has failed the test in randomized clinical trials. Because many breast cancer sufferers seek in phytoestrogen a relief of estrogen deficiency symptoms, the possible interaction of such remedies with risk of recurrence of breast cancer or interference with tamoxifen action should not be overlooked. PMID- 20840283 TI - Is the decrease in breast cancer incidence related to a decrease in postmenopausal hormone therapy? AB - Following the Women's Health Initiative (WHI) publication in mid 2002, a drastic decrease in hormone therapy for postmenopausal women has been observed worldwide. Since 2007, the reported incidence in breast cancer has declined. Most authors have linked this decline to the reduction in hormone treatment. In this paper we discuss why these ecological observations are not fully convincing and focus on the importance of screening and variations in other risk factors to interpret this decline in breast cancer. PMID- 20840284 TI - Bone anabolic versus bone anticatabolic treatment of postmenopausal osteoporosis. AB - Increased bone fragility after menopause is commonly associated with accelerated bone loss and aggressive osteoclastic function. This is attributed to increased RANKL production and impaired osteoprotegerin synthesis. Fast bone loss leads to trabecular perforations, dramatic diminution of bone strength, and unexpected fractures. To avoid osteoporotic fractures, elimination of fast bone loss is recommended. Antiosteoclastic drugs, apart from estrogens, are the selective estrogen receptor modulators, calcitonins, and amino-bisphosphonates. These drugs increase bone mass by 1-5%, but reduce the relative risk of a vertebral fracture by 30-70%. Long-term exposure to bisphosphonates may be related to low bone turnover. In elderly and severe osteoporosis, antiosteoclastic regimens hardly correct the depressed osteoblastic function. Intermittent teriperatide stimulates osteoblastic function, improves bone geometry, and has an additional analgesic effect. While both anticatabolic and anabolic agents increase bone mass and decrease the risk of spinal fractures and occasionally of the fracture of the femoral neck, there are differences in the mode of their action. These pathophysiological differences are tentative therapeutic tools for the prevention of osteoporotic fractures. A fast bone loss, associated with increased biochemical markers, is the main indicator for anticatabolic agents, while impaired bone geometry, normal or low bone markers, and established bone architectural changes are in favor of the anabolic agents. Strontium ranelate combines the anticatabolic effect with an additional anabolic action. PMID- 20840285 TI - A comparison of palmar dermatoglyphics in two ethnic Indian populations of north Bengal, India. AB - Dermatoglyphic print comparisons can be utilized to establish personal identification in forensic cases. The northern part of the state of West Bengal, India, is the home to many ethnic populations. Two such populations are the Rajbanshi and the Mech. Palm prints were collected from 192 adult Rajbanshi (105 men and 87 women) and 100 adult Mech (50 men and 50 women) individuals for print comparison using the standard ink and roll print method. The dermatoglyphic variables studied were mainline formulae, termination of mainline, positional variation of axial triradii, and true pattern of hypothenar and thenar configuration area. There were differences between the Rajbanshi and Mech individuals with respect to these dermatoglyphic variables. The uses of these variables appear to be limited only to ethnic identification, not personal identification. The present investigation further highlights the racial affinity, sex, and bilateral differences among Rajbanshi individuals using dermatoglyphic palmar variables. PMID- 20840286 TI - Estimating the number of contributors to forensic DNA mixtures: does maximum likelihood perform better than maximum allele count? AB - Determining the number of contributors to a forensic DNA mixture using maximum allele count is a common practice in many forensic laboratories. In this paper, we compare this method to a maximum likelihood estimator, previously proposed by Egeland et al., that we extend to the cases of multiallelic loci and population subdivision. We compared both methods' efficiency for identifying mixtures of two to five individuals in the case of uncertainty about the population allele frequencies and partial profiles. The proportion of correctly resolved mixtures was >90% for both estimators for two- and three-person mixtures, while likelihood maximization yielded success rates 2- to 15-fold higher for four- and five-person mixtures. Comparable results were obtained in the cases of uncertain allele frequencies and partial profiles. Our results support the use of the maximum likelihood estimator to report the number of contributors when dealing with complex DNA mixtures. PMID- 20840287 TI - Effect of investigator disturbance in experimental forensic entomology: carcass biomass loss and temperature. AB - Often carrion decomposition studies are conducted using a single carcass or a few carcasses sampled repeatedly through time to reveal trends in succession community composition. Measurements of biomass and other abiotic parameters (e.g., temperature) are often collected on the same carcasses but are rarely a focal point of the studies. This study investigated the effects that repeated sampling during experiments have on the decomposition of carrion, measured as both gross biomass (carcass plus fauna) and net biomass (carcass only), on carcasses disturbed on every visit (with weighing only or also with the collection of fauna) and on carcasses disturbed only once. Each trial lasted at least 21 days, with samples taken in triplicate. Rat carcasses used in this study were placed in the field on the same day and either weighed on every visit or ignored until a given day. Internal and ambient air temperatures were recorded on each carcass at the time of sampling and on undisturbed carcasses using temperature loggers. The presence of succession fauna did not result in significant biomass loss on most days; however, there were individual days early in decomposition (days 3 through 6) when the succession fauna comprised a large portion of the gross biomass. With the exception of biomass loss by the emigration of maggots on days 4 and 5, neither repeated weighing of the carcasses nor repeated weighing and faunal sampling of the carcasses statistically affected the rate of biomass loss. Internal temperatures of carcasses sampled repeatedly were frequently 2-5 degrees C lower than those that had not been disturbed, and ambient temperatures differed significantly depending on the location of measurement device. Results indicate that methods used historically for biomass loss determination in experimental forensic entomology studies are adequate, but further refinements to experimental methodology are desirable. PMID- 20840288 TI - An STR melt curve genotyping assay for forensic analysis employing an intercalating dye probe FRET. AB - The most common markers used in forensic genetics are short tandem repeats (STRs), the alleles of which are separated and analyzed by length using capillary electrophoresis (CE). In this work, proof of concept of a unique STR genotyping approach has been demonstrated using asymmetric PCR and a fluorescence resonance energy transfer (FRET)-based hybridization analysis that combines fluorophore labeled allele-specific probes and a DNA intercalating dye (dpFRET) in a melt match/mismatch analysis format. The system was successfully tested against both a simple (TPOX) and a complex (D3S1358) loci, demonstrated a preliminary detection limit of <10 genomic equivalents with no allelic dropout and mixture identification in both laboratory-generated and clinical samples. With additional development, this approach has the potential to contribute to advancing the use of STR loci for forensic applications and related fields. PMID- 20840289 TI - Amussat's sign in hanging--A prospective autopsy study. AB - Amussat's sign is typically a transverse laceration of the intimal layer of carotid arteries described in cases of hanging. Subtotal laceration of the carotid artery is not strictly specific for hanging and can be also caused by blunt neck trauma, extreme overstretching, or whiplash-injuries. In a prospective autopsy study of 178 cases of hanging, Amussat's sign was found in 29 cases (a relative frequency of 16.1%). A statistically significant association between the occurrence of tears in the intimal layer of carotid arteries and the victims' age was discovered in the cases studied (the frequency increased with age; p<0.05). The occurrence of Amussat's sign was independent of gender, weight, completeness of the victim's body suspension, and position of the ligature knot on the neck. The study demonstrates the fact that the most probable cause of Amussat's sign is a combination of direct compression of the artery by the rope and indirect stretching because of the gravitational drag produced by the weight of the body. PMID- 20840290 TI - Quantitative MRI in isotropic spatial resolution for forensic soft tissue documentation. Why and how? AB - A quantification of T1, T2, and PD in high isotropic resolution was performed on corpses. Isotropic and quantified postmortem magnetic resonance (IQpmMR) enables sophisticated 3D postprocessing, such as reformatting and volume rendering. The body tissues can be characterized by the combination of these three values. The values of T1, T2, and PD were given as coordinates in a T1-T2-PD space where similar tissue voxels formed clusters. Implementing in a volume rendering software enabled color encoding of specific tissues and pathologies in 3D models of the corpse similar to computed tomography, but with distinctively more powerful soft tissue discrimination. From IQpmMR data, any image plane at any contrast weighting may be calculated or 3D color-encoded volume rendering may be carried out. The introduced approach will enable future computer-aided diagnosis that, e.g., checks corpses for a hemorrhage distribution based on the knowledge of its T1-T2-PD vector behavior in a high spatial resolution. PMID- 20840291 TI - A study of the human decomposition sequence in central Texas. AB - Decomposition studies utilizing nonhuman subjects as human analogues are well established, but fewer studies utilizing intact human remains exist. This study provides data from a controlled decomposition study involving human remains in Central Texas. A 63.5-kg unmodified cadaver was placed in an open-air site and observed over a 10-week period from April 11 through June 19, 2008. A wire enclosure restricted scavenger access. State of decomposition and environmental conditions were recorded daily for the first 36 days and then every 2 weeks thereafter. Results indicated a high degree of correlation with other decomposition studies originating in the southwestern United States, although slight deviations for the average duration of early events were noted. The data were also utilized to test a quantitative method for estimating the postmortem interval. Results indicated preliminary support for a quantitative approach. Additional research is encouraged to further establish the human decomposition data set for Central Texas. PMID- 20840292 TI - Discrimination of soils at regional and local levels using bacterial and fungal T RFLP profiling. AB - DNA profiling of microbial communities has been proposed as a tool for forensic comparison of soils, but its potential to discriminate between soils from similar land use and/or geographic location has been largely unexplored. We tested the ability of terminal restriction fragment length polymorphism (T-RFLP) to discriminate between soils from 10 sites within the Greater Wellington region, New Zealand, based on their bacterial and fungal DNA profiles. Significant differences in bacterial and fungal communities between soils collected from all but one pair of sites were demonstrated. In some instances, specific terminal restriction fragments were associated with particular sites. Patch discrimination was evident within several sites, which could prove useful for site-specific matching (e.g., matching shoe/car tire print to an object). These results support the need for further understanding of the spatial distribution of soil microbial communities before DNA profiling of soil microbial communities can be applied to the forensic context. PMID- 20840293 TI - Characterization of mitochondrial DNA sequence heteroplasmy in blood tissue and hair as a function of hair morphology. AB - This study characterizes mitochondrial DNA (mtDNA) sequence heteroplasmy in blood tissue and hair as a function of hair morphology. Bloodstains (127 individuals) and head hairs (128 individuals) were typed using the mtDNA LINEAR ARRAYTM assay. A total of 1589 hairs were interpreted: 1478 (93%) were homoplasmic and 111 (7%) exhibited heteroplasmy at one or more positions. Seventy-one percent (82/116) of individuals were homoplasmic, whereas 29% (34/116) exhibited heteroplasmy in at least one hair. The results demonstrate intra- and inter-tissue differences in heteroplasmy within individuals. Sequence heteroplasmy among hairs from each individual varied from 0 to 90%; the frequency does not differ significantly with population group, cosmetic treatment, age, gender, medulla morphology, region of the scalp, hair growth phase, or, when comparing living and deceased donors. However, the results support a correlation between heteroplasmy and hair pigmentation; typically, lighter-pigmented hairs exhibit a higher incidence of sequence heteroplasmy compared to darker hairs. PMID- 20840294 TI - Antidepressants at autopsy in Hispanic suicidal youth in Miami-Dade County, Florida. AB - Controversy has surrounded the use of antidepressants and suicidal behaviors in youth. This study reviewed the Medical Examiner's Office records of 253 persons aged 24 years or younger classified as suicides in Miami-Dade County, Florida, from 1990 to 2007. Information was collected regarding demographic information, suicidal characteristics, psychiatric and psychosocial factors, and toxicology results. Eighty-five percent of the sample was men, and 53.4% of the subjects were Hispanic. Consistent with previous literature, the existence of antidepressants at autopsy was rare; present in only 6% (n=15) of the victims. The occurrence of antidepressants was not significantly different between Hispanics (n=7) and non-Hispanics (n=8). The incidence of antidepressants was weakly correlated with a tendency to be men and no history of psychiatric illness. The presence of antidepressants in Hispanic youth suicide victims was similar to non-Hispanics. PMID- 20840295 TI - Comparison of decomposition rates and faunal colonization of carrion in indoor and outdoor environments. AB - Decomposition and insect colonization of pig (Sus scrofa L.) carcasses were observed over a 42-day period inside and outside a house in a suburban region of Edmonton, Alberta. Three freshly killed pig carcasses were placed outdoors on grass and three carcasses were placed in separate rooms inside a house in a suburban residential area. The carcasses were examined and sampled regularly. Outside carcasses were colonized rapidly by Calliphora vicina (R-D), Lucilia sericata (Meigen), Lucilia illustris (Meigen), Eucalliphora latifrons (Hough), Cynomya cadaverina (R-D), Phormia regina (Meigen), and Protophormia terraenovae (R-D). There was a delay of 5 days before inside carcasses were first colonized but all species except E. latifrons and L. illustris readily colonized at this time. Many more insects colonized the outside carcasses, and these were rapidly skeletonized. Inside, much fewer insects were present and decomposition was slowed and colonization extended. Dispersal patterns of postfeeding larvae inside the house on hard substrate were greatly expanded compared with those from carcasses on grass. PMID- 20840296 TI - Sexual dimorphism of the arm bones in a modern greek population. AB - Several studies have shown that sex determination methods based on measurements of the skeleton are population specific. Metric traits of the long bones of the arm have been reported as reliable indicators of sex. This study was designed to determine whether the three long bones of the arm can be used for sex determination on a skeletal population from Greece. The material used consists of the arm bones of 204 adult individuals (111 males and 93 females) coming from the Modern Human Skeletal Collection of the University of Athens. The age range is 19 96 years for males and 20-99 years for females. The maximum lengths and epiphyseal widths were measured in the long bones of the arm (humerus, radius, and ulna). The discriminant analysis of the metrical data of each long bone gave very high discrimination accuracies. The rate of correct sex discrimination based on different long bones ranges from 90.30% (ulna) to 95.70% (humerus). In addition, intra- and inter-observer error tests were performed. These indicated that replication of measurements was satisfactory for the same observer over time and between observers. The results of this study show that metric characteristics of the arm bones can be used for the determination of sex in skeletal remains from Greece and that bone dimensions are population specific. PMID- 20840297 TI - Neuritis of the cauda equina in a dog. AB - This study presents the first case report of neuritis of the cauda equina in a dog, including characterisation of the inflammatory infiltrate. The dog in question, a 6-year-old Welsh springer spaniel, was presented with flaccid tail and faecal and urinary incontinence. The histological lesions included severe mononuclear cell infiltration of the nerve roots of the cauda equina and of the lumbar nerve roots. The infiltrate was composed of large numbers of T-lymphocytes and B-lymphocytes and small numbers of macrophages. Polymerase chain reactions of brain and spinal tissues were positive for Neospora caninum. PMID- 20840298 TI - Postoperative analgesic efficacy of meloxicam compared to tolfenamic acid in cats undergoing orthopaedic surgery. AB - OBJECTIVES: To investigate the efficacy of meloxicam or tolfenamic acid administered preoperatively and postoperatively (five days in total) to cats undergoing surgical fracture repair. METHODS: Eighty-eight otherwise healthy cats were matched according to fracture site and then randomly allocated to one of two groups, receiving 0.2 mg/kg meloxicam by subcutaneous injection (group M) or 1.5 to 3 mg/kg tolfenamic acid orally (group T) before anaesthesia. Analgesia was continued with 0.05 mg/kg oral meloxicam once daily or 1.5 to 3 mg/kg oral tolfenamic acid twice daily for four days postoperatively. Pain was assessed by a blinded observer using visual analogue scales and a functional limb score. The drug administrator assessed feed intake and palatability of the treatment. RESULTS: Data from 66 cats were analysed. Visual analogue scale pain scores and functional limb scores decreased over time in both groups but were not significantly different between treatments. Feed intake was similar in both groups. Meloxicam was significantly more palatable than tolfenamic acid on all treatment days. CLINICAL SIGNIFICANCE: Meloxicam and tolfenamic acid demonstrated comparable analgesia, without clinically observable side effects. Meloxicam may be associated with superior compliance in clinical practice due to the higher palatability and once daily treatment resulting in better ease of administration. PMID- 20840299 TI - Predictors of clinical remission in cats with diabetes mellitus. AB - BACKGROUND: Clinical remission is frequent in cats with well-controlled diabetes mellitus, but few studies explored predictors of this phenomenon. HYPOTHESIS: Data retrieved from medical records at admission might be valuable to identify likelihood of remission and its duration in diabetic cats. ANIMALS: Ninety cats with newly diagnosed diabetes, followed-up until death or remission. METHODS: Retrospective cohort study. Data were collected from records at admission, including history, signalment, physical examination, haematology, and biochemical profile, and the occurrence and duration of remission, defined as normoglycemia without insulin for >=4 weeks. Predictors of remission were studied with univariate and multivariate logistic regression. Factors associated with remission duration were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Forty-five (50%) cats achieved remission, after a median time of 48 days (range: 8-216). By study end, median remission duration was 114 days (range: 30-3,370) in cats that died and 151 days (range: 28-1,180) in alive cats. Remission was more likely with higher age (OR: 1.23, 95% CI: 1.04-1.46; P=.01) and less likely with increased serum cholesterol (OR: 0.36, 95% CI: 0.11-0.87; P=.04). Remission was longer with higher body weight (HR: 0.65, 95% CI: 0.42 0.99; P=.04) and shorter with higher blood glucose (HR: 1.01, 95% CI: 1.00-1.02; P=.02). CONCLUSIONS AND CLINICAL IMPORTANCE: Age, body weight, cholesterol, and glucose levels are suggested for prediction of remission or its duration in diabetic cats. Older cats developing diabetes may have a better outcome, possibly suggesting a slower disease progression. PMID- 20840300 TI - Comparisons of 3-, 2-dimensional, and M-mode echocardiographical methods for estimation of left chamber volumes in dogs with and without acquired heart disease. AB - BACKGROUND: Real-time 3-dimensional echocardiography (RT3D) is a recent technique based on volumetric scanning, eliminating the need for geometric modeling of the cardiac chambers and minimizing the errors caused by foreshortened views. HYPOTHESIS: Estimations of left ventricular (LV) end-diastolic (EDV) and end systolic volume (ESV), and left atrial (LA) size, differ depending on the echocardiographic technique of estimation. ANIMALS: Fifty-one dogs with acquired heart disease and 34 healthy control dogs. METHODS: Prospective observational study by M-mode (Teichholz method), Simpson's modified 2-dimensional (2D) method, and RT3D methods for estimation of LV volumes. LA size was evaluated by 2D and RT3D methods. RESULTS: RT3D showed good agreement with 2D for EDV and ESV, whereas Teichholz method overestimated LV volumes in comparison with the other 2 methods by approximately a factor 2. There were no statistically significant differences among the 3 methods in estimating ejection fraction. Comparison between RT3D assessment of LA end-systolic volume per kilogram (LAs/kg) and LA to aortic ratio (LA/Ao) measured by 2D relative to each other showed that the RT3D method underestimated LAs/kg at lower values, and overestimated it at higher values. The difference between methods increased with increasing LA size. CONCLUSIONS AND CLINICAL IMPORTANCE: There was good agreement between RT3D and 2D methods of estimating EDV and ESV, whereas the Teichholz method overestimated LV volumes by approximately a factor 2. In comparison with RT3D, LA/Ao underestimated LA size, especially when LA was enlarged. PMID- 20840301 TI - The effects of illness on urinary catecholamines and their metabolites in dogs. AB - BACKGROUND: Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines currently are unknown. OBJECTIVES: To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. ANIMALS: Twenty-five critically ill dogs and 25 healthy age- and sex-matched control dogs. METHODS: Prospective observational study. Urine was collected from healthy and critically ill dogs, and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography with electrochemical detection. Urinary catecholamine and metanephrine:creatinine ratios were calculated and compared between groups. RESULTS: Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine:creatinine ratios were higher in critically ill dogs when compared with a healthy control population (P=.0009, P<0.0001, P<0.0001, and P<0.0001, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool; however, the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness. PMID- 20840302 TI - Concurrent diseases and conditions in dogs with splenic vein thrombosis. AB - BACKGROUND: Splenic venous thrombosis (SVT) is usually considered an incidental finding on abdominal ultrasound examination but can indicate the presence of underlying disease. Concurrent disease processes and conditions in dogs with SVT have not been identified previously. OBJECTIVES: To identify concurrent diseases and conditions in dogs with SVT. ANIMALS: Eighty dogs with SVT. METHODS: Retrospective review. Medical records from 1994 through 2008 were searched for dogs with SVT identified by ultrasound examination. These records were then reviewed for signalment, medical history, clinicopathologic testing, diagnostic imaging, and clinical diagnosis. RESULTS: The most common concurrent conditions were neoplasia (54%), exogenous corticosteroid administration (43%), systemic inflammatory response syndrome (26%), disseminated intravascular coagulation (20%), pancreatitis (18%), and immune-mediated disease (16%). The most common neoplastic disease was lymphoma, and the most common immune-mediated disease was immune-mediated hemolytic anemia. Protein-losing nephropathy and naturally occurring hyperadrenocorticism were identified in <10% of the dogs. Concurrent splenic infarcts were identified in 33% of dogs, and concurrent portal vein thrombi were found in 18% of dogs. CONCLUSIONS: SVT is a sonographic finding of clinical importance, and dogs with SVT can have 1 or more coexisting diseases. PMID- 20840303 TI - The influence of high-intensity moderate duration exercise on cardiac troponin I and C-reactive protein in sled dogs. AB - BACKGROUND: C-reactive protein (CRP) and cardiac troponin I (cTnI) are biomarkers of systemic inflammation and cardiac damage, respectively. OBJECTIVE: To investigate the effects of short-duration high-intensity exercise on plasma cTnI and serum CRP concentrations in sprint racing sled dogs. ANIMALS: Twenty-two Alaskan sled dogs of 2 different teams participating in a 2-day racing event. METHODS: In this prospective field study, cephalic venipuncture was performed on all dogs before racing and immediately after racing on 2 consecutive days. Plasma cTnI and serum CRP concentrations were evaluated at each time point. RESULTS: There was a mild, significant rise (P<.01) in median cTnI concentrations from resting (0.02 ng/mL; 0.0-0.12 ng/mL) on both days after racing (day 1=0.06, 0.02 0.2 ng/mL; day 2=0.07, 0.02-0.21 ng/mL). Serum CRP concentrations showed a mild significant increase (P<.01) on day 2 after racing mean (9.2+/-4.6 MUg/mL) as compared with resting (6.5+4.3 MUg/mL) and day 1 after racing (5.0+2.9 MUg/mL). Neither cTnI or CRP concentrations exceeded the upper reference range for healthy dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Strenuous exercise of short duration did not result in cTnI concentrations above the reference range for healthy dogs. Although increased after 2 days of short-duration strenuous exercise, CRP did not reach concentrations suggestive of inflammation, as reported previously in the endurance sled dogs. Therefore, we surmise that moderate exercise does not present a confounding variable in the interpretation of cTnI and CRP concentrations in normal dogs. PMID- 20840304 TI - Detection of congestive heart failure in dogs by Doppler echocardiography. AB - BACKGROUND: Echocardiographic prediction of congestive heart failure (CHF) in dogs has not been prospectively evaluated. HYPOTHESIS: CHF can be predicted by Doppler echocardiographic (DE) variables of left ventricular (LV) filling in dogs with degenerative mitral valve disease (MVD) and dilated cardiomyopathy (DCM). ANIMALS: Sixty-three client-owned dogs. METHODS: Prospective clinical cohort study. Physical examination, thoracic radiography, analysis of natriuretic peptides, and transthoracic echocardiography were performed. Diagnosis of CHF was based upon clinical and radiographic findings. Presence or absence of CHF was predicted using receiver-operating characteristic (ROC) curve, multivariate logistic and stepwise regression, and best subsets analyses. RESULTS: Presence of CHF secondary to MVD or DCM could best be predicted by E:isovolumic relaxation time (IVRT) (area under the ROC curve [AUC]=0.97, P<.001), respiration rate (AUC=0.94, P<.001), Diastolic Functional Class (AUC=0.93, P<.001), and a combination of Diastolic Functional Class, IVRT, and respiration rate (R2=0.80, P<.001) or Diastolic Functional Class (AUC=1.00, P<.001), respiration rate (AUC=1.00, P<.001), and E:IVRT (AUC=0.99, P<.001), and a combination of Diastolic Functional Class and E:IVRT (R2=0.94, P<.001), respectively, whereas other variables including N-terminal pro-brain natriuretic peptide, E:Ea, and E:Vp were less useful. CONCLUSION AND CLINICAL IMPORTANCE: Various DE variables can be used to predict CHF in dogs with MVD and DCM. Determination of the clinical benefit of such variables in initiating, modulating, and assessing success of treatments for CHF needs further study. PMID- 20840305 TI - Temporal variation in glucocorticoid levels during the resting phase is associated in opposite way with maternal and paternal melanic coloration. AB - Sex-dependent selection can help maintain sexual dimorphism. When the magnitude of selection exerted on a heritable sex trait differs between the sexes, it may prevent each sex to reach its phenotypic optimum. As a consequence, the benefit of expressing a sex trait to a given value may differ between males and females favouring sex-specific adaptations associated with different values of a sex trait. The level of metabolites regulated by genes that are under sex-dependent selection may therefore covary with the degree of ornamentation differently in the two sexes. We investigated this prediction in the barn owl, a species in which females display on average larger black spots on the plumage than males, a heritable ornament. This melanin-based colour trait is strongly selected in females and weakly counter-selected in males indicating sex-dependent selection. In nestling barn owls, we found that daily variation in baseline corticosterone levels, a key hormone that mediates life history trade-offs, covaries with spot diameter displayed by their biological parents. When their mother displayed larger spots, nestlings had lower corticosterone levels in the morning and higher levels in the evening, whereas the opposite pattern was found with the size of paternal spots. Our study suggests a link between daily regulation of glucocorticoids and sex-dependent selection exerted on sexually dimorphic melanin based ornaments. PMID- 20840306 TI - Limb-bone histology of temnospondyls: implications for understanding the diversification of palaeoecologies and patterns of locomotion of Permo-Triassic tetrapods. AB - The locomotion of early tetrapods has long been a subject of great interest in the evolutionary history of vertebrates. However, we still do not have a precise understanding of the evolutionary radiation of their locomotory strategies. We present here the first palaeohistological study based on theoretical biomechanical considerations among a highly diversified group of early tetrapods, the temnospondyls. Based on the quantification of microanatomical and histological parameters in the humerus and femur of nine genera, this multivariate analysis provides new insights concerning the adaptations of temnospondyls to their palaeoenvironments during the Early Permian, and clearly after the Permo-Triassic crisis. This study therefore presents a methodology that, if based on a bigger sample, could contribute towards a characterization of the behaviour of species during great evolutionary events. PMID- 20840307 TI - The adaptive value of gluttony: predators mediate the life history trade-offs of satiation threshold. AB - Animals vary greatly in their tendency to consume large meals. Yet, whether or how meal size influences fitness in wild populations is infrequently considered. Using a predator exclusion, mark-recapture experiment, we estimated selection on the amount of food accepted during an ad libitum feeding bout (hereafter termed 'satiation threshold') in the wolf spider Schizocosa ocreata. Individually marked, size-matched females of known satiation threshold were assigned to predator exclusion and predator inclusion treatments and tracked for a 40-day period. We also estimated the narrow-sense heritability of satiation threshold using dam-on-female-offspring regression. In the absence of predation, high satiation threshold was positively associated with larger and faster egg case production. However, these selective advantages were lost when predators were present. We estimated the heritability of satiation threshold to be 0.56. Taken together, our results suggest that satiation threshold can respond to selection and begets a life history trade-off in this system: high satiation threshold individuals tend to produce larger egg cases but also suffer increased susceptibility to predation. PMID- 20840308 TI - Evolutionary dynamics of mating system shifts in Arabidopsis lyrata. AB - Outcrossing is the prevalent mode of reproduction in plants and animals despite its substantial costs, while selfing and mixed mating occur at much lower frequency. Comparative research on plants has demonstrated the lability of self incompatibility, but there is little information about the transition on a within species level from self-incompatibility to predominant selfing. We studied variation in mating system among 18 populations of Arabidopsis lyrata within a phylogenetic context to shed light on the evolution of selfing. Realized and potential mating systems were assessed by genetic analysis with microsatellite markers and hand-self-pollinations on 30 plants from each population. The fraction of self-incompatible plants in a population was highly correlated with the outcrossing rate, showing that the spread of self-compatibility is accompanied by or soon followed by an increase in the rate of selfing. The four predominantly selfing populations (outcrossing rates <0.25) fell into more than one phylogenetic cluster, suggesting that the transition to selfing occurred more than once independently. Hence, A. lyrata offers an opportunity for the comparative analysis of outcrossing as a predominant mode of reproduction in plants and of the causes of the shift to selfing. PMID- 20840309 TI - The role of historical factors and natural selection in the evolution of breeding systems of Oxalis alpina in the Sonoran desert 'Sky Islands'. AB - Pleistocene climatic oscillations are known to influence the patterns of genetic diversity and the distribution of traits that are the target of selection. Here, we combine phylogeographical and ecological niche modelling (ENM) approaches to explore the influence of historical factors (Pleistocene climatic shifts) and natural selection on the evolution of distyly (two floral morphs) from tristyly (three floral morphs) of Oxalis alpina in the Sky Islands of the Sonoran Desert. Molecular data and ENM indicate that historical factors have had a strong influence on the genetic structure and the geographical distribution of reproductive systems of O. alpina. Moreover, genetic results suggest the possibility that distylous populations do not represent a monophyletic group. We propose that the combined effects of natural selection and genetic drift have influenced the tristyly-distyly transition. PMID- 20840310 TI - Fossils and phylogeny uncover the evolutionary history of a unique antipredator behaviour. AB - Recently, two squirrel species (Spermophilus spp.) were discovered to anoint their bodies with rattlesnake scent as a means of concealing their odour from these chemosensory predators. In this study, we tested multiple species with predator scents (rattlesnake and weasel) to determine the prevalence of scent application across the squirrel phylogeny. We reconstructed the evolutionary history of the behaviour using a phylogenetic analysis and fossil records of historic predator co-occurrence. Squirrels with historical and current rattlesnake co-occurrence all applied rattlesnake scent, whereas no relationship existed between weasel scent application and either weasel or rattlesnake co occurrence. This was surprising because experimental tests confirmed rattlesnake and weasel scent were both effective at masking prey odour from hunting rattlesnakes (the primary predator of squirrels). Ancestral reconstructions and fossil data suggest predator scent application in squirrels is ancient in origin, arising before co-occurrences with rattlesnakes or weasels in response to some other, now extinct, chemosensory predator. PMID- 20840311 TI - Symbiont-mediated phenotypic variation without co-evolution in an insect-fungus association. AB - Recent studies have shown that symbionts can be a source of adaptive phenotypic variation for their hosts. It is assumed that co-evolution between hosts and symbionts underlies these ecologically significant phenotypic traits. We tested this assumption in the ectosymbiotic fungal associate of the gall midge Asteromyia carbonifera. Phylogenetic analysis placed the fungal symbiont within a monophyletic clade formed by Botryosphaeria dothidea, a typically free-living (i.e. not associated with an insect host) plant pathogen. Symbiont isolates from four divergent midge lineages demonstrated none of the patterns common to heritable microbial symbioses, including parallel diversification with their hosts, substitution rate acceleration, or A+T nucleotide bias. Amplified fragment length polymorphism genotyping of the symbiont revealed that within-lineage genetic diversity was not clustered along host population lines. Culture-based experiments demonstrated that the symbiont-mediated variation in gall phenotype is not borne out in the absence of the midge. This study shows that symbionts can be important players in phenotypic variation for their hosts, even in the absence of a co-evolutionary association. PMID- 20840312 TI - Experimental test of a trade-off between moult and immune response in house sparrows Passer domesticus. AB - A trade-off between immune system and moulting is predicted in birds, given that both functions compete for resources. However, it is unclear whether such a trade off exists during post-breeding moult. This study tests such a trade-off in the house sparrow (Passer domesticus). Males injected with an antigen (lipopolysaccharide) significantly moulted slower than sham-injected males. Moreover, males whose seventh primaries were plucked to simulate moult showed smaller immune response to phytohaemagglutinin than control males, in which seventh primaries were clipped. A trade-off between moult speed and body mass was also found. The results show a clear trade-off between moult and immune response in the house sparrow: immune response negatively affected moult and moult negatively affected immune response. These findings suggest that only individuals in good condition may have an efficient moult and simultaneously respond effectively in terms of immunity to pathogens, which could explain how plumage traits honestly indicate parasite resistance in birds. PMID- 20840313 TI - Much more than a ratio: multivariate selection on female bodies. AB - Studies of the attractiveness of female bodies have focussed strongly on the waist, hips and bust, but sexual selection operates on whole phenotypes rather than the relative proportions of just two or three body parts. Here, we use body scanners to extract computer-generated images of 96 Chinese women's bodies with all traits unrelated to body shape removed. We first show that Chinese and Australian men and women rate the attractiveness of these bodies the same. We then statistically explore the roles of age, body weight and a range of length and girth measures on ratings of attractiveness. Last, we use nonlinear selection analysis, a statistical approach developed by evolutionary biologists to explore the interacting effects of suites of traits on fitness, to study how body traits interact to determine attractiveness. Established proxies of adiposity and reproductive value, including age, body mass index and waist-to-hip ratio, were all correlated with attractiveness. Nonlinear response surface methods using the original traits consistently outperform all of these indices and ratios, suggesting that indices of youth and abdominal adiposity tell only part of the story of body attractiveness. In particular, our findings draw attention to the importance of integration between abdominal measures, including the bust, and the length and girth of limbs. Our results provide the most comprehensive analysis to date of the effect of body shape and fat deposition on female attractiveness. PMID- 20840314 TI - Association of blood monocyte and lymphocyte count and disease-free interval in dogs with osteosarcoma. AB - BACKGROUND: Identification of biomarkers that predict outcomes in dogs with osteosarcoma (OSA) would be valuable to veterinarians and owners. Leukocyte numbers in peripheral blood are associated with outcomes in some types of cancer in humans. HYPOTHESIS/OBJECTIVES: We hypothesized that increased numbers of monocytes would be associated with reduced disease-free interval (DFI) in dogs with OSA. ANIMALS: Medical data from 69 dogs with appendicular OSA treated with amputation and chemotherapy were selected for study. METHODS: Retrospective study. Statistical associations were assessed by univariate and multivariate analysis. Information about DFI and leukogram values, tumor location, and serum alkaline phosphatase was abstracted from the medical record. RESULTS: Higher numbers of circulating monocytes (>0.4*10(3) cells/MUL) and lymphocytes (>1.0*10(3) cells/MUL) before treatment were found to be significantly (P<.05) associated with shorter DFI in dogs with OSA. Other parameters associated with poor outcomes were increased alkaline phosphatase, primary tumor location, and age. CONCLUSION AND CLINICAL IMPORTANCE: These results indicated that pretreatment evaluation of monocyte and lymphocyte counts provided prognostic information for dogs with appendicular OSA. Notably, most animals in this study had monocyte counts within the normal reference range, indicating that variations within the reference range of leukocyte values might also have prognostic significance. PMID- 20840315 TI - Cancer chemotherapy: an annotated history. AB - Treating cancer with drugs is an ancient art, but it is from discoveries made during and after the Second World War that real clinical success with cancer chemotherapy has occurred. Human and veterinary cancer chemotherapy have coevolved in the context of fascinating historical, political, and scientific events created by equally fascinating individuals. PMID- 20840316 TI - Spontaneous closure of a ventricular septal defect in a horse. PMID- 20840317 TI - Controversial technology: the Chunnel and the laparoscopic retroperitoneal lymph node dissection (RPLND). AB - * Laparoscopic retroperitoneal lymph node dissection (L-RPLND) was first introduced in 1992, initially as a staging procedure. * With advances in instrumentation and laparoscopic techniques, as well as improved understanding of laparoscopic anatomy, L-RPLND has developed to duplicate open RPLND. * Unlike the relatively rapid adoption of laparoscopy for other applications including nephrectomy and prostatectomy, L-RPLND has been slow to be universally accepted. * The limited numbers of patients requiring RPLND and technical challenges in performing the dissection have undoubtedly contributed to its delayed reception. * This review will present available data on this technique and discuss issues potentially inhibiting acceptance by traditional surgeons. PMID- 20840318 TI - Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial. AB - OBJECTIVES: To report the final analysis of a Phase II trial, which investigated the safety and efficacy of the specific endothelin A receptor antagonist zibotentan (AstraZeneca, Macclesfield, UK) in patients with metastatic castration resistant prostate cancer (CRPC). PATIENTS AND METHODS: Patients with CRPC and bone metastases who were pain free or mildly symptomatic for pain were randomized to receive once-daily oral tablets of zibotentan 10 mg, 15 mg or placebo. The primary endpoint was the time to progression and secondary endpoints included overall survival, change in the number of bone metastases, and safety. RESULTS: In total, 312 patients were randomized (placebo, n= 107; zibotentan 10 mg, n= 107; zibotentan 15 mg, n= 98). The median duration of study treatment and median follow-up time were 4 and 22 months, respectively. At the final analysis, there were no statistical differences of the primary outcome of time to progression between treatment groups, although an improvement in overall survival was observed in the zibotentan groups compared to placebo. Consistent with the previous analyses for overall survival, hazard ratios (HRs) of less than one were sustained for both zibotentan 15 mg (HR, 0.76; 80% CI, 0.61-0.94; P= 0.103) and 10 mg (HR, 0.83; 80% CI, 0.67-1.02; P= 0.254). The most commonly reported adverse events considered to be related to zibotentan treatment were peripheral oedema, headache and nasal congestion. CONCLUSIONS: The results obtained in the present study support endothelin A receptor antagonism as an approach for treating patients with CRPC. To confirm the survival signal observed in the present study, zibotentan is being investigated further in the ENdoTHelin A USE (ENTHUSE) Phase III clinical trial programme. PMID- 20840319 TI - A 'level playing field' for urological disorders. Who sets the rules? PMID- 20840320 TI - The 1-year outcome of the transobturator retroluminal repositioning sling in the treatment of male stress urinary incontinence. PMID- 20840322 TI - Laparoscopic varicocelectomy. PMID- 20840323 TI - Spontaneous closure of a recurrent myopic macular hole previously repaired by pars plana vitrectomy. PMID- 20840324 TI - Transforming growth factor beta-receptor II protein expression in benign prostatic hyperplasia is associated with prostate volume and inflammation. AB - OBJECTIVE: To assess transforming growth factor beta-receptor II (TGFBRII) protein expression in benign prostatic hyperplasia (BPH) using immunohistochemistry analysis, and to compare the analysis with phenotypic properties. METHODS: TGFBRII protein expression was profiled using three clinical outcome tissue microarrays (TMAs), sampled from 231 patients who underwent surgery for BPH. Using these TMAs, five inflammatory cell markers were also assessed, including CD3, CD4, CD8, CD20, and CD163. The surgical procedure was open prostatectomy in 95 patients and transurethral resection of the prostate in 136 patients. RESULTS: TGFBRII protein expression was found in BPH epithelium cells for both basal and secretory cells, as well as in fibromuscular stromal cells. TGFBRII staining was also strong in most of the lymphocytes infiltrating the prostate. TGFBRII stromal staining was found to be significantly associated with prostate volume (P = 0.04), whereas TGFBRII epithelial staining was found to be significantly associated with 5-alpha-reductase-inhibitor medical therapy received by patients before surgery (P = 0.004). Both stromal and epithelial TGFBRII staining were found to be associated with CD4 T-lymphocyte infiltrate, independently of prostate volume (P < 0.001 and P = 0.002). CONCLUSIONS: TGFBRII protein expression in BPH is associated with prostate gland volume and with CD4 T lymphocyte prostatitis. TGFBRII might be a promising therapeutic target to prevent prostate enlargement or even to decrease prostate volume. PMID- 20840325 TI - Microstructure and cytocompatibility of collagen matrices for urological tissue engineering. AB - OBJECTIVES: * To analyse the in vitro cytocompatibility of several engineered collagen-based biomaterials for tissue engineering of the urinary tract. * Tissue engineered implants for the reconstruction of the urinary tract are of major interest for urological researchers as well as clinicians. Although several materials have been investigated, the ideal replacement has still to be identified. MATERIALS AND METHODS: * Several collagen matrices were tested. * Electron microscopy was used to visualize the microstructure of the tested matrices. * Examination of cell attachment and growth of primary porcine urothelial and smooth muscle cells were performed and cell phenotypes were analysed using immunohistochemical stains. * Urea permeability was investigated using Ussing chamber experiments. RESULTS: * The best cytocompatibility for both urinary tract-specific cell types was obtained with OptiMaix((r)) (Matricel GmbH, Herzogenrath, Germany) materials. * Cell-specific phenotypes were maintained during culture as shown by immunohistochemical staining. * Furthermore, simultaneous cultivation of both cell types for 7 and 14 days significantly reduced urea permeability. CONCLUSION: * These results show the potential of OptiMaix materials in tissue engineering approaches of urinary tract tissues. PMID- 20840326 TI - Complications and conversions of upper tract urological laparoendoscopic single site surgery (LESS): multicentre experience: results from the NOTES Working Group. AB - Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Several studies have shown the feasibility of performing both complex and reconstructive laparoendoscopic single site (LESS) surgical procedures in urology. To date, no studies have evaluated the rates of conversion to conventional laparoscopy and complications at the time of LESS procedures in urology. This study, a compilation of results from members of the NOTES working group, is the first study to address the rates of complications and conversions to conventional laparoscopy at the time of LESS surgery in urology. OBJECTIVE: * To present complications and rates of conversion from LESS to conventional laparoscopy (CL) at the time of upper tract LESS urologic procedures. PATIENTS AND METHODS: * Patients undergoing LESS upper tract procedures between September, 2007 and November, 2008 (n = 125) were identified at six high-volume academic centers pioneering urologic LESS procedures. All LESS procedures were performed transperitoneally via a single umbilical incision using either adjacent conventional trocars or a dedicated single-site access device. Reconstructive procedures incorporating a single planned 2 mm accessory needle port were included as LESS procedures and were not considered conversions. * Patients, undergoing LESS procedures requiring conversion to CL with the placement of additional ports were identified. Conversion was defined as the placement of additional 5 or 10/12 mm ports beyond the primary incision. In each case the operative reports were reviewed, the reason for conversion was determined, and the number and types of additional ports and complications were noted. RESULTS: * Upper tract LESS procedures were performed in 125 patients comprising 13.3% of the total 937 laparoscopic procedures performed at the participating institutions during this time period. Conversion to CL was necessary in 7 patients (5.6%) undergoing LESS requiring the addition of 2-5 ports. * Reasons for conversion included: facilitate dissection in 3 (43%), facilitate reconstruction in 3 (43%), and control of bleeding in 1 (14%). All attempted LESS cases were completed laparoscopically without need for open conversion. * Complications occurred in 15.2% of patients undergoing LESS surgery. Three of the 7 patients that required conversion to CL developed postoperative complications (Clavien grade II in two and IIIa in one). * Limitations of this study included the inability to standardize LESS patient selection criteria, instrumentation and surgical technique as well as the lack of available complete data from a CL control group for comparison. CONCLUSION: * LESS surgery is technically feasible for a variety of upper urinary tract reconstructive and ablative procedures, although it appears to be associated with higher rates of complications than in mature CL series. Conversion to CL occurs infrequently and may be a reflection of stringent patient selection. PMID- 20840327 TI - Emphysematous pyelonephritis. AB - Emphysematous pyelonephritis (EPN) is a severe necrotizing infection of the renal parenchyma. The clinical course of EPN can be severe and life-threatening if not recognized and treated promptly. Most of the information has been from case reports, a few large series have also been reported. Using an evidence-based approach, this review describes the pathogenesis, classification, complications, and management of EPN. Emphysematous pyelonephritis (EPN) is an acute severe necrotizing infection of the renal parenchyma and its surrounding tissues that results in the presence of gas in the renal parenchyma, collecting system, or perinephric tissue. The cause for mortality in EPN is primarily due to septic complications. Up to 95% of the cases with EPN have underlying uncontrolled diabetes mellitus. The risk of developing EPN secondary to a urinary tract obstruction is about 25-40%. There are three classifications of EPN based on radiological findings. Acute renal failure, microscopic or macroscopic haematuria, severe proteinuria are other positive findings in EPN. Escherichia coli is the most common causative pathogen with the organism isolated on urine or pus cultures in nearly 70% of the reported cases. A plain radiograph shows an abnormal gas shadow in the renal bed raising the suspicion whereas an ultrasound scan or computed tomography (CT) will confirm the presence of intra-renal gas thus supporting the diagnosis of EPN. Gas may extend beyond the site of inflammation to the sub capsular, perinephric and pararenal spaces. In some cases, gas was found to be extending into the scrotal sac and spermatic cord. Subsequent case studies have shown patients being successfully treated with PCD when used in addition to medical management, with significant reduction in the morality rates. PCD should be performed on patients who have localized areas of gas and functioning renal tissue is present. The treatment strategies include MM alone, PCD plus MM, MM plus emergency nephrectomy, and PCD plus MM plus emergency nephrectomy. In small proportion of patients managed with MM and PCD, subsequent nephrectomy will be required and in these patients the reported mortality is 6.6% Nephrectomy in patients with EPN can be simple, radical or laparoscopic. PMID- 20840328 TI - Association of steroid and xenobiotic receptor (SXR) and multidrug resistance 1 (MDR1) gene expression with survival among patients with invasive bladder carcinoma. AB - What's known on the subject? and What does the study add? SXR and MDR1 are known as responsible for chemo and radiotherapy resistance in some cancers, like kidney cancer (MDR1). Invasive bladder cancer is an aggressive disease, with different behaviour upon its tumoral stage, and also within the same tumoral stage, therefore molecular markers are sought. This study shows a new molecular marker, which has shown as a predictor for bad prognosis cancers, therefore, allowing us for a better patient selection for aggressive therapies. OBJECTIVE: To investigate the prognostic value of steroid and xenobiotic receptor (SXR) and multidrug resistance 1 (MDR1) gene expression in relation to survival among patients with invasive bladder cancer. PATIENTS AND METHODS: The prospective study included 67 patients diagnosed with invasive bladder cancer and treated with radical cystectomy at one of two institutions. SXR and MDR1 gene expression was assessed by real-time quantitative polymerase chain reaction (RT-PCR) in tumoral and normal tissue from frozen surgical specimens. RESULTS: Patients were followed for a mean of 29 months; 31 patients (46%) had progression. In univariate analysis, significant predictors of overall survival (OS) were pathological stage, lymph node (LN) status, histological grade, vascular lymphatic invasion, and SXR expression. In multivariate analysis, independent predictors of OS were LN status (odds ratio [OR], 2.96; P=0.034), vascular lymphatic invasion (OR, 2.50; P=0.029), and SXR expression (OR, 1.05, P=0.03). Among the 51 patients with negative LNs (pN0), univariate predictors of OS were SXR expression, MDR1 expression, and pathological stage. In multivariate analysis, SXR expression (OR, 1.06; P=0.01) and MDR1 expression (OR, 3.27; P=0.03) were independently associated with survival. Within the pN0 group, patients with SXR expression had shorter progression-free survival than did those without expression (P=0.004). This association persisted in the N0 subgroup with stage pT3-pT4 disease (P=0.028). However, in the pN1 group SXR expression did not have any influence. CONCLUSIONS: For patients with invasive bladder cancer, SXR expression has value as a predictor of survival independent of the standard pathological predictors. Its maximum importance appears to be in patients with stage pT3-pT4 pN0 disease. PMID- 20840329 TI - Serial analysis of resected prostate cancer suggests up-regulation of type 1 IGF receptor with disease progression. AB - OBJECTIVE: * To compare immunostaining protocols using different antibodies for the type 1 insulin-like growth factor receptor (IGF-1R) in channel transurethal resection of the prostate (chTURP) chips, and to investigate how IGF-1R expression varies with time in serial prostate cancer specimens from individual patients. METHODS: * We studied IGF-1R expression in 44 prostate cancer specimens from 18 patients who had undergone serial chTURP at least 3 months apart. * Retrospective analysis of the hospital notes was undertaken to obtain clinical information, including age, Gleason score, prostate-specific antigen (PSA) level, hormone treatment and metastatic disease status at the time of each operation. * After an optimization process using three commercially-available IGF-1R antibodies, we used two antibodies for semiquantititve immunostaining of serial chTURP chips. RESULTS: * Santa Cruz antibody sc713 gave positive staining in IGF 1R null R- cells, and was not used further. Antibodies from Cell Signaling Technology (Beverly, MA, USA) (CS) and NeoMarkers Inc. (Fremont, CA, USA) (NM) did not stain R- cells and, in prostate tissue, showed staining of the glandular epithelium, with negligible stromal staining. All 44 chTURP samples contained identifiable malignant tissue and, of these, 73% and 64% scored moderately or strongly (score 3 or 4) with the CS and NM antibodies respectively. * There was significant correlation of IGF-1R scores of malignant tissue between the two antibodies (P < 0.001). By contrast, staining of benign glands showed poor correlation between antibodies: CS gave significantly weaker staining than malignant epithelium in the same sections (P < 0.001), whereas NM showed poor discrimination between malignant and benign glands. IGF-1R staining scores generated by the CS antibody were used to analyze the clinical data. * Most patients (six of seven) with falling IGF-1R staining scores were responding to androgen deprivation therapy (confirmed by PSA response) between operations. Conversely, in seven of eight patients who had progression to androgen independence between procedures, IGF-1R levels increased or remained high. Finally, seven of 11 patients who developed radiologically confirmed metastases between procedures showed stable or increasing IGF-1R staining scores. CONCLUSION: * The present study is the first to assess changes in IGF-1R expression in serial prostate cancer samples. The results obtained indicate that IGF-1R expression usually remains high throughout the course of histologically proven disease progression in serial specimens, suggesting that the IGF-1R remains a valid treatment target for advanced prostate cancer. PMID- 20840330 TI - Re: Basal cell carcinoma with perineural invasion: reexcision perineural invasion? PMID- 20840331 TI - Endpoints of hepatitis B treatment. AB - The goal of hepatitis B treatment is to prevent the development of cirrhosis, liver failure, and hepatocellular carcinoma. Ideally, clinical studies should demonstrate that hepatitis B therapies can prevent liver-related complications; however, these clinical endpoints evolve over years or decades. Therefore, clinical trials have relied on intermediate endpoints to evaluate the efficacy of treatment and to determine when treatment can be stopped. Intermediate endpoints that have been used include biochemical, histological, virological, and serological endpoints. This review will discuss the validity of these intermediate endpoints as surrogates of clinical endpoints, and the rates at which these intermediate endpoints can be achieved with currently available therapies. PMID- 20840332 TI - The effect of changes in thyroxine and thyroid-stimulating hormone levels on the coagulation system. PMID- 20840333 TI - Cephalosporin and fluoroquinolone combinations are highly associated with CTX-M beta-lactamase-producing Escherichia coli: a case-control study in a French teaching hospital. AB - The aim of this study was to investigate the risk factors associated with CTX-M producing Escherichia coli strains isolated from infected or colonized patients. From 191 clinical samples, a case-control study was designed. From January 2005 to December 2007, 98 hospitalized patients infected or colonized with CTX-M producing E. coli were included in the study. They were matched 1 : 1 with controls that had a non-CTX-M-producing E. coli infection on the basis of the site of sample, the unit of hospitalization and the time at risk. The rate of CTX M-producing E. coli among those producing extended spectrum beta-lactamases was always >=90% from 2005 to 2008. All strains were susceptible to carbapenems. However, we observed a high rate of co-resistance to ciprofloxacin (61%), sulphonamides (86%) and gentamicin (34%). Significant risk factors identified by multivariate analysis were recurrent infections (OR = 2.93), presence of artificial nutrition (OR = 3.99), and recent exposure to quinolones (OR = 4.39), third- or fourth-generation cephalosporin (OR = 3.49) and the combination of both antibiotic classes (OR = 5.50). This report highlights the dramatic increase of CTX-M-producing E. coli and the need for changes in the use of antimicrobial drugs and in infection control measures to manage this major health concern. PMID- 20840335 TI - Brain activation patterns associated with cue reactivity and craving in abstinent problem gamblers, heavy smokers and healthy controls: an fMRI study. AB - Abnormal cue reactivity is a central characteristic of addiction, associated with increased activity in motivation, attention and memory related brain circuits. In this neuroimaging study, cue reactivity in problem gamblers (PRG) was compared with cue reactivity in heavy smokers (HSM) and healthy controls (HC). A functional magnetic resonance imaging event-related cue reactivity paradigm, consisting of gambling, smoking-related and neutral pictures, was employed in 17 treatment-seeking non-smoking PRG, 18 non-gambling HSM, and 17 non-gambling and non-smoking HC. Watching gambling pictures (relative to neutral pictures) was associated with higher brain activation in occipitotemporal areas, posterior cingulate cortex, parahippocampal gyrus and amygdala in PRG compared with HC and HSM. Subjective craving in PRG correlated positively with brain activation in left ventrolateral prefrontal cortex and left insula. When comparing the HSM group with the two other groups, no significant differences in brain activity induced by smoking cues were found. In a stratified analysis, the HSM subgroup with higher Fagerstrom Test for Nicotine Dependence scores (FTND M = 5.4) showed higher brain activation in ventromedial prefrontal cortex, rostral anterior cingulate cortex, insula and middle/superior temporal gyrus while watching smoking-related pictures (relative to neutral pictures) than the HSM subgroup with lower FTND scores (FTND M = 2.9) and than non-smoking HC. Nicotine craving correlated with activation in left prefrontal and left amygdala when viewing smoking-related pictures in HSM. Increased regional responsiveness to gambling pictures in brain regions linked to motivation and visual processing is present in PRG, similar to neural mechanisms underlying cue reactivity in substance dependence. Increased brain activation in related fronto-limbic brain areas was present in HSM with higher FTND scores compared with HSM with lower FTND scores. PMID- 20840337 TI - Specific protein content of pools of plasma for fractionation from different sources: impact of frequency of donations. AB - BACKGROUND AND OBJECTIVES: Plasma pools for the production of human plasma medicinal products are distinguished according to the collection method (recovered or apheresis plasma) and the donor remuneration status. National regulations and the physical status of the donor determine the donation frequency and plasma volume per session. Relevant protein contents of different types of pools have not fully been compared. MATERIALS AND METHODS: We compared the levels of total protein, 15 main relevant plasma protein markers, and anti-B19 and anti Streptococcus pneumoniae IgG in single-type pools of donations from different countries (Belgium, Finland, France, the Netherlands, Germany, United States). Both recovered plasma from non-remunerated donors and apheresis plasma from remunerated and non-remunerated donors were studied. RESULTS: Pools from paid US high-frequency, high-volume plasmapheresis donors showed significantly lower total protein (-9%), albumin (-15%), total IgG (-24%), IgM (-28%), hemopexin ( 11%) and retinol-binding protein (-10%) but higher C1-inhibitor, pre-albumin and C-reactive protein contents than pools from unpaid European Union (EU) or US whole-blood or plasmapheresis donors. In contrast to pools from compensated EU plasmapheresis donors, pools from unpaid whole-blood or plasmapheresis donors showed no significant differences, whatever the collection method or country. Reductions in specific protein contents correlated well with protein half-life. CONCLUSION: These results should be taken into account with regard to donor health management and protein recovery. PMID- 20840338 TI - The effect of prion reduction in solvent/detergent-treated plasma on haemostatic variables. AB - BACKGROUND: Octapharma PPGmbH has recently modified its manufacturing process for solvent/detergent-treated plasma to incorporate a prion reduction step, in which a 3 log reduction has been demonstrated. The current study was undertaken to assess the impact of this procedure on haemostatic variables in the new product OctaplasLG in comparison with standard Octaplas. METHODS: Production batches of standard Octaplas (n=4) and OctaplasLG (n=16) were assessed for levels of coagulation factors, physiological protease inhibitors, markers of activation and procoagulant microparticles. Global haemostasis was assessed by a thrombin generation test (TGT) and rotational thromboelastometry (ROTEM). RESULTS: Mean levels of factors: II, V, VII, IX, X, XI, XII and XIII, VWF:Ag, antithrombin, protein C and free protein S were all >75 u/dl. ADAMTS-13 activity levels were normal. Factor VIII and VWF:RCo were >55 u/dl. TGT and ROTEM were similar in both preparations, and microparticles were present at negligible levels. Two units of OctaplasLG had slightly elevated levels of Prothrombin Fragments 1+2, but D-Dimer and thrombin-antithrombin complexes were normal in all batches. CONCLUSION: These studies indicate that the affinity chromatography procedure used in OctaplasLG does not appear to adversely affect the proven haemostatic quality of Octaplas, while offering a selective reduction in the concentration of pathological prion proteins. PMID- 20840339 TI - Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. AB - BACKGROUND: Fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC) reverse oral anticoagulants. We compared PCC and FFP intraoperative administration in patients undergoing heart surgery with cardiopulmonary bypass (CPB). METHODS: Forty patients [with international normalized ratio (INR)>= 2.1] assigned semi-urgent cardiac surgery were randomized to receive either FFP (n = 20) or PCC (n = 20). Prior to CPB, they received either 2 units of FFP or half of the PCC dose calculated according to body weight, initial INR and target INR ( <= 1.5). After CPB and protamine administration, patients received either another 2 units of FFP or the other half PCC dose. Additional doses were administered if INR was still too high ( >= 1.5). RESULTS: Fifteen minutes after CPB, more patients reached INR target with PCC (P = 0.007): 7/16 patients vs. 0/15 patients with FFP; there was no difference 1 h after CPB (6/15 patients with PCC vs. 4/15 patients with FFP reached target). Fifteen minutes after CPB, median INR (range) decreased to 1.6 (1.2-2.2) with PCC vs. 2.3 (1.5-3.5) with FFP; 1 h after CPB both groups reached similar values [1.6 (1.3-2.2) with PCC and 1.7 (1.3-2.7) with FFP]. With PCC, less patients needed additional dose (6/20) than with FFP (20/20) (P < 0.001). Both groups differed significantly on the course of factor II (P = 0.0023) and factor X (P = 0.008) over time. Dilution of coagulation factors was maximal at CPB onset. Safety was good for both groups, with only two related oozing cases with FFP. CONCLUSION: PCC reverses anticoagulation safely, faster and with less bleeding than FFP. PMID- 20840340 TI - Red-blood-cell alloimmunization and female sex predict the presence of HLA antibodies in patients undergoing liver transplant. AB - BACKGROUND: Refractoriness to platelet transfusion because of HLA antibodies can jeopardize the outcome of patients who require platelet support during surgery. As routine screening for HLA antibodies would pose a huge burden on presurgical work-ups, a stratification of patients according to the risk of having HLA antibodies is warranted. STUDY DESIGN AND METHODS: Clinical and laboratory data from 1351 patients submitted to liver transplant were analyzed to determine the accuracy of RBC alloimmunization and other patient features to predict the concomitant presence of HLA antibodies. Predictive variables were selected through binary logistic regression and their accuracy to prognosticate HLA alloimmunization was calculated by contingent table methods. RESULTS: RBC and HLA antibodies were detected in 70 (5.2%) and 71 (5.3%) patients, respectively. Female sex and RBC alloimmunization were the only patient features associated with HLA aloimmunization. Risk of being HLA immunized increased from male patients without RBC antibodies (n = 842; 1.5% with HLA antibodies) to female patients with RBC alloimmunization (n = 36, 36.2% with HLA antibodies), being of 9.7% in the remaining 473 patients. In women, the positive and negative predictive values of RBC alloimmunization to prognosticate HLA alloimmunization were 36% and 90%, respectively. In male patients, such values were 12% and 99%, respectively. The incidence of HLA immunization decreased after the introduction of universal leukoreduction in 2002. CONCLUSIONS: RBC alloimmunized female patients that may require platelet support during liver transplant should be preoperatively evaluated for HLA antibodies. Such evaluation is unnecessary in male patients without detectable RBC antibodies. Decision-making in the remaining patients must be individualized. PMID- 20840341 TI - Adverse reactions during transfusion of thawed haematopoietic progenitor cells from apheresis are closely related to the number of granulocyte cells in the leukapheresis product. AB - BACKGROUND AND OBJECTIVES: The infusion of thawed haematopoietic progenitor cells from apheresis (HPC-A) is associated with minor but frequent adverse reactions (ARs), which has been mainly attributed to dimethyl sulphoxide (DMSO). Nevertheless, other factors may play a role in the pathogenesis of such toxicity. MATERIALS AND METHODS: The ARs on a cohort of 423 cryopreserved HPC-A infusions for 398 patients in HPC transplantation program were analysed. RESULTS: ARs were reported in 105 graft infusions (24.8%) and most of them were graded as mild to moderate. The most frequently reported ARs were gastrointestinal and respiratory, and three patients presented epileptic seizure. The volume of DMSO/kg (P < 0.001), volume of red-blood-cells/kg (P = 0.02), number of nuclear cells (NCs)/kg (P <0.001) and number of granulocytes/kg (P<0.001) in the infused graft were significant in the univariate analysis for the occurrence of ARs. The amount of granulocytes/kg remained significant in the multivariate analysis (P<0.001). The grade of ARs also correlated with the amount of cryopreserved granulocytes. CONCLUSION: The incidence and grade of ARs during infusion of cryopreserved HPC-A are related to the amount of granulocytes in the graft. PMID- 20840342 TI - Scalp neurofibromas associated with bone dysplasia. PMID- 20840343 TI - Different phenotypes of segmental vitiligo based on a clinical observational study. AB - BACKGROUND: Segmental vitiligo and generalized vitiligo are in general considered separate entities. However, clinico-epidemiological data on segmental vitiligo are scarce compared with those of generalized vitiligo. OBJECTIVE: To analyse the clinical profile and distribution pattern of lesions in segmental vitiligo patients. METHODS: Segmental vitiligo patients were examined and questioned in a prospective and retrospective setting. The distribution and extent of the lesions were evaluated using clinical photographs. RESULTS: Different phenotypes of segmental vitiligo were found, including the unilateral segmental type (124 patients; group 1), the bilateral segmental type (three patients; group 2) and the mixed segmental and generalized type (14 patients; group 3). Furthermore, lesions were present with (10%) or without associated halo naevi. The age of onset of segmental vitiligo (median 14years) was significantly different between the three subgroups (P=0.028). Extensive involvement of segmental vitiligo lesions on trunk and extremities was significantly (P=0.031) more observed in patients with a lower age of onset, while the generalized vitiligo lesions in the mixed vitiligo group were mostly very mild. Associated autoimmune diseases were reported in 11%, whereas a positive family history for vitiligo was present in 14.9% of patients. Lesions were not strictly dermatomal nor Blaschkolinear, although a typical recurring pattern could be observed. CONCLUSION: Our data provide clinical evidence that segmental vitiligo and generalized vitiligo are parts of the same disease spectrum and that segmental vitiligo could have a polygenetic background as well. Whether different aetiopathological mechanisms underlie the different clinical phenotypes of segmental vitiligo remain to be elucidated. PMID- 20840344 TI - Acne on an area of post-traumatic neuralgia: an instance of immunocompromised district. PMID- 20840345 TI - Comparative trial of moisturizer containing licochalcone A vs. hydrocortisone lotion in the treatment of childhood atopic dermatitis: a pilot study. AB - BACKGROUND: Although moisturizer usage has been considered a mainstay of treatment for atopic dermatitis (AD) patients, few clinical studies have been investigated. Recently, moisturizers containing non-steroidal anti-inflammatory agents, such as licochalcone A (LA) and vitamin B(12) are of emerging interest. OBJECTIVE: To compare the effectiveness of moisturizer containing LA with hydrocortisone (HC) lotion in treatment of childhood AD. Methods The randomized, controlled, investigator-blinded 6-week study was conducted. Patients were administered with twice-daily application of LA lotion on one side of the body and HC lotion on the opposite side. The clinical outcome was assessed by the scoring of atopic dermatitis (SCORAD) index. The relapse rate was comparatively analysed by survival analysis. RESULTS: From 30 patients enrolled, 26 patients completed the protocol. The mean age of the children was 5.8 years. The average baseline SCORAD score is about 28 on both sides. The response rates of both agents were equal to 73.33%. There is no statistical significant group difference in reduction of SCORAD score. Although we observed more rapid resolution of oedema and erythema in areas treated with HC lotion, both agents exhibited no significant difference. The relapse rate of HC group was higher than in LA group; however, there was no significant difference. No side-effect was observed from both agents. CONCLUSION: The effectiveness of LA lotion is equal to that of HC lotion. It was suggested that moisturizer containing LA could be used both for treatment of acute and maintenance phase in mild-to-moderate childhood AD. PMID- 20840346 TI - Psoriasis and non-alcoholic fatty liver disease. AB - Several recent studies have found an increased prevalence of non-alcoholic fatty liver disease within psoriasis patients. The exact pathophysiological mechanisms behind these observations are unclear, but are likely related to the high prevalence of obesity and metabolic syndrome within this patient population. Chronic inflammation, mediated by either proinflammatory adipokines or skin derived cytokines, may contribute to fatty liver disease development by increasing insulin resistance which in turn promotes hepatic lipid accumulation. These same adipokines in addition to hepatic cytokines may act on the skin to influence psoriasis disease severity. PMID- 20840347 TI - A randomized clinical trial in psoriasis: synchronous balneophototherapy with bathing in Dead Sea salt solution plus narrowband UVB vs. narrowband UVB alone (TOMESA-study group). AB - BACKGROUND: Synchronous balneophototherapy (sBPT) simulates treatment conditions at the Dead Sea for outpatient use. In the past, sBPT proved to be an effective treatment for psoriasis. However, there is a lack of sufficiently large randomized controlled clinical trials evaluating the additional benefit of sBPT compared with ultraviolet B (UVB) monotherapy. OBJECTIVES: The purpose of this study was to compare the effectiveness and safety of sBPT with UVB phototherapy (PT) alone in a randomized controlled effectiveness study. METHODS: In this phase III, multicentre effectiveness study, 367 patients with moderate to severe psoriasis were randomly allocated in a 1 : 1 ratio to receive either sBPT consisting of narrowband UVB PT with 311 nm and synchronous bathing in 10% Dead Sea salt solution or PT with 311 nm alone. Primary endpoint, analysed on an intention-to-treat basis (n = 356), was the relative improvement of the Psoriasis Area and Severity Index (PASI) from baseline to end of treatment (35 sessions or clearance). Sample size calculation aimed at the detection of superiority of at least 10%. RESULTS: Median PASI values were comparable at baseline (sBPT: 15.1, interquartile range: 10.9-24.3; PT: 15.3, interquartile range: 10.0-23.7). A clinically relevant and statistically significant difference of 49.5% between sBPT and PT could be proven at the end of the therapy phase (P < 0.001; Wilcoxon Mann-Whitney test). Exploratory testing showed a statistically significant superiority of sBPT after 6 months. CONCLUSIONS: In routine clinical practice, sBPT is superior to PT alone after 35 treatment sessions and a follow-up of 6 months. Both treatments demonstrated to be safe. PMID- 20840348 TI - Trends in the incidence of basal cell carcinoma by histopathological subtype. AB - BACKGROUND: As a result of the high prevalence, basal cell carcinoma (BCC) causes a significant and expensive health care problem. OBJECTIVE: In this study, we evaluate the proportional increase in BCC by histological subtype over the last two decades. METHODS: We retrospectively reviewed all primary histological confirmed BCCs diagnosed in the Maastricht University Medical Centre in The Netherlands in the years 1991, 1999 and 2007. RESULTS: An annual increase of the number of BCCs of 7% for both genders was shown. The age-standardized incidence rates for BCC increased between 1991 and 2007 from 54.2 to 162.1 per 100, 000 men and from 61.7 to 189.8 per 100, 000 women. The proportion of superficial BCC increased significantly from 17.6% to 30.7%. CONCLUSION: The incidence of BCC is continuing to increase this century. The observed shift to the superficial histological subtype, which can be treated non-surgically, might reduce the workload in the busy dermatologists practice. PMID- 20840349 TI - Combination of skin, joint and quality of life outcomes with etanercept in psoriasis and psoriatic arthritis in the PRESTA trial. AB - BACKGROUND: Psoriasis and psoriatic arthritis (PsA) affect skin, and/or joints and quality of life (QoL). OBJECTIVE: To better assess the success in multiple attributes in subjects with both active psoriasis and PsA, the objective was to quantify the proportion of those who achieved substantial improvement in a composite measure of skin symptoms, joint manifestations, and QoL, on one of two treatment regimens. METHODS: Subjects (n=752) with psoriasis and PsA (mean age: 46.5 years, 62.9% male) received etanercept (ETN) 50mg twice weekly (BIW; n = 379) or 50 mg weekly (QW; n=373) for 12 weeks, followed by open-label ETN 50mg QW for 12 weeks. Skin and joint symptoms and QoL were assessed using psoriasis area and severity index (PASI), American College of Rheumatology criteria (ACR) and Euro-QoL (EQ-5D), respectively. RESULTS: By week 24, 30.6% and 25.8% of subjects receiving ETN 50 mg BIW/QW and ETN 50 mg QW/QW, respectively (P = 0.198) achieved the composite measure of efficacy for skin plus joints plus QoL (PASI 75 + ACR 50 + EQ-5D VAS >82). CONCLUSION: At 24 weeks, 25.8-30.6% met the triad of rigorous efficacy outcomes. Evaluation of treatment efficacy should address the multiple components of this disease complex; therefore it may be important to consider this composite measure in future trials. PMID- 20840350 TI - Factors associated with specialist assessment and treatment for hepatitis C virus infection in New South Wales, Australia. AB - Assessment and treatment for hepatitis C virus (HCV) in the community remains low. We evaluated factors associated with HCV specialist assessment and treatment in a cross-sectional study to evaluate treatment considerations in a sample of 634 participants with self-reported HCV infection in New South Wales, Australia. Participants having received HCV specialist assessment (n = 294, 46%) were more likely to be have been older (vs <35 years; 35-44 OR 1.64, P = 0.117; 45-54 OR 2.00, P = 0.024; >=55 OR 5.43, P = 0.002), have greater social support (vs low; medium OR 3.07, P = 0.004; high OR 4.31, P < 0.001), HCV-related/attributed symptoms (vs none; 1-10 OR 3.89, P = 0.032; 10-21 OR 5.01, P = 0.010), a diagnosis of cirrhosis (OR 2.40, P = 0.030), have asked for treatment information (OR 1.91, P = 0.020), have greater HCV knowledge (OR 2.49, P = 0.001), have been told by a doctor to go onto treatment (OR 3.00, P < 0.001), and less likely to be receiving opiate substitution therapy (OR 0.10, P < 0.001) and never to have seen a general practitioner (OR 0.24, P < 0.001). Participants having received HCV treatment (n = 154, 24%) were more likely to have greater fibrosis (vs no biopsy; none/minimal OR 3.45, P = 0.001; moderate OR 11.47, P < 0.001; severe, OR 19.51, P < 0.001), greater HCV knowledge (OR 2.57; P = 0.004), know someone who has died from HCV (OR 2.57, P = 0.004), been told by a doctor to go onto treatment (OR 3.49, P < 0.001), were less likely to have been female (OR 0.39, P = 0.002), have recently injected (OR 0.42, P = 0.002) and be receiving opiate substitution therapy (OR 0.22, P < 0.001). These data identify modifiable patient-, provider- and systems-level barriers associated with HCV assessment and treatment in the community that could be addressed by targeted interventions. PMID- 20840351 TI - The adult human pubic symphysis: a systematic review. AB - The pubic symphysis is a unique joint consisting of a fibrocartilaginous disc sandwiched between the articular surfaces of the pubic bones. It resists tensile, shearing and compressive forces and is capable of a small amount of movement under physiological conditions in most adults (up to 2 mm shift and 1 degrees rotation). During pregnancy, circulating hormones such as relaxin induce resorption of the symphyseal margins and structural changes in the fibrocartilaginous disc, increasing symphyseal width and mobility. This systematic review of the English, German and French literature focuses on the normal anatomy of the adult human pubic symphysis. Although scientific studies of the joint have yielded useful descriptive data, comparison of results is hampered by imprecise methodology and/or poorly controlled studies. Several aspects of the anatomy of the pubic symphysis remain unknown or unclear: the precise attachments of surrounding ligaments and muscles; the arrangement of connective tissue fibres within the interpubic disc and the origin, structure and function of its associated interpubic cleft; the biomechanical consequences of sexual dimorphism; potential ethnic variations in morphology; and its precise innervation and blood supply. These deficiencies hinder our understanding of the normal form and function of the joint, which is particularly relevant when attempting to understand the mechanisms underlying pregnancy-related pubic symphyseal pain, a neglected and relatively common cause of pubic pain. A better understanding of the normal anatomy of the human pubic symphysis should improve our understanding of such problems and contribute to better treatments for patients suffering from symphyseal pain and dysfunction. PMID- 20840352 TI - Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia telangiectasia. AB - BACKGROUND: Ataxia-telangiectasia (A-T) is a non-curable neurodegenerative disorder, associated with progressive neurological dysfunction, oculocutaneous telangiectasia, immunodeficiency, predisposition to cancer and radiosensitivity. A recent study documented improvement in neurological symptoms after a short-term therapy with betamethasone in patients with A-T. Aim of this study was to evaluate the minimum therapeutically effective dosage of betamethasone on neurological symptoms of A-T. METHODS: Six responsive patients with A-T, received two 20-day cycles of oral betamethasone at 0.01 and 0.03 mg/kg/day (10% and 30% of the previously used full dosage), each followed by a 20-day washout period. Clinical and laboratory evaluations were carried out at T0 and at the end of each cycle. Neurological assessment was performed through the Scale for the Assessment and Rating of Ataxia (SARA). The glucocorticoid-induced leucine zipper (GILZ) and glucocorticoid receptor (GR) RNA expression were evaluated before and during the trial through real-time PCR. RESULTS: SARA scores significantly improved in all patients at the dosage of 0.03 mg/kg/day. In particular, three patients exhibited an improvement in 5/8 variables and two patients of 7 and 8 variables, respectively. Furthermore, the clinical improvement was already evident after the lower dosage. The basal GILZ and GR RNA expression were significantly lower in patients than in controls. GILZ expression increased in all patients after the beginning of the therapy, whereas no correlation between GR and the response was found. CONCLUSION: Our data indicate that betamethasone is effective in A-T at a minimal dosage and that GILZ may be a useful biomarker of the clinical response. This study provides Class IIIA evidence that betamethasone at very low dosage is effective in improving neurological signs of patients affected with ataxia telangiectasia. PMID- 20840353 TI - Gender-specific aspects in the clinical presentation of cardiovascular disease. AB - More than a quarter of a million women die each year in the industrialized countries from cardiovascular diseases (CVD), and current projections indicate that this number will continue to rise with our ageing population. Important sex related differences in the prevalence, presentation, management and outcomes of different CVD have discovered in the last two decades of cardiovascular research. Nevertheless, much evidence supporting contemporary recommendations for testing, prevention and treatment of CVD in women is still extrapolated from studies conducted predominantly in men. The compendium of CVD indicates that current research and strategy development must focus on gender-specific issues to address the societal burden and costs related to these incremental shifts in female gender involvement. Indeed, this significant burden of CVD in women places unique diagnostic, treatment and financial encumbrances on our society that are only further intensified by a lack of public awareness about the disease on the part of patients and clinicians alike. This societal burden of the disease is, in part, related to our poor understanding of gender-specific pathophysiologic differences in the presentation and prognosis of CVD and the paucity of diagnostic and treatment guidelines tailored to phenotypic differences in women. In this, scenario is of outmost importance to know these differences to provide the best care for female patients, because under-recognition of CVD in women may contribute to a worse clinical outcome. This review will provide a synopsis of available evidence on gender-based differences in the initial presentation, pathophysiology and clinical outcomes of women affected by CVD. PMID- 20840355 TI - Work-based learning--a change in culture. PMID- 20840354 TI - The intrinsic innervation of the lung is derived from neural crest cells as shown by optical projection tomography in Wnt1-Cre;YFP reporter mice. AB - Within the embryonic lung, intrinsic nerve ganglia, which innervate airway smooth muscle, are required for normal lung development and function. We studied the development of neural crest-derived intrinsic neurons within the embryonic mouse lung by crossing Wnt1-Cre mice with R26R-EYFP reporter mice to generate double transgenic mice that express yellow fluorescent protein (YFP) in all neural crest cells (NCCs) and their derivatives. In addition to utilizing conventional immunohistochemistry on frozen lung sections, the complex organization of lung innervation was visualized in three dimensions by combining the genetic labelling of NCCs with optical projection tomography, a novel imaging technique that is particularly useful for the 3D examination of developing organs within embryos. YFP-positive NCCs migrated into the mouse lung from the oesophagus region at embryonic day 10.5. These cells subsequently accumulated around the bronchi and epithelial tubules of the lung and, as shown by 3D lung reconstructions with optical projection tomography imaging, formed an extensive, branching network in association with the developing airways. YFP-positive cells also colonized lung maintained in organotypic culture, and responded in a chemoattractive manner to the proto-oncogene, rearranged during transfection (RET) ligand, glial-cell-line derived neurotrophic factor (GDNF), suggesting that the RET signalling pathway is involved in neuronal development within the lung. However, when the lungs of Ret( /-) and Gfralpha1(-/-) embryos, deficient in the RET receptor and GDNF family receptor alpha 1 (GFRalpha1) co-receptor respectively, were examined, no major differences in the extent of lung innervation were observed. Our findings demonstrate that intrinsic neurons of the mouse lung are derived from NCCs and that, although implicated in the development of these cells, the role of the RET signalling pathway requires further investigation. PMID- 20840356 TI - Understanding the essential elements of work-based learning and its relevance to everyday clinical practice. AB - AIM: To critically review the work-based learning literature and explore the implications of the findings for the development of work-based learning programmes. BACKGROUND: With NHS budgets under increasing pressure, and challenges to the impact of classroom-based learning on patient outcomes, work based learning is likely to come under increased scrutiny as a potential solution. Evidence from higher education institutions suggests that work-based learning can improve practice, but in many cases it is perceived as little more than on-the-job training to perform tasks. EVALUATION: The CINAHL database was searched using the keywords work-based learning, work-place learning and practice based learning. Those articles that had a focus on post-registration nursing were selected and critically reviewed. KEY ISSUES: Using the review of the literature, three key issues were explored. Work-based learning has the potential to change practice. Learning how to learn and critical reflection are key features. For effective work-based learning nurses need to take control of their own learning, receive support to critically reflect on their practice and be empowered to make changes to that practice. CONCLUSIONS: A critical review of the literature has identified essential considerations for the implementation of work-based learning. A change in culture from classroom to work-based learning requires careful planning and consideration of learning cultures. IMPLICATIONS FOR NURSING MANAGEMENT: To enable effective work-based learning, nurse managers need to develop a learning culture in their workplace. They should ensure that skilled facilitation is provided to support staff with critical reflection and effecting changes in practice. CONTRIBUTION TO NEW KNOWLEDGE: This paper has identified three key issues that need to be considered in the development of work-based learning programmes. PMID- 20840357 TI - Creating the conditions for growth: a collaborative practice development programme for clinical nurse leaders. AB - AIM: To evaluate a 3-year practice development (PD) programme for clinical nurse leaders. BACKGROUND: The development of effective leaders is a key objective to progress the modernization agenda. This programme aimed to develop the participants alongside development of the culture and context of care. METHODS: Programme evaluation methodology to determine the 'worth' of the programme, inform the experience of the participation, effect on workplace cultures and determine effectiveness of the process used. RESULTS: Created the conditions for growth under two broad themes: process outcomes demonstrating growth as leaders contributing to cultural shifts; and general outcomes demonstrating practice changes. CONCLUSIONS: Developing communities of reflective leaders are required to meet demands within contemporary healthcare. PD provides a model to develop leaders to achieve sustainable changes and transform practice. IMPLICATIONS FOR NURSING MANAGEMENT: Active collaboration and participation of managers is crucial in the facilitation of and sustainability of cultural change. Approaches adopted to develop and sustain the transformation of practice need to focus on developing the skills and attributes of leaders and managers as facilitators. PMID- 20840358 TI - Challenges in designing an All-Wales professional development programme to empower ward sisters and charge nurses. AB - AIM: To discuss the challenges of designing a professional development programme for ward managers working in in-patient facilities in Wales. BACKGROUND: In 2008, the Minister of Health launched the Free to Lead, Free to Care initiative to empower ward managers. One work-stream involved the creation of a universal professional development programme to ensure they had the skills and knowledge to function effectively in their roles in the newly restructured NHS in Wales. METHODS: A collaborative, staged approach, involving multiple stakeholders, resulted in the design of a programme founded in principles of action and work based learning tailored to the needs of the individual in attaining accredited competencies. KEY ISSUES: Achieving buy-in and ownership from stakeholders are essential to ensure standardization and consistency of implementation of a universal programme. Shared responsibility and acceptance of key principles underpinning an individualized, work-based programme are fundamental to ensuring equity of outcome achievement. IMPLICATIONS FOR MANAGEMENT: Managerially facilitated cultural change is needed to embed individual work-based professional development programmes in the clinical environment, with practitioners supported through a variety of learning strategies appropriate to their learning needs. PMID- 20840359 TI - Meeting changing service need through role development: a case study for Band 4 assistant practitioners. AB - AIM: To debate the evolution of the Assistant Practitioner (AP) role and its impact on workforce development and Higher Education provision. BACKGROUND: The Band 4, AP, has been identified in England as a means for supporting Registered Nurses and enhancing patient care. However, the education and training of Band 4 AP requires new ways of partnership working between Trusts and Higher Education Institutions (HIEs) to ensure that programmes reflect employers needs and that the AP is fit for purpose. METHOD(S): This case study focuses on the first cohort of 13 students who were supported by a local NHS Trust to undertake a Foundation Degree (FD) in Health and Social Care (Adult Care). RESULTS: Issues include: supporting the clinical development for new roles, role boundaries, regulation of APs and supervision in training/education. CONCLUSION(S): There is a need for regulation and understanding of role boundaries, shared learning and development of new ways of working which HEIs need to consider in the next decade. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers need to consider skill mix and challenge established clinical roles. There is a need for FD students to be supernumerary and provided with effective support while undertaking work-based learning. PMID- 20840360 TI - Growing leaders in a professional membership organization. AB - AIMS: This study describes the background, development and delivery of an innovative approach to prepare elected state association leaders for their new leadership roles in their respective state organizations. BACKGROUND: State-based professional associations face unprecedented threats to scope of practice in the current volatile healthcare environment. In 2009 the American Association of Nurse Anesthetists (AANA) began offering a Leadership Development 'Boot Camp' for all nurse anesthetist state association presidents-elect designed with the intent of providing the participants with information, resources and tools they need in their new role. METHODS: An organizational assessment examined the philosophy of and need for leadership development across the entire organizational structure. RESULTS: Recommendations from the assessment included the need for intensive leadership development at the state level. A 3-day intensive workshop was designed and implemented. Adult learning theory was used for its development. CONCLUSIONS: The success of this programme has lead to its implementation as part of leadership development of the AANA. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers and elected volunteer leaders in state-based professional associations face similar challenges requiring sound leadership ability. Principles applied to the development of the AANA programme can be applied to leadership development for new nurse managers. PMID- 20840361 TI - Evaluation of the clinical supervision and professional development of student nurses. AB - AIM: The aim of the present study was to evaluate the clinical supervision and professional development of student nurses during their undergraduate education. BACKGROUND: Nursing education has undergone radical changes as a result of improvements in the academic-based clinical education required for the Bachelor's degree. METHODS: The sample consisted of student nurses (n = 147) and data were collected by means of questionnaires. RESULTS: The results demonstrated that the frequency of sessions and the supervision model employed influence the student nurses' professional development. Several significant correlations were found, most of which were related to the development of the student nurses' professional relationships with their supervisors and reflection on the development of their skills. From the patients' perspective, a high correlation was found between the factors 'preserving integrity' and 'protecting participation by patients and family members'. CONCLUSIONS: Clinical supervision strongly influences the student nurses' development of a professional identity, enhancing decision-making ability and personal growth. However, development of documentation skills should include a greater level of user involvement. IMPLICATIONS FOR NURSING MANAGEMENT: The findings highlight the need for management and staff nurses to engage in on going professional development. Transformative leadership, which is value driven, can facilitate and enhance the supervision and development of student nurses. PMID- 20840362 TI - Group supervision for nursing students during their clinical placements: its content and meaning. AB - AIM: To explore what situations students focus on during group supervision sessions, and what this supervision meant to nursing students during their clinical placements. BACKGROUND: Knowledge about clinical supervision of nursing students in groups is scarce concerning what situations the students bring to the sessions. METHOD: Open-ended questionnaires were filled out by students after each session. Qualitative content analysis was performed. RESULTS: The content evolved as: being a nursing student, encountering demanding situations and becoming a nurse. The meaning of group supervision was captured in the categories: 'satisfaction of being together in the supervision group', 'new understanding and insights' and 'hesitation and discomfort'. A change of pattern was found over time showing a development among the students from a self-centred focus to a profession-centred focus. CONCLUSION: The value of group supervision as a tool to support nursing students' personal and professional development was emphasized. The students' great need for and lack of support in 'bed-side nursing' was obvious. IMPLICATIONS FOR NURSING MANAGEMENT: Our findings would be valuable for nurse managers when striving for a good learning environment in clinical placements, as well as for nursing teachers, in their supportive role to both students and preceptors. PMID- 20840363 TI - Clinical supervision: outsider reports of a research-driven implementation programme in Queensland, Australia. AB - AIM: The aim of the present study was to explore substantive issues related to the implementation of Clinical Supervision (CS). BACKGROUND: Historically, the treatment of mental illness in Australia has been inadequate. CS has shown promise as a positive contribution to the clinical governance agenda, as a structured staff support mechanism. EVALUATION: Within the wider context of a randomized controlled trial (RCT) of CS, semi-structured interviews (n = 17) were conducted with staff who worked alongside colleagues that attempted to implement CS. KEY ISSUES: Senior managers embraced CS and were disappointed when junior managerial colleagues did not hold a similar conviction, when tested by the realities of CS implementation. If CS was regarded as an additional activity, it stretched human resources and created inter-staff tensions. CONCLUSIONS: The personal testimony of these 'outsiders' spoke about the practicalities of implementing CS and the prevailing culture into which they were introduced. When perceived as a tour de force for culture change, CS was polarized as an opportunity by many, but also as a threat by some. IMPLICATIONS FOR NURSING MANAGEMENT: A single, cohesive and explicit management position on CS in each Health Service entity may obviate some of the impediments to CS implementation. PMID- 20840364 TI - Staff nurses' experiences as preceptors and mentors: an integrative review. AB - AIM: The aim of this integrative review is to describe staff nurses' experience when functioning as a preceptor or mentor for student nurses. BACKGROUND: The preceptor's role is to guide students from the theory of nursing to the application of nursing theory, teaching clinical skills and clinical thinking. Relatively few research studies focus on the staff nurses' experience. EVALUATION: Research studies and topical articles from Australia, Canada, Sweden, the United Kingdom and the United States were drawn from databases. The theoretical framework for the analysis was the Kahn et al. (1964) role episode model. KEY ISSUES: Reservations over the efficacy of preceptor experiences have been identified. Along with intrinsic rewards, there is considerable stress and responsibility associated with precepting or mentoring. Nurse preceptors experience role ambiguity, conflict and overload when interacting with students. CONCLUSIONS: Research indicates what might reduce the amount of stress for the nurse preceptor and increase job satisfaction and nurse retention. IMPLICATIONS FOR NURSING MANAGEMENT: Defining and formalising the preceptor role can improve the standing of this function. Adjustments can be made to decrease the stress of the role. Preceptors and mentors request recognition and support for the amount of work involved in teaching students. PMID- 20840365 TI - A framework for recognition of prior learning within a Postgraduate Diploma of Nursing Management in South Africa. AB - AIMS: The present study focuses on the development of an initial framework to guide educators in nursing management in designing a portfolio for the recognition of prior learning for accreditation of competencies within a postgraduate diploma in South Africa. BACKGROUND: In South Africa, there is a unique educational need, arising from the legacy of apartheid and previous political regimes, to facilitate educational development in groups previously unable to access higher education. Awareness of the need for continuous professional development in nursing management practice and recognition of prior learning in the educational environment has presented the possibility of using one means to accomplish both aims. EVALUATION: Although the content of the present study is pertinent to staff development of nurse managers, it is primarily written for nurse educators in the field of nursing management. KEY ISSUES: The findings identify focus areas to be addressed in a recognition of prior learning portfolio to comply with the programme specific outcomes of Nursing Service Management. Further work to refine these focus areas to criteria that specify the level of performance required to demonstrate achievement is needed. CONCLUSION AND IMPLICATIONS FOR NURSE MANAGERS: Managers need to facilitate continuous professional development through portfolio compilation which acknowledges the learning opportunities within the workplace and can be used as recognition of prior learning. PMID- 20840366 TI - Nursing leadership style and psychosocial work environment. AB - AIM: This study examines the relationship between leadership style and the psychosocial work environment of registered nurses. BACKGROUND: Research consistently supports the positive relationship between transformational leadership style and job satisfaction. There is less evidence, which identifies the relationship between leadership style and psychosocial work environment. METHOD: The Multifactor Leadership Questionnaire 5* was used to identify the leadership style. The Copenhagen Psychosocial Questionnaire was used to measure psychosocial work environment dimensions. Statistical analysis included Pearson's r correlation between leadership style and psychosocial work environment and anova to analyse group means. RESULTS: There is a significant correlation between leadership style and 22 out of the 37 dimensions of the psychosocial work environment. This correlation was significant ranging from r = 0.88, P < 0.01 to r = 0.18, P < 0.05. Nurses divided into groups based on transformational leadership scores of the immediate supervisor report significant differences in their psychosocial work environment. CONCLUSION: This study supports the significant correlation between leadership style and psychosocial work environment for registered nurses. IMPLICATIONS FOR NURSING MANAGEMENT: The results of this study suggest that there would be an improvement in the nursing psychosocial work environment by implementation of transformational and contingent reward leadership behaviours. PMID- 20840367 TI - A phenomenological exploration of intellectual disability: nurse's experiences of managerial support. AB - AIM: The present study aimed to explore Registered Nurse Intellectual Disabilities (RNIDs) experiences of managerial support. BACKGROUND: The current work environment for RNIDs is undergoing immense change. These changes include the introduction of social care leaders and care staff to care for people with an intellectual disability (ID) and community-based approaches to care. This has led to ambiguity and marginalization for RNIDs thus requiring them to re-establish their role boundaries. Support is thus required, through this change process, with managers required to lead and support RNIDs through this process. METHODS: A Heideggerian constructivist phenomenological approach was used. FINDINGS: Four overarching themes emerged from the data: The Professional Role of the Clinical Nurse Manager (CNM), Leadership Role of the CNM, Personal Supports and the Effects of CNM support. CONCLUSION: The themes found in this research study correlate with findings of other research studies on nurses' experiences of managerial support in various nurse settings. IMPLICATIONS FOR NURSING MANAGEMENT: The findings of this research study will illuminate and create an understanding for nurses, nurse managers and ID services of what managerial supports are to this specific group of RNIDs working in this service for people with an ID. PMID- 20840368 TI - Leadership and management skills of first-line managers of elderly care and their work environment. AB - AIM: To study the leadership and management skills of first-line managers (FLMs) of elderly care and their work environment in Egypt and Sweden. BACKGROUND: FLMs in Egypt and Sweden are directly responsible for staff and quality of care. However, FLMs in Sweden, in elderly care, have smaller units/organizations to manage than do their colleagues in Egypt. Furthermore, family care of the elderly has been the norm in Egypt, but in recent years institutional care has increased, whereas in Sweden, residential living homes have existed for a longer period. METHODS: A convenience sample of FLMs, 49 from Egypt and 49 from Sweden, answered a questionnaire measuring leadership and management skills, structural and psychological empowerment, job satisfaction and psychosomatic health. RESULTS: In both countries, FLMs' perceptions of their leadership and management skills and psychological empowerment were quite high, whereas scores for job satisfaction and psychosomatic health were lower. FLMs had higher values in several factors/study variables in Egypt compared with in Sweden. CONCLUSION AND IMPLICATIONS: The work environment, both in Egypt and Sweden, needs to be improved to increase FLMs' job satisfaction and decrease stress. The cultural differences and levels of management have an effect on the differences between the two countries. PMID- 20840369 TI - Perceptions of ethical practices in Hong Kong public hospitals: inter- and intra professional similarities and differences. AB - AIM: To investigate similarities and differences in the perception of hospital ethical practices using different seniority of doctors, nurses and administrators, and between these healthcare professionals (HCPs). IMPORTANCE: Intra- and inter-professional similarities and differences had implications for HCPs' morale, hospital ethics climate and quality of patient care. METHOD: HCPs (n = 1.910) with different levels of seniority in 14 Hong Kong public hospitals were randomly surveyed between November 2004 and April 2005. RESULTS: Intra professional differences in perception between senior and junior doctors or nurses were found in nine ethical themes including: quality of care, patient satisfaction, disagreements among HCPs and between HCPs and patient family, end of-life care, professional incompetence and misconducts and communication. Inter professional similarities in perception were also found among different HCPs in senior positions and as a group they differ from the perceptions of junior HCPs. CONCLUSIONS: Significant intra-professional and inter-professional polarizations of perception of ethical practices between senior and junior HCPs were found and they potentially undermine the trusting relationships between HCPs. IMPLICATIONS: As nursing managers were found to align with senior doctors and administrators, junior nurses might feel unsupported, isolated and frustrated, creating a nursing management challenge that must be faced. PMID- 20840370 TI - Nurse Managers' prerequisite for nursing development: a survey on pressure ulcers and contextual factors in hospital organizations. AB - AIM: To describe and compare pressure ulcer prevalence in two county councils and concurrently explore Nurse Managers' perspective of contextual factors in a hospital organization. BACKGROUND: Despite good knowledge about risk factors and prevention of pressure ulcers, the prevalence of pressure ulcers remains high. Nurse Managers' have a key role in implementing evidence-based practice. METHODS: The present study included five hospitals in two Swedish county councils: county council A (non-university setting) and county council B (university setting). A pressure ulcer prevalence study was conducted according to the methodology developed by the European Pressure Ulcer Advisory Panel. The Nurse Managers' answered a (27-item) questionnaire on contextual factors. RESULTS: County council B had significantly less pressure ulcers grade (2-4) (7.7%) than county council A (11.3%). The Nurse Managers' assessed only two out of the 27 general contextual items significantly differently. Some significant differences were observed in ward organization. CONCLUSIONS: In county council B, the Nurse Managers' seemed more aware of prevention strategies compared with Nurse Managers' in county council A. The Nurse Managers' should take more responsibility to develop the prerequisite for quality improvement in nursing. IMPLICATION FOR NURSING MANAGEMENT: Nursing outcomes (e.g. pressure ulcers) should be incorporated into national quality registries for benchmarking and Nurse Managers' competence in evidence-based practice and research methodology increased. PMID- 20840371 TI - Patient rehabilitation in hospitals a prioritized discipline after hospital reform: a Norwegian perspective. AB - AIM: The purpose of the present study was to highlight the effects of hospital reform introduced in Norway 2002 on patient rehabilitation. BACKGROUND: The Norwegian hospital reform is an activity-controlled financing system with diagnosis-related groups (DRG). METHOD: A multi-case study with embedded design methods was used. Document analysis and interviews are sources of evidence. RESULTS: The rehabilitation service offered a treatment service that was inadequately funded. The focus of the rehabilitation team was negatively affected by the lack of organization. The different patient groups did not receive optimal and individualized rehabilitation as required by individual treatment plans. There were two different levels of rehabilitation at the hospitals. CONCLUSIONS: The financing system did not provide for a differentiated treatment service tailored to each patient's individual plan, as stipulated by health policy. An increase in the number of patients receiving rehabilitation in the health authorities was not accompanied by an increase in allocated resources, leading to an insufficient overall rehabilitation service. The organizations included in the case study were not those who finance specialized rehabilitation at specialized rehabilitation centres. IMPLICATIONS FOR NURSING MANAGEMENT: Specially trained nurses are strategically placed to shape and influence funding of rehabilitation programmes through leadership. PMID- 20840372 TI - Geographic patterns in the distribution of social systems in terrestrial arthropods. AB - The role of ecology in the evolution and maintenance of arthropod sociality has received increasing research attention in recent years. In some organisms, such as halictine bees, polistine wasps, and social spiders, researchers are investigating the environmental factors that may contribute to high levels of variation in the degree of sociality exhibited both among and within species. Within lineages that include only eusocial members, such as ants and termites, studies focus more on identifying extrinsic factors that may contribute to the dramatic variation in colony size, number of queens, and division of labour that is evident across these species. In this review, I propose a comparative approach that seeks to identify environmental factors that may have a common influence across such divergent social arthropod groups. I suggest that seeking common biogeographic patterns in the distribution of social systems or key social traits may help us to identify ecological factors that play a common role in shaping the evolution of sociality across different organisms. I first review previous studies of social gradients that form along latitudinal and altitudinal axes. Within families and within species, many organisms show an increasing degree of sociality at lower latitudes and altitudes. In a smaller number of cases, organisms form larger groups or found nests cooperatively at higher latitudes and altitudes. I then describe several environmental factors that vary consistently along such gradients, including climate variables and abundance of predators, and outline their proposed role in the social systems of terrestrial arthropods. Finally, I map distributions of a social trait against several climatic factors in five case studies to demonstrate how future comparative studies could inform empirical research. PMID- 20840373 TI - Intestinal epithelial cell proliferation, apoptosis and expression of tight junction proteins in patients with obstructive jaundice. AB - BACKGROUND: Intestinal hyperpermeability has been repeatedly confirmed in patients with obstructive jaundice and is considered a pivotal factor in the development of septic and renal complications in these patients. However, little is known on the mechanism(s) leading to this phenomenon. This study was undertaken to investigate the cellular and subcellular intestinal alterations in patients with obstructive jaundice. DESIGN: Sixteen patients with obstructive jaundice of malignant (n = 8, group A) or benign (n = 8, group B) aetiology, without concomitant cholangitis, and eight healthy controls (group C) were subjected to duodenal biopsy distal to the ampulla of Vater. Specimens were examined histologically and the apoptotic activity in the cryptal epithelium was recorded. Epithelial proliferation was evaluated by immunohistochemical expression of Ki67 antigen. The expression of the tight junction (TJ) proteins occludin, claudin-1, claudin-4 and claudin-7 in the intestinal epithelium was also evaluated by immunohistochemistry. RESULTS: Patients with malignant or benign obstructive jaundice presented significantly decreased intestinal epithelial cell proliferation rates compared with controls (P < 0.05), whereas no differences were detected in apoptotic activity. In a semiquantitative analysis of TJ protein expression, occludin, claudin-1 and -7 were significantly decreased (P < 0.001), whereas claudin-4 was significantly increased (P < 0.01) in jaundiced patients and their distribution was altered. No differences were detected between patients with malignant or benign obstructive jaundice for all intestinal barrier parameters studied. CONCLUSION: Decreased enterocyte proliferation and altered TJ protein expression might represent important mechanisms for intestinal barrier dysfunction and hyperpermeability in patients with extrahepatic cholestasis. The potential pharmacological modulation of these factors may lead to better control of intestinal permeability in the jaundiced patient with improved clinical outcome. PMID- 20840374 TI - Mutations in connexin genes and disease. AB - BACKGROUND: Connexins are a family of transmembrane proteins that are widely expressed in the human body. Connexins play an important role in cell-cell communication and homeostasis in various tissues by forming gap junction channels, which enable a direct passage of ions or metabolites from one cell to another. Twenty-one different connexins are expressed in humans, each having distinct expression patterns and regulation properties. Knowledge on this family of proteins can be gained by making an inventory of mutations and associated diseases in human. DESIGN: PubMed and other relevant databases were searched. In addition, key review articles were screened for relevant original publications. Sections of representative organs were photographed and annotated. RESULTS: The crucial role of connexins is highlighted by the discovery of mutations in connexin genes which cause a variety of disorders such as myelin-related diseases, skin disorders, hearing loss, congenital cataract, or more complex syndromes such as the oculodendrodigital dysplasia. This review systematically addresses current knowledge on mutations in connexin genes and disease, focusing on the correlation between genetic defects, cellular phenotypes and clinical manifestations. CONCLUSIONS: The review of diseases caused by mutations in connexin genes highlights the essential nature of connexin function and intercellular communication in tissue homeostasis. PMID- 20840375 TI - Electronic nose analysis of bronchoalveolar lavage fluid. AB - BACKGROUND: Electronic nose (E-nose) technology has been successfully used to diagnose a number of microbial infections. We have investigated the potential use of an E-nose for the diagnosis of ventilator-associated pneumonia (VAP) by detecting micro-organisms in bronchoalveolar lavage (BAL) fluid in a prospective comparative study of E-nose analysis and microbiology. MATERIALS AND METHODS: BAL samples were collected using a blind technique from 44 patients following a minimum of 72 h mechanical ventilation. Control samples were collected from six patients mechanically ventilated on the intensive care unit (ICU) immediately following elective surgery. Quantitative microbiological culture and E-nose headspace analysis of the BAL samples were undertaken. Multivariate analysis was applied to correlate E-nose response with microbiological growth. RESULTS: E-nose fingerprints correctly classified 77% of the BAL samples, with and without microbiological growth from patients not on antibiotics. Inclusion of patients on antibiotics resulted in 68% correct classification. Seventy per cent of isolates, cultured in the laboratory from the clinical samples, were accurately discriminated into four clinically significant groups. CONCLUSIONS: E-nose technology can accurately discriminate between different microbial species in BAL samples from ventilated patients on ICU at risk of developing VAP with accuracy comparable with accepted microbiological techniques. PMID- 20840376 TI - The responsiveness of different APTT reagents to mild factor VIII, IX and XI deficiencies. AB - INTRODUCTION: The sensitivity of APTT reagents to deficiencies of factors VIII, IX, XI and XII varies because of their composition. The APTT is used as a screening test for these factors, and a deficiency should manifest with a prolongation to the APTT, which may trigger the need for specific factor assays to be performed. METHODS: The suitability of APTT reagents to detect mild deficiencies can be assessed by the analysis of the APTT of plasma, which has an increasing concentration of the factor in question. The APTT responsiveness can be determined from the intersection of the curve and the upper limit of the APTT normal reference range for that APTT reagent. We assessed the APTT responsiveness (in U/dl) to factors VIII, IX and XI of four APTT reagents; Actin FS (Siemens), Synthasil (IL), STA-PTTA (Stago) and Dapttin (Technoclone). RESULTS: Actin FS was the most sensitive reagent to mild reductions of factors VIII, IX and XI [Correction added on 26 October 2010, after first online publication: Synthasil was corrected to Actin FS]. STA-PTTA showed less sensitivity than Synthasil and Actin FS; Dapttin was insensitive to mild deficiencies of factors IX and XI and should not be used as a screening test. CONCLUSION: Both Synthasil and Actin FS are acceptable reagents to screen for reduced factors VIII, IX and XI, and the number of mildly reduced factors not diagnosed will be limited. PMID- 20840377 TI - Comparison of the BioRad Variant and Primus Ultra2 high-pressure liquid chromatography (HPLC) instruments for the detection of variant hemoglobins. AB - INTRODUCTION: Hemoglobin variants are a result of genetic changes resulting in abnormal or dys-synchronous hemoglobin chain production (thalassemia) or the generation of hemoglobin chain variants such as hemoglobin S. Automated high pressure liquid chromatography (HPLC) systems have become the method of choice for the evaluation of patients suspected with hemoglobinopathies. METHODS: In this study, we evaluated the performance of two HPLC methods used in the detection of common hemoglobin variants: Variant and Ultra2. RESULTS: There were 377 samples tested, 26% (99/377) with HbS, 8.5% (32/377) with HbC, 20.7% (78/377) with other hemoglobin variant or thalassemia, and 2.9% with increased hemoglobin A(1) c. The interpretations of each chromatograph were compared. There were no differences noted for hemoglobins A(0), S, or C. There were significant differences between HPLC methods for hemoglobins F, A(2), and A(1) c. However, there was good concordance between normal and abnormal interpretations (97.9% and 96.2%, respectively). CONCLUSION: Both Variant and Ultra2 HPLC methods were able to detect most common hemoglobin variants. There was better discrimination for fast hemoglobins, between hemoglobins E and A(2), and between hemoglobins S and F using the Ultra2 HPLC method. PMID- 20840378 TI - Economic burden of Parkinson's disease in Singapore. AB - BACKGROUND: This study was carried out to evaluate the economic burden of Parkinson's disease (PD) and factors independently associated with individual components of total cost in Singapore. METHODS: A consecutive sample of 195 patients with PD (mean age: 68.2, men: 51.8%) attending a tertiary neuroscience clinic were identified and interviewed using standardized questionnaires including a financial burden questionnaire, two Health Related Quality of Life (HRQoL) questionnaires and the Beck Depression Inventory questionnaire. RESULTS: Annual total cost of PD from a societal perspective was SGD11345 (USD10129) per patient, with direct cost accounted for 38.5% and indirect cost 61.5%. The main cost components for direct medical cost, direct non-medical cost, and indirect cost was pharmacotherapy (50.4%), home care (76.1%), and productivity loss (97.9%), respectively. In multiple linear regression analysis, higher education, younger age and longer duration of PD were associated with higher total cost. CONCLUSIONS: Parkinson's disease exerts a considerable burden on patients, health care system and society in Singapore. As productivity loss accounts for a large share of the economic burden imposed by PD, treatments and health care programmes with potential for returning patients to higher productivity are urgently needed. PMID- 20840379 TI - Acute transverse myelitis and antiphospholipid antibodies in lupus. No evidence for anticoagulation. AB - Current views suggest that prothrombotic properties of antiphospholipid antibodies (aPL) have a role in the development of acute transverse myelitis (ATM) in patients with systemic lupus erythematosus (SLE). Consequently, empiric anticoagulation may be included in these patients' treatment. We performed a systemic review of the literature to explore the clinical value of the presence of aPL in patients with lupus myelitis and the possible effectiveness of anticoagulation. We analyzed clinical and laboratory data extracted from published cases of SLE-associated ATM, fulfilling the Transverse Myelitis Consortium Working Group diagnostic criteria, that provided information on aPL. We report on a total of 70 patients. aPL, detected upon ATM onset in 54% of patients, neither predicted the involvement of the thoracic part of the spine, which has been postulated to reflect a predominantly thrombosis-induced injury, nor correlated with relapsing ATM, additional lupus CNS manifestations, or worse clinical outcome. An unfavorable outcome could be predicted by paralysis (P=0.02) and abnormal CSF findings at presentation (P=0.02). Whilst all patients received major immunosuppressive regimens, severe neurologic impairment (estimated Expanded Disability Status Scale score>7) was found primarily in aPL-negative patients (P=0.03). Anticoagulation was more frequently applied in aPL-positive patients (P=0.04), but any additional therapeutic effect was not evident. Detection of circulating aPL at ATM onset appears unreliable to suggest a thrombotic cause and perhaps not enough to dictate therapeutic anticoagulation. Registry creation of ATM in patients with SLE is needed to obtain more definite answers on the role of aPL in this condition. PMID- 20840380 TI - Stroke unit care in clinical practice: an observational study in the Florence center of the European Registers of Stroke (EROS) Project. AB - BACKGROUND: Randomized trials and meta-analyses indicate positive effects of stroke unit (SU) care on survival and dependency of patients with stroke. However, data on the advantages of SU in 'real-world' settings are limited. We prospectively assessed, in a large University Hospital, the effect of SU versus other conventional wards (OCW) care on all-cause mortality, death or dependency, death or institutionalization. METHODS: In a prospective observational study in the European Registers of Stroke Project, patients hospitalized for first-in-a lifetime stroke were evaluated for demographics, risk factors, clinical presentation, resource use, 3-month and 1-year survival, and functional outcome. RESULTS: Overall, 355 patients (54.1% men, mean age 73.4 +/- 14.5 years) were registered, 140 (39.4%) admitted to the SU, and 215 (60.6%) to OCW. OCW patients were older, whilst SU patients had more severe strokes according to NIHSS (P for trend = 0.025). SU patients were significantly more often treated by specialists in stroke medicine, stroke nurses, physiotherapists and speech therapists (all P < 0.001), psychologists (P = 0.025), dietitians (P < 0.001), and social workers (P = 0.003). MRI, carotid, and transcranial Doppler were significantly more often performed in SU patients (all P < 0.001). Intravenous fluids (P = 0.003) and intravenous anticoagulation (P < 0.001) were more often prescribed in SU. Controlling for case-mix, SU significantly reduced 1-year mortality (P = 0.020), death or dependency at 3 months (P = 0.006) and 1 year (P = 0.043), and death or institutionalization at 3 months (P = 0.001) and 1 year (P = 0.009). CONCLUSIONS: We confirmed the benefits of SU care in a clinical setting. Further analyses should define the contribution of individual components of care to stroke outcome. PMID- 20840383 TI - Letter to the editors regarding the scientific paper by Gonzalez, Moreno, Fumuso, et al. PMID- 20840381 TI - 'You'd think this roller coaster was never going to stop': experiences of adult children of parents with serious mental illness. AB - AIMS AND OBJECTIVES: The aims of this qualitative study were to explore the experience of being an adult child of a parent with serious mental illness and how adult children have coped with their experience. BACKGROUND: Children of parents with serious mental illness are a potentially vulnerable group because of risk factors associated with parental mental illness. While there has been considerable research into factors that may strengthen or impair their well being, there has been little exploration of the subjective experience of growing up with parental mental illnesses such as schizophrenia. DESIGN: An interpretive qualitative design including autoethnography. METHODS: Unstructured narrative interview and written narrative data from 10 participants were analysed using van Manen's hermeneutic method. RESULTS: Four themes that captured the experience of being the adult child of a parent with serious mental illness were revealed: (1) Being uncertain: 'you'd think this roller coaster was never going to stop'; (2) Struggling to connect: 'we were super close and now we're not'; (3) Being responsible: 'I think I grew up in a hurry'; (4) Seeking balance: 'I had to be in control of the situation so awful things wouldn't happen'. CONCLUSIONS: Being the adult child of a parent with serious mental illness can involve a chaotic family life where adult children assume substantial caregiving roles. Relationships between parents and adult children can become strained. However, support from others including health professionals can strengthen adult children's resilience and ability to cope with these challenges. RELEVANCE TO CLINICAL PRACTICE: Nurses in a range of health care settings are in prime positions to intervene early and provide information and support for children and families where parents have a mental illness. Family-focused care can strengthen children's and parent's relationships and support the family's ability to cope. PMID- 20840385 TI - Current challenges facing the determination of product bioequivalence in veterinary medicine. AB - Despite the pharmacological and statistical advances that have occurred since the early days of bioequivalence assessments, there remain many unresolved issues associated with the bioequivalence evaluation of human and veterinary pharmaceuticals. While many of these issues are common to both human and veterinary medicine, there are also challenges specific to veterinary drug products. Examples of complex problems that remain to be resolved include the assessment of drugs associated with complex kinetics (e.g., sustained release formulations that produce multiple peaks), the evaluation of intramammary formulations, uncertainty associated with conditions under which specific enantiomers of metabolites need to be factored into the bioequivalence evaluation, the study design for products and active pharmaceutical ingredients that exhibit highly variable kinetics, equivalence of biomass products, methods for evaluating topical formulations or formulations with very long duration of release, the evaluation of products where destructive sampling is necessary (e.g., aquaculture products), and the evaluation of bioequivalence for Type A medicated articles. This manuscript highlights many of the unresolved challenges currently impacting the evaluation of product bioequivalence in veterinary medicine, and provides a summary of the associated scientific complexities with each of these issues. PMID- 20840386 TI - The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, and verapamil on the cardiovascular influences of dexmedetomidine in conscious sheep. AB - We investigated whether administration of L-659,066, a peripheral alpha(2) adrenoceptor antagonist, or verapamil, a calcium-channel antagonist, would prevent the cardiovascular effects of dexmedetomidine. Eleven sheep received three intravenous treatments with a randomized, cross-over design: dexmedetomidine (5 MUg/kg, DEX); DEX with L-659,066 (250 MUg/kg, DEX + L); and verapamil (0.05 mg/kg) 10 min prior to DEX (Ver + DEX). Haemodynamics were recorded at intervals upto 40 min. Acute increases in mean arterial pressure (MAP) (106 +/- 10.7 to 120.8 +/- 11.7 mmHg), central venous pressure (CVP) (3.3 +/- 3.2 to 14.7 +/- 5.0 mmHg) and systemic vascular resistance (SVR) (1579 +/- 338 to 2301 +/- 523 dyne s/cm(5) ), and decreases in cardiac output (CO) (5.36 +/ 0.87 to 3.93 +/- 1.30 L/min) and heart rate (HR) (88.6 +/- 15.3 to 49.7 +/- 5.5/min) were detected with DEX. The peak SVR remained lower after Ver + DEX (1835 +/- 226 dyne s/cm(5) ) than DEX alone, but the other parameters did not significantly differ between these treatments. 2 min after drug delivery, differences between DEX and DEX + L were statistically significant for all measured haemodynamic parameters. With DEX + L, an early decrease in MAP (99.9 +/ 6.8 to 89.3 +/- 6.6 mmHg) was detected, and DEX + L induced a slight but significant increase in CVP and a decrease in HR at the end of the observation period, while SVR and CO did not significantly change. All animals were assessed as deeply sedated from 2-20 min with no differences between treatments. L-659,066 has great potential for clinical use to prevent the cardiovascular effects of dexmedetomidine mediated by peripheral alpha(2) -adrenoceptors, whereas the effects of verapamil were marginal. PMID- 20840387 TI - Caudal epidural injection of lidocaine, tramadol, and lidocaine-tramadol for epidural anesthesia in cattle. AB - Caudal epidural anesthesia is commonly utilized in veterinary medicine to allow diagnostic, obstetrical, and surgical intervention, in the perineal region of large animal. The aim of this study is to directly compare the time of onset and duration of analgesia produced by a tramadol and lidocaine-tramadol combination with that produced by lidocaine administration in the epidural space of Cattle. Five healthy adult Holstein dairy cows were selected to this study. Epidural anesthesia was produced in all cows by lidocaine, with 2 weeks intervals repeated by a combination of lidocaine-tramadol and tramadol. Time to onset and duration of analgesia were recorded. Heart rate, respiratory rate and body temperature were recorded at 0 min and at 5, 10, 15, 30, 60, and 75 min after the epidural administrations of each treatments. The tramadol produced a significant (P < 0.05) longer duration of analgesia (306.8 +/- 8.58 min) than lidocaine (69.40 +/- 8.96 min) alone and lidocaine-tramadol combination (174 +/- 4.84 min). Also, lidocaine-tramadol combination produced a significant (P < 0.05) longer duration of analgesia than lidocaine alone. Complete analgesia began at 14.10 +/- 1.57 min in the tramadol treatment, being more delayed than in the treatments with lidocaine-tramadol (4.84 +/- 0.68 min) and lidocaine (3.90 +/- 0.89 min). Body temperatures, heart rates, and respiratory rates were not significantly different in comparison with baseline values throughout the study in the all treatments. The combination of lidocaine-tramadol produced anesthesia of longer duration than lidocaine and the onset time was approximately same as for the lidocaine group. Utilizing this combination, long duration of anesthesia could commence relatively soon after epidural injection and might be used without re-administration of anesthetic agent in long-duration obstetrical and surgical procedures. PMID- 20840388 TI - In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study. AB - Robenacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animals. Whole blood assays were used to characterize in the cat the pharmacodynamics of robenacoxib for inhibition of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in comparison with other NSAIDs. Based on in vitro IC(50) COX-1:IC(50) COX-2 ratios, robenacoxib was COX-2 selective (ratio = 32.2), diclofenac (ratio = 3.9) and meloxicam (ratio = 2.7) were only weakly COX-2 preferential, and ketoprofen (ratio = 0.049) was COX-1 selective. In an in vivo pharmacokinetic ex vivo pharmacodynamic study, after both p.o. (1-2 mg/kg) and subcutaneous (2 mg/kg) dosing, robenacoxib achieved peak blood concentrations rapidly (T(max) = 1 h for both administration routes) and was cleared from blood relatively rapidly (mean residence time was 1.70 h after p.o. and 1.79 h after subcutaneous dosing). In ex vivo COX isoform inhibition assays, orally (1-2 mg/kg) or subcutaneously (2 mg/kg) administered robenacoxib significantly inhibited COX-2, with a relatively short duration of action in the central compartment, and had no effect on COX-1. Therefore robenacoxib was COX-2 selective and spared COX-1 in vivo. In contrast, meloxicam (0.3 mg/kg via subcutaneous injection) inhibited both COX-1 and COX-2 isoforms significantly for at least 24 h, indicating nonselectivity in vivo. PMID- 20840389 TI - Oral bioavailability of P-glycoprotein substrate drugs do not differ between ABCB1-1Delta and ABCB1 wild type dogs. AB - Previous studies have indicated that intestinal P-glycoprotein (P-gp) limits the oral bioavailability of substrate drugs and alters systemic pharmacokinetics. In this study, dogs lacking functional P-gp were used to determine the contribution of P-gp to the oral bioavailability and systemic pharmacokinetics of several P-gp substrate drugs. The P-gp substrates quinidine, loperamide, nelfinavir, cyclosporin and the control (non P-gp substrate) drug diazepam were individually administered intravenously and per os to ABCB1-1Delta dogs, which have a P-gp null phenotype and ABCB1 wildtype dogs. ABCB1-1Delta dogs have been shown to have greater brain penetration of P-gp substrates, but limited information is available regarding oral bioavailability of P-gp substrate drugs in this animal model. Plasma drug concentration vs. time curves were generated and pharmacokinetic parameters were calculated for each drug. There were no differences in oral bioavailability between ABCB1-1Delta dogs and ABCB1 wildtype dogs for any of the drugs studied, suggesting that intestinal P-gp does not significantly affect intestinal absorption of these particular substrate drugs in ABCB1-1Delta dogs. However, small sample sizes and individual variability in CYP enzyme activity may have affected the power of the study to detect the impact of P-gp on oral bioavailability. PMID- 20840390 TI - The pharmacokinetics of mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs. AB - The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL.h/kg, and the apparent volume of distribution at steady state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t(1/2) ) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t(1/2) for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks. PMID- 20840391 TI - Pharmacokinetics and tissue depletion of florfenicol in Leghorn and Taiwan Native chickens. AB - Florfenicol (Ff) is a synthetic antibiotic with a broad antibacterial spectrum and high therapeutic effectiveness that was specifically developed for veterinary use. In the present study, tissue residual levels and the pharmacokinetics of Ff after oral administration of 30 mg/kg to Leghorn and Taiwan Native chicken were studied. Furthermore, differential pharmacokinetics between leg and breast muscles were compared using samples collected from an optimized microdialysis model designed for avian species. Significant differences in C(max) were detected between the plasma and muscle microdialysates, and between the breast and leg microdialysates of the Leghorn chickens by noncompartmental pharmacokinetic analysis. After a single oral dose of Ff at 30 mg/kg, the drug was quickly absorbed and widely distributed with tissue penetration factors significantly different between leg and breast muscles. The serum protein binding of Ff was estimated to be 16.8 +/- 1.2%. Significant breed differences in tissue depletion were noted and characterized by higher Ff concentration in the brain, lung, kidney and at least 12 h longer resident times in kidney, heart and spleen for Taiwan Native chicken. Results from this investigation demonstrate the practicality of using in vivo microdialysis in chickens for pharmacokinetic studies and reveal significant time-dependent differences in the free concentrations of Ff in leg and breast muscles. The tissue depletion study signified breed differences in tissue residue concentration and detection times between Leghorn and Taiwan Native chickens. Therefore, currently used withdrawal times for Ff in chickens can not be assumed safe for Taiwan Native chickens. PMID- 20840392 TI - Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. AB - The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma T(max) was 0.083 h and plasma C(max) was 18,135 +/- 22,720 ng/mL. Plasma AUC was 4484 +/- 1,398 ng.h/mL. Plasma t(1/2beta) was 1.80 +/- 0.50 h and mean residence time was 0.794 +/- 0.318 h with total body clearance of 1.29 +/- 0.70 L/h/kg. The mean plasma steady-state volume of distribution was calculated as 0.990 +/- 0.530 L/kg and volume of distribution based on area was calculated as 3.23 +/- 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 +/- 11.8 ng/mL. Milk T(max) was detected at 0.67 +/- 0.26 h with C(max) of 2495 +/- 904 ng/mL. Milk AUC till the last time was 6593 +/- 2617 ng.h/mL with mean AUC milk to AUC plasma ratio of 1.99 +/- 2.15. The last measurable time that ketamine was detected in milk was 44 +/- 10.0 h with a mean concentration of 16.0 +/- 9.0 ng/mL. PMID- 20840393 TI - Pharmacokinetic profile and behavioral effects of gabapentin in the horse. AB - Gabapentin is being used in horses although its pharmacokinetic (PK) profile, pharmacodynamic (PD) effects and safety in the equine are not fully investigated. Therefore, we characterized PKs and cardiovascular and behavioral effects of gabapentin in horses. Gabapentin (20 mg/kg) was administered i.v. or p.o. to six horses using a randomized crossover design. Plasma gabapentin concentrations were measured in samples collected 0-48 h postadministration employing liquid chromatography-tandem mass spectrometry. Blood pressures, ECG, and sedation scores were recorded before and for 12 h after gabapentin dosage. Nineteen quantitative measures of behaviors were evaluated. After i.v. gabapentin, the decline in plasma drug concentration over time was best described by a 3 compartment mammillary model. Terminal elimination half-life (t(1/2gamma) ) was 8.5 (7.1-13.3) h. After p.o. gabapentin terminal elimination half-life () was 7.7 (6.7-11.9) h. The mean oral bioavailability of gabapentin (+/- SD) was 16.2 +/- 2.8% indicating relatively poor absorption of gabapentin following oral administration in horses. Gabapentin caused a significant increase in sedation scores for 1 h after i.v. dose only (P < 0.05). Among behaviors, drinking frequency was greater and standing rest duration was lower with i.v. gabapentin (P < 0.05). Horses tolerated both i.v. and p.o. gabapentin doses well. There were no significant differences in and . Oral administration yielded much lower plasma concentrations because of low bioavailability. PMID- 20840394 TI - Allergy to rodents: an update. AB - Allergy to rodents in the workplace is an important occupational health problem affecting research, pharmaceutical and toxicological sectors and can have a serious impact on employees working in this area. Despite measures to reduce aeroallergen exposures to rodents in the workplace, there are few signs that this occupational health problem is declining. Rodent allergens are well characterized and exposure-response relationships have been demonstrated to be complex. More recently, the importance of rodent allergens outside of the workplace has been demonstrated in several studies of individuals with asthma. This review focuses on rodent allergy both in the workplace and in the home and examines the complex exposure-response relationships between allergen exposure and sensitization and asthma. Risk factors for rodent allergy and mechanisms of tolerance to rodent allergens are discussed. PMID- 20840395 TI - Caesarean sections and risk of wheezing in childhood and adolescence: data from two birth cohort studies in Brazil. AB - BACKGROUND: There is evidence from two meta-analyses that children born through caesarean section (C-section) may have an increased risk of developing asthma compared with those born through vaginal delivery. Objective To evaluate the association between mode of delivery and wheezing (current and persistent) in childhood and adolescence, in two birth cohort studies in Brazil. METHODS: The outcome variable was based on the International Study of Allergy and Asthma questionnaire, which collects information about wheezing within the 12 months before the interview. Persistent wheezing was defined when it was present in more than one follow-up at different ages, in the 1993 cohort. The questions were asked to mothers when children were aged 4 years (1993 and 2004 cohorts) and directly to cohort participants at 11 and 15 years (1993 cohort). Mode of delivery was collected by the research team of each cohort when children were born. RESULTS: Response rates in the last follow-up visit of the 1993 and 2004 cohorts were 85% and 92%, respectively. The prevalence of current wheezing increased from 20% to 28% at 4 years from 1993 to 2004; at 11 and 15 years, the prevalence was around 14% and 12%, in the 1993 cohort. The proportion of C sections increased from 30.5% to 45% between 1993 and 2004. In each cohort, the prevalence of current wheezing was similar among children born through vaginal and C-section. The risk for persistent wheezing in the 1993 cohort was higher among girls born through C-section than boys. CONCLUSION: Despite the increase in the proportion of C-section in two cohorts in Southern Brazil, we found no evidence of an association between mode of delivery and the subsequent risk of wheezing. Among girls, although there was no statistical significance, the risk was higher for those born by C-section, especially regarding persistent wheezing. PMID- 20840396 TI - HBcrAg is a predictor of post-treatment recurrence of hepatocellular carcinoma during antiviral therapy. AB - BACKGROUND/AIMS: The recurrence rate of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is high even in patients receiving curative therapy. In this study, we analysed the risk factors for tumour recurrence after curative therapy for HBV-related HCC while under treatment with nucleot(s)ide analogues (NAs) by measuring serum HBcrAg and intrahepatic covalently closed circular DNA (cccDNA) levels to elucidate the viral status associated with HCC recurrence. METHODS: We enrolled 55 patients who developed HCC during NA therapy and underwent either curative resection or percutaneous ablation for HCC. RESULTS: Hepatocellular carcinoma recurred in 21 (38%) of the patients over a period of 2.2 (range, 0.2-7.4) years. In multivariate analysis, serum HBcrAg levels >=4.8 log U/ml at the time of HCC diagnosis (hazard ratio, 8.96; 95% confidential interval, 1.94-41.4) and portal vein invasion (3.94, 1.25-12.4) were independent factors for HCC recurrence. The recurrence-free survival rates of the high cccDNA group were significantly lower than those of the low cccDNA group only in patients who underwent resection (P=0.0438). A positive correlation (P=0.028; r=0.479) was observed between the intrahepatic cccDNA and the serum HBcrAg levels at the incidence of HCC. CONCLUSION: HBcrAg is a predictor of the post-treatment recurrence of HCC during antiviral therapy. Serum HBcrAg and intrahepatic cccDNA suppression by NAs may be important to prevent HCC recurrence. PMID- 20840397 TI - The homeostasis model assessment of the insulin resistance score is not predictive of a sustained virological response in chronic hepatitis C patients. AB - OBJECTIVES: To investigate the independent association between the homeostasis model assessment of the insulin resistance (HOMA-IR) score and rapid virological response (RVR) and sustained virological response (SVR) in chronic hepatitis C (CHC). METHODS: Observational prospective cohort study of 412 CHC patients [59% males; mean age 45 years; genotype 1 (44%), 2 (32%), 3 (19%) and 4 (5%)] treated with pegylated interferon alpha plus ribavirin. RESULTS: A HOMA-IR >=2.0 was present in 49% and a metabolic syndrome in 4% of patients. By multivariate analysis, independent predictors of SVR were the lack of advanced fibrosis (>=F3) in genotype 1 and a lower body mass index in genotype 3 patients. In the subgroup of patients in whom HCV-RNA was evaluated at week 4 (n = 281), independent predictors of RVR were HCV-RNA <700,000 IU/ml, age <40 years and lower aspartate aminotransferase:alanine aminotransferase ratio in genotype 1 and baseline HOMA IR <=2 in genotype 3 patients. No predictive factor of RVR was identified among genotype 2 patients. RVR was the strongest predictor of SVR among genotype 1 or 3 patients. CONCLUSIONS: In this series of treatment-naive, Caucasian CHC patients at a low risk for the metabolic syndrome, HOMA-IR is not a predictor of SVR, irrespective of the HCV genotype, although it may predict RVR in genotype 3 infection. PMID- 20840398 TI - Surgical simulators in training: are we there yet? PMID- 20840399 TI - A randomized trial evaluating a cognitive simulator for laparoscopic appendectomy. AB - BACKGROUND: The Integrated Cognitive Simulator (ICS) is a software application that integrates text, anatomy, video and simulation for training clinical procedures. The aim of this randomized controlled trial was to determine the usability of the ICS laparoscopic appendectomy module, and to determine its effectiveness in training the cognitive skills required for the procedure. METHODS: Junior surgical trainees were randomized into control and intervention groups. The latter had access to the ICS. Participants had three assessments: a pre-study questionnaire to determine demographics, 20 multiple choice questions to assess procedural knowledge (training effectiveness) after 2 weeks, and a questionnaire to assess usability after 4 months. RESULTS: Fifty-eight trainees were randomized. The overall response rate was 57%. The median scores for interface, functionality, usefulness and likelihood of utilization (usability) were 5/7 or higher. In the multiple choice questions (training effectiveness), first-year trainees in the intervention group scored higher than the control group (14.9 versus 12.1, P= 0.04), but second-year trainees did not. Use of the ICS did not alter the participants' perceived need for intra-operative guidance. CONCLUSIONS: The ICS is considered highly usable by trainees. The ICS is effective for training cognitive skills for laparoscopic appendectomy among first year surgical trainees. Training cognitive skills alone does not increase confidence in the ability to perform motor tasks. PMID- 20840400 TI - Total knee replacement in the morbidly obese: a literature review. AB - BACKGROUND: The 'obesity epidemic' is expected to result in an increased incidence of knee osteoarthritis and hence total knee replacements (TKRs). Reviews have demonstrated the conflicting results of TKR for all obese (body mass index (BMI) >30). The aim of this literature review was to specifically evaluate outcomes of TKR in patients with morbid obesity (MO; BMI >40). METHODS: A systematic review of medical databases (PubMed, Medline, Cochrane Library, ScienceDirect) by use of keywords from January 1990 to September 2009 was undertaken. RESULTS: Clinical and functional Knee Society Scores (KSS) improve after TKR for patients with MO. The post-operative functional KSS was, in general, less than in controls. Radiographic analysis was inconclusive because of small study populations and short duration of follow-up. All studies reporting complications noted a greater prevalence in MO patients (10-30%). Of concern was the significantly higher prevalence of deep prosthetic infection (3-9-times that of controls). The morbidly obese also had a significantly higher incidence of wound complications. TKR did not result in weight loss for MO patients, and therefore has no benefit on weight-related medical conditions. Bariatric surgery in MO under 65 years of age has been shown to be a cost-effective and clinically effective method of weight reduction. This surgery also results in significant improvement in weight-related medical conditions, the KSS and knee pain. CONCLUSIONS: Given the increase in complications for MO patients after TKR, these patients should be advised to lose weight before surgery and, if suitable, would probably benefit from bariatric surgery. PMID- 20840401 TI - Endoscopic ultrasound of pancreatic cystic lesions. AB - BACKGROUND: The impact of endoscopic ultrasonography (EUS) on the management of pancreatic cystic lesions remains unclear, and there are no published studies of the Australian experience in this area. The aim of this study was to review the experience of EUS for such lesions within our institution. METHODS: A retrospective review was undertaken of data collected prospectively over a two year period within the EUS database of St. Vincent's Hospital. Patients who underwent EUS for suspected pancreatic cystic lesions were identified. Data were collected on demographic variables, EUS findings, the results of EUS-guided fine needle aspiration (FNA) and the findings on clinical and radiological follow-up. RESULTS: Fifty-nine patients were identified. Two thirds were female. Most lesions were located at the pancreatic head. Median diameter was 25 mm. FNA was performed in 36 cases (61%). On cytology, six (17%) showed features of mucinous tumours and five (14%) showed adenocarcinoma. The remainder contained either non specific benign cells or insufficient epithelial tissue. Follow-up data on 48 cases (83%), after a median duration of 15 months, revealed that 15 lesions (31%) had been resected, including six serous and six mucinous tumours. The level of carcinoembryonic antigen in FNA specimens appeared to be higher in mucinous than in serous neoplasms. Twenty-four lesions had undergone repeat radiological imaging: only three had grown in size. CONCLUSIONS: EUS and FNA are useful procedures for assessing pancreatic cystic lesions. Malignant features are demonstrated in only a small minority. The majority of the remainder show no signs of progression during follow-up. PMID- 20840402 TI - Pancreaticoduodenectomy - outcomes from an Australian institution. AB - BACKGROUND: Operative morbidity and mortality rates have improved markedly since the first single-stage pancreaticoduodenectomy (PD) was performed by A. O. Whipple in 1940. There is a lack of published data regarding outcomes of PD from Australian centres. The aim of this study was primarily to establish post operative morbidity and mortality rates of an Australian unit, and secondly, to investigate the value of preoperative investigation with endoscopic ultrasound and laparoscopy upon tumour stage and survival following PD. METHOD: A retrospective analysis was conducted on consecutive patients undergoing PD at St Vincent's Hospital from 1990 to 2006. Data were collected with particular reference to preoperative investigations, including endoscopic ultrasonography (EUS) and staging laparoscopy, and post-operative complications. Patient survival was determined from the hospital and consultant surgeons' records and telephone interviews with the patients' general practitioners. RESULTS: Eighty-one patients underwent PD, of which 58 were Whipple's procedures and 23 were pylorus preserving pancreaticoduodenectomies (PPPD). Twenty-six patients had EUS, and 22 had a staging laparoscopy before PD. The post-operative morbidity rate was 55% and included intra-abdominal collections (17%), major haemorrhage (10.7%), pancreatic anastomotic leakage (9%) and delayed gastric emptying (22%). The operative (30-day) mortality rate was 1.6%. There was no survival advantage in the EUS or the laparoscopy group. CONCLUSION: EUS and laparoscopy are useful modalities in the preoperative investigation and staging of patients being considered for PD. PD is a safe procedure with acceptable complication rates when carried out in a specialist unit experienced in this operation. PMID- 20840403 TI - A simple, safe technique for the drainage of pancreatic pseudocysts. AB - BACKGROUND: A number of methods are available for the drainage of pancreatic pseudocysts, including percutaneous, endoscopic and open approaches. In Leicester, we developed a combined radiological and endoscopic technique (predating the use of endoscopic/ultrasound) to allow drainage of pancreatic pseudocysts into the stomach. The aim of the study was to evaluate the long-term results of this approach. METHODS: This is a retrospective study of patients undergoing combined endoscopic/ultrasound-guided percutaneous stenting between 1994 and 2007. Data were extracted from case records and our computerised radiology database. RESULTS: Thirty-seven combined endoscopic/ultrasound-guided procedures were undertaken. Median patient age was 52 years (range 26-84 years). Nineteen pseudocysts were secondary to acute pancreatitis and 18 were in patients with chronic pancreatitis. The diameter of pseudocysts on pre-procedure imaging ranged from 4 to 21 cm (median 11 cm). Median duration of hospital stay was 7 days (range 1-44 days) and 30-day mortality was 0%. Stents were inserted in 70.3% of patients (n= 26). Of those patients stented during the combined procedure, three developed infection of the pseudocyst, necessitating open cystgastrostomy within the first month. During a mean follow-up period of 41 months, two patients developed recurrent pseudocysts which were successfully drained with a further combined procedure (16 and 43 months). Repeat imaging in the remainder of patients failed to show any evidence of a persistent or recurrent pseudocyst beyond 2 months. CONCLUSION: Combined radiological and endoscopic drainage is safe, cost-effective and highly efficient in preventing recurrent pseudocyst formation. PMID- 20840404 TI - Pancreatic solid pseudopapillary tumours - EUS FNA is the ideal tool for diagnosis. AB - BACKGROUND: Solid pseudopapillary tumour (SPT) is a rare tumour of the pancreas with low malignant potential affecting mainly young women difficult to diagnose preoperatively. The aim of this study is to describe the endoscopic ultrasound (EUS) features and utility of EUS-guided fine needle aspiration (FNA) in diagnosing these tumours. METHODS: A retrospective analysis of SPTs identified in a tertiary institution EUS database between April 2002 and April 2009 was performed. Medical records, imaging, EUS features, cytology and histology specimens were reviewed. Patients were followed up until April 2009. RESULTS: Seven cases of SPTs were indentified out of 2400 EUS performed. All patients were females with a mean age of 41 years (range 22-69). The tumours were solitary with a mean diameter of 2.9 cm (range 2-4.3 cm). Five tumours were located in the body and tail of the pancreas and two in the neck. All lesions were hypoechoic, heterogenous and well circumscribed, with five having a cystic component and two having a calcified rim. FNA using a 22-gauge needle was performed in six cases with no complications. A preoperative diagnosis of SPT based on cytology was obtained in 5/6 cases (83%). Surgical resection was done in six cases with confirmation of SPT and no metastatic disease. CONCLUSION: EUS-guided FNA is a minimally invasive, safe and reliable way of diagnosing SPT by providing characteristic cytological specimens. Definitive preoperative diagnosis leads to targeted and minimally invasive surgical resection. PMID- 20840405 TI - Pancreatic fistula after distal pancreatectomy: incidence, risk factors and management. AB - BACKGROUND: Pancreatic fistulae post distal pancreatectomy still leads to significant morbidity and if not properly managed, may lead to mortality. The identification of risk factors and effective management of patients with pancreatic fistulae is important in the prevention of these complications. METHODS: There were 75 open consecutive distal pancreatectomies in the Department of Surgery, Changi General Hospital from May 2001 to May 2007. RESULTS: The indications for operation were neuroendocrine tumours (n= 15), adenocarcinoma (n= 20), Intraductal papillary mucinous tumour (IPMT) (n= 20), serous cysts (n= 15) and trauma (n= 5). There were 20 patients (27%) who developed pancreatic fistulae in the whole series. On univariate analysis, the patients with pancreatic fistulae had significantly more pre-morbidities, softer pancreas and use of staplers as a method of closure of the pancreatic remnant. On multivariate analysis, the use of staplers and soft pancreas were significant independent risk factors for the development of pancreatic fistulae in our patient population. All of the patients with pancreatic fistulae were successfully treated non-surgically with no mortality in the whole series. CONCLUSIONS: The use of stapler on soft pancreas leads to a higher risk for pancreatic fistulae after distal pancreatectomies. Most pancreatic fistulae can be managed non-surgically with good outcome. PMID- 20840406 TI - Outcomes of the overlay graft technique in tympanoplasty. AB - BACKGROUND: This audit was undertaken to review the outcomes achieved with the overlay graft technique of tympanic membrane repair in tympanoplasty surgery. METHODS: The charts of all patients who underwent tympanoplasty, in whom an overlay graft technique of temporalis fascia tympanic membrane repair was used, between 1994 and 2007 were reviewed. Information with respect to patient demographics, presence of cholesteatoma or active infection and perforation size was documented. Details of the surgical procedure and clinical outcomes and pre- and post-operative hearing thresholds were recorded in a computer database. RESULTS: A total of 147 overlay graft procedures were performed in 130 patients. Graft failure with reperforation occurred following five procedures, for an overall success rate of 96.6%. Eighty Type 1 tympanoplasty procedures were performed in which one failure occurred for a 98.75% success rate. Overlay grafting was combined with intact canal wall mastoidectomy (ICW) in 38 cases and with modified radical mastoidectomy (MRM) in 17 cases for a success rate of 93.8 and 95%, respectively. Delayed graft healing as a result of infection, problems such as epithelial pearl, blunting and myringitis occurred in 39 cases (26.5%). Thirty-one cases underwent procedures for ossicular chain reconstruction, 21 of which were 2nd stage procedures. Hearing outcomes were significantly better with Type 1 tympanoplasty compared with ICW or MRM procedures. CONCLUSION: This review demonstrates the overlay graft technique of tympanoplasty to be highly successful for tympanic membrane repair, particularly for the more difficult cases such as revision surgery, subtotal perforations and mesotympanic cholesteatoma. PMID- 20840407 TI - Prevalence of abdominal aortic aneurysm in Chinese patients with severe coronary artery disease. AB - BACKGROUND: The Asian population is believed to have lower incidence of abdominal aortic aneurysm (AAA), and hence, the benefit of screening is uncertain. The size of native aorta in Asians, which shall affect the definition of AAA, has also never been reported. Our study investigated the prevalence of AAA and the infra renal aortic diameter (AD) in Chinese patients with severe coronary artery disease. METHODS: This is a prospective observational study of infra-renal aortic size for patients who had coronary artery bypass surgery by ultrasound. The patients' demographics, important co-morbidities and maximum AD were recorded. RESULTS: The study included 624 consecutive Chinese patients (mean age = 63.2 years). The mean maximum infra-renal AD was 17.5 mm for men and 14.8 mm for women. The presence of AAA was defined as maximum AD greater than 30 mm. The result was also compared with an alternate definition that defines AAA as maximum AD of greater than 1.5 times of the group's mean. Eleven patients had an AD greater than 30 mm, and the prevalence of AAA was only 1.8%. With AAA defined as maximum AD of 1.5 times greater than the group's mean, 19 patients had AAA. The prevalence of AAA in this high-risk group would become 3% overall. CONCLUSION: The prevalence of AAA in Chinese patients was low, and the result did not support routine screening. The smaller mean infra-renal AD in Chinese merits validation by large-scale study and consideration when deciding threshold for small AAA repair in our locality. PMID- 20840408 TI - The impact of volume on outcomes after oesophageal cancer surgery. AB - Oesophageal cancer is an aggressive disease with a poor prognosis. Oesophagectomy is an established, potentially curative treatment, for patients with resectable oesophageal cancer. The anatomical location of the oesophagus explains why this type of operation is one of the most demanding and traumatic surgical procedures undertaken in general surgery. Unfortunately, the risk for severe post-operative complications is high and the chance for cure remains low. It is, however, encouraging that the post-operative morbidity has been decreasing and the survival has been improving during recent years. Several factors might have contributed to this improvement, including the centralization of oesophageal cancer surgery to high volume centres. This review focuses on the impact of hospital and surgeon volume on various outcomes after oesophagectomy for oesophageal cancer. Most available research indicates that, as far as post operative complications, early post-operative mortality and health economics after oesophagectomy are concerned, high surgery volume is to be recommended, while the few studies evaluating long-term survival and health-related quality of life adjusted for tumour stage found no evidence of a role for volume. In conclusion, the available literature supports the centralization of oesophagectomy for cancer to dedicated centres with a multidisciplinary approach and a good track record of valid clinical research. PMID- 20840409 TI - Ulceration and antihypertensive use are risk factors for infection after skin lesion excision. AB - BACKGROUND: A prospective audit was performed of wound complications of skin lesion excision in a private practice setting. METHODS: For 924 consecutive skin lesion excisions performed by a single surgeon, information was collected on tumour size and site, closure method and on risk factors of age, known diabetes, use of steroids, antihypertensives or anticoagulants and ulceration of the lesion. Patients were given written instructions to wet the wound in the shower after one or two days. A wound 'infection' event was recorded if the wound appeared inflamed or if the patient had been treated with antibiotics by any practitioner. Wound bleeding was recorded if the patient returned or attended elsewhere for management of bleeding. RESULTS: Sixty-seven wounds (7.25%) met the broad definition of 'infection' and 18 (1.9%) wounds suffered bleeding. Ulceration (odds ratio (OR) 3.15, P= 0.008) and use of antihypertensives (OR 2.5, P= 0.006) were independent risk factors for infection along with site and closure method. The patients who did not wet their wounds post-operatively were also at an increased risk of infection (OR 2.1, P= 0.018). Aspirin caused a slight, non statistically significant increase in bleeding rate, and warfarin caused a larger, but still not statistically significant, increase in bleeding. Use of other anticoagulants caused a significant increase in bleeding (OR 10.9, P= 0.006). CONCLUSION: Ulceration of the skin lesion and use of antihypertensives are significant risk factors for wound infection. Wetting surgical wounds with clean tap water does not increase, and may even reduce, wound infection rate. PMID- 20840410 TI - Predicting occult malignancy in nipple discharge. AB - BACKGROUND: This study was a retrospective analysis of patients who underwent minor or major duct surgery for pathological nipple discharge. The results of clinical examination, mammography, ultrasonography and cytodiagnosis of the nipple discharge were studied in order to predict those patients at risk of underlying or occult malignancy. METHODS: Between January 2004 and December 2006, 55 female patients aged between 24 and 82 years old underwent major or minor duct excision, 49 of which were for pathological nipple discharge. Results of several preoperative investigations were compared with the surgical pathology to determine how their sensitivity and specificity faired in predicting malignant ductal pathology. RESULTS: Of the 49 patients undergoing surgery for nipple discharge, 21 were diagnosed with intraductal papilloma, 19 with duct ectasia, 6 with carcinoma, 2 with benign breast disease and 1 with lobular carcinoma in situ. In all of the patients determined to have malignancy, none demonstrated malignant changes on mammography or ultrasonography. Only 2 of the 6 patients with malignancy were found to have atypical cells on cytological analysis. The sensitivity of blood detected in nipple discharge at predicting malignancy was 0.83, specificity of 0.53, positive predictive value of 0.20 and negative predictive value 0.96. CONCLUSIONS: Despite the various tests used in the assessment of pathological nipple discharge, this study highlights their limited help at predicting the cause. This, together with several other studies, demonstrates that ductal surgery remains the only reliable way of providing a diagnosis, in addition to being the major therapeutic measure. PMID- 20840413 TI - Pain or gain: new innovations and trends in hernia repair (ANZ J. Surg. 2009; 79: 778-80). PMID- 20840414 TI - Use of face masks by non-scrubbed operating room staff (ANZ J. Surg. 2010; 80: 169-73). A note of caution. PMID- 20840415 TI - Trauma may cause Spigelian herniae in children. PMID- 20840416 TI - Congenital metacarpal malformation: fifth metacarpal complete absence or fourth and fifth metacarpal synostosis. PMID- 20840417 TI - A twist in the line could save time: insertion of central venous access catheter. PMID- 20840418 TI - Severe perineal burns. PMID- 20840419 TI - Pancreatic remnant carcinoma after pancreaticoduodenectomy for bile duct cancer. PMID- 20840420 TI - Pericardial cyst presented in an unusual location. PMID- 20840421 TI - Angiodysplasia resistant to endoscopic therapy. PMID- 20840422 TI - Beware of kissing carotids. PMID- 20840423 TI - Sublingual gland tumor: do not forget to rule out a metastasis. PMID- 20840424 TI - Subcostal approach laparoscopic cholecystectomy in patients with previous abdominal surgery. PMID- 20840425 TI - Response to: Use of face masks by non-scrubbed operating room staff: a randomized controlled trial. PMID- 20840427 TI - The second modern condition? Compressed modernity as internalized reflexive cosmopolitization. AB - Compressed modernity is a civilizational condition in which economic, political, social and/or cultural changes occur in an extremely condensed manner in respect to both time and space, and in which the dynamic coexistence of mutually disparate historical and social elements leads to the construction and reconstruction of a highly complex and fluid social system. During what Beck considers the second modern stage of humanity, every society reflexively internalizes cosmopolitanized risks. Societies (or their civilizational conditions) are thereby being internalized into each other, making compressed modernity a universal feature of contemporary societies. This paper theoretically discusses compressed modernity as nationally ramified from reflexive cosmopolitization, and, then, comparatively illustrates varying instances of compressed modernity in advanced capitalist societies, un(der)developed capitalist societies, and system transition societies. In lieu of a conclusion, I point out the declining status of national societies as the dominant unit of (compressed) modernity and the interactive acceleration of compressed modernity among different levels of human life ranging from individuals to the global community. PMID- 20840428 TI - Redefining second modernity for East Asia: a critical assessment. AB - The aim of this paper is to critically assess the extent to which the concept of second modernity and reflexive modernization proposed by Beck and Grande is relevant to East Asia. Concepts such as driving forces, human agency, objective structural versus cultural-discursive dimensions, radicalizing versus deficiencies aspects of modernity, push versus pull factors are used to clarify the basic conditions of this historical transformation. Utilizing these conceptual schemes, this paper has advanced the following central claims: 1) Second modernity and reflexive modernization, as a global trend, affects East Asia as deeply as it does in the West, especially when we see this as a structurally conditioned historical transformation; 2) Global risks, as a driving force of second modernity, are more relevant in East Asia because, as a result of the side-effects of the rush-to development, East Asian countries face complex risks of far greater intensity than in the West; 3) The action-mediated pull factor of second-modern transformation in East Asia, expressed through the cultural-discursive articulation of collective desire and aspiration, differs significantly from the West. Consequently, the East Asian pathways to individualization display distinctive characteristics despite the common structural background where push factors operate; 4) East Asia also differs from the West in terms of the normative vision anchored in second modernity; 5) Nevertheless, concrete pathways to second modernity within East Asia differ from one country to another. PMID- 20840429 TI - The Chinese path to individualization. AB - This article explores the rise of the individual and the consequential individualization of society which should be viewed as a reflexive part of China's state-sponsored quest for modernity. It traces the origin of the individualization process to the Maoist era, arguing that some collectivist programmes of social engineering and the socialist path of modernization under Maoism ironically resulted in a partial individualization of Chinese society. Examining profound social changes during the three decades of the post-Mao reforms, the article reveals a number of similarities with the individualization process in Western Europe but also demonstrates some important differences. In the last section, the theoretical implications of the Chinese case in light of Ulrich Beck's theory of individualization and second modernity are discussed. PMID- 20840430 TI - Individualizing Japan: searching for its origin in first modernity. AB - Since the mid-1990s Japanese society has entered a period of major change. The previous patterns of social order and social integration have collapsed, and it has become increasingly difficult to envision a stable life course for oneself. The 'secure' foundation has been weakening and anxiety has spread at an accelerated pace. Japan could enter the age of second modernity, or reflexive modernization. In Japan's first modernity, the mechanism responsible for risk management, an integrated society, and stabilized social order, was, first, private corporations that guaranteed long-term stability for employees and their families (company-centrism) and, second, land development rapidly implemented under the guidance of bureaucrats (developmentalism). From the 1990s, these systems were fundamentally destroyed by globalization and neoliberal policies. Private corporations limited the groups that could benefit from the seniority wage system, undermining in-house welfare benefits. The government abandoned its role of improving the industrial and economic conditions of surrounding areas through offering public works projects. After these risk-stabilizing mechanisms were gone, two problems became conspicuous - poverty among young workers in urban areas and the collapse of the local community in marginal areas. As the seniority wage system and lifetime employment were substitutes for the public social security system, public measures to deal with poverty remain inadequate. Now, the individualization of the family has advanced somewhat under compulsion as the rate of unmarried people and the divorce rate have climbed. The Japanese have a tendency to seek 'self-realization'; at the same time, they also want 'secure employment'. Thus, they are torn between individualization and the desire for security. What is now necessary is a more stable system that will ensure them adequate material and spiritual 'elbowroom' to allow them to make their own choices. PMID- 20840431 TI - The stranded individualizer under compressed modernity: South Korean women in individualization without individualism. AB - South Korean families have functioned as a highly effective receptacle for the country's highly compressed conditions of modernity and late modernity. It is as much due to the success of South Korean families as an engine of compressed modernity as due to their failure that they have become functionally overloaded and socially risk-ridden. Such familial burdens and risks are particularly onerous to South Korean women because of the fundamentally gender-based structure of family relations and duties that has in part been recycled from the Confucian past and in part manufactured under industrial capitalism. Under these complicated conditions, South Korean women have had to dramatically restructure their family relations and duties as well as their individual life choices. Furthermore, under the most recent condition of what Beck calls second modernity, other institutions of modernity, such as the state, industrial economy, firms, unions, schools, and welfare systems, have become increasingly ineffective in helping to alleviate such (gender-based) familial burdens and dilemmas. As a result South Korean women have experienced dramatic changes in marriage patterns, fertility, family relations, etc. South Korean women's individualization has thereby taken place primarily as a matter of practicality rather than ideational change. A brief analysis of the situation in the neighbouring societies of Japan and Taiwan reinforces the conclusion that individualization without individualism, particularly among women, is a region-wide phenomenon in East Asia. PMID- 20840432 TI - 'Small change of the universal': beyond modernity? AB - The paper is a sounding of Ulrich Beck's and Edgar Grande's conceptual map of the varieties of second modernity - Western and Non-Western, European and beyond - that makes up today's world. Their mapping is examined in the light of two, striking analytical perspectives associated with Ulrich Beck: everyday 'cosmopolitization' and his call for a methodological cosmopolitanism. A line of inquiry explores whether contemporary modernities are essentially expressions of a single, underlying modernization drive or whether they are utterly disparate entities. The implications of treating them as 'variants and variations' are unpacked with reference to musical models and how they generate difference. The probe into methodological cosmopolitanism touches on 'de-provincialization' that is somewhat at odds with the postcolonial project of 'provincializing' Europe. It looks at the attempt to go beyond 'nation-bound' sociological dualisms in determining the appropriate 'unit of analysis' for our ever-morphing current reality. Does this imply engaging with 'singularity'- with a mode of conceptualization that sidesteps the universal/particular couple and related either/or thinking? References to the making of the 'first modernity' under unequal centre/periphery relations of colonial power are aired for possible lessons in mappings of the second. Ulrich Beck's 'impure, really-existing cosmopolitanism'- in contrast to its speculative counterpart derived from the realm of pure ideas - springs from humdrum global economic and political links and institutions that span out across, above and beyond the 'container of the national space'. With the inadvertent cosmopolitical impact of the migrations it amounts in practice to a functioning 'cosmopolitan realpolitik'. Is there room for it to develop or will it stall as a mere front for national, tribal territorial interests - going the way of 'multiculturalism and diversity' that seem increasingly to serve as governmental ideologies for managing global difference? Whether each of the varieties of second modernity throws up a 'cosmopolitan vision' of its own remains to be determined more fully. It seems possible that friction between the modernities might fetch up on a higher plane as clashing cosmopolitanisms. Historical precedents give scant comfort if we look at the fate of the ecumenic empires of the ancient world of the 'first cosmopolitan age' or at landmark cosmopolitan endeavours such as Aby Warburg's and WEB Du Bois' on the eve of counter-cosmopolitan currents of the 1930s. An abiding scepticism prevails about the capacity of 'impure cosmopolitanism' to bootstrap and elaborate itself from an involuntary, reflex condition into a self reflexive, critical dispensation. PMID- 20840433 TI - Recursive cosmopolitization: Argentina and the global Human Rights Regime. AB - This paper illustrates how varieties of cosmopolitanism are shaped through a mutually constitutive set of cultural dispositions and institutional practices that emerge at the interstices of global human right norms and local legal practices. Converging pressures of 'cosmopolitan imperatives' and the multiplicity of particularized manifestations are co-evolving in the context of intercrossings during which distinctive cosmopolitanisms are established. This complex relationship of global normative expectations and their local appropriations is elucidated through the dynamic of recursive cosmopolitization. Suggesting that, local problems are resolved with recourse to global prescriptions while local solutions are inscribed in international institutions consolidating the global Human Rights Regime. The Argentinean case carries conceptual and empirical weight as it underscores the recursivity of cosmopolitization by calibrating the tensions of universalism and particularism at the intersection of global, national and regional scales. Argentina is a paradigmatic instantiation for how cosmopolitanism can emanate in the periphery as local problems are globalized. This, in turn, has resulted in the institutionalization of a global Human Rights Regime which exercises normative and political-legal pressures on how states legitimately deal with human rights abuses. It is this cosmopolitan balance, rather than presuppositions of universalistic exogenous pressures or particularistic national exceptions, which is shaping the cultural and political relevance of human rights norms. PMID- 20840434 TI - Beck, Asia and second modernity. AB - The work of Ulrich Beck has been important in bringing sociological attention to the ways issues of risk are embedded in contemporary globalization, in developing a theory of 'reflexive modernization', and in calling for social science to transcend 'methodological nationalism'. In recent studies, he and his colleagues help to correct for the Western bias of many accounts of cosmopolitanism and reflexive modernization, and seek to distinguish normative goals from empirical analysis. In this paper I argue that further clarification of this latter distinction is needed but hard to reach within a framework that still embeds the normative account in the idea that empirical change has a clear direction. Similar issues beset the presentation of diverse patterns in recent history as all variants of 'second modernity'. Lastly, I note that ironically, given the declared 'methodological cosmopolitanism' of the authors, the empirical studies here all focus on national cases. PMID- 20840435 TI - Planetarity and cosmopolitics. AB - This comment responds to the articles assembled by Beck and Grande (BJS 2010). It argues that their important approach has been extended in novel directions by these contributions and that the goal represented by a cosmopolitan sociology is pending in the expansion of the dialogue these pieces initiate. PMID- 20840436 TI - Rewriting the Persian letters. PMID- 20840437 TI - Transplantation of adult-sized kidneys in low-weight pediatric recipients achieves short-term outcomes comparable to size-matched grafts. AB - Low-weight pediatric recipients are disadvantaged by scarcity of size-matched donors. ASK have been successfully used for pediatric recipients. We report the results of renal transplantation using ASK in low-weight pediatric recipients and compare outcomes in weight-matched and unmatched donor-recipient pairs. The outcomes of renal transplants using ASK grafts in low-weight (<20 kg) recipients from a single center over a 10-yr period were reviewed. Two groups, comprising recipients of grafts from weight-matched and mismatched donors, were compared. Primary outcome was one-yr graft survival. Secondary outcomes were one- and two yr calculated eGFR, changes in recipient body weight, perioperative cardiovascular stability, rates of AR and DGF. Twenty-three low-weight recipients were transplanted. Eleven received ASK grafts from high-weight donors and 12 grafts from low-weight donors. One patient in each group had early graft loss. No significant difference was observed in rates of DGF, AR, one-yr graft or patient survival and perioperative cardiovascular parameters. ASK with considerable donor:recipient weight discrepancies can be safely transplanted into small pediatric recipients with comparable outcomes to grafts with less weight discrepancy. PMID- 20840438 TI - Testing new drugs in naked apes and getting the dose right in their young. PMID- 20840439 TI - Clinical pharmacodynamics and pharmacokinetics of the antifungal extended spectrum triazole posaconazole: an overview. AB - In recent years, the antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. Although oral bioavailability of posaconazole can be enhanced by concomitant food intake and administration in divided daily doses, increased gastric pH or gut motility, as well as enzyme-inducing drugs, can result in lower plasma concentrations than expected. Whether therapeutic drug monitoring can reduce the risk of treatment failures by avoiding sub-therapeutic plasma concentrations needs further examination. Based on the ability of posaconazole to inhibit cytochrome P450 3A4, several drug interactions can be expected, especially with agents that undergo extensive first-pass effect through the gut and the liver. However, more information is needed regarding dose modifications during concomitant administration of posaconazole with drugs in certain categories, such as vinca alkaloids and retinoids, along with selected individual drugs such as everolimus. PMID- 20840440 TI - Information about adverse drug reactions reported in children: a qualitative review of empirical studies. AB - AIM: To review the literature on adverse drug reactions (ADRs) in children with respect to occurrence, seriousness, type, therapeutic group, age and gender of the child and category of reporter. METHODS: Medline and Embase databases were searched from origin and updated until February 2010. We included empirically based articles on ADRs in populations aged 0 to 17 years. Studies monitoring ADRs in patients with particular conditions or drug exposure were excluded. We extracted information about types and seriousness of ADRs, therapeutic groups, age and gender of the child and category of reporter. ADR occurrence was calculated as incidence rate and prevalence. RESULTS: We included 33 studies monitoring ADRs in general paediatric populations. The highest numbers of ADRs were reported in national ADR databases where data were collected over a longer period than in studies monitoring inpatients and outpatients. However, prevalence and incidence were much lower in the national databases. Types of reported ADRs, seriousness of ADRs and types of medicines differed substantially between studies due to differences in time periods and patient populations. Information about ADRs was mainly provided by health care professionals, although parents also contributed reports. CONCLUSIONS: We found a higher incidence rate of ADRs in hospitalized children and outpatients than in national databases. There seems to be considerable potential for increasing the knowledge of ADRs by advocating the submission of reports to the spontaneous reporting systems. Our study underscores that ADRs in children constitute a significant public health problem. PMID- 20840441 TI - eDrugCalc: an online self-assessment package to enhance medical students' drug dose calculation skills. AB - AIMS: Dose calculation errors can cause serious life-threatening clinical incidents. We designed eDrugCalc as an online self-assessment tool to develop and evaluate calculation skills among medical students. METHODS: We undertook a prospective uncontrolled study involving 1727 medical students in years 1-5 at the University of Edinburgh. Students had continuous access to eDrugCalc and were encouraged to practise. Voluntary self-assessment was undertaken by answering the 20 questions on six occasions over 30 months. Questions remained fixed but numerical variables changed so each visit required a fresh calculation. Feedback was provided following each answer. RESULTS: Final-year students had a significantly higher mean score in test 6 compared with test 1 [16.6, 95% confidence interval (CI) 16.2, 17.0 vs. 12.6, 95% CI 11.9, 13.4; n= 173, P < 0.0001 Wilcoxon matched pairs test] and made a median of three vs. seven errors. Performance was highly variable in all tests with 2.7% of final-year students scoring < 10/20 in test 6. Graduating students in 2009 (30 months' exposure) achieved significantly better scores than those in 2007 (only 6 months): mean 16.5, 95% CI 16.0, 17.0, n= 184 vs. 15.1, 95% CI 14.5, 15.6, n= 187; P < 0.0001, Mann-Whitney test. Calculations based on percentage concentrations and infusion rates were poorly performed. Feedback showed that eDrugCalc increased confidence in calculating doses and was highly rated as a learning tool. CONCLUSIONS: Medical student performance of dose calculations improved significantly after repeated exposure to an online formative dose-calculation package and encouragement to develop their numeracy. Further research is required to establish whether eDrugCalc reduces calculation errors made in clinical practice. PMID- 20840442 TI - Development and validation of a new Prescription Quality Index. AB - AIMS: The aims were to develop and validate a new Prescription Quality Index (PQI) for the measurement of prescription quality in chronic diseases. METHODS: The PQI were developed and validated based on three separate surveys and one pilot study. Criteria were developed based on literature search, discussions and brainstorming sessions. Validity of the criteria was examined using modified Delphi method. Pre-testing was performed on 30 patients suffering from chronic diseases. The modified version was then subjected to reviews by pharmacists and clinicians in two separate surveys. The rater-based PQI with 22 criteria was then piloted in 120 patients with chronic illnesses. Results were analysed using SPSS version 12.0.1 RESULTS: Exploratory principal components analysis revealed multiple factors contributing to prescription quality. Cronbach's alpha for the entire 22 criteria was 0.60. The average intra-rater and inter-rater reliability showed good to moderate stability (intraclass correlation coefficient 0.76 and 0.52, respectively). The PQI was significantly and negatively correlated with age (correlation coefficient -0.34, P<0.001), number of drugs in prescriptions (correlation coefficient -0.51, P<0.001) and number of chronic diseases/conditions (correlation coefficient -0.35, P<0.001). CONCLUSIONS: The PQI is a promising new instrument for measuring prescription quality. It has been shown that the PQI is a valid, reliable and responsive tool to measure quality of prescription in chronic diseases. PMID- 20840443 TI - Prescribing pattern of anti-epileptic drugs in an Italian setting of elderly outpatients: a population-based study during 2004-07. AB - AIMS: The aims of the study were to assess the trend of older and newer anti epileptic drugs (AEDs) in the elderly population and to analyze the effects of a health-policy intervention with regard to AED use in general practice in a setting in Southern Italy. METHODS: Data were extracted from the 'Caserta-1' Local-Health-Unit Arianna database in the years 2004-07. Patients aged over 65 years, receiving at least one AED prescription and registered in the lists of 88 general practitioners, were selected. The use of older and newer AEDs was calculated as 1 year prevalence and incidence of use and defined daily dose (DDD) per 1000 inhabitants day(-1) . Sub-analyses by gender, age and indication of use were performed. RESULTS: Most of AED users were treated because of neuropathic pain (64.8%). However, the main indication of use for older AEDs (57.8%) was epilepsy, whereas newer AEDs (79.5%) were used for neuropathic pain. Prevalence and incidence of newer AED use increased until 2006, followed by a reduction in 2007. Newer AEDs, particularly gabapentin and pregabalin, were used in the treatment of more patients than older AEDs. However phenobarbital, accounting for more than 50% of total AED volume, was the most prescribed medication during the entire study period. CONCLUSIONS: An increasing use of AEDs has been observed during 2004-07, mostly due to the prescription of newer compounds for neuropathic pain. The fall in the use of newer AEDs during 2007 coincides with revised re imbursement criteria for gabapentin and pregabalin. The large use of phenobarbital in the elderly should be considered in the light of a risk of adverse drug reactions. PMID- 20840444 TI - Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug-drug interaction trials. AB - AIMS: To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6 mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates. RESULTS: The mean population estimates of the first order absorption rate constant (k(a) ), apparent clearance (CL/F) and apparent volume of distribution at steady state (V(ss) /F) were 0.15h(-1) , 111 lh(-1) and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 lh(-1) with between-subject variability of 84%. d-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second d-optimal sample was earlier at 14 and 19h, respectively, compared with 24h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates. CONCLUSIONS: A two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds. PMID- 20840445 TI - Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine. AB - AIM: To evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed. METHODS: Three open-label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration-time data were analyzed using standard non-compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs). RESULTS: The AUC(0,infinity) of midazolam was increased 1.44-fold (90% CI 1.35, 1.54) and 1.52-fold (90% CI 1.41, 1.65) after co-administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,infinity) was increased 1.45- (90% CI 1.32, 1.59), 2.02- (90% CI 1.75, 2.32), and 2.67-fold (90% CI 2.18, 3.27) after co administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,infinity) was increased 1.51- (90% CI 1.40, 1.63) to 3.49-fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,infinity) was increased 1.56- (90% CI 1.37, 1.78) and 1.77-fold (90% CI 1.54, 2.04) after co-administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration. CONCLUSIONS: Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A. PMID- 20840446 TI - The genome-wide expression profile of Curcuma longa-treated cisplatin-stimulated HEK293 cells. AB - AIM: The rhizome of turmeric, Curcuma longa (CL), is a herbal medicine used in many traditional prescriptions. It has previously been shown that CL treatment showed greater than 47% recovery from cisplatin-induced cell damage in human kidney HEK 293 cells. This study was conducted to evaluate the recovery mechanisms of CL that occur during cisplatin induced nephrotoxicity by examining the genome wide mRNA expression profiles of HEK 293 -cells. METHOD: Recovery mechanisms of CL that occur during cisplatin-induced nephrotoxicity were determined by microarray, real-time PCR, immunofluorescent confocal microscopy and Western blot analysis. RESULTS: The results of microarray analysis and real time PCR revealed that NFkappaB pathway-related genes and apoptosis-related genes were down-regulated in CL-treated HEK 293 cells. In addition, immunofluorescent confocal microscopy and Western blot analysis revealed that NFkappaB p65 nuclear translocation was inhibited in CL-treated HEK 293 cells. Therefore, the mechanism responsible for the effects of CL on HEK 293 cells is closely associated with regulation of the NFkappaB pathway. CONCLUSION: CL possesses novel therapeutic agents that can be used for the prevention or treatment of cisplatin-induced renal disorders. PMID- 20840447 TI - Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children. AB - AIMS: This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS: The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n= 27) or by mouth as syrup (n= 37). A single cerebrospinal fluid (CSF) sample (n= 60) was collected at the induction of anaesthesia, and plasma samples (n= 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS: Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96l h(-1) 70 kg(-1) . Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (V(ss) ) was 8.1 l 70 kg(-1) . Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS: Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6months, while more research is needed in neonates and in younger infants. PMID- 20840448 TI - Population pharmacokinetics of mycophenolic acid in children and young people undergoing blood or marrow and solid organ transplantation. AB - AIMS: To characterize the population pharmacokinetics of mycophenolic acid (MPA) and evaluate dose regimens using a simulation approach and accepted therapeutic drug monitoring targets in children and young people undergoing blood or marrow, kidney and liver transplantation. METHODS: MPA concentration-time data were collected using an age specific sampling protocol over 12h. Some patients provided randomly timed but accurately recorded blood samples. Total and unbound MPA were measured by HPLC. NONMEM was employed to analyze MPA pharmacokinetic data. Simulations (n= 1000) were conducted to assess the suitability of the MPA dose regimens to maintain total MPA AUC(0,12h) within the range 30 and 60mg l(-1) h associated with optimal outcome. RESULTS: A two-compartment pharmacokinetic model with first-order elimination best described MPA concentration-time data. Population mean estimates of MPA clearance, inter-compartmental clearance, volumes of distribution in the central and peripheral compartments, absorption rate constant and bioavailability were 6.42 l h(-1) , 3.74 l h(-1) , 7.24 l, 16.8l, 0.39h(-1) and 0.48, respectively. Inclusion of bodyweight and concomitant ciclosporin reduced the inter-individual variability in CL from 54.3% to 31.6%. Children with a bodyweight of 10kg receiving standard MPA dose regimens achieve an MPA AUC below the target range suggesting they may be at a greater risk of acute rejection. CONCLUSIONS: The population pharmacokinetic model for MPA can be used to explore dosing guidelines for safe and effective immunotherapy in children and young people undergoing transplantation. PMID- 20840449 TI - Degarelix, a novel GnRH antagonist, causes minimal histamine release compared with cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples. AB - AIMS: Early studies on gonadotrophin-releasing hormone (GnRH) antagonists pointed out histamine-mediated anaphylactic reactions as a potential adverse effect of these drug candidates. In this study we have compared the histamine-releasing potential of four approved and marketed antagonists, degarelix, cetrorelix, abarelix and ganirelix in an ex vivo model of human skin samples. METHODS: Human skin samples were obtained during cosmetic plastic surgery and kept in oxygenated saline solution. The samples were incubated either without or at different concentrations of the antagonists (3, 30 or 300 ug ml(-1) for all, except for ganirelix 1, 10 or 100 ug ml(-1) ). The drug-induced effect was expressed as the increase relative to basal release. The histamine-releasing capacity of the skin was verified by a universal histamine releaser, compound 40/80. RESULTS: Degarelix had no significant effect on basal histamine release in the 3 to 300 ug ml(-1) concentration range. The effect of ganirelix was moderate causing a nonsignificant increase of 81 +/- 27% at the 100 ug ml(-1) concentration. At 30 and 300 ug ml(-1) concentrations abarelix (143 +/- 29% and 362 +/- 58%, respectively, P < 0.05) and cetrorelix (228 +/- 111% and 279 +/- 46%, respectively, P < 0.05) caused significantly increased histamine release. CONCLUSIONS: In this ex vivo human skin model, degarelix displayed the lowest capacity to release histamine followed by ganirelix, abarelix and cetrorelix. These findings may provide indirect hints as to the relative likelihood of systemic anaphylactic reactions in clinical settings. PMID- 20840451 TI - Development of learning outcomes for an undergraduate prescribing curriculum (British Pharmacological Society prescribing initiative). AB - AIMS: The question of whether new medical graduates are adequately prepared for the challenge of prescribing has been raised. Although broad outcomes for prescribing competency have been agreed, clarity is needed on the detailed outcomes expected of new graduates. This study aimed to create a consensus on the required competencies for new graduates in the area of prescribing. METHODS: We used a modified Delphi approach based on the findings of a systematic review of educational interventions for improved prescribing. Panellists were asked to rank the importance of a list of 53 possible learning outcomes and to add any additional outcomes felt to be missing. RESULTS: Of the 48 experts who were invited to participate, 28 agreed (58%). Forty-five learning outcomes were included from the original list of 53. A further nine outcomes were suggested by panellists, of which five were included. The wording of three outcomes was changed in line with suggestions from the panellists. Many of the agreed outcomes relate to improving patient safety through medication review, checking appropriateness of the drug for the patient, recognizing the prescriber's limitations and seeking advice when needed. Enhanced communication with the patient and healthcare team, better documentation in the notes and discharge letters were key areas featured in this Delphi exercise. DISCUSSION: This study has identified 50 learning outcomes for teaching prescribing. These build on the existing British Pharmacological Society document by focusing specifically on prescribing, with greater emphasis on avoiding medication errors and better communication. PMID- 20840450 TI - Do selected drugs increase the risk of lupus? A matched case-control study. AB - AIM: To investigate the association between risk of lupus and exposure to selected drugs implicated in risk of lupus in a number of case reports. METHODS: In this matched nested case-control study we utilized primary care data from the UK General Practice Research Database recorded between 1987 and 2001. Cases with at least one medical code for systemic lupus erythematosus or drug-induced lupus in their computerized records were matched to controls without a medical code for lupus or any other autoimmune disorder. Using conditional logistic regression we computed odds ratios (OR) and 95% confidence intervals (CI) for risk of lupus associated with exposure to selected drugs. RESULTS: There were 875 incident cases, of which 12% (n= 107) had evidence of a prescription for one or more of the suspected drugs, and 3632 matched controls. For some drugs, prescriptions were too uncommon to be able to estimate associated risk of lupus. Despite small numbers of exposed patients and low statistical precision we observed an increased risk of lupus for hydralazine (OR = 6.62, 95% CI 1.03, 42.74), minocycline (OR = 4.23, 95% CI 2.65, 6.75) and carbamazepine (OR = 1.88, 95% CI 1.09, 3.22). There was some indication that the effect of carbamazepine was restricted to women (P for interaction by gender = 0.047). CONCLUSION: This study shows that even those drugs suggested by case reports as causing lupus cannot all be clearly shown to be associated, even in a very large population-based database. Our findings support causal relationships for carbamazepine, minocycline and possibly hydralazine. Overall, drugs do not seem to be a major cause of lupus. PMID- 20840452 TI - Proteome mapping of overexpressed membrane-enriched and cytosolic proteins in sodium antimony gluconate (SAG) resistant clinical isolate of Leishmania donovani. AB - AIMS: This study aimed to identify differentially overexpressed membrane-enriched as well as cytosolic proteins in SAG sensitive and resistant clinical strains of L. donovani isolated from VL patients which are involved in the drug resistance mechanism. METHODS: The proteins in the membrane-enriched as well as cytosolic fractions of drug-sensitive as well as drug-resistant clinical isolates were separated using two-dimensional gel electrophoresis and overexpressed identified protein spots of interest were excised and analysed using MALDI-TOF/TOF. RESULTS: Six out of 12 overexpressed proteins were identified in the membrane-enriched fraction of the SAG resistant strain of L. donovani whereas 14 out of 18 spots were identified in the cytosolic fraction as compared with the SAG sensitive strain. The major proteins in the membrane-enriched fraction were ABC transporter, HSP-83, GPI protein transamidase, cysteine-leucine rich protein and 60S ribosomal protein L23a whereas in the cytosolic fraction proliferative cell nuclear antigen (PCNA), proteasome alpha 5 subunit, carboxypeptidase, HSP-70, enolase, fructose-1,6-bisphosphate aldolase, tubulin-beta chain have been identified. Most of these proteins have been reported as potential drug targets, except 60S ribosomal protein L23a and PCNA which have not been reported to date for their possible involvement in drug resistance against VL. CONCLUSION: This study for the first time provided a cumulative proteomic analysis of proteins overexpressed in drug resistant clinical isolates of L. donovani indicating their possible role in antimony resistance of the parasite. Identified proteins provide a vast field to be exploited for novel treatment strategies against VL such as cloning and overexpression of these targets to produce recombinant therapeutic/prophylactic proteins. PMID- 20840453 TI - Frequency and nature of drug-drug interactions in a Dutch university hospital. PMID- 20840454 TI - Acceptance of drug-drug interaction alerts and alert system design. PMID- 20840455 TI - Comparative effectiveness of white blood cell growth factors on neutropenia, infection, and survival in older people with non-Hodgkin's lymphoma treated with chemotherapy. AB - OBJECTIVES: To determine the effect of colony-stimulating factor (CSF) on incidence of febrile neutropenia, infection, and survival in older people with non-Hodgkin's lymphoma (NHL) treated with chemotherapy. DESIGN: Retrospective cohort study. SETTING: The Surveillance, Epidemiology, and End Results-Medicare database. PARTICIPANTS: Thirteen thousand two hundred twenty-three people diagnosed with NHL at age 65 and older (mean age 74.9, range 65-102) in 1992 to 2002 who received chemotherapy within 12 months of diagnosis. MEASUREMENTS: Primary prophylaxis was defined as CSF administered at the start of chemotherapy before febrile neutropenia or infection; secondary prophylaxis was defined as CSF use after febrile neutropenia or infection. RESULTS: Participants with five to nine administrations of primary prophylactic CSF had a 42% lower risk of febrile neutropenia (odds ratio (OR)=0.58, 95% confidence interval (CI)=0.41-0.83), and participants with 10 or more administrations had a 48% lower risk (OR=0.52, 95% CI=0.36-0.76) after adjusting for age, stage, histology, and comorbidity. Results did not differ significantly after adjusting for propensity score of receiving CSF. There was no significant association between primary prophylactic CSF and overall survival, but secondary prophylactic CSF was significantly associated with better survival. Four to 10 administrations of secondary prophylactic CSF was associated with 9% lower mortality risk (hazard ratio (HR)=0.91, 95% CI=0.84 0.99), 11 to 23 administrations was associated with 23% lower mortality risk (HR=0.77, 95% CI=0.71-0.84) and 24 or more administrations was associated with 13% lower mortality risk (HR=0.87, 95% CI+0.79-0.95) than in participants not receiving CSF after neutropenia or infection. CONCLUSION: Primary prophylactic CSF was observed to be effective in reducing the incidence of neutropenia and infection. These findings substantiate the clinical guidelines for recommending prophylactic CSF in older people with NHL receiving chemotherapy. PMID- 20840456 TI - Dynamics and regulation of endocytotic fission pores: role of calcium and dynamin. AB - Although endocytosis involves the fission pore, a transient structure that produces the scission between vesicle and plasma membranes, the dimensions and dynamics of fission pores remain unclear. Here we report that the pore resistance changes proceed in three distinct phases: an initial phase where the resistance increases at 31.7 +/- 2.9 GOmega/second, a slower linear phase with an overall slope of 11.7 +/- 1.9 GOmega/second and a final increase in resistance more steeply (1189 +/- 136 GOmega/second). The kinetics of these changes was calcium dependent. These sequential stages of the fission pore may be interpreted in terms of pore geometry as changes, first in pore diameter and then in pore length, according to which, before fission, the pore diameter consistently decreased to a value near 4 nm, whereas the pore length ranged between 20 and 300 nm. Dynamin, a mechanochemical GTPase, plays an important role in accelerating the fission event, preferentially in endocytotic vesicles of regular size, by increasing the rates of pore closure during the first and second phases of the fission pore, but hardly affected larger and longer-lived endocytotic events. These results suggest that fission pores are dynamic structures that form thin and long membrane necks regulated by intracellular calcium. Between calcium mediators, dynamin functions as a catalyst to increase the speed of single vesicle endocytosis. PMID- 20840457 TI - Medical student perspectives on geriatrics and geriatric education. AB - OBJECTIVE: To ascertain medical students' perspectives on geriatrics. DESIGN: Interpretative phenomenological analysis. SETTING: An allopathic, Liaison Committee on Medical Education-accredited, former Donald W. Reynolds Foundation grant recipient, U.S. medical school. PARTICIPANTS: Thirty fourth-year medical students who completed geriatric educational activities in all 4 years of medical school. MEASUREMENTS: Two researchers independently reviewed verbatim transcripts from five focus groups and identified themes using the constant comparative method. RESULTS: Seventeen themes that elaborate on students' perspectives on geriatrics were identified. Students reported not feeling appropriately engaged in geriatrics, despaired at the futility of care, were depressed by the decline and death of their patients, were frustrated by low reimbursement rates and low prestige despite fellowship training, were concerned about patients' unrealistic expectations and opportunities for litigation, felt unsure how to handle ethical dilemmas, and found communicating with older adults to be enjoyable but time consuming and challenging. They felt they had too much exposure to geriatrics in medical school. CONCLUSION: Current attitude scales fail to capture some of the dimensions uncovered in this study, whereas students did not mention other dimensions commonly included in attitude scales. Regarding curriculum development, students may find an integrated preclinical geriatric curriculum to be more relevant to their careers than a stand-alone curriculum. Clinical clerkships might be in a better position to emphasize the positive aspects of geriatrics and develop strategies to address students' negative attitudes. PMID- 20840458 TI - Systematic review: helping the young to understand the old. Teaching interventions in geriatrics to improve the knowledge, skills, and attitudes of undergraduate medical students. AB - It is unclear whether geriatrics-specific educational interventions lead to improvement in students' knowledge, skills, and attitudes and whether successful interventions possess any consistent features. This review examines the effect of educational interventions on undergraduate knowledge, skills, and attitudes in geriatric medicine and concludes that a wide range of innovative designs have the potential to improve each of these parameters, although evidence of interventions that improve student skills is lacking, and further research is necessary to confirm the efficacy of specific teaching strategies in geriatrics. PMID- 20840459 TI - Teaching undergraduate geriatrics in the anatomy laboratory. PMID- 20840460 TI - Sleep duration and mortality according to health status in older adults. AB - OBJECTIVES: To examine the association between usual sleep duration and mortality according to physical and mental health status in older adults. DESIGN: Prospective study conducted from 2001 to 2008. SETTING: Community-based study. PARTICIPANTS: Cohort study of 3,820 persons representative of the noninstitutionalized population aged 60 and older in Spain. MEASUREMENTS: Sleep duration was self-reported at baseline. Analyses were performed using Cox regression and adjusted for the main confounders. The analyses were then stratified according to numerous indicators of health status. RESULTS: During follow-up, 897 persons died. Mortality was higher in those who slept 8 hours (relative risk (RR)=1.34, 95% confidence interval (CI)=1.02-1.76), 9 hours (RR 1.48, 95% CI=1.12-1.96), 10 hours (RR 1.73, 95% CI=1.30-2.29) and 11 hours or more (RR 1.66, 95% CI=1.23-2.24) than in those who slept 7 hours (P for trend <.001). The association between long sleep duration (>=10 vs 7 hours) and mortality was observed even in persons with good health status: optimal perceived health, good cognitive function (Mini-Mental State Examination score >27), no depression, quality of life better than the cohort median (Medical Outcomes Study 36-item Short Form Survey Physical Component Summary score >=46 and Mental Component Summary score >=52), and without disability in instrumental activities of daily living. Sleeping 6 hours or less was not associated with higher mortality than sleeping 7 hours in persons with good health status. CONCLUSION: Self-reported sleep duration was associated with 7-year mortality in this cohort of older adults, even when adjusted for health status. Further research is needed to determine the mechanisms and clinical implications of these findings. PMID- 20840461 TI - Mild cognitive impairment: incidence and risk factors: results of the leipzig longitudinal study of the aged. AB - OBJECTIVES: To provide information on age- and sex-specific incidence rates of mild cognitive impairment (MCI) and risk factors for incident MCI. DESIGN: Prospective longitudinal cohort. SETTING: Leipzig Longitudinal Study of the Aged, a population-based German study of the epidemiology of dementia and mild cognitive impairment. PARTICIPANTS: At baseline, 1,692 subjects aged 75 and older were included in the sample. MEASUREMENTS: Trained psychologists and physicians conducted structured clinical interviews including neuropsychological assessment and questions about sociodemographics, familial history of dementia, activities of daily living, subjective memory impairment, and lifestyle (alcohol consumption, smoking) at participants' homes. Structured third-party interviews were conducted with proxies. Incidence was calculated according to the person years-at-risk method. Cox proportional hazards models were used to examine the association between risk factors and incident MCI. RESULTS: During an 8-year follow-up period, 26.4% (n=137) of the 519 study participants (population at risk) were identified as incident MCI cases (person-years=1,791.1). The overall incidence rate of MCI was 76.5 (95% confidence interval=64.7-90.4) per 1,000 person-years. Older age, subjective memory impairment, impairment in instrumental activities of daily living, and antecedent lower cognitive performance were found to be significantly associated with the development of future MCI. CONCLUSION: MCI is highly incident in the elderly population. For the purpose of early detection of dementia, subjective memory impairment should be taken seriously as a possible prestage of MCI. PMID- 20840462 TI - Sexual aggression between residents in nursing homes: literature synthesis of an underrecognized problem. AB - Evidence exists suggesting that most sexual aggression against older adults occurs in long-term care facilities. Fellow residents are the most common perpetrators, often demonstrating inappropriate hypersexual behavior caused by dementing illness. This resident-to-resident sexual aggression (RRSA) is defined as sexual interactions between long-term care residents that, in a community setting, at least one of the recipients would be likely to construe as unwelcome and that have high potential to cause physical or psychological distress in one or both of the involved residents. Although RRSA may be common, and physical and psychological consequences for victims may be significant, this phenomenon has received little direct attention from researchers. This is a review of the existing literature and relevant related research examining elder sexual abuse and hypersexual behavior that describes the epidemiological features of this phenomenon, including risk factors for perpetrators and victims. The legitimate and recognized need for nursing home residents, even those with advanced dementing illness, to express themselves sexually makes preventing and managing sexual aggression in nursing homes more challenging. This review discusses the ethical dilemma this situation creates and the need to evaluate the capacity to consent to sexual activity of residents with dementing illness and to re-evaluate capacity as the diseases progress. Suggestions are offered for managing incidents of RRSA and for future research, including the importance of designing effective interventions. PMID- 20840463 TI - The role of MRI-detected left atrial delayed enhancement in selecting the right patient and choosing the optimal strategy for catheter ablation of atrial fibrillation. PMID- 20840464 TI - Pulmonary vein anatomy: atypical is typical. PMID- 20840465 TI - Evaluation of noncontact mapping by comparison with simultaneous multisite contact recordings in acute ischemic ventricular fibrillation. AB - AIM: The study aim was to determine the utility of noncontact mapping in acute ischemic ventricular fibrillation, by direct comparison with simultaneously acquired multisite contact needle recordings. MATERIALS AND METHODS: Noncontact mapping has emerged as a promising tool to make percutaneous high-density intracardiac electrical recordings in clinical and research settings. Previous large-animal mapping studies of ischemic VF have used electrodes in contact with the fibrillating myocardium. A previous report of noncontact mapping in VF used a single intracardiac catheter to validate noncontact recordings. RESULTS: We studied the spontaneous onset of VF in 8 sheep, after acute occlusion of the left anterior descending coronary artery. Simultaneous unipolar recordings of endocardial electrical activation were made with the most endocardial electrode of 32 transmural plunge needles (contact electrograms; CE), and an Ensite noncontact catheter in the left ventricle (noncontact virtual electrograms; NCVE). The lag-shifted morphology cross-correlation between individual NCVE and CE pairs during VF was calculated. DISCUSSION: The mean lag-shifted cross correlation coefficient during manually selected sinus rhythm beats was 0.89 +/- 0.006, and 0.80 +/- 0.009 in VF (P < 0.05). The mean absolute time shift was 7.3 +/- 0.5 ms in sinus rhythm, and 23.8 +/- 0.9 ms in VF (P < 0.001). Fast Fourier transform demonstrated well-correlated dominant frequencies between CE and NCVE. VF myocardial activation maps of NCVE showed organized wavefronts, but dyssynchronous activation in CE. CONCLUSION: These data demonstrate errors in activation timing and sequence with noncontact mapping more prominent during VF than sinus rhythm. PMID- 20840466 TI - Antiarrhythmic drug effects on microvolt T-wave alternans: measurement nuisance or indicator of therapeutic action? PMID- 20840467 TI - Zenker's and epiphrenic diverticula in a patient with cutis laxa: should the surgical technique be modified? AB - Currently, most of esophageal diverticula arise as the result of a pulsion effect. Some esophageal motor disorders increase the intraluminal pressure and after some time, the diverticula grow through a weak point of esophageal wall. In these cases, the surgical treatment of choice is the myotomy associated with diverticulopexy or diverticulectomy. Adding a fundoplication is accepted to avoid the consequences of gastroesophageal reflux after myotomy in the epiphrenic diverticula surgery. There are other causes of esophageal diverticula that change the resistance of esophageal wall. Cutis laxa, a congenital or acquired connective disease, is a strange one. In our patient, a good result was reached modifying the standard technique accord to its ethiopathogenic mechanism. PMID- 20840468 TI - Calcium signalling mediated through alpha7 and non-alpha7 nAChR stimulation is differentially regulated in bovine chromaffin cells to induce catecholamine release. AB - BACKGROUND AND PURPOSE: Ca(2+) signalling and exocytosis mediated by nicotinic receptor (nAChR) subtypes, especially the alpha7 nAChR, in bovine chromaffin cells are still matters of debate. EXPERIMENTAL APPROACH: We have used chromaffin cell cultures loaded with Fluo-4 or transfected with aequorins directed to the cytosol or mitochondria, several nAChR agonists (nicotine, 5-iodo-A-85380, PNU282987 and choline), and the alpha7 nAChR allosteric modulator PNU120596. KEY RESULTS: Minimal [Ca(2+) ](c) transients, induced by low concentrations of selective alpha7 nAChR agonists and nicotine, were markedly increased by the alpha7 nAChR allosteric modulator PNU120596. These potentiated responses were completely blocked by the alpha7 nAChR antagonist alpha-bungarotoxin (alpha7 modulated-response). Conversely, high concentrations of the alpha7 nAChR agonists, nicotine or 5-iodo-A-85380 induced larger [Ca(2+) ](c) transients, that were blocked by mecamylamine but were unaffected by alpha-bungarotoxin (non alpha7 response). [Ca(2+) ](c) increases mediated by alpha7 nAChR were related to Ca(2+) entry through non-L-type Ca(2+) channels, whereas non-alpha7 nAChR mediated signals were related to L-type Ca(2+) channels; Ca(2+) -induced Ca(2+) release contributed to both responses. Mitochondrial involvement in the control of [Ca(2+) ](c) transients, mediated by either receptor, was minimal. Catecholamine release coupled to alpha7 nAChRs was more efficient in terms of catecholamine released/[Ca(2+) ](c) . CONCLUSIONS AND IMPLICATIONS: [Ca(2+) ](c) and catecholamine release mediated by alpha7 nAChRs required an allosteric modulator and low doses of the agonist. At higher agonist concentrations, the alpha7 nAChR response was lost and the non-alpha7 nAChRs were activated. Catecholamine release might therefore be regulated by different nAChR subtypes, depending on agonist concentrations and the presence of allosteric modulators of alpha7 nAChRs. PMID- 20840469 TI - Anti-inflammatory effects of the R2 peptide, an inhibitor of transglutaminase 2, in a mouse model of allergic asthma, induced by ovalbumin. AB - BACKGROUND AND PURPOSE: Transglutaminase 2 (TGase 2) expression is increased in inflammatory diseases, and TGase 2 inhibitors block these increases. We examined whether the R2 peptide inhibited the expression of TGase 2 in a mouse model of inflammatory allergic asthma. EXPERIMENTAL APPROACH: C57BL/6 mice were sensitized and challenged by ovalbumin (OVA) to induce asthma. OVA-specific serum IgE and leukotrienes (LTs) levels were measured by enzyme-linked immunosorbent assay. Recruitment of inflammatory cells into bronchoalveolar lavage (BAL) fluid or lung tissues and goblet cell hyperplasia were assessed histologically. Airway hyperresponsiveness was determined in a barometric plethysmographic chamber. Expression of TGase 2, eosinophil major basic protein (EMBP), the adhesion molecule vascular cell adhesion molecule-1, Muc5ac and phospholipase A(2) (PLA(2) ) protein were determined by Western blot. Expression of mRNAs of Muc5ac, cytokines, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) were measured by reverse transcriptase-polymerase chain reaction and nuclear factor-kappaB (NF-kappaB) by electrophoretic mobility shift assay. KEY RESULTS: R2 peptide reduced OVA-specific IgE levels; the number of total inflammatory cells, macrophages, neutrophils, lymphocytes and eosinophils in BAL fluid and the number of goblet cells. Airway hyperresponsiveness, TGase 2 and EMBP levels, mRNA levels of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-13, RANTES, tumour necrosis factor-alpha, and MMP2/9, Muc5ac, NF-kappaB activity, PLA(2) activity and expressions, and LT levels in BAL cells and lung tissues were all reduced by R2 peptide. R2 peptide also restored expression of TIMP1/2. CONCLUSION AND IMPLICATIONS: R2 peptide reduced allergic responses by regulating NF-kappaB/TGase 2 activity in a mouse model of allergic asthma. This peptide may be useful in the treatment of allergic asthma. PMID- 20840470 TI - The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury. AB - BACKGROUND AND PURPOSE: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, and three subtypes (alpha, beta and gamma) have been identified. PPAR activation has been reported to decrease renal injury and markers of glomerular dysfunction in models of renal ischemia/reperfusion (I/R). However, both the I/R effects and the effects of PPAR agonists on podocytes, an integral cellular part of the glomerular filtration barrier, remain to be established. EXPERIMENTAL APPROACH: By using oxygen/glucose deprivation-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of PPAR agonists on podocyte death were compared. Human immortalized podocytes were treated with gemfibrozil, GW0742, pioglitazone or rosiglitazone, as a single or repeated challenge. Cell loss, necrotic and apoptotic cell death were measured. KEY RESULTS: Only the repeated treatment with each PPAR agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum deprivation-induced apoptosis, both treatments were effective, although the repeated treatment achieved the more pronounced effect. Finally, our results showed that preservation of Bcl-2, Bax and nephrin expression accompanied the anti-apoptotic effects exerted by PPAR agonists in human podocytes. CONCLUSION AND IMPLICATIONS: These findings contribute to clarification of the pathophysiological role of renal PPARs and suggest that selective PPARalpha, PPARbeta or PPARgamma agonists may exert similar protective effects on podocytes by decreasing apoptotic cell death. PMID- 20840471 TI - Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats. AB - BACKGROUND AND PURPOSE: The RhoA/Rho associated kinases (ROCK) pathway has been implicated in the pathophysiology of diabetic nephropathy (DN). Early stages of diabetes are associated with renal haemodynamic changes, contributing to later development of DN. However, the role of RhoA/ROCK, known regulators of vascular tone, in this process has not been studied. EXPERIMENTAL APPROACH: Blood pressure (BP), glomerular filtration (GFR), effective renal plasma flow and filtration fraction (FF) in response to the ROCK inhibitors Y27632 (0.1 and 0.5 mg.kg(-1) ) and fasudil (0.3 and 1.5 mg.kg(-1) ) were examined in streptozotocin-diabetic rats and non-diabetic controls. KEY RESULTS: Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)beta inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys. CONCLUSIONS AND IMPLICATIONS: The results indicate greater dependence of renal haemodynamics on RhoA/ROCK and beneficial haemodynamic effects of ROCK inhibitors in diabetes, which were additive to the effects of losartan. In this process, the RhoA/ROCK pathway operated downstream of or interacted with, PKCbeta in some segments of the renal vascular tree. PMID- 20840472 TI - Rosuvastatin restored adrenergic and nitrergic function in mesenteric arteries from obese rats. AB - BACKGROUND AND PURPOSE: We investigated whether high-fat diet (HFD)-induced obesity was associated with changed function of components of the mesenteric innervation (adrenergic, sensory and nitrergic), the mechanisms involved and the possible effects of rosuvastatin on these changes. EXPERIMENTAL APPROACH: Male Wistar rats were divided into three groups. (i) rats fed a standard diet (control group); (ii) rats fed a HFD (33.5% fat) for 7 weeks; and (iii) rats fed a HFD and treated with rosuvastatin (15 mg.kg(-1) .day(-1) ) for 7 weeks. Segments of isolated mesenteric arteries were exposed to electric field stimulation (EFS) with or without tetrodotoxin, phentolamine, 7-nitroindazole (7NI) or N(omega) nitro-L-arginine methyl ester (L-NAME). Noradrenaline, ATP and NO release, and nNOS expression were also measured. KEY RESULTS: EFS induced a greater frequency dependent contraction in obese than in control rats. In HFD rats, phentolamine reduced contractions elicited by EFS, but noradrenaline release was greater and ATP release decreased. L-NAME and 7NI increased contractions to EFS in segments from control rats, but not in those from HFD rats. NO release and nNOS expression were lower in arterial segments from HFD rats than in control rats. All these changes in HFD rats were reversed by treatment with rosuvastatin. CONCLUSIONS AND IMPLICATIONS: Neural control of mesenteric vasomotor tone was altered in HFD rats. Enhanced adrenergic and diminished nitrergic components both contributed to increased vasoconstrictor responses to EFS. All these changes were reversed by rosuvastatin, indicating novel mechanisms of statins in neural regulation of vascular tone. PMID- 20840473 TI - De novo therapy with everolimus, low-dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. AB - The number of acute rejections and infections after pediatric kidney transplantation (KTX) could not be reduced in the last years. To reduce these events, we investigated a new immunosuppressive protocol in a prospective trial. After KTX, 20 children (median age 12 years, range 1-17) were initially treated with Basiliximab, ciclosporine A (CsA) (trough-level = C0 200-250 ng/mL) and prednisolone. After 2 weeks, CsA dose was reduced to 50% (C0 75-100 ng/mL, after 6 months: 50-75 ng/mL) and everolimus (1.6 mg/m2) /day) was started (C0 3-6 ng/mL). Six months after KTX prednisolone was set to alternate dose and stopped 3 months later. All 20 protocol biopsies 6 months after KTX showed no acute rejection or borderline findings. Indication biopsies resulted in no acute rejections and two borderline findings. Mean glomerular filtration rate (GFR) 1 year after KTX was 71 +/- 25 mL/min/1.73 m2. Without cytomegalovirus (CMV) prophylaxis, only two primary CMV infections were seen despite a donor/recipient CMV-constellation pos./neg. in 10/20 children. In pediatric KTX, de novo immunosuppression with low-dose CsA, everolimus and steroid withdrawal after 9 months led to promising results according to numbers of acute rejections and infections. Further follow up is needed. Future larger trials will have to confirm our findings. PMID- 20840474 TI - Renal failure five years after lung transplantation due to polyomavirus BK associated nephropathy. AB - Polyomavirus-associated nephropathy (PyVAN) is rare in nonrenal solid organ transplantation and only limited information is available from single cases. We describe a 67-year-old female presenting with hypertension and progressive kidney failure due to PyVAN 60 months after lung transplantation. Plasma BK virus (BKV) loads were 4.85 log10 copies/mL at diagnosis and cleared slowly over 14 months after switching from tacrolimus, mycophenolate and prednisone to low-dose tacrolimus, sirolimus and leflunomide, the latter being discontinued for anemia and diarrhea. BKV- and JC virus-specific immunoglobulins were detectable prior to transplantation. Only BKV-specific IgG and IgM increased during follow-up. BKV specific T cells were detectable in blood following in vitro expansion, but cleared with reincreased sirolimus, yet BKV viremia remained undetectable. We identified eight other cases of PyVAN in nonrenal solid organ transplantation including lung (n = 1), heart (n = 6) and pancreas (n = 1). Overall, diagnosis was later than commonly seen in kidney transplants (median 18 months, interquartile range 10-29). Seven patients were male, five received triple immunosuppression consisting of tacrolimus, mycophenolate, prednisone. Immunosuppression was reduced in four cases and cidofovir and/or leflunomide administered in five and two cases, respectively. Renal function deteriorated in five requiring hemodialysis in four. We discuss mTOR inhibitors versus cidofovir and leflunomide as potential PyVAN rescue therapy. PMID- 20840475 TI - 25-OH-vitamin D deficiency and cellular alloimmunity as measured by panel of reactive T cell testing in dialysis patients. AB - Primed antidonor alloreactive T cells are detrimental to transplant outcome, but factors that impact the strength of this immune response prior to transplantation are unknown. We tested peripheral blood mononuclear cells from dialysis patients, against panels of allogeneic, primary B-cell lines in a newly standardized IFNgamma ELISPOT panel of reactive T cell (PRT) assay. Results were correlated with known alloantibody-sensitizing events and other clinical parameters. As 25 OH-vitamin D deficiency is associated with enhanced cellular immunity, is common in dialysis patients and is correctable, we assessed the relationship between serum 25-OH-vitamin D and the PRT. Using independent test and validation cohorts we found that low serum levels of 25-OH-vitamin D (<26 ng/mL) correlated with high-PRT values (in the upper 50th percentile, OR 0.02, p = 0.01) independent of age, sex, race, previous transplant, transfusion, pregnancy, time on dialysis, panel of reactive antibody, iPTH, and treatment with 1,25-OH-vitamin D. The data provide a potential mechanism for the possible relationship between vitamin D deficiency and poor posttransplant outcome, and support studies to test the impact of 25-OH-vitamin D repletion on alloimmunity and allograft injury in kidney transplant candidates. PMID- 20840476 TI - Process of care events in transplantation: effects on the cost of hospitalization. AB - Deviations in the processes of healthcare delivery that affect patient outcomes are recognized to have an impact on the cost of hospitalization. Whether deviations that do not affect patient outcome affects cost has not been studied. We have analyzed process of care (POC) events that were reported in a large transplantation service (n = 3,012) in 2005, delineating whether or not there was a health consequence of the event and assessing the impact on hospital resource utilization. Propensity score matching was used to adjust for patient differences. The rate of POC events varied by transplanted organ: from 10.8 per 1000 patient days (kidney) to 17.3 (liver). The probability of a POC event increased with severity of illness. The majority (81.5%) of the POC events had no apparent effect on patients' health (63.6% no effect and 17.9% unknown). POC events were associated with longer length of stay (LOS) and higher costs independent of whether there was a patient health impact. Multiple events during the same hospitalization were associated with the highest impact on LOS and cost. POC events in transplantation occur frequently, more often in sicker patients and, although the majority of POC events do not harm the patient, their effect on resource utilization is significant. PMID- 20840477 TI - Loss of nephrin expression in glomeruli of kidney-transplanted patients under m TOR inhibitor therapy. AB - The development of proteinuria has been observed in kidney-transplanted patients on m-TOR inhibitor (m-TORi) treatment. Recent studies suggest that m-TORi(s) may alter the behavior and integrity of glomerular podocytes. We analyzed renal biopsies from kidney-transplanted patients and evaluated the expression of nephrin, a critical component of the glomerular slit-diaphragm. In a group of patients on 'de novo' m-TORi-treatment, the expression of nephrin within glomeruli was significantly reduced in all cases compared to pretransplant donor biopsies. Biopsies from control transplant patients not treated with m-TORi(s) failed to present a loss of nephrin. In a group of patients subsequently converted to m-TORi-treatment, a protocol biopsy performed before introduction of m-TORi was also available. The expression of nephrin in the pre-m-TORi biopsies was similar to that observed in the pretransplant donor biopsies but was significantly reduced after introduction of m-TORi(s). Proteinuria increased after the m-TORi inititiation in this group. However, in some cases proteinuria remained normal despite reduction of nephrin. In vitro, sirolimus downregulated nephrin expression by human podocytes. Our results suggest that m-TORi(s) may affect nephrin expression in kidney-transplanted patients, consistently with the observation in vitro on cultured podocytes. PMID- 20840478 TI - Renal transplantation in HIV-infected patients: the Paris experience. AB - Kidney transplantation is now considered as a reasonable option for HIV-infected patients with end-stage renal disease. We describe here a retrospective study conducted in five transplantation centers in Paris. Twenty-seven patients were included. Immunosuppressive protocol associated an induction therapy and a long term treatment combining mycophenolate mofetil, steroids and either tacrolimus or cyclosporine. All the patients had protocol biopsies at 3 months and 1 year. Patient's survival was 100% at 1 year and 98% at 2 years. Graft survival at 1 and 2 years is 98% and 96% at 1 and 2 years, respectively. The mean glomerular filteration rate values at 12 and 24 months were 60.6 mL/min/1.73 m2 (range 23 98) and 65.4 mL/min/1.73 m2 (range 24-110), respectively. Acute cellular rejection was diagnosed in four cases (15%). Because of high trough levels of calcineurin inhibitor, protease-inhibitor therapies were withdrawn in 11 cases. HIV disease progression was not observed. One patient developed B-cell lymphoma. In conclusion, our study confirms the safety of renal transplantation in HIV infected patients with few adverse events and a low incidence of acute rejection. PMID- 20840479 TI - Transgenic overexpression of CD39 protects against renal ischemia-reperfusion and transplant vascular injury. AB - The vascular ectonucleotidases CD39[ENTPD1 (ectonucleoside triphosphate diphosphohydrolase-1), EC 3.6.1.5] and CD73[EC 3.1.3.5] generate adenosine from extracellular nucleotides. CD39 activity is critical in determining the response to ischemia-reperfusion injury (IRI), and CD39 null mice exhibit heightened sensitivity to renal IRI. Adenosine has multiple mechanisms of action in the vasculature including direct endothelial protection, antiinflammatory and antithrombotic effects and is protective in several models of IRI. Mice transgenic for human CD39 (hCD39) have increased capacity to generate adenosine. We therefore hypothesized that hCD39 transgenic mice would be protected from renal IRI. The overexpression of hCD39 conferred protection in a model of warm renal IRI, with reduced histological injury, less apoptosis and preserved serum creatinine and urea levels. Benefit was abrogated by pretreatment with an adenosine A2A receptor antagonist. Adoptive transfer experiments showed that expression of hCD39 on either the vasculature or circulating cells mitigated IRI. Furthermore, hCD39 transgenic kidneys transplanted into syngeneic recipients after prolonged cold storage performed significantly better and exhibited less histological injury than wild-type control grafts. Thus, systemic or local strategies to promote adenosine generation and signaling may have beneficial effects on warm and cold renal IRI, with implications for therapeutic application in clinical renal transplantation. PMID- 20840480 TI - Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. AB - This multicenter, 1:1-randomized, parallel-group, noninferiority study compared the efficacy and safety of twice-daily tacrolimus (Tacrolimus BID; Prograf) and once-daily tacrolimus prolonged release (Tacrolimus QD; Advagraf), combined with steroids and low-dose mycophenolate mofetil without antibody induction, in 667 de novo kidney transplant recipients. A double-blind, double-dummy 24-week period was followed by an open extension of up to 12 months posttransplant. Biopsy proven acute rejection rate at 24 weeks (primary endpoint, per-protocol analysis) was 15.8% for Tacrolimus BID versus 20.4% for Tacrolimus QD (p = 0.182; treatment difference 4.5%, 95% confidence interval-1.8%, 10.9%, just outside the prespecified 10% noninferiority margin). Kaplan-Meier 12-month patient and graft survival rates were 97.5% and 92.8% for Tacrolimus BID and 96.9% and 91.5% for QD. Both treatment groups showed equally well-maintained renal function at 12 months (mean creatinine clearance approximately 67 mL/min) and similar adverse event profiles. Overall results obtained with either Tacrolimus QD or BID, without antibody induction, were good, supporting use of the once-daily formulation as an effective alternative to the established twice-daily formulation. PMID- 20840482 TI - Mycophenolate mofetil: a possible cause of hemophagocytic syndrome following renal transplantation? PMID- 20840481 TI - Once-daily prolonged-release tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. AB - The efficacy and safety of dual-therapy regimens of twice-daily tacrolimus (BID; Prograf) and once-daily tacrolimus (QD; Advagraf) administered with steroids, without antibody induction, were compared in a multicenter, 1:1-randomized, two arm, parallel-group study in 475 primary liver transplant recipients. A double blind, double-dummy 24-week period was followed by an open extension to 12 months posttransplant. The primary endpoint, event rate of biopsy-proven acute rejection (BPAR) at 24 weeks, was 33.7% for tacrolimus BID versus 36.3% for tacrolimus QD (Per-protocol set; p = 0.512; treatment difference 2.6%, 95% confidence interval 7.3%, 12.4%), falling within the predefined 15% noninferiority margin. At 12 months, BPAR episodes requiring treatment were similar for tacrolimus BID and QD (28.1% and 24.7%). Twelve-month patient and graft survival was 90.8% and 85.6% for tacrolimus BID and 89.2% and 85.3% for tacrolimus QD. Adverse event (AE) profiles were similar for both tacrolimus BID and QD with comparable incidences of AEs and serious AEs. Tacrolimus QD was well tolerated with similar efficacy and safety profiles to tacrolimus BID. PMID- 20840483 TI - Prediction model for delayed kidney transplant function: no need for new regulation. PMID- 20840484 TI - Operational tolerance after liver transplantation: raising the bar or tripping up? PMID- 20840486 TI - Studies that use experimental designs to understand behaviors and reactions to communications. PMID- 20840485 TI - Challenges and opportunities for discovery of disease biomarkers using urine proteomics. AB - Modern medicine has experienced a tremendous explosion in knowledge about disease pathophysiology, gained largely from understanding the molecular biology of human disease. Recent advances in mass spectrometry and proteomics now allow for simultaneous identification and quantification of thousands of unique proteins and peptides in complex biological tissues and fluids. In particular, proteomic studies of urine benefit from urine's less complex composition as compared to serum and tissues, and have been used successfully to discover novel markers of a variety of infectious, autoimmune, oncological, and surgical conditions. This perspective discusses the challenges of such studies that stem from the compositional variability and complexity of human urine, as well as instrumental sampling limitations and the effects of noise and selection bias. Strategies for the design of observational clinical trials, physical and chemical fractionation of urine specimens, mass spectrometry analysis, and functional data annotation are outlined. Rigorous translational investigations using urine proteomics are likely to discover novel and accurate markers of both rare and common diseases. This should aid the diagnosis, improve stratification of therapy, and identify novel therapeutic targets for a variety of childhood and adult diseases, all of which will be essential for the development of personalized and predictive medicine of the future. PMID- 20840487 TI - Analyzing evacuation versus shelter-in-place strategies after a terrorist nuclear detonation. AB - We superimpose a radiation fallout model onto a traffic flow model to assess the evacuation versus shelter-in-place decisions after the daytime ground-level detonation of a 10-kt improvised nuclear device in Washington, DC. In our model, ~ 80k people are killed by the prompt effects of blast, burn, and radiation. Of the ~ 360k survivors without access to a vehicle, 42.6k would die if they immediately self-evacuated on foot. Sheltering above ground would save several thousand of these lives and sheltering in a basement (or near the middle of a large building) would save of them. Among survivors of the prompt effects with access to a vehicle, the number of deaths depends on the fraction of people who shelter in a basement rather than self-evacuate in their vehicle: 23.1k people die if 90% shelter in a basement and 54.6k die if 10% shelter. Sheltering above ground saves approximately half as many lives as sheltering in a basement. The details related to delayed (i.e., organized) evacuation, search and rescue, decontamination, and situational awareness (via, e.g., telecommunications) have very little impact on the number of casualties. Although antibiotics and transfusion support have the potential to save ~ 10k lives (and the number of lives saved from medical care increases with the fraction of people who shelter in basements), the logistical challenge appears to be well beyond current response capabilities. Taken together, our results suggest that the government should initiate an aggressive outreach program to educate citizens and the private sector about the importance of sheltering in place in a basement for at least 12 hours after a terrorist nuclear detonation. PMID- 20840488 TI - Trust and terrorism: citizen responses to anti-terrorism performance history. AB - The "intuitive detection theorists" model of trust posits greater trust for correctly distinguishing danger from safety and an activist response under uncertainty about danger. An American sample evaluated U.S. Department of Homeland Security (DHS) performance after two possible terrorism events in which DHS has the same activist or nonactivist response bias. Outcomes were two successes (bombing prevented or lack of threat accurately foretold), two failures (bombing or DHS action against high school prank leads to student deaths), or a mix. Hindsight empathy (a belief one would have made the same decision) differed across treatments but trust less so; contrary to a similar one-event experiment in Germany, an active but incorrect response did not raise trust relative to passive incorrect action. Political conservatives were much more trusting and empathetic than liberals, and all ideological groups (including moderates) exhibited little internal variation reflecting experimental conditions. Consistently accurate outcomes rated significantly higher in empathy than either inconsistent results or consistent inaccuracy (the lowest rated); trust exhibited no significant differences. Results in this study show actual (experimentally manipulated) performance being trumped by the interpretive screen of political ideology, but this seemed less the case in the earlier German study, despite its finding of a strong moderating effect of right-wing authoritarianism. Trust scholars need to attend more to effects of performance history (i.e., a sequence of events) and their limiting factors. More systematic testing of effects of ideology and performance history would enhance future research on trust. PMID- 20840489 TI - Domain effects and financial risk attitudes. AB - We investigated whether financial risk preferences are dependent on the financial domain (i.e., the context) in which the risky choice options are presented. Previous studies have demonstrated that risk attitudes change when gambles are framed as gains, losses, or as insurance. Our study explores this directly by offering choices between identical gambles, framed in terms of seven financial domains. Three factors were extracted, explaining 68.6% of the variance: Factor 1 (Positive)-opportunity to win, pension provision, and job salary change; Factor 2 (Positive-Complex)-investments and mortgage buying; Factor 3 (Negative) possibility of loss and insurance. Inspection of the solution revealed context effects on risk perceptions across the seven scenarios. We also found that the commonly accepted assumption that women are more risk averse cannot be confirmed with the context structure suggested in this research; however, it is acknowledged that in the students' population the variance across genders might be considerably less. These results suggest that our financial risk attitude measures may be tapping into a stable aspect of "context dependence" of relevance to real-world decision making. PMID- 20840490 TI - Who by accident? The social morphology of car accidents. AB - Prior studies in the sociology of accidents have shown that different social groups have different rates of accident involvement. This study extends those studies by implementing Bourdieu's relational perspective of social space to systematically explore the homology between drivers' social characteristics and their involvement in specific types of motor vehicle accident. Using a large database that merges official Israeli road-accident records with socioeconomic data from two censuses, this research maps the social order of road accidents through multiple correspondence analysis. Extending prior studies, the results show that different social groups indeed tend to be involved in motor vehicle accidents of different types and severity. For example, we find that drivers from low socioeconomic backgrounds are overinvolved in severe accidents with fatal outcomes. The new findings reported here shed light on the social regularity of road accidents and expose new facets in the social organization of death. PMID- 20840491 TI - Is eradication of the pinewood nematode (Bursaphelenchus xylophilus) likely? An evaluation of current contingency plans. AB - The pinewood nematode (PWN) is one of the worst tree-killing exotic pests in East Asian countries. The first European record of establishment in Portugal in 1999 triggered extensive surveys and contingency plans for eradication in European countries, including immediate removal of large areas of conifer host trees. Using Norway as an example, we applied a simulation model to evaluate the chance of successful eradication of a hypothetical introduction by the current contingency plan in a northern area where wilting symptoms are not expected to occur. Despite a highly variable spread of nematode infestations in space and time, the probability of successful eradication in 20 years was consistently low (mean 0.035, SE 0.02). The low success did not change significantly by varying the biological parameters in sensitivity analyses (SA), probably due to the late detection of infestations by the survey (mean 14.3 years). SA revealed a strong influence of management parameters. However, a high probability of eradication required unrealistic measures: achieving an eradication probability of 0.99 in 20 years required 10,000 survey samples per year and a host tree removal radius of 8,000 m around each detection point. PMID- 20840492 TI - A risk analysis model in concurrent engineering product development. AB - Concurrent engineering has been widely accepted as a viable strategy for companies to reduce time to market and achieve overall cost savings. This article analyzes various risks and challenges in product development under the concurrent engineering environment. A three-dimensional early warning approach for product development risk management is proposed by integrating graphical evaluation and review technique (GERT) and failure modes and effects analysis (FMEA). Simulation models are created to solve our proposed concurrent engineering product development risk management model. Solutions lead to identification of key risk controlling points. This article demonstrates the value of our approach to risk analysis as a means to monitor various risks typical in the manufacturing sector. This article has three main contributions. First, we establish a conceptual framework to classify various risks in concurrent engineering (CE) product development (PD). Second, we propose use of existing quantitative approaches for PD risk analysis purposes: GERT, FMEA, and product database management (PDM). Based on quantitative tools, we create our approach for risk management of CE PD and discuss solutions of the models. Third, we demonstrate the value of applying our approach using data from a typical Chinese motor company. PMID- 20840493 TI - The efficacy of photodynamic diagnosis in defining the lateral border between a tumor and a tumor-free area during Mohs micrographic surgery. AB - BACKGROUND: Photodynamic diagnosis (PDD) is a preoperative procedure that simplifies Mohs micrographic surgery (MMS) by allowing more accurate demarcation of neoplastic lesions involving the skin. After topical application of aminolevulinic acid (ALA), protoporphyrin IX (PpIX) is selectively induced in neoplastic cells with a high tumor-to-surrounding tissue ratio and can be visualized after excitation using a Wood's lamp. OBJECTIVES: To evaluate the efficacy of PpIX fluorescence images in accurately determining the boundaries of tumors during MMS. METHODS: A retrospective evaluation of biopsy-proven basal cell carcinoma (BCC; n=163), squamous cell carcinoma (SCC; n=51), and Bowen's disease (n=8) in 222 patients treated with MMS was conducted. In the PDD group, 20% ALA ointment was applied 6 hours before the surgery, and then the boundaries were mapped based on the red fluorescence of the Wood's lamp in the operating room. Each of the PDD (n=142) and non-PDD (n=80) groups was surgically staged and compared. RESULTS: The average number of stages was 1.59, with more in the PDD group (1.66) than the non-PDD group (1.44) (p=.05). The average number of stages was 1.77 in the PDD group and 1.50 in the non-PDD group (p=.06) for BCC, was 1.40 in the PDD group and 1.37 in the non-PDD group (p=.90) for SCC, and 1.25 in the PDD group and 1.00 in the non-PDD group (p=.36) for Bowen's disease. CONCLUSIONS: In previous studies, the fluorescence of induced porphyrins was effective in detecting and delineating neoplastic skin areas, but, in the present study, PDD did not support surgical efficacy during MMS. PMID- 20840494 TI - Treatment of striae distensae using an ablative 10,600-nm carbon dioxide fractional laser: a retrospective review of 27 participants. AB - BACKGROUND: Late-stage striae distensae is a type of scar characterized by a loss of collagen and elastic fibers in the dermis. Ablative 10,600-nm carbon dioxide fractional laser systems (CO2 FS) have been used successfully for the treatment of various types of scars. OBJECTIVE: To investigate the therapeutic efficacy of using CO2 FS for the treatment of striae distensae. METHODS: Twenty-seven women with striae distensae were treated in a single session with a CO2 FS. Deep FX mode with a pulse energy of 10 mJ and a density of 2 (percent coverage of 10%) was used. Clinical improvement was assessed by comparing pre- and post-treatment clinical photographs and participant satisfaction rates. RESULTS: The evaluation of clinical results 3 months after treatment showed that two of the 27 participants (7.4%) had grade clinical 4 improvement, 14 (51.9%) had grade 3 improvement, nine (33.3%) had grade 2 improvement, and two (7.4%) had grade 1 improvement. None of the participants showed worsening of their striae distensae. Mean clinical improvement score was 2.6. Surveys evaluating overall participant satisfaction administered after the treatment was completed showed that six of the 27 participants (22.2%) were very satisfied, 14 (51.9%) were satisfied, five (18.1%) were slightly satisfied, and two (7.4%) were unsatisfied. CONCLUSION: Our observations demonstrated that the use of CO2 FS can have a positive therapeutic effect on late-stage striae distensae. PMID- 20840495 TI - Comparison of two Q-switched lasers and a short-pulse erbium-doped yttrium aluminum garnet laser for treatment of cosmetic tattoos containing titanium and iron in an animal model. AB - BACKGROUND: Cosmetic tattoos contain titanium and ferric oxide and darken through reduction after Q-switched laser irradiation. The optimal treatment for removing these pigments remains unknown. OBJECTIVE: To compare the effects of two Q switched lasers and a short-pulse erbium-doped yttrium aluminum garnet (SP Er:YAG) laser to remove cosmetic tattoos in an animal model. MATERIALS AND METHODS: Rats were tattooed using white, flesh-colored, and brown inks (4 bands of each color) on their backs. For each color, one band was left untreated, and one each was treated with a Q-switched neodymium-doped YAG laser, a Q-switched alexandrite laser, and a SP Er:YAG laser every 3 weeks until the pigments were clear. RESULTS: The two Q-switched lasers were equally effective; all three pigments darkened initially and then resolved gradually. Up to 20, 18, and 10 sessions were required to remove white, flesh-colored, and brown tattoos, respectively. Only six sessions were required with the SP Er:YAG laser. Minimal scarring was observed with all lasers. Skin biopsies confirmed pigment granule fragmentation after Q-switched laser treatment and a decrease in the amount of pigment after SP Er:YAG laser treatment. CONCLUSION: The SP Er:YAG laser was superior to the Q-switched lasers for removing cosmetic tattoos. PMID- 20840496 TI - Anatomical changes in retronychia and onychomadesis detected using ultrasound. PMID- 20840497 TI - A simple method to treat venous lakes. PMID- 20840498 TI - Identification of social-emotional problems among young children in foster care. AB - BACKGROUND: Little is known about how best to implement behavioral screening recommendations in practice, especially for children in foster care, who are at risk for having social-emotional problems. Two validated screening tools are recommended for use with young children: the Ages and Stages Questionnaire: Social Emotional (ASQ-SE) identifies emotional problems, and the Ages and Stages Questionnaire (ASQ) identifies general developmental delays in five domains, including personal-social problems. The current study examined: (1) whether systematic use of a social-emotional screening tool improves the detection rate of social-emotional problems, compared to reliance on clinical judgment; (2) the relative effectiveness of two validated instruments to screen for social emotional problems; and (3) the patterns of social-emotional problems among children in foster care. METHODS: We used retrospective chart review of children in foster care ages 6 months to 5.5 years: 192 children before and 159 after screening implementation, to measure detection rates for social-emotional problems among children. The ASQ-SE and the ASQ were used in multivariable logistic regression analyses to examine associations between children with social emotional problems. RESULTS: Use of the screening tool identified 24% of the children as having a social-emotional problem, while provider surveillance detected 4%. We identified significantly more children with social-emotional problems using the ASQ-SE than using the ASQ, and agreement between the instruments ranged from 56% to 75%, when data were stratified by age group. Multivariable modeling showed that preschool children were more likely to have a social-emotional problem than toddlers and infants (aOR = 3.4, 95% CI = 1.1 10.8). CONCLUSIONS: Systematic screening using the ASQ-SE increased the detection rate for social-emotional problems among young children in foster care, compared to provider surveillance and the ASQ. A specific social-emotional screening tool appears to detect children with psychosocial concerns who would not be detected with a broader developmental screening tool. PMID- 20840499 TI - Functional characterization of Arabidopsis thaliana isopropylmalate dehydrogenases reveals their important roles in gametophyte development. AB - * Isopropylmalate dehydrogenases (IPMDHs) catalyze the oxidative decarboxylation of 3-isopropylmalate (3-IPM) in leucine biosynthesis in microorganisms. The Arabidopsis thaliana genome contains three putative IPMDH genes. * IPMDH2 and IPMDH3 proteins exhibited significantly higher activity toward 3-IPM than IPMDH1, which is indicative of a pivotal role in leucine biosynthesis. Single mutants of IPMDH2 or IPMDH3 lacked a discernible phenotype. Genetic analysis showed that ipmdh2 ipmdh3 was lethal in male gametophytes and had reduced transmission through female gametophytes. The aborted pollen grains were small, abnormal in cellular structure, and arrested in germination. In addition, half of the double mutant embryo sacs exhibited slowed development. * The IPMDH2/ipmdh2 ipmdh3/ipmdh3 genotype exhibited abnormal vegetative phenotypes, suggesting haplo insufficiency of IPMDH2 in the ipmdh3 background. This mutant and a triple mutant containing one allele of IPMDH2 or IPMDH3 had decreased leucine biosynthetic enzyme activities and lower free leucine concentrations. The latter mutant showed changes in glucosinolate profiles different from those in the ipmdh1 mutant. * The results demonstrate that IPMDH2 and IPMDH3 primarily function in leucine biosynthesis, are essential for pollen development and are needed for proper embryo sac development. PMID- 20840500 TI - Editorial: Tracking the impact of early adversity. PMID- 20840501 TI - Intrusive thoughts and young children's knowledge about thinking following a natural disaster. AB - BACKGROUND: Hurricane Katrina devastated the Mississippi Gulf Coast in August 2005. Intrusive re-experiencing is a common posttraumatic stress symptom. However, young children with limited introspection skills might have difficulties identifying their intrusive thoughts. METHOD: A sample of 165 5- to 9-year-old children were surveyed about their unwanted intrusive thoughts and their knowledge about thinking, 10 months following the hurricane. RESULTS: Results replicate and extend the findings from a previous study (Sprung, 2008). Although there was no difference in the overall occurrence of intrusive thoughts, there was a striking difference between hurricane-exposed and control children in their contents. Children's knowledge about thinking was linked to their ability to report on their negative intrusive thoughts, even taking language ability into account. CONCLUSION: There is a shift toward negative content following hurricane exposure compared with non-hurricane-exposed children and knowledge about thinking is linked to the reporting of such intrusive thoughts. Implications for current research on autobiographical memory and for interventions following potentially traumatic events are discussed. PMID- 20840502 TI - Exposure to potentially traumatic events in early childhood: differential links to emergent psychopathology. AB - OBJECTIVE: To examine associations between exposure to potentially traumatic events (PTEs) and clinical patterns of symptoms and disorders in preschool children. METHOD: Two hundred and thirteen referred and non-referred children, ages 24 to 48 months (MN = 34.9, SD = 6.7 months) were studied. Lifetime exposure to PTEs (family violence and non-interpersonal events) and recent stressful life events were assessed with the Preschool Age Psychiatric Assessment (PAPA) and Child Life Events Scale. Child psychiatric symptoms and disorders were assessed with parent-reports in the PAPA, a comprehensive, developmentally sensitive interview. Sociodemographic risk, parental anxiety and depressive symptoms (Center for Epidemiologic Studies Depression, Beck Anxiety Inventory), and child developmental level (Mullen Scales of Early Learning) also were assessed. RESULTS: Violence exposure was broadly associated with psychiatric status in the areas of depression, separation anxiety, posttraumatic stress, and conduct problems, whereas potentially traumatic non-interpersonal exposure was associated with phobic anxiety. The majority of the associations between violence exposure and preschoolers' symptoms were significant even when other key factors, including economic disadvantage and parental mood and anxiety symptoms, were controlled statistically. However, parental depressive/anxious symptoms may have partially or fully mediated the relationships between violence exposure and depressive and conduct symptoms. CONCLUSIONS: Evidence of robust associations between violence exposure and early childhood internalizing and externalizing disorders and symptoms highlights the need for longitudinal prospective research concerning neurodevelopmental mechanisms and pathways. Findings underscore the relevance of assessing trauma exposure, particularly interpersonal violence, to identify young children at risk. PMID- 20840503 TI - Psychosocial mediators and moderators of the effect of peer-victimization upon depressive symptomatology. AB - BACKGROUND: Intervention strategies and developmental models of stress have been criticized for failing to integrate social psychological variables. This study investigates both self-referential cognitive mediators (perceived threat and control) and a social psychological moderator (ethnic/religious identity) of the effect of peer-victimization upon depressive symptomatology. METHODS: Self report questionnaires were completed by 924 students (46% female), aged 8 to 12 years. Experiences of discriminatory and non-discriminatory peer-victimization, threat and control appraisals, depressive symptoms, and strength of main identity were assessed. RESULTS: Perceived threat partially mediated the effect of peer victimization (regardless of whether it was discriminatory or not) on depressive symptoms. Perceived control partially mediated the effect of non-discriminatory peer-victimization on depressive symptoms. Strength of ethnic/religious identity buffered the effect of peer-victimization on depressive symptoms. Victimization perceived to be discriminatory in nature was more strongly associated with depressive symptoms than non-discriminatory victimization. CONCLUSIONS: Findings support calls for a greater emphasis to be placed on social psychological variables in explaining depressive symptomatology. For clinical, counseling and intervention purposes, it is important to examine whether victims perceive peer-victimization as discriminatory and whether their own strength of identity affects symptomatology. PMID- 20840504 TI - The effects of maternal postnatal depression and child sex on academic performance at age 16 years: a developmental approach. AB - BACKGROUND: Postnatal depression (PND) is associated with poor cognitive functioning in infancy and the early school years; long-term effects on academic outcome are not known. METHOD: Children of postnatally depressed (N = 50) and non depressed mothers (N = 39), studied from infancy, were followed up at 16 years. We examined the effects on General Certificate of Secondary Education (GCSE) exam performance of maternal depression (postnatal and subsequent) and IQ, child sex and earlier cognitive development, and mother-child interactions, using structural equation modelling (SEM). RESULTS: Boys, but not girls, of PND mothers had poorer GCSE results than control children. This was principally accounted for by effects on early child cognitive functioning, which showed strong continuity from infancy. PND had continuing negative effects on maternal interactions through childhood, and these also contributed to poorer GCSE performance. Neither chronic, nor recent, exposure to maternal depression had significant effects. CONCLUSIONS: The adverse effects of PND on male infants' cognitive functioning may persist through development. Continuing difficulties in mother-child interactions are also important, suggesting that both early intervention and continuing monitoring of mothers with PND may be warranted. PMID- 20840505 TI - Why do British Indian children have an apparent mental health advantage? AB - BACKGROUND: Previous studies document a mental health advantage in British Indian children, particularly for externalising problems. The causes of this advantage are unknown. METHODS: Subjects were 13,836 White children and 361 Indian children aged 5-16 years from the English subsample of the British Child and Adolescent Mental Health Surveys. The primary mental health outcome was the parent Strengths and Difficulties Questionnaire (SDQ). Mental health was also assessed using the teacher and child SDQs; diagnostic interviews with parents, teachers and children; and multi-informant clinician-rated diagnoses. Multiple child, family, school and area factors were examined as possible mediators or confounders in explaining observed ethnic differences. RESULTS: Indian children had a large advantage for externalising problems and disorders, and little or no difference for internalising problems and disorders. This was observed across all mental health outcomes, including teacher-reported and diagnostic interview measures. Detailed psychometric analyses provided no suggestion of information bias. The Indian advantage for externalising problems was partly mediated by Indian children being more likely to live in two-parent families and less likely to have academic difficulties. Yet after adjusting for these and all other covariates, the unexplained Indian advantage only reduced by about a quarter (from 1.08 to .71 parent SDQ points) and remained highly significant (p < .001). This Indian advantage was largely confined to families of low socio-economic position. CONCLUSION: The Indian mental health advantage is real and is specific to externalising problems. Family type and academic abilities mediate part of the advantage, but most is not explained by major risk factors. Likewise unexplained is the absence in Indian children of a socio-economic gradient in mental health. Further investigation of the Indian advantage may yield insights into novel ways to promote child mental health and child mental health equity in all ethnic groups. PMID- 20840507 TI - Variations of vessel diameter and delta13C in false rings of Arbutus unedo L. reflect different environmental conditions. AB - Woody species in Mediterranean ecosystems form intra-annual density fluctuations (IADFs) in tree rings in response to changes in environmental conditions, especially water availability. Dendrochronology, quantitative wood anatomy and high-resolution isotopic analysis (using a laser ablation technique) were used to characterize IADFs in Arbutus unedo shrubs grown on two sites with different water availability on the island of Elba (Italy). Our findings show that IADF characterization can provide information about the relationship between environmental factors and tree growth at the seasonal level. At the more xeric site, IADFs mainly located in the early and middle parts of the annual ring, showed a decrease in vessel size and an increase in delta(13) C as a result of drought deficit. Opposite trends were found at the more mesic site, with IADFs located at the end of the ring and associated with a lower delta(13) C. Moreover, at the first site, IADFs are induced by drought deficit, while at the second site IADFs are linked with the regrowth in the last part of the growing season triggered by favourable wet conditions. This combined approach is a promising way for dating problematic wood samples and interpreting the phenomena that trigger the formation of IADFs in the Mediterranean environment. PMID- 20840506 TI - OsHMA3, a P1B-type of ATPase affects root-to-shoot cadmium translocation in rice by mediating efflux into vacuoles. AB - * The cadmium (Cd) over-accumulating rice (Oryza sativa) cv Cho-Ko-Koku was previously shown to have an enhanced rate of root-to-shoot Cd translocation. This trait is controlled by a single recessive allele located at qCdT7. * In this study, using positional cloning and transgenic strategies, heavy metal ATPase 3 (OsHMA3) was identified as the gene that controls root-to-shoot Cd translocation rates. The subcellular localization and Cd-transporting activity of the gene products were also investigated. * The allele of OsHMA3 that confers high root-to shoot Cd translocation rates (OsHMA3mc) encodes a defective P(1B) -ATPase transporter. OsHMA3 fused to green fluorescent protein was localized to vacuolar membranes in plants and yeast. An OsHMA3 transgene complemented Cd sensitivity in a yeast mutant that lacks the ability to transport Cd into vacuoles. By contrast, OsHMA3mc did not complement the Cd sensitivity of this yeast mutant, indicating that the OsHMA3mc transport function was lost. * We propose that the root cell cytoplasm of Cd-overaccumulating rice plants has more Cd available for loading into the xylem as a result of the lack of OsHMA3-mediated transportation of Cd to the vacuoles. This defect results in Cd translocation to the shoots in higher concentrations. These data demonstrate the importance of vacuolar sequestration for Cd accumulation in rice. PMID- 20840508 TI - Hydraulic constraints limit height growth in trees at high altitude. AB - * Low temperatures limit the fixation of photosynthates and xylogenesis. Here, we hypothesized that reduced longitudinal growth in trees at high altitude is related to the lower hydraulic efficiency of the transport system. * Apical buds of Norway spruce (Picea abies) trees at high and low elevation were heated during 2006 and 2007. At the end of the experiment, trees were felled. Longitudinal increments and tracheid lumen areas were measured along the stem. Apical hydraulic conductivity (k) was estimated from anatomical data. * Before heating, high-altitude trees showed fewer (P = 0.002) and smaller (P = 0.008) apical conduits, and therefore reduced k (P = 0.016) and stem elongation (P < 0.0001), in comparison with trees at low elevation. After 2 yr of heating, k increased at both high (P = 0.014) and low (P = 0.047) elevation. Only high-altitude trees showed increased stem elongation, which reached the same magnitude as that of controls at low elevation (P = 0.735). Heating around the apical shoots did not appear to induce significant changes in conduit dimension along the rest of the stem. * The total number and size of xylem elements at the stem apex are strongly constrained by low temperatures. Trees at high altitude are therefore prevented from building up an efficient transport system, and their reduced longitudinal growth reflects strong hydraulic limitations. PMID- 20840509 TI - Plant responses to low [CO2] of the past. AB - During the Last Glacial Maximum (LGM; 18,000-20,000 yr ago) and previous glacial periods, atmospheric [CO(2)] dropped to 180-190 ppm, which is among the lowest concentrations that occurred during the evolution of land plants. Modern atmospheric CO(2) concentrations ([CO(2)]) are more than twice those of the LGM and 45% higher than pre-industrial concentrations. Since CO(2) is the carbon source for photosynthesis, lower carbon availability during glacial periods likely had a major impact on plant productivity and evolution. From the studies highlighted here, it is clear that the influence of low [CO(2)] transcends several scales, ranging from physiological effects on individual plants to changes in ecosystem functioning, and may have even influenced the development of early human cultures (via the timing of agriculture). Through low-[CO(2)] studies, we have determined a baseline for plant response to minimal [CO(2)] that occurred during the evolution of land plants. Moreover, an increased understanding of plant responses to low [CO(2)] contributes to our knowledge of how natural global change factors in the past may continue to influence plant responses to future anthropogenic changes. Future work, however, should focus more on the evolutionary responses of plants to changing [CO(2)] in order to account for the potentially large effects of genetic change. PMID- 20840510 TI - Spatial distribution of arsenic and temporal variation of its concentration in rice. AB - * In order to gain insights into the transport and distribution of arsenic (As) in intact rice (Oryza sativa) plants and its unloading into the rice grain, we investigated the spatial distribution of As and the temporal variation of As concentration in whole rice plants at different growth stages. To the best of our knowledge, this is the first time that such a study has been performed. * Inductively coupled plasma mass spectroscopy (ICP-MS) and high-performance liquid chromatography (HPLC)-ICP-MS were used to analyze total As concentration and speciation. Moreover, synchrotron-based X-ray fluorescence (SXRF) was used to investigate in situ As distribution in the leaf, internode, node and grain. * Total As concentrations of vegetative tissues increased during the 2 wk after flowering. The concentration of dimethylarsinic acid (DMA) in the caryopsis decreased progressively with its development, whereas inorganic As concentration remained stable. The ratios of As content between neighboring leaves or between neighboring internodes were c. 0.6. SXRF revealed As accumulation in the center of the caryopsis during its early development and then in the ovular vascular trace. * These results indicate that there are different controls on the unloading of inorganic As and DMA; the latter accumulated mainly in the caryopsis before flowering, whereas inorganic As was mainly transported into the caryopsis during grain filling. Moreover, nodes appeared to serve as a check-point in As distribution in rice shoots. PMID- 20840511 TI - Hypoxia responsive gene expression is mediated by various subsets of transcription factors and miRNAs that are determined by the actual oxygen availability. AB - * Reduced oxygen availability is not only associated with flooding, but occurs also during growth and development. It is largely unknown how hypoxia is perceived and what signaling cascade is involved in activating adaptive responses. * We analysed the expression of over 1900 transcription factors (TFs) and 180 microRNA primary transcripts (pri-miRNAs) in Arabidopsis roots exposed to different hypoxic conditions by means of quantitative PCR. We also analysed the promoters of genes induced by hypoxia with respect to over-represented DNA elements that can act as potential TF binding sites and their in vivo interaction was verified. * We identified various subsets of TFs that responded differentially through time and in an oxygen concentration-dependent manner. The regulatory potential of selected TFs and their predicted DNA binding elements was validated. Although the expression of pri-miRNAs was differentially regulated under hypoxia, only one corresponding mature miRNA changed accordingly. Putative target transcripts of the miRNAs were not significantly affected. * Our results show that the regulation of hypoxia-induced genes is controlled via simultaneous interaction of various combinations of TFs. Under anoxic conditions, an additional set of TFs is induced. Regulation of gene expression via miRNAs appears to play a minor role during hypoxia. PMID- 20840512 TI - Outcome of drowned hypothermic children with cardiac arrest treated with cardiopulmonary bypass. AB - BACKGROUND: There is a lack of data on the outcome of cardiopulmonary bypass (CPB) rewarming of hypothermic children with cardiac arrest following drowning. AIM OF THE STUDY: To retrospectively analyze single-center outcome of drowning victims treated with CPB. MATERIALS AND METHODS: This retrospective study included all hypothermic drowning victims admitted to the Hospital for Children and Adolescents with attempted resuscitation on CPB between 1994 and 2008 inclusive. Median sternotomy and cannulation of the ascending aorta and the right atrium for CPB were performed on all victims. RESULTS: Nine hypothermic drowning victims, comprising five boys and four girls, with a median age of 3.8 years (range, 1.5-10 years). The median submersion time was 38 min (range, 5-75 min) and the median water temperature was 6.5 degrees C (range, 0.2-16.5 degrees C). The median core temperature was 21.9 degrees C (range 17.7-32.8 degrees C) at arrival to the hospital. All nine children were able to be weaned from CPB. Only one child, with mild to moderate neurological deficit, became a long-term survivor. She was slowly rewarmed up to 33 degrees C with CPB and kept in mild hypothermia for 48 h. CONCLUSIONS: Large numbers of submerged children can be primarily resuscitated with CPB. Unfortunately, many of them will decease from severe hypoxic brain injury. Slow rewarming with CPB may improve the likelihood of a better neurological outcome. PMID- 20840513 TI - Maize- or potato-derived hydroxyethyl starches: is there any thromboelastometric difference? AB - BACKGROUND: Hydroxyethyl starches (HES) could differ with regard to the origin, and the influence on the coagulation of the raw material is unknown. This study compared the effects of a new potato-derived HES with a maize-derived HES and two crystalloid solutions. METHODS: Whole blood from 10 healthy individuals was diluted by 20% and 40% using either non-balanced potato-derived HES 130/0.42/6:1, non-balanced maize-derived HES 130/0.4/9:1, isotonic saline or Ringer's lactate solution. Samples were analysed by thromboelastometry ROTEM((r)) : Coagulation was initiated by acid ellagic [intrinsic thromboelastometry (INTEM)] or tissue factor (extrinsic thromboelastometry) with and without cytochalasin to determine the functional component of fibrinogen [cytochalasin-d-modified thromboelastometry (FIBTEM)]. Platelet count and fibrinogen activity were measured. RESULTS: No effect of raw material was found as no difference was detected among the HES solutions. Whatever the solution, progressive haemodilution impaired haemostasis in a dose-dependant manner: For INTEM, the clot formation time was increased up to 308% and the maximum clot firmness (MCF) was decreased down to 49%. As dilution increased, initiation of coagulation was also impaired. Thromboelastometric alterations were more severe with HES than with crystalloids, especially regarding fibrin polymerization explorations: MCF of FIBTEM was considerably reduced from 12[10-14] to 2[2-3] mm (P<0.05). Fibrinogen activity and platelet count were reduced by dilution in a dose dependant manner and decreased similarly in all groups. CONCLUSION: Maize- and potato-derived HES have similar effects on coagulation. Both the starch preparations tested lead to more severe haemostatic defects than crystalloids, and impairment of fibrin polymerization appears to be a leading determinant of this coagulopathy. PMID- 20840514 TI - Effects of different respiratory maneuvers on esophageal sphincters in obese patients before and during anesthesia. AB - BACKGROUND: Data on esophageal sphincters in obese individuals during anesthesia are sparse. The aim of the present study was to evaluate the effects of different respiratory maneuvers on the pressures in the esophagus and esophageal sphincters before and during anesthesia in obese patients. METHODS: Seventeen patients, aged 28-68 years, with a BMI >= 35 kg/m2, who were undergoing a laparoscopic gastric by-pass surgery, were studied, and pressures from the hypopharynx to the stomach were recorded using high-resolution solid-state manometry. Before anesthesia, recordings were performed during normal spontaneous breathing, Valsalva and forced inspiration. The effects of anesthesia induction with remifentanil and propofol were evaluated, and positive end-expiratory pressure (PEEP) 10 cmH2O was applied during anesthesia. RESULTS: During spontaneous breathing, the lower esophageal sphincter (LES) pressure was significantly lower during end-expiration compared with end-inspiration (28.5 +/- 7.7 vs. 35.4 +/- 10.8 mmHg, P<0.01), but barrier pressure (BrP) and intra-gastric pressure (IGP) were unchanged. LES, BrP (P<0.05) and IGP (P<0.01) decreased significantly during anesthesia. BrP remained positive in all patients. IGP increased during Valsalva (P<0.01) but was unaffected by PEEP. Esophageal pressures were positive during both spontaneous breathing and mechanical ventilation. Esophageal pressures increased during PEEP from 9.4 +/- 3.8 to 11.3 +/- 3.3 mmHg (P<0.01). CONCLUSION: During spontaneous breathing, the LES pressure was the lowest during end-expiration but there were no differences in BrP and IGP. LES, BrP and IGP decreased during anesthesia but BrP remained positive in all patients. During the application of PEEP, esophageal pressures increased and this may have a protective effect against regurgitation. PMID- 20840515 TI - Effect of an intravenous infusion of lidocaine on cisatracurium-induced neuromuscular block duration: a randomized-controlled trial. AB - BACKGROUND: Intravenous lidocaine can be used intraoperatively for its analgesic and antihyperalgesic properties but local anaesthetics may also prolong the duration of action of neuromuscular blocking agents. We hypothesized that intravenous lidocaine would prolong the time to recovery of neuromuscular function after cisatracurium. METHODS: Forty-two patients were enrolled in this randomized, double-blind, placebo-controlled study. Before induction, patients were administered either a 1.5 mg/kg bolus of intravenous lidocaine followed by a 2 mg/kg/h infusion or an equal volume of saline. Anaesthesia was induced and maintained using propofol and remifentanil infusions. After loss of consciousness, a 0.15 mg/kg bolus of cisatracurium was administered. No additional cisatracurium injection was allowed. Neuromuscular function was assessed every 20 s using kinemyography. The primary endpoint was the time to spontaneous recovery of a train-of-four (TOF) ratio >= 0.9. RESULTS: The time to spontaneous recovery of a TOF ratio >= 0.9 was 94 +/- 15 min in the control group and 98 +/- 16 min in the lidocaine group (P=0.27). CONCLUSIONS: No significant prolongation of spontaneous recovery of a TOF ratio >= 0.9 after cisatracurium was found in patients receiving intravenous lidocaine. PMID- 20840516 TI - Bed-sharing among six-month-old infants in western Sweden. AB - AIM: In spite of several reports of an increased risk of sudden infant death syndrome (SIDS) in connection with bed-sharing, it is not an uncommon practice. The aim of this study was to examine bed-sharing at 6 months of age and the factors that are associated with bed-sharing. METHODS: Our cohort comprised 8176 randomly chosen families. At 6 month of age, the families received an invitation to the study, with a questionnaire, which was completed by 5605 families (response rate 68.5%). RESULTS: Of the families, 19.8% bed-shared. In the multivariate analysis, we found a correlation between breast-feeding and bed sharing (breast-feeding at 6 months: OR 1.94; 95% CI 1.56, 2.41). Moreover, we found an association with 3+ nightly awakenings at 6 months (2.70; 2.20, 3.32). It was more common to share a bed if the parent was single (2.04; 1.19, 3.51) and less common if the infant was bottle-fed in the first week (0.70; 0.54, 0.90). Never using a pacifier was associated with a higher frequency of bed-sharing. CONCLUSION: We found a correlation between breast-feeding and bed-sharing as well as between sleeping problems and a single parent. A lower percentage of infants sleeping in the parental bed were seen in association with formula feeding in the first week after birth. PMID- 20840517 TI - The role of surgical debridement in healing of diabetic foot ulcers. AB - An estimated 15% of patients with diabetes mellitus will develop a foot ulcer during their lifetime. Debridement is included in multiple guidelines and algorithms for the care of patients with diabetic neuropathic foot ulcers, and it has long been considered an essential step in the protocol for treating diabetic foot ulcers. In addition to altering the environment of the chronic wound, debridement is a technique aimed at removing nonviable and necrotic tissue, thought to be detrimental to healing. This is accomplished by removing abnormal wound bed and wound edge tissue, such as hyperkeratotic epidermis (callus) and necrotic dermal tissue, foreign debris, and bacteria elements known to have an inhibitory effect on wound healing. While the rationale for surgical debridement seems logical, the evidence for its role in enhancing healing is deficient. In this paper, we systematically review five published clinical trials, which met the criteria and investigated surgical debridement of diabetic foot ulcers to enhance healing. Most existing studies are not randomized clinical trials optimized to test the relationship between debridement of diabetic foot ulcers and wound healing. Therefore, a focused, well-designed study is needed to elucidate the effect of surgical debridement on the healing status of chronic wounds. PMID- 20840518 TI - The differential effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers with respect to foot ulcer and limb amputation in those with diabetes. AB - Diabetic foot ulcers (DFU) or lower extremity amputation (LEA) are complications of diabetes. In those with diabetes, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) are commonly used to prevent the progression of kidney disease. Recent studies have indicated that angiotensin may affect angiogenesis and wound repair. Our goal was to evaluate in those with diabetes the likelihood of developing a DFU or LEA among users of ACEi or ARB using a retrospective cohort design of general practices in the United Kingdom. We studied 40,342 individuals at least 35 years of age with diabetes who were first prescribed ACEi or ARB between 1995 and 2006. A total of 35,153 individuals were treated with ACEi, 12,437 individuals with ARB, and 7,310 both. The hazard ratio for DFU was 0.50 (95% confidence intervals: 0.43, 0.59), showing an increased risk of DFU for those using ACEi vs. ARB. The hazard ratio for LEA was 0.72 (0.48, 1.01). However, among those with lower extremity peripheral arterial disease the hazard ratio was 0.45 (0.22, 0.91) for the new onset of a LEA. In conclusion, among those with diabetes, exposure to ACEi as compared with ARB increases the risk of developing a DFU or LEA. PMID- 20840519 TI - Nanotechnology promotes the full-thickness diabetic wound healing effect of recombinant human epidermal growth factor in diabetic rats. AB - We utilized a modified double-emulsion method with poly(lactic-co-glycolic acid) as the carrier to prepare recombinant human epidermal growth factor (rhEGF) nanoparticles. The morphology of the nanoparticles was detected by a transmission electron microscope. The particle size distribution was measured by a laser analyzer with a zeta potential meter. Enzyme-linked immunosorbent assays were performed to determine the rhEGF encapsulation efficiency and release model, and the proliferation of the mouse fibroblasts was analyzed by the MTT method. Diabetic rats with full-thickness wounds were divided into four groups according to different treatments: rhEGF nanoparticles, rhEGF stock solution, empty nanoparticles, and phosphate-buffered saline. Photographs were taken after the treatments to calculate the wound healing rates, and the granulation tissue of the wounds was sampled for pathologic slides. Proliferating cell nuclear antigen was assayed by immunohistochemistry. Our results showed that the rhEGF nanoparticles were around 193.5 nm (diameter), and the particle size distribution was uniform and dispersible. The encapsulation efficiency was 85.6% and rhEGF release lasted 24 hours. Compared with other groups, the rhEGF nanoparticles promoted the highest level of fibroblast proliferation, and this group showed the fastest healing rate. The number of proliferating cell nuclear antigen positive cells in the rhEGF nanoparticles group was higher than the other groups. We concluded that controlled release of rhEGF encapsulated in the nanoparticles enhanced rhEGF effects to stimulate cell proliferation and shorten the wound healing time. PMID- 20840520 TI - Promotion of cutaneous wound healing by local application of mesenchymal stem cells derived from human umbilical cord blood. AB - This study aimed to determine whether mesenchymal stem cells (MSCs) derived from umbilical cord blood (UCB) would promote cutaneous wound healing. MSCs from human UCB were isolated and identified. The characteristics of the isolated MSCs' growth and proliferation were assayed in vitro. The MSCs labeled with 5 bromodeoxyuridine (BrdU) were applied on fresh cutaneous mice wounds. The healing rates were surveyed. The distribution and the differentiation into keratinocytes of the labeled MSCs in the wound tissue were checked by immunohistochemistry staining. The isolated MSCs could grow and proliferate well in vitro. The isolated MSCs from UCB could be labeled by 5-bromodeoxyuridine successfully. The MSCs derived from UCB could enhance the healing of mice skin defect wounds, and it was found that the implanted MSCs could differentiate into keratinocyte in the wound tissue. It was demonstrated that MSCs from UCB can be isolated and proliferated successfully. The local administration of MSCs derived from UCB improves skin defect wound healing in mice. PMID- 20840522 TI - NDRG2 in rat liver regeneration: role in proliferation and apoptosis. AB - Liver regeneration is a complex process that is orchestrated by the precise interplay of cell proliferation, differentiation control, and molecular pathways, but this complicated molecular signaling network is not fully understood. In this study, we showed that N-Myc downstream-regulated gene 2 (NDRG2) is involved in this process. The mRNA and protein levels of NDRG2 were strongly reduced when liver regeneration reached a peak of activity. In addition, we found that rat NDRG2 expression and C-Myc expression were inversely correlated during this process. A low level of NDRG2 was observed as the C-Myc expression increased during regeneration. Moreover, a dramatic cell cycle arrest was found in normal rat liver-derived BRL cells 48 hours after being infected by adenoviral vectors expressing rat NDRG2. Meanwhile, the apoptotic rates were increased from 9.4% in control group to 64.7% in adenoviral vectors expressing rat NDRG2 group. These phenomena could also be observed in BRL 3A and L-02 cells. Further analysis revealed that NDRG2 overexpression may mediate the antiproliferative effect by inducing p53 and p21 regulated Bax/Bcl-2 increase and cyclin E-Cdk2 inhibition. In conclusion, our findings point to physiological roles for NDRG2 in liver regeneration. PMID- 20840521 TI - Reactive response of fibrocytes to vocal fold mucosal injury in rat. AB - Fibrocytes hold a prominent role in inflammatory and tissue repair processes in various organ systems. In this study, we identified and quantified a reactive fibrocyte population in the vocal fold mucosa postinjury using immunohistochemistry and stereological analysis. These cells, which expressed CD11b on their surface and prolyl-4-hydroxylase beta (P4H-beta) intracellularly, were largely restricted to the lamina propria, and were morphologically and immunochemically distinguishable from newly recruited epithelial cells. We validated our immunohistochemistry findings using flow cytometry, and additionally characterized a reactive fibrocyte population in circulating peripheral blood using a novel detection panel (CD16(-) CD11b(+) P4H-beta(+) ). Fibrocyte recruitment peaked at 3 days postinjury in peripheral blood, and 5 days postinjury in the vocal fold mucosa. These findings suggest that circulating fibrocytes are recruited to sites of tissue injury in the vocal fold mucosa, and may play an important role in vocal fold tissue repair. The results of this study are consistent with published data from other organ systems and strongly suggest the importance of fibrocytes as therapeutic targets. Our newly reported antigen panel facilitating the direct characterization of fibrocytes via flow cytometry is a useful tool with the potential to facilitate improved study of this cell population. PMID- 20840523 TI - Limb regeneration is impaired in an adult zebrafish model of diabetes mellitus. AB - The zebrafish (Danio rerio) is an established model organism for the study of developmental processes, human disease, and tissue regeneration. We report that limb regeneration is severely impaired in our newly developed adult zebrafish model of type I diabetes mellitus. Intraperitoneal streptozocin injection of adult, wild-type zebrafish results in a sustained hyperglycemic state as determined by elevated fasting blood glucose values and increased glycation of serum protein. Serum insulin levels are also decreased and pancreas immunohistochemisty revealed a decreased amount of insulin signal in hyperglycemic fish. Additionally, the diabetic complications of retinal thinning and glomerular basement membrane thickening (early signs of retinopathy and nephropathy) resulting from the hyperglycemic state were evident in streptozocin injected fish at 3 weeks. Most significantly, limb regeneration, following caudal fin amputation, is severely impaired in diabetic zebrafish and nonspecific toxic effects outside the pancreas were not found to contribute to impaired limb regeneration. This experimental system using adult zebrafish facilitates a broad spectrum of genetic and molecular approaches to study regeneration in the diabetic background. PMID- 20840524 TI - Fetal tendon wound size modulates wound gene expression and subsequent wound phenotype. AB - The fetal response to small tendon injury results in regenerative or scarless healing and is characterized by a markedly diminished cellular inflammatory response, lack of fibroplasia, and restoration of normal tissue architecture. We hypothesized that an increasing fetal tendon wound size would lead to increased wound inflammation and a change from regenerative to reparative healing and scar formation. We created small or large tendon wounds in early gestation fetal sheep and used histology to assess tissue architecture, immunohistochemistry to assess the cellular inflammatory response, ovine-specific gene microarrays, and real time reverse transcription-polymerase chain reaction to measure the gene expression in response to injury. Small tendon wounds showed a regenerative healing phenotype with orderly deposition of collagen fibers while large tendon wounds showed disorderly collagen deposition consistent with scar formation. Small tendon wounds had few inflammatory cells at 7 and 28 days after injury, whereas the large wounds showed a significant inflammatory cell infiltrate at 7 days that resolved by 28 days. At 3 days, the differential expression of genes involved in the response to injury and inflammation were seen between large and small tendon wounds. By real-time polymerase chain reaction at 7 days, large tendon wounds also had significantly increased expression of interleukin-6, interleukin-8, transforming growth factor-beta1, and transforming growth factor beta3, compared with the small wounds. Increasing the fetal tendon wound size results in increased proinflammatory gene expression, inflammatory cell infiltration, and a change from regenerative to reparative healing. This model allows the process of regenerative healing to be examined without the confounding variable of gestational age. PMID- 20840525 TI - A new tool for the validation of umbilical cord acid-base data. AB - OBJECTIVE: To identify the distribution of carbon dioxide tension (pCO(2) ) relative to pH in validated umbilical cord acid-base data. DESIGN: Observational study. SETTING: European hospital labour wards. POPULATION: Data for 36,432 term newborns were obtained from three sources: two trials of fetal monitoring with electrocardiography (ECG; the Swedish randomised controlled trial and the European Union Fetal ECG trial) and data from Molndal Hospital. METHODS: From the total study population, cases with missing values or obvious typing errors were excluded. The remaining data were validated based on specified criteria. Percentiles of arterial pCO(2) by pH were calculated using multilevel regression modelling. MAIN OUTCOME MEASURES: Umbilical cord pH, pCO(2) and base deficit. RESULTS: Acid-base values were considered invalid in one out of seven cases. Percentiles for arterial pCO(2) corresponding to specified values of arterial pH were developed from the validated data of 26, 690 cases. CONCLUSIONS: Percentiles for arterial pCO(2) for a specified arterial pH can be used as a tool to identify cases with erroneously low pCO(2) values, and thus avoid an incorrect interpretation of the newborn's acid-base status. PMID- 20840526 TI - An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre-eclampsia at term (HYPITAT trial). AB - OBJECTIVE: To assess the economic consequences of labour induction compared with expectant monitoring in women with gestational hypertension or pre-eclampsia at term. DESIGN: An economic analysis alongside the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: Women diagnosed with gestational hypertension or pre-eclampsia between 36(+0) and 41(+0) weeks of gestation, randomly allocated to either induction of labour or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a societal perspective during a 1-year time horizon. MAIN OUTCOME MEASURES: One-year costs were estimated and health outcomes were expressed as the prevalence of poor maternal outcome defined as either maternal complications or progression to severe disease. RESULTS: The average costs of induction of labour (n = 377) were ?7077 versus ?7908 for expectant monitoring (n = 379), with an average difference of -?831 (95% CI -?1561 to -?144). This 11% difference predominantly originated from the antepartum period: per woman costs were ?1259 for induction versus ?2700 for expectant monitoring. During delivery, more costs were generated following induction (?2190) compared with expectant monitoring (?1210). No substantial differences were found in the postpartum, follow-up and for non-medical costs. CONCLUSION: In women with gestational hypertension or mild pre-eclampsia at term, induction of labour is less costly than expectant monitoring because of differences in resource use in the antepartum period. As the trial already demonstrated that induction of labour results in less progression to severe disease without resulting in a higher caesarean section rate, both clinical and economic consequences are in favour of induction of labour in these women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825. PMID- 20840527 TI - Proportion of excision and cervical healing after large loop excision of the transformation zone for cervical intraepithelial neoplasia. AB - OBJECTIVE: To determine how the proportion of the cervical volume excised affects cervical regeneration. DESIGN: Prospective observational study. SETTING: University Hospital. POPULATION: Women planning to undergo excisional treatment for cervical intraepithelial neoplasia who wish to have future pregnancies. METHODS: The cervical volume (and dimensions) is calculated with magnetic resonance imaging (MRI) before treatment. The volume (and dimensions) of the cone is assessed before fixation by a volumetric tube and a ruler; the percentage (%) of excision is computed. Cervical regeneration is estimated by repeat MRI at 6 months. MAIN OUTCOME MEASURES: Cervical regeneration in relation to proportion of excision. Statistical analysis was performed by box plots and analysis of variance. RESULTS: A total of 48 women have been recruited; 29 have completed 6 months follow up. Both the total cervical volume (from MRI) before treatment and the volume of the excised/ablated cone varied substantially. The estimated proportion of excision varied significantly between 4% and 39% (median 11%). Multivariate linear regression revealed that the proportional deficit at 6 months post-treatment was determined mainly by the proportion of the excised volume. CONCLUSIONS: Careful assessment of risks and benefits of treatment is essential when deciding to treat women who wish to have future pregnancies. Assessment of the proportion of the cervical volume and length excised might identify those that need further surveillance during future pregnancy. PMID- 20840528 TI - Do pregnancies with pre-eclampsia have smaller placentas? A population study of 317 688 pregnancies with and without growth restriction in the offspring. AB - OBJECTIVE: To study whether placental weight is related to pre-eclampsia risk, independent of offspring birthweight. DESIGN: Registry study. SETTING: Medical Birth Registry of Norway. POPULATION: All singleton pregnancies in Norway from 1999 to 2004, 317 688 births. METHODS: Placental weight was grouped into deciles of placental weight z-scores. The proportion of pregnancies in each placental weight decile was calculated by maternal pre-eclampsia status for pregnancies with and without small-for-gestational-age (SGA) offspring. MAIN OUTCOME MEASURES: Pre-eclampsia risk (proportions and odds ratios) according to placental weight. RESULTS: In pregnancies with SGA offspring, approximately 60% of pregnancies were in the lowest decile of placental weight, 59.9% in pregnancies with and 61.4% in pregnancies without pre-eclampsia. Pregnancies without SGA offspring were evenly distributed across placental weight deciles, but were slightly higher in the lowest (9.5% versus 8.5%) and highest (11.9% versus 10.2%) deciles in pre-eclamptic pregnancies compared with pregnancies without pre eclampsia. A weak U-shaped association of placental weight with pre-eclampsia was also estimated as odds ratios in pregnancies with SGA, but not without SGA, in the offspring. CONCLUSIONS: Placental weight is linked to the offspring's birthweight, but is not clearly associated with pre-eclampsia risk, suggesting that placental weight is not a useful indicator for the placental dysfunction in pre-eclampsia. PMID- 20840529 TI - The impact of mode of anaesthesia on postoperative recovery from fast-track abdominal hysterectomy: a randomised clinical trial. AB - OBJECTIVE: to determine whether the duration of hospital stay after abdominal hysterectomy in a fast-track setting differed between women operated under general anaesthesia or in spinal anaesthesia with intrathecal morphine. DESIGN: an open randomised controlled multicentre study. SETTING: five hospitals in the south-east of Sweden. POPULATION: one hundred and eighty women scheduled for benign hysterectomy were randomised: 162 completed the study, 82 were allocated to spinal anaesthesia and 80 were allocated to general anaesthesia. METHODS: fast track model comprising no use of sedatives for premedication, pre-emptive anti emetic therapy, intravenous fluid restriction, analgesics based on non-opioids, early enteral nutrition and mobilisation, and standard criteria for discharge. Spinal anaesthesia with 20 mg hyperbaric bupivacaine and 0.2 mg morphine. General anaesthesia with propofol, fentanyl and rocuronium, and with continuous propofol and ventilation with oxygen-in-air for maintenance of anaesthesia. MAIN OUTCOME MEASURES: hospital stay, consumption of analgesics, vomiting, pruritus and bowel function recovery. RESULTS: median hospitalisation did not differ significantly between women who had hysterectomy with spinal or general anaesthesia (46 and 50 hours, respectively). Spinal anaesthesia was associated with a significantly lower use of opioids and a faster recovery of bowel function, although vomiting and pruritus were more prevalent. CONCLUSIONS: in a fast-track model the duration of hospitalisation after abdominal hysterectomy was < 50 hours, independent of the mode of anaesthesia. Spinal anaesthesia reduced the need for postoperative morphine compared with general anaesthesia. In order to improve patient recovery after gynaecological surgery further studies based on fast-track programmes are needed. PMID- 20840530 TI - Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. AB - INTRODUCTION: Flibanserin is a novel pharmacologic agent in late-stage clinical testing for hypoactive sexual desire disorder (HSDD) in premenopausal women. AIM: The aim of this article is to review the hypothetical mechanism of action of flibanserin in HSDD. METHODS: A literature review was conducted of all published works on flibanserin and on related studies of serotonin (5-HT)(1A) receptors and 5-HT(2A) receptors, including their actions on monoamines and on sexual function. MAIN OUTCOME MEASURES: The main outcome measures are preclinical pharmacologic actions, especially changes in regional monoamines following treatment with flibanserin. RESULTS: At clinically relevant doses, flibanserin acts predominantly at 5-HT(1A) receptors as an agonist and secondarily at 5-HT(2A) receptors as an antagonist. Additional binding actions within an order of magnitude of its 5-HT(1A) affinity, which are not likely to be clinically relevant, include weaker antagonist actions at 5-HT(2C) and 5-HT(2B) receptors, and less defined activity at dopamine (DA) D4 receptors. The 5-HT(1A) actions of flibanserin are only seen postsynaptically, which is unlike other agents such as buspirone that act at presynaptic 5-HT(1A) receptors. Furthermore, the postsynaptic actions of chronic flibanserin administration appear to demonstrate a preference for some populations of postsynaptic 5-HT receptors, particularly those that are located on the prefrontal cortex (PFC) pyramidal neurons, which regulate monoamine release in certain selective brain regions. CONCLUSIONS: The regional selectivity of flibanserin results in a unique pattern of monoamine modulation. Sustained increases in baseline of DA and norepinephrine (NE) are observed in the PFC, and flibanserin dosing increases DA and NE levels above the basal changes. Conversely, flibanserin induces transient decreases in 5-HT levels in some brain areas such as the PFC, nucleus accumbens, and hypothalamus, but not in other brain areas such as the hippocampus. Therefore, since DA and NE are excitatory and 5-HT is inhibitory to sexual desire and arousal, it is tempting to postulate that the actions of flibanserin on serotonin receptors at the PFC pyramidal neurons, resulting in increased DA and NE yet reduced 5-HT in the PFC, are the mechanistic underpinnings of enhancing sexual desire in HSDD. PMID- 20840531 TI - When condom use is not condom use: an event-level analysis of condom use behaviors during vaginal intercourse. AB - INTRODUCTION: Little is known about event-level condom use errors during vaginal sex. AIMS: The aim of this article is to examine factors associated with complete condom use compared to forms of incomplete condom use, including delayed condom application and early condom removal, over a 30-day period. METHODS: Data were collected in 2008 from 1,875 men during a prospective daily diary study of sexual behavior and condom use. Incomplete condom use was assessed during vaginal intercourse considering situational, relational, intrapersonal, and behavioral predictors. Analyses were generalized estimating equation multinomial logistic regression. MAIN OUTCOME MEASURES: Condom use during vaginal sex: complete use, delayed application, early removal, and both delayed application/early removal. RESULTS: Of 29,714 diary reports, 30% (8,876) included vaginal intercourse. Analyses were conducted (in 2009) on 83.2% of these intercourse events (6,325), during which condoms were used and for which participants provided complete data. Incomplete condom use included penetration before applying condoms during 12% of events (749), removing condoms before intercourse ended during 3.1% (198), and both types of incomplete use during 2% (129) of events. Erection quality (less than typical erect penile length and circumference, less rigidity, and difficulty maintaining erection) was associated with greater odds of incomplete use, as was a participant's history of other recent incomplete use. Perceptions of condom comfort and recent previous complete use were protective factors against incomplete use. CONCLUSIONS: Men's incomplete condom use is associated with recent condom use patterns, as well as with their physiological characteristics and perceptions of condoms during sexual intercourse. Event-level analyses such as these help describe how incomplete condom use occurs among individuals incorporating condoms into their sexual activities. PMID- 20840532 TI - Robot-assisted laparoscopic prostatectomy in patients with preexisting three piece inflatable penile prosthesis. AB - INTRODUCTION: Robotic-assisted laparoscopic radical prostatectomy (RARP) is becoming the preferred surgical treatment option for management of organ-confined prostate cancer. Although not a contraindication, previous pelvic surgery can make RARP challenging. Presence of a three-piece inflatable penile prosthesis, with a perivesical pelvic reservoir, has the potential to induce steric hindrance making RARP difficult. AIM: The main purpose of this publication is to report our experience with RARP in patients with previously inserted three-piece inflatable penile prostheses. METHODS: Two patients with previously inserted AMS 700 penile prosthesis and with organ-confined, biopsy proven adenocarcinoma of the prostate underwent RARP. We describe intraoperative findings, surgical technique, oncologic and functional outcomes. RESULTS: Both patients underwent safe and successful RARP with out any complications. Surgical margins were not affected with pelvic reservoir-sparing technique. In both patients, the penile prosthesis remained functional postoperatively. CONCLUSIONS: RARP can be safely performed in patients with previously inserted three-piece inflatable penile prosthesis. Nontraumatic handling of the pelvic reservoir is mandatory to preserve prosthesis' integrity. PMID- 20840533 TI - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor (DR5) in Peyronie's disease. A biomolecular study of apoptosis activation. AB - INTRODUCTION: Peyronie's disease (PD) is a connective tissue disorder of tunica albuginea (TA), a thick fibrous sheath surrounding the corpora cavernosa of the penis. Relatively, little is known about the disease itself. AIM: To investigate whether the apoptosis cascade in degenerated and macroscopically deformed TA from men with PD is activated through the extrinsic pathway, by assessing the immunoexpression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptor, DR5. METHODS: TA plaques from 15 men with PD and from four unaffected men were processed for TRAIL and DR5 immunohistochemistry and Western blot analysis. MAIN OUTCOME MEASURES: A greater understanding of the pathophysiology of PD through a molecular approach, to gain insights that may lead to novel forms of treatment. RESULTS: Activation of the apoptosis mechanisms through the extrinsic pathway was demonstrated by TRAIL and DR5 overexpression in fibroblasts and myofibroblasts from affected TA. CONCLUSION: The finding that apoptosis activation in TA plaques occurs, at least in part, via the extrinsic pathway may help devise novel therapeutic options for these patients. PMID- 20840534 TI - Contribution of attitudinal factors to blood donation in African American church attendees. AB - BACKGROUND: Historically, African Americans have a general mistrust for the health care system that has contributed to significant health disparities. The goal of this study was to evaluate whether this distrust among African Americans affects attitudes toward blood donation. STUDY DESIGN AND METHODS: Fifteen African American churches in metropolitan Atlanta participated in an 81-item self administered survey. The questionnaire assessed barriers and motivators for, and knowledge and beliefs about, blood donation in African Americans. Bivariate analysis and logistic regression models were performed. RESULTS: A total of 930 individuals responded to the survey. This group was 99% African Americans, 71% female, and 84% college educated, 54% with a household income of at least $50,000 and mean age of 47+/-14 years. Donation history was 3% current donors, 46% lapsed donors, and 40% nondonors. Respondents who trusted versus distrusted hospitals had more knowledge of the blood supply and less fear of donation and were more likely to respond to blood needs of the community. In a multivariate logistic regression model, donors were more likely to trust hospitals (p=0.003) and were more likely to have participated in research (p<0.001) than nondonors. CONCLUSION: African American distrust of the health care system is associated with decreased likelihood of previous blood donation. This may be secondary to donor centers being viewed as a component of the health care system. Building trust between donor centers and African American community by ensuring the safety of donation may increase African American blood donation rates. PMID- 20840535 TI - Expression and function of the K+ channel KCNQ genes in human arteries. AB - BACKGROUND AND PURPOSE: KCNQ-encoded voltage-gated potassium channels (K(v) 7) have recently been identified as important anti-constrictor elements in rodent blood vessels but the role of these channels and the effects of their modulation in human arteries remain unknown. Here, we have assessed KCNQ gene expression and function in human arteries ex vivo. EXPERIMENTAL APPROACH: Fifty arteries (41 from visceral adipose tissue, 9 mesenteric arteries) were obtained from subjects undergoing elective surgery. Quantitative RT-PCR experiments using primers specific for all known KCNQ genes and immunohistochemsitry were used to show K(v) 7 channel expression. Wire myography and single cell electrophysiology assessed the function of these channels. KEY RESULTS: KCNQ4 was expressed in all arteries assessed, with variable contributions from KCNQ1, 3 and 5. KCNQ2 was not detected. K(v) 7 channel isoform-dependent staining was revealed in the smooth muscle layer. In functional studies, the K(v) 7 channel blockers, XE991 and linopirdine increased isometric tension and inhibited K(+) currents. In contrast, the K(v) 7.1-specific blocker chromanol 293B did not affect vascular tone. Two K(v) 7 channel activators, retigabine and acrylamide S-1, relaxed preconstricted arteries, actions reversed by XE991. K(v) 7 channel activators also suppressed spontaneous contractile activity in seven arteries, reversible by XE991. CONCLUSIONS AND IMPLICATIONS: This is the first study to demonstrate not only the presence of KCNQ gene products in human arteries but also their contribution to vascular tone ex vivo. LINKED ARTICLE: This article is commented on by Mani and Byron, pp. 38-41 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.01065.x. PMID- 20840536 TI - Mechanisms of actions of hydrogen sulphide on rat distal colonic epithelium. AB - BACKGROUND AND PURPOSE: The aim of this study was to clarify the mechanisms by which hydrogen sulphide (H2S) affects ion secretion across rat distal colonic epithelium. EXPERIMENTAL APPROACH: Changes in short-circuit current induced by the H2S-donor, sodium hydrosulphide (NaHS; 10 mmol.L-1), were measured in Ussing chambers after permeabilization of the apical membrane with nystatin. Cytosolic Ca2(+) concentration ([Ca2(+)](i)) and Ca2(+) in intracellular stores were measured with fluorescent dyes. Changes in mitochondrial membrane potential were estimated with rhodamine 123. KEY RESULTS: NaHS had a biphasic effect on overall currents across the basolateral membrane: an initial inhibition followed by a secondary stimulation. Both a scilliroside-sensitive action on the Na(+) -K(+) ATPase and modulation of glibenclamide-sensitive and tetrapentylammonium sensitive (i.e. ATP-sensitive and Ca2(+)-dependent) basolateral K(+) channels were involved in this action. Experiments with rhodamine 123 revealed that NaHS induced a hyperpolarization of the mitochondrial membrane. NaHS evoked a biphasic change in [Ca2(+)](i) , an initial decrease followed by a secondary increase, known to be mediated by the release of stored Ca2(+). Initial falls in [Ca2(+)](i) were not mediated by a sequestration of Ca2(+) in intracellular Ca2(+) storing organelles, as the Mag-Fura-2 signal was unaffected by NaHS. Falls in [Ca2(+)](i) were inhibited by 2',4'-dichlorobenzamil, an inhibitor of the Na(+)-Ca2(+)-exchanger, and attenuated in Na(+)-free buffer, suggesting a transient stimulation of Ca2(+) outflow by this transporter, directly demonstrated by Mn2(+) quenching experiments. CONCLUSIONS AND IMPLICATIONS: ATP sensitive and Ca2(+)-dependent basolateral K(+) conductances, the basolateral Na(+)-K(+)-pump as well as Ca2(+) transporters were involved in the action of H2S in regulating colonic ion secretion. PMID- 20840537 TI - Receptor localization, native tissue binding and ex vivo occupancy for centrally penetrant P2X7 antagonists in the rat. AB - BACKGROUND AND PURPOSE: The P2X7 receptor is implicated in inflammation and pain and is therefore a potential target for therapeutic intervention. Here, the development of a native tissue radioligand binding, localization and ex vivo occupancy assay for centrally penetrant P2X7 receptor antagonists is described. EXPERIMENTAL APPROACH: Autoradiography studies using the P2X7 antagonist radioligand [3H]-A-804598 were carried out in rat brain and spinal cord. Subsequent in vitro binding and ex vivo occupancy assays were performed using rat cortex homogenate. KEY RESULTS: P2X7 expression was shown to be widespread throughout the rat brain, and in the grey matter of the spinal cord. In binding assays in rat cortex homogenate, ~60% specific binding was achieved at equilibrium. In kinetic binding assays, k(on) and k(off) values of 0.0021.min 1.nM-1 and 0.0070.min-1 were determined, and the K(d) derived from kinetic measurements was consistent with that derived from saturation analysis. Novel P2X7 antagonists inhibited the binding of [3H]-A-804598 to rat cortex P2X7 receptors with K(i) values of <40 nM. In an ex vivo occupancy assay, a P2X7 antagonist dosed orally to rats caused a concentration-dependent inhibition of the specific binding of [3H]-A-804598 to rat cortex. CONCLUSIONS AND IMPLICATIONS: The present study describes the development of an assay that allows localization of P2X7 receptors, the measurement of the binding affinity of P2X7 receptor antagonists in native tissue, and provides a means of determining central P2X7 receptor occupancy. These assays could form an important part of a P2X7 drug discovery programme. PMID- 20840538 TI - KMUP-3 attenuates ventricular remodelling after myocardial infarction through eNOS enhancement and restoration of MMP-9/TIMP-1 balance. AB - BACKGROUND AND PURPOSE: Previously, 7-[2-[4-(4-nitrobenzene)piperazinyl]ethyl]-1, 3-dimethylxanthine (KMUP-3) has been shown to induce aortic smooth muscle relaxation through K(ATP) channel opening and endothelial nitric oxide synthase (eNOS) enhancement. We further investigated whether KMUP-3 protects against myocardial remodelling after myocardial infarction (MI), and whether KMUP-3 increases the expression of eNOS in MI rats. EXPERIMENTAL APPROACH: Wistar rats were randomly allocated into three groups: MI (n= 10), MI + KMUP-3 group (n= 10) and sham group (n= 10). MI was induced by ligation of the left anterior descending coronary artery. After recovery, the MI + KMUP-3 group received KMUP-3 (0.3 mg.kg(-1) .day(-1) ) infusion for 4 weeks, while the MI and sham group received vehicle only. To further confirm that the effect of KMUP-3 is dependent on eNOS, KMUP-3 was applied in the culture of transforming growth factor-beta stimulated human cardiac fibroblasts. KEY RESULTS: KMUP-3 treatment attenuated cardiac hypertrophy post-MI and improved cardiac function. The fibrotic area was reduced by KMUP-3 both in central-, peri- and non-infarction areas. KMUP-3 enhanced the expression of eNOS and tissue inhibitor of metalloproteinase-1 (TIMP 1), but reduced matrix metalloproteinase-9 (MMP-9) expression. In vitro, the activities of KMUP-3 were blocked by pretreatment with the eNOS inhibitor N(omega) -nitro-L-arginine methyl ester. CONCLUSIONS AND IMPLICATIONS: The K(ATP) channel opener KMUP-3 preserved cardiac function after MI by enhancing the expression of eNOS. In addition, KMUP-3 restored the myocardial MMP-9/TIMP-1 balance and attenuated ventricular remodelling by an eNOS-dependent mechanism. PMID- 20840539 TI - Impairment of both nitric oxide-mediated and EDHF-type relaxation in small mesenteric arteries from rats with streptozotocin-induced diabetes. AB - BACKGROUND AND PURPOSE: To investigate whether diabetes affects either or both nitric oxide (NO)-mediated and endothelium-derived hyperpolarizing factor (EDHF) type relaxation in endothelium-dependent relaxation of mesenteric arteries from streptozotocin-induced diabetic rats. EXPERIMENTAL APPROACH: Wire myography was employed to examine endothelial function of mesenteric arteries. Superoxide levels were measured by L-012 and lucigenin-enhanced chemiluminescence. Western blotting was used to quantify protein expression levels. KEY RESULTS: Superoxide levels were significantly increased in diabetic mesenteric arteries compared with normal arteries. Diabetes significantly reduced the sensitivity to the endothelium-dependent relaxant, acetylcholine (ACh) in mesenteric arteries. When the contribution of NO to relaxation was abolished by N-nitro-L-arginine (L-NNA) + a soluble guanylate cyclase inhibitor (ODQ), the sensitivity to ACh was significantly decreased in the diabetic arteries compared with normal arteries, indicating an impaired EDHF-type relaxation despite increased expression of intermediate- and small-conductance calcium-activated potassium channels. Conversely, when the contribution of EDHF was inhibited with TRAM-34 + apamin + iberiotoxin, maximum relaxations to ACh were significantly decreased in diabetic compared with normal arteries, suggesting that the contribution of NO was also impaired by diabetes. Basal levels of NO release, indicated by contraction to L NNA, were also significantly decreased in diabetic arteries. Western blot analysis demonstrated that diabetic arteries had an increased expression of Nox2, decreased pSer473 Akt and a reduced proportion of endothelial NO synthase (eNOS) expressed as a dimer, indicating uncoupling. CONCLUSION AND IMPLICATIONS: The contribution of both NO and EDHF-type relaxations was impaired in diabetes and was caused by increased oxidative stress, decreased pSer473 Akt and/or eNOS uncoupling. PMID- 20840541 TI - Epidemiology of invasive fungal infections in neonates and children. AB - Invasive fungal infections are major causes of morbidity and mortality in neonates and in both immunocompromised and immunocompetent children. Although these infections have been well characterized in adults, the incidence and analysis of risk factors, diagnostic tools, treatments and outcomes have not been well described for large cohorts of paediatric or neonatal patients. Paediatric exclusion has limited our knowledge of the epidemiology and pathophysiology of paediatric fungal disease, and has also resulted in a paucity of data regarding the safety and efficacy of paediatric antifungal therapy. Previous paediatric cooperative models in other disciplines have successfully advanced our understanding and treatments of childhood diseases, but in the past there has not been a similar organization for paediatric invasive fungal infections. Although there are numerous other reviews outlining the differences in paediatric antifungal dosing pharmacokinetics, there are only smaller epidemiological reports depicting the exact distribution and outcomes of paediatric invasive fungal infections treated with these antifungals. This review will highlight some of the available epidemiological data on paediatric invasive fungal infections. PMID- 20840540 TI - Protocatechuic acid inhibits cancer cell metastasis involving the down-regulation of Ras/Akt/NF-kappaB pathway and MMP-2 production by targeting RhoB activation. AB - BACKGROUND AND PURPOSE: Protocatechuic acid (PCA) is plentiful in edible fruits and vegetables and is thus one anti-oxidative component of normal human diets. However, the molecular mechanisms involved in the chemopreventive activity of PCA are poorly understood. Here, we investigated the mechanism(s) underlying the anti metastatic potential of PCA. EXPERIMENTAL APPROACH: We used AGS cells in a wound healing model and Boyden chamber assays in vitro and injection of B16/F10 melanoma cells in mice (metastasis model in vivo) to analyse the effect of PCA on cancer cell invasion and metastasis. The activities and expression of molecular proteins were measured by zymographic assay, real-time RT-PCR and Western blotting. KEY RESULTS: PCA inhibited cell migration and invasion at non-cytotoxic concentrations. Decreased expression of matrix metalloproteinase (MMP)-2 and a coincident increase in tissue inhibitor of MMP followed treatment with PCA. The PCA-inhibited MMP-2 activity and expression was accompanied by inactivation of NF kappaB. All these effects of PCA could be mediated via the RhoB/ protein kinase Cepsilon (PKCepsilon) and Ras/Akt cascade pathways, as demonstrated by inhibition of PKCepsilon and transfection of PKCepsilon siRNA and ras overexpression vector. Finally, PCA inhibited metastasis of B16/F10 melanoma cells to the liver in mice. CONCLUSION AND IMPLICATIONS: Our data imply that PCA down-regulated the Ras/Akt/NF-kappaB pathway by targeting RhoB activation, which in turn led to a reduction of MMP-mediated cellular events in cancer cells and provides a new mechanism for the anti-cancer activity of PCA. PMID- 20840542 TI - Invasive fungal infections in congenital immunodeficiencies. AB - Both acquired and congenital immunodeficiencies may be associated with increased susceptibility to invasive fungal infections (IFIs), depending on the type of immune deficit. IFIs frequently occur in patients with phagocytic and cellular immune defects, but are rarely observed in those with humoral or complement deficits. Among congenital immune disorders, chronic granulomatous disease and hyper-IgE syndrome are most frequently associated with IFIs; variable susceptibility to fungal pathogens is also seen in patients with severe combined immunodeficiency, X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome, DiGeorge syndrome, common variable immunodeficiency, defects in the interferon-gamma interleukin-12 axis, and myeloperoxidase deficiency. Aspergillus, Candida, Cryptococcus, Histoplasma and other fungal genera are variably implicated in causing invasive infections in these patients. Prompt diagnosis of IFIs in this patient population requires a high degree of suspicion, together with a knowledge of their clinical presentation and the limitations of diagnostic modalities. Apart from administration of appropriate antifungal agents, successful management often requires the addition of surgical intervention. Adjunctive immunotherapy may be considered, although this has not been systematically studied. Prophylactic interferon-gamma and itraconazole administration have been shown to reduce the risk of IFIs in patients with chronic granulomatous disease; however, the possibility of infections with azole-resistant organisms following long-term itraconazole prophylaxis should not be overlooked. PMID- 20840543 TI - Rosiglitazone reverses salbutamol-induced beta(2) -adrenoceptor tolerance in airway smooth muscle. AB - BACKGROUND AND PURPOSE: beta2-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)gamma agonist rosiglitazone modulated salbutamol-induced beta2-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous beta2-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent beta2-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of beta2-adrenoceptor gene and a marked decrease in beta-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored beta2-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPARgamma agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro beta2-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and beta2-adrenoceptor expression. Rosiglitazone and 15-deoxy-Delta12(,)14-prostaglandin J2 restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPARgamma agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease. PMID- 20840544 TI - Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense. AB - BACKGROUND AND PURPOSE: Frankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood. EXPERIMENTAL APPROACH: A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E(2) synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo. KEY RESULTS: Human mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H(2) to PGE(2) mediated by mPGES1 (IC(50) = 3-10 uM). Also, in intact A549 cells, BAs selectively inhibited PGE(2) generation and, in human whole blood, beta-BA reduced lipopolysaccharide-induced PGE(2) biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF(1alpha) and thromboxane B(2) . Intraperitoneal or oral administration of beta-BA (1 mg.kg(-1) ) suppressed rat pleurisy, accompanied by impaired levels of PGE(2) and beta-BA (1 mg.kg(-1) , given i.p.) also reduced mouse paw oedema, both induced by carrageenan. CONCLUSIONS AND IMPLICATIONS: Suppression of PGE(2) formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti inflammatory properties. PMID- 20840545 TI - Is radical prostatectomy a viable therapeutic option in clinically locally advanced (cT3) prostate cancer? AB - According to the literature, the current preferred treatment for T3 prostate cancer is a combination of radiotherapy and extended hormone therapy. The preoperative staging based on digital rectal examination results alone now appears obsolete from the investigated series, in which 20% of T3 prostate cancer is over-staged during physical examination. Prostatic magnetic resonance imaging is becoming increasingly necessary to evaluate extraprostatic extension during the preoperative evaluation. European Association of Urology guidelines recommend the use of radical prostatectomy only in selected patients with cT3a who have a PSA <20 ng/mL and a biopsy Gleason score <=8. The cancer control obtained after the implementation of radical prostatectomy is variable from one series to another, with PSA-free survival rates at 5, 10 and 15 years ranging from 45 to 62%, 43 to 51% and 15 to 49%, respectively. The specific survival rates at 5, 10 and 15 years are between 84 and 98%, 84 and 91% and 76 and 84%, respectively. The surgical margins rate varies from 22% to 61% depending on the specific operative technique used and the surgeon's own experience level. Regarding urinary continence, functional outcomes are in line with those of prostatectomy for localized prostate cancer. Upon consideration of erectile dysfunction, the rates are linked with the type of surgery performed, which can at times be fairly extensive. There is no impact on the overall or specific survival rate of neoadjuvant treatments. One of the problems currently depends on the efficacy of early adjuvant treatment after prostatectomy, especially regarding the use of adjuvant external beam radiotherapy. Radical prostatectomy can be considered in selected cases as a viable alternative to the first-line treatment option. However, patients must be counselled that they may undergo complementary treatments during the postoperative course of the disease. PMID- 20840546 TI - A tie-over dressing for graft application in distal penectomy and glans resurfacing: the TODGA technique. AB - OBJECTIVES: * To describe a novel method of split-skin graft (SSG) fixation for neo-glans formation after distal penectomy for penile cancer and glans resurfacing for carcinoma in situ or lichen sclerosus (LS); the TODGA technique. * Rather than 'quilting' the graft onto the neo-glans, which requires up to 5 days bed rest, the tie-over method fixes the graft adequately enough to allow immediate patient mobilization. PATIENTS AND METHODS: * In all, 41 consecutive operations, with a follow-up of >= 12 months, were performed on 40 patients (mean age 62 years, range 32-83) from December 2000 to October 2008, where a SSG was applied to the raw glans or penile stump. * The protocol varied for the first 12 operations on 11 patients. The tie-over dressing was left in place for 6 (one patient) or 7 days (11) and various materials were used; paraffin gauze (one), expanded foam (five) and proflavine-soaked gauze (six). The first two patients had their dressing removed under general anaesthetic but all subsequent patients had their dressing removed on the ward. * The subsequent 29 operations used the same protocol where a proflavine-soaked gauze dressing was left undisturbed for 10 days. RESULTS: * In the original 11 patients, two required re-grafting. After this initial development period, we amended the technique to use stronger sutures and left the dressing undisturbed for 10 days. * In addition, we standardized the use of proflavin-soaked gauze, as we found it easy to apply and remove. Since we adopted this protocol, we have performed 29 operations over a 3-year period. * The cosmetic results were excellent with only one patient requiring re-grafting. The mean and median postoperative length of stay was 2 days. * One patient with a urethral squamous cell carcinoma associated with urethral and glans LS required a urethral dilatation to allow a check cystoscopy, and a further asymptomatic patient had a meatal dilatation in the clinic but meatal stenosis was otherwise not seen, with no patients requiring regular meatal dilatation. CONCLUSION: * The TODGA technique of SSG application and fixation allows immediate mobilization and reduces hospital stay whilst providing excellent cosmetic results with a high percentage of graft uptake. PMID- 20840547 TI - Induction chemotherapy for unresectable urothelial carcinoma of the bladder. AB - OBJECTIVE: * To analyse the outcome in selected patients with initially unresectable or minimally metastatic muscle-invasive urothelial bladder cancer who underwent induction chemotherapy (IC) followed by radical cystectomy (RC). PATIENTS AND METHODS: * Thirty patients with initially unresectable, locally advanced or minimally metastatic bladder cancer underwent platinum-based IC followed by RC with curative intent at our institution from 2000 to 2007. * They received a median of four cycles (range 2-6 cycles) of cisplatin and gemcitabine (n= 19), carboplatin and gemcitabine (n= 9) or other platinum combinations (n= 2). * We retrospectively analysed all 30 patients for complete pathological remission (pT0), disease free survival (DFS) and overall survival (OS). Chi square tests, Kaplan-Meier analyses, and Cox univariate modelling were used. RESULTS: * Before IC, 30 patients were deemed unresectable because of locally advanced tumour classification (cT4, 18/30) and/or clinically suspected lymph node (LN) metastasis (21/30) or suspected distant metastasis (3/30). * At re staging after IC there was a complete regression of all enlarged LN in 16/21 patients, a partial LN response in one patient or stable LN size in the remaining four patients. * After RC, 9/30 (30%) of patients had attained pT0. * The median follow-up was 28 months (range 4-97 months). The 5-year DFS and OS rates were 42% and 46%, respectively, for all patients. * In the pT0 patients, the DFS (83%) and OS (71%) rates were significantly higher than in non-pT0 patients. CONCLUSION: * Patients undergoing IC followed by RC showed encouraging response and survival rates, suggesting that selected patients with initially unresectable bladder cancer benefit from this combined regimen. PMID- 20840548 TI - Clinical and immunomodulatory effects of bevacizumab and low-dose interleukin-2 in patients with metastatic renal cell carcinoma: results from a phase II trial. AB - OBJECTIVE: Low-dose interleukin-2 (IL-2) is a historical treatment for metastatic renal cell carcinoma (mRCC). Increased vascular endothelial growth factor (VEGF) levels inhibit dendritic cell (DC) differentiation and augment production of immunosuppressive regulatory T (Treg) cells. Bevacizumab is an antibody that binds to VEGF, has activity in mRCC and may augment the anti-tumour immune effects of IL-2. To determine the clinical and immunomodulatory effects of this combination, a prospective, phase II trial of bevacizumab plus low-dose IL-2 was conducted. PATIENTS AND METHODS: Patients with untreated mRCC received bevacizumab (10 mg/kg i.v. every 2 weeks) and IL-2 (125,000 units/kg/day subcutaneously from Monday to Friday for 6 consecutive weeks followed by a 2-week rest period). Endpoints included progression-free survival, Response Evaluation Criteria in Solid Tumors-defined objective response rate, immunomodulatory effects and safety. RESULTS: Between January 2005 and September 2007, twenty-six patients with untreated mRCC were enrolled. The median progression-free survival was 9.6 months (95% CI, 4.1-16.9 months) The objective response rate was 15% and an additional 38% of patients had tumour burden reduction of <30%. Grade 3 constitutional adverse events (fatigue, fever/chills) and neutropenia were observed in 42% and 12% of patients, respectively. Peripheral blood CD1c(+) myeloid and CD303(+) plasmacytoid DC increased during treatment as did IL-8 levels and CD4(+) CD25(+) FoxP3(+) Treg cells. No changes in T helper type 1/2 associated cytokines were observed. CONCLUSION: Bevacizumab plus low-dose IL-2 has modest clinical activity in mRCC. Toxicity was largely IL-2 related without enhancement of bevacizumab-related toxicity. Biological data indicate inhibition of VEGF levels and increase of immunosuppressive Treg cells without an effect on DC activation. PMID- 20840549 TI - Gleason score concordance on biopsy-confirmed prostate cancer: is pathological re evaluation necessary prior to radical prostatectomy? AB - OBJECTIVES: * Gleason sum from prostate biopsy (bGS) is an important tool in classifying severity of disease, ultimately influencing clinical management. * Commonly, pathology specimens are re-evaluated internally prior to surgery. * We evaluate agreement of bGS with prostatectomy Gleason sum (pGS) and the impact of re-grading on prediction of true underlying tumor architecture. MATERIALS AND METHODS: * Retrospective analysis of men who underwent robotic-assisted radical prostatectomy (RARP) by two surgeons from 2005-2009. Initial transrectal ultrasound (TRUS) biopsy demonstrated carcinoma at an outside lab. Specimens were re-evaluated by our GU pathologists prior to surgery. Biopsy data were correlated with pGS. * Kappa (kappa) statistics for agreement and linear regression analyses were used for categorical variables. Coefficient of concordance was used for continuous variables. RESULTS: * 100 patients had 331 positive biopsies. Agreement (kappa) for bGS between outside labs and our pathologists was 0.55 (p < 0.001). * Internal read was twice as likely to upgrade vs. downgrade outside bGS (23% vs. 11%). * When re-evaluation resulted in a change in bGS, agreement with pGS was kappa= 0.29, vs. kappa=-0.04 for agreement of initial (outside) bGS with pGS. * When no change was made to bGS, agreement with pGS was kappa= 0.40 (p < 0.001). CONCLUSION: * Good reproducibility seen between outside labs and our institution on bGS. Internal pathology re-reads correlated better with pGS than original community bGS. When re-reads result in a change in bGS, there is a marked improvement in prediction of underlying tumor architecture confirming the value of re-evaluating all external biopsies prior to definitive surgery. PMID- 20840550 TI - Adhesion capability of first two domains at N terminus of NP_785232 protein and their interaction with a UV-absorbing component from human mucus. AB - AIMS: This work aims to investigate the binding capability of certain domains at N terminus of the protein NP_785232 of Lactobacillus plantarum to Caco-2 cells and to test the usage of affinity chromatography to isolate the human mucus component that interacts with them. METHODS AND RESULTS: Recombinant proteins containing the first and both the first and second domains at N terminus of NP_785232 fused to a His tag were constructed and used to bind the Caco-2 cells. The interacting molecule from human mucus was isolated by affinity chromatography through immobilizing the recombinant proteins onto a Sepharose matrix. It was found both recombinant proteins could block the adhesion of Lact. plantarum to Caco-2 cells and bind to a human mucus component. CONCLUSIONS: The first and both the first and second domains at N terminus of the protein NP_785232 have the capability to adhere Caco-2 cells and by affinity chromatography, an interacting UV-absorbing component from human mucus was isolated. SIGNIFICANCE AND IMPACT OF THE STUDY: The protein domains characterized in this study may be displayed on probiotics to promote adhesion, and further characterization of the human mucus component might be helpful to identify host factors required for prolonging probiotics persistence in the gastrointestinal tract. PMID- 20840551 TI - Heat stress adaptation of Escherichia coli under dynamic conditions: effect of inoculum size. AB - AIMS: When subjected to dynamic temperatures surpassing the expected maximum growth temperature, Escherichia coli K12 MG1655 shows disturbed growth curves. These irregular population dynamics were explained by considering two subpopulations, i.e. a thermoresistant and a thermosensitive one (Van Derlinden et al. 2010a). In this paper, the influence of the initial cell concentration on the subpopulations' dynamics is evaluated. METHODS AND RESULTS: Experiments were performed in a bioreactor with the temperature increasing from 42 to 65.2 degrees C (1 and 4 degrees C h(-1)) with varying initial cell concentrations [6, 12 and 18 ln(CFU ml(-1))]. When started from the highest cell concentration, the population was characterized by a higher overall maximum growth temperature and a higher inactivation temperature. For all experimental set-ups, resistant cells were still growing at the final temperature of 65.2 degrees C. CONCLUSIONS: The initial cell concentration had no effect on temperature resistance. The increase in temperature resistance of the sensitive subpopulation was because of the change of the physiological state to the stationary phase. SIGNIFICANCE AND IMPACT OF THE STUDY: A higher initial cell concentration leads to higher heat stress adaptation when cultures reach a maximum cell concentration. The observed growth at a temperature of 65.2 degrees C is very important for food safety and the temperature treatment of micro-organisms. PMID- 20840552 TI - Antibiotic resistance patterns and sequencing of class I integron from uropathogenic Escherichia coli in Lebanon. AB - AIM: To study the prevalence and molecular basis of antimicrobial resistance in UPEC. METHODS AND RESULTS: PCR was used to detect the presence of the Class I integron variable region (VR). The VR amplicons were then characterized by partial sequencing and restriction digestion with AluI. VR negative isolates showed more antibiotic susceptibility than VR positive isolates. 30% of the isolates were positive for the VR and carried the genes dfrA7, dfrA17-aadA5, dfrA1-aadA1, dfrA12-orf5-aadA2 and bla(OXA-30)-aadA1. Five restriction patterns were detected and isolates with the same VR amplicon size had the same restriction pattern. CONCLUSIONS: Our data demonstrated that Class I integrons are widely disseminated in Lebanon and showed their importance for the occurrence and transmission of multidrug resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings will facilitate greater understanding of the factors that contribute to the presence and transfer of integron-associated antibiotic resistance genes in UPEC. PMID- 20840553 TI - Reduction of Salmonella on alfalfa seeds using peroxyacetic acid and a commercial seed washer is as effective as treatment with 20 000 ppm of Ca(OCl)2. AB - AIMS: The efficacy of a commercial seed washer and 1 and 3% peroxyacetic acid or 20 000 ppm calcium hypochlorite for reducing Salmonella on alfalfa seeds was investigated. METHODS AND RESULTS: Alfalfa seeds were inoculated with Salmonella Stanley to achieve c. 5 log CFU g(-1). Seeds were then treated with 1 or 3% peroxyacetic acid or 20 000 ppm calcium hypochlorite for 15 min in a commercial seed washer that uses air to enhance contact of the sanitizer with the seed. Experiments were also conducted using industry and laboratory methods. An c. 1 log reduction in number of Salm. Stanley was demonstrated regardless of the chemical treatment or method of treatment. Although this 1-log reduction was significant (P < 0.05), differences among the treatments were not significant. Treating the seed with 1 and 3% peroxyacetic acid resulted in similar Salm. Stanley reductions of 1.77 and 1.34 log, respectively, not being statistically significant (P > 0.05). CONCLUSIONS: These results suggest that under conditions tested, 1 or 3% peroxyacetic acid solutions are equally effective as 20 000 ppm of Ca(OCl)2 in the reduction of Salm. Stanley on alfalfa seed when used in conjunction with a commercial seed washer. SIGNIFICANCE AND IMPACT OF THE STUDY: A 1% peroxyacetic acid solution could potentially be used in place of 20 000 ppm of Ca(OCl)2 for treatment of seeds used for sprouting. The commercial seed washer did not enhance removal of Salm. Stanley from alfalfa seeds, but did facilitate removal of excess soil from seeds. PMID- 20840554 TI - Antiviral activity of Bignoniaceae species occurring in the State of Minas Gerais (Brazil): part 1. AB - AIMS: To evaluate the antiviral activity of Bignoniaceae species occurring in the state of Minas Gerais, Brazil. METHODS AND RESULTS: Ethanol extracts of different anatomical parts of bignoniaceous plant species have been evaluated in vitro against human herpesvirus type 1 (HSV-1), vaccinia virus (VACV) and murine encephalomyocarditis virus (EMCV) by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. A total of 34 extracts from 18 plant species selected according to ethnopharmacological and taxonomic criteria were screened. Fifteen of the 34 extracts (44.1%) have disclosed antiviral activity against one or more of the viruses assayed with EC(50) values in the range of 23.2 +/- 2.5 422.7 +/- 10.9 MUg ml(-1). CONCLUSIONS: Twelve of the 34 extracts (35.3%) might be considered promising sources of antiviral natural products, as they have shown EC50 <= 100 MUg ml(-1). The present screening discloses the high potential of the Bignoniaceae family as source of antiviral agents. SIGNIFICANCE AND IMPACT OF THE STUDY: Active extracts were identified and deserve bioguided studies for the isolation of antiviral compounds and studies on mechanism of action. PMID- 20840555 TI - Reduced predator species richness drives the body gigantism of a frog species on the Zhoushan Archipelago in China. AB - 1. Shifts in the body size of insular vertebrates have been an interesting theme in ecological and evolutionary studies. Four primary factors, including predation pressures, resource availability, inter-species competition and immigrant selection, have been proposed to explain the trend in insular body size. Life history theory predicts that body size, average age, the proportion of old-aged members and the density of insular populations are negatively correlated with predator species richness, and that body size and population density are positively related to resource availability. The niche expansion hypothesis argues that a positive relationship is expected to exist between insular body size and prey size, which varies in response to extinction due to small or large competitors. The immigrant hypothesis predicts that insular body size is positively correlated with distance to the mainland. 2. We tested these hypotheses by using populations of rice frogs Rana limnocharis on 20 islands in the Zhoushan Archipelago and two sites of nearby mainland China. 3. The body size (snout-vent length) of rice frogs on half of the islands was larger before and after the variable of age was controlled for; rice frog density and prey availability was higher and prey size was larger on most of the islands as compared to the two mainland sites. On the islands, the body size and other features [e.g. average age, the proportion of old-aged frogs (ages 3 and 4) and density] of the rice frogs were negatively associated with predator species richness; female body size and other features were positively associated with prey availability. The inference of multivariate linear models based on corrected Akaike Information Criterion (AIC(c) ) showed that the relative importance of predator species richness on body size and each of the other features was larger than that of prey availability, prey size and distance to the mainland. In addition, the parameters for predator species richness were all negative. 4. The results provided strong support for the life-history theory of predation pressures, but weak evidence for the life-history theory of prey availability, the niche expansion or the immigrant hypothesis. The reduced predator species richness was a dominant factor contributing to the body gigantism of rice frogs on the islands. PMID- 20840556 TI - International Consensus Conference "Performance in top sports involving intense exercise". PMID- 20840557 TI - Training for intense exercise performance: high-intensity or high-volume training? AB - Performance in intense exercise events, such as Olympic rowing, swimming, kayak, track running and track cycling events, involves energy contribution from aerobic and anaerobic sources. As aerobic energy supply dominates the total energy requirements after ~75s of near maximal effort, and has the greatest potential for improvement with training, the majority of training for these events is generally aimed at increasing aerobic metabolic capacity. A short-term period (six to eight sessions over 2-4 weeks) of high-intensity interval training (consisting of repeated exercise bouts performed close to or well above the maximal oxygen uptake intensity, interspersed with low-intensity exercise or complete rest) can elicit increases in intense exercise performance of 2-4% in well-trained athletes. The influence of high-volume training is less discussed, but its importance should not be downplayed, as high-volume training also induces important metabolic adaptations. While the metabolic adaptations that occur with high-volume training and high-intensity training show considerable overlap, the molecular events that signal for these adaptations may be different. A polarized approach to training, whereby ~75% of total training volume is performed at low intensities, and 10-15% is performed at very high intensities, has been suggested as an optimal training intensity distribution for elite athletes who perform intense exercise events. PMID- 20840558 TI - Speed endurance training is a powerful stimulus for physiological adaptations and performance improvements of athletes. AB - The present article reviews the physiological and performance effects of speed endurance training consisting of exercise bouts at near maximal intensities in already trained subjects. Despite a reduction in training volume, speed endurance training of endurance-trained athletes can maintain the oxidative capacity and improve intense short-duration/repeated high-intensity exercise performance lasting 30 s to 4 min, as it occurs in a number of sports. When combined with a basic volume of training including some aerobic high-intensity sessions, speed endurance training is also useful in enhancing performance during longer events, e.g. 40 K cycling and 10 K running. Athletes in team sports involving intense exercise actions and endurance aspects can also benefit from performing speed endurance training. These improvements don't appear to depend on changes in maximum oxygen uptake (VO2max), muscle substrate levels, glycolytic and oxidative enzymes activity, and membrane transport proteins involved in pH regulation. Instead they appear to be related to a reduced energy expenditure during submaximal exercise and a higher expression of muscle Na(+) ,K(+) pump alpha subunits, which via a higher Na(+) ,K(+) pump activity during exercise may delay fatigue development during intense exercise. In conclusion, athletes from disciplines involving periods of intense exercise can benefit from the inclusion of speed endurance sessions in their training programs. PMID- 20840559 TI - Intense training: the key to optimal performance before and during the taper. AB - The training load is markedly reduced during the taper so that athletes recover from intense training and feel energized before major events. Load reduction can be achieved by reducing the intensity, volume and/or frequency of training, but with reduced training load there may be a risk of detraining. Training at high intensities before the taper plays a key role in inducing maximal physiological and performance adaptations in both moderately trained subjects and highly trained athletes. High-intensity training can also maintain or further enhance training-induced adaptations while athletes reduce their training before a major competition. On the other hand, training volume can be markedly reduced without a negative impact on athletes' performance. Therefore, the training load should not be reduced at the expense of intensity during the taper. Intense exercise is often a performance-determining factor during match play in team sports, and high intensity training can also elicit major fitness gains in team sport athletes. A tapering and peaking program before the start of a league format championship or a major tournament should be characterized by high-intensity activities. PMID- 20840560 TI - Effects of strength training on muscle fiber types and size; consequences for athletes training for high-intensity sport. AB - Training toward improving performance in sports involving high intense exercise can and is done in many different ways based on a mixture of tradition in the specific sport, coaches' experience and scientific recommendations. Strength training is a form of training that now-a-days have found its way into almost all sports in which high intense work is conducted. In this review we will focus on a few selected aspects and consequences of strength training; namely what effects do strength training have of muscle fiber type composition, and how may these effects change the contractile properties of the muscle and finally how will this affect the performance of the athlete. In addition, the review will deal with muscle hypertrophy and how it develops with strength training. Overall, it is not the purpose of this review to give a comprehensive up-date of the area, but to pin-point a few issues from which functional training advises can be made. Thus, more than a review in the traditional context this review should be viewed upon as an attempt to bring sports-physiologists and coaches or others working directly with the athletes together for a mutual discussion on how recently acquired physiological knowledge are put into practise. PMID- 20840561 TI - Effects of strength training on endurance capacity in top-level endurance athletes. AB - The effect of concurrent strength (S) and endurance (E) training on adaptive changes in aerobic capacity, endurance performance, maximal muscle strength and muscle morphology is equivocal. Some data suggest an attenuated cardiovascular and musculoskeletal response to combined E and S training, while other data show unimpaired or even superior adaptation compared with either training regime alone. However, the effect of concurrent S and E training only rarely has been examined in top-level endurance athletes. This review describes the effect of concurrent SE training on short-term and long-term endurance performance in endurance-trained subjects, ranging from moderately trained individuals to elite top-level athletes. It is concluded that strength training can lead to enhanced long-term (>30 min) and short-term (<15 min) endurance capacity both in well trained individuals and highly trained top-level endurance athletes, especially with the use of high-volume, heavy-resistance strength training protocols. The enhancement in endurance capacity appears to involve training-induced increases in the proportion of type IIA muscle fibers as well as gains in maximal muscle strength (MVC) and rapid force characteristics (rate of force development), while likely also involving enhancements in neuromuscular function. PMID- 20840562 TI - Fueling strategies to optimize performance: training high or training low? AB - Availability of carbohydrate as a substrate for the muscle and central nervous system is critical for the performance of both intermittent high-intensity work and prolonged aerobic exercise. Therefore, strategies that promote carbohydrate availability, such as ingesting carbohydrate before, during and after exercise, are critical for the performance of many sports and a key component of current sports nutrition guidelines. Guidelines for daily carbohydrate intakes have evolved from the "one size fits all" recommendation for a high-carbohydrate diets to an individualized approach to fuel needs based on the athlete's body size and exercise program. More recently, it has been suggested that athletes should train with low carbohydrate stores but restore fuel availability for competition ("train low, compete high"), based on observations that the intracellular signaling pathways underpinning adaptations to training are enhanced when exercise is undertaken with low glycogen stores. The present literature is limited to studies of "twice a day" training (low glycogen for the second session) or withholding carbohydrate intake during training sessions. Despite increasing the muscle adaptive response and reducing the reliance on carbohydrate utilization during exercise, there is no clear evidence that these strategies enhance exercise performance. Further studies on dietary periodization strategies, especially those mimicking real-life athletic practices, are needed. PMID- 20840563 TI - Development of hydration strategies to optimize performance for athletes in high intensity sports and in sports with repeated intense efforts. AB - Hypohydration - if sufficiently severe - adversely affects athletic performance and poses a risk to health. Strength and power events are generally less affected than endurance events, but performance in team sports that involve repeated intense efforts will be impaired. Mild hypohydration is not harmful, but many athletes begin exercise already hypohydrated. Athletes are encouraged to begin exercise well hydrated and - where opportunities exist - to consume fluid during exercise to limit water and salt deficits. In high-intensity efforts, there is no need, and may be no opportunity, to drink during competition. Most team sports players do not drink enough to match sweat losses, but some drink too much and a few may develop hyponatremia because of excessive fluid intake. Athletes should assess their hydration status and develop a personalized hydration strategy that takes account of exercise, environment and individual needs. Pre-exercise hydration status can be assessed from urine markers. Short-term changes in hydration can be estimated from the change in body mass. Sweat salt losses can be determined by collection and analysis of sweat samples. An appropriate drinking strategy will take account of pre-exercise hydration status and of fluid, electrolyte and substrate needs before, during and after exercise. PMID- 20840564 TI - Hip abduction strength training in the clinical setting: with or without external loading? AB - The side-lying hip abduction exercise is one of the most commonly used exercises in rehabilitation to increase hip abduction strength, and is often performed without external loading. The aim of this study was to compare the effect of 6 weeks of side-lying hip abduction training, with and without external loading, on hip abduction strength in healthy subjects. Thirty-one healthy, physically active men and women were included in a randomised controlled trial and allocated to side-lying hip abduction training, with or without external loading. Training without external loading was performed using only the weight of the leg as resistance, whereas training with external loading was performed with a relative load corresponding to 10 repetition maximum. Hip abduction strength was measured pre- and post-intervention. Isometric and eccentric hip abduction strength of the trained leg increased after hip abduction training with external loading by 12% and 17%, respectively, (P<0.05). Likewise, isometric and eccentric hip abduction strength of the trained leg increased after hip abduction training without external loading by 11% and 23%, respectively, (P<0.001). The strength increases were not different between groups (P>0.05). Six weeks of side-lying hip abduction training, with or without external loading, increases isometric and eccentric hip abduction strength to the same extent. PMID- 20840565 TI - Psychological skills training as a way to enhance an athlete's performance in high-intensity sports. AB - The importance of psychological skills training (PST) in the development of athletic performance is widely recognized. This paper is a comprehensive review of PST in elite sports, with a special focus on high-intensity sports (HIS). The reviewed literature showed a lack of convincing evidence and theoretical underpinning concerning traditional psychological skills to enhance performance in HIS. Therefore, a model with three conceptual levels (psychological demands, skills and techniques) is presented. The model facilitates the identification of the psychological demands of a specific sport, which in turn enables distinguishing which psychological skills are required. This allows an expert to choose psychological techniques to improve the athlete's psychological skill. Considerations based on our model and the limited HIS-related literature available revealed self-skills, personal development and life skills, arousal regulation skills, volitional skills, motivational skills and recovery skills as the most important skills to address in order to enhance performance. Development of harmonious passion, in-practice integration of volitional strategies, use of associative attentional techniques, pain management techniques, use of the mindfulness-acceptance approach and the facilitative interpretation of cognitive and somatic sensations are regarded as suitable to meet the psychological demands of HIS. They are recommended for systematic application by athletes and coaches. PMID- 20840566 TI - A lifespan perspective on the career of talented and elite athletes: perspectives on high-intensity sports. AB - Elite athletes will be confronted during as well as after their athletic career with transitional challenges that will impact the course and progress of their athletic development. This article provides in first instance a description of a lifespan model exemplifying a "whole career/whole person" conceptualization of career transitions in the elite athletic career. Second, four specific career transitions in the development of talented and elite athletes are detailed with special attention for high-intensity sports (HIS). Finally, perspectives are formulated on future lifespan research and the provision of career support services in HIS. PMID- 20840567 TI - Preventing overtraining in athletes in high-intensity sports and stress/recovery monitoring. AB - In sports, the importance of optimizing the recovery-stress state is critical. Effective recovery from intense training loads often faced by elite athletes can often determine sporting success or failure. In recent decades, athletes, coaches, and sport scientists have been keen to find creative, new methods for improving the quality and quantity of training for athletes. These efforts have consistently faced barriers, including overtraining, fatigue, injury, illness, and burnout. Physiological and psychological limits dictate a need for research that addresses the avoidance of overtraining, maximizes recovery, and successfully negotiates the fine line between high and excessive training loads. Monitoring instruments like the Recovery-Stress Questionnaire for Athletes can assist with this research by providing a tool to assess their perceived state of recovery. This article will highlight the importance of recovery for elite athletes and provide an overview of monitoring instruments. PMID- 20840568 TI - Psychology and socioculture affect injury risk, response, and recovery in high intensity athletes: a consensus statement. AB - This consensus statement summarizes key contemporary research themes relevant to understanding the psychology and socioculture of sport injury. Special consideration is given toward high-intensity sport in which elite athlete training and performance efforts are characterized by explosive physical speed and strength, mental fortitude to push physical limits, and maximum effort and commitment to highly challenging goals associated with achieving exceptional performance. Sport injury occurrence in high-intensity sport is an adverse and stressful health event associated with a complex multitude of risks, consequences and outcomes. A biopsychosocial (Engel, 1980) view is advocated which contextualizes an understanding of the psychological aspects of sport injury in light of influential sociocultural, ethical, and biomedical issues. Outcomes related to athlete health and performance excellence are of equal importance in considering how psychological scholarship, expertise and services can be used to improve efforts focused on the prevention and management of sport injury among high-intensity athletes. The consensus view is that psychology and socioculture do affect sport injury risk, response and recovery in high-intensity athletes, and that continued efforts in psychological research and professional practice are needed to protect athlete physical and mental health and contribute toward performance excellence and career longevity. PMID- 20840569 TI - Aspects of disordered eating continuum in elite high-intensity sports. AB - Dieting is an important risk factor for disordered eating and eating disorders. Disordered eating occurs on a continuum from dieting and restrictive eating, abnormal eating behavior, and finally clinical eating disorders. The prevalence of eating disorders is increased in elite athletes and for this group the cause of starting to diet is related to (a) perception of the paradigm of appearance in the specific sport, (b) perceived performance improvements, and (c) sociocultural pressures for thinness or an "ideal" body. Athletes most at risk for disordered eating are those involved in sports emphasizing a thin body size/shape, a high power-to-weight ratio, and/or sports utilizing weight categories, such as in some high-intensity sports. In addition to dieting, personality factors, pressure to lose weight, frequent weight cycling, early start of sport-specific training, overtraining, injuries, and unfortunate coaching behavior, are important risk factors. To prevent disordered eating and eating disorders, the athletes have to practice healthy eating, and the medical staff of teams and parents must be able to recognize symptoms indicating risk for eating disorders. Coaches and leaders must accept that disordered eating can be a problem in the athletic community and that openness regarding this challenge is important. PMID- 20840570 TI - Successful talent development in track and field: considering the role of environment. AB - Track and field includes a number of high-intensity disciplines with many demanding practices and represents a motivational challenge for talented athletes aiming to make a successful transition to the senior elite level. Based on a holistic ecological approach, this study presents an analysis of a particular athletic talent development environment, the IFK Vaxjo track and field club, and examines key factors behind its successful history of creating top-level athletes. The research takes the form of a case study. Data were collected from multiple perspectives (in-depth interviews with administrators, coaches and athletes), from multiple situations (observation of training, competitions and meetings) and from the analysis of documents. The environment was characterized by a high degree of cohesion, by the organization of athletes and coaches into groups and teams, and by the important role given to elite athletes. A strong organizational culture, characterized by values of open co-operation, by a focus on performance process and by a whole-person approach, provided an important basis for the environment's success. The holistic ecological approach encourages practitioners to broaden their focus beyond the individual in their efforts to help talented junior athletes make a successful transition to the elite senior level. PMID- 20840571 TI - A new broom: The editorial chair for volume 43 (2011). PMID- 20840572 TI - Single layer centrifugation of stallion spermatozoa consistently selects the most robust spermatozoa from the rest of the ejaculate in a large sample size. AB - REASONS FOR PERFORMING STUDY: An improvement in sperm quality after single layer centrifugation (SLC) has been seen in previous studies using small sample sizes (for example, n = 10 stallions). There is a need to investigate whether this improvement is repeatable over several breeding seasons with a larger number of stallions (n >= 30 stallions). OBJECTIVE: To make a retrospective analysis of the results of SLC performed on more than 250 sperm samples (176 ejaculates) from 31 stallions in 3 consecutive breeding seasons. METHODS: Sperm quality (motility, proportion of morphologically normal spermatozoa and the proportion of spermatozoa with undamaged chromatin) was assessed before and after SLC. RESULTS: All parameters of sperm quality examined were significantly better in sperm samples after SLC than in their unselected counterparts (P<0.001 for each parameter). The yield of spermatozoa obtained after SLC was influenced by the type of extender used and also by the concentration of spermatozoa in the original ejaculate, with fewer spermatozoa being recovered when the loading dose contained a high concentration of spermatozoa. The optimal concentration was approximately 100 * 106/ml. Sperm concentration in the samples loaded on to the colloid influenced the sperm yield while the type of semen extender affected sperm quality and survival. Furthermore, the scaled-up SLC method was found to be suitable for use with a range of ejaculates, with similar sperm kinematics being observed for standard and scaled-up preparations. CONCLUSIONS: SLC consistently improved the quality of stallion sperm samples from a large number of ejaculates. The method could be scaled-up, allowing larger volumes of ejaculate to be processed easily from a wide range of stallions. PMID- 20840573 TI - Lag screw fixation of dorsal cortical stress fractures of the third metacarpal bone in 116 racehorses. AB - REASONS FOR PERFORMING STUDY: The effectiveness and best method to manage dorsal cortical stress fractures is not clear. This study was performed to evaluate the success of lag screw fixation of such fractures in a population of Thoroughbred racehorses. HYPOTHESIS: Lag screw fixation of dorsal cortical stress fractures is an effective surgical procedure allowing racehorses to return to their preoperative level of performance. METHODS: The records of 116 racehorses (103 Thoroughbreds) admitted to Equine Medical Centre, California between 1986 and 2008 were assessed. Information obtained from medical records included subject details, limb(s) affected, fracture configuration, length of screw used in repair and presence of concurrent surgical procedures performed. Racing performance was evaluated relative to these factors using Fisher's exact test and nonparametric methods with a level of significance of P<0.05. RESULTS: Of 92 Thoroughbred horses, 83% raced preoperatively and 83% raced post operatively, with 63% having >=5 starts. There was no statistically significant association between age, gender, limb affected, fracture configuration or presence of concurrent surgery and likelihood of racing post operatively or of having 5 or more starts. The mean earnings per start and the performance index for the 3 races following surgery were lower compared to the 3 races prior to surgery; however, 29 and 45% of horses either improved or did not change their earnings per start and performance index, respectively. CONCLUSIONS AND POTENTIAL RELEVANCE: Data show that lag screw fixation is successful at restoring ability to race in horses suffering from dorsal cortical stress fractures. PMID- 20840574 TI - Clinical significance of osseous spurs on the dorsoproximal aspect of the third metatarsal bone. AB - REASONS FOR PERFORMING STUDY: Osseous spurs on the dorsoproximal aspect of the third metatarsal bone (MtIII) are common, but their clinical significance is unknown. OBJECTIVES: To verify the sites of insertion of the dorsal metatarsal ligament and the tendons of tibialis cranialis and fibularis tertius in order to determine if periarticular osteophytes and entheseophytes could be differentiated radiologically; and to determine the frequency of occurrence of osseous spurs on the dorsoproximal aspect of MtIII. HYPOTHESES: The frequency of osseous spurs on the dorsoproximal aspect of MtIII would be higher in lame than in clinically normal horses and higher in horses with distal hock joint pain or proximal suspensory desmitis than in horses with other causes of hindlimb lameness. METHODS: A retrospective study of data from the clinical work up and tarsal radiographs of 455 horses was performed. Horses were divided into: Group 1, clinically normal horses; Groups 2-5, according to the diagnosis of hindlimb lameness. Radiographs were examined for the presence of an osseous spur on the dorsoproximal aspect of MtIII; pathology of the distal tarsal joints was graded. The associations between the presence of a spur and lameness, diagnosis group and the grade of distal tarsal joint abnormalities were analysed statistically using Chi-squared tests. RESULTS: An osseous spur was present in 25% of horses; 13% of horses with bilateral radiographs had bilateral spurs. There was no significant difference in frequency of the presence of a spur between lame and nonlame horses, or between horses with other causes of hindlimb lameness and horses with proximal suspensory desmitis and/or distal tarsal joint pain. The presence of an osseous spur was significantly associated with the grade of radiological abnormality in the distal tarsal joints (tarsometatarsal joint P = 0.018: centrodistal joint P = 0.027). In many horses it was not possible to differentiate accurately between osteophytes and entheseophytes. CONCLUSIONS AND POTENTIAL RELEVANCE: The presence of an osseous spur on the dorsoproximal aspect of MtIII in the absence of other radiological abnormalities may be an incidental finding. Osseous spurs occur more frequently in hocks with radiological abnormalities in the distal tarsal joints and may be an indicator of distal tarsal joint osteoarthritis. The clinical significance must be established by intra-articular analgesia. PMID- 20840575 TI - Effect of dietary restriction on body condition, composition and welfare of overweight and obese pony mares. AB - REASONS FOR PERFORMING STUDY: Increased prevalence of obesity among UK horses and ponies demands evidence-based advice to promote weight loss. HYPOTHESIS: Restriction of dry matter intake (DMI) to 1% of body mass (BM, 67% [corrected] of predicted maintenance digestible energy [DE] requirements) would promote weight loss without compromise to health. METHODS: Five mature (mean +/- s.e. 10 +/- 2 years), overweight/obese pony mares (BM, 257 +/- 20 kg: body condition score [BCS] 6.8/9 +/- 0.5) were studied over 12 weeks. Animals were individually housed. Daily provision of a chaff-based, complete diet (measured DE, 8.5 MJ/kg DM) was restricted to 1% of actual BM as DMI daily. BCS, girth measurements and ultrasound-derived measures of subcutaneous fat depth overlying the gluteal region and 12th intercostal space (rib-eye) were recorded weekly. Body fat content was estimated at the beginning and end of the study by deuterium oxide dilution methods. Clinical biochemistry was monitored weekly. Behaviour was observed (24 h, 3/5 ponies) on 3 occasions. RESULTS: BM decreased by 4.3 +/- 1.1% during the first week and thereafter by 0.7 +/- 0.1% of BM at end of Week 1 each week. BCS remained constant. Heart and belly girths, rump width and subcutaneous fat depth at rib-eye decreased significantly with time and BM. Fat comprised 45 +/- 19% of BM loss. Fatter animals lost relatively more fat. With decreased feeding activity, time spent in 'play' and rest increased by 36 +/- 11% and 438 +/- 95%, respectively. CONCLUSIONS: This plane of nutrition resulted in an overall rate of weight loss of 1% of outset BM weekly. BCS was not a useful index of early weight loss but heart and belly girths and subcutaneous rib-eye fat were identified as alternative markers. POTENTIAL RELEVANCE: This study provides an evidence-base for the management of weight loss in obese animals, especially those for which exercise may be contra-indicated. PMID- 20840576 TI - Regional differences in biochemical, biomechanical and histomorphological characteristics of the equine suspensory ligament. AB - REASONS FOR PERFORMING STUDY: Desmopathies of the suspensory ligament are relatively frequent and vary in prevalence over different anatomical regions. This variation may be because of regional differences in tissue characteristics. OBJECTIVE: To characterise different regions of healthy forelimb suspensory ligaments (SLs) by means of biochemical, biomechanical and histomorphological techniques. HYPOTHESIS: There is substantial topographical heterogeneity in the SL with respect to structural, compositional and functional characteristics. METHODS: SLs were harvested from 38 limbs and used for biochemical (n = 20), biomechanical (n = 14) and histomorphological (n = 4) evaluation. Sulphated glycosaminoglycan (S-GAG), DNA and collagen content, degree of lysyl hydroxylation and numbers of enzymatic and nonenzymatic cross-links were determined in 7 regions of the SL: lateral and medial part of the origin (OM, OL), mid-body (MB), axial and abaxial parts of the lateral and medial branches (ILAX, ILAB, IMAX and IMAB, respectively). Passive resistance to tensile loading was measured in 5 regions of the SL (all except OL and OM). RESULTS: DNA content was lower in OL and OM than in all other parts. GAG content was also lower in OL and OM and highest in ILAB and IMAB. Collagen content was lower in OL/OM and highest in ILAX/IMAX. Pentosidine levels were highest in OL and significantly lower in the lateral insertion (ILAX/ILAB). There were no differences in hydroxylysylpyridinoline (HP) cross-links or lysyl hydroxylation. Stiffness (P<0.01) and modulus of elasticity (P<0.01) were substantially higher in the MB region than in all other regions except for IMAB. Strain at failure was lower in the MB region (P<0.0001), resulting in a comparable force at rupture as in the other regions. CONCLUSIONS: Matrix composition differs to a relatively limited extent between different regions of the SL. The mid-body of the ligament is stiffer than the branches, which have similar properties and relevance and mechanical differences between mid-body and branches/origin may explain some use related differences in the prevalence of lesions. PMID- 20840577 TI - Colic in geriatric compared to mature nongeriatric horses. Part 1: Retrospective review of clinical and laboratory data. AB - REASON FOR PERFORMING STUDY: It is the impression of some surgeons that geriatric horses have a lower survival rate compared to mature nongeriatric horses following colic surgery. One possible reason for this is that geriatric horses may be more critically ill at admission and have more severe disease than mature nongeriatric horses. OBJECTIVE: To compare admission historical, physical examination and laboratory data for geriatric and mature nongeriatric horses referred for signs of colic. METHODS: Medical records of horses admitted with a presenting complaint of colic between 2000 and 2006 were reviewed. Geriatric horses >=16 years (n = 300) and mature nongeriatric horses 4-15 years (n = 300). Information obtained included duration of colic prior to admission, admission level of pain, heart rate, intestinal borborygmi, packed cell volume (PCV), plasma creatinine and blood lactate concentrations and peritoneal fluid total protein. Data were analysed using a Chi-squared test or an analysis of variance. Level of significance was P<0.05. RESULTS: There was no difference between geriatric and mature horses in the duration of colic prior to admission or in admission heart rate, PCV, or plasma creatinine or blood lactate concentrations. However, geriatric horses were more likely to be moderately painful and less likely to be bright and alert than mature horses; and less likely to have normal intestinal borborygmi than mature horses. Peritoneal fluid total protein concentration was higher in geriatric than mature horses. CONCLUSIONS AND POTENTIAL RELEVANCE: Geriatric horses presenting with signs of colic had a similar admission cardiovascular status based on heart rate, PCV, and plasma creatinine and blood lactate concentration to mature horses. Geriatric horses, however, may have different causes of colic, which may be more serious than mature horses based on pain, lack of intestinal borborygmi and peritoneal fluid total protein concentration. PMID- 20840578 TI - Colic in geriatric compared to mature nongeriatric horses. Part 2: Treatment, diagnosis and short-term survival. AB - REASON FOR PERFORMING STUDY: Owners and veterinarians are often concerned about mortality of geriatric horses following colic surgery. OBJECTIVE: To compare treatment, diagnosis and short-term survival for geriatric compared to mature nongeriatric horses with colic. METHODS: Medical records of horses admitted with a presenting complaint of colic between 2000 and 2006 were reviewed. Geriatric horses were aged >=16 years (n = 300) and subcategorised as age >=20 years (n = 134). Mature nongeriatric horses were age 4-15 years (n = 300). Information obtained included medical (included horses subjected to euthanasia without surgery) vs. surgical management, lesion location, type and classification, surgical procedures performed and short-term survival. Data were analysed using a Chi-squared test or an analysis of variance. Level of significance was P<0.05. RESULTS: The overall short-term survival of geriatric horses was lower than that for mature horses (59 vs. 76%, respectively). The survival of medically managed geriatric horses was lower than that for mature horses (58 vs. 80%, respectively). The survival of surgically managed geriatric horses was not different to that for mature horses (59 vs. 70%, respectively) except for geriatric horses age >=20 years (53%). There was no difference in survival between geriatric and mature horses with small (86 and 83%, respectively) or large (78 vs. 70%, respectively) intestinal strangulating lesions or those undergoing jejunojejunostomy (75 vs. 70%, respectively). Geriatric horses with a large colon simple obstruction had a lower survival compared to mature horses (80 vs. 97%, respectively). CONCLUSIONS AND POTENTIAL RELEVANCE: The survival of geriatric horses with a strangulating lesion or requiring jejunojejunostomy was not different to that for mature horses. Geriatric horses presenting with colic were more likely than mature horses to be subjected to euthanasia without surgery (i.e. lower survival with medical treatment). Geriatric horses undergoing surgery for a large colon simple obstruction had a lower survival than mature horses. PMID- 20840579 TI - Equine embryonic stem-like cells and mesenchymal stromal cells have different survival rates and migration patterns following their injection into damaged superficial digital flexor tendon. AB - REASONS FOR PERFORMING STUDY: Injury to the superficial digital flexor tendon (SDFT) is common in racing and sport horses and poor tendon regeneration leads to high reinjury rates. Autologous mesenchymal stromal cells (MSCs) are being used clinically to improve tendon regeneration but they have some practical limitations. Embryonic stem cells (ESCs) may overcome these limitations but their fate following injection into the damaged SDFT is unknown. OBJECTIVE: To inject MSCs and ESCs into distinct areas of damage in the SDFT and monitor their survival over a 3 month period. METHODS: MSCs and ESCs expressing different reporter genes were injected into separate sites of mechanically induced damage in SDFTs. Cell survival and distribution were examined post mortem after 10, 30, 60 and 90 days and host immune responses determined. RESULTS: Neither MSCs nor ESCs produced signs of cell-mediated immune response or tumour formation. ESC survival was high and numbers were maintained at a constant level over 90 days. ESCs were present at all sites of damage. In contrast, MSCs showed <5% survival at 10 days and numbers declined over the course of the experiment. MSCs were detected only at the site into which they were injected. CONCLUSIONS: ESCs survived in greater numbers than MSCs in the damaged tendon and did not induce an immune response, or form tumours at the injection sites in the 90 day time period studied. ESCs also demonstrated an ability to migrate to other areas of damage within the same tendon, whereas MSCs did not. POTENTIAL RELEVANCE: ESCs can be used allogeneically, therefore providing a possible 'off the shelf' source of cells for therapeutic use which overcomes the practical limitations of autologous MSCs. Furthermore, MSCs and ESCs have different survival rates and migration patterns in the damaged tendon, suggesting that they may produce different functional effects. This may have clinical relevance to treating tendon injuries in the horse. PMID- 20840580 TI - Serum biomarker levels for musculoskeletal disease in two- and three-year-old racing Thoroughbred horses: A prospective study of 130 horses. AB - REASON FOR PERFORMING STUDY: Biomarkers have shown some in vivo promise for the detection of musculoskeletal injuries, but further study to assess biomarker levels in clinical orthopaedic disease is required. OBJECTIVE: To assess 7 serum biomarkers for the detection of musculoskeletal injuries. METHODS: Two- and 3 year-old racehorses were entered into the study (n = 238). Exit criteria were lack of training for >30 days, or completion of 10 study months. Data from horses with solitary musculoskeletal injuries and completion of >2 months were analysed. Musculoskeletal injury was considered intra-articular fragmentation (IAF), tendon or ligamentous injury (TL), stress fractures (SF) and dorsal metacarpal disease (DMD). Monthly lameness examination and serum collection were performed. Serum was analysed for glycosaminoglycan (GAG), type I and II collagen degradation (C1, 2C), type II collagen synthesis (CPII), type II collagen degradation (Col CEQ), aggrecan synthesis (CS846), osteocalcin (OC) as a marker of bone formation and (C terminal telopeptide of type I collagen) CTX as a marker of bone degradation. RESULTS: Of the 238 horses 59 injured and 71 uninjured control horses met the analysis criteria. Based on injury no significant differences in the proportions were observed for age, gender or lesion type, although a higher proportion of injuries occurred at the beginning of the study. Of injured horses, 16 (27%) sustained an IAF, 17 (29%) a TL injury, 7 (12%) SF and 19 (32%) were diagnosed with DMD. There were significant changes seen in biomarkers based on the injury incurred when longitudinal samples were assessed. Furthermore, based on the serum biomarkers collected prior to injury, horses could be correctly classified as injured or uninjured 73.8% of the time. CONCLUSIONS: A unique biomarker pattern occurred before each injury and this was beneficial in classifying horses as injured or uninjured. POTENTIAL RELEVANCE: Biomarkers have the potential to be used as a screening aid prior to musculoskeletal injury. PMID- 20840581 TI - Large intestinal mast cell count and proteinase expression is associated with larval burden in cyathostomin-infected horses. AB - REASONS FOR PERFORMING STUDY: Cyathostomins are the principal pathogenic nematode of equidae worldwide. In other species mast cell (MC) proteinases, in particular chymases, appear to have protective roles. Knowledge of the equine intestinal immune response to cyathostomins is limited. OBJECTIVE: To investigate MC numbers and proteinase expression in equine cyathostomin-infected large intestine. HYPOTHESIS: MC populations in the large intestine are positively associated with cyathostomin burden and predominantly express chymase. METHODS: The caecal cyathostomin burden of naturally infected horses (n = 25) was determined by luminal counts and pepsin digest (mural count). MC were identified and enumerated in caecal tissue using toluidine blue (TB). Immunofluorescent labelling with polyclonal rabbit antibodies was used to demonstrate expression of equine tryptase and the chymase equine mast cell proteinase-1 (eqMCP-1) in Carnoy's fixed caecal sections. RESULTS: Significant positive linear relationships were found between TB-stained mucosal and submucosal MC counts and total cyathostomin burden (P<0.001, r2 >36%), and both luminal (P<0.010, r2 >25%) and mural (P<0.001, r2 >36%) larval counts. Similar relationships were found with mucosal and submucosal chymase and tryptase-labelled MC counts (total: P<0.004, r2 >29%; luminal: P<0.004, r2 >30%; and mural: P<0.030, r2 >19%). With all three MC labels, mean MC counts were higher in the submucosa compared to the mucosa (P<0.001). All caecal MC appeared to express chymase, with a small number of MC expressing both tryptase and chymase. CONCLUSIONS AND POTENTIAL RELEVANCE: Large intestinal MC counts are significantly associated with cyathostomin burden, with a predominance of chymase-positive MC. The burden is significantly associated with expression of MC proteinases, supporting their likely involvement in the intestinal immune response to cyathostomin infection. Further work to investigate the kinetics of proteinase expression, the possibility of differential proteinase expression and the role of these MC proteinases is warranted. PMID- 20840582 TI - Equine clinical genomics: A clinician's primer. AB - The objective of this review is to introduce equine clinicians to the rapidly evolving field of clinical genomics with a vision of improving the health and welfare of the domestic horse. For 15 years a consortium of veterinary geneticists and clinicians has worked together under the umbrella of The Horse Genome Project. This group, encompassing 22 laboratories in 12 countries, has made rapid progress, developing several iterations of linkage, physical and comparative gene maps of the horse with increasing levels of detail. In early 2006, the research was greatly facilitated when the US National Human Genome Research Institute of the National Institutes of Health added the horse to the list of mammalian species scheduled for whole genome sequencing. The genome of the domestic horse has now been sequenced and is available to researchers worldwide in publicly accessible databases. This achievement creates the potential for transformative change within the horse industry, particularly in the fields of internal medicine, sports medicine and reproduction. The genome sequence has enabled the development of new genome-wide tools and resources for studying inherited diseases of the horse. To date, researchers have identified 11 mutations causing 10 clinical syndromes in the horse. Testing is commercially available for all but one of these diseases. Future research will probably identify the genetic bases for other equine diseases, produce new diagnostic tests and generate novel therapeutics for some of these conditions. This will enable equine clinicians to play a critical role in ensuring the thoughtful and appropriate application of this knowledge as they assist clients with breeding and clinical decision-making. PMID- 20840583 TI - Spatial scaling of arbuscular mycorrhizal fungal diversity is affected by farming practice. AB - Evidence suggests that microbial communities show patterns of spatial scaling which can be driven by geographical distance and environmental heterogeneity. Here we demonstrate that human management can have a major impact on microbial distribution patterns at both the local and landscape scale. Mycorrhizal fungi are vital components of terrestrial ecosystems, forming a mutualistic symbiosis with plant roots which has a major impact on above ground ecology and productivity. We used contrasting agricultural systems to investigate the spatial scaling of the most widespread mycorrhizal fungus group, the arbuscular mycorrhizal fungi (AMF). Using multiple sampling sites with a maximum separation of 250 km we describe for the first time the roles which land management, environmental heterogeneity and geographical distance play in determining spatial patterns of microbial distribution. Analysis of AMF taxa-area relationships at each sampling site revealed that AMF diversity and spatial turnover was greater under organic relative to conventional farm management. At the regional scale (250 km) distance-decay analyses showed that there was significant change in AMF community composition with distance, and that this was greater under organic relative to conventional management. Environmental heterogeneity was found to be the major factor determining turnover of AMF taxa at the landscape scale. Overall we demonstrate that human management can play a key role in determining the turnover of microbial communities at both the local and regional scales. PMID- 20840585 TI - Proteoglycans in health and disease: the multiple roles of syndecan shedding. AB - Proteolytic processes in the extracellular matrix are a major influence on cell adhesion, migration, survival, differentiation and proliferation. The syndecan cell-surface proteoglycans are important mediators of cell spreading on extracellular matrix and respond to growth factors and other biologically active polypeptides. The ectodomain of each syndecan is constitutively shed from many cultured cells, but is accelerated in response to wound healing and diverse pathophysiological events. Ectodomain shedding is an important regulatory mechanism, because it rapidly changes surface receptor dynamics and generates soluble ectodomains that can function as paracrine or autocrine effectors, or competitive inhibitors. It is known that the family of syndecans can be shed by a variety of matrix proteinase, including many metzincins. Shedding is particularly active in proliferating and invasive cells, such as cancer cells, where cell surface components are continually released. Here, recent research into the shedding of syndecans and its physiological relevance are assessed. PMID- 20840584 TI - Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. AB - The small leucine-rich proteoglycans (SLRPs) are involved in many aspects of mammalian biology, both in health and disease. They are now being recognized as key signaling molecules with an expanding repertoire of molecular interactions affecting not only growth factors, but also various receptors involved in controlling cell growth, morphogenesis and immunity. The complexity of SLRP signaling and the multitude of affected signaling pathways can be reconciled with a hierarchical affinity-based interaction of various SLRPs in a cell- and tissue specific context. Here, we review this interacting network, describe new relationships of the SLRPs with tyrosine kinase and Toll-like receptors and critically assess their roles in cancer and innate immunity. PMID- 20840587 TI - Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. AB - The expression of proteoglycans (PGs), essential macromolecules of the tumor microenvironment, is markedly altered during malignant transformation and tumor progression. Synthesis of stromal PGs is affected by factors secreted by cancer cells and the unique tumor-modified extracellular matrix may either facilitate or counteract the growth of solid tumors. The emerging theme is that this dual activity has intrinsic tissue specificity. Matrix-accumulated PGs, such as versican, perlecan and small leucine-rich PGs, affect cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Furthermore, expression of cell-surface-associated PGs, such as syndecans and glypicans, is also modulated in both tumor and stromal cells. Cell-surface-associated PGs bind various factors that are involved in cell signaling, thereby affecting cell proliferation, adhesion and motility. An important mechanism of action is offered by a proteolytic processing of cell-surface PGs known as ectodomain shedding of syndecans; this facilitates cancer and endothelial cell motility, protects matrix proteases and provides a chemotactic gradient of mitogens. However, syndecans on stromal cells may be important for stromal cell/cancer cell interplay and may promote stromal cell proliferation, migration and angiogenesis. Finally, abnormal PG expression in cancer and stromal cells may serve as a biomarker for tumor progression and patient survival. Enhanced understanding of the regulation of PG metabolism and the involvement of PGs in cancer may offer a novel approach to cancer therapy by targeting the tumor microenvironment. In this minireview, the implication of PGs in cancer development and progression, as well as their pharmacological targeting in malignancy, are presented and discussed. PMID- 20840586 TI - Proteoglycans in health and disease: new concepts for heparanase function in tumor progression and metastasis. AB - Heparanase is an endo-beta-D-glucuronidase capable of cleaving heparan sulfate side chains at a limited number of sites, yielding heparan sulfate fragments of still appreciable size. Importantly, heparanase activity correlates with the metastatic potential of tumor-derived cells, attributed to enhanced cell dissemination as a consequence of heparan sulfate cleavage and remodeling of the extracellular matrix and basement membrane underlying epithelial and endothelial cells. Similarly, heparanase activity is implicated in neovascularization, inflammation and autoimmunity, involving the migration of vascular endothelial cells and activated cells of the immune system. The cloning of a single human heparanase cDNA 10 years ago enabled researchers to critically approve the notion that heparan sulfate cleavage by heparanase is required for structural remodeling of the extracellular matrix, thereby facilitating cell invasion. Progress in the field has expanded the scope of heparanase function and its significance in tumor progression and other pathologies. Notably, although heparanase inhibitors attenuated tumor progression and metastasis in several experimental systems, other studies revealed that heparanase also functions in an enzymatic activity independent manner. Thus, inactive heparanase was noted to facilitate adhesion and migration of primary endothelial cells and to promote phosphorylation of signaling molecules such as Akt and Src, facilitating gene transcription (i.e. vascular endothelial growth factor) and phosphorylation of selected Src substrates (i.e. endothelial growth factor receptor). The concept of enzymatic activity-independent function of heparanase gained substantial support by the recent identification of the heparanase C-terminus domain as the molecular determinant behind its signaling capacity. Identification and characterization of a human heparanase splice variant (T5) devoid of enzymatic activity and endowed with protumorigenic characteristics, elucidation of cross-talk between heparanase and other extracellular matrix-degrading enzymes, and identification of single nucleotide polymorphism associated with heparanase expression and increased risk of graft versus host disease add other layers of complexity to heparanase function in health and disease. PMID- 20840588 TI - The role of prohibitin in cell signaling. AB - Prohibitin-1 (PHB, also known as PHB1), a member of the Band-7 family of proteins, is highly conserved evolutionarily, widely expressed, and present in different cellular compartments. Genetic studies with different organism models have provided strong evidence for an important biological role of PHB in mitochondrial function, cell proliferation, and development. Recent discoveries regarding the involvement of PHB in phophatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) and transforming growth factor-beta (TGF-beta)/signal transducers and activators of transcription signaling pathways, and earlier reports on the interaction of PHB with Raf and its critical role in Ras/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling opened up the possibility that PHB has functions outside of the mitochondria (extramitochondrial) and may be a multifunctional protein. The PI3K/Akt and Ras/MAPK/ERK signaling cascades are versatile signaling processes that diverge from the same receptor tyrosine kinase root, and are involved in cell metabolism, proliferation, and development. Here, we review the emerging role of PHB and its post-translational modifications in signal transduction pathways, especially in PI3K/Akt and Ras/MAPK/ERK signaling. A recent discovery of opposing effects of PHB on longevity under different metabolic states and its potential connection with insulin/insulin-like growth factor-I signaling is also discussed. PMID- 20840589 TI - NO synthase isoforms specifically modify peroxynitrite reactivity. AB - Nitric oxide synthases (NOSs) are multi-domain hemothiolate proteins that are the sole source of nitric oxide (NO) in mammals. NOSs can also be a source or a sink for peroxynitrite (PN), an oxidant that is suspected to be involved in numerous physiopathological processes. In a previous study, we showed that the oxygenase domain of the inducible NOS (iNOSoxy) reacts with PN and changes its oxidative reactivity [Marechal A, Mattioli TA, Stuehr DJ & Santolini J (2007) J Biol Chem 282, 14101-14112]. Here we report a similar analysis on two other NOS isoforms, neuronal NOS (nNOS) and a bacterial NOS-like protein (bsNOS). All NOSs accelerated PN decomposition, with accumulation of a similar heme intermediate. The kinetics of PN decomposition and heme transitions were comparable among NOSs. However, their effects on PN reactivity differ greatly. All isoforms suppressed PN two-electron oxidative activity, but iNOSoxy enhanced PN one-electron oxidation and nitration potencies, the oxygenase domain of nNOS (nNOSoxy) affected them minimally, and bsNOS abolished all PN reactivities. This led to the loss of both NOS and PN decomposition activities for nNOSoxy and iNOSoxy, which may be linked to the reported alterations in their electronic absorption spectra. Bacterial bsNOS was affected to a lesser extent by reaction with PN. We propose that these differences in PN reactivity among NOSs might arise from subtle differences in their heme pockets, and could reflect the physiological specificity of each NOS isoform, ranging from oxidative stress amplification (iNOS) to detoxification (bsNOS). PMID- 20840590 TI - Frontal affinity chromatography analysis of constructs of DC-SIGN, DC-SIGNR and LSECtin extend evidence for affinity to agalactosylated N-glycans. AB - Dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a member of the C-type lectin family selectively expressed on immune related cells. In the present study, we performed a systematic interaction analysis of DC-SIGN and its related receptors, DC-SIGN-related protein (DC-SIGNR) and liver and lymph node sinusoidal endothelial cell C-type lectin (LSECtin) using frontal affinity chromatography (FAC). Carbohydrate-recognition domains of the lectins, expressed as Fc-fusion chimeras, were immobilized to Protein A Sepharose and subjected to quantitative FAC analysis using 157 pyridylaminated glycans. Both DC-SIGN-Fc and DC-SIGNR-Fc showed similar specificities for glycans containing terminal mannose and fucose, but great difference in affinity under the given experimental conditions. By contrast, LSECtin-Fc showed no affinity to these glycans. As a common feature, the DC-SIGN-related lectin-Fc chimeras, including LSECtin, exhibited binding affinity to mono- and/or bi-antennary agalactosylated N-glycans. The detailed FAC analysis further implied that the presence of terminal GlcNAc at the N-acetylglucosaminyltransferase I position is a key determinant for the binding of these lectins to agalactosylated N-glycans. By contrast, none of the lectins showed significant affinity to highly branched agalactosylated N-glycans. All of the lectins expressed on the cells were able to mediate cellular adhesion to agalactosylated cells and endocytosis of a model glycoprotein, agalactosylated alpha1-acid glycoprotein. In this context, we also identified three agalactosylated serum glycoproteins recognized by DC-SIGN-Fc (i.e. alpha-2-macroglobulin, serotransferrin and IgG heavy chain), by lectin blotting and MS analysis. Hence, we propose that 'agalactosylated N-glycans' are candidate ligands common to these lectins. PMID- 20840591 TI - Evidence for the slow reaction of hypoxia-inducible factor prolyl hydroxylase 2 with oxygen. AB - The response of animals to hypoxia is mediated by the hypoxia-inducible transcription factor. Human hypoxia-inducible factor is regulated by four Fe(II)- and 2-oxoglutarate-dependent oxygenases: prolyl hydroxylase domain enzymes 1-3 catalyse hydroxylation of two prolyl-residues in hypoxia-inducible factor, triggering its degradation by the proteasome. Factor inhibiting hypoxia-inducible factor catalyses the hydroxylation of an asparagine-residue in hypoxia-inducible factor, inhibiting its transcriptional activity. Collectively, the hypoxia inducible factor hydroxylases negatively regulate hypoxia-inducible factor in response to increasing oxygen concentration. Prolyl hydroxylase domain 2 is the most important oxygen sensor in human cells; however, the underlying kinetic basis of the oxygen-sensing function of prolyl hydroxylase domain 2 is unclear. We report analyses of the reaction of prolyl hydroxylase domain 2 with oxygen. Chemical quench/MS experiments demonstrate that reaction of a complex of prolyl hydroxylase domain 2, Fe(II), 2-oxoglutarate and the C-terminal oxygen-dependent degradation domain of hypoxia-inducible factor-alpha with oxygen to form hydroxylated C-terminal oxygen-dependent degradation domain and succinate is much slower (approximately 100-fold) than for other similarly studied 2-oxoglutarate oxygenases. Stopped flow/UV-visible spectroscopy experiments demonstrate that the reaction produces a relatively stable species absorbing at 320 nm; Mossbauer spectroscopic experiments indicate that this species is likely not a Fe(IV)=O intermediate, as observed for other 2-oxoglutarate oxygenases. Overall, the results obtained suggest that, at least compared to other studied 2-oxoglutarate oxygenases, prolyl hydroxylase domain 2 reacts relatively slowly with oxygen, a property that may be associated with its function as an oxygen sensor. PMID- 20840592 TI - The 3-ureidopropionase of Caenorhabditis elegans, an enzyme involved in pyrimidine degradation. AB - Pyrimidines are important metabolites in all cells. Levels of cellular pyrimidines are controlled by multiple mechanisms, with one of these comprising the reductive degradation pathway. In the model invertebrate Caenorhabditis elegans, two of the three enzymes of reductive pyrimidine degradation have previously been characterized. The enzyme catalysing the final step of pyrimidine breakdown, 3-ureidopropionase (beta-alanine synthase), had only been identified based on homology. We therefore cloned and functionally expressed the 3 ureidopropionase of C. elegans as hexahistidine fusion protein. The purified recombinant enzyme readily converted the two pyrimidine degradation products: 3 ureidopropionate and 2-methyl-3-ureidopropionate. The enzyme showed a broad pH optimum between pH 7.0 and 8.0. Activity was highest at approximately 40 degrees C, although the half-life of activity was only 65 s at that temperature. The enzyme showed clear Michaelis-Menten kinetics, with a K(m) of 147 +/- 26 MUM and a V(max) of 1.1 +/- 0.1 U.mg protein(-1). The quaternary structure of the recombinant enzyme was shown to correspond to a dodecamer by 'blue native' gel electrophoresis and gel filtration. The organ specific and subcellular localization of the enzyme was determined using a translational fusion to green fluorescent protein and high expression was observed in striated muscle cells. With the characterization of the 3-ureidopropionase, the reductive pyrimidine degradation pathway in C. elegans has been functionally characterized. PMID- 20840593 TI - Modularity and scaling in fast movements: power amplification in mantis shrimp. AB - Extremely fast animal actions are accomplished with mechanisms that reduce the duration of movement. This process is known as power amplification. Although many studies have examined the morphology and performance of power-amplified systems, little is known about their development and evolution. Here, we examine scaling and modularity in the powerful predatory appendages of a mantis shrimp, Gonodactylaceus falcatus (Crustacea, Stomatopoda). We propose that power amplified systems can be divided into three units: an engine (e.g., muscle), an amplifier (e.g., spring), and a tool (e.g., hammer). We tested whether these units are developmentally independent using geometric morphometric techniques that quantitatively compare shapes. Additionally, we tested whether shape and several mechanical features are correlated with size and sex. We found that the morphological regions that represent the engine, amplifier, and tool belong to independent developmental modules. In both sexes, body size was positively correlated with the size of each region. Shape, however, changed allometrically with appendage size only in the amplifier (both sexes) and tool (males). These morphological changes were correlated with strike force and spring force (amplifier), but not spring stiffness (amplifier). Overall, the results indicate that each functional unit belongs to different developmental modules in a power amplified system, potentially allowing independent evolution of the engine, amplifier, and tool. PMID- 20840594 TI - Ancient urbanization predicts genetic resistance to tuberculosis. AB - A link between urban living and disease is seen in recent and historical records, but the presence of this association in prehistory has been difficult to assess. If the transition to urban living does result in an increase in disease-based mortality, we might expect to see evidence of increased disease resistance in longer-term urbanized populations, as the result of natural selection. To test this, we determined the frequency of an allele (SLC11A1 1729 + 55del4) associated with natural resistance to intracellular pathogens such as tuberculosis and leprosy. We found a highly significantly correlation with duration of urban settlement-populations with a long history of living in towns are better adapted to resisting these infections. This correlation remains strong when we correct for autocorrelation in allele frequencies due to shared population history. Our results therefore support the interpretation that infectious disease loads became an increasingly important cause of human mortality after the advent of urbanization, highlighting the importance of population density in determining human health and the genetic structure of human populations. PMID- 20840595 TI - Plant responses to climate in the Cape Floristic Region of South Africa: evidence for adaptive differentiation in the Proteaceae. AB - Local adaptation along environmental gradients may drive plant species radiation within the Cape Floristic Region (CFR), yet few studies examine the role of ecologically based divergent selection within CFR clades. In this study, we ask whether populations within the monophyletic white protea clade (Protea section Exsertae, Proteaceae) differ in key functional traits along environmental gradients and whether differences are consistent with local adaptation. Using seven taxa, we measured trait-environment associations and selection gradients across 35 populations of wild adults and their offspring grown in two common gardens. Focal traits were leaf size and shape, specific leaf area (SLA), stomatal density, growth, and photosynthetic rate. Analyses on wild and common garden plants revealed heritable trait differences that were associated with gradients in rainfall seasonality, drought stress, cold stress, and less frequently, soil fertility. Divergent selection between gardens generally matched trait-environment correlations and literature-based predictions, yet variation in selection regimes among wild populations generally did not. Thus, selection via seedling survival may promote gradient-wide differences in SLA and leaf area more than does selection via adult fecundity. By focusing on the traits, life stages, and environmental clines that drive divergent selection, our study uniquely demonstrates adaptive differentiation among plant populations in the CFR. PMID- 20840596 TI - Variation in acoustic signalling traits exhibits footprints of sexual selection. AB - Phenotypic variation is ubiquitous in nature and a precondition for adaptive evolution. However, theory predicts that the extent of phenotypic variation should decrease with increasing strength of selection on a trait. Comparative analyses of trait variability have repeatedly used this expectation to infer the type or strength of selection. Yet, the suggested influence of selection on trait variability has rarely been tested empirically. In the present study, I compare estimates of sexual selection strength and trait variability from published data. I constricted the analysis to acoustic courtship traits in amphibians and insects with known variability and corresponding results of female binary choice experiments on these traits. Trait variability and strength of sexual selection were significantly correlated, and both were correlated with signal duration. Because traits under stronger selection had lower variation even after the effect of signal duration was eliminated, I conclude that traces of the strength of selection can be observed with respect to variation of acoustic signaling traits in insects and amphibians. The analysis also shows that traits under stabilizing selection have significantly lower phenotypic variability than traits under directional selection. PMID- 20840597 TI - Ecological barriers to gene flow between riparian and forest species of Ainsliaea (Asteraceae). AB - Understanding the role of habitat-associated adaptation in reducing gene flow resulting in population differentiation and speciation is a major issue in evolutionary biology. We demonstrate a significant role for habitat divergence in species isolation between two naturally hybridizing riparian and nonriparian plants, Ainsliaea faurieana and A. apiculata (Asteraceae), on Yakushima Island, Japan. By analyzing the fine-scale population structure at six sympatric sites, we found that variations in leaf shape, geography, light conditions, and genotype were strongly correlated across riverbank-forest transitions. No evidence of effective gene flow was found between the two species across the majority of the transition zones, although the NewHybrid clustering analysis confirmed interspecific hybridization. However, a relatively high level of gene flow was observed across one zone with a more diffuse ecotone and intermediate flooding and light conditions, possibly generated by human disturbances. These results suggest that the barriers to gene flow between the riparian and forest species are primarily ecological. Additional common garden experiments indicated that the two species are adaptively differentiated to contrasting flooding and light environments. Overall, our study suggests that adaptations to different habitats can lead to the formation of reproductive isolating barriers and the maintenance of distinct species boundaries. PMID- 20840599 TI - Slatkin's Paradox: when direct observation and realized gene flow disagree. A case study in Ficus. AB - In flying insects, there is frequently a lack of congruence between empirical estimates of local demographic parameters and the prediction that differentiation between populations should decrease with increasing dispersal, a puzzling phenomenon known as Slatkin's Paradox. Here, we generalize Slatkin's Paradox to other taxa, drawing from available information on dispersal to predict the relative importance of pollen vs. seed migration in structuring broad-scale patterns of genetic variation in Ficus hirta, a dioecious fig whose pollen is dispersed by minute, species-specific fig wasps and whose seeds are disseminated by a variety of vagile vertebrates (especially bats and birds). Local-scale observational and genetic studies of dioecious understory figs suggest comparable rates of pollen and seed migration. In contrast, we found unusually low nuclear differentiation (F(ST) =0.037, R(ST) =0.074) and high chloroplast differentiation (G(ST) =0.729, N(ST) =0.798) among populations separated by up to 2850km, leading us to reject the hypothesis of equal pollen and seed migration rates and to obtain an equilibrium estimate of the ratio of pollen to seed migration of r=16.2-36.3. We reconcile this example of Slatkin's Paradox with previously published data for dioecious figs and relate it to the picture of exceptionally long-distance wasp-mediated pollen dispersal that is emerging for large monoecious fig trees. More generally, we argue that Slatkin's Paradox is a general phenomenon and suggest it may be common in plants and animals. PMID- 20840600 TI - Life without putrescine: disruption of the gene-encoding polyamine oxidase in Ustilago maydis odc mutants. AB - In previous communications the essential role of spermidine in Ustilago maydis was demonstrated by means of the disruption of the genes encoding ornithine decarboxylase (ODC) and spermidine synthase (SPE). However, the assignation of specific roles to each polyamine in different cellular functions was not possible because the spermidine added to satisfy the auxotrophic requirement of odc/spe double mutants is partly back converted into putrescine. In this study, we have approached this problem through the disruption of the gene-encoding polyamine oxidase (PAO), required for the conversion of spermidine into putrescine, and the construction of odc/pao double mutants that were unable to synthesize putrescine by either ornithine decarboxylation or retroconversion from spermidine. Phenotypic analysis of the mutants provided evidence that putrescine is only an intermediary in spermidine biosynthesis, and has no direct role in cell growth, dimorphic transition, or any other vital function of U. maydis. Nevertheless, our results show that putrescine may play a role in the protection of U. maydis against salt and osmotic stress, and possibly virulence. Evidence was also obtained that the retroconversion of spermidine into putrescine is not essential for U. maydis growth but may be important for its survival under natural conditions. PMID- 20840601 TI - Computational prediction and transcriptional analysis of sRNAs in Nitrosomonas europaea. AB - Bacterial small noncoding RNAs (sRNAs) have been discovered in many genetically well-studied microorganisms and have been shown to regulate critical cellular processes at the post-transcriptional level. In this study, we used comparative genomics and microarray data to analyze the genome of the ammonia-oxidizing bacterium Nitrosomonas europaea for the presence and expression of sRNAs. Fifteen genes encoding putative sRNAs (psRNAs) were identified. Most of these genes showed altered expression in a variety of experimental conditions. The transcripts of two psRNAs were further characterized by mapping their 5'- and 3' ends and by real-time PCR. The results of these analyses suggested that one of them, psRNA11, is involved in iron homeostasis in N. europaea. PMID- 20840602 TI - Development of a new PCR primer system for selective amplification of Actinobacteria. AB - The occurrence of Actinobacteria in water-damaged building materials as well as the clinical relevance of some Actinobacteria (e.g. Saccharopolyspora spp., Mycobacterium spp., Nocardia spp., etc.), led us to develop a detection system to examine the actinobacterial community. A new primer system, Com2xf/Ac1186r (16S rRNA gene based) specific for Actinobacteria was designed. The adequacy for the intended use of the primer system was first investigated in silico using sequences of 164 different species belonging to 75 different genera of the class Actinobacteria. To test the primer specificity in complex environmental samples, four 16S rRNA gene clone libraries were generated (plaster material, compost material, compost plant- and duck house bioaerosols). Overall, 87% of obtained sequences were assigned to actinobacterial genera. To verify the applicability of the new designed primer system in water-damaged building material, 16S rRNA gene clone libraries of 18 different water-damaged materials were screened for their affiliation to Actinobacteria. A total of 88% of all 'Actinobacteria-positive' detected plasmid inserts were affiliated correctly. Results of SSCP fingerprinting clearly showed differences of the species detected by the Actinobacteria-specific primer system within the different samples. Overall results obtained in this study indicate the applicability of the developed primer system for its intended use. PMID- 20840603 TI - Long-term enteral administration of melatonin reduces plasma insulin and increases expression of pineal insulin receptors in both Wistar and type 2 diabetic Goto-Kakizaki rats. AB - This paper represents an essential aspect of recent investigations into the functional and clinical implications of insulin-melatonin interrelationships. The aim of the study was to analyze whether melatonin reduces insulin secretion in an animal in a manner comparable to the pattern observed in previous in vitro experiments; to this end, we used two models: Wistar and type 2-diabetic Goto Kakizaki (GK) rats. Thirty-two Wistar and 32 GK rats were divided into two subgroups of 16 rats each; each subgroup was treated either with or without melatonin. The daily administration of melatonin, starting in 8-wk-old rats, was adjusted to 2.5 mg/kg body weight. Melatonin was given daily during the dark period for 12 hr. After 9 wk of treatment, the rats were sacrificed in the middle of the dark period. Melatonin administration strongly enhanced the plasma melatonin level and diminished the expression of pancreatic melatonin receptor mRNA, whereas the expression of pineal AA-NAT and HIOMT was unchanged. Furthermore, the experiments showed in agreement with recent in vitro results of pancreatic islets that plasma insulin levels were diminished after melatonin treatment. However, the pineal insulin receptor expression was increased after melatonin administration. The pancreatic expression of glucagon, GLUT2, and glucokinase was decreased in GK rats, whereas the glucose levels, as well as the parameters of glucose sensing, GLUT2-mRNA, and glucokinase-mRNA, were unchanged after melatonin administration in both Wistar and GK rats. In summary, the results show that melatonin administration decreases plasma insulin levels in vivo and, furthermore, that an insulin-melatonin antagonism exists. PMID- 20840604 TI - Patient safety incidents involving neuromuscular blockade: analysis of the UK National Reporting and Learning System data from 2006 to 2008. AB - Neuromuscular blockade is a powerful anaesthetic tool that has the potential for significant adverse outcomes. We sought to explore the national picture by analysing incidents relating to neuromuscular blockade in anaesthesia from the National Reporting and Learning System from England and Wales between 2006 and 2008. We searched the database of incidents using SNOMED CT search terms and reading the free text of relevant incidents. There were 231 incidents arising from the use or reversal of neuromuscular blocking agents. The main themes identified were: non-availability of drugs (45 incidents, 19%), possible unintentional awareness under general anaesthesia (42 incidents, 18%), potential allergic reaction (31 incidents, 13%), problems with reversal of blockade (13 incidents, 6%), storage (13 incidents, 6%) and prolonged apnoea (11 incidents, 5%). We make recommendations to reduce human error in the use of neuromuscular blocking agents and on future incident reporting in anaesthesia. PMID- 20840607 TI - Contrasted demographic responses facing future climate change in Southern Ocean seabirds. AB - 1. Recent climate change has affected a wide range of species, but predicting population responses to projected climate change using population dynamics theory and models remains challenging, and very few attempts have been made. The Southern Ocean sea surface temperature and sea ice extent are projected to warm and shrink as concentrations of atmospheric greenhouse gases increase, and several top predator species are affected by fluctuations in these oceanographic variables. 2. We compared and projected the population responses of three seabird species living in sub-tropical, sub-Antarctic and Antarctic biomes to predicted climate change over the next 50 years. Using stochastic population models we combined long-term demographic datasets and projections of sea surface temperature and sea ice extent for three different IPCC emission scenarios (from most to least severe: A1B, A2, B1) from general circulation models of Earth's climate. 3. We found that climate mostly affected the probability to breed successfully, and in one case adult survival. Interestingly, frequent nonlinear relationships in demographic responses to climate were detected. Models forced by future predicted climatic change provided contrasted population responses depending on the species considered. The northernmost distributed species was predicted to be little affected by a future warming of the Southern Ocean, whereas steep declines were projected for the more southerly distributed species due to sea surface temperature warming and decrease in sea ice extent. For the most southerly distributed species, the A1B and B1 emission scenarios were respectively the most and less damaging. For the two other species, population responses were similar for all emission scenarios. 4. This is among the first attempts to study the demographic responses for several populations with contrasted environmental conditions, which illustrates that investigating the effects of climate change on core population dynamics is feasible for different populations using a common methodological framework. Our approach was limited to single populations and have neglected population settlement in new favourable habitats or changes in inter-specific relations as a potential response to future climate change. Predictions may be enhanced by merging demographic population models and climatic envelope models. PMID- 20840608 TI - Rarity, life history and scaling of the dynamics in time and space of British birds. AB - 1. Many patterns in macroecology are closely related to the total abundance of a species in a region. Here we show that interspecific differences in the pattern of population fluctuations of British bird species can be predicted from knowledge of their overall abundance and some basic life-history characteristics. 2. We identify a rarity syndrome that arises through an increased stochastic influence on population fluctuations with decreasing population size, mainly resulting from an inverse density-dependent effect of demographic stochasticity. This syndrome involves an increase in the annual changes in population size with increasing rarity in the United Kingdom. 3. The relationship between the magnitude of temporal variation and local mean population size differs between species dependent on their life history, i.e. species with larger clutch size and lower survival tended to have larger annual changes in population size than low reproducing long-lived species. 4. The probability of local disappearance from a study plot depended on the population size and was hence closely related to the overall abundance of the species in UK. For a given population size, this probability was also related to species-specific life-history characteristics, being higher in species with larger clutch sizes and smaller survival rates. 5. Rareness results in a spatial decoupling of the temporal variation in population size. 6. These patterns show that once a species has become rare, e.g. due to human activities, key population dynamical characteristics will change because of density-dependent stochastic effects, which in turn are dependent on species specific life-history characteristics. PMID- 20840605 TI - MicroRNA-21 protects neurons from ischemic death. AB - MicroRNAs are small RNAs that attenuate protein expression by complementary binding to the 3'-UTR of a target mRNA. Currently, very little is known about microRNAs after cerebral ischemia. In particular, microRNA-21 (miR-21) is a strong antiapoptotic factor in some biological systems. We investigated the role of miR-21 after stroke in the rat. We employed in situ hybridization and laser capture microdissection in combination with real-time RT-PCR to investigate the expression of miR-21 after stroke. In situ hybridization revealed that miR-21 expression was upregulated in neurons of the ischemic boundary zone, and quantitative real-time RT-PCR analysis revealed that stroke increased mature miR 21 levels by approximately threefold in neurons isolated from the ischemic boundary zone by laser capture microdissection as compared with homologous contralateral neurons 2 days (n = 4; P < 0.05) and 7 days (n = 3; P < 0.05) after stroke. In vitro, overexpression of miR-21 in cultured cortical neurons substantially suppressed oxygen and glucose deprivation-induced apoptotic cell death, whereas attenuation of endogenous miR-21 by antisense inhibition exacerbated cell death after oxygen and glucose deprivation. Moreover, overexpression of miR-21 in neurons significantly reduced FASLG levels, and introduction of an miR-21 mimic into 293-HEK cells substantially reduced luciferase activity in a reporter system containing the 3'-UTR of Faslg. Our data indicate that overexpression of miR-21 protects against ischemic neuronal death, and that downregulation of FASLG, a tumor necrosis factor-alpha family member and an important cell death-inducing ligand whose gene is targeted by miR-21, probably mediates the neuroprotective effect. These novel findings suggest that miR-21 may be an attractive therapeutic molecule for treatment of stroke. PMID- 20840609 TI - Mannitol permeation and radial flow of water in maize roots. AB - * The postulated nonselective hydraulic route through the root apoplast has not yet been supported by experimental findings on solvent drag. * Therefore, mannitol transport from the medium to the shoot of young maize plants was studied at different rates of transpiration in hydroculture. The concentration of mannitol was determined by gas chromatography. * Mannitol utilization in shoot metabolism was not detectable. Experiments with exuding roots showed that the radial transport of mannitol was mainly apoplastic. The ratio alpha between the mannitol concentration in xylem vessels and that of the external medium was calculated from mannitol translocation to the shoot or measurement of the mannitol concentration in the root exudate, where it reached c. 0.07 in the steady state. In transpiring plants, alpha decreased with increasing water flux from 0.04 to values below 0.01. These findings demonstrate that the root reflection coefficient for mannitol is above 0.99. * It is concluded that the radial movement of water to the vessels is under complete protoplastic control, whereas solutes can diffuse on an apoplastic path. The absence of a significant volume flux through the root apoplast is of physiological importance as it prevents the coupling of the apoplastic permeation of ballast solutes, such as NaCl, to transpiration. PMID- 20840610 TI - The role of abscisic acid and water stress in root herbivore-induced leaf resistance. AB - * Herbivore-induced systemic resistance occurs in many plants and is commonly assumed to be adaptive. The mechanisms triggered by leaf-herbivores that lead to systemic resistance are largely understood, but it remains unknown how and why root herbivory also increases resistance in leaves. * To resolve this, we investigated the mechanism by which the root herbivore Diabrotica virgifera induces resistance against lepidopteran herbivores in the leaves of Zea mays. * Diabrotica virgifera infested plants suffered less aboveground herbivory in the field and showed reduced growth of Spodoptera littoralis caterpillars in the laboratory. Root herbivory did not lead to a jasmonate-dependent response in the leaves, but specifically triggered water loss and abscisic acid (ABA) accumulation. The induction of ABA by itself was partly responsible for the induction of leaf defenses, but not for the resistance against S. littoralis. Root-herbivore induced hydraulic changes in the leaves, however, were crucial for the increase in insect resistance. * We conclude that the induced leaf resistance after root feeding is the result of hydraulic changes, which reduce the quality of the leaves for chewing herbivores. This finding calls into question whether root-herbivore induced leaf-resistance is an evolved response. PMID- 20840611 TI - Do quantitative vessel and pit characters account for ion-mediated changes in the hydraulic conductance of angiosperm xylem? AB - * The hydraulic conductance of angiosperm xylem has been suggested to vary with changes in sap solute concentrations because of intervessel pit properties. * The magnitude of the 'ionic effect' was linked with vessel and pit dimensions in 20 angiosperm species covering 13 families including six Lauraceae species. * A positive correlation was found between ionic effect and vessel grouping parameters, especially the portion of vessel walls in contact with neighbouring vessels. Species with intervessel contact fraction (F(C)) values < 0.1 showed an ionic effect between 2% and 17%, while species with F(C) values > 0.1 exhibited a response between 10% and 32%. The ionic effect increased linearly with the mean fraction of the total vessel wall area occupied by intervessel pits as well as with the intervessel contact length. However, no significant correlation occurred between the ionic effect and total intervessel pit membrane area per vessel, vessel diameter, vessel length, vessel wall area, and intervessel pit membrane thickness. * Quantitative vessel and pit characters are suggested to contribute to interspecific variation of the ionic effect, whereas chemical properties of intervessel pit membranes are likely to play an additional role. PMID- 20840612 TI - Review of the Australian hagfishes with description of two new species of Eptatretus (Myxinidae). AB - This paper revises and updates taxonomic and distributional information about hagfishes (Myxinidae) from Australia. It covers five species of the genus Eptatretus: Eptatretus cirrhatus known from eastern Australia and also distributed around New Zealand, Eptatretus longipinnis endemic to South Australia, Eptatretus strahani originally described from the Philippines and reported here as a new record from Western Australia and two new species described herein as Eptatretus alastairi and Eptatretus gomoni, both from Western Australia. Eptatretus alastairi is distinguished from all congeners by the unique combination of the following characters: six pairs of gill pouches; three-cusp multicusps on the anterior and posterior rows of cusps; anterior unicusps 9-12; posterior unicusps 8-11; total cusps 48-56; prebranchial pores 13-16; branchial pores 5-6; trunk pores 50-55; tail pores 11-13; total pores 83-88; two bilaterally symmetrical nasal-sinus papillae in the dorsal surface of the nasal sinus. Eptatretus gomoni is distinguished from all congeners by the unique combination of the following characters: eight pairs of gill pouches; three-cusp multicusps on the anterior and two-cusp multicusps on the posterior row of cusps; anterior unicusps 10-11; posterior unicusps 9-10; total cusps 50; prebranchial pores 12-13; branchial pores 7-8; trunk pores 57-58; tail pores 14-15; total pores 91-93; no nasal-sinus papillae. An identification key for the Australian species of Eptatretus is also provided. PMID- 20840613 TI - Sexual dimorphism of head morphology in three-spined stickleback Gasterosteus aculeatus. AB - This study examined sexual dimorphism of head morphology in the ecologically diverse three-spined stickleback Gasterosteus aculeatus. Male G. aculeatus had longer heads than female G. aculeatus in all 10 anadromous, stream and lake populations examined, and head length growth rates were significantly higher in males in half of the populations sampled, indicating that differences in head size increased with body size in many populations. Despite consistently larger heads in males, there was significant variation in size-adjusted head length among populations, suggesting that the relationship between head length and body length was flexible. Inter-population differences in head length were correlated between sexes, thus population-level factors influenced head length in both sexes despite the sexual dimorphism present. Head shape variation between lake and anadromous populations was greater than that between sexes. The common divergence in head shape between sexes across populations was about twice as important as the sexual dimorphism unique to each population. Finally, much of the sexual dimorphism in head length was due to divergence in the anterior region of the head, where the primary trophic structures were found. It is unclear whether the sexual dimorphism was due to natural selection for niche divergence between sexes or sexual selection. This study improves knowledge of the magnitude, growth rate divergence, inter-population variation and location of sexual dimorphism in G. aculeatus head morphology. PMID- 20840614 TI - Prediction and verification of possible reef-fish spawning aggregation sites in Los Roques Archipelago National Park, Venezuela. AB - This study attempts to predict and verify possible spawning aggregation sites and times in the Los Roques Archipelago National Park, Venezuela, based on physical reef characteristics and the knowledge of experienced local fishermen. Three possible aggregation sites were selected for monitoring based on satellite images, low-cost bathymetric mapping and interviews with experienced local fishermen. Abundances and sizes of 18 species that are known to form reproductive aggregations were monitored at these sites using underwater visual census for 7 days after each full moon from February to August, 2007. While spawning events were not observed, possible indirect evidence of spawning aggregations was found for Lutjanus analis at Cayo Sal and Boca de Sebastopol, Lutjanus apodus at Cayo Sal, Lutjanus cyanopterus at Cayo Sal and Piedra La Guasa and Epinephelus guttatus at Bajo California and Cayo de Agua. Additionally, indirect evidence was identified for the past existence of a spawning aggregation of Epinephelus striatus in the northern part of the archipelago, which may have been eliminated by overfishing c.15 years ago. Bathymetric mapping showed that the shelf edge at sites monitored in this study was shallower than at spawning aggregation sites in other parts of the Caribbean, and that sites were not proximal to deep water. While this study does not prove the existence or locations of spawning aggregations of reef fishes in the archipelago, it does add insight to a growing understanding of generalities in the relationship between seafloor characteristics and the locations of transient reef-fish spawning aggregations in the Caribbean. PMID- 20840615 TI - Review of the Halieutichthys aculeatus species complex (Lophiiformes: Ogcocephalidae), with descriptions of two new species. AB - The Halieutichthys aculeatus species complex is reviewed. Members of this clade are distinguished by the presence of tubercles on the tail and a reticulate dorsal pigmentation pattern. Three species are recognized, including two species new to science. A neotype is chosen for H. aculeatus. Halieutichthys bispinosus n. sp. is characterized by having relatively strong tubercles on the dorsal surface, a row of tubercles almost always present dorsal to the orbit, both sphenotic tubercles well developed and sharp, trifid principal tubercles on the disk margin with anterior spinelet enlarged, dense arrangement of tubercles on the tail and a comparatively large adult body size. Halieutichthys intermedius n. sp. can be distinguished from congeners by having both sphenotic tubercles strongly reduced, the tubercles almost always absent dorsal to the orbit, principal tubercles on the disk margin uniformly short and blunt tubercles, with all spinelets generally reduced. PMID- 20840616 TI - Acute toxic effects of 8-epidiosbulbin E, a 19-norclerodane diterpene from yam Dioscorea antaly, on medaka Oryzias latipes embryos. AB - The fractionation of an aqueous extract of yam Dioscorea antaly from Madagascar led to the isolation of terpenoids and flavonoids. Compounds were identified on the basis of modern mass spectrometry and two-dimensional nuclear magnetic resonance (2D-NMR). Toxicological effects of the most abundant isolated compound, 8-epidiosbulbin E were studied on medaka Oryzias latipes embryo-larval development. The lethal concentration (killing 50%; LC(50) ) to embryos treated 24 h before hatching and for 3 days after hatching was estimated to be 0.56 mg ml(-1) (P< 0.05). No mortality was observed with O. latipes larvae exposed after hatching until day 4. Anatomo-pathological studies of embryos exposed to 0.56 mg ml(-1) showed development anomalies of the central nervous system, liver, muscle and intestine. The present data thus extend the model of O. latipes embryos as a useful animal model to analyse the effects of food toxins. PMID- 20840617 TI - Moenkhausia celibela: a new species from the Amazon basin, Brazil (Characiformes: Characidae). AB - A new species of Characidae, Moenkhausia celibela, is described from the Rio Amazonas at Santarem, Rio Marau, several localities in the Rio Tapajos, Rio Curua Una, Rio Xingu and Rio Jari, all from the Amazon basin, Brazil. The new species is distinguished from its congeners, except species included in Gery's 1992 Moenkhausia lepidura group, by presenting a dark blotch on the upper caudal-fin lobe, and the lower lobe is hyaline or light grey. Moenkhausia celibela is distinguished from the species of the M. lepidura group by the absence of a humeral spot and the presence of a roughly triangular and dark spot at the caudal fin base, extending posteriorly along the middle caudal-fin rays, and distinctly separate from the spot on the upper caudal-fin lobe. PMID- 20840618 TI - Nest-site fidelity in parental male bluegill Lepomis macrochirus: spatial patterns and the influence of prior mating success. AB - A 4 year mark-recapture study examined the pattern of nesting site fidelity of parental-type male bluegill Lepomis macrochirus. The study results indicated that iteroparous male L. macrochirus choose new nest sites near their own previously used sites. The scale of site fidelity varied, but generally males choose to renest within shoreline areas rather than specific or exact nest locations (94% within-year, 86% among-years). Iteroparous males also displayed no preference to nest in proximity to neighbouring males from previous colonies to suggest social fidelity. Contrary to expectation, manipulating males' reproductive success had no significant effect on the pattern or scale of male reproductive site fidelity. PMID- 20840619 TI - Composition and structure of reef fish communities in Paraiba State, north eastern Brazil. AB - The composition and trophic structure of reef fish communities in two natural and two artificial reefs along the coast of Paraiba State in north-eastern Brazil were investigated. A total of 114 species of fish belonging to 47 families were recorded during 120 stationary visual surveys, slightly less than half (46.55%) of which were recorded at all four surveyed localities. Most species are widely distributed on the western Atlantic coast, but several are endemic to Brazil. The greatest diversity and equitability indexes were recorded at the reefs of Sapatas and Cabeco dos Cangulos, whereas the greatest richness and abundance were found at the Queimado shipwreck. The Alvarenga shipwreck reef had the least richness, diversity and equitability. The four localities studied had very similar ichthyofaunas, especially in relation to species composition. The reefs along the Paraiba coast are considered priority conservation areas by the Brazilian Ministry of the Environment, and the information generated by this study will be useful for comparison with other reefs in the region and can be directly applied to programmes seeking to protect and manage these environments. PMID- 20840620 TI - Deposition of Atlantic salmon Salmo salar carcasses in a Scottish upland catchment. AB - Radio telemetry was utilized to track 38 Atlantic salmon Salmo salar across space and time during and following their spawning run on the Conon system, Scotland. The data collected were used to assess the proportion of S. salar able to migrate successfully from an upland oligotrophic area of the catchment and the distribution of the carcasses of those fish that remained. Of these fish, 35% successfully migrated from the study area after the spawning period. The fish that remained were distributed approximately equally between riverine and lacustrine areas, but with a strong tendency to accumulate in regions of relatively slow water flows. PMID- 20840621 TI - An investigation on the effect of photoperiod and temperature on vertebral band deposition in little skate Leucoraja erinacea. AB - An investigation was undertaken to determine whether photoperiod or temperature have an effect on the timing of vertebral opaque-transluscent band-pair deposition in captive young-of-the-year (YOY) little skate Leucoraja erinacea. The experimental design consisted of a randomized complete block split plot design with two factors: temperature and light. Temperature was nested within light and therefore four variables were tested: 1) constant light, 2) constant temperature, 3) seasonal light and 4) seasonal temperature. For 18 months, L. erinacea experienced accelerated seasonal conditions of temperature and light to mimic 3 years of growth. This study provides primary and supporting evidence that seasonal photoperiod and temperature, respectively, have no effect on timing of vertebral band-pair deposition in captive L. erinacea. Vertebral analysis of surviving L. erinacea (n = 6, time = 18 months) showed that all produced 1-1.5 band pairs, while centrum edge analysis (n = 56) showed timing of winter and summer band deposition were similar regardless of treatment. The winter band (translucent) appeared in February 2007 and January 2008 while the summer band (opaque) showed up in July for both 2007 and 2008 and mimicked patterns observed in the wild. While temperature and photoperiod appear to have no effect on timing of band-pair deposition in YOY L. erinacea, other mechanisms which may influence band deposition should be investigated including the effect of food ration and the presence of a circa-annual rhythm and hormone secretion. PMID- 20840622 TI - Chemical excretions of angled bonefish Albula vulpes and their potential use as predation cues by juvenile lemon sharks Negaprion brevirostris. AB - Bonefish Albula vulpes (n = 7) exercised to exhaustion and air exposed for 1 min as part of a catch-and-release angling event were found to excrete both ammonia and urea, but cortisol and lactate were below detectable levels. Urea made up a greater proportion of total nitrogen excretion from these fish at all time points following an angling event. When captive juvenile lemon sharks Negaprion brevirostris (n = 12) were exposed to a 30 s pulse of these chemicals [ammonia (500 mM), cortisol (20 ug l(-1) ), lactate (6 mM) or urea (3 mM)], they showed a significant reduction in the frequency of resting behaviours when exposed to ammonia and urea than when exposed to control water. It appears that products excreted by A. vulpes, particularly ammonia and urea, may provide an olfactory cue for the post-release predation of A. vulpes by N. brevirostris during catch and-release angling events. PMID- 20840623 TI - Egg capsules of the dusky catshark Bythaelurus canescens (Carcharhiniformes, Scyliorhinidae) from the south-eastern Pacific Ocean. AB - The external morphology of the egg capsule of Bythaelurus canescens and its fixation to the substratum are described. Bythaelurus canescens egg capsules are typically vase-shaped, dorso-ventrally flattened, pale yellow in colour when fresh and covered by 12-15 longitudinal ridges. The anterior border of the capsule is straight, whereas the posterior border is semicircular. Two horns bearing long, coiled tendrils arise from the anterior and posterior ends of the capsule. The presence of longitudinal ridges and long coiled tendrils at both anterior and posterior ends of the capsule readily distinguish these egg capsules from those of other chondrichthyans occurring in the south-east Pacific Ocean. PMID- 20840624 TI - Reconstructing riverine mesohabitat unit composition using fish community data and an autecology matrix. AB - This research proposes a simplified method for estimating the mesohabitat composition that would favour members of a given set of aquatic species. The simulated composition of four types of mesohabitat units (deep pool, shallow pool, deep riffle and shallow riffle) could guide the design of in-stream structures in creating pool-riffle systems with ecological reference. Fish community data and an autecology matrix are used to support the development of a stream mesohabitat simulation based on regression models for reaches in mid to upper-order streams. The fish community-mesohabitat model results constitute a reference condition that can be used to guide stream restoration and ecological engineering decisions aimed at maintaining the natural ecological integrity and diversity of rivers. PMID- 20840625 TI - Individual growth trajectories of sibling Brycon moorei raised in isolation since egg stage, and their relationship with aggressive behaviour. AB - The growth of sibling dorada Brycon moorei (Characidae) housed individually in small enclosures (0.25 l; 27.0 degrees C, range +/-0.5 degrees C; 12L:12D) from the egg stage was examined at regular intervals until 36 days after hatching (dah) and compared with their behaviour. From 1 to 8 dah, when cannibalism is intense among B. moorei raised in groups, there was no significant increase of size heterogeneity among isolated fish (c.v. of total length of 3.1 and 3.6%, at 1 and 8 dah, respectively) and no primacy of early size differences either. These results suggest that cannibals of B. moorei raised in groups are not natural-born killers with greater growth capacities than others. Size heterogeneity among isolated fish increased significantly first when B. moorei were weaned on formulated feed (8-15 dah), then again from 24 to 36 dah when the average growth rate was half as fast as before (c. 0.5 v. 1.0 mm day(-1) ), despite fish consistently feeding. During both periods, there was a significant, positive relationship between individual growth and aggression or boldness. These results suggest that (1) boldness can favour the transition to a new food type and (2) fish exhibited a variable responsiveness to spatial restriction in small enclosures, which may have been alleviated in some individuals by establishment of territorial behaviour, as suggested by their enhanced aggression. PMID- 20840626 TI - A new species of hagfish (Myxinidae: Eptatretus) from Papua New Guinea. AB - A new species of seven-gilled hagfish Eptatretus astrolabium (Myxinidae) is described from a 400 mm total length female trapped 1 km east from Planet Rock, Astrolabe Bay, Papua New Guinea, at c. 500 m depth. This is the first hagfish species reported from the waters around New Guinea. It can be distinguished from other hagfishes by a combination of characters including seven pairs of gill apertures, three-cusp multicusps on the anterior and posterior rows of cusps, 10 posterior unicusps, 52 total cusps, 18-19 prebranchial pores, five branchial pores, 48-49 trunk pores, 83-84 total pores and no nasal-sinus papillae. PMID- 20840627 TI - The utilization of a Pacific salmon Oncorhynchus nerka subsidy by three populations of charr Salvelinus spp. AB - The L(F) -at-age trajectories differentiated two populations of Dolly Varden charr Salvelinus malma and a population of Arctic charr Salvelinus alpinus from the eastern end of Iliamna Lake, Alaska. Salvelinus malma from the Pedro Bay ponds were the smallest for a given age, followed by Salvelinus alpinus from the lake, and S. malma from the Iliamna River were much larger. The utilization of a large sockeye salmon Oncorhynchus nerka subsidy by the three Salvelinus spp. populations was then investigated by comparing diet data and mixing model (MixSIR) outputs based on carbon and nitrogen stable isotopes. Stomach contents indicated that both S. malma populations fed on O. nerka products, especially eggs and larval Diptera that had scavenged O. nerka carcasses, whereas S. alpinus fed on a variety of prey items such as three-spined sticklebacks Gasterosteus aculeatus and snails. Stable-isotope analysis corroborated the diet data; the two S. malma populations incorporated more O. nerka-derived nutrients into their tissues than did S. alpinus from the lake, although all populations showed substantial utilization of O. nerka-derived resources. Salvelinus alpinus also seemed to be much more omnivorous, as shown by stable-isotope mixing models, than the S. malma populations. The dramatic differences in growth rate between the two S. malma populations, despite similar trophic patterns, indicate that other important genetic or environmental factors affect their life history, including proximate temperature controls and ultimate predation pressures. PMID- 20840628 TI - Age-related thermal habitat use by Pacific salmon Oncorhynchus spp. AB - Age-related thermal habitat use by sockeye Oncorhynchus nerka, chum Oncorhynchus keta and pink Oncorhynchus gorbuscha salmon was examined using trawl data obtained in spring in the North Pacific Ocean. Thermal habitat use differed by species and age. Larger and older fishes inhabited cooler areas, whereas smaller and younger fishes inhabited warmer areas. PMID- 20840629 TI - Spawning frequency of brood dams and sires in a marine fish stock-enhancement hatchery. AB - Parentage analysis, employing five hypervariable microsatellite markers, was used to follow spawning patterns of red drum Sciaenops ocellatus broodfish in two spawning tanks through most of a calendar year in a marine fish hatchery dedicated to stock enhancement. Five of six dams and all four sires spawned at least once during the year. Variation in dam and sire spawning incidence and in number of progeny produced per dam and per sire translated into reduced genetic effective size (N e) per spawn by 40.6% in one tank and 50.8% in the other. PMID- 20840631 TI - Interleukin-25 fails to activate STAT6 and induce alternatively activated macrophages. AB - Interleukin-25 (IL-25), a T helper type 2 (Th2) -related factor, inhibits the production of inflammatory cytokines by monocytes/macrophages. Since Th2 cytokines antagonize classically activated monocytes/macrophages by inducing alternatively activated macrophages (AAMs), we here assessed the effect of IL-25 on the alternative activation of human monocytes/macrophages. The interleukins IL 25, IL-4 and IL-13 were effective in reducing the expression of inflammatory chemokines in monocytes. This effect was paralleled by induction of AAMs in cultures added with IL-4 or IL-13 but not with IL-25, regardless of whether cells were stimulated with lipopolysaccharide or interferon-gamma. Moreover, pre incubation of cells with IL-25 did not alter the ability of both IL-4 and IL-13 to induce AAMs. Both IL-4 and IL-13 activated signal transducer and activator of transcription 6 (STAT6), and silencing of this transcription factor markedly reduced the IL-4/IL-13-driven induction of AAMs. In contrast, IL-25 failed to trigger STAT6 activation. Among Th2 cytokines, only IL-25 and IL-10 were able to activate p38 mitogen-activated protein kinase. These results collectively indicate that IL-25 fails to induce AAMs and that Th2-type cytokines suppress inflammatory responses in human monocytes by activating different intracellular signalling pathways. PMID- 20840632 TI - Porcine circovirus type 2 DNA influences cytoskeleton rearrangements in plasmacytoid and monocyte-derived dendritic cells. AB - Functional disruption of dendritic cells (DC) is an important strategy for viral pathogens to evade host defences. In this context, porcine circovirus type 2 (PCV2), a single-stranded DNA virus, impairs plasmacytoid DC (pDC) and conventional DC activation by certain viruses or Toll-like receptor (TLR) ligands. This inhibitory capacity is associated with the viral DNA, but the impairment does not affect all signalling cascades; TLR7 ligation by small chemical molecules will still induce interleukin-6 (IL-6) and tumour necrosis factor-alpha secretion, but not interferon-alpha or IL-12. In this study, the molecular mechanisms by which silencing occurs were investigated. PP2, a potent inhibitor of the Lyn and Hck kinases, produced a similar profile to the PCV2 DNA interference with cytokine secretion by pDC, efficiently inhibiting cell activation induced through TLR9, but not TLR7, ligation. Confocal microscopy and cytometry analysis strongly suggested that PCV2 DNA impairs actin polymerization and endocytosis in pDC and monocyte-derived DC, respectively. Altogether, this study delineates for the first time particular molecular mechanisms involved in PCV2 interference with DC danger recognition, which may be responsible for the virus-induced immunosuppression observed in infected pigs. PMID- 20840633 TI - Is translation possible? PMID- 20840634 TI - How translations of Freud's writings have influenced French psychoanalytic thinking. AB - Translations of Freud 's writings have had a lasting influence on psychoanalytic thinking in France. They have, all the same, given rise to some conceptual distortions as regards the ego and the id, the ideal ego and the ego ideal, and splitting. Lacan's 'return to Freud ' certainly reawakened interest in Freud 's writings; however, by focusing mainly on Freud 's early work, Lacan's personal reading played down the importance of the texts Freud wrote after his metapsychological papers of 1915. The fact that there is no French edition of Freud 's complete works makes it difficult for French psychoanalysts to put them in a proper context with respect to his developments as a whole. The Oeuvres Completes [Complete Works] edition may well turn out to be the equivalent of the Standard Edition, but it is as yet far from complete - and, since the vocabulary employed is far removed from everyday language, those volumes already in print tend to make the general public less likely to read Freud. In this paper, the author evokes certain questions that go beyond the French example, such as the impact that translations have within other psychoanalytic contexts. Now that English has become more or less the lingua franca for communication between psychoanalysts, we have to face up to new challenges if we are to avoid a twofold risk: that of mere standardization, as well as that of a 'Babelization' of psychoanalysis. PMID- 20840635 TI - Relative motion: translation and therapy. AB - The central argument is that analysts/therapists and translators/interpreters have a great deal more in common than is commonly supposed. The key element in this sharing is their essential aloneness in the moment and act of interpreting, and their intellectual and affective response to that aloneness. What marks this off as both important and exceptional is its contrast with the untroubling world of study and the comforting world of professional membership and practice. The professional worlds are abundantly documented; the individual experience has had nothing like so much attention. The focus of the argument is on how significant meanings are established, in a context in which no meanings can be taken for granted. The purpose of the argument is to show that each kind of practitioner may have much to learn from the other. PMID- 20840636 TI - The two time vectors of Nachtraglichkeit in the development of ego organization: significance of the concept for the symbolization of nameless traumas and anxieties. AB - The author describes Freud 's conception of Nachtraglichkeit as an active process that bridges the gap between past affective vicissitudes and the cognitive present by way of meaning. Symbolization is thereby subsequently [nachtraglich] conferred on early traumatic events, which thus become susceptible to omnipotent control. The two time vectors of Nachtraglichkeit are discussed: the first is a causal process operating in the forward direction of time against the background of a factual reality, while the second is a backward movement that permits an understanding of unconscious scenes and phantasies taking place at primary process level. This twofold temporal motion was observed and described by Freud early on. However, its significance often remained hidden prior to his study of Moses. It was mostly overlooked in English and French translations, thus giving rise to a one-sided understanding of the concept in the various psychoanalytic cultures, as either deferred action or apres-coup. Freud 's Moses study addresses both temporal aspects of Nachtraglichkeit, seeking not only to reconstruct a past event on a causal, deterministic basis, but also to understand the subjective truth of that event in the transference along the retrograde time line. The decisive criterion for the conceptual and clinical separation of the two time vectors is the development of ego organization and the capacity for symbolization. The two vectors should not be separated on the factual level, as both aspects of Nachtraglichkeit are essential to the understanding of unconscious processes, combining as they do in a relationship of circular complementarity. PMID- 20840637 TI - Coincidences in analysis: Sigmund Freud and the strange case of Dr Forsyth and Herr von Vorsicht. AB - Freud's interest in thought transference opens the possibility for psychoanalytic research on the primary preverbal language and the maternal function, which the emphasis on verbal and paternal communication had hidden in the background of the setting. The author advances a new interpretation of coincidences in analysis and of the psychopathology of everyday life of the setting. Starting from a strange coincidence, new hypotheses are submitted following additional readings of the unpublished manuscript of the 'Forsyth case', recovered by the author, in regard to a significant moment of transformation, both in Freud and in psychoanalysis, at the end of the war. This phase corresponds first to a change of language, from German to English, as well as to the foundation of the International Journal of Psychoanalysis by Ernest Jones. In particular, the roots of the metapsychological turn of the 1920s are explored, together with the opening of private and productive thoughts in the area of 'telepathy' that joined Freud, Ferenczi, and Anna Freud in a true 'dialogue of unconsciouses'. The free association between A Child Is Being Beaten, Beyond the Pleasure Principle, and the clinical experience with 'Herr B.' is outlined in order to understand Freud's heroic self-analysis at the time when he was treating his daughter Anna and grieving the death of his beloved Sophie. PMID- 20840638 TI - Narcissism lost: on translating and being translated. AB - The authors present a detailed account of the experiences shared in translating and having one's work translated. Carneiro maintains that, in order to communicate with their readers, writers should relinquish the narcissistic satisfaction they derive from their texts in the original. Beyond this, she feels that, owing to a good understanding between her and her translator, the creativity in her original text persists in the translation. Brakel introduces himself to the IJPA readership and shows how he works when translating the cultural and linguistic nuances and peculiarities of Brazilian Portuguese. He concludes with some thoughts about the affect he experiences from his original work and the work he has translated. PMID- 20840639 TI - Representante-representativo, representant-representation, ideational representative: which one is a Freudian concept? On the translation of Vorstellungsreprasentanz in Spanish, French and English. AB - The Freudian expression Vorstellungsreprasentanz (Freud, 1915b, 1915c), which is rendered in the Standard Edition as ideational representative, is commonly translated in Spanish as representante-representativo and in French as representant-representation, among other renderings. An interdisciplinary conceptual inquiry, which applies linguistic semantics to the evaluation of the available Spanish and French renderings, concludes that this compound expression should be translated in these languages as representante ideativo and representant ideatif, respectively, renderings which happen to correspond to Strachey's translation into English in the SE. In contrast to most Spanish and French translations, this proposal conforms to the semantic principle of compositionality. On the one hand, it provides a suitable translation of the two parts of the compound. Thus it renders Vorstellung as idea, with the classical meaning of image or mental representation, which can be traced back to Hume's empiricist philosophy, and it renders Reprasentanz as representative, with the meaning of delegate. On the other hand, its linguistic form preserves the attributive meaning relationship which exists between both concepts in the original German expression. Against the background of these semantic considerations, a theoretical question concerning Freudian metapsychology is discussed: the drive has a psychic representative, but is there a (mental) representation of the drive? PMID- 20840640 TI - Notes on 'Bemachtigungstrieb' and Strachey's translation as 'instinct for mastery'. AB - This short paper looks at Freud's use of the term 'Bemachtigungstrieb' and its translation by Strachey as 'instinct for mastery' when Freud was describing the motives behind his grandson's game with the wooden reel and string in Beyond the Pleasure Principle. The word 'Macht' [power], which is contained in the word 'Bemachtigung' points to Freud's difficult relationship with Alfred Adler, whose early theories on the aggressive drive and later theories on 'striving for power' were initially rejected by Freud. Looking at the changes in Freud's reception of Adlerian terms, some of which he later integrated into his own theory, throws light on his choice of the word 'Bemachtigungstrieb' in 1920, when he was just beginning to introduce his thoughts on the death instinct. A slightly different translation of the word 'Bemachtigungstrieb', one which takes these historical and theoretical aspects into account, could make these connections clearer for the English reader. PMID- 20840641 TI - The deconstruction of primary narcissism. AB - The author examines Winnicott 's contribution to Freud 's concept of primary narcissism. In Mourning and melancholia, Freud laid the foundations for this contribution, but it was Winnicott who turned it into a clinically useful concept. There are three of Winnicott's ideas that can be seen as preliminary stages to his theory of transitional phenomena and illusion. They serve as an introduction to thinking about the analysis of the analysand 's primary narcissism and the theoretical prerequisites that make the interpretation of primary narcissism possible. Through the exploration of three main points in Winnicott's writings the author shows how Winnicott's conceptualizations are both new and a continuation of Freud 's thinking. His ideas are thus part of the overall theoretical pattern of Freud 's metapsychology. The three main points are as follows: 1. In bringing maternal care and the presence of the psychic environment into the construction of primary narcissism, Winnicott made it possible to analyse narcissism. His ideas enable us to stand back from the characteristic solipsism of narcissism, which holds that everything comes from the self and only from the self. The latter concept tends to eliminate the role of the object and environment in the construction of the self. At the same time, by deconstructing the way in which the self is infiltrated by a certain number of narcissistic postulates, Winnicott made it possible to interpret the theory of narcissism itself. 2. Between the individual and the sense of self, Winnicott inserted the maternal object and her function as a mirror of affects who acts as a medium for the organization of self-identity. Primary identity is established through the construction and elimination of a narcissistic identification that becomes meaningful in the context of a primary homosexual relationship functioning as a 'double'. 3. A process of differentiation that governs the discovery of the object is in a dialectical relationship with narcissistic identification. That process can be understood only in terms of the responses made by the primary psychic environment to the baby's primary aggression. PMID- 20840642 TI - Hidden gifts of love: a clinical application of object relations theory. AB - Using an extended clinical example, the author applies aspects of Kleinian, Fairbairnian, and Bionian theory to demonstrate how individuals may come to hide away feelings of both love and aggression. In the clinical material presented, a version of a schizoid retreat was understood as a pervasive response to trauma. The author attempts to explore more specifically the nature of a 'traumatizing outer world' ( Guntrip, 1969 ) and how these experiences cause an individual to retreat and undermine movement toward healthy adult dependency. An understanding of these dynamics helps inform the psychoanalytic treatment process and can serve as a type of roadmap in navigating through challenging transference countertransference enactments. PMID- 20840643 TI - Levels of analytic work and levels of pathology: the work of calibration. AB - This paper identifies three points on a continuum of levels of analytic work and levels of meaning. The thinking arose out of many years of work with autistic and borderline children, who were not able, for reasons of profound ego impairment, to respond to the more traditional explanatory interpretation as a method of ascribing meaning. Their capacity for introjection was limited. The author suggests that a prior level - lending meaning via description or amplification - is more effective in helping them to think. The paper argues that this second method, where appropriate to the patient's developmental and psychopathological level, need not be seen as inferior to or less complete than the former type. A third, more intensified level of work - an urgent insistence on meaning - is illustrated with a patient where the deficit was not only in the ego, but in the self and the internal object. The suggestion is that the issue at this third level - with emptied out patients - concerns, not thinking about feeling, nor even identifying feeling, but gaining access to feeling itself. The paper involves an attempt both to elaborate certain of the author's earlier ideas on technique and to consolidate these into a wider schema of priorities. PMID- 20840644 TI - Marie Bonaparte, her first two patients and the literary world. AB - Marie Bonaparte (1882-1962) played a critical role in the development of psychoanalysis in France. Her clinical activity is not well known yet she was one of the first female French psychoanalysts. The journalist-writers Alice and Valerio Jahier were Bonaparte's first two patients. She conducted this dual analysis with Rudolph Loewenstein (1898-1976). Alice and Valerio exchanged analysts on several occasions. During his analysis, Valerio began corresponding with Italo Svevo (1861-1928), the author of La Coscienza di Zeno, who imparted his doubts on the therapeutic merits of psychoanalysis. Valerio described his difficult analysis in his letters to Svevo. Bonaparte consulted Freud on the subject, but was not able to prevent Valerio's suicide in 1939. The Princess of Greece encouraged Alice in her vocation as a writer and enabled her to benefit from her connections in literary circles. On the margins of this unpublished story of the two analyses, which is based on archived documents recently made available, we discover the importance of the links which were formed - around Marie Bonaparte - between psychoanalysis and literature. In addition to Italo Svevo, we come across the acerbic writer, Maurice Sachs, as well as the famous novelist, Stefan Zweig. PMID- 20840645 TI - Benign and disruptive disturbances of the supervisory field. AB - Inspired by Baranger, Baranger and Mom's notion of psychoanalytic bastion, we describe an unconscious collusion between analytic supervisors and supervisees. This collusion's purpose is to avoid the anxiety inherent in the psychoanalytic field and that enters unprocessed into the supervisory field. The supervisor/supervisee dyad's emotional experience can be fleeting, with moderate intensity, but can slow down the process. This can happen sometimes in any supervisory situation. Or it can become permanent and with greater intensity and bring the entire process to a standstill and to a disruption of the supervisory field. We call the first situation a 'benign disturbance of the supervisory field', the second a 'disruptive disturbance of the supervisory field'. We illustrate both disturbances using supervisory material. Our purpose is to show how to detect these disturbances, understand them, and manage them. PMID- 20840646 TI - Reading minds: mentalization, irony and literary engagement. AB - The concept of 'mentalization' has recently provided a fertile resource for thinking about various issues in psychoanalysis, including attachment, children's play, personality disorders and the work of interpretation within the analytic setting. Mentalization also provides fruitful ways of thinking about how we read. This paper will suggest that book reading is akin to mind reading: engaging with certain literary texts is akin to understanding the minds of others from the subjective perspective required by mentalization. This way of thinking about literature provides a useful way of understanding its value. The paper will focus specifically on the uses of irony and free indirect speech in Jane Austen's novel Persuasion. Austen's use of literary techniques provides a way of understanding the inner lives of her characters via the ironic voice of the implied author, and requires the reader to engage in the kinds of understanding and insight required for mentalization. PMID- 20840647 TI - The evolved function of the oedipal conflict. AB - Freud based his oedipal theory on three clinical observations of adult romantic relationships: (1) Adults tend to split love and lust; (2) There tend to be sex differences in the ways that men and women split love and lust; (3) Adult romantic relationships are unconsciously structured by the dynamics of love triangles in which dramas of seduction and betrayal unfold. Freud believed that these aspects of adult romantic relationships were derivative expressions of a childhood oedipal conflict that has been repressed. Recent research conducted by evolutionary psychologists supports many of Freud's original observations and suggests that Freud's oedipal conflict may have evolved as a sexually selected adaptation for reproductive advantage. The evolution of bi-parental care based on sexually exclusive romantic bonds made humans vulnerable to the costs of sexual infidelity, a situation of danger that seriously threatens monogamous bonds. A childhood oedipal conflict enables humans to better adapt to this longstanding evolutionary problem by providing the child with an opportunity to develop working models of love triangles. On the one hand, the oedipal conflict facilitates monogamous resolutions by creating intense anxiety about the dangers of sexual infidelity and mate poaching. On the other hand, the oedipal conflict in humans may facilitate successful cheating and mate poaching by cultivating a talent for hiding our true sexual intentions from others and even from ourselves. The oedipal conflict in humans may be disguised by evolutionary design in order to facilitate tactical deception in adult romantic relationships. PMID- 20840648 TI - On: Fairbairn and dynamic structure. PMID- 20840650 TI - Do cyborgs dream? Post-human landscapes in Shinya Tsukamoto's Nightmare Detective (2006). PMID- 20840651 TI - Induction of interleukin-23 p19 by serum amyloid A (SAA) in rheumatoid synoviocytes. AB - In this study, we investigated the roles of serum amyloid A (SAA) in T helper 17 (Th17)-related cytokine induction in rheumatoid arthritis (RA) synoviocytes. Synoviocytes isolated from rheumatoid arthritis (RA) patients were stimulated with recombinant SAA and IL-23 expression was investigated using reverse transcriptase-polymerase chain reaction and Western blot. The involvement of mitogen-activated protein kineases (MAPKs) and nuclear factor (NF)-kappaB in SAA induced interleukin (IL)-23 p19 expression was investigated using pharmacological inhibitors. In RA synoviocytes, SAA induced the expression of IL-23 p19 and p40 mRNA expression. The SAA-stimulated expression of p19 was rapid (< 3 h), and insensitive to polymyxin B treatment. This SAA-stimulated expression of IL-23 p19 was inhibited completely by inhibitors of NF-kappaB, p38MAPK and dexamethasone. Interestingly, the SAA-induced IL-23, p19 and p40 production was accompanied by enhanced expression of IL-1beta, but not transforming growth factor-beta. These results indicate that SAA is a significant inducer of IL-23 and IL-1beta in RA synoviocytes and potentially activates the IL-23/IL-17 pathway in the RA synovium. Our data present a novel interaction between inflammation and autoimmunity by an acute-phase protein. PMID- 20840653 TI - Ectopic lymphoid tissue formation in the lungs of mice infected with Chlamydia pneumoniae is associated with epithelial macrophage inflammatory protein-2/CXCL2 expression. AB - Infection with Chlamydia pneumoniae (Cp) accounts for around 10% of community acquired bacterial pneumonia and has been associated with other chronic inflammatory conditions. We describe a C57/Bl6 murine model of Cp lung infection characterized by a dose-dependent, resolving neutrophilia followed by lymphocytic infiltration of the lungs. By 21 days post-infection, mice exhibit a T helper type 1 (Th1) polarized serum antibody response with local mucosal antibody secretion and organization of ectopic lymphoid tissue which persisted in the absence of detectable Cp DNA. Macrophage inflammatory protein (MIP)-2/CXCL2, which recruits neutrophils and lymphocytes and is associated with ectopic lymphoid tissue formation, was secreted in the lungs post-infection. In vitro, lung epithelial cells up-regulated MIP-2/CXCL2 in response to both rough lipopolysaccharide (reLPS) and Cp infection. We conclude that Cp infection can have long-term inflammatory effects on tissue that persist after clearance of active infection. PMID- 20840652 TI - Increased morbidity and mortality in murine cytomegalovirus-infected mice following allogeneic bone marrow transplant is associated with reduced surface decay accelerating factor expression. AB - Infection with cytomegalovirus (CMV) remains a significant cause of morbidity and mortality following allogeneic bone marrow transplantation (allo-BMT). The manifestations of CMV infection can range from neurological and haematological abnormalities to diminished graft survival and, in extreme cases, death. Many clinical studies have shown a direct correlation between cytomegalovirus infection and increased morbidity and mortality post allo-BMT, yet the exact mechanism is not well understood. Although driven primarily by T cell responses, the role of complement activation in acute and chronic graft-versus-host disease (GVHD) has also become more evident in recent years. The present studies were performed to examine the effects of murine cytomegalovirus (MCMV) infection on decay accelerating factor (DAF) and MCMVs role in exacerbating morbidity and mortality post-allo-BMT. Mice infected previously with a sublethal dose of MCMV (1 * 105 plaque-forming units) have reduced expression of DAF on lung tissues and lymphocytes following allo-BMT. More importantly, mortality rates post-allo-BMT in recipient DAF knock-out mice receiving wild-type bone marrow are increased, similar to wild-type MCMV-infected recipient mice. Similarly, DAF knock-out mice showed greater intracellular interferon (IFN)-gamma production by lung CD8 T cells, and infection with MCMV further exacerbated both intracellular IFN-gamma production by CD8 T cells and mortality rates post-allo-BMT. Together, these data support the hypothesis that MCMV infection augments morbidity and mortality post allo-BMT by reducing surface DAF expression. PMID- 20840654 TI - Rapid migration of thymic emigrants to the colonic mucosa in ulcerative colitis patients. AB - Inflammatory bowel disease (IBD) is associated with imbalances of the local intestinal immune responses, with dysregulated CD4(+) T cells contributing to the chronic inflammation. Having demonstrated altered T cell maturation in the thymus in two different mouse models of colitis, we set out to investigate whether abnormalities in T cell maturation is present in patients with ulcerative colitis (UC) or Crohn's disease (CD). Specimens were obtained from peripheral blood (CD; n = 14, UC; n = 22), colon and small intestinal specimens (CD; n = 6, UC; n = 13). As controls, peripheral blood specimens were obtained from healthy volunteers, patients with adenocarcinomas (n = 18) and colonic specimens from patients with adenocarcinomas (n = 14). Recent thymic emigrants were estimated by analysis of the normalized ratio of T cell receptor excision circles (TRECs) by real-time polymerase chain reaction (PCR). The frequency of naive- and proliferating T lymphocytes and markers of extrathymic T cell maturation in the mucosa was analyzed by flow cytometry and real time-PCR. TREC levels in peripheral blood T lymphocytes were similar between IBD patients and controls. In contrast, UC patients demonstrated significantly increased levels of TRECs both in intraepithelial and lamina propria lymphocytes from the colonic mucosa compared to patients with adenocarcinomas and CD. However, markers for extrathymic T cell maturation in the mucosa were not different between controls and IBD patients. The increased TREC levels in mucosal but not peripheral blood lymphocytes in UC patients in the absence of increased extrathymic maturation in situ in the mucosa together demonstrate that recent thymic emigrants are recruited rapidly to the inflamed mucosa of these patients. PMID- 20840655 TI - Diabulimia and the role of school health personnel. AB - BACKGROUND: Diabulimia, the omission or reduction of insulin use by persons with type 1 diabetes, is a harmful method of weight control. The purpose of this article is to present school health personnel with the information they may need to become more aware of the possibility of diabulimia in their students especially females-with type 1 diabetes. METHODS: A review of the somewhat limited medical and diabetes-related organizations' literature on diabulimia was conducted to establish the role that school health personnel could play in raising awareness of students with this condition as well as education for diabulimia prevention. RESULTS: Since insulin encourages fat storage, many with type 1 diabetes have discovered the relationship between reducing the amount of insulin they take and corresponding weight loss. Improper regulation of needed insulin treatments poses serious health problems that may require immediate medical attention. CONCLUSION: School personnel, especially those in the Coordinated School Health Program areas of comprehensive school health education, school health services, and guidance and counseling services have key roles to play in the prevention and recognition of diabulimia in students with diabetes. PMID- 20840656 TI - Leisure-time physical activity in elementary schools: analysis of contextual conditions. AB - BACKGROUND: Little is known about children's leisure-time physical activity (PA) at school and how it is associated with contextual variables. The purpose of this study was to objectively assess children's voluntary PA during 3 daily periods and examine modifiable contextual factors. METHODS: We conducted SOPLAY (System for Observing Play and Leisure Activity in Youth) observations before school, during recess, and at lunchtime in 137 targeted activity areas in 13 elementary schools over 18 months. During observations, each child was coded as Sedentary, Walking, or Vigorous, and simultaneous entries were made for area characteristics (accessibility, usability, presence of supervision, loose equipment, and organized activities). Logistic regression analysis was used to test associations between PA and area characteristics. RESULTS: Assessors made 2349 area visits and observed 36,995 children. Boys had more moderate-to-vigorous physical activity (MVPA; 66.2 vs 60.0%, p < .001) and more vigorous PA (29.8 vs 24.6%; p < .001) than girls. Areas were typically accessible and usable, but provided organized activities infrequently (16.5%). Odds of engaging in MVPA were greater during lunch and recess than before school and in areas with play equipment (p < .05). CONCLUSIONS: Children accrued a substantial amount of voluntary PA during leisure time at school. Their PA would likely be increased if school playground equipment was more readily available and if supervisors were taught to provide active games and promote PA rather than suppress it. PMID- 20840657 TI - Evaluating the impact of a Connecticut program to reduce availability of unhealthy competitive food in schools. AB - BACKGROUND: This article seeks to inform state and local school food policies by evaluating the impact of Connecticut's Healthy Food Certification (HFC), a program which provides monetary incentives to school districts that choose to implement state nutrition standards for all foods sold to students outside reimbursable school meals. METHODS: Food service directors from all school districts participating in the National School Lunch Program (NSLP) (N = 151) in Connecticut were surveyed about the availability of competitive foods before and after the 2006-2007 implementation of HFC. Food categories were coded as healthy or unhealthy based on whether they met the Connecticut Nutrition Standards. Data on NSLP participation were provided by the State Department of Education. Changes in NSLP participation and availability of unhealthy competitive foods in elementary, middle, and high schools were compared pre- and post-HFC across districts participating (n = 74) versus not participating (n = 77) in HFC. RESULTS: On average, all districts in Connecticut reduced the availability of unhealthy competitive foods, with a significantly greater reduction among HFC districts. Average NSLP participation also increased across the state. Participating in HFC was associated with significantly greater NSLP participation for paid meals in middle school; however, implementing HFC did not increase overall NSLP participation beyond the statewide upward trend. CONCLUSION: The 2006-2007 school year was marked by a significant decrease in unhealthy competitive foods and an increase in NSLP participation across the state. Participation in Connecticut's voluntary HFC further reduced the availability of unhealthy competitive foods in local school districts, and had either a positive or neutral effect on NSLP participation. PMID- 20840658 TI - Associations between school meals offered through the National School Lunch Program and the School Breakfast Program and fruit and vegetable intake among ethnically diverse, low-income children. AB - BACKGROUND: Despite evidence in support of the health benefits associated with fruit and vegetable (FV) intake, national data indicate that FV consumption among school-aged children is below recommended levels, particularly among low-income children. School meals offered through the School Breakfast Program and National School Lunch Program can provide an important contribution to child FV intake. This study examines the proportion of fruits and vegetables consumed from school meals programs among ethnically diverse, low socioeconomic status children. METHODS: Participants (n = 103) included fourth to sixth grade boys and girls from 4 urban elementary schools in St. Paul, Minnesota serving primarily low income populations. Research staff interviewed children during school hours and recorded dietary intake via 24-hour recall. Analysis included descriptive statistics using cross tabulations and means. RESULTS: Average reported mean (SD) daily FV intake was 3.6 (2.5) servings, with 80% of children consuming fewer than 5 daily servings of FV. On average, children consumed over half of their daily FV intake within school. Children with low FV intake (<5 FV servings daily) consumed a higher proportion of their daily intake at school than children with higher FV intake (>=5 FV servings daily) (39% vs 59%; p = .002). CONCLUSIONS: Child FV intake is below recommended levels. School meals provide an important contribution to the daily FV intake among ethnically diverse, low socioeconomic status children, particularly among those with the lowest FV intake. School meals programs promoting FV intake within the school environment may provide an opportunity to encourage increased FV consumption. PMID- 20840659 TI - A structured, interactive method for youth participation in a school district university partnership to prevent obesity. AB - BACKGROUND: The involvement of school-age children in participatory research is described in the context of a school district-university partnership to prevent obesity in children. The purpose of this study was to elicit, from children in kindergarten (K) through sixth grade, perceptions of foods and activities that would inform the design of developmentally appropriate interventions to prevent and reduce childhood obesity. METHODS: Children (N = 218) were selected through a random sample of K through sixth grade classrooms in 3 schools. They participated in structured, interactive, small group exercises focused on perceptions of foods (taste and healthy/unhealthy) and activities (fun and active/sedentary). High school students in the same school district were trained to facilitate the children's groups in collaboration with university faculty and students. RESULTS: Qualitative data analysis was used to discern patterns across grade levels. There were grade-level differences in perceptions of the taste and healthfulness of foods. Younger children (K-1) equated foods that tasted good with foods that were "good for you." Older children were more discriminating and gave reasons for their perceptions. For activities, fun was positively associated with the number of people involved and the amount of movement. There were fewer differences across grade levels in preferences for types of sedentary activities, compared with sports and other activities that "make you move." CONCLUSIONS: The findings have implications for developmentally appropriate health promotion interventions to prevent obesity. These structured but highly interactive methods could be used by school personnel to assess the unique needs of a school population. PMID- 20840660 TI - Elements for successful collaboration between K-8 school, community agency, and university partners: the lead peace partnership. AB - BACKGROUND: Researchers, schools, and community organizations are increasingly interested in forming partnerships to improve health and learning outcomes for adolescents. School-based service learning programs with young adolescents have been shown to improve students' health and educational outcomes. Quality school based service learning practice requires partnerships that are collaborative, mutually beneficial, and address community needs. This article examines core elements of a community-school-university partnership engaged in implementing and evaluating Lead Peace, a service learning program for urban middle school youth. METHODS: The partnership was assessed through (1) semistructured group interviews with program facilitators at each school at the end of the 2006 to 2007 and 2007 to 2008 school years; (2) key informant interviews with school administrators; and (3) participant observations of partnership meetings. Qualitative analysis was conducted to identify common and emerging themes that contribute to the success of the Lead Peace partnership. RESULTS: Ten themes were identified as keys to the success of the Lead Peace partnership: (1) communication; (2) shared decision making; (3) shared resources; (4) expertise and credibility; (5) sufficient time to develop and maintain relationships; (6) champions and patron saints; (7) being present; (8) flexibility; (9) a shared youth development orientation; and (10) recognition of other partners' priorities. CONCLUSIONS: Partnerships that are essential to quality service learning practice require deliberate planning and ongoing attention. Elements of the successful Lead Peace partnership may be useful for other collaborators to consider. PMID- 20840661 TI - Liability risks for after-hours use of public school property to reduce obesity: a 50-state survey. AB - BACKGROUND: One way to address childhood obesity is to create outlets for children to engage in physical activity. Schools are well equipped to provide an active environment. However, some school boards and administrators are concerned about liability risks. This study describes the legal rules applicable to potential claims against public schools during recreational use of school grounds and facilities. METHODS: Using traditional legal methods including the use of legal databases and treatises, the legal rules from 50 states were surveyed to determine what type of liability schools face when opening their grounds for after-school recreational use. RESULTS: Schools would, at most, be held to a reasonable standard of care, under which a person would be found liable if he did not act prudently in a given set of circumstances. This standard is no more onerous than that applied to most activities in the United States. Schools in many states, including California, also receive the benefit of governmental immunity. Furthermore, 21 states have recreational use statutes, which result in more lenient liability rules for injuries during recreational use of school facilities. CONCLUSIONS: Public schools in most states can be subject to liability in certain cases arising out of recreational use of their facilities. However, schools have important defenses. In combination with empirical research about liability in other contexts, this survey suggests that liability risks are unlikely to justify the denial of recreational access to children who are at risk of obesity. PMID- 20840663 TI - Lamellar body counts on gastric aspirates for prediction of respiratory distress syndrome. AB - AIM: To develop a rapid method for diagnosing lung maturity at birth with the purpose of administering surfactant early to infants with immature lungs and to spare infants with mature lungs from this treatment. METHODS: Lamellar body counts (LBC) on gastric aspirates from 191 newborns were counted in the platelet window in automatic blood cell counters. A preliminary study was performed on 108 aspirates from 2000 in infants with <32 weeks' gestation. Furthermore, 83 aspirates from 2004 to 2005 in infants with <30 weeks' gestation were analysed. RESULTS: Lamellar bodies in gastric aspirate were identified by electron microscopy. Seventy of the aspirates from 2004 to 2005 were analysed with a Sysmex XE-2100 (Sysmex, Holbaek, Naestved, Odense and Rigshospitalet, Denmark) counter. Twenty-four of these infants developed moderate to severe respiratory distress syndrome (RDS). The best cut-off value was 8000/MUL with a sensitivity of 75% and a specificity of 72%. Forty-four of the 70 aspirates from 2004 to 2005 were analysed by Sysmex, Advia 120 and Cell-Dyn 4000. Thirteen other aspirates from 2004 to 05 were analysed by Sysmex and Coulter Counter LH755. Using Advia and Coulter the results were similar to Sysmex, but LBC obtained with Cell-Dyn were not correlated with the development of RDS. CONCLUSION: Lamellar body counts on gastric aspirate is a promising tool for prediction of development of RDS in infants of <30 weeks' gestation. PMID- 20840665 TI - A survey of intensive care unit visiting policies in the United Kingdom. AB - Admission to an intensive care unit is a highly stressful event for both patients and their relatives. Feelings of anxiety, pain, fear and a sense of isolation are often reported by survivors of a critical illness, whilst the majority of relatives report symptoms of anxiety or depression while their relative was in the intensive care unit. Traditionally, infection control concerns and a belief that liberal visiting by patients' relatives interferes with the provision of patient care have led many units to impose restricted visiting policies. However, recent studies suggest that an open visiting policy with unrestricted visiting hours improve visitors' satisfaction and reduces anxiety. In order to determine current visiting practice and provision for relatives within intensive care units, a questionnaire was sent to the principal nurse in all units within the United Kingdom. A total of 206 hospitals out of 271 completed the survey (76%). We found that 165 (80.1%) of responding units still impose restricted visiting policies, with wide variations in the facilities available to patients' relatives. PMID- 20840666 TI - The effect of anti-TfR mouse/human chimeric antibody on anti-transplant rejection. AB - The expression of TfR/CD71 in T-cell surface plays a pivotal role in T-cell activation and proliferation. Anti-human-TfR monoclonal antibody could be used as an immunosuppressant in transplant therapy because of their potential to suppress T-cell responses to alloantigens. We therefore examined the feasibility of an anti-human-TfR chimeric antibody (D2C) in suppression of T-cell activation in vitro and graft-versus-host reaction (GVHR) in animals. D2C is a chimeric antibody produced by introducing the human Fc fragment. This antibody showed low antigenicity but high suppressive effect manifested by high potency to block the activation and proliferation of lymphocytes in response to alloantigens. D2C also showed capability to mediate complement-dependent cytotoxicity, which could be correlated with TfR expression in peripheral blood mononuclear cells (PBMCs). Importantly, administration of D2C significantly prolonged survival time of nude mice transplanted with human PBMCs when compared with that of control IgG-treated animals (61.2 +/- 4.46 vs. 22.1 +/- 5.5 days), which is associated with inhibited GVHR characterized by decreased interleukin-1 and tumor necrosis factor alpha production derived from transplanted PBMCs. Human-TfR chimeric antibody such as D2C could be a valuable option for the treatment of acute form of graft-versus host disease. PMID- 20840667 TI - Methylation profiles of hereditary and sporadic ovarian cancer. AB - AIMS: Tumour suppressor gene silencing through promoter hypermethylation plays an important role in oncogenesis. Carcinogenesis of hereditary cancers usually differs from that of their sporadic counterparts, but methylation has hardly been studied in hereditary ovarian cancer. The aim of this study was to investigate promoter methylation of a set of common tumour suppressor genes in BRCA1-related ovarian cancer in comparison with sporadic ovarian cancer. METHODS AND RESULTS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess the extent of promoter methylation of 24 different tumour suppressor genes in BRCA1-associated (n = 25) and matched sporadic ovarian tumours (n = 50). A cumulative methylation index (CMI) was calculated and differences between individual genes were analysed. There was no significant difference in cumulative methylation between BRCA1-associated and sporadic ovarian carcinomas (median CMI 108; CMI 110; P = 0.86). Also, methylation patterns of individual genes did not show distinct differences after correction for multiple comparisons. CDH13, GSTP1 and RASSF1 were frequently methylated in both sporadic and hereditary ovarian cancers. BRCA1 methylation occurred in 14% of sporadic tumours, but was not detected in BRCA1-associated tumours. CONCLUSIONS: CDH13, GSTP1 and RASSF1 are frequently methylated in both sporadic and BRCA1-associated ovarian cancers. Interestingly, methylation of BRCA1, while frequent in sporadic ovarian cancer, never occurred in the hereditary group. BRCA1-associated ovarian cancers mimic their sporadic counterparts in extent and pattern of promoter methylation of several common tumour suppressor genes. This finding could have implications for future chemotherapy regimens based on epigenetic changes. PMID- 20840664 TI - Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. AB - OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47.6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men. PMID- 20840668 TI - YKL-40 and mast cells are associated with detrusor fibrosis in patients diagnosed with bladder pain syndrome/interstitial cystitis according to the 2008 criteria of the European Society for the Study of Interstitial Cystitis. AB - AIMS: Bladder pain syndrome/interstitial cystitis (BPS/IC), diagnosed according to the new 2008 criteria of the European Society for the Study of Interstitial Cystitis (ESSIC), may lead to detrusor fibrosis. In some inflammatory diseases, fibrosis is related to YKL-40. The aims were to examine YKL-40 antigenic expression in bladder tissue and levels in serum and urine in BPS/IC and to evaluate whether YKL-40 could be a non-invasive, prognostic biomarker for bladder fibrogenesis and treatment intensity. METHODS AND RESULTS: Immunohistochemistry, immunoelectron microscopy and enzyme-linked immunosorbent assay (ELISA) analyses in 45 patients showed YKL-40 expression in detrusor mast cell granules and submucosal macrophages, and elevated YKL-40 levels in serum and urine compared to healthy individuals (median 72 versus 7 MUg/l, P < 0.001). Clinicopathological parameters showed associations of detrusor fibrosis with YKL-40-positive cells (P = 0.001), mast cells (P = 0.014) and urine YKL-40 (P = 0.009). Bladder capacity correlated inversely with YKL-40-positive cells (P < 0.001) and mast cells (P = 0.029). Treatment intensity was not associated with YKL-40. CONCLUSION: Serum and urine levels of YKL-40 may be used as non-invasive biomarkers in BPS/IC for the evaluation of bladder fibrogenesis. PMID- 20840669 TI - Overexpression of aldo-keto reductase 1C2 is associated with disease progression in patients with prostatic cancer. AB - AIMS: Prostatic cancer is resistant to chemotherapy. Expression of aldo-keto reductase 1C (AKR1C) has been associated with drug resistance and disease progression in several cancers. The aim was to investigate the relationship between AKR1C expression and disease progression in prostatic cancer. METHODS AND RESULTS: From January 1996 to December 2005, 86 pathological samples were collected from patients with prostatic cancer. A tissue microarray containing 31 prostatic cancers from American patients was used for comparison between Chinese and American patients. Using immunohistochemistry, aldo-keto reductase family 1, member C2 (AKR1C2) expression was assessed in tissue sections. The AKR1C2 was determined by two-dimensional immunoblotting and DNA sequencing of reverse transcriptase-polymerase chain reaction products. The relationship between AKR1C2 expression and clinicopathological variables was statistically analysed. In vitro, the association between AKR1C2 expression and drug resistance was investigated in androgen-sensitive and androgen-insensitive prostatic cancer cells. DNA sequencing and two-dimensional immunoblotting showed that prostatic cancer expressed AKR1C2. It was overexpressed in 77 of 86 (89.5%) Chinese and in 28 of 31 (90.3%) American samples. No difference was found in AKR1C2 expression between Chinese and American prostatic cancer patients. In vitro, increased expression of AKR1C2 and prostaglandin F2alpha correlated with cytoprotection against anticancer drugs and lycopene. CONCLUSION: Overexpression of AKR1C2 is associated with disease progression in prostatic cancer. PMID- 20840670 TI - Human salivary gland morphogenesis: myoepithelial cell maturation assessed by immunohistochemical markers. AB - AIMS: Myoepithelial cells are important components of salivary gland structure, aiding the expulsion of saliva from acinar lobules. The aim was to evaluate the expression of smooth muscle actin (SMA), calponin, caldesmon, CD10, CD29, S100 protein, glial fibrillary acidic protein (GFAP) and p63 in myoepithelial cells during salivary gland morphogenesis to understand the maturation process of these cells and their possible use in the diagnosis of salivary gland lesions. METHODS AND RESULTS: Major and minor human salivary glands at various stages of development, derived from fetuses at 8-26 weeks of gestation, were studied immunohistochemically. Fully developed salivary glands were used as controls. The protein p63 was present in all stages of salivary gland morphogenesis from initial bud to terminal bud stage. CD29, S100 and calponin were detected increasingly as salivary gland structure matured and in fully developed salivary gland. Proteins GFAP, CD10 and caldesmon were not observed in myoepithelial cells of salivary glands. CONCLUSIONS: The proteins SMA, calponin, CD29, S100 and p63, which are present from the earliest stages of salivary gland maturation, are valuable myoepithelial markers but, although very specific, are not exclusive markers for this cell type. PMID- 20840671 TI - Homogeneous EGFR amplification defines a subset of aggressive Barrett's adenocarcinomas with poor prognosis. AB - AIMS: The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) involved in the tumour progression of many cancer types and may serve as an important therapeutic target (erlotinib, cetuximab). Heterogeneity of EGFR amplification and expression could represent a major drawback for anti-EGFR therapy. The aim of this study was performed to determine the potential impact of tumour heterogeneity on anti-EGFR therapy in Barrett's adenocarcinoma (BAC). METHODS AND RESULTS: Tissue microarray (TMA) sections of 112 BAC and 45 lymph node metastases were analysed for EGFR amplification and expression using fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). A subset of 20 samples was also sequenced for EGFR exons 18-21 and Kirsten rat sarcoma viral oncogene homologue (KRAS) exons 2-3 mutations. EGFR amplification was seen in seven (6.25%) of 112 interpretable BAC and typically high-level with more than 10-20 EGFR copies per tumour cell (EGFR/centromere 7 ratio >3). EGFR amplification was associated with high pT, pN and poor prognosis (P = 0.0004). Identical EGFR amplification status was found in 29 primary tumours and 29 matched lymph node metastases. Moreover, FISH analysis of three to 16 large sections from all amplified BAC and corresponding lymph node metastases did not reveal any heterogeneity of EGFR amplification. No EGFR mutation but one KRAS mutation was found. CONCLUSION: The high level and homogeneity of EGFR amplification in primary tumours and metastases suggests the potential therapeutic utility of anti-EGFR drugs in BAC. PMID- 20840672 TI - Connective tissue growth factor expression is increased in collagenous colitis and coeliac disease. AB - AIMS: Subepithelial collagen deposition is a classical feature of collagenous colitis (CC), but is also seen in untreated coeliac disease. The end-stage mediator of excess cellular collagen production is connective tissue growth factor (CTGF). The aim of this study was to investigate CTGF expression by in situ hybridization (ISH) and polymerase chain reaction (PCR) in CC and coeliac disease as well as lymphocytic colitis (LC), Crohn's colitis and ulcerative colitis (UC). METHODS AND RESULTS: For coeliac disease we analysed fresh frozen material by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and archival material for ISH. PCR transcripts in coeliac disease were moderately elevated and labelled cells were significantly increased in the subepithelial zone. For CC, LC and UC we investigated archival material because of the rarity of the first two conditions. There was a marked increase in CTGF expression in the subepithelial zone in CC, localizing to cells with the morphology of smooth muscle cells, which was not seen in LC. CONCLUSIONS: The colocalization of CTGF transcripts with areas of excessive collagen deposition in coeliac disease and CC suggest that it might be the end-stage mediator of local fibrosis in these conditions. PMID- 20840673 TI - Quantitative determination of the diagnostic accuracy of the synovitis score and its components. AB - AIMS: To assess the diagnostic accuracy of a three-component synovitis score and to determine the relative contribution of each of its components to its overall discriminatory power. METHODS AND RESULTS: The synovitis score was determined in 666 synovial specimens: normal synovium, n = 33; post-traumatic arthropathy (PtA), n = 29; osteoarthritis (OA), n = 221; psoriatic arthritis (PsA), n = 42; and rheumatoid arthritis (RA), n = 341. The discriminatory abilities of the score and its components were quantified with binary and multicategory receiver operating characteristic (ROC) analysis. The score differentiated all arthropathies accurately from normal tissue (area under the ROC curve, AUC: 0.87 0.98) and RA from OA or PtA (AUC: 0.85 for both), but could not distinguish well within pairs of inflammatory or degenerative arthropathies. AUCs of the intimal hyperplasia and stromal cellularity components correlated with the AUCs of the complete score markedly more strongly (r = 0.94 and 0.91, respectively) than the inflammatory infiltration component (r = 0.60). Multicategory ROC analysis ranked the score several-fold higher than any of its components, and the components in the order stromal cellularity>intimal hyperplasia>infiltration. CONCLUSION: Combining three distinct histological parameters into a three-component score produces greatly increased overall diagnostic power. The discriminatory ability of the score stems more from measuring proliferative than infiltrative aspects of synovitis. PMID- 20840674 TI - RET rearrangements and BRAF mutation in undifferentiated thyroid carcinomas having papillary carcinoma components. AB - AIMS: To elucidate the genetic background of anaplastic transformation, RET rearrangements and BRAF mutation were studied in composite undifferentiated carcinomas (UCs) of the thyroid, which are UCs having papillary carcinoma (PC) components. METHODS AND RESULTS: Reverse transcription-polymerase chain reaction (RT-PCR) was performed for RET rearrangements and PCR for BRAF mutation in UC and PC components that were microdissected separately from seven composite UCs. Forty two thyroid cancers with single component histology (14 UCs and 28 PCs) were also studied in the same manner. RET/PTC1 was undetectable in both components from all seven composite UCs, and RET/PTC3 was identified in both components of one composite UC. BRAF mutation was identified in both components from three composite UCs and only in the PC components from two composite UCs. In contrast, in thyroid carcinomas with single component histology, RET/PTC1 was detected in 11% of PCs and in none of the UCs, and RET/PTC3 was not found in any of the tumours studied. BRAF mutation was identified in 82% of PCs and in 21% of UCs. CONCLUSIONS: The high frequency of BRAF mutation and the absence of RET rearrangements in UC components from composite UCs supports the hypothesis that UCs may actually represent progressive malignant degeneration of a BRAF-mutated, well-differentiated thyroid carcinoma. PMID- 20840675 TI - Prognostic relevance of tumour cell-associated uPAR expression in invasive ductal breast carcinoma. AB - AIMS: The urokinase-type plasminogen activator receptor (uPAR) is a key molecule for pericellular proteolysis in tumour cell invasion and metastasis. The aim was to evaluate the prognostic impact of uPAR in invasive breast cancer dependent on which cell types within the tumour express uPAR. METHODS AND RESULTS: uPAR expression was analysed by immunohistochemistry in 270 tumour tissue specimens of invasive ductal breast carcinomas using tissue microarrays. For evaluation of uPAR immunoexpression we used the epitope-mapped, uPAR domain II-specific monoclonal antibody IID7. High uPAR score values in both tumour cells (uPAR-Tc) and stromal cells were significantly related to high tumour grade (G3), and inversely correlated with oestrogen receptor status. On multivariate analysis, high uPAR-Tc values contributed independent prognostic information for disease free survival (hazard ratio 1.93, P = 0.007) when adjusted for prognostically relevant clinicopathological parameters, whereas uPAR expression in stromal cells was not related to prognosis. In addition, elevated uPAR-Tc values were found to be prognostic indicators in clinically relevant subgroups of patients with invasive breast cancer. CONCLUSIONS: In invasive breast cancer uPAR expression in invasive carcinoma cells, but not in stromal cells, has a significant impact on patients' prognosis, and contributes to a more aggressive tumour phenotype. PMID- 20840676 TI - Expression and clinicopathological significance of human growth and transformation-dependent protein (HGTD-P) in uterine cervical cancer. PMID- 20840677 TI - Mutational analysis of E-cadherin, beta-catenin and APC genes in synovial sarcomas. PMID- 20840678 TI - Mixed adenoma-endocrine tumour of the stomach. PMID- 20840679 TI - Positioning patient counselling as a measurable cornerstone of medication therapy management. PMID- 20840680 TI - Non-adherence to antihypertensive medication and impaired cognition: which comes first? AB - OBJECTIVE: Antihypertensive medications are important in the prevention of serious consequences of hypertension, such as stroke and heart failure. Up to one third of elderly hypertensive patients, however, do not adhere to their medication. Adherence to medication decreases with increasing age, and with decreasing cognitive ability, thus elderly, cognitively-impaired patients have poorer control of blood pressure. Good control of blood pressure is associated with decreased prevalence of dementia and Alzheimer's disease. This study assessed the evidence that antihypertensive medications have effects on the prevalence or severity of mild cognitive impairment, dementia or Alzheimer's disease. METHODS: The ISI Web of Knowledge database was searched; including replicates, the nine searches identified 14400 publications since 1952, of which 9.9% had been published in 2009. This review considers the 18 studies meeting the set criteria published in 2009 or later. KEY FINDINGS: Not all antihypertensive medications are equivalent in their positive cognitive effects, with brain penetrating angiotensin-converting-enzyme inhibitors and possibly angiotensin receptor antagonists being the most effective. CONCLUSIONS: Based on evidence of blood-pressure control and cost, UK National Institute for Health and Clinical Excellence guidelines recommend calcium-channel blockers or thiazide-type diuretics for the treatment of hypertension in patients over 55 years. These guidelines take no account of the potential cognitive effects of the antihypertensive therapies, consideration of which might lead to a review. There may be benefit in stressing that adherence to antihypertensive medication not only decreases the risk of cardiovascular disease and death, but may also decrease the risk or severity of mild cognitive impairment, dementia and Alzheimer's disease. PMID- 20840681 TI - Eleven themes of patient-centred professionalism in community pharmacy: innovative approaches to consulting. AB - OBJECTIVES: The study aimed to clarify patient-centred professionalism within and across community pharmacy settings; position that knowledge in a modern-day environment, accessing the opinions and experiences of patients and professionals; inform the literature on the value of consultation workshops within this context; and develop a template of positive and challenging exemplars of patient-centred professionalism within these contexts. METHODS: Thirty-nine study participants contributed to extended consultation workshops. Sessions were supported by bio-photographic data of healthcare practices across a range of different settings, and a final forum event. KEY FINDINGS: Thematic analysis of qualitative data, supported by the Nominal Group Work technique, led to a template containing 11 themes of positive and challenging aspects of patient centred professionalism: safety, professional characteristics, relationships with patients, confidentiality and privacy, accessibility, training, professional pressures, services, environment, changing professional roles and patient characteristics. Themes, while descriptive and rich, highlight difficulties in defining this notion, which is both nuanced and ambiguous. While study participants were interested in the everyday examples of practice and interaction, they were strongly influenced by their different agendas and experiences. Patients, for example, wanted a quick and efficient dispensing service, where their needs and expectations came first. Pharmacists, on the other hand, found that pressing patient demands and overarching company policies led to professional anxiety that distracted them from what they perceived to be the defining aspect of their professionalism, dispensary work. CONCLUSIONS: The study outcomes indicate, in line with international literature, that while proud of supporting patients, many pharmacists feel demoralised, torn between pressing public and professional demands and the expectations of advice-giving in unfamiliar, formal situations within nondescript, corporate workspaces. PMID- 20840682 TI - Prescribing and sale of ophthalmic chloramphenicol following reclassification to over-the-counter availability. AB - OBJECTIVES: The impact of over-the-counter (OTC) availability of chloramphenicol eye drops and eye ointment was investigated on the prescribing and overall supply of ophthalmic chloramphenicol in primary care. METHODS: Primary care prescription data for ophthalmic chloramphenicol and ophthalmic antibacterials in England and Wales were analysed from December 2003 (month 1) to September 2008 (month 58). OTC data were analysed from June 2005 when the first OTC product was launched (months 19 to 58). KEY FINDINGS: In the 40 months following reclassification more than 2.9 million packs (53.9 per 1000 population) of chloramphenicol were sold in England and 152024 (51.7 per 1000 population) in Wales. In the 12 months to September 2008 sales of the drops and ointment were 67 and 40% of their respective prescription volumes in England. In Wales sales of drops were 52% and ointment 26% of their respective prescription volumes. The number of chloramphenicol packs sold was 2.2 times greater than the calculated reduction in ophthalmic antibacterial prescription items in England and 2.9 times greater than the reduction seen in Wales. CONCLUSION: Following the reclassification of chloramphenicol there have been significant increases in the supply of the ophthalmic antibacterials in both England and Wales. PMID- 20840683 TI - Discussing side effects of over-the-counter medicines: impact of adding percentage data. AB - OBJECTIVES: Discussing side effects with patients continues to be a difficult area of practice. Questions arise as to how many should be mentioned and which ones. The way such information is presented can affect drug-taking decisions. This study examined how over-the-counter (OTC) medicine users are influenced by numerical risk estimates of side effects. METHODS: As part of a larger study on patient decision-making, 30 participants aged over 50 years were asked to consider three OTC headache medicines. They responded to one of two headache scenarios, one with symptoms described as mild but common and the other severe but rare. Participants made their selection based on drug efficacy and side effects, at first not linked to occurrence rates and then with this information provided. KEY FINDINGS: Average age was 66.6 years and the majority were female. Most were currently using some form of drug therapy. Drug choices differed in relation to mild versus severe headache scenarios. A stronger preference for drug X (50% effective and two side effects) was evident when the headaches were mild, shifting to a more effective agent (but with more side effects) when more severe. Addition of occurrence rates to the side effects had the greatest effect within the severe headache scenario, where more participants opted for the most effective agent (drug Z at 100% effective but six side effects) upon seeing the numbers. Overall, however, most kept the same drug in spite of the numerical information. CONCLUSIONS: Inclusion of numerical data for side effects did not negatively influence potential OTC medicine users. For most, effectiveness and side effects were the concern before receiving the percentages, while effectiveness became more important when the frequency data seemed to instil a sense of reassurance. PMID- 20840685 TI - Estimating problem drinking among community pharmacy customers: what did pharmacists think of the method? AB - OBJECTIVES: Community pharmacists have successfully been involved in brief interventions in many areas of health, and also provide services to substance misusers. There has been recent interest in community pharmacists providing screening and brief interventions (SBI) to problem drinkers. The aim of this study was to develop a method for measuring prevalence of risky drinking among community pharmacy customers and to explore acceptability of this method to participating pharmacists. METHODS: Forty-three pharmacies (from 80 randomly selected) in New Zealand agreed to participate in data collection. On a set, single, randomly allocated day during one week, pharmacies handed out questionnaires about alcohol consumption, and views on pharmacists providing SBI, to their customers. At the end of the data collection period semi-structured telephone interviews were carried out with participating pharmacists. KEY FINDINGS: Pharmacists were generally positive about the way the study was carried out, the support and materials they were provided with, and the ease of the data collection process. They reported few problems with customers and the majority of pharmacists would participate again. CONCLUSIONS: The method developed successfully collected data from customers and was acceptable to participating pharmacists. This method can be adapted to collecting data on prevalence of other behaviours or medical conditions and assessing customer views on services. PMID- 20840684 TI - How do patients read, understand and use prescription labels? An exploratory study examining patient and pharmacist perspectives. AB - OBJECTIVES: The aim of the study was to investigate ease of reading, understanding and usefulness of prescription labels in a real-world setting from patients' and pharmacists' perspectives. METHODS: A prospective, cross-sectional, exploratory study was conducted by interviewing 179 patients and 40 pharmacists in selected community pharmacies. KEY FINDINGS: The average age of patients was 55 years, 65% were females, and 56.4% had a high-school education or more. Pharmacists' mean age was 40.4 years with 12.8 years of experience. Self-reported ease of reading and understanding was rated as very or somewhat easy by 97.8 and 97.2%, respectively. Most of the patients correctly read (91.6%) and interpreted (89.4%) the label. A majority (90.5%) of patients found the label somewhat or very useful. About half of the pharmacist sample believed patients had difficulty reading or understanding the labels. CONCLUSIONS: This study, conducted with a sample that approximated the US population in level of education, found that prescription labels were reported to be useful and easy to read and understand. These results deviated from previous studies that were conducted in specific populations. Current prescription labels are useful and easy to read and understand by those who have college or higher education but improvements may be needed for specific vulnerable populations. PMID- 20840686 TI - Drug-related problems at discharge: results on the Spanish pharmacy discharge programme CONSULTENOS. AB - OBJECTIVES: The aim of this study was to describe the most common drug-related problems (DRPs) found after discharge, pharmacist interventions and their results for the patients enrolled on the CONSULTENOS programme. METHODS: An observational, prospective, multicentre study was conducted to evaluate the results of a pharmaceutical care programme at discharge. Patients from 10 hospitals participating in the CONSULTENOS programme were enrolled. Pharmacists conducting this programme were newly graduated and worked under the supervision of a pharmacy staff member; only two pharmacists had previous hospital pharmacy experience. DRPs were identified and classified according to the Iaser methodology. Frequencies, types of DRP, interventions and outcomes were registered prospectively, at discharge and during a follow-up call 7 days after leaving the hospital. KEY FINDINGS: A total of 7711 patients were included in the study. DRPs were detected in 23.7% of the patients, with a total of 2120 DRPs (1788 at discharge and 332 in the follow-up). The most common problems identified at discharge were twofold: firstly the need of an additional treatment (34.1%) and secondly an unnecessary treatment (18.1%). In the follow-up phone call the most frequent DRPs were adverse effects (29.2%). Besides the standard educational interventions at discharge, 3313 extra interventions were performed, of which 85% were accepted. The outcomes for the patients were positive in 80% of the cases, although documentation with objective or subjective data was rare. CONCLUSIONS: DRPs occur frequently after patient discharge. A pharmaceutical care programme can identify and solve DRPs in this scenario. The clinical impact of the pharmacists' interventions should be better addressed. PMID- 20840687 TI - Testing a trigger tool as a method of detecting harm from medication errors in a UK hospital: a pilot study. AB - OBJECTIVES: The aim was to adapt a US adverse drug event (ADE) trigger tool for UK use, and to establish its positive predictive value (PPV) and sensitivity in comparison to retrospective health record review for the identification of preventable ADEs, in a pilot study on one hospital ward. METHODS: An established US trigger tool was adapted for UK use. We applied it retrospectively to 207 patients' health records, following up positive triggers to identify any ADEs (both preventable and non-preventable). We compared the preventable ADEs to those identified using full health record review. KEY FINDINGS: We identified 168 positive triggers in 127 (61%) of 207 patients. Seven ADEs were identified, representing an ADE in 3.4% of patients or 0.7 ADEs per 100 patient days. Five were non-preventable adverse drug reactions and two were due to preventable errors. The prevalence of preventable ADEs was 1.0% of patients, or 0.2 per 100 patient days. The overall PPV was 0.04 for all ADEs, and 0.01 for preventable ADEs. PPVs for individual triggers varied widely. Five preventable ADEs were identified using health record review. The sensitivity of the trigger tool for identifying preventable ADEs was 0.40, when compared to health record review. CONCLUSIONS: Although we identified some ADEs using the trigger tool, more work is needed to further refine the trigger tool to reduce the false positives and increase sensitivity. To comprehensively identify preventable ADEs, retrospective health record review remains the gold standard and we found no efficiency gain in using the trigger tool. PMID- 20840688 TI - Exploring pharmacists' perceptions of the feasibility and value of pharmacist prescribing of antimicrobials in secondary care in Scotland. AB - OBJECTIVES: The introduction of non-medical prescribing in the UK has provided opportunities and challenges for pharmacists to help ensure prudent use of antimicrobials. The objective of this research was to explore pharmacists' perceptions of the feasibility and value of pharmacist prescribing of antimicrobials in secondary care in Scotland. METHODS: Pharmacists' perceptions were explored using focus groups in five Scottish regions representing (a) urban and rural areas and (b) district general hospitals and large teaching centres. Senior hospital pharmacists, both prescribers and non-prescribers, working in specialities where antimicrobials are crucial to patient management, were invited to participate. A topic guide was developed to lead the discussions, which were audio-recorded and transcribed. The framework approach to data analysis was used. KEY FINDINGS: Six focus groups took place and some emerging themes and issues are presented. Pharmacists believed that the feasibility of antimicrobial prescribing is dependent upon the patient's clinical condition and the area of clinical care. They identified potential roles and opportunities for pharmacist prescribing of antimicrobials. Perceived benefits included giving patients quicker access to medicines, reducing risk of resistance and better application of evidence-based medicine. CONCLUSIONS: Pharmacists feel they have a good knowledge base to prescribe and manage antimicrobial treatment, identifying possible opportunities for intervention. Roles within a multidisciplinary antimicrobial team need to be clearly defined. PMID- 20840689 TI - Periodontal infection and preterm birth: successful periodontal therapy reduces the risk of preterm birth. AB - OBJECTIVE: This study tested the hypothesis that successful periodontal treatment was associated with a reduction in the incidence of spontaneous preterm birth (PTB). DESIGN: This was a randomised, controlled, blinded clinical trial. SETTING: Hospital outpatient clinic. POPULATION: Pregnant women of 6-20 weeks of gestation were eligible. METHODS: Of 322 pregnant women with periodontal disease, 160 were randomly assigned to receive scaling and root planing (SRP, cleaning above and below the gum line), plus oral hygiene instruction, whereas the remaining 162 received only oral hygiene instruction and served as an untreated control group. Subjects received periodontal examinations before and 20 weeks after SRP, and were classified blindly according to the results of treatment into two groups: successful ('non-exposure') and unsuccessful ('exposure') treatment. Groups were compared using standard inferential statistics; dichotomous variables were compared using the chi-square test or logistic regression. Results are presented in terms of odds ratios. MAIN OUTCOME MEASURE: The main outcome measure was spontaneous preterm birth before 35 weeks of gestation. RESULTS: No significant difference was found between the incidence of PTB in the control group (52.4%; n = 162) and the periodontal treatment group (45.6%; n = 160) (P < 0.13, Fisher's exact test). The incidence of PTB was compared within the periodontal treatment group, considering the success of therapy. A logistic regression analysis showed a strong and significant relationship between successful periodontal treatment and full-term birth (adjusted odds ratio 6.02; 95% CI 2.57-14.03). Subjects refractory to periodontal treatment were significantly more likely to have PTB. CONCLUSIONS: A beneficial effect on PTB may be dependent on the success of periodontal treatment. PMID- 20840691 TI - Interventions during pregnancy to reduce excessive gestational weight gain: a systematic review assessing current clinical evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. AB - BACKGROUND: Excessive weight gain during pregnancy is common in developed countries and increases the risk of complications during pregnancy, delivery and the postpartum period, which can affect both maternal and fetal outcome. Interventions to reduce excessive gestational weight gain have previously not been systematically evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. OBJECTIVES: To determine whether published trials of interventions to reduce excessive gestational weight gain are of sufficient quality and provide sufficient data to enable evidence-based recommendations to be developed for clinical practice in antenatal care. SEARCH STRATEGY: A literature search was conducted in the scientific databases PubMed, Cochrane Library, Cinhal and Pedro, and the reference lists of relevant articles were reviewed. The literature search was concluded on 15 August 2009. SELECTION CRITERIA: All randomised controlled trials (RCTs) were considered for inclusion. As the number of published RCTs was limited, we also considered for inclusion all nonrandomised intervention studies that included a control group. Systematic reviews were examined to identify additional original studies. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the methods and results of all included articles. Extracted data were classified using the GRADE system. MAIN RESULTS: Four intervention studies with a randomised controlled design and four intervention trials with a nonrandomised controlled design met the inclusion criteria. As a consequence of important limitations in study design, inconsistency and lack of directness, the overall quality of evidence was judged to be very low using the GRADE system. AUTHORS' CONCLUSIONS: The results of published intervention trials are of insufficient quality to enable evidence-based recommendations to be developed for clinical practice in antenatal care. PMID- 20840692 TI - Caesarean section surgical techniques: a randomised factorial trial (CAESAR). AB - OBJECTIVE: In women undergoing delivery by caesarean section, do the following alternative surgical techniques affect the risk of adverse outcomes: single- versus double-layer closure of the uterine incision; closure versus nonclosure of the pelvic peritoneum; liberal versus restricted use of a subrectus sheath drain? DESIGN: Pragmatic, 2 * 2 * 2 factorial randomised controlled trial. SETTING: Hospitals in the UK and Italy providing intrapartum care. POPULATION: Women undergoing their first caesarean section. METHODS: The interventions were alternative approaches to the three aspects of the caesarean section operation. A telephone randomisation service was used. Surgeons could not be masked to allocation, but women were unaware of which allocations had been used. The analysis was by intention-to-treat, with a prespecified subgroup analysis for women 'in labour' or 'not in labour' at the time of caesarean section. MAIN OUTCOME MEASURES: Maternal infectious morbidity. RESULTS: A total of 3033 women were recruited. Overall, the risk of maternal infectious morbidity was 17%. For each pair of interventions, there were no differences between the arms of the trial for the primary outcome: single- versus double-layer closure of the uterine incision [relative risk (RR) = 1.00, 95% confidence interval (95% CI) = 0.85 1.18]; closure versus nonclosure of the pelvic peritoneum (RR = 0.92, 95% CI = 0.78-1.08); liberal versus restricted use of a subrectus sheath drain (RR = 0.92, 95% CI = 0.78-1.09). There were no differences in any of the secondary morbidity outcomes and no significant adverse effects of any of the techniques used. CONCLUSIONS: These results have implications for clinical practice, particularly in relation to current guidance on the closure of the peritoneum, which suggests that nonclosure is preferable. The potential effects of these different surgical techniques on longer term outcomes, including the functional integrity of the uterine scar during subsequent pregnancies, are now becoming increasingly important for guiding clinical practice. PMID- 20840693 TI - First-trimester placental protein 13 and placental growth factor: markers for identification of women destined to develop early-onset pre-eclampsia. AB - OBJECTIVE: To investigate the predictive value of maternal serum pregnancy associated plasma protein A (PAPP-A), free beta subunit of human chorionic gonadotrophin (fbeta-hCG), placental protein 13 (PP13), placental growth factor (PlGF) and a desintegrin and metalloproteinase 12 (ADAM12), for first-trimester identification of early-onset pre-eclampsia. DESIGN: Nested case-control study. SETTING: Routine first-trimester screening for trisomy 21 in the Netherlands. POPULATION: Eighty-eight women who developed pre-eclampsia or haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome before 34 weeks of gestation and 480 controls. METHODS: PP13, PlGF and ADAM12 were measured in stored first-trimester serum, previously tested for PAPP-A and fbeta-hCG. All marker levels were expressed in multiples of the gestation-specific normal median (MoMs). Model predicted detection rates for fixed false-positive rates were obtained for statistically significant markers alone and in combination. MAIN OUTCOME MEASURES: Development of pre-eclampsia or HELLP syndrome. RESULTS: PP13 and PlGF were reduced in women with pre-eclampsia, with medians 0.68 MoM and 0.73 MoM respectively (P < 0.0001 for both). PAPP-A was reduced (median 0.82 MoM, P < 0.02) whereas ADAM12 and fbeta-hCG did not differ between control women and those with pre-eclampsia. In pre-eclampsia complicated by a small-for-gestational age fetus, all markers except fbeta-hCG had lower values, compared with pregnancies involving fetuses of normal weight. The model-predicted pre-eclampsia detection rate for a combination of PP13 and PlGF was 44% and 54%, respectively, for a fixed 5% and 10% false-positive rate. CONCLUSION: This study demonstrates that PP13 and PlGF in the first-trimester might be promising markers in risk assessment for early pre-eclampsia/HELLP syndrome but for an adequate screening test additional characteristics are necessary. PMID- 20840694 TI - Can vaginal birth after caesarean be justified? PMID- 20840696 TI - Changing trends: uterine rupture in the UK. PMID- 20840699 TI - Uterine artery Doppler and low-dose aspirin to predict and prevent preeclampsia. PMID- 20840700 TI - A series of 400 laparoscopic hysterectomies for benign disease: a single center, single surgeon prospective study of complications confirming previous retrospective study. PMID- 20840703 TI - Increased risk of low birthweight and small for gestational age infants among women with tuberculosis. PMID- 20840707 TI - Credentials, skills, and recognition. PMID- 20840708 TI - Psychological and physical abuse among pregnant women in a Medicaid-sponsored prenatal program. AB - OBJECTIVES: To document psychological and physical abuse during pregnancy among women enrolled in enhanced prenatal services (EPS); explore the associations between maternal risk factors and type of abuse; and examine the relationship between abuse and EPS participation. DESIGN AND SAMPLE: Cross-sectional study utilizing screening data collected between 2005 and 2008. Convenience sample of Medicaid-insured pregnant women enrolled in EPS selected from urban and rural providers. MEASURES: A prenatal screening tool that included measures such as Cohen's Perceived Stress Scale-4, Patient Health Questionnaire-2, and Abuse Assessment Screen was used. RESULTS: Logistic regressions showed that high perceived stress and lack of father support were associated with all types of abuse and abuse history. Women with risk factors, such as a positive depression screen (odds ratio [OR]=2.36), were associated with psychological abuse but not with physical abuse during pregnancy. Less than a 12th-grade education was associated with physical abuse (OR=1.64) but not psychological abuse during pregnancy. The amount or the timing of EPS participation was not significantly associated with abuse history or abuse during pregnancy. CONCLUSIONS: Risk factors, such as high perceived stress and lack of father support, may alert nurses to further explore abuse during pregnancy. Additional research is needed for understanding the relationship between abuse and EPS participation. PMID- 20840710 TI - Low-income African American and non-Hispanic White mothers' self-efficacy, "picky eater" perception, and toddler fruit and vegetable consumption. AB - OBJECTIVES: To examine whether and how toddlers' vegetable and fruit consumption is associated with maternal vegetable and fruit consumption, mothers' perceptions of toddlers as "picky eaters," maternal efficacy, and sociodemographic characteristics of the family. DESIGN AND SAMPLE: A cross-sectional survey. One hundred and ninety-nine African American and 200 Non-Hispanic White low-income, mother-toddler dyads enrolled in 8 Early Head Start programs in a Midwestern state. MEASURES: Mothers completed the Feeding Self-Efficacy Scale, Toddler Parent Mealtime Behavior Questionnaire, and Mothers' and Toddlers' Food Frequency Questionnaires. Data were analyzed using linear and logistic regression models. RESULTS: Toddlers were less likely to consume vegetables 4 or more times a week if their mothers: viewed them as "picky eaters" (OR: 2.5), did not consume vegetables 4 or more times a week themselves (OR: 10.1), and were African American (OR: 2.2). Toddlers were less likely to consume fruits 4 or more times a week if their mothers: viewed them as "picky eaters" (OR: 1.6) and did not consume fruit 4 or more times a week (OR: 9.9) themselves. CONCLUSIONS: Health professionals need to consider mothers' own consumption of fruits and vegetables when developing strategies to increase toddler consumption of fruits and vegetables. PMID- 20840709 TI - Factors influencing mothers' abilities to engage in a comprehensive parenting intervention program. AB - OBJECTIVE: This research identified the possible factors influencing the ability of mothers perceived to be at the highest risk for child maltreatment to engage in a home visitation program. This study holds significance to public health nursing since home visitation is an integral component of public health nursing practice, with engagement being essential for human interaction and thus nursing care to occur. DESIGN AND SAMPLE: A qualitative descriptive design was used to offer a thematic summary of the experiences of program engagement from the perspective of 4 home visitation coach interventionists from health-related fields and a small sample of purposefully selected mothers involved in a longitudinal prevention study. RESULTS: Qualitative content analysis revealed 3 major themes related to engagement: (1) mothers struggle to meet the emotional needs of the self and the child; (2) mothers lack support in navigating complicated and stressful life events; and (3) mothers' consistency with program engagement is mediated through a trusting and caring relationship with coaches. CONCLUSIONS: Home visitation coaches in this study demonstrated a continuous process of engagement by supporting mothers to explore and discover self-care strategies and ways to navigate life struggles. Over time, a foundation of trust and caring was developed, which in turn increased relationship building and program engagement. PMID- 20840711 TI - What has changed about vaginal douching among African American mothers and daughters? AB - OBJECTIVES: To explore African American mothers' and daughters' practices and influences related to vaginal douching. DESIGN AND SAMPLE: Our overall study used a sequential mixed-method design with 3 phases. Phase 1, the focus of this report, used grounded theory methods and in-depth, semistructured individual interviews. Two generations of African American girls and women: 24 girls ("daughters") aged 14-18 and 17 women ("mothers" or "mother figures") aged 22-43, recruited from 1 adolescent health clinic in Baltimore, MD. MEASURES: In-depth interviews were taped and transcribed and data analysis used the constant comparison method. RESULTS: Daughters were much less likely to douche or to have been exposed to douching information than mothers. Many mothers and daughters were influenced by health care providers and/or family members to not initiate, to decrease, or to stop douching. Women who currently douche often do so because of the perception of improved smell and cleanliness around menstruation and sexual intercourse. CONCLUSIONS: These data indicate that although some women continue to believe that vaginal douching has therapeutic value, others have been influenced to stop or not start douching by family and health care providers. Health care providers should continue efforts to educate patients on the risks of vaginal douching. PMID- 20840712 TI - Reinvigorating performance evaluation: first steps in a local health department. AB - The ability of a local health department to assess and improve employee performance through an effective evaluation process is critical to overall organizational success. A constructive performance evaluation process not only provides meaningful feedback on work performance but also provides opportunities to reinforce work behaviors that support the organization's mission, to recognize exceptional work, and to guide future growth and learning. The Los Angeles County Department of Public Health is creating a new approach to performance evaluation that recognizes 3 distinct components of work performance: standard business practices, competencies, and standards of practice. This multidimensional perspective acknowledges that the expectations of workers are complex and that evaluations of performance are not easily captured with single-dimension assessment tools. This report describes the conceptual relationships of these 3 components and how they integrate to form a single performance evaluation process. Key elements within this structure include a base document of competencies for all workers, expanded competency sets for professional staff, role-specific duty statements for workers who perform similar work, and standards of competent practice related to the mission of units to which individuals are assigned. Key first steps are to define the terminology of performance evaluation and to create role-specific duty statements. PMID- 20840713 TI - Organizational attributes that assure optimal utilization of public health nurses. AB - Optimal utilization of public health nurses (PHNs) is important for strengthening public health capacity and sustaining interest in public health nursing in the face of a global nursing shortage. To gain an insight into the organizational attributes that support PHNs to work effectively, 23 focus groups were held with PHNs, managers, and policymakers in diverse regions and urban and rural/remote settings across Canada. Participants identified attributes at all levels of the public health system: government and system-level action, local organizational culture of their employers, and supportive management practices. Effective leadership emerged as a strong message throughout all levels. Other organizational attributes included valuing and promoting public health nursing; having a shared vision, goals, and planning; building partnerships and collaboration; demonstrating flexibility and creativity; and supporting ongoing learning and knowledge sharing. The results of this study highlight opportunities for fostering organizational development and leadership in public health, influencing policies and programs to optimize public health nursing services and resources, and supporting PHNs to realize the full scope of their competencies. PMID- 20840714 TI - Hospital nurse staffing and public health emergency preparedness: implications for policy. AB - Hospital restructuring policies and an impending nursing workforce shortage have threatened the nation's emergency preparedness. Current emergency response plans rely on sources of nurses that are limited and overestimated. A national investment in nursing education and workforce infrastructure, as well as incentives for hospitals to efficiently maximize nurse staffing, are needed to ensure emergency preparedness in the United States. This review highlights the challenges of maintaining hospital nursing surge capacity and policy implications of a nursing shortage. PMID- 20840715 TI - Health promotion and disease prevention among nurses working in local public health organizations in Montreal, Quebec. AB - OBJECTIVE: This study investigates conceptualizations of disease prevention and health promotion (DPHP) among nurses from local public health organizations in Montreal, Quebec. DESIGN AND SAMPLE: A collaborative qualitative study was conducted among a purposive sample of 41 nurses. MEASURES: Semi-structured interviews investigated two themes: meanings attributed to DPHP as well as nurses' recent DPHP activities. RESULTS: Although the meaning attributed to prevention referred to standard definitions, health promotion was often defined as large-scale health education oriented toward the attainment of positive results, such as health and well-being. Almost completely absent from participants' discourse were central notions such as empowerment and health determinants, including socioenvironmental dimensions of health. With regard to activity descriptions, there was a very partial coverage of the full spectrum of DPHP. Participants rarely went beyond traditional health education activities aimed at an individual target. Finally, a sizeable number of participants appeared to be unable to provide a clear distinction between the terms "health promotion" and "prevention." CONCLUSIONS: The results are consistent with a conclusion frequently drawn by commentators and researchers alike that highlight a narrow range of DPHP nursing practices. PMID- 20840716 TI - Challenges and opportunities associated with preceptored community health clinical experiences. AB - Preceptored community experiences present challenges different from those of preceptored experiences in the acute care setting. Instead of focusing on psychomotor skills, faculty must address population-based skills and assess students' abilities to practice these skills. Faculty and preceptors' lack of knowledge to teach these skills further complicate the experiences, an issue indirectly related to faculty and nursing shortages. Although preceptors guide students, faculty are responsible for evaluating students in community preceptored experiences. The Association of Community Health Nursing Educators (ACHNE) Essentials of Baccalaureate Education (Essentials) offers opportunities for guiding and evaluating community health preceptored clinical experiences. Assignments and activities that reflect the ACHNE Essentials provide a firm foundation for the population focus of the course. This focus is validated through faculty visits to students in a variety of community settings. To plan successful community experiences and evaluate students, faculty must be knowledgeable about the population focus of community courses, apply this knowledge to students in a variety of settings, and ask challenging questions to assess student learning. PMID- 20840718 TI - Abstracts of the 19th Annual Congress of the German Transplantation Society. Hamburg, Germany. October 7-9, 2010. PMID- 20840717 TI - How to develop exceptional ability in nurses. 1930. AB - This historical reprint from The Public Health Nurse, Volume 22, Number 11, published in November 1930, came from a speech presented at the National Organization for Public Health Nursing Round Table for Supervisors at the Biennial NOPHN convention in Milwaukee, Wisconsin, June 30, 1930. Ruth Telind was a supervisor with the Henry Street Visiting Nurse Service of New York. Her message about the orientation and development of staff nurses has relevance today. The work of visiting nurses has changed substantially, of course. The methods by which the aims of community education, recreation, health promotion, child welfare, and care for those who are chronically and acutely ill are accomplished today may seem far removed from the makeshift approaches of this Depression-era supervisor's experience. Nevertheless, the message that nurses have unique talents and interests that can be fostered to improve outcomes for the organization and to increase the satisfaction and retention of those nurses reminds supervisors, nurse educators, and executive directors of any nursing organization that the same principles apply 80 years later. PMID- 20840719 TI - Ghrelin receptor agonists: a new class of prokinetic agents. PMID- 20840720 TI - Assessment of microbial fermentation products in fecal samples. PMID- 20840722 TI - 7th international conference on conservative management of spinal deformities montreal, Canada. 20-22 may 2010. Abstracts. PMID- 20840721 TI - Role of microbial fermentation products in irritable bowel syndrome. PMID- 20840723 TI - Optimization meets systems biology. AB - A report of the 3rd International Symposium on Optimization and Systems Biology, 20-22 September 2009, Zhangjiajie, China. PMID- 20840724 TI - Determining modular organization of protein interaction networks by maximizing modularity density. AB - BACKGROUND: With ever increasing amount of available data on biological networks, modeling and understanding the structure of these large networks is an important problem with profound biological implications. Cellular functions and biochemical events are coordinately carried out by groups of proteins interacting each other in biological modules. Identifying of such modules in protein interaction networks is very important for understanding the structure and function of these fundamental cellular networks. Therefore, developing an effective computational method to uncover biological modules should be highly challenging and indispensable. RESULTS: The purpose of this study is to introduce a new quantitative measure modularity density into the field of biomolecular networks and develop new algorithms for detecting functional modules in protein-protein interaction (PPI) networks. Specifically, we adopt the simulated annealing (SA) to maximize the modularity density and evaluate its efficiency on simulated networks. In order to address the computational complexity of SA procedure, we devise a spectral method for optimizing the index and apply it to a yeast PPI network. CONCLUSIONS: Our analysis of detected modules by the present method suggests that most of these modules have well biological significance in context of protein complexes. Comparison with the MCL and the modularity based methods shows the efficiency of our method. PMID- 20840725 TI - Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer's disease brains. AB - BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder leading to amnesia, cognitive impairment and dementia in the elderly. Usually this type of lesions results from dysfunctional protein cooperations in the biological pathways. In addition, AD progression is known to occur in different brain regions with particular features. Thus identification and analysis of crosstalk among dysregulated pathways as well as identification of their clusters in various diseased brain regions are expected to provide deep insights into the pathogenetic mechanism. RESULTS: Here we propose a network-based systems biology approach to detect the crosstalks among AD related pathways, as well as their dysfunctions in the six brain regions of AD patients. Through constructing a network of pathways, the relationships among AD pathway and its neighbor pathways are systematically investigated and visually presented by their intersections. We found that the significance degree of pathways related to the fatal disorders and the pathway overlapping strength can indicate the impacts of these neighbored pathways to AD development. Furthermore, the crosstalks among pathways reveal some evidence that the neighbor pathways of AD pathway closely cooperate and play important tasks in the AD progression. CONCLUSIONS: Our study identifies the common and distinct features of the dysfunctional crosstalk of pathways in various AD brain regions. The global pathway crosstalk network and the clusters of relevant pathways of AD provide evidence of cooperativity among pathways for potential pathogenesis of the neuron complex disease. PMID- 20840726 TI - FGsub: Fusarium graminearum protein subcellular localizations predicted from primary structures. AB - BACKGROUND: The fungal pathogen Fusarium graminearum (telomorph Gibberella zeae) is the causal agent of several destructive crop diseases, where a set of genes usually work in concert to cause diseases to crops. To function appropriately, the F. graminearum proteins inside one cell should be assigned to different compartments, i.e. subcellular localizations. Therefore, the subcellular localizations of F. graminearum proteins can provide insights into protein functions and pathogenic mechanisms of this destructive pathogen fungus. Unfortunately, there are no subcellular localization information for F. graminearum proteins available now. Computational approaches provide an alternative way to predicting F. graminearum protein subcellular localizations due to the expensive and time-consuming biological experiments in lab. RESULTS: In this paper, we developed a novel predictor, namely FGsub, to predict F. graminearum protein subcellular localizations from the primary structures. First, a non-redundant fungi data set with subcellular localization annotation is collected from UniProtKB database and used as training set, where the subcellular locations are classified into 10 groups. Subsequently, Support Vector Machine (SVM) is trained on the training set and used to predict F. graminearum protein subcellular localizations for those proteins that do not have significant sequence similarity to those in training set. The performance of SVMs on training set with 10-fold cross-validation demonstrates the efficiency and effectiveness of the proposed method. In addition, for F. graminearum proteins that have significant sequence similarity to those in training set, BLAST is utilized to transfer annotations of homologous proteins to uncharacterized F. graminearum proteins so that the F. graminearum proteins are annotated more comprehensively. CONCLUSIONS: In this work, we present FGsub to predict F. graminearum protein subcellular localizations in a comprehensive manner. We make four fold contributions to this filed. First, we present a new algorithm to cope with imbalance problem that arises in protein subcellular localization prediction, which can solve imbalance problem and avoid false positive results. Second, we design an ensemble classifier which employs feature selection to further improve prediction accuracy. Third, we use BLAST to complement machine learning based methods, which enlarges our prediction coverage. Last and most important, we predict the subcellular localizations of 12786 F. graminearum proteins, which provide insights into protein functions and pathogenic mechanisms of this destructive pathogen fungus. PMID- 20840727 TI - Comparing biological networks via graph compression. AB - BACKGROUND: Comparison of various kinds of biological data is one of the main problems in bioinformatics and systems biology. Data compression methods have been applied to comparison of large sequence data and protein structure data. Since it is still difficult to compare global structures of large biological networks, it is reasonable to try to apply data compression methods to comparison of biological networks. In existing compression methods, the uniqueness of compression results is not guaranteed because there is some ambiguity in selection of overlapping edges. RESULTS: This paper proposes novel efficient methods, CompressEdge and CompressVertices, for comparing large biological networks. In the proposed methods, an original network structure is compressed by iteratively contracting identical edges and sets of connected edges. Then, the similarity of two networks is measured by a compression ratio of the concatenated networks. The proposed methods are applied to comparison of metabolic networks of several organisms, H. sapiens, M. musculus, A. thaliana, D. melanogaster, C. elegans, E. coli, S. cerevisiae, and B. subtilis, and are compared with an existing method. These results suggest that our methods can efficiently measure the similarities between metabolic networks. CONCLUSIONS: Our proposed algorithms, which compress node-labeled networks, are useful for measuring the similarity of large biological networks. PMID- 20840728 TI - On finite-horizon control of genetic regulatory networks with multiple hard constraints. AB - BACKGROUND: Probabilistic Boolean Networks (PBNs) provide a convenient tool for studying genetic regulatory networks. There are three major approaches to develop intervention strategies: (1) resetting the state of the PBN to a desirable initial state and letting the network evolve from there, (2) changing the steady state behavior of the genetic network by minimally altering the rule-based structure and (3) manipulating external control variables which alter the transition probabilities of the network and therefore desirably affects the dynamic evolution. Many literatures study various types of external control problems, with a common drawback of ignoring the number of times that external control(s) can be applied. RESULTS: This paper studies the intervention problem by manipulating multiple external controls in a finite time interval in a PBN. The maximum numbers of times that each control method can be applied are given. We treat the problem as an optimization problem with multi-constraints. Here we introduce an algorithm, the "Reserving Place Algorithm'', to find all optimal intervention strategies. Given a fixed number of times that a certain control method is applied, the algorithm can provide all the sub-optimal control policies. Theoretical analysis for the upper bound of the computational cost is also given. We also develop a heuristic algorithm based on Genetic Algorithm, to find the possible optimal intervention strategy for networks of large size. CONCLUSIONS: Studying the finite-horizon control problem with multiple hard constraints is meaningful. The problem proposed is NP-hard. The Reserving Place Algorithm can provide more than one optimal intervention strategies if there are. Moreover, the algorithm can find all the sub-optimal control strategies corresponding to the number of times that certain control method is conducted. To speed up the computational time, a heuristic algorithm based on Genetic Algorithm is proposed for genetic networks of large size. PMID- 20840729 TI - Identification of transcription factor's targets using tissue-specific transcriptomic data in Arabidopsis thaliana. AB - BACKGROUND: Transcription factors (TFs) regulate downstream genes in response to environmental stresses in plants. Identification of TF target genes can provide insight on molecular mechanisms of stress response systems, which can lead to practical applications such as engineering crops that thrive in challenging environments. Despite various computational techniques that have been developed for identifying TF targets, it remains a challenge to make best use of available experimental data, especially from time-series transcriptome profiling data, for improving TF target identification. RESULTS: In this study, we used a novel approach that combined kinetic modelling of gene expression with a statistical meta-analysis to predict targets of 757 TFs using expression data of 14,905 genes in Arabidopsis exposed to different durations and types of abiotic stresses. Using a kinetic model for the time delay between the expression of a TF gene and its potential targets, we shifted a TF's expression profile to make an interacting pair coherent. We found that partitioning the expression data by tissue and developmental stage improved correlation between TFs and their targets. We identified consensus pairs of correlated profiles between a TF and all other genes among partitioned datasets. We applied this approach to predict novel targets of known TFs. Some of these putative targets were validated from the literature, for E2F's targets in particular, while others provide explicit genes as hypotheses for future studies. CONCLUSION: Our method provides a general framework for TF target prediction with consideration of the time lag between initiation of a TF and activation of its targets. The framework helps make significant inferences by reducing the effects of independent noises in different experiments and by identifying recurring regulatory relationships under various biological conditions. Our TF target predictions may shed some light on common regulatory networks in abiotic stress responses. PMID- 20840730 TI - Computational inference and analysis of genetic regulatory networks via a supervised combinatorial-optimization pattern. AB - BACKGROUND: Post-genome era brings about diverse categories of omics data. Inference and analysis of genetic regulatory networks act prominently in extracting inherent mechanisms, discovering and interpreting the related biological nature and living principles beneath mazy phenomena, and eventually promoting the well-beings of humankind. RESULTS: A supervised combinatorial optimization pattern based on information and signal-processing theories is introduced into the inference and analysis of genetic regulatory networks. An associativity measure is proposed to define the regulatory strength/connectivity, and a phase-shift metric determines regulatory directions among components of the reconstructed networks. Thus, it solves the undirected regulatory problems arising from most of current linear/nonlinear relevance methods. In case of computational and topological redundancy, we constrain the classified group size of pair candidates within a multiobjective combinatorial optimization (MOCO) pattern. CONCLUSIONS: We testify the proposed approach on two real-world microarray datasets of different statistical characteristics. Thus, we reveal the inherent design mechanisms for genetic networks by quantitative means, facilitating further theoretic analysis and experimental design with diverse research purposes. Qualitative comparisons with other methods and certain related focuses needing further work are illustrated within the discussion section. PMID- 20840731 TI - Discovering conditional co-regulated protein complexes by integrating diverse data sources. AB - BACKGROUND: Proteins interacting with each other as a complex play an important role in many molecular processes and functions. Directly detecting protein complexes is still costly, whereas many protein-protein interaction (PPI) maps for model organisms are available owing to the fast development of high throughput PPI detecting techniques. These binary PPI data provides fundamental and abundant information for inferring new protein complexes. However, PPI data from different experiments do not overlap very much usually. The main reason is that the functions of proteins can activate only on certain environment or stimulus. In a short, PPI is condition-specific. Therefore specifying the conditions on when complexes are present is necessary for a deep understanding of their behaviours. Meanwhile, proteins have various interaction ways and control mechanisms to form different kinds of complexes. Thus the discovery of a certain type of complexes should depend on their own distinct biological or topological characteristics. We do not attempt to find all kinds of complexes by using certain features. Here, we integrate transcription regulation data (TR), gene expression data (GE) and protein-protein interaction data at the systems biology level to discover a special kind of protein complex called conditional co regulated protein complexes. A conditional co-regulated protein complex has three remarkable features: the coding genes of the member proteins share the same transcription factor (TF), under a certain condition the coding genes express co ordinately and the member proteins interact mutually as a complex to implement a common biological function. RESULTS: A framework of discovering the conditional co-regulated protein complexes is proposed. Testing on the Yeast data sets under the Cell Cycle, DNA Damage and Dauxic Shift conditions, we identified a total of 29 conditional co-regulated complexes, among which the coding genes in 14 complexes show a strong association with their TFs activity. Based on the close relationship among co-regulation, co-expression and protein-protein interactions in the conditional co-regulated protein complexes, 39 novel TRs were predicted and explained. CONCLUSIONS: This paper was initiated to study conditional co regulated protein complexes by integrating multiple data sources. Taking into consideration the influence of TFs activity on the protein interactions, we found that the expression coherence of the protein complexes' coding genes changed in accordance to their TFs' activity, which implied that the proteins' interactions also changed in response to the environments. Based on the three features of conditional co-regulated protein complexes, new transcriptional regulation interactions were predicted. PMID- 20840732 TI - Shrunken methodology to genome-wide SNPs selection and construction of SNPs networks. AB - BACKGROUND: Recent development of high-resolution single nucleotide polymorphism (SNP) arrays allows detailed assessment of genome-wide human genome variations. There is increasing recognition of the importance of SNPs for medicine and developmental biology. However, SNP data set typically has a large number of SNPs (e.g., 400 thousand SNPs in genome-wide Parkinson disease data set) and a few hundred of samples. Conventional classification methods may not be effective when applied to such genome-wide SNP data. RESULTS: In this paper, we use shrunken dissimilarity measure to analyze and select relevant SNPs for classification problems. Examples of HapMap data and Parkinson disease (PD) data are given to demonstrate the effectiveness of the proposed method, and illustrate it has a potential to become a useful analysis tool for SNP data sets. We use Parkinson disease data as an example, and perform a whole genome analysis. For the 367440 SNPs with less than 1% missing percentage from all 22 chromosomes, we can select 357 SNPs from this data set. For the unique genes that those SNPs are located in, a gene-gene similarity value is computed using GOSemSim and gene pairs that has a similarity value being greater than a threshold are selected to construct several groups of genes. For the SNPs that involved in these groups of genes, a statistical software PLINK is employed to compute the pair-wise SNP-SNP interactions, and SNPs with significance of P < 0.01 are chosen to identify SNPs networks based on their P values. Here SNPs networks are constructed based on Gene Ontology knowledge, and therefore each SNP network plays a role in the biological process. An analysis shows that such networks have relationships directly or indirectly to Parkinson disease. CONCLUSIONS: Experimental results show that our approach is suitable to handle genetic variations, and provide useful knowledge in a genome-wide SNP study. PMID- 20840733 TI - Semi-supervised drug-protein interaction prediction from heterogeneous biological spaces. AB - BACKGROUND: Predicting drug-protein interactions from heterogeneous biological data sources is a key step for in silico drug discovery. The difficulty of this prediction task lies in the rarity of known drug-protein interactions and myriad unknown interactions to be predicted. To meet this challenge, a manifold regularization semi-supervised learning method is presented to tackle this issue by using labeled and unlabeled information which often generates better results than using the labeled data alone. Furthermore, our semi-supervised learning method integrates known drug-protein interaction network information as well as chemical structure and genomic sequence data. RESULTS: Using the proposed method, we predicted certain drug-protein interactions on the enzyme, ion channel, GPCRs, and nuclear receptor data sets. Some of them are confirmed by the latest publicly available drug targets databases such as KEGG. CONCLUSIONS: We report encouraging results of using our method for drug-protein interaction network reconstruction which may shed light on the molecular interaction inference and new uses of marketed drugs. PMID- 20840734 TI - A systems biology approach to identify effective cocktail drugs. AB - BACKGROUND: Complex diseases, such as Type 2 Diabetes, are generally caused by multiple factors, which hamper effective drug discovery. To combat these diseases, combination regimens or combination drugs provide an alternative way, and are becoming the standard of treatment for complex diseases. However, most of existing combination drugs are developed based on clinical experience or test-and trial strategy, which are not only time consuming but also expensive. RESULTS: In this paper, we presented a novel network-based systems biology approach to identify effective drug combinations by exploiting high throughput data. We assumed that a subnetwork or pathway will be affected in the networked cellular system after a drug is administrated. Therefore, the affected subnetwork can be used to assess the drug's overall effect, and thereby help to identify effective drug combinations by comparing the subnetworks affected by individual drugs with that by the combination drug. In this work, we first constructed a molecular interaction network by integrating protein interactions, protein-DNA interactions, and signaling pathways. A new model was then developed to detect subnetworks affected by drugs. Furthermore, we proposed a new score to evaluate the overall effect of one drug by taking into account both efficacy and side effects. As a pilot study we applied the proposed method to identify effective combinations of drugs used to treat Type 2 Diabetes. Our method detected the combination of Metformin and Rosiglitazone, which is actually Avandamet, a drug that has been successfully used to treat Type 2 Diabetes. CONCLUSIONS: The results on real biological data demonstrate the effectiveness and efficiency of the proposed method, which can not only detect effective cocktail combination of drugs in an accurate manner but also significantly reduce expensive and tedious trial-and-error experiments. PMID- 20840736 TI - Parameter optimization by using differential elimination: a general approach for introducing constraints into objective functions. AB - BACKGROUND: The investigation of network dynamics is a major issue in systems and synthetic biology. One of the essential steps in a dynamics investigation is the parameter estimation in the model that expresses biological phenomena. Indeed, various techniques for parameter optimization have been devised and implemented in both free and commercial software. While the computational time for parameter estimation has been greatly reduced, due to improvements in calculation algorithms and the advent of high performance computers, the accuracy of parameter estimation has not been addressed. RESULTS: We propose a new approach for parameter optimization by using differential elimination, to estimate kinetic parameter values with a high degree of accuracy. First, we utilize differential elimination, which is an algebraic approach for rewriting a system of differential equations into another equivalent system, to derive the constraints between kinetic parameters from differential equations. Second, we estimate the kinetic parameters introducing these constraints into an objective function, in addition to the error function of the square difference between the measured and estimated data, in the standard parameter optimization method. To evaluate the ability of our method, we performed a simulation study by using the objective function with and without the newly developed constraints: the parameters in two models of linear and non-linear equations, under the assumption that only one molecule in each model can be measured, were estimated by using a genetic algorithm (GA) and particle swarm optimization (PSO). As a result, the introduction of new constraints was dramatically effective: the GA and PSO with new constraints could successfully estimate the kinetic parameters in the simulated models, with a high degree of accuracy, while the conventional GA and PSO methods without them frequently failed. CONCLUSIONS: The introduction of new constraints in an objective function by using differential elimination resulted in the drastic improvement of the estimation accuracy in parameter optimization methods. The performance of our approach was illustrated by simulations of the parameter optimization for two models of linear and non-linear equations, which included unmeasured molecules, by two types of optimization techniques. As a result, our method is a promising development in parameter optimization. PMID- 20840735 TI - Inhibition of the interactions between eosinophil cationic protein and airway epithelial cells by traditional Chinese herbs. AB - BACKGROUND: The eosinophil cationic protein (ECP) is cytotoxic to bacteria, viruses, parasites and mammalian cells. Cells are damaged via processes of pore formation, permeability alteration and membrane leaking. Some clinical studies indicate that ECP gathers in the bronchial tract of asthma sufferers, damages bronchial and airway epithelial cells, and leads to in breathing tract inflammation; therefore, prevention of the cytotoxicity caused by ECP may serve as an approach to treat airway inflammation. To achieve the purpose, reduction of the ECP-cell interactions is rational. In this work, the Chinese herbal combinative network was generated to predict and identify the functional herbs from the pools of prescriptions. It was useful to select the node herbs and to demonstrate the relative binding ability between ECP and Beas-2B cells with or withour herb treatments. RESULTS: Eighty three Chinese herbs and prescriptions were tested and five effective herbs and six prescription candidates were selected. On the basis of effective single-herbal drugs and prescriptions, a combinative network was generated. We found that a single herb, Gan-cao, served as a node connecting five prescriptions. In addition, Sheng-di-huang, Dang-guei and Mu-tong also appeared in five, four and three kinds of prescriptions, respectively. The extracts of these three herbs indeed effectively inhibited the interactions between ECP and Beas-2B cells. According to the Chinese herbal combinative network, eight of the effective herbal extracts showed inhibitory effects for ECP internalizing into Beas-2B cells. The major components of Gang cao and Sheng-di-huang, glycyrrhizic acid and verbascose, respectively, reduced the binding affinity between ECP and cells effectively. CONCLUSIONS: Since these Chinese herbs reduced the binding affinity between ECP and cells and inhibited subsequent ECP entrance into cells, they were potential for mitigating the airway inflammation symptoms. Additionally, we mentioned a new concept to study the Chinese herbs using combinative network in the field of systems biology. The functional single herbs could be identified from the set of prescriptions. PMID- 20840737 TI - Developing and analysing a curriculum map in Occupational- and Environmental Medicine. AB - BACKGROUND: During the last 5 years a fundamental curriculum reform was realized at the medical school of the Ludwig-Maximilians-University. In contrast to those efforts, the learning objectives were not defined consistently for the curriculum and important questions concerning the curriculum could not be answered. This also applied to Occupational and Environmental Medicine where teachers of both courses were faced with additional problems such as the low number of students attending the lectures.The aims of the study were to develop and analyse a curriculum map for Occupational and Environmental Medicine based on learning objectives using a web-based database.Furthermore we aimed to evaluate student perception about the curricular structure. METHODS: Using a web-based learning objectives database, a curriculum map for Occupational and Environmental Medicine was developed and analysed. Additionally online evaluations of students for each course were conducted. RESULTS: The results show a discrepancy between the taught and the assessed curriculum. For both curricula, we identified that several learning objectives were not covered in the curriculum. There were overlaps with other content domains and redundancies within both curricula. 53% of the students in Occupational Medicine and 43% in Environmental Medicine stated that there is a lack of information regarding the learning objectives of the curriculum. CONCLUSIONS: The results of the curriculum mapping and the poor evaluation results for the courses suggest a need for re-structuring both curricula. PMID- 20840738 TI - Neopterin and procalcitonin are suitable biomarkers for exclusion of severe Plasmodium falciparum disease at the initial clinical assessment of travellers with imported malaria. AB - BACKGROUND: Most clinicians in developed, non-malaria endemic countries have limited or no experience in making clinical assessments of malaria disease severity and subsequent decisions regarding the need for parenteral therapy or high-level monitoring in febrile patients with imported malaria. In the present study, the diagnostic accuracy of plasma soluble Triggering Receptor Expressed on Myeloid cells 1 (TREM-1), neopterin and procalcitonin levels as biomarkers for severe Plasmodium falciparum disease was evaluated in 104 travellers with imported malaria (26 patients with non-P. falciparum malaria, 64 patients with uncomplicated P. falciparum malaria and 14 patients with severe P. falciparum malaria). METHODS: TREM-1, neopterin and procalcitonin were determined in serum using commercially available ELISA or EIA tests. The diagnostic performance of these biomarkers for severe disease was compared with plasma lactate, a well validated parameter for disease severity in patients with malaria, as reference. Severe malaria was defined according to the modified WHO criteria. RESULTS: No significant differences in TREM-1 levels were detected between the different patient groups. Patients with severe P. falciparum malaria had significantly higher neopterin and procalcitonin levels on admission when compared to patients with uncomplicated P. falciparum malaria or non-P. falciparum malaria. Receiver Operating Characteristic (ROC) curve analysis showed that neopterin had the highest Area-Under-the-ROC curve (AUROC 0.85) compared with plasma lactate (AUROC 0.80) and procalcitonin (AUROC 0.78). At a cut-off point of 10.0 ng/ml, neopterin had a positive and negative predictive value of 0.38 and 0.98 whereas procalcitonin, at a cut-off point of 0.9 ng/ml, had a positive and negative predictive value of 0.30 and 1.00. CONCLUSION: Although the diagnostic value of neopterin and procalcitonin is limited, the high negative predictive value of both neopterin and procalcitonin may be helpful for a rapid exclusion of severe malaria disease on admission. This may be a valuable tool for physicians only occasionally dealing with ill-returned travellers from malaria-endemic regions and who need to decide on subsequent oral anti-malarial treatment or timely referral to a specialized centre for high-level monitoring and intensified parenteral treatment. PMID- 20840739 TI - Relative validation of a food frequency questionnaire for national health and nutrition monitoring. AB - BACKGROUND: Validation of a food frequency questionnaire (FFQ) is important as incorrect information may lead to biased associations. Therefore the relative validity of an FFQ developed for use in the German Health Examination Survey for Adults 2008-2011 (DEGS) was examined. METHODS: Cross-sectional comparisons of food consumption data from the FFQ and from two 24-hour recalls were made in a sample of 161 participants (aged 18 to 80 years) of an ongoing nationwide survey, the German National Nutrition Monitoring (NEMONIT). The data collection took place from November 2008 to April 2009. RESULTS: Spearman rank correlations between the FFQ and the 24-hour dietary recalls ranged from 0.15 for pizza to 0.80 for tea, with two third of the correlation coefficients exceeding 0.30. All correlation coefficients were statistically significant except those for pizza and cooked vegetables. The proportion of participants classified into the same or adjacent quartile of intake assessed by both methods varied between 68% for cooked vegetables and 94% for coffee. There were no statistically significant differences in food consumption estimates between both methods for 38% of the food groups. For the other food groups, the estimates of food consumption by the FFQ were not generally higher or lower than estimates from the 24-hour dietary recalls. CONCLUSIONS: The FFQ appears to be reasonably valid in the assessment of food consumption of German adults. For some food groups, such as raw and cooked vegetables, relative risks estimates should be interpreted with caution because of the poor ranking agreement. PMID- 20840740 TI - End-tidal carbon dioxide monitoring during bag valve ventilation: the use of a new portable device. AB - BACKGROUND: For healthcare providers in the prehospital setting, bag-valve mask (BVM) ventilation could be as efficacious and safe as endotracheal intubation. To facilitate the evaluation of efficacious ventilation, capnographs have been further developed into small and convenient devices able to provide end- tidal carbon dioxide (ETCO2). The aim of this study was to investigate whether a new portable device (EMMATM) attached to a ventilation mask would provide ETCO2 values accurate enough to confirm proper BVM ventilation. METHODS: A prospective observational trial was conducted in a single level-2 centre. Twenty-two patients under general anaesthesia were manually ventilated. ETCO2 was measured every five minutes with the study device and venous PCO2 (PvCO2) was simultaneously measured for comparison. Bland- Altman plots were used to compare ETCO2, and PvCO2. RESULTS: The patients were all hemodynamically and respiratory stable during anaesthesia. End-tidal carbon dioxide values were corresponding to venous gases during BVM ventilation under optimal conditions. The bias, the mean of the differences between the two methods (device versus venous blood gases), for time points 1-4 ranges from -1.37 to -1.62. CONCLUSION: The portable device, EMMATM is suitable for determining carbon dioxide in expired air (kPa) as compared to simultaneous samples of PvCO2. It could therefore, be a supportive tool to asses the BVM ventilation in the demanding prehospital and emergency setting. PMID- 20840741 TI - A lifeline to treatment: the role of Indian generic manufacturers in supplying antiretroviral medicines to developing countries. AB - BACKGROUND: Indian manufacturers of generic antiretroviral (ARV) medicines facilitated the rapid scale up of HIV/AIDS treatment in developing countries though provision of low-priced, quality-assured medicines. The legal framework in India that facilitated such production, however, is changing with implementation of the World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights, and intellectual property measures being discussed in regional and bilateral free trade agreement negotiations. Reliable quantitative estimates of the Indian role in generic global ARV supply are needed to understand potential impacts of such measures on HIV/AIDS treatment in developing countries. METHODS: We utilized transactional data containing 17,646 donor-funded purchases of ARV tablets made by 115 low- and middle-income countries from 2003 to 2008 to measure market share, purchase trends and prices of Indian-produced generic ARVs compared with those of non-Indian generic and brand ARVs. RESULTS: Indian generic manufacturers dominate the ARV market, accounting for more than 80% of annual purchase volumes. Among paediatric ARV and adult nucleoside and non-nucleoside reverse transcriptase inhibitor markets, Indian-produced generics accounted for 91% and 89% of 2008 global purchase volumes, respectively. From 2003 to 2008, the number of Indian generic manufactures supplying ARVs increased from four to 10 while the number of Indian manufactured generic products increased from 14 to 53. Ninety-six of 100 countries purchased Indian generic ARVs in 2008, including high HIV-burden sub Saharan African countries. Indian-produced generic ARVs used in first-line regimens were consistently and considerably less expensive than non-Indian generic and innovator ARVs. Key ARVs newly recommended by the World Health Organization are three to four times more expensive than older regimens. CONCLUSIONS: Indian generic producers supply the majority of ARVs in developing countries. Future scale up using newly recommended ARVs will likely be hampered until Indian generic producers can provide the dramatic price reductions and improved formulations observed in the past. Rather than agreeing to inappropriate intellectual property obligations through free trade agreements, India and its trade partners--plus international organizations, donors, civil society and pharmaceutical manufacturers--should ensure that there is sufficient policy space for Indian pharmaceutical manufacturers to continue their central role in supplying developing countries with low-priced, quality-assured generic medicines. PMID- 20840742 TI - A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers. AB - BACKGROUND: Familial amyloidosis with polyneuropathy (FAP) is an autosomal dominant disease caused by transthyretin (TTR) mutations, of which V30M (TTR c.148G > A, p.Val50Met, "Val30Met") is the most common. Swedish V30M carriers display later age at onset and lower penetrance compared to other populations. METHODS: In the study, 130 Swedish V30M carriers (32 early, 30 late onset and 68 asymptomatic carriers) and 50 controls, 23 French symptomatic V30M carriers and 29 controls and 18 Japanese symptomatic V30M carriers and 29 controls were included. We aimed to identify additional genetic factors in the TTR gene and its surrounding region that could have an impact on phenotype. RESULTS: We identified three SNPs (rs71383038, rs3794885 and rs62093482) with a significant difference in allele frequency between Swedish V30M carriers and controls. The two Swedish V30M homozygous patients present in the study also displayed homozygosity for the CA10 (rs71383038), A (rs3794885) and T (rs62093482) alleles in these SNPs. Hence, these alleles are present on the Swedish V30M haplotype. Of these, rs62093482 is located in the 3'UTR of TTR gene and thus more interesting since SNPs in the 3'UTR can affect gene expression levels by modifying microRNA (miRNA) targeting activity. miRNA target predictions revealed four potential miRNAs with predicted targets unique for the polymorphic allele. CONCLUSIONS: Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population. PMID- 20840743 TI - Eligibility for and outcome of treatment of latent tuberculosis infection in a cohort of HIV-infected people in Spain. AB - BACKGROUND: Previous studies have demonstrated the efficacy of treatment for latent tuberculosis infection (TLTBI) in persons infected with the human immunodeficiency virus, but few studies have investigated the operational aspects of implementing TLTBI in the co-infected population.The study objectives were to describe eligibility for TLTBI as well as treatment prescription, initiation and completion in an HIV-infected Spanish cohort and to investigate factors associated with treatment completion. METHODS: Subjects were prospectively identified between 2000 and 2003 at ten HIV hospital-based clinics in Spain. Data were obtained from clinical records. Associations were measured using the odds ratio (OR) and its 95% confidence interval (95% CI). RESULTS: A total of 1242 subjects were recruited and 846 (68.1%) were evaluated for TLTBI. Of these, 181 (21.4%) were eligible for TLTBI either because they were tuberculin skin test (TST) positive (121) or because their TST was negative/unknown but they were known contacts of a TB case or had impaired immunity (60). Of the patients eligible for TLTBI, 122 (67.4%) initiated TLTBI: 99 (81.1%) were treated with isoniazid for 6, 9 or 12 months; and 23 (18.9%) with short-course regimens including rifampin plus isoniazid and/or pyrazinamide. In total, 70 patients (57.4%) completed treatment, 39 (32.0%) defaulted, 7 (5.7%) interrupted treatment due to adverse effects, 2 developed TB, 2 died, and 2 moved away. Treatment completion was associated with having acquired HIV infection through heterosexual sex as compared to intravenous drug use (OR:4.6; 95% CI:1.4-14.7) and with having taken rifampin and pyrazinamide for 2 months as compared to isoniazid for 9 months (OR:8.3; 95% CI:2.7-24.9). CONCLUSIONS: A minority of HIV-infected patients eligible for TLTBI actually starts and completes a course of treatment. Obstacles to successful implementation of this intervention need to be addressed. PMID- 20840744 TI - TKA following high tibial osteotomy versus primary TKA--a matched pair analysis. AB - BACKGROUND: High tibial osteotomy (HTO) is a well established technique for the treatment of medial osteoarthritis of the knee with varus malalignment. Results of total knee arthroplasty (TKA) after previous HTO are still discussed controversially. The aim of this study was to elucidate the clinical and radiological results as well as perioperative data of prior HTO on TKA. METHODS: Forty-one TKA after HTO were compared to 41 primary TKA at minimum of six years follow-up. Patients were matched according to age, gender, follow-up, etiology, and prosthetic design. Surgical data and complications were evaluated. Clinical outcome was assessed using a number of clinical scores and the visual analogue scale (VAS) for pain. X-rays were evaluated by the method of the American Knee Society. The patellar position was measured by the Insall-Salvati ratio. RESULTS: There was no significant difference in mean operation time (p = 0.47) and complication rate (p = 0.08). The Knee Score of the KSS (p = 0.0007) and the ROM (p = 0.006 for extension and p = 0.004 for flexion, respectively) were significantly better in the control group. Mid-term results of the VAS, WOMAC, Lequesne, UCLA, Feller's Patellar Score and SF-36 showed no significant difference. Femoral and tibial component alignment were similar in both groups. One tibial component showed suspect radiolucencies in the HTO group. The Insall Salvati ratio showed three patients with patella alta and one patient with patella baja in the HTO group. At latest follow-up all implants were still in place. CONCLUSIONS: Evaluating the clinical and radiological outcome, significant differences were only detected for range of motion and the Knee Score of the KSS. The present study suggests that the results of TKA with and without prior HTO are mainly identical. Although patients with a previous HTO had more complications, no statistically significant differences were noted with this group size. PMID- 20840745 TI - Comparative study of three commonly used continuous deterministic methods for modeling gene regulation networks. AB - BACKGROUND: A gene-regulatory network (GRN) refers to DNA segments that interact through their RNA and protein products and thereby govern the rates at which genes are transcribed. Creating accurate dynamic models of GRNs is gaining importance in biomedical research and development. To improve our understanding of continuous deterministic modeling methods employed to construct dynamic GRN models, we have carried out a comprehensive comparative study of three commonly used systems of ordinary differential equations: The S-system (SS), artificial neural networks (ANNs), and the general rate law of transcription (GRLOT) method. These were thoroughly evaluated in terms of their ability to replicate the reference models' regulatory structure and dynamic gene expression behavior under varying conditions. RESULTS: While the ANN and GRLOT methods appeared to produce robust models even when the model parameters deviated considerably from those of the reference models, SS-based models exhibited a notable loss of performance even when the parameters of the reverse-engineered models corresponded closely to those of the reference models: this is due to the high number of power terms in the SS-method, and the manner in which they are combined. In cross-method reverse engineering experiments the different characteristics, biases and idiosynchracies of the methods were revealed. Based on limited training data, with only one experimental condition, all methods produced dynamic models that were able to reproduce the training data accurately. However, an accurate reproduction of regulatory network features was only possible with training data originating from multiple experiments under varying conditions. CONCLUSIONS: The studied GRN modeling methods produced dynamic GRN models exhibiting marked differences in their ability to replicate the reference models' structure and behavior. Our results suggest that care should be taking when a method is chosen for a particular application. In particular, reliance on only a single method might unduly bias the results. PMID- 20840746 TI - A case report of mesenteric mucinous cystoadenoma with review of the literature. AB - BACKGROUND: Few cases of primary retroperitoneal mucinous cystoadenoma, a rare benign tumor, have been reported in the literature so far. The pathogenesis of this tumour is not completely understood yet.Our case is particularly significant since the localization in the mesentery has been described only once before in the literature. Unless biologically benign, this tumour can cause relevant clinical symptoms related to the size and site (compression or obstruction of organs). CASE PRESENTATION: We describe the case of a 52-years old woman who had presented with abdominal pain and underwent surgery in order to remove a palpable lump in the mesentery with histological diagnosis of primary mucinous cystoadenoma. The patient was followed-up for two years with no evidence of recurrence. CONCLUSIONS: Mucinous cystoadenoma is more frequent in women, particularly when there is history of one or more pregnancies. A complete preoperative study with abdominal and pelvic tomographic images and an accurate physical examination are essentials for the management of the patient. Surgical resection is the only way to treat mucinous cystoadenomas, and to have the histological confirmation that the removed mass is a benign tumor. PMID- 20840747 TI - Psychological stress and coeliac disease in childhood: a cohort study. AB - BACKGROUND: Psychological stress has previously been associated with several immunological diseases, e.g. inflammatory bowel disease. Through questionnaire data from the ABIS study (All Babies In southeast Sweden) we examined the association between psychological stress in the family and biopsy-proven coeliac disease (CD) in the child. METHODS: We used serious life event, parenting stress, and parental worries as measures of psychological stress. Data were collected when the child was 1 and 2.5 years old in some 11,000 and 8,800 children, respectively. CD was confirmed through small intestinal biopsy (with villous atrophy), and the diagnosis was validated through patient chart data. RESULTS: Serious life event in the family in the child's first 1 or 2.5 years after childbirth was not associated with future CD in the child (Odds Ratio (OR) = 0.45; 95% Confidence Interval (CI) = 0.01-2.65; P = 0.72; and OR = 1.21; 95% CI = 0.43-3.05; P = 0.64, respectively). Neither did we see any association between CD and parenting stress at age 1 year and at 2.5 years (OR = 0.40; 95% CI = 0.01 2.38; P = 0.73 and OR = 0.74; 95% CI = 0.01-4.56; P = 1.00, respectively). Among children exposed to parental worries at 2.5 years, no child had a diagnosis of CD before end of follow-up, compared to 25/8082 (0.3%) among non-exposed children (OR = 0.00; 95% CI = 0.00-2.34; P = 0.64). There was no association between the combined measures of stress and CD. CONCLUSION: This study found no association between psychological stress and later development of CD in Swedish children. However, we cannot rule out that the lack of such an association is due to limited statistical power. PMID- 20840748 TI - Analysis of human synovial and bone marrow mesenchymal stem cells in relation to heat-inactivation of autologous and fetal bovine serums. AB - BACKGROUND: Though sera are essential for Mesenchymal stem cells (MSCs), the effect of heat-inactivation remains unknown. Autologous human serum is recommended for clinical use; however, it is unclear whether differentiation potentials are maintained. To examine whether heat-inactivation of serum affected the proliferation and whether autologous human serum influenced their multipotentiality. METHODS: After whole blood collection, human synovium and bone marrow were harvested. Nucleated cells were expanded with autologous human serum and FBS. RESULTS: Heat-inactivation of autologous human serum enhanced proliferation of synovial MSCs. Heat-inactivation of each types of serum didn't affect calcification of synovial MSCs. The induction of calcification increased ALP activity, with the exception of bone marrow MSCs with autologous human serum. For adipogenesis of synovial MSCs, the Oil Red-O positive colony forming efficiency with autologous human serum was similar to or less than that with FBS. CONCLUSION: These clarified the processing of human autologous serum and the influence of different sera for differentiation of synovial and bone marrow MSCs. PMID- 20840749 TI - PGF2alpha-F-prostanoid receptor signalling via ADAMTS1 modulates epithelial cell invasion and endothelial cell function in endometrial cancer. AB - BACKGROUND: An increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer. In endometrial adenocarcinoma F-prostanoid (FP) receptor expression is elevated, along with its ligand prostaglandin (PG)F2alpha, where it regulates expression and secretion of a host of growth factors and chemokines involved in tumorigenesis. This study investigates the expression, regulation and role of a disintegrin and metalloproteinase with thrombospondin repeat 1 (ADAMTS1) in endometrial adenocarcinoma cells by PGF2alpha via the FP receptor. METHODS: Human endometrium and adenocarcinoma tissues were obtained in accordance with Lothian Research Ethics Committee guidance with informed patient consent. Expression of ADAMTS1 mRNA and protein in tissues was determined by quantitative RT-PCR analysis and immunohistochemistry. Signal transduction pathways regulating ADAMTS1 expression in Ishikawa cells stably expressing the FP receptor to levels seen in endometrial cancer (FPS cells) were determined by quantitative RT-PCR analysis. In vitro invasion and proliferation assays were performed with FPS cells and human umbilical vein endothelial cells (HUVECs) using conditioned medium (CM) from PGF2alpha-treated FPS cells from which ADAMTS1 was immunoneutralised and/or recombinant ADAMTS1. The role of endothelial ADAMTS1 in endothelial cell proliferation was confirmed with RNA interference. The data in this study were analysed by T-test or ANOVA. RESULTS: ADAMTS1 mRNA and protein expression is elevated in endometrial adenocarcinoma tissues compared with normal proliferative phase endometrium and is localised to the glandular and vascular cells. Using FPS cells, we show that PGF2alpha-FP signalling upregulates ADAMTS1 expression via a calmodulin-NFAT-dependent pathway and this promotes epithelial cell invasion through ECM and inhibits endothelial cell proliferation. Furthermore, we show that CM from FPS cells regulates endothelial cell ADAMTS1 expression in a rapid biphasic manner. Using RNA interference we show that endothelial cell ADAMTS1 also negatively regulates cellular proliferation. CONCLUSIONS: These data demonstrate elevated ADAMTS1 expression in endometrial adenocarcinoma. Furthermore we have highlighted a mechanism whereby FP receptor signalling regulates epithelial cell invasion and endothelial cell function via the PGF2alpha-FP receptor mediated induction of ADAMTS1. PMID- 20840750 TI - Identification of two amino acids in the C-terminal domain of mouse CRY2 essential for PER2 interaction. AB - BACKGROUND: Cryptochromes (CRYs) are a class of flavoprotein blue-light signaling receptors found in plants and animals, and they control plant development and the entrainment of circadian rhythms. They also act as integral parts of the central circadian oscillator in humans and other animals. In mammals, the CLOCK-BMAL1 heterodimer activates transcription of the Per and Cry genes as well as clock regulated genes. The PER2 proteins interact with CRY and CKIepsilon, and the resulting ternary complexes translocate into the nucleus, where they negatively regulate the transcription of Per and Cry core clock genes and other clock regulated output genes. Recent studies have indicated that the extended C-termini of the mammalian CRYs, as compared to photolyase proteins, interact with PER proteins. RESULTS: We identified a region on mCRY2 (between residues 493 and 512) responsible for direct physical interaction with mPER2 by mammalian two-hybrid and co-immunoprecipitation assays. Moreover, using oligonucleotide-based degenerate PCR, we discovered that mutation of Arg-501 and Lys-503 of mCRY2 within this C-terminal region totally abolishes interaction with PER2. CONCLUSIONS: Our results identify mCRY2 amino acid residues that interact with the mPER2 binding region and suggest the potential for rational drug design to inhibit CRYs for specific therapeutic approaches. PMID- 20840751 TI - A high resolution spatial population database of Somalia for disease risk mapping. AB - BACKGROUND: Millions of Somali have been deprived of basic health services due to the unstable political situation of their country. Attempts are being made to reconstruct the health sector, in particular to estimate the extent of infectious disease burden. However, any approach that requires the use of modelled disease rates requires reasonable information on population distribution. In a low-income country such as Somalia, population data are lacking, are of poor quality, or become outdated rapidly. Modelling methods are therefore needed for the production of contemporary and spatially detailed population data. RESULTS: Here land cover information derived from satellite imagery and existing settlement point datasets were used for the spatial reallocation of populations within census units. We used simple and semi-automated methods that can be implemented with free image processing software to produce an easily updatable gridded population dataset at 100 * 100 meters spatial resolution. The 2010 population dataset was matched to administrative population totals projected by the UN. Comparison tests between the new dataset and existing population datasets revealed important differences in population size distributions, and in population at risk of malaria estimates. These differences are particularly important in more densely populated areas and strongly depend on the settlement data used in the modelling approach. CONCLUSIONS: The results show that it is possible to produce detailed, contemporary and easily updatable settlement and population distribution datasets of Somalia using existing data. The 2010 population dataset produced is freely available as a product of the AfriPop Project and can be downloaded from: http://www.afripop.org. PMID- 20840752 TI - Candidate gene prioritization by network analysis of differential expression using machine learning approaches. AB - BACKGROUND: Discovering novel disease genes is still challenging for diseases for which no prior knowledge--such as known disease genes or disease-related pathways -is available. Performing genetic studies frequently results in large lists of candidate genes of which only few can be followed up for further investigation. We have recently developed a computational method for constitutional genetic disorders that identifies the most promising candidate genes by replacing prior knowledge by experimental data of differential gene expression between affected and healthy individuals.To improve the performance of our prioritization strategy, we have extended our previous work by applying different machine learning approaches that identify promising candidate genes by determining whether a gene is surrounded by highly differentially expressed genes in a functional association or protein-protein interaction network. RESULTS: We have proposed three strategies scoring disease candidate genes relying on network based machine learning approaches, such as kernel ridge regression, heat kernel, and Arnoldi kernel approximation. For comparison purposes, a local measure based on the expression of the direct neighbors is also computed. We have benchmarked these strategies on 40 publicly available knockout experiments in mice, and performance was assessed against results obtained using a standard procedure in genetics that ranks candidate genes based solely on their differential expression levels (Simple Expression Ranking). Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene on average at position 17 with an AUC value of 83.7%. CONCLUSION: In this study we could identify promising candidate genes using network based machine learning approaches even if no knowledge is available about the disease or phenotype. PMID- 20840753 TI - Injury induced activation of extracellular signal-regulated kinase (ERK) in the rat rostral ventromedial medulla (RVM) is age dependant and requires the lamina I projection pathway. AB - Descending controls originating in part from the rostral ventromedial medulla (RVM) regulate the excitability of dorsal horn neurons and maintain peripheral pain states. Activation of extracellular signal regulated kinase (ERK) in RVM neurons has been shown following peripheral inflammation and is involved in generating the accompanying inflammatory hyperalgesia. Here, we show that spared nerve injury (SNI), a model of neuropathic pain, results in an increase in ERK activity in RVM neurons of adult rats 3 and 8 days following surgery. We carried out two experimental procedures to demonstrate that this increase in ERK activation was related to the increased mechanical sensitivity associated with SNI. First, we showed that lesions of the lamina I/III ascending pathway from the dorsal horn attenuated both mechanical hyperalgesia and ERK activation in the RVM. Second, we performed SNI in P10 rats. At this age, SNI did not result in mechanical hypersensitivity, as previously shown, and did not activate ERK in the RVM. Finally, the percentage of pERK expressing neurones that were also serotonergic was always around 60%, independent of pain state and age, indicating an important role for serotonin in descending controls of pain states. PMID- 20840754 TI - Dose escalation improves therapeutic outcome: post hoc analysis of data from a 12 week, multicentre, double-blind, parallel-group trial of trospium chloride in patients with urinary urge incontinence. AB - BACKGROUND: Flexible dosing of anticholinergics used for overactive bladder (OAB) treatment is a useful strategy in clinical practice for achieving a maximum effective and maximum tolerated level of therapeutic benefit. In this post hoc analysis we evaluated the efficacy and tolerability of trospium chloride treatment for urinary urge incontinence (UUI) with focus on flexible dosing. METHODS: The data came from a 12-week, randomised, double-blind, phase IIIb study in which 1658 patients with urinary frequency plus urge incontinence received trospium chloride 15 mg TID (n = 828) or 2.5 mg oxybutynin hydrochloride TID (n = 830). After four weeks, daily doses were doubled and not readjusted in 29.2% (242/828) of patients in the trospium group, and in 23.3% (193/830) in the oxybuytnin group, until the end of treatment. We assessed the absolute reduction in weekly UUI episodes and the change in intensity of dry mouth, recorded in patients' micturition diaries. Adverse events were also evaluated. Statistics were descriptive. RESULTS: Dose escalation of either trospium or oxybutynin increased reduction in UUI episodes in the population studied. At study end, there were no relevant differences between the "dose adjustment" subgroups and the respective "no dose adjustment" subgroups (trospium: P = 0.249; oxybutynin: P = 0.349). After dose escalation, worsening of dry mouth was higher in both dose adjusted subgroups compared to the respective "no dose adjustment" subgroups (P < 0.001). Worsening of dry mouth was lower in the trospium groups than in the oxybutynin groups (P < 0.001). Adverse events were increased in the dose adjusted subgroups. CONCLUSIONS: Flexible dosing of trospium was proven to be as effective, but better tolerated as the officially approved adjusted dose of oxybutynin. TRIAL REGISTRATION (PARENT STUDY): The study was registered with the German Federal Institute for Drugs and Medical Devices (BfArM, Berlin, Germany), registration number 4022383, as required at the time point of planning this study. PMID- 20840755 TI - Brain natriuretic peptide precursor (NT-pro-BNP) levels predict for clinical benefit to sunitinib treatment in patients with metastatic renal cell carcinoma. AB - BACKGROUND: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor that has been approved for the treatment of metastatic renal cell carcinoma. Although the majority of sunitinib-treated patients receive a clinical benefit, almost a third of the patients will not respond. Currently there is no available marker that can predict for response in these patients. METHODS: We estimated the plasma levels of NT-pro-BNP (the N-terminal precursor of brain natriuretic peptide) in 36 patients that were treated with sunitinib for metastatic clear-cell renal carcinoma. RESULTS: From the 36 patients, 9 had progressive disease and 27 obtained a clinical benefit (objective response or disease stabilization). Increases in plasma NT-pro-BNP were strongly correlated to clinical outcome. Patients with disease progression increased plasma BNP at statistically significant higher levels than patients that obtained a clinical benefit, and this was evident from the first 15 days of treatment (a three-fold increase in patients with progressive disease compared to stable NT-pro-BNP levels in patients with clinical benefit, p < 0.0001). Median progression-free survival was 12.0 months in patients with less than 1.5 fold increases (n = 22) and 3.9 months in patients with more than 1.5 fold increases in plasma NT-pro-BNP (n = 13) (log rank test, p = 0.001). CONCLUSIONS: This is the first time that a potential "surrogate marker" has been reported with such a clear correlation to clinical benefit at an early time of treatment. Due to the relative small number of accessed patients, this observation needs to be further addressed on larger cohorts. More analyses, including multivariate analyses are needed before such an observation can be used in clinical practice. PMID- 20840756 TI - Population history, phylogeography, and conservation genetics of the last Neotropical mega-herbivore, the lowland tapir (Tapirus terrestris). AB - BACKGROUND: Understanding the forces that shaped Neotropical diversity is central issue to explain tropical biodiversity and inform conservation action; yet few studies have examined large, widespread species. Lowland tapir (Tapirus terrrestris, Perissodactyla, Tapiridae) is the largest Neotropical herbivore whose ancestors arrived in South America during the Great American Biotic Interchange. A Pleistocene diversification is inferred for the genus Tapirus from the fossil record, but only two species survived the Pleistocene megafauna extinction. Here, we investigate the history of lowland tapir as revealed by variation at the mitochondrial gene Cytochrome b, compare it to the fossil data, and explore mechanisms that could have shaped the observed structure of current populations. RESULTS: Separate methodological approaches found mutually exclusive divergence times for lowland tapir, either in the late or in the early Pleistocene, although a late Pleistocene divergence is more in tune with the fossil record. Bayesian analysis favored mountain tapir (T. pinchaque) paraphyly in relation to lowland tapir over reciprocal monophyly, corroborating the inferences from the fossil data these species are sister taxa. A coalescent-based analysis rejected a null hypothesis of allopatric divergence, suggesting a complex history. Based on the geographic distribution of haplotypes we propose (i) a central role for western Amazonia in tapir diversification, with a key role of the ecological gradient along the transition between Andean subcloud forests and Amazon lowland forest, and (ii) that the Amazon river acted as an barrier to gene flow. Finally, the branching patterns and estimates based on nucleotide diversity indicate a population expansion after the Last Glacial Maximum. CONCLUSIONS: This study is the first examining lowland tapir phylogeography. Climatic events at the end of the Pleistocene, parapatric speciation, divergence along the Andean foothill, and role of the Amazon river, have similarly shaped the history of other taxa. Nevertheless further work with additional samples and loci is needed to improve our initial assessment. From a conservation perspective, we did not find a correspondence between genetic structure in lowland tapir and ecogeographic regions proposed to define conservation priorities in the Neotropics. This discrepancy sheds doubt into this scheme's ability to generate effective conservation planning for vagile species. PMID- 20840757 TI - Studies of Anopheles gambiae s.l (Diptera: Culicidae) exhibiting different vectorial capacities in lymphatic filariasis transmission in the Gomoa district, Ghana. AB - BACKGROUND: Two lymphatic filariasis endemic communities Mampong and Hwida in Ghana have been regularly monitored for impact on transmission after annual mass drug administration (MDA) with albendazole and ivermectin. After six MDAs even though the ABR for Mampong was 55883/person/year and that of Hwida was 2494/person/year, they both had ATPs of 15.21 infective larvae/person/year. Interestingly the human microfilaraemia levels had reduced significantly from 14% to 0% at Mampong and 12% to 3% at Hwida. In an attempt to understand this anomaly, we collected mosquitoes over a 5-month period using human landing catches to determine the species composition, the number of cibarial teeth, the lengths and widths of the cibarium and the cibarial dome of the vector populations. RESULTS: Out of 2553 mosquitoes caught at Mampong, 42.6% were An. gambiae s.l. All 280 identified further by PCR were An. gambiae s.s (275 M and 5 S molecular forms). At Hwida, 112 mosquitoes were obtained; 67 (59.8%) were An. gambiae s.l, comprised of 40 (59.7%) An. melas, 24 (35.8%) An. gambiae s.s (17 and 5 M and S molecular forms respectively) and 3 (4.5%) unidentified. The mean number of teeth for An. melas was 14.1 (median = 14, range = 12-15), An. gambiae s.s., 15.7 (median = 15, range = 13-19) M form 15.5 (median = 15 range = 13-19) and S form 16 (median = 16, range 15-17). The observed differences in teeth numbers were significantly different between An. melas and An. gambiae s.s (p = 0.004), and the M form (p = 0.032) and the S form (p = 0.002). CONCLUSIONS: In this study, An. gambiae s.s was the main vector at Mampong and was found to possess significantly more cibarial teeth than An. melas, the principal vector at Hwida. We postulate that the different impact observed after 6 MDAs may be due to An. gambiae s.s exhibiting 'facilitation' at Mampong and at Hwida An. melas the main vector exhibits 'limitation'. Thus it may be necessary to compliment MDA with vector control to achieve interruption of transmission in areas where An. melas may exhibit limitation. PMID- 20840758 TI - Design and technical construction of a tactile display for sensory feedback in a hand prosthesis system. AB - BACKGROUND: The users of today's commercial prosthetic hands are not given any conscious sensory feedback. To overcome this deficiency in prosthetic hands we have recently proposed a sensory feedback system utilising a "tactile display" on the remaining amputation residual limb acting as man-machine interface. Our system uses the recorded pressure in a hand prosthesis and feeds back this pressure onto the forearm skin. Here we describe the design and technical solution of the sensory feedback system aimed at hand prostheses for trans radial/humeral amputees. Critical parameters for the sensory feedback system were investigated. METHODS: A sensory feedback system consisting of five actuators, control electronics and a test application running on a computer has been designed and built. Firstly, we investigate which force levels were applied to the forearm skin of the user while operating the sensory feedback system. Secondly, we study if the proposed system could be used together with a myoelectric control system. The displacement of the skin caused by the sensory feedback system would generate artefacts in the recorded myoelectric signals. Accordingly, EMG recordings were performed and an analysis of the these are included. The sensory feedback system was also preliminarily evaluated in a laboratory setting on two healthy non-amputated test subjects with a computer generating the stimuli, with regards to spatial resolution and force discrimination. RESULTS: We showed that the sensory feedback system generated approximately proportional force to the angle of control. The system can be used together with a myoelectric system as the artefacts, generated by the actuators, were easily removed using a simple filter. Furthermore, the application of the system on two test subjects showed that they were able to discriminate tactile sensation with regards to spatial resolution and level of force. CONCLUSIONS: The results of these initial experiments in non-amputees indicate that the proposed tactile display, in its simple form, can be used to relocate tactile input from an artificial hand to the forearm and that the system can coexist with a myoelectric control systems. The proposed system may be a valuable addition to users of myoelectric prosthesis providing conscious sensory feedback during manipulation of objects. PMID- 20840759 TI - Comparative analysis of four methods to extract DNA from paraffin-embedded tissues: effect on downstream molecular applications. AB - BACKGROUND: A large portion of tissues stored worldwide for diagnostic purposes is formalin-fixed and paraffin-embedded (FFPE). These FFPE-archived tissues are an extremely valuable source for retrospective (genetic) studies. These include mutation screening in cancer-critical genes as well as pathogen detection. In this study we evaluated the impact of several widely used DNA extraction methods on the quality of molecular diagnostics on FFPE tissues. FINDINGS: We compared 4 DNA extraction methods from 4 identically processed FFPE mammary-, prostate-, colon- and lung tissues with regard to PCR inhibition, real time SNP detection and amplifiable fragment size. The extraction methods, with and without proteinase K pre-treatment, tested were: 1) heat-treatment, 2) QIAamp DNA-blood mini-kit, 3) EasyMAG NucliSens and 4) Gentra Capture-Column-kit.Amplifiable DNA fragment size was assessed by multiplexed 200-400-600 bp PCR and appeared highly influenced by the extraction method used. Proteinase K pre-treatment was a prerequisite for proper purification of DNA from FFPE. Extractions with QIAamp, EasyMAG and heat-treatment were found suitable for amplification of fragments up to 400 bp from all tissues, 600 bp amplification was marginally successful (best was QIAamp). QIAamp and EasyMAG extracts were found suitable for downstream real time SNP detection. Gentra extraction was unsuitable. Hands-on time was lowest for heat-treatment, followed by EasyMAG. CONCLUSIONS: We conclude that the extraction method plays an important role with regard to performance in downstream molecular applications. PMID- 20840760 TI - Study protocol: a pilot study to determine the safety and efficacy of induction therapy, de novo MPA and delayed mTOR-inhibition in liver transplant recipients with impaired renal function. PATRON-study. AB - BACKGROUND: Patients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free "bottom-up" regimens in patients with impaired renal function undergoing liver transplantation. This is a single center study pilot-study (PATRON07) investigating safety and efficacy of CNI free, "bottom-up" immunosuppressive (IS) strategy in patients undergoing liver transplantation (LT) with renal impairment prior to LT. METHODS/DESIGN: Patients older than 18 years with renal impairment at the time of liver transplantation eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients in will receive a CNI-free combination therapy (basiliximab, MMF, steroids and delayed Sirolimus). Primary endpoint is the incidence of steroid resistant acute rejection within the first 30 days after LT. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step, 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary endpoint the regimen is regarded to be safe and efficient. DISCUSSION: If a CNI free-"bottom-up" IS strategy is safe and effective, this may be an innovative concept in contrast to classic top-down strategies that could improve the patient short and long-time renal function as well as overall complications and survival after LT. The results of PATRON07 may be the basis for a large multicenter RCT investigating the new "bottom-up" immunosuppressive strategy in patients with poor renal function prior to LT.http://www.clinicaltrials.gov-identifier: NCT00604357. PMID- 20840762 TI - Chicken model of steroid-induced bone marrow adipogenesis using proteome analysis: a preliminary study. AB - BACKGROUND: Steroid-induced adipogenesis increases fat-cell volume and pressure in bone marrow. This may be a contributing factor in some forms of osteonecrosis. In this observational study, we aimed to determine the protein expression relating to steroid-induced adipogenesis of femoral bone marrow with use of a chicken model. We compared the histologic features of the femoral marrow of eight methylprednisolone (MP)-treated chickens with those of three control chickens and assessed differential proteins with 2-dimensional gel electrophoresis and differential proteins were identified by MALDI-TOF MS. RESULTS: One MP-induced chicken died of overdose anesthesia. Methylprednisolone-induced proliferation of adipose tissue and new bone formation were found on histologic examination. In our study, 13 proteins in the control and MP-induced groups were differently expressed and nine protein spots showed marked threefold downregulation after 19 weeks of MP treatment. These were serum amyloid P-component precursor, zinc finger protein 28, endothelial zinc finger protein 71, T-box transcription factor 3, cyclin-dependent kinase inhibitor 1, myosin 1D, dimethylaniline monooxygenase, and two uncharacterized proteins. CONCLUSIONS: Proteomic profiling can be a useful dynamic approach for detecting protein expression in MP-induced adipogenesis of the femur in chickens. PMID- 20840761 TI - Gene signatures in wound tissue as evidenced by molecular profiling in the chick embryo model. AB - BACKGROUND: Modern functional genomic approaches may help to better understand the molecular events involved in tissue morphogenesis and to identify molecular signatures and pathways. We have recently applied transcriptomic profiling to evidence molecular signatures in the development of the normal chicken chorioallantoic membrane (CAM) and in tumor engrafted on the CAM. We have now extended our studies by performing a transcriptome analysis in the "wound model" of the chicken CAM, which is another relevant model of tissue morphogenesis. RESULTS: To induce granulation tissue (GT) formation, we performed wounding of the chicken CAM and compared gene expression to normal CAM at the same stage of development. Matched control samples from the same individual were used. We observed a total of 282 genes up-regulated and 44 genes down-regulated assuming a false-discovery rate at 5% and a fold change > 2. Furthermore, bioinformatics analysis lead to the identification of several categories that are associated to organismal injury, tissue morphology, cellular movement, inflammatory disease, development and immune system. Endothelial cell data filtering leads to the identification of several new genes with an endothelial cell signature. CONCLUSIONS: The chick chorioallantoic wound model allows the identification of gene signatures and pathways involved in GT formation and neoangiogenesis. This may constitute a fertile ground for further studies. PMID- 20840763 TI - Engineering the cell surface display of cohesins for assembly of cellulosome inspired enzyme complexes on Lactococcus lactis. AB - BACKGROUND: The assembly and spatial organization of enzymes in naturally occurring multi-protein complexes is of paramount importance for the efficient degradation of complex polymers and biosynthesis of valuable products. The degradation of cellulose into fermentable sugars by Clostridium thermocellum is achieved by means of a multi-protein "cellulosome" complex. Assembled via dockerin-cohesin interactions, the cellulosome is associated with the cell surface during cellulose hydrolysis, forming ternary cellulose-enzyme-microbe complexes for enhanced activity and synergy. The assembly of recombinant cell surface displayed cellulosome-inspired complexes in surrogate microbes is highly desirable. The model organism Lactococcus lactis is of particular interest as it has been metabolically engineered to produce a variety of commodity chemicals including lactic acid and bioactive compounds, and can efficiently secrete an array of recombinant proteins and enzymes of varying sizes. RESULTS: Fragments of the scaffoldin protein CipA were functionally displayed on the cell surface of Lactococcus lactis. Scaffolds were engineered to contain a single cohesin module, two cohesin modules, one cohesin and a cellulose-binding module, or only a cellulose-binding module. Cell toxicity from over-expression of the proteins was circumvented by use of the nisA inducible promoter, and incorporation of the C terminal anchor motif of the streptococcal M6 protein resulted in the successful surface-display of the scaffolds. The facilitated detection of successfully secreted scaffolds was achieved by fusion with the export-specific reporter staphylococcal nuclease (NucA). Scaffolds retained their ability to associate in vivo with an engineered hybrid reporter enzyme, E. coli beta-glucuronidase fused to the type 1 dockerin motif of the cellulosomal enzyme CelS. Surface-anchored complexes exhibited dual enzyme activities (nuclease and beta-glucuronidase), and were displayed with efficiencies approaching 104 complexes/cell. CONCLUSIONS: We report the successful display of cellulosome-inspired recombinant complexes on the surface of Lactococcus lactis. Significant differences in display efficiency among constructs were observed and attributed to their structural characteristics including protein conformation and solubility, scaffold size, and the inclusion and exclusion of non-cohesin modules. The surface-display of functional scaffold proteins described here represents a key step in the development of recombinant microorganisms capable of carrying out a variety of metabolic processes including the direct conversion of cellulosic substrates into fuels and chemicals. PMID- 20840765 TI - Transcriptional profiling of ErbB signalling in mammary luminal epithelial cells- interplay of ErbB and IGF1 signalling through IGFBP3 regulation. AB - BACKGROUND: Members of the ErbB family of growth factor receptors are intricately linked with epithelial cell biology, development and tumourigenesis; however, the mechanisms involved in their downstream signalling are poorly understood. Indeed, it is unclear how signal specificity is achieved and the relative contribution each receptor has to specific gene expression. METHODS: Gene expression profiling of a human mammary luminal epithelial cell model of ErbB2-overexpression was carried out using cDNA microarrays with a common RNA reference approach to examine long-term overlapping and differential responses to EGF and heregulin beta1 treatment in the context of ErbB2 overexpression. Altered gene expression was validated using quantitative real time PCR and/or immunoblotting. One gene of interest was targeted for further characterisation, where the effects of siRNA mediated silencing on IGF1-dependent signalling and cellular phenotype were examined and compared to the effects of loss of ErbB2 expression. RESULTS: 775 genes were differentially expressed and clustered in terms of their growth factor responsiveness. As well as identifying uncharacterized genes as novel targets of ErbB2-dependent signalling, ErbB2 overexpression augmented the induction of multiple genes involved in proliferation (e.g. MYC, MAP2K1, MAP2K3), autocrine growth factor signalling (VEGF, PDGF) and adhesion/cytoskeletal regulation (ZYX, THBS1, VCL, CNN3, ITGA2, ITGA3, NEDD9, TAGLN), linking them to the hyper poliferative and altered adhesive phenotype of the ErbB2-overexpressing cells. We also report ErbB2-dependent down-regulation of multiple interferon-stimulated genes that may permit ErbB2-overexpressing cells to resist the anti-proliferative action of interferons. Finally, IGFBP3 was unique in its pattern of regulation and we further investigated a possible role for IGFBP3 down-regulation in ErbB2 dependent transformation through suppressed IGF1 signalling. We show that IGF1 dependent signalling and proliferation were enhanced in ErbB2-overexpressing cells, whilst loss of ErbB2 expression by siRNA silencing reduced IGF1 signalling. Furthermore, IGFBP3 knockdown resulted in basal ERK and Akt activation in luminal epithelial cells and increased invasiveness and anchorage independent colony formation in SKBR3 cells. CONCLUSIONS: These data show IGFBP3 as a negative regulator of transformation and that its down-regulation enhances IGF1-dependent signalling. They also show that ErbB2 can up-regulate IGF1 dependent signalling, possibly via the regulated expression of IGFBP3. PMID- 20840766 TI - Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils. AB - BACKGROUND: Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia. RESULTS: Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia), 1 d, 3 d and 7 d (n = 4 in each group). Sham-operated animals (n = 4) were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2). Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1)-positive cells were detected in the same areas in all animals. CONCLUSION: These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils. PMID- 20840764 TI - Pathological axes of wound repair: gastrulation revisited. AB - Post-traumatic inflammation is formed by molecular and cellular complex mechanisms whose final goal seems to be injured tissue regeneration.In the skin an exterior organ of the body- mechanical or thermal injury induces the expression of different inflammatory phenotypes that resemble similar phenotypes expressed during embryo development. Particularly, molecular and cellular mechanisms involved in gastrulation return. This is a developmental phase that delineates the three embryonic germ layers: ectoderm, endoderm and mesoderm. Consequently, in the post-natal wounded skin, primitive functions related with the embryonic mesoderm, i.e. amniotic and yolk sac-derived, are expressed. Neurogenesis and hematogenesis stand out among the primitive function mechanisms involved.Interestingly, in these phases of the inflammatory response, whose molecular and cellular mechanisms are considered as traces of the early phases of the embryonic development, the mast cell, a cell that is supposedly inflammatory, plays a key role.The correlation that can be established between the embryonic and the inflammatory events suggests that the results obtained from the research regarding both great fields of knowledge must be interchangeable to obtain the maximum advantage. PMID- 20840767 TI - Correlating pharmaceutical data with a national health survey as a proxy for estimating rural population health. AB - BACKGROUND: Chronic disease accounts for nearly three-quarters of US deaths, yet prevalence rates are not consistently reported at the state level and are not available at the sub-state level. This makes it difficult to assess trends in prevalence and impossible to measure sub-state differences. Such county-level differences could inform and direct the delivery of health services to those with the greatest need. METHODS: We used a database of prescription drugs filled in the US as a proxy for nationwide, county-level prevalence of three top causes of death: heart disease, stroke, and diabetes. We tested whether prescription data are statistically valid proxy measures for prevalence, using the correlation between prescriptions filled at the state level and comparable Behavioral Risk Factor Surveillance System (BRFSS) data. We further tested for statistically significant national geographic patterns. RESULTS: Fourteen correlations were tested for years in which the BRFSS questions were asked (1999-2003), and all were statistically significant. The correlations at the state level ranged from a low of 0.41 (stroke, 1999) to a high of 0.73 (heart disease, 2003). We also mapped self-reported chronic illnesses along with prescription rates associated with those illnesses. CONCLUSIONS: County prescription drug rates were shown to be valid measures of sub-state estimates of diagnosed prevalence and could be used to target health resources to counties in need. This methodology could be particularly helpful to rural areas whose prevalence rates cannot be estimated using national surveys. While there are no spatial statistically significant patterns nationally, there are significant variations within states that suggest unmet health needs. PMID- 20840768 TI - Temporal diversification of Central American cichlids. AB - BACKGROUND: Cichlid fishes are classic examples of adaptive radiation because of their putative tendency to explosively diversify after invading novel environments. To examine whether ecological opportunity increased diversification (speciation minus extinction) early in a species-rich cichlid radiation, we determined if Heroine cichlids experienced a burst of diversification following their invasion of Central America. RESULTS: We first reconstructed the Heroine phylogeny and determined the basal node to use as the root of Central American Heroine diversification. We then examined the influence of incomplete taxon sampling on this group's diversification patterns. First, we added missing species randomly to the phylogeny and assessed deviations from a constant rate of lineage accumulation. Using a range of species numbers, we failed to recover significant deviations from a pure-birth process and found little support for an early burst of diversification. Then, we examined patterns of lineage accumulation as nodes were increasingly truncated. We assumed that as we removed more recently diverged lineages that sampling would become more complete thereby increasing the power to detect deviations from a pure-birth model. However, truncation of nodes provided even less support for an early burst of diversification. CONCLUSIONS: Contrary to expectations, our analyses suggest Heroine cichlids did not undergo a burst of diversification when they invaded from South America. Throughout their history in Central America, Heroine cichlids appear to have diversified at a constant rate. PMID- 20840770 TI - First-time patellar dislocation with resultant habitual dislocation two years later, which was not demonstrated on plain X-rays halfway: a case report. AB - We present an instructive case of habitual left patellar dislocation in which the patella had appeared odd due to lateral tilt relative to contralateral side, but had been radiologically confirmed to be on the trochlea at 1 year prior to the referral. An 11-year-old girl presented to our hospital 2 years after the left patella had dislocated with a 'giving way' when cutting to the left. Our physical and radiological examinations confirmed that the left patella was laterally tilted in the patellar groove with the knee in extension but was dislocated in flexion beyond 45 degrees . In spite of these findings, she had been untreated at the previous hospital since all plain X-rays, including a skyline patellar view, had failed to demonstrate the dislocation. Consequently, in addition to reconstruction of medial patellofemoral ligament, she had to undergo a lateral retinacular release, which might have been unnecessary if treated earlier. This case illustrates that first-time patellar dislocation can gradually lead to habitual dislocation subsequently, and that cautious physical examinations in regard to patella tracking are essential since radiological examinations do not always reveal the pathophysiology of patellar instability. PMID- 20840769 TI - Antiproliferative effect of Tualang honey on oral squamous cell carcinoma and osteosarcoma cell lines. AB - BACKGROUND: The treatment of oral squamous cell carcinomas (OSCC) and human osteosarcoma (HOS) includes surgery and/or radiotherapy which often lead to reduced quality of life. This study was aimed to study the antiproliferative activity of local honey (Tualang) on OSCC and HOS cell lines. METHODS: Several concentrations of Tualang honey (1% - 20%) were applied on OSCC and HOS cell lines for 3, 6, 12, 24, 48 and 72 hours. Morphological characteristics were observed under light and fluorescent microscope. Cell viability was assessed using MTT assay and the optical density for absorbance values in each experiment was measured at 570 nm by an ELISA reader. Detection of cellular apoptosis was done using the Annexin V-FITC Apoptosis Detection Kit. RESULTS: Morphological appearance showed apoptotic cellular changes like becoming rounded, reduction in cell number, blebbed membrane and apoptotic nuclear changes like nuclear shrinkage, chromatin condensation and fragmented nucleus on OSCC and HOS cell lines. Cell viability assay showed a time and dose-dependent inhibitory effect of honey on both cell lines. The 50% inhibitory concentration (IC50) for OSCC and HOS cell lines was found to be 4% and 3.5% respectively. The maximum inhibition of cell growth of >=80% was obtained at 15% for both cell lines. Early apoptosis was evident by flow cytometry where percentage of early apoptotic cells increased in dose and time dependent manner. CONCLUSION: Tualang honey showed antiproliferative effect on OSCC and HOS cell lines by inducing early apoptosis. PMID- 20840771 TI - Implementation of exon arrays: alternative splicing during T-cell proliferation as determined by whole genome analysis. AB - BACKGROUND: The contribution of alternative splicing and isoform expression to cellular response is emerging as an area of considerable interest, and the newly developed exon arrays allow for systematic study of these processes. We use this pilot study to report on the feasibility of exon array implementation looking to replace the 3' in vitro transcription expression arrays in our laboratory.One of the most widely studied models of cellular response is T-cell activation from exogenous stimulation. Microarray studies have contributed to our understanding of key pathways activated during T-cell stimulation. We use this system to examine whole genome transcription and alternate exon usage events that are regulated during lymphocyte proliferation in an attempt to evaluate the exon arrays. RESULTS: Peripheral blood mononuclear cells form healthy donors were activated using phytohemagglutinin, IL2 and ionomycin and harvested at 5 points over a 7 day period. Flow cytometry measured cell cycle events and the Affymetrix exon array platform was used to identify the gene expression and alternate exon usage changes. Gene expression changes were noted in a total of 2105 transcripts, and alternate exon usage identified in 472 transcript clusters. There was an overlap of 263 transcripts which showed both differential expression and alternate exon usage over time. Gene ontology enrichment analysis showed a broader range of biological changes in biological processes for the differentially expressed genes, which include cell cycle, cell division, cell proliferation, chromosome segregation, cell death, component organization and biogenesis and metabolic process ontologies. The alternate exon usage ontological enrichments are in metabolism and component organization and biogenesis. We focus on alternate exon usage changes in the transcripts of the spliceosome complex. The real-time PCR validation rates were 86% for transcript expression and 71% for alternate exon usage. CONCLUSIONS: This study illustrates that the Exon array technology has the potential to provide information on both transcript expression and isoform usage, with very little increase in expense. PMID- 20840772 TI - Candidate genes associated with bud dormancy release in blackcurrant (Ribes nigrum L.). AB - BACKGROUND: The detrimental effects of mild winter temperatures on the consistency of cropping of blackcurrant (Ribes nigrum L.) in parts of Europe have led to increasing interest in the genetic control of dormancy release in this species. This study examined patterns of gene expression in leaf buds of blackcurrant to identify key differential changes in these profiles around the time of budbreak. RESULTS: Using leaf bud tissue of blackcurrant, a cDNA library was generated as a source of blackcurrant ESTs for construction of a custom microarray, which was used to identify differential gene expression during dormancy release. Gene activity was lowest in early stages of dormancy, increasing to reach a maximum around the time of budbreak. Genes with significantly changing expression profiles were clustered and evidence is provided for the transient activity of genes previously associated with dormancy processes in other species. Expression profiling identified candidate genes which were mapped onto a blackcurrant genetic linkage map containing budbreak-related QTL. Three genes, which putatively encode calmodulin-binding protein, beta tubulin and acetyl CoA carboxylase respectively, were found to co-localise with budbreak QTL. CONCLUSIONS: This study provides insight into the genetic control of dormancy transition in blackcurrant, identifying key changes in gene expression around budbreak. Genetic mapping of ESTs enabled the identification of genes which co-localise with previously-characterised blackcurrant QTL, and it is concluded that these genes have probable roles in release of dormancy and can therefore provide a basis for the development of genetic markers for future breeding deployment. PMID- 20840773 TI - International recommendations for glucose control in adult non diabetic critically ill patients. AB - INTRODUCTION: The purpose of this research is to provide recommendations for the management of glycemic control in critically ill patients. METHODS: Twenty-one experts issued recommendations related to one of the five pre-defined categories (glucose target, hypoglycemia, carbohydrate intake, monitoring of glycemia, algorithms and protocols), that were scored on a scale to obtain a strong or weak agreement. The GRADE (Grade of Recommendation, Assessment, Development and Evaluation) system was used, with a strong recommendation indicating a clear advantage for an intervention and a weak recommendation indicating that the balance between desirable and undesirable effects of an intervention is not clearly defined. RESULTS: A glucose target of less than 10 mmol/L is strongly suggested, using intravenous insulin following a standard protocol, when spontaneous food intake is not possible. Definition of the severe hypoglycemia threshold of 2.2 mmol/L is recommended, regardless of the clinical signs. A general, unique amount of glucose (enteral/parenteral) to administer for any patient cannot be suggested. Glucose measurements should be performed on arterial rather than venous or capillary samples, using central lab or blood gas analysers rather than point-of-care glucose readers. CONCLUSIONS: Thirty recommendations were obtained with a strong (21) and a weak (9) agreement. Among them, only 15 were graded with a high level of quality of evidence, underlying the necessity to continue clinical studies in order to improve the risk-to-benefit ratio of glucose control. PMID- 20840774 TI - Personality and the physician-patient relationship as predictors of quality of life of cardiac patients after rehabilitation. AB - BACKGROUND: Numerous studies document the influence of psychosocial variables on the course of coronary heart disease. This study examines the influence of personality traits (trait anger, cynicism) and aspects of the physician-patient relationship (promoting patient participation by the physician, active communication behavior of the patient, trust in the physician) on the health related quality of life (HRQOL) of cardiac patients after rehabilitation. METHODS: N = 331 patients with chronic ischemic heart disease were surveyed using questionnaires at two time points (beginning and end of 3-weeks inpatient rehabilitation). In addition, characteristics of the disease and cardiac risk factors were provided by the physician. HRQOL was measured using a total of six scales and three instruments: SF-12, MacNew questionnaire, and SAQ. Hierarchical regression analyses were carried out to predict HRQOL after rehabilitation, in which the baseline values of HRQOL, sociodemographic variables, characteristics of the disease and risk factors, personality traits, and finally the aspects of the physician-patient relationship were included stepwise. As a number of variables were used for the regression models, multiple imputation was conducted. RESULTS: The baseline values explain most of the variance (42%-60%). After controlling the baseline values, the sociodemographic variables explain up to 5% incremental variance of HRQOL, with income being the most important predictor. The characteristics of the disease and cardiac risk factors explain between 0.4% and 3.8% incremental variance, however, variance increase is often not significant. The personality traits added in the fourth step explain up to 2% additional variance; trait anger is a significant predictor of HRQOL in three of the six scales. The features of the physician-patient relationship included in the last step lead to a significant increase in explained variance (between 1.3% and 3.9%) for all six scales. In particular, the physician's promotion of patient participation has a significant influence. The overall explanation of variance for HRQOL is between 50% and 64%. CONCLUSIONS: Low income, a high level of trait anger, and low patient participation are significant risk factors, even if a number of potential confounders are adjusted. Research is needed that shows which causal pathway low income functions on and what therapies in rehabilitation can mitigate the disadvantage of persons with a high level of trait anger. The providers should implement measures to actively integrate rehabilitation patients in treatment (e.g. encourage them to ask questions). PMID- 20840775 TI - The nontoxic natural compound Curcumin exerts anti-proliferative, anti-migratory, and anti-invasive properties against malignant gliomas. AB - BACKGROUND: New drugs are constantly sought after to improve the survival of patients with malignant gliomas. The ideal substance would selectively target tumor cells without eliciting toxic side effects. Here, we report on the anti proliferative, anti-migratory, and anti-invasive properties of the natural, nontoxic compound Curcumin observed in five human glioblastoma (GBM) cell lines in vitro. METHODS: We used monolayer wound healing assays, modified Boyden chamber trans-well assays, and cell growth assays to quantify cell migration, invasion, and proliferation in the absence or presence of Curcumin at various concentrations. Levels of the transcription factor phospho-STAT3, a potential target of Curcumin, were determined by sandwich-ELISA. Subsequent effects on transcription of genes regulating the cell cycle were analyzed by quantitative real-time PCR. Effects on apoptosis were determined by caspase assays. RESULTS: Curcumin potently inhibited GBM cell proliferation as well as migration and invasion in all cell lines contingent on dose. Simultaneously, levels of the biologically active phospho-STAT3 were decreased and correlated with reduced transcription of the cell cycle regulating gene c-Myc and proliferation marking Ki-67, pointing to a potential mechanism by which Curcumin slows tumor growth. CONCLUSIONS: Curcumin is part of the diet of millions of people every day and is without known toxic side effects. Our data show that Curcumin bears anti proliferative, anti-migratory, and anti-invasive properties against GBM cells in vitro. These results warrant further in vivo analyses and indicate a potential role of Curcumin in the treatment of malignant gliomas. PMID- 20840776 TI - Developing criteria for cesarean section using the RAND appropriateness method. AB - BACKGROUND: Cesarean section rates are increasing worldwide, and a rapid increase has been observed in Iran. Disagreement exists between clinicians about when to use cesarean section. We aimed to identify the appropriateness criteria for the use of cesarean section in Iran. METHOD: A consensus development study using a modified version of the RAND Appropriateness Method (RAM). We generated scenarios from valid clinical guidelines and expert opinions. A panel of experts participated in consensus development: first round via mail (12 members), second round face-to-face (9 members). We followed the RAM recommendations for the development of the scenario lists, rating scales, and statistical analyses. RESULTS: 294 scenarios relevant to cesarean section were identified. 191 scenarios were considered appropriate, of which 125 scenarios were agreed upon. The panel found cesarean inappropriate for 21% of scenarios, and 'equivocal' for 14% of scenarios. CONCLUSION: RAM is useful for identifying stakeholder views in settings with limited resources. The participants' views on appropriateness of certain indications differed with available evidence. A large number of scenarios without agreement may partly explain why it has been difficult to curb the growth in cesarean section rate. PMID- 20840777 TI - Determining the role of external beam radiotherapy in unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary liver cancer. Only few studies have focused on palliative radiotherapy used for patients who weren't suitable for resection by surgery. This study was conducted to investigate the effect of external beam radiotherapy (EBRT) for patients with unresectable ICC. METHODS: We identified 84 patients with ICC from December 1998 through December 2008 for retrospective analysis. Thirty-five of 84 patients received EBRT therapy five times a week (median dose, 50 Gy; dose range, 30-60 Gy, in fractions of 1.8-2.0 Gy daily; EBRT group); the remaining 49 patients comprised the non-EBRT group. Tumor response, jaundice relief, and survival rates were compared by Kaplan-Meier analysis. Patient records were reviewed and compared using Cox proportional hazard analysis to determine factors that affect survival time in ICC. RESULTS: After EBRT, complete response (CR) and partial response (PR) of primary tumors were observed in 8.6% and 28.5% of patients, respectively, and CR and PR of lymph node metastases were observed in 20% and 40% of patients. In 19 patients with jaundice, complete and partial relief was observed in 36.8% and 31.6% of patients, respectively. Median survival times were 5.1 months for the non-EBRT group and 9.5 months for the EBRT group (P = 0.003). One-and two-year survival rates for EBRT versus non-EBRT group were 38.5% versus 16.4%, and 9.6% versus 4.9%, respectively. Multivariate analysis revealed that clinical symptoms, larger tumor size, no EBRT, multiple nodules and synchronous lymph node metastases were associated with poorer prognosis. CONCLUSIONS: EBRT as palliative care appears to improve prognosis and relieve the symptom of jaundice in patients with unresectable ICC. PMID- 20840778 TI - The potential role of appetite in predicting weight changes during treatment with olanzapine. AB - BACKGROUND: Clinically significant weight gain has been reported during treatment with atypical antipsychotics. It has been suggested that weight changes in patients treated with olanzapine may be associated with increased appetite. METHODS: Data were used from adult patients for whom both appetite and weight data were available from 4 prospective, 12- to 24-week clinical trials. Patients' appetites were assessed with Eating Behavior Assessment (EBA, Study 1), Platypus Appetite Rating Scale (PARS, Study 2), Eating Inventory (EI, Study 3), Food Craving Inventory (FCI, Study 3), and Eating Attitude Scale (EAS, Study 4). RESULTS: In Studies 1 (EBA) and 4 (EAS), patients who reported overall score increases on appetite scales, indicating an increase in appetite, experienced the greatest overall weight gains. However, in Studies 2 (PARS) and 3 (EI, FCI), patients who reported overall score increases on appetite scales did not experience greater weight changes than patients not reporting score increases. Early weight changes (2-4 weeks) were more positively correlated with overall weight changes than early or overall score changes on any utilized appetite assessment scale. No additional information was gained by adding early appetite change to early weight change in correlation to overall weight change. CONCLUSIONS: Early weight changes may be a more useful predictor for long-term weight changes than early score changes on appetite assessment scales. CLINICAL TRIALS REGISTRATION: This report represents secondary analyses of 4 clinical studies. Studies 1, 2, and 3 were registered at http://clinicaltrials.gov/ct2/home, under NCT00190749, NCT00303602, and NCT00401973, respectively. Study 4 predates the registration requirements for observational studies that are not classified as category 1 observational studies. PMID- 20840779 TI - Host adaptive immunity deficiency in severe pandemic influenza. AB - INTRODUCTION: Pandemic A/H1N1/2009 influenza causes severe lower respiratory complications in rare cases. The association between host immune responses and clinical outcome in severe cases is unknown. METHODS: We utilized gene expression, cytokine profiles and generation of antibody responses following hospitalization in 19 critically ill patients with primary pandemic A/H1N1/2009 influenza pneumonia for identifying host immune responses associated with clinical outcome. Ingenuity pathway analysis 8.5 (IPA) (Ingenuity Systems, Redwood City, CA) was used to select, annotate and visualize genes by function and pathway (gene ontology). IPA analysis identified those canonical pathways differentially expressed (P < 0.05) between comparison groups. Hierarchical clustering of those genes differentially expressed between groups by IPA analysis was performed using BRB-Array Tools v.3.8.1. RESULTS: The majority of patients were characterized by the presence of comorbidities and the absence of immunosuppressive conditions. pH1N1 specific antibody production was observed around day 9 from disease onset and defined an early period of innate immune response and a late period of adaptive immune response to the virus. The most severe patients (n = 12) showed persistence of viral secretion. Seven of the most severe patients died. During the late phase, the most severe patient group had impaired expression of a number of genes participating in adaptive immune responses when compared to less severe patients. These genes were involved in antigen presentation, B-cell development, T-helper cell differentiation, CD28, granzyme B signaling, apoptosis and protein ubiquitination. Patients with the poorest outcomes were characterized by proinflammatory hypercytokinemia, along with elevated levels of immunosuppressory cytokines (interleukin (IL)-10 and IL 1ra) in serum. CONCLUSIONS: Our findings suggest an impaired development of adaptive immunity in the most severe cases of pandemic influenza, leading to an unremitting cycle of viral replication and innate cytokine-chemokine release. Interruption of this deleterious cycle may improve disease outcome. PMID- 20840780 TI - No observed effect of homologous recombination on influenza C virus evolution. AB - The occurrence of homologous recombination in influenza viruses has been under some debate recently. To determine the extent of homologous recombination in influenza C virus, recombination analyses of all available gene sequences of influenza C virus were carried out. No recombination signal was found. With the previous evidence in influenza A and B viruses, it seems that homologous recombination has minimal or no effect on influenza virus evolution. PMID- 20840781 TI - Phosphatidylinositol 3 kinase modulation of trophoblast cell differentiation. AB - BACKGROUND: The trophoblast lineage arises as the first differentiation event during embryogenesis. Trophoblast giant cells are one of several end-stage products of trophoblast cell differentiation in rodents. These cells are located at the maternal-fetal interface and are capable of invasive and endocrine functions, which are necessary for successful pregnancy. Rcho-1 trophoblast stem cells can be effectively used as a model for investigating trophoblast cell differentiation. In this report, we evaluated the role of the phosphatidylinositol 3-kinase (PI3K) signaling pathway in the regulation of trophoblast cell differentiation. Transcript profiles from trophoblast stem cells, differentiated trophoblast cells, and differentiated trophoblast cells following disruption of PI3K signaling were generated and characterized. RESULTS: Prominent changes in gene expression accompanied the differentiation of trophoblast stem cells. PI3K modulated the expression of a subset of trophoblast cell differentiation-dependent genes. Among the PI3K-responsive genes were those encoding proteins contributing to the invasive and endocrine phenotypes of trophoblast giant cells. CONCLUSIONS: Genes have been identified with differential expression patterns associated with trophoblast stem cells and trophoblast cell differentiation; a subset of these genes are regulated by PI3K signaling, including those impacting the differentiated trophoblast giant cell phenotype. PMID- 20840782 TI - Co-option of EDM2 to distinct regulatory modules in Arabidopsis thaliana development. AB - BACKGROUND: Strong immunity of plants to pathogenic microorganisms is often mediated by highly specific mechanisms of non-self recognition that are dependent on disease resistance (R) genes. The Arabidopsis thaliana protein EDM2 is required for immunity mediated by the R gene RPP7. EDM2 is nuclear localized and contains typical features of transcriptional and epigenetic regulators. In addition, to its role in immunity, EDM2 plays also a role in promoting floral transition. This developmental function of EDM2, but not its role in RPP7 mediated disease resistance, seems to involve the protein kinase WNK8, which physically interacts with EDM2 in nuclei. RESULTS: Here we report that EDM2 affects additional developmental processes which include the formation of leaf pavement cells and leaf expansion as well as the development of morphological features related to vegetative phase change. EDM2 has a promoting effect of each of these processes. While WNK8 seems not to exhibit any vegetative phase change related function, it has a promoting effect on the development of leaf pavement cells and leaf expansion. Microarray data further support regulatory interactions between WNK8 and EDM2. The fact that the effects of EDM2 and WNK8 on leaf pavement cell formation and leaf expansion are co-directional, while WNK8 counteracts the promoting effect of EDM2 on floral transition, is surprising and suggests that WNK8 can modulate the activity of EDM2. CONCLUSION: We propose that EDM2 has been co-opted to distinct regulatory modules controlling a set of different processes in plant immunity and development. WNK8 appears to modulate some functions of EDM2. PMID- 20840783 TI - Staged cardiovascular magnetic resonance for differential diagnosis of troponin T positive patients with low likelihood for acute coronary syndrome. AB - BACKGROUND: Cardiac troponin-T (cTnT) is a cardio-specific indicator of myocardial necrosis due to ischemic or non-ischemic events. Considering the multiple causes of myocardial injury and treatment consequences there is great clinical need to clarify the underlying reason for cTnT release. We sought to implement acute CMR as a non-invasive imaging method for differential diagnosis of elevated cTnT in chest-pain unit (CPU) patients with non-conclusive symptoms and ECG-changes and a low to intermediate probability for coronary artery disease (CAD). RESULTS: CPU patients (n = 29) who had positive cTnT were scanned at 1.5T with a new step-by-step CMR algorithm including cine-, perfusion-, T2-, angiography-and late gadolinium enhancement (LGE) imaging. For comparison patients also underwent echocardiography and coronary angiography if necessary. CMR was conducted successfully in all patients and detected 93% of cTnT releases of unknown cause, without adverse hemodynamic or arrhythmic events. Acute myocardial infarction was detected in 11, pulmonary embolism in 6, myocarditis in 5, renal disease and cardiomyopathy in 2, storage disorder in 1 patient. In 2 patients CMR was unable to reveal the cause of cTnT elevations. Mean CMR scan time was 35 +/- 8 min. In 4 patients, CMR led to immediate coronary angiography with correct prediction of the infarct related artery. CONCLUSIONS: We implemented a novel CMR algorithm to show the clinical value and practical feasibility of acute CMR in a non-conclusive patient cohort with unclear cTnT elevation. Since this pilot study has shown the feasibility of CMR in CPU patients, further prospective studies are warranted to compare CMR with other imaging modalities. PMID- 20840784 TI - Mothers' knowledge and utilization of prevention of mother to child transmission services in northern Tanzania. AB - BACKGROUND: More than 90% of children living with HIV have been infected through mother to child transmission. The aims of our present study were to: (1) assess the utilization of the prevention of mother to child transmission (PMTCT) services in five reproductive and child health clinics in Moshi, northern Tanzania, after the implementation of routine counselling and testing; (2) explore the level of knowledge the postnatal mothers had about PMTCT; and (3) assess the quality of the counselling given. METHODS: This study was conducted in 2007 and 2008 in rural and urban areas of Moshi in the Kilimanjaro region of Tanzania. Mixed methods were used. We interviewed 446 mothers when they brought their four-week-old infants to five reproductive and child health clinics for immunization. On average, the urban clinics included in the study had implemented the programme two years earlier than the rural clinics. We also conducted 13 in depth interviews with mothers and nurses, four focus group discussions with mothers, and four observations of mothers receiving counselling. RESULTS: Nearly all mothers (98%) were offered HIV testing, and all who were offered accepted. However, the counselling was hasty with little time for clarifications. Mothers attending urban antenatal clinics tended to be more knowledgeable about PMTCT than the rural attendees. Compared with previous studies in the area, our study found that PMTCT knowledge had increased and the counsellors had greater confidence in their counselling. CONCLUSIONS: Routine counselling and testing for HIV at the antenatal clinics was greatly accepted and included practically every mother in this time period. However, the counselling was suboptimal due to time and resource constraints. We interpret the higher level of PMTCT knowledge among the urban as opposed to the rural attendees as a result of differences in the start up of the PMTCT programme and, thus, programme maturation. After comparison with earlier studies conducted in this setting, we conclude that when the programme has had time to get established, both its acceptance and the understanding of the topics dealt with during the counselling increases. PMID- 20840785 TI - The inverse association of serum HBV DNA level with HDL and adiponectin in chronic hepatitis B infection. AB - BACKGROUND: The natural history of hepatitis B virus (HBV) is complex and influenced by the level of viral replication and host factors. The hepatoprotective role of high density lipoproteins (HDL) and adiponectin as host factors on HBV persistence is less well understood. METHODS: To investigate correlation between HBV DNA level with clinical parameters in patients with chronic hepatitis B, 92 male subjects with HBV infection without any risk factors for diabetes were enrolled in this study. Age and BMI of the study population were matched and HBV DNA, ALT, tumor necrosis factor alpha (TNF-alpha), adiponectin and lipid levels was measured. RESULTS: Serum HBV DNA correlated inversely with serum HDL level (r = -0.23; P = 0.014). The median of log copies/ml for HBV DNA (3.67) was considered as cut off point. Patients with HBV DNA level higher than cut off point had lower adiponectin (8.7 +/- 5.3 vs 10.7 +/ 4.9 MUg/ml p = 0.05). Also, adiponectin had a negative correlation with TNF alpha (r = -0.21, P = 0.04) and positive correlations with HDL (r = 0.18, P = 0.043). Multivariate regression models show that serum HDL level is an independent factor to predict serum HBV DNA. CONCLUSION: Our findings showed that higher HBV DNA levels are associated with lower HDL and adiponectin but induced TNF-alpha values. PMID- 20840786 TI - Autonomous indoor wayfinding for individuals with cognitive impairments. AB - BACKGROUND: A challenge to individuals with cognitive impairments in wayfinding is how to remain oriented, recall routines, and travel in unfamiliar areas in a way relying on limited cognitive capacity. While people without disabilities often use maps or written directions as navigation tools or for remaining oriented, this cognitively-impaired population is very sensitive to issues of abstraction (e.g. icons on maps or signage) and presents the designer with a challenge to tailor navigation information specific to each user and context. METHODS: This paper describes an approach to providing distributed cognition support of travel guidance for persons with cognitive disabilities. A solution is proposed based on passive near-field RFID tags and scanning PDAs. A prototype is built and tested in field experiments with real subjects. The unique strength of the system is the ability to provide unique-to-the-user prompts that are triggered by context. The key to the approach is to spread the context awareness across the system, with the context being flagged by the RFID tags and the appropriate response being evoked by displaying the appropriate path guidance images indexed by the intersection of specific end-user and context ID embedded in RFID tags. RESULTS: We found that passive RFIDs generally served as good context for triggering navigation prompts, although individual differences in effectiveness varied. The results of controlled experiments provided more evidence with regard to applicabilities of the proposed autonomous indoor wayfinding method. CONCLUSIONS: Our findings suggest that the ability to adapt indoor wayfinding devices for appropriate timing of directions and standing orientation will be particularly important. PMID- 20840787 TI - High-resolution melting curve analysis for rapid detection of mutations in a Medaka TILLING library. AB - BACKGROUND: During the last two decades, DNA sequencing has led to the identification of numerous genes in key species; however, in most cases, their functions are still unknown. In this situation, reverse genetics is the most suitable method to assign function to a gene. TILLING (Targeting Induced Local Lesions IN Genomes) is a reverse-genetic strategy that combines random chemical mutagenesis with high-throughput discovery of the induced mutations in target genes. The method has been applied to a variety of plant and animal species. Screening of the induced mutations is the most important step in TILLING. Currently, direct sequencing or nuclease-mediated screening of heteroduplexes is widely used for detection of mutations in TILLING. Both methods are useful, but the costs are substantial and turnaround times are relatively long. Thus, there is a need for an alternative method that is of higher throughput and more cost effective. RESULTS: In this study, we developed a high resolution melting (HRM) assay and evaluated its effectiveness for screening ENU-induced mutations in a medaka TILLING library. We had previously screened mutations in the p53 gene by direct sequencing. Therefore, we first tested the efficiency of the HRM assay by screening mutations in p53, which indicated that the HRM assay is as useful as direct sequencing. Next, we screened mutations in the atr and atm genes with the HRM assay. Nonsense mutations were identified in each gene, and the phenotypes of these nonsense mutants confirmed their loss-of-function nature. CONCLUSIONS: These results demonstrate that the HRM assay is useful for screening mutations in TILLING. Furthermore, the phenotype of the obtained mutants indicates that medaka is an excellent animal model for investigating genome stability and gene function, especially when combined with TILLING. PMID- 20840788 TI - Use of serum squamous cell carcinoma antigen for follow-up monitoring of cervical cancer patients who were treated by concurrent chemoradiotherapy. AB - BACKGROUND: To investigate the significance of monitoring the levels of the serum squamous cell carcinoma antigen (SCC-Ag) for the detection of recurrent disease in patients with cervical cancer treated by concurrent chemoradiotherapy. METHODS: The records of 112 patients with cervical cancer were reviewed. Serum SCC-Ag levels were measured at regular follow-up visits. A SCC-Ag level of 2 ng/mL was considered the upper limit of normal. Biochemical failure was defined as two consecutively increasing SCC-Ag values above normal. Recurrent disease was confirmed by histologic and radiographic studies. RESULTS: Eighteen patients (16%) developed recurrent disease. Sixteen patients had initially elevated SCC Ag, post-treatment normalization of SCC-Ag, and tumor recurrence. The SCC-Ag difference (DeltaSCC-Ag), defined as the difference between the last value after two consecutively increases above normal and the value immediately before the elevation, had good clinical performance in predicting cancer recurrence. The cutoff value of DeltaSCC-Ag was 0.95 ng/mL. CONCLUSIONS: SCC-Ag is a relatively good method for the detection of disease recurrence in patients with cervical cancer who were treated by concurrent chemoradiotherapy. PMID- 20840789 TI - Soluble L1CAM promotes breast cancer cell adhesion and migration in vitro, but not invasion. AB - BACKGROUND: Neural recognition molecule L1CAM, which is a key protein involved in early nervous system development, is known to be abnormally expressed and shed in several types of cancers where it participates in metastasis and progression. The distinction of L1CAM presence in cancerous vs. normal tissues has suggested it to be a new target for cancer treatment. Our current study focused on the potential role of soluble L1CAM in breast cancer cell adhesion to extracellular matrix proteins, migration, and invasion. RESULTS: We found L1 expression levels were correlated with breast cancer stage of progression in established data sets of clinical samples, and also were high in more metastatic breast cancer cell lines MDA-MB-231 and MDA-MB-435, but low in less migratory MDA-MB-468 cells. Proteolysis of L1 into its soluble form (sL1) was detected in cell culture medium from all three above cell lines, and can be induced by PMA activation. Over expression of the L1 ectodomain in MDA-MB-468 cells by using a lentiviral vector greatly increased the amount of sL1 released by those cells. Concomitantly, cell adhesion to extracellular matrix and cell transmigration ability were significantly promoted, while cell invasion ability through MatrigelTM remained unaffected. On the other hand, attenuating L1 expression in MDA-MB-231 cells by using a shRNA lentiviral vector resulted in reduced cell-matrix adhesion and transmigration. Similar effects were also shown by monoclonal antibody blocking of the L1 extracellular region. Moreover, sL1 in conditioned cell culture medium induced a directional migration of MDA-MB-468 cells, which could be neutralized by antibody treatment. CONCLUSIONS: Our data provides new evidence for the function of L1CAM and its soluble form in promoting cancer cell adhesion to ECM and cell migration. Thus, L1CAM is validated further to be a potential early diagnostic marker in breast cancer progression and a target for breast cancer therapy. PMID- 20840790 TI - Use of Multiple Displacement Amplification as Pre-polymerase Chain Reaction (Pre PCR) to amplify genomic DNA of siphonapterids preserved for long periods in scientific collections. AB - The recently developed Multiple Displacement Amplification technique (MDA) allows for the production of a large quantity of high quality genomic DNA from low amounts of the original DNA. The goal of this study was to evaluate the performance of the MDA technique to amplify genomic DNA of siphonapterids that have been stored for long periods in 70% ethanol at room temperature. We subjected each DNA sample to two different methodologies: (1) amplification of mitochondrial 16S sequences without MDA; (2) amplification of 16S after MDA. All the samples obtained from these procedures were then sequenced. Only 4 samples (15.4%) subjected to method 1 showed amplification. In contrast, the application of MDA (method 2) improved the performance substantially, with 24 samples (92.3%) showing amplification, with significant difference. Interestingly, one of the samples successfully amplified with this method was originally collected in 1909. All of the sequenced samples displayed satisfactory results in quality evaluations (Phred >= 20) and good similarities, as identified with the BLASTn tool. Our results demonstrate that the use of MDA may be an effective tool in molecular studies involving specimens of fleas that have traditionally been considered inadequately preserved for such purposes. PMID- 20840791 TI - Buccal mucosa carcinoma: surgical margin less than 3 mm, not 5 mm, predicts locoregional recurrence. AB - BACKGROUND: Most treatment failure of buccal mucosal cancer post surgery is locoregional recurrence. We tried to figure out how close the surgical margin being unsafe and needed further adjuvant treatment. METHODS: Between August 2000 and June 2008, a total of 110 patients with buccal mucosa carcinoma (25 with stage I, 31 with stage II, 11 with stage III, and 43 with Stage IV classified according to the American Joint Committee on Cancer 6th edition) were treated with surgery alone (n = 32), surgery plus postoperative radiotherapy (n = 38) or surgery plus adjuvant concurrent chemoradiotherapy (n = 40). MAIN OUTCOME MEASURES: The primary endpoint was locoregional disease control. RESULTS: The median follow-up time at analysis was 25 months (range, 4-104 months). The 3-year locoregional control rates were significantly different when a 3-mm surgical margin (<=3 versus >3 mm, 71% versus 95%, p = 0.04) but not a 5-mm margin (75% versus 92%, p = 0.22) was used as the cut-off level. We also found a quantitative correlation between surgical margin and locoregional failure (hazard ratio, 2.16; 95% confidence interval, 1.14 - 4.11; p = 0.019). Multivariate analysis identified pN classification and surgical margin as independent factors affecting disease-free survival and locoregional control. CONCLUSIONS: Narrow surgical margin <=3 mm, but not 5 mm, is associated with high risk for locoregional recurrence of buccal mucosa carcinoma. More aggressive treatment after surgery is suggested. PMID- 20840792 TI - Decreased health-related quality of life in disease-free survivors of differentiated thyroid cancer in Korea. AB - BACKGROUND: Concern regarding the health-related quality of life (HRQOL) of long term survivors of thyroid cancer has risen due to the rapid increase in the incidence of thyroid cancer, which generally has an excellent prognosis. The aim of this study was to evaluate the status of HRQOL in disease-free survivors of differentiated thyroid carcinoma (DTC) and to evaluate the important determinants of HRQOL. METHODS: This was a cross-sectional study in which we interviewed consecutive disease-free survivors of DTC. Three different validated questionnaires ("EORTC QLQ-C30" for various functional domains, the "brief fatigue inventory (BFI)" and the "hospital anxiety and depression scale" (HADS)) were used. Data from a large, population based survey of 1,000 people were used as a control. RESULTS: The response rate for the questionnaires was 78.9% (316/401). Disease-free survivors of DTC showed a decreased HRQOL in all five functional domains (physical, role, cognitive, emotional, and social) on the EORTC QLQ-C30 compared with controls (P < 0.01). BFI and HADS-anxiety scores also showed greater distress in disease-free survivors of DTC than in controls (P < 0.05). A multiple regression analysis for the determinants of HRQOL showed that the HADS-anxiety, HADS-depression, and BFI scores were the most significant components of decreased HRQOL. CONCLUSIONS: Although disease-free survivors of DTC are expected to have disease-specific survival comparable to the general population, they experience a significantly decreased HRQOL. Anxiety, depression, and fatigue were the major determinants of the decreased HRQOL. Supportive psychological care should be integrated into the management of long-term survivors of DTC. PMID- 20840793 TI - Young patients with colorectal cancer have poor survival in the first twenty months after operation and predictable survival in the medium and long-term: analysis of survival and prognostic markers. AB - OBJECTIVES: This study compares clinico-pathological features in young (<40 years) and older patients (>50 years) with colorectal cancer, survival in the young and the influence of pre-operative clinical and histological factors on survival. MATERIALS AND METHODS: A twelve year prospective database of colorectal cancer was analysed. Fifty-three young patients were compared with forty seven consecutive older patients over fifty years old. An analysis of survival was undertaken in young patients using Kaplan Meier graphs, non parametric methods, Cox's Proportional Hazard Ratios and Weibull Hazard models. RESULTS: Young patients comprised 13.4 percent of 397 with colorectal cancer. Duration of symptoms and presentation in the young was similar to older patients (median, range; young patients; 6 months, 2 weeks to 2 years, older patients; 4 months, 4 weeks to 3 years, p > 0.05). In both groups, the majority presented without bowel obstruction (young--81%, older--94%). Cancer proximal to the splenic flexure was present more in young than in older patients. Synchronous cancers were found exclusively in the young. Mucinous tumours were seen in 16% of young and 4% of older patients (p < 0.05). Ninety four percent of young cancer deaths were within 20 months of operation. At median follow up of 50 months in the young, overall survival was 70% and disease free survival 66%. American Joint Committee on Cancer (AJCC) stage 4 and use of pre-operative chemoradiation in rectal cancer was associated with poor survival in the young. CONCLUSION: If patients, who are less than 40 years old with colorectal cancer, survive twenty months after operation, the prognosis improves and their survival becomes predictable. PMID- 20840794 TI - MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients. AB - BACKGROUND: Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis. MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA. The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients. METHODS: IL-17 producing cells were expanded from CD4+T cell. MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells. Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients. Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium. RESULTS: Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells. The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration. MiR-146a intensely expressed in RA synovium in comparison to OA. MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity. Double staining revealed that miR-146a expressed in IL-17 expressing cells. CONCLUSION: These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients. There is the possibility that miR-146a participates in the IL-17 expression. PMID- 20840795 TI - Qualitative insights into general practitioners views on polypharmacy. AB - BACKGROUND: Polypharmacy is common among older people. The purpose of this study is to describe GPs' views and beliefs on polypharmacy in order to identify the role of the GP in relation to improving prescribing behaviour. The awareness of these often established beliefs is key for understanding behaviour and promoting change which can guide action towards more rational prescribing. METHODS: A qualitative descriptive methodology was used with semi-structured interviews. Interviews were conducted with 65 GPs from the region of Aalst, a district of a mixed urban and rural population in Belgium. The aim of the study was to describe the GPs' perspectives on polypharmacy in primary care. RESULTS: GPs acknowledge that polypharmacy is a problem in their older patient population, especially because of the risk of adverse drug reactions, interactions and lowered adherence. GPs mention that difficulties in keeping an overview of the exact medication intake is an important problem caused by polypharmacy. The patients' strong belief in their medication and self-medication are seen as important barriers in reducing the number of drugs taken. Next to these patient related factors, there are some factors related to the prescriber, such as the lack of regular evaluation of the medication schedule by GPs and the involvement of several prescribers, especially in a hospital setting. According to the respondents, prevention and evidence based medicine guidelines often induce polypharmacy. CONCLUSIONS: GPs point out that polypharmacy is an important problem in their older patient population. They see an important role for themselves in optimizing drug regimens for their patients. However, they do not have a readymade solution for polypharmacy. The limited set of options for addressing polypharmacy leave GPs feeling powerless to tackle the problem. There is a need for simple GP friendly tools and access to pharmacotherapeutic advice. Future research in this area and interventions seeking to improve prescribing for the elderly will have to focus on practical tools and take into account the GPs' sense of helplessness. PMID- 20840796 TI - On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations. AB - Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER), which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH) and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs). The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer.The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools. PMID- 20840797 TI - Fluorescence in situ hybridization in combination with the comet assay and micronucleus test in genetic toxicology. AB - Comet assay and micronucleus (MN) test are widely applied in genotoxicity testing and biomonitoring. While comet assay permits to measure direct DNA-strand breaking capacity of a tested agent MN test allows estimating the induced amount of chromosome and/or genome mutations. The potential of these two methods can be enhanced by the combination with fluorescence in situ hybridization (FISH) techniques. FISH plus comet assay allows the recognition of targets of DNA damage and repairing directly. FISH combined with MN test is able to characterize the occurrence of different chromosomes in MN and to identify potential chromosomal targets of mutagenic substances. Thus, combination of FISH with the comet assay or MN test proved to be promising techniques for evaluation of the distribution of DNA and chromosome damage in the entire genome of individual cells. FISH technique also permits to study comet and MN formation, necessary for correct application of these methods. This paper reviews the relevant literature on advantages and limitations of Comet-FISH and MN-FISH assays application in genetic toxicology. PMID- 20840798 TI - Estimation of dead space fraction can be simplified in the acute respiratory distress syndrome. AB - Acute lung injury and acute respiratory distress syndrome are characterized by a non-cardiogenic pulmonary edema responsible for a significant impairment of gas exchange. The pulmonary dead space increase, which is due primarily to an alteration in pulmonary blood flow distribution, is largely responsible for carbon dioxide retention. Previous studies, computing the pulmonary dead space by measuring the expired carbon dioxide and the Enghoff equation, found that the dead space fraction was significantly higher in the non-survivors; it was even an independent risk of death. The computation of the dead space not by measuring the expired carbon dioxide but by applying a rearranged alveolar gas equation that takes into account only the weight, age, height, and temperature of the patient could lead to widespread clinical diffusion of this measurement at the bedside. PMID- 20840799 TI - The endless race between Trypanosoma cruzi and host immunity: lessons for and beyond Chagas disease. AB - Infection with the protozoan parasite Trypanosoma cruzi, the agent of Chagas disease, is characterised by a variable clinical course - from symptomless cases to severe chronic disease with cardiac and/or gastrointestinal involvement. The variability in disease outcome has been attributed to host responses as well as parasite heterogeneity. In this article, we review studies indicating the importance of immune responses as key determinants of host resistance to T. cruzi infection and the pathogenesis of Chagas disease. Particular attention is given to recent studies defining the role of cognate innate immune receptors and immunodominant CD8+ T cells that recognise parasite components - both crucial for host-parasite interaction and disease outcome. In light of these studies we speculate about parasite strategies that induce a strong and long-lasting T-cell mediated immunity but at the same time allow persistence of the parasite in the vertebrate host. We also discuss what we have learned from these studies for increasing our understanding of Chagas pathogenesis and for the design of new strategies to prevent the development of Chagas disease. Finally, we highlight recent studies employing a genetically engineered attenuated T. cruzi strain as a vaccine shuttle that elicits potent T cell responses specific to a tumour antigen and protective immunity against a syngeneic melanoma cell line. PMID- 20840800 TI - On quantifying quality. PMID- 20840801 TI - Measuring quality of mental health care: a review of initiatives and programs in selected countries. AB - This review article presents a systematic review of grey literature describing current initiatives that assess the quality of mental health care in 12 countries, as collected by the International Initiative for Mental Health Leadership.There have been increased efforts in many countries to develop and implement mental health indicator schemes to measure and monitor the quality of mental health care at the national and subnational level. Most mental health indicator sets are part of larger health policy initiatives at the national and (or) provincial or state level, with indicators and domains regularly reviewed and revised. The indicator sets described in health care quality initiatives vary widely in their scope, intended use, and degree of development, and they often cut across a broad range of domains, reflecting not only a country's specific health system and how it is organized and structured but also the implementation of such schemes (that is, collection and analysis of data) and the sociopolitical realities that determine mental health priorities. PMID- 20840802 TI - Challenges and opportunities in measuring the quality of mental health care. AB - The purpose of our paper is to delineate the barriers to mental health quality measurement, and to identify strategies to enhance the development and use of quality measures by mental health providers, programs, payers, and other stakeholders in the service of improving outcomes for people with mental health and substance use disorders. Key reasons for the lag in mental health performance measurement include lack of sufficient evidence regarding appropriate mental health care, poorly defined quality measures, limited descriptions of mental health services from existing clinical data, and lack of linked electronic health information. We discuss strategies for overcoming these barriers that are being implemented in several countries, including the need to have quality improvement as part of standard clinical training curricula, refinement of technologies to promote adequate data capture of mental health services, use of incentives to promote provider accountability for improving care, and the need for mental health researchers to improve the evidence base for mental health treatment. PMID- 20840803 TI - Mortality hazard associated with anxiolytic and hypnotic drug use in the National Population Health Survey. AB - OBJECTIVE: Although widely used in the general population, sleeping pills and minor tranquilizers, also known as antianxiety agents, have been associated with undesirable outcomes. Reports about the association of these drugs with an elevated mortality rate are inconsistent and controversial. This study was designed to assess the mortality hazard associated with anxiolytic and hypnotic drug use in the National Population Health Survey in Canada. It was hypothesized that anxiolytic and hypnotic drug use would be associated with an elevated mortality hazard. METHOD: A population-based sample of 14 117 people aged 18 to 102 years participated in a longitudinal panel survey, with data collected every second year from 1994 to 2007. The primary outcome measures reported in this study are self-report use of anxiolytic and hypnotic drugs, and death. RESULTS: For respondents who reported anxiolytic or hypnotic drug use in the past month the odds of mortality were 3.22 times more (95% CI 2.70 to 3.84) than for those who did not use anxiolytic or hypnotic drugs in the past month. After controlling for confounding sociodemographic, lifestyle, and health factors (including depression), the odds ratio was reduced to 1.36 (95% CI 1.09 to 1.70) but remained significant. CONCLUSION: Sedative drug use is associated with a small but significant increase in mortality risk. Further research is required to confirm the mechanisms by which sedative drug use increases mortality risk. Where possible, physicians should systematically consider possibilities for nonpharmacological treatment of sleep disturbances and anxiety. PMID- 20840804 TI - Frequency and correlates of gambling problems in outpatients with major depressive disorder and bipolar disorder. AB - OBJECTIVE: To investigate the frequency of gambling in people who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BD). Secondary objectives were to examine: sex differences in the rates of gambling behaviour, the temporal relation between onset of mood disorders and problem gambling, psychiatric comorbidities associated with problem gambling, and the influences of problem gambling on quality of life. METHOD: People (aged 18 years and older) who met criteria for lifetime Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision-defined MDD or BD I or II, and were confirmed by the Mini International Neuropsychiatric Interview, were enrolled. Participants were recruited from 5 sites in Canada and 1 in the United States. Prevalence of past-year problem gambling was assessed with the Canadian Problem Gambling Index. Associated comorbidities with problem gambling are presented. RESULTS: A total of 579 participants were enrolled (female: n = 379, male: n = 200). Prevalence of problem gambling did not differ significantly between the MDD (12.5%) and the BD (12.3%) groups. There was a significant difference in the prevalence of problem gambling between males (19.5%) and females (7.8%) in the BD group (chi-square = 8.695, df = 1, P = 0.003). Among people meeting criteria for problem gambling, the mood disorder was the primary onset condition in 71% of cases. People with a mood disorder with comorbid current panic disorder (OR = 1.96; 95% CI 1.02 to 3.75), obsessive-compulsive disorder (OR = 1.86; 95% CI 1.01 to 3.45), specific phobia (OR = 2.36; 95% CI 1.17 to 4.76), alcohol dependence (OR = 5.73; 95% CI 3.08 to 10.65), or lifetime substance dependence (OR = 2.05; 95% CI 1.17 to 3.58), had significantly increased odds of problem gambling. Problem gambling across MDD and BD populations was also associated with lower quality of life ratings. CONCLUSION: These results reaffirm a higher prevalence of gambling both in BD and in MDD populations, compared with previously published community samples. Our study also identifies risk factors for gambling behaviours within these populations. PMID- 20840805 TI - Associations of risk of depression with sexual risk taking among adolescents in Nova Scotia high schools. AB - OBJECTIVE: Several interrelated factors, including depression, influence adolescents' chances of risky sexual behaviour. We examined the relation between depression and sexual risk-taking behaviours in adolescents after accounting for the effects of other variables. METHOD: We surveyed male (n = 1120) and female (n = 1177) adolescents at 4 high schools in central Nova Scotia, measuring factors known to be associated with sexual risk taking. Risk of depression was assessed using the Center for Epidemiologic Studies Depression Scale. Outcomes were self reported sexual behaviours. We used logistic regression to assess associations of multiple factors with sexual risk taking. RESULTS: In univariate analyses, risk of depression was associated with 3 risk-taking behaviours for females (being sexually active, having unplanned sex when using substances, and not using effective contraception at last intercourse) and 2 for males (having unplanned sex when using substances and having more than 1 partner in the previous year). In full multivariate models, risk of depression in females remained significantly associated with unplanned sex and nonuse of effective contraception at last intercourse, but was no longer associated with being sexually active. For males, both associations remained significant. CONCLUSIONS: Risk of depression is consistently and independently associated with adolescent sexual risk behaviours after adjusting for other variables. Health care providers working with teenagers should screen for risky sexual behaviours and sexually transmitted infections if depression is apparent in their patients. PMID- 20840806 TI - Seeking help for mental health problems outside the conventional health care system: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD). AB - OBJECTIVE: In certain countries, it is not uncommon to turn to professionals outside the conventional health care system for psychological problems. As this situation is not well documented in Europe, we assessed use of nonconventional care for mental health in 6 European countries. METHOD: A cross-sectional survey was conducted in representative samples of noninstitutionalized adults in 6 European countries. Participants (n = 8796) completed a survey, which included, among other items, the Composite International Diagnostic Interview 3.0 and in depth questions about lifetime consultations for mental health problems. RESULTS: Among the respondents (n = 2928) who reported having already sought help in their lifetime for psychological problems (20.0%), 8.6% turned to complementary and alternative medicine (CAM) providers, such as chiropractors and herbalists, and a similar proportion (8.4%) to religious advisers such as ministers, priests, or rabbis. Only a small proportion (2.9%) consulted only these professionals for their problems. CAM providers were more frequently used in the Netherlands (13.5%) and Germany (9.4%), while religious advisers were more often consulted in Italy (12.6%) and Germany (11.6%). Multivariate analyses confirmed differences between countries and revealed that people turning to religious advisers tended to be older, foreign born, and with alcohol problems, whereas those consulting CAM providers were younger, wealthier, and more frequently depressed. CONCLUSIONS: In Europe, patients who turn to CAM therapists and those who seek help from religious advisers for psychological problems are not exactly the same. In addition, these professionals are not consulted frequently in most countries, and are almost always associated with more traditional follow-up when used. PMID- 20840807 TI - The prevalence of mental disorders in the working population over the period of global economic crisis. AB - OBJECTIVES: The ongoing global economic crisis may have affected people's mental health. This study aimed to, among a sample of the working population, estimate and compare the prevalence of depressive and anxiety disorders in different time intervals from January 2008 to October 2009 and to examine the demographic and socioeconomic correlates of mental disorders. METHODS: From January 2008 to October 2009, 3579 employees in Alberta were recruited using the random digit dialing method. Mental disorders were assessed using the World Health Organization's Composite International Diagnostic Interview-Auto 2.1. The lifetime and 12-month prevalence of depressive and anxiety disorders in different time intervals were estimated and compared. RESULTS: The 12-month prevalence of major depressive disorder (MDD) before September 1, 2008; between September 1, 2008, and March 1, 2009; and between March 1, 2009, and October 30, 2009, was 5.1%, 6.8%, and 7.6% (P = 0.03), respectively. The lifetime prevalence of dysthymia reported during the 3 periods was 0.4%, 0.7%, and 1.5% (P = 0.006), respectively. No changes in the 12-month prevalence of social phobia, panic disorder, and generalized anxiety disorder were found over time. CONCLUSIONS: The ongoing global economic crisis may have contributed to the increased prevalence of MDD. Future studies are needed to monitor the changes in the prevalence and to describe how the event may affect people's employment status, income, and health. PMID- 20840808 TI - Assessing the prevalence of nonmedical prescription opioid use in the general Canadian population: methodological issues and questions. AB - OBJECTIVE: To assess the prevalence of nonmedical prescription opioid use (NMPOU) in the Canadian general adult population in the context of rising overall prescription opioid (PO) consumption and related problems in North America. METHOD: The prevalence of NMPOU was assessed as a multiitem construct in the Canadian Alcohol and Drug Use Monitoring Survey (CADUMS; n = 16 672), an ongoing cross-sectional monthly random digit dialing telephone survey representative of the general Canadian population, aged 15 years and older. CADUMS data were collected between April and December of 2008 with a response rate of 43.5%. RESULTS: About 22% of CADUMS respondents reported PO use in the last year, while 0.5% reported NMPOU during the same time frame. PO use was significantly higher among women than among men, and highest in the group aged 25 to 54 years. NMPOU was similar among men and women, and highest in the group aged 15 to 24 years. CONCLUSIONS: CADUMS data indicate an extremely low rate of NMPOU, especially given the levels of overall PO use, other PO-use related problems, and NMPOU levels estimated in the general US population where NMPOU has been assessed to be 10 times higher than in Canada. NMPOU survey item construction and response rates appear to strongly influence and potentially compromise NMPOU survey data. Existing NMPOU data and survey methods need to be validated for this important indicator in Canada, where increasing PO use and problem levels have been recognized as a significant and rising public health problem. PMID- 20840809 TI - [Salpetriere erythrophobia questionnaire validation]. AB - OBJECTIVE: To study the main psychometric characteristics of the Salpetriere Erythrophobia Questionnaire (SEQ) in a clinical and non-clinical sample. METHOD: Patients with social phobia (SP) (n = 212), patients with other anxiety disorders (n = 146), and participants from the general population (n = 171) were distributed in the 3 study groups. They completed the SEQ as well as several anxiety and depression scales. Erythrophobia was diagnosed according to standardized criteria and assessed using the Clinical Global Impression Scale. RESULTS: The SEQ scale factor pattern is clear, with only 1 factor explaining 83.9% of total score and a Cronbach's alpha consistency coefficient of 0.96. The SEQ score is significantly correlated to a dimensional hetero-evaluation of the fear of blushing (rho = 0.91) and SP measures (rho = 0.23 to 0.55). The SEQ mean score is higher in the SP group and even higher in the erythrophobia group. A score of 7 out of 24 makes it possible to identify erythrophobia with 92.1% sensitivity and 87.7% specificity. The SEQ test-retest reliability at 15-day interval is satisfactory (ICC = 0.83). CONCLUSION: The SEQ is a valid and sensitive tool to screen and measure erythrophobia. It can be used in psychopathological and therapeutic studies of this pathology. PMID- 20840810 TI - [Effect of Bufalin on proliferation and apoptosis of human non-small cell lung cancer A549 cell]. AB - BACKGROUND AND OBJECTIVE: Bufalin, a component of the Chinese medicine chan'su, induces apoptosis in various human tumor cell lines. The aim of this study is to investigate the mechanism of anti-proliferation and the induction of apoptosis of Bufalin on non-small cell lung cancer cell. METHODS: The effect of Bufalin on A549 cell proliferation was measured using MTT assay; the morphological change was observed with Wright-Giemsa stain; cell cycle phase distribution and hypodiploid DNA were determined by flow cytometry with PI; expressions of Livin, Caspase-3 were detected by Western blot. RESULTS: MTT assay showed that Bufalin inhibited A549 cell proliferation in time and dose-dependent manner. The inhibition concentration of 50% cell growth (IC50) at 48 h, 72 h and 96 h were (56.14+/-6.72) nmol/L, (15.57+/-4.28) nmol/L and (7.39+/-4.16) nmol/L, respectively; apoptosis of A549 cells could be effectively induced by Bufalin; apoptotic bodies and sub-G1 peak (representing apoptosis) emerged when cells were treated with different concentrations, compared with the untreated control group (P < 0.01). The expression of Livin protein was downregulated (P < 0.01) and Caspase-3 protein was activated during Bufalin-induced apoptosis in A549 cells. CONCLUSIONS: Bufalin suppresses the growth of A549 cells and induces apoptosis; inhibition of Livin and activation of Caspase-3 may be involved in its mechanism. PMID- 20840811 TI - [Enhanced cisplatin cytotoxicity by RNA interfering the excision repair cross complementing gene 1 in lung cancer cell A549/DDP]. AB - BACKGROUND AND OBJECTIVE: The excision repair cross-complementing gene 1 (ERCC1), which is important in the repair of cisplatin-DNA adducts, was reported to be related to cisplatin resistance in tumor cells. The aim of this study is to investigate the changes of cisplatin sensitivity by silencing ERCC1 gene in lung cancer cell. METHODS: The small interfering RNA (siRNA) targeting ERCC1 gene was designed and synthesized, and transfected to lung cancer cell A549/DDP. The mRNA and protein expression levels of ERCC1 were evaluated by RT-PCR and Western blot. The changes of cisplatin sensitivity after RNA interference were examined by methyl thiazolyl assay. RESULTS: In A549/DDP cell, the mRNA and protein levels of ERCC1 were decreased and the sensitivity to cisplatin was increased from 12.49 MUg/mL to 9.27 MUg/mL after transfection. CONCLUSIONS: The sensitivity to cisplatin of lung cancer cell A549/DDP could be enhanced by RNA interfering ERCC1 gene targeted code 346. PMID- 20840812 TI - [Detection of epidermal growth factor receptor mutations in non-small cell lung cancer tumor specimens from various ways by denaturing high-performance liquid chromatography]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) is the most important therapeutic target in non-small cell lung cancer (NSCLC). EGFR mutations may predict responsiveness to tyrosine kinase inhibitors (TKIs). These mutations are commonly identified using direct sequencing, which is considered the gold standard. But direct sequencing is time-consuming and hyposensitive. In addition, this method requires a lot of tumor specimens. Denaturing highperformance liquid chromatography (DHPLC) is a rapid automated sensitive and specific method in mutant gene detection. The aim of this study is to evaluate DHPLC as a rapid detection method for EGFR mutations in NSCLC tumor specimens. METHODS: DHPLC was used to evaluate the accuracy and sensitivity of detection the serial dilutions of mutant and wild type EGFR plasma DNA. Frozen tumor specimens of 83 NSCLC patients from various ways had been included, after DNA extraction and polymerase chain reaction (PCR) on EGFR exon 19 and 21, the results from the direct sequencing and DHPLC were compared. RESULTS: Mutant plasma DNA can be detected in the serial dilution of 1:100 by DHPLC and 1:10 by direct sequencing respectively. The results from DHPLC showed 22 EGFR mutations were detected in 83 NSCLC patients, and only 19 mutation samples had been conformed by direct sequencing. Moreover, the other 61 samples were deemed as wild type by DHPLC and direct sequencing. The sensitivity and specificity of DHPLC was 100% and 95.13% respectively. The detection of the tumor specimens from CT-guided transthoracic needle lung biopsy, lymph node biopsy and surgical resection all showed high sensitivity and specificity. EGFR mutation has strong correlation with gender and pathologic type, but irrelevant to age and smoking status. CONCLUSIONS: DHPLC was a precise rapid preliminary screening method for detection of NSCLC EGFR genotype. PMID- 20840813 TI - [High expression of DNMT1 was correlated with beta-catenin accumulation and malignant phynotype of lung squamous cell carcinoma and adenocarcinoma]. AB - BACKGROUND AND OBJECTIVE: DNA methyltransferase 1 (DNMT1) is one of the important molecules regulating DNA methylation. The abnormal expression of DNMT1 was associated with the methylation and inactivation of tumor suppressor gene and tumorigenesis. The aim of this study is to clarify the difference of DNMT1 expression between lung cancer tissues and corresponding normal lung tissues, to analyze the relationships between DNMT1 expression and clinicopathologic characteristics of lung squamous cell carcinoma and adenocarcinoma, and to investigate the correlation between the expressions of DNMT1 and beta-catenin. METHODS: The expressions of DNMT1 and beta-catenin were examined in 84 lung squamous cell carcinoma and adenocarcinoma tissues and corresponding normal lung tissues using tissue microarray and immunohistochemistry. RESULTS: The average positive rate of DNMT1 was significantly higher in 84 lung cancer tissues [(58.04+/-35.07)%] than that in corresponding normal lung tissues [(6.88+/ 10.26)%](t=12.835, P<0.001). The high expression of DNMT1 was positively correlated with adenocarcinoma histological type (r=0.365, P=0.001), poor differentiation (r=0.253, P=0.021) and lymph node metastasis (r=0.246, P=0.024) in lung cancer. The expression of DNMT1 was significantly correlated with the cytoplasmic expression of beta-catenin (r=0.571, P<0.001). CONCLUSIONS: The high expression of DNMT1 was a common phenomenon in lung squamous cell carcinoma and adenocarcinoma. The high expression of DNMT1 was correlated with the malignant phynotype of lung cancer. DNMT1 may express coordinately with beta-catenin in lung cancer. PMID- 20840814 TI - [Expression of carbonic anhydrase IX in NSCLC and its relationship with VEGF and Ki67 expression]. AB - BACKGROUND AND OBJECTIVE: It has been shown that carbonic anhydrase IX (CAIX) was closely related to tumor hypoxia. Proliferating cell nuclear antigen (Ki67) is considered to be an objective indicator which could reliable and comprehensive response to cell population proliferation; vascular endothelial growth factor (VEGF) was positively correlated with tumor angiogenesis. The aim of this study is to investigate the significance of the expression of CAIX in non-small cell lung cancer (NSCLC) tissues by analyzing the correlation between CAIX and clinical characteristics of patients with lung cancer and VEGF, Ki67 expressions. METHODS: CAIX, VEGF and Ki67 protein were detected in 76 cases of NSCLC and 10 cases of lung inflammatory pseudotumor by immunohistochemistry. RESULTS: CAIX was expressed in 45 of 64 cases of NSCLC and not expressed in benign lesion pulmonary tissues. VEGF was expressed in 55 of 76 cases and Ki67 was expressed in 30 of 76 cases. The expression of CAIX in squamous cell carcinoma (SC) was higher than that in adenocarcinoma (AC) (69.7% vs 27.9%, P=0.001). In 34 cases who received radiotherapy, the objective response rates of CAIX positive and negative groups were 27.8% and 62.5% respectively; the expression of CAIX was positively correlated with VEGF (r=0.231, P=0.043) and was not correlated with Ki67 (r=0.064, P=0.583). CONCLUSIONS: Compared with benign lesion pulmonary tissue, the expression of CAIX in NSCLC tissues is significantly increased and is positively correlated with VEGF. The expression of CAIX was also correlated with the objective response rate of radiotherapy, which provided new evidence about that hypoxia can increase NSCLC radiotherapy resistance. PMID- 20840815 TI - [Relationship between the expression of PRDM14 in non-small cell lung cancer and the clinicopathologic characteristics]. AB - BACKGROUND AND OBJECTIVE: The positive regulatory domain proteins (PRDM) are family of transcriptional regulation related to the formation of human tumor factor and play key roles in the cell differentiation and malignant transformation. PRDM14 is a member of the PRDM family. The aim of this study is to detect the expression of PRDM14 in non-small cell lung cancer (NSCLC) tissues, and analyze its relationship with clinicopathologic characteristics of NSCLC. METHODS: PRDM14 expression was detected in 70 NSCLC specimens and 7 paracancerous tissues using the immunohistochemistry (SP method). The PRDM14 protein expression was determined in 42 NSCLC specimens and 42 paracancerous tissues by Western blot. RESULTS: Among 70 NSCLC specimens, 8 specimens showed weak expression of PRDM14 (11.43%, 8/70), 62 specimens showed moderate to strong staining of PRDM14 (88.57%, 62/70), whereas 7 paracancerous specimens showed weak staining extent. PRDM14 expression level was positively correlated with differentiation (P=0.046) and histological type (P=0.047). The positive cytoplasmic expression of PRDM14 in highly differentiated NSCLC, the low expression of PRDM14 in poorly differentiated NSCLC. The results of Western blot showed that there were significant difference between the two groups (P<0.001); expression of PRDM14 was conspicuous in NSCLC specimens but low in paracancerous tissues. PRDM14 expression level was positively correlated with differentiation (P=0.017). The positive cytoplasmic expression of PRDM14 in highly differentiated NSCLC, the low expression of PRDM14 in poorly differentiated NSCLC. CONCLUSIONS: The high expression of PRDM14 in NSCLC is associated with differentiation and histological type. The PRDM14 may play an important role in the development of NSCLC. PMID- 20840816 TI - [Research on the relationship between non-small cell lung cancer with neuroendocrine differentiation and the biological characteristics and prognosis]. AB - BACKGROUND AND OBJECTIVE: Recently it has been proven that non-small cell lung cancer (NSCLC) also had the feature of neuroendocrine (NE) differentiation. The aim of this study is to investigate the correlation between NE differentiation of NSCLC and its biological behaviors, together with prognosis. METHODS: All NSCLC paraffin-embedded specimens and cases, followed up over than 3 years, were randomly obtained from 206 patients from January 2005 to December 2007, who underwent surgical resection and confirmed pathologically. All of them were not underwent radiation and chemotherapy before operation. Immunohistochemical Envision two-step method was used to detect the expressions of NSE, CgA and Syn. And all data were analyzed using SPSS statistics software and Kaplan-Meier survival curves were constructed, and Log-rank test was also conducted. RESULTS: Of the 206 patients, 84 cases with NE differentiation (39.8%) and CgA, NSE and Syn positive rates were 53 (25.7%), 104 (50.5%), 91 (44.2%) respectively; a statistically significant difference between NSCLC with NE differentiation were showed. The positive expression of Syn was closely correlated with histological differentiation, lymph node metastasis. The survival of single-factor analysis by the Log-rank test showed that Syn had relation to the postoperative survival rate of patients (Chi2=4.164, P=0.041), while the relevance between patients with NE and survival had no significant difference (P>0.05). CONCLUSIONS: NE differentiation is an important indicator of biological behavior of NSCLC; and the detection of Syn markers of neuroendocrine differentiation may be recommended to detect NE differentiation of NSCLC, and the positive expression of Syn suggests poor prognosis. PMID- 20840817 TI - [Expression and clinical significance of SHP2 in the tumor tissues of smokers with lung cancer]. AB - BACKGROUND AND OBJECTIVE: It has been proved that protein phosphorylation and dephosphorylation were important mechanisms in lung cancer development, and tobacco smoking is an important risk factor of lung cancer. The aim of this study is to investigate the expression and clinical significance of protein tyrosine phosphatase SHP2 in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); the relationship between tobacco smoking and the expression of SHP2 is also studied. METHODS: Immunohistochemistry (Invision) and fluorescence in situ hybridization (FISH) were used to detect the expression of SHP2 and the augment of SHP2 mRNA in the 53 lung cancer specimens. RESULTS: The weak positive rate of SHP2 was 80% (which was also the total positive rate) in normal bronchial epithelium. The weak, moderate and strong positive rates were 35.4%, 43.8% and 6.2% (total positive rate was 85.4%) in 48 NSCLC patients, 0%, 80% and 20% (total positive rate was 100%) in 5 SCLC patients, 40.7%, 37.4% and 3.7% (total positive rate was 81.5%) in the tumor tissues of 27 NSCLC patients who didn't smoke and 23.8%, 71.4% and 4.7% (total positive rate was 100%) in the tumor tissues of 21 NSCLC patients whose smoking indexes were >= 400. Significant differences of SHP2 expression were observed between tumor tissues and normal bronchial epithelium, NSCLC and SCLC, and between different smoking indexes (P<0.05). CONCLUSIONS: The enhancement of SHP2 expression in the tumor tissues of NSCLC patients who smoke may be correlated with tobacco smoking; SHP2 may play certain role in the development of lung cancer; SHP2 prospectively provides new ideas for the drug research and development of lung cancer treatment. PMID- 20840818 TI - [Comparison of EGFR and KRAS status between primary non-small cell lung cancer and corresponding metastases: a systematic review and meta-analysis]. AB - BACKGROUND AND OBJECTIVE: Epidermal growth factor receptor (EGFR) and KRAS status were particularly critical for the choice of first-line targeted therapy of non small cell lung cancer (NSCLC), while the primary tumor and metastases might be different in the EGFR and KRAS gene status. The aim of this pooled analysis is to compare EGFR and KRAS status in matching primary NSCLC and metastases and further to guide clinical practice. METHODS: Systematic computerized searches of the Pubmed and Medline databases (up to May 10, 2010) meeting specified search criteria were performed, followed by a further screening according to inclusive and exclusive criteria. RESULTS: Fourteen articles were selected into the final meta-analysis with paired primary and metastatic cases of 598. Expression level of EGFR protein and mutation frequency of KRAS gene in primary tumors were higher than that in metastases, relative risk (RR)=1.13 (95%CI: 0.98-1.31, P=0.09) and RR=1.39 (95%CI: 0.95-2.03, P=0.09), respectively. EGFR gene copy number in metastases was higher than that in primary tumor, RR=0.74 (95%CI: 0.53-1.02, P=0.06). There was no statistically significant difference of EGFR mutation frequency in primary tumors and metastases (P=0.31). The discordant rate in primary and metastases was 17.09% for EGFR mutation, 27.07% for EGFR amplification, 27.84% for EGFR protein expression and 25.91% for KRAS mutation. CONCLUSIONS: The systematic analysis showed that the EGFR mutation status in primary lung cancer and corresponding metastases was more stable than KRAS gene. KRAS mutation in primary lung cancerous foci seems to better reflect systemically cancerous genetic characteristics of KRAS gene. Determination of KRAS gene status based merely on metastatic foci might lead to more resistant selections of EGFR tyrosine kinase inhibitor (TKI) therapy. Combined detection of EGFR and KRAS mutation from primary NSCLC foci might serve as a better predictive biomarker for anti-EGFR targeted therapy. PMID- 20840819 TI - [A meta-analysis of the timing of chest radiotherapy in patients with limited stage small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: Although evidence for a significant survival benefit of chest radiotherapy has been proven, no conclusion could be drawn regarding the optimal timing of chest radiation. The aim of this study is to explore whether the timing of chest radiation may influence the survival of the patients with limited-stage small-cell lung cancer (LSSCLC) by performing a literature-based meta-analysis. METHODS: By searching Medline, CENTRAL (the Cochrane central register of controlled trials), CBM, and CNKI, et al, we collected both domestic and overseas published documents about randomized trials comparing different timing chest radiotherapy in patients with LS-SCLC. Early chest radiation was regarded as beginning within 30 days after the start of chemotherapy. Random or fixed effect models were applied to conduct meta-analysis on the trials. The combined odds ratio (OR) and the 95% confidence interval (CI) were calculated to estimate the mortality in 2 or 3 years and toxicity of the two treatments. The statistical heterogeneity was determined by cochran's Chi-square test (Q test). The Begg' test was used to determine the publication bias. RESULTS: Six trials that included a total of 1 189 patients were analyzed in the meta-analysis 587 patients were in the early radiation group and 602 patients were in the late radiation group. Considering all 6 eligible trials, the overall survival at 2/3 years was not significantly different between early and late chest radiation (OR=0.78, 95%CI: 0.55-1.05, Z=1.68, P=0.093). For the toxicity, no obvious difference was observed for early chest radiotherapy compared with late irradiation in pneumonitis (OR=1.93, 95%CI: 0.97-3.86, P=0.797), esophagitis (OR=1.43, 95%CI: 0.95-2.13, P=0.572) and thrombocytopenia (OR=1.23, 95%CI: 0.88 1.77, P=0.746), respectively. CONCLUSIONS: No statistical difference was observed in 2/3 years survival and toxicity, including pneumonitis, esophagitis and thrombocytopenia, between early radiation and late radiotherapy in LS-SCLC. PMID- 20840820 TI - [Argon plasma coagulation combined with covered stent placement for management of tracheobronchial stenoses/occlusions as well as esophagorespiratory fistulas]. AB - BACKGROUND AND OBJECTIVE: It is a complex problem and difficult treatment for tracheobronchial stenoses/occlusions involving in carina. The aim of this study is to investigate the feasibility and efficiency of argon plasma coagulation (APC) and bifurcated covered Z-type stents (CZTS) placement for the treatment of tracheobronchus stenoses and esophagorespiratory fistula (ERF). METHODS: Thirty two cases with airway disorders were retrospectively reviewed for the treatment of APC and CZTS placement. Under the bronchoscopic guidance, APC was first given in patients with airway stenoses, then CZTS was placed under the fluoroscopic and flexible bronchoscopic guidance either with airway stenoses or ERF. RESULTS: APC was first given in 19 patients with airway stenoses. Airway structures were significantly improved after APC procedure (57.4%-72.1% before APC vs 12.8%-25.8% after APC). Thirty-two CZTS were technically successfully placed in 30 out of 32 cases involving in carinal bifurcation. After APC and stent placement, short breath index was significantly reduced and karnofsky physical score (KPS) increased obviously. The endobronchial defects were successfully palliated with bifurcated CZTS placed under fluoroscopy and flexible bronchoscopy in 12 out of 13 patients with ERFs. There is no bleeding introprocedure. Mucous retention was very common in all types of the stents less than 2 weeks after stenting, which required debridement by bronchoscopy and could be prevented by normal saline solution nebulizations. Granuloma developed at the ends of stents after 1 month of stenting which all of them were treated successfully with APC and CO2 cryosurgery. CONCLUSIONS: Utilization of APC and retrieval bifurcated CZTS placement is a simple and safe protocol for the management of airway complex stenoses involving the tracheal carina and ERF. PMID- 20840821 TI - [Autoantibodies as the early diagnostic biomarkers for lung cancer]. PMID- 20840822 TI - [Advances of tissue factor in lung cancer]. PMID- 20840823 TI - [Advances of treatment of small cell lung cancer in 2010 American Society of Clinical Oncology annual meeting]. PMID- 20840824 TI - [A case report of pulmonary hypertrophic osteoarthropathy secondary to pulmonary carcinoma]. PMID- 20840825 TI - [Treatment of large cell neuroendocrine lung cancer by implantation of radioactive 125I seeds: a case report]. PMID- 20840826 TI - Review: behaviour management techniques in paediatric dentistry. AB - BACKGROUND: Behaviour management is widely agreed to be a key factor in providing dental care for children. Indeed, if a child's behaviour in the dental surgery/office cannot be managed then it is difficult if not impossible to carry out any dental care that is needed. It is imperative that any approach to behavioural management for the dental child patient must be rooted in empathy and a concern for the well being of each child. REVIEW: Based on various presentations given at Congresses of the European Academy of Paediatric Dentistry (EAPD), documents reviewing behaviour management prepared by the Clinical Affairs Committee of the EAPD, and written submissions to the Executive Board of the EAPD, a review of the various approaches to the behaviour management of the child dental patient was completed. All aspects of non-pharmacological behavioural management techniques described in the literature over the past 80 years were reviewed. FINDINGS: There is a very wide diversity of techniques used but not all are universally accepted by specialist paediatric and general dentists. Wide cultural and philosophical differences are apparent among European paediatric dentists that seem difficult to bridge when forming agreed guidelines. Accordingly, this review highlights those behaviour techniques that are universally accepted such as tell, show, do (TSD) or positive reinforcement, but nevertheless describes the most commonly mentioned techniques for which there are descriptions in the literature. CONCLUSION: A wide variety of behavioural management techniques are available to paediatric dentists which must be used as appropriate for the benefit of each child patient, and which, importantly, must take into account all cultural, philosophical and legal requirements in the country of dental practice of every dentist concerned with dental care of children. PMID- 20840827 TI - Acceptance by Spanish parents of behaviour-management techniques used in paediatric dentistry. AB - AIM: This was to examine the attitude of a group of Spanish parents towards behaviour-management techniques used in paediatric dentistry. METHODS: A video with 8 different behaviour-management techniques used in paediatric dentistry was shown to 50 parents whose children were being treated at the International University of Catalonia (Barcelona, Spain). The techniques shown were: tell-show do, nitrous-oxide sedation, passive restraint, voice control, handover- mouth (HOM), oral premedication, active restraint and general anaesthesia. Parents gave an acceptance rating of each of these techniques according to a scale of 0 to 10, with 0 being the lowest level of acceptance and 10 the highest. RESULTS: The technique rated as most acceptable was the tell-show-do technique, while the least accepted was the HOM technique. An association was found between acceptance of the different techniques and the socioeconomic status and gender of the parent, and the differences were statistically significant. No statistically significant differences were found regarding the age or gender of the child treated, or the previous dental experiences of those interviewed or of their children, with acceptance of each of the techniques. CONCLUSIONS: The techniques were well accepted by all those surveyed with the exception of HOM technique and the use of the papoose board. On comparing this study to other studies previously carried out in other areas of the world, similar results were found. PMID- 20840828 TI - Diversity of Lactobacillus species in deep carious lesions of primary molars. AB - AIM: This was to determine the prevalence of Lactobacilli (LB) species in different stages of caries progression and are considered as secondary invaders of existing carious lesions and specialists for caries progression. METHODS: Carious dentine samples were collected from 70 primary molars (M) during step wise (S1, S2: n = 35 M) or one-step (O1: n = 35 M) caries treatment and after 11 months of temporary restorations (S3, O2). LB were identified by selected physiological and biochemical characteristics, ratio of lactic acid isomers, electrophoretic mobilities of lactic acid dehydrogenases, and shotgun mass mapping by MALDI mass spectrometry. RESULTS: LB were isolated from 46% of soft dentine samples (S1). The prevalence of LB from hard dentine collected during caries excavation (O1) reached 34%, after 8 weeks of temporary filling (S2) 11%, and 9% each after 11 months of temporary restoration (S3, O2). The mean total bacterial counts (cfu) of soft dentine (S1) were 3.6 x 105. From hard dentine during caries excavation (O1) 4.4x104 cfu were calculated, at S2 3.7 x 103 cfu, at S3 0.1 x 103 cfu, and at O2 1.8 x 103 cfu. The percentages of LB in the cfu for LB positive dentine samples were for S1 / S2 / S3 / O1 / O2: 60% (16 M)/34% (4 M)/54% (3 M)/57% (9 M), and 64% (3 M). Five LB species were identified from carious dentine: L. paracasei subsp. paracasei, L. paracasei subsp. tolerans, L. rhamnosus, L. gasseri, and L. alimentarius. CONCLUSIONS: While L. rhamnosus and L. paracasei subsp. paracasei occurred in all caries progression stages, the other species were found only sporadically. L. paracasei subsp. paracasei and L. rhamnosus might be the specialists of the LB in carious progression. PMID- 20840829 TI - Saliva profiles in children using heart failure medication: a pilot study. AB - AIM: To study the saliva profiles in children with severe heart disease taking heart failure medication compared with the saliva from healthy age and gender matched controls. STUDY DESIGN: Cross sectional case-control design. METHODS: Twenty-four age and gender matched pairs of children, mean age 12.0 years participated. Stimulated saliva was collected in a standardized way before lunchtime and the subjects were asked to refrain from all eating, drinking and tooth brushing 90 mins before sampling. Stimulated salivary secretion rate, buffering capacity, total salivary viable count of bacteria, mutans streptococci and lactobacilli, calcium, chloride, magnesium, potassium, sodium and salivary IgA were determined. RESULTS: There were 7 of the 24 children in the cardiac group who had secretions below 0.5 ml/min compared with no child in the control group (p<0.01). Lower [corrected] total viable counts of bacteria (TVC) were detected in the cardiac group 1.4x106 +/- 1.2x107 vs. 2.7x106 +/- 2.9x107 in the control group (p<0.05). Mutans streptococci (MS) in the cardiac group were 5.2x104 +/- 1.5x105 vs. 8.1 x103 +/- 1.3x104 in the control group, (p>0.05) and MS ratio of TVC constituted 0.11+/-0.35 per cent compared to 0.01+/-0.02 per cent for the control group (p>0.05). STATISTICS: Continuous data were analysed by an analysis of variance (ANOVA) and categorical data by chi-square test. CONCLUSION: Reduced salivary secretion could be a caries risk factor in children taking heart failure medication. PMID- 20840830 TI - Prevalence of sleep bruxism in a group of Brazilian schoolchildren. AB - AIM: This was to investigate the prevalence of sleep bruxism in Brazilian schoolchildren. METHODS: A cross-sectional study was carried out examining 652 randomly selected children aged from 7 to 10 years of age from both public and private schools in Belo Horizonte, Brazil. Sleep bruxism among children was reported by parents by means of a pretested questionnaire based on the criteria of the American Academy of Sleep Disorders. The Social Vulnerability Index from Municipal database was used to determine social classification of families. A chi square test was used with a significance level of 5%. RESULTS: Sleep bruxism was present in 230 children, showing a prevalence of 35.3%. Among the 652 children, 340 (52.0%) were girls and 312 (48.0%) were boys, predominatly of 8-year-olds (84.2%). Sleep bruxism was present in 56.5% of the girls and 43.5% of the boys. The majority of the families were of a low social vulnerability (54.2%), whereas another 45.8% were of a high social vulnerability. More than half of the children without sleep bruxism (55.2%) were of low socio-economic background. CONCLUSIONS: The high prevalence of 35.3% demonstrates the need for further research on this issue. PMID- 20840831 TI - Conventional endodontic treatment of primary molars using metronidazole as an intra-canal medicament: a pilot study. AB - AIM: This was to evaluate the clinical and radiographic outcomes of an antibacterial drug (Metronidazole, Nidazol, IE Ulagay Ilac A.S) application as an intra-canal medicament combined with pulpectomy in infected primary molar teeth. METHODS: The study material consisted of data collected from children treated at the Dental School Dept. of Paediatric Dentistry in Marmara University between 2000 and 2004. Clinical and radiographic data were collected over 2 years from patients who had received a topical application of metronidazole in root canal dressing before a pulpectomy was completed. Clinical success parameters were: no abscess formation, no fistula, no pain and no pathologic mobility at treated teeth with metranidazole dressing. The overall success and failure rates were analysed. Radiographic diagnosis was standardized between investigators and intra and inter-rater reliability assessed. Both investigators read and evaluated all radiographs, after a comparison of results, a consensus was agreed upon for each result. STATISTICS: All data were entered into an Excel format and SPSS 11.0 P < 0.05 were used for Windows and Chi-square for statistical analyses. RESULTS: There were 64 molars assessed for clinical and radiographic success. Considering the eruption times, success rate was 75% as determined by the last follow up clinically and radiographically according to predetermined success criteria. In the 64 molars, 4 cases demonstrated loss of the alveolar bone, 3 exhibited varying degrees of root resorptions on radiographic examination and 3 showed clinical pathologic mobility. Fistulae were observed in only 1 case and early loss was detected in 5 cases. CONCLUSION: These results suggest that main factors responsible for failure may be associated with uncertain mixing proportions of the metronidazole paste and inadequate maxillary restorations. But some modifications in preparing the paste could increase its efficacy. PMID- 20840832 TI - Case series: clinical findings and oral rehabilitation of patients with amelogenesis imperfecta. AB - BACKGROUND: Children with amelogenesis imperfecta (AI) experience many oral difficulties including sensitivity and aesthetics. The methods of treating AI children are limited and therefore a program of care was evaluated in order to assess the clinical efficacy of providing preventive and restorative treatments. CASE REPORTS: A non-randomised convenience sample of 12 patients with AI was evaluated. A comprehensive patient history was recorded, followed by a clinical and radiographic assessment of oral health. In 8/12 patients a hypoplastic form of AI was diagnosed, in 2/12 cases hypomaturation and in 2/12 cases hypocalcified form were noted. Chief complaints were mainly related to unsatisfactory aesthetics and dental sensitivity. In 8 patients there was active dental caries. Most of the patients had gingivitis and showed fair oral hygiene. The presence of non-enamel dental anomalies was recorded in 9 patients. TREATMENT: All patients received meticulous preventive care. Initial treatment depended on AI type and oral health of the patient. During the transition period, both conventional and resin modified glassionomer cements, as well as composite resin materials, were used to restore posterior teeth. Direct composite resin restorations were used to improve the appearance of anterior teeth. In 4 patients a long-lasting interdisciplinary approach including orthodontics, metal-ceramic crowns and fixed partial dentures, and direct composite restorations was required. FOLLOW-UP: Follow-up periods varied between 2-11 years. All children have been regularly recalled at 3 monthly intervals. Caries prevalence has remained low during the follow-up postoperative period and patients have reported satisfaction with the treatment they have received. CONCLUSION: AI is associated with multiple non enamel anomalies and requires a complex treatment. Treatment planning is related to the age of the patient, the type and severity of the disorder, and the oral health of the patient. Early diagnosis, preventive care and timely treatment are of foremost importance to improve oral health in children with AI. PMID- 20840833 TI - Shoulder model validation and joint contact forces during wheelchair activities. AB - Chronic shoulder impingement is a common problem for manual wheelchair users. The loading associated with performing manual wheelchair activities of daily living is substantial and often at a high frequency. Musculoskeletal modeling and optimization techniques can be used to estimate the joint contact forces occurring at the shoulder to assess the soft tissue loading during an activity and to possibly identify activities and strategies that place manual wheelchair users at risk for shoulder injuries. The purpose of this study was to validate an upper extremity musculoskeletal model and apply the model to wheelchair activities for analysis of the estimated joint contact forces. Upper extremity kinematics and handrim wheelchair kinetics were measured over three conditions: level propulsion, ramp propulsion, and a weight relief lift. The experimental data were used as input to a subject-specific musculoskeletal model utilizing optimization to predict joint contact forces of the shoulder during all conditions. The model was validated using a mean absolute error calculation. Model results confirmed that ramp propulsion and weight relief lifts place the shoulder under significantly higher joint contact loading than level propulsion. In addition, they exhibit large superior contact forces that could contribute to impingement. This study highlights the potential impingement risk associated with both the ramp and weight relief lift activities. Level propulsion was shown to have a low relative risk of causing injury, but with consideration of the frequency with which propulsion is performed, this observation is not conclusive. PMID- 20840835 TI - Impact of prior seasonal influenza vaccination and infection on pandemic A (H1N1) influenza virus replication in ferrets. AB - Early epidemiologic and serologic studies have suggested pre-existing immunity to the pandemic A (H1N1) 2009 influenza virus (H1N1pdm) may be altering its morbidity and mortality in humans. To determine the role that contemporary seasonal H1N1 virus infection or trivalent inactivated vaccine (TIV) might be playing in this immunity we conducted a vaccination-challenge study in ferrets. Vaccination with TIV was unable to alter subsequent morbidity or contact transmission in ferrets following challenge with H1N1pdm. Conversely, prior infection with the contemporary seasonal H1N1 strain altered morbidity, but not transmission, of H1N1pdm despite the detection of only minimal levels of cross reactive antibodies. PMID- 20840834 TI - TNFalpha and IFNgamma contribute to F1/LcrV-targeted immune defense in mouse models of fully virulent pneumonic plague. AB - Immunization with the Yersinia pestis F1 and LcrV proteins improves survival in mouse and non-human primate models of pneumonic plague. F1- and LcrV-specific antibodies contribute to protection, however, the mechanisms of antibody-mediated defense are incompletely understood and serum antibody titers do not suffice as quantitative correlates of protection. Previously we demonstrated roles for tumor necrosis factor-alpha (TNFalpha) and gamma-interferon (IFNgamma) during defense against conditionally attenuated pigmentation (pgm) locus-negative Y. pestis. Here, using intranasal challenge with fully virulent pgm-positive Y. pestis strain CO92, we demonstrate that neutralizing TNFalpha and IFNgamma interferes with the capacity of therapeutically administered F1- or LcrV-specific antibody to reduce bacterial burden and increase survival. Moreover, using Y. pestis strain CO92 in an aerosol challenge model, we demonstrate that neutralizing TNFalpha and IFNgamma interferes with protection conferred by immunization with recombinant F1-LcrV fusion protein vaccine (p<0.0005). These findings establish that TNFalpha and IFNgamma contribute to protection mediated by pneumonic plague countermeasures targeting F1 and LcrV, and suggest that an individual's capacity to produce these cytokines in response to Y. pestis challenge will be an important co-determinant of antibody-mediated defense against pneumonic plague. PMID- 20840836 TI - Efficacy of combination immunotherapy of IgM MAb B6.1 and amphotericin B against disseminated candidiasis. AB - We previously reported that the IgM MAb B6.1, specific for beta-1,2-mannotriose on the surface of the cell wall of Candida albicans, prevents mice from disseminated candidiasis. The preventive activity of the antibody is mediated by enhanced phagocytosis that caused killing of the fungus and involvement of the complement system. In the present study, MAb B6.1 was tested if the antibody enhances therapeutic efficacy of amphotericin B (Amp B) in a murine model of disseminated candidiasis due to C. albicans. Determination by the kidneys-cfu (colony forming unit) and survival times was used to assess treatment. Mice treated intraperitoneally with MAb B6.1 at 1h post-infection with C. albicans (5 x 105 yeast cells/mouse) developed fewer 28%cfu and prolonged survival rates than negative controls, whereas administration of B6.1 to mice at 2h post-infection was ineffective. Therapeutic effect of Amp B on mice with the disseminated disease was dose-dependent, but dosage of Amp B (0.5mg/kg body weight of mice) was not effective. A combination of MAb B6.1 given at 1h post-infection plus Amp B (0.5mg dose) enhanced survival times beyond the effect due to only antibody (P<0.05). The MST (mean survival times) value resulted from the combination therapy-received mice was as almost the same as MST value from 2mg dose of Amp B given animals (P<0.05). In case mice given a combination of Amp B (0.5mg dose) plus MAb B6.1 at 2h post-infection - a condition of developing no therapeutic efficacy, the combination also reduced disease severity. All these data indicate that MAb B6.1 acts in concert with Amp B, the antibody enhances therapeutic efficacy of Amp B, and this combination therapy augments protection which implies a possibility of reducing Amp B dose. The augmentation of the response appeared to be specific because an irrelevant IgM carbohydrate-specific MAb was not protective. In conclusion, these studies show that Amp B combined with MAb B6.1 may be an option of solving the problem of limited antifungal drug choices due to drug-resistant C. albicans. PMID- 20840837 TI - Carbon monoxide induces cyclooxygenase-2 expression through MAPKs and PKG in phagocytes. AB - Many biological functions of heme oxygenase (HO) have been attributed to its enzymatic byproduct carbon monoxide (CO). CO has been demonstrated to play an important role in down-regulation of pro-inflammatory cytokines, but few studies have investigated the effects of CO on the cyclooxygenase-2 (COX-2) expression in macrophage. Here, we assessed the induction of COX-2 by CO in macrophage with or without lipopolysaccharide (LPS) stimulation. Tricarbonyldichloro ruthenium (II) dimmer (CORM-2) is a well known CO-releasing molecule, and exhibits anti inflammatory activity in several cell types. In this study, both CORM-2 and CO gas were used to investigate the induction of COX-2 and the underlying molecular mechanisms in macrophage. Western blot and RT-PCR analysis demonstrated that CORM 2 and CO gas (500 ppm) significantly inhibited the protein and mRNA expression of iNOS in LPS-activated macrophages. In contrast, CORM-2 and CO gas up-regulated COX-2 expression and prostaglandin E2 (PGE2) production in the macrophage with or without LPS. CORM-2 time-dependently induced the phosphorylation of Akt and MAPKs, and the induction of COX-2 could be blocked by Akt, PKG, and MAPKs inhibitors. Indomethacin was used to decrease CORM-2-induced PGE2 production by inhibiting COX-2 enzyme activity. Indomethacin was unable to reverse the decrease of iNOS, but it could restore the IL-1beta expression and decrease the IL-10 expression in CORM-2-treated cells. The results suggest that CO induced COX-2 expression and PGE2 production through activating the Akt, PKG, and MAPK pathways, and CO-induced PGE2 may modulate inflammation during macrophage activation by suppressing IL-1beta expression and inducing IL-10 production. PMID- 20840838 TI - L-arginine reduces mitochondrial dysfunction and airway injury in murine allergic airway inflammation. AB - Bronchial epithelial injury is the hall mark of asthma which is a chronic airway inflammatory disease. We have shown the mitochondrial ultrastructural changes and dysfunction in bronchial epithelia of OVA induced mice. Reduced L-arginine bioavailability in asthma leads to increased formation of peroxynitrite which could induce mitochondrial dysfunction. We have also shown that L-arginine administration attenuates experimental asthma and reduces peroxynitrite. In this study, we wanted to determine the effect of L-arginine on mitochondrial dysfunction and airway injury in allergic airway inflammation. To determine this, L-arginine was administered to ovalbumin sensitized and challenged mice during allergen challenges. Mitochondrial and cytosolic fractions were purified from the lung to determine key mitochondrial functions, and mitochondrial ultrastructural changes in bronchial epithelia of first generation bronchi were determined. It was found that L-arginine administration increased mitochondrial cytochrome c oxidase activity, reduced cytosolic cytochrome c, increased lung ATP levels, reduced DNA fragmentation in bronchial epithelia and restored the ultrastructural changes of mitochondria of bronchial epithelia. In addition, L-arginine administration reduced the widening of intercellular spaces between adjacent bronchial epithelia. These findings indicated that L-arginine administration reduced airway injury and restored mitochondrial dysfunction in murine allergic airway inflammation. PMID- 20840839 TI - Role of Ca(2+) in structure and function of Complex I from Escherichia coli. AB - The dependence of E. coli Complex I activity on cation chelators such as EDTA, EGTA, NTA and o-phenanthroline was studied in bacterial membranes, purified solubilized enzyme and Complex I reconstituted into liposomes. Purified Complex I was strongly inhibited by EDTA with an I(50) of approximately 2.5MUM. The effect of Mg(2+) and Ca(2+) on EGTA inhibition of purified Complex I activity indicated that Ca(2+) is tightly bound to the enzyme and essential for the activity. Low sensitivity to o-phenanthroline argues against the occupation of this cation binding site by Fe(2+) or Zn(2+). The sensitivity of Complex I to EDTA/EGTA strongly depends on the presence of monovalent cations in the medium, and on whether the complex is native, membrane-bound, or purified. The data is discussed in terms of a possible loss either of an additional 14th, subunit of E. coli Complex I, analogous to Nqo15 in the T. thermophilus enzyme, or another component of the native membrane that affects the affinity and/or accessibility of the Ca(2+) binding site. PMID- 20840840 TI - Analysis of high temperature stress on the dynamics of antenna size and reducing side heterogeneity of Photosystem II in wheat leaves (Triticum aestivum). AB - This study demonstrates the effect of high temperature stress on the heterogeneous behavior of PSII in Wheat (Triticum aestivum) leaves. Photosystem II in green plant chloroplasts displays heterogeneity both in the composition of its light harvesting antenna i.e. on the basis of antenna size (alpha, beta and gamma centers) and in the ability to reduce the plastoquinone pool i.e. the reducing side of the reaction centers (Q(B)-reducing centers and Q(B)-non reducing centers). Detached wheat leaves were subjected to high temperature stress of 35 degrees C, 40 degrees C and 45 degrees C. The chlorophyll a (Chl a) fluorescence transient were recorded in vivo with high time resolution and analyzed according to JIP test which can quantify PS II behavior using Plant efficiency analyzer (PEA). Other than PEA, Biolyzer HP-3 software was used to evaluate different types of heterogeneity in wheat leaves. The results revealed that at high temperature, there was a change in the relative amounts of PSII alpha, beta and gamma centers. As judged from the complementary area growth curve, it seemed that with increasing temperature the PSII(beta) and PSII(gamma) centers increased at the expense of PSII(alpha) centers. The reducing side heterogeneity was also affected as shown by an increase in the number of Q(B)-non reducing centers at high temperatures. The reversibility of high temperature induced damage on PSII heterogeneity was also studied. Antenna size heterogeneity was recovered fully up to 40 degrees C while reducing side heterogeneity showed partial recovery at 40 degrees C. An irreversible damage to both the types of heterogeneity was observed at 45 degrees C. The work is a significant contribution to understand the basic mechanism involved in the adaptation of crop plants to stress conditions. PMID- 20840841 TI - Solution structure of subunit F (Vma7p) of the eukaryotic V(1)V(O) ATPase from Saccharomyces cerevisiae derived from SAXS and NMR spectroscopy. AB - Vacuolar ATPases use the energy derived from ATP hydrolysis, catalyzed in the A(3)B(3) sector of the V(1) ATPase to pump protons via the membrane-embedded V(O) sector. The energy coupling between the two sectors occurs via the so-called central stalk, to which subunit F does belong. Here we present the first low resolution structure of recombinant subunit F (Vma7p) of a eukaryotic V-ATPase from Saccharomyces cerevisiae, analyzed by small angle X-ray scattering (SAXS). The protein is divided into a 5.5nm long egg-like shaped region, connected via a 1.5nm linker to a hook-like segment at one end. Circular dichroism spectroscopy revealed that subunit F comprises of 43% alpha-helix, 32% beta-sheet and a 25% random coil arrangement. To determine the localization of the N- and C-termini in the protein, the C-terminal truncated form of F, F(1-94) was produced and analyzed by SAXS. Comparison of the F(1-94) shape with the one of subunit F showed the missing hook-like region in F(1-94), supported by the decreased D(max) value of F(1-94) (7.0nm), and indicating that the hook-like region consists of the C-terminal residues. The NMR solution structure of the C-terminal peptide, F(90-116), was solved, displaying an alpha-helical region between residues 103 and 113. The F(90-116) solution structure fitted well in the hook-like region of subunit F. Finally, the arrangement of subunit F within the V(1) ATPase is discussed. PMID- 20840842 TI - Potential therapeutic effects of curcumin: relationship to microtubule-associated proteins 2 in Abeta1-42 insult. AB - Curcumin can bind senile plaques and promote disaggregation of existing amyloid deposits and prevent aggregation of new amyloid deposits. Curcumin can also reverse distorted and curvy neurites around senile plaques and repair the neuritic abnormalities. We hypothesized whether altered neurite morphologies resulting from Abeta production had anything to do with the changes of expression of microtubule-associated protein 2 (MAP2), but curcumin could reverse damaged neurites by upregulation of MAP2 expression. In present study we designed and chemically synthesized curcumin and its six derivatives. After screening the protective effect of curcumin and derivatives, we found that the viability of SK N-SH cell model induced by Abeta1-42 was significantly increased by curcumin and Cur1, and the expression of MAP-2 protein was obviously up-regulated in immunocytochemical staining and Western blot. The cell morphologies, including the number of neurites, neurite growth and neurite extension, were significantly improved. Cur1 showed more significant protective effect on SK-N-SH cells than curcumin. Our study revealed for the first time that the neuroprotective effect of curcumin and curcumin derivatives not only directly depends on their special chemical constitution, but they can resist to Abeta damage by up-regulation of MAP-2 expression. In view of the special advantages of curcumin and Cur1, we reasonably believe that curcumin and Cur1 may be considered as an ideal therapeutic agent for the treatment of AD. PMID- 20840843 TI - 2-(-2-benzofuranyl)-2-imidazoline induces Bcl-2 expression and provides neuroprotection against transient cerebral ischemia in rats. AB - Stroke is the third leading cause of death and disability in North America and is becoming the most frequent cause of death in the rapid developing China. Protecting neurons in order to minimize brain damage represents an effective approach towards stroke therapeutics. Our recent study demonstrated that 2-(-2 benzofuranyl)-2-imidazoline (2-BFI), a ligand for imidazoline I(2) receptors, is potently neuroprotective against stroke, possibly through transiently antagonizing NMDA receptor activities. In this study, we further investigated the characteristics and mechanisms of 2-BFI-mediated neuroprotection using a rat stroke model of transient occlusion of the middle cerebral artery. Here, we show that 2-BFI was most effective at the dose of 3mg/kg in vivo, with significantly reduced brain infarct size and improved neurological deficits. Lower doses of 2 BFI at 1.5mg/kg, or higher dose of 2-BFI at 6 mg/kg, were either not effective, or toxic to the brain, respectively. Treating stroke rats with 3mg/kg 2-BFI significantly reduced the number of TUNEL positive cells and preserved the integrity of subcellular structures such as nuclear membranes and mitochondria as shown under the electron microscope, confirming neuroprotection. Most interestingly, 2-BFI-treated brains exhibited significant expression of Bcl-2, a gene with a known function in neuroprotection. Taken together, these studies not only demonstrated that 2-BFI at 3mg/kg was effective in neuroprotection, but also, for the first time, showed that 2-BFI provided neuroprotection through up regulating the neuroprotective gene Bcl-2. 2-BFI can be further developed as a therapeutic drug for stroke treatment. PMID- 20840844 TI - Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder-pelvic afferent nerve preparation of the rat. AB - Effects of a muscarinic receptor agonist oxotremorine-M (oxo-M) on bladder afferent nerve (BAN) activity were studied in an in vitro bladder-pelvic nerve preparation. Distension of the bladder induced rhythmic bladder contractions that were accompanied by multiunit afferent firing. Intravesical administration of 25 and 50 MUM oxo-M significantly increased afferent firing from 41 +/- 2 spikes/s to 51 +/- 4 spikes/s and 60.5 +/- 5 spikes/s, respectively, but did not change the maximum amplitude of spontaneous bladder contractions. The afferent nerve firing induced by isotonic distension of the bladder (10-40 cmH(2)O) was increased 22-100% by intravesical administration of 50 MUM oxo-M. Electrical stimulation on the surface of the bladder elicited action potentials (AP) in BAN. Oxo-M significantly decreased the voltage threshold by 40% (p<0.05) and increased by 157% (p<0.05) the area of the AP evoked at a submaximal stimulus intensity. These effects were blocked by intravesical injection of 5 MUM atropine methyl nitrate (AMN). Intravesical administration of 5 MUM AMN alone did not alter BAN firing or the amplitude of bladder contractions. The facilitatory effects induced by oxo-M on BAN activity were also suppressed (p<0.05) by intravesical administration of 2',3'-0-trinitrophenyl-ATP (TNP-ATP) (30 MUM). In preparations pretreated with capsaicin (125 mg/kg, s.c.) the facilitatory effects of 50 MUM oxo-M on BAN activity were absent. These results suggest that activation of muscarinic receptors facilitates mechano-sensitive, capsaicin-sensitive BAN activity in part by mechanisms involving purinergic receptors located near the luminal surface of the bladder and ATP release which presumably occurs in the urothelium. PMID- 20840845 TI - The selective dopamine uptake inhibitor, D-84, suppresses cocaine self administration, but does not occasion cocaine-like levels of generalization. AB - A successful replacement pharmacotherapy for treating cocaine dependency would likely reduce cocaine's abuse, support a low abuse liability, overlap cocaine's subjective effects, and have a long duration of action. Inhibitors with varying selectivity at the dopamine transporter (DAT) have approximated these properties. The objective of the present study was to characterize the behavioural effects of an extremely selective DAT inhibitor, (+) trans-4-(2-Benzhydryloxyethyl)-1-(4 fluorobenzyl) piperadin-3-ol (D-84), a 3-hydroxy substituted piperidine derivative of GBR-12935, for its cocaine-like discriminative stimulus effects, its effects on cocaine self-administration, and for its own self-administration. During cocaine discrimination tests, cocaine occasioned the 10 mg/kg cocaine training stimulus with an ED(50) value of 3.13 (1.54-6.34) mg/kg, and reduced response rates with an ED(50) value of 20.39 (7.24-57.44) mg/kg. D-84 incompletely generalized to the cocaine stimulus occasioning a maximal 76% cocaine-lever responding, while reducing response rates with lower potency than cocaine (ED(50)=30.94 (12.34-77.60) mg/kg). Pretreatment with D-84 (9.6-30.4 mg/kg) significantly (P<0.05) reduced cocaine intake at 17.1 mg/kg D-84 when cocaine was self-administered at 0.5 mg/kg/infusion, and at 30.4 mg/kg D-84 when cocaine was self-administered at 0.1, 0.5 .and 1.0 mg/kg/infusion. During self administration tests with D-84 (0.1-1 mg/kg/infusion), numbers of infusions significantly exceeded vehicle levels at 0.3 mg/kg/infusion. These results show that D-84 pretreatment can decrease cocaine intake especially when high doses of cocaine are being self-administered. This observation, combined with its incomplete generalization to the cocaine discriminative stimulus and its reported long duration of action, provides a profile consistent with a potential replacement therapy for treating cocaine-abusing patients. PMID- 20840846 TI - Photodynamic activity of aloe-emodin induces resensitization of lung cancer cells to anoikis. AB - Aloe-emodin was found to be a photosensitizer and possess anti-tumor activity. However, the detailed mechanism underlying the biological effects of aloe-emodin remains unknown. In this study, we explored the mechanisms of photocytotoxicity induced by aloe-emodin in lung cancer H460 cells. According to the results of the photoactivated aloe-emodin-induced disruption of cytoskeleton, we verify that aloe-emodin with irradiation induces anoikis of H460 cells. Photosensitized aloe emodin-induced anoikis is associated with the protein expression of alpha-actinin and mitogen-activated protein (MAP) kinase members. In this study, a rapid opening of the mitochondrial permeability transition pore and the change in apoptosis-related protein expression were involved in photoactivated aloe-emodin induced cell death. We also demonstrated that anoikis induced by aloe-emodin with irradiation is mediated through the intrinsic and extrinsic death pathways in a caspase-dependent manner in H460 cells. PMID- 20840847 TI - 3,6-Dihydroxyflavone induces apoptosis in leukemia HL-60 cell via reactive oxygen species-mediated p38 MAPK/JNK pathway. AB - We have previously selected a promising anti-cancer agent 3,6-dihydroxyflavone by pharmacodynamic experiments. In the present study, we investigated its pro apoptosis mechanisms in leukemia HL-60 cell. Our data revealed that 3,6 dihydroxyflavone dose- and time-dependently decreases cell viability and induces apoptosis by activating caspase cascade, cleaving poly (ADP-ribose) polymerase (PARP). The anti-cancer effects of 3,6-dihydroxyflavone are associated with the generation of reactive oxygen species, the altered glutathione-redox balance as significantly decreased glutathione (GSH) and its ratio to gluthatione disulfide (GSSG), and the accumulation of lipid peroxidation indicator malondialdehyde. Addition of antioxidant N-acetylcysteine (NAC) prevents the elevation of reactive oxygen species induced by 3,6-dihydroxyflavone and partially suppresses the cytotoxic effects. Furthermore, 3,6-dihydroxyflavone reduces cell membrane fluidity and induces the loss of mitochondrial membrane potential. 3,6 Dihydroxyflavone was also found to modulate the activities of mitogen-activated protein kinase (MAPK) family members, which includes increased protein kinase of 38 kDa (p38), c-Jun N-terminal kinase (JNK), and decreased extracellular signal regulated kinase (ERK) activation. The effect of 3,6-dihydroxyflavone on MAPKs pathway could be abrogated by co-treatment with NAC. Taking together, our data suggested that 3,6-dihydroxyflavone increases intracellular oxidative stress and lipid peroxidation, thereby affecting the physical and functional properties of plasma membrane, as well as MAPKs signal pathway, which are likely to play a role in the 3,6-dihydroxyflavone-induced HL-60 cell cytotoxicities. PMID- 20840848 TI - Exogenous expression of synaptotagmin XIII suppresses the neoplastic phenotype of a rat liver tumor cell line through molecular pathways related to mesenchymal to epithelial transition. AB - The molecular pathogenesis of hepatocellular carcinoma is well-studied but not completely understood. We utilized a microcell-hybrid model of tumor suppression in rat liver tumor cells to facilitate the identification of liver tumor suppressor genes located on human chromosome 11. These investigations confirmed a liver tumor suppressor locus at human 11p11.2, identified Wt1 as a potential effector of 11p11.2-mediated tumor suppression, and subsequently identified human SYT13 as a strong candidate for the 11p11.2 liver tumor suppressor gene. In the studies presented here, we introduced SYT13 into the GN6TF rat liver tumor cell line to characterize a functional role for SYT13 in this model system. Transfected clones expressing an SDS-resistant dimer form of the SYT13 protein displayed induction of Wt1 gene expression and a significant attenuation of the neoplastic phenotype exhibited by the parental tumor cell line. Saturation densities and anchorage-independent growth of SYT13 dimer-positive cell lines were reduced in vitro, and tumorigenicity was significantly decreased or ablated in syngeneic host rats in vivo. In addition, restoration of the contact inhibited, epithelioid morphology observed in normal liver epithelial cells accompanied ectopic expression of the SYT13 protein dimer, suggesting that SYT13 may be mediating an epithelial differentiation coordinate with tumor suppression in these cells. Accordingly, the expression of E-cadherin (Cdh1) mRNA was increased >100-fold in SYT13-dimer-positive cell lines and the Cdh1 transcriptional repressor Snail was decreased >3-fold in these cells compared to the parental tumor cells. These studies combine to suggest that SYT13 is a liver tumor suppressor gene and that its function may be mediated through pathways implicated in mesenchymal to epithelial transition. PMID- 20840849 TI - Rab4a signaling unmasks a pivotal link between myocardial homeostasis and metabolic remodeling in the diabetic heart. PMID- 20840850 TI - Intrahippocampal injection of TsTX-I, a beta-scorpion toxin, causes alterations in electroencephalographic recording and behavior in rats. AB - AIMS: TsTX-I scorpion toxin, also known as gamma-toxin, is a beta-toxin which binds to site 4 of the sodium channel, shifting its activation potential. There are few studies about its pharmacological action in the central nervous system. The objective of this work was to determine the electroencephalographic, behavioral and histopathological effects of intrahippocampal injection of TsTX-I. MAIN METHODS: Rats were anesthetized and fitted with cannulae for injection into the hippocampus and with electrodes for cerebral recording. The animals were treated with Ringer solution, some doses of TsTX-I, DMSO 0.1% or veratridine. Behavioral and electrographic recordings were observed for 4 hours after the injection. After 7 days, the rats were perfused, and their brains removed for histological analysis. KEY FINDINGS: Increasing doses of the toxin evoked epileptic-like discharges, wet dog shakes, and in some cases hind limb paralysis and intense respiratory difficulty followed by death. The histopathological analysis demonstrated no cell loss. Animals injected with veratridine developed epileptiform activity in the electrographic recording and neuronal loss. SIGNIFICANCE: The results suggest that TsTX-I toxin may be responsible, at least in part, for the epileptic and behavioral effects observed with the crude venom, and although veratridine and TsTX-I act on Na-channel, the differences between them are remarkable, demonstrating that toxins can have different functional effects depending on the site of action in the channel. Thus, animal neurotoxins are often highly selective and may be useful for the identification of the sequence of events underlying neurotransmission. PMID- 20840851 TI - Protective effect of curcumin against seizures and cognitive impairment in a pentylenetetrazole-kindled epileptic rat model. AB - AIM: Epilepsy as well as chronic use of most antiepileptic drugs predisposes to cognitive impairment. Curcumin has been reported to possess antioxidant, anticonvulsant as well as neuroprotective potential. Hence, this study was conducted to evaluate the effect of curcumin against seizures, cognitive impairment and oxidative stress in pentylenetetrazole-induced kindling in rats. MAIN METHODS: The effect of pretreatment with curcumin (100, 200 and 300 mg/kg, orally) on pentylenetetrazole (PTZ)-induced kindling, kindling-induced cognitive impairment and oxidative stress was evaluated. Male Wistar rats were injected PTZ (30 mg/kg, i.p.) once every alternate day (48+/-1h) until the development of kindling. Cognitive impairment was assessed using elevated plus maze and passive avoidance test while the oxidative stress parameters (malondialdehyde and glutathione) were estimated in the whole brain at the end of experiments. KEY FINDINGS: PTZ, 30 mg/kg, induced kindling in rats after 31.0+/-1.4 days. Curcumin showed dose-dependent anti-seizure effect. Curcumin (300 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ kindling induced a significant oxidative stress and cognitive impairment which was reversed by pretreatment with curcumin in a dose dependent manner. SIGNIFICANCE: The results indicate that pretreatment with curcumin ameliorates seizures, oxidative stress and cognitive impairment in PTZ induced kindling in rats. These results thus suggest the potential of curcumin as an adjuvant in epilepsy both to prevent seizures as well as to protect against seizure induced memory impairment. PMID- 20840852 TI - Mono-hydroxy methoxychlor alters levels of key sex steroids and steroidogenic enzymes in cultured mouse antral follicles. AB - Methoxychlor (MXC) is an organochlorine pesticide that reduces fertility in female rodents by decreasing antral follicle numbers and increasing follicular death. MXC is metabolized in the body to mono-hydroxy MXC (mono-OH). Little is known about the effects of mono-OH on the ovary. Thus, this work tested the hypothesis that mono-OH exposure decreases production of 17beta-estradiol (E2) by cultured mouse antral follicles. Antral follicles were isolated from CD-1 mice (age 35-39 days) and exposed to dimethylsulfoxide (DMSO), or mono-OH (0.1-10 MUg/mL) for 96 h. Media and follicles were collected for analysis of sex steroid levels and mRNA expression, respectively. Mono-OH treatment (10 MUg/mL) decreased E(2) (DMSO: 3009.72+/-744.99 ng/mL; mono-OH 0.1 MUg/mL: 1679.66+/-461.99 ng/mL; 1 MUg/mL: 1752.72+/-532.41 ng/mL; 10 MUg/mL: 45.89+/-33.83 ng/mL), testosterone (DMSO: 15.43+/-2.86 ng/mL; mono-OH 0.1MUg/mL: 17.17+/-4.71 ng/mL; 1 MUg/mL: 13.64+/-3.53 ng/mL; 10 MUg/mL: 1.29+/-0.23 ng/mL), androstenedione (DMSO: 1.92+/ 0.34 ng/mL; mono-OH 0.1 MUg/mL: 1.49+/-0.43ng/mL; 1 MUg/mL: 0.64+/-0.31 ng/mL; 10 MUg/mL: 0.12+/-0.06 ng/mL) and progesterone (DMSO: 24.11+/-4.21 ng/mL; mono-OH 0.1MUg/mL: 26.77+/-4.41 ng/mL; 1 MUg/mL: 20.90+/-3.75 ng/mL; 10 MUg/mL: 9.44+/ 2.97 ng/mL) levels. Mono-OH did not alter expression of Star, Hsd3b1, Hsd17b1 and Cyp1b1, but it did reduce levels of Cyp11a1, Cyp17a1 and Cyp19a1 mRNA. Collectively, these data suggest that mono-OH significantly decreases levels of key sex steroid hormones and the expression of enzymes required for steroidogenesis. PMID- 20840854 TI - Non-dioxin-like PCBs interact with benzo[a]pyrene-induced p53-responses and inhibit apoptosis. AB - Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants often co-existing in contaminated environments. However, there are few studies on the effects of co-exposure, in particular on effects of pure NDL-PCB congeners and PAHs. We have evaluated the effects of some highly purified NDL-PCBs and benzo[a]pyrene (BP) on BP-induced Raf, Erk, Mdm2, p53 signaling and on BP-induced apoptosis and cell cycle arrest. PCBs (1 MUM) were added to HepG2 cells 1h prior to BP and the incubation was stopped at 24 h. Employing Western blotting we found that NDL-PCBs (28, 101 and 153) amplified the BP-induced inactivating phosphorylation of Raf (pRaf Ser 259) and decreased levels of pErk Tyr 204. This treatment also resulted in the attenuation of BP-induced Mdm2 phosphorylation at Ser166 and amplification of the p53 Ser15 response. These effects were associated with an unexpected inhibition of BP-induced apoptosis. A dioxin-like PCB (DL-PCB 126) was used as reference and gave results that were predictable from previous studies, i.e. it attenuated BP induced p53 response and apoptosis. In an effort to explain why the NDL-PCB induced amplification of the p53 response was associated with a decreased apoptotic response we analyzed FoxO3a, which may translocate p53 to the cytoplasm. We found that NDL-PCBs reduced the level of phosphorylated FoxO3a at Thr32. This phosphorylation promotes a cytoplasmic translocation of FoxO3a and p53 and our data suggest that NDL-PCBs may inhibit BP-induced apoptosis by preventing a FoxO3a-dependent translocation of p53 to the cytoplasm. PMID- 20840855 TI - Mechanisms of olfactory toxicity of the herbicide 2,6-dichlorobenzonitrile: essential roles of CYP2A5 and target-tissue metabolic activation. AB - The herbicide 2,6-dichlorobenzonitril (DCBN) is a potent and tissue-specific toxicant to the olfactory mucosa (OM). The toxicity of DCBN is mediated by cytochrome P450 (P450)-catalyzed bioactivation; however, it is not known whether target-tissue metabolic activation is essential for toxicity. CYP2A5, expressed abundantly in both liver and OM, was previously found to be one of the P450 enzymes active in DCBN bioactivation in vitro. The aims of this study were to determine the role of CYP2A5 in DCBN toxicity in vivo, by comparing the extents of DCBN toxicity between Cyp2a5-null and wild-type (WT) mice, and to determine whether hepatic microsomal P450 enzymes (including CYP2A5) are essential for the DCBN toxicity, by comparing the extents of DCBN toxicity between liver-Cpr-null (LCN) mice, which have little P450 activity in hepatocytes, and WT mice. We show that the loss of CYP2A5 expression did not alter systemic clearance of DCBN (at 25 mg/kg); but it did inhibit DCBN-induced non-protein thiol depletion and cytotoxicity in the OM. Thus, CYP2A5 plays an essential role in mediating DCBN toxicity in the OM. In contrast to the results seen in the Cyp2a5-null mice, the rates of systemic DCBN clearance were substantially reduced, while the extents of DCBN-induced nasal toxicity were increased, rather than decreased, in the LCN mice, compared to WT mice. Therefore, hepatic P450 enzymes, although essential for DCBN clearance, are not necessary for DCBN-induced OM toxicity. Our findings form the basis for a mechanism-based approach to assessing the potential risks of DCBN nasal toxicity in humans. PMID- 20840853 TI - Expression of proliferative and inflammatory markers in a full-thickness human skin equivalent following exposure to the model sulfur mustard vesicant, 2 chloroethyl ethyl sulfide. AB - Sulfur mustard is a potent vesicant that induces inflammation, edema and blistering following dermal exposure. To assess molecular mechanisms mediating these responses, we analyzed the effects of the model sulfur mustard vesicant, 2 chloroethyl ethyl sulfide, on EpiDerm-FTTM, a commercially available full thickness human skin equivalent. CEES (100-1000 MUM) caused a concentration dependent increase in pyknotic nuclei and vacuolization in basal keratinocytes; at high concentrations (300-1000 MUM), CEES also disrupted keratin filament architecture in the stratum corneum. This was associated with time-dependent increases in expression of proliferating cell nuclear antigen, a marker of cell proliferation, and poly(ADP-ribose) polymerase (PARP) and phosphorylated histone H2AX, markers of DNA damage. Concentration- and time-dependent increases in mRNA and protein expression of eicosanoid biosynthetic enzymes including COX-2, 5 lipoxygenase, microsomal PGE2 synthases, leukotriene (LT) A4 hydrolase and LTC4 synthase were observed in CEES-treated skin equivalents, as well as in antioxidant enzymes, glutathione S-transferases A1-2 (GSTA1-2), GSTA3 and GSTA4. These data demonstrate that CEES induces rapid cellular damage, cytotoxicity and inflammation in full-thickness skin equivalents. These effects are similar to human responses to vesicants in vivo and suggest that the full thickness skin equivalent is a useful in vitro model to characterize the biological effects of mustards and to develop potential therapeutics. PMID- 20840856 TI - The diffuse nervous network of Camillo Golgi: facts and fiction. AB - The name of Camillo Golgi is inextricably associated, in the mind of most neuroscientists, with the theory that nerve cells communicate with one another by means of an intricate network of anastomosing axonal branches contained in the neuropil intervening between cell bodies in the gray matter of the brain and spinal cord. Examination, however, of Golgi's drawings in the papers published in the decade intervening between publication of his method (1873) and the beginning of his studies on malaria (1885) shows that axonal arborization in the cerebellar cortex and olfactory bulb are depicted as independent of one other. This is in striking contrast with the drawings included by Golgi in his 1906 Nobel lecture where the entire granular layer of the cerebellar cortex is occupied by a network of branching and anastomosing nerve processes. Thus, Golgi in his original papers on the cerebellum represents nerve cells as discrete units and only later in life merges axonal arborizations in the context of a lecture in defense of the reticular theory. PMID- 20840859 TI - A multifunctional envelope type nano device (MEND) for gene delivery to tumours based on the EPR effect: a strategy for overcoming the PEG dilemma. AB - Gene and nucleic acid therapy are expected to play a major role in the next generation of medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel non-viral gene delivery system. Poly(ethylene glycol) (PEG)ylation is a useful method for achieving a longer circulation time for delivery of the MEND to a tumour via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity for the delivery system. For successful gene delivery for cancer treatment, the crucial issue associated with the use of PEG, the 'PEG dilemma' must be addressed. In this review, we describe the development and applications of MEND, and discuss strategies for overcoming the PEG dilemma, based on the manipulation of intracellular trafficking of cellular uptake and endosomal release using functional devices such as specific ligands, cleavable PEG systems and endosomal fusogenic/disruptic peptides. PMID- 20840857 TI - Activation of the sonic hedgehog signaling controls human pulmonary arterial smooth muscle cell proliferation in response to hypoxia. AB - The hedgehog signal pathway plays a crucial role in the angiogenesis and vascular remodeling. However, the function of this pathway in the pulmonary vascular smooth cell proliferation in response to hypoxia remains unknown. In this study, we have demonstrated that the main components of the hedgehog pathway, including sonic hedgehog (SHH), patched1 (PTCH1), smoothened (SMO), GLI and hypoxia inducible factor 1 (HIF1) are expressed in the human pulmonary arterial smooth muscle cells (HPASMCs). Interestingly, hypoxia significantly enhanced the expression of SHH and HIF1, facilitated the translocation of GLI1 into the nuclei, and promoted the proliferation of HPASMCs. Furthermore, direct activation of the SHH pathway through incubation with the purified recombinant human SHH or with purmorphamine and SAG, two Smo agonists, also enhanced the proliferation of HPASMCs. Importantly, the treatment with anti-SHH and anti-HIF1 antibodies or cyclopamine, a specific SMO inhibitor, markedly inhibited the nuclear translocation of GLI1 and cell proliferation in the HPASMCs induced by hypoxia and activation of the SHH pathway. Moreover, the treatment with cyclopamine increased apoptosis in the hypoxic HPASMCs. These data strongly demonstrate for the first time that the SHH signaling plays a crucial role in the regulation of HPASMC growth in response to hypoxia. PMID- 20840860 TI - p53 and PPP1R13L (alias iASPP or RAI) form a feedback loop to regulate genotoxic stress responses. AB - BACKGROUND: PPP1R13L gene has been found to be over-expressed in variety of cancers and its expression in p53 wild-type background is sufficient to promote tumor growth in vivo. However, in the non-transformed cells it acts as a tumor suppressor which suggests that the role of PPP1R13L is multifaceted. METHODS: We have used siRNA optimized for inhibition of p53, PPP1R13L, BAX and GADD45 alpha expression and investigated the role of those gene products for PPP1R13L expression and induction in a variety of mouse and human cells with different p53 status. In addition we have applied Western Blot, Q-PCR and proteasome inhibition analysis to further ascertain the link between PPP1R13L induction and p53 status. RESULTS: We show that the pattern and extent of the PPP1R13L expression depend on the presence of active p53. Downregulation of p53 target genes BAX and/or GADD45 alpha led to decreased in PPP1R13L activation after adriamycin and/or etoposide treatments. Treatment of the cells with the proteasome inhibitor MG-132 resulted in the accumulation of both p53 and PPP1R13L proteins. CONCLUSIONS: We have provided evidence that endogenous PPP1R13L acts as a negative regulator of p53 function, presumably by direct binding. p53 accumulation and activity after DNA damage is compromised by PPP1R13L expression. We suggest that PPP1R13L and p53 form a negative feedback loop which regulates their amount and activity. GENERAL SIGNIFICANCE: The profound modulatory effect of the PPP1R13L protein on the ability of p53 to cause cellular apoptosis has important implications in cancer and presents new therapeutic possibilities. PMID- 20840861 TI - Molecular basis for age-related changes in ileum: involvement of Bax/caspase dependent mitochondrial apoptotic signaling. AB - Previous studies indicate that in the elderly, a morphological change in the small intestine is accompanied by apoptosis. However, currently little information is available on the molecular events leading up to the apoptotic process in aged ileum. Our current study assessed mitochondrial apoptotic signaling along with key factors known to be involved in mitochondrial permeabilization in rat ileum. Experimentations were carried out utilizing Sprague-Dawley rats at 6 and 24 months of age. The histological analysis showed a significant loss in thickness of the intestinal mucosa during aging, which was accompanied by higher reactive species. Molecular analysis revealed the mitochondrial translocation of Bax showed a significant increase with aging. However, the expression of cyclophilin D, adenine nucleotide translocator, and the voltage-dependent anion channel that regulates the mitochondria permeability transition pore decreased or remained unchanged. Furthermore, the expression of caspase 3 was enhanced in aged ileum with increased DNA fragmentation, while nuclear translocation of apoptosis-inducing factor and endonuclease G were decreased with aging. In conclusion, our findings indicate that the mitochondrial translocation of Bax by increased oxidative stress may result in cell death through caspase-dependent apoptosis in aged ileum, thereby leading to a decrease in intestinal mucosal thickness during aging. PMID- 20840863 TI - Inhibition of liver X receptor-alpha-dependent hepatic steatosis by isoliquiritigenin, a licorice antioxidant flavonoid, as mediated by JNK1 inhibition. AB - Isoliquiritigenin (ILQ), a flavonoid obtained from Glycyrrhizae species, has an antioxidant effect. This study investigated the potential of ILQ for inhibiting liver X receptor-alpha (LXRalpha)-mediated lipogenesis and steatosis in hepatocytes and its underlying molecular basis. Treatment with ILQ antagonized the ability of an LXRalpha agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), thereby repressing transcription of fatty acid synthase, acetyl-CoA carboxylase, ATP-binding cassette transporter-A1, and stearoyl-CoA desaturase-1. ILQ treatment inhibited activating phosphorylation of JNK1 elicited by palmitate or TNFalpha. JNK1, but not JNK2, increased LXRalpha phosphorylation at serine residues, promoting LXRalpha activation. The ability of ILQ to inhibit JNK1 downstream of ASK1-MKK7 led to the repression of T0901317 inducible LXRalpha and SREBP-1c activation. In mice fed a high-fat diet, ILQ treatment inhibited hepatic steatosis, as shown by a decrease in fat accumulation and repression of lipogenic genes. The results of blood biochemistry and histopathology confirmed attenuation of high-fat diet-induced liver injury by ILQ. Moreover, ILQ inhibited oxidative stress, as indicated by decreases in thiobarbituric acid-reactive substance formation, iNOS and COX2 induction, and nitrotyrosinylation. Our results demonstrate that ILQ has the ability to repress LXRalpha-dependent hepatic steatosis through JNK1 inhibition and protect hepatocytes from oxidative injury inflicted by fat accumulation. PMID- 20840862 TI - Heat shock proteins and Drosophila aging. AB - Since their discovery in Drosophila, the heat shock proteins (Hsps) have been shown to regulate both stress resistance and life-span. Aging is characterized by increased oxidative stress and the accumulation of abnormal (malfolded) proteins, and these stresses induce Hsp gene expression through the transcription factor HSF. In addition, a subset of Hsps is induced by oxidative stress through the JNK signaling pathway and the transcription factor Foxo. The Hsps counteract the toxicity of abnormal proteins by facilitating protein refolding and turnover, and through other mechanisms including inhibition of apoptosis. The Hsps are up regulated in tissue-specific patterns during aging, and their expression correlates with, and sometimes predicts, life span, making them ideal biomarkers of aging. The tools available for experimentally manipulating gene function and assaying healthspan in Drosophila provides an unparalleled opportunity to further study the role of Hsps in aging. PMID- 20840864 TI - Polymorphism in glutathione S-transferase P1 is associated with susceptibility to Plasmodium vivax malaria compared to P. falciparum and upregulates the GST level during malarial infection. AB - Glutathione S-transferase P1 (GSTP1) is a member of the GST superfamily, which has well-established multiple roles in various infectious and parasitic diseases. The genetic regulation of GSTP1 has been extensively studied. Thus, its biological significance and disease association prompted us to investigate the role of GSTP1 polymorphisms in Plasmodium-mediated pathogenesis in infected humans. The genotypic distribution of Ile105Val in Plasmodium vivax infection was observed to be significant and strongly associated (OR=4.5) with the progression of pathology, whereas in P. falciparum infection no significant association was observed compared to healthy subjects. Interestingly, we observed significant elevation of GST in vivax infection, with both genotypes Ile105Val and Val105Val, compared to healthy subjects, whereas in P. falciparum infection we found marginally elevated GST levels of mutated genotypes but significantly depleted compared to healthy subjects. Further, during vivax and falciparum infection overall significant elevations of glutathione, glutathione peroxidase, and GST levels were observed. Expression of both GSTP1 mRNA and protein was significantly upregulated during vivax infection compared to falciparum infection and both were significantly upregulated compared to the levels in healthy subjects as well. These studies suggest that GSTP1 polymorphism is involved in the pathogenesis of malaria and it may serve as a valuable molecular marker, possessing a promising rationale for diagnostic potential in assessing disease progression during clinical malaria. PMID- 20840866 TI - SHP-1 inhibits beta-catenin function by inducing its degradation and interfering with its association with TATA-binding protein. AB - beta-catenin plays a dual role both as a key effector in the regulation of adherens junctions and as a transcriptional coactivator. Tyrosine phosphorylation of beta-catenin is implicated as a means for its release from E-cadherin complexes and correlates with enhanced transcriptional activity. However, it remains unclear whether or not tyrosine phosphorylated beta-catenin degrades slower or faster than its unphosphorylated form or transactivates the downstream target genes differently. We have recently demonstrated that tyrosine phosphatase SHP-1 negatively regulates the nuclear transcriptional function of beta-catenin. The mechanism by which SHP-1 specifically inhibits beta-catenin/TCF transcriptional activity remains, however, to be elucidated. Herein, we demonstrate that inhibition of tyrosine phosphatases with pervanadate induced both c-src-dependent tyrosine phosphorylation and nuclear translocation of beta catenin. Moreover, ectopic expression of SHP-1 but not the inactive form of SHP-1 (C453S) inhibited src-induced tyrosine phosphorylation of beta-catenin on tyrosines 86 and 654. SHP-1 expression and mutations of tyrosine-86 and tyrosine 654 to phenylalanine significantly and similarly decreased the transactivation potential of beta-catenin on the TOPFLASH reporter. SHP-1 expression as well as mutations of tyrosine-86 and tyrosine-654 to phenylalanine also significantly interfered with the association of beta-catenin with TBP. Mutations of tyrosine 86 and/or tyrosine-654 did not markedly alter beta-catenin stability whereas SHP 1 expression promoted proteasomal beta-catenin degradation through a GSK3beta dependent mechanism. In conclusion, SHP-1 negatively regulates beta-catenin transcriptional activity i) by dephosphorylating beta-catenin on tyrosines 86 and 654, ii) by impairing its capacity to interact with the basal transcriptional factor TBP and iii) by promoting beta-catenin degradation in a GSK3beta-dependent manner. PMID- 20840868 TI - Lentiviral delivery of meteorin protects striatal neurons against excitotoxicity and reverses motor deficits in the quinolinic acid rat model. AB - Meteorin is a newly discovered secreted protein involved in both glial and neuronal cell differentiation, as well as in cerebral angiogenesis during development; but effects in the adult nervous system are unknown. The growth factor-like properties and expression of Meteorin during the development of the nervous system raises the possibility that it might possess important neuroprotective or regenerative capabilities. This report is the first demonstration that Meteorin has potent neuroprotective effects in vivo. Lentiviral-mediated striatal delivery of Meteorin to rats two weeks prior to injections of quinolinic acid (QA) dramatically reduced the loss of striatal neurons. The cellular protection afforded by Meteorin was associated with normalization of neurological performance on spontaneous forelimb placing and cylinder behavioral tests and a complete protection against QA-induced weight loss. These benefits were comparable in magnitude to those obtained with lentiviral-mediated delivery of ciliary neurotrophic factor (CNTF), a protein with known neuroprotective properties in the same model system. In naive animals, endogenous levels of both Meteorin and CNTF were increased in glial cells in response to QA lesion indicating that Meteorin may exert its protective effects as part of the reactive gliosis cascade in the injured brain. In summary, these data demonstrate that Meteorin strongly protects striatal neurons and deserves additional evaluation as a novel therapeutic for the treatment of neurological disorders with an excitotoxic component such as Huntington's Disease. PMID- 20840867 TI - ERK1 and ERK2 kinases activate hydroxyurea-induced S-phase checkpoint in MCF7 cells by mediating ATR activation. AB - Modulation of MEK has been demonstrated to affect hydroxyurea (HU) induced-DNA damage response (DDR), implying the involvement of ERK1 and ERK2 in the process. To directly examine how the ERK kinases function in HU-initiated DDR, we knocked down either ERK1 or ERK2 in MCF7 cells. This resulted in reduction of HU-induced phosphorylation of CHK1 S345 (serine 345), p53 S15, and H2AX S139. While HU potently induced CDC2 Y15 (tyrosine 15) phosphorylation, an event causing CDC2 inactivation, inhibition of ERK kinases using U0126 (a MEK inhibitor), MEK1K97M (a dominant negative MEK1), and knockdown of either ERK1 or ERK2 significantly attenuated HU-induced CDC2 Y15 phosphorylation. As CDC2 kinase activity is required for mitosis, our observations reveal that ERK1 and ERK2 kinases play important roles in preventing mitotic entry in response to HU. Consistent with ATR being the apical kinase to initiate HU-induced DDR, knockdown of ERK1 or ERK2 significantly inhibited HU-induced ATR recruitment to the stalled replication forks (ATR foci), an event required for ATR activation. Mechanistically, knockdown of ERK1 or ERK2 resulted in relocation of ATR from the nucleoplasm to the nucleolus in response to HU, therefore making ATR unavailable to the sites of DNA damage. Taken together, we demonstrate that ERK kinases sit upstream of ATR to facilitate its activation. PMID- 20840869 TI - Olfactory ensheathing cells moderate nuclear factor kappaB translocation in astrocytes. AB - Nuclear factor kappaB (NFkappaB) is a key transcriptional regulator of inflammatory genes. We investigated the modulatory effects of olfactory ensheathing cells (OECs), microglia and meningeal fibroblasts on translocation of NFkappaB to astrocyte nuclei. The percentage of activated astrocytes in co cultures with OECs was significantly less than for co-cultures with microglia (p<0.001) and fibroblasts (p<0.05). Phorbol myristate acetate (PMA) and calcium ionophore stimulation of p65 NFkappaB translocation to nuclei provided an in vitro model of astrocyte inflammatory activation. Soluble factors released by OECs significantly moderated the astrocytic NFkappaB translocation induced by either PMA/calcium ionophore or microglia-derived factors (p<0.001). Insulin-like growth factor-1 may contribute to these effects, since it is expressed by OECs and also significantly moderated the astrocytic NFkappaB translocation (p<0.05), albeit insufficiently to fully account for the OEC-induced moderation (p<0.01). Olfactory ensheathing cells significantly moderated the increased transcription of the pro-inflammatory cytokine, granulocyte macrophage-colony stimulating factor in the activated astrocytes (p<0.01). These results suggest that transplanted OECs could improve neural repair after CNS injury by moderating astrocyte activation. PMID- 20840870 TI - Leptin reduces Atlantic salmon growth through the central pro-opiomelanocortin pathway. AB - Leptin (Lep) is a key factor for the energy homeostasis in mammals, but the available data of its role in teleosts are not conclusive. There are large sequence differences among mammalian and teleost Lep, both at the gene and protein level. Therefore, in order to characterize Lep function in fish, the use of species-specific Lep is crucial. In this study, the cDNA sequence of salmon leptin a1 (lepa1) was used to establish a production protocol for recombinant salmon LepA1 (rsLepA1) in Escherichia coli, that enabled a final yield of 1.7 mg pure protein L-1 culture. The effects of 20-day administration of rsLepA1 on growth and brain neuroendocrine peptide gene expression [npy, cart, agrp (-1 and 2), pomc (-a1, -a2, -a2s, and -b)] were studied in juvenile, immature Atlantic salmon (96.5+/-2.1g) fed a commercial diet to satiation. Intraperitoneal osmotic pumps were used to deliver rsLepA1 at four different concentrations (calculated pumping rates were 0, 0.1, 1.0 and 10 ng g-1 h-1). In the highest dosage group (10 ng g-1 h-1), the growth rate was significantly reduced, and pomc-a1 gene expression was higher than in controls. The results support the lipostatic hypothesis and suggest that sLepA1 reduces growth in Atlantic salmon by affecting food intake through the central pro-opiomelanocortin pathway. PMID- 20840865 TI - Oxidative stress, inflammation, and cancer: how are they linked? AB - Extensive research during the past 2 decades has revealed the mechanism by which continued oxidative stress can lead to chronic inflammation, which in turn could mediate most chronic diseases including cancer, diabetes, and cardiovascular, neurological, and pulmonary diseases. Oxidative stress can activate a variety of transcription factors including NF-kappaB, AP-1, p53, HIF-1alpha, PPAR-gamma, beta-catenin/Wnt, and Nrf2. Activation of these transcription factors can lead to the expression of over 500 different genes, including those for growth factors, inflammatory cytokines, chemokines, cell cycle regulatory molecules, and anti inflammatory molecules. How oxidative stress activates inflammatory pathways leading to transformation of a normal cell to tumor cell, tumor cell survival, proliferation, chemoresistance, radioresistance, invasion, angiogenesis, and stem cell survival is the focus of this review. Overall, observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked. PMID- 20840871 TI - The effect of acidity on gill variations in the aquatic air-breathing fish, Trichogaster lalius. AB - Climate change affects organisms that inhabit not only in aerial but also in aquatic environments by making water more hypoxic and acidic. In the past, we evaluated morphological and functional variations in the gills of 12 species of aquatic air-breathing fishes. The aim of the present study is to examine the degree of gill modification in the aquatic air-breathing fish, Trichogaster lalius, in response to acidic stress. This provides a link between the ecological and physiological studies. We evaluated the changes in morphology and function of the gills, labyrinth organ, and kidney when the fish were subjected to acidic water and deionized water (DW). In the first experiment, fish were sampled at 1, 2, 4, and 7 days after acidic treatment. Apparent morphological modification was observed on day 4 and recovery was noted on day 7. Protein expression and enzyme activity of vacuolar-type H+-ATPase (VHA) and the protein expression of the proliferating cell nuclear antigen (PCNA) of the 1st and 4th gill arches both increased in the 4-day and 7-day acidic groups while the enzyme activity of Na+/K+-ATPase (NKA) decreased. In the second experiment, fish were tested for changes in the 1st and 4th gill arches and kidney after exposure to DW and acidic water for 4days. The gill structure of the fish in the DW was not different from that of the control group (fresh water). The protein expression and enzyme activity of the VHA of the 1st and 4th gill arches increased in both the DW and acidic groups for 4 days. We found a decrease in the protein expression of NKA in the kidney and in the enzyme activity of NKA in the 1st and 4th gill arches in the DW and acidic groups. From these results, we suggest that T. lalius exhibited significantly different ionic regulation and acid-base regulatory abilities in the DW and acidic groups in the 1st and 4th gill arches and kidney. The responses of the gills in T. lalius were different from those fish that show apparent morphological variations between the 1st and 4th gill arches. PMID- 20840872 TI - Involvement of asymmetric dimethylarginine and Rho kinase in the vascular remodeling in monocrotaline-induced pulmonary hypertension. AB - Recent studies have shown that the plasma level of asymmetric dimethylarginine (ADMA) was increased accompanied by the decreased dimethylarginine dimethylaminohydrolase (DDAH) activity in pulmonary hypertension (PH) and ADMA was able to regulate pulmonary endothelial cells mobility through increasing the activity of Rho kinase (ROCK). This work was conducted to explore the role of ADMA/DDAH pathway in vascular remodeling in PH and the underlying mechanisms. The rat model of PH was established by a single injection of monocrotaline (60 mg/kg, s.c.). The pulmonary arterial pressure, the remodeling of pulmonary artery, the hypertrophy of right ventricle, the plasma levels of ADMA and NO, the expression of DDAH2, ROCK1 or ROCK2 and the ROCK activity were determined. In vitro studies, the pulmonary artery smooth muscle cells (PASMCs) were isolated and cultured. The effect of ADMA on PASMCs proliferation and ROCK activation was investigated. The results showed that the injection of monocrotaline successfully induced PH characterized by the increased pulmonary arterial pressure, vascular remodeling and right ventricle hypertrophy. The plasma level of ADMA was elevated concomitantly with the increased ROCK activity and ROCK1 expression as well as the decreased DDAH2 expression in pulmonary arteries. In the cultured PASMCs, ADMA promoted cellular proliferation accompanied by the increased ROCK1 expression and ROCK activity, which was attenuated by the ROCK inhibitor or by the intracellular antioxidant. These results suggest that ADMA could promote the proliferation of PASMCs through activating ROCK pathway, which may account for, at least partially, the vascular remodeling in monocrotaline-induced PH. PMID- 20840873 TI - Handling missing data issues in clinical trials for rheumatic diseases. AB - Missing data are ubiquitous in clinical trials for rheumatic diseases, and it is important to accommodate them using appropriate statistical techniques. We review some of the basic considerations for missing data and survey a range of statistical techniques for analysis of longitudinal clinical trial data with missingness. Using clinical trial data from patients with diffuse systemic sclerosis, we show that different approaches to handling missing data can lead to different conclusions on the efficacy of the treatment. We then suggest how such discrepancies might be addressed. In particular, we emphasize that the commonly used method in rheumatic clinical trials of carrying the last observation forward to impute missing values should not be the primary analysis. We review software for analyzing different types of missing data and discuss our freely available software library for analyzing the more difficult but more realistic situation when the probability of dropout or missing data may depend on the unobserved missing value. PMID- 20840874 TI - Do messages of scarcity increase trial recruitment? AB - INTRODUCTION: Psychological theory suggests that participants may be more likely to volunteer to join a clinical trial if they perceive places in the trial are a scarce commodity. MATERIAL AND METHODS: We conducted a single blind, randomized controlled trial to test recruitment strategies within the larger txt2stop smoking cessation trial. 1862 people who were eligible for the txt2stop trial but had not yet consented to join were randomized to receive either A) a reminder about the txt2stop trial plus a message that there were only 300 places left, or B) a reminder about the trial only. The outcome was the participant's consent to join the txt2stop trial 3days after messages were sent. RESULTS: Of 895 participants randomized to the intervention group, 90 (10.1%) had consented to join the txt2stop trial. Of the 967 participants randomized to the control group, 67 (6.9%) had consented to join the txt2stop trial (OR=1.50, 95% CI 1.07-2.12). DISCUSSION: Scarcity messages were an effective way to increase recruitment into the txt2stop trial and could be relevant to other trials. CONCLUSIONS: Communicating scarcity is an effective way to increase trial recruitment. PMID- 20840875 TI - Participation in randomised clinical trials is linked to emotion regulation strategies. AB - OBJECTIVES: Cancer patients' anxiety may curb their enrolment in clinical trials (CTs). Thus, the strategies they employ to reduce their anxiety may also determine their enrolment in CTs. The purposes of this study are (1) to compare the anxiety and emotion regulation strategies between patients who are enrolled in CTs (cases) and patients receiving standard cancer treatments who have never taken part in any CT (controls), and (2) to assess the links between these strategies and anxiety. METHODS: In total, 76 cases and 108 controls completed two validated questionnaires assessing their emotion regulation style (ERQ) and anxiety (STAI-Y). RESULTS: Overall, anxiety scores in cases and controls do not differ. The two groups do not differ in regards to their cognitive reappraisal of situations. However, cases inhibit their emotional expressions less than controls. Both cognitive reappraisal and emotional expressions are linked to lower scores of anxiety. CONCLUSIONS: Patients enrolled in CTs do not seem to be more anxious than those receiving a standard treatment. However, cancer patients' anxiety depends on the emotion regulation strategies they use. Emotion regulation during physician-patient interactions should be investigated further as a possible factor for CT enrolment determination. PMID- 20840876 TI - Drug cost avoidance resulting from cancer clinical trials. AB - The purpose of the study was to determine if economic benefits result when cancer clinical trial patients receive sponsor-provided drug, thereby avoiding standard care drug costs for which institutions are financially responsible. All open, closed and terminated oncology trial protocols and drug dispensing data from 1992 2007 were reviewed for the lung, hematology, neurology, genitourinary and gynecology tumor groups at the Tom Baker Cancer Centre. Actual and projected, potential drug cost avoidance per patient and per drug from the trials was determined. Forty-two percent of the 101 reviewed studies offered drug cost avoidance. Drug specific cost avoidance ranged from $11.74 to $249,731.70 per patient, while potential drug specific cost avoidance ranged from $14.14 to $286,650.70 per patient. Actual drug cost avoidances, according to tumor group, were calculated showing a median range of $1377.00 to $23,751.00 per patient between tumor groups. The median range for potential drug cost avoidance was substantially higher, from $9868.00 to $46,640.00 per patient. Economic benefits result for the institution when patients participating in clinical trials receive drug provided by an external source. Drug cost avoidance varies due to type and cost of standard of care drug used and due to the design of individual trials. The existence of drug cost avoidance is an additional benefit that clinical trials can bring to an institution (in our case, Alberta Health Services). PMID- 20840878 TI - DNA methylation and demethylation probed by small molecules. AB - DNA methylation is a covalent modification of DNA that plays an important role in setting gene expression programs during development. Recent evidence suggests that changes in DNA methylation patterns are involved in human disease through altering normal gene expression programming. In contrast to genetic changes aberrant DNA methylation patterns are potentially reversible raising the hope for DNA methylation based therapeutics. It was previously believed that the only relevant DNA methylation reaction in mature cells is DNA methyltransferase (DNMT), which accurately copies the DNA methylation pattern during cell division. The major effort in the field has therefore focused on developing DNMT inhibitors for cancer a disease of mitotic cells. However, recent evidence suggests that the DNA methylation state in both mitotic and postmitotic cells is a balance of DNA methylating and demethylating activities. This expands the scope of DNMT inhibitors to postmitotic tissues such as the brain. Since the identity of the DNA demethylating activity is still a mystery, the development of DNA demethylation inhibitors has been lagging. This review will discuss DNA methylation and demethylation machineries, and their therapeutic potentials as targets for small molecule inhibitors. PMID- 20840879 TI - Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro. AB - Theca cells with dexamethasone-induced insulin resistance showed defective glucose uptake and excessive testosterone production, both of which were effectively antagonized by berberine. Therefore, insulin-resistant theca cells may contribute to the pathogenesis of hyperandrogenism in polycystic ovary syndrome. PMID- 20840877 TI - The role of the proteasome in heart disease. AB - Intensive investigations into the pathophysiological significance of the proteasome in the heart did not start until the beginning of the past decade but exciting progress has been made and summarized here as two fronts. First, strong evidence continues to emerge to support a novel hypothesis that proteasome functional insufficiency represents a common pathological phenomenon in a large subset of heart disease, compromises protein quality control in heart muscle cells, and thereby acts as a major pathogenic factor promoting the progression of the subset of heart disease to congestive heart failure. This front is represented by the studies on the ubiquitin-proteasome system (UPS) in cardiac proteinopathy, which have taken advantage of a transgenic mouse model expressing a fluorescence reporter for UPS proteolytic function. Second, pharmacological inhibition of the proteasome has been explored experimentally as a potential therapeutic strategy to intervene on some forms of heart disease, such as pressure-overload cardiac hypertrophy, viral myocarditis, and myocardial ischemic injury. Not only between the two fronts but also within each one, a multitude of inconsistencies and controversies remain to be explained and clarified. At present, the controversy perhaps reflects the sophistication of cardiac proteasomes in terms of the composition, assembly, and regulation, as well as the intricacy and diversity of heart disease in terms of its etiology and pathogenesis. A definitive role of altered proteasome function in the development of various forms of heart disease remains to be established. This article is part of a Special Issue entitled The 26S Proteasome: When degradation is just not enough! PMID- 20840880 TI - Altered ultrastructure of mitochondrial membranes is strongly associated with unexplained asthenozoospermia. AB - OBJECTIVE: To explore the contribution of an altered structure of sperm mitochondria to human asthenozoospermia. DESIGN: A retrospective study. SETTING: Andrology Clinic, University of L'Aquila. PATIENT(S): Fifteen ejaculates with forward motility (FM) >= 50%, and 57 asthenozoospermic ejaculates (FM <50%, sperm vitality >50%), including 14 ejaculates with systematic genetic defects of tail principal piece, and 43 ejaculates with unexplained asthenozoospermia. INTERVENTION(S): Fifty sections of tail middle piece (MP) were blindly analyzed by transmission electron microscopy in each ejaculate for normal mitochondrial membrane organization, after exclusion of tails with disrupted cell membranes. MAIN OUTCOME MEASURE(S): Percentage of MPs with normal mitochondrial membranes (% normal MPs). RESULT(S): Percent normal MPs showed a strong correlation with forward motility. Variation of % normal MPs explained a 45% variation of sperm motility at multivariate linear regression analysis, confirming the strong association between the two parameters in a population including ejaculates with normal motility and with unexplained asthenozoospermia. Percent normal MPs was significantly reduced in severe unexplained asthenozoospermia (FM <10%; n = 16) compared with samples with normal motility (FM >= 50%; n = 15); 21% (10.5%-38%) and 68% (52%-73%), respectively. CONCLUSION(S): Structural defects in mitochondrial membranes represent a main feature of severe unexplained asthenozoospermia. PMID- 20840881 TI - Prolyl hydroxylase in human corpora lutea during menstrual cycle and early pregnancy. AB - Immunohistochemical staining for human prolyl hydroxylase revealed intense staining of the human corpora lutea (CL) parencyma during early pregnancy compared with those in the menstrual cycle. These results suggest that human prolyl hydroxylase might play an important role in determining the physiology and structure of the CL during the menstrual cycle and early pregnancy. PMID- 20840882 TI - Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy. AB - OBJECTIVE: To report the occurrence of Candida glabrata chorioamnionitis complicating an in vitro fertilization (IVF) pregnancy. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 30-year-old woman, primagravida, with an IVF dichorionic-diamniotic pregnancy who presented at 15 weeks with vaginal bleeding. INTERVENTION(S): Before embryo transfer in next IVF cycle, vaginal culture from the patient revealed colonization with C. glabrata, which was treated with boric acid. MAIN OUTCOME MEASURE(S): Subsequent pregnancy after eradication of fungal organisms. RESULT(S): The patient's first pregnancy was treated with indomethacin and broad-spectrum antibiotics, but her membranes ruptured, and she delivered both twins at 16 weeks; the autopsy and pathology reports were consistent with C. glabrata chorioamnionitis. After boric acid treatment eradicated the organisms, two embryos were transferred in subsequent IVF treatment; the second pregnancy was uncomplicated, with dichorionic diamniotic twins, delivered by cesarean section at 38 weeks. CONCLUSION(S): Eradication of vaginal colonization with C. glabrata may prevent infection of the next IVF pregnancy. PMID- 20840883 TI - Measures of exercise capacity in adults with congenital heart disease. AB - BACKGROUND: Exercise capacity in grown-ups with congenital heart disease (GUCH) is mostly reported by peak oxygen consumption (peak VO(2)). Our aim was to evaluate the maximal character of exercise tests, and to investigate submaximal measures of exercise capacity. METHODS: Adults with Coarctation of the Aorta (COA, n=155), Tetralogy of Fallot (TOF, n=98), dextro-Transposition of the Great Arteries (dTGA, n=68) and Univentricular Heart (UVH, n=10), and 122 healthy adults performed cardiopulmonary exercise testing until exhaustion. Gas exchange was measured breath by breath. The maximal performance of the test was evaluated by respiratory exchange ratio (RER), ventilatory equivalent for oxygen and Borg scale. Oxygen uptake efficiency slope (OUES), VE/VCO(2) slope and VO(2)/WR slope were calculated and ventilatory anaerobic threshold (VAT) was defined. Correlations of these measures with peak VO(2) were calculated. RESULTS: GUCH showed significantly lower peak VO(2) than controls (p<0.001), declining from 80% in COA, 74% in TOF, 64% in dTGA, to 55% in UVH. Compared to suggested criteria, mean peak RER and median Borg scale indicated a maximal effort in GUCH, however these results were significantly lower than controls (p<0.05). OUES, VO(2)/WR slope and VAT were significantly lower in patients compared to controls. OUES (r=0.853) and VAT (r=0.840) correlated best with peak VO(2); VO(2)/WR slope (r=0.551) and VE/VCO(2) slope (r=-0.421) correlated to a lesser degree (p<0.001). CONCLUSION: The investigated GUCH show reduced exercise tolerance compared to controls, related to the underlying heart defect. Different expressions of exercise tolerance clearly reveal the same differences in exercise capacity across groups of GUCH. PMID- 20840884 TI - Atrial flutter after non-congenital cardiac surgery: incidence, predictors and outcome. AB - BACKGROUND: Atrial arrhythmias (AAs) occur frequently after cardiac surgery. However, most authors do not differentiate postoperative atrial fibrillation (AF) from atrial flutter (AFL). Our study sought to investigate the incidence and predictors of AFL following non-congenital cardiac surgery, and the long-term outcome of this arrhythmia. METHODS AND RESULTS: We conducted an observational, retrospective, single-centre study. Among 821 patients in sinus rhythm (SR) before non-congenital cardiac surgery, AFL occurred in 42 patients (5.1%) and AF in 77 (9.4%). Independent predictors of AAs were older age (odds ratio (OR): 1.06, 95% confidence interval (CI): 1.01-1.11, p = 0.02), low postoperative hemoglobin level (OR: 0.43, CI: 0.29-0.63, p < 0.0001) and long cross-clamp time (OR: 1.02, CI: 1.002-1.037, p = 0.03). Compared to AF patients, those with AFL were younger (67 +/- 10 versus 72 +/- 8 years, p = 0.005) and less likely to have valve surgery (57% versus 76%, p = 0.03). After conversion to SR, of 41/42 patients with AFL, 5 (12%) developed AFL and 5 (12%) had AF within a mean follow up of 9.6 +/- 8.4 months: only 32% of patients were on long-term antiarrhythmic therapy and 5% had radiofrequency ablation of AFL in the early postoperative period. CONCLUSION: AFL following non-congenital cardiac surgery is not frequent. Compared to patients in AF, those with AFL are younger and less likely to have valve surgery. After conversion of AFL to SR, recurrence rate of AAs is relatively low. Therefore, AFL occurring in this setting does not require systematic catheter ablation in the postoperative period. PMID- 20840885 TI - Promiscuous DNA alkyladenine glycosylase dramatically favors a bound lesion over undamaged adenine. AB - The human DNA alkyladenine glycosylase (AAG) is a DNA repair enzyme catalyzing the initial step of DNA repair via lesion excision. Its binding site has an incredible plasticity, and recognizes a variety of DNA lesions resulting from deamination or alkylation of adenine. Based on this plasticity, it is natural to wonder how, and if AAG can discriminate against undamaged adenine. It has even been proposed that it cannot. If, however, AAG is specific, the specificity can be expressed at the stage of the base binding, or base excision. There is also a possibility that the propensity of the base to flip out of the DNA double helix governs its selective subsequent removal. Here, we show that binding to AAG is, in fact, dramatically more thermodynamically favorable for hypoxanthine, at least, a specific lesion, produced by oxidative deamination of adenine, than for undamaged adenine. This preference originates from the more constructive interactions of the lesion with the binding site. Of these, a shorter hydrogen bond between the lesion and the backbone of His136 that does not cause a structural distortion of the base in a major player, in agreement with an earlier kinetic study (P.J. O'Brien and T. J. Ellenberger, J. Biol. Chem. 279 (2004), 9750-9757). Mutating His136 to Pro almost completely eliminates the selectivity. Otherwise, bound adenine and the lesion are positioned very similarly at the binding site, suggesting no predisposition to selective removal. The base flip out of the double helix that precedes the binding has approximately equal thermodynamic facility for the lesion and undamaged adenine. This study employs the Monte Carlo simulations in conjunction with Free Energy Perturbation, and Density Functional Theory (DFT) calculations. PMID- 20840886 TI - The Self-screen-Prodrome as a short screening tool for pre-psychotic states. AB - BACKGROUND: Early detection of psychosis is an important issue in current research. Early intervention helps to improve the outcome of the disorder. Therefore, a comprehensive examination in large populations, necessary as it might be, is economically almost not feasible. A screening via self-report is more practicable as it helps focus on individuals with high symptom loads. AIM: To examine aspects of validity of the Self-screen-Prodrome (SPro) as a new screening tool for prodromal states of psychosis in a military sample. METHOD: 938 Swiss conscripts were assessed with the SPro, the Eppendorf Schizophrenia Inventory (ESI) and the Symptom-Checklist-90-Revised (SCL-90-R). Conscripts with potential psychosis-like pathology (T-transformed Severity Index of the SCL-90-R subscales Psychoticism [PSYC] and Paranoid Ideation [PARA]>=63) were compared with those not meeting the criteria of this condition (non-cases). RESULTS: Both groups (cases and non-cases) showed significant differences in their mean scores on SPro and ESI, although only the SPro had satisfactory effect sizes. In hierarchic logistic regression models the SPro turned out to be highly predictive for caseness while ESI-scales were not significant. A cut-off score of >=2 on the SPro subscale for psychotic risk (SPro-Psy-Risk) was found to identify caseness best with a sensitivity of 74% and a specificity of 61%. CONCLUSION: The SPro has proven to be a valid and very economic screening tool for general and prodromal pathology in large populations. PMID- 20840887 TI - Methanogenic communities on the electrodes of bioelectrochemical reactors without membranes. AB - Methane fermentation was successfully carried out in bioelectrochemical reactors without membranes under a working potential of -0.6 or -0.8 V (vs. Ag/AgCl) and neutral pH conditions. The hydrogenotrophic methanogens that dominated on the anodic and cathodic electrodes differed from those found on the electrodes in the control reactors without electrochemical reactions. PMID- 20840888 TI - Radiotelemetric and symptomatic evaluation of pain in the rat after laparotomy: long-term benefits of perioperative ropivacaine care. AB - Effective relief of acute and long-term postoperative pain is of utmost importance to patients undergoing surgery. Here, we worked on a controlled procedure of abdominal surgery in the rat inducing persistent postoperative pain symptoms for up to 10 days and tested the efficacy of perioperative care with the local anesthetic ropivacaine. Laparotomy was likewise used to implant radiotelemetric probes by which electrocardiogram, body temperature, and locomotor activity were recorded in freely moving animals. We showed that postoperative pain symptoms (mechanical allodynia) measured in periphery of the scar were associated over time with persistent tachycardia, elevated heart rate variability, and loss of mobility. Furthermore, a single subcutaneous infiltration of the local anesthetic ropivacaine in the periphery of the abdominal incision was sufficient to prevent the appearance of allodynia and the associated cardiac and motor signs of pain, monitored by radiotelemetry. These beneficial effects were observed when the infiltration was performed in the perioperative period, but not later. This study on freely moving animals exhibiting long-lasting postoperative pain symptoms and altered autonomic/motor function illustrates well the importance of the timing of preemptive analgesia care with long-acting local anesthetics. Moreover, it emphasizes the utility of monitoring heart rate variability to quantify spontaneous expression of long lasting postoperative pain. PERSPECTIVE: Speeding the recovery time after surgery using perioperative ropivacaine care is of significant clinical relevance because it might limit the risk of chronic pain and postoperative complications. In humans, chronobiological analysis of heart rate variability could also help quantify spontaneous pain expression with minimal emotional bias. PMID- 20840889 TI - Inhaled medication and inhalation devices for lung disease in patients with cystic fibrosis: poor adherence and the need to address it. PMID- 20840890 TI - Depolarization changes during acute myocardial ischemia by evaluation of QRS slopes: standard lead and vectorial approach. AB - Diagnosis and risk stratification of patients with acute coronary syndromes can be improved by adding information from the depolarization phase (QRS complex) to the conventionally used ST-T segment changes. In this study, ischemia-induced changes in the main three slopes of the QRS complex, upward ( I(US)) and downward ( I(DS) ) slopes of the R wave as well as the upward ( I(TS)) slope of the terminal S wave, were evaluated as to represent a robust measure of pathological changes within the depolarization phase. From ECG recordings both in a resting state (control recordings) and during percutaneous coronary intervention (PCI) induced transmural ischemia, we developed a method for quantification of I(US), I(DS), and I(TS) that incorporates dynamic ECG normalization so as to improve the sensitivity in the detection of ischemia-induced changes. The same method was also applied on leads obtained by projection of QRS loops onto their dominant directions. We show that I(US), I(DS), and I(TS) present high stability in the resting state, thus providing a stable reference for ischemia characterization. Maximum relative factors of change ( R(I)) during PCI were found in leads derived from the QRS loop, reaching 10.5 and 13.7 times their normal variations in the control for I(US) and I(DS), respectively. For standard leads, the relative factors of change were 6.01 and 9.31. The I(TS) index presented a similar behavior to that of I(DS). The timing for the occurrence of significant changes in I(US) and I(DS) varied with lead, ranging from 30 s to 2 min after initiation of coronary occlusion. In the present ischemia model, relative I(DS) changes were smaller than ST changes in most leads, however with only modest correlation between the two indices, suggesting they present different information about the ischemic process. We conclude that QRS slopes offer a robust tool for evaluating depolarization changes during myocardial ischemia. PMID- 20840891 TI - A novel method for assessing sense of body ownership using electroencephalography. AB - A successful substitution of an upper limb is possible when the prosthesis is recognized by amputees as a part of their body scheme. A new system alternative to functional magnetic resonance imaging for evaluating the sense of ownership during the rubber hand experiment, using noninvasive electroencephalography recordings, is described, and encouraging results are presented. PMID- 20840892 TI - Identification of electroencephalographic arousals in multichannel sleep recordings. AB - Electroencephalographic arousals are defined as abrupt shifts in electroencephalogram (EEG) frequency during sleep. Occurrence of arousals results in fragmented sleep, being one of the most important causes of daytime sleepiness among sleep disorders. Detection of arousals requires a polysomnographic (PSG) recording to be made during the patient's sleep. The resulting PSG is then analyzed offline by the physician. This is a time-consuming task, hence, automation of this process is pursued. The analysis, which involves the correlation of various events in time occurring among the different channels, in conjunction with the complexity of the related biomedical signals, makes this task also difficult to achieve in the computer algorithm. In this paper, we present a method for the detection of EEG arousals working on multichannel PSGs. The algorithm detects arousals using the information available through two EEG channels and the electromyography. A signal-processing technique is first proposed for the analysis of biomedical signals and extraction of relevant information. Individual events are detected from the signals and subsequently are related in time. Finally, a classification phase carries out the final decision on the presence of the event. Classifiers based on Fisher's linear and quadratic discriminants, support vector machines and artificial neural networks are compared at this phase. Experiments conducted on 20 patients reported a sensitivity and specificity respectively of 0.86 and 0.76 in the detection of the arousal events. PMID- 20840893 TI - Compensation of modelling errors due to unknown domain boundary in electrical impedance tomography. AB - Electrical impedance tomography is a highly unstable problem with respect to measurement and modeling errors. This instability is especially severe when absolute imaging is considered. With clinical measurements, accurate knowledge about the body shape is usually not available, and therefore an approximate model domain has to be used in the computational model. It has earlier been shown that large reconstruction artefacts result if the geometry of the model domain is incorrect. In this paper, we adapt the so-called approximation error approach to compensate for the modeling errors caused by inaccurately known body shape. This approach has previously been shown to be applicable to a variety of modeling errors, such as coarse discretization in the numerical approximation of the forward model and domain truncation. We evaluate the approach with a simulated example of thorax imaging, and also with experimental data from a laboratory setting, with absolute imaging considered in both cases. We show that the related modeling errors can be efficiently compensated for by the approximation error approach. We also show that recovery from simultaneous discretization related errors is feasible, allowing the use of computationally efficient reduced order models. PMID- 20840894 TI - Nonrigid registration of 2-D and 3-D dynamic cell nuclei images for improved classification of subcellular particle motion. AB - The observed motion of subcellular particles in fluorescence microscopy image sequences of live cells is generally a superposition of the motion and deformation of the cell and the motion of the particles. Decoupling the two types of movements to enable accurate classification of the particle motion requires the application of registration algorithms. We have developed an intensity-based approach for nonrigid registration of multichannel microscopy image sequences of cell nuclei. First, based on 3-D synthetic images we demonstrate that cell nucleus deformations change the observed motion types of particles and that our approach allows to recover the original motion. Second, we have successfully applied our approach to register 2-D and 3-D real microscopy image sequences. A quantitative experimental comparison with previous approaches for nonrigid registration of cell microscopy has also been performed. PMID- 20840895 TI - HAIRIS: a method for automatic image registration through histogram-based image segmentation. AB - Automatic image registration is still an actual challenge in several fields. Although several methods for automatic image registration have been proposed in the last few years, it is still far from a broad use in several applications, such as in remote sensing. In this paper, a method for automatic image registration through histogram-based image segmentation (HAIRIS) is proposed. This new approach mainly consists in combining several segmentations of the pair of images to be registered, according to a relaxation parameter on the histogram modes delineation (which itself is a new approach), followed by a consistent characterization of the extracted objects--through the objects area, ratio between the axis of the adjust ellipse, perimeter and fractal dimension--and a robust statistical based procedure for objects matching. The application of the proposed methodology is illustrated to simulated rotation and translation. The first dataset consists in a photograph and a rotated and shifted version of the same photograph, with different levels of added noise. It was also applied to a pair of satellite images with different spectral content and simulated translation, and to real remote sensing examples comprising different viewing angles, different acquisition dates and different sensors. An accuracy below 1 degrees for rotation and at the subpixel level for translation were obtained, for the most part of the considered situations. HAIRIS allows for the registration of pairs of images (multitemporal and multisensor) with differences in rotation and translation, with small differences in the spectral content, leading to a subpixel accuracy. PMID- 20840896 TI - An orientation inference framework for surface reconstruction from unorganized point clouds. AB - In this paper, we present an orientation inference framework for reconstructing implicit surfaces from unoriented point clouds. The proposed method starts from building a surface approximation hierarchy comprising of a set of unoriented local surfaces, which are represented as a weighted combination of radial basis functions. We formulate the determination of the globally consistent orientation as a graph optimization problem by treating the local implicit patches as nodes. An energy function is defined to penalize inconsistent orientation changes by checking the sign consistency between neighboring local surfaces. An optimal labeling of the graph nodes indicating the orientation of each local surface can, thus, be obtained by minimizing the total energy defined on the graph. The local inference results are propagated over the model in a front-propagation fashion to obtain the global solution. The reconstructed surfaces are consolidated by a simple and effective inspection procedure to locate the erroneously fitted local surfaces. A progressive reconstruction algorithm that iteratively includes more oriented points to improve the fitting accuracy and efficiently updates the RBF coefficients is proposed. We demonstrate the performance of the proposed method by showing the surface reconstruction results on some real-world 3-D data sets with comparison to those by using the previous methods. PMID- 20840897 TI - Kernel maximum autocorrelation factor and minimum noise fraction transformations. AB - This paper introduces kernel versions of maximum autocorrelation factor (MAF) analysis and minimum noise fraction (MNF) analysis. The kernel versions are based upon a dual formulation also termed Q-mode analysis in which the data enter into the analysis via inner products in the Gram matrix only. In the kernel version, the inner products of the original data are replaced by inner products between nonlinear mappings into higher dimensional feature space. Via kernel substitution also known as the kernel trick these inner products between the mappings are in turn replaced by a kernel function and all quantities needed in the analysis are expressed in terms of this kernel function. This means that we need not know the nonlinear mappings explicitly. Kernel principal component analysis (PCA), kernel MAF, and kernel MNF analyses handle nonlinearities by implicitly transforming data into high (even infinite) dimensional feature space via the kernel function and then performing a linear analysis in that space. Three examples show the very successful application of kernel MAF/MNF analysis to: 1) change detection in DLR 3K camera data recorded 0.7 s apart over a busy motorway, 2) change detection in hyperspectral HyMap scanner data covering a small agricultural area, and 3) maize kernel inspection. In the cases shown, the kernel MAF/MNF transformation performs better than its linear counterpart as well as linear and kernel PCA. The leading kernel MAF/MNF variates seem to possess the ability to adapt to even abruptly varying multi and hypervariate backgrounds and focus on extreme observations. PMID- 20840898 TI - From point to local neighborhood: polyp detection in CT colonography using geodesic ring neighborhoods. AB - Existing polyp detection methods rely heavily on curvature-based characteristics to differentiate between lesions. These assume that the discrete triangulated surface mesh or volume closely approximates a smooth continuous surface. However, this is often not the case and because curvature is computed as a local feature and a second-order differential quantity, the presence of noise significantly affects its estimation. For this reason, a more global feature is required to provide an accurate description of the surface at hand. In this paper, a novel method incorporating a local neighborhood around the centroid of a surface patch is proposed. This is done using geodesic rings which accumulate curvature information in a neighborhood around this centroid. This geodesic-ring neighborhood approximates a single smooth, continuous surface upon which curvature and orientation estimation methods can be applied. A new global shape index, S is also introduced and computed. These curvature and orientation values will be used to classify the surface as either a bulbous polyp, ridge-like fold or semiplanar structure. Experimental results show that this method is promising (100% sensitivity, 100% specificity for lesions > 10 mm) for distinguishing between bulbous polyps, folds and planar-like structures in the colon. PMID- 20840899 TI - An augmented Lagrangian approach to the constrained optimization formulation of imaging inverse problems. AB - We propose a new fast algorithm for solving one of the standard approaches to ill posed linear inverse problems (IPLIP), where a (possibly nonsmooth) regularizer is minimized under the constraint that the solution explains the observations sufficiently well. Although the regularizer and constraint are usually convex, several particular features of these problems (huge dimensionality, nonsmoothness) preclude the use of off-the-shelf optimization tools and have stimulated a considerable amount of research. In this paper, we propose a new efficient algorithm to handle one class of constrained problems (often known as basis pursuit denoising) tailored to image recovery applications. The proposed algorithm, which belongs to the family of augmented Lagrangian methods, can be used to deal with a variety of imaging IPLIP, including deconvolution and reconstruction from compressive observations (such as MRI), using either total variation or wavelet-based (or, more generally, frame-based) regularization. The proposed algorithm is an instance of the so-called alternating direction method of multipliers, for which convergence sufficient conditions are known; we show that these conditions are satisfied by the proposed algorithm. Experiments on a set of image restoration and reconstruction benchmark problems show that the proposed algorithm is a strong contender for the state-of-the-art. PMID- 20840900 TI - Compressibility-aware media retargeting with structure preserving. AB - A number of algorithms have been proposed for intelligent image/video retargeting with image content retained as much as possible. However, they usually suffer from some artifacts in the results, such as ridge or structure twist. In this paper, we present a structure-preserving media retargeting technique that preserves the content and image structure as best as possible. Different from the previous pixel or grid based methods, we estimate the image content saliency from the structure of the content. A block structure energy is introduced with a top down strategy to constrain the image structure inside to deform uniformly in either x or y direction. However, the flexibilities for retargeting are quite different for different images. To cope with this problem, we propose a compressibility assessment scheme for media retargeting by combining the entropies of image gradient magnitude and orientation distributions. Thus, the resized media is produced to preserve the image content and structure as best as possible. Our experiments demonstrate that the proposed method provides resized images/videos with better preservation of content and structure than those by the previous methods. PMID- 20840901 TI - Regularized background adaptation: a novel learning rate control scheme for gaussian mixture modeling. AB - To model a scene for background subtraction, Gaussian mixture modeling (GMM) is a popular choice for its capability of adaptation to background variations. However, GMM often suffers from a tradeoff between robustness to background changes and sensitivity to foreground abnormalities and is inefficient in managing the tradeoff for various surveillance scenarios. By reviewing the formulations of GMM, we identify that such a tradeoff can be easily controlled by adaptive adjustments of the GMM's learning rates for image pixels at different locations and of distinct properties. A new rate control scheme based on high level feedback is then developed to provide better regularization of background adaptation for GMM and to help resolving the tradeoff. Additionally, to handle lighting variations that change too fast to be caught by GMM, a heuristic rooting in frame difference is proposed to assist the proposed rate control scheme for reducing false foreground alarms. Experiments show the proposed learning rate control scheme, together with the heuristic for adaptation of over-quick lighting change, gives better performance than conventional GMM approaches. PMID- 20840902 TI - Image denoising in mixed Poisson-Gaussian noise. AB - We propose a general methodology (PURE-LET) to design and optimize a wide class of transform-domain thresholding algorithms for denoising images corrupted by mixed Poisson-Gaussian noise. We express the denoising process as a linear expansion of thresholds (LET) that we optimize by relying on a purely data adaptive unbiased estimate of the mean-squared error (MSE), derived in a non Bayesian framework (PURE: Poisson-Gaussian unbiased risk estimate). We provide a practical approximation of this theoretical MSE estimate for the tractable optimization of arbitrary transform-domain thresholding. We then propose a pointwise estimator for undecimated filterbank transforms, which consists of subband-adaptive thresholding functions with signal-dependent thresholds that are globally optimized in the image domain. We finally demonstrate the potential of the proposed approach through extensive comparisons with state-of-the-art techniques that are specifically tailored to the estimation of Poisson intensities. We also present denoising results obtained on real images of low count fluorescence microscopy. PMID- 20840903 TI - An optimized tongue image color correction scheme. AB - The color images produced by digital cameras are usually device-dependent, i.e., the generated color information (usually presented in RGB color space) is dependent on the imaging characteristics of specific cameras. This is a serious problem in computer-aided tongue image analysis because it relies on the accurate rendering of color information. In this paper, we propose an optimized correction scheme that corrects the tongue images captured in different device-dependent color spaces to the target device-independent color space. The correction algorithm in this scheme is generated by comparing several popular correction algorithms, i.e., polynomial-based regression, ridge regression, support vector regression, and neural network mapping algorithms. We test the performance of the proposed scheme by computing the CIE L(*)a(*)b(*) color difference (?E(ab)(*)) between estimated values and the target reference values. The experimental results on the colorchecker show that the color difference is less than 5 (?E(ab)(*) < 5), while the experimental results on real tongue images show that the distorted tongue images (captured in various device-dependent color spaces) become more consistent with each other. In fact, the average color difference among them is greatly reduced by more than 95%. PMID- 20840904 TI - Probability theory-based SNP association study method for identifying susceptibility loci and genetic disease models in human case-control data. AB - One of the most challenging points in studying human common complex diseases is to search for both strong and weak susceptibility single-nucleotide polymorphisms (SNPs) and identify forms of genetic disease models. Currently, a number of methods have been proposed for this purpose. Many of them have not been validated through applications into various genome datasets, so their abilities are not clear in real practice. In this paper, we present a novel SNP association study method based on probability theory, called ProbSNP. The method firstly detects SNPs by evaluating their joint probabilities in combining with disease status and selects those with the lowest joint probabilities as susceptibility ones, and then identifies some forms of genetic disease models through testing multiple locus interactions among the selected SNPs. The joint probabilities of combined SNPs are estimated by establishing Gaussian distribution probability density functions, in which the related parameters (i.e., mean value and standard deviation) are evaluated based on allele and haplotype frequencies. Finally, we test and validate the method using various genome datasets. We find that ProbSNP has shown remarkable success in the applications to both simulated genome data and real genome-wide data. PMID- 20840905 TI - Mixed-SAM surfaces monitoring CTX-protein, part II: Analysis using molecular dynamics simulations. AB - Molecular dynamics simulations are performed to study the physical mechanism of cobra cardiotoxin (CTX) proteins adsorption on alkanethiol self-assembled monolayers (SAMs) composed of S(CH(2))(5)CH(3) and S(CH(2))(9)CH(3). The binding energy of the CTX protein to the SAM surface of different mixing ratios of alkanethiol chains is calculated. The results show that the affinity of CTX to SAM reaches a maximum value when the ratio S(CH(2))(5)CH(3):S(CH(2))(9)CH(3) is 1:1, which agrees with the measurements of atomic force microscope obtained in Part I of our dual paper. Moreover, the binding energy is found to be linearly proportional to the CTX-SAM contact area. The hydrophobicity on CTX residues, the flexibility of SAMs and the behavior of water molecules near the SAM surface are examined to understand how these parameters affect the adsorption of a CTX protein on SAM surfaces. In addition, the importance of modeling water molecules explicitly in the study of protein adsorption is demonstrated by applying different solvent models. PMID- 20840906 TI - Mixed-SAM surfaces monitoring CTX-protein part I: Using atomic force microscope measurements. AB - Fast and efficient detection of Cobra cardiotoxin (CTX) protein molecules on biochip surfaces is an example of application in biotechnology. One potential application of mixed self assembled monolayers (SAMs) as chip surfaces yield different binding affinities of the CTX proteins, a series of studies on the interaction force between CTX proteins and the mixed SAMs surfaces formed from mixtures of two thiols with the same/different chain lengths and/or with the same/different terminal groups will be investigated. In these dual papers, the mixed SAMs of n-alkinethiol SAMs of different chain lengths are chosen as the first examples of this series due to the simple functions of the mixed SAMs surface structure. Thus, the adhesion force measurements of CTX protein molecules on mixed SAMs of n-alkinethiol SAMs of different chain lengths: 1-decanethiol (C9) and 1-hexanethiol (C5) with different mixing ratios are developed and conducted using atomic force microscope (AFM). There are two major tasks in Part I of the dual papers: the development of the AFM measurements providing reliable information, and selection of the surface with highest binding affinity among this mixed SAMs group. Results indicate that the adhesion forces for CTX protein molecules on mixed SAMs with mixing ratio (chi(C9)) of 0.25, 0.5, 0.75 and 1, are 1.26, 1.8, 1.38, and 1.25 folds respectively, compared with the adhesion force of CTX protein molecules on the C5 surface only. Therefore, the SAM surfaces of chi(C9) = 0.5 is the best choice as a biomaterial sensor of this group of mixed SAMs because the strongest binding force and highest efficiency. Effects of the loading force of the AFM operation, the radius of curvature of the AFM tip, and the AFM tip endurance as well as control experiments were examined to ensure the quantitative determination of adhesion force for AFM measurement. The physical mechanism of protein adsorption on SAM surfaces will be studied and analyzed by molecular dynamics (MD) simulations and will be reported in Part II of the dual papers to compensate the limited information on the interaction taking place at atomic level that experiments cannot provide. PMID- 20840907 TI - DNA word set design based on minimum free energy. AB - The problem of data and information encoding on DNA bears an increasing interest for both biological and nonbiological applications of biomolecular computing. Recent experimental and theoretical advances have produced and tested to obtain large code sets of oligonucleotides to support virtually any kind of application. In this paper, we have developed an algorithm to design DNA short-word sets based on minimum free energy (MFE) criteria. The MFE constraint is the minimum value among free energies of all the possible structures and the effective approach to control the generation of unexpected secondary structure of DNA sequences may cause error. The algorithm is constructive and directly produces the actual DNA words of the sets, unlike other academic and statistical numbers. According to the previous values, our experimental results can succeed in generating better DNA word sets based on MFE constraint. More importantly, using our results could decrease the emergence of false hybridization reaction, and improve the reliability and the scale of DNA computing. PMID- 20840908 TI - Silver nanoparticles compromise neurodevelopment in PC12 cells: critical contributions of silver ion, particle size, coating, and composition. AB - BACKGROUND: Silver exposures are rising because of the increased use of silver nanoparticles (AgNPs) in consumer products. The monovalent silver ion (Ag+) impairs neurodevelopment in PC12 cells and zebrafish. OBJECTIVES AND METHODS: We compared the effects of AgNPs with Ag+ in PC12 cells for neurodevelopmental end points including cell replication, oxidative stress, cell viability, and differentiation. First, we compared citrate-coated AgNPs (AgNP-Cs) with Ag+, and then we assessed the roles of particle size, coating, and composition by comparing AgNP-C with two different sizes of polyvinylpyrrolidone-coated AgNPs (AgNP-PVPs) or silica nanoparticles. RESULTS: In undifferentiated cells, AgNP-C impaired DNA synthesis, but to a lesser extent than an equivalent nominal concentration of Ag+, whereas AgNP-C and Ag+ were equally effective against protein synthesis; there was little or no oxidative stress or loss of viability due to AgNP-C. In contrast, in differentiating cells, AgNP-C evoked robust oxidative stress and impaired differentiation into the acetylcholine phenotype. Although the effects of AgNP-PVP showed similarities to those of AgNP-C, we also found significant differences in potencies and differentiation outcomes that depended both on particle size and coating. None of the effects reflected simple physical attributes of nanoparticles, separate from composition or coating, as equivalent concentrations of silica nanoparticles had no detectable effects. CONCLUSIONS: AgNP exposure impairs neurodevelopment in PC12 cells. Further, AgNP effects are distinct from those of Ag+ alone and depend on size and coating, indicating that AgNP effects are not due simply to the release of Ag+ into the surrounding environment. PMID- 20840909 TI - Low-level gestational lead exposure increases retinal progenitor cell proliferation and rod photoreceptor and bipolar cell neurogenesis in mice. AB - BACKGROUND: Gestational lead exposure (GLE) produces novel and persistent rod mediated electroretinographic (ERG) supernormality in children and adult animals. OBJECTIVES: We used our murine GLE model to test the hypothesis that GLE increases the number of neurons in the rod signaling pathway and to determine the cellular mechanisms underlying the phenotype. RESULTS: Blood lead concentrations ([BPb]) in controls and after low-, moderate-, and high-dose GLE were <= 1, <= 10, approximately 25, and approximately 40 ug/dL, respectively, at the end of exposure [postnatal day 10 (PND10)]; by PND30 all [BPb] measures were <= 1 ug/dL. Epifluorescent, light, and confocal microscopy studies and Western blots demonstrated that late-born rod photoreceptors and rod and cone bipolar cells (BCs), but not Muller glial cells, increased in a nonmonotonic manner by 16-30% in PND60 GLE offspring. Retinal lamination and the rod:cone BC ratio were not altered. In vivo BrdU (5-bromo-2-deoxyuridine) pulse-labeling and Ki67 labeling of isolated cells from developing mice showed that GLE increased and prolonged retinal progenitor cell proliferation. TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and confocal studies revealed that GLE did not alter developmental apoptosis or produce retinal injury. BrdU birth-dating and confocal studies confirmed the selective rod and BC increases and showed that the patterns of neurogenesis and gliogenesis were unaltered by GLE. CONCLUSIONS: Our findings suggest two spatiotemporal components mediated by dysregulation of different extrinsic/intrinsic factors: increased and prolonged cell proliferation and increased neuronal (but not glial) cell fate. These findings have relevance for neurotoxicology, pediatrics, public health, risk assessment, and retinal cell biology because they occurred at clinically relevant [BPb] and correspond with the ERG phenotype. PMID- 20840911 TI - Essential oils: renewal of interest and toxicity. AB - Essential oils are complex mixtures of substances from vegetable matter, the definition of which is based on their method of extraction. They are characterized by their ambivalence, their ambiguity and their disparity: plant families from which essential oils are extracted are numerous; the composition of each essential oil depends not only on the family but also on the part of the plant from which it is extracted, and sometimes on the soil where the plant grows, or even on the time of the harvest. Gas chromatography is therefore necessary to characterize an essential oil. Essential oils can be found in cosmetics, in drugs, and in food. They are natural substances, but natural is not synonymous with harmless. Evaluation of the toxicity of essential oils and European regulation are underway. PMID- 20840910 TI - The NC1 domain of type XIX collagen inhibits melanoma cell migration. AB - Type XIX collagen is a minor collagen that localizes to basement membrane zones. We previously demonstrated that the C-terminal NC1 domain of type XIX collagen inhibits tumor growth in vivo. In the present study, we analyzed the effects of the NC1(XIX) collagen domain on migratory behaviour of melanoma B16F10 cells. We found that NC1(XIX) do not inhibit melanoma cell proliferation. On the contrary, NC1(XIX) strongly inhibited the migratory capacities of melanoma cells in the scratch wound model and in Ibidi(r) devices: cell migration speed was 7.69 +/- 1.49 MUm/h for the controls vs 6.64 +/- 0.82 MUm/h for cells incubated with 30 MUmol/L NC1(XIX) and 5.72 +/- 0.67 MUmol/h with 60 MUmol/L NC1(XIX). Similar results were obtained with UACC 903 human melanoma cells. Further work will be necessary to elucidate the molecular mechanisms of this migration inhibition. It may, however, explain, at least partially, the inhibition of tumor growth that we observed in vivo. PMID- 20840912 TI - [Food supplements on the Hungarian market: regulations of marketing and of the composition of the products]. AB - According to recent legislation, food supplements are foodstuffs with the purpose of supplementing normal diet. Food supplements are concentrated sources of nutrients such as vitamins and minerals and other substances with a physiological or nutritional effect. In Hungary, marketing of food supplements has not been bound to pre-market authorization since joining to the European Union. The food business operator, who is responsible for production or distribution of the product, must notify it at National Institute for Food and Nutrition Science latest at the time when the product has been placed on the market and it can be distributed simultaneously. Distribution, ingredients, and all those information which appear on the label are determined by numerous regulations and prescriptions but at the same time the lack of harmonized legislation at certain places may cause a lot of problems on Community level. The first part of the study shows the laws and regulations influencing the distribution and ingredients of food supplements, while the main target of the second part is to introduce the evaluation process of components from nutritional and physiological point of view, and the role played by the food supplements in nutrition. PMID- 20840913 TI - [Intrauterine development, functions and diseases of male reproductive organs]. AB - This article discusses the role of the central nervous system and testosterone hormone and its derivatives in the intrauterine development of male reproductive organs. The characteristics that define male personality first emerge in fetal stage of human development. Thereafter they continue to evolve during childhood. They become increasingly apparent after puberty and then remain prevalent throughout the individual's life time. The cited process affects both male phenotype and masculine behavior. Testosterone and its derivatives control the development of male reproductive organs. Their absence leads to predominance of female sexual characteristics even in the presence of a male chromosome pattern. The clinical entity of testicular feminization is a typical example for this phenomenon. The presented study pays special attention to those abnormalities of male reproductive organs that are identifiable by ultrasound during the fetal period. Most of these anomalies cannot be treated effectively before birth. Those conditions that are also incurable in extra uterine life, may serve as indication for pregnancy termination if they can be detected by ultrasound examination in early gestation. PMID- 20840914 TI - [Significance of ultrasound-measured visceral fat thickness in obesity]. AB - Ultrasound examination is a simple, easily available method for the measurement of visceral fat thickness. According to the literature, visceral fat thickness correlates well with the computer tomographic determined "gold standard" values of visceral fat quantity, predicting cardiovascular risk of obesity. The probability of indicating the presence of two major risk factors of obesity, fatty liver and cardiovascular complications was investigated by ultrasound. Ultrasound measurement of visceral fat thickness and ultrasound liver attenuation were assessed in 201 patients and correlated with each other and with other parameters. Significant correlation (p<0.001) was found between visceral fat thickness and visceral fat area measured by bioimpedance examinations and body mass index, but no correlation existed between visceral fat thickness, liver ultrasound attenuation and serum lipid level. It was concluded, that presence of fatty liver disease is not certainly connected to the increase of abdominal fat. PMID- 20840915 TI - [Acute atrioventricular block in chronic Lyme disease]. AB - The tick bite transmitted Lyme disease is one of the most common antropozoonosis, about 10 000 new infections are reported in Hungary each year. The progress and clinical presentation can vary, and carditis can occur in later stages. A serologically verified Lyme disease caused third degree atrioventricular block in young male presenting with presyncope. Based on the tick-bites mentioned a few weeks prior to hospital admission, Lyme carditis was considered with the administration of antibiotics and monitor observation. Typical skin lesions were not recognized and laboratory findings showed no pathology. An electrophysiological study recorded a predominant supra-His atrioventricular block. Total regression of conduction could be detected later and the serological tests established an underlying Lyme disease. Currently no definite treatment recommendation is available for the potentially reversible Lyme carditis. The tick bite seemed to be the key on our way to diagnosis; however, serological tests proved the disease to be older than one year. A detailed medical history and serological tests are essential in identifying the cause and pacemaker implantation can be avoided. PMID- 20840916 TI - [Case of a diabetic man cured of rhinocerebral zygomycosis]. AB - Zygomycosis (mucormycosis) is a rare, highly aggressive opportunistic fungal disease caused by saprophytic fungi, belonging to the division Zygomycota, class Zygomycetes. Patients with immunodeficiency, neutropenia, iron overload, hematological malignancies, as well as diabetics with ketoacidosis are typically affected. CASE PRESENTATION: Authors describe the case of an eighteen-year old man with poor compliance suffering from diabetes since the age of nine. He was admitted with ketoacidotic somnolence in severe general condition with unilateral periorbital erythematous edema. Though from nasal exudates gained by the fibero endoscopic sinus surgery Methicillin-resistant Staphylococcus aureus and Pseudomas aeruginosa was cultured, amphotericin-B was administered as the medical history, clinical picture suggested presence of zygomycosis. An invasive infection caused by Rhizopus oryzae was confirmed by histology and microbiology. DISCUSSION: The combination of antifungal therapy, repeated surgical interventions and granulocyte colony-stimulating factor resulted in good clinical response. Four month after discharge he is alive and doing well. PMID- 20840918 TI - Community response to social marketing: filters for guineaworm control. AB - Guineaworm is a tropical helminthic disease which is responsible for much disability in rural areas from African to South Asia. Control interventions focus mainly on improving the quality of water supply at the health promotion level of prevention. This includes such technologies as dug wells, cloth filters, and chemicals added to pond water. Each technology has an appropriate health education strategy to aid in its promotion. The community of Idere in rural Nigeria was chosen to test the social acceptability of a new monofilament nylon cloth water filter. A social marketing strategy was used that built upon an existing primary health care program that utilized volunteer primary health workers (PHWs). The PHWs proved effective in marketing the filters in Idere as one-third of households in monitored areas purchased a filter during the six month sales period in 1985-86. Those who bought filters were more likely to live in hamlets/family compounds where PHWs resided, belong to a modern religion, and have a preventive orientation toward health. Those who did not buy complained mostly of lack of money, but other overt and inferred reasons included attitudes that filters were inferior to wells, traditional beliefs that guinea-worm cannot be prevented and availability of cheaper but ineffective alternatives. Filters were found to be a particularly useful technology in the smaller, isolated farm hamlets surrounding the main town. Recommendations are made to improve the marketing strategy through modifications in filter design, price, distribution, and promotion. PMID- 20840919 TI - The purdue stepped approach model: sequencing community and clinical interventions to reduce cardiovascular risk factors. AB - The Purdue Stepped Approach Model (PM) is applied to the reduction of cardiovascular risk factors. The PM is schema for service delivery that increases the intensity of interventions presented in a series. Community interventions are sequentially introduced followed by clinical programs. Benefits of community interventions and clinical programs are discussed which include target of a large number of people, optimal utilization of technology and human capital, responsiveness to individual differences, and increased likelihood of permanence of behavior change. Empirical support from community and clinical research are provided. The five steps of the model are described and an heuristic example is illustrated. The PM may expand the role of community health educators and may lead to the evolution of more inclusive means of delivering community and clinical health programs. PMID- 20840920 TI - Integrating organizational development skills with community organization practice: the key to successful national health care programs. AB - The article describes the developmental stages of a health care project from the inception as a demonstration project until its establishment as a large scale national program. The skills and competencies required of a project administrator during the demonstration stage are more related to the practice of community organization. However, in expanding a demonstration project to a large scale national program, these administrators are confronted with a multitude of bureaucratic and organizational constraints. The skills and competencies required of a program manager at this stage are best grouped under the field of organizational development. The failure of many large programs can be traced to the lack of organizational development skills among those involved in managing them. The implications for organizational development training within the curriculum of instruction in health education are also discussed. PMID- 20840921 TI - Teenage suicide expressions: echoes from the past. AB - A typology of suicide expressions gathered from official case records demonstrates the varied reasons individuals document to justify their acts of self-destruction. Intended to highlight the psychosocial conditions affecting the writer, the statements suggest these youthful committers reacted to external constraints and a perceived lack of succorance from significant others. PMID- 20840922 TI - Policy: practical and research challenges and options for health education in Nigeria. AB - Nigeria's new policy on health is based on a primary health care (PHC) system. It consists of hospital services and primary health care services subsystems. The subsystems are interlinked by referral services, and the strength of the total system, should be augmented by intersectoral-, community participation-, and traditional medical-inputs. A functional proportion model (FPM) is proposed here to show interrelationships as well as ideal/relative extent of primary, secondary, and tertiary levels of care within each subsystem. The health policy vividly enunciates a clear-cut role of health education as an enabling tool for PHC implementation. But it fails to commit itself to actual mechanisms for implementation support. Consequently, health education in Nigeria, at present, lacks professional identity and leadership, despite sporadic initiatives by the academia. It is suggested here that the situation could be remedied by deliberate expanded policy on health education-strengthening public policy support for health education practice and research. PMID- 20840923 TI - Community-based approaches to health promotion: guidelines for community mobilization. AB - This article examines the processes of community mobilization for health promotion. First, five community-based health promotion interventions designed to reduce the risk of cardiovascular disease (CVD) are reviewed, with particular attention paid to the processes of community mobilization in these programs. Second, several guidelines for community mobilization for effective health promotion are distilled from the experiences of these programs. The guidelines that are outlined provide a working model for future community-based health promotion interventions. Finally, the limitations of CVD prevention programs are briefly discussed. PMID- 20840924 TI - The process of health care decision making among cambodian immigrant women. AB - This qualitative study examined the congruence between health beliefs and behavior as reported by thirty Cambodian (Khmer) refugee women in Southern California. Utilizing in-home interviewing in the Khmer language, data were gathered on 226 illness episodes occurring among 157 family members tracked over an eight-month span. Informants reported a strong maternal role in health care decision making with all ages of children. Adult decision making demonstrated an individualistic pattern. Causes of illness were attributed primarily to humoral imbalances and illness avoidance behavior reflected these beliefs. Treatment was a blend of scientific and traditional medicine. Health care was accessed in settings of linguistic and cultural comfort regardless of distance. Disease prevention was linked to adequate food quantity. Chronic degenerative disease, stress, and reproductive complications were reported frequently. The adolescents and women appeared to be at high risk for cultural stress. PMID- 20840925 TI - Prevention of handgun accidents through owner training. AB - Government control of handguns for the purpose of reducing the incidence of accidental and/or intentional death and injury has not proven effective. Much of the research concerning accidental death and injury from firearms approaches the problem epidemiologically and identifies the gun as the agent. This study examined "control" of the handgun user through required training which stressed safety and legal use of the handgun. This study examined data involving 294 handgun owners for a five-year time period to determine the effectiveness of handgun training on accident reduction. The results were significant and supported the need for owner training in handgun use to reduce the incidence of accidents. PMID- 20840926 TI - Using the Health Belief Model to Assess the HIV Education Needs of Junior and Senior High School Students. AB - The purpose of this study was to use the Health Belief Model as a conceptual framework to examine the HIV education needs of seventh, ninth, and eleventh grade students. A statewide stratified random sample was drawn during the Spring of 1988. Results reveal serious misconceptions regarding HIV transmission and the nature of AIDS. High levels of fear of AIDS were reported. While students perceive themselves to be highly susceptible to AIDS they clearly misunderstand the seriousness of the disease. Barriers to preventive actions and social pressures to increase risk were reported. Based on the results specific recommendations regarding the design of effective AIDS education are offered. PMID- 20840927 TI - Comparison of health Status of International and American University Students: Implications for Health Education. AB - The study examined the differences between a sample of 311 international and 251 American university students relative to their self-perceived health status, health attitudes, behaviors, and locus of control using the International Student Health Inventory (ISHI). More specifically, the study compared demographics, current health history, health care obtained by students within the university milieu, health locus of control, wellness attitudes and behaviors. The study addressed the rationale for student health care professionals to improve health services for the international students. Data were analyzed using both descriptive and inferential statistics. Results indicated that sociocultural (external) and self-perceived (internal) stressors may influence both groups' health status and care. American students experienced more common minor stress related illnesses/ailments than international students. Both groups indicated they functioned more from an internal health locus of control. Healthiest and poorest wellness attitudes were reported by the international male and American male students respectively. No observed differences were noticed on the groups' wellness behaviors. PMID- 20840928 TI - The "heartscore" program: a case study in limited evaluation. AB - In greater Youngstown, Ohio coronary heart disease (CHD) is the number one cause of death and disability. Moreover, mortality rates from CHD are higher in this region than in any other part of Ohio. In response to the obvious need for risk reduction programs in this area the "Heartscore" program was created. Heartscore is a hospital-based community health promotion effort designed to help decrease the incidence of death and disability resulting from CHD by increasing the public's awareness of risk factors and the ways that they can be controlled. A total of 2,135 people took part in Heartscore. Resources for a comprehensive evaluation of the Heartscore program were scarce, therefore only a limited evaluation of the screening programs was conducted. Even a limited evaluation, however, can produce useful results. This article describes Heartscore giving particular attention to how information gathered during the evaluation of the screenings is being used to fine-tune Heartscore and to plan more specific interventions. PMID- 20840929 TI - The effects of message framing and feelings of susceptibility to breast cancer on reported frequency of breast self-examination. AB - One of two types of pamphlets on breast self-examination (BSE) attitudes and behavior was administered to subjects who were classified as high or low in feelings of susceptibility to breast cancer. Half of the subjects received pamphlets stressing the positive consequences of doing BSE and the other half received pamphlets stressing the negative consequences of not doing BSE. A previous study found negatively framed pamphlets to be superior in BSE promotion and these results were explained in terms of Tversky and Kahneman's framing postulate. The original framing postulate includes characteristics of the decision-maker as well as the type of frame presented, thus, we hypothesized an interaction between pamphlet type and level of susceptibility with the largest effect on the group with low perceived susceptibility who received negatively framed pamphlets. The hypothesized interaction did not occur, nor was there a significant effect for pamphlet type. However, there were significant differences between the BSE performance at follow-up of women who were high or low in perceived susceptibility prior to the intervention. These results are discussed in terms of implications for BSE training in the future, more specifically-the need to consider perceived level of susceptibility as an important subject characteristic that could have a large impact on the effectiveness of training programs. PMID- 20840930 TI - Cultural factors in aedes aegypti and dengue control in latin america: a case study from the dominican republic. AB - Dengue and Aedes aegypti infestation in Latin America pose substantial health risks. Total reliance on chemical interventions is no longer feasible and, increasingly, programs of control will need to rely on education, behavior change and community participation. Findings from applied behavioral research in the Dominican Republic conducted from July through September of 1987 are discussed in the light of cultural constraints on intervention efforts. Perception of risk, the choices for curative care as opposed to prevention, and explanatory models of environmental risks are considered. The article concludes with a discussion of the benefits of health education messages that possess simplicity and economy of effort. Additionally, the potential importance of biological controls are suggested in light of cultural constraints. PMID- 20840931 TI - Ethnic differences in knowledge of AIDS transmission and attitudes towards gays and people with AIDS. AB - Epidemiological studies have shown disproportionately elevated risk rates of AIDS among Hispanics and blacks, particularly among the heterosexual population. Intense preventive education has resulted in dramatic infection reduction among the gay population. Yet these educational efforts aimed at the gay population failed to reach many of the minority population at risk. This study looked at some structural and cultural factors that might be preventing beneficial effects generated from existing educational programs designed to prevent AIDS. The same variables were compared among whites and Hispanics. The research showed that while all groups had a high level of knowledge regarding AIDS transmission, Hispanics had many misconceptions about the way AIDS is transmitted. In this study, Hispanics were not more intolerant toward homosexuals than whites; nor were they more intolerant towards people with AIDS. Thus AIDS education campaigns directed towards Hispanics need to be designed to address specific misconceptions regarding AIDs transmission. Homophobia does not appear to be an insurmountable barrier preventing Hispanics from dealing with this topic. PMID- 20840932 TI - Breaking the barriers: strategies for a comprehensive u.s. Tobacco control program. AB - Given the health and social consequences of tobacco, a policy analysis strategy consisting of three approaches; legal, market, and health education is presented. A unifying feature of the strategy recommendations is that each addresses both prevention of the initiation of tobacco habits and encouragement of cessation. Overall, the strategies focus exclusively on policy alternative initiatives oriented toward reducing the toll of smoking within the United States. The manuscript addresses the conflict that public policy must resolve between the long-term negative health effects and the short-term positive economic interests of tobacco. The critical idea is that policy makers must think beyond local efforts and recognize that they can be a part of a larger network movement working in different ways, yet cooperating for better effectiveness and support to decrease and ultimately stop the use of tobacco products. PMID- 20840933 TI - Tobacco use by samples of american and Turkish students: a cross-cultural study. AB - Tobacco use is a world-wide problem with a significant impact on the health and well-being of many people. To design an effective smoking education program, it is important to understand smoking patterns and factors associated with this additive habit from a cross-cultural perspective. The purpose of this study was to investigate some of the patterns of and certain factors associated with smoking and chewing tobacco behavior among the students of the United States and Turkey. A questionnaire, designed, reviewed, and revised by experts, was administered to a representative sample of 450 college students in a major public university in the United States. It was then translated and reviewed by bilingual authorities. The investigator administered the questionnaire to a sample of 450 representative college students in a counterpart public university in Turkey. The results indicate that a significant number of college students in both countries use tobacco. The patterns of smoking and various factors associated with tobacco use, however, are different in the two cultures. It was concluded that international health education programs which are sensitive to cultural differences are the key to ultimately eliminating this major health crisis. PMID- 20840934 TI - AIDS in the african press. AB - Newspapers have the potential to take a leading role in AIDS education in Africa. With their relatively small circulations, they mainly reach educated urban citizens, a population particularly hard hit by the epidemic. This study reports findings of a content analysis of AIDS coverage of government owned newspapers in Senegal, Togo, Nigeria, Uganda and Kenya. Although most papers have printed educational articles, they have undertaken only a very minor role in any national effort. Coverage has tended to reflect government reaction, usually moving through stages of denial, scapegoating and blame before responding constructively to the epidemic. African countries surveyed are still largely engaged in epidemiological response to the epidemic; widespread education has not yet occurred. Newspapers have not yet fulfilled their potential as educational media. PMID- 20840935 TI - Efforts to promote lifestyle change and better health: whither symbolic interactionism? AB - Symbolic interactionism is a body of thought which attends to how the meaning of a message may be mutually defined in the process of social interaction. As interactionism and its qualitative methodologies have been increasingly recognized as useful and appropriate complements to other approaches, health education has been slow to respond. Proposed here is the application of an interactionist perspective to the study of contemporary efforts made to promote lifestyle change and better health. A specific case is made for examining the interaction which takes place when employers strive to promote employee health. Particular attention is paid to the following questions: 1. How may employer communication of corporate goals for employee lifestyle change best be studied?; 2. Are the messages transmitted by employers and those received by employees the same?; 3. What may be some unanticipated consequences of the health promotion effort and its messages?; and 4. Can the interactionist perspective be used to enlighten the planning process for health promotion programs? PMID- 20840936 TI - Sociology of AIDS within black communities: theoretical considerations. AB - This article looks retrospectively at the 1980s AIDS/HIV crisis among black Americans. A brief chronology of the epidemiology of AIDS is reviewed, then three social theories are proposed to understand AIDS related behavior in black communities: conflict theory is employed to examine economic statification; functionalist theory is used in the discussion of social dysfunction and marginality; and interactionist theory, in terms of deviance and labeling. The overall purpose is to provide theoretical frameworks to help health educators understand and create interventions within black at-risk communities. Policy considerations and recommendations are provided for more meaningful disease prevention programs to combat AIDS infections as well as chemical dependency problems in the 1990s. PMID- 20840937 TI - Reciprocal determinism at the stages of behavior change: an integration of community, personal and behavioral perspectives. AB - Effective community health education requires theories which combine the perspectives of behavior change at the levels of the individual with those at the levels of the community. Within the framework of reciprocal determinism, a variety of theories and concepts are integrated to understand behavior change at levels of the individual and levels of the community. These concepts are applied at each step in the behavior change process, and categories of intervention are explained within the proposed framework. A variety of specific intervention procedures are generated from the framework for promoting behavior change at each level and stage of change. Such a comprehensive integrated framework holds promise of designing more effective health education programs. PMID- 20840938 TI - The press and policymaking: clues for creating a health-promoting climate. AB - The press speaks by what it does not say, as well as by what it says. In so doing it influences what is placed on the public agenda and how the issues are framed. This agenda-setting process includes health policy issues, how they are defined and how they might be dealt with. This perspective is demonstrated in a content analysis of the Australian press as it covered the initiation and development of community health policy from 1973-1985. The coverage is viewed within the context of political and social changes and the organization and operation of the mass media as revealed in documents and through semi-structured interviews. A broader understanding of the media and its impact is important to health educators who want to communicate with the public but who tend to use the media mainly for advertising and promotion. PMID- 20840939 TI - Mass media usage among black smokers: a first look. AB - This article discusses preliminary results of a National Cancer Institute sponsored pilot baseline survey in 1989 of smoking knowledge, attitude and habits among black smokers in four major U.S. cities: two in the North (Springfield, Massachusetts and Hartford, Connecticut) and two in the South (Durham, North Carolina and Columbia, South Carolina). It focuses on mass media readership, viewing and listening habits and a preliminary discussion of their application to practice. PMID- 20840940 TI - Considering environmental factors in community health needs assessments. AB - An examination of environmental factors as they relate to disease etiology, health status, and quality of life is an important component of any community health needs assessment. In many of the coalfield communities of Appalachia, the dust generated from strip and long-wall mining is pervasive, diminishing the quality of life there. In addition, the mountainous terrain constrains many residents to live immediately adjacent to unpaved public roads which are also used for hauling coal. This study was prompted by concern about potential public health threat to residents living along unpaved coal haul roads posed by sustained high levels of dust exposure. Respirable dust concentrations (PM-10) were measured periodically over nine months along both paved and unpaved segments of a public road used for hauling coal. On the paved road segment, dust levels remained within safe limits. On the unpaved road segment, dust levels often exceeded EPA standards, creating a public health risk. Recommendations for behavioral and non-behavioral strategies to reduce community health risk associated with environmental exposures are discussed. PMID- 20840941 TI - Action-oriented community diagnosis: a health education tool. AB - Health education research and practice have found individuals' health decisions and behaviors to be related to their perceptions of need. It has also been found that physical, social, and political conditions generated by one's community can exert important influences on individuals' ability to act on the basis of need. It appears that conducting a needs assessment is a necessary component of program planning, but the information is not sufficient for designing sustainable interventions. An Action-Oriented Community Diagnosis procedure has been developed over several years to: 1) identify normative and comparative needs determined by service agencies as well as expressed and perceived needs experienced by clients; 2) assess community conditions contributing to collective competence as well as the barriers and gaps contributing to disease and illness; and 3) increase collective competence of communities and agencies to collaborate in defining problems and needs. One of the many health education projects that have conducted such a diagnosis has been selected to illustrate the features of the procedure, the rationale behind the methods and sequence of steps, how the methods can be operationalized, and the outcomes. PMID- 20840942 TI - Field supervision for quality control of local family planning workers in developing countries. AB - On-the-job supervision is the most crucial and most often neglected mechanism for promoting program effectiveness. This article focuses on promoting the quality of worker performance, based on experience with the community-based distribution of contraceptives in Zaire and Zimbabwe. A three-tiered approach to evaluating worker performance, based on testing distributor acknowledge, observing distributors in the field, and interviewing their clients, proved overambitious for routine evaluation purposes, but elements from it are included in a proposed supervisory system. Under this system, the supervisor reviews the performance of workers relative to each other based on output prior to a supervisory visit and tries to identify explanations for observed deficiencies. During the visit, he/she evaluates distributor performance and records these observations on a supervisory chart, presented herein. These charts are reviewed and updated on subsequent visits. Quantitative data on distributor performance may be interpreted in light of such factors as the difficulty of working in a specific area or competing demands on distributors' time. The proposed system is presented for relevant modification rather than as a rigid set of procedures. PMID- 20840943 TI - Five-year knowledge retention by volunteer primary health workers in Western Nigeria. AB - A volunteer primary health worker (PHW) must acquire a basic knowledge of preventive and curative medicine to approach his community with authority. Knowledge gained during training must be retained as a foundation for village level action. This study is a follow-up survey of knowledge among PHWs in a Western Nigerian town five years after training. The same end of course test was administered and results compared with age, sex, level of education and level of activity in PHC programming. The follow-up test scores showed an expected decrease in information retained. The only demographic factor consistently associated with knowledge after training and at follow-up was level of education. In addition level of PHC activity (e.g., attending PHW meetings, maintaining a village drug box) was associated with greater knowledge, but was also positively related to level of education. It is therefore recommended that PHC programs ideally recruit PHWs with vernacular literacy, but where this is not possible, extra effort must be put into close follow-up supervision of trainees. PMID- 20840944 TI - Needle sharing for the use of therapeutic drugs as a potential AIDS risk behavior among migrant Hispanic farmworkers in the eastern stream. AB - In the United States, 41 percent of the AIDS cases are found in ethnic minorities. While it is true that AIDS is disproportionately represented among minorities, not enough research has been directed at identifying risk factors peculiar to different ethnic groups. This study explored critical knowledge of AIDS, patterns of sexual behavior, and self-injection for therapeutic reasons among migrant workers. Data were collected through face to face interviews with 378 hispanic migrant workers. Respondents, seventy-nine (21.4 percent), reported self-injecting antibiotics and vitamins for medicinal reasons while only 2.6 percent self-injected recreational drugs. The likelihood of contracting AIDS escalates as the number of risk factors increase. Self-injection of therapeutic agents is a great risk when considered in concert with the other risk factors present in the migrant farmworker population. Exposure to additional factors such as sexual promiscuity, frequenting prostitutes, homosexual behavior and having vaginal or anal intercourse without a condom creates a potentially dangerous situation. Hence, each of the individual AIDS risk factors may be multiplied and broadcast through the needle risk. AIDS health education needs to deal with this cultural pattern of self-injection in its intervention programs. PMID- 20840945 TI - Analysis of the competent community: support for the community organization role of the health educator. AB - This study looks at the implications of emphasizing macro-change strategies for achieving a well society by examining the impact of community competence in the delivery of services on health status, as measured by years of productive life lost (YPLL), in thirty-three counties of Eastern North Carolina. Results of rankings and canonical analyses indicate that agency use of networks in planning is related to lower YPLL rates overall, but knowledge of services was related to lower white rates only. Community competence as a framework for evaluating community organization techniques is defined and the implications of the findings for community health practice are discussed. PMID- 20840946 TI - Problems associated with conducting illness prevention and health promotion research in developing countries. AB - Conducting research projects that are related to illness prevention in developing countries is complex and challenging. In this article we discuss those areas common to health programs which pose potential problems to researchers; especially those foreign to the community in which a research project is taking place. Results from past experiences have indicated that failure to involve community members and indigenous research workers can lead to mistrust, misconceptions, and self-protection. Also, whenever villagers feel that the information they give may be used against them, they may be forced to alter or conceal true data. Health investigators and granting agencies must be prepared to acquaint themselves with problems related to communication, transportation, weather, and how local governments function officially and unofficially so as to guard against unrealistic assumptions and expectations. It has also been noted that students from developing countries are often faced with the double dilemma of attempting to ride the roller coaster between two cultures; and in essence, be a part of both when working on research projects with their professors from developed countries. PMID- 20840947 TI - Introduction to the Community Intervention Trial for Smoking Cessation (COMMIT). AB - The Community Intervention Trial for smoking cessation (COMMIT) is sponsored by the National Cancer Institute and involves eleven pairs of communities in North America. COMMIT emphasizes a partnership between the eleven research institutions and their respective intervention communities in developing the structures needed to implement the intervention protocol. We summarize the epidemiological data and describe the prior community interventions that set the stage for COMMIT, and discuss how COMMIT may inform state-wide tobacco reduction demonstration programs. An overview of the articles that describe the COMMIT intervention and evaluation plan is presented. PMID- 20840948 TI - Principles of Community Organization and Partnership for Smoking Cessation in the Community Intervention Trial for Smoking Cessation (COMMIT). AB - The Community Intervention Trial for Smoking Cessation (COMMIT) has adopted a community approach to smoking cessation. State-of-the-art interventions that have proven efficacious for smoking cessation are delivered to smokers through community-based organizations. An innovative adaptation of community organization methods accommodated the need for a standardized protocol with the flexibility required for diverse and unique communities. The unique characteristics of the eleven intervention communities are examined with a focus on differences in size, location, availability and importance of the intervention channels, and other factors that were important for community mobilization. Initial results of the mobilization process are summarized. Although there were some differences in the structures formed and the time required to complete the initial project activities, all eleven intervention sites were mobilized around the COMMIT goals and activities. PMID- 20840949 TI - Media Advocacy and Public Education in the Community Intervention Trial To Reduce Heavy Smoking (COMMIT). AB - The Community Intervention Trial (COMMIT) is designed to reduce the rate of heavy smoking in eleven pairs of North American communities over an eight-year period. The intervention, consisting of a minimum of fifty-one activities, is being implemented through local community boards and task forces. This article describes the goals and activities for the public education task force with a specific focus on "media advocacy," an innovative use of mass media that follows more closely political activist models than traditional public service models. Two brief case studies are presented to illustrate some applications of media advocacy. The reasons for relatively infrequent use of media advocacy are discussed. PMID- 20840950 TI - Health Care Providers as Key Change Agents in the Community Intervention Trial for Smoking Cessation (COMMIT). AB - The Community Intervention Trial for Smoking Cessation (COMMIT) is a multi-center collaborative trial sponsored by the National Cancer Institute. COMMIT utilizes multiple, community-based channels to facilitate quit attempts among heavy cigarette smokers. The "health care provider channel" is important, in that physicians, dentists, and other health care providers can effect changes in smoking behavior at both the individual and community level. There are over 1,600 primary care physicians and general practice dentists in the COMMIT intervention communities. This article describes the conceptual basis for the health care provider activities; results of a survey of community attitudes and behaviors regarding smoking and health care; specific training and intervention activities; and the role of health care providers as community change agents in the smoking cessation arena. PMID- 20840951 TI - Promoting Smoking Control Through Worksites in the Community Intervention Trial for Smoking Cessation (COMMIT). AB - This article describes the worksite intervention and assessment aspects of the COMMIT project. Following a brief review of the rationale for worksite smoking control efforts and how planning for such activities can be conducted as part of community-based interventions, we describe the COMMIT worksite protocol. All intervention communities conduct specified activities in the areas of smoking policy, motivational and incentive procedures to encourage smoking cessation, and provision of self-help materials and cessation services for employees. Assessment procedures include a computerized process objectives system, surveys of worksites in each of the 22 COMMIT communities, and work related questions on surveys of community residents. Baseline data that have informed the process objectives for the worksite channel are presented, as are examples of how intervention activities have been tailored to different communities. PMID- 20840952 TI - Enhancing resources for smoking cessation through community intervention: commit as a prototype. AB - Of the 17 million smokers in North America who attempt to quit smoking each year, fewer than one in ten succeed [1, 2]. How can communities improve smokers' chances of quitting? The National Cancer Institute addresses this question through COMMIT, the Community Intervention Trial for Smoking Cessation. COMMIT is the largest smoking intervention trial in the world, involving over 2 million people in twenty-two North American communities. The study protocol requires that the implementation of mandated interventions in each community be managed by a Community Board and at least four task forces (Health Care, Worksites and Organizations, Cessation Resources, and Public Education, including Media and Youth). Three required and three optional interventions in the COMMIT protocol relate to the availability of cessation resources and services. The Cessation Resources Task Force, composed of community volunteers, supervises implementation of these interventions at each site. The activities of each task force are integrated with the others in a community action plan. How COMMIT activities enhance the utilization of cessation resources and services and how these services fit into a community intervention is the subject of this article. Descriptions of the study design and evaluation plan, and of the community mobilization process are presented elsewhere [3, 4]. PMID- 20840953 TI - Evaluation Plan for the Community Intervention Trial for Smoking Cessation (COMMIT). AB - The National Cancer Institute is sponsoring the Community Intervention Trial for Smoking Cessation (COMMIT), a multi-center research project designed to test the value of a community-based effort to promote smoking cessation. The trial involves eleven matched pairs of communities with random assignment of one community per pair to the intervention or to the comparison condition. This article reviews the rationale and methodology of the COMMIT evaluation plan which is organized into four components: 1) outcome assessment, monitoring changes in community smoking patterns; 2) impact assessment, measuring the effect of the COMMIT intervention on mediating factors thought to be important in facilitating changes in community smoking behavior (e.g., social norms supporting nonsmoking); 3) process assessment, monitoring the quality and timeliness of intervention delivery; and 4) economic assessment, estimating the cost effectiveness of the intervention. PMID- 20840954 TI - Process Evaluation in the Community Intervention Trial for Smoking Cessation (COMMIT). AB - The reach and complexity of the multi-site Community Intervention Trial for Smoking Cessation (COMMIT) project call for an extensive, comprehensive evaluation plan. This article reports on the objectives, methods, and data sets of the part of the plan designed for process evaluation. We describe the systems developed for: monitoring progress in the sites, the quality of local intervention activities and data collection, and compliance with the trial-wide protocol; disseminating information for formative purposes; and generating and using process data for outcome evaluation. The process evaluation approach includes both quantitative and qualitative methods. We provide examples from community mobilization and intervention in different communities. PMID- 20840955 TI - Maternal influences on preventive health behavior in children. AB - The aim of the Child Survival Revolution, of which the Expanded Programs on Immunization is a part, is to immunize all children against six preventable diseases. Considerable progress has been made. However, high dropout rates, and the lack of participation by the target groups still continue to present problems for the success of the program. This article examines data on a sample survey of 1,000 households undertaken in three areas of Accra in 1982. The critical factors which determine mother-initiated preventive health behavior for their children are identified. The implications for preventive health behavior in Ghana, and in other developing countries, are examined. PMID- 20840956 TI - Development and implementation of an intervention to increase cervical cancer screening in inner-city women. AB - Community interventions are increasingly recognized as an effective method for reaching individuals in need of health behavior change. We present our experience in developing and implementing an intervention to increase Pap test screening in an inner-city community with a high rate of cervical cancer mortality. Results of a baseline needs assessment survey showed that: almost one-half of the population was inadequately screened; 66 percent of inadequately screened women reported belonging to a church; and, a significant proportion of those who tended to rely on the physician for screening did not receive adequate testing. These results formed the basis of our community intervention strategy: lay peer educators, recruited predominantly from churches, were trained to motivate inadequately screened women to actively seek testing. The implementation of the intervention was flexible and responsive to insights gained in the field and process evaluation data. Recommendations for future community-based interventions are offered. PMID- 20840957 TI - Primary health care as an educational process: a model and a freirean perspective. AB - This is a discussion that attempts to open up to reflection some of the deeper aspects of Primary Health Care. A model originally derived to assist reflection on philosophies of education is drawn on and illustrated with the very pertinent ideas of Paulo Freire. The article aims at assisting that deeper level of deliberation which is especially important to a comprehensively conceived Primary Health Care. PMID- 20840958 TI - AIDS prevention: application of health education principles to different subcultures. AB - AIDS is the subject of unparalleled media attention and a primary target of public health efforts. It is widely acknowledged that until a cure or vaccine for AIDS is developed, the only realistic means for controlling the spread of infection and AIDS is through prevention and education. This public health effort to educate all of those at risk includes the crucial provision of ways and means for reducing or eliminating their risk of exposure to the virus. PMID- 20840959 TI - APACT: Its Organization and Impact on Resistance to U.S. Tobacco Imperialism. AB - This article presents a case study of the formation and first year activities of the Asia Pacific Association for the Control of Tobacco Products (APACT). The case study is organized around five key concepts that address the organizing activity that led this coalition of antismoking groups to create a multinational association in the Asia Pacific region. These concepts are need, team building, funding, management and program development. APACT was born out of the need for Asia Pacific anti-smoking groups to resist US trade sanctions. Sanctions which the US threatened to apply to a number of Asia Pacific nations if those nations refused to eliminate trade barriers to US tobacco marketing and sales. The development of APACT's social action program and its impact is presented for the year 1989-90. Also included is a brief statement of APACT's five-year plan for controlling tobacco related diseases. PMID- 20840960 TI - Sociocultural factors affecting reproductive health in latin america and the Caribbean. AB - This article provides an overview of the socio-economic, health and fertility conditions in the countries of the Americas. Among those considered are GNP and annual growth and inflation rates, fertility rates, increasing urbanization, life expectancy at birth, infant and child mortality, and maternal mortality particularly due to complication from pregnancy and childbirth. Barriers for women and men on contraception use are discussed. Among the most important influencing factors are ethical and moral considerations, lack of access to information and supplies, women holding a lower status than men throughout Latin America and some parts of the Caribbean resulting in women's unregulated fertility, poor quality health services being available, and lower educational opportunities and levels than men. Additionally, the extremely poor quality of the interface women have with the health care system sends many of them away. Although a major proportion of pregnancies occur in adolescent women, no special provisions are made to provide education or services to this population. The article ends by proposing some alternative actions to improve options for contraceptive choices in the populations of Latin America and the Caribbean. PMID- 20840961 TI - Improving access to prenatal care for latina immigrants in california: outreach and inreach strategies. AB - The Latina Women's Project was developed to assess strategies for improving prenatal care outreach to low income Latina immigrant women in San Francisco. For this purpose, twelve focus group sessions with sixty-seven providers and consumers of prenatal care in the community were conducted in 1990. According to the participants, the principal barriers to effective utilization of care are socioeconomic and legal barriers, newcomer status, cultural attitudes and beliefs, cross-cultural communication and institutional constraints. The findings indicate that structural and cultural barriers to care can be addressed through improved outreach strategies. Outreach, which includes casefinding and motivation to seek early and sustained care, can be increased in a variety of ways ranging from improved information and health education, to cross-referral linkages with other programs or self-help networks and by providing free or low cost pregnancy tests that include counseling. The results also suggest that the removal of institutional barriers may require inreach strategies which modify policies, behaviors and management tools at the prenatal care site. The effective implementation of inreach and outreach strategies is recommended to design prenatal care programs for the Latino population. PMID- 20840962 TI - Family Planning Information, Education and Communication: Current Activities in the People's Republic of China. AB - Based on observation of family planning activities in China in 1989 and 1990, this article takes a close look at education and publicity to promote family planning. Today these activities rely heavily on modern communication technology, especially TV and video, and continue to reflect an urban bias in content. The absence of male involvement in family planning was also noted. Family planning education has been strengthened in certain areas with the "five phases" approach and with the organization of "key households." The Family Planning Association with is 200,000 grassroots associations throughout the country and its 17,000,000 members has greatly increased the manpower pool for the delivery of educational services. It has also been instrumental in developing insurance schemes for one child families, and in some areas the primary function of Association members is surveillance aimed at detecting unplanned pregnancies. There is a need for improved training in the development of educational materials for family planning and in the provision of contraceptive services in rural areas. PMID- 20840963 TI - Evaluation of factors affecting the adoption and use of sugar-salt-solution by mothers in ibadan city, oyo state, Nigeria. AB - A cross-sectional evaluative survey was carried out in six geographical wards in the city of Ibadan, to investigate the level of adoption and use of home-made sugar-salt-solution (SSS) among mothers with under-five years old children. The results showed most mothers interviewed were aware of the existence of SSS, but became cognizant of it at different times during the last five years. There were some significant differences in women's knowledge pattern of SSS which affecting the adoption and use-only one-fifth of the respondents reported adopting the recipe for treatment of dehydration resulting from diarrhoea in their children. The study also identified factors affecting the adoption and use of SSS in Ibadan City. These included lack of adequate knowledge about SSS preparation and use, belief about its effectiveness, non-availability of materials for preparation, refusal by children, and problems with storage among others. The study recommends the need for standardization of activities in ORT units in the city and reinforcement of the inter-personal approach to ORT education. PMID- 20840964 TI - Factors associated with obesity among women in bahrain. AB - A sample of 420 women who attended a physical fitness program run by General Organization for Youth and Sport, was selected to study the association between obesity and some factors among adult females in Bahrain. Women were grouped into two categories, obese and non-obese, based on Body Mass Index (wt/ht2). The results revealed that age, education, employment, marital status, family size and practicing exercises before joining the fitness program have a statistically significant association with obesity, while ownership of cars, availability of housemaids, family history of obesity and meal patterns have no statistically significant association. There were no differences in source of nutrition information between obese and non-obese women. The study suggested that health education programs should focus on both sociocultural factors and health factors for preventing obesity in the community. PMID- 20840965 TI - Health problems of mexican and american workers at three maquilas in ciudad juarez, Mexico. AB - With the increase in numbers of American companies opening plants on the Mexican side of the border (maquilas), comes an increase in daily contact among workers from a developed country and workers from a developing country. Reviews of medical consultation reports in three twin plants indicate a high incidence of gastrointestinal disorders, respiratory disorders, and headaches. Respiratory problems were more prevalent in winter months (54-89% incidence), and gastrointestinal complaints soared in summer (65-77% incidence). White collar workers with greater education consistently had high incidences of gastrointestinal and respiratory problems. Health professionals on both sides of the border should be aware of the possibilities for transmitting these diseases from one country to another. PMID- 20840966 TI - Profile of latino health and implications for health education. AB - Latinos are the fastest growing population in the United States. Yet in spite of their growing numbers, the health needs of Latinos are not met, they lack adequate access to health care and lack appropriate health education interventions. This article discusses key factors to be considered in dealing effectively with the health education needs of Latinos. These factors include demographic characteristics of this population; acculturation and its relationship to health practices; major health issues among Latinos and beliefs and practices which influence Latino health. Communication strategies most widely used by Latinos and most credible sources of health information are discussed. Recommendations for effective communication strategies to reach Latinos with culturally appropriate health messages are presented. PMID- 20840967 TI - Structural impediments in the development of a community-based drug prevention program for youth: preliminary analysis from a qualitative formative evaluation study. AB - In response to community pressure to "do something" about increased drug related problems, a consortium was formed to refocus existing community services towards at-risk youth with special needs and few resources. Using a lead agency approach, ethnically matched case counselors allocated services which included jobs, tutoring, recreation, mentors, family workshops, and drug counselling. The lead agency and case counselors worked in parallel with the newly formed consortium of service providers to reshape and customize services as client needs become clarified. This article reports on the initial six months of this program's implementation, focusing on the problems which arose due to the structural relations amongst the service providers, lead agency and case counselors. The beneficial role of the formative evaluation process itself-in highlighting these problems as they surfaced-is also discussed. PMID- 20840968 TI - Community-based trial and ethnographic techniques for the development of hygiene intervention in rural bangladesh. AB - Community-based three-stage iterative trials were performed to develop interventions for improving hygiene practices to reduce childhood diarrhea in rural Bangladesh. Ethnographic techniques were used to identify practices associated with diarrhea, to understand cultural beliefs and reasoning related to causes of diarrhea, and to tap community resources. Hygiene behaviors and products designed through in-home problem diagnosis went through trials sequentially at three socio-economic levels consisting of ten educated project workers, twenty-five volunteer mothers and twenty-five very low- income mothers. These levels, chosen in order to meet the needs of all including the poorest, permitted new practices which proved feasible in the workers' trial to be then tried by the volunteers. The results were synthesized, with successful behavioral advice translated into simple verbal messages created to resemble locally popular proverbs, poems and folk songs. The messages and products were finalized after pretesting and revision among the very low-income group of mothers. Evaluation of the community-wide campaign showed very high rates of adoption (85%-95%) of the interventions. The involvement of target groups and their opinion leaders in the intervention development process contributed to the sense of ownership reflected in the high rate of adoption. Program organizers' comprehensive understanding of practices associated with diarrhea and its cultural context, and the community's empowerment to find local solutions are both critical to the success of such interventions. PMID- 20840969 TI - Evaluating minimal intervention health promotion in a clinical context. AB - This article has two objectives. The first objective is to summarize the evaluation of a minimal intervention cardiovascular health promotion program offered to a sample of forty-seven persons having percutaneous transluminal coronary angioplasty procedures. The second objective is to highlight several issues concerning the utility of small-scale program evaluation in a clinical context, as exemplified by this study. Results of a four month follow-up evaluation of the intervention showed significant findings in the areas of knowledge gain and lifestyle behavior change; these findings are illustrated through binomial effect size displays. The study failed to demonstrate statistically significant results on several measures of physiological and self reported risk factors. Difficulties in interpreting results due to methodological limitations raise issues concerning the utility of conducting program evaluation efforts with limited resources. Dilemmas often confronted in small-scale evaluation projects and the importance of considering their relative, practical utility are discussed. PMID- 20840970 TI - A preliminary study of job-related depression among professional health education specialists in taiwan. AB - This study examined the extent of job-related depressive symptoms and demographic factors and professional status related to depressive symptoms among health education specialists in Taiwan. A translated and modified version of the Center for Epidemiological Studies Depression Scale (CES-D) was used to assess feelings and behaviors related to depressive symptoms. Mean scores for the group was 14.12, and 35.22 percent of subjects had high levels of depressive symptoms. Data analysis also indicated that younger subjects scored higher than older subjects and subjects who practiced less than fifteen years scored higher than subjects who were in the profession longer than fifteen years. There were no other significant differences of depressive symptoms when comparing gender, practice settings, and levels of religiosity. PMID- 20840971 TI - The role of threat and efficacy in AIDS prevention. AB - Studies examining the role of fear, threat, and efficacy, in promoting protective health behavior changes have yielded diverse results. These constructs were examined in a theoretically-based 3 (low, moderate, high threat) x 2 (low, high efficacy) factorial experiment promoting condom use to prevent HIV-transmission. Pre-screened sexually-active college students not involved in long-term relationships (N = 146) served as subjects. As predicted, when threat of AIDS was high and condom efficacy low, people failed to use condoms; when both threat and efficacy were high, people reported more condom use. The more fearful people were of AIDS, the more they denied its threat and the more manipulated they felt. Overall, the results indicated that threatening messages can motivate behavior change, as long as the recommended response is portrayed as effective. This study is useful for public health practitioners in that specific and practical guidelines for campaign message development are offered. PMID- 20840972 TI - Costa rica: moving toward "health for all". AB - Health status indicators for Costa Rica compare favorably to those in more developed countries. This impressive achievement and the narrowing of health status differentials between population sub-groups have been attributed to a strategy for delivering primary care. This commentary examines the primary health care program and the role of the Health Assistant in its implementation. Also considered are contemporary challenges presented by the transition to a disease profile more typical of a developed country, a health care system still favoring care in an urban, hospital setting, and economic stagnation. It is concluded that these challenges threaten to erode the health gains made. Achieving "Health For All 2000" will require an enduring commitment, dedication, and will to live within current economic constraints without sacrificing the primary care program. PMID- 20840973 TI - Sexual practices among the quiche-speaking mayan population of guatemala. AB - The purpose of this focus group research was to learn more about the sexual behaviors and practices of this population, in part to better understand their resistance to family planning. The Mayan population is made up of some twenty three linguistically distinct groups, which collectively constitute 37-42 percent of the Guatemalan population. The largest of these groups, the Quiche- speakers, were the focus of the first phase of this research, reported in this article. Years of economic and social subjugation have resulted in a far lower standard of living among the Mayans than the dominant ethnic group in Guatemala, the Ladinos. This difference is reflected in numerous health indicators, including one of the lowest contraceptive prevalence rates in the hemisphere.A total of thirteen groups were conducted among men and women of different age groups. All groups were organized and moderated by a team of five Mayan field workers who spoke the language and were familiar with the culture of the area. While there was initial hesitation to the idea of discussing the highly sensitive topic of sexual behavior in a group setting, the methodology proved appropriate and yielded detailed data on the subject. All sessions were taped, translated to Spanish and transcribed for purposes of analysis. PMID- 20840974 TI - Application of focus group and survey methods in the study of rural primary health care development in Nigeria. AB - This study illustrates the application of focus group techniques in baseline studies involving rural primary health care development. Conventional survey methods were combined with focus group approach in seeking information about community diagnosis, community initiative, KAP, and mobilization. Phase-1 of the study generated data with questionnaire; while Phase-2 used a flow-chart model guided by specific trigger questions which stimulated responses and discussions on topics similar to Phase-1. Analysis and comparison of information from both sources indicated that the two techniques were complementary. However, the focus group approach had additional advantages of permitting uninhibited discussion and expression of cultural nuances among participants. It also revealed certain sociocultural information which may be pertinent to the planning and implementation of rural primary health care development. PMID- 20840975 TI - Case study: application of precede and proceed as a framework for designing culturally sensitive diarrhea prevention programs and policy in arab countries. AB - This study utilized the diagnostic approach of the PRECEDE-PROCEED model. The constituents of this model were identified by utilizing participant observation field studies, traditionally applied by ethnographers to collect data describing the multiple facets of a culture, including linguistic patterns that capture and define characteristic semantics and viewpoints. The household study sample was randomly selected from a defined list of households known to have at least one child less than five years of age. An open-ended questionnaire format was used to interview the 115 mothers in the selected household sample. Kalama, the study community, is characteristically an agricultural village, situated in the Governorate of Kaliobia and located approximately 25 km (about 15.5 miles) from the capital, Cairo, Egypt. The latest 1986 census indicates a population size of about 13,328 people in 4,818 households. There were sixty-five deaths occurring among children less than five years in 1986. The causes of death were primarily related to diarrhea, followed by upper respiratory infections, congenital anomalies and birth injuries. This study outlines a) practices related to the management of diarrhea, including the administration of foods and drinks during such episodes; b) influences of governmental policies; and c) recommended strategies for overcoming barriers and promoting effective diarrhea intervention programs. PMID- 20840976 TI - The potential of drama and songs as channels for AIDS education in Africa: a report on focus group findings from ghana. AB - Among those concerned with fighting AIDS worldwide, it is agreed that the best weapon to change people's behavior is education. In this educational effort, all available channels have to be explored. In Ghana, the Health Education Division (HED) of the Ministry of Health set up three drama troupes to carry out AIDS education on a pilot basis. This study evaluates the impact of one of the troupes on AIDS knowledge, attitude and behavior using the focus group research approach. The findings confirm that drama about a well thought out AIDS-related theme does increase knowledge about AIDS and promotes commendable attitudes toward AIDS. It could also lead to changes in sexual behavior. The study also revealed that songs with AIDS-related themes could serve as important cues to "healthful" action in the environment by reminding listeners to adopt safer sexual behaviors. PMID- 20840977 TI - Professional public health training in international health: the six-year experience of the international public health internship in latin america and the Caribbean. AB - Since 1986, the MCH International Public Health Internship Program (IPHI Program) at the Center for Population and Family Health at Columbia University has provided short-term technical assistance to MCH/FP agencies in Latin America and the Caribbean while at the same time offering substantive field experience to masters level public health students. Agencies submit project proposals in the area of utilization of health and family services, reproductive health education, AIDS prevention and education and the status of women. IPHI Program faculty visit agencies and selected interns are matched to agency needs. Interns participate in a one-week orientation and training prior to their six-week field assignment; the program provides round-trip transportation and a modest per diem. They are supervised in data analysis and report writing for agencies. Interns collaborate with agency personnel to submit abstracts for presentation at professional meetings. Agencies, interns and faculty evaluate the program favorably. PMID- 20840978 TI - Information, education and communication needs in family planning: the case of pakistan. AB - In spite of three decades of national family planning programmes, Pakistan's contraceptive prevalence rate was only 12 percent in 1991. Furthermore, the government family planning service delivery systems, primarily the family welfare center (FWC), cover less than 10 percent of the people in rural areas. Although there are cultural and religious constraints to social change, it can be argued effectively from recent surveys that there is a considerable need for family planning that has yet to be met. Certain barriers to, and options for, meeting this need are reviewed, particularly in terms of strengthening information, communication and education (IEC) at the community level. PMID- 20840979 TI - Perceptions about Prenatal Care Among Health Providers and Mexican-American Community Women: An Exploratory Study. AB - Latino women in California have less access to health care, particularly prenatal care, than any other ethnic group. This exploratory study identified perceptions about prenatal care needs, barriers to utilization of health services and common health behaviors during pregnancy among a sample of Mexican American women and a sample of prenatal care providers. The research used a combination of written questionnaires and focus-group discussions to gather data from a sample of sixty Mexican American community women, and a written questionnaire only to get information from a sample of forty providers. Results showed that providers perceived Mexican American women as doing better than non-Latino women regarding a series of health behaviors during pregnancy and as doing worse regarding another set of prenatal care behaviors. Results also showed that Mexican American pregnant teenagers are at particularly high risk regarding prenatal care due to a combination of structural and cultural factors. Acculturation was found to be an important factor affecting prenatal care beliefs and behaviors among this population. This relationship deserves further study. The influence of acculturation also needs to be considered in the design of prenatal care communication strategies with Mexican American women. PMID- 20840980 TI - Interpersonal education by rural yemeni women for promoting child survival and maternal health. AB - This study reports the results of an evaluation of an education and training effort for promoting diarrheal control, nutritional health and general maternal and child health among rural Yemeni women. Eight hundred and five volunteer women and men from twenty Yemeni villages in the governorates of Al Beida and Hajja, were trained to disseminate basic health messages to friends and neighbors in their villages. Evaluators visited four villages that had received the training and two that had not, to determine whether the dissemination had actually occurred. Mothers contacted by their recently-trained neighbors correctly responded to all knowledge and practice questions related to diarrhea control, oral rehydration therapy and breast feeding, whereas mothers in control villages averaged 60 percent correct responses. The results suggest the potential for interpersonal education for improving child survival and maternal health in Yemen. PMID- 20840981 TI - Maternal and child health care of haitian families living on a sugarcane plantation in the dominican republic. AB - Data regarding the maternal and child health care of Haitians living in the Dominican Republic were collected by questionnaire. Respondents were contacted in their homes with the assistance of missionary personnel working in the area around LaRomana. One-hundred and seven questionnaires were administered in four bateys (clusters of homes located on the plantation). The questionnaire included items regarding family demographics, prenatal and postnatal care, medical supervision during delivery, perceived health, family planning, and the availability, accessibility, and affordability of medical service. The most important findings were: that mothers perceived the health of the family to be high while the availability of health care was low; and that desirability of family planning was high while prevalence of contraception was low. PMID- 20840982 TI - A Multifaceted Approach to health Education: A Case Study from Rural Egypt. AB - This article describes and evaluates an environmental health education project, focusing on water and sanitation issues, which was carried out in two Egyptian villages in the Nile delta. The study is multifaceted as it involves various hygiene education strategies carried out by health unit staff, teachers, graduate volunteers and local village leaders who deliver simple environmental health messages in a variety of different settings. The project is also multifaceted in that it looks at health education in relation to specific health interventions, in this case in water and sanitation; it identifies the full context of relevant local behavior; and it collaborates with local people, especially women, in the design and implementation of the program. Based on the experience gained during this project, a broad based model for health education is presented. PMID- 20840983 TI - Generating Demand for contraceptives in India: A Case Study of IEC Activities in Uttar Pradesh. AB - The article presents a review of current Governmental family welfare program information, education and communications (IEC) activities in Uttar Pradesh, the most populous state in India (139 million in 1991). The review is based on available literature. The extent of general outreach of mass media as well as constraints and problems related to provision of appropriate IEC are discussed. Suggestions for improvement are made, particularly in terms of interpersonal communication. PMID- 20840984 TI - Maternal sexuality during pregnancy and after childbirth in kuwait. AB - Although pregnancy had an adverse effect on sexuality, many women improved at the mid-trimester and early postpartum period. Sociocultural attitudes and pre pregnancy sexuality level are important determinants. A study of sexual adjustment of 160 pregnant Muslim women of Kuwait revealed that pregnant women showed a decline in sexual activity soon after the diagnosis of pregnancy that continued throughout the whole pregnancy with a second trimester and early third trimester increase in sexuality, but continued to be below the pre-pregnancy base line. Resumption of sexual activities was not problematic for many of our patients at eight or twelve weeks postpartum, except for those with marital disharmony. For some women, pregnancy and labor improved their sexuality in general. But the majority of our subjects had a consistent pattern of sexuality during pregnancy that reflects their pre-pregnancy level of sexuality. This study shows clearly the important influence of the father-to-be on the sexuality of his wife. Sociocultural taboos influence sexual adjustment during pregnancy, as this highly important topic is always ignored during discussion between patients and doctors at ante- and post-natal clinics. It is recommended for obstetricians to counsel patients about sexual activity, keeping in mind the prevailing sociocultural attitudes. PMID- 20840985 TI - An integrated approach to operations research for strengthening family planning programs: a case example in kenya. AB - The Africa Operations Research/Technical Assistance Project developed an integrated approach to introducing and institutionalizing family planning in Kenya. This approach consisted of: 1) the development of the Situation Analysis methodology to diagnose problems; 2) the development of a computer simulation model for choosing operations research (OR) strategies; 3) an OR training workshop; 4) the implementation of three OR field studies testing educational approaches to several program problems; 5) a conference to review the findings and implications from the three studies. Technical assistance was provided in all phases. Results from the field studies indicated that all of the tested educational interventions had at least some short-term impact. Health talks with waiting maternal and child health (MCH) clients doubled the proportion adopting family planning; a simple educational package for clinic supervisors, along with a day of training, raised the proportion of family planning clients receiving education and referral for voluntary surgical sterilization (VSC) and increased the number of tubal ligations at a referral hospital. Waiting time was reduced. The Division of Family Health of the Ministry of Health has submitted plans to introduce these interventions into several districts of the country in the near future. Full institutionalization of OR requires additional cycles of program activities. PMID- 20840986 TI - Knowledge of oral rehydration and response to diarrhea: a comparison among healthcom sites. AB - This article examines evidence for the relationship between knowledge of diarrhea and oral rehydration and treatments given for diarrhea among young children in seven different research sites. The evidence comes from cross-sectional analyses of household surveys conducted for the evaluation of oral rehydration programs. The cross-site comparisons show that mothers or caretakers who understand most about the dangers of diarrhea are not more likely to treat the diarrhea, but that those who understand the benefits of using oral rehydration are more likely to give fluids, particularly oral rehydration solutions, than those without such understanding. PMID- 20840987 TI - Preventing tractor-related injuries and deaths in rural populations: using a persuasive health message framework in formative evaluation research. AB - Though agriculture is the most dangerous occupation in the United States, two key issues impede the effectiveness of farm safety interventions. First, little is known about what farmers think about farm equipment accidents and safety procedures. Second, current safety interventions are typically atheoretical and focus on information exchange, instead of persuasion. Formative evaluation is desperately needed, but rarely used in farm safety campaigns. The study reported here represents a formative evaluation based on a theoretically-grounded persuasive health message framework. The goal of this formative evaluation was to discover farmers' safety practices, as well as their beliefs about farm equipment accidents and safety. Methodological triangulation was achieved by assessing farmers' beliefs, attitudes, and behaviors via face-to-face interviews (N = 46), telephone interviews (N = 48), and mailed surveys (N = 177). The formative evaluation revealed that farmers believe farm equipment accidents to be severe and dangerous, yet believe themselves to be invulnerable to these accidents. PMID- 20840988 TI - A Community Organizing Case Study: An Analysis of Cap-It's Strategy to Prevent the Location of a Toxic Waste Incinerator in Their Community. AB - With the great proliferation of chemical manufacturing in the past half-century, the dilemma of dealing with the waste produced has become an increasing problem facing communities. One method that is gaining increased acceptance by both government and industry is incineration. Many citizens have formed groups to protest these facilities because of their concerns about health risks, especially exposure to carcinogens. This case study profiles one such group, CAP-IT, a collection of middle-class residents living in a small working-class town and their successful battle to prevent the siting of a hazardous waste incinerator. CAP-IT's strategy will be critiqued using methods advanced by Lee Staples, Nicholas Freudenburg and Kurt Lewin to demonstrate the power of community organizing activities. PMID- 20840989 TI - Accessibility of health care for elderly mexicans living in ciudad juarez, Mexico. AB - The issue of access to health care for the elderly and the quality of that care is of growing importance not only in the United States but also in less developed nations such as Mexico. An area of special interest is the U.S.-Mexico border region, where an increasing number of people are relocating to seek jobs they believe will open up as the North American Free Trade Agreement (NAFTA) loosens trade barriers. Workers flocking to the border often bring their families, including elderly relatives. This study examines a sample of lower-middle and mid middle class Mexicans aged sixty to eighty-nine who reside in the border city of Ciudad Juarez, focusing on the principal ailments which affect these individuals and available treatment. A concluding section makes brief comparative remarks on access to health care for the elderly in Mexico and in the United States. PMID- 20840990 TI - Health beliefs and practices of kenyan primary school students. AB - A study of 224 primary school students in Kenya was conducted to determine if health belief model variables predicted their health behavior, specifically, using safe drinking water. One health belief model construct, belief in benefits, was associated with the behavior (p = .05). Living in an urban environment (p = .01), and proximity to a tap (p = .004) were also significant predictors of safe water use. Implications for further research and health education programs are discussed. PMID- 20840991 TI - HIV/AIDS in Asian and Pacific Islander Communities in the U.S.: A Review, Analysis, and Integration. AB - In the United States, HIV/AIDS is invisible in Asian and Pacific Islander (A/PI) communities even though it has affected them since 1981. As the AIDS crisis enters its second decade, A/PI communities continue to face a classic Catch-22: They receive modest, if any, funding for services, education, or research because there are relatively few reported Asian AIDS cases, but no one can financially, socially, and ethically afford to wait for an explosion of HIV infection in these communities. This article, using the AIDS Risk Reduction Model (ARRM) as an organizing framework, reviews, analyzes, and integrates the current state of knowledge, attitudes, beliefs, and behaviors associated with HIV/AIDS among Asians and Pacific Islanders. Implications for community health education programs and future directions for research are discussed. PMID- 20840992 TI - Care or cash: assessing quality of care provided by drug retailers in Nepal. AB - Staff in the pharmacies of urban Lalitpur, Nepal, were interviewed, observed in their work, and tested through the use of a researcher posing as a client to assess the quality of care they provide, and their potential as health informants to the general public. Note was made of advice given to clients describing cough symptoms and diarrhoea, symptoms underlying two major causes of morbidity and mortality in Nepal. Data were also collected on the uses made of pharmacies by the general public, in terms of the provision of health care. Results show that people do indeed frequently use pharmacies as a primary care service. However, staff have minimal training. The quality of the advice they provide is varied, but many ask for no additional information on symptoms, and give average or poor advice on the use of the drugs they recommend. Drug retailers are particularly weak on giving explanations to clients about possible side effects and contraindications and rarely refer clients to health professionals. Most "consultations" last less than two minutes. Drug retail staff perceive the provision of health information to be an important and necessary part of their work, and many express a desire for further training. One obvious constraint to developing their health care role, however, would be the undoubted conflict between the financial interests of the drug retailer and the importance for the vast majority of clients of receiving adequate treatment but at limited cost. An important question is whether much higher priority is to provide the drug retailer with more training on drug use and control. PMID- 20840993 TI - An empirical exploration of a conceptual model for community-based health promotion. AB - Community-based approaches to health promotion and disease prevention are often based on underlying theoretical models of behavior change, but evaluations of these programs have not attempted to assess empirically the validity of these models. This article uses data from the Henry J. Kaiser Family Foundation Community Health Promotion Grants Program (CHPGP) evaluation to examine a conceptual model which guided the program evaluation. The model posits relationships among six theoretical constructs: community activation, program activity, norms, environment, role models, and health behaviors. Correlational analyses using two waves of survey data were used to examine whether the hypothesized relationships were actually present. Positive cross-sectional associations between the constructs at each point in time were found but the associations between changes in the constructs over time were weak. The stability of these cross-sectional patterns suggests that there may be forces leading communities to have an underlying "consistency" with respect to community norms, the environment, health behaviors and perhaps other community characteristics. If so, effective community-based programs may need to target a wide range of community characteristics rather than to focus narrowly on a single dimension. PMID- 20840994 TI - Study of participation barriers in family-focused prevention: research issues and preliminary results. AB - There is a growing body of literature which argues for more research on barriers to participation in family-focused interventions, particularly among at-risk families. Following a review of research needs and issues suggested by the literature, this article presents results from a study which 1) evaluates reasons for decisions against participation in a family-focused prevention intervention project and 2) compares characteristics of intervention project participants with those of non-participants. Data on reasons for refusing participation were collected from non-participants during a recruitment telephone interview and via a mail survey. Results indicated that the most frequent reasons given for decisions against participation concerned intervention time demands and research related requirements such as videotaping. There were no significant differences between participants and non-participants on any sociodemographic variables. Analyses of the relationships between reasons for participation refusal and sociodemographic subgroupings of non-participants, however, suggested that variations exist among these subgroups. Overall, results highlight the feasibility and importance of data collection on intervention project non participants, both to clarify potential participation barriers and to gather data on sample representativeness. PMID- 20840995 TI - Continuing education experiences of district level health staff in Nigeria. AB - Primary health care (PHC) implementation has stimulated the need and interest in developing continuing education (CE) programs in Nigeria. A population study of 144 government (69%) and private (31%) health workers in the Ibarapa District of Oyo State in Nigeria documented their CE opportunities. Only 39 percent had attended an in-service training (IST) program in the past five years. Fewer (32%) had received a supervisory visit within the previous month, and most of these visits contained little of educational relevance according to respondents. Slightly over half (54%) reported attending a staff meeting in the previous month, but 72 percent had attended at least one in the past six months. Like supervisory visits, these meetings were not primarily educational in nature. Only 58 percent engaged in self-study through reading in the past six months, but quality reading materials were scarce, forcing health workers to rely on old texts and popular health magazines. Local government staff and workers with formal health training were most likely to have taken advantage of an IST. Trained workers and males were more likely to have engaged in self-study. New PHC management structures have the potential filling CE gaps and redressing imbalances in CE opportunities in this and other rural districts throughout the country. PMID- 20840996 TI - Risk assessment-risk perception: who shall decide? AB - Since the Chernobyl disaster, the people of the world have become concerned with environmental pollution and its effect on their health and safety. This article addresses a fundamental question arising from that concern, namely, how safe is safe enough and who should make this decision? The controversy arising from this question is between the private stakeholders and the technicians who assess risk, control information and influence public policy and both the public's perception of risk and their desire to participate directly in public policy decisions affecting their health and safety. This article proposes a solution to this controversy that is relevant to all people, since all people are stakeholders in a fair and balanced solution. PMID- 20840997 TI - Operations research diagnostic studies: formative evaluation in India, indonesia, pakistan. PMID- 20840998 TI - A situation analysis of public family planning service delivery in pakistan. AB - A nationally representative sample of 8 percent of the Government of Pakistan's primary family planning service facilities, the Family Welfare Centres (FWC), was carried out at the request of the Ministry of Population Welfare in mid-1992. The "situation analysis" approach used involved: 1) observation and inventory of services, facilities, supplies and record keeping reviews; 2) observation of interaction between service providers and FP clients at FWC's; 3) interviews with service providers; and 4) exit interviews with FP clients after service provision. This one-day on-site observation by teams of three interviewers provided a unique overview and baseline assessment of the availability of services, the staff functioning and the quality of service. Significant findings include a low caseload, inadequacies of facilities, some stockouts, lack of educational materials, insufficient outreach, unnecessary medical and social barriers to providing contraception as well as in some cases insufficient information to clients about contraindications to contraceptive usage and possible side-effects. The need to bolster in-service training and supervision is emphasized. PMID- 20840999 TI - Norplant(r) implant use-dynamics diagnostic study: indonesia 1991. AB - Indonesia's national family planning program constitutes the largest introduction of the NORPLANT(r) implant in the world. With the first five-year removals occurring in late 1991, the program was at a critical stage. In Fall 1991, the ANEORTA Project conducted a Use-Dynamics Study to look systematically at NORPLANT(r) implant use in the field. To prepare for that study, and to get early information on program functioning, BKKBN and the Population Council, in conjunction with Andalas University in West Sumatra and BKS-PENFIN in West Java, undertook a diagnostic study of six clinics in each of two provinces, interviewing service providers and examining records. A total of 120 acceptors were visited to determine the feasibility of locating them and whether they were still using implants. About 70 percent of the acceptors had accepted from non clinical sources, either "safaris" or mobile team visits. The four-year life table continuation rate was 78 percent. No written information specifically devoted to the NORPLANT(r) implant was available either to providers or to clients. Available records generally matched official records, although significant gaps were found. All physicians and nurse-midwives, as well as many nurses, had some training, formal or informal in NORPLANT(r) implant insertion and removal. Contrary to expectation, clinical staff, records, and logistics all seemed generally adequate for five-year removal, although some problems were anticipated. PMID- 20841000 TI - The state of family planning in uttar pradesh, India: a literature synthesis. AB - A 1993 review of the state of the family welfare program in the State of Uttar Pradesh (UP) India. With 139 million people, UP is larger than all but six countries in the world. This synthesis of previous studies and recent Census and other existing data provides: 1) a socio-economic and demographic profile with emphasis on fertility and mortality; 2) a review of family size and family planning preferences; 3) an evaluation of the performance of the family welfare services in place; and 4) a review of the extent of involvement of NGO's and the organized sector in the family welfare program. PMID- 20841001 TI - Another crack in the mirror: the politics of AIDS prevention in Mexico. AB - Beginning in the mid-1980s, nongovernmental groups and the government in Mexico launched efforts to combat AIDS by addressing the population openly and directly. The content and tone of AIDS prevention messages in Mexico have been strongly influenced by models developed in the United States, even when the social conditions of Mexico are strikingly different. However, the local organization of AIDS prevention efforts in Mexico has differed sharply from efforts in large U.S. cities in terms of the distribution of funds and the role played by civil society in the creation of programs. Based on the premise that social and political forces may strongly influence the success, or failure, of health education interventions, this article analyzes the emergence of AIDS prevention in the Mexican context. The epidemiological characteristics of AIDS in Mexico, the governmental response to the epidemic, the role of nongovernmental groups, the availability of funds, the opposition of the political right, and the adoption of models imported from the United States are all considered to be important factors that shape current efforts. The article highlights possible directions for future development of AIDS prevention in Mexico. PMID- 20841002 TI - Awareness and knowledge of alcohol beverage warning labels among homeless persons in cook county, illinois. AB - In 1988 Congress passed the Alcohol Beverage Labeling Act, requiring that two specific health warning labels appear on all alcoholic beverage containers sold in the United States after November 1989. The following year, a random sample of 481 homeless persons interviewed in shelters, soup kitchens, drop-in centers, and single room occupancy (SRO) hotels in Cook County, Illinois were asked about their awareness and knowledge of these messages. As a group traditionally considered at high risk for alcohol abuse, the degree to which the newly-mandated warning messages have been communicated to homeless persons has important implications for the success of this public health measure. Findings revealed that age and level of alcohol consumption were each associated with label awareness and content familiarity, suggesting that alcohol beverage warning labels may be reaching homeless persons. PMID- 20841003 TI - Using the newspaper to disseminate vasectomy information in kenya. AB - Recent research in Kenya shows that, although there is still a high population growth rate, there is increasing interest among men as well as women in family planning and in limiting family size. Vasectomy, however, is little known and practiced in Kenya. A major reason for this is a general lack of knowledge about the procedure and where it may be obtained. Little effort has been put into addressing the barriers to vasectomy acceptance in Kenya, partly because of the commonly held assumption that Kenyan men would not be interested in the method. Innovative Communication Systems, with the support of the Association for Voluntary Surgical Contraception, implemented a study using the print media to examine this perception. Advertisements providing information about the method were placed in newspapers and a magazine. An unexpectedly large response was received-over 800 written requests for information from all parts of the country. The majority of inquiries were from rural areas, and there was a high proportion of requests from the coastal district, a Muslim area generally considered to be extremely resistant to family planning. A large proportion of inquiries came through a Kiswahili newspaper appealing to lower socioeconomic groups. PMID- 20841004 TI - Empowerment in a supplementary food program in a rural community in ghana. AB - This article examines the concept of empowerment in the context of a supplementary food program in a rural community in Ghana. Both quantitative and qualitative methods were used to understand key empowerment processes and outcomes for women and their children. While the women felt positively about the outcomes of the program, they were less satisfied with program processes. Self determination of the mothers and service-provider conduct were predictive of positive outcomes. The qualitative data served to temper the positive quantitative outcome data in showing that mothers are dependent on the food program. The findings were discussed in terms of the concept of empowerment and its implications for social change and program improvement. PMID- 20841005 TI - Using social learning theory to assess the exercise related health education needs of post-retirement adults. AB - The purpose of this study was to determine the exercise related health education needs of post-retirement adults. Social Learning Theory (SLT) was used as the conceptual framework. The target population for this study was post-retirement adults aged sixty years and over living in Columbus, Ohio. Results revealed a serious lack of knowledge regarding the benefits and attributes of exercise. Overall it appeared that few older adults received social support for exercise. Approximately one-half of the sample reported high levels of exercise self efficacy. Over 50 percent of the sample reported to exercise for health-related benefits. Based on the results, specific recommendations for the promotion of exercise in post-retirement adults are offered. PMID- 20841006 TI - Assessment of job-related burnout among health education specialists in taiwan. AB - This study examined the degree of job-related burnout and the relationship between burnout and gender, age, practice settings, years in the profession, and the level of religiosity among health education specialists in Taiwan. A Chinese version of Maslach Burnout Inventory (MBI) was used to assess burnout symptoms among 184 respondents. Results indicated that younger respondents had a significantly higher degree of burnout symptoms on both emotional exhaustion and depersonalization than older respondents and female respondents had a higher score on emotional exhaustion symptoms than male counterparts. There were no other significant differences of burnout symptoms between groups concerning practice setting, years in profession, and level of religiosity. It was concluded that some health education specialists were suffering from burnout symptoms, especially women and younger professionals and there is a need for stress management training for retention and training of health education specialists. PMID- 20841007 TI - Community-Based Prevention and the Health Equity AIM-An Ideal Match? An Evaluation of the Kirseberg Community Action Project. AB - This article presents results and conclusions from a qualitative process evaluation study of an alcohol preventive community action project, in the city of Malmo, Sweden. The community action approach has been proposed as a promising preventive strategy in relation to the health equity aim, and our overall goal has been to investigate the tenability of this connection. The starting point in our analysis is the socially stratified pattern of participation in the project. How do we explain the fact that the well-educated middle-class groups and their organizations became the driving force in the community action program, while the working-class majority and the economically underprivileged residents were left out? The excluding mechanisms which were revealed in the study indicate that the community action approach can hardly be seen as a strategy necessarily promoting the health equity aim. PMID- 20841008 TI - Development of culturally appropriate educational material to improve home case management of diarrhea in rural lombok, indonesia. AB - In order to develop a culturally sensitive health education campaign on appropriate home case management of diarrhea, we first conducted formative research with mothers of young children and health care providers in West Lombok, Indonesia. This research showed that the people recognize four different types of diarrhea according to signs and symptoms and perceived etiology. Based on the results of the formative research, a flipchart was designed incorporating five messages. The flipchart was then revised on the basis of two pretests. The pretest results showed that visual messages about child health, the course and treatment of diarrheal diseases, and the preparation of oral rehydration solutions were often misinterpreted or not considered in accordance with local cultural norms. Most of the respondents understood the messages but felt that several of the illustrations did not accurately reflect their ways of living. After changes were made, the materials were easily understood and accepted by respondents. To maximize the benefit of educational materials, the national health education sector should be more flexible in the adaptation of materials to local customs and perceptions. PMID- 20841009 TI - Community participation for schistosomiasis control: a participatory research project in egypt. AB - Schistosomiasis remains one of the major public health problems in rural Egypt. Many rural people continue to be exposed to the disease as they enter irrigation canals during agricultural, domestic and recreational activities. Current control strategies focus on testing and treatment of cases in rural health units; apart from a TV media campaign, health education plays a small role. This article reports on an on-going participatory research project involving all the people and institutions in two villages who have an interest in schistosomiasis control at the village level. The project is studying human behavior and the transmission of schistosomiasis, with the ultimate aim of recommending appropriate control strategies. The research team worked with local staff at the clinic to improve testing and treatment for villagers, especially school children. It also trained local residents in social research techniques, so that they work with local villagers to understand why exposure to canal water persists and what can be done to minimize this contact. PMID- 20841010 TI - Working with communities to increase the use of health services: an experience from togo, west Africa. AB - A project in Togo, West Africa, demonstrated that motivated and skilled district health teams can increase community involvement in promoting positive health behavior. Village health committees, village volunteers, health workers, itinerant health agents, and school teachers collaborated with district health personnel in village-wide efforts to increase the use of health services targeted to children under five years of age. The project also demonstrated that in areas where health services are accessible, high levels of service utilization can be achieved by villages through a combination of strategies that rely on person-to person and group methods of communication. Village-level educational programs, which included theater, storytelling, patient education at health facilities, and child-to-child activities in schools contributed to improvements in immunization coverage levels in children twelve to twenty-three months of age after less than one year following the educational intervention. The major factors responsible for the success of the project are summarized, and issues related to project replication and diffusion are discussed. PMID- 20841011 TI - AIDS-related knowledge, attitudes, beliefs, and behavioral intentions of adolescents in trinidad: a pilot study. AB - Ninety-six percent of respondents knew the cause of AIDS and mode of transmission, but 26 percent felt that they could get AIDS from insect bites. Student knowledge did not correlate with behavior intentions, but there was a high correlation with perception of risk and their intention to use condom or abstain from sexual practice. There appears to be some association between level of education and likelihood of safe sexual practices (p = .06). There was a significant (p < .05) relationship between students attending all girls school and behavior intentions. There was also a significant relationship (p < .05) between knowledge level and newspapers or magazines as the sources of knowledge. PMID- 20841012 TI - Assessment of the effects of teaching germ theory on changes in hygiene behaviors, cleanliness, and diarrheal incidence in rural bangladesh. AB - Germ theory was taught as part of a hygiene intervention in five villages in Bangladesh in which 87 percent of mothers were illiterate. Volunteer mothers taught other community mothers interactively in small groups using demonstration and teaching aids developed by a community working group. At final measurement 91 percent of mothers could explain five simple messages defining germ theory. Using germ theory in groups they identified forty high risk day-to-day practices and modified them to reduce diarrheal transmission. They adopted these new hygiene practices at rates ranging from 65 percent to 100 percent. Regression analysis suggests that understanding of germ theory was an important determinant of hygiene practices, cleanliness, and reduction in diarrheal incidence. Understanding of germ theory appeared to reduce diarrheal incidence not only through the interventions designed by the project but also changing perceptions of risk in the environment which led to spontaneous improvement in hygiene behaviors. We believe that accurate understanding of causes, transmission, and prevention of disease can 1) empower community and individual actions; and 2) contribute significantly to the impact of hygiene interventions. Therefore, it may be imperative to integrate teaching germ theory into community health education. PMID- 20841013 TI - Smoking or health? International trends and marketing of tobacco and possible interventions. AB - This article focuses on the trends in cigarette smoking in both developed and developing countries. There is a change in the smoking patterns from developed to the developing countries due to the shift of emphasis upon marketing of tobacco in the developing countries by the transnational tobacco industry. This is achieved due to the tobacco company's advertising strategies and its impact on the population. The harmful effects of tobacco production and its impact on the environment and health levels in these countries is discussed. Intervention strategies for smoking cessation and the benefits of such interventions is also discussed. This article focuses on these changes from a political economic of illness approach rather than just focusing on individual smokers and holding only them responsible for their healthy or non-healthy conditions. PMID- 20841014 TI - Use of health belief model to predict condom use among university students in Nigeria. AB - The purpose of this study is to use the concepts of the Health Belief Model (HBM) to predict self-reported condom use among university students in Nigeria. A sample of 395 students enrolled in a required course at a University in Nigeria completed a self-administered questionnaire. The HBM guided instrument design. Regression analyses were used to test the HBM variables (susceptibility to and severity of AIDS; benefits and barriers to condom use; cues to action; AIDS knowledge; and demographics) in predicting condom use, past and intended. The results indicate that condom benefit beliefs, condom barrier beliefs, cues to action, knowledge and male gender were significant predictors of past condom use. Perceived barriers to condom use, perceived benefits of condoms use, and male gender were significant predictors of intentions to use condoms. These findings have important implications for the design of interventions to increase condom use among young adults in Nigeria. PMID- 20841015 TI - Development of a questionnaire for assessing the school environment. AB - This article describes the development of a school environment questionnaire to assess students' perception of their school environment. The dimensions and internal consistency reliability were examined utilizing various statistical methods-factor analysis and alpha coefficient. The sample consisted of 705 students from two high schools with ages ranging from ten to nineteen years. Results showed that the students perceived their school as having various aspects, rather than a global point of view. Factor analysis identified seven dimensions in the school environment: external characteristics of the environment, aesthetic and functional elements of the classroom, students' bathroom, the canteen and staffroom, the aesthetic and functional elements of the school as a whole and sanitation. Overall the internal reliability of the factors was high. Implications for school health programs are addressed. PMID- 20841016 TI - Immunization for the migrant fulani: identifying an under-served population in southwestern Nigeria. AB - Rural populations are often at a disadvantage for receiving health services. Although Nigeria launched its Expanded Programme of Immunization in 1978, and has revised it twice since then, rural immunization coverage is still low. These problems may be compounded when the population is nomadic; thus a study was designed to learn about immunization coverage among a minority group of nomadic Fulani cattle herders living in southwestern Nigeria. It was necessary to conduct a census of the target population first because local government maps and records did not reflect their presence in study area, Ifeloju Local Government Area (LGA) of Oyo State. Sixty Fulani settlements were located and contained 2197 residents, 22.1 percent of whom were below five years of age and 21.5 percent of whom were women of child bearing age. Only 2.6 percent of children below twenty-four months of age (the EPI target group in Nigeria) had received full immunization, compared to an estimated coverage of 48 percent among all target age children in the LGA. Only 2.1 percent of the women had at least two tetanus toxoid immunization contacts. Immunization coverage was associated with proximity to a town, length of residence in the LGA and awareness of the settlement's leader about EPI. The latter factor gave rise to suggestions that greater outreach efforts should be targeted at Fulani leaders, using staff of the local nomadic education center to help design culturally appropriate health education programs. PMID- 20841017 TI - Multiple methods for workshop evaluation. AB - Evaluation is a necessary component of all training, including workshops. Evaluation can provide information about the teaching and learning that occur during a workshop and document the extent to which long-term objectives were achieved after a workshop. Multiple methods for evaluating the process and outcomes of a regional workshop on Program Planning and Management for Malaria Control were developed and implemented by an evaluation team composed of African program managers and technical assistance partners, all of whom served as workshop trainers. Among the five methods used to assess the process of workshop implementation and participant satisfaction, a questionnaire administered at the close of the two-week workshop was found least useful in improving the training. Much more useful were the results of daily trainers' meetings and of two qualitative evaluation methods: large group feedback sessions and focused group discussions. Among the three methods used to evaluate the workshop outcomes, a review of the quality of the pre- and post-workshop national malaria control program plans by a panel of experts was found to be the most useful in providing information about the extent to which learning objectives were achieved. The involvement of trainers in evaluation activities permitted immediate action based on results. Our experience suggests that during brief workshops, evaluation should not compete with training activities for time and resources but must be considered an essential part of the curriculum. Effective and efficient workshop evaluation will require advance planning by trainers, support and training in evaluation methods for all members of the evaluation team, and advance consideration of how evaluation results will be summarized and translated into action. PMID- 20841018 TI - Physicians' knowledge of dietary fat and advice to patients. AB - A mailed survey of 239 Texas physicians selected by a stratified random sample was completed in 1990 (response ratio = 39.5%) concerning physician's background in nutrition, nutrition knowledge, and recommended treatments to patients with hypercholesterolemia. Twenty-one percent reported taking a nutrition seminar and 41 percent read a nutrition text during the past year. Less than a third had taken a nutrition course after medical school; half had taken such a course during medical school. Over 46 percent achieved a perfect score on nine knowledge questions regarding dietary fat. Only 35 percent identified the latest American Heart Association nutrition education effort. Seventy-four percent said they ate chicken or fish instead of red meat three or more times a week. Over 80 percent selected exercise, weight reduction, and low fat diets as the most important treatment types. Physicians continue to have limited knowledge of nutrition and should be encouraged to make greater use of dietitians as consultants. PMID- 20841019 TI - "US Planning Prevention for Them": The Social Construction of Community Prevention for Youth. AB - Recently, prevention programs for youth have been aimed at the social spheres presumed to influence health behavior decisions. Community-level programs have emerged as part of this trend. Communities are, however, dynamic, complex, and fluid. Describing community prevention efforts within the bounds of "normal" science has rendered invisible certain important features. We combined open- and close-ended research methods to study the grassroots prevention efforts of ten communities in the upper midwest. Three basic questions formed our inquiry: 1) how were community prevention actions constructed or planned?; 2) toward whom were these actions aimed?; and 3) what were the major success and problems in carrying out prevention actions? A central finding was the existence of an automatic yet tacit "filtering" process whereby certain people became involved in prevention while others did not. This "us versus them" pattern was expressed as a major barrier to the effectiveness and sustainability of community prevention efforts. Existing as informal, "everyday" knowledge, this problem has largely been rendered invisible by the heavy reliance on close-ended, "check the box" communication between the researcher and the researched. PMID- 20841020 TI - Improving the home management of childhood diarrhoea in bolivia. AB - This article reports on a rapid assessment of beliefs and practices related to child diarrhoea, conducted in the city of El Alto, Bolivia, and discusses its utility for developing communication activities aimed at improving home care of children with diarrhoea. PMID- 20841021 TI - The political economy of health: a useful theoretical tool for health education practice. AB - Political economy is a broad theoretical framework which can help health educators better understand the many economic, political, and socio-historical forces which shape contemporary health problems, and our approaches to these problems. Its attention to the dynamics of race, class and gender, as these interact to effect the lives of individuals and broader social groups, makes a political economy approach an important supplement and complement to other macro and micro level theories at the base of health education practice. This article defines political economy, highlighting several of its key theoretical assumptions and describing their relevance for our understanding of health issues. Implications and applications then are provided demonstrating the utility of a political economy perspective in such diverse areas as occupational health education, physician-patient interactions, grass roots organizing and self help among African American women, and health care reform. PMID- 20841022 TI - Factors Associated with the use of SSS Among Mothers in Nsukka Zone of Enugu State, Nigeria. AB - The study was designed to identify factors influencing mothers' use of SSS in the management of diarrhoea in children. A survey questionnaire was used and a total of 652 mothers drawn from both rural and urban communities were interviewed. The two perceptual factors, perceived seriousness of diarrhoea and perceived efficacy of salt sugar solution (SSS) were found to relate significantly with SSS use. Similar associations were found between knowledge of SSS preparation and beliefs about diarrhoeal illness causation. Of the three demographic factors tested, only one, education, showed potential for influencing SSS use. Religion and residence (rural, urban) were not found to be predictors of SSS use. The positive association of clinic use (as measured by place where the mother gave birth to her last child) with SSS points to the need to improve the quality of facility based health education with special focus on improving knowledge of SSS preparation procedures and perception of SSS efficacy. PMID- 20841023 TI - Assessing the self-reported health risks of urban street children working in the dominican republic. AB - Children throughout the world work on street corners selling newspapers, washing car windows, shining shoes, or hustling anything that will earn cash for the day. Many of them start early in the morning, work all day without attending school, and then return home late in the evening. A 26-item questionnaire was given to a sample of forty children working the streets of Santo Domingo. Examination of the responses revealed that the mean age was 14.5 years. Over 92 percent of the children had contact with a relative in the past thirty days. Fifty percent responded that they were victims of physical abuse at home, while 97 percent said they believe they are healthy. Qualitative data on family, friends, and future goals are discussed. PMID- 20841024 TI - Preventing HIV Infection Among Juvenile Delinquents: Educational Diagnosis Using the Health Belief Model. AB - The purpose of this study was to use an enhanced version of the Health Belief Model as a conceptual framework to describe health beliefs and safer sex intentions for HIV prevention educational needs of juvenile delinquents between the ages of thirteen to eighteen years incarcerated in state supported training schools in Ohio. An accessible sample (n = 452) of juvenile delinquents from four of nine institutions was the study population. Juvenile delinquents in this study were at high risk for HIV infection. They reported low rates of safer sex intentions. Rates of perceived barriers to condom use and perceived social barriers to safer sex were high and consistent with low rates of safer sex intention. Rates of self-efficacy for condom use were high but inconsistent with intentions. While a majority of subjects reported self-efficacy for discussion of sexual histories, a larger majority reported low efficacy for disclosing previous high-risk behavior. This suggests that discussion of sexual history with a partner may not be effective in reducing risk among this population. The primary source of information about HIV was the mass media. HIV prevention programs for juvenile delinquents should consider the current health beliefs of this high risk, hard-to-reach population. PMID- 20841025 TI - AIDS communication: what predicts health professionals' decisions? AB - Theoretical models from the persuasion/health communication literature have identified many components such as message appeal, audience attributes and channel characteristics that need to be addressed as a prerequisite to designing any successful AIDS communication program, but a variety of models compete in the marketplace of ideas, and many are divergent with respect to focus and to specific recommendations. The question then arises of what theoretical perspectives predominate in AIDS communication practice and why. This article explores the decisions and theoretical perspectives behind the thinking of health and health communication specialists who were asked to design an AIDS communication program aimed at a target audience of students. Results show two different theoretical predispositions: a fact-based formal teaching approach and a skills-oriented approach using interactive methods. Preference for one of these over the other is predicted by level of education, religion, and institutional affiliation. PMID- 20841026 TI - The process evaluation of a dutch community health project. AB - This article reports on the design and results of the process evaluation of the Dutch community project "Healthy Bergeyk." The major goal of this project was a reduction in cancer-related risk behavior prevalence, especially smoking and high fat consumption. The project was designed to integrate health education theory and methods with community organization principles. An intersectoral local project group was formed for project implementation. The main objectives of the process evaluation were to assess what was done and how this was evaluated by participants and leaders of activities, project group members and the community in general. Data were gathered throughout the implementation period using minutes of meetings, registration forms, pre-structured telephone interviews, written questionnaires, and semi-structured interviews. Community members were involved in the data collection. The results indicate that the project group organized many health activities in their community in a short time period. Positive elements of the project concern the intersectoral co-operation and the workbook supplied to the project group. Time pressure and limited possibilities for community initiatives were the main negative aspects of the project. The implications of the findings for both the community health project and the process evaluation are discussed. PMID- 20841027 TI - Gender differences in the sexual behavior of latino adolescents: an exploratory study in a public high school in the san francisco bay area. AB - PURPOSE: The purpose of this study was to examine factors associated with sexual behavior among urban, first-generation Latino adolescents. METHODS: Data were collected with self-administered questionnaires on 176 (98 girls and 78 boys) Latino high school students between the ages of Fifteen and nineteen years, of whom 76 percent were born in Latin America and 34 percent had lived in the United States for two years or less. The outcome variables measured three levels of sexual activity, defined as: sexual abstinence, "making out" (kissing passionately, or kissing "using one's tongue"), and sexual intercourse. The key predictors were gender and acculturation. Other variables included information on socio-demographics, self and body-image, college aspirations, and family structure/relationships. Stratified analysis was conducted for each gender. RESULTS: Twenty percent of boys and 27 percent of girls were abstainers. Whereas girls were more likely than boys to "make out" only (47% vs. 26%), boys were more likely to engage in sexual intercourse (54% vs. 26%). For girls, there was a negative association between making out and maternal punishment, feeling close to both parents and paternal love. Sexual intercourse was inversely associated with having educational goals beyond high school and presence of parental love, and positively correlated with age and maternal communication about sex. In boys, the predictors of "making out" were feeling close to both parents and Spanish language spoken with friends, and for sexual intercourse the significant predictors were feeling close to both parents, presence of an older sister, and body-image. CONCLUSIONS: The results indicate that family structure and relationships, personal characteristics, and acculturation play important but different roles in the sexual development of Latino adolescent girls and boys. Sex education curricula should take these gender and family influences into account. PMID- 20841028 TI - The Viral Model for AIDS: Paradigmatic Dominance, Politics, or Best Approximation of Reality? AB - In 1981, a non-infectious disease hypothesis was offered by the Centers for Disease Control to explain the cluster of atypical pneumonias which had appeared among gay men in the United States. Although quickly supplanted by the now widely held viral hypothesis and largely ignored by professional and media sources, that view has persisted. This article raises the question of why one explanation for the epidemic of immune system suppression has dominated the discourse on AIDS, despite the anomalies attributed to it by the proponents of other viewpoints. Alternative responses to the question are set forth drawing upon literatures in the philosophy of science and public policy formulation. Some discussion is provided of what the consequences may be if one of the contrarian hypotheses proves to be the closer approximation to the truth about AIDS etiology. PMID- 20841029 TI - Using Theory to Design an Intervention for HIV/AIDS Prevention in Farm Workers in Rural Zimbabwe. AB - A variety of primary prevention strategies are used in HIV prevention programs in Africa. However, these are often developed through intuition and the theoretical basis for many interventions is limited to the knowledge/attitude model. This article illustrates how research findings from a base-line survey are combined with Paulo Freire's social change theory and the Ecological Model for Health Promotion to develop a participatory intervention for HIV/AIDS prevention in farm workers in Zimbabwe. The article addresses the need to focus attention on the process of change at the interpersonal level, organizational and policy levels of the community. Dialogue is central to the range of strategies proposed for the intervention. The effect will be measured through process and outcome evaluation. PMID- 20841030 TI - The perth amboy community partnership for youth: assessing its effects at the environmental and individual levels of analysis. AB - This article describes the Perth Amboy Community Partnership for Youth (PACPY), a comprehensive community-based intervention designed to reduce risk factors for alcohol, tobacco, and other drug use among Latino youth. The intervention is grounded in the principles of community empowerment and participatory education, and attempts to facilitate within the community a broad understanding of the societal factors that increase risk of drug use and related problems among young people. PACPY attempts to bring about change at both the individual level and the environmental level within the domains of the school, the family, and the community. The present article describes the types of interventions introduced through PACPY within each of these domains, and examines their impact on individual and environmental changes in the use and availability of tobacco products. We conclude with a discussion of some of the methodological issues that have arisen over the course of the evaluation, and outline the changes that have occurred in our underlying conceptual framework. PMID- 20841031 TI - The role of community health workers in the management of essential drugs. AB - The ability to provide essential drugs not only fulfills part of the primary health care (PHC) duties of the community health worker (CHW), but also helps legitimize the role of the CHW in the community. Essential drugs are often routed through relatively inefficient government structures before reaching the CHW, thus creating problems of regular supplies and timely distribution. Few examples are said to exist where CHWs take charge of essential drug programs to the fullest: planning, purchasing, and maintaining their own stocks. An association of CHWs in Idere Nigeria has been doing just that since 1986-87. Self-assessment of this scheme was stimulated by several factors including rising wholesale prices and subsequent community member reluctance to pay for medicines. In addition, the local government had begun its own CHW training in line with national PHC guidelines and priorities. It became possible to examine the two systems side by side. The main variable used to determine system functioning was whether CHWs had replenished their village drug box stocks in the previous year. Among five factors tested, group (Idere CHW association member or local government trainee) sex, age, residence (town or hamlet), and perceived willingness to pay by villagers, only group was shown to be significantly associated with stock replenishment purchases. Most (63%) of the independent Idere group had replenished their stocks compared to 35 percent of local government CHWs. Cultural factors such as elders' predisposition to provide free service to those in need were also identified. The Idere association used this information to suggest ways of improving supervision, support, and purchasing so as to strengthen their service to the community. PMID- 20841032 TI - Maternal Exhaustion as an Obstetric Complication: Implications of TBA Training. AB - Maternal exhaustion is a common diagnosis for Guatemalan women referred to community hospitals by traditional birth attendants (TBAs). Maternal exhaustion is associated with prolonged labor, bearing down for > 2 hours, and oxytocin administration by TBAs. The strongest association is with prolonged bearing down which is a practice commonly encouraged by Guatemalan TBAs. Training TBAs in instructing the mother not to bear down until she has an urge to push and not to administer oxytocin to their patients had little impact in curtailing these practices. This lack of effect may be due to cultural beliefs about appropriate birthing practices and their importance for the women in the community. PMID- 20841033 TI - Theory and action for effective condom promotion: illustrations from a behavior intervention project for sex workers in singapore. AB - Acquired immunodeficiency virus (AIDS) and sexually transmitted diseases (STD) control programs targeted at sex workers have focused on condom use. Reasons for non-condom use among female brothel-based sex workers in Singapore were found to be low self-efficacy, lack of condom negotiation skills, and barriers such as fear of annoying clients. Green's PRECEDE framework and Bandura's self-efficacy theory were applied to develop a project aimed at equipping sex workers with negotiation skills, overcoming barriers to condom use, and gathering support from brothel keepers and peers. The experimental group showed significant improvements in negotiation skills and outcome behavior of always refusing sex without a condom, that were supported by a decline in gonorrhea incidence. This article describes the application of behavior change and health education theories to achieve reduction in gonorrhea risk. PMID- 20841034 TI - Linking implementation to outcomes: evaluation of a community-based breast and cervical cancer screening program. AB - An implementation analysis of the first eighteen months of the Maryland Breast and Cervical Cancer Program examined the variability among participating local agencies in the extent of screening services delivered; local program implementation processes; and the relationships between extent of screening and the local level processes. The study used: 1) a mail and telephone survey of local health departments (LHD, N = 24) and 2) state program surveillance data, with correlational methods. OUTCOMES MEASURED: 1) "Penetration," the proportion of the target population screened; and 2) "Efficiency," the number of women screened per program staff member. Categories of implementation variables were: 1) Environment, 2) Staffing, 3) Collaboration with community organizations, 4) Outreach, 5) Provider variables, 6) Relationships with State and LHDs, 7) Organizational variables, and 8) Service delivery. Results showed wide local variability in screening levels. Availability of local resources; provider involvement; success of community linkages; and local health department readiness showed relationships with the extent of local screening. Studying implementation is needed to improve the effectiveness and efficiency of community-based programs. PMID- 20841035 TI - Was the intervention implemented as intended?: a process evaluation of an AIDS prevention intervention in rural zimbabwe. AB - End-point evaluations are still the most commonly used method of assessing the success or failure of interventions. This article describes how a process evaluation was used to measure "what happened" during an HIV/AIDS prevention program for farm workers in Zimbabwe. The intervention was developed according to the Paulo Freirian theory of Social Change and the Ecological Model for health promotion. The stages of the intervention were cyclical; in the first stage innovative methods were used to encourage appraisal of vulnerability to HIV/AIDS through activities which raised critical thinking and dialogue. In the next phase, emphasis was placed on developing cognitive and attitude change in the target group. Self-protective behavior was encouraged through condom use and an increase in self-efficacy with respect to negotiating safe sex, especially among women. In the last stage of the intervention, efforts were made to create a climate for maintenance of behavior and socially responsible action within the community. The process evaluation provided valuable insight into factors which, when aggregated, provided an overview of a program whose successes and failures may well have been determined by issues outside the scope of the intervention. The effect of seasonal fluctuations of labor, income, and farming activity on program activity, patterns of STD, and condom demand were marked. This leads back to the researchers' initial question: "Was the intervention implemented as planned?" and the answer-only partially. PMID- 20841036 TI - Social and behavioural baseline for guiding implementation of an efficacy trial of insecticide impregnated bed nets for malaria control at nsukka, Nigeria. AB - Insecticide impregnated bed nets are being tested in many tropical areas as a major tool to control malaria. In a few African countries, there is a history of local bed net production and use, while in most others, ownership of commercially produced nets is rare due to high costs relative to local income. Such variations in pre-existing bed net use behavior must be studied prior to designing new intervention trials. A "baseline" diagnostic study in Nsukka Local Government of Enugu State, Nigeria, found that local beliefs about malaria causation, which include heat from the sun and hard work, may reduce the perceived efficacy of bed nets as an appropriate malaria control action. While the belief that mosquitos can cause malaria increased with level of formal education, the study also documented that educated people simultaneously hold both indigenous and scientific perceptions about malaria. Although the project provided bed nets, curtains and residual house spray for free, long-term sustainability may be influenced by the main constraint to current ownership of a bed net, i.e., cost. Issues, such as concern about feeling hot under the nets, a tendency to sleep outside during the hot dry season, and variations in people's ideas about what constitutes a malaria episode, point to the need to monitor the bed net intervention. This is recommended as a means of learning how people perceive the efficacy of the nets, whether they use them correctly and whether the intervention can be sustained and integrated into local primary health care programs. PMID- 20841037 TI - Alcohol and Drug use by Students on a University Campus in Thailand. AB - This survey was conducted with 501 students from a university in eastern Thailand. The questionnaire was based on the Core Alcohol and Drug Survey designed to survey U.S. higher-education students throughout the United States. It has been translated into Thai language with some modifications in content. Stratified cluster sampling was done based on year in attendance and Faculty (School) affiliation. Two-thirds of the respondents were female. Results showed that males are more involved in alcohol and drug use than females and suffer more consequences as a result. Although Thai students do not use these addictive substances as frequently as U.S. students, there is still cause for concern regarding alcohol use. The number of family members reported by students as having a problem with alcohol or drugs is especially significant. PMID- 20841038 TI - Child survival and baseline surveys: a description of literacy rates of women of child bearing age in abia and imo States, Nigeria. AB - The results of a literacy need assessment conducted in eight autonomous communities, four from both Abia and Imo States, is presented and discussed. Data were obtained via survey interview and administered to 209 and 235 subjects respectively for Abia and Imo States. The information was collected to form a baseline level of operation prior to the Literacy for Health Intervention implemented by Africare/Owerri and the Imo State Ministry of Health. Results suggest both similar and varied trends regarding literacy abilities of participants and their attitudes regarding adult literacy instruction in the samples from both communities. This study emphasizes the literacy needs items of the survey. Findings support the need for literacy for health interventions in these areas and confirm the need for interventions to improve literacy skills and enhance the quality of life of families living in these communities. It is anticipated that data obtained regarding baseline assessments and interviews may be used to examine the long-term effectiveness and impact of literacy for health care activities under the auspices of child survival projects. PMID- 20841039 TI - Establishing health status indicators by surveying youth risk behaviors of high school students in the dominican republic. AB - The purpose of this survey was to determine the health-risk behaviors among high school students in the Dominican Republic. Samples were taken from communities with an industrial base and an increasing population (n = 1175). The communities under study had dissimilar population sizes (i.e., 5,000, 30,000, 50,000) and were located in various geographical locations. Frequency data are compared by gender and population differences for high-risk health behavior indicators associated with urban migration. We found significant differences in tobacco, alcohol, and crack use among the different population sites, with higher rates reported by the more populous communities. Boys reported more fighting and sexual activity. Girls reported higher rates of suicide ideation and attempts. These results can be used to 1) help focus on those behaviors rooted during the school years that most influence health, 2) monitor those behaviors by establishing baseline data, and 3) supply data that are comparable with recognized categories of high-risk behaviors. PMID- 20841040 TI - Women and the Risk of HIV Infection in Nigeria: Implications for Control Programs. AB - AIDS is a growing public health problem in Nigeria. Since 1984 when AIDS was officially reported in the country, the number of persons infected with HIV and those with AIDS continue to increase rapidly. This trend is likely to persist in the coming years because, in spite of a high level of public awareness about AIDS, many Nigerians continue to engage in behaviors, such as unprotected sexual networking, which would raise their risk of exposure to HIV. Women in Nigeria are particularly susceptible to HIV infection and its consequences because existing sexual norms place them at a disadvantage in that they are unable to control the sexually risky behaviors of their spouses or take action that would limit their risk of exposure. The current economic crisis in Nigeria has also caused many women to go into full-time commercial sex work or enter other occupations in which they are predisposed to being lured or forced to having sexually risky relationships with men. Unfortunately, the current AIDS control intervention in Nigeria do not address these issues. This article draws attention to the biological, cultural, and economic conditions which make women in Nigeria susceptible to HIV infection and recommends how to overcome them. PMID- 20841041 TI - Spanish language television news portrayals of youth and violence in california. AB - Language is central to Latino1 culture and to the current multicultural multilingual realities of the United States. This exploratory study takes those who may be unfamiliar with Spanish language television news through a comparative analysis of television portrayals of youth and violence. Findings from this ethnographic content analysis reveal that local Spanish language television news stories on youth and/or violence are framed thematically (with a social, political, and economic context) three and a half times more often than English language local television news. This study highlights the importance of engaging the Spanish media in the future health promotion efforts. Public health advocates can share information related to the socioeconomic factors associated with violence and outline policy and programmatic solutions with Spanish language journalists. PMID- 20841042 TI - Perceptions and use of the Male Condom Among African American University Students. AB - This study examines differences in condom use among female and male African American young adults; investigates how perceptions of contraceptive characteristics vary by gender; and determines which combination of contraceptive attitudes best discriminates between condom users and nonusers. In a classroom setting, 244 African-American college students completed the Contraceptive Attributes Questionnaire-2. Significantly more men than women reported condom use, both actual and intended. Women and men differed in the importance they place on contraceptive characteristics and in their perceptions of both the condom and the contraceptive pill. Finally, perceived contraceptive attributes significantly differentiated men and women who used condoms from those who did not and predicted those who reported that they definitely intend to use condoms from those who do not. These findings suggest that prevention efforts to promote condom use must be gender specific as well as culture specific if they are to be effective. PMID- 20841043 TI - Child care practices of mexican-american working mothers: a pilot study. AB - There is scarce information on child care strategies among Hispanics in the United States. The purpose of this pilot study was to identify and understand child care practices in a sample of forty-five Mexican-American working mothers living in northern California by means of conducting six focus groups. Results included data on child care selection, problems, and preferences. Results also expose myths based on ethnic stereotyping that have obscured the understanding of this issue. Suggestions for further research are discussed as well as child care policy considerations. PMID- 20841044 TI - Breast self-examination among female students in tertiary institutions in a nigerian city. AB - The breast self-examination (BSE) of 690 female students in two tertiary institutions of a cosmopolitan city was investigated. The students were interviewed about their BSE practices including variables that might have influenced their BSE behavior. Results revealed that although 84.6 percent of the respondents were aware of BSE, 65.1 percent did not know the correct step and sequence of BSE. While respondents attitudinal disposition to BSE was generally favorable, only 11.6 percent of the respondents correctly practiced BSE in the last six months and standing before the mirror position was the most popular technique employed (29.6%). In addition, previous breast problems were found to affect BSE but not history of breast cancer in the family. Of the 234 respondents (33.9%) who had never practiced BSE, 23 percent attributed it to lack of knowledge and 18 percent felt it was not important. Based on these findings we recommend that school based BSE educational programs should be organized with the participation of student and non-student associations. PMID- 20841045 TI - Evaluation of a drug prevention program for young high risk students. AB - This article provides results of an evaluation of the effectiveness of a multi faceted drug prevention program for high-risk elementary and younger junior high school students. Participants were selected for the program by public school teachers and guidance counselors. These students participated in a series of meetings where they practiced skills to help them effectively handle pressures to use drugs. Researchers evaluated changes in participants' levels of knowledge about drugs, attitudes about drug use, and self-concept. Results indicate that young high-risk students will benefit from multifaceted drug prevention programs that teach life skills. PMID- 20841046 TI - Which prevention strategies for child pedestrian injuries? A review of the literature. AB - In 1992, motor vehicle-related injury was the leading cause of injury-specific death in the United States for children aged zero to fourteen years. In the five to nine years age group, childhood pedestrian injury was exceeded only by motor vehicle occupant injuries as the leading cause of death. The prevention of these injuries is a multifactorial problem involving individual characteristics of the child, environmental design, and the mutual dependence between the child and his or her environment. This article considers the plethora of descriptive and analytical research and proposes suitable strategies to reduce the rate of child pedestrian injury. PMID- 20841047 TI - Improving primary school teachers' ability to promote visual health in ibadan, Nigeria. AB - Primary schools in developing countries, even in urban centers, lack general school health personnel as well as eye-care professionals. In this situation pupils' visual acuity problems may often go undetected, setting the stage for poor performance in school and later in life. Students and staff of the African Regional Health Education Centre in Ibadan, Nigeria worked with primary school teachers in one traditional poor inner-core community of Ibadan to identify their willingness to undertake visual acuity (VA) screening training and their knowledge about eye care and VA. Nineteen teachers participated in a fifteen-hour in-service training course based on their stated needs. After training they were able to preform VA screening and also showed significant knowledge gains about eye care. A six-month follow-up visit found that 322 pupils had been screened, of whom forty-two had visual acuity problems. Parents of half of these pupils followed through with recommended referrals, and teachers assisted all with problems to find more appropriate classroom seating arrangements. This pilot project shows that teachers can become effective primary care workers, but that continuing education programs must be organized by school authorities to prevent deterioration in knowledge and interest in school health. PMID- 20841048 TI - Health promotion outreach for rural family physicians: a feasibility study. AB - This project examined the feasibility of using an educational representative, modeled in part on a drug detailing representative, to increase health promotion counseling by rural family physicians in east Texas. The physicians were offered, at no charge, materials for patients and training for themselves and their office staff on patient education regarding smoking, weight problems, sedentary living, and stress. Visits from the representative were accepted by 76 percent of the physicians, about half of whom requested training for themselves and/or their office staffs. A high degree of satisfaction with the training was expressed by trainees in follow-up interviews. Pretest data indicated that the physicians were using at least one counseling technique before the introduction of the intervention. Posttest data suggested that use of more effective counseling techniques and materials increased. Use of an educational representative when travel time and costs are minimized appears to merit further exploration. PMID- 20841049 TI - An HIV/AIDS Awareness Prevention Project in Sri Lanka: Evaluation of Drama and Flyer Distribution Interventions. AB - An evaluation was done on an AIDS Awareness Project targeting the West Coast of Sri Lanka. Dramas, performed primarily by volunteers, depicted the causes and consequences of HIV/AIDS. Flyers illustrating specific facts about HIV/AIDS were given at the dramas and at specific sites, such as bus stations. A pencil and paper pre-post design was used to evaluate the dramas and revealed that the primary respondent was an educated male who was very knowledgeable about basic HIV/AIDS information and had learned this primarily from the media (television and newspapers). Changes in attitude occurred as a result of the intervention, with respondents becoming more aware of their susceptibility to the disease and more willing to seek out advice from the Buddhist clergy if diagnosed with HIV/AIDS. The flyer distribution intervention revealed that brochures that address various levels of literacy may be more accepted by the general public. PMID- 20841050 TI - Perception of malaria infection in two rural communities in Nigeria. AB - This investigation was concerned with how and when parents and other members of two rural communities (Awi and Ikot Edem Odo) in Cross River State, Nigeria, recognized malaria infection, what they do to prevent the disease, and what triggers their treatment seeking behaviour (cue to action). The psychological and sociocultural contexts of these complex factors were considered. Focus group discussion (FGD) techniques were employed. A total of eight groups selected using theoretical sampling matrix method were categorized. A thirty-three-item FGD battery of guide questions was used. Information and data on knowledge, attitude, and practice (KAP) and the perception of malaria infection were generated. Analysis showed that both communities recognized the symptoms, morbidity and mortality of malaria infection in both adults and children. The mosquito vector was identified among numerous other causes of malaria. The pervasive role of ethnomedical sociocultural, and belief systems on KAP and perception of malaria were revealed. Both communities will likely benefit from health education interventions which recognize the belief systems of the two communities. PMID- 20841051 TI - The Development and Implementation of a Cognitive-Based Intervention Aimed at Culturally Diverse Women at Risk for HIV/AIDS. AB - The development and implementation of a culturally and gender sensitive, cognitive behavioral-intervention program aimed at preventing high-risk sexual and drug-use behaviors among culturally diverse women at risk for HIV/AIDS is described. The intervention stressed education, cultural/social barriers to change, and assertiveness/negotiation skill building. Methodological problems and their solutions are presented. The article stresses ways to recruit poor at-risk women, how to reduce attrition using incentives such as providing transportation, having food and child care at the intervention sessions, financial rewards, and a tracking system that includes many friends and family members of the participant. Preliminary findings indicated that the intervention was successful in promoting knowledge about HIV/AIDS. At the end of the six-week intervention protocol, the intervention group compared to the control group showed significant improvements in HIV/AIDS knowledge items dealing with clinical aspects of the disease, transmission knowledge, and partner risk knowledge. Knowledge, along with motivation to reduce risk and negotiation skills are essential in changing behaviors that put one at risk. PMID- 20841052 TI - AIDS prevention programs: a critical review. AB - A critical review of the content of those articles published during the 1990s in this Journal provides a diversity of views about the kinds of theoretical models and typologies that are applicable to HIV/AIDS educational interventions. It also suggests the crying need to focus more of these social and behavioral models in a cultural context. This article provides a brief overview of AIDS in the U.S. and international settings, a description of the complexity of application of social and behavioral change models in their present context, and a review of the three categories of articles which have been published in the Journal: dogma, dissent, and innovation. PMID- 20841053 TI - A program to reduce cardiovascular and cerebrovascular disease in the czech republic: design and methods of the healthy dubec project. AB - Cardiovascular Disease (CVD) morbidity and mortality rates in the Czech Republic are among the highest in the industrialized world. Due to the substantial burden CVD plays on the health and well being of the Czech society, a variety of health promotion/disease management strategies to reduce CVD risk need to be designed and implemented. A project that combined community-based health education programs designed to address pervasive perceptions and cultural traditions that influence lifestyle factors, with secondary and tertiary prevention clinical strategies to aggressively treat high-risk individuals was recently conducted in Dubec, a small Czech community. This article describes the methods used in this project (i.e., the Healthy Dubec Project) which took American-based technology and experiences in community risk reduction methods and clinical management strategies for high risk patients and adapted them to fit the Czech people and their attitudes about CVD risk behaviors. PMID- 20841054 TI - Tai chi chuan, an alternative form of exercise for health promotion and disease prevention for older adults in the community. AB - Thirty-six men and women age fifty or older participated in a study to examine the health effects of Tai Chi Chuan on older adults in a community setting. Participants in the experimental group (n = 23) received thirty-two one-hour sessions of Tai Chi Chuan instruction in sixteen weeks. Health effects were determined by measuring heart rate, blood pressure, muscle tension, anxiety, and flexibility. Results of data analysis indicated participants received training in Tai Chi Chuan had a greater improvement in flexibility and muscle relaxation than participants who did not receive training. In addition to retaining improved flexibility and muscle relaxation, participants in the experimental group also showed significant improvements in blood pressure, anxiety scores at the follow up session. These results appear to support the beneficial effects of practicing Tai Chi Chuan for health promotion and disease prevention for older adults in the community. PMID- 20841055 TI - Reproductive knowledge, attitudes and behaviour of secondary school students in akure, Nigeria. AB - Adolescents are subject to many life changes as their secondary sexual characteristics emerge. Contrary to parents' and society's wishes, these young people are more sexually active then previous generations and thus at greater risk of unwanted pregnancies, sexually transmitted diseases, and related problems. Adolescents enrolled in school have the potential opportunity to learn ways to prevent these reproductive and sexual health problems, but there is concern whether schools are living up to this challenge. Therefore, this study was designed to learn whether adolescents in secondary school in the Ondo State capital of Akure have reproductive health education and are practicing healthy sexual behaviors. The study was based on a sample of six of the twenty-eight secondary schools in Akure that fell under the jurisdiction of the Ondo State Post-Primary Schools' Management Board. Focus was placed on pupils in the final years of both Junior Secondary School (JSS 3) and Senior Secondary School (SSS 3). Overall, 30 percent of the young people reported having sexual intercourse: 21 percent of females and 38 percent of males. Also 39 percent in SSS 3 reported having had sex compared to 21 percent in JSS 3. Forty percent of students in coeducational school compared to 19 percent in boy's school and 8 percent in girl's school had sex. Respondents averaged only 11 points on a 33-point scale of reproductive health knowledge. Students in the senior classes and those in single sex schools scored higher. The mass media was stated to be the major source of reproductive health knowledge; only one-third reported that they had actually talked with someone about their reproductive health concerns. Attitudes toward pre-marital sex were more favorable among male students, pupils in mixed sex schools and those whose parents had lower levels of education. These findings suggest not only that the schools must take a more active role in providing reproductive health education, but that this should be done in the junior secondary years before most pupils become sexually active. PMID- 20841056 TI - Qualitative health research and health promotion at the local level. AB - The Municipal Health Service for Rotterdam area in the Netherlands has developed a health research strategy with special focus on qualitative methods. This article describes one of the first and most instructive cases in which this strategy has been applied: a local health study in "Feijenoord." The research in Feijenoord was carried out between 1989 and 1990 making it possible to look both at the short-term and long-term effects. Quantitative data were used to describe the neighborhood health situation. Qualitative data were used to expand on this description. The qualitative information was obtained from residents and workers in health care and welfare using focused interviews and nominal group interviews. The results and effects of the research presented were influential. The research started a train of activity that could not have been predicted, and of which the Municipal Health Service had little control at first. An important effect in the short-term was that, as bringer of unpleasant news, the Municipal Health Service was unfavorably regarded. In the long-term, the Municipal Health Service participated significantly in the activities set up within the health framework. After evaluating these effects it was possible to formulate the conditions for an effective use of qualitative methods in public health research. PMID- 20841057 TI - Sexual and AIDS-related knowledge, attitudes and behaviors of adolescents in sierra leone, west Africa. AB - A survey of 307 Sierra Leonean adolescents between the ages of thirteen and nineteen was assessed to determine their sexual and AIDS-related knowledge, attitudes, and behaviors. Results indicate high sexual activity rates among the sampled group; 89 percent of the males and 68 percent of the females had engaged in sexual intercourse. The mean age at first sexual intercourse was found to be 14.4 years for males and 15.1 years for females. Sixty-five percent of the males and 35 percent of the females reported having three or more sexual partners over their lifetime. Other findings included high rates of STDs and HIV/AIDS, low reported condom use, low reported use of other birth control methods, and low knowledge scores concerning pregnancy prevention, HIV/AIDS and STDs. Implications of these findings are discussed. PMID- 20841058 TI - A multi-city community based smoking research intervention project in the african american populatio. AB - OBJECTIVE: To carry out a community-based research approach to determine the most effective educational interventions to reduce smoking among African-American smokers. The intervention included preparation of the community, planning and developing a model of change, and developing a community-based intervention. The study population consisted of 2,544 randomly selected adult African-American smokers residing in four sites in the northeastern and southeastern parts of the United States. The research design provided a comparison of active intervention sites with passive control sites as well as low income and moderate income areas. MAJOR OUTCOME MEASURES: Point prevalence of non-smoking at the time of interview; Period prevalence of non-smoking at the time of interview; Period prevalence of quit attempts in the prior six months; Number of smoke-free days in the prior six months; Number of cigarettes smoked daily at the time of interview. RESULTS: Based upon a survey eighteen months after baseline data was collected, all four measures of cigarette smoking behavior showed a strong statistically significant reduction of personal smoking behavior among those receiving active interventions versus the passive group. On the basis of process variable analysis, direct contact with the project staff in the prior six months was significantly higher in the active intervention areas. There was only a small non-significant increase in personal smoking behavior in moderate income groups as opposed to low income groups. CONCLUSION: An analysis of process variables strongly suggests that, within this African-American Community, "hands on" or "face to face" approaches along with mass media, mailings, and other less personal approaches were more effective in reducing personal smoking behavior than media, mailings, and other impersonal approaches alone addressed to large audiences. PMID- 20841059 TI - Participation of South african youth in the design and development of AIDS photocomics. AB - In response to an increasing incidence in HIV prevalence among South Africa's youth, a group of interdisciplinary professionals have developed a series of photocomics to address issues around HIV/AIDS communication and sexually transmitted diseases. This article examines the theory behind the use of photocomics in health, and the way the stories work to influence behavior. Results from evaluation of the comics support their use as tools with which to increase information and knowledge while role modeling desirable behavior. Lastly, the article describes the participatory process by which youth were involved in the process of developing and producing the comics. This method of developing culturally relevant and appealing health media is recommended for use in future health promotion strategies that seek to transcend a narrower approach of provision of health information and work to address the social factors that influence youth's decision making. PMID- 20841060 TI - Sociocultural considerations in schistosomiasis control: focus group data from 3 egyptian villages. AB - Transmission, control, and prevention of schistosomiasis are linked with a range of individual and collective human behaviors, perceptions, and social and environmental conditions. The objective of this study was to describe the social and cultural factors related to schistosomiasis transmission in three Egyptian villages where prevalence rates of diseases are high. Data reported are based on focus group interviews collected among children and adults. Topics discussed were knowledge about disease, transmission behaviors (risky behaviors), risk perceptions, prevention behaviors (response to risk), symptoms, treatment behaviors, treatment satisfaction, knowledge of prevention, source of information, and more general concerns and grievances. Both adults and children were concerned about schistosomiasis, and were knowledgeable about disease symptoms, transmission, control, and risky behaviors such as swimming in canals or polluting their banks. The adults were concerned with lack of collective solutions such as limited piped water supply, little sewage control, and governmental responsibility to solve village health problems. Findings support the notion that schistosomiasis transmission and control must be understood as sustained by environmental conditions and patterned sets of behaviors that are culturally embedded, their alteration a key to changing schistosomiasis' long history and widespread prevalence in Egypt. PMID- 20841061 TI - Using distance education to educate and empower community coalitions: a case study. AB - This article focuses on a community activism program about the issue of youth tobacco control across fourteen communities. The article highlights an interesting and innovative methodology to provide staff development workshops to each community site where participants received consistent messages with preparation for coalition building and local action planning to address youth tobacco control issues. The article concludes with recommendations for educators considering the use of distance education technologies to educate and empower collective activism in a limited time period. PMID- 20841062 TI - A worksite strategy in coronary heart disease prevention. AB - A strategy in heart disease prevention at worksites was developed based on target group analysis on determinants of health behavior among Danish men. The target group analysis provided information on credibility problems and negative attitudes toward health education. Men operate with more knowledge types and direct their health behavior toward experiential knowledge rather than theoretical knowledge. The strategy aims at the needs of the target group by focusing on experiences and action-oriented information at individual and social levels. Supportive environments and policies within the areas of smoking, dieting, and exercising are sought to be established at the organizational level. PMID- 20841064 TI - Editorial: multiculturalism, racism and the training of public health professionals. PMID- 20841063 TI - Male involvement in the bangladesh family planning and reproductive health program. AB - Increasing the involvement of men in family planning and reproductive health program is a challenge which Bangladesh has begun to face. Encouraging their active participation as family planning method users of vasectomy, condoms, as well as their supportive partnership of contracepting women is the major goal of the national program. Evidence for national surveys indicates that male dominated decision making may not be the norm in Bangladesh. Rather, there is high agreement between couples about family size and family planning. Findings suggest that men know about family planning methods and many take an active role in the decision making process. Male attitudes were generally positive about contraceptive methods and also about having a small family. Women rarely mention their husband's disapproval as a reason for contraceptive discontinuation. Unfortunately neither men nor women seem to be sufficiently informed about the relative safety of menstrual regulation (MR) and often opt for traditional abortions. Men's knowledge of obstetric emergencies is minimal, consequently when they are called upon to make an emergency decision they often make an incorrect one. PMID- 20841065 TI - Dialogic education and the schemas to guide dialogue: an example from malaria research in Guinea. AB - This article first reviews the importance of dialogical education in general and in malaria control specifically. Dialogical education requires knowledge of how people think as well as what people think. Through a mutual appreciation of the educators' and learners' respective frame of reference, the intended learners may come to appreciate differences between the educators' and learners' viewpoints and the ways these differences may constrain understanding and acceptance of new knowledge and practices. Dialogical education is presented as a means by which all involved in health education (professionals and non-professionals, those educating on-the-job, and those doing it informally) may be involved in health education. The appropriate presentation of research findings is central to the task of preparing for dialogical education. This article then discusses the discovery and the presentation of a culture's schemas. Schemas are concisely stated formulations of cultural orientation. They are core principles and rules. The schemas of the intended learner are critical for the educator to know so as to educate in a dialogic mode, to motivate acceptance and understanding. The schemas for malaria held by the Fulani of Guinea, West Africa, are presented as a case in point for a presentation of research findings in a form that is concise, comprehensible, accessible, and useful for nourishing dialogical education. PMID- 20841066 TI - Condom use behavior: an assessment of United States college students' health education needs. AB - Descriptive studies regarding sexual activity and condom use among college persons have found that college students are particularly permissive and do not use condoms regularly. Within a social cognitive theory (SCT) framework, the present study determined the condom use related health education needs of college students. Data regarding condom use frequency, appropriateness of condom use, social support for condom use, perceived barriers regarding condom use, perceived social norm regarding the use of condoms, perceived outcomes of using a condom, and condom use self-efficacy were collected from 569 students enrolled in health, physical education, and recreation classes at a large mid-Western United States university. Results indicated a serious lack of consistent and appropriate use of condoms. Strengths and weaknesses of SCT scales were described. Women could improve on their physical and emotional outcome expectations of using a condom. Areas for men that could be improved include perceived physical and emotional outcomes of condom use, self-efficacy related to partner disapproval and embarrassment, and self-efficacy related to intoxicants. Several recommendations for college health education programs were made. PMID- 20841067 TI - Sexual behavior and knowledge of AIDS among female trade apprentices in a yoruba town in South-Western Nigeria. AB - This exploratory study was carried out among unmarried female trade apprentices in Ikorodu, a Yoruba town in south-western Nigeria, to identify sexual risk behaviors, assess knowledge on HIV/AIDS, and recommend an appropriate AIDS education program. Four focus groups were conducted to gain insight into the social-cultural and economic factors influencing sexual risk behaviors, followed by a survey involving 280 randomly selected respondents. Findings showed that many group discussants approved of premarital sex and believed that sex with multiple partners occurred mainly because of the economic difficulties encountered by female apprentices. Most of the survey respondents (70.9%) were sexually experienced, with age of first sexual intercourse ranging from eleven to twenty-two years. One hundred and fifty-five (78.2%) were sexually active; of these, 37.4 percent said that their last sexual encounter occurred because they could not resist the pressure put on them by their male partners, were under the influence of alcohol, were in need of money, and raped. Sixty percent of the sexually active respondents did not take any action to prevent STD or pregnancy during their last sexual encounter. Of the fifty-eight who did, 37.9 percent used the condom. Of those sexually experienced (45.3%) have had at least one STD symptom in the year before, half of them did not do anything about their condition; 37 percent practiced self-medication or received injections from quacks. Although 70.9 percent had heard about AIDS, many had limited knowledge about the non-sexual routes of HIV transmission. Appropriate intervention strategies were recommended to educate the apprentices. PMID- 20841068 TI - A qualitative investigation of alcohol drinking among male high school students from three communities in the cape peninsula, South Africa. AB - This article reports on a qualitative study using focus group discussions about alcohol binge drinking with tenth grade male high-school students. Groups were run separately with binge drinking and non-binge drinking adolescents in three different communities. The Theory of Planned Behaviour with two additional constructs was used to provide a theoretical framework for the semi-structured discussions and for the analysis of the data. Although the findings are complex some clear differences did emerge between binge drinkers and non-binge drinkers and between participants from the three different communities. The binge drinkers perceived positive outcomes from binge drinking, were embedded within a peer group culture of binge drinking, and found few obstacles of obtaining alcohol. The non-binge drinkers were more concerned with longer term life goals and were motivated to comply with family pressures not to drink excessively. The implications of these findings for preventive programs and for future research are discussed. PMID- 20841069 TI - Effects of a peer led intervention program on smoking prevention: a case example in Greece. AB - This pilot study evaluates the effects of a peer developed, smoking prevention program on the smoking behavior, intent to smoke, knowledge, and attitudes toward smoking of high school students. An experimental group of 237 first and second grade high school students (mean ages 12.2 and 13.2 respectively) from an Athenian school was compared to a control group of ninety students from the first and second high school grades (mean ages 12.1 and 13.3 respectively) in another school. A randomly drawn subgroup of thirty-seven student volunteers from the experimental group developed antismoking audiovisual material which they subsequently presented and discussed with the whole group. Findings indicated that this intervention significantly limited the increase of smoking behavior of the experimental group a year following the first assessment. However, intent to smoke in the future, attitudes toward smoking, and knowledge were not affected by the intervention. Results suggest that the intervention was partially successful in curbing experimental smoking in these adolescents. Implications of the findings are discussed. PMID- 20841070 TI - Cultural perceptions of diarrhea and illness management choices among yoruba mothers in oyo state, Nigeria. AB - Home management of childhood illness is a norm throughout most of the world. Decisions about treatment are influenced by cultural perceptions of the illness, and diarrheal illnesses are no exception. A group of 473 mothers and their pre school age children in rural communities outside Ibadan metropolis in Nigeria were followed over a two-month period. Data were collected on actual diarrhea illness episodes: mothers' names for these illnesses were recorded, and reported treatment actions were noted. Six major ethno-medical diarrheal illnesses were identified and were grouped broadly into watery diarrheas and dysentery-like diarrheas. Although few (40%) women used home-made sugar-salt solution (SSS) in case management, those who labeled their child's illness as a watery diarrhea were more likely to use SSS. Modern and herbal medicines were commonly and equally applied to both groups of diarrheal illnesses. While very few mothers reported decreased fluid intake by their children, many said the child had reduced appetite, especially if the child had a watery diarrhea. The findings indicate that twelve years after the national Oral Rehydration Therapy (ORT) Program was launched, few mothers practice the recommended actions of giving SSS, increasing food intake and avoiding drugs. Lack of attention to studies that describe the cultural basis for mothers' decisions could be part of the reason why the ORT has not been more successful. PMID- 20841071 TI - Evaluation of a learner-produced photocomic in South Africa. AB - The use of participatory research in developing culturally appropriate health promotion media is now universally recognized. However, although much has been written with respect to the effects of this process on the participants themselves, little evaluation has been conducted on their effectiveness with the larger target group. The photocomic "Between Us" was produced with South African youth to address the issue of communications as it relates to safe sex and non violent conflict resolution. This article considers its qualitative evaluation. The article first addresses the theory behind the comic's development, and its objectives. It then examines the qualitative results with respect to these objectives: the evaluation showed the comic to be successful in that it elicited identification among youth with the comic's characters and issues presented. This type of medium offers much potential as a Health Promotion tool to be used in educational settings. PMID- 20841072 TI - Physical activity levels and self-reported risk-taking behavior among rural Australian and american 7th-9th grade adolescents. AB - This study compares self-reported physical activities and selected health behaviors (i.e., participation in physical activity, alcohol and cigarette use, perceived level of energy, and satisfaction with body weight) of a sample of seventh and ninth grade adolescents from Australia and the United States. A modified version of the Personal Wellness Profile 400TM (PWP 400) was used to measure adolescents' participation in physical activity and health behaviors. Five of the seven items studied showed significant differences (p < .05). Ninety seven percent of Australian adolescents reported they engaged in physical activity long enough to work up a sweat four or more times per week, compared to 94 percent of U.S. adolescents. The Australian cohort, however, reported a significantly higher level of ever smoking (34.1% vs. 12.3%), and drinking alcohol during the past year than did U.S. adolescents (55.0% vs. 16.0%). Male adolescents demonstrated significant differences on five of the seven items measured. Australian males reported greater participation in physical activity, smoking and drinking, and reported they had higher levels of energy than did U.S. males. The female adolescents also demonstrated significant differences on five of the seven items measured, e.g., over 76 percent of Australian females reported engaging in strength exercises at least once a week compared to 59 percent of U.S. females, and only 23 percent of Australian females reported they were sedentary compared to 41 percent of U.S. females. Finally, the relationship between physical activity and involvement with risk-taking behaviors and health related attitudes for both samples was examined. Increased activity was associated with less smoking, more satisfaction with body weight, and perceived higher energy level for U.S. adolescents. Drinking alcohol was not associated with activity level for U.S. adolescents. For Australian adolescents there was no association between physical activity and risk-taking behaviors and health related attitudes. Future research should continue to examine cultural differences. PMID- 20841073 TI - Australian students' preferences for school-based smoking cessation programs. AB - Estimates of daily smoking as high as 15 percent by Year 10 students (average age 15) suggest there is an urgent need to focus attention on the formulation of school-based cessation programs for young smokers, as an adjunct to existing prevention focused programs which serve the majority of young non-smokers. The purpose of this study was to gather recommendations from student smokers (in the middle high school years, about 15 years of age) which may be used in the design of school-based smoking cessation programs. This study investigated the opinions of 2865 smoking and nonsmoking Year 10 students drawn from twenty-one metropolitan high schools in Brisbane, Australia. The majority of students, including smokers, were supportive of school-based smoking cessation programs. Smokers reported a preference for the program to be voluntary, to be accessible during school time, and facilitated by other students or non-teaching personnel. A clear preference for individualized attempts to quit over more structured or group programs was evident. The majority of smokers reported that they preferred to quit on their own. They, however, also recognized the value of assistance from a supportive friend or being in a group of students who helped one other. In general, male and female students expressed the same preferences regarding methods of quitting. Males, however, appeared more difficult to motivate and more skeptical of quitting programs. Specific ideas for identifying students who may have higher support needs when quitting are provided. PMID- 20841074 TI - AIDS concerns among adolescents attending seventh-day adventist high schools in trinidad and tobago. AB - The purpose of this study was to identify AIDS-related knowledge, attitudes, beliefs, and short-term behavioral intentions of adolescents attending five Seventh-day Adventist (SDA) parochial high schools in the Republic of Trinidad and Tobago. This is the first known research on AIDS to be conducted in parochial and specifically, SDA schools in the Caribbean and particularly, Trinidad and Tobago. Information gathered from this research will be useful in planning appropriate AIDS education and prevention programs for the schools represented in this survey. PMID- 20841075 TI - Vietnamese perceptions of community and health: implications for the practice of community health education. AB - This article examines the perceptions of community, community-based organizations, and their attributed influence on health and behavior. This case study is based on data from sixty survey questionnaires and forty-three in-depth interviews conducted with Vietnamese community residents, including a group of health workers. Some participants attributed the same supportive role and function to the community as a social unit ("cong dong") and the community-based organizations ("co quan cong dong"). Health was considered by far the most important component when compared to family, finance, and community. While the influence of the community on their own personal health was perceived as limited, significant influence was attributed to community expectations in personal behaviors. Findings are examined within the context of an evolving process of adaptation to a new environment, the role of culture as a barrier or facilitator for health promotion, and the limitations of the study. PMID- 20841076 TI - Jackson county partnership: developing an effective coalition. AB - The Community Partnership Demonstration Program allows a community to develop and carry out a long-range, comprehensive, and self-sustaining alcohol and other drug abuse prevention program. A case study that shows the use of coalition building to carry out a prevention program is presented. The case study is followed by a discussion of the principles involved in forming and maintaining a coalition. Discussion about using the coalition method for implementing health promotion and prevention programs in rural or underserved communities and the important role that health educators can play follow. PMID- 20841077 TI - Alternative healing and health education. AB - As new and unorthodox methods of health care become increasingly popular, more and more stories appear in magazines, television, and even professional journals. Advocates of alternative healing appear as conference speakers for lay and professional groups alike-including health educators. Such therapies appeal to a public eager to take control of their own health and bodies. Via the Internet, new ideas and treatments can spread through the population incredibly fast. The abundance of new healing techniques coupled with an interested audience and the wonders of mass communication present a challenge to the health educator. The author believes health educators need to be aware of trends in popular culture and new forms of alternative health care. Health educators should have the insight, by virtue of their training, to distinguish real from fantasy, science from pseudoscience. They need to become health information specialists and competent in operating the latest technology. Most importantly, health educators need to remain objective and keep an open mind coupled with a healthy degree of skepticism. PMID- 20841078 TI - The case of the mysteriously appearing child. AB - The story of how a family planning postage stamp managed to get pasted on several million envelopes in Taiwan. Its chronological unfolding illustrates the complexity of applying research findings to an ongoing program in a developing country setting. The need for involving program planners early in research development, for in-service staff education, for linkage between related agencies implementing programs, and for caution in using western theoretical orientations is considered. Suggestions for discussion are provided. PMID- 20841079 TI - Urban community health education in Africa. AB - African urban populations are growing at a fast rate. The resulting health problems pose a challenge to health education. A community development, self-help approach is recommended. Experiences of health educators-in-training in Ibadan, Nigeria, show this approach to be relevant if practitioners are able to creatively deal with certain community variables-community identity, internal integration, group orientation, external linkage and resource characteristics. At times students express concern about the relevance of this approach to the African setting. Their failures in applying the approach can be traced back to the western bias in teaching materials and the general educational system. The challenge to health educators is to provide training experiences with a cultural sensitivity which encourages students to work with the community as they find it and not how it should be according to a foreign textbook. PMID- 20841080 TI - Social ecology, human behavior and social change. AB - Individual and group responses to programs of planned social change are discussed from a social ecological perspective. Social ecology is defined in terms of how peoples' beliefs and ideas are related to behavior in response to organized efforts at individual, group and societal change. Health educators must understand how people organize and reorganize their social knowledge of the world, including how they define the world, how they interpret the meaning of events in their lives, how they determine their courses of action and how they ultimately choose to act. PMID- 20841081 TI - Typical activities of health educators in public and private settings in california. AB - Some typical activities of health educators employed in public and private settings in California are reported. These reports are based upon interviews with a number of directors of health education programs and the chairpersons of two university programs. Typical activities include the generalist role of rural health educators, the emphasis of urban health educators on health promotion programs, patient education as a major activity of health educators in medical care settings, and the continued commitment of health educators in occupational settings to community health education. The diversity of activities in which health educators in California are engaged suggests the outlook for the eighties is for many arenas for the practice of health education. PMID- 20841082 TI - Community Health Education in Rural Ghana: The Danfa Project-an Assessment of Accomplishments. AB - The Danfa Comprehensive Rural Health and Family Planning Project was a joint effort of the Ghana Medical School, the Ministry of Health, UCLA, and USAID. A health education component was developed as an integral part of program inputs during the initial conceptual phase of the project. As a result non-equivalent experimental and control areas were designated permitting an assessment of program impact during a five-year period (1972-1977) for which baseline and follow-up study data were available. A new cadre of community-based workers (Health Education Assistants) was developed from existing health personnel in the country, and trained in health education and multipurpose health work. Although the HEAs were found to have difficulty in bringing about changes in health practices when other support services were not available, they did have measurable impact on villagers' adoption of family planning methods and a number of specific health practices. PMID- 20841083 TI - Variations in health perception between black and white elderly. AB - In a sample of 414 residents of public housing for the elderly, health perception is significantly lower among Black residents than among Whites. The relationship of health perception to several measures of objective health status, to cultural background, to social participation, and to morale is analyzed separately for the two ethnic groups. The relationship of measures of health to health perception is more direct among Whites than among Blacks, except for an Index of Daily Well Being, in which the relationship is similar for both groups.Social participation also influences health perception. With Blacks, participation in church-related activities is the most direct influence. While health perception is related to morale, life orientation (an index of morale) is higher for Blacks than for Whites.The implications for health education professionals seem to lie in the lack of direct links between objective measures of health and self-perception of health for Blacks. The need for health education, so that there may be a realistic appraisal of one's own health condition, is shown here. The relatively low educational level of many older citizens, especially elderly Blacks, suggests that newspaper releases are not an adequate tool for health education for the elderly. PMID- 20841084 TI - Factors in consistency between attitudes and behavior: implications for policies and programs. AB - The paper deals with the factors which affect contraceptive attitudes, behaviors, and the relationship between the two. The analysis is based upon original survey data from 2,446 women in Venezuela and related literature. The results suggest that both positive attitudes and contraceptive accessibility are major determinants of contraception but at the aggregate level neither has a decisive advantage over the other. The three best predictors of contraceptive use are: specific contraceptive attitudes, social support, and accessibility of contraceptives. Their impacts on behavior are direct and additive; however, their impacts vary significantly by education and number of living children. In general attitude change strategy is more effective with younger women while improving accessibility affects older women more often. Implications for policy and programs are presented. PMID- 20841085 TI - Research Utilization in Taiwan's Family Planning Program. AB - This paper deals with why the applied research carried out in the Taiwan family planning program facilitated the planned program of social change - both in the productive integration of research findings into community health education action programs and in the dissemination of these ideas to other Asian countries. A summary of the factors that assisted or hindered research utilization and an analysis of some of the especially favorable factors in the Taiwan situation are presented. The viewpoint presented is that of the Taiwan Provincial Institute of Family Planning Director and his former resident program advisor. PMID- 20841086 TI - Regionalization of cancer control efforts in the u.s.a. AB - The Johns Hopkins Oncology Center, one of the first of the nation's twenty-one Comprehensive Cancer Centers, established a cancer control program to mobilize resources to improve patient care and prevent the occurrence of neoplastic diseases. Initial efforts were based on the results of a series of investigations conducted in four communities. Findings from these studies were then converted into a series of programmatic interventions. The strategy included integrated approaches to creating a community education program within the overall effort. PMID- 20841087 TI - Modernizing approaches to public health training: a case example. AB - The plans, materials, content, methods, evaluation and conceptual foundations of a "training of trainers" session in a S. E. Asian country are presented in an unusual simulation format. The session was designed to create interest, awareness, and positive attitudes toward using alternatives to lecturing among ninety participating public health trainers. This article illustrates how individual self-study, group discussion, facilitation and handouts are used to create experiential-based learning. The "modern" approach to training is contrasted with more "traditional" ones. Evaluations indicate that participants reacted favorably to the session and that the majority demonstrated achievement of the specific behavioral objectives. Potential uses for the material are suggested. PMID- 20841088 TI - Health promotion and the use of appropriateness review. AB - This paper reviews research regarding institutional sponsorship of health education programs and makes a case for mobilizing planning agency review powers to support health promotion goals. Specifically, the paper urges that institutions be reviewed for appropriateness in terms of their efforts to promote health. The processes of developing review criteria and reviewing institutions to facilitate change are discussed; sample review criteria for health education are included. PMID- 20841089 TI - Applied research, evaluation and case study readings from the seventies: part 2 of a national faculty survey. AB - Faculty teaching in accredited graduate programs of community health education in U.S. universities were surveyed by mail to determine which articles published during the 1970's they would recommend that their colleagues read. The suggested readings were collected and abstracted and are presented herewith in annotated bibliographic form. Part 1 covering Community Health Education Policy, Theory and Social Issues appeared in the 1980-81 Volume (1:2) of this journal. PMID- 20841090 TI - Improving Practice Through Updating our Theoretical Base. PMID- 20841091 TI - Promotion of health through consumer protection: Nigeria. AB - This paper investigates the attitudes of Nigerian health consumers towards modern health care facilities. It examines both the traditional beliefs and customs which stand in the way of accepting modern health care, and the modern health care facilities themselves which discourage patients through their red tape, lack of interpersonal communication and mass production atmosphere. The paper attempts to explain the communication gap between patients and modern medical practitioners in Nigeria by examining the historical development of medical science in the country. It concludes that there is no continuity between the traditional and modern practitioners and that modern health care is totally derived from the Western world without consideration for the social and cultural background of the population. Special training in interpersonal relationship of all medical and paramedical personnel including the observation of psychological methods used by the traditional healers, as well as "a patient's bill of right" aimed at promoting health consumer awareness of the part he has to play in the proper delivery of health care are proposed. PMID- 20841092 TI - Exporting Exploitation: The Dumping of U.S. Banned Pharmaceuticals in LDC's. AB - United States pharmaceutical companies are marketing or manufacturing drugs in less developed countries which add hazards to the diseases they are intended to control. For many pharmaceutical companies the financial benefits outweigh any possible risks. In many cases U.S. export laws and other nations' import laws are not enforced and people are denied their right to be provided with full unbiased disclosure of all medications they are considering consenting to. PMID- 20841093 TI - Training trainers of primary health care workers: kiribati. AB - The importance of training trainers is often overlooked in considering the task of training primary health care workers. The results of a WHO-assisted project to train nurse-trainers in Kiribati (Gilbert Islands) are described and guidelines for training of trainers in LDC's provided. The necessity of adequate preparation in all aspects of the training process is stressed: training design, teaching methods, PHC content, and training evaluation. PMID- 20841094 TI - A longitudinal study of the impact of village health education on environmental sanitation. AB - Health educators working in developing nations commonly encounter administrative constraints and methodological problems which prevent rigorous program evaluation. Using a time-series design, this study followed approximately 600 families in two Guatemalan villages during a four-year period to measure the impact of community health education on seven indicators of change in environmental sanitation.Adoption of new behavior was accompanied by widespread change in village attitudes and perceptions of health benefits. At the level of the family, change in perception was not predictive of change in behavior. A strong relationship between participation in planned educational events and the adoption of sanitation changes suggests that the formative educational strategy was responsible for stimulating change for five of seven indicators. Suggestions are made about the usefulness of the methodology, ways that private behavioral changes may be measured are discussed, and the advantages of the time-series design for health education evaluation and monitoring are noted. PMID- 20841095 TI - An evaluation of a biofeedback smoking education program. AB - This study was designed to evaluate the efficacy of a biofeedback smoking education program in influencing students' smoking behavior and attitudes. It included a total of 486 secondary students in suburban Boston area, 293 in experimental group and 193 in control group. The biofeedback package included a cardiotach, digital thermometer, tremor tester, and an Ecolyzer. The educational program lasted six days in each school. The questionnaire included variables taken from Horn's Smoking Model and the Health Belief Model. The completion rate for both pre-test and post-test was 84.4 per cent for experimental group and 76.9 per cent for control group. The results showed that the experimental program was effective in bringing about a significant change in smoking behavior and belief variables of health consequences of smoking, personal relevance, perceived severity, capability for cessation, and perceived salience. Discussion was made regarding the efficacy of the underlying theory of the biofeedback method as an educational aid in health education and as an innovative smoking education initiative. PMID- 20841096 TI - Social support and social action organizing in a "grey ghetto": the tenderloin experience. AB - The Tenderloin Senior Outreach Project (TSOP) is presented as a case study of effective community-based organizing among the isolated elderly in one of America's large "grey ghettos." Based on the theoretical underpinnings of social support theory and Freire's "education for critical consciousness," the Project has attempted to address the interrelated problems of poor health, social isolation and powerlessness endemic among the elderly in Single Room Occupancy hotels.The Project's metamorphosis is traced from a university-sponsored community development effort to a community-controlled organization focused on broad social action objectives. The transference of leadership from health education facilitators to indigenous elderly leaders within the hotels is examined, as are some of the strategies employed in increasing Project visibility, preventing burn-out, and facilitating replication in other areas. PMID- 20841097 TI - Family planning decision-making in a polygynous nepalese family. AB - This chronological study describes decision making about contraceptive usage by a polygynous family in Nepal. Open-ended interviews with the husband, separate structured interviews with each of three wives, discussions with officials at a laparoscopic sterilization camp, reports from family planning fieldworkers, the author's field notes, and a follow-up report a year later are the basis of the case description. The social reasons for polygyny, the role of the husband and wives in decision making, and the value of children are discussed in terms of the national family planning programs. PMID- 20841098 TI - The impact of u.s. Energy policy on international health: alternate paths into the future. AB - Historical, sociological, and epidemiological research shows that international health and mortality levels are determined primarily not by health sector policies but, instead, by national and international policies that shape the broader sociopolitical and economic systems within which health sectors are embedded. Such policies have traditionally been considered to lie outside the domain of the health sector and, therefore, not of concern to health educators. One such national policy with the potential to powerfully influence international health and mortality levels is the looming choice between alternate American energy paths: the capital-intensive, large-scale, and centralized "hard" path of non-renewable energy resources; and the labor-intensive, small-scale, and decentralized "soft" path of renewable energy sources. Substantial effort has been directed to projecting the physical environmental impacts in the United States for both paths. But the social environmental impacts of each path and their implications for international health have been ignored. This article reviews links between alternate U.S. energy paths and alternate international health futures, and their implications for health educators around the world. PMID- 20841099 TI - Reweaving the social fabric: antecedents of social support facilitation. AB - Contemporary society leaves many individuals without a continuing support group. Continued integration into a network of supportive social relationships is demonstrably related to the prevention of breakdown in health in the widest variety of mental and physical forms. Yet the task of assuring continuity of supportive relationships has not been central to any professional discipline. The facilitation of social support is likely to become more central to community health education.To address this issue we examine seven different forms of intervention which address the problem of augmenting supportive relationships. The goal is to extract the essence of the professional role in the provision of social support and to suggest its relevance to community health education. PMID- 20841100 TI - Agency coalitions for targeted service delivery: foiled designs, failed development, but final delight. AB - In light of recent federal attempts at promoting agency coalitions for developing and coordinating health education-risk reduction programs, the earlier experience of one state in promoting such a coalition is reviewed. A review of the literature on human service organization structure (domain theory), interorganizational collaboration and professional conceptual styles, revealed four necessary but not sufficient guidelines for promoting agency coalitions. First, some source of adequate outside funding must be obtained. Second, the coalition should have an organizational structure which has committees in each of the three domains of organization. Third, the self-interests of the various competing agencies must be recognized and capitalized upon. Fourth, to the extent competing agencies are involved, the collaborative projects should be either short-term and structured (if high interdependence is required) or long-term noninteracting projects. PMID- 20841101 TI - The silent sympathy: a study of attitudes toward spontaneous abortion. AB - A study of 560 health professionals and students indicated widespread sympathy for miscarriage patients: 83 per cent of respondents rated the emotional support needs of miscarriage patients above the average rating they provided for seventeen other medical conditions. Interestingly, those involved in the delivery of health care were less likely than those not involved to rate emotional support needs of miscarriage patients higher than average. The need to provide strong emotional support systems for these women and training for health care professionals is stressed. PMID- 20841102 TI - Health education in u.s. Medical care settings: history and future prospects. AB - This article traces the extraordinary transfer of control over an increasingly broadly defined sphere of living known as "health" to medical institutions and personnel in the U.S.A.-and examines the role of federal policy and secular trends in shaping the future of medical care, Changes in the prevalence and quality of health education in these settings are described in relationship to these organizational structures, and the "leading edges" of health education in medical care are identified. PMID- 20841103 TI - Health educators: change agents or techno/peasants? AB - Technology has become such a potent force in industrialized society that it influences virtually every aspect of our daily lives. Electronics, energy and genetic engineering are having major effects on society and the individual. Yet the role of technology in health largely has been ignored in public health literature, research and training. Health education has a valuable part to play in the process of this technological application but health educators need to become better informed about the nature of current technologies and their accompanying social issues. They also need to learn how to apply new technology to their profession. The question is whether the change agents to the future will be the educators, organizers, activists and human helpers who have trained for the task of fostering social and individual change or the technocrats who change our social fabric almost inadvertently in the process of inventing a more competitive microchip or mutant bacterium? PMID- 20841104 TI - A health education approach to training village health workers in Nigeria. AB - Health education plays an important role in the primary health care process, particularly in the training of village health workers. Three educational concepts, training based on community felt needs, trainee involvement and social and cultural realism, are essential in designing these programs. These concepts were applied over a three year period in the training of village health caretakers in Idere town of Oyo State, Nigeria. Volunteer village health workers from ten villages were able to bring about changes in knowledge, behaviour and health status of their fellow villagers indicating that the health education approach fostered skill transfer to the communities. PMID- 20841105 TI - Insider/Outsider dilemmas in the development of an appalachian self-care health education program. AB - This case study examines the process whereby a community based self-care health education program was developed and implemented in a poverty-struck coal mining region of southern Appalachia. One of the principle dynamics explored here in depth is the tension between "insiders" (persons who know the area but may not be well versed in program planning, implementation or evaluation) and "outsiders"; persons who may be professionally prepared for mounting programs but are hampered in their ability to adjust to or handle the vicissitudes of an unfamiliar social or cultural situation. Suggestions are advanced as to how this tension might be better managed. PMID- 20841106 TI - Getting research utilized: the taichung study revisited. AB - This case study describes how an action-oriented research program served as the base for national expansion of the Taiwan family planning program; what kind of organizational setup and approaches expedited getting research results utilized; and how the results were disseminated to other countries considering starting similar programs. PMID- 20841107 TI - Alcohol and the media: a review and critique of the 'effects' model. AB - A review of the available empirical material bearing upon the question of alcohol advertising having 'effects' on the general level of consumption suggests that this question is insufficiently precise as a basis for research. Studies suggesting some relationship between advertising for particular brands or products and shifts in brand or product use are potentially more interesting, if considered from a point of view that recognises that such shifts may involve shifts in milieux, comparisons, styles and meanings associated with consumption. Future research should be attentive to such qualitative changes in drinking practices attendant upon advertising or preventive campaigns (as well as to quantitative changes). The authors suggest that such quantitative and qualitative changes in drinking practices of individuals and social groups need to be considered within the context of more general, ideological and economic, consequences of alcohol advertising. These consequences-including reinforcement of images about 'social drinking,' and shifting of consumers onto more profitable products-consolidate the profitability of the alcohol industry (a consideration more important to the industry than levels of consumption per se). A framework broader than that of 'effects' on individuals' levels of consumption is required if health educators are to learn anything from advertising. PMID- 20841108 TI - Evaluating primary prevention: the california "winners" alcohol program. AB - The "Winners" program was a three year primary prevention effort sponsored by the California Department of Alcohol and Drug Programs. The demonstration attempted to alter drinking behavior through the use of paid mass media messages and community-based educational and organizational strategies. The evaluation design included three communities: a media plus community organization and education site; a media only site; and, a comparison site. This article describes the "Winners" program and presents some results of the evaluation. The findings are discussed in terms of their implications for prevention efforts in general. PMID- 20841109 TI - Can Adolescents be Motivated to Learn about Birth Control? AB - A field experiment designed to test a social comparison model for delivery information on human sexuality and birth control to adolescents is discussed. The model addresses the difficult issue of motivation for communication and learning in peer groups. The results of the field experiment have some important implications for the design of informational and educational programs in schools and community settings. PMID- 20841110 TI - Consultation in afghanistan: a case study. AB - This case describes the experiences of one consultant working in Afghanistan, for ten weeks. The case is organized around the consultation cycle, and the problems for which consultation was requested. It raises important questions in terms of how consultants from one culture work in another; how multilateral agencies contract for consultant services - a process which usually prevents the consultant and consultee from interacting around the problems prior to the actual consultation; and how one consultation builds upon the previous consultations, albeit by different consultants. Implicit is the recognition of the need for special preparation in consultation for health educators and for working in cross cultural contexts. PMID- 20841111 TI - The effect of tax reform on school health education programs. AB - A number of Massachusetts schools implemented a health course as a result of passage of a 1974 law requiring teaching of health. This surge of health teaching now appears to be in danger in 1982 because of the passage of a recent tax referendum (Proposition 2 1/2). To determine projected impact of this tax reform on school health education, a questionnaire was sent to administrators of 200 school districts. The results showed that there was a significant increase in the number of schools implementing health courses since 1974. However, the tax referendum produced severe pressure for many newly developed programs to lay-off health teachers or eliminate health courses. School administrators recommended several coping strategies, including: employment of dual-major teachers, shifting required courses to electives, and marshalling support of the program through a viable School Health Advisory Committee. It was observed that Massachusetts serves as a case study forecasting impending fiscal crisis in other states. PMID- 20841112 TI - Major barriers to effective delivery of health services in Nigeria. AB - Major barriers to effective delivery of health services associated with health service organizations, professionals, and care recipients in Nigeria are reviewed. Discussed are: lack of health planning efforts by health agencies; problems of health services accessibility; poor public health image; and inadequate health manpower and training programs. Remedies suggested include comprehensive health planning and consumer involvement in community health decision-making. PMID- 20841113 TI - Training of trainers for community primary health care workers. AB - Training community-based health care workers in "developing" countries is essential to improving the quality of life in both rural and urban areas. Two major obstacles to such training are the tremendous social distance gap between these community workers and their more highly-educated and upper-class trainers (often medical officers) and the didactic, formal educational system. Bridging this gap demands a participant-centered, field-oriented approach which actively involves the trainee in the design, implementation and evaluation of the training program. A description of a philosophic learning approach based on self-initiated change, educational objectives related to planning, organizing, conducting and evaluating training, and specific learning methodologies utilizing participatory learning, non-formal educational techniques, field experience, continuing feedback and learner participation are reviewed. Included are: role playing, story telling, case studies, self-learning and simulation exercises, visuals, and Portapak videotape. PMID- 20841114 TI - A global review of training of community health workers. AB - Community Health Workers (CHWs) are often the most important deliverers of health care services. This review brings together relevant information on CHWs and their training. These materials concern themselves with training techniques as they have been developed in various programs in various countries around the world. Because of the relative newness of the field the bulk of the materials have been written only in the last ten years. Four phases in training CHWs to undertake primary health care work are reviewed. These are: assessing the community's health needs and priorities and specifying the CHWs' tasks, adapting CHW training to the community, selecting CHWs and providing the CHWs with training and support. Issues of concern relating to these phases are: who is the trainer, what training strategies are to be followed, how is the training to be monitored and evaluated and, finally, what is the cost. A guide to twenty-two manuals that have been developed in various countries for use in training CHWs is included. PMID- 20841115 TI - Training consultation to the cairo family planning association, egypt. AB - A case history of the consultation process between the Cairo Family Planning Association in Egypt and a Ford Foundation short-term health education and training consultant. The viewpoint is that of the consultant and the then resident Ford population and family planning program advisor. Gordon and Ronald Lippitt's six phases of the consulting process are used as a framework for presentation. PMID- 20841116 TI - The health concerns of young american and egyptian women: a cross cultural study. AB - The health concerns of 99 Egyptian and 135 American young women indicated that the Egyptian sample was significantly more concerned (p < .001) about most items compared to the American group, and that there was very little association (r = .39) between the mean scores of the two groups. The top ten concerns of the Egyptian women ranked by mean score were Halitosis/Body Odor, Colds, Cancer, Poor Teeth, Population Explosion, Overweight, Birth Control, Water Pollution, Headaches, and Heart Disease. The top ten concerns of the American women ranked by mean score were Birth Control, What I'll be like in ten years, Auto Accidents, Overweight, Cancer, Use of Contraceptives, Death, Nuclear War, Childbirth, and Air Pollution. The differences in their health concerns have implications for community health education planning and promotion. PMID- 20841117 TI - The application of social network theory to hospital cost containment. AB - Using Massachusetts as an example of a state which is burdened with high health care costs, Social Network Theory is used as a basis for examining some factors which contribute to these high costs. Vignettes are described to indicate that some hospitalization may be a consequence of inappropriate social service intervention prior to onset of symptoms requiring medical attention. PMID- 20841118 TI - Adaptation to transition in late adulthood: implications for health education. AB - Older individuals experience many situational changes associated with aging. Perhaps the most pervasive of these in their effects on lifestyle are relocation, retirement and widowhood. An examination of existing literatures on these three major life events is used to identify common contextual factors which influence adaptation to these transitions. These include predictability of the event, control and social supports. A number of health education interventions targeted to those individuals who are most likely to experience these transitions and who are greatest at risk of negative outcomes are suggested. PMID- 20841119 TI - Health promotion among older populations. AB - This article advocates the importance of health promotion among the aged. Basic issues regarding health education are explored along with barriers against and arguments for increasing such activities. Ways in which the surrounding environment has changed because of the "aging" of America are described. Proposed strategies focus on promotion of health, particularly on maintenance and rehabilitation as aspects of secondary prevention. PMID- 20841120 TI - Black elders: viability during a time of cutbacks. AB - Black elders in the United States have fewer resources than their white cohorts. They have less income, poorer housing, shorter life expectancy, and more barriers to service. Recent federal cutbacks have been differentially damaging to black elders who were more dependent upon the programs being cut and who have fewer alternative resources. This is a matter of fiscal policy that has relevance to the physical and mental well-being of the largest segment of minority elderly in the United States. PMID- 20841121 TI - Sexual attitudes in traditional and modern yoruba society. AB - This article examines sexual attitudes and beliefs in Nigeria, from the traditional society to the modern one; focusing specificially on Yoruba culture describing sexual attitudes and sex education in the traditional Yoruba Society and examining its evolution under the influence of the British Colonial rules. It concludes that the sexual attitude was much healthier and sexual life more disciplined in the traditional society before the colonizers broke down the community structure causing children to turn against their parents. The children were presented a confused system of values, which combined sexual permissiveness with the idea of sin-confusion became more pronounced in the aftermath of the Civil War-with the young people unable to identify or understand either the old traditional or the new western system of values. In conclusion, the paper examines the efforts made by the Nigerian government to introduce sex education in schools by encouraging the students to rediscover their own traditional values and place them in perspective in the modern context. PMID- 20841122 TI - Early childhood experience in Nepal: a study of sickness, treatment and mortality. AB - This article reports on a longitudinal study of almost 7,000 children under six years in selected villages in Nepal, giving their morbidity and mortality history, treatments given and costs involved. The study suggests that about two children out of three are defined as sick by their mothers in any given year and that treatment is sought for about 40 percent of sickness in small children. Three of four children treated are treated by scientific medicine, that is by physicians, nurses or pharmacists. The principal causes of death are fevers and diarrhea. Education of mothers in spacing of births, hygiene, nutrition and rehydration therapy would appear to be the most important primary health care service, along with increased access to potable water and to medical clinics. PMID- 20841123 TI - Assessment: a keystone to geriatric care. AB - Geriatric care is emerging in importance and will continue to be a priority until late into the twenty-first century. Demographers report that there are more older Americans, particularly in the oldest group. Although chronic illness can develop at any age, it is clearly associated with advancing years and particularly with the group of advanced age, eighty and older, that is growing so rapidly. The health care system, traditionally designed to be responsive to acute care needs on an episodic basis, is attempting to make the changes that are needed, but generally is responding in an ad hoc manner rather than by careful comprehensive analysis and planning. In order to foster a more rational approach to the changes in the health care system, comprehensive assessment of the older patient must be considered a critical component of geriatric health care. PMID- 20841124 TI - Mothers' and physicians' sources of information on infant feeding: relation to nutrition knowledge and attitudes. AB - A survey was conducted with 148 women patients (131 first-time mothers and 17 pregnant women) of ten physicians to determine their channels of information and specific sources within each channel on infant feeding and to examine where they receive their information in relation to their level of nutrition knowledge and selected nutrition-related attitudes and beliefs. It was shown that physicians are frequently used as a source of information on infant nutrition, but are not the women's primary source. Several information channels (formal, media, professional, and interpersonal) and different sources within each channel were used according to the type of information needed. Specific channels of nutrition information were related to whether the mothers breast-fed or bottle-fed their infants, their nutrition knowledge score, and to certain attitudes about nutrition and health. PMID- 20841125 TI - International health education in perspective. AB - This article presents a broad view from the WHO viewpoint to highlight the important fact that Health Education is the top priority program in Primary Health Care in the world. However, the nations of the world today are in sharp contrast regarding their health situations. On the one hand they have the possibility of international cooperation and coordination of health-related organizations, and on the other hand have a number of powerful destructive forces working against the health of mankind. Challenging problems that health education faces today include: 1) use of limited resources, 2) the threat of war, 3) poverty, and 4) the deterioration of human environment. A clear policy in support of health education that can bring forward international collaboration to achieve better health for all is suggested. PMID- 20841126 TI - Roles for health educators in a time of health care cutbacks: preventive and ameliorative approaches. AB - Cutbacks in public health care programs at federal, state, and local levels have reduced the health care access of many low-income persons. Based on findings from several California studies, this article suggests several roles for health educators intended to prevent cutbacks or mitigate their impact. Methods of preventing cutbacks rely on community organization methods and coalitions including health education professional groups. When preventive actions are unsuccessful, health educators may ease the impact of cutbacks by developing adequate education interventions for users of affected services and community organization strategies to improve access to remaining services. Specific methods are suggested and discussed. PMID- 20841127 TI - Education in the medical care setting: needs assessment for nursing services. AB - This case study is designed to demonstrate examples of various procedures necessary for the establishment, implementation, and evaluation of a formal patient education program that meets the standards of the Joint Commission on Accreditation of Hospital Standards on Patient Care Evaluation. Presented are some "real world" strategies necessary for task accomplishment. PMID- 20841128 TI - Psychosocial environment: a health promotion model. AB - This article presents a multidimensional model of psychosocial determinants of health behavior for health promotion research and policy analysis. Frequently, health promotion focuses almost exclusively on intrapsychic determinants and on individual level behavior. Based upon Field Theory and attitude theories, this proposed model holds that in populations with comparable sociodemographic and biological status (exogenous variables) a health behavior is a function of direct and interaction effects of five key intrapsychic and external variables. These are: behavioral intentions, social support, accessibility of means for action, personal autonomy, and action situation. Empirical tests with cross-cultural studies in Venezuela, Kenya, and the Philippines provide substantial support for the model. The findings suggest that while health promotion strategies should deal with intrapsychic determinants of behavior, key extrapsychic factors (such as social support, quality and accessibility of health care measures, and situational factors) all have direct and independent effects on health behavior as well. Health promotion research and interventions which aim exclusively at intrapsychic determinants would thus have rather limited overall value. The article discusses key research and policy implications of the model presented. PMID- 20841129 TI - Sterilization among american Indian and chicano mothers. AB - In a large study concerning family size and birth control among women from five cultures in the Miami, Florida, area, it was noted that 60 percent of the Miccosukee and Seminole Indians having five or more children were surgically sterile. Compared with the incidence for whites (30%) and a similar socio economic group of Chicanos (20%), the incidence among Indian women seemed highly inflated. To examine why this should be so and whether or not there were negative effects of such sterilization, analyses examined both pre- and post-operative differences between the Indians and a comparison group of Chicanos. Though there were significant cultural differences found for the women, these differences did not interact significantly in predicting sterilization. However, sterilized women reported significantly more pregnancy complications. Factors which may have contributed to the greater incidence of tubal ligation among Indian women are explored. PMID- 20841130 TI - Who engages in health protective behaviors? A replication. AB - The purpose of this article is to replicate Berkanovic's study suggesting that general health orientations are weak mediators of the relationship between sociodemographic characteristics and health protective behaviors, and thus, health education campaigns attempting to alter health orientations in target populations would have little effect on health protective behaviors. Our methodology is similar to that used by Berkanovic although additional sociodemographic factors as well as measures of general health orientations are included in the analysis of the three types of health protective behaviors (i.e., voluntary life style change, physician recommended life style change, and physician recommended treatment). Our results support Berkanovic's earlier view. The effect of attitudes toward physicians on asymptomatic life style change is also considered, and the implications for health education are discussed. PMID- 20841131 TI - Community health education literature from the seventies: a field practitioner survey. AB - A national sample of community health education practitioners in the United States was surveyed by mail and asked to select five articles published during the 1970's they would recommend that their colleagues read. The study was conducted in late 1979 after a comparable national survey of university health education faculty by Cernada and Chen (International Quarterly of Community Health Education, 1:2 and 2:1). The recommended readings were collected and abstracted, and are presented in annotated bibliographic form. A comparison of practitioner and academic selections is in preparation. PMID- 20841132 TI - A community approach to the prevention of alcohol-related problems: the san francisco experience. AB - This article describes the San Francisco Prevention Project, a community level intervention designed to prevent alcohol-related problems. The intervention is based on a systems perspective and merges academic and practical perspectives at the community level. The project uses a three component approach of research, community education, and planning for action. Each component is described and a summary of the first year experience is provided. PMID- 20841133 TI - A critique of the life style concept in public health education. AB - A review and critique of the "life style" concept in health education is presented. The conceptual origins, evolution, and current operational definitions of the term are examined in light of its implications for health education practice oriented toward behavioral intervention at the level of the individual. Antecedents to the rise of life style change strategies are traced to concurrent developments in popular culture, health policy, and social science theory. The authors take the position that, in many respects, life style intervention departs significantly from the public health ethic, and call for a critical reappraisal of the concept by health educators. PMID- 20841134 TI - Opinions, Attitudes, and Beliefs About Self-Treatment Practices in a Nigerian urban Setting: Implications for Health Education. AB - The universality of self-care is well documented but there is a lack of data on the manifestations of self-care in a particular environment: information which is sorely required for health planning purposes. This study conducted in Ibadan, Nigeria, attempts to provide some detailed information on opinions, attitudes and beliefs on self-treatment - an important aspect of self-care. Within the three month period prior to the study, 80 percent of respondents had self-treated themselves or a member of their family, and 55 percent bought modern drugs without a doctor's prescription. On the one hand, common, self-limiting diseases were self-treated with modern drugs. On the other, people with chronic diseases usually sought professional help. In the people's perception, the elderly and mothers of young children are most suited to engage in self-treatment. Most importantly, people view self-treatment as a right of the individual to take responsibility for and to take an active part in maintaining his/her health, rather than a substitute or alternative to professional care. PMID- 20841135 TI - Perceptions of health concept among jordanian high school students. AB - Health education as a school subject and community awareness program has been gaining importance in many countries. Understanding the nature of the health concept is vital for planning the health education curricula and programs. Using a sample of 996 eighth, tenth, and twelfth grade, male and female, rural and urban, Jordanian high school students, differential perceptions of health concept were investigated by means of free word associations and definitions tests. Concurrent validity was established between the two measures. Both the tests yielded eleven categories each defining a different perspective of health concept. Category means were determined and the relative importance of each perceived aspect of health was discussed. Treating the eleven category scores as dependent variables and area, sex, and grade as independent variables, data were analyzed by MANOVA. The results showed some interesting interaction effects highlighting the differential perceptions of the health concept among various area gender and grade defined groups of students. Findings have implications for designing health education curricula. PMID- 20841136 TI - Community health education literature from the seventies: a field practitioner survey-part 2. AB - A national sample of community health education practitioners in the United States was surveyed by mail and asked to select five articles published during the 1970's that they would recommend their colleagues read. The study was conducted in late 1979 after a comparable national survey of university health education faculty by Cernada and Chen (International Quarterly of Community Health Education, 1:2 and 2:1). The recommended readings were collected and abstracted, and are presented in annotated bibliographic form. This annotated bibliography follows up on the collection published in Volume 4, Number 4, of the International Quarterly of Community Health Education which covered Community Health Education Policy, Theory, and Social Issues-its focus is on Applied Research, Evaluation, and Case Studies. PMID- 20841137 TI - Workplace health education: results from a national survey. AB - A national survey of individuals responsible for workplace health education was conducted by self-administered mailed questionnaire. The present analysis examines the responses to the questions on the types of health education activities undertaken and the prior training in health education of those responsible for this work. Results suggest that interest and activity in workplace health education is increasing but that there is a serious lack of training in health education on the parts of those responsible for this work. PMID- 20841138 TI - Introducing integrated health services in a traditional society: the Sudan community-based family health project. AB - The Sudan Community Based Family Health Project, begun in 1980, has sought to demonstrate that the existing cadre of practicing government-trained village midwives in the Sudan can be utilized to extend maternal and child health services to rural areas. A majority of these midwives are nonliterate, and attention was placed on effectively implementing a limited set of services, namely, oral rehydration, birth-spacing, nutrition education, and immunization. Carefully planned inservice training programs for midwives and local health workers and an intensive service introduction campaign implemented in phases resulted in mixed success over a relatively short period of observation. Perhaps the most important lessons that have emerged from the program have been about how to design and implement a rural MCH program building on local resources. The experience has since lead project staff to undertake, in a new area, a follow-up program designed to be a more cost-effective and replicable version of the original one. PMID- 20841139 TI - Hypertension in a Caribbean population. AB - This cross-sectional study presents an assessment of factors associated with elevated blood pressure in Seventh-Day Adventists in the Caribbean. Four-hundred thirty-three subjects were randomly selected from the English-speaking Caribbean population. Subjects ranged in age from twenty-one to sixty; 150 were males and 283 females. Eighty percent were Negroes of African descent, 12 percent mixed, 8 percent Indians of East Indian descent, and 3 percent of Spanish background. The study utilized the PRECEDE model developed by Green and associates to examine factors for hypertension. A positive correlation was found between body mass index (weight in Kg/height in M2) and hypertension in both sexes. Age was also significantly associated with hypertension. Normotensive females had a slightly higher intake of potassium than hypertensives, while hypertensive males tended to have higher levels of calcium. Other factors, such as parental history of blood pressure, vegetarian diet, sugar and fat intake, or Type A/B personality showed no relationship to hypertension. The vast majority of participants were Type B. This study provides baseline information for use in selecting those features which will be emphasized in a health education program, as well as baseline data for evaluation of health education in the Caribbean. PMID- 20841140 TI - National human resource development policies: issues for health education administrators. AB - The pathway to achievement of the goal "Health for All by The Year 2000" is lined with good intentions, but one that in the remaining fifteen years of this century may not lead very far. Although development of human resources and support of local autonomy are promoted as the keys to success, in truth much greater attention must be devoted to infrastructures, administration, policies, and data base planning for education and health services. For health education administrators the decisions may be at odds with current economic and social change theory and perhaps at odds with their own values. PMID- 20841141 TI - Issues in collaborative research between health educators and medical scientists: a case study. AB - The inclusion of health education in medical research schemes, if it happens at all, is usually after major social, behavioral, and educational problems have surfaced that threaten the success or survival of the project. Lack of collaboration arises not only from a narrowly and inappropriately conceived role for health education but also from communications barriers inherent in differing professional orientations and methodologies. A case study on malaria research in a rural Nigerian community demonstrates that health educators need to take initiative in defining a role for themselves in biomedical research, even if the opportunity may seem to come too late. Any chance for interaction provides potential for learning and understanding that will pave the way for collaboration in the future. PMID- 20841142 TI - Continuing Evaluation and Research Needs in National Family Planning Promotion: Plus a Change, Plus C'est La M me Chose. AB - A priority listing of existing health promotion research needs in large-scale family planning programs in East and Southeast Asia is presented. Areas of needed research include: family planning Provider/User Interaction; Contraceptive Use Continuation; Perceptions of Service Source; Comparative Educational and Social Marketing Approaches; and Psyco-Social Needs. Interestingly, many of the present needs were identified by researchers and program planners in national and international agencies more than a decade ago. Possible reasons for their not being implemented are discussed. PMID- 20841143 TI - Reaganomics: implications for peace and the public health. AB - This article explores the implications of "Reaganomics" for both the health of the public and international peace. The first two sections examine the fields of health and peace, and find that both have been traditionally defined in terms of their opposite condition; that is, health has been operationally defined as the absence of disease, and peace has been defined as the absence of war. For reasons discussed in some detail, a paradigm shift is underway that is forcing a fundamental redefinition of both these terms, with consequent profound implications for professional practice and intervention strategies in each field. Examined from the perspective of these redefinitions, both health and peace are found to be closely linked with the degree to which equity (distributive justice) is pursued as a guiding purpose and goal of domestic and foreign policies. The third section analyzes the impact of Reagan Administration policies on national and international equity, and finds that they have systematically increased existing inequities, with the following consequences: measurable and increasing decrements in the health of the public; and an enormously increased probability of nuclear war. The final section deals with implications for practice of those concerned with promoting both the health of the public and international peace. PMID- 20841144 TI - Effects of the federal risk reduction grants on state health education units. AB - Beginning in 1979, the Centers for Disease Control (CDC) awarded risk reduction grants to health education units in state health departments. One of CDC's main policy objectives was to use the risk reduction grants to strengthen those state level health education units. The present study had two purposes: 1) investigate the impact of the risk reduction grants on the organization, structure, and function of state health education units; and 2) identify factors associated with program success and failure. Twelve state health education units were selected and interviews were conducted with the risk reduction program coordinators in each. Results indicated that in some states the risk reduction grants helped health education units adopt a health promotion philosophy and provided a framework for a more distinct health education program identity and purpose. The most important factor associated with risk reduction program success was support of the philosophy of health promotion by high-level health department administrators. In some states the risk reduction program was placed in a chronic disease unit rather than the health education unit. Program guidance from CDC was inconsistent and led to confusion among program coordinators and wide variations in implementation. PMID- 20841145 TI - Community health education in refugee camps. AB - The importance of developing and maintaining health education programs in refugee camps, while highlighting special constraints, is discussed. A literature review, interviews with organizations sending international health workers to refugee communities, and a survey of refugees, national and international health workers were all carried out to ascertain the interest in, and practice of health promotion, information and communication. The study revealed that there is very little health education being undertaken in refugee camps and that there is little consensus as to what health education is. There also is a lack of community involvement and most of those workers involved in health neither have the training nor feel they often have the time to devote to health education, more interested as they are in curative medicine. The health policies of national and international organizations appear to support but not define, integrate or evaluate the practice of health education in refugee camps. This is despite a strong consensus that health education is an essential component of refugee community health care. Field experience, discussions, and the review also highlighted the need for the advocacy of the health needs and problems of refugees at an international level. PMID- 20841146 TI - Age Differences in Health Attitudes and Beliefs: Aging and/or Cohort Effects? AB - The study examines age differences in selected health attitudes and beliefs. Using one indicator for cohort effects and one indicator of aging effects, an attempt is made to identify the origins of these age differences. The study population is comprised of a random sample of 2603 adults from a large health maintenance organization. The subjects participated in an indepth household interview. Analytic approaches include bivariate to multivariate methods. The findings indicate that there are significant age differences in health attitudes and beliefs and that both aging and cohort contribute to these differences. The findings must be interpreted as only tentative. However, they do highlight the need to examine the degree to which these health attitudes and beliefs are actually predictive of medical care utilization and other health and illness behaviors. The policy and research implications are discussed. PMID- 20841147 TI - Health professionals' interpersonal skills and patient outcome indices. AB - This article examines the relationship between health professionals' interpersonal skills (e.g., active listening, information presentation, expression of warmth, and nonverbal behavior) and patient outcomes. Patient outcomes demonstrated to be related to interpersonal skills include level of post operative pain, length of hospital stay, patient satisfaction and compliance. Patient compliance is one patient outcome of particular concern to the health care system, and it is argued that improvements in interpersonal skill, leading to increased patient satisfaction, should reduce noncompliance rates. Several studies attempting to reduce noncompliance rates in this way are reviewed, and the importance of training health professionals in interpersonal skills is stressed. PMID- 20841148 TI - The Ramah Navajo Child-to-Child Program. AB - The international CHILD-to-child program, conceptualized by Dr. David Morley of the University of London, is based on the concept that children in developing nations act as caregivers, teachers, and health workers in their families and communities. The critical component in the program is the ability and willingness of children to become actively involved as care givers. CHILD-to-child is an action-oriented approach that draws upon a vast reservoir of similar programs that have been successful in over forty developing countries of the Third World. Similarities between the Ramah Navajo Community in New Mexico and many Third World nations served as a stimulus in the initiation and development of this project. The Ramah Navajo CHILD-to-child Health Education Project involved the development of a school health education curriculum that supported Native American children in a community-based effort to improve the quality of health care and the standard of living for their families. With funding from the U.S. Department of Education as a national demonstration project, a needs assessment was conducted and a seven-unit curriculum was developed. PMID- 20841149 TI - Illness behavior in guineaworm disease. AB - Guineaworm, a waterborne helminthic disease, affects a large portion of the population in Idere, Nigeria. Although preventive health education interventions are experiencing success, it is slow due to the low economic status of the community. In the meantime people suffer and seek treatment. The decision-making process during illness with guineaworm does not fit neatly into individual psychosocial theoretical models. Concepts of the disease and potential remedies are strongly influenced by the local culture. In the process of studying these cultural influences, suggestions for new models have arisen. These suggest a mediating role for health education between traditional and Western scientific viewpoints in promoting efficacious illness behavior in endemic tropical diseases. PMID- 20841150 TI - The training component of the maasai health services project, Tanzania. AB - Tanzania, one of the many developing countries, has devised health policies incorporating innovative ideas and strategies toward improving primary health care. The Arusha Region has become a pilot area in investigating the potential of Community Health Workers as part of a community-based health education and service project. In designing a project strategy to respond to the different levels of training needs, several issues relevant to the structure and theory of training are included: CHW selection criteria, identification of trainers, training content, approach and methods, locale, schedule, and evaluation. PMID- 20841151 TI - Evaluating the effectiveness of utilizing traditional birth attendants for maternal and child health/family planning programs in the rural Philippines. AB - A pilot project was designed to measure the effectiveness of utilizing traditional birth attendants (hilots) as family planning motivators in the Philippines. A total of 492 hilots underwent a one-week training program in maternal and child health and family planning. Following the training, a quasi experimental design was used to test the effects of training alone, training plus supervision, and the combination of training, supervision and a monetary incentive on family planning activities. In addition to these three program inputs, the type of training method was also assessed to determine its relationship on post-training knowledge scores and field performance. Analysis of the one-year program statistics indicated that a combination of training methods (lecture, audio-visual demonstrations, and role-playing) significantly increased both test performance and field performance. Hilots who received supervision recruited twice as many acceptors as hilots who received only the training input (p <.01). Adding a monetary incentive did not significantly increase the average monthly number of acceptors recruited. Cost effectiveness of the three experimental approaches are contrasted with each other as well as with the national program utilizing family planning motivators. PMID- 20841152 TI - Differential perceptions of health among eighth-grade girls and boys in amman, jordan. AB - Controlling for age, education, socio-economic background, and residential location, sex differences were investigated between male and female pupils' perception of health. A twenty-item multiple response questionnaire was given to 190 girls and 181 boys studying in the eighth grade in well-to-do area city schools. Tests of significance for independent sample proportions were used to determine differences in the proportions of girls and boys endorsing each item. Nine out of twenty differences were statistically significant (p < .05 or p < .01). Twenty items were rank ordered separately for girls' and boys' samples and Spearman rank order correlation was calculated to test for the degree of similarity of ordered preferences of girls and boys. A relatively high value of rho .924 indicated close similarity between the preferential patterns of girls' and boys' perceptions of health. Possibility of reaching alternative conclusions from different analyses of the same data is indicated and implications for health education curriculum development are suggested. PMID- 20841153 TI - An assessment of health needs in selected Nigeria villages. AB - Two hundred and fifty five heads of households in Iyekuselu District, Bendel State Nigeria, were interviewed. Fifteen villages were randomly selected from the 107 villages that make up the district. There is high morbidity of infectious diseases identified in the study. Limited number of medical professionals and medical institutions present problems of availability of services. This is compounded by high cost of medical services and poor access to health care facilities. The self-perceived health care needs of the heads of households are disease prevention, availability of health services, improved accessibility to health care facilities and reduced cost of care. There is a strong need for health education programs in these villages. This should be attempted with the cooperation of community members, so as to attain the goal of promoting health and preventing diseases. PMID- 20841154 TI - Television portrayals of drinking and driving. AB - Cases of drinking and driving on U.S. prime-time television programs over an eight-year period are described and analyzed. They are also judged according to criteria developed within the industry. Some stories are rated as consonant with public health education, some are not. Central criteria for analysis involve the portrayed consequences of DWI, the way humor is used, and the potential for identification between TV characters and viewers. Recent episodes have reduced the stereotyping found earlier and have presented the greater complexity and subtlety as well as the everyday nature of DWI. PMID- 20841155 TI - Worker Training in Job Safety and Health: how do we know it Works? AB - Two methods of occupational disease and injury prevention specifically required by Federal law are education and training of workers in job safety and health. Basic assumptions underlying these strategies are that they will increase safe behavior thereby reducing health risk. However, questions continue to arise regarding the effect of ongoing training as a preventive measure and, therefore, about the practical usefulness of these assumptions. The purpose of this study was to examine the extent to which evaluations of ongoing training programs can provide information to test the basic assumptions. A self-administered mail survey concerning the evaluation practices of occupational health professionals responsible for the evaluation of health and safety training programs was conducted. Results suggest that for many evaluations the information collected is inappropriate for the uses to which it is put. Furthermore, the results also suggest that measurement validity is a problem. Thus, in effect, we have no way of knowing whether or not the majority of training programs are effective. PMID- 20841156 TI - Critical public health problems perceived by urban chinese health workers. AB - This study surveyed a cross section of urban Chinese health workers' perception of problems, needs and priorities in health care delivery. Eleven categories of problems were identified by the health workers. When asked to prioritize what they perceived as critical public health problems in China, more respondents (25.9%) cited family planning and maternal child health as the most critical problem. However, in terms of response frequency, family planning and maternal child health ranked fifth (10.7%) behind disease prevention (18.4%), health education of the public (15.4%), health services administration (13.1%), and environmental health (12.1%). Other critical problems identified were medical education (10.0%). industrial health (5.3%), research (4.5%), nutrition and food sanitation (4.5%), young adults (3.6%), and the elderly (3.6%). Apparently, family planning is perceived as the most critical societal health problem affecting the welfare of the state, but heart disease, cancer, dysentery, hepatitis, and others were perceived as personal health problems critical to the individual and the public. The delineation suggests a distinction of state versus individual priorities. The Chinese health workers saw solutions to these critical problems more often in combined measures of health education, policy regulation, and medical care, than in single measures. They recognized the importance of an enlightened public and felt that educating the public must undergrid all health measures to reach the goal of Health for All by the Year 2000. PMID- 20841157 TI - Supervising Community health Workers in Community-Based Delivery of Primary Health/Family Planning Services: Experiences in Mexico, 1977-1982. AB - The supervision of CHWs in the Mexican Rural Health Program (1977-82) illustrates a wide range of problems and strengths because it was developed within a program based on a strong political mandate to deliver services to an extremely large, as well as culturally and geographically diverse population. This article presents an in-depth perspective on the issues involved in the supervision of community health workers with a focus on the myriad roles and responsibilities which are expected from supervisory personnel. The information and observations which are offered come from program evaluation materials as well as the long-term, first hand experience of the authors with the program discussed. PMID- 20841158 TI - Using teachers as change agents in the control of tropical diseases-an extra curricular approach. AB - For years the teaching of health education has always been a problem in the Nigerian schools either due to the absence of the subject on the curriculum or inadequate professional preparation of teachers to handle it. This study introduces an extracurricular approach using four endemic diseases as an example in the teaching of health education in five secondary schools. The findings revealed that: 1) teachers can be successfully used as informal agents in the school environment if exposed to appropriate health education techniques, and 2) endemic diseases can be controlled through the provision of learning experiences in the school environment where feasible. PMID- 20841159 TI - Focusing on women for water and sanitation: the case of mapo community in ibadan, Nigeria. AB - Geographical and topographic limitations have hindered community efforts to get wholesome water for domestic purposes. In response to this expressed need of the people an educational intervention using women as unit of practice and solution as water purification and management in order to reduce water-borne infections was embarked upon. Health talks, motivation of the participants, seminar/workshop for professional health providers, and laboratory sessions for water purification methods and techniques were some of the components of the learning process to achieve the goal. During and at the end of the project, participants showed interest and enthusiasm and demonstrated behavioral changes as far as making sure that the water they use is clean and kept so in clean receptacles. It is hoped that the process set up will continue through the Community Development Health Committee and the Mapo Zonal Health Office, Ibadan. PMID- 20841160 TI - Teachers' smoking worldwide: a review of nineteen countries (1966-1983). AB - A secondary analysis of thirty-eight investigations of teachers' tobacco consumption was carried out in nineteen countries during 1966-1983. Studies are analyzed in terms of smoking behavior, recognition of the non-smoking teacher as a role model, and the extent of their participation in smoking reduction among students and the general population. Non-smokers were found to be more likely to affirm the importance of non-smoking teachers as role models for students. Only a minority of smokers recognized the importance of this role. PMID- 20841161 TI - Community involvement in social marketing: guineaworm control. AB - Social marketing as a health education strategy has the potential for encouraging the adoption of new health technologies. The focus on the individual, though, holds the risk of victim blaming. This can be overcome if the consumers/community are involved in the four major components of the marketing strategy-product design, price, distribution and promotion. The community of Idere, Nigeria, has recently been involved in marketing a monofilament nylon cloth filter to prevent the water-borne helminthic disease, guineaworm. Local tailors produced the filters. Volunteer primary health workers debated pricing, sold the product and educated each consumer. Coverage in those neighborhoods and farm settlements where primary health workers were resident was nearly double that of other sections showing the value of local action to market health changes. PMID- 20841162 TI - The family, research, and prime-time television in alcohol education. AB - Television programs contain materials relevant to health practices generally, and to drinking problems in particular. Research has found that these materials are often inaccurate and misleading. A method called cooperative consultation has succeeded in transmitting these findings to writers and producers in the industry. The response from the industry has been encouraging. The method is illustrated by using two programs and their contrasting depiction of how family members responded to an alcoholic husband and father. PMID- 20841163 TI - "The unequal society": descriptive evaluation of a community education project. AB - Poverty, unemployment, and other forms of social inequality are strongly associated with increased mortality and morbidity rates. Public health interventions into socioeconomic or structural causes of illness must be multidimensional, involving health promotion, health education, health advocacy and community development strategies. A specific health education project designed to increase professional and community awareness of social inequality as a public health risk factor is described as a model for similar undertakings by other health departments. PMID- 20841164 TI - Psychoeducation: applications in community health education settings. AB - The development and implementation of the behavioral sciences' contribution to the health-related disciplines, depends on each discipline's willingness to develop new perspectives, make a joint effort, and present relevant challenges. This article attempts to present a collaboration modality to encourage meaningful participation of psychologists/counselors in health education within a community framework. Psychoeducation and a five-level intervention modality are suggested as the basis for new perspectives and methodologies. PMID- 20841165 TI - Family, community and government: the value and the limits of local caregiving. AB - More frail elderly, more seriously disabled infants, and more chronically ill persons are part of the contemporary health delivery scene than in times past. Their prime caregivers are family members, most frequently women, whose contribution is limited by the facts of geographic distance, competing pressures, and smaller families to share the burden. Added to the caregiving task are the special needs of individuals at stressful points, which, if unmet, increase the incidence of breakdowns. The support of families is often augmented by local services and by mutual help groups, but the need has far surpassed the resources now, and this has resulted in some unhealthy local competition. The caregiving issue is a matter of national priorities that cannot be solved without a shift from military to domestic spending. PMID- 20841166 TI - Integrating qualitative and quantitative survey techniques. AB - An "educational diagnosis," which targetted the health behaviors of mothers with regards, to malaria and diarrhea in their young children, was carried out over a three-week period in November 1985 in Rwanda, East Africa. The study used the methodological technique of triangulation, in which both quantitative and quantitative data collection efforts are used to find answers to the same or similar sets of questions. Findings include estimates of health care utilization and medication usage and illustrate how multiple methods of data collection can maximize both the amount of usable data and the degree of confidence in the validity of data obtained, even with relatively small samples. In particular, the qualitative technique of focus group interviewing, which provided information on the sociocultural, economic, and historical contexts of the Rwandese health care system, provided an explanation of why there is relatively little self-care or home treatment for these diseases in Rwandese society. PMID- 20841167 TI - Antismoking public policies as envisioned by bangladeshi smokers and non-smokers. AB - Tobacco use is growing quickly in the developing countries. International tobacco companies often escape the strict labeling laws of their national origins by operating in developing societies where such laws are lacking. Bangladesh is a prime example of a developing society where tobacco use and its subsequent social costs are increasing. A survey of Bangladeshis in the capital city of Dhaka shows that both smokers and non-smokers believe public programs aimed at educating the public on the dangers of tobacco use should be implemented. Schools were seen as a viable medium for educating the young. Government warnings concerning any dangers were mandated by both smokers and non-smokers. Limitations on where persons would be allowed to smoke was seen as a viable government policy by the respondents. A promising finding was that the more aware a person was of the dangers of tobacco consumption, the less likely the person was to use tobacco. Implications for government policy makers are discerned. PMID- 20841168 TI - Health worker awareness of cultural health attitudes and practices in rural Colombia. AB - Health workers' awareness and understanding of clients' attitudes and practices regarding "health" is an important but insufficiently studied factor in planning health promotion programs. A group of thirty-seven rural Colombian campesino (peasant) women were interviewed to determine their health beliefs and practices. Following interviews and observation, the health workers (doctors, nurses, and nursing assistants) who worked with these women and their families, were interviewed regarding their perceptions and awareness of the campesinos' health attitudes and practices. The results show that the women had both western and "popular" (traditional) health practices. The health workers' awareness of their clients' beliefs and practices varied greatly and was influenced by various factors including: professional level, type of illness, local conditions, and experience. In general, however, the health workers were largely unaware of the more subtle health attitudes and practices-those attitudes which may strongly influence health seeking and health maintenance behavior. Concerted efforts must be made to determine the health beliefs and practices of a client or community in order for health promotion programs to be successful. PMID- 20841169 TI - Citizen participation in health planning in the u.s. And the u.k.: implications for health education strategies. AB - The role of citizen involvement in the health planning process in Great Britain and the United States makes for interesting comparisons. Within both systems, the record of citizen participation in health planning has been mixed. Both the philosophical goals and political and economic realities of the two countries have contributed to the development of markedly different systems of health care delivery and for the perceived role of the citizens within this delivery system. While previous comparisons have primarily centered on the nature of the delivery systems and potential effectiveness and cost, this study focuses upon the citizen's role in effecting meaningful health planning in both societies. Furthermore, the study relates findings to implications for developing effective health education strategies based upon these understandings. PMID- 20841170 TI - A review of the antituberculosis campaign in Mexico. AB - Tuberculosis, a major cause of death in the nineteenth century, has consistently and steadily declined in industrialized countries. Such decline antedates the introduction of specific treatment or immunization programs. In the United States of America, the tuberculosis problem is almost exclusively confined to ethnic minorities, socially marginal groups, and migratory workers. All the countries of Latin America have adopted the programs for tuberculosis control recommended by the World Health Organization and the Pan American Health Association. The degree to which these programs are followed in Mexico is critically discussed. A number of suggestions are offered to improve a program that appears to be insufficient in terms of controlling this disease. PMID- 20841171 TI - The health educator as a team leader in primary health care. AB - Health teams naturally vary in size and composition according to their goals and objectives. Leadership of these teams should also be based on these goals. The goals of community-based primary health care, local involvement, cultural relevance, effective use of local resources, imply an important leadership role for health educators. The experience in the Ibarapa Local Government Area in Nigeria shows that health educators can be effective leaders in guiding a primary health care work group through various stages of program development. The use of a flexible, contractual model of team formation fits in well with the health educator's abilities to coordinate various program inputs and serve as mediator between professionals and the communities they serve. The ultimate mark of the health educator's leadership skills is the incorporation of community members into the health team. PMID- 20841172 TI - Sexual behavior and AIDS in sociocultural perspective. AB - AIDS, its cause, effect, and possible cure, has become a complex sociopsychological issue with ramifications extending far beyond the purely medical sphere. Spreading rapidly, with a higher incidence rate recorded among young people, the disease transcended the biomedical sphere, presenting sociocultural and psychological ramifications that go beyond its physical impact. With a higher incidence rate among male homosexuals, the epidemic raises morally sensitive questions which further confuse an already clouded picture. Current knowledge on the sexual transmission of AIDS and the role of male homosexuality demonstrates the need for more serious research into the various social and cultural aspects of homosexuality itself. To this end, medical anthropology may provide important information to those dealing with educational and preventive programs for the general population, as well as those in high risk groups for acquiring the disease. PMID- 20841173 TI - How Basic Beliefs about Human Life Relate to Ethical Judgments about Induced Abortion. AB - This survey explores family planning field workers' basic beliefs and value assessments related to a new human life and their relationship to their verbal statements of ethical judgments about induced abortion under varying circumstances. It also relates these beliefs to stated experience of abortion referrals. Implications for education and research with application to many international social issues are discussed. PMID- 20841174 TI - Public health knowledge levels of different types of jordanian teachers. AB - This study examines the level of health knowledge of specific categories of Jordanian teachers to see which category is competent enough to teach health as a separate school subject. The Health Awareness Test (HAT) was administered to 670 teachers of whom there were seventy-four science teachers at the compulsory stage, 139 Arabic language teachers at the upper elementary stage, 342 elementary grades teachers, thirty-four high school physics teachers, thirty-three high school chemistry teachers, and forty-eight high school biology teachers. The data analysis revealed that of the target groups, only female teachers of biology, chemistry, and physics and male teachers of biology, reached the acceptable level in knowledge about health as measured by HAT. Sex as well as specialization (the subject the teacher teaches) differences were found to be significant favoring female over male and biology teachers followed by chemistry teachers over the rest of the groups. The interaction between sex and specialization was not significant The implications of the above results for curriculum planning are discussed. PMID- 20841175 TI - Health education and prevention: designing community initiatives. AB - Health is a community as well as individual concern. Efforts to address public health problems should be based on an integrated approach to prevention that addresses community level as well as individual level concerns. This article reviews five basic principles of a planning approach to prevention. Planning concepts that follow from the principles include: entrance into the community, problem identification, identification and understanding of assumptions, force field analysis and public education. The implications of the planning process for intervention are discussed. PMID- 20841176 TI - Community participation: the maasai health services project, Tanzania. AB - The Maasai Health Services Project in northern Tanzania is a primary health care undertaking in which individuals chosen by their communities are trained as providers of selected preventive and curative services, including family planning, and as facilitators of change in their areas. The communities, through the selection, support, and supervision of these community health workers (CHWs), are actively involved in every stage of project activities. This article examines in detail the process through which community management of the project is promoted. Important elements within this process include: 1) holding several unhurried meetings with community members and leaders to discuss health problems and solutions fully; 2) cultivating leadership and management from within the community while providing technical assistance from the outside; 3) working with CHWs who are selected by their communities; 4) conducting the training of CHWs in their own communities instead of at a distant site; and 5) integrating community organization skills and activities into CHW training. Some of the lessons learned are that 1) project staff must resist the role of expert and maintain that of facilitator; 2) the pace of the project must be in step with the communities' understanding and readiness to accept it; 3) the role of the CHW must respond to the urgently felt need for curative services; the real need for preventive services, such as family planning; and the long-range need for social change; and 4) the project must respect the traditional social structure of the Maasai and Waarusha groups served and must also recognize and adapt to the differences between them. PMID- 20841177 TI - Promoting primary health care in contiguous urban and rural populations: Nigeria. AB - The World Health Organization's goal of "Health for All by Year 2000" through Primary Health Care (PHC) is commendable, but can only be attained with the involvement and collaboration of the non-health sectors as well as the health community. Thirteen rural and urban communities in Nigeria were assessed to develop social, health and primary health care profiles. A model for introducing PCH applicable to these communities was prepared. PMID- 20841178 TI - Teaching Medical Students How to Talk with Patients about Cardiovascular Risk Factor Modification. AB - Although medical students are increasingly taught about the nature and importance of cardiovascular risk factors, they are less often taught how to talk about them with patients and how to encourage patients to modify certain behaviors (e.g., smoking), which are associated with high risk for cardiovascular disease. The authors describe a short educational module designed to help third year psychiatry clerks learn some practical, patient-oriented aspects of preventive cardiology. From a small group discussion that encourages active participation, students learn to assess and explore environmental factors, skill deficits, cognitive distortions and emotions that may prevent patients from changing high risk behavior. Strategies for change are then suggested, discussed and assessed for effectiveness in sample situations. This type of module is readily adoptable into most medical school psychiatry curricula and, if widely used, could promote the necessary skills to effectively change high-risk behaviors and lead to a further reduction in cardiovascular disease. PMID- 20841179 TI - The life and death of a health promotion program: an institutionalization case study. AB - This article presents a case study of a health promotion program that successfully operated for four years but terminated when its federal and state funding ended, i.e., it failed to become institutionalized. The program, which was funded under the federal health education-risk reduction grants, was directed at preventing use of alcohol and tobacco among young adolescents. Evaluations indicated that the program was highly successful. The authors argue that health promotion programs can be viewed as organizational innovations in which institutionalization is the final stage of the innovation process. In the case study, institutionalization did not occur for two reasons: 1) demonstration of effective implementation was the health department's primary goal, and program institutionalization was only a latent concern and; 2) both the county commissioners and the community feared federal and state "dumping." The "CODAPT" model of health education program planning is presented as one way of dealing with the problem of "deep" program implementation but "shallow" institutionalization. Implications of these findings for health education practice and policy are discussed. PMID- 20841180 TI - Asking Sensitive Behavioral questions in Telephone Interviews. AB - This article presents the results of a small pilot study to test the feasibility of telephone interviews for collecting highly sensitive data for a study of the etiology of trophoblastic disease. The study design allowed us to compare data from telephone and face-to-face interviews. The results suggest that very sensitive information can be obtained by telephone and that respondents interviewed by telephone may be more willing to report socially proscribed behavior than respondents interviewed face-to-face. A number of unanswered issues are suggested for future research. PMID- 20841181 TI - Interest in information as a function of worry and perceived control in the aftermath of nuclear disaster. AB - A survey of residents in the vicinity of the Three Mile Island nuclear generating facility four years after the accident examined level of interest in cancer detection and treatment, radiation monitoring, and epidemiology of cancer as a function of degree of ongoing worry, perceived control and demographic variables. Interest in information was found to be related to worry for all three topics, indicating that residents who had higher degrees of worry were more interested in seeking information than avoiding it. Control expectancy was related to interest in information about epidemiological distribution of cancer. Implications for the dissemination of information in the aftermath of a disaster are discussed. PMID- 20841182 TI - Participation in child health and family planning activities in rural southern ghana. AB - A variety of child health and family planning activities, conducted by the Danfa Project in Ghana, were evaluated from a behavioral standpoint to determine features of programs which encourage participation by village mothers. Interest, intent to participate, and actual participation rates were measured. Contrary to expectations, activities which demand greater participation were more popular than more passive activities which involved lectures. Activities related to child health were better received than family planning activities alone. Barriers to participation which were best predictors of actual participation included "selling goods in town," "cooking," or "busy with housework." That these were ranked by respondents as weak barriers suggests that it didn't take much to dissuade mothers from participation in those activities that they felt had little merit. Study findings suggest a need for greater integration of activities into village schedules, more systematic targetting of activities to high-risk groups, more activities demanding greater participation, and direct promotion of activities through influential individuals (community leaders, traditional healers). PMID- 20841183 TI - Doctor, Tell me I am Sick: Physician Response to Patient Psyco-Social Problems. AB - Considerable evidence indicates that non-psychiatric physicians devote considerable time in dealing with the psychosocial problems of patients. At the same time little is known about the kinds of problems patients present or how the physician responds to these problems. In an effort to determine both the kinds of problems presented and physician response, direct observation of physician/patient interactions and content analysis of patient records were carried out. Five dominant responses of physicians were identified and discussed in detail. In addition, patient expectations and interactions with physicians are explored. PMID- 20841184 TI - Community health intervention program (chip): re-educating health professionals for primary health care. AB - Primary health care (PHC) in most developing countries remains largely inaccessible to a vast proportion of urban and rural populations. It is neither influenced by, nor integrated with, preventive care/community development. This may be attributed partly to lack of community participation by communities. Professional health care is isolated and impervious to the influence of health care users. In Nigeria all functional correlates are available in the existing health systems; yet, the impact is not felt. What is needed, and urgently, is an intervention to extend meaningful health care delivery into the urban poor and rural communities. The Nigerian Youth Service Corps (NYSC) scheme, through a rational and systematic mobilization and utilization of its health manpower, offers an excellent opportunity to demonstrate that PHC can work. A two-step intervention process is proposed: a reorientation during NYSC "orientation," and a community-based practice module, during the NYSC "Primary Assignment" phase. Health professionals working as a "team," and led by NYSC doctor(s), undertake their medical care responsibilities as well as community development projects as integrated aspects of PHC. It is envisaged that experiences accruing from such a deliberate intervention with a pilot project, will form a basis for operational adoption of the proposed CHIP as a national model. PMID- 20841185 TI - Building families through intercountry adoption. AB - In the United States today, one in six couples face the problem of infertility. Although advanced medical techniques will be able to help about half of those couples, the remainder will stay childless. For those adults who desire the parenting experience, adoption is an important solution. Since healthy, adoptable infants are increasingly difficult to find in the United States, parents wanting to adopt are looking elsewhere. Intercountry adoption offers a solution to the problem of not being able to find healthy infants for adoption. Adopting from a foreign country is an option which is being selected by more and more Americans who wish to add to their family. PMID- 20841186 TI - Marketing corporate wellness programs to small firms: a challenge for health educators. AB - Despite significant growth in the number of corporate wellness programs during the past decade, their full potential for improving health and reducing corporate health costs has yet to be realized. Most small firms still fail to offer any health promotion programs to their workers and many programs presently in place are poorly organized and fail to address employee needs. In order for the corporate wellness movement to gain momentum, health educators must overcome the misconceptions many small business people share about corporate wellness programs. In order for these programs to become viable, health educators need to become effective marketers incorporating the social marketing components of product, price, place, and promotion. Based on these components, this article outlines strategies the health educator can utilize when approaching, planning, or implementing health promotion programs for small businesses and concludes with a number of recommendations concerning appropriate program evaluation and follow up. PMID- 20841187 TI - Education and family planning among black american women. AB - The factors which relate to family planning and fertility-related attitudes and practices among black Americans are not well understood. This study evaluates the importance of three demographic factors (level of education, age, and region) in predicting such fertility related variables. Black women between the ages of fifteen and forty-five (N = 1,074) living in either a northern or a southern city were interviewed. The fertility-related variables included knowledge of, attitudes toward, and usage of various family planning methods; desired, ideal, and actual family size; and fears of race genocide. Using a three-factor (education, age, and region) Analysis of Variance for each of the dependent variables, education emerged as the most powerful and the only consistent predictor of the several fertility-related variables. Only desired number of children was unrelated to level of education. Such findings provide support for the contention that black fertility levels would be the same as that among whites, if access to equal educational opportunity were available to Blacks. PMID- 20841188 TI - Patterns and Predictors of Cigarette use Among Public School Children in Tijuana, Mexico. AB - The use of cigarettes and other forms of tobacco poses a major and growing health threat to populations of developing countries. The present study examined the onset of cigarette use among public school students in Tijuana, Mexico. Fifty four percent of the males and 34 percent of the females had experimented with smoking. Maternal smoking was more strongly associated with smoking among girls, while peer smoking had a relatively stronger association with future intentions to smoke among boys. Rates of smoking behavior among Mexican-American school children in nearby San Diego more closely resembled the higher rates of their Tijuana than those of their Anglo-American counterparts. PMID- 20841189 TI - A multicomponent minimal intervention health promotion program: preliminary results. AB - This article reports two preliminary studies examining whether a minimal intervention cardiac risk education program incorporating behavioral components to enhance self-efficacy could effectively change health behaviors. The first study utilized a quasi-experimental design in evaluating workshop outcome among 131 AFL-CIO union members. A MANCOVA performed on self-report and physiological outcome measures suggested a significant difference between treatment and waiting list control groups, primarily in the area of nutrition. In the second true experimental study, participants were 307 "at-risk" employees of a local school system. A MANCOVA at a four month follow-up revealed significant differences in several reported health behaviors including Type A behavior, smoking, and nutrition. Results also showed the program's effectiveness was consistent across sex, age, and severity of participants' health risk. Implications for further research on the cost-effectiveness of brief health promotion interventions are discussed in light of the observed impact and the high level (80%) of employee interest and participation. PMID- 20841190 TI - Nutritional assessment of primary school children in papua new Guinea: implications for community health. AB - The nutritional status of primary school children (N = 1453) was assessed using weight-for-height (W/H) and twenty-four hour food recall records. Using WHO standards, 21 percent of the students were within the standard W/H. Of the remainder, 71 percent were within 5 kg. of standard W/H, and 8 percent deviated more than 5 kg. from the standard W/H (5% underweight and 3% overweight). The dietary data collected from Grades 5 and 6 (N = 425) revealed a daily food intake of 1.6, 2.8, and 7.7 servings of protein, protective, and energy foods, respectively, as recorded in local servings. Sixty-five percent of the subjects consumed foods from all three food groups. Twenty-four percent consumed no protein, 14 percent consumed no protective food, and 2 percent consumed neither protein nor protective food. The variety of foods available varied from school to school-3-11 protein foods, 7-15 energy foods, and 8-18 protective foods. To improve nutritional status, government leadership in the areas of education, health, and primary industry will be required. All divisions adhere to the National Food and Nutrition Policy which promotes local rather than imported food. PMID- 20841191 TI - A community organization-peer facilitated senior citizen health promotion program. AB - This project addressed hypertension, considering the variables of exercise, weight, blood pressure measurement, medication compliance, and nutritional practices while incorporating principles of self-responsibility for health. Major intervention activities included a three-times weekly exercise program; weekly weigh-ins; bi-weekly blood pressure checks; physician referral for anti hypertensive prescriptions/maintenance; diet instruction; and peer facilitated health educational activities. Additionally, community support and project volunteers were obtained via various community organization strategies, such as community meetings, newspaper articles, or from advisory board activities. Major "everyday grass roots" responsibilities for program implementation were carried out by a peer senior citizen community organizer and a peer senior citizen health educator, with strong guidance from the Area Agency on Aging. Evaluation activities were based on the measurable impact and process objectives. T-tests were used to analyze weight and blood pressure pre-post data for the seventeen mostly female clients with an age range of sixty-four to eighty-eight and a mean age of seventy-five. T-values for weight, systolic blood pressure, and diastolic blood pressure were 21.02, 2.09, and 11.08, respectively, indicating significance (.00 or .05 level). Lastly, fourteen individuals lost a total of eighty-nine pounds; six individuals were able to re-enter acceptable blood pressure limits; and participants are accepting greater responsibility for their own health. PMID- 20841192 TI - Focus group methods for formative research in child survival: an ivoirian example. AB - The study reported here represents the ongoing development of focus group interview methods in support of health education planning for child survival programs in the CCCD project in Sub-Saharan Africa. Using illustrative examples from a field experience in Cote d'lvoire, methods that enhance the usefulness and validity of focus group interviews for health program planning are discussed. PMID- 20841193 TI - A View from within: Midwife Practices in South Texas. AB - This article describes midwife practices and recommends a possible training program for midwives in South Texas. A 100-item questionnaire was administered to twenty-five practicing midwives in South Texas. All the interviews were tape recorded. The midwives were all women and they ranged in age from thirty-eight to eighty years old. A qualitative analysis of these interviews indicates that a midwife training program is necessary to standardize and upgrade the practice of midwifery in this area. In addition, all midwives interviewed expressed an interest in participating in a training program. Finally, recommendations are made for designing a training program that would be efficient and culturally relevant to this midwife population. PMID- 20841194 TI - Patterns of mass media use among Hispanic smokers: implications for community interventions. AB - A relatively large percentage of Hispanics in the United States smoke. Yet a large proportion of Hispanics are light smokers, smoking ten or fewer cigarettes per day. Previous research has shown that most light smokers quit smoking on their own and that health education and an environment conducive to non-smoking can have a significant impact in reducing smoking rates. Given the current smoking patterns of Hispanics, culturally appropriate media-based community intervention to promote smoking cessation can have a significant impact. This study identified patterns of media use and language preference among a sample of 263 Hispanic smokers from the San Francisco Bay Area. Based on this study, recommendations to reach Hispanic smokers with a series of communication strategies are suggested. PMID- 20841195 TI - Organizational Development as a Health Education Strategy to Maintain Community Involvement in PHC Management. AB - Primary Health Care programs should not stop with the training of PHWs. Not only do these village-based workers need regular supervision; they also need continual access to the resources required for them to carry out their duties. Formal health agencies have had difficulties in meeting these demands for supervision and management on the scale required to bring health to all in even the remotest hamlet. There is consequently a need to look for ways that a community can manage its own PHC program. Efforts to develop a PHW Association in Idere, Nigeria, have shown that self-management is a realistic goal. They have also shown the need for health educators to focus on organizational and leadership development as part of their contribution to primary health care. PMID- 20841196 TI - Promoting safer foods in latin america and the Caribbean. AB - This article describes the current trends in public health promotion and education in Latin America and the Caribbean. It gives examples of approaches that work and highlights some of the difficulties of concentrating strictly on the use of mass media communication. Various programs and projects for promoting the safe handling of foods are cited from specific countries and subregions in the Americas. Looking back on what has worked and what has failed, the authors recognize that some advancements have been achieved in improving the public's handling and protection of food, particularly in the tourism sector, and yet many challenges lie ahead for improving upon what has already been done. PMID- 20841197 TI - Objectives and the past-community health education. PMID- 20841198 TI - Orchestrating the points of community intervention: enhancing the diffusion process. AB - Recent interest in community-based health education programs has emphasized the need to promote change in social systems, as well as individual behaviors. The problem is where and when to intervene to effect these multiple levels of change. Components of community programs have tended to be implemented simultaneously at only one or two points within a community. A potentially more effective approach would consider both where differing types of people can be reached, and the appropriate time to intervene at each point, to maximize the effective diffusion of information and behavior change across the community. The present article outlines eight points of community intervention including centers, institutions, major media, minor media, special events, formal social networks, informal social networks, and created social networks. A sequencing of intervention efforts at these points is proposed which is predicated on their role in regard to the need for preparation, public awareness, notification about planned events and implementation of the program. The proposed orchestration of the points for community program implementation capitalizes on the diffusion process and on the synergistic effects of multimodal education efforts. PMID- 20841199 TI - A community health education program on malaria in Nigeria. AB - This study determined the effect of a health education program on malaria disease control among the citizens of Nkanu-local government area, a community in Nigeria. Participants consisted of subjects that used the Nkanu community hospital for their health care. Initially, 300 subjects were randomly selected for the study (150 experimental and 150 control) from Ama-nkanu village, but only 202 subjects completed the study. Results of the pre- and posttest on field tests and that of posttest on knowledge acquisition demonstrated significant differences between the two groups on knowledge and environmental improvements. The treatment group performed better than the control group on the knowledge test. On the environmental tests, the experimental group also demonstrated noticeable changes (improvements) when compared to the control group. PMID- 20841200 TI - Eating attitudes, dieting, and bulimia among junior high school students. AB - Students in a western New England (U.S.) junior high school (ages 11-15) were surveyed in 1986 to identify attitudes and behaviors about eating and dieting which might foster disordered eating habits. Although few students met official criteria for disordered eating habits, at least 12 percent did practice dieting and 28 percent were frequently preoccupied with the desire to be thinner and/or were terrified of being overweight. One-quarter of girls (vs. only 3.2% of boys) mistakenly classified themselves overweight. Perception of one's own weight seems to be more highly correlated with measures of eating attitude and behavior than does actual weight. Differences also were found in how males and females viewed their own weight although both dieted to about the same extent. Females also were more interested in having school classes on eating and dieting. Recommendations were made for prevention and education regarding eating disorders among this age group. PMID- 20841201 TI - Health knowledge of nursery school teachers in northern jordan. AB - This study investigates the level of health knowledge of nursery school teachers in Northern Jordan. The Health Awareness Test (HAT) was administered to a sample of sixty teachers (66.7% of the population). The data analysis revealed that health knowledge among these teachers, in general, was much lower than the acceptable level determined by the HAT. Neither the teaching experience, academic degree, or marital status seemed to have influence on health knowledge on any of the dimensions covered by the HAT. In addition to the above results, the study revealed that the major sources of health knowledge among these teachers, ranked by order, were: self-education, mass media, education programs of the Ministry of Health, family, inservice training programs, and academic preparation. The implications of the above results are discussed. PMID- 20841202 TI - Sexual behavior and contraceptive use by adolescent pupils in the republic of bophuthatswana. AB - Cluster sampling was used to identify thirty clusters from which a total random sample of 210 pupils aged thirteen to eighteen were drawn to assess their sexual and contraceptive behavior. The mean age of the sample was 15.2 with a mean age at menarche of 13.8, a mean age at first coital experience of 14.9 and a mean age at commencement of contraception of 15.6. One hundred and seventy-four (82.9%) of the respondents reported general knowledge about contraceptives that was obtained from a variety of sources, 101 (48.1%) reported to be sexually active and thirty one (14.8%) to be using contraceptives. Although no statistically significant relationship was found between age and contraceptive use, a statistically significant correlation (p < .001) was found between age and age at first coitus. PMID- 20841203 TI - Citizen Involvement in Community Health Promotion: A Role Application of CDC's PATCH Model. AB - In response to the need for population-based strategies for health promotion, the U.S. Centers for Disease Control (CDC) have been conducting "The Planned Approach to Community Health" (PATCH) since 1984. PATCH is a demonstration process to strengthen the collective capacities of states and communities to plan and deliver community health promotion programs targeted at community-determined priorities. Drawing upon lessons learned from mobilizing citizens in an upstate New York population of 9000 households, the five elements of the PATCH process: 1) coalition building, 2) data collection, 3) problem specification and priority setting, 4) intervention planning and implementation, and 5) evaluation, are illustrated. PMID- 20841204 TI - Predicting adolescent blood pressure: implications for health education practice. AB - The study was set up to potentially determine if a stepwise multiple regression model composed of such factors as sociodemographics, attitudes, and behaviors in combination with selected biomedical measures can be used to predict adolescent at risk health conditions such as hypertension and to examine the implications for health education practice. The study population consisted of 650 ninth grade (14-16-year-old) students in the baseline survey (1981) and 606 twelfth grade students in the final survey of 1985. Data collected included clinical measures of height, weight, triceps skinfold thickness, blood pressure, body mass index (BMI), resting pulse, and percent ideal body weight (PIBW). Self-reported health behaviors, attitudes, and sociodemographic variables were also assessed. Principal factor analysis with varimax rotation was employed to determine the grouping of the behavioral/attitudinal test items. Stepwise multiple regression analysis was used to determine the variables' potentials as predictors of blood pressure in adolescents. Significant potential predictors of male diastolic blood pressure included smoking, alcohol intake habits, obesity, pulse, race, age and parents' socioeconomic status; while predictors for the females focused on smoking, alcohol intake habits, stress, obesity, pulse and race. Potential indicators for male systolic blood pressure were smoking, alcohol habits, weight, height, race, parent's socioeconomic status; while smoking, alcohol habits, stress, obesity, pulse and race for the females. Community health promotion, prevention and educational programs directed at these potential predictors need to be implemented to encourage healthful lifestyles in the younger generation. PMID- 20841205 TI - Factors Affecting the Perceived Confidence of Extension Home Economists to be Community Health Promoters. AB - Change agent activity is critical to how rapidly innovations in health such as exercise, diet modification, and cancer screening get diffused in populations. Because many rural areas lack health educators, and needs in rural areas tend to be more acute because of poverty, lower levels of education, and lack of access to health care services, diffusion is often slower and more uneven. A mail survey of 110 extension home economists (EHEs) in Virginia (response rate = 89%) found considerable interest among this group in undertaking expanded professional roles as community health promoters. In a multiple regression analysis, EHE exercise and weight control practices were predictive of their confidence in initiating a variety of professional activities related to exercise (p < .01) and weight control (p < .05), but the same relationships were not observed with other health practices. Perceived importance in helping clients following the health practices above was the variable in the regression model most highly predictive of expressed confidence in undertaking a range of health promotion activities. Several extension home economists expressed reluctance to become involved with smoking cessation activities because tobacco is a major cash crop in their counties and their organization provides technical assistance to tobacco growers there. PMID- 20841206 TI - Enlisting the support of traditional healers in an AIDS education campaign in zambia. AB - A nationwide AIDS education campaign in Zambia was constrained by lack of support from traditional healers. First, some of them did not appreciate the nature of the new disease, and second, others hampered the education efforts by publicly claiming that they possessed curative and/or preventive medicines for HIV infection. To overcome communication barriers, the health education unit convened a workshop for traditional medical practitioners and their orthodox counterparts. An important feature of the workshop was interactive participatory small group discussion. At the close of the workshop significantly more healers understood the nature of AIDS and were willing to participate in the national information and education effort against AIDS. PMID- 20841207 TI - Reorientation in primary health care implementation: an educational intervention. AB - The study was designed as a three-phase approach to reorient Community Health Officers working in Odukpani (one of the first model PHC Centers in Nigeria) toward Primary Health Care: 1) knowledge, attitude, and practice determination; 2) a PHC-based training module; and 3) teacher-learner evaluation. The results strongly suggest that this type of deliberate intervention to remove an identified program constraint, is crucial to the anticipated role of PHC workers as agents of change. The implications of the results for PHC system development in Nigeria are highlighted. PMID- 20841208 TI - The secret health care system: guatemala 1988. AB - There is currently widespread use of health care by undemocratic governments in an effort to control elements of their populations. A number of recently published articles have dealt with this problem. What has not been widely reported is the peoples' response to this situation. This article relates the response of the people of Guatemala and addresses those conditions in Guatemala that reflect the health needs of the people and the government's measures to meet and use these needs for political and military ends. The peoples' response, namely the creation of a clandestine health care system based on the secret training and practice of village health workers is presented. The data were obtained by personal observations, interviews and accounts from recently published periodicals. PMID- 20841209 TI - Consulting to change media contents: two cases in alcohol education. AB - Two ten-year studies featuring intervention with media on the topic of alcohol are presented. The method of intervention, called cooperative consultation, is described and contrasted with other methods. Earlier experience dealing with prime-time television program personnel is reported. The first study involved a soap opera, which proved different from prime-time programs. Using the methods of content analysis, before-and-after studies found change in the desired direction. The second study was done with a business columnist on a daily newspaper. Again, before-and-after tests showed the indicated change-in some categories more than others. The efficacy of particular characteristics of the method of cooperative consultation are noted, and further work in related areas is suggested. PMID- 20841210 TI - Promotion of breast self-exam behavior: an attempt to modify health beliefs. AB - The aim of this project was to alter health beliefs to promote the regular practice of breast self-examination (BSE). A total of fifty-seven female university students ranging in age from nineteen to forty-four were selected to participate. Experimental subjects viewed a videotaped message designed to educate them about breast cancer and BSE. Control subjects viewed a presentation about preventive health behaviors other than BSE. The no-treatment control subjects received no behavioral intervention. All subjects completed a pretest and posttest measure of health beliefs. Follow-up data obtained included BSE reports each month for a six-month period for experimental and control subjects. The overall rate of BSE for both the experimental and control subjects increased at the outset of the experiment and declined during the course of the project. The present investigation appeared to be as successful as other interventions attempting to encourage the regular practice of BSE. PMID- 20841211 TI - Immunization drop-outs and maternal behavior: evaluation of reasons given and strategies for maintaining gains made in the national vaccination campaign in liberia. AB - Through annual National Vaccination Weeks, Liberia, one of thirteen African countries participating in the CCCD program, has achieved good rates of initial vaccination coverage against childhood diseases. However, rates of completion have been disappointing. Described is a community-based operations research methodology for a.) identifying reasons for non-completion of the vaccination series according to groups of mothers, front-line health workers and country level administrators, b.) for making recommendations for alternatives in the delivery system, and c.) for critiquing the focus group methodology as a tool for increasing commitment to program goals. PMID- 20841212 TI - Perceived advantages and disadvantages of nonsmoking sections in restaurants: topics to communicate to restaurateurs. AB - Results from interviews with 315 restaurateurs in San Francisco are reported on their perceptions of the advantages and disadvantages of having a nonsmoking section in their restaurants. The major advantage of having a nonsmoking section independent of whether one is present is to please customers. The most commonly mentioned disadvantage for those restaurants with nonsmoking sections is the fact that it is inconvenient to clients' seating preferences primarily because it breaks up dining parties. Efforts at convincing restaurateurs to set up nonsmoking sections may be directed at pointing out savings in cleaning, labor, insurance, and the improvement of the health of their employees together with meeting clients' desires. PMID- 20841213 TI - Treatment of malaria and febrile convulsions: an educational diagnosis of yoruba beliefs. AB - An understanding of community perceptions of illness, especially disease definitions that are unique to a particular culture, is essential for developing culturally appropriate primary health care programs. Malaria is endemic in the Ibarapa District of Oyo State, Nigeria, and one of its major complications, febrile convulsions, affects nearly one-third of preschool children at least once in their lifetime. Perceptions among the local Yoruba people categorize malaria and convulsions as part of two different disease processes. Ideas of causation, severity, seasonality, and treatment are in many ways opposites. This means that parents do not perceive the dangers of convulsions when their children suffer malaria. Unfortunately the small children themselves cannot be part of the decision-making process which involves potentially toxic treatment practices. Based on an understanding of Yoruba beliefs, primary health care and health education interventions have been designed that encourage parents to take prompt action when they recognize that their child has malaria. PMID- 20841214 TI - Healthy public policy in Canada: a survey of ontario health professionals. AB - "Healthy public policy" has become a catchphrase of the "new" health promotion. The concept, however, remains vague and lacking in practice. A survey of Ontario public health workers was conducted in June 1988, using the World Health Organization's Second Health Promotion Conference Declaration on Healthy Public Policy as a source of policy statements and action areas. Results are constrained by a low response rate (22.5%, N = 180), but indicate a high degree of support for healthy public policy concepts by senior level public health workers. Social environment policy issues (notably child poverty and unaffordable housing) are highest ranked priority issues, although physical environment (pollution) ranked most important when respondents were asked to choose a single issue. Lifestyle health issues are relatively low-ranked, although they remain priorities for action by respondents and their employers. The Canadian and Ontario Public Health Associations are thought to have the best analyses of healthy public policies, but are not seen as prominent policy actors. Government and media are considered weakest in their analysis of healthy public policy. Respondents' comments indicate a willingness to strengthen their role, and that of their health associations, in advocacy for healthy public policies. PMID- 20841215 TI - Direct contract public health training between an asian government and a u.s. University: 1984 - 1988. AB - A one-semester, non-degree public health training program for staff of various levels of health agencies in Taiwan conducted at the School of Public Health, University of Massachusetts, Amherst during 1984-88 is described. The project's evolvement, organization, specific training objectives and methodology, operation, cost, and evaluation are reviewed. Attention is paid to training feasibility and the advantages of avoiding third-party sponsoring agencies in international projects. PMID- 20841216 TI - Monitoring use of monofilament nylon water filters for guineaworm control in a rural nigerian community. AB - Guineaworm, a disabling waterborne helminthic disease, has been targeted for eradication from endemic areas of Africa and South Asia. One short-term intervention consists of filtering pond water through a clean cloth. Monofilament nylon cloth has been found to be more effective in straining out the vector various species of the small crustacean, cyclops-than local cotton cloth, though the former is more expensive. A concern with any new technique is whether the community will accept the idea and subsequently use it properly. Previous reports in this series have documented the process by which the rural community of Idere, Nigeria, through its volunteer primary health workers, was involved in production, distribution, and education concerning filters. One-third of households in monitored sections of the community bought filters, while others thought that filters could not prevent the disease, cost too much, or were inferior to other solutions (e.g., wells). This report looks at filter use and factors associated with use and durability. Monthly monitoring visits by a field assistant served to identify problems and reinforce correct and continued filtration. Mobility of the population between farm and town hampered regular use. Difficulty in understanding the nature of the nearly invisible vectors meant that users did not perceive tiny holes in their filters as dangerous. While filters were ultimately seen as useful in guineaworm eradication efforts, they should not take the place of more long-term community water supply interventions which will have a greater impact on community and women's development. PMID- 20841217 TI - An examination of the performance and motivation of indonesian village health volunteers. AB - Indonesian "kader Posyandu" or village health post volunteers are a key link in the provision of primary health care services and health education to this country's 170,000,000 inhabitants. Yet little is known about the quality of service that they actually provide, with most existing data being derived from their own self-reports or from those of the mothers they serve. Moreover, it is widely acknowledged that inadequate kader motivation and subsequent high rates of dropout are a chronic problem for the Indonesian primary health care strategy, creating frequent disruptions in service as well as the necessity for continual recruitment and training efforts. The present study was conducted to shed further light on these issues through observations of kader behavior during village health post clinic days. These observations emphasized the amount and type of health education related to child survival that was performed by the kader. Subsequent interviews with kader, mothers, and village leaders complemented these observational data and provided further information on present and potential motivators for kader. The observations indicated that while kader performed growth monitoring, immunization, and other village health post clinic activities appropriately, they failed to take advantage of opportunities to educate mothers in nutrition, oral rehydration, and other important skill areas. In turn, interviews indicated that while money for services rendered could be a powerful motivator for these volunteers, they felt that even more important, given limited resources, was an expression of appreciation on the part of the community being served. These data have proved critical for the design of a health communication campaign seeking to improve kader performance and lengthen their term of service. PMID- 20841218 TI - Components of self-rated health among adults: analysis of multiple data sources. AB - Four data sources were used to examine competing interpretations of self-rated health measures: whether they are best classified as summary indicators of both physical and psychological health status, or merely as surrogate measures of physical health. Multiple regression analysis revealed that, within each data source, measures of physical health and depression were each independently associated with general health status ratings after six sociodemographic indicators (sex, race, age, education, income, and residence) were held constant. These results were confirmed using both cross-sectional and longitudinal models, and using several different indicators of physical health. They suggest that researchers should be cautious in interpreting global health ratings, as they contain significant information regarding the psychological, as well as physical, health status of respondents. PMID- 20841219 TI - Health behavior research toward health for all: issues and schema. AB - Health behavior research is concerned with the social, cultural and psychological determinants of health. Implicit in this is a focus on action that will lead to real-world improvements in health for the individual and in the community. Research in this area should not lose this focus. Programmatic needs must be understood if support is to be gained from policy makers. Along with the relevance of research, staff training is a key part of bridging the gap between the discovery of new knowledge and action to improve health. PMID- 20841220 TI - A conceptual model for culturally appropriate health education programs in developing countries. AB - Increasing numbers of health educators in industrial nations are showing interest in and developing health education programs for developing nations. Cultural sensitivity and appropriateness, or the lack thereof, are often cited as significant factors in program successes or failures. In this article, a conceptual model (The PEN-3 Model) that focuses on cultural appropriateness in the development of health education programs in developing countries is presented. Health educators are encouraged to use this model to ensure empowerment through promotion of positive behaviors, and to recognize and appreciate unfamiliar behaviors while attempting to modify negative behaviors. PMID- 20841221 TI - Health, race, and academia in america: survival of the fittest? AB - Health educators need to understand how the cultural environment of academe contributes to the problem of Black underrepresentation particularly in the health/academic professions. The issue of the public health of Blacks is linked to the levels of Black representation at the predominantly White institutions of higher education. Several points are articulated: 1) The health of African Americans is inextricably influenced by socio-economic status, of which education attainment is a major factor; 2) Black scholars play a significant role in Black student matriculation, thus enhancing the well-being of Blacks as a group; and 3) Institutionalized racism is built upon a foundation of an individualistic ethic regarding university faculty promotions, which in turn provides a traditional advantage to White faculty and hinders Black faculty within White academic institutions. Unless the representation of Black faculty and students is increased, the 1990s is likely to exacerbate still further conditions of inequalities in health, academe, and society. PMID- 20841222 TI - Health for all by the year 2000-cultural handicaps and possible solutions. AB - Health conditions, as part-and-parcel of man's project of life, reflect the way people choose to live together as a collective body. Health behavior analysis cannot ignore cultural conditions that foster different ways of life. Health practices are not a matter of mere compliance to a set of norms, but a cultural product. Professional competencies ask for a sufficient curriculum, a full proficiency. Myth and logos should be related and the symbolic form everyday experience assumes should be discussed. Paradigmatic thought should give place to mutual growth and subjective and objective aspects of reality should have an equal and complementary standing. Disciplinarity and multidisciplinarity should evolve into interdisciplinarity, as a paradigm of cooperation, interconnection, equality, and flexibility in order to define curricula and programs. Conceptual ecology of science should be emphasized. New concepts of growth, wealth, work, and power should be discussed as a way of attaining health for all in the year 2000. PMID- 20841223 TI - How teens think about drugs: insights from moral reasoning and social bonding theory. AB - This article reports the results of a qualitative analysis of in-depth interviews focusing on the relationship between moral reasoning and the decision to initiate adolescent substance use. Ninety-five eighth-grade students, roughly equally divided among non-users, experimental users and experienced users, were interviewed following an open-ended, semi-structured protocol on issues pertaining to the psychological and sociological domains of moral reasoning. Drawing on cognitive-developmental psychology and social bonding theory, the analysis reveals three contrasting patterns of thinking in students' decisions about whether or not to try drugs. In ascending levels of importance, these three patterns are: 1) perceptions of harm; 2) perceptions of personal choice; and, 3) perceived degree of institutional embeddedness. The implications of these findings for current policies and prevention programs are discussed. PMID- 20841224 TI - Improving vaccination completion rates in liberia: evaluation of an intervention trial. AB - Reported are findings from an evaluation of a community-based strategy employing local chiefs and traditional midwives as extenders of the Ministry vaccination team for the purpose of increasing vaccination completion in Liberia, West Africa. The intervention strategy-a training workshop and two subsequent supervisory visits-was selected from among those generated in Stage 1 of a three stage operational research design. Evaluation of the intervention was carried out after an eight-month follow-up period. Visits to intervention and control villages, for the purpose of interviewing chiefs, traditional midwives (TMs) nand mothers of children under one year of age, were the means by which data were gathered. Both process and outcome indicators were identified as means of assessing the effectiveness of the strategy. Vaccination rosters and holding of a town meeting were used as evidence of the former. A vaccination coverage survey using a cluster sample methodology was used to evaluate differences in vaccination coverage. Results showed that knowledge about vaccination, treatment of side effects and the importance of the RTH Card was greater among chiefs/TMs and mothers in the intervention districts than in control districts. Coverage rates for fully immunized children were greater in the intervention districts (56% intervention vs. 45% control). When stratified by type of leadership, coverage rates were higher in intervention districts where TMs rather than chiefs served as vaccination team extenders, although chiefs were more effective than controls. As a result of this study, the Ministry of Health has decided to extend this activity into other counties and to add additional information on other PHC messages. PMID- 20841225 TI - From qualitative community data collection to program design: health education planning in niger. AB - In order to develop health education programs which are adapted to specific sociocultural contexts, in-depth, qualitative data are necessary for program planning. For this purpose, informal data collection techniques are often more appropriate than conventional, formal research methods. In addition to the type of data collection used as a basis for program planning, three other aspects of the program planning process contribute to the quality of programs developed: who is involved in preliminary data collection and program planning; the degree of contact between program planners and target communities; whether program planning is viewed as a top-down, mechanical process or as a collaborative, problem solving process. This article describes the methodology used to develop a diarrhoeal disease health education program in the Zinder region of Niger in which particular attention was given to these four aspects of the planning process. PMID- 20841226 TI - Perceptions of Neonatal Tetanus and Immunization During Pregnancy: A report of Focus Group Discussions in Kaduna, Nigeria. AB - Focus group discussions were held with mothers in Kaduna, Nigeria, to investigate health practices during pregnancy and childbirth and perceptions of neonatal tetanus (NNT) and tetanus toxoid (TT) immunization. Mothers' responses indicated that while home births and traditional practices still predominate, health clinics are regarded as useful sources of health services and information during pregnancy or ill health. However, there is little recognition of the symptoms and causation of NNT; immunizations during pregnancy are reportedly associated with family planning and are therefore avoided. Group discussions conducted with traditional birth attendants and health clinic staff confirmed these findings. Recommendations are made for improving acceptance of tetanus toxoid immunizations. PMID- 20841227 TI - Ethnomedical beliefs, health education, and malaria eradication in ethiopia. AB - It has been widely recognized that worldwide efforts to eradicate malaria have generally failed because they were largely based on biotechnological interventions while neglecting the human factor. WHO's Primary Health Care orientation emphasized the importance of situating disease eradication programs within the context of the medical beliefs, values, and needs of the target community. This study presents the results of a survey conducted in a rural Southern Ethiopian community on malaria-related beliefs and practices. The findings show that ethnomedical beliefs prevailed in the causational conceptualization of the disease. The majority of the respondents failed to acknowledge the Anopheline mosquitoes as a potential source of ill-health. This lack of vector awareness is discussed in relation to the need for community health education programs. Various organizational and infrastructural innovations introduced by the 1974 Ethiopian Socialist Revolution could be successfully utilized to disseminate basic medical information concerning the malaria cycle and to raise community participation in eradication programs. PMID- 20841228 TI - Beliefs as motivational influences at stages in behavior change. AB - A problem for health education practice is how to interest people in making a health behavior change and maintain that interest throughout the behavior change process. Beliefs can provide motivational force for people to perform health behaviors. Five theories: 1) Diffusion of Innovations (DIT); 2) Health Belief Model (HBM); 3) Reasoned Action (TRA); 4) Locus of Control (LOC); and 5) Social Learning (SLT), are reviewed for motivational factors in promoting health behavior changes at each of six stages in the behavior change process: precontemplation, decision, training, initiation, and maintenance. A degree of overlap and complementariness are identified among the theories resulting in a syntheoretical model of beliefs as motivators in the behavior change process. The common emphasis among the theories on expectancies or cost-benefit calculations is highlighted, suggesting several strategies for employing these considerations in health education campaigns. The paucity of motivational ideas for promoting change among the externally controlled-late majority is noted. Further research must be conducted before these ideas should be generally implemented in practice. PMID- 20841229 TI - Health, recreation, and the unemployed: an interactive model. AB - Researchers in disciplines of health, recreation/leisure, and labor point out how their respective fields address individual health and societal well-being. However, such perspectives are more often expressed in single tracks or combinations of health and recreation, health and employment, or recreation and unemployment, but seldom all three together. This article suggests the adaptation of a more inclusive conceptual model which triangulates the interdependence between individual or social health, access to public sector recreational activities, and target populations of unemployed people. An inclusive systems model which articulates theoretical and practical linkages between health, recreation, and joblessness is proposed. This interdisciplinary approach can help social service agencies ameliorate individual and social pathologies brought on by unemployment. PMID- 20841230 TI - Assessment of the quality of prenatal care: the transmission of information to pregnant women in maternal and child health centers in jordan. AB - The quality of information provided to pregnant women seeking prenatal care from public maternal and child health (MCH) facilities was assessed in Irbid, the principal city in the North of Jordan. The structural setup of the settings, as well as the process of information transmission, were examined using interviews of the managing physicians and recipients, as well as observation of encounters between pregnant women and health care providers (physicians and midwives) at the health facility. The results of the study showed that pregnant women's needs for health information were not being adequately met Women were dissatisfied with the quality of information delivered. Inadequacies in both the structure and the process of information provision are discussed. PMID- 20841231 TI - An assessment of the impact of two communication channels on knowledge, attitude and practices of mothers regarding food and nutrition in Jamaica. AB - A study was carried out in St. Elizabeth during the period July to December 1991 to evaluate the effectiveness of two communication channels on mothers' knowledge, attitudes and practices regarding food and nutrition. Five communities with high levels of malnutrition and similar socioeconomic and geographical characteristics were selected for the study and assigned to three experimental conditions: a group that was not exposed to any communication channel (group 1); another group that was exposed to group discussion and facilitator (group 2); and a third group that was exposed to facilitator only (group 3). In all, fifteen mothers were assigned to group 1, another fifteen to group 2, and nineteen to group 3. The results showed that positive changes in mothers' knowledge, attitudes and practices occurred in all three groups during the period between the baseline and the end of survey evaluation. However, these changes were more substantial in groups 2 and 3, particularly group 2. Although all groups showed improvement in nutritional status the facilitator-only group made the most improvement. Consideration should therefore be given to both communication channels when planning nutrition education programs, especially for underweight children. The type of facilitator may be critical in terms of outcome (nutritional status). PMID- 20841232 TI - Organizing communities to prevent the sale of tobacco products to minors. AB - In New York State, it is illegal to sell tobacco products to persons under the age of eighteen. A 1989 survey of 120 retail stores in Erie County, New York, found that 82 percent sold cigarettes illegally to fourteen and fifteen year olds. In an effort to address this problem, Project SCAN (Stop Children's Addiction to Nicotine) was launched by Roswell Park Cancer Institute in the Spring of 1990. Project SCAN had three objectives: 1) to increase public awareness of the problem of youth tobacco use; 2) to educate merchants about the tobacco access law to promote voluntary compliance; and 3) to encourage local law enforcement agencies to enforce the access law. This article describes our experience in implementing Project SCAN including strategies used to recruit volunteers to deliver merchant education materials, reaction of merchants to the program, and the involvement of local police departments in enforcement efforts. Case examples describing how Project SCAN has been implemented in two communities illustrate the importance of community participation and law enforcement in the success of the program. PMID- 20841233 TI - Village Health Worker Attrition and Function Levels in the ILE-IFE Area of Nigeria. AB - Volunteer village health workers (VHWs) form the backbone of primary health care (PHC) from both philosophical and logistical perspectives. They represent an underlying PHC ethic of community involvement as well as a practical means for delivering health care at the grassroots. Although VHW recruitment and training does not rival the cost of training formal medical and health workers, the investment in not insubstantial. Thus when VHW dropout rates approach 50 percent in many countries, there is cause for alarm and for investigation into the possible causes of attrition. Nigeria embarked on a national PHC program in 1986, supported by national PHC policy in 1987. Nearly 1500 VHWs have been trained in model local government areas (LGAs) during the intervening years. Although there have been anecdotal reports of VHW attrition, little study into the reasons for drop-out from this large scale and expensive operation have been undertaken. This study looked at the former Oranmiyan LGA (now divided into three) where 115 VHWs had been trained. Only 79 percent of trainees took up PHC tasks, and another 7 percent left their villages shortly thereafter due to school admission or job opportunities. Two to three years after the initial training, 58 percent of the original trainees self-reported that they were still functioning as VHWs. A PHC function test, based on VHW job descriptions, was developed and administered within a questionnaire among the VHWs still living in their villages. Three factors were associated with function score: farming as an occupation, reported recent supervision and reported attendance at a continuing education activity. The results indicate two main points of intervention for preventing VHW attrition. During recruitment, effort should be made to explain the voluntary nature of the work and to encourage villagers to select people (like farmers) who will reside permanently in the village. After training, supervision and continuing education must be planned to maintain a high level of VHW functioning. PMID- 20841234 TI - Knowledge and attitudes of university female students toward obesity. AB - A cross-sectional study on 203 university female students aged eighteen to thirty years was carried out to determine their knowledge and attitudes toward obesity. The findings revealed that most of the girls believed that overeating (53%) or overeating in addition to inactivity (26.1%) are the main causes of obesity. However, 50 percent of the girls reported that they did not know the health complications of obesity. In general, attitudes toward certain food fads related to obesity was found to be unsatisfactory. Only 50 percent of the girls knew their height compared to 76 percent who knew their weight. Body-weight perception was found to be inaccurate in 30 percent of girls with acceptable weight, while 80 percent of overweight girls considered themselves obese. Magazines and television are the main sources of nutrition information for these girls. Intervention programs to correct the food fads and change the food habits of adolescent girls are highly recommended. PMID- 20841235 TI - Influence of american tobacco imports on smoking rates among women and youth in Asia. AB - This study addresses the question: has the opening of their markets to American tobacco products in Japan, South Korea, and Taiwan led to an increase in smoking behavior among women and youth? The data on smoking rates for women and youth is presented. This data was obtained for each country before markets were opened to the importation of American tobacco products through the agency of non governmental organizations in these countries. Comparison data was obtained from similar Asian countries whose markets were not opened. The data from Japan, South Korea, and Taiwan show a sizeable increase in smoking rates for women and youth. The authors believe, based upon anecdotal data, that importation of tobacco products combined with aggressive marketing and advertising by American firms is, in a good measure, responsible for the reported increase. PMID- 20841236 TI - The cepa project: a new model for community-based program planning. AB - The article describes a new model of community-based program planning developed by the Centro de Educacion, Prevencion y Accion (CEPA) project, an HIV prevention program for Puerto Ricans located in Holyoke, Massachusetts. Based on models of critical thinking, empowerment and participatory education, the basic philosophy of the CEPA project is to narrow the gap between program developers and program recipients to the greatest extent possible. The article discusses the successes and challenges encountered in approaching this ideal. The article concludes with recommendations for public health professionals considering the use of community based approaches to address public health issues. PMID- 20841237 TI - Qualitative research supports health education for ethnic minority women: how to reach "inaccessible" women. AB - In Holland, health education for ethnic minority women is provided in the mother tongue of these groups. Moroccan women constitute one of the target groups for this kind of health education. It proved to be difficult, however, to get Moroccan women to participate. Therefore the Municipal Health Service in Rotterdam organized a study of the health situation and social contacts of Moroccan women. This project provided information about the living conditions of Moroccan women, about places they do and do not visit and about ways in which they gather information on health and health care facilities. This evidently holds implications for the planning of health education for foreign women in the future. PMID- 20841238 TI - A community trial involving religious leaders to improve water preparation hygiene as part of diarrheal disease prevention in South kalimantan, indonesia. AB - In an earlier study we found that there is a habit of mixing boiled and unboiled water to prepare drinks, particularly cold tea, in South Kalimantan, Indonesia. Ulamas (Islamic religious leaders) have a very influential role in that community. This study was designed to implement and evaluate a health educational campaign using local ulamas. Three study communities were selected. The first intervention area received education through Al Quran (Koranic) reading clubs. In the second area the intervention was implemented by home visits as well as by Al Quran reading clubs, since participation in Al Quran reading clubs was low. The third area served as the control. A message and intervention development was designed by the ulamas and the investigators using sarasehan (ulamas' meeting). A positive impact on knowledge and practices of drinking water preparation was observed in the first area where the community members were active participants in the Al Quran reading club. Involving ulamas in a health education campaign was indicated to be effective in changing knowledge and practices. PMID- 20841239 TI - Sexual Practices That May Favor the Transmission of HIV in a Rural Community in Nigeria. AB - The Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS) have been documented as a primarily urban phenomenon in Nigeria. The risk of spread to rural communities, where the largest portion of the population still lives, exists. This article presents a qualitative research study that was designed to explore sexual practices in a rural Nigerian community that held potential risk for introducing HIV into the community and for enabling HIV transmission should an infected person enters local sexual networks, in the small town of Ago-Are, Oyo State. Seven key informant interviews, in-depth interviews and observations with five commercial sex workers (CSWs), and focus group discussions (FGD) with married and single male and female residents were held. CSWs were found to be the most likely route whereby HIV could enter the community, both because of their own mobility, being resident in the community on average only nine months, and because of the mobility of their main clients, migrant farm laborers and commercial drivers. This did not preclude local patronage, which was more discrete. Another possible point of entry for HIV was through casual sexual relations during ceremonies, holidays and festivals, when towns' people working in the large urban centers came home. Within the community, extramarital sexual relations were posited as a likely route for spread within the community. The continued existence of a taboo against sexual intercourse while a mother is breastfeeding, frequent informal divorces and a tendency toward polygamy were identified by FGD members as factors that encourage extra-marital sex. The strong role that social and religious associations play in the community was identified as an ideal mechanism for health education to prevent HIV/AIDS. PMID- 20841240 TI - Taking chances, taking charge: a report on a drug abuse intervention conceived, created and controlled by a community. AB - The high visibility and expensive federal efforts in the "war on drugs" has led to few victories. Substantial evidence suggests that the basic failure of the federal "war on drugs" is the result of long-standing reliance on traditional approaches based upon criminal and medicalized interventions. The present program, reported here, emphasizes a community up, rather than a social planning, hierarchy down, approach. Community creation has led to community control and a sense of hope that this intractable problem, at least in Berkeley, can be effectively controlled. PMID- 20841241 TI - Cancer control activities in Australian public hospitals. AB - Cancer is a major cause of death in Australia and there is considerable interest in the role health education in hospital settings has in reducing this burden. Based on a survey of medical superintendents and other hospital staff, this article describes the cancer control activities routinely conducted in Australian public hospitals. The survey considered cigarette smoking, alcohol, diet and nutrition, exercise, and the early detection of skin cancer, cervical cancer, and breast cancer. Overall 112 medical superintendents (93%) participated and a further 163 hospital staff members provided additional details. Not unexpectedly, the survey confirmed the very low level of activity and identified a number of specific issues that need to be addressed in order to enhance cancer control activities in public hospitals. Given the relatively higher level of activity, and the prominence of cigarette smoking and alcohol consumption as health issues, one approach might be to initially concentrate on these areas when they are related to the patient's condition. PMID- 20841242 TI - Dissemination of family life education to adolescents by their parents in suburban ibadan, Nigeria. AB - Family life education (FLE) is a process of imparting both factual knowledge about human development, sexual relationships, preparation for parenthood, pregnancy, contraception and sexually transmitted diseases and also values, attitudes and perceptions that will enhance health self-concepts and relationships. Although experts agree that the home is the best place to begin FLE, parents themselves are sometimes reluctant as discussion of these topics may be embarrassing or even taboo between generations. Parents also express concern that they may not be knowledgeable enough to handle FLE. The inhibitions on FLE in the home may be exacerbated by urbanization that reduces traditional social support systems. With this background, the investigators looked at the nature and level of family life communication between parents and their adolescent children in homes in the suburban community of Apata in Ibadan, Nigeria. Of six FLE topics, the 253 families interviewed discussed only an average of three. Some parents did not feel competent and others felt that raising such issues might encourage undesirable behavior by the youth. Mothers were found to be the major initiators of FLE. A 12-point communication score was constructed based on potential FLE topics that could be discussed at home. The level of FLE communication was found to increase with parents' level of education. Greater time at home by parents was also associated with better scores. A positive perception of a parental role in FLE was reflected in higher scores. Strategies to increase parents' knowledge on FLE topics as well as their self-efficacy in providing FLE is suggested with special focus on the facilitating potential of schools and women's groups in the community. PMID- 20841243 TI - Perceived Barriers to HIV Prevention Among University Students in Sierra Leone, West Africa. AB - This article presents the results of a small pilot study of students at Fourah Bay College in Freetown, the capital of Sierra Leone, West Africa, to provide baseline data to the National AIDS Programme in planning educational interventions aimed at preventing the spread of HIV. Results of the survey indicate that barriers to HIV prevention in Sierra Leone include persistence of belief in the idea that AIDS is not real but is a conspiracy to prevent Africans from having sex or having children, an ambivalence among women students regarding sexuality issues, a lack of familiarity with the parameters of the epidemic in Africa, and a belief that condom use behavior is not amenable to change. Implications of these findings are discussed. Further research is needed to include the portion of the population that is not literate. PMID- 20841244 TI - Identifying risk factors for drug abuse among portuguese speaking youth in the Boston area: a preliminary assessment using key informant networks. AB - This article presents the results of a key-informant mail survey conducted with thirty-nine community leaders and local workers of the three main groups of the Boston area Portuguese speaking community, namely Brazilians, Cape Verdeans, and Portuguese. They were asked to rank on the questionnaire the frequency with which some youth problems-identified in the literature as risk factors for substance abuse-were present in the community. Six of the ten most cited problems were family-related, such as inter-generational cultural differences, poor family management skills, and social isolation of family. PMID- 20841245 TI - Street theater as a tool to reduce family planning misinformation. AB - Mass media campaigns can be effective at communicating health information to a mass audience rather inexpensively. Critics of mass media health campaigns often contend, however, that interpersonal communication is more effective at changing behavior. Conversely, interpersonal communication activities to promote health can be effective at changing behavior, but critics have argued that they have certain limitations such as being expensive and personal (perhaps intrusive), and that they provide nonstandardized information. The present study is an evaluation of a street theater format in Peru that combined the advantages of mass and interpersonal communication to improve family planning knowledge and attitudes. The street theater was effective in decreasing misinformation concerning modern contraceptive methods. PMID- 20841246 TI - Family planning operations research and program evaluation literature review; * a selected annotated bibliography: pakistan 1968-1993. AB - A selected annotated bibliography of operations research and program evaluation articles and reports on family planning program activities in Pakistan from 1968 1993. Some thirty references are summarized including study design, methodology, and major findings. PMID- 20841247 TI - Pasting your Umbrella Before the Rain: A Case Study. AB - This case study tells from a participant's viewpoint how the results of large scale social surveys and demographic projections are translated into educational program objectives and, more importantly, an educational product that gears into the thinking patterns of a younger generation. Cultural, bureaucratic and political obstacles to change and how they were overcome or not are reviewed in this chronological unfolding of the development of Taiwan's first population education approach in the classroom. PMID- 20841248 TI - Perinatal care services for Hispanic women: a study of provider-receiver communication. AB - The present case study 1) identified and evaluated perinatal care needs among Hispanics in Albuquerque, New Mexico, as perceived by a sample of perinatal care providers and receivers in the community, and 2) compared those needs with needs previously identified by a national team of Hispanic health experts and political and academic leaders.Results showed that while Hispanic experts emphasized technical needs, the community emphasized humanistic and communication needs in perinatal care services. Within the community, there were also differences between providers' and receivers' identification of barriers. Providers thought that cultural biases of receivers toward the medical profession prevented effective use of services. Receivers identified structural, mainly service related, limitations as barriers to effective perinatal care. This study shows the need to not base programs on "expert" opinion of public needs only. PMID- 20841249 TI - Self-Help within A Medical Institution: Its Potentials and Limits. AB - The current health self-help movement has its roots in the social movements of the 1960's. Frustrated with the practices and priorities of established medicine, many groups organized to meet their health needs outside the medical care system. Now self-help is becoming more attractive to health care providers. Hospitals, physicians and funding agencies are putting new emphasis on teaching self-help skills to a variety of patients.This report describes one such program established for asthmatic children and their parents in a medical center in New York City. By analyzing the different perspectives of parents, children, educators, physicians, hospital administrators and the funding agency, it shows how self-help programs within a hospital setting are shaped by an interaction of forces. The potential and limits of self-help as an instrument for social and institutional change are described. The article concludes with recommendations on how health workers can contribute to the self-help process. PMID- 20841250 TI - Who engages in health protective behaviors? AB - The concept of health protective behaviors explicitly calls attention to the fact that individuals undertake behaviors they believe are protective of their health whether or not their beliefs correspond to professional medical advice. There are four types of health protective behaviors: life style changes undertaken with and without medical advice, and treatment regimens undertaken with and without medical advice. The present paper, which presents data on three of these four types of health protective behaviors, finds only weak associations between these behaviors and both sociodemographics and general health orientations. The implications of these findings for both health education aimed at changing these behaviors and sociological analysis aimed at understanding these behaviors is discussed. PMID- 20841251 TI - Population learning among rural Turkish youth from an adult-oriented family planning program. AB - This study indicates that rural Turkish youth learn indirectly from family planning programs directed toward adults. Female youth in villages, however, seem to pick up much more family planning information than male youth. Two program implications emerge: first, that unmarried youth should be included in ongoing family planning program efforts and second, that stronger efforts must be made to reach adolescent males who eventually will be major decision-makers on family size. PMID- 20841252 TI - Socio-educational influences on nepali women and their association with innovative values and behaviors. AB - The introduction of health and family planning services in developing countries often requires extensive changes in the values and behaviors of the women of those countries. A better understanding of the factors influencing change in rural women would provide a stronger scientific base for the introduction of health services.The authors gathered data from 1,417 rural women in Nepal. Indicators of social change were contraceptive use, desired family size and scientific treatment of sick children. Major influences associated with change were regionality, having children in school, ownership of money and access to media. However, the strength of association with the indices of change varied, suggesting that change in values and behaviors is meaning specific and not a general phenomenon. PMID- 20841253 TI - Bibliographies on health promotion programs for business and industry. AB - Health promotion programs have been developing at a rapid pace throughout the United States. Business and industry have been major targets for and supporters of these new ventures. This intense interest in health promotion programs has produced a need for a systematic review of past experience. The Center for Health Services Administration at Arizona State University prepared two comprehensive bibliographies of references on occupational health promotion programs. The annotated bibliography includes ninety references that were deemed most relevant to the subject at the time the searches were made in Spring of 1982. The second bibliography, which is not annotated, is supplemental and provides eighty-eight additional related references. PMID- 20841254 TI - Volunteers who work: the community health care project in burma. AB - The Community Health Care Project in Burma stimulates villager involvement in health issues and, simultaneously, extends the coverage of the government health services beyond existing subcenters, down to the village level. The Project, which began in 1977, is based on two voluntary part-time workers-a Community Health Worker (CHW) and an Auxiliary Midwife (AMW). CHWs have substantial curative as well as preventive and promotive responsibilities. AMWs are expected to perform deliveries as well as give pre-natal and post-natal advice. Village People's Councils select the CHWs and AMWs, develop drug resupply schemes, hold and spend funds, and participate in motivational campaigns. The majority of the volunteers in this national-scale program continue to perform their tasks several years after their initial training.Many similar programs, following an initial period of enthusiasm, have failed-or have succeeded only if their scale is kept small. Why is this program continuing to operate? Buddhism and other aspects of Burmese culture, the strong political support for voluntarism, the substantial quantity and power of community involvement vis-a-vis the voluntary workers, the large amount of supervision and an emphasis on drugs and deliveries appear to be the major reasons. PMID- 20841255 TI - Destigmatizing mental health in the workplace: a union-based occupational stress program. AB - This article examines the effectiveness of an innovative program aimed at training union activists to become mental health primary prevention agents and organizers in their workplaces. The three-year occupational stress training project is described and analyzed, and its successes and failures are examined in light of relevant theories of health education and community organization. The training program attempted to combine psychological theories of group dynamics and individual change with community organization and social change strategies. The project is viewed as successful to the extent that it included the trainees in the planning and implementation of strategies and activities in their own unions. It fell short, however, of its goal of "de-stigmatizing" mental health in the participating unions. The contradictions between training group facilitators and community organizers are examined. The experience of this union program points up the need for the continued development of practical and theoretical links between personal and political change. PMID- 20841256 TI - Perceptions of health education of selected health and social service providers in the bahamas. AB - Health education is a new component of the health care delivery system in the Bahamas. In the past, confusion and uncertainty was expressed regarding the contribution of health education to the health care services. The intention of this study was to investigate the perceptions of selected health and social service providers to health problems, their most likely solutions, and to health education and health education related issues in the Bahamas. A questionnaire was either mailed or hand delivered to 412 selected health and social service providers in New Providence and the Family Islands in the Bahamas. Of these 127 (31%) usable questionnaires were returned. A discussion of the study findings, study limitations, implications for health education and suggestions for future research are presented. The survey results showed that a majority of respondents indicated consistent support for health education and health education related issues. This support was evident even when responses were crosstabulated with such variables as age, profession, and years of experience in present occupation. PMID- 20841257 TI - Attitudes toward sex education among black, Hispanic and white inner-city residents. AB - Telephone survey data gathered from residents of a New York City neighborhood indicate that Hispanics are significantly less likely to approve of sex education for adolescents than are either blacks and whites. Hispanics also perceive the appropriate ages for sex education to be older, and are more conservative about the topics and places for sex education than are the other ethnic groups. These differences remain after controls are introduced for sex, age, religion, education, number of children in the household, family income, or perception of teenage pregnancy as a problem. Age and education, however, are also important predictors of attitudes toward sex education. PMID- 20841258 TI - An Evaluation of an Urban Health Department's Prenatal Education Program. AB - This study evaluated the impact of a prenatal patient education program on the knowledge and attitudes of pregnant women receiving care from an urban health department clinic. The evaluation was undertaken to determine whether attendance at prenatal classes was related to either higher levels of pregnancy-specific knowledge or more favorable attitudes toward childbearing and child rearing. Data were collected from 139 nulliparous and primiparous women; 43 percent had not attended any classes and served as a comparison group. Analyses were performed within strata formed by stage of pregnancy and levels of parity, as well as for the sample as a whole. Despite high levels of satisfaction with the instruction, class attendance and knowledge were not related for nulliparous women or among those in the early stages of pregnancy. However, class attenders in the third trimester (p < .05) or who had already given birth (p < .02) had significantly higher knowledge scores. With the exception of an indirect relationship between classes and the intention to breastfeed, no difference in attitudes was found. It would appear that prenatal patients at different points in their pregnancy may differ in their level of knowledge, possibly as a result of variability in their motivation to learn, without differing in their attitudes toward child rearing. Multiple methods and an individualized approach to prenatal education are therefore recommended. Suggestions for program changes based on general principles of health education are presented. PMID- 20841259 TI - China's One Child Family Program: Policies, Barriers and Communication Network. AB - China's experience in the one child family campaign is impeded by forces which are political, economic, cultural and administrative. The infrastructure for family planning can be enhanced by a vigorous communication strategy directed to the citizenry and cadres. The disincentive system created by some provincial and municipal authorities may signify a trend which is crucial to China's ability to bring its population growth under control. PMID- 20841260 TI - Training health educators for social change. AB - Health education practice reflects the ideology of the social forces that support it. Currently, health educators approach their task from two divergent viewpoints: one group emphasizes changing individual behavior while the other focuses on organizing people to change health-damaging institutions, policies and environments. This report provides a rationale and examples of the latter approach. It then describes the kind of training program that would be necessary to prepare health educators to work effectively for social change. Specifically, it is suggested that graduate students in health education need more preparation in social epidemiology, environmental sciences and policy analysis, particularly the analysis of the impact of non-health policies on health status. Health education training programs also need new approaches to the process of learning. The social movement of the last decades, health education programs in developing and socialist countries and some projects in this country provide a rich source of case studies. Training programs also need to recruit students who will be prepared to serve populations most in need of help. This suggests attracting students who have in the past been excluded from graduate education. Finally, several methods are suggested by which students, faculty and practitioners can begin the process of transforming the institutions that prepare professional health educators. PMID- 20841261 TI - Marketing public health services. AB - Marketing techniques that have proved their worth in the private sector can be applied successfully to public and non-profit agencies. This paper explores the applicability of marketing practices to public health departments. Many health departments are now facing pressures to re-examine and update roles in light of changes in morbidity and mortality and changes in consumer wants and needs. Marketing techniques can be helpful in evaluating services systematically in regard to consumer needs and preferences, planning and improving services to meet those needs and increasing agency visibility and credibility. One health department's experience in using marketing techniques is shared. Problems faced, solutions developed and recommendations for future activities are discussed. PMID- 20841262 TI - The concept of participation in a program of bronchial asthma control. AB - An experiment involving the participation of mothers of asthmatic children was carried out at the Child Institute of the University of Sao Paulo, Brazil, a Children's Teaching Hospital. The experiment emphasized an intensive educational program input based on dialogue and problem solving involving both mothers and health professionals. The study demonstrated the possibilities of adoption of an open educational attitude by health professionals which permits participation of patients in a self-care process. It also helped to improve knowledge, attitudes, and practice of the mothers of asthmatic children. PMID- 20841263 TI - The evaluation of health and safety training. AB - A national survey of individuals responsible for health and safety training at the workplace was conducted by self-administered mailed questionnaires in 1982 83. This analysis examines the responses to the questions on evaluation. Descriptive data on the extent to which health and safety training programs are being evaluated, the types of evaluation that are done, and the technical approaches used are presented. Results suggest that the majority of current training programs are being evaluated in some way, but also that a substantial portion of these evaluations are not rigorous and do not validly assess the extent to which training is effective. PMID- 20841264 TI - A survey of eating/dieting attitudes and bulimic behavior among university undergraduate women. AB - A random sample of female undergraduates at a large New England state university was surveyed by mail in 1983 to determine their attitudes and behavior relating to eating, dieting, and body weight. Results indicated dissatisfaction with and negative attitudes about eating habits and body weight. Forty-five percent had ever experienced uncontrolled binge-eating; 18 percent had a combination of bulimia symptoms, and 10 percent had used self-induced vomiting for weight control. The health education needs and interests of these students also were assessed and recommendations for university programs were made. PMID- 20841265 TI - Do Foreign Medical Graduates (FMGs) Have Different Attitudes Toward Health Care Management? AB - A sample study of 216 physicians in the St. Louis Metropolitan area reveals a statistically significant difference in dealing with important issues in patient management between Foreign Medical and U.S. Medical graduates. Using the prospective payment systems (PPS) as a test case, this study shows that attitude toward patient management is significantly different in three controversial areas: consumer benefit, inclusion of physician's fee into the PPS, and quality of care. This study raises important questions in health care policy. PMID- 20841266 TI - Selecting alternative strategies for community health education in guineaworm control. AB - Community health education strategies in guineaworm control can be applied at several intervention levels. Community development mobilizes local resources to provide safe water supplies such as wells. Mass education in schools and communities can teach personal protection measures such as filtering water. Training of volunteer community health workers produces front line staff, who by being culturally in tune with the community can demonstrate and promote the use of appropriate prevention and treatment measures. Advocacy assists community members to express their needs to government and ministry decision makers. All of these strategies have been applied in a community health education/primary health care program in Idere, Ibarapa District, Oyo State. Community development for well construction was found to be a long-term strategy that first must overcome problems of village organization and resource location. Mass education, to be effective, must have a simple and acceptable technology to promote. Trained village health workers must overcome traditional beliefs that inhibit use of preventive and treatment measures. Advocacy requires basic political education of community leaders. A variety of health education strategies is needed to address short- and long-term priorities as well as to overcome the different barriers to guineaworm control. PMID- 20841267 TI - Fishbein's Model of Behavioral Intentions: A Framework for Health Education Research and Curriculum Development. AB - A review of Fishbein's model of Behavioral Intentions is used as a framework for health education research and curriculum development. Particular emphasis is given to Jaccard's analysis of the model's practical application in health education programs: as a guide to assessing the relative importance of attitudinal and normative components in determining intentions for intended audiences. PMID- 20841268 TI - Generating grounded theory: two case studies. AB - An inductive research method known as grounded theory is described as a means of building conceptual bridges between real-life situations and formal theory. The procedures are detailed and illustrated via two case studies. The first is a study of the social-psychological problem of cutting losses among heart patients through three stages of recovery. The process of extending the theory generated with the heart patients to other invisible physical impairments and across both visible and invisible chronic conditions is outlined. The second case study offers an example of a structurally-oriented theory, developed from participant observations of the processes of managing patients, staff, and neighbors for an "antipsychiatric" treatment facility for juvenile schizophrenics. PMID- 20841269 TI - Primary prevention in public health: an analysis of basic assumptions. AB - The common definition of primary prevention is straightforward; but how it is transformed into a framework to guide action is based on personal and societal feelings and beliefs about the basis for social organization. This article focuses on the two contending primary prevention strategies of health promotion and health protection. The contention between the two strategies stems from a basic disagreement about disease causality in modern society. Health promotion is based on the "lifestyle" theory of disease causality, which sees individual health status linked ultimately to personal decisions about diet, stress, and drug habits. Primary prevention, from this perspective, entails persuading individuals to forgo their risk-taking, self-destructive behavior. Health protection, on the other hand, is based on the "social-structural" theory of disease causality. This theory sees the health status of populations linked ultimately to the unequal distribution of social resources, industrial pollution, occupational stress, and "anti-health promotion" marketing practices. Primary prevention, from this perspective, requires changing existing social and, particularly, economic policies and structures. In order to provide a basis for choosing between these contending strategies, the demonstrated (i.e., past) impact of each strategy on the health of the public is examined. Two conclusions are drawn. First, the health promotion strategy shows little potential for improving the public health, because it systematically ignores the risk-imposing, other-destructive behavior of influential actors (policy-makers and institutions) in society. And second, effective primary prevention efforts entail an "upstream" approach that results in far-reaching sociopolitical and economic change. PMID- 20841270 TI - Beyond family planning: incentives in taiwan. AB - Two large-scale, long-term research projects to test the feasibility of using positive and non-coercive incentives to encourage having fewer children and spacing were carried out in Taiwan during the 1970s. The results of these long term projects are presented. The Educational Savings Plan, begun in 1971, provided financing for the secondary school education of children whose parents had limited family size to no more than three children. The Spacing Incentive Plan, begun in 1975, encouraged prolonging the interval between first and second births to at least three years by providing free birth delivery of the second child. Although both were less successful than anticipated, much was learned about the social, economic, and practical difficulties of program implementation. PMID- 20841271 TI - Patient education in Nepal. AB - The authors, using the definition of health education as a deliberately, planned, structured learning opportunity about health that occurs in a setting at a given point in time involving an interaction between an educator and learner, recommend patient education in hospitals. The authors make a strong recommendation for the health education department within the Ministry of Health in Nepal to develop patient educational programs collaboratively with the nursing division. Such programs in the authors' opinion would limit the spread of infections, decrease diseases, and allow for maximum use of equipment and facilities unfamiliar to most Nepalese. Patient education would also promote adequate utilization of existing manpower. PMID- 20841272 TI - Experiential training of primary health workers in Nigeria. AB - A training program which encourages trained primary health workers in Nigeria to develop and integrate theoretical and community-relevant skills, is described. Prior to field work (field posting), students received lectures on health concepts related to their prospective field assignments. They were then tested on these concepts at the end of the lectures. Practice modules, as an operational approach in the community were developed. There was evidence to suggest enhanced knowledge base, better understanding of the principles of primary health care, and an appreciation of the role and desirability of community-oriented training. The applicability of these findings to the training of other cadres of health workers, including medical students, is suggested. Their implications for the development and practice of primary health care are discussed. PMID- 20841273 TI - Value Dilemmas and Public Health: A Psychologist's Perspective. PMID- 20841274 TI - Socio-economic factors influencing the health status of black americans. AB - Although the health status of Americans has improved, particularly decreases in incidence and prevalence rates of diseases, these improvements are not consistent and equally distributed within all population groups - particularly black Americans. To describe the relative differences, an analytical procedure of calculating the differential deficit ratio (DDR) was developed. It was observed that for males the death rate from all causes increased in 1950 from a .426 to a .473 DDR or 47.3 percent in 1982 with black males dying at a much higher rate than white males. For females there was a closing of the gap. In 1950 the rate was .703, higher in black females than white females, but in 1982 the ratio was .431. These trends were also observed for deaths due to heart disease, cerebrovascular, malignant neoplasms, diabetes mellitus, pneumonia and influenza and chronic liver disease and cirrhosis. An epidemic in homicide exists among black males. The rate among black Americans is more than 5 times higher than among white. Infant mortality DDR in 1950 was .638 and in 1982 it was .949, the highest in more than 32 years. Also the infant mortality rate among blacks was higher than in any other ethnic or racial group. Indices show that there is a direct correlation between level of poverty, income level, education and infant mortality. Future directions indicate a need for overall change in the health care system, re-education for the consuming public, rebasing health care in the community and correlating health care with other social problems which impact on health. PMID- 20841275 TI - Worker produced health education material for the construction trades. AB - There is broad acceptance of the philosophic foundations of health education as grounded in the collaborative model of client and professional partnership. In practice, however, this partnership is largely dominated by the professional side. Workers may be particularly sensitive to professional domination as issues associated with health promotion vs. safety and health programs at the workplace are often politicized. This polarization is particularly evident in the area of asbestos-related hazard prevention, reduction, and education. Using asbestos hazards as the unifying theme, we participated in a program to facilitate active participation of workers in the production of their own occupational health education materials through the use of the photonovel. Representatives from some seven building trade locals worked with a staff to produce a twenty-four-page photonovel for their co-workers. A random sample of 500 members of building trades locals received either a copy of the photonovel or a popular NCI asbestos pamphlet with an evaluation questionnaire. Differences between the groups were evident in favor of the photonovel in readability, factual recall, general credibility, and attitudes toward future involvement in health and safety issues. PMID- 20841276 TI - Social and demographic characteristics of nicaraguan health volunteers. AB - Although the training and mobilization of volunteer health aides is widely promoted in Third World countries, little is known about those who volunteer. A survey of Nicaraguan volunteers in 1982 revealed findings which are similar to results found elsewhere. Women, young people, and students have tended to be those groups which volunteer most often. Less is known about the level of responsibility and organizational affiliation of volunteers. In the Nicaraguan case, it was found that although most volunteers are female, they usually do not represent a women's organization. A majority of the volunteers represent non traditional organizations or no organization at all. Those volunteers with greater responsibility tend to be older, better educated, are more likely to be female, and more commonly represent an organization which came into existence after the country's 1979 revolution. Changes in the organization of health promotion campaigns in Nicaragua are likely to soon influence the recruitment and retention of volunteers. PMID- 20841277 TI - Attitudes and practice of kuwaiti women toward breastfeeding. AB - A survey was conducted to assess the attitudes towards breastfeeding, its prevalence and duration among Kuwaiti married women. Five hundred eighty-five women from different regions of the country with at least one child of their own, willing to furnish data were included in the survey. The results of this study show that 71 percent of newborns are breastfed at birth. The percentage of breast fed infants declines to 50 percent by the time they are one month old, and to 10 percent among five-month-old infants. The expected duration of breastfeeding is about two months. This study also reveals a wide gap existing between the attitudes, knowledge and practice of breastfeeding among Kuwaiti women. Their attitude towards breastfeeding is largely positive. This study emphasizes that with appropriate health education and supportive measures sensitive to the needs of this community, breastfeeding can retain its integral part in the process of human reproduction and child development. PMID- 20841278 TI - Improving rural health: the lessons of Mississippi and Tanzania. AB - This article summarized major features and processes of a radical improvement in health, especially for black people, in Mississippi since 1965. It stresses the need for initial epidemiological, social-structural and social-psychological surveys in poorly known areas prior to intervention. Also essential is a progressive shift from external to local control, accompanied by modifications of organization and operating mode facilitating local accommodation, consistant with public health goals. An evaluation of chemoprophylaxis against malaria in Tanzania indicates that problems in developing sensitive, effective programs are widespread. In its entirety, this article seeks to improve approaches to community health in rural areas. PMID- 20841279 TI - A public sector health promotion program. AB - The use of a volunteer model in the provision of health promotion programs in the public sector is described based on the experiences of the Carolina Healthstyle Project, originally a health promotion project for state employees in the Columbia, South Carolina metropolitan area and now expanding to all state employees, public school district employees, and, in a more limited fashion, to state government retirees. The revised models for this project may be particularly helpful to other modestly-funded health promotion efforts. PMID- 20841280 TI - Guest editorial: the impact of u.s. Policy on tobacco trade with taiwan. PMID- 20841281 TI - The healthcom project and the behavioral management of diarrhea. AB - Sixteen million children die annually from causes which are largely preventable. Many of these deaths stem from malnutrition and diarrheal disease. This article presents a model of nutritional health and describes activities of the HEALTHCOM project related to nutritional health promotion and diarrheal disease control in developing countries. Specifically, HEALTHCOM includes a unique combination of communication and behavioral techniques for promoting health. One HEALTHCOM project took place in The Gambia where mass media and behavioral incentives proved a powerful combination in increasing mothers' knowledge of oral rehydration. PMID- 20841282 TI - The East cumbria community health project. AB - The East Cumbria Health Project is in its second year and aims to encourage and support groups and individuals to explore, identify and action their own health education needs. The project is a unique joint venture between a local health authority, the United Kingdom's Open University and the Manpower Services Commission, who fund the project. The project employs one full-time co-ordinator and fourteen part-time community health facilitators. All facilitators were previously unemployed local residents. The project serves a mixed rural and urban community of approximately 180,000 in the North West of England between the Lake District and the Scottish Border. The project to date has demonstrated that non professional health workers with appropriate training can work effectively to complement existing professional community health workers. The project has also demonstrated that workers drawn from the local population can be effective in stimulating local communities and groups of people to become more involved with health and health care issues. Finally, the project has demonstrated that community health workers drawn from the local population can act as useful links between the statutory and voluntary health services and local communities. PMID- 20841283 TI - The ethicality of child-finding in third world countries for the purpose of adoption. AB - Because of a scarcity of adoptable infants in the United States, adoption agencies are looking overseas for children. In their efforts at finding overseas "sources" they sometimes become associated with persons who see intercountry adoption as a means of easy financial gain. The author's commentary questions the behavior of U.S.-based adoption programs in forming these associations as well as the system which weighs the interests of North American adoptive parents against those of impoverished, Third World birthmothers. PMID- 20841284 TI - The development and use of graphically presented algorithms in community-based family planning services. AB - Graphically presented algorithms are presently used in many settings worldwide for the diagnosis, management, and teaching of curative health services. There is potential as well for using such algorithms for teaching and counseling in the preventive services, especially in family planning services. The employment of paramedical or lesser trained workers in family planning or management requires careful attention to skill development in all phases of training. The use of graphically presented algorithms may simplify this process of skill development. In addition, the algorithms provide guidelines for use in the field by those providing family planning services, and for program management and supervision. Examples of algorithms used in paramedical services are presented. The development of two algorithms are discussed in detail, 1) an algorithm for introduction of contraceptives during lactation, and 2) an algorithm for supervision of data collection. PMID- 20841285 TI - A preferred target population for comprehensive health promotion. AB - Health promotion (HP) strategies have been advocated as a means of enhancing individual responsibility for health maintenance, while reducing client dependence on the medical care system. Similarly, advocates of HP have suggested that it may positively affect medical costs and physical/behavioral risk factors among others. To properly test the long-term effects of carefully planned HP interventions, a preferred target population is proposed. It is suggested that clientele would be drawn from moderate or low risk individuals who are seldom the population-of-interest within the traditional medical care model. The authors offer a model for comprehensive HP and discuss the implications of defining a target population for HP strategies. PMID- 20841286 TI - A community-based health education analysis of an infectous disease control program in Nigeria. AB - This descriptive study utilized the strategy of primary health care in program development-especially a community-based health education intervention approach in the control of guinea-worm in rural communities of Nigeria. Two closely related rural communities in two states served as target groups. Committee system approach, nominal group process, interview methods, audio-visual aids, and health care volunteer trainingship were the educational strategies employed in a control and experimental set up. The PRECEDE model was applied in the analysis. Results show a significant control action on guinea-worm infestation in the experimental community and a tremendous achievement in preventive health education interventions through organized community participation/involvement and ultimate self-reliance and individual responsibility. A positive increase in health knowledge and attitude examined through interview method, and observable changes in health behavior were noticed. Wells were provided, drinking water treated, while personal and community health promotion strategies were encouraged by all. The study has shown the effectiveness/efficacy of a community-based effort facilitated by a health educator. PMID- 20841287 TI - Mass media in health promotion: a compilation of expert opinion. AB - This paper reports on an open-ended survey of experts in the field of mass media and health promotion. The study was designed to read between the lines of published reports to identify new directions in the use of mass media in health promotion; to identify areas of consensus and controversy in the design and use of such campaigns; and to compare expert opinion with the literature. Survey responses are synthesized and reported in terms of (1) ingredients for successful mass media programs relative to program purpose, structure, and methods; and (2) obstacles to effective use of mass media for health promotion, including information overload and inconsistency, demand characteristics of the target behavior, dissemination, and unsupportive social milieus. Conclusions are presented as guidelines for pursuit of the optimal program and principles to guide further inquiry. PMID- 20841288 TI - The urban poor: an appropriate population for breastfeeding promotion programs. AB - Breastfeeding has won universal endorsement as a major contributor to child survival. The proliferation of breastfeeding promotion programs demonstrates the importance health professionals and funding agencies place on improving the incidence and duration of breastfeeding. An effective, cost-efficient breastfeeding promotion program should be directed at those who will receive the greatest health benefit from such an intervention, i.e., the group who 1) would experience the greatest threat to health by decreasing its breastfeeding practice, and 2) is at greatest risk of changing its breastfeeding habits. Since it is the urban poor primarily who satisfy both of these criteria breastfeeding promotion strategies should focus on them. PMID- 20841289 TI - A Behavior Analysis of the Promotion of Oral Rehydration Therapy (ORT) in Guatemala. AB - The present report presents the results and preliminary recommendations of a behavior analysis study of an oral rehydration therapy (ORT) promotion in four localities in San Marcos, Guatemala. In this study, we used behavioral observation techniques to look at one-to-one communication and health education efforts in health clinics as well as to evaluate the effectiveness of these health education efforts by observing mothers' behavioral skills in their own homes. Subsequently, we also observed canalization (outreach) strategies to see whether we could learn more from these health workers' activities, and conducted "behavioral focus group" research with teams of health workers to determine how best to promote effective health education activities to other health workers. Results of our study indicate that health workers already spent a substantial amount of time doing health education and primary prevention, and were fairly effective at doing so. Their communication, however, tended to be relatively unilateral and failed to involve some of the more progressive aspects of behavioral skills training. PMID- 20841290 TI - Influence of rural and urban environments on the health outlook of twelfth grade students in jordan. AB - Using a sample of 312 grade twelve male and female students from rural and urban area schools in Jordan, the influence of rural and urban sociological environments on their health outlook was explored. The concept HEALTH was evaluatd on sixteen Semantic Differential scales. MANOVA and univariate F-tests revealed different effects of rural and urban environments on each gender. There were statistically significant (p < .00) sex differences in the urban school students but not in the rural school students. Also there were statistically significant (p < .03) environmental effects on the female students but not on the male students. In general urban female students held brighter perspectives of health than did urban male as well as rural female students. Between the males, rural students tended to show sunnier outlook toward health than did their urban cohorts but the differences were not statistically significant at alfa = .05 level. Implications for the development of health education curricula and public health programs were discussed. PMID- 20841291 TI - Data for empowerment! The application of small area analysis in community health education and evaluation. AB - This article describes the use of Small Area Analysis (SAA) techniques in public health education planning and evaluation efforts. An array of health and social indicators for a mid-size metropolitan city (150,000+) were collected as part of the evaluation of a Center for Substance Abuse Prevention (CSAP) community partnership grant for alcohol and other drug prevention. Data sources included the state public health department, school system, hospitals, census bureau, police department, and the city administration. Germane health and social indicators were then calculated for each of the city's socio-historical neighborhoods or zip code area. The process of gaining access to these diverse data and how they were used for planning and evaluation purposes are detailed and typical problems encountered in utilizing SAA techniques are enumerated. Finally, the potential for SAA as a community organizing tool for galvanizing community responses is discussed. PMID- 20841292 TI - Alcohol misuse in South african male adolescents: a qualitative investigation. AB - Previous investigations of risk behaviors among high-school students in the Cape Peninsula, South Africa, revealed a high prevalence of binge drinking among boys. Qualitative methods were used to identify and gain insights into the social context of alcohol misuse in male adolescents. Two focus groups were held with eight adolescent binge drinkers. The content of the discussions were analyzed using the grounded theory method. Three key findings emerged. First, adolescents drink because they derive benefits from the use or misuse of alcohol, such as increased self-confidence and adult status. Factors which facilitate the use of alcohol include the alleviation of boredom, experimentation, peer pressure, and parental influences. Second, participants attributed negative characteristics to teetotallers such as being conservative and immature. Binge drinkers were attributed negative characteristics such as lacking self-control and self respect. Moderate drinkers were attributed with positive characteristics such as being mature and socially adept. Finally, the influential role of alcohol promoting advertising was highlighted. Although participants minimized the effects of advertising it was clear that it played a role in their perception of themselves and of their peers especially with respect to drinking behaviors. The findings suggest some useful prevention strategies among adolescent males at risk for alcohol misuse. PMID- 20841293 TI - Evaluation of a peer health education project in the gambia, west Africa. AB - The purpose of this study was to evaluate a peer health education program among high school students in The Gambia, West Africa. Using convenience sampling, two of the ten high schools targeted by the program (one urban and one rural) were selected for evaluation. A total of eighty respondents, forty from each school, were randomly selected for participation. A validated questionnaire with both open and closed-ended questions was the data collection instrument which was subject to qualitative content analysis and quantitative descriptive analysis. Altogether, seventy-four participants completed the questionnaire for a response rate of 92.5 percent. Respondents' almost universal awareness of the peer health education program and their ability to recall the presentations suggested that peer education is an effective and acceptable means of disseminating information among youths. Over 90 percent of respondents applied the health information to their own lives, suggesting that peer health education can also have an influence on health behaviors of youths. Within the context of a developing country, peer health education was found to be culturally appropriate and allowed for the efficient utilization of local resources. PMID- 20841294 TI - Evaluation of a nutrition education program in oman: a case study. AB - The aim of this article is to evaluate the nutrition education program for women in Oman. The multisectorial program used various methods of education especially television spots, radio programs, booklets, and posters. A sample of 1024 mothers aged fifteen to fifty years were selected from all geographical regions of Oman, and asked about radio listening and television watching behavior as well as their understanding of nutrition messages. The findings revealed that ownership of televisions was higher than radios (95% and 85%, respectively). Of mothers, 61 percent watched the health and nutrition program on television compared to 41 percent who listened to these programs on radio. Three posters were tested for their understanding by mothers. The percentage of mothers who gave the right explanation of the message in these posters ranged from 28 percent to 70 percent. Although many mothers were exposed to the nutrition education messages, it is difficult to say that the mothers changed their nutrition behavior. Mothers (or target group) should be involved in planning the educational materials and these materials should be pretested. The role of television as the most important educational tool is discussed. Suggestions to improve nutrition education programs in Oman are given. PMID- 20841295 TI - Socio-demographic features and knowledge of diabetes mellitus among diabetic patients in kuwait. AB - OBJECTIVE: To determine the socio-demographic profile and assess knowledge about the nature, symptoms, complications, and treatment of diabetes mellitus among diabetic patients in Kuwait. METHODS AND RESULTS: A cross-sectional sample survey of 788 patients attending specialized diabetic clinics was conducted in 1995. Kuwaitis were significantly more represented in this sample than in the general population (52.5% versus 37%). Female to male ratio among Kuwait population was 1.07 and among non-Kuwaitis it was 0.28. Age at diagnosis ranged between sixteen to eighty years with a mean of 48 +/- 10.8 years. Overall knowledge was assessed by percentage of correct responses for individual knowledge questions. There was no significant difference in knowledge of diabetes seen among Kuwaitis (66%) and non-Kuwaitis (64%). No sex difference in knowledge was seen. Knowledge about diabetes was highest among diabetic patients with increasing educational achievement but lowest with advantage age. CONCLUSION: Most patients lack a lot of information that could have a significant impact on their motivation and ability to remain healthy. To overcome this growing problem, instructing a standard diabetes education system was found to be one way of improving in morbidity due to diabetes and reduced hospital admission. PMID- 20841296 TI - Assessment of health awareness and its sources among journalism and mass communication students at yarmouk university, jordan. AB - This study assesses the overall health awareness level of students of the Department of Journalism and Mass Communication at Yarmouk University/Jordan who are supposed to have an important leadership role among mass media professionals in Jordan. A Health Awareness Test (HAT) was administered to a random sample of 139 students of this group (52.85% of the target population). Findings revealed that their overall average performance on the HAT was significantly much lower than the acceptable criterion score determined by the HAT authors. Female students' performance on the HAT was significantly higher than males' performance. The academic level of these students (2nd, 3rd or 4th academic year) did not have significant influence on their scores. Furthermore, the two-way ANOVA analysis showed that there was no significant difference in the achievement of the study subjects on the HAT by sex and academic level. The major sources of the health awareness information of these students ranked by order were: mass media, self-education, academic preparation (information included in the curricula), family and peers, and finally cultural events in the form of extra curricular activities at the University. Recommendations based upon these results are given. PMID- 20841297 TI - Smoking survey of dental clinic patients in the saudi military hospital. AB - A survey of 200 dental clinic patients in Saudi Arabia's only military hospital. An appropriate health education smoking prevention program is described based on knowledge, attitude, and behavior derived from the survey and existing anti smoking educational programs in the United States. PMID- 20841298 TI - Sex differences in health and illness orientation. AB - Recent studies indicate that gender role socialization and obligations may have considerable influence in shaping health attitudes, beliefs and behaviors. This article reviews these studies, focusing on sex differences in health and illness orientations, and explores in some depth differences in an interest and concern with health. The findings from several studies suggest that men and women differ in health perceptions, values, attitudes, interests and behaviors. The implications of these sex differences for health education research and practice are discussed. PMID- 20841299 TI - Attitude change among health educators studying abroad. AB - This study examined change in attitudes about international health efforts among health educators who participated in graduate study-abroad programs in Japan and Jamaica. No statistically significant changes were found in levels of hostility toward other nations or attitude toward international health cooperation. However, correlations found between individual attitude change and measures of dogmatism and tolerance for ambiguity suggest that participants may vary in their receptiveness to the messages of such programs, and that openness of participant's belief systems may have some role in the success of such programs. The nature of this role is unclear since more dogmatic participants in the Japan group reported greater attitude change than their more open minded peers. This result was opposite to that expected and was not found for the Jamaica group. PMID- 20841300 TI - Yoruba disease classifications for planning in health care. AB - An understanding of local concepts of illness and disease that underlie disease classification systems is essential for designing culturally relevant training programs in primary health care. Prior to training personnel in primary health care in Idere, Nigeria, residents were interviewed revealing that two main groups of disease exist. Generally, arun is serious, chronic and contagious, while aisan represents temporary indispositions. When given seventeen conditions to classify, respondents clearly demarked five as arun and five as aisan while the remainder fell in a grey area in between. Ironically, malaria which is a dangerous disease to young children, was classified as aisan.The disease classification system is being used as a general point of departure for discussion during training. Concerning training on the specific diseases, appropriate ideas are reinforced while others are modified all within the context of the local classification system. PMID- 20841301 TI - Hispanic students face barriers to health careers. AB - Holyoke, Massachusetts was selected as the site of this study to identify barriers preventing Hispanic youth from entering the health occupations. The attitudes of students from the local high school towards selected health occupations were assessed. High school guidance counselors were interviewed to determine how they perceived these barriers. Health care agencies in the area were interviewed to determine the number of Hispanics currently in their employ and to assess their willingness to employ others. The most important finding is that Hispanic youth do not differ significantly from Non-Hispanic youth in either their attitudes or their aspirations towards careers in health. The finding is at variance with the perceptions of the majority of the guidance counselors. Health care agencies in the area expressed a willingness to hire trained Hispanics for health occupations. Four major barriers were identified. Recommendations for their removal are presented. PMID- 20841302 TI - From hygiene to public health education. AB - This paper is a review of the development of health education in Brazil (identified as "hygiene" in early times, it has evolved to "public health education"). The field has passed through infancy and adolescence facing all kinds of problems, and is entering adulthood with health education leadership now in the hands of an increasing number of specialists trained in the country. The authors suggest that to hasten progress, more attention should be given to integration of health education to health programs, to stimulation of research, to preparation of health personnel, and to administrative support of health education services. PMID- 20841303 TI - Guidelines for developing effective health education service in a national health agency. AB - The constraints facing health education include: the fragmentation and dispersal of health-educational services among different agencies and personnel; lack of policy guidelines; ineffectively organized and inefficiently managed health education systems; poor hierarchical status and inadequacy of resources. To resolve these constraints, national health education systems in health agencies should be developed on the basis of stipulated guidelines that could ensure their viability, efficiency and effectiveness. A study at the African Regional Health Education Centre, Ibadan, Nigeria, has yielded thirty synthesized guidelines. The "guidelines" were empirically tested as an evaluation tool by assessing the operational and organizational status of Oyo State Health Education Unit, Ibadan, Nigeria. These guidelines are adaptable to local conditions to enhance the re organization, re-orientation and consolidation of health education in national health agencies. PMID- 20841304 TI - Visual vignette. Ascites due to hypothyroidism. PMID- 20841305 TI - Visual vignette. Familial hypercholesterolemia. PMID- 20841306 TI - Durability of effects of exenatide treatment on glycemic control, body weight, systolic blood pressure, C-reactive protein, and triglyceride concentrations. AB - OBJECTIVE: To determine (1) whether long-term treatment with exenatide is associated with reductions in C-reactive protein (CRP), systolic blood pressure (BP), and triglyceride concentrations in addition to reductions in body weight and hemoglobin A(1c) (A1C) levels and (2) whether these beneficial results persist without any loss of effect while exenatide is being used, and whether they reverse after its cessation. METHODS: We conducted a retrospective review of 141 patients with type 2 diabetes mellitus treated with exenatide at a tertiary clinic. RESULTS: Exenatide (mean duration of treatment, 1.4 years) decreased A1C (0.7%), weight (5 kg), systolic BP (8 mm Hg), and triglyceride concentrations (46 mg/dL) (P<.05 for all). Sixty-one patients continued exenatide therapy throughout the study (mean duration of use, 2.4 years). Exenatide treatment reduced their mean weight by 7 kg, systolic BP by 8 mm Hg, triglycerides by 52 mg/dL, A1C by 1.3%, and CRP by 2.4 mg/L (P<.05 for all). Reductions in systolic BP and CRP were not related to weight loss. The reduction in CRP concentration was significantly related to the baseline CRP concentration (r = 0.78; P<.001) and to change in A1C (r = 0.68; P = .02). Patients who stopped taking exenatide had a reversal of the benefits within 6 months after cessation of treatment. CONCLUSION: Exenatide treatment in patients with type 2 diabetes has durable and persistent beneficial effects on A1C, weight, CRP, systolic BP, and triglyceride concentrations. Cessation of treatment reverses all these beneficial effects within 6 months. There was no evidence of loss of its effects while exenatide treatment was continued. PMID- 20841307 TI - 46, XX SRY-positive male syndrome presenting with primary hypogonadism in the setting of scleroderma. AB - OBJECTIVE: To describe a case of SRY gene translocation in a man with scleroderma presenting with primary hypogonadism. METHODS: We present the clinical, physical, laboratory, and pathologic findings of the study patient and discuss the cytogenetic analysis and the cause of the sexual dysfunction. Relevant literature is reviewed. RESULTS: A 35-year-old man with a recent diagnosis of diffuse cutaneous sclerosis was referred by his rheumatologist because of a low testosterone level. His medical history was notable for right cryptorchidism corrected after birth. He had no history of sexual activity, but reported normal erectile function before his current presentation. Physical examination findings were remarkable for a height of 157.5 cm; weight of 72.7 kg; extensive, diffuse thickening of the skin; mild gynecomastia; little axillary and pubic hair; and soft testes (1-2 mL bilaterally). Initial laboratory testing revealed the following values: follicle-stimulating hormone, 22.1 mIU/mL (reference range, 1.4 18.1 mIU/mL); luteinizing hormone, 19.7 mIU/mL (reference range, 1.5-9.3 mIU/mL); total testosterone, 25 ng/dL (reference range, 241-827 ng/dL); and free direct testosterone, 0.8 pg/mL (reference range, 8.7-25.1 pg/mL). Laboratory test results were consistent with primary hypogonadism. A urologist performed testicular biopsy, which showed severe testicular atrophy with absent spermatogenesis. Primary hypogonadism due to Klinefelter syndrome or testicular fibrosis secondary to scleroderma was suspected. Karyotype analysis showed a 46, XX karyotype, and fluorescence in situ hybridization was consistent with a 46, XX, Xp22.3(SRY+) gene translocation. After a normal prostate-specific antigen level was documented, testosterone replacement therapy was initiated, and he was referred for genetic counseling. CONCLUSIONS: The 46, XX SRY-positive male syndrome is rare. Adult diagnosis can be challenging because of normal sexual development. Scleroderma, which rarely can occur in Klinefelter-type syndromes, further complicated the diagnosis in this case. PMID- 20841308 TI - Vitamin D status and its seasonal variability in healthy young adults in an Asian Indian urban population. AB - OBJECTIVE: To assess the vitamin D status and its seasonal variability in healthy young adults in Chandigarh, a city in northern India. METHODS: The history was elicited and examination was performed pertaining to metabolic bone disease in 329 young adults (18 to 25 years of age) at the end of summer and 237 subjects from the same cohort at the end of winter. The calcium profile, 25-hydroxyvitamin D [25(OH)D], and intact parathyroid hormone were measured during both the seasons. RESULTS: Among the young adults in this study cohort, 25(OH)D sufficiency (>= 30 ng/mL) was found in 72.5% in summer and in 50.7% in winter. A significantly higher number of men were 25(OH)D sufficient in comparison with women in summer (P = .001). The mean (standard deviation) serum 25(OH)D levels were significantly higher at the end of summer-52.9 (33.7) ng/mL-in comparison with that at the end of winter-31.8 (21.1) ng/mL; P<.001. The intact parathyroid hormone levels were significantly lower in the 25(OH)D-sufficient group (P = .001) and began to increase at 25(OH)D levels below 25 ng/mL. The serum 25(OH)D levels correlated positively with the duration of exposure to sunlight during summer (r = 0.111; P = .05) and also the calcium intake during summer (r = 0.129; P = .03). CONCLUSION: Vitamin D sufficiency may be a reality with a combination of young skin, optimal and effective exposure to sunlight, and adequate calcium intake. PMID- 20841309 TI - P450C17 (CYP17) deficiency in native Mexican patient with a novel CYP17A1 mutation. AB - OBJECTIVE: To report a case of congenital adrenal hyperplasia due to CYP17 deficiency caused by a novel CYP17A1 mutation. METHODS: We describe the clinical, biochemical, genetic, and radiologic findings of a sporadic case of congenital adrenal hyperplasia due to CYP17 deficiency in a young patient. RESULTS: An 18 year-old woman presented with hypogonadism and progressive muscle weakness and had not yet undergone thelarche, adrenarche, and menarche. Blood pressure was 155/90 mm Hg, she had no axillary or pubic hair, breasts were Tanner stage 1, and female genitalia were Tanner stage 1. Further laboratory studies showed hypokalemia with metabolic alkalosis, hypergonadotropic hypogonadism, a 46, XY karyotype, a low 17-hydroxyprogesterone level, and a high deoxycorticosterone level. Sequencing of the CYP17A1 gene demonstrated homozygous transversion of cytosine to adenine (TCA->TAA) in exon 5, which causes a premature stop codon at position 288 (Ser288X). Imaging studies showed large adrenal glands, cystic picture in the inguinal canal (suggestive of intra-abdominal testes), and absent Mullerian structures. Exploratory laparotomy was performed to remove the remaining gonads, and the final histologic examination showed atrophic testes. CONCLUSIONS: Congenital adrenal hyperplasia due to CYP17 deficiency should be suspected in patients with hypertension, hypokalemic alkalosis, and hypogonadism. In such cases, it is mandatory to assess the karyotype and perform hormonal and molecular genetic studies. PMID- 20841310 TI - Autoimmune thyroid disease: a risk factor for thyroid cancer. AB - OBJECTIVE: To examine the relationship between clinical markers of autoimmune thyroid disease and the risk of thyroid cancer in patients with thyroid nodules. METHODS: A retrospective cohort analysis was performed in a single clinical practice. In 2,500 consecutive patients, fine-needle aspiration biopsy (FNAB) was performed on all 3,658 ultrasonography-positive thyroid nodules that were >= 1.0 cm in diameter or >= 0.5 cm in diameter with ultrasound features suspicious for thyroid cancer. Serum concentrations of thyroglobulin antibodies (TgAb), thyroid peroxidase antibodies, and thyroid-stimulating hormone were measured before FNAB. Diagnosis of thyroid cancer was based on pathologic analysis of thyroidectomy tissue. Associations of thyroid cancer with the independent variables were determined by multivariate logistic regression analysis and reported as the adjusted odds ratio (OR) with the 95% confidence interval (CI). RESULTS: There were 202 patients with malignant thyroid nodules, 51 patients with microscopic unsuspected thyroid cancer distal to the nodule under investigation (found at thyroidectomy), and 2,247 patients with benign thyroid nodules. To evaluate the association of clinical markers for autoimmune thyroid disease with thyroid cancer, we included all 253 patients with thyroid cancer in the malignant cohort. Thyroid cancer was associated with elevated levels of TgAb (OR = 1.57; CI = 1.11 to 2.23) and age <55 years (OR = 2.01; CI = 1.45 to 2.78), and a strong trend was demonstrated for association with male sex (OR = 1.45; CI = 0.99 to 2.12). Thyroid cancer was not associated with elevated levels of thyroid peroxidase antibodies. CONCLUSION: In patients who have thyroid nodules with indications for FNAB, elevated levels of TgAb are associated with thyroid cancer. PMID- 20841311 TI - Hemoglobin A(1c) criterion for diabetes diagnosis among Hispanic and non-Hispanic populations. AB - OBJECTIVE: To report on the performance of the recently recommended hemoglobin A(1c) (A1C) criterion for diabetes diagnosis in comparison with the standard fasting plasma glucose and 2-hour post-glucose challenge (PG) test criteria across racial and ethnic groups. METHODS: We evaluated local and national survey data from 689 Dominican, 4,862 Hispanic, 4,694 African American, and 6,883 white study subjects. We compared rates of diabetes classification by diagnostic criteria, agreement and disagreement between A1C and PG criteria for diagnosing diabetes, and differences in cardiometabolic risk among the 3 diagnostic groups across racial and ethnic stratifications. RESULTS: The A1C-based diabetes diagnoses were higher among Dominican and African American study subjects (81.6% and 67.0%, respectively), and lower among Hispanic and white subjects (46.0% and 37.9%, respectively). Among those not meeting any PG criterion for diabetes, the A1C criterion identified diabetes in 8.3% of Dominican, 3.5% of African American, 0.9% of Hispanic, and 0.5% of white study subjects. The A1C criterion, however, did not identify diabetes in 64.5% of white, 46.1% of Dominican, 44.0% of African American, and 41.9% of Hispanic subjects who were diagnosed with diabetes by a PG criterion. For single tests, the agreement was greatest between A1C and fasting plasma glucose test criteria among Dominican, Hispanic, and African American study populations-76.9%, 65.6%, and 60.7%, respectively. There was no clear difference in selected cardiometabolic risks between A1C and PG-only diabetes diagnoses across racial and ethnic groups. CONCLUSION: The A1C criterion yields racial- and ethnic-specific differences in diagnosing diabetes and in test agreements with PG-based criteria. Furthermore, diagnostic differences were observed between the Dominican subgroup and the Hispanic study population, of whom 91.5% were Mexican American. PMID- 20841312 TI - The pathway from diabetes and obesity to cancer, on the route to targeted therapy. AB - OBJECTIVE: To review the epidemiologic studies that describe the relationships among diabetes, obesity, and cancer; animal studies that have helped to decipher the mechanisms of cancer development; and some of the therapeutic targets undergoing investigation. METHODS: An electronic search was performed of Medline, Scopus, Google Scholar, and ClinicalTrials.gov to identify English-language articles and studies published from 1995 through 2010 relating to obesity, insulin, insulinlike growth factors, diabetes mellitus, and cancer. RESULTS: Epidemiologic studies have reported that diabetes and obesity are linked to an increased risk of certain cancers in association with higher levels of insulin, C peptide, and insulinlike growth factor 1. Animal models have demonstrated that increased insulin, insulinlike growth factor 1, and insulinlike growth factor 2 signaling can enhance tumor growth, while inhibiting this signaling can reduce tumorigenesis. Therapies that target insulin and insulinlike growth factor 1 signaling pathways have been developed and are currently in clinical trials to treat cancer. CONCLUSIONS: Insulin, insulinlike growth factor 1, and insulinlike growth factor 2 signaling through the insulin receptor and the insulinlike growth factor 1 receptor can induce tumorigenesis, accounting to some extent for the link between diabetes, obesity, and cancer. Knowledge of these pathways has enhanced our understanding of tumor development and allowed for the discovery of novel cancer treatments. PMID- 20841313 TI - Autoimmune hyperthyroidism due to secondary adrenal insufficiency: resolution with glucocorticoids. AB - OBJECTIVE: To describe the course of autoimmune hyperthyroid disease in a patient with corticotropin (ACTH) deficiency treated with glucocorticoids. METHODS: We report the clinical presentation, laboratory data, imaging studies, and management of a patient with weight loss, fatigue, apathy, hallucinations, and arthritis. RESULTS: Autoimmune hyperthyroidism (positive thyroperoxidase and thyroglobulin antibodies and borderline positive thyrotropin receptor antibody) was diagnosed in a 71-year-old woman. New psychotic symptoms prompted brain magnetic resonance imaging, which revealed a partially empty sella. Undetectable morning cortisol, undetectable ACTH, and failure to stimulate cortisol with synthetic ACTH (cosyntropin 250 mcg) secured the diagnosis of long-standing secondary adrenal insufficiency. Hydrocortisone replacement improved the patient's symptoms, resolved the thyroid disease, and decreased thyroid antibody titers. In retrospect, the patient recalled severe postpartum hemorrhage requiring blood transfusion at age 38 years. A Sheehan event probably occurred 33 years before the patient presented with corticotropin deficiency. Hyperthyroidism accelerated cortisol metabolism and provoked symptoms of adrenal insufficiency. CONCLUSIONS: The hypocortisolemic state may precipitate hyperimmunity and autoimmune thyroid disease. Rapid resolution of hyperthyroidism and decreased thyroid antibody titers with glucocorticoid treatment support this hypothesis. PMID- 20841314 TI - Effects of fluorosis on the shear bond strength of orthodontic brackets bonded with a self-etching primer. AB - The aim of this study was to compare the shear bond strength (SBS) of brackets bonded to fluorosed and non-fluorosed teeth with self-etching primer (SEP) and phosphoric acid (PA). The study involved 40 mildly fluorosed [Thylstrup-Fejerskov (TFT) Index = 1-3] and 40 non-fluorosed human premolar teeth. The fluorosed and non-fluorosed teeth were randomly divided into two subgroups. In the first subgroup, 37 per cent PA was applied for 30 seconds and in the second, a SEP (Transbond Plus) was used. The brackets were bonded with light-cure adhesive paste (Transbond XT) and cured for 20 seconds. The SBSs were measured after 1000 thermocyclies. Two-way analysis of variance, Tukey's multiple comparison test, and Weibull analysis were used for the evaluation of SBS values. Bond failure locations were determined with the adhesive remnant index (ARI) and were compared with the Kruskal-Wallis and Mann-Whitney U-tests. The mean SBS was 9.01 MPa for the fluorosed teeth bonded with SEP. This value was significantly different from those of fluorosed teeth etched with PA (15.22 MPa) and non-fluorosed teeth conditioned with SEP (12.95 MPa) and PA (15.37 MPa). The ARI scores of the fluorosed teeth conditioned with SEP were significantly lower than those of non fluorosed teeth conditioned with SEP or PA. The results of this in vitro study suggest that there are no differences in the SBS of orthodontic brackets between mildly fluorosed and non-fluorosed enamel etched with 37 per cent PA for 30 seconds. The SEP showed lower SBS values for orthodontic brackets bonded to mildly fluorosed enamel. The findings provide some evidence that routine clinical use of a SEP to bond brackets to mildly fluorosed teeth cannot be supported. PMID- 20841315 TI - Craniofacial morphological characteristics of Chinese adults with normal occlusion and different skeletal divergence. AB - The aim of the present study was to examine the craniofacial morphologic characteristics of different vertical dysplasias in a population of Chinese adults with normal occlusion. Sixty-nine subjects (39 males and 30 females) were selected from 800 healthy students between 18 and 24 years of age. Lateral cephalograms were obtained and 27 hard and 10 soft tissue measurements were analysed. The subjects were then divided into three groups: high angle, low angle, or control according to the value of FH-MP. Intraclass correlation coefficient was determined for the repeated measurements. One-way analysis of variance was used to determine the differences between the groups. The results showed that the low-angle group had a larger cranial basis angle (N-S-Ar) and the high-angle group had a shorter maxilla (Ans-Ptm; P < 0.01). The high-angle group displayed vertical hyperdivergency with increased PP-OP, OP-MP, gonial, and lower gonial angles, whereas the low-angle group showed significant hypodivergence with decreased values for all variables (P < 0.01). The low-angle group displayed a more protrusive chin and the high-angle group a more retrusive chin (P < 0.01). Differences in dentoalveolar measurements in the divergent groups were mainly in the anterior region. Moreover, the low-angle group had a thicker and the high angle group a thinner lower dentoalveolus (P < 0.01). For face height measurements, the main differences in the divergent groups were at the anterior lower third (P < 0.01). Soft tissue deviations were less obvious in the high angle group and in general less significant than those of the hard tissues in both divergent groups. Significantly different morphological characteristics exist in Chinese adults with vertical dysplasia but normal occlusion. Major skeletal cephalometric changes were found for the lower facial third. The soft tissues showed a well-adapting mechanism of soft tissue coverage for the skeletal dysplasia. PMID- 20841317 TI - Sickness absence in student nursing assistants following a preventive intervention programme. AB - BACKGROUND: We have previously shown that a multidimensional programme combining physical training, patient transfer techniques and stress management significantly reduced sickness absence rates in student nurse assistants (NAs) after 14 months of follow-up. At follow-up, the control group had reduced SF-36 scores for general health perception [general health (GH)], psychological well being [mental health (MH)] and energy/fatigue [vitality (VT)] compared with the intervention group, which remained at the baseline level for all three measures. AIMS: To ascertain whether this effect remained after a further 36 months of follow-up and to analyse the association of GH, MH and VT scores with sickness absence. METHODS: This was a cluster randomized prospective study. The original study involved assessment at baseline and follow-up at 14 months (the duration of the student NA course). Of 568 subjects from the original intervention study, 306 (54%) completed a postal questionnaire at 36 months. RESULTS: Sickness absence increased in both groups between the first and second follow-up. At the second follow-up, the intervention group had a mean of 18 days of sickness absence compared with 25 in the control group but this was not significant. GH at 14 months follow-up was found to predict sickness absence levels after 3 years. MH and VT scores showed an inverse association with sickness absence but the results were not significant. CONCLUSIONS: The results suggest that the initial intervention did not have a sustained effect on sickness absence 36 months after initial follow-up of the study group. PMID- 20841316 TI - High genetic differentiation among French populations of the Orsini's viper (Vipera ursinii ursinii) based on mitochondrial and microsatellite data: implications for conservation management. AB - The Orsini's viper (Vipera ursinii) is one of the most threatened snakes in Europe due to its highly fragmented distribution and specific open environment (steppic habitat) requirement. French populations are isolated on top of mountain massifs of the southern Prealps/Alps. Mitochondrial sequences (cytochrome b) and 6 microsatellite loci have been used to estimate the levels of genetic diversity and isolation within and among 11 French fragmented populations (a total of 157 individuals). Eleven cytochrome b haplotypes with a limited divergence were observed (mean divergence between haplotypes: 0.31%). However, we detected considerable genetic differentiation among populations (global F(ST) = 0.76 and 0.26 for mitochondrial and nuclear DNA, respectively). Results indicate that 3 populations possibly went through a bottleneck and 1 population showed low genetic diversity compared with the others. Although a significant isolation by distance was detected for both markers, strong differentiation was also observed between geographically close populations, probably due to the ragged landscape that constitutes a serious barrier to gene flow owing to the limited dispersal capability of the viper. Despite some discrepancies between the 2 markers, 8 Management Units have been identified and should be considered for future management projects. PMID- 20841318 TI - Towards evidence-based, quality-controlled health promotion: the Dutch recognition system for health promotion interventions. AB - Registration or recognition systems for best-practice health promotion interventions may contribute to better quality assurance and control in health promotion practice. In the Netherlands, such a system has been developed and is being implemented aiming to provide policy makers and professionals with more information on the quality and effectiveness of available health promotion interventions and to promote use of good-practice and evidence-based interventions by health promotion organizations. The quality assessments are supervised by the Netherlands Organization for Public Health and the Environment and the Netherlands Youth Institute and conducted by two committees, one for interventions aimed at youth and one for adults. These committees consist of experts in the fields of research, policy and practice. Four levels of recognition are distinguished inspired by the UK Medical Research Council's evaluation framework for complex interventions to improve health: (i) theoretically sound, (ii) probable effectiveness, (iii) established effectiveness, and (iv) established cost effectiveness. Specific criteria have been set for each level of recognition, except for Level 4 which will be included from 2011. This point of view article describes and discusses the rationale, organization and criteria of this Dutch recognition system and the first experiences with the system. PMID- 20841319 TI - Modeled comparisons of health risks posed by fluorinated solvents in a workplace spill scenario. AB - The purpose of this study was to illustrate how available physical-chemical exposure models can be used to compare potential risks and define risk management measures for non-routine exposure events, such as spills, leaks, or process upset conditions. A two-zone physical-chemical model was used to quantify and compare the potential exposure risks from five fluorinated solvents used in the manufacturing of electronic materials during an anticipated spill scenario. A 1-l spill scenario in a room measuring 2.74 m (9 ft) high by 3.66 m (12 ft) wide by 9.14 m (30 ft) long was constructed for modeling exposures using 'The Two-zone Model with An Exponentially Decreasing Contaminant' in available freeware 'IH MOD' (a PC based program available from the American Industrial Hygiene Association). This treatment was followed by using the results from an experimental chamber study in which the evaporation rates and vapor concentrations of the five fluorinated solvents were measured under realistic conditions and then compared to exposure model outputs. The breathing zone concentration/time profiles predicted for the five solvents were compared to their exposure limits to estimate the relative risk. This information was used to help define operationally sufficient risk management options for the safe handling of spills in laboratories, warehouses, or manufacturing facilities. The model indicated that each solvent presented very different risk profiles for the same 1-l liquid spill scenario. Potential exposure concentrations relative to short-term exposure limit (15 min) and Ceiling (C) exposure limit available for some of the solvents are predicted to be exceeded within a few minutes in the area near the spill and in the far field. In addition, the model showed that near field concentrations for one solvent exceeded the published LC-50 (the concentration predicted to cause 50% mortality in the test animals), which indicates a very high degree of risk for this material in similar scenarios. Given the speed of evaporation during these spills for the materials tested in this study, donning personal protective equipment in the area may not be a viable option and short-term evacuation of the area immediately surrounding the spill would appear to be a practical risk management response. PMID- 20841320 TI - Tracing the temporal and spatial origins of island endemics in the Mediterranean region: a case study from the citrus family (Ruta L., Rutaceae). AB - Understanding the origin of island endemics is a central task of historical biogeography. Recent methodological advances provide a rigorous framework to determine the relative contribution of different biogeographic processes (e.g., vicariance, land migration, long-distance dispersal) to the origin of island endemics. With its complex but well-known history of microplate movements and climatic oscillations, the Mediterranean region (including the Mediterranean basin and Macaronesia) provides the geographic backdrop for the diversification of Ruta L., the type genus of Rutaceae (citrus family). Phylogenetic, molecular dating, and ancestral range reconstruction analyses were carried out to investigate the extent to which past geological connections and climatic history of the Mediterranean region explain the current distribution of species in Ruta, with emphasis on its island endemics. The analyses showed that Ruta invaded the region from the north well before the onset of the Mediterranean climate and diversified in situ as the climate became Mediterranean. The continental fragment island endemics of the genus originated via processes of land migration/vicariance driven by connections/disconnections between microplates, whereas the oceanic island endemics were the product of a single colonization event from the mainland followed by in situ diversification. This study emphasizes the need for an integrative, hypothesis-based approach to historical biogeography and stresses the importance of temporary land connections and colonization opportunity in the biotic assembly of continental fragment and oceanic islands, respectively. PMID- 20841322 TI - Sensitivity of V1 neurons to direction of spectral motion. AB - Motion-in-depth causes changes in the size of retinal images in addition to producing optic flow patterns. A previous psychophysical study showed that human subjects can perceive expansion motion in texture stimuli that exhibit increases in the scale of image elements but no consistent optic flow pattern. The neural mechanisms by which the scale-change information is processed remain unknown. Here, we measured the responses of cat V1 and the lateral geniculate nucleus (LGN) neurons to a sequence of random images whose spatial frequency spectrum changed over time (i.e., average spatial scale expanded or contracted). We found that V1 neurons exhibit direction sensitivity to scale changes, with more cells preferring expansion than contraction motion. This direction sensitivity can be partly accounted for by the spectrotemporal receptive field of V1 neurons. Comparison of the direction sensitivity between V1 and LGN neurons showed that the sensitivity in V1 may originate from LGN neurons. Repetitive stimulation with expansion or contraction motion can decrease the sensitivity to the adapted direction in V1, and the effect can be transferred interocularly, suggesting that intracortical connections may be critically involved in the adaptation. Together, our results suggest that direction sensitivity to scale change in V1 may contribute to motion-in-depth processing. PMID- 20841321 TI - Morphometric differences in the Heschl's gyrus of hearing impaired and normal hearing infants. AB - This study investigates the morphometry of Heschl's gyrus and its included primary auditory cortex (PAC) in hearing impaired (HI) and normal hearing (NH) infants. Fourty-two infants, age 8-19 months, with NH (n = 26) or hearing impairment (n = 16) were studied using high-resolution 3D magnetic resonance imaging. Gray matter (GM) and white matter (WM) volumes were obtained using software for automatic brain imaging segmentation to estimate the volume of each tissue within manually defined regions for the anterior portion of Heschl's gyrus (aHG) in each individual subject, transformed to an infant brain template space. Interactions among group (HI, NH), tissue type (GM, WM), and hemisphere (left, right) were examined using analysis of variance. Whole-brain voxel-based morphometry was utilized to explore volume differences between groups across the entire brain. The HI group showed increased GM and decreased WM in aHG compared with the NH group; likely effects of auditory deprivation. The HI group did not exhibit their typical L > R asymmetry pattern that the NH group showed. Increased GM in aHG in HI infants may represent abnormal cortical development in PAC as seen in animal models of sensory deprivation. Lower WM volume is consistent with studies with deaf adults. PMID- 20841323 TI - Return to work after treatment for breast cancer: single-center experience in a cohort of 273 patients. PMID- 20841324 TI - SynBioWave--a real-time communication platform for molecular and synthetic biology. AB - SUMMARY: Synthetic Biology is advanced by many users and relies on the assembly of genetic elements to devices, systems and finally genomes. SynBioWave is a software suite that enables multiple distributed users to analyze and construct genetic parts in real-time collaboration. It builds on Google Wave and provides an extensible robot-robot-user communication framework, a menu driven user interface, biological data handling including DAS and an internal database communication. We demonstrate its use by implementing robots for gene-data retrieval, manipulation and display. The initial development of SynBioWave demonstrates the power of the underlying Google Wave protocol for Synthetic Biology and lays the foundation for continuous and user-friendly extensions. Specialized wave-robots with a manageable set of capabilities will divide and conquer the complex task of creating a genome in silico. AVAILABILITY: The robot is available at SynBioWave@appspot.com, the source code at http://synbiowave.sourceforge.net PMID- 20841325 TI - Identification of preferential target sites for human DNA methyltransferases. AB - DNA methyltransferases (DNMTs) play an important role in establishing and maintaining DNA methylation. Aberrant expression of DNMTs and their isoforms has been found in many types of cancer, and their contribution to aberrant DNA methylation has been proposed. Here, we generated HEK 293T cells stably transfected with each of 13 different DNMTs (DNMT1, two DNMT3A isoforms, nine DNMT3B isoforms and DNMT3L) and assessed the DNA methylation changes induced by each DNMT. We obtained DNA methylation profiles of DNA repetitive elements and 1505 CpG sites from 808 cancer-related genes. We found that DNMTs have specific and overlapping target sites and their DNA methylation target profiles are a reflection of the DNMT domains. By examining H3K4me3 and H3K27me3 modifications in the 808 gene promoter regions using promoter ChIP-on-chip analysis, we found that specific de novo DNA methylation target sites of DNMT3A1 are associated with H3K4me3 modification that are transcriptionally active, whereas the specific target sites of DNMT3B1 are associated with H3K27me3 modification that are transcriptionally inactive. Our data suggest that different DNMT domains are responsible for targeting DNA methylation to specific regions of the genome, and this targeting might be associated with histone modifications. PMID- 20841326 TI - The continuum of psychotic symptoms in the general population: a cross-national study. AB - OBJECTIVE: To identify the cross-national prevalence of psychotic symptoms in the general population and to analyze their impact on health status. METHOD: The sample was composed of 256,445 subjects (55.9% women), from nationally representative samples of 52 countries worldwide participating in the World Health Organization's World Health Survey. Standardized and weighted prevalence of psychotic symptoms were calculated in addition to the impact on health status as assessed by functioning in multiple domains. RESULTS: Overall prevalences for specific symptoms ranged from 4.80% (SE = 0.14) for delusions of control to 8.37% (SE = 0.20) for delusions of reference and persecution. Prevalence figures varied greatly across countries. All symptoms of psychosis produced a significant decline in health status after controlling for potential confounders. There was a clear change in health impact between subjects not reporting any symptom and those reporting at least one symptom (effect size of 0.55). CONCLUSIONS: The prevalence of the presence of at least one psychotic symptom has a wide range worldwide varying as much as from 0.8% to 31.4%. Psychotic symptoms signal a problem of potential public health concern, independent of the presence of a full diagnosis of psychosis, as they are common and are related to a significant decrement in health status. The presence of at least one psychotic symptom is related to a significant poorer health status, with a regular linear decrement in health depending on the number of symptoms. PMID- 20841327 TI - Changes in alcohol-related harm in Sweden after increasing alcohol import quotas and a Danish tax decrease--an interrupted time-series analysis for 2000-2007. AB - BACKGROUND: Denmark decreased its tax on spirits by 45% on 1 October 2003. Shortly thereafter, on 1 January 2004, Sweden increased its import quotas of privately imported alcohol, allowing travellers to bring in much larger amounts of alcohol from other European Union countries. Although these changes were assumed to increase alcohol-related harm in Sweden, particularly among people living close to Denmark, analyses based on survey data collected before and after these changes have not supported this assumption. The present article tests whether alcohol-related harm in southern Sweden was affected by these changes by analysing other indicators of alcohol-related harm, e.g. harm recorded in different kinds of registers. METHODS: Interrupted time-series analysis was performed with monthly data on cases of hospitalization due to acute alcohol poisoning, number of reported violent assaults and drunk driving for the years 2000-07 in southern Sweden using the northern parts of Sweden as a control and additionally controlling for two earlier major changes in quotas. RESULTS: The findings were not consistent with respect to whether alcohol-related harm increased in southern Sweden after the decrease in Danish spirits tax and the increase in Swedish alcohol import quotas. On the one hand, an increase in acute alcohol poisonings was found, particularly in the 50-69 years age group, on the other hand, no increase was found in violent assaults and drunk driving. CONCLUSIONS: The present results raise important questions about the association between changes in availability and alcohol-related harms. More research using other methodological approaches and data is needed to obtain a comprehensive picture of what actually happened in southern Sweden. PMID- 20841328 TI - Religion and assisted and non-assisted suicide in Switzerland: National Cohort Study. AB - BACKGROUND: In the 19th century, eminent French sociologist Emile Durkheim found suicide rates to be higher in the Protestant compared with the Catholic cantons of Switzerland. We examined religious affiliation and suicide in modern Switzerland, where assisted suicide is legal. METHODS: The 2000 census records of 1,722,456 (46.0%) Catholics, 1,565,452 (41.8%) Protestants and 454,397 (12.2%) individuals with no affiliation were linked to mortality records up to December 2005. The association between religious affiliation and suicide, with the Protestant faith serving as the reference category, was examined in Cox regression models. Hazard ratios (HRs) with 95% confidence intervals (CIs) were adjusted for age, marital status, education, type of household, language and degree of urbanization. RESULTS: Suicide rates per 100,000 inhabitants were 19.7 in Catholics (1664 suicides), 28.5 in Protestants (2158 suicides) and 39.0 in those with no affiliation (882 suicides). Associations with religion were modified by age and gender (P < 0.0001). Compared with Protestant men aged 35-64 years, HRs (95% CI) for all suicides were 0.80 (0.73-0.88) in Catholic men and 1.09 (0.98-1.22) in men with no affiliation; and 0.60 (0.53-0.67) and 1.96 (1.69 2.27), respectively, in men aged 65-94 years. Corresponding HRs in women aged 35 64 years were 0.90 (0.80-1.03) and 1.46 (1.25-1.72); and 0.67 (0.59-0.77) and 2.63 (2.22-3.12) in women aged 65-94 years. The association was strongest for suicides by poisoning in the 65-94-year-old age group, the majority of which was assisted: HRs were 0.45 (0.35-0.59) for Catholic men and 3.01 (2.37-3.82) for men with no affiliation; 0.44 (0.36-0.55) for Catholic women and 3.14 (2.51-3.94) for women with no affiliation. CONCLUSIONS: In Switzerland, the protective effect of a religious affiliation appears to be stronger in Catholics than in Protestants, stronger in older than in younger people, stronger in women than in men, and particularly strong for assisted suicides. PMID- 20841329 TI - Republished paper: Assuring validity of multisource feedback in a national programme. AB - OBJECTIVE: To report the evidence for and challenges to the validity of Sheffield Peer Review Assessment Tool (SPRAT) with paediatric Specialist Registrars (SpRs) across the UK as part of Royal College of Paediatrics and Child Health workplace based assessment programme. DESIGN: Quality assurance analysis, including generalisability, of a multisource feedback questionnaire study. SETTING: All UK Deaneries between August 2005 and May 2006. PARTICIPANTS: 577 year 2 and 4 Paediatric SpRs. INTERVENTIONS: Trainees were evaluated using SPRAT sent to clinical colleagues of their choosing. Data were analysed reporting totals, means and SD, and year groups were compared using independent t tests. A factor analysis was undertaken. Reliability was estimated using generalisability theory. Trainee and assessor demographic details were explored to try to explain variability in scores. MAIN OUTCOME MEASURES: 4770 SPRAT assessments were provided about 577 paediatric SpRs. The mean scores between years were significantly different (Year 2 mean=5.08, SD=0.34, Year 4 mean=5.18, SD=0.34). A factor analysis returned a two-factor solution, clinical care and psychosocial skills. The 95% CI showed that trainees scoring >=4.3 with nine assessors can be seen as achieving satisfactory performance with statistical confidence. Consultants marked trainees significantly lower (t=-4.52) whereas Senior House Officers and Foundation doctors scored their SpRs significantly higher (SHO t=2.06, Foundation t=2.77). CONCLUSIONS: There is increasing evidence that multisource feedback (MSF) assesses two generic traits, clinical care and psychosocial skills. The validity of MSF is threatened by systematic bias, namely leniency bias and the seniority of assessors. Unregulated self-selection of assessors needs to end. PMID- 20841330 TI - Ischaemic heart disease assessment by cardiovascular magnetic resonance imaging. AB - Ischaemic heart disease (IHD) related mortality has been on the decline, although its prevalence has been on the rise since the late 1970s. One of the contributing factors to this decline has been improved diagnosis and therapeutic management. Every clinician seeks to answer four key questions while evaluating patients with suspected or known IHD: What is the global ventricular function? What is the regional ventricular function? Is the myocardium viable? What is the status of the coronary arteries? In the past decade cardiovascular magnetic resonance (CMR) imaging has emerged as an important clinical technique with the potential of answering all the pertinent questions in a single study. This has led to a significant increase in demand and utilisation of this modality. However, many clinicians are not well versed with this technology, its clinical utility, limitations and future prospects. With the increasing prevalence of IHD, CMR imaging is likely to be used more often in its diagnosis, prognostication and management. The review describes the basic principles and practical aspects of CMR imaging, and then discusses in detail the role of CMR in the diagnosis and management of IHD, its complications, and its utility in patients with acute myocardial infarction. PMID- 20841331 TI - Republished paper: Arterial stiffness in chronic kidney disease: causes and consequences. AB - Chronic kidney disease is associated with elevated cardiovascular risk, and heart failure and arrhythmias are the biggest causes of cardiovascular death in this population. Increased arterial stiffness is a hallmark of chronic kidney disease and is associated with adverse alterations in cardiac structure and function that may predispose to an increased risk of cardiovascular death. These changes are already apparent in early kidney disease, which is highly prevalent in the developed world. The mechanisms underlying increased arterial stiffness in chronic kidney disease are undoubtedly complex, but an understanding is paramount to enable the development of novel therapeutic strategies to prevent or reverse this pathophysiology and therefore reduce the cardiovascular disease burden in this high-risk cohort. PMID- 20841332 TI - Risk assessments by female victims of intimate partner violence: predictors of risk perceptions and comparison to an actuarial measure. AB - Recent studies support the validity of both structured risk assessment tools and victim perceptions as predictors of risk for repeat intimate partner violence (IPV). Combining structured risk assessments and victim risk assessments leads to better predictions of repeat violence than either alone, suggesting that the two forms of assessment provide unique and complementary information. However, very little is known about elements involved in women's risk assessments. The present study explores predictors of women's risk assessment and differences in factors linked to victim and actuarial risk assessments in a large sample of women (N = 728) shortly after the arrest of their male partner for IPV. In multivariate analyses, women's risk assessments were strongly related to past relationship violence and their partner's substance abuse but weakly related to demographic factors, family constellation, and the partner's criminal history. Women who perceived high risk but had a low risk score on an actuarial measure were more likely to report the presence of dynamic risk factors, such as escalating violence and violence during separations, along with a history of emotional and psychological abuse. Qualitative findings paralleled quantitative findings, with women's stated reasons for expecting high or low risk indicating that women were attending to IPV history and dynamic factors. Implications for risk assessment and safety planning are discussed. PMID- 20841333 TI - Model structure analysis to estimate basic immunological processes and maternal risk for parvovirus B19. AB - After a steep monotone rise with age, the seroprevalence profiles for human parvovirus B19 (PVB19) display a decrease or plateau between the ages of 20 and 40, in each of 5 European countries. We investigate whether this phenomenon is induced by waning antibodies for PVB19 and, if this is the case, whether secondary infections are plausible, or whether boosting may occur. Several immunological scenarios are tested for PVB19 by fitting different compartmental dynamic transmission models to serological data using data on social contact patterns. The social contact approach has already been shown informative to estimate transmission rates and the basic reproduction number for infections transmitted predominantly through nonsexual social contacts. Our results show that for 4 countries, model selection criteria favor the scenarios allowing for waning immunity at an age-specific rate over the assumption of lifelong immunity, assuming that the transmission rates are directly proportional to the contact rates. Different views on the evolution of the immune response to PVB19 infection lead to altered estimates of the age-specific force of infection and the basic reproduction number. The scenarios which allow for multiple infections during one lifetime predict a higher frequency of PVB19 infection in pregnant women and of associated fetal deaths. When prevaccination serological data are available, the framework developed in this paper could prove worthwhile to investigate these different scenarios for other infections as well, such as cytomegalovirus. PMID- 20841334 TI - Estimation and selection in high-dimensional genomic studies for developing molecular diagnostics. AB - In the development of molecular diagnostics, the main objective in high dimensional genomic studies such as DNA microarray studies is to screen out genes strongly associated with clinical phenotypes to significantly improve diagnostic capabilities. The basic statistical task is thus estimation of the strengths of association or effect sizes for individual genes. We develop an empirical Bayes estimation method based on hierarchical mixture models for a gene-based statistic regarding effect size, without respect to the direction of differential expressions. A nonparametric prior is specified because of limited information on the distributional form of effect size in many genomic studies. Our methods provide some posterior indices useful for selecting candidate genes for further studies. We can assess the predictive capability for any gene sets, possibly those selected via incorporation of biological considerations. Applications to 2 gene expression data sets from cancer clinical studies with microarrays are provided. PMID- 20841336 TI - Outcomes for street children and youth under multidisciplinary care in a drop-in centre in Tegucigalpa, Honduras. AB - BACKGROUND: There is little evidence to describe the feasibility and outcomes of services for the care of street children and youth in low-income countries. AIMS: To describe the outcomes of a multidisciplinary case management approach delivered in a drop-in centre for street children and youth. METHODS: A longitudinal study of street children and youth followed in an urban drop-in centre. Four hundred (400) street children and youth received a multidisciplinary case management therapeutic package based on the community reinforcement approach. The main outcomes were changes in psychological distress, substance abuse and social situation scores. RESULTS: The median follow-up time for the cohort was 18 months. There were reductions in the levels of psychological distress (p = 0.0001) and substance abuse (p <= 0.0001) in the cohort as well as an improvement in the social situation of street children and youth (p = 0.0001). There was a main effect of gender (p < 0.001) and a significant interaction of gender over time (p < 0.001) on improvements in levels of psychological distress. Survival analysis showed that the probability of remaining on substances at 12 months was 0.76 (95% CI: 0.69-0.81) and 0.51 (95% CI: 0.42-0.59) at 24 months. At 12 months, fewer female patients remained using substances compared to male (p < 0.01). CONCLUSION: To be most effective, programmes and strategies for children and youth in street situations in developing countries should target both their health and social needs. PMID- 20841337 TI - Plant-microbe communications for symbiosis. PMID- 20841339 TI - Quality-of-life predictor factors in patients with SLE and their modification after cognitive behavioural therapy. AB - OBJECTIVE: The aim of the study was to determine the clinical and psychological factors linked to health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE) and test the effectiveness of cognitive behavioural therapy in changing these factors. METHODS: We evaluated 34 patients with SLE over a period of 15 months. In order to study the variables related to items of QOL and the physical (PCS) and mental (MCS) component summaries of the SF-36, several multiple linear regression models were constructed. Patients were randomized and distributed into two similar groups; one of them received cognitive behavioural therapy and the other received the usual controlled care. The psychological aspects as well as the related-disease factors were evaluated four times during the study. RESULTS: Self-perceived stress (R2 corrected: 0.314, t: -2.476, p < 0.021), vulnerability to stress (R2 corrected: 0.448, T: -2.166, p < 0.04) and anxiety (R2 corrected: 0.689, T: -7.294, p < 0.00) were predictor variables of MCS. The group of patients who received the therapy improved their level of physical role functioning, vitality, general health perceptions and mental health, compared with the group of patients who only received conventional care. CONCLUSION: QOL usually depends on multiple factors, some of which are stress and anxiety, which can be modified by a cognitive behavioural therapy, in order to obtain a significant improvement in the HRQOL, irrespective of the activity level of the disease. Frequent evaluations of the quality of life in patients with SLE and psychological treatment should also be considered. PMID- 20841340 TI - Complexities of self. PMID- 20841341 TI - Engaging with the self: Mirror behaviour in autism, Down syndrome and typical development. AB - Children with autism achieve mirror self-recognition appropriate to developmental age, but are nonetheless reported to have problems in other aspects of a sense of self. We observed behaviour in the mirror in 12 pre-school children with autism, 13 pre-school children with Down syndrome (DS) and 13 typically developing (TD) toddlers. Reliable differences in reflecting actions, social relatedness and positive affect towards themselves, and an absence of coy smiles differentiated the children with autism from the others. The children with DS showed the highest interest in their own faces. These differences were largely independent of mirror self-recognition (MSR), broadly supporting arguments for dissociation between interpersonal and conceptual aspects of self. Mirror behaviour may be a subtle but easily elicited measure of the social quality of a sense of self. PMID- 20841342 TI - Judgements of self-understanding in adolescents with Asperger syndrome. AB - Previous research has demonstrated that adults with high functioning autism (HFA)/Asperger syndrome (AS) judge others as having as much knowledge about their inner mental states as they do. The current study examined whether this pattern also applies to adolescents with HFA/AS because typically developing adolescents, in contrast to younger children, regard themselves as experts on their own inner states. Twenty-two adolescents with HFA/AS and 22 controls judged how much they versus a comparison person knew about 6 aspects of their inner states. In contrast to typically developing adolescents, those with HFA/AS judged the comparison person as having more knowledge about themselves than they did. This study suggests that adolescents with HFA/AS have more pronounced difficulties with this aspect of self-knowledge than do adults with this condition. The implications of this deficit for social functioning are discussed. PMID- 20841343 TI - Self-conceptualisation in autism: Knowing oneself versus knowing self-through other. AB - This study aimed to extend Lee and Hobson's (1998) findings regarding self conceptualisation in autism by using a more verbally able sample. The study also investigated the ability to conceptualise self through other. Sixteen typically developing and sixteen adolescents with ASD matched for chronological and verbal mental age were administered a modified version of Damon and Hart's (1988) self as-subject interview, which also required participants to conceptualise themselves from another's perspective. Self-conceptualisation ability was similar between groups across the categories of distinctiveness and continuity, but reduced in the ASD group under the category of agency. Participants with ASD were, however, less able to conceptualise themselves from another's perspective. These results are discussed in relation to second-person processes and narrative abilities. PMID- 20841344 TI - Can you tell me something about yourself?: Self-presentation in children and adolescents with high functioning autism spectrum disorder in hypothetical and real life situations. AB - The self-presentation skills of children and adolescents with high-functioning autistic spectrum disorder (HFASD) and typically developing (TD) controls were compared, in response to both hypothetical and real life situations. In both situations, 26 HFASD and 26 TD participants were prompted to describe themselves twice, first in a baseline condition, and later in a goal-directed condition where specific information was given about the preferences and demands of the audience. Confirming and extending previous research, both TD and HFASD participants exhibited a tendency to be more positive when describing themselves in a goal-directed condition. However, HFASD participants were less strategic than TD participants in responding to the information they were given about the audience preferences and demands. Possible explanations and implications of the results are discussed. PMID- 20841345 TI - Subclinical zinc deficiency in Alzheimer's disease and Parkinson's disease. AB - To evaluate zinc status in Alzheimer's disease and Parkinson's disease, 29 patients with Alzheimer's disease, 30 patients with Parkinson's disease, and 29 age- and sex-matched controls were studied. All patients and controls were older than age 50, and all zinc and copper supplements were prohibited beginning 30 days prior to study. Patients were diagnosed by standard criteria. Blood zinc and urine zinc were measured. Urine zinc was measured in a casual specimen, standardized for dilution by reference to creatinine content. Results showed a significantly lower blood zinc in patients with Alzheimer's and patients with Parkinson's than in controls. Urine zinc excretion, normalized to urine creatinine excretion, was not significantly different in either patient group compared to controls. These patients are probably zinc deficient because of nutritional inadequacy. PMID- 20841346 TI - Multiple imputation for missing data via sequential regression trees. AB - Multiple imputation is particularly well suited to deal with missing data in large epidemiologic studies, because typically these studies support a wide range of analyses by many data users. Some of these analyses may involve complex modeling, including interactions and nonlinear relations. Identifying such relations and encoding them in imputation models, for example, in the conditional regressions for multiple imputation via chained equations, can be daunting tasks with large numbers of categorical and continuous variables. The authors present a nonparametric approach for implementing multiple imputation via chained equations by using sequential regression trees as the conditional models. This has the potential to capture complex relations with minimal tuning by the data imputer. Using simulations, the authors demonstrate that the method can result in more plausible imputations, and hence more reliable inferences, in complex settings than the naive application of standard sequential regression imputation techniques. They apply the approach to impute missing values in data on adverse birth outcomes with more than 100 clinical and survey variables. They evaluate the imputations using posterior predictive checks with several epidemiologic analyses of interest. PMID- 20841347 TI - Raising BRN: growth of a journal. PMID- 20841349 TI - Photosynthesis, water use, and root viability under water stress as affected by expression of SAG12-ipt controlling cytokinin synthesis in Agrostis stolonifera. AB - Water stress reduces endogenous cytokinin (CK) content and may inhibit CK production. Maintenance of endogenous CK levels by genetic transformation with ipt in leaves and roots undergoing senescence may promote stress tolerance. This study was designed to determine the physiological effects of ipt expression on immature and mature leaves and in roots for plants exposed to different levels of water stress for creeping bentgrass (Agrostis stolonifera). Plants containing the ipt gene, encoding the enzyme adenine isopentenyl phosphotransferase for CK synthesis ligated to a senescence-activated promoter (SAG12), and wild-type 'Penncross' (WT) were grown hydroponically in a growth chamber and exposed to water stress by weekly additions of polyethylene glycol 8000 to reduce the growing solution osmotic potential from -0.05 to -0.3, -0.5, -0.7, -1.0, and -1.4 MPa. Immature and mature leaves and roots of SAG12-ipt creeping bentgrass were evaluated for ipt expression, CK content, leaf relative water content (RWC), chlorophyll content (Chl), photochemical efficiency (F(v)F(m)), osmotic adjustment (OA), photosynthesis rate (Pn), stomatal conductance (g(s)), transpiration (E), water use efficiency (WUE), carbon isotope discrimination (Delta), and root viability. Expression of ipt was detected in all plant parts and a higher CK content, primarily in the form of isopentyladenine (iPa), was found in SAG12-ipt plants but not in the WT plants under water stress. Immature leaves exhibited higher iPa and OA at all treatment levels. Mature leaves of SAG12-ipt plants maintained higher OA, Pn, Chl, WUE, and Delta, whereas g(s) and E were relatively unaffected compared to the WT. Roots of SAG12-ipt plants had higher levels of iPa and greater root viability than the WT. The results demonstrate that expression of ipt enhanced the tolerance of creeping bentgrass to water stress, which could be attributed to the positive effects on osmotic adjustment, efficient water use, and maintaining higher photosynthetic rate primarily for mature leaves, as well as increased root viability. PMID- 20841350 TI - Altered glucose homeostasis in mice with liver-specific deletion of Src homology phosphatase 2. AB - The Src homology 2 domain-containing protein-tyrosine phosphatase Shp2 has been implicated in a variety of growth factor signaling pathways, but its role in insulin signaling has remained unresolved. In vitro studies suggest that Shp2 is both a negative and positive regulator of insulin signaling, although its physiological function in a number of peripheral insulin-responsive tissues remains unknown. To address the metabolic role of Shp2 in the liver, we generated mice with either chronic or acute hepatic Shp2 deletion using tissue-specific Cre LoxP and adenoviral Cre approaches, respectively. We then analyzed insulin sensitivity, glucose tolerance, and insulin signaling in liver-specific Shp2 deficient and control mice. Mice with chronic Shp2 deletion exhibited improved insulin sensitivity and increased glucose tolerance compared with controls. Acute Shp2 deletion yielded comparable results, indicating that the observed metabolic effects are directly caused by the lack of Shp2 in the liver. These findings correlated with, and were most likely caused by, direct dephosphorylation of insulin receptor substrate (IRS)1/2 in the liver, accompanied by increased PI3K/Akt signaling. In contrast, insulin-induced ERK activation was dramatically attenuated, yet there was no effect on the putative ERK site on IRS1 (Ser(612)) or on S6 kinase 1 activity. These studies show that Shp2 is a negative regulator of hepatic insulin action, and its deletion enhances the activation of PI3K/Akt pathway downstream of the insulin receptor. PMID- 20841351 TI - Core2 O-glycan structure is essential for the cell surface expression of sucrase isomaltase and dipeptidyl peptidase-IV during intestinal cell differentiation. AB - Alterations in glycosylation play an important role during intestinal cell differentiation. Here, we compared expression of mucin-type O-glycan synthases from proliferating and differentiated HT-29 and Caco-2 cells. Mucin-type O-glycan structures were analyzed at both stages by mass spectrometry. Core2 beta1,6-N acetylglucosaminyltransferase-2 (C2GnT-2) was markedly increased in differentiated HT-29 and Caco-2 cells, but the core3 structure was hardly detectable. To determine whether such differential expression of mucin-type O glycan structures has physiological significance in intestinal cell differentiation, expression of sucrase isomaltase (SI) and dipeptidyl-peptidase IV (DPP-IV), two well known intestinal differentiation markers, was examined. Interestingly, the fully glycosylated mature form of SI was decreased in C2GnT-2 knock-out mice but not in core2 N-acetylglucosaminyltransferase-3 (C2GnT-3) nulls. In addition, expression of SI and DPP-IV was dramatically reduced in C2GnT 1-3 triple knock-out mice. These patterns were confirmed by RNAi analysis; C2GnT 2 knockdown significantly reduced cell surface expression of SI and DPP-IV in Caco-2 cells. Similarly, overexpression of the core3 structure in HT-29 cells attenuated cell surface expression of both enzymes. These findings indicate that core3 O-glycan structure regulates cell surface expression of SI and DPP-IV and that core2 O-glycan is presumably an essential mucin-type O-glycan structure found in both molecules in vivo. Finally, goblet cells in the upper part of the crypt showed impaired maturation in the core2 O-glycan-deficient mice. These studies are the first to clearly identify functional mucin-type O-glycan structures modulating cell surface expression of SI and DPP-IV during the intestinal cell differentiation. PMID- 20841352 TI - Calcium-mediated stress kinase activation by DMP1 promotes osteoblast differentiation. AB - Calcium signaling and calcium transport play a key role during osteoblast differentiation and bone formation. Here, we demonstrate that DMP1 mediated calcium signaling, and its downstream effectors play an essential role in the differentiation of preosteoblasts to fully functional osteoblasts. DMP1, a key regulatory bone matrix protein, can be endocytosed by preosteoblasts, triggering a rise in cytosolic levels of calcium that initiates a series of downstream events leading to cellular stress. These events include release of store-operated calcium that facilitates the activation of stress-induced p38 MAPK leading to osteoblast differentiation. However, chelation of intracellular calcium and inhibition of the p38 signaling pathway by specific pharmacological inhibitors and dominant negative plasmid suppressed this activation. Interestingly, activated p38 MAPK can translocate to the nucleus to phosphorylate transcription factors that coordinate the expression of downstream target genes such as Runx 2, a key modulator of osteoblast differentiation. These studies suggest a novel paradigm by which DMP1-mediated release of intracellular calcium activates p38 MAPK signaling cascade to regulate gene expression and osteoblast differentiation. PMID- 20841354 TI - Hepatic overexpression of a constitutively active form of liver glycogen synthase improves glucose homeostasis. AB - In this study, we tested the efficacy of increasing liver glycogen synthase to improve blood glucose homeostasis. The overexpression of wild-type liver glycogen synthase in rats had no effect on blood glucose homeostasis in either the fed or the fasted state. In contrast, the expression of a constitutively active mutant form of the enzyme caused a significant lowering of blood glucose in the former but not the latter state. Moreover, it markedly enhanced the clearance of blood glucose when fasted rats were challenged with a glucose load. Hepatic glycogen stores in rats overexpressing the activated mutant form of liver glycogen synthase were enhanced in the fed state and in response to an oral glucose load but showed a net decline during fasting. In order to test whether these effects were maintained during long term activation of liver glycogen synthase, we generated liver-specific transgenic mice expressing the constitutively active LGS form. These mice also showed an enhanced capacity to store glycogen in the fed state and an improved glucose tolerance when challenged with a glucose load. Thus, we conclude that the activation of liver glycogen synthase improves glucose tolerance in the fed state without compromising glycogenolysis in the postabsorptive state. On the basis of these findings, we propose that the activation of liver glycogen synthase may provide a potential strategy for improvement of glucose tolerance in the postprandial state. PMID- 20841353 TI - AMP-activated protein kinase mediates apoptosis in response to bioenergetic stress through activation of the pro-apoptotic Bcl-2 homology domain-3-only protein BMF. AB - Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN) HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKalpha gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2 modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation. PMID- 20841355 TI - Serine 59 phosphorylation of {alpha}B-crystallin down-regulates its anti apoptotic function by binding and sequestering Bcl-2 in breast cancer cells. AB - The small heat shock protein (sHSP) alphaB-crystallin is a new oncoprotein in breast carcinoma that predicts poor clinical outcome in breast cancer. However, although several reports have demonstrated that phosphorylation of sHSPs modify their structural and functional properties, the significance of alphaB-crystallin phosphorylation in cancer cells has not yet been investigated. In this study, we have characterized the phosphorylation status of alphaB-crystallin in breast epithelial carcinoma cells line MCF7 submitted to anti-cancer agents like vinblastine. We have showed that the main phosphorylation site of alphaB crystallin in response to vinblastine is serine 59 and determined a correlation between this post-translational modification and higher apoptosis level. The overexpression of the serine 59 "pseudophosphorylated" mutant (S59E) induces a significant increase in the apoptosis level of vinblastine-treated MCF7 cells. In contrast, overexpression of wild-type alphaB-crystallin or "nonphosphorylatable" mutant (S59A) result in a resistance to this microtubule-depolymerizing agent, while inhibition of endogenous levels of alphaB-crystallin by expression of shRNA lowers it. Analyzing further the molecular mechanism of this phenomenon, we report for the first time that phosphorylated alphaB-crystallin preferentially interacts with Bcl-2, an anti-apoptotic protein, and this interaction prevents the translocation of Bcl-2 to mitochondria. Hence, this study identifies serine 59 phosphorylation as an important key in the down-regulation of alphaB crystallin anti-apoptotic function in breast cancer and suggests new strategies to improve anti-cancer treatments. PMID- 20841356 TI - Regulation and identification of Na,K-ATPase alpha1 subunit phosphorylation in rat parotid acinar cells. AB - The stimulation of fluid and electrolyte secretion in salivary cells results in ionic changes that promote rapid increases in the activity of the Na,K-ATPase. In many cell systems, there are conflicting findings concerning the regulation of the phosphorylation of the Na,K-ATPase alpha subunit, which is the catalytic moiety. Initially, we investigated the phosphorylation sites on the alpha1 subunit in native rat parotid acinar cells using tandem mass spectrometry and identified two new phosphorylation sites (Ser(222), Ser(407)), three sites (Ser(217), Tyr(260), Ser(47)) previously found from large scale proteomic screens, and two sites (Ser(23), Ser(16)) known to be phosphorylated by PKC. Subsequently, we used phospho-specific antibodies to examine the regulation of phosphorylation on Ser(23) and Ser(16) and measured changes in ERK phosphorylation in parallel. The G-protein-coupled muscarinic receptor mimetic carbachol, the phorbol ester phorbol 12-myristate 13-acetate, the Ca(2+) ionophore ionomycin, and the serine/threonine phosphatase inhibitor calyculin A increased Ser(23) alpha1 phosphorylation. Inhibition of classical PKC proteins blocked carbachol-stimulated Ser(23) alpha1 subunit phosphorylation but not ERK phosphorylation, which was blocked by an inhibitor of novel PKC proteins. The carbachol-initiated phosphorylation of Ser(23) alpha1 subunit was not modified by ERK or PKA activity. The Na,K-ATPase inhibitor ouabain reduced and enhanced the carbachol-promoted phosphorylation of Ser(23) and Ser(16), respectively, the latter because ouabain itself increased Ser(16) phosphorylation; thus, both sites display conformational-dependent phosphorylation changes. Ouabain-initiated phosphorylation of Ser(16) alpha1 was not blocked by PKC inhibitors, unlike carbachol- or phorbol 12-myristate 13-acetate-initiated phosphorylations, suggesting that this site was also a substrate for a kinase other than PKC. PMID- 20841357 TI - Characterization of androgen receptor structure and nucleocytoplasmic shuttling of the rice field eel. AB - Androgen receptor (AR) plays a critical role in prostate cancer and male sexual differentiation. We have identified AR from a primitive vertebrate with a sex reversal characteristic, the rice field eel. AR of this species (eAR) is distinct from human AR, especially in the ligand binding domain (LBD), and its expression in gonads shows an increasing tendency during gonadal transformation from ovary via ovotestis to testis. eAR has a restricted androgen-dependent transactivation function after a nuclear translocation upon dihydrotestosterone exposure. A functional nuclear localization signal was further identified in the DNA binding domain and hinge region. Although nuclear export is CRM1-independent, eAR has a novel nuclear export signal, which is negatively charged, indicating that a nuclear export pathway may be mediated by electrostatic interaction. Further, our studies have identified critical sequences for ligand binding in the C terminus. A structure of three alpha-helices in the LBD has been conserved from eels to humans during vertebrate evolution, despite a distinct amino acid sequence. Mutation analysis confirmed that the LBD is essential for dihydrotestosterone induced nuclear import of eAR and following transactivation function in the nucleus. In addition, eAR interacts with both Sox9a1 and Sox9a2, and their interaction regulates transactivation of eAR. Our data suggest that the primitive species conserves and especially acquires key novel domains, the nuclear export signal and LBD, for the eAR function in spite of a rapid sequence evolution. PMID- 20841358 TI - Nuclear retention of unspliced pre-mRNAs by mutant DHX16/hPRP2, a spliceosomal DEAH-box protein. AB - Defective or imbalanced expression of spliceosomal factors has been linked to human disease; however, how a defective spliceosome affects intron-containing gene transcripts in human cells is largely unknown. DEAH-box protein DHX16 is a human orthologue of Saccharomyces cerevisiae spliceosomal protein Prp2, an RNA dependent ATPase that activates the spliceosome before the first catalytic step of splicing. Yeast prp2 mutants accumulate unspliced RNAs from the vast majority of intron-containing genes. Here we used a genomic tiling microarray to screen transcripts from four chromosomes in human cells expressing a dominant negative DHX16 mutant and identified a number of gene transcripts that retained their introns. The mutant protein also affected gene transcripts that are sensitive to pladienolide, an SF3b inhibitor. The unspliced RNAs were retained in the nucleus, and block of nonsense-mediated decay did not affect their accumulation. Thus, a perturbation of human PRP2/DHX16 results in accumulation of unspliced transcripts, similar to the outcome in yeast prp2 mutants. The results further suggest that mutant DHX16/hPRP2 causes a defective spliceosome to retain unspliced gene transcripts in the nuclei of human cells. PMID- 20841359 TI - Inhibitory phosphorylation of GSK-3 by CaMKII couples depolarization to neuronal survival. AB - Glycogen synthase kinase-3 (GSK-3) plays a critical role in neuronal apoptosis. The two mammalian isoforms of the kinase, GSK-3alpha and GSK-3beta, are inhibited by phosphorylation at Ser-21 and Ser-9, respectively. Depolarization, which is vital for neuronal survival, causes both an increase in Ser-21/9 phosphorylation and an inhibition of GSK-3alpha/beta. However, the role of GSK-3 phosphorylation in depolarization-dependent neuron survival and the signaling pathway contributing to GSK-3 phosphorylation during depolarization remain largely unknown. Using several approaches, we showed that both isoforms of GSK-3 are important for mediating neuronal apoptosis. Nonphosphorylatable GSK-3alpha/beta mutants (S21A/S9A) promoted apoptosis, whereas a peptide encompassing Ser-9 of GSK-3beta protected neurons in a phosphorylation-dependent manner; these results indicate a critical role for Ser-21/9 phosphorylation on depolarization-dependent neuron survival. We found that Ser-21/9 phosphorylation of GSK-3 was mediated by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) but not by Akt/PKB, PKA, or p90(RSK). CaMKII associated with and phosphorylated GSK-3alpha/beta. Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation. These findings identify a novel Ca(2+)/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival. PMID- 20841360 TI - Induction of SENP1 in endothelial cells contributes to hypoxia-driven VEGF expression and angiogenesis. AB - SENP1 (SUMO-specific protease 1) has been shown to be essential for the stability and activity of hypoxia-inducible factor 1 (HIF-1alpha) under hypoxia conditions. However, it is unknown how SENP1 activation and hypoxia signaling are coordinated in the cellular response to hypoxia. Here, we report the essential role of SENP1 in endothelial cells as a positive regulator of hypoxia-driven VEGF production and angiogenesis. SENP1 expression is increased in endothelial cells following exposure to hypoxia. Silencing of HIF-1alpha blocks SENP1 expression in cell response to hypoxia. Mutation of the hypoxia response element (HRE) on the Senp1 promoter abolishes its transactivation in response to hypoxia. Moreover, silencing of SENP1 expression decreases VEGF production and abrogates the angiogenic functions of endothelial cell. We also find that the elongated endothelial cells in embryonic brain section and vascular endothelial cells in embryonic renal glomeruli in Senp1(-/-) mice are markedly reduced than those in wild-type. Thus, these results show that hypoxia implies a positive feedback loop mediated by SENP1. This feedback loop is important in VEGF production, which is essential for angiogenesis in endothelial cells. PMID- 20841361 TI - Roles for stress-inducible lambda glutathione transferases in flavonoid metabolism in plants as identified by ligand fishing. AB - The glutathione transferases (GSTs) of plants are a superfamily of abundant enzymes whose roles in endogenous metabolism are largely unknown. For example, the lambda class of GSTs (GSTLs) have members that are selectively induced by chemical stress treatments and based on their enzyme chemistry are predicted to have roles in redox homeostasis. However, using conventional approaches these functions have yet to be determined. To address this, recombinant GSTLs from wheat and Arabidopsis were tagged with a Strep tag and after affinity immobilization, incubated with extracts from Arabidopsis, tobacco, and wheat. Bound ligands were then recovered by solvent extraction and identified by mass spectrometry (MS). With the wheat enzyme TaGSTL1, the ligand profiles obtained with in vitro extracts from tobacco closely matched those observed after the protein had been expressed in planta, demonstrating that these associations were physiologically representative. The stress-inducible TaGSTL1 was found to selectively recognize flavonols (e.g. taxifolin; K(d) = 25 nM), with this binding being dependent upon S-glutathionylation of an active site cysteine. In the case of the wheat extracts, this selectivity in ligand recognitions lead to the detection of flavonols that had not been previously described in this cereal. Subsequent in vitro assays showed that the co-binding of flavonols, such as quercetin, to the thiolated TaGSTL1 represented an intermediate step in the reduction of the respective S-glutathionylated quinone derivatives to yield free flavonols. These results suggest a novel role for GSTLs in maintaining the flavonoid pool under stress conditions. PMID- 20841362 TI - Fyn kinase is involved in cleavage furrow ingression during meiosis and mitosis. AB - Fertilization of mammalian oocytes triggers their exit from the second meiotic division metaphase arrest. The extrusion of the second polar body (PBII) that marks the completion of meiosis is followed by the first mitotic cleavage of the zygote. Several lines of evidence in somatic cells imply the involvement of Fyn, an Src family kinase (SFK), in cell cycle control and actin functions. In this study, we demonstrate, using live cell confocal imaging and microinjection of Fyn cRNAs, the recruitment of Fyn to the oocyte's cortical area overlying the chromosomes and its colocalization with filamentous actin (F-actin) during exit from the meiotic metaphase. Fyn concentrated asymmetrically at the cortical site designated for ingression of the PBII cleavage furrow, where F-actin had already been accumulated, and then redispersed throughout the entire cortex only to be recruited again to the cleavage furrow during the first mitotic division. Although microinjection of dominant negative Fyn did not affect initiation of the cleavage furrow, it prolonged the average duration of ingression, decreased the rates of PB extrusion and of the first cleavage, and led to the formation of bigger PBs and longer spindles. Extrusion of the PBII was blocked in oocytes exposed to SU6656, an SFK inhibitor. Our results demonstrate, for the first time, a continuous colocalization of Fyn and F-actin during meiosis and imply a role for the SFKs, in general, and for Fyn, in particular, in regulating pathways that involve actin cytoskeleton, during ingression of the meiotic and mitotic cleavage furrows. PMID- 20841363 TI - Extracellular matrix metalloproteinase inducer expression in the baboon endometrium: menstrual cycle and endometriosis. AB - Extracellular matrix metalloproteinase inducer (EMMPRIN; BSG) regulates tissue remodeling through matrix metalloproteinases (MMPs). In human and non-human primates, endometrial remodeling is important for menstruation and the pathogenesis of endometriosis. We hypothesized that as in humans, BSG and MMPs are expressed in the endometrium of cycling baboons, and their expression is hormonally regulated by ovarian hormones, but endometriosis disrupts this regulation. BSG expression was evaluated in the baboon endometrium by q-PCR and immunohistochemistry. In the endometrium of control cycling animals, BSG mRNA levels were highest in late secretory stage tissue. BSG protein localized to glandular epithelial cells during the proliferative phase; whereas, secretory stage tissues expressed BSG in glandular and luminal epithelia with weak stromal staining. Several MMPs were differentially expressed throughout the menstrual cycle with the highest levels found during menstruation. In ovariectomized animals, BSG endometrial mRNA levels were highest with treatment of both estrogen and progesterone than that with only estrogen. Estrogen alone resulted in BSG protein localization primarily in the endometrial glandular epithelia, while estrogen and progesterone treatment displayed BSG protein localization in both the glandular and stromal cells. Exogenous hormone treatment resulted in differential expression patterns of all MMPs compared with the control cycling animals. In the eutopic endometrium of endometriotic animals, BSG mRNA levels and protein were elevated early but decreased later in disease progression. Endometriosis elevated the expression of all MMPs except MMP7 compared with the control animals. In baboons, BSG and MMP endometrial expression is regulated by both ovarian hormones, and their expression patterns are dysregulated in endometriotic animals. PMID- 20841365 TI - Retraction. Endoplasmic reticulum stress is involved in myocardial apoptosis of streptozocin-induced diabetic rats. PMID- 20841366 TI - Seasonal variations of immunochemical and gaiac faecal occult blood tests. PMID- 20841364 TI - The efficacy of post-cardiopulmonary bypass dosing of vancomycin in cardiac surgery. AB - Objective. Vancomycin is administered widely to patients undergoing cardiac surgery as prophylaxis against resistant Gram-positive sternal wound and venous donor site infections. The purpose of this study was to determine the efficacy of a standardized prebypass and postbypass dosing regimen of vancomycin by assessing plasma concentrations in the immediate postoperative period and postoperative surgical site infections (SSIs). Design. Retrospective cohort study. Setting . Cardiothoracic surgical intensive care unit in a tertiary care academic medical center. Methods. A total of 34 consecutive adult patients who had undergone cardiac surgery with cardiopulmonary bypass (CPB) were analyzed retrospectively. Each patient received 1000 mg of vancomycin administered over 1 hour around the time of induction of anesthesia and 500 mg after discontinuation of CPB. Trough vancomycin levels were sampled in the intensive care unit 12 hours after the last dose given in the operating room. Along with patient characteristics, postoperative readmission rates and SSIs were recorded for 1 year after surgery. Results. The nadir serum vancomycin level before the next dose was 9.3 +/- 4.5 ug/mL (mean +/- standard deviation). One superficial SSI was noted. Readmission rate for SSIs was 2.94%. Conclusion . Vancomycin concentrations in the serum were greater than the minimum inhibitory concentration for most staphylococci ranging from 4 to 19.3 ug/mL producing acceptable therapeutic serum concentrations and low rate of infectious complications. Thus postbypass dosing is acceptable in vancomycin cardiac surgical prophylaxis. PMID- 20841367 TI - Presentation and outcome of gastrointestinal involvement in hepatitis C virus related systemic vasculitis: a case-control study from a single-centre cohort of 163 patients. AB - BACKGROUND: During primary systemic vasculitides gastrointestinal (GI) involvement is associated with a poor outcome, leading to the use of immunosuppressive therapy. The significance of GI involvement during hepatitis C virus (HCV)-related systemic vasculitis has never been evaluated. OBJECTIVE: To evaluate the significance of GI involvement during HCV-related systemic vasculitis in the antiviral therapy era. METHODS: Data from 163 patients were retrospectively reviewed to describe the presentation and outcome of patients with HCV-related systemic vasculitis with GI involvement (GI+), and to compare them with patients without GI involvement (GI-). RESULTS: GI manifestations were present in 12 (7.4%) patients. Abdominal pain was consistently present in GI+ patients, and half of patients presented with surgical abdomen and/or intestinal bleeding. GI+ compared to GI- patients had more frequent renal (75% vs 30%; p=0.003) and cardiac involvement (25% vs 2%; p=0.006), medium-vessel vasculitis (67% vs 22%; p=0.003) and higher mixed cryoglobulinaemia levels (2.2 g/l vs 1.2 g/l; p=0.07). After treatment, GI+ and GI- patients had similar rates of overall clinical response of the vasculitis and immunological and virological responses. HCV-MC vasculitis patients with GI involvement did not have poorer overall survival than those without. CONCLUSION: GI involvement is a rare manifestation of HCV-related vasculitis, associated with acute-onset and life-threatening manifestations. In contrast with primary vasculitides, GI+ patients do not seem to have poorer overall survival than GI- patients. PMID- 20841368 TI - Clinical comparison of progressive aphasia associated with Alzheimer versus FTD spectrum pathology. AB - OBJECTIVE: Recent post-mortem studies indicate that 30-40% of patients with clinically diagnosed progressive aphasia (PA) have Alzheimer's disease pathology, while the remainder have pathology in the FTD spectrum. This study aimed to compare the clinical features of patients from these two groups. MATERIALS AND METHODS: A retrospective chart review was conducted on 33 pathologically verified PA patients: n=13 AD and n=20 FTD-spectrum pathology. Demographics, global cognitive function, non-verbal memory, neuropsychiatric symptoms and structural imaging were compared between the two pathology-confirmed groups. RESULTS: The median survival was 6.3 years in the FTD group versus 8.1 years in the AD group, in spite of the fact that onset for AD was on average 2.0 years older than FTD. Features highly specific in predicting FTD-spectrum pathology were age of onset before 60 years, preference for sweet food, disinhibition and focal knife-edge frontotemporal atrophy, although the sensitivity for each of these was remarkably low (highest sensitivity was 45% for disinhibition). Some clinical features hypothesised to distinguish AD from FTD-spectrum pathology, such as global functional impairment within 2 years of onset and poor non-verbal memory ability, were not useful in separating the two groups. CONCLUSIONS: If present, certain clinical and imaging features can help to identify PA with FTD-spectrum pathology, notably the presence of the neuropsychiatric features seen with behavioural presentations of FTD and knife-edge atrophy on structural imaging. The profile of non-linguistic cognitive deficits does not appear to be discriminatory, though prospective studies are needed to evaluate this issue further. PMID- 20841370 TI - Which patients with dystonia benefit from deep brain stimulation? A metaregression of individual patient outcomes. AB - There is substantial variability in the responsiveness of dystonia patients to deep brain stimulation (DBS), presumably due to the multiple causes of dystonia. This article presents the results of an analysis of the combined published results of individual patient outcomes following DBS for all types of dystonia. From 157 papers reporting clinical outcomes of DBS for dystonia, individual quantitative data were available for 466 patients with all forms of dystonia. The subclassification of these patients included 344 with primary forms of dystonia, 10 with myoclonus dystonia, 19 with heredodegenerative dystonias and 93 who had DBS for secondary dystonia. Patients with primary forms of dystonia, myoclonus dystonia, subtypes of heredo-degenerative dystonia and tardive dystonia have a greater than 50% mean improvement in dystonia severity following DBS. Among patients with primary generalised dystonia, multiple regression analysis showed that a shorter duration of symptoms (p=0.008), a lower baseline severity score (p=0.024) and DYT1 positive status (p=0.002) were all independently associated with a significantly higher percentage improvement from surgery. Patients with other forms of heredodegenerative and secondary dystonia have variable responses, making prediction of response in future patients difficult. The degree of dystonia response that justifies DBS is a highly subjective issue. Emphasis should be placed on both safety of surgical technique and an in-depth evaluation of patients' own perception of their life before and after DBS by using validated quality of life measures, in addition to existing use of objective severity scales. PMID- 20841369 TI - Polymorphisms in complement component 3 (C3F) and complement factor H (Y402H) increase the risk of postoperative neurocognitive dysfunction following carotid endarterectomy. AB - BACKGROUND: Up to 28% of patients undergoing carotid endarterectomy (CEA) are estimated to experience neurocognitive dysfunction following surgery. The complement cascade plays a central role in ischaemia-reperfusion injury. The authors investigated the effect of common polymorphisms in the complement component 3 (C3F) and complement factor H (CFH Y402H) genes on incidence of neurocognitive dysfunction post-CEA. METHODS: This study examined a nested cohort of prospectively recruited patients receiving elective CEA, who were genotyped for the C3F or Y402H polymorphisms. Each patient underwent a standard battery of eight neuropsychometric tests before, and 1 day and 30 days after, surgery. RESULTS: 57 of 142 (40%) CEA patients had at least one copy of the C3F allele (C3F+), and 17 of 137 (12%) patients had two copies of the CFH Y402H allele (Y402H++). At postoperative day 1, patients were three times (OR 3.05, p=0.045) or six times (OR 6.41, p=0.006) more likely to experience moderate-to-severe neurocognitive dysfunction if they carried the C3F+ or Y402H++ genotype, respectively. Patients with both risk genotypes had an almost eightfold risk of dysfunction (OR 7.67, p=0.046). Right-hand-dominant C3F+ subjects undergoing right-side CEA performed significantly worse on tests of visuospatial function than C3F- subjects. At day 30, C3F+ and Y402H++ genotypes trended towards significance as predictors of dysfunction (p=0.07 and p=0.22, respectively). CONCLUSION: The C3F and Y402H polymorphisms are strong independent predictors of moderate-to-severe neurocognitive dysfunction at 1 day following CEA. Furthermore, patients undergoing right-sided CEA are predisposed to deficits associated with cortex ipsilateral to the operative carotid artery. PMID- 20841371 TI - Socioeconomic position and incidence of acute myocardial infarction: a meta analysis. AB - BACKGROUND: A negative socioeconomic gradient is established for coronary heart disease (CHD) mortality and survival, while socioeconomic patterning of disease incidence is less well investigated. To study socioeconomic inequalities in the incidence of acute myocardial infarction (AMI), the major component of CHD, a meta-analysis was undertaken to summarise existing evidence on the issue. METHODS: A systematic search was performed in PubMed and EMBASE databases for observational studies on AMI incidence and socioeconomic position (SEP), published in English to April 2009. A random-effects model was used to pool the risks estimates from the individual studies. RESULTS: Among 1181 references, 70 studies fulfilled the inclusion criteria. An overall increased risk of AMI among the lowest SEP was found for all three indicators: income (pooled RR 1.71, 95% CI 1.43 to 2.05), occupation (pooled RR 1.35, 95% CI 1.19 to 1.53) and education (pooled RR 1.34, 95% CI 1.22 to 1.47). The strongest associations were seen in high-income countries such as USA/Canada and Europe, while the results were inconsistent for middle and low-income regions. CONCLUSION: AMI incidence is associated with low SEP. The nature of social stratification at the level of economic development of a country could be involved in the differences of risk of AMI between social groups. PMID- 20841372 TI - Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment. AB - BACKGROUND: Statin use and serum cholesterol reduction have been proposed as preventions for dementia and mild cognitive impairment (MCI). METHODS: 1604 and 1345 eligible participants from the Baltimore Longitudinal Study of Aging (BLSA) were followed after age 50 for a median time of around 25 years, to examine the incidence of dementia (n=259) and MCI (n=138), respectively. Statin use (ever-use and time-dependent use), total cholesterol levels (TC; first visit and time dependent), TC change trajectory from first visit and high-density lipoprotein (HDL-C):TC ratio (first visit and time-dependent) were the main exposures of interest. Cox proportional hazards models were used. RESULTS: Participants with incident dementia had a higher first-visit TC compared with participants who remained free of dementia and MCI, while first-visit TC was higher among statin ever-users compared with never-users (age-unadjusted associations). Statin users had a two- to threefold lower risk of developing dementia (HR=0.41; 95% CI 0.18 to 0.92), but not MCI, when considering time-dependent 'statin use' with propensity score model adjustment. This association remained significant independently of serum cholesterol exposures. An elevated first-visit TC was associated with reduced MCI risk (upper quartile (Q(4)) vs Q(1): HR=0.51; 95% CI 0.29 to 0.90). Compared with the lowest quartile (Q(1): 0.00-0.19), HDL-C:TC (time-dependent) in (Q(2): 0.19-0.24) was associated with reduced MCI risk (HR=0.58; 95% CI 0.34 to 0.98). Among men only, TC decline from first visit was significantly associated with increased dementia risk (HR=4.21; 95% CI 1.28 to 13.85). CONCLUSIONS: Statins may have multifactorial effects on dementia but not MCI risk. Future interventions may be warranted, and research should focus on optimal serum TC, HDL-C:TC ratio and TC change trajectories. PMID- 20841373 TI - Socioeconomic correlates and trends in smoking in pregnancy in New South Wales, Australia. AB - OBJECTIVE: This study describes trends (1994-2007) in smoking in pregnancy (SIP) among an Australian population sample of women. This study also examines trends in the socioeconomic distribution of SIP over the 14-year period. METHODS: Bivariate and multiple logistic regression analyses of the NSW Midwives Data Collection were used to explore the associations and trends in SIP by sociodemographic factors. RESULTS: The prevalence of SIP in New South Wales (NSW) declined from 22.1% (1994) to 13.5% in 2007. However, the largest decrease in SIP rates was among the highest socioeconomic group (67.9% decline), and smaller declines were observed among teenage and remote rural mothers. Maternal age, ethnicity, Aboriginality, area of remoteness and socioeconomic status were independently associated with SIP. The distribution of NSW mothers has changed, with fewer younger mothers and more from an Asian background. CONCLUSION: This study reported large declines in SIP prevalence, with a population effect similar to that expected following exposure to (Cochrane-defined) intensive behavioural interventions. However, no specially targeted public health efforts were made during this period to influence SIP, so that social norm change is the likely explanation for these population health changes. The relative decline in SIP was smaller among low-socioeconomic status mothers, by language spoken at home, Aboriginality and area of remoteness, suggesting that inequalities in SIP have increased over this 14-year period. This information informs equity-based approaches to targeting further smoking cessation programs for pregnant Australian women. PMID- 20841374 TI - Associations between maternal experiences of intimate partner violence and child nutrition and mortality: findings from Demographic and Health Surveys in Egypt, Honduras, Kenya, Malawi and Rwanda. AB - BACKGROUND: If effective interventions are to be used to address child mortality and malnutrition, then it is important that we understand the different pathways operating within the framework of child health. More attention needs to be given to understanding the contribution of social influences such as intimate partner violence (IPV). AIM: To investigate the relationship between maternal exposure to IPV and child mortality and malnutrition using data from five developing countries. METHODS: Population data from Egypt, Honduras, Kenya, Malawi and Rwanda were analysed. Logistic regression analysis was used to generate odds ratios of the associations between several categories of maternal exposure to IPV since the age of 15 and three child outcomes: under-2-year-old (U2) mortality and moderate and severe stunting (<-2 Z-score height-for-age and <-3 Z-score height for-age) in 6-59-month-old children. Analyses were adjusted for potential confounders, and the role of mediating factors was explored. RESULTS: The prevalence of physical and/or sexual IPV since the age of 15 years ranged from 15.5% (Honduras) to 46.2% (Kenya). For child stunting, prevalence ranged from 25.4% (Egypt) to 58.0% (Malawi) and for U2 mortality from 3.6% (Honduras) to 15.2% (Rwanda). In Kenya, maternal exposure to IPV was associated with higher U2 mortality (adjusted odds ratio (OR)=1.42, 95% CI 1.18 to 1.71) and child stunting (adjusted OR=1.36, 95% CI 1.16 to 1.61). In Malawi and Honduras, marginal associations were observed between IPV and severe stunting and U2 mortality, respectively, with strength of associations varying by type of violence. CONCLUSION: The relationship between IPV and U2 mortality and stunting in Kenya, Honduras and Malawi suggests that, in these countries, IPV plays a role in child malnutrition and mortality. This contributes to a growing body of evidence that broader public health benefits may be incurred if efforts to address IPV are incorporated into a wider range of maternal and child health programmes; however, the authors highlight the need for more research that can establish temporality, use data collected on the basis of the study's objectives, and further explore the causal framework of this relationship using more advanced statistical analysis. PMID- 20841375 TI - Knockdown of inwardly rectifying potassium channel Kir2.2 suppresses tumorigenesis by inducing reactive oxygen species-mediated cellular senescence. AB - Senescence is an important determinant of treatment outcome in cancer therapy. In the present study, we show that knockdown of the inwardly rectifying K(+) channel Kir2.2 induced growth arrest without additional cellular stress in cancer cells lacking functional p53, p16, and/or Rb. Kir2.2 knockdown also induced senescence associated beta-galactosidase activity and upregulated senescence marker proteins in multiple cancer cell lines derived from different tissues, including prostate, stomach, and breast. Interestingly, knockdown of Kir2.2 induced a significant increase in reactive oxygen species (ROS) that was accompanied by cell cycle arrest, characterized by significant upregulation of p27, with concomitant downregulation of cyclinA, cdc2, and E2F1. Kir2.2 knockdown cells displayed increased levels of PML bodies, DNA damage (gammaH2AX) foci, senescence associated heterochromatin foci, mitochondrial dysfunction, secretory phenotype, and phosphatase inactivation. Conversely, overexpression of Kir2.2 decreased doxorubicin-induced ROS accumulation and cell growth inhibition. Kir2.2 knockdown induced cellular senescence was blocked by N-acetylcysteine, indicating that ROS is a critical mediator of this pathway. In vivo tumorigenesis analyses revealed that tumors derived from Kir2.2 knockdown cells were significantly smaller than those derived from control cells (P < 0.0001) and showed a remarkable increase in senescence-associated proteins, including senescence-associated beta galactosidase, p27, and plasminogen activator inhibitor-1. Moreover, the preestablished tumors are reduced in size after the injection of siKir2.2 (P = 0.0095). Therefore, we propose for the first time that Kir2.2 knockdown induces senescence of cancer cells by a mechanism involving ROS accumulation that requires p27, but not Rb, p53, or p16. PMID- 20841376 TI - Quantifying and predicting the promiscuity and isoform specificity of small molecule cytochrome P450 inhibitors. AB - Drug promiscuity (i.e., inhibition of multiple enzymes by a single compound) is increasingly recognized as an important pharmacological consideration in the drug development process. However, systematic studies of functional or physicochemical characteristics that correlate with drug promiscuity are handicapped by the lack of a good way of quantifying promiscuity. In this article, we present a new entropy-based index of drug promiscuity. We apply this index to two high throughput data sets describing inhibition of cytochrome P450 isoforms by small molecule drugs and drug candidates, and we demonstrate how drug promiscuity or specificity can be quantified. For these drug-metabolizing enzymes, we find that there is essentially no correlation between a drug's potency and specificity. We also present an index to quantify the susceptibilities of different enzymes to inhibition by diverse substrates. Finally, we use partial least-squares regression to successfully predict isoform specificity and promiscuity of small molecules, using a set of fingerprint-based descriptors. PMID- 20841377 TI - Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial-mesenchymal transition-like state in breast cancer cells in vitro. AB - Fibroblasts were extracted from tissue in tumor burden zones, distal normal zones and interface zones between tumor and normal tissue of human breast carcinomas, and the corresponding fibroblasts were designated as cancer-associated fibroblasts (CAFs), normal zone fibroblasts (NFs) and interface zone fibroblasts (INFs). The crosstalk between three types of fibroblasts and breast cancer cells was evaluated using an in vitro direct co-culture model. We found that INFs grew faster and expressed higher levels of fibroblast activation protein than did NFs and CAFs. Compared with CAFs and NFs, INFs grown with breast cancer cells were significantly more effective in inducing an epithelial-mesenchymal transition (EMT) in cancer cells, as indicated by induction of vimentin and N-cadherin and downregulation of E-cadherin. This EMT process was also accompanied by activation of extracellular signal-regulated kinase (ERK) and modulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) expression. Additionally, INFs promoted breast cell migration to a larger extent compared with NFs and CAFs. Taken together, these findings indicate that INFs isolated from the tumor interface zone exhibited more robust biological modulatory activity than did NFs and CAFs isolated from normal and tumor zones of the same tumor tissue, suggesting that the interface zone of the tumor represents a dynamic region vital to tumor progression. PMID- 20841378 TI - Syt1p promotes activation of Arl1p at the late Golgi to recruit Imh1p. AB - In yeast, Arl3p recruits Arl1p GTPase to regulate Golgi function and structure. However, the molecular mechanism involved in regulating activation of Arl1p at the Golgi is unknown. Here, we show that Syt1p promoted activation of Arl1p and recruitment of a golgin protein, Imh1p, to the Golgi. Deletion of SYT1 resulted in the majority of Arl1p being distributed diffusely throughout the cytosol. Overexpression of Syt1p increased Arl1p-GTP production in vivo and the Syt1-Sec7 domain promoted nucleotide exchange on Arl1p in vitro. Syt1p function required the N-terminal region, Sec7 and PH domains. Arl1p, but not Arl3p, interacted with Syt1p. Localization of Syt1p to the Golgi did not require Arl3p. Unlike arl1Delta or arl3Delta mutants, syt1Delta did not show defects in Gas1p transport, cell wall integrity or vacuolar structure. These findings reveal that activation of Arl1p is regulated in part by Syt1p, and imply that Arl1p activation, by using more than one GEF, exerts distinct biological activities at the Golgi compartment. PMID- 20841379 TI - Rac controls PIP5K localisation and PtdIns(4,5)P2 synthesis, which modulates vinculin localisation and neurite dynamics. AB - In N1E-115 cells, neurite retraction induced by neurite remodelling factors such as lysophosphatidic acid, sphingosine 1-phosphate and semaphorin 3A require the activity of phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks). PIP5Ks synthesise the phosphoinositide lipid second messenger phosphatidylinositol(4,5)bisphosphate [PtdIns(4,5)P2], and overexpression of active PIP5K is sufficient to induce neurite retraction in both N1E-115 cells and cerebellar granule neurones. However, how PIP5Ks are regulated or how they induce neurite retraction is not well defined. Here, we show that neurite retraction induced by PIP5Kbeta is dependent on its interaction with the low molecular weight G protein Rac. We identified the interaction site between PIP5Kbeta and Rac1 and generated a point mutant of PIP5Kbeta that no longer interacts with endogenous Rac. Using this mutant, we show that Rac controls the plasma membrane localisation of PIP5Kbeta and thereby the localised synthesis of PtdIns(4,5)P2 required to induce neurite retraction. Mutation of this residue in other PIP5K isoforms also attenuates their ability to induce neurite retraction and to localise at the membrane. To clarify how increased levels of PtdIns(4,5)P2 induce neurite retraction, we show that mutants of vinculin that are unable to interact with PtdIns(4,5)P2, attenuate PIP5K- and LPA-induced neurite retraction. Our findings support a role for PtdIns(4,5)P2 synthesis in the regulation of vinculin localisation at focal complexes and ultimately in the regulation of neurite dynamics. PMID- 20841380 TI - A role for the dynamin-like protein Vps1 during endocytosis in yeast. AB - Dynamins are a conserved family of proteins involved in membrane fusion and fission. Although mammalian dynamins are known to be involved in several membrane trafficking events, the role of dynamin-1 in endocytosis is the best characterised role of this protein family. Despite many similarities between endocytosis in yeast and mammalian cells, a comparable role for dynamins in yeast has not previously been demonstrated. The reported lack of involvement of dynamins in yeast endocytosis has raised questions over the general applicability of the current yeast model of endocytosis, and has also precluded studies using well-developed methods in yeast, to further our understanding of the mechanism of dynamin function during endocytosis. Here, we investigate the yeast dynamin-like protein Vps1 and demonstrate a transient burst of localisation to sites of endocytosis. Using live-cell imaging of endocytic reporters in strains lacking vps1, and also electron microscopy and biochemical approaches, we demonstrate a role for Vps1 in facilitating endocytic invagination. Vps1 mutants were generated, and analysis in several assays reveals a role for the C-terminal self assembly domain in endocytosis but not in other membrane fission events with which Vps1 has previously been associated. PMID- 20841382 TI - Drosophila I-R hybrid dysgenesis is associated with catastrophic meiosis and abnormal zygote formation. AB - The Drosophila I-R type of hybrid dysgenesis is a sterility syndrome (SF sterility) associated with the mobilization of the I retrotransposon in female germ cells. SF sterility results from a maternal-effect embryonic lethality whose origin has remained unclear since its discovery about 40 years ago. Here, we show that meiotic divisions in SF oocytes are catastrophic and systematically fail to produce a functional female pronucleus at fertilization. As a consequence, most embryos from SF females rapidly arrest their development with aneuploid or damaged nuclei, whereas others develop as non-viable, androgenetic haploid embryos. Finally, we show that, in contrast to mutants affecting the biogenesis of piRNAs, SF egg chambers do not accumulate persistent DNA double-strand breaks, suggesting that I-element activity might perturb the functional organization of meiotic chromosomes without triggering an early DNA damage response. PMID- 20841383 TI - Gaps in the systematic reviews of the telemedicine field. PMID- 20841381 TI - Negative regulation of Drosophila JAK-STAT signalling by endocytic trafficking. AB - Appropriate regulation of signal transduction pathways is essential for normal development and is often disrupted in disease. Therefore, many regulatory mechanisms and feedback loops have evolved to ensure appropriate signalling. One mechanism previously suggested to modulate a range of signal transduction pathways involves the internalisation and destruction of transmembrane receptors by the endocytic trafficking machinery. Strikingly, a recent report has suggested that the endocytic trafficking of the Drosophila JAK-STAT pathway receptor Domeless (Dome) does not act to downregulate pathway activity, but rather is necessary for in vivo signalling. Here, we examine this relationship to address the interaction of Drosophila JAK-STAT pathway signalling and endocytic trafficking. We show that Dome is trafficked through clathrin-mediated endocytosis and a directed RNAi screen identified several components of the endocytic machinery as negative regulators of pathway signalling. We demonstrate that Dome signals both from the plasma membrane and internalised vesicles and show, using knockdown experiments, that endocytic components negatively regulate JAK-STAT signalling in vivo. As such, disruption in endocytic trafficking represents a potent negative regulator of the disease relevant JAK-STAT signalling cascade. PMID- 20841384 TI - Telemedicine-supported insulin optimisation in primary care. AB - We investigated the feasibility of a mobile-phone based system for patients with type 2 diabetes who had recently commenced insulin therapy but remained poorly controlled. The system was evaluated in a feasibility study in a general practice setting with 23 patients over six months. A total of 22 patients successfully completed the study and used the system for a mean of 217 days (range 162-376). Blood glucose control improved, as reflected by a mean decrease in HbA(1c) of 0.66% (P = 0.05), with the mean insulin dose increasing by 17 units (P = 0.006). Blood glucose monitoring compliance was high, with readings available for 6.2 days per week, although use of the mobile phone decreased during the study. On average, the mobile phone diary was used for 3.5 days per week. Insulin dose adjustments were made throughout the study by all patients, but not as frequently as would be expected for the degree of hyperglycaemia observed. PMID- 20841385 TI - Method of detection and breast cancer survival disparities in Hispanic women. AB - BACKGROUND: Hispanic women in New Mexico (NM) are more likely than non-Hispanic women to die of breast cancer-related causes. We determined whether survival differences between Hispanic and non-Hispanic women might be attributable to the method of detection, an independent breast cancer prognostic factor in previous studies. METHODS: White women diagnosed with invasive breast cancer from 1995 through 2004 were identified from NM Surveillance Epidemiology End Results (SEER) files (n = 5,067) and matched to NM Mammography Project records. Method of cancer detection was categorized as "symptomatic" or "screen-detected." The proportion of Hispanic survival disparity accounted for by included variables was assessed using Cox models. RESULTS: In the median follow-up of 87 months, 490 breast cancer deaths occurred. Symptomatic versus screen-detection was classifiable for 3,891 women (76.8%), and was independently related to breast cancer-specific survival [hazard ratio (HR), 1.6; 95% confidence interval (95% CI), 1.3-2.0]. Hispanic women had a 1.5-fold increased risk of breast cancer-related death, relative to non-Hispanic women (95% CI, 1.2-1.8). After adjustment for detection method, the Hispanic HR declined from 1.50 to 1.45 (10%), but after inclusion of other prognostic indicators the Hispanic HR equaled 1.23 (95% CI, 1.01-1.48). CONCLUSIONS: Although the Hispanic HR declined 50% after adjustment, the decrease was largely due to adverse tumor prognostic characteristics. IMPACT: Reduction of disparate survival in Hispanic women may rely not only on increased detection of tumors when asymptomatic but on the development of greater understanding of biological factors that predispose to poor prognosis tumors. PMID- 20841386 TI - Alcohol-folate interactions in the risk of oral cancer in women: a prospective cohort study. AB - BACKGROUND: The aim of this cohort study was to quantify the effect of alcohol on the risk of oral cancer in different strata of folate intake, controlling for known confounders. METHODS: A cohort of 87,621 women in the Nurses' Health Study was followed up from 1980 to 2006, and 147 incident oral cancer cases were reported and confirmed. Data on alcohol intake and diet were obtained through self-reported food frequency questionnaires every 4 years. Cox proportional regression analysis was conducted to estimate the adjusted risk ratios (RR) and 95% confidence intervals (95% CI). RESULTS: When compared with nondrinkers, the adjusted RRs (95% CIs) for alcohol intake were 0.59 (0.39-0.87) for 0.1-14.9 g/d, 1.15 (0.67-1.97) for 15-29.9 g/d, and 1.92 (1.08-3.40) for >=30 g/d. We observed a significant interaction between alcohol and folate intakes (P = 0.02). The cancer risk for subjects with high alcohol (>=30 g/d) and low folate (<350 MUg/d) intakes was significantly elevated (RR, 3.36; 95% CI, 1.57-7.20) as compared with nondrinkers with low folate intake. The risk associated with high alcohol intake (>=30 g/d) was reduced to 0.98 (0.35-2.70) in the high-folate (>=350 MUg/d) group as compared with nondrinkers with high folate intake. CONCLUSIONS: High alcohol intake is associated with significantly increased oral cancer risk, especially in women with low folate intake. IMPACT: A significant interaction between alcohol and folate intakes seems to affect oral cancer risk in women, a finding with potential public health utility. PMID- 20841387 TI - Cruciferous vegetable intake and lung cancer risk: a nested case-control study matched on cigarette smoking. AB - BACKGROUND: Due predominantly to cigarette smoking, lung cancer is the leading cancer-related cause of death worldwide. Cruciferous vegetables may reduce lung cancer risk. The association between intake of cruciferous vegetables and lung cancer risk was investigated in the CLUE II study, a community-based cohort established in 1989. METHODS: We matched 274 incident cases of lung cancer diagnosed from 1990 to 2005 to 1,089 cancer-free controls on age, sex, and cigarette smoking. Dietary information was collected at baseline. Multivariable odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. RESULTS: Intake of cruciferous vegetables was inversely associated with lung cancer risk (highest-versus-lowest fourth: OR (Q4vsQ1), 0. 57; 95% CI, 0.38-0.85; P-trend = 0.01). The inverse associations held true for former smokers (OR(Q4vsQ1), 0.49; 95% CI, 0.27-0.92; P-trend = 0.05) and current smokers (OR(Q4vsQ1), 0.52; 95% CI, 0.29-0.95; P-trend = 0.02). CONCLUSIONS: After carefully controlling for cigarette smoking, higher intake of cruciferous vegetable was associated with lower risk of lung cancer. IMPACT: The observed inverse association coupled with accumulating evidence suggests that intake of cruciferous vegetables is inversely associated with lung cancer risk, and this association seems to hold true beyond the confounding effects of cigarette smoking. PMID- 20841388 TI - Global levels of specific histone modifications and an epigenetic gene signature predict prostate cancer progression and development. AB - BACKGROUND: Epigenetic alterations are common in prostate cancer, yet how these modifications contribute to carcinogenesis is poorly understood. We investigated whether specific histone modifications are prognostic for prostate cancer relapse, and whether the expression of epigenetic genes is altered in prostate tumorigenesis. METHODS: Global levels of histone H3 lysine-18 acetylation (H3K18Ac) and histone H3 lysine-4 dimethylation (H3K4diMe) were assessed immunohistochemically in a prostate cancer cohort of 279 cases. Epigenetic gene expression was investigated in silico by analysis of microarray data from 23 primary prostate cancers (8 with biochemical recurrence and 15 without) and 7 metastatic lesions. RESULTS: H3K18Ac and H3K4diMe are independent predictors of relapse-free survival, with high global levels associated with a 1.71-fold (P < 0.0001) and 1.80-fold (P = 0.006) increased risk of tumor recurrence, respectively. High levels of both histone modifications were associated with a 3 fold increased risk of relapse (P < 0.0001). Epigenetic gene expression profiling identified a candidate gene signature (DNMT3A, MBD4, MLL2, MLL3, NSD1, and SRCAP), which significantly discriminated nonmalignant from prostate tumor tissue (P = 0.0063) in an independent cohort. CONCLUSIONS: This study has established the importance of histone modifications in predicting prostate cancer relapse and has identified an epigenetic gene signature associated with prostate tumorigenesis. IMPACT: Our findings suggest that targeting the epigenetic enzymes specifically involved in a particular solid tumor may be a more effective approach. Moreover, testing for aberrant expression of epigenetic genes such as those identified in this study may be beneficial in predicting individual patient response to epigenetic therapies. PMID- 20841389 TI - Do steroid hormones play a role in the etiology of glioma? AB - Gliomas are the most common type of primary malignant brain tumor and have a very poor prognosis. Little is known, however, about the etiology of these tumors. Evidence from a number of sources suggests that endogenous steroid hormones may play a role in the development of gliomas. First, the descriptive epidemiology of glioma suggests a relative protection of females compared with males, particularly during the premenopausal years. Second, some gliomas and glioblastomas express estrogen receptors (ER), especially ERbeta, as well as aromatase, the enzyme responsible for the conversion of testosterone to estradiol, and possibly other steroid hormone receptors. Third, experimental studies indicate that glioblastomas transplanted into animals grow at a slower rate in females compared with males. Finally, experimental studies show that estradiol, 2-methoxyestradiol, and a number of selective estrogen receptor modulators inhibit proliferation of gliomas and induce cell death. These hormonal agonists and antagonists may act either through classical steroid hormone receptors or independently of such receptors. In view of these findings, further clinical, experimental, and epidemiologic studies are needed to elucidate the role of steroid hormone agonists and antagonists in the development and proliferation of glioma. If hormonal pathways are involved in gliomagenesis, this could eventually lead to the design of preventive strategies. PMID- 20841390 TI - Baseline plasma total homocysteine and adenoma recurrence: results from a double blind randomized clinical trial of aspirin and folate supplementation. AB - BACKGROUND: Elevated plasma total homocysteine (tHcy) is an accepted marker of functional folate deficiency but may have independent effects on colorectal neoplasia risk. It is uncertain whether plasma tHcy is associated with risk at the low levels common in a folate-fortified population. METHODS: Study subjects, about half of whom were recruited after fortification of grain products with folic acid in the United States and Canada, consisted of 871 individuals with a recent history of one or more colorectal adenomas who were randomized to receive either a 1 mg/day folic acid supplement or a placebo within one of three randomly assigned aspirin treatment groups (placebo, 81, or 325 mg/day). Nonfasting plasma tHcy was determined by a gas chromatograph mass chromatography method. We estimated adjusted risk ratios and 95% confidence intervals (95% CI) for one or more adenoma recurrences for each quartile of baseline plasma tHcy using generalized linear regression with an overdispersed Poisson approximation to the binomial. RESULTS: The Q4/Q1 adjusted risk ratio for any adenoma was 0.98 (95% CI, 0.70-1.38; P trend = 0.17) in the placebo group, and 0.81 (95% CI, 0.58-1.12; P-trend = 0.17) in the folic acid group. Results were similar for adenomas with advanced features. There was no modification by sex, aspirin treatment group or MTHFR 677C>T genotype. CONCLUSIONS: Plasma tHcy is not an independent marker for an increase in colorectal adenoma recurrence risk in postfortification populations in which plasma tHcy levels are in the lower range of values. IMPACT: Controlling plasma tHcy levels is unlikely to favorably modify adenoma recurrence risk in folate-fortified populations. PMID- 20841391 TI - Five-year and lifetime risk of breast cancer among U.S. subpopulations: implications for magnetic resonance imaging screening. AB - BACKGROUND: Guidelines from the American Cancer Society recommend annual breast magnetic resonance imaging (MRI) screening for women with a projected lifetime risk of >=20% based on risk models that use family history. Because MRI screening is costly and has limited specificity, estimates of the numbers of U.S. women with >=20% breast cancer risk would be useful. METHODS: We used data from the 2000 and 2005 National Health Interview Survey and the National Cancer Institute (NCI) Breast Cancer Risk Assessment Tool (i.e., Gail model 2 with a revision for African Americans) to calculate estimates of U.S. women by age and race/ethnicity categories with a lifetime absolute breast cancer risk of >=20%. Distributions of 5-year and lifetime absolute risk of breast cancer were compared across demographic groups. RESULTS: We estimated that 1.09% (95% confidence interval, 0.95-1.24%) of women age 30 to 84 years have a lifetime absolute breast cancer risk of >=20%, which translates to 880,063 U.S. women eligible for MRI screening. The 5-year risks are highest for white non-Hispanics and lowest for Hispanics. The lifetime risks decrease with age and are generally highest for white non Hispanics, lower for African American non-Hispanic, and lowest for Hispanics. CONCLUSION: We provide national estimates of the number of U.S. women who would be eligible for MRI breast screening and distributions of 5-year and lifetime risks of breast cancer using the NCI Breast Cancer Risk Assessment Tool. IMPACT: These estimates inform the potential resources and public health demand for MRI screening and chemopreventive interventions that might be required for U.S. women. PMID- 20841392 TI - Language and the (im)possibilities of articulating spirituality. AB - Despite growing interest in spiritual matters throughout society, definitions and descriptions of spirituality seem incomplete or otherwise unsatisfactory. In this article, the authors consider the possibility that such incompleteness is perhaps necessary and welcomed in addressing spirituality. In particular, they investigate the challenges of using metaphor and metonymic approaches to "languaging" spirituality. By exploring these figures of speech they hope to diversify how nurses articulate deeply personal and perhaps enigmatic human phenomena such as spirituality. Metaphoric language uses everyday structures to help make sense of complex, emotional, and abstract experience. Whereas metaphor creates substitutive relationships between things and provides insights into conceptualizing spirituality, metonymy and metonymic writing establish relationships of contiguity. Whereas metaphor functions to represent and facilitates understanding and feelings about spirituality, metonymy disrupts while opening possibilities of moving beyond binary thinking. Attending to language and its various ontological assumptions opens diverse and potentially more inclusive possibilities. PMID- 20841393 TI - Can electrocardiographic screening prevent sudden death in athletes? No. PMID- 20841394 TI - Can electrocardiographic screening prevent sudden death in athletes? Yes. PMID- 20841395 TI - Fertility organisations call for cross border regulations to protect IVF patients. PMID- 20841396 TI - Lack of clear diagnoses leaves incontinence untreated. PMID- 20841397 TI - Experts pool ideas on how to cut maternal mortality. PMID- 20841398 TI - Health budgets would benefit from ambitious climate change goals. PMID- 20841399 TI - Australian study shows how to get best value from preventive measures. PMID- 20841401 TI - Insurance industry mustn't blame price rises on reforms, says US government. PMID- 20841402 TI - Are the millennium development goals on target? PMID- 20841403 TI - GP based primary care is only just starting to emerge in China. PMID- 20841405 TI - Genetics for the pediatric anesthesiologist: a primer on congenital malformations, pharmacogenetics, and proteomics. AB - Molecular genetics is the study, at the molecular level, of how genetic information is stored, inherited, and expressed and of how it influences the structure and function of cells in health and in disease. Although molecular approaches have been used for decades in the laboratory and are at the core of modern medical education, they are only now beginning to influence clinical practice. A variety of sophisticated techniques permit rapid and affordable DNA sequencing, gene expression profiling, gene cloning, gene manipulation, gene transfer, recombinant protein production, and other technologies of enormous biomedical importance. Success in genomics has spawned additional ambitious endeavors, including proteomics, pharmacogenomics, and bioinformatics. These techniques are providing new diagnostic, prognostic, and therapeutic opportunities in all areas of medicine, including anesthesiology. With the use of molecular criteria and the diminishing cost of analytic technologies, anesthetic practice will become more individualized, and greater emphasis will be placed on the patient's genetic makeup. Both surgical and nonsurgical decisions will increasingly accommodate molecular data crucial to perioperative anesthetic management. In this article we have summarized three lectures on congenital malformations, pharmacogenetics, and proteomics presented at the 22nd Annual Meeting of the Society for Pediatric Anesthesia. PMID- 20841404 TI - Do cytokines contribute to the Andean-associated protection from reduced fetal growth at high altitude? AB - Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1beta [IL-1beta]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-alpha (TNF alpha) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1beta in ANDs only near term. Higher IL-1beta levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1beta may play a role in AND protection from altitude associated reductions in fetal growth. PMID- 20841406 TI - A decision-tree model for predicting extubation outcome in elderly patients after a successful spontaneous breathing trial. AB - BACKGROUND: The commonly used single tests, based on a 1-time measurement of a physiologic variable, are often poorly predictive of tracheal extubation outcome because they examine only a single aspect of physiological function that affects the extubation outcome. We hypothesized that the construction of a decision-tree model, which includes multiple variables and considers the changes of these variables, may more accurately predict successful extubation. METHODS: This was a prospective observational study. From 2007 to 2008, 113 elderly patients in the medical intensive care unit on ventilation for >48 hours were enrolled. All patients underwent a 60-minute spontaneous breathing trial (SBT) [positive end expiratory pressure of 5 cm H(2)O; automatic tube compensation, 100%]. Patients tolerating the trial were extubated immediately. The mouth occlusion pressure (P(0.1)), rapid shallow breathing index (RSBI,) and their combination (P(0.1) * RSBI) were recorded at the first, 30th, and 60th minute of the SBT. The changes in RSBI, which were determined at the 30th and 60th minute of the SBT (DeltaRSBI30, DeltaRSBI60), were assessed as the ratio (of RSBI30 or RSBI60) to RSBI at the first minute of the SBT. RESULTS: Twenty-two patients (19.5%) failed the SBT and were not included in the analysis, and 91 tolerated the trial and were extubated. At 48 hours, 73 (80.2%) remained extubated (successful extubation), and 18 (19.8%) required reintubation (extubation failure). Although theDeltaRSBI(30) was significantly higher in the extubation failure patients (118% +/- 34%) than that in the successful extubation patients (93% +/- 35%, P = 0.01), the receiver operating characteristic (ROC) analysis demonstrated that this index, with the threshold of <98%, presented poor performance in predicting successful extubation with area under the ROC curve (AUC) of only 0.76. The classification and regression-tree analysis selected 3 variables (P(0.1) * RSBI(30), RSBI(1), DeltaRSBI(30)) and began with P(0.1) * RSBI(30). For patients with P(0.1) * RSBI-(30) >474 cmH(2)O*breaths/min/L, DeltaRSBI(30) >98% defined a group including all failure patients but no success patients, whereas DeltaRSBI(30) <=98% included all success patients with no failure patients. For patients with P(0.1) * RSBI(30) <=474 cm H(2)O*breaths/min/L, the combination of both a P(0.1) * RSBI(30) >328 cm H(2)O*breaths/min/L and RSBI(1) >112 breaths/min/L also defined a group including all success patients but no failure patients. Indeed, the diagnostic accuracy (DA) of the tree model, which was 89.1% with only the P(0.1) * RSBI(30) included, increased to 94.5% when both the P(0.1) * RSBI(30) and ?RSBI(30) were included. The final tree model with the inclusion of all 3 discriminators could capture the successful extubation with diagnostic accuracy of 96.7%, AUC of 0.94 (95% confidence interval [CI], 0.87 to 0.98). CONCLUSION: If the current tree model is confirmed by a prospective study with a larger sample size, it would be useful in guiding physicians making extubation decisions in elderly medical intensive care unit patients. PMID- 20841407 TI - Case report: pediatric liver retransplantation on an extracorporeal membrane oxygenation-dependent child. AB - We describe the perioperative management of a venovenous extracorporeal membrane oxygenator-dependent child requiring liver retransplantation after emergent hepatectomy because of an ischemic liver graft. This child required renal replacement and inotropic support as well as treatment for heparin-induced thrombocytopenia (HIT). We describe each step in this child's perioperative management leading to the successful liver retransplantation. This is the first description, to our knowledge, of a pediatric patient undergoing liver transplantation while supported by extracorporeal membrane oxygenation (ECMO). PMID- 20841408 TI - The effects of 6% hydroxyethyl starch-hypertonic saline in resuscitation of dogs with hemorrhagic shock. AB - BACKGROUND: Hemodynamic and global oxygen transport variables have failed to reflect splanchnic hypoperfusion, resulting in a failure to recognize inadequately treated hemorrhagic shock. Volemic expansion after fluid resuscitation is essential to improve global and regional oxygen in hemorrhagic shock. We hypothesized that, in contrast to conventional plasma expanders, the smaller volemic expansion from 7.5 NaCl/6% hydroxyethyl starch (HHES) solution administration in hemorrhagic shock may provide lesser systemic oxygen delivery and gastric perfusion. We used hemorrhaged dogs to compare intravascular volume expansion and the early systemic oxygenation and gastric perfusion effects of fixed fluid bolus administration, which are usually used in clinical situations with severe hemorrhage, of HHES, lactated Ringer (LR), and 6% hydroxyethyl starch (HES) solutions. METHODS: Thirty dogs were bled (30 mL . kg(-1)) to hold mean arterial blood pressure at 40 to 50 mm Hg over 45 minutes and were resuscitated in 3 groups: LR (n = 10) at 3:1 ratio to shed blood; HES (mean molecular weight 130 kDa, degree of substitution 0.4) (n = 10) at 1:1 to shed blood; and HHES (n = 10), 4 mL . kg(-1). Intravascular volume expansion (Evans blue and hemoglobin dilution), hemodynamic, systemic oxygenation, venous-to-arterial CO(2) gradient (Pv-aCO(2)), and gastric intramucosal-arterial PCO(2) gradient (PCO(2) gap) variables were measured at baseline, after 45 minutes of hemorrhage, and 5, 45, and 90 minutes after fluid resuscitation. RESULTS: HHES increased blood volume because of the high volume expansion efficiency, but intravascular volume expansion with this solution was the smallest of the solutions (P < 0.05). All 3 solutions induced a similar hemodynamic performance but HHES showed lower mixed venous PO(2) and higher systemic oxygenation extraction, Pv-aCO(2), and PCO(2) gap than LR and HES (P < 0.05). CONCLUSIONS: In dogs submitted to pressure-guided hemorrhagic shock and fixed-volume resuscitation, the smaller intravascular volume expansion from HHES solutions provides worse recovery of systemic oxygenation and gastric perfusion compared with LR and HES solutions despite its high volume expansion efficiency, which was limited by low infused volume. PMID- 20841409 TI - The pharmacokinetics of ropivacaine after intraperitoneal administration: instillation versus nebulization. AB - BACKGROUND: Intraperitoneal local anesthetic administration provides perioperative analgesia during laparoscopic procedures. We compared the pharmacokinetics of intraperitoneal ropivacaine administered by instillation or nebulization. METHODS: A crossover study was performed on 5 pigs under standardized general anesthesia with a carbon dioxide pneumoperitoneum of 12 mm Hg for 1 hour. Each animal, acting as its own control, was studied twice with an 8-day interval and received, in a randomized sequence, 3 mg/kg ropivacaine either by intraperitoneal instillation at the time of pneumoperitoneum exsufflation or by continuous nebulization in the carbon dioxide insufflation tubing. Arterial blood samples were taken every 10 minutes up to 120 minutes, and then hourly up to 6 hours. Ropivacaine concentrations were measured using high-performance liquid chromatography with ultraviolet-visible detection. The plasma-free fraction was evaluated after plasma ultracentrifugation. Pharmacokinetic parameters were calculated using both noncompartmental and compartmental analysis. The mean values were compared using the Student t test, or Wilcoxon test for paired series. RESULTS: The data were described by a 1-compartment model for both ropivacaine administration techniques, with a delay of 10 minutes for the nebulization group. The maximal ropivacaine concentrations were 0.96 MUg/mL for the nebulization group and 0.92 MUg/mL for the instillation group (P = 0.66). The ropivacaine absorption constant was lower in the nebulization group (0.043 vs 0.083 min(-1), P = 0.02). There were no differences in the elimination half-life, elimination constant, mean total body clearance, distribution volume, mean area under the curve, and mean residence time. The free fraction of ropivacaine was also similar in the 2 groups. CONCLUSIONS: The pharmacokinetic profile of ropivacaine nebulization is similar to direct intraperitoneal instillation, but with a lower absorption rate. PMID- 20841410 TI - Forced-air and a novel patient-warming system (vitalHEAT vH2) comparably maintain normothermia during open abdominal surgery. AB - BACKGROUND: The vitalHEAT vH(2) (Dynatherm Medical, Inc., Fremont, California) system transfers heat through a single extremity using a combination of conductive heat (circulating warm water within soft fluid pads) with mild vacuum, which improves both vasodilation and contact between the heating element and the skin surface. We tested the hypothesis that core temperatures were not >0.5 degrees C lower in patients warmed with the vitalHEAT system than with forced air. METHODS: Patients having general anesthesia for open abdominal surgery were randomly assigned to the circulating-water sleeve on 1 arm (n = 37) or an upper body forced-air warming cover (n = 34). Patients were eligible to participate when body mass index was 20 to 36 kg/m(2), age was 18 to 75 years, and ASA physical status was 1 to 3. Intraoperative distal esophageal (core) temperatures were recorded. Repeated-measures analysis and 1-tailed t tests were used to assess noninferiority of vitalHEAT to forced air using a noninferiority delta of 0.5 degrees C. RESULTS: Demographic and morphometric characteristics were similar, as were surgical details. Preoperative core temperatures were similar in each group. Intraoperative core temperatures were also similar with each warming system and were significantly noninferior during the first four hours of surgery. The observed difference in means was never more than about 0.2 degrees C. After 4 hours of surgery, the average temperature was 36.3 degrees C +/- 0.6 degrees C (mean +/- sd) with the circulating-water sleeve (n = 18) and 36.4 degrees C +/- 0.5 degrees C with forced air (n = 20), for a difference (95% confidence interval) of -0.21 degrees C (-0.47, 0.06). CONCLUSIONS: The 2 systems thus apparently transfer comparable amounts of heat. Both appear suitable for maintaining normothermia even during large and long operations. PMID- 20841411 TI - The accuracy of the anesthetic conserving device (AnaConDa(c)) as an alternative to the classical vaporizer in anesthesia. AB - BACKGROUND: The Anesthetic Conserving Device--AnaConDa(r) (ACD)--has been compared with a conventional vaporizer. However, the accuracy of the administered concentration of volatile anesthetics was not examined. In the present study we measured the accuracy of the ACD when used as a portable vaporizer. METHODS: This prospective study included 30 ASA I-III patients scheduled for elective surgery under general anesthesia. The patients were randomly organized into 3 groups of 10 patients per group. In each group, the sevoflurane infusion rate was adjusted to deliver 1.0 vol%, 1.5 vol%, and 2.0 vol% alveolar concentration. Hemodynamic data, bispectral index, and end-tidal sevoflurane concentrations were recorded every 2 minutes. RESULTS: We analyzed 801 data points from 30 patients. The mean difference between the end-tidal sevoflurane concentration and the target concentration was -11.0 +/- 9.3% of the target when the target was 1.0 vol%, -5.4 +/- 6.4% when the target was 1.5 vol%, and -4.0 +/- 7.4% when the target was 2.0 vol%. No significant differences were found in the error at the different target concentrations. CONCLUSIONS: We found that the ACD may be a valid alternative to the conventional vaporizer. The ACD is very simple to use, delivery rate needs to be adjusted only once per hour, and the anesthetic savings are independent of the circuit characteristics and fresh gas flow rate. PMID- 20841412 TI - Improved accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia. AB - BACKGROUND: Methemoglobin in the blood cannot be detected by conventional pulse oximetry and may bias the oximeter's estimate (Spo(2)) of the true arterial functional oxygen saturation (Sao(2)). A recently introduced "pulse CO-oximeter" (Masimo Rainbow SET(r) Radical-7) that measures SpMet, a noninvasive measurement of the percentage of methemoglobin in arterial blood (%MetHb), was shown to read spuriously high values during hypoxia. In this study we sought to determine whether the manufacturer's modifications have improved the device's ability to detect and accurately measure methemoglobin and deoxyhemoglobin simultaneously. METHODS: Twelve healthy adult volunteer subjects were fitted with sensors on the middle finger of each hand, and a radial arterial catheter was placed for blood sampling. Intravenous administration of ~300 mg of sodium nitrite elevated subjects' methemoglobin levels to a 7% to 11% target level, and hypoxia was induced to different levels of Sao(2) (70% to 100%) by varying fractional inspired oxygen. Pulse CO-oximeter readings were compared with arterial blood values measured with a Radiometer ABL800 FLEX multi-wavelength oximeter. Pulse CO oximeter methemoglobin reading performance was analyzed by the bias (SpMet %MetHb), and by observing the incidence of meaningful reading errors and predictive value at the various hypoxia levels. Spo(2) bias (Spo(2)--Sao(2)), precision, and root-mean-square error were evaluated during conditions of elevated methemoglobin. RESULTS: Observations spanned 74% to 100% Sao(2) and 0.4% to 14.4% methemoglobin with 307 blood draws and 602 values from the 2 oximeters. Masimo methemoglobin reading bias and precision over the full Sao(2) span was 0.16% and 0.83%, respectively, and was similar across the span. Masimo Spo(2) readings were biased -1.93% across the 70% to 100% Sao(2) range. CONCLUSIONS: The Rainbow's methemoglobin readings are acceptably accurate over an oxygen saturation range of 74%-100% and a methemoglobin range of 0%-14%. PMID- 20841413 TI - Prolonged high-dose isoflurane for refractory status epilepticus: is it safe? AB - Isoflurane is an alternative treatment for refractory status epilepticus. Little is known regarding human toxicities caused by isoflurane. We present 2 patients with prolonged refractory status epilepticus treated with high concentrations of isoflurane who developed signal abnormalities on magnetic resonance imaging. Patient 1 was treated with isoflurane for 85 days with 1975.2% concentration hours. Patient 2 was treated with isoflurane for 34 days with 1382.4% concentration-hours. Serial brain magnetic resonance images in both showed progressive T2 signal hyperintensity involving thalamus and cerebellum, which improved after discontinuation of isoflurane. These cases suggest that isoflurane may be neurotoxic when used in high doses for long time periods. PMID- 20841414 TI - Feedback mechanisms including real-time electronic alerts to achieve near 100% timely prophylactic antibiotic administration in surgical cases. AB - BACKGROUND: Administration of prophylactic antibiotics during surgery is generally performed by the anesthesia providers. Timely antibiotic administration within the optimal time window before incision is critical for prevention of surgical site infections. However, this often becomes a difficult task for the anesthesia team during the busy part of a case when the patient is being anesthetized. METHODS: Starting with the implementation of an anesthesia information management system (AIMS), we designed and implemented several feedback mechanisms to improve compliance of proper antibiotic delivery and documentation. This included generating e-mail feedback of missed documentation, distributing monthly summary reports, and generating real-time electronic alerts with a decision support system. RESULTS: In 20,974 surgical cases for the period, June 2008 to January 2010, the interventions of AIMS install, e-mail feedback, summary reports, and real-time alerts changed antibiotic compliance by -1.5%, 2.3%, 4.9%, and 9.3%, respectively, when compared with the baseline value of 90.0% +/- 2.9% when paper anesthesia records were used. Highest antibiotic compliance was achieved when using real-time alerts. With real-time alerts, monthly compliance was >99% for every month between June 2009 and January 2010. CONCLUSIONS: Installation of AIMS itself did not improve antibiotic compliance over that achieved with paper anesthesia records. However, real-time guidance and reminders through electronic messages generated by a computerized decision support system (Smart Anesthesia Messenger, or SAM) significantly improved compliance. With such a system a consistent compliance of >99% was achieved. PMID- 20841415 TI - Perioperative mortality in patients with pulmonary hypertension undergoing major joint replacement. AB - BACKGROUND: There is a paucity of perioperative outcomes data for patients with chronic pulmonary hypertension (PHTN) undergoing noncardiac surgery. Clinicians, therefore, have little information on which to evaluate the risk for morbidity and mortality in this patient population. In this study, we evaluated the incidence and risks of perioperative morbidity and mortality in patients with PHTN undergoing primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Using the largest inpatient database in the United States (National Inpatient Sample), we identified entries for THA and TKA between the years of 1998 and 2006. Patients with the diagnosis of PHTN were identified and matched to those without the disease based on health-related demographic variables. Perioperative mortality was considered the primary outcome. Multivariate logistic regression models were fitted to assess the impact of PHTN on in-hospital mortality. RESULTS: We identified 670,516 entries for TKA and 360,119 for THA. Of those patients, 2184 (0.3%) and 1359 (0.4%), respectively, had the diagnosis of PHTN (average annual rate of 1180 for TKA [range, 507-2073] and 739 for THA [range, 467-1054]). Patients with PHTN undergoing THA experienced an approximately 4-fold increased adjusted risk of mortality (2.4% vs 0.6%), and those undergoing TKA a 4.5-fold increased adjusted risk of mortality (0.9% vs 0.2%) compared with patients without PHTN in the matched sample (P < 0.001 for each comparison). Patients with primary PHTN undergoing THA experienced the highest mortality rate (5% [95% CI, 2.3%-7.7%]). CONCLUSIONS: This analysis demonstrates that patients with PHTN are at increased risk for perioperative mortality after THA and TKA. PMID- 20841416 TI - Propofol decreases neuronal population spiking activity in the subthalamic nucleus of Parkinsonian patients. AB - BACKGROUND: Implantation of deep brain stimulation (DBS) electrodes in the subthalamic nucleus (STN) for the treatment of Parkinson disease is often performed using microelectrode recording (MER) of STN population spike activity. The extent to which sedative drugs interfere with MER is unknown. We recorded the population activity of STN neurons during propofol sedation and examined its effect on neuronal activity. METHODS: The procedure was performed during DBS surgery for Parkinson disease. We administered propofol (50 MUg/kg/min) at a constant electrode location in the STN until stable sedation was achieved. We recorded the electrical activity, and calculated its root mean square (RMS) before, during, and after the propofol infusions. RESULTS: The activity of 24 electrode trajectories was recorded in 16 patients. The RMS of STN activity decreased significantly after propofol administration in 18 of the 24 trajectories. The average normalized RMS decreased by 23.2%+/- 9.1% (mean +/- SD) during propofol administration (P < 0.001), and returned to baseline 9.3 +/- 4.0 minutes after it was stopped. CONCLUSIONS: Propofol administration leads to a significant decrease of STN neuronal activity. Thus, it may interfere with MER identification of the STN borders. However, activity returns to baseline shortly after administration stops. Therefore, propofol can be safely used until shortly before MER for DBS. PMID- 20841417 TI - An organized, comprehensive, and security-enabled strategic response to the Haiti earthquake: a description of pre-deployment readiness preparation and preliminary experience from an academic anesthesiology department with no preexisting international disaster response program. AB - BACKGROUND: On Tuesday, January 12, 2010 at 16:53 local time, a magnitude 7.0 M(w) earthquake struck Haiti. The global humanitarian attempt to respond was swift, but poor infrastructure and emergency preparedness limited many efforts. Rapid, successful deployment of emergency medical care teams was accomplished by organizations with experience in mass disaster casualty response. Well intentioned, but unprepared, medical teams also responded. In this report, we describe the preparation and planning process used at an academic university department of anesthesiology with no preexisting international disaster response program, after a call from an American-based nongovernmental organization operating in Haiti requested medical support. The focus of this article is the pre-deployment readiness process, and is not a post-deployment report describing the medical care provided in Haiti. METHODS: A real-time qualitative assessment and systematic review of the Hospital of the University of Pennsylvania's communications and actions relevant to the Haiti earthquake were performed. Team meetings, conference calls, and electronic mail communication pertaining to planning, decision support, equipment procurement, and actions and steps up to the day of deployment were reviewed and abstracted. Timing of key events was compiled and a response timeline for this process was developed. Interviews with returning anesthesiology members were conducted. RESULTS: Four days after the Haiti earthquake, Partners in Health, a nonprofit, nongovernmental organization based in Boston, Massachusetts, with >20 years of experience providing medical care in Haiti contacted the University of Pennsylvania Health System to request medical team support. The departments of anesthesiology, surgery, orthopedics, and nursing responded to this request with a volunteer selection process, vaccination program, and systematic development of equipment lists. World Health Organization and Centers for Disease Control guidelines, the American Society of Anesthesiology Committee on Trauma and Emergency Preparedness, published articles, and in-country contacts were used to guide the preparatory process. CONCLUSION: An organized strategic response to medical needs after an international natural disaster emergency can be accomplished safely and effectively within 6 to 12 days by an academic anesthesiology department, with medical system support, in a center with no previously established response system. The value and timeliness of this response will be determined with further study. Institutions with limited experience in putting an emergency medical team into the field may be able to quickly do so when such efforts are executed in a systematic manner in coordination with a health care organization that already has support infrastructure at the site of the disaster. PMID- 20841418 TI - The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. AB - BACKGROUND: Hypotension is the most common serious side effect of spinal anesthesia for cesarean delivery. There has been a move recently toward the use of phenylephrine as a vasopressor infusion to improve maternal cardiovascular stability and fetal outcome. Although it seems safe in the elective setting, there have been concerns about its propensity for causing an increase in afterload and a baroreceptor-mediated bradycardia in the mother, with a consequent reduction in maternal cardiac output (CO). Using a noninvasive measure of CO, our aim was to investigate whether there were any dose-dependent effects of phenylephrine on maternal cardiovascular stability and, if so, any impact on fetal outcome. METHODS: In this randomized, double-blind study, 75 women scheduled for elective cesarean delivery were allocated to receive a phenylephrine infusion at 25 MUg/min, 50 MUg/min, or 100 MUg/min. This infusion was titrated to maintain maternal baseline systolic blood pressure (SBP), from induction of spinal anesthesia until delivery. The maternal cardiovascular variables recorded included heart rate (HR) and SBP. A suprasternal Doppler monitor measured CO and stroke volume, as well as measures of venous return (corrected flow time) and contractility, at baseline, and then every 5 minutes for 20 minutes after initiation of spinal anesthesia. Apgar scores and umbilical cord blood gases were recorded. RESULTS: SBP control was satisfactory in all groups; however, the group receiving phenylephrine 100 MUg/min required significantly higher doses to achieve arterial blood pressure control compared with the lower infusion rates. There were no significant differences in the number of times SBP decreased below 80% of baseline, or the numbers of boluses of ephedrine or phenylephrine required to maintain SBP above 80% of baseline. There were significant time and dose-dependent reductions in HR and CO with phenylephrine, such that HR and CO were seen to decrease with time in each group, and also with increasing concentrations of phenylephrine. Stroke volume remained stable throughout. Apgar scores and umbilical cord blood gases were similar among groups. CONCLUSION: By infusing a higher concentration (100 MUg/min), we subject the mother and fetus to a much higher dose of phenylephrine, with significant effects on maternal HR and CO (up to a 20% reduction). Future investigation is required to determine whether this reduction in maternal CO has detrimental effects when providing anesthesia for an emergency cesarean delivery for a compromised fetus. PMID- 20841419 TI - Assessment of linezolid resistance mechanisms among Staphylococcus epidermidis causing bacteraemia in Rome, Italy. AB - OBJECTIVES: To characterize linezolid resistance among blood cultured Staphylococcus epidermidis from patients at the Polyclinic Agostino Gemelli (2006 08). Isolates also showed elevated MICs of macrolide, lincosamide and streptogramin (MLS) compounds, which were investigated. METHODS: Ten S. epidermidis exhibiting linezolid MICs >= 4 mg/L were included. Isolates were screened for cfr mutations in 23S rRNA, L3, L4 and L22, and MLS genes by PCR/sequencing. Ribosomal proteins were compared with those from a linezolid susceptible (MIC, 1 mg/L) clinical strain and ATCC 12228. cfr location was determined by Southern blot/hybridization. The cfr strain was submitted to plasmid curing. Epidemiology was assessed by PFGE and multilocus sequence typing (MLST). RESULTS: S. epidermidis displayed linezolid MICs of 4 or 8 mg/L, except for strain 4303A (MIC, 64 mg/L). These organisms and a linezolid-susceptible strain exhibited L3 Leu101Val compared with ATCC 12228. Isolates also showed L3 Phe147Leu and Ala157Arg, and L4 Asn158Ser. Strain 12375A possessed L4 Lys68Arg. Isolates were wild-type for 23S rRNA and L22. cfr was plasmid located in strain 4303A and the plasmid-cured strain exhibited a linezolid MIC (4 mg/L) similar to that for cfr-negative strains (4-8 mg/L). All organisms harboured erm(A) and msr(A), while vga(A) was detected in several isolates. All isolates were clonally related and ST-23. CONCLUSIONS: L3 Phe147Leu and/or Ala157Arg appeared responsible for the elevated linezolid MIC, since adjacent alterations have been associated with resistance. L4 Asn158Ser has been reported in a linezolid susceptible isolate and Lys68Arg detected here did not seem to provide an additive effect. Acquisition of cfr markedly increased (8- to 16-fold) the linezolid MICs. vga(A) was associated with higher MICs of quinupristin/dalfopristin and retapamulin. PMID- 20841420 TI - Noncanonical cytoplasmic processing of viral microRNAs. AB - Cellular utilization of RNA interference (RNAi) as a mechanism to combat virus infection is thought to be restricted to plants and invertebrates. In vertebrates, antiviral defenses are largely dependent on interferons (IFNs), with the use of small RNAs restricted to microRNA (miRNA)-mediated targeting of host transcripts. Here we demonstrate that incorporation of a primary miRNA into a cytoplasmic virus results in the formation of a Dicer-dependent, DGCR8 independent, mature miRNA capable of conferring RNAi-like activity. Processing of the viral mirtron-like product (virtron) is indistinguishable from endogenous miRNA maturation and elicits post-transcriptional gene silencing, albeit at a reduced level. Furthermore, virtrons impose Dicer-dependent, microprocessor independent, and IFN-independent interference on virus replication in a sequence specific manner. Taken together, these results suggest the existence of a noncanonical, small-RNA-based activity capable of processing cytoplasmic hairpins and perhaps contributing to the cell's antiviral arsenal. PMID- 20841421 TI - Host density drives the postglacial migration of the tree parasite, Epifagus virginiana. AB - To survive changes in climate, successful species shift their geographic ranges to remain in suitable habitats. For parasites and other highly specialized species, distributional changes not only are dictated by climate but can also be engineered by their hosts. The extent of host control on parasite range expansion is revealed through comparisons of host and parasite migration and demographic histories. However, understanding the codistributional history of entire forest communities is complicated by challenges in synthesizing datasets from multiple interacting species of differing datatypes. Here we integrate genetic and fossil pollen datasets from a host-parasite pair; specifically, the population structure of the parasitic plant (Epifagus virginiana) was compared with both its host (Fagus grandifolia) genetic patterns and abundance data from the paleopollen record of the last 21,000 y. Through tests of phylogeographic structure and spatial linear regression models we find, surprisingly, host range changes had little effect on the parasite's range expansion and instead host density is the main driver of parasite spread. Unlike other symbionts that have been used as proxies to track their host's movements, this parasite's migration routes are incongruent with the host and instead reflect the greater importance of host density in this community's assembly. Furthermore, these results confirm predictions of disease ecological models regarding the role of host density in the spread of pathogens. Due to host density constraints, highly specialized species may have low migration capacities and long lag times before colonization of new areas. PMID- 20841422 TI - Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence. AB - Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors. PMID- 20841423 TI - CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia. AB - Here, we report that primary leukemic cells from infants with newly diagnosed B precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.2208 c.2327) (CD22DeltaE12) and results in a truncating frameshift mutation. The splicing defect is associated with multiple homozygous mutations within a 132-bp segment of the intronic sequence between exons 12 and 13. These mutations cause marked changes in the predicted secondary structures of the mutant CD22 pre-mRNA sequences that affect the target motifs for the splicing factors hnRNP-L, PTB, and PCBP that are up-regulated in infant leukemia cells. Forced expression of the mutant CD22DeltaE12 protein in transgenic mice perturbs B-cell development, as evidenced by B-precursor/B-cell hyperplasia, and corrupts the regulation of gene expression, causing reduced expression levels of several genes with a tumor suppressor function. We further show that CD22DeltaE12-associated unique gene expression signature is a discriminating feature of newly diagnosed infant leukemia patients. These striking findings implicate CD22DeltaE12 as a previously undescribed pathogenic mechanism in human B-precursor leukemia. PMID- 20841424 TI - Arabidopsis snc2-1D activates receptor-like protein-mediated immunity transduced through WRKY70. AB - Plant immune receptors belonging to the receptor-like protein (RLP) family contain extracellular leucine-rich repeats (LRRs) and a short cytoplasmic tail linked by a single transmembrane motif. Here, we report the identification of snc2-1D (for suppressor of npr1-1, constitutive 2), a semidominant Arabidopsis thaliana mutant with constitutively activated defense responses. Map-based cloning of snc2-1D showed that it encodes an RLP. The point mutation in snc2-1D leads to substitution of the second Gly for Arg in the conserved GXXXG motif of the transmembrane helix, suggesting that this residue is important for negative regulation of the protein. Epistasis analysis revealed that the snc2-1D mutant phenotype is not affected by mutations in genes known to be required for the nucleotide binding (NB)-LRR Resistance (R) protein signaling. A suppressor screen of snc2-1D was performed, and map-based cloning of one suppressor revealed that mutations in WRKY70 suppress the constitutive defense responses in snc2-1D, suggesting that WRKY70 functions downstream of snc2-1D. The identification of snc2-1D provides us with a unique system for genetic analysis of resistance pathways downstream of RLPs, which may be distinct from those downstream of NB LRR type R proteins. PMID- 20841425 TI - Crystal structures of a Populus tomentosa 4-coumarate:CoA ligase shed light on its enzymatic mechanisms. AB - 4-Coumaric acid:CoA ligase (4CL) is the central enzyme of the plant-specific phenylpropanoid pathway. It catalyzes the synthesis of hydroxycinnamate-CoA thioesters, the precursors of lignin and other important phenylpropanoids, in two step reactions involving the formation of hydroxycinnamate-AMP anhydride and then the nucleophilic substitution of AMP by CoA. In this study, we determined the crystal structures of Populus tomentosa 4CL1 in the unmodified (apo) form and in forms complexed with AMP and adenosine 5'-(3-(4-hydroxyphenyl)propyl)phosphate (APP), an intermediate analog, at 2.4, 2.5, and 1.9 A resolution, respectively. 4CL1 consists of two globular domains connected by a flexible linker region. The larger N-domain contains a substrate binding pocket, while the C-domain contains catalytic residues. Upon binding of APP, the C-domain rotates 81 degrees relative to the N-domain. The crystal structure of 4CL1-APP reveals its substrate binding pocket. We identified residues essential for catalytic activities (Lys 438, Gln-443, and Lys-523) and substrate binding (Tyr-236, Gly-306, Gly-331, Pro 337, and Val-338) based on their crystal structures and by means of mutagenesis and enzymatic activity studies. We also demonstrated that the size of the binding pocket is the most important factor in determining the substrate specificities of 4CL1. These findings shed light on the enzymatic mechanisms of 4CLs and provide a solid foundation for the bioengineering of these enzymes. PMID- 20841426 TI - Structural sterols are involved in both the initiation and tip growth of root hairs in Arabidopsis thaliana. AB - Structural sterols are abundant in the plasma membrane of root apex cells in Arabidopsis thaliana. They specifically accumulate in trichoblasts during the prebulging and bulge stages and show a polar accumulation in the tip during root hair elongation but are distributed evenly in mature root hairs. Thus, structural sterols may serve as a marker for root hair initiation and growth. In addition, they may predict branching events in mutants with branching root hairs. Structural sterols were detected using the sterol complexing fluorochrome filipin. Application of filipin caused a rapid, concentration-dependent decrease in tip growth. Filipin-complexed sterols accumulated in globular structures that fused to larger FM4-64-positive aggregates in the tip, so-called filipin-induced apical compartments, which were closely associated with the plasma membrane. The plasma membrane appeared malformed and the cytoarchitecture of the tip zone was affected. Trans-Golgi network/early endosomal compartments containing molecular markers, such as small Rab GTPase RabA1d and SNARE Wave line 13 (VTI12), locally accumulated in these filipin-induced apical compartments, while late endosomes, endoplasmic reticulum, mitochondria, plastids, and cytosol were excluded from them. These data suggest that the local distribution and apical accumulation of structural sterols may regulate vesicular trafficking and plasma membrane properties during both initiation and tip growth of root hairs in Arabidopsis. PMID- 20841427 TI - Involvement of the orphan nuclear estrogen receptor-related receptor alpha in osteoclast adhesion and transmigration. AB - The orphan nuclear receptor, estrogen receptor-related receptor alpha (ERRalpha) is expressed in osteoblasts and osteoclasts (OCs) and has been proposed to be a modulator of estrogen signaling. To determine the role of ERRalpha in OC biology, we knocked down ERRalpha activity by transient transfection of an siRNA directed against ERRalpha in the RAW264.7 monocyte-macrophage cell line that differentiates into OCs in the presence of receptor activator of nuclear factor kappaB-ligands and macrophage colony-stimulating factor. In parallel, stable RAW cell lines expressing a dominant-negative form of ERRalpha and green fluorescent protein (RAW-GFP-ERRalphaDeltaAF2) were used. Expression of OC markers was assessed by real-time PCR, and adhesion and transmigration tests were performed. Actin cytoskeletal organization was visualized using confocal microscopy. We found that RAW264.7 cells expressing siRNA directed against ERRalpha and RAW-GFP ERRalphaDeltaAF2 OCs displayed abnormal spreading, and decreased osteopontin and beta3 integrin subunit expression compared with the corresponding control cells. Decreased adhesion and the absence of podosome belts concomitant with abnormal localization of c-src were also observed in RAW-GFP-ERRalphaDeltaAF2-derived OCs. In addition, RAW-GFP-ERRalphaDeltaAF2-derived OCs failed to transmigrate through osteoblast cell layers. Our data show that the impairment of ERRalpha function does not alter OC precursor proliferation and differentiation but does alter the adhesion/spreading and migration capacities of mature OCs. PMID- 20841429 TI - Overlapping codes within protein-coding sequences. AB - Genomes encode multiple signals, raising the question of how these different codes are organized along the linear genome sequence. Within protein-coding regions, the redundancy of the genetic code can, in principle, allow for the overlapping encoding of signals in addition to the amino acid sequence, but it is not known to what extent genomes exploit this potential and, if so, for what purpose. Here, we systematically explore whether protein-coding regions accommodate overlapping codes, by comparing the number of occurrences of each possible short sequence within the protein-coding regions of over 700 species from viruses to plants, to the same number in randomizations that preserve amino acid sequence and codon bias. We find that coding regions across all phyla encode additional information, with bacteria carrying more information than eukaryotes. The detailed signals consist of both known and potentially novel codes, including position-dependent secondary RNA structure, bacteria-specific depletion of transcription and translation initiation signals, and eukaryote-specific enrichment of microRNA target sites. Our results suggest that genomes may have evolved to encode extensive overlapping information within protein-coding regions. PMID- 20841428 TI - Skeletal progenitors and the GNAS gene: fibrous dysplasia of bone read through stem cells. AB - Activating mutations of the GNAS gene, which causes fibrous dysplasia of bone (FD), lead to remarkable changes in the properties of skeletal progenitors, and it is these changes that mediate the pathological effect of this gene on bone. Mutated skeletal stem cells lose the ability to differentiate into adipocytes, and to maintain in situ, and transfer heterotopically, the hematopoietic microenvironment, leading to abnormal bone marrow histology in FD. They overexpress molecular effectors of osteoclastogenesis, thus promoting inappropriate bone resorption leading to fragility of FD bone. They express the phosphate-regulating hormone FGF-23 at normal levels, whose excess in the serum of FD patients correlates with the mass of osteogenic cells within FD lesions, leading to osteomalacia and deformity of the FD bone, and revealing that bone is an endocrine organ regulating renal handling of phosphate. Mechanisms of allelic selection and stem cell selection occur in mutated skeletal stem cells and contribute to the inherent diversity and evolution over time in FD. The definition of the etiological role of GNAS mutations marks the watershed between many decades of descriptive observation and the definition of cellular and molecular mechanisms that would explain and hopefully allow for a cure for the disease. Placing stem cells at center stage has permitted substantial advances in one decade, and promises more for the one to come. PMID- 20841430 TI - De novo rates and selection of large copy number variation. AB - While copy number variation (CNV) is an active area of research, de novo mutation rates within human populations are not well characterized. By focusing on large (>100 kbp) events, we estimate the rate of de novo CNV formation in humans by analyzing 4394 transmissions from human pedigrees with and without neurocognitive disease. We show that a significant limitation in directly measuring genome-wide CNV mutation is accessing DNA derived from primary tissues as opposed to cell lines. We conservatively estimated the genome-wide CNV mutation rate using single nucleotide polymorphism (SNP) microarrays to analyze whole-blood derived DNA from asthmatic trios, a collection in which we observed no elevation in the prevalence of large CNVs. At a resolution of ~30 kb, nine de novo CNVs were observed from 772 transmissions, corresponding to a mutation rate of MU = 1.2 * 10(-2) CNVs per genome per transmission (MU = 6.5 * 10(-3) for CNVs >500 kb). Combined with previous estimates of CNV prevalence and assuming a model of mutation-selection balance, we estimate significant purifying selection for large (>500 kb) events at the genome-wide level to be s = 0.16. Supporting this, we identify de novo CNVs in 717 multiplex autism pedigrees from the AGRE collection and observe a fourfold enrichment (P = 1.4 * 10(-3)) for de novo CNVs in cases of multiplex autism versus unaffected siblings, suggesting that many de novo CNV mutations contribute a subtle, but significant risk for autism. We observe no parental bias in the origin or transmission of CNVs among any of the cohorts studied. PMID- 20841431 TI - A unique H3K4me2 profile marks tissue-specific gene regulation. AB - Characterization of the epigenetic landscape fundamentally contributes toward deciphering the regulatory mechanisms that govern gene expression. However, despite an increasing flow of newly generated data, no clear pattern of chromatin modifications has so far been linked to specific modes of transcriptional regulation. Here, we used high-throughput genomic data from CD4(+) T lymphocytes to provide a comprehensive analysis of histone H3 lysine 4 dimethylation (H3K4me2) enrichment in genomic regions surrounding transcriptional start sites (TSSs). We discovered that a subgroup of genes linked to T cell functions displayed high levels of H3K4me2 within their gene body, in sharp contrast to the TSS-centered profile typical of housekeeping genes. Analysis of additional chromatin modifications and DNase I hypersensitive sites (DHSS) revealed a combinatorial chromatin signature characteristic of this subgroup. We propose that this epigenetic feature reflects the activity of an as yet unrecognized, intragenic cis-regulatory platform dedicated to refining tissue-specificity in gene expression. PMID- 20841433 TI - College women's HPV vaccine decision narratives. AB - Drawing on 38 in-depth qualitative interviews with college women and college health clinicians, we collected human papillomavirus (HPV) vaccine decision narratives to identify the implicit and explicit values underlying HPV vaccine decision making. Narratives of vaccine acceptance and resistance were identified. Vaccine acceptance narratives consisted of four themes: supportive family messages, explicit health care provider endorsement, peer descriptive norms reducing stigma of vaccination, and disease framing (e.g., cancer, HPV) shaping vaccine benefit perceptions. Vaccine resistance narratives consisted of five themes: skepticism of vaccine safety, invoking alternative prevention strategies, articulating stigmatizing HPV messages, overcoming self-efficacy barriers (e.g., cost, availability, time, and fear of parental disclosure), and delay strategies. Common to all decision narratives was that relationship status framed college women's perceptions of HPV susceptibility. Theoretical and practical implications for designing HPV vaccine messages aimed at college-aged women are discussed. PMID- 20841432 TI - Functional metagenomics to mine the human gut microbiome for dietary fiber catabolic enzymes. AB - The human gut microbiome is a complex ecosystem composed mainly of uncultured bacteria. It plays an essential role in the catabolism of dietary fibers, the part of plant material in our diet that is not metabolized in the upper digestive tract, because the human genome does not encode adequate carbohydrate active enzymes (CAZymes). We describe a multi-step functionally based approach to guide the in-depth pyrosequencing of specific regions of the human gut metagenome encoding the CAZymes involved in dietary fiber breakdown. High-throughput functional screens were first applied to a library covering 5.4 * 10(9) bp of metagenomic DNA, allowing the isolation of 310 clones showing beta-glucanase, hemicellulase, galactanase, amylase, or pectinase activities. Based on the results of refined secondary screens, sequencing efforts were reduced to 0.84 Mb of nonredundant metagenomic DNA, corresponding to 26 clones that were particularly efficient for the degradation of raw plant polysaccharides. Seventy three CAZymes from 35 different families were discovered. This corresponds to a fivefold target-gene enrichment compared to random sequencing of the human gut metagenome. Thirty-three of these CAZy encoding genes are highly homologous to prevalent genes found in the gut microbiome of at least 20 individuals for whose metagenomic data are available. Moreover, 18 multigenic clusters encoding complementary enzyme activities for plant cell wall degradation were also identified. Gene taxonomic assignment is consistent with horizontal gene transfer events in dominant gut species and provides new insights into the human gut functional trophic chain. PMID- 20841434 TI - Unpacking social hypersensitivity: vulnerability to the absence of positive feedback. AB - Navigating social life requires accurately calibrated sensitivity to external feedback, thus extreme sensitivity to external feedback may be maladaptive. Using a daily diary design, the authors investigated whether the relationship between social hypersensitivity and daily events predicted level, lability, and reactivity of both self-esteem and affect. Relative to their less sensitive peers, socially hypersensitive people exhibited lower levels of self-esteem and greater negative affect and experienced greater fluctuations in self-esteem and negative affect. Although most people were negatively reactive to the presence of negative feedback, socially hypersensitive people were negatively reactive to the absence of positive feedback as well. The authors argue that reactivity to the absence of positive feedback is a fundamental, heretofore untested aspect of what makes social hypersensitivity a pernicious orientation. PMID- 20841435 TI - Comparison focus in intergroup comparisons: who we compare to whom influences who we see as powerful and agentic. AB - In intergroup comparisons one group usually becomes the implicit norm that other groups are compared to. Three studies address the consequences that the direction of the comparison has for perceptions of the compared groups. For real groups (Experiment 1) and fictitious groups (Experiments 2 and 3) participants perceived a group as more powerful and higher in status when it had been the norm rather than the effect to be explained in a text comparing two groups. Moreover, norm groups and their "typical" members were perceived as more agentic and less communal than comparison groups, and these attributions were mediated by the ascription of power. The authors conclude that systematic ways of explaining one group rather than another could serve as a subtle tool to perpetuate the status quo of intergroup power relations. PMID- 20841436 TI - It takes one to tango: the effects of dyads' epistemic motivation composition in negotiation. AB - This study examined the effects of epistemic motivation composition in negotiation. Results from Experiment 1 revealed that dyads in which at least one member had high epistemic motivation (measured by personal need for structure) reached higher joint outcomes than dyads in which both members had low epistemic motivation. In Experiment 2, epistemic motivation was manipulated and negotiators were provided with full information or incomplete information about their counterpart's preferences. Two competing sets of hypotheses were developed and tested. Negotiation behavior was coded, and mediation analysis established that the presence of one negotiator with high epistemic motivation helped negotiators overcome information insufficiency and benefited the dyad as a whole because of increased information search rather than heuristic trial and error. Theoretical implications are discussed. PMID- 20841437 TI - Oral thrush to candidemia: a morbid outcome. AB - A 35-year-old female living with AIDS presented with oral thrush 3 months after the initiation of antiretroviral therapy (ART). On investigation, it was found to be due to Candida albicans. She was started on fluconazole. After 4 months on ART, she presented with fever. Blood culture was performed. After 4 days, she expired due to septic shock. Two days after her death, C albicans strain was isolated from the blood culture which was similar to the C albicans strain (by DNA fingerprinting) isolated from oral thrush. Both strains of C albicans were found to be resistant to fluconazole by broth microdilution method. A high index of suspicion in high-risk patients along with early and aggressive management of the patient with antigen detection would go a long way in the management of these patients. Guidelines for treatment of candidiasis need to be re-evaluated, keeping in mind the increasing emergence of resistance to azoles and its effect on morbidity outcome. PMID- 20841438 TI - Offering of HIV screening to men who have sex with men by their health care providers and associated factors. AB - OBJECTIVE: in 2006, the US Centers for Disease Control and Prevention (CDC) recommended offering HIV testing at least annually to men who have sex with men (MSM), but few studies describe the extent to which routine offering occurred after 2006. METHODS: data were collected from March to April 2009 using an online survey of US MSM aged >=18 years. Multivariable logistic regression estimated the odds of being offered HIV testing for demographic factors and for having disclosed male-male sex behavior to the health care provider. RESULTS: of 4620 MSM reporting visiting a health care provider in the past year, 1385 (30%) were offered HIV testing. Being offered testing was associated with disclosing male male sex to the provider (decreasing odds by age from age 20: adjusted odds ratio [aOR] 19.22, 95% confidence interval [CI]: 15.79-23.41) and other demographic factors. CONCLUSIONS: less than one third of the MSM visiting a provider reported being offered HIV testing. Providers should actively assess male-male sex risk to potentially improve offering of HIV screenings. PMID- 20841439 TI - Lopinavir/ritonavir dosage form affects quality of life during monotherapy in HIV positive adults. AB - This was a single-center, open-label study of lopinavir/ritonavir (LPV/r) single agent therapy in antiretroviral-naive, HIV-infected participants initiating therapy with twice-daily soft-gelatin capsules (SGC) and switched to tablets after >=4 weeks. The objective was to evaluate quality of life and tolerability of the 2 formulations. Participants quality of life, depression, and tolerability were measured using the Medical Outcomes Study-HIV (MOS-HIV), Modified Global Condition Improvement (GCI), and Center for Epidemiologic Studies-Depression (CES D), prior to and 4 weeks following switch. MOS-HIV showed significant improvements in general health perception (+6 (16), mean (SD); P = .047) and role functioning (+8 (19), mean (SD); P = .023) post-switch. GCI showed significant improvement in ease of taking medications with tablets (56.7% vs 83.3%; P = .021). No change was observed in CES-D. Tolerability improved in 47%. Reported diarrhea (grade 2) was higher during SGC (33.3% vs3.3%; P = .004). Quality-of life measures, tolerability, and diarrhea improved with the LPV/r tablet formulation compared to SGC in HIV-positive patients not receiving other antiretroviral therapy (ART). PMID- 20841440 TI - Seroprevalence of HIV, hepatitis B, and syphilis among pregnant women at the general hospital, Guatemala City, 2005-2009. AB - BACKGROUND: sexually transmitted infection (STI) screening in pregnancy provides an excellent opportunity for secondary prevention. OBJECTIVE: to document the epidemiology of HIV, hepatitis B, and syphilis among pregnant women at a Guatemalan national hospital. RESULTS: from 2004 to 2009, 118 (0.76%) of 15 563 of women tested in the prenatal clinic had HIV infection, 29 (0.22%) of 13 028 women tested had hepatitis B virus infection, and 78 (0.60%) of 13 027 had a positive test for syphilis. From August 1, 2007 through December 31, 2009, 29 482 women were tested in the obstetrical emergency room. A total of 63 were HIV positive (0.21%), 48 had hepatitis B (0.16%), and 196 had syphilis (0.66%). Of the 9196 births between August 2007 and July of 2008, 33 (0.36%) were to HIV infected mothers. CONCLUSION: these 3 STIs were uncommon in our population and did not increase in incidence during the study period. HIV maternal-to-child transmission (MTCT) prevention programs were feasible in our setting. PMID- 20841441 TI - HIV-associated histoplasmosis in a nonendemic area of the United States during the HAART era: role of migration from endemic areas and lack of antiretroviral therapy. AB - Histoplasmosis is known to be an AIDS-associated infection, with scattered areas of endemicity throughout the world. Although the Atlanta, GA, metropolitan area is not a highly endemic area, a significant number of cases have been noted at our institution in recent years. Cases of histoplasmosis over a 4-year period were reviewed. All 27 patients (100%) were HIV infected. Thirty percent of patients with histoplasmosis were from Latin American countries. Patients from Latin America were younger than patients from the United States, tended to be more likely to have proven disease, and were exclusively male. Patients with proven disease had significantly higher urine histoplasma antigen levels, lower platelets counts, and lower neutrophil counts than patients with probable disease. The majority of patients survived after treatment with antifungals and initiation of antiretroviral therapy. Histoplasmosis is thus an important consideration in the workup of patients with advanced HIV in nonendemic areas of the United States. PMID- 20841442 TI - Changes in gait symmetry and velocity after stroke: a cross-sectional study from weeks to years after stroke. AB - BACKGROUND: There is little information about the quality of gait in the years following stroke. Long-term changes in mobility, using global indices of function, suggest a decline well after initial rehabilitation. However, global indices of mobility do not reveal more specific changes in walking competency or underlying gait-specific impairment. OBJECTIVES: The authors used a cross sectional design with gait-specific measures (velocity and symmetry) to investigate whether deterioration in gait occurs over the long term poststroke. METHODS: Data were abstracted from a standardized database containing clinical assessments and spatiotemporal gait analyses for 171 individuals with stroke. Velocity and 3 expressions of symmetry ratios (swing time, stance time, and step length) were calculated for each individual; they were then assigned to 1 of the 5 following groups: 0 to 3, 3 to 12, 12 to 24, 24 to 48, and >48 months poststroke. RESULTS: Swing time, stance time, and step length symmetry demonstrated a systematic linear trend toward greater asymmetry in groups in the later stages poststroke, whereas velocity, neurological deficit, and lower extremity (LE) motor impairment did not. CONCLUSIONS: The quality of gait, as measured by spatial and temporal symmetry, appears to worsen in later years. These results suggest a dissociation between quantitative measures of gait, such as velocity versus symmetry, and that these parameters may measure independent features. A longitudinal study is needed to confirm the presence and to interpret the clinical meaning of a long-term decline in specific parameters of poststroke gait. PMID- 20841443 TI - Review of chronic graft-versus-host disease in children after allogeneic stem cell transplantation: nursing perspective. AB - This review presents a summary of the research literature related to the incidence and risk factors for chronic graft-versus-host disease in children following allogeneic hematopoietic stem cell transplantation. The range of incidence of chronic graft-versus-host disease in children found in this review was large, from 0% to 46%. Incidence of chronic graft-versus-host disease was influenced by sample size, time posttransplantation, and stem cell source. Characteristics of the person (eg, child's age and gender) and disease/treatment (eg, sources of transplant) are associated with chronic graft-versus-host disease in children after stem cell transplantation. Person and disease/treatment characteristics provide a framework for understanding the factors associated with chronic graft-versus-host disease symptom experiences in children after stem cell transplantation. Timely assessment of presenting chronic graft-versus-host disease symptoms is critical for treatment and prognosis. Nursing interventions should focus on educating children and parents about the signs and symptoms of chronic graft-versus-host disease. The summary of supportive nursing care for children with chronic graft-versus-host disease provides important information to tailor effective management strategies for children with chronic graft-versus host disease. PMID- 20841444 TI - A multidisciplinary approach to determine heparin dosing in pediatric vascular devices. AB - In the health care community, nurses are important agents of change and vehicles for improvements in clinical practice and policy. Pediatric nurses empowered with the tools of evidence-based practice and clinical expertise collaborated in 2007 with other health care professionals to make changes in clinical practice for pediatric patients with vascular access devices (VADs). Nurses recognized that there was a need for a change in the heparinization policy for children with short- and long-term VADs. Data were methodically collected over a 1-year period on 500 VAD. Data collection demonstrated a range of VAD volumes that did not exceed 2 mL. The group analysis of the results gave support for changes in the volumes needed for heparinization. Establishment of appropriate heparin dosing based on scientific data led to a decrease in heparin used to maintain pediatric VAD patency and aided in lowering the risk of side effects in patients. PMID- 20841445 TI - Professional caregivers' perceptions of providing information to parents of children with cancer. AB - Information has been described as a critical part of the care for parents of children with cancer, but not much is known about how caregivers makes decisions about informing parents. This study aims to illuminate professional caregivers' perceptions of providing information to parents of children with cancer. Twenty caregivers at a Swedish pediatric oncology ward participated in four focus group interviews. The interviews were transcribed verbatim and subjected to qualitative content analysis. Two themes were found: Matching the amount of information to the parents' needs concerned situations where the amount of information provided according to the caregivers' assessment is deemed too small, appropriate, or too large. Navigating through a vague structure dealt with a disrupted setting, unclear responsibilities within the team, difficult timing, unintelligible information, and underused tools for communication. Implications for intervention development are discussed. PMID- 20841446 TI - A narrative review summarizing the state of the evidence on the health-related quality of life among childhood cancer survivors. AB - This narrative review summarizes the state of the evidence about the phenomenon of health-related quality of life (HRQOL) among survivors of childhood cancer. A major strength of the state of the evidence on the HRQOL among survivors of childhood cancer is the availability and quality of the data generated from the Childhood Cancer Survivor Study (CCSS). Findings from most studies find comparable levels of HRQOL among survivors and constructed cohort samples; however, a poorer level of HRQOL exists among female survivors. Factors that predict a lower or poorer level of HRQOL among survivors include age at diagnosis, age attained, time since diagnosis, socioeconomic status (education level, household income, and employment status), physical role functioning, and health insurance. Those survivors who received cranial radiation, especially survivors of central nervous system tumors, are at an increased risk for poorer HRQOL and long-term negative effects. PMID- 20841447 TI - A glimpse into the lives of 3 children: their cancer journey. AB - Three stories of children with advanced cancer are presented in this article. The goal was to ascertain what these children were experiencing and thinking as well as what interventions were helpful. Interviews used open-ended questions as well as the Memorial Symptom Assessment Scale, Symptom Management Record, the Body Outline, Child Depression Inventory, Revised Children's Manifest Anxiety Scale, Pediatric Quality of Life Inventory, Common Toxicity Criteria, Lansky's Play Performance Scale, and Spirituality quality of life (QOL) and provided an opportunity for the children to describe their symptoms and QOL. The findings illustrated that the child's social, psychological, and spiritual concerns are important for nurses to address along with the child's physical needs. PMID- 20841448 TI - Weight gain by hyperalimentation elevates C-reactive protein levels but does not affect circulating levels of adiponectin or resistin in healthy subjects. AB - OBJECTIVE: Increase of resistin and/or reduction of adiponectin have been implicated in the development of insulin resistance following weight gain. We aimed to study this prospectively in humans. DESIGN: Prospective and interventional with parallel control group. METHODS: Twelve healthy men and six healthy women (age 26 +/- 6.6 years) and an age-matched control group were recruited. Subjects in the intervention group aimed for a bodyweight increase of 5-15% by doubling the baseline caloric intake by eating at least two fast food based meals a day in combination with adoption of a sedentary lifestyle for 4 weeks. RESULTS: Bodyweight increased from 67.6 +/- 9.1 to 74.0 +/- 11 kg, P<0.001, by the intervention. Insulin levels increased (before: 27.4 +/- 12 pmol/l, after: 53.0 +/- 22 pmol/l, P=0.004), while plasma levels of adiponectin (before: 5038 +/- 3736 ng/ml, after: 6739 +/- 7949 ng/ml, P=0.18) and resistin (before: 21.8 +/- 19 ng/ml, after: 14.4 +/- 6.8 ng/ml, P=0.074) remained unchanged by the weight gain and were similar as in controls. On the other hand, leptin levels increased about threefold following the intervention (before: 5.7 +/- 7.4, after: 16 +/- 20 ng/ml, P=0.008), and also the inflammatory marker C reactive protein (CRP) increased from 0.34 +/- 0.44 to 0.71 +/- 0.87 mg/l, P=0.03, when two outliers >10 mg/l were disregarded. CONCLUSIONS: Hyperalimentation reduces insulin sensitivity when weight gain of 9% was combined with reduction of exercise. However, the levels of resistin and adiponectin were unaffected by the intervention, while CRP levels increased within this short time period suggesting that low-grade inflammation can occur early in the process of developing a metabolic syndrome. PMID- 20841449 TI - Correlation between leptin level and hypertension in normal and obese pre- and postmenopausal women. AB - OBJECTIVE: The present study was aimed at evaluating the correlation between leptin and hypertension in normal and obese hypertensive pre- (Pre-M) and postmenopausal (Post-M) women of Jalandhar city (Punjab, India). DESIGN: For the present study, 78 Pre-M and Post-M women were recruited in four categories as follows: i) normal normotensive, ii) obese normotensive, iii) normal hypertensive, and iv) obese hypertensive. Body mass index was considered as the index of obesity. Guidelines given by JNC-VII were followed for the assessment of hypertension. Leptin was assayed by sandwich ELISA, and estradiol (E(2)) was assayed by competitive ELISA. RESULTS: Leptin level was found to be significantly higher in normal Pre-M women (P<0.02) than that of normal Post-M women. Obese subjects had significantly higher leptin level (P<0.001) than the normal women. In the case of hypertensive subjects, leptin level was significantly higher than that of normotensive counterparts. E(2) level was found significantly lower in Post-M women (P<0.001) than that of Pre-M women as well as in hypertensive women than that of normotensive subjects. A positive correlation was observed between blood pressure (BP) and leptin, but significant association was observed in hypertensive normal and obese Pre-M and Post-M women only. CONCLUSION: It is concluded from the present findings that leptin contributes to the regulation of BP in hypertensive normal as well as in the obese Pre-M and Post-M women. So, leptin may be a regulator of BP in hypertensive women independent of the degree of obesity and the menopausal status. PMID- 20841450 TI - Glucocorticoid receptor gene haplotypes are not associated with birth anthropometry, blood pressure, glucose and insulin concentrations, and body composition in subjects born small for gestational age. AB - OBJECTIVE: Smaller size at birth has been associated with an increased risk of metabolic and cardiovascular disorders in adult life. Fetal programming of the hypothalamic-pituitary-adrenal axis has been suggested as a possible explanation. Fetal glucocorticoid (GC) overexposure has effects that suggest a role of GCs in this programming. The effects of GCs are mediated through the GC receptor (GR or NR3C1). Several functional polymorphisms have been described, which are associated with relative GC resistance or hypersensitivity. Our aim is to compare frequencies of GR haplotypes, characterized by the R23K, N363S, Bcl1, or 9beta polymorphisms, in subjects born small for gestational age (SGA) and associate birth anthropometry data, response to GH treatment, blood pressure, glucose and insulin concentrations, and body composition with these haplotypes. DESIGN: In total, 418 SGA subjects and 697 healthy controls were enrolled in this study. Methods Anthropometry data were obtained, as well as blood samples to determine fasting glucose and insulin concentrations. Dual energy X-ray absorptiometry scans were used to measure the amount of fat and lean mass. RESULTS: No differences were found between GR haplotype frequencies in SGA children compared with healthy controls. No associations were found between GR haplotypes and birth length and birth weight, growth response during GH treatment, blood pressure, glucose and insulin concentrations, and body composition. CONCLUSION: GR haplotypes and their effect on GC sensitivity do not seem to play a significant role in GH-induced catch-up growth and the risk factors of developing metabolic and cardiovascular disorders in adult life of SGA children. PMID- 20841451 TI - The dynamics of embolism repair in xylem: in vivo visualizations using high resolution computed tomography. AB - Water moves through plants under tension and in a thermodynamically metastable state, leaving the nonliving vessels that transport this water vulnerable to blockage by gas embolisms. Failure to reestablish flow in embolized vessels can lead to systemic loss of hydraulic conductivity and ultimately death. Most plants have developed a mechanism to restore vessel functionality by refilling embolized vessels, but the details of this process in vessel networks under tension have remained unclear for decades. Here we present, to our knowledge, the first in vivo visualization and quantification of the refilling process for any species using high-resolution x-ray computed tomography. Successful vessel refilling in grapevine (Vitis vinifera) was dependent on water influx from surrounding living tissue at a rate of 6 * 10(-4) MUm s(-1), with individual droplets expanding over time, filling vessels, and forcing the dissolution of entrapped gas. Both filling and draining processes could be observed in the same vessel, indicating that successful refilling requires hydraulic isolation from tensions that would otherwise prevent embolism repair. Our study demonstrates that despite the presence of tensions in the bulk xylem, plants are able to restore hydraulic conductivity in the xylem. PMID- 20841452 TI - The influence of fruit load on the tomato pericarp metabolome in a Solanum chmielewskii introgression line population. AB - It has been recently demonstrated, utilizing interspecific introgression lines of tomato, generated from the cross between Solanum lycopersicum and the wild species Solanum pennellii, that the efficiency of photosynthate partitioning exerts a considerable influence on the metabolic composition of tomato fruit pericarp. In order to further evaluate the influence of source-sink interaction, metabolite composition was determined by gas chromatography-mass spectrometry in a different population. For this purpose, we used 23 introgression lines resulting from an interspecific cross between S. lycopersicum and the wild species Solanum chmielewskii under high (unpruned trusses) and low (trusses pruned to one fruit) fruit load conditions. Following this strategy, we were able to contrast the metabolite composition of fruits from plants cultivated at both fruit loads as well as to compare the network behavior of primary metabolism in the introgression line population. The study revealed that while a greater number of metabolic quantitative trait loci were observed under high fruit load (240) than under low fruit load (128) cultivations, the levels of metabolites were more highly correlated under low fruit load cultivation. Finally, an analysis of genotype * fruit load interactions indicated a greater influence of development and cultivation than genotype on fruit composition. Comparison with previously documented transcript profiles from a subset of these lines revealed that changes in metabolite levels did not correlate with changes in the levels of genes associated with their metabolism. These findings are discussed in the context of our current understanding of the genetic and environmental influence on metabolic source-sink interactions in tomato, with particular emphasis given to fruit amino acid content. PMID- 20841453 TI - Pea chloroplast DnaJ-J8 and Toc12 are encoded by the same gene and localized in the stroma. AB - Toc12 is a novel J domain-containing protein identified in pea (Pisum sativum) chloroplasts. It was shown to be an integral outer membrane protein localizing in the intermembrane space of the chloroplast envelope. Furthermore, Toc12 was shown to associate with an intermembrane space Hsp70, suggesting that Toc12 is important for protein translocation across the chloroplast envelope. Toc12 shares a high degree of sequence similarity with Arabidopsis (Arabidopsis thaliana) DnaJ J8, which has been suggested to be a soluble protein of the chloroplast stroma. Here, we isolated genes encoding DnaJ-J8 from pea and found that Toc12 is a truncated clone of one of the pea DnaJ-J8s. Protein import analyses indicate that Toc12 and DnaJ-J8s possess a cleavable transit peptide and are localized in the stroma. Arabidopsis mutants with T-DNA insertions in the DnaJ-J8 gene show no defect in chloroplast protein import. Implications of these results in the energetics and mechanisms of chloroplast protein import are discussed. PMID- 20841455 TI - Protein association and dissociation regulated by extension peptide: a mode for iron control by phytoferritin in seeds. AB - Most of the iron in legume seeds is stored in ferritin located in the amyloplast, which is used during seed germination. However, there is a lack of information on the regulation of iron by phytoferritin. In this study, soluble and insoluble forms of pea (Pisum sativum) seed ferritin (PSF) isolated from dried seeds were found to be identical 24-mer ferritins comprising H-1 and H-2 subunits. The insoluble form is favored at low pH, whereas the two forms reversibly interconvert in the pH range of 6.0 to 7.8, with an apparent pK(a) of 6.7. This phenomenon was not observed in animal ferritins, indicating that PSF is unique. The pH of the amyloplast was found to be approximately 6.0, thus facilitating PSF association, which is consistent with the role of PSF in long-term iron storage. Similar to previous studies, the results of this work showed that protein degradation occurs in purified PSF during storage, thus proving that phytoferritin also undergoes degradation during seedling germination. In contrast, no degradation was observed in animal ferritins, suggesting that this degradation of phytoferritin may be due to the extension peptide (EP), a specific domain found only in phytoferritin. Indeed, removal of EP from PSF significantly increased protein stability and prevented degradation under identical conditions while promoting protein dissociation. Correlated with such dissociation was a considerable increase in the rate of ascorbate-induced iron release from PSF at pH 6.0. Thus, phytoferritin may have facilitated the evolution of EP to enable it to regulate iron for storage or complement in seeds. PMID- 20841454 TI - High-throughput confocal imaging of intact live tissue enables quantification of membrane trafficking in Arabidopsis. AB - Membrane compartmentalization and trafficking within and between cells is considered an essential cellular property of higher eukaryotes. We established a high-throughput imaging method suitable for the quantitative detection of membrane compartments at subcellular resolution in intact epidermal tissue. Whole Arabidopsis (Arabidopsis thaliana) cotyledon leaves were subjected to quantitative confocal laser microscopy using automated image acquisition, computational pattern recognition, and quantification of membrane compartments. This revealed that our method is sensitive and reliable to detect distinct endomembrane compartments. We applied quantitative confocal laser microscopy to a transgenic line expressing GFP-2xFYVE as a marker for endosomal compartments during biotic or abiotic stresses, and detected markedly quantitative adaptations in response to changing environments. Using a transgenic line expressing the plasma membrane-resident syntaxin GFP-PEN1, we quantified the pathogen-inducible extracellular accumulation of this fusion protein at fungal entry sites. Our protocol provides a platform to study the quantitative and dynamic changes of endomembrane trafficking, and potential adaptations of this machinery to physiological stress. PMID- 20841456 TI - Diagnostic ultrasound patterns of parotid glands in human immunodeficiency virus positive patients in Mulago, Uganda. AB - OBJECTIVES: The purpose of this study was to determine sonographically, in parotid glands of human immunodeficiency virus-positive patients, the condition of glands with or without enlargement, and propose a classification system for the patterns observed using diagnostic ultrasound imaging. METHODS: In this prospective clinical study, ultrasound scans were performed on 200 patients aged 4-62 years at Mulago Hospital, Uganda. RESULTS: There were four main distinct ultrasound pathological patterns in the parotids, i.e. lymphocytic aggregations (LAs), lymphoepithelial cysts (LECs), fatty infiltration (FI) and lymphadenopathy only. There were additional subdivisions depending on the presence of echogenic foci and intraparotid lymphadenopathy. Of those patients (n = 64) without parotid enlargement, only 8% showed normal ultrasound features, whereas 34% showed LECs and 31% showed LAs. Of those (n = 136) with parotid enlargement, 46% showed LECs, 23% showed FI and 15% showed LAs. The overall prevalence of LECs in the study sample was 42%. LECs were multiple, mainly between 7 mm and 12 mm in diameter and 26% showed internal echogenic foci either mobile or stationary. In contrast, LAs tended to be ill-defined, less than 5 mm and were not associated with posterior acoustic enhancement. Features differentiating LAs from LECs have not been previously described. Parotid FI (lipodystrophy) was noted in patients on highly active antiretroviral therapy, who showed lesser prevalence of LECs after 12 months of treatment. CONCLUSIONS: Our study of 200 patients is probably the largest such study in the English language literature. The wide spectrum of diagnostic ultrasound patterns was categorized into four main groups (ten subgroups). PMID- 20841457 TI - Sensitivity analysis for plane orientation in three-dimensional cephalometric analysis based on superimposition of serial cone beam computed tomography images. AB - OBJECTIVES: The purpose of this study was to evaluate the potential errors associated with superimposition of serial cone beam CT (CBCT) images utilizing reference planes based on cranial base landmarks using a sensitivity analysis. METHODS: CBCT images from 62 patients participating in a maxillary expansion clinical trial were analysed. The left and right auditory external meatus (AEM), dorsum foramen magnum (DFM) and the midpoint between the left and right foramen spinosum (ELSA) were used to define a three-dimensional (3D) anatomical reference co-ordinate system. Intraclass correlation coefficients for all four landmarks were obtained. Transformation of the reference system was carried out using the four landmarks and mathematical comparison of values. RESULTS: Excellent intrareliability values for each dimension were obtained for each landmark. Evaluation of the method to transform the co-ordinate system was first done by comparing interlandmark distances before and after transformations, giving errors in lengths in the order of 10-14% (software rounding error). A sensitivity evaluation was performed by adding 0.25 mm, 0.5 mm and 1 mm error in one axis of the ELSA. A positioning error of 0.25 mm in the ELSA can produce up to 1.0 mm error in other cranial base landmark co-ordinates. These errors could be magnified to distant landmarks where in some cases menton and infraorbital landmarks were displaced 4-6 mm. CONCLUSIONS: Minor variations in location of the ELSA, both the AEM and the DFM landmarks produce large and potentially clinically significant uncertainty in co-ordinate system alignment. PMID- 20841458 TI - The relation between bone mineral density in the heel and pixel intensity in the mandibular jaw bone among elderly women. AB - OBJECTIVES: The purpose of this study was to investigate the correlation between pixel intensity (PI) in digital radiographs of the lower jaw and bone mineral density (BMD) in the heels of post-menopausal women (as measured with DXL, a combination of dual energy X-ray absorptiometry and lasers). METHODS: Two intraoral periapical digital radiographs were taken in the right and left mandible premolar region, and the digital images were analysed by a computer program (Dimaxis) regarding PI. As the radiographs were taken, the BMD of the patient's left heel was measured via a portable Calscan device. The patient answered a questionnaire concerning risk factors. The correlation between variables was analysed using statistical tests. RESULTS: A significant correlation was found between the PI in the left (P = 0.001) and right (P = 0.004) mandible and the BMD of the left heel for the whole group. A pronounced correlation was found to exist for women > 70 years old. Based on a cut-off value of the PI, to differentiate between healthy individuals and those who required further analysis for osteoporosis, the following values were obtained: sensitivity 0.74, specificity 0.50, positive predictive value 0.77 and negative predictive value 0.46. CONCLUSION: A positive correlation was found between PI in digital radiographs of the mandible and the BMD of the heel. The low predictive value does not allow any definite conclusions to be drawn from the present study. A reasonable recommendation could be for future studies to employ a larger study population to explore the effect on this value. PMID- 20841459 TI - Influence of a programme of professional calibration in the variability of landmark identification using cone beam computed tomography-synthesized and conventional radiographic cephalograms. AB - OBJECTIVES: The validity of any measurement obtained through a cephalogram largely depends on the reproducibility of the cephalometric landmarks. The purpose of this study is to evaluate the influence of a programme of professional calibration (PPC) on the variability of landmark identification comparing conventional radiographs and cone beam CT (CBCT)-synthesized cephalograms. METHODS: 5 graduate students in oral radiology identified 20 cephalometric landmarks from cephalograms generated from conventional radiographs (RADs), Ray Sum CBCT-synthesized cephalograms (CBTs) and half-skull CBT (HSTs) from 10 patients. After a period of reinforcement on instruction and calibration with inter- and intraexaminer assessment of reproducibility (intraclass coefficient correlation scores > 0.75) for RADs, CBTs and HSTs obtained from 5 different patients, observers were asked to repeat the analysis of the first 10 patients under the same circumstances. Values in millimetres represented each landmark in a table of Cartesian co-ordinates (x- and y-axes). RESULTS: ANOVA showed significant reduction in variability levels after the PPC, and there were no differences among the methods of image acquisition. Repeated measures ANOVA indicated that the PPC accounted for reduction in variability levels in 14 of 20 landmarks. CONCLUSIONS: The results suggest that a PPC has more influence than the type of image acquisition on variability of landmark identification based on two-dimensional cephalometric analysis. Cephalograms obtained from RAD or CBCT can be considered equivalent for clinical and experimental applications. PMID- 20841460 TI - Perception of anatomical structures in digitally filtered and conventional panoramic radiographs: a clinical evaluation. AB - OBJECTIVES: The aims of the study were to compare subjective image quality of clinical images obtained with a storage phosphor plate (SPP)-based digital and conventional film-based panoramic system for the visualization of various anatomical structures and to evaluate the effect of various processing algorithms on image interpretation. METHODS: Panoramic radiographs were taken in 42 patients both with film and with a SPP system. SPP images were treated with shadow, sharpen, negative, greyscale sigma and greyscale exponential filters. Four observers subjectively evaluated films and unfiltered and filtered SPP images for the visibility of anatomical structures with various radiodensities as well as for overall image quality on a three-point rating scale. The statistical methods used were Kruskal-Wallis, odds ratio analysis and Cohen's kappa. RESULTS: No statistically significant difference was found between film and unfiltered digital images except for low-contrast structures (P > 0.05). Film images were preferred for the visibility of low-contrast structures (P < 0.05). Best overall image quality was obtained with sharpened images (P < 0.05) followed by films and unfiltered digital images. Among all filtered images, sharpened ones received the highest ratings for the visibility of all anatomical structures (P < 0.05). The intra- and interobserver agreement ranged between moderate and substantial and between fair and moderate, respectively. CONCLUSIONS: Film and unfiltered SPP based panoramic images performed equally well in terms of overall quality; however, films were best for the perception of low-contrast structures. The sharpening filter may be recommended for enhancing SPP panoramic images to improve the visual perception of most of the anatomical structures as well as overall quality. PMID- 20841461 TI - Comparison of digital systems and conventional dental film for the detection of approximal enamel caries. AB - OBJECTIVES: The aims of this study were (1) to compare the accuracy of the detection of approximal enamel caries lesions using three intraoral storage phosphor plate digital systems and one conventional film-based radiographic system; and (2) to determine whether there is a correlation between the histological and radiographic measurements of enamel caries. METHODS: 160 approximal surfaces were radiographed under standardized conditions using three storage phosphor stimulable systems (DenOptix and Digora FMX with white and blue plates), and one film system (Insight film). 17 observers scored the images for the presence and depth of caries using a 4-point scale. The presence of caries was validated histologically (gold standard). Two-way analysis of variance was used to test the differences in sensitivity, specificity and overall accuracy (TP + TN). The data from the radiographic and histological measurements were statistically analysed by Spearman's rank correlation coefficient. RESULTS: Two way analysis of variance and the post hoc t-test demonstrated that Digora (white plate) had higher specificity and overall accuracy values than DenOptix (P = 0.021); there was no statistically significant difference among the other imaging modalities (P > 0.05). There was no significant correlation between the histological depth measurements and the radiographic measurements from Digora (blue plate) (P = 0.43), Digora (white plate) (P = 0.15), DenOptix (P = 0.17) and Insight film (P = 0.06). CONCLUSIONS: The results suggest that (1) the performance of the three storage phosphor image plate systems was similar to that of the Insight film for detection of approximal enamel caries, and (2) the increase in histological depth of enamel caries was not significantly correlated with radiographic measurements. PMID- 20841462 TI - Mutagenicity and cytotoxicity assessment in patients undergoing orthodontic radiographs. AB - OBJECTIVES: The aim of the present study was to evaluate DNA damage (micronucleus) and cellular death (pyknosis, karyolysis and karyorrhexis) in exfoliated buccal mucosa cells from individuals following radiography. METHODS: Lateral and frontal cephalometric X-ray and panoramic dental X-rays were taken of a total of 18 healthy patients (6 male and 12 female) referred for orthodontic therapy. Exfoliated oral mucosa cells were collected immediately before X-ray exposure and after 10 days. RESULTS: The results revealed no statistically significant difference (P > 0.05) in the frequency micronucleated oral mucosa cells after X-ray exposure. However, X-ray was able to increase other nuclear alterations closely related to cytotoxicity, such as karyorrhexis, pyknosis and karyolysis. CONCLUSIONS: Data indicated that exposure to certain radiography may not be a factor in inducing chromosomal damage, but it does promote cytotoxicity. PMID- 20841463 TI - Establishment of temporomandibular joint puncture technique in rats using in vivo micro-computed tomography (R_mCT(r)). AB - The aim of the report was to establish puncture techniques for the temporomandibular joint (TMJ) cavity in rats. The experimental sample comprised 30 male Sprague-Dawley rats. Under general anaesthesia the superior joint cavity of the rat was punctured either laterally (lateral puncture technique (LPT), n = 11), anteriorly (anterosuperior puncture technique (ASPT), n = 13) or anteroinferior puncture technique (AIPT), n = 6) using a 27-gauge needle. After the tip of the needle was confirmed by micro-CT (R-mCT(r), Rigaku, Tokyo, Japan) located on the mandibular fossa, 0.05 ml of contrast media was injected under micro-CT fluoroscopic guidance. After confirmation that the joint cavity was filled with contrast media, micro-CT imaging was carried out. The puncture for LPT was accurate in 5 of the 11 animals. The ASPT was accurate in all 13 animals. The AIPT punctured 3 of the 6 animals. Furthermore, the ASPT and AIPT demonstrated improved preservation of the needle; it was harder to detach the needle, which led to greater stability. These results suggest that ASPT assisted by R-mCT(r) is useful for basic research, including drug discovery and pathogenesis of TMJ diseases. PMID- 20841464 TI - Congenital angiomyoma of the tongue: case report. AB - Angiomyomas of the oral cavity are rare benign vascular neoplasms. In particular, the congenital form has not been reported before in the English language literature. We present a congenital angiomyoma of the tongue that was found on the posterior middle of the tongue in an infant. On MRI, the mass showed an isointense signal to muscle on the T1 weighted image and a slightly hyperintense signal on the T2 weighted image. Immunohistochemically, tumour cells were positive to desmin and smooth muscle actin, but negative to vimentin and S100. The treatment was surgical excision and no recurrence was found during the 26 month follow-up period. PMID- 20841465 TI - Ameloblastic carcinoma of the mandible with metastasis to the skull and lung: advanced imaging appearance including computed tomography, magnetic resonance imaging and positron emission tomography computed tomography. AB - Ameloblastic carcinoma is a very rare malignant odontogenic tumour with characteristic histopathological and clinical features, which requires aggressive surgical treatment and surveillance and, therefore, differs from ameloblastoma. Metastasis typically occurs in the lung. Only one patient with metastasis to the skull has previously been described and no prior case reports have presented MRI and positron emission tomography-CT (PET-CT) imaging findings. We describe a case of ameloblastic carcinoma with metastasis to the skull and lung with emphasis on imaging features including MRI and PET-CT. PMID- 20841467 TI - ASKing the kids: how children view their abilities after perinatal stroke. AB - A total of 19 children with a history of perinatal stroke were asked how they saw their own motor abilities and disabilities using the Activities Scale for Kids (ASK) performance and capability questionnaires. The median ASK performance score was significantly lower (86.7) than the median ASK capability score (93.4; P = .03), suggesting children felt they were not doing everything they were capable of doing. Performance and capability total scores were not associated with gender or stroke type; lower performance and capability scores were associated with cerebral palsy. Within groups, performance scores were significantly lower than capability scores in girls (P = .02), children with presumed perinatal stroke (P = .02), children with unilateral stroke (P = .02), and children with large versus small branch unilateral middle cerebral artery stroke (P = .03). Further work is needed to understand why these children's performance does not match perceived capability. PMID- 20841468 TI - Activation of murine double minute 2 by Akt in mammary epithelium delays mammary involution and accelerates mammary tumorigenesis. AB - Amplification or overexpression of murine double minute 2 (MDM2) promotes a variety of human tumors by degrading tumor suppressor proteins such as p53. Phosphorylation of MDM2 on Ser(166) and Ser(186) by the survival kinase Akt inhibits p53-mediated apoptosis. However, it is unclear whether this pathway contributes to normal or malignant pathophysiology in vivo. To address these questions, we generated transgenic mice expressing the Akt-phosphorylated form of MDM2 (MDM2DDS166D/S186D) in the mammary epithelium. Activation of MDM2 delayed mammary gland involution and accelerated tumor progression in mouse mammary tumor virus/neu transgenic mice by inhibiting apoptosis in a manner associated with decreased p53 expression. Our findings offer in vivo evidence that activation of MDM2 by Akt contributes to mammary development and tumorigenesis. PMID- 20841469 TI - Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells. AB - Loss of NM23-H1 expression correlates with the degree of metastasis and with unfavorable clinical prognosis in several types of human carcinoma. However, the mechanistic basis for the metastasis suppressor function of NM23-H1 is obscure. We silenced NM23-H1 expression in human hepatoma and colon carcinoma cells and methodologically investigated effects on cell-cell adhesion, migration, invasion, and signaling linked to cancer progression. NM23-H1 silencing disrupted cell-cell adhesion mediated by E-cadherin, resulting in beta-catenin nuclear translocation and T-cell factor/lymphoid-enhancing factor-1 transactivation. Further, NM23-H1 silencing promoted cellular scattering, motility, and extracellular matrix invasion by promoting invadopodia formation and upregulating several matrix metalloproteinases (MMP), including membrane type 1 MMP. In contrast, silencing the related NM23-H2 gene was ineffective at promoting invasion. NM23-H1 silencing activated proinvasive signaling pathways involving Rac1, mitogen-activated protein kinases, phosphatidylinositol 3-kinase (PI3K)/Akt, and src kinase. Conversely, NM23-H1 was dispensable for cancer cell proliferation in vitro and liver regeneration in NM23-M1 null mice, instead inducing cellular resistance to chemotherapeutic drugs in vitro. Analysis of NM23-H1 expression in clinical specimens revealed high expression in premalignant lesions (liver cirrhosis and colon adenoma) and the central body of primary liver or colon tumors, but downregulation at the invasive front of tumors. Our findings reveal that NM23-H1 is critical for control of cell-cell adhesion and cell migration at early stages of the invasive program in epithelial cancers, orchestrating a barrier against conversion of in situ carcinoma into invasive malignancy. PMID- 20841470 TI - Anti-alphav integrin monoclonal antibody intetumumab enhances the efficacy of radiation therapy and reduces metastasis of human cancer xenografts in nude rats. AB - We previously reported that intetumumab (CNTO 95), a fully human anti-alphav integrin monoclonal antibody, is a radiosensitizer in mice with xenograft tumors. Because intetumumab does not cross-react with mouse integrins, but has cross reactivity with rat integrins, we next studied the potential combined use of radiation therapy and intetumumab in human cancer xenograft models in nude rats to assess effects on both tumor cells and the tumor microenvironment. Nude rats bearing human head and neck cancer and non-small cell lung cancer (NSCLC) xenografts were treated with intetumumab and fractionated local tumor radiotherapy. Effects on tumor growth and metastasis, blood perfusion, oxygenation, and gastrointestinal toxicity were studied. Intetumumab alone had a moderate effect on tumor growth. When combined with fractionated radiation therapy, intetumumab significantly inhibited tumor growth and produced a tumor response rate that was significantly better than with radiation therapy alone. Treatment with intetumumab also significantly reduced lung metastasis in the A549 NSCLC xenograft model. The oxygenation and blood perfusion in xenograft tumors measured by microbubble-enhanced ultrasound imaging were substantially increased after treatment with intetumumab. The combined use of intetumumab and radiation therapy reduced the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. Toxicity studies showed that treatment with intetumumab did not cause the histopathologic changes in the lungs and did not sensitize the sensitive gastrointestinal epithelium to the effect of radiation therapy. Intetumumab can potentiate the efficacy of fractionated radiation therapy in human cancer xenograft tumors in nude rats without increased toxicity. PMID- 20841471 TI - Zoledronic acid as a new adjuvant therapeutic strategy for Ewing's sarcoma patients. AB - Ewing's sarcoma (ES) is the second most frequent pediatric bone tumor also arising in soft tissues (15% of cases). The prognosis of patients with clinically detectable metastases at diagnosis, not responding to therapy or with disease relapse, is still very poor. Among new therapeutic approaches, bisphosphonates represent promising adjuvant molecules to chemotherapy to limit the osteolytic component of bone tumors and to protect from bone metastases. The combined effects of zoledronic acid and mafosfamide were investigated on cell proliferation, viability, apoptosis, and cell cycle distribution of human ES cell lines differing in their p53 and p16/ink4 status. ES models were developed to reproduce both soft tissue and intraosseous tumor development. Mice were treated with 100 MUg/kg zoledronic acid (two or four times per week) and/or ifosfamide (30 mg/kg, one to three cycles of three injections). ES cell lines showed different sensitivities to zoledronic acid and mafosfamide at the cell proliferation level, with no correlation with their molecular status. Both drugs induced cell cycle arrest, but in the S or G(2)M phase, respectively. In vivo, zoledronic acid had no effect on soft tissue tumor progression, although it dramatically inhibited ES development in bone. When combined with ifosfamide, zoledronic acid exerted synergistic effects in the soft tissue model: Its combination with one cycle of ifosfamide resulted in an inhibitory effect similar to three cycles of ifosfamide alone. This very promising result could allow clinicians to diminish the doses of chemotherapy. PMID- 20841472 TI - Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling. AB - Cisplatin is an antineoplastic drug, mostly documented to cause cell death through the formation of DNA adducts. In patients, it exhibits a range of short term side effects that are unlikely to be related to its genomic action. As cisplatin has been shown to modify membrane properties in different cell systems, we investigated its effects on mechanosensitive ion transporters and channels. We show here that cisplatin is a noncompetitive inhibitor of the mechanosensitive Na(+)/H(+) exchanger NHE-1, with a half-inhibition concentration of 30 MUg/mL associated with a decrease in V(max) and Hill coefficient. We also showed that it blocks the Cl(-) and K(+) mechanosensitive channels VSORC and TREK-1 at similar concentrations. In contrast, the nonmechanosensitive Cl(-) and K(+) channels CFTR and TASK-1 and the Na(+)-coupled glucose transport, which share functional features with VSORC, TREK-1, and NHE-1, respectively, were insensitive to cisplatin. We next investigated whether cisplatin action was due to a direct effect on membrane or to cortical actin remodeling that would affect mechanosensors. Using scanning electron microscopy, in vivo actin labeling, and atomic force microscopy, we did not observe any modification of the Young's modulus and actin cytoskeleton for up to 60 and 120 MUg/mL cisplatin, whereas these concentrations modified membrane morphology. Our results reveal a novel mechanism for cisplatin, which affects mechanosensitive channels and transporters involved in cell fate programs and/or expressed in mechanosensitive organs in which cisplatin elicits strong secondary effects, such as the inner ear or the peripheral nervous system. These results might constitute a common denominator to previously unrelated effects of this drug. PMID- 20841474 TI - Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells. AB - The cellular origins from which most tumors arise are poorly defined, especially in mesenchymal neoplasms. Aggressive fibromatosis, also known as desmoid tumor, is a locally invasive soft tissue tumor that has mesenchymal characteristics. We found that aggressive fibromatosis tumors express genes and cell surface markers characteristic of mesenchymal stem cells (MSC). In mice that are genetically predisposed to develop aggressive fibromatosis tumors (Apc(wt/1638N)), we found that the number of tumors formed was proportional to the number of MSCs present. Sca-1(-/-) mice, which develop fewer MSCs, were crossed with Apc(wt/1638N) mice. Doubly mutant mice deficient in Sca-1 developed substantially fewer aggressive fibromatosis tumors than wild-type (WT) littermates, but Sca-1 deficiency had no effect on the formation of epithelial-derived intestinal polyps. MSCs isolated from Apc(wt/1638N) mice (or mice expressing a stabilized form of beta-catenin) induced aberrant cellular growth reminiscent of aggressive fibromatosis tumors after engraftment to immunocompromised mice, but WT cells and mature fibroblasts from the same animals did not. Taken together, our findings indicate that aggressive fibromatosis is derived from MSCs, and that beta-catenin supports tumorigenesis by maintaining mesenchymal progenitor cells in a less differentiated state. Protecting this progenitor cell population might prevent tumor formation in patients harboring a germline APC mutation, where fibromatosis is currently the leading cause of mortality. PMID- 20841473 TI - Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. AB - T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their role in tumor progression is poorly understood. Targeted deletion of the hypoxia-responsive transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although vascular endothelial growth factor-A levels and vascularization were unchanged. Tumor associated macrophages can suppress tumor-infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T cell suppression in vitro in a manner dependent on macrophage expression of HIF 1alpha. Our findings link the innate immune hypoxic response to tumor progression through induction of T-cell suppression in the tumor microenvironment. PMID- 20841475 TI - The role of telomeres and telomerase in cancer research. AB - The fourth AACR Special Conference on The Role of Telomeres and Telomerase in Cancer Research was held February 27 to March 2, 2010 in Fort Worth, TX. The meeting was organized to bring together those interested in the basic molecular mechanisms that govern telomere dynamics and stability with those interested in the clinical implications of telomere dysfunction and the use of telomeres and telomerase as therapeutic targets. The meeting was extremely successful as evidenced by the attendance and quality of the presentations. Indeed, several important themes emerged including (a) the intricate connection between the DNA replication and repair machineries in basic telomere replication and stability, (b) the complex interplay between the telomere-specific shelterin components and DNA repair proteins, (c) the nontelomeric functions of TERT in numerous cell types including stem cells, (d) a growing appreciation for the connection that exists between telomere maintenance deficiency states and diverse conditions such as idiopathic pulmonary fibrosis and hematopoietic malignancies, and (e) the successful progression of agents targeting telomerase directly and immunologically to phase III clinical trials. Evident at the meeting was the vibrant energy that permeates the telomere field and the important biological and medical findings that it continues to yield. PMID- 20841476 TI - Image-based chemical screening identifies drug efflux inhibitors in lung cancer cells. AB - Cancer cells with active drug efflux capability are multidrug resistant and pose a significant obstacle for the efficacy of chemotherapy. Moreover, recent evidence suggests that high drug efflux cancer cells (HDECC) may be selectively enriched with stem-like cancer cells, which are believed to be the cause for tumor initiation and recurrence. There is a great need for therapeutic reagents that are capable of eliminating HDECCs. We developed an image-based high-content screening (HCS) system to specifically identify and analyze the HDECC population in lung cancer cells. Using the system, we screened 1,280 pharmacologically active compounds that identified 12 potent HDECC inhibitors. It is shown that these inhibitors are able to overcome multidrug resistance (MDR) and sensitize HDECCs to chemotherapeutic drugs, or directly reduce the tumorigenicity of lung cancer cells possibly by affecting stem-like cancer cells. The HCS system we established provides a new approach for identifying therapeutic reagents overcoming MDR. The compounds identified by the screening may potentially be used as potential adjuvant to improve the efficacy of chemotherapeutic drugs. PMID- 20841477 TI - ERBB receptor activation is required for profibrotic responses to transforming growth factor beta. AB - Engagement of the transforming growth factor-beta (TGF-beta) receptor complex activates multiple signaling pathways that play crucial roles in both health and disease. TGF-beta is a key regulator of fibrogenesis and cancer-associated desmoplasia; however, its exact mode of action in these pathologic processes has remained poorly defined. Here, we report a novel mechanism whereby signaling via members of the ERBB or epidermal growth factor family of receptors serves as a central requirement for the biological responses of fibroblasts to TGF-beta. We show that TGF-beta triggers upregulation of ERBB ligands and activation of cognate receptors via the canonical SMAD pathway in fibroblasts. Interestingly, activation of ERBB is commonly observed in a subset of fibroblast but not epithelial cells from different species, indicating cell type specificity. Moreover, using genetic and pharmacologic approaches, we show that ERBB activation by TGF-beta is essential for the induction of fibroblast cell morphologic transformation and anchorage-independent growth. Together, these results uncover important aspects of TGF-beta signaling that highlight the role of ERBB ligands/receptors as critical mediators in fibroblast responses to this pleiotropic cytokine. PMID- 20841479 TI - MET and KRAS gene amplification mediates acquired resistance to MET tyrosine kinase inhibitors. AB - The establishment of the role of MET in human cancer has led to the development of small-molecule inhibitors, many of which are currently in clinical trials. Thus far, nothing is known about their therapeutic efficacy and the possible emergence of resistance to treatment, a problem that has been often observed with other receptor tyrosine kinase (RTK) inhibitors. To predict mechanisms of acquired resistance, we generated resistant cells by treating MET-addicted cells with increasing concentrations of the MET small-molecule inhibitors PHA-665752 or JNJ38877605. Resistant cells displayed MET gene amplification, leading to increased expression and constitutive phosphorylation of MET, followed by subsequent amplification and overexpression of wild-type (wt) KRAS. Cells harboring KRAS amplification progressively lost their MET dependence and acquired KRAS dependence. Our results suggest that MET and KRAS amplification is a general mechanism of resistance to specific MET inhibitors given that similar results were observed with two small inhibitors and in different cell lines of different histotypes. To our knowledge, this is the first report showing that overexpression of wt KRAS can overcome the inhibitory effect of a RTK inhibitor. In view of the fact that cellular models of resistance to inhibitors targeting other tyrosine kinases have predicted and corroborated clinical findings, our results provide insights into strategies for preventing and/or overcoming drug resistance. PMID- 20841478 TI - Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients. AB - Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent. PMID- 20841481 TI - Targeting Stat3 in the myeloid compartment drastically improves the in vivo antitumor functions of adoptively transferred T cells. AB - Improving effector T-cell functions is highly desirable for preventive or therapeutic interventions of diverse diseases. Signal transducer and activator of transcription 3 (Stat3) in the myeloid compartment constrains Th1-type immunity, dampening natural and induced antitumor immune responses. We have recently developed an in vivo small interfering RNA (siRNA) delivery platform by conjugating a Toll-like receptor 9 agonist with siRNA that efficiently targets myeloid and B cells. Here, we show that either CpG triggering combined with the genetic Stat3 ablation in myeloid/B cell compartments or administration of the CpG-Stat3siRNA drastically augments effector functions of adoptively transferred CD8+ T cells. Specifically, we show that both approaches are capable of increasing dendritic cell and CD8(+) T-cell engagement in tumor-draining lymph nodes. Furthermore, both approaches can significantly activate the transferred CD8(+) T cells in vivo, upregulating effector molecules such as perforin, granzyme B, and IFN-gamma. Intravital multiphoton microscopy reveals that Stat3 silencing combined with CpG triggering greatly increases killing activity and tumor infiltration of transferred T cells. These results suggest the use of CpG Stat3siRNA, and possibly other Stat3 inhibitors, as a potent adjuvant to improve T-cell therapies. PMID- 20841480 TI - Cancer-related epigenome changes associated with reprogramming to induced pluripotent stem cells. AB - The ability to induce pluripotent stem cells from committed, somatic human cells provides tremendous potential for regenerative medicine. However, there is a defined neoplastic potential inherent to such reprogramming that must be understood and may provide a model for understanding key events in tumorigenesis. Using genome-wide assays, we identify cancer-related epigenetic abnormalities that arise early during reprogramming and persist in induced pluripotent stem cell (iPS) clones. These include hundreds of abnormal gene silencing events, patterns of aberrant responses to epigenetic-modifying drugs resembling those for cancer cells, and presence in iPS and partially reprogrammed cells of cancer specific gene promoter DNA methylation alterations. Our findings suggest that by studying the process of induced reprogramming, we may gain significant insight into the origins of epigenetic gene silencing associated with human tumorigenesis, and add to means of assessing iPS for safety. PMID- 20841482 TI - Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. AB - Urothelial cancer (UC) develops along two different genetic pathways, resulting in noninvasive or invasive tumors. However, it is unknown whether there are also different epigenetic pathways in UC. UC is also characterized by a high rate of recurrence, and the presence of a field defect has been postulated. In this study, we compared the DNA methylation patterns between noninvasive and invasive UC and the DNA methylation patterns between normal-appearing urothelium from bladders with cancer and urothelium from cancer-free bladders. We used the Illumina GoldenGate methylation assay at 1,370 loci in 49 noninvasive urothelial tumors, 38 invasive tumors with matched normal-appearing urothelium, and urothelium from 12 age-matched UC-free patients. We found distinct patterns of hypomethylation in the noninvasive tumors and widespread hypermethylation in the invasive tumors, confirming that the two pathways differ epigenetically in addition to genetically. We also found that 12% of the loci were hypermethylated in apparently normal urothelium from bladders with cancer, indicating an epigenetic field defect. X-chromosome inactivation analysis indicated that this field defect did not result in clonal expansion but occurred independently across the urothelium of bladders with cancer. The hypomethylation present in noninvasive tumors may counterintuitively provide a biological explanation for the failure of these tumors to become invasive. In addition, an epithelium-wide epigenetic defect in bladders with cancer might contribute to a loss of epithelial integrity and create a permissible environment for tumors to arise. PMID- 20841483 TI - Overexpression of the protein tyrosine phosphatase PRL-2 correlates with breast tumor formation and progression. AB - The PRL-1, PRL-2, and PRL-3 phosphatases are prenylated protein tyrosine phosphatases with oncogenic activity that are proposed to drive tumor metastasis. We found that PRL-2 mRNA is elevated in primary breast tumors relative to matched normal tissue, and also dramatically elevated in metastatic lymph nodes compared with primary tumors. PRL-2 knockdown in metastatic MDA-MB-231 breast cancer cells decreased anchorage-independent growth and cell migration, suggesting that the malignant phenotype of these cells is mediated at least in part through PRL-2 signaling. In different mouse mammary tumor-derived cell lines overexpressing PRL 2, we confirmed its role in anchorage-independent growth and cell migration. Furthermore, injection of PRL-2-overexpressing cells into the mouse mammary fat pad promoted extracellular signal-regulated kinase 1/2 activation and tumor formation. MMTV-PRL-2 transgenic mice engineered to overexpress the enzyme in mammary tissue did not exhibit spontaneous tumorigenesis, but they exhibited an accelerated development of mammary tumors initiated by introduction of an MMTV ErbB2 transgene. Together, our results argue that PRL-2 plays a role in breast cancer progression. PMID- 20841484 TI - MicroRNA mediates DNA demethylation events triggered by retinoic acid during neuroblastoma cell differentiation. AB - Neuroblastoma is an often fatal pediatric cancer arising from precursor cells of the sympathetic nervous system. 13-Cis retinoic acid is included in the treatment regimen for patients with high-risk disease, and a similar derivative, all-trans retinoic acid (ATRA), causes neuroblastoma cell lines to undergo differentiation. The molecular signaling pathways involved with ATRA-induced differentiation are complex, and the role that DNA methylation changes might play are unknown. The purpose of this study was to evaluate the genome-wide effects of ATRA on DNA methylation using methylated DNA immunoprecipitation applied to microarrays representing all known promoter and CpG islands. Four hundred and two gene promoters became demethylated, whereas 88 were hypermethylated post-ATRA. mRNA expression microarrays revealed that 82 of the demethylated genes were overexpressed by >2-fold, whereas 13 of the hypermethylated genes were underexpressed. Gene ontology analysis indicated that demethylated and re expressed genes were enriched for signal transduction pathways, including NOS1, which is required for neural cell differentiation. As a potential mechanism for the DNA methylation changes, we show the downregulation of methyltransferases, DNMT1 and DNMT3B, along with the upregulation of endogenous microRNAs targeting them. Ectopic overexpression of miR-152, targeting DNMT1, also negatively affected cell invasiveness and anchorage-independent growth, contributing in part to the differentiated phenotype. We conclude that functionally important, miRNA mediated DNA demethylation changes contribute to the process of ATRA-induced differentiation resulting in the activation of NOS1, a critical determinant of neural cell differentiation. Our findings illustrate the plasticity and dynamic nature of the epigenome during cancer cell differentiation. PMID- 20841486 TI - Functional microRNA is transferred between glioma cells. AB - MicroRNAs (miRNA) are single-stranded 17- to 27-nucleotide RNA molecules that regulate gene expression by posttranscriptional silencing of target mRNAs. Here, we transformed rat 9L gliosarcoma cells to express cel-miR-67, a miRNA that lacks homology in rat. Coculture of these cells with cells that expressed a luciferase reporter that contained a complementary sequence to cel-miR-67 resulted in significant suppression of luciferase expression. This effect was also observed in the U87-MG human glioma cell line. Moreover, luciferase suppression was inhibited by the addition of carbenoxolone to cocultures, suggesting that gap junction communication regulates intercellular transfer of miRNA. Finally, in situ hybridization revealed the presence of cel-miR-67 in cel-miR-67-null 9L cells after coculture with cel-miR-67-expressing cells. Our data show that miRNA transcribed in glioma cells can be transferred to adjacent cells and induces targeted inhibition of protein expression in the acceptor cells. These findings reveal a novel mechanism of targeted intercellular protein regulation between brain tumor cells. PMID- 20841485 TI - Heat shock protein 90 inhibition depletes LATS1 and LATS2, two regulators of the mammalian hippo tumor suppressor pathway. AB - Heat shock protein 90 (HSP90), which regulates the functions of multiple oncogenic signaling pathways, has emerged as a novel anticancer therapeutic target, and multiple small-molecule HSP90 inhibitors are now in clinical trials. Although the effects of HSP90 inhibitors on oncogenic signaling pathways have been extensively studied, the effects of these agents on tumor suppressor signaling pathways are currently unknown. Here, we have examined how HSP90 inhibitors affect LATS1 and the related protein LATS2, two kinases that relay antiproliferative signals in the Hippo tumor suppressor pathway. Both LATS1 and LATS2 were depleted from cells treated with the HSP90 inhibitors 17-allylamino-17 demethoxygeldanamycin (17-AAG), radicicol, and PU-H71. Moreover, these kinases interacted with HSP90, and LATS1 isolated from 17-AAG-treated cells had reduced catalytic activity, thus showing that the kinase is a bona fide HSP90 client. Importantly, LATS1 signaling was disrupted by 17-AAG in tumor cell lines in vitro and clinical ovarian cancers in vivo as shown by reduced levels of LATS1 and decreased phosphorylation of the LATS substrate YAP, an oncoprotein transcriptional coactivator that regulates genes involved in cell and tissue growth, including the CTGF gene. Consistent with the reduced YAP phosphorylation, there were increased levels of CTGF, a secreted protein that is implicated in tumor proliferation, metastasis, and angiogenesis. Taken together, these results identify LATS1 and LATS2 as novel HSP90 clients and show that HSP90 inhibitors can disrupt the LATS tumor suppressor pathway in human cancer cells. PMID- 20841487 TI - A 28-amino-acid peptide fragment of the cupredoxin azurin prevents carcinogen induced mouse mammary lesions. AB - Azurin, a member of the cupredoxin family of redox proteins, preferentially penetrates human cancer cells and exerts cytostatic and apoptotic effects. Azurin and amino acids 50-77 (p28) of azurin also produce a dose-dependent reduction in the proliferation of human mammary cancer by increasing the level of the tumor suppressor protein p53 in the cancer cell nucleus. We show that the development of 7,12-dimethylbenz[a]anthracene-induced hormone-dependent premalignant mammary ductal lesions and hormone-independent mammary alveolar lesions in mouse mammary gland organ culture is also significantly reduced by azurin and p28. The dose dependent reduction in carcinogen-induced mammary cell proliferation by p28 was associated with an increase in the expression of p53. p28 also enhanced the inhibitory effect of a low dose of the antiestrogen tamoxifen on the development of hormone-dependent mammary ductal lesions, but did not enhance the inhibitory activity of fenretinide (N-4-hydroxyphenyl retinamide) on hormone-independent mammary alveolar lesions. These observations suggest that cupredoxins and fragments derived from them can exert a chemopreventive effect on carcinogen induced mammary gland transformation, irrespective of hormonal environment, and enhance the inhibitory effects of tamoxifen in this model of preneoplastic mammary development. PMID- 20841488 TI - Transcriptional attenuation in colon carcinoma cells in response to butyrate. AB - The short-chain fatty acid sodium butyrate (NaB), produced in the colonic lumen, induces cell cycle arrest, differentiation, and/or apoptosis in colorectal carcinoma cells in vitro, establishing a potential role for NaB in colon cancer prevention. We have previously shown that butyrate decreases cyclin D1 and c-myc expression, each essential for intestinal tumor development, by transcriptional attenuation. Here, we determined that butyrate-induced transcriptional attenuation of the cyclin D1 and c-myc genes in SW837 human colorectal adenocarcinoma cells occurs at ~100 nucleotides downstream of the transcription start site, with a similar positioning in Caco-2 cells. A concomitant decrease in RNA polymerase II occupancy at the 5' end of each gene was observed. Because transcriptional regulation is associated with chromatin remodeling, we investigated by chromatin immunoprecipitation whether the histone deacetylase inhibitory activity of butyrate altered chromatin structure at the attenuated loci. Although the distributions of histone H3 trimethylated on K4 and K36 along the cyclin D1 and c-myc genes were consistent with current models, butyrate induced only modest decreases in these modifications, with a similar effect on acetylated H3 and a modest increase in histone H3 trimethylated on K27. Finally, transcriptome analysis using novel microarrays showed that butyrate-induced attenuation is widespread throughout the genome, likely independent of transcriptional initiation. We identified 42 loci potentially paused by butyrate and showed that the transcription patterns are gene specific. The biological functions of these loci encompass a number of effects of butyrate on the physiology of intestinal epithelial cells. PMID- 20841489 TI - Outcomes in patients on home haemodialysis in England and Wales, 1997-2005: a comparative cohort analysis. AB - BACKGROUND: The UK national policy promotes expansion of home haemodialysis, but there are no recent data on characteristics and outcomes of a national home haemodialysis population. METHODS: We compared incident home haemodialysis patients in England and Wales (n = 225, 1997-2005) with age- and sex-matched incident peritoneal dialysis, hospital haemodialysis and satellite haemodialysis patients with follow-up until 31 December 2006. Cox regression analyses included time-dependent changes of wait-listing for transplantation (a proxy for health status), start of home haemodialysis and transplantation. RESULTS: There was a median delay of 12 months between starting renal replacement therapy (RRT) and home haemodialysis. During that first year of RRT, > 50% of home haemodialysis patients were wait-listed for kidney transplantation; hospital haemodialysis patients had a lower rate of wait-listing over time [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.70; P < 0.001]. In crude analyses, there was a marked survival advantage of home haemodialysis patients compared with other modalities (log-rank P-value < 0.001). In adjusted analyses, being on home haemodialysis yielded a long-term survival benefit compared with peritoneal dialysis (HR 0.61, 95% CI 0.40-0.93), and a borderline advantage compared with hospital haemodialysis (HR 0.68, 95% CI 0.44-1.03). There was no evidence of an advantage compared with satellite haemodialysis (HR 0.94, 95% CI 0.65-1.37). CONCLUSIONS: Home haemodialysis patients have better survival compared with other dialysis modalities. Some of this crude survival advantage is due to selection of a healthier patient cohort as evidenced by higher transplant wait-listing rates. The advantage over peritoneal dialysis persisted after adjustment for wait listing and transplantation over time. PMID- 20841490 TI - Spontaneous remission of nephrotic syndrome in patients with IgA nephropathy. AB - BACKGROUND: IgA nephropathy (IgAN) can be complicated by nephrotic syndrome. Because the spontaneous resolution of heavy proteinuria is rare, corticosteroid therapy should be considered in such cases, particularly when IgAN is combined with minimal-change disease. Here, we report our experience of spontaneous remission of nephrotic syndrome in patients with IgAN and the long-term outcomes of these patients. METHODS: Two hundred and thirty-three patients with biopsy proven IgAN were enrolled between January 2001 and March 2009. Demographic, clinical and laboratory data were collected retrospectively based on medical records. In addition, pathologic findings were reviewed for glomerular and tubulointerstitial lesions. Outcome data for complete or partial remission, spontaneous remission, relapse, deterioration of renal function, and end-stage renal disease were recorded. RESULTS: Twenty-four patients (10.3%) presented nephrotic syndrome. Among them, five patients underwent spontaneous remission within 6 months after the presentation of nephrotic syndrome. Interestingly, spontaneous remission occurred even in two patients who had elevated serum creatinine levels and advanced renal damage. During follow-up, neither recurrence nor relapse occurred, and no patients showed progressive deterioration of kidney function. Conclusions. This study suggests that spontaneous remission of nephrotic syndrome may occur in any stage of IgAN and carries a favourable long term outcome without relapse. Given the possibility of under-reported cases, large-scale studies are required, and careful attention should be paid to such complicated cases. PMID- 20841491 TI - Anti-C1q autoantibodies do not correlate with the occurrence or severity of experimental lupus nephritis. AB - BACKGROUND: In systemic lupus erythematosus patients, a strong association between the occurrence of antibodies against complement C1q (anti-C1q) and lupus nephritis can be observed. However, the predictive value of anti-C1q titres for a renal flare remains to be determined. Increasing titres of anti-C1q before the occurrence of clinical apparent nephritis might not only serve as a clinical parameter but also indicate a direct pathogenic mechanism of anti-C1q. METHODS: The aim of this study was to analyse the occurrence of anti-C1q before the onset of experimental lupus nephritis in MRL/MpJ +/+ mice and to correlate anti-C1q titres with the type and severity of glomerulonephritis (GN) developing at advanced age. RESULTS: As judged by a number of morphological and immunological analyses, GN in MRL/MpJ +/+ mice resembled human lupus nephritis and occurred in variable degrees of severity. We also observed an abundant and early presence of anti-C1q. However, anti-C1q neither correlated with overall survival nor with any histological marker of severity of GN. CONCLUSIONS: The absence of a correlation between the presence of anti-C1q and the occurrence of experimental lupus nephritis contradicts the hypothesis that anti-C1q are pathogenic. However, different pathogenic mechanisms of experimental lupus nephritis and human proliferative lupus nephritis cannot be excluded. PMID- 20841492 TI - A possible rare cause of renal failure in streptococcal infection. AB - To the best of our knowledge, this is the first biopsy-proven case of streptococcal infection-associated acute interstitial nephritis (AIN) with existence of streptococcal pyrogenic exotoxin B (SPE B) by a controlled immunohistochemical method. Both the intact tubular epithelial cells and oedematous interstitium had strong positive signals, whereas only interstitial inflammation was dominant without tubular necrosis. Reflective of the nature of AIN is that the injury from the hypersensitivity reaction was specific for renal interstitium instead of tubules. SPE B is potentially allergenic and may confuse the clinicians due to its clinical mimicry of drug-induced AIN. Although very rare, AIN might be included into the differential diagnosis of patients with streptococcal sepsis and acute renal failure. PMID- 20841494 TI - Breastfeeding throughout legal separation: women's experiences of the Australian Family Law system. AB - In 2006, the Australian Government introduced the Family Law Amendment (Shared Parental Responsibility) Act 2006 (Cth), which put in place a legal presumption of shared parental responsibility for children after separation and which emphasizes "equal-time" parenting arrangements regardless of the child's age. A qualitative approach was taken to investigate breastfeeding women's experiences of the implementation of the act and its impact on their ability to maintain breastfeeding. Fifteen women responded to questions related to their breastfeeding and their engagement with the family law system. Interviews were audio recorded and transcribed, and data were then analyzed thematically. These women experienced inconsistent advice from all facets of legal services, including opinions about the inappropriateness of breastfeeding for infants over 6 months of age. Breastfeeding was considered only as nutrition, without recognition of its immunological and cognitive benefits and the security and comfort it provides. Many participant women felt that they had been persuaded against discussing breastfeeding in the legal system, resulting in a sense of disempowerment. PMID- 20841493 TI - Changes in parathyroid hormone, body mass index and the association with mortality in dialysis patients. AB - BACKGROUND: Obesity is associated with secondary hyperparathyroidism in the general population. It is unknown whether body mass index (BMI) affects parathyroid hormone (PTH) level and its association with mortality in dialysis patients. METHODS: From a prospective cohort study of incident dialysis patients in the Netherlands (NECOSAD), we selected all patients with recorded BMI and PTH at 3 months (baseline) after the start of dialysis [n = 1628, age 59 +/- 15 years, BMI 24.7 +/- 4.1 kg/m(2), median PTH 13.0 (interquartile range 5.3-29.0) pmol/L]. We assessed associations between BMI and PTH at baseline and between their changes over 3 months by correlation and linear regression analyses. The effect of the changes in PTH on all-cause mortality during a subsequent mean follow-up of 3.2 +/- 2 years was assessed by Cox regression analyses. RESULTS: Median PTH levels at baseline were lowest in underweight patients (10.2 pmol/L), followed by normal weight (12.1 pmol/L), overweight (14.0 pmol/L) and obese patients (17.5 pmol/L). The associations were similar in diabetic and non diabetic patients. A >= 5% decrease in BMI (n = 101) over 3 months was accompanied by a 26% decrease in PTH (PTH(ratio) 0.74; P = 0.039), whereas a >= 5% increase in BMI (n = 143) was associated with an 11% increase in PTH (PTH(ratio) 1.11; P = 0.026). Compared to patients with stable PTH levels, patients with decreasing PTH in the presence of weight loss showed a 2-fold higher mortality (hazard ratio 2.02, 95% confidence interval 1.45-2.83; P < 0.001), in contrast to those with decreasing PTH in the absence of weight loss. Additional analyses showed that the weight loss was responsible for increased deaths. CONCLUSIONS: PTH is associated with BMI and its longitudinal changes in dialysis patients, both in patients with and without diabetes mellitus. An increased mortality seen for patients with concurrent decreases in PTH and BMI was explained by the weight loss, representing an important confounder for outcome analyses according to levels of PTH. Low and decreasing PTH levels may be symptoms of wasting, which should be taken into account in the care of dialysis patients. PMID- 20841495 TI - Oral administration of L-mR18L, a single domain cationic amphipathic helical peptide, inhibits lesion formation in ApoE null mice. AB - We have shown that Ac-hE18A-NH2, a dual-domain cationic apolipoprotein-mimetic peptide, reduces plasma cholesterol levels in dyslipidemic mice. Two single domain cationic peptides based on the lytic class L peptide 18L were developed to test the hypothesis that a single-domain cationic amphipathic peptide can reduce atherosclerosis in apolipoprotein (apo)E null mice when orally administered. To incorporate anti-inflammatory properties, aromatic residues were clustered in the nonpolar face similar to peptide 4F, resulting in modified 18L (m18L). To reduce lytic properties, the Lys residues of 18L were replaced with Arg with the resulting peptide called modified R18L (mR18L). Biophysical studies showed that mR18L had stronger interactions with lipids than did m18L. Peptide mR18L was also more effective than m18L in promoting LDL uptake by HepG2 cells. ApoE null mice received normal chow or chow containing m18L or mR18L for six weeks. A significant reduction in plasma cholesterol and aortic sinus lesion area was seen only in the mR18L group. Plasma from mice administered mR18L, unlike those from the control and m18L groups, did not enhance monocyte adhesion to endothelial cells. Thus oral administration of mR18L reduces plasma cholesterol and lesion formation and inhibits monocyte adhesion. PMID- 20841496 TI - Vascular responses in aortic rings of a consomic rat panel derived from the Fawn Hooded Hypertensive strain. AB - The present experiments, utilizing the high-throughput vascular protocol of PhysGen (Program for Genomic Applications) characterized the responses of aortic rings to vasoconstrictor (phenylephrine) and vasodilator (acetylcholine, sodium nitroprusside, and reduced tissue bath Po(2)) stimuli in consomic rat strains derived from a cross between the Fawn Hooded Hypertensive rat (FHH/EurMcwi) and the Brown Norway normotensive (BN/NHsdMcwi) rat. The effects of substituting individual BN chromosomes into the FHH genetic background were determined in animals that were maintained on a low-salt (0.4% NaCl) diet or switched to a high salt (4% NaCl) diet for 3 wk. Sex-specific differences were evaluated in male and female consomic rats on similar dietary salt intake. Multiple chromosomes affected various vascular reactivity phenotypes in the FHH * BN consomic panel, and substantial salt-dependent changes in vascular reactivity and sex-specific differences in aortic reactivity were observed in individual consomic strains. However, compared with earlier studies of consomic rats derived from a cross between the BN rat and the Dahl salt-sensitive (SS) rat, only 3-7% of the vascular phenotypes were affected in a similar manner by substituting specific BN chromosomeschromosomes into the FHH genetic background versus the SS genetic background. The findings of the present study stress the potential value of consomic rat panels in gaining insight into genetic factors influencing vascular reactivity and suggest that the chromosomes that appear to be involved in the determination of aortic ring reactivity in different rodent models of hypertension are highly strain- and sex specific. PMID- 20841497 TI - Can microRNAs control vascular smooth muscle phenotypic modulation and the response to injury? AB - Vascular smooth muscle cell (VSMC) migration and proliferation are critical events in vascular proliferative diseases. Recent studies have established microRNAs (miRNAs) as important mediators for the modulation of VSMC phenotype by targeting transcription factors and the cytoskeleton, which act as molecular switches for VSMC differentiation. The importance of miRNAs for VSMC development, differentiation, and function is evident by the fact that loss of the miRNA processing enzyme Dicer in VSMCs results in embryonic lethality due to severe vascular abnormalities. Similar abnormalities are observed in adult miR-143/145 knockout mice, indicating that these miRNAs are important for VSMC differentiation and function. However, since miR-143/145 knockout is not embryonically lethal, additional miRNA must be required during embryonic development of VSMCs. In addition, specific miRNAs such as miR-145, miR-21, and miR-221 have been found to regulate neointimal hyperplasia following vascular injury, which provides interesting possibilities for future therapeutical targets against vascular disease. Herein, we summarize recent advances regarding the role of miRNAs in VSMC phenotype modulation and response to injury. PMID- 20841498 TI - Temporal microRNA expression during in vitro myogenic progenitor cell proliferation and differentiation: regulation of proliferation by miR-682. AB - MicroRNAs (miRNAs) regulate gene expression by repressing target genes at the posttranscriptional level. Since miRNAs have unique expression profiles in different tissues, they provide pivotal regulation of many biological processes. The present study defined miRNA expression during murine myogenic progenitor cell (MPC) proliferation and differentiation to identify miRNAs involved in muscle regeneration. Muscle-related gene expression analyses revealed that the time course and expression of myosin heavy chain (MHC) and transcription factors (Myf5, MyoD, myogenin, and Pax7) were similar during in vitro MPC proliferation/differentiation and in vivo muscle regeneration. Comprehensive profiling revealed that 139 or 16 miRNAs were significantly changed more than twofold [false discovery rate (FDR) < 0.05] during MPC differentiation or proliferation, respectively; cluster analyses revealed five distinct patterns of miRNA expression during the time course of MPC differentiation. Not unexpectedly, the largest miRNA changes occurred in muscle-specific miRNAs (miR-1, -133a, and 499), which were upregulated >10-fold during MPC differentiation (FDR < 0.01). However, several previously unreported miRNAs were differentially expressed, including miR-10b, -335-3p, and -682. Interestingly, the temporal patterns of miR 1, -499, and -682 expression during in vitro MPC proliferation/differentiation were remarkably similar to those observed during in vivo muscle regeneration. Moreover, in vitro inhibition of miR-682, the only miRNA upregulated in proliferating compared with quiescent MPC, led to decreased MPC proliferation, further validating our in vitro assay system for the identification of miRNAs involved in muscle regeneration. Thus the differentially expressed miRNAs identified in the present study could represent new regulatory elements in MPC proliferation and differentiation. PMID- 20841500 TI - Both isoforms of ketohexokinase are dispensable for normal growth and development. AB - Dietary fructose intake has dramatically increased over recent decades and is implicated in the high rates of obesity, hypertension, and type 2 diabetes (metabolic syndrome) in Western societies. The molecular determinants of this epidemiologic correlation are incompletely defined, but high-flux fructose catabolism initiated by ketohexokinase (Khk, fructokinase) is believed to be important. The Khk gene encodes two enzyme isoforms with distinctive substrate preferences, the independent physiological roles of which are unclear. To investigate this question, and for testing the importance of Khk in metabolic syndrome, isoform-selective genetic lesions would be valuable. Two deficiency alleles of the mouse Khk gene were designed. The first, Khk(3a), uses targeted "knock-in" of a premature termination codon to induce a selective deficiency of the minor Khk-A isoform, preserving the major Khk-C isoform. The second, the Khk(Delta) allele, ablates both isoforms. Mice carrying each of these Khk deficiency alleles were generated and validated at the DNA, RNA, and protein levels. Comparison between normal and knockout animals confirmed the specificity of the genetic lesions and allowed accurate analysis of the cellular distribution of Khk within tissues such as gut and liver. Both Khk(3a/3a) and Khk(Delta/Delta) homozygous mice were healthy and fertile and displayed minimal biochemical abnormalities under basal dietary conditions. These studies are the first demonstration that neither Khk isoform is required for normal growth and development. The new mouse models will allow direct testing of various hypotheses concerning the role of this enzyme in metabolic syndrome in humans and the value of Khk as a pharmacological target. PMID- 20841499 TI - MicroRNA in ischemic stroke etiology and pathology. AB - Small, noncoding, microRNAs (miRNAs) have emerged as key mediators of posttranscriptional gene silencing in both pathogenic and pathological aspects of ischemic stroke biology. In stroke etiology, miRNA have distinct expression patterns that modulate pathogenic processes including atherosclerosis (miR-21, miR-126), hyperlipidemia (miR-33, miR-125a-5p), hypertension (miR-155), and plaque rupture (miR-222, miR-210). Following focal cerebral ischemia, significant changes in the miRNA transcriptome, independent of an effect on expression of miRNA machinery, implicate miRNA in the pathological cascade of events that include blood brain barrier disruption (miR-15a) and caspase mediated cell death signaling (miR-497). Early activation of miR-200 family members improves neural cell survival via prolyl hydroxylase mRNA silencing and subsequent HIF-1alpha stabilization. Pro- (miR-125b) and anti-inflammatory (miR-26a, -34a, -145, and let-7b) miRNA may also be manipulated to positively influence stroke outcomes. Recent examples of successfully implemented miRNA-therapeutics direct the future of gene therapy and offer new therapeutic strategies by regulating large sets of genes in related pathways of the ischemic stroke cascade. PMID- 20841501 TI - Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue. AB - Recent studies have shown that microRNAs (miRNAs) act as posttranscriptional regulators and that they play important roles during heart development and in cardiac function. Thus, they may provide new means of altering stem cell fate and differentiation processes. However, information about the correlation between global miRNA and mRNA expression in cardiomyocyte clusters (CMCs) derived from human embryonic stem cells (hESC) and in fetal and adult heart tissue is lacking. In the present study the global miRNA and mRNA expression in hESC-derived CMCs and in fetal and adult heart tissue was investigated in parallel using microarrays. Target genes for the differentially expressed miRNAs were predicted using computational methods, and the concordance in miRNA expression and mRNA levels of potential target genes was determined across the experimental samples. The biology of the predicted target genes was further explored regarding their molecular functions and involvement in known regulatory pathways. A clear correlation between the global miRNA expression and corresponding target mRNA expression was observed. Using three different sources of cardiac tissue-like samples, we defined the similarities between in vitro hESC-derived CMCs and their in vivo counterparts. The results are in line with previously reported observations that miRNAs repress mRNA expression and additionally identify a number of novel miRNAs with potential important roles in human cardiac tissue. The concordant miRNA expression pattern observed among all the cardiac tissue like samples analyzed here provide a starting point for future ambitious studies aiming towards assessment of the functional roles of specific miRNAs during cardiomyocyte differentiation. PMID- 20841502 TI - Arginine-induced stimulation of protein synthesis and survival in IPEC-J2 cells is mediated by mTOR but not nitric oxide. AB - Arginine is an indispensable amino acid in neonates and is required for growth. Neonatal intestinal epithelial cells (IEC) are capable of arginine transport, catabolism, and synthesis and express nitric oxide (NO) synthase to produce NO from arginine. Our aim was to determine whether arginine directly stimulates IEC growth and protein synthesis and whether this effect is mediated via mammalian target of rapamycin (mTOR) and is NO-dependent. We studied neonatal porcine IEC (IPEC-J2) cultured in serum- and arginine-free medium with increasing arginine concentrations for 4 or 48 h. Our results show that arginine enhances IPEC-J2 cell survival and protein synthesis, with a maximal response at a physiological concentration (0.1-0.5 mM). Addition of arginine increased the activation of mTOR, p70 ribosomal protein S6 (p70 S6) kinase, and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) in a time- and dose-dependent manner. The arginine induced protein synthesis response was not inhibited by the NO inhibitors nitro-l arginine methyl ester (l-NAME) and aminoguanidine, despite inducible NO synthase expression in IPEC-J2 cells. Moreover, protein synthesis was not increased or decreased in some cases by addition of an NO donor (S-nitroso-N acetylpenicillamine), arginine precursors (proline and citrulline) in the absence of arginine, or insulin; S-nitroso-N-acetylpenicillamine suppressed phosphorylation of mTOR, p70 S6 kinase, and 4E-BP1. We found a markedly higher arginase activity in IPEC-J2 cells than in primary pig IEC. Furthermore, mTOR inhibition by rapamycin partially (42%) reduced the arginine-induced protein synthesis response and phosphorylation of mTOR and 4E-BP1. We conclude that arginine-dependent cell survival and protein synthesis signaling in IPEC-J2 cells are mediated by mTOR, but not by NO. PMID- 20841503 TI - beta-Cell-specific pyruvate dehydrogenase deficiency impairs glucose-stimulated insulin secretion. AB - Glucose-stimulated insulin secretion (GSIS) by beta-cells requires the generation of ATP from oxidation of pyruvate as well as generation of coupling factors involving three different pyruvate cycling shuttles. The roles of several key enzymes involved in pyruvate cycling in beta-cells have been documented using isolated islets and beta-cell clonal lines. To investigate the role of the pyruvate dehydrogenase (PDH) complex (PDC) in GSIS, a murine model of beta-cell specific PDH deficiency (beta-PDHKO) was created. Pancreatic insulin content was decreased in 1-day-old beta-PDHKO male pups and adult male mice. The plasma insulin levels were decreased and blood glucose levels increased in beta-PDHKO male mice from neonatal life onward. GSIS was reduced in isolated islets from beta-PDHKO male mice with about 50% reduction in PDC activity. Impairment in a glucose tolerance test and in vivo insulin secretion during hyperglycemic clamp was evident in beta-PDHKO adults. No change in the number or size of islets was found in pancreata from 4-wk-old beta-PDHKO male mice. However, an increase in the mean size of individual beta-cells in islets of these mice was observed. These findings show a key role of PDC in GSIS by pyruvate oxidation. This beta PDHKO mouse model represents the first mouse model in which a mitochondrial oxidative enzyme deletion by gene knockout has been employed to demonstrate an altered GSIS by beta-cells. PMID- 20841504 TI - Adipose tissue macrophages in insulin-resistant subjects are associated with collagen VI and fibrosis and demonstrate alternative activation. AB - Adipose tissue macrophages are associated with insulin resistance and are linked to changes in the extracellular matrix. To better characterize adipose macrophages, the extracellular matrix, and adipocyte-macrophage interactions, gene expression from adipose tissue and the stromal vascular fraction was assessed for markers of inflammation and fibrosis, and macrophages from obese and lean subjects were counted and characterized immunohistochemically. Coculture experiments examined the effects of adipocyte-macrophage interaction. Collagen VI gene expression was associated with insulin sensitivity and CD68 (r = -0.56 and 0.60, P < 0.0001) and with other markers of inflammation and fibrosis. Compared with adipose tissue from lean subjects, adipose tissue from obese subjects contained increased areas of fibrosis, which correlated inversely with insulin sensitivity (r = -0.58, P < 0.02) and positively with macrophage number (r = 0.70, P < 0.01). Although macrophages in crownlike structures (CLS) were more abundant in obese adipose tissue, the majority of macrophages were associated with fibrosis and were not organized in CLS. Macrophages in CLS were predominantly M1, but most other macrophages, particularly those in fibrotic areas, were M2 and also expressed CD150, a marker of M2c macrophages. Coculture of THP-1 macrophages with adipocytes promoted the M2 phenotype, with a lower level of IL-1 expression and a higher ratio of IL-10 to IL-12. Transforming growth factor-beta (TGF-beta) was more abundant in M2 macrophages and was further increased by coculture with adipocytes. Downstream effectors of TGF-beta, such as plasminogen activator inhibitor-1, collagen VI, and phosphorylated Smad, were increased in macrophages and adipocytes. Thus adipose tissue of insulin-resistant humans demonstrated increased fibrosis, M2 macrophage abundance, and TGF-beta activity. PMID- 20841505 TI - SGLT1 protein expression in plasma membrane of acinar cells correlates with the sympathetic outflow to salivary glands in diabetic and hypertensive rats. AB - Salivary gland dysfunction is a feature in diabetes and hypertension. We hypothesized that sodium-glucose cotransporter 1 (SGLT1) participates in salivary dysfunctions through a sympathetic- and protein kinase A (PKA)-mediated pathway. In Wistar-Kyoto (WKY), diabetic WKY (WKY-D), spontaneously hypertensive (SHR), and diabetic SHR (SHR-D) rats, PKA/SGLT1 proteins were analyzed in parotid and submandibular glands, and the sympathetic nerve activity (SNA) to the glands was monitored. Basal SNA was threefold higher in SHR (P < 0.001 vs. WKY), and diabetes decreased this activity (~50%, P < 0.05) in both WKY and SHR. The catalytic subunit of PKA and the plasma membrane SGLT1 content in acinar cells were regulated in parallel to the SNA. Electrical stimulation of the sympathetic branch to salivary glands increased (~30%, P < 0.05) PKA and SGLT1 expression. Immunohistochemical analysis confirmed the observed regulations of SGLT1, revealing its location in basolateral membrane of acinar cells. Taken together, our results show highly coordinated regulation of sympathetic activity upon PKA activity and plasma membrane SGLT1 content in salivary glands. Furthermore, the present findings show that diabetic- and/or hypertensive-induced changes in the sympathetic activity correlate with changes in SGLT1 expression in basolateral membrane of acinar cells, which can participate in the salivary glands dysfunctions reported by patients with these pathologies. PMID- 20841506 TI - Follicular dendritic cell-dependent drug resistance of non-Hodgkin lymphoma involves cell adhesion-mediated Bim down-regulation through induction of microRNA 181a. AB - Follicular dendritic cells (FDCs), an essential component of the lymph node microenvironment, regulate and support B-lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrate that adhesion of mantle cell lymphoma and other non-Hodgkin lymphoma cells to FDCs reduces cell apoptosis and is associated with decreased levels of the proapoptotic protein, Bim. Bim down regulation is posttranscriptionally regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreases, whereas miR-181a inhibition increases Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim apoptosis signaling pathway. miR-181a inhibition and Bim upregulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell adhesion-mediated drug resistance and a potential therapeutic target in B-cell lymphomas. PMID- 20841508 TI - Interleukin-7 treatment counteracts IFN-alpha therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques. AB - Interferon-alpha (IFN-alpha)-based therapy is presently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-alpha-induced lymphopenia. We showed that low-dose IFN-alpha treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high dose IFN-alpha treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-alpha. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8(+) T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients. PMID- 20841507 TI - BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. AB - BAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (>= 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene-embedded microRNAs were up regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients. PMID- 20841509 TI - Low-dose rituximab and alemtuzumab combination therapy for patients with steroid refractory autoimmune cytopenias. AB - Treatment of autoimmune cytopenias remains unsatisfactory for patients refractory to first-line management. We evaluated the safety and efficacy of low-dose rituximab plus alemtuzumab in patients with steroid-refractory autoimmune hemolytic anemia and immune thrombocytopenic purpura. Nineteen of 21 included patients were assessable for response (11 with immune thrombocytopenic purpura, 8 with autoimmune hemolytic anemia). Treatment with 10 mg of alemtuzumab subcutaneously on days 1 to 3, plus 100 mg of rituximab intravenously weekly in 4 doses, was administered. The overall response rate was 100%, with complete response in 58%. The median response duration was 46 weeks (range, 16-89 weeks). Median follow-up was 70 weeks (range, 37-104 weeks). Most toxicity was grade 1 fever related to the first dose. Six patients developed infections. The combination of rituximab and alemtuzumab is feasible and has an acceptable safety profile and remarkable clinical activity in this group of patients. This study is registered at www.clinicaltrials.gov as #NCT00749112. PMID- 20841510 TI - A novel form of human STAT1 deficiency impairing early but not late responses to interferons. AB - Autosomal recessive STAT1 deficiency is associated with impaired cellular responses to interferons and susceptibility to intracellular bacterial and viral infections. We report here a new form of partial STAT1 deficiency in 2 siblings presenting mycobacterial and viral diseases. Both carried a homozygous missense mutation replacing a lysine with an asparagine residue at position 201 (K201N) of STAT1. This mutation causes the abnormal splicing out of exon 8 from most STAT1 mRNAs, thereby decreasing (by ~ 70%) STAT1 protein levels. The mutant STAT1 proteins are not intrinsically deleterious, in terms of tyrosine phosphorylation, dephosphorylation, homodimerization into gamma-activating factor and heterotrimerization into ISGF-3, binding to specific DNA elements, and activation of the transcription. Interestingly, the activation of gamma-activating factor and ISGF3 was impaired only at early time points in the various cells from patient (within 1 hour of stimulation), whereas sustained impairment occurs in other known forms of complete and partial recessive STAT1 deficiency. Consequently, delayed responses were normal; however, the early induction of interferon-stimulated genes was selectively and severely impaired. Thus, the early cellular responses to human interferons are critically dependent on the amount of STAT1 and are essential for the appropriate control of mycobacterial and viral infections. PMID- 20841511 TI - Continuous terlipressin infusion as rescue treatment in a case series of children with refractory septic shock. AB - BACKGROUND: Despite intensive therapy, refractory pediatric septic shock has a high rate of morbidity and mortality. Additional treatments are needed to improve outcomes in such cases. OBJECTIVE: To report the clinical effects of continuous terlipressin infusion as rescue treatment for children with septic shock refractory to high catecholamine doses. METHODS: Sixteen episodes of catecholamine-resistant septic shock were recorded in 15 children (aged from newborn to 15 years) who received compassionate rescue treatment with terlipressin at 6 pediatric intensive care units. Terlipressin treatment consisted of a loading dose (20 MUg/kg) followed by continuous infusion at a rate of 4-20 MUg/kg/h. Terlipressin was titrated at increases of 1 MUg/kg/h to maintain mean arterial pressure (MAP) in normal range for age and to reduce catecholamine dosage. The main outcome was survival of the episode. Secondary outcomes included hemodynamic effects, ischemia, and terlipressin-related adverse events. RESULTS: Terlipressin increased median MAP from 48 (range 42-63) to 68 (45-115) mm Hg 30 minutes after terlipressin administration (p < 0.01). MAP was subsequently sustained, which allowed for the reduction of norepinephrine infusion from 2 MUg/kg/min (1-4) at baseline to 1.5 MUg/kg/min (0.4-4) at 1 hour, 1.3 MUg/kg/min (0-8) at 4 hours, 1 MUg/kg/min (0-2) at 12 hours, 0.45 MUg/kg/min (0-1.4) at 24 hours, and 0 MUg/kg/min (0-0.6) at 48 hours (p < 0.05 vs baseline in all cases). In 8 (50%) of the 16 septic shock episodes the patients survived, 7 (44%) without sequelae. One patient survived with sequelae (minor amputation and mild cutaneous ischemia). Eight patients had signs of ischemia at admission; terlipressin induced reversible ischemia in another 4 patients. Meningococcal infection, prior ischemia, and MAP were risk factors for mortality. CONCLUSIONS: Continuous terlipressin infusion may improve hemodynamics and survival in some children with refractory septic shock. Terlipressin could contribute to tissue ischemia. PMID- 20841512 TI - The pharmacotherapy of the HeartMate II, a continuous flow left ventricular assist device, in patients with advanced heart failure: integration of disease, device, and drug. AB - Advanced heart failure continues to be a significant cause of morbidity and mortality in the US. Patients with advanced heart failure have a poor prognosis without cardiac transplantation. The use of left ventricular assist devices (LVADs) as destination therapy for these patients is therefore expected to increase in the coming years as technology advances. The HeartMate II, a continuous flow implantable device, is currently the only LVAD that has been approved by the Food and Drug Administration for destination therapy in patients with advanced heart failure. The pharmacotherapy associated with this device is very complex and, therefore, the need for expertly trained clinical pharmacists to care for this expanding patient population will also likely increase. Unfortunately, most pharmacists are unfamiliar with the effect of LVADs on the physiology and pharmacotherapy of a patient's heart failure. The purpose of this article is to give clinical pharmacists an introduction to the most common pharmacotherapeutic issues for patients with LVADs and present practical solutions for managing common drug therapy problems. PMID- 20841513 TI - Pharmacists' preferences for providing patient-centered services: a discrete choice experiment to guide health policy. AB - BACKGROUND: In Canada, most pharmacists are not paid to provide patient-centered services. In other areas of the world these services have suffered from poor adoption by pharmacists. OBJECTIVE: To determine pharmacists' preferences for providing patient-centered services. METHODS: Senior pharmacy students and pharmacists in British Columbia and Alberta were recruited to complete a discrete choice experiment. In 18 different choice-sets, respondents were asked to choose 1 of 3 options that included 2 different hypothetical patient-centered services and a status quo option. For each hypothetical service, we described the following attributes: service type and setting, personal income and job satisfaction, professional fee, and educational requirements. Multinomial logit and latent class regression models determined respondents' relative preference weights for each attribute. RESULTS: Of 539 respondents who completed the questionnaire, 49% were dispensary pharmacists or managers, 12% were dispensary owners or regional managers, 21% were clinical pharmacists, and 16% were students. When choosing new services, respondents were very averse to having their personal income or job satisfaction decrease. They also preferred a higher professional fee for the service (to be paid to the pharmacy) and preferred a weeklong course or a preceptorship over no education before embarking on new services. Respondents also preferred medication or disease management services, were not interested in screening, and were averse to typical pharmacy services. Finally, respondents preferred the clinic setting over the dispensary. Preferences differed according to several factors including respondents' employment and time in practice. CONCLUSIONS: Pharmacists prefer to provide patient-centered services over typical pharmacy services. Most will need to be assured that their income and job satisfaction will be maintained or increased and that they will have access to suitable advanced education. Decision-makers should carefully consider these preferences to improve program success and sustainability. PMID- 20841514 TI - Treatment of systolic heart failure in the elderly: an evidence-based review. AB - OBJECTIVE: To review relevant literature supporting the use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, digoxin, aldosterone antagonists, and vasodilators in the management of heart failure in an elderly patient population aged >=65 years. DATA SOURCES: PubMed, EMBASE, and MEDLINE searches (January 1960-April 2010) were utilized to identify primary literature using the key terms heart failure, treatment, and elderly. Additionally, reference citations from publications identified were utilized, as well as the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for the Diagnosis and Management of Chronic Heart Failure in the Adult. STUDY SELECTION AND DATA EXTRACTION: Primary and tertiary literature, including subgroup analyses, published in English and relating to the use of pharmacotherapy in the treatment of systolic heart failure in the elderly was reviewed. DATA SYNTHESIS: The aging of the US population is creating a higher prevalence of systolic heart failure in the elderly. Most clinical trials have established the mortality and morbidity benefit of pharmacotherapy in heart failure in nonelderly patients; however, the current ACC/AHA guidelines do not clearly delineate this benefit in persons >=65 years of age. CONCLUSIONS: Clinical trial data, based on limited numbers of individuals aged >=65 years, suggest that use of beta-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and vasodilators (hydralazine/nitrates) have similar mortality benefit to that observed in younger patients. As supported in the ACC/AHA guidelines, these agents should be prescribed with clinical judgment to all elderly patients, with close monitoring for adverse events. Future clinical trials with greater inclusion of patients >=65 years will help to elucidate the magnitude of benefits of optimal pharmacotherapy on mortality and morbidity rates in this population. PMID- 20841515 TI - Retrospective analysis of the consequences of acid suppressive therapy on ketoconazole efficacy in advanced castration-resistant prostate cancer. AB - BACKGROUND: The area under the curve of a single ketoconazole dose has been shown to decrease significantly when administered with acid suppressive therapy. No published studies have examined the clinical impact of concurrent ketoconazole and acid suppressive therapy in patients with castration-resistant prostate cancer (CRPC). OBJECTIVE: To evaluate the effect of acid suppressive therapy on prostate-specific antigen (PSA) response rate in CRPC patients receiving ketoconazole. METHODS: This retrospective study evaluated CRPC patients treated with ketoconazole 3 times daily between January 1, 1999, and September 30, 2009. Patients included in the analysis had failed androgen deprivation therapy, and were subsequently initiated on ketoconazole. Response (PSA decline >=50% maintained >=4 weeks) was evaluated in patients receiving ketoconazole with (group 1 [G1]) or without (group 2 [G2]) concurrent acid suppressive therapy. RESULTS: Thirty patients (G1: 11 patients; G2: 19 patients) were included in the analysis. Mean age in G1 and G2 was 71.8 and 69.6 years, respectively. Most patients had received prior therapy with an antiandrogen (90.9% G1; 100% G2) and fewer patients received antiandrogen withdrawal therapy (27.3% G1; 21.1% G2). Median baseline PSA was 109.4 (G1) and 86.9 ng/mL (G2) (p = 0.55). Median duration of ketoconazole was 7.2 months in G1 and 5.8 months in G2 (p = 0.09). Ketoconazole adherence was 82% (G1) and 100% (G2). Median duration of concurrent acid suppressive therapy was 3.8 months (range 2.0-20.4) in G1. PSA response (72.7% and 47.4%; p = 0.26) and time to PSA response (1.2 vs 0.9 mo; p = 0.53) were statistically similar between G1 and G2, respectively. Median progression free survival was higher in G1 (11.5 vs 6.9 months in G2; p = 0.047). CONCLUSIONS: Use of concurrent acid suppressive therapy and ketoconazole in CRPC patients did not decrease PSA response rate, and progression free survival was unexpectedly higher compared with the non-acid suppressive therapy group. Larger studies are needed to verify the clinical impact of acid suppressive therapy in combination with ketoconazole. PMID- 20841516 TI - Fixed-dose rasburicase 6 mg for hyperuricemia and tumor lysis syndrome in high risk cancer patients. AB - BACKGROUND: Rasburicase is indicated for the initial management of plasma uric acid levels in adults receiving anticancer therapy who are at risk for acute tumor lysis syndrome (TLS) and subsequent hyperuricemia. The labeled dose is 0.2 mg/kg/day administered intravenously over 30 minutes for up to 5 days. Our institutional adult guidelines recommend rasburicase 6 mg for uric acid levels >8 mg/dL in most adults with TLS, or 4-8 mg/dL in high-risk patients. Repeat dosing is indicated for uric acid levels >4 mg/dL determined >=12 hours following the initial dose. OBJECTIVE: To determine the efficacy of a single dose of rasburicase 6 mg per institutional adult TLS guidelines to decrease uric acid levels to <4 mg/dL by day 3, as well as to determine the effect on serum creatinine and phosphorus concentrations. The secondary objectives were to evaluate the appropriateness of our institutional guidelines and identify TLS risk factors. METHODS: The study was approved by the University of Maryland Medical Center Institutional Review Board. A retrospective review of all adults between July 2008 and February 2009 who received at least one 6-mg dose of rasburicase, with redosing, if indicated, before day 3, was conducted. Subsequent TLS monitoring over 7 days after initial dosing was recorded. Patients were excluded if dosing did not adhere to institutional guidelines. RESULTS: We observed a decline in median uric acid levels from 9.2 mg/dL (interquartile range 8.1-10.4) on day 1 to between 1.8 (1.0-3.8) on day 3 and 3.8 mg/dL (2.1-4.4) on day 7 (p < 0.0001) with 2 patients requiring repeat dosing before day 3 (n = 34). The majority of the population was hyperuricemic (>8 mg/dL; 76%) or at high risk for TLS (85%). CONCLUSIONS: A 6-mg dose of rasburicase effectively decreased uric acid to <4 mg/dL by day 3, rarely requiring repeat dosing, in a high-risk population. PMID- 20841517 TI - The impact of continuing professional development versus traditional continuing pharmacy education on pharmacy practice. AB - BACKGROUND: The Institute of Medicine states that the new vision for continuing education (CE) for health-care professionals will be based on continuing professional development (CPD); however, information on the utility of CPD is lacking. OBJECTIVE: To assess the effect of CPD, compared with that of traditional continuing pharmacy education (CPE), on perceptions of factors related to pharmacy practice. METHODS: This 10-month, nonblinded, randomized controlled study recruited licensed pharmacists employed at a health maintenance organization (HMO). After completing a basic CPD course, participants were randomized to the intervention or control group. The control group was instructed to continue with traditional CPE. The intervention group participants completed 3 CPD workshops and were instructed to utilize the CPD approach for their learning needs. At baseline and follow-up, all participants completed a study questionnaire on perceptions of their pharmacy practices. The outcome measures were comparisons on follow-up and changes from baseline to follow-up in responses to the study questionnaire. RESULTS: One hundred pharmacists were enrolled. The intervention (n = 44, 7 lost to follow-up) and control (n = 47, 2 lost to follow up) groups were similar at baseline. At follow-up, a higher percentage of intervention participants reported that they had better interactions with other health-care providers (always/frequently 32% vs 6%, respectively) and initiated practice/work changes (always/frequently 21% vs 0%, respectively) (both p < 0.01) as a result of their education activities. Compared with control participants at follow-up, intervention participants reported that their education activities improved patient care changes (46% vs 23%), professional knowledge (34% vs 6%), skills (48% vs 17%), and attitudes/values (43% to 11%) (all p < 0.05). However, intervention participants reported more often that time was a barrier to completing education activities (75% vs 32%, p < 0.001). CONCLUSIONS: Pharmacists who participated in CPD reported more often that their perceptions of various aspects of their pharmacy practice improved as a result of their education activities compared with pharmacists who participated in traditional CPE. PMID- 20841518 TI - Mitiglinide: a novel agent for the treatment of type 2 diabetes mellitus. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide, a rapid-acting insulin secretion-stimulating agent to determine its potential role in therapy for the treatment of type 2 diabetes mellitus. DATA SOURCES: A MEDLINE search (1966-May 2010) was conducted for English-language, human studies using the terms mitiglinide, KAD 1229, S 21403, and meglitinide analogs. Abstracts presented at the American Association and European Association for the Study of Diabetes annual meetings from 2005 to 2009 were also evaluated for relevant data. STUDY SELECTION AND DATA EXTRACTION: Articles pertinent to the pharmacology, pharmacokinetics, efficacy, and safety of mitiglinide were reviewed. DATA SYNTHESIS: Mitiglinide has been shown through small clinical studies (N <400) to modestly decrease hemoglobin A(1c), postprandial hyperglycemia, and oxidative stress and inflammatory markers associated with postprandial hyperglycemia. Mitiglinide exerts its hypoglycemic activity by closing adenosine triphosphate (ATP)-sensitive potassium channels in the beta islet cells of the pancreas. This agent has a rapid onset and short duration of action, mimicking a physiologic pattern of insulin release in nondiabetic people. Studies suggest a starting dose of 5 mg 3 times daily with meals and a maximum dose of 20 mg 3 times daily. Overall, mitiglinide is well tolerated, with the most common adverse effect being hypoglycemia. CONCLUSIONS: Mitiglinide is the third agent in the class of meglitinides that targets postprandial hyperglycemia. Because of a more intensive dosing regimen, potential cost, and lack of studies assessing the clinical impact of mitiglinide therapy on oxidative stress and inflammatory markers secondary to postprandial hyperglycemia, we cannot recommend this therapy over currently approved therapies. PMID- 20841519 TI - Acute generalized exanthematous pustulosis as a manifestation of anticonvulsant hypersensitivity syndrome. PMID- 20841520 TI - FDA's recommendations on the use of long-acting {beta}2 agonists in the management of asthma. AB - The revised labeling for long-acting beta(2) agonists (LABAs) by the Food and Drug Administration (FDA) is controversial and in part is inconsistent with the 2007 National Asthma Education and Prevention Program asthma guidelines. Two large randomized controlled studies, the Serevent Nationwide Surveillance (SNS) study and the Salmeterol Multicenter Asthma Research Trial (SMART), and a 2008 meta-analysis conducted by the FDA were the main sources of information used to determine the label changes. A paucity of large, well-designed, controlled, prospective studies evaluating the asthma-related risks associated with LABAs makes it difficult to reach a consensus regarding how best to use LABAs in patients with asthma. PMID- 20841521 TI - Stress ulcer prophylaxis: reducing non-indicated prescribing after hospital discharge. AB - BACKGROUND: Gastric acid suppressant medications used as stress ulcer prophylaxis (SUP) in the intensive care unit (ICU) are often prescribed inappropriately after discharge. We present tools to reduce the use and cost of non-indicated SUP. OBJECTIVE: To reduce the non-indicated use of SUP after hospital discharge originally started in the ICU, using an education intervention and pharmacist-led medication reconciliation on patient care rounds and at hospital discharge. METHODS: In a retrospective medical record review using a historic control, 356 consecutively admitted patients to the medical/surgical ICU at the University of Wisconsin Hospital were assessed for the appropriate use of SUP at admission to the ICU, at transfer to a general care unit, and at hospital discharge. The education intervention involved teaching both the medical and pharmacist staff about indications for SUP using a memorandum and a pocket guide. Pharmacists also conducted medication reconciliation during daily patient care rounds and at discharge to justify medication use. The outcome of this study is the percentage of patients prescribed non-indicated gastric acid suppressants at hospital discharge. This outcome is compared to a previous study conducted at our hospital. RESULTS: Of 356 eligible patients, 308 (86.5%) received SUP while in the ICU. Thirty-nine (11%) were given continuing SUP after discharge from the hospital, of which 31 (8.7%) had no clear indication. This was a 64.3% reduction from the 24.4% found in the prior study (p < 0.0001). CONCLUSIONS: Educational materials that guide prescribing, pharmacist interaction on patient care rounds, and pharmacist-conducted medication reconciliation significantly reduced the prescribing of non-indicated gastric acid suppressant medications after hospital discharge. PMID- 20841523 TI - The cover. Monhegan, Maine. PMID- 20841522 TI - Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms. AB - BACKGROUND: Interpatient variability in efavirenz concentrations may be due to CYP2B6 genetic polymorphisms. Efavirenz concentration and pharmacogenomic data are scarce in Latino patients. OBJECTIVE: To evaluate the difference in trough and midpoint efavirenz plasma concentrations between HIV-positive Latino and white patients. In addition, this study evaluated the association between efavirenz concentrations and CYP2B6 polymorphisms in Latino and white HIV positive subjects. METHODS: This pilot study included 10 Latinos and 10 whites. Two efavirenz blood concentrations were determined: a trough and a midpoint. CYP2B6 genetic polymorphisms were analyzed at the 516 (G to T) and 785 (A to G) codons. The Mann-Whitney test was used to determine whether efavirenz concentrations varied with ethnicity. The Kruskal-Wallis test was used to determine whether efavirenz concentrations varied with CYP2B6 genetic polymorphisms. Efavirenz concentrations were expressed as medians (minimum, maximum). RESULTS: Midpoint concentrations were 1.58 MUg/mL (1.36, 6.02) and 3.14 MUg/mL (1.74, 7.72) for whites and Latinos, respectively (p < 0.05). Trough concentrations did not vary as a function of ethnicity. Ten percent of Latinos and whites tested positive for homozygous variants of CYP2B6-516 and CYP2B6-785. One white subject tested positive for the homozygous variant of CYP2B6-1459. Trough concentrations for 516TT, 516GT, and 516GG (wild type) were 5.13 MUg/mL (4.13, 6.12), 2.13 MUg/mL (1.33, 3.37), and 1.44 MUg/mL (0.59, 2.92), respectively (p < 0.05). Trough concentrations for 785GG, 785AG, and 785AA (wild type) were 5.12 MUg/mL (4.13, 6.12), 1.98 MUg/mL (1.33, 3.37), and 1.27 MUg/mL (0.59, 2.92), respectively (p < 0.05). None of the patients took concomitant medications that impacted CYP2B6 metabolism. CONCLUSIONS: Trough efavirenz concentrations were significantly higher in patients with the 785 (A to G) and 516 (G to T) variants. Midpoint efavirenz concentrations in Latinos were significantly higher than those of whites. PMID- 20841524 TI - A piece of my mind. "Taking" a history. PMID- 20841525 TI - Balancing responsibilities in health care. PMID- 20841526 TI - Patient decisions to undergo surgery for early-stage lung cancer. PMID- 20841527 TI - Presenteeism among resident physicians. PMID- 20841528 TI - Graduating US medical students who do not obtain a PGY-1 training position. PMID- 20841529 TI - Association of institutional financial support of a core teaching faculty with educational productivity. PMID- 20841530 TI - Relationship between burnout and professional conduct and attitudes among US medical students. AB - CONTEXT: The relationship between professionalism and distress among medical students is unknown. OBJECTIVE: To determine the relationship between measures of professionalism and burnout among US medical students. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional survey of all medical students attending 7 US medical schools (overall response rate, 2682/4400 [61%]) in the spring of 2009. The survey included the Maslach Burnout Inventory (MBI), the PRIME-MD depression screening instrument, and the SF-8 quality of life (QOL) assessment tool, as well as items exploring students' personal engagement in unprofessional conduct, understanding of appropriate relationships with industry, and attitudes regarding physicians' responsibility to society. MAIN OUTCOME MEASURES: Frequency of self reported cheating/dishonest behaviors, understanding of appropriate relationships with industry as defined by American Medical Association policy, attitudes about physicians' responsibility to society, and the relationship of these dimensions of professionalism to burnout, symptoms of depression, and QOL. RESULTS: Of the students who responded to all the MBI items, 1354 of 2566 (52.8%) had burnout. Cheating/dishonest academic behaviors were rare (endorsed by <10%) in comparison to unprofessional conduct related to patient care (endorsed by up to 43%). Only 14% (362/2531) of students had opinions on relationships with industry consistent with guidelines for 6 scenarios. Students with burnout were more likely to report engaging in 1 or more unprofessional behaviors than those without burnout (35.0% vs 21.9%; odds ratio [OR], 1.89; 95% confidence interval [CI], 1.59-2.24). Students with burnout were also less likely to report holding altruistic views regarding physicians' responsibility to society. For example, students with burnout were less likely to want to provide care for the medically underserved than those without burnout (79.3% vs 85.0%; OR, 0.68; 95% CI, 0.55-0.83). After multivariable analysis adjusting for personal and professional characteristics, burnout was the only aspect of distress independently associated with reporting 1 or more unprofessional behaviors (OR, 1.76; 95% CI, 1.45-2.13) or holding at least 1 less altruistic view regarding physicians' responsibility to society (OR, 1.65; 95% CI, 1.35-2.01). CONCLUSION: Burnout was associated with self-reported unprofessional conduct and less altruistic professional values among medical students at 7 US schools. PMID- 20841531 TI - Depression, stigma, and suicidal ideation in medical students. AB - CONTEXT: There is a concerning prevalence of depression and suicidal ideation among medical students, a group that may experience poor mental health care due to stigmatization. OBJECTIVE: To characterize the perceptions of depressed and nondepressed medical students regarding stigma associated with depression. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional Web-based survey conducted in September-November 2009 among all students enrolled at the University of Michigan Medical School (N = 769). MAIN OUTCOME MEASURES: Prevalence of self-reported moderate to severe depression and suicidal ideation and the association of stigma perceptions with clinical and demographic variables. RESULTS: Survey response rate was 65.7% (505 of 769). Prevalence of moderate to severe depression was 14.3% (95% confidence interval [CI], 11.3%-17.3%). Women were more likely than men to have moderate to severe depression (18.0% vs 9.0%; 95% CI for difference, 14.8% to -3.1%; P = .001). Third- and fourth-year students were more likely than first- and second-year students to report suicidal ideation (7.9% vs 1.4%; 95% CI for difference, 2.7%-10.3%; P = .001). Students with moderate to severe depression, compared with no to minimal depression, more frequently agreed that "if I were depressed, fellow medical students would respect my opinions less" (56.0% vs 23.7%; 95% CI for difference, 17.3%-47.3%; P < .001), and that faculty members would view them as being unable to handle their responsibilities (83.1% vs 55.1%; 95% CI for difference, 16.1%-39.8%; P < .001). Men agreed more commonly than women that depressed students could endanger patients (36.3% vs 20.1%; 95% CI for difference, 6.1%-26.3%; P = .002). First- and second-year students more frequently agreed than third- and fourth-year students that seeking help for depression would make them feel less intelligent (34.1% vs 22.9%; 95% CI for difference, 2.3%-20.1%; P < .01). CONCLUSIONS: Depressed medical students more frequently endorsed several depression stigma attitudes than nondepressed students. Stigma perceptions also differed by sex and class year. PMID- 20841532 TI - An educational intervention for contextualizing patient care and medical students' abilities to probe for contextual issues in simulated patients. AB - CONTEXT: A contextual error occurs when a physician does not identify elements of a patient's environment or behavior, such as access to care, that must be addressed to appropriately plan care. Research has demonstrated that contextual errors can be identified using standardized patients. OBJECTIVE: To evaluate an educational intervention designed to increase physicians' skills in incorporating the patient's context in assessment and management of care and to thereby decrease the rate of contextual errors. DESIGN, SETTING, AND PARTICIPANTS: Quasi randomized controlled trial, with assessments by blinded observers. Fourth-year medical students (n = 124) in internal medicine subinternships at the University of Illinois at Chicago or Jesse Brown Veterans Administration Medical Center between July 2008 and April 2009 and between August 2009 and April 2010 participated and were assessed. INTERVENTION: A 4-hour course on contextualization. MAIN OUTCOME MEASURES: Probing for contextual issues in an encounter, probing for medical issues in an encounter, and developing an appropriate treatment plan. Outcomes were assessed using 4 previously validated standardized patient encounters performed by each participant and were adjusted for subinternship site, academic year, time of year, and case scenario. RESULTS: Students who participated in the contextualization workshops were significantly more likely to probe for contextual issues in the standardized patient encounters than students who did not (90% [95% confidence interval {CI}, 87%-94% ] vs 62% [95% CI, 54%-69%], respectively) and significantly more likely to develop appropriate treatment plans for standardized patients with contextual issues (69% [95% CI, 57%-81%] vs 22% [95% CI, 12%-32%]. There was no difference between the groups in the rate of probing for medical issues (80% [95% CI, 75%-85%] vs 81% [95% CI, 76%-86%]) or developing appropriate treatment plans for standardized patients with medical issues (54% [95% CI, 42%-67%] vs 66% [95% CI, 53%-79%]). CONCLUSION: Medical students who underwent an educational intervention were more likely to contextualize care for individual standardized patients. PMID- 20841533 TI - Effect of availability bias and reflective reasoning on diagnostic accuracy among internal medicine residents. AB - CONTEXT: Diagnostic errors have been associated with bias in clinical reasoning. Empirical evidence on the cognitive mechanisms underlying biases and effectiveness of educational strategies to counteract them is lacking. OBJECTIVES: To investigate whether recent experience with clinical problems provokes availability bias (overestimation of the likelihood of a diagnosis based on the ease with which it comes to mind) resulting in diagnostic errors and whether reflection (structured reanalysis of the case findings) counteracts this bias. DESIGN, SETTING, AND PARTICIPANTS: Experimental study conducted in 2009 at the Erasmus Medical Centre, Rotterdam, with 18 first-year and 18 second-year internal medicine residents. Participants first evaluated diagnoses of 6 clinical cases (phase 1). Subsequently, they diagnosed 8 different cases through nonanalytical reasoning, 4 of which had findings similar to previously evaluated cases but different diagnoses (phase 2). These 4 cases were subsequently diagnosed again through reflective reasoning (phase 3). MAIN OUTCOME MEASURES: Mean diagnostic accuracy scores (perfect score, 4.0) on cases solved with or without previous exposure to similar problems through nonanalytical (phase 2) or reflective (phase 3) reasoning and frequency that a potentially biased (ie, phase 1) diagnosis was given. RESULTS: There were no main effects, but there was a significant interaction effect between "years of training" and "recent experiences with similar problems." Results consistent with an availability bias occurred for the second-year residents, who scored lower on the cases similar to those previously encountered (1.55; 95% confidence interval [CI], 1.15-1.96) than on the other cases (2.19; 95% CI, 1.73-2.66; P =.03). This pattern was not seen among the first-year residents (2.03; 95% CI, 1.55-2.51 vs 1.42; 95% CI, 0.92 1.92; P =.046). Second-year residents provided the phase 1 diagnosis more frequently for phase 2 cases they had previously encountered than for those they had not (mean frequency per resident, 1.44; 95% CI, 0.93-1.96 vs 0.72; 95% CI, 0.28-1.17; P =.04). A significant main effect of reasoning mode was found: reflection improved the diagnoses of the similar cases compared with nonanalytical reasoning for the second-year residents (2.03; 95% CI, 1.49-2.57) and the first-year residents (2.31; 95% CI, 1.89-2.73; P =.006). CONCLUSION: When faced with cases similar to previous ones and using nonanalytic reasoning, second year residents made errors consistent with the availability bias. Subsequent application of diagnostic reflection tended to counter this bias; it improved diagnostic accuracy in both first- and second-year residents. PMID- 20841534 TI - Effect of reminders of personal sacrifice and suggested rationalizations on residents' self-reported willingness to accept gifts: a randomized trial. AB - CONTEXT: Despite expanding research on the prevalence and consequences of conflicts of interest in medicine, little attention has been given to the psychological processes that enable physicians to rationalize the acceptance of gifts. OBJECTIVE: To determine whether reminding resident physicians of the sacrifices made to obtain training, as well as suggesting this as a potential rationalization, increases self-stated willingness to accept gifts from industry. DESIGN, SETTING, AND PARTICIPANTS: Three hundred one US resident physicians from 2 sample populations (pediatrics and family medicine) who were recruited during March-July 2009 participated in a survey presented as evaluating quality of life and values. INTERVENTION: Physicians were randomly assigned to receive 1 of 3 different online surveys. The sacrifice reminders survey (n = 120) asked questions about sacrifices made in medical training, followed by questions regarding the acceptability of receiving gifts from industry. The suggested rationalization survey (n = 121) presented the same sacrifice questions, followed by a suggested possible rationalization (based on sacrifices made in medical training) for acceptance of gifts, before the questions regarding the acceptability of gifts. The control survey (n = 60) asked about the acceptability of gifts before asking questions about sacrifices or suggesting a rationalization. MAIN OUTCOME MEASURES: Physician self-stated acceptability of receiving gifts from industry. RESULTS: Reminding physicians of sacrifices made in obtaining their education resulted in gifts being evaluated as more acceptable: 21.7% (13/60) in the control group vs 47.5% (57/120) in the sacrifice reminders group (odds ratio, 1.81; 95% confidence interval, 1.27-2.58; P = .001). Although most residents disagreed with the suggested rationalization, exposure to it further increased the perceived acceptability of gifts to 60.3% (73/121) in that group (odds ratio relative to sacrifice reminders group, 1.45; 95% confidence interval, 1.22-1.72; P < .001). CONCLUSIONS: Providing resident physicians with reminders of sacrifices increased the perceived acceptability of industry-sponsored gifts. Including a rationalization statement further increased gift acceptability. PMID- 20841535 TI - Prematriculation variables associated with suboptimal outcomes for the 1994-1999 cohort of US medical school matriculants. AB - CONTEXT: The relationship between increasing numbers and diversity of medical school enrollees and the US physician workforce size and composition has not been described. OBJECTIVE: To identify demographic and prematriculation factors associated with medical school matriculants' outcomes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study using deidentified data for the 1994-1999 national cohort of 97,445 matriculants who were followed up through March 2, 2009, and had graduated, had withdrawn, or were dismissed. Data were analyzed using multivariable logistic regression to identify factors associated with suboptimal outcomes. MAIN OUTCOME MEASURES: Academic withdrawal or dismissal, nonacademic withdrawal or dismissal, and graduation without first-attempt passing scores on the US Medical Licensing Examination Step 1 and/or Step 2 Clinical Knowledge (CK) compared with graduation with first-attempt passing scores on both of the examinations. RESULTS: Of 84,018 matriculants (86.2%), 74,494 graduated and had first-attempt passing scores on both the Step 1 and Step 2 CK (88.7%), 6743 graduated and did not have first-attempt passing scores on the Step 1 and/or Step 2 CK (8.0%), 1049 withdrew or were dismissed for academic reasons (1.2%), and 1732 withdrew or were dismissed for nonacademic reasons (2.1%). Variables associated with greater likelihood of graduation without first-attempt passing scores on the Step 1 and/or Step 2 CK and of academic withdrawal or dismissal, respectively, were (1) Medical College Admission Test scores (scores of 18-20 [2.9% of sample] vs > 29: adjusted odds ratio [AOR], 13.06 [95% confidence interval {CI}, 11.56-14.76] and AOR, 11.08 [95% CI, 8.50-14.45]; scores of 21-23 [5.6% of sample] vs > 29: AOR, 7.52 [95% CI, 6.79-8.33] and AOR, 5.97 [95% CI, 4.68-7.62]; and scores of 24-26 [13.9% of sample] vs > 29: AOR, 4.27 [95% CI, 3.92-4.65] and AOR, 3.56 [95% CI, 2.88-4.40]), (2) race/ethnicity (Asian or Pacific Islander [18.2% of sample] vs white: AOR, 2.15 [95% CI, 2.00-2.32] and AOR, 1.69 [95% CI, 1.37-2.09]; underrepresented minority [14.9% of sample] vs white: AOR, 2.30 [95% CI, 2.13-2.48] and AOR, 2.96 [95% CI, 2.48-3.54]), and (3) premedical debt (> or = $50,000 [1.0% of sample] vs no debt: AOR, 1.68 [95% CI, 1.35-2.08] and AOR, 2.33 [95% CI, 1.57-3.46]). CONCLUSIONS: Lower scores on the Medical College Admission Test, nonwhite race/ethnicity, and premedical debt of at least $50,000 were independently associated with a greater likelihood of academic withdrawal or dismissal and graduation without first-attempt passing scores on the US Medical Licensing Examination Step l and/or Step 2 CK. PMID- 20841536 TI - Association of third-year medical students' first clerkship with overall clerkship performance and examination scores. AB - CONTEXT: Anecdotal experience has suggested that third-year medical students whose first clerkship is internal medicine may have superior performance throughout the academic year. OBJECTIVE: To determine whether the order of clerkships by specialty is associated with student performance. DESIGN, SETTING, AND PARTICIPANTS: Clerkship performance records of medical students at all 4 campuses of the University of Illinois College of Medicine who completed their third-year core clerkships from July 2000 through June 2008 (N = 2236) were reviewed. MAIN OUTCOME MEASURES: Analysis of covariance was used to test for between-group differences (by first clerkship) in mean National Board of Medical Examiners subject examination scores (range, 0-100), preceptor ratings of clerkship clinical performances (range, 12-30), total overall clerkship grades (range, 12-30), and United States Medical Licensing Examination (USMLE) Step 2 scores, adjusted for sex, campus, and USMLE Step 1 score. RESULTS: First clerkship specialty was significantly associated with mean subject examination scores (family medicine, 71.96 [95% confidence interval {CI}, 70.90-72.98], internal medicine, 73.86 [95% CI, 73.33-74.39], obstetrics/gynecology, 72.36 [95% CI, 71.64-73.04], pediatrics, 73.11 [95% CI, 72.38-73.84], psychiatry, 72.17 [95% CI, 71.52-72.81], surgery, 72.37 [95% CI, 71.73-73.02]; P < .001) and overall clerkship grades (family medicine, 24.20 [95% CI, 23.90-24.90], internal medicine, 25.33 [95% CI, 25.07-25.60], obstetrics/gynecology, 24.68 [95% CI, 24.32-25.05], pediatrics, 24.92 [95% CI, 24.59-25.27], psychiatry, 24.61 [95% CI, 24.33-25.01], surgery 24.97 [95% CI, 24.64-25.30]; P = .01). There was no significant association with preceptor ratings or USMLE Step 2 scores. Pairwise comparisons for mean total overall clerkship grades showed a significant difference for students taking internal medicine first compared with obstetrics/gynecology (mean difference, 0.65; 95% CI, 0.18-1.12), psychiatry (mean difference, 0.66; 95% CI, 0.20-1.12), and family medicine (mean difference, 0.93; 95% CI, 0.37-1.50). CONCLUSION: Among students at 4 campuses of a US medical school, clerkship order was significantly associated with performance on clerkship subject examinations and overall grades but not with clerkship clinical performance or USMLE Step 2 scores. PMID- 20841537 TI - Biomedical informatics in the education of physicians. PMID- 20841538 TI - Incorporating economic reality into medical education. PMID- 20841539 TI - Understanding depression and distress among medical students. PMID- 20841540 TI - How (should) physicians think?: a journey from behavioral economics to the bedside. PMID- 20841541 TI - Are you sure this is right?: insights into the ways trainees act, feel, and reason. PMID- 20841542 TI - Medical schools in the United States, 2009-2010. PMID- 20841543 TI - Graduate medical education, 2009-2010. PMID- 20841544 TI - JAMA patient page. Medical licensure. PMID- 20841545 TI - Echocardiographic assessment of dyssynchrony: moving forward. PMID- 20841546 TI - A global rank end point for clinical trials in acute heart failure. PMID- 20841547 TI - Improving the care for myocardial infarction: editor's perspective. PMID- 20841548 TI - Moving toward improved care for the patient with ST-elevation myocardial infarction: a mandate for systems of care. PMID- 20841549 TI - A general propensity to psychological distress affects cardiovascular outcomes: evidence from research on the type D (distressed) personality profile. PMID- 20841550 TI - Quality improvement initiative for rapid induction of hypertension control in primary care. PMID- 20841551 TI - Letter by Shroff regarding article, "prognostic implications of left ventricular filling pressure with exercise". PMID- 20841552 TI - Letter by Stone and Mintz regarding article, "unreliable assessment of necrotic core by virtual histology intravascular ultrasound in porcine coronary artery disease". PMID- 20841554 TI - Single-photon emission computed tomography perfusion imaging: is using a "warranty period" warranted? PMID- 20841555 TI - A case of partial congenital absence of pericardium revealed by MRI. PMID- 20841556 TI - Skeletal status in psychotic disorders: a population-based study. AB - OBJECTIVE: To compare the skeletal status of subjects with primary psychotic disorders with the general population by means of bone ultrasound measurements. Schizophrenia seems to be associated with low bone mineral density through a still unclear mechanism, although information on other psychotic disorders is scarce. METHODS: In a nationally representative sample, quantitative ultrasound values of the heel, i.e., broadband ultrasound attenuation (BUA) and speed of sound, were measured from subjects with schizophrenia (n = 48), other nonaffective psychosis (n = 56), affective psychosis (n = 37), and from 6,100 population controls. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision lifetime psychosis diagnoses were based both on Structured Clinical Interview and case note data. Information on the most common risk factors for bone fragility was elicited through an interview, health examination, and questionnaires. In addition, serum 25-hydroxyvitamin D was measured. RESULTS: Women with schizophrenia and men with affective psychosis had significantly lower bone ultrasound values as compared with the age- and sex matched population controls (Z-BUA = -0.54, p = .001 and Z-BUA = -0.37, p = .04, respectively). Significantly lower vitamin D levels were observed in subjects with schizophrenia in comparison with the general population (p = .006). Schizophrenia remained an independent determinant of poor skeletal status in women even after controlling for common risk factors for osteoporosis, vitamin D status, and antipsychotic and mood-stabilizing medication (Z-BUA = -0.54, p = .002). CONCLUSIONS: In this population-based study, schizophrenia was found to be independently associated with poor skeletal status in women. PMID- 20841557 TI - Psychosocial factors in the development of heart disease in women: current research and future directions. AB - OBJECTIVE: To review the recent (1995-2009) literature on psychosocial risk and protective factors for coronary heart disease (CHD) among women, including negative emotions, stress, social relationships, and positive psychological factors. METHODS: Articles for the review were identified using PubMed and bibliographies of relevant articles. Eligible studies included at least 100 women and either focused on a) exclusively female participants or b) both men and women, conducting either gender-stratified analyses or examining interactions with gender. Sixty-seven published reports were identified that examined prospective associations with incident or recurrent CHD. RESULTS: In general, evidence suggests that depression, anxiety disorders, anger suppression, and stress associated with relationships or family responsibilities are associated with elevated CHD risk among women, that supportive social relationships and positive psychological factors may be associated with reduced risk, and that general anxiety, hostility, and work-related stress are less consistently associated with CHD among women relative to men. CONCLUSIONS: A growing literature supports the significance of psychosocial factors for the development of CHD among women. Consideration of both traditional psychosocial factors (e.g., depression) and factors that may be especially important for women (e.g., stress associated with responsibilities at home or multiple roles) may improve identification of women at elevated risk as well as the development of effective psychological interventions for women with or at risk for CHD. PMID- 20841558 TI - Depression is associated with increased mortality 10 years after coronary artery bypass surgery. AB - OBJECTIVE: To determine if depression is independently associated with cardiac and all-cause mortality 10 years after coronary artery bypass graft (CABG) surgery. Although many studies have examined the relationship of depression and mortality in patients with myocardial infarction, there is less understanding of the relationship between depression and long-term mortality after CABG surgery. METHODS: In a prospective study, we collected data on 309 patients hospitalized after CABG surgery. Before discharge, patients were assessed for depression using the Diagnostic Interview Schedule and the Beck Depression Inventory (BDI). Subsequently, mortality data were obtained from the National Center for Health Statistics and supplemented with phone interviews. RESULTS: Sixty-three (20%) patients met modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder (MDD) and 87 (28%) had BDI scores of >=10, indicating elevated depressive symptoms. Time-to-event or last follow-up phone contact ranged from 9 days to 11.5 years (median, 9.3 years). The overall mortality rate was 37.9% (117 of 309), with 20.1% (62 of 309) due to cardiac causes. Cox proportional hazard modeling showed that age (hazard ratio [HR], 1.04; p = .005), left ventricular ejection fraction (EF) (EF <0.35 [HR], 3.9; p < .001; EF, 0.35-0.49 [HR], 1.9; p = .03), and MDD (HR, 1.8; p = .04) were independent predictors of cardiac mortality. The BDI and the cognitive-affective symptoms subset of BDI symptoms were also predictors of cardiac mortality. Age, EF, and diabetes predicted all-cause mortality, but MDD did not. CONCLUSIONS: Depression, assessed both in structured interview and by BDI, was significantly associated with elevated cardiac mortality 10 years after CABG surgery. PMID- 20841559 TI - Serum folate, vitamin B-12, and homocysteine and their association with depressive symptoms among U.S. adults. AB - OBJECTIVE: To examine, in a nationally representative sample of U.S. adults, the associations of serum folate, vitamin B-12, and total homocysteine (tHcy) levels with depressive symptoms. Several nutritional and physiological factors have been linked to depression in adults, including low folate and vitamin B-12 and elevated tHcy levels. METHODS: Data on U.S. adults (age, 20-85 years; n = 2524) from the National Health and Nutrition Examination Survey during the period 2005 to 2006 were used. Depressive symptoms were measured with the Patient Health Questionnaire (PHQ), and elevated symptoms were defined as a PHQ total score of >=10. Serum folate, vitamin B-12, and tHcy were mainly expressed as tertiles. Multiple ordinary least square (OLS), logistic, and zero-inflated Poisson regression models were conducted in the main analysis. RESULTS: Overall, mean PHQ score was significantly higher among women compared with men. Elevated depressive symptoms (PHQ score of >=10) were inversely associated with folate status, particularly among women (fully adjusted odds ratio [tertiles T(3) versus T(1)] = 0.37; 95% confidence interval, 0.17-0.86), but not significantly related to tHcy or vitamin B-12. No interaction was noted between the three exposures in affecting depressive symptoms. In older adults (>=50 years) and both sexes combined, tHcy was positively associated with elevated depressive symptoms (fully adjusted odds ratio [tertiles T(2) versus T(1)] = 3.01; 95% confidence interval, 1.01-9.03), although no significant dose-response relationship was found. CONCLUSIONS: Future interventions to improve mental health outcomes among U.S. adults should take into account dietary and other factors that would increase levels of serum folate. PMID- 20841560 TI - Momentary work worries, marital disclosure, and salivary cortisol among parents of young children. AB - OBJECTIVE: To investigate whether worries about work are linked to people's own cortisol levels and their spouses' cortisol levels in everyday life and whether marital factors may moderate these links. Although research has shown that satisfying marriages can buffer the physiological effects of everyday stress, the specific mechanisms through which marriage influences the processing and transmission of stress have not yet been identified. METHODS: Thirty-seven healthy married couples completed baseline measures and then provided saliva samples and indicated their worries about work for six times a day from a Saturday morning through a Monday evening. RESULTS: Wives' cortisol levels were associated positively with their own work worries (p = .008) and with their husbands' work worries (p = .006). Husbands' cortisol levels were associated positively only with their own work worries (p = .015). Wives low in both marital satisfaction and disclosure showed a stronger association between work worries and cortisol compared with wives reporting either high marital satisfaction and/or high marital disclosure. CONCLUSIONS: These results suggest that momentary feelings of stress affect not only one's own cortisol levels but affect close others' cortisol levels as well. Furthermore, they suggest that, for women, the stress-buffering effects of a happy marriage may be partially explained by the extent to which they disclose their thoughts and feelings with their spouses. PMID- 20841561 TI - Anxiety increases acid-induced esophageal hyperalgesia. AB - OBJECTIVE: Anxiety at the time of gastrointestinal injury or inflammation increases the risk of developing visceral hyperalgesia. Distal esophageal acidification induces hyperalgesia in the non-acid exposed proximal esophagus, due to the sensitization of spinal dorsal horn neurones. The objective was to determine whether anxiety influences acid-induced hyperalgesia. METHODS: A total of 19 healthy volunteers (n = 12 females; age, 22-57 years; mean, 35.7 years) completed a 10-minute mood induction paradigm (anxiety or neutral) with autonomic monitoring (visit 1). On visits 2 and 3, pain thresholds to electrical stimulation, in milliamperes (mA), were determined in the proximal esophagus and foot (control) before and after a 30-minute infusion of 0.15 M of hydrochloric acid. During esophageal acid infusion, the subjects randomly received anxiety or neutral mood induction with autonomic monitoring, in a crossover design. Anxiety and pain ratings were recorded pre and post infusion. RESULTS: Visit 1: Anxiety induction increased anxiety scores (p < .001), mean arterial pressure (p < .001), and cardiac sympathetic index (p = .007), and reduced parasympathetic measures (cardiac vagal tone [p = .05] and cardiac sensitivity to baroreflex [p = .006)]). Visit 2: Anxiety induction conferred greater acid-induced hyperalgesia compared with neutral (-4.9 mA versus 2.7 mA, p = .009, analysis of covariance). No differences in autonomic measures were found during acid infusion with anxiety or neutral mood induction. CONCLUSIONS: Anxiety induction increases acid-induced esophageal hyperalgesia; anxiety, thus, facilitates central sensitization in the esophagus. Our studies provide a new model for studying the effects of anxiety on esophageal hyperalgesia and may allow testing of therapeutic strategies to reduce this effect. PMID- 20841562 TI - Cortisol and depressive symptoms in a population-based cohort of midlife women. AB - OBJECTIVE: To determine whether there is a relationship between depressive symptoms and cortisol assessed at first morning awakening, 6 PM, and 9 PM in a population-based sample of midlife women. If this relationship is not linear, we aim to test whether this relationship is nonlinear, only present in those with more severe depressive symptoms, better accounted for by diurnal slope, or only apparent under uncontaminated conditions. METHODS: We investigated the cross sectional association between cortisol and depressive symptoms, assessed by the Center for Epidemiological Studies Depression scale (CES-D) in 408 midlife women (45.7% African Americans, 54.3% white; mean age, 50.4 years) participating in the Chicago site of the Study of Women's Health Across the Nation. RESULTS: Diurnal cortisol slope is significantly flatter for women with higher CES-D scores than for less depressed women (p < .05 for the interaction). This relationship remains significant even after adjusting for age, smoking status, race, education, income, menopausal status, hormone replacement therapy, body mass index, medications, and wake time, as well as possibly contaminating factors, including physical activity, smoking, eating, or caffeine or alcohol consumption before saliva collection. Results using depression assessed categorically (CES-D cutoff >=16) were similar to those using continuous depression in both unadjusted and adjusted analyses (p = .005 for the interaction of CES-D by time). CONCLUSIONS: In this population-based sample of midlife women, greater depressive symptoms were associated with a significantly flatter diurnal cortisol slope than those with fewer symptoms, even after adjusting for covariates and possibly contaminating behaviors. PMID- 20841564 TI - Focus issue: Evolution III--domains for change. AB - This third installment in the series on the evolution of signaling molecules and networks highlights domains as a medium for evolution. Two Perspectives highlight how changes in domains can lead to new protein interactions or the evolution of new signaling events. Research in this issue highlights the evolution of proteins with domains involved in extrinsic apoptosis, a particular form of cell death caused by extracellular ligands that bind to "death receptors," and shows that this cell death pathway occurred earlier in evolution than was previously thought. A Review describes the evolution of the ABL family of tyrosine kinases, which have acquired isoform-specific functions through the unique combinations of domains and which are of particular importance in cancer. PMID- 20841563 TI - Overnight changes of immune parameters and catecholamines are associated with mood and stress. AB - OBJECTIVES: To test the hypothesis that a nocturnal decrease of secretion of inflammation markers and catecholamines would be associated with mood and stress variables even after controlling for objective sleep variables. METHODS: A total of 130 healthy volunteers participated in this study, spending 2 nights in the Gillin Laboratory of Sleep and Chronobiology at the University of California, San Diego, General Clinical Research Center. Blood samples were obtained before sleep (10:30 PM) and after awakening (6:30 AM) on the first day, and these samples were assayed for inflammatory biomarkers and catecholamines. On the second night, polysomnographic records were scored for objective sleep variables, e.g., total sleep time and wake after sleep onset. Self-rating scales for mood, stress, depression, and daily hassles were administered the second day. RESULTS: The nocturnal decrease in interleukin-6 was smaller in people who reported more negative mood or fatigue and greater in those who reported more uplift events (e.g., with Profile of Mood States fatigue r(p) = -.25 to -.30). People with high stress or high depression levels had smaller nocturnal decreases of epinephrine. That relationship was even stronger when partial correlations were used to control for morning level and sleep variables. The associations between nocturnal changes of C-reactive protein, soluble tumor necrosis factor-receptor I, and norepinephrine with psychological states were nonremarkable. CONCLUSIONS: The analyses of nocturnal change scores (difference scores) add substantial information compared with the traditional analyses of morning levels of immune variables and catecholamines alone. Subjective well-being is significantly associated with a greater nocturnal decrease of interleukin-6 and epinephrine. More research on nocturnal adaptation processes is warranted. PMID- 20841565 TI - Domain recombination: a workhorse for evolutionary innovation. AB - Although the combination of modular domains within proteins has been proposed as a determining feature of evolutionary innovation and flexibility, direct evidence for this mechanism of evolution has been sketchy. Two papers, one creating new domain combinations in the yeast mating pathway and another involving a comprehensive analysis of protein function and domain architecture across major organisms, have provided firm evidence that the recombining of domains can lead to evolutionary innovation. The results will guide future studies in synthetic and evolutionary biology. PMID- 20841566 TI - Signals: tinkering with domains. AB - Evolution reuses established modules. At the level of cell signaling, protein domains are used in many contexts to transfer different messages. A frequently occurring binding domain uses a structural scaffold to allow for sequence variation at critical sites without compromising structural stability. Even random mutations have a high chance of conferring a novel function, and only a small fraction of available sequence space is actually explored. Accordingly, current lab techniques allow us to infer evolutionary routes, exploring the possible and the attainable in terms of complex structure-function relationships. PMID- 20841567 TI - Characterization of the extrinsic apoptotic pathway in the basal chordate amphioxus. AB - The death receptor (DR)-mediated apoptosis pathway is thought to be unique to vertebrates. However, the presence of DR-encoding genes in the sea urchin and the basal chordate amphioxus prompted us to reconsider, especially given that amphioxus contains 14 DR proteins and hundreds of death domain (DD)-containing adaptor proteins. To understand how the extrinsic apoptotic pathway was originally established and what the differences in signaling are between invertebrates and vertebrates, we performed functional studies of several genes that encode DDs in the amphioxus Branchiostoma belcheri tsingtauense (Bbt). First, we observed that the increased abundance of Bbt Fas-associated death domain 1 (BbtFADD1) in HeLa cells resulted in the formation of death effector filamentous structures in the cytoplasm and the activation of the nuclear factor kappaB pathway, whereas BbtFADD2 protein was restricted to the nucleus, although its death effector domain induced apoptosis when in the cytoplasm. We further demonstrated that formation of a FADD-caspase-8 complex recruited amphioxus DR1 (BbtDR1), which bound to the adaptor proteins CRADD or TRAF6 (tumor necrosis factor receptor-associated factor 6) to convey distinct signals, ranging from apoptosis to gene activation. Thus, our study not only reveals the evolutionary origin of the extrinsic apoptotic pathway in a basal chordate but also adds to our understanding of the similarities and differences between invertebrate and vertebrate FADD signaling. PMID- 20841570 TI - How do IMGs compare with Canadian medical school graduates in a family practice residency program? AB - OBJECTIVE: To compare international medical graduates (IMGs) with Canadian medical school graduates in a family practice residency program. DESIGN: Analysis of the results of the in-training evaluation reports (ITERs) and the Certification in Family Medicine (CCFP) examination results for 2 cohorts of IMGs and Canadian-trained graduates between the years 2006 and 2008. SETTING: St Paul's Hospital (SPH) in Vancouver, BC, a training site of the University of British Columbia (UBC) Family Practice Residency Program. PARTICIPANTS: In training evaluation reports were examined for 12 first-year and 9 second-year Canadian-trained residents at the SPH site, and 12 first-year and 12 second-year IMG residents at the IMG site at SPH; CCFP examination results were reviewed for all UBC family practice residents who took the May 2008 examination and disclosed their results. MAIN OUTCOME MEASURES: Pass or fail rates on the CCFP examination; proportions of evaluations in each group of residents given each of the following designations: exceeds expectations, meets expectations, or needs improvement. The May 2008 CCFP examination results were reviewed. RESULTS: Compared with the second-year IMGs, the second-year SPH Canadian-trained residents had a greater proportion of exceeds expectations designations than the IMGs. For the first-year residents, both the SPH Canadian graduates and IMGs had similar results in all 3 categories. Combining the results of the 2 cohorts, the Canadian-trained residents had 310 (99%) ITERs that were designated as either exceeds expectations or meets expectations, and only 3 (1%) ITERs were in the needs improvement category. The IMG results were 362 (97.6%) ITERs in the exceeds expectations or meets expectations categories; 9 (2%) were in the needs improvement category. Statistically these are not significant differences. Seven of the 12 (58%) IMG candidates passed the CCFP examination compared with 59 of 62 (95%) of the UBC family practice residents. CONCLUSION: The IMG residents compared favourably with their Canadian-trained colleagues when comparing ITERs but not in passing the CCFP examination. Further research is needed to elucidate these results. PMID- 20841571 TI - Relationship between spinal magnetic resonance imaging findings and candidacy for spinal surgery. AB - OBJECTIVE: To compare the prevalence of spinal abnormalities found on magnetic resonance imaging (MRI) in symptomatic surgical candidates and non-surgical patients. DESIGN: Retrospective cohort study. SETTING: A single academic spine surgery practice in Toronto, Ont. PARTICIPANTS: A total of 1586 symptomatic patients referred during a 32-month period; based on chart review, patients were classified as surgical candidates (n=722), non-surgical patients (n=690), or indeterminate regarding surgical candidacy (n=174). MAIN OUTCOME MEASURES: Prevalence rates of different spinal abnormalities between the 2 cohorts, including type, severity, and number of levels of abnormalities detected on lumbar MRI. RESULTS: The total number of abnormalities did not differ between the 2 groups (P=.26). The non-surgical group exhibited more degenerative disk disease (P<.01), while surgical candidates had a higher prevalence of spinal stenosis and spondylolisthesis (P<.01). In multivariate analysis, age (adjusted odds ratio [AOR] per 10-year increase 3.33, 95% confidence interval [CI] 3.32 to 3.33), disk herniation (AOR 1.49, 95% CI 1.16 to 1.89), spinal stenosis (AOR 1.61, 95% CI 1.26 to 2.05), and spondylolisthesis (AOR 2.83, 95% CI 2.08 to 3.88) were independent predictors of surgical candidacy. CONCLUSION: These results might enable physicians without specialty training in spinal disorders to more effectively use MRI reports when deciding on referral to surgical or non-surgical specialists. In jurisdictions with long wait times for elective spinal surgery consultation, a more directed referral is one of many steps necessary to improve patient access and management. PMID- 20841572 TI - First Nations women's knowledge of menopause: experiences and perspectives. AB - OBJECTIVE: To understand and describe the menopause experiences and perspectives of First Nations women residing in northwestern Ontario. DESIGN: Phenomenologic approach using in-depth qualitative interviews. SETTING: Sioux Lookout, Ont, and 4 surrounding First Nations communities. PARTICIPANTS: Eighteen perimenopausal and postmenopausal First Nations women, recruited by convenience and snowball sampling techniques. METHODS: Semistructured interviews were audiotaped and transcribed. Themes emerged through a crystallization and immersion analytical approach. Triangulation of methods was used to ensure reliability of findings. MAIN FINDINGS: This study confirms the hypothesis that menopause is generally not discussed by First Nations women, particularly with their health care providers. The generational knowledge gained by the women in this study suggests that a variety of experiences and symptoms typical of menopause from a medical perspective might not be conceptually linked to menopause by First Nations women. The interview process and initial consultation with translators revealed that there is no uniform word in Ojibway or Oji-Cree for menopause. A common phrase is "that time when periods stop," which can be used by caregivers as a starting point for discussion. Participants' interest in the topic and their desire for more information might imply that they would welcome the topic being raised by health care providers. CONCLUSION: This study speaks to the importance of understanding the different influences on a woman's menopause experience. Patient communication regarding menopause might be enhanced by providing women with an opportunity or option to discuss the topic with their health care providers. Caregivers should also be cautious of attaching preconceived ideas to the meaning and importance of the menopause experience. PMID- 20841568 TI - ABL tyrosine kinases: evolution of function, regulation, and specificity. AB - ABL-family proteins comprise one of the best conserved branches of the tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2 tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. This cassette is coupled to an actin-binding and -bundling domain, which makes ABL proteins capable of connecting phosphoregulation with actin-filament reorganization. Two vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain through which it mediates DNA damage-repair functions, whereas ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. Information on ABL regulatory mechanisms is being mined to provide new therapeutic strategies against hematopoietic malignancies caused by BCR-ABL1 and related leukemogenic proteins. PMID- 20841573 TI - Family physicians' choices of and opinions on colorectal cancer screening modalities. AB - OBJECTIVE: To determine FPs' choices of and opinions on colorectal cancer (CRC) screening options in the context of a new provincewide screening program. METHODS: Mailed survey, using a modified Dillman protocol, which asked about 5 recommended CRC screening modalities. SETTING: Ontario. PARTICIPANTS: Computer generated random sample of 894 eligible FPs and GPs from a commercially available physician directory. MAIN OUTCOME MEASURES: Physicians' preferences for personal CRC screening; perceptions of patients' preferences for CRC screening; knowledge of screening test characteristics; and opinions on cost-effectiveness and mortality reduction of screening modalities. RESULTS: Of the 894 eligible FPs and GPs who received the mailed survey, 465 physicians responded (response rate of 52%). Respondents were diverse in demographic and practice characteristics. Decennial colonoscopy and biennial fecal occult blood testing (FOBT) were the 2 most popular screening methods. There was a statistically significant difference between physicians' preferences of screening options and their perceptions about patient preferences (P<.001), with 50.8% of physicians preferring colonoscopy (vs 39.6% FOBT) but 64.1% believing the average patient prefers FOBT (vs 29.0% colonoscopy). Opinions on the cost-effectiveness and effect on mortality of screening modalities and FOBT sensitivity, but not colonoscopy wait times, significantly influenced both physician preferences and their perceptions of patient preferences. Of the respondents, 54.4% believed colonoscopy had the greatest mortality reduction, while 66.1% chose FOBT as the most cost-effective CRC screening method. CONCLUSION: There was a significant difference between primary care physicians' preferences and their perceptions of patient preferences for CRC screening (P<.001). Screening choice was influenced by physicians' perceptions of FOBT sensitivity and their opinions on cost-effectiveness and mortality reduction of the screening modality. Colonoscopy wait times did not influence physicians' screening choices. As some screening programs emphasize FOBT for most people, this might result in fewer physican-patient discussions about options of other screening modalities. Further research into patient preferences for screening is warranted. PMID- 20841576 TI - An unexpected glimpse. PMID- 20841574 TI - Game-based versus traditional case-based learning: comparing effectiveness in stroke continuing medical education. AB - OBJECTIVE: To evaluate family physicians' enjoyment of and knowledge gained from game-based learning, compared with traditional case-based learning, in a continuing medical education (CME) event on stroke prevention and management. DESIGN: An equivalence trial to determine if game-based learning was as effective as case-based learning in terms of attained knowledge levels. Game questions and small group cases were developed. Participants were randomized to either a game based or a case-based group and took part in the event. SETTING: Ontario provincial family medicine conference. PARTICIPANTS: Thirty-two family physicians and 3 senior family medicine residents attending the conference. INTERVENTION: Participation in either a game-based or a case-based CME learning group. MAIN OUTCOME MEASURES: Scores on 40-item immediate and 3-month posttests of knowledge and a satisfaction survey. RESULTS: Results from knowledge testing immediately after the event and 3 months later showed no significant difference in scoring between groups. Participants in the game-based group reported higher levels of satisfaction with the learning experience. CONCLUSION: Games provide a novel way of organizing CME events. They might provide more group interaction and discussion, as well as improve recruitment to CME events. They might also provide a forum for interdisciplinary CME. Using games in future CME events appears to be a promising approach to facilitate participant learning. PMID- 20841577 TI - Canadian Family Physician editorial fellowship. PMID- 20841579 TI - How have you used your SOAP today?: Considering the effects of food and environment on gene expression. PMID- 20841581 TI - Improving Medicare. PMID- 20841583 TI - Food-borne illnesses during pregnancy. PMID- 20841584 TI - CPS information lacking. PMID- 20841585 TI - Out-of-office BP measurement vital. PMID- 20841586 TI - Bariatric surgery: a primer. AB - OBJECTIVE: To review the management of bariatric surgical patients. QUALITY OF EVIDENCE: MEDLINE, EMBASE, and Cochrane Library databases were searched, as well as PubMed US National Library, from January 1950 to December 2009. Evidence was levels I, II, and III. MAIN MESSAGE: Bariatric surgery should be considered for obese patients at high risk of morbidity and mortality who have not achieved adequate weight loss with lifestyle and medical management and who are suffering from the complications of obesity. Bariatric surgery can result in substantial weight loss, resolution of comorbid conditions, and improved quality of life. The patient's weight-loss history; his or her personal accountability, responsibility, and comprehension; and the acceptable level of risk must be taken into account. Complications include technical failure, bleeding, abdominal pain, nausea or vomiting, excess loose skin, bowel obstruction, ulcers, and anastomotic stricture. Lifelong monitoring by a multidisciplinary team is essential. CONCLUSION: Limited long-term success of behavioural and pharmacologic therapies in severe obesity has led to renewed interest in bariatric surgery. Success with bariatric surgery is more likely when multidisciplinary care providers, in conjunction with primary care providers, assess, treat, monitor, and evaluate patients before and after surgery. Family physicians will play a critical role in counseling patients about bariatric surgery and will need to develop skills in managing these patients in the long-term. PMID- 20841587 TI - Safety of using montelukast during pregnancy. AB - QUESTION: Montelukast is used more and more by my patients with asthma. Is it safe to use during pregnancy? ANSWER: Cumulative data, including a recent Motherisk study, are very reassuring regarding the use of this drug to treat pregnant patients with asthma. PMID- 20841588 TI - Management of painful wounds in advanced disease. PMID- 20841589 TI - Motivating patients to activity: a light at the end of the couch? PMID- 20841590 TI - Primary biliary cirrhosis associated with pernicious anemia. PMID- 20841591 TI - Ophthaproblem. Question: Can you identify this condition? Diagnosis: Acute anterior granulomatous uveitis. PMID- 20841592 TI - Dermacase. Question: Can you identify this condition? Diagnosis: Meningococcemia. PMID- 20841593 TI - Taking the stress out of treating erectile dysfunction. PMID- 20841594 TI - APNEIC: an easy-to-use screening tool for obstructive sleep apnea. PMID- 20841595 TI - Adoption of open-access scheduling in an academic family practice. AB - PROBLEM ADDRESSED: Patients have to wait too long to see their family physicians. Open access, a new approach to office scheduling, has shown promise in reducing patient wait times to see primary care physicians. OBJECTIVE OF PROGRAM: To offer same-day appointments to most patients who call the office, thus reducing wait times as measured by the third available appointment. Reductions in no-show rates have also been reported by those who have adopted the open-access system. PROGRAM DESCRIPTION: Following extensive preparation, a 2-site academic practice in Halifax, NS, adopted open-access booking in October 2008. Data on third available appointment times, no-show appointments, and patient volumes were tracked before and during the yearlong implementation. CONCLUSION: The clinics recorded a substantial, sustained reduction in third available appointment time, indicating improved patient access. There was also a decline in no-show appointments. Patient volumes were unaffected. PMID- 20841596 TI - Examination outcomes for international medical graduates pursuing or completing family medicine residency training in Quebec. AB - OBJECTIVE: To review the success of international medical graduates (IMGs) who are pursuing or have completed a Quebec residency training program and examinations. DESIGN: We retrospectively reviewed IMGs' success rates on the pre residency College des medecins du Quebec medical clinical sciences written examination and objective structured clinical examination, as well as on the post residency Certification Examination in Family Medicine. SETTING: Quebec. PARTICIPANTS: All IMGs taking their examinations between 2001 and 2008, inclusive, and Canadian and American graduates taking their examinations during this same period. MAIN OUTCOME MEASURES: Success rates for IMGs on the pre residency and post-residency examinations, compared with success rates for Canadian and American graduates. RESULTS: Success rates on the pre-residency clinical examinations remained below 50% from 2001 to 2008 for IMGs. Similarly, during the same period, the average success rate on the Certification examination was 56.0% for IMGs, compared with 93.5% for Canadian and American medical graduates. CONCLUSION: Despite pre-residency competency screening and in-program orientation and supports, a substantial number of IMGs in Quebec are not passing their Certification examinations. Another study is under way to analyze reasons for some IMGs' lack of success and to find ways to help IMGs complete residency training successfully and pass the Certification examination. PMID- 20841597 TI - Haiti, we can see your halo. PMID- 20841601 TI - Structured teaching and assessment: a new chart-stimulated recall worksheet for family medicine residents. PMID- 20841602 TI - Maternity care in Canada: what can we deliver? PMID- 20841605 TI - Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. AB - BACKGROUND: Infection with high-risk human papillomavirus (HPV) is the main cause of high-grade cervical intraepithelial neoplasia (CIN) and cancer. It has been suggested that information about high-risk HPV type-specific infection might make cervical cancer screening more effective. Persistent HPV infection could also be a useful screening marker. We estimated the long-term risk of high-grade CIN after one-time detection of high-risk HPV DNA and after persistent infection with individual high-risk HPV types. METHODS: A cohort of 8656 women from the general population of Denmark was examined twice, 2 years apart (first study examination: May 15, 1991, to January 31, 1993; second study examination: October 1, 1993, to January 31, 1995). The women underwent a gynecological examination and cervical cytology and had swabs taken for HPV DNA analysis by the Hybrid Capture 2 and line probe assays. The women were followed up through the nationwide Danish Pathology Data Bank for cervical neoplasia for up to 13.4 years. The absolute risk of developing cervical lesions before a given time was estimated as a function of time. RESULTS: For women with normal cytological findings who were concurrently HPV16 DNA positive at the second examination, the estimated probability of developing CIN grade 3 (CIN3) or worse within 12 years of follow up was 26.7% (95% confidence interval [CI] = 21.1% to 31.8%). The corresponding risks among those infected with HPV18 was 19.1% (95% CI = 10.4% to 27.3%), with HPV31 was 14.3% (95% CI = 9.1% to 19.4%), and with HPV33 was 14.9% (95% CI = 7.9% to 21.1%). The absolute risk of CIN3 or worse after infection with high-risk HPV types other than HPV16, HPV18, HPV31, or HPV33 was 6.0% (95% CI = 3.8% to 8.3%). The estimated absolute risk for CIN3 or cancer within 12 years of the second examination among women who were HPV16 DNA positive at both examinations was 47.4% (95% CI = 34.9% to 57.5%); by contrast, the risk of CIN3 or worse following a negative Hybrid Capture 2 test was 3.0% (95% CI = 2.5% to 3.5%). CONCLUSION: HPV16, HPV18, HPV31, and HPV33 infection and especially HPV16 persistence were associated with high absolute risks for progression to high-grade cervical lesions. The results indicate the potential value of genotyping in cervical cancer screening. Given that HPV DNA-negative women retained their low risk of CIN3 or worse for many years, frequent screening of these women may be unnecessary. PMID- 20841606 TI - Persistent HPV infection and cervical cancer risk: is the scientific rationale for changing the screening paradigm enough? PMID- 20841607 TI - Intrinsic depot-specific differences in the secretome of adipose tissue, preadipocytes, and adipose tissue-derived microvascular endothelial cells. AB - OBJECTIVE: Visceral adipose tissue (VAT) is more closely linked to insulin resistance than subcutaneous adipose tissue (SAT). We conducted a quantitative analysis of the secretomes of VAT and SAT to identify differences in adipokine secretion that account for the adverse metabolic consequences of VAT. RESEARCH DESIGN AND METHODS: We used lectin affinity chromatography followed by comparison of isotope-labeled amino acid incorporation rates to quantitate relative differences in the secretomes of VAT and SAT explants. Because adipose tissue is composed of multiple cell types, which may contribute to depot-specific differences in secretion, we isolated preadipocytes and microvascular endothelial cells (MVECs) and compared their secretomes to those from whole adipose tissue. RESULTS: Although there were no discrete depot-specific differences in the secretomes from whole adipose tissue, preadipocytes, or MVECS, VAT exhibited an overall higher level of protein secretion than SAT. More proteins were secreted in twofold greater abundance from VAT explants compared with SAT explants (59% versus 21%), preadipocytes (68% versus 0%), and MVECs (62% versus 15%). The number of proteins in the whole adipose tissue secretome was greater than the sum of its cellular constituents. Finally, almost 50% of the adipose tissue secretome was composed of factors with a role in angiogenesis. CONCLUSIONS: VAT has a higher secretory capacity than SAT, and this difference is an intrinsic feature of its cellular components. In view of the number of angiogenic factors in the adipose tissue secretome, we propose that VAT represents a more readily expandable tissue depot. PMID- 20841608 TI - In vivo expression of HGF/NK1 and GLP-1 From dsAAV vectors enhances pancreatic beta-cell proliferation and improves pathology in the db/db mouse model of diabetes. AB - OBJECTIVE: The purpose of the current study was to determine whether double stranded adeno-associated virus (dsAAV)-mediated in vivo expression of beta-cell growth factors, glucagon-like peptide-1 (GLP-1) and the NK1 fragment of hepatocyte growth factor (HGF/NK1) in beta-cells, improves pathology in the db/db mouse model of type 2 diabetes. RESEARCH DESIGN AND METHODS; The glucoregulatory actions of GLP-1 and full-length HGF are well characterized. Here, we test the ability of HGF/NK1 to induce proliferation of exogenous islets and MIN6 beta cells. In addition, we target both GLP-1 and HGF/NK1 to endogenous beta-cells using dsAAV vectors containing the mouse insulin-II promoter. We compare the abilities of these gene products to induce islet proliferation in vitro and in vivo and characterize their abilities to regulate diabetes after AAV-mediated delivery to endogenous islets of db/db mice. RESULTS: Recombinant HGF/NK1 induces proliferation of isolated islets, and dsAAV-mediated expression of both GLP-1 and HGF/NK1 induces significant beta-cell proliferation in vivo. Furthermore, both GLP-1 and HGF/NK1 expressed from dsAAV vectors enhance beta-cell mass and insulin secretion in vivo and significantly delay the onset of hyperglycemia in db/db mice. CONCLUSIONS: A single treatment with dsAAV vectors expressing GLP-1 or HGF/NK1 enhances islet growth and significantly improves pathology in a mouse model of type 2 diabetes. This represents the first example of a successful use of HGF/NK1 for diabetes therapy, providing support for direct AAV-mediated in vivo delivery of beta-cell growth factors as a novel therapeutic strategy for the treatment of type 2 diabetes. PMID- 20841609 TI - Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. AB - OBJECTIVE: Recent data suggested that sex hormone-binding globulin (SHBG) levels decrease when fat accumulates in the liver and that circulating SHBG may be causally involved in the pathogenesis of type 2 diabetes in humans. In the present study, we investigated mechanisms by which high SHBG may prevent development to diabetes. RESEARCH DESIGN AND METHODS: Before and during a 9-month lifestyle intervention, total body and visceral fat were precisely measured by magnetic resonance (MR) tomography and liver fat was measured by (1)H-MR spectroscopy in 225 subjects. Insulin sensitivity was estimated from a 75-g oral glucose tolerance test (IS(OGTT)) and measured by a euglycemic hyperinsulinemic clamp (IS(clamp), n = 172). Insulin secretion was measured during the OGTT and an ivGTT (n = 172). RESULTS: SHBG levels correlated positively with insulin sensitivity (IS(OGTT), P = 0.037; IS(clamp), P = 0.057), independently of age, sex, and total body fat. In a multivariate model, these relationships were also significant after additional adjustment for levels of the adipokine adiponectin and the hepatokine fetuin-A (IS(OGTT), P = 0.0096; IS(clamp), P = 0.029). Adjustment of circulating SHBG for liver fat abolished the relationships of SHBG with insulin sensitivity. In contrast, circulating SHBG correlated negatively with fasting glycemia, before (r = -0.17, P = 0.009) and after (r = -0.14, P = 0.04) adjustment for liver fat. No correlation of circulating SHBG with adjusted insulin secretion was observed (OGTT, P = 0.16; ivGTT, P = 0.35). The SNP rs1799941 in SHBG was associated with circulating SHBG (P <= 0.025) but not with metabolic characteristics (all P > 0.18). CONCLUSIONS: Possible mechanisms by which high circulating SHBG prevents the development of type 2 diabetes involve regulation of fasting glycemia but not alteration of insulin secretory function. PMID- 20841610 TI - Transgenic restoration of long-chain n-3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat-fed mice. AB - OBJECTIVE: The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contributes to obesity-linked inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: We used transgenic expression of the fat 1 n-3 fatty acid desaturase from C. elegans to endogenously restore n-3 fatty acids in HF-fed mice. After 8 weeks on HF or chow diets, wild-type and fat-1 transgenic mice were subjected to insulin and glucose tolerance tests and a resolution assay was performed. Metabolic tissues were then harvested for biochemical analyses. RESULTS: We report that the n-3 docosanoid resolution mediator protectin D1 is lacking in muscle and adipose tissue of HF-fed wild-type mice. Accordingly, HF-fed wild-type mice have an impaired capacity to resolve an acute inflammatory response and display elevated adipose macrophage accrual and chemokine/cytokine expression. This is associated with insulin resistance and higher activation of iNOS and JNK in muscle and liver. These defects are reversed in HF-fed fat-1 mice, in which the biosynthesis of this important n-3 docosanoid resolution mediator is improved. Importantly, transgenic restoration of n-3 fatty acids prevented obesity-linked inflammation and insulin resistance in HF-fed mice without altering food intake, weight gain, or adiposity. CONCLUSIONS: We conclude that inefficient biosynthesis of n-3 resolution mediators in muscle and adipose tissue contributes to the maintenance of chronic inflammation in obesity and that these novel lipids offer exciting potential for the treatment of insulin resistance and diabetes. PMID- 20841611 TI - Congenic mesenchymal stem cell therapy reverses hyperglycemia in experimental type 1 diabetes. AB - OBJECTIVE: A number of clinical trials are underway to test whether mesenchymal stem cells (MSCs) are effective in treating various diseases, including type 1 diabetes. Although this cell therapy holds great promise, the optimal source of MSCs has yet to be determined with respect to major histocompatibility complex matching. Here, we examine this question by testing the ability of congenic MSCs, obtained from the NOR mouse strain, to reverse recent-onset type 1 diabetes in NOD mice, as well as determine the immunomodulatory effects of NOR MSCs in vivo. RESEARCH DESIGN AND METHODS: NOR MSCs were evaluated with regard to their in vitro immunomodulatory function in the context of autoreactive T-cell proliferation and dendritic cell (DC) generation. The in vivo effect of NOR MSC therapy on reversal of recent-onset hyperglycemia and on immunogenic cell subsets in NOD mice was also examined. RESULTS: NOR MSCs were shown to suppress diabetogenic T-cell proliferation via PD-L1 and to suppress generation of myeloid/inflammatory DCs predominantly through an IL-6-dependent mechanism. NOR MSC treatment of experimental type 1 diabetes resulted in long-term reversal of hyperglycemia, and therapy was shown to alter diabetogenic cytokine profile, to diminish T-cell effector frequency in the pancreatic lymph nodes, to alter antigen-presenting cell frequencies, and to augment the frequency of the plasmacytoid subset of DCs. CONCLUSIONS: These studies demonstrate the inimitable benefit of congenic MSC therapy in reversing experimental type 1 diabetes. These data should benefit future clinical trials using MSCs as treatment for type 1 diabetes. PMID- 20841612 TI - Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. AB - OBJECTIVE: Neuropathic pain due to small-fiber sensory neuropathy in type 2 diabetes can be diagnosed by skin biopsy with quantification of intra-epidermal nerve fiber (IENF) density. There is, however, a lack of noninvasive physiological assessment. Contact heat-evoked potential (CHEP) is a newly developed approach to record cerebral responses of Adelta fiber-mediated thermonociceptive stimuli. We investigated the diagnostic role of CHEP. RESEARCH DESIGN AND METHODS: From 2006 to 2009, there were 32 type 2 diabetic patients (20 males and 12 females, aged 51.63 +/- 10.93 years) with skin denervation and neuropathic pain. CHEPs were recorded with heat stimulations at the distal leg, where skin biopsy was performed. RESULTS: CHEP amplitude was reduced in patients compared with age- and sex-matched control subjects (14.8 +/- 15.6 vs. 33.7 +/- 10.1 MUV, P < 0.001). Abnormal CHEP patterns (reduced amplitude or prolonged latency) were noted in 81.3% of these patients. The CHEP amplitude was the most significant parameter correlated with IENF density (P = 0.003) and pain perception to contact heat stimuli (P = 0.019) on multiple linear regression models. An excitability index was derived by calculating the ratio of the CHEP amplitude over the IENF density. This excitability index was higher in diabetic patients than in control subjects (P = 0.023), indicating enhanced brain activities in neuropathic pain. Among different neuropathic pain symptoms, the subgroup with evoked pain had higher CHEP amplitudes than the subgroup without evoked pain (P = 0.011). CONCLUSIONS: CHEP offers a noninvasive approach to evaluate the degeneration of thermonociceptive nerves in diabetic neuropathy by providing physiological correlates of skin denervation and neuropathic pain. PMID- 20841613 TI - Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. AB - OBJECTIVE: Injected volume and subcutaneous adipose tissue blood flow (ATBF) affect insulin absorption. Pharmacokinetics of short-acting insulin analogs were established by assessing injection of small doses in lean subjects, healthy or with type 1 diabetes. In obese patients, however, daily dosages are larger and ATBF is decreased. This study assessed the kinetics of a short-acting insulin analog in obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Euglycemic clamps after subcutaneous lispro injections were performed. Six healthy control subjects received 10 units. Seven obese (BMI 38.3 +/- 7.0 kg/m(2)) subjects with type 2 diabetes received 10, 30, and 50 units. Plasma lispro was measured by specific radioimmunoassay and ATBF by the (133)Xe-washout technique. RESULTS: ATBF was 64% lower in subjects with type 2 diabetes than in control subjects. After 10 units injection, time to lispro plasma peak (T(max)) was similar (48.3 vs. 55.7 min; control subjects versus type 2 diabetic subjects), although maximal concentration (C(max))/dose was 41% lower in subjects with type 2 diabetes, with lower and delayed maximal glucose infusion rate (GIR(max): 9.0 vs. 0.6 mg/kg/min, P < 0.0001, 69 vs. 130 min, P < 0.0001, respectively). After 30- and 50-unit injections, T(max) (88.6 and 130.0 min, respectively) and time to GIR(max) (175 and 245 min) were further delayed and dose related (r(2) = 0.51, P = 0.0004 and r(2) = 0.76, P < 0.0001, respectively). CONCLUSIONS: Absorption and hypoglycemic action of increasing dosages of lispro are critically delayed in obese subjects with type 2 diabetes. PMID- 20841615 TI - Patellar tendinopathy alters the distribution of lower extremity net joint moments during hopping. AB - The purpose of the current investigation was to test the hypothesis that subjects with patellar tendinopathy would demonstrate altered sagittal plane joint moment contributions during hopping tasks. Fourteen subjects (7 patellar tendinopathy, 7 controls) participated. Sagittal net joint moments of the lower extremity, total support moment, and joint contributions to the total support moment were calculated while subjects hopped continuously at a self-selected frequency and at 1.67 Hz. Significant differences were observed for contributions to the total support moment (p=.022). When averaged across hopping frequencies, subjects with patellar tendinopathy demonstrated greater hip contribution (p=.030) and lesser knee contribution (p=.006) compared with the control subjects. Shifting the workload away from the knee and toward the hip may result in a detrimental increase in hip demand and potentially harmful long-term effects on the articular cartilage of the hip. PMID- 20841614 TI - The acute effect of clamped hyperglycemia on the urinary excretion of inflammatory cytokines/chemokines in uncomplicated type 1 diabetes: a pilot study. AB - OBJECTIVE: Acute glycemic variability contributes to diabetic complications potentially through induction of inflammation. Our objective was to determine whether acute hyperglycemia affects urinary secretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes. RESEARCH DESIGN AND METHODS: Blood pressure, renal hemodynamics (inulin and paraaminohippurate clearances), and urine samples were obtained after 6 h of clamped euglycemia (4-6 mmol/l) and hyperglycemia (9-11 mmol/l) on two consecutive days in subjects with type 1 diabetes (n = 25). Forty-two urinary cytokines/chemokines were measured using a Luminex platform. RESULTS: Clamped hyperglycemia produced an expected increase in glomerular filtration rate (131 +/ 4 to 148 +/- 8 ml/min/1.73 m2). Clamped hyperglycemia was associated with significant increases in urinary eotaxin, fibroblast growth factor-2, granulocyte macrophage colony-stimulating factor, interferon-alpha 2, interleukin-2 and -12, monocyte chemoattractant protein-3, macrophage-derived chemokine, macrophage inflammatory protein-1alpha, platelet-derived growth factor, tumor necrosis factor-alpha, and CD40 ligand (P < 0.05). CONCLUSIONS: Acute hyperglycemia results in increased urinary excretion of inflammatory cytokines/chemokines in humans with uncomplicated type 1 diabetes, and this may contribute to kidney injury. PMID- 20841616 TI - Force enhancement of quadriceps femoris in vivo and its dependence on stretch induced muscle architectural changes. AB - The purpose of this study was to investigate if force enhancement (FE) in vivo is influenced by stretch-induced changes of muscle architecture. Therefore, 18 subjects performed maximum voluntary isometric (100 degree knee flexion angle) and isometric-eccentric-isometric stretch contractions (80 degrees-100 degrees; omega=60 degrees.s(-1)) whereby pennation angle and fascicle length of vastus lateralis was determined using ultrasonography. We found significant (2-way repeated ANOVA; alpha=0.05) enhanced torque of 5-10% after stretch as well as significant passive FE but no significant differences in muscle architecture between isometric and stretch contractions at final knee angle. Furthermore, EMG recordings during a follow-up study (n=10) did not show significant differences in activation and mean frequency of contraction conditions. These results indicate that FE in vivo is not influenced by muscle architectural changes due to stretch. PMID- 20841617 TI - Quantitative analysis of the limits of stability in sitting. AB - This study defines the limits of stability in sitting, and quantitatively assesses two measures of postural control relative to these limits. Young, healthy subjects sat, feet unsupported, on an elevated force plate. The limits of stability were determined by a least square fit of an ellipse to the center of pressure (CoP) excursion during maximal leaning in 8 directions. These were highly symmetrical and centered within the base of support. The ellipses had a mean eccentricity of 0.66 (major axis in the sagittal plane) and covered an area approximately 1/3 of the base of support. The CoP was then monitored over 4 min of quiet sitting, during which the postural sway covered an area<0.05% of the limits of stability and was closely centered within the latter. Finally, target directed trunk movements were performed, in 5 directions, at 4 movement speeds and 3 target distances. Increased target distance and movement speed both decreased the margin of stability (distance between the CoP and the limits of stability), as did movement in the frontal plane, reflecting the eccentricity of the limits of stability. These combined findings support the validity of this quantitative method of defining the limits of stability in sitting, for healthy individuals. PMID- 20841618 TI - A Morlet wavelet signal analysis with a Daubechies filter for the wear assessment of hip prostheses coated with diamond-like carbon by triboadhesion. AB - In the present work, based on high frequency wavelet analysis of dynamic signals of mechanical systems, a multiple-resolution wavelet analysis is carried out, to the signal obtained from an accelerometer mounted on the structure of a hip prosthesis wearing test device. The prostheses employed had a femoral head made of aluminum oxide and the acetabular cup of ultra-high-molecular-weight polyethylene. The first two aluminum oxide femoral heads were coated with diamond like carbon and a third one was tested without coating and used as a reference. The coating was carried out by triboadhesion. Tests results showed that maximum vibration amplitude reached after 32 hr for the coated prostheses was 0.2 g. The noncoated prosthesis amplitude presented was 0.75 g in the same time interval. These values were attributed to wear damage on the surface of the prostheses, indicating that thin film DLC coating caused an increase of stiffness on the surface and therefore an increase in wear resistance approximately of 314%. PMID- 20841619 TI - The effectiveness of wrist guards for reducing wrist and elbow accelerations resulting from simulated forward falls. AB - The effectiveness of wrist guards and modifying elbow posture for reducing impact induced accelerations at the wrist and elbow, for the purpose of decreasing upper extremity injury risk during forward fall arrest, has not yet been documented in living people. A seated human pendulum was used to simulate the impact conditions consistent with landing on outstretched arms during a forward fall. Accelerometers measured the wrist and elbow response characteristics of 28 subjects following impacts with and without a wrist guard, and with elbows straight or slightly bent. Overall, the wrist guard was very effective, with significant reductions in peak accelerations at the elbow in the axial and off axis directions, and in the off-axis direction at the wrist by almost 50%. The effect of elbow posture as an intervention strategy was mixed; a change in magnitude and direction of the acceleration response was documented at the elbow, while there was little effect at the wrist. Unique evidence was presented in support of wrist guard use in activities like in-line skating where impacts to the hands are common. The elbow response clearly shows that more proximal anatomical structures also need to be monitored when assessing the effectiveness of injury prevention strategies. PMID- 20841620 TI - Pelvifemoral kinematics while ascending single steps of different heights. AB - Motion of the femur and pelvis during hip flexion has been examined previously, but principally in the sagittal plane and during nonfunctional activities. In this study we examined femoral elevation in the sagittal plane and pelvic rotation in the sagittal and frontal planes while subjects flexed their hips to ascend single steps. Fourteen subjects ascended single steps of 4 different heights leading with each lower limb. Motion of the lead femur and pelvis during the flexion phase of step ascent was tracked using an infrared motion capture system. Depending on step height and lead limb, step ascent involved elevation of the femur (mean 47.2 degrees to 89.6 degrees) and rotation of the pelvis in both the sagittal plane (tilting: mean 2.6 degrees to 9.7 degrees) and frontal plane (listing: mean 4.2 degrees to 11.9 degrees). Along with maximum femoral elevation, maximum pelvic rotation increased significantly (p<.001) with step height. Femoral elevation and pelvic rotation during the flexion phase of step ascent were synergistic (r=.852-.999). Practitioners should consider pelvic rotation in addition to femoral motion when observing individuals' ascent of steps. PMID- 20841621 TI - Sex differences and discriminative value of lower extremity alignments and kinematics during two functional tasks. AB - The purpose of this study was to formulate a predictive equation to discriminate males from females using static and dynamic lower extremity (LE) alignments. Twenty-four healthy adults volunteered to participate. Three-dimensional motion analysis was used to assess the kinematics of the right hip and knee during two functional tasks. Six measures of static LE alignment were also performed. Statistical comparisons were made between males and females for all variables. Static and dynamic variables that were significantly different by sex were entered into separate discriminant analyses for each task. The resulting equations were each able to correctly predict 87% of the subjects by sex. Fifty eight percent and 55% of the variance was explained by sex for the vertical jump and plant & jump, respectively. The frontal plane hip angle was the best predictor of sex for both tasks. While there were statistically significant differences between the sexes for static measures of LE alignment, kinematic measures were better at discriminating between sexes. PMID- 20841622 TI - A marker-based mean finite helical axis model to determine elbow rotation axes and kinematics in vivo. AB - The predominance of upper-limb elbow models have been based on earlier lower-limb motion analysis models. We developed and validated a functionally based 2 degree of-freedom upper-limb model to measure rotations of the forearm using a marker based approach. Data were collected from humans and a mechanical arm with known axes and ranges of angular motion in 3 planes. This upper-limb model was compared with an anatomically based model following the proposed ISB standardization. Location of the axes of rotation relative to each other was determined in vivo. Data indicated that the functional model was not influenced by cross-talk from adduction-abduction, accurately measuring flexion-extension and pronation supination. The functional flexion-extension axis in vivo is angled at 6.6 degrees to the anatomical line defined from the humeral medial to lateral epicondyles. The pronation-supination axis intersected the anatomically defined flexion-extension axis at 88.1 degrees. Influence of cross-talk on flexion extension kinematics in the anatomical model was indicated by strong correlation between flexion-extension and adduction-abduction angles for tasks performed by the subjects. The proposed functional model eliminated cross-talk by sharing a common flexion axis between the humerus and forearm. In doing so, errors due to misalignment of axes are minimized providing greater accuracy in kinematic data. PMID- 20841623 TI - Effects of training on muscle and tendon in knee extensors and plantar flexors in vivo. AB - The purpose of this study was to compare the effects of resistance training on muscle and tendon properties between knee extensors and plantar flexors in vivo. Twenty healthy young men voluntarily participated in this study. The subjects were randomly divided into two training groups: knee extension group (n=10) and plantar flexion group (n=10). They performed five sets of exercises with a 1-min rest between sets, which consisted of unilateral knee extension for the knee extension group and plantar flexion for the plantar flexion group at 80% of 1 repetition maximum with 10 repetitions per set (4 days/wk, 12 wk). Before and after training, muscle strength, neural activation level (by interpolated twitch), muscle volume (by magnetic resonance imaging), and tendon stiffness (by ultrasonography) were measured. There were no differences in the training-induced increases in muscle strength, activation level, muscle volume, and tendon stiffness between knee extensors and plantar flexors. These results suggested that if the used protocol of training (i.e., intensity, repetition, etc.) were the same, there were no differences in the training-induced changes in muscle and tendon properties between knee extensors and plantar flexors. PMID- 20841624 TI - Determination of the drag coefficient during the first and second gliding positions of the breaststroke underwater stroke. AB - The purpose of the current study was to assess and to compare the hydrodynamics of the first and second gliding positions of the breaststroke underwater stroke used after starts and turns, considering drag force (D), drag coefficient (CD) and cross-sectional area (S). Twelve national-level swimmers were tested (6 males and 6 females, respectively 18.2+/-4.0 and 17.3+/-3.0 years old). Hydrodynamic parameters were assessed through inverse dynamics from the velocity to time curve characteristic of the underwater armstroke of the breaststroke technique. The results allow us to conclude that, for the same gliding velocities (1.37+/-0.124 m/s), D and the swimmers' S and CD values obtained for the first gliding position are significantly lower than the corresponding values obtained for the second gliding position of the breaststroke underwater stroke (31.67+/-6.44 N vs. 46.25+/-7.22 N; 740.42+/-101.89 cm2 vs. 784.25+/-99.62 cm2 and 0.458+/-0.076 vs. 0.664+/-0.234, respectively). These differences observed for the total sample were not evident for each one of the gender's subgroups. PMID- 20841625 TI - Responses of the trunk to multidirectional perturbations during unsupported sitting in normal adults. AB - Understanding how the human body responds to unexpected force perturbations during quiet sitting is important to the science of motor behavior and the design of neuroprostheses for sitting posture. In this study, the performance characteristics of the neck and trunk in healthy individuals were assessed by measuring the kinematic responses to sudden, unexpected force perturbations applied to the thorax. Perturbations were applied in eight horizontal directions. It was hypothesized that displacement of the trunk, settling time and steady state error would increase when the perturbation direction was diagonal (i.e., anterior-lateral or posterior-lateral) due to the increased complexity of asymmetrical muscle responses. Perturbation forces were applied manually. The neck and trunk responded in a synchronized manner in which all joints achieved peak displacement simultaneously then returned directly to equilibrium. Displacement in the direction of perturbation and perpendicular to the direction of perturbation were both significantly greater in response to diagonal perturbations (p<.001). The center of mass returned to equilibrium in 3.64+/-1.42 s after the onset of perturbation. Our results suggest that the trunk sometimes behaves like an underdamped oscillator and is not controlled by simple stiffness when subjected to loads of approximately 200 N. The results of this study are intended to be used to develop a neuroprosthesis for artificial control of trunk stability in individuals with spinal cord injury. PMID- 20841626 TI - Treatment with pharmacological agents in peripheral arterial disease patients does not result in biomechanical gait changes. AB - Pharmacological treatment has been used to alleviate the claudication symptoms and improve walking performance in peripheral arterial disease (PAD) patients. However, the effects of claudication treatments on gait mechanics have not been objectively identified with biomechanical techniques. For this study, 20 PAD patients were assigned to take either pentoxifylline (n=11) or cilostazol (n=9), the two FDA-approved pharmacological therapies used to treat intermittent claudication symptoms. All patients completed a gait evaluation protocol that involved the acquisition of kinematic and kinetic gait data before use of the medication and after 12 weeks of treatment. Results showed that treatment with either pentoxifylline or cilostazol resulted in limited overall improvement in gait parameters including joint angles and joint moments. Walking speed was unchanged, in either treatment group, as a result of the medication. These results suggest that to improve biomechanical walking parameters of PAD patients, clinicians cannot rely on drug therapies alone. PMID- 20841627 TI - The reliability and validity of a three-camera foot image system for obtaining foot anthropometrics. AB - The purpose was to develop a foot image capture and measurement system with web cameras (the 3-FIS) to provide reliable and valid foot anthropometric measures with efficiency comparable to that of the conventional method of using a handheld anthropometer. Eleven foot measures were obtained from 10 subjects using both methods. Reliability of each method was determined over 3 consecutive days using the intraclass correlation coefficient and root mean square error (RMSE). Reliability was excellent for both the 3-FIS and the handheld anthropometer for the same 10 variables, and good for the fifth metatarsophalangeal joint height. The RMSE values over 3 days ranged from 0.9 to 2.2 mm for the handheld anthropometer, and from 0.8 to 3.6 mm for the 3-FIS. The RMSE values between the 3-FIS and the handheld anthropometer were between 2.3 and 7.4 mm. The 3-FIS required less time to collect and obtain the final variables than the handheld anthropometer. The 3-FIS provided accurate and reproducible results for each of the foot variables and in less time than the conventional approach of a handheld anthropometer. PMID- 20841628 TI - Variability and symmetry of force platform variables in maximum-speed running in young and older athletes. AB - Eighteen young (23+/-4 yr) and 25 older (70+/-4 yr) male sprinters were examined for ground reaction force (GRF) and temporal-spatial variables. The data were collected during maximum-speed phase, and variability and symmetry indices were calculated from a total of 8 steps. There was little variation (CV<6%) in vertical and resultant GRF and kinematic variables, while impact loading had high variability (CV: 10-21%). Overall, the pattern of variability was similar in both groups. Yet, a small but significant age-related increase in CV was evident in horizontal GRFs. There was a variable-specific asymmetry between legs but it was not related to leg dominance. No age differences existed in the symmetry indices. Results indicate that only selected force platform variables are symmetric and repeatable enough so that their use for comparison purposes is appropriate. Data also suggest that aging may increase variability in certain biomechanical measures, whereas symmetry is not affected by age. PMID- 20841629 TI - Quantification of soft-tissue vibrations in running: accelerometry versus high speed motion capture. AB - Soft-tissue vibrations can be used to quantify selected properties of human tissue and their response to impact. Vibrations are typically quantified using high-speed motion capture or accelerometry. The aim of this study was to compare the amplitude and frequency of soft-tissue vibrations during running when quantified by highspeed motion capture and accelerometry simultaneously. This study showed: (a) The estimated measurement errors for amplitude and frequency were of the same order of magnitude for both techniques. (b) There were no significant differences in the mean peak frequencies and peak amplitudes measured by the two methods. (c) The video method showed an inability to capture high frequency information. This study has shown that a tradeoff has to be made between the accuracy in amplitude and frequency when these methods are employed to quantify soft tissue vibrations in running. PMID- 20841630 TI - The shoulder distraction force in cricket fast bowling. AB - This preliminary study aimed to quantify the magnitude of the peak shoulder distraction force during the bowling action of female cricket fast bowlers. An eight camera Vicon motion analysis system operating at 120 Hz recorded the fast bowling actions of 18 Australian female fast bowlers. A three segment inverse solution model of the bowling arm was used to calculate the shoulder distraction force. A large peak shoulder distraction force was recorded during the early stages of the follow-through of the bowling action. When normalized for body weight, the distraction force was within the range of values reported for baseball and softball pitchers, who are considered to be at high risk of shoulder injury. Therefore, the relative importance of the peak shoulder distraction force in the fast bowling action for the development of shoulder pain in female cricket fast bowlers warrants further investigation. PMID- 20841631 TI - Giuseppe Sergi, "champion" of Darwinism? AB - The Italian anthropologist, psychologist and evolutionist Giuseppe Sergi (1841 1936) may be regarded in some respects today as an "atypical" Darwinist, but, almost paradoxically, he was considered a "champion" of Darwinism by colleagues and commentators of his own time. Probably, two aspects of his work are responsible for this apparent anomaly: his faith in the so-called soft inheritance and his claims regarding a theory concerning the polyphyletic origin of human races. The soft inheritance theory, however, was needed by Sergi to support ideas regarding the complexity of inheritance in man, a fact that, in his opinion, could not completely be put down to mechanical laws, and polygeny was useful when trying to rectify the problem concerning the incompleteness of the fossil record. In both cases, it is possible to show that he was involved in supporting Darwinian theory during the most severe crisis of its consensus in Italy and at International level, between the end of the 19th century and the beginning of the 20th. Finally, the apparent unorthodox features which can be found in Sergi's ideas appear to be, in Kuhnian terms, ad hoc hypotheses put forward by Sergi himself in order to support the paradigm. PMID- 20841632 TI - Forensic anthropology in Europe: an assessment of current status and application. AB - Forensic anthropology is the discipline that traditionally deals with the examination of human remains for legal purposes and it derives from the fields of anatomy, physical anthropology and forensic medicine. For more than a century, forensic anthropologists in the United States have been offering their services in the court of law complementing the medico-legal investigation of other forensic professionals. The current status in European countries is presented here. The development of forensic anthropology varies significantly among the countries of Europe. Whereas some countries show a long history of research activity in the forensic sciences, including forensic anthropology (i.e. France, Germany and Spain), others are exhibiting a recent, rapid development (i.e. United Kingdom). In some cases, forensic anthropologists are employed within the academic realm (i.e. U.K., Denmark, Portugal, Turkey), forensic institutions (Netherlands) or government organizations (Spain, Hungary), although the vast majority of them remain limited to freelance activities on a sporadic basis. Often, European scientists that deal with skeletal remains come from nonphysical anthropology disciplines such as archaeology, forensic medicine and biology. In many cases they do not have adequate training equivalent to the forensic anthropologists in the USA. Naturally, without common training and a common legal system, an accreditation system for Europe will be difficult to implement. PMID- 20841633 TI - Computer models and applications for the management of anthropological data. PMID- 20841634 TI - Ethno-anthropological and genetic study of the Yaghnobis;an isolated community in Central Asia. A preliminary study. PMID- 20841635 TI - Instantaneous estimation of motor cortical neural encoding for online brain machine interfaces. AB - Recently, the authors published a sequential decoding algorithm for motor brain machine interfaces (BMIs) that infers movement directly from spike trains and produces a new kinematic output every time an observation of neural activity is present at its input. Such a methodology also needs a special instantaneous neuronal encoding model to relate instantaneous kinematics to every neural spike activity. This requirement is unlike the tuning methods commonly used in computational neuroscience, which are based on time windows of neural and kinematic data. This paper develops a novel, online, encoding model that uses the instantaneous kinematic variables (position, velocity and acceleration in 2D or 3D space) to estimate the mean value of an inhomogeneous Poisson model. During BMI decoding the mapping from neural spikes to kinematics is one to one and easy to implement by simply reading the spike times directly. Due to the high temporal resolution of the encoding, the delay between motor cortex neurons and kinematics needs to be estimated in the encoding stage. Mutual information is employed to select the optimal time index defined as the lag for which the spike event is maximally informative with respect to the kinematics. We extensively compare the windowed tuning models with the proposed method. The big difference between them resides in the high firing rate portion of the tuning curve, which is rather important for BMI-decoding performance. This paper shows that implementing such an instantaneous tuning model in sequential Monte Carlo point process estimation based on spike timing provides statistically better kinematic reconstructions than the linear and exponential spike-tuning models. PMID- 20841636 TI - A maximum mutual information approach for constructing a 1D continuous control signal at a self-paced brain-computer interface. AB - This paper addresses an important issue in a self-paced brain-computer interface (BCI): constructing subject-specific continuous control signal. To this end, we propose an alternative to the conventional regression/classification-based mechanism for building the transformation from EEG features into a univariate control signal. Based on information theory, the mechanism formulates the optimum transformation as maximizing the mutual information between the control signal and the mental state. We introduce a non-parametric mutual information estimate for general output distribution, and then develop a gradient-based algorithm to optimize the transformation using training data. We conduct an offline simulation study using motor imagery data from the BCI Competition IV Data Set I. The results show that the learning algorithm converged quickly, and the proposed method yielded significantly higher BCI performance than the conventional mechanism. PMID- 20841637 TI - Changes in biphasic electrode impedance with protein adsorption and cell growth. AB - This study was undertaken to assess the contribution of protein adsorption and cell growth to increases in electrode impedance that occur immediately following implantation of cochlear implant electrodes and other neural stimulation devices. An in vitro model of the electrode-tissue interface was used. Radiolabelled albumin in phosphate buffered saline was added to planar gold electrodes and electrode impedance measured using a charge-balanced biphasic current pulse. The polarization impedance component increased with protein adsorption, while no change to access resistance was observed. The maximum level of protein adsorbed was measured at 0.5 ug cm(-2), indicating a tightly packed monolayer of albumin molecules on the gold electrode and resin substrate. Three cell types were grown over the electrodes, macrophage cell line J774, dissociated fibroblasts and epithelial cell line MDCK, all of which created a significant increase in electrode impedance. As cell cover over electrodes increased, there was a corresponding increase in the initial rise in voltage, suggesting that cell cover mainly contributes to the access resistance of the electrodes. Only a small increase in the polarization component of impedance was seen with cell cover. PMID- 20841638 TI - Modeling carbachol-induced hippocampal network synchronization using hidden Markov models. AB - In this work we studied the neural state transitions undergone by the hippocampal neural network using a hidden Markov model (HMM) framework. We first employed a measure based on the Lempel-Ziv (LZ) estimator to characterize the changes in the hippocampal oscillation patterns in terms of their complexity. These oscillations correspond to different modes of hippocampal network synchronization induced by the cholinergic agonist carbachol in the CA1 region of mice hippocampus. HMMs are then used to model the dynamics of the LZ-derived complexity signals as first order Markov chains. Consequently, the signals corresponding to our oscillation recordings can be segmented into a sequence of statistically discriminated hidden states. The segmentation is used for detecting transitions in neural synchronization modes in data recorded from wild-type and triple transgenic mice models (3xTG) of Alzheimer's disease (AD). Our data suggest that transition from low-frequency (delta range) continuous oscillation mode into high-frequency (theta range) oscillation, exhibiting repeated burst-type patterns, occurs always through a mode resembling a mixture of the two patterns, continuous with burst. The relatively random patterns of oscillation during this mode may reflect the fact that the neuronal network undergoes re-organization. Further insight into the time durations of these modes (retrieved via the HMM segmentation of the LZ derived signals) reveals that the mixed mode lasts significantly longer (p < 10( 4)) in 3xTG AD mice. These findings, coupled with the documented cholinergic neurotransmission deficits in the 3xTG mice model, may be highly relevant for the case of AD. PMID- 20841639 TI - The role of patients in transiting personal health information: a field study. AB - Recent consumer health informatics initiatives advocate individual access and management of personal medical records. However, little is known regarding the impact of personal access of health information on clinical practice. This paper introduces a field study investigating the usage patterns of personal health records in medical consultations. The self-managed records provide patients with a strong sense of ownership and control over their own health information. Personal medical records have been used primarily for transiting information among different providers. This behavior changed patient-provider communication into a records sharing. Doing so effectively eliminated the potential errors in the verbal reporting process. This study indicates that patients can be effective contributors to their own health and suggest the design of health information systems to rethink the role of patients in the healthcare process and shift the responsibility of healthcare to the patients' side. PMID- 20841640 TI - Need for a new care model--getting to grips with collaborative home care. AB - In this paper we discuss the fact that more and more patients are treated in their homes by a set of organizations, sometimes with different ownership, and how this fact places new and severe demands on health care and home service staff to communicate and collaborate. We point to the need for managers in different organizations to agree on ways of communicating and collaborating on the operational level and how this aspect needs to be considered during procurement of home care services. Most importantly, by reasoning around a set of problematic areas, we derive a set of related problems and suggest solutions for dealing with them. The solutions are a mix of organizational/administrative measures and IT support for communication and coordination. PMID- 20841641 TI - Barriers and facilitators that affect public engagement with eHealth services. AB - It is commonly accepted that public engagement with eHealth is beneficial. However, engagement is also variable. This article presents the findings of a review of published evaluation studies around eHealth services. A targeted search of MEDLINE, CINAHL and EMBASE returned 2622 unique abstracts. 50 articles met the inclusion criteria and were subjected to further analysis. 6 review articles were used for post hoc validation. Four main types of eHealth service or resource were identified: health information on the Internet; custom-built online health information; online support; and telehealth. 5 key themes emerged in terms of facilitators or barriers to engagement: characteristics of users; technological issues; characteristics of eHealth services; content issues; social aspects of use; and eHealth services in use. Recommendations arising from the review include: targeting efforts to engage those underserved by eHealth; maximizing exposure to eHealth across all sections of society; improving access to computers and the internet; appropriate design and delivery; ensuring content is relevant to different audiences; capitalizing on the interest in social computing; and clarifying the role of health workers in the delivery of eHealth. PMID- 20841642 TI - Barriers of obtaining health information among diabetes patients. AB - While healthcare information plays an essential role in the process of disease management, previous studies have shown that many patients may be unaware of the availability of certain healthcare information, thus leading to the progression of their diseases and deterioration of their health. This study explores the information seeking behaviors among patients with type-2 diabetes and explores the barriers that hinder effective healthcare information usages. 19 semi structured interviews were carried out with patients and caregivers in various stages of diabetes disease management. Data analysis identified five major barriers for seeking health information: lack of motivation, passiveness, inconsistency of information, generality of information and loss of information. These findings call for the designing of active and personalized information delivery mechanisms. PMID- 20841643 TI - Pathways Home: comparing voluntary IT and non-IT users participating in a mentored self-management project. AB - This research paper examines the challenges in the development and adoption of an electronic patient diary within the Pathways Home for Respiratory Illness Project. This project supported community-based patients suffering from chronic obstructive pulmonary disease (COPD) to achieve increased levels of self management and self-efficacy using electronic-monitoring techniques and mentoring by community health nurses. Participants had the option of voluntarily adopting an electronic patient diary to support their self-monitoring, which provided patients, nurses and clinicians with access to symptom and psycho-social data. This aimed to improve the identification, comprehension and initiation of early action in relation to alterations in their conditions. The paper presents data on technology adoption, electronic diary usage and, self-reported data quality, as well as examining the impact of the technology on hospitalisations (frequency and duration). The participants who chose to use the online patient diary continued their involvement with the project for the entire trial period (85% vs 54% completion). Participants were more likely to maintain use of the online patient diary than the paper diary. Both the groups experienced a positive improvement in their self-efficacy to self-manage their condition scores. The data highlight the problems implicit in some of the assumptions underpinning existing information systems models, especially in evaluating impact and the end-points presumed to be relevant in systems development life cycles. PMID- 20841644 TI - Usage and effect of a web-based intervention for the prevention of overweight; a RCT. AB - Web-based interventions can be effective in changing behaviour of people faced with health problems. However, it is unclear whether they are effective in preventing health problems like overweight. The aim of this study was to investigate usage and effectiveness of the Healthy Weight Assistant (HWA), a web based application to increase healthy behaviour in adults with a healthy weight or slight overweight, by means of a Randomised Controlled Trial (RCT). 297 respondents were randomly assigned to the intervention (n=147) or the waiting list group (n=150). The intervention group received access to the intervention for 12 weeks. At pre- and post-test we measured dietary and physical activity behaviour (primary outcomes) and BMI, knowledge, attitude, self-efficacy, subjective behaviour and insight in behaviour (secondary outcomes). All participants, regardless of group, show improvement in healthy behaviour and subjective assessment of healthy behaviour. People who are older, score higher on dietary behaviour and under-estimate their dietary behaviour are more likely to use the HWA. Using the HWA leads to improvement in physical activity behaviour and insight in physical activity behaviour. PMID- 20841645 TI - The influence of crowds on consumer health decisions: an online prospective study. AB - This paper presents an online prospective study investigating whether the strength of social feedback, i.e. the proportion of persons who concur or do not concur with one's own answer to a question, influences the way one answers health related questions. Two hundred and twenty-seven undergraduate students were recruited to use an online search engine to answer six health-related questions. Subjects recorded their pre- and post-search answers to each question and their level of confidence in these answers. After answering each question post-search, subjects were presented with a summary of post-search answers provided by previous subjects and were asked to answer the question again. There was a statistically significant relationship between the absolute number of others with a different answer (the crowd's opinion volume) and the likelihood of an individual changing an answer (P<.0001). Subjects' likelihood of changing answer increased as the percentage of others with a different answer (the crowd's opinion density) increased (P=0.047). Overall, 98.3% of subjects did not change their answer when it concurred with the majority (i.e. >50%) of subjects. When subjects had a post-search answer that did not concur with the majority, they were 24% more likely to change answer than those with answers that concurred (P<.0001). This study provides empirical evidence that strength of social feedback influences the way healthcare consumers answer health-related questions. PMID- 20841646 TI - Patient web empowerment index (PWEI): an index for assessment of healthcare providers' web strategies. Case study: PWEI application in Italy. AB - The arrival of the Internet contributes to the growth of new areas for patient empowerment. In the presence of a challenge such as this, we nevertheless note that the adequacy and characteristics of the web strategies of healthcare providers have, up to the present, not been subjected to thoroughgoing critical analysis. The aim of this paper is to: (a) provide an analysis of the key factors of an efficient web strategy for healthcare organizations with regard to the issue of patient empowerment (b) build a concise indicator for measuring the degree of empowerment potential of healthcare providers' web sites (Patient Web Empowerment Index -PWEI-). PWEI was calculated in order to assess the web sites of 340 Italian National Health Service healthcare organizations, the aim being the appraisal of the current degree of maturity of their web strategies in relation to potentials for an effective increase in patient empowerment. PMID- 20841647 TI - Development and implementation of an integrated EHR for Homecare Service: a South American experience. AB - This paper describes the development and implementation of a web based electronic health record for the Homecare Service program in the Hospital Italiano de Buenos Aires. It reviews the process of the integration of the new electronic health record to the hospital information system, allowing physicians to access the clinical data repository from their Pc's at home and with the capability of consulting past and present history of the patient health care, order, tests, and referrals with others professionals trough the new Electronic Health Record. We also discuss how workflow processes were changed and improved for the physicians, nurses, and administrative personnel of the Homecare Services and the educational methods used to improve acceptance and adoption of these new technologies. We also briefly describe the validation of physicians and their field work with electronic signatures. PMID- 20841648 TI - A home-centered ICT architecture for health-enabling technologies. AB - Population ageing needs health-enabling technologies for delivering pervasive health care. Home care plays an import role in pervasive health care. In this paper, we aim to construct a home-centered health information system architecture which can efficiently manage multi sensors, actuators and decision support systems. Open Services Gateway initiative (OSGI) was used for constructing the service oriented architecture. HL 7 Arden Syntax for medical logic module (MLM) was used to describe the medical knowledge; An Arden compiler was used to interpret the MLMs. The Arden compiler was packed in an OSGI bundle. All of the knowledge bases can share the compiler within the OSGI platform. System within the OSGI-based architecture can change their behaviors during runtime. The proposed prototype architecture was deployed in a case study. PMID- 20841649 TI - Information needs in home based healthcare in South Africa. AB - Home based health care (HBHC) is advocated by the WHO "to ensure better accessibility to effective and efficient health care in community and home settings to improve health and well-being, and contribute to morbidity and mortality reduction". In South Africa the government and many other role players see an increasingly important role for HBHC. Many researchers believe that the evolution of HBHC will follow the socio-technical network evolution. There can be no doubt that the focus is on using information and communication technologies (ICT) to implement HBHC solutions. The objective of this paper is to provide a rich picture of the current situation and needs for improvement in HBHC in South Africa today through descriptive research in one specific case. The longer-term purpose is to identify pain-points that require socio-technical solutions, including but not exclusively ICT-supported solutions. PMID- 20841650 TI - Integration of cognitive and physical training in a smart home environment for the elderly people. AB - Our research work is towards a service that can support senior citizens towards their independent living and active ageing. As it is suggested, physical and cognitive exercise training can contribute to a significant prolongation of personal autonomy and participation in society across prevailing age-related impairments such as cognitive decline. In the current paper, the approach of combination of both physical and cognitive training--adopted by LLM project--is discussed related to other similar projects that have taken place in the area of elderly home care and training. The aim of this work is to describe the technical design details of the integration process of the LLM service, which is based on a Web service architecture and to discuss alternative interface elements to be included in the LLM platform in terms of enabling user accessibility and acceptance. PMID- 20841651 TI - A configurable home care platform for monitoring patients with reminder messaging and compliance tracking services. AB - This paper illustrates a platform based on a general architecture for implementing home care services for chronic patients composed of a Remote Care Unit located at a patient's home and a Health Care Center Unit located at the treating center. The Remote Care Unit may be deployed on multiple platforms including PCs, mobile phones and even embedded devices not equipped with monitor, and may be configured to support many interoperability issues occurring among the parties involved in a health care delivery process. The platform may be tailored to match the specific issues of any chronic disease supporting either data acquisition as well as customized reminders and notifications from the center. Remote Care Unit platforms are also able to exploit multiple channels for acquiring data, including wireless links with medical devices, speech interaction and graphical user interaction. In this paper a couple of applications addressing the needs of diabetic and nephropatic patients developed on top of that platform are also introduced. PMID- 20841652 TI - Daily activities and fall risk--a follow-up study to identify relevant activities for sensor-based fall risk assessment. AB - The demographic change will lead to an increase in the incidence of falls in the elderly. Technological progress allows for unobtrusive physical activity measurement with miniature sensors, e.g. accelerometers. Yet it is unclear which activities or activity patterns are associated with an increased fall risk. The aim of the research for this paper is to identify daily physical activities associated with a high fall risk. A one-year follow-up study was conducted with n=50 geriatric patients who took part in a telephone interview to assess fall events, their consequences and a set of daily physical activities. Descriptive analysis of the data shows that there are marked differences between fallers (n=21) and non-fallers (n=29) in the overall activity level, the amount of shopping activity and associated locomotion, and in the intensity of light household work. The results confirm that there are differences in typical daily activities between fallers and non-fallers that may be used as parameters to enhance fall prediction models. PMID- 20841653 TI - Can multilingual machine translation help make medical record content more comprehensible to patients? AB - With the development of electronic personal health records, more patients are gaining access to their own medical records. However, comprehension of medical record content remains difficult for many patients. Because each record is unique, it is also prohibitively costly to employ human translators to solve this problem. In this study, we investigated whether multilingual machine translation could help make medical record content more comprehensible to patients who lack proficiency in the language of the records. We used a popular general-purpose machine translation tool called Babel Fish to translate 213 medical record sentences from English into Spanish, Chinese, Russian and Korean. We evaluated the comprehensibility and accuracy of the translation. The text characteristics of the incorrectly translated sentences were also analyzed. In each language, the majority of the translations were incomprehensible (76% to 92%) and/or incorrect (77% to 89%). The main causes of the translation are vocabulary difficulty and syntactical complexity. A general-purpose machine translation tool like the Babel Fish is not adequate for the translation of medical records; however, a machine translation tool can potentially be improved significantly, if it is trained to target certain narrow domains in medicine. PMID- 20841654 TI - Measurement of the utilization of an installed electronic health record. AB - For the past decade, adoption of electronic health records (EHRs) has been proposed as one of the most viable approaches to improving the United States health care system. Although there is evidence that EHR adoption is slowly progressing, current methods of assessing adoption have yielded significant variance in estimates of EHR utilization. We conducted an environmental scan consisting of a review of the literature as well as a series of discussions with health center and health center network representatives and experts in the field to understand the current state of EHR adoption and use in the United States and assess the feasibility of developing a systematic approach to tracking EHR usage. PMID- 20841655 TI - Measuring use of electronic health record functionality using system audit information. AB - Meaningful and efficient methods for measuring Electronic Health Record (EHR) adoption and functional usage patterns have recently become important for hospitals, clinics, and health care networks in the United State due to recent government initiatives to increase EHR use. To date, surveys have been the method of choice to measure EHR adoption. This paper describes another method for measuring EHR adoption which capitalizes on audit logs, which are often common components of modern EHRs. An Audit Data Mart is described which identified EHR functionality within 836 Departments, within 22 Hospitals and 170 clinics at Intermountain Healthcare, a large integrated delivery system. The Audit Data Mart successfully identified important and differing EHR functional usage patterns. These patterns were useful in strategic planning, tracking EHR implementations, and will likely be utilized to assist in documentation of "Meaningful Use" of EHR functionality. PMID- 20841656 TI - A scheme for assuring lifelong readability in computer based medical records. AB - Medical records must be kept over an extended period of time, meanwhile computer based medical records are renewed every 5-6 years. Readability of medical records must be assured even though the systems are renewed by different vendors. To achieve this, we proposed a method called DACS, in which a medical record is considered as an aggregation of documents. A Document generated by a system is transformed to a format read by free software such as PDF, which is transferred with the document meta-information and important data written on the XML to the Document Deliverer. It stores these data into the Document Archiver, the Document Sharing Server and the Data Warehouse (DWH). We developed the Matrix View which shows documents in chronological order, and the Tree View showing documents in class tree structure. By this method all the documents can be integrated and be viewed by a single viewer. This helps users figure out patient history and find a document being sought. In addition, documents' data can be shared among systems and analyzed by DWH. Most importantly DACS can assure the lifelong readability of medical records. PMID- 20841657 TI - Experience implementing a point-of-care electronic medical record system for primary care in Malawi. AB - Due to the fact that health care professionals in Malawi are often overstretched, the use and quality of health data can be compromised. The Malawi Health Management Information System (HMIS) has streamlined data collection and reporting and increased the use of data to improve care. Obstacles remain, including incomplete reporting and low staff morale. With the Baobab Health Trust and the Malawi Ministry of Health, Partners In Health piloted an innovative point of-care data system for primary care that functions alongside OpenMRS, an open source medical record platform. The system has given access to a patient-level primary care dataset in real time. Initial results highlight some of the benefits of a point-of-care system such as improved data quality, emphasize the importance of sharing data with clinical practitioners, and shed light on how this approach could strengthen HMIS. PMID- 20841658 TI - Touchscreen task efficiency and learnability in an electronic medical record at the point-of-care. AB - The objective of this study was to determine the relative efficiency of novices compared to a prediction of skilled use when performing tasks using the touchscreen interface of an EMR developed in Malawi. We observed novice users performing touchscreen tasks and recorded timestamp data from their performances. Using a predictive human performance modeling tool, the authors predicted the skilled task performance time for each task. Efficiency and rates of error were evaluated with respect to user interface design. Nineteen participants performed 31 EMR tasks seven times for a total of 4,123 observed performances. We analyzed twelve representative tasks leaving 1,596 performances featuring six user interface designs. Mean novice performance time was significantly slower than mean predicted skilled performance time (p<0.001). However, novices performed faster than the predicted skilled level in 208 (13%) of successful task performances. These findings suggest the user interface design supports a primary design goal of the EMR--to allow novice users to perform tasks efficiently and effectively. PMID- 20841659 TI - Process-aware EHR BPM systems: two prototypes and a conceptual framework. AB - Systematic methods to improve the effectiveness and efficiency of electronic health record-mediated processes will be key to EHRs playing an important role in the positive transformation of healthcare. Business process management (BPM) systematically optimizes process effectiveness, efficiency, and flexibility. Therefore BPM offers relevant ideas and technologies. We provide a conceptual model based on EHR productivity and negative feedback control that links EHR and BPM domains, describe two EHR BPM prototype modules, and close with the argument that typical EHRs must become more process-aware if they are to take full advantage of BPM ideas and technology. A prediction: Future extensible clinical groupware will coordinate delivery of EHR functionality to teams of users by combining modular components with executable process models whose usability (effectiveness, efficiency, and user satisfaction) will be systematically improved using business process management techniques. PMID- 20841660 TI - Understanding resistance towards electronic patient health data in South Australian family practice. AB - This paper reports the results from a survey of 131 medical practitioners in South Australian General Practice concerning adoption of a computerised system for storing and potentially amalgamating health information from several practices. Practitioners were primarily influenced by the positively perceived potential for such technology use to improve patient health and well-being outcomes and secondarily by the negatively perceived potential for unwanted change in the status, control and autonomy of their professional role. Practitioner attitude reflected how they resolved the competing influences. The data suggest that strategies for implementing such systems should address individual perceptions by increasing belief in the potential for patient improvement or by decreasing belief of the inevitability of unwanted role change. PMID- 20841661 TI - Usefulness of the functionalities of an electronic medical record on a Latin American medical web portal. AB - The medical record is a key component in the modern health systems, a fundamental basis of higher functionalities that guaranties quality care and the possibility of improved clinical management. The dissemination of information systems for the electronic medical record (EMR) has a growing acceptance and use in developed countries. This type of recognition however has not been widespread in Latin America. Realizing this we conducted a web survey to users of a Latin American medical portal to assess their perception of the EMRs usefulness. Among the results we found that over 90% of respondents were in favor of its use, with values that exceed 80% in the analysis of the utilities by categories. More in depth studies are needed to determine the reasons for the lack of dissemination and implementation of EMR in our region. PMID- 20841662 TI - How are clinicians involved in EHR planning? A process analysis case study of a region in Denmark. AB - Experience shows that to achieve a successful implementation of EHR clinicians must obtain joint ownership of the decisions made during the EHR-process. The EHR planning process in the Region of North Jutland, Denmark was studied with the aim of answering the question; "Why are not all Danish physicians overjoyed by the introduction of EHR? A case study was carried out from Oct. 2003 till April 2006 using process analysis. The EHR project management's strategy meant that there was no workload reduction. This was seen as one of the main barriers for the physicians to achieve real influence. History shows that clinician's on the one hand and administrators on the other have different perceptions of the purpose of the patient record and that they both have struggled to influence this definition. To date, the administrators have won the battle. This was the major reason for the approach chosen for the EHR planning process in North Jutland, Denmark. It explains the conditions made available for the physicians, which led to their role being reduced to clinical consultants--rather than real participants. PMID- 20841663 TI - Integration of healthcare information: from enterprise PACS to patient centered multimedia health record. AB - Every single piece of healthcare information should be fully integrated and transparent within the electronic health record. The Italian Hospital of Buenos Aires initiated the project Multimedia Health Record with the goal to achieve this integration while maintaining a holistic view of current structure of the systems of the Hospital, where the axis remains are the patient and longitudinal history, commencing with section Computed Tomography. Was implemented DICOM standard for communication and image storage and bought a PACS. It was necessary adapt our generic reporting system for live up to the commercial RIS. The Computerized Tomography (CT) Scanners of our hospital were easily integrated into the DICOM network and all the CT Scans generated by our radiology service were stored in the PACS, reported using the Structured Reporting System (we installed diagnostic terminals equipped with 3 monitors) and displayed in the EHR at any point of HIBA's healthcare network. PMID- 20841664 TI - The avoidable misfortune of a computerized patient chart. AB - The implementation of clinical information systems is demanding, particularly in hospitals, where reliable and well functioning information and communication tools are critical. In this paper we present different approaches to understanding and identifying challenges concerning the implementation of new electronic patient chart functionality. The context of the study was the development and implementation of the new system, which was withdrawn shortly after deployment in a medium-sized University Hospital. One year prior to the deployment we performed an observational study of current information and communication system usage in two hospital wards. Eight months later we conducted a usability test of the new functionality in a laboratory configured as a hospital ward. Four months after system deployment, the studies were followed up by interviews with healthcare personnel, members from the hospital implementation project group, and vendor representatives. The results of the studies show how the different approaches identify and reveal important issues that, if they had been taken into account, could have increased the chance of successful implementation of the system. PMID- 20841665 TI - A usability study of patient-friendly terminology in an EMR system. AB - Misunderstandings due to terminology differences between health care providers and consumers may cause communication problems and adversely affect consumer access to health information, resulting in poor satisfaction for patients and providers. To investigate the usage patterns of consumer health vocabulary and evaluate controlled terminologies used in electronic medical records, we conducted a usability study of patient-friendly terms used in an ambulatory electronic medical record (EMR) and associated patient web portal. After identifying 340 unique diagnosis term/patient-friendly term pairs, we mapped the term pairs determined by UMLS to be pairs of synonyms, near-synonyms, or closely related terms to the keywords of search queries extracted from a consumer health information web portal to learn the comparative frequency of use of members of each pair by consumers. We found out that use of patient-friendly terms could help to bridge the language gap between providers and consumers but not always. In some cases the professional diagnosis terms were used more frequently than their patient-friendly counterparts, typically in cases where the professional terms were more simple or common than the patient-friendly terms. PMID- 20841666 TI - A conceptual framework for analyzing how Canadian physicians are using electronic medical records in clinical care. AB - Our electronic medical record (EMR) case study research pursued a set of questions to provide Canadian physicians with practical information on best practices and lessons learned regarding implementation and use of EMRs in ambulatory clinical care. The study's conceptual framework included an EMR System and Use Assessment Survey, interview guide, transcription codes, observation guide and case study report template. The common message that emerged was that no clinic would return to paper-based charts after experiencing the benefits of EMR. In seeking to corroborate our findings with success factors in an EMR implementation meta-framework, we further investigated the role of information incentives as a key factor in sustainable EMR implementations. The sections of our conceptual framework that best enabled us to capture information incentives were the 12 survey questions about information quality, EMR adoption questions in the interview guide and a subset of 26 items from our transcription coding scheme that were linked to physicians quotations about knowing more about the patient when using the EMR than when using paper. PMID- 20841667 TI - Towards automating the initial screening phase of a systematic review. AB - Systematic review authors synthesize research to guide clinicians in their practice of evidence-based medicine. Teammates independently identify provisionally eligible studies by reading the same set of hundreds and sometimes thousands of citations during an initial screening phase. We investigated whether supervised machine learning methods can potentially reduce their workload. We also extended earlier research by including observational studies of a rare condition. To build training and test sets, we used annotated citations from a search conducted for an in-progress Cochrane systematic review. We extracted features from titles, abstracts, and metadata, then trained, optimized, and tested several classifiers with respect to mean performance based on 10-fold cross-validations. In the training condition, the evolutionary support vector machine (EvoSVM) with an Epanechnikov or radial kernel is the best classifier: mean recall=100%; mean precision=48% and 41%, respectively. In the test condition, EvoSVM performance degrades: mean recall=77%, mean precision ranges from 26% to 37%. Because near-perfect recall is essential in this context, we conclude that supervised machine learning methods may be useful for reducing workload under certain conditions. PMID- 20841668 TI - Balancing centralised and decentralised EHR approaches to manage standardisation. AB - Balancing regional and national electronic health record (EHR) approaches requires cooperation between clinical and technical experts at different organisational levels. Bridging is necessary to achieve interoperability between regional EHR systems, without neglecting the clinical usefulness. This study has investigated the approaches chosen in modelling the clinical content of EHRs in two out of five regions in Denmark. Based on the knowledge obtained in these studies a 'clinical content format' was developed to facilitate the work of the regions, where the clinical content of EHR systems is modelled. The objective of the clinical content format is to enable share and reuse across organisations, furthermore an objective is to gradually introduce standards. The results of the first iteration of a 'clinical content format' are presented and future adjustments are discussed based on the results. PMID- 20841669 TI - Towards iconic language for patient records, drug monographs, guidelines and medical search engines. AB - Practicing physicians have limited time for consulting medical knowledge and records. We have previously shown that using icons instead of text to present drug monographs may allow contraindications and adverse effects to be identified more rapidly and more accurately. These findings were based on the use of an iconic language designed for drug knowledge, providing icons for many medical concepts, including diseases, antecedents, drug classes and tests. In this paper, we describe a new project aimed at extending this iconic language, and exploring the possible applications of these icons in medicine. Based on evaluators' comments, focus groups of physicians and opinions of academic, industrial and associative partners, we propose iconic applications related to patient records, for example summarizing patient conditions, searching for specific clinical documents and helping to code structured data. Other applications involve the presentation of clinical practice guidelines and improving the interface of medical search engines. These new applications could use the same iconic language that was designed for drug knowledge, with a few additional items that respect the logic of the language. PMID- 20841670 TI - Building a logical EHR architecture based on ISO 13606 standard and semantic web technologies. AB - Among the existing patterns of EHR interoperability, the ISO 13606 standard is an important consideration. It is believed that the use of this norm, in conjunction with semantic technologies, may aid in the construction of a robust architecture, keeping in mind the challenges of semantic interoperability. The objective of this paper is to present a proposal for an EHR architecture, based on ISO 13606 and on the utilization of semantic technologies, for a real EHR scenario. In order to accomplish that, a real EHR scenario is described, as well as its main interoperability requirements and a candidate architecture is proposed to solve the presented challenges of interoperability. The ability of the ISO 13606 EHR reference model to accommodate the scenario was highlighted, together with the support provided by the use of the ontology specification languages--RDF and OWL- in respect to the maintenance of a controlled vocabulary. PMID- 20841671 TI - Case study: analysis of end-user requests on electronic medical record and computerized physician order entry system of Seoul National University Hospital in Korea. AB - Seoul National University Hospital (SNUH) in Korea has utilized the full Electronic Medical Record (EMR) system since October 2004. Unlike other countries, most EMR systems in Korean teaching and general hospitals are in-house development systems. Therefore, we can actively respond to user requests on EMR. Here, based on 5 years of experience in EMR system operation, we analyzed 2,339 SNUH EMR user requests from 2006 to 2008 for improvement of EMR system operation and management. We classify user requests into 9 criteria based on guidelines from the SNUH medical information management team. In conclusion, the most common requests (73%) are for improvement of improving quality of care. However, requests associated with hospital enterprise, public policy, and customer service are gradually increased every year. Therefore, we suggest that suitable EMR management criteria are necessary for reliable EMR operation and management. PMID- 20841672 TI - Does CPOE actually disrupt physicians-nurses communications? AB - This study addresses the question of the respective impact of organizational vs. technical environment variables on the collaborative aspects of healthcare work situations. It analyzes the physicians-nurses communications during the medication use process, according to both the organization of their work and their technical environment. Participant observations, interviews and recording of the dialogs were performed in 4 hospitals functioning with either a CPOE or a Paper based system. The study (i) presents the identification and description of the communications' processes involving doctors-nurses face-to-face communications and the supports that mediate medication information and (ii) focuses on the amount of face-to-face communications depending on the organization of work and the technical system used. The analyses demonstrate that the organizational variables have a larger impact than the technical environment on the quality and quantity of the communications and cooperation activities. PMID- 20841673 TI - Discuss now, document later: CIS/CPOE perceived to be a 'shift behind' in the ICU. AB - Effective communication is essential to safe and efficient patient care. We aimed to understand the current patterns and perceptions of communication of common goals in the ICU using the distributed cognition and clinical communication space theoretical frameworks. We conducted a focus group and 5 interviews with ICU clinicians and observed 59.5 hours of interdisciplinary ICU morning rounds. Clinicians used a CIS/CPOE system and paper artifacts for documentation; yet, preferred verbal communication as a method of information exchange because they perceived that the documentation was often not updated or efficient for information retrieval. These perceptions that the CIS/CPOE is a "shift behind" may lead to a further reliance on verbal information exchange, which is a valuable clinical communication activity, yet, is subject to information loss. Electronic documentation tools that, in real time, capture information that is currently verbally communicated may increase the effectiveness of communication. PMID- 20841674 TI - Method for testing a CPOE system in the medication process in a cardiology ward. AB - Medication errors are of major concern in most countries. The European PSIP project aims to identify and prevent medication errors by enabling data mining and designing contextualized decision support functionalities using a human factors engineering approach. To create a basic understanding of the work practice in the medication process members of the staff in a cardiology department in a Danish hospital were asked to take pictures of their workplace. The pictures were used as a memory trigger in a subsequent interview. Furthermore a video based observation of a full day of work was carried out. In this paper the methodological considerations and experiences are presented and discussed. PMID- 20841675 TI - Steps towards single source--collecting data about quality of life within clinical information systems. AB - Information about the quality of life from patients being treated in routine medical care is important for the attending physician. This data is also needed in research for example to evaluate the therapy and the course of the disease respectively. Especially skin diseases often negatively affect the quality of life. Therefore we aimed to design a concept to collect such data during treatment and use it for both medical care and research in the setting of dermatology. We performed a workflow analysis and implemented a designated form using the tools of the local clinical information system. Quality of life data is now collected within the clinical information system during treatment and is used for discharge letters, progress overviews as well as research about the treatment and course of disease. This concept which contributes to the single source approach was feasible within dermatology and is ready to be expanded into other domains. PMID- 20841676 TI - Methodology of integration of a clinical data warehouse with a clinical information system: the HEGP case. AB - Clinical Data Warehouses (CDW) can complement current Clinical Information Systems (CIS) with functions that are not easily implemented by traditional operational database systems. Here, we describe the design and deployment strategy used at the Pompidou University Hospital in southwest Paris. Four realms are described: technological realm, data realm, restitution realm, and administration realm. The corresponding UML use cases and the mapping rules from the shared integrated electronic health records to the five axes of the i2b2 CDW star model are presented. Priority is given to the anonymization and security principles used for the 1.2 million patient records currently stored in the CDW. Exploitation of a CDW by clinicians and investigators can facilitate clinical research, quality evaluations and outcome studies. These indirect benefits are among the reasons for the continuous use of an integrated CIS. PMID- 20841677 TI - TEDIS: an information system dedicated to patients with pervasive developmental disorders. AB - Pervasive Development Disorders (PDD) represent a life disorder which significantly affects individuals and families. It requires long term specialized institutions health care, education and social accompaniment. In France, 350,000 to 600,000 patients are estimated to be affected and 5,000 to 8,000 newborns will develop the disorder every year. In 2005, Autism Resource Centres were created in each of the 23 regions in France, to support the PDD hospital reference centres in providing formal clinical assessment for each patient. Such assessments will support the prescription of health care measures, educative and intuitional orientation and accompaniment. An information system called TEDIS was designed to assist the psychiatrists and multidisciplinary medical experts at Necker child psychiatry hospital, in organizing PDD patient's information and providing ground for improving knowledge about the disorder, its epidemiology and underlying biological mechanisms. The professionals' involvement from the beginning in the development process facilitated TEDIS design and implementation. The results of first experimentations are encouraging. They are described as well as the short term and mid-term deployment planning. PMID- 20841678 TI - Developing a user-centered voluntary medical incident reporting system. AB - Medical errors are one of leading causes of death among adults in the United States. According to the Institute of Medicine, reporting of medical incidents could be a cornerstone to learn from errors and to improve patient safety, if incident data are collected in a properly structured format which is useful for the detection of patterns, discovery of underlying factors, and generation of solutions. Globally, a number of medical incident reporting systems were deployed for collecting observable incident data in care delivery organizations (CDO) over the past several years. However, few researches delved into design of user centered reporting system for improving completeness and accuracy of medical incident collection, let alone design models created for other institutes to follow. In this paper, we introduce the problems identified in a current using voluntary reporting system and our effort is being made towards complete, accurate and useful user-centered new reporting system through a usability engineering process. PMID- 20841679 TI - CEDRIC: a computerized chronic disease management system for urban, safety net clinics. AB - To meet the challenge of improving health care quality in urban, medically underserved areas of the US that have a predominance of chronic diseases such as diabetes, we have developed a new information system called CEDRIC for managing chronic diseases. CEDRIC was developed in collaboration with clinicians at an urban safety net clinic, using a community-participatory partnered research approach, with a view to addressing the particular needs of urban clinics with a high physician turnover and large uninsured/underinsured patient population. The pilot implementation focuses on diabetes management. In this paper, we describe the system's architecture and features. PMID- 20841680 TI - Determinants of clinical information system post-adoption success. AB - The diffusion of information technology (IT) in healthcare systems to support clinical processes makes the evaluation of physician and nurse post-adoption an important challenge for clinical information systems (CIS). This paper examines the relationships between the determinants of success of a CIS based on an expectation-confirmation paradigm in a cross-sectional survey performed at the Sherbrooke University Hospital (CHUS). 32.2% (161) of physicians and 27.1% (352) of nurses responded to the survey questionnaires. Results suggested that physician and nurse satisfaction is determined differently according to post adoption expectations: compatibility, confirmation of expectations, usefulness, ease of use, and support. The best predictor of physician satisfaction was perceived usefulness (r=.25, p=.0003) whereas for nurses it was ease of use (r=.18, p=.0003). Confirmation of expectations was strongly associated with each post-adoption expectation and positions its importance in CIS design and redesign. This study draws attention to the differences between physician and nurse perceptions of information technology and emphasizes post-adoption evaluation to measure CIS success. Physicians and nurses post-adoption expectations were key factors to warn again potential discontinuance. PMID- 20841681 TI - MEDAL: measuring of emergency departments' adaptive load. AB - We propose an innovative approach for measuring real-time operational load within emergency departments. Medical informatics, operations researchers, and other decision makers in the health care field have yet to come to an agreement regarding standardized matrices for measuring operational load within emergency departments. As a result, it is difficult to develop methods and approaches for reducing operational load. We propose a flexible framework based on neural networks. These networks can calculate user-tuned load value, based on a set of well-defined operational and clinical indicators. The operational load value is calculated by learning the weights of the raw operational indicators within a particular emergency department. PMID- 20841682 TI - What effect does electronic ordering have on the organisational dynamics of a hospital pathology service? AB - The aim of this triangulated (multi-method, multi-setting, multi-staged) study was to identify the consequences of an electronic ordering system on the functioning and organisational dynamics of a hospital pathology service. The study was carried out in five pathology departments during the period August 2005 to April 2006. It included five focus groups involving 21 participants and 67 interviews with 38 participants, along with a total of 21 hours of observation. The findings revealed three key themes with implications for the functioning and organisational dynamics of the pathology service. These included: a) work process changes that affect the output of the pathology laboratories; b) temporal considerations, particularly as they related to efficiency of laboratory processes; and c) communication channels and the resulting changes in the mode of information exchange and communication. These themes emerged from a close analysis of the contextual setting of each department. Successful CPOE implementation should be premised on a solid understanding of the organisational, communication, information and temporal circumstances in which the system will operate. PMID- 20841683 TI - Clinicians, security and information technology support services in practice settings--a pilot study. AB - This case study of 9 information technology (IT) support staff in 3 Australian (Victoria) public hospitals juxtaposes their experiences at the user-level of eHealth security in the Natural Hospital Environment with that previously reported by 26 medical, nursing and allied healthcare clinicians. IT support responsibilities comprised the entire hospital, of which clinician eHealth security needs were only part. IT staff believed their support tasks were often fragmented while work responsibilities were hampered by resources shortages. They perceived clinicians as an ongoing security risk to private health information. By comparison clinicians believed IT staff would not adequately support the private and secure application of eHealth for patient care. Preliminary data analysis suggests the tension between these cohorts manifests as an eHealth environment where silos of clinical work are disconnected from silos of IT support work. The discipline-based silos hamper health privacy outcomes. Privacy and security policies, especially those influencing the audit process, will benefit by further research of this phenomenon. PMID- 20841684 TI - Learning lessons from electronic prescribing implementations in secondary care. AB - This paper reports a study undertaken in the UK to gather lessons learned from hospital sites that have implemented electronic prescribing systems. The work was commissioned by NHS Connecting for Health, the UK Department of Health agency responsible for the implementation of the National Programme for Information Technology. The aim was to capture front-line experience of the project and systems implementation, and to share it with staff who will in the future participate in other implementations. Data were drawn from detailed interviews with staff and a survey in 13 hospitals in England, as well as a review of published studies of implementations. The study output is a report and six user facing briefing documents targeted at key stakeholder groups; nurses, pharmacist, doctors, senior executives, implementation team members and IM&T staff. PMID- 20841685 TI - Implementation, monitoring and utilization of an integrated Hospital Information System--lessons from a case study. AB - In most hospitals several heterogeneous Information Systems (IS) store parts of a still scattered patient record. Virtual Patient Records (VPR) are systems that aggregate known data elements about the patient from different IS in real-time. This papers aims to present the main lessons learned from the implementation and the usage during 6 years of a VPR system. Ten major lessons were divided in recommendations for software developers, information managers and institutional policy makers. Implementing and using a VPR is a difficult journey but can generate great value for the institution if most of these recommendations are taken in consideration. PMID- 20841686 TI - Model-driven traceability in healthcare information systems development. AB - To improve the quality of software used in healthcare information systems, traceability can play an important role. The concept of traceability establishes explicit trace links in the design, development and maintenance processes, keeping documentation complete and updated. Trace information allows validating bodies, domain experts, system designers and programmers to easily navigate along artefact dependencies and perform simple traceability analysis such as coverage and change impact. This paper presents a novel solution for traceability applied in model-driven development for services in a distributed healthcare environment. The results demonstrate the feasibility of explicitly modelling dependencies using a formal language such as UML. Based on the experience from implementing two full-scale homecare systems in the EU-IST MPOWER project, the potential improvements and challenges with a traceability solution are discussed. PMID- 20841687 TI - The evolution of hospital information systems and the role of electronic patient records: from the Italian scenario to a real case. AB - Health care organizations can gain great value from Information and Communication Technologies (ICT), yet, although there is growing awareness of the potential benefits associated with their use, results often fall far short of expectations. Each year, the "ICT in Health Care" Observatory--part of the Politecnico di Milano School of Management--outlines a profile of the role of ICT in the Italian health care industry, investigating current projects in terms of their impact on processes and organizations, implementation state of the art, governance models, and prospective pathways. The 2009 collaborative research process outlines the need for a change in the way health care CIOs approach technological and organizational evolutions. ICT departments lack vision, governance mechanisms, skilled resources, and top management commitment. This has led to a series of distortions in the innovation of Hospital Information Systems (HISs) and ICT departments themselves. Currently they are too concerned with day-to-day operations and delay comprehensive initiatives capable of leading to effective ICT-driven innovations. The paper points out the problems that health care organizations are tackling and how they are trying to solve them. The case of the Italian National Cancer Institute in Milan provides a valuable example of how a health care organization is developing its HIS. PMID- 20841688 TI - Evaluation of a French medical multi-terminology indexer for the manual annotation of natural language medical reports of healthcare-associated infections. AB - BACKGROUND: Surveillance of healthcare-associated infections is essential to prevention. A new collaborative project, namely ALADIN, was launched in January 2009 and aims to develop an automated detection tool based on natural language processing of medical documents. OBJECTIVE: The objective of this study was to evaluate the annotation of natural language medical reports of healthcare associated infections. METHODS: A software MS Access application (NosIndex) has been developed to interface ECMT XML answer and manual annotation work. ECMT performances were evaluated by an infection control practitioner (ICP). Precision was evaluated for the 2 modules and recall only for the default module. Exclusion rate was defined as ratio between medical terms not found by ECMT and total number of terms evaluated. RESULTS: The medical discharge summaries were randomly selected in 4 medical wards. From the 247 medical terms evaluated, ECMT proposed 428 and 3,721 codes, respectively for the default and expansion modules. The precision was higher with the default module (P1=0.62) than with the expansion (P2=0.47). CONCLUSION: Performances of ECMT as support tool for the medical annotation were satisfactory. PMID- 20841689 TI - A Lab-EMR interoperability profile as an eHealth architecture component for resource-constrained settings. AB - Implementation of computerized systems in resource-constrained settings have been gaining traction as a means of improving the delivery of health care, the use and reuse of information, and providing a standards-based capacity for assessing the process and impact of health care. In a resource-constrained environment, systems are often implemented as stand-alone entities focused on specific care activities (for example, delivering antiretroviral therapy). As such, in many countries, taking a generalized approach to linking electronic medical record systems with laboratory information systems (EMR-LIS) is an important area in which to achieve interoperability. In this paper we describe a scenario of use and information interaction interoperability profile based on our experience implementing EMR-LIS integration in two resource-constrained settings. Of significance, the profile emphasizes queued matching in order to avoid mutual dependence while achieving interoperability between systems. PMID- 20841690 TI - eVisit: a pilot study of a new kind of healthcare delivery. AB - Patient online eVisits are gaining momentum due to increasing consumer demand for improved access to clinical services, availability of new technologies to deploy such services and development of reimbursement initiatives by major payers. The eVisit service provides patients with an online consultation through a series of structured, secure message exchanges with a physician, providing an alternative for onsite office visits and non-reimbursed phone-based care. In this study, we evaluate a pilot deployment of eVisits in a primary care clinic providing online consultation service for 7 simple health conditions at its three locations. We examine usage data over 3 months and survey and interview results for trends in adoption, demographic and temporal patterns of usage, clinician and patient expectations and experiences, and challenges to sustainability of the service. Based on our analysis, we conclude that the eVisit pilot was a success. Patients valued the new service being offered as demonstrated by a rapid increase in usage. The quality of service was good with fast turnaround times and few exchanges to resolve a request. These positive outcomes combined with a reimbursement model are promising indications of sustainability but several challenges remain. PMID- 20841691 TI - Patients' needs assessment documentation in multidisciplinary electronic health records. AB - The purpose of this study is to describe and discuss physicians' and nurses' documentation of the patient's needs assessment in electronic health records (EHR) in the neurological care setting. Both physicians and nurses collect, record and interpret data during patient care episodes. Assessment of patient's need for care and treatment is an important part of the care process. Planning, implementation and outcome assessment of the care process are based on needs assessment data. The data of this study consist of 48 neurological medical narratives and nursing care plans. The data were analyzed using descriptive statistics and content analysis. Physician's medical narratives include referrals to physiotherapy and consultations in other care specialties in which they have recorded the reason for the care, anamnesis and status praesens data. Nurses have documented patient's needs assessment in nursing care plans using Finnish Classification of Nursing Diagnoses (FiCND) and additional narrative text. Physicians' and nurses' patient needs assessment documentation complement each other. Nursing documentation includes more detailed information about patients' needs for care due the use of FiCND in documentation. The use of standardised documentation improves quality documentation and retrieval of data from EHR. PMID- 20841692 TI - Impact of a critical care clinical information system on interruption rates during intensive care nurse and physician documentation tasks. AB - Computerized documentation methods in Intensive Care Units (ICUs) may assist Health Care Providers (HCP) with their documentation workload, but evaluating impacts remains problematic. A Critical Care clinical Information System (CCIS) is an electronic charting tool designed for ICUs that may fit seamlessly into HCP work. Observers followed ICU nurses and physicians in two ICUs in Edmonton, Canada, in which a CCIS had recently been introduced. Observers recorded amounts of time HCPs spent on documentation related tasks, interruptions encountered by HCPs, and contextual information in field notes. Interruption rates varied depending on the charting medium used, with physicians being interrupted less frequently when performing documentation tasks using the CCIS, than when performing documentation tasks using other methods. In contrast, nurses were interrupted more frequently when charting using the CCIS than when using other methods. Interruption rates coupled with qualitative observations suggest that physicians utilize strategies to avoid interruptions if interfaces for entering textual notes are not well adapted to interruption-rich environments such as ICUs. Potential improvements are discussed such that systems like the CCIS may better integrate into ICU work. PMID- 20841693 TI - Conceptualization of an electronic system for documentation of nursing diagnosis, outcomes, and intervention. AB - Electronic nursing documentation constitutes technical, scientific, legal, and ethical documents. The objective of this study was to develop an electronic nursing documentation system. The system was developed in four phases (conceptualization, detailing, prototype building, implementation), and the knowledge base was based on domains and classes according to the NANDA-I, NIC, and NOC unified framework. The result is an electronic system (PROCEnf--USP- Nursing Process Electronic Documentation System of the University of Sao Paulo) which allows documenting nursing process generating reports of nursing process, besides supporting decisions on nursing diagnosis, expected outcomes, and interventions. Integration of different fields of knowledge, as well as the institutional feature of valuing continuous theoretical and practical improvement of nursing process were factors of success of this technological project. PMID- 20841694 TI - Medication counseling: analysis of electronic documentation using the clinical care classification system. AB - Medication counseling is a central aspect of medication safety. Counseling refers to the process of informing, advising and administering medication to help patients manage their medication regimen. This pilot study examined 379 descriptions of medication counseling carried out in surgical care and documented in an electronic patient record system by using the Clinical Care Classification System. The objective was to identify counseling methods and to evaluate the need for additional counseling descriptor codes in the record. Eleven counseling methods were identified and the data were classified according to counseling methods with and without documentation of the nature of the interaction with patients. There were no descriptions of the nature of counseling conducted in 127 of the documented entries. These results can be used when developing the documentation of medication care in electronic patient records. PMID- 20841695 TI - HL7 CDA implementation guide for structured anatomic pathology reports methodology and tools. AB - Anatomic pathology reports (APR) provide diagnostic and prognostic information crucial to patient care, clinical research and epidemiology. Currently, it is difficult to collect and exchange APR data between different healthcare organizations at an international level. OBJECTIVE: IHE and HL7 anatomic pathology joint efforts aim at providing a methodology and tools to define an international HL7 "Clinical Document Architecture" (CDA) implementation guide for APRs and especially in the domain of cancer. METHODS: A four-step methodology is employed, consisting of comparing existing clinical model of APRs originating from different countries; deriving consensus-based clinical models (Delphi technique); providing the corresponding HL7 CDA implementation guide ("CDA templates") and validating these templates. RESULTS: International experts defined HL7 CDA implementation guides for breast and colon cancer APRs within an IHE content profile. CDA templates include required data elements, as well as optional ones, that can be further specified as required in national extensions. CONCLUSION: This study demonstrates that it is possible to define an international HL7 CDA implementation guide for cancer APRs. Further efforts are needed to provide CDA templates for approximately 60 other cancer APRs dedicated to different organs, diagnoses, and procedures as well as for APRs of non neoplastic pathologies. The methodology is not confined to APRs and could be applied to clinical documents of any type. PMID- 20841696 TI - Peri-operative communication patterns and media usage--implications for systems design. AB - Inter-hospital communication amounts for a great deal of clinicians' work time. While communication is essential to coordinate care, it can also be time consuming and interruptive, and breakdown in communication is an important source of medical errors. One contributor to the interruptive nature of communication is the use of synchronous media, and there is clearly a potential for novel technologies. To assess communication patterns and media usage we performed an ethnographic field study in the peri-operative environment at a Norwegian hospital, as well as interviews with nurses. We analyze the results with regards to choice of media, characteristics of the conversations taking place and meta messages, and account for addressing, obtrusiveness and information richness in the message exchanges. We find a relative high degree of interruptiveness in communication, and ascribe it to 1) a lack of situational awareness between locations in the peri-operative domain, as well as 2) use of synchronous media. This suggests that design of novel technology for intra-hospital communication should aim at supporting sender-receiver awareness and signaling of availability. PMID- 20841697 TI - Goal-based design pattern for delegation of work in health care teams. AB - We show how a domain and language independent design pattern, defined as networks of tasks and goals, can be used to formally specify the transfer of responsibility and accountability when tasks are delegated in healthcare teams. The pattern is general enough to be applied unchanged across a broad range of different healthcare situations. PMID- 20841698 TI - Participatory interaction design in user requirements specification in healthcare. AB - Healthcare information systems are accused of poor usability even in the popular media in Finland. Doctors especially have been very critical and actively expressed their opinions in public. User involvement and user-centered design methods are seen as the key solution to usability problems. In this paper we describe a research case where participatory methods were experimented within healthcare information systems development in medicinal care in a hospital. The study was part of a larger research project on Activity-driven Information Systems Development in healthcare. The study started by finding out about and modeling the present state of medicinal care in the hospital. After that it was important to define and model the goal state. The goal state, facilitated by the would-be software package, was modeled with the help of user interface drawings as one way of prototyping. Traditional usability methods were extended during the study. According to the health professionals' feedback, the use of participatory and user-centered interaction design methods, particularly user interface drawings enabled them to describe their requirements and create common understanding with the system developers. PMID- 20841699 TI - Cognitive evaluation of a physician data query tool for a national ICU registry: comparing two think aloud variants and their application in redesign. AB - Applying usability methods in formative evaluations of interactive healthcare information systems design is recognized as of extreme importance to the final success of these systems. However, it seems that the merits of specific methodological approaches for conducting these studies have received little attention. This study reports on a cognitive evaluation of a Physician Data Query Tool, which offers physicians the opportunity to query quality of care data collected by the Dutch National Intensive Care Evaluation (NICE) foundation. A comparison in terms of usefulness and utility of two variants of the Think Aloud method is addressed, the Concurrent and Retrospective Think Aloud. These methods are well known in the field of Human Computer Interaction in the context of usability evaluation. The results of this research indicate that though both methods have their disadvantages and benefits, in redesigning the Physician Data Query tool the Retrospective Think Aloud provided more useful input to the Tool's redesign. However, in deciding which method to apply in a formative evaluation study, end users' cognitive workload of performing the system's tasks and the system characteristics need to be considered as well. PMID- 20841700 TI - Can brain computer interfaces become practical assistive devices in the community? AB - A Brain Computer Interface (BCI) provides direct communication from the brain to a computer or electronic device. In order for BCIs to become practical assistive devices it is necessary to develop robust systems, which can be used outside of the laboratory. This paper appraises the technical challenges, and outlines the design of an intuitive user interface, which can be used for smart device control and entertainment applications, of specific interest to users. We adopted a user centred approach, surveying two groups of participants: fifteen volunteers who could use BCI as an additional technology and six users with complex communication and assistive technology needs. Interaction is based on a four way choice, parsing a hierarchical menu structure which allows selection of room location and then device (e.g. light, television) within a smart home. The interface promotes ease of use which aim to improve the BCI communication rate. PMID- 20841701 TI - Supporting human interaction and human resources coordination in distributed clinical guidelines. AB - Clinical guidelines (GL) play an important role in medical practice: the one of optimizing the quality of patient care on the basis of the best and most recent evidence based medicine. In order to achieve this goal, the interaction between different actors, who cooperate in the execution of the same GL, is a crucial issue. As a matter of fact, in many cases (e.g. in chronic disease treatment) the GL execution requires that patient treatment is not performed/completed in the hospital, but is continued in different contexts (e.g. at home, or in the general practitioner's ambulatory), under the responsibility of different actors. In this situation, the correct interaction and communication between the actors themselves is critical for the quality of care, and human resources coordination is a key issue to be addressed by the managers of the involved healthcare service. In this paper we describe how computerized GL management can be extended in order to support such needs, and we illustrate our approach by means of a practical case study. PMID- 20841702 TI - LuMiR: the region-wide EHR-S in Basilicata. AB - The Lucania-Medici in Rete (LuMiR) project aims to support the shift from organization-centric to patient-centric healthcare in Basilicata, a region in the southern Italy. Main objective of the project is to foster collaborative, multidisciplinary and cross-organizational healthcare processes by developing and stimulating the adoption of a region-wide, software infrastructure, the LuMiR system. It is a suite of e-services that facilitates the sharing of patient related clinical data among authorized professionals, by enabling the interoperability among Electronic Medical. In the paper the LuMiR project approach is discussed, pointing out the methodology adopted in the design and development of the LuMiR system, the peculiarities of the system architecture and interventions scheduled to mitigate the risks related to the large scale adoption of the LuMiR system itself. PMID- 20841703 TI - Experience implementing OpenMRS to support maternal and reproductive health in Northern Nigeria. AB - In Northern Nigeria a deteriorating health system has resulted in one of the World's highest rates of maternal and infant deaths. The dire situation in Northern Nigeria is only amplified by the lack of an effective health information system, leaving hospitals and clinics to make decisions about patient care with only uninformed guesses about medical history and access to unreliable and unintelligible patient registers and summary reports. In 2009 we implemented an electronic medical records system using OpenMRS for the Family Health Unit of the Shehu Idris College. The three-month process resulted in electronic forms for all clinical areas, greatly reduced data duplication and a monthly reporting process that takes minutes instead of days. This system provides not only access to the first patient-based health indicators in Nigeria (as opposed to previously error prone aggregate data) but is also an example of the potential to overcome the harsh computing environment in Nigeria to implement eHealth systems that will improve the quality of patient care. PMID- 20841704 TI - Using electronic medical records for HIV care in rural Rwanda. AB - Partners In Health (PIH) implemented an electronic medical record (EMR) system in Rwanda in 2005 to support and improve HIV and TB patient care. The system holds detailed patient records, accessible to clinicians through printed reports or directly via a computer in the consultation rooms. Ongoing assessment of data quality and clinical data use has led multiple interventions to be put in place. One such evaluation cycle led to the implementation of a system which identified 15 previously undiagnosed pediatric patients with HIV. Another cycle led to an EMR intervention which helped to decrease the proportion of completed critical CD4 lab results that did not reach clinicians by 34.2% (p=.002). Additionally an automated data quality improvement system reduced known errors by 92% by providing local data officers a tool and training to allow them to easily access and correct data errors. Electronic systems can be used to support care in rural resource-poor settings, and frequent assessment of data quality and clinical use of data can be used to support that goal. PMID- 20841705 TI - Key common determinants for adoption of wireless technology in healthcare for India and Pakistan: development of a conceptual model. AB - This study explores the perception and views of healthcare professionals in the subcontinent (India and Pakistan) towards the wireless handheld technology in the healthcare setting. A mixed methodology was adopted to explore the determinants of the wireless handheld devices in the healthcare setting. Interviews were conducted with 30 healthcare professionals to explore the initial themes. This was followed up with a survey instrument, specifically developed for this study, and distributed to 300 healthcare professionals in Pakistan and India. 200 usable surveys from India and 97 from Pakistan were received. The results of the study indicate that healthcare professionals felt that to use the wireless technology, the integration of the clinical and operational process is essential. Factor analysis through SPSS showed that any development of technological solutions for handheld devices would benefit, by considering the clinical, technological, and operational influences of the wireless technology in addition to clinical influences, clinical preference, training, and technical support. The study culminated in the development of an initial conceptual framework. The scope of this study is restricted to wireless handheld devices such as the smart phones, handheld PCs and PDAs. PMID- 20841706 TI - Factors associated with health information system success: results of a survey of hospitals in South Africa. AB - A survey of computerised hospital information system (CHIS) use was conducted in two South African provinces, in order to test a conceptual model of CHIS use developed in previous phases of this study. Relationships between factors of the conceptual model and user assessment of CHIS success; and between pairs of conceptual model factors, were derived from the survey data. The results confirmed that factors of the conceptual model were associated with CHIS success. Analysis of the relationships between factors yielded results which supported some of the conceptual model relationships, and were inconclusive for others. None of the conceptual model relationships was contradicted by the survey results. Further investigation is required to demonstrate statistical relationships between factors of the conceptual model more conclusively. The results to date support arguments for the applicability of the conceptual model of CHIS use beyond the study hospitals to other level 1 and level 2 hospitals in South Africa. PMID- 20841707 TI - The evolution and uptake of a drug information system: the case of a small Canadian province. AB - In 2008 the province of PEI, Canada implemented a province-wide, web-based drug information system for the purpose of improving patient safety. An evaluation study using grounded theory examined the human and workflow impact. Results indicated a need for great attention to the details of change management during implementation, including: ensuring application quality of all informational and technical elements, just-in-time training and technical support, on-site preparation for changed workflow processes, and collaboration among all stakeholders throughout. PMID- 20841708 TI - Social networking in the National Health Service in England: a quantitative analysis of the online identities of 152 primary care trusts. AB - Increasing numbers of the public are becoming digitally connected. In particular, younger "born digital" generations now use the World Wide Web as their primary source of information alongside conventional media such as television and print. Little is known as to whether health organisations are using new media channels such as Facebook and Twitter to engage with the public and patients. This quantitative analysis investigates the online identities of Primary Care Trusts (PCTs) in the NHS in England to inspect their usage of social utilities. Results showed that a total of 61 organisations (40.13%) use at least one utility with the most popular being Twitter (n=30) and Bebo the least (n=1). However, organisations appear to be failing to take advantage of the interactive nature of social utilities instead using them as unidirectional information "push" channels. The ways in which health organisations could use social utilities for engagement is underexplored and so we must look to other research disciplines for best practice and evidence. PMID- 20841709 TI - Standardizing implementation of a surgical information system in Danish hospitals -a comparative study. AB - Implementation of IT-systems in modern healthcare organizations is associated with large, complex, and expensive projects. Purchase of the system is costly, but resources used to implement the organizational changes that follow, can be extensive. In an attempt to reduce costs, and at the same time to provide a thorough basis for local implementation, Corporate IT in The Capital Region of Denmark developed a standardized system-specific implementation concept for use by the hospitals' local implementations of a Surgical Information system. The system has been implemented in five hospitals within the Capital Region. Through document analysis and interviews with the local project managers, we investigated the use and effectiveness of the standardized implementation concept across five hospitals involved. The study shows that total resource requirements and duration of projects are difficult to compare due to different constructions of the project organizations. We conclude that the implementation concept supports local IT-implementations, but parts of the concept are difficult to translate into practice, while other parts are directly operational. PMID- 20841710 TI - Interoperability prototype between hospitals and general practitioners in Switzerland. AB - Interoperability in data exchange has the potential to improve the care processes and decrease costs of the health care system. Many countries have related eHealth initiatives in preparation or already implemented. In this area, Switzerland has yet to catch up. Its health system is fragmented, because of the federated nature of cantons. It is thus more difficult to coordinate efforts between the existing healthcare actors. In the Medicoordination project a pragmatic approach was selected: integrating several partners in healthcare on a regional scale in French speaking Switzerland. In parallel with the Swiss eHealth strategy, currently being elaborated by the Swiss confederation, particularly medium-sized hospitals and general practitioners were targeted in Medicoordination to implement concrete scenarios of information exchange between hospitals and general practitioners with a high added value. In this paper we focus our attention on a prototype implementation of one chosen scenario: the discharge summary. Although simple in concept, exchanging release letters shows small, hidden difficulties due to the multi-partner nature of the project. The added value of such a prototype is potentially high and it is now important to show that interoperability can work in practice. PMID- 20841711 TI - Experience implementing electronic health records in three East African countries. AB - INTRODUCTION: Efficient use of health care resources in low-income countries by providers and local and national managers requires timely access to patient data. OBJECTIVE: To implement electronic health records (EHRs) in HIV clinics in Kenya, Tanzania, and Uganda. RESULTS: We initially developed and implemented an EHR in Kenya through a mature academic partnership. The EHR was then implemented in six HIV clinics in Tanzania and Uganda in collaboration with their National AIDS Control Programmes. All implementations were successful, but the system's use and sustainability varied depending on who controlled clinic funding. CONCLUSIONS: Successful EHR use and sustainability were enhanced by local control of funds, academic partnerships (mainly by leveraging research funds), and in-country technology support. PMID- 20841712 TI - eHealth in Thailand: the current status. AB - The World Health Organization (WHO) defines eHealth as the use of information and communication technologies (ICT) for health. Thailand is one of the leading countries in emerging and developing economy that the use of ICT applications is pervasive including eHealth. However, the status of eHealth in Thailand hasn't been assessed. Employing the WHO global Observatory for eHealth development model and its instrument, this study describes the uptake of eHealth foundations and the extent of eHealth applications and services implemented in the country. A group of the nation 18 eHealth experts met and evaluated country eHealth status and provided recommendations. The results show that the development of the country's eHealth foundations is inadequate and need to be the priority for national eHealth development. PMID- 20841713 TI - Diffusion and use of Electronic Health Record systems in Norway. AB - This paper sums up some of the findings from a national survey on the diffusion and use of Electronic Health Record (EHR) systems in the Norwegian health sector. The survey shows that almost all hospitals and GPs use their EHR systems on a daily basis, while the municipalities are lagging behind, All three view costs and missing functionality as the most important challenges. The GPs are very concerned with the complexity of the daily operation of the systems, while the hospitals are mostly concerned with costs of daily operations, maintenance and further development of the systems. Better integration with support systems is requested. User involvement and ownership seem to have contributed to the development and diffusion of the most successful EHR systems. National diffusion processes require good planning and are time consuming. It has taken 15 years from the first EHR systems were introduced until 90% of the actors used the systems. This has to be taken into account in national strategy processes in the health sector. PMID- 20841714 TI - eHealth vision towards cooperative patient care--domain fields and architectural challenges of regional health care networks. AB - Numerous eHealth projects and efforts to establish inter-organizational communication and to build up regional health care networks could be observed in the last ten years. Nevertheless the success of such efforts is profoundly different. The aim of this paper is to introduce the lately started regional initiative eHealth.Braunschweig compounding of the major health care players (hospitals, physician offices, nursing services and nursing homes) in the region of Braunschweig, participants from research institutions and industry. We propose in this paper the main goals of the regional initiative eHealth.Braunschweig, its constitution and major approaches. Based on respective literature and our former projects as well as experiences in this field we discuss our vision of a patient oriented cooperative health care by depicting regional distinctions, identifying the major domain fields in this context and discussing the architectural challenges for the regional health care network eHealth.Braunschweig. In our view this work can be considered as a systematical approach to the establishment of regional health care networks with lasting and sustainable effects on patient centered health care in a region. PMID- 20841715 TI - A countrywide clinical informatics project in Uruguay. AB - FEMI is a federation of 23 private not-for-profit health care organizations across Uruguay. It covers approximately 700 thousand people (20 percent of the Uruguayan population) and owns a tertiary center in Montevideo. Pressure from ongoing national changes in health funding and regulation have pushed FEMI to develop a project, in order to improve efficiency in health care through the use of information and communications technologies. In particular, a federal electronic health record and a strategic management system are pursued. This project is supported by the Inter American Development Bank. The project has four lines of action: Specification, construction and implementation of the systems; Alignment through the use of standards; Cultural change through training and prototype systems; and Infrastructure. Short term results include a federal balanced scorecard, federal identification and authorization services, a terminology service, telemedicine applications and massive training of interdisciplinary teams at the local level. The importance of collaboration at the regional level and the advantages of having a multi-institutional commitment are stressed. PMID- 20841716 TI - EHR implementation in South Africa: how do we get it right? AB - In an environment of expanding demand on the health care system to provide equitable, accessible and safe health care, usage of information communication technology is one of the strategies identified to fulfil such expectations. Electronic Health Record (EHR) is an important tool towards achieving better health care using such technology, although, across the world EHR implementation has experienced a high failure rate. Nevertheless South Africa has made a strategic decision to implement EHR system in the public health sector. An evaluation toolkit was developed, to measure the state of readiness of health institutions in South Africa in implementing EHR based on Kaplan and Norton's work on Balanced Score Card (BSC), and the subsequent variant model developed by Protti. A Critical Success Factor (CSF) scorecard to assess the state of readiness and a Balanced Score Card matrix to be used as a strategic framework was developed. These tools were validated using critiques by a panel of experts. The toolkit developed has the potential to assist the organization towards a better EHR implementation path. PMID- 20841717 TI - Monitoring diseases across borders: African regional integrative information systems. AB - In African countries, communicable diseases remain the chief cause of a heavy disease burden. Regional economic, political and social integration bring new challenges in the management of these diseases, many of which are treatable. Information Communication Technology (ICT) applied through electronic health systems has the potential to strengthen healthcare service delivery and disease surveillance within these countries. This paper discusses the importance of well defined e-Health strategies within countries and, in addition, proposes that countries within regions collaborate in planning for health information exchange across borders. It is suggested that particular attention be paid to technical and data standards enabling interoperability, and also to issues of security, patient privacy and governance. PMID- 20841718 TI - A socio-technical approach to continuity of care and electronic records in the South African context. AB - Paper-based techniques of record keeping are contributing greatly to the discontinuity of patient care among healthcare providers. To achieve continuity, access to the information contained in medical records collected by various healthcare providers is necessary. To improve the sharing of information contained in these medical records the use of electronic methods of record keeping as opposed to paper-based records becomes very important. Even though the benefits of using electronic methods of record keeping are widely documented, the majority of South African healthcare practitioners still use paper-based methods. This paper describes an explorative study to determine barriers to the adoption of electronic records in the private primary care sector of South Africa. An interpretive approach using a socio-technical systems theory perspective was used to conduct the study. Based on the analysis of the socio-technical subsystems in the South African context it was revealed that there is not sufficient information available on the barriers to adoption of electronic records and further research will be necessary to identify the barriers to the adoption of electronic records. PMID- 20841719 TI - Implementing OpenMRS for patient monitoring in an HIV/AIDS care and treatment program in rural Mozambique. AB - We have adopted the Open Medical Record System (OpenMRS) framework to implement an electronic patient monitoring system for an HIV care and treatment program in Mozambique. The program provides technical assistance to the Ministry of Health supporting the scale up of integrated HIV care and support services in health facilities in rural resource limited settings. The implementation is in use for adult and pediatric programs, with ongoing roll-out to cover all supported sites. We describe early experiences in adapting the system to the program needs, addressing infrastructure challenges, creating a regional support team, training data entry staff, migrating a legacy database, deployment, and current use. We find that OpenMRS offers excellent prospects for in-country development of health information systems, even in severely resource limited settings. However, it also requires considerable organizational infrastructure investment and technical capacity building to ensure continued local support. PMID- 20841720 TI - Combining vital events registration, verbal autopsy and electronic medical records in rural Ghana for improved health services delivery. AB - This paper describes the process of implementing a low-cost 'real-time' vital registration and verbal autopsy system integrated within an electronic medical record within the Millennium Village cluster in rural Ghana. Using MGV-Net, an open source health information architecture built around the OpenMRS platform, a total of 2378 births were registered between January 2007 and June 2009. The percentage of births registered in the health facility under supervision of a skilled attendant increased substantially over the course of the project from median of 35% in 2007 to 64% in 2008 and 85% midway through 2009. Building additional clinics to reduce distance to facility and using the CHEWs to refer women for delivery in the clinics are possible explanations for the success in the vital registration. The integration of vital registration and verbal autopsies with the MGV-Net information system makes it possible for rapid assessment of effectiveness and provides important feedback to local providers and the Millennium Villages Project. PMID- 20841721 TI - Adopting the national structure of nursing documentation is consequential in the development of care. AB - When healthcare units adopt the national structure of electronic nursing documentation, the process requires managerial support in nursing development as well as theoretical education arranged prior to the implementation. According to the experiences of the pilot units in the Central Finland Health Care District, nursing core data documentation in accordance with the national structure promotes care planning, clarifies and constructs documentation and furthermore unifies the documentation system. The change process gives rise to juridical aspects of documentation as well as a critical evaluation of the documentation contents. The early period of implementing the new theoretical aspect and proceeding from paper-based to electronic documentation required learning, training and agreement on common policy. In health care practice, there is at present one collective structure and model for nursing documentation based on national guidelines. A documented nursing plan is available when a patient is transferred between units or even into extended care. The structured care plan is also helpful when new nurses are introduced to praxis. The continuity of care is at stake when employees are transferred between units to meet the demands of resource allocation. PMID- 20841722 TI - Symptoms from patients as the primary information source for real-time surveillance. AB - The aim of this study was to identify whether patients could become the primary data source for symptom based real-time surveillance. The study investigated people's attitude towards providing symptom information electronically before a consultation, and how they preferred to carry out the reporting. Data was collected by distributing questionnaires to 83 respondents. The results show that 96 percent of the respondents had a positive attitude towards providing information about their symptoms to the GP's office as soon as possible after falling ill. Over half of the respondents preferred to use e-mail or a web interface to perform this task. Eighty four percent were willing to have their symptom data stored in their EPR and 76 percent agreed that the GP might access and present the symptoms together with the prevalence of matching diseases in order to assist the diagnostic process during the next consultation. This study indicates that patients could become the primary data source for symptom based surveillance in countries with high e-readiness. PMID- 20841723 TI - Electronic surveillance of healthcare-associated infections with MONI-ICU--a clinical breakthrough compared to conventional surveillance systems. AB - Surveillance of clinical entities such as healthcare-associated infections (HCAI) by conventional techniques is a time-consuming task for highly trained experts. Such are neither available nor affordable in sufficient numbers on a permanent basis. Nevertheless, expert surveillance is a key parameter for good clinical practice, especially in intensive care medicine. MONI-ICU (monitoring of nosocomial infections in intensive care units) has been developed methodically and practically in a stepwise manner over the last 20 years and is now a reliable tool for clinical experts. It provides an almost real-time view of clinical indicators for HCAI--at the cost of almost no additional time on the part of surveillance staff or clinicians. We describe the use of this system in clinical routine and compare the results generated automatically by MONI-ICU with those generated in parallel by trained surveillance staff using patient chart reviews and other available information ("gold standard"). A total of 99 ICU patient admissions representing 1007 patient days were analyzed. MONI-ICU identified correctly the presence of an HCAI condition in 28/31 cases (sensitivity, 90.3%) and their absence in 68/68 of the non-HCAI cases (specificity, 100%), the latter meaning that MONI-ICU produced no "false alarms". The time taken for conventional surveillance at the 52 ward visits was 82.5 hours. MONI-ICU analysis of the same patient cases, including careful review of the generated results required only 12.5 hours (15.2%). PMID- 20841724 TI - Using ProMED-Mail and MedWorm blogs for cross-domain pattern analysis in epidemic intelligence. AB - In this work we motivate the use of medical blog user generated content for gathering facts about disease reporting events to support biosurveillance investigation. Given the characteristics of blogs, the extraction of such events is made more difficult due to noise and data abundance. We address the problem of automatically inferring disease reporting event extraction patterns in this more noisy setting. The sublanguage used in outbreak reports is exploited to align with the sequences of disease reporting sentences in blogs. Based our Cross Domain Pattern Analysis Framework, experimental results show that Phase-Level sequences tend to produce more overlap across the domains than Word-Level sequences. The cross domain alignment process is effective at filtering noisy sequences from blogs and extracting good candidate sequence patterns from an abundance of text. PMID- 20841725 TI - Improving general practice based epidemiologic surveillance using desktop clients: the French Sentinel Network experience. AB - INTRODUCTION: Web-based applications are a choice tool for general practice based epidemiological surveillance; however their use may disrupt the general practitioners (GPs) work process. In this article, we propose an alternative approach based on a desktop client application. This was developed for use in the French General Practitioners Sentinel Network. METHODS: We developed a java application running as a client on the local GP computer. It allows reporting cases to a central server and provides feedback to the participating GPs. XML was used to describe surveillance protocols and questionnaires as well as instances of case descriptions. An evaluation of the users' feelings was carried out and the impact on the timeliness and completeness of surveillance data was measured. RESULTS: Better integration in the work process was reported, especially when the software was used at the time of consultation. Reports were received more frequently with less missing data. This study highlights the potential of allowing multiple ways of interaction with the surveillance system to increase participation of GPs and the quality of surveillance. PMID- 20841726 TI - Attempting to predict the fate of an ongoing epidemic. Lessons from A(H1N1) influenza in USA. AB - A simple method is proposed for predicting the fate of an epidemic outburst from early data. The method is based on the Richards model, and linearizations are proposed for obtaining preliminary values. A second step with nonlinear estimation fed with preliminary values as initial guess values may be attempted if field conditions allow the computation. The method was tested on data from 2001 dengue outbursts in both Havana and Winward Islands (French Polynesia). Predictions were satisfactory and an attempt of true prediction based on daily data for the 2009 H1N1 influenza outburst in the USA was undertaken. Comparison of early predictions with actual values obtained 3 months later suggests that some of the discrepancies are not due to method's inaccuracy, but to real improvement of infection rate as the H1N1 outburst proceeded. The method can be applied in any setting where cumulative number of cases is properly recorded. PMID- 20841727 TI - Design and assessment of a common, multi-national public health informatics infrastructure to enable H1N1 influenza surveillance. AB - Public health organizations in different nations face similar needs for gathering and analyzing population health data to detect and manage infectious disease outbreaks, including outbreaks of the 2009 Novel H1N1 Influenza A virus or "swine flu." This paper presents our progress to date on the design and assessment of a multi-national public health informatics infrastructure for data collection and disease surveillance. This initial work, under the aegis of an open health tools collaborative, lays the foundation for best practices in patient care and public health preparedness in the national health IT sector. This multinational collaboration is the first to identify essential electronic health record (EHR) data sets as well as standard public health informatics indicators to electronically monitor a notifiable public health condition internationally. PMID- 20841728 TI - Towards a multi-level game model for influenza epidemics. AB - Although game theory has been first invented to reason with economic scenarios with rational agents, it has since been extended into many other fields including biological and medical sciences. In this paper we propose to model the interactions between virus and human in an influenza epidemic in a two player, adversarial game scenario with multiple levels of abstraction. As conventional game representations are inadequate in this complex problem domain, we propose Object Oriented Multi-Agent Influence Diagrams (OO-MAID), a novel graphical representation for multi-level games, which takes advantage of both organizational information and probabilistic independence in the problem domain. The OO-MAID representation can be readily applied in similar medical independent characteristics. We demonstrate the feasibility of this novel approach with sample models in the domain. PMID- 20841729 TI - Is population-oriented IT supported preventive care in general practice feasible? A database study. AB - BACKGROUND: Introducing a clinical decision support system (CDSS) in general practice that provides broad support based on all available guidelines for preventive care might dramatically increase the workload of a general practitioner. AIM: We evaluated the potential effect on workload of a CDSS that aims to support the whole breadth of preventive guidelines currently used in The Netherlands. METHODS: We analysed the guidelines of the Dutch college of General Practitioners (DCGP) for preventive activities, developed a CDSS based on the guidelines and studied the behaviour of the system on real patient data. RESULTS: 20 of the 87 DCGP guidelines contained data on preventive activities which was incorporated in the system. Out of 485,793 patients, the system indicated that for 138,885 (28.6%) a preventive action was needed. CONCLUSION: A CDSS that aims to support the whole breadth of preventive activities in general practice will have a substantial effect on workload. Further tailoring of the support will be needed. PMID- 20841730 TI - Exploring new directions in disease surveillance for people with diabetes: lessons learned and future plans. AB - The main objective of this paper is to report our achievements in investigating new directions in the disease surveillance field. Targeting the vulnerable group of people with diabetes, we explored the possibility of early detection of infections using an electronic disease surveillance system (eDSS); this system could collect data for certain physiology indicators, e.g. blood glucose and white blood cell count, by incorporating specific point-of-care (POC) devices. We performed an analysis using the data of two large-scale clinical studies that involved people with type-1 and type-2 diabetes correspondingly; also, we conducted a feasibility study to examine the available POC technology. Even though the analyses provided us with some evidence for further investigation, the available technological solutions appeared to have significant limitations, mainly in terms of usability. Based on our first-hand findings we defined the next steps of our research, i.e. the data collection in a controlled study and the subsequent development of the eDSS. Furthermore, the lessons learned in our project could facilitate the related research for other vulnerable population groups. PMID- 20841731 TI - A 3-step eHealth approach to transfer knowledge on HIV and sexual violence in developing countries. AB - This paper discusses an innovative 3-step eHealth approach to translate research for target audiences' knowledge uptake in developing countries. The first step uses a knowledge transfer model for the identification and packaging of health content as well as the selection of appropriate Information and Communication Technologies (ICT) platforms; followed by consumer health informatics studies to evaluate the efficacy of addressing health consumers' information needs; and the final step recommends forming of strategic partnerships to strengthen and support knowledge transfer and sharing. The 3-step eHealth approach is based on a convergence of ICTs, and application of the practices and principles of informatics and knowledge management. It was refined during the development of AfroAIDSinfo, an AIDS information portal of the SA Medical Research Council (MRC). The approach was evaluated during the forming of a strategic partnership between the AfroAIDSinfo project of the MRC's Web and Media Technologies Platform and the Sexual Violence Research Initiative. The successful outcome of the eHealth approach served to collect evidence for good practice in informatics and knowledge management. PMID- 20841732 TI - Using a file audit to evaluate retention in care and patient outcomes in a programme to decentralise antiretroviral treatment to primary health care facilities in a high prevalence setting in KwaZulu-Natal, South Africa. AB - HIV care and antiretroviral treatment (ART) provision is largely hospital-based with an over-reliance on doctors. Existing ART sites are reaching capacity and are increasingly unable to initiate new patients and also see follow up patients. In response, the Reproductive Health and HIV Research Unit (RHRU), has supported the KwaZulu-Natal provincial Department of Health with developing a model to decentralise services to primary health care (PHC) level. The programme has been in operation since 2006, and currently nine ART initiation sites down refer stable patients to 24 PHC clinics. Data on patient numbers, treatment outcomes and patient retention rates were collected through a file audit of 2071 adult patient files and analyzed. Results indicate that a file audit is a feasible mechanism to provide this data and can be used to identify gaps and improve quality of care. PHC sites in resource-constrained settings are able to manage stable patients on ART; however, sites need support with monitoring and evaluation and with tracking patients that have been down referred. In terms of quality of care, PHC sites need to ensure that clients receive CD4 count tests and viral load monitoring at six monthly intervals to ensure that treatment failure does not go undetected. Patients suspected of experiencing adverse events or treatment failure appear to be managed according to standard operating procedures, but there is a need to ensure that adverse events are clearly documented in patient files. PMID- 20841733 TI - CEMARA an information system for rare diseases. AB - Rare diseases cover a group of conditions characterized by a low prevalence, affecting less than 1 in 2,000 people; 5000 to 7000 rare diseases have been currently identified in Europe. Most diseases do not have any curative treatment. They represent thus an important public health concern. CEMARA is based on a n tier architecture. Its main objective is to collect continuous and complete records of patients with rare diseases, and their follow-up through a web-based Information System, and to analyse the epidemiological patterns. In France, 41 out of 131 labelled Reference Centres (RC) are sharing CEMARA. Presently 56,593 cases have been registered by more than 850 health care professionals belonging to 171 clinical sites. The national demand of care was explored in relation with the offer of care in order to reach an improved match. Within 2 years, CEMARA stimulated sharing a common platform, a common ontology with Orphanet and initiating new cohorts of rare diseases for improving patient care and research. PMID- 20841734 TI - IMPACT: A generalisable system for simulating public health interventions. AB - Populations are under-served by local health policies and management of resources, partly because of a lack of realistically complex models to enable a wide range of potential options to be appraised. Rising computing power coupled with advances in machine learning and healthcare information now enables such models to be constructed and executed. However, such models are not generally accessible to public health practitioners because they do not have the requisite technical knowledge or skills. This paper presents a system for creating, executing and analyzing the results of simulated public health and healthcare policy interventions, which is more accessible and usable by modellers and policy makers alike. PMID- 20841735 TI - A full-text information retrieval system for an epidemiological registry. AB - Case finding for epidemiologic registries still relies mainly on a manual process. In this paper, we show that retrieval information tools could be a complementary way to identify cases for a pediatric malformation registry. We developed a full-text and metadata search engine plugged to a clinical documents repository and used it to identify Epi/Hypospadia and Spina bifida cases. The queries were enriched with Snomed terminologies. We compared the performances of this prototype versus the hospital DRG database (classical method). The best precisions of prototype for identification of Spina bifida and Epi/Hypospadia were respectively 73% and 87%. The prototype overlap with the DRG system was 83% and 97%. Compared to DRG, 13 new not referenced and 2 miscoded cases were detected. This free full-text retrieval system prototype allows efficiently reusing clinical documents for case finding for an epidemiologic purpose. PMID- 20841736 TI - Obesity atlas and methodbox: towards an open framework for sharing public health intelligence workflows. AB - The large growth in data sources relevant to public health has not been matched by a growth in human resource for producing intelligence to support decisions or generate new insights. There is a need to bring scarce public health expertise into closer alignment with data and data processing methods to support timely public health analysis. The difficulties of developing and sharing this expertise in large organisations such as the UK's National Health Service have long been recognised. We report findings in this area across two projects Obesity Atlas and Methodbox, which are developing and sharing best practice between Public Health Analysts in England, and we address the relevant generic knowledge management problems in the Public Health community. PMID- 20841737 TI - Spatiotemporal antibiotic resistance pattern monitoring using geographical information system based hierarchical cluster analysis. AB - Bacterial antimicrobial resistance in both the medical and agricultural fields has become a serious problem worldwide. Antibiotic resistant strains of bacteria are an increasing threat to human health, with resistance mechanisms having been described to all known antimicrobials currently available for clinical use. Monitoring the geotemporal variations of antibiotic resistance pattern is crucial factor in planning a successful therapeutic guidelines preventing further emergence of antibiotic resistance. This study is based on the retrospective spatiotemporal analysis of laboratory results of Antibiotic Sensitivity Tests, time stamped with the date and time of the microbiological specimen dispatched to the laboratory. Geographic location of the isolated bacterial colony is specified with the latitude and the longitude of the patient's location. Agglomerative Hierarchical Clustering was performed on antimicrobial resistance findings based on the geographic locations generating series of Heatmaps to visualize the extent of the resistance pattern. Sequential Hierarchical cluster analysis was proven to be effective in visualization of antibiotic resistance using Heatmaps demonstrating the temporal variations of the antibiotic resistance patterns. PMID- 20841738 TI - Traffic accidents in Crete (1996-2006): the role of the emergency coordination center. AB - The general decline in traffic accidents throughout Europe is not the case for Crete, a favorite holiday destination. The extent of problem and reflections on the significant impact of the interplay of organizational, educational, & technological interventions by the Emergency Coordination Center of Crete (ECC Crete) are presented. 10-year data from 1996-2006 have been analyzed revealing demographic, topological, and qualitative issues of traffic accidents in Grete. Primary source of data is 315000 emergency calls answered by ECC-Crete. Over this 10 year period, ECC-Crete gradually employed advanced medical technologies and electronic protocol-based handling in all phases of an emergency episode contributing to its timely and effective management. GIS/GPS technology and telemetry for biosignals in ambulances, up-to-date triage protocols combined with incidence analysis provide vital information for continuous process improvement. In 2000-2006, process improvement due to technological and organizational changes has led to increased efficiency. The mean reduction was ~75% in dispatch time, ~50% in the time at accident scene for metropolitan areas, and ~75% in time at the emergency ward, mainly due to medical interventions on site. PMID- 20841739 TI - Traffic accident in Cuiaba-MT: an analysis through the data mining technology. AB - The traffic road accidents (ATT) are non-intentional events with an important magnitude worldwide, mainly in the urban centers. This article aims to analyzes data related to the victims of ATT recorded by the Justice Secretariat and Public Security (SEJUSP) in hospital morbidity and mortality incidence at the city of Cuiaba-MT during 2006, using data mining technology. An observational, retrospective and exploratory study of the secondary data bases was carried out. The three database selected were related using the probabilistic method, through the free software RecLink. One hundred and thirty-nine (139) real pairs of victims of ATT were obtained. In this related database the data mining technology was applied with the software WEKA using the Apriori algorithm. The result generated 10 best rules, six of them were considered according to the parameters established that indicated a useful and comprehensible knowledge to characterize the victims of accidents in Cuiaba. Finally, the findings of the associative rules showed peculiarities of the road traffic accident victims in Cuiaba and highlight the need of prevention measures in the collision accidents for males. PMID- 20841740 TI - Investigating health information needs of community radio stations and applying the World Wide Web to disseminate audio products. AB - The Web and Media Technologies Platform (WMTP) of the South African Medical Research Council (MRC) conducted a pilot project amongst community radio stations in South Africa. Based on previous research done in Africa WMTP investigated the following research question: How reliable is the content of health information broadcast by community radio stations? The main objectives of the project were to determine the 1) intervals of health slots on community radio stations, 2) sources used by community radio stations for health slots, 3) type of audio products needed for health slots, and 4) to develop a user friendly Web site in response to the stations' needs for easy access to audio material on health information. PMID- 20841741 TI - Documentation in pharmacovigilance: using an ontology to extend and normalize Pubmed queries. AB - OBJECTIVES: To assess and understand adverse drug reactions (ADRs), a systematic review of reference databases like Pubmed is a necessary and mandatory step in Pharmacovigilance. In order to assist pharmacovigilance team with a computerized tool, we performed a comparative study of 4 different approaches to query Pubmed through ADR-drug terms. The aim of this study is to assess how an ontology of adverse effects, used to normalize and extend queries, could improve this search. MATERIAL AND METHOD: The ontological resource OntoEIM contains 58,000 classes and integrates MedDRA terminology. The entry point is a ADR-Drug term and the four methods are (i) a direct search on Pubmed (ii) a search with a normalized query enhanced with domain-specific Mesh Heading criteria, (iii) a search with the same elaborated query extended to the MeSH sub-hierarchy of the adverse effect entry and (iv) a search with a set of MedDRA terms grouped by subsomption in the OntoEIM ontology. For each of the 16 queries performed and analysed, relevant publications are selected "manually" by two pharmacovigilant experts. RESULTS: The recall is respectively of 63%, 50%, 67% and 74%, the precision of 13%, 26%, 29% and 4%. The best recall is provided by the ontology-based method, for 4 cases out of 16 this method returns relevant publications when the others return no results. CONCLUSION: Results show that an ontology-based search tool improves the recall performance, but other tools and methods are needed to raise the precision. PMID- 20841742 TI - Leapfrogging paper-based records using handheld technology: experience from Western Kenya. AB - PROBLEM: There is limited experience with broad-based use of handheld technologies for clinical care during home visits in sub-Saharan Africa. OBJECTIVE: We describe the design, development, implementation, and evaluation of a PDA/GPS-based system currently used during home visits in Western Kenya. RESULTS: The system, built on Pendragon Forms, was used to create electronic health records for over 40,000 individuals over a three-month period. Of these, 1900 represented cases where the individual had never received care for the identified condition in an established care facility. On a five-point scale, and compared to paper-and-pen systems, end-users felt that the handheld system was faster (4.4+/-0.9), easier to use (4.5+/-0.8), and produced higher quality data (4.7+/-0.7). Projected over three years to cover two million people, use of the handheld technologies would cost about $0.15 per person--compared to $0.21 per individual encounter entered manually into a computer from a paper form. CONCLUSION: A PDA/GPS system has been successfully and broadly implemented to support clinical care during home-based visits in a resource-limited setting. PMID- 20841743 TI - Cell phone short messaging service (SMS) for HIV/AIDS in South Africa: a literature review. AB - The HIV/AIDS pandemic is one of the most serious threats to global health. HIV/AIDS is a chronic illness, requiring patient empowerment to enhance adherence to treatment regimes if it is to be managed effectively. While healthcare costs are rising, people still have expectations of high-quality care. This literature review-based study explored the use of cell phone (mobile phone) short messaging services (SMS) in health care, in particular for HIV/AIDS in South Africa. From an initial corpus of 212 papers, 28 were reviewed. The main findings include that SMS can improve service delivery through appointment reminders and improve communication between healthcare workers. It improves diagnosis, prevention, treatment and rehabilitation by supporting adherence to medication, and monitoring illness and medical interventions. SMS is useful in public health programmes, such as contact tracing and partner notification, therefore playing an important role in control of HIV/AIDS. As South Africa has one of the highest uptakes and demographic distributions of cellular technology in the world, SMS is feasible as a tool to deliver quality health care with low cost. PMID- 20841744 TI - Exploring feasibility of home telemanagement in African Americans with congestive heart failure. AB - Existing telemonitoring systems provide limited support in implementing personalized treatment plans. We developed a Home Automated Telemanagement (HAT) system for patients with congestive heart failure (CHF) to provide support in following individualized treatment plans as well as to monitor symptoms, weight changes, and quality of life, while educating the patient on their disease. The system is designed to be placed in the patient's home and to communicate all patient data to a central server implementing real-time clinical decision support. The system questions the patient daily on their condition, monitors their weight, and provides the patient with instant feedback on their condition in the form of a 3-zone CHF action plan. Their medication regimen and suggested actions are determined by their care management team and integrated into the system, keeping a personalized approach to disease management while taking advantage of the technology available. The system is designed to be as simple as possible, making it usable by patients with no prior computer experience. A feasibility assessment in African American patients with CHF and without prior computer experience demonstrated high level of acceptance of the CHF HAT system. PMID- 20841745 TI - The emergence of mobile-supported national health information systems in developing countries. AB - A major challenge for national health information systems in developing countries is their scalability and sustainability at the lowest levels where primary health care is delivered. This paper contributes to the discourse on how national health information systems can scale to the lower levels and how mobile technology is supporting the collection, handling and dissemination of data. But can mHealth go beyond the 'hype' and visions it has come to be associated with? Using an action research methodology in a long-term action research project, the usability and then scalability of mobile solutions for large scale national health information systems are studied. In this paper, initial successes and challenges with using m Health for national public health information systems is reported and discussed. PMID- 20841746 TI - Clinical users' perspective on telemonitoring of patients with long term conditions: understood through concepts of Giddens's structuration theory & consequence of modernity. AB - This study involves conducting focus group discussions with clinical users (nurses and technicians) prior to the launch of telehealth service in Nottingham, UK, to elicit their initial perceptions about the service. It describes the findings from preliminary phase of otherwise a larger longitudinal study. Using Giddens's concepts from structuration theory and consequence of modernity, we were able to acknowledge trust and sense of security as two very salient aspects that govern adoption of new technological innovation. Unattended, these aspects contribute to arousal of conflict and contradiction within a system. In order for successful telehealth implementations in health care setting, providers of the service, need to focus on ways in which clinical users' trust can be gained and sense of security can be promoted while using the telehealth service and technology. PMID- 20841747 TI - Usage of international standards for integrating extramural monitoring and personal health device data into medical information infrastructure. AB - Integrating extramural measured devices data into medical information systems is becoming more and more attractive for integrated medical care. A lot of devices already have the ability to transfer measured data to mobile devices or computers and a few systems offer submitting data to a centralized information database or information system. Unfortunately, all of these devices use proprietary protocols and processes which makes integration into other systems a major problem. To address this problem the Healthy Interoperability project has been created with the objective of creating a framework for transferring health data based on international standards. The paper outlines how the framework architecture takes full advantage from the definitions of the international standards ISO 11073, HL7, IHE and CEN 13606. Even the definition of the user profiles and the security framework is based on standards from ETSI, ISO and CEN. By using these standards the framework can also perfectly be used for intramural communication. PMID- 20841748 TI - Deploying portable ultrasonography with remote assistance for isolated physicians in Africa: lessons from a pilot study in Mali. AB - OBJECTIVE: Demonstrate the feasibility of deploying portable ultrasonography with remote assistance to improve the diagnostic capabilities of isolated physicians in Africa. METHODS: The approach is based on the training of general practitioners for the use of ultrasonography, and the remote support by radiologists using dedicated tools for image transfer over low-bandwidth internet connections. RESULTS: Our early results in a pilot project in Mali show that this approach is feasible, and that isolated physicians can productively use ultrasonography to improve diagnosis and management decisions such as the need for a medical evacuation towards a reference hospital. CONCLUSION: These encouraging early results must be confirmed by larger-scale studies, in order to better understand the organizational requirements and demonstrate outcomes and return on investments for such telemedicine services. This scale-up project will start in 2010 in collaboration with the International Development Research Center of Canada. PMID- 20841749 TI - Web-based asynchronous teleconsulting for consumers in Colombia: a 2-year follow up. AB - BACKGROUND: Remote consultation was implemented in 2006 in our institution, through an open-access Web-based Teleconsulting service: Doctor Chat. This tool was created with the aim of improving access to health care services in Colombia, especially in underserved areas. OBJECTIVE: The aim of this paper is to report our experience with the free Web-based application for teleconsultation. METHODS: After validating the tool, we analyzed the queries submitted between May 2007 and June 2009. Requests were classified into three axes: purpose of the query, specialty, and geographic area of origin. Descriptive statistics were gathered for each category (name, email, city, country, age, gender). RESULTS: We received 1624 consultations, with an average of 59 requests per month. 52.7% of the users were aged 18 to 29 years. Users asked mainly about sexual and reproductive health issues. 79.2% of consultations came from Colombia and 32.91% of the users were students. CONCLUSIONS: Doctor Chat is an innovative tool to deliver health care information, but advertising, preventive and technical strategies must be implemented to improve its impact on Colombia's health system. PMID- 20841750 TI - Medical education & health informatics: time to join the 21st century? AB - This paper reports a component of a larger study, Informatics: enhancing the Clinical Experience? (ICE), which explored the impact on the therapeutic relationship of the implementation and use of Electronic Medical Records (EMR) in British Columbia, Canada. As anticipated, EMRs were found to negatively affect the relationship in many clinics. However, surprisingly paper-based clinics were as likely as EMR-based clinics to report problems with maintaining eye contact with their patients. This led to an interesting finding; that as a result of this difficulty few family care providers actually chart when their patients are with them, preferring to build rapport and chart at a later time. Consequently three recommendations are made: 1) Improve medical education in the area of charting (paper & EMR-based) with the patient present; 2) Explore the affect different technologies and skills have on the ability of providers to chart with the patient present and 3) Develop an understanding that unless the technology and training improve Canadian family medicine will never gain the asserted benefits of EMRs, and that other incentives are needed if Canada is to meet its target of delivering Electronic Health Records (EHR) to 100% of all Canadians by 2015. PMID- 20841751 TI - Investigating the potential of e-Learning in healthcare postgraduate curricula: a structural equation model. AB - The objective of this paper is to assess the future adaptability of e-Learning platforms within postgraduate modules. An ongoing empirical assessment was conducted amongst postgraduate students, based on the Technology Acceptance Model (TAM). The current paper presents the outcomes from the second phase of a survey, involving fifty six participants. Data analysis was performed using a structural equation model, based on partial least squares. Results highlighted the very strong effect of perceived usefulness and perceived ease of use to attitude towards using e-Learning platforms. Consequently, attitude towards use proved to be a very strong predictor of behavioral intention. Perceived usefulness, on the contrary, did not prove to have an effect to behavioral intention. Implications on the potential of using e-Learning platforms are discussed along with limitations and future directions of the study. PMID- 20841752 TI - Earnings in e-learning: knowledge, CME credits or both? Hints from analysis of attendance dynamics and users' behaviour. AB - Many papers report and convey positive opinion about the use of e-learning in the healthcare sector. The issue is how to exploit at best such a powerful instrument. Starting from data regarding the usage of a CME e-learning course, attendance dynamics and users' behaviour have been inspected with the aim of getting some hints about how to improve the development and the delivery of e learning courses for CME, and to promote knowledge acquisition at best. The different paths followed by 7811 users have been modeled, from enrolment to conclusion/drop-out, then the behaviour in terms of effort, elapsed time, achieved result have been analyzed. The obtained results point out: good acceptance (retention rate 83%) of a not basic educational model and effectiveness (success rate 79%). At the same time the inspection of behaviour has shown that there is a good margin of possible improvement in terms of knowledge acquisition. Conclusions provide a list of issues to keep in mind during system development, in order to provide CME e-learning meeting both credit and knowledge acquisition goals. PMID- 20841753 TI - Multidisciplinary education in medical informatics--a course for medical and informatics students. AB - Design and implementation of healthcare information systems affect both computer scientists and health care professionals. In this paper we present our approach to integrate the management of information systems in the education of healthcare professionals and computer scientists alike. We designed a multidisciplinary course for medical and informatics students to provide them with practical experience concerning the design and implementation of medical information systems. This course was implemented in the curriculum of the University of Munster in 2009. The key element is a case study that is performed by small teams of medical and informatics students. A practical course on management of information systems can be useful for medical students who want to enhance their knowledge in information systems as well as for informatics students with particular interests in medicine. PMID- 20841754 TI - Training software developers for electronic medical records in Rwanda. AB - In many developing countries, electronic medical record (EMR) systems are being implemented in resource-poor settings. Essential to such implementations are software developers with a high technical capacity, a good understanding of medical informatics and an awareness of local clinical needs. This paper describes a training program which has been run in Rwanda to enable local computer science graduates to play a significant role in that country's forthcoming implementation of a national EMR system. Such a training program is unique in that region of Africa and we discuss the challenges inherent in such an undertaking. We describe the development of the curriculum and the evolution of the teaching methodologies over the course of the year and discuss its potential integration with academic institutions in Rwanda. Finally we propose that training programs of this nature which produce local software developers who are familiar with medical informatics are a requirement for successful and sustainable eHealth implementations in the developing world. PMID- 20841755 TI - Strengthening health systems through training of health care providers in the conduct of routine waiting time and system efficiency surveys. AB - The effective functioning of Health Systems is reliant on good quality information being available for decision-making. Routine surveys exemplify an under-utilised source of such information that could enable Health Departments to gain insights into the performance of health service provision, from both the stand-point of the providers and users. Amongst these, Waiting Time and System Efficiency Surveys (WTSES) directly responds to the commonest complaint of users of healthcare services. There is, however, little information on approaches to routinely implement robust and sustainable facility-based WTSES especially in resource-constrained settings. This paper describes the conceptual and methodological basis for implementing WTSES in health care facilities, using a method that places the conduct of the survey within the purview of the normal service activities of health care providers, and thus makes the routine assessment of Waiting Times possible at low cost and with high benefit. The authors aver that the universal implementation of the WTSES presents the potential for enriching patient and health facility information systems, particularly in resource-constrained settings, where efficient use of limited resources is critical. PMID- 20841756 TI - Learning of each other--online: on the division of labour between technology and supervisors. AB - The article discuss challenges and solutions when an existing course programme, in which contributions from the group form an integral part, is to be converted into an online programme. The focus is on division of labour between technology and supervisors. The case is the Norwegian online version of Chronic Disease Self Management Program from Stanford University. The interplay between humans and technology is discussed from a theoretical framework developed from the works of Latour and Nonaka. In special difference between human modelling and a technological systematic and rule-based approach is emphasised. By delegating parts of the role in classroom courses to the e-learning solution, it has been possible to create a solution where participants are learning from each other. This demands knowledge on the part of the supervisors so that they help to increase the effect of the technology and not work against it. PMID- 20841757 TI - eBug--teaching children hygiene principles using educational games. AB - Technology enhanced education has been recently established as a new approach for all stages of education. However, among these new IT media it is computer games playing the central role in delivering education in particular to children and teenagers, however, real world sound evaluation is often given little attention. The EU funded e-Bug project developed web games aimed at children to teach basic principles of prudent antibiotics use, hand and respiratory hygiene and aims to reinforces an awareness of microbes, hand and respiratory hygiene among junior and senior school children in 10 countries in Europe. An educational pack implemented in schools across Europe is complemented by Internet web games for two age groups teaching a set of learning objectives (LOs) using a fast and interactive platform game design for junior children and investigate detective games based on PBL principles for senior children. In this paper, we present the design of e-Bug junior and senior games and evaluation results. PMID- 20841758 TI - Ambulatory orthopaedic surgery patients knowledge with Internet-based education. AB - There is a growing need for patient education and evaluation of the outcomes of it. The aim of this study was to compare the ambulatory orthopaedic surgery patients' knowledge with Internet-based education and face to face education with a nurse. The following hypothesis was set: Internet-based patient education (experiment) is as effective as face to face education with a nurse (control) in increasing patients' level of knowledge and sufficiency of knowledge. In addition the correlations of demographic variables were tested. The patients were randomised to either the experiment (n=72) or to a control group (n=75). Empirical data were collected with two instruments. Patients in both groups showed improvement in their knowledge during their care. Patients in experiment group improved their knowledge level significantly more in total than those patients in control group. There were no differences in patients' sufficiency of knowledge between the groups. Knowledge was correlated especially with patients' age, gender and earlier ambulatory surgery. As a conclusion, with the Internet based education could achieve positive results on patients' knowledge. Internet is usable method in ambulatory care. PMID- 20841759 TI - An open repositories network development for medical teaching resources. AB - The lack of interoperability between repositories of heterogeneous and geographically widespread data is an obstacle to the diffusion, sharing and reutilization of those data. We present the development of an open repositories network taking into account both the syntactic and semantic interoperability of the different repositories and based on international standards in this field. The network is used by the medical community in France for the diffusion and sharing of digital teaching resources. The syntactic interoperability of the repositories is managed using the OAI-PMH protocol for the exchange of metadata describing the resources. Semantic interoperability is based, on one hand, on the LOM standard for the description of resources and on MESH for the indexing of the latter and, on the other hand, on semantic interoperability management designed to optimize compliance with standards and the quality of the metadata. PMID- 20841760 TI - Using the virtual reality world of second life to teach nursing faculty simulation management. AB - Healthcare faculty members have come to depend on the advantages of teaching with clinical simulation, but not all faculty are competent in their ability to manage students during the simulation experience. This federally funded proposal provided the opportunity for nursing faculty to participate in a synchronous learning event using the virtual reality world of Second Life (SL). Based on competencies, faculty participants were guided through the simulation process by a "Master Teacher." Participants then became the teacher and chose the settings, objectives, and clinical data to manage their own simulation using avatar role assignments. Feedback populated the participant informatics dashboard, so that progress towards their competencies was recorded. Another unique informatics application was the use of the Synthetic Derivative project to use de-identified patient data to promote better clinical realism. Additional evaluation activities regarding content, appropriate use of the technology, and design features were assessed. The development of the SL environment for this educational study provides the setting in which to pilot test the provision of actual clinical care that does not require "hands-on" interventions. PMID- 20841761 TI - Teaching during a pandemic event: are universities prepared? AB - As the threat of pandemic events streaks across the planet, the question then becomes can universities, particularly health science centers charged with producing the next generation of health care providers, continue their teaching and educational mission by offering classes in a distance environment, completely uncentralized, away from the traditional centralized campus? A sampling of campus websites were reviewed to gather a sense of how well prepared we are, followed up with a survey administered to faculty and staff in the School of Nursing at Vanderbilt University. The concern being that if a technology rich environment such as Vanderbilt is not fully prepared to continue teaching in a pandemic event, what concerns should we have for other institutions providing health care provider education that may not have access to the resources a Vanderbilt has? Finally, a set of recommendations to schools is presented, based on the findings. PMID- 20841762 TI - An approach to simulate and visualize intraoperative scattered radiation exposure to improve radiation protection training. AB - Intraoperative radiography based on mobile image intensifier systems (C-arms) is widely used during the treatment of trauma and emergency patients. These devices produce scattered radiation, potential hazardous for surgeon and operation room personal (ORP). The propagation and intensity of scattered radiation is not intuitive, is not perceivable by human senses and depends on many variables. At courses on radiation protection the knowledge of the behavior of scattered radiation and the modus operandi to minimize the radiation exposure should be taught to ORP and surgeons. Currently this can only be done theoretically using fixed pictures and precalculated videos. This paper presents an approach to interactively simulate and visualize scattered radiation with a computer based training system for mobile image intensifier systems. The simulation depicts radiation propagation and intensity for arbitrary C-arm adjustments and different irradiated materials. This teaching component focuses on improving the current radiation protection training with interactive visual and practical aspects. PMID- 20841763 TI - A compositional personalization approach for designing personalized patient educational interventions for cardiovascular risk management. AB - Providing patients with personalized educational messages can improve self management of Cardiovascular Disease (CVD) risk factors. We present our compositional personalization approach that generates personalized educational material by dynamically selecting fine-grained information snippets, as per the patient profile, and then synthesizing them in a educational template to yield personalized patient education interventions. We apply our personalization approach in the PULSE system--Personalization Using Linkages of SCORE and behavior change readiness to web-based Education--that generates personalized patient education for CVD risk management. The PULSE framework involves the calculation of CVD risk assessment using the Systematic COronary Risk Evaluation (SCORE) algorithm, the estimation of readiness to change using the Transtheoretical Model (TTM) of intentional behavior change. The educational interventions were derived from evidence-based staged lifestyle modification materials and Canadian guidelines for CVD risk management. PMID- 20841764 TI - Augmented notebooks for pervasive learning in medical practice. AB - Medical e-learning can benefit from the new technologies, and pervasive learning resources and tools worth to be introduced in the medical context. Micro-learning seems to be an interesting way for pervasive learning. But it is still difficult to propose pedagogical resources that are built by learners, from meaningful experiments. We conducted an analysis of the exchanges performed by Health care professionals in the hospital in order to understand where and when educational exchanges appear. We analyzed the type of documents exchanged. The residents' paper notebooks caught our attention first because it answers some clinician needs and second because the computerization of such a notebook could add a collaborative dimension to the pedagogical resources. We propose a model of an augmented resident's notebook and we briefly describe an implementation using Content Management System and WIKI, before setting the discussion and the conclusion sections. PMID- 20841765 TI - Advancing the state-of-the-art for Virtual Autopsies--initial forensic workflow study. AB - There are numerous advantages described of how imaging technology can support forensic examinations. However, postmortem examinations of bodies are mainly performed to address demands which differ from those of traditional clinical image processing. This needs to be kept in mind when gathering information from image data sets for forensic purposes. To support radiologists and forensic clinicians using Virtual Autopsy technologies, an initial workflow study regarding post-mortem imaging has been performed, aiming to receive an improved understanding of how Virtual Autopsy workstations, image data sets and processes can be adjusted to support and improve conventional autopsies. This paper presents potential impacts and a current forensic Virtual Autopsy workflow aiming to form a foundation for collaborative procedures that increase the value of Virtual Autopsy. The workflow study will provide an increased and mutual understanding of involved professionals. In addition, insight into future forensic workflows based on demands from both forensic and radiologist perspectives bring visualization and medical informatics researchers together to develop and improve the technology and software needed. PMID- 20841766 TI - An analysis of nursing education's immersion into Second Life, a multi-user virtual environment (MUVE). AB - Second Life (SL) is a multi-user virtual environment (MUVE) using 3-D modeling to replicate real world settings and experiences. However, little is known of the extent to which nursing education is involved in SL activities. This study used four different search strategies to conduct a comprehensive review of print, blog, web and media sources. Twenty-nine unique nursing communities, groups or educational activities were identified. This study identified a number of barriers identified that made the analysis both difficult and time-consuming. Two main categories emerged: explorers and developers. The explorers used SL for a support group, networking, and uncovering health-related sites. The developers were associated with land ownership and were involved in distance learning and simulation activities. Seven unique simulations for nursing education were identified. Given the number of registered users, the number of universities currently involved in SL, the availability of health-related sites for consumers, and the emerging interest in telehealth in SL substantial growth in the use of SL in nursing education is likely. PMID- 20841767 TI - Trust--can it be controlled? AB - Trust is an important component in the security of an information system. The advent of the electronic health record (EHR) and the health information system (HIS) have raised it to greater prominence. These systems and their intended benefits are rendered less effective through a low level of trust between the stakeholders. The potential reciprocal relationship between accountability and trust is investigated. A literature study examines both concepts and their interrelationship. The accountability and audit controls provided by the NIST SP 800-53 security guide and the ISO 27799 security standard are extracted, collated and expanded to strengthen the accountability mechanisms within an HIS security program. A dedicated set of accountability controls (NIM) which is specific to the healthcare environment is produced. It is proposed that through the strengthening of the accountability function of the HIS, its level of trustworthiness may be improved. PMID- 20841768 TI - Informatics and evidence-based medicine: prescription for success. AB - This article reports on the experience of one organization between 2004 and 2009 to develop an effective people-process-technology system to better manage the quality of health care. The creation of this system started with creating a strategic plan for quality and then establishing a structure to implement the plan. The next phase consisted of establishing a number of simultaneous steps that ranged from identifying and leveraging the appropriate informatics tools to the oversight process, and from the implementation team to strategies for working with clinical groups. The outcome as of 2009 is a well established evidence-based quality process and team in place. There are over 450 evidence-based medicine quality sets. More than 52% of all patients are admitted on quality evidence based medicine pathways and protocols. This article reflects a successful prescription for combining informatics and evidence-based medicine to improve the quality of health care. PMID- 20841769 TI - The trajectory of scientific discovery: concept co-occurrence and converging semantic distance. AB - The paradigm of literature-based knowledge discovery originated by Swanson involves finding meaningful associations between terms or concepts that have not occurred together in any previously published document. While several automated approaches have been applied to this problem, these generally evaluate the literature at a point in time, and do not evaluate the role of change over time in distributional statistics as an indicator of meaningful implicit associations. To address this issue, we develop and evaluate Symmetric Random Indexing (SRI), a novel variant of the Random Indexing (RI) approach that is able to measure implicit association over time. SRI is found to compare favorably to existing RI variants in the prediction of future direct co-occurrence. Summary statistics over several experiments suggest a trend of converging semantic distance prior to the co-occurrence of key terms for two seminal historical literature-based discoveries. PMID- 20841770 TI - Access control in healthcare: the methodology from legislation to practice. AB - Translating legislation and regulations into access control systems in healthcare is, in practice, not a straightforward task. Excessive regulation can create barriers to appropriate patient treatment. The main objective of this paper is to present a new methodology that can define, from legislation to practice, an access control policy as well as a RBAC model, in order to comprise generic legislation and regulation issues together with the access control needs from the ends users of a healthcare information system. The methodology includes the use of document analysis as well as grounded theory and mixed methods research. This methodology can be easily applied within a healthcare practice or any other domain with similar requirements. It helps to bridge the gap between legislation and end users' needs, while integrating information security into the healthcare processes in a more meaningful way. PMID- 20841771 TI - Can signalling theory and the semaphoric nature of information systems explain clinicians' ambivalence to informatics? AB - Investment in information systems has traditionally been justified in terms of productivity or value-added gain. From this point of view the slow rate of adoption of IT in the healthcare sector appears paradoxical because the rapid increase in medical costs has created an urgent need for productivity improvements. Spence's market signal theory may explain why some information system investment decisions are made and may, in part, explains the reluctance of clinicians to embrace informatics. Case studies are presented where we argue that information system investment was made primarily to send a market signal. We call information systems that are used primarily to send a market signal, semaphoric information systems. Characteristics of semaphoric information systems are presented. It is postulated that the therapeutic relationship between doctor and patient is central to current models of healthcare, and that the semaphoric 'message' of the current generation of IT systems may be detrimental to this relationship. This suggests that clinicians will continue to be reluctant to embrace information systems until information systems are developed that can send signals that enhance the doctor-patient relationship. PMID- 20841772 TI - Why do people want a paper copy of their electronic patient record? AB - Changes have recently been passed in the Norwegian legislation, allowing for more exchange of patient information between health personnel. These legal changes came as a result of a long and still ongoing debate concerning the potential conflict between confidentiality issues and patient safety as health care is getting more fragmented. At the same time, an increasing number of patients now make use of their legal right to access their patient record. In this paper, we shed light on some of the reasons why patients request a copy of their record. We report the preliminary results from an interview study in which seventeen patients who have asked for a copy of their patient record following a hospital stay have been interviewed. In our interview study, securing transmission of information between health care workers is one of the main reasons for requesting a copy of the record. We will discuss how this finding might contribute to the ongoing debate. PMID- 20841773 TI - Exploring control in health information systems implementation. AB - Health information systems promise opportunities for improved healthcare. However, these opportunities may become challenges and obstacles to practice. This research reflects on the outcomes of implementing healthcare information systems in three English hospitals. In each case qualitative methods were used to observe and interview doctors, nurses and pharmacists as they carried out their daily healthcare routines. The changes that the implementation of health information systems brought for both the clinical encounter, as well as health care professionals' work flow, were explored. We argue that such technologies have become a central orchestrator of the clinical setting, to the extent that they often impose control on healthcare practices. Using a socio-technical approach we seek to understand how information systems technology and healthcare professionals can work together rather than apart, or around one another. PMID- 20841774 TI - Ghost charts and shadow records: implication for system design. AB - Ghost charts, sometimes referred to as shadow charts, are duplicate medical records. Governance documents in several countries suggest that ghost charts present a risk to patient safety, to the extent that they contain information which may not appear in an official hospital record. Although most would agree ghost charts should not exist, their existence is widespread. This paper reports on an in depth multi-method qualitative study of ghost charts undertaken in two ambulatory care settings in a Canadian hospital. The study was undertaken in order to inform the design and implementation of a clinical information system which it is hoped will eliminate the need for duplicate charts. Our research demonstrated that ghost charts filled a variety of needs only some of which are typically accounted for in electronic record design. We suggest that if the functions ghost charts fill are not addressed, their existence will persist. This work is significant in that few studies of ghost charts have been undertaken, and in the in-depth understanding it contributes to design requirements for electronic record systems. PMID- 20841775 TI - Why don't innovation models help with informatics implementations? AB - This paper describes various models that have been postulated to understand and explain the acceptance and diffusion of technological innovation. The wide range of factors relating to the innovation itself, and, most importantly, the human and organisational factors which will impinge on these processes, is detailed. Attempts to apply the model to healthcare settings are explored. In particular a systematic review in 2005 which attempted to integrate the models and apply them in the UK's National Health Service will be critiqued. The strengths and weaknesses of the models are explored, particularly in relation to the minimal testing they have been subjected to. It is argued that the complexity of the theoretical models makes them difficult to apply and questions their efficacy in supporting informatics implementations. The need for a clearer understanding of the factors which make staff positively disposed towards informatics innovation, and those which are likely to make them resist them is made apparent. PMID- 20841776 TI - The Information Quality Triangle: a methodology to assess clinical information quality. AB - Building qualitative clinical decision support or monitoring based on information stored in clinical information (or EHR) systems cannot be done without assessing and controlling information quality. Numerous works have introduced methods and measures to qualify and enhance data, information models and terminologies quality. This paper introduces an approach based on an Information Quality Triangle that aims at providing a generic framework to help in characterizing quality measures and methods in the context of the integration of EHR data in a clinical datawarehouse. We have successfully experimented the proposed approach at the HEGP hospital in France, as part of the DebugIT EU FP7 project. PMID- 20841777 TI - Understanding effective clinical communication in medical errors. AB - Clinical Communication failures are considered the leading cause of medical errors [1]. Minimizing communication problems among clinical team members could directly reduce medical errors and hence, increase patient safety and improve health care quality. Our main focus is, through knowledge representation approach, to develop an understanding of communication problems applied to health care settings. This will serve as the foundation to our long term goal of building an ontology-driven educational tool that will be used to educate clinicians about miscommunication issues and as a means to improve it. PMID- 20841778 TI - Combining relevance assignment with quality of the evidence to support guideline development. AB - Clinical practice guidelines are used to disseminate best practice to clinicians. Successful guidelines depend on literature that is both relevant to the questions posed and based on high quality research in accordance with evidence-based medicine. Meeting these standards requires extensive manual review. We describe a system that combines symbolic semantic processing with a statistical method for selecting both relevant and high quality studies. We focused on a cardiovascular risk factor guideline, and the overall performance of the system was 56% recall, 91% precision (F0.5-score 0.81). If quality of the evidence is not taken into account, performance drops to 62% recall, 79% precision (F0.5-score 0.75). We suggest that this system can potentially improve the efficiency of the literature review process in guideline development. PMID- 20841779 TI - Theories, models and frameworks for diagnosing technology-induced error. AB - Information technology has the potential to greatly streamline healthcare and reduce the chance of human error. However, there is a growing literature indicating that if systems are not designed adequately they may actually increase the possibility of error in the complex interaction between clinician and machine in healthcare (i.e. they may lead to technology-induced errors). In other domains the study of error has been guided by a variety of theories, models and frameworks for understanding human error. In this paper we argue for the need to consider and extend this work to the study of technology-induced error in healthcare. Insights from the software engineering, human factors and organizational behaviour literature will be described, including a set of models and frameworks that we have been using to guide our work in detecting and preventing technology-induced error in healthcare. PMID- 20841780 TI - The nature of unintended effects of health information systems concerning patient safety: a systematic review with thematic synthesis. AB - In order to understand the nature and causes through which Health Information Systems (HIS) can affect patient safety negatively, a systematic review with thematic synthesis of the qualitative studies was performed. 26 papers met our criteria and were included into content analysis. 40 error contributing factors in working with HIS were recognized. Upon which, 4 main categories of contributing factors were defined. Analysis of the semantic relation between contributing reasons and common types of errors in healthcare practice revealed 6 mechanisms that can function as secondary contributing reasons. Results of this study can support care providers, system designers, and system implementers to avoid unintended negative effects for patient safety. PMID- 20841781 TI - A system for solution-orientated reporting of errors associated with the extraction of routinely collected clinical data for research and quality improvement. AB - BACKGROUND: We have used routinely collected clinical data in epidemiological and quality improvement research for over 10 years. We extract, pseudonymise and link data from heterogeneous distributed databases; inevitably encountering errors and problems. OBJECTIVE: To develop a solution-orientated system of error reporting which enables appropriate corrective action. METHOD: Review of the 94 errors, which occurred in 2008/9. Previously we had described failures in terms of the data missing from our response files; however this provided little information about causation. We therefore developed a taxonomy based on the IT component limiting data extraction. RESULTS: Our final taxonomy categorised errors as: (A) Data extraction Method and Process; (B) Translation Layer and Proxy Specification; (C) Shape and Complexity of the Original Schema; (D) Communication and System (mainly Software-based) Faults; (E) Hardware and Infrastructure; (F) Generic/Uncategorised and/or Human Errors. We found 79 distinct errors among the 94 reported; and the categories were generally predictive of the time needed to develop fixes. CONCLUSIONS: A systematic approach to errors and linking them to problem solving has improved project efficiency and enabled us to better predict any associated delays. PMID- 20841782 TI - Toward a human-centered voluntary medical incident reporting system. AB - Voluntary medical incident reports are a valuable source for studying adverse events and near misses. Underreporting and low quality of reports in local organizations, however, have become the impediments in identifying trends and patterns relating at the local, regional and national level. Human factors on usefulness and ease of use have shown their important role in acceptance of voluntary reporting systems. To understand and identify the obstacles of quality reporting, we employed a set of human-centered analysis methods to examine one year voluntary medical incident reports of a University Hospital. We found about 30% of the reports labeled as "miscellaneous" and "other", and their real incident types or error descriptions were identified through an in-depth recoding. Human-centered analyses show that the pre-defined reporting categories could serve well for the voluntary reporting need if reporters' tasks were better represented on user-friendly interfaces. We suggest that a human-centered, ontology based system design for voluntary reporting is feasible which could help improve completeness, accuracy, and interoperability among national and international standards. PMID- 20841783 TI - Enhanced notification of infusion pump programming errors. AB - Hospitalized patients receive countless doses of medications through manually programmed infusion pumps. Many medication errors are the result of programming incorrect pump settings. When used appropriately, smart pumps have the potential to detect some programming errors. However, based on the current use of smart pumps, there are conflicting reports on their ability to prevent patient harm without additional capabilities and interfaces to electronic medical records (EMR). We developed a smart system that is connected to the EMR including medication charting that can detect and alert on potential pump programming errors. Acceptable programming limits of dose rate increases in addition to initial drug doses for 23 high-risk medications are monitored. During 22.5 months in a 24 bed ICU, 970 alerts (4% of 25,040 doses, 1.4 alerts per day) were generated for pump settings programmed outside acceptable limits of which 137 (14%) were found to have prevented potential harm. Monitoring pump programming at the system level rather than the pump provides access to additional patient data in the EMR including previous dosage levels, other concurrent medications and caloric intake, age, gender, vitals and laboratory results. PMID- 20841784 TI - Extraction of adverse drug effects from clinical records. AB - With the rapidly growing use of electronic health records, the possibility of large-scale clinical information extraction has drawn much attention. We aim to extract adverse drug events and effects from records. As the first step of this challenge, this study assessed (1) how much adverse-effect information is contained in records, and (2) automatic extracting accuracy of the current standard Natural Language Processing (NLP) system. Results revealed that 7.7% of records include adverse event information, and that 59% of them (4.5% in total) can be extracted automatically. This result is particularly encouraging, considering the massive amounts of records, which are increasing daily. PMID- 20841785 TI - SeReM2--a meta-model for the structured definition of quality requirements for electronic health record services. AB - Quality assurance is a major task with regard to Electronic Health Records (EHR). Currently there are only a few approaches explicitly dealing with the quality of EHR services as a whole. The objective of this paper is to introduce a new Meta Model to structure and describe quality requirements of EHRs. This approach should support the transnational quality certification of EHR services. The Model was developed based on interviews with 24 experts and a systematic literature search and comprises a service and requirements model. The service model represents the structure of a service whereas the requirements model can be used to assign specific predefined aims and requirements to a service. The new model differs from existing approaches as it accounts for modern software architectures and the special attributes of EHRs. PMID- 20841786 TI - Exploiting UMLS semantics for checking semantic consistency among UMLS concepts. AB - OBJECTIVES: To quantify semantic inconsistency in UMLS concepts from the perspective of their hierarchical relations and to show through examples how semantically-inconsistent concepts can help reveal erroneous synonymy relations. METHODS: Inconsistency is defined in reference to concepts from the UMLS Metathesaurus. Consistency is evaluated by comparing the semantic groups of the two concepts in each pair of hierarchically-related concepts. A limited number of inconsistent concepts was inspected manually. RESULTS: 81,512 concepts are inconsistent due to the differences in semantic groups between a concept and its parent. Four examples of wrong synonymy are presented. CONCLUSIONS: A vast majority of inconsistent hierarchical relations are not indicative of any errors. We discovered an interesting semantic pattern along hierarchies, which seems associated with wrong synonymy. PMID- 20841787 TI - Empirical analysis of the reduction of medical expenditures by e-health. AB - This paper aims to examine reduction of medical expenditures by utilizing the system of Nishi-aizu Town, Fukushima Prefecture. The town office has been implementing it since 1994 and keeps receipts on medical expenditures of its approximately 4,000 residents paid by National Health Insurance for 5 years from 2002 to 2006. We select (1) users; and (2) non-users of the e-health system, and by comparing their medical expenditures, we examine: (i) difference in medical expenditures between two groups; and (ii) negative correlation between medical expenditures and the length of usage of the e-health system. We find that total medical expenditures of users are larger than those of non-users, whereas by restricting to lifestyle-related illnesses such as high blood pressure, cerebral infarction, strokes, and diabetes, medical expenditures of users are found to be smaller than those of non-users. The results we obtained here provide the rigorous economic foundation of the e-health system. PMID- 20841788 TI - Using a business rule management system to improve disposition of traumatized patients. AB - We propose a business rule management system that is used to optimize the dispatchment on a mass casualty incident. Using geospatial information from available ambulances and rescue helicopters, a business rule engine calculates an optimized transportation plan for injured persons. It automatically considers special needs like ambulances equipped for baby transportation or special decontamination equipment, e.g. to deal with an accident in a chemical factory. The rules used in the system are not hardcoded; thus, it is possible to redefine them on the fly without changing the program's source code. It is possible to load and save a rule set in case of a catastrophe. Furthermore, it is possible to automatically recalculate an already planned operation if it becomes clear that the rescue vehicles assigned are needed by a person with life-threatening injuries. PMID- 20841789 TI - Measuring the effectiveness of hospital-acquired infection prevention. AB - This article deals with data on nosocomial infections acquired in the Geneva University Hospitals. Goal of the work is to derive a model from a hospital acquired infection (HAI) prevalence survey of year Y and apply them to a prevalence survey of years Y+1, Y+2. This analysis permits to evaluate the effectiveness of preventive measures taken after the prevalence survey in year Y. It also analyzes the robustness of the SVM algorithm on time-variable attributes. The model build on the dataset of year Y gives better results than in a previous study. The application of the model on the Y+1 and Y+2 prevalence surveys shows simultaneously improvements and deteriorations of 5 performance measures. This highlights the effectiveness of prevention and reduces the risk of HAI after the prevalence survey of year Y. We introduce a new method to detect redundancy in a dataset with the SVM algorithm. PMID- 20841790 TI - Evaluating the relevance of disability weights for adjusting disease-cost and comorbidity calculations at the Kigali University Teaching Hospital. AB - Evaluating the burden of diseases treated in hospitals in terms of (co)morbidity and financial impact is a long standing problem. Proposed solutions often rely on very sophisticated medical registration systems that are less suitable for developing countries. The authors have developed a simple prototype method for calculating financial impact and comorbidity of clinical conditions treated in a Sub-Saharan hospital environment (CALCO method) using disability weights. The developed method has been tested for 4 major clinical entities (tuberculosis, nutritional deficiencies, perinatal complications and malaria) on a dataset of 8.309 electronically registered admissions between February 1st 2009 and September 1st 2009 at the Kigali University Teaching Hospital. Results suggest that the method consists an acceptable instrument for estimating the financial burden of diseases treated in the hospital and that the proposed algorithms provide a useful formal method for quantifying hospital-bound comorbidity. The CALCO method might find its use in future implementations of Performance Based Financing (PBF) programs in Africa. PMID- 20841791 TI - Analysis of data captured by barcode medication administration system using a PDA; aiming at reducing medication errors at point of care in Japanese Red Cross Kochi Hospital. AB - Preventing medication errors by using a barcode administration system has become prevalent in patient safety. Analyses of data captured by bar code systems provide opportunities to understand the actual situation at the point of care. Our study aims at understanding issues of medication safety as well as investigating measures taken to prevent medication accidents, by analyzing data captured by a bar code system and a personal digital assistant (PDA). The barcode administration system named Point-of-Act-System implemented in Japanese Red Cross Kochi Hospital was designed to capture every activity at the bedside. Complete activity data captured by the system, which included injections, treatment and other nursing activity, as well as injection warning data, were used for our analyses. We describe the data and analyze them statistically to find potentially times of risk and to ascertain the relation between busyness and error. The injection warning rate as a whole was 6.1% on average. The results showed there was a negative correlation between the number of injections given and the injection warning rate (-0.48, p<0.05). The warning rate was low during the hours when a large number of injections were administered. The data also showed that a variation in activities being performed has a negative effect on medication safety. A bar code administration system is quite an effective way not only to prevent medication error at point of care, but also to improve patient safety through analyses of data captured by such a system. PMID- 20841792 TI - A business case for HIT adoption: effects of "meaningful use" EHR financial incentives on clinic revenue. AB - The goal of this study is to describe a framework that allows decision makers to efficiently evaluate factors that affect Electronic Health Record (EHR) adoption and test suitable interventions; specifically financial incentives. The United States healthcare delivery system is experiencing a transformation to improve population health. There is strong agreement that "meaningful use" of Health Information Technology (HIT) is a major enabler in this effort. However it's also understood that the high cost of implementing an EHR is an obstacle for adoption. To help understand these complexities we developed a simulation model designed to capture the dynamic nature of policy interventions that affect the adoption of EHR. We found that "Effective" use of HIT approaches break-even-point and larger clinic revenue many times faster that "average" or "poor" use of HIT. This study uses a systems perspective to the evaluate EHR adoption process through the "meaningful use" redesign as proposed in the American Reinvestment and Recovery Act 2009 in the United States healthcare industry by utilizing the System Dynamics methodology and Scenario Analysis. PMID- 20841793 TI - Why is it so difficult to measure the effects of interruptions in healthcare? AB - Interruptions are a complex phenomenon where multiple variables including the characteristics of primary tasks, the interruptions themselves, and the environment may influence patient safety and workflow outcomes. Observational studies present significant challenges for recording many of the process variables that influence the effects of interruptions. Controlled experiments provide an opportunity to examine the specific effects of variables on errors and efficiency. Computational models can be used to identify the situations in which interruptions to clinical tasks could be disruptive and to investigate the aggregate effects of interruptions. PMID- 20841794 TI - Optimizing medication reminders using a decision-theoretic framework. AB - We discuss a new approach to patients' adherence to enhance to their medication taking regimen by developing a context-aware alerting system that would optimize the expected utility of alerts. Each patient's instantaneous context is assessed using a real-time sensor network deploying a variety of sensors. The alerts are generated to optimize the expected value to the patient. This paper is focused on the initial assessment of the utility of alerts, including the tradeoff between effectiveness and annoyance. PMID- 20841795 TI - Factors affecting physicians compliance with enrollment suggestions into a clinical reminders intervention. AB - Clinical reminders can promote adherence with evidence-based clinical guidelines, but they may also have unintended consequences such as alert fatigue, false alarms and increased workload, which cause clinicians to ignore them. The described clinical reminder system identifies patients eligible for primary prevention of cardiovascular diseases and lets the physician to choose which patients will be included in the reminders intervention. We analyzed data of 87,165 visits of 35,699 patients and evaluated factors which may affect clinicians' decision to enroll patients to the intervention. The physicians included most of the patients suggested for inclusion (85.7%). Yet, they skipped the enrollment suggestion in 62.6% of the visits. Patients with a cardiovascular disease, dyslipidemia, diabetes, or hypertension were more likely to be included in the intervention, while older patients were less likely to be included. Insights regarding the usability of clinical reminders are discussed. PMID- 20841798 TI - Integration of workflow and rule engines for clinical decision support services. AB - Although recent studies have suggested the feasibility of integrating workflow and rule technology in a Clinical Decision Support System (CDSS), their implementation has not been verified yet. This paper proposes a knowledge engine which integrates workflow and rule engine as a tool for interpretation and execution of computer interpretable clinical guidelines. The objective of this paper is to validate its feasibility in two perspectives: clinical knowledge coverage and execution performance. The two open source engines which were selected and integrated were chosen due to their reliability and consistency. Implementation of workflow and rule engine integration has shown that the integrated knowledge engine (uBrain) is an effective CDSS for the execution of clinical guidelines. PMID- 20841797 TI - Identifying best practices for clinical decision support and knowledge management in the field. AB - To investigate best practices for implementing and managing clinical decision support (CDS) in community hospitals and ambulatory settings, we carried out a series of ethnographic studies to gather information from nine diverse organizations. Using the Rapid Assessment Process methodology, we conducted surveys, interviews, and observations over a period of two years in eight different geographic regions of the U.S.A. We first utilized a template organizing method for an expedited analysis of the data, followed by a deeper and more time consuming interpretive approach. We identified five major categories of best practices that require careful consideration while carrying out the planning, implementation, and knowledge management processes related to CDS. As more health care organizations implement clinical systems such as computerized provider order entry with CDS, descriptions of lessons learned by CDS pioneers can provide valuable guidance so that CDS can have optimal impact on health care quality. PMID- 20841796 TI - Impact of content-specific email reminders on provider participation in an online intervention: a dental PBRN study. AB - Engaging busy healthcare providers in online continuing education interventions is challenging. In an Internet-delivered intervention for dental providers, we tested a series of email-delivered reminders - cues to action. The intervention included case-based education and downloadable practice tools designed to encourage providers to increase delivery of smoking cessation advice to patients. We compared the impact of email reminders focused on 1) general project announcements, 2) intervention related content (smoking cessation), and 3) unrelated content (oral cancer prevention focused content). We found that email reminders dramatically increased participation. The content of the message had little impact on the participation, but day of the week was important - messages sent at the end of the week had less impact, likely due to absence from clinic on the weekend. Email contact, such as day of week an email is sent and notice of new content post-ing, is critical to longitudinal engagement. Further research is needed to understand which messages and how frequently, will maximize participation. PMID- 20841799 TI - Implementation of a clinical decision support system using a service model: results of a feasibility study. AB - Numerous studies have shown that the quality of health care is inadequate, and healthcare organizations are increasingly turning to clinical decision support systems (CDSS) to address this problem. In implementing CDSS, a highly promising architectural approach is the use of decision support services. However, there are few reported examples of successful implementations of operational CDSS using this approach. Here, we describe how Hospital Italiano de Buenos Aires evaluated the feasibility of using the SEBASTIAN clinical decision support Web service to implement a CDSS integrated with its electronic medical record system. The feasibility study consisted of three stages: first, end-user acceptability testing of the proposed CDSS through focus groups; second, the design and implementation of the system through integration of SEBASTIAN and the authoring of new rules; and finally, validation of system performance and accuracy. Through this study, we found that it is feasible to implement CDSS using a service-based approach. The CDSS is now under evaluation in a randomized controlled trial. The processes and lessons learned from this initiative are discussed. PMID- 20841800 TI - Evaluation of the use of an "ask-the-expert" e-consultation service for support on health-related requests. AB - E-consultation in health care can be used to respond to an increasing demand for care by offering support on health-related requests. In this study we evaluated the use of an "ask-the-expert" e-consultation service in order to assess whether the service is efficient and useful. A content analysis of e-mail exchange between clients and online health professionals was performed to gain insight in the purposes of use of the service. Our findings show that the e-consultation service was used for health requests on not urgent, minor ailments. Clients asked for health information to increase knowledge on the cause of their injury or disease, its consequences, possible self-care solutions and treatment options. Decision support on assessing the necessity to visit a doctor for a certain health problem was another important reason to use the service. We believe that web-based triage systems could be used to more easily assess whether certain symptoms need to be investigated. PMID- 20841801 TI - Analyzing effects of providing performance feedback at ward rounds on guideline adherence - the importance of feedback usage analysis and statistical control charts. AB - OBJECTIVE: Feedback to clinicians on their past performance is often aimed at increasing adherence to guidelines. We investigate how various analytical approaches influence the interpretation of adherence data. The analytical approaches vary in considering the actual or the intended use of the feedback, and whether outcomes are inspected over time. MATERIAL AND METHODS: At base line, a computerized decision support system was employed at the ICU bedside to increase adherence to a mechanical ventilation strategy. We intervened by providing feedback about adherence to the guideline at the daily ward rounds. The outcome measure was the percentage of ventilation time (VT) in excess of the guideline's recommendation. Actual usage of the feedback was logged and data analysis was carried out using two approaches: classical statistics, and statistical process control (SPC) that inspect progress of an outcome over time. DESIGN: Prospective, before/after study. RESULTS: The classical analysis stated that the percentage of ventilation time in excess of the guideline's recommendation decreased significantly due to the feedback (5% reduction, p < 0.001). When SPC analysis of the outcome was applied, the effect was deemed not significant. When the actual delivery of feedback over time was also included it showed that the experiment does not allow for conclusive results. CONCLUSIONS: The concluded effect of providing feedback on adherence to a guideline depends on whether the actual usage pattern of the feedback and the inspection of the outcome over time are considered. Future evaluative studies should report on usage patterns and progression of outcomes over time. PMID- 20841802 TI - Processing gradual information with Fuzzy Arden syntax. AB - The programming language Arden Syntax is especially adapted to the needs of computer-based clinical decision support. Recently, an extension of Arden Syntax, named Fuzzy Arden Syntax, was proposed by the authors. Fuzzy Arden Syntax is a conservative extension of Arden Syntax and offers special functionality to process gradual information. The background is the observation that in medicine we frequently deal with statements which are neither clearly false nor clearly true but hold to some intermediate degree. In this paper, we demonstrate under which circumstances a Medical Logic Module (a program unit written in Arden Syntax) may show unintended behavior and how the situation can easily be improved by means of the possibilities offered by Fuzzy Arden Syntax. To this end, an example from the domain of nosocomial infection control is discussed in detail. PMID- 20841803 TI - Design of a continuous multifaceted guideline-implementation strategy based on computerized decision support. AB - Implementation of clinical practice guidelines into daily care is hindered by a variety of barriers related to professional knowledge, collaboration in teams and organizations, and practicability of the guidelines. Clinical computerized decision support (CCDS) has been shown to be one of the most effective instruments to improve compliance to practice guidelines by tackling barriers related to professional knowledge. To address other barriers, however, additional interventions are needed. In this study, a continuous multifaceted guideline implementation strategy was developed which is based on CCDS but extends beyond the professional knowledge barrier. Two additional interventions were designed and embedded with CCDS in a continuous quality improvement framework. First, to address barriers within teams and organizations guideline compliance data are periodically aggregated into feedback reports for care providers. Second, barriers related to practicability of the underlying guidelines are addressed in a guideline-maintenance cycle. A case study in the field of cardiac rehabilitation is presented to demonstrate the feasibility of the developed strategy. PMID- 20841804 TI - MET3-AE system to support management of pediatric asthma exacerbation in the emergency department. AB - A decision making process behind the management of pediatric patients with asthma exacerbations in the Emergency Department includes three stages: data collection, diagnosis formulation and treatment planning. These stages are associated with activities involving different types of clinical knowledge: factual, conceptual and procedural. Effective decision support should span over the entire decision making process and facilitate the use of diversified clinical knowledge. In this paper we present MET3-AE - a point of care decision support system that satisfies this requirement. The system helps emergency physician collect data, evaluate exacerbation severity, plan corresponding treatment and retrieve clinical evidence associated with a given treatment plan. It was developed using ontology driven and multi-agent methodologies and implemented with open source software. The system is accessible on tablet and desktop computers and smartphones, and it interacts with other hospital information systems. It was successfully verified in a simulated clinical setting and now it is undergoing testing in a teaching hospital. PMID- 20841805 TI - AALIM: a cardiac clinical decision support system powered by advanced multi-modal analytics. AB - Modern Electronic Medical Record (EMR) systems often integrate large amounts of data from multiple disparate sources. To do so, EMR systems must align the data to create consistency between these sources. The data should also be presented in a manner that allows a clinician to quickly understand the complete condition and history of a patient's health. We develop the AALIM system to address these issues using advanced multimodal analytics. First, it extracts and computes multiple features and cues from the patient records and medical tests. This additional metadata facilitates more accurate alignment of the various modalities, enables consistency check and empowers a clear, concise presentation of the patient's complete health information. The system further provides a multimodal search for similar cases within the EMR system, and derives related conditions and drugs information from them. We applied our approach to cardiac data from a major medical care organization and found that it produced results with sufficient quality to assist the clinician making appropriate clinical decisions. PMID- 20841806 TI - TADAA: towards automated detection of anaesthetic activity. AB - Task analysis is a valuable research method for better understanding the activity of anaesthetists in the operating room (OR), providing evidence for designing and evaluating improvements to systems and processes. It may also assist in identifying potential error paths to adverse events, ultimately improving patient safety. Human observers are the current 'gold standard' for capturing task data, but they are expensive and have cognitive limitations. Our current research - Towards Automated Detection of Anaesthetic Activity (TADAA) - aims to produce an automated task analysis system, employing Radio Frequency Identification (RFID) technology to capture anaesthetists' location, orientation and stance (LOS), and machine learning techniques to translate that data into low-level and high-level activity labels. In this paper we present details of the system design and promising results from LOS sensing testing in laboratory and high fidelity OR simulator settings. PMID- 20841807 TI - A model driven approach to imbalanced data sampling in medical decision making. AB - Classification is an important medical decision support function that can be seriously affected by disproportionate class distribution in the training data. In medical decision making, the rate of misclassification and the cost of misclassifying a minority (positive) class as a majority (negative) class are especially high. In this paper, we propose a new model-driven sampling approach to balancing data samples. Most existing data sampling methods produce new data points based on local, deterministic information. Our approach extends the idea of generative sampling to produce new data points based on an induced probabilistic graphical model. We present the motivation and the design of the proposed algorithm, and compare it with two representative imbalanced data sampling approaches on four medical data sets varying in size, imbalance ratio, and dimension. The empirical study helped identify the challenges in imbalanced data problems in medicine, and highlighted the strengths and limitations of the relevant sampling approaches. Performance of the model driven approach is shown to be comparable with existing approaches; potential improvements could be achieved by incorporating domain knowledge. PMID- 20841808 TI - Feature importance analysis for patient management decisions. AB - The objective of this paper is to understand what characteristics and features of clinical data influence physician's decision about ordering laboratory tests or prescribing medications the most. We conduct our analysis on data and decisions extracted from electronic health records of 4486 post-surgical cardiac patients. The summary statistics for 335 different lab order decisions and 407 medication decisions are reported. We show that in many cases, physician's lab-order and medication decisions are predicted well by simple patterns such as last value of a single test result, time since a certain lab test was ordered or time since certain procedure was executed. PMID- 20841809 TI - Deployment of a highly secure clinical data repository in an insecure international environment. AB - We have designed and deployed a novel approach to protecting Personal Healthcare Information in environments where a data center is remote and its physical security cannot be assured. Our "KeyServer" methodology uses a server-client server architecture to dynamically serve keys from a distant server in a separate secure data center in the US. The approach combines pre-existing and novel techniques into a layered protective barrier around compromise of patient data. We describe how this technology provides scalable security that makes security breaches highly unlikely. With some careful planning a Clinical Data Repositories fed by Electronic Health Records can be placed in relatively insecure settings, with a high-level of security surrounding data theft, even in the event of hardware theft. Such security architecture is ideal for not only developing nations, but for the evolution of health information to cloud computing platforms. PMID- 20841810 TI - Healthcare system evolution towards SOA: a security perspective. AB - Healthcare providers often face the challenge of integrating diverse and geographically disparate IT systems to respond to changing requirements and to exploit the capabilities of modern technologies. Hence, systems evolution, through modification and extension of the existing IT infrastructure, becomes a necessity. This paper assumes a healthcare systems evolution towards a service oriented architecture (SOA) and places emphasis on the development of an appropriate authorization model and mechanism that ensures authorized access to integrated patient information through web service invocations. PMID- 20841811 TI - Healthcare chains - enabling application and data privacy controls for healthcare information systems. AB - Healthcare applications that have access control, disclosure management and or privacy enforcement requirements may implement the respective solutions to these issues at the application level or at the database level or in both. Unfortunately, there are technical and non-technical factors that influence what can be done. In this paper we present a flexible, simple and novel approach to seamlessly imbuing current healthcare applications and their supporting infrastructure with security and privacy functionality, while being cognizant of these factors. This approach is called the Chain method. This paper will highlight the smaller design footprint, the increased ease of implementation and use of the Chain method, while demonstrating that it is as powerful and effective as traditional methods. PMID- 20841812 TI - HIPAA compliance and patient privacy protection. AB - Recent prosecution of violations of the Health Insurance Portability and Accountability Act (HIPAA), and the amendments currently in process to strengthen the Act of 1996, has led many companies to take serious notice of the measures they must take to be a compliance. A company's privacy policy states the business' privacy practices and embodies the firm's commitments to its users and is normally mandatory step in reaching legislative compliance. in the face of this, the patient has to decipher if the company's privacy practices are congruent with their thoughts on the level of privacy protection they should be receiving. This is the core of our investigation. In this paper, we explore the question "Is a healthcare entity's compliance with regulation sufficient to provide the patient with adequate privacy protection?" in the context of the United States of America. PMID- 20841813 TI - Implementation of a secure and interoperable generic e-Health infrastructure for shared electronic health records based on IHE integration profiles. AB - INTRODUCTION: The ubiquitous availability of medical or care data for authorized clinicians and nurses is expected to increase quality while reducing costs in the health care sector. The standardized, distributed provision of medical or care data is capable to support the vision of patient centered shared electronic health records (SEHRs). A main contribution to cross-institutional data exchange is provided by Integrating the Healthcare Enterprise (IHE). However, holistic implementations of IHE based eHealth infrastructures for SEHRs are currently rare and security and privacy regulations are not fully covered by existing IHE Integration Profiles. This work aims to point out our experiences and lessons learned from five years of development and the implementation of IHE compliant products. METHODS: Cross-Enterprise Document Sharing (XDS) describes the base components for exchanging medical or care data. A unique patient Identification is described by the Patient Identifier Cross-referencing (PIX) and the Patient Demographics Query (PDQ) Integration Profile. All interactions are logged in an "Audit Record Repository" deployed once per Affinity Domain and defined in the Audit Trail and Node Authentication (ATNA) Integration Profile. RESULTS: Based on the IHE Integration Profile XDS and other Integration Profiles high-level components for eHealth infrastructures and applications, supporting a holistic, secure concept and, based on these concepts, software products for a technical cooperative care infrastructure, has been developed. The products are practically evaluated in a project for setting up an IHE XDS Affinity Domain in the Austrian district of Tyrol and a number of lessons have been learned. PMID- 20841815 TI - Complexities in securing sustainable IT infrastructures in hospitals: the many faces of local technical support. AB - This paper contributes to an understanding of the complexity of support work and stress the need for local technical support in hospitals in order to maintain a sustainable infrastructure of information systems (IS) and information technology (IT). Given this complexity it is pointed out that a naive trust in formal stylized models of support organization is problematic. With an increasing number of critical systems in the hospitals technical support is becoming an essential service needed for maintenance, acute failure of systems and help with the everyday use of hardware and software. In order for the health informatics technologies and systems to work, the healthcare institutions need strong IT organizations to support and maintain the IS/IT infrastructure on which these technologies and systems rely. Through a qualitative study of IS/IT support at hospitals I have examined the work and competencies of the service level in the IT organization. On this basis I recommend a nuanced understanding of the complexity of the work of these local technical supporters. I contrast this to the understanding of the organization of IT support through rationalized, formal 'best practice' models that emphasize centralization and cost-effectiveness through single point of contact. It is argued that there is a need for local technical supporters in hospitals with organizational and local knowledge because a) the local circumstances are key to supplying effective support and b) the supporter supply pro-active support that aid to secure the sustainability of the IT infrastructure. PMID- 20841814 TI - Desiderata for a computer-assisted audit tool for clinical data source verification audits. AB - Clinical data auditing often requires validating the contents of clinical research databases against source documents available in health care settings. Currently available data audit software, however, does not provide features necessary to compare the contents of such databases to source data in paper medical records. This work enumerates the primary weaknesses of using paper forms for clinical data audits and identifies the shortcomings of existing data audit software, as informed by the experiences of an audit team evaluating data quality for an international research consortium. The authors propose a set of attributes to guide the development of a computer-assisted clinical data audit tool to simplify and standardize the audit process. PMID- 20841816 TI - Citizen Centric Architecture approach - taking e-health forward by integrating citizens and service providers. AB - In this paper, two related research problems will be discussed in the development of e-health services: First, an architectural approach is needed to provide a holistic view for solving the ICT challenges in e-health development. Second, solving the needs of the citizens should be the focus of the architecture solution. To overcome these problems we suggest a Citizen Centric Architecture (CCA) approach for providing a holistic and appropriately balanced view of the integration. Naturally, enterprises' information systems and citizens' information systems are the key elements of CCA. In addition, for solving the topology challenge brought by a large number of involved parties, a role of trusted third party is proposed to provide an environment for the information exchange and service mediation among the various parties. We believe this approach will enable the large scale growth in citizen centric e-health services that is poorly facilitated by the prevailing models: the improved integration of information will attract more citizens and health care service providers, which in turn, improve the health care information and quality of service. PMID- 20841817 TI - Ensuring HL7-based information model requirements within an ontology framework. AB - This paper describes the building of an HL7-based Information Model Ontology (IMO) that can be exploited by a domain ontology in order to distribute querying over different clinical data repositories. We employed the Open Medical Development Framework (OMDF) based on a model driven development methodology. OMDF provides model transformation features to build an HL7-based information model that covers the conceptual scope of a target project. The resulting IMO is used to mediate between ontologically queries and information retrieval from semantically less defined Hospital Information Systems (HIS). In the context of the DebugIT project - which scope corresponds to the control of infectious diseases and antimicrobial resistances - Information Model Ontology is integrated to the DebugIT domain ontology in order to express queries. PMID- 20841818 TI - Foundations for a nursing services reference model. AB - The Nursing Services Reference Model (NSRM) is presented as a theoretical position and discussion paper. The aims are to describe the components of the NSRM concept, to explain why such a model needs to be developed and to explore methodological issues in the development of a NSRM. The concept is important to address as it may illuminate a most pressing problem faced by the Australian health care industry where the content and activity of nursing practice is not embedded as computer processable data in health information system structures. Digital documentation of nursing content and activity is urgently needed to enable reliable electronic processing of nursing services. However, it is necessary, prior to this, to develop a reference model that describes the range of nursing services in an unambiguous manner. PMID- 20841819 TI - The Health Service Bus: an architecture and case study in achieving interoperability in healthcare. AB - Interoperability in healthcare is a requirement for effective communication between entities, to ensure timely access to up to-date patient information and medical knowledge, and thus facilitate consistent patient care. An interoperability framework called the Health Service Bus (HSB), based on the Enterprise Service Bus (ESB) middleware software architecture is presented here as a solution to all three levels of interoperability as defined by the HL7 EHR Interoperability Work group in their definitive white paper "Coming to Terms". A prototype HSB system was implemented based on the Mule Open-Source ESB and is outlined and discussed, followed by a clinically-based example. PMID- 20841820 TI - Applying a user centered design methodology in a clinical context. AB - A clinical decision support system (CDSS) is an interactive application that is used to facilitate the process of decisionmaking in a clinical context. Developing a usable CDSS is a challenging process; mostly because of the complex nature of domain knowledge and the context of use of those systems. This paper describes how a user centered design (UCD) approach can be used in a clinical context for developing a CDSS. In our effort, a design-based research methodology has been used. The outcomes of this work are as follow; a customized UCD approach is suggested that combines UCD and openEHR. Moreover, the GUI developed in the design phase and the result of the GUI evaluation is briefly presented. PMID- 20841821 TI - Bridging the HL7 template - 13606 archetype gap with detailed clinical models. AB - The idea of two level modeling has been taken up in healthcare information systems development. There is ongoing debate which approach should be taken. From the premise that there is a lack of clinician's time available, and the need for semantic interoperability, harmonization efforts are important. The question this paper addresses is whether Detailed Clinical Models (DCM) can bridge the gap between existing approaches. As methodology, a bottom up approach in multilevel comparison of existing content and modeling is used. Results indicate that it is feasible to compare and reuse DCM with clinical content from one approach to the other, when specific limitations are taken into account and precise analysis of each data-item is carried out. In particular the HL7 templates, the ISO/CEN 13606 and OpenEHR archetypes reveal more commonalties than differences. The linkage of DCM to terminologies suggests that data-items can be linked to concepts present in multiple terminologies. This work concludes that it is feasible to model a multitude of precise items of clinical information in the format of DCM and that transformations between different approaches are possible without loss of meaning. However, a set of single or combined clinical items and assessment scales have been tested. Larger groupings of clinical information might bring up more challenges. PMID- 20841822 TI - Data mining techniques for analyzing stroke care processes. AB - Controlled randomized clinical trials and meta-analyses show that stroke patients benefit from access to specialized Stroke Units, in terms of mortality, disability and dependency. However, many issues relating to stroke diagnosis and therapy and to the organization of stroke care remain to be solved and little is known about what interventions make Stroke Units more effective. It is also agreed that compliance with clinical practice guidelines improves health outcomes for these patients, but little is known about the relative weight of the different guideline recommendations. Over the last decade, many hospital- or population-based stroke registers have been set up with the aim of identifying specific key indicators able to monitor the quality and adequacy of acute stroke care. Registers seem to be adequate tools for collecting the data needed to analyze care processes, providing data useful for both national healthcare planning and scientific research. In this paper we applied data mining techniques to data collected within the stroke register of the Lombardia region in Italy. From our analyses both expected and unexpected results have been found: not always compliance to recommendations is related to a good patients' outcome. PMID- 20841823 TI - Automatically detecting medications and the reason for their prescription in clinical narrative text documents. AB - An important proportion of the information about the medications a patient is taking is mentioned only in narrative text in the electronic health record. Automated information extraction can make this information accessible for decision support, research, or any other automated processing. In the context of the "i2b2 medication extraction challenge," we have developed a new NLP application called Textractor to automatically extract medications and details about them (e.g., dosage, frequency, reason for their prescription). This application and its evaluation with part of the reference standard for this "challenge" are presented here, along with an analysis of the development of this reference standard. During this evaluation, Textractor reached a system-level overall F1-measure, the reference metric for this challenge, of about 77% for exact matches. The best performance was measured with medication routes (F1-measure 86.4%), and the worst with prescription reasons (F1-measure 29%). These results are consistent with the agreement observed between human annotators when developing the reference standard, and with other published research. PMID- 20841824 TI - Extracting medication information from French clinical texts. AB - Much more Natural Language Processing (NLP) work has been performed on the English language than on any other. This general observation is also true of medical NLP, although clinical language processing needs are as strong in other languages as they are in English. In specific subdomains, such as drug prescription, the expression of information can be closely related across different languages, which should help transfer systems from English to other languages. We report here the implementation of a medication extraction system which extracts drugs and related information from French clinical texts, on the basis of an approach initially designed for English within the framework of the i2b2 2009 challenge. The system relies on specialized lexicons and a set of extraction rules. A first evaluation on 50 annotated texts obtains 86.7% F measure, a level higher than the original English system and close to related work. This shows that the same rule-based approach can be applied to English and French languages, with a similar level of performance. We further discuss directions for improving both systems. PMID- 20841825 TI - Text Mining approaches for automated literature knowledge extraction and representation. AB - Due to the overwhelming volume of published scientific papers, information tools for automated literature analysis are essential to support current biomedical research. We have developed a knowledge extraction tool to help researcher in discovering useful information which can support their reasoning process. The tool is composed of a search engine based on Text Mining and Natural Language Processing techniques, and an analysis module which process the search results in order to build annotation similarity networks. We tested our approach on the available knowledge about the genetic mechanism of cardiac diseases, where the target is to find both known and possible hypothetical relations between specific candidate genes and the trait of interest. We show that the system i) is able to effectively retrieve medical concepts and genes and ii) plays a relevant role assisting researchers in the formulation and evaluation of novel literature-based hypotheses. PMID- 20841826 TI - Performance analysis of a POS tagger applied to discharge summaries in Portuguese. AB - Part of speech taggers need a considerable amount of data to train their models. Such data is not readily available for medical texts in Portuguese. We evaluated the accuracy of a morphological tagger against a gold standard when trained with corpora of different sizes and domains. Accuracy was the highest with a medical corpus during the complete training process, achieving 91.5%. Training on a newswire corpus achieved 75.3% only. Furthermore, an active learning technique has been adapted to the POS tagging task. The algorithm uses a POS tagger committee to isolate the sentences with the highest disagreement indexes for manual correction. However, the method was not able to reduce training and tagging times when compared to a random selection strategy. We encourage that future works employ some effort in order to annotate a small amount of random data in the domain of study, which should be enough for higher accuracy rates. PMID- 20841827 TI - Identification of relations between risk factors and their pathologies or health conditions by mining scientific literature. AB - Risk factors discovery and prevention is an active research field within the biomedical domain. Despite abundant existing information on risk factors, as found in bibliographical databases or on several websites, accessing this information may be difficult. Methods from Natural Language Processing and Information Extraction can be helpful to access it more easily. Specifically, we show a procedure for analyzing massive amounts of scientific literature and for detecting linguistically marked associations between pathologies and risk factors. This approach allowed us to extract over 22,000 risk factors and associated pathologies. The performed evaluations pointed out that (1) over 88% of risk factors for coronary heart disease are correct, (2) associated pathologies, when they could be compared to MeSH indexing, are correct in about 70%, and (3) in existing terminologies links between risk factors and their pathologies are seldom recorded. PMID- 20841828 TI - A qualitative approach to signal mining in pharmacovigilance using formal concept analysis. AB - "Pharmacovigilance is the process and science of monitoring the safety of medicines, consisting in (i) collecting and managing data on the safety of medicines (ii) looking at the data to detect 'signals' (any new or changing safety issue)" [1]. Pharmacovigilance is mainly based on spontaneous reports: when suspecting an adverse drug reaction, health care practitioners send a report to a spontaneous reporting system (SRS). This produces huge databases containing numerous reports and their manual exploration is both cost and time prohibitive. Existing techniques that automatically extract relevant signals rely on statistics or Bayesian models but do not provide information to the experts about possible biases lying in the data, nor about the specificity of a signal to a particular patient profile. Our extraction method combines numerical methods from the state of the art with a qualitative approach that helps interpretation. We build a synthetic representation of the database that is used to (i) identify unexpected patterns and biases (ii) extract potentially relevant signals w.r.t. patient profiles (iii) provide traceability facilities between extracted signals and raw data. PMID- 20841829 TI - Data mining to assess variations in oral anticoagulant treatment. AB - Variations in International Normalized Ratio's (INR) are closely related to bleeding and thrombosis incidents in patients on oral anticoagulation treatment. This study investigates predictive factors that affect INR values. Data sampled with relatively high frequency allows for detection of local INR variations, and hence also allows detection and evaluation of predictive factors where time is taken into consideration. Univariate linear regression was applied and different models were reduced into a final predictive model. F-tests were utilized to test whether or not a model reduction would benefit INR predictions, in terms of decreasing observed variance. In addition to an INR submodel, the final model includes individual interaction from the last three days change in mean warfarin intake and three days change in mean vitamin K intake. Prediction residual error was mainly reduced by the INR submodel, while the warfarin model and the vitamin K submodel did not benefit predictions to same extend compared to the INR submodel. However, more studies on the temporal aspects of the effect of warfarin seem to be relevant. PMID- 20841830 TI - Addressing SNOMED CT implementation challenges through multi-disciplinary collaboration. AB - This article describes the challenges of implementing SNOMED CT into electronic clinical documentation systems for discharge summaries, synoptic operative notes and ambulatory documentation. Four significant implementation challenges were identified throughout these projects, which required collaboration between specialists across several disciplines to resolve. The challenges included: designing the graphical user interface for selecting SNOMED CT values, gathering and validating template specifications that use SNOMED CT subsets, handling SNOMED CT subsets and extensions, and, creating algorithms and the technological infrastructure to generate fast, meaningful, non-redundant search results. Our experiences suggest that, while the usage of SNOMED CT in tertiary care settings is promising, collaboration between specialists from multiple disciplines is needed to utilize their unique project management, data modeling, technical, and clinical skills in overcoming implementation challenges. PMID- 20841831 TI - Semantic reasoning with XML-based biomedical information models. AB - The Extensible Markup Language (XML) is increasingly being used for biomedical data exchange. The parallel growth in the use of ontologies in biomedicine presents opportunities for combining the two technologies to leverage the semantic reasoning services provided by ontology-based tools. There are currently no standardized approaches for taking XML-encoded biomedical information models and representing and reasoning with them using ontologies. To address this shortcoming, we have developed a workflow and a suite of tools for transforming XML-based information models into domain ontologies encoded using OWL. In this study, we applied semantics reasoning methods to these ontologies to automatically generate domain-level inferences. We successfully used these methods to develop semantic reasoning methods for information models in the HIV and radiological image domains. PMID- 20841832 TI - Characterizing consumer health terminology in the breast cancer field. AB - Despite the large availability of medical information on the Internet, health consumers still encounter problems to find, interpret and understand this information. These problems are mainly due to their lack in medical knowledge and the difference between their language and the language of health professionals. In order to propose information retrieval services more adapted to health consumers language and knowledge, we have developed techniques to collect, identify and analyze the terms and the expressions used by lay persons to talk about breast cancer. The study of health consumers' language is a relatively recent research field. Many studies have been conducted to analyze and characterize the vocabulary used by health consumers to talk about medical subjects in English. We have conducted the same study for the French language in the breast cancer field. We have gathered a corpus of texts to identify terms and expressions used by health consumers who talk about breast cancer in French. The terms have been organized in a concept-based terminology. This terminology has been analyzed on several levels: concept level, term level, term-concept level and finally relation level. PMID- 20841833 TI - Exploring relations among semantic groups: a comparison of concept co-occurrence in biomedical sources. AB - It has been observed and reported that the patient's mental model of the medical domain is different from that of a health professional and this difference is one of the primary obstacle in the effective communication of health information to patients. In this study, to better understand these mental models, we explored the relations among different semantic groups of concepts in consumer- and professional-generated health content by analyzing concept co-occurrence information in three biomedical sources. We found significant differences in the prevalence of the semantic groups and the strength of co-occurrences between semantic groups in the three sources. The co-occurrence defined by consumers differs from that defined by professionals. The two professional sources have noticeable differences with each other as well. We believe that addressing these differences can help us generate more informative and consumer-friendly health content as well as develop better consumer health informatics applications. PMID- 20841834 TI - Bridging the semantics gap between terminologies, ontologies, and information models. AB - SNOMED CT and other biomedical vocabularies provide semantic identifiers for all kinds of linguistic expressions, many of which cannot be considered terms in a strict sense. We analyzed such "non-terms" in SNOMED CT and concluded that many of them cannot be interpreted as directly referring to objects or processes, but rather to information entities. Discussing two approaches to represent information entities, viz. the OBO Information artifact ontology (IAO) and the HL7 v3 Reference Information Model (RIM), we propose an integrative solution for representing information entities in SNOMED CT, in a way that is still compatible with RIM and the IAO and uses moderately enhanced description logics. PMID- 20841835 TI - Modeling, building and evaluating an ontology for the automatic characterization of adverse drug effects during pharmacovigilance. AB - BACKGROUND: The characterization of spontaneous reported cases is fundamental for pharmacovigilance. This task is time consuming and its reproducibility is low. OBJECTIVE: To develop a system founded on an ontology that automatically instantiates spontaneous reported cases as "known" adverse drug effects (ADE) only if the reported ADEs are described in drug compendia. METHODS: A simple ontology of drugs and their related adverse effects represented in description logics was developed from a drug database. Manual evaluation was carried out on 378 spontaneous reported cases instantiated as "known ADE of a chemical class". The initial manual characterization was reviewed by a pharmacovigilance expert to validate the generated automatic characterization. RESULTS: The ontology is composed by 57,04 concepts and 5 relations. It was successfully validated thanks to Pellet reasoner and it contains neither inconsistencies nor cycles. In this validation, 86% of the instantiated spontaneous reported cases effectively concerned notorious ADEs, whereas only 75% were initially identified manually as related to notorious ADEs. CONCLUSION: This system can assist characterization by applying a reasoning process similar to that used by experts in the search for ADEs. PMID- 20841836 TI - Internal structure of a disease name and its application for ICD coding. AB - ICD-coding is a complex and difficult task. Coding results vary a great deal depending on each coder's ability. Although the Japanese Standard Disease-Code Master facilitates the coding tasks, it also engenders post-coordination problems derived from combinations of basic diseases (with ICD code) and modifiers. Post coordination sometimes alters the original ICD code dramatically. To solve this problem, this paper presents a proposal for using internal structures of disease names to correct the ICD code. First, we built an internal structure analyzer, which achieved high (83.7%) accuracy. Results demonstrated that the analyzed output is helpful for precise ICD-coding tasks. PMID- 20841837 TI - Exploitation of linguistic indicators for automatic weighting of synonyms induced within three biomedical terminologies. AB - Acquisition and enrichment of lexical resources is an important research area for the computational linguistics. We propose a method for inducing a lexicon of synonyms and for its weighting in order to establish its reliability. The method is based on the analysis of syntactic structure of complex terms. We apply and evaluate the approach on three biomedical terminologies (MeSH, Snomed Int, Snomed CT). Between 7.7 and 33.6% of the induced synonyms are ambiguous and cooccur with other semantic relations. A virtual reference allows to validate 9 to 14% of the induced synonyms. PMID- 20841838 TI - Auto-selection of DRG codes from discharge summaries by text mining in several hospitals: analysis of difference of discharge summaries. AB - Recently, electronic medical record (EMR) systems have become popular in Japan, and number of discharge summaries is stored electronically, though they have not been reutilized yet. We performed text mining with Tf-idf method and morphological analysis in the discharge summaries from three Hospitals (Chiba University Hospital, St. Luke's International Hospital and Saga University Hospital). We showed differences in the styles of summaries, between hospitals, while the rate of properly classified DPC (Diagnosis Procedure Combination) codes were almost the same. Beyond different styles of the discharge summaries, text mining method could obtain proper extracts of proper DPC codes. Improvement was observed by using integrated model data between the hospitals. It seemed that huge database which contains the data of many hospitals can improve the precision of text mining. PMID- 20841839 TI - Can F-MTI semantic-mined drug codes be used for adverse drug events detection when no CPOE is available? AB - BACKGROUND: Adverse Drug Events (ADEs) endanger the patients. Their detection and prevention is essential to improve the patients' safety. In the absence of computerized physician order entry (CPOE), discharge summaries are the only source of information about the drugs prescribed during a hospitalization. The French Multierminology Indexer (F-MTI) can help to extract drug-related information from those records. METHODS: In first and second validation steps, the performance of the F-MTI tool is evaluated to extract ICD10 and ATC codes from free-text documents. In third step, potential ADE detection rules are used and the confidences of those rules are compared in several hospitals: using a CPOE vs. using semantic mining of free-text documents, diagnoses and lab results being available in both cases. RESULTS: The F-MTI tool is able to extract ATC codes from documents. Moreover, the evaluation shows coherent and comparable results between the hospitals with CPOEs and the hospital with drugs information extracted from the reports for potential ADE detection. CONCLUSION: semantic mining using F-MTI can help to identify previous cases of potential ADEs in absence of CPOE. PMID- 20841840 TI - Aligning UniProt and MeSH - a case study on human protein terms. AB - Terminologies which lack semantic connectivity hamper the effective search in biomedical fact databases and document retrieval systems. We here focus on the integration of two such isolated resources, the term lists from the protein fact database UNIPROT and the indexing vocabulary MESH from the bibliographic database MEDLINE. The generated semantic ties result from string matching and term set inclusion. We investigated the implicit terminological overlap between both resources in the domain of human proteins and evaluated our approach on a sample of 550 randomly selected UNIPROT entries that were manually mapped to their corresponding MESH headings. We achieved 90% precision and 79% recall (applying taxonomy-sensitive metrics). Fortunately, those proteins we were able to map to the MESH are ten times as frequently discussed in the literature as those on which we failed. PMID- 20841841 TI - Using SNOMED CT to identify a crossmap between two classification systems: a comparison with an expert-based and a data-driven strategy. AB - A crossmap between successive versions of classification systems is necessary to maintain the continuity of health care documentation. A reference terminology can serve as an intermediary to support this task. Within this study we evaluated the use of SNOMED CT to create a crossmap between two versions of an intensive care classification system. Firstly, the SNOMED CT crossmap was compared with an expert-based and a data-driven crossmap. Next, the influence of these crossmap strategies on the health care outcome was evaluated. For 50% of the analyzed cases, the three mapping strategies resulted in the same crossmaps. In other cases, there was an overlap between the SNOMED CT crossmaps and the crossmaps provided by one of the two other strategies. Differences in the crossmap results had however no significant influence on the health care outcomes. SNOMED CT can be used as an intermediary to solve the problem of crossmapping between versions of classification systems. PMID- 20841842 TI - An automated approach to map a French terminology to UMLS. AB - BACKGROUND: CCAM is a French terminology for coding clinical procedures. CCAM is a multi-hierarchical structured classification for procedures used in France for reimbursement in health care, which is external to UMLS. OBJECTIVE: The objective of this work is to describe a French lexical approach allowing mapping CCAM procedures to the UMLS Metathesaurus to achieve interoperability to multiple international terminologies. This approach used a preliminary step intended to take only the significant characters used to code CCAM corresponding to anatomical and actions axes. RESULTS: According to the 7,926 CCAM codes used in this study, 5,212 possible matches (exact matching, single to multiple matching, partial matching) are found using the French CCAM to UMLS based mapping, 65% of the corresponding anatomical terms in the CCAM code are mapped to at least one UMLS Concept and 37% of the corresponding action terms in the CCAM code are mapped to at least one UMLS Concept. For all the exact matches found (n=200), 91% were rated by a human expert as narrower than the mapped UMLS Concepts, while only 3% were irrelevant. PMID- 20841843 TI - Implementing rules to improve the quality of concept post-coordination with SNOMED CT. AB - The use of SNOMED CT as a standard reference terminology enables interoperability between clinical systems. This reference tool provides a method for creating post coordinated terms by users according to local needs. While the creation of these terms is free, there are a number of rules, as defined in the user manual of SNOMED CT that must be followed.The Hospital Italiano of Buenos Aires has a Terminology Server that encodes medical terms, using SNOMED CT as the reference vocabulary. An interoperability analysis performed with the Nebraska Medical Center in 2006 found a high error rate (26%) in post-coordinated terms. Therefore, we implemented an automatic system of rules within the Terminology Server as defined in the user manual. Following rules implementation, the error rate decreased from 26% to 2%. PMID- 20841844 TI - A unified framework for biomedical terminologies and ontologies. AB - The goal of the OBO (Open Biomedical Ontologies) Foundry initiative is to create and maintain an evolving collection of non-overlapping interoperable ontologies that will offer unambiguous representations of the types of entities in biological and biomedical reality. These ontologies are designed to serve non redundant annotation of data and scientific text. To achieve these ends, the Foundry imposes strict requirements upon the ontologies eligible for inclusion. While these requirements are not met by most existing biomedical terminologies, the latter may nonetheless support the Foundry's goal of consistent and non redundant annotation if appropriate mappings of data annotated with their aid can be achieved. To construct such mappings in reliable fashion, however, it is necessary to analyze terminological resources from an ontologically realistic perspective in such a way as to identify the exact import of the 'concepts' and associated terms which they contain. We propose a framework for such analysis that is designed to maximize the degree to which legacy terminologies and the data coded with their aid can be successfully used for information-driven clinical and translational research. PMID- 20841845 TI - Enhancing a taxonomy for health information technology: an exploratory study of user input towards folksonomy. AB - The U.S. Agency for Healthcare Research and Quality has created a public website to disseminate critical information regarding its health information technology initiative. The website is maintained by AHRQ's Natiomal Resource Center (NRC) for Health Information Technology. In the latest continuous quality improvement project, the NRC used the site's search logs to extract user-generated search phrases. The phrases were then compared to the site's controlled vocabulary with respect to language, grammar, and search precision. Results of the comparison demonstrate that search log data can be a cost-effective way to improve controlled vocabularies as well as information retrieval. User-entered search phrases were found to also share many similarities with folksonomy tags. PMID- 20841846 TI - The DebugIT core ontology: semantic integration of antibiotics resistance patterns. AB - Antibiotics resistance development poses a significant problem in today's hospital care. Massive amounts of clinical data are being collected and stored in proprietary and unconnected systems in heterogeneous format. The DebugIT EU project promises to make this data geographically and semantically interoperable for case-based knowledge analysis approaches aiming at the discovery of patterns that help to align antibiotics treatment schemes. The semantic glue for this endeavor is DCO, an application ontology that enables data miners to query distributed clinical information systems in a semantically rich and content driven manner. DCO will hence serve as the core component of the interoperability platform for the DebugIT project. Here we present DCO and an approach thet uses the semantic web query language SPARQL to bind and ontologically query hospital database content using DCO and information model mediators. We provide a query example that indicates that ontological querying over heterogeneous information models is feasible via SPARQL construct- and resource mapping queries. PMID- 20841847 TI - Mapping BFO and DOLCE. AB - Upper level ontologies are key technology for integrating heterogeneous information coming from different sources. DOLCE and BFO, are the favorite candidates which propose rigorous foundational principles to model any domain. The objective of the AKENATON project is to improve alert management and to support patient-centered medical decision in telecardiology. This requires to integrate information transmitted by implantable cardiac devices with clinical data extracted from patient health records. To achieve this goal, we have designed an ontology of telecardiology based on DOLCE. In order to integrate ontologies based on BFO such as FMA, we have developed a framework for mapping BFO and DOLCE categories in terms of equivalence and subsumption between categories. PMID- 20841848 TI - Using the abstraction network in complement to description logics for quality assurance in biomedical terminologies - a case study in SNOMED CT. AB - OBJECTIVES: To investigate errors identified in SNOMED CT by human reviewers with help from the Abstraction Network methodology and examine why they had escaped detection by the Description Logic (DL) classifier. Case study; Two examples of errors are presented in detail (one missing IS-A relation and one duplicate concept). After correction, SNOMED CT is reclassified to ensure that no new inconsistency was introduced. CONCLUSIONS: DL-based auditing techniques built in terminology development environments ensure the logical consistency of the terminology. However, complementary approaches are needed for identifying and addressing other types of errors. PMID- 20841849 TI - Information-content-based measures for the structure of terminological systems and for data recorded using these systems. AB - Terminological systems such as SNOMED CT play an increasingly important role in contemporary record keeping. This drives the need of assessing the content of these systems, as well as the content of medical records captured using these systems. In this paper, the use of information content as a measure for the structure of terminological systems and the content in medical records is explored. Two complementary information-content-based measures for terminological systems are proposed: the proportion of concepts with zero information content, and the average information content. The measures are applied to the latest releases of SNOMED CT. The measures are useful as an indicator of the overall structure of terminological systems or parts thereof. Furthermore, two measures are described which can provide an estimate for the content of medical records that is captured using a terminological system. Information content is shown to provide a useful basis for assessing the structure of terminological systems and the content of medical records. PMID- 20841850 TI - Development of structured ICD-10 and its application to computer-assisted ICD coding. AB - This paper presents: (1) a framework of formal representation of ICD10, which functions as a bridge between ontological information and natural language expressions; and (2) a methodology to use formally described ICD10 for computer assisted ICD coding. First, we analyzed and structurized the meanings of categories in 15 chapters of ICD10. Then we expanded the structured ICD10 (S ICD10) by adding subordinate concepts and labels derived from Japanese Standard Disease Names. The information model to describe formal representation was refined repeatedly. The resultant model includes 74 types of semantic links. We also developed an ICD coding module based on S-ICD10 and a 'Coding Principle,' which achieved high accuracy (>70%) for four chapters. These results not only demonstrate the basic feasibility of our coding framework but might also inform the development of the information model for formal description framework in the ICD11 revision. PMID- 20841851 TI - Design and evaluation of a semantic approach for the homogeneous identification of events in eight patient databases: a contribution to the European EU-ADR project. AB - The overall objective of the EU-ADR project is the design, development, and validation of a computerised system that exploits data from electronic health records and biomedical databases for the early detection of adverse drug reactions. Eight different databases, containing health records of more than 30 million European citizens, are involved in the project. Unique queries cannot be performed across different databases because of their heterogeneity: Medical record and Claims databases, four different terminologies for coding diagnoses, and two languages for the information described in free text. The aim of our study was to provide database owners with a common basis for the construction of their queries. Using the UMLS, we provided a list of medical concepts, with their corresponding terms and codes in the four terminologies, which should be considered to retrieve the relevant information for the events of interest from the databases. PMID- 20841852 TI - The ObTiMA system - ontology-based managing of clinical trials. AB - Clinical Trial Management Systems promise to help researchers in managing the large amounts of data occurring in clinical trials. In such systems Case Report Forms for capturing all patient data can usually be defined freely for a given trial. But if database definitions are automatically derived from such trial specific definitions then the collected data cannot be easily compared to or integrated into other trials. We address this interoperability issue with an approach based on ontology and semantic data mediation. This resulted in the development of the ObTiMA system which is composed of a component for setting-up clinical trials and another for handling patient data during trials. Both components offer data reusability by relying on shared concepts defined in an ontology covering the whole cancer care and research spectrum. PMID- 20841853 TI - Querying the National Drug File Reference Terminology (NDFRT) to assign drugs to decision support categories. AB - INTRODUCTION: The accurate categorization of drugs is a prerequisite for decision support rules. The manual process of creating drug classes can be laborious and error-prone. METHODS: All 142 drug classes currently used at Regenstrief Institute for drug interaction alerts were extracted. These drug classes were replicated as fully-defined concepts in our local instance of the NDFRT knowledge base. The performance of these two strategies (manual classification vs. NDFRT based queries) was compared, and the sensitivity and specificity of each was calculated. RESULTS: Compared to existing manual classifications, NDFRT-based queries made a greater number of correct class-drug assignments: 1528 vs. 1266. NDFRT queries have greater sensitivity (74.9% vs. 62.1%) to classify drugs. However, they have less specificity (85.6% vs. 99.8%). CONCLUSION: The NDFRT knowledge base shows promise for use in an automated strategy to improve the creation and update of drug classes. The chief disadvantage of our NDFRT-based approach was a greater number of false positive assignments due to the inclusion of non-systemic doseforms. PMID- 20841854 TI - Visualization of disease distribution with SNOMED CT and ICD-10. AB - Methods for presentation of disease and health problem distribution in a health care environment rely among other things on the inherent structure of the controlled terminology used for coding. In the present study, this aspect is explored with a focus on ICD-10 and SNOMED CT. The distribution of 2,5 million diagnostic codes from primary health care in the Stockholm region is presented and analyzed through the "lenses" of ICD-10 and SNOMED CT. The patient encounters, originally coded with a reduced set of ICD-10 codes used in primary health care in Sweden, were mapped to SNOMED CT concepts through a mapping table. The method used for utilizing the richer structure of SNOMED CT as compared to ICD-10 is presented, together with examples of produced disease distributions. Implications of the proposed method for enriching a traditional classification such as ICD-10 through mappings to SNOMED CT are discussed. PMID- 20841855 TI - Ontology based modeling and execution of Nursing Care Plans and Practice Guidelines. AB - Nursing Care Plans (NCP) and Nursing Clinical Practice Guidelines (NCPG) promote evidence-based patient care, but in their paper form they are difficult to be applied at the point-of-care. We present our approach to generate patient specific nursing care plans by modeling and computerizing these nursing knowledge resources. We present a Nursing CarePlan Ontology (NCO) that models the NCP and NCPG to realize an integrated knowledge base for designing and executing patient specific nursing CarePlans. We adapted METHONTOLOGY methodology for ontology engineering to develop our OWL-based NCO, and instantiated a set of NCP and NCPG. We have developed an execution engine that provides recommendations to nurses based on the patient's data. NCO was successfully evaluated for representational accuracy and completeness using a set of test NCP and NCPG. PMID- 20841856 TI - Mapping ICNP Version 1 concepts to SNOMED CT. AB - The purpose of this study is to evaluate the ability of SNOMED CT to represent concepts of the ICNP Version 1 - the 7-Axis model. We selected the 1568 concepts of the ICNP 7-Axis model. From January 2007 through June 2007, the first author mapped the ICNP Version 1 concepts to the SNOMED CT using CLUE browser 5.0. The second author from the SNOMED Terminology Solutions and the third author from the ICN validated mapping result. In total, SNOMED CT covered 1381 concepts of 1658 (83%) ICNP 7-Axis model concepts ranging from 65% coverage rate of the Actions Axis concepts to 94% coverage rate of the Judgment Axis concepts. SNOMED CT can represent most (83%) of the ICNP Version 1 concepts. Improvements in ICNP Version 1 in terms of concept naming and definition, and adding missing concepts to the SNOMED CT would lead to greater coverage of the ICNP Version 1 concepts. PMID- 20841857 TI - Facilitating secondary use of medical data by using openEHR archetypes. AB - Clinical trials are of high importance for medical progress. But even though more and more clinical data is available in electronic patient records (EPRs) and more and more electronic data capture (EDC) systems are used in trials, there is still a gap which makes EPR / EDC interoperability difficult and hampers secondary use of medical routine data. The openEHR architecture for Electronic Health Records is based on a two level modeling approach which makes use of 'archetypes'. We want to analyze whether archetypes can help to bridge this gap by building an integrated EPR / EDC system based on openEHR archetypes. We used the 'openEHR Reference Framework and Application' (Opereffa) and existing archetypes for medical data. Furthermore, we developed dedicated archetypes to document study meta data. We developed a first prototype implementation of an archetype based integrated EPR / EDC system. Next steps will be the evaluation of an extended prototype in a real clinical trial scenario. Opereffa was a good starting point for our work. OpenEHR archetypes proved useful for secondary use of health data. PMID- 20841858 TI - The impact of a growing minority population on identification of duplicate records in an enterprise data warehouse. AB - Patient medical records are often fragmented across disparate healthcare databases, potentially resulting in duplicate records that may be detrimental to health care services. These duplicate records can be found through a process called record linkage. This paper describes a set of duplicate records in a medical data warehouse found by linking to an external resource containing family history and vital records. Our objective was to investigate the impact database characteristics and linkage methods have on identifying duplicate records using an external resource. Frequency counts were made for demographic field values and compared between the set of duplicate records, the data warehouse, and the external resource. Considerations for understanding the relationship that records labeled as duplicates have with dataset characteristics and linkage methods were identified. Several noticeable patterns were identified where frequency counts between sets deviated from what was expected including how the growth of a minority population affected which records were identified as duplicates. Record linkage is a complex process where results can be affected by subtleties in data characteristics, changes in data trends, and reliance on external data sources. These changes should be taken into account to ensure any anomalies in results describe real effects and are not artifacts caused by datasets or linkage methods. This paper describes how frequency count analysis can be an effective way to detect and resolve anomalies in linkage results and how external resources that provide additional contextual information can prove useful in discovering duplicate records. PMID- 20841859 TI - Record Linkage system in a complex relational database - MINPHIS example. AB - In the health sector, record linkage is of paramount importance as clinical data can be distributed across different data repositories leading to duplication. Record Linkage is the process of tracking duplicate records that actually refers to the same entity. This paper proposes a fast and efficient method for duplicates detection within the healthcare domain. The first step is to standardize the data in the database using SQL. The second is to match similar pair records, and third step is to organize records into match and non-match status. The system was developed in Unified Modeling Language and Java. In the batch analysis of 31, 177 "supposedly" distinct identities, our method isolates 25, 117 true unique records and 6, 060 suspected duplicates using a healthcare system called MINPHIS (Made in Nigeria Primary Healthcare Information System) as the test bed. PMID- 20841860 TI - Towards an implicit treatment of periodically-repeated medical data. AB - Temporal information plays a crucial role in medicine, so that in Medical Informatics there is an increasing awareness that suitable database approaches are needed to store and support it. Specifically, a great amount of clinical data (e.g., therapeutic data) are periodically repeated. Although an explicit treatment is possible in most cases, it causes severe storage and disk I/O problems. In this paper, we propose an innovative approach to cope with periodic medical data in an implicit way. We propose a new data model, representing periodic data in a compact (implicit) way, which is a consistent extension of TSQL2 consensus approach. Then, we identify some important types of temporal queries, and present query answering algorithms to answer them. We also sketch a temporal relational algebra for our approach. Finally, we show experimentally that our approach outperforms current explicit approaches. PMID- 20841861 TI - Achieving interoperability for metadata registries using comparative object modeling. AB - Achieving data interoperability between organizations relies upon agreed meaning and representation (metadata) of data. For managing and registering metadata, many organizations have built metadata registries (MDRs) in various domains based on international standard for MDR framework, ISO/IEC 11179. Following this trend, two pubic MDRs in biomedical domain have been created, United States Health Information Knowledgebase (USHIK) and cancer Data Standards Registry and Repository (caDSR), from U.S. Department of Health & Human Services and National Cancer Institute (NCI), respectively. Most MDRs are implemented with indiscriminate extending for satisfying organization-specific needs and solving semantic and structural limitation of ISO/IEC 11179. As a result it is difficult to address interoperability among multiple MDRs. In this paper, we propose an integrated metadata object model for achieving interoperability among multiple MDRs. To evaluate this model, we developed an XML Schema Definition (XSD)-based metadata exchange format. We created an XSD-based metadata exporter, supporting both the integrated metadata object model and organization-specific MDR formats. PMID- 20841862 TI - Verification & validation of the knowledge base for the hypertension management CDSS. AB - To implement a knowledge-based clinical decision support system for clinical information systems, it is crucial to verify and validate the knowledge base. This study developed and tested the hypertension management CDSS, named LIGHT. This study used a knowledge representation framework based on SAGE and developed a knowledge converter to translate knowledge encoded into the knowledge engine. To verify knowledge converted through the knowledge converter that is included in the knowledge representation framework, expected recommendations were made according to the knowledge encoded based on 201 test cases. The expected recommendations were compared to those generated by the knowledge engine. To validate the knowledge base, two physicians reviewed the test cases and made medication orders according to the knowledge base. These medication orders were compared to recommendations generated by the LIGHT. The concordance rates for compelling indication and absolute contraindication were 85% and 100%, respectively. Another senior physician reviewed and analyzed the discrepancy cases between the orders of the two other physicians and system recommendations. Accordingly, the authors conclude that the knowledge base for hypertension management became more accurate and practical through the testing process. PMID- 20841863 TI - A self-organizing map based morphological analysis of oral glucose tolerance test curves in women with gestational diabetes mellitus. AB - Gestational diabetes mellitus (GDM) makes women at risk of type 2 diabetes during their life. In order to predict this later abnormal glucose intolerance, several antepartum and postpartum predictors have been identified. In this study we conjecture that future evolution is predictable from morphology of the oral glucose tolerance test (OGTT) curves at baseline. To test our hypothesis, as a first step we evaluated the association between the curve morphologies of normal and diabetic patient condition at baseline. In particular, we analysed glucose and insulin curves of a group of women with a history of GDM. A Self-organizing map (SOM) was proposed to evaluate shape differences among control, normal, impaired glucose tolerance and diabetic curves shape. We compared our results with the currently applied clinical classification. We found that morphology contains information about the current status of the patient, because the SOM analysis clearly allows to discriminate subjects belonging to healthy or diabetic group. Moreover, SOMs highlighted additional information that could be used for prognostic purposes. PMID- 20841864 TI - Temporal clustering for blood glucose analysis in the ICU: identification of groups of patients with different risk profile. AB - Blood Glucose (BG) analysis and control in critically ill patients became an important research challenge in the last few years. Despite the big improvements that have been achieved both in research and in clinical practice, there are still many aspects that need to be elucidated. A first step towards a better comprehension of the phenomena underlying BG dynamics is represented by the study of retrospectively collected data. In this paper we propose an analysis of blood glucose time series through a combined temporal clustering and standard statistical analysis approach. The ultimate goal of the analysis is the identification of groups of patients showing different BG dynamics and evaluate their risk profiles, which is a very important issue in the Intensive Care Units. The method is applied to a set of patients treated at the Mediterranean Institute for Transplantation and Advanced Specialized Therapies in Palermo, Italy. We show that it is possible to identify two groups based on the initial blood glucose trends, and that the two groups significantly differ in terms of their future BG behaviour. PMID- 20841865 TI - A Markov chain probability model of glucose tolerance in post gestational diabetes follow up study. AB - Women with gestational diabetes mellitus (GDM) are at increased risk of developing type 2 diabetes (T2DM). However, the degree of risk and the timing of progression from normal to a pre-diabetic or diabetic state have not been clearly quantified. In this study we analyzed data from a longitudinal study on a group of women with a history of GDM, that were inserted in an oral glucose tolerance test (OGTT) annual screening program and followed up for 5 years after partum. A three state Markov chain model was proposed to represent the dynamics of changes between metabolic states. We used the data to empirically estimate the one-year transition parameters of the model and make predictions about the possibility that women with normal glucose tolerance or impaired glucose metabolism just after partum will develop overt T2DM in three or five years. Results show that subjects with an impaired glucose metabolism few months after partum will hardly (10%) be in the same state after three years. Women with normal glucose tolerance after partum will have a high probability (0.80) to be in the same state three years after. PMID- 20841866 TI - Development and validation of data specifications for nursing problems in maternal nursing care. AB - The aims of this study were to develop data specifications for nursing problems related to maternal nursing care and to test the applicability of those data specifications. First, we identified focus concepts and characterizing concepts of nursing problems by analyzing nursing-problem statements from nursing records, reviewing the literature, and interviewing experts. Second, we identified relationships between the focus concepts and characterizing concepts. Third, value sets of characterizing concepts were identified and types and cardinalities of the characterizing concepts were defined based on those value sets. Finally, data specifications were evaluated by a group of experts and by applying them to published case reports. The adequacy of the characterizing concepts and value sets, and the types and cardinalities of the characterizing concepts were validated. In total, 58 data specifications were developed with 53 characterizing concepts, relationships, and value sets. Their validity was established by the experts and by their application to case reports. The data specifications developed in this study can ensure that electronic health records contain meaningful and valid information, and support the semantic interoperability of nursing information. PMID- 20841867 TI - A model-driven approach for biomedical data integration. AB - A core challenge in biomedical data integration is to enable semantic interoperability between its various stakeholders as well as other interested parties. Promoting the adoption of worldwide accepted information standards along with common controlled terminologies is the right path to achieve this. Our paper describes a solution to this fundamental problem by proposing an approach to semantic data integration based on information models serving as a common language to represent health data coupled with technology that is able to represent the data semantics. We used the HL7 v3 Reference Information Model (RIM) [1] to derive a specific data model for the integrated data, the Web Ontology Language (OWL) [2] to build an ontology that harmonizes the metadata from the disparate data sources, the Unified Modeling Language (UML) [3] to model the data representation, and the Object Constraint Language (OCL) [4] to specify UML model constraints. To illustrate the approach, we use the Essential Hypertension Summary CDA document and related models from Hypergenes, a European Commission funded project [5] exploring the Essential Hypertension disease model. PMID- 20841868 TI - The need for standardised documents in continuity of care: results of standardising the eNursing summary. AB - Continuity of care is a concept that is defined as the uninterrupted and coordinated care provided to a patient and that includes an informational dimension which describes the information exchange between the parties involved. In nursing, the nursing summary is the main instrument to ensure informational continuity of care. The aim of this paper is to present an HL7 Clinical Document Architecture based document standard for the eNursing Summary and to discuss the need for harmonizing these results at international level. The eNursing Summary proposed in this paper was developed on the basis of several internationally accepted concepts, primarily the nursing process, the ISO 18104 Reference Terminology Model for Nursing and various data sets. The standardisation process embraced several phases of involving nursing experts for validating its structure and content. It was finally evaluated by a network of 100 healthcare organizations. We argue that the eNursing Summary is a good starting point for standardising nursing discharge and transfer documents on a global level. However, further work is needed to bring together the different national and international strands in standardisation. . PMID- 20841869 TI - Clinical task-specific query expansion for the retrieval of scientifically rigorous research documents. AB - To support the practice of evidence-based medicine (EBM), clinically relevant and scientifically sound articles should be easily accessible. Due to the huge volume of medical literature and the low performance of present retrieval models, clinicians could only get relevant documents in the order of publication time. This study propose a new clinical task-specific retrieval technique that improves retrieval accuracy by exploiting clinical task-specific EBM terms to query expansion using co-occurrence analysis technique. The idea is aimed at selecting query expansion terms that are relevant to a specific clinical-task using task specific EBM terms. Focusing on treatment and diagnosis tasks, the new method which was performed on the OHSUMED collection showed a further improved result than the existing method. PMID- 20841870 TI - Finding knowledge translation articles in CINAHL. AB - BACKGROUND: The process of moving research into practice has a number of names including knowledge translation (KT). Researchers and decision makers need to be able to readily access the literature on KT for the field to grow and to evaluate the existing evidence. METHODS: To develop and validate search filters for finding KT articles in the database Cumulative Index to Nursing and Allied Health (CINAHL). A gold standard database was constructed by hand searching and classifying articles from 12 journals as KT Content, KT Applications and KT Theory. MAIN OUTCOME MEASURES: Sensitivity, specificity, precision, and accuracy of the search filters. RESULTS: Optimized search filters had fairly low sensitivity and specificity for KT Content (58.4% and 64.9% respectively), while sensitivity and specificity increased for retrieving KT Application (67.5% and 70.2%) and KT Theory articles (70.4% and 77.8%). CONCLUSION: Search filter performance was suboptimal marking the broad base of disciplines and vocabularies used by KT researchers. Such diversity makes retrieval of KT studies in CINAHL difficult. PMID- 20841871 TI - Pediatric pain management knowledge linkages: mapping experiential knowledge to explicit knowledge. AB - The goal of this project is to augment clinician communication by connecting it to evidence-based research, providing explicit knowledge to corroborate the experiential knowledge shared between health care practitioners. The source of tacit knowledge sharing is the Pediatric Pain Mailing List (PPML), a forum for practicing clinicians to contact peers on the subject of pain in children. The messages, dating back to 1993, are processed for pertinent information and gathered together into threads. They are then parsed and connected to a set of MeSH keywords, which is used to search Pubmed and return a set of papers that correspond to the subject being discussed. The results are presented in an online forum, providing clinicians with an arena in which they can browse the archives of the PPML and connect those conversations to pertinent medical literature. PMID- 20841872 TI - Retrieving similar cases from the medical literature - the ImageCLEF experience. AB - An increasing number of clinicians, researchers, educators and patients routinely search for relevant medical images using search engines on the internet as well as in image archives and PACS systems. However, image retrieval is far less understood and developed compared to text-based searching. The ImageCLEF medical image retrieval task is an international challenge evaluation that enables researchers to assess and compare techniques for medical image retrieval using test collections. In this paper, we describe the development of the ImageCLEF medical image test collection, consisting of a database of images and their associated annotations, as well as a set of realistic search topics and relevance judgments obtained using a set of experts. 2009 was the sixth year for the ImageCLEF medical retrieval task and had strong participation from research groups across the globe. We will provide results from this year's evaluation and discuss the successes that we have had as well as challenges going forward. PMID- 20841873 TI - Computerization of a preanesthetic evaluation and user satisfaction evaluation. AB - Preanesthetic evaluation purpose is to reduce morbidity and mortality through the review of the patient's medical history, clinical examination, and targeted clinical studies, providing referrals for medical consultations when appropriated. Changes in patient care, standards of health information management and patterns of perioperative care, have resulted in a re-conceptualization of this process where the documentation of patient medical information, the efforts in training and maintaining the integrity of the medical-legal evaluation are areas of concern. The aim of this paper is to describe the design, development, training, and implementation of a computerized preanesthetic evaluation form associated to the evaluation of the user satisfaction with the system. Since the system went live in September 2008 there were 15121 closed structured forms, 60% for ambulatory procedures and 40 % for procedures that required hospital admission. 82% of total closed structured forms had recorded a risk of the procedures of 1-2, according to the American Society of Anesthesiologists classification. The survey indicates a positive general satisfaction of the users with the system. PMID- 20841874 TI - Usability of clinician order entry systems in Singapore: an assessment of end user satisfaction. AB - OBJECTIVES: To gather end-user feedback and evaluate factors that influence end user satisfaction of order entry systems used in the hospitals under National Healthcare Group, Singapore. DESIGN: Questionnaires were sent to a randomly selected group of 100 doctors and nurses. RESULTS & CONCLUSIONS: 52 doctors and nurses responded to the survey. The users' satisfaction with the clinical systems was average. (Mean satisfaction score is 3.85 on a scale of 1 to 7). Users generally agree that the systems could help reduce patient care errors and improve delivery of quality care to patients. System reliability, intuitive navigational capabilities and ease of use are strongly and positively correlated with user satisfaction. System response time however, is found to be strongly but negatively correlated with user satisfaction with a correlation coefficient of 0.717 (p<0.001). These findings suggest that more efforts should be made to improve these aspects in order to improve user satisfaction. These elements should also form important considerations in all future clinical systems development. PMID- 20841875 TI - Mini Stare-HI: guidelines for reporting health informatics evaluations in conference papers. AB - BACKGROUND: To improve the quality of reports of health informatics evaluations we recently devised and published a guideline named STARE-HI, now formally endorsed by IMIA. OBJECTIVE: To develop a prioritization framework of ranked items (a mini-STARE-HI) to assist authors when reporting health informatics evaluation studies in a restricted space conference paper. METHOD: We invited 111 editors of health informatics conference proceedings and reviewers and authors of health informatics evaluation studies to score 106 reporting items on a scale ranging from "0 - not necessary" through to "10 - essential" by a web-based survey. RESULTS: The response rate for the survey was 63% (70 out of 111). The most important items (score >9) were "Interpret the data and give an answer to the study question", "Whether it is a laboratory, simulation or field study" and "Description of the outcome measure/evaluation criteria". Four items had a mean score <6. CONCLUSION: It has been possible to produce a ranking of reporting items from STARE-HI according to their prioritized relevance for inclusion in space-limited conference papers. We believe that this prioritization framework can improve quality and utility of conference papers on health informatics evaluation studies. PMID- 20841876 TI - Formatively evaluating the importance of different aspects of an electronic blood transfusion system from the end users' point of view: a questionnaire study. AB - Blood transfusion is a process in which potential errors may result in serious adverse events to patients. To help improve the safety and efficiency of the blood transfusion process an electronic clinical transfusion management system is being piloted by NHS Connecting for Health. Evaluation of the implementation is being carried out in parallel. One component of the evaluation project aims to assess the importance placed in the various potential benefits of this new system by patients and healthcare workers. A questionnaire was generated and completed by healthcare workers and patients. Results indicate respondents viewing all factors as at least "important". "System" factors were deemed most important. Overall, clinical workers expressed the lowest importance to new process factors. Ultimately these results will be measured against final satisfaction with the system to assess 'fit' between perceived importance and satisfaction to guide areas for attention and resource allocation. PMID- 20841877 TI - Towards a National Health Information System evaluation. AB - Most EU Member States have a documented policy on eHealth. Documented follow-up and evaluation strategies for assessing whether national level systems have reached their set aims and outcomes are, however, rare. Methodologies for large scale information system assessment and evaluation are poorly established. This article describes the approach used to generate the Finnish National Health Information System (NHIS) evaluation plan. The core elements of the plan are illustrated, discussing also challenges and solutions in implementation. The article is based on NHIS evaluation planning project [15] and its presentation in the MIE workshop in Sarajevo in 2009 [16], where core issues and challenges of large-scale evaluations were discussed using the Finnish NHIS evaluation plan as a frame of reference.The Finnish plan offers other countries tools with which to assess their own plans and generate national methodologies for NHIS evaluation. PMID- 20841878 TI - Mapping stakeholders for system evaluation - the case of the Electronic Prescription Service in England. AB - This paper discusses the process of identifying stakeholders for the evaluation of health information systems through a map. Defining the multiplicity of stakeholders associated with a new system as well as the nature of their relationships is an important aspect of evaluating any intervention. We report a study of the Electronic Prescription Service (EPS) in primary care in England. We describe the complexity associated with the process of identifying stakeholders and illustrating their dynamic relationships. Reflecting upon our experience of map-making and map-using, we discuss the role of a stakeholder map to generate and communicate knowledge. The EPS stakeholder map - in its variety of possible alternative representations - reveals the complexity of the electronic prescribing scenario and the challenge of its evaluation. Recognising the drawbacks of a static two dimensional representation, we argue that a dynamic use of a stakeholder map and a reflective map-making practice is useful and important for the evaluation of IT programmes in healthcare. PMID- 20841879 TI - Development and testing of a work measurement tool to assess caregivers' activities in residential aged care facilities. AB - The introduction of computerized information systems into health care practices may cause changes to the way healthcare workers conduct their routine work activities, such as work flow and the time spend on each activity. To date the available work measurement tools are confined to activities in hospitals and do not cover residential aged care facilities (RACFs). There is little evidence about the effects of technology on caregivers' work practices, including the distribution of time on activities in a RACF. This requires the measurement of caregivers' activities using a valid and reliable measurement tool. The contribution of this research is to develop and test such a tool. The tool was developed based on literature research and validation in two RACFs. The final instrument contains 48 activities that are grouped into seven categories. They include direct care, indirect care, communication, documentation, personal activities, in-transit and others. This measurement tool can be used to measure the changes in caregivers' work activities associated with the introduction of computerized information systems in RACFs, including the efficiency gains of such systems. PMID- 20841880 TI - A multi-method approach to evaluate health information systems. AB - Systematic evaluation of the introduction and impact of health information systems (HIS) is a challenging task. As the implementation is a dynamic process, with diverse issues emerge at various stages of system introduction, it is challenge to weigh the contribution of various factors and differentiate the critical ones. A conceptual framework will be helpful in guiding the evaluation effort; otherwise data collection may not be comprehensive and accurate. This may again lead to inadequate interpretation of the phenomena under study. Based on comprehensive literature research and own practice of evaluating health information systems, the author proposes a multimethod approach that incorporates both quantitative and qualitative measurement and centered around DeLone and McLean Information System Success Model. This approach aims to quantify the performance of HIS and its impact, and provide comprehensive and accurate explanations about the casual relationships of the different factors. This approach will provide decision makers with accurate and actionable information for improving the performance of the introduced HIS. PMID- 20841881 TI - Why GPs do not follow computerized guidelines: an attempt of explanation involving usability with ASTI guiding mode. AB - Clinical decision support systems (CDSSs) have the potential to increase guideline adherence, but factors of success are not well understood. ASTI-GM is an on demand guideline-based CDSS where the user interactively characterizes her patient by browsing the system knowledge base to obtain the recommended treatment. We conducted a web-based evaluation of ASTI-GM as a before-after study to assess whether the system improves general practitioners' (GPs) performance and how they would use it. Five clinical cases had to be solved, as usual in the before phase, and using ASTI-GM in the after phase. On a 2-month period, 266 GPs participated and 1,981 prescription orders were collected. The overall guideline adherence rate increased from 27.2% to 64.3%. Only 56.4% of ASTI-GM uses corresponded to a "good use" of the system. Adherence increased from 28.5% to 86.1% in the sub-group of "good uses", whereas it only increased from 28.1% to 36.6% in the complementary sub-group. Reasons for non "good uses" of CDSSs should be investigated since they impede their potential impact. PMID- 20841882 TI - A qualitative analysis of Emergency Department physicians' practices and perceptions in relation to test result follow-up. AB - Follow-up of abnormal test results for discharged Emergency Department (ED) patients is a critical safety issue. This study aimed to explore ED physicians' perceptions, practices, and suggestions for improvements of test result follow-up when using an electronic provider order entry system to order all laboratory and radiology tests and view results. Interviews were conducted with seven ED physicians and one clinical information system support person. Interviews were analyzed to elicit key concepts relating to physicians' perceptions of test result follow-up and how the process could be improved. Results described the current electronic test result follow-up system with two paper-based manual back up systems for microbiology and radiology results. The key issues for physicians were: responsibility for test follow-up; the unique ED environment and time pressures, and the role of the family physician in test result follow-up. The key suggestion for improvement was a complete integrated electronic information system with on-line result endorsement. The study highlighted the complexity of the test result follow-up process and the importance of engaging clinicians in devising solutions for improvements. PMID- 20841883 TI - Evaluation methodology for automatic radiology reporting transcription systems. AB - This article describes a usability evaluation methodology for automatic transcription system used for radiology reporting. In order to assess this class of system's limitations and strengths, a review of the concepts involved in this kind of system is done in a critical way. Specific requirements, for this category of application, that are forgotten when a product is launched in the market, are listed and a methodology for their evaluation is presented. PMID- 20841884 TI - A new approach for goal-oriented analysis of healthcare processes. AB - The development of efficient e-services for patient-centered healthcare requires insight into concrete problems in administrative and clinical work processes as well as an understanding of the strategic goals that should guide these healthcare processes. However, considering both concrete process related problems and high-level strategic goals during process analysis and solution design can be problematic. To address this, we propose a structured approach for analyzing both high- and low-level goals in a healthcare process and relating these to identified problems. Thereby proposed solutions for each problem in form of, e.g. e-services can be connected to strategic goals. The approach consists of five steps; process modeling; process-based problem identification and classification; process goal identification; mapping to strategic goals; and solution proposal. The approach is illustrated by examples from a case study of Swedish stroke care. In conclusion, the approach enables analysis of high- and low-level goals in a healthcare process by relating these to identified problems. The results thereof form a basis for redefinition of current care processes, as well as for design of supporting e-health solutions. PMID- 20841885 TI - Implementation of a patient data management system - an evaluation study of workflow alterations. AB - This paper describes a combined evaluation approach for an information system on intensive care units. Staff self assessment of time needed for documentation activities during admission, daily treatment and discharge/transfer has been compared to a workflow analysis which demonstrated that the system eliminated process steps mainly in daily documentation activities. Interestingly, nursing staff reported major time savings rather during discharge/transfer than in daily documentation, whereas physicians noticed no time savings at all. We conclude that combining workflow analysis with either self assessment of time needed or alternatively appropriate time measurements or both increases insight into organizational changes and their implications after system implementation. PMID- 20841887 TI - Evaluation of methods for bolus arrival time determination using a four dimensional MRA flow phantom. AB - In this paper an evaluation of methods determining the bolus arrival time (BAT) using a four-dimensional flow phantom to simulate 4D MR angiography is presented. Spatiotemporal 4D MRA images were acquired for analyzing the hemodynamic characteristics of cerebral vessel anomalies. Model-independent and model dependent methods for BAT extraction are published. Generally, for the evaluation no gold standard exists and datasets with known BAT values are required. Here, a 4D flow phantom is generated based on a synthetic 3D MRA dataset with BAT values defining the time point of blood inflow for each voxel. Then, voxel-by-voxel concentration-time curves based on the gamma-variate function were computed leading to a simulated 4D MRA dataset. Additionally, partial volume effects and Gaussian noise were integrated. The simulated 4D MRA was visually inspected and regarded as similar to clinical data. Finally, phantom datasets with different vessel diameter and signal-to-noise ratio are computed. Three state-of-the-art methods were used to extract BAT values. Computed and known values were compared. The results suggest that model-dependent approaches perform better than the model independent method. PMID- 20841888 TI - Automatic analysis of the anatomy of arteriovenous malformations using 3D and 4D MRA image sequences. AB - The cerebral arteriovenous malformation (AVM) is an abnormal connection between arteries and veins without capillaries in between, leading to increased blood pressure which might result in a rupture and acute bleeding. Exact knowledge about the patient's individual anatomy of the AVM is needed for improved therapy planning. This paper describes a method for automatic extraction of the AVM and automatic recognition of its feeders and draining veins and en passage vessels based on 3D and 4D MRA image sequences. After registration of the MRA datasets the AVM is segmented using a support vector machine based on blood velocity information, a vesselness measure and the bolus arrival time. The extracted hemodynamic information is then used to detect feeders and draining veins of the AVM. The segmentation of the AVM was validated based on manual segmentations for five patient datasets, whereas a mean Dice value of 0.74 was achieved. The presented hemodynamic characterization was able to detect feeders and draining veins with an accuracy of 100%. In summary the presented approach can improve presurgical planning of AVM surgeries. PMID- 20841889 TI - A web service for enabling medical image retrieval integrated into a social medical image sharing platform. AB - Content-based visual image access is in the process from a research domain towards real applications. So far, most image retrieval applications have been in one specialized domain such as lung CTs as diagnosis aid or for classification of general images based on anatomic region, modality, and view. This article describes the use of a content-based image retrieval system in connection with the medical image sharing platform MEDTING, so a data set with a very large variety. Similarity retrieval is possible for all cases of the social image sharing platform, so cases can be linked by either visual similarity or similarity in keywords. The visual retrieval search is based on the GIFT (GNU Image Finding Tool). The technology for updating the index with new images added by users employs RSS (Really Simple Syndication) feeds. The ARC (Advanced Resource Connector) middleware is used for the implementation of a web service for similarity retrieval, simplifying the integration of this service. Novelty of this article is the application/integration and image updating strategy. Retrieval methods themselves employ existing techniques that are all open source and can easily be reproduced. PMID- 20841890 TI - Indexing the medical open access literature for textual and content-based visual retrieval. AB - Over the past few years an increasing amount of scientific journals have been created in an open access format. Particularly in the medical field the number of openly accessible journals is enormous making a wide body of knowledge available for analysis and retrieval. Part of the trend towards open access publications can be linked to funding bodies such as the NIH1 (National Institutes of Health) and the Swiss National Science Foundation (SNF2) requiring funded projects to make all articles of funded research available publicly. This article describes an approach to make part of the knowledge of open access journals available for retrieval including the textual information but also the images contained in the articles. For this goal all articles of 24 journals related to medical informatics and medical imaging were crawled from the web pages of BioMed Central. Text and images of the PDF (Portable Document Format) files were indexed separately and a web-based retrieval interface allows for searching via keyword queries or by visual similarity queries. Starting point for a visual similarity query can be an image on the local hard disk that is uploaded or any image found via the textual search. Search for similar documents is also possible. PMID- 20841891 TI - A Block-matching based technique for the analysis of 2D gel images. AB - Research at protein level is a useful practice in personalized medicine. More specifically, 2D gel images obtained after electrophoresis process can lead to an accurate diagnosis. Several computational approaches try to help the clinicians to establish the correspondence between pairs of proteins of multiple 2D gel images. Most of them perform the alignment of a patient image referred to a reference image. In this work, an approach based on block-matching techniques is developed. Its main characteristic is that it does not need to perform the whole alignment between two images considering each protein separately. A comparison with other published methods is presented. It can be concluded that this method works over broad range of proteomic images, although they have a high level of difficulty. PMID- 20841892 TI - Three-dimensional morphometric analysis of the distal femur: a validity method for allograft selection using a virtual bone bank. AB - Tumor excision is the primary treatment of aggressive or recurrent benign bone tumors and malignant bone sarcomas. This requires a surgical resection with the potential for large residual osseous defects that could be reconstructed using fresh frozen allografts. Virtual bone banks enable the creation of databases allowing a 3D pre-surgery evaluation of such allgorafts, based on segmentation of DICOM-CT images. This study demonstrates the usefulness of patient specific 3D models for an accurate host-donor allograft match. We describe one way to select the best match according to size and shape. The results suggest that a robust and reliable technique has been established. Since it is difficult to plan an allograft on a distal femur deformed by the tumor, we propose to plan the surgery on the contralateral side. Our results support this limb symmetry hypothesis. The use of this measurement protocol enables accurate selection of allografts from a contralateral healthy femur 3D CT model achieving the best match possible considering the geometry of available allograft candidate femur specimens. PMID- 20841893 TI - Using local context information to improve automatic mammographic mass detection. AB - Despite their promising application, current Computer-Aided Detection (CAD) systems face difficulties, especially in the detection of malignant masses -a major mammographic sign for breast cancer. One of the main problems is the large number of false positives prompted, which is a critical issue in screening programs where the number of normal cases is considerably large. A crucial determinant for this problem is the dependence of the CAD output on the single pixel-based locations initially detected. To refine the initial detection step, in this paper, we propose a novel approach by considering the context information between the neighbouring pixel features and classes for every initially detected suspicious location. Our modelling scheme is based on the Conditional Random Field technique and the mammographic features extracted by image processing techniques. In experimental study, we demonstrated the practical application of the approach and we compared its performance to that of a previously developed CAD system. The results demonstrated the superiority of the context modelling in terms of significantly improved accuracy without increase in computation efforts. PMID- 20841894 TI - The clinical research data repository of the US National Institutes of Health. AB - The US National Institutes of Health (NIH) includes 27 institutes and centers, many of which conduct clinical research. Previously, data collected in research trials has existed in multiple, disparate databases. This paper describes the design, implementation and experience to date with the Biomedical Translational Research Information System (BTRIS), being developed at NIH to consolidate clinical research data. BTRIS is intended to simplify data access and analysis of data from active clinical trials and to facilitate reuse of existing data to answer new questions. Unique aspects of the system includes a Research Entities Dictionary that unifies all controlled terminologies used by source systems and a hybrid data model that unifies parts of the source data models and include other data in entity-attribute value tables. BTRIS currently includes over 300 million rows of data, from three institutes, ranging from 1976 to present. Users are able to retrieve data on their own research subjects in identified form as well as deidentified data on all subjects. PMID- 20841895 TI - Scientific discovery workflows in bioinformatics: a scenario for the coupling of molecular regulatory pathways and gene-expression profiles. AB - Scientific workflow technologies and tools have become an important weapon in the arsenal of the bioinformaticians and computational biologists. To support this view we present a typical exploratory data analysis scenario involving the combination of information from Gene Regulatory Networks and gene expression data. We further describe the implementation of this scenario using the Workflow Environment implemented in the context of a large EU funded project. In this process desirable features that similar environments should offer are identified and analyzed. The ICT platform presented is evaluated using the chosen scenario as a benchmark. Finally we conclude with an outlook to future work. PMID- 20841896 TI - A framework for comparing phenotype annotations of orthologous genes. AB - OBJECTIVES: Animal models are a key resource for the investigation of human diseases. In contrast to functional annotation, phenotype annotation is less standard, and comparing phenotypes across species remains challenging. The objective of this paper is to propose a framework for comparing phenotype annotations of orthologous genes based on the Medical Subject Headings (MeSH) indexing of biomedical articles in which these genes are discussed. METHODS: 17,769 pairs of orthologous genes (mouse and human) are downloaded from the Mouse Genome Informatics (MGI) system and linked to biomedical articles through Entrez Gene. MeSH index terms corresponding to diseases are extracted from Medline. RESULTS: 11,111 pairs of genes exhibited at least one phenotype annotation for each gene in the pair. Among these, 81% have at least one phenotype annotation in common, 80% have at least one annotation specific to the human gene and 84% have at least one annotation specific to the mouse gene. Four disease categories represent 54% of all phenotype annotations. CONCLUSIONS: This framework supports the curation of phenotype annotation and the generation of research hypotheses based on comparative studies. PMID- 20841897 TI - Discovering novelty in sequential patterns: application for analysis of microarray data on Alzheimer disease. AB - Analyzing microarrays data is still a great challenge since existing methods produce huge amounts of useless results. We propose a new method called NoDisco for discovering novelties in gene sequences obtained by applying data-mining techniques to microarray data. METHOD: We identify popular genes, which are often cited in the literature, and innovative genes, which are linked to the popular genes in the sequences but are not mentioned in the literature. We also identify popular and innovative sequences containing these genes. Biologists can thus select interesting sequences from the two sets and obtain the k-best documents. RESULTS: We show the efficiency of this method by applying it on real data used to decipher the mechanisms underlying Alzheimer disease. CONCLUSION: The first selection of sequences based on popularity and innovation help experts focus on relevant sequences while the top-k documents help them understand the sequences. PMID- 20841898 TI - Designing a concept for an IT-infrastructure for an integrated research and treatment center. AB - Healthcare and medical research in Germany are heading to more interconnected systems. New initiatives are funded by the German government to encourage the development of Integrated Research and Treatment Centers (IFB). Within an IFB new organizational structures and infrastructures for interdisciplinary, translational and trans-sectoral working relationship between existing rigid separated sectors are intended and needed. This paper describes how an IT infrastructure of an IFB could look like, what major challenges have to be solved and what methods can be used to plan such a complex IT-infrastructure in the field of healthcare. By means of project management, system analyses, process models, 3LGM2-models and resource plans an appropriate concept with different views is created. This concept supports the information management in its enterprise architecture planning activities and implies a first step of implementing a connected healthcare and medical research platform. PMID- 20841899 TI - The REUSE project: EHR as single datasource for biomedical research. AB - Integrating biomedical research and patient care is a challenging issue requiring interoperability solutions. During a clinical trial, clinical data are captured twice, first in the Electronic Health Record (EHR) and then in the Clinical trials Data Management System (CDMS). The aim of REUSE (Retrieving EHR Useful data for Secondary Exploitation) project is to provide a single source solution for electronic data capture to the investigators of a university hospitals involved in a multi-centric clinical trial. We first investigated the differences between the workflows of patient care and biomedical research to specify the use of EHR for clinical trials. Then we defined a semantic interoperability framework in order to enable the reuse of EHR clinical data and implemented a mediator that transforms CDISC Operational Data Model (ODM) XML into proprietary XML document templates of different EHR solutions and vice-versa. Implementing electronic data capture for biomedical research within EHR eliminates redundant data entry, thus improving data quality and processing speed. Moreover, unlike other initiatives such as IHE integration profile "Retrieve Form for Data Capture" (RFD), the REUSE approach ensures that all clinical data is kept in the EHR whatever the context of data capture is. PMID- 20841900 TI - 10 years experience with pioneering open access publishing in health informatics: the Journal of Medical Internet Research (JMIR). AB - Peer-reviewed journals remain important vehicles for knowledge transfer and dissemination in health informatics, yet, their format, processes and business models are changing only slowly. Up to the end of last century, it was common for individual researchers and scientific organizations to leave the business of knowledge transfer to professional publishers, signing away their rights to the works in the process, which in turn impeded wider dissemination. Traditional medical informatics journals are poorly cited and the visibility and uptake of articles beyond the medical informatics community remain limited. In 1999, the Journal of Medical Internet Research (JMIR; http://www.jmir.org) was launched, featuring several innovations including 1) ownership and copyright retained by the authors, 2) electronic-only, "lean" non-for-profit publishing, 3) openly accessible articles with a reversed business model (author pays instead of reader pays), 4) technological innovations such as automatic XML tagging and reference checking, on-the-fly PDF generation from XML, etc., enabling wide distribution in various bibliographic and full-text databases. In the past 10 years, despite limited resources, the journal has emerged as a leading journal in health informatics, and is presently ranked the top journal in the medical informatics and health services research categories by impact factor. The paper summarizes some of the features of the Journal, and uses bibliometric and access data to compare the influence of the Journal on the discipline of medical informatics and other disciplines. While traditional medical informatics journals are primarily cited by other Medical Informatics journals (33%-46% of citations), JMIR papers are to a more often cited by "end-users" (policy, public health, clinical journals), which may be partly attributable to the "open access advantage". PMID- 20841901 TI - The IT-infrastructure of a biobank for an academic medical center. AB - For high quality research in biomedicine an operable biobank is essential. In order to make optimal use of the material and the huge amount of data a sustainable IT-infrastructure is indispensable. Therefore, we developed a concept for the IT-infrastructure of a biobank for an academic medical center. The conclusions for this concept are deduced from our experience with the biobank and IT-infrastructure of a clinical research unit. Our results indicate that the IT infrastructure plays a pivotal role in successfully establishing a biobank. Several aspects of the IT-infrastructure are similarly found in other areas as, e.g. data protection and storage and quality management. Finally, we conclude that although a research database is not required for operating a biobank, the need for it will definitely emerge, especially with regard to personalized medicine and high-throughput gene expression analysis. PMID- 20841902 TI - Reaching for the cloud: on the lessons learned from grid computing technology transfer process to the biomedical community. AB - Natural scientists such as physicists pioneered the sharing of computing resources, which led to the creation of the Grid. The inter domain transfer process of this technology has hitherto been an intuitive process without in depth analysis. Some difficulties facing the life science community in this transfer can be understood using the Bozeman's "Effectiveness Model of Technology Transfer". Bozeman's and classical technology transfer approaches deal with technologies which have achieved certain stability. Grid and Cloud solutions are technologies, which are still in flux. We show how Grid computing creates new difficulties in the transfer process that are not considered in Bozeman's model. We show why the success of healthgrids should be measured by the qualified scientific human capital and the opportunities created, and not primarily by the market impact. We conclude with recommendations that can help improve the adoption of Grid and Cloud solutions into the biomedical community. These results give a more concise explanation of the difficulties many life science IT projects are facing in the late funding periods, and show leveraging steps that can help overcoming the "vale of tears". PMID- 20841903 TI - A mobile phone based telemonitoring concept for the simultaneous acquisition of biosignals physiological parameters. AB - Congestive Heart Failure (CHF) is a common chronic heart disease with high socioeconomic impact. Conventional treatment of CHF is often ineffective and inefficient, since self-management is complex and patients are insufficiently involved in therapy management. With telemedical concepts, continuous monitoring of the health status can be ensured, and consequently therapy management can be adapted to the individual requirements of every individual patient. Therefore, a mobile phone based patient terminal for the concurrent acquisition of biosignals (e.g. ECG) and bioparameters (e.g. blood pressure) for patients with CHF has been developed and prototypically implemented. Usability and interoperability aspects were especially considered by using Bluetooth and Near Field Communication (NFC) technology for data acquisition and standardized data formats for transmission of the data to a central monitoring centre. Results indicated that even complicated measurements like the acquisition of ECG signals could be accomplished autonomously by the patients in an intuitive and easy-to-use way. Through the usage of IHE conform HL7 messages, self-measured data could easily be integrated into a higher-ranking eHealth infrastructure. PMID- 20841916 TI - Symmetry of platelet defects in diamond: new insights with synchrotron light. AB - Mapping of reciprocal space for Ia-type diamond single crystals with synchrotron radiation has uncovered a variety of diffuse scattering features, some of them have not been observed before. The main component of diffuse scattering in the form of diffuse rods corresponds to a set of platelets which join together blocks of diamond structure. The platelets are ordered structural entities with lattice periodicity 8(1/2)a(0) x (1/2)(1/2)a(0) x 0.55a(0), where a(0) is a unit-cell dimension of diamond. Intensity distribution along the rods has been measured and used for recognition of symmetry elements of the platelet structure. These findings, together with previously reported transmission electron microscopy (TEM) observations, provide strong constraints for atomistic modelling of the platelet structure. PMID- 20841917 TI - Single-crystal neutron diffraction investigation on crystals belonging to the langasite family: a comparative study. AB - Crystals of the langasite family are of interest as they are piezoelectric in different devices. The properties of these classes of crystals can be modified within certain limits by isomorphous substitution. Single-crystal neutron diffraction studies were carried out for LGT (La(3)Ga(5.5)Ta(0.5)O(14)), LGST (La(3)Ga(5.25)Ta(0.25)Si(0.5)O(14)) and LGZrT (La(3)Ga(5.25)Ta(0.25)Zr(0.5)O(14)) as the neutron study gives a better average picture of the crystal properties over a macroscopic region of the grown crystal. The effect of small substitutions at various sites on the piezoelectric properties of the crystal was studied. PMID- 20841918 TI - Bond catastrophes in rhodium complexes: experimental charge-density studies of [Rh(C7H8)(P(t)Bu3)Cl] and [Rh(C7H8)(PCy3)Cl]. AB - Rhodium complexes have potential uses in both catalysis and promoting the cleavage of C-C bonds. In order to further our understanding of these species and their potential applications, it is vital to obtain insight into the bonding within the species, particularly the Rh-C interactions, and to this end experimental charge-density studies have been undertaken on the title complexes. High-resolution single-crystal datasets to sin theta/lambda = 1.06 A(-1) were obtained at 100 K and analysed using Bader's 'Atoms in Molecules' (AIM) approach. The results of the studies have provided unique insights into the bonding involving rhodium and highlight the importance of undertaking such investigations for transition metal compounds. PMID- 20841919 TI - Experimental and predicted crystal structures of Pigment Red 168 and other dihalogenated anthanthrones. AB - The crystal structures of 4,10-dibromo-anthanthrone (Pigment Red 168; 4,10 dibromo-dibenzo[def,mno]chrysene-6,12-dione), 4,10-dichloro- and 4,10-diiodo anthanthrone have been determined by single-crystal X-ray analyses. The dibromo and diiodo derivatives crystallize in P2(1)/c, Z = 2, the dichloro derivative in P1, Z = 1. The molecular structures are almost identical and the unit-cell parameters show some similarities for all three compounds, but the crystal structures are neither isotypic to another nor to the unsubstituted anthanthrone, which crystallizes in P2(1)/c, Z = 8. In order to explain why the four anthanthrone derivatives have four different crystal structures, lattice-energy minimizations were performed using anisotropic atom-atom model potentials as well as using the semi-classical density sums (SCDS-Pixel) approach. The calculations showed the crystal structures of the dichloro and the diiodo derivatives to be the most stable ones for the corresponding compound; whereas for dibromo anthanthrone the calculations suggest that the dichloro and diiodo structure types should be more stable than the experimentally observed structure. An experimental search for new polymorphs of dibromo-anthanthrone was carried out, but the experiments were hampered by the remarkable insolubility of the compound. A metastable nanocrystalline second polymorph of the dibromo derivative does exist, but it is not isostructural to the dichloro or diiodo compound. In order to determine the crystal structure of this phase, crystal structure predictions were performed in various space groups, using anisotropic atom-atom potentials. For all low-energy structures, X-ray powder patterns were calculated and compared with the experimental diagram, which consisted of a few broad lines only. It turned out that the crystallinity of this phase was not sufficient to determine which of the calculated structures corresponds to the actual structure of this nanocrystalline polymorph. PMID- 20841920 TI - Conformational polymorphism in a Schiff-base macrocyclic organic ligand: an experimental and theoretical study. AB - Polymorphism in the highly flexible organic Schiff-base macrocycle ligand 3,6,9,17,20,23-hexa-azapentacyclo(23.3.1.1(11,15).0(2,6).0(16,20))triaconta 1(29),9,11,13,15(30),23,25,27-octaene (DIEN, C(24)H(30)N(6)) has been studied by single-crystal X-ray diffraction and both solid-state and gas-phase density functional theory (DFT) calculations. In the literature, only solvated structures of the title compound are known. Two new polymorphs and a new solvated form of DIEN, all obtained from the same solvent with different crystallization conditions, are presented for the first time. They all have P?bar 1 symmetry, with the macrocycle positioned on inversion centres. The two unsolvated polymorphic forms differ in the number of molecules in the asymmetric unit Z', density and cohesive energy. Theoretical results confirm that the most stable form is (II degrees ), with Z' = 1.5. Two distinct molecular conformations have been found, named 'endo' or 'exo' according to the orientation of the imine N atoms, which can be directed towards the interior or the exterior of the macrocycle. The endo arrangement is ubiquitous in the solid state and is shared by two independent molecules which constitute an invariant supramolecular synthon in all the known crystal forms of DIEN. It is also the most stable arrangement in the gas phase. The exo form, on the other hand, appears only in phase (II degrees ), which contains both the conformers. Similarities and differences among the occurring packing motifs, as well as solvent effects, are discussed with the aid of Hirshfeld surface fingerprint plots and correlated to the results of the energy analysis. A possible interconversion path in the gas phase between the endo and the exo conformers has been found by DFT calculations; it consists of a two-step mechanism with activation energies of the order of 30-40 kJ mol(-1). These findings have been related to the empirical evidence that the most stable phase (II degrees ) is also the last appearing one, in accordance with Ostwald's rule. PMID- 20841921 TI - Validation of experimental molecular crystal structures with dispersion-corrected density functional theory calculations. AB - This paper describes the validation of a dispersion-corrected density functional theory (d-DFT) method for the purpose of assessing the correctness of experimental organic crystal structures and enhancing the information content of purely experimental data. 241 experimental organic crystal structures from the August 2008 issue of Acta Cryst. Section E were energy-minimized in full, including unit-cell parameters. The differences between the experimental and the minimized crystal structures were subjected to statistical analysis. The r.m.s. Cartesian displacement excluding H atoms upon energy minimization with flexible unit-cell parameters is selected as a pertinent indicator of the correctness of a crystal structure. All 241 experimental crystal structures are reproduced very well: the average r.m.s. Cartesian displacement for the 241 crystal structures, including 16 disordered structures, is only 0.095 A (0.084 A for the 225 ordered structures). R.m.s. Cartesian displacements above 0.25 A either indicate incorrect experimental crystal structures or reveal interesting structural features such as exceptionally large temperature effects, incorrectly modelled disorder or symmetry breaking H atoms. After validation, the method is applied to nine examples that are known to be ambiguous or subtly incorrect. PMID- 20841922 TI - Charge density distribution in aminomethylphosphonic acid. AB - The experimental charge density distribution in aminomethylphosphonic acid has been determined from X-ray diffraction and its topological features have been analyzed. The results have shown that the P-O bonds are highly polarized, moreover the P-OH bond is weaker than the bonds to unprotonated O atoms. These facts have been confirmed by theoretical density functional theory (DFT) calculations, which have shown that the single, strongly polarized bonds within the phosphonate group are modified by hyperconjugation effects. PMID- 20841923 TI - Validation of experimental charge densities: refinement of the macrolide antibiotic roxithromycin. AB - Multipole refinements of larger organic molecules have so far been limited to a few exceptional cases. We report an investigation of the detailed experimental electron-density distribution (EDD) of roxithromycin, a macrolide antibiotic consisting of 134 atoms. Although the experimental multipole refinement on high resolution synchrotron data converged smoothly, validation of the electron density by calculation of an 'experiment minus invariom' difference density revealed conformational disorder of the H atoms. Hydrogen disorder is shown to affect the EDD, the electrostatic potential and atomic properties as defined by Bader's quantum theory of atoms in molecules. A procedure to obtain the electron density distribution in the presence of disorder is proposed. PMID- 20841924 TI - [Ocular disorders of anticancer drugs--ocular side effects]. AB - Although there are some sporadic reports about the ocular side effects (see below named ocular disorders) of anticancer drugs, extremely few well-organized reports have been published. We report have eye disorders caused by anticancer drugs on the ocular surface (eyelids, conjunctiva, cornea), retina, optic nerve, and sites of the lacrymal ducts. For disorders of the anterior ocular segment, we use gefitinib (Iressa(r)) and erlotinib (Tarceba(r)), cetuximab (Arbitax(r)) for trichomegaly while for lacrymal duct disorders and retinas with corneal problems revolt biochemistry, S-1 (TS-1(r)), erlotinib, docetaxel, paclitaxel and tamoxifen, paclitaxel, tamoxifen, optic neuropathy with 5-fluorouracil (5-FU), S 1 and docetaxel have been reported. Eye disorders can be relieved by discontinuation of the anticancer drug, but one may cause irreversible change, and early diagnosis and treatment are required. In future, there is a need for examinations for large-scale eye disorders due to anticancer drugs and their prevention (about S-1 in particular) including the provision of information to ophthalmologists. PMID- 20841925 TI - [Acquired disorders and epigenetics]. AB - Epigenetic modifications, involving DNA methylation and histone modifications, are maintained upon somatic cell replication, and are fundamental mechanisms for cellular memory. DNA methylation of promoter CpG islands of tumor-suppressor genes can silence their downstream genes, and can be causally involved in cancer development and progression. Since this effect is the same with that of inactivating mutations, the natures of DNA methylation were once considered to be similar to mutations. However, recently, it was revealed that a large number of epigenetic alterations are present in a single cancer cell, that a large number of cells have an epigenetic alteration of a specific gene in non-cancerous, thus polyclonal, tissues, that gene specificity in methylation induction is present according to tissue types and inducers, and that chronic inflammation is deeply involved in methylation induction. These facts suggest that epigenetic alterations of key genes involved in acquired chronic disorders can be present in a significant fraction of cells in a tissue, and thus can impair the function of the tissue. Associations between epigenetic alterations and behavior, memory, mental disorders, neurological disorders, metabolic disorders, allergy, autoimmune disorders, and other disorders have been reported. Further research in the field is necessary to clarify the causal roles of these epigenetic alterations in disease development, and to apply the findings to new strategies of disease prevention, diagnosis, and treatment. PMID- 20841926 TI - [Molecular mechanisms involved in epigenetic alterations in cancer]. AB - Epigenetic alterations such as DNA methylation and histone modification play a role in gene silencing in tumorigenesis. DNA methylation affects the expression of genes involved in cell cycle checkpoint, apoptosis, and DNA repair. Recently, epigenetic alterations are shown to play a role in silencing microRNA. Mutations of DNA methyltransferase and histone modification enzymes such as DNMT3A, UTX and EZH2 have been shown in various types of tumors. Genes involved in epigenetic regulation may be novel targets of cancer therapy in the near future. PMID- 20841927 TI - [Targeting epigenetics plasticity as a novel target for human neoplasia]. AB - Epigenetics mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in normal cells. Certain forms of histone methylation induce local heterochromatin formation, which is readily reversible, whereas DNA methylation leads to stable long-term repression. The precise epigenomic landscape present in normal cells undergoes extensive distortion in cancer. These characteristic epigenetic mechanisms are thought to be associated with tumor formation and progression. The reversible nature of epigenetic changes has led to the emergence of the field of epigenetic therapy, which may lead to potent and promising cancer treatment. PMID- 20841928 TI - [Promoter hypermethylation and CpG island methylator phenotype in colorectal carcinogenesis]. AB - Amino acid alterations or insufficient protein synthesis caused by the mutation on genes has long been recognized as the main mechanism of silencing of suppressor genes leading to carcinogenesis. However, epigenetic silencing of the cancer related genes induced by hyper-methylation of promoter is recognized as an additional important molecular mechanism for carcinogenesis. Differing molecular mechanisms of colorectal carcinogenesis have become known after advanced understanding of genes silenced by promoter methylation. PMID- 20841929 TI - [Development of HDAC inhibitors]. AB - In the mechanisms of carcinogenesis, it is becoming apparent that not only genetic abnormalities including DNA mutations, but also epigenetic abnormalities are heavily involved. Simultaneously, certain kinds of compounds indicated anti tumor activity through their epigenetic effects. Typical drugs, which have the epigenetic effects, are histone deacetylase(HDAC) inhibitors. So far, two types of HDAC inhibitors, vorinostat and romidepsin, are approved by the Food Drug Administration for cutaneous T-cell lymphoma in the U. S. A. Not only these two compounds but also many HDAC inhibitors are under clinical trials in monotherapy and combination therapy. For a better outcome, it is very important to establish the appropriate biomarkers and appropriate combination based on mode-of-action for HDAC inhibitors, similar to other molecular-target antitumor drugs. PMID- 20841930 TI - [A modified myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation, consisting of intravenous busulfan, cyclophosphamide and total lymphoid irradiation, in advanced leukemia]. AB - In nine patients with advanced acute or chronic leukemia, we performed allogeneic hematopoietic stem cell transplantation (HSCT) following a modified myeloablative conditioning regimen intended to optimize the intensity of conditioning. This regimen consisted of intravenous busulfan 8mg/kg, cyclophosphamide 120mg/kg and total lymphoid irradiation 7.5 Gy. The median age of the patients was 30 years (range 18-59). Stem cell sources were related bone marrow in two, related peripheral blood in one, and unrelated bone marrow in six patients. Prophylaxis against acute graft-versus-host disease (GVHD) was cyclosporine and short-term methotrexate. Acute GVHD appeared in six patients (67%), grade II in all. Extensive chronic GVHD occurred in three of seven evaluable patients. The median follow-up period after HSCT was 813 days (248- 1,702). Of nine patients, five relapsed or progressed after HSCT. However, no patient relapsed or progressed within 100 days after HSCT. During the full follow-up period, transplant-related mortality (TRM) was not observed. The two-year overall survival and event-free survival were 88.9% and 50.0%, respectively. Our results suggested that we might reduce the incidence of TRM and simultaneously control disease by using an optimized conditioning regimen for HSCT. PMID- 20841931 TI - [Comparative studies of paclitaxel injection "SAWAI" and Taxol(r) Injection on pharmacokinetics in dogs and in vitro/vivo antitumor activities]. AB - We performed bioequivalent assessments of the generic (Paclitaxel Injection "SAWAI") and branded (Taxol Injection) formulations of paclitaxel injection on pharmacokinetics in dogs and in vitro/vivo antitumor activities. In the pharmacokinetics study in dogs, the 90% confidence intervals (CIs) for the differences in logarithm of C(max) and AUC(0-48) were log (1.01) to log (1.17) and log (1.01) to log (1.08), respectively. These were within the bioequivalent criteria of log (0.80) to log (1.25). In the in vitro study, both products showed concentration-dependent inhibition of the growth of 5 cultured human cancer cell lines, MCF7 (breast adenocarcinoma), A2780 (ovarian carcinoma), A549 (lung carcinoma), MKN45 (gastric adenocarcinoma) and MKN74 (gastric adenocarcinoma). The 90% CIs for the differences in logarithm of half maximal inhibitory concentration (IC(50)) were log (0.876) to log (1.110), log (0.856) to log (1.097), log (0.977) to log (1.167), log (0.879) to log (1.093) and log (0.936) to log (1.081), respectively. These were within the bioequivalent criteria. In the in vivo study, both products showed concentration-dependent inhibition of the growth of 3 human cancer cells, A2780 (ovarian carcinoma), A549 (lung carcinoma) and MDA-MB-231 (breast adenocarcinoma), xenografted in nude mice. And there are no significant differences between Paclitaxel Injection "SAWAI" and Taxol Injection. These results showed that Paclitaxel Injection "SAWAI" is bioequivalent to Taxol Injection. PMID- 20841932 TI - [A retrospective study of carboplatin and weekly paclitaxel combination chemotherapy for elderly patients with advanced non-small cell lung cancer]. AB - OBJECTIVE: To perform a retrospective analysis of carboplatin (CBDCA) and weekly paclitaxel (PTX) combination chemotherapy for elderly patients with unresectable non-small cell lung cancer (NSCLC) in order to evaluate both treatment efficacy and toxicity. SUBJECTS: 48 patients aged more than 70 years with non-resectable NSCLC who received CBDCA+weekly PTX from January 2001 to March 2008. RESULTS: The median age of the patients (32 male, 16 female) was 74 years. Patients received 1 6 courses of this chemotherapy (median 4 courses). The overall response rate, time to progression, median survival time and 1-year survival rate was 51%, 183 days, 411 days and 52%, respectively. With regard to toxicity, grade 3-4 neutropenia was observed in 38% of patients and anemia in 25% of the patients, and 29% of the patients had grade 2 and above periferal nerve disorder. CONCLUSION: This regimen showed a good response and was safe for elderly patients with advanced NSCLC, but a high incidence of neuropathy was observed. PMID- 20841933 TI - [Bi-weekly docetaxel and doxifluridine combination therapy in pretreated patients with unresectable and/or advanced gastric cancer]. AB - We report an investigation of the therapeutic efficacy and safety of combination chemotherapy with docetaxel (DOC) and doxifluridine (5'-DFUR) administered as second-line or third-line chemotherapy in 23 cases of unresectable and/or advanced gastric cancer. Treatment consisted of intravenous DOC (40mg/m/2) on day 1 and 15, and oral 5'-DFUR (600mg/body) on days 1 to 28 every 4 weeks. The response rate for its antitumor efficacy was 17.4 %, with partial response in 4 cases, no change in 6 cases, progressive disease in 12 cases, and one case not evaluable. By site, the response rate was 11. 8% for primary tumors (2/17), 33.3% for lymph nodes (3/9) , and 26.9% for liver metastasis (1/7). Median time to treatment failure was 2.6 months, median overall survival was 4.6 months. The one year survival rate was 26.1 %, and the two-year survival rate was 13.0%. The most common grade 3 to 4 toxicities were neutropenia( 4.3%), fatigue (8.7%), stomatitis (8.7%), anorexia(4.3% ), and rash (4.3%). Our data suggest that the combination of docetaxel and 5'-DFUR has a promising therapeutic index in patients with unresectable advanced gastric cancer as second-line or third-line chemotherapy. PMID- 20841934 TI - [European Organization for Research and Treatment of Cancer QLQ-C30 and functional assessment of cancer therapy- general for measurement of quality of life in colorectal cancer patients who received adjuvant chemotherapy- a comparison]. AB - Quality of life (QOL) was measured prospectively using the European Organization for Research and Treatment of Cancer QLQ-C30 (QLQ-C30) and Functional Assessment of Cancer Therapy-General (FACT-G) in 94 colorectal cancer patients who received adjuvant chemotherapy with oral uracil/tegafur plus leucovorin. Two QOL questionnaires were then compared with reference to corresponding scales. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all scales except social well-being of the FACT-G. All scales except social well-being in patients with Grade 0-1 toxicities were better than those with Grade 2-3 toxicities. Social well-being in patients with Grade 2 3 toxicities were worse than those with Grade 0-1. When corresponding scales between the two QOL questionnaires were compared, a high correlation for physical domain or emotional domain was found, whereas no correlation was noticed for social domain. In conclusion, the social domain of the two QOL questionnaires may evaluate different aspects of QOL. PMID- 20841935 TI - [Pharmacokinetic study of S-1 for the treatment of peritoneal metastasis from colon cancer--using a mouse peritoneal metastasis model]. AB - OBJECTIVE: To investigate the usefulness of S-1 for the treatment of peritoneal metastasis from colon cancer using a colon cancer peritoneal metastasis model. METHODS: Colon 26 PMF-15 cells were transplanted intraperitoneally into mice. The concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) in the plasma and peritoneal tissue of the mice were determined at 6 sampling time points, i. e., pre-dosing and at 30min, 1, 2, 4 and 8 hrs after oral administration of S-1 (10mg/kg equivalent of FT) on day 20 post-transplantation. RESULTS: The AUC0-8h values of both 5-FU and CDHP were greater in the peritoneal tumor tissue than in the normal peritoneal tissue. The AUC of 5-FU in the peritoneal tumor tissue was 2. 90 times higher than that in plasma. CONCLUSION: The results suggest that S-1 may exert an antitumor effect on peritoneal metastasis arising from colon cancer and be potentially useful as a therapeutic agent in cases of colon cancer with peritoneal metastasis, which is generally recognized as carrying an unfavorable prognosis. PMID- 20841936 TI - [Adverse events in patients treated with capecitabine as adjuvant chemotherapy after surgery for colorectal cancer--countermeasures against hand-foot syndrome]. AB - Although the 2009 edition of the Guidelines for Colorectal Cancer Therapy recommend capecitabine as a standard postoperative adjuvant chemotherapy for colorectal cancer therapy, a characteristic adverse event, hand-foot syndrome, develops at a high incidence, and appropriate management is necessary to continue therapy. We investigated countermeasures against adverse events, particularly hand-foot syndrome, in patients treated with capecitabine. The subjects were 47 patients aged 64 years (27-84 years) who underwent surgery for colorectal cancer. They received 8 (2-16) courses of drug administration. No grade 3 blood or non blood toxicity was noted, and the therapy was relatively safe excluding an enhanced anticoagulant effect. Grade-3 hand-foot syndrome developed in 3 patients, but there were only 10 grade-2/3 cases (21.7%) because humectants and oral vitamin B6 preparation (supportive therapy) were administered from therapy initiation. The incidence increased to 32.6% (15 patients) after June. Symptoms aggravated due to mechanical stimulation of the hands and legs in 5 patients because they were farmers growing cherries, suggesting that investigation of patient living background is also important. The incidence of grade-2/3 hand-foot syndrome was 21.1 and 75% in 39 and 8 patients, respectively, who were treated with supportive therapy from the initiation of drug administration and after several courses of drug administration or development of symptoms. This suggested the usefulness of early supportive therapy. The importance of preventive measures against hand-foot syndrome will increase as capecitabine is increasingly administered. Information exchange between medical staffs and providing patients with appropriate information may lead to management of adverse events and subsequently to continuation and obtaining effects of therapy. PMID- 20841937 TI - [Optic lesions in patients with epiphora during S-1 therapy]. AB - PURPOSE: To elucidate the features of optic lesions in patients with epiphora during S-1 therapy. PATIENTS: Twelve patients with epiphora in 123 patients during S-1 therapy. RESULTS: Age range was 38-84 years (mean 68.4 years). There were 4 cases in 81 men (5%) and 8 in 42 women (19%). Epiphora occurred significantly more often in women (p=0.02). The administration period was from 10 days to 36 months. Lesions were superficial punctate keratopathy in 10 cases with cornea and obstruction of inferior punctum in 2, stenosis of nasolacrimal duct in 1 and suspected occlusion of the nasolacrimal duct in 1 with lacrimal duct. Local therapy was eye drops in all cases. Of the whole 12 patients, S-1 was continued or discontinued in 6 each of all 12 cases, in 5 each of 10 cases with superficial punctate keratopathy, and in 2 each of 4 cases with lacrimal duct lesions. Epiphora/optic lesions improved with a range from 10 days to 1.5 months in cases of discontinuation and with that from 2 weeks to 1 month in cases of continuation. DISCUSSION: Our results revealed superficial punctate keratopathy in many cases, lacrimal duct lesions in a few cases, and discontinuation of medication provided improvement of optic events. CONCLUSIONS: When epiphora is observed in patients on S-1 therapy, it is necessary to assess optic disorders by an opthalmologist immediately because of suspicion of injury to the cornea and lacrimal duct. PMID- 20841938 TI - [Preventing dermatopathy of patients receiving cancer chemotherapy]. AB - Anticancer drug-associated dermatopathy tends to be disregarded because of its small systemic influence. However, it may affect daily living activities, and mental distress due to its appearance may interfere with the continuation of therapy. In this study, we surveyed the state of skin care, and found that patients had anxiety over vomiting and depilation rather than dermatopathy. Patients who developed dermatopathy performed skin care, but none performed preventive skin care. For patients to perform skin care to prevent adverse effects, we provided information on appropriate self-skin care methods based on pharmaceutical management/instruction and instruction in an outpatient chemotherapy room using documents. On conducting the second questionnaire survey after providing information, 74.3% of patients answered that information provided by pharmacists was useful. Since skin care is a form of self-care, it is necessary to continuously provide information to support patients. PMID- 20841939 TI - [A phase II clinical study of once-a-day fentanyl citrate patch in patients with cancer pain--switching from once-every-three-days fentanyl patch to once-a-day fentanyl citrate patch]. AB - We examined the efficacy and safety of a new transdermal fentanyl citrate patch (HFT-290), which was applied once daily in patients with cancer pain who were receiving a stable dose of once-every-three-day application transdermal fentanyl patch [TDF (72 hr)]. After TDF (72 hr) was applied for three days at the same dose used before starting the study, treatment was switched to HFT-290 (once daily) for 9 days. The analgesic effect was judged with a 5-point scale based on each patient's assessment of pain on a 100-mm visual analog scale (VAS). Seventy eight patients were enrolled. The efficacy rate (95% confidence interval) of the analgesic effect at the time of final removal of HFT-290 (the primary efficacy end-point) was high at 83.9% (71.7-92.4%; 47/56 patients). Furthermore, based on the shift of the VAS, good pain control was achieved after switching. All adverse drug reactions were either mild or moderate, and the main reactions were those commonly observed with opioid analgesics. No respiratory depression was observed. HFT-290 demonstrated good tolerability after switching from TDF (72 hr) and provided stable pain control. PMID- 20841940 TI - [Availability evaluation of closed systems by using practical training kits for preparation of antitumor drugs]. AB - The recent guidelines of the Japanese Society of Hospital Pharmacists on the antitumor drug preparation have recommended the use of closed systems such as the PhaSeal(r) system for preventing cytotoxicity in health care workers involved in the preparation of these drugs. The PhaSeal(r) system and Clave(r) Oncology system were evaluated using a practical training kit for the preparation of antitumor drugs. The two systems were compared in terms of handling time, satisfaction as to availability, leakage of drugs from the connections in the system and area of drug spillage because improvements in convenience or lower cost system were available. With the closed systems, the average handling time increased by 10~20%. The area of drug spillage did not significantly decrease. Leakage of drugs from the system was detected for all samples prepared with the Clave(r) Oncology system, and for some samples prepared with the PhaSeal(r) system. In terms of availability, the PhaSeal(r) system was better than the Clave(r) Oncology system. In conclusion, to decrease the exposure of health care workers to antitumor drugs during their preparation in a closed system, it is important to evaluate the handling time, operability, robustness with regard to drug leakage and spillage, and proficiency in handling of the closed system. PMID- 20841941 TI - [A case with parotid carcinoma showing a pathologically complete response after treatment with S-1 alone]. AB - We report a 57-year-old male case of adenocarcinoma of the parotid gland with metastases to the cervical lymph nodes (T3N2bM0, Stage IV A). S-1 was administered at the conventional dose of 120mg/day for 4 weeks followed by a 2 week rest. After 4 courses of S-1, PET findings showed a remarkable regression of the tumor resulting in a partial response (PR) for the primary lesion. After this treatment, partial parotidectomy and upper neck dissection were performed. The histological effect was Grade 3. PMID- 20841942 TI - [Combination chemotherapy of S-1, docetaxel and CDDP produces a remarkable response in a patient with metastases of supraclavicular lymph nodes and gingival carcinoma of the mandible]. AB - We report a 53-year-old female patient with an unresectable metastasis to the supraclavicular lymph node from a primary gingival carcinoma of the mandible. The patient had a history of tongue carcinoma and had undergone a radical neck dissection for the treatment of gingival carcinoma. She underwent combined chemotherapy consisting of S-1 (80 mg on days 1-14, followed by a 7-day rest), docetaxel (35mg/m2 by intravenous infusion on days 1 and 8), and CDDP (10mg/m2 by intravenous infusion on days 1 and 8) every 3 weeks. After three courses of the above chemotherapy regimen, a computerized tomography examination revealed a complete response. The patient did not experience any severe side effects during the course of chemotherapy. Combined S-1, docetaxel, and CDDP chemotherapy can thus be effective for unresectable recurrences of oral cancer in lymph nodes. PMID- 20841943 TI - [A case of small cell carcinoma arising in submandibular gland]. AB - The patient was a 53-year-old male. He presented with swelling of the left submandibular region. Histopathological examination of a biopsy specimen showed small cell carcinoma. Computed tomography (CT) and bone scintigraphy revealed multiple liver, bone and lymph node metastases. He was diagnosed with small cell carcinoma of the submandibular gland with multiple metastases, Stage IV. Systemic chemotherapy consisting of CPT -11 plus CDDP as first-line and amrubicin as second-line therapy was given. Once CT showed a partial response of the tumors, but he passed away after about 10 months. Small cell carcinoma arising in the submandibular gland is extremely rare, and there are few clinical reports. PMID- 20841944 TI - [A case of gallbladder cancer which completely responded to gemcitabine]. AB - A 7 9-year-old man with advanced gallbladder cancer (stage IVa) underwent chemotherapy with single-agent gemcitabine (1,400mg/body: day 1, 8, 15, every 4 weeks) as first-line chemotherapy. As soon as the chemotherapy started, the carbohydrate antigen 19-9 (CA19-9) level was notably reduced, and after 4 courses, CT scan revealed that the tumor was markedly reduced in size. We thought he could undergo curative operation, and performed and extended cholecystectomy and lymph node dissection. Intraoperative findings revealed that the gallbladder atrophied and, with no obvious invasion to adjacent organs, a small hard mass like only fibrosis was confirmed. Then, 18 days after the operation, he was discharged without any complication. In the histological findings, cancer tissue was replaced by fibrosis, and malignant cells could not be detected. Now the patient has remained well without recurrence after 6-month follow-up. Many clinical trials show that gemcitabine, which is used as a single agent or combined with other agents (for example, cisplatin), demonstrated high efficacy with manageable toxicity in patients with advanced or metastatic biliary tract cancer. For this disease, including gallbladder cancer, gemcitabine is the mainstay of chemotherapy, and it is thought that this agent could have high efficacy in many cases. PMID- 20841945 TI - [S-1+gemcitabine (GEM) therapy effective in a case of pancreatic body cancer with multiple liver metastasis]. AB - OBJECTIVE: The prognosis for pancreatic cancer with distant metastases is not good. The case reported here is of pancreatic body cancer with multiple liver metastasis in which S-1+gemcitabine (GEM) therapy proved to be effective. CASE: A 77-year old female. She was asymptomatic and diagnosed as a pancreatic body cancer with multiple liver metastases at the end of December 2008 by periodical ultrasonography. After careful examination, GEM 1,200mg/body was administered on days 1 and 15, and S-1 was administered orally at 80mg/day for two weeks, followed by two weeks rest. Currently, at the end of the 10th course, tumor size has been reduced from 26.5mm to 18.9 mm, and two of the five liver metastatic lesions have disappeared, while the remaining three liver lesions have been revealed as scars by CT examination. Tumor marker levels have been remarkably decreased. Ten months from the initial diagnosis, there has been no side effect and chemotherapy is being continued. CONCLUSION: In pancreatic cancer with distant metastases, S-1+GEM therapy may be able to provide a long-term prognosis. PMID- 20841946 TI - [A case report of advanced gallbladder cancer with multiple liver metastases effectively treated by concentrated therapy with S-1]. AB - A 65 -year-old male was admitted to our hospital because of epigastregia. Computed tomography (CT) and abdominal ultrasonography (AUS) revealed advanced gallbladder cancer and two S5 liver metastases. Selective gallbladder angiogram revealed his cystic vein was draining into the portal vein (P5), so cholecystectomy and S4a+S5-subsegmentectomy were performed. Pathological study of the resected specimens showed three liver metastases. After surgical resection lumbar metastasis was suspected, so radiotherapy and UFT at 300mg/day were started. Next, we started oral administration of S-1 alone (100mg/body) for 4 weeks followed by a 2-week rest period as one course. 100mg/day was changed to 80mg/body after 3 courses because of grade 2 neutropenia. A total of 31 courses of S-1 80mg/day were administered postoperatively for five years. The patient is alive and free of disease five years and ten months after the operation. PMID- 20841947 TI - [Acute liver injury with hepatic encephalopathy associated with gemcitabine administration for adjuvant chemotherapy in an HBV carrier with pancreatic cancer]. AB - A 75-year-old woman was admitted to our department because of epigastric pain. Imagings revealed cancer of the head of the pancreas. She was an HBV carrier, although no liver dysfunction was observed. Her serum HBV-DNA level was lower than 2.6. We performed pancreaticoduodenectomy for pancreatic cancer. No postoperative complication was observed. The histopathological diagnosis was tubular adenocarcinoma of the pancreas. As a postoperative adjuvant chemotherapy, gemcitabine hydrochloride (GEM) was injected at a dose of 800mg/m2 once a week. Disorientation and jaundice were observed after six doses of GEM. Blood chemistry revealed that total bilirubin and ammonia were abnormally elevated, and that blood coagulant factors were diminished. Serum HBV-DNA level was lower than 2.6. It showed no reactivation of HBV. Abdominal CT showed no recurrence but fatty liver. Fresh frozen plasma was supplied and branched chain amino acids were injected after GEM was administration discontinued. Lactulose was also given orally. With these conservative treatments, she recovered completely. Careful monitoring of liver function during GEM administration is required in a HBV carrier. PMID- 20841948 TI - [A case of SIADH developed during neoadjuvant chemotherapy using nedaplatin and 5 fluorouracil in a patient with esophageal cancer]. AB - A 77-year-old male with thoracic esophageal cancer (cT3N3M0, Stage III) received nedaplatin at 80mg/m2 for 1 day and 5-fluorouracil at 800mg/m2 for 5 days as neoadjuvant treatment. On the fifth day of treatment, he lapsed into a coma (Japan Coma Scale 30), and his serum sodium concentration was found to be decreased to 116mEq/L. We concluded hyponatremia due to SIADH (syndrome of inappropriate secretion of antidiuretic hormone) induced by chemotherapy based on the fact that the patient had no finding of dehydration, particular history of related disorders, serum hypoosmolality accompanied by urine hyperosmolality and persistent urinary sodium excretion. We treated him with fluid restriction, sodium supplement and administration of loop diuretic. Then he regained consciousness and appropriate serum sodium level. Thereafter, hyponatremia was corrected without recurrence, and the patient underwent radical esophagectomy safely. He has been in good condition without recurrence of esophageal cancer after surgery. PMID- 20841949 TI - [A case of bisphosphonate-associated osteonecrosis of the jaw in a patient with bone metastasis of breast cancer]. AB - A 5 6-year-old woman underwent modified radical mastectomy for left breast cancer in 2002. Bone metastases developed in November 2005, and she received pamidronate from February 2006. Pamidronate was changed to zoledronate in November 2006. In November 2007, she was referred to a dentist for pain and swelling of the right lower gum. Conservative therapy with local irrigation and antibiotics was performed, but the lesion progressed and showed ulceration with exposed bone. She was diagnosed as bisphosphonate-associated osteonecrosis of the jaws, and zoledronate was withdrawn in January 2008. Conservative therapy was continued but the necrotic lesion caused pathological fracture and fistula. In February 2009, surgical intervention was performed for the improvement of her QOL. PMID- 20841950 TI - [Problems with topical use of Mohs paste for local recurrence of breast cancer]. AB - Recently, several reports have been made concerning topical use of Mohs paste for local recurrence of breast cancer tumors. Since January 2008, after the introduction of Mohs paste for palliation in patients with local recurrences of breast cancer, we have encountered some problems such as pain, draining off of the paste and ulceration of the lesion. In this study, we have reported the advantages and disadvantage of using Mohs paste, the difference in the procedure depending on the purpose, and the management of problems. When using Mohs paste for the purpose of palliative therapy, these side effects are problems we should not ignore to prevent patient pain. PMID- 20841951 TI - [A case of solitary splenic metastasis from an ovarian cancer 12 years after primary resection]. AB - A 57-year-old woman underwent total hysterectomy and bilateral salpingo oophorectomy for bilateral ovarian tumors (T1b, N0, M0; Stage I b, serous cystoadenocarcinoma) in May 1994. She received 4 courses of CAP (cyclophosphamide 500 mg/m2+epirubicin 50 mg/m2+cisplatin 60 mg/m2) therapy as adjuvant chemotherapy. An increase of the serum CA125 was detected in December 2006, and abdominal CT revealed a mass in the spleen. Since whole-body FDG-PET-CT showed no evidence of local recurrence of the ovarian cancer or multiple organ metastases, a solitary splenic metastasis from ovarian cancer, even though very rare, was strongly suspected. Splenectomy with distal pancreatectomy was undertaken in December 2007. Histopathological examination revealed poorly-differentiated adenocarcinoma, suggesting the final diagnosis of solitary splenic metastasis from ovarian cancer. Periodic CA125 measurements are considered very important even over 10 years after surgery for ovarian cancer. Once solitary splenic metastasis is diagnosed, surgical resection would be the treatment of choice. PMID- 20841952 TI - [Two cases of colorectal cancer presenting with periodic, transient elevation of serum iron due to hemolysis after chemotherapy including 5-FU]. AB - The serum iron level reportedly shows transient elevation after chemotherapy in some cases. However, the cause of this phenomenon has not been clearly described. We report two cases of colorectal cancer whose serum iron level demonstrated recurrent elevation after chemotherapy. Both were advanced colorectal cancer cases with liver metastases, so we started chemotherapy with modified FOLFOX6+bevacizumab. After several courses, we changed the regimen to simplified LV5FU2+ bevacizumab in both cases. The serum iron level showed transient, periodical elevation irrespective of the therapeutic regimen. Additionally, indirect bilirubin also showed transient elevation, which was completely synchronized with the fluctuation of the serum iron level. These observations suggest that hemolysis is the main cause of periodic, transient elevation of serum iron level after chemotherapy including 5-FU. PMID- 20841953 TI - [A case of colon cancer with multiple lung metastases responding completely to FOLFIRI and FOLFOX therapy]. AB - A 74-year-old man was administered FOLFIRI therapy, followed by modified FOLFOX therapy and FOLFIRI therapy due to ascending colon carcinoma with multiple lung metastases. After 19 months, the tumor marker became normal, and CT and PET-CT revealed the multiple lung metastases had disappeared. He was operated due to stenosis of the ascending colon carcinoma, and is now being treated with chemotherapy due to liver metastasis. There has been no regrowth of lung metastases for 21 months since the disappearance of multiple lung metastases. PMID- 20841954 TI - [A case of sigmoid colon cancer with peritoneal dissemination responding to third line therapy employing bevacizumab combination therapy after failure of FOLFOX and FOLFIRI]. AB - A58 -year-old man with sigmoid colon cancer with peritoneal dissemination was treated with bevacizumab (BV) plus mFOLFOX6 therapy as third-line chemotherapy after treatment failures with FOLFOX4 and FOLFIRI regimen. BV combination therapy resulted in a decrease in ascites and disappearance of the primary lesion. His ECOG performance status (PS) recovered from level 3 to level 1, and BV combination therapy improved his quality of life. This case suggested that BV in combination with chemotherapy could be a promising systemic chemotherapy for patients with colorectal cancer with peritoneal dissemination, and this regimen may be useful for patients progressing after receiving FOLFOX, FOLFIRI regimen. PMID- 20841955 TI - [A case of advanced rectal cancer with multiple liver metastases successfully treated by perioperative administration of UFT and oral leucovorin]. AB - The patient was a sixty-five-year-old man who had an advanced rectal cancer (Ra, type 2) with liver metastases. Low anterior resection with lymphnode dissection (D3) was done, but hepatectomy was not performed because of the multiple metastases besides the five tumors detected preoperatively. The pathological finding was moderately-differentiated adenocarcinoma. He was treated with 5-FU via the hepatic artery, but the therapy failed due to catheter infection after 3 postoperative months. Then, he received general 5-FU/l-LV therapy intravenously from 3 to 8 months after the operation, and oral UFT/LV (Uzel(r)) from 9 to 22 months. Next, we switched to single UFT therapy at 23 months because CT findings showed remarkable calcification in the liver metastases. But only one tumor of the liver (S6) among liver metastases enlarged at 27 months. We switched the chemotherapy again to UFT/Uzel and mFOLFOX6, but decided to perform hepatectomy of S6/7 at 39 months since it proved ineffective. The pathological finding was 90% necrosis and calcification of the tumor. Metastasis of the right 10th rib was newly found and was removed at 63 months after the first operation. Now, NC in the liver is continued 67 months after the first operation, and the patient is doing well. PMID- 20841956 TI - [A case of pseudomembranous colitis with febrile neutropenia induced by chemotherapy and effectively treated by vancomycin enemas]. AB - Pseudomembranous colitis, an antibiotic-associated diarrhea, needs early diagnosis and treatment for the high fatality rate in severe cases. We report a case of pseudomembranous colitis following the use of antibiotics in febrile neutropenia (FN). A 74-year-old man with non-curative resected sigmoid colon cancer was treated with cefepime in FN induced by chemotherapy. Complications of diarrhea were seen on day 2. Paralytic ileus and disseminated intravascular coagulation were also complications. He was diagnosed as pseudomembranous colitis for Clostridium difficile toxin-positive. Vancomycin enemas were administered because oral administrations were impossible, and the effect was provided. Vancomycin enemas are an effective therapy for patients with severe pseudomembranous colitis unable to tolerate oral medications because of ileus. PMID- 20841957 TI - [The role of occupational therapist in Palliative Care Team]. PMID- 20841958 TI - [The approach to "cancer clinical trial" of clinical research coordinator in Hoshigaoka Koseinenkin Hospital]. PMID- 20841960 TI - Chronic olanzapine, serotonin receptors, and subsequent serotonin toxicity. PMID- 20841959 TI - Role of inducible nitric oxide synthase on the development of virus-associated asthma exacerbation which is dependent on Th1 and Th17 cell responses. AB - Asthma is characterized by airway inflammation induced by immune dysfunction to inhaled antigens. Although respiratory viral infections are the most common cause of asthma exacerbation, immunologic mechanisms underlying virus-associated asthma exacerbation are controversial. Clinical evidence indicates that nitric oxide (NO) levels in exhaled air are increased in exacerbated asthma patients compared to stable patients. Here, we evaluated the immunologic mechanisms and the role of NO synthases (NOSs) in the development of virus-associated asthma exacerbation. A murine model of virus-associated asthma exacerbation was established using intranasal challenge with ovalbumin (OVA) plus dsRNA for 4 weeks in mice sensitized with OVA plus dsRNA. Lung infiltration of inflammatory cells, especially neutrophils, was increased by repeated challenge with OVA plus dsRNA, as compared to OVA alone. The neutrophilic inflammation enhanced by dsRNA was partly abolished in the absence of IFN-gamma or IL-17 gene expression, whereas unaffected in the absence of IL-13. In terms of the roles of NOSs, dsRNA-enhanced neutrophilic inflammation was significantly decreased in inducible NOS (iNOS) deficient mice compared to wild type controls; in addition, this phenotype was inhibited by treatment with a non-specific NOS inhibitor (L-NAME) or an specific inhibitor (1400 W), but not with a specific endothelial NOS inhibitor (AP-CAV peptide). Taken together, these findings suggest that iNOS pathway is important in the development of virus-associated exacerbation of neutrophilic inflammation, which is dependent on both Th1 and Th17 cell responses. PMID- 20841961 TI - The participation of cytochrome P450 3A4 in clozapine biotransformation is detected in people with schizophrenia by high-throughput in vivo phenotyping. PMID- 20841963 TI - Effect of adjunctive duloxetine on the plasma concentrations of clozapine, olanzapine, and risperidone in patients with psychotic disorders. PMID- 20841962 TI - Metabolic syndrome and its potential effect on treatment response to aripiprazole: a post hoc analysis of the stabilization phase of a long-term, double-blind study in patients with bipolar disorder (CN138-010). PMID- 20841964 TI - Association between symptom improvement and change of body mass index, lipid profile, and leptin, ghrelin, and cholecystokinin levels during 6-week olanzapine treatment in patients with first-episode psychosis. PMID- 20841965 TI - Neutropenia as a class effect of antipsychotic agents: a case report. PMID- 20841966 TI - A case of milnacipran-related sweating alleviated by duloxetine substitution. PMID- 20841967 TI - An additional consideration for comparisons of antidepressants versus placebo. PMID- 20841968 TI - Milnacipran-associated urinary retention: a case report. PMID- 20841969 TI - Improving fragile X-associated tremor/ataxia syndrome symptoms with memantine and venlafaxine. PMID- 20841971 TI - Mixed-type (limb-truncal and orofacial) bupropion-associated dyskinesia. PMID- 20841972 TI - Sertraline-related anisocoria. PMID- 20841973 TI - A case report of tramadol abuse-associated tics. PMID- 20841974 TI - Withdrawal symptoms after Internet purchase of phenibut (beta-phenyl-gamma aminobutyric acid HCl). PMID- 20841975 TI - Comments on article by Maguire et al: pagoclone trial: questionable findings for stuttering treatment. PMID- 20841978 TI - Homonymous hemianopia detected by short wavelength automated perimetry in a patient with normal standard perimetry and MRI. AB - PURPOSE: To report a case of homonymous hemianopia detected by short wavelength automated perimetry (SWAP) in a patient with normal standard automated perimetry (SAP) and magnetic resonance imaging (MRI) of the brain and orbits. METHODS: A 61 year-old woman with a history of motor vehicle accident with head injury nearly 50 years before presentation was referred for further evaluation as a glaucoma suspect. Complete ophthalmic examination, corneal pachymetry, SAP, SWAP, retinal nerve fiber layer analysis by ocular coherence tomography, and brain and orbital MRI were done. RESULTS: The patient had intraocular pressure (IOP) of 18-mm Hg and vertical cup-to-disc ratios of 0.8 in each eye. Superior neuroretinal rim pallor was detected in both optic discs on dilated optic nerve examination, and corresponding retinal nerve fiber layer thinning was detected with ocular coherence tomography. SAP indicated minimal nonspecific changes in the right eye, whereas the left eye had a normal visual field. SWAP revealed a left homonymous hemianopia. Neurologic examinations and MRI of the brain and orbits were found to be normal. CONCLUSIONS: SWAP can detect subtle hemianopic field defects in patients with normal standard perimetry. PMID- 20841979 TI - There is an "i" in team. PMID- 20841980 TI - Federal oversight of infusion pumps stepped up by Obama Administration and Food and Drug Administration. PMID- 20841981 TI - Utilizing evidence-based research and practice to support the infusion alliance. AB - Evidence-based practice (EBP) is a problem-solving approach to clinical practice that integrates the use of best evidence in combination with a clinician's expertise, along with patient preferences and values, to formulate a plan of care. EBP can validate and promote an infusion alliance. A review is presented of what constitutes evidence, how to access evidence, the importance of critique appraisal, incorporation of evidence through integration, and the need for perpetuation with contribution to EBP. PMID- 20841982 TI - Development of an infusion alliance. AB - Infusion therapy is one of the most invasive, complex, and pervasive therapies in the current health care system, yet there is very little investment in organizational knowledge management and intellectual human capital required to maintain patient safety. Catheter complications, fluid and medication errors, inadequate nutritional support, and transfusion of incompatible blood products manifest evidence of the ongoing problem. The number of infusion therapy teams has greatly decreased because of questionable cost-cutting strategies; however, it is clear from identified trends in health care that infusion teams and the concept of an infusion alliance has a distinct place within a modern health care organization. PMID- 20841983 TI - Implementing and maintaining an infusion alliance. AB - Infusion therapy models are ever changing and growing in modern health care. New technologies and problems arise daily as researchers and clinicians explore our world. As technologies advance, health care costs are also skyrocketing. The vast majority of hospitalized patients will receive some form of infusion therapy during their stay, and many will continue to receive therapy after they are discharged from the inpatient setting. Infusion alliances can aid cost containment by decreasing infusion-related complication rates, affect customer satisfaction, and promote interdisciplinary collaboration. This article discusses the potential benefits of an infusion alliance, details steps for using the performance improvement process when implementing and maintaining an alliance, and outlines the components of a successful business plan. PMID- 20841984 TI - Financial analysis for the infusion alliance. AB - Providing high-quality, cost-efficient care is a major strategic initiative of every health care organization. Today's health care environment is transparent; very competitive; and focused upon providing exceptional service, safety, and quality. Establishing an infusion alliance facilitates the achievement of organizational strategic initiatives, that is, increases patient throughput, decreases length of stay, prevents the occurrence of infusion-related complications, enhances customer satisfaction, and provides greater cost efficiency. This article will discuss how to develop a financial analysis that promotes value and enhances the financial outcomes of an infusion alliance. PMID- 20841985 TI - Infusion alliances: benchmarking and data collection. AB - Benchmarking is the process of comparing the cost, cycle time, productivity, or quality of a specific process or method to that of another method that is widely considered to be an industry standard or best practice. The result is often a business case for making changes to make improvements. Benchmarking in the specialty of infusion therapy can be used to validate an infusion alliance. This article's focus is identifying the problem areas, comparing them with successful infusion alliances, and demonstrating how to collect and interpret the data for success. PMID- 20841989 TI - The anatomy of health care team training and the state of practice: a critical review. AB - PURPOSE: As the U.S. health care system enters a new era, the importance of team based care approaches grows. How is the health care community ensuring that providers and administrators are equipped with the knowledge, skills, and attitudes (KSAs) foundational for effective teamwork? Are these KSAs transferring into daily practice? This review summarizes the present state of practice for health care team training described in published literature. Drawing from empirical investigations of training effectiveness, the authors explore training design, implementation, and evaluation to provide insight into the shape, structure, and anatomy of team training in health care. METHOD: A 2009 literature search yielded 40 peer-reviewed articles detailing health care team training evaluations. Guided by 11 focal questions, two trained raters extracted details regarding training design, implementation, evaluation metrics, and outcomes. RESULTS: Findings indicate that team training is being implemented across a wide spectrum of providers and is primarily targeting communication, situational awareness, leadership, and role clarity. Relatively few details indicate how training needs were established. Most studies collected data immediately posttraining; however, less than 30% collected data six months or more posttraining. Content analyses highlight the need for enhanced detail in published training evaluation reports. CONCLUSIONS: In many respects, health care team training implementation and evaluation align with best practices suggested from the science of training, adult learning, and human performance; however, opportunities for improvement exist. The authors suggest several mechanisms for furthering the health care team training evidence base to enhance patient safety and work environment quality for clinicians. PMID- 20841990 TI - Entry and retention in medical care among HIV-diagnosed persons: a meta-analysis. AB - OBJECTIVE: A 'test and treat' strategy to reduce HIV transmission hinges on linking and retaining HIV patients in care to achieve the full benefit of antiretroviral therapy. We integrated empirical findings and estimated the percentage of HIV-positive persons in the United States who entered HIV medical care soon after their diagnosis; and were retained in care during specified assessment intervals. METHODS: We comprehensively searched databases and bibliographic lists to identify studies that collected data from May 1995 through 2009. Separate meta-analyses were conducted for entry into care and retention in care (having multiple HIV medical visits during specified assessment intervals) stratified by methodological variables. All analyses used random-effects models. RESULTS: Overall, 69% [95% confidence interval (CI) 66-71%, N = 53 323, 28 findings] of HIV-diagnosed persons in the United States entered HIV medical care averaged across time intervals in the studies. Seventy-two percent (95% CI 67 77%, N = 6586, 12 findings) entered care within 4 months of diagnosis. Seventy six percent (95% CI 66-84%, N = 561, 15 findings) entered care after testing HIV positive in emergency/urgent care departments and 67% (95% CI 64-70%, N = 52 762, 13 findings) entered care when testing was done in community locations. With respect to retention in care, 59% (95% CI 53-65%, N = 75 655, 28 findings) had multiple HIV medical care visits averaged across assessment intervals of 6 months to 3-5 years. Retention was lower during longer assessment intervals. CONCLUSION: Entry and retention in HIV medical care in the United States are moderately high. Improvement in both outcomes will increase the success of a test and treat strategy. PMID- 20841991 TI - HIV protease inhibitors alter innate immune response signaling to double-stranded RNA in oral epithelial cells: implications for immune reconstitution inflammatory syndrome? AB - In this investigation, several HIV protease inhibitors altered the virally associated, double-stranded RNA (dsRNA)-stimulated, innate immune response. Lopinavir, the most potent inducer of interleukin (IL)-8 expression, also inhibited dsRNA-induced monocyte chemotactic protein 1 expression. Further analyses demonstrated that nuclear factor-kappaB is required for lopinavir's induction of IL-8. These findings demonstrate that protease inhibitors, such as lopinavir, differentially dysregulate innate immune signaling in a manner that could affect immune (reconstitution) inflammatory responses in oral epithelium. PMID- 20841992 TI - Management of the virulent influenza virus infection by oral formulation of nonhydrolized carnosine and isopeptide of carnosine attenuating proinflammatory cytokine-induced nitric oxide production. AB - Inducible nitric oxide synthase (iNOS) plays an important role in mediating inflammation. In our studies, we found that iNOS-derived NO was significantly increased in the serum samples of 150 patients infected with influenza A virus in comparison with samples of 140 healthy individuals. In human lung epithelial cells, infection with influenza A virus or stimulation with poly(I:C) + interferon-gamma resulted in increased mRNA and protein levels of both interleukin-32 and iNOS, with subsequent release of NO. Activated macrophages are also a source of nitric oxide (NO), which is largely produced by iNOS in response to proinflammatory cytokines. In this review article, the presented findings have many important implications for understanding the Influenza A (H1N1) viral pathogenesis, prevention, and treatment. The direct viral cytotoxicity (referred cytopathic effect) is only a fraction of several types of events induced by virus infection. Nitric oxide and oxygen free radicals such as superoxide anion (O2-) are generated markedly in influenza A (including H1N1) virus-infected host boosts, and these molecular species are identified as the potent pathogenic agents. The mutual interaction of NO with O2- resulting in formation of peroxynitrite is operative in the pathogenic mechanism of influenza virus pneumonia. The toxicity and reactivity of oxygen radicals, generated in excessive amounts mediate the overreaction of the host's immune response against the organs or tissues in which viruses are replicating, and this may explain the mechanism of tissue injuries observed in influenza virus infection of various types. The authors revealed the protection that carnosine and its bioavailable nonhydrolized forms provide against peroxynitrite damage and other types of viral injuries in which immunologic interactions are usually involved. Carnosine (beta-alanyl-L histidine) shows the pharmacologic intracellular correction of NO release which might be one of the important factors of natural immunity in controlling the initial stages of influenza A virus infection (inhibition of virus replication) and virus-induced regulation of cytokine gene expression. The protective effects of orally applied nonhydrolized formulated species of carnosine include at least direct interaction with nitric oxide, inhibition of cytotoxic NO-induced proinflammatory condition, and attenuation of the effects of cytokines and chemokines that can exert profound effects on inflammatory cells. These data are consistent with the hypothesis that natural products, such as chicken soup and chicken breast extracts rich in carnosine and its derivative anserine (beta alanyl-1-methyl-L-histidine) could contribute to the pathogenesis and prevention of influenza virus infections and cold but have a limitation due to susceptibility to enzymatic hydrolysis of dipeptides with serum carnosinase and urine excretion after oral ingestion of a commercial chicken extract. The developed and patented by the authors formulations of nonhydrolized in digestive tract and blood natural carnosine peptide and isopeptide (gamma-glutamyl carnosine) products have a promise in the Influenza A (H1N1) virus infection disease control and prevention. PMID- 20841993 TI - Surgical normalization of the shoulder joint in obstetric brachial plexus injury. AB - Obstetric brachial plexus injuries (OBPI) result in bony derangements that include posterior humeral head subluxation, glenoid retroversion, and joint incongruity. Often these deformities are accompanied by scapular hypoplasia, elevation, and rotation, which further exacerbate shoulder dysfunction. The purpose of the current study was to investigate the effects of triangle tilt surgery on glenohumeral joint anatomy in 100 OBPI patients. The triangle tilt surgery restores the distal acromioclavicular triangle from an abnormal superiorly angled position to a neutral position, thereby restoring normal glenohumeral anatomic relationships.Axial computed tomography and magnetic resonance images taken before and 12- to 38-months after surgery showed significant improvements in both posterior subluxation and glenoid version. Patients with complete posterior glenohumeral dislocation improved from 19% preoperatively, to 11% postoperatively. Glenoid shape was also improved, with 81% of patients classified as concave or flat after surgery compared with 53% before surgery.Triangle tilt surgery allows for both repositioning and remodeling of the glenohumeral joint. These anatomic improvements after triangle tilt surgery hold promise for improving shoulder function and quality of life for OBPI patients. PMID- 20841994 TI - Revision rhinoplasty in asians. AB - Revision rhinoplasty is increasing in the Asian population. We present causes of revision rhinoplasty in Asians, introduce operative techniques, report surgical results, and make implications for ways to assist in their prevention. During a period of 3 years, 52 patients (among 623 rhinoplasties) who had undergone revision rhinoplasty with at least 1 year follow-up were included in this study. A retrospective review was performed using chart review, graphic operation records, pre- and postoperative photographs. Outcome was determined by subjective assessment of 2 blinded rhinoplasty surgeons. The patients were classified into 2 groups; revision because of alloplastic implant-related problems (33 cases) and revision unrelated to alloplastic implants (19 cases). The most common reason for revision in the alloplastic implant-related group was deviation of the implant, followed by implant extrusion, foreign body reaction, and infection. Reasons for revision in the alloplastic implant-unrelated group included upper two-thirds problems in 12 cases, and tip problems in 7. Autologous cartilage was used in the majority of revision cases. Subjective evaluation of postoperative results were good in 29 (69%), fair in 10 (24%), and poor in 3 (7%). Revision rhinoplasty in Asians was most commonly associated with alloplastic implants. Proper and judicious use of alloplastic implants is important to reduce the chances for revision surgery in Asians. PMID- 20841995 TI - Application of the lateral orbital flap to reconstruction of the upper and lower eyelids and the eye socket after enucleation. AB - The wide applications of the subcutaneous pedicle flap "lateral orbital flap" named by the author is presented. The flap is designed between the lateral canthus and the sideburn as a spindle or crescent shaped island 2- to 3-cm wide and 5-cm long. To reconstruct the upper or lower eyelids, the flap is elevated as thin as possible, whereas for the eye socket reconstruction, an adequate volume of subcutaneous fat tissue is attached to the flap. The pedicle is designed inferomedially for the reconstruction of the recipient, any shape of the flap can be designed. As the anatomic structure of the donor site is similar to the eyelid, the excellent result can be obtained both functionally and cosmetically. The donor site is primarily closed without a marked scar. The cases of reconstructions using lateral orbital flap for the upper eyelid and the eye socket in the anophtalmic condition are presented. PMID- 20841996 TI - Vertical mastopexy and lateral intercostal artery perforator (LICAP) flap with pectoralis muscle sling for autologous tissue breast augmentation in the bariatric patient. AB - Breast contouring surgery after massive weight loss is challenging because of unfavorable features such as inelastic skin, volume depletion, loss of upper pole fullness, and significant ptosis. An approach is presented for autoaugmentation using a lateral intercostal artery perforator (LICAP) flap secured with a pectoralis muscle sling, along with mastopexy based on vertical scar principles. In a total of 8 patients (average age: 39.3 years, range: 29-57; average body mass index: 30.8 kg/m2, range: 25.7-39.1) with breast ptosis and volume depletion after a mean weight loss of 121.9 pounds (range: 80-210), LICAP flap (n = 16) was used with turnover flap design to increase breast volume under a pectoralis muscle sling. Vertical design mastopexy (n = 16) was achieved at the same time, resulting in an L-shaped final scar. All the patients were followed for at least 1 year after the surgery. Patient satisfaction was high at long-term follow-up (average: 16.8 months, range: 12-24), with stable and pleasing breast shape and a mean patient ranking for aesthetic outcome of 4.2 (of 5). None of the patients developed any flap necrosis or fat necrosis. An alternative approach is described for the combined treatment of breast ptosis and volume loss in the bariatric patient, with promising long-term results. The muscle sling seems to help prevent tissue descent, without evidence of pseudoptosis at long term. It is shown that vertical scar techniques can be successfully used even in bariatric patients. PMID- 20841997 TI - From surgery to pharmacology to gene therapy: the past, present, and future of hair restoration. AB - The hair follicle is a complex structure containing many cell types that produce highly specialized proteins. These proteins govern the continuous cycling of the follicle through its stages of anagen, catagen, telogen, and exogen. Most common forms of alopecia result from the changes in the follicular cycling pattern and the morphology of the hair follicle. Hair restoration has traditionally been performed using scalp reduction techniques and the rearrangement of local hair bearing flaps. Over the recent decades, hair transplantation has been the mainstay of hair restoration, whereas the pharmacological treatment of androgenic alopecia has halted the progression of hair loss. Over recent years, significant advances in the understanding of the biology and the molecular mechanisms of the follicle and its cycling have been made. This understanding, combined with new techniques for delivering molecules to the follicle, has made gene therapy for alopecia a possibility. PMID- 20841998 TI - Management of split-thickness donor sites with synthetic wound dressings: results of a comparative clinical study. AB - This prospective, randomized, single-blinded, clinical study aimed at evaluating 3 different synthetic wound dressings for treating split-thickness skin graft donor sites. Seventy-seven patients were randomly assigned to 3 study groups: Suprathel, Biatain-Ibu, Mepitel. Wounds were inspected daily until complete reepithelization. Ease of care, treatment costs, and scar development after a 6 months follow-up were evaluated. Suprathel showed significant (P <= 0.001) pain reduction after 24 hours but increasing pain scores on the 5th day of treatment. Biatain-Ibu showed significant pain relief immediately after application and during the entire treatment period (P < 0.05). Mepitel did not show any significant pain reduction. No differences were seen with regard to healing time, quality of reepithelization, and scar development. Biatain-Ibu had the lowest overall treatment costs (P <= 0.001). The investigated materials did not differ with regard to quality and acceleration of the healing process, but Biatain-Ibu seems to be the most appropriate dressing material in terms of cost effectiveness. PMID- 20841999 TI - Modified pull-out wire suture technique for the treatment of chronic bony mallet finger. AB - Twenty-three patients with a chronic bony mallet finger deformity (more than 3 months after the injury) and fracture fragment involving more than one-third of the articular surface underwent surgical treatment. The fracture fragment was fixed, and the mallet finger deformity was corrected in all patients using a modified pull-out wire (wire passed through the dorsal fragment directly) with a transarticular Kirschner wire fixation technique. Active motion of the proximal interphalangeal and metacarpophalangeal joints was not restricted. According to Crawford's evaluation criteria, there were 17 excellent, 4 good, and 2 fair results. Four patients showed radiologic signs of mild degenerative changes, which did not limit their daily activities. The modified pull-out wire suture with the transarticular Kirschner wire fixation technique provides an alternative and acceptable treatment modality for the treatment of chronic bony mallet finger deformities with or without subluxation of the distal phalanx. PMID- 20842000 TI - The free dorsoradial forearm perforator flap: anatomical study and clinical application in finger reconstruction. AB - The perforator flaps are characterized by their thinness and the adjustable length of their vascular pedicle. The purpose of this investigation is to refine the anatomy of the perforators in the middorsoradial forearm and present our clinical experience using this free perforator flap in the reconstruction of finger defects. Anatomic study was conducted on 46 cadaver forearms. It was noted that a perforator was consistently observed in the midforearm exhibiting 4 patterns, in which a dorsoradial perforator was present with 37 cases (80.4%) originating from the interosseous artery system (patterns 1-3) and 9 cases (19.6%) from the descending branch of the radial recurrent artery (pattern 4). This perforator consistently emerged in the intermuscular septum between the extensor carpi radialis longus and extensor digitorum communis. Twenty free flaps based on this middorsoradial cutaneous perforator were elevated for the coverage of soft tissue defects of fingers (range: 3 cm * 2.0 cm to 5 cm * 2.5 cm) in 17 patients. All the flaps survived with satisfactory outcomes. Clinical findings on this perforator in terms of its origins and courses coincided with the anatomic results (chi2 = 0.287, P = 0.962). The free flap based on this perforator is a reliable perforator flap in spite of varied origins. PMID- 20842001 TI - Alginate microencapsulation technology for the percutaneous delivery of adipose derived stem cells. AB - BACKGROUND: Autologous fat is the ideal soft-tissue filler; however, its widespread application is limited because of variable clinical results and poor survival. Engineered fillers have the potential to maximize survival. Alginate is a hydrogel copolymer that can be engineered into spheres of <200 MUm, thus facilitating mass transfer, allowing for subcutaneous injection, and protecting cells from shearing forces. METHODS: Alginate powder was dissolved in saline, and adipose-derived stem cells (ADSCs) were encapsulated (1 million cells/mL) in alginate using an electrostatic bead generator. To assess effects of injection on cell viability, microspheres containing ADSCs were separated into 2 groups: the control group was decanted into culture wells and the injection group was mixed with basal media and injected through a 21-gauge needle into culture wells. Microbeads were cultured for 3 weeks, and cell number and viability were measured weekly using electron and confocal microscopy. To assess effects of percutaneous injection in vivo, twenty-four male nude mice were randomly separated into 2 groups and injected with either empty microcapsules or ADSC-laden microcapsules. Mice were harvested at 1 and 3 months, and the implants were examined microscopically to assess bead and cell viability. RESULTS: A flow rate of 5 mL/h and an electrostatic potential of 7 kV produced viable ADSC-laden microbeads of <200 MUm. There were no differences in bead morphology and ADSC viability between microcapsules placed versus injected into tissue culture plates for up to 3 weeks. Microspheres implanted in a nude mouse model show durability up to 3 months with a host response around each individual sphere. ADSCs remained viable and showed signs of mitosis. CONCLUSIONS: ADSCs can be readily cultured, encapsulated, and injected in alginate microspheres. Stem cells suspended in alginate microspheres survive in vivo and are seen to replicate in vitro. PMID- 20842002 TI - Accuracy of intraoral vertical ramus osteotomy with a stereolithographic template. AB - Various modifications have been described to improve the accuracy in intraoral vertical ramus osteotomy (IVRO), but there was not a measurable facility to determine the osteotomy line. The purpose of this study was to evaluate the accuracy of the computer tomography (CT)-based osteotomy template on cadaver mandibles and to assess the outcome after IVRO correcting mandibular prognathism. Four human wet cadaver heads were subjected to a high-resolution multislice spiral CT scan. After the virtual osteotomies in the planning program, the individual osteotomy templates were produced by stereolithography. A stable and secure fit of the stereolithographic templates was achieved via the individual CT based osteotomy template. The osteotomy lines were performed exactly as planned in the virtual osteotomies planning program. Similar sound outcome was also observed in the clinic. Use of the CT-based osteotomy templates is a safe method for osteotomy. It is rather convenient for vertical osteotomy in IVRO increasing the intraoperative accuracy and efficiency. PMID- 20842003 TI - A decision analysis of amputation versus reconstruction for severe open tibial fracture from the physician and patient perspectives. AB - Although reconstruction is often the primary choice of surgeons after an open tibial fracture, there is no evidence to support the long-term effectiveness of flap reconstruction over below-knee amputation. The aim of this study was to perform a decision analysis to evaluate treatment preferences for type IIIB and IIIC tibial fractures. Reconstructive microsurgeons, physical medicine physicians, and patients with lower extremity trauma completed a Web-based standard gamble utility survey to generate quality-adjusted life years (QALYs). Physicians assigned quite high utility values, and there was a slight preference for reconstruction over amputation, with a gain of only 0.55 QALY. Patients assigned significantly lower utility values and also favored reconstruction over amputation, but with a larger gain of 5.54 QALYs. The disparate utilities assigned by the physicians and the patients highlight the necessity of realistic discussion of outcomes, regardless of the management methods. PMID- 20842004 TI - The development of sensory hypoesthesia after whiplash injury. AB - OBJECTIVES: (1) To investigate the development of hypoesthesia from soon after the whiplash injury to 6 months postinjury and (2) to determine differences in detection thresholds between those with initial features of poor recovery and those without these signs. METHODS: Fifty-two participants with acute whiplash associated disorders (WAD) (<1 mo) were classified as either "high-risk" (n=17; Neck Disability Index >30; sensory hypersensitivity) or "low risk" (n=35; without these signs). Detection thresholds to electrical, thermal, and vibration stimuli and psychological distress were prospectively measured within 1 month of injury and then 3 and 6 months postinjury. Detection thresholds were also measured in the 38 controls. RESULTS: Both WAD groups showed hypoesthesia (vibration, electrical, and cold) at 1 month postinjury. Vibration and electrocutaneous hypoesthesia persisted to 3 and 6 months only in the high-risk WAD group. Heat detection thresholds were not different between the groups at 1 month postinjury but were elevated in the high-risk group at 3 and 6 months. Both WAD groups were distressed at 1 month but this decreased by 3 months in the low-risk group. The differences in the Impact of Event Scale did not impact on any of the sensory measures. DISCUSSION: Sensory hypoesthesia is a feature of acute WAD but persists only in those at higher risk of poor recovery. These findings suggest the involvement of the central inhibitory mechanisms that may be sustained by ongoing nociception. PMID- 20842005 TI - A prospective study of the herpes zoster severity of illness. AB - OBJECTIVE: MASTER, a multicenter prospective study, was conducted to provide a thorough understanding of the burden of herpes zoster (HZ) and postherpetic neuralgia (PHN). Objectives are to: (1) describe the herpes zoster severity-of illness (HZSOI), a composite measure of pain duration and severity; and (2) to identify the characteristics at recruitment predictive of greater HZSOI at the different phases of HZ. METHODS: From October, 2005 to July, 2006, 261 outpatients with HZ, aged more than equal to 50 years, were recruited within 14 days of rash onset across Canada. The pain was measured by the Zoster Brief Pain Inventory at recruitment and 7, 14, 21, 30, 60, 90, 120, 150, and 180 days later. The HZSOI represents the area under the curve of pain severity over time and ranges from 0 (no pain) to 1800 (pain=10 for 180 d). RESULTS: Median pain duration was 32.5 days. The predictors of greater HZSOI varied according to the different phases of HZ. Higher pain severity at recruitment, more lesions, lower income, and being immunocompromised were the predictors of a greater acute HZSOI. Higher acute pain severity, lower income, being immunocompromised, older age, and not receiving antivirals were the predictors of greater postherpetic HZSOI. DISCUSSION: Using an informative measure capturing simultaneously the burden caused by pain duration and severity, we identified subgroups that suffer most during the different phases of HZ. It is interesting to note that, younger participants were as likely to suffer as the older ones during the acute phase of HZ. This information should aid in optimizing the treatment and prevention of HZ. PMID- 20842006 TI - Neck pain treatment with acupuncture: does the number of needles matter? AB - OBJECTIVES: Acupuncture has been successfully used in myofascial pain syndromes. However, the number of needles used, that is, the dose of acupuncture stimulation, to obtain the best antinociceptive efficacy is still a matter of debate. The question was addressed comparing the clinical efficacy of two different therapeutic schemes, characterized by a different number of needles used on 36 patients between 29-60 years of age with by a painful cervical myofascial syndrome. METHODS: Patients were divided into two groups; the first group of 18 patients were treated with 5 needles and the second group of 18 patients were treated with 11 needles, the time of needle stimulation was the same in both groups: 100 seconds. Each group underwent six cycles of somatic acupuncture. Pain intensity was evaluated before, immediately after and 1 and 3 months after the treatment by means of both the Mc Gill Pain Questionnaire and the Visual Analogue Scale (VAS). In both groups, the needles were fixed superficially excluding the two most painful trigger points where they were deeply inserted. RESULTS: Both groups, independently from the number of needles used, obtained a good therapeutic effect without clinically relevant differences. CONCLUSIONS: For this pathology, the number of needles, 5 or 11, seems not to be an important variable in determining the therapeutic effect when the time of stimulation is the same in the two groups. PMID- 20842007 TI - A meta-analysis of the efficacy of laser phototherapy on pain relief. AB - OBJECTIVE: Laser phototherapy has been widely used to relieve pain for more than 30 years, but its efficacy remains controversial. To ascertain the overall effect of phototherapy on pain, we aggregated the literature and subjected the studies to statistical meta-analysis. METHODS: Relevant original studies were gathered from every available source and coded. Articles that met preestablished inclusion criteria were subjected to statistical meta-analysis, using Cohen's d statistic to determine treatment effect sizes. RESULTS: Fifty-two effect sizes were computed from the 22 articles that met the inclusion criteria. The resulting overall mean effect size was highly significant; d = +0.84 (95% confidence interval = 0.44-1.23). The effect size remained significant even when a high outlying d value was conservatively excluded from the analysis; d = +0.66 (95% confidence interval = 0.46-0.86). The fail-safe number associated with the overall treatment effect, that is, the number of additional studies in which phototherapy has negative or no effect on pain needed to negate the overall large effect size of +0.84, was 348. DISCUSSION: These findings warrant the conclusion that laser phototherapy effectively relieves pain of various etiologies; making it a valuable addition to contemporary pain management armamentarium. PMID- 20842008 TI - The association between chronic low back pain and sleep: a systematic review. AB - OBJECTIVES: chronic low back pain (CLBP) adversely affects many quality of life components, and is reported to impair sleep. The aim of this review was to determine the association between CLBP and sleep. METHODS: this review comprised 3 phases: an electronic database search (PubMed, Cinahl Plus, EMBASE, PsychInfo, Pedro, and Cochrane Library) identified potential articles; these were screened for inclusion criteria by 2 independent reviewers; extraction of data from accepted articles; and rating of internal validity by 2 independent reviewers and strength of the evidence using valid and reliable scales. RESULTS: the search generated 17 articles that fulfilled the inclusion criteria (quantitative n=14 and qualitative n=3). CLBP was found to relate to several dimensions of sleep including: sleep disturbance and duration (n=15), sleep affecting day-time function (n=5), sleep quality (n=4), sleep satisfaction and distress (n=4), sleep efficiency (n=4), ability to fall asleep (n=3), and activity during sleep (n=3). Consistent evidence found that CLBP was associated with greater sleep disturbance; reduced sleep duration and sleep quality; increased time taken to fall asleep; poor day-time function; and greater sleep dissatisfaction and distress. Inconsistent evidence was found that sleep efficiency and activity were adversely associated with CLBP. DISCUSSION: many dimensions of sleep are adversely associated with CLBP. Management strategies for CLBP need to address these to maximize quality of life in this patient cohort. PMID- 20842009 TI - Clinical Investigation of Pain-related Fear and Pain Catastrophizing for Patients With Low Back Pain. AB - OBJECTIVE: to investigate select psychometric properties of fear-avoidance model measures commonly used to assess pain-related fear and catastrophizing in clinical studies of low back pain. METHODS: a convenience sample was recruited from patients (n=80) seeking outpatient physical therapy for low back pain. All patients completed self-report questionnaires for pain-related fear [Fear avoidance Beliefs Questionnaire-physical activity (FABQ-PA), FABQ-work scale (W), and Tampa Scale for Kinesiophobia -11] and pain catastrophizing (PCS) at initial evaluation session. Patients also completed clinical measures for pain intensity (numerical rating scale) and self-report of disability (Oswestry Disability Index) at the initial evaluation session. Construct redundancy of the fear avoidance questionnaires was assessed by factor analysis for individual items and Pearson correlation for total questionnaire scores. Concurrent validity was investigated with multiple regression models for pain intensity and disability. RESULTS: item analysis indicated all PCS and FABQ-W items loaded on 2 separate factors. The FABQ-PA and Tampa Scale for Kinesiophobia-11 loaded together on a third factor. As expected, all of the fear-avoidance questionnaires were significantly correlated with each other to varying degrees (rs ranged from 0.28 to 0.55, P<0.05 for all). In the multiple regression models only the FABQ-PA and PCS contributed unique variance to pain intensity and disability measures. Further analysis indicated the PCS mediated the relationship of the FABQ-PA by weakening its association with pain intensity and disability. DISCUSSION: these analyses suggest clinical assessment of the Fear-Avoidance Model of Musculoskeletal Pain likely captures 3 factors including PCS, beliefs about work, and beliefs about physical activity. The FABQ-PA and PCS can be recommended for clinical use because of their unique associations with pain intensity and disability. The FABQ-W may only be appropriate for those interested in assessing work specific beliefs. PMID- 20842010 TI - Pneumorrhachis mimicking meningitis after a paramedian lumbar interlaminar injection. AB - We report a case of a 76-year-old female with chronic back pain owing to a degenerative disc disease at L5 to S1. She underwent a paramedian lumbar interlaminar injection in the prone position at the level of L5-S1 using loss of resistance technique and without fluoroscopic guidance. The patient was admitted to the intensive care unit on the day after the procedure with objective signs of meningeal irritation. A computed tomography scan of the spine showed presence of multiple air levels within the spinal canal. The patient's symptoms resolved spontaneously and she was discharged to home the next day. PMID- 20842011 TI - Characteristics of Chronic Pain and Its Impact on Quality of Life of Patients With HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). AB - OBJECTIVES: we describe the prevalence of chronic pain and their characteristics in 43 consecutive patients presenting with human T-lymphotropic virus Type I (HTLV-1) associated myelopathy (HAM) /tropical spastic paraparesis in Salvador, Brazil. METHODS: in this cross-sectional study, we included 43 consecutive patients with HAM/TSP from Sarah Salvador Unit of the Rehabilitation, in Bahia, Brazil. They were evaluated from September 2007 to July 2008. We used the following scales: Functional disability scales (EDSS, OSAME e HOFFER); visual analogue scale; Hospital Anxiety and Depression Scale; McGill Pain Questionnaire; DN4 Questionnaire and SF-36 Quality-of-Life Questionnaire. RESULTS: chronic pain was highly prevalent (38 patients---88.4%) in this population. We detected an inverse correlation between duration of the disease and the likelihood of patients to present with chronic pain (P<0.05). Individuals with greater neurologic deficits had much more neuropathic, whereas those with lower motor deficit had mainly the characteristics of nociceptive pain (P<0.05). A positive correlation was observed between the score of the dominant pain or the additional pain, and the number of pain descriptors (P<0.05 for both evaluations). The patients with chronic pain had worst Quality-of-Life scores (P<0.05). CONCLUSION: chronic pain was significantly associated with a higher likelihood of signs/symptoms of anxiety and depression, reflecting a negative impact of pain on patients' quality of life. PMID- 20842012 TI - Cross validation of the current opioid misuse measure to monitor chronic pain patients on opioid therapy. AB - OBJECTIVES: The Current Opioid Misuse Measure (COMM) is a self-report measure of risk for aberrant medication-related behavior among persons with chronic pain who are prescribed opioids for pain. It was developed to complement predictive screeners of opioid misuse potential and improve a clinician's ability to periodically assess a patient's risk for opioid misuse. The aim of this study was to cross-validate the COMM with a sample of chronic noncancer pain patients. METHODS: Two hundred and twenty-six participants prescribed opioids for pain were recruited from 5 pain management centers in the United States. Participants completed the 17-item COMM and a series of self-report measures. Patients were rated by their treating physician, had a urine toxicology screen, and were classified on the Aberrant Drug Behavior index. RESULTS: The reliability and predictive validity in this cross validation as measured by the area under the curve (AUC) were found to be highly significant (AUC=0.79) and not significantly different from the AUC obtained in the original validation study (AUC=0.81). Reliability (coefficient alpha) was 0.83, which is comparable to the 0.86 obtained in the original sample. DISCUSSION: Results of the cross validation suggest that the psychometric parameters of the COMM are not based solely on unique characteristics of the initial validation sample. The COMM seems to be a reliable and valid screening tool to help detect current aberrant drug-related behavior among chronic pain patients. PMID- 20842013 TI - Myofascial trigger points in neck and shoulder muscles and widespread pressure pain hypersensitivtiy in patients with postmastectomy pain: evidence of peripheral and central sensitization. AB - OBJECTIVE: To describe the presence of widespread pressure pain hyperalgesia and myofascial trigger points (TrPs) in neck and shoulder muscles in patients with postmastectomy pain. METHODS: Twenty-nine women (mean age: 50+/-8 y) with postmastectomy pain and 23 matched healthy controls (mean age: 50+/-9 y) participated. Pressure pain thresholds (PPT) were bilaterally assessed over the C5-C6 zygapophyseal joint, the deltoid muscle, the second metacarpal, and the tibialis anterior muscle. TrPs in the upper trapezius, suboccipital, levator scapulae, sternocleidomastoid, scalene, infraspinatus, and pectoralis major muscles were explored. TrPs were considered active if the local and referred pain reproduced symptoms and the patient recognized the pain as familiar. RESULTS: Twenty-five (86%) patients reported neck pain whereas 20 (69%) patients showed shoulder/axillary pain. The results showed that PPT levels were significantly decreased bilaterally over the C5-C6 zygapophyseal joint, deltoid muscle, second metacarpal, and tibialis anterior muscle in patients with postmastectomy pain as compared with controls (all sites, P<0.001). No significant differences in the magnitude of PPT decrease between sites were found (P=0.222). The mean number of active TrPs for each woman with postmastectomy pain was 5.4+/-1.8. Healthy controls only had latent TrPs (0.5+/-0.6). Patients with postmastectomy pain showed a greater number of TrPs than controls (P<0.001). In all muscles, there was significantly more active TrPs in patients with postmastectomy pain as compared with controls (P<0.001). Active TrPs in the pectoralis major (n=27, 93%), infraspinatus (n=23, 79%), and upper trapezius (n=19, 65%) muscles were the most prevalent in the affected side in the postmastectomy group. The number of active TrPs was positively correlated with neck (rs=0.392, P=0.036) and shoulder/axillary (rs=0.437, P=0.018) pain intensity. CONCLUSIONS: Our findings revealed bilateral widespread pressure pain hypersensitivity in patients with postmastectomy pain. In addition, the local and referred pain elicited by active TrPs reproduced neck and shoulder/axillary complaints in these patients. These results suggest peripheral and central sensitization in patients with postmastectomy pain. PMID- 20842014 TI - Comparing the STarT back screening tool's subgroup allocation of individual patients with that of independent clinical experts. AB - OBJECTIVES: The STarT Back Screening Tool (SBST) is validated to subgroup primary care patients with back pain into risk groups relevant to initial decision making. However, it remains unclear how the tool's allocation of individuals compares with subjective clinical decision-making. We evaluated agreement between clinicians and the SBST's allocation to risk subgroups, and explored reasons for differences observed. METHODS: Twelve primary care back pain patients underwent a video-recorded clinical assessment. The SBST was completed on the same day. Clinical experts (3 general practitioners, 3 physiotherapists, and 3 pain management specialists) individually reviewed the patient videos (4 each), blind to SBST allocation. Their task was to subgroup patients into low, medium, or high risk groups. RESULTS: Interrater agreement between clinicians was "fair" (kappa=0.28), with consistent allocation between experts in 4 of 12 patients. There was observed agreement with the SBST in 17 of 36 cases (47%) and Cohen's weighted kappa was 0.22, indicating fair agreement. Two reasons for differences emerged. Clinicians tailor their decisions according to patient expectations and demands for treatment and clinicians use knowledge of difficult life circumstances that may be unrelated back pain. DISCUSSION: Clinicians make inconsistent risk estimations for primary care patients with back pain when using intuition alone, with little agreement with a formal subgrouping tool. Unlike clinicians, the SBST could not make a sophisticated synthesis of patient preferences, expectations, and previous treatment history. Although acknowledging the limitations of back pain subgrouping tools, more research is needed to test whether their use improves consistency in primary care decision-making. PMID- 20842015 TI - A population-based cohort study on chronic pain: the role of opioids. AB - OBJECTIVES: The aims of this study were 2-fold: (1) to investigate the consequences of opioid use in individuals with chronic pain in the Danish population, and (2) to investigate the development of and recovery from chronic pain from 2000 to 2005. METHODS: Data derived from the Danish Health Interview Survey in 2000, which were linked on the individual level with register-based follow-up data. The survey was based on a county-stratified random sample of 16,684 individuals, out of which 10,434 individuals (62.5%) completed a face-to face interview and returned a self-administered questionnaire. In addition, a subsample of the sample in 2000 was reinvited to a follow-up survey in 2005. In total, 3649 individuals (61.7%) of this subsample completed the interview and returned the questionnaire at baseline in 2000. At follow-up, 2354 of these participants completed the interview and returned the self-administered questionnaire. Respondents with cancer diagnosis were excluded from all analyses. Respondents with chronic pain were identified as having chronic/long-lasting pain more than 6 months. RESULTS AND DISCUSSION: The annual incidence for the development of and the recovery from chronic pain was 2.7% and 9.4%, respectively. Increasing age up to 64 years, short education, poor self-rated health, high body mass index, and physical strain at work were predictors of chronic pain. The odds of recovery from chronic pain were almost 4 times higher among individuals not using opioids compared with individuals using opioids. In addition, use of strong opioids was associated with poor health-related quality of life. Furthermore, the results indicated that individuals with chronic pain using strong opioids pain had a higher risk of death than individuals without chronic pain (HR: 1.67; 95% CI: 1.03-2.70). However, this study cannot exclude disease severity as the primary cause of increased mortality. PMID- 20842016 TI - Emotional and neuropsychological profiles of children with complex regional pain syndrome type-I in an inpatient rehabilitation setting. AB - OBJECTIVE: Examine the emotional and neuropsychological profiles of pediatric Complex Regional Pain Syndrome Type-I in an inpatient setting. METHODS: Seventeen children and adolescents (all female; ages 9 to 18 y) admitted to an inpatient rehabilitation facility who completed neuropsychological assessments that included emotional functioning questionnaires, projective personality measures, and neuropsychological measures. RESULTS: Consistent evidence for somatization was found. Thirty-eight percent of patients exhibited at-risk/elevated mood symptoms (anxiety or depression) based on self-report or parent report. Overall, few patients exhibited at risk/impaired neuropsychological test composite scores. A sizable proportion of patients (36%), however, showed at risk/impaired attention/working memory composite scores. DISCUSSION: Children with Complex Regional Pain Syndrome Type-I may experience emotional distress that is better identified through using multiple assessment methods. Results provide support for an elevated risk of somatic symptoms and emotional distress, especially anxiety, among certain individuals in this population. Results also provide preliminary evidence for an elevated risk of difficulties with attention/working memory. PMID- 20842017 TI - The fear avoidance model disentangled: improving the clinical utility of the fear avoidance model. AB - BACKGROUND: The model of fear avoidance proposes that fear of movement in back pain patients is an obstacle to recovery and leads over time to increased disability. Therefore, fear of movement should be targeted explicitly by interventions. AIMS: To review the evidence (1) for the causal components proposed by the model, and (2) about interventions that attempt to reduce fear of movement. In addition, we aim to propose alternatives and extensions to the current model in order to increase the clinical utility of the model. METHODS: A collaborative narrative review. RESULTS: The fear avoidance model needs to be conceptually expanded and further tested to provide adequate and appropriate clinical utility. Currently, although there is experimental support for the model, observational studies in patients show contradictory results. Interventions based on the model have not delivered convincing results, only partly due to methodological shortcomings. Some assumptions inherent in the current model need adjusting, and other factors should be incorporated to indicate subgroupings within patients high in avoidance behavior. In addition, both theoretical and methodological limitations were identified in measurements of fear and avoidance. CONCLUSIONS: Future research should elucidate whether the proposed subgrouping of patients with avoidance behavior is helpful. Further research should focus on developing more accurate and psychometrically sound assessment tools as well as targeted interventions to improve activities and participation of patients with chronic disabling musculoskeletal pain disorders. PMID- 20842018 TI - Memory functions in chronic pain: examining contributions of attention and age to test performance. AB - OBJECTIVES: Previous studies have revealed that memory performance is diminished in chronic pain patients. Few studies, however, have assessed multiple components of memory in a single sample. It is currently also unknown whether attentional problems, which are commonly observed in chronic pain, mediate the decline in memory. Finally, previous studies have focused on middle-aged adults, and a possible detrimental effect of aging on memory performance in chronic pain patients has been commonly disregarded. This study, therefore, aimed at describing the pattern of semantic, working, and visual and verbal episodic memory performance in participants with chronic pain, while testing for possible contributions of attention and age to task performance. METHODS: Thirty-four participants with chronic pain and 32 pain-free participants completed tests of episodic, semantic, and working memory to assess memory performance and a test of attention. RESULTS: Participants with chronic pain performed worse on tests of working memory and verbal episodic memory. A decline in attention explained some, but not all, group differences in memory performance. Finally, no additional effect of age on the diminished task performance in participants with chronic pain was observed. DISCUSSION: Taken together, the results indicate that chronic pain significantly affects memory performance. Part of this effect may be caused by underlying attentional dysfunction, although this could not fully explain the observed memory decline. An increase in age in combination with the presence of chronic pain did not additionally affect memory performance. PMID- 20842019 TI - Outcome evaluation of the Veterans Affairs Salt Lake City Integrative Health Clinic for Chronic Nonmalignant Pain. AB - OBJECTIVES: the purpose of this longitudinal outcome study was to investigate the effectiveness of the Integrative Health Clinic and Program, an innovative outpatient clinical service that provides nonpharmacologic, biopsychosocial interventions using research based mind-body skills and complementary and alternative therapies. The study assessed improvement in chronic nonmalignant pain and related depression, anxiety, and health-related quality of life. METHODS: the study was a retrospective post-hoc quasi-experimental design with a group analysis comparing chronic nonspinal-related pain (CNSP) (eg, joint pain, headache, and fibromyalgia) (n=53) to chronic spinal-related pain (CSP) (eg, back pain and neck pain) (n=88). Data were collected at intake and up to 4 follow-up visits. Hierarchical Linear Modeling was used for statistical analysis. Outcome measures included: Quality of Life (Short Form-36), the Beck Depression Inventory, and Beck Anxiety Inventory. RESULTS: there were statistically significant differences within and between the CNSP and CSP groups across all follow-up visits. For the CNSP group, depression, anxiety, and bodily pain significantly improved with moderate-to-large effect sizes at 6 months (Cohen's d=0.74, 0.53, and 0.66, respectively) and these benefits persisted across all follow-up visits. The CSP group showed an improvement trend in bodily pain (Cohen's d=0.26). DISCUSSION: significant study findings revealed that the greatest improvement after participation in Integrative Health Clinic and Program were seen in the CNSP group with benefits persisting to 24 months in mood and in some health-related quality of life subcategories. PMID- 20842020 TI - Catecholamine-o-methyltransferase polymorphisms are associated with postoperative pain intensity. AB - OBJECTIVES: single nucleotide polymorphisms (SNPs) in the genes for catecholamine O-methyltransferase (COMT), MU-opioid receptor and GTP cyclohydrolase (GCH1) have been linked to acute and chronic pain states. COMT polymorphisms are associated with experimental pain sensitivity and a chronic pain state. No such association has been identified perioperatively. We carried out a prospective observational clinical trial to examine associations between these parameters and the development of postoperative pain in patients undergoing third molar (M3) extraction. METHODS: psychologic and clinical parameters were measured prospectively in a single homogeneous cohort of 100 patients undergoing M3 extraction. We genotyped the patients for SNPs within GCH1, COMT, and MU-opioid receptor 1. Primary outcome was the occurrence of pain, 3 months after surgery. Other outcomes included pain measures in the early postoperative period and the week after surgery. RESULTS: seven patients (7/98; 7.1%) had persistent pain. Patients with and without persistent pain were similar in terms of perioperative demographic, psychological, and clinical parameters. The proportion who reported adequate postoperative analgesia was greater amongst those with the GG genotype for either rs4818 or rs6269 than those without (P<0.0001). The rare forms of COMT SNPs rs4818 and rs6269 were associated with postoperative pain of lesser intensity at rest (P=0.02, 0.03 respectively) and on movement (P=0.02, 0.01, respectively). The number of days until analgesia was not required during the first postoperative week was associated with GCH1 SNPs (rs8007267, P=0.05; rs3783641, P=0.01; rs10483636, P=0.002). DISCUSSION: we report an early demonstration of a COMT SNP association with a clinically meaningful pain outcome after elective surgery. PMID- 20842021 TI - A preliminary report of parent/nurse-controlled analgesia (PNCA) in infants and preschoolers. AB - BACKGROUND: infants and young children are often unable to verbalize pain or advocate for themselves which may increase their risk for poor pain assessment and management. Although patient-controlled analgesia (PCA) has been shown to be safe, effective, and superior to intermittent opioid dosing, infants and young children are not able to operate PCA independently. Allowing a parent or nurse to operate the PCA for the child [parent/nurse-controlled analgesia (PNCA)] may be an option for these children. However, the use of PNCA has been heavily scrutinized and more evidence of safety is needed to support this practice. OBJECTIVES: the primary purpose of this study was to evaluate safety outcomes associated with PNCA for infants and preschool aged children. Secondary outcomes regarding the frequency of untoward side effects and clinical effectiveness were also examined. METHODS: a retrospective review of treatment with PNCA was conducted from a convenience sample of charts for 107 infants and preschoolers. Data were collected for 72 hours or until the PNCA was discontinued. RESULTS: one hundred and seven infants and preschoolers with a mean age of 19.6 months (+/ 12.12) were represented in this study. Mean pain scores were low, as was the number of PNCA injections and attempts and amount of opioid administered. Common opioid side effects were reported. Naloxone was administered to 1.9% of patients for respiratory depression, and potential contributing factors were identified. DISCUSSION: diligent monitoring and education are crucial to ensure safety. Untoward side effects adverse events and pain scores suggest PNCA may be an effective method of pain control for this patient population. PMID- 20842022 TI - Noncardiac chest pain during war. AB - OBJECTIVES: Noncardiac chest pain (NCCP) has emerged as one of the biggest challenges facing military healthcare providers. The objectives of this study are to determine disease burden and diagnostic breakdown of NCCP, and to identify factors associated with return-to-duty (RTD). METHODS: Data were prospectively collected from the Deployed Warrior Medical Management Center in Germany on 1935 service and nonservice members medically evacuated out of Operations Iraqi and Enduring Freedom for a primary diagnosis of NCCP between 2004 and 2007. Electronic medical records were reviewed to examine the effect myriad factors had on RTD. RESULTS: One thousand nine hundred thirty-five personnel were medically evacuated with a diagnosis of NCCP, of whom 92% were men, 70% were in the Army, and 79% sustained their injury in Iraq. Fifty-eight percent returned to duty. The most common causes were musculoskeletal (23.4%), unknown (23%), cardiac (21%), pulmonary (13.9%), and gastrointestinal (11.9%). Factors associated with a positive outcome were being a commissioned officer [adjusted odds ratio (OR) 1.87, P=0.009]; serving in the navy (OR 2.25, P=0.051); having a noncardiac etiology, including gastrointestinal (adjusted OR 5.65, P<0.001), musculoskeletal (OR 4.19, P<0.001), pulmonary (OR 1.80, P=0.018), psychiatric (OR 2.11, P=0.040), or neuropathic (OR 5.05, P=0.040) causes; smoking history (OR 1.54, P=0.005); and receiving no treatment for chest pain (OR 2.17, P=0.006). Covariates associated with a decreased likelihood of RTD were service in Iraq (OR 0.68, P=0.029) and treatment with opioids (OR 0.59, P=0.006) or adjuvants (OR 0.61, P=0.026). CONCLUSIONS: NCCP represents a significant cause of soldier attrition during combat operations, but is associated with the highest RTD rate among any diagnostic category. Among various causes, gastrointestinal is associated with the highest RTD rate. PMID- 20842023 TI - Pressure and activity-related allodynia in delayed-onset muscle pain. AB - OBJECTIVES: Muscle pain from different activities was tested with the muscle pain expected to vary in ways that may clarify mechanisms of activity-induced exacerbation of myofascial pain. METHODS: Participants [N=20; 45% women; 23 y old (SD=2.09)] consented to participate in a 6 session protocol. Bilateral muscle pain ratings and pressure pain thresholds (PPTs) were collected before and for 4 days after lengthening (ie, eccentric) muscle contractions were completed with the nondominant elbow flexors to induce delayed-onset muscle pain. The muscle pain ratings were collected with the arms in several conditions (eg, resting, moving, and contracting in a static position) and PPTs were collected with the arms. RESULTS: In the ipsilateral arm, muscle pain ratings at rest and during activity significantly increased whereas PPTs significantly decreased after the eccentrics (etas=0.17 to 0.54). The greatest increases in pain occurred during arm extension without applied load, in which there was more stretching but less force than isometrics. In the contralateral arm, neither muscle pain nor PPTs changed from baseline. DISCUSSION: These results resemble earlier electrophysiology studies showing differential sensitization across stimuli and support that increased depth of information about aggravating activities from clinical patients is needed. PMID- 20842025 TI - Further validation of the BDI-II among people with chronic pain originating from musculoskeletal disorders. AB - OBJECTIVE: One criticism of the BDI-II for assessing depressive symptoms in people experiencing chronic pain has been the potential overlap between the physical or psychological origins of some of the symptoms. Furthermore, previous studies have reported both two-factor and three-factor solutions, so that the factor solution of the instrument in this population remains unclear. The main objective of the present study was to validate the BDI-II with a chronic pain population experiencing musculoskeletal disorders. Three specific objectives were: (1) to modify the BDI-II for people with musculoskeletal disorders by adding sub-questions to better identify the perceived cause of the depressive symptoms, (2) to assess the validity and reliability of this modified version of the BDI-II, and (3) to explore the perceptions of the causes/origins of symptoms reported on the BDI-II. Results of the confirmatory factor analysis supported the presence of three dimensions within the BDI- : Cognitive, Affective and Somatic. METHODS: A total of 206 participants experiencing chronic pain answered a modified version of the BDI-II, the CES-D and a sociodemographic questionnaire. RESULTS: Results confirmed the three-dimensional factorial structure of the BDI for this population. Overall, participants experienced higher levels of somatic symptoms compared to symptoms belonging to other dimensions. The percentages of answers to the sub-questions were also similarly distributed between "pain", and "pain and state of mind", regardless of the dimension. DISCUSSION: The importance of assessing somatic symptoms of depression in pain patients and of thoroughly examining the underlying perceived cause of symptoms, regardless of the dimension, are discussed. PMID- 20842026 TI - Nutritional modulation of nonalcoholic fatty liver disease and insulin resistance: human data. AB - PURPOSE OF REVIEW: Concomitant with the obesity epidemic, a fatty liver due to nonalcoholic causes has become the most common liver disorder. Nonalcoholic fatty liver disease (NAFLD) covers a range from benign steatosis to nonalcoholic steatohepatitis (NASH), which in turn may progress to cirrhosis. NAFLD predicts, independent of obesity, the metabolic syndrome and type 2 diabetes and can progress to cirrhosis. This review focuses on studies in humans addressing effects of dietary changes in NAFLD. RECENT FINDINGS: Cross-sectionally, increased intake of fructose and simple sugars characterizes patients with NAFLD compared with weight-matched controls. Increased fructose intake is also associated with hepatic insulin resistance and fibrosis severity in NASH. Intake of saturated fat may also be increased in NAFLD. Dietary intervention studies have shown that liver volume and fat content changes significantly within a few days in response to caloric restriction or excess despite no or small changes in body weight. Weight loss by bariatric surgery decreases liver fat and inflammation but effects on fibrosis are uncertain. Hepatic insulin sensitivity generally changes in parallel with changes in liver fat content in NAFLD. Human data are limited regarding effects of isocaloric changes in diet composition on liver fat content. SUMMARY: Maintenance of normal body weight and avoidance of intake of excess lipogenic simple sugars would seem beneficial for prevention of NAFLD and its metabolic consequences. PMID- 20842027 TI - Immune modulating effects of beta-glucan. AB - PURPOSE OF REVIEW: To examine the recent scientific literature on the immune modulating effects of beta-glucans and subsequent benefits on infection and cancer. RECENT FINDINGS: beta-Glucans have been investigated for their ability to protect against infection and cancer and more recently for their therapeutic potential when combined with cancer therapy. Their immune modulating effects are attributed to the ability to bind to pattern recognition receptors including complement receptor 3, scavenger receptors, lactosylceramide, and dectin-1 that results in activation of different aspects of the immune response depending on the cell types and species involved although there is some controversy about the relative importance of each of these receptors. Most of the available evidence comes from preclinical data and human studies are just now beginning to appear in the literature, therefore firm conclusions on its clinical importance cannot yet be made. Perhaps the most promising evidence to date in human trials has come from recent studies on a benefit of beta-glucan on quality of life and survival when given in combination with cancer treatment. We identify the need for future studies that compare purified forms of beta-glucans from different sources to further the understanding of the mechanisms of action and aid in the development of clinical studies. SUMMARY: beta-Glucans appear to be effective at enhancing immune function and reducing susceptibility to infection and cancer. A better understanding of the mechanisms of beta-glucan recognition and subsequent immune activation is necessary for the design of effective treatment approaches in future clinical trials. PMID- 20842024 TI - Epidemiology and pattern of care of breakthrough cancer pain in a longitudinal sample of cancer patients: results from the Cancer Pain Outcome Research Study Group. AB - OBJECTIVE: Breakthrough cancer pain (BTcP) is a frequent event in cancer patients, with a prevalence from 19% to 95%. The reasons for such variability are explained by several factors, including different definitions across studies. In the framework of a wider initiative, we have analyzed the epidemiology of BTcP and identified factors associated with the pattern of care. METHODS: This study reports the results from a multicenter, prospective, nonrandomized, longitudinal study carried out in Italy between 2006 and 2007 on patients with cancer and pain. Transient exacerbations of pain were assessed with 3 different questions, and 1 composite variable to operationally define BTcP was then used as main outcome. After univariate analysis, a logistic model was also fitted to identify prognostic and predictive factors. RESULTS: One hundred and ten centers recruited 1801 cases of which 40.3% had BTcP at baseline. Most patients did not receive rescue therapy at the time of study inclusion. Univariate analysis identified several associations with clinical variables. A strong association has been also found with the type of recruiting centers, with oncologic wards reporting a somewhat lower proportion of patients with BTcP (-30%) when compared with palliative centers. Patients with BTcP had a high probability of dying (OR=1.4, 95% CI: 1.1-1.7, P-value 0.006) and to change of the opioid with another for analgesic failure or for side effects (OR=1.4, 95% CI: 1.0-1.9, P-value 0.040) DISCUSSION: These findings confirm the high prevalence of BTcP and substantial undertreatment and identify a few factors associated with prevalence and prognosis. PMID- 20842028 TI - Inflammatory signaling in skeletal muscle insulin resistance: green signal for nutritional intervention? AB - PURPOSE OF REVIEW: To review the evidence implying a role of inflammatory signaling pathways, specifically nuclear factor-kappaB and c-Jun NH2-terminal kinase, in fatty acid-induced skeletal muscle insulin resistance and to discuss the potential of dietary interventions to interfere with these processes. RECENT FINDINGS: Fatty acids can induce skeletal muscle insulin resistance via inflammatory signaling after binding Toll-like receptors at the cell membrane of muscle cells or after accumulating as intramyocellular lipid metabolites. In both processes, activation of intracellular inflammatory signaling is involved. The majority of literature addressing the causality of muscle nuclear factor-kappaB activation in skeletal muscle insulin resistance suggests that insulin resistance does not require muscle nuclear factor-kappaB activation. Recently, strong evidence was given that c-Jun NH2-terminal kinase signaling is an important inflammatory pathway involved in skeletal muscle insulin resistance. Furthermore, it is well established that proinflammatory cytokines originating from the enlarged adipose tissue or from activated adipose tissue macrophages can cause muscle insulin resistance. Recently, also macrophages resided in the muscle have been proposed to play an important role in muscle insulin resistance. Because of their anti-inflammatory characteristics, several dietary components like polyphenols may be interesting candidates for manipulating skeletal muscle insulin resistance. SUMMARY: Several dietary components, like polyphenols, have been reported to interfere with inflammatory signaling. To test whether these compounds can be used to prevent or reverse insulin resistance, well controlled human intervention studies have to be designed. PMID- 20842029 TI - The growing role for genetic counseling in endocrinology. AB - PURPOSE OF REVIEW: The field of cancer genetics and genetic testing is expanding rapidly. As our understanding of the hereditary nature of endocrine tumors increases, the role of genetic counseling on the multidisciplinary endocrinology team is becoming more critical. This brief review will highlight the role of the certified genetic counselor in this setting. RECENT FINDINGS: Genetic counseling and testing may aid in the management of the endocrine patient through early diagnosis and detection of disease, by optimizing surgical decision-making and improving overall survival. Certified genetic counselors assist the endocrinology team by eliciting a detailed pedigree, determining the appropriate genetic test to order, obtaining informed consent, interpreting complex genetic test results, providing psychosocial and family counseling, and assessing which family members are at risk. Many endocrine tumors can be caused by a variety of different genes and investment in the genetic counseling process likely increases the chance that the correct genetic test is ordered, results are interpreted accurately, and adequate informed consent and counseling is offered. SUMMARY: The field of endocrine genetics is growing exponentially and testing will likely play an even greater role in surveillance, medical management, and surgical decision-making in the next decade. Genetic counseling both pretesting and posttesting is essential to accurate, cost-efficient care for the endocrine patient and the entire family. PMID- 20842030 TI - Implication of tumor microenvironment in the resistance to chemotherapy in breast cancer patients. AB - PURPOSE OF REVIEW: Chemotherapy is a cornerstone treatment in patients with early breast cancer. Although some cancer cell-related predictors are emerging, the indications of chemotherapy and the choice of chemotherapy regimen are not individualized enough, emphasizing the need for new predictors. This review will summarize recent advances concerning the implication of tumor microenvironment in the response to chemotherapy. RECENT FINDINGS: In recent years, some data have emerged suggesting that microenvironment could be involved in chemotherapy efficacy. The infiltration of tumor by lymphocytes has been highly correlated with the sensitivity to chemotherapy. These data are consistent with the discovery that anthracyclines could induce immune activation through immunogenic cell death. At the opposite, gene expression analyses have suggested that a stroma signature could predict resistance to neoadjuvant chemotherapy. Finally, chemotherapy has been shown to induce a spike of progenitors for endothelial cells, a mechanism that in turns mediates angiogenesis repopulation. SUMMARY: Preliminary data from pioneer studies suggest that tumor microenvironment could be involved in chemotherapy sensitivity and resistance. Such knowledge could generate two advances: simple predictors for chemotherapy efficacy based on pathology could be generated and strategies that aim at reversing drug resistance could be developed. PMID- 20842031 TI - Molecular imaging of HER2-positive breast cancer: a step toward an individualized 'image and treat' strategy. AB - PURPOSE OF REVIEW: HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate individual approaches to targeted therapy of HER2-positive breast cancers. RECENT FINDINGS: Because of the heterogeneity of breast cancer and possible discordance in HER2 status between primary tumors and distant metastases, assessment of HER2 expression by noninvasive imaging may become an important complement to immunohistochemistry or fluorescence in-situ hybridization analyses of biopsied tissue. Monoclonal antibodies such as trastuzumab and pertuzumab, or small scaffold proteins such as affibody molecules are used as HER2-targeting agents. For imaging purposes, these agents are labeled with positron or gamma-emitting radionuclides, optical dyes, or paramagnetic contrast molecules for positron emission tomography single photon emission tomography optical, and magnetic resonance imaging, respectively. HER2-specific molecular probes, combined with modern imaging techniques to provide information on HER2 expression not only in primary tumors but also in distant metastases not amenable to biopsy, may reduce problems with false negative results and, thereby, influence patient management by selecting patients that would benefit from HER2 targeted therapies. SUMMARY: The new 'image and treat' strategy, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, may potentially improve efficacy of cancer treatment while reducing side effects. PMID- 20842032 TI - An update on the cause and treatment of scleritis. AB - PURPOSE OF REVIEW: To review new clinically relevant data regarding the cause and treatment of scleritis that has been identified over the past 36 months. RECENT FINDINGS: A recently described T-helper cell population, known as Th-17, has been implicated in scleritis. Large-scale, retrospective reviews of standard corticosteroid-sparing systemic therapies, published in the last few years, have demonstrated only moderate efficacy for any particular immunomodulatory agent, whereas new data have confirmed excellent efficacy and tolerability to subconjunctival corticosteroids. SUMMARY: Improved understanding of the immunopathophysiology of scleritis offers hope for future molecule-specific drug design. Data continue to support the use of local steroids as a reasonable therapeutic option for nonnecrotizing, noninfectious anterior scleritis. PMID- 20842033 TI - Tissue engineering for treatment of vocal fold scar. AB - PURPOSE OF REVIEW: Creating a neovocal fold or lamina propria by tissue engineering is a potential scheme for treating severe vocal fold scar. Although still investigational, multiple approaches have recently been described in tissue culture or animal models. RECENT FINDINGS: Proposed cell types for vocal fold application have been native vocal fold fibroblasts, autologous fibroblasts from nonlaryngeal tissues, and adult-derived stem cells. Scaffolds of interest include decellularized matrix, biological polymers, and synthetic or chemically modified biopolymers. Chemical, mechanical, and spatial signals have been applied, such as hepatocyte growth factor, cyclic stretch, and air interface. Cells, matrix, and signals are combined in an effort to replicate normal vocal fold tissue as closely as possible. Each of these components of vocal fold tissue engineering is discussed here. SUMMARY: Multiple tissue engineering approaches hold promise for reproducing functional vocal fold tissue. Scar prevention techniques have been the most successful. Modifying existing scar is more difficult and may necessitate complete scar excision and replacement with a three-dimensional neotissue. Functional assessment in vivo is essential to the ongoing evaluation of techniques. PMID- 20842034 TI - Autologous fat implantation for vocal fold scar. AB - PURPOSE OF REVIEW: To evaluate current information and practice regarding autologous fat implantation for treatment of vocal fold scar and to summarize the surgical technique. RECENT FINDINGS: There has been no recent literature on this topic. SUMMARY: Autologous fat implantation is useful and effective for severe and/or extensive vocal fold scar. PMID- 20842035 TI - Pulse dye and other laser treatments for vocal scar. AB - PURPOSE OF REVIEW: Vocal fold scar is a challenging clinical problem, resulting in a spectrum of voice-related complaints. While there are a variety of treatment options available, it is rare to obtain outcomes similar to the perfectly normal voice. The pulsed dye and other lasers are an emerging treatment option for cutaneous scar and have shown promise for the treatment of vocal fold scarring. The purpose of this review is to summarize the theory, and describe clinical outcomes from both cutaneous and vocal fold scarring treated with lasers. RECENT FINDINGS: There are a growing number of papers in the literature substantiating the use of pulsed dye and other lasers used to treat cutaneous scars. Some experimental models describe potential mechanisms of laser effect, which include the development of a sub-basement membrane cleavage plane, as well as up regulation of proteins which may actively modulate continued fibrosis. One prospective pilot study of 11 patients with vocal fold scarring treated with the pulsed dye laser has also shown statistically significant improvement in subjective and objective voice measures, as well as laryngeal stroboscopy findings after treatment. SUMMARY: The pulsed dye and other lasers have shown effectiveness and potential in treating cutaneous and vocal scarring. PMID- 20842036 TI - Whither adaptive servo-ventilation? PMID- 20842037 TI - Surgical treatment of obstructive sleep apnea: standard and emerging techniques. AB - PURPOSE OF REVIEW: Patients with obstructive sleep apnea (OSA), as well as their physicians, seek alternative therapies to continuous positive airway pressure (CPAP) due to problems with CPAP adherence. A large variety of surgical options exist, and each intervention must be individually evaluated. The author performed a literature search concerning surgery for sleep apnea until May 2010. The studies were evaluated according to evidence-based medicine criteria. RECENT FINDINGS: An increasing number of controlled and even randomized controlled trials are available. Minimally invasive surgery remains under debate due to the very limited efficacy versus very low morbidity. Uvulopalatopharyngoplasty is still the standard procedure for many patients with moderate OSA, whereas maxillomandibular advancement is as effective as CPAP in severe OSA. Multilevel surgery is reserved to secondary treatment after CPAP failure. Tonsillectomy and maxillomandibular advancement may be offered as a first-line treatment in certain patients. There is increasing evidence that upper airway surgery has a positive impact on arterial hypertension, markers of cardiovascular disease, insomnia, daytime symptoms, quality of life, and CPAP adherence. SUMMARY: Patients who are nonadherent to CPAP must be thoroughly evaluated before choosing any of the available surgical options. Upper airway surgery may improve disease markers of OSA, if appropriately chosen and properly indicated and performed. PMID- 20842038 TI - Neurologists are from Mars. Rheumatologists are from Venus: differences in approach to classifying the idiopathic inflammatory myopathies. AB - PURPOSE OF REVIEW: Inflammatory myopathy (IIM) classification criteria have been the source of considerable debate. In the three decades since Bohan and Peter published their criteria which have long stood as the gold standard for diagnosis in clinical practice as well as inclusion into clinical trials, more sophisticated understanding of immunopathogenesis, histology, and specific autoantibody associations has broadened our understanding of these diseases. This editorial review examines the diverse approaches between different subspecialists in deriving appropriate IIM classification utilizing this updated knowledge. RECENT FINDINGS: Several investigators have proposed improved IIM classification criteria. More recently, larger scale consensus efforts have been undertaken by various expert groups including the European Neuromuscular Centre (ENMC) and The International Myositis Assessment and Clinical Studies Group (IMACS). The intent is to refine the classification criteria utilizing our enhanced understanding which has matured since the original publication of Bohan and Peter's proposal in 1975. SUMMARY: Many diagnostic/classification criteria have been proposed for different forms of IIM over the last three decades. The majority of these have been based on clinical impressions rather than rigorous data analyses or expert consensus and none has been fully tested for sensitivity or specificity using appropriately powered studies that take into account relevant disease confounders. Different sets of criteria proposed and adopted by different specialties hamper the ability to compare clinical studies and assess clinical trials' outcomes. Large, multicentered, multispecialty studies are required to develop improved IIM criteria. PMID- 20842039 TI - Case report: intraoperative hypoglycaemia in a child treated with propranolol following a short preoperative fast. PMID- 20842040 TI - The utility of shock index in differentiating major from minor injury. AB - OBJECTIVE: The importance of early recognition of hemorrhagic shock and its effects on outcome have long been recognized. Traditional vital signs are relatively insensitive as early diagnostic markers of hemorrhage. The shock index (SI); heart rate (HR) divided by systolic blood pressure (SBP), has been suggested as such a marker. We tested the diagnostic utility of the SI in differentiating major from minor injury in trauma patients. METHODS: Retrospective study of a prospectively collected observational cohort at a level I trauma center. Demographics, injury mechanism, HR, SBP, base deficit and lactate were recorded and Injury Severity Score were calculated. Major injury was defined as either a change in hematocrit greater than 10 or blood transfusion requirement during initial 24 h, or Injury Severity Score greater than 15. RESULTS: One thousand four hundred and thirty-five trauma patients were enrolled, average age 35.2+/-16.9 years. Two hundred and forty-two were classified as major injury. The area under the receiver operator characteristic curves for SI [0.63 95% confidence interval (CI) 0.59-0.67] was significantly less than that for base deficit (0.72, 95% CI: 0.69-0.76) or lactate (0.69, 95% CI: 0.65-0.73). The diagnostic performance of SI was slightly better than HR (0.58) but not SBP (0.61). To reach sensitivity of 90%, the SI must be 0.5, well in the range of a normal SBP and HR. CONCLUSION: The SI can be a valuable tool, raising suspicion when it is abnormal even when other parameters are not, but is far too insensitive for use as a screening device to rule out disease. A normal SI should not lower the suspicion of major injury. PMID- 20842041 TI - Comparison of GlideScope video laryngoscope and intubating laryngeal mask airway with direct laryngoscopy for endotracheal intubation. AB - The aim of this study was to determine whether GlideScope video laryngoscope (GVL) and intubating laryngeal mask airway (i-LMA) improve the intubation success rate and could be easily learned and performed by paramedic students when compared with the direct laryngoscopic (DL) method. The study was designed as a prospective randomized crossover trial that included 121 paramedic students. All participants were asked to intubate each Ambu Airway Management Trainer manikins after the lecture and demonstration. Successful intubation was defined as the passage of the tube through the vocal cord within 60 s. At the end of the study, a questionnaire survey was given to all participants about their preferences, and they were requested to define each method on an easy-difficult scale. Successful intubation was achieved by 95 students (78.5%) with DL, 112 students (92.6%) with i-LMA, and 111 students (91.7%) with GVL. Mean time of intubation was 25.06+/-14 s for DL, 22.32+/-12 s for i-LMA, and 22.63+/-10 s for GVL. Success rates of i LMA and GVL were significantly higher compared with DL (P=0.005 and P=0.006, respectively). No significant difference was determined between i-LMA and GVL in terms of successful intubation (P>0.05). This study showed that GVL and i-LMA provided better intubation success rates and were easier for paramedic students when compared with the classic DL method. PMID- 20842044 TI - Metabolic syndrome: identification and management in cardiac rehabilitation. AB - PURPOSE: The prevalence of metabolic syndrome in cardiac rehabilitation (CR) makes CR an ideal place to offer interventions to address metabolic syndrome related risk. There is a lack of research related to the metabolic syndrome practices in CR. Therefore, the purpose of this research was to describe practices to assess CR patients for metabolic syndrome, interventions specific to metabolic syndrome, and staff knowledge and beliefs related to metabolic syndrome. METHODS: This was a cross-sectional study of CR providers in Ohio (n = 94). Program practices and interventions and staff knowledge and beliefs were assessed and stratified on the program use of case management, program certification by the American Association of Cardiovascular and Pulmonary Rehabilitation, and staff profession. RESULTS: At CR entry, 26% of the programs assessed patients for the metabolic syndrome and 8% had written guidelines for metabolic syndrome. Less than half of the staff (47%) was able to name 3 or more risk factors for metabolic syndrome. Programs using case management were more likely to identify metabolic syndrome (P < .001), measure waist circumference (P < .001), order a new lipid profile (P = .04) at program entry, and have written guidelines for managing metabolic syndrome (P = .01) than programs not using case management. No differences were observed in stratified analyses for the program certification or staff profession. CONCLUSIONS: The majority of CR programs do not assess patients for metabolic syndrome or have written guidelines for the metabolic syndrome. Opportunities exist for better management of metabolic syndrome in CR. PMID- 20842042 TI - Contraceptive efficacy of oral and transdermal hormones when co-administered with protease inhibitors in HIV-1-infected women: pharmacokinetic results of ACTG trial A5188. AB - BACKGROUND: Pharmacokinetic (PK) interactions between lopinavir/ritonavir (LPV/r) and transdermally delivered ethinyl estradiol (EE) and norelgestromin (NGMN) are unknown. METHODS: Using a standard noncompartmental PK analysis, we compared EE area under the time-concentration curve (AUC) and NGMN AUC during transdermal contraceptive patch administration in HIV-1-infected women on stable LPV/r to a control group of women not on highly active antiretroviral therapy (HAART). In addition, EE AUC after a single dose of a combination oral contraceptive pill including EE and norethindrone was measured before patch placement and was compared with patch EE AUC in both groups. Contraceptive effects on LPV/r PKs were estimated by measuring LPV/r AUC at baseline and during week 3 of patch administration. RESULTS: Eight women on LPV/r, and 24 women in the control group were enrolled. Patch EE median AUC0-168 h was 45% lower at 6010.36 pg.h.mL in those on LPV/r versus 10911.42 pg.h.mL in those on no HAART (P = 0.064). Pill EE median AUC0-48 hours was similarly 55% lower at 344.67 pg.h.mL in those on LPV/r versus 765.38 pg.h.mL in those on no HAART (P = 0.003). Patch NGMN AUC0-168 h however, was 138.39 ng.h.mL, 83% higher in the LPV/r group compared with the control AUC of 75.63 ng.h.mL (P = 0.036). After 3 weeks on the patch, LPV AUC0-8 h decreased by 19%, (P = 0.156). CONCLUSIONS: Although PKs of contraceptive EE and NGMN are significantly altered with LPV/r, the contraceptive efficacy of the patch is likely to be maintained. Larger studies are indicated to fully assess contraceptive efficacy versus risks of the transdermal contraceptive patch when co-administered with protease inhibitors. PMID- 20842043 TI - Antiretroviral therapy outcomes of HIV-infected children in the TREAT Asia pediatric HIV observational database. AB - INTRODUCTION: We report responses to combination antiretroviral therapy (cART) in the Therapeutics Research, Education, and AIDS Training in Asia Pediatric HIV Observational Database. METHODS: Children included were those who had received cART (ie, >=3 antiretrovirals) at <18 years. The analysis was intention-to-treat by the first cART regimen. Median values are provided with interquartile ranges; hazard ratios (HRs) with 95% confidence intervals. RESULTS: Of the 1655 children included, 50.4% were male, with a median age at cART of 7.0 (3.9-9.8) years and CD4 of 8% (2.0%-15%); 92.5% were started on an NNRTI; median duration of follow up was 2.9 (1.4-4.6) years. Loss-to-follow-up and death rates were 4.2 (3.7-4.8) and 2.1 (1.7-2.5) per 100 person-years, respectively. At 36 months, median CD4 was 26% (21%-31%); 81% of those with viral load (n = 302) were <400 copies per milliliter. Children who reached CD4 >=25% within 5 years were more likely to be females (HR: 1.4; 1.2-1.7), start before 18 months old (HR: 3.8; 2.4-6.2), lack a history of monotherapy/dual therapy (HR: 1.7; 1.4-2.5), and have a higher baseline CD4 (per 10% increase: HR: 2; 1.9-2.2). CONCLUSIONS: These data underscore the need for early diagnosis and cART initiation to preserve immune function. PMID- 20842045 TI - Antihypertensive treatment after first stroke in primary care: results from the General Practitioner Research Database. AB - OBJECTIVES: Secondary stroke prevention guidelines emphasize antihypertensive treatment (AHT). Routine data on recommended AHT are lacking. AIM: To estimate the use of any antihypertensive and guideline-recommended antihypertensive use in first ever stroke patients and their effects on survival and recurrence after 1 year in an unbiased population. METHODS: The General Practitioner Research Database (GPRD) contains primary care information across the UK. Forty-eight thousand two hundred and thirty-nine registered patients with first stroke between 1997 and 2006 were identified. Guideline AHT was defined based on guidelines of the British Hypertension Society. The impact of AHT on survival or recurrence-free survival was estimated using Cox regression adjusting for treatment propensity scores. RESULTS: AHT was prescribed to 75% of hypertensive stroke patients surviving 3 months after stroke, increasing from 66% in 1997 to 83% in 2006 (P < 0.001). Eighteen per cent of hypertensive stroke patients surviving 3 months had no AHT prior to stroke, of whom 45% received any AHT after stroke but only 31% received AHT recommended by guidelines (increasing from 24% in 1997 to 37% in 2006; P < 0.001). AHT was associated with lower mortality [adjusted hazard ratio compared to no treatment 0.79, 95% confidence interval (CI) 0.63-1.00 for nonguideline treatment and hazard ratio 0.63, 95% CI 0.53-0.75 for guideline treatment); guideline treatment also reduced risk of recurrent stroke (hazard ratio 0.82, 95% CI 0.71-0.96). CONCLUSIONS: Prescription of AHT and most appropriate AHT improved over time. Guideline-recommended AHT was beneficial compared with no or other AHT. PMID- 20842046 TI - The progressive pathway of microalbuminuria: from early marker of renal damage to strong cardiovascular risk predictor. AB - There is clear evidence that urinary albumin excretion levels, even below the cut off values currently used to diagnose microalbuminuria, are associated with an increased risk of cardiovascular events. The relationships of microalbuminuria with a variety of risk factors, such as hypertension, diabetes and metabolic syndrome and with several indices of subclinical organ damage, may contribute, at least in part, to explain the enhanced cardiovascular risk conferred by microalbuminuria. Nonetheless, several studies showed that the association between microalbuminuria and cardiovascular disease remains when all these risk factors are taken into account in multivariate analyses. Therefore, the exact pathophysiological mechanisms explaining the association between microalbuminuria and cardiovascular risk remain incompletely understood. The simple search for microalbuminuria in hypertensive patients may enable the clinician to better assess absolute cardiovascular risk, and its identification may induce physicians to encourage patients to make healthy lifestyle changes and perhaps would prompt to more aggressive modification of standard cardiovascular risk factors. PMID- 20842047 TI - Endogenous ouabain and the renin-angiotensin-aldosterone system: distinct effects on Na handling and blood pressure in human hypertension. AB - OBJECTIVE: To evaluate whether the renin-angiotensin-aldosterone system (RAAS) and endogenous ouabain system differently affect renal Na handling and blood pressure. METHODS: Three hundred and one patients in whom we compared blood pressure, and renal Na tubular reabsorption in the basal condition and 2 h (T120) after saline infusion. RESULTS: Following multivariate-adjusted linear and quartiles analysis, baseline mean blood pressure (MBP) was significantly higher (113.7 +/- 1.33 mmHg) in the fourth versus the first endogenous ouabain quartile (103.8 +/- 1.04 mmHg) and the trend across the quartiles was highly significant (beta = 0.23, P = 3.53e-04). In contrast, an inverse relationship was present in the renin activity (PRA) quartiles with MBP highest in the first (112.5 +/- 1.26) and lowest in the fourth PRA quartile (107.6 +/- 1.48, P = 0.039). Following an acute saline load, changes in MBP and the slope of the pressure-natriuresis relationship were inversely related across the PRA quartiles. The fractional excretion of sodium (FENa) showed a negative linear trend going from the first to the third endogenous ouabain quartiles (2.35 +/- 0.17 and 1.90 +/- 0.14%, P = 0.05). Patients in the fourth endogenous ouabain quartile (>323 pmol/l) showed increased FENa T120 (2.78 +/- 0.18%, P < 0.01) and increased Na tubular rejection fraction (P = 0.007) after Na load. After the saline load, there was a biphasic relationship between plasma endogenous ouabain and FENa favoring Na retention at low endogenous ouabain and Na excretion at high endogenous ouabain levels. CONCLUSION: The RAAS and endogenous ouabain system are two independent and complementary systems having an inverse (RAAS) or a direct (endogenous ouabain system) relationship with hemodynamic parameters. PMID- 20842048 TI - Hepatocyte growth factor attenuates renal fibrosis through TGF-beta1 suppression by apoptosis of myofibroblasts. AB - OBJECTIVE: The progression of chronic kidney disease (CKD) is characterized by the persistent accumulation of extracellular matrix. Especially, alpha-SMA positive myofibroblasts producing large amounts of TGF-beta1 are considered to play a key role in interstitial fibrosis. Although hepatocyte growth factor (HGF) improved renal fibrosis in various models, the molecular mechanisms involved are not yet fully understood. METHODS AND RESULTS: In this study, the molecular mechanisms of the inhibition of fibrosis by HGF was examined using HGF transgenic mice (HGF-Tg) with angiotensin II (Ang II) infusion in 4 weeks models. HGF-Tg mice showed significantly decreased Ang II-induced renal fibrosis and lesser numbers of interstitial myofibroblasts, whereas the antifibrotic effect of HGF was abrogated using HGF-neutralizing antibody. The antifibrotic action in HGF-Tg mice was concordant with a decrease in TGF- beta1, collagen type I and IV mRNA expression and an increase in MMP-2 and MMP-9 expression. Furthermore, HGF-Tg mice treated with Ang II showed apoptosis of myofibroblasts. To further investigate the antifibrotic effect of HGF, cultured human mesangial cells were used. HGF induced apoptosis of myofibroblast. Inhibition of the FAK-ERK-MMP signaling cascade by specific inhibitor or siRNA significantly decreased HGF induced myofibroblast apoptosis. CONCLUSION: The present study demonstrates that the increase in metalloproteinases through FAK-ERK signaling by HGF promotes myofibroblast apoptosis. Activation of metalloproteinases by HGF in the fibrotic kidney might be considered to attenuate the progression of CKD. PMID- 20842049 TI - Comparison of two automatic methods for the assessment of brachial artery flow mediated dilation. AB - OBJECTIVES: Brachial artery flow-mediated dilation (FMD) is associated with risk factors providing information on cardiovascular prognosis. Despite the large effort to standardize the methodology, the FMD examination is still characterized by problems of reproducibility and reliability that can be partially overcome with the use of automatic systems. We developed real-time software for the assessment of brachial FMD (FMD Studio, Institute of Clinical Physiology, Pisa, Italy) from ultrasound images. The aim of this study is to compare our system with another automatic method (Brachial Analyzer, MIA LLC, IA, USA) which is currently considered as a reference method in FMD assessment. METHODS: The agreement between systems was assessed as follows. Protocol 1: Mean baseline (Basal), maximal (Max) brachial artery diameter after forearm ischemia and FMD, calculated as maximal percentage diameter increase, have been evaluated in 60 recorded FMD sequences. Protocol 2: Values of diameter and FMD have been evaluated in 618 frames extracted from 12 sequences. RESULTS: All biases are negligible and standard deviations of the differences are satisfactory (protocol 1: -0.27 +/- 0.59%; protocol 2: -0.26 +/- 0.61%) for FMD measurements. Analysis times were reduced (-33%) when FMD Studio is used. Rejected examinations due to the poor quality were 2% with the FMD Studio and 5% with the Brachial Analyzer. CONCLUSIONS: In conclusion, the compared systems show a optimal grade of agreement and they can be used interchangeably. Thus, the use of a system characterized by real-time functionalities could represent a referral method for assessing endothelial function in clinical trials. PMID- 20842050 TI - Impact of prolonged cardiac unloading on left ventricular mass and longitudinal myocardial performance: an experimental bed rest study in humans. AB - OBJECTIVE: This study evaluated the impact of prolonged circulatory unloading and subsequent left ventricular (LV) mass decrease on LV myocardial performance. Five week head-down tilt (-6 degrees ) bed rest (HDTBR) was used as a model of prolonged circulatory unloading. METHODS: Ten young healthy male volunteers (age 23 +/- 2 years) were studied a day before and within the first 24 h after the end of HDTBR by two-dimensional Doppler echocardiography and carotid applanation tonometry. LV preload and afterload, cardiac workload, LV mass and wall stress, LV chamber function and diastolic filling were assessed. Longitudinal, radial and circumferential myocardial strain rate were evaluated by tissue tracking algorithm. RESULTS: After HDTBR, stroke volume (P < 0.01), stroke work (P = 0.01) and LV mass (P < 0.001) decreased, whereas relative wall thickness, peak and end systolic wall stress and ejection fraction remained unchanged. HDTBR was also followed by a decrease in longitudinal systolic strain rate (-1.11 +/- 0.05 vs. 1.00 +/- 0.05 s, P = 0.02) and a prolongation of isovolumic relaxation time (IVRT) (74 +/- 2 vs. 82 +/- 3 ms, P < 0.01). Bed rest-induced changes in LV mass index were directly related to changes in stroke work index (r = 0.65, P < 0.05), and changes in longitudinal systolic strain rate and IVRT correlated with changes in stroke volume index, directly and inversely, respectively (r = 0.69 and -0.64, P < 0.05 for both). CONCLUSION: A decrease in LV mass following HDTBR parallels the reduction in cardiac workload and is associated with an attenuation of longitudinal systolic myocardial deformation rate and prolongation of IVRT that seem to reflect a functional adaptation of cardiac muscle to lower LV volume load. PMID- 20842052 TI - Tumor infiltrating lymphocyte therapy for metastatic melanoma: analysis of tumors resected for TIL. AB - Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) can mediate objective tumor regression in 49% to 72% of patients with many long-term durable responses. To undergo treatment a patient must have (1) a resectable tumor from which (2) TIL can be generated that (3) exhibit tumor-specific reactivity. From July 2002 to July 2007, 787 tumors from 402 patients were processed for possible use in the generation of TIL, leading to the eventual treatment of 107 patients (27%). Viable TILs were generated in 376 patients (94%), and active, specific TILs were identified in 269 patients (67%). Patient demographics and tumor characteristics were analyzed for possible prognostic factors for growth and activity. Gastrointestinal-derived TIL grew less frequently, whereas lymph node and lung-derived TIL exhibited specific activity more often. TIL that grew and exhibited specific reactivity were from tumors that were larger in diameter and digests that had a higher percentage of lymphocytes. Despite these considerations, active, specific TIL could be generated from almost any site of metastasis. As more centers begin exploring the use of adoptive transfer with TIL, this compendium may provide a framework for therapeutic decision making and future investigation. PMID- 20842051 TI - Memory and effector CD8 T-cell responses after nanoparticle vaccination of melanoma patients. AB - Induction of cytotoxic CD8 T-cell responses is enhanced by the exclusive presentation of antigen through dendritic cells, and by innate stimuli, such as toll-like receptor ligands. On the basis of these 2 principles, we designed a vaccine against melanoma. Specifically, we linked the melanoma-specific Melan A/Mart-1 peptide to virus-like nanoparticles loaded with A-type CpG, a ligand for toll-like receptor 9. Melan-A/Mart-1 peptide was cross-presented, as shown in vitro with human dendritic cells and in HLA-A2 transgenic mice. A phase I/II study in stage II-IV melanoma patients showed that the vaccine was well tolerated, and that 14/22 patients generated ex vivo detectable T-cell responses, with in part multifunctional T cells capable to degranulate and produce IFN gamma, TNF-alpha, and IL-2. No significant influence of the route of immunization (subcutaneous versus intradermal) nor dosing regimen (weekly versus daily clusters) could be observed. It is interesting to note that, relatively large fractions of responding specific T cells exhibited a central memory phenotype, more than what is achieved by other nonlive vaccines. We conclude that vaccination with CpG loaded virus-like nanoparticles is associated with a human CD8 T-cell response with properties of a potential long-term immune protection from the disease. PMID- 20842053 TI - Sarcoidosis induced by interferon-alpha in melanoma patients: incidence, clinical manifestations, and management strategies. AB - Treatment with interferon-alpha has been recommended for patients with melanoma in case of micrometastases, or high risk melanoma, for example, ulcerated melanoma. Furthermore, regular dermatologic examination and regular imaging to detect recurrence or progression of disease is part of the management of melanoma patients. Sarcoidosis has been described as an adverse effect of treatment with interferon-alpha. Especially in hepatitis C patients, there is a series of case reports on sarcoidosis induced by interferon treatment whereas in melanoma this has rarely been reported. In a retrospective study, all melanoma patients treated with interferon-alpha at our hospital between 2007 and 2009 were screened for occurrence of sarcoidosis. Three of 16 melanoma patients treated with interferon alpha (19%) presented with sarcoidosis. All 3 patients showed lesions with higher uptake in the positron emission tomography-computed tomography scan leading to the differential diagnosis of melanoma metastases or inflammation. Skin lesions were present in 1 patient. Diagnosis was confirmed by histologic assessment of lesions showing epithelioid granuloma-negative on Ziehl Neelson. Additional work up included blood and urinalysis, electrocardiography, and ophthalmologic examination. Cessation of interferon-alpha led to regression of granulomas. Sarcoidosis induced by interferon-alpha in melanoma patients could be more common than previously thought. This is an important complication to be aware of as it can be mistaken for metastatic spread of melanoma and thus lead to incorrect therapy. PMID- 20842054 TI - Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. AB - New, effective therapies are needed for pancreatic ductal adenocarcinoma. Ipilimumab can mediate an immunologic tumor regression in other histologies. This phase II trial evaluated the efficacy of Ipilimumab for advanced pancreatic cancer. Subjects were adults with locally advanced or metastatic pancreas adenocarcinoma with measurable disease, good performance status, and minimal comorbidities. Ipilimumab was administered intravenously (3.0 mg/kg every 3 wk; 4 doses/course) for a maximum of 2 courses. Response rate by response evaluation criteria in solid tumors criteria and toxicity were measured. Twenty-seven subjects were enrolled (metastatic disease: 20 and locally advanced: 7) with median age of 55 years (27 to 68 y) and good performance status (26 with Eastern Cooperative Oncology Group performance status =0 to 1). Three subjects experienced >= grade 3 immune-mediated adverse events (colitis:1, encephalitis:1, hypohysitis:1). There were no responders by response evaluation criteria in solid tumors criteria but a subject experienced a delayed response after initial progressive disease. In this subject, new metastases after 2 doses of Ipilimumab established progressive disease. But continued administration of the agent per protocol resulted in significant delayed regression of the primary lesion and 20 hepatic metastases. This was reflected in tumor markers normalization, and clinically significant improvement of performance status. Single agent Ipilimumab at 3.0 mg/kg/dose is ineffective for the treatment of advanced pancreas cancer. However, a significant delayed response in one subject of this trial suggests that immunotherapeutic approaches to pancreas cancer deserve further exploration. PMID- 20842055 TI - Changes in dendritic cell phenotype after a new high-dose weekly schedule of interleukin-2 therapy for kidney cancer and melanoma. AB - High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2 induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer. PMID- 20842056 TI - CD40 expression by human melanocytic lesions and melanoma cell lines and direct CD40 targeting with the therapeutic anti-CD40 antibody CP-870,893. AB - Anti-CD40 antibodies are in clinical development in patients with metastatic melanoma, a cancer that has been reported earlier to express CD40. The antitumor activity of anti-CD40 antibodies may be mediated by direct cytotoxic effects on CD40-positive melanoma cells or indirectly through modulation of host cells. In these studies, biopsies of patients with primary and metastatic melanoma, short term cultures, and established melanoma cell lines were analyzed for CD40 expression using a combination of methods including immunohistochemistry, flow cytometry, and gene expression profiling, and the cytotoxic effects of the anti CD40 antibody CP-870,893 on melanoma cell lines were tested using cell viability assays. CD40 was expressed at a higher frequency in metastatic melanoma lesions compared with primary melanomas. There was a variable expression of CD40 in synchronous and metachronous melanoma metastases. Expression of CD40 was present in slightly over half of a large panel of short-term primary melanoma cultures, with a wide range of expression levels by flow cytometry. Similar results were obtained in established melanoma cell lines when analyzed at the mRNA level or by surface protein staining. In approximately one-third of cell lines, the expression of CD40 could be up-regulated with a histone deacetylase inhibitor. Treatment with increasing concentrations of CP-870,893 had no antitumor activity against either CD40-positive or negative melanoma cell lines. In conclusion, approximately one-third to one-half of melanomas expresses CD40 at variable levels. Direct exposure to a CD40-activating antibody does not lead to antitumor activity in melanoma cell lines, suggesting that the antitumor effects of these antibodies in the clinic may be indirectly mediated. PMID- 20842057 TI - Adjuvant therapy with agonistic antibodies to CD134 (OX40) increases local control after surgical or radiation therapy of cancer in mice. AB - The tumor recurrence from residual local or micrometastatic disease remains a problem in cancer therapy. In patients with soft tissue sarcoma and the patients with inoperable nonsmall cell lung cancer, local recurrence is common and significant mortality is caused by the subsequent emergence of metastatic disease. Thus, although the aim of the primary therapy is curative, the outcome may be improved by additional targeting of residual microscopic disease. We display in a murine model that surgical removal of a large primary sarcoma results in local recurrence in approximately 50% of animals. Depletion of CD8 T cells results in local recurrence in 100% of animals, indicating that these cells are involved in the control of residual disease. We further show that systemic adjuvant administration of alphaOX40 at surgery eliminates local recurrences. In this model, alphaOX40 acts to directly enhance tumor antigen-specific CD8 T-cell proliferation in the lymph node draining the surgical site, and results in increased tumor antigen-specific cytotoxicity in vivo. These results are also corroborated in a murine model of hypofractionated radiation therapy of lung cancer. Administration of alphaOX40 in combination with radiation significantly extended the survival compared with either agent alone, and resulted in a significant proportion of long-term tumor-free survivors. We conclude that alphaOX40 increases tumor antigen-specific CD8 T-cell cytotoxic activity resulting in improved endogenous immune control of residual microscopic disease, and we propose that adjuvant alphaOX40 administration may be a valuable addition to surgical and radiation therapy for cancer. PMID- 20842058 TI - Mature B cells are critical to T-cell-mediated tumor immunity induced by an agonist anti-GITR monoclonal antibody. AB - An agonistic antibody DTA-1, to glucocorticoid-induced TNFR-related protein (GITR), induces T-cell activation and antitumor immunity. CD4(+) effector T cells are essential in initiating GITR-induced immune activation, and the sequentially activated cytolytic CD8(+) T cells are sufficient to induce tumor rejection. Administration of DTA-1 to a tumor-bearing mouse also induces B-cell activation illustrated by CD69 expression. Substantial evidence suggests that resting B cells are tumor promoting, which has prompted the idea of B-cell depletion by Rituximab, to be combined with other agents in the clinic to augment antitumor response. In this study, we have found that mature B cells are needed for the mechanism of anti-GITR agonist to kill tumors. The treatment of GITR agonist induces profound B-cell activation, differentiation, and antibody production. In a mature B-cell-deficient mouse (JHD), DTA-1 fails to induce tumor regression with a reduced early activation of CD4(+) and CD8(+) T cells. B-cell deficiency disables the capability of the DTA-1 in generating cytolytic CD8(+) T cells and significantly reduces the cytokine production in tumor bearing mice. The tumor killing activities of DTA-1 are still present albeit reduced in the CD40(-/-) mice, in which IgG production is impaired. We have also shown that the dependence on B cells to kill tumors differentiates GITR costimulation from CTLA4 blockade and OX40 agonism in tumor immunotherapy. The findings underscore the reciprocal T cell-B-cell interaction to enhance antitumor immunity upon GITR costimulation. The results provide the insight that attenuating B-cell functions may not be beneficial in cancer immunotherapy based on GITR agonism. PMID- 20842059 TI - Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. AB - For adoptive T-cell therapy to be effective against solid tumors, tumor-specific T cells must be able to migrate to the tumor site. One requirement for efficient migration is that the effector cells express chemokine receptors that match the chemokines produced either by tumor or tumor-associated cells. In this study, we investigated whether the tumor trafficking of activated T cells (ATCs) bearing a chimeric antigen receptor specific for the tumor antigen GD2 (GD2-CAR) could be enhanced by forced coexpression of the chemokine receptor CCR2b, as this receptor directs migration toward CCL2, a chemokine produced by many tumors, including neuroblastoma. Neuroblastoma cell lines (SK-N-SH and SK-N-AS) and primary tumor cells isolated from 6 patients all secreted high levels of CCL2, but GD2-CAR transduced ATCs lacked expression of CCR2 (<5%) and migrated poorly to recombinant CCL2 or tumor supernatants. After retroviral transduction, however, ATCs expressed high levels of CCR2b (>60%) and migrated well in vitro. We expressed firefly luciferase in CCR2b-expressing ATCs and observed improved homing (>10-fold) to CCL2-secreting neuroblastoma compared with CCR2-negative ATCs. As a result, ATCs co-modified with both CCR2b and GD2-CAR had greater antitumor activity in vivo. PMID- 20842061 TI - The impact of ex vivo clinical grade activation protocols on human T-cell phenotype and function for the generation of genetically modified cells for adoptive cell transfer therapy. AB - Optimized conditions for the ex vivo activation, genetic manipulation, and expansion of human lymphocytes for adoptive cell therapy may lead to protocols that maximize their in vivo function. We analyzed the effects of 4 clinical grade activation and expansion protocols over 3 weeks on cell proliferative rate, immunophenotype, cell metabolism, and transduction efficiency of human peripheral blood mononuclear cells (PBMCs). Peak lentiviral transduction efficiency was early (days 2 to 4), at a time when cells showed a larger size, maximal uptake of metabolic substrates, and the highest level of proximal T-cell receptor signaling engagement. Anti-CD2/3/28 activation beads induced greater proliferation rate and skewed PBMCs early on to a CD4 phenotype when compared with the cells cultured in OKT3. Multicolor surface phenotyping demonstrated that changes in T-cell surface markers that define T-cell functional phenotypes were dependent on the time spent in culture as opposed to the particular activation protocol. In conclusion, ex vivo activation of human PBMCs for adoptive cell therapy demonstrate defined immunophenotypic and functional signatures over time, with cells early on showing larger sizes, higher transduction efficiency, maximal metabolic activity, and zeta-chain-associated protein-70 activation. PMID- 20842060 TI - Control of established melanoma by CD27 stimulation is associated with enhanced effector function and persistence, and reduced PD-1 expression of tumor infiltrating CD8(+) T cells. AB - The immune response to the tumor can be enhanced by targeting costimulatory molecules on T cells. As the CD70-CD27 costimulatory axis plays an important role in the activation, survival, and differentiation of lymphocytes, we have examined the efficacy of agonistic anti-CD27 antibodies as monotherapies for established melanoma in a murine model. We show that this approach leads to a substantial reduction in the outgrowth of both experimental lung metastases and subcutaneous tumors. Anti-CD27 treatment supports the maintenance of tumor-specific CD8(+) T cells within the tumor, reduces the frequency of FoxP3-expressing CD4(+) T cells within tumors, and potentiates the ability of NK1.1(+) and CD8(+) tumor infiltrating cells to secrete IFNgamma upon coculture with tumor cells. The enhanced effector function correlated with lower levels of PD-1 expression on CD8(+) T cells from anti-CD27-treated mice. Despite the modulating effect of anti CD27 on multiple cell types, only CD8(+) T cells were absolutely required for tumor control. The CD4(+) T cells were dispensable, whereas NK1.1(+) cells were needed during early stages of tumor growth but not for the effectiveness of anti CD27. Thus, CD27-mediated costimulation provides a potent boost to multiple aspects of the endogenous responses to tumor, and may be exploited to enhance tumor immunity. PMID- 20842063 TI - Modified upgaze technique for pupil examination. AB - Assessing pupil reactivity using the swinging flashlight technique in patients with miotic pupils or heavily pigmented irides can be difficult due to the reflection of the examination light off the cornea. We describe a modification of the standard method of detecting pupil reactivity in these difficult-to-see pupils. With the patient facing forward and eyes looking in maximal upgaze, fixed at distance, the examiner shines the light at the limbus in the straight ahead direction. Improved view of the pupil in upgaze results from reduction of the blink reflex and elimination of the Purkinje-1 image with minimal refractive distortion by the cornea. Optical calculations and multimedia demonstrations are provided to document these findings. PMID- 20842062 TI - Preclinical qualification of a new multi-antigen candidate vaccine for metastatic melanoma. AB - New therapies are urgently required for the treatment of patients with melanoma. Here we describe the generation and preclinical evaluation of 3 new recombinant ALVAC(2) poxviruses vCP2264, vCP2291, and vCP2292 for their ability to induce the desired cellular immune responses against the encoded melanoma-associated antigens. This was done either in HLA-A2/K transgenic mice or using in vitro antigen-presentation studies. These studies demonstrated that the vaccine was able to induce HLA-A*0201-restricted T-cell responses against gp100 and NY-ESO-1, detectable directly ex vivo, in HLA-A2/K-transgenic mice. The in vitro antigen presentation studies, in the absence of appropriate animal models, demonstrated that target cells infected with the vaccine construct were lysed by MAGE-1, MAGE 3 or MART-1 peptide-specific T cells. These data indicate that ALVAC(2)-encoded melanoma-associated antigens can be properly processed and presented to induce antigen-specific cytotoxic T-cell responses. To enhance the immunogenicity of the melanoma antigens, a TRIad of COstimulatory Molecules (TRICOM) were also cloned into all 3 vectors. Increased in vitro proliferation and IFN-gamma production was observed with all ALVAC(2) poxviruses encoding TRICOM, confirming the immune enhancing effect of the ALVAC-encoded TRICOM. These studies demonstrated that all components of the vaccine were functionally active and provide a rationale for moving this candidate vaccine to the clinic. PMID- 20842064 TI - Peer education: an innovative approach for integrating standards into practice. AB - The purpose of this article is to describe how a nurse-driven peer education process was developed, implemented, and evaluated to improve the integration of new patient care standards into practice. This process was an innovative, interactive, and nonjudgmental approach to learning, whereby the staff members participated in the education and development of their peers. It allowed nurses to expand their knowledge base, critical thinking, and clinical skills, which were evident in their daily practice. PMID- 20842065 TI - Application of the Ponseti principle for deformity correction in neglected and relapsed clubfoot using the Ilizarov fixator. AB - We treated 15 cases of neglected and relapsed clubfeet by the Ilizarov distraction method using the Ponseti principle in 12 children (mean age 7.3 years). The deformities were corrected around the talar head in the sequence of the cavus, adduction, varus and finally equinus (as per the Ponseti principle). Clinical and functional outcome after 2.5 years was significant (P<0.05) with a mean reduction of 11.7 in Dimeglio's score and an average Laaveg and Ponseti functional score of 75.47. The average time taken for correction was 4.2 weeks. Differential distraction according to the Ponseti principle leads to early correction with minimal number of residual deformities and complications. PMID- 20842066 TI - Regulator of G-protein signaling 14 protein modulates Ca2+ influx through Cav1 channels. AB - Calcium flux through L-type voltage-activated calcium (Cav1) channels is crucial for regulating brain functions including memory formation and behavior. Alterations in Ca2+ homeostasis have been linked to many cognitive disorders, and understanding the regulation of this process is crucial for their remedy. Therefore, here, we have evaluated the effect of a multifunctional protein known to be involved in memory functions called regulator of G-protein signaling 14 (RGS-14) on Cav1 channel activity in neuronal cell lines NG108-15 and SH-SY5Y. RGS-14 protein produced significant reduction in Ca2+ influx in both cell lines and this effect was dependent on nifedipine-sensitive Cav1 channels. Thus, our results provide evidence supporting the idea that RGS-14 may facilitate the cognitive processing by modulating Cav1 channel-mediated intracellular Ca2+ transients. PMID- 20842067 TI - Effect of Iyengar yoga on mental health of incarcerated women: a feasibility study. AB - BACKGROUND: Incarcerated women share a disproportionate burden of mental illness. Although psychotropic medications are available to women in prison, adjunctive treatment modalities, such as Iyengar yoga, may increase psychological well being. OBJECTIVES: The purposes of this study were (a) to address the feasibility of providing a gender-responsive exercise intervention within a correctional institution and (b) to observe the effect of a group-format Iyengar yoga program that met two sessions a week for 12 weeks on levels of depression symptoms, anxiety symptoms, and perceived stress among incarcerated women. METHODS: A repeated measures design, in which each participant served as her own control, was used. Participants completed three self-administered instruments: the Beck Depression Inventory, the Beck Anxiety Inventory, and the Perceived Stress Scale before treatment (baseline) and during treatment (Weeks 4, 8, and 12). Linear mixed effects models were used to examine statistically significant changes in mental health measures over time, taking advantage of all available data. RESULTS: Although 21 women initially participated in the intervention, 6 women completed the 12-week intervention. A significant linear decrease was demonstrated in symptoms of depression over time, with mean values changing from 24.90 at baseline to 5.67 at Week 12. There was a marginally significant decrease in anxiety over time (12.00 at baseline to 7.33 at Week 12) and a nonlinear change in stress over time, with decreases from baseline to Week 4 and subsequent increases to Week 12. DISCUSSION: Women who participated in this program experienced fewer symptoms of depression and anxiety over time. Findings from this study may be used to improve future interventions focusing on the health outcomes of incarcerated women. PMID- 20842068 TI - Meningoencephalitis caused by varicella-zoster virus reactivation in a child with dominant partial interferon-gamma receptor-1 deficiency. AB - We describe a previously symptom-free 13-year-old boy with dominant partial interferon-gamma receptor-1 deficiency and unusual varicella-zoster virus reactivation. This case supports the unsettled notion that some interferon-gamma R-deficient patients are at enhanced risk for viral disease. PMID- 20842069 TI - Short- versus long-term antimicrobial treatment for acute hematogenous osteomyelitis of childhood: prospective, randomized trial on 131 culture-positive cases. AB - BACKGROUND: Considerable uncertainty exists on the optimal duration of antimicrobials for acute hematogenous osteomyelitis (AHOM) in children. Often they are administered for 1 to 2 months, the first 1 to 2 weeks intravenously, and decompressive surgery is usually added. No prospective, randomized, sufficiently powered comparative trial has been available. METHODS: Children aged 3 months to 15 years with culture-positive AHOM were randomly assigned to receive clindamycin or a first-generation cephalosporin for 20 or 30 days, including an intravenous phase for the first 2 to 4 days. Surgery was kept at minimum. Illness was monitored with preset criteria. Antimicrobial was discontinued once most signs had subsided and serum C-reactive protein decreased <=20 mg/L. The primary end point was full recovery without need for further antimicrobial therapy because of an osteoarticular indication during the 12 months after the primary therapy. RESULTS: Of the 131 cases, 18% also involved the adjacent joint. Staphylococcus aureus caused 89% of cases, and all strains were methicillin susceptible. The median duration of treatment was 20 days for 67 children, and 30 days for 64 children. Most children underwent only the diagnostic percutaneous aspiration or drilling, and 24% had no surgery. Except for 1 mild sequela in both treatment groups, all patients recovered entirely. CONCLUSIONS: Most cases of childhood AHOM can be treated for 20 days, including a short period intravenously, with large doses of a well-absorbed antimicrobial such as clindamycin or a first-generation cephalosporin, provided the clinical response is good and C-reactive protein normalizes within 7 to 10 days. Extensive surgery is rarely needed. PMID- 20842070 TI - Safety, Reactogenicity, and Immunogenicity of Human Rotavirus Vaccine RIX4414 in Human Immunodeficiency Virus-positive Infants in South Africa. AB - BACKGROUND: rotavirus and human immunodeficiency virus (HIV) infections are a cause of great public health concern in developing countries. The current study evaluated the safety, reactogenicity, and immunogenicity of RIX4414 vaccine in asymptomatic or mildly symptomatic (clinical stages I and II according to WHO classification) HIV-infected South African infants. METHODS: a total of 100 HIV positive infants aged 6 to 10 weeks enrolled in this double-blind, 1:1 randomized, placebo-controlled study were allocated into 2 groups to receive 3 doses of RIX4414 vaccine/placebo according to a 0-, 1-, and 2-month schedule. Routine vaccines were concomitantly administered. Solicited and unsolicited symptoms were recorded for 15 and 31 days after each dose, respectively. Serious adverse events were recorded throughout the study period. Serum antirotavirus IgA concentrations (enzyme-linked immunosorbent assay, cut-off >= 20 U/mL) and the immunodeficiency status were determined at screening and 2 months post-Dose 3. Stool samples were analyzed for rotavirus using enzyme-linked immunosorbent assay at predetermined points and during diarrhea episodes. RESULTS: all symptoms (solicited and unsolicited) occurred at a similar frequency in both groups. Six fatal serious adverse events in RIX4414 and 9 in placebo groups were reported. At 2 months post-Dose 3, the seroconversion rates were 57.1% (95% CI: 34-78.2) in RIX4414 and 18.2% (95% CI: 5.2-40.3) in the placebo group. The mean absolute CD4 cell count, CD4 percentage, and HIV-1 viral load were comparable in both groups at screening and 2 months post-Dose 3. Rotavirus shedding peaked at Day 7 after Dose 1 of RIX4414 with prolonged shedding was observed in 1 infant only. CONCLUSIONS: : Three doses of RIX4414 vaccine was tolerated well by the South African HIV-positive infants. A satisfactory immune response was mounted without aggravating their immunologic or HIV condition. PMID- 20842071 TI - Event-level marijuana use, alcohol use, and condom use among adolescent women. AB - BACKGROUND: It is widely believed that marijuana use and alcohol use directly intercede on successful condom use. However, measurement differences and inconsistent findings in past research remain unclear whether marijuana and alcohol work directly to influence condom behavior, or spuriously function through other factors that actually reflect an increased likelihood of vaginal sex. The current study prospectively disentangles the association of marijuana and alcohol use on condom behavior among adolescent women. METHODS: Young women (N=387; 14-17 years) provided daily sexual diaries as part of a longitudinal cohort study (1999-2009) of sexual behavior and sexual relationships. To separate the effects of marijuana and alcohol use on vaginal sex from condom use (when vaginal sex occurs), we estimated a 3-category outcome variable (no vaginal sex, vaginal sex with a condom, vaginal sex without a condom), alternating no sex (Model 1) and sex without a condom (Model 2) as the referent categories. Generalized estimating equation multinomial logistic regression adjusted odds ratios for multiple sexual events from the same young woman over time. RESULTS: Subjects contributed 14,538 coital events; 30% of these events were condom protected. Neither marijuana nor alcohol use was directly associated with lower condom use; the strongest effect of condom use (adjusted odds ratio) and nonuse was performance of these behaviors in the past week. CONCLUSIONS: This study finds no evidence of a relationship between marijuana or alcohol use and condom nonuse. Both condom use and nonuse were identified as consistent behavioral patterns, regardless of the effect of marijuana and alcohol use. PMID- 20842072 TI - Hepatitis B vaccination among a national sample of gay and bisexual men. AB - Less than half of gay and bisexual men indicated they had received some doses of hepatitis B virus vaccine. Hepatitis B virus vaccination was higher among men who were 18 to 29 years old (compared to those 50-59 years old), gay, or had received flu vaccine within the last year. PMID- 20842074 TI - Metabonomic analysis of serum metabolites in kidney transplant recipients with cyclosporine A- or tacrolimus-based immunosuppression. AB - BACKGROUND: Cyclosporine A (CsA) and tacrolimus (TAC) affect the body metabolism of renal transplant recipients differently. We applied a novel method of H nuclear magnetic resonance-based metabonomics to integrate the serum metabolic profiles of transplant recipients with normal allograft function and identify time-dependent changes in the levels of serum metabolites in response to CsA- or TAC-based immunosuppression after kidney transplantation (KT). METHODS: Fifty seven consecutive renal transplant recipients were treated with CsA-based (CsA, mycophenolate mofetil, and steroid, n=27) or TAC-based (TAC, mycophenolate mofetil, and steroid, n=30) regimens. Serum samples were analyzed at baseline (pretransplant) and 1, 3, and 6 months after KT. RESULTS: The Partial Least Squares-Discriminant Analysis score plots showed a clear separation between levels at baseline and at 1, 3, and 6 months after KT in both groups. The levels of lipid metabolites were increased after KT in both groups, and importantly, CsA group demonstrated higher levels than TAC group. The metabolites for which the levels differed between the CsA and TAC groups and that changed according to treatment duration were glucose, hypoxanthine, lactate, succinate, and taurine. In contrast, trimethylamine-N-oxide levels, known to be associated with graft dysfunction, did not differ between the two groups. CONCLUSIONS: These data indicate that CsA- and TAC-based immunosuppressions elicit unique changes in serum metabolic profiles after KT. H-nuclear magnetic resonance-based metabonomics could provide new insights regarding the side effects of immunosuppressive regimens. PMID- 20842073 TI - Co-occurrence of Trichomonas vaginalis and bacterial vaginosis among HIV-positive women. AB - Trichomonas vaginalis (TV) and bacterial vaginosis (BV) were examined among human immunodeficiency virus+ women. The prevalence rates were 28.0% for TV, 51.4% for BV, and 17.5% for TV/BV co-infection. Among human immunodeficiency virus+/TV+ women, the rate of BV was 61.0%. Research is needed to examine how BV affects the clinical course and treatment of T. vaginalis. PMID- 20842075 TI - Edentulous jaws rehabilitation with yttrium-stabilized zirconium dioxide implants: two years follow-up experience. AB - AIM: The aim of this study was to present authors' two-year clinical experience with Yttrium-stabilized zirconium dioxide implants placed in native bone or regenerated bone. METHODS: Yttrium-stabilized zirconium dioxide implants made of brezirkon (whiteSKY, Bredent medical, Senden, Germany) were used for the treatment of edentulous ridge rehabilitation in the Dental Clinic of the University of Milan (Head of the Department, Prof. F. Santoro). Zirconium dioxide is a highly resistant ceramic material obtained by cleaning zirconium dioxide and zirconium silicate. The implant used in the clinical study featured a conical one piece implant with double cylindrical thread with a sandblasted rough surface. The prosthetic section was smooth. RESULTS: Forty-six implants have been inserted in 18 patients from January 2007 to January 2009, the follow-up period was comprised between 6 and 24 months. The overall success rate was 89%; the success rate in native bone was 97% and 74% in augmented bone. It can be stated that the success rate is comparable to titanium fixtures. CONCLUSION: It would be logical to use a ceramic material for the esthetic regions; zirconium dioxide is particularly suitable since it features tissue friendliness and resistance comparable to titanium. The good mechanical properties, possibility of easy fabrication of the prosthetic restoration and the good integration into the tissue and the esthetics provide perfect preconditions for yttrium-stabilized zirconium dioxide to become the most commonly used material in implant dentistry. PMID- 20842076 TI - Durability of feldspathic veneering ceramic on glass-infiltrated alumina ceramics after long-term thermocycling. AB - AIM: This study compared the bond strength durability of a feldspathic veneering ceramic to glass-infiltrated reinforced ceramics in dry and aged conditions. METHODS: Disc shaped (thickness: 4 mm, diameter: 4 mm) of glass-infiltrated alumina (In-Ceram Alumina) and glass-infiltrated alumina reinforced by zirconia (In-Ceram Zirconia) core ceramic specimens (N=48, N=12 per groups) were constructed according to the manufacturers' recommendations. Veneering ceramic (VITA VM7) was fired onto the core ceramics using a mold. The core-veneering ceramic assemblies were randomly divided into two conditions and tested either immediately after specimen preparation (Dry) or following 30000 thermocycling (5 55 oC+/-1; dwell time: 30 seconds). Shear bond strength test was performed in a universal testing machine (cross-head speed: 1 mm/min). Failure modes were analyzed using optical microscope (x20). The bond strength data (MPa) were analyzed using ANOVA (alpha=0.05). RESULTS: Thermocycling did not decrease the bond strength results for both In-Ceram Alumina (30.6+/-8.2 MPa; P=0.2053) and In Ceram zirconia (32.6+/-9 MPa; P=0.3987) core ceramic-feldspathic veneering ceramic combinations when compared to non-aged conditions (28.1+/-6.4 MPa, 29.7+/ 7.3 MPa, respectively). There were also no significant differences between adhesion of the veneering ceramic to either In-Ceram Alumina or In-Ceram Zirconia ceramics (P=0.3289). Failure types were predominantly a mixture of adhesive failure between the veneering and the core ceramic together with cohesive fracture of the veneering ceramic. CONCLUSION: Long-term thermocycling aging conditions did not impair the adhesion of the veneering ceramic to the glass infiltrated alumina core ceramics tested. PMID- 20842077 TI - The effect of a new finishing process on the torsional resistance of twisted nickel-titanium rotary instruments. AB - AIM: The process of twisting has been used for decades to fabricate stainless steel instruments, but it was previously thought to be an impractical method for nickel-titanium (Ni-Ti) instrument manufacture A manufacturing method of twisting Nickel-Titanium wire to produce Ni-Ti files has been recently developed: the twisted files (TF). Theoretically, this new manufacturing process should overcome the problems associated with a grinding process, which previously limited instrument strength. Since TF manufacturing process is new and different from grinding, the aim of the present study was to evaluate the effects of a final deoxidation process (Deox) on torsional resistance of TF instruments. METHODS: Testing was performed in accordance with the International Standard (ISO 3630-1) by comparing 20 TF instruments versus 20 TF prototype instruments produced without the final deoxidation process. Data were collected and statistically analyzed (t-test). RESULTS: Results show that TF instruments withstood 90% more torque (max. torque) than TF prototype instruments manufactured without the deoxidation process (88.7 vs. 53.3 g/cm). This difference was found to be statistically significant at the 0.05 level of significance. CONCLUSION: Since design and dimensions of tested instruments were the same, the deoxidation process could be the only explanation of the improvement in torsional resistance. PMID- 20842078 TI - Effect of cyclic loading on fracture strength and microleakage of a quartz fiber dowel with different adhesive, cement and resin core material combinations. AB - AIM: This study evaluated the performance of different adhesive-cement-core combinations coupled with quartz fiber dowels after cyclic loading and fracture strength tests and assessed the microleakage using dye penetration method. METHODS: Forty maxillary canines (N=10 per group) were restored with fiber dowels (Quartz fiber DT Light Post) and four adhesive-cement-core material combinations (Group 1: All-Bond 2+C&B [root]/All-Bond 2+Biscore [core]; Group 2: All-Bond 2+Bisfil 2B [root]/All-Bond 2+Bisfil 2B [core]; Group 3: Scotchbond 1+RelyX ARC [root]/Scotchbond 1+Supreme [core]; Group 4: RelyX Unicem [root]/Scotchbond 1+Filtek Supreme [core]). The specimens were initially cyclic loaded (x2,000,000, 8 Hz, 3 to 100 N at 45 degrees C under 37+/-3 degrees C water irrigation) and then immersed in 0.5% basic fuchsine at 37 degrees C for 24 hours for dye penetration and interface failure detection. The failure surfaces were observed under the stereomicroscope (x100 magnification). Circumferential and centripetal dye penetration was scored at the buccal and lingual sites. RESULTS: Only three specimens failed macroscopically during cyclic loading. No significant difference was found among the groups for the number of resisted cycles (P=0.9). Mean fracture strength between the groups were also not statistically significant (213+/-63-245+/-71 N) (P=0.740) (ANOVA). All four groups showed high values of dye penetration along the restoration interfaces being not significant from each other (P=0.224) (Kruskal-Wallis). The lingual sides of the teeth where the load applied, showed significantly higher incidence of detachment between the core and the dentin (100%, 90%, 100%, 90% for groups 1, 2, 3, 4, respectively) compared to the buccal side (30%, 30%, 60%, 40%) (P=0.032, c2 test). In 13 specimens (32.5%) crack lines at the coronal area were observed. Fracture strength was not significantly correlated with dye penetration (P=0.1803, r=-0.2162, Linear Regression and Correlation test). CONCLUSION: Different combinations of adhesive cement-composite core materials for the fiber post tested performed similar under cyclic loading and fracture strength tests. PMID- 20842079 TI - Antimicrobial analysis of chlorhexidine gel and intracanal medicaments against microorganisms inoculated in root canals. AB - AIM: The aim of this paper was to evaluate the antimicrobial activity of 2% chlorhexidine gel (CLX) associated with various intracanal medicaments against Candida albicans and Enterococcus faecalis inoculated in root canals. METHODS: Thirty six human single-rooted teeth were contaminated with C.albicans and E.faecalis. The canals were instrumented using 2% CLX gel and were divided into three groups according to the intracanal medicaments (ICM) used. Group 1: calcium hydroxide paste [Ca(OH)2], Group 2: 2% chlorhexidine gel (CLX) and Group 3: 2% CLX gel + Ca(OH)2. The root canal collections were performed after 21 days of contamination (control collection), after instrumentation (1st collection), after 14 days of intracanal medicament (2nd collection) and 7 days after medicament removal (3rd collection). The microbiological samples were plated in culture media and incubated for 48 hours. The results were submitted to Kruskal-Wallis test (P <= 0.05). RESULTS: It was verified that the instrumentation with CLX reduced the number of CFU/ml significantly when compared with the confirmation collection (control). However, the use of the ICM was only capable to eliminate completely the microorganisms in the root canals without difference statistics between them. CONCLUSION: Although the use of 2% chlorherixidine gel reduces the number of microorganisms significantly, only the ICM calcium hydroxide and calcium hydroxide associated with chlorhexidine are able to eliminate these microorganisms completely. PMID- 20842080 TI - Evaluation of facial asymmetry and masticatory muscle thickness in children with normal occlusion and functional posterior crossbite. AB - AIM: The aim of this study was to evaluate facial asymmetry and the thickness of the masticatory muscles in young children with normal occlusion and functional posterior crossbite. METHODS: The sample comprised 72 children of both genders (64.71+/-7.04 months) in the primary and early mixed stage of dentition, divided into four groups: primary-normal occlusion (PriN; N=19), primary-crossbite (PriC; N=19), mixed-normal occlusion (MixN; N=27), and mixed-crossbite (MixC; N=16). The thickness of the masseter and anterior portion of the temporalis muscle at rest and during maximal clenching were assessed by ultrasonography. Facial morphology and asymmetry were evaluated by standardized front-view photographs, in which the following measurements were recorded: anterior face height (AFH), bizygomatic facial width (BFW), angle of the eye (AE) and angle of the mouth (AM) (interpupillary and commissure planes in relation to mid-sagittal plane, respectively). RESULTS: The results showed that muscle thickness did not differ significantly between the sides of the dental arches in all groups (paired t test). Only the groups with normal occlusion presented significant positive correlation between AE and AM (Pearson's correlation test). In PriN, only body weight was significantly related to masseter thickness; in MixN, facial morphology contributed significantly to masseter thickness at rest and maximal clenching, while the covariates weight, height and age did not relate to muscle thickness (stepwise backward multiple regression). CONCLUSION: In the studied sample, children with crossbite presented greater facial asymmetry than those with normal occlusion, and a greater masseter thickness was related to larger faces in the mixed dentition. PMID- 20842081 TI - Alveolar distraction in post traumatic mandibular atrophy: report of two cases. AB - The main indication to use vertical alveolar distraction is post-traumatic mandibular atrophy. This technique allows to obtain an adequate bone volume for insertion of osseointagrated implants. The authors present in this article two patients cases in whom alveolar vertical distraction was applied to atrophy post traumatic, using endoral twin track distraction. In both cases it was prepared a stereolithography model to mimic the box of the bone to be distracted, to align the preoperative distractor and to obtain the more effective carrier. At the distractive stage followed the implant prosthesis stage which was designed to rehabilitate the previously atrophic bone area. In both patients it has been possible to insert the planned number of implants. PMID- 20842082 TI - A clinical case of necrotizing sialometaplasia and conjunctival hemorrhage. AB - The first case reported in the literature of a rare disease called necrotizing scialometaplasia (NS), dates back to 1973 when Abrams et al. described the main histological features of this disease. In this article we describe the rare clinical case of a young woman came to our observation for a double ulcer in the middle portion of the hard palate, aching, that histological examination showed compatible with a diagnosis of NS and preceded his appearance a haemorrhagic conjunctival suffusion left. We have provided a complete description of all the investigations in which the patient underwent and its treatment. We have also outlined the major etiological hypotheses of SN, histological features that point to a correct diagnosis, clinical features and prognostic and finally we reflected on the rare and interesting overlap in clinical manifestations palatal and conjunctival those trying to find a possible explanation. PMID- 20842083 TI - Effect of gender on fatigue and recovery following maximal intensity repeated sprint performance. AB - AIM: This study investigated the effects of gender on repeated, maximal-intensity intermittent sprint exercise following variable day-to-day recovery periods. METHODS: Sixteen volunteers (8 men, 8 women) performed four trials of high intensity intermittent sprint exercise consisting of three bouts of eight 30 m sprints (total of 24 sprints). Following completion of the baseline trial, in repeated-measures design, participants were assigned, in counter-balanced order, variable recovery periods of 24, 48, and 72 h whereupon they repeated an identical exercise trial. RESULTS: Results from a series of 4 (trial) x 3 (bout) repeated measures ANOVAs revealed men produced significantly (P < 0.01) faster times throughout all bouts and trials of repeated sprint exercise. Additionally, women exhibited significantly lower (P < 0.05) blood lactate concentration and significantly lower (P < 0.05) decrement in performance, indicating increased resistance to fatigue during repeated exercise sessions. There were no significant differences (P > 0.05) between genders for heart rate or rating of perceived exertion during or following trials. There were no significant differences for overall sprint performance within either gender among trials. CONCLUSION: These results indicate men, while able to produce higher absolute power outputs (i.e., lower sprint time), demonstrate higher decrement scores within a trial compared to women, thus suggesting women may recover faster and fatigue less. Also, gender differences affecting recovery within in a trial were observed to be diminished between trials (i.e., day-to-day recovery) of maximal intermittent sprint work evidenced by the observed stability of performance between trials following various recovery durations. PMID- 20842084 TI - The acute effects of performing drop jumps of different intensities on concentric squat strength. AB - AIM: To investigate the acute effects of performing drop jumps of different intensities on subsequent squat 1 repetition maximum (1RM). METHODS: 14 participants with strength training experience completed two familiarization sessions to become accustomed with the testing procedures and 1RM-like loads. Following this, four different 1RM testing sessions were completed. In each testing session subjects performed a 5-min bicycle warm-up followed by a series of sets with increasingly heavier loads until squat 1RM was achieved. During the first of these four sessions squat 1RM was assessed without the addition of drop jumps to the 1RM warm-up routine, thus was designated the control (CTRL) condition. In the final 3 testing sessions, two drop jumps from either 30 (DJ30), 45 (DJ45), or 60 (DJ60) cm were added to the warm-up routine that preceded squat 1RM assessment. EMG activity of the vastus lateralis was also monitored during 1RM testing. RESULTS: Squat 1RM without prior plyometric activity was 128.4+/ 36.1 kg. Following DJ30, DJ45, and DJ60 squat 1RM equaled 130.4+/-36.4 kg, 130.9+/-38.3 kg, 131.0+/-38.9 kg, respectively. A repeated measures ANOVA uncovered a significant main effect of warm-up condition (P=0.021). Post hoc analysis revealed that differences in the 1RM values were only significant between DJ30 and CTRL (P=0.002). No significant differences in muscle activation of the vastus lateralis were noted between the conditions. CONCLUSION: These findings indicate lower body strength in individuals familiar with resistance training can be acutely enhanced when preceded by a warm-up incorporating a low volume of low intensity drop jumps. PMID- 20842085 TI - The effect of 6-week combined agility-balance training on neuromuscular performance in basketball players. AB - AIM: The study evaluates the effect of 6-week combined agility-balance training on neuromuscular performance in basketball players. METHODS: Subjects divided into experimental (EG, n = 17) and control group (CG, n = 17) underwent a combined agility-balance training (in duration of 30 min) for a period of 6 weeks (4-5 sessions/week). Both groups performed reaction tasks similar to game-like situations, however EG on wobble boards and CG on stable surface. Prior to and after the training parameters of agility, balance, speed of step initiation, strength differentiation accuracy, and explosive power of lower limbs were evaluated. Postural stability was assessed under both static and dynamic conditions (wobble board) with eyes open and eyes closed, respectively. The velocity of the centre of pressure (COP) was registered at 100 Hz by means of posturography system FiTRO Sway check based on dynamometric platform. Using FiTRO Reaction check simple and multi-choice reaction times were measured. The same system was applied to evaluate the agility performance including reaction and movement task. Speed of step initiation was measured using FiTRO Dyne Premium. Jumping abilities were evaluated by means of FiTRO Jumper (10-seconds maximal jumps, Countermovement jump, Squat jump, Drop jump). Using the same system, the subject's ability to match 50 % of their maximal height of the jump was evaluated. RESULTS: Results showed that a combined agility-balance training improved dynamic balance not only under visual control but also in eyes closed conditions. Training also increased run-out speed that likely contributed to better agility performance, reduced ground contact time during drop jump, and improved the ability to differentiate the force of muscle contraction during repeated jumps. However, such training has been found to be insufficient to improve both simple and multi-choice reaction time, and jumping performance. On the other hand, control group failed to show any significant improvement in examined abilities except for enhancement of jumping performance (Pact, Delta CMJ & SJ). CONCLUSION: It may be concluded that balance exercises performed simultaneously with reaction tasks represent an effective means for improvement of neuromuscular performance in elite athletes. PMID- 20842086 TI - Effects of acute exercise on inspiratory muscle strength and endurance in untrained women and men. AB - AIM: The purpose of this study was to determine if sex differences are present in exercise-induced inspiratory muscle function in untrained humans. METHODS: Eight young untrained women (23.8 +/- 1.5 y, VO2max = 33.7 +/- 4.0 mL/kg/min) and men (26.1 +/- 2.0 y, VO2max = 36.7 +/- 1.2 mL/kg/min) performed high-intensity cycling exercise (80% WRmax) to exhaustion. Inspiratory muscle strength and endurance were assessed pre- and post-exercise by measuring maximal inspiratory pressure (PImax) and time to task failure during a constant-load breathing test (CLBT), respectively. RESULTS: Relative intensity and time to exhaustion during high-intensity exercise was similar between women and men. Prior to exercise, PImax was similar between sexes. After exercise, women and men showed similar reductions in PImax (W: 140.4 +/- 9.9 to 124.6 +/- 6.7 cm H2O, P<0.05; M: 147.7 +/- 10.2 to 128.1 +/- 11.1 cm H2O, P<0.05). No sex difference was found in the magnitude change in PImax following exercise (W: 15.8 +/- 7.9 vs. M: 19.6 +/- 4.7 cm H2O). Time to task failure on the CLBT was reduced following exercise in women (360 +/- 54 to 135 +/- 29 s, P<0.05) and men (270 +/- 36 to 150 +/- 17 s, P<0.05). Women exhibited a greater reduction in time to task failure following exercise than men (W: 225 +/- 55 vs. M: 120 +/- 38 s, P=0.05). CONCLUSION: These data demonstrate that women exhibit a greater reduction in inspiratory muscle endurance following an acute bout of high-intensity exercise than men. PMID- 20842087 TI - Estimation of peak oxygen uptake from maximal power output among 9-10 year-old children in Lhasa, Tibet. AB - AIM: The aims of the present study of Tibetan and Han Chinese children were to establish prediction equations for peak oxygen uptake (VO2peak) using conventional power output measures, and to compare with prediction models based on data from sea level. METHODS: In 25 Tibetan children and 15 Han Chinese children aged 9-10 years, living in Lhasa at 3700 meters above sea level, VO2peak was measured directly using a portable oxygen analyzer, and predicted from maximal power output (Wmax) using a maximal cycle ergometer test. RESULTS: In multiple regression analyses with VO2peak as dependent variable and Wmax and sex as covariates, a total adjusted R2 of 0.76 and 0.82 were found in Tibetan and Han Chinese children, separately. Sex made a unique, and statistically significant, contribution to the prediction of VO2peak. Three equations derived from sea level data were compared with the equations from the present study. None of the three could accurately predict the direct measured V.O2peak, and predictions differed in an unsystematic manner, including over- or underestimation and no differentiation between genders. CONCLUSION: Peak oxygen uptake could be estimated from Wmax and sex in a progressive cycle ergometer test among children living at 3700 meters in Tibet. The estimate of VO2peak is probably more valid using the present equations than prediction models based on data from sea level. The equations used for the prediction are: Bianba(eqT): (l.min(-1)) = 0.5419 + (0.0096. Wmax) - (0.0562. sex); boys=0; girls=1 Bianba(eqH): (l.min(-1)) = 0.4060 + (0.0124. Wmax) - (0.1775. sex); boys=0; girls=1. PMID- 20842088 TI - Effects of music during exercise in different training status. AB - AIM: This study examined the interaction of exercise and music to establish the impact of these factors on state-anxiety and time to exhaustion comparing trained and active participants. METHODS: Twenty-six university students (13 trained, 13 active) completed the State-anxiety Inventory questionnaire before and after a submaximal treadmill running until volitional exhaustion in both music and no music condition. RESULTS: ANOVA showed that both trained and active groups significantly reduced their State-Anxiety scores after exercise tasks (P<0.01, partial eta2=0.26) independently by the presence of music. Finding also revealed that active group reported a higher significant reduction of their state anxiety score after exercise in music condition compared to no-music task (P<0.05, d=0.80), while this effect in trained group was not significant. Moreover, data showed that only active-subjects significantly prolonged their exercise experience in presence of music (P<0.05, d=0.47), while trained group did not. CONCLUSION: This study supports the general finding that exercise is associated with state-anxiety reduction, and suggests that music during exercise may improve this effect in active but not in trained participants. Further, listening to music during exercise may prolong the participants' exercise experience but different training status seems to qualify differently this response. PMID- 20842089 TI - Can a fatigue test of the isolated lumbar extensor muscles of untrained young men predict strength progression in a resistance exercise program? AB - AIM: The aim of this exploratory study was to investigate the predictive value of a fatigue test of the lumbar extensor muscles for training progression in a group of 28 healthy but predominantly sedentary male students, in an 8-week resistance exercise program. METHODS: A three-phased fatigue test of the lumbar extensor muscles was designed, consisting of two consecutive measurements of full-range isometric back strength on a lumbar measurement device, separated by a dynamic back extension set to volitional fatigue. Differences between the strength values of the 1st and 3rd step is thought to reflect individual back muscle fatigue characteristics. The training program was primarily aimed at improving lumbar extensor endurance, by using a relative high number of repetition and low training loads. Linear regression analysis was used to evaluate the relationship between lumbar strength progression and several fatigue test parameters. RESULTS: The main fatigue indicator in our regression models (isometric strength decline between 1st and 3rd step) did not show predictive value in lumbar strength progression in training and testing, respectively. On the other hand, the work capacity that subjects delivered in the dynamic set (2nd step) had some predictive value. CONCLUSION: Based on the results, isometric strength decline measurement has no additional value to a standardized set of repetitions until failure in predicting future training performance. In practice, this means that a lower back training machine could be used at baseline to assist in tailoring individual lumbar training regimes, without the additional use of an isometric strength testing module. PMID- 20842090 TI - Energy expenditure and dietary intake of athletes during an ultraendurance event developed by hiking, cycling and mountain climbing. AB - AIM: To investigate exercise intensity, energy expenditure and energy balance of athletes during an ultraendurance event (UE) consisting in hiking, cycling and mountain climbing. METHODS: Four athletes participated in this study. Maximal oxygen uptake (VO2max) and "VO2-heart rate" relationships during cycling and walking were determined by indirect calorimetry during two graded exercise tests. Body mass and body fat mass were measured before and after the UE. During the UE, heart rate (HR), diet intake, gastrointestinal disturbances and route characteristics were monitored. RESULTS: UE duration was 19 h29 min over a distance of 108 km, with 6768 meters of altitude difference. Body mass and percent of body fat mass tended to decrease after UE (-3.2% and -8.9%, respectively). During the locomotion phases, mean exercise intensity was 50.8+/ 10.4% of VO2max and 65.8+/-7.6% of HRmax. Energy expenditure amounted to 51.0+/ 3.4 MJ. Energy supplied from diet and body fat mass oxidation was 20.4+/-10.7 MJ and 17.3+/-2.4 MJ, respectively. During the UE, athletes did not suffer of any gastrointestinal disorder. CONCLUSION: Mean exercise intensity corresponded to 51% VO2max: it was independent from the locomotion type, and it can be considered an adequate intensity for UEs with similar characteristics. Although athletes successfully completed the UE, the self regulation of energy intake led athletes to a negative energy balance. Estimation of energy expenditure prior the begin of UEs would allow athletes to better plan the diet energy intake. PMID- 20842091 TI - Physical fitness, bone mineral density and associations with physical activity in females with longstanding eating disorders and non-clinical controls. AB - AIM: To examine (i) aerobic fitness, muscular strength, and bone mineral density (BMD) in female inpatients with longstanding eating disorders and non-clinical controls, and (ii) associated and explanatory factors for BMD among the inpatients. METHODS: Adult females with DSM-IV anorexia nervosa (AN), bulimia nervosa (BN) or eating disorders not otherwise specified (EDNOS) (n=59, mean(SD) age 30.1(8.5) yrs and ED duration 14.3 yrs) and non-clinical age-matched controls (n=53, mean(SD) age 31.3(8.3) yrs) accepted participation in this cross-sectional study. Measurements included accelerometer assessed and self reported amount of different types of physical activities, VO2max on treadmill, 1RM in leg and chest press, and BMD in lumbar spine (L2-L4), femur neck and total body analyzed by DXA. RESULTS: Muscular strength and BMD were lower in patients with AN, not in patients with BN or EDNOS, compared to controls. Aerobic fitness did not differ between patients and controls. BMD in the patients was positively associated with body weight, muscular strength and self reported high impact PA (min.w-1), not self reported general weight-bearing PA (min.w-1) or accelerometer assessed PA (counts.min). History of AN (28%) and muscular strength (9%) contributed significantly to explain the variance in total body BMD. CONCLUSION: Muscular strength and only high impact PA are associated with BMD in patients with longstanding ED. An implication of this is the need for more specific guidelines regarding types of PA recommended for this patient population. Special considerations should be made for severely malnourished patients, and for patients with osteoporosis. PMID- 20842092 TI - Relationships between physical exercise practice, dietary behaviour and body composition in female university students. AB - AIM: The relationship between female body composition, total energy expenditure and physical exercise energy expenditure is not very strong because women can compensate by increasing their energy intake. The aim of this study was to investigate the relationship between total minutes of exercise per week, dietary habits and body composition in female university students using physical activity and the habit to cook as covariates. METHODS: Fifty-one female university students were investigated for body composition, dietary habits, aerobic fitness, physical activity and physical exercise practice. Participants were grouped in three sub-samples (1, 2 and 3) according to the 33rd and 66th percentiles of weekly minutes (min/wk) of training. RESULTS: Group 1 had 0.00 min/wk, group 2 had 95+/-35.59 min/wk and group 3 had 231.66+/-85.97 min/wk of training. Sub samples did not differ for IPAQ parameters while differed for aerobic fitness (P=0.001). Group 3 had a higher energy intake (EI) (P=0.008), a higher intake of lipids (P=0.017), saturated (P=0.042) and monounsaturated fat (P=0.024) and a lower intake of carbohydrates (P=0.007). Group 3 maintained the higher EI and the worse composition of lipid intake considering the habit to cook as covariate. Group 3 also had higher muscle mass. CONCLUSION: In order to positively affect body composition, in the sedentary women it is enough to control the energy balance, whereas in those that trained regularly it is necessary to control both energy balance and composition of daily meals. PMID- 20842093 TI - Active cervical range of motion recovery following the rugby off-season. AB - AIM: It has been established that Rugby players have reduced active cervical function that further declines with increased number of playing years; noticeable even over a single season. Here we examine one possible reason, namely insufficient recovery during the off-season, which will only be exacerbated by the trend towards a decreasing off-season period. METHODS: Twenty-six elite rugby players (12 Forwards 24.9+/-1.2 years; and 14 Backs 23.8+/-1.2 years) from two English Premiership rugby clubs had their Active Cervical Range of Motion (ACROM) measured at the end of one playing season and the beginning of the next. The ACROM was measured for flexion, extension, left and right side flexion, plus left and right rotation. Players engaged in active rehabilitation during the off- and pre-season. RESULTS: Although, the results of paired T-test analysis showed no statistical difference in ACROM, nearly all calculated percentage changes were positive (range from -4.1% to 21%) suggesting a degree of recovery. Rugby Backs had significantly greater ACROM than the Forwards at both measurement points, but did not appear to show a greater percentage change. CONCLUSION: Although these results indicate a degree of recovery, they reinforce the possibility that the off-season is not long enough to allow significant restoration in neck range of motion, alternatively, players do not undertake sufficient or appropriate neck related rehabilitation to aid their recovery. PMID- 20842094 TI - Impact of fire-fighters training on a female with smoldering multiple myeloma. AB - The purpose of this study was to examine the influence of a fire-fighting training regime on the cardiac autonomic control of a middle-aged female diagnosed with smoldering multiple myeloma (SMM). Cardiac autonomic control was monitored by heart rate variability (HRV) analysis in the patient during the last six-week period of a one and half year training period. Compared with healthy, physically active age-matched females, the patient demonstrated similar HRV parameters. Furthermore, the patient experienced a positive evolution of the SMM during this training period. These findings indicate: 1) the beneficial effects of high intensity physical training on cardiac autonomic function in a SMM patient; 2) the potential value of HRV monitoring in cancer patients undertaking regular physical activity. PMID- 20842095 TI - Adiponectin responses to acute moderate and heavy exercises in overweight middle aged subjects. AB - AIM: The purpose of this study was to investigate the effect of acute moderate and heavy exercises on adiponectin, leptin and insulin concentrations in untrained subjects. METHODS: Seven overweight middle-aged males participated in this study (age: 36.00 +/- 5.16 years; body weight: 93.94 +/- 6.48 kg; percent body fat: 26.64 +/- 2.75%; Body Mass Index: 28.32 +/- 1.74 kg.m2). They took part in two sub-maximal cycling exercises; moderate; 20 min cycling at 60% of peak aerobic power (PAP) and heavy: 20 min cycling at 80% of PAP. Venous blood samples were obtained before, after 30, 60 and 90 min recovery. RESULTS: Adiponectin concentrations were unchanged (P>0.05) after exercises. However, leptin was significantly decreased under resting values after 30 min (-12.74%, P=0.0023), 60 min (-11.66%, P=0.0084) and 90 min (-8.42%, P=0.0023) after the heavy exercise. Similarly, insulin was lowered after 90 min after the heavy exercise (-55.96%, P=0.014). Basal adiponectin during moderate exercise was significantly and negatively related to BMI (r=-0.778, P=0.033) and percent body fat (r=-0.897, P=0.0061). CONCLUSION: In conclusion our results suggested that 20 min moderate or heavy sub-maximal exercises not stimulate the production and the release of adiponectin during 1.5 hour recovery post-acute exercises. Furthermore, it appears that after acute heavy exercise adiponectin is not associated with leptin or/and insulin modifications. PMID- 20842096 TI - Exercise with vibration dumb-bell enhances neuromuscular excitability measured using TMS. AB - AIM: The purpose of the study was to examine the effects of exercise without vibration and exercise with vibration (27 Hz) on the cortical silent period (CSP) and cortical motor threshold (CMT) measured using transcranial magnetic stimulation (TMS). METHODS: In 22 university athletes, a circular coil attached to a TMS stimulator was applied over the contralateral motor cortex of the target forearm. Resting cortical motor thresholds for dominant and non-dominant extremities were measured for each participant. Then, 15 biceps curls (15 flexion and 15 extension movements) were performed with the dominant arm using a single vibration dumbbell with the vibration turned off. On a different day, the same biceps curl protocol was performed with the dumbbell vibrating at 27 Hz (2 mm amplitude). A supra-threshold TMS stimulus (1.5x CMT) was delivered while participants were voluntarily contracting the flexor digitorum sublimus muscle (30% MVC grip strength) to determine cortical silent periods before and after each upper extremity exercise protocol. Cortical motor thresholds were measured at rest and after the vibration exercise protocol. RESULTS: All subjects completed the study protocol as designed. After TMS, the CSP in the dominant (exercised) extremities increased after exercise without vibration from a resting (pre-exercise) mean of 57.3 ms to 70.4 ms (P<0.05) and after exercise with vibration, the CSP decreased to a mean of 49.4 ms (P<0.02). The CSP in the non dominant (unexercised) extremities decreased from resting values of 75.6 ms to 69.3 ms (P=0.935) after the exercise-only protocol and decreased to 49.4 ms (P<0.01) after the vibration exercise protocol. The cortical motor threshold in exercised extremities decreased from a resting mean of 41.4 MUV to a postvibration exercise mean of 38.6 MUV (P<0.01). In non-exercised extremities, the CMT also decreased, from mean of 43.5 MUV to 39.9 MUV after the vibration exercise (P<0.01). CONCLUSION: Vibration exercise enhances bilateral corticospinal excitability, as demonstrated by a shortened cortical silent period and lower cortical motor threshold in both exercised and non-exercised extremities. PMID- 20842097 TI - A longitudinal assessment of ghrelin and bone mineral density with advancing pubertal maturation in adolescent female athletes. AB - AIM: The aim of the present study was to investigate changes in ghrelin and bone mineral density (BMD) during further biological maturation after onset of puberty in female adolescent swimmers. METHODS: Swimmers (n=17) were tested once a year during a two year study period. At the first year, swimmers were at pubertal stages 2 & 3. Fasting plasma ghrelin, leptin, estradiol, insulin-like growth factor-1 (IGF-I) and BMD of the total body, lumbar spine and femoral neck were measured. RESULTS: Ghrelin did not change during the further pubertal development after onset of puberty. No differences in leptin were also seen during the study period. Estradiol and IGF-I were increased during further pubertal development. Total and lumbar spine BMD increased along with further biological maturation. In contrast, further pubertal development had no effect on femoral neck BMD in adolescent female swimmers. Ghrelin was not related to measured BMD values after adjusting for pubertal status at any measurement time. CONCLUSION: Ghrelin concentration did not change with advancing age and pubertal stage after onset of puberty and had no direct influence on bone mineralisation in adolescent female swimmers. PMID- 20842098 TI - ACE ID genotype and leg power in Rugby Union players. AB - AIM: The present study examined the hypothesis that there were no significant differences between forwards and backs in the elements of leg power between the ID and DD genotypes of the ACE (I/D) gene in developing young adult Rugby Union players. METHODS: Sixty-eight players were recruited to identify the distribution of genotypes between forwards and backs. Fifty-eight players were investigated for leg power. Forwards (n=28) comprised 15 ID and 13 DD genotypes, and backs (n=30) 19 ID and 11 DD genotypes. Leg power was measured on a force platform using a counter movement jump; the parameters of interest were peak and relative force, peak and relative power, displacement and velocity. The three-primer polymerase chain reaction was used to assay the region of interest for I and D variants of the ACE gene. The distribution of genotypes was determined by chi square and comparisons between forwards and backs made using the independent t test. RESULTS: No significant differences were identified in the distribution of genotypes between forwards and backs (chi2=2.2, P=0.336). However, significant differences were identified between forwards and backs in a number of components of leg power. Backs had significantly larger values than forwards for relative force (1.50 vs. 1.30 Wt%, P=0.001) and relative power (27.1 vs. 24.3 W.kg-1, P=0.034) for the ID genotype, whereas backs had significantly larger values than forwards for displacement (0.42 vs. 0.38 m, P=0.049) and velocity (2.76 vs. 2.55 m.s.(-1), P=0.007) for the DD genotype. CONCLUSION: The characteristics of leg power identified will enhance the functional requirements of players according to playing position and commitment. PMID- 20842099 TI - Oxidative stress biomarkers response to high intensity interval training and relation to performance in competitive swimmers. AB - AIM: Aim of the study is to investigate the modulations of oxidative stress biomarkers and some antioxidants induced by high intensity interval training bout and its relation to swimming performance. METHODS: Ten swimmers performed a set of 8 maximal swims along 100 m by style of their specialty, with 10 minute for a rest. The concentration of blood lactate ([Lac]) was determined after each swim. The lactate tolerance index (LTI) was determined by the ratio between [Lac] and the respective times of execution of the 8 swims. The time to complete first 100 m swim at maximum effort (P100) and the international point score (IPS) reached in a specific competition were considered performance parameters. Venous blood was collected before and after the anaerobic training effort. RESULTS: Mean blood lactate concentration in the eight swims was 10.9 +/- 1.2 mM. Significant increases were observed for TBARS (pre: 4.1+/-0.7 ?mol/L; post: 4.9+/-1.1. ?mol/L), CK (pre: 206.4+/-170.7 U/L; post: 244.4+/-176.9. U/L), GSH (pre: 0.52+/ 0.06; post: 0.62+/-0.05. mM), and ascorbic acid (pre: 0.06+/-0.02; post: 0.11+/ 0.03. mg/dL) after the anaerobic training bout compared to the values obtained before it. In addition, significant correlations (P < 0.05) were detected between LTI and P100 (r = -0.87) and IPS (r = 0.64) and between variation of ascorbic acid and P100 (r = -0.60). CONCLUSION: Anaerobic training bout proposed induces oxidative stress and cell muscle damage markers as well as modulates some antioxidants of competitive swimmers. The modulation of ascorbic acid seems to play an important role in the performance of these athletes. PMID- 20842100 TI - Immune responses during and after exercise of constant and alternating intensity above the lactate threshold. AB - AIM: Intense and prolonged exercise greatly affects circulating cytokine levels. The purpose of this study was to investigate the possible changes in tumour necrosis factor -a (TNF-a), interleukin 6 (IL-6) and cortisol concentrations during and after prolonged exercise of constant and alternating intensity of the same duration and total work performed. METHODS: Ten male subjects underwent two main cycling exercise trials lasting one hour each. On one occasion, exercise intensity was alternated between 46.5+/-1.9% of maximal oxygen uptake (VO2max ) for 40 s and 120% of VO2max for 20 s, so that the mean intensity corresponded to 105% of the lactate threshold. On the other occasion, exercise intensity was constant at 105% of the lactate threshold. Levels of TNF-a, IL-6 after lipo polysaccharide (LPS) stimulation as well as cortisol were measured at rest, 30 and 60 minutes of exercise and 1 hour after. RESULTS: No significant differences were observed in TNF-a concentrations between the two exercise protocols (P= 0.75), but there was a significant time effect (P<0.01). TNF-a was increased in both groups from a resting value of 436.1+/-102.5 to 649.5+/-187.7 pg/mL (P<0.05) at the end of exercise and was subsequently decreased 1 hour post exercise to 305.9+/-78.8 pg/mL (P<0.01). No significant difference in IL-6 and cortisol concentrations was observed between the two exercise protocols (P=0.13, P=0.10 accordingly). CONCLUSION: In conclusion, prolonged constant and alternating intensity exercise of the same mean intensity and duration seemed to provoke similar changes in aspects of immune response in healthy subjects. PMID- 20842101 TI - Relationships between salivary testosterone and cortisol concentrations and training performance in Olympic weightlifters. AB - AIM: This study examined the relationships between salivary testosterone (Sal-T) and cortisol (Sal-C) concentrations and training performance in Olympic weightlifters. METHODS: Four male and four female Olympic weightlifters each provided saliva samples before and after four workouts during a four-week training period. Training involved the same three exercises; snatch, clean and jerk, and front squat with the one repetition maximum (1RM) calculated for each exercise during each workout. RESULTS: Significant (P < 0.05-0.01) training improvements in 1RM performance (4.0-5.2%) were noted during the snatch and clean and jerk exercises, along with the Olympic total lift. For male participants only, the pre-workout concentrations of Sal T were significantly (P < 0.05-0.01) correlated with the snatch (r = 0.70) and clean and jerk 1RM (r = 0.62), and the Olympic total lift (r = 0.66). CONCLUSION: A short period of training improved the 1RM performance of Olympic weightlifters in two exercises (snatch and clean and jerk) and the Olympic total. For male participants, their Sal-T concentrations before each workout was also related to 1RM performance during these exercises, thereby highlighting one possible short-term causative mechanism. Limitations of this study include the short duration of hormonal monitoring, the limited number of workouts assessed and the small number of participants recruited. Also, correlations between the outcome variables still only reflect casual associations. PMID- 20842102 TI - Optimization of speed and accuracy of decoding in translation. AB - The speed and accuracy of protein synthesis are fundamental parameters for understanding the fitness of living cells, the quality control of translation, and the evolution of ribosomes. In this study, we analyse the speed and accuracy of the decoding step under conditions reproducing the high speed of translation in vivo. We show that error frequency is close to 10-3, consistent with the values measured in vivo. Selectivity is predominantly due to the differences in k(cat) values for cognate and near-cognate reactions, whereas the intrinsic affinity differences are not used for tRNA discrimination. Thus, the ribosome seems to be optimized towards high speed of translation at the cost of fidelity. Competition with near- and non-cognate ternary complexes reduces the rate of GTP hydrolysis in the cognate ternary complex, but does not appreciably affect the rate-limiting tRNA accommodation step. The GTP hydrolysis step is crucial for the optimization of both the speed and accuracy, which explains the necessity for the trade-off between the two fundamental parameters of translation. PMID- 20842104 TI - Paracrine factors of multipotent stromal cells ameliorate lung injury in an elastase-induced emphysema model. AB - Multipotent stromal cells (MSCs) ameliorate several types of lung injury. The differentiation of MSCs into specific cells at the injury site has been considered as the important process in the MSC effect. However, although MSCs reduce destruction in an elastase-induced lung emphysema model, MSC differentiation is relatively rare, suggesting that MSC differentiation into specific cells does not adequately explain the recuperation observed. Humoral factors secreted by MSCs may also play an important role in ameliorating emphysema. To confirm this hypothesis, emphysema was induced in the lungs of C57BL/6 mice by intratracheal elastase injection 14 days before intratracheal MSC or phosphate-buffered saline (PBS) administration. Thereafter, lungs were collected at several time points and evaluated. Our results showed that MSCs reduced the destruction in elastase-induced emphysema. Furthermore, double immunofluorescence staining revealed infrequent MSC engraftment and differentiation into epithelial cells. Real-time PCR showed increased levels of hepatocyte growth factor (HGF) and epidermal growth factor (EGF). Real-time PCR and western blotting showed enhanced production of secretory leukocyte protease inhibitor (SLPI) in the lung. In-vitro coculture studies confirmed the in vivo observations. Our findings suggest that paracrine factors derived from MSCs is the main mechanism for the protection of lung tissues from elastase injury. PMID- 20842105 TI - VSV oncolysis in combination with the BCL-2 inhibitor obatoclax overcomes apoptosis resistance in chronic lymphocytic leukemia. AB - In chronic lymphocytic leukemia (CLL), overexpression of antiapoptotic B-cell leukemia/lymphoma 2 (BCL-2) family members contributes to leukemogenesis by interfering with apoptosis; BCL-2 expression also impairs vesicular stomatitis virus (VSV)-mediated oncolysis of primary CLL cells. In the effort to reverse resistance to VSV-mediated oncolysis, we combined VSV with obatoclax (GX15-070)-a small-molecule BCL-2 inhibitor currently in phase 2 clinical trials-and examined the molecular mechanisms governing the in vitro and in vivo antitumor efficiency of combining the two agents. In combination with VSV, obatoclax synergistically induced cell death in primary CLL samples and reduced tumor growth in severe combined immunodeficient (SCID) mice-bearing A20 lymphoma tumors. Mechanistically, the combination stimulated the mitochondrial apoptotic pathway, as reflected by caspase-3 and -9 cleavage, cytochrome c release and BAX translocation. Combination treatment triggered the release of BAX from BCL-2 and myeloid cell leukemia-1 (MCL-1) from BAK, whereas VSV infection induced NOXA expression and increased the formation of a novel BAX-NOXA heterodimer. Finally, NOXA was identified as an important inducer of VSV-obatoclax driven apoptosis via knockdown and overexpression of NOXA. These studies offer insight into the synergy between small-molecule BCL-2 inhibitors such as obatoclax and VSV as a combination strategy to overcome apoptosis resistance in CLL. PMID- 20842103 TI - Inhibition of mitochondrial fusion by alpha-synuclein is rescued by PINK1, Parkin and DJ-1. AB - Aggregation of alpha-synuclein (alphaS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of alphaS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that alphaS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, alphaS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous alphaS. In contrast, siRNA-mediated downregulation of alphaS results in elongated mitochondria in cell culture. alphaS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, alphaS prevents fusion of differently labelled mitochondrial populations. Thus, alphaS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of alphaS is rescued by coexpression of PINK1, parkin or DJ 1 but not the PD-associated mutations PINK1 G309D and parkin Delta1-79 or by DJ-1 C106A. PMID- 20842106 TI - T cells expressing constitutively active Akt resist multiple tumor-associated inhibitory mechanisms. AB - Adoptive transfer of antigen-specific cytotoxic T lymphocytes has shown promise for the therapy of cancer. However, tumor-specific T cells are susceptible to diverse inhibitory signals from the tumor microenvironment. The Akt/protein kinase B plays a central role in T-cell proliferation, function, and survival and we hypothesized that expression of constitutively active Akt (caAkt) in T cells could provide resistance to many of these tumor-associated inhibitory mechanisms. caAkt expression in activated human T cells increased proliferation and cytokine production, a likely result of their sustained expression of nuclear factor kappaB (NF-kappaB) and provided resistance to apoptosis by upregulating antiapoptotic molecules. caAkt expressing T cells (caAkt-T-cells) were also relatively resistant to suppression by and conversion into regulatory T cells (Tregs). These characteristics provided a survival advantage to T cells cocultured with tumor cells in vitro; CD3/28-stimulated T cells expressing a chimeric antigen receptor (CAR) specific for disialoganglioside (GD2) that redirected their activity to the immunosuppressive, GD2-expressing neuroblastoma cell line, LAN-1, resisted tumor-induced apoptosis when co-expressing transgenic caAkt. In conclusion, caAkt-transduced T cells showed resistance to several evasion strategies employed by tumors and may therefore enhance the antitumor activity of adoptively transferred T lymphocytes. PMID- 20842107 TI - The effect of cell cycle synchronization on tumor sensitivity to reovirus oncolysis. AB - The potential for increased sensitivity of tumor cells to oncolytic reovirus by altering the normal cell cycle using clinically available pharmacological agents was investigated. B16.F10 mouse melanoma cells were partially synchronized with hydroxyurea, thymidine, or by mitotic shake-off. Cell survival was determined using MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4 sulfophenyl)-2H-tetrazolium)] survival assay and virus yield in tumors by plaque assay. An enhanced sensitivity to reovirus was observed following the removal of either hydroxyurea or thymidine from the culture medium (P < 0.0001). The greatest survival difference compared to normal cycling cells was noted when the majority of cells were in S and G2/M phases, and was associated with increased viral replication. Cells collected by mitotic shake-off were nearly devoid of cells in S phase and were less susceptible to reovirus-induced cell kill than their nonsynchronized counterparts (P < 0.0001). In vivo combination of hydroxyurea followed by intratumoral reovirus resulted in reduced tumor growth and increased survival compared to monotherapy (P = 0.0041) at 15 days. Increased amounts of virus were retrieved from tumors from mice treated with sequential hydroxyurea/reovirus compared to concomitant treatment or reovirus monotherapy. These data justify clinical evaluation of this approach supported by the extensive experience, low cost, simple administration, and availability of hydroxyurea. PMID- 20842108 TI - Intra-arterial targeted islet-specific expression of Sirt1 protects beta cells from streptozotocin-induced apoptosis in mice. AB - Gene therapy provides a promising approach to curing diabetes. However, an effective route for islet-specific targeting has yet to be established. Toward this end, the pancreatic blood circulation system in Balb/c mice was determined by the injection of rhodamine-containing beads. The efficiency of islet targeting was then measured by the injection of adenoviral vectors carrying a green fluorescence gene via the celiac trunk (C.T.). The results showed that >95% of islets and about 60% of beta cells within the pancreatic body and tail could be labeled 3 days after surgery. alpha-Cell labeling was not as efficient, whereas labeling of nonendocrine tissues was barely detectable. For proof of principle, adenoviral vectors carrying a Sirtuin transgene were injected similarly to test the islet protection effect in the streptozotocin (STZ)-induced type 1 diabetic model. The results demonstrated that overexpression of Sirtuin in STZ-treated mice reduced the level of beta-cell death and extent of glucose intolerance. This study reports on efficient islet-specific targeting by using adenoviral injection. This procedure could be invaluable to the treatment of diabetes and the study of islet biology. PMID- 20842109 TI - Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is defined as the spectrum of benign fatty liver to necroinflammation and fibrosis. Its prevalence has been found to be as high as 39%. It is estimated that up to 15% of those affected will go on to have progressive liver disease. Currently, there is no proven therapy for NAFLD. In this study, we aim to determine whether statin therapy may be an effective treatment for NAFLD and identify independent predictors of NAFLD. METHODS: In all, 1,005 men and women, aged 50-70 years were randomized to receive either a daily combination of atorvastatin 20 mg, vitamin C 1 g, and vitamin E 1,000 IU vs. matching placebo, as part of the St Francis Heart Study randomized clinical trial. Liver to spleen (LS) ratios were calculated on 455 subjects with available computed tomography scans performed at baseline and follow-up to determine NAFLD prevalence. Baseline and final LS ratios were compared within treatment groups, and results were compared between the treatment and placebo groups using univariate and multivariate analyses. Mean duration of follow-up was 3.6 years. RESULTS: There were 80 patients with NAFLD at baseline. We identified baseline triglyceride levels (odds ratio (OR)=1.003, P<0.001) and body mass index (OR=0.10, P<0.001) as independent correlates of NAFLD. Treatment with atorvastatin combined with vitamins E and C significantly reduced the odds of NAFLD at the end of follow-up, 70 vs. 34% (OR=0.29, P<0.001). CONCLUSIONS: In conclusion, atorvastatin 20 mg combined with vitamins C and E is effective in reducing the odds of having hepatic steatosis by 71% in healthy individuals with NAFLD at baseline after 4 years of active therapy. PMID- 20842110 TI - The gain in quality-adjusted life months by switching to esomeprazole in those with continued reflux symptoms in primary care: EncomPASS--a cluster-randomized trial. AB - OBJECTIVES: Proton pump inhibitors (PPIs) are effective in gastroesophageal reflux disease (GERD), but their cost effectiveness is unknown. This is usually determined by cost/quality-adjusted life year (QALY) gained, but whether PPI therapy improves QALYs has not been assessed in a randomized trial. The PPI acid suppression symptom (PASS) test is a five-item questionnaire that identifies patients with persistent acid-related symptoms. We evaluated whether a PASS test based management strategy of changing GERD therapy to esomeprazole in those with continued symptoms on another PPI or H(2) receptor antagonist therapy would be cost effective. We expressed the data in terms of cost per quality-adjusted life months (QALM), as this was a 4-week trial. METHODS: This is a multicenter, cluster-randomized, open-label study in primary care physician centers across Canada. Primary care physician centers were randomized to intervention or control arms. Patients on acid-suppressing medication were identified from primary care records and asked to complete the PASS test. PASS test failures at baseline assessment continued current therapy in control practices or switched to esomeprazole 20 or 40 mg daily (the dose was at the clinician's discretion) for 4 weeks in intervention practices. A planned secondary end point was QALM gain, measured using the validated Euroqol (EQ-5D) completed at baseline and 4 weeks. Medication use was also assessed by questionnaire. Canadian unit generic costs were applied to all GERD drugs, except to esomeprazole and lansoprazole, wherein proprietary costs were used (all costs in Canadian $). Data were analyzed using bootstrap sampling. RESULTS: A total of 1,564 patients were recruited from 134 intervention sites and 92 control sites. Data were evaluable for 808 intervention and 445 control patients. The mean (+/-standard deviation) QALM at 4 weeks in the intervention group was 0.885+/-0.164 compared with 0.814+/-0.179 in the control group, resulting in a mean 0.071 (95% CI=0.091-0.051) QALM gain (P<0.0001). Esomeprazole was cost effective for PASS test failures, with a mean cost of $763 (95% CI=456-1,414) per QALM gain. CONCLUSIONS: Esomeprazole was associated with a statistically significant gain in QALMs and was cost effective in primary care patients with persistent acid-related symptoms identified by the PASS test. PMID- 20842111 TI - A comparison of optical colonoscopy and CT colonography screening strategies in the detection and recovery of subcentimeter adenomas. AB - OBJECTIVES: Evidence has shown that computerized tomographic colonography (CTC) and optical colonoscopy (OC) can detect advanced adenomas at an equal rate; however, a comparison of the subcentimeter adenoma detection has not been performed. The objective of this study is to compare CTC and OC screening programs, with a focus on the detection and recovery of subcentimeter adenomas. METHODS: In all, 1,700 screening OC examinations in average-risk patients were compared with 1,307 CTC examinations in similar patients drawn from the same referral pool completed in 2006-2008. The detection rate for adenomas <= 5 mm, 6 9 mm, and <10 mm with advanced histology were compared. RESULTS: In the OC group, 23.2% of patients had at least one adenoma removed; in the CTC screening group, 5.9% of patients had at least one adenoma detected and removed, P<0.001. There were significantly more <= 5 mm adenomas (detection rate 0.22, 378/1,700) detected by OC than by CTC (detection rate 0.04, 56/1,307), P<0.001. There were significantly more adenomas 6-9 mm (detection rate 0.12, 204/1,700) detected by OC than by CTC (detection rate 0.05, 67/1,307), with 70 patients with polyps of unknown histology in CTC surveillance, P<0.001. The number of advanced lesions <10 mm detected by OC (15/1,700) compared with CTC (4/1,307) were not significantly different, P=0.06. In the OC group, 27.1% of patients had non adenomatous polyps removed; in the CTC group, 4.1% of patients had non adenomatous polyps removed, P<0.001. CONCLUSIONS: (i) An OC screening program detects and recovers a significant four and a half fold greater number of non advanced adenomas compared with a CTC screening program. (ii) The primary difference between screening with OC and CTC is the recovery and management of the subcentimeter adenoma. PMID- 20842112 TI - Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways. AB - BACKGROUND: Wilms' tumour 1 (WT1) gene was discovered as a tumour suppressor gene. Later findings have suggested that WT1 also can be oncogenic. This complexity is partly explained by the fact that WT1 has a number of target genes. METHOD: WT1 and its target gene human telomerase reverse transcriptase (hTERT) were analysed in clear cell renal cell carcinoma (ccRCC). In vitro experiments were performed to examine the functional link between WT1 and hTERT by overexpression of WT1 isoforms in the ccRCC cell line, TK-10. RESULTS: WT1 demonstrated lower RNA expression in ccRCC compared with renal cortical tissue, whereas hTERT was increased, showing a negative correlation between WT1 and hTERT (P=0.005). These findings were experimentally confirmed in vitro. The WT1 generated effect on hTERT promoter activity seemed complex, as several negative regulators of hTERT transcription, such as SMAD3, JUN (AP-1) and ETS1, were activated by WT1 overexpression. Downregulation of potential positive hTERT regulators, such as cMyc, AP-2alpha, AP-2gamma, IRF1, NFX1 and GM-CSF, were also observed. Chromatin immunoprecipitation analysis verified WT1 binding to the hTERT, cMyc and SMAD3 promoters. CONCLUSION: The collected data strongly indicate multiple pathways for hTERT regulation by WT1 in ccRCC. PMID- 20842113 TI - microRNA-22, downregulated in hepatocellular carcinoma and correlated with prognosis, suppresses cell proliferation and tumourigenicity. AB - BACKGROUND: Recently, microRNAs in cancer development have attracted much attention, but their roles in tumorigenesis are still largely unknown. In this study, a functional role of miR-22 in hepatocellular carcinoma (HCC) development has been identified. METHODS: Quantitative real-time PCR was used to determine the level of miR-22 transcript in HCC clinical samples, and its correlation with disease-free survival was determined using Kaplan-Meier method. Restoration of miR-22 expression was carried out in HCC cell lines to assess its influence on HCC cell proliferation and tumourigenicity. RESULTS: In the 160 paired HCC tissue samples, miR-22 expression was downregulated in HCC, and low miR-22 expression in HCC was predictive of poor survival in HCC patients. Functional studies indicated that ectopic expression of miR-22 significantly inhibits HCC cell proliferation and tumourigenicity. Furthermore, histone deacetylase 4 (HDAC4), known to have critical roles in cancer development, was proved to be directly targeted and regulated by miR-22. Furthermore, HDAC4 was upregulated in miR-22-downregulated HCC tissues, suggesting that downregulation of miR-22 might participate in HCC carcinogenesis and progression through potentiation of HDAC4 expression. In addition, cell proliferation was also suppressed by knockdown of HDAC4 or treatment with HDAC inhibitor trichostatin A in HCC cell lines. CONCLUSION: miR 22, downregulated in HCC, has an anti-proliferative effect on HCC cells both in vitro and in vivo. Furthermore, miR-22 may have considerable potential in identification of the prognosis and application of cancer therapy for HCC patients. PMID- 20842114 TI - Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas. AB - BACKGROUND: Lung squamous cell carcinomas (SqCCs) occur at higher rates following arsenic exposure. Somatic DNA copy-number alterations (CNAs) are understood to be critical drivers in several tumour types. We have assembled a rare panel of lung tumours from a population with chronic arsenic exposure, including SqCC tumours from patients with no smoking history. METHODS: Fifty-two lung SqCCs were analysed by whole-genome tiling-set array comparative genomic hybridisation. Twenty-two were derived from arsenic-exposed patients from Northern Chile (10 never smokers and 12 smokers). Thirty additional cases were obtained for comparison from North American smokers without arsenic exposure. Twenty-two blood samples from healthy individuals from Northern Chile were examined to identify germline DNA copy-number variations (CNVs) that could be excluded from analysis. RESULTS: We identified multiple CNAs associated with arsenic exposure. These alterations were not attributable to either smoking status or CNVs. DNA losses at chromosomes 1q21.1, 7p22.3, 9q12, and 19q13.31 represented the most recurrent events. An arsenic-associated gain at 19q13.33 contains genes previously identified as oncogene candidates. CONCLUSIONS: Our results provide a comprehensive approach to molecular characteristics of the arsenic-exposed lung cancer genome and the non-smoking lung SqCC genome. The distinct and recurrent arsenic-related alterations suggest that this group of tumours may be considered as a separate disease subclass. PMID- 20842115 TI - Risk of breast cancer according to clinicopathologic features among long-term survivors of Hodgkin's lymphoma treated with radiotherapy. AB - BACKGROUND: It is unknown whether breast cancer (BC) characteristics among young women treated with radiotherapy (RT) for Hodgkin's lymphoma (HL) differ from sporadic BC. METHODS: Using population-based data, we calculated BC risk following HL according to clinicopathologic features. RESULTS: Compared with BC in the general population, risks of oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive and ER-negative/PR-negative BC in young, irradiated HL survivors were increased five-fold (95% confidence interval (CI)=3.81-6.35) and nine-fold (95% CI=6.93-12.25), respectively. Among 15-year survivors, relative risk of ER-negative/PR-negative BC exceeded by two-fold (P=0.002) than that of ER positive/PR-positive BC. CONCLUSION: Radiotherapy may disproportionately contribute to the development of BC with adverse prognostic features among young HL survivors. PMID- 20842116 TI - New relationships between breast microcalcifications and cancer. AB - BACKGROUND: Breast microcalcifications are key diagnostically significant radiological features for localisation of malignancy. This study explores the hypothesis that breast calcification composition is directly related to the local tissue pathological state. METHODS: A total of 236 human breast calcifications from 110 patients were analysed by mid-Fouries transform infrared (FTIR) spectroscopy from three different pathology types (112 invasive carcinoma (IC), 64 in-situ carcinomas and 60 benign). The biochemical composition and the incorporation of carbonate into the hydroxyapatite lattice of the microcalcifications were studied by infrared microspectroscopy. This allowed the spectrally identified composition to be directly correlated with the histopathology grading of the surrounding tissue. RESULTS: The carbonate content of breast microcalcifications was shown to significantly decrease when progressing from benign to malignant disease. In this study, we report significant correlations (P<0.001) between microcalcification chemical composition (carbonate content and protein matrix : mineral ratios) and distinct pathology grades (benign, in-situ carcinoma and ICs). Furthermore, a significant correlation (P<0.001) was observed between carbonate concentrations and carcinoma in-situ sub-grades. Using the two measures of pathology-specific calcification composition (carbonate content and protein matrix : mineral ratios) as the inputs to a two-metric discriminant model sensitivities of 79, 84 and 90% and specificities of 98, 82 and 96% were achieved for benign, ductal carcinoma in situ and invasive malignancies, respectively. CONCLUSIONS: We present the first demonstration of a direct link between the chemical nature of microcalcifications and the grade of the pathological breast disease. This suggests that microcalcifications have a significant association with cancer progression, and could be used for future objective analytical classification of breast pathology. A simple two-metric model has been demonstrated, more complex spectral analysis may yeild greater discrimination performance. Furthermore there appears to be a sequential progression of calcification composition. PMID- 20842117 TI - Prolonging hormone sensitivity in prostate cancer xenografts through dual inhibition of AR and mTOR. AB - BACKGROUND: To determine the mechanisms associated with loss of androgen dependency and disease progression in prostate cancer (PCa), we investigated the relationship between the androgen receptor (AR) and mTOR pathways and the impact of inhibiting both pathways in androgen-dependent and castration-resistant PCa models. EXPERIMENTAL DESIGN: Androgen-dependent (LNCaP) and castration-resistant PCa (HP-LNCaP) cells were grown as tumours in SCID mice. Once tumours reached 500 mm(3), animals were grouped and injected subcutaneous with vehicle, our novel anti-androgen/androgen synthesis inhibitor, VN/124-1, bicalutamide, and everolimus. Tumour volumes were measured biweekly. The PSA and protein analyses were performed after completion of the treatment. RESULTS: The addition of everolimus to bicalutamide treatment of resistant tumours significantly reduced tumour growth rates and tumour volumes. Anti-androgen treatment also increased protein expression of multiple signal transduction pathways earlier than vehicle treated control xenografts. VN/124-1 plus everolimus acted in concert to reduce tumour growth rates in our castration-resistant xenograft model. CONCLUSIONS: This study suggests that dual inhibition of AR and mTOR in castration-resistant xenograft models can restore sensitivity of tumours to anti-androgen therapy. Furthermore, after bicalutamide failure, dual inhibition with VN/124-1 and everolimus was the most effective treatment. PMID- 20842119 TI - Cancer incidence among the south Asian and non-south Asian population under 30 years of age in Yorkshire, UK. AB - BACKGROUND: Few studies have examined epidemiological differences between ethnic groups for children and young adults with cancer. METHODS: Subjects aged 0-29 years, diagnosed between 1990 and 2005 in the former Yorkshire Regional Health Authority, were included in the analysis. Ethnicity (south Asian or not) was assigned using name analysis program and Hospital Episode Statistics data. Differences in incidence (per 1,000,000 person-years) rates and trends were analysed using joinpoint and Poisson regression analysis. RESULTS: Overall cancer incidence was similar for south Asians (12.1, 95% CI: 10.7-13.5; n=275) and non south Asians (12.6, 95% CI: 12.2-13.1; n=3259). Annual incidence rates increased significantly by 1.9% per year on average (95% CI: 1.2-2.6%), especially for south Asians (7.0%; 95% CI: 4.2-9.9%). CONCLUSION: If present trends continue, the higher rate of increase seen among south Asians aged 0-29 years in Yorkshire will result in three times higher cancer incidence than non-south Asians by 2020. PMID- 20842118 TI - Beclin 1 over- and underexpression in colorectal cancer: distinct patterns relate to prognosis and tumour hypoxia. AB - INTRODUCTION: Autophagy enables cells to recycle long-lived proteins or damaged organelles. Beclin 1, the mammalian orthologue of the yeast Apg6/Vps30 gene, functions as a scaffold for the formation of autophagosomes. MATERIALS AND METHOD: The immunohistochemical patterns of Beclin 1 expression and their prognostic relevance were studied in formalin-fixed tissues from 155 patients with colorectal adenocarcinoma treated with surgery alone. RESULTS: Using the weak homogeneous expression of Beclin 1 in normal colonic tissues as a basis for assessing tumours, the following grouping/staining patterns were recognised in colorectal carcinomas: a normal-like pattern in 62 of 155 (40%) cases, an underexpression pattern in 24 of 155 (15.5%) cases, extensive overexpression of Beclin 1 in 33 of 155 (21.3%) tumours and limited overexpression of the protein in 36 of 155 (23.2%) tumours. Extensive overexpression of Beclin 1 was significantly linked with overexpression of HIF1alpha and LDH5, as well as with high histological grade, vascular invasion and nodal involvement. Furthermore, patients with extensive over- or underexpression of Beclin 1 had a significantly poorer overall survival compared with the other two groups (P<0.0001). Beclin 1 had an independent prognostic relevance in multivariate analysis. CONCLUSIONS: Beclin 1 has an important role in growth and metastasis of colorectal cancer. Loss of Beclin 1 expression (allelic loss or microRNA regulatory activity, as suggested in the literature) defines poor prognosis presumably by promoting anti apoptotic pathways, while overexpression of the protein, being linked with tumour hypoxia and acidity, also defines subgroups of tumours with aggressive clinical behaviour. PMID- 20842120 TI - Hospitalisation for venous thromboembolism in cancer patients and the general population: a population-based cohort study in Denmark, 1997-2006. AB - BACKGROUND: Venous thromboembolism (VTE) frequently complicates cancer. Data on tumour-specific VTE predictors are limited, but may inform strategies to prevent thrombosis. METHODS: We computed incidence rates (IRs) with 95% confidence intervals (CIs) for VTE hospitalisation in a cohort of cancer patients (n=57,591) and in a comparison general-population cohort (n=287,476) in Denmark. The subjects entered the study in 1997-2005, and the follow-up continued through 2006. Using Cox proportional-hazards regression, we estimated relative risks (RRs) for VTE predictors, while adjusting for comorbidity. RESULTS: Throughout the follow-up, VTE IR was higher among the cancer patients (IR=8.0, 95% CI=7.6 8.5) than the general population (IR=4.7, 95% CI=4.3-5.1), particularly in the first year after cancer diagnosis (IR=15.0, 95% CI=13.8-16.2, vs IR=8.6, 95% CI=7.6-9.9). Incidence rates of VTE were highest in patients with pancreas (IR=40.9, 95% CI=29.5-56.7), brain (IR=17.7, 95% CI=11.3-27.8) or liver (IR=20.4, 95% CI=9.2-45.3) tumours, multiple myeloma (IR=22.6, 95% CI=15.4-33.2) and among patients with advanced-stage cancers (IR=27.7, 95% CI=24.0-32.0) or those who received chemotherapy or no/symptomatic treatment. The adjusted RR (aRR) for VTE was highest among patients with pancreas (aRR=16.3, 95% CI=8.1-32.6) or brain cancer (aRR=19.8 95% CI=7.1-55.2), multiple myeloma (aRR=46.1, 95% CI=13.1-162.0) and among patients receiving chemotherapy, either alone (aRR=18.5, 95% CI=11.9 28.7) or in combination treatments (aRR=16.2, 95% CI=12.0-21.7). CONCLUSIONS: Risk of VTE is higher among cancer patients than in the general population. Predictors of VTE include recency of cancer diagnosis, cancer site, stage and the type of cancer-directed treatment. PMID- 20842121 TI - Mechanism of genotoxicity induced by targeted cytoplasmic irradiation. AB - BACKGROUND: Direct damage to DNA is generally accepted as the main initiator of mutation and cancer induced by environmental carcinogens or ionising radiation. However, there is accumulating evidence suggesting that extracellular/extranuclear targets may also have a key role in mediating the genotoxic effects of ionising radiation. As the possibility of a particle traversal through the cytoplasm is much higher than through the nuclei in environmental radiation exposure, the contribution to genotoxic damage from cytoplasmic irradiation should not be ignored in radiation risk estimation. Although targeted cytoplasmic irradiation has been shown to induce mutations in mammalian cells, the precise mechanism(s) underlying the mutagenic process is largely unknown. METHODS: A microbeam that can target the cytoplasm of cells with high precision was used to study mechanisms involved in mediating the genotoxic effects in irradiated human-hamster hybrid (A(L)) cells. RESULTS: Targeted cytoplasmic irradiation induces oxidative DNA damages and reactive nitrogen species (RNS) in A(L) cells. Lipid peroxidation, as determined by the induction of 4-hydroxynonenal was enhanced in irradiated cells, which could be suppressed by butylated hydroxyl toluene treatment. Moreover, cytoplasmic irradiation of A(L) cells increased expression of cyclooxygenase-2 (COX-2) and activation of extracellular signal-related kinase (ERK) pathway. CONCLUSION: We herein proposed a possible signalling pathway involving reactive oxygen/nitrogen species and COX 2 in the cytoplasmic irradiation-induced genotoxicity effect. PMID- 20842122 TI - EVI1 controls proliferation in acute myeloid leukaemia through modulation of miR 1-2. AB - BACKGROUND: The EVI1(ecotropic virus integration site 1) gene codes for a zinc finger transcription factor, whose transcriptional activation leads to a particularly aggressive form of acute myeloid leukaemia (AML). Although, EVI1 interactions with key proteins in hematopoiesis have been previously described, the precise role of this transcription factor in promoting leukaemic transformation is not completely understood. Recent works have identified specific microRNA (miRNA) signatures in different AML subgroups. However, there is no analysis of miRNAs profiles associated with EVI1 overexpression in humans. METHODS: We performed QT-RT-PCR to assess the expression of 250 miRNAs in cell lines with or without EVI1 overexpression and in patient samples. We used ChIP assays to evaluated the possible binding of EVI1 binding to the putative miRNA promoter. Proliferation of the different cell lines transfected with the anti- or pre-miRs was quantified by MTT. RESULTS: Our data showed that EVI1 expression was significantly correlated with the expression of miR-1-2 and miR-133-a-1 in established cell lines and in patient samples. ChIP assays confirmed that EVI1 binds directly to the promoter of these two miRNAs. However, only miR-1-2 was involved in abnormal proliferation in EVI1 expressing cell lines. CONCLUSIONS: Our data showed that EVI1 controls proliferation in AML through modulation of miR 1-2. This study contributes to further understand the transcriptional networks involving transcription factors and miRNAs in AML. PMID- 20842123 TI - Adiposity, adult weight change and breast cancer risk in postmenopausal Japanese women: the Miyagi Cohort Study. AB - BACKGROUND: The role of adult weight change in breast cancer (BC) risk is unclear in Japanese women. METHODS: A total of 10,106 postmenopausal women aged 40-64 years (the Miyagi Cohort) were followed from 1990 to 2003, and 108 BC cases were identified. Hazard ratios (HRs) were estimated according to body mass index (BMI) at the current age and at the of age 20 years, and weight change since age 20 years. RESULTS: Higher current BMI was associated with an increased risk of BC (P for trend=0.02), whereas higher BMI at the age 20 years was inversely associated with this risk (P for trend=0.002). There was a significant association between weight change since age 20 years and BC risk (P for trend=0.0086). Compared with stable weight, HR was 0.35 for weight loss of 5 kg or more (P for weight loss trend=0.04) and 1.55 for weight gain of 12 kg or more (P for weight gain trend=0.05). CONCLUSION: Adiposity at younger and current age has differential effects on BC risk among postmenopausal women; weight gain in adulthood being associated with an increased, and weight loss with a decreased risk. PMID- 20842124 TI - Smoking cessation and lung cancer risk in an Asian population: findings from the Singapore Chinese Health Study. AB - BACKGROUND: Smoking cessation is an important strategy for reducing the harmful effects of tobacco, particularly in the prevention of lung cancer; however, prospective data on the impact of smoking cessation on lung cancer risk in Asian populations are limited. METHODS: We studied a population-based cohort of Chinese men and women aged 45-74 years--participants of the Singapore Chinese Health Study. Information on smoking, lifestyle and dietary habits was collected at the time of recruitment in 1993-1998; and smoking status was assessed again at a second interview in 1999-2004 (mean interval 5.8 years). Participants were followed up to 31 December 2007, and incident cases of lung cancer were ascertained by linkage with population-wide registries. RESULTS: Among 45,900 participants, there were 463 incident cases of lung cancer. Relative to current smokers, those who quit smoking subsequent to baseline assessment had a 28% decrease in the risk of lung cancer (adjusted hazard ratio (HR) 0.72; 95% CI (95% confidence interval): 0.53-0.98). The risk was less than half in ex-smokers who had quit before the first interview and maintained their status (HR 0.42; 95% CI: 0.32-0.56). CONCLUSIONS: Reduction in lung cancer incidence with smoking cessation in Asian populations is substantial and can be observed within a few years after quitting. PMID- 20842125 TI - Elevated dietary linoleic acid increases gastric carcinoma cell invasion and metastasis in mice. AB - BACKGROUND: Dietary (n-6)-polyunsaturated fatty acids influence cancer development, but the mechanisms have not been well characterised in gastric carcinoma. METHODS: We used two in vivo models to investigate the effects of these common dietary components on tumour metastasis. In a model of experimental metastasis, immunocompromised mice were fed diets containing linoleic acid (LA) at 2% (LLA), 8% (HLA) or 12% (VHLA) by weight and inoculated intraperitoneally (i.p.) with human gastric carcinoma cells (OCUM-2MD3). To model spontaneous metastasis, OCUM-2MD3 tumours were grafted onto the stomach walls of mice fed with the different diets. In in vitro assays, we investigated invasion and ERK phosphorylation of OCUM-2MD3 cells in the presence or absence of LA. Finally, we tested whether a cyclooxygenase (COX) inhibitor, indomethacin, could block peritoneal metastasis in vivo. RESULTS: Both the HLA and VHLA groups showed increased incidence of tumour nodules (LA: 53%; HLA: 89%; VHLA: 100%; P<0.03); the VHLA group also displayed increased numbers of tumour nodules and higher total volume relative to LLA group in experimental metastasis model. Both liver invasion (78%) and metastasis to the peritoneal cavity (67%) were more frequent in VHLA group compared with the LLA group (22% and 11%, respectively; P<0.03) in spontaneous metastasis model. We also found that the invasive ability of these cells is greatly enhanced when exposed to LA in vitro. Linoleic acid also increased invasion of other scirrhous gastric carcinoma cells, OCUM-12, NUGC3 and MKN-45. Linoleic acid effect on OCUM-2MD3 cells seems to be dependent on phosphorylation of ERK. The data suggest that invasion and phosphorylation of ERK were dependent on COX. Indomethacin decreased the number of tumours and total tumour volume in both LLA and VHLA groups. Finally, COX-1, which is known to be an important enzyme in the generation of bioactive metabolites from dietary fatty acids, appears to be responsible for the increased metastatic behaviour of OCUM 2MD3 cells in the mouse model. CONCLUSION: Dietary LA stimulates invasion and peritoneal metastasis of gastric carcinoma cells through COX-catalysed metabolism and activation of ERK, steps that compose pathway potentially amenable to therapeutic intervention. PMID- 20842127 TI - Cetuximab in small bowel adenocarcinoma: a new friend? PMID- 20842126 TI - 1H nuclear magnetic resonance spectroscopy characterisation of metabolic phenotypes in the medulloblastoma of the SMO transgenic mice. AB - BACKGROUND: Human medulloblastomas exhibit diverse molecular pathology. Aberrant hedgehog signalling is found in 20-30% of human medulloblastomas with largely unknown metabolic consequences. METHODS: Transgenic mice over-expressing smoothened (SMO) receptor in granule cell precursors with high incidence of exophytic medulloblastomas were sequentially followed up by magnetic resonance imaging (MRI) and characterised for metabolite phenotypes by 1H MR spectroscopy (MRS) in vivo and ex vivo using high-resolution magic angle spinning (HR-MAS) 1H MRS. RESULTS: Medulloblastomas in the SMO mice presented as T2 hyperintense tumours in MRI. These tumours showed low concentrations of N-acetyl aspartate and high concentrations of choline-containing metabolites (CCMs), glycine, and taurine relative to the cerebellar parenchyma in the wild-type (WT) C57BL/6 mice. In contrast, 1H MRS metabolite concentrations in normal appearing cerebellum of the SMO mice were not different from those in the WT mice. Macromolecule and lipid 1H MRS signals in SMO medulloblastomas were not different from those detected in the cerebellum of WT mice. The HR-MAS analysis of SMO medulloblastomas confirmed the in vivo 1H MRS metabolite profiles, and additionally revealed that phosphocholine was strongly elevated in medulloblastomas accounting for the high in vivo CCM. CONCLUSIONS: These metabolite profiles closely mirror those reported from human medulloblastomas confirming that SMO mice provide a realistic model for investigating metabolic aspects of this disease. Taurine, glycine, and CCM are potential metabolite biomarkers for the SMO medulloblastomas. The MRS data from the medulloblastomas with defined molecular pathology is discussed in the light of metabolite profiles reported from human tumours. PMID- 20842128 TI - Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy. AB - BACKGROUND: Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear. METHODS: We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworak's tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed. RESULTS: Tumour regression grade 4 and TRG3-4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found. CONCLUSION: Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation. PMID- 20842130 TI - A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. AB - BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor alpha (TNF-alpha) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-alpha monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg 1) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg-1 were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS6 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC. PMID- 20842133 TI - Patient struggles for philosophy. PMID- 20842129 TI - Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323). AB - BACKGROUND: The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients' health-related quality of life (HRQOL) and symptoms was investigated. METHODS: HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol. RESULTS: Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent. CONCLUSION: Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner. PMID- 20842131 TI - Inhibition of Id proteins by a peptide aptamer induces cell-cycle arrest and apoptosis in ovarian cancer cells. AB - BACKGROUND: Inhibitors of DNA-binding proteins (Id1-4), lacking the basic DNA binding domain, function as dominant inhibitors of cell-cycle regulators. Overexpression of Id proteins promotes cancer cell proliferation and resistance against apoptosis. Level of Id protein expression, especially of Id1, correlates with poor differentiation, enhanced malignant potential and more aggressive clinical behaviour of ovarian tumours. Although overexpression of Ids has been found and shown to correlate with poor clinical outcome, their inhibition at protein level has never been studied. METHODS: A peptide aptamer, Id1/3-PA7, targeting Id1 and Id3, was isolated from a randomised combinatorial expression library using yeast and mammalian two-hybrid systems. Id1/3-PA7 was fused, expressed and purified with a cell-penetrating protein transduction domain. RESULTS: Intracellular-delivered Id1/3-PA7 colocalised to Id1 and Id3. It induced cell-cycle arrest and apoptosis in ovarian cancer cells ES-2 and PA-1. It activated the E-box promoter and increased the expression level of cyclin dependent kinase inhibitor (CDKN2A) in a dose-dependent manner that is paralleled by the cleavage of poly-ADP ribose polymerase. These effects were counteracted by ectopically overexpressed Id1 and Id3. CONCLUSION: Id1/3-PA7 could represent an exogenous anti-tumour agent that can significantly trigger cell-cycle arrest and apoptosis in ovarian cancer. PMID- 20842134 TI - Physicians help move research from bench to bedside. PMID- 20842138 TI - Why is your sunscreen not working? PMID- 20842139 TI - Evaluation of and perspectives on guidelines: what is important? AB - Tan et al. critically appraised the quality of eight guidelines for the treatment of psoriasis published by five working groups between 2006 and 2009, using the Appraisal of Guidelines Research and Evaluation (AGREE) instrument. Four groups used the standards established by the AGREE instrument. All guidelines received high scores for "scope and purpose" and "clarity and presentation," but each of the guidelines was found to have important shortcomings in at least one item, including "stakeholder involvement," "development rigor," "applicability," and "editorial independence." The investigators conclude that, despite the use of predefined standards in their development, important deficiencies exist in the most recent clinical treatment guidelines for psoriasis. PMID- 20842140 TI - Circulating tumor cells and melanoma progression. AB - Circulating tumor cells (CTCs) are cancer cells shed from either a primary tumor or its metastases that circulate in the peripheral blood. CTCs are potential seeds for metastases, and analyses of CTCs may allow earlier detection of metastasis-capable malignancy, monitoring for tumor recurrence, and accurate prognostication. Studies on CTCs have focused mainly on the detection of epithelial cancer cells. In this issue, De Giorgi et al. show that CTCs can be detected in melanoma patients using a filtration method, and that a higher percentage of patients with metastatic melanoma have detectable CTCs than do patients with primary melanoma. PMID- 20842142 TI - Actinohivin: specific amino acid residues essential for anti-HIV activity. AB - Actinohivin (AH) is a microbial lectin containing 114 amino acids, which inhibits human immunodeficiency virus (HIV) infection. This effect is brought about by its specific binding to Man-alpha(1-2)-Man unit(s) of high-mannose type glycan (HMTG) bound to HIV gp120. The recently determined crystal structure of AH suggests that three repeated segments (the residue numbers 1-38, 39-76 and 77-114 for segments 1, 2 and 3, respectively) form three sugar-binding pockets to accommodate Man alpha(1-2)-Man units. The strong specific binding of AH to gp120 is considered to be due to multivalent interaction of the three sugar-binding pockets with three HMTGs of gp120 via the 'cluster effect' of lectin. It remains to be seen which residues of the sugar-binding pockets are essential for acceptance of Man-alpha(1 2)-Man. To identify the amino acid residues critical for anti-HIV effect, we performed mutational analysis. Mutant AHs were subjected to enzyme-linked immunosorbent assay testing for gp120-binding activity and to syncytium formation assay. As a result, it was revealed that Asp15, Tyr23, Leu25, Asn28 and Tyr32 in segment 1, Tyr61 in segment 2 and Tyr99 in segment 3 are essential for anti-HIV activity. The conserved residues, Asp53, Leu63, Asn66 and Tyr70, in segment 2 and, Asp91, Leu101, Asn104 and Tyr108, in segment 3 are also necessary. Furthermore, aromatic residues at positions 23 and 32 are required for creation of potency. These data will be useful for predicting the detailed mechanism of AH Man-alpha(1-2)-Man/HMTG/gp120 interaction by computational analysis and for possible development of more potent microbicides for prevention of HIV transmission. PMID- 20842143 TI - Structure-activity relationships of 11 new congeners of the SMTP plasminogen modulator. AB - The fungal metabolite Stachybotrys microspora triprenyl phenols (SMTPs) are small molecule plasminogen modulators that enhance plasminogen activation. The SMTP molecule consists of a tricyclic gamma-lactam moiety, an isoprene side-chain and an N-linked side-chain. Previous investigations have demonstrated that the N linked side-chain is crucial for its activity. In this study, we have isolated 11 new SMTP congeners with a variety of N-linked side-chain structures, to investigate structure-activity relationships. Active compounds included congeners with a carboxyl or a sulfonic acid group in the N-linked side-chain, whereas not all the congeners with a carboxyl group were active. Of these congeners, that with methionine or tyrosine as the N-linked side-chain moiety was more active than that with an aliphatic amino acid. Congeners without ionizable group in the N-linked side-chain were essentially inactive. PMID- 20842147 TI - Obesity-related renal damage: changing diet to avoid progression. AB - Obesity is increasingly recognized as a risk factor for the development of end stage renal disease. However, few studies have investigated the influence of dietary changes on kidney function in the obese. Friedman et al. report that dietary protein intake is unlikely to fully account for elevations in glomerular filtration rate and proteinuria observed in obesity. The relationship between diet and renal hemodynamics in obesity is complex, and more studies (including ones on the effect of caloric restriction) are needed. PMID- 20842148 TI - Corin: an ANP protease that may regulate sodium reabsorption in nephrotic syndrome. AB - The serine/threonine protease corin, which proteolytically activates atrial natriuretic peptide (ANP), is reduced in the kidneys of animals with nephrotic syndrome and glomerular nephritis. Polzin et al. provide evidence for a linkage between the decreased corin and beta-epithelial sodium channel, phosphodiesterase 5, and cGMP-dependent protein kinase II in the nephrotic kidney. They propose that decreases in cGMP resulting from the reduced corin may be responsible for the Na(+) retention and volume expansion that are hallmarks of these kidney diseases. PMID- 20842149 TI - Kidney transplantation from older donors: proceed with caution. AB - Kidney transplantation from living and deceased donors above age 60 increased in recent years in response to organ shortage. With careful screening, short-term follow-up of living elderly donors demonstrated stable remaining kidney function even in those with mild and controlled hypertension. The need for confirmation of long-term safety is heightened by the report by Tan et al. of a high prevalence of nephrosclerotic changes in these donors and evidence for a decreased number of glomeruli in elderly deceased donors. PMID- 20842151 TI - Sugar-sweetened soda consumption, hyperuricemia, and kidney disease. PMID- 20842153 TI - Non-infected central venous catheters in hemodialysis patients are not associated with inflammation. PMID- 20842154 TI - Importance of 3 h when dialyzing daily. PMID- 20842156 TI - In defense of the Stewart approach to acid-base analysis. PMID- 20842157 TI - Magnetic resonance lymphography of chyluria. PMID- 20842159 TI - Framingham cardiovascular risk profile correlates with impaired hippocampal and cortical vasoreactivity to hypercapnia. AB - Vascular risk factors affect cerebral blood flow (CBF) and cerebral vascular reactivity, contributing to cognitive decline. Hippocampus is vulnerable to both Alzheimer's disease (AD) pathology and ischemia; nonetheless, the information about the impact of vascular risk on hippocampal perfusion is minimal. Cognitively, healthy elderly (NL=18, 69.9+/-6.7 years) and subjects with mild cognitive impairment (MCI=15, 74.9+/-8.1 years) were evaluated for the Framingham cardiovascular risk profile (FCRP). All underwent structural imaging and resting CBF assessment with arterial spin labeling (ASL) at 3T magnetic resonance imaging (MRI). In 24 subjects (NL=17, MCI=7), CBF was measured after a carbon dioxide rebreathing challenge. Across all subjects, FCRP negatively correlated with hippocampal (rho=-0.41, P=0.049) and global cortical (rho=-0.46, P=0.02) vasoreactivity to hypercapnia (VR(h)). The FCRP-VR(h) relationships were most pronounced in the MCI group: hippocampus (rho=-0.77, P=0.04); global cortex (rho= 0.83, P=0.02). The FCRP did not correlate with either volume or resting CBF. The hippocampal VR(h) was lower in MCI than in NL subjects (Z=-2.0, P=0.047). This difference persisted after age and FCRP correction (F([3,20])=4.6, P=0.05). An elevated risk for vascular pathology is associated with a reduced response to hypercapnia in both hippocampal and cortical tissue. The VR(h) is more sensitive to vascular burden than either resting CBF or brain volume. PMID- 20842160 TI - Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies. AB - Ultrasound methods in conjunction with microbubbles have been used for brain drug delivery, treatment of stroke, and imaging of cerebral blood flow. Despite advances in these areas, questions remain regarding the range of ultrasound parameters that disrupt the blood-brain barrier (BBB). In this study, several conditions were investigated to either enhance or reduce the likelihood of BBB disruption. Pulsed focused ultrasound (frequency: 1.5 MHz, pressure: 0.46 MPa, pulse repetition frequency (PRF): 0.1 to 25 Hz, pulse length (PL): 0.03 to 30 milliseconds) was noninvasively and locally administered to a predetermined region in the left hemisphere in the presence of circulating preformed microbubbles (Definity, Lantheus Medical Imaging, N. Billerica, MA, USA; 0.01, 0.05, 0.25 MUL/g). Trans-BBB delivery of 3-kDa dextran was observed at PRFs as low as 1 Hz, whereas consistent delivery was observed at 5 Hz and above. Delivery was demonstrated at a PL as low as 33 microseconds. Although the delivered dextran concentration increased with the PL, this also increased the heterogeneity of the resulting distribution. In conclusion, key parameters that disrupt the BBB were identified out of a wide range of conditions. Reducing the total number of emitted acoustic cycles by shortening the PL, or decreasing the PRF, was also found to facilitate a more spatially uniform distribution of delivered dextran. PMID- 20842161 TI - Determination of the brain-blood partition coefficient for water in mice using MRI. AB - Cerebral blood flow (CBF) quantification is a valuable tool in stroke research. Mice are of special interest because of the potential of genetic engineering. Magnetic resonance imaging (MRI) provides repetitive, noninvasive CBF quantification. Many MRI techniques require the knowledge of the brain-blood partition coefficient (BBPC) for water. Adopting an MRI protocol described by Roberts et al (1996) in humans, we determined the BBPC for water in 129S6/SvEv mice from proton density measurements of brain and blood, calibrated with deuterium oxide/water phantoms. The average BBPC for water was 0.89 +/- 0.03 mL/g, with little regional variation within the mouse brain. PMID- 20842162 TI - A dynamic in vitro BBB model for the study of immune cell trafficking into the central nervous system. AB - Although there is significant evidence correlating overreacting or perhaps misguided immune cells and the blood-brain barrier (BBB) with the pathogenesis of neuroinflammatory diseases, the mechanisms by which they enter the brain are largely unknown. For this purpose, we revised our humanized dynamic in vitro BBB model (DIV-BBBr) to incorporate modified hollow fibers that now feature transmural microholes (2 to 4 MUm O) allowing for the transendothelial trafficking of immune cells. As with the original model, this new DIV-BBBr reproduces most of the physiological characteristics of the BBB in vivo. Measurements of transendothelial electrical resistance (TEER), sucrose permeability, and BBB integrity during reversible osmotic disruption with mannitol (1.6 mol/L) showed that the microholes do not hamper the formation of a tight functional barrier. The in vivo rank permeability order of sucrose, phenytoin, and diazepam was successfully reproduced in vitro. Flow cessation followed by reperfusion (Fc/Rp) in the presence of circulating monocytes caused a biphasic BBB opening paralleled by a significant increase of proinflammatory cytokines and activated matrix metalloproteinases. We also observed abluminal extravasation of monocytes but only when the BBB was breached. In conclusion, the DIV-BBBr represents the most realistic in vitro system to study the immune cell trafficking across the BBB. PMID- 20842163 TI - Limitations of collateral flow after occlusion of a single cortical penetrating arteriole. AB - Occlusions of penetrating arterioles, which plunge into cortex and feed capillary beds, cause severe decreases in blood flow and are potential causes of ischemic microlesions. However, surrounding arterioles and capillary beds remain flowing and might provide collateral flow around the occlusion. We used femtosecond laser ablation to trigger clotting in single penetrating arterioles in rat cortex and two-photon microscopy to measure changes in microvessel diameter and red blood cell speed after the clot. We found that after occlusion of a single penetrating arteriole, nearby penetrating and surface arterioles did not dilate, suggesting that alternate blood flow routes are not actively recruited. In contrast, capillaries showed two types of reactions. Capillaries directly downstream from the occluded arteriole dilated after the clot, but other capillaries in the same vicinity did not dilate. This heterogeneity in capillary response suggests that signals for vasodilation are vascular rather than parenchymal in origin. Although both neighboring arterioles and capillaries dilated in response to topically applied acetylcholine after the occlusion, the flow in the territory of the occluded arteriole did not improve. Collateral flow from neighboring penetrating arterioles is neither actively recruited nor effective in improving blood flow after the occlusion of a single penetrating arteriole. PMID- 20842164 TI - The influence of carbon dioxide on brain activity and metabolism in conscious humans. AB - A better understanding of carbon dioxide (CO(2)) effect on brain activity may have a profound impact on clinical studies using CO(2) manipulation to assess cerebrovascular reserve and on the use of hypercapnia as a means to calibrate functional magnetic resonance imaging (fMRI) signal. This study investigates how an increase in blood CO(2), via inhalation of 5% CO(2), may alter brain activity in humans. Dynamic measurement of brain metabolism revealed that mild hypercapnia resulted in a suppression of cerebral metabolic rate of oxygen (CMRO(2)) by 13.4% +/- 2.3% (N=14) and, furthermore, the CMRO(2) change was proportional to the subject's end-tidal CO(2) (Et-CO(2)) change. When using functional connectivity MRI (fcMRI) to assess the changes in resting-state neural activity, it was found that hypercapnia resulted in a reduction in all fcMRI indices assessed including cluster volume, cross-correlation coefficient, and amplitude of the fcMRI signal in the default-mode network (DMN). The extent of the reduction was more pronounced than similar indices obtained in visual-evoked fMRI, suggesting a selective suppression effect on resting-state neural activity. Scalp electroencephalogram (EEG) studies comparing hypercapnia with normocapnia conditions showed a relative increase in low frequency power in the EEG spectra, suggesting that the brain is entering a low arousal state on CO(2) inhalation. PMID- 20842165 TI - Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke. AB - Reduced infarct volume in TLR2-knockout mice compared with C57Bl/6 wild-type mice has recently been shown in experimental stroke and confirmed in this study. We now also show a significant decrease of CD11b-positive cell counts and decreased neuronal death in the ischemic hemispheres of TLR2-deficient mice compared with C57Bl/6wt mice 2 days after transient focal cerebral ischemia. To examine the potential benefit of intravascular TLR2 inhibition, C57Bl/6wt mice were treated intraarterially with TLR2-blocking anti-TLR2 antibody (clone T2.5) after 45 minutes of cerebral ischemia and compared with control antibody (isotype) treated wild-type mice. Whereas T2.5-treated mice had no reduction in infarct volumes at 48 hours after reperfusion, they did have decreased numbers of CD11b-positive inflammatory cells and decreased neuronal death compared with isotype-treated control mice. Comparison of the isotype antibody treatment to control (saline) treatment showed no effects on infarct volumes or neuronal survival. However, mice treated with the control isotype antibody had increased numbers of CD11b positive inflammatory cells compared with saline-treated animals. Thus, antibody treatment itself (i.e., control isotype antibody, but potentially of any antibody) may have adverse effects and limit therapeutic benefit of anti-TLR2 antibody therapy. We conclude that TLR2 mediates leukocyte and microglial infiltration and neuronal death, which can be attenuated by TLR2 inhibition. The TLR2 inhibition in vivo improves neuronal survival and may represent a future stroke therapy. PMID- 20842166 TI - A comparison of the bioavailability of ferrous fumarate and ferrous sulfate in non-anemic Mexican women and children consuming a sweetened maize and milk drink. AB - BACKGROUND/OBJECTIVES: Ferrous fumarate is recommended for the fortification of complementary foods based on similar iron absorption to ferrous sulfate in adults. Two recent studies in young children have reported that it is only 30% as well absorbed as ferrous sulfate. The objective of this study was to compare iron absorption from ferrous fumarate and ferrous sulfate in infants, young children and mothers. SUBJECTS/METHODS: Non-anemic Mexican infants (6-24 months), young children (2-5 years) and adult women were randomly assigned to receive either 4 mg Fe (women) or 2.5 mg Fe (infants and young children) as either [(57)Fe] ferrous fumarate or [(58)Fe]-ferrous sulfate added to a sweetened drink based on degermed maize flour and milk powder. Iron absorption was calculated based on incorporation of isotopes into erythrocytes after 14 days. RESULTS: Within each population group, no significant differences (P > 0.05) in iron absorption were found between ferrous fumarate and ferrous sulfate. Mean iron absorption from ferrous fumarate vs ferrous sulfate was 17.5 vs 20.5% in women (relative bioavailability (RBV) =86), 7.0 vs 7.2% in infants (RBV = 97) and 6.3 vs 5.9% in young children (RBV = 106). CONCLUSIONS: Ferrous fumarate is as well absorbed as ferrous sulfate in non-anemic, iron sufficient infants and young children, and can be recommended as a useful fortification compound for complementary foods designed to prevent iron deficiency. Further studies are needed to clarify its usefulness in foods designed to treat iron deficiency. PMID- 20842167 TI - Low dietary diversity is a predictor of child stunting in rural Bangladesh. AB - BACKGROUND/OBJECTIVES: Dietary diversity is associated with overall quality and nutrient adequacy of the diet in low-income countries. We determined the association between dietary diversity and stunting among children aged 6-59 months in rural Bangladesh. SUBJECTS/METHODS: In total, 165 111 under-fives who participated in the National Surveillance Project in 2003-2005 were included in the analysis. Dietary diversity score (DDS) was constructed through the summation of the number of days each of the nine food groups was consumed in the previous week. The association between stunting and DDS was determined adjusting for confounders using logistic regression models. All analyses were performed separately for children aged 6-11, 12-23 and 24-59 months. RESULTS: One-half of the children were stunted. In multivariate analyses, compared with low DDS, high dietary diversity was associated with a 15, 26 and 31% reduced odds of being stunted among children aged 6-11, 12-23 and 24-59 months, respectively, after adjusting for all potential confounders (odds ratio (OR)=0.85, 95% confidence interval (CI): 0.76-0.94; OR=0.74, 95% CI: 0.69-0.79; OR=0.69, 95% CI: 0.66 0.73). In all groups, children who were still breastfed were more likely to have limited diversity (OR=1.88, 95% CI: 1.32-2.67; OR=1.71, 95% CI: 1.52-1.92; OR=1.15, 95% CI: 1.11-1.19). Those having diarrhea in the past week and coming from families with low socioeconomic status were more likely to have decreased diversity (P<0.05). CONCLUSIONS: Reduced dietary diversity is a strong predictor of stunting in rural Bangladesh. The inclusion of a variety of food groups into complementary foods may be essential to improve child nutritional status. PMID- 20842168 TI - Effect of a relatively high-protein, high-fiber diet on body composition and metabolic risk factors in overweight women. AB - BACKGROUND: Obesity and its comorbidities are worldwide problems. Approaches to reducing obesity and its associated metabolic derangements typically emphasize fat and energy restriction, but for many achieving and maintaining weight loss is difficult. Diets that focus on substantially altering macronutrient distribution rather than energy restriction are promising alternatives, but have generally included large amounts of protein, fiber or fat. OBJECTIVE: To compare the effects of dietary advice including moderate increases in protein and fiber without specifying energy intake with standard low-fat, high-carbohydrate dietary recommendations on body composition and metabolic risk factors. METHODS: 89 overweight or obese women aged 18-65 years were randomized to either a standard diet that was intended to be low in fat and relatively high in carbohydrate (n=42) or to a relatively high-protein (up to 30% of energy), relatively high fiber (>35g per day; HPHF) diet (n=47) for 10 weeks. Advice regarding strict adherence to energy intake goals was not given. RESULTS: Participants on the HPHF diet lost more body weight (1.3kg; 95% CI, 0.7, 1.9; P<0.0001), total fat (1.0kg; 95% CI, 0.2, 1.8; P<0.0001) and truncal fat (0.7kg; 95% CI, 0.1, 1.3; P=0.034) than participants on the standard diet. Total cholesterol and low-density lipoprotein (LDL) cholesterol were also significantly lower after the HPHF diet. CONCLUSION: An ad libitum diet relatively high in both protein and fiber improved body composition and metabolic risk factors compared with standard dietary advice. PMID- 20842169 TI - Impact of maternal vitamin A supplementation on the mother-infant pair in Brazil. AB - BACKGROUND/OBJECTIVES: Vitamin A deficiency (VAD) is a major public health problem. The supplementation of lactating women could be an effective strategy to combat it. The objective of this study was to assess the impact of maternal vitamin A supplementation on the mother-infant pair. SUBJECTS/METHODS: This was a double blind, placebo-controlled randomized clinical assay in which 33 women received 200 000 IU of vitamin A and 33 women received soy oil between 20th and 30th postpartum days. Maternal blood and milk samples were collected immediately before supplementation and 3 months after delivery, when blood was also collected from the babies. Retinol concentrations ?0.70 MUmol/l in serum and 1.05 MUmol/l in milk were considered to indicate VAD. RESULTS: Increase in serum retinol level was observed in the supplemented group compared with the pre-supplementation levels (1.05 and 1.17 MUmol/l, respectively; P=0.026) and to the post supplementation levels of the control group (1.02 MUmol/l; P=0.032). Reduction in breast milk retinol was observed in the control group compared with the pre supplementation levels (1.93 and 1.34 MUmol/l, respectively; P<0.0001) and to the post-supplementation levels of the supplemented group (1.56 MUmol/l; P=0.0003). There was significant difference in the prevalence of VAD in breast milk after supplementation, 55.6% (15/27) in the control group and 16.1% (5/31) in the supplemented group (P=0.002). VAD was present in 66.1% (39/59) of infants, with mean serum retinol levels of 0.64+/-0.30 MUmol/l in the control group and of 0.69+/-0.26 MUmol/l in the supplemented group. CONCLUSIONS: Supplementation had a positive impact on maternal vitamin A status. No effect on infant status was detectable 2 months after supplementation with a single dose. PMID- 20842170 TI - Effect of carbohydrate digestibility on appetite and its relationship to postprandial blood glucose and insulin levels. AB - BACKGROUND/OBJECTIVES: 'Slowly digestible' carbohydrates have been claimed to reduce appetite through their effects on postprandial glucose and insulin levels, but literature is inconsistent. The inconsistencies between studies might be explained by factors other than glycemic effects per se, for example, nutritional or physical properties. We tested this possibility by examining postprandial glucose, insulin and appetite responses to drinks differing only in rate and extent of digestibility of carbohydrates. This was accomplished by comparing different glucose polymers: maltodextrin (rapidly digestible) versus medium-chain pullulan (slowly but completely digestible) versus long-chain pullulan (indigestible). SUBJECTS/METHODS: In a randomized double-blind balanced crossover design, 35 subjects received drinks with 15 g test carbohydrate polymers. Key outcome measures were appetite scores, digestibility (in vitro test and breath hydrogen), and (in a subset) glucose and insulin levels. RESULTS: Digestibility, glucose and insulin data confirmed the rapid, slow and nondigestible nature of the test carbohydrates. Despite its low digestibility, only long-chain pullulan reduced appetite compared with the maltodextrin control, whereas the medium-chain pullulan did not. CONCLUSIONS: We conclude that glycemic responses per se have minimal effects on appetite, when tested in products differing in only carbohydrate digestibility rate and extent. PMID- 20842171 TI - In vivo precision of the GE Lunar iDXA densitometer for the measurement of total body composition and fat distribution in adults. AB - In vivo precision for body composition measurements using dual energy X-ray absorptiometry (DXA; GE Lunar iDXA, GE Healthcare, Bucks, UK) was evaluated in 52 men and women, aged 34.8 (s.d. 8.4; range 20.1-50.5) years, body mass index (25.8 kg/m(2); range 16.7-42.7 kg/m(2)). Two consecutive total body scans (with re positioning) were conducted. Precision was excellent for all measurements, particularly for total body bone mineral content and lean tissue mass (root mean square 0.015 and 0.244 kg; coefficients of variation (CV) 0.6 and 0.5%, respectively). Precision error was CV 0.82% for total fat mass and 0.86% for percentage fat. Precision was better for gynoid (root mean square 0.397 kg; CV 0.96%) than for android fat distribution (root mean square 0.780 kg, CV 2.32%). There was good agreement between consecutive measurements for all measurements (slope (s.e.) 0.993-1.002; all R(2) = 0.99). The Lunar iDXA provided excellent precision for total body composition measurements. Research into the effect of body size on the precision of DXA body fat distribution measurements is required. PMID- 20842172 TI - Individually timing high-protein preloads has no effect on daily energy intake, peptide YY and glucagon-like peptide-1. AB - BACKGROUND/OBJECTIVES: Gut hormones have been shown to influence energy intake (EI). To our knowledge, no study has investigated the effects of dietary patterns aimed at optimizing fullness on EI, appetite and gut hormones. SUBJECT/METHODS: To determine whether individually timing high-protein preloads would impact EI, appetite, and peptide YY and glucagon-like peptide-1 (GLP-1) levels. Ten men (body mass index = 25.5 +/- 2.6 kg/m(2)) participated in a randomized crossover trial. The three conditions consisted of the self-selection of snacks (condition 1), or the consumption of a preload (300 kcal: 40% protein, 40% carbohydrates and 20% fat) at either 15 min (condition 2) or ~ 50 min (individually set) (condition 3) before lunch and dinner. During each condition, a standardized breakfast was served, whereas lunch and dinner were self-selected from a five-item menu, and eaten ad libitum. Mealtime and daily EI were measured. Appetite, peptide YY and GLP-1 were sampled over 9 h. RESULTS: No differences in daily EI were noted across conditions (1 = 3078 +/- 720 kcal; 2 = 2929 +/- 264 kcal; 3 = 2998 +/- 437 kcal; not significant). For the most part, daily profiles as well as premeal levels of peptide YY and GLP-1 were not different between conditions. Desire to eat, hunger and prospective food consumption were found to be lowest during condition 1 (P < 0.05). CONCLUSIONS: According to these results, it would seem that individually timing high-protein preloads does not reduce daily EI in healthy human subjects. PMID- 20842173 TI - A polarity factor takes the lead in chromosome segregation. PMID- 20842174 TI - Target practice: Zic2 hits the bullseye! PMID- 20842176 TI - The crucial role of pulsatile activity of the HPA axis for continuous dynamic equilibration. AB - The classical concept of hypothalamus-pituitary-adrenal (HPA) homeostasis comprises a feedback system within which circulating levels of glucocorticoid hormones maintain the brain and body in an optimal steady state. However, studies involving new techniques for investigating the real-time dynamics of both glucocorticoid hormones and glucocorticoid receptor function paint a different picture--namely, of continuous dynamic equilibration throughout this neuroendocrine system. This dynamic state is dictated by feedforward and feedback regulatory loops and by stochastic interactions at the level of DNA binding. We propose that this continuous oscillatory activity is crucial for optimal responsiveness of glucocorticoid-sensitive neural processes. PMID- 20842175 TI - Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. AB - There is a long-standing paradox that NMDA (N-methyl-D-aspartate) receptors (NMDARs) can both promote neuronal health and kill neurons. Recent studies show that NMDAR-induced responses depend on the receptor location: stimulation of synaptic NMDARs, acting primarily through nuclear Ca(2+) signalling, leads to the build-up of a neuroprotective 'shield', whereas stimulation of extrasynaptic NMDARs promotes cell death. These differences result from the activation of distinct genomic programmes and from opposing actions on intracellular signalling pathways. Perturbations in the balance between synaptic and extrasynaptic NMDAR activity contribute to neuronal dysfunction in acute ischaemia and Huntington's disease, and could be a common theme in the aetiology of neurodegenerative diseases. Neuroprotective therapies should aim to both enhance the effect of synaptic activity and disrupt extrasynaptic NMDAR-dependent death signalling. PMID- 20842177 TI - Pathways of mammalian replication fork restart. AB - Single-molecule analyses of DNA replication have greatly advanced our understanding of mammalian replication restart. Several proteins that are not part of the core replication machinery promote the efficient restart of replication forks that have been stalled by replication inhibitors, suggesting that bona fide fork restart pathways exist in mammalian cells. Different models of replication fork restart can be envisaged, based on the involvement of DNA helicases, nucleases, homologous recombination factors and the importance of DNA double-strand break formation. PMID- 20842178 TI - Rapid testing versus karyotyping in Down's syndrome screening: cost-effectiveness and detection of clinically significant chromosome abnormalities. AB - In all, 80% of antenatal karyotypes are generated by Down's syndrome screening programmes (DSSP). After a positive screening, women are offered prenatal foetus karyotyping, the gold standard. Reliable molecular methods for rapid aneuploidy diagnosis (RAD: fluorescence in situ hybridization (FISH) and quantitative fluorescence PCR (QF-PCR)) can detect common aneuploidies, and are faster and less expensive than karyotyping.In the UK, RAD is recommended as a standalone approach in DSSP, whereas the US guidelines recommend that RAD be followed up by karyotyping. A cost-effectiveness (CE) analysis of RAD in various DSSP is lacking. There is a debate over the significance of chromosome abnormalities (CA) detected with karyotyping but not using RAD. Our objectives were to compare the CE of RAD versus karyotyping, to evaluate the clinically significant missed CA and to determine the impact of detecting the missed CA. We performed computer simulations to compare six screening options followed by FISH, PCR or karyotyping using a population of 110948 pregnancies. Among the safer screening strategies, the most cost-effective strategy was contingent screening with QF-PCR (CE ratio of $24084 per Down's syndrome (DS) detected). Using karyotyping, the CE ratio increased to $27898. QF-PCR missed only six clinically significant CA of which only one was expected to confer a high risk of an abnormal outcome. The incremental CE ratio (ICER) to find the CA missed by RAD was $66608 per CA. These costs are much higher than those involved for detecting DS cases. As the DSSP are mainly designed for DS detection, it may be relevant to question the additional costs of karyotyping. PMID- 20842179 TI - Acute pulmonary embolism. Part 2: treatment. AB - The clinical presentation of pulmonary embolism (PE) varies widely, ranging from only limited symptoms to severe cardiogenic shock. Treatment of PE comprises initial therapy--with low-molecular-weight heparin (LMWH), fondaparinux, or unfractionated heparin--and long-term treatment, most commonly with vitamin-K antagonists (VKAs). Methods of risk stratification, to determine whether a patient will benefit from thrombolysis, are currently under investigation. However, at present, insufficient evidence exists that hemodynamically stable patients who demonstrate echocardiographic right ventricular strain (submassive PE) benefit from thrombolysis. By contrast, thrombolysis is a widely accepted treatment strategy for patients with hemodynamic shock (massive PE). The duration of VKA treatment is commonly 3-12 months and depends on the type of PE and on the balance between the risks of recurrent PE, major bleeding, and the patient's preference. In patients with a malignancy, treatment with LMWH during the first 6 months after diagnosis of PE is recommended. Several new oral anticoagulants, such as factor IIa and factor Xa inhibitors, are now being investigated. For prevention of recurrent PE in situations where anticoagulation is contraindicated, a temporary inferior vena cava filter might be useful. Some patients with PE can be safely treated at home, but few outcome studies in this setting have been published. PMID- 20842180 TI - Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. AB - Cardiotoxicity of anticancer treatments has become an increasingly important clinical problem faced by cardiologists. Left ventricular systolic dysfunction and heart failure generate the most concern, but clinical features and prognosis vary considerably depending on the causative agent. Anthracycline-related cardiomyopathy differs fundamentally from effects associated with newer targeted agents, such as trastuzumab. Other forms of cardiovascular disease that occur as a result of cancer treatment include hypertension, thromboembolic disease, pericardial disease, arrhythmia, and myocardial ischemia. The approach to cardiovascular disease in patients with cancer is often different from that in the general population, not only because of distinct underlying mechanisms and clinical features of their heart disease, but also because of the potential ongoing need for additional cancer treatment as well as the altered duration of anticipated survival. In an effort to maximize both quality of life and survival, cardiologists and oncologists should collaborate with the aim of balancing the risks of cardiotoxicity with the benefits of oncologic therapy. PMID- 20842181 TI - Morbid obesity in pediatric diabetes mellitus: surgical options and outcomes. AB - The current obesity epidemic has led to a dramatic increase in insulin resistance and type 2 diabetes mellitus among adolescents, along with other obesity-related comorbidities, such as hypertension, hyperlipidemia, obstructive sleep apnea, psychosocial impairment and nonalcoholic fatty liver disease. Medical treatment of severe obesity is effective in only a small percentage of adolescent patients. In light of the potentially life-threatening complications of obesity, bariatric surgery can be considered a treatment option for adolescent patients with morbid obesity. Indications for surgery rely on both BMI and comorbidity criteria, as well as the ability of the adolescents and their family to understand and comply with perioperative protocols. The long-term effects of bariatric surgery in adolescents are not known; therefore, participation in prospective outcome studies is important. The risk associated with bariatric surgery in adolescents seems to be similar to that observed in adult patients in the short term. Data suggest that bypass procedures successfully reverse or improve abnormal glucose metabolism in the majority of patients and may be more effective in adolescents than adults. This improvement in glucose metabolism occurs before marked weight loss in patients undergoing bypass procedures, suggesting a direct effect on the hormonal control of glucose metabolism. PMID- 20842182 TI - Focal congenital hyperinsulinism in a patient with septo-optic dysplasia. AB - BACKGROUND: An infant diagnosed as having hypopituitarism and on adequate hydrocortisone replacement therapy was referred to a tertiary endocrine unit at 5 weeks of age with persistent hypoglycemia that required a high rate of intravenous glucose infusion (up to 18 mg/kg*min-1) to maintain euglycemia. INVESTIGATIONS: A controlled hypoglycemia screen was performed to measure levels of plasma glucose, insulin, C-peptide and 3-beta-hydroxybutyrate concentrations. The pancreas was analyzed by fluorine-18-L-3,4-dihydroxyphenylalanine ((18)F DOPA) PET scan. Genetic analyses were performed on the peripheral blood leukocytes, and loss of heterozygosity within the resected focal lesion of the pancreas was investigated by microsatellite analysis. A glucagon stimulation test helped determine pituitary function, and an MRI of the brain and pituitary gland was performed to define the anatomy of the intracranial structures and the pituitary gland. DIAGNOSIS: Focal form of congenital hyperinsulinism localized to the head of the pancreas, septo-optic dysplasia and pituitary hormone deficiencies. MANAGEMENT: Resection of the focal lesion from the head of the pancreas and hormonal replacement therapy for hypopituitarism. PMID- 20842184 TI - Extreme hypoglycorrhachia: not always bacterial meningitis. AB - BACKGROUND: A 55-year-old man presented with 4 months of chronic meningitis, neutrophilic pleocytosis and extreme hypoglycorrhachia-an abnormally low concentration of glucose in the cerebrospinal fluid (CSF). A previous neurological work-up had revealed no noteworthy abnormalities. Despite the brief improvements that were seen after numerous trials of antibiotics and corticosteroids, the symptoms relapsed soon after corticosteroids were discontinued. Lumbar puncture revealed cholesterol crystals in the CSF and imaging studies revealed a sickle-shaped sacrum, partial rectal stenosis, and a communicating presacral meningocele with an epidermoid-dermoid mass. Extreme hypoglycorrhachia seems almost always to be bacterial in origin, but its differential diagnosis is, nevertheless, extensive. The definition, physiology, pathophysiology and differential diagnosis of hypoglycorrhachia are reviewed here. INVESTIGATIONS: Physical examination, laboratory testing, multiple imaging studies including CT and MRI of the brain and spinal cord, as well as myelography and CSF analysis. DIAGNOSIS: Cholesterol-induced leptomeningitis in a patient with Currarino syndrome, a triad that consists of sacral bone defects, congenital hindgut anomaly, and a presacral tumor. MANAGEMENT: The patient was initially treated with multiple antimicrobials and steroids. However, once the cholesterol crystals and communicating presacral cyst were identified, the condition was successfully managed with surgically resection of the cyst. PMID- 20842183 TI - How does diabetes accelerate Alzheimer disease pathology? AB - Diabetes and Alzheimer disease (AD)-two age-related diseases-are both increasing in prevalence, and numerous studies have demonstrated that patients with diabetes have an increased risk of developing AD compared with healthy individuals. The underlying biological mechanisms that link the development of diabetes with AD are not fully understood. Abnormal protein processing, abnormalities in insulin signaling, dysregulated glucose metabolism, oxidative stress, the formation of advanced glycation end products, and the activation of inflammatory pathways are features common to both diseases. Hypercholesterolemia is another factor that has received attention, owing to its potential association with diabetes and AD. This Review summarizes the mechanistic pathways that might link diabetes and AD. An understanding of this complex interaction is necessary for the development of novel drug therapies and lifestyle guidelines aimed at the treatment and/or prevention of these diseases. PMID- 20842185 TI - Imaging in the surgical treatment of epilepsy. AB - Medically refractory focal epilepsy is potentially curable by surgery. This Review considers the application of recent advances in structural and functional brain imaging to increase the number of patients with epilepsy who are treated surgically, and to reduce the risk of complications arising from such intervention. Current optimal MRI of brain structure can identify previously undetectable lesions, with voxel-based and quantitative analyses further increasing the diagnostic yield. If MRI proves unremarkable, PET (with (18)F fluorodeoxyglucose) and single-photon emission CT of ictal-interictal cerebral blood flow might identify the brain region that contains the epileptic focus. Magnetoencephalography plus simultaneous EEG and functional MRI can map the location of interictal epileptic discharges, thereby facilitating placement of intracranial recording electrodes to define the site of seizure onset. Functional MRI can also lateralize language and localize primary motor, somatosensory and language areas, and shows promise for predicting the effects of temporal lobe resection on memory. Tractography can visualize the main cerebral white matter tracts, thereby predicting and reducing surgery risk. Currently, displays of the optic radiation and pyramidal tracts are the most relevant for epilepsy surgery. Reliable integration of structural and functional data into surgical image guidance systems is being pursued, and promises safer neurosurgery for epilepsy in the future. PMID- 20842186 TI - Imaging of acute stroke. AB - Brain imaging provides an objective basis for the clinical inferences that direct individual patient management in the acute stroke setting. A brain CT or MRI scan is required for all patients with suspected stroke or transient ischemic attack. Thrombolytic therapy is arguably the most important aspect of acute stroke management; however, most decisions in acute stroke do not relate to this treatment. Stroke imaging must, therefore, provide information beyond the presence or absence of intracranial hemorrhage (ICH) and early evidence of a large infarct. Noncontrast CT and gradient-recalled echo MRI show comparable accuracy in the diagnosis of acute ICH. Diffusion-weighted MRI is more sensitive than noncontrast CT for differentiation of acute ischemic stroke from nonstroke conditions. Combined multimodal parenchymal, perfusion and vascular imaging with CT or MRI has the potential to identify patients with an ischemic penumbra that might be appropriate for acute reperfusion therapies. MRI identifies a broader range of acute and chronic cerebrovascular pathologies than does CT and, hence, could aid decisions about acute intervention, in-hospital management, and secondary prevention. Here, we present an overview of the diagnostic information that clinicians might gain from CT and MRI in the setting of acute stroke, along with the advantages and disadvantages of these techniques. PMID- 20842188 TI - Neuroendocrine carcinoma in a patient with Birt-Hogg-Dube syndrome. AB - BACKGROUND: A patient with Birt-Hogg-Dube syndrome (BHD) presented with gross hematuria of 6 months' duration. Imaging revealed the presence of a mass in the left prostatic lobe, in addition to a previously observed renal mass. Prostate biopsy and imaging findings indicated an inflammatory etiology, and the patient was discharged. 5 months later, the patient presented once again with urinary retention. During transurethral resection of the prostate, a mass adjacent to the bladder was observed. Postoperative imaging revealed a large pelvic mass, a second mass impinging on the rectum, and extensive lymphadenopathy. The patient died 2 weeks later. INVESTIGATIONS: CT and MRI, physical examination, measurement of serum markers, urinalysis, transrectal prostate biopsy, histopathological and genetic examination of tumor specimens, postmortem immunohistochemical analysis. DIAGNOSIS: Neuroendocrine carcinoma of prostate or bladder origin. MANAGEMENT: The patient died before planned chemotherapy or radiation therapy could be implemented. More-frequent monitoring of the patient might have led to earlier diagnosis and allowed treatment to be started before widespread tumor metastasis and invasion. PMID- 20842187 TI - Focal therapy in prostate cancer: modalities, findings and future considerations. AB - Focal therapy is emerging as an alternative to active surveillance for the management of low-risk prostate cancer in carefully selected patients. The aim of focal therapy is long-term cancer control without the associated morbidity that plagues all radical therapies. Different energy modalities have been used to focally ablate cancer tissue, and available techniques include cryotherapy, laser ablation, high-intensity focused ultrasound and photodynamic therapy. The majority of evidence for focal therapy has come from case series and small phase I trials, and larger cohort studies with longer follow-up are only now being commenced. More data from large trials on the safety and efficacy of focal therapy are therefore required before this approach can be recommended in men with prostate cancer; in particular, studies must confirm that no viable cells remain in the region of ablation. Focal therapy might eventually prove to be a 'middle ground' between active surveillance and radical treatment, combining minimal morbidity with cancer control and the potential for re-treatment. PMID- 20842189 TI - Intermittent androgen suppression for prostate cancer. AB - Although androgen deprivation therapy (ADT) has been a cornerstone of the management of prostate cancer for more than 50 years, controversy remains regarding its optimum application. Intermittent androgen suppression (IAS) has been researched since the mid-1980s as a way of reducing the adverse effects and cost of continuous androgen suppression. With preclinical evidence suggesting a potential benefit in terms of time to androgen independence, IAS has been the focus of a number of clinical phase II and III trials. Overall, these trials suggest that IAS is neither inferior nor superior to continuous androgen suppression, with respect to time to castration resistance and cancer-specific survival, but has significant advantages in terms of adverse effects, quality of life and cost. A number of unresolved questions remain, however, including how to select patients for therapy, the optimum duration of therapy, when to restart therapy after the off cycle, and how to define progression to castration resistant disease. Landmark randomized clinical trials comparing IAS to continuous androgen suppression are in progress and will hopefully answer many of these questions. In future, the use of second-line drugs in the off-treatment phase holds potential for delaying disease progression in men on IAS. At present, men with advanced disease who are deemed candidates for ADT should be informed of IAS as a treatment option, considered experimental from an informed consent point of view, but promising based on current evidence. PMID- 20842190 TI - Blending of animal colour patterns by hybridization. AB - Biologists have long been fascinated by the amazing diversity of animal colour patterns. Despite much interest, the underlying evolutionary and developmental mechanisms contributing to their rich variety remain largely unknown, especially the vivid and complex colour patterns seen in vertebrates. Here, we show that complex and camouflaged animal markings can be formed by the 'blending' of simple colour patterns. A mathematical model predicts that crossing between animals having inverted spot patterns (for example, 'light spots on a dark background' and 'dark spots on a light background') will necessarily result in hybrid offspring that have camouflaged labyrinthine patterns as 'blended' intermediate phenotypes. We confirmed the broad applicability of the model prediction by empirical examination of natural and artificial hybrids of salmonid fish. Our results suggest an unexplored evolutionary process by means of 'pattern blending', as one of the possible mechanisms underlying colour pattern diversity and hybrid speciation. PMID- 20842191 TI - Upright human gait did not provide a major mechanical challenge for our ancestors. AB - Habitual bipedalism is considered as a major breakthrough in human evolution and is the defining feature of hominins. Upright posture is presumably less stable than quadrupedal posture, but when using external support, for example, toddlers assisted by their parents, postural stability becomes less critical. In this study, we show that humans seem to mimic such external support by creating a virtual pivot point (VPP) above their centre of mass. A highly reduced conceptual walking model based on this assumption reveals that such virtual support is sufficient for achieving and maintaining postural stability. The VPP is experimentally observed in walking humans and dogs and in running chickens, suggesting that it might be a convenient emergent behaviour of gait mechanics and not an intentional locomotion behaviour. Hence, it is likely that even the first hominis may have already applied the VPP, a mechanism that would have facilitated the development of habitual bipedalism. PMID- 20842192 TI - Non-muscle myosin II regulates survival threshold of pluripotent stem cells. AB - Human pluripotent stem (hPS) cells such as human embryonic stem (hES) and induced pluripotent stem (hiPS) cells are vulnerable under single cell conditions, which hampers practical applications; yet, the mechanisms underlying this cell death remain elusive. In this paper, we demonstrate that treatment with a specific inhibitor of non-muscle myosin II (NMII), blebbistatin, enhances the survival of hPS cells under clonal density and suspension conditions, and, in combination with a synthetic matrix, supports a fully defined environment for self-renewal. Consistent with this, genetically engineered mouse embryonic stem cells lacking an isoform of NMII heavy chain (NMHCII), or hES cells expressing a short hairpin RNA to knock down NMHCII, show greater viability than controls. Moreover, NMII inhibition increases the expression of self-renewal regulators Oct3/4 and Nanog, suggesting a mechanistic connection between NMII and self-renewal. These results underscore the importance of the molecular motor, NMII, as a novel target for chemically engineering the survival and self-renewal of hPS cells. PMID- 20842193 TI - Automated home-cage behavioural phenotyping of mice. AB - Neurobehavioural analysis of mouse phenotypes requires the monitoring of mouse behaviour over long periods of time. In this study, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviours. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviours of two standard inbred and two non-standard mouse strains. From these data, we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor-based automated approaches and enable an adaptable, comprehensive, high-throughput, fine-grained, automated analysis of mouse behaviour. PMID- 20842194 TI - Rapid calcium-dependent activation of Aurora-A kinase. AB - Oncogenic hyperactivation of the mitotic kinase Aurora-A (AurA) in cancer is associated with genomic instability. Increasing evidence indicates that AurA also regulates critical processes in normal interphase cells, but the source of such activity has been obscure. We report here that multiple stimuli causing release of Ca(2+) from intracellular endoplasmic reticulum stores rapidly and transiently activate AurA, without requirement for second messengers. This activation is mediated by direct Ca(2+)-dependent calmodulin (CaM) binding to multiple motifs on AurA. On the basis of structure-function analysis and molecular modelling, we map two primary regions of CaM-AurA interaction to unfolded sequences in the AurA N- and C-termini. This unexpected mechanism for AurA activation provides a new context for evaluating the function of AurA and its inhibitors in normal and cancerous cells. PMID- 20842195 TI - Phase seeding of a terahertz quantum cascade laser. AB - The amplification of spontaneous emission is used to initiate laser action. As the phase of spontaneous emission is random, the phase of the coherent laser emission (the carrier phase) will also be random each time laser action begins. This prevents phase-resolved detection of the laser field. Here, we demonstrate how the carrier phase can be fixed in a semiconductor laser: a quantum cascade laser (QCL). This is performed by injection seeding a QCL with coherent terahertz pulses, which forces laser action to start on a fixed phase. This permits the emitted laser field to be synchronously sampled with a femtosecond laser beam, and measured in the time domain. We observe the phase-resolved buildup of the laser field, which can give insights into the laser dynamics. In addition, as the electric field oscillations are directly measured in the time domain, QCLs can now be used as sources for time-domain spectroscopy. PMID- 20842196 TI - Sustaining the Internet with hyperbolic mapping. AB - The Internet infrastructure is severely stressed. Rapidly growing overheads associated with the primary function of the Internet-routing information packets between any two computers in the world-cause concerns among Internet experts that the existing Internet routing architecture may not sustain even another decade. In this paper, we present a method to map the Internet to a hyperbolic space. Guided by a constructed map, which we release with this paper, Internet routing exhibits scaling properties that are theoretically close to the best possible, thus resolving serious scaling limitations that the Internet faces today. Besides this immediate practical viability, our network mapping method can provide a different perspective on the community structure in complex networks. PMID- 20842197 TI - Regional insight into savanna hydrogeomorphology from termite mounds. AB - Global vegetation models predict the spread of woody vegetation in African savannas and grasslands under future climate scenarios, but they operate too broadly to consider hillslope-scale variations in tree-grass distribution. Topographically linked hydrology-soil-vegetation sequences, or catenas, underpin a variety of ecological processes in savannas, including responses to climate change. In this study, we explore the three-dimensional structure of hillslopes and vegetation, using high-resolution airborne LiDAR (Light Detection And Ranging), to understand the long-term effects of mean annual precipitation (MAP) on catena pattern. Our results reveal that the presence and position of hillslope hydrological boundaries, or seeplines, vary as a function of MAP through its long term influence on clay redistribution. We suggest that changes in climate will differentially alter the structure of savannas through hydrological changes to the seasonally saturated grasslands downslope of seeplines. The mechanisms underlying future woody encroachment are not simply physiological responses to elevated temperatures and CO(2) levels but also involve hydrogeomorphological processes at the hillslope scale. PMID- 20842198 TI - Breeding latitude drives individual schedules in a trans-hemispheric migrant bird. AB - Despite clear benefits of optimal arrival time on breeding grounds, migration schedules may vary with an individual bird's innate quality, non-breeding habitat or breeding destination. Here, we show that for the bar-tailed godwit (Limosa lapponica baueri), a shorebird that makes the longest known non-stop migratory flights of any bird, timing of migration for individual birds from a non-breeding site in New Zealand was strongly correlated with their specific breeding latitudes in Alaska, USA, a 16,000-18,000 km journey away. Furthermore, this variation carried over even to the southbound return migration, 6 months later, with birds returning to New Zealand in approximately the same order in which they departed. These tightly scheduled movements on a global scale suggest endogenously controlled routines, with breeding site as the primary driver of temporal variation throughout the annual cycle. PMID- 20842199 TI - Nanostructural hierarchy increases the strength of aluminium alloys. AB - Increasing the strength of metallic alloys while maintaining formability is an interesting challenge for enabling new generations of lightweight structures and technologies. In this paper, we engineer aluminium alloys to contain a hierarchy of nanostructures and possess mechanical properties that expand known performance boundaries-an aerospace-grade 7075 alloy exhibits a yield strength and uniform elongation approaching 1 GPa and 5%, respectively. The nanostructural architecture was observed using novel high-resolution microscopy techniques and comprises a solid solution, free of precipitation, featuring (i) a high density of dislocations, (ii) subnanometre intragranular solute clusters, (iii) two geometries of nanometre-scale intergranular solute structures and (iv) grain sizes tens of nanometres in diameter. Our results demonstrate that this novel architecture offers a design pathway towards a new generation of super-strong materials with new regimes of property-performance space. PMID- 20842200 TI - No-go theorem for superradiant quantum phase transitions in cavity QED and counter-example in circuit QED. AB - In cavity quantum electrodynamics (QED), the interaction between an atomic transition and the cavity field is measured by the vacuum Rabi frequency Omega(0). The analogous term 'circuit QED' has been introduced for Josephson junctions, because superconducting circuits behave as artificial atoms coupled to the bosonic field of a resonator. In the regime with Omega(0) comparable with the two-level transition frequency, 'superradiant' quantum phase transitions for the cavity vacuum have been predicted, for example, within the Dicke model. In this study, we prove that if the time-independent light-matter Hamiltonian is considered, a superradiant quantum critical point is forbidden for electric dipole atomic transitions because of the oscillator strength sum rule. In circuit QED, the analogous of the electric dipole coupling is the capacitive coupling, and such no-go property can be circumvented by Cooper pair boxes capacitively coupled to a resonator, because of their peculiar Hilbert space topology and a violation of the corresponding sum rule. PMID- 20842201 TI - Boosted protease inhibitor monotherapy. What have we learnt after seven years of research? AB - Boosted protease inhibitor monotherapy has emerged as an antiretroviral alternative option to avoid the use of nucleosides. After more than seven years of research with hundreds of patients exposed to this kind of therapy, controversy about its use remains. While European and Spanish guidelines for the use of antiretroviral therapy in adults include monotherapy as an alternative for simplification, experts in the USA express the view that this strategy cannot be currently recommended. Our conclusion, after more than seven years of research, is that simplification of a suppressive triple antiretroviral therapy to boosted protease inhibitor monotherapy has demonstrated safety and efficacy in a high proportion of patients. Although this is not a strategy to implement indiscriminately in all patients, it could be a good option for those patients with toxicity related to nucleoside reverse transcriptase inhibitors, or for trying to avoid such toxicities in virologically controlled patients without previous failure to protease inhibitors, restarting nucleosides if the viral load does not remain undetectable. If simplification to monotherapy is selected to treat some patients, twice-daily lopinavir/ritonavir, or preferably once-daily darunavir/ritonavir, should be chosen as data with other boosted protease inhibitors are inconclusive or even nonexistent. Nevertheless, more studies focusing on the control of HIV replication in viral reservoirs with monotherapy, as with triple therapy, are warranted. PMID- 20842202 TI - Genotypic determination of HIV tropism - clinical and methodological recommendations to guide the therapeutic use of CCR5 antagonists. AB - The approval of maraviroc (Selzentri(r)), the first CCR5 antagonist, with specific antiviral activity against CCR5 (R5)-tropic HIV variants, has promoted the determination of HIV coreceptor usage in the clinical setting. The phenotypic assay TrofileTM, which is based on recombinant virus technology, has been the most widely used diagnostic test, given that it was the only assay which provided tropism information in the pivotal maraviroc clinical trials. However, this method displays logistical and technical limitations that make it far from convenient as a diagnostic test in clinical practice. Genotypic methods based on V3 genotyping represent a more feasible alternative and progressively are replacing phenotypic assays. Even though their sensitivity to detect X4-tropic variants is lower compared to TrofileTM, recent studies have demonstrated that specific genotypic tools (geno2pheno and PSSM) are comparable to TrofileTM and ES TrofileTM in predicting virologic response to maraviroc. This review summarizes clinical and methodological recommendations for the genotypic determination of HIV tropism to guide therapeutic decisions with CCR5 antagonists in HIV therapeutics. PMID- 20842203 TI - Distribution of xenotropic murine leukemia virus-related virus (XMRV) infection in chronic fatigue syndrome and prostate cancer. AB - In 2006, sequences described as xenotropic murine leukemia virus-related virus (XMRV) were discovered in prostate cancer patients. In October 2009, we published the first direct isolation of infectious XMRV from humans and the detection of infectious XMRV in patients with chronic fatigue syndrome. In that study, a combination of classic retroviral methods were used including: DNA polymerase chain reaction and reverse transcriptase polymerase chain reaction for gag and env, full length genomic sequencing, immunoblotting for viral protein expression in activated peripheral blood mononuclear cells, passage of infectious virus in both plasma and peripheral blood mononuclear cells to indicator cell lines, and detection of antibodies to XMRV in plasma. A combination of these methods has since allowed us to confirm infection by XMRV in 85% of the 101 patients that were originally studied. Since 2009, seven studies, predominantly using DNA polymerase chain reaction of blood products or tumor tissue, have reported failures to detect XMRV infection in patients with either prostate cancer or chronic fatigue syndrome. A review of the current literature on XMRV supports the importance of applying multiple independent techniques in order to determine the presence of this virus. Detection methods based upon the biological and molecular amplification of XMRV, which is usually present at low levels in unstimulated blood cells and plasma, are more sensitive than assays for the virus by DNA polymerase chain reaction of unstimulated peripheral blood mononuclear cells. When we examined patient blood samples that had originally tested negative by DNA polymerase chain reaction by more sensitive methods, we observed that they were infected with XMRV; thus, the DNA polymerase chain reaction tests provided false negative results. Therefore, we conclude that molecular analyses using DNA from unstimulated peripheral blood mononuclear cells or from whole blood are not yet sufficient as stand-alone assays for the identification of XMRV-infected individuals. Complementary methods are reviewed, that if rigorously followed, will likely show a more accurate snapshot of the actual distribution of XMRV infection in humans. PMID- 20842204 TI - Community associated methicillin-resistant Staphylococcus aureus in HIV-infected patients. AB - Until recently, methicillin-resistant Staphylococcus aureus was considered an uncommon community pathogen, almost exclusively associated with healthcare exposure. Over the last decade, however, methicillin-resistant S. aureus infection, particularly skin and soft tissue infection, has emerged in healthy individuals with no traditional risk factors for its acquisition. Several risk factors, including certain lifestyle behaviors, have been associated with community-acquired methicillin-resistant S. aureus colonization and infection. Regardless of other concurrent risk factors, HIV-infected patients have an increased risk for acquiring this pathogen. This article summarizes the current knowledge regarding associated risk factors, clinical manifestations, and management of community-acquired methicillin-resistant Staphylococcus aureus infections in HIV-infected patients. PMID- 20842205 TI - Clarifying the role of G protein signaling in HIV infection: new approaches to an old question. AB - Whether or not HIV gp120-elicited signal transduction through the coreceptors CCR5 and CXCR4 is required for productive viral replication has long been a subject of controversy. The complexity and diversity of G protein signal transduction initiated by chemokine receptor activation has hindered efforts to understand the contributions of these pathways to the HIV life cycle. Several recent studies have demonstrated an important role for G proteins in mediating signaling events through both CCR5 and CXCR4 that are necessary for productive HIV infection. In addition to gp120-mediated G protein activation, there is still much to learn about the impact of G protein signaling during HIV infection, including the role of T-cell receptor/CXCR4 cross-talk, regulation of G protein expression during infection and the contribution of G protein subunit genetic polymorphisms to disease progression. This review will describe the effects of G protein signaling in immune cells, summarize the current understanding of CCR5 and CXCR4-initiated signal transduction in HIV replication, and discuss important gaps that still remain in our understanding of G protein signaling and its contribution to HIV pathogenesis. PMID- 20842206 TI - Influenza A virus expresses high levels of an unusual class of small viral leader RNAs in infected cells. AB - Evidence has recently accumulated suggesting that small noncoding RNAs, and particularly microRNAs, have the potential to strongly affect the replication and pathogenic potential of a range of human virus species. Here, we report the use of deep sequencing to comprehensively analyze small viral RNAs (18 to 27 nucleotides [nt]) produced during infection by influenza A virus. Although influenza A virus differs from most other RNA viruses in that it replicates its genome in the nucleus and is therefore exposed to the nuclear microRNA processing factors Drosha and DGCR8, we did not observe any microRNAs encoded by influenza virus genes. However, influenza virus infection did induce the expression of very high levels-over 100,000 copies per cell by 8 h postinfection-of a population of 18- to 27-nt small viral leader RNAs (leRNAs) that originated from the precise 5' ends of all eight influenza virus genomic RNA (vRNA) segments. Like the vRNAs themselves, our data indicate that the leRNAs also bear a 5'-terminal triphosphate and are therefore not capable of functioning as microRNAs. Instead, the high-level production of leRNAs may imply a role in another aspect of the viral life cycle, such as regulation of the switch from viral mRNA transcription to genomic RNA synthesis. PMID- 20842207 TI - Immune globulin subcutaneous (human), 20% liquid. PMID- 20842208 TI - Tolerating diabetes: an alternative therapeutic approach for diabetic neuropathy. AB - It is becoming apparent that a number of pathogenic mechanisms contribute to diabetic neuropathy, so that therapeutic interventions that target one particular mechanism may have limited success. A recently published preclinical study has adopted an alternative approach by using a novel small molecule to induce heat shock protein 70. This confers upon neurons, and perhaps other cells of the nervous system, the ability to better tolerate the diverse stresses associated with diabetes rather than intervening in their production. PMID- 20842209 TI - Predicting Acute Hypotensive Episodes: The 10th Annual PhysioNet/Computers in Cardiology Challenge. AB - This year's PhysioNet/Computers in Cardiology Challenge aimed to stimulate development of methods for identifying intensive care unit (ICU) patients at imminent risk of acute hypotensive episodes (AHEs), motivated by the possibility of improving care and survival of these patients. Participants were asked to forecast the occurrence of an AHE up to an hour in advance, in two groups of ICU patient records from the MIMIC II Database, drawing on data that included at least 10 hours of physiologic waveforms, time series, and accompanying clinical data prior to the one-hour forecast window. In event 1, most participants were able to identify without errors, in a group of 10 high-risk patients receiving pressor medication, which five of the patients experienced AHEs during the forecast window. In event 2, participants were able to classify correctly as many as 37 (93%) of a diverse group of 40 patients, including nearly all of those who experienced AHEs. PMID- 20842210 TI - The Privileges of Rank: The Peacetime Draft and Later-life Attainment. AB - This article examines the effects of peacetime cold war military service on the life course according to four potentially overlapping theories that state that military service (1) was a disruption, (2) was a positive turning point, (3) allowed veterans to accumulate advantage, and (4) was an agent of social reproduction. The article argues that the extent to which the effect of military service on veterans' lives corresponds with one or another of the preceding theories depends on historical shifts in three dimensions: conscription, conflict, and benefits. Military service during the peacetime draft era of the late 1950s had a neutral effect on the socioeconomic attainment of enlisted veterans. However, it had a positive effect on veterans who served as officers, which partly stemmed from status reproduction and selection. Yet net of pre service and educational differences by rank, officers in this peacetime draft era were still able to accumulate advantage. PMID- 20842211 TI - The Alternatively Spliced Form "b" of the Epithelial Sodium Channel alpha subunit (alpha ENaC): Any Prior Evidence of its Existence? AB - The epithelial sodium channel (ENaC) is critical in maintaining sodium balance across aldosterone-responsive epithelia. ENaC is a combined channel formed of three subunits (alphabetagamma) with alpha ENaC subunit being the most critical for channel functionality. In a previous report, we have demonstrated the existence and mRNA expression levels of four alternatively spliced forms of the alpha ENaC subunit denoted by -a, -b, -c and -d in kidney cortex of Dahl S and R rats. Of the four alternatively spliced forms presently identified, alpha ENaC-b is considered the most interesting for the following reasons: Aside from being a salt-sensitive transcript, alpha ENaC-b mRNA expression is ~32 fold higher than alpha ENaC wildtype in kidney cortex of Dahl rats. Additionally, the splice site used to generate alpha ENaC-b is conserved across species. Finally, alpha ENaC-b mRNA expression is significantly higher in salt-resistant Dahl R rats versus salt sensitive Dahl S rats. As such, this commentary aims to highlight some of the previously published research articles that described the existence of an additional protein band on alpha ENaC western blots that could account for alpha ENaC-b in other rat species. PMID- 20842212 TI - Subaortic (type 6) muscular band-innocent bystander or pathologic structure? AB - Intraventricular tendons are structures that was identified more than a hundred years ago. It has been suggested that they represent intracavitary radiations of the bundle of His and that they may be an isolated finding or be associated with structural cardiac abnormalities.Loukas et al divided these structures into five categories and recently a sixth type have been added.Various physiological disturbances have been observed due to the sixth type of tendon, such as ST segment elevation and right bundle branch block. It has been noted that this peculiar structure appears too thick to be called a tendon, thus the term band.This retrospective analysis analyzed the incidence of the thick, subaortic (type 6) muscular band in a cardiovascular clinic. PMID- 20842213 TI - Peptide-Functionalized Click Hydrogels with Independently Tunable Mechanics and Chemical Functionality for 3D Cell Culture. AB - Multifunctionalized macromers react via a copper-free click chemistry to form an idealized 3D hydrogel. Subsequently, thiol-containing biomolecules are spatially patterned within the material with precise control over the amount and location of functionalization. Both the network formation and subsequent patterning reactions are fully cytocompatible, allowing these systems to be used to study individual cell behavior at user-defined locations throughout the material. PMID- 20842215 TI - "Dwelling-mobility": An existential theory of well-being. AB - In this article we offer an existential theory of well-being that is guided by Heidegger's later writings on "homecoming". We approach the question of what it is about the essence of well-being that makes all kinds of well-being possible. Consistent with a phenomenological approach, well-being is both a way of being-in the-world, as well as a felt sense of what this is like as an experience. Drawing on Heidegger's notion of Gegnet (abiding expanse), we characterise the deepest possibility of existential well-being as "dwelling-mobility". This term indicates both the "adventure" of being called into expansive existential possibilities, as well as "being-at-home-with" what has been given. This deepest possibility of well-being carries with it a feeling of rootedness and flow, peace and possibility. However, we also consider how the separate notions of existential mobility and existential dwelling as discrete emphases can be developed to describe multiple variations of well-being possibilities. PMID- 20842214 TI - Molecular Data are Transforming Hypotheses on the Origin and Diversification of Eukaryotes. AB - The explosion of molecular data has transformed hypotheses on both the origin of eukaryotes and the structure of the eukaryotic tree of life. Early ideas about the evolution of eukaryotes arose through analyses of morphology by light microscopy and later electron microscopy. Though such studies have proven powerful at resolving more recent events, theories on origins and diversification of eukaryotic life have been substantially revised in light of analyses of molecular data including gene and, increasingly, whole genome sequences. By combining these approaches, progress has been made in elucidating both the origin and diversification of eukaryotes. Yet many aspects of the evolution of eukaryotic life remain to be illuminated. PMID- 20842216 TI - Monitoring the millennium development goals: the potential role of the INDEPTH Network. AB - The Millennium Declaration, adopted by the United Nations (UN) in 2000, set a series of Millennium Development Goals (MDGs) as priorities for UN member countries, committing governments to realising eight major MDGs and 18 associated targets by 2015. Progress towards these goals is being assessed by tracking a series of 48 technical indicators that have since been unanimously adopted by experts. This concept paper outlines the role member Health and Demographic Surveillance Systems (HDSSs) of the INDEPTH Network could play in monitoring progress towards achieving the MDGs. The unique qualities of the data generated by HDSSs lie in the fact that they provide an opportunity to measure or evaluate interventions longitudinally, through the long-term follow-up of defined populations. PMID- 20842217 TI - Increased inhibitor of differentiation 4 (id4) expression in glioblastoma: a tissue microarray study. AB - BACKGROUND: The inhibitor of differentiation/DNA binding protein family (Id1-4) is involved in cell cycle control, tumorigenesis and angiogenesis through the negative regulation of helix-loop-helix transcription factors. Of these proteins, Id4 is known to play an important role in neural stem cell differentiation, and deregulation has been implicated in glial neoplasia. However, the expression and significance of Id4 in astrocytomas has not been fully addressed. Herein we report the differential expression of Id4 in astrocytomas of various grades using tissue microarrays (TMA) and immunohistochemistry (IHC). DESIGN: The GBM TMA was constructed from 53 archival cases at Georgetown University Hospital and a TMA with normal brain controls and grades II-III astrocytoma was obtained from Cybrdi (Rockville, MD). TMA sections were stained with Id4 antibody and the slides were scored according to the percentage of staining astrocytic nuclei (<9% -, 10-50% +, >51% ++). The Fisher Exact test was used to test for statistical significance. RESULTS: Nuclear staining for Id4 was seen in 73.58% GBMs, 25% grade III, and 12.5% grade II astrocytomas; staining was absent in normal brain tissue. There was a statistically significant difference between GBM and grades II, III astrocytoma (p <0.01). Significant Id4 expression was not detected in normal brain. CONCLUSIONS: Our study confirms the frequent upregulation of Id4 expression in GBM, which lends support to its role in tumorigenesis, possibly in the transformation of low to high-grade astrocytoma (i.e. GBM). Further studies are warranted to determine the precise role of Id4 in glial neoplasia and its potential use in targeted therapy for GBM. PMID- 20842218 TI - Breast cancer heterogeneity: mechanisms, proofs, and implications. AB - Human breast cancer represents a group of highly heterogeneous lesions consisting of about 20 morphologically distinct subtypes with substantially different molecular and/or biochemical signatures, clinical courses, and prognoses. This study analyzed the possible correlation between the morphological presentations of breast cancer and two hypothesized models of carcinogenesis, in order to identify the intrinsic mechanism(s) and clinical implications of breast cancer heterogeneity. PMID- 20842220 TI - Age and tumor size predicts lymph node involvement in Hurthle Cell Carcinoma. AB - INTRODUCTION: Hurthle cell carcinoma (HCC) is a rare tumor that tends to metastasize to the lymph nodes. Some studies have correlated size of Hurthle cell tumors with the risk of malignancy. Whether the size of HCC correlates with the risk of lymph node (LN) metastases, to our knowledge has not been addressed. METHODS: A retrospective analysis was performed on all patients diagnosed with HCC on final pathology between 1997 and 2008. The tumor size and lymph node status was obtained for each patient. The data were analyzed utilizing Student's t-test and the Fisher's exact test to calculate the two-tailed p-value. RESULTS: Out of 39 patients diagnosed with HCC 3(8%) had LN metastases; 1 had ipsilateral central LN metastasis and 2 had ipsilateral central and lateral LN metastasis. LN dissection was performed in patients with known metastasis (2 were evident on preoperative ultrasound and 1 intraoperatively). Patients with LN metastasis were older than those without (mean age: 86.7 and 56.4 years, respectively), had larger tumors (mean size: 6 and 4 cm) and were commonly male (2 of 3). No tumor < 5cm presented with lymph node involvement (3/15 with >5cm cancer had node metastasis, 0/24 with <5cm cancer had node metastasis). CONCLUSIONS: Similar to what has been found in patients with papillary thyroid cancer, older male patients with Hurthle cell carcinomas greater than 5cm are more likely to have lymph node metastasis. Our data suggest that these patients may benefit from a prophylactic ipsilateral central neck dissection at the time of their initial operation. PMID- 20842219 TI - Tumor Suppressor RARRES1 Regulates DLG2, PP2A, VCP, EB1, and Ankrd26. AB - Retinoic Acid Receptor Responder (RARRES1) initially identified as a novel retinoic acid receptor regulated gene in the skin is a putative tumor suppressor of unknown function. RARRES1 was knocked down in immortalized human prostatic epithelial cell line PWR-1E cells and differential protein expression was identified using differential in-gel electrophoresis (DIGE) followed by matrix assisted laser desorption ionization (MALDI) mass spectrometry and western Blot analysis excluding highly abundant proteins routinely identified in almost all proteomics projects. Knock-down of RARRES1: 1- down-regulates PP2A, an enzyme involved in the negative regulation of the growth hormone-stimulated signal transduction pathways; 2- down-regulates Valosin-containing protein causing impaired autophagy; 3- up-regulates the tumor suppressor disks large 2; 4- up regulates Ankrd26 that belongs to the POTE family of genes that are highly expressed in cancer patients with poor outcome; and 5- down-regulates EB1, a protein that is involved in spindle dynamics and chromosome alignment during mitosis. PMID- 20842221 TI - Ovarian cancer metastatic to the breast presenting as inflammatory breast cancer: a case report and literature review. AB - Background. Primary ovarian carcinoma with metastasis to the breast is rare, with only 39 cases reported in the current literature. Ovarian metastasis to the breast presenting as inflammatory breast carcinoma is even more infrequent, with only 6 cases reported.Case. We present a patient who developed metastatic inflammatory cancer of the breast from a stage IIIC papillary serous ovarian adenocarcinoma approximately 1 year after the original diagnosis. Pathologic analysis confirmed the origin of the tumor: a high-grade adenocarcinoma morphologically similar to the previously diagnosed ovarian cancer. In addition, the tumor was strongly positive on immunohistochemistry for CA-125, identical to the ovarian primary. The patient died of diffuse metastasis 5 months after the breast tumor was noted.Conclusion. Although ovarian metastasis to the breast presenting as inflammatory breast cancer is rare, it should be included in the differential diagnosis for any patient with a personal history of ovarian cancer. Accurate differentiation is necessary because treatment differs significantly for patients with ovarian metastasis to the breast, as compared with patients with primary inflammatory breast cancer. Ovarian metastasis to the breast confers a poor prognosis: patient survival ranged from 3 to 18 months, with a median survival of 6 months after the diagnosis of the breast metastasis. PMID- 20842222 TI - Tumor cell budding from focally disrupted tumor capsules: a common pathway for all breast cancer subtype derived invasion? AB - Human breast cancer represents a group of highly heterogeneous lesions consisting of about 20 morphologically and immnohistochemically distinct subtypes with substantially different prognoses. Our recent studies have suggested that all breast cancer subtypes, however, may share a common pathway, tumor cell budding from focally disrupted tumor capsules, for their invasion. The potential mechanisms and clinical implications of our observations are discussed. PMID- 20842223 TI - Undetectable and Decreased Expression of KIAA1949 (Phostensin) Encoded on Chromosome 6p21.33 in Human Breast Cancers Revealed by Transcriptome Analysis. AB - Cytogenetic aberration and loss of heterozygosity (LOH) are documented on chromosome 6 in many cancers and the introduction of a neo-tagged chromosome 6 into breast cancer cell lines mediates suppression of tumorigenicity. In this study, we described the identification of KIAA1949 (phostensin) as a putative tumor suppressor gene. Our microarray analysis screened 25,985 cDNAs between a tumorigenic and metastatic breast cancer cell line MDA-MB-231 and the chromosome 6-mediated suppressed, non-tumorigenic and non-metastatic derivative cell line MDA/H6, resulting in the identification of 651 differentially expressed genes. Using customized microarrays containing these 651 cDNAs and 117 controls, we identified 200 frequently dysregulated genes in 10 breast cancer cell lines and 5 tumor tissues using MDA/H6 as reference. Our bioinformatics analysis revealed that chromosome 6 encodes 25 of these 200 genes, with 4 downregulation and 21 upergulation. Northern analysis validated microarray results and was used to detect the size and number of RNA species of 2 downregulated (KIAA1949, PTK7) and 2 upregulated (SFRS3, HMGN3) genes in the cell lines. Particularly, the KIAA1949 gene at 6p21.33, a band region with the frequent cytogenetic aberration and LOH encodes 4 poly(A)-RNA species (4.6-, 4-, 3- and 1.5-kb) in multiple normal and breast cancer samples. Microarray analysis revealed KIAA1949 downregulation in 86.7% (n=15) of breast cancer cell lines and tumor tissues. Northern analysis demonstrated undetectable and decreased expression of KIAA1949 in 100% (n=10) of breast cancer cell lines. Taken together, these results strongly suggest KIAA1949 is a novel candidate breast cancer suppressor gene. PMID- 20842224 TI - The Role of F-FDG-Positron Emission Tomography/Computed Tomography in Staging Primary Breast Cancer. AB - Despite Medicare approving the use of positron emission tomography/computed tomography (PET/CT) in staging primary breast cancer, little evidence is available to support the use of (18)F-FDG-PET/CT for the detection of distant metastases in the initial staging of breast cancer. In this review of the literature listed in MEDLINE, we examine whether (18)F-FDG-PET/CT may play a role in the initial staging of breast cancer. We discuss studies comparing PET/CT with conventional imaging for diagnosing distant metastases and axillary and extra axillary lymph node metastases. PMID- 20842225 TI - BP1 Homeoprotein Enhances Metastatic Potential in ER-negative Breast Cancer. AB - Tumor invasion and metastasis remain a major cause of mortality in breast cancer patients. It was reported that BP1, a homeobox isoform of DLX4, is overexpressed in 80% of breast cancer patients and in 100% of estrogen receptor negative (ER-) tumors. The prevalence of BP1 positive cells and the intensity of BP1 immunoreactivity increased with the extent of ductal proliferation and tumorigenesis. These findings imply that BP1 may play an important role in ER- breast cancer. We sought to determine the effects and mechanisms of BP1 on cell proliferation and metastasis using ER- Hs578T cells as a model. Cells were transfected with either pcDNA3.2 plasmid containing BP1 gene, or pcDNA3.2 vector, then selected and cloned. Overexpression of BP1 increased cell proliferation rate by 2-5 fold (p<0.005), and enhanced the in vitro invasive activity by 25-65 fold (p<0.001). Microarray experiments were performed to identify differentially expressed genes when BP1 is overexpressed. The gene expression profile of the transfected cell lines were compared, resulting in 71 differentially expressed genes with a fold-change of >=2.0. Of those genes, 49 were up-regulated and 22 were down-regulated. Significant pathways were identified involving cell proliferation and metastasis. These data demonstrated that overexpression of BP1 significantly enhanced cell proliferation and metastatic potential in ER- Hs578T cells. Further analysis with more ER- cell lines and patient samples is warranted to establish BP1 as a therapeutic target for ER- breast cancer. PMID- 20842226 TI - A seemingly most effective target for early detection and intervention of prostate tumor invasion. AB - This commentary proposes that budding tumor cell projections from focally disrupted tumor capsules represent a most effective target for early detection and intervention of prostate tumor invasion. The rationale, supporting data, and clinical applications of the hypothesis are discussed. PMID- 20842227 TI - Protein profiling of isolated leukocytes, myofibroblasts, epithelial, Basal, and endothelial cells from normal, hyperplastic, cancerous, and inflammatory human prostate tissues. AB - In situ neoplastic prostate cells are not lethal unless they become invasive and metastatic. For cells to become invasive, the prostate gland must undergo degradation of the basement membrane and disruption of the basal cell layer underneath the luminal epithelia. Although the roles of proteinases in breaking down the basement membrane have been well-studied, little is known about the factors that induce basal cell layer disruption, degeneration, and its eventual disappearance in invasive cancer. It is hypothesized that microenvironmental factors may affect the degradation of the basal cell layer, which if protected may prevent tumor progression and invasion. In this study, we have revealed differential protein expression patterns between epithelial and stromal cells isolated from different prostate pathologies and identified several important epithelial and stromal proteins that may contribute to inflammation and malignant transformation of human benign prostate tissues to cancerous tissues using matrix assisted laser desorption ionization time-of-flight mass spectrometry and proteomics methods. Cellular retinoic acid-binding protein 2 was downregulated in basal cells of benign prostate. Caspase-1 and interleukin-18 receptor 1 were highly expressed in leukocytes of prostate cancer. Proto-oncogene Wnt-3 was downregulated in endothelial cells of prostatitis tissue and tyrosine phosphatase non receptor type 1 was only found in normal and benign endothelial cells. Poly ADP-ribose polymerase 14 was downregulated in myofibroblasts of prostatitis tissue. Interestingly, integrin alpha-6 was upregulated in epithelial cells but not detected in myofibroblasts of prostate cancer. Further validation of these proteins may generate new strategies for the prevention of basal cell layer disruption and subsequent cancer invasion. PMID- 20842228 TI - Cancer Response Criteria and Bone Metastases: RECIST 1.1, MDA and PERCIST. AB - Response criteria represent the standard by which the efficacy of therapeutic agents is determined in cancer trials. The most widely used criteria are based on the anatomic measurement of solid tumors. Because bone metastases are typically located in irregularly shaped bones and are difficult to measure with rulers, they have been previously considered unmeasurable disease. New developments in cancer response criteria have increased awareness of the importance of the response of bone metastases to therapy. The recently updated Response Evaluation Criteria in Solid Tumors (RECIST 1.1) now consider bone metastases with soft tissue masses > 10 mm to be measurable disease. Response criteria specific to bone metastases have been developed at The University of Texas MD Anderson Cancer Center (MDA criteria) and can be used to assess therapeutic response in numerous types of bone metastases. Functional imaging criteria, such as the recently developed Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) allow response to be measured in the absence of anatomic change through assessment of metabolic activity. As monitoring tumor response of bone metastases becomes more important in the management of cancer, so does the demand on radiologists and nuclear medicine physicians for accurate interpretation of the behavior of these lesions. This article reviews anatomic, bone, and metabolic response criteria, providing illustrations for the interpretation of therapy induced change in bone metastases. PMID- 20842229 TI - Dual use of a single Wilms' tumor 1 immunohistochemistry in evaluation of ovarian tumors: a preliminary study of 20 cases. AB - Our previous studies revealed that a single Wilms' tumor 1 (WT-1) immunohistochemistry can be used to elucidate both the myoepithelial cells and blood vessels of human breast tumors. As the human ovary is rich in blood vessels, and WT-1 has been used as a biomarker for ovarian tumors, our current study attempted to assess if a single WT-1 immunohistochemistry has dual usages in evaluation of ovarian tumor and endothelial cells. Paraffin-embedded tissue sections were prepared from 20 cases of ovarian tumors. A set of four consecutive sections from each case were subjected to immunohistochemistry with a mouse monoclonal antibody against the human WT-1 protein, a well defined ovarian tumor marker, CA-125, and a endothelial cell phenotypic marker, CD34, respectively. From each case, 4-5 randomly selected fields were photographed, and expression of these molecules in the same structures were compared. Distinct WT-1 immunoreactivities were seen in both ovarian tumor and endothelial cells. Over 90% of WT-1 positive tumor and endothelial cells were positive for CA-125 and CD34, respectively. Similarly, over 90% of CA-125 or CD34 positive cells co express WT-1 in tumor or endothelial cells, respectively. Our findings suggest that a single WT-1 immunohistochemistry can be used to assess both the tumor cells and micro-vascular density in ovarian tumors. Our findings also suggest that as WT-1 is expressed in both tumor and endothelial cells, the development of therapeutic agents to target WT-1 may provide an effective treatment option for ovarian cancer. PMID- 20842230 TI - Chloroma/Granulocytic sarcoma: abdominal & pelvic presentation of acute myelogenous leukemia. AB - There is limited literature documenting granulocytic sarcoma of the colon. We report a case of a 28 year-old female with a colonic granulocystic sarcoma of the colon as a complication of AML, as it is an important consideration with surgical management of typhilitis. PMID- 20842232 TI - Adrenocortical carcinoma and synchronous malignancies. AB - OBJECTIVE: Adrenocortical carcinoma (ACC) is an aggressive tumor that accounts for 0.02% of all reported cancers. ACC commonly arises in a sporadic manner, but may also manifest as part of a familial syndrome. Regardless of the setting, ACC rarely arises concurrent with other malignant tumors. METHODS: In this report we describe a 32-year-old woman who on work-up for abnormal vaginal bleeding was diagnosed with synchronous uterine adenocarcinoma, ovarian adenocarcinoma and ACC. We also provide a literature review of the past 20 years to identify other patients with ACC and synchronous malignant tumors, and those with familial syndromes associated with an increased risk of developing ACC. RESULTS AND CONCLUSIONS: To our knowledge this is the first report of a patient with synchronous malignant tumors of the uterus, ovary and adrenal gland. Review of the literature revealed only 5 other cases in which a patient had concurrent ACC and malignant tumors in other organs. PMID- 20842231 TI - Vitamin D in combination cancer treatment. AB - As a steroid hormone that regulates mineral homeostasis and bone metabolism, 1alpha, 25-dihydroxycholecalciferol (calcitriol) also has broad spectrum anti tumor activities as supported by numerous epidemiological and experimental studies. Calcitriol potentiates the anti-tumor activities of multiple chemotherapeutics agents including DNA-damaging agents cisplatin, carboplatin and doxorubicin; antimetabolites 5-fluorouracil, cytarabine, hydroxyurea, cytarabine and gemcitabine; and microtubule-disturbing agents paclitaxel and docetaxel. Calcitriol elicits anti-tumor effects mainly through the induction of cancer cell apoptosis, cell cycle arrest, differentiation, angiogenesis and the inhibition of cell invasiveness by a number of mechanisms. Calcitriol enhances the cytotoxic effects of gamma irradiation and certain antioxidants and naturally derived compounds. Inhibition of calcitriol metabolism by 24-hydroxylase promotes growth inhibition effect of calcitriol. Calcitriol has been used in a number of clinical trials and it is important to note that sufficient dose and exposure to calcitriol is critical to achieve anti-tumor effect. Several trials have demonstrated that safe and feasible to administer high doses of calcitriol through intermittent regimen. Further well designed clinical trials should be conducted to better understand the role of calcitriol in cancer therapy. PMID- 20842233 TI - Practice and effectiveness of outpatient psycho-oncological counseling for cancer patients. AB - OBJECTIVE: Because of various types of psychological distress, cancer patients are encouraged to attend outpatient psycho-oncological and psychosocial counseling. The aim of this prospective study was an analysis of the impact and success of existing counseling resources. METHODS: All cancer patients who had applied at a central counseling center were given a standardized questionnaire (FBK-R23), designed to assess the type and degree of cancer patients' difficulties prior to their first counseling session. Additionally, the psychological condition of the patients was assessed psycho-oncologically by a third party (PO-Bado). After at least 2 and no more than 5 sessions, patients underwent both self-evaluation and third-party assessment, using the same instruments. RESULTS: During the period from September 2008 and August 2009, we looked at a total of 447 people seeking counseling, including 186 family members (42%), 33 professional caregivers (7%), and 228 patients (51%). Out of the 228 patients, 48 attended our counseling sessions personally and 20 of these additionally completed the second questionnaire. Counseling led to only a tendency toward improvement, on average, of total psychological distress (p=0.08). In individual areas - for example, "Social Distress" and "Everyday Limitations"- no change could be measured. Only the problem area identified as "Information Deficit" was improved, on average, after 3 counseling sessions (p=0.008). CONCLUSION: Our results indicate that while short-term counseling has no concrete effect on the improvement of a patient's psychological well-being, these support sessions do serve to decrease the patient's so-called "Information Deficit", thereby bringing about an indirect improvement in the sufferer's psychological state. The course of treatment offered should be determined according to the patient's needs. In order to ensure that even the very sickest of the tumor patient group seek outreach groups, we must target this particular group with additional evaluative questions. Further studies must determine whether short-term counseling or other counseling strategies are most effective. PMID- 20842234 TI - WT-1 expression in a spectrum of melanocytic lesions: Implication for differential diagnosis. AB - A previous in vitro study revealed that Wilms's tumor 1 (WT-1) transcripts were detectable in 7 of 9 melanoma cell lines, but not in any of 5-normal melanocyte strains tested. Our current study assessed the expression levels of WT-1 protein in clinical samples, to determine whether the expression levels of the WT-1 protein may be used as a novel marker to assist differential diagnosis. Paraffin embedded tissue sections from 15 cases of malignant melanomas and 25 cases of benign nevi were subjected to immunohistochemistry with a monoclonal antibody against the human WT-1 protein. The expression levels of WT-1 protein among normal, benign, and malignant melanocytes were semi-quantitatively assessed. Strong and uniform WT-1 immunoreactivities were seen in all or nearly all tumor cells in both the junctional and dermal components of all malignant melanomas, and also in a vast majority of the tumor cells of Spitz's (n = 8), recurrent (n = 2), and junction (n = 2) nevi. Distinct WT-1 immunoreactivities were also seen in some isolated individual tumor cells or tumor cell clusters in the junctional component of compound nevus (9) and in intradermal nevus (2). It is interesting to note that some isolated normal appearing melanocytes or cell clusters, and all morphologically distinct endothelial cells were strongly positive to WT-1. However, all tumor cells within the dermal component of compound (n = 9) or deep penetrating nevi (n = 1), or capsular nevus inclusion of lymph node (1) were devoid of WT-1 expression. Our findings suggest that the expression level of the WT-1 protein has no significant value in distinguishing between Spitz's nevi and malignant melanoma, but it may be a useful marker in differentiating between benign and malignant melanocytes within the dermal component. Our findings also suggest that aberrant WT-1 expression may have oncogenic properties that promote the initiation and progression of melanocytic lesions. PMID- 20842236 TI - The dilemma of safe sex and having children: challenges facing HIV sero discordant couples in Uganda. AB - BACKGROUND: Sixty percent of new HIV infections in Uganda occur in stable relationships between HIV discordant couples. Given the importance of fertility in Uganda, we hypothesized that unsafe sexual practices may be used to found a family/replace a dead child. Thus, we explored sexual practices to understand to what extent these are influenced by the desire to have children and the implications for HIV transmission among discordant couples. METHODS: A cross sectional survey of 114 HIV discordant couples in Kampala, and in-depth interviews with 15 purposively selected couples. Quantitative data were analysed using STATA. Multivariate logistic regression analysis done to identify factors associated with consistent condom use. Thematic content analysis of qualitative data was done using NVIVO 2. RESULTS: Participants wanting children and those with multiple sexual partners were less likely to use condoms (Adj OR 0.51, and 0.36 respectively). Three of the five types of sexual practices used by couples do not allow pregnancy to occur. Main reasons for wanting a child included: ensuring lineage continuity and posterity, securing relationships and pressure from relatives to reproduce. Challenges included: risk of HIV transmission to partner and child, lack of negotiating power for safer sex, failure of health systems to offer safe methods of reproduction CONCLUSIONS: HIV sero-discordant couples with strong desire for childbearing have a dilemma of risking HIV infection or infecting their spouse. Some risk transmission of HIV infection to reproduce. We need to address gender issues, risky behaviour and reproductive health services for HIV sero-discordant couples. PMID- 20842237 TI - Bacterial contamination of donor blood at the Tamale Teaching Hospital, Ghana. AB - BACKGROUND: Transfusion of bacterially contaminated blood can result in sepsis and will constitute a substantial health burden to the patient. OBJECTIVE: To assess the level of transfusion related sepsis and the bacterial types responsible for the contamination at the Tamale Teaching Hospital in Ghana. METHOD: We sampled 80 refrigerated donor blood at the blood bank and cultured them for bacteria. The antimicrobial sensitivities of the isolates were also determined. RESULTS: 14 blood bags representing 17.5% grew isolates of various bacteria. Ten (10) of the 14 isolates were Gram positive cocci representing 71.42% making it the commonest contaminant. 50% of the gram positive cocci were identified to be coagulase negative staphylococci and 21.42% were Staphylococcus aureus. There were 14.28% isolates which were Gram positive rods, and were identified to be Corynebacterium diphtheroids. There were two isolates which were Gram negative rods; one was identified as Escherichia coli and the other one Klebsiella pneumoniae. Sensitivity among the organisms were varied; as all the 14 (100%) of the organisms isolated were sensitive to amikacin, only 14.28% of the coagulase negative staphylococci were sensitive to co-trimoxazole, 28.5% were sensitive to ampicillin, 42.8% were sensitive to cefuroxime and 71.4% were sensitive to ciprofloxacin. Sensitivity to gentamicin was observed to be 85.7% and 28.5% were sensitive to Tetracycline. Only the 10 Gram positive cocci were tested against erythromycin and Cloxacillin; where 70.00% were sensitive to cloxacillin and 90% were sensitive to erythromycin. CONCLUSION: All the Staphylococcus aureus isolated were resistant to both ampicillin and cotrimoxazole. Potential dangers and consequences of transfusing multidrug resistance bacteria have been discussed. PMID- 20842238 TI - Potential risk of HIV transmission in barbering practice among professional barbers in Ibadan, Nigeria. AB - BACKGROUND: There is a growing concern that barbering procedures could create opportunities for HIV transmission. However, little is known about Nigerian barbers' practices relating to the prevention of HIV. OBJECTIVES: This study assessed the precautionary measures for the prevention of HIV among commercial barbers in Ibadan, Nigeria. METHODS: Data were collected using validated checklist to directly observe ninety barbering procedures in forty-five barber shops randomly selected from three communities that have been categorized as inner-core, transitory and peripheral. RESULTS: Respondents were all males with mean age of 36(+/-10.2) years. Ninety-eight percent had at least primary school education and all of them learnt barbering through apprenticeship. The instruments used were razor blades (11.1%), manual clippers (8.9%) and electric clippers (80%). Clippers were sterilized in 10% and disinfected in 72.5%, while no decontamination was carried out in 17.5% of the sessions. Fifty two percent of the disinfections involved the use of kerosene, a disinfectant not recommended for HIV inactivation; 48.3% of the disinfectants were not in the original containers while 53.4% of the sessions involved the use of same brush for cleaning clipper and brushing hair. Hand-held flame and Ultra-violet light sterilizer were used in 50% of the sterilization process. Barbers in the high class peripheral communities were more likely to practice appropriate equipment decontamination than those from lower-class inner-core communities. There was blade-to-skin contact in all and accidental cuts occurred in three of the sessions and none was properly managed. CONCLUSION: The risk of transmitting HIV is high in the barbershops in the study area. Health education strategies such as training, supportive supervision and peer education are needed to facilitate the adoption of effective precautionary measures against HIV infection among barbers. PMID- 20842239 TI - Factors influencing disclosure of HIV positive status in Mityana district of Uganda. AB - BACKGROUND: Disclosure of HIV positive sero-status to sexual partners, friends or relatives is useful for prevention and care. Identifying factors associated with disclosure is a research priority as a high proportion of persons living with HIV/AIDS (PHA) never disclose. OBJECTIVE: To identify factors associated with disclosure among PHAs in Mityana district of Uganda. METHODS: Using a case control design, we compared 139 PHAs who had disclosed to 139 PHA who had not disclosed regarding socio demographic characteristics, sexual behaviour, individual experiences and perceptions about disclosure, as well as on health facility/community correlates of disclosure. RESULTS: The independent factors that favour disclosure are not fearing negative outcomes of disclosure adjusted odds ratio (AOR) 7.00, 95 % confidence interval (95% CI) 3.03-16.95, having communication skills to disclose (AOR 12.08, 95% CI 4.94-29.51), having initiated anti-retroviral therapy (AOR 7.51, 95% CI 3.42-16.49), not having tested for HIV during ante-natal clinic (AOR 5.07, 95% CI 1.95-13.10), receiving ongoing counselling (AOR 4.33, 95% CI 1.50-12.51) and having ever seen a PHA publicly disclose his/her HIV status AOR 2.73, 95% CI 1.24-6.02). CONCLUSIONS: PHAs that have not initiated anti-retroviral therapy (ART), test for HIV in ante-natal clinic and fear negative outcomes need more help in disclosure. Measures that empower PHA to disclose such as those that lead to improved communication skills should be reinforced during ongoing counselling. PMID- 20842240 TI - The in vitro antimicrobial activity of fruit and leaf crude extracts of Momordica charantia: a Tanzania medicinal plant. AB - OBJECTIVE: To evaluate the antimicrobial activity of Momordica charantia extracts on reference strains and microorganisms isolated from clinical specimens. METHOD: Petroleum ether and methanolic crude extracts of fruits and leaves of the plant were evaluated for antimicrobial activity using the disk diffusion method on four reference microorganisms (Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Staphylococcus aureus; and four clinical strains of Klebsiella pneumoniae, Proteus vulgaris, Salmonella typhi and Cryptococcus neoformans. RESULT: Antimicrobial activity was observed against all the tested microorganisms with exception to P. mirabilis and C. neoformans. Methanolic crude extracts exhibited relatively broader antimicrobial spectrum of activity than petroleum ether extracts with the as lower concentration as 0.075mg/ul. Methanolic fruit crude extract displayed the broadest antimicrobial spectrum by inhibiting majority (75%) of the tested microorganisms. Neither was there synergistic nor addition effect upon mixing leaf and fruit extracts of equal concentrations derived from the same solvent. CONCLUSION: Extracts of M.charantia demonstrated antimicrobial activity on tested microorganisms except on Proteus mirabilis and Cryptococcus neoformans. Fruit extracts showed higher antimicrobial activity than leaf extract. Further studies are recommended that will involve various parts of the plant, select different fractions of extracts and purify the active antimicrobial components. PMID- 20842241 TI - The anti-mycobacterial activity of Lantana camara a plant traditionally used to treat symptoms of tuberculosis in South-western Uganda. AB - INTRODUCTION: Tuberculosis continues to be a devastating public health problem. Many communities in Uganda use medicinal plants to treat various infections, including respiratory tract infections. There are claims that some can treat tuberculosis. Verifying some of these claims could lead to discovery of lead compounds for development of a TB drug. METHODS: Chloroform and methanol extracts of L. camara collected from South-western Uganda were screened against three strains of Mycobacterium tuberculosis using the agar-well diffusion method. H37Rv, the rifampicin-resistant TMC-331 and a non-resistant wild strain (28 25271). The MIC and MBC were determined using the Agar dilution method on Middle brook 7H11. RESULTS: The methanol extract showed the highest activity against all the three strains used, with zones of inhibition of 18.0-22.5 mm and MIC values of 20 ug/ml for H37Rv and 15 ug/ml for both TMC-331 and wild stain. The values for rifampicin were 1.0 ug/ml for both H37Rv and wild strain but rifampicin hardly showed any activity on TMC-331. The MBC value for the methanol extract of L. camara was 30ug/ml for the H37Rv, and 20ug/ml for both the TMC-331 and wild strains of M. tuberculosis. The MBC for rifampicin was 2.0ug/ml for both H37Rv and the wild strain. CONCLUSION: We conclude that L. camara contains principles active against M. tuberculosis, which merit further research. PMID- 20842242 TI - Beta thalassaemia trait in western Nigeria. AB - BACKGROUND: Genes for thalassaemia, haemoglobin S, Glucose-6-phosphate dehydrogenase which confer resistance to malaria are found in high frequencies in Nigeria, 25% of the population being carriers of the sickle cell trait while another 25% are hemizygous for the G6PD gene. The frequency of alpha thalassaemia is equally high among Nigerians but there is little information on beta thalassaemia in this population. A recent study however suggest a high prevalence of beta thalassaemia in the same population, hence the need for this study. METHODS: Haemoglobin A(2) and HbF were determined in healthy adults who have haemoglobin A genotype by elution after electrophoresis and alkaline denaturation methods respectively. RESULTS: The mean HbA(2) among the subjects was 3.3% (range 2.0-5.6%) while the mean HbF was 2.6% (range 0.4-8.8%). Twenty-six percent of the subjects had HbA(2) values higher than 3.9% while 86% had HbF values greater than 1%, twenty-four percent had elevated HbA(2) and HbF. The mean HbA(2) value was 2.7% among those with HbF <1%, 3.6% among those with HbF 1-3% and 3.1% among those with HbF >3%. CONCLUSION: These findings confirm that the frequency of beta thalassaemia in western Nigeria is higher than previously thought and that many of the individuals studied may be silent carriers of the beta thalassaemia trait. Its presence may also have been masked by the high prevalence of alpha thalassaemia in the same environment. It is therefore important to consider beta thalassaemia trait as a differential diagnosis in patients who present with haemolytic anaemia in this environment. PMID- 20842243 TI - Reproductive effects of Ficus asperifolia (Moraceae) in female rats. AB - The reproductive effects of Ficus asperifolia in female rats were investigated in the present study. Sperm-positive adult female rats were orally administered (P.O.) either the aqueous and methanol extracts of Ficus asperifolia (100 and 500mg/kg), distilled water (10ml/kg) or 5%Tween 80 (10ml/kg) for seven days. On day 10 of pregnancy, the implantation sites were recorded. In the fertility study, adult female rats received the same test substances for 21 days and, the fertility index and litter size determined. In the uterotrophic test, normal and ovariectomized immature rats were treated for seven days with the dry extract of Ficus asperifolia (100 and 500mg/kg) in the absence and presence of 17a-estradiol benzoate 1ug/animal/day, s.c. On day 8, the uterine growth index was measured. Results of the study showed a significant increase (p<0.05) in the implantation sites and litter size of animals receiving 100mg/kg of the aqueous extract of Ficus asperifolia. In the estrogenic assay, normal immature rats were sensitive to the treatment with Ficus asperifolia than the ovariectomized ones. Our results give added scientific support to the popular use of Ficus asperifolia in the treatment of some cases of women's sterility/infertility related problems. PMID- 20842244 TI - Severe depression following a-interferon usage in a patient with chronic myeloid leukemia. AB - BACKGROUND: Chronic myeloid leukaemia (CML), with a median age of 40 years, is one of the commonest haematological malignancies in Nigeria. Cytoreductive agents, which were hitherto the mainstay of treatment, neither induce cytogenetic nor haematologic remission. Alphainterferon (a-IFN), an endogenous glycoprotein with cytotoxic and natural killer cell enhancer effects has been found to induce haematologic and cytogenetic remission in patients with CML, but neuro psychiatric complications of a -interferon (a-IFN) usage were not reported in Nigeria. OBJECTIVE: To report a case of deliberate self-harm in University Lecturer as a side effect of a-IFN in the treatment of CML METHOD: Clinical and laboratory follow up of a patient receiving a-IFN in the management of CML from the time of diagnosis of CML to the point of loss of contact. RESULT: Severe depression is a complication that may adversely influence the clinical outcome of a-IFN usage CONCLUSIONS/RECOMMENDATIONS: Although interferon related depression is uncommon, it is suggested that pre-therapy interferon assays and neuro psychiatric assessment are carried out in prospective users of a-IFN. PMID- 20842245 TI - Oxygen cylinders: "life" or "death"? AB - Oxygen is crucial to maintain and save human life. Other than medical purposes it is widely used for manufacture of mineral water, fabrication works and other industrial activities. If adequate precautionary measures are not adopted while handling, storage or transport of oxygen cylinder or container, accidental blast may claim human life and other damage as well. The case involving three victims is presented to highlight various relevant aspects i.e. autopsy findings, cause/s of blast and recommended precautions are discussed in the light of oxygen cylinder blast case in an" oxygen filling factory", claiming three human lives. PMID- 20842246 TI - Witchcraft in Transkei Region of South African: case report. AB - Witchcraft and witch-hunt have been practiced widely almost all over the world. It is known as magic in Europe, maleficium (wrong-doing) in Latin America, and superpower in Asia. In Africa those accused of being witches often face execution. A range of accusations are leveled against witches such as causing impotence, turning milk sour, causing disease and death.Three cases are presented here to highlight the issues related to witch craft in Transkei area. The information was given by the next of kin at the time of autopsy. All were elderly women over 50 years of age. The first was related to tuberculosis of the brother of the perpetrator the second, death of the culprit's relative and third the death of culprits brother in Johannesburg. The first and third victims were brutally chopped by axe and in the second it was a firearm injury. The case history, the type of wounds, and medico-legal aspects of death are discussed in these reports. There law related to witchcraft and their implementations to prevent such deaths are discussed. PMID- 20842247 TI - Progress of our journal at glance. PMID- 20842248 TI - Management of female uro-genital fistulas: Framing certain guidelines. AB - BACKGROUND: The study was carried out to discuss the pathogenesis and management protocol of seven different varieties of female uro-genital fistulas (FUGFs). PATIENTS AND METHODS: During 2000-2007, total of 15 FUGFs were operated, which belonged to seven different varieties requiring different routes and surgical procedures for their repair. Different fistulas with different pathophysiological factors required specific examinations and investigations preoperatively. RESULTS: The results of the repaired FUGFs, following the general surgical principles, were acceptable with formation of only one residual fistula. CONCLUSIONS: Successful correction of FUGFs is a surgical challenge. Detailed history, through examination and planning, atraumatic tissue handling, routine use of the interposition or onlay reinforcement flaps and vigilant postoperative care were found the key factors in successful outcome of the repaired fistulas. PMID- 20842249 TI - Erratum: Testicular sperm retrieval at the time of bilateral radical orchiectomy. AB - [This corrects the article on p. 22 in vol. 1.]. PMID- 20842250 TI - Antibiotic susceptibility pattern in urinary isolates of gram negative bacilli with special reference to AmpC beta-lactamase in a tertiary care hospital. AB - INTRODUCTION: Resistance to higher antimicrobial agent is commonly seen in gram negative bacilli. This issue is a challenging problem to the medical practitioners in addition to it is financial impact on the health care system. OBJECTIVES: To document the prevalence of multi drug resistant gram negative bacilli isolated from urine of patients attending the Urology Department of Tertiary care Hospital of western India in year 2008. RESULTS: Out of total 328 isolates, 118 (35.98%) E.coli, 72 (21.95 %) Klebsiella, 64 (19.51%) Pseudomonas aeruginosa, 30 (9.15%) Acinetobacter, 18 (5.49%) Proteus vulgaris, 18 (5.49%) Proteus mirabilis, 6 (1.83%) Providencia rettgerii, 2 (0.61%) Citrobacter freundii. Out of these isolates, 228 (69.51%) were beta-lactamase positive, while 100 (30.51%) were beta-lactamase negative. Out of 228 beta-lactamase positive, 104 (45.61%) were AmpC beta-lactamase positive. CONCLUSIONS: Stringent protocol such as Antibiotic policy and Hospital infection control program are mandatory to curb these microbes in a tertiary care hospital. PMID- 20842251 TI - A decade of clinical experience with extra-adrenal paragangliomas of retroperitoneum: Report of 67 cases and a literature review. AB - OBJECT: The purpose was to highlight the diagnosis and treatment of extra-adrenal para-gangliomas, which often causes catecholamine hypersecretion and hypertension. METHODS: 67 cases of extra-adrenal paraganglioma of retroperitoneum proven pathologically from 1999 to 2009 were reviewed and studied after operation. Endocrine secretion examinations, B-US, CT, MRI, 131-MIBG, octreotide and hands microcirculation inspection were used to diagnose the disease. RESULTS: All patients underwent successful surgical resection of the tumors, which proved to be paragangliomas. They were from 3 cm to 25 cm in size. Almost all of them were diffusely positive for cgA, syn, NSE and s-100 by immunohitochemical staining. There were nine cases assayed malignant paraganglioma by the follow-up. CONCLUSIONS: 131-MIBG and octreotide have high sensitivity and accuracy in diagosing extra-adrenal paraganglioma. Surgical treatment should be carried out on the basis of correct drug preparation of alpha-receptor blocker, such as prazosin and phenoxybenzamine. Complete surgical excision is the treatment of choice for extra-adrenal paragangliomas as well as recurrent or metastatic disease, which could be resected laparoscopically. Intimate lifelong follow-up is necessary and important. PMID- 20842252 TI - Ureteral injuries from gunshots and shells of explosive devices. AB - CONTEXT: Penetrating rather than blunt trauma is the most common cause of ureteral injuries. The approach to management differs from the far more common iatrogenic injury. AIMS: The purpose of this series is to report our experience in ureteral trauma management, with attention to the diagnosis, repair, and outcome of these injuries. MATERIALS AND METHODS: From April 2003 to October 2009, all abdominal trauma cases received alive, reviewed for penetrating ureteric injuries RESULTS: A total of twenty (fifteen male, five female) penetrating ureteral injuries were evaluated. All penetrating ureteric injuries were due to (9 gunshot and 11 shells from explosive devices). Since the patients had a clear indication for surgery, no IVU or CT scan was done preoperatively, major intra-abdominal injuries were often associated. The diagnosis of ureteric injury was made intraoperatively in 8 cases (40%) While, twelve cases (60%) were diagnosed postoperatively. Eight ureteric injuries (40%) were proximal 1/3, 4 (20%) to middle 1/3 and 8 (40%) to the distal 1/3. Management was with stenting in 2 patients, ureteroureterostomy in 8, ureteroneocystostomy in 6, and nephrectomy in 4. CONCLUSIONS: In this study, a delay in diagnosis was a contributory factor in morbidity related to ureteral injury, the need for second operation in already compromised patients from associated injuries, The presence of shock on admission, delayed diagnosis, and colon injuries were associated with a high complication rate. Ureteral injuries must be considered early during the evaluation of penetrating abdominal injuries. PMID- 20842253 TI - Pattern of management of urologic cancer in Saudi Arabia. AB - BACKGROUND: To compare the current uro-oncologic practice pattern in Saudi Arabia with the standard of care practice and to identify obstacles in our health care system that prevent offering such a treatment. MATERIALS AND METHODS: We surveyed 247 practicing urologists in Saudi Arabia using a designed questionnaire. This questionnaire contains 19 questions focusing on management of bladder and renal cancers. RESULTS: Of the 247 contacted urologists, 86 completed the questionnaire. Seventy six percent see more than 10 bladder cancer cases/year and 83% used rigid cystoscope for diagnosis under general anesthesia. Eighty two percent perform over 10 bladder tumor resections/year; however, 90% of them perform less than five cystectomies/year, if any. Seventy nine percent had intravesical therapy available at their hospitals and majority of them use it after resection in selected patients. Fifty percent preferred re-resection within 2-4 weeks for T1 and/or G3 tumors and majority of them (86%) perform cystectomy for muscle invasive disease and ninety six percent perform ileal conduit. Thirty four percent see over 10 renal cancers/year. Forty nine percent perform radical nephrectomy for less than 4 cm renal masses and for more than 4 cm, only 9% do laparoscopic nephrectomy while the majority preferred open technique although 77% of the hospitals participated in this survey have a urologist capable of doing laparoscopy. CONCLUSION: A significant number of urologists in Saudi Arabia do not apply some of the well-accepted standard practices in urologic cancer. To improve this, we need to work on our referral system and establish education and training programs to make the urologist familiar with the new modalities of treatment. PMID- 20842254 TI - Computed tomography findings in bilateral perinephric lymphangiomatosis. AB - Perinephric lymphangioma is rare disorder that may be confused with various forms of renal cystic diseases and urinomas. In this disorder a developmental malformation results in failure of developing lymphatic tissue to establish normal communication with the rest of lymphatic system. Once there is restricted drainage of lymphatic fluid the lymphatic channels dilate to form cystic masses that may be unilocular or multilocular and may be seen unilaterally or bilaterally .This condition presents with various signs and symptoms or can be just an incidental finding which in presence of misleading clinical history may be confused with other diseases. CT scan with delayed cuts and USG guided aspiration with biochemical analysis of fluid will help us in arriving to final diagnosis. PMID- 20842256 TI - Superior vena cava syndrome: A rare complication of percutaneous nephrolithotripsy laser lithotripsy. AB - PURPOSE: To describe a case of acute superior vena cava syndrome during percutaneous nephrolithotomy (PCNL), and to review the associated clinical features, management and complications. CLINICAL FEATURES: A 34-year-old man, diagnosed as right renal calculi and nodal tachycardia, was admitted to receive percutaneous nephroscope laser lithotripsy. Shortly after stone disintegration, he suffered acute hypoxic and hypotension, and showed cyanoderma of face and chest skin, ocular proptosis, jugular filling and ventricular fibrillation. Dopamine and adrenaline was intravenously injected. The patient was turned over to supine position and external cardiac massage and electric defibrillation were carried out immediately. The patient finally cardioverted. His vital signs subsequently became stable and cyanoderma faded. The patient was eventually discharged from the intensive care unit three days following the event. CONCLUSION: Severe complications such as cardiac arrest could happen during PCNL. Close monitoring the vital signs is essential for early finding and quick response to rescue. PMID- 20842255 TI - Perinephric abscess caused by ruptured retrocecal appendix: MDCT demonstration. AB - Acute appendicitis may occasionally become extraordinarily complicated and life threatening yet difficult to diagnose. One such presentation is described in a 60 year-old man who was brought to the hospital due to right lumbar pain and fever for the last 15 days. Ultrasonography showed a right perinephric gas and fluid collection. Abdominal computed tomography with multidetector-row CT (MDCT) revealed gas-containing abscess in the right retroperitoneal region involving the perinephric space, extending from the lower pole of the right kidney up to the bare area of the liver. Inflamed retrocecal appendix was seen on thick multiplanar reformat images with its tip at the lower extent of the abscess. Laparotomy and retroperitoneal exploration were performed immediately and a large volume of foul smelling pus was drained. A ruptured retrocecal appendix was confirmed as the cause of the abscess. PMID- 20842257 TI - Capsular renal leiomyosarcoma with encasement of the inferior vena cava - Diagnosed by immunostaining and review of literature. AB - We report and describe the presentation, pathological diagnosis with immunostaining and management of a rare case of capsular renal leiomyosarcoma encasing the inferior vena cava (IVC). We have reviewed and tabulated other such similar cases. The present case was successfully managed by radical nephrectomy and adjuvant radio-chemotherapy. Immunostaining should be freely used to define the histological type of renal sarcoma in order to accurately counsel and deliver a prognosis for patients with renal leiomyosarcomas with a poor prognosis. PMID- 20842258 TI - Primary retroperitoneal synovial sarcoma in CT and MRI. AB - Synovial sarcomas are most commonly localized in the extermities, especially the lower thigh and knee areas. Retroperitoneal synovial sarcoma is very rare. We decribe the radiological findings of an adult retroperitoneal synovial sarcoma. PMID- 20842259 TI - Primary adenocarcinoma of ureter mimicking pyelonephritis. AB - Tumors of the ureter are rare. We present a case of primary mucinous adenocarcinoma of the ureter diagnosed as chronic pyelonephritis preoperatively. This tumor is postulated to arise from metaplastic glandular mucosa in response to chronic irritation of the urothelium. PMID- 20842260 TI - Castleman's disease: A rare differential diagnosis for retroperitoneal tumors. PMID- 20842261 TI - Pseudo tumor of the urinary bladder in a child. PMID- 20842262 TI - The power of Prana. PMID- 20842263 TI - A review of the scientific studies on cyclic meditation. PMID- 20842264 TI - Cardiovascular and metabolic effects of intensive Hatha Yoga training in middle aged and older women from northern Mexico. AB - BACKGROUND: Hatha Yoga (HY) can be an alternative to improve physical activity in middle-aged and older women. However, conventional HY (CHY) exercising may not result in enough training stimulus to improve cardiovascular fitness. The purpose of this study was to evaluate the effect of an intensive HY intervention (IHY) on cardiovascular risk factors in middle-aged and older women from Northern Mexico. MATERIALS AND METHODS: In this prospective quasiexperimental design, four middle aged and nine older CHY practicing females (yoginis) were enrolled into an 11 week IHY program consisting of 5 sessions/week for 90 min (55 sessions). The program adherence, asana performance, and work intensity were assessed along the intervention. Anthropometric [body mass index (BMI), % body fat and Sigma skin folds], cardiovascular fitness [maximal expired air volume (VE(max)), maximal O(2) consumption (VO(2max)), maximal heart rate (HR(max)), systolic (BPs) and diastolic blood pressure (BPd)], biochemical [glucose, triacylglycerols (TAG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C)], and dietary parameters were evaluated before and after IHY. RESULTS: Daily caloric intake (~1,916 kcal/day), program adherence (~85%), and exercising skills (asana performance) were similar in both middle-aged and older women. The IHY program did not modify any anthropometric measurements. However, it increased VO(2max) and VE(max) and HDL-C while TAG and LDL-C remained stable in both middle-aged and older groups (P < 0.01). CONCLUSIONS: The proposed IHY program improves different cardiovascular risk factors (namely VO(2max) and HDL-C) in middle-aged and older women. PMID- 20842265 TI - Effect of yogic education system and modern education system on memory. AB - BACKGROUND/AIM: Memory is more associated with the temporal cortex than other cortical areas. The two main components of memory are spatial and verbal which relate to right and left hemispheres of the brain, respectively. Many investigations have shown the beneficial effects of yoga on memory and temporal functions of the brain. This study was aimed at comparing the effect of one Gurukula Education System (GES) school based on a yoga way of life with a school using the Modern Education System (MES) on memory. MATERIALS AND METHODS: Forty nine boys of ages ranging from 11-13 years were selected from each of two residential schools, one MES and the other GES, providing similar ambiance and daily routines. The boys were matched for age and socioeconomic status. The GES educational program is based around integrated yoga modules while the MES provides a conventional modern education program. Memory was assessed by means of standard spatial and verbal memory tests applicable to Indian conditions before and after an academic year. RESULTS: Between groups there was matching at start of the academic year, while after it the GES boys showed significant enhancement in both verbal and visual memory scores than MES boys (P < 0.001, Mann-Whitney test). CONCLUSIONS: The present study showed that the GES meant for total personality development adopting yoga way of life is more effective in enhancing visual and verbal memory scores than the MES. PMID- 20842266 TI - Motion analysis of sun salutation using magnetometer and accelerometer. AB - BACKGROUND: Sun salutation is a part of yoga. It consists of a sequence of postures done with synchronized breathing. The practice of few cycles of sun salutation is known to help in maintaining good health and vigor. The practice of sun salutation does not need any extra gadgets. Also it is very much aerobic and invigorates the body and the mind. sun salutation, which comprises 10 postures, involves most of the joints of the body. Understanding the transition phase during motion is a challenging task, and thus, new convenient methods need to be employed. AIMS: The purpose of this study was to get an insight into the motion analysis of sun salutation during the transition from each of the 10 postures. MATERIALS AND METHODS: A device MicroStrain sensor 3DM-GX1, which is a combination of magnetometers, accelerometers, and gyroscopes was used to measure the inclination and the acceleration of the body along the three axes. The acceleration obtained was then separated into gravitational and kinematic components. RESULTS AND CONCLUSIONS: The value of the gravitational component helps us to understand the position of the body and the kinematic component helps us to analyze the grace of the motion. PMID- 20842267 TI - Normative data for the digit-letter substitution task in school children. AB - BACKGROUND/AIMS: To establish the norms for the substitution task, a measure of psychomotor performance. MATERIALS AND METHODS: Eight hundred and forty three school students were selected in the present study aged between 9-16 years (mean age = 12.14; SD = 1.77). Subjects were assessed one at a time for Digit-Letter Substitution Task (DLST). RESULTS: Both age and sex influenced performance on the DLST; therefore, correction scores were obtained on the basis of these factors. CONCLUSIONS: The availability of the Indian normative data for the DLST will allow wider application of this test in clinical practice. PMID- 20842268 TI - Effects of yoga on symptom management in breast cancer patients: A randomized controlled trial. AB - OBJECTIVES: This study compares the effects of an integrated yoga program with brief supportive therapy on distressful symptoms in breast cancer outpatients undergoing adjuvant radiotherapy. MATERIALS AND METHODS: Eighty-eight stage II and III breast cancer outpatients were randomly assigned to receive yoga (n = 44) or brief supportive therapy (n = 44) prior to their radiotherapy treatment. Intervention consisted of yoga sessions lasting 60 min daily while the control group was imparted supportive therapy once in 10 days during the course of their adjuvant radiotherapy. Assessments included Rotterdam Symptom Check List and European Organization for Research in the Treatment of Cancer-Quality of Life (EORTC QoL C30) symptom scale. Assessments were done at baseline and after 6 weeks of radiotherapy treatment. RESULTS: A GLM repeated-measures ANOVA showed a significant decrease in psychological distress (P = 0.01), fatigue (P = 0.007), insomnia (P = 0.001), and appetite loss (P = 0.002) over time in the yoga group as compared to controls. There was significant improvement in the activity level (P = 0.02) in the yoga group as compared to controls. There was a significant positive correlation between physical and psychological distress and fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, and constipation. There was a significant negative correlation between the activity level and fatigue, nausea and vomiting, pain, dyspnea, insomnia, and appetite loss. CONCLUSION: The results suggest beneficial effects with yoga intervention in managing cancer-and treatment-related symptoms in breast cancer patients. PMID- 20842270 TI - Engaging children, youth and families - more than a good idea. PMID- 20842269 TI - Forward. PMID- 20842271 TI - Creating a provincial family council to engage youth and families in child & youth mental health systems. AB - OBJECTIVE: To create a mechanism in British Columbia (BC) for youth and families to directly engage with key provincial committees that develop policy and implement service delivery for child and youth mental health. METHOD: In 2009, a plan was initiated to increase the involvement and influence of youth and families in research, policy, practices and programs related to child and youth mental health. This initiative, led by a provincial family advocacy society in partnership with representatives from health services and government, resulted in the establishment of the Provincial Family Council for Child and Youth Mental Health (PFC). Formation of the PFC occurred in two phases: initially, a Working Group co-chaired by a parent and a youth was tasked with developing the Terms of Reference and framework for the PFC; phase two involved ensuring important constituencies/demographics and competencies were represented in the membership of the PFC. RESULT: The Provincial Family Council is officially endorsed by the provincial government and is informing key provincial committees in British Columbia. CONCLUSION: In BC, the PFC is the vehicle through which youth and families can now work in partnership with "the system" to promote and improve the mental health of BC's children and youth. PMID- 20842272 TI - Family-driven care in america: more than a good idea. AB - OBJECTIVES: This paper will provide a history of how family-driven care has evolved in the United States. METHODS: Several examples of family-driven care including the National Policy Academy led by the Federation of Families for Children's Mental Health, the Jefferson County Kentucky's Parent Advocacy Program, and the Family Ties Resource Centers in Westchester, New York, and the 2009 American Academy of Child and Adolescent Psychiatry's Policy Statement are used to illustrate the development of family-driven care. RESULTS: In the past twenty-five years the mental health field has shifted from viewing parents as the cause of their child's issues to active participants in treatment and active participants in policy development and system reform efforts. Research shows that better outcomes are achieved when family members and youth have meaningful roles in their treatment. CONCLUSIONS: Family-driven care has advanced in the child and youth mental health system in America and next steps are needed to further develop the ability of families to become true partners in treatment planning, service and system development, enhance research as to the effectiveness of these activities and reform policies and practices to reflect needs of families. PMID- 20842274 TI - Before and after conception . . . Engaging parents of today and parents of tomorrow. AB - OBJECTIVE: This paper describes a unique relationship and engagement of a leading NGO Family Organization (The FORCE); a highly respected and extensively distributed magazine directed towards parents (Today's Parent) and an academic institution (The Sun Life Financial Chair in Adolescent Mental Health: Dalhousie University and the IWK Health Center in a project that was able to take the national pulse of parent perspectives on child and youth mental health. METHOD: A survey was co-created by parents, academia and media and went live in June 2009 on the Today's Parent website. Such a survey had not been done before. RESULTS: The national survey resulted in a response from almost 4,500 parents. Some of the preliminary findings included: parents do think about mental health concerns of children, including parents of children who don't have any problems and it is often media coverage often prompts parents to think about these issues. One quarter of the respondents were not aware of mental health programs and services for children and youth in their community. Many families waited for more than a year to obtain services. The respondents believed that schools should become more active in addressing mental health needs for children and youth. CONCLUSION: Partnerships involving parent organizations, media and academia have the potential to collaboratively develop processes and methods that can provide a unique window on how to understand various aspects of child and youth mental health. Such partnerships should be considered for future research and information gathering activities. PMID- 20842275 TI - Engaging families in research to determine health literacy needs related to the use of second-generation antipsychotics in children and adolescents. AB - OBJECTIVES: We sought to engage parents and caregivers in research to understand their health literacy needs related to the use of second-generation antipsychotic medications (SGAs) in children and youth. METHODS: Two focus groups with a total of 14 participants were conducted in two distinct geographical regions of British Columbia. RESULTS: Participants expressed that they had numerous questions about the medications but had few reliable resources available to them. They currently obtain information from a wide variety of sources including: psychiatrists, pharmacy print-outs, pediatricians, other parents, the Internet, and books. They expressed a preference for information to be initially delivered verbally, on a 'one-to-one' basis by their medical professional (preferably psychiatrist, psychologist, pediatrician), and then supplemented by accessible, written- and video-reference materials that would also be available online from a single reputable source (e.g., BC Children's Hospital). The weight gain and other potential metabolic side effects were of great concern to parents. Educational resources that address healthy nutrition and promotion of physical activity need to address the specific issues that parents looking after children with mental health concerns face. CONCLUSIONS: Families are key partners in the management and treatment of child and adolescent psychiatric disorders. The findings from this study support the value of including the "family" voice in developing educational strategies related to medications such as SGAs. PMID- 20842273 TI - Engaging families into child mental health treatment: updates and special considerations. AB - OBJECTIVE: The current paper reviews recent findings regarding how to conceptualize engagement and factors influencing engagement, treatment attendance rates, and interventions that work. METHOD: Research related to the definition of engagement, predictors of engagement and treatment termination, attendance rates, and engaging interventions are summarized as an update to the McKay and Bannon (2004) review. RESULTS: Despite ongoing advances in evidence-based treatments and dissemination strategies, engaging families into mental health treatment remains a serious challenge. Within the last several years, a number of technological advances and interventions have emerged to address this problem. Families with children who present disruptive behavior challenges and symptoms of trauma are considered in terms of the unique barriers they experience regarding engagement in treatment. CONCLUSIONS: Potential solutions to increase treatment utilization and further research in this area are discussed. PMID- 20842277 TI - Interview with sir Michael rutter: interviewed by normand carrey, MD, june 9th 2010. PMID- 20842276 TI - Delayed diagnosis of Crohn's disease in an adolescent: psychiatric implications. PMID- 20842278 TI - Do Hospital and Community SSRI Usage Patterns in Children and Adolescents Match the Evidence? AB - OBJECTIVES: 1) To review SSRI prescribing patterns for children and adolescents in our hospital and provincial prescription database and 2) To evaluate whether prescribing practices are consistent with expectations, based on published evidence and practice recommendations. METHODS: A PubMed online search was conducted to obtain all randomized controlled trials assessing efficacy of SSRI use in children and adolescents. The inpatient hospital pharmacy database at BC Children's Hospital (BCCH) and the BC Pharmacare database were used to identify all unique patients (under 19 years of age) seen in the inpatient department of psychiatry at BCCH or as outpatients in the province of BC receiving SSRI prescriptions between 2005-2009. RESULTS: Fluoxetine, citalopram, escitalopram and sertraline have evidence supporting their efficacy in the treatment of depressive disorders. Fluoxetine, fluvoxamine, sertraline, paroxetine and venlafaxine have evidence for use in the treatment of anxiety disorders. Between 2005-2009, BCCH inpatient data revealed that fluoxetine is the most frequently prescribed SSRI, followed by citalopram, sertraline, fluvoxamine, venlafaxine, paroxetine and escitalopram. In the community outpatients, fluoxetine was most frequently prescribed SSRI followed by citalopram, venlafaxine, sertraline, paroxetine, fluvoxamine and escitalopram. CONCLUSIONS: Prescribing patterns for SSRIs at BC Children's Hospital are consistent with the available evidence in the pediatric population. Furthermore, with the exception of citalopram, provincial outpatient and inpatient prescriptions appear to follow published national guidelines. Hospital SSRI usage more closely reflects the available literature than outpatient community usage does. PMID- 20842279 TI - Explaining odds ratios. PMID- 20842280 TI - Revisiting duty hour restrictions: any evidence that patients have benefited? PMID- 20842281 TI - Management strategies for painful bladder syndrome. AB - Painful bladder syndrome/interstitial cystitis (PBS/IC) is a condition of chronic pelvic pain associated with irritative voiding symptoms. Management of PBS/IC has been a challenge for generations of physicians, owing to a lack of consensus on its definition, an incompletely understood pathophysiology, and numerous available therapies without high-quality evidence to guide their usage. This article reviews the most current conception of PBS/IC and data on effective treatments to recommend a management strategy. PMID- 20842282 TI - The role of in vitro directed chemotherapy in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) continues to be the most lethal gynecologic malignancy. Efforts to personalize chemotherapy treatments by utilizing in vitro tumor assays to predict chemotherapeutic response have been tested in both the primary and recurrent treatment setting. To date, several retrospective studies have suggested improved response rates to predicted chemotherapeutic agents. However, a prospective, controlled trial merely found equivalence between in vitro prediction and empirical treatment selection. This review summarizes the current data regarding in vitro directed chemotherapy in EOC. PMID- 20842283 TI - Hormonal contraceptive options for women with headache: a review of the evidence. AB - Migraine affects as many as 37% of reproductive-age women in the United States. Hormonal contraception is the most frequently used form of birth control during the reproductive years, and given the significant proportion of reproductive-age women affected by migraine, there are several clinical considerations that arise when considering hormonal contraceptives in this population. In this review, key differences among headache, migraine, and migraine with aura, as well as strict diagnostic criteria, are described. The recommendations of the World Health Organization and the American College of Obstetricians and Gynecologists regarding hormonal contraception initiation and continuation in women with these diagnoses are emphasized. Finally, information about the effect of hormonal fluctuations on headache is provided with recommendations regarding contraception counseling in patients who experience headache while taking hormonal contraception. PMID- 20842284 TI - HIV and Pregnancy in Resource-Poor Settings. AB - There are 33.4 million people living with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome. Globally, HIV/AIDS is the leading cause of death among women of reproductive age. In the United States and other developed countries, aggressive efforts to treat HIV-positive pregnant women with highly active antiretroviral therapy have decreased the maternal-to-child transmission (MTCT) from over 20% to less than 2%. However, in resource-poor settings, access to antiretroviral therapy (ART) is not readily available, and perinatal transmission rates remain as high as 45%. Women are at greater risk of heterosexual transmission of HIV, which is compounded by lack of condom use, imbalance of social power, and the high fertility rate. Prevention programs are needed to empower and educate women and engender community awareness for condom use. Prenatal screening and treatment, intrapartum ART, and postpartum prophylaxis must be made available to all women and children to prevent MTCT. PMID- 20842285 TI - Antioxidants and preeclampsia. PMID- 20842286 TI - Treatment for recurrent miscarriage. PMID- 20842287 TI - More breast screening data. PMID- 20842288 TI - Snippets. PMID- 20842289 TI - Eating in labor. PMID- 20842290 TI - The 5' regulatory sequence of the PMP22 in the patients with Charcot-Marie-Tooth disease. AB - Little is known about the molecular background of clinical variability of Charcot Marie-Tooth type 1A (CMT1A) disease and hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A and HNPP disorders result from duplication and deletion of the PMP22 gene respectively. In a series of studies performed on affected animal transgenic models of CMT1A disease, expression of the PMP22 gene (gene dosage) was shown to correlete with severity of CMT course (gene dosage effect). In this study we hypothesized that single nucleotide polymorphisms (SNPs) located within the 5' regulatory sequence of PMP22 gene may be responsible for the CMT1A/HNPP clinical variability. We have sequenced the PMP22 5' upstream regulatory sequence in a group of 45 CMT1A/HNPP patients harboring the PMP22 duplication (37) /deletion (8). We have identified five SNPs in the regulatory sequence of the PMP22 gene. Three of them i.e. -819C>T, -4785G>T, -4800C>T were detected both in the patients and in the control group. Thus, their pathogenic role in the regulation of the expression of the PMP22 gene seems not to be significant. Two SNPs i.e. -4210T>C and -4759T>A were found only in the CMT patients. Their role in the regulation of the PMP22 gene expression can not be excluded. Additionally we have detected the Thr118Met variant in exon 4 of the PMP22 gene, which was previously reported by other authors, in one patient. We conclude that the 5' regulatory sequence of the PMP22 gene is conserved at the nucleotiode level, however rarely occurring SNPs variant in the PMP22 regulatory sequence may be associated with the gene dosage effect. PMID- 20842291 TI - Regulation of sporulation in the yeast Saccharomyces cerevisiae. AB - Sporulation of the budding yeast Saccharomyces cerevisiae - equivalent to gametogenesis in higher organisms, is a complex differentiation program induced by starvation of cells for nitrogen and carbon. Such environmental conditions activate coordinated, sequential changes in gene expression leading to production of haploid, stress-resistant spores. Sporulation comprises two rounds of meiosis coupled with spore morphogenesis and is tightly controlled to ensure viable progeny. This review concerns the regulation of differentiation process by nutritional and transcriptional signals. PMID- 20842292 TI - Microbial transformation of citral by Penicillium sp.. AB - Thymol is present in the essential oils from herbs and spices, such as thyme. It is produced by these plant species as a chemical defense against phytopathogenic microorganisms. Therefore, this compound has attracted great attention in food industry, i.e., it has been used as a natural preservative in foods such as cheese to prevent fungal growth. Previous studies concerning the biotransformation of nerol by Penicillium sp. and microbial transformation of citral by sporulated surface cultures method (SSCM) of Penicillium digitatum have been reported. The objective of this research was to study the pathway involved during biotransformation of citral by Penicillium sp. using two methods. The culture preparation was done using different microbial methods and incubation periods to obtain Penicillium for citral biotransformation. The biotransformation products were identified by gas chromatography (GC) and gas chromatography/mass spectroscopy (GC/MS). A comparison of the two methods showed that SSCM was more effective, its major products were thymol (21.5 %), geranial (18.6 %) and nerol (13.7 %). LM produced only one compound - thymol - with a low efficiency. PMID- 20842293 TI - Functionalized Ni@SiO2 core/shell magnetic nanoparticles as a chemosensor and adsorbent for Cu2+ ion in drinking water and human blood. AB - Fluorogenic based nitrobenzofuran-functionalized Ni@SiO(2) core/shell magnetic nanoparticles have been prepared by sol-gel grafting reaction. Their ability to detect and remove metal ions was evaluated by fluorophotometry. The nanoparticles exhibited a high affinity and selectivity for Cu(2+) over competing metal ions. Furthermore, the nanoparticles efficiently removed Cu(2+) in drinking water and human blood. PMID- 20842294 TI - Nano-sized TiN on carbon black as an efficient electrocatalyst for the oxygen reduction reaction prepared using an mpg-C3N4 template. AB - The direct synthesis of TiN nanoparticles on carbon black (CB) was achieved using an mpg-C(3)N(4)/CB composite as a template. The obtained TiN/CB composites ensured improved contact between TiN and CB, functioning as an efficient cathode catalyst for oxygen reduction reaction (ORR) in polymer electrolyte fuel cells (PEFCs). The preparation procedure developed in this study is applicable for the synthesis of a variety of supported nano-nitride catalysts. PMID- 20842295 TI - New virial equation of state for hard-disk fluids. AB - Although many equations of state of hard-disk fluids have been proposed, none is capable of reproducing the currently calculated or estimated values of the first eighteen virial coefficients at the same time as giving very good accuracy when compared with computer simulation values for the compressibility factor over the whole fluid range. A new virial-based expression is here proposed which achieves these aims. For that, we use the fact that the currently accepted estimated values for the highest virial coefficients behave linearly with their order, and also that virial coefficients must have a limiting behaviour that permits the closest packing limit in the compressibility factor to be also adequately reproduced. PMID- 20842296 TI - Single-cell bacteria growth monitoring by automated DEP-facilitated image analysis. AB - Growth monitoring is the method of choice in many assays measuring the presence or properties of pathogens, e.g. in diagnostics and food quality. Established methods, relying on culturing large numbers of bacteria, are rather time consuming, while in healthcare time often is crucial. Several new approaches have been published, mostly aiming at assaying growth or other properties of a small number of bacteria. However, no method so far readily achieves single-cell resolution with a convenient and easy to handle setup that offers the possibility for automation and high throughput. We demonstrate these benefits in this study by employing dielectrophoretic capturing of bacteria in microfluidic electrode structures, optical detection and automated bacteria identification and counting with image analysis algorithms. For a proof-of-principle experiment we chose an antibiotic susceptibility test with Escherichia coli and polymyxin B. Growth monitoring is demonstrated on single cells and the impact of the antibiotic on the growth rate is shown. The minimum inhibitory concentration as a standard diagnostic parameter is derived from a dose-response plot. This report is the basis for further integration of image analysis code into device control. Ultimately, an automated and parallelized setup may be created, using an optical microscanner and many of the electrode structures simultaneously. Sufficient data for a sound statistical evaluation and a confirmation of the initial findings can then be generated in a single experiment. PMID- 20842297 TI - Supramolecular gold nanoparticle-polymer composites formed in water with cucurbit[8]uril. AB - A gold nanoparticle-polymer composite material has been prepared in water using cucurbit[8]uril as a supramolecular "handcuff" to hold together viologen functionalised gold nanoparticles and a naphthol-functionalised acrylamide copolymer. PMID- 20842298 TI - Left-handed DNA: intercalation of the cyanine thiazole orange and structural changes. A kinetic and thermodynamic approach. AB - The conditions under which different structures of left-handed DNA (poly(dG me(5)dC).poly(dG-me(5)dC)) can exist are investigated by spectrofluorometric, spectrophotometric, circular dichroism and calorimetric measurements and the kinetics of the transformations are analysed. The effects of temperature, salt and ethanol content on the transitions are also studied. The left-handed structure obtained by addition of either Mg(2+) ions or EtOH corresponds to Z DNA, whereas the structure obtained using the mixture Mg(2+)/EtOH corresponds to the aggregate Z*-DNA. Upon addition of the fluorescent cyanine Thiazole Orange (TO), the transition Z -> B immediately starts, whereas Z*-DNA retains its left handed configuration in the presence of TO provided that the ratio [dye]/[polymer] <= 0.1. The equilibria and kinetics of the TO binding to Z*-DNA are investigated under the above conditions using the T-jump technique. The reaction mechanism consists of two series steps, the first one being characterized by the formation of an external electrostatic complex and the second corresponding to the dye penetration between the base pairs. A comparison with the B-DNA/TO system is drawn. PMID- 20842299 TI - Synthesis and characterisation of alkylaluminium benzimidazolates and their use in the ring-opening polymerisation of epsilon-caprolactone. AB - The stoichiometric reactions of 2-(benzimidazol-2-yl)-6-methylpyridine (L1) or 8 (benzimidazol-2-yl)quinaldine (L2) with trialkylaluminium reagents R(3)Al (R = Me, Et and iBu) afforded the corresponding dialkylaluminium benzimidazolate complexes R(2)AlL (L1, R = Me (1), Et (2), iBu (3); L2 R = Me (4), Et (5), iBu (6)). Treatment of L1 with one or two equivalents of Et(2)AlCl led to the adducts EtAl(L1)(2).AlEtCl(2) (7) or Et(2)AlL1.AlEtCl(2) (8), respectively. Complex 7 was also available via treatment of 8 with one equivalent of L1. Reaction of L1 with two equivalents of AlR(3) (R = Me or Et) afforded R(2)AlL1.AlR(3) (R = Me, 9; R = Et, 10), which were also formed when 1 or 2 were reacted with AlR(3). Reaction of L2 with two equivalents of AlR(3) (R = Me or Et) gave the complexes R(2)AlL2.AlR(3) (R = Me, 11; R = Et, 12), which were also formed in the stoichiometric reaction of 4 or 5 with AlR(3) (R = Me or Et). Screening of these complexes in the presence of BnOH, for the ring-open polymerisation of epsilon caprolactone, revealed appreciable activities. Only the aluminium compounds ligated by 2-(benzimidazol-2-yl)-6-methylpyridine maintained high activity in the absence of BnOH. In all cases, polymers with bi- or multi-modal characteristics were produced. PMID- 20842301 TI - A novel electrochemiluminescence immunosensor via polymerization-assisted amplification. AB - A novel electrochemiluminescent immunosensor with polymerization-assisted signal amplification has been developed and enhanced sensitivity was achieved by increasing tertiary amine loading on polymers. PMID- 20842300 TI - First synthesis, characterization, and evidence for the presence of hydroxycinnamic acid sulfate and glucuronide conjugates in human biological fluids as a result of coffee consumption. AB - A systematic investigation of the human metabolism of hydroxycinnamic acid conjugates was carried out. A set of 24 potential human metabolites of coffee polyphenols has been chemically prepared, and used as analytical standards for unequivocal identifications. These included glucuronide conjugates and sulfate esters of caffeic, ferulic, isoferulic, m-coumaric and p-coumaric acids as well as their dihydro derivatives. A particular focus has been made on caffeic and 3,4 dihydroxyphenylpropionic acid derivatives, especially the sulfate conjugates, for which regioselective preparation was particularly challenging, and have so far never been identified as human metabolites. Ten out of the 24 synthesized conjugates have been identified in human plasma and/or urine after coffee consumption. A number of these conjugates were synthesized, characterized and detected as hydroxycinnamic acid metabolites for the first time. This was the case of dihydroisoferulic acid 3'-O-glucuronide, caffeic acid 3'-sulfate, as well as the sulfate and glucuronide derivatives of 3,4-dihydroxyphenylpropionic acid. PMID- 20842302 TI - Zirconocene complexes bearing novel 3-dimethylamino-1,2-dihydropentalene derived ligand systems. AB - Coupling of the N,N-dimethylacrylamides 6a-c with cyclopentadienide resulted in the formation of the substituted 3-dimethylamino-1,2-dihydropentalnenes 2a-c. Deprotonation followed by metallation with CpZrCl(3).DME gave the substituted zirconocenes 12a-c. The reaction of 3-dimethylamino-1-methyl-dihydropentalene 2a with ZrCl(2)(NMe(2))(2).2THF resulted in a unique coupling between a pair of the aminodihydropentalene derivatives to yield an unsymmetrically bridged novel ansa zirconocene framework (9a). Treatment of the 1,1-dimethyl-substituted substrate 2b with this Zr-amido reagent in contrast resulted in a clean deprotonation and formation of the unbridged bis(dimethylaminohydropentalenyl)ZrCl(2) complexes 10b. The compounds 2a, 9a, meso-10b, 12a and 12c were characterized by X-ray diffraction. PMID- 20842303 TI - Mechanisms of solute rejection in solvent resistant nanofiltration: the effect of solvent on solute rejection. AB - The separation performance of solvent resistant nanofiltration (SRNF) membranes was studied in a systematic way to elucidate the complex mechanisms involved in rejection of solutes. Rejection of three dyes (Sudan II, Sudan Black, Sudan 408) from common organic solvents (methanol, ethanol, acetone, methyl ethyl ketone, toluene and n-hexane) through a polyimide based SRNF membrane, STARMEMTM122, was studied. It was found that the rejection of the STARMEMTM122 membrane was lower than that indicated by the manufacturer. The experimental observations for Sudan II were not promising for the rejection study as they were lower than expected. Sudan Black and Sudan 408, which are larger solutes than Sudan II, provided more interesting insights. The effects of the solvent on the membrane and solute were studied separately. A higher permeation rate of ketones and alcohols was observed, while permeabilities of non-polar solvents were low which shows that this membrane shows higher affinity toward semi-polar solvents (alcohols, ketones). The effect of the solvent on the solute's rejection, based on the results for Sudan Black and Sudan 408, was studied for solvents in the same chemical groups, since the membrane showed a similar separation performance for solvents with similar functional groups (e.g. alcohols). The effect of solvent on solute molecular size was investigated by using simulation with Molecular Dynamics. It was shown that the effective size of a molecule is dependent on the solvent due to solvation and hydration of the solute by the solvent. The size of the solute in the solvent belonging to a similar family was studied separately. It was clear that the rejection was influenced by molecular size of the solute in the same group of solvents. A surprising negative rejection of solutes was achieved for n-hexane. Although solutes in n-hexane have higher volume compared to those in other solvents, the affinity between the solute and membrane increases the solute permeation in the presence of n-hexane. The affinity of solvent and solute for the membrane was investigated by means of solubility parameters for solvents within the same chemical family. In two different systems including two different solvents and one solute (Sudan Black and methanol, Sudan Black and ethanol), lower rejection (in this case for Sudan Black and methanol) was achieved when the solutes have higher affinity toward the solvent. Finally, it was found that in a system comprising the solvent, solute and membrane, interactions between solvent and membrane have much more effect on separation than solvent-solute interactions. PMID- 20842304 TI - Thermal spin-crossover in the [M(3)Zn(6)Cl(6)L(12)] (M = Zn, Fe(II); L = 5,6 dimethoxy-1,2,3-benzotriazolate) system: structural, electrochemical, Mossbauer, and UV-Vis spectroscopic studies. AB - Fusion of pentanuclear Kuratowski-type coordination units leads to homo- and heterononanuclear coordination compounds, two of which are presented, having structural formulae [Zn(9)Cl(6)(OMe(2)bta)(12)].DMF (1), and [Fe(II)(3)Zn(6)Cl(6)(OMe(2)bta)(12)].DMF (2), respectively; (OMe(2)btaH = 5,6 dimethoxy-1,2,3-benzotriazole; DMF = N,N'-dimethylformamide). Single crystal X ray structure analyses reveal the presence of {M(3)Zn(6)L(12)}(6+) cores (M = Zn or Fe(II); L = 5,6-dimethoxy-1,2,3-benzotriazolate) in which the M(II) ions are bridged by MU(3)-OMe(2)bta ligands. In both compounds, the six peripheral Zn ions are tetracoordinated, whereas the remaining three metal ions M are hexacoordinated. The charge of each {M(3)Zn(6)L(12)}(6+) moiety is balanced by six chloride anions that are monodentately bound to the peripheral Zn ions. Based on differences in experimental Fe-N-donor bond lengths (deduced from single crystal data of 2 recorded at 223 K), two out of three Fe(II) ions are found in a high-spin (HS) state, whereas one Fe(II) ion shows a low-spin (LS) state. The assignment of different energetic ground states of Fe(II) ions is corroborated by spectroscopic studies: Both solid-state and solution UV-Vis spectra of 2 (at ambient temperature) display absorption bands owing to the presence of both HS and LS Fe(II) ions. Removal of occluded DMF molecules from the crystal lattices of 1 and 2 in high vacuum leads to fully desolvated powders, termed hereafter 1a and 2a, respectively. Mossbauer studies on 2a show that all three Fe(II) ions are in HS state at 160 K, and upon cooling to 7 K, the central Fe(II) ion undergoes a HS->LS transition while the HS states of the other Fe(II) ions remains unchanged. The cyclic voltammogram of 2 (chloroform solution) exhibits a single reversible oxidation regardless of different Fe(II) spin states in the nonanuclear core of 2. PMID- 20842305 TI - Synthesis of sterically encumbered 2,4-bis-m-terphenyl-1,3-dichloro-2,4-cyclo dipnictadiazanes [m-TerNPnCl](2), (Pn = P, As). AB - The reaction of m-terphenyl amine (2,6-bis-(2,4,6-trimethylphenyl)aniline, m-Ter = m-terphenyl = 2,6-bis-(2,4,6-trimethylphenyl)) and ECl(3) (E = P, As) in the presence of different bases (Et(3)N, n-BuLi, LDA, DBU) and under different reaction conditions was studied. The reaction with excess Et(3)N yielded m-Ter N(H)-AsCl(2) for E = As, while for E = P m-Ter-N(PCl(2))(2) was formed. m-Ter N(H)-ECl(2) was obtained in the reaction of m-terphenyl amine with n-BuLi and ECl(3) for E = As and P. Further treatment of m-Ter-N(H)-PCl(2) with Et(3)N led to the formation of 1,3-dichloro-cyclo-1,3-diphospha-2,4-diazane, a synthesis protocol which cannot be applied to the analogous arsenic species. 1,3-dichloro cyclo-1,3-diarsa-2,4-diazane was isolated when DBU was added to m-Ter-N(H) AsCl(2) at low temperature (-80 degrees C). PMID- 20842306 TI - Complexation of NpO(2)(+) with N-methyl-iminodiacetic acid: a comparison with iminodiacetic and dipicolinic acids. AB - Complexation of Np(v) with N-methyl-iminodiacetic acid (MIDA) in 1 M NaClO(4) solution was studied with multiple techniques including potentiometry, spectrophotometry, and microcalorimetry. The 1 : 2 complex, NpO(2)(MIDA)(2)(3-) was identified for the first time in aqueous solution. The correlation between its optical absorption properties and symmetry was discussed, in comparison with Np(v) complexes with two structurally related nitrilo-dicarboxylic acids, iminodiacetic acid (IDA) and dipicolinic acid (DPA). The order of the binding strength (DPA > MIDA > IDA) is explained by the difference in the structural and electronic properties of the ligands. In general, the nitrilo-dicarboxylates form stronger complexes with Np(v) than oxy-dicarboxylates due to a much more favorable enthalpy of complexation. PMID- 20842307 TI - DNA hybridization mechanism on silicon nanowires: A molecular dynamics approach. AB - We report on a computational study of DNA detection systems, based on the hybridization between a DNA target, present in solution, and its complementary probe tethered to a solid support. Classical all-atom molecular dynamics were used to simulate the association process and to fully characterize the motion of the formed duplex. The hybridization event starts with a random collision, controlled by diffusion. Subsequently, the resulting complex evolves in a few nanoseconds towards the final duplex, the latter being stable for the rest of the simulation time (70 ns). The complex adopted upright and tilted orientations, with respect to the functionalized layer, sometimes reaching it at hydrogen bonding distance. Although the duplex conformation fluctuated for the entire run, it remained close to a B-like structure. PMID- 20842308 TI - Recent advancements in boron nitride nanotubes. AB - This article provides a concise review of the recent research advancements in boron nitride nanotubes (BNNTs) with a comprehensive list of references. As the motivation of the field, we first summarize some of the attractive properties and potential applications of BNNTs. Then, latest discoveries on the properties, applications, and synthesis of BNNTs are discussed. In particular, we focus on low-temperature and patterned growth, and mass production of BNNTs, since these are the major challenges that have hindered investigation of the properties and application of BNNTs for the past decade. Finally, perspectives of future research on BNNTs are discussed. PMID- 20842309 TI - Aqueous solution synthesis of SnO nanostructures with tuned optical absorption behavior and photoelectrochemical properties through morphological evolution. AB - We have studied the aqueous solution synthesis of divalent tin oxide (SnO) nanostructures, changes in their optical absorption behavior, and their photoelectrochemical properties. A number of SnO nanostructures including sheets and wires, and their composite morphologies were obtained in aqueous solution containing urea at low temperatures. Parallel control of both oxidation state and morphology was achieved through the urea-mediated solution process. Nanoscale morphological variation facilitated changes in optical absorption behavior and the generation of a photocurrent. As for the nanostructured SnO, the absorption of visible light decreased and absorption in UV region increased. In contrast, bulk black SnO crystals showed strong absorption over the entire range of UV to visible light. A photocurrent was generated from the SnO nanostructures with irradiation of UV and visible light. PMID- 20842310 TI - Differentiation of photocycle characteristics of flavin-binding BLUF domains of alpha- and beta-subunits of photoactivated adenylyl cyclase of Euglena gracilis. AB - Photoactivated adenylyl cyclase (PAC), an FAD-containing photoreceptor of Euglena gracilis, appears to be a heterotetrameric structure composed of 2 homologous subunits (PACalpha and PACbeta), each with a pair of BLUF domains (F1 and F2). PAC promotes blue light-induced activation of adenylyl cyclase. In our previous report, we demonstrated that a recombinant version of the PACalphaF2 domain displays blue light-induced photocycle similar to those of prokaryotic BLUFs (Ito et al., Photochem. Photobiol. Sci., 2005, 4, 762-769). Here, we further examine the recombinant PACbetaF2 domain, which like PACalphaF2 exhibits a blue light induced photocycle. The estimated quantum efficiency for the phototransformation of PACbetaF2 was 0.06-0.08, and the half-life for dark relaxation was 3-6 s while the corresponding values for the PACalphaF2 were 0.28-0.32 and 34-44 s. The remarkable differences between PACalphaF2 and PACbetaF2 may be related to the sensitivity of the photoactivation. In PACalphaF2, amino acid position 556, which is equivalent to Trp104 in the BLUF domain of the purple bacterial AppA protein, is occupied by a Leu residue, while in PACbetaF2 the equivalent BLUF domain site is conserved as Trp560. Amino acid substitution at this site in PACbetaF2 Trp560Leu markedly increased the estimated quantum efficiency (0.23) and accelerated the half-life of the dark-relaxation (2 s). These results indicate that Trp560 in PACbetaF2 plays a main role in suppressing the quantum efficiency. PMID- 20842311 TI - Multiple functions of Schiff base counterion in rhodopsins. AB - In rhodopsins, visible-light absorption is achieved by the protonation of the chromophore Schiff base. The Schiff base proton is stabilized by the negative charge of an amino acid residue called the Schiff base counterion. Since E113 was identified as the counterion in bovine rhodopsin, there has been growing evidence that the counterion has multiple functions besides proton stabilization. Here, we first introduce generally accepted findings as well as some controversial theories about the identity of the Schiff base counterion in the dark and in intermediate states and then review multiple functions of the counterion in vertebrate visual pigments. Special focus is placed on the recently demonstrated role in photoisomerization efficiency. Finally, differences in the position of the counterion between vertebrate visual pigments and other opsins and its relevance to the molecular evolution of opsins are discussed. PMID- 20842312 TI - Sirtuin mechanism and inhibition: explored with N(epsilon)-acetyl-lysine analogs. AB - Silent information regulator 2 (Sir2) enzymes or sirtuins are a family of intracellular protein deacetylases that can catalyze the beta-nicotinamide adenine dinucleotide (beta-NAD(+))-dependent deacetylation of N(epsilon)-acetyl lysine on protein substrates, with the formation of lysine N(epsilon) deacetylated protein species and small molecule products, i.e. nicotinamide and 2'-O-acetyl-ADP-ribose (2'-O-AADPR). These enzymes are evolutionarily conserved among all the three kingdoms of life, with the yeast Sir2 being the founding family member. In humans, seven sirtuins, i.e. SIRT1-7, have been identified. The past a few years have witnessed a tremendous interest in investigating the unique mechanism for the sirtuin-catalyzed deacetylation reaction. We have also seen a lot of research employing different strategies to identify different types of the inhibitors for this enzymatic deacetylation reaction. These inhibitors hold great potential toward a fuller exploration of sirtuin biology and pharmacology as well as toward developing novel therapeutics for metabolic and age-related diseases and cancer. Here we would like to review the significant contributions that the judicious use of a variety of N(epsilon)-acetyl-lysine analogs has been able to make toward our enhanced mechanistic understanding and capability of pharmacological exploitation of the sirtuin-catalyzed deacetylation reaction. PMID- 20842313 TI - Comparison of soil phosphorus tests for assessing plant availability of phosphorus in an ultisol amended with water-soluble and phosphate rock sources. AB - The effectiveness of different soil tests in assessing soil phosphorus (P) in soils amended with phosphate rocks (PRs) is uncertain. We evaluated the effects of triple superphosphate (TSP) and PRs on extractable P by conventional soil tests (Mehlich 3 [Meh3] and Bray-1 [B1]) and a nonconventional test (iron oxide impregnated paper, strip). Extracted amounts of P were in the order: Meh3 >B1 > strip. All the tests were significantly correlated (p = 0.001). Acidic reagents extracted more P from TSP than PRs, while the strip removed equal amounts from the two sources. The P removed by the three tests was related significantly to dry matter yield (DMY), but only in the first harvest, except for B1. Established critical P levels (CPLs) differed for TSP and PRs. In PR-fertilized soils, CPLs were 27, 17, and 12 mg P kg(-1) soil for Meh3, B1, and strip, respectively, and 42, 31, and 12 mg P kg(-1) soil, respectively, in TSP-fertilized soils. Thus, the strip resulted in a common CPL for TSP and PRs (12 mg P kg(-1) soil). This method can be used effectively in soils where integrated nutrient sources have been used, but there is need to establish CPLs for different crops. For cost-effective fertilizer P recommendations based on conventional soil tests, there is a need to conduct separate calibrations for TSP- and PR-fertilized soils. PMID- 20842314 TI - Examination of Chinese gambling problems through a socio-historical-cultural perspective. AB - The aim of this review is to highlight emerging trends about Chinese people and gambling addiction over the last 15 years, and to provide a discourse on the potential link between gambling and Chinese culture and history. The authors reported on the phenomenon of gambling among Chinese people using relevant research studies and reports and traditional Chinese literature. Chinese people have elevated levels of gambling addiction compared to their Western counterparts. These elevated rates are coupled with the rapid expansion of gambling venues within the Pan-Pacific region. While there is an accumulated body of research on Chinese and gambling, a systematic cultural analysis of Chinese gambling is still under development. We undertook a brief comparison between two ancient civilizations, China and Rome, in order to gain better understanding about gambling among Chinese people. To effectively deal with gambling addictions among Chinese people, it is imperative to develop culturally responsive interventions. PMID- 20842315 TI - Dermoscopy of tick bite. AB - A 54-year-old woman presented with a 12-h history of the appearance of numerous, intensively pruritic, erythematous papules on her trunk. Dermoscopy showed the presence of small-sized ticks in the majority of lesions. By using medium-tipped, angled forceps, 28 ticks were finally removed. The application of dermoscopy to detect the tick in the lesion is easy, inexpensive, and effective for confirming the diagnosis. PMID- 20842316 TI - Ureteral obstruction by the vas deferens after urostomy. AB - A male patient with spina bifida and paraplegia, born in 1968, underwent urostomy in 1973. In 1999, he developed urine infections. Intravenous urography showed bilateral hydronephrosis and hydroureter. This patient continued to get recurrent urine infections. In 2009, computed tomography of the abdomen revealed dilatation of the ureters, but the ureters reverted to normal calibre as they passed forward through the anterior abdominal wall. The vas deferens on either side was crossing and kinking the ureter. Magnetic resonance imaging of the abdomen confirmed that the level of obstruction in both ureters was at the site where the vas deferens crossed the ureter and kinked it. While performing urostomy, the ureters below the crossover by the vas deferens were detached from the bladder and attached to the skin for urinary diversion, thus causing the vas deferens to hook the lower end of the ureters. As the patient gained height and weight, thereby increasing abdominal girth, kinking of the ureters by the vas deferens was accentuated. In hindsight, bilateral midline cutaneous urostomy using the ureters below the crossover by the vas deferens represents a poor surgical technique for urinary diversion. PMID- 20842317 TI - Endometrioid adenocarcinoma in the native ureter of a renal transplant patient: case report and review of the literature. AB - Endometriosis is characterized by endometrial-like tissue outside the uterus, primarily on the pelvic peritoneum, ovaries, and rectovaginal septum, and, in rare cases, within the urinary tract (1-3%). Although endometriosis is a benign condition, malignant transformation of endometriosis is a well-described phenomenon. Malignancies arising in endometriosis are uncommon at extragonadal pelvic sites. A case of endometrioid adenocarcinoma in the native ureter of a postmenopausal renal transplant patient presented with painless gross hematuria and hydroureteronephrosis. The patient had a history of total abdominal hysterectomy and bilateral salpingo-oophrectomy 14 years prior for menorrhagia and had since been on unopposed estrogen replacement therapy. Workup revealed a filling defect in the native left mid-ureter secondary to a large 2.5-cm ureteral tumor. Endoscopic biopsies of the native left ureteral mass showed endometrioid adenocarcinoma, grade II-III. The patient ultimately underwent an open native left nephroureterectomy and temporary diverting colostomy. Final pathology confirmed endometrioid adenocarcinoma, grade II-III, arising in a background of endometriosis with negative perirectal lymph nodes. This case of ureteral endometrioid adenocarcinoma highlights the importance of obtaining a careful history and maintaining a high index of suspicion for malignant degeneration, especially in the context of hyperestrogenism. PMID- 20842318 TI - Synthesis, cytotoxicity, and antileishmanial activity of N,N'-disubstituted ethylenediamine and imidazolidine derivatives. AB - This paper describes the preparation of N,N'-disubstituted ethylenediamine and imidazolidine derivatives and their in vitro biological activities against Leishmania species. Of the nine synthesized compounds, five displayed a good activity in both L. amazonensis and L. major promastigotes. The compounds 1,2 Bis(p-methoxybenzyl) ethylenediamine (4) and 1,3-Bis(p methoxybenzyl)imidazolidines (5) showed the best activity on intracellular amastigotes, with IC50 values of 2.0 and 9.4 microgram/mL, respectively. In addition, none of compounds were cytotoxic against mammalian cells. The leishmanicidal activity can be related with inhibition of polyamine synthesis and cellular penetration within biological membranes. PMID- 20842319 TI - Role of neutrophil apoptosis in the resolution of inflammation. AB - Neutrophil granulocytes play a central role in host defense to infection and tissue injury. Their timely removal is essential for resolution of inflammation. Increasing evidence identified neutrophil apoptosis as an important control point in the development and resolution of inflammation. Delayed apoptosis and/or impaired clearance of neutrophils aggravate and prolong tissue injury. This review will focus on outside-in signals that provide survival cues for neutrophils, the hierarchy of pro- and antiapoptotic signals, and molecular targets in the antiapoptotic signaling network that can be exploited by endogenously produced bioactive lipids, such as lipoxins or pharmacological inhibitors, including cyclin-dependent kinase inhibitors, to redirect neutrophils to apoptosis in vivo, thus promoting resolution of inflammation. PMID- 20842320 TI - Multiple roles of the Y chromosome in the biology of Drosophila melanogaster. AB - The X and Y chromosomes of Drosophila melanogaster were the first examples of chromosomes associated with genetic information. Thanks to the serendipitous discovery of a male with white eyes in 1910, T.H. Morgan was able to associate the X chromosome of the fruit fly with a phenotypic character (the eye color) for the first time. A few years later, his student, C.B. Bridges, demonstrated that X0 males, although phenotypically normal, are completely sterile. This means that the X chromosome, like the autosomes, harbors genes that control several phenotypic traits, while the Y chromosome is important for male fertility only. Notwithstanding its long history--almost 100 years in terms of genetic studies- most of the features of the Y chromosome are still a mystery. This is due to the intrinsic nature of this genetic element, namely, (1) its molecular composition (mainly transposable elements and satellite DNA), (2) its genetic inertia (lack of recombination due to its heterochromatic nature), (3) the absence of homology with the X (with the only exception of the nucleolar organizer), (4) the lack of visible phenotypes when it is missing (indeed, except for their sterility, X0 flies are normal males), and (5) its low density as for protein-coding sequences (to date, only 13 genes out of approximately 14,000 have been mapped on this chromosome in D. melanogaster, i.e., ~0.1% of the total). Nonetheless, a more accurate analysis reveals that this chromosome can influence several complex phenotypes: (1) it has a role in the fertility of both sexes and viability of males when over-represented; (2) it can unbalance the intracellular nucleotide pool; (3) it can interfere with the gene expression either by recruiting proteins involved in chromatin remodeling (PEV) or, to a higher extent, by influencing the expression of up to 1,000 different genes, probably by changing the availability of transcription factors; (4) it plays a major role (up to 50%) in the resistance to heat-induced male sterility; (5) it affects the behavior; and (6) it plays a role in genetic imprinting. In the present paper, all these Y-related phenotypes are described and a potential similarity with the human Y chromosome is drawn. PMID- 20842321 TI - Role of adenosine A(2A) receptors in modulating synaptic functions and brain levels of BDNF: a possible key mechanism in the pathophysiology of Huntington's disease. AB - In the last few years, accumulating evidence has shown the existence of an important cross-talk between adenosine A(2A) receptors (A(2A)Rs) and brain derived neurotrophic factor (BDNF). Not only are A(2A)Rs involved in the mechanism of transactivation of BDNF receptor TrkB, they also modulate the effect of BDNF on synaptic transmission, playing a facilitatory and permissive role. The cAMP-PKA pathway, the main transduction system operated by A(2A)Rs, is involved in such effects. Furthermore, a basal tonus of A(2A)Rs is required to allow the regulation of BDNF physiological levels in the brain, as demonstrated by the reduced protein levels measured in A(2A)Rs KO mice. The crucial role of adenosine A(2A)Rs in the maintenance of synaptic functions and BDNF levels will be reviewed here and discussed in the light of possible implications for Huntington's disease therapy, in which a joint impairment of BDNF and A(2A)Rs seems to play a pathogenetic role. PMID- 20842323 TI - Co-morbidities of COPD in primary care: frequency, relation to COPD, and treatment consequences. AB - INTRODUCTION: In the Western world, chronic obstructive pulmonary disease (COPD) is predominantly caused by long-term smoking, which results in pulmonary inflammation that is often associated with systemic inflammation. A number of co morbid conditions, such as cardiovascular disease, muscle wasting, type 2 diabetes and asthma, may coexist with COPD; these and other co-morbidities not directly related to COPD are major causes of excess morbidity and mortality. AIM: This review sets out to explore the most frequent co-morbidities in COPD and their implications for treatment. METHOD: Review of the literature on co morbidities of COPD. RESULTS: Co-morbidities are frequent, but often remain undiagnosed in the COPD patient. In order to provide the best possible care for people with COPD, the physician should be aware of all potential co-morbidities that may arise, and the critical role that effective management of these co morbidities can play in improving patient outcomes. CONCLUSIONS: Increased awareness of the potential co-morbidities of COPD, although potentially adding to the general practitioner's work burden, may provide insights into this difficult disease state and possibly improve each individual's prospects for effective management. PMID- 20842324 TI - Acute respiratory illness as a trigger for detecting chronic bronchitis in adults at risk of COPD: a primary care survey. AB - AIM: To evaluate the impact of chronic bronchitis in patients identified among subjects at risk of chronic obstructive pulmonary disease (COPD) but currently free from any known chronic respiratory disorder, visiting a general practitioner for an acute respiratory episode. METHOD: A multicentre, cross-sectional survey carried out in primary care. RESULTS: Primary care practitioners (n = 772) examined 14,030 patients with acute cough (male: 56.9%, age 50.6 +/- 16.5 years). Of these, 3,615 were at risk of COPD (> 40 years and tobacco use > 10 pack-years) and constituted the study population: 79.8% reported current symptoms of chronic bronchitis. Compared to patients without chronic bronchitis, they were older, more frequently exposed to occupational pollutants or to passive smoking, had more tobacco use (p < 0.001), reported dyspnoea > Grade 2 more frequently, and had poorer quality of life as assessed by the EuroQOL-5D questionnaire. CONCLUSIONS: In this survey, previously unrecognised chronic bronchitis was diagnosed in a high proportion of at-risk patients with acute respiratory episodes. Chronic bronchitis was associated with significantly poorer health status. Acute respiratory illness could be an appropriate opportunity for screening those patients at risk of COPD with lung function testing. PMID- 20842325 TI - Evaluation of the diagnostic yield of D-dimer testing in suspected venous thromboembolism in primary care: a 2-year retrospective analysis. PMID- 20842322 TI - Beta-carboline alkaloids and essential tremor: exploring the environmental determinants of one of the most prevalent neurological diseases. AB - Essential tremor (ET) is among the most prevalent neurological diseases, yet its etiology is not well understood. Susceptibility genotypes undoubtedly underlie many ET cases, although no genes have been identified thus far. Environmental factors are also likely to contribute to the etiology of ET. Harmane (1-methyl-9H pyrido[3,4-beta]indole) is a potent, tremor-producing beta-carboline alkaloid, and emerging literature has provided initial links between this neurotoxin and ET. In this report, we review this literature. Two studies, both in New York, have demonstrated higher blood harmane levels in ET cases than controls and, in one study, especially high levels in familial ET cases. Replication studies of populations outside of New York and studies of brain harmane levels in ET have yet to be undertaken. A small number of studies have explored several of the biological correlates of exposure to harmane in ET patients. Studies of the mechanisms of this putative elevation of harmane in ET have explored the role of increased dietary consumption, finding weak evidence of increased exogenous intake in male ET cases, and other studies have found initial evidence that the elevated harmane in ET might be due to a hereditarily reduced capacity to metabolize harmane to harmine (7-methoxy-1-methyl-9H-pyrido[3,4-beta]-indole). Studies of harmane and its possible association with ET have been intriguing. Additional studies are needed to establish more definitively whether these toxic exposures are associated with ET and are of etiological importance. PMID- 20842326 TI - Asthma severity in primary care asthma patients: a comparative study of four different approaches to severity classification. AB - AIMS: To explore the factor structure of asthma severity and asthma control and to compare the results of different approaches to asthma severity classification on the distribution of costs of asthma medication. METHODS: Comparison of four different approaches to asthma severity classification and factor analysis of asthma control descriptors. A correlation analysis between costs and the different approaches to severity classification was performed. RESULTS: The factor analysis suggests that asthma control consists of at least two factors. Four approaches to severity classification were explored and all except the 'GINA EXPANDED' classification tended to place patients in the most severe category. The pharmaceutical costs varied between 0 and 75 SEK per day (0 and 5.31 GBP; 0 and 7.68 EURO). CONCLUSIONS: There is a considerable overlap between asthma control and asthma severity. None of the approaches used in this study present a superior satisfactory solution to the classification problem. PMID- 20842327 TI - [Eccentric infrarenal aortic stenosis. Surgical and endovascular treatment]. AB - The management of coral reef lesions reported in this case study demonstrates the complementary and non-competing character of the open and endovascular treatment. The minimally invasive procedure of stent-optimized angioplasty seems to be advantageous as the primary therapy in selected cases. In the case of clinical deterioration the endovascular technique allows surgical reconstruction without significantly diminishing the result. Catheter-based techniques therefore remain an additional instrument for treatment in the hands of vascular surgeons which substantially broadens the range of therapy options for this disease entity. PMID- 20842328 TI - [Omalizumab for therapy-resistant chronic urticaria with angioedema]. AB - A 29-old man presented with severe chronic urticaria and angioedema. Routine evaluation including history, laboratory parameters and imaging procedures did not reveal any pathologic findings. We tried combined therapy regimes including high-dose systemic corticosteroids and antihistamines, leukotriene antagonist, cyclosporine and antibiotics. Because of a poor response and dramatic escalation of symptoms, we initiated therapy with omalizumab resulting in the complete remission of the chronic urticaria after two weeks. PMID- 20842329 TI - [A bone of contention: further medical training regulations]. AB - German physicians often criticize the medical associations but obviously without any background information. This article will try to explain the duties of medical associations especially concerning residency programs and supervision of post-graduate medical training. The integration of the medical associations of the 17 German States into the democratic and legal system of the State is presented. The goal is to explain the role of the medical associations and to enhance the participation of physicians in the given structures. PMID- 20842330 TI - [Lack of new trainees in trauma surgery and orthopedics. An approach to a solution]. AB - The reasons for a shortage of young people in trauma surgery and orthopedics have often been discussed. Atypical progression of medical operating levels, antisocial working hours and an inadequate financial compensation for on-call duties have been given as the reasons for a lack of interest in the discipline. Additionally a progressive feminization of the medical profession and rejection of surgical disciplines because of a mismatch with family interests and the demands of advanced surgical training have also been named. Surveys on the choice of medical specialization reveal that experiences during the course of studying have a great influence on future prospects and are immensely important for the further focusing on the future as a medical doctor. In order to increase the attractiveness of the specialization, programs for students were initiated by the heads of the Conventions of Higher Education Lecturers for Orthopedics and Trauma Surgery and the management of the German Society for Orthopedics and Trauma Surgery. Due to the enormous popularity auxiliary projects were demanded. Consequently a "Trauma Surgery and Orthopedic Day for Students" was organized on 16th February 2010 in the Musculoskeletal Centre of the Charite in Berlin. The aim was to convey practical skills and to inspire the choice of this specialization in the future. PMID- 20842331 TI - [Concomitant injuries of distal radius fractures]. AB - BACKGROUND: Following treatment of distal radius fractures poor functional results can still be found despite satisfactory radiological findings. This may be due to concomitant carpal lesions occurring together with these fractures. The aim of this prospective study was to analyze the clinical outcome depending on the type of fracture and concomitant carpal lesions. PATIENTS AND METHODS: A total of 66 patients with distal radius fractures treated over a 1-year period could be assessed. The functional results were compared with the uninjured contralateral side. The follow-up examination included patient history, physical and radiographic examination as well as the DASH (Disability of the arm, shoulder and hand) questionnaire and the modified Mayo wrist score. RESULTS: The average follow-up time was 12.7 months and the mean age of the examined patients was 53 years. The fracture classification according to AO (AO Working party for osteosynthesis questions) showed 32% type A, 10% type B and 58% type C fractures. In 55% a concomitant carpal lesion was found and 44% of the patients required surgical treatment. All fractures united without complications. In all cases X rays showed no loss of reduction postoperatively. Overall grip strength and wrist motion was reduced to 81% compared to the uninjured side. Patients regained good function represented in a mean DASH score of 24.8 points and a Mayo score of 70.6 points. The number of complete intraarticular fractures (type C) was significantly higher in patients who needed surgical treatment for carpal lesions compared to the groups where concomitant carpal lesions did not require invasive treatment or those where no carpal lesions were found. However, due to the operative treatment a comparable functional result could be obtained in all groups independent of the injury severity. CONCLUSIONS: The results demonstrate, if a correct restoration and surgical stabilization technique is used, clinical outcome following fractures of the distal radius also depends on an optimized management of concomitant carpal lesions. PMID- 20842332 TI - [Posttraumatic correction of malunited childhood radial condyle fracture]. PMID- 20842333 TI - [Non-union of pediatric lateral humeral condyle following post-traumatic cubitus valgus]. AB - Non-union of the pediatric lateral humeral condyle following post-traumatic cubitus valgus is a severe complication after inadequate treatment. We report on a then 14-year-old male patient who developed an increasingly defective position in terms of cubitus valgus after conservative treatment of a lateral humeral condyle fracture. After performing screw osteosynthesis and achieving consolidation, a successful supracondylar dome osteotomy was performed which led to relief from pain and free range of motion of the elbow joint. PMID- 20842334 TI - [The importance of depressive syndromes for incipient Alzheimer-type dementia in advanced age]. AB - Based on epidemiological data on the risk for dementia conveyed by depression, we report recent findings on the effects of depressive disorders on cognition in later life and its relationship to incipient Alzheimer's disease. We review the current literature on possible mechanisms underlying the depression-dementia association. The findings summarized in this review underline the central importance of depressive disorders for the diagnosis and treatment of psychiatric disorders in later life. PMID- 20842335 TI - [Blended learning in continuing medical education. Evaluation of an innovative curriculum "bipolar and bipolar spectrum disorders"]. AB - BACKGROUND: In this article a blended learning concept in continuing medical education is evaluated over a broad range of ages, as there is little data on this topic so far. The aims of this study were to document the blended learning concept, to evaluate the subjective gain of knowledge, as well as didactic and virtual means. Finally the actual usage and accreditation are reported. MATERIAL AND METHODS: The curriculum referred to the topic of bipolar disorder, combined episodes of face-to-face instruction and individual web-based learning over a period of 3 months. RESULTS: The didactic concept was very well accepted by the participants (N=346) and was evaluated as very user-friendly. The most appreciated dimensions were "subjective gain of knowledge" and "support by media tutor". Nearly 80% participated in both face-to-face as well in both web-based episodes. The component of web-based learning was accredited by the responsible institution (State Medical Association) with increasing number of credits over a period of 3 years. CONCLUSION: Blended learning is a useful didactic concept in continuing medical education of psychiatrists independent of the age of the participants. PMID- 20842336 TI - [Carer burden in dementia: origins and intervention]. AB - Caring for a demented elderly indiviudal in the home is associated with a high burden on care-providing family members. Factors contributing to this burden include invariable context conditions such as gender, type of relationship and severity of symptoms as well as role change, coping style, available support and appraisal of the caring role. Most interventions for family carers have focused on providing dementia-related information and problem solving skills but have placed less emphasis on the emotional facets of the burden. Controlled studies evaluating the efficacy of support programs for family carers suggest that the greatest benefits can be achieved by interventions which are intensive, long term, individually tailored and targeted to the everyday context. From these findings and experiences the outline of a psychologically based behavioral intervention for family carers of dementia patients is derived. PMID- 20842338 TI - [The future of depression research]. AB - As in the past, future depression research will be oriented to the genetics and pharmacology of antidepressants as well as molecular and clinical biomarkers. Using new technologies patient populations with practically equal disease mechanisms will be identified which can be specifically treated with new drugs or a combination of presently available drugs. This signifies the integration of neuroscientific knowledge into the diagnostics of depression. The application of a personalized depression therapy supported by genetic testing and biomarkers raises the possibility of early recognition of the risk of disease and a targeted intervention before the symptoms of disease emerge. PMID- 20842337 TI - [Oral fingolimod in multiple sclerosis: therapeutic modulation of the sphingosine 1-phosphate system]. AB - In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon beta1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile. PMID- 20842339 TI - [Molecular principles of tau-induced toxicity: new experimental therapy strategies for treatment of Alzheimer's disease]. AB - Neurofibrillary tangles are the hallmark of Alzheimer's disease together with amyloid plaques. They are composed of hyperphosphorylated and aggregated Tau proteins. Consequently, experimental disease modifying approaches include kinase and aggregation inhibitors as well as substances which increase degradation of Tau proteins. PMID- 20842340 TI - [Child and adolescent psychiatry and adult psychiatry: cooperation over the life span]. AB - Child and adolescent psychiatry and adult psychiatry have important common research and working fields, in particular the diagnostics and treatment of disorders with onset in childhood or adolescence and persistence over the life span. Other important aspects in common are the treatment of families (e.g., special wards for children and their parents, children of mentally ill parents), in medical teaching and postgraduate education as well as representative functions in societal and political issues. PMID- 20842341 TI - [Imaging of genetic aspects of Parkinson's disease]. AB - Although the mechanisms which cause Parkinson's disease (PD) are still poorly understood, research on monogenic forms of PD have demonstrated a significant genetic contribution to its etiology. Monogenic forms of PD only account for a minority of cases but offer a unique avenue of research into the pathogenesis of PD. In this article the potential of structural and functional neuroimaging in monogenic forms to provide general insights into the pathophysiology of PD, including the more common idiopathic disease is reviewed. The review has a particular focus on neuroimaging of non-manifesting mutation carriers to study functional and structural changes in the brain at the asymptomatic stage of PD. This line of research has started to provide valuable insights into how the brain can cope with a latent nigrostriatal dopaminergic deficit and thereby delay the clinical onset of PD. PMID- 20842344 TI - Heparin-induced skin necrosis: HIT-2 without thrombocytopenia. PMID- 20842343 TI - Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice. AB - AIMS/HYPOTHESIS: Hepatic steatosis is characterised by excessive triacylglycerol accumulation and is strongly associated with insulin resistance. An inability to efficiently mobilise liver triacylglycerol may be a key event mediating hepatic steatosis. Adipose triacylglycerol lipase (ATGL) is a key triacylglycerol lipase in the liver and we hypothesised that liver-specific overproduction of ATGL would reduce steatosis and enhance insulin action in obese rodents. METHODS: Studies of fatty acid metabolism were conducted in primary hepatocytes isolated from wild type and Atgl (also known as Pnpla2)-(/)- mice. An ATGL adenovirus was utilised to overproduce ATGL in the livers of obese insulin-resistant C57Bl/6 mice (Ad ATGL). Blood chemistry, hepatic lipid content and insulin sensitivity were assessed in mice. RESULTS: Triacylglycerol content was increased in Atgl-(/)- hepatocytes and was associated with increased fatty acid uptake and impaired fatty acid oxidation. ATGL adenovirus administration in obese mice increased the production of hepatic ATGL protein and reduced triacylglycerol, diacylglycerol and ceramide content in the liver. Overproduction of ATGL improved insulin signal transduction in the liver but did not affect fasting glycaemia or insulinaemia. Inflammatory signalling was not suppressed by ATGL overproduction. While ATGL overproduction increased plasma non-esterified fatty acids, neither lipid deposition nor insulin-stimulated glucose uptake were affected in skeletal muscle. CONCLUSIONS/INTERPRETATION: Liver ATGL overproduction decreases hepatic steatosis and mildly enhances liver insulin sensitivity. These effects are not sufficient to improve fasting glycaemia or insulinaemia in rodent obesity. PMID- 20842342 TI - [Functional and molecular imaging of breast tumors]. AB - Molecular imaging is concerned with the presentation, description and quantification of biological and physiological processes at the cellular and molecular level. Most recently molecular imaging has started to become established in breast diagnostics. This review article will give an overview of procedures which are either in the preclinical development stage or which have already become clinically established. Molecular nuclear medicine breast imaging (breast-specific gamma imaging [BSGI] and positron emission mammography [PEM]) together with specific radiotracers and contrast media will be discussed. The possibilities for magnetic resonance imaging in functional (DWI) and metabolic (MRSI) imaging of breast lesions and the combined application of nuclear medicine and magnetic resonance imaging (PET/MRI) will be explained. Furthermore, an overview on the preclinical procedure and the possible clinical applications of optical and photoacoustic imaging will be given. PMID- 20842346 TI - Ziram induces apoptosis and necrosis in human immune cells. AB - Ziram as a dithiocarbamate fungicide is widely used throughout the world in agriculture and as an accelerating agent is used in latex production. In order to investigate ziram-induced apoptosis/necrosis and its underlying mechanism in human immune cells, a human monocyte-like cell line (U937) was treated with ziram at 0.0312-2 MUM for 2-24 h at 37 degrees C in a 5% CO2 incubator. Apoptosis/necrosis induced by ziram was determined by analysis of FITC-Annexin V/PI staining and the intracellular level of active caspase-3 by flow cytometry and DNA fragmentation analysis. We found that ziram induced apoptosis/necrosis in U937 in a time- and dose-dependent manner, as shown by FITC-Annexin-V/PI staining. DNA fragmentation was detected when cells were treated with 0.5, 1, or 2 MUM ziram for 24 h. Ziram also induced an increase in intracellular active caspase-3 in U937 cells in a dose-dependent manner, and a caspase-3 inhibitor, Z DEVD-FMK, significantly inhibited the ziram-induced apoptosis. Moreover, it was found that ziram induced mitochondrial cytochrome c release in U937 cells. These findings indicate that ziram can induce apoptosis/necrosis in U937 cells, and this effect is partially mediated by activation of intracellular caspase-3 and mitochondrial cytochrome c release. PMID- 20842347 TI - Evaluation of biotechnology-derived novel proteins for the risk of food-allergic potential: advances in the development of animal models and future challenges. AB - Increasing concern from the public about the safety of genetically modified food has made critical to have suitable methods for recognizing associated potential hazards. Hierarchical approaches to allergenicity determination were proposed, and these include evaluation of the structural and sequence homology and serological identity of novel proteins with existing allergens, measuring the resistance to proteolytic digestion and assessment of sensitizing potential using animal models. Allergic individuals have a predisposed (i.e. atopic) genetic background, and a close resemblance to this setup is therefore desirable in animal models, which is possible by using a strain of an animal species that is prone for allergic disorders. So far, none of the animal model has been validated for the purpose of hazard identification in the context of safety assessment. However, the available knowledge suggests that the judicious use of an appropriate animal model could provide important information about the allergic potential of novel proteins. This paper provides an up-to-date review of the progress made in the field of development of in vivo models in this direction and the further goals that have to be achieved. PMID- 20842348 TI - Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine? AB - Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10-15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re evaluated. PMID- 20842349 TI - SERS nanosensors that report pH of endocytic compartments during FcepsilonRI transit. AB - Recently, the development of an IgE receptor (FcepsilonRI)-targeted, pH sensitive, surface-enhanced Raman spectroscopy (SERS) nanosensor has been demonstrated by Nowak-Lovato and Rector (Appl Spectrosc 63:387-395, 2009). The targeted nanosensor enables spatial and temporal pH measurements as internalized receptors progress through endosomal compartments in live cells. Trafficking of receptor-bound nanosensors was compared at physiological temperature (37 degrees C) versus room temperature (25 degrees C). As expected, we observed markedly slower progression of receptors through low-pH endocytic compartments at the lower temperature. We also demonstrate the utility of the nanosensors to measure directly changes in the pH of intracellular compartments after treatment with bafilomycin or amiloride. We report an increase in endosome compartment pH after treatment with bafilomycin, an H(+) ATPase pump inhibitor. Decreased endosomal luminal pH was measured in cells treated with amiloride, an inhibitor of Na(+)/H(+) exchange. The decrease in amiloride-treated cells was transient, followed by a recovery period of approximately 15-20 min to restore endosomal pH. These experiments demonstrate the novel application of Raman spectroscopy to monitor local pH environment in live cells with the use of targeted SERS nanosensors. PMID- 20842350 TI - Identification of the neuronal effects of ethanol on C. elegans by in vivo fluorescence imaging on a microfluidic chip. AB - Caenorhabditis elegans (C. elegans) is a well-established model organism for investigating the correlations between behavioral and neuronal activities. Here, we demonstrated a microfluidic-based method that allowed stimulation-based neuronal analysis of immobilized C. elegans for identifying the neuronal effects of ethanol on the chemosensory responses of the right ASE (ASER) neuron. A one piece microvalve was developed for the immobilization of C. elegans. Stimulations were realized by interface shifting of laminar flows. Well-fed transgenic worms expressing the calcium indicator G-CaMP in ASER neurons were used for in vivo fluorescence imaging. To evaluate the developed method, we first studied the effects of ethanol on the ASER neurons in response to a single NaCl stimulus. Results indicated that ethanol acutely suppressed the ON responses of ASER neurons to NaCl rather than the OFF response. Further studies of the adaptation of ASER neurons in response to NaCl and in the presence of ethanol suggested that ethanol interfered with the adaptation of neurons. The developed method exhibited the advantages of ease of operation and high throughput. We expect this new method to open up a new avenue for investigating the correlations between the behavioral and neuronal activities of C. elegans. PMID- 20842351 TI - Chromatography-bioluminescence coupling reveals surprising bioactivity of inthomycin A. AB - By employing a novel technique for the direct coupling of a bacterial bioassay with chromatography, we discovered a gyrA promotor active compound in myxobacterial extracts and elucidated the structure directly without any isolation step. As a result, we identified inthomycin A as the bioactive substance. Our method is based on a whole-cell bioluminescent reporter gene assay coupled with thin-layer chromatography for primary hit detection and with liquid chromatography (LC)/mass spectrometry or LC/NMR for dereplication and structure elucidation. Previously, inthomycin A has been isolated from Streptomycetes and was associated with the inhibition of cellulose biosynthesis and herbicidal activity. Thus, our findings support the basic principle that completely different microbial phyla are able to synthesize the same natural product. Moreover, our results indicate that inthomycin A affects bacterial DNA supercoiling, which reveals an unexpected bioactivity for this compound. These results can possibly promote further investigation of the biosynthesis as well as the biological activity of inthomycins and related natural products. PMID- 20842352 TI - Detection of free radicals by isolated perfusion of the rat brain following hemorrhagic stroke: a novel approach to cerebrovascular biomarker research. AB - Blood-borne biomarkers are a mainstay of diagnosis and follow-up in many diseases. For stroke, however, no reliable biomarkers have thus far been identified. To remedy this situation, we investigated the usefulness of a modified in situ isolated brain perfusion (IBP) technique for screening potential biomarker candidates. As a proof of concept, the production of reactive oxygen species (ROS) was estimated in a rat model of experimental intracerebral hemorrhage (ICH). After stereotactic infusion of whole blood into the rat striatum, we initiated IBP without intracranial manipulation or discontinuation of cerebral blood flow. To detect ROS, we employed the salicylate trapping method, which involves the hydroxylation of salicylic acid during oxidative stress into dihydroxybenzoic acid (DHBA), and quantification of the latter in venous eluate by using high-performance liquid chromatography. Venous eluate was collected separately from both injured and healthy hemispheres (n=10). Control groups consisted of sham-injured (n=4) and healthy animals (n=3). In animals subjected to ICH (n=10), 50% more 2,5-DHBA was detected in venous eluate on the injured side than in eluate on the contralateral side. Hemorrhagic hemispheres produced more 2,5-DHBA than hemispheres in sham-injured and healthy animals (72 and 110% more 2,5-DHBA, respectively). Isolated brain perfusion combined with salicylate trapping produced data indicating an elevation in the formation of ROS subsequent to ICH. Our findings suggest that isolated in situ brain perfusion is a promising approach to detecting biomarkers of cerebrovascular pathologic conditions. PMID- 20842353 TI - Tactile suppression of displacement. AB - In vision, the discovery of the phenomenon of saccadic suppression of displacement has made important contributions to the understanding of the stable world problem. Here, we report a similar phenomenon in the tactile modality. When scanning a single Braille dot with two fingers of the same hand, participants were asked to decide whether the dot was stationary or whether it was displaced from one location to another. The stimulus was produced by refreshable Braille devices that have dots that can be swiftly raised and recessed. In some conditions, the dot was stationary. In others, a displacement was created by monitoring the participant's finger position and by switching the dot activation when it was not touched by either finger. The dot displacement was of either 2.5 mm or 5 mm. We found that in certain cases, displaced dots were felt to be stationary. If the displacement was orthogonal to the finger movements, tactile suppression occurred effectively when it was of 2.5 mm, but when the displacement was of 5 mm, the participants easily detected it. If the displacement was medial lateral, the suppression effect occurred as well, but less often when the apparent movement of the dot opposed the movement of the finger. In such cases, the stimulus appeared sooner than when the brain could predict it from finger movement, supporting a predictive rather than a postdictive differential processing hypothesis. PMID- 20842354 TI - Benzodiazepine discontinuation among community-dwelling older people: a population-based cohort study. PMID- 20842355 TI - VKORC1-1639G>A, CYP2C9, EPHX1691A>G genotype, body weight, and age are important predictors for warfarin maintenance doses in patients with mechanical heart valve prostheses in southwest China. AB - OBJECTIVE: To investigate the contribution of genetic polymorphisms of vitamin K epoxide reductase complex subunit 1 gene VKORC1-1639G>A, cytochrome P450 2C9 gene (CYP2C9), EPHXI, and clinical factors to warfarin sensitivity in southwest Chinese Han patients with mechanical heart valve prostheses. METHODS: A total of 127 patients with mechanical heart valve prostheses who have been followed up at our department during the past 23 years were enrolled in this study and compared to a control group that consisted of 133 randomly selected healthy blood donors. These Chinese patients met stable warfarin dosage requirements and had reached the target international normalized ratio (INR) of 1.5-2.0. PCR and direct sequencing were carried out to identify the polymorphisms of VKORC1-1639G>A (rs9923231), CYP2C9*3 (rs1057910), CYP2C9 IVS3-65G>C (rs9332127), and EPHX1691A>G (rs4653436). In addition, total and free (non-protein-bound) warfarin concentrations were analyzed. RESULTS AND CONCLUSIONS: There were great interindividual differences in warfarin maintenance dosage (ranging from 0.6 to 8.4 mg/day) among the 127 patients with mechanical heart valve prostheses. VKORC1 1639G>A, CYP2C9, EPHX1691A>G polymorphism, body weight, and age were found to affect the dose demands. Multiple linear regression models incorporating genetic polymorphisms of VKORC1, CYP2C9, EPHX1691A>G, and the nongenetic factors of age and body weight were developed, and explained up to 76.8% of the total variation (adjusted R (2) of 0.743) in warfarin maintenance doses in southwest Chinese patients with mechanical heart valve prostheses. PMID- 20842357 TI - Analysis of HLA-ABC locus-specific transcription in normal tissues. AB - We developed a novel human leukocyte antigen HLA-ABC locus-specific quantitative real-time polymerase chain reaction (PCR) to determine the locus-specific gene expression of HLA-ABC in peripheral blood leukocytes (PBLs, n = 53), colon mucosa (n = 15), and larynx mucosa (n = 15). Laser-assisted tissue microdissection allowed us to study the selected cells without interference from surrounding stroma. We report evidence on the specificity of the technique, describing the HLA-ABC locus-specific gene expression patterns found in the PBLs and two solid tissues studied. PBLs showed a higher gene expression of HLA-B than of HLA-A or HLA-C (p = 4.7 * 10(-10) and p = 1.6 * 10(-6), respectively). In solid tissue, HLA-A and HLA-B gene expressions were similar and HLA-C expression lower. In particular, in larynx mucosa, significant differences were found between HLA-A and HLA-C expressions and between HLA-B and HLA-C expressions (p = 6.5 * 10(-4) and p = 8.1 * 10(-4), respectively). The same differences were observed in colon mucosa, but significance was not reached (p = 0.08 and p = 0.06, respectively). Differences in locus-specific regulation may be related to the control of cytotoxic responses of NK and CD8 positive T cells. Gene expression of HLA-ABC specific locus showed no intra-individual variability, but there was a high inter individual variability. This may result from differences in the expression of common regulatory factors that control HLA-ABC constitutive expression. PMID- 20842358 TI - Use of the usp45 lactococcal secretion signal sequence to drive the secretion and functional expression of enterococcal bacteriocins in Lactococcus lactis. AB - Replacement of the signal peptide (SP) of the bacteriocins enterocin P (EntP) and hiracin JM79 (HirJM79), produced by Enterococcus faecium P13 and Enterococcus hirae DCH5, respectively, by the signal peptide of Usp45 (SP(usp45)), the major Sec-dependent protein secreted by Lactococcus lactis, permits the production, secretion, and functional expression of EntP and HirJM79 by L. lactis. Chimeric genes encoding the SP(usp45) fused to either mature EntP (entP), with or without the immunity gene (entiP) or to mature HirJM79 (hirJM79), with or without the immunity gene (hiriJM79), were cloned into the expression vector pMG36c, carrying the P(32) constitutive promoter, and into pNZ8048 under control of the inducible PnisA promoter. The production of EntP and HirJM79 by most of the L. lactis recombinant strains was 1.5- to 3.7-fold higher and up to 3.6-fold higher than by the E. faecium P13 and E. hirae DCH5 control strains, respectively. However, the specific antimicrobial activity of the recombinant EntP was 1.1- to 6.2-fold higher than that produced by E. faecium P13, while that of the HirJM79 was a 40% to an 89% of that produced by E. hirae DCH5. Chimeras of SP(usp45) fused to mature EntP or HirJM79 drive the production and secretion of these bacteriocins in L. lactis in the absence of specific immunity and secretion proteins. The supernatants of the recombinant L. lactis NZ9000 strains, producers of EntP, showed a much higher antimicrobial activity against Listeria spp. than that of the recombinant L. lactis NZ9000 derivatives, producers of HirJM79. PMID- 20842359 TI - False-positive axillary lymphadenopathy due to silicone granuloma on FDG PET/CT. PMID- 20842360 TI - Loop ileostomy closure: comparison of cost effectiveness between suture and stapler. AB - BACKGROUND: Closure of loop ileostomy can be safely performed using sutures or staplers. The aim of the present study was to compare the cost effectiveness of three different techniques. METHODS: A total of 128 consecutive patients who underwent closure of loop ileostomy between January 2002 and December 2008 were analyzed retrospectively. The primary outcome parameter was operative cost. RESULTS: Closure of ileostomy was performed in 66 patients with hand-sewn anastomosis, in 25 patients with stapler only, and in 37 patients with a combination of stapler and suture. There were no differences in terms of early and late postoperative complications. Operative time was significantly longer for "suture only" (101.4 +/- 26 min) than for "stapler/suture" (-4.9 min) and "stapler only" (-17.8 min); the difference between the three groups is significant (p = 0.05). Duration of hospital stay was not different among the three groups. Operative costs with "stapler/suture" (1,755.9 +/- 355.6 EUR) were significantly higher than with "suture only" (-254 EUR; p = 0.001) and "stapler only" (-236 EUR; p = 0.005). CONCLUSIONS: Operative time using the stapler only is significantly shorter than with hand-sewn anastomosis or combinations of stapler and suture. Operative costs are significantly higher for a procedure that includes suture and stapler. PMID- 20842361 TI - Presence and persistence of nutrition-related symptoms during the first year following esophagectomy with gastric tube reconstruction in clinically disease free patients. AB - BACKGROUND: Esophagectomy with gastric tube reconstruction results in a variety of postoperative nutrition-related symptoms that may influence the patient's nutritional status. METHODS: We developed a 15-item questionnaire, focusing on the nutrition-related complaints the first year after an esophagectomy. The questionnaire was filled out the first week after discharge and 3, 6, and 12 months after surgery. The use of enteral nutrition, meal size and frequency, social aspects related to eating, defecation pattern, and body weight were recorded at the same time points. We analyzed the relationship between the baseline characteristics and the number of nutrition-related symptoms, as well as the relationship between those symptoms and body weight with linear mixed models. RESULTS: We found no significant within-patient change for the total number of nutrition-related symptoms (P = 0.67). None of the baseline factors were identified as predictors of the complaint scores. The most frequently experienced complaints were early satiety, postprandial dumping syndrome, inhibited passage due to high viscosity, reflux, and absence of hunger. One year after surgery, meal sizes were still smaller, the social aspects of eating were influenced negatively, and patients experienced an altered stool frequency. Directly after the surgical procedure 78% of the patients lost weight, and the entire postoperative year the mean body weight remained lower (P = 0.47). We observed no association between the complaint scores and body weight (P = 0.15). CONCLUSIONS: After an esophagectomy, most patients struggle with nutrition-related symptoms, are confronted with nutrition-related adjustments and a reduced body weight. PMID- 20842362 TI - Iatrogenic subtotal stenosis of the right subclavian artery treated with percutaneous transluminal angioplasty. AB - This report describes a rare vascular complication of surgical placement of a marking clip and a possible approach to problem solving. A 55-year-old patient presented with loss of sensation in the fingers and loss of peripheral pulsations in the right arm 4 days after right upper lobectomy for a pT2N1 moderately differentiated adenocarcinoma of the lung. Duplex examination and computed tomography were performed the same day and showed a subtotal stenosis of the right subclavian artery, which was caused by the surgical placement of a metal clip to mark the surgical boundary. Selective angiography was subsequently performed. Percutaneous transluminal angioplasty (PTA) successfully dilated the stenosis and pushed the clip off. Flow in the right subclavian artery (RSA) was completely restored as were neurology and peripheral pulses. In conclusion, arterial stenosis by a surgical (marking) clip may be feasibly treated with PTA. PMID- 20842363 TI - Integrative systems biology and networks in autophagy. AB - The growing recognition that autophagy has important roles in many biological pathways, physiological systems, and infection and disease states necessitates a multidimensional perspective and systems-wide understanding of how autophagy is triggered or modulated by diverse stimuli. To delineate the nonlinearity and combinatorial complexity of biological networks and signaling pathways impinging on autophagy requires an integrative framework that brings together diverse information from genome-scale data (genomics, transcriptomics, proteomics, interactomics, functional RNAi screens) to dynamic time-series analyses and biochemical assays across a variety of biological and clinical contexts. We outline recent applications of genome-wide approaches to studying autophagy and highlight how some of these could be integrated to derive sub-networks that are more functionally focused. Viewed from a network perspective, the extensive interconnectivity between pathway systems converging on autophagy provides the essential foundation from which to systematically elucidate the regulatory nuances and crosstalks that orchestrate autophagic processes in different pathophysiological contexts. PMID- 20842364 TI - Transformation of carotenoid biosynthetic genes using a micro-cross section method in kiwifruit (Actinidia deliciosa cv. Hayward). AB - Genetic transformation using a micro-cross section (MCS) technique was conducted to improve the carotenoid content in kiwifruit (Actinidia deliciosa cv. Hayward). The introduced carotenoid biosynthetic genes include geranylgeranyl diphosphate synthase (GGPS), phytoene desaturase (PDS), zeta-carotene desaturase (ZDS), beta carotene hydroxylase (CHX), and phytoene synthase (PSY). The transformed explants were selected on half-strength MS medium containing 0.001 mg l(-1) of 2,4-D and 0.1 mg l(-1) of zeatin, either 5 mg l(-1) hygromycin or 25 mg l(-1) kanamycin, and 500 mg l(-1) cefotaxime. The genomic PCR, genomic Southern blot analysis, and RT-PCR were performed to confirm the integration and expression of the transgenes. The transformation efficiencies of either kanamycin- or hygromycin resistant shoots ranged from 2.9 to 22.1% depending on the target genes, and from 2.9 to 24.2% depending on the reporter genes. The selection efficiencies ranged from 66.7 to 100% for the target genes and from 95.8 to 100% for the reporter genes. Changes of carotenoid content in the several PCR-positive plants were determined by UPLC analysis. As a result, transgenic plants expressing either GGPS or PSY increased about 1.2- to 1.3-fold in lutein or beta-carotene content compared to non-transgenic plants. Our results suggest that the Agrobacterium mediated transformation efficiency of kiwifruit can be greatly increased by this MCS method and that the carotenoid biosynthetic pathway can be modified in kiwifruit by genetic transformation. Our results further suggest that GGPS and PSY genes could be major target genes to increase carotenoid contents in kiwifruit. PMID- 20842365 TI - Quality evaluation of snow lotus (Saussurea): quantitative chemical analysis and antioxidant activity assessment. AB - Snow lotus is commonly used as a medicinal plant and has great pharmacological value. To protect these endangered plants, in vitro propagation and cell cultures have been established in order to meet the growing market demand. The phenolic composition, antioxidant activities, total phenolic content (TPC) and total flavonoid content (TFC) from three most commonly used species, in vitro propagated lines and the cell cultures were investigated to qualify their pharmacological value. Quantitative analysis showed that the phenolics varied greatly among different species and the same species at different habitats. From this it can be inferred that the phenolics were influenced by genetic background and the environmental conditions. Significant correlations were observed between the antioxidant activity and several phenolics/TPC/TFC, suggesting that the phenolics are a major contributor of the antioxidant activity and are important for quality evaluation of snow lotus. Based on the abundance of phenolics, TPC, TFC and antioxidant activity, the order of the quality for wild species would be Saussurea involucrata > Saussurea medusa > Saussurea gossypiphora. For S. medusa, its quality judged by origin would be Shigatse > Lhasa > Nagqu. For in vitro propagated plants, the matured plants could be a reliable substitute for wild plants, and the dynamics of phenolics is critical for quality control of this monocarpic species. We provide the first report of quality comparison between the wild plants and the cell cultures. The advantages of developing cell cultures as alternatives for plants collected from the wild are discussed. PMID- 20842366 TI - Metal-on-metal hip resurfacings--a radiological perspective. AB - It is important to be aware of the various complications related to resurfacing arthroplasty of the hip (RSA) and the spectrum of findings that may be encountered on imaging. The bone conserving metal-on-metal (MOM) hip resurfacing has become increasingly popular over the last ten years, especially in young and active patients. Initial reports have been encouraging, but long-term outcome is still unknown. Early post operative complications are rare and have been well documented in the literature. Medium and long term complications are less well understood. A rare but important problem seen at this stage is the appearance of a cystic or solid periarticular reactive mass, which occurs predominately in women and usually affects both hips when seen in patients with bilateral RSAs. The following imaging findings are illustrated and their significance discussed; Uncomplicated hip resurfacing arthroplasty, radiolucency around the femoral peg, femoral neck fracture, loosening and infection, suboptimal component position, femoral notching, dislocation, heterotopic ossification, femoral neck thinning and reactive masses. The radiologist should be aware of the normal radiographic appearances and the variety of complications that may occur following RSA and should recommend ultrasound or MRI in patients with an unexplained symptomatic hip and normal radiographs. PMID- 20842367 TI - Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features. AB - Mutations of three different genes, encoding beta-amyloid precursor protein (APP), presenilin 1 and presenilin 2 are associated with familial Alzheimer's disease (AD). Recently, the APP mutation A673V has been identified that stands out from all the genetic defects previously reported in these three genes, since it causes the disease only in the homozygous state (Di Fede et al. in Science 323:1473-1477, 2009). We here provide the detailed neuropathological picture of the proband of this family, who was homozygous for the APP A673V mutation and recently came to death. The brain has been studied by histological and immunohistochemical techniques, at the optical and ultrastructural levels. Cerebral Abeta accumulation and tau pathology were severe and extensive. Peculiar features were the configuration of the Abeta deposits that were of large size, mostly perivascular and exhibited a close correspondence between the pattern elicited by amyloid stainings and the labeling obtained with immunoreagents specific for Abeta40 or Abeta42. Moreover, Abeta deposition spared the neostriatum while deeply affecting the cerebellum, and therefore was not in compliance with the hierarchical topographical sequence of involvement documented in sporadic AD. Therefore, the neuropathological picture of familial AD caused by the APP recessive mutation A673V presents distinctive characteristics compared to sporadic AD or familial AD inherited as a dominant trait. Main peculiar features are the morphology, structural properties and composition of the Abeta deposits as well as their topographic distribution in the brain. PMID- 20842368 TI - A novel multidisciplinary educational programme for patients with chronic skin diseases: Ghent pilot project and first results. AB - Chronic inflammatory skin disorders have a major impact on the patients' health related quality of life. Preliminary studies to date have suggested that additional educational and psychological training programmes may be effective in the management of chronic skin diseases, although more rigid methodology is needed. Our purpose was to investigate the effect on quality of life of a novel multidisciplinary educational programme for patients, 18 years or older, with chronic skin diseases. The 12-week intervention encompasses cognitive education on skin and general health issues, and stress-reducing techniques. Quality of life questionnaires were used to assess the participants at baseline and at the end of the program. These comprehend Dermatology Life Quality Index (DLQI), Skindex-29, Psoriasis Disability Index (PDI) and Quality of Life Index for Atopic Dermatitis (QoLIAD). Fifty-five patients participated in six programmes since 2006. Forty-three patients completed the programme. Overall, compared to baseline, DLQI (n = 39) improved by 5.64 points (p < 0.001; SD +/-6.09), Skindex 29 (n = 27) by 19.67 points (p < 0.001; SD +/-17.37), PDI (n = 9) improved by 7.44 points (p = 0.019; SD +/-7.60) and QoLIAD (n = 13) improved by 4.39 points (p = 0.036; SD +/-6.69) by the end of the intervention. Preliminary results show that the quality of life of the patients with chronic skin diseases improved significantly after participation to the programme. These positive initial results are stimulating to set up a prospective controlled randomised trial investigating the impact on quality of life, the clinical efficacy and the cost effectiveness of this educational intervention programme. PMID- 20842370 TI - An exploratory study of serum urate levels in patients with amyotrophic lateral sclerosis. AB - Urate is a natural antioxidant, and high serum urate levels could be protective against the development of amyotrophic lateral sclerosis (ALS). To determine if serum urate concentrations were lower in ALS patients than in healthy controls, we compared serum urate levels in 132 ALS patients and 337 age/sex-matched controls. Median urate levels were lower in ALS patients compared to controls (4.2mgl/dL [range:1.4-8.2], vs. 4.7 [1.7-13.1]; p = 0.04). In univariate analysis, high urate levels were less likely to be associated with ALS (odds ratio [OR]: 0.53; 95% CI: 0.29-0.97; p = 0.04), but after adjusting for age, sex and kidney function, the association was not statistically significant (OR: 0.63; 95% CI: 0.32-1.24; p = 0.18). Urate levels were lower in bulbar-onset ALS (3.9 mg/dL), compared to limb-onset ALS (4.3; p = 0.001), and in cases with longer disease duration compared to controls (4.1 mg/dL, vs. 4.7; p = 0.01). In this cross-sectional study, lower levels of serum urate were evident in ALS cases with bulbar-onset and longer disease duration, but were likely to be related to the malnutrition induced by ALS. PMID- 20842369 TI - A two-mutation model of radiation-induced acute myeloid leukemia using historical mouse data. AB - From studies of the atomic bomb survivors, it is well known that ionizing radiation causes several forms of leukemia. However, since the specific mechanism behind this process remains largely unknown, it is difficult to extrapolate carcinogenic effects at acute high-dose exposures to risk estimates for the chronic low-dose exposures that are important for radiation protection purposes. Recently, it has become clear that the induction of acute myeloid leukemia (AML) in CBA/H mice takes place through two key steps, both involving the Sfpi1 gene. A similar mechanism may play a role in human radiation-induced AML. In the present paper, a two-mutation carcinogenesis model is applied to model AML in several data sets of X-ray- and neutron-exposed CBA/H mice. The models obtained provide good fits to the data. A comparison between the predictions for neutron-induced and X-ray-induced AML yields an RBE for neutrons of approximately 3. The model used is considered to be a first step toward a model for human radiation-induced AML, which could be used to estimate risks of exposure to low doses. PMID- 20842371 TI - Surgical results of heavy silicone oil HWS-45 3000 as internal tamponade for inferior retinal detachment with PVR: a pilot study. AB - PURPOSE: To report the results of a prospective pilot study using a new heavy agent, HWS-45 3000, as endotamponade in complicated inferior retinal detachment. METHODS: Ten consecutive patients satisfying the enrolment criteria were studied. Inclusion criteria was the presence of inferior retinal detachment complicated by PVR grade C2 or more (according to Retina Society classification) or retinal detachment due to penetrating ocular trauma or giant retinal tears. Heavy silicone oil was injected at the end of surgery after peeling of retinal membranes and/or retinotomy. Follow-up protocol visits were scheduled at 1 day, 1 week, 1 month, and 2 months after the initial surgery and 1 week, 1 month and 6 months after HWS-45 3000 removal surgery. Oil removal was planned after about 2 months from the main surgery. RESULTS: At the 1-month protocol visit, eight eyes presented retinal reattachment and two eyes presented a retinal detachment not involving the posterior pole. Visual acuity ranged from 2.2 logMAR to 1.0 (mean: 1.45, SD: 0.53). Oil removal surgery was scheduled about 60 days postoperatively. All eyes required additional endolaser treatment during removal surgery, and four eyes epiretinal membrane peeling. In two eyes that presented retinal detachment not involving the posterior pole, tamponading with 5700 cSt silicone oil was necessary. At 3- and 6-month protocol visits, all patients presented retina reattached; two eyes had silicone oil as internal tamponade. CONCLUSION: From our first results, HWS-45 3000 appears to be a well-tolerated heavy oil suitable for the treatment of complicated inferior retinal detachment. PMID- 20842373 TI - Roles of load-induced reorganization of multi-digit physiological tremors for a tracking maneuver. AB - This study was undertaken to investigate the effect of low-level loading on digit tracking and the associated physiological tremors in the moving and the stationary digits. Sixteen healthy adults conducted positional tracking with the middle finger under the loaded and unloaded conditions; meanwhile, trajectory of the middle finger, electromyographic activities of the extensor digitorum (ED)/flexor digitorum superficialis, and physiological tremors of the index, middle, ring, and little fingers were recorded. The results showed that load imposition (<70 g) on the middle finger improved tracking congruency, in association with reduction of inter-digit tremor coupling and enhancement of tiny movement jerks. Principal component analysis suggested that inertial load suppressed the 8-12 Hz central rhythm but potentiated the 25-40 Hz coherence spectra of major principal components and electromyographic signals of the ED. It was concluded that low-level inertial load could facilitate corrective movement adjustments and selective digit control during manual tracking, relevant implicitly to decreased common central drive and enhanced heteronymous reflex loops. PMID- 20842374 TI - Seasonal variations of haematological parameters in athletes. AB - The influence of training and competition workloads is crucial for evaluation of longitudinal haematological data in athletes. There are only a few papers on the variation of haematological parameters during long-lasting periods and, especially, during an entire competitive season. We summarized that some haematological parameters can be influenced by long-term training and competition periods. Haemoglobin (Hb) and haematocrit (Ht) are decreased during the more intense periods of training, throughout the season. In different sport disciplines, the decline of Hb ranges from 3 to 8% during the competition season, while the range of reticulocytes (Ret%) varies from 5 to 21%. Reticulocytes are also decreased after long periods of training and competitions, but their variation is not necessarily associated with that of Hb. The qualitative variations (trend of modifications) of haematological parameters are roughly independent of the sport discipline, but quantitatively (amount of modifications) dependent on sport discipline. The modifications are more evident in cycling, running, swimming than they are in football and rugby. The variations of haematological parameters within the same sport discipline are qualitatively concordant and quantitatively different among separate but consecutive competitive seasons. These findings are described in aerobic and team sports sportsmen. The definition of reliable reference ranges in sportsmen would only be possible by following the best laboratory practices. For antidoping purposes more studies investigating haematological modifications during the season are advisable. PMID- 20842375 TI - A comprehensive evaluation of commonly used accelerometer energy expenditure and MET prediction equations. AB - Numerous accelerometers and prediction methods are used to estimate energy expenditure (EE). Validation studies have been limited to small sample sizes in which participants complete a narrow range of activities and typically validate only one or two prediction models for one particular accelerometer. The purpose of this study was to evaluate the validity of nine published and two proprietary EE prediction equations for three different accelerometers. Two hundred and seventy-seven participants completed an average of six treadmill (TRD) (1.34, 1.56, 2.23 ms(-1) each at 0 and 3% grade) and five self-paced activities of daily living (ADLs). EE estimates were compared with indirect calorimetry. Accelerometers were worn while EE was measured using a portable metabolic unit. To estimate EE, 4 ActiGraph prediction models were used, 5 Actical models, and 2 RT3 proprietary models. Across all activities, each equation underestimated EE (bias -0.1 to -1.4 METs and -0.5 to -1.3 kcal, respectively). For ADLs EE was underestimated by all prediction models (bias -0.2 to -2.0 and -0.2 to -2.8, respectively), while TRD activities were underestimated by seven equations, and overestimated by four equations (bias -0.8 to 0.2 METs and -0.4 to 0.5 kcal, respectively). Misclassification rates ranged from 21.7 (95% CI 20.4, 24.2%) to 34.3% (95% CI 32.3, 36.3%), with vigorous intensity activities being most often misclassified. Prediction equations did not yield accurate point estimates of EE across a broad range of activities nor were they accurate at classifying activities across a range of intensities (light <3 METs, moderate 3-5.99 METs, vigorous >= 6 METs). Current prediction techniques have many limitations when translating accelerometer counts to EE. PMID- 20842376 TI - Pure perceptual-based learning of second-, third-, and fourth-order sequential probabilities. AB - There is evidence that sequence learning in the traditional serial reaction time task (SRTT), where target location is the response dimension, and sequence learning in the perceptual SRTT, where target location is not the response dimension, are handled by different mechanisms. The ability of the latter mechanism to learn sequential contingencies that can be learned by the former mechanism was examined. Prior research has established that people can learn second-, third-, and fourth-order probabilities in the traditional SRTT. The present study reveals that people can learn such probabilities in the perceptual SRTT. This suggests that the two mechanisms may have similar architectures. A possible neural basis of the two mechanisms is discussed. PMID- 20842377 TI - A non-catecholamine-producing sympathetic paraganglioma of the spermatic cord: the importance of performing candidate gene mutation analysis. AB - BACKGROUND: Catecholamine-producing tumours are called pheochromocytomas when they are located in the adrenal gland and sympathetic paragangliomas when they are located elsewhere in the abdomen. Rarely these tumours do not produce catecholamines and even more rarely they arise in the spermatic cord. Over the past decade, systematic mutation analysis of apparently sporadic cases of pheochromocytomas and paragangliomas has elucidated the frequent presence of germ line mutations in one of five candidate genes, including RET, VHL, SDHB, SDHC, and SDHD. CLINICAL HISTORY AND METHODS: We describe a 45-year-old man with a non catecholamine-producing paraganglioma of the spermatic cord. We performed SDHB immunohistochemistry and performed mutation analysis of the SDHB, SDHC, and SDHD genes. RESULTS: There was no staining of tumour cells with SDHB immunohistochemistry, indicative of an SDH mutation. Mutation analysis demonstrated a germ line SDHD mutation (p.Val147Met). CONCLUSIONS: Systematic mutation analysis is required in paraganglioma patients for the detection of germ line mutations. This should be preceded by SDHB immunohistochemistry to limit the number of genes to be tested. PMID- 20842378 TI - Endotracheal intubation in a neonatal population remains associated with a high risk of adverse events. AB - INTRODUCTION: There has been a significant increase in premedication use for neonatal intubation in the UK over the past decade. We aimed to determine the adverse events during neonatal intubation using the most commonly used premedication regimen in the UK. DISCUSSION: We prospectively studied all intubations performed using morphine, suxamethonium and atropine during a 3-month period in three UK tertiary neonatal units. Premedication was administered for 87/93 (94%) of intubations. Median time taken to prepare premedication was 16 min (IQR 10-35). Median time to successful intubation was 5 min (IQR 2-9) following premedication. Median lowest recorded oxygen saturation after administration of premedication was 65% (IQR 39-85). A bradycardia in the range 61-99/min accompanied the procedure in 24/93 (26%) intubations, with a median duration of bradycardia of 8 s (IQR 1-10). CONCLUSION: Despite the widespread move to premedication for neonatal intubation, many deficiencies in everyday practice remain. The rate of haemodynamic complications is high in this commonly used premedication regimen. This study shows that there are important factors to control at the local level in terms of timely preparation and administration of premedication drugs, training and supervision of staff carrying out this high risk procedure. PMID- 20842379 TI - Primary care-based surveillance to estimate the burden of rotavirus gastroenteritis among children aged less than 5 years in six European countries. AB - This observational, prospective study was undertaken to estimate the burden of rotavirus (RV) gastroenteritis (GE) leading to general practitioner (GP)/family paediatrician (FP) visits among children aged <5 years in Czech Republic, Germany, Italy, Poland, Spain and the UK. Children aged <5 years presenting with acute GE provided stool samples for rapid RV testing. RV+ samples were confirmed and typed by RT-PCR. Demographic and clinical data were collected for all RVGE episodes. Transmission patterns among other household children aged <5 years were also assessed. From November 2005 to May 2007, excluding data from the UK, 497/3,813 (13.0%) children aged <5 years presenting with acute GE to GP/FP and tested were RV+ by PCR. Most RVGE cases (69.1%) occurred in children aged <2 years, occurred between December and May (93.1%) and were moderate or severe by Vesikari score (92.9%). RV strain distribution varied between countries: G9P[8] was the most common type in Poland (54/76) and Spain (172/196), G1P[8] was predominant in the Czech Republic (56/64) and Italy (46/107), and G4P[8] and G1P[8] both prevailed in Germany (17/54 and 13/54, respectively). A total of 24/122 (19.7%) children aged <5 years resident in the same household as a PCR+ study participant also developed RVGE. Conclusion. This multinational epidemiological study in Europe shows that RV is easily transmitted among household children, with RVGE burden highest among children aged <2 years accessing primary healthcare for acute GE. PMID- 20842380 TI - Comparing demographic parameters for philopatric and immigrant individuals in a long-lived bird adapted to unstable habitats. AB - Theoretical models about the benefits of philopatry predict that immigrant fitness can be higher, lower or similar to that of philopatrics depending on habitat heterogeneity, dispersal costs, distance between patches or population densities. In this study, we compared transience rates, local survival and recruitment among philopatric and immigrant individuals of Audouin's gull Larus audouinii, a long-lived bird with high dispersal capacities. Several previous studies have shown that these capacities were probably the result of adaptation to unstable and highly discrete habitats; hence, we tested the hypothesis that fitness components for philopatrics and immigrants were similar. During 1988 2006, ca. 27,800 chicks were marked in 31 colonies in the western Mediterranean metapopulation, and more than 52,000 resightings were made in a single, high quality colony, to estimate local demographic parameters by capture-recapture analyses. Results suggest that, even though parameters related to site-tenacity (e.g. recapture rates) were higher for philopatrics than for immigrants, survival and recruitment were fundamentally similar. Small differences between philopatrics and immigrants were probably influenced by a highly suitable habitat at the study site, which reduced dispersal costs for immigrants; furthermore, the similarities in most fitness components were also probably the result of a life history strategy of a species living in unpredictable, unstable habitats with high emigration rates among local populations, and with a relatively low cost of dispersal. PMID- 20842381 TI - Reassessment of the environmental model of developmental polyphenism in spadefoot toad tadpoles. AB - Polyphenism is the expression of multiple, discrete phenotypes from one genotype, and understanding the environmental factors that trigger development of alternative phenotypes is a critical step toward understanding the evolution of polyphenism and its developmental control. While much is known about the ecology of the well-known carnivore/omnivore polyphenism in spadefoot toad tadpoles, the environmental cues for the development of the specialized carnivore phenotype are not completely clear. We examined 27 different experimental treatments in two spadefoot toad species and used over 1,000 tadpoles in an attempt to elucidate those cues. While only 44 carnivores developed in these treatments, they were concentrated at cooler water temperatures and a diet that included fairy shrimp. However, while a diet of fairy shrimp promoted carnivore development, it was not necessary for inducing carnivore development at lower and intermediate water temperatures. Evidence also suggested a role for social inhibition that limited the proportion of interacting tadpoles that become carnivores. Tadpoles of Spea multiplicata grew larger at cooler temperatures and larger when their diets included fairy shrimp, whereas tadpoles of S. bombifrons grew larger at warmer temperatures and when their diets did not include fairy shrimp. These results indicate that carnivore induction can occur through different cues and that our current model for carnivore development is too limited. Finally, we argue that the carnivore/omnivore spadefoot system is neither a polyphenism nor a polymorphism but is a continuously distributed plasticity. PMID- 20842383 TI - Diplochory in western chokecherry: you can't judge a fruit by its mesocarp. AB - Western chokecherry (Prunus virginiana var. demissa, Rosaceae) is dispersed by frugivorous birds and carnivores, but it has large seeds that are potentially attractive to rodents that could act as seed predators and dispersers. Here, we quantify the benefits of primary dispersal by birds and secondary dispersal by scatter-hoarding rodents. In the fall, avian frugivores (mostly American robins, Turdus migratorius, and cedar waxwings, Bombycilla cedrorum) consumed 87% of the fruit crop and dispersed 67% of the fruit crop away from parent plants. Rodents removed 89% of seeds that simulated bird-dispersed seed rain from transects in riparian zones and 58% from transects in upland habitats. Rodents scatter-hoarded 91.6% of the seeds they removed, burying most in small caches (two to eight seeds) 8-25 mm deep. About 39% of the seeds in spring caches produced seedlings. Inside rodent-proof exclosures, 52.1% of seeds buried to simulate rodent caches produced seedlings, 29.7% of which were still alive after 1 year. In contrast, only 3.8% of seeds placed on the soil surface, simulating dispersal by avian frugivores, produced seedlings. Seed dispersal by frugivorous birds likely contributes to colonization of unoccupied habitat through long-range dispersal and to escape from distance-dependent seed mortality near the parent plant. Despite seed losses, rodents offer short-range seed dispersal and bury seeds in more favorable sites for germination, improving seedling emergence and establishment. The combined mechanisms of seed dispersal significantly enhanced chokecherry seedling recruitment by providing more dispersal-related benefits than either frugivorous bird or scatter-hoarding rodents could provide alone. PMID- 20842382 TI - Defoliation negatively affects plant growth and the ectomycorrhizal community of Pinus pinaster in Spain. AB - In this work, by artificially reproducing severe (75%) and moderate (25%) defoliation on maritime pines Pinus pinaster in NW Spain, we investigated, under natural conditions, the consequences of foliage loss on reproduction, abundance, diversity and richness of the fungal symbionts growing belowground and aboveground. The effect of defoliation on tree growth was also assessed. Mature needles were clipped during April 2007 and 2008. Root samples were collected in June-July 2007 and 2008. Collection of sporocarps was performed weekly from April 2007 to April 2009. Taxonomic identity of ectomycorrhizal fungi was assessed by using the internal transcribed spacer (ITS) regions of rDNA through the polymerase chain reaction (PCR) method, subsequent direct sequencing and BLAST search. Ectomycorrhizal colonization was significantly reduced (from 54 to 42%) in 2008 by 75% defoliation, accompanied with a decline in species richness and diversity. On the other hand, sporocarp abundance, richness and diversity were not affected by foliage loss. Some ECM fungal symbionts, which are assumed to have a higher carbon cost according to the morphotypes structure, were reduced due to severe (75%) defoliation. Furthermore, 75% foliage loss consistently depressed tree growth, which in turn affected the ectomycorrhizal growth pattern. Defoliation impact on ECM symbionts largely depends on the percentage of foliage removal and on the number of defoliation bouts. Severe defoliation (75%) in the short term (2 years) changed the composition of the ECM community likely because root biomass would be adjusted to lower levels in parallel with the depletion of the aboveground plant biomass, which probably promoted the competition among mycorrhizal types for host resources. The persistence of fungal biomass in mycorrhizal roots would be crucial for nutrient up-take and recovery from defoliation stress of the host plants. PMID- 20842384 TI - Progress of oral care and reduction of oral mucositis--a pilot study in a hematopoietic stem cell transplantation ward. AB - PURPOSE: Oral mucositis is a common symptomatic complication associated with hematopoietic stem cell transplantation (HCT). We use simple strategies aimed to reduce oral mucositis by keeping the oral cavity clean and moist. Here, we report on the progress of oral care and the changes in the degree of oral mucositis. The purpose of this pilot study is to evaluate the effects of our strategies on the prevalence and the severity of oral mucositis. METHODS: Fifty-three consecutive patients from 2003 to 2006 administered with conventional allogeneic HCT were enrolled in this study. The degree of oral mucositis was evaluated daily in all patients. Our oral care program was divided into two periods: "examination and trial period (2003 and 2004)" and "intensive oral care period (2005 and 2006)." In the latter, an oral care regimen was carried out systematically by a multidisciplinary team. RESULTS: Using our oral care strategies, the prevalence of ulcerative oral mucositis was decreased significantly. The rate was reduced from 76% (10 of 13) of patients with ulcerative oral mucositis in 2003 to only 20% (3 of 15) in 2006. CONCLUSIONS: Our pilot study suggests that oral mucositis in HCT patients can be alleviated by simple strategies aimed at keeping the oral cavity clean and moist. PMID- 20842385 TI - The role of fiberoptic endoscopy in the evaluation and management of long gap isolated esophageal atresia. AB - Accurate measurement of gap length is useful for operative planning in cases of esophageal atresia (EA) without distal fistula. This paper demonstrates how fiberoptic endoscopy of the distal esophagus enables measurement of the gap in the case of isolated EA, and compares other commonly practiced techniques. PMID- 20842387 TI - Repair of cleft lip and simultaneous repair of cleft hard palate with vomer flap in unilateral complete cleft lip and palate: a comparative study. AB - Repair of anterior palate after repairing the cleft lip in complete cleft lip and palate patient is sometimes very difficult. It needs wide, extensive and difficult dissection, and has later chances of wound infection, wound dehiscence, complete wound disruption, recurrent oronasal fistula formation and also maxillary hypoplasia. In this study, we compare the outcome of simultaneous repair of cleft lip and cleft hard palate with vomer flap against cleft lip repair alone in patients with unilateral complete cleft lip and palate (UCLP). METHODS: A prospective study was carried out in 43 patients with UCLP. In Group A, 23 patients underwent cleft lip and cleft hard palate repair with vomer flaps simultaneously, and only cleft lip repair was done in another 20 patients in Group B at the first sitting. After 3 months in both groups, repair of the cleft soft palate and cleft entire palate was done. The gaps of the cleft alveolus and posterior border of the cleft hard palate were measured during the first and second operation, and duration of operations, postoperative complications and requirement of blood transfusion during the operation were also recorded. RESULTS: The procedure of simultaneous repair of cleft lip and closure of cleft hard palate with a vomer flap is easy to perform. Cleft alveolar and gap of the posterior border of the cleft hard palate were reduced remarkably. No fistula formation occurred and no blood transfusion was needed, but the procedure took some extra operating time. These were compared with simple cleft lip repair. CONCLUSION: Repairs of cleft lip and simultaneous closure of cleft hard palate with vomer flaps are safe in patients with UCLP, and it makes easy the closure of the soft palate later on and decreases the chance of oronasal fistula. PMID- 20842386 TI - Influence of fetal stabilization on postnatal status of patients with congenital diaphragmatic hernia. AB - PURPOSE: Fetal stabilization (FS) is a way to decrease stresses to the fetus during the perinatal period to control persistent pulmonary hypertension in neonates (PPHN). Although FS in congenital diaphragmatic hernia (CDH) patients has been reported, the effect of FS has not been evaluated sufficiently. The present study retrospectively evaluated influences of FS on the postnatal status of CDH patients. METHODS: Twenty-three cases of prenatally diagnosed CDH which were treated after birth in our institution from April 1998 to March 2010 were reviewed. From April 1998 to May 2007, FS was performed by administration of fentanyl and midazolam to the mother before subsequent cesarean section (FS group, n = 10). Beginning from June 2007, FS was discontinued (non-FS, n = 13). RESULTS: At the first postnatal estimation, flow pattern of the ductus arteriosus had no difference between two groups. The oxygenation index of the FS group was significantly higher than that in the non-FS group (p = 0.045). Only the non-FS group had correlations between estimated standardized lung volume (% lung volume) and alveolar-arterial oxygen tension difference (p = 0.022), and between % lung volume and the oxygenation index (p = 0.0037). CONCLUSION: During the period immediately after birth, FS had no obvious therapeutic effect on PPHN, and had a negative impact on respiratory status. PMID- 20842388 TI - Posterior lumbar interbody fusion using non resorbable poly-ether-ether-ketone versus resorbable poly-L-lactide-co-D,L-lactide fusion devices. Clinical outcome at a minimum of 2-year follow-up. AB - Previous papers on resorbable poly-L-lactide-co-D,L-lactide (PLDLLA) cages in spinal fusion have failed to report adequately on patient-centred clinical outcome measures. Also comparison of PLDLLA cage with a traditionally applicable counterpart has not been previously reported. This is the first randomized prospective study that assesses clinical outcome of PLDLLA cage compared with a poly-ether-ether-ketone (PEEK) implant. Twenty-six patients were randomly assigned to undergo instrumented posterior lumbar interbody fusion (PLIF) whereby either a PEEK cage or a PLDLLA cage was implanted. Clinical outcome based on visual analogue scale scores for leg pain and back pain, as well as Oswestry Disability Index (ODI) and SF-36 questionnaires were documented and analysed. When compared with preoperative values, all clinical parameters have significantly improved in the PEEK group at 2 years after surgery with the exception of SF-36 general health, SF-36 mental health and SF-36 role emotional scores. No clinical parameter showed significant improvement at 2 years after surgery compared with preoperative values in the PLDLLA patient group. Only six patients (50%) in the PLDLLA group showed improvement in the VAS scores for leg and back pain as well as the ODI, as opposed to 10 patients (71%) in the PEEK group. One-third of the patients in the PLDLLA group actually reported worsening of their pain scores and ODI. Three cases of mild to moderate osteolysis were seen in the PLDLLA group. Following up on our preliminary report, these 2-year results confirm the superiority of the PEEK implant to the resorbable PLDLLA implant in aiding spinal fusion and alleviating symptoms following PLIF in patients with degenerative spondylolisthesis associated with either canal stenosis or foramen stenosis or both and emanating from a single lumbar segment. PMID- 20842389 TI - The importance of anti-insulin antibody in patients with type 1 diabetes mellitus treated with continuous subcutaneous insulin infusion or multiple daily insulin injections therapy. AB - To investigate the influence of two insulin administration modalities, continuous subcutaneous insulin infusion (CSII) and multiple daily insulin injections (MDI) therapy with insulin analogues, on the development of insulin antibodies (IAs) in patients with type 1 diabetes mellitus and to assess the impact of IAs on glucose control and hypoglycaemia. 96 patients with type 1 diabetes mellitus treated with CSII (n = 48) or MDI (n = 48) were included in the study. Age, duration of diabetes, A1c, preprandial and postprandial blood glucose and hypoglycaemic events were compared between IA positive and negative patients. IA levels were higher in the CSII group (% 24.6 +/- 14.2) than the MDI group (% 13.2 +/- 9.9). Duration of diabetes and age were not associated with IA positiveness. While A1c, preprandial blood glucose and the frequency of hypoglycaemic events were similar in two groups, postprandial blood glucose was lower in IA positive group (P = 0.03). Patients with type 1 diabetes mellitus treated with CSII with insulin analogues had higher IA levels when compared to MDI therapy. However, the development of IAs did not impair the glycaemic control. PMID- 20842390 TI - Complete genome sequence of Brugmansia suaveolens mottle virus, a potyvirus from an ornamental shrub. AB - Brugmansia suaveolens mottle virus (BsMoV) was the first potyvirus isolated from "angel trumpet" (Brugmansia suaveolens), described in Brazil. In this study, the complete nucleotide (nt) genome sequence of BsMoV was determined, and the deduced amino acid (aa) sequence was analyzed. The BsMoV RNA genome consists of 9870 nt without a poly-A tail, encoding a putative typical potyviral polyprotein of 3090 aa. Pairwise comparisons of the complete BsMoV genome with those of the most closely related potyviruses revealed a maximum nucleotide identity of 63.7% with pepper mottle virus. These results and phylogenetic analyses based on the complete genome sequence of the most closely related potyviruses confirmed that BsMoV should be considered a member of a distinct species of the genus Potyvirus. PMID- 20842391 TI - Interaction of the hepatitis C virus (HCV) core with cellular genes in the development of HCV-induced steatosis. AB - Hepatitis C virus (HCV) has chronically infected a large number of patients, leading to the development of steatosis, cirrhosis and, ultimately, hepatocellular carcinoma. The pathogenesis of HCV has not been fully explained, although steatosis is considered to contribute greatly to liver fibrosis progression, modulating host-cell lipid metabolism. Suspected underlying molecular mechanisms include interactions between HCV proteins and intracellular lipid metabolic pathways. Recent studies have suggested that the nucleocapsid of HCV (core) acts as a pathogenic factor involved in lipid droplet accumulation, changes in lipogenic gene expression and/or the activity of lipogenic proteins in a genotype-specific manner. In this review, we have tried to summarize the current knowledge regarding HCV-induced steatosis and the regulation of expression of host genes and receptors that aid in the viral life cycle and promote liver diseases. PMID- 20842392 TI - Isolation of bluetongue virus serotype 1 (BTV-1) from goats and its phylogenetic relationship to other BTV-1 isolates worldwide based on full-length sequence of genome segment-2. AB - Eight bluetongue viruses (BTV) were isolated in BHK-21 cell culture from blood of goats suffering from peste des petits ruminants. These viruses were identified as BTV serotype 1 (BTV-1) by RT-PCR using VP2-gene-based primers coupled with sequencing of the PCR products. All of the isolates showed similar genome migration profile in 8% polyacrylamide gel electrophoresis. The genome segment-2 (seg-2) of one isolate (MKD18/India/2008) was amplified piecemeal by overlapping PCR, and the products were sequenced to obtain full-length seg-2. Phylogenetic analysis based on the seg-2 sequence revealed that MKD18 is closely related to Australian BTV-1 isolates, with 86.3-86.8% nucleotide identity. Phylogenetic analysis based on the partial sequence of seg-2 (541 bp, nucleotides 1,304-1,844) showed that the Indian BTV-1 isolates, namely, MKD18, Avikanagar, Sirsa-3 and Chennai, are very closely related to each other, with more than 99.6% nucleotide identity. Although a high degree of similarity exists, the Indian BTV-1 isolates collected over the past 25 years should be studied to demonstrate the co existence of different VP2 antigenic profiles. PMID- 20842393 TI - Persistence in darkness of virulent alphaviruses, Ebola virus, and Lassa virus deposited on solid surfaces. AB - Ebola, Lassa, Venezuelan equine encephalitis, and Sindbis viruses were dried onto solid surfaces, incubated for various time periods under controlled conditions of temperature and relative humidity, and quantitatively eluted from surfaces, and viral titers in the recovered samples were determined. The viral inactivation kinetics that were obtained indicated that viral resistance to natural inactivation in the dark follows (in decreasing order of stability) alphavirus > Lassa virus > Ebola virus. The findings reported in this study on the natural decay in the dark should assist in understanding the biophysical properties of enveloped RNA viruses outside the host and in estimating the persistence of viruses in the environment during epidemics or after an accidental or intentional release. PMID- 20842394 TI - Hepatitis C virus quasispecies in chronically infected children subjected to interferon-ribavirin therapy. AB - Accumulating evidence suggests that certain features of hepatitis C virus (HCV), especially its high genetic variability, might be responsible for the low efficiency of anti-HCV treatment. Here, we present a bioinformatic analysis of HCV-1a populations isolated from 23 children with chronic hepatitis C (CHC) subjected to interferon-ribavirin therapy. The structures of the viral quasispecies were established based on a 132-amino-acid sequence derived from E1/E2 protein, including hypervariable region 1 (HVR1). Two types of HCV populations were identified. The first type, found in non-responders, contained a small number of closely related variants. The second type, characteristic for sustained responders, was composed of a large number of distantly associated equal-rank variants. Comparison of 445 HVR1 sequences showed that a significant number of variants present in non-responding patients are closely related, suggesting that certain, still unidentified properties of the pathogen may be key factors determining the result of CHC treatment. PMID- 20842395 TI - Composition of amino acids in feed ingredients for animal diets. AB - Dietary amino acids (AA) are crucial for animal growth, development, reproduction, lactation, and health. However, there is a scarcity of information regarding complete composition of "nutritionally nonessential AA" (NEAA; those AA which can be synthesized by animals) in diets. To provide a much-needed database, we quantified NEAA (including glutamate, glutamine, aspartate, and asparagine) in feed ingredients for comparison with "nutritionally essential AA" (EAA; those AA whose carbon skeletons cannot be formed by animals). Except for gelatin and feather meal, animal and plant ingredients contained high percentages of glutamate plus glutamine, branched-chain AA, and aspartate plus asparagine, which were 10-32, 15-25, and 8-14% of total protein, respectively. In particular, leucine and glutamine were most abundant in blood meal and casein (13% of total protein), respectively. Notably, gelatin, feather meal, fish meal, meat and bone meal, and poultry byproduct had high percentages of glycine, proline plus hydroxyproline, and arginine, which were 10-35, 9.6-35, and 7.2-7.9% of total protein, respectively. Among plant products, arginine was most abundant in peanut meal and cottonseed meal (14-16% of total protein), whereas corn and sorghum had low percentages of cysteine, lysine, methionine, and tryptophan (0.9-3% of total protein). Overall, feed ingredients of animal origin (except for gelatin) are excellent sources of NEAA and EAA for livestock, avian, and aquatic species, whereas gelatin provides highest amounts of arginine, glycine, and proline plus hydroxyproline. Because casein, corn, soybean, peanut, fish, and gelatin are consumed by children and adults, our findings also have important implications for human nutrition. PMID- 20842396 TI - How many hydrogen-bonded alpha-turns are possible? AB - The formation of alpha-turns is a possibility to reverse the direction of peptide sequences via five amino acids. In this paper, a systematic conformational analysis was performed to find the possible isolated alpha-turns with a hydrogen bond between the first and fifth amino acid employing the methods of ab initio MO theory in vacuum (HF/6-31G*, B3LYP/6-311 + G*) and in solution (CPCM/HF/6-31G*). Only few alpha-turn structures with glycine and alanine backbones fulfill the geometry criteria for the i<-(i + 4) hydrogen bond satisfactorily. The most stable representatives agree with structures found in the Protein Data Bank. There is a general tendency to form additional hydrogen bonds for smaller pseudocycles corresponding to beta- and gamma-turns with better hydrogen bond geometries. Sometimes, this competition weakens or even destroys the i<-(i + 4) hydrogen bond leading to very stable double beta-turn structures. This is also the reason why an "ideal" alpha-turn with three central amino acids having the perfect backbone angle values of an alpha-helix could not be localized. There are numerous hints for stable alpha-turns with a distance between the C(alpha)-atoms of the first and fifth amino acid smaller than 6-7 A, but without an i<-(i + 4) hydrogen bond. PMID- 20842397 TI - Retrospective study on PET-SPECT imaging in a large cohort of myotonic dystrophy type 1 patients. AB - The aim was to study brain involvement in myotonic dystrophy type 1 by single photon emission tomography (SPECT) and positron emission tomography (PET). 58 DM1 patients were subjected to SPECT; 17 to both SPECT and PET. SPECT patients were grouped as 'normally perfused' and 'abnormally perfused'; PET patients as 'normal performers' and 'abnormal performers'. To quantify hypoperfusion and/or hypometabolism, we used a semi-quantitative scale. To localize focal hypoperfusion/hypometabolism, nine cerebral areas of involvement were identified. The Chi-square, Wilcoxon, McNemar tests were used for statistics. SPECT showed abnormalities in 52/58 patients. PET showed an abnormal glucidic uptake in 15/17. Hypoperfusion was mild/moderate in 50/58 patients, mostly involving the left supratentorial areas. Abnormal glucidic uptake was mainly observed in the left frontal lobe. Abnormalities in blood perfusion and/or glucose metabolism are frequent in DM1. These abnormalities involve the left more often than the right hemisphere, the frontal lobe more than other lobes. Such abnormalities are more often cortical than subcortical. PMID- 20842398 TI - Intracranial cavernoma and speckled lentiginous nevus: extending the spectrum of phakomatoses? AB - Phakomatosis refers to several malformation syndromes with simultaneous involvement of the skin, the eye, and the central nervous system by developmental lesions. Speckled lentiginous nevus (SLN), a subtype of congenital melanocytic nevi, is usually an isolate, harmless finding. Here, we report the case of a 52 year-old woman with congenital left laterocervical SLN associated with an ipsilateral intracranial extra-axial cavernous angioma, a yet not described association to date. After revision of the literature, we suggest that both these lesions could be correlated in the setting of an atypical, yet unclassifiable form of phakomatosis, such as phakomatosis pigmentovascularis or SLN syndrome. We also propose that patients with bizarre, geometrical, pigmented or vascular cervicocranial skin lesions should undergo a thorough neurologic and ophthalmologic evaluation. PMID- 20842400 TI - Audit and improve! Evaluation of a real-time probe-based PCR assay with internal control for the direct detection of Mycobacterium tuberculosis complex. AB - We retrospectively audited the performance of the commercial kit in use in our laboratory for the detection of Mycobacterium tuberculosis complex (MTBC) and found the sensitivity to be unacceptably low at 69% (52/75). We developed an in house end-point polymerase chain reaction (PCR) detecting IS6110, an IS-like element of MTBC, and achieved a sensitivity of 90% (66/73) with the same DNA samples, re-emphasising the poor performance of the commercial kit. In order to avoid specificity issues surrounding gel-based PCR, we developed a probe-based real-time PCR assay with an internal control and achieved a sensitivity of 84%, specificity of 97% and diagnostic odds ratio (DOR) of 207. The evaluation was performed on clinically requested samples, so we expect the performance of the assay in real life to match the data from this evaluation. Centers for Disease Control and Prevention (CDC) guidelines recommending nucleic acid tests for the investigation of possible cases of tuberculosis are expected to promote the use of molecular assays. It is important that clinical laboratories do not assume that assays, in-house or commercial, will perform well or that they will continue to perform well. Audit at regular intervals is necessary to maintain confidence and to demonstrate that the assay works to specification in the real test population. PMID- 20842399 TI - Neurophysiological correlates of cognitive disturbances in multiple sclerosis. AB - Cognitive impairment is common in multiple sclerosis, mostly attributed to involvement of cortico-cortical and cortico-subcortical connections. The latter may be explored using the analysis of bioelectrical activity such as power and coherence of the electroencephalogram at rest and its reactivity to stimulus processing and cognitive activities, such as event-related desynchronization and event-related potentials. Although these methods are very useful for assessing information processing during cognitive tasks and other activities, their value in detecting cognitive impairment concerning sensitivity and specificity needs to be validated and they have been mostly used for understanding the physiopathology of cognitive impairment in different forms and stages of the diseases. Nevertheless, newer applications such as longitudinal monitoring and effects of treatment, although explored only in pilot studies, seem quite promising allowing objective measures potentially useful as secondary endpoints in clinical trials aimed at preserving or improving cognition in MS patients. PMID- 20842401 TI - Cytomegalovirus seroprevalence in exposed and unexposed populations of hospital employees. AB - The objective of this work was to compare the seroprevalence of cytomegalovirus in an unexposed and exposed population, both working in a hospital, and to study the occupational risk factors related to seropositivity, while taking personal risk factors into account. We conducted a cross-sectional study in a French hospital over a period of 12 months. The overall seroprevalence among the 550 subjects was 49.5%. The multivariate analysis showed that seropositivity was significantly associated with age (36-43 years: odds ratio [OR] = 1.7; 95% confidence interval [CI]: [1.1-2.8]) and working as a pediatric nurse's aide (OR = 1.8; 95% CI: [1.1-2.8]). This study confirms the need to improve prevention procedures in the workplace, including screening, information, and hygiene rules. PMID- 20842402 TI - Utility of CT perfusion with 64-row multi-detector CT for acute ischemic brain stroke. AB - We investigated the utility of computed tomographic (CT) perfusion (CTP) with 64 row multi-detector row CT (MDCT) to diagnose acute infarction and ischemic penumbra. We reviewed 58 clinical cases with acute ischemic stroke with CTP, compared the size of the area with long mean transit time (MTT) to that with abnormal intensity in magnetic resonance (MR) diffusion-weighted imaging (DWI) to diagnose penumbra, and compared the size of the area with reduced cerebral blood volume (CBV) in CTP to that in MR DWI to evaluate sensitivity for infarction. The total sensitivity of MTT to acute ischemic lesions was 81% (47/58). Sensitivity of MTT to segmental lesions was 100% (42/42) and for spot and focal lesions, 31% (5/16). In 13 patients, penumbra was diagnosed as lesions mismatched between MTT in CTP and MR DWI. When we regarded a lesion with decreased CBV as infarction, the sensitivity of CBV to segmental lesions was 85% (11/13), and the sensitivity to small infarction was 14% (4/28). Use of 64-row MDCT improves coverage and radiation exposure in head CTP. The combination of plain CT, CT angiography, and CTP with MDCT can demonstrate all segmental ischemic lesions and most large segmental infarctions, and their combined application is useful in considering indication and contraindication for thrombolysis. The problem of low sensitivity for small lesions remains, and MR DWI may be required to assess small infarctions when findings from combined plain CT, CT angiography, and CTP are negative in patients with suspected acute brain stroke. PMID- 20842405 TI - Incidence of falls and fear of falling in Japanese patients with rheumatoid arthritis. AB - The objective of this study is to determine the incidence of falls and fear of falling by gender and age in Japanese patients with rheumatoid arthritis (RA). Among the Japanese patients who participated in a single-institute-based prospective observational cohort study of patients with RA, namely the Institute of Rheumatology Rheumatoid Arthritis, 765 men (median age 63 years) and 4,231 women (median age 60 years) with RA responded to questions related to falls. Eight percent of men and 11% of women reported one or more falls during the previous 6 months. At least one fall and multiple falls were significantly more frequent in men (p < 0.05) and in women (p < 0.001) with RA over age 65 and age 75 years, respectively, although there was no significant linear increase in risk with age. Sixteen percent of men and 22% of women reported fear of falling. More men over age 65 tended to report fear of falling than those under age 65 (p < 0.001), although the incidence of women with fear of falling increased with advancing age. Japanese patients with RA over age 65 and age 75 appeared to have a high risk of at least one fall and multiple falls, respectively. PMID- 20842403 TI - The compact Brachypodium genome conserves centromeric regions of a common ancestor with wheat and rice. AB - The evolution of five chromosomes of Brachypodium distachyon from a 12-chromosome ancestor of all grasses by dysploidy raises an interesting question about the fate of redundant centromeres. Three independent but complementary approaches were pursued to study centromeric region homologies among the chromosomes of Brachypodium, wheat, and rice. The genes present in pericentromeres of the basic set of seven chromosomes of wheat and the Triticeae, and the 80 rice centromeric genes spanning the CENH3 binding domain of centromeres 3, 4, 5, 7, and 8 were used as "anchor" markers to identify centromere locations in the B. distachyon chromosomes. A total of 53 B. distachyon bacterial artificial chromosome (BAC) clones anchored by wheat pericentromeric expressed sequence tags (ESTs) were used as probes for BAC-fluorescence in situ hybridization (FISH) analysis of B. distachyon mitotic chromosomes. Integrated sequence alignment and BAC-FISH data were used to determine the approximate positions of active and inactive centromeres in the five B. distachyon chromosomes. The following syntenic relationships of the centromeres for Brachypodium (Bd), rice (R), and wheat (W) were evident: Bd1-R6, Bd2-R5-W1, Bd3-R10, Bd4-R11-W4, and Bd5-R4. Six rice centromeres syntenic to five wheat centromeres were inactive in Brachypodium chromosomes. The conservation of centromere gene synteny among several sets of homologous centromeres of three species indicates that active genes can persist in ancient centromeres with more than 40 million years of shared evolutionary history. Annotation of a BAC contig spanning an inactive centromere in chromosome Bd3 which is syntenic to rice Cen8 and W7 pericentromeres, along with BAC FISH data from inactive centromeres revealed that the centromere inactivation was accompanied by the loss of centromeric retrotransposons and turnover of centromere-specific satellites during Bd chromosome evolution. PMID- 20842404 TI - Survival and prognosticators of node-positive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. AB - OBJECTIVE: Lymph node metastasis (LNM) is known to be the most important prognostic factor in cervical cancer. We analyzed the number of positive lymph nodes and other clinicopathological factors as prognostic factors for survival in node-positive patients with cervical cancer. METHODS: Node-positive cervical cancer patients (n = 108) who underwent radical hysterectomy and systematic lymphadenectomy in Hokkaido University Hospital from 1982 to 2002 were enrolled. Clinicopathological data including age, stage, histologic subtype, and the number of LNM sites were collected. The main outcome was the overall survival (OS) rate for Stage Ib-IIb patients treated with surgery and postoperative radiotherapy. RESULTS: The 5-year OS rate of patients with 1 positive node was 93.3%, that for 2 nodes was 77.3%, for 3 nodes it was 33.3%, and for 4 or more it was 13.8%. The OS rate of patients with 1 or 2 LNM sites was significantly better than that for patients with more than 2 LNM sites. The OS rate of patients with adenocarcinoma (Ad) (28.6%) was significantly lower than that for patients with other histologic subtypes (squamous cell carcinoma; 66.7%, adenosquamous carcinoma; 75.0%, p = 0.0003). Multivariate analysis revealed that >2 LNM sites and Ad were independent prognostic factors for survival. The 5-year OS rate of patients with 1 or 2 LNM sites was 86.8%, a more favorable prognosis than the OS rates in other reports. CONCLUSION: More than two LNM sites and adenocarcinoma were independent prognostic factors for node-positive patients with cervical cancer. PMID- 20842406 TI - A comparison of the pharmacokinetics of the anticancer MET inhibitor foretinib free base tablet formulation to bisphosphate salt capsule formulation in patients with solid tumors. AB - PURPOSE: This phase I, open-label, randomized, 2-part crossover study assessed the safety, pharmacokinetics and relative bioavailability of single doses of the anticancer MET inhibitor foretinib (formerly known as GSK1363089, EXEL-2880 and XL-880) free base tablet formulation compared to a bisphosphate salt capsule formulation (Part 1), and assessed the safety, efficacy, and pharmacokinetics of the bisphosphate salt capsule administered 3 times a week in cancer patients (Part 2). PATIENTS AND METHODS: In Part 1, patients were randomized in a crossover manner to receive a single oral dose of foretinib formulated as a bisphosphate salt capsule (240 mg; 183 mg free base equivalent) followed one week later by a single dose of a free base tablet (180 mg), or vice versa where the treatment sequence was reversed. In Part 2, patients self-administered oral doses of bisphosphate salt capsules (200 mg) 3 times a week until disease progression. RESULTS: Twelve patients with solid tumors were enrolled and completed Part 1, and 10 patients continued into Part 2. Most AEs were mild or moderate in severity. The most common drug-related AEs were fatigue, diarrhea, and nausea. The least-squares (LS) mean total area under the curve was 3144 and 3514 ng*h/mL for the free base tablet and bisphosphate salt capsule, respectively, with a ratio of 0.89 (90% confidence interval, CI: 0.69, 1.16). The LS mean maximal concentration (Cmax) was 81.6 and 98.5 ng/mL for the free base and bisphosphate salt, respectively, with a ratio of 0.83 (90% confidence interval, CI: 0.67, 1.02). The time to reach Cmax was ~4 h for both formulations. The pharmacokinetics of foretinib were not clinically different between the 2 formulations. Of the 10 patients assessed for efficacy, 3 patients achieved stable disease. CONCLUSIONS: Foretinib was well tolerated as single doses of both the free base and bisphosphate salt formulations. The pharmacokinetics and relative bioavailability of the 2 formulations were not clinically different. The bisphosphate salt formulation was well tolerated on a 3-times a week dosing schedule, and reached steady-state plasma concentration after 2 weeks. PMID- 20842407 TI - Ventriculoperitoneal shunt complications in hydrocephalus patients with intracranial tumors: an analysis of relevant risk factors. AB - Patients with intracranial tumors are predisposed to persistent hydrocephalus, often requiring a permanent CSF diversion procedure with shunts. This study reviews the long-term experience with ventriculoperitoneal shunts for the management of hydrocephalus in patients with intracranial tumors. Patients with intracranial tumors who underwent ventriculoperitoneal shunt placement for hydrocephalus from October 1990 to October 2009 were included in this study. During the 19-year period, medical charts, operative reports, imaging studies, and clinical follow- up evaluations were reviewed and analyzed retrospectively for all patients. A total of 187 intracranial tumor patients with hydrocephalus were included. The median follow up was 391 days. Malignant tumors were present in 40% of the patients. Overall shunt failure was 27.8%. Single shunt revision occurred in 13% of the patients and 14% had multiple shunt revision. Tumor histology, age and a procedure prior to shunt placement (ventriculostomy/Ommaya reservoirs) were significantly associated with the shunt revisions. Shunt system replacement and proximal shunt complication were significantly attributed to multiple shunt revisions. The overall shunt revision within 3 months, 6 months, 1 year and 5 years was 17.7%, 18.7%, 19.8% and 24.1%, respectively. The results of the study demonstrate that VP shunting is an effective for the management of hydrocephalus in patients with intracranial tumors. The overall incidence of shunt revision was 27.8%. Age, tumor histology, and a procedure prior to shunt placement (ventriculostomy/Ommaya reservoirs) were significantly associated with the shunt revisions. Additional studies using minimally invasive techniques are being explored for the management of hydrocephalus in patients with intracranial tumors. PMID- 20842408 TI - Calibrative approaches to protein solubility modeling of a mutant series using physicochemical descriptors. AB - A set of physicochemical properties describing a protein of known structure is employed for a calibrative approach to protein solubility. Common hydrodynamic and electrophoretic properties routinely measured in the bio-analytical laboratory such as zeta potential, dipole moment, the second osmotic virial coefficient are first estimated in silico as a function a pH and solution ionic strength starting with the protein crystal structure. The utility of these descriptors in understanding the solubility of a series of ribonuclease Sa mutants is investigated. A simple two parameter model was trained using solubility data of the wild type protein measured at a restricted number of solution pHs. Solubility estimates of the mutants demonstrate that zeta potential and dipole moment may be used to rationalize solubility trends over a wide pH range. Additionally a calibrative model based on the protein's second osmotic virial coefficient, B22 was developed. A modified DVLO type potential along with a simplified representation of the protein allowed for efficient computation of the second viral coefficient. The standard error of prediction for both models was on the order of 0.3 log S units. These results are very encouraging and demonstrate that these models may be trained with a small number of samples and employed extrapolatively for estimating mutant solubilities. PMID- 20842409 TI - Induction chemotherapy response and recurrence rates in correlation with N0 or N+ stage in oral squamous cell cancer (OSCC). AB - The authors compared N0 with N+ cases in neoadjuvant chemotherapy regression and recurrence. During a 12-year period, 180 consecutive oral squamous cell cancer patients were observed. Of these patients, 78 were N0 and 102 N+ stages. The drugs used were as follows: bleomycin, vincristine, methotrexate, and mitolactol. After three courses of chemotherapy, the regression (complete response (CR), partial response (PR), and no response (NR)) and side effect rate were determined. All patients were operated on and observed for the number and localization of recurrences during 3 year follow-up time. The N0 cases came from T2-3, while N+ was from T2-4a (AJCC 2002). The regression in the N0 group was CR 46%, PR 53%, and NR 1%; but in the N+ group, it was CR 12%, PR 72%, and NR 16%. The regression rate was significantly higher (p = 0.00025) for N0 group than N+ group. The regression rate for T3 N0 was significantly higher (p = 0.055) than for T3 N+ cases. In the N0 stage, the regression rate was significantly higher (p = 0.0174) for T2 than T3. In N+ stage, there was no significant difference (p = 0.183) for T2-4a. The side effects were slight. The recurrence rate for the N0 group was significantly lower (15%, p = 0.000069), while for N+ group, it was 59%. The dependence in the T3 cases was also significant (p = 0.009) in the 3 year tumor-free survival. The N stage seems a more important prognostic factor for chemotherapy response and recurrence rate than the T stage. Stage III can be divided into subgroups without metastasis (III.a) and with metastasis (III.b.), based on significant difference in regression and recurrence rate. PMID- 20842410 TI - Comparative morphology and ultrastructure of the mouthparts in unfed larvae of Platytrombidium fasciatum and Camerotrombidium pexatum (Acariformes: Microtrombidiidae). AB - The mouthparts of unfed larvae of Platytrombidium fasciatum (C. L. Koch, 1836) and Camerotrombidium pexatum (C. L. Koch, 1837) (Acariformes: Microtrombidiidae) were studied using both light optical (whole-mounted specimens, toluidine blue stained semi-thin sections) and electron microscope (TEM, SEM) methods. The mouth apparatus incorporated within the gnathosoma occupies an axial position and is covered from above by the arched dorsal shield, or scutum. The chelicerae are comparatively long and separated, and the lateral lips form a permanent apomorphic sucker provided with an internal cuticular sclerite. The pharynx is extremely wide and totally fused with the bottom of the infracapitulum. The pharyngeal dilators originate on the posterior portions of the cervix (epistome) and on the capitular apodemes and run nearly parallel to the cervix to the dorsal pharyngeal wall. Comparatively short sigmoid pieces serve as origin of the muscles--cheliceral levators inserting on the posterior wall of the basal cheliceral segments. There are two sets of the extrinsic gnathosomal muscles originating on the posterior portion of the scutum: retractors of chelicerae inserting on the posterior portions of the basal cheliceral segments, and retractors of the gnathosoma inserting on the very posterior parts of the capitular apodemes. The labrum and the cervix delimit the pharynx and the subcheliceral space. The labrum and the cervix for the most part are weakly sclerotized cuticular plates and do not have own muscles. The larval mouth apparatus, in comparison with that of adult microtrombidiid mites, is simply organized and more specialized for ingestion of large masses of liquid food. PMID- 20842411 TI - Design of a semisolid vaginal microbicide gel by relating composition to properties and performance. AB - PURPOSE: Develop a preclinical in vitro algorithm enabling de novo design of semisolid vaginal drug delivery gels, by using biomechanical modeling of gel spreading in the vaginal canal and empirically relating gel composition to mechanical properties and predicted performance. METHODS: Gel performance was defined through a multivariate objective function constructed from gels' mechanical properties and selected performance criteria for gel spreading within the vaginal canal. Mixture design of experiment was used to establish a semi empirical relationship linking composition-property and property-performance relationships for gels with varying concentrations of hydroxyethylcellulose and Carbopol 974P. This permits definition of a local optimum for gel composition and volume of administration, within a defined gel composition space. RESULTS: Rheological behavior and, consequently, the value of the objective function varied broadly with composition. The algorithm indicated a 3.0 wt% HEC gel as the near optimal composition for a 3.5 mL applied volume for gels designed to spread throughout the vagina. CONCLUSIONS: The algorithm introduced herein is a novel tool that facilitates an understanding of the composition-property-performance relationship for vaginal semisolid drug delivery gels. This approach has promise as a scientific methodology for evaluation and optimization of vaginal gels prior to in vivo investigations. PMID- 20842412 TI - Effects of volatiles from Maruca vitrata larvae and caterpillar-infested flowers of their host plant Vigna unguiculata on the foraging behavior of the parasitoid Apanteles taragamae. AB - The parasitoid wasp Apanteles taragamae is a promising candidate for the biological control of the legume pod borer Maruca vitrata, which recently has been introduced into Benin. The effects of volatiles from cowpea and peabush flowers and Maruca vitrata larvae on host selection behavior of the parasitoid Apanteles taragamae were investigated under laboratory conditions by using a Y tube olfactometer. Naive and oviposition-experienced female wasps were given a choice between several odor sources that included (1) uninfested, (2) Maruca vitrata-infested, and (3) mechanically damaged cowpea flowers, as well as (4) stem portions of peabush plants carrying leaves and flowers, (5) healthy M. vitrata larvae, and moribund (6), and live (7) virus-infected M. vitrata larvae. Responses of naive and oviposition-experienced female wasps did not differ for any of the odor source combinations. Wasps were significantly attracted to floral volatiles produced by cowpea flowers that had been infested with M. vitrata larvae and from which the larvae had been removed. Apanteles taragamae females also were attracted to Maruca vitrata-infested flowers after removal of both the larvae and their feces. Female wasps discriminated between volatiles from previously infested flowers and mechanically damaged flowers. Uninfested cowpea flowers attracted only oviposition-experienced wasps that had received a rewarding experience (i.e. the parasitization of two M. vitrata larvae feeding on cowpea flowers) before the olfactometer test. Wasps also were attracted to uninfested leaves and flowers of peabush. Moreover, they were also attracted to healthy and live virus-infected M. vitrata larvae, but not when the latter were moribund. Our data show that, similarly to what has been extensively been reported for foliar volatiles, flowers of plants also emit parasitoid-attracting volatiles in response to being infested with an herbivore. PMID- 20842413 TI - Partitioning of new carbon as 11C in Nicotiana tabacum reveals insight into methyl jasmonate induced changes in metabolism. AB - We examined the timeline by which methyl jasmonate (MeJA) reprograms new carbon partitioning into key metabolite pools. The radioactive isotope 11C (t(1/2) 20.4 min), administered to intact leaves of Nicotiana tabacum L. (cv Samsun) as 11CO(2) gas enabled us to measure changes in new carbon partitioning into soluble sugar and amino acid pools of [11C]photosynthate. A 500 MUM MeJA treatment resulted in a decrease in the [11C]soluble sugar pool and an increase in the [11C]amino acid pool after 4 h. This pattern was more pronounced 15 h after treatment. We also examined the timeline for 11C-partitioning into aromatic amino acid metabolites of the shikimate pathway. [11C]Tyrosine, [C11C]phenylalanine and [11C]tryptophan were elevated 1.5-fold, 12-fold and 12-fold, respectively, relative to controls, 4 h after MeJA treatment, while endogeneous pools were unchanged. This suggests that only new carbon is utilized during early stages of defense induction. By 15 h, [C11C]tyrosine and [11C]phenylalanine returned to baseline while [11C]tryptophan was elevated 30-fold, suggesting that MeJA exerts selective control over the shikimate pathway. Finally, we measured trans-cinnamic acid levels as a gauge of downstream phenolic metabolism. Levels were unchanged 4 h after MeJA treatment relative to controls, but were increased 2-fold by 15 h, indicating a lag in response of secondary metabolism. PMID- 20842415 TI - Staying cool across the first year of middle school. AB - As students transition into middle school they must successfully negotiate a new, larger peer context to attain or maintain high social standing. The goal of this study was to examine the extent to which the maintenance, attainment, and loss of a cool status over the course of the sixth grade is associated with student and classroom levels of physical, verbal, and relational aggression. To address this goal, we studied a sample of 1985 (55% girls) ethnically diverse adolescents from 99 sixth grade classrooms in the United States. Attaining a cool status at any point across the school year was associated with stronger aggressive reputations. Additionally, classroom norms for aggressive behavior moderated the association between changes in aggression over the school year and the stability of coolness such that students who maintained their coolness across the school year showed greater increases in their verbally aggressive reputations from fall to spring when they were in classrooms with higher levels of aggression. The findings illustrate the importance of fitting in with social norms for maintaining a high social status among a new set of peers in middle school. PMID- 20842416 TI - Depressive symptoms among adolescent girls in relationships with older partners: causes and lasting effects? AB - Previous research on adolescent girls in relationships with older partners suggests a range of negative outcomes for the adolescent. Using three waves of data from the National Longitudinal Survey of Adolescent Health and a life course perspective, we explore the connection between involvement in age discordant relationships (girls dating males three or more years older) and the course of depressive symptoms among adolescent girls. Our analyses are conducted on the 1,307 girls with data at all three waves who had been in a relationship in the last 18 months. The sample is 55% White, 22% Black, 7% other race and 16% Latina. When comparing early adolescent girls (13-15) and late adolescent girls (16-18), the younger girls are no more likely to have depressive symptoms before entry into the age discordant relationship, yet have greater depressive symptoms shortly after the relationship onset and 5 years later. Older adolescent girls in age discordant relationships, however, have similar levels of depressive symptoms at any time point relative to their peers. These data suggest that a girl's developmental stage influences whether or not she experiences emotional distress as a result of being in an age discordant relationship. PMID- 20842417 TI - Clinical observation of immunity for severe acute pancreatitis. AB - The aim of our study was to observe the dynamic changes of immunity for patients with severe acute pancreatitis (SAP) and intervention by traditional Chinese medicine. Twenty-three patients who met the inclusion criteria were randomized to combined treatment of traditional Chinese medicine and Western medicine (TCM) or conventional western medicine treatment (WM) groups. The clinical data for all patients were collected. Peripheral venous blood samples were obtained from patients on days 1, 7, 14, and 28 after admission. Biochemical data including the percentage of CD4+/CD8+/natural killer (NK) cells/B lymphocytes/HLA-DR and CD4+/CD8+ ratio in serum were determined by flow cytometer. Patients' characteristics and immunity at admission were similar between the two groups. The secondary infection was different. The levels of T-lymphocyte subsets in the TCM group were quite different from the WM group, with much more the percentage of CD4+ and the CD4+/CD8+ ratio on days 7, 14, and 28 and much less the percentage of CD8+ on days 4 and 28. On days 14 and 28, the levels of NK cells and B lymphocytes were significantly higher in the TCM group compared with the controls. Compared with the TCM group, the levels of HLA-DR were significantly decreased in the WM group on days 7, 14, and 28. The immune dysregulation exists in the development and progression of SAP. The combined treatment of traditional Chinese medicine and western medicine can upregulate the patient's immune and maintain the immune balance. PMID- 20842418 TI - The role of hyaluronic acid binding assay in choosing the fertilization method for patients undergoing IVF for unexplained infertility. AB - PURPOSE: Patients with unexplained infertility may have fertilization problems. Split fertilization (ICSI and conventional IVF on sibling oocytes) is often used to avoid poor fertilization. Our aim was to assess the ability of hyaluronic acid binding (HA-binding) assay to predict spontaneous fertilization during IVF. METHODS: Prospective, blinded, controlled trial. Patients undergoing their first IVF cycle for unexplained infertility were eligible. Split fertilization was used. IVF and ICSI fertilization rates and embryo development based on 3 HA binding cut-offs (< 60%; 60-80%; >80%) were compared. RESULTS: ICSI fertilization was higher than IVF, but none of the HA-binding cut-off levels predicted those cases where IVF was less effective, therefore ICSI only would have lead to improved outcome. Embryo development and morphology were similar in all cut-off groups. CONCLUSIONS: HA-binding did not predict spontaneous fertilization in patients with unexplained infertility undergoing IVF treatment. When it was used for "screening" it did not help to select the method of fertilization. PMID- 20842419 TI - Whole sheep ovary cryopreservation: evaluation of a slow freezing protocol with dimethylsulphoxide. AB - PURPOSE: To evaluate a slow freezing method for whole ovary cryopreservation by evaluating effects of added cryoprotectant. METHODS: Sheep ovaries were isolated during surgery, flushed with either Ringer-Acetate or dimethylsulphoxide and cryopreserved by slow freezing. After rapid thawing, viability was assessed by ovarian in vitro perfusion, cell culture, histology and fluorescent live-dead assay. RESULTS: Production of cyclic AMP and progesterone was slightly higher in the dimethylsulphoxide group. Cultured ovarian cells from dimethylsulphoxide preserved ovaries secreted larger amounts of progesterone than cells from Ringer Acetate preserved. Light microscopy of ovarian biopsies obtained after perfusion, revealed well-preserved tissue in the dimethysulphoxide group but not in the Ringer-Acetate group. The density of small follicles and ovarian cell viability were higher in dimethysulphoxide ovaries compared to Ringer-Acetate ovaries. CONCLUSIONS: Equilibrium with its protective effect can be achieved by slow freezing protocol, with an additional protective effect by the presence of dimethylsulphoxide. PMID- 20842421 TI - Characterization of the avian aryl hydrocarbon receptor 1 from blood using non lethal sampling methods. AB - The amino acid sequence of the aryl hydrocarbon receptor 1 ligand binding domain (AHR1 LBD) is an important determinant of sensitivity to dioxin-like compounds in avian species. We are interested in surveying AHR1 LBD sequences in a large number of birds as a means of identifying species that are particularly sensitive to dioxin-like compounds. Our original method for determining AHR1 LBD genotype used liver tissue and required lethal sampling. Here we present two alternate methods for determining AHR1 LBD genotype which use non-lethal sampling and are more appropriate for ecologically sensitive species. First, we establish that AHR1 LBD mRNA is expressed in avian blood and test a variety of blood collection and handling protocols in order to establish a method that is convenient for field collections. Our findings also identify which types of archival blood samples might be appropriate for AHR1 LBD sequence determination. Second, we present a method for obtaining AHR1 LBD coding sequences from DNA. A DNA-based method is advantageous because DNA can be isolated from many tissue types, is more stable than RNA, and requires less specific sample handling and preservation. This work extends applicability of a genetic screen for dioxin sensitivity to a larger number of species and sample types including endangered species and potentially museum specimens. PMID- 20842420 TI - A perspective of the dynamic structure of the nucleus explored at the single molecule level. AB - Cellular life can be described as a dynamic equilibrium of a highly complex network of interacting molecules. For this reason, it is no longer sufficient to "only" know the identity of the participants in a cellular process, but questions such as where, when, and for how long also have to be addressed to understand the mechanism being investigated. Additionally, ensemble measurements may not sufficiently describe individual steps of molecular mobility, spatial-temporal resolution, kinetic parameters, and geographical mapping. It is vital to investigate where individual steps exactly occur to enhance our understanding of the living cell. The nucleus, home too many highly complex multi-order processes, such as replication, transcription, splicing, etc., provides a complicated, heterogeneous landscape. Its dynamics were studied to a new level of detail by fluorescence correlation spectroscopy (FCS). Single-molecule tracking, while still in its infancy in cell biology, is becoming a more and more attractive method to deduce key elements of this organelle. Here we discuss the potential of tracking single RNAs and proteins in the nucleus. Their dynamics, localization, and interaction rates will be vital to our understanding of cellular life. To demonstrate this, we provide a review of the HIV life cycle, which is an extremely elegant balance of nuclear and cytoplasmic functions and provides an opportunity to study mechanisms deeply integrated within the structure of the nucleus. In summary, we aim to present a specific, dynamic view of nuclear cellular life based on single molecule and FCS data and provide a prospective for the future. PMID- 20842422 TI - Taurine and brain development: trophic or cytoprotective actions? AB - The decline of taurine content during brain maturation as well as the consequences of taurine deficiency disturbing brain development, suggest its involvement in basic processes of developing brain cells. If taurine participates in cell protection, differentiation or proliferation in the developing brain is as yet unclear. Extensive and solid evidence supports taurine cytoprotective actions, directly or indirectly related to an antioxidant effect. Since redox status and oxidative stress are now implicated in signalling processes regulating cell differentiation and proliferation, the question is raised of whether the taurine antioxidant activity is on the basis of its requirement during brain development. PMID- 20842423 TI - Pyruvate carboxylation in different model systems studied by (13)C MRS. AB - Pyruvate carboxylation is of great importance in the brain since it is responsible for adding net carbons to the tricarboxylic acid cycle following removal of carbon backbone for synthesis of the two most abundant neurotransmitters, glutamate and GABA. Despite having such a pivotal role, there is still much uncertainty in the exact metabolic details about where and how this carbon is returned. Pyruvate carboxylation has been studied in various model systems of the brain and (13)C magnetic resonance spectroscopy is an excellent tool for doing this. This review will focus on results dealing with the extent and cellular location of pyruvate carboxylation and its role in pathophysiology and concludes that pyruvate carboxylation is an extraordinarily important predominantly astrocytic pathway which plays a pivotal part in a number of diseases. PMID- 20842424 TI - Effect of resveratrol on gliotransmitter levels and p38 activities in cultured astrocytes. AB - Accumulating evidence suggests that resveratrol may have beneficial effects against traumatic brain injury. However, its effect on the regulation of extracellular levels of gliotransmitter and on the activation of p38 MAPK in astrocytes is still unknown. We have examined whether resveratrol regulates extracellular levels of gliotransmitter as well as the activation of p38 MAPK in cultured astrocytes before and after stretch injury. The extracellular levels of glutamate, D-/L-serine and D-serine were apparently reduced by 100 MUM resveratrol in control astrocyte cultures. The dramatic increase of glutamate and D-serine release induced by stretch injury was also clearly inhibited by resveratrol. Resveratrol mediates this response by reduction of release through inhibition of extracellular calcium influx and increment of gliotransmitter uptake through enhancement of amino acid transporter expressed in the membrane of astrocyte. In addition, resveratrol definitely reduced the activation of p38 MAPK in cultured astrocytes following stretch injury. AMPA receptor is involved in the activation of p38 following injury. Conversely, the levels of glutamine and glycine were not obviously affected by resveratrol before and after injury. Intracellular levels of glutamate and D-serine are not apparently changed by stretch injury. Collectively, our data suggest that resveratrol might play an important role in protection of the nervous system after injury by decreasing the extracellular levels of gliotransmitter and inhibiting activation of p38 MAPK following injury. PMID- 20842425 TI - Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. AB - Hepatocellular carcinoma (HCC) is one of the most common solid cancers, representing the third cause of cancer-related death among cirrhotic patients. Treatment of advanced HCC has become a very active area of research. Perifosine, a new synthetic alkylphospholipid Akt inhibitor, has shown anti-tumor activity by inhibition of Akt phosphorylation. In this study, the effect of perifosine on the cell proliferation and apoptosis in hepatoma cells has been investigated. Cell growth inhibition was detected by MTT assay, cell cycle was analyzed by flow cytometry, AnnexinV-FITC apoptosis detection kit was used to detect cell apoptosis, and protein expression was examined by Western blotting analysis. Our present studies showed that Akt phosphorylation was inhibited by perifosine in HepG2 and Bel-7402 human hepatocellular carcinoma cells. Perifosine inhibited the growth of HepG2 cells and Bel-7402 cells in a dose-dependent manner, and arrested cell cycle progression at the G(2) phase. Apoptosis induction became more effective with increasing perifosine concentration. The caspase cascade and its downstream effectors, Poly (ADP-ribose) polymerase (PARP), were also activated simultaneously upon perifosine treatment. The proapoptotic effect of perifosine was in part depending on regulation of the phosphorylation level of ERK and JNK. Perifosine cotreatment substantially increased cytotoxic effects of cisplatin in HepG2 cells. Down-regulating the expression of Bcl-2 and up-regulating the level of Bax may be the potential mechanism for this synergistic effect. Our findings suggest that the small molecule Akt inhibitor perifosine shows substantial anti tumor activity in human hepatoma cancer cell lines, and is a good candidate for treatment combinations with classical cytostatic compounds in hepatocellular carcinoma. PMID- 20842426 TI - Age-dependent prevalence of equid herpesvirus 5 infection. AB - Equid herpesvirus 5 (EHV-5) infection was detected in a farm in Italy by the use of a semi-nested polymerase chain reaction (PCR) targeting glycoprotein B of EHV 5 on nasal swabs and blood samples of clinically healthy and randomly selected Lipizzaner horses (n = 55). Twenty-five horses at the age of 4-17 years and 30 at an age of 1-3 years were sampled once. The association of the infection with these age-groups and the gender of the horses was investigated. The apparent prevalence of EHV-5 infection was significantly different between age-cohorts: it was higher in the younger group of horses with 73,3% and 80% positives in nasal swabs and blood respectively, compared to 40% of nasal swabs and 20% of blood in the older horses. An age-dependence therefore was observed: the young age is more frequently associated with EHV-5 infection. PMID- 20842428 TI - Arginase type I as a marker of coronary heart disease in hemodialysis patients. AB - BACKGROUND: Cardiovascular disease, and mainly coronary heart disease (CHD), is the leading cause of death in hemodialysis (HD) patients. Non-traditional risk factors may play an important role in this population. Arginase is known to contribute directly to atherosclerosis progression and to counteract the beneficial effects of nitric oxide. HD could be considered as an inflammatory condition. Inflammation contributes to atherosclerosis progression and influences both arginase and nitric oxide synthase expression. In the present study, serum arginase type I was evaluated as a marker of CHD in HD patients. The markers of inflammation interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were also assessed. PATIENTS AND METHODS: Sixty-eight HD patients and 24 healthy volunteers were enrolled into the study. Twenty HD patients suffered from CHD confirmed with coronary angiography, while the remaining 48 HD patients were asymptomatic. Serum arginase type I, IL-6 and TNF-alpha were measured with ELISA. During 24 months follow-up, none of the asymptomatic subjects developed symptoms of CHD. RESULTS: IL-6 and TNF-alpha levels were increased in HD patients, but did not differ between HD patients with or without CHD. On the contrary, arginase levels did not differ between healthy subjects and HD patients, but were twice higher in HD patients with CHD than in HD patients without CHD (22.41 +/- 15.47 ng/ml vs. 10.16 +/- 8.13 ng/ml). CONCLUSION: Arginase type I may contribute to the pathogenesis of CHD in HD patients and its serum levels could be used as a marker of CHD in this population. PMID- 20842429 TI - Effects of exercise training on physical impairment, arterial stiffness and health-related quality of life in patients with chronic kidney disease: a pilot study. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have impaired performance in physical tasks, lower health-related quality of life and high cardiovascular morbidity and mortality. Moderate intensity exercise has been shown to provide cardiovascular and metabolic benefits in healthy individuals and patients without CKD. Long-term exercise training is recommended as a vital component in the management of a number of chronic diseases. This randomized controlled pilot project examined the effects of exercise in predialysis CKD patients. METHODS: Ten patients were randomized to 12 months of exercise (EX) and 10 to standard care (CT). We compared the difference between the two groups in physical impairment (VO(2peak) and endurance time [ET]), arterial stiffness (augmentation index [AI]) and health-related quality of life (EuroQol EQ-5D and Short Form-36 questionnaires) (all measured at baseline and 12 months). RESULTS: The difference between EX and CT was statistically significant for VO(2peak) (3.59 ml O(2)/kg/min; 95% CI 0.92, 6.26; P = 0.01), ET (10.97 min; 95% CI 4.34, 17.59; P = 0.003) and AI (-11.7%; 95% CI -18.79, -4.61; P = 0.003). Clinically important changes were noted in EQ-5D and SF-36. CONCLUSIONS: This study suggests that long term exercise training improves physical impairment, arterial stiffness and health-related quality of life in patients with predialysis CKD. A larger randomized trial is required to examine the impact of exercise on markers of cardiovascular risk and quality of life in predialysis CKD patients. PMID- 20842432 TI - RETRACTED ARTICLE: Cytotoxic activities of tubeimoside-2 on human hepatoma HepG2 cells by induction of G2/M phase arrest and apoptosis in a p53-dependent manner. PMID- 20842431 TI - Survival of chondrocytes in rabbit septal cartilage after electromechanical reshaping. AB - Electromechanical reshaping (EMR) has been recently described as an alternative method for reshaping facial cartilage without the need for incisions or sutures. This study focuses on determining the short- and long-term viability of chondrocytes following EMR in cartilage grafts maintained in tissue culture. Flat rabbit nasal septal cartilage specimens were bent into semi-cylindrical shapes by an aluminum jig while a constant electric voltage was applied across the concave and convex surfaces. After EMR, specimens were maintained in culture media for 64 days. Over this time period, specimens were serially biopsied and then stained with a fluorescent live-dead assay system and imaged using laser scanning confocal microscopy. In addition, the fraction of viable chondrocytes was measured, correlated with voltage, voltage application time, electric field configuration, and examined serially. The fraction of viable chondrocytes decreased with voltage and application time. High local electric field intensity and proximity to the positive electrode also focally reduced chondrocyte viability. The density of viable chondrocytes decreased over time and reached a steady state after 2-4 weeks. Viable cells were concentrated within the central region of the specimen. Approximately 20% of original chondrocytes remained viable after reshaping with optimal voltage and application time parameters and compared favorably with conventional surgical shape change techniques such as morselization. PMID- 20842433 TI - Update on mitochondrial fatty acid oxidation disorders. PMID- 20842434 TI - Relationship between atrial septal aneurysms and atrial electromechanical delay. AB - Atrial septal aneurysm (ASA) is a saccular deformity located in the atrial septum. Atrial arrhythmias are common in patients with ASA. Atrial electromechanical delay (AEMD) can be used to evaluate development of atrial arrhythmias in various settings. The aim of the study was to investigate the relationship between ASA, cardiac arrhythmias and AEMD. Seventy patients with ASA served as the study group (30 men; mean age, 33.6 +/- 10.9 years) and 70 healthy volunteers served as the control group (34 men; mean age, 31.4 +/- 7.8 years). ASAs were diagnosed by transthoracic echocardiography based on the criteria of a minimal aneurysmal base of >= 15 mm; and an excursion of >= 10 mm. Inter-AEMD and intra-AEMDs of both atrium were measured from parameters of tissue Doppler imaging. There was no significant difference between the study and control groups in terms of age, gender, left atrium diameter, and left ventricular ejection fraction. Inter-AEMD (50.7 +/- 22.5 ms vs. 36.9 +/- 12.0 ms) and intra-left AEMD (44.6 +/- 17.4 ms vs. 30.7 +/- 11.6 ms) were significantly higher in patients with ASA with respect to control group. Inter-AEMD (63.6 +/- 20.1 ms vs. 45.1 +/- 21.5 ms, P = 0.001), intra-left AEMD (55.3 +/- 15.6 ms vs. 40.1 +/- 16.2 ms, P = 0.001), diameter of the ASA (19.9 +/- 3.6 mm vs. 17.1 +/- 2.7 mm, P = 0.001) and P wave dispersion (18.5 +/- 6.7 ms vs. 11.8 +/- 7.3 ms, P = 0.001) were significantly greater in the subgroup with arrhythmias compared to the subgroup without arrhythmias. Inter-AEMD and intra-left AEMD were found to be significantly prolonged in patients with ASA. Being a non-invasive, inexpensive and simple technique AEMD may provide significant contributions to assess the risk for paroxysmal supraventricular arrhythmia in patients with ASA. PMID- 20842435 TI - Disseminated Penicillium marneffei infection in an SLE patient: a case report and literature review. AB - Penicillium marneffei is an important opportunistic pathogen in Southeast Asia in HIV-positive individuals, but it rarely infects non-HIV ones. Four SLE patients with disseminated penicilliosis had been previously reported out of which 3 died. We describe a 46-year-old Chinese woman who had a 10 years history of SLE, associated with disseminated Penicillium marneffei infection, which presented as fever, subcutaneous masses, and fine nodular shadows disseminated over lung fields. She was initially misdiagnosed as miliary tuberculosis and panniculitis that did not respond to anti-tubercular drugs and prednisone. The correct diagnosis was finally made by histopathology and tissue culture and also culture from exudate. She responded well to antifungal therapy in the form of intravenous amphotericin B for 2 weeks followed by itraconazole plus fluconazole. The cutaneous lesions were cured leaving behind scars by secondary suture after times of epluchage, and the fine nodular shadows over lungs disappeared finally. She had no recurrence on 8 months of follow-up. We also review the literature on this topic. PMID- 20842436 TI - Season- and age-associated telomerase activity in Ginkgo biloba L. AB - Telomeres have lately received considerable attention in the development of broad leaved tree species. In order to determine tissue-, sex-, season- and age specific changes in telomerase activity in ginkgo trees, analyses of the telomerase repeat amplification protocol were carried out. In all of the tissues detected (embryonal callus, microspore tissues and leaves) telomerase activity was found, with differences between these activities statistically significant (P < 0.05). The highest telomerase activity was found in embryonal callus, suggesting that ginkgo trees have tissue-specific telomerase activity. Tissues containing high levels of dividing cells also have high levels of telomerase activity. No significant difference of telomerase activity was found between male and female trees (P > 0.05). In the annual development cycle, the highest telomerase activity was found in April and a decreasing trend over time in the four age groups studied: 10, 20, 70 and 700 year. The most obvious decline appeared in trees of the 700 year old group, suggesting that ginkgo trees have season-specific telomerase activities and trees of various ages react differently to seasonal changes. The mean annual telomerase activity showed a regular decreasing trend in all leaf samples analyzed from 10 to 700 year old ginkgo trees. We conclude that maintenance of telomere length depends on season- and age associated telomerase activity. An optimal telomere length is regulated and maintained by telomerase in Ginkgo biloba L. PMID- 20842437 TI - Polymorphisms in 5'-flanking regions of genes encoding adiponectin, leptin, and resistin are not associated with obesity of Polish children and adolescents. AB - Genes encoding adipokines are important functional candidates for development of obesity. In this study we screened for polymorphism 5'-flanking regions of the adiponectin (ADIPOQ), leptin (LEP) and resistin (RETN) genes in a cohort of Polish obese children and adolescents (n = 243) and a control group of non-obese adults (n = 100). Altogether 13 SNPs (single nucleotide polymorphisms) and 1 InDel (insertion/deletion polymorphism) were found. Among them five polymorphisms, localized in the LEP gene, turned out to be novel, but their distribution was insufficient for association studies. We found no consistent evidence for association between obesity and the SNPs demonstrating minor allele frequency (MAF) above 0.2 (ADIPOQ: -11377C>G, LEP: -2548C>T, 19A>G, RETN: 1300G>A, -1258C>T, -420C>G). Comparison of polymorphisms distribution in patients and control group suggested association with ADIPOQ -11377C>G (Pearson test P = 2.76 * 10(-11)), however, we did not observe any effect of this polymorphism on BMI or relative BMI (RBMI) within obese patients (P = 0.41). We conclude that the tested SNPs are not useful markers of childhood and adolescence obesity in Polish population. PMID- 20842438 TI - Molecular and biochemical analysis of the alpha class carbonic anhydrases in Caenorhabditis elegans. AB - In this study, in silico analysis of the Caenorhabditis elegans genome revealed six genes (cah-1, cah-2, cah-3, cah-4, cah-5, and cah-6) possibly encoding alpha class CAs (carbonic anhydrase). Real-time RT-PCR analysis revealed the temporal expression pattern of each gene, as well as changes in expression levels under different atmospheric conditions (stress). Cah-3 and cah-4 showed the highest levels of transcript accumulation, while most genes responded to the stress conditions. Yeast complementation showed that cah-3 was able to complement the function of Saccharomyces cerevisiae CA (NCE103) in vivo. Recombinant CAH-3, CAH 4a and CAH-5 enzymes, expressed in Escherichia coli were used for in vitro measurement of CA activity. However, in vitro activity was only detectable for CAH-4a. RNAi by feeding was performed on wild-type C. elegans for all genes. The worms were examined for a visible phenotype under normal and stress conditions (pH, CO(2)/O(2)). Silencing cah-3 and cah-4 may reduce the life-span of the worms (at 22 degrees C). PMID- 20842439 TI - Novel SNPs in the ATP1B2 gene and their associations with milk yield, milk composition and heat-resistance traits in Chinese Holstein cows. AB - Genetic association analysis was applied to examine the effect of the Na(+)/K(+) ATPase beta 2 subunit (ATP1B2) gene on rectal temperature, milk traits, K(+) levels and Na(+)/K(+)-ATPase (NKA) activity in the red blood cells of 1001 Chinese Holstein cows under normal and heat-stress conditions. We detected two novel single nucleotide polymorphisms, G2258A and C2833T, in the second and fourth introns, respectively, of ATP1B2. G2258A significantly affected milk fat content (P < 0.05) and 305-day milk yield (P < 0.01), but not milk protein content. C2833T significantly affected milk protein content (P < 0.01) and 305 day milk yield (P < 0.05), but not milk fat content. Calculated gene substitution effects suggested that A to G substitution in G2258A, and T to C substitution in C2833T, positively affected milk fat content, 305-day milk yield and somatic cell score, but negatively affected milk protein content. We also detected significant variation in milk fat content, milk protein content, 305-day milk yield and somatic cell scores (P < 0.05 or P < 0.01) among the nine ATP1B2 haplotypes. Under heat-stress, the C2833T polymorphism was significantly related to rectal temperature (P < 0.01), red blood cell K(+) levels, NKA activity and milk yield (P < 0.05). Cows with the TT genotype showed the desirable characteristics of low rectal temperature and red blood cell K(+), low decline rate in milk yield and red blood cell NKA activity. This study suggests that the ATP1B2 single nucleotide polymorphism C2833T is a genetic marker of heat-resistance traits in Chinese Holstein cows. PMID- 20842440 TI - Association of GSTM1T1 genes with COPD and prostate cancer in north Indian population. AB - The glutathione S-transferase (GST) family of enzymes is known to play a pivotal role in phase II of biotransformation of xenobiotics, environmental carcinogens and pharmacological drugs. The objective of the present study was to investigate the role of GSTM1 and GSTT1 null genotypes as risk factors for chronic obstructive pulmonary disease (COPD) and prostate cancer. The subjects appraised were 200 COPD cases, 150 prostate cancer cases, 150 benign prostatic hyperplasia (BPH) cases, 200 age matched controls for COPD and 172 age matched controls for prostate cancer. GSTM1 and GSTT1 null genotype was found to confer 2.5 (OR 2.45; 95% CI 1.56-3.82; P value = 0.00008) and 2.4-fold (OR 2.39; 95% CI 1.36-4.20; P value = 0.002) significant higher risk for prostate cancer. Smoking imparted a 2.2-fold significant risk of prostate cancer cases (OR 2.23; 95% CI 1.36-3.65 P value = 0.001) and twofold risk in BPH (OR 2.09; 95% CI 1.26-3.46; P value = 0.005). In case of COPD only null genotype of GSTT1 has shown 2.1-fold (OR 2.11; 95% CI 1.22-3.62; P value = 0.007) significant increased risk. PMID- 20842441 TI - Protective effects of adenosine in rabbit sinoatrial node ischemia-reperfusion model in vivo: control of arrhythmia by hyperpolarization-activated cyclic nucleotide-gated (HCN)4 channels. AB - Disturbance of cardiac rhythm is one of the consequences of myocardial ischemia/reperfusion injury. Many researchers have prompted considerable interests in developing therapeutic approaches for its control. In present study, we want to determine whether that adenosine pre- and postconditioning have protective effects on sinoatrial node ischemia/reperfusion injury on morphology, arrhythmia score, serological markers (CK-MB and cTnT), SOD activities, MDA levels and expression of HCN4 channels in SA node cells. According to the arrhythmia score recorded, whether adenosine used in terms of ischemia or reperfusion, the total number of arrhythmia was significantly reduced, as well as the number of its episodes was also markedly decreased. We have also shown a clear correlation between HCN4 channels expression and the dysfunction of SA node cells. HCN4 immunoreactivity decreased after adenosine pre- and postconditioning, but changes were significantly smaller in the cells of the SA node compared with cells of I/R group. The content of cTnT, CK-MB and MDA in adenosine pre- and postconditioning group reduced significantly; but the level of SOD increased significantly. Histological examination and electron microscopy observations found in adenosine pre- and postconditioning group sinoatrial node injury also mitigated. These findings suggested that adenosine pre- or postconditioning were to reduce the incidence of ischemia/reperfusion arrhythmias, reduce myocardial ischemia reperfusion injury. The mechanism was to stabilize the SA node cells membrane and one possible mechanism involves modulation of HCN4 channels in pacemaker cells of the sinoatrial node. PMID- 20842442 TI - Molecular analysis and heavy metal detoxification of ABCC1/MRP1 in zebrafish. AB - ABCC1/MRP1 belongs to the ATP-binding cassette superfamily and its elevated expression is closely associated with the multidrug resistance of various tumor cells. In normal tissues, ABCC1 confers resistance to a wide variety of xenobiotics and toxicants, demonstrating its important roles in tissue defense. Here, we report the cloning and functional characterization of abcc1 gene in zebrafish. This gene is localized on zebrafish chromosome 3 and contains a 4,557 bp open-reading frame. The deduced polypeptide is composed of 1,518 amino acids, which shares 70% identity with human ABCC1. Phylogenetic analysis revealed that ABCC1 proteins from thirteen vertebrate species are highly conserved during evolution. Transcriptional expression of zebrafish abcc1 gene in developing embryos was examined by whole-mount in situ hybridization and real-time PCR. Transcripts of zebrafish abcc1 gene were detectable in four-cell stage embryos, indicating that this gene is maternally expressed. ABCC1 mRNAs were ubiquitously distributed in embryos before 12 h post-fertilization (hpf) and mainly localized in eyes and brain from 24 to 72 hpf, and in gills from 96 to 120 hpf. In addition, zebrafish abcc1 gene was highly expressed in 1-hpf embryos and detected in all adult tissues examined, with highest expression in testis and lowest in heart and liver. Exposure of ZF4 cells and embryos to CdCl(2).2.5H(2)O, HgCl(2), Pb(NO(3))(2), or Na(3)AsO(4).12H(2)O significantly induced transcriptional expression of abcc1 gene. Furthermore, overexpression of abcc1 improved the survival rates of embryos exposed to Cd, Hg or As, while overexpression of a abcc1 mutant (ABCC1-G1420D) sensitized zebrafish embryos to toxic metals. These data indicate that zebrafish ABCC1 has crucial roles in heavy metals detoxification. PMID- 20842443 TI - Association between HLA-DRB1, HLA-DRQB1 alleles, and CD4(+)CD28(null) T cells in a Chinese population with coronary heart disease. AB - CD4(+)CD28(null) T cells are present in increased numbers in the peripheral blood of patients with acute coronary syndrome. However, the triggers of expansion of these cells are unclear. Susceptibility to coronary heart disease (CHD) is strongly associated with alleles of human leukocyte antigen (HLA), but it is not equally strong in different human populations. The objective of the study was to investigate association between CD4(+)CD28(null) T cells and HLA-DRB1 alleles. The HLA alleles were determined by polymerase chain reaction with sequence specific primers (PCR-SSP) method, in a group of CHD patients and control subjects from the same area. The number of CD4(+)CD28(null) T cells was measured using the flow cytometry technique. The HLA-DRB1*01 (RR = 4.705, P < 0.005) and DRB1*04 (RR = 3.554, P < 0.005) alleles showed the strongest association with CHD in the Chinese population, and increased numbers of CD4(+)CD28(null) T cells were found in association with HLA-DRB1*04 (17.1%) and DRB*01 (12.9%), while decreased numbers of CD4(+)CD28(null) T cells were present in subjects with DRB1*15 (0.8%). CHD in Chinese population is strongly associated with HLA-DRB1*01 and DRB1*04 haplotypes, and formation of CD4(+)CD28(null) T cells was related to HLA-DRB1*01, DRB1*04, and DRB1*15 alleles. PMID- 20842444 TI - Apolipoprotein A1 -75 G/A and +83 C/T polymorphisms: susceptibility and prognostic implications in breast cancer. AB - Apolipoprotein A1 (ApoA1) is the major apoprotein constituent of high-density lipoprotein that can play important roles in tumor invasion and metastasis. In the current report, we evaluated the role of the functional ApoA1 polymorphisms ( 75 G/A and +83 C/T) as genetic markers for breast cancer susceptibility and prognosis. We used the polymerase chain reaction and restriction enzyme digestion (RFLP-PCR) to characterize the variations of the ApoA1 gene in 295 unrelated Tunisian patients with breast carcinoma and 197 healthy control subjects. No association was found between the +83 C/T genetic variation in ApoA1 gene and the risk of breast cancer occurrence. The presence of the (+83) T allele appeared however to be associated with an increased risk of lymph node metastasis occurrence (OR = 2.94; P = 0.01). Furthermore, a positive association was found between ApoA1 -75 A allele carriers and breast cancer risk (OR = 1.57; P = 0.02). Regarding prognostic indicators, a significant association was found between ApoA1 (-75) A allele carriers and the premenopausal status of breast cancer patients (OR = 1.73; P = 0.03). Additionally, the presence of the -75 A allele was correlated with the oestrogen receptor status among premenopausal women (OR = 2.45; P = 0.02). This is the first report on the studies of ApoA1 single nucleotide polymorphisms (SNPs) in breast carcinomas. Our data suggest that these genetic variations of ApoA1 may represent a marker for the increased risk of breast cancer. PMID- 20842445 TI - Genetic variation in microRNA genes and prostate cancer risk in North Indian population. AB - Recent evidence indicates the involvement of microRNAs (miRNAs), in cell growth control, differentiation, and apoptosis, thus playing a role in tumorigenesis. Single-nucleotide polymorphisms (SNPs) located at miRNA-binding sites (miRNA binding SNPs) are likely to affect the expression of the miRNA target and may contribute to the susceptibility of humans to common diseases. We genotyped SNPs hsa-mir196a2 (rs11614913), hsa-mir146a (rs2910164), and hsa-mir499 (rs3746444) in a case-control study including 159 prostate cancer patients and 230 matched controls. Patients with heterozygous genotype in hsa-mir196a2 and hsa-mir499, showed significant risk for developing prostate cancer (P = 0.01; OR = 1.70 and P <= 0.001; OR = 2.27, respectively). Similarly, the variant allele carrier was also associated with prostate cancer, (P = 0.01; OR = 1.66 and P <= 0.001; OR = 1.97, respectively) whereas, hsa-mir146a revealed no association in prostate cancer. None of the miRNA polymorphisms were associated with Gleason grade and bone metastasis. This is the first study on Indian population substantially presenting that individual as well as combined genotypes of miRNA-related variants may be used to predict the risk of prostate cancer and may be useful for identifying patients at high risk. PMID- 20842446 TI - Association of p53 codon 72 polymorphism with prostate cancer: a meta-analysis. AB - Relationship of prostate cancer with the polymorphism of p53 codon 72 was reported with inconsistent results. The purpose of this study was to quantitatively evaluate the association between p53 codon 72 polymorphism and prostate cancer susceptibility. We performed an extensive search of relevant studies and made a meta-analysis, including 8 studies with 815 prostate cancer cases and 1047 controls. The combined results showed that there were no significant differences in genotype distribution between prostate cancer cases and control on the basis of all studies, CC/GC versus GG (OR = 1.24, 95% CI: 0.93 1.65), GG/GC versus CC (OR = 0.96, 95% CI: 0.60-1.55), GC versus GG (OR = 1.27, 95% CI: 0.91-1.77), CC versus GG (OR = 1.25, 95% CI:0.74-2.12), GC versus CC (OR = 1.09, 95% CI: 0.63-1.87). When stratifying for the race, there were also no statistically significant differences in genotype distribution between prostate cancer cases and controls. This meta-analysis did not provide an evidence of confirming association between p53 codon 72 polymorphism and prostate cancer. PMID- 20842447 TI - New SNP of the porcine perilipin 2 (PLIN2) gene, association with carcass traits and expression analysis in skeletal muscle. AB - PLIN2 (perilipin 2) is a cytosolic protein that promotes the formation and stabilization of the intracellular lipid droplets, organelles involved in the storage of lipid depots. Porcine PLIN2 gene represents a biological and positional candidate for fat deposition, a polygenic trait that affects carcass and meat quality. The aim of the present study was to screen PLIN2 gene for polymorphisms, to evaluate the association with carcass quality traits, and to investigate the gene expression in skeletal muscle. Six new single nucleotide polymorphisms (SNP) were detected by sequencing 32 samples from five pig breeds (Italian Large White, Italian Duroc, Italian Landrace, Belgian Landrace, Pietrain). Two SNP localized in introns, two in the 3'-untranslated region (UTR), and two missense SNP were found in exons. A 3'-UTR mutation (GU461317:g.98G>A), genotyped in 290 Italian Duroc pigs by High Resolution Melting, resulted significantly associated (P < 0.01) with average daily gain, feed conversion ratio, lean cuts and hams weight estimated breeding values. PLIN2 gene expression analysis in skeletal muscle of Italian Large White and Italian Duroc pigs divergent for backfat thickness and visible intermuscular fat showed a trend of higher expression level in pigs with higher intermuscular fat. These results suggest that PLIN2 can be a marker for carcass quality in pigs. Further investigation at both gene and protein level could elucidate its role on fat deposition. PMID- 20842448 TI - SNP discovery and haplotype analysis in the bovine PRKAA2 gene. AB - The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a cellular fuel gauge that regulates metabolic pathways in glucose and fatty acid metabolism and protein synthesis, and recent data demonstrate that it also plays a critical role in systemic energy balance. PRKAA2, the gene that encodes the alpha2 catalytic subunit of AMPK, showed be involved in the glucose and lipid metabolism. To date, genetic variants in human PRKAA2 have been shown associations with type 2 diabetes (T2D) in several populations, but few studies show a complete description of the variability of bovine PRKAA2. In the present study, we reported the investigation of PRKAA2 genetic polymorphisms in three Chinese indigenous bovine breeds [Qinchuan (n = 328), Nanyang (n = 278), Jiaxian (n = 148)] and yak (n = 57). The screening of all exons including adjacent splice sites of the gene was performed using a PCR SSCP strategy, and following sequence analysis revealed fifteen single nucleotide polymorphisms (SNPs). Five SNPs were identified in exons, which all generate synonymous mutations, and other identified variations were located in introns. Linkage disequilibrium (LD) coefficients and haplotype frequencies for some SNPs were investigated. In total, six haplotypes were found in the cattle breeds. Two LD blocks were found in Qinchuan cattle and three common haplotypes were identified based on four SNPs, with the most common haplotype (TGCT) occurring at a frequency of 53.7%; three of the four possible haplotypes were found in Nanyang cattle, with the most common haplotype (CT) occurring at a frequency of 56.3%; whereas, no suitable haplotypes were found in Jiaxian cattle and yak. Phylogenetic analysis showed that Qinchuan and Jiaxian were firstly clustered together, and then Nanyang was added to the branch. The yak (Poephagus grunniens) diverged strongly from the branch of the Bos Taurus. These data will provide a background for more extensive characterization of the bovine PRKAA2 gene, its diversity in different cattle breeds, and evolutionary information of Chinese cattle breeds. PMID- 20842449 TI - Down-regulation of achaete-scute complex homolog 1 (ASCL1) in neuroblastoma cells induces up-regulation of insulin-like growth factor 2 (IGF2). AB - Neuroblastoma (NB) is the most common extra-cranial solid pediatric tumor. The prognosis of patients with NB has been improved during the last decades. However, treatment results for patients with advanced tumor stages are still unsatisfying. NB cells are characterized by a high tendency for spontaneous or induced differentiation. During differentiation, down-regulation of the basic helix-loop helix transcription factor achaete-scute complex homolog 1 (ASCL1) has been observed but the consequences of ASCL1 down-regulation have not been elucidated. We used RNA interference to knock-down ASCL1 in NB cells. DNA microarray analysis was used for the identification of ASCL1-regulated genes. Furthermore, conventional and quantitative reverse transcription-polymerase chain reaction (RT PCR) was used for validation of ASCL1-regulated genes. Down-regulation of ASCL1 influenced the expression of several genes. After down-regulation of ASCL1, we observed very high expression of insulin-like growth factor 2 (IGF2), a factor that is known to be induced during differentiation of NB cells. RT-PCR indicated up-regulation of multiple IGF2 transcript variants after ASCL1 knock-down. Our data suggest that the ASCL1-pathway is responsible for the up-regulation of IGF2 during NB differentiation. PMID- 20842450 TI - Effects of selected genetic polymorphisms in xeroderma pigmentosum complementary group D on gastric cancer. AB - DNA repair capacity (DRC) can be altered based on sequence variations in DNA repair genes, which may result in cancer susceptibility. The current study was to evaluate the association between genetic polymorphisms, including associated haplotypes of xeroderma pigmentosum complementary group D (XPD), and individual susceptibility to gastric cancer. Two-hundred-eight patients with gastric cancer and 339 healthy controls were enrolled in this study. Their genomic DNA was extracted from peripheral blood leukocytes. The genotypes at exon 6, 10 and 23 were identified by polymerase chain reaction (PCR). Unconditional logistic regression model was used to analyze the effects of the polymorphisms, including the corresponding haplotypes, on the susceptibility to develop gastric cancer. The proportion of genotypes GA or AA at exon 10 in cases was showed to be significantly higher than that in controls (P < 0.01, P < 0.01, respectively). The risk of genotype GA or AA carriers to develop gastric cancer was simultaneously much higher (OR = 3.38, 95% CI 2.30-4.95; OR = 6.13, 95% CI 2.45 15.31, respectively). The allele A at exon 10 was also observed to manifest a substantially higher frequency in cases compared to controls (P < 0.01), which might indicate an increased tendency to gastric cancer (OR = 2.40, 95% CI 1.81 3.17). No significant differences were found in the distribution of genotypes at exon 6 or 23 between the two groups (P = 0.23, P = 0.52; P = 0.44, P = 0.56, respectively). By haplotype analysis, haplotype AAA could individually increase incidence of gastric cancer (P < 0.01, OR = 3.39, 95% CI 2.21-5.21). In contrast, haplotypes CGA and AGA were showed a decline in gastric cancer susceptibility (OR = 0.67, 95% CI 0.46-0.97; OR = 0.58, 95% CI 0.41-0.83, respectively). The rest of haplotypes made no statistically significant difference between cases and controls. Taken together, this study demonstrates that the genetic variation at exon 10 and haplotype AAA may be contributing factors in developing gastric cancer. PMID- 20842451 TI - Discovery of a pyrazole derivative promoting angiogenesis through modulating reactive oxygen species and interferon-inducible protein 10 levels. AB - Human umbilical cord vascular endothelial cells (HUVECs) cultured without serum and fibroblast growth factor-2 is an in vitro model of ischemic conditions. Our previous study showed that ethyl 3-(o-chlorophenyl)-5-methyl-1-phenyl-1H-pyrazole 4-carboxylate (MPD) could inhibit apoptosis of HUVECs in this model. In this study, we investigated the effect of MPD on angiogenesis and the possible mechanisms. Capillary-like tube formation assay on Matrigel and cell migration assay were performed to investigate the effect of MPD on angiogenesis. The reactive oxygen species (ROS) and interferon-inducible protein 10 (IP-10) levels were respectively evaluated by intracellular ROS assay and western blot analysis. MPD at 5 and 10 MUM promoted vascular structure formation and HUVEC migration in an in vitro ischemic model. MPD promoted angiogenesis through elevating ROS levels and depressing IP-10 level. ROS seemed to be necessary for angiogenesis, and a high level of IP-10 inhibited angiogenesis in ischemic state. ROS provide clues for seeking new key factors involved in angiogenesis. IP-10 may become a new target for future therapeutic intervention. MPD is a good tool for investigating the mechanism of angiogenesis, and MPD might be useful in the development of new drugs in therapy of ischemic diseases. PMID- 20842452 TI - Golgi phosphoprotein 2 (GOLPH2/GP73/GOLM1) interacts with secretory clusterin. AB - Golgi phosphoprotein 2 (GOLPH2/GP73/GOLM1), a type-II Golgi transmembrane protein of unknown function, is up-regulated in many cancers. Its Golgi luminal domain is potentially the major functional domain. The goal of this study is to identify the proteins interacting with GOLPH2. Using secretory GOLPH2 (sGOLPH2, amino acid residues 55-401) as bait, secretory clusterin (sCLU) was identified as one interacting candidate by yeast two-hybrid screening, and the coiled-coil domain of GOLPH2 was found to be sufficient for interaction with sCLU. The interaction between GOLPH2 and sCLU was confirmed intracellularly and extracellularly. The intracellular co-localization of GOLPH2 and sCLU in Golgi was also shown. These results can help in understanding the biological and pathological significance of GOLPH2. PMID- 20842453 TI - Vascular endothelial growth factor stimulates osteoblastic differentiation of cultured human periosteal-derived cells expressing vascular endothelial growth factor receptors. AB - Angiogenesis plays an important role in bone development and postnatal bone fracture repair. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptors (VEGFRs) are primarily involved in angiogenesis. This study investigated the expression of VEGF isoforms, VEGFR-1, and VEGFR-2 during the osteoblastic differentiation of cultured human periosteal derived cells. In addition, the effect of exogenous VEGF on the osteoblastic differentiation of cultured human periosteal-derived cells was also examined. The expression of the VEGF isoforms (VEGF(121), VEGF(165), VEGF(189), and VEGF(206)), VEGFR-1, and VEGFR-2 was observed in the periosteal-derived cells. Administration of KRN633, a VEGFR-1 and VEGFR-2 inhibitor, decreased the alkaline phosphatase (ALP) activity during the osteoblastic differentiation of cultured human periosteal-derived cells. However, the administration of VEGFR2 Kinase Inhibitor IV, a VEGFR-2 inhibitor, did not affect the ALP activity. The addition of recombinant human VEGF(165) elevated the ALP activity and increased the calcium content in the periosteal-derived cells. Treating the periosteal-derived cells with recombinant human VEGF(165) resulted in an increase in Runx2 transactivation in the periosteal-derived cells. These results suggest that exogenous VEGF stimulates the osteoblastic differentiation of cultured human periosteal-derived cells and VEGF might act as an autocrine growth factor for the osteoblastic differentiation of cultured human periosteal-derived cells. PMID- 20842454 TI - Vascular regrowth following photodynamic therapy in the chicken embryo chorioallantoic membrane. AB - Photodynamic therapy (PDT) induces damage to the endothelium, which can lead to increased vascular permeability and, under intensive PDT conditions, even to platelet aggregation, vasoconstriction, and blood flow stasis. Eventually, ischemia, hypoxia, and inflammation can occur, resulting in angiogenesis. We studied the sequence of the vascular events after Visudyne-PDT in the chicken chorioallantoic membrane (CAM) at day 11 of development. Using epi-fluorescence microscopy, we monitored the regrowth of capillaries in the PDT treated area. Immediately after irradiation, the treatment resulted in blood flow arrest. And 24 h post PDT, sprouting of new blood vessels was observed at the edge of the PDT zone. Neovessels looping out from the edge of the PDT zone gave rise to specialized endothelial tip structures guiding the vessels towards the center of the treated area. At 48 h almost all of the treated area was repopulated with functional but morphologically altered vasculature. These observations also showed reperfusion of some of the vessels that had been closed by the PDT treatment. CAM samples were immunohistochemically stained for Ki-67 showing proliferation of endothelial cells in the PDT area. Also, several markers of immature and angiogenic blood vessels, such as alphaVbeta3-integrin, vimentin and galectin-1, were found to be enhanced in the PDT area, while the endothelial maturation marker intercellular adhesion molecule (ICAM)-1 was found to be suppressed. These results demonstrate that the new vascular bed is formed by both neo-angiogenesis and reperfusion of existing vessels. Both the quantitative real time RT-PCR profile and the response to pharmacological treatment with Avastin, an inhibitor of angiogenesis, suggest that angiogenesis occurs after PDT. The observed molecular profiling results and the kinetics of gene regulation may enable optimizing combination therapies involving PDT for treatment of cancer and other diseases. PMID- 20842455 TI - CDH1 gene mutations do not contribute in hereditary diffuse gastric cancer in Poland. AB - Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome characterized by a high risk of diffuse stomach cancer and lobular breast cancer. HDGC is caused by germline mutations in the CDH1 gene encoding the E-cadherin which is a member of the transmembrane glycoprotein family responsible for calcium-dependent, cell-to-cell adhesion and plays a fundamental role in the maintenance of cell differentiation and the normal architecture of epithelial tissues. Mutations in the CDH1 gene are detected in 30-46% of families that fulfil strong clinical criteria for HDGC and in about 11% of families fulfilling the modified criteria. In the present study, we investigated germline mutations in the CDH1 gene in Polish patients with HDGC. The entire coding sequence of CDH1 gene was analyzed by sequencing in 86 Polish cancer patients from families fulfilling the modified criteria of HDGC. We found several silent mutations including one common variant (c.2076T>C) present in 56 patients, and three rare variants (c.2253C>T, c.1896C>T, c.2634C>T) detected in 2 patients. In addition, we found four rare sequence variants of unknown significance localized in introns. We did not detect any deleterious mutations of the CDH1 gene. CDH1 gene mutations are not present in Polish families with HDGC defined by the modified clinical criteria. Further studies of families with HDGC matching the restrictive criteria for HDGC are needed. PMID- 20842456 TI - Contribution of CDKN2A/P16 ( INK4A ), P14 (ARF), CDK4 and BRCA1/2 germline mutations in individuals with suspected genetic predisposition to uveal melanoma. AB - Uveal melanoma arises from melanocytes of the uveal tract (iris, ciliary body and choroid) and represents the most common intraocular malignancy in adults. Some rare clinical situations (young age at diagnosis, bilateral or multifocal forms, association with cutaneous malignant melanoma and/or familial aggregations of melanomas) are suggestive of genetic susceptibility. The aim of this study was to evaluate the contribution of CDKN2A/P16INK4A, P14ARF and CDK4 gene germline mutations in a series of patients with uveal melanoma recruited in a single institution with a clinical presentation indicative of genetic predisposition. Molecular analyses were proposed to 36 patients and were performed in 25 cases. The contribution of BRCA1/2 gene germline mutations in patients with uveal melanoma and a personal and/or family history of breast/ovarian cancers was also evaluated. Molecular analysis of BRCA1/2 genes was proposed to 35 patients and was performed in 25 patients. No deleterious germline mutation was identified in either group of patients. These results indicate that the CDKN2A/P16INK4A, P14ARF, CDK4 genes are not responsible for the vast majority of genetic susceptibility to uveal melanoma. They also suggest that one case of uveal melanoma in a family with a history of breast cancer is not sufficient to justify BRCA1/2 genetic testing when the classical criteria for molecular analysis are not present. International studies are ongoing in melanoma-prone families in an attempt to identify uveal melanoma susceptibility loci and genes. PMID- 20842457 TI - In vitro sarcoma cells release a lipophilic substance that activates the pain transduction system via TRPV1. AB - BACKGROUND: Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transduction system. MATERIALS AND METHODS: Trigeminal ganglia were harvested from rats and cultured. A rhabdomyosarcoma (CRL1598) and osteosarcoma (CRL 1543) cell line were grown to 75% confluency. Conditioned media (CM) was collected after 24 h of exposure and subjected to reverse phase chromatography. Neuronal activation in the presence of CM was measured using iCGRP RIA and calcium imaging after treatment with vehicle or I-RTX, a potent TRPV1 antagonist. Data were analyzed by ANOVA/Bonferroni or t test. RESULTS: The rhabdomyosarcoma CM produced a 4-fold increase in iCGRP release compared with control media (P < 0.001). The osteosarcoma cell line CM produced a 7-fold increase in iCGRP release compared with control media (P < 0.001). This evoked iCGRP release was via TRPV1 activation since the effect was blocked by the antagonist I-RTX. The application of rhabdomyosarcoma CM produced about a 4-fold increase in [Ca(2+)]I levels (P < 0.001), and this effect was blocked by pretreatment with the TRPV1 antagonist, I-RTX. CONCLUSIONS: We have shown that certain sarcoma cell lines produce a soluble, lipophilic factor that activates the peripheral nociceptor transduction system via TRPV1 activation, thereby contributing to cancer pain. Further investigations are needed to develop tumor-specific analgesics that do not produce unwanted or harmful side-effects. PMID- 20842458 TI - Outcome standards for an organ preservation strategy in stage II and III rectal adenocarcinoma after neoadjuvant chemoradiation. AB - BACKGROUND: Neoadjuvant chemoradiotherapy is the standard of care for patients with locally advanced mid and distal rectal cancer. Tumor regression is variable, and this study was designed to evaluate the pathological response and impact on long-term disease control in responders and nonresponders. METHODS: A total of 303 consecutive patients with cStage II and III mid and distal rectal adenocarcinoma were identified. The mean age was 64 years and 63% were men. Patients received neoadjuvant chemoradiotherapy (45 Gy) with a continuous infusion of 5-fluorouracil. Total mesorectal excision (TME) was performed after an interval of 6-8 weeks. Tumors were stratified as responders (ypT0 or ypT1) and nonresponders (>=ypT3). All ypT2 were separately categorized. RESULTS: Tumors of 84 patients were classified as responders (27.5%) versus nonresponders in 144 patients (47.5%). Pathological tumor stage was ypT2 in 75 patients (25%). After a median follow-up of 55 months, the 5-year cancer-specific survival rate was 98% and the disease-free survival rate was 91% in responders versus 82% (P < 0.0025) and 60% (P < 0.0001), respectively, for the nonresponders. CONCLUSIONS: After neoadjuvant chemoradiotherapy and TME surgery for locally advanced rectal cancer and complete or near-complete pathological tumor response oncological outcome is very good. These results set the standards for a rectum-sparing strategy. PMID- 20842459 TI - CIP2A is overexpressed in non-small cell lung cancer and correlates with poor prognosis. AB - BACKGROUND: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein inhibiting proteolytic degradation of c-MYC. In this study, we investigated the clinical relevance of CIP2A in NSCLC. MATERIALS AND METHODS: We analyzed CIP2A mRNA expression in 29 NSCLC tissues using quantitative reverse transcription polymerase chain reaction (RT-QPCR). We also examined the expression of CIP2A protein by immunohistochemistry in 90 lung cancer specimens and correlated its expression with c-MYC expression and clinicopathological parameters. The functional roles of CIP2A in lung cancer cell lines were evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and invasion. RESULTS: In 29 lung cancer tissues examined, 24 of them (82.7%) exhibited much stronger levels of CIP2A mRNA compared with their corresponding normal tissues. Moreover, CIP2A mRNA expression levels correlated with c-MYC mRNA levels. Furthermore, CIP2A protein was found to be overexpressed in 72.2% of 90 human lung cancer samples and correlated with poor survival (P < 0.05). In addition, the CIP2A status was a significant prognostic factor for NSCLC patients (P = 0.0136). Depleting CIP2A expression inhibited growth and clonogenic potential in lung cancer cell lines. CONCLUSIONS: CIP2A is an oncoprotein overexpressed in NSCLC, and its expression is associated with poor prognosis and malignant cell proliferation. PMID- 20842460 TI - Retrospective evaluation of the influence of postoperative tumor marker status on survival and patterns of recurrence after surgery for pancreatic cancer based on RECIST guidelines. AB - PURPOSE: The purpose of this study was to obtain a comprehensive understanding of the impact of postoperative tumor marker (TM) normalization on survival after pancreatectomy for pancreatic carcinoma. We propose the concept of surgical RECIST based on residual tumor and TM status. METHODS: A total of consecutive patients with pancreatic carcinoma underwent pancreatectomy between August 1, 1989, and August 1, 2008. Pre- and postoperative TM values were available for 194 patients. The relationship between TM status, survival, and other clinical and demographic data was determined with univariate log-rank tests and Cox proportional hazards analysis. RESULTS: Postoperative TM levels remained elevated in 92 patients (47.4%; partial responders). TM levels normalized in 102 patients (52.6%; complete responders). Lymph node metastases, portal vein resection, absence of retroperitoneal clearance, residual tumor, preoperative high CA19-9, and surgical partial response were associated with decreased survival. Nodal stage (P = 0.0227) and surgical RECIST (P = 0.025) were significant predictors of survival. Partial responders had a significantly lower median survival time (P = 0.0008) and significantly higher frequency of hepatic metastasis (P = 0.0299). CONCLUSIONS: Postresection TM normalization is a strong prognostic factor for pancreatic cancer. The efficacy of pancreatic cancer surgery should be evaluated in the context of both local clearance and serum TM kinetics. PMID- 20842461 TI - Examining the safety profile of angiogenesis inhibitors: implications for clinical practice. AB - Dysregulation of angiogenesis in solid tumors enables tumor growth and metastasis. Receptors that mediate angiogenesis, and their ligands, have been identified; among these, vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase play a central role. In non-small cell lung cancer (NSCLC), clinical benefit has been shown with bevacizumab, which blocks VEGF binding to its receptors. In addition, small-molecule tyrosine kinase inhibitors are currently in clinical practice or development in several indications. The potential clinical benefit of antiangiogenic agents is accompanied by the need to understand their safety profiles, seek suitable combination regimens and identify patients able to tolerate one treatment over another. This is particularly relevant in cancers for which patients often present with advanced disease and suffer co-morbidities, requiring an agent that is both efficacious and well tolerated over long-term continuous treatment. Using literature from peer reviewed journals, this review considers different antiangiogenic agents and their safety profiles, focusing on the potential impact of these data on the treatment of patients with NSCLC. PMID- 20842462 TI - Mental health service use before and after diagnosis of early-onset bipolar disorder. AB - To investigate patterns of mental health services, psychotropic treatments, and psychiatric diagnoses received by youth diagnosed with bipolar disorder, insurance claims of 323 youth (ages 6-18 years) were examined from the 2000-2001 Thomson/Medstat-MarketScan(c) database. Longitudinal patterns are assessed 6 months prior and following a new treatment episode of bipolar disorder. Youth subgroups (i.e., continuous, intermittent, and discontinuous services), defined by persistence of claims associated with a bipolar diagnosis, are compared by demographic and clinical characteristics. Virtually all youth had high rates of mental health service use and treatment immediately following initial bipolar diagnosis, but only half continued to receive services 6 months following diagnosis. A continuous pattern of claims associated with a bipolar diagnosis was associated with using more resources, receiving initial diagnosis from a mental health professional, being in a managed care plan, and having more psychiatric diagnoses following index bipolar diagnosis. Further research should examine how continuity of claims for bipolar is related to treatment quality and clinical outcomes. PMID- 20842463 TI - Effect of organic ligands on accumulation of copper in hyperaccumulator and nonaccumulator Commelina communis. AB - Better understanding of copper uptake and accumulation regulation in plants is critical to the phytoremediation of copper contaminated soil. This study employed a 30-day pot experiment to assess the relationship between organic ligands and copper accumulation in plants. Hyperaccumulator and nonaccumulator varieties of Commelina communis were used, different organic ligands were applied, and the data of copper accumulation in shoots were collected. The six organic ligands included ethylenediaminetetraacetic acid and organic acids (formic acid, citric acid, malic acid, tartaric acid, and succinic acid). The results showed that organic ligands added to culture increased the copper accumulation both varieties. The results of the copper accumulation in shoots agreed with the study of the root uptake kinetics of copper influx. The addition of organic acids could increase copper accumulation in shoots because the copper influx in roots was increased. The results also indicated that the copper influx of hyperaccumulator roots was higher than that of nonaccumulator roots. This is one of the mechanisms by which a hyperaccumulator could amass large amounts of copper in its shoots. In this accumulation process, little effect on the leaf relative water content was in the hyperaccumulator and nonaccumulator of leaves and normal physiological condition of plants. PMID- 20842464 TI - Association of the Met-196-Arg variation of human tumor necrosis factor receptor 2 (TNFR2) with paranoid schizophrenia. AB - Research has provided strong evidence for oligodendrocyte and myelin-related genes dysfunction in schizophrenia. Several studies have suggested abnormalities in the expression of myelin-related genes including tumor necrosis factor receptor 2 (TNFR2) involved in the neurodegeneration and remyelination. In order to further assess the role of TNFR2 in schizophrenia, we examined a functional bi allelic polymorphism associated with an impaired NF-KB signaling and cell survival. In the present case/control study, 220 patients with schizophrenia and 176 healthy controls were genotyped by RFLP-PCR for the T/G polymorphism at the position 676 in exon 6 of the TNFR2 gene. We found a trend towards over representation of TNFR2 676G in the patients compared to the controls (p=0.19 and 0.09 respectively). Interestingly, when we evaluated the association between this genetic polymorphism and the clinical variables of schizophrenia, our findings indicated that the frequencies of the G/G genotype and the G allele were significantly higher in paranoid (p=0.014 and p=0.012 respectively) and adult onset paranoid (p=0.004 and p=0.004 respectively) schizophrenia patient group compared to the controls. The potential association was confirmed by a logistic regression model only for development of the paranoid form of schizophrenia (p=0.022) indicating a substantially increased risk for paranoid schizophrenia with inheritance of the TNFR2(G) allele. In conclusion, this polymorphism in TNFR2 or a gene in proximity seems to be associated specifically with paranoid schizophrenia, at least in the Tunisian population. A replication of our findings in other and larger populations could be of particular importance to establish TNFR2 as one of the susceptibility genes of paranoid schizophrenia. PMID- 20842466 TI - Simultaneous PET-MR acquisition and MR-derived motion fields for correction of non-rigid motion in PET. AB - OBJECTIVE: Positron emission tomography (PET) provides an accurate measurement of radiotracer concentration in vivo, but performance can be limited by subject motion which degrades spatial resolution and quantitative accuracy. This effect may become a limiting factor for PET studies in the body as PET scanner technology improves. In this work, we propose a new approach to address this problem by employing motion information from images measured simultaneously using a magnetic resonance (MR) scanner. METHODS: The approach is demonstrated using an MR-compatible PET scanner and PET-MR acquisition with a purpose-designed phantom capable of non-rigid deformations. Measured, simultaneously acquired MR data were used to correct for motion in PET, and results were compared with those obtained using motion information from PET images alone. RESULTS: Motion artefacts were significantly reduced and the PET image quality and quantification was significantly improved by the use of MR motion fields, whilst the use of PET-only motion information was less successful. CONCLUSIONS: Combined PET-MR acquisitions potentially allow PET motion compensation in whole-body acquisitions without prolonging PET acquisition time or increasing radiation dose. This, to the best of our knowledge, is the first study to demonstrate that simultaneously acquired MR data can be used to estimate and correct for the effects of non-rigid motion in PET. PMID- 20842465 TI - Mechanisms of anthracycline cardiotoxicity and strategies to decrease cardiac damage. AB - Anthracyclines are common chemotherapeutic agents used to treat many different types of cancer. Unfortunately, the use of anthracyclines is limited by their cardiotoxic effects, which may become manifest as late as 20 years from initial exposure. Studies in cells and animals suggest that the mechanism of anthracycline-induced cardiotoxicity (AIC) is multifactorial. Anthracyclines induce multiple forms of cellular injury by free radical production. In addition, anthracyclines alter nucleic acid biology by intercalation into DNA and modulate intracellular signaling, leading to cell death and the disruption of homeostatic processes such as sarcomere maintenance. In an effort to decrease AIC, many strategies have been tested, but no specific therapies are universally acknowledged to prevent or treat anthracycline-induced cardiac dysfunction. Newer imaging modalities and cardiac biomarkers may be useful in improving early detection of cardiac injury and dysfunction. As long as there is no cardiac specific therapy for AIC, evidence suggests that high-risk patients will benefit from prophylactic treatment with neurohormonal blockade by angiotensin-converting enzyme inhibitors and beta-adrenergic receptor blockers. PMID- 20842467 TI - Rheumatoid vasculitis: vanishing menace or target for new treatments? AB - Rheumatoid vasculitis is a rare but serious complication of rheumatoid arthritis. Herein we examine the pathophysiology, epidemiology, clinical diagnosis, and treatment of rheumatoid vasculitis. Seropositivity, specific HLA variations, and tobacco use are among the genetic and environmental predictors of rheumatoid vasculitis. Fortunately, recent reports have noted declines in the prevalence of rheumatoid vasculitis. Nevertheless, proper recognition of systemic manifestations may assist in pathologically confirming the diagnosis, determining the extent of disease, and guiding treatment. Contemporary treatment reports are discussed in the context of the ongoing debate regarding whether new agents may trigger, treat, or even prevent rheumatoid vasculitis. Evolving genetic, histopathologic, and immunologic studies partnered with ongoing clinical experience with biologics offer promise to inform future prevention and treatment of rheumatoid vasculitis. PMID- 20842468 TI - Assessment of metabolic phenotypes in patients with non-ischemic dilated cardiomyopathy undergoing cardiac resynchronization therapy. AB - Studies of myocardial metabolism have reported that contractile performance at a given myocardial oxygen consumption (MVO2) can be lower when the heart is oxidizing fatty acids rather than glucose or lactate. The objective of this study is to assess the prognostic value of myocardial metabolic phenotypes in identifying non-responders among non-ischemic dilated cardiomyopathy (NIDCM) patients undergoing cardiac resynchronization therapy (CRT). Arterial and coronary sinus plasma concentrations of oxygen, glucose, lactate, pyruvate, free fatty acids (FFA), and 22 amino acids were obtained from 19 male and 2 female patients (mean age 56 +/- 16) with NIDCM undergoing CRT. Metabolite fluxes/MVO2 and extraction fractions were calculated. Flux balance analysis (FBA) was performed with MetaFluxNet 1.8 on a metabolic network of the cardiac mitochondria (189 reactions, 230 metabolites) reconstructed from mitochondrial proteomic data (615 proteins) from human heart tissue. Non-responders based on left ventricular ejection fraction (LVEF) demonstrated a greater mean FFA extraction fraction (35% +/- 17%) than responders [18 +/- 10%, p = 0.0098, area under the estimated ROC curve (AUC) was 0.8238, S.E. 0.1115]. Calculated adenosine triphosphate (ATP)/MVO2 using FBA correlated with change in New York Heart Association (NYHA) class (rho = 0.63, p = 0.0298; AUC = 0.8381, S.E. 0.1316). Non-responders based on both LVEF and NYHA demonstrated a greater mean FFA uptake/MVO2 (0.115 +/- 0.112) than responders (0.034 +/- 0.030, p = 0.0171; AUC = 0.8593, S.E. 0.0965). Myocardial FFA flux and calculated maximal ATP synthesis flux using FBA may be helpful as biomarkers in identifying non-responders among NIDCM patients undergoing CRT. PMID- 20842469 TI - SDF-1-enhanced cardiogenesis requires CXCR4 induction in pluripotent stem cells. AB - Transformation of pluripotent stem cells into cardiac tissue is the hallmark of cardiogenesis, yet pro-cardiogenic signals remain partially understood. Preceding cardiogenic induction, a surge in CXCR4 chemokine receptor expression in the early stages of stem cell lineage specification coincides with the acquisition of pre-cardiac profiles. Accordingly, CXCR4 selection, in conjunction with mesoderm specific VEGF type II receptor FLK-1 co-expression, segregates cardiogenic populations. To assess the functionality of the CXCR4 biomarker, targeted activation and disruption were here exploited in the context of embryonic stem cell-derived cardiogenesis. Implicated as a cardiogenic hub through unbiased bioinformatics analysis, induction of the CXCR4/SDF-1 receptor-ligand axis triggered enhanced beating activity in stem cell progeny. Gene expression knockdown of CXCR4 disrupted spontaneous embryoid body differentiation and blunted the expression of cardiogenic markers MEF2C, Nkx2.5, MLC2a, MLC2v, and cardiac-MHC. Exogenous SDF-1 treatment failed to rescue cardiogenic-deficient phenotype, demonstrating a requirement for CXCR4 expression in mediating SDF-1 effects. Thus, a pro-cardiogenic signaling role for the CXCR4/SDF1 axis is herein revealed within pluripotent stem cell progenitors, exposing a functional target to promote lineage-specific differentiation. PMID- 20842470 TI - Pretreatment T lymphocyte numbers are contributing to the prognostic significance of absolute lymphocyte numbers in B-cell non-Hodgkins lymphomas. AB - Targeted immuno-chemotherapy resulted in greatly improved survival of B cell lymphoma patients. Several prognostic markers are investigated, amongst them the pretreatment absolute lymphocyte numbers. We investigated lymphocyte subpopulations and correlated this data with prognosis of patients. 88 patients (mean age: 56 years, 18-88, median follow up 32 months) with B cell lymphomas were investigated. There were 51 DLBCL, 16 Follicular NHL, 4 MALT, 7 Marginal Zone NHL, 10 Small lymphocytic cases were investigated. Our data showed that overall survival was statistically significant up to the 0.9 G/l absolute lymphocyte numbers as dividers between the subgroups. The CD19+ B cell numbers, or the CD56+/CD3- NK cell numbers did not represent any significant differences between subgroups. However CD3+, CD4+ and CD8+ T cells were differentiating statistically significant subgroups. Pretreatment CD3+ cell number less than 700/ul and CD8+ cell number less than 200/ul were corresponding with significantly inferior overall survival. These could be verified in the bad prognostic IPI group as well. Our data further support the importance of pretreatment lymphocyte numbers and highlight CD3+ and CD8+ lymphocytes to be the key factors in predicting outcome. PMID- 20842471 TI - Parental overprotection and heart-focused anxiety in adults with congenital heart disease. AB - BACKGROUND: The care of adult patients with congenital heart disease (CHD) is challenging from a mental health perspective, as these patients continue to face a variety of biopsychosocial issues that may impact emotional functioning. Despite these issues, there are limited data on the psychosocial functioning of adults with CHD, and there are no data on the impact of parental overprotection on heart-focused anxiety in this patient population. PURPOSE: The aim of this study was to examine the relationships between patient recollections of parental overprotection and current heart-focused anxiety in adults with CHD. METHOD: A cross-sectional sample of 190 adult patients with CHD (51% male; mean age = 32.28, SD = 11.86 years) completed validated measures of perceived parental overprotection (Parental Bonding Instrument) and heart-focused anxiety (Cardiac Anxiety Questionnaire). RESULTS: The results indicated that perceived parental overprotection (beta = 0.19, p = 0.02) and heart defect complexity (beta = 0.17, p = 0.03) were significantly related to heart-focused anxiety. Contrary to hypotheses, perceived parental overprotection did not vary as a function of heart defect complexity (F (2, 169) = 0.02, p = 0.98). CONCLUSION: Perceived parental overprotection and heart defect complexity are associated with heart-focused anxiety in adults with congenital heart disease. These results can inform the development of clinical interventions aimed at improving the psychosocial adjustment of this patient population. PMID- 20842473 TI - [Regeneration in cardiology--innovation or illusion?]. PMID- 20842472 TI - Evaluation of the role of oxidative stress in chemopreventive action of fish oil and celecoxib in the initiation phase of 7,12-dimethyl benz(alpha)anthracene induced mammary carcinogenesis. AB - Cyclooxygenase-2 (COX-2) enzyme plays an important role in cancer development. COX-2 inhibition by non-steroidal anti-inflammatory drugs is a useful approach for cancer prevention, but its usage has been associated with side effects. n-3 polyunsaturated fatty acids also exhibit a chemopreventive effect mediated by COX 2 inhibition. Therefore, the present study was designed to evaluate the effect of combined dosage of celecoxib and fish oil in experimental mammary carcinogenesis. Female Wistar rats were distributed as control, 7,12-dimethyl benz(alpha)anthracene (DMBA) treated, celecoxib + fish oil (20 mg/kg b.w. + 0.5 ml), celecoxib + fish oil (30 mg/kg b.w. + 0.25 ml), and their corresponding controls treated with fish oil or celecoxib only. The treatment was given for 7 days, and on the 8th day animals of all the groups except the control group received DMBA orally and sacrificed after 90 days. The histopathology, DNA fragmentation, total sialic acid (TSA), lipid-associated sialic acid (LASA), and oxidative stress were measured in mammary tissue and liver mitochondrial fraction. The results showed ductal hyperplasia and an increase in TSA, LASA, lipid peroxidation, and nitrite levels with a decrease in the antioxidants on DMBA treatment. Pretreatment with celecoxib and fish oil in DMBA-treated animals led to normal histology, increase in DNA fragmentation, and decrease in TSA and LASA levels with reduced oxidative stress, and the effect was more pronounced than animals pretreated with either celecoxib/fish oil alone suggesting a synergistic effect of the two regimens. To conclude, a combination of celecoxib and fish oil is a better strategy for cancer chemoprevention than celecoxib/fish oil alone. PMID- 20842474 TI - Regeneration of the vascular compartment. AB - Throughout life, damage to the vascular endothelium is pivotal in the development of cardiovascular disease. Therefore, a detailed understanding of the underlying mechanisms involved in endothelial cell restoration is of fundamental importance for preventive and therapeutic concepts in cardiovascular disease. The goal of regenerative medicine is the use of tissue-specific progenitor cells for a more effective repair process with reduction of fibrocellular remodelling, fibrosis and loss of functional properties.According to the hitherto assumed primary model of endothelial regeneration only adjacent and intact mature endothelial cells replace damaged endothelium. Since Asahara and colleagues first described that a peripheral blood mononuclear cell population was able to differentiate into endothelial cells in vitro and incorporate into ischemic tissue at sites of angiogenesis in vivo, the model of endothelial regeneration has been extended. The majority of clinical trials on human cell therapy for ischemic vascular disease are based on cell surface antigen expression of CD34 or VEGFR2 to identify endothelial progenitor cells.A precise characterization of the angiogenic properties of different subsets of endothelial regenerating cells and their course of action to gain sufficient long-term regeneration of the injured vessel is a necessary precondition before clinical trials of human cell therapy become a routine reality. PMID- 20842476 TI - [Co-editors and editors with Jewish origins of the first German journals for anaesthesia. Their fate under National Socialism and an attempt at a biographical appreciation]. AB - The decision to publish the journals Der Schmerz and Narkose und Anaesthesie in 1928 was an important step towards the professionalization of anaesthesiology in Germany. The appearance of both journals, which for economic reasons merged into Schmerz - Narkose - Anaesthesie 1 year later, was initiated and vehemently supported by Jewish physicians. As editors and co-editors they were deeply involved with the editorial tasks of the journals for years from the early beginnings. When the National Socialistic Party took over the government in Germany many of the Jewish colleagues were forced to quit their editorial tasks, were eliminated and replaced by "Arians", they were persecuted and often arrested, forced to emigrate or decided to commit suicide due to inhumane personal circumstances. It is our intention to recall the biography and the terrible fate of the nearly unknown Jewish members of the editorial board of the first German anaesthesia journals. Moreover the biographic sketches promote a continuous discussion about the victims of an inhumane and barbarous ideology. PMID- 20842477 TI - Understanding and promoting effective self-care during heart failure. AB - OPINION STATEMENT: Heart failure (HF) self-care relates to the decisions made outside clinical settings by the individual with HF to maintain life, healthy functioning, and well-being. The people who help patients most (ie, caregivers/family members) should be involved in care, and general principles of health behavior change should be used to guide support. Medicines should be prescribed with once-daily dosing, with pharmacists providing medication review and support. Pill boxes should be provided and patients' health literacy levels assessed. Psychosocial interventions for smoking cessation should be undertaken. Regular aerobic exercise may benefit patients with mild to moderate HF and some with severe but stable HF; therefore, referral to cardiac rehabilitation should be considered. Exercise regimen must take into account patient-related factors, including functional status, comorbid conditions, and patient preferences. Intake of salt, alcohol, and fluid should be restricted, although these steps are supported by limited evidence. Patients should be educated on appropriate sources of help. They should seek help immediately for persistent chest pain, palpitations, syncope, breathlessness at rest, or a weight increase of >= 2 lb. Depression, if present, should be addressed with antidepressants (sertraline and citalopram), cognitive behavioral therapy, and regular exercise. HF disease management programs should be offered if available. PMID- 20842478 TI - What is the Value of CT Angiography for Patients with Acute Chest Pain? AB - OPINION STATEMENT: Coronary CT angiography (CCTA) is an innovative technique to visualize the coronary arteries in patients with suspected coronary artery disease. CCTA has been validated in patients with non acute symptoms. Because of its high negative predictive value in this population, some have advocated using it in patients admitted to the emergency department with chest pain to determine the presence of coronary artery disease and acute coronary syndrome (ACS). With current CCTA protocols, adequate evaluation of the coronary arteries is feasible using radiation doses similar to, and even lower than, those for single-photon emission CT, which is commonly used to stratify these patients. In addition to its unique capability of visualizing the coronary tree in a noninvasive fashion, CCTA evaluates extracardiac pathologic conditions, which are part of the differential diagnosis in patients with chest pain, such as pulmonary embolism and acute aortic syndrome. These conditions, although less common than ACS, are also life threatening and their timely diagnosis and treatment may have a positive impact on survival. Other less frequent conditions, such as coronary artery anomalies, also are easily detected with CCTA. Overall, CCTA has an excellent negative predictive value and sensitivity for ACS in patients presenting with chest pain and simultaneously can aid in the diagnoses of other relevant intrathoracic abnormalities. PMID- 20842479 TI - Value of weight reduction in patients with cardiovascular disease. AB - OPINION STATEMENT: Obesity is an independent risk factor for cardiovascular (CV) disease and contributes markedly to individual CV risk factors, including hypertension, diabetes mellitus, dyslipidemia, and other chronic conditions, such as osteoarthritis, obstructive sleep apnea, and physical deconditioning. Obesity, defined as a body mass index >=30 kg/m(2), is associated with increased morbidity and mortality, particularly in severely obese patients with a body mass index >=35 kg/m(2). Physical activity, healthy eating and behavioral modification are three pivotal approaches to treating obesity. Some individuals may benefit from pharmacologic agents to achieve meaningful weight loss. Unfortunately, there are few such agents at present with proven efficacy and safety profiles. In this review, we discuss the obesity epidemic and its detrimental effects on the CV system, and focus on exercise training and on established pharmacologic agents as well as those on the horizon. We conclude by summarizing the surgical therapeutic options available to treat obesity and the evidence supporting the CV benefits of surgery, and discuss the potential adverse effects of both pharmacologic and surgical options. PMID- 20842480 TI - Coronary artery bypass graft versus drug-eluting stent for high-risk proximal left anterior descending stenosis. AB - OPINION STATEMENT: Determining how to treat a patient with symptomatic isolated proximal left anterior descending coronary artery disease may present a challenge. Previous randomized trials comparing percutaneous coronary intervention (PCI) with bare metal stents with minimally invasive direct coronary artery bypass surgery demonstrated significantly higher reintervention rates for stenting, with similar mortality and reinfarction rates. However, current evidence suggests that the use of drug-eluting stents may reduce the need for repeat revascularization. Also, in recent studies there were fewer periprocedural complications in patients undergoing PCI, with similar death and reinfarction rates. Moreover, the quality of life for patients who have received drug-eluting stents is similar to that of patients who have undergone minimally invasive direct coronary artery bypass surgery. Therefore, PCI with drug-eluting stents is the current treatment of choice for patients with isolated proximal left anterior descending coronary artery disease, unless they have complex lesions or repeated in-stent restenosis. In this article, the current treatment options are reviewed and outlined. PMID- 20842481 TI - Coronary stent thrombosis in the current era: challenges and opportunities for treatment. AB - OPINION STATEMENT: The introduction of the drug-eluting stent has raised concerns regarding the occurrence of stent thrombosis (ST), particularly late (and very late) thrombosis. This renewed attention shows that ST remains a major concern after implantation of both bare metal and drug-eluting stents. Cardiologists should be aware of this dreadful complication, because it is associated with substantial morbidity and mortality. Numerous clinical, procedural, and angiographic risk factors have been identified. Moreover, the influence of novel determinants, such as high on-treatment reactivity, genetic predisposition, and the stent's direct effects on the (healing of the) vessel wall, now are recognized. Consequently, the pathophysiology of ST has evolved into a complex multifactorial model. This broader understanding of the pathophysiology of ST enables cardiologists to perform extensive risk stratification to identify patients at higher risk and provides clues to important treatment options. The core of primary prevention after stent implantation, as well as secondary prevention after ST, should consist of a) the prevention of modifiable risk factors and b) optimal individualized treatment for each patient. Future developments, such as genetic bedside testing, point-of-care platelet testing, and sophisticated imaging modalities, might aid in this approach. PMID- 20842483 TI - Drug-eluting stents in the elderly. AB - OPINION STATEMENT: The introduction of drug-eluting stents (DES) in 2003 has had a great impact on the management of coronary artery disease in the United States. The application of DES to older adults, the population with the highest prevalence of and worst prognosis for coronary artery disease, remains relatively more controversial. Dual-antiplatelet therapy, which is recommended for at least 12 months after DES placement, is particularly problematic for older patients because of greater age-related bleeding risks. Unfortunately, few current data are available to gauge the balance of risk and benefit in elderly community dwelling DES patients. Although trial data show a benefit for DES among elderly patients, many older adults typically are excluded from randomized trials because of comorbidities, making generalizability of DES safety based on trial data less certain. New, more potent thienopyridines may place the elderly at a particularly elevated bleeding risk. There is a fine balance between efficacy and safety for older DES patients that still needs to be clarified. As the population ages, these issues become more pervasive and of widespread concern. This review summarizes the current literature on DES therapy in the elderly, with a focus on effectiveness and safety profiles of DES versus bare metal stents. PMID- 20842482 TI - Evolving approaches to the management of heart failure with preserved ejection fraction in patients with coronary artery disease. AB - OPINION STATEMENT: Coronary artery disease (CAD) is a major cause of heart failure with preserved ejection fraction (HFpEF). In studies of HFpEF, the reported prevalence of CAD varies widely, which may be the result of inconsistent definitions of CAD, geographic and ethnic differences in CAD burden, varying definitions of HFpEF (including different cutoffs for "preserved ejection fraction"), and differences in study design. Despite these limitations, pooled analysis of prospective HFpEF studies demonstrates that CAD is common in HFpEF, with an estimated prevalence of approximately 50%. Based on available data, patients with signs and symptoms of heart failure who have preserved left ventricular ejection fraction and evidence of CAD (HFpEF-CAD) most likely comprise a distinct etiologic and pathophysiologic subset of HFpEF. Therefore, future clinical trials in HFpEF should a priori stratify by CAD or specifically target patients with CAD, strategies that may improve the disappointing track record of therapies tested in HFpEF. The combination of systematic evaluation and management of CAD in HFpEF, along with promising future therapies for HFpEF-CAD, may lead to improved outcomes for this challenging clinical syndrome. PMID- 20842484 TI - Antithrombotics in acute coronary syndromes: updates from the past year. AB - OPINION STATEMENT: Acute coronary disease remains a major cause of morbidity and mortality. Investigation in established and novel therapies aimed at treating acute coronary syndromes continues. The resulting increase in available options will present a significant challenge to practitioners determining the optimal regimen for specific patients. The addition of newer, more potent antiplatelet agents, such as prasugrel and possibly ticagrelor, will require careful patient selection and risk assessment for both recurrent ischemic events and bleeding. The likely addition of newer oral anticoagulants will require knowledge as to their specific characteristics and risk/benefit ratios. Incremental updates to guideline recommendations from established expert groups will be important in providing guidance. PMID- 20842485 TI - Sleep and headache. AB - OPINION STATEMENT: Headache has been linked to a wide range of sleep disorders that may impact headache management. There are no evidence-based guidelines, but the authors believe that literature supports the following clinical recommendations: 1. Diagnose headache according to standardized criteria. Specific diagnoses are associated with increased risk for specific sleep and psychiatric disorders. 2. Collect sleep history in relation to headache patterns. Screening questionnaires and prediction equations are cost-effective. 3. Rule out sleep apnea headache in patients with awakening headache or higher-risk headache diagnoses (cluster, hypnic, chronic migraine, and chronic tension-type headache); patients with signs and symptoms of obstructive sleep apnea warrant polysomnography and treatment according to sleep medicine practice guidelines. There is no evidence for suspending conventional headache treatment in suspected or confirmed cases of sleep apnea. Treatment of sleep apnea with CPAP may improve or resolve headache in a subset of patients. The impact on sleep apnea headache of other treatments for sleep apnea (eg, oral appliances, surgery, weight loss) is largely untested. At a minimum, sedative-hypnotic drugs should be avoided in suspected apneics until the sleep apnea is treated. 4. Among patients with migraine and tension-type headache, insomnia is the most common sleep complaint, reported by one half to two thirds of clinic patients. Patients who suffer from chronic migraine or tension-type headache may benefit from behavioral sleep modification. Pharmacologic treatment may be considered on a case-by-case basis, with hypnotics, anxiolytics, or sedating antidepressants used to manage insomnia, tailoring treatment to the symptom pattern. 5. Individuals with chronic headache are at increased risk for psychiatric disorders. Assessment for depression and anxiety may be warranted when either insomnia or hypersomnia is present. Psychiatric symptoms affect the choice of sedating versus alerting versus neutral pharmacologic agents for headache. 6. All headache patients, particularly those with episodic migraine and tension-type headaches, may benefit from inclusion of sleep variables in trigger management. PMID- 20842486 TI - Myotonia congenita and myotonic dystrophy: surveillance and management. AB - OPINION STATEMENT: Myotonia can be treated both pharmacologically and by lifestyle modifications. Cell membrane stabilizers are the medications most commonly used for symptomatic treatment of myotonia. Most patients do not require treatment for the myotonia itself, unless it is severe, but physicians must be aware of anesthesia risks in both myotonia congenita and myotonic dystrophy. A mainstay of management of myotonic dystrophy is the surveillance and treatment of its various systemic complications. PMID- 20842487 TI - Prevention and treatment of peripheral neuropathy after bariatric surgery. AB - OPINION STATEMENT: Given the ever-increasing problem of obesity, it is not surprising that the number of patients who undergo bariatric surgery continues to rise. For patients who have gastric banding, the amount of food they can consume is limited, and nausea and vomiting may further limit nutritional intake early on. More extensive procedures, such as the Roux-en-Y or biliopancreatic diversion with or without a duodenal switch, not only restrict intake but also limit absorption in the small intestine. As a result, deficiencies in vitamins, minerals, and trace elements may develop, leading to a variety of neurologic complications. The peripheral neuropathies best described with a clear-cut cause are an acute, frequently painful neuropathy or polyradiculoneuropathy associated with thiamine deficiency, and an isolated neuropathy or myeloneuropathy associated with deficiencies of either vitamin B12 or copper. Thiamine deficiency tends to occur in the first weeks or months after surgery, vitamin B12 deficiency may develop at any time from a few years to many years after surgery, and copper deficiency tends to be a fairly late complication, developing several years to many years following surgery. Patients who have undergone bariatric surgery may also have an increased risk of developing focal neuropathies, though these are less clearly related to specific nutritional deficiencies.Ideally, one would like to prevent these neuropathies, but there is no consensus of opinion as to what vitamins and micronutrients need to be taken following bariatric surgery. In addition, many patients who take supplements early on fail to maintain the regimen even though some of the neuropathies can occur fairly late. Supplements frequently recommended include a multivitamin, iron, vitamin D, folic acid, calcium citrate, and vitamin B12. Although thiamine is typically included in a multivitamin, the amount is fairly small, so I recommend adding 100 mg daily for at least the first year. Some have suggested zinc supplementation, but this is potentially problematic because exogenous zinc may interfere with copper absorption. Obtaining blood work every 6 months after surgery will help to identify and treat nutritional deficiencies early.For those patients who have had a bariatric procedure and then develop a neuropathy, evaluating levels of thiamine, copper, vitamin B12, methylmalonic acid, and homocystine is indicated. In addition, since one deficiency is frequently associated with others, obtaining levels of vitamin A, C, D, K, and E, as well as iron, zinc, selenium, and magnesium is worthwhile. Checking total protein, albumin, and cholesterol also gives a sense of general nutritional status. Occasionally, no clear-cut deficiency of a vitamin, mineral, or trace element can be identified in patients with various peripheral nervous system manifestations. Nevertheless, these patients may have at least some recovery with improving nutritional intake and vitamin supplementation, suggesting that we still do not fully understand how nutritional status affects the peripheral nervous system. PMID- 20842488 TI - Nonvestibulocochlear cranial nerve schwannomas. AB - OPINION STATEMENT: Nonvestibulocochlear cranial nerve schwannomas traditionally have been managed by surgical excision. Although debulking surgery is still considered the first treatment option for larger tumors, stereotactic radiosurgery is now preferred for smaller tumors because of its high tumor control rate and low treatment-related morbidity. Furthermore, an initial period of radiologic and clinical observation following the diagnosis should be strongly considered for smaller tumors because some may not grow or may grow at a slow rate. Medical management of tumor-associated symptoms (when present) should not be ignored. Most importantly, the time has come to embark on the first randomized controlled trials comparing clinical and radiologic observation, surgery, and radiosurgery in the management of cranial nerve schwannomas. PMID- 20842489 TI - Treatment of carotid cavernous fistulas. AB - OPINION STATEMENT: The treatment of a carotid cavernous fistula (CCF) depends on the severity of the clinical symptoms, its angiographic characteristics, and the risk it presents for intracranial hemorrhage. In most instances, endovascular treatment is preferred.High-flow direct CCFs usually are traumatic or are caused by rupture of a cavernous aneurysm into the sinus, but a small percentage can be spontaneous. They usually present with sudden development of a clinical triad: exophthalmos, bruit, and conjunctival chemosis. All direct CCFs should receive treatment, because they carry a high probability of intracranial hemorrhage or neurologic deterioration.Low-flow indirect or dural CCFs, either incidental or with minimal symptoms, are not associated with significant risk of intracranial hemorrhage. The accepted practice is to treat ocular symptoms conservatively with medical management or manual carotid compression. If the patient cannot tolerate the symptoms, or if signs of ocular morbidity occur, endovascular treatment is offered.The first treatment option should be endovascular embolization with a combination of detachable balloons, coils, stents, or liquid embolic agents. The procedure can be performed from either an arterial or venous approach. Use of these materials and techniques can yield a high cure rate with minimal complications.If the patient is not amenable to embolization or if the embolization fails, then surgery (surgical ligation of the internal carotid artery or packing of the cavernous sinus) should be offered.Stereotactic radiosurgery may be an elective treatment for low-flow CCFs, but it has no role in the treatment of high-flow CCFs. PMID- 20842490 TI - Treatment of melanoma-associated retinopathy. AB - OPINION STATEMENT: Melanoma-associated retinopathy is a rare paraneoplastic disorder that is challenging to diagnose and even more difficult to treat. Because of the rarity of the disease, therapy is based on analysis of case series and case reports. Based on evidence from these reports, first-line therapy is cytoreduction of metastatic disease through metastasectomy, chemotherapy, and radiation. This can be combined with intravenous immunoglobulin. For refractory visual symptoms, additional therapies include systemic corticosteroids and plasmapheresis, but the success of these strategies has been limited. Because of the rarity of the disorder, new therapies should be evaluated and reported in the literature to expand our clinical understanding of this autoimmune disease. PMID- 20842491 TI - Treatment of thyroid eye disease. AB - OPINION STATEMENT: Thyroid eye disease (TED) is an autoimmune disease characterized by varying degrees of proptosis, congestion and inflammation of the extraocular tissues, and eyelid retraction. It is usually seen in the setting of Graves' disease, but the severity of TED does not necessarily correlate with the level of systemic disease in a given patient. It is very important, nonetheless, to try to achieve a euthyroid state to minimize the chances of exacerbation of TED. Treatment of TED is based on the signs and symptoms displayed by the patient; there is no "one size fits all" approach. Generally, it is advisable to start with conservative measures, such as ocular lubrication with artificial tears, to manage symptoms of chronic irritation and redness. It is also imperative that the patient be advised to quit smoking, because there is a clear link between smoking and disease activity. Medical treatment with systemic oral or pulsed intravenous corticosteroids should be reserved for patients with active inflammation resulting in increased orbital pressure, compressive optic neuropathy, severe periorbital edema, or similar presentations. Once there is significant improvement in the acute inflammation, it is useful to treat patients who have residual inflammation with external beam radiation in order to be able to wean the patient off steroids and avoid their well-known complications.If there is significant corneal exposure due to lid retraction, and the lid position has been stable for at least 6 months, eyelid surgery can be considered. If exposure is minimal, this may consist of a lateral tarsorrhaphy. For larger amounts of exposure, recession of the levator muscle, Muller's muscle, or both can be performed. Those patients who have stable diplopia for at least 6 months are candidates for strabismus surgery. Patients who progress to severe proptosis or compressive optic neuropathy may need orbital decompression surgery. Generally, if more than one type of surgical procedure is necessary, orbital decompression is performed first, followed by strabismus surgery; eyelid surgery is performed last. PMID- 20842492 TI - Migratory and resident blue tits Cyanistes caeruleus differ in their reaction to a novel object. AB - Individuals differ consistently in their behavioural reactions towards novel objects and new situations. Reaction to novelty is one part of a suit of individually consistent behaviours called coping strategies or personalities and is often summarised as bold or shy behaviour. Coping strategies could be particularly important for migrating birds exposed to novel environments on their journeys. We compared the average approach latencies to a novel object among migrants and residents in partially migratory blue tits Cyanistes caeruleus. In this test, we found migrating blue tits to have shorter approach latencies than had resident ones. Behavioural reactions to novelty can affect the readiness to migrate and short approach latency may have an adaptive value during migration. Individual behaviour towards novelty might be incorporated among the factors associated with migratory or resident behaviour in a partially migratory population. PMID- 20842493 TI - [Megaprostheses of the knee joint]. AB - The development of modern modular reconstructive endoprosthetic systems (megaprostheses) has enhanced or at least simplified the joint reconstruction in limb-sparing surgery. Orthopaedic oncology can demonstrate better treatment outcomes as a consequence of the close collaboration with other disciplines, such as internal and pediatric oncology or diagnostic and therapeutic radiology, or improved surgical procedures. The present article summarizes all current information about megaprostheses of the knee joint based on the literature as well as our own collective. Evaluation of the literature was not easy. There are great differences in the surgical and accompanying (adjuvant/neoadjuvant) procedures, among the patient collectives as well as the definition of treatment success and complications. Furthermore, a variety of different implants exist. PMID- 20842494 TI - Prevalence and risk factors for mesh erosion after laparoscopic-assisted sacrocolpopexy. AB - INTRODUCTION AND HYPOTHESIS: The purpose of this study is to identify risk factors for mesh erosion in women undergoing minimally invasive sacrocolpopexy (MISC). We hypothesize that erosion is higher in subjects undergoing concomitant hysterectomy. METHODS: This is a retrospective cohort study of women who underwent MISC between November 2004 and January 2009. Demographics, operative techniques, and outcomes were abstracted from medical records. Multivariable regression identified odds of erosion. RESULTS: Of 188 MISC procedures 19(10%) had erosions. Erosion was higher in those with total vaginal hysterectomy (TVH) compared to both post-hysterectomy (23% vs. 5%, p = 0.003) and supracervical hysterectomy (SCH) (23% vs. 5%, p = 0.109) groups. In multivariable regression, the odds of erosion for TVH was 5.67 (95% CI: 1.88-17.10) compared to post hysterectomy. Smoking, the use of collagen-coated mesh, transvaginal dissection, and mesh attachment transvaginally were no longer significant in the multivariable regression model. CONCLUSION: Based on this study, surgeons should consider supracervical hysterectomy over total vaginal hysterectomy as the procedure of choice in association with MISC unless removal of the cervix is otherwise indicated. PMID- 20842495 TI - Mixed incontinence and cystocele: postoperative urge symptoms are not predicted by preoperative urodynamics. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) frequently presents with urinary incontinence, either urge (UUI), stress (SUI), or mixed (MUI). We sought to determine the effect of high-grade prolapse repair on MUI. METHODS: A retrospective review was performed for 111 patients with anterior POP repair and sling over 4 years. RESULTS: Sixty patients (54%) presented symptomatically with MUI, 25% with SUI, and 9% with UUI, 12% asymptomatic. Occult SUI was found in 21% (UUI plus asymptomatic). Success was seen for SUI in 92% and for POP in 89%. Urge symptoms were present in 63% pre-op and 30% post-op. MUI patients were significantly more likely to experience post-op urgency (p = 0.033). Detrusor overactivity (DO) was seen in 22 MUI patients, but was not predictive of post-op urgency (p = 0.91). CONCLUSIONS: Cystocele patients with MUI are at significant risk for postoperative urge symptoms regardless of DO, and counseling regarding persistent urgency is imperative. PMID- 20842496 TI - Potential of resveratrol analogues as antagonists of osteoclasts and promoters of osteoblasts. AB - The plant phytoalexin resveratrol was previously demonstrated to inhibit the differentiation and bone resorbing activity of osteoclasts, to promote the formation of osteoblasts from mesenchymal precursors in cultures, and inhibit myeloma cell proliferation, when used at high concentrations. In the current study, we screened five structurally modified resveratrol analogues for their ability to modify the differentiation of osteoclasts and osteoblasts and proliferation of myeloma cells. Compared to resveratrol, analogues showed an up to 5,000-fold increased potency to inhibit osteoclast differentiation. To a lesser extent, resveratrol analogues also promoted osteoblast maturation. However, they did not antagonize the proliferation of myeloma cells. The potency of the best-performing candidate in vitro was tested in vivo in an ovariectomy induced model of osteoporosis, but an effect on bone loss could not be detected. Based on their powerful antiresorptive activity in vitro, resveratrol analogues might be attractive modulators of bone remodeling. However, further studies are required to establish their efficacy in vivo. PMID- 20842497 TI - Molecular characterization of coprophilous fungal communities reveals sequences related to root-associated fungal endophytes. AB - This paper reports the use of molecular methods to characterize the coprophilous fungal communities (CFC) that inhabit the dung of four species of mammalian herbivores at two sites, Sevilleta National Wildlife Refuge (SNWR) in New Mexico and Wind Cave National Park (WCNP) in South Dakota. Results reveal that CFC from domesticated cattle (Bos taurus) at SNWR, and bison (Bison bison) and black tailed prairie dogs (Cynomys ludovicianus) at WCNP were diverse but dominated primarily by members within eight taxonomic orders, including the rarely cultured and anaerobic order Neocallimastigales. In addition, 7.7% (138 of 1,788) of the sequences obtained from all dung samples were at least 97% similar to root associated fungal (RAF) sequences previously described from blue grama (Bouteloua gracilis), a common forage grass found throughout North America and growing at both study sites. In contrast, 95.8% (295 of 308) of the sequences and four of the total seven operational taxonomic units obtained from pronghorn antelope (Antilocapra americana) dung belonged to the Pleosporalean order. We hypothesize that some herbivore vectors disperse non-systemic (non-clavicipitaceous) fungal endophytes. These dispersal events, it is argued, are most likely to occur via herbivores that occasionally forage and masticate root tissue, especially in arid regions where aboveground vegetation is sparse. The results of this study suggest that some (possibly many) members of the RAF community can expand their ecological role to include colonizing dung. PMID- 20842498 TI - Prospective study of double-eccentric hemi shoulder arthroplasty in different aetiologies: midterm results. AB - This prospective study aimed to analyse the effect of a newly developed double eccentric adjustable stemmed prosthesis on reconstruction of the osseous anatomy, range of motion, strength and pain relief. A total of 91 consecutive hemiprostheses were evaluated preoperatively and three, six, 12, 24 and 48 months postoperatively (mean+/-SD 46.2 +/- 10.9 months) by the American Shoulder and Elbow Surgeons (ASES) and Constant scores as well as radiological assessment. Clinical evaluations showed an increase in Constant score from 21.9 to 64.8 points and in ASES score from 24.9 to 77.9 points after two years. The results depend mainly on the underlying pathology. The best results were observed for primary osteoarthritis and avascular necrosis of the humeral head. All heads were eccentrically positioned. Specific stem-related complications were not observed. Because of the eccentric positioning of all heads it is reasonable to use adjustable shaft prostheses. The clinical results are comparable to data in the literature. Additional study provided a better or comparable clinical outcome and a low revision rate, when compared with other modern adjustable implants in the literature. PMID- 20842499 TI - Toward a conceptual framework for blending social and biophysical attributes in conservation planning: a case-study of privately-conserved lands. AB - There has been increasing recognition within systematic conservation planning of the need to include social data alongside biophysical assessments. However, in the approaches to identify potential conservation sites, there remains much room for improvement in the treatment of social data. In particular, few rigorous methods to account for the diversity of less-easily quantifiable social attributes that influence the implementation success of conservation sites (such as willingness to conserve) have been developed. We use a case-study analysis of private conservation areas within the Little Karoo, South Africa, as a practical example of the importance of incorporating social data into the process of selecting potential conservation sites to improve their implementation likelihood. We draw on extensive data on the social attributes of our case study obtained from a combination of survey questionnaires and semi-structured interviews. We discuss the need to determine the social attributes that are important for achieving the chosen implementation strategy by offering four tested examples of important social attributes in the Little Karoo: the willingness of landowners to take part in a stewardship arrangement, their willingness to conserve, their capacity to conserve, and the social capital among private conservation area owners. We then discuss the process of using an implementation likelihood ratio (derived from a combined measure of the social attributes) to assist the choice of potential conservation sites. We conclude by summarizing our discussion into a simple conceptual framework for identifying biophysically-valuable sites which possess a high likelihood that the desired implementation strategy will be realized on them. PMID- 20842500 TI - Expression of myelopoiesis-associated microRNA in bone marrow cells of atypical chronic myeloid leukaemia and chronic myelomonocytic leukaemia. AB - The microRNA/miR deregulation in BCR-ABL-negative myelodysplastic myeloproliferative neoplasms (MDS/MPN) is not known. Myelopoiesis-associated miR 10a, miR-17-5p, miR-155, miR-223 and miR-424 were analysed by real-time polymerase chain reaction (PCR) in bone marrow cells of atypical chronic myeloid leukaemia (aCML, n = 7) and chronic myelomonocytic leukaemia (CMML, n = 8) and were compared to BCR-ABL-positive chronic myelogenous leukaemia (CML, n = 10) and non-neoplastic haematopoiesis (n = 10). Down-regulation of miR-10a was found in CMML but also in CML (each p < 0.05, versus controls). Overexpression of miR-424 was detected in aCML (p < 0.05, versus CML and controls). Despite different compositions of bone marrow cells, expression of myelopoiesis-associated microRNA shows mainly similar patterns in aCML and its main differential diagnosis CMML and does not allow discrimination of these two MDS/MPN entities. Therefore, the link of deregulated microRNA expression to disease-related phenotype and the underlying molecular mechanism are still unknown. PMID- 20842501 TI - Should medical treatment options be exhausted before splenectomy is performed in adult ITP patients? A debate. AB - Patients with primary immune thrombocytopenia (ITP) may require treatment to reduce the risk of serious bleeding if platelets remain consistently below 30 * 10(9)/L. While approximately 70-80% of patients respond to an initial course of corticosteroids, relapse is common. For steroid-refractory patients, there is a choice between surgical splenectomy and further medical treatments, based on many factors including the patient's bleeding history, fitness for surgery, comorbidities, tolerance of adverse events, lifestyle and preferences. Treatments that have traditionally been used (corticosteroids, azathioprine, danazol) suppress the immune system, potentially predisposing patients to infection. Recent insights into the underlying pathophysiology of the disease have allowed the development of targeted therapies, including the thrombopoietin (TPO) receptor agonists, which enhance platelet production. Phase III trials have found romiplostim and eltrombopag to be well tolerated and effective in elevating platelet counts and reducing bleeding in both splenectomised and nonsplenectomised patients with chronic ITP. The B-cell targeted monoclonal antibody rituximab has also shown some potential in this setting, although data are currently limited and there are toxicity concerns. The decision whether to proceed to splenectomy or try other medical therapies in corticosteroid refractory patients remains patient-specific. Splenectomy has its risks (including perioperative and long-term risks), and relapse/nonresponse are relatively common, but it offers the possibility of cure in the majority of patients. However, newer treatments may potentially allow splenectomy to be deferred for prolonged periods, as well as providing alternative treatment options for patients who fail splenectomy. PMID- 20842502 TI - Severe traumatic tricuspid insufficiency detected 10 years after blunt chest trauma. PMID- 20842503 TI - Prevalence of rhinosinusitis among atypical cystic fibrosis patients. AB - The objective of this paper is to study the correlation between sinonasal involvement and type of cystic fibrosis (CF) in Israeli's CF patients. The comparative study includes 70 CF patients: 40 typical and 30 atypical CF patients. History and physical examination data were recorded, including endoscopic nasal examination as well as sinus computer tomography scan. The data collected from the two groups were statistically analyzed. Twenty-seven percent of atypical CF patients compared with 2.5% of typical CF patients had CF presenting symptoms of chronic rhinosinusitis (CRS) or obstructive nasal polyps (p < 0.001). Although severe CRS was found slightly more often in patient with atypical CF (43 vs. 32.5%), this difference did not reach statistical significance. Nine patients with severe CRS underwent endoscopic sinus surgery. Among these patients, six (66.6%) had atypical CF and only three (33.3%) had typical CF (p = 0.09). In conclusion, severe CRS is a common diagnosis among patients with typical and atypical CF disease. In the current study, no significant difference in the frequency of CRS was found between the two groups. High awareness toward the diagnosis of atypical CF, careful medical history focusing on sinonasal involvement and physical examination, including nasal endoscopy, for all CF patients (typical and atypical CF) may contribute to an early detection and treatment of significant sinonasal involvement, and may improve the quality of life of the patients. PMID- 20842504 TI - Long-term result of management of otitis media with effusion in patients with post-irradiated nasopharyngeal carcinoma. AB - The treatment of post-irradiated otitis media with effusion (OME) remains controversial. Hence the aim of this study was to understand the long-term result of management of post-irradiated OME. Eighty-five nasopharyngeal carcinoma patients with post-irradiated OME were prospectively enrolled. All were followed up with close observation and a hearing aid was advised for those with hearing loss. If patients were still bothered by aural fullness, tinnitus or hearing impairment and did not want to continue conservative treatment, tympanostomy plus aspiration was performed. Only those who had persistent OME and failed repeated tympanostomy for at least 3 months were suggested to undergo grommet insertion. After a mean follow-up of 842.1 +/- 49.0 days from the completion of radiotherapy, OME was present in 45 patients (52.9%). Another 16 (18.8%) had chronic discharging ears with or without perforated eardrums. Grommets remained on the eardrums in eight patients. Among them, five were without otorrhea but discharge came from grommet tubes intermittently in three patients. Only 15 (17.6%) were free of OME, and one patient had a dry perforated eardrum. Our results showed current methods did not result in long-term resolution of some recalcitrant post-irradiated OME. PMID- 20842505 TI - Prolene mesh mentoplasty. AB - Augmentation mentoplasty is a cosmetic surgical procedure to correct chin retrusion or microgenia which usually requires placement of an alloplastic material over the pogonion, and which results in increased chin projection and a more aesthetically balanced facial profile. Polypropylene mesh is easy to purchase, widely available in a general hospital and most commonly used by general surgeons. In this series of 192 patients, we wanted to demonstrate our simple mentoplasty technique using prolene mesh that can easily be combined with a rhinoplasty procedure, with possible causes of infection and the rationale for using prolene mesh in such procedures. PMID- 20842506 TI - Laryngeal transplantation in minipigs: vascular, myologic and functional outcomes. AB - There is no effective way of replacing all the functions of the larynx in those requiring laryngectomy. Regenerative medicine offers promise, but cannot presently deliver implants with functioning neuromuscular units. A single well documented laryngeal transplant in man was a qualified success, but more information is required before clinical trials may be proposed. We studied the early response of the larynx to laryngeal transplantation between 17 pairs of NIH minipigs full matched at the MHC2 locus. Following iterative technical improvements, pigs had good swallowing and a patent airway at 1 week. No significant changes in mucosal blood flux were observed compared with pre operative measurements. Changes in muscle morphology and fibre phenotype were observed in transplant muscles retrieved after 7 days: the levels of fast and slow myosin heavy chain (MyHC) protein were reduced and embryonic MyHC was up regulated consistent with denervation induced atrophy. At 1 week laryngeal transplantation can result in good swallowing, and is not associated with clinical evidence of ischemia-reperfusion injury in MHC-matched pigs. PMID- 20842507 TI - Job strain, effort-reward imbalance and ambulatory blood pressure: results of a cross-sectional study in call handler operators. AB - OBJECTIVES: To examine the association between two job stress models-the job strain (JDC) and the effort-reward imbalance (ERI) model-and ambulatory blood pressure monitoring in call handler operators. METHODS: Participants included 74 women (age, 34.9 +/- 9.9 years) and 26 men (age 36.0 +/- 10.8 years) who were monitored on 2 workdays for ambulatory blood pressure. Measures of both job stress models were related to blood pressure by the generalized estimating equations (GEE) method while adjusting for potential confounders (gender, age, cigarette smoking, alcohol consumption, educational level, marital status, time of day, and work schedule). RESULTS: Workshifts were associated with an increase of 3-4 and 14 mmHg in mean arterial pressure (MAP) compared with diurnal activities out of work and sleeping period, respectively (P < 0.001). Ambulatory blood pressure was also significantly related with work schedule preference: unpleasant work schedule was associated with an increase of 2 mmHg in MAP compared with pleasant work schedule (P = 0.013). In the ERI model, subjects scoring high in work stress have higher ambulatory blood pressure at work, at home, and during sleep. Work stress by time interaction was not longer significant when controlling for potential confounders: generalized estimating equations revealed that MAP was influenced by BMI (>25 vs. <25: 0.7 (0.2-1.1) mmHg), workshift preference (unpleasant vs. pleasant: 2 (0.4-3.6) mmHg), and time of day. Weak not significant relation was found between ABP and psychosocial factors evaluated by the JDC and ERI models. CONCLUSION: These results do not support work stress as a significant factor influencing ABP in a homogeneous group of call-handlers. Complementary information independently obtained from the two work stress models could provide more exhaustive explanations on the stress related effects on blood pressure. PMID- 20842509 TI - GC-MS analysis and antileishmanial activities of two Turkish propolis types. AB - Propolis is a honeybee product with a very complex chemical composition and various pharmacological properties. This study was aimed to investigate antileishmanial activities of "Bursa" and "Hatay" propolis samples against Leishmania infantum and Leishmania tropica strains. Propolis samples were analysed with the gas chromatography-mass spectrometry technique. Promastigotes were incubated in Roswell Park Memorial Institute culture medium in the absence and presence of several concentrations (50, 100, 250, 500, 750, and 1,000 MUg/mL) of each propolis sample. The viability and cell morphology of promastigotes in each concentration were examined after 24, 48, 72, and 96 h of incubation. The growth of leishmania parasites was significantly suppressed in the presence of 500, 750, and 1,000 MUg/mL of Hatay propolis. Bursa propolis was found to be efficient in inhibiting the growth of leishmania promastigotes in culture media at these concentrations, 250, 500, 750, and 1,000 MUg/mL. Thus, the in vitro results showed that the Hatay and Bursa propolis samples decreased significantly the proliferation of L. infantum and L. tropica parasites (p < 0.001); however, Bursa propolis was found to be more effective than Hatay propolis against leishmania promastigotes. These two natural products may be useful agents in the prevention of leishmanial infections. PMID- 20842511 TI - Unusual extrusion of ventriculoperitoneal shunt. PMID- 20842510 TI - A simple clinical scoring system using ferritin, fasting insulin, and type IV collagen 7S for predicting steatohepatitis in nonalcoholic fatty liver disease. AB - BACKGROUND: Liver histology is the gold standard for the diagnosis of nonalcoholic steatohepatitis (NASH). Noninvasive, simple, reproducible, and reliable biomarkers are greatly needed to differentiate NASH from nonalcoholic fatty liver disease (NAFLD). METHODS: To construct a scoring system for predicting NASH, 177 Japanese patients with biopsy-proven NAFLD were enrolled. To validate the scoring system, 442 biopsy-proven NAFLD patients from eight hepatology centers in Japan were also enrolled. RESULTS: In the estimation group, 98 (55%) patients had NASH. Serum ferritin [>=200 ng/ml (female) or >=300 ng/ml (male)], fasting insulin (>=10 MUU/ml), and type IV collagen 7S (>=5.0 ng/ml) were selected as independent variables associated with NASH, by multilogistic regression analysis. These three variables were combined in a weighted sum [serum ferritin >=200 ng/ml (female) or >=300 ng/ml (male) = 1 point, fasting insulin >=10 MUU/ml = 1 point, and type IV collagen 7S >=5.0 ng/ml = 2 points] to form an easily calculated composite score for predicting NASH, called the NAFIC score. The area under the receiver operating characteristic (AUROC) curve for predicting NASH was 0.851 in the estimation group and 0.782 in the validation group. The NAFIC AUROC was the greatest among several previously established scoring systems for detecting NASH, but also for predicting severe fibrosis. CONCLUSIONS: NAFIC score can predict NASH in Japanese NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use. PMID- 20842512 TI - The association between single-nucleotide polymorphisms of NCF2 and systemic lupus erythematosus in Chinese mainland population. AB - Systemic lupus erythematosus (SLE) is a complex immune disease. The genetic variation in the NCF2 gene was found to associate with SLE in US and European populations. However, the association of rs10911363 with SLE was not extensively studied in Chinese mainland population. A total of 488 SLE patients and 380 controls were recruited. Unlabeled probe-based high-resolution melting analysis (HRMA) was used in genotyping. HRMA with unlabeled probe successfully distinguished all genotypes. Neither genotype nor allele frequencies of single nucleotide polymorphism (SNP) rs10911363 showed statistically significant differences between SLE patients and controls. The association of SNP rs10911363 with the diagnostic criteria of SLE was also examined. Minor allele (G) of rs10911363 was found to significantly associate with the incidence of arthritis (p = 0.024, odds ratio (OR) = 1.35, and 95% confidence interval (CI) = 1.04-1.75) and increased abnormalities of antinuclear antibody (p = 0.002, OR = 1.51, and 95%CI = 1.17-1.95) and anti-DNA (p = 0.013, OR = 1.40, and 95%CI = 1.07-1.82). Polymorphisms of rs13277113 in NCF2 gene were associated with arthritis and autoantibody production, but not disease risk, of SLE in Chinese population. PMID- 20842513 TI - Evaluation of current therapeutic strategies in Behcet's disease. AB - Behcet's disease (BD) is a chronic relapsing vasculitis with multifunctional pathogenesis. The mucocutaneous and ocular lesions are the commonest manifestations, but BD also affects the musculoskeletal, intestinal, cardiac, and central nervous system. BD therapy is based on the suppression of the inflammatory process, using immunomodulating and immunosuppressive agents. In selected cases, invasive procedures may be required. PMID- 20842514 TI - Vertebroplasty: a point of view on this surgical treatment. PMID- 20842515 TI - Case report: successful use of short-term add-on tocilizumab for multirefractory systemic flare of adult-onset Still's disease. AB - We report on a 64-year-old woman with multirefractory flare of adult-onset Still's disease successfully treated with six-month course of add-on anti interleukin 6 receptor antibody, tocilizumab. Before administration of tocilizumab, the combination therapy with 80 mg/day of prednisolone and cyclosporine or tacrolimus for five weeks, two courses of pulse methylprednisolone, and high-dose intravenous immunoglobulin could not control the disease. Add-on tocilizumab dramatically improved her disease state and enabled tapering of corticosteroid and tacrolimus. Furthermore remission has been maintained on low-dose corticosteroid and tacrolimus after withdrawal of tocilizumab. This case report suggests that short-term add-on tocilizumab might be a useful therapeutic option for patients with multirefractory flare of polycyclic systemic adult-onset Still's disease. PMID- 20842516 TI - The determination of matrix metalloproteinase 9 activity and gene expression levels in Behcet's disease patients with aneurysmal complications. AB - The information concerning aneurysmal progress in Behcet's disease is still insufficient, while researches in the role of matrix metalloproteinases (MMPs) in aneurysmal formation are rapidly expanding. The goal of the present study is to investigate the role of metalloproteinase 9 (MMP-9) in vascular complications which is observed in 10% of Behcet's disease patients. Three groups have been studied; patients with Behcet's disease, patients with Behcet's disease who have vascular problems (vasculo-Behcet's), and patients with abdominal aortic aneurysm (AAA). The third group was used as a control. The activity and gene expression levels of MMP-9 in plasma have been determined. We showed that compared to AAA patients there was no difference in the MMP-9 activity in Behcet's disease patients (vascular and non-vascular). We also evaluated the gene expression level and activity of MMP-9 for every patient. The increase in the gene expression level for MMP-9 could only be detected at two patients. One of them was Behcet's, the other was AAA patient. It is surprising that MMP levels of these patients were different. While the patient with Behcet's had low protein level, another patient with AAA had high of MMP-9 level. This result suggested to us that the relationship between gene expression and active protein level is not correlated. It is not sufficient alone to determine MMPs levels for evaluating the pathogenesis. At the same time gene expression and the level of active protein should be assessed together. PMID- 20842517 TI - Comparison of the Er,Cr:YSGG laser with a chemical vapour deposition bur and conventional techniques for cavity preparation: a microleakage study. AB - The aim of this study was to compare the effects of the Er,Cr:YSGG laser using chemical vapour deposition (CVD) bur cavity preparation with conventional preparation methods including a diamond bur and a carbide bur on the microleakage with two different adhesive systems. A total of 40 extracted human premolars were randomly assigned to four experimental groups according to the cavity preparation technique: group I diamond bur (Diatech); group II carbide bur (Diatech); group III Er,Cr:YSGG laser (Biolase Millennium II); and group IV CVD bur (CVDentUS). Using the different preparation techniques, Class V standardized preparations were performed on the buccal and lingual surfaces with gingival margins on the dentin and occlusal margins on the enamel. Each preparation group was randomly assigned to two subgroups (five teeth, ten preparations) according to the type of adhesive: an etch-and-rinse adhesive (Adper Single Bond), and a single-step self etch adhesive (AdheSE One). All preparations were restored with a nanohybrid composite resin in a single increment. Following thermocycling (*500; 5-55 degrees C), the teeth were immersed in basic fuchsin and sectioned in the orovestibular direction. Dye penetration was evaluated under a light microscope by two blinded examiners. Data were statistically analysed with the Kruskal Wallis and Wilcoxon tests (p<0.05). There were no statistically significant differences between the preparation techniques with either of the two adhesive systems (p>0.05). Comparing the enamel and dentin leakage scores within each group, no statistically significant differences were found (p>0.05). The Er,Cr:YSGG laser cavity preparation did not differ from preparation with CVD, diamond or carbide bur in terms of microleakage with the different adhesive systems. PMID- 20842518 TI - Successful treatment of lipoprotein glomerulopathy in a daughter and a mother using niceritrol. AB - We report two patients, a daughter and a mother, with lipoprotein glomerulopathy (LPG) who were successfully treated with niceritrol. Both patients carried a mutation in the apolipoprotein E (apoE) gene known as ApoE Tokyo/Maebashi. The daughter was found to have proteinuria at the age of 4 years. Four years later, she was diagnosed as having LPG based on a renal biopsy. She was treated with several medications including pravastatin, ethyl icosapentate, enalapril, warfarin and cyclophosphamide, all of which failed to reduce her proteinuria. At the age of 17 years, she exhibited an increase in proteinuria and a decline in renal function, despite ongoing treatment with pravastatin and enalapril. After switching from pravastatin to niceritrol, a marked reduction in the proteinuria and an improvement in renal function were observed. Her mother was found to have proteinuria at the age of 57 years and was diagnosed as having LPG based on a renal biopsy. She was also treated with niceritrol, resulting in an improvement in her proteinuria and renal function. These cases suggest that niceritrol might be a useful therapeutic option for LPG. PMID- 20842519 TI - Efficacy of topical dorzolamide for treatment of cystic macular lesions in a patient with enhanced S-cone syndrome. AB - The purpose of this study was to evaluate the efficacy of topical dorzolamide 2% eye drops on macular function and thickness in a case of enhanced S-cone syndrome (ESCS). A 24-year-old Asian man with enhanced S-cone syndrome treated with topical dorzolamide in the left eye participated in the study. Examinations performed before and during treatment were included visual acuity (VA), contrast sensitivity measured with briefly presented grating targets (grating CS) and the Pelli-Robson chart (P-R CS), microperimetry (MP), and spectral-domain optical coherence tomography (SD-OCT). Following 4 months of treatment, the mean thickness of the central 1-mm foveal subfield of the left eye, as measured by SD OCT, decreased from 551 to 242 MUm. Mean MP sensitivity within the central 12 degrees (28 points) increased from 9.4 dB at baseline to 11.2 dB. Although Pelli Robson contrast sensitivity improved only minimally in the left eye, grating contrast sensitivity improved by more than a factor of two. Mean log MAR VA was 0.22 OD and 1.00 OS (at baseline), which improved to 0.10 OD and 0.66 OS after 4 months of treatment. The results indicate that in our patient with enhanced S cone syndrome, treatment with topical dorzolamide was effective in improving macular thickness, VA, microperimetry sensitivity, and grating contrast sensitivity. These measures of retinal structure and function are sensitive tools for evaluating the effects of treatment in enhanced S-cone syndrome patients with cystoid macular edema. Further investigation is warranted to assess the relationships among visual performance for daily activities, visual sensitivity, and macular thickness. PMID- 20842521 TI - HIV/AIDS and the gendering of stigma in Tamil Nadu, South India. AB - Drawing on the seminal theoretical work on stigma by Goffman, this article analyzes stigma through the lens of Parker and Aggleton, who call for the joining of Goffman and Foucault to better grasp relationships among stigma, power and social inequality. Studies on the social impact of HIV/AIDS globally have demonstrated that women tend to be blamed for the spread of HIV/AIDS, and as a result, HIV-positive women face greater stigma and discrimination than HIV positive men. Based on ethnographic research among 50 HIV-positive women in South India in 2002-2003 and 2004, my research supports this standard argument. However, my findings suggest that the gendering of stigma and discrimination is more complex and context specific. The gendering of stigma varies depending on the social context of private versus public spheres. The tendency to stigmatize women is due in part to cultural constructions of gendered bodies and not only to a gendered double standard of sexual morality, as has been previously reported. Even when a cultural argument about women's wayward sexuality is evoked, this rhetoric must be understood in part as a strategy to mask economically motivated responses, rather simply being attributed to sexist ideology per se. PMID- 20842520 TI - Corticosteroids affect nitric oxide generation, total free radicals production, and nitric oxide synthase activity in monocytes of asthmatic patients. AB - Airways inflammation, a pathological hallmark of asthma, is associated with the recruitment of pro-inflammatory and inflammatory cells like eosinophils, polymorphonuclear leucocytes cells, mononuclear cells, macrophages, epithelial desquamation, and airways remodeling with sub-epithelial fibrosis. Activated inflammatory cells along with the resident cells can generate pro-inflammatory mediators including oxidants such as superoxide radicals, reactive oxygen species (ROS), and reactive nitrogen species. One of such inflammatory mediator that has received considerable attention is the nitric oxide (NO(*)) generated by pulmonary macrophageal/epithelial cells. In this study, we have explored that systemic monocytes also get activated in asthma to produce oxidants like ROS and NO(*). We estimated the NO(*) production, nitric oxide synthase (NOS) activity, inducible NOS (iNOS) mRNA levels and total free radical activity (TFRA) in blood monocytes of healthy control subjects, untreated asthmatic patients, patients on corticosteroid for less than 6 months and patients on corticosteroid for more than 6 months. Increase in NOS activity, NO(*) levels, and TFRA was observed in monocytes of asthmatic patients. The increase was found to be associated with the transcriptional upregulation of iNOS gene and severity of disease. Highest values of NOS activity, NO(*), and iNOS mRNA were found in the patients with acute asthma. Corticosteroid administration was found to be effective in reversing the induction of iNOS mRNA levels, NOS activity and NO(*) levels. Corticosteroids controlled asthma appears to have association with NOS, NO(*), and TFRA in systemic monocytes of the patients. PMID- 20842522 TI - Tobacco education and counseling in obstetrics and gynecology clerkships: a survey of medical school program directors. AB - The 16,000 medical students completing OB/GYN clerkship programs each year provide a unique opportunity to motivate and mentor students in facilitating tobacco cessation. To determine the scope of current tobacco teaching in obstetrics/gynecology (OB/GYN) education at US medical schools and to assess opportunities for including new tobacco teaching, a 28-question survey was administered to directors and assistant directors at US medical school OB/GYN clerkship programs. Surveys were completed at 71% of schools. Only 9% reported having at least 15 min of dedicated teaching time for improving tobacco cessation skills. Nearly three-fourths of respondents reported teaching students how to intervene to reduce smoking during a work-up in the OB/GYN clinic, but only 43% reported that students would know where to refer someone wishing to quit. Only a third of respondents reported teaching students both to intervene with and refer OB/GYN patients who smoke. These findings suggest that although medical students see many OB and GYN patients who smoke, they have few opportunities to learn comprehensive cessation skills during their clerkships. PMID- 20842523 TI - Introduction of solid food to young infants. AB - Timing of the first introduction of solid food during infancy may have potential effects on life-long health. To understand the characteristics that are associated with the timing of infants' initial exposure to solid foods. The 2000 National Survey of Early Childhood Health (NSECH) was a nationally representative telephone survey of 2,068 parents of children aged 4-35 months, which profiled content and quality of health care for young children. African-American and Latino families were over-sampled. Analyses in this report include bivariate tests and logistic regressions. 62% of parents reported introducing solids to their child between 4-6 months of age. African-American mothers (OR=0.5 [0.3, 0.9]), English-speaking Latino mothers (OR=0.4 [0.2, 0.7]), White mothers with more than high school education (OR=0.5 [0.2, 1.0]), and mothers who breastfed for 4 months or longer (OR=0.4 [0.3, 0.7]) were less likely to introduce solids early. Most parents (92%) of children 4-9 months of age reported that their pediatric provider had discussed introduction of solids with them since the child's birth, and provider discussion of feeding was not associated with the timing of introduction of solids. Although most parents recall discussing the introduction of solid foods with their child's physician, several subgroups of mothers introduce solid foods earlier than the AAP recommendation of 4-6 months. More effective discussion of solid food introduction linked to counseling and support of breastfeeding by the primary health care provider may reduce early introduction of solids. PMID- 20842524 TI - High RASSF1A promoter methylation levels are predictive of poor prognosis in fine needle aspirate washings of breast cancer lesions. AB - Previously, we reported that the accuracy of cytological diagnosis of breast lesions could be augmented through the quantitative assessment of DNA methylation of fine-needle aspirate (FNA) washings. Herein, we aimed at the evaluation of the prognostic value of quantitative promoter methylation at three gene loci (APC, CCND2, and RASSF1A) in a large series of FNA washings from breast lesions. Methylation levels of three gene promoters were assessed by quantitative methylation-specific PCR in bisulfite-modified DNA from 211 FNA washings, comprising 178 carcinomas and 33 benign lesions, both histopathologically confirmed. Receiver operator characteristic (ROC) curve analysis was used to determine the diagnostic performance of the gene panel in distinguishing cancer from non-cancerous lesions. Relevant clinicopathologic data and time to progression and/or death from breast cancer were correlated with methylation findings. Log-rank test and Cox-regression model identified independent predictors of prognosis. APC, CCND2, and RASSF1A methylation levels differed significantly between malignant and benign lesions. ROC curve analysis confirmed the diagnostic performance of the gene panel. In univariate analysis, stage was significantly associated with overall, disease-specific and disease-free survival, whereas tumor grade was associated with disease-specific and disease free survival. Remarkably, RASSF1A methylation was significantly and independently associated with worse disease-free survival in the final multivariate analysis. We confirmed that quantitative gene promoter methylation augments the diagnostic performance of cytopathology. Importantly, and in addition to standard clinicopathologic parameters, RASSF1A high-methylation levels are independent predictors of worse outcome in breast cancer. Thus, epigenetic biomarkers provide valuable tools for breast cancer patient management. PMID- 20842525 TI - Gene expression array testing of FFPE archival breast tumor samples: an optimized protocol for WG-DASL sample preparation. AB - Archived formalin-fixed, paraffin embedded (FFPE) tissues constitute a vast, well annotated, but underexploited resource for the molecular study of cancer progression, largely because degradation, chemical modification, and cross linking, render FFPE RNA a suboptimal substrate for conventional analytical methods. We report here a modified protocol for RNA extraction from FFPE tissues which maximized the success rate (with 100% of samples) in the expression profiling of a set of 60 breast cancer samples on the WG-DASL platform; yielding data of sufficient quality such that in hierarchical clustering (a) 12/12 (100%) replicates correctly identified their respective counterparts, with a high self correlation (r = 0.979), and (b) the overall sample set grouped with high specificity into ER+ (38/40; 95%) and ER- (18/20; 90%) subtypes. These results indicate that a large fraction of decade-old FFPE samples, of diverse institutional origins and processing histories, can yield RNA suitable for gene expression profiling experiments. PMID- 20842527 TI - Highly selective deuteration of pharmaceutically relevant nitrogen-containing heterocycles: a flow chemistry approach. AB - A simple and efficient flow-based technique is reported for the catalytic deuteration of several model nitrogen-containing heterocyclic compounds which are important building blocks of pharmacologically active materials. A continuous flow reactor was used in combination with on-demand pressure-controlled electrolytic D(2) production. The D(2) source was D(2)O, the consumption of which was very low. The experimental set-up allows the fine-tuning of pressure, temperature, and flow rate so as to determine the optimal conditions for the deuteration reactions. The described procedure lacks most of the drawbacks of the conventional batch deuteration techniques, and additionally is highly selective and reproducible. PMID- 20842526 TI - Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome. AB - Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages-proliferating macrophages (promacs)-with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P = 0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions. PMID- 20842528 TI - Pharmacy education in Cuba. AB - BACKGROUND: In Cuba, as in other countries around the world, professional pharmacy has moved from a product orientation (dispensing medications) to a focus on the patient. AIM: To provide an overview of the current status of pharmacy education in Cuba. METHODS: Research was conducted on the historical records of the curriculums used in pharmacy education in Cuba. RESULTS: All programs require a minimum of 5 years of postsecondary education prior to attainment of the Bachelor of Science in Pharmacy degree, which is currently the entry-level degree for the profession. The main change currently affecting practice of and education in pharmacy in Cuba is the introduction of pharmaceutical care concept. CONCLUSIONS: All University Schools of Pharmacy are formally involved in the continuing professional development of practitioners as an important part of the educational life cycle for pharmacists. PMID- 20842529 TI - Religiosity, self-efficacy for exercise, and African American women. AB - Physical inactivity among African American women persists despite health promotion efforts targeting this population. In the African American faith community, thinking patterns related to personal versus divine control over health status could affect self-efficacy beliefs and physical activity behavior. Religiosity, a determinate of self-efficacy for exercise, is influenced by culture. This exploratory pilot study assessed the psychometric properties and relevance of selected study instruments and relationships among the study variables in African American women recruited through a rural church. Findings indicated a trend toward significance among study variables and that the God Locus of Health Control and Physical Exercise Self-Efficacy Scales were reliable for capturing attitudes about ability to engage in physical activity and religiosity in this sample. Six of the twenty-five women recruited failed to complete the Stanford Brief Activity Survey for Work and Leisure Time Activity correctly, suggesting the need to revise instructions prior to future instrument administration. PMID- 20842530 TI - Endothelial cell behaviour within a microfluidic mimic of the flow channels of a modular tissue engineered construct. AB - To study the effect of disturbed flow patterns on endothelial cells, the channels found within a modular tissue engineering construct were reproduced in a microfluidic chip and lined with endothelial cells whose resulting phenotype under flow was assessed using confocal microscopy. Modular tissue engineered constructs formed by the random packing of sub-millimetre, cylindrically shaped, endothelial cell-covered modules into a larger container creates interconnected channels that permit the flow of fluids such as blood. Due to the random packing, the flow path is tortuous and has the potential to create disturbed flow, resulting in an activated endothelium. At an average shear stress of 2.8 dyn cm 2, endothelial cells within channels of varying geometries showed higher amounts of activation, as evidenced by an increase in ICAM-1 and VCAM-1 levels with respect to static controls. VE-cadherin expression also increased, however, it appeared discontinuous around the perimeter of the cells. An increase in flow (15.6 dyn cm-2) was sufficient to reduce ICAM-1 and VCAM-1 expression to a level below that of static controls for many disturbed flow-prone channels that contained branches, curves, expansions and contractions. VE-cadherin expression was also reduced and became discontinuous in all channels, possibly due to paracrine signaling. Other than showing a mild correlation to VE-cadherin, which may be linked through a cAMP-initiated pathway, KLF2 was found to be largely independent of shear stress for this system. To gauge the adhesiveness of the endothelium to leukocytes, THP-1 cells were introduced into flow-conditioned channels and their attachment measured. Relative to static controls, THP-1 adhesion was reduced in straight and bifurcating channels. However, even in the presence of flow, areas where multiple channels converged were found to be the most prone to THP-1 attachment. The microfluidic system enabled a full analysis of the effect of the tortuous flow expected in a modular construct on endothelial cell phenotype. PMID- 20842531 TI - Ex vivo expansion of a hematopoietic stem cell on a murine stromal cell by 3D micro-pillar device. AB - Stromal cells alter their mode of attachment, cellular shape, and protein expression when placed on square arrays of micro-pillars. All the pillars we studied had 50 MUm diameters, 85 MUm pillar heights, were separated by 50 MUm, and had an identical surface chemistry. We found that these micro-pillars provided many opportunities for mechanical interlocking and were more suitable attachment matrixes for cell adhesion and stretching of the overlying biomaterials. When the feeder layer cells of hematopoietic stem cells (HSCs) were cultured into the micro-pillar device, they could screen more hematopoietic cytokines, such as interleukin-3 (IL-3), and laminin into the medium. Consequently, the micro-pillar device provides a greater degree of HSCs expansion relative to the 25 T flask. The maximal expansion of the HSCs and the colony forming unit (CFU) on the micro-pillar device increased 62.72-fold and 16.95-fold for 28 day culture, but there were only 58.08-fold and 6.8-fold expansion on the 25 T flask. The results showed a significantly higher expansion in the pillar device compared to the 25 T flask; moreover, the stemness was maintained. Therefore, the 3D micro-pillar device appears to be a more suitable culture substrate for HSCs expansion ex vivo. PMID- 20842533 TI - Plasma biomarkers of mouse aging. AB - Normal aging is accompanied by a series of physiological changes such as gray hair, cataracts, reduced immunity, and increased susceptibility to disease. To identify novel biomarkers of normal aging, we analyzed plasma proteins of male mice longitudinally from 2 to 19 months of age. Plasma proteins were analyzed by two-dimensional gel electrophoresis and identified using mass spectrometry (MS), MS/MS and liquid chromatography MS/MS. We found that many plasma proteins exist as multiple isoforms with different masses and/or charges. Thirty-nine protein spots (corresponding to six distinct proteins) have been identified, 13 of which exhibited significant changes with age. For example, several proteins increased significantly during aging including one isoform of transthyretin, two isoforms of haptoglobin, and three isoforms of immunoglobulin kappa chain. Conversely, several proteins decreased significantly during aging including peroxiredoxin-2, serum amyloid protein A-1, and five isoforms of albumin. Identification of these proteins provides new biomarkers of normal aging in mice. If validated in humans, these biomarkers may facilitate therapeutic interventions to identify premature aging, delay aging, and/or improve healthspan of the elderly. PMID- 20842534 TI - Advanced glycation end products in diabetic and non-diabetic human subjects suffering from cataract. AB - Advanced glycation end products (AGEs) play a pivotal role in loss of lens transparency, i.e., cataract. AGEs formation occurs as a result of sequential glycation and oxidation reaction between reducing sugars and protein. AGEs production takes place throughout the normal aging process but its accumulation is found to be more rapid in diabetic patients. In this study, we quantified AGEs and N-(carboxyethyl) lysine (CEL) in human cataractous lenses from non-diabetic (n=50) and diabetic patients (n=50) using ELISA. We observed significantly higher (p<0.001) levels of lens AGEs and CEL in diabetic patients with cataract as compared with their respective controls. The presence of AGEs and CEL was also determined by western blotting and immuno-histochemical analysis. Furthermore, isolated beta-crystallin from cataractous lenses of non-diabetic and diabetic patients was incubated with different sugars to evaluate the extent of glycation in a time dependent manner. Our data indicated more pronounced glycation in patients suffering from diabetes as compared to non-diabetics subjects demonstrating the need to focus on developing normoglycemic approaches. Such studies may provide an insight in developing therapeutic strategies and may have clinical implications. PMID- 20842532 TI - Biological pathways and genetic variables involved in pain. AB - PURPOSE: This paper summarizes current knowledge of pain-related and analgesic related pathways as well as genetic variations involved in pain perception and management. METHODS: The pain group of the GENEQOL Consortium was given the task of summarizing the current status of research on genetic variations in pain and analgesic efficacy. This review is neither exhaustive nor comprehensive; we focus primarily on single-nucleotide polymorphisms. RESULTS: Two categories of potential genetic pain-perception pathways were identified: neurotransmission modulators and mechanisms that affect inflammation. Four categories were identified for analgesic efficacy: genes related to receptor interaction, modulation of opioid effects, metabolism, and transport. Various genetic variations involved in these pathways are proposed as candidate genetic markers for pain perception and for individual sensitivity to analgesics. CONCLUSIONS: Candidate gene association studies have been used to provide evidence for the genetic modulation of pain perception and response to analgesics. However, the nature and range of genetic modulation of pain is not well addressed due to the limited number of patients and the limited number of genes and genetic variants investigated in studies to date. Moreover, personalized analgesic treatments will require a more complete understanding of the effects of genetic variants and gene gene interactions in response to analgesics. PMID- 20842535 TI - Adiponectin protects rat hippocampal neurons against excitotoxicity. AB - Adiponectin exerts multiple regulatory functions in the body and in the hypothalamus primarily through activation of its two receptors, adiponectin receptor1 and adiponectin receptor 2. Recent studies have shown that adiponectin receptors are widely expressed in other areas of the brain including the hippocampus. However, the functions of adiponectin in brain regions other than the hypothalamus are not clear. Here, we report that adiponectin can protect cultured hippocampal neurons against kainic acid-induced (KA) cytotoxicity. Adiponectin reduced the level of reactive oxygen species, attenuated apoptotic cell death, and also suppressed activation of caspase-3 induced by KA. Pretreatment of hippocampal primary neurons with an AMPK inhibitor, compound C, abolished adiponectin-induced neuronal protection. The AMPK activator, 5 aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, attenuated KA-induced caspase-3 activity. These findings suggest that the AMPK pathway is critically involved in adiponectin-induced neuroprotection and may mediate the antioxidative and anti-apoptotic properties of adiponectin. PMID- 20842537 TI - Incarceration, restitution, and lifetime debarment: legal consequences of scientific misconduct in the Eric Poehlman case: Commentary on: "Scientific forensics: how the office of research integrity can assist institutional investigations of research misconduct during oversight review". AB - Following its determination of a finding of scientific misconduct the Office of Research Integrity (ORI) will seek redress for any injury sustained. Several remedies both administrative and statutory may be available depending on the strength of the evidentiary findings of the misconduct investigation. Pursuant to federal regulations administrative remedies are primarily remedial in nature and designed to protect the integrity of the affected research program, whereas statutory remedies including civil fines and criminal penalties are designed to deter and punish wrongdoers. This commentary discusses the available administrative and statutory remedies in the context of a specific case, that of former University of Vermont nutrition researcher Eric Poehlman, and supplies a possible rationale for the legal result. PMID- 20842538 TI - Application of support vector machine in cancer diagnosis. AB - To investigate the clinical application of tumor marker detection combined with support vector machine (SVM) model in the diagnosis of cancer. Tumor marker detection results for colorectal cancer, gastric cancer and lung cancer were collected. With these tumor mark data sets, the SVM models for diagnosis with best kernel function were created, trained and validated by cross-validation. Grid search and cross-validation methods were used to optimize the parameters of SVM. Diagnostic classifiers such as combined diagnosis test, logistic regression and decision tree were validated. Sensitivity, specialty, Youden Index and accuracy were used to evaluate the classifiers. Leave-one-out was used as the algorithm test method. For colorectal cancer, the accuracy of 4 classifiers were 75.8, 76.6, 83.1, 96.0%, respectively; for gastric cancer, the accuracy of 4 classifiers were 45.7, 64.5, 63.7, 91.7%; for lung cancer, the results were 71.9, 68.6, 75.2, 97.5%. The accuracy of SVM classifier is especially high in 4 kinds of classifiers, which indicates the potential application of SVM diagnostic model with tumor marker in cancer detection. PMID- 20842536 TI - Raising suspicions with the Food and Drug Administration: detecting misconduct. AB - The clinical Bioresearch Monitoring (BIMO) oversight program of the US Food and Drug Administration (FDA) assesses the quality and integrity of data submitted to the FDA for new product approvals and human subjects protection during clinical studies. A comprehensive program of on-site inspections and data verification, the BIMO program routinely performs random inspections to verify studies submitted to the FDA to support a marketing application. On occasion the FDA will conduct a directed inspection of a specific site or study to look for problems that may have previously been identified. The inspection of a clinical study sometimes uncovers evidence of research fraud or misconduct and it must be decided how to deal with the investigator and the suspect data. The prevention of [or] decreasing the incidence of fraud and misconduct through monitoring by the sponsor is one way to manage compliance issues and can help prevent misconduct. A training program is another way to manage compliance issues in clinical research. While training does not guarantee quality, it does help to ensure that all individuals involved understand the rules and the consequences of research misconduct. PMID- 20842539 TI - Validation of a static Franz diffusion cell system for in vitro permeation studies. AB - Over the years, in vitro Franz diffusion experiments have evolved into one of the most important methods for researching transdermal drug administration. Unfortunately, this type of testing often yields permeation data that suffer from poor reproducibility. Moreover, this feature frequently occurs when synthetic membranes are used as barriers, in which case biological tissue-associated variability has been removed as an artefact of total variation. The objective of the current study was to evaluate the influence of a full-validation protocol on the performance of a tailor-made array of Franz diffusion cells (GlaxoSmithKline, Harlow, UK) available in our laboratory. To this end, ibuprofen was used as a model hydrophobic drug while synthetic membranes were used as barriers. The parameters investigated included Franz cell dimensions, stirring conditions, membrane type, membrane treatment, temperature regulation and sampling frequency. It was determined that validation dramatically reduced derived data variability as the coefficient of variation for steady-state ibuprofen permeation from a gel formulation was reduced from 25.7% to 5.3% (n = 6). Thus, validation and refinement of the protocol combined with improved operator training can greatly enhance reproducibility in Franz cell experimentation. PMID- 20842540 TI - Considerations in developing a target product profile for parenteral pharmaceutical products. AB - A target product profile (TPP) describes how a product will be utilized by the end user. A systematically developed TPP can ensure alignment of objectives across company departments, accelerate development timelines, minimize development risks, and eventually lead to an optimal product. A TPP is particularly important for parenteral products due to the need for administration devices, the variety of possible end users (nurses, patients, pharmacists, and physicians), and requirements specific to sterile products. This manuscript describes key components of a TPP from a formulation development perspective and provides guidance on practical issues common to parenteral products. PMID- 20842541 TI - Physicochemical characterization of berberine chloride: a perspective in the development of a solution dosage form for oral delivery. AB - The objective of the present research was to evaluate the physicochemical characteristics of berberine chloride and to assess the complexation of drug with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), a first step towards solution dosage form development. The parameters such as log P value were determined experimentally and compared with predicted values. The pH-dependent aqueous solubility and stability were investigated following standard protocols at 25 degrees C and 37 degrees C. Drug solubility enhancement was attempted utilizing both surfactants and cyclodextrins (CDs), and the drug/CD complexation was studied employing various techniques such as differential scanning calorimetry, Fourier transform infrared, nuclear magnetic resonance, and scanning electron microscopy. The experimental log P value suggested that the compound is fairly hydrophilic. Berberine chloride was found to be very stable up to 6 months at all pH and temperature conditions tested. Aqueous solubility of the drug was temperature dependent and exhibited highest solubility of 4.05 +/- 0.09 mM in phosphate buffer (pH 7.0) at 25 degrees C, demonstrating the effect of buffer salts on drug solubility. Decreased drug solubility was observed with increasing concentrations of ionic surfactants such as sodium lauryl sulfate and cetyl trimethyl ammonium bromide. Phase solubility studies demonstrated the formation of berberine chloride-HPbetaCD inclusion complex with 1:1 stoichiometry, and the aqueous solubility of the drug improved almost 4.5-fold in the presence of 20% HPbetaCD. The complexation efficiency values indicated that the drug has at least threefold greater affinity for hydroxypropyl-beta-CD compared to randomly methylated-beta-CD. The characterization techniques confirmed inclusion complex formation between berberine chloride and HPbetaCD and demonstrated the feasibility of developing an oral solution dosage form of the drug. PMID- 20842542 TI - Modified nanoprecipitation method for preparation of cytarabine-loaded PLGA nanoparticles. AB - The present investigation was aimed at developing cytarabine-loaded poly(lactide coglycolide) (PLGA)-based biodegradable nanoparticles by a modified nanoprecipitation which would have sustained release of the drug. Nine batches were prepared as per 3(2) factorial design to optimize volume of the co-solvent (0.22-0.37 ml) and volume of non-solvent (1.7-3.0 ml). A second 3(2) factorial design was used for optimization of drug: polymer ratio (1:5) and stirring time (30 min) based on the two responses, mean particle size (125 +/- 2.5 nm), and percentage entrapment efficiency (21.8 +/- 2.0%) of the Cyt-PLGA nanoparticles. Optimized formulation showed a zeta potential of -29.7 mV indicating good stability; 50% w/w of sucrose in Cyt-PLGA NP was added successfully as cryoprotectant during lyophilization for freeze-dried NPs and showed good dispersibility with minimum increase in their mean particle sizes. The DSC thermograms concluded that in the prepared PLGA NP, the drug was present in the amorphous phase and may have been homogeneously dispersed in the PLGA matrix. In vitro drug release from the pure drug was complete within 2 h, but was sustained up to 24 h from PLGA nanoparticles with Fickian diffusion. Stability studies showed that the developed PLGA NPs should be stored in the freeze-dried state at 2-8 degrees C where they would remain stable in terms of both mean particle size and drug content for 2 months. PMID- 20842543 TI - The influence of the compression force on zidovudine release from matrix tablets. AB - The aim of the present work is the study of different zidovudine (AZT) formulations containing polymers (both cellulosic and acrylic), in order to evaluate the influence of the compression force on the antiviral release from the matrix tablets. The results evidenced that the formulations compressed at 500 and 1,000 MPa exhibit a higher hardness than those prepared at 100 MPa. The effect of the compression force on the drug release was analyzed and a statistically significant difference was observed (P < 0.05). Using lower compression forces leads to slightly better release profiles, i.e., profiles close to an ideal Higuchi kinetics for a total release of drug in a 12-h period, allowing to conclude that a compression force higher than 100 MPa is unnecessary. PMID- 20842544 TI - Control of ionic selectivity by a pore helix residue in the Kv1.2 channel. AB - Interaction between the selectivity filter and the adjacent pore helix of voltage gated K(+) (Kv) channels controls pore stability during K(+) conduction. Kv channels, having their selectivity filter destabilized during depolarization, are said to undergo C-type inactivation. We examined the functionality of a residue at the pore helix of the Kv1.2 channel (V370), which reportedly affects C-type inactivation. A mutation into glycine (V370G) caused a shift in reversal potential from around -72 to -9 mV. The permeability ratios (P(Na)/P(K)) of the wild type and V370G mutant are 0.04 and 0.76, respectively. In the wild-type, P(Rb)/P(K), P(Cs)/P(K) and P(Li)/P(K) are 0.78, 0.10 and 0.05, respectively. Kv1.2 V370G channels had enhanced permeability to Rb(+) and Cs(+) (P(Rb)/P(K) and P(Cs)/P(K) are 1.63 and 1.18, respectively); however, Li(+) permeability was not significantly augmented (P(Li)/P(K) is 0.13). Therefore, in addition to its known effect on pore stability, V370 of Kv1.2 is also crucial in controlling ion selectivity. PMID- 20842545 TI - Endovascular treatment of thoracoabdominal aneurysm. AB - OPINION STATEMENT: The use of endovascular modalities for the treatment of simple descending thoracic aneurysms has become standard of care. Expanding endovascular techniques for the treatment of thoracoabdominal aneurysms is now possible with the evolution of branched and fenestrated grafts. PMID- 20842546 TI - Using advanced MRI techniques for patient selection before acute stroke therapy. AB - OPINION STATEMENT: Results of acute MRI studies may help guide the management of acute stroke. Patients with a malignant MRI pattern may be poor candidates for reperfusion therapies yet may benefit from hemicraniectomy. Preliminary data suggest that patients with a carefully identified diffusion weighted imaging (DWI)/perfusion weighted imaging (PWI) mismatch may benefit from intravenous recombinant tissue plasminogen activator in a 3- to 6-hour time window; however, confirmatory studies with larger sample sizes are required before clinical use of this strategy can be generally recommended. Post hoc analyses of recent studies suggest that PWI techniques that use a threshold to exclude benign oligemia from penumbra and DWI techniques that use apparent diffusion coefficient thresholds to exclude reversible DWI lesions to distinguish the ischemic core from penumbra appear to provide more accurate determinations of the volume of salvageable tissue. New automated software programs are now implementing these techniques to generate quantitative PWI and DWI maps within minutes. Prospective trials are in progress to investigate these new techniques. The results of these studies will further refine the application of MRI to select patients for acute recanalization therapies. PMID- 20842547 TI - New approaches to stroke prevention in atrial fibrillation. AB - OPINION STATEMENT: It is estimated that atrial fibrillation (AF) is responsible for almost 15% of all strokes. Several randomized clinical trials have demonstrated the superiority of adjusted-dose warfarin over aspirin for stroke prevention in AF patients, particularly in high-risk individuals. Current national guidelines from the American Heart Association/American Stroke Association recommend the use of adjusted-dose warfarin with an international normalized ratio goal of 2.0 to 3.0 for patients with ischemic stroke or transient ischemic attack with persistent or paroxysmal AF, and aspirin for those who cannot take oral anticoagulants. However, the use of warfarin may be challenging in some patients, and there is a need for alternative treatments. We describe alternative treatments for AF and provide an overview on emerging therapies. PMID- 20842548 TI - Thrombi of different pathologies: implications for diagnosis and treatment. AB - OPINION STATEMENT: Stroke is the second leading cause of cardiovascular mortality in the modern world, accounting for 80% of strokes of ischemic origin. There are two main etiologies of ischemic stroke: 70% to 80% are caused by carotid atherosclerotic plaque rupture and superimposed thrombus formation, whereas 30% are caused by systemic embolism of a cardiac thrombus (mainly in atrial fibrillation [AF] patients). Therefore, antithrombotic therapy is the cornerstone of stroke treatment. In AF patients, thrombotic risk should be assessed by means of the CHADS2 score. Patients with a score of 0 should be treated with aspirin; for those with a score of 1, oral anticoagulation (target international normalized ratio, 2-3) or aspirin is recommended. For patients with a CHADS2 score >=2, oral anticoagulation with warfarin should be initiated (unless contraindicated). If warfarin is contraindicated, antithrombotic treatment should be prescribed (the combination of aspirin and clopidogrel seems to be superior to aspirin alone). For primary prevention in atherosclerotic patients, low-dose aspirin is useful only in women older than 45 years who are not at risk for intracranial hemorrhage and do not have gastrointestinal intolerance (a very small but significant effect). For secondary prevention in atherosclerotic patients, antithrombotic therapy should be administered. It is recommended that patients who do not require anticoagulation receive clopidogrel or a combination of aspirin and dipyridamole. Alternatively, aspirin alone or triflusal may be used. Within 4.5 h of onset of acute stroke, thrombolytic therapy (recombinant tissue plasminogen activator) must be injected urgently (unless contraindicated). Dabigatran is a new oral anticoagulant (competitive thrombin inhibitor) with a promising role in stroke prevention; at low doses, it is noninferior to warfarin for stroke prevention and is safer, whereas at high doses, it is superior to warfarin in stroke prevention with the same incidence of bleeding. Percutaneous left atrial appendage occluders recently were approved for systemic embolism prevention. The use of warfarin after implantation is still under discussion. Dronedarone, a new antiarrhythmic agent, has been shown to decrease cardiovascular mortality and stroke in patients with AF. Carotid endarterectomy surgery is indicated in symptomatic patients with stenosis greater than 70% and in selected patients with 50% to 70% stenosis. Currently, carotid endarterectomy surgery is superior to carotid angioplasty and stenting. PMID- 20842550 TI - Venous leg ulcerations: a treatment update. AB - OPINION STATEMENT: Selecting the appropriate treatment for venous leg ulcerations is essential for optimal wound healing and patient quality of life. Compression therapy remains the mainstay of treatment for these wounds. Compression methods should be carefully selected and tailored for compatibility with patients' daily life. Pain management should not be neglected. When response to compression therapy is limited, adjuvant therapy such as medication, debridement, or surgical procedures should be considered on an individual basis. PMID- 20842549 TI - Pathology and vulnerability of atherosclerotic plaque: identification, treatment options, and individual patient differences for prevention of stroke. AB - OPINION STATEMENT: Vulnerable carotid plaques at risk for rupture/ulceration do not always correlate with the severity of stenosis at bifurcation sites. Therefore, information on plaque morphology and composition is essential for identifying patients at high risk for acute major cerebrovascular events. Traditional imaging modalities, including angiography and ultrasound, are slowly being replaced by CT imaging, as this technology is readily available in most hospitals and provides high-resolution capabilities at relatively low cost. Improvements in MRI, particularly high-resolution gadolinium-enhanced MRI, currently make this modality the most informative technology, as it allows easy identification of lesion morphometry, calcification, and hemorrhage. Further, multimodal imaging of carotid artery plaques using fluorodeoxyglucose positron emission tomography/CT is slowly growing out of its infancy and is providing valuable information on the inflammatory component of the plaque, a critical indicator of lesion instability. These recent advancements in imaging technologies will no doubt dictate early treatment options for symptomatic and asymptomatic patients with noncritical carotid stenosis in the near future. Ultimately, however, the identification of important molecular surrogates in early lesion progression may eventually predict late-term risk and likely will provide the ideal strategy for reducing the morbidity and mortality of stroke. PMID- 20842551 TI - Current concepts in the management of chronic mesenteric ischemia. AB - OPINION STATEMENT: Treatment of chronic mesenteric ischemia has evolved during the past two decades. Endovascular treatment has emerged as an alternative to bypass in elderly and higher-risk patients and is now the primary treatment modality for most patients with suitable lesions, independent of their surgical risk. Open surgical revascularization still has an important role for patients with more extensive disease, including those with long-segment stenosis or occlusions, small vessel diameter, multiple tandem lesions, or severe calcification. This article summarizes current concepts in the epidemiology, natural history, treatment selection, and outcomes of open and endovascular mesenteric reconstruction for chronic mesenteric ischemia. PMID- 20842552 TI - New and emerging anticoagulant therapies for venous thromboembolism. AB - OPINION STATEMENT: Anticoagulation therapy remains the cornerstone for prevention and treatment of venous thromboembolism. Currently available parenteral anticoagulants, such as heparin, low molecular weight heparin, and fondaparinux, are used widely for short-term therapy, but the need for parenteral administration limits their utility for long-term use. Vitamin K antagonists, such as warfarin, are the only oral anticoagulants available for long-term use. Although effective, these drugs produce a variable anticoagulant response and require routine coagulation monitoring and frequent dose adjustments. New anticoagulants that can be given in fixed doses without monitoring have been developed to overcome the limitations of existing agents. These drugs are in advanced stages of development and have the potential to streamline the prevention and treatment of venous thromboembolism. PMID- 20842553 TI - Complex regional pain syndrome: state of the art update. AB - OPINION STATEMENT: Although the pathophysiology of complex regional pain syndrome (CRPS) is not fully understood, it appears to reflect multiple interacting mechanisms. In addition to altered autonomic function, a role for inflammatory mechanisms and altered somatosensory and motor function in the brain is increasingly suggested. Several possible risk factors for development of CRPS, including genetic factors, have been identified. Few treatments have been proven effective for CRPS in well-designed clinical trials. However, recent work suggests that bisphosphonates may be useful in CRPS management and that the N methyl-D: -aspartate receptor antagonist ketamine significantly reduces CRPS pain when administered topically or intravenously at subanesthetic dosages. Extended use of ketamine at anesthetic dosages ("ketamine coma") remains a controversial and unproven treatment for CRPS. Spinal cord stimulation may be effective for reducing pain in approximately two thirds of CRPS patients not responding to other treatments, but its efficacy appears to diminish over time. PMID- 20842554 TI - Management of Pulmonary Embolism: 2010 State-of-the-Art Update. AB - OPINION STATEMENT: The morbidity and mortality of venous thromboembolism remain underrecognized and underappreciated. Suspected pulmonary embolism should be risk stratified using a validated clinical risk prediction tool; intermediate to high clinical suspicion requires objective diagnostic testing to confirm or refute the diagnosis. Therapy with unfractionated heparin, low molecular weight heparin, or fondaparinux should be initiated while diagnostic testing is pursued. Conversion to vitamin K antagonists requires a minimum of 5 days' overlap between the parenteral agent and the vitamin K antagonist. Anticoagulation should be continued for a minimum of 3 to 6 months. Longer or even indefinite therapy may be required with a persistent hypercoagulable state. In patients with cancer, low molecular weight heparin monotherapy for the initial 3 to 6 months is preferred. In stable patients with normal biomarkers and a normal echocardiogram, accelerated discharge and outpatient therapy may be considered. In patients with hemodynamic instability, systemic thrombolytic therapy, catheter-directed therapy, or surgical embolectomy may be considered. Cancer screening and/or thrombophilia testing should be pursued only if the findings will directly affect patient therapy or long-term care. PMID- 20842555 TI - Management of Raynaud's Phenomenon in the Patient with Connective Tissue Disease. AB - OPINION STATEMENT: Raynaud's phenomenon is characterized by intense vasospasm of digital arteries on cold exposure or with emotional stress, leading to well defined color changes of digital skin. It may be primary (Raynaud's disease) or secondary to an underlying condition, including autoimmune rheumatic diseases. Although Raynaud's disease is predominantly a vasospastic condition, Raynaud's phenomenon in connective tissue diseases often is a result of an underlying vaso occlusive process. As a result, the manifestations are more severe and persistent and often warrant pharmacologic therapy. Dihydropyridine calcium channel blockers are by far the most commonly studied and prescribed class of agents for the treatment of Raynaud's phenomenon. There is some evidence for the efficacy of other classes of drugs, such as topical nitrates, alpha-antagonists, angiotensin receptor blockers, selective serotonin reuptake inhibitors, and pentoxifylline. However, the data on the efficacy of these agents are not as convincing, and they are not proven to be more effective than calcium channel blockers. Hence, their place in the therapy of Raynaud's phenomenon is limited to patients who fail to respond adequately to or are unable to tolerate calcium channel blockers. More expensive second-line agents, such as phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and intravenous prostanoids, are reserved for refractory cases of secondary Raynaud's phenomenon with severe digital ischemia leading to ulceration or gangrene. These drugs may be used in isolation or as adjunct therapy to the first-line agents. Chemical and/or surgical sympathectomy may be considered if sympathetically driven digital ischemia is severe and resistant to pharmacologic intervention. These procedures may temporarily reverse the digital ischemia and help tide over the crisis, whereas the improvement thus achieved can be maintained by continuing medical therapy. In cases of ischemic digital ulceration, it is important to achieve adequate analgesia and to identify and treat superadded infection. PMID- 20842556 TI - High-density lipoprotein therapy: is there hope? AB - OPINION STATEMENT: The treatment of lipid abnormalities generally has focused on low-density lipoprotein cholesterol (LDL-C) reduction based on extensive clinical trials and the National Cholesterol Education Program Adult Treatment Panel III guidelines. Unfortunately, it has become increasingly clear that a significant percentage of patients continue to have cardiovascular events despite being on LDL-C-lowering medications and having LDL-C levels below 100 mg/dL. Numerous epidemiologic studies have associated low high-density lipoprotein cholesterol (HDL-C) levels with increased risk of cardiovascular disease (CVD). Furthermore, recent data show that up to 55% of patients hospitalized for CVD have low HDL-C levels (<40 mg/dL) on admission, suggesting a possible target for further reducing CVD. Low HDL-C also is part of the atherogenic phenotype associated with obesity, glucose intolerance, and hypertension, termed the metabolic syndrome, and often is seen in patients with insulin resistance states. In general, the first line of therapy for increasing HDL-C in patients with levels below 40 mg/dL is lifestyle modification with smoking cessation, exercise, weight loss, and diet modifications. The pharmacologic treatment of isolated low HDL-C in patients without coronary disease is controversial but should be considered in those with a strong family history of CVD. In patients with coronary artery disease and isolated low HDL-C, statins remain the first-line therapy and should be instituted after lifestyle modifications, with the goal of increasing HDL-C above 40 mg/dL. If concomitant hypertriglyceridemia is present, a fibrate or niacin should be considered. Although statins do offer some HDL-C-raising properties, they tend to have modest effects. If treatment goals have not been achieved with either lifestyle changes or statin therapy, then the next agent of choice is niacin. Among the various HDL-C-raising therapies, niacin continues to be the most potent therapeutic option available. There are several novel HDL-C therapies in the research pipeline; however, only one class of medications is relatively close to clinical use, the cholesteryl ester transferase protein (CETP) inhibitors. Although one of the CETP inhibitors, torcetrapib, has received much negative attention from a large randomized trial showing increased mortality associated with its use, the overall class of therapeutic agents may still hold some benefit. Currently, two new CETP inhibitors without the off-target effects of torcetrapib are undergoing clinical research. Overall, the use of HDL-C modifying agents likely will increase over the next decade. PMID- 20842557 TI - Exercise as a treatment for the risk of cardiovascular disease. AB - OPINION STATEMENT: Regular physical activity decreases the risk of cardiovascular disease and modifies multiple cardiovascular risk factors. The optimum amount of exercise continues to generate debate; however, the general recommendation is that all adults should engage in 30 min of moderate-intensity physical activity on five, and preferably all, days of the week. Despite extensive data and recommendations, a significant proportion of the US adult population remains sedentary. Promoting physical activity at a public level remains a major challenge because of the presence of multiple behavioral, physical, and environmental barriers. Health care providers have an opportunity and a responsibility to include exercise counseling in routine office visits. PMID- 20842558 TI - Obstructive sleep apnea and cardiovascular disease. AB - OPINION STATEMENT: Obstructive sleep apnea is a highly prevalent disease that often goes undetected for many years before diagnosis. Although most patients seek treatment to improve symptoms of daytime sleepiness, a growing body of literature suggests that treatment may also modulate cardiovascular risk. This article summarizes the current literature regarding the associations between sleep-disordered breathing and adverse cardiovascular outcomes and reviews the lesser body of data demonstrating the cardiovascular benefits of therapy. PMID- 20842560 TI - Omega-3 Fatty acids for cardiovascular disease prevention. AB - OPINION STATEMENT: Major dietary sources of omega-3 fatty acids are fish containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as nuts, seeds, and vegetable oils containing alpha-linolenic acid (ALA). Omega-3 fatty acids, especially those derived from marine sources, may be a useful tool for the primary and secondary prevention of cardiovascular disease. Omega-3s exert their cardioprotective effects through multiple mechanisms, including reducing arrhythmias and altering production of prostaglandins, which reduces inflammation and improves platelet and endothelial function. To date, no serious adverse effects of omega-3s have been identified, despite extensive study. In adults, any potential harm from mercury exposure from consuming fish rich in omega-3s is outweighed by the proven cardiovascular benefits of eating fish. Concerns over increased bleeding complications have not materialized despite the increased concomitant use of aspirin and clopidogrel. We recommend one serving (200-400 g) of fatty fish two times per week and a diet that includes foods rich in ALA for the primary prevention of cardiovascular disease. We recommend one serving (200-400 g) of fatty fish or a fish oil supplement containing 900 mg of EPA + DHA every day and a diet rich in ALA for patients with known cardiovascular disease or congestive heart failure. PMID- 20842559 TI - Treatment of angina and microvascular coronary dysfunction. AB - OPINION STATEMENT: Microvascular coronary dysfunction (MCD) is an increasingly recognized cause of cardiac ischemia and angina that is diagnosed more commonly in women. Patients with MCD present with the triad of persistent chest pain, ischemic changes on stress testing, and no obstructive coronary artery disease on cardiac catheterization. Data from the National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation (WISE) study show that the diagnosis of MCD is not benign, with a 2.5% annual risk of adverse cardiac events including myocardial infarction, stroke, congestive heart failure, and death. The gold standard diagnostic test for MCD is the invasive coronary reactivity test (CRT), which uses acetylcholine, adenosine, and nitroglycerin to test endothelial dependent and -independent microvascular and macrovascular coronary function. The CRT allows for diagnostic and treatment options as well as further risk stratification of patients for future cardiovascular events. Treatment of angina and MCD should be aimed at ischemia disease management to reduce the risk of adverse cardiac events, ameliorate symptoms to improve quality of life, and decrease morbidity from unnecessary and repeated cardiac catheterization in patients with open coronary arteries. A comprehensive treatment approach aimed at risk factor management, including lifestyle counseling regarding smoking cessation, nutrition, and physical activity, should be initiated. Current pharmacotherapy for MCD may include treatment of microvascular endothelial dysfunction (with statins, angiotensin-converting enzyme inhibitors, or low-dose aspirin), as well as treatment for angina and myocardial ischemia (with beta blockers, calcium channel blockers, nitrates, or ranolazine). Additional symptom management techniques may include tricyclic medication, enhanced external counterpulsation, hypnosis, and spinal cord stimulation. Although our current therapies are effective in treating angina and MCD, large randomized outcome trials are needed to optimize strategies to improve morbidity and mortality. PMID- 20842561 TI - Therapeutic approaches to obesity. AB - OPINION STATEMENT: Obesity in the United States has become a public health crisis, with one third of the US population having a body mass index >=30 kg/m(2). Given the profound impact of obesity on cardiovascular disease (CVD), studies of lifestyle modification, pharmacotherapy, and surgical interventions must be reappraised to better define the roles of these approaches in preventing cardiovascular events. Recent clinical trials have attempted to quell the debate over macronutrient composition versus caloric restriction in the dietary approach to weight loss. Our interpretation of these results is that caloric reduction and adherence to diets are of greater consequence than the particular dietary content for weight reduction. For cardiovascular risk factor modification, however, specific macronutrient composition of the diet may have additional impact outside weight loss, although the ultimate relationship between various dietary macronutrients and clinical cardiovascular outcomes is unclear. Although pharmacotherapy has been used for decades to treat obesity, there currently are limited options and recurrent cautionary tales; therefore, we use these agents sparingly. Sibutramine, one of only two medications approved by the US Food and Drug Administration for the long-term treatment of obesity, recently came under intense scrutiny because of a possible increase in cardiovascular events, and it now is contraindicated in patients with established CVD. Orlistat and its over the-counter form, Alli (GlaxoSmithKline, Research Triangle Park, NC), can induce modest weight loss but frequently are not tolerated because of unpleasant gastrointestinal side effects. Fortunately, there are new medications in phase 3 clinical trials that hold promise as potential alternatives for obesity treatment. Finally, bariatric surgery for morbid obesity refractory to lifestyle interventions has become considerably more common. Surgery can effectively reduce body weight and treat cardiovascular risk factors, particularly diabetes, with acceptable complication rates and should be considered a viable option for appropriate patients. Ongoing clinical trials will clarify the impact of bariatric surgery on cardiovascular events and mortality, as well as the role of surgery as a treatment option that may be considered earlier than currently recommended. PMID- 20842562 TI - Do We Know When and How to Lower Lipoprotein(a)? AB - : OPINION STATEMENT: Currently, there are significant data to support a link between lipoprotein(a) [Lp(a)] levels and cardiovascular risk. However, there has not been a clinical trial examining the effects of Lp(a) reduction on cardiovascular risk in a primary prevention population. Until such a trial is conducted, current consensus supports using an Lp(a) percentile greater than 75% for race and gender as a risk stratification tool to target more aggressive low density lipoprotein cholesterol (LDL-C) or apolipoprotein B (apoB) goals. Therefore, Lp(a) measurements should be considered in the following patients: individuals with early-onset vascular disease determined by clinical presentation or subclinical imaging, intermediate and high Framingham risk patients with a family history of premature coronary disease, and low Framingham risk patients with a family history and low high-density lipoprotein cholesterol (HDL-C) levels. Once LDL-C goals are met, Lp(a) levels may be taken into account in selecting secondary agents to reach more aggressive secondary goals, including non-HDL-C and apoB. To achieve Lp(a) reduction, one evidence-based approach is to initiate therapy with low-dose aspirin and extended-release niacin, titrated from 0.5 g up to 2 g over several weeks. If higher doses of niacin are desired, crystalline niacin allows for titration to a dosage as high as 2 g three times a day; however, the flushing side effect usually is quite prominent. Although hormone replacement therapy (HRT) has been shown to lower Lp(a), there are no indications for using HRT for primary or secondary prevention; therefore, we do not advocate initiating it solely for Lp(a) reduction. LDL apheresis is an option to lower LDL-C levels in patients with homozygous familial hypercholesterolemia who are not responsive to medical therapy. Although it does lower Lp(a), there is no treatment indication for this. A recent study supports the cholesterol absorption inhibitor ezetimibe's ability to lower Lp(a), a finding that deserves further investigation as it has not been previously reported in multiple ezetimibe trials. Additionally, the apoB messenger RNA antisense therapy mipomersen currently is in phase 3 trials and may serve as a potential inhibitor of Lp(a) production. Ultimately, more trial evidence is needed to determine whether lowering Lp(a) actually reduces cardiovascular risk, although this may be difficult to isolate without a specific Lp(a)-lowering therapy. PMID- 20842563 TI - Inotropic therapy for end-stage heart failure patients. AB - OPINION STATEMENT: Positive inotropic agents play an important role in the management of acute decompensated heart failure (HF) patients with reduced cardiac output and poor end-organ perfusion. However, despite their acute hemodynamic benefits, the role of inotropes in the management of chronic advanced HF remains limited. Although digoxin has demonstrated the ability to improve symptoms in HF patients, numerous small, mostly nonrandomized studies have shown that patients with advanced HF improve symptomatically when administered continuous or intermittent intravenous beta-agonists or phosphodiesterase inhibitors. However, this improvement occurs at the expense of an increased risk of cardiac arrhythmias, sudden cardiac death, and mortality. Similarly, several oral inotropes have been developed and studied in larger randomized clinical trials. The PROMISE study found that oral milrinone is associated with increased mortality, whereas the ESSENTIAL study showed that oral enoximone does not result in any significant improvement in symptoms, exercise capacity, or survival. The calcium-sensitizing inotrope levosimendan has shown some promise in the management of acute HF patients, but the PERSIST trial showed no improvement in survival or hospitalization rates with chronic oral therapy. This agent is still under investigation and is not available in the United States. Istaroxime, an inotrope with lusitropic properties, is also being investigated for its potential use in advanced HF patients. The current American College of Cardiology/American Heart Association, European Society of Cardiology, and Heart Failure Society of America guidelines indicate that, other than digoxin, inotropic agents should be reserved for patients presenting with acute decompensated HF and low-output states and reduced end-organ perfusion, who typically are admitted to an intensive care unit. These agents also are of benefit in advanced HF patients as a bridge to transplantation to optimize end-organ function and may be used in the outpatient setting, usually in patients with an implantable cardioverter defibrillator. Finally, inotropes should be used to palliate symptoms in end stage HF patients who have severe symptoms and are not candidates for heart transplantation or mechanical circulatory support. PMID- 20842564 TI - Diagnosis and management of right-sided heart failure in subjects supported with left ventricular assist devices. AB - OPINION STATEMENT: Right ventricular failure (RVF) is a cause of major morbidity and mortality in the left ventricular assist device (LVAD) population. Many LVAD candidates have clinical or subclinical right ventricular (RV) dysfunction, and the perioperative period is fraught with insults that may provoke reactive pulmonary vascular hypertension and acute or chronic development of RVF. Thus, preoperative patient optimization using diuretics, pulmonary vasodilators, and inotropes to reduce RV wall stress and improve contractility is critical. An assessment of the LVAD candidate's risk for developing postoperative RVF is also key, especially in the destination therapy population for whom good options for long-term RV support currently are lacking. Intraoperatively, various pharmacologic and surgical interventions are available to reduce RVF risk. This review discusses RVF diagnosis and management strategies in subjects undergoing LVAD implantation. PMID- 20842565 TI - Cardiac resynchronization therapy in asymptomatic or mildly symptomatic heart failure patients. AB - OPINION STATEMENT: Heart failure is a constantly progressing disease involving patients with ischemic and nonischemic cardiac disease. Cardiac resynchronization therapy (CRT) has been used successfully in patients with severe heart failure symptoms, poor left ventricular (LV) function, and a prolonged QRS duration. Large trials in patients with New York Heart Association (NYHA) class III/IV heart failure have demonstrated that heart failure symptoms can be reduced and exercise capacity improved, overall mortality decreased, and ventricular function increased. How long these beneficial effects of CRT will last in patients with an already advanced stage of heart failure, particularly in NYHA IV, is still unknown. Therefore, it is more reasonable to initiate CRT in appropriate patients who have structural heart disease but have not yet developed severe heart failure symptoms. Slowing heart failure progression seems to be the most important target. Medical treatment alone has not demonstrated that this can be achieved in patients with poor ventricular function and prolonged QRS (>120 ms). The recently published results of MADIT-CRT, as well as the extended follow-up of the REVERSE substudy of the European patient cohort, have shown that prevention of heart failure progression can be well accomplished with CRT and implantable cardioverter-defibrillator (ICD) backup (CRT-D). Heart failure events and death occurred significantly less often in patients with CRT-D than in those with an ICD only. A clinically important reversal of ventricular remodeling with reduced ventricular volumes and increased LV ejection fraction was found in the CRT-D treated patients. The benefit was seen in patients with ischemic and nonischemic cardiomyopathy and in those with NYHA class I or II heart failure; the most benefit was demonstrated in patients showing a "classic" left bundle branch block electrocardiogram pattern (about 70% of the enrolled patients) and in female patients. Results from both trials support the view that future efforts regarding heart failure treatment should concentrate more on prevention of heart failure progression in mildly symptomatic or even asymptomatic candidates for CRT-D. It is time to change the guidelines for heart failure treatment. PMID- 20842566 TI - Driving guidelines and restrictions in patients with a history of cardiac arrhythmias, syncope,or implantable devices. AB - OPINION STATEMENT: The need to drive is universal in many countries. Patients with syncope, cardiac arrhythmias, or implantable cardioverter-defibrillators (ICDs) have an ongoing risk of sudden incapacitation that may cause harm to themselves and/or others when driving. Restrictions on driving and driving guidelines have been developed with the intent to reduce and prevent motor vehicle accidents, thereby improving personal and public safety. Several guidelines and consensus statements recently were updated. This review focuses on the syncope-related driving guidelines and restrictions. Driving issues related to other causes of loss of consciousness, such as drug or alcohol intoxication, epilepsy, or metabolic disorders, are not included in this review. Approximately 1% to 3% of all motor vehicle accidents are caused by the driver's sudden incapacitation; of these accidents, 5% to 10% are related to cardiac causes, with or without syncope. Major cardiac causes of syncope are neurally mediated mechanisms, bradycardia, and tachycardia. When the cause of syncope is determined and adequately treated, no driving restrictions are usually required after treatment is implemented. Patients who receive ICD therapy for primary or secondary sudden cardiac death prevention are at risk for future device discharges and sudden incapacitation whether or not they are driving. When the cause of syncope is unknown, the response to treatment is uncertain (such as treating the neurocardiogenic/vasovagal syncope), or ICD discharge is possible, driving recommendations are based on the estimation of "risk of harm while driving" and the general consensus on the threshold of "acceptable risk of harm." The annual risk of harm while driving can be estimated by the following formula: driving time (%) * vehicle type (commercial to private) * annual risk of syncope or incapacitation * probability of injury or accident. PMID- 20842568 TI - Treatment of vasovagal syncope: an update. AB - OPINION STATEMENT: Vasovagal syncope (VVS) remains the most common cause of syncope and transient loss of consciousness in all age groups. The treatment of VVS focuses on measures that interrupt or prevent its pathophysiologic mechanism, as well as on avoidance of triggers. Although the evidence supporting an increase in salt and water intake is weak, it is a cost-effective and safe strategy that should always be used as first-line therapy. Patients should be educated on how to respond to further episodes of syncope, especially if they experience prodromal warning signs. In these cases, counterpressure maneuvers in younger patients are clearly effective. Orthostatic training exercises may improve symptoms in patients with recurrent VVS; however, this strategy is only effective in younger, highly motivated patients. Multiple medications have been tested in small trials, and there is sparse evidence on efficacy. beta-Adrenergic antagonists and selective serotonin reuptake inhibitors have shown contradictory results on efficacy in a variety of studies; thus, their use should be restricted. Midodrine is the only drug proven to prevent VVS recurrence; however, no consistent prescription guidelines exist. The ongoing Second Prevention of Syncope Trial (POST II) is investigating the benefits of fludrocortisone in this population. In the meantime, measures such as increased salt and water intake and counterpressure maneuvers should be used in all cases if no contraindications are present. Pharmacologic treatment should be restricted to midodrine and fludrocortisone, with the other treatments as options in highly refractory cases. Implantation of a permanent pacemaker should be a measure of last resort in highly refractory cases, particularly in the cardioinhibitory type of VVS. PMID- 20842567 TI - Cardiac arrhythmias during pregnancy. AB - OPINION STATEMENT: This article reviews the appropriate evaluation and management of cardiac arrhythmias in the pregnant patient. Any treatment strategy in this patient population has the inherent potential to adversely affect the health of the unborn child. As such, there is no room for empiric therapy in these patients. Adequate arrhythmia documentation is paramount, preferably by noninvasive means. The decision to treat should be based on symptom severity and the risk to both mother and fetus posed by potentially recurring arrhythmia episodes throughout the pregnancy. Minimal symptoms in the setting of a structurally normal heart call for a conservative approach. Less is better. If pharmacologic therapy is justified, drugs with historically demonstrated safety profiles in pregnancy should be tried first. The safety profiles of virtually all drugs used to treat cardiac arrhythmias during human pregnancy are based solely on an accumulation of past clinical experience. Newer antiarrhythmics therefore carry a largely unknown risk. Most inherent rhythm disorders manifest long before a woman reaches childbearing age. Women with previously diagnosed arrhythmias frequently experience a recurrence or worsening of their arrhythmia during the pregnancy. Counseling of these individuals and perhaps preemptive treatment by means such as arrhythmia ablation prior to a planned pregnancy would seem optimal. PMID- 20842569 TI - Immunosuppression therapy for pediatric heart transplantation. AB - OPINION STATEMENT: Outcomes following cardiac transplantation in childhood continue to improve. Advances in immunosuppressive therapy over the past two decades likely have contributed to this trend. The evolution in the management of immunosuppression in children has been based on clinical experience rather than on evidence-based medicine; indeed, there have been no pivotal randomized controlled trials of any form of immunosuppression in pediatric thoracic transplantation. Important trends in immunosuppressive therapy and transplant outcomes have been obtained from large transplant registries. Several trends have been identified since the last review of this topic in this journal. First, there is increased knowledge of the pharmacodynamics and pharmacokinetics of immunosuppressive drugs in children, with notable advances in the field of pharmacogenomics. These studies help explain individual variations in drug exposure, efficacy, and adverse events. They also help explain racial and ethnic variations in drug metabolism and efficacy. Second, there have been clear trends in the use of specific immunosuppressive medications. Use of induction therapy, especially polyclonal T cell-depleting antibody preparations, has increased significantly in recent years. The calcineurin inhibitor (CNI) tacrolimus is being used as the cornerstone of maintenance therapy in lieu of cyclosporine in more and more centers. Mounting evidence suggests that use of adjunctive agents (notably mycophenolate mofetil [MMF]) may improve outcomes, including survival, suggesting that monotherapy with CNIs is not the ideal maintenance therapy. Despite its increased cost, MMF has largely replaced azathioprine as the adjunctive agent of choice. Inhibitors of the mammalian target of rapamycin (i.e., sirolimus and everolimus) have not yet assumed a major place as adjunctive agents, as their safety and efficacy have not been well established in children. With the improvements in immunosuppressive therapy, the justification for routine corticosteroid use is far from clear, and many centers have shown excellent outcomes with complete steroid avoidance. Third, there is increasing interest in the importance of anti-HLA antibodies as important risk factors for adverse graft and patient outcomes. This is generating intense interest in treatments that target B cells and plasma cells. Finally, there is increasing realization that the "one size fits all" approach to immunosuppressive therapy is an obsolete concept and that the ultimate goal is to tailor immunosuppressive therapy to the needs of the individual patient. The development of reliable biomarkers of the patient's immune response to the allograft will be essential for optimal individualized immunosuppressive management. PMID- 20842570 TI - Diastolic dysfunction in pediatric cardiac patients: evaluation and management. AB - OPINION STATEMENT: The heart is a complex and sophisticated pump that cycles between two phases: diastole, during which a compliant chamber (ventricle) allows the blood to fill from a reservoir chamber (atrium) of low pressure, and systole, during which a stiff chamber with rapidly rising pressure ejects the blood into an arterial circuit of high pressure. However, the systolic and diastolic cycles are not dichotomous. They have complex interactions with interrelated segments of the cardiac cycle. Although the entity of "diastolic heart failure with preserved systolic function" has been applied in adult patients, a discrete diagnosis of systolic and diastolic heart failure may be difficult to apply in pediatric patients. Advances in echocardiography have helped decipher the morphologic and physiologic expression of congenital and acquired heart disease and have increased our understanding the diastolic function and dysfunction. The evolving concept of systolic and diastolic heart failure is helping us develop a strategy for its management in pediatric patients with complex heart diseases. PMID- 20842571 TI - Pathogenesis and Treatment of Anti-MAG Neuropathy. AB - OPINION STATEMENT: Polyneuropathies associated with IgM monoclonal gammopathies comprise a distinct entity. In spite of the apparent pathogenicity of the IgM antibodies and the specific immunoreactivity to myelin antigens, the disease has been difficult to treat. This review describes the clinical phenotype, addresses recent data on immunoreactivity of IgM to various nerve antigens, and discusses the latest progress on treatment.Most of these patients present with paresthesias and sensory ataxia followed by a varying degree of sensorimotor deficits. In more than 75% of the patients, the monoclonal IgM recognizes myelin-associated glycoprotein (MAG) and sulfoglucuronyl glycosphingolipid (SGPG), best detected by ELISA, or other peripheral nerve glycolipids. Recent experiments have demonstrated that animals immunized with SGPG develop sensory ataxia, suggesting a pathogenic role for this antigen. Although cladribine, cyclophosphamide with prednisone, and intravenous immunoglobulin have offered transient benefits to some patients, most have remained treatment-resistant. Open label studies and a recent randomized controlled trial indicate that rituximab is emerging as the best agent available, providing long-term benefits to almost half of these patients. Rituximab appears to work by suppressing the IgM as well as the anti MAG antibodies and by inducing immunoregulatory T cells. Patients with more sensory deficits and higher anti-MAG antibodies are more likely to respond but may require re-treatment after several months.These encouraging results need confirmation with a larger trial. Data on long-term efficacy and immune markers associated with response to therapy or need for re-treatment are still needed. PMID- 20842572 TI - Treatment of chronic inflammatory demyelinating polyneuropathy. AB - OPINION STATEMENT: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, immune-mediated, non-length-dependent polyradiculoneuropathy that is progressive or relapsing over a period of at least 8 weeks, often evolving over time to a relatively symmetric pattern. Although the exact pathogenesis is unclear, it is thought to be mediated by both cellular and humoral reaction to the peripheral nerve myelin sheath involving nerve roots and proximal and distal nerves. Early medical treatment of CIDP is important to prevent axonal loss occurring as a secondary effect of progressive demyelination. Only three treatments for CIDP have demonstrated benefit in randomized controlled studies: corticosteroids, plasma exchange, and intravenous immunoglobulin. About 25% of patients fail to respond to these treatments or respond inadequately. These treatments have similar efficacy but differ significantly in cost and adverse effects. These factors are considered in treatment selection. PMID- 20842573 TI - Treatment of diabetic and nondiabetic lumbosacral radiculoplexus neuropathy. AB - OPINION STATEMENT: Lumbosacral radiculoplexus neuropathy (LRPN) is a multifocal, asymmetric, painful neuropathic disorder affecting multiple levels of lumbosacral plexus, nerve roots, and distal nerves that emerge from the plexus. The disorder was first described in diabetic patients (DLRPN) and was later found to occur in nondiabetic patients as well. There have been debates as to the pathogenesis of DLRPN and LRPN. Recent detailed and extensive pathologic studies, however, have shown that the main pathogenesis is inflammation and microvasculitis affecting various components in the peripheral nerves, resulting in ischemic injury to the nerves. Even though studies on the natural history of this disorder have shown that the majority of patients recover within a few years after the attack without any treatment (although recovery is incomplete in many cases), it is a common practice, based on the pathophysiology and case series, to administer immunotherapy. Preliminary data from a controlled clinical trial failed to show significant improvement in outcomes measured by neurologic deficits (as judged by the Neuropathy Impairment Score) but did show improvement in symptoms (pain and positive sensory symptoms). Choices of immunotherapy include corticosteroids, intravenous immunoglobulin, plasma exchange, or a combination. Pain management, physical therapy, and treatment of depression remain mainstays for managing this disorder. PMID- 20842574 TI - Treatment options in the management of status epilepticus. AB - OPINION STATEMENT: Status epilepticus treatment involves the use of several pharmacologic compounds, which are conceptually divided into three successive and additional lines of action. Because of their rapid onset of action, benzodiazepines represent the first approach; these are followed by classic antiepileptic drugs that are administered intravenously. In refractory episodes, pharmacologic coma induction with an appropriate anesthetic is advocated. Apart from first-line compounds, the level of evidence for medications used in status epilepticus is extremely limited. It is important to specifically address etiology in order to maximize the impact of the antiepileptic therapy. Fine tuning of the treatment strategy, mainly regarding the choice of whether to induce coma, should be approached by balancing the benefits of rapid control of the status epilepticus with the risks of adverse effects. Although each status epilepticus episode should be treated as rapidly as possible, it appears advisable to reserve coma induction for those forms, such as generalized convulsive status, that have been shown to present a consistent risk of neurologic sequelae. PMID- 20842575 TI - Treatment of coagulopathy in intracranial hemorrhage. AB - OPINION STATEMENT: Intracranial hemorrhage (ICH) complicated by coagulopathy is a medical emergency, which can delay neurosurgical intervention, lead to larger hematoma size, and increase mortality until the coagulopathy is corrected. Prompt recognition of coagulopathy during ICH is essential for correct, rapid treatment to reduce ongoing bleeding and improve survival. The proper treatment of a coagulopathic ICH patient is centered on rapid identification of the coagulopathic defect and correction of the underlying coagulopathy to stop acute bleeding. Patients with coagulopathic ICH require admission to a neuro-intensive unit care with management of airway, oxygenation, and systemic arterial and cerebral perfusion pressure; optimization of serum glucose; aggressive treatment of fever; and rehabilitation. Once the coagulopathic defect is reversed, some patients benefit from emergent neurosurgical intervention to prevent secondary brain injury from raised intracranial pressure, hydrocephalus, or mass effect. The management of ICH patients prescribed common antithrombotics such as aspirin, clopidogrel, warfarin, or heparin, as well as thrombolytic agents such as tissue plasminogen activator, is the focus of this review. PMID- 20842576 TI - Treatment of brain edema in acute liver failure. AB - OPINION STATEMENT: Cerebral edema is very common in patients with acute liver failure and encephalopathy. In severe cases, it produces brain tissue shift and potentially fatal herniation. Brain swelling in acute liver failure is produced by a combination of cytotoxic (cellular) and vasogenic edema. Accumulation of ammonia and glutamine leads to disturbances in the regulation of cerebral osmolytes, increased free radical production and calcium-mediated mitochondrial injury, and alterations in glucose metabolism (inducing high levels of brain lactate), resulting in astrocyte swelling. Activation of inflammatory cytokines can cause increased blood-brain barrier permeability leading to vasogenic edema, although the relative contribution of vasogenic edema is probably minor compared with cellular swelling. Cerebral blood flow is disturbed and generally increased in patients with acute liver failure; persistent vasodilatation and loss of autoregulation may generate hyperemia, and the consequent augmentation in cerebral blood volume may exacerbate brain edema.Adequate management of intracranial hypertension demands continuous monitoring of intracranial pressure and cerebral perfusion pressure. Coagulation status should be assessed and bleeding diathesis should be treated prior to insertion of the intracranial pressure monitor. Standard treatment measures such as hyperventilation and osmotic agents (e.g., mannitol, hypertonic saline) remain useful first-line interventions. Although hypertonic saline may be preferred in patients with coexistent hyponatremia, the rate of correction of hyponatremia must be gradual to avoid the risk of osmotic demyelination. Barbiturate coma and intravenous indomethacin are available options in refractory cases. The most promising novel therapeutic alternative is the induction of moderate hypothermia (aiming for a core temperature of 32-34 degrees C). However, the safety and efficacy of therapeutic hypothermia for brain swelling caused by liver failure still needs to be proven in randomized, controlled clinical trials. Management of intracranial pressure in patients with acute liver failure should be guided by well-defined treatment protocols. PMID- 20842577 TI - Management of traumatic brain injury. AB - OPINION STATEMENT: Traumatic brain injury (TBI) is a complex disease process that requires constant attention as one manages the associated body systems. Even though an "isolated" brain injury may be the cause for admission to the hospital, the injured brain cannot be thought of in isolation from the remainder of the body. All body systems, from cardiac to pulmonary, need to be addressed as one moves from the initial to the long-term management of the TBI. The multiple issues are best addressed with a dedicated neurocritical care team that is in continuous communication with the neurosurgical team throughout the course of treatment. To date, no pharmacologic treatment has led to improved outcomes after TBI, but it is becoming increasingly clear that advances in the critical care of TBI patients are contributing to better results.During resuscitation of the TBI patient, medical management in its simplest form strives to return measurable vital signs and laboratory values (eg, intracranial pressure, mean arterial pressure, blood glucose, PaO(2), or PaCO(2)) to their normal range. The initial goal is to maintain or reestablish normal homeostasis.The initial injury to the brain is irreversible by any medical modalities available today. After the initial resuscitation, medical maneuvers are directed at limiting secondary damage to the brain. Secondary brain injury occurs in response to inflammatory changes, expanding hematomas, cellular swelling, seizures, and systemic complications (ie, hemodynamic or pulmonary changes, fever, pain); vulnerable surrounding brain tissue can be damaged through alterations in cerebral perfusion and metabolism. Treatments to address these issues include, but are not limited to, analgesics, sedatives, anticonvulsants, hyperosmotic agents, and hypothermia.The future of TBI care likely lies in the areas of better injury classification to guide therapeutic interventions, management of secondary injury, improved technology for intracranial monitoring, and regeneration/rehabilitation. Studies focusing on signaling pathways, neural stem cells, and reparative medications are all in the early stages of development; their use is currently experimental at best.There are few areas in medicine where clinicians have the opportunity to impact a patient's life to the degree seen in the management of TBI. Although parts of the proverbial puzzle certainly remain unsolved, it is the remarkable recoveries that patients make with the therapeutic modalities available today that keep management of TBI one of the most exciting areas in medicine. PMID- 20842578 TI - Reperfusion therapies for acute ischemic stroke. AB - OPINION STATEMENT: Ischemic stroke is most often caused by an acute extracranial or intracranial thromboembolic lesion obstructing an artery. It has been demonstrated that recanalization is the most important modifiable predictor of a good clinical outcome. Reperfusion strategies focus on early reopening of the vessel to reestablish antegrade flow within the penumbra.Current standard therapy within 4.5 h is intravenous thrombolysis (IVT) with tissue plasminogen activator (tPA, 0.9 mg/kg body weight, maximum dose 90 mg). Thrombolytic therapy appears to be safe and effective across various types of hospitals, if the treatment is conducted by a physician with stroke expertise.New imaging methods (MR diffusion/perfusion, CT perfusion) are being investigated in order to better select patients who are most likely to benefit from recanalization therapy based on current clinical evidence. Neither perfusion imaging with CT or MR nor the mismatch concept are recommended for routine treatment decisions within or beyond the 4.5 h available for IVT.If major vessel occlusion is proven but IVT is contraindicated, intra-arterial thrombolysis (IAT) with tPA or mechanical thrombectomy with the Merci Retriever or Penumbra System may be a treatment option. The availability of IAT generally should not preclude the intravenous administration of tPA in otherwise eligible patients. Intra-arterial treatment can be performed within 8 h after stroke onset. Combining intravenous tPA pretreatment with subsequent IAT or mechanical thrombectomy may improve the recanalization rate and may be used as a rescue therapy in cases of persistent major vessel occlusion after unsuccessful IVT.Despite testing, no thrombolytic agent other than tPA (e.g., IIb/IIIa antagonists, heparin, etc.) has yet been approved for routine practice for either intravenous or intra-arterial application, alone or in combination with tPA.Continuous transcranial Doppler (TCD) monitoring of an occluded vessel may increase the rate of early recanalization after tPA; this effect may be facilitated by the administration of microbubbles. This method is still considered experimental. PMID- 20842579 TI - Tick paralysis. AB - OPINION STATEMENT: Tick paralysis is a toxin-mediated cause of acute flaccid paralysis. Most practitioners will go through their entire career without ever encountering a case. An important veterinary disease, tick paralysis is rare in humans. Although it has certain geographical proclivities, it exists worldwide. Although it tends to occur in young girls, it can occur in any age group. Due to its rarity, doctors often forget to consider tick paralysis in the differential diagnosis of the weak patient. Therefore it is perhaps not surprising that the literature is full of cases in which a mother stroking her child's head or an alert nurse bathing her patient made the diagnosis serendipitously.Physicians should consider tick paralysis in any patient with an acute flaccid paralysis. As a general rule, aimed more towards patient safety than the likelihood of making a correct diagnosis, never definitively diagnose Guillain-Barre syndrome without first searching the entire body for a tick. The treatment of tick paralysis is among the simplest and most gratifying in all of medicine. Tick removal results in rapid improvement of all symptoms. Some patients may require mechanical ventilation and support in an intensive care unit as the toxin clears. Since tick paralysis is toxin-mediated and not caused by an infectious agent, antimicrobials are not indicated. Finally, prevention of tick paralysis, as with most tick-borne diseases, involves changing behavior to avoid tick exposure and performing frequent tick checks to remove them if they have already attached. PMID- 20842580 TI - Treatment of acute migraine in the pediatric population. AB - OPINION STATEMENT: The recognition of the diagnosis of migraine in the pediatric population is increasing. Early and aggressive treatment of migraine in children and adolescents with the use of over-the-counter medications has proven effective. In addition, the off-label use of many migraine-specific medications is often accepted in the absence of sufficient evidence-based trials. Mild to severe cases of migraine should be treated with NSAIDs, with triptans used for moderate to severe headaches that are unresponsive to over-the-counter therapy. Rescue medication including dihydroergotamine (DHE) should be used for intractable migraines, preferably in the hospital setting. In patients with associated symptoms of nausea and vomiting, antiemetics with antidopaminergic properties can be helpful through their action on central migraine generation. Furthermore, patients and families should be educated about nonpharmacologic aspects of management such as preventing episodic migraine through lifestyle modification and avoidance of triggers. PMID- 20842581 TI - Parkinson's disease and motor fluctuations. AB - OPINION STATEMENT: Many important advances for the treatment of Parkinson's disease (PD) have been made over the past decade, and quality of life has improved for most patients. Nonetheless, motor fluctuations in the form of wearing off with the re-emergence of parkinsonian symptoms and hyperkinetic movements (dyskinesias) often arise as a complication of long-term dopaminergic therapy and can be disabling. Because treatment of motor fluctuations is difficult, clinicians should attempt to prevent them by using low doses of dopaminergic drugs in early PD, targeting functionally relevant symptoms. Instead of levodopa, dopamine agonists, amantadine, and rasagiline can be used with the aim of delaying the onset of motor fluctuations. Once motor fluctuations arise, off time can initially be addressed with more frequent dosing of levodopa. Later, adjunctive therapy with a dopamine agonist, COMT-inhibitor, or MAO-B inhibitor becomes necessary. For treatment of dyskinesias, reduction of the levodopa dose should be the first step. If this is not tolerated because of increased off time, then adjunctive therapy with levodopa-sparing agents should be attempted. The addition of amantadine (the only currently available antidyskinetic drug) is another useful strategy but is often only a temporary solution. Once medical attempts at treating motor fluctuations fail, deep brain stimulation (DBS) can be considered. Careful patient selection and skilled placement of DBS electrodes are important determinants of the surgical outcome. PMID- 20842583 TI - Treatment of paraneoplastic neurologic disorders. AB - OPINION STATEMENT: Paraneoplastic neurologic disorders are rare, autoimmune disorders, which can be broken down into two groups: those in which antibody response is directed against intracellular neuronal or neuroglial proteins (Group 1) and those in which the immune response is directed against antigens within or subjacent to the neuronal cell membrane (Group 2). In both groups, detection and treatment of the underlying neoplasm is critical and carries the best chance of clinical stabilization or remission.Syndromes in Group 2 frequently respond to therapy. This may involve corticosteroids, plasma exchange (PE), or intravenous immunoglobulin G (IgG), depending on the specific paraneoplastic syndrome. Cyclophosphamide or rituximab may be helpful in patients who fail to stabilize or improve on less aggressive therapies.Treatment of syndromes in Group 1 is far more difficult, and proven treatment strategies do not exist. Younger men (< 40 years of age) with limbic or brainstem syndromes, testicular or germ cell tumors, and anti-Ma2 antibodies may respond to specific tumor treatment together with immunotherapy. Patients with paraneoplastic syndromes and anti-Ri antibodies may respond to corticosteroids and/or cyclophosphamide. Evidence-based treatment guidelines do not exist for patients with other central paraneoplastic syndromes such as cerebellar degeneration or encephalomyeloneuritis. Approaches to therapy, apart from treating the underlying tumor, are thus speculative.In patients with rapidly progressive symptoms classically suggestive of a paraneoplastic neurologic syndrome, time is of the essence in arresting neurologic deterioration. Clinical improvement in patients with longstanding symptoms is unlikely. At the outset, one should move rapidly to define the antibody response involved, as this may also assist tumor diagnosis. Treatment may include prednisone, intravenous IgG, and cyclophosphamide; rituximab plus prednisone may be an alternative, either initially or in the face of continued disease progression despite treatment with intravenous IgG or cyclophosphamide. Although PE is of questionable benefit, a single cycle of PE may be considered before other treatment, to achieve rapid lowering of circulating paraneoplastic autoantibodies. PMID- 20842582 TI - Parkinson's psychosis. AB - OPINION STATEMENT: Psychosis is a leading reason for nursing home placement of patients with Parkinson's disease (PD). It may also be the single greatest stressor for caregivers of PD patients, it is generally persistent, and its presence markedly increases the risk of mortality. For these reasons, it is essential to recognize and appropriately treat psychosis in PD. Treatment of psychotic symptoms should be initiated after potential medical and environmental causes of delirium (eg, infection) have been eliminated or addressed. Initial pharmacologic changes should include limiting the patient's anti-PD medications to those that are necessary to preserve motor function (ie, eliminating adjunctive agents). Should that fail, an atypical antipsychotic agent is the treatment of choice. Clozapine is presently the gold standard, and quetiapine represents another option because of its ease of use and good tolerability profile. Emerging treatment options include the use of acetylcholinesterase inhibitors, antidepressants, and cognitive behavioral therapy. This article reviews what is currently known about treatment strategies in PD psychosis. PMID- 20842584 TI - Myasthenia gravis. AB - OPINION STATEMENT: Treatment of patients with acquired (autoimmune) myasthenia gravis should rely on evidence-based therapeutic choices, taking into account the individual's needs according to disease severity (mild to severe), extent (ocular or generalized), comorbidities (including other autoimmune diseases, infections, thymoma, and pregnancy), age, iatrogenic factors (the risks and benefits of therapy), patient autonomy and quality of life, financial burden to the patient, and associated health care costs. Therapy is aimed at managing symptoms by improving neuromuscular junction transmission (cholinesterase inhibitors) and/or modifying the underlying immunopathogenetic cause of acquired myasthenia gravis via immunosuppression or immunomodulation. Myasthenic patients with operable thymoma should be referred for surgery and closely followed up for tumor recurrence. A concerted international effort is addressing treatment recommendations for thymectomy in myasthenic patients with no radiologic evidence of thymoma who are positive for circulating acetylcholine receptor antibodies. There is a lack of evidence-based treatment guidelines for both acute and long term management of ocular myasthenia. Acute management of myasthenic crisis requires intensive monitoring of the patient and institution of an efficient and safe treatment such as plasma exchange. Patient education is essential to a comprehensive long-term treatment plan. PMID- 20842585 TI - Neuromyelitis optica. AB - OPINION STATEMENT: Neuromyelitis optica (NMO) or Devic's disease typically involves the optic nerves and the spinal cord and is most often relapsing. The pathogenesis is one of an acute inflammatory process targeting astrocytes and resulting in demyelination, as well as axonal injury. In a high proportion of recognized cases of NMO, there is a highly specific autoantibody (NMO-IgG), which is directed to the common central nervous system water channel, aquaporin-4. NMO attacks usually result in severe residual visual impairment or myelopathy. Despite the publication of new diagnostic criteria for NMO, uncertainty at the time of the index event as to whether the attack is due to multiple sclerosis or NMO can cause therapeutic hesitancy. Nevertheless, whenever a reasonable degree of suspicion exists, therapies directed to limiting acute injury and to preventing subsequent further injury mediated by humoral mechanisms should be instituted immediately. Investigations can then be completed and the therapeutic direction confirmed.For an acute attack, high-dose methylprednisolone and plasma exchange (generally given sequentially) are most useful.For the prevention of further attacks, selective or nonselective immunosuppressive therapy directed to humoral mechanisms is preferred. Agents recommended are oral azathioprine or mycophenolate mofetil with or without low-dose prednisolone or rituximab. Therapy should be planned to continue for up to 5 years in all patients, including those with a single attack who are at high risk of further relapse.Regrettably, there are no controlled trials for the treatment of either the classic manifestations of NMO or the so-called limited manifestations known as NMO spectrum disorders. The therapeutic opinions expressed in this article are therefore based on the current understanding of the pathogenesis of this disorder, reports of small series of patients receiving a range of treatments, and expert opinions. PMID- 20842586 TI - Therapeutic interventions in the primary hereditary ataxias. AB - OPINION STATEMENT: The treatment of hereditary ataxia is primarily supportive. With very few exceptions (eg, ataxia associated with vitamin E deficiency), there are no disease-modifying therapies. Despite the lack of disease-modifying treatments, there can be great value in obtaining an accurate diagnosis of hereditary ataxia subtype. Benefits include determining prognosis, facilitating family counseling, improving research access, and providing some psychological benefit in ending the often frustrating search for an accurate etiology. Hereditary ataxias may have certain clinical features that respond very well to symptomatic medical therapy. Parkinsonism, dystonia, spasticity, urinary urgency, sleep pathology, fatigue, and depression are all common in many of the ataxia subtypes and very often respond to pharmacologic intervention as in other diseases. Much of the clinical interaction between neurologist and ataxia patient should focus on identifying and treating these symptoms. Treatment of the core clinical feature of these diseases-ataxia-is predominantly rehabilitative. The value of good physical therapy far exceeds any potential benefit from medications that a physician might prescribe to improve balance and coordination. Speech and swallowing are often affected. In more severe cases, aspiration risk can be very significant and life-threatening. Routine monitoring of swallowing by speech therapists, often including modified barium swallowing tests, is indicated in most patients. Recently there have been very encouraging advances in clinical ataxia research. Collaborative study groups throughout the world have developed and validated ataxia rating scales and instrumented outcome measures and have begun to rigorously define the natural history of these diseases, thus laying the foundation for well-designed clinical trials. The promise of disease-modifying treatments is closer than ever. PMID- 20842587 TI - Tourette's Disorder. AB - OPINION STATEMENT: Tourette's disorder (TD) is a common childhood-onset neuropsychiatric disorder characterized by chronic motor and vocal tics. TD frequently occurs with other neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), and may contribute to reduced quality of life and disability. Currently available treatments to reduce tics are limited by variable clinical response and frequent adverse effects. They include alpha-2 agonists, antipsychotics (first and second generation), tetrabenazine, benzodiazepines, and habit reversal therapy. Some new and emerging (but unproven) treatments are also discussed, including topiramate and dopamine agonists. In addition, there is increasing interest in deep brain stimulation, but this is not yet ready for general use. PMID- 20842588 TI - New antiepileptic drugs: lacosamide, rufinamide, and vigabatrin. AB - OPINION STATEMENT: The treatment of epilepsy is complicated by the multiple seizure types and epilepsy syndromes needing therapy. In addition, seizures in up to 30% of epilepsy patients are resistant to available medications. The three newest antiepileptic medications (lacosamide, rufinamide, and vigabatrin) all putatively have novel mechanisms of action, which might increase the chance of treatment success in patients failing previous antiepilepsy drug trials and the chance of successful synergy with currently available medications. In our experience, all three drugs generally are well tolerated, although the risk for serious long-term complications with vigabatrin presents special challenges and precautions. Lacosamide is approved for the adjunctive therapy of complex partial seizures in adults and also is available in an intravenous formulation. Rufinamide is a new treatment option for seizures associated with Lennox-Gastaut syndrome, and although it is not FDA approved for partial seizures, it has shown efficacy for that indication as well. Vigabatrin has been approved in adults for drug-resistant complex partial seizures and in infants as a treatment option for infantile spasms. PMID- 20842589 TI - Antiepileptic drugs and markers of vascular risk. AB - OPINION STATEMENT: The most-used treatments for epilepsy worldwide are older generation drugs such as phenytoin, carbamazepine, phenobarbital, and valproic acid, which have prominent enzymatic effects. Our sense of comfort with these treatments is starting to fade, however, as more and more potential long-term consequences of these drugs come to light. Epidemiologic studies demonstrate that ischemic disease of the heart and brain is more common among patients with epilepsy. Enzyme-inducing drugs are associated with elevations in a host of surrogate markers of vascular risk, suggesting that they could be responsible for increased rates of cardiovascular and cerebrovascular disease. The enzyme inhibiting drug valproate may have adverse consequences of its own pertaining to glucose and lipid metabolism. These effects stand in addition to those well established in the literature regarding bone metabolism, hormonal abnormalities, and drug-drug interactions. Because patients with epilepsy require medication for years, and often for life, it is difficult to justify the long-term use of these agents when there are capable alternatives. Many of the adverse effects of the older drugs appear to be rapidly reversible, prompting consideration of whether patients who are currently treated with these agents should be switched to alternative therapies, even in the absence of obvious side effects. Newer medications without effects on hepatic enzymes likely do not have these chronic metabolic consequences, and we recommend their use over older-generation drugs whenever possible. PMID- 20842590 TI - Newly diagnosed high-grade gliomas. AB - OPINION STATEMENT: High-grade or malignant gliomas are aggressive cancers. The World Health Organization (WHO) grading system recognizes grade III and grade IV primary brain tumors of astrocytic, oligodendroglial, or mixed lineage. Identification of these tumors is prompted by symptoms such as insidious headaches, seizures, or focal weakness or numbness, with imaging findings of an enhancing mass lesion. Following surgery, radiation therapy has been known since the late 1970s to improve survival in malignant gliomas. More recently, the concurrent use of temozolomide (TMZ) and radiation therapy and the incorporation of bevacizumab have offered hope for patients with glioblastoma (WHO grade IV glioma). Although radiation is regularly used for up-front treatment of grade III gliomas, the role of chemotherapy is still being refined. In the past, patients with high-grade gliomas were often referred to a dedicated neuro-oncology center, but with improved outcomes and increased survival, these patients now are often treated by community oncologists. We believe substantial changes will develop with pending investigations that refine the dose and length of TMZ treatment, define specialized treatment for the elderly, and assess efficacy of bevacizumab in up-front therapy. The field is also conducting the required studies to define the role of chemotherapy for grade III malignant gliomas. These promising advances are needed as most patients with high-grade gliomas still succumb to their disease. PMID- 20842591 TI - Recurrent high-grade glioma. AB - OPINION STATEMENT: Opinions vary on the best treatment options for recurrent high grade glioma. Some argue that bevacizumab should become standard of care for patients with recurrent glioblastoma, especially in light of recent FDA approval for this indication. However, this opinion is not uniformly accepted. Age, performance status, histology, tumor size and location, O6-methylguanine-DNA methyltransferase (MGMT) methylation status for glioblastoma, 1p/19q status for oligodendroglial tumors, and the number and types of prior therapies are important considerations. In addition, recurrent disease must be distinguished from "pseudoprogression" due to treatment effects. Enrollment in a clinical trial is the optimal choice for most patients with recurrent high-grade glioma after failure of radiation therapy and temozolomide. For patients who are ineligible or do not have access to clinical trials, then either bevacizumab monotherapy or bevacizumab in combination with a second agent such as irinotecan is recommended. Involved-field external beam radiation should be considered for patients with anaplastic gliomas who have not received radiation. For patients with anaplastic astrocytoma who progress after radiotherapy, temozolomide may be used. For patients with anaplastic oligodendroglioma who progress after radiotherapy, PCV chemotherapy and temozolomide are options. Oligodendroglial tumors with 1p/19q deletions are more likely to respond to treatment. In the past, carmustine was commonly used to treat recurrent high-grade glioma, but the utility of carmustine in the modern era is unknown because most studies were performed prior to the widespread use of temozolomide. High-precision re-irradiation such as stereotactic radiosurgery is another option in high-grade glioma, especially for patients with poor bone marrow reserve or inability to tolerate chemotherapy, but there is a paucity of studies with adequate controls. Surgery may be useful as adjuvant treatment for patients with symptoms due to mass effect or for patients requiring definitive histopathology, but it generally should be combined with another treatment modality. Emerging therapies, including dose-intense temozolomide regimens, targeted molecular inhibitors, other antiangiogenic therapies, viral gene therapies, immunotherapies, and convection-enhanced delivery of targeted immunotoxins, are still under investigation. PMID- 20842592 TI - Management of brain metastases. AB - OPINION STATEMENT: As systemic cancer therapies have improved, the natural history and importance of treating brain metastases continues to evolve. Historically, most patients with brain metastases have been managed with whole brain radiation therapy (WBRT) with surgical resection or radiosurgery added for patients with single or few metastases. Because the potential late toxicity of WBRT is increasingly recognized when systemic tumor is more effectively controlled, there has been increased interest in the use of focal therapies such as radiosurgery with deferred WBRT even for patients with larger numbers of metastases. Although WBRT in combination with radiosurgery or surgical resection significantly reduces central nervous system recurrences at the treated site and elsewhere in the brain, it is not clear whether a patient's quality of life is more affected by tumor recurrence or by treatment with WBRT. In our practice, most patients with fewer than 7 to 10 tumors are treated with radiosurgery alone, with WBRT initially deferred because of concerns about its late toxicity. The ongoing technical improvements in radiosurgery have made this transition away from WBRT clinically feasible. This approach also allows patients to begin systemic therapy sooner, rather than waiting 2 to 4 weeks to complete WBRT. For patients with large or very symptomatic tumors, surgical resection is performed, followed by postoperative radiosurgery to the resection cavity, again initially deferring WBRT for many patients. This focal-only approach in the postoperative setting is associated with a higher rate of subdural dissemination and needs further prospective study, as some would argue that tumor progression is the major determinant of loss of function. Ultimately, better survival will require better systemic therapy that both controls extracranial disease and penetrates the brain to reduce intracranial recurrences. Unfortunately, many clinical trials of novel agents exclude patients with brain metastases. PMID- 20842593 TI - Primary central nervous system lymphoma. AB - OPINION STATEMENT: Management goals for patients with primary central nervous system lymphoma (PCNSL) include long-term disease control, management of neurologic complications, and preservation of neurocognitive function. Various treatment options can achieve several of these goals. Chemotherapy as monotherapy or as combination therapy has emerged as the cornerstone of therapy for patients with newly diagnosed PCNSL. Outside of a clinical trial, patients with newly diagnosed PCNSL should receive high-dose intravenous methotrexate (MTX) as a single agent or as part of a combination regimen with radiation therapy reserved for relapse. The regimen should have an adequate MTX dose (>3 g/m(2)) to reach cytotoxic concentrations in the cerebrospinal fluid (CSF) to treat occult leptomeningeal disease (LMD). Alternative modes of chemotherapy delivery for selected patients, preferably in the context of a clinical trial, include high dose chemotherapy with autologous stem cell rescue and intra-arterial chemotherapy with blood-brain barrier disruption. Whole brain radiation therapy (WBRT) in standard doses and fractionation carries an unacceptable rate of long term neurocognitive toxicity. However, lower doses in daily divided fractions may offer the possibility of adding this modality with preservation of cognition but should be performed only in the context of a clinical trial. The long-term efficacy and toxicity of this approach is currently under investigation. Certain presentations of PCNSL require different strategies. Patients with ocular lymphoma at diagnosis should receive high-dose MTX as this drug can reach cytotoxic intravitreal concentrations. Recurrence in the eyes is managed with intravitreal chemotherapy including MTX or rituximab or with radiation therapy. The field of treatment (eyes vs whole brain) should be individualized. Intrathecal (IT) MTX should be included in the treatment regimen for those patients with a positive CSF cytology, or in regimens in which lower doses of MTX are delivered over longer periods of time. It is probably reasonable to withhold IT chemotherapy in those patients who have no detectable subarachnoid disease and who can receive higher doses of MTX (>3 g/m(2)) over shorter infusion periods (2 4 h). Patients who develop leptomeningeal involvement despite high- dose MTX can be managed with IT chemotherapy such as liposomal cytarabine or MTX or even rituximab. Areas of bulky or symptomatic LMD should probably be treated with radiation therapy as well. Because PCNSL is an uncommon disease, entry into clinical trials must be pursued to advance the state of the art. PMID- 20842594 TI - Meningiomas. AB - OPINION STATEMENT: Meningiomas are extra-axial dural-based tumors. They are the most common intracranial tumors, occur in mid to late life, and have a female predilection. Symptoms are a function of location. Meningiomas are usually benign, but atypical and malignant forms exist. Treatment is indicated for symptomatic lesions or when neurologic symptoms may shortly occur. Surgical resection can be curative; however, because of their location, some lesions are amenable only to partial resection. Radiation therapy is used for incompletely removed symptomatic lesions, lesions that are not surgically accessible, and small symptomatic lesions. For higher grade meningiomas, radiation is used after surgery. For lesions that recur or grow despite surgery and radiation, systemic chemotherapy can be tried. There is no optimal agent, but hydroxyurea is used most often with very modest success; hormonal approaches have not been successful. Targeting somatostatin receptors or receptor tyrosine kinases using novel agents appears to have some activity and is an area of clinical research. PMID- 20842595 TI - Treatment of childhood obstructive sleep apnea. AB - OPINION STATEMENT: An array of surgical, medical and orthodontic treatments is available for treating childhood obstructive sleep apnea. Adenotonsillectomy remains the first choice in treatment, with a need for subsequent clinical and polysomnographic reassessment in selected cases to determine residual sleep disordered breathing. Residual obstructive sleep apnea is more likely in patients with craniofacial abnormalities or obesity. It may require the use of a positive airway pressure breathing device. Topical corticosteroids, leukotriene antagonists, weight reduction, and positional therapy also play a role in ameliorating childhood obstructive sleep apnea. The published evidence for the efficacy of various treatment modalities consists largely of case-controlled studies and case reports. PMID- 20842596 TI - Management of sleep disorders in stroke. AB - OPINION STATEMENT: Scientific studies have proven a very strong association between stroke and obstructive sleep apnea (OSA). The prevalence of OSA is very high in patients with acute stroke, and untreated OSA is a stroke risk factor. In the stroke patient population, symptoms of OSA may atypically appear as isolated insomnia, hypersomnia, a dysfunction of circadian rhythm, a parasomnia, or a sleep-related movement disorder. Thus, we believe that in patients with acute stroke, OSA should be addressed first, using full in-laboratory, attended polysomnography (PSG), before other specific sleep disorders are aggressively addressed with specific therapeutic interventions. When OSA is diagnosed, supportive techniques including the application of continuous positive airway pressure (CPAP) therapy, positional therapies, or both should be considered first line treatments. If OSA is ruled out by PSG, the therapeutic emphasis for sleep related complaints is routinely based on instituting good sleep hygiene practices and using cognitive behavioral techniques (cognitive therapies, sleep restriction, stimulus control, and progressive relaxation therapies) because patients with stroke may be prone to the adverse effects of many of the medications that are otherwise routinely prescribed for a variety of specific sleep disorders. PMID- 20842597 TI - Treatment of shift work disorder and jet lag. AB - OPINION STATEMENT: With the growth of the 24-hour global marketplace, a substantial proportion of workers are engaged in nontraditional work schedules and frequent jet travel across multiple time zones. Thus, shift work disorder and jet lag are prevalent in our 24/7 society and have been associated with significant health and safety repercussions. In both disorders, treatment strategies are based on promoting good sleep hygiene, improving circadian alignment, and targeting specific symptoms.Treatment of shift work must be tailored to the type of shift. For a night worker, circadian alignment can be achieved with bright light exposure during the shift and avoidance of bright light (with dark or amber sunglasses) toward the latter portion of the work period and during the morning commute home. If insomnia and/or excessive sleepiness are prominent complaints despite behavioral approaches and adequate opportunity for sleep, melatonin may be administered prior to the day sleep period to improve sleep, and alertness during work can be augmented by caffeine and wake-promoting agents.For jet lag, circadian adaptation is suggested only for travel greater than 48 h, with travel east more challenging than travel west. Although advancing sleep and wake times and circadian timing for eastward travel with evening melatonin and morning bright light several days prior to departure can help avoid jet lag at the new destination, this approach may be impractical for many people, Therefore, strategies for treatment at the destination, such as avoidance of early morning light and exposure to late-morning and afternoon light alone or in conjunction with bedtime melatonin, can accelerate re-entrainment following eastward travel. For westward travel, a circadian delay can be achieved after arrival with afternoon and early-evening light with bedtime melatonin.Good sleep hygiene practices, together with the application of circadian principles, can improve sleep quality, alertness, performance, and safety in shift workers and jet travelers. However, definitive multicenter randomized controlled clinical trials are still needed, using traditional efficacy outcomes such as sleep and performance as well as novel biomarkers of health. PMID- 20842598 TI - Cognitive rehabilitation in traumatic brain injury. AB - OPINION STATEMENT: Traumatic brain injury (TBI) is a major public health problem with neurobehavioral sequelae contributing to the long-term disability that is often associated with the moderate to severe levels of injury. Rehabilitation of cognitive skills is central to encouraging the full participation of the individual in home, vocational, and social roles. The review of available evidence points to four major recommendations for the rehabilitation of cognition following brain injury: 1) Access to subacute rehabilitation that is holistic in nature and involves a multidisciplinary or transdisciplinary team to work in an integrated fashion to support physical, cognitive, and social skill retraining is vital to support positive outcome following TBI. The collaborative effort of these individuals allows for continual reinforcement and evaluation of treatment goals and will often involve the family and/or important others in the individual's life to prepare for community re-entry. 2) Trials of medication, especially methylphenidate, to assist individuals with significant attention and memory impairment appear well supported by the available evidence. Though some data suggest that the use of cholinesterase inhibitors may be of use for individuals with memory impairments, there is less support for this practice and there are indications that it may worsen the behavioral sequelae of the injury. 3) Randomized controlled trials demonstrate the utility of specific rehabilitation approaches to attention retraining and retraining of executive functioning skills. Future research is needed on rehabilitation techniques in other domains of cognition. 4) Training in the use of supportive devices (either a memory book or more technologically enhanced compensatory devices) to support the individual's daily activities remains central to the independent function of the individual in the community. Though emerging treatments (eg, virtual reality environments) show relative degrees of promise for inclusion in the rehabilitation of the individual with TBI, these need further evaluation in systematic trials. PMID- 20842599 TI - Electrical stimulation in epilepsy: vagus nerve and brain stimulation. AB - OPINION STATEMENT: Vagus nerve stimulation (VNS) for epilepsy is a well established and effective treatment for medically intractable epilepsy. VNS is indicated if resective epilepsy surgery is unsuccessful or is not an option. About 50% of patients with VNS have a seizure reduction greater than 50%, but less than 10% become seizure-free. VNS also has an alerting effect on patients and may allow a reduction in sedating medications. The major adverse event is hoarseness, but treatment is generally well tolerated. The therapeutic effect can be delayed: patients may improve several months after VNS implantation. Direct brain stimulation (DBS) is an emerging treatment for epilepsy. Scheduled stimulation is similar to brain stimulation in Parkinson's disease. Only the anterior thalamic nucleus has been studied in a larger randomized, controlled trial, in which patients with the stimulator turned on had a significantly reduced seizure frequency. Responsive stimulation applies an electrical stimulus at the site of seizure onset to terminate the seizure if one occurs. The seizure onset zone must be well defined before implantation. Responsive stimulation requires seizure detection and application of a stimulus online. A large pivotal trial showed a significant reduction in seizure frequency. Both DBS and responsive neurostimulation are well tolerated, but there has been some concern about depression with DBS. Infection, hemorrhage, and lead breakage are adverse events possible with any type of stimulator. None of the brain stimulation devices have been approved by the US Food and Drug Administration, but final approval is expected soon. These devices are indicated for patients with bilateral seizure onset or seizure onset in eloquent areas. Although the initial trials of brain stimulation do not show overwhelming improvement in seizure frequency, the technology will improve with time as we continue to learn about the use of brain stimulation for epilepsy. Optimization of VNS has been going on for 10 years, and we need to ensure that brain stimulation is similarly developed further. In addition, sophisticated devices such as responsive neurostimulators can greatly enhance our understanding of the pathophysiology of epilepsy. PMID- 20842600 TI - Triptans: where things stand. AB - OPINION STATEMENT: Triptans, selective serotonin receptor agonists, were developed almost 20 years ago and represented a major breakthrough in the treatment of acute migraine attacks. Since then, the triptans have become first line agents for most patients with migraine, both with and without aura, unless contraindicated. This article reviews the development of triptans, discusses reasons for their success or failure, and examines the limitations and controversies surrounding this class of medication. PMID- 20842601 TI - Meningococcal meningitis. AB - OPINION STATEMENT: Meningococcal meningitis (MM) is the most common presentation of meningococcal disease and an important cause of morbidity and mortality worldwide. When MM is associated with shock, early recognition and treatment of shock is essential. No investigation should delay starting antibiotics once the diagnosis is suspected. Corticosteroids can be started at the same time as the antibiotics or just before, but this is not a specific recommendation for MM. Low dose steroids should be used in meningococcal disease with refractory shock. Altered blood flow, cerebral edema, and raised intracranial pressure are problems that should be considered in all patients with MM and decreased consciousness level. When mechanical ventilation is required, the target carbon dioxide level is 4.0 to 4.5 kPa, with avoidance of hypocapnia. Seizures, although not frequent, can occur in MM and require prompt treatment. Other treatments, such as mannitol and activated protein C, should be avoided. Potential new treatments requiring further investigation include neuroprotection with hypothermia or glycerol. PMID- 20842602 TI - Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels. AB - Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)alpha, PPARbeta/delta and PPARgamma are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARalpha are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARalpha also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARgamma controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARbeta/delta increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARbeta/delta ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARalpha favours skin healing during the inflammatory phase that follows injury, whilst PPARbeta/delta enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies. PMID- 20842603 TI - [Personalized treatment of cancer: utopia or chance?]. PMID- 20842604 TI - [Relapsed pulmonary lymphomatoid granulomatosis grade III: curative treatment with radioimmune therapy and autologous stem cell transplantation]. AB - HISTORY AND ADMISSION FINDINGS: A 36-year-old woman presented with dyspnea, dry cough and severe chest pain. She had been treated for persistent shoulder pain for several months. Clinical findings were non-conclusive. Lactate dehydrogenase was slightly elevated, C-reactive protein was increased. INVESTIGATIONS: A chest X-ray and subsequent computed tomography (CT) scans showed a lesion measuring 10*8 cm in the right upper pulmonary lobe. A CT-guided biopsy was obtained and the histological examination revealed a dense lymphocytic infiltrate with abundant blasts in addition to areas of necrosis and fibrosis. These findings were consistent with lymphomatoid granulomatosis grade III. TREATMENT AND COURSE: After 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristin and prednisolone (R-CHOP), an early relapse developed which was treated with rituximab, ifosphamid, methotrexate and etoposide. Good partial remission was achieved after consolidating high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). After two years of rituximab maintenance treatment positron emission tomography (PET-CT) revealed an increase of metabolic activity. A second high-dose therapy was then combined with Y-90 ibritumomab tiuxetan, which was well tolerated. During remission the previously present lymphoma lesion of the lung was resected. Histology did not reveal any residual active lymphomatoid granulomatosis. Complete remission has so far been maintained for one year after ASCT. CONCLUSIONS: Combination of Y-90 ibritumomab tiuxetan and high-dose chemotherapy followed by ASCT may offer an efficacious and well tolerated targeted treatment approach for patients with relapsed lymphomatoid granulomatosis. PMID- 20842605 TI - [56-year-old female patient with jaundice and paraparesis]. PMID- 20842606 TI - [Current treatment options for myelodysplastic syndromes]. PMID- 20842607 TI - [Prophylaxis of fungal infections in haematological patients: pro]. PMID- 20842608 TI - [Prophylaxis of fungal infections in haematological patients: contra]. PMID- 20842609 TI - [Metastatic gastric cancer: does second-line chemotherapy make sense?]. PMID- 20842610 TI - [Indication for platelet transfusion in patients with haematological diseases: less is more]. PMID- 20842611 TI - [Evaluation of overweight, hyperprolactinaemia and suspected Cushing's syndrome]. PMID- 20842612 TI - [Ethical insolvency--losing medical identity in the DRG era]. PMID- 20842615 TI - [Placement of stimulus electrodes and heart rate during electroconvulsive therapy]. AB - OBJECTIVE: Bifrontal stimulation in electroconvulsive therapy (ECT) has been increasingly administered and evaluated over the past years. However, no attention has been paid to cardiac side effects of this novel form of treatment during the application of the electrical stimuli. METHOD: Cardiac responses to different electrode positions were compared intraindividually, using synchronised electrocardiograms and waveforms of pulse oximetry. RESULTS: Unilateral ECT gave rise to a marked cardiac response during stimulation. Intervals between two consecutive heartbeats increased from 0.6 +/- 0.0 sec to 4.1 +/- 3.4 sec (mean +/ standard deviation). In contrast, stable heart actions were documented in the same patients during bifrontal stimulation. CONCLUSION: The placement of the stimulus electrodes for ECT determines the incidence of asystole events during stimulation. Bifrontal electrode positioning results in less activation of the vagus nerve than unilateral treatment. The longer distance from the electrode site to the nerve in bifrontal treatment could account for these findings. PMID- 20842614 TI - Metabolism of fructose to oxalate and glycolate. AB - Much attention has been recently directed at fructose consumption because of its association with obesity and subsequent development of chronic diseases. It was recently reported that an increased fructose intake increases the risk of forming kidney stones. It was postulated that fructose consumption may increase urinary oxalate, a risk factor for calcium oxalate kidney stone disease. However, conflicting results have been obtained in human studies examining the relationship between fructose metabolism and oxalate synthesis. To test whether fructose intake influences urinary excretions impacting kidney stone risk, healthy subjects consumed diets controlled in their contents of fructose, oxalate, calcium, and other nutrients. Subjects consumed diets containing 4, 13, and 21% of calories as fructose in a randomized order. No changes in the excretions of oxalate, calcium, and uric acid were observed. In vitro investigations with cultured liver cells incubated with (13)C-labeled sugars indicated that neither fructose nor glucose was converted to oxalate by these cells. Fructose metabolism accounted for 12.4 +/- 1.6% of the glycolate detected in the culture medium and glucose 6.4 +/- 0.9%. Our results suggest that mechanisms for stone risk associated with fructose intake may lie in factors other than those affecting the major stone risk parameters in urine. PMID- 20842616 TI - Predicting significant maternal morbidity in women attempting vaginal birth after cesarean section. AB - Attempting vaginal birth after cesarean section (VBAC) places women at an increased risk for complications. We set out to identify factors that are predictive of major morbidity in women who attempt VBAC. A nested case-control study was performed within a large retrospective cohort study of women with a history of at least one cesarean. Women who attempted VBAC were identified and those who experienced at least one complication of a composite adverse outcome consisting of uterine rupture, bladder injury, and bowel injury (cases) were compared with those who did not experience one of these adverse outcomes (controls). We analyzed risk factors for major maternal morbidity using univariable and multivariable methods. The accuracy of the multivariable prediction model was assessed with receiver operator characteristic (ROC) curve analysis. Of 25,005 women with a history of previous cesarean, 13,706 (54.9%) attempted VBAC. The composite outcome occurred in 300 (2.1%) women attempting VBAC. Using logistic regression analysis, prior abdominal surgery (odds ratio [OR] 1.58, 95% confidence interval [CI] 1.2 to 2.1), augmented labor (OR 1.78, 95% CI 1.29 to 2.46), and induction of labor (OR 2.03, 95% CI 1.48 to 2.76) were associated with an increased risk of the composite outcome. Prior vaginal delivery (OR 0.39, 95% CI 0.29 to 0.54) was associated with decreased risk for the composite outcome. The ROC curve generated from the regression model has an area under the curve of 0.65 and an unfavorable tradeoff between sensitivity and specificity. Women attempting VBAC with a history of abdominal surgery or those who undergo augmentation or induction of labor are at an increased risk for major maternal morbidity, and women with a prior vaginal delivery have a decreased risk of major morbidity. The multivariable model developed cannot accurately predict major maternal morbidity. PMID- 20842618 TI - Nocturnal administration of ghrelin does not promote memory consolidation. PMID- 20842617 TI - Assessment of medication adherence in a cohort of patients with bipolar disorder. AB - INTRODUCTION: This study aimed to identify factors associated with medication adherence in bipolar disorder (BPD) patients. METHODS: EMBLEM is a 2-year, prospective, observational study on the outcomes of BPD patients initiating or changing treatment for a manic/mixed episode. Data were collected at baseline, during the first 12 weeks of treatment (acute phase) and up to 24 months of follow-up (maintenance phase). Adherence was assessed by investigators at every visit. Repeated measures logistic regression analyses identified variables associated with adherence. RESULTS: Of 1,831 patients included in the analysis, 76.6% were adherent and 23.4% were non-adherent with their BPD medication during the maintenance phase. Patients were more likely to be adherent if they had insight into their illness at week 12. Patients were less likely to be adherent if they had cannabis abuse/dependence during the acute phase, work impairment or higher CGI hallucinations/delusions at baseline DISCUSSION: Psychotic symptoms, poor insight, cannabis abuse/dependence and work impairment are negatively related to medication adherence during maintenance therapy of bipolar disorder. Patients with these characteristics may need a different therapeutic approach. PMID- 20842621 TI - [Unconventional removal of large bronchial foreign bodies]. PMID- 20842622 TI - Bias and efficiency of multiple imputation compared with complete-case analysis for missing covariate values. AB - When missing data occur in one or more covariates in a regression model, multiple imputation (MI) is widely advocated as an improvement over complete-case analysis (CC). We use theoretical arguments and simulation studies to compare these methods with MI implemented under a missing at random assumption. When data are missing completely at random, both methods have negligible bias, and MI is more efficient than CC across a wide range of scenarios. For other missing data mechanisms, bias arises in one or both methods. In our simulation setting, CC is biased towards the null when data are missing at random. However, when missingness is independent of the outcome given the covariates, CC has negligible bias and MI is biased away from the null. With more general missing data mechanisms, bias tends to be smaller for MI than for CC. Since MI is not always better than CC for missing covariate problems, the choice of method should take into account what is known about the missing data mechanism in a particular substantive application. Importantly, the choice of method should not be based on comparison of standard errors. We propose new ways to understand empirical differences between MI and CC, which may provide insights into the appropriateness of the assumptions underlying each method, and we propose a new index for assessing the likely gain in precision from MI: the fraction of incomplete cases among the observed values of a covariate (FICO). PMID- 20842624 TI - A faster strategy for prenatal diagnosis of fragile X syndrome. PMID- 20842623 TI - Surface plasmon resonance analysis of the binding of high-risk mucosal HPV E6 oncoproteins to the PDZ1 domain of the tight junction protein MAGI-1. AB - The E6 oncoproteins from high-risk mucosal human papillomavirus (HPV) induce cervical cancer via two major activities, the binding and the degradation of the p53 protein and PDZ domain-containing proteins. Human MAGI-1 is a multi-PDZ domain protein implicated into protein complex assembly at cell-cell contacts. High-risk mucosal HPV E6 proteins interact with the PDZ1 domain of MAGI-1 via a C terminal consensus binding motif. Here, we developed a medium throughput protocol to accurately measure by surface plasmon resonance affinity constants of protein domains binding to peptidic sequences produced as recombinant fusions to the glutathione-S-transferase (GST). This approach was applied to measure the binding of MAGI-1 PDZ1 to the C-termini of viral or cellular proteins. Both high-risk mucosal HPV E6 C-terminal peptides and cellular partners of MAGI-1 PDZ1 bind to MAGI-1 PDZ1 with comparable dissociation constants in the micromolar range. MAGI 1 PDZ1 shows a preference for C-termini with a valine at position 0 and a negative charge at position -3, confirming previous studies performed with HPV18 E6. A detailed combined analysis via site-directed mutagenesis of the HPV16 C terminal peptide and PDZ1 indicated that interactions mediated by charged residues upstream the PDZ-binding motif strongly contribute to binding selectivity of this interaction. In addition, our work highlighted the K(499) residue of MAGI-1 as a novel determinant of binding specificity. Finally, we showed that MAGI-1 PDZ1 also binds to the C-termini of LPP and Tax proteins, which were already known to bind to PDZ proteins but not to MAGI-1. PMID- 20842625 TI - Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. AB - OBJECTIVE: Molecular diagnosis and prenatal care of two pregnant women at risk of transmitting immunodysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome. METHODS: FOXP3 coding sequence and exon boundaries were analyzed in the two consultants and family members. Non-invasive sex determination and specific prenatal diagnosis was realized. RESULTS: Following sequence analysis a new FOXP3 mutation was identified in each consultant. Sex diagnosis realized by amplification of Y sequences from the plasma of the two mothers revealed a male and a female fetus, respectively. Prenatal diagnosis showed that the male fetus was unaffected. The baby is now born and healthy. Subsequent ultrasound examinations confirmed the sex in the second pregnancy but unfortunately led to the diagnosis of a 69,XXX triploidy. The pregnancy was thus interrupted. CONCLUSION: Two new FOXP3 mutations were identified and prenatal diagnosis could be proposed. Due to the rarity of the disease, clinical diagnosis is often considered with delay. Both patients reported here were already pregnant at the beginning of the genetic investigation and one had previously interrupted a male pregnancy for lack of diagnosis. When faced with children with severe refractory diarrhea, clinicians should entertain the possibility of IPEX. PMID- 20842626 TI - Legal challenges in international drug testing: a service agent's perspective. PMID- 20842627 TI - In vivo synthesis of diverse metal nanoparticles by recombinant Escherichia coli. PMID- 20842628 TI - Pathway-based analysis for genome-wide association studies using supervised principal components. AB - Many complex diseases are influenced by genetic variations in multiple genes, each with only a small marginal effect on disease susceptibility. Pathway analysis, which identifies biological pathways associated with disease outcome, has become increasingly popular for genome-wide association studies (GWAS). In addition to combining weak signals from a number of SNPs in the same pathway, results from pathway analysis also shed light on the biological processes underlying disease. We propose a new pathway-based analysis method for GWAS, the supervised principal component analysis (SPCA) model. In the proposed SPCA model, a selected subset of SNPs most associated with disease outcome is used to estimate the latent variable for a pathway. The estimated latent variable for each pathway is an optimal linear combination of a selected subset of SNPs; therefore, the proposed SPCA model provides the ability to borrow strength across the SNPs in a pathway. In addition to identifying pathways associated with disease outcome, SPCA also carries out additional within-category selection to identify the most important SNPs within each gene set. The proposed model operates in a well-established statistical framework and can handle design information such as covariate adjustment and matching information in GWAS. We compare the proposed method with currently available methods using data with realistic linkage disequilibrium structures, and we illustrate the SPCA method using the Wellcome Trust Case-Control Consortium Crohn Disease (CD) data set. PMID- 20842629 TI - Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory. AB - Loss of cholinergic cortical input is associated with diseases in which episodic memory impairment is a prominent feature, but the degree to which this neurochemical lesion can account for memory impairment in humans with neurodegenerative diseases remains unclear. Removal of cholinergic input to hippocampus impairs some of its functions in memory, perhaps by reducing the plasticity of information representation within the hippocampus, but the role of cholinergic hippocampal input in episodic-like memories has not been investigated. To address this question, we tested rats with selective lesions of basal forebrain neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), which contains hippocampal-projecting cholinergic neurons, on a task of integrated memory for objects, places, and contexts ("what-where-which" memory). This task serves as a rodent model of human episodic memory (episodic like memory) and is sensitive to damage to the hippocampal system. Rats with lesions of cholinergic MS/VDB neurons performed as well on the what-where-which task as controls, but were impaired in a task that simply required them to associate places with contexts ("where-which" memory). Thus, episodic-like memories that rely on the hippocampus do not require cholinergic neuromodulation to be formed. Nevertheless, some more specific aspects of where-which memory, which may be more dependent on the plasticity of hippocampal spatial representations, require acetylcholine. These results suggest that cholinergic projections to hippocampus are not necessary for episodic memory and, furthermore, that hippocampal spatial representations may be to some extent dissociable from episodic memory function. PMID- 20842630 TI - Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. AB - Interleukin-22 (IL-22), a recently identified member of the IL-10 family of cytokines that is produced by Th17 and natural killer cells, plays an important role in controlling bacterial infection, homeostasis, and tissue repair. Here, we tested the effect of IL-22 on alcohol-induced liver injury in a murine model of chronic-binge ethanol feeding. Feeding male C57BL/6 mice with a Lieber-DeCarli diet containing 5% ethanol for 10 days, followed by a single dose of ethanol (5 g/kg body weight) by gavage, induces significant fatty liver and liver injury with peak serum levels of approximately 250 IU/L alanine aminotransferase and 420 IU/L aspartate aminotransferase 9 hours after gavage. Moreover, chronic-binge ethanol administration increases expression of hepatic and serum inflammatory cytokines and hepatic oxidative stress. Using this model, we demonstrate that treatment with IL-22 recombinant protein activates hepatic signal transducer and activator of transcription 3 (STAT3) and ameliorates alcoholic fatty liver, liver injury, and hepatic oxidative stress. Administration with IL-22 adenovirus also prevents alcohol-induced steatosis and liver injury. Deletion of STAT3 in hepatocytes abolishes the hepatoprotection provided by IL-22 in alcoholic liver injury. In addition, IL-22 treatment down-regulates the hepatic expression of fatty acid transport protein, but up-regulates several antioxidant, antiapoptotic, and antimicrobial genes. Finally, expression of IL-22 receptor 1 is up-regulated whereas IL-22 is undetectable in the livers from mice with chronic-binge ethanol feeding or patients with alcoholic hepatitis. CONCLUSION: Chronic-binge ethanol feeding may be a useful model to study the early stages of alcoholic liver injury. IL-22 treatment could be a potential therapeutic option to ameliorate alcoholic liver disease, due to its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects with the added benefit of potentially few side effects. PMID- 20842631 TI - Raised hepatic bile acid concentrations during pregnancy in mice are associated with reduced farnesoid X receptor function. AB - Pregnancy alters bile acid homeostasis and can unmask cholestatic disease in genetically predisposed but otherwise asymptomatic individuals. In this report, we show that normal pregnant mice have raised hepatic bile acid levels in the presence of procholestatic gene expression. The nuclear receptor farnesoid X receptor (FXR) regulates the transcription of the majority of these genes, and we show that both ablation and activation of Fxr prevent the accumulation of hepatic bile acids during pregnancy. These observations suggest that the function of Fxr may be perturbed during gestation. In subsequent in vitro experiments, serum from pregnant mice and humans was found to repress expression of the Fxr target gene, small heterodimer partner (Shp), in liver-derived Fao cells. Estradiol or estradiol metabolites may contribute to this effect because coincubation with the estrogen receptor (ER) antagonist fulvestrant (ICI 182780) abolished the repressive effects on Shp expression. Finally, we report that ERalpha interacts with FXR in an estradiol-dependent manner and represses its function in vitro. CONCLUSION: Ligand-activated ERalpha may inhibit FXR function during pregnancy and result in procholestatic gene expression and raised hepatic bile acid levels. We propose that this could cause intrahepatic cholestasis of pregnancy in genetically predisposed individuals. PMID- 20842633 TI - Prooxidant action of carazolol in the Fenton-like reaction. AB - Carazolol [4-(2-hydroxy-3-isopropyl-amino-propoxy)-carbazole], a beta(3) adrenoceptor agonist, is clinically used in the treatment of hypertension, cardiac arrhythmias and angina pectoris. Despite the beneficial effect of the drug, its high dose may contribute to cardiotoxicity. This study was conducted to examine whether carazolol can influence hydroxyl radical formation by a Fenton like reaction [Co(II) + H(2)O(2) + HO(-)] in the presence of ethylenediaminetetraacetic acid. The oxygen free radicals and singlet oxygen ((1)O(2)) formation was traced by three different assay methods: chemiluminescence (CL), an electron spin resonance (ESR) spin trapping with 2,2,6,6-tetramethyl-4-piperidine and 5,5-dimethyl-1-pyrroline-1-oxide, and spectrophotometric determination of (1)O(2) based on bleaching of p nitrosodimethylaniline. The effect of hydroxyl radical inhibitors and (1)O(2) quenchers on peroxidation of carazolol was also examined. The results indicated that carazolol enhanced the HO radical and (1)O(2) formation in a Fenton-like reaction. PMID- 20842632 TI - Liver-enriched transcription factors regulate microRNA-122 that targets CUTL1 during liver development. AB - MicroRNA-122 (miR-122) is a liver-specific microRNA whose expression is specifically turned on in the mouse liver during embryogenesis, thus it is expected to be involved in liver development. However, the role of miR-122 in liver development and its potential underlying mechanism remain unclear. Here, we show that the expression of miR-122 is closely correlated with four liver enriched transcription factors (LETFs)-hepatocyte nuclear factor (HNF) 1alpha, HNF3beta, HNF4alpha, and CCAAT/enhancer-binding protein (C/EBP) alpha-in the livers of developing mouse embryos and in human hepatocellular carcinoma (HCC) cell lines. Correspondingly, promoter analysis revealed that these LETFs are coordinately involved in the transcriptional regulation of miR-122, and three HNFs directly bind to the miR-122 promoter as transcriptional activators. Using a luciferase reporter system, we identified a group of miR-122 targets involved in proliferation and differentiation regulation. Among these targets, the most prominently repressed target was CUTL1, a transcriptional repressor of genes specifying terminal differentiation in multiple cell lineages, including hepatocytes. We show that CUTL1 expression is gradually silenced at the posttranscriptional level during mouse liver development. Overexpression and knockdown studies both showed that miR-122 repressed CUTL1 protein expression in HCC cell lines. Finally, we show that the stable restoration of miR-122 in HepG2 cells suppresses cellular proliferation and activates the expression of three hepatocyte functional genes, including the cholesterol-7alpha hydroxylase gene (CYP7A1), a known target of CUTL1 in hepatocytes. CONCLUSION: Our study provides a model in which miR-122 functions as an effector of LETFs and contributes to liver development by regulating the balance between proliferation and differentiation of hepatocytes, at least by targeting CUTL1. PMID- 20842634 TI - His-tag binding by antibody C706 mimics beta-amyloid recognition. AB - Alzheimer's disease is a progressive neurodegenerative disease characterized by extracellular deposits of beta-amyloid (Abeta) plaques. Aggregation of the Abeta(42) peptide leading to plaque formation is believed to play a central role in Alzheimer's disease pathogenesis. Anti-Abeta monoclonal antibodies can reduce amyloid plaques and could possibly be used for immunotherapy. We have developed a monoclonal antibody C706, which recognizes the human Abeta peptide. Here we report the crystal structure of the antibody Fab fragment at 1.7 A resolution. The structure was determined in two crystal forms, P2(1) and C2. Although the Fab was crystallized in the presence of Abeta(16), no peptide was observed in the crystals. The antigen-binding site is blocked by the hexahistidine tag of another Fab molecule in both crystal forms. The poly-His peptide in an extended conformation occupies a crevice between the light and heavy chains of the variable domain. Two consecutive histidines (His4-His5) stack against tryptophan residues in the central pocket of the antigen-binding surface. In addition, they form hydrogen bonds to the acidic residues at the bottom of the pocket. The mode of his-tag binding by C706 resembles the Abeta recognition by antibodies PFA1 and WO2. All three antibodies recognize the same immunodominant B-cell epitope of Abeta. By similarity, residues Phe-Arg-His of Abeta would be a major portion of the C706 epitope. PMID- 20842636 TI - Acute lymphoblastic leukemia in a patient with type 1 Gaucher disease developing 1 year after discontinuation of enzyme replacement therapy. PMID- 20842635 TI - Development of prolactin receptor antagonists with reduced pH-dependence of receptor binding. AB - The cytokine hormone prolactin has a vast number of diverse functions. Unfortunately, it also exhibits tumor growth promoting properties, which makes the development of prolactin receptor antagonists a priority. Prolactin binds to its cognate receptor with much lower affinity at low pH than at physiological pH and since the extracellular environment around solid tumors often is acidic, it is desirable to develop antagonists that have improved binding affinity at low pH. The pK(a) value of a histidine side chain is ~6.8 making histidine residues obvious candidates for examination. From evaluation of known molecular structures of human prolactin, of the prolactin receptor and of different complexes of the two, three histidine residues in the hormone-receptor binding site 1 were selected for mutational studies. We analyzed 10 variants by circular dichroism spectroscopy, affinity and thermodynamic characterization of receptor binding by isothermal titration calorimetry combined with in vitro bioactivity in living cells. Histidine residue 27 was recognized as a central hot spot for pH sensitivity and conservative substitutions at this site resulted in strong receptor binding at low pH. Pure antagonists were developed earlier and the histidine mutations were introduced within such background. The antagonistic properties were maintained and the high affinity at low pH conserved. The implications of these findings may open new areas of research in the field of prolactin cancer biology. PMID- 20842637 TI - Diagnostic imaging in hematology. Gastrointestinal graft-versus-host disease due to donor lymphocyte administration for rising autologous chimerism. PMID- 20842638 TI - IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia. AB - IgM multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty-one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non-IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study. PMID- 20842639 TI - Predicting survival for diffuse large B-cell lymphoma patients using baseline neutrophil/lymphocyte ratio. AB - The neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor for survival in solid tumors. The N/L ratio at diagnosis as a prognostic factor for non-Hodgkin lymphoma (NHL) has not been studied. Thus, we studied N/L ratio at diagnosis as a prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL)treated with R-CHOP. From 2000 until 2007, 255 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP, and followed at Mayo Clinic, Rochester, were included in this study. With a median follow-up of 4.0 years (range: 0.3-9.0 years), patients with an N/L ratio<3.5 at diagnosis experienced a superior overall survival (OS) and progression-free survival (PFS) compared with those patient with an N/L ratio >= 3.5 at diagnosis. The median OS was not reached versus 6.8 years, P < 0.0001; and the median PFS was not reached versus 3.3 years, P < 0.0001, respectively. Multivariate analysis showed N/L ratio to be an independent prognostic factor for OS and PFS. This study suggests that baseline N/L ratio at diagnosis is a simple, inexpensive,standardized prognostic factor to assess clinical outcomes in DLBCL patients treated with R-CHOP. PMID- 20842640 TI - Diversity of DNA-hydrolyzing antibodies from the sera of autoimmune-prone MRL/MpJ lpr mice. AB - It has been shown for the first time that polyclonal IgG abzymes (Abzs) with DNase activity from the sera of autoimmune-prone MRL/MpJ-lpr mice can be separated by isoelectric focusing into many subfractions having the isoelectric points (pI) from 4.5 to 9, with the maximal activity for Abzs with pI = 6.5-9.0. Affinity chromatography on DNA-cellulose separated DNase IgGs into many subfractions demonstrating a range of affinities for DNA and different levels of the relative DNase activities (RDA) due to intrinsically bound metals and after addition of external Mg(2+) , Mn(2+) , Ca(2+), and Mg(2+) +Ca(2+). Some fractions significantly increase RDAs in the presence of external ions (Mg(2+) + Ca(2+) > Mg(2+) > Mn(2+) > Ca(2+)), while each of this cofactor can also inhibit or have no influence on the RDAs of another fractions. It is known that complexes of DNA with histones and other proteins of apoptotic cells are the primary immunogens in systemic lupus erythematosus (SLE). Bovine serum albumin (BSA) and methylated BSA (mBSA) increase the RDAs of only some fractions, while have no effect or inhibit other IgG fractions. The ratio of the RDAs in the presence of all metal ions, BSA, and mBSA was individual for every abzyme fraction. Mn(2+) and Ca(2+) stimulated accumulation of only relaxed form of supercoiled DNA (scDNA) in the case of all subfractions, while in the presence of Mg(2+) antibodies (Abs) of some subfractions (and in the presence of Mn(2+) +Ca(2+) all subfractions) produced relaxed DNA (rDNA) and linear DNA (linDNA) in a variable extent. The data obtained show that the polyclonal Abzs of mice may be a cocktail of Abs directly to DNA, RNA, and their complexes with proteins and anti-idiotypic Abs to active centers of different nucleases. The diversity of the physicochemical and kinetic characteristics of the Abzs seems to be significantly widened when pre diseased mice spontaneously develop the disease. PMID- 20842641 TI - Design, synthesis, and biological evaluation of 1,5-diaryl-1,2,4-triazole derivatives as selective cyclooxygenase-2 inhibitors. AB - A series of 1,5-diaryl-1,2,4-triazole derivatives were synthesized and evaluated as cyclooxygenase-2 (COX-2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b, 6b, 6c, 7c, 8b, 8d, 9c, and 9d have potent anti-inflammatory activity (P < 0.01), while compounds 6b, 6c, and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX-2 (COX-2 IC(50) = 0.37 uM; SI = 0.018), being equipotent to celecoxib (COX-2 IC(50) = 0.26 uM; SI = 0.015). In a rat carrageenan-induced paw edema assay, 6c exhibited moderate anti-inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX-2 in a similar mode to that of the known selective COX-2 inhibitor SC-558. PMID- 20842642 TI - Identifying persons feigning limitations in their competence to proceed in the legal process. AB - Accurate assessment of the response styles criminal defendants adopt when undergoing evaluations of their competence to proceed with the legal process is critical because some feign limitations in their abilities in an attempt to delay or avoid prosecution. This study examined the utility of the Inventory of Legal Knowledge (ILK) to identify persons motivated to feign competence related limitations. That the ILK has good potential as a screening tool is indicated by findings that the measure (1) has adequate test-retest reliability and (2) classified correctly the large majority of participants in two samples (i.e., college students and psychiatric patients) who completed the measure under "honest" or "fake bad" conditions. PMID- 20842643 TI - IL-10RA truncation mutations and Semite populations. PMID- 20842644 TI - MD-2: another important piece of the puzzle? PMID- 20842646 TI - Transient monoclonal CD3+ T large granular lymphocyte proliferation in a case of mantle cell lymphoma with Rituximab-associated late onset neutropenia. PMID- 20842645 TI - Renal manifestations and complications of inflammatory bowel disease. AB - Renal manifestations and complications are not rare in patients with inflammatory bowel disease (IBD) and may present as nephrolithiasis, amyloidosis, tubulointerstitial nephritis, and glomerulonephritis. Symptoms of renal impairment are not always specific and since the underlying bowel disease is preponderant, renal function deterioration may be underestimated. Additionally, medical treatment of patients with IBD such as aminosalicylates, cyclosporine, and tumor necrosis factor-alpha inhibitors can cause renal complications, although direct correlation to bowel disease is not always clear. The well documented renal manifestations and complications of IBD, as well as the possible renal side effects of new drugs, emphasize the need for periodic evaluation of renal function. New markers of renal function may facilitate early diagnosis and unravel the complex mechanisms responsible for kidney damage. The purpose of this review is to summarize the renal manifestations and complications as well as the markers of renal function utilized in IBD, attempting to shed more light on the pathophysiology of renal damage in IBD. PMID- 20842648 TI - Birth defects surveillance in Florida: infant death certificates as a case ascertainment source. AB - BACKGROUND: Completeness of case ascertainment is a concern for all birth defects registries and generally requires a multisource approach. Using infant death certificates as one case ascertainment source may identify cases of birth defects that would have otherwise been missed. We sought to examine the utility of adding infant death certificates to the Florida Birth Defect Registry's (FBDR) case ascertainment methods and to determine what factors are associated with the registry's failure to capture infants that die from birth defects. METHODS: FBDR cases from 1999 to 2006 were matched to a statewide linked birth-infant death file. Descriptive statistics were used to assess the FBDR's ability to capture infants with a birth defect-related cause of death (COD) and identify conditions most commonly missed. Factors associated with the FBDR's failure to capture an infant who died from a birth defect during the first year of life were identified with logistic regression models. RESULTS: There were 2558 (21.1%) infant deaths with birth defects listed as the underlying or an associated COD, of which the FBDR captured 73.3%. Most often missed defects included malformation of the coronary vessels, lung hypoplasia/dysplasia, anencephaly, and unspecified congenital malformations. Logistic regression identified gestational age/birth weight, age at death, autopsy decision, plurality, adequacy of prenatal care, and maternal nativity as factors associated with the FBDR's failure to capture an infant with a birth defect-related COD. CONCLUSIONS: Although the overall potential contribution of infant death certificates to the FBDR is small, this source contributes to the prevalence of specific defects. PMID- 20842647 TI - Magnetic resonance microscopy-based analyses of the brains of normal and ethanol exposed fetal mice. AB - BACKGROUND: The application of magnetic resonance microscopy (MRM) to the study of normal and abnormal prenatal mouse development has facilitated discovery of dysmorphology following prenatal ethanol insult. The current analyses extend this work, providing a regional brain volume-based description of normal brain growth and illustrating the consequences of gestational day (GD) 10 ethanol exposure in the fetal mouse. METHODS: To assess normal growth, control C57Bl/6J fetuses collected on GD 16, GD 16.5, and GD 17 were scanned using a 9.4-T magnet, resulting in 29-MUm isotropic resolution images. For the ethanol teratogenicity studies, C57Bl/6J dams were administered intraperitoneal ethanol (2.9 g/kg) at 10 days, 0 hr, and 10 days, 4 hr, after fertilization, and fetuses were collected for analyses on GD 17. From individual MRM scans, linear measurements and regional brain volumes were determined and compared. RESULTS: In control fetuses, each of the assessed brain regions increased in volume, whereas ventricular volumes decreased between GD 16 and GD 17. Illustrating a global developmental delay, prenatal ethanol exposure resulted in reduced body volumes, crown-rump lengths, and a generalized decrease in regional brain volumes compared with GD 17 controls. However, compared with GD 16.5, morphologically matched controls, ethanol exposure resulted in volume increases in the lateral and third ventricles as well as a disproportionate reduction in cortical volume. CONCLUSIONS: The normative data collected in this study facilitate the distinction between GD 10 ethanol-induced developmental delay and frank dysmorphology. This work illustrates the utility of MRM-based analyses for developmental toxicology studies and extends our knowledge of the stage-dependency of ethanol teratogenesis. PMID- 20842649 TI - Craniosynostosis and nutrient intake during pregnancy. AB - OBJECTIVE: To examine the association of craniosynostosis with maternal intake of folic acid-containing supplements and dietary nutrients. METHODS: The study included deliveries from 1997 to 2005 from the National Birth Defects Prevention Study. Nonsyndromic infants with craniosynostosis (n = 815) were compared to nonmalformed, population-based liveborn control infants (n = 6789), by estimating adjusted odds ratios (AORs) and 95% confidence intervals (CIs) from logistic regression models that included mother's age, parity, race-ethnicity, education, body mass index, smoking, alcohol, fertility treatments, plurality, and study center. We compared quartiles of intake and specified nutrients as continuous. RESULTS: Intake of folic acid-containing supplements was not associated with craniosynostosis (AORs were close to 1). Analyses of dietary nutrients were restricted to mothers who took supplements during the first trimester (i.e., most women). Based on continuous specifications of nutrients, sagittal synostosis risk was significantly lower among women with higher intake of riboflavin and vitamins B6, E, and C; metopic synostosis risk was significantly higher among women with higher intakes of choline and vitamin B12; and coronal synostosis risk was significantly lower among women with higher intake of methionine and vitamin C. As examples, AORs for sagittal synostosis among women with intakes of vitamin B6 and riboflavin in the highest versus lowest quartiles were 0.4 (95% CI, 0.2-0.6) and 0.5 (95% CI, 0.3-0.7), respectively. CONCLUSION: This analysis suggests that dietary intake of certain nutrients may be associated with craniosynostosis, and results may vary by suture type. PMID- 20842650 TI - Maternal periconceptional exposure to cigarette smoking and alcohol consumption and congenital diaphragmatic hernia. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a major birth defect that occurs when abdominal organs herniate through a diaphragmatic opening into the thoracic cavity and is associated with high mortality (>50%). The etiology of CDH is not well understood. METHODS: Using data from the National Birth Defects Prevention Study, we examined associations between CDH and maternal periconceptional exposure (1 month before through the third month of pregnancy) to cigarette smoking and alcohol. Interview reports of exposures were provided by mothers of CDH (n = 503) and unaffected control (n = 6703) infants delivered from October 1997 through December 2005. Any exposure (yes/no), as well as quantity (average number of cigarettes or drinks), type (active/passive smoking; beer, wine, distilled spirits), and duration (e.g., number of months exposed) were examined. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated for all CDH cases combined, selected subtypes (Bochdalek, Morgagni, not otherwise specified), and phenotypes (infants with/without additional major birth defects). RESULTS: The aOR for any smoking was nonsignificantly elevated for all CDH cases combined. Odds of any smoking was significant for isolated Bochdalek CDH (aOR, 1.9; 95% CI, 1.2-3.0). The aORs associated with all measures of alcohol consumption were near unity for each CDH category examined. Stratification of smoking exposure by alcohol consumption and stratification of alcohol consumption by smoking exposure did not appreciably change the aORs. CONCLUSIONS: These findings identified periconceptional smoking exposure as a potential risk factor for CDH. Future studies need to confirm our findings and explore possible pathways accounting for the teratogenic effect of smoking. PMID- 20842651 TI - The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis. AB - Retinoic acid (RA) is a pleiotropic derivative of vitamin A, or retinol, which is responsible for all of the bioactivity associated with this vitamin. The teratogenic influences of vitamin A deficiency and excess RA in rodents were first observed more than 50 years ago. Efforts over the last 15-20 years have refined these observations by defining the molecular mechanisms that control RA availability and signaling during murine embryonic development. This review will discuss our current understanding of the role of RA in teratogenesis, with specific emphasis on the essential function of the RA catabolic CYP26 enzymes in preventing teratogenic consequences caused by uncontrolled distribution of RA. Particular focus will be paid to the RA-sensitive tissues of the caudal and cranial regions, the limb, and the testis, and how genetic mutation of factors controlling RA distribution have revealed important roles for RA during embryogenesis. PMID- 20842652 TI - Effect of temperature on intense green emitting Na2Ca(PO4)F:Mn2+ phosphor. AB - An intense green luminescent Na2Ca(PO4)F:Mn2+ phosphor has been prepared at high temperature by reduction treatment in a charcoal environment. The emission band of Mn2+ was obtained at around 522 nm (green) under 259 nm excitation. Enhancement in emission intensity arising from the thermal treatment is reported. The intense emission of the spectrum was assigned to electronic transitions 4T1 > 6A1 of Mn2+ ions. Intense PL emission suggested that temperature employed plays an important role in the present matrix. X-ray diffraction pattern, photoluminescence and morphology by SEM of the host lattice of phosphors at different temperatures have been reported in this paper. The results obtained show that the present phosphor has potential for application in green emitting phosphors for the lamp industry. PMID- 20842653 TI - Chemiluminescence determination of antioxidant property of Zizyphus mistol and Prosopis alba during oxidative stress generated in blood by Hemolytic Uremic Syndrome-producing Escherichia coli. AB - This study was undertaken to elucidate the antioxidant effect of Zizyphus mistol and Prosopis alba, with the hypothesis that these fruits can counteract the induction of reactive oxygen species (ROS) caused by toxins produced by Escherichia coli. In the search of nutrients effective against the Hemolytic Uremic Syndrome (HUS), we detected by chemiluminescence a protective role of both plants, due to their natural antioxidants significantly decreasing the levels of ROS induced by toxins from E. coli in blood. The ferric reducing antioxidant power (FRAP) was found to be higher in Z. mistol than in P. alba. The chemical analyses of the phenols and flavonoids present in the fruit extracts indicated that the FRAP correlated with the amount of phenolic compounds, but not with the flavonoids analyzed. Both fruits studied reduce the induction of ROS, and in this way help to prevent the development of complications related to oxidative stress generated in the blood of patients with HUS. PMID- 20842654 TI - Cardiac intervention using high-intensity focused ultrasound: creation of interatrial communication in beating heart of an anesthetized rabbit. AB - OBJECTIVE: Current fetal cardiac intervention for restrictive atrial septum is invasive and technically demanding. We investigated the feasibility of computer assisted high-intensity focused ultrasound (HIFU) for cardiac intervention on the atrial septum of a beating heart. METHODS: To create an interatrial communication in the beating heart of nine anesthetized rabbits, the heart was exposed surgically and placed under a water-filled tank, in contact with the tank's membranous base. A HIFU transducer (3.3 MHz) coupled with a diagnostic ultrasound probe (10.0 MHz) was placed in the tank over the beating heart. The focus of the HIFU transducer was set so that it could create a hole in the target area on the atrial septum during the early diastolic phase. HIFU delivery was controlled based on ultrasound images captured with real-time image-recognition software. We attempted to create interatrial communication using HIFU and assessed the cardiac tissue specimen pathologically. RESULTS: In eight of nine rabbits, small holes in the atrial septum were successfully created. Serious complications occurred in two animals: a fatal atrioventricular block in one and a cardiac tamponade in the other. CONCLUSION: HIFU combined with a computer-assisted imaging system might be useful to create interatrial communication in beating hearts. This procedure may be helpful for making current fetal cardiac intervention less invasive. PMID- 20842655 TI - Practice guidelines for performance of the routine mid-trimester fetal ultrasound scan. PMID- 20842656 TI - Selection of CHO host cell subclones with increased specific antibody production rates by repeated cycles of transient transfection and cell sorting. AB - Optimization of host cell lines both for transient and stable protein production is typically hampered by the inherent heterogeneity of cells within a population. This heterogeneity is caused not only by "hard fact" gene mutations, but also by subtle differences in the cellular network of regulation, which may include epigenetic variations. Taking advantage of this heterogeneity, we sorted for naturally occurring variants of CHO-K1 and CHO-S host cells that possess an improved cellular machinery for transient antibody production. The long-term goal of this study was both to identify host cells that yield recombinant cell lines with on average higher productivity, but also to study the molecular differences that characterize such cells, independent of the site of gene integration or gene amplification. To identify such cells we optimized the procedure for transient transfection by electroporation to a degree that gave uniform transfer of plasmid DNA into nearly 100% of the cells and resulted in reproducible average productivities, with a standard deviation of 16% between independent experiments. Using this optimized protocol, the 1% of cells with the highest specific productivity was sorted and subcloned with a cold capture secretion assay. Upon re-transfection, the resulting subclones showed the same specific productivity as their respective parental cell line. To enrich for cells with potentially stable improved properties, the 1% highest producers were sorted three times, 2 days after transient transfection each, and the enriched population was again sorted into microtiter plates for subcloning. For each of the two parental cell lines tested, three subclones were obtained that had a threefold higher specific productivity after transient transfection. This property was stable for approximately 3 months, indicating that the changes in productivity were regulatory and not mutational. PMID- 20842657 TI - Recent developments in top-emitting organic light-emitting diodes. AB - Organic light-emitting diodes (OLEDs) have rapidly progressed in recent years due to their unique characteristics and potential applications in flat panel displays. Significant advancements in top-emitting OLEDs have driven the development of large-size screens and microdisplays with high resolution and large aperture ratio. After a brief introduction to the architecture and types of top-emitting OLEDs, the microcavity theory typically used in top-emitting OLEDs is described in detail here. Then, methods for producing and understanding monochromatic (red, green, and blue) and white top-emitting OLEDs are summarized and discussed. Finally, the status of display development based on top-emitting OLEDs is briefly addressed. PMID- 20842658 TI - Infrared colloidal quantum dots for photovoltaics: fundamentals and recent progress. AB - Colloidal quantum dots (CQDs) are solution-processed semiconductors of interest in low-cost photovoltaics. Tuning of the bandgap of CQD films via the quantum size effect enables customization of solar cells' absorption profile to match the sun's broad visible- and infrared-containing spectrum reaching the earth. Here we review recent progress in the realization of low-cost, efficient solar cells based on CQDs. We focus in particular on CQD materials and approaches that provide both infrared and visible-wavelength solar power conversion CQD photovoltaics now exceed 5% solar power conversion efficiency, achieved by the introduction of a new architecture, the depleted-heterojunction CQD solar cell, that jointly maximizes current, voltage, and fill factor. CQD solar cells have also seen major progress in materials processing for stability, recently achieving extended operating lifetimes in an air ambient. We summarize progress both in device operation and also in gaining new insights into materials properties and processing - including new electrical contact materials and deposition techniques, as well as CQD synthesis, surface treatments, film-forming technologies - that underpin these rapid advances. PMID- 20842659 TI - Engineering the extracellular environment: Strategies for building 2D and 3D cellular structures. AB - Cell fate is regulated by extracellular environmental signals. Receptor specific interaction of the cell with proteins, glycans, soluble factors as well as neighboring cells can steer cells towards proliferation, differentiation, apoptosis or migration. In this review, approaches to build cellular structures by engineering aspects of the extracellular environment are described. These methods include non-specific modifications to control the wettability and stiffness of surfaces using self-assembled monolayers (SAMs) and polyelectrolyte multilayers (PEMs) as well as methods where the temporal activation and spatial distribution of adhesion ligands is controlled. Building on these techniques, construction of two-dimensional cell sheets using temperature sensitive polymers or electrochemical dissolution is described together with current applications of these grafts in the clinical arena. Finally, methods to pattern cells in three dimensions as well as to functionalize the 3D environment with biologic motifs take us one step closer to being able to engineer multicellular tissues and organs. PMID- 20842660 TI - Mesoporous LiFePO4/C nanocomposite cathode materials for high power lithium ion batteries with superior performance. PMID- 20842661 TI - Moving to a solid-state configuration: a valid approach to making lithium-sulfur batteries viable for practical applications. PMID- 20842662 TI - Photoresist templates for wafer-scale defect-free evaporative lithography. PMID- 20842663 TI - External-strain induced insulating phase transition in VO2nanobeam and its application as flexible strain sensor. PMID- 20842664 TI - Surface properties dictate uptake, distribution, excretion, and toxicity of nanoparticles in fish. PMID- 20842665 TI - Viral coat proteins as flexible nano-building-blocks for nanoparticle encapsulation. AB - Viral capsid-nanoparticle hybrid structures offer new opportunities for nanobiotechnology. We previously generated virus-based nanoparticles (VNPs) of simian virus 40 (SV40) containing quantum dots (QDs) for cellular imaging. However, as an interesting issue of nano-bio interfaces, the mechanism of nanoparticle (NP) encapsulation by viral coat proteins remains unclear. Here, four kinds of QDs with the same core/shell but different surface coatings are tested for encapsulation. All the QDs can be encapsulated efficiently and there is no correlation between the encapsulation efficiency and the surface charge of the QDs. All the SV40 VNPs encapsulating differently modified QDs show similar structures, fluorescence properties, and activity in entering living cells. These results demonstrate the flexibility of SV40 major capsid protein VP1 in NP encapsulation and provide new clues to the mechanism of NP packaging by viral shells. PMID- 20842666 TI - Serum miRNA-21: elevated levels in patients with metastatic hormone-refractory prostate cancer and potential predictive factor for the efficacy of docetaxel based chemotherapy. AB - BACKGROUND: miR-21 has been recognized as an "onco-microRNA" with the activity of negatively modulating the expression of tumor-suppressor genes. However, its role in prostate cancer (CaP) has not been well-documented. We designed this study to assess the potential function of serum miR-21 in the progression of CaP. METHODS: Serum samples of 56 patients, including 20 patients with localized CaP, 20 with androgen-dependent prostate cancer (ADPC), 10 with hormone-refractory prostate cancer (HRPC), and 6 with benign prostatic hyperplasia (BPH), were collected for the measurement of miR-21. The 10 HRPC patients were administered docetaxel-based chemotherapy. Quantification of miR-21 was assayed by specific TaqMan qRT-PCR. RESULTS: Serum miR-21 level was found to correlate to serum PSA level in patients with ADPC and HRPC, P = 0.012 and 0.049, respectively. There was no significant difference in serum miR-21 level between BPH, localized CaP and ADPC with PSA level <4 ng/ml. Higher levels of miR-21 were detected in patients with HRPC and ADPC with PSA level >4 ng/ml. Six of the 10 HRPC patients reached partial remission with a decreased PSA level of >50% after chemotherapy. Serum miR-21 levels were higher in patients who were resistant to docetaxel-based chemotherapy when compared to those sensitive to chemotherapy, P = 0.032. CONCLUSIONS: Serum miR-21 levels are elevated in HRPC patients, especially in those resistant to docetaxel-based chemotherapy. It may be applicable as a marker to indicate the transformation to hormone refractory disease, and a potential predictor for the efficacy of docetaxel-based chemotherapy. PMID- 20842667 TI - ETS1 regulates NKX3.1 5' promoter activity and expression in prostate cancer cells. AB - BACKGROUND: NKX3.1 controls the differentiation and proliferation of prostatic epithelial cells both during development and in the adult, while its expression is frequently downregulated in prostate cancers. Transcriptional control of NKX3.1 expression and in particular, factors that function via the NKX3.1 5' proximal promoter are poorly characterized. METHODS: Deletion reporter analyses, bioinformatics, electromobility shift assays (EMSA), chromatin immunoprecipitation (ChIP) and Western blotting were performed to identify and functionally characterize sites of transcription factor binding within the initial 2,062 bp of the NKX3.1 5' promoter. RESULTS: Deletion reporter studies of the 2,062 bp NKX3.1 5' promoter sequence localized positive transcriptional activity between -1069 and -993. Bioinformatic analyses identified the presence of two overlapping ETS1 binding sites within this region, designated EBS1 and EBS2, which exhibited 82% and 74% homology, respectively, to the ETS consensus binding sequence. EMSA and supershift assays indicated binding of both endogenous ETS1 and a recombinant GST-ETS1 protein solely to EBS1, a result that was confirmed in vivo by ChIP analysis. ETS1 overexpression transactivated NKX3.1 promoter reporter activity and upregulated endogenous NKX3.1 mRNA and protein levels in the LNCaP prostate cancer cell line, demonstrating a functional role for ETS1 in the regulation of NKX3.1 expression. CONCLUSIONS: ETS1 upregulation of NKX3.1 expression in LNCaP cells is mediated in part via its interaction with an EBS located in the NKX3.1 5' proximal promoter. ETS1 may regulate NKX3.1 during prostate development, with the aberrant ETS1 expression and cellular localization frequently observed in human prostate tumors potentially contributing to the abnormal expression of NKX3.1. PMID- 20842668 TI - Multipotent adipose stromal cells and breast cancer development: Think globally, act locally. AB - It has long been appreciated that stromal cells within the breast tumor microenvironment contribute to mammary carcinogenesis. However, to date, very little is known regarding the role of local adipose-derived stromal cells (ASCs) in the development of breast cancer. Based on pathological, epidemiological and experimental data, we postulate that breast-derived ASCs are unique mesenchymal stem-like cells that play a critical role in the development of breast cancer and discuss the global implications of this working model in terms of breast cancer prevention, early detection, and new targeted therapies. PMID- 20842669 TI - Polymorphisms of death pathway genes FAS and FASL and risk of nasopharyngeal carcinoma. AB - The FAS receptor/ligand system is a key regulator of apoptotic cell death and corruption of this signaling pathway has been shown to participate in carcinogenesis. Functional polymorphisms in the FAS (FAS -1377G/A) and FASL (FASL -844T/C) genes alter their transcriptional activity. Therefore, we examined the association between these polymorphisms and the risk of developing nasopharyngeal carcinoma (NPC). FAS -1377G/A and FASL -844T/C genotypes were determined by PCR based RFLP analysis in 582 patients with NPC and 613 frequency-matched controls. We observed a significantly increased risk of NPC associated with the FAS -1377AA genotype [odds ratio (OR) = 1.69, 95% confidence interval (CI) = 1.21-2.35] compared with the FAS -1377 GG genotype. In addition, elevated NPC risk was also found among subjects carrying both FAS -1377AA and FASL -844CC genotypes compared with both FAS -1377GG and FASL -844CT or -844TT, the OR was 2.39 (95% CI = 1.50 3.79). After stratification by smoking status, heavy smokers (>=15 pack-years) carrying FAS -1377AA genotype had an increased risk of NPC compared with FAS 1377GG genotype (OR = 3.48, 95% CI = 1.66-7.30). Furthermore, we observed a statistically significant interaction between the two polymorphisms and heavy smoking status (OR = 5.92, 95% CI = 1.91-18.3). Our study provides the first evidence that functional FAS -1377 G/A and FASL -844 T/C polymorphisms are associated with the risk of NPC, and this association is especially noteworthy in tobacco smokers. PMID- 20842670 TI - Reversible photoswitching of rotaxane character and interplay of thermodynamic stability and kinetic lability in a self-assembling ring-axle molecular system. AB - We have designed, synthesized, and investigated a self-assembling system that can be reversibly interconverted between thermodynamically stable (pseudorotaxane) and kinetically inert (rotaxane) forms by light irradiation. The system is composed of a dibenzo[24]crown-8 ring and an axle comprised of a dibenzylammonium recognition site and two azobenzene end groups. The isomeric form of the azobenzene units of the axle has a little influence on the stability constants of the respective pseudorotaxanes but greatly affects the threading-dethreading rate constants. In fact, equilibration of the ring and the axle in its EE isomeric form occurs within seconds in acetonitrile at room temperature, whereas the ZZ axle threads-dethreads the ring at least four orders of magnitude slower. Moreover, we show that a change in the stability of the complex, achieved by deprotonating the dibenzylammonium recognition site on the axle, affects its kinetic behavior. We compare the results of these experiments with those observed upon dethreading the (pseudo)rotaxane by using a competitive guest for the ring, an approach which does not inherently destabilize the ring-axle interaction. This study outlines a general strategy for the reversible photochemical control of motion kinetics in threaded and interlocked compounds and constitutes a starting point for the construction of multicomponent structures that can behave as photochemically driven nanomachines. PMID- 20842671 TI - Functionalized alkynylplatinum(II) polypyridyl complexes for use as sensitizers in dye-sensitized solar cells. AB - A series of platinum(II) alkynyl-based sensitizers has been synthesized and found to show light-to-electricity conversion properties. These dyes were developed as sensitizers for the application in nanocrystalline TiO(2) dye-sensitized solar cells (DSSCs). Their photophysical and electrochemical properties were studied. The excited-state property was probed using nanosecond transient absorption spectroscopy, which showed the formation of a charge-separated state that arises from the intramolecular photoinduced charge transfer from the platinum(II) alkynylbithienylbenzothiadiazole moiety (donor) to the polypyridyl ligand (acceptor). A lifetime of 3.4 MUs was observed for the charge-separated state. A dye-sensitized solar cell based on one of the complexes showed a short-circuit photocurrent of 7.12 mA cm(-2), an open circuit voltage of 780 mV, and a fill factor of 0.65, thus giving an overall power conversion efficiency of 3.6%. PMID- 20842672 TI - Controlled dispersion and purification of protein-carbon nanotube conjugates using guanidine hydrochloride. AB - For the development of biofunctional carbon nanotubes for biosensors, drug carriers, and nanobiocatalysts, their aggregation and biofouling in aqueous solutions are crucial problems because this behavior leads to a reduction of their excellent optical and electrical properties and nanoscale size effects. This paper presents a new method for enhancing the dispersibility of protein carbon nanotube conjugates and for exfoliating the protein from the carbon nanotube sidewalls through controlling the concentration of guanidine hydrochloride (Gdn.HCl) in the solution. In medium concentrations (2-3 M) of Gdn.HCl, the dispersibility of protein-carbon nanotube conjugates was found to be substantially increased without denaturation or aggregation of the proteins. At higher concentrations (>6 M) of Gdn.HCl, pristine carbon nanotubes were precipitated instantly as a result of dissociation of the protein. These phenomena indicate that Gdn.HCl functions not only as a dispersion adjuvant for biofunctional protein-carbon nanotube conjugates, but also as a cleaning agent for the purification of biofouled carbon nanotubes. The dissociation concentrations of Gdn.HCl were higher than the midpoint of protein denaturation, suggesting that protein adsorption on carbon nanotubes is more stable than protein folding toward Gdn.HCl. PMID- 20842673 TI - A versatile iron-catalyzed protocol for the one-pot synthesis of isoxazoles or isoxazolines from the same propargylic alcohols. AB - The use N-sulfonyl-protected hydroxylamines as bi-nucleophiles in iron-catalyzed propargylic substitutions allows the selective one-pot synthesis of four classes of substituted isoxazoles or isoxazolines from the same propargylic alcohols (21 examples) by simply tuning the nature of the base. By using an iron(III) catalyst and a base such as triethylamine (3 equiv), isoxazoles 3 are obtained in good isolated yields (56-95%), whereas N-sulfonyl-protected isoxazolines 6 are selectively obtained (77-93% yield) by using iron and gold catalysts in the presence of a catalytic amount of pyridine (10 mol%). PMID- 20842674 TI - Zeolites efficiently promote the cyclization of nonactivated unsaturated alcohols. PMID- 20842675 TI - Synthesis and molecular modeling of a nitrogen mustard DNA interstrand crosslink. PMID- 20842677 TI - Inorganic arsenite inhibits IgE receptor-mediated degranulation of mast cells. AB - Millions of people worldwide are exposed to arsenic (As), a toxicant which increases the risk of various cancers, cardiovascular disease and several other health problems. Arsenic is a potent endocrine disruptor, including of the estrogen receptor. It was recently shown that environmental estrogen-receptor disruptors can affect the signaling of mast cells, which are important players in parasite defense, asthma and allergy. Antigen (Ag) or allergen crosslinking of IgE-bound receptors on mast cells leads to signaling, culminating in degranulation, the release of histamine and other mediators. Because As is an endocrine disruptor and because endocrine disruptors have been found to affect degranulation, here we have tested whether sodium arsenite affects degranulation. Using the rat basophilic leukemia (RBL) mast cell model, we have measured degranulation in a fluorescence assay. Arsenic alone had no effect on basal levels of degranulation. However, As strongly inhibited Ag-stimulated degranulation at environmentally relevant concentrations, in a manner that is very dependent on concentrations of both As and Ag. The concentrations of As effective at inhibiting degranulation were not cytotoxic. This inhibition may be a mechanism underlying the traditional Chinese medicinal use of As to treat asthma. These data indicate that As may inhibit the ability of humans to fight off parasitic disease. PMID- 20842676 TI - Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. AB - Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. PMID- 20842678 TI - Praeruptorin A inhibits lipopolysaccharide-induced inflammatory response in murine macrophages through inhibition of NF-kappaB pathway activation. AB - Praeruptorin A (PA) is a pyranocoumarin compound isolated from the dried root of Peucedanum praeruptorum Dunn (Umbelliferae). However, the antiinflammatory effect of PA has not been reported. The present study investigated the antiinflammatory effect of PA in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. PA significantly inhibited the LPS-induced production of nitric oxide (NO), interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). The mRNA and protein expressions of inducible nitric oxide synthase (iNOS), IL-1beta and TNF-alpha were also suppressed by this compound. Further study showed that PA decreased the cytoplasmic loss of inhibitor kappaB-alpha (IkappaB-alpha) protein and inhibited the translocation of NF-kappaB from cytoplasm to nucleus. Taken together, the results suggest that PA may exert antiinflammatory effects in vitro in LPS-stimulated RAW 264.7 macrophages through inhibition of NF-kappaB signal pathway activation. PMID- 20842679 TI - Does inflammation play a role in kava hepatotoxicity? AB - The pathophysiology of kava hepatotoxicity remains inconclusive. There is circumstantial evidence for the roles of toxic metabolites, inhibition of cyclooxygenase (COX) enzymes and depletion of liver glutathione. Pharmacogenomic effects are likely, particularly for Cytochrome P450 genes. Experimental and clinical cases of hepatotoxicity show evidence of hepatitis. The question remains whether this inflammation is caused by components of kava directly, or indirectly due to the downstream effects. PMID- 20842680 TI - Valuing health technologies at NICE: recommendations for improved incorporation of treatment value in HTA. PMID- 20842681 TI - IQWiG methods--a response to two critiques. PMID- 20842682 TI - Some essential clarifications: IQWiG comments on two critiques of the efficiency frontier approach. PMID- 20842683 TI - Electrospun functionalized polyaniline copolymer-based nanofibers with potential application in tissue engineering. AB - Nanofibrous blends of HCl-doped poly(aniline-co-3-aminobenzoic acid) (3ABAPANI) copolymer and poly(lactic acid) (PLA) were fabricated by electrospinning solutions of the polymers, in varying relative proportions, in dimethyl sulfoxide/tetrahydrofuran mixture. The morphology, mechanical and electrical properties of the nanofibers were characterized and an assessment of their bioactivity performed. To assess cell morphology and biocompatibility, pure PLA and 3ABAPANI-PLA nanofibrous mats were deposited in the form of three-dimensional networks with a high degree of connectivity, on glass substrates, and their ability to promote proliferation of COS-1 fibroblast cells was determined. The nanofibrous electrospun 3ABAPANI-PLA blends gave enhanced cell growth, potent antimicrobial capability against Staphylococcus aureus and electrical conductivity. This new class of nanofibrous blends can potentially be employed as tissue engineering scaffolds, and in particular have showed promise as the basis of a new generation of functional wound dressings that may eliminate deficiencies of currently available antimicrobial dressings. PMID- 20842685 TI - Rhinorrhea: a common nondopaminergic feature of Parkinson's disease. AB - We compared the frequency of rhinorrhea between 34 Parkinson's disease (PD) subjects and 15 normal controls (NC) and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using [(11)C]dihydrotetrabenazine (DTBZ) brain positron emission tomography imaging. Sixty-eight percent (23 of 34) of PD subjects reported rhinorrhea of any cause compared with 27% (4 of 15) of NC (chi(2) = 7.07, P = 0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12 of 34) of PD versus 7% (1 of 15) of NC (chi(2) = 4.38, P = 0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or nonmotor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, chi(2) = 5.85, P = 0.02). Rhinorrhea is a common nondopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD. PMID- 20842684 TI - Risk prediction using genome-wide association studies. AB - Over the last few years, many new genetic associations have been identified by genome-wide association studies (GWAS). There are potentially many uses of these identified variants: a better understanding of disease etiology, personalized medicine, new leads for studying underlying biology, and risk prediction. Recently, there has been some skepticism regarding the prospects of risk prediction using GWAS, primarily motivated by the fact that individual effect sizes of variants associated with the phenotype are mostly small. However, there have also been arguments that many disease-associated variants have not yet been identified; hence, prospects for risk prediction may improve if more variants are included. From a risk prediction perspective, it is reasonable to average a larger number of predictors, of which some may have (limited) predictive power, and some actually may be noise. The idea being that when added together, the combined small signals results in a signal that is stronger than the noise from the unrelated predictors. We examine various aspects of the construction of models for the estimation of disease probability. We compare different methods to construct such models, to examine how implementation of cross-validation may influence results, and to examine which single nucleotide polymorphisms (SNPs) are most useful for prediction. We carry out our investigation on GWAS of the Welcome Trust Case Control Consortium. For Crohn's disease, we confirm our results on another GWAS. Our results suggest that utilizing a larger number of SNPs than those which reach genome-wide significance, for example using the lasso, improves the construction of risk prediction models. PMID- 20842686 TI - Magnetic resonance spectroscopy in two siblings with chorea-acanthocytosis. PMID- 20842687 TI - Severe dystonic encephalopathy without hyperphenylalaninemia associated with an 18-bp deletion within the proximal GCH1 promoter. AB - In a recent GCH1 mutation screen, an 18-bp deletion was identified within the proximal promoter in two patients with early-onset Parkinson's disease. The mutation removes cAMP response element critical for adequate GTP cyclohydrolase I activity in selected cell types, including dopaminergic neurons, but its biological significance was unclear as it was also detected in one control individual. We present an 11-year-old boy with infantile-onset severe dystonic encephalopathy without hyperphenylalaninemia whom we found compound heterozygous for the same promoter GCH1 deletion and another common missense mutation associated with classical dopa-responsive dystonia. Extensive diagnostic work up excluded other causes of dystonia, and comprehensive mutation scan did not reveal any additional GCH1 sequence variations, supporting the association between the promoter deletion and disease phenotype. PMID- 20842688 TI - Camptocormia and myopathy. PMID- 20842690 TI - Use of smell test identification in Parkinson's disease in Mexico: a matched case control study. AB - Smell tests can be useful in the differential diagnosis of Parkinson's disease (PD) but are affected by cultural factors. Currently there is no smell test tailored for the Mexican population but the brief smell identification test (B SIT) was created as a cross-cultural SIT. We have created a translation of this test into Spanish adapted to the Mexican population and have applied it to 70 PD patients and 70 age- and gender-matched controls. The B-SIT differentiated PD and controls with 71.4% sensitivity and 85.7% specificity, when subjects were divided into two age groups. PMID- 20842689 TI - Familial aggregation of Parkinson's disease in a multiethnic community-based case control study. AB - To assess the familial aggregation of Parkinson's disease (PD), we compared the cumulative incidence of PD among first-degree relatives of PD cases and controls. We identified newly diagnosed patients with PD (n = 573) during 1994 to 1995 within Kaiser Permanente Medical Care Program of Northern California and recruited 496 cases (87%) for the case-control study. Of 720 eligible controls matched by birth year and sex to cases, 541 (75%) agreed to participate. Information on family history of PD and other neurodegenerative diseases was obtained by in-person structured interview. We used the reconstructed cohort approach that provides a better estimate of the risk. The cumulative incidence of PD was significantly higher among relatives of PD patients compared with relatives of controls (2.0 vs. 0.7%; relative risk (RR) = 3.4, 95% confidence interval (CI) 1.9-5.9; P = 0.0001). The degree of familial aggregation was higher among first-degree relatives of Hispanic PD cases compared with Hispanic controls (3.7% vs. 0.4%; RR = 8.5, 95% CI 1.0-68.9) than it was among non-Hispanic Caucasian cases and controls (2.0% vs. 0.8%; RR = 2.7, 95% CI 1.5-5.1; P = 0.02). The familial aggregation of PD was stronger among the siblings of PD cases (RR = 5.4, 95% CI 1.8-16.0) than among parents (RR = 2.7, 95% CI 1.3-5.2). The incidence and familial aggregation of PD is highest among Hispanics, warranting further studies of genetic and environmental risk factors in the Hispanic population. PMID- 20842691 TI - Eye movement disorders in ATP13A2 mutation carriers (PARK9). PMID- 20842692 TI - Reduced but not oxidized cerebrospinal fluid glutathione levels are lowered in Lewy body diseases. AB - Reduced (GSH(R)) but not oxidized glutathione (GSSG) has been shown to be dramatically altered in the substantia nigra (SN) of Lewy body disease (LBD) patients post mortem; but up to now, there is no convincing evidence that these changes can be monitored in vivo. We investigated GSH(R) and GSSG in rapidly processed cerebrospinal fluid (CSF) and plasma samples of 80 LBD and 35 control subjects and detected reduced CSF GSH(R) levels in LBD subjects. The reduction was negatively associated with age but not with disease-associated parameters. Plasma GSH(R), CSF GSSG, and plasma GSSG levels did not significantly differ between the groups. Our findings confirm the results from neuropathologic studies, which demonstrated an alteration of the glutathione system in LBD. We hypothesize that alterations of the glutathione system occur in a very early stage of the disease or may even represent a risk marker for LBD. PMID- 20842693 TI - PRICKLE1 progressive myoclonus epilepsy in Southern Italy. PMID- 20842694 TI - Testing for non-random mating: evidence for ancestry-related assortative mating in the Framingham heart study. AB - Population stratification leads to a predictable phenomenon-a reduction in the number of heterozygotes compared to that calculated assuming Hardy-Weinberg Equilibrium (HWE). We show that population stratification results in another phenomenon-an excess in the proportion of spouse-pairs with the same genotypes at all ancestrally informative markers, resulting in ancestrally related positive assortative mating. We use principal components analysis to show that there is evidence of population stratification within the Framingham Heart Study, and show that the first principal component correlates with a North-South European cline. We then show that the first principal component is highly correlated between spouses (r = 0.58, p = 0.0013), demonstrating that there is ancestrally related positive assortative mating among the Framingham Caucasian population. We also show that the single nucleotide polymorphisms loading most heavily on the first principal component show an excess of homozygotes within the spouses, consistent with similar ancestry-related assortative mating in the previous generation. This nonrandom mating likely affects genetic structure seen more generally in the North American population of European descent today, and decreases the rate of decay of linkage disequilibrium for ancestrally informative markers. PMID- 20842695 TI - Mouse Rad9b is essential for embryonic development and promotes resistance to DNA damage. AB - RAD9 participates in promoting resistance to DNA damage, cell cycle checkpoint control, DNA repair, apoptosis, embryogenesis, and regulation of transcription. A paralogue of RAD9 (named RAD9B) has been identified. To define the function of mouse Rad9b (Mrad9b), embryonic stem (ES) cells with a targeted gene deletion were constructed and used to generate Mrad9b mutant mice. Mrad9b(-/-) embryos are resorbed after E7.5 while some of the heterozygotes die between E12.5 and a few days after birth. Mrad9b is expressed in embryonic brain and Mrad9b(+/-) embryos exhibit abnormal neural tube closure. Mrad9b(-/-) mouse embryonic fibroblasts are not viable. Mrad9b(-/-) ES cells are more sensitive to gamma rays and mitomycin C than Mrad9b(+/+) controls, but show normal gamma-ray-induced G2/M checkpoint control. There is no evidence of spontaneous genomic instability in Mrad9b(-/-) cells. Our findings thus indicate that Mrad9b is essential for embryonic development and mediates resistance to certain DNA damaging agents. PMID- 20842696 TI - Beyond the closed suture in apert syndrome mouse models: evidence of primary effects of FGFR2 signaling on facial shape at birth. AB - Apert syndrome is a congenital disorder caused mainly by two neighboring mutations on fibroblast growth factor receptor 2 (FGFR2). Premature closure of the coronal suture is commonly considered the identifying and primary defect triggering or preceding the additional cranial malformations of Apert phenotype. Here we use two transgenic mouse models of Apert syndrome, Fgfr2(+/S252W) and Fgfr2(+/P253R), to explore variation in cranial phenotypes in newborn (P0) mice. Results show that the facial skeleton is the most affected region of the cranium. Coronal suture patency shows marked variation that is not strongly correlated with skull dysmorphology. The craniofacial effects of the FGFR2 mutations are similar, but Fgfr2(+/S252W) mutant mice display significantly more severe dysmorphology localized to the posterior palate. Our results demonstrate that coronal suture closure is neither the primary nor the sole locus of skull dysmorphology in these mouse models for Apert syndrome, but that the face is also primarily affected. PMID- 20842697 TI - Diagnosis of hepatocellular carcinoma in cirrhosis by dynamic contrast imaging: the importance of tumor cell differentiation. AB - Dynamic contrast imaging techniques are considered the standard of care for the radiological diagnosis of hepatocellular carcinoma (HCC) in cirrhosis. However, the accuracy of radiological diagnosis depends largely on the degree of arterial hypervascularization, which increases with tumor size. Owing to the interplay and prognostic relevance of tumor vascularization and cell differentation, we asked ourselves whether tumor grade also affects the outcome of radiological diagnosis. Sixty-two HCCs (47 of which measured 1-2 cm) were consecutively detected in 59 patients with compensated cirrhosis under surveillance with ultrasound and confirmed by way of echo-guided biopsy and concurrent investigations with contrast-enhanced ultrasound (CE-US), computed tomography (CT), and gadolinium magnetic resonance imaging (MRI). Tumor cell differentiation was evaluated using Edmondson-Steiner criteria in liver cores of 0.9-5.0 cm (median 1.6 cm). Eighteen (29%) HCCs were grade I (1.5 cm), 28 (45%) were grade II (1.5 cm), 16 (26%) were grade III (1.8 cm), and none were grade IV. Contrast wash-in and wash-out were concurrently demonstrated in 21 (34%) tumors by way of CE-US, including three (16%) grade I and 18 (41%) grade II-III (P = 0.08); in 32 (52%) tumors by way of CT, including three (16%) grade I and 29 (66%) grade II-III (P = 0.0006); and 28 (47%) tumors by way of MRI, including three grade I (16%) and 25 (57%) grade II III (P = 0.01). Among 1- to 2-cm tumors, the radiological diagnosis was achieved in two of 16 grade I and 17 of 31 grade II-III tumors (P = 0.006). CONCLUSION: Tumor grade, a relevant predictor of disease severity, influences the accuracy of dynamic contrast techniques in the diagnosis of HCC. PMID- 20842698 TI - Acellular dermal matrix graft: synergistic effect of rehydration and natural crosslinking on mechanical properties. AB - This investigation studied how the incorporation of a natural crosslinking agent, genipin (Gp), into the AlloDerm(r) (AD) rehydration protocol affects the biomechanical properties and the stability of the collagenous matrix. AD is a minimally processed, noncrosslinked, freeze-dried collagen-based graft. Samples were immersed in a saline solution for 5 min and then randomly assigned for further rehydration (30 min) into three groups, according to the crosslinking agent: G1-control (saline), G2-1 wt % genipin, and G3-1 wt % glutaraldehyde. Gp crosslinking for a prolonged time of 6 h (G4) was also investigated. After washing (5 min), samples were mechanically tested wet in tension. G2 demonstrated a significantly higher ultimate tensile strength (UTS) and E relative to G1. However, G3 did not show a noteworthy increase in these properties. A significant enhancement in UTS was found when Gp exposure time was increased from 30 min to 6 h. FT-IR revealed a protein backbone with no significant peak shifting for all samples due to crosslinking. However, a considerable decrease in -NH(2) peak intensity occurred due to crosslinking reactions. Additionally, DSC analyses indicated an important shift in the denaturation temperature for crosslinked samples. SEM micrographs revealed no alterations in the native fibrous morphology after crosslinking. Simultaneous genipin incorporation during the rehydration protocol of AlloDerm significantly enhances its biomechanical properties. PMID- 20842699 TI - Simultaneous determination of three acidic herbicide residues in food crops using HPLC and confirmation via LC-MS/MS. AB - 2,4-D, dicamba and 4-CPA with auxin-like activity have been intensively used in agriculture, for the control of unwanted broadleaf weeds. An analytical method involving HPLC coupled with UVD was developed for the simultaneous analysis of these three analytes in Chinese cabbage, apple and pepper fruits (representative non-fatty samples) and brown rice and soybean (representative fatty samples) using liquid-liquid partitioning and column cleanup procedures. The residues were confirmed via tandem mass spectrometry (MS/MS) in ion electrospray ionization (ESI) mode. The standard curves were linear over the range of the tested concentrations (0.25-10 microg/mL), as shown by a marked linearity in excess of 0.9999 (r(2) ). The average recoveries (mean, n = 3) ranged from 94.30 to 102.63 in Chinese cabbage, from 94.76 to 108.47 in apple, from 97.52 to 102.27 in pepper, from 76.19 to 101.90 in brown rice, and from 74.60 to 107.39 in soybean. The relative standard deviations (RSDs) were <9% in all tested matrices. The limits of detection and quantitation were 0.006 and 0.02 mg/kg, respectively. Samples purchased from local markets were analyzed to evaluate the applicability of the methods developed herein. The concentration of the 2,4-D residue was measured at 0.102 mg/kg in the soybean sample; however, this level is exactly the same MRL set by the Korea Food and Drug Administration. This developed method deserves full and complete consideration, as it clearly displays the sensitivity, accuracy and precision required for residue analysis of 2,4-D, dicamba and 4-CPA in food crops. PMID- 20842700 TI - Age dependence of oval cell responses and bile duct carcinomas in male fischer 344 rats fed a cyclic choline-deficient, ethionine-supplemented diet. AB - The age dependence of the oval cell response and bile duct carcinomas of male F344 rats exposed to a cyclic choline deficiency-ethionine (CDE) diet (2 weeks on, 1 week off) supports the concept of loss of potential of liver stem cells to form cancers with aging. Livers of rats exposed at 3 weeks of age demonstrated a robust and widespread oval cell proliferation followed by cholangiofibrosis and bile duct metaplasia with extensive mucinous cysts throughout all lobes, and induction of cholangiocarcinomas (CCAs) in seven of eight rats. Livers of rats exposed beginning at 8 weeks of age had much less oval cell response and cholangiofibrosis with only 1 of 15 rats developing a CCA. Livers in old (10-12 months when started) rats remained virtually unaffected, with minimal oval cell proliferation, only occasional and small foci of ductular dysplasia, and none of 16 rats developed CCAs. In contrast to most published studies using uninterrupted choline deficiency plus a carcinogen, hepatocellular carcinoma (HCC) was not observed under the conditions of this study. CONCLUSION: With aging, male F344 rats exposed to cyclic CDE diet display a diminished oval cell response and fewer CCAs. The absence of HCC is possibly due to the fact that during cyclic CDE, the week off may allow putative liver stem cells to avoid death or differentiation and survive to give rise to CCAs, whereas with continuous CDE exposure, the stem cells are forced to differentiate and develop into HCCs with relatively few CCAs. PMID- 20842702 TI - Arterial anatomy of the second toe nail bed related to toenail transfer. AB - The aim of this study was to elucidate the exact course of the terminal branches of the plantar digital artery (PDA) to the nail bed of the second toe. Thirteen second toes from seven fresh Korean cadavers were dissected (age range 74-92 years, four men and three women). The terminal segmental branches (TSB) branched off from the PDA at 7.6 +/- 0.7 mm proximal to the nail fold. The fibro-osseous hiatus branch (FHB) branched off from the PDA at 3.3 +/- 0.7 mm from the nail fold. They were 3.8 +/- 1.0 mm lateral to the paronychium. Diameters of TSB and FHB were 0.8 +/- 0.2 mm and 0.7 +/- 0.1 mm, respectively. Diameter of PDA was 1.4 +/- 0.2 mm. Surgeons should stay at least 4 mm proximal to the nail fold to avoid injury to the terminal branch. We believe that second toenail with minimum amount of soft tissue may be transferred using FHB-based vascularized toenail flap. Perfusion study and clinical application should be followed. PMID- 20842701 TI - Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing. AB - Studies were performed evaluating the role of Smad3, a transcription factor mediating canonical TGF-beta signaling, on scarring and adhesion formation using an established flexor digitorum longus (FDL) tendon repair model. In unoperated animals the metatarsophalangeal (MTP) range of motion (ROM) was similar in Smad3( /-) and wild-type (WT) mice while the basal tensile strength of Smad3(-/-) tendons was significantly (39%) lower than in WT controls. At 14 and 21 days following repair Smad3(-/-) MTP ROM reached approximately 50% of the basal level and was twice that observed in WT tendon repairs, consistent with reduced adhesion formation. Smad3(-/-) and WT maximal tensile repair strength on post operative day 14 was similar. However, Smad3(-/-) tendon repairs maximal tensile strength on day 21 was 42% lower than observed in matched WT mice, mimicking the relative decrease in strength observed in Smad3(-/-) FDL tendons under basal conditions. Histology showed reduced "healing callus" in Smad3(-/-) tendons while quantitative PCR, in situ hybridization, and immunohistochemistry showed decreased col3a1 and col1a1 and increased MMP9 gene and protein expression in repaired Smad3(-/-) tendons. Thus, Smad3(-/-) mice have reduced collagen and increased MMP9 gene and protein expression and decreased scarring following tendon FDL tendon repair. PMID- 20842703 TI - Isogenic venous graft supported with bone marrow stromal cells as a natural conduit for bridging a 20 mm nerve gap. AB - In this study, we introduce a technique for bridging large neural gaps, using an isogenic vein graft supported with isogenic bone marrow stromal cells (BMSC). In three groups a nerve defect of 20 mm was bridged with a vein graft. Our first experimental group comprized an empty venous graft, in group II the venous nerve graft was filled with saline where as in group III the venous nerve graft was filled with BMSC. The animals were tested for functional recovery up to 3 months post repair. Our results show that the BMSC filled venous graft resulted in significantly better regeneration of the nerve defect compared to controls, as confirmed by the functional recovery measured by somatosensory evoked potentials, toe spread, pin prick, and gastrocnemius muscle index. Conclusively, the results confirm that the vein graft supported with BMSC is associated with better functional nerve regeneration. PMID- 20842704 TI - Historical development of bipolar coagulation. AB - In 1926, a physicist at Harvard named William T. Bovie created an instrument, which revolutionized the medical profession--the unipolar electrocautery device. This incredible device could make surgical incisions and provide hemostasis as well. It came with a price, however, as it also created new risks and dangers in the operating room, such as electrical burns and fires. To resolve some of these problems, a bipolar electrocautery device was developed. The historical development and principles of both unipolar and bipolar electrocautery will be discussed in this article. PMID- 20842705 TI - The transverse upper gracilis flap for breast reconstruction following liposuction of the thigh. AB - A particular flap with rising prominence in breast reconstruction is the transverse upper gracilis (TUG) flap. With the increasing prevalence of patients opting for various forms of elective liposuctions, breast reconstruction with flaps has necessitated a more meticulous yet perhaps more flexible screening for potential donor sites. We present a case of a bilateral breast reconstruction using TUG flaps in a patient with a previous history of liposuction to her abdomen and thighs. The dimensions of the TUG flaps were 7 * 31 cm2. The patient did not undergo any flap or donor site complications. We speculate that perhaps much of the tissue and muscle in the medial thigh region is more robust than previously thought and that there is high potential for neo-vascularization in the thigh region following a liposuction. Accordingly, we advocate the effective use of the TUG flap for breast reconstruction in spite of previous liposuctions to the thighs. PMID- 20842707 TI - Minimally invasive peripheral nerve surgery: a short scar technique. AB - INTRODUCTION: As peripheral nerve specialists can have a wide variety of training backgrounds, few standards of care exist with respect to necessary incision length, amount of dissection, and operative technique for common nerve decompressions. METHODS: Approaches for the following 12 common peripheral nerve surgeries were minimized using shorter incisions and a simple lighted retractor: zygomatico-temporal and auriculotemporal, greater occipital, brachial plexus, ulnar, radial, median, lateral femoral cutaneous nerve of the thigh, peroneal at the groin, fibular neck and lateral calf, and tibial and inner ankle. The new "minimal" incision length was recorded as was that of the "classical" approach as taught to the senior author and frequently represented in atlases. A Mann-Whiney analysis was independently performed to evaluate for significance between the lengths of incisions for each procedure. RESULTS: The average length of the "minimal" incisions was 3.9 +/- 0.6 cm (range, 3.1-6.1 cm), with an average reduction in length of 51% as compared with the "classical" incisions (range, 30 75%; P < 0.001). There were no perioperative morbidities. CONCLUSIONS: Minimally invasive peripheral nerve surgery applied to the above procedures yields successful surgical outcomes while shortening incision lengths and maximizing patient satisfaction without sacrificing patient safety. PMID- 20842708 TI - Bedside maneuvers and waveform changes in the interpretation of the implantable Doppler probe signal for free-flap monitoring. PMID- 20842706 TI - A modified vascularized whole knee joint allotransplantation model in the rat. AB - Previous papers have shown surgical neoangiogenesis to allow long-term bone allotransplant survival without immunosuppression. Whole joint composite tissue allotransplants (CTA) might be treated similarly. A novel rat knee CTA model is described for further study of the roles of neoangiogensis in joint allotransplant survival and adjustment of immunosuppression. Microvascular knee CTA was performed in nine rats across a major histocompatibility barrier with both pedicle repair and implantation of host-derived arteriovenous ("a/v") bundles. In the control group (N = 3), the pedicle was ligated. Immunosuppression was given daily. Joint mobility, weight-bearing, pedicle patency, bone blood flow, and sprouting from a/v bundles were assessed at 3 weeks. All but the nonrevascularized control knees had full passive motion and full weight bearing. One nutrient pedicle thrombosed prematurely. Blood flow was measurable in transplants with patent nutrient pedicles. Implanted a/v bundles produced new vascular networks on angiography. This new rat microsurgical model permits further study of joint allotransplantation. Patency of both pedicles and implanted a/v bundles was maintained, laying a foundation for future studies. PMID- 20842710 TI - Next-generation imaging development for nanoparticle biodistribution measurements. AB - As nanotechnologies move closer to use in humans, quantitative imaging methods will play a vital role in answering questions of biodistribution. Accurate knowledge of the location and quantity of in vivo nanoconstructs and carriers is a challenging task, and new methods of quantitative imaging at appropriate resolutions are being developed and tested. Sustaining simultaneous advancement in both imaging development and nanotechnology research requires multidisciplinary research teams conducting experiments with interconnected goals. On an even greater scale, networks of multidisciplinary teams focused on similar issues of imaging and probe development offer opportunities for leveraging resources, as well as providing a forum for sharing ideas and creating consensus on solutions to common challenges. The Network for Translational Research (NTR): Optical Imaging in Multimodal Platforms from the National Cancer Institute is just such a network. Four multidisciplinary centers are accepting the challenges of developing and optimizing multimodal imaging hardware and software along with imaging probe development. These efforts are similar to the efforts that will be required for future studies of in vivo nanoparticle biodistribution. In addition to technology development and optimization, the network is organized to confront the challenges of validation of the imaging hardware and associated imaging agents, similar to the methods needed for validating nanomedicine. PMID- 20842711 TI - A green fluorescent protein solubility screen in E. coli reveals domain boundaries of the GTP-binding domain in the P element transposase. AB - Guanosine triphosphate (GTP) binding and hydrolysis events often act as molecular switches in proteins, modulating conformational changes between active and inactive states in many signaling molecules and transport systems. The P element transposase of Drosophila melanogaster requires GTP binding to proceed along its reaction pathway, following initial site-specific DNA binding. GTP binding is unique to P elements and may represent a novel form of transpositional regulation, allowing the bound transposase to find a second site, looping the transposon DNA for strand cleavage and excision. The GTP-binding activity has been previously mapped to the central portion of the transposase protein; however, the P element transposase contains little sequence identity with known GTP-binding folds. To identify soluble, active transposase domains, a GFP solubility screen was used testing the solubility of random P element gene fragments in E. coli. The screen produced a single clone spanning known GTP binding residues in the central portion of the transposase coding region. This clone, amino acids 275-409 in the P element transposase, was soluble, highly expressed in E.coli and active for GTP-binding activity, therefore is a candidate for future biochemical and structural studies. In addition, the chimeric screen revealed a minimal N-terminal THAP DNA-binding domain attached to an extended leucine zipper coiled-coil dimerization domain in the P element transposase, precisely delineating the DNA-binding and dimerization activities on the primary sequence. This study highlights the use of a GFP-based solubility screen on a large multidomain protein to identify highly expressed, soluble truncated domain subregions. PMID- 20842712 TI - Autoinhibition of GEF activity in Intersectin 1 is mediated by the short SH3-DH domain linker. AB - Intersectin 1L (ITSN1L) acts as a specific guanine nucleotide exchange factor (GEF) for the small guanine nucleotide binding protein Cdc42 via its C-terminal DH domain. Interestingly, constructs of ITSN1L that comprise additional domains, for instance the five SH3 domains amino-terminal of the DH domain, were shown to be inhibited in their exchange factor activity. Here, we investigate the inhibitory mechanism of ITSN1L in detail and identify a novel short amino acid motif which mediates autoinhibition. We found this motif to be located in the linker region between the SH3 domains and the DH domain, and we show that within this motif W1221 acts as key residue in establishing the inhibitory interaction. This assigns ITSN1L to a growing class of GEFs that are regulated by a short amino acid motif inhibiting GEF activity by an intramolecular interaction. Moreover, we quantify the interaction between the ITSN1L SH3 domains and the Cdc42 effector N-WASP using fluorescence anisotropy binding experiments. As the SH3 domains are not involved in autoinhibition, binding of N-WASP does not release inhibition of nucleotide exchange activity in kinetic experiments, in contrast to earlier observations. PMID- 20842713 TI - Predicting the disruption by UO2(2+) of a protein-ligand interaction. AB - The uranyl cation (UO(2) (2+)) can be suspected to interfere with the binding of essential metal cations to proteins, underlying some mechanisms of toxicity. A dedicated computational screen was used to identify UO(2) (2+) binding sites within a set of nonredundant protein structures. The list of potential targets was compared to data from a small molecules interaction database to pinpoint specific examples where UO(2) (2+) should be able to bind in the vicinity of an essential cation, and would be likely to affect the function of the corresponding protein. The C-reactive protein appeared as an interesting hit since its structure involves critical calcium ions in the binding of phosphorylcholine. Biochemical experiments confirmed the predicted binding site for UO(2) (2+) and it was demonstrated by surface plasmon resonance assays that UO(2) (2+) binding to CRP prevents the calcium-mediated binding of phosphorylcholine. Strikingly, the apparent affinity of UO(2) (2+) for native CRP was almost 100-fold higher than that of Ca(2+). This result exemplifies in the case of CRP the capability of our computational tool to predict effective binding sites for UO(2) (2+) in proteins and is a first evidence of calcium substitution by the uranyl cation in a native protein. PMID- 20842714 TI - Measuring process of arthritis care: a proposed set of quality measures for the process of care in juvenile idiopathic arthritis. AB - OBJECTIVE: The ability to assess quality of care is a necessary component of continuous quality improvement. The assessment typically is accomplished by determination of compliance with a defined set of quality measures (QMs). The objective of this effort was to establish a set of QMs for the assessment of the process of care in juvenile idiopathic arthritis (JIA). METHODS: A 12-member working group composed of representatives from the American College of Rheumatology, American Academy of Pediatrics, American Board of Pediatrics, and Association of Rheumatology Health Professionals was assembled to guide the project. Delphi questionnaires were sent to 237 health professionals involved in the care of children with JIA. A total of 471 items in 23 domains were identified. The working group met via 4 live e-meetings during which results from the Delphi questionnaires were distilled to a reduced draft set. Each working group member selected a proposed QM to investigate and present evidence from the literature as to its attributes and appropriateness for inclusion into the set. Nominal group technique was used to come to consensus on a proposed set of QMs. RESULTS: The proposed set contains 12 QMs within 4 health care domains. Each QM consists of a statement of 1) the assessment to be completed, 2) when the first assessment should be completed and a suggested frequency of assessment during followup, 3) recommendations of appropriate tools or methods of assessment, and 4) initial performance goals. CONCLUSION: Implementation of the proposed QM set will improve the process of care, facilitate continuous quality improvement, and eventuate in improved health outcomes of children with JIA. PMID- 20842715 TI - Reaching those most in need: a scoping review of interventions to improve health care quality for disadvantaged populations with osteoarthritis. AB - OBJECTIVE: To conduct a systematic review to identify and describe the scope and nature of the research evidence on the effectiveness of interventions to improve health care quality or reduce disparities in the care of disadvantaged populations with osteoarthritis (OA) as an example of a common chronic disease. METHODS: We searched electronic databases from 1950 through February 2010 and grey literature for relevant articles using any study design. Studies with interventions designed explicitly to improve health care quality or reduce disparities in the care of disadvantaged adult populations with OA and including an evaluation were eligible. We used the PROGRESS-Plus framework to identify disadvantaged population subgroups. RESULTS: Of 4,701 citations identified, 10 met the inclusion criteria. Eight were community based and 6 targeted race/ethnicity/culture. All 10 studies evaluated interventions aimed at people with OA; 2 studies also targeted the health care system. No studies targeted health care providers. Nine of 10 studies evaluated arthritis self-management interventions; all showed some benefit. Only 1 study compared the difference in effect between the PROGRESS-Plus disadvantaged population and the relevant comparator group. CONCLUSION: There are few studies evaluating the effectiveness of interventions to improve health care quality in disadvantaged populations with OA. Further research is needed to evaluate interventions aimed at health care providers and the health care system, as well as other patient-level interventions. Gap intervention research is also needed to evaluate whether interventions are effective in reducing documented health care inequities. PMID- 20842718 TI - Cannabinoid effects on CB1 receptor density in the adolescent brain: an autoradiographic study using the synthetic cannabinoid HU210. AB - The short- and long-term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 MUg/kg HU210 for 4 or 14 days, or received a single dose of 100 MUg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [(3)H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 MUg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [(3)H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose dependent, region-specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross-tolerance and the long-lasting, adverse psychological consequences of cannabinoid exposure during adolescence. PMID- 20842717 TI - Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole. AB - Aromatase catalyzes the last step in estrogen biosynthesis. Brain aromatase is involved in diverse neurophysiological and behavioral functions including sexual behavior, aggression, cognition, and neuroprotection. Using positron emission tomography (PET) with the radiolabeled aromatase inhibitor [N-methyl (11)C]vorozole, we characterized the tracer distribution and kinetics in the living human brain. Six young, healthy subjects, three men and three women, were administered the radiotracer alone on two separate occasions. Women were scanned in distinct phases of the menstrual cycle. Specificity was confirmed by pretreatment with a pharmacological (2.5 mg) dose of the aromatase inhibitor letrozole. PET data were acquired over a 90-min period and regions of interest placed over selected brain regions. Brain and plasma time activity curves, corrected for metabolites, were used to derive kinetic parameters. Distribution volume (V(T)) values in both men and women followed the following rank order: thalamus > amygdala = preoptic area > medulla (inferior olive) > accumbens, pons, occipital and temporal cortex, putamen, cerebellum, and white matter. Pretreatment with letrozole reduced V(T) in all regions, though the size of the reduction was region-dependent, ranging from ~70% blocking in thalamus andpreoptic area to ~10% in cerebellum. The high levels of aromatase in thalamus and medulla (inferior olive) appear to be unique to humans. These studies set the stage for the noninvasive assessment of aromatase involvement in various physiological and pathological processes affecting the human brain. PMID- 20842719 TI - Serotonin release variations during recovery of motor function after a spinal cord injury in rats. AB - Current literature suggests that serotonin (5-HT) release within the ventral horn of the spinal cord plays a role in motor function. We hypothesized that endogenous 5-HT release is involved in the recovery of motor function after spinal cord injury. To appreciate the functional parameters of regenerating serotonergic fibers, a microdialysis probe was stereotactically implanted in the ventral horn of subhemi-lesioned rats. Microdialysis in combination with HPLC was used to measure concentrations of 5-HT in the lumbar ventral horn during periods of rest (90 min), treadmill run (60 min) and postexercise rest (90 min) for a 1 month time period of recovery following the surgical lesion. Within the same period of time, 5-HT levels varied significantly. A significant (202%) increase was observed at day 18 postlesion relative to day 8, and a 16.4% decrease was observed at day 34 relative to day 18. Treadmill exercise challenge induced a 10% decrease of 5-HT release relative to rest at days 18 and 34. In conclusion, overtime treadmill locomotor recovery is parallel to amounts (rest basal levels) and patterns (exercise and postexercise levels) of 5-HT release suggesting that changes in serotonergic system occurred within the same time frame than locomotor recovery using treadmill challenge. PMID- 20842720 TI - Evidence for noncompetitive modulation of substrate-induced serotonin release. AB - Prior work indicated that serotonin transporter (SERT) inhibitors competitively inhibit substrate-induced [(3)H]5-HT release, producing rightward shifts in the substrate-dose response curve and increasing the EC(50) value without altering the E(max). We hypothesized that this finding would not generalize across a number of SERT inhibitors and substrates, and that the functional dissociation constant (Ke) of a given SERT inhibitor would not be the same for all tested substrates. To test this hypothesis, we utilized a well-characterized [(3)H]5-HT release assay that measures the ability of a SERT substrate to release preloaded [(3)H]5-HT from rat brain synaptosomes. Dose-response curves were generated for six substrates (PAL-287 [naphthylisopropylamine], (+)-fenfluramine, (+) norfenfluramine, mCPP [meta-chlorophenylpiperazine], (+/-)-MDMA, 5-HT) in the absence and presence of a fixed concentration of three SERT inhibitors (indatraline, BW723C86, EG-1-149 [4-(2-(benzhydryloxy)ethyl)-1-(4 bromobenzyl)piperidine oxalate]). Consistent with simple competitive inhibition, all SERT inhibitors increased the EC(50) value of all substrates. However, in many cases a SERT inhibitor decreased the E(max) value as well, indicating that in the presence of the SERT inhibitor the substrate became a partial releaser. Moreover, the Ke values of a given SERT inhibitor differed among the six SERT substrates, indicating that each inhibitor/substrate combination had a unique interaction with the transporter. Viewed collectively, these findings suggest that it may be possible to design SERT inhibitors that differentially regulate SERT function. PMID- 20842721 TI - Effects of asenapine on prefrontal N-methyl-D-aspartate receptor-mediated transmission: involvement of dopamine D1 receptors. AB - Asenapine is a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder. Like clozapine, asenapine facilitates cortical dopaminergic and N-methyl-D-aspartate (NMDA) receptor-mediated transmission in rats. The facilitation of NMDA-induced currents in cortical pyramidal cells by clozapine is dependent on dopamine and D(1) receptor activation. Moreover, previous results show that clozapine prevents and reverses the blockade of NMDA-induced currents and firing activity in the pyramidal cells by the noncompetitive NMDA receptor antagonist phencyclidine (PCP). Here, we investigated the effects of asenapine in these regards using intracellular electrophysiological recording in vitro. Asenapine (5 nM) significantly facilitated NMDA-induced currents (162 +/- 15% of control) in pyramidal cells of the medial prefrontal cortex (mPFC). The asenapine induced facilitation was blocked by the D(1) receptor antagonist SCH23390 (1 MUM). Furthermore, the PCP-induced blockade of cortical NMDA-induced currents was effectively reversed by 5 nM asenapine. Our results demonstrate a clozapine-like facilitation of cortical NMDA-induced currents by asenapine that involves prefrontal dopamine and activation of D(1) receptors. Asenapine and clozapine also share the ability to reverse functional PCP-induced hypoactivity of cortical NMDA receptors. The ability of asenapine to increase both cortical dopaminergic and NMDA receptor-mediated glutamatergic transmission suggests that this drug may have an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms. PMID- 20842722 TI - Postnatal and ovariectomic regulation of postsynaptic density protein-95 in the hippocampus of female Sprague-Dawley rats. AB - Postsynaptic density protein-95 (PSD-95) is hypothesized to control the excitatory-to-inhibitory ratio and plays an important role in the regulation of hippocampal synaptic plasticity, synaptogenesis, and learning and memory. In this report, we used immunoblotting to study the effects of aging and ovariectomy (OVX) on the expression of PSD-95 in the hippocampus of female rats. The results indicated that postnatal expression of hippocampal PSD-95 correlated with the fluctuation of circulating female sex hormones such as estrogen. Neonatal PSD-95 level was very low, but dramatically increased within the first month. The highest expression of PSD-95 was detected at postnatal day 30 (P30) and significantly decreased by 18 months. In the adult hippocampus, OVX significantly decreased PSD-95 expression within the first week, but it had recovered to adult levels 2 weeks later. Taken together, we conclude that circulating ovarian hormones may play a crucial role in the regulation of excitatory synapses within the hippocampus. Depletion of ovarian hormones can transiently and dramatically decrease the level of excitatory synapses for a limited time. PMID- 20842723 TI - Chirally dimorphic male genitalia in praying mantids (Ciulfina: Liturgusidae). AB - Although male polymorphisms occur widely in nature and have received considerable recent attention from studies of alternative mating strategies, male genital polymorphisms are less well known. Here, we describe a dimorphism in the orientation of the male genitalic complex of the praying mantid genus Ciulfina. Populations of Ciulfina species vary in the proportion of males with dextral (right-oriented) and sinistral (left-oriented) genitalia, ranging from directional asymmetry (single orientation only) to apparent antisymmetry (equal proportions of both orientations). The proportion of dextral males varied between species (C. baldersoni: 46%; C. rentzi: 24%; C. klassi: 100%; C. biseriata: 83%) and between populations. We used elliptic Fourier analysis to quantify shape and size variation between the genitalia of dextral and sinistral males and determined that the two forms were mirror images of one another in two species. We found that the level of mechanical reproductive isolation between heterospecific populations of opposite genital orientation was no greater than that between heterospecific populations with the same orientation or of mixed orientation. Genital orientation therefore did not influence premating isolation between these species, despite complete postmating isolation. The geographic proximity of populations to heterospecifics also showed no particular pattern with respect to genital orientation. These results suggest that reversible trait asymmetry in Ciulfina is not driven by reproductive isolation, and add to the growing evidence against the species isolation hypothesis for rapid genital evolution. PMID- 20842724 TI - Comparative morphology of the foot structure of four genera of Loxosomatidae (Entoprocta): Implications for foot functions and taxonomy. AB - Entoprocta is a group of mostly cryptic, benthic invertebrates with a sedentary lifestyle. Here, we investigate the morphology of the entoproct foot, which is an important structure in attachment and locomotion. We describe the foot structure of four solitary entoprocts, Loxosoma monilis, Loxosomella stomatophora, Loxocorone allax, and Loxomitra mizugamaensis, by means of light and transmission electron microscopy. Gland cells containing secretory granules were found in the foot of all the four species. In L. monilis, the gland cells densely paved the underside of the disc-shaped foot, but no duct or groove was found. In L. stomatophora and L. allax, a foot gland was present at the frontal end of a foot groove. The foot gland was a solid cell mass in the former species but a sac-like structure in the latter. Two types of groove accessory cells were recognized in both species; groove bulge cells (GBCs) showed large cytoplasmic bulges extending into the groove lumen, while groove microvillus cells have microvillus mats in the lateral wall of the groove. The bulges of GBCs in L. stomatophora are slender and attached to one another with desmosomes, forming appendages that extend down to the substratum, hinting at their contribution to attachment and locomotion. The bulges in L. allax form large swellings that fill the groove lumen and are connected to the surrounding cells with hemidesmosomes. In the liberated buds of L. mizugamaensis, tripartite gland cell masses were found at the basal end of the stalk, but no groove was found. A small invagination, which may be the opening of the gland, was found at the center of the foot tip, where the liberated buds attach themselves to the substratum and then metamorphose into adults. No openings were found at the lateral terminal wings, which support locomotion in Loxomitra species. PMID- 20842727 TI - A prognostic DNA signature for T1T2 node-negative breast cancer patients. AB - Predicting evolution of small node-negative breast carcinoma is a real challenge in clinical practice. The aim of this study was to search whether qualitative or quantitative DNA changes may help to predict metastasis of small node-negative breast carcinoma. Small invasive ductal carcinomas without axillary lymph node involvement (T1T2N0) from 168 patients with either good (111 patients with no event at 5 years after diagnosis) or poor (57 patients with early metastasis) outcome were analyzed with comparative genomic hybridization (CGH) array. A CGH classifier, identifying low- and high-risk groups of metastatic recurrence, was established in a training set of 78 patients, then validated, and compared with clinicopathological parameters in a distinct set of 90 patients. The genomic status of regions located on 2p22.2, 3p23, and 8q21-24 and the number of segmental alterations were defined in the training set to classify tumors into low- or high-risk groups. In the validation set, in addition to estrogen receptors and grade, this CGH classifier provided significant prognostic information in multivariate analysis (odds ratio, 3.34; 95% confidence interval 1.01-11.02; P = 4.78 * 10(-2), Wald test). This study shows that tumor DNA contains important prognostic information that may help to predict metastasis in T1T2N0 tumors of the breast. PMID- 20842728 TI - Differential regulation of TP73 isoforms by 1alpha,25-dihydroxyvitamin D3 and survivin in human colon and breast carcinomas. AB - We evaluate whether 1,25(OH)(2)D(3) downregulates TP73 variants in colon and breast carcinomas, the role of survivin in this context, and the significance of this network in the clinic. Tumor cells were treated/untreated with 1,25(OH)(2)D(3) and transiently transfected with survivin. Levels of survivin and TP73 variants were evaluated by quantitative RT-PCR and Western blotting. In 75 colon and 60 breast cancer patients, the expressions of survivin and TP73 isoforms were determined. Tumor characteristics were examined in each patient. Survivin protein levels were also evaluated in a subgroup of patients and cell lines. Decrease in survivin and TAp73 transcripts and protein and DeltaNp73 mRNA was detected after 1,25(OH)(2)D(3) treatment. Ectopic survivin expression led to an increase in the TAp73, DeltaNp73, DeltaEx2p73, and DeltaEx2-3p73 transcripts. In cancer patients, direct correlations were observed between TP73 variants and survivin levels. 1,25(OH)(2)D(3) negatively regulate survivin and TP73 variants in colon and breast cancer cells. Positive regulation of TP73 isoforms by survivin may exist, which reinforces the possibility that the downregulation of TP73 forms by 1,25(OH)(2)D(3) is survivin-dependent. PMID- 20842729 TI - BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer. AB - Hereditary breast cancers (BCs) are incompletely explained by BRCA genes abnormalities, as ~70% of them are not associated with known genetic alterations. Array-based comparative genomic hybridization (aCGH) of tumors provides an opportunity for identifying new BC susceptibility genes. By analyzing our database of high-resolution aCGH profiles of 330 BCs, we identified a case with homozygous deletion of the entire BARD1 gene. The BARD1-deleted case displayed a familial history of BC and other clinico-pathological features of BRCAness, and a 17% probability of BRCA1/2 mutation. Analysis of constitutional DNA showed a BARD1 germline heterozygous deletion without BRCA1/2 mutation. Gene expression analysis using DNA microarrays classified the tumor as basal-like, with very low BARD1 and ID4 expression, but high expression of BRCA1, RAD51, PARP1, CHEK1, and FANCA. The tumor displayed a BRCA1-mutated expression profile. This is the first report of a non-BRCA1/2-mutated BC with somatic homozygous and germ-line heterozygous deletion of the entire BARD1 gene. This observation suggests that BARD1 might be a BC susceptibility gene that follows the Knudson rule. Identification of BARD1 deletion could have clinical applications including screening for hereditary forms. (c) 2010 Wiley-Liss, Inc. PMID- 20842730 TI - Genetic instability in inherited and sporadic leukemias. AB - Genetic instability due to increased DNA damage and altered DNA repair is of central significance in the initiation and progression of inherited and sporadic human leukemias. Although very rare, some inherited DNA repair insufficiency syndromes (e.g., Fanconi anemia, Bloom's syndrome) have added substantially to our understanding of crucial mechanisms of leukemogenesis in recent years. Conversely, sporadic leukemias account for the main proportion of leukemias and here DNA damaging reactive oxygen species (ROS) play a central role. Although the exact mechanisms of increased ROS production remain largely unknown and no single pathway has been detected thus far, some oncogenic proteins (e.g., the activated tyrosine kinases BCR-ABL1 and FLT3-ITD) seem to play a key role in driving genetic instability by increased ROS generation which influences the disease course (e.g., blast crisis in chronic myeloid leukemia or relapse in FLT3-ITD positive acute myeloid leukemia). Of course other mechanisms, which promote genetic instability in leukemia also exist. A newly emerging mechanism is the genome-wide alteration of epigenetic marks (e.g., hypomethylation of histone H3K79), which promotes chromosomal instability. Taken together genetic instability plays a critical role both in inherited and sporadic leukemias and emerges as a common theme in both inherited and sporadic leukemias. Beyond its theoretical impact, the analysis of genetic instability may lead the way to the development of innovative therapy strategies. PMID- 20842732 TI - YAP1 and VGLL3, encoding two cofactors of TEAD transcription factors, are amplified and overexpressed in a subset of soft tissue sarcomas. AB - In a series of 404 adult soft tissue sarcomas, analyzed by array-CGH, we have observed in approximately 10% of them a genomic amplification of either chromosome bands 11q22 or 3p12. These two amplicons likely target the YAP1 and VGLL3 genes, respectively. Both genes encode proteins that are cofactors of the TEAD family of transcription factors. Very good correlations between amplification and expression levels were observed. Welch test analyses of transcriptome data demonstrate that tumors with amplicons share a large set of upregulated and downregulated genes. Inhibition of YAP1 and VGLL3 in cell lines with these amplifications/overexpressions leads to similar phenotypes: decrease of proliferation rate, and to a lesser extent decrease of migration properties. These data, and the fact that these amplicons are observed either in de differentiated liposarcomas or in undifferentiated pleomorphic sarcomas, suggest that these genetics events could be involved in oncogenesis and progression of soft tissue sarcomas. PMID- 20842733 TI - Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. AB - Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. PMID- 20842731 TI - Disseminated peritoneal leiomyomatosis after laparoscopic supracervical hysterectomy with characteristic molecular cytogenetic findings of uterine leiomyoma. AB - Disseminated peritoneal leiomyomatosis (DPL) is a rare condition characterized by scattered smooth muscle nodules over the peritoneal surfaces. The pathogenesis of DPL remains unclear. Herein, we report a case of DPL occurring 7 years after laparoscopic supracervical hysterectomy with morcellation for uterine leiomyomata (UL). We analyzed both the original UL and the subsequent DPL by molecular cytogenetics to assess the role of chromosomal abnormalities in DPL pathobiology. Interestingly, all of the chromosomal aberrations detected in this case of DPL, including r(1)(p34.3q41), del(3)(q23q26.33), and t(12;14)(q14.3;q24.1), are characteristic chromosomal abnormalities detected in UL. Fluorescence in situ hybridization analysis of the initial UL confirmed an interstitial deletion spanning at least 3q24 and 3q25.1, suggesting that functional alteration of a potential gene in this chromosomal region may play a role in DPL development from UL. With the increasing rate of hysterectomy through laparoscopic approach to UL, the unique complications of laparoscopy with morcellation, especially seeding and proliferation of tumor cells over abdominal organs and peritoneum, are becoming more significant and may necessitate review of current surgical protocols to prevent future seeding of the pelvic region with tumor particles. PMID- 20842734 TI - Musculocontractural Ehlers-Danlos Syndrome (former EDS type VIB) and adducted thumb clubfoot syndrome (ATCS) represent a single clinical entity caused by mutations in the dermatan-4-sulfotransferase 1 encoding CHST14 gene. AB - We present clinical and molecular findings of three patients with an EDS VIB phenotype from two consanguineous families. The clinical findings of EDS kyphoscoliotic type (EDS type VIA and B) comprise kyphoscoliosis, muscular hypotonia, hyperextensible, thin and bruisable skin, atrophic scarring, joint hypermobility and variable ocular involvement. Distinct craniofacial abnormalities, joint contractures, wrinkled palms, and normal urinary pyridinoline ratios distinguish EDS VIB from EDS VIA. A genome-wide SNP scan and sequence analyses identified a homozygous frameshift mutation (NM_130468.2:c.145delG, NP_569735.1:p.Val49*) in CHST14, encoding dermatan-4 sulfotransferase 1 (D4ST-1), in two Turkish siblings. Subsequent sequence analysis of CHST14 identified a homozygous 20-bp duplication (NM_130468.2:c.981_1000dup, NP_569735.1:p.Glu334Glyfs*107) in an Indian patient. Loss-of-function mutations in CHST14 were recently reported in adducted thumb clubfoot syndrome (ATCS). Patients with ATCS present similar craniofacial and musculoskeletal features as the EDS VIB patients reported here, but lack the severe skin manifestations. By identifying an identical mutation in patients with EDS VIB and ATCS, we show that both conditions form a phenotypic continuum. Our findings confirm that the EDS-variant associated with CHST14 mutations forms a clinical spectrum, which we propose to coin as "musculocontractural EDS" and which results from a defect in dermatan sulfate biosynthesis, perturbing collagen assembly. PMID- 20842735 TI - Thrombo-cardiology. AB - As a medical student I, along with my classmates, learned the coagulation cascade. Later, in 1968 when I passed my internal medicine boards and was on my way to becoming a cardiologist, I thought that was the last I had to remember that complicated series of events and the drugs used to alter coagulation. Little did I know at that time how important coagulation and anti-coagulation would become for cardiovascular patients. PMID- 20842736 TI - Renin inhibitors in chronic heart failure: the Aliskiren Observation of Heart Failure Treatment study in context. AB - Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogen to angiotensin I. Theoretical benefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and beta-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Copyright (c) 2010 Wiley Periodicals, Inc.The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 20842737 TI - Combined effects of glycated hemoglobin A1c and blood pressure on carotid artery atherosclerosis in nondiabetic patients. AB - BACKGROUND: The relationship between HbA(1c), blood pressure, and carotid atherosclerosis in nondiabetic patients is not clear. HYPOTHESIS: HbA(1c) and blood pressure can affect carotid-artery atherosclerosis in nondiabetic patients. METHODS: This retrospective cross-sectional study included 216 patients without diabetes mellitus. A positive carotid ultrasonographic result was defined as intima-media thickness of the common carotid artery >= 0.9 mm, or presence of carotid plaque. RESULTS: Compared with patients without carotid atherosclerosis, patients with carotid atherosclerosis had significantly higher levels of HbA(1c) and systolic blood pressure (SBP). Higher levels of HbA(1c) and SBP were found to be associated with increased carotid atherosclerosis. Given similar SBP levels, higher HbA(1c) (>5.6%) was also related to increased carotid atherosclerosis. In multiple logistic regression analysis, HbA(1c) (odds ratio: 4.1, P = 0.009) emerged as the only statistically significant modifiable factor that was associated with carotid atherosclerosis, independent of smoking, body mass index, fasting plasma glucose, 2-hour plasma glucose, SBP, diastolic blood pressure, low density lipoprotein cholesterol, and high-density lipoprotein cholesterol. CONCLUSIONS: Our study shows that a slight increase of HbA(1c) may associate with carotid atherosclerosis in nondiabetic patients. Moreover, the coexistence of an elevated SBP level and a slightly increased HbA(1c) level may have a more significant effect on carotid atherosclerosis. PMID- 20842738 TI - The p66shc gene expression in peripheral blood monocytes is increased in patients with coronary artery disease. AB - BACKGROUND: The p66(shc) protein has been shown to control cellular responses to oxidative stress, being involved in atherosclerosis in animal models. However, the relationship between the p66(shc) gene expression levels and coronary artery disease (CAD) in humans remains unknown. In this study, we examined whether the p66(shc) gene expression in peripheral blood monocytes (PBMs) was increased in patients with CAD, compared with age- and sex-matched subjects without CAD. HYPOTHESIS: We hypothesize that the p66(shc) gene expression level in PBMs is increased in patients with CAD. METHODS: Forty consecutive Japanese subjects who underwent coronary angiography for suspected CAD were enrolled in this study. The p66(shc) gene expression levels in PBMs were quantitatively measured by real-time reverse transcription-polymerase chain reactions. Uni- and multivariate analyses were applied for the correlates of CAD. CAD was diagnosed if there was > 75% obstruction of at least 1 major coronary artery or a history of percutaneous coronary intervention. RESULTS: There were no significant differences of blood chemistries and clinical characteristics between the patients with and without CAD, except the number of subjects who were on hypertension medication. The p66(shc) gene expression levels in PBMs were significantly higher in CAD patients compared with non-CAD subjects. Multiple stepwise regression analysis revealed that the p66(shc) gene expression levels and hypertension medication were independently related to CAD (R(2)=0.287). Further, the p66(shc) gene expres- sion levels were significantly increased (P < 0.05) in proportion to the number of diseased vessels. CONCLUSIONS: The present study is the first demonstration that increased the p66(shc) gene expression in PBMs is independently associated with CAD in Japanese subjects. The p66(shc) gene expression level in PBMs may be a novel biomarker of CAD in humans. PMID- 20842739 TI - Aspirin use is associated with an improved long-term survival in an unselected population presenting with unstable angina. AB - BACKGROUND: Few published data are available on the benefits of aspirin use in patients with unstable angina (UA). HYPOTHESIS: Aspirin use carries a mortality benefit in a population-based cohort of patients presenting with UA. METHODS: All residents of Olmsted County, Minnesota presenting to local emergency departments with acute chest pain from January 1985 through December 1992 having symptoms consistent with UA were identified through medical records. A total of 1628 patients were identified with UA and were stratified by aspirin use in-hospital and at discharge. Cardiovascular mortality and nonfatal myocardial infarction and stroke were assessed over a median of 7.5 years follow-up and all-cause mortality data over a median of 16.7 years. The mean age of patients with UA was 65 years, and 60% were men. RESULTS: After a median of 7.5 years follow-up, all-cause and cardiovascular-mortality rates were lower among patients prescribed versus not prescribed aspirin on discharge. There were 949 postdischarge deaths over the median follow-up of 16.7 years. After multivariable adjustment, aspirin use at discharge was associated with a lower long-term mortality (hazard ratio 0.78; 95% confidence interval, 0.65-0.93). CONCLUSIONS: Aspirin use at hospital discharge following UA is associated with a reduction in long-term mortality. This long term study extends prior trial results from select populations to a population based cohort. PMID- 20842740 TI - Diagnostic value of poor R-wave progression in electrocardiograms for diabetic cardiomyopathy in type 2 diabetic patients. AB - BACKGROUND: Diabetic cardiomyopathy (DCMP) is a common complication of diabetes and is associated with increased mortality. It has been suggested that a poor R wave progression in a resting electrocardiogram (ECG) could be a sign of cardiomyopathy. HYPOTHESIS: The aim of this study was primarily to analyze the relationship between poor R-wave progression and DCMP, and the effect of poor R wave progression on cardiac functions in long-term follow-up. METHODS: Seventy type 2 normotensive diabetics (33 female, 37 male; mean age, 52.9 +/- 10.4 years) were included in the study. Poor R-wave progression in an ECG was defined as an R wave < 3 mm in V1-3 derivations. The patients were randomized in 2 groups, which were those without (group I, n = 34) and those with poor R-wave progression (group II, n = 36). All patients underwent conventional and tissue Doppler echocardiography and were followed in an outpatient clinic setting for 4 years. RESULTS: Demographic variables were similar between the 2 groups. In group II, left ventricular (LV) relaxation abnormality was more prevalent, the Tei index was higher, and in tissue Doppler mitral annulus Em velocities were significantly lower and Am velocities were higher than those with normal R-wave progression. At the end of the 4-year follow-up period, LV ejection fraction was decreased in group II, whereas LV mass index and Tei index were significantly increased. CONCLUSIONS: LV diastolic dysfunction is more frequently observed in diabetic patients with poor R-wave progression in ECG, which may be an early sign of LV dysfunction and DCMP in diabetics. PMID- 20842741 TI - Missed opportunities in the management of ST-segment elevation myocardial infarction in the Arab Middle East: patient and physician impediments. AB - BACKGROUND: Lack of timely reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI) has been associated with worse outcomes. The aim of this study is to identify the frequency and predictors of delayed presentation and missed reperfusion in patients with STEMI in the Gulf Register of Acute Coronary Events (Gulf RACE) registry. Delayed Presentation and missed reperfusion is associated with increased in hospital mortality in STEMI patients. METHODS: Gulf RACE is a prospective, multinational study of all consecutive patients hospitalized with the final diagnosis of acute coronary syndrome in 65 centers in 6 Arab countries. In this analysis, we included 3197 patients with STEMI. The independent predictors of delayed presentation and missed reperfusion therapy were identified using multivariate logistic regression. RESULTS: In total, 929 patients presented > 12 hours after symptom onset. The independent predictors of late presentation are older age, atypical symptoms, no family history of coronary artery disease, and being in Yemen. Of the 2268 STEMI patients presenting early, a total of 205 patients (9.3%) did not receive reperfusion therapy despite no contraindications (shortfall). The independent predictors of not receiving appropriate reperfusion therapy are older age, prior stroke, being in Yemen, and atypical symptoms. Lack of reperfusion therapy due to shortfall or delayed presentation was associated with increased in-hospital mortality. CONCLUSIONS: Nearly one-third of patients with STEMI in the Arab Middle East present to the hospital > 12 hours after symptom onset, and nearly 1 in 10 eligible patients do not receive any reperfusion therapy. Community and physician awareness programs are needed to increase the utilization of appropriate lifesaving therapies. PMID- 20842742 TI - The effect of aldosterone antagonists for ventricular arrhythmia: a meta analysis. AB - BACKGROUND: Sudden cardiac death (SCD) from cardiac arrest, one of the most common types of cardiac-related death, is most often triggered by ventricular arrhythmia (VA). It has been reported that aldosterone antagonists (AAs) have the benefit of reducing SCD in patients with heart failure (HF). It also has been indicated in animal experiments and clinical trials that AAs may have an antiarrhythmic effect. HYPOTHESIS: AAs have an effect on VA in patients with HF or coronary artery disease. METHODS: We searched the Cochrane Central Register of Controlled Trials, PubMed, Current Controlled Trials, and the National Research Register, and identified randomized controlled trials on the effect of AAs on VA. RESULTS: All together, 7 trials with a total of 8635 patients were identified and extracted. AAs reduced the risk of SCD in patients with HF by 21% (relative risk [RR]: 0.79, 95% confidence interval [CI]: 0.67-0.93). AAs significantly reduced the episodes of ventricular premature complexes (mean difference 705 +/- 646 episodes per 24 hours). Risk of ventricular tachycardia was reduced by 72% (RR: 0.28, 95% CI: 0.10-0.77). CONCLUSIONS: The additional administration of AAs in patients with HF or coronary artery disease shows a benefit in reducing the risk of SCD and may also be effective for reducing episodes of ventricular premature complexes and ventricular tachycardia. PMID- 20842743 TI - Tricuspid annular plane systolic excursion evaluation improves selection of cardiac resynchronization therapy patients. AB - BACKGROUND: The beneficial effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) remodeling have been extensively described. Few data are available about the effects of CRT on right ventricular (RV) function and remodeling. HYPOTHESIS: We hypothesized that CRT could also induce reverse remodeling in the right ventricle and that RV baseline functional status expressed as tricuspidal annular plane systolic excursion (TAPSE) could affect CRT response. METHODS: Echocardiographic investigation was performed before and 6 months after CRT. In 192 patients, TAPSE, LV, and RV dimensions with functional parameters and LV dyssynchrony index were evaluated. RESULTS: At 6 months' follow up, 86 patients (45%) were responders to CRT according to at least 15% LV end systolic volume reduction. Among baseline echocardiographic parameters, responders had significantly lower TAPSE, larger LV volumes, and higher LV dyssynchrony index. In responders, LV volume reduction, ejection fraction increase, and mitral regurgitation improvement were associated with RV dimensions reduction, increased TAPSE, and improved LV dyssynchrony. Receiver operating characteristic curve analysis showed that TAPSE, at 17 mm optimal cutoff, yielded 64% sensitivity and 60% specificity in predicting CRT response; similarly, LV dyssynchrony index, at 41.25 ms optimal cutoff, predicted CRT response with 60% sensitivity and 62% specificity. A subgroup analysis demonstrated that the coexistence of high TAPSE and high dyssynchrony index values increased probability of CRT response. CONCLUSIONS: Our results show that CRT induces RV and LV reverse remodeling and that CRT patient selection can be improved by simply measuring TAPSE value. PMID- 20842744 TI - Comparison of sirolimus- and paclitaxel-eluting stents in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials. AB - BACKGROUND: It has been reported that sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) have been more effective than bare-metal stents in reducing restenosis and cardiac events in a broad range of patients with coronary artery disease. However, it is unknown whether there might be differences between these two drug-eluting stents in terms of efficacy and safety in the setting of acute ST-segment elevation myocardial infarction (STEMI). HYPOTHESIS: The aim of the present study was to compare SES with PES in patients with acute STEMI undergoing primary percutaneous coronary intervention (PCI). METHODS: The published research was scanned by formal searches of electronic databases (PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials) from January 2001 to February 2010. Internet-based sources of information on the results of clinical trials in cardiology were also searched. RESULTS: A total of 4 randomized trials were included in the present meta-analysis, involving 1105 patients (550 in the SES group, 555 in the PES group). SES were significantly more effective in the reduction of angiographic binary (>=50%) restenosis (4.0% vs 9.6%, odds ratio 0.38, 95% confidence interval 0.19 to 0.74, P = 0.004) compared to PES. The differences between SES and PES were not statistically significant with respect to target vessel revascularization (TVR), stent thrombosis, cardiac death, and myocardial infarction. CONCLUSIONS: SES are superior to PES in reducing the incidence of restenosis in patients undergoing primary PCI for STEMI, with nonsignificant differences in terms of TVR, cardiac death, myocardial infarction, and stent thrombosis. PMID- 20842745 TI - The role of the hospitalist in quality improvement: systems for improving the care of patients with acute coronary syndrome. AB - Quality improvement (QI) initiatives for systems of care are vital to deliver quality care for patients with acute coronary syndrome (ACS) and hospitalists are instrumental to the QI process. Core hospitalist competencies include the development of protocols and outcomes measures that support quality of care measures established for ACS. The hospitalist may lead, coordinate, or participate in a multidisciplinary team that designs, implements, and assesses an institutional system of care to address rapid identification of patients with ACS, medication safety, safe discharge, and meeting core measures that are quality benchmarks for ACS. The use of metrics and tools such as process flow mapping and run charts can identify quality gaps and show progress toward goals. These tools may be used to assess whether critical timeframes are met, such as the time to fibrinolysis or percutaneous coronary intervention (PCI), or whether patients receive guideline-recommended medications and counseling. At the institutional level, Project BOOST (Better Outcomes for Older Adults Through Safe Transitions) is an initiative designed to improve outcomes in elderly patients who are at higher risk for adverse events during the transition from inpatient to outpatient care. BOOST offers resources related to project management and data collection, and tools for patients and physicians. Collection and analysis of objective data are essential for documenting quality gaps or achievement of quality benchmarks. Through QI initiatives, the hospitalist has an opportunity to contribute to an institution's success beyond direct patient care, particularly as required for public disclosure of institutional performance and financial incentives promoted by regulatory agencies. PMID- 20842746 TI - Acute coronary syndrome update for hospitalists. AB - Acute coronary syndromes (ACSs)--unstable angina, non-ST-segment (ST, part of an electrocardiogram between the QRS complex and the T wave) or ST-segment elevation myocardial infarction (MI)--remain extremely common and clinically challenging. In addition to electrocardiography and biomarkers, formal risk stratification using risk scores has become an important part of the initial evaluation of patients with ACS. On the basis of the estimated risk of subsequent ischemic events, the optimal use and timing of cardiac catheterization and revascularization procedures can be determined. Additionally, antiplatelet and anticoagulant therapy can be instituted, with consideration given to both the ischemic and bleeding risks in an individual patient. A particular challenge in ACS management has been the rapid evolution of guidelines in response to new randomized clinical trial and registry data. Understanding and implementing the recommendations in these evidence-based guidelines are important parts of hospitalists' practice. PMID- 20842747 TI - Transitioning the patient with acute coronary syndrome from inpatient to primary care. AB - Patients with acute coronary syndrome (ACS) undergo several transitions in care throughout the hospital stay, from prehospitalization to the postdischarge period when patients return to primary care. Hospitalist core competencies promote safe transitions in care for patients with ACS, including hospital discharge. These competencies also highlight the central role of the hospitalist in facilitating the continuity of care and as a key link between the patient and the primary care provider (PCP). Core competencies address key decision points and processes that occur during hospitalization for ACS including the initial evaluation and risk stratification, medication reconciliation, and discharge planning. Discharge is a crucial transition and one where hospitalists can both facilitate the transition to primary care and improve adherence to quality measures established for ACS. Poor communication during discharge reportedly results in postdischarge adverse events, most often related to medications and lack of follow-up related to pending test results. Standards for a safe discharge such as Project RED (Re Engineered Discharge), initiatives to improve outcomes after discharge like Project BOOST (Better Outcomes for Older Adults Through Safe Transitions), and adaptive tools including the ACS Transitions Tool support timely and accurate communication of complex information between the hospitalist, the PCP, and the patient. While the role of hospitalists is evolving, it is clear that they have a central role in ensuring safe transitions in care for ACS. PMID- 20842748 TI - Cerebral arterial stenoses and stroke: novel features of Aicardi-Goutieres syndrome caused by the Arg164X mutation in SAMHD1 are associated with altered cytokine expression. AB - Aicardi-Goutieres syndrome (AGS) is a rare inborn multisystemic disease, resembling intrauterine viral infection and resulting in psychomotor retardation, spasticity and chilblain-likeskin lesions. Diagnostic criteria include intracerebral calcifications and elevated interferon-alpha and pterin levels in cerebrospinal fluid (CSF). We report on four adult siblings with unknown neurodegenerative disease presenting with cerebrovascular stenoses, stroke and glaucoma in childhood, two of whom died at the age of 40 and 29 years. Genome wide homozygosity mapping identified 170 candidate genes embedded in a common haplotype of 8Mb on chromosome 20q11-13. Next generation sequencing of the entire region identified the c.490C>T (p.Arg164X) mutationin SAMHD1, a gene most recently described in AGS, on both alleles in all affected siblings.Clinical diagnosis of AGS was then confirmed by demonstrating intracerebral calcifications on cranial computed tomography in all siblings and elevated pterin levels in CSF in three of them. Inpatient fibroblasts, lack of SAMHD1 protein expression was associated with increased basal expression of IL8, while stimulated expression of IFNB1 was reduced. We conclude that cerebrovascular stenoses and stroke associated with the Arg164X mutation in SAMHD1 extend the phenotypic spectrum of AGS. The observed vascular changes most likely reflect a vasculitis caused by dysregulated inflammatory stress response. PMID- 20842750 TI - Solitary plasmacytoma of the proximal tibia in an adolescent. AB - This is the case report of a 14-year young female who was diagnosed with solitary bone plasmacytoma (SBP) of proximal tibia and was treated by local involved field radiotherapy. We present the clinical, radiological and pathological findings of the case and review of the available treatment options and prognosis of this rare site presentation of plasmacytoma in an adolescent female. PMID- 20842749 TI - Deontological and altruistic guilt: evidence for distinct neurobiological substrates. AB - The feeling of guilt is a complex mental state underlying several human behaviors in both private and social life. From a psychological and evolutionary viewpoint, guilt is an emotional and cognitive function, characterized by prosocial sentiments, entailing specific moral believes, which can be predominantly driven by inner values (deontological guilt) or by more interpersonal situations (altruistic guilt). The aim of this study was to investigate whether there is a distinct neurobiological substrate for these two expressions of guilt in healthy individuals. We first run two behavioral studies, recruiting a sample of 72 healthy volunteers, to validate a set of stimuli selectively evoking deontological and altruistic guilt, or basic control emotions (i.e., anger and sadness). Similar stimuli were reproduced in a event-related functional magnetic resonance imaging (fMRI) paradigm, to investigate the neural correlates of the same emotions, in a new sample of 22 healthy volunteers. We show that guilty emotions, compared to anger and sadness, activate specific brain areas (i.e., cingulate gyrus and medial frontal cortex) and that different neuronal networks are involved in each specific kind of guilt, with the insula selectively responding to deontological guilt stimuli. This study provides evidence for the existence of distinct neural circuits involved in different guilty feelings. This complex emotion might account for normal individual attitudes and deviant social behaviors. Moreover, an abnormal processing of specific guilt feelings might account for some psychopathological manifestation, such as obsessive-compulsive disorder and depression. PMID- 20842751 TI - Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. AB - Hemophagocytic lymphohistiocytosis (HLH) is difficult to diagnose and treat. Highly elevated ferritin is strongly associated with HLH and levels may provide a prognostic marker. A comprehensive review of ferritin data from our patients during treatment was analyzed with respect to mortality. A patient was 17 times more likely to die when percent ferritin decrease was less than 50% as compared to a 96% or greater decrease as indicated with multivariate logistic modeling. Higher maximum ferritin levels in the first 3 weeks also contributed to the odds of death (OR = 5.6; 90% CI = 1.2-24.9). Regular ferritin measurements may be useful predicting outcomes in HLH patients. PMID- 20842752 TI - Acute myelogenous leukemia in a patient with severe factor IX deficiency. AB - We present a case of acute myelogenous leukemia in a patient with severe hemophilia and our approach to the prevention of bleeding complications during chemotherapy. In the few reports of acute leukemia occurring in patients with hemophilia, management of bleeding has mostly consisted of replacement of factor and platelets on demand. By prophylactically treating our patient with Factor IX at 50% correction three times per week and maintaining his platelet count above 30 * 10(3)/mm(3), bleeding complications were avoided. However, due to the rarity of this combination, it is difficult to draw a best practice recommendation. PMID- 20842753 TI - Caregivers' perspectives on barriers to transcranial Doppler screening in children with sickle-cell disease. AB - BACKGROUND: Current guidelines recommend that children with HbSS or HbSbeta degrees thal undergo yearly transcranial Doppler screenings (TCD) to identify those at high risk for stroke. Compliance is low with yearly TCD screenings. Our objective was to describe caregiver experiences and knowledge of TCD screenings as well as barriers that may prevent screening. PROCEDURE: Qualitative, in-depth interviews structured around the Health Belief Model were conducted with 36 caregivers of children eligible for annual TCD screenings. Interviews were coded and general themes were extracted. RESULTS: Two-thirds (69%) of caregivers believed that stroke occurs sometimes (33%) or frequently (36%) in children with sickle-cell disease (SCD). Lack of knowledge was the most commonly described barrier to annual TCD screening, with 22% of caregivers reporting no knowledge of screening, and 42% unaware that the screen should be performed annually. Lack of self-efficacy and fear of chronic transfusions were other barriers endorsed by caregivers. Barriers less commonly identified (endorsed by <10% of caregivers) included financial barriers, transportation issues, missed appointments, and hours of radiology clinic. Fifty-eight percent of the caregivers' children with SCD had undergone a TCD in the 18 months prior to the study interview. CONCLUSIONS: From the caregiver perspective, lack of knowledge and low self efficacy play a larger role than practical barriers in compliance with annual TCDs. Ongoing education at multiple patient encounters and encouragement of caregivers' empowerment and role in obtaining annual screenings may increase TCD compliance. PMID- 20842754 TI - Anti-emetic effect of ginger powder versus placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy. AB - PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of chemotherapy. Ginger has been used in postoperative and pregnancy induced nausea and vomiting. Data on its utility in reducing CINV in children and young adults are lacking. PATIENTS AND METHODS: Sixty chemotherapy cycles of cisplatin/doxorubicin in bone sarcoma patients were randomized to ginger root powder capsules or placebo capsules as an additional antiemetic to ondensetron and dexamethasone in a double-blind design. Acute CINV was defined as nausea and vomiting occurring within 24 hr of start of chemotherapy (days 1-4) and delayed CINV as that occurring after 24 hr of completion of chemotherapy (days 5-10). CINV was evaluated as per Edmonton's Symptom Assessment Scale and National Cancer Institute criteria respectively. RESULTS: Acute moderate to severe nausea was observed in 28/30 (93.3%) cycles in control group as compared to 15/27 (55.6%) cycles in experimental group (P = 0.003). Acute moderate to severe vomiting was significantly more in the control group compared to the experimental group [23/30 (76.7%) vs. 9/27 (33.33%) respectively (P= 0.002)]. Delayed moderate to severe nausea was observed in 22/30 (73.3%) cycles in the control group as compared to 7/27 (25.9%) in the experimental group (P < 0.001). Delayed moderate to severe vomiting was significantly more in the control group compared to the experimental group [14/30 (46.67%) vs. 4/27 (14.81%) (P = 0.022)]. CONCLUSION: Ginger root powder was effective in reducing severity of acute and delayed CINV as additional therapy to ondensetron and dexamethasone in patients receiving high emetogenic chemotherapy (ClinicalTrials.gov identifier: NCT00940368). PMID- 20842755 TI - The effectiveness of, and predictors of response to, inpatient treatment of anorexia nervosa. AB - OBJECTIVE: The inpatient treatment of anorexia nervosa lacks a clear evidence base. We sought to determine the effectiveness of, and predictors of response to, a specialist inpatient programme for adults with anorexia nervosa, and to survey satisfaction with the same. METHOD: Demographic and clinical data were collected, at three time points, for 90 consecutive admission episodes over a three-year period. RESULTS: Both a completers and an intention-to-treat analysis indicated the effectiveness of the programme. A longer length of hospital stay was associated with a greater degree of change in BMI, but no other predictors of treatment outcome were detected. Participants reported a high degree of satisfaction with the programme. CONCLUSION: Adults suffering from anorexia nervosa improved significantly with a specialist programme delivered in an inpatient setting. Future research should investigate the potential role of factors other than obvious demographic and clinical history variables in determining treatment outcome. PMID- 20842756 TI - Semi-parametric time-domain quantification of HR-MAS data from prostate tissue. AB - High Resolution--Magic Angle Spinning (HR-MAS) spectroscopy provides rich biochemical profiles that require accurate quantification to permit biomarker identification and to understand the underlying pathological mechanisms. Meanwhile, quantification of HR-MAS data from prostate tissue samples is challenging due to significant overlap between the resonant peaks, the presence of short T2* metabolites such as citrate or polyamines (T2 from 25 to 100 msec) and macromolecules, and variations in chemical shifts and T2*s within a metabolite's spin systems. Since existing methods do not address these challenges completely, a new quantification method was developed and optimized for HR-MAS data acquired with an ultra short T(E) and over 30,000 data points. The proposed method, named HR-QUEST (High Resolution--QUEST), iteratively employs the QUEST time-domain semi-parametric strategy with a new model function that incorporates prior knowledge from whole and subdivided metabolite signals. With these features, HR-QUEST is able to independently fit the chemical shifts and T2*s of a metabolite's spin systems, a necessity for HR-MAS data. By using the iterative fitting approach, it is able to account for significant contributions from macromolecules and to handle shorter T2 metabolites, such as citrate and polyamines. After subdividing the necessary metabolite basis signals, the root mean square (RMS) of the residual was reduced by 52% for measured HR-MAS data from prostate tissue. Monte Carlo studies on simulated spectra with varied macromolecular contributions showed that the iterative fitting approach (6 iterations) coupled with inclusion of long T2 macromolecule components in the basis set improve the quality of the fit, as assessed by the reduction of the RMS of the residual and of the RMS error of the metabolite signal estimate, by 27% and 71% respectively. With this optimized configuration, HR-QUEST was applied to measured HR-MAS prostate data and reliably quantified 16 metabolites and reference signals with estimated Cramer Rao Bounds <=5%. PMID- 20842757 TI - Dynamic in vivo mapping of model moisturiser ingress into human skin by GARfield MRI. AB - We describe the development of in vivo one-dimensional MRI (profiling) using a GARField (Gradient At Right angles to Field) magnet for the characterisation of side-of-hand human skin. For the first time and in vivo, we report measurements of the NMR longitudinal and transverse relaxation parameters and self-diffusivity of the upper layers of human skin with a nominal spatial resolution better than 10 um. The results are correlated with in vivo confocal Raman spectroscopy measurements of water concentration and natural moisturiser factors, and discussed in terms of known skin biology and microstructure of the stratum corneum and viable epidermis. The application of model moisturiser solutions to the skin is followed and their dynamics of ingress are characterised using the MRI methodology developed. Selected hydrophilic and lipophilic formulations are studied. The results are corroborated by standard in vivo measurements of transepidermal water loss and hydration status. A further insight into moisturisation mechanisms is gained. The effect of two different penetration enhancers on a commonly used skin care oil is also discussed, and different timescales of oil penetration into the skin are reported depending on the type of enhancer. PMID- 20842759 TI - A telephone-delivered psychosocial intervention improves dementia caregiver adjustment following nursing home placement. AB - OBJECTIVE: Study the preliminary efficacy of a telephone intervention, Family Intervention: Telephone Tracking-Nursing Home (FITT-NH) for improving dementia caregivers' adjustment following nursing home placement. METHODS: Caregivers were enrolled on average 6 weeks following the care-recipients' placement in a nursing home. Baseline assessment included self-report measures of caregiver emotional functioning, staff-caregiver interactions, placement satisfaction, health-related quality of life, and social support. Caregivers were randomly assigned to FITT-NH (n = 24) or a non-contact control condition (n = 22). Caregivers were urn randomized to balance groups on caregiver gender, relationship (spouse versus other), and facility type (dementia special care versus general). The intervention was entirely telephone-delivered in 10 contacts over 3 months. Caregivers randomized to non-contact control were not prevented from using other community-based mental health or support resources, therefore reflecting standard care. Intervention strategies were based on assessment of caregiver emotional adjustment, family functioning, staff-caregiver interactions, health, and social support. Treatment strategies are based on models of stress and coping process and family functioning. RESULTS: Groups did not differ in caregiver age, education, gender, relationship to the care recipient, length of caregiving, length of dementia diagnosis, or time since placement. Using mixed model analysis of variance, caregivers receiving FITT-NH showed a significant reduction in feelings of guilt related to placement, F(1,43) = 5.00, p < 0.05, and reported more positive perceptions of interactions with staff, F(1,43) = 4.59, p < 0.05, compared to standard care. CONCLUSION: Findings provide preliminary evidence for FITT-NH as a potentially efficacious, brief, targeted psychosocial intervention for improving caregiver emotional adjustment following nursing home placement. PMID- 20842760 TI - Identification of chemical constituents in Rhizoma Paridis Saponins and their oral administration in rat plasma by UPLC/Q-TOF/MS. AB - On-line ultra-performance liquid chromatography (UPLC) coupled with diode-array detection (UPLC/DAD) and electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS) were used for separation, identification and structural analyses of saponins in Rhizoma Paridis saponins (RPS) and rat plasma after oral administration of RPS. Thirty steroidal saponins in RPS were identified by comparing their retention time, accurate mass measurement and positive and negative mass spectrometry data with that of reference compounds. The UPLC/Q-TOF-MS method was proved to be rapid and efficient in that 30 steroidal saponins, including three kinds of saponins (prototype, pennogenyl and diosgenyl saponins) were tentatively characterized within 6 min. After oral administration of RPS, 21 original saponins were absorbed in RPS-treated rat plasma. Our results indicated that UPLC/Q-TOF-MS is a rapid and effective tool for identification of a series of saponins at trace level. PMID- 20842758 TI - Fluorine (19F) MRS and MRI in biomedicine. AB - Shortly after the introduction of (1)H MRI, fluorinated molecules were tested as MR-detectable tracers or contrast agents. Many fluorinated compounds, which are nontoxic and chemically inert, are now being used in a broad range of biomedical applications, including anesthetics, chemotherapeutic agents, and molecules with high oxygen solubility for respiration and blood substitution. These compounds can be monitored by fluorine ((19)F) MRI and/or MRS, providing a noninvasive means to interrogate associated functions in biological systems. As a result of the lack of endogenous fluorine in living organisms, (19)F MRI of 'hotspots' of targeted fluorinated contrast agents has recently opened up new research avenues in molecular and cellular imaging. This includes the specific targeting and imaging of cellular surface epitopes, as well as MRI cell tracking of endogenous macrophages, injected immune cells and stem cell transplants. PMID- 20842761 TI - Risk of hyperkalemia associated with selective COX-2 inhibitors. AB - BACKGROUND: Selective cyclooxygenase-2 (COX-2) inhibitors have been linked to cardiac death. The mechanism for this adverse effect appears to be by ischemic insult; however another mechanism could involve hyperkalemia. The objective of this study was to determine the effects of selective COX-2 inhibitors and non selective nonsteroidal anti-inflammatory drugs (NSAIDs) on serum potassium concentration and the electrocardiogram. METHODS: A retrospective cohort study was conducted using propensity score matching of patients from an inner-city academic medical center at Indianapolis, Indiana. Two hundred and two patients prescribed selective COX-2 inhibitors were matched to 202 patients prescribed non selective NSAIDs using propensity scores methods. Outcomes included change in serum potassium concentration from baseline and the risk of an abnormal electrocardiogram. RESULTS: Compared to patients prescribed non-selective NSAIDs, those prescribed a selective COX-2 inhibitor had a higher risk of serum potassium increase greater than 5 mEq/L (OR, 2.56; 95%CI, 1.03-6.36). However, patients prescribed selective COX-2 inhibitors had no greater risk of electrocardiogram abnormality (OR, 1.16; 95%CI, 0.74-1.82). CONCLUSIONS: Selective COX-2 inhibitors may have a greater risk of hyperkalemia than non-selective NSAIDs. This study was exploratory with small numbers of patients. Further studies are needed to confirm these results and any association with cardiovascular events. PMID- 20842762 TI - The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. AB - BACKGROUND: Zinc transporter-8 (ZnT8) was recently identified as a novel autoantigen in human type 1 diabetes (T1D). Autoantibody to ZnT8 (ZnT8A) was detected in up to 80% of patients with new-onset T1D and 26% of patients with T1D otherwise classified as negative on the basis of existing markers. As no data of ZnT8A in Chinese have been reported, we aim to evaluate the utility of ZnT8A for diagnosis of autoimmune T1D in Chinese relative to other autoantibody markers. METHODS: Radioligand binding assays were performed on 539 T1D sera using human ZnT8 carboxyterminal 325Arg construct or a dimer incorporating 325Arg and 325Trp alongside antibodies to glutamic acid decarboxylase (GADA) or insulinoma associated protein 2 (IA-2A). The antigenic specificity was analysed in the context of clinical characteristics of the patients. RESULTS: ZnT8A were present in 24.1% (130 of 539) of patients with T1D versus 1.8% (10 of 555; P < 0.001) in type 2 diabetes. At diagnosis, ZnT8A and IA-2A were less prevalent in Chinese subjects with T1D than in Caucasian populations (both P < 0.001) but similar to Japanese. The diagnostic sensitivity of combined GADA, IA-2A and ZnT8A measurements reached 65.5% with ZnT8A detected in 13.5% (29 of 215) of GADA and/or IA-2A-negative subjects. ZnT8A prevalence was lower in older and fatter patients. ZnT8A+ alone patients were distinguished from Ab- ones (P < 0.05-0.001) on the basis of higher insulin requirement and lower systolic blood pressure level. CONCLUSION: ZnT8A is an independent marker for T1D in Chinese and combined with GADA and IA-2A enhances diagnostic sensitivity. ZnT8A may be associated with different clinical phenotypes than GADA or IA-2A. PMID- 20842764 TI - Proceedings of the 37th Workshop of the Committee of Experimental Cardiology, October 14-19, 2009, Blansko, Czech Republic. PMID- 20842763 TI - [Imaging findings in cerebral toxoplasmosis]. PMID- 20842765 TI - Abstracts of the 17th European Congress on Obesity. May 6-9, 2009, Amsterdam, The Netherlands. PMID- 20842766 TI - Images in clinical medicine. Asterixis. PMID- 20842767 TI - Health-care dynamics in Haiti. PMID- 20842768 TI - Ethiopia struggles to make its voice heard. PMID- 20842770 TI - Abstracts of the 35th Congress of the Society of Biomechanics, 25-27 August 2010, Le Mans, France. PMID- 20842769 TI - When praise is worth considering in a difficult conversation. PMID- 20842771 TI - Rehabilitation following a minimally invasive procedure for the repair of a combined anterior cruciate and posterior cruciate ligament partial rupture in a 15-year-old athlete. AB - STUDY DESIGN: Case report. BACKGROUND: The healing response procedure is a minimally invasive arthroscopic surgical technique used to stimulate healing in the treatment of partial cruciate ligament tears. The purpose of this report is to provide information on the surgical procedure, the postoperative rehabilitation, and the overall functional results in a patient who underwent such a procedure. CASE DESCRIPTION: A 15-year-old male, who sustained a partial tear of both the anterior cruciate and posterior cruciate ligament while playing football, underwent arthroscopic surgical management utilizing a healing response technique. Precautions concerning range of motion and resisted activities were followed postoperatively to protect the healing cruciate ligaments. The postoperative protocol consisted of 3 phases, culminating in return-to-sport training. Treatment incorporated cardiovascular, proprioceptive, strength, power, plyometric, and sport-specific activities. Treatment was progressed based on specific criteria emphasizing proper movement patterns and eccentric control during functional activities. OUTCOMES: The patient attended 31 physical therapy sessions over 17 weeks. Strength improved from 3/5 to 5/5, knee range of motion returned to normal, Lower Extremity Functional Scale scores improved from 21/80 to 80/80, and successful outcomes on functional return-to-sport testing allowed the patient to return to competitive athletics. DISCUSSION: Primary repair of cruciate ligament tears has yielded poor results, and partial cruciate ligament tears may not require complete surgical reconstruction. The healing response technique offers a possible solution for the treatment of partial cruciate ligament tears. A criterion-based postoperative protocol was derived based on current evidence regarding rehabilitation following cruciate ligament reconstruction and evidence regarding lower extremity rehabilitation principles and injury prevention. LEVEL OF EVIDENCE: Therapy, level 4. PMID- 20842772 TI - Combination lipid therapy in type 2 diabetes. PMID- 20842773 TI - Combination lipid therapy in type 2 diabetes. PMID- 20842774 TI - Blood pressure control in type 2 diabetes. PMID- 20842775 TI - Blood pressure control in type 2 diabetes. PMID- 20842776 TI - Interactive medical case. Hard to conceive. PMID- 20842777 TI - NICE issues guidance on cancer of unknown primary. PMID- 20842778 TI - Image processing with cellular nonlinear networks implemented on field programmable gate arrays for real-time applications in nuclear fusion. AB - In the past years cameras have become increasingly common tools in scientific applications. They are now quite systematically used in magnetic confinement fusion, to the point that infrared imaging is starting to be used systematically for real-time machine protection in major devices. However, in order to guarantee that the control system can always react rapidly in case of critical situations, the time required for the processing of the images must be as predictable as possible. The approach described in this paper combines the new computational paradigm of cellular nonlinear networks (CNNs) with field-programmable gate arrays and has been tested in an application for the detection of hot spots on the plasma facing components in JET. The developed system is able to perform real time hot spot recognition, by processing the image stream captured by JET wide angle infrared camera, with the guarantee that computational time is constant and deterministic. The statistical results obtained from a quite extensive set of examples show that this solution approximates very well an ad hoc serial software algorithm, with no false or missed alarms and an almost perfect overlapping of alarm intervals. The computational time can be reduced to a millisecond time scale for 8 bit 496560-sized images. Moreover, in our implementation, the computational time, besides being deterministic, is practically independent of the number of iterations performed by the CNN-unlike software CNN implementations. PMID- 20842779 TI - Images in clinical medicine. Gestational pituitary-tumor apoplexy. PMID- 20842780 TI - Proceedings from the Global Discussion Forum on Worldwide Mycotoxin Reduction in Food and Feed Chains, September 9-11,2009 in Tulln, Austria. PMID- 20842781 TI - Tributes to Richard F. Bakemeier, MD. PMID- 20842782 TI - Disease mechanisms in neuroscience. Multiple sclerosis: a degenerative disease? PMID- 20842783 TI - Blood pressure control in type 2 diabetes. PMID- 20842784 TI - Retraction: "P39/Tsugane cells are a false cell line contaminated with HL-60 cells and are not suitable for mechanistic studies in myelodysplastic syndromes." by David P.Steensma. Haemato logica. 2010 Feb 23. [Epub ahead of print] with doi:10.3324/haematol.2009.022988 . PMID- 20842785 TI - ACGME duty-hour recommendations - a national survey of residency program directors. PMID- 20842787 TI - Retraction: "CKS1B nuclear expression is inversely correlated with p27Kip1 expression and is predictive of an adverse survival in multiple myeloma" by Hong Chang, Nan Jiang, Hua Jiang, Manujendra N. Saha, Connie Qi, Wei Xu, and Donna Reece. Haematologica. 2010 Apr 7th. [Epub ahead of print] with doi:10.3324/haematol.2009.022210. PMID- 20842786 TI - Images in clinical medicine. Bladder diverticula. PMID- 20842788 TI - Retraction: "Expanded and highly active proliferation centers identify a histological subtype of chronic lymphocytic leukemia ("accelerated" chronic lymphocytic leukemia) with aggressive clinical behavior" by Eva Gine', Antonio Martinez, Neus Villamor, Armando Lopez-Guillermo, Mireia Camos, Daniel Martinez, Jordi Esteve, Xavier Calvo, Ana Muntanola, Pau Abrisqueta, Maria Rozman, Ciril Rozman, Francesc Bosch, Elias Campo, and Emili Montserrat. Haematologica. 2010 Apr 7. [Epub ahead of print] with doi:10.3324/haematol. 2009.022277. PMID- 20842789 TI - Dutasteride and prostate cancer. PMID- 20842790 TI - Dutasteride and prostate cancer. PMID- 20842791 TI - Dutasteride and prostate cancer. PMID- 20842792 TI - Ultrasound-guided internal jugular vein cannulation. PMID- 20842793 TI - Abstracts of the Irish Paediatric Association Meeting, November 16, 2007, Dublin, Ireland; the Irish Paediatric Association Meeting, May 22-23, 2008, Westmeath, Ireland; and the Joint Irish Paediatric Association/Welsh Paediatric Society Meeting, May 14-16, 2009, Fota Islands, Cork, Ireland. PMID- 20842794 TI - Abstracts from the 6th European Congress of Andrology. September 29-October 1, 2010. Athens, Greece. PMID- 20842795 TI - Re: assessing safe and independent living in vulnerable older adults: perspectives of professionals who conduct home assessments. PMID- 20842796 TI - Re: lifetime follow-up care after childhood cancer. PMID- 20842797 TI - 25 years after the Bhopal gas tragedy. PMID- 20842799 TI - Abstracts of the Sixteenth International Conference of the Inflammation Research Association. September 26-29, 2010. Chantilly, Virginia, USA. PMID- 20842798 TI - Evidence that the impact of hearing impairment on psychosis risk is moderated by the level of complexity of the social environment. AB - BACKGROUND: It has been suggested that part of the increased vulnerability for psychosis in individuals with hearing impairment (HI) is the consequence of a decreased ability to form correct representations of the social world and attributions of intention of others. It was therefore hypothesized that associations between HI and psychosis risk would be sensitive to contextual variables representing higher level of social complexity, conceptualized as the population density of the social environment ('urbanicity'). METHODS: Urbanicity and objective HI were assessed in the Maastricht Aging Study (MAAS), a longitudinal study of 1,823 participants from the general population in Maastricht, the Netherlands. Participants were tested at baseline (T0) and at 6 year (T2) and 12-year follow-up (T4). The degree to which the association between HI (T0-T2) and psychotic experiences at T4 was moderated by T0 urbanicity was examined. RESULTS: The association between HI and psychosis was conditional on level of urbanicity (interaction chi2=7.51, p=.006), with low effect size in non urbanized areas (b=-0.81, 95% CI:-2.98, 1.36) and high effect size in the most urbanized areas (b=2.56, 95% CI: 0.47, 4.65). Although social isolation (b=1.74, p=.022) and loneliness (b=0.61, pb.001) were both associated with psychosis, they could not explain the observed interaction. CONCLUSION: The findings suggest that level of complexity of the social world, in interaction with the individual's ability to correctly process this information, may impact on risk for psychotic experiences. PMID- 20842800 TI - Abstracts of the 9th International Society for the Study of Xenobiotics (ISSX) Meeting. September 4-8, 2010. Istanbul, Turkey. PMID- 20842801 TI - Abstracts of ASCIA 2010, the 21st Annual Scientific Meeting of the Australian Society of Clinical Immunology and Allergy. September 1-3, 2010. Broadbeach, Queensland, Australia. PMID- 20842802 TI - Concerning SNOMED-CT content for public health case reports. PMID- 20842803 TI - Note on Friedman's 'fundamental theorem of biomedical informatics'. PMID- 20842805 TI - From journal to bedside. PMID- 20842806 TI - [Current status of prostate TUR in patients with high PSA]. PMID- 20842807 TI - Semen parameters, fertility and Factor V Leiden. PMID- 20842804 TI - In-vacuum Faraday isolation remote tuning. AB - In-vacuum Faraday isolators (FIs) are used in gravitational wave interferometers to prevent the disturbance caused by light reflected back to the input port from the interferometer itself. The efficiency of the optical isolation is becoming more critical with the increase of laser input power. An in-vacuum FI, used in a gravitational wave experiment (Virgo), has a 20 mm clear aperture and is illuminated by an almost 20 W incoming beam, having a diameter of about 5 mm. When going in vacuum at 10(-6) mbar, a degradation of the isolation exceeding 10 dB was observed. A remotely controlled system using a motorized lambda=2 waveplate inserted between the first polarizer and the Faraday rotator has proven its capability to restore the optical isolation to a value close to the one set up in air. PMID- 20842808 TI - Images in urology. BPH, indwelling catheter and multiple bladder stones. PMID- 20842809 TI - Takotsubo cardiomyopathy and arrhythmias: it's time we paid greater attention. PMID- 20842810 TI - Flow cytometric immunophenotyping for the diagnosis of a rare T-LGL neoplasm. PMID- 20842811 TI - A variant of PTPN22 gene conferring risk to autoimmune diseases may protect against tuberculosis. PMID- 20842812 TI - Freud in Trieste: journey to an ambiguous city. AB - This article provides an insightful exploration of the relationship between Sigmund Freud and the city of Trieste. Through an analysis of the correspondence between Freud and his friend Eduard Silberstein, Gandolfi follows those places visited by the future father of psychoanalysis and analyses their link to Freud's life. The journey to Trieste is considered as an experience that played a fundamental role in his future decisions as well as in the development of some of his psychoanalytic theories. The article eventually relates the ambiguous nature of the city - a peculiar space in with North and South, East and West converge - to Freud's own Triestine experience, that not only remits to his initial scientific researches, but also symbolizes a first significant contact with the world of sexuality. PMID- 20842813 TI - Travelling the path from fantasy to history: the struggle for original history within Freud's early circle, 1908-1913. AB - Between 1908 and 1913, Freud and his disciples debated different theories of the origins of mankind, which Freud analysed in the context of his theory of neuroses. Wittels was the first of this group to present, in 1908, what Freud labelled a "fantasy" on the subject. Wittels contemplated various prehistoric scenarios (such as a murder of the father by his children) which he postulated as potential explanations for the origin of man's conception of religion, law and state. Freud (1913) eventually conceived his own human prehistory which differed significantly from the ideas of Wittels and his other disciples (Jung, Tausk) and allowed him to claim he now held a "historical" point of view that his disciples were missing. PMID- 20842814 TI - Towards a history of operatic psychoanalysis. AB - This paper examines the history of the trope of psychoanalytic therapy in musical dramas, from Richard Wagner to Kurt Weill, concluding that psychoanalysis and the musical drama are, in some ways, companions and take cues from each other, beginning in the mid-19th century. In Wagner's music dramas, psychoanalytic themes and situations - specifically concerning the meaning and analysis of dreams - are presaged. In early modernist music dramas by Richard Strauss and Arnold Schoenberg (contemporaries of Freud), tacit representations of the drama of hysteria, its aetiology and "treatment" comprise key elements of the plot and resonate with dissonant musical soundscapes. By the middle of the 20th century, Kurt Weill places the relationship between analyst and patient in the foreground of his musical "Lady in the Dark," thereby making manifest what is latent in a century-spanning chain of musical works whose meaning centres, in part, around representations of psychoanalysis. PMID- 20842815 TI - Additional comments on the cause of spinal cord compression in a dog. PMID- 20842816 TI - Another perspective on feral cat control. PMID- 20842817 TI - [The role of osteopontin in cardiovascular diseases]. AB - Osteopontin (OPN) is an acid phosphorylated glycoprotein secreted by cells of the immune system, epithelial cells, smooth muscle cells, osteoblasts, osteoclasts, tumor cells and many more. Osteopontin is a multifunctional protein. Due to characteristic molecular structure containing integrin bining domains, OPN can interact with several integrin receptors, thus it play a role in activation, adhesion and migration of many cell types in such processes as inflammation, tissue mineralization and tumor genesis. This broad biological action of osteopontin underlie its presumed role in the pathogenesis of cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm formation. PMID- 20842818 TI - [Return of sinus rhythm in permanent atrial fibrillation patients at the time of the testing defibrillation during cardioverter-defibrillator implantation]. AB - Among patients, who underwent implantable cardioverter-defibrillator (ICD) implantation procedure, there are some, who have permanent atrial fibrillation (AF). There is a theoretical possibility of return of sinus rhythm at these patients during ventricular defibrillation testing at the time of the ICD implantation procedure. The aim of the study was to attempt to find agents which can promote return of sinus rhythm at the time of the defibrillation testing during ICD implantation. MATERIAL AND METHODS: Seventy-two (mean age 65.8 years, 60 men) of the 611 patients (mean age 63.3 years, 501 men) who underwent ICD induction over this period had permanent AF before and at the time of the procedure. RESULTS: The return of sinus rhythm was observed in 17 patients (Group A, mean age 64.2 years, 14 men) during ICD implantation, at the time of the defibrillation testing. The return of sinus rhythm after ICD intervention could be associated with presence of 2-coil electrode (p < 0.001), with lower left atrial diameter (p < 0.001), with lower NYHA class (p < 0.05) and greater use of antiarrhythmic drugs (p < 0.025). CONCLUSIONS: Atrial fibrillation was present in 11.7% of 611 ICD patients. We observed the return of sinus rhythm after ICD intervention in 2.7% persons. The return of sinus rhythm could be associated with presence of 2-coil electrode, lower left atrial diameter, lower NYHA class and greater use of antiarrhythmic drugs. To prevent embolic complication oral anticoagulation should be standard treatment in this group of patients. PMID- 20842819 TI - [Serum and urinary concentration of selected metalloproteinases and their tissue inhibitors in children with vesicoureteral reflux]. AB - Vesicoureteral reflux (VUR) in children may lead to the renal fibrosis and scarring due to the overproduction and accumulation of extracellular matrix proteins (ECM) in interstitial tissue. Metalloproteinases produced in the kidneys are called biological markers of fibrosis. THE AIM OF THE STUDY was to assess if the presence of VUR in children disturb the balance between the serum and urinary concentrations of matrix metalloproteinases 2 and 9 and their tissue inhibitors 1 (TIMP-1) and 2 (TIMP-2) and predispose to excessive renal fibrosis. MATERIAL AND METHODS. The study was performed in 88 children, median aged 5.5 years (0.08-16 yrs) with VUR confirmed by voiding cystouretrography (VCUG). In 95% of estimated children the pyelonephritis indicated for VCUG performance. Control group consisted of 30 healthy children at similar age. Concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 were estimated using immunoenzymatic ELISA method in urine of all examined children, additionally all the mentioned parameters in children with high (ll-V) grade of VUR were assessed in serum. RESULTS revealed that the urinary and serum concentrations of TIMP-1 and TIMP-2 were higher in healthy controls (p < 0.05). MMP-9 levels were higher only in the urine (p < 0.05) and MMP-2 in serum (p < 0.05). Increase in TIMP concentrations was connected with parallel increase in MMP levels in children with I-V grades of VUR, what was confirmed by the normal values of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (p > 0.05). Only children with Ill-rd grade of VUR revealed reduced values of MMP/TIMP ratios (p < 0.05). Children's with Ill-V grade VUR revealed higher increase in serum concentrations of TIMP than in MMP, it was also seen in decrease in MMP/TIMP ratios (p < 0.05). No correlation was found between serum and urinary results of estimated parameters (p > 0.05). CONCLUSION: MMP-2 and MMP-9 and TIMP 1 and TIMP-2 play role in pathogenesis of VUR disturbances, what was confirmed by the change in their serum and urinary concentrations. In serum and urine of children with high (Ill-V) grade VUR the biggest disturbances were observed in MMPs: TIMPs system with the TIMP levels higher than MMP values, what indirectly indicated ECM degradation disturbances and increase in renal fibrosis. PMID- 20842820 TI - [Serum C-peptide concentration in overweight and obese women with polycystic ovary syndrome]. AB - It is believed that important pathogenic mechanism in polycystic ovary syndrome (PCOS) is hyperinsulinemia. Insulin synthesis is linked to C-peptide release, but the role of C-peptide in PCOS is not well described. THE AIM OF THE STUDY was to evaluate C-peptide serum levels in overweight or obese women with PCOS and assessment of correlation between serum concentrations of C-peptide and androgens and metabolic disturbances in PCOS. MATERIALS AND METHODS: 65 women diagnosed with PCOS were included to the study. I group consisted of 5 overweight PCOS women (27.2 +/- 3.6 years old; BMI 27.3 +/-1.5 kg/m2), and II group included 60 obese PCOS women (26.2 +/- 6.3 years old; BMI 35.0 +/- 4.45 kg/m2). The control group consisted of 10 healthy, ovulatory women with normal weight (aged 28.8 +/- 4.8 years; BMI 21.2 +/- 2.1 kg/m2). Folliculotrophin (FSH), lutrophin (LH), 17beta-estradiol (E2), testosterone (T), dehydroepiandrosterone sulfate (DHEAS) and insulin concentrations were measured in serum. Serum fasting glucose levels and lipid profile was assessed: total cholersterol (Ch), triglycerides (TG), low (LDL) and high density lipoproteins (HDL). C-peptide levels were measured using commercially available test (Human C-Peptide ELISA Kit, Dako). RESULTS: C-peptide concentrations in PCOS overweight group were 1.39 +/- 0.9, and in PCOS obese group were 1.31 +/- 1.05 nmol/I, whereas among healthy women 1.62 +/- 1.56 nmol/I. Those differences were not statistically significant. C-peptide serum levels did not correlated significantly with FSH, LH, E2, T, DHEAS serum levels within studied groups. Negative correlation between C-peptide and glucose serum levels was found in control group (R = -0.71; p < 0.05). Positive correlation between these values in PCOS overweight group was found (R = 0.90; p < 0.05). In PCOS obese group there was no correlation between these values. CONCLUSIONS: Young obese or overweight women with PCOS are characterized by comparable serum C peptide levels to serum C-peptide concentration in healthy young women. There is no correlation between serum C-peptide and androgens in obese or overweight patients with PCOS. The link between C-peptide and hyperinsulinemia and other metabolic disturbances in PCOS is very complex and requires further studies. PMID- 20842821 TI - [The risk of death following the consumption of ethanol based on forensic research material]. AB - The number of abusers in Poland is estimated at about 2.8-3.5 million, including about 600-900 thousands dependent. In this group a variety of somatic disorders and mental health are diagnosed. Mortality among persons with alcohol dependence is several times higher than among those abstainers. Alcohol dependence increases the risk to attempt suicide. Health damage caused by alcohol depends on: the frequency and quantity of drinking of alcohol, age, gender, duration of addiction. THE AIM OF THIS STUDY was to analyze the causes of death in the aftermath of alcohol consumption based on sectional material. MATERIALS AND METHODS: We analyzed 336 autopsy protocols. In order to analyze the collected material was used a questionnaire created for this study. Deaths have been divided into two groups: violent deaths, resulting from trauma and natural deaths. RESULTS: It was observed significant relationship between alcohol consumption and the nature of death. CONCLUSIONS: Most of the deaths associated with alcohol consumption is a sudden deaths, not due to natural causes. Among the sudden deaths domination of ethyl alcohol poisoning, traffic accidents, murder, hanging and drowning. PMID- 20842823 TI - [The case of arteriovenous malformation in midbrain in patient with vision disorders]. AB - The authors present a case of 39 years old male who was admitted to the hospital with non-specific vision disorders. The clinical features and radiological examination have led to the diagnosis of arteriovenosum malformation in midbrain. In case of that patient it is worth noticing the difference between the size and location of malformation and its clinical symptoms. The neurological symptoms didn't indicate that there is arteriovenous malformation of that size in midbrain and shows the importance of radiological examination in neurological practice. Location of malformation was also a problem in choosing the way of treatment. Radiotherapy was chosen as less invasive in case of that patient. The patient is currently undergoing radiotherapy in Oncology Center in Gliwice, in general satisfactory condition. PMID- 20842822 TI - [Antiviral treatment of chronic B hepatitis; 2010 - therapeutic recommendations]. AB - The drugs currently approved for treatment of HBV infections are: interferon alpha2a and alpha2b, pegylated interferon (PeglFN-al-pha2a) natural interferons and nucleos(t)ide analogues (NA): adefovir, entecavir, lamivudine, telbivudine (currently not available in Poland) and tenofovir. The following questions are described: the primary goal of antiviral treatment, criteria in therapeutic decision-making (including extrahepatic manifestations, compensated and decompensated cirrhosis of the liver), treatment failure (including: drug resistance), management of patients with HBV-positive markers, in whom chemotherapy or other immunosuppressive therapy is planned. In treatment-naive patients with chronic hepatitis B the first line therapy should be PeglFN-alpha2a monotherapy, and the first-line should be entecavir or tenofovir (highest potential for HBV replication suppression and high genetic barrier to resistance). In drug resistance the patient should be switched to another, preferably high-potency NA (entecavir or tenofovir) or start PeglFN-alpha2a therapy. PMID- 20842825 TI - [Peripheral neuropathies in Lyme borreliosis]. AB - Lyme borreliosis is a multisystem disease and when involves the nervous system it is termed neuroborreliosis. The symptomatology of peripheral neuroborreliosis is rich and varied. The early symptoms are asymmetric polyradiculopathies and paralysis of the cranial nerves (most commonly facial nerve). Thereafter, there are multifocal mononeuropathies and sensory-motorpolyneuropathies. Difficulties in making a correct diagnosis can result from the long time lag between tick bite and the occurrence of neurological symptoms. In the treatment the most important role play antibiotics. CASE REPORTS: We report the cases of three patients with symptoms of damage to various structures of the peripheral nervous system in the course of Borrelia burgdorferi infection. In all cases, clinical improvement was obtained after treatment with antibiotics, which further confirms the diagnosis of neuroborreliosis. CONCLUSIONS: About neuroborreliosis as a cause of peripheral neuropathy we should always think in the case of vague symptoms of peripheral nervous system lesions in patients with potential exposure to tick bites. Peripheral neuropathies may occur a long interval from the tick bite and are not always preceded by other forms of the disease. PMID- 20842824 TI - [Xanthinuria type I as the cause of nephrolithiasis in 17-years old girl]. AB - Classic xanthinuria is a rare metabolic defect concerning the final reactions of purine catabolism. There are two types of the disorder: type I results from xanthine dehydrogenase (XDH) deficiency, while type II is characterized by lack of both XDH and aldehyde oxidase activity. Both types are clinically similar and are characterized by elevated xanthine concentration in body fluids that can lead to xanthine crystallisation. The most common manifestation of the disease is urolithiasis, but in most cases xanthinuria remains asymptomatic and the diagnosis is accidental. In the paper we report the first case study of xanthinuria in Poland in a child presenting with urolithiasis. 17-years old female patient was diagnosed because of recurrent urinary lithiasis and hypouricemia was detected during routine tests. Plasma and urine concentrations of oxypurines were measured by high-performance liquid chromatography (HPLC) and showed typical features of xanthinuria: hypouricemia, hypouricosuria, xanthinuria and elevated plasma xanthine. The allopurinol loading test demonstrated type I xanthinuria. The presented case report supports that first symptoms of xanthinuria can appear at any age and this disorder should be considered during diagnosing urolithiasis. PMID- 20842826 TI - [Hereditary stomatocytoses--diagnostic problems and their molecular basis]. AB - Hereditary stomatocytosis (HSt) is a group of haemolytic anaemias in which the common symptom is an increased permeability of the red cell membrane for monovalent cations. HSt is diagnosed really seldom and the difficulties in diagnosing are connected to the fact that the clinical presentation of individual subtypes of HSt is very diverse. Many cases are characterised by unique phenotypes. Nevertheless, the number of diagnosed HSt cases is increasing each year. The aim of this review was the presentation of current information and an attempt to systematize it, what might be helpful in clinical diagnostic of the new cases of this anaemia. The most frequent mistake is to classify a case of HSt as the most common haemolytic anaemia--hereditary spherocytosis (HS), in which to improve patient condition a splenectomy is often recommended. Most cases of HSt no positive response to splenectomy and often thromboembolic complications are observed. It is interesting that commonly present in blood film stomatocytes and in many cases absent or severely reduced stomatin in HSt red cell membrane are not correlated with nucleotide sequence changes of the gene encoding stomatin. Many diagnosed cases are related to mutations in SLC4A1 and RHAG genes. Extensive research carried out on HSt in the entire world will certainly permit to know the molecular basis of the disease, the diversify of its subtypes and to estimate the real incidence of HSt. PMID- 20842828 TI - [Usefulness of evaluation of soluble fragment cytokeratin 18, carcinoembryonic antigen and gastrointestinal carcinoma-associated antigen in diagnostic of patients with colorectal cancer]. AB - Colorectal cancer is one of the most frequent malignant neoplasms which affects humans. Last year studies indicate a constantly increasing inception rate. Multidisciplinary teams direct all their efforts towards detection of cancer in it's asymptomatic phase. In parallel with development of diagnostic imaging is development of clinical immunodiagnostics. The last allows for quantitative determination of active neoplasmic process markers. In the following article authors show the most frequent markers used in immunodiagnostic. Colorectal cancer known as "tumor burden markers CEA, CA 19-9 as well as the "new one" tissue polypeptide specific antigen proliferation marker--TPS. PMID- 20842827 TI - [Wilson's disease]. AB - Wilson's disease is caused by a P-type ATP-ase gene mutations with reduced biliary copper excretion and accumulation copper in the liver and other tissues. Clinical symptoms can be heterogeneous but in many cases on the first stage the only abnormalities is elevation of aminotransferase activity. In some cases the first fatal symptom of disease is acute liver failure, therefore early diagnosis and treatment is essential. We present an actual recommendations for diagnosis and treatment of patients with Wilson's disease. PMID- 20842829 TI - [Rituximab in systemic lupus erythematosus. Part I. Theoretical basis]. AB - Rituximab is a chimeric human-mouse monoclonal antibody, which binds to the CD20 antigen on B lymphocytes and causes depletion of CD20+ cells in the mechanism of complement-dependent and independent cytolysis, cell cytotoxicity and antibody dependent mechanism and apoptosis. Rituximab is currently registered for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis. Rituximab also demonstrated efficacy in a number of other autoimmune diseases, including systemic lupus erythematosus. In patients with systemic lupus erythematosus rituximab decreases the number of autoreactive VH4.34 B cells, what contributes to sustaining B cell homeostasis and immune tolerance. A decrease in levels of circulating anti-dsDNA antibodies and an increase of C3 concentration is observed parallel to clinical improvement. Diagnostic procedures performed before initiation of rituximab therapy and during treatment include basic laboratory tests as well as exclusion of heart insufficiency and infections. PMID- 20842830 TI - [Rituximab in systemic lupus erythematosus. Part II: review of clinical experience]. AB - Rituximab is a chimeric human-mouse monoclonal antibody, which binds to the CD20 antigen on B lymphocytes and causes depletion of CD20+ cells. Rituximab is currently registered for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis. Rituximab also demonstrated efficacy in a number of other autoimmune diseases, including systemic lupus erythematosus. Data available from over published 200 cases may indicate that 50 75% of patients with lupus achieve at least partial remission after rituximab therapy. This effect was not confirmed in a randomized, double-blind phase II/III clinical trial. However methodological inaccuracies which might have led to incorrect conclusions in this trial were pointed out. Further studies are needed to evaluate efficacy of rituximab in different clinical and immunological subtypes of systemic lupus erythematosus. PMID- 20842831 TI - [The role of sonic hedgehog pathway in skin carcinogenesis]. AB - Non melanoma skin cancers (NMSC) involving basal (BCC)--and squamosus cell carcinomas (SCC) and are the most frequent skin cancers in Caucasians. Ultraviolet radiation is the main environmental risk factor for NMSC development. The aim of this paper is to review the latest opinions concerning the role of sonic hedgehog pathway in non-melanoma skin cancers development. Experimental data indicate that sonic hedgehog pathway might be involved in skin carcinogenesis. Under physiological conditions sonic hedgehog pathway is responsible for normal embryogenesis, regeneration of damaged tissues and for regulation of cell proliferation. It was revealed that UVR caused inactivated mutation in PATCHED gene encoding Ptch1 protein. These events lead to deregulation of sonic hedgehog pathway trough activation of Smo protein and Gli transcriptional factors what stimulates cell proliferation and in consequence NMSC development. Literature data indicate that understanding of molecular background of skin cancers might be a reason for introduction of new therapeutic approaches including sonic hedgehog pathway inhibitors. PMID- 20842832 TI - [A medical image color correction method based on supervised color constancy]. AB - This paper presents a medical image acquisition and analysis method-TRM (Topology Resolve-Map) Model-under natural light condition indoors. Firstly, in accordance to medical image color characteristics, a colorful and grayscale color control patch was made for use as supervised color. "Topology Resolve-Map-Restoration" was carried on in LAB color space of the one-dimensional L* space and the two dimensional a* b* space. Then, L* value was regulated by subsection regulation and a* b* value was regulated by triangulation topological cutting--close in on center of gravity method. After correction of the 198 color blocks in 22 pictures, the results showed that, by comparison with the standard value, the deltaL*, deltaC* and deltaE decreased significantly (P < 0.01) after correction by TRM. After correction, the difference in image's color is reduced, the color saturation is improved and the value is closer to true value. TRM model can significantly reduce the color difference of the medical image under natural light condition; it has a good effect on color correction. PMID- 20842833 TI - [Blind estimation of evoked potentials based on covariations in non-gaussian noise]. AB - Evoked potentials (EPs) have been widely used to quantify neurological system properties. Traditional EP analysis has been developed under the condition that the background noises in EP are Gaussian distributed. Recently some researches indicate that electroencephalogram (EEG) is non-guassian in some especial conditions. Alpha stable distribution can model impulsive EEG in especial experimentation such as acceleration bump and devoid oxygen. In this paper, blind signals separation based on covariations is analyzed and discussed by the nonexistence of the finite second or higher order statistic. The simulation experimental results show that the method has good performance to separate Evoked potentials (EPs) from fractional lower order alpha stable distribution noise. PMID- 20842834 TI - [Human amniotic fluid influenced by different sampling methods during 1H NMR based metabonomics analysis]. AB - To assess the influence of different sampling methods on Human Amniotic Fluid (HAF) during metabonomics analysis, and to establish a metabolite profile database for normal human amniotic fluid, four experimental groups (the group of freeze-drying, of freeze-thawing, of storage at -20 degrees C, and of keeping in room temperature) and a control group were investigated by use of 1H-NMR spectroscopy, respectively; the data of H-NMR spectroscopy was treated by principal components analysis (PCA). The results showed that, by comparison with the control, there were distinct differences in the experimental groups except the group of storage at -20 degrees C. Therefore, It is possible to use 1H-NMR based metabonomics technique for analysis of HAF; moreover, during the tests, careful treatments of HAF should be institued to minimize the influence on the samples. PMID- 20842835 TI - [Effects of echo time on the liver fat quantification using proton magnetic resonance spectroscopy]. AB - This study was aimed to evaluate the effects of different echo time (TE) on the liver fat quantification using proton magnetic resonance spectroscopy (1H-MRS). Liver 1H-MRS was performed on 24 adult male wistar rats on a 1.5 T superconductor MR scanner. Spectrums were collected with a TR of 1500 ms and different TE of 35, 45, 55, 65, 75, 85, 95, 105, 144 ms, respectively. The water and lipid peaks, baseline of the spectrum and lipid to water ratio were evaluated. With the increment of TE, the amplitude and integrated area of the water and lipid peaks decreased, and the baseline of the spectrum and the lipid to water ratio became unstable. The lipid to water ratio determined by 1H-MRS was highly correlated with the liver fat content determined by pathological analysis at TE between 35 and 55 ms (r > 0.9) and poorly to moderately correlated at TE > or =65 ms (r < 0.9). The results indicated that long TE would compromise the liver fat quantification using 1H-MRS, and therefore short TE was strongly recommended for liver fat quantification. PMID- 20842836 TI - [Extraction of evoked related potentials by using the combination of independent component analysis and wavelet analysis]. AB - In this paper we present a new method of combining Independent Component Analysis (ICA) and Wavelet de-noising algorithm to extract Evoked Related Potentials (ERPs). First, the extended Infomax-ICA algorithm is used to analyze EEG signals and obtain the independent components (Ics); Then, the Wave Shrink (WS) method is applied to the demixed Ics as an intermediate step; the EEG data were rebuilt by using the inverse ICA based on the new Ics; the ERPs were extracted by using de noised EEG data after being averaged several trials. The experimental results showed that the combined method and ICA method could remove eye artifacts and muscle artifacts mixed in the ERPs, while the combined method could retain the brain neural activity mixed in the noise Ics and could extract the weak ERPs efficiently from strong background artifacts. PMID- 20842837 TI - [The continuous analysis of EEG's alpha wave by morlet wavelet transform]. AB - Complex Morlet wavelets, as a wavelet function, is most commonly used in the time frequency analysis of EEG signal and in the extraction of the instantaneous power and phase. This article explains how to use the Morlet wavelet transform for obtaining EEG's alpha wave energy distribution over time, and how to use the EEG data of mental arithmetic experiment for obtaining the changes of the alpha wave duration. PMID- 20842839 TI - [Scale invariance based analysis of pathological ECG signals]. AB - In this paper, the multifractal detrended fluctuation analysis method was used to study the multifractal characteristics of atrial premature beat (APB) signals, of premature ventricular contraction (PVC) signals and of normal ECG signals. By analyses of Hurst index, Renyi index and multifractal spectrum, three kinds of signals were noted to have different degrees of long-range correlation and multifractal characteristics. Normal ECG signals had the strongest fractality, the PVC beats had stronger fractality and the APB beats had the weakest fractality. When the fluctuations function order was positive, the three kinds of signals showed distinct long-range correlation properties. These findings are of good reference to diagnosing and distinguishing between PVC and APB signals in clinical medicine. PMID- 20842838 TI - [Research for transcutaneous energy transfer based on PCB coreless planar circular spiral inductor coils]. AB - In this paper is proposed a new PCB coreless planar circular spiral inductor coils-based transcutaneous energy transfer method for use in implantable biomedical devices. Firstly, the main factor, coupling coefficient k between transmitting and receiving coils, which affected the efficiency of the energy transfer, was determined by setting up the circuit model of transcutaneous energy transfer. Then, the coupling coefficient was analyzed and calculated by using the method of equivalent circular filaments. Finally, experiments were carried out to demonstrate the feasibility of the proposed method. PMID- 20842840 TI - [Research on information extraction of electronic medical records in Chinese]. AB - This is a research to enhance the application of natural language understanding and ontology in the Chinese medical text semantic annotation and content analysis, and so to provide technology support for the computer-readable electronic medical records (EMR). The Chinese EMR information extraction and statistical analysis of related subjects in accordance to the user's demands were performed through building the named entity rules, the classified word list and field ontology by using GATE platform on the basis of EMR text set's construction and pre-processing. The automatic and artificial semantic annotation of EMR text set was implemented. The situation of drugs used in medicinal treatment and the distribution of patients' age and sex were obtained. The ontology-based semantic information extraction can improve the function of computer for text understanding, and the discovery of knowledge in EMR through field ontology is feasible. PMID- 20842842 TI - [The lower limb blood pressure measurement of ankle-brachial index based on underdetermined blind signal]. AB - As there are a number of ankle arteries and some of them can not be blocked completely under higher pressure from the external inflate cuff, we can not accurately identify the starting point of the pulse wave, so the errors of lower limb systolic blood pressure measurement take place and affect the accuracy of ankle-brachial index in diagnosing vascular disease. In this paper, we constructed delay vectors from the data we already collected from lower limb pulse wave and formed an embedding matrix; thus solving the problem of inadequate sensor dimensions. We extracted a single arterial pulse wave through the blind signal separation on the basis of embedding matrix, and we identified the lower limb systolic blood pressure corresponding to the starting point. Simulation and clinical experiments show the method can be used to separate the wave signals of ankle artery which contains information of systolic blood pressure. It improves the accuracy of lower limb systolic blood pressure measurement and hence provides accurate data for the clinical diagnosis of arterial disease. PMID- 20842841 TI - [Research on non-rigid medical image registration algorithm based on SIFT feature extraction]. AB - In allusion to non-rigid registration of medical images, the paper gives a practical feature points matching algorithm--the image registration algorithm based on the scale-invariant features transform (Scale Invariant Feature Transform, SIFT). The algorithm makes use of the image features of translation, rotation and affine transformation invariance in scale space to extract the image feature points. Bidirectional matching algorithm is chosen to establish the matching relations between the images, so the accuracy of image registrations is improved. On this basis, affine transform is chosen to complement the non-rigid registration, and normalized mutual information measure and PSO optimization algorithm are also chosen to optimize the registration process. The experimental results show that the method can achieve better registration results than the method based on mutual information. PMID- 20842843 TI - [Features of tumor perfusion of gastric cancer with 64-MDCT: a pilot study]. AB - This is a prospective study using first-pass perfusion CT with volume-based technique to investigate perfusion features of gastric cancer. Perfusion CT was performed with 64-section MDCT on 35 patients with gastric cancer; these patients were subdivided into three subgroups according to the location of the tumor; besides, 24 patients with normal stomach served as controls. Four perfusion parameters, including perfusion (PF), peak enhancement (PE), time to peak (TTP), and blood volume (BV), were obtained and compared between the test and control groups, and between the groups with and without lymph-node metastases. ROC analysis was performed to determine the cutoff value for discriminating the microcirculation of gastric cancer from that of the normal stomach. The results showed that blood volume was significantly increased in the test group, compared with the control group. The threshold of 8.6 ml x 100 g(-1) of blood volume was noted to be corresponding to a sensitivity of 88.6% and a specificity of 62.9%. In conclusion, the first-pass perfusion CT with whole tumor acquisition technique could assess tumor vascularity and be useful for the diagnosis of gastric cancer. PMID- 20842844 TI - [Support vector data description for finding non-coding RNA gene]. AB - In the field of computational molecule biology, there is still a challenging question of how to detect non-coding RNA gene in lots of unlabeled sequences. Generally, the methods of machine learning and classification are employed to answer this question. However, only a limited number of positive training samples and unlabeled samples are available. The negative samples are difficult to define appropriately, yet they are necessary for usual learning-then-classification method. The common way for most of the existing non-coding RNA gene finding methods is to produce a number of random sequences as negative samples, which may hold some characteristic of positive sample sequences. Consequently, the contrived uncertain factor was introduced and the performance of methods was not good enough. In this paper, Support Vector Data Description (SVDD) is in use for to learning and classification as well as for detecting non-coding RNA gene in lots of unlabeled sequences, and the k-means clustering algorithm is employed before SVDD training to deal with the high flase positive fault in the result of SVDD. The training samples (target samples) are non-coding RNA genes validated by experiment. Moreover, appropriate features were constructed by Principal Component Analysis (PCA). The effectiveness and performance of the method are demonstrated by testing the cases in NONCODE databases and E. coli genome. PMID- 20842845 TI - [Numerical simulation of the distribution of shear stress on the bottom of parallel plate flow chamber under different inlet velocity conditions]. AB - The distribution of shear stress on the bottom of the parallel plate flow chamber under different inlet velocities was analyzed by numerical simulation. In the present experimental study, the projection planes of the relative errors at 0.7% level were obtained, and then the efficient region and the actual entrance length were further corrected by introducing the concept of relative error. The results showed that the efficient region of the chamber increased with the direction of length while the inlet velocity was increased, and the actual entrance length was much greater than that of the theoretical entrance length. Therefore, in accordance to the needed range of shear stress in experiment and to the needed efficient region area, the optimum design of the flow chamber is necessary. PMID- 20842846 TI - [The potential field-based trajectory planning of needle invasion in soft tissue]. AB - Soft tissue is one kind of elastic tissue which includes the blood vessel and nerve, and brachytherapy is a radioactive and non-invasive way for the treatment of cancer in which soft tissue is always deformed. Aiming at this soft tissue induced-problem, the present authors have made a research on the trajectory planning in operation. The 3D artificial potential field of organ is set up by the function definition of cancer attracting force and blood vessel repulsion force, the dynamic finite element model is also built for the important displacement parameters of deformation node in needle invasion process. Moreover, the minimum potential direction in each node, and the static and dynamic trajectory planning are investigated. Finally, the experimental simulation shows the validation and correctness of the above-mentioned method. PMID- 20842848 TI - [Electrical stimulation enhances viability of osteoblasts on conductive biodegradable material]. AB - This study was aimed at exploring the viability of osteoblasts on conductive tissue engineering material. Conductive biodegradable Polyprrole/Polylactide (PPy/PLA) was prepared by emulsion polymerization. Scanning electron microscope (SEM) and spectroscopy showed evenly dispersed PPy in PLA. PPy/PLA membrane was found being able to keep conductive stability for more than one month to provide electric circumstances (ECs) for osteoblasts. SEM displayed that osteoblasts adhered and spread well on PPy/PLA. ECs of 12.5, 25, 50, 75, 100, 125, 150, 175, 200 microA/cm2 were separately used to stimulate osteoblasts for 24h, 48h, 72h and 96h. Methyl-thiazole-tetrazolium (MTT) assay after 24h revealed that 50 microA/cm2 evidently accelerated osteoblasts proliferation. Alkaline phosphatase (ALP) activity assay revealed that, 48h later, 50 microA/cm2, and 75 microA/cm2 promoted osteoblasts differentiation. 50 microA/cm2 enhanced osteoblasts mineration. Conclusively, 50 microA/cm2 can strengthen osteoblasts' function and promote their viability. PMID- 20842847 TI - [Pressure change-mediated effects on vasoactive protein of endothelial cells in the flow field in vitro]. AB - Lining the inner surface of the walls of blood vessels, Endothelial cells (ECs) go beyond providing selective membrane to maintain the natural structure and function of vessels; they also synthesize varieties of vasoactive proteins to modify the pressure shift in the local flow field and hence they adapt the physiological activities of vessels. In this experiment, ELISA and RT-PCR technologies were adopted. We set up five different pressure loaded ECs groups,one non-activated cultured ECs group and one single shear stress loaded ECs group. Such a design was intended to demonstrate the effects of pressure shift on the expression of vasoactive protein synthesized by ECs [Endothelin-1(ET 1), endothelial Nitric Oxide Synthase (eNOS), Cyclooxygenase-2(COX-2) and Vascular Endothelial Growth Factor(VEGF)]. Our aim was to elucidate the mechanism of the pressure shift mediated dysfunction in ECs and the related dose-effect relationship. Based on these data, we suggest that ECs could modify the expression of vasoactive protein for adapting to the pressure shift in the local flow field; while in the process of--40 cmH2O induced ECs' dysfunction, the vasoactive proteins eNOS, COX-2 and VEGF play an important role in protecting ECs. PMID- 20842849 TI - [The surface modification of eguus asinus augment fibroblast adhesion and proliferation on silk fibroin materials]. AB - Eguus asinus is one of the rare Chinese drugs famous for promoting blood circulation. In this experiment, it was employed to modify the silk fibroin (SF) by physical blending. Mouse embryonic fibroblasts NIH-3T3 were seeded on pure and modified SF surfaces. The morphological changes of cell on SF surfaces were characterized by optical microscope images. The cell adhesion diameter, the attachment force (F) of a single cell and cell proliferation on SF surfaces were measured by micropipette aspiration system and MTT assay. The results indicated that the fibroblasts seeded on modified SF had larger cell adhesion area, stronger initial attachment force and higher cell proliferation than did the pure SF. In conclusion, eguus asinus improved the adhesion and proliferation of fibroblasts on SF. The research promoted the further use of Chinese drug eguus asinus in tissue engineering. PMID- 20842850 TI - [A new radiopharmaceutical for bone imaging: experimental study of 99mTc-HEDTMP]. AB - The purpose of this study is to prepare 99mTc-HEDTMP [N-(2-hydroxyethyl) ethlenediamine-1,1,2-tri (methylene phosphonic acid), a new kind of bone seeking compound; to investigate its biological properties; and to explore the possibility of using it as a potential radiopharmaceutical for skeleton scintigraphy. HEDTMP was labeled with 99mTc by "pretinning" method, the radiochemical purity was 97.00% +/- 0.34%. 99mTc-HEDTMP was found to be stable in 5 hours in vitro with the radiochemical purity over 95% even after being diluted by physiological saline with the factor of dilution 100. The plane bone scanning of rabbits showed that 99mTc-HEDTMP was principally absorbed by skeletal system. Skull, spine and legs could be observed clearly, and were more legible than the images of 99mTc-MDP. Mice trial also indicated the high bone seeking of 99mTc HEDTMP. The skeletal uptake was 11.92% ID/g, 13.19% ID/g, 10.14% ID/g, 10.04% ID/g, 7.71% ID/g separately at 30 minutes, 1 hour, 3 hours, 6 hours and 24 hours after the injection. Kidney seemed to be the major excretory organ. The clearance of blood was quick and the retaining amount in non-target organs was small. These results indicate that 99mTc-HEDTMP can be prepared easily, and its biological properties can be compared favorably with the commonly used bone imaging agent, and it is well worth further researching as a promising potential radiopharmaceutical in nuclide diagnosis for skeleton diseases. PMID- 20842851 TI - [Study on 5-carboxyfluorescein N-succinimidyl ester in detecting the degree of cross-linked allogenic tissue]. AB - This study was designed to creat a new method for detecting the degree of cross linked allogenic tissue based on fluorescent technique. The thoracic aorta of New Zealand rabbits were divided randomly into four groups according to the concentration of Glutaraldehyde (GA), which were group A (control group-with no GA), group B (cross-linked with GA of 0.625%), group C (1.25%), and group D (2.5%). Each group was cross-linked with GA and reacted with 5-FAMSE, and then the fluorescence intensity was observed via fluorescence microscopy (analyzed with Image-Pro Plus 6.0, a professional image analysis software). The differences between groups in order of fluorescence intensity were found to be: group A > roup B > group C > group D (P < 0.01). Meanwhile, the tissue proteins extracted from aorta in each group were submitted to conventional polyacrylamide gel electrophoresis (PGE) after being cross-linked with GA; the result from this method was compared with that from the method of 5-FAMSE. In group A, the tissue proteins extracted from the aorta cross-linked with GA were obviously less than those not cross-linked with GA. However, this phenomenom was not clearly seen among the B, C and D groups. Nevertheless, 5-FAMSE can detect the degree of cross linkage more conveniently and directly. PMID- 20842852 TI - [The preparation of collagen sponge as tissue engineering scaffolds and analysis of its pore structure]. AB - The preparation of collagen sponges was studied in order to develop tissue engineering scaffolds. Collagen solutions with varying concentrations were obtained by condensing the initial collagen with polyethylene glycol (PEG) at 4 degrees C for different periods of time, and then were freeze-dried to make collagen scaffolds. The porous characteristics of the prepared scaffolds were characterized by use of different methods, including laser scanning confocal microscopy (LSCM), scanning electron microscopy (SEM) and tensile tests. All collagen sponges were shown to have similar interconnected porous structures but were found to have different pore size, porosity, water capacity and the mechanical property, depending on the concentration of collagen solutions. These findings indicate that the way of controlling the concentration of collagen solutions with PEG permits the freeze-drying fabrication of collagen sponges with varying porous features suitable for different tissue engineering purposes. PMID- 20842853 TI - [Experimental research on osteogenic abilities of new bone tissue engineering scaffolds by recombinant bone morphogenetic protein]. AB - This research sought to asses the efficacity of a new type of tissue engineering bone developed by PDLLA/ PLA-PEG-PLA and BMP as a kind of bone graft substitute in the rabbit model of mandibular defects; 15 mm x 6 mm bilateral mandibular periosteum bone defects were made surgically in 20 New Zealand adult rabbits. The porous scaffolds impregnated with rhBMP-2 were used for the purpose, and the scaffolds without rhBMP-2 were used as control. The methods adopted in this research were: macroscopy, histomorphologic exam, X-ray exam, SEM micrography, computer-aided analysis and graphics. The experimental group was shown to have an earlier inception of bone forming. New bone formation was seen along the border of the original mandibular bone and in the middle. At 12 weeks after surgery,the defects were almost filled with new bone. In the control group, the defects could not be repaired in its entirety, and there was no new bone in the middle. The porous scaffold is a promising carrier for BMP. This kind of bone graft substitute can serve as an osteoconductive and osteoinductive matrix. PMID- 20842854 TI - [Study on the selective removal of plasma low-density lipoprotein and fibrinogen by degraded carrageenan]. AB - The selective removal of low density lipoprotein (LDL) and fibrinogen (Fib) by degraded carrageenan was studied by the present authors. Degraded carrageenan was prepared by acid with carrageenan as the main material. The effects of acid conditions on the molecular weight were investigated, and the proper reaction conditions were ascertained. The results of infrared spectrometry indicated that the degraded carrageenan is a heparin-like polysaccharide. Then the selective removal of LDL/Fibrinogen by degraded carrageenan was studied. When molecular weight was about 10,000, pH was 5.10 and the concentration of degraded carrageenan was 800 mg/L, the average reduction percentages were 60.0% for total cholesterol(TC), 79.4% for LDL and very low-density lipoprotein (VLDL), and 93.8% for fibrinogen. There were no significant changes with relation to the level of high-density lipoprotein (HDL) and total protein (TP). So, degraded carrageenan was shown to be of good selectivity on plasma LDL/Fibrinogen apheresis. PMID- 20842855 TI - [Expression, purification and activity analyses of three Bcl-2 family proteins]. AB - Bcel-2 family proteins (Bcl-x(L), Bcl-2, Mel-1 etc.) are key regulators of some life processes, including apoptosis and autophagy. They are currently considered as promising targets for developing new anti-tumor therapies. In our study, the human Bcl-2/Bcl-x(L) chimeric gene and the human/mouse Mel-1 chimeric gene were designed and cloned, and the prokaryotic expression vectors for expressing glutathione S-transferase (GST) fusion proteins and histidine tag fusion proteins were constructed respectively. These two proteins as well as the GST-Bcl-x(L) fusion protein were all successfully expressed in E. coli and subsequently purified. In addition, we measured the binding of these Bcl-2 family proteins to the Bid BH3 peptide by fluorescence polarization-based assay. The dissociation constants (Kd) obtained by us were in general agreement with the data reported in literature. The Kd values of all three proteins with or without the GST tag were almost identical. All these results validate the biological functions of these Bcl-2 family proteins obtained by us. These proteins can be used in the experimental screening of small-molecule regulators of Bcl-2 family proteins in vitro. PMID- 20842856 TI - [Isolation and purification of antimicrobial polypeptide HMGN2 from human lymph node and analysis of its distribution]. AB - This study was conducted to isolate and purify antimicrobial polypeptides HMGN2 (high mobility group nucleosomal-binding domain2) from human lymph node, to detect the antimicrobial activity of HMGN2, and to determine the subcellular location of HMGN2 in human lymph node. The antimicrobial polypeptides were purified by the Reverse Phase HPLC and identified by Tricine-SDS-PAGE. The antimicrobial activity was detected by agar diffusion test. Mass spectrum and Western-blot analysis indicated the individual character of protein. HMGN2 was isolated and purified from human lymph node, and it showed antimicrobial potency against the pathogenic strain E. coli 54,080. The immunocytochemistry staining indicated that HMGN2 was present both in human lymph node cells' nucleus and cytoplasm. In conclusion, HMGN2 protein is of antimicrobial activity and it is probably involved in the defence of innate immunity in vivo. PMID- 20842857 TI - [Construction of prokaryotic expression vector of HPV16E6 gene and its expression]. AB - Prokaryotic expression vector of mouse HPV16E6 gene was constructed. A pair of primers were designed according to the digestion sites in plasmid pGEX-KG and the HPV16E6 gene sequence published by GenBank. The DNA fragment of 321bp was amplified by PCR from the HPV recombinant plasmid with HPV16E6 gene, then cloned into pGEX-KG and transformed into the host E. coli strain JM109. The fragment was conformed to the original sequence, which indicated that fusion expression vector pGEX-KG-HPV16E6 was constructed. The pGEX-KG-HPV16E6 plasmid was taken and transformed into BL21(DE3) for expression. Induced by IPTG at 37 degrees C, the expression product of HPV16E6 gene was identified by SDS-PAGE and Western blot. HPV16E6 fusion protein had been expressed successfully in the form of inclusion bodies, the molecular weight of fusion protein being 38 kD. Meanwhile, the optimum condition of HPV16E6 fusion protein expression was induced with 1.0 mmol/L IPTG for 4h. The fusion protein reacted specifically with the antibodies against HPV16E6. HPV16E6 gene was successfully expressed in E. coli, which could be used as a basis for preparing HPV16E6 vaccine in human. PMID- 20842858 TI - [Lungs absorbed dose in radioiodine therapy of differentiated thyroid carcinoma with diffuse pulmonary metastases]. AB - The objective of this work was to estimate the absorbed dose of 131I to lungs in 131I therapy of differentiated thyroid carcinoma(DTC) with diffuse pulmonary metastases. Ten DTC patients with diffuse pulmonary metastases were recruited prospectively. Whole body planar scintigrams were acquired serially after administration of 7.4 GBq 131I to patients. The counts from the regions of interest of lungs and total body were obtained and converted to the percent of administered activity. The time-activity curves of lungs and total body were fit, and the areas under the curves were calculated. It was assumed that beta-eletron emissions from 131I deposited in lungs were completely absorbed by the diffuse DTC metastatic lesions, and that gamma-photon emissions from 131I deposited in the lungs and the remainder of body were irradiating the lungs. The absorbed dose to lungs was calculated according to Medical Internal Radiation Dosimetry (MIRD) formula. The median lungs absorbed dose was 0.33 Gy (range, 0.22-8.21 Gy). Based on the empiric fixed activity therapy of DTC with diffuse pulmonary metastases,the absorbed dose to lungs is low. PMID- 20842859 TI - [In vitro study for detecting the effects of Bazhen decoction on proliferation and activation of T lymphocytes]. AB - This study was designed to detect the effects of Bazhen decoction on the proliferation and activation of T lymphocytes. T lymphocytes were isolated. The effects of Bazhen decoction on the prolifertion and activation of T lymphocytes, and on the secretion of IFN-gamma IL-2 from T lymphocytes, were detected by MTT, Flow cytometry and ELISA. Results showed that proliferation of T lymphocytes was promoted significantly by different concentration of Bazhen decoction; and after different time, the relationships of "the longer the time, the higher the concentration, and the more enhanced the proliferation" came to be apparent. After 72h, T lymphocytes were activated with different concentration of Bazhen decoction, the rate of CD69+ T cells increased signficantly, the secretion of IFN gamma and IL-2 increased signficicantly, and the effect exhibited a dose dependent manner. The results of this epxeriment indicated that Bazhen decoction could promote the proliferation and activation of T lymphocytes. PMID- 20842860 TI - [Study on characterization of the complexes of FUS1/hIL-12 with cationic liposome]. AB - This study was aimed to shed light on the biological and pharmaceutical characterization of the complexes of FUS1/hIL-12 double gene with cationic liposome, and to assess such complexes' transfection efficiency, stability and cytotoxicity; for they have the potential for use as drugs in gene therapy of lung cancer. Gel retardation assay, diameter measurement, and surface charge by photon correlation spectroscopy (PCS) were employed to select the appropriate ratio of "cationic liposome to DNA" of the double-gene and liposome complexes. The plasmid EGFP and plasmid PVITO2-hIL12-FUS1 mediated by cationic liposome were transfected into A549 lung cancer cells respectively, and the expression levels of EGFP and FUS1 and hIL-12 were determined by inverted fluorescence microscope and immunohistochemical and enzyme linked immunosorbent assay (ELISA) respectively. Agarose gel electrophoresis was performed to detect the stability of the double-gene and liposome complexes, after they were incubated with serum and Dnase I respectively. After the erythrocytes being incubated with the complexes of FUS1/hIL-12 with cationic liposome, the morphology of erythrocyte was observed by microscopy. The result of this study provides a basis for the use of the complexes of FUS1/hIL-12 with cationic liposome in gene therapy of lung cancer. PMID- 20842862 TI - [Phylogenetic analysis of 2009 H1N1 (A) influenza virus based on genomic sequence features]. AB - From April 2009 onward, a new strain of human H1N1 influenza virus has swept over the world. The genome of influenza virus consists of 8 segments, encoding 10 proteins, respectively. The reassortments among the 8 segments cause the variation of influenza virus. Therefore, phylogenetic analysis of the 8 genes is very important. In this paper, we choose neighboring word frequency as the genomic features, using VC++ programming to analyze evolution of the 8 segments of H1N1 virus. As a result, we found that PB2 genes and PA genes of these three isolated virus were originated from North American avian influenza virus, that PB1 genes were originated from the seasonal influenza virus of human, and that HA genes, NS genes and NP genes came from the North American classical swine influenza A virus. The NA segments and M segments were originated from the European swine influenza virus. PMID- 20842861 TI - [The relationship between bone mass and the skin fold thickness in Chinese Hans]. AB - In this paper is reported an investigation on the relationship between bone mass (bone mass content, BMC, bone mass density, BMD) and the skin fold thickness of anterior superior iliac spine and abdomen in Chinese Hans residing in Ji'nan. From Jan. to Dec. 2006, 287 healthy volunteers (M116, F171; mean age 37.3 +/- 17.4 yrs) were recruited in Ji'nan Maternity And Child Care Hospital. BMC and BMD of all subjects were measured by dual energy X-ray absorptiometry. The skin fold thickness of anterior superior iliac spine and of abdomen were measured. Correlation analyses on BMC and BMD of the skin fold thickness(anterior superior iliac spine and abdomen) were made with respect to partial correlation. The results showed a linearity positive correlation between bone mass and the skin fold thickness (anterior superior iliac spine and abdomen). Being adjusted for gender and age, the correlation coefficients of the skin fold thickness (anterior superior iliac spine and abdomen) with BMD and BMC in all parts of body; extremitas superior, extremitas inferior, pars trunci, ribs, pelvis and backbone of Pearson coefficients of correlation were 0.281 and 0.235, 0.175 and 0.150, 0.182 and 0.137, 0.245 and 0.198, 0.326 and 0.269, 0.299 and 0.261, 0.296 and 0.247, 0.322 and 0.279, 0.324 and 0.267, 0.341 and 0.293, 0.290 and 0.235, 0.220 and 0.194, 0.245 and 0.221 (P < 0.05). There is a positive relationship between the skin fold thickness (anterior superior iliac spine and abdomen) and bone mass (BMC and BMD) in Chinese Hans. PMID- 20842863 TI - [Influence of the concentration of silver nanoparticles on the proliferation behavior of human umbilical vein endothelial cell and human umbilical artery smooth muscle cells]. AB - The proliferation difference between Human Umbilical Vein Endothelial Cells (HUVEC) and Human Umbilical Artery Smooth Muscle Cells (HUASMC) in response to the concentration of silver nanoparticles was investigated via MTT, BCA and FCM tests. The obtained experimental data were statistically analyzed and discussed in order to know the causation of the proliferation difference. The results show there is significant difference in proliferation between HUVEC and HUASMC corresponding to the concentration of silver nanoparticles, and such difference can be attributed to the varied adhesion shape and apoptosis of the cells being influenced by nano-Ag content and Fetal bovine serum (FBS) content in culture medium. PMID- 20842864 TI - [Development of the first head finite element model based on Chinese visible human data]. AB - The second Chinese visible human (CVH) data has been used to build a more precise finite element model of Chinese head via 3-D image reconstruction, solid model reconstruction, finite element meshing, and assembling of finite element model. This second case of finite element model of Chinese head contains skull, facial bones, inferior maxilla, cerebral falx, brain, cerebellum brainstem, and so on. All the mesh elements, according to their main quality check results in line with the engineering requirements, were identified as solid elements, and the numbers of nodes and elements were determined to be 31 223 and 19 911 respectively. The model is coincident with the anatomy of human head; and its accuracy in some region, especially in fundus cranii and fundus cranii, is more excellent than that of the other models based on CT/MRL The development of the first head finite element model based on CVH data has brought on a remarkable progress in the application of CVH platform. PMID- 20842865 TI - [Study on navigation path correction in neuro-navigation based on near infrared spectroscopy]. AB - At present, navigation path deviation caused by brain shift is the main factor that affects the accuracy of neurosurgical navigation. A new method of near infrared spectroscopy (NIRS) based neurosurgical navigation is presented in the paper. The correlation between NIRS optical parameters and medical image is used and the gray information of navigation path is regarded as the priori knowledge, sample-points curvatures are calculated by Hermite interpolation and the Mean Hausdorff distance as measurement criterion is used to match feature segments, then the real-time correction model is established. The algorithm of the given model is simple and can realize the best match within the error, it provides an effective method for real-time navigation path correction. PMID- 20842866 TI - [Study on the classification of motor unit action potentials from single-channel surface EMG signal based on the wavelet analysis]. AB - A method of motor unit action potentials (MUAP) detection and classification was introduced to explore the firing information of recruited motor units in the neural muscular system. Based on the continuous wavelet transform, the first order Hermite-Rodriguez (HR) function was used as the mother wavelet, and the binary hypothesis testing algorithm was combined to detect and localize the MUAP waveforms in the surface electromyography (sEMG) signal. Then, the fuzzy k-means clustering and minimum distance classifying algorithms were applied to the primary clustering of the detected MUAPs. Finally, the template matching method was used to solve the problem of the unclassified waveforms. The experimental results showed that the kinds of MUAP information from the recorded sEMG signal could be acquired by waveform detection and pattern recognition. The proposed method does not require multi-channel sEMG signals; it just utilizes the single channel signal to analyze the MUAPs, and it can improve the decomposition efficiency. PMID- 20842867 TI - [A preliminary study on data mining techniques for utilizing the breast ultrasound database]. AB - Based on the breast ultrasound database of West China Hospital from January 1, 2002 to December 31, 2007, a study of data mining techniques for utilizing the diagnostic information of breast ultrasound and breast pathology was carried out. An innovative computerized retrieval system was invented. With the visual user interface of the system, the data of benignancy or malignancy diagnosed by ultrasound and pathologic examination, and the data on the diagnostic correlation of ultrasound and pathology were obtained, respectively. The qualities of data mining were 99. 98%-100%. By means of the retrieval system, the users can secure numerous data from the breast ultrasound database rapidly and accurately; so it contributes to the rational utilization of information from medical database for serving various medical studies. This method may also be helpful for doctors to utilize ultrasound database in other fields. PMID- 20842868 TI - [Introduction and advantage analysis of the stepwise method for the construction of vascular trees]. AB - A new method for constructing the model of vascular trees was proposed in this paper. By use of this method, the arterial trees in good agreement with the actual structure could be grown. In this process, all vessels in the vascular tree were divided into two groups: the conveying vessels, and the delivering branches. And different branches could be built by different ways. Firstly, the distributing rules of conveying vessels were ascertained by use of measurement data, and then the conveying vessels were constructed in accordance to the statistical rule and optimization criterion. Lastly, delivering branches were modeled by constrained constructive optimization (CCO) on the conveying vessel trees which had already been generated. In order to compare the CCO method and stepwise method proposed here, two 3D arterial trees of human tongue were grown with their vascular tree having a special structure. Based on the corrosion casts of real arterial tree of human tongue, the data about the two trees constructed by different methods were compared and analyzed, including the averaged segment diameters at respective levels, the distribution and the diameters of the branches of first level at respective directions. The results show that the vascular tree built by stepwise method is more similar to the true arterial of human tongue when compared against the tree built by CCO method. PMID- 20842869 TI - [A new approach to mammogram detection by using morphological and laplacion-of-a gaussian filter]. AB - Microcalcification is an early sign of breast cancer appearing as isolated bright spots in mammogram images. However, there is a difficulty in detecting the spots because they are small-sized and have noisy and big image background. Morphological bandpass filter (MBF) is a fast method for detecting microcalcifications, but the accuracy there-by is not satisfied. Though Laplacion of-a-Gaussian (LoGF) method can achieve high accuracy in location, it is time consuming. For these reasons, a new detection method for combining the two above mentioned methods is proposed in this paper. We conducted the experiments on the breast cancer database of Nanjing Zhongda Hospital. The experimental results confirm that the detecting speed for microcalcifications is comparable to that with the use of morphological filter method, and the detection precision is comparable to that with the use of LoGF method. PMID- 20842870 TI - [Design of a mechanical system for the balanceable system of ambulance]. AB - This is the design of a mechanical systems for use in the balanceable system of ambulance, which can keep the medical service bed at the ambulance level, whatever the terrain is. A level detector will detect the level state of the bed and turn it to a signal. The central processing unit will use this signal to analyse and control the movement of the motor. By this design (which uses the rolling rail as a drive transmission and makes three supports of the bed go up and down), the bed will keep level. With the use of this design, the balanceable system of ambulance can counteract 35 degrees. The error is controlled within +/- 1 degree. And the response time is within 0.3 s. The method of registration can be effective for keeping the bed at the ambulance level, and for reducing the chance of making the patient get hurt on the way to hospital. PMID- 20842871 TI - [Electrical impedance method for bacteriological study of drug sensitivity test]. AB - In this study, our self-made micro-electrical impedance sensors and experimental apparatus were used to measure the impedance of bacteria-inoculated medium. Then the bacteria in the culture of all values obtained during the period were recorded into the trace impedance curve. Seeing the obvious difference in morphological change, we utilized the differed impedance curves in an attempt to estimate the morphological difference between the drug sensitivity of bacteria. The studies of clinical medicine for achieving rapid drug sensitivity test, automation and intelligentization of drug sensitivity are of practical significance. PMID- 20842872 TI - [Research advances in effects of mechanical stimulation on bone marrow mesenchymal stem cells]. AB - Bone marrow mesenchymal stem cells (BMSCs) have shown great promise in tissue repair. While these cells induce little immune response, they show marked self renewal properties and can differentiate into many cell types. Recent evidence shows that mechanical factors can regulate the biological behaviors of BMSCs through various signaling pathways. In this review, we will high-light the effects of strain, shear stress, compressive stress and gravity on the proliferation, cytoskeleton and differentiation of BMSCs. PMID- 20842873 TI - [Recent progress in multiple sequence alignment]. AB - Multiple sequence alignment is one of the basic techniques in bioinformatics, and it plays a vital role in structure modeling, functional site prediction, and phylogenetic analysis. In this paper, we review the methodologies and recent advances in the multiple protein sequence alignment, e.g., speeding up the calculation of distances among sequences and employing the iterative refinement and consistency-based scoring function, with emphasis on the use of additional sequence and structural information for improving alignment quality. PMID- 20842874 TI - [Cross-modal stochastic resonance--a special multisensory integration]. AB - Cross-modal stochastic resonance is a ubiquitous phenomenon, that is, a weak signal from one sensory pathway can be enhanced by the noise from a different sensory pathway. It is a special multisensory integration (MI) that can not be explained by the inverse-effectiveness rule. According to cross-modal stochastic resonance, the detection of signal is an inverted U-like function of the intensity of noise at different levels. In this paper, we reviewed the research of cross-modal stochastic resonance and put forward some possible explanations for it. These efforts raise a new idea for neural encoding and information processing of the brain. PMID- 20842875 TI - [An overview of the evolution of EV71 vaccine]. AB - EV71 infection has become a serious public health threat especially among young children. Yet, at present, no specific antiviral drug against EV71 infection is available. A number of scientists are studying various kinds of vaccines, including inactivated vaccine, virus-like particle vaccine, DNA vaccine, synthetic peptide vaccines, and transgenic oral vaccine. This article reviews the recent advancement in the design of various kinds of vaccine against EV71 as well as their prospective usefulness, effectiveness, weakness and developments in the foreground. PMID- 20842876 TI - [Current situation and prospect of treatment for radiation-induced lung injury]. AB - Radiation-induced lung injury (RILI) is the most common complication of the radiotherapy for thoracic tumor. It can lower the ratio of local control and seriously affect the patients' quality of life. At present, the clinical management of RILI is not more than the use of glucocorticoid and anti inflammatory agent for symptomatic treatments. These treatments do not have any preventive effect but cause much side reactions. In this paper, we review the data from the contigency researches on the mechanism of RILI, from the researches on gene therapy and stem cell-therapy, and we dicuss the more safe, more stable and more efficacious treatment of RILI. PMID- 20842877 TI - [Research progress in reanimation of peripheral facial paralysis by use of functional electrical stimulation]. AB - With the development of electronics and information technology, the application of functional electrical stimulation in the medical field has been expanding. However, the use of functional electrical stimulation to treat patients with peripheral facial paralysis is still in its infancy. The main problems include: (1) Finding in the signals which could fire the stimulator; (2) Exploring the parameters for the stimulator; (3) The effects on the muscle attributed to the electrical stimulation. A review on these problems is presented. PMID- 20842878 TI - [Wnt signal transduction pathways and hair follicle stem cells]. AB - Hair follicle stem cells (FSCs), which have characteristics of slow cycling and multipotential differentiations, play an important role in maintaining hair follicle cycling and repairing the epidermis during wound healing. The researches in this subject may be helpful to provide new ideals in treating the diseases of hair and skin. As we know, the Wnt signal transduction pathway has a significant meaning in controlling the proliferation and differentiation of FSCs, and different Wnt proteins have different functions in this process. In this paper, we review how the Wnt signal transduction pathway controls the FSCs and what the functions of different Wnt proteins are. PMID- 20842879 TI - [The development of techniques for liquid level detection in auto clinical laboratory analyzers]. AB - Liquid level detection (LLD) is necessary for eliminating carry-over of needle's outside by limiting the depth the needle probes into liquid in auto clinical laboratory analyzers. This paper listed various demands of liquid-handling system under different situations; reviewed various LLD techniques, such as capacitive, air pressure, mechanical vibration, ultrasound, light reflection, CCD imaging etc.; briefly introduced the working principles, features, and limitation of the LLDs; and recapitulated the characteristics of contact and non-contact LLDs. Lastly, the next generation technique of LLD is prospected. PMID- 20842880 TI - [Progress in researches on synthetic antimicrobial macromolecular polymers]. AB - Broad-spectrum antimicrobial peptides provide a new way to address the urgent growing problem of bacterial resistance. However, the limited natural resources and the high cost of extraction and purification of natural antimicrobial peptides can not meet the requirements of clinical application. In order to solve this problem, researchers have utilized two basic common structural features (amphiphilic and cationic) for designing and preparing synthetic antimicrobial macromolecular polymers. During the last decade, several kinds of amphiphilic polymers, including arylamide oligomers, phenylene ethynylenes, polymethacrylates, polynorbornenes as well as nylon-3 polymers have been synthesized. In this paper, the structures, antibacterial activities and selectivities of these polymers are reviewed, and the effects of molecular size, polarity and ratio of hydrophobic groups, positive charge density on antibacterial activity and selectivity are also summarized. PMID- 20842881 TI - [Integration of extra-nuclear and nuclear estrogen receptor actions]. AB - Estrogen receptors localized to many sites within the cell are giving comprehensive contribution to estrogen functions. In recent years, researches have identified that some estrogen receptors are localized to the plasma membrane, while other estrogen receptors exist in cytoplasm besides nucleus. Cross-talk occurs between extra-nuclear estrogen receptor and nuclear estrogen receptor signalings. The integration of estrogen and its receptor actions from different sites within the cell leads to the rapid and prolonged actions of estrogen, thus they produce important biological functions in the sex organ and other organs. PMID- 20842882 TI - [Subjective difficulties in young people related to extensive loud music listening]. AB - INTRODUCTION: For human ear, noise represents every undesirable and valueless sound. In disco clubs, as in some other places with loud music mostly attended by young people, the level of noise sometimes attains over 100 dB. As reported by numerous studies, a high noise level could induce subjective difficulties (ear buzzing, audition loss, vertigo and palpitations, anxiety, high blood pressure, decreased concentration, lowered memory storing). OBJECTIVE: Assessment of subjective difficulties occurring in young people when staying in places with a high noise level (cafes, disco clubs, rock concerts), which can produce health problems, due to loud music, in association with demographic data, addictions and personal life style data. One of the goals is to find factors leading to subjective difficulties, which would be objectively studied in the second stage of the research and marked as early predictors of possible health problems. METHODS: The study was conducted among 780 students of the Higher Healthcare School of Professional Studied in Belgrade. We used a questionnaire with 20 questions, divided into four categories: demographic data, case-history data, subjective problems and addictions of the subjects. In the statistical data processing we used the methods of descriptive and exploratory analysis, chi square tests, correlation tests and Mantel-Haenszel odds ratio. RESULTS: After listening loud music, 54.0% of examined subjects felt ear buzzing, and 4.6% had hearing damage. The habit of visiting places with loud music, mostly once a week in duration of 2-3 hours per visit had 80.4% of subjects. The presence of subjective complaints after listening of loud music was in association with loud music listening and disco clubs visits.The major reasons of the present subjective difficulties could be predicated by listening of loud music and club visits (r = 0.918 and r = 0.857). A relative risk for subjective difficulties presentation was 1.599. CONCLUSION: According to the results of our study, over half of children develop loud music-induced subjective problems involving ear buzzing and occasionally hearing loss. PMID- 20842883 TI - Ocular anomalies in incontinentia pigmenti: literature review and meta-analysis. AB - INTRODUCTION: Incontinentia pigmenti (IP) is an X-linked genodermatosis in which skin changes are combined with dental, eye and central nervous system anomalies. OBJECTIVE: The goal of the study was to analyze ocular findings, IP minor criteria in available literature concerning IP cases published until now. METHODS: We have done meta-analysis of 1931 IP patients found in 302 references published until 2010. Comparison of data published for the 1906-1976 and 1976 2010 periods was made. The collected data were mainly frequencies of ocular anomalies. Chi-square test was used to compare observed frequencies with their expectations. RESULTS: Of total number of IP patients, 1227 were ophthalmologically investigated. In 449 such patients 972 eye anomalies were registered, 2.16 anomalies per patient. Proportion of ophthalmologically investigated IP patients in the period 1906-1975 (70%) was higher than corresponding proportion (60%) for the period 1976-2010. For 1906-2010 period 36.5% IP patients with eye anomalies were diagnosed. The number of amaurotic eyes per patient did not significantly differ for the two periods (p = 0.50; > 0.05). The total number of eye anomalies per patient significantly differed for the same periods (p = 0.00005; < 0.05). Retinal anomalies were most frequent in both periods. CONCLUSION: This study suggests that IP is far more frequent than anyone could estimate. We believe that this study, covering 1906-2010 period, gives more reliable information about ophthalmological findings in IP; considering them as severe anomalies. Early detection and treatment of ophthalmological, neurological etc. findings may prevent severe consequences that IP may cause. PMID- 20842884 TI - [Morphological characteristics of mesiobuccal root canals of the first maxillary molars]. AB - INTRODUCTION: The first maxillary molar is a tooth with three roots, and mesiobuccal one is with the most complex canal morphology. Factors influencing variations of its morphology are numerous, and may significantly complicate endodontic treatment. OBJECTIVE: The objective was to investigate the number, configuration and curvature orientation of the mesiobuccal root canals in the maxillary first molars. METHODS: The study was conducted on 200 mesiobuccal (MB) roots of extracted first molars in human subjects using radiography. In each canal Flexofile was introduced until reaching the apical foramen and the root was then radiographed in series from two projections. Number of root canals (MB1, MB2 and MB3), configuration according to Vertucci classification, and the orientation of the curvature were established. Relevant statistical parameters and the significance of differences were computed (p < 0.05). RESULTS: Of total 200 mesiobuccal roots 86.5% were with two, 9% with three, and 4.5% with a single canal. Most frequent configurations were type IV (36%) and II (34.5%). From the clinical projection all MB, canals were oriented distally, from the proximal 78% palatally and 22% buccally. The orientation of all MB2 canals was distal from the clinical projection, from the proximal projection 76% were oriented palatally, and 24% buccally. The MB3 canal was always oriented distally from the clinical projection, and buccally from the proximal aspect. CONCLUSION: The mesiobuccal roots of the first maxillary molars showed multiple canals in 96%, with dominant Vertucci type II and IV of configuration. All canals were curved. PMID- 20842885 TI - [Oral health status in patients with diabetes mellitus type 2 in relation to metabolic control of the disease]. AB - INTRODUCTION: As a systemic disease, diabetes mellitus may lead to several complications affecting both the quality and the length of life. While periodontal disease is one of the major oral health problems in patients with diabetes, reports of an increased risk of dental caries among diabetics are controversial. OBJECTIVE: The aim of this study was to investigate oral health status in patients with diabetes mellitus type 2 in relation to metabolic control of the disease. METHODS: The study included 47 randomly sampled diabetics patients, divided into two groups; those with poorly controlled diabetes (glycosylated haemoglobin--HbA1c > or =9%) and those with better controlled diabetes (HbA1c < 9%). All patients completed a questionnaire about their medical and oral health. Decayed, missing, and filled teeth (DMFT) and plaque index (PI), bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment loss (CAL) were recorded. RESULTS: The patients with poorly controlled diabetes had a significantly higher number of tooth caries compared to those with better controlled diabetes (6.5 +/- 4.3 vs. 4.3 +/- 2.9; p < 0.05). Of periodontal parameters, only PPD was significantly higher in the patients with poorly controlled diabetes than in those with better controlled diabetes (5.8 +/- 0.9 vs. 5.2 +/- 0.8; p < 0.05). DMFT index, PI, PPD and CAL exhibited positive correlation only with patients' age. CONCLUSION: The study indicates that there is a relationship between poor control of diabetes and caries, and periodontal disease. PMID- 20842886 TI - [Surgical treatment of ishemic mitral regurgitation: repair, replacement or revascularization alone?]. AB - INTRODUCTION: Treatment of ischemic mitral regurgitation in patients that require revascularization of myocardium is still debatable. OBJECTIVE: The aim of this study was to compare three surgical approaches: valve repair and revascularization; valve replacement and revascularization, and revascularization alone. METHODS: In 2006 and 2007 at the Institute for Cardiovascular Diseases, Clinical Centre of Serbia, Belgrade, 1,040 patients with coronary disease underwent surgery. Forty-three patients (4.3%) had also mitral insufficiency 3 4+. The patients were examined clinically, echocardiographically and haemodynamically. In group I there were 14 (32.3%) patients, in group II 16 (37.2%) patients and in group III 3 (30.5%) patients. Ninety-three per cent of patients were classified as New York Heart Association (NYHA) class III and IV, and three (7%) patients had congestive heart weakness with ejection fraction < or =30%. The decision as to surgical procedure was made by the surgeon. Postoperatively, patients were checked clinically and echocardiographically after 3, 6 and 12 months. The follow-up period was approximately 15 months (8-20). RESULTS: Hospital mortality for the whole group was 6.9% (3 patients). In group I mortality was 14.2% (2 patients), in group II 6.25% and in group III there was no mortality. Long term results, up to 15 months, showed 100% survival in groups I and II, and in group III one patient died (7.7%). CONCLUSION: Short term results upto 30 days were best in group III, but longer term results were better in groups I and II. PMID- 20842887 TI - [The influence of stress hyperglycemia on the prognosis of patients with acute myocardial infarction and temporary electrical cardiac pacing]. AB - INTRODUCTION: Elevated glucose levels on admission in many emergency conditions, including acute myocardial infarction (AMI), have been identified as a predictor of hospital mortality. OBJECTIVE: Since there are no data in the literature related to stress hyperglycaemia (SH) in patients with both AIM and temporary electrical cardiac pacing, we aimed to investigate the influence of stress hyperglycaemia on the prognosis of patients with AMI and temporary electrical cardiac pacing. METHODS: The prospective study included 79 patients with diagnosed AMI with ST-segment elevation (STEMI), admitted to the Coronary Care Unit of the Clinic for Cardiovascular Diseases, Clinical Centre Nis, from 2004 to 2007, who were indicated for temporary electrical cardiac pacing. The blood was sampled on admission for lab analysis, glucose levels were determined (as well as markers of myocardial necrosis troponin I, CK-MB). Echocardiographic study was performed and ejection fraction was evaluated by using area length method. RESULTS: The ROC analysis indicated that the best glycaemic level on admission, which could be used as a predictor of mortality, was 10.00 mmol/l, and the area under the curve was 0.82. In the group without SH, hospital mortality was 3-fold lower 11/48 (22.91%) compared to the group with SH 19/31 (61.29%), p < 0.0001. Patients with SH were more likely to have higher troponin levels, Killip >1, lower ejection fraction and heart rate, as well as systolic blood pressure. CONCLUSION: The best cut-off value for SH in patients with AMI (STEMI) and temporary electrical cardiac pacing is 10 mmol/l (determined by ROC curve) and may be used in risk stratification; patients with glucose levels <10 mmol/l on admission are at 3-fold lower risk compared to those with glucose levels >10 mml/l. Our results suggest that SH is a more reliable marker of poor outcome in AMI patients with temporary pace maker, without previously diagnosed DM. PMID- 20842888 TI - [The degree of coronary atherosclerosis as a marker of insulin resistance in non diabetics]. AB - INTRODUCTION: The metabolic syndrome and its influence on coronary artery disease development and progression remains in focus of international research debates, while insulin resistance, which represents its core, is the key component of hypertension, dyslipidaemias, glucose intolerance and obesity. OBJECTIVE: The aim of this study was to establish relationship between basal glucose and insulin levels, insulin sensitivity and lipid panel and the degree of coronary atherosclerosis in nondiabetic patients. METHODS: The coronary angiograms were evaluated for the presence of significant stenosis, insulin sensitivity was assessed using the intravenous glucose tolerance test with a minimal model according to Bergman, while baseline glucose (GO), insulin (10) and lipid panel measurements (TC, HDL, LDL, TG) were taken after a 12-hour fasting. RESULTS: The protocol encompassed 40 patients (19 men and 21 women) treated at the Institute for Cardiovascular Diseases of the Clinical Centre of Serbia, Belgrade. All were non-diabetics who were divided into 3 groups based on their angios: Group A (6 patients, 15%, with no significant stenosis), Group B (18 patients, 45%, with a single-vessel disease) and Group C (16 patients, 40%, with multi-vessel disease). Presence of lower insulin sensitivity, higher 10 and TC in the group of patients with a more severe degree of coronary atherosclerosis (insulin sensitivity: F = 4.279, p = 0.023, A vs. C p = 0.012, B vs. C p = 0.038; 10: F = 3.461 p = 0.042, A vs. B p = 0.045, A vs. C p = 0.013; TC: F = 2.572, p = 0.09), while no significant difference was found for GO, LDL, HDL and TG. CONCLUSION: Baseline insulinaemia, more precisely, fasting hyperinsulinaemia could be a good predictor of significant coronary atherosclerosis in non-diabetic patients, which enables a more elegant cardiometabolic risk assessment in the setting of everyday clinical practice. PMID- 20842889 TI - Do bacterial vaginosis and chlamydial infection affect serum cytokine level? AB - INTRODUCTION: Serbia is the country with extremely low birth rate and a relatively high percentage of preterm deliveries (8%). With this in mind, discovering new diagnostic methods that could be used for the prediction of preterm delivery is of great importance. In this study we tried to determine whether bacterial vaginosis and chlamydial infection could provoke preterm delivery by activation of systemic cytokine network. OBJECTIVE: The aim of this study was to determine serum levels of proinflammatory cytokines (IL-1beta, IL-8, IFN-gamma, IL-6 and TNF-alpha) in pregnant women with symptoms of preterm delivery and to make correlation between these parameters and the presence of bacterial vaginosis or chlamydial infection. Method In the serum of 35 pregnant women, which were divided in groups according to the presence or absence of bacterial vaginosis and chlamydial infection, commercial ELISA tests for proinflammatory cytokines were performed. RESULTS: The serum level of IFN-gamma was significantly increased in pregnant women having chlamydial infection, as well as the level of IL-1beta in women with bacterial vaginosis. The levels of TNF-alpha, IL-6 and IL-8 were not significantly different between the investigated groups. CONCLUSION: The preliminary results obtained in this research point out the possibility that not only intrauterine or systemic infections, but also bacterial vaginosis and chlamydial infection can cause a partial activation of systemic cytokine network and contribute to the occurrence of preterm delivery. PMID- 20842890 TI - [Main morphological characteristics of the vascular pedicle of Latissimus dorsi muscle and their relevance in operative treatment]. AB - INTRODUCTION: Considering operative treatment of various pathological conditions and traumatic injuries of extremities latissimus dorsi flap presents the most frequently used flap in reconstructive surgery. OBJECTIVE: The aim of this paper was to analyze anatomical characteristics of the vascular pedicle of the latissimus dorsi muscle followed by morphometric analyzes of vascular elements. METHODS: This paper was carried out in cooperation with the Institute of Anatomy of the School of Medicine, University of Belgrade. The study was based on 40 cadaver dissections followed by anatomical and morphometric analyzes. The first analysis included the determination of thoracodorsal artery (TDA) origin and its lateral and terminal branches, and the second one the observation of artery path. Furthermore the same features were analyzed on the thoracodorsal vein. During morphometric analyzes artery and vein length and diameter were recorded. RESULTS: Our results showed that TDA always contains one lateral branch, while three other lateral branches were inconstant. In most cases TDA terminated in two branches, upper and lower, with average distance of 3.4 cm from the muscle. The mean recorded pedicle length was 9.9 cm. The average inner diameter of TDA was 1.85 mm. In further analyses the average observed thoracodorsal vein length was 10.5 cm with mean diameter of 2.93 mm. The result showed that vein origin was usually represented with two branches. CONCLUSION: The thoracodorsal artery is a blood vessel of considerable length and diameter which represents a great advantage in reconstructive flap surgery. PMID- 20842891 TI - [Moral judgment of alcohol addicts]. AB - INTRODUCTION: Alcoholism could represent an important factor of crime and different forms of abuse of family members (physical and emotional) exist in many alcohol-addict cases, as well as characteristics of immoral behaviour. OBJECTIVE: The objective of our study was to determine the predominating forms in moral judgment of alcohol addicts, and to examine whether there was any statistically significant difference in moral judgment between alcohol addicted persons and non alcoholics from general population. METHODS: The sample consisted of 62 subjects, divided into a study (alcoholics) and a control group (non-alcoholics from general population). The following instruments were used: social-demographic data, AUDIT, MMPI-201, cybernetic battery of IQ tests (KOG-3) and the TMR moral reasoning test. RESULTS: Mature forms of moral judgment prevailed in both group of subjects, alcohol addicted persons and non-alcoholics. Regarding mature forms of moral judgment (driven by emotions and cognitive) non-alcoholics from the general population had higher scores, but the difference was not statistically significant. Regarding socially adapted and egocentric orientation alcohol addicted persons had higher scores. However, only regarding intuitive-irrational orientation there was a statistically significant difference in the level of moral judgment (p < 0.05) between alcoholics and non-alcoholics, in favour of the alcoholics. CONCLUSION: Moral judgment is not a category differing alcohol addicted persons from those who are not. Nevertheless, the potential destructivity of alcoholism is reflected in lower scores regarding mature orientations in moral judgment. PMID- 20842892 TI - Some risk factors for the development of type 2 diabetes in men and women of Belgrade population. AB - INTRODUCTION: In the last two decades there has been an increase in the prevalence of type 2 diabetes in both developed and in developing countries. OBJECTIVE: To determine whether personal habits like smoking, alcohol and coffee consumption or physical inactivity are different between genders in patients with type 2 diabetes. METHODS: The study was conducted in Belgrade, during the period 2007-2008, and included newly diagnosed patients with type 2 diabetes. We included 80 men and 99 women diagnosed with diabetes mellitus type 2, referred to the Primary Health Care Centre "Savski venac". A questionnaire was used to collect data on demographic and anthropometric characteristics, as well as data on healthy habits. The chi2 test and two-tailed t-test were used for data analysis. RESULTS: The men were significantly more engaged in industry and crafts, while the women worked significantly more frequently in administrative jobs. The men were married significantly more frequently than the women (p < 0.05) and had a higher level of education (p < 0.05). Regarding to the level of implementation of nutritional and physical activity, there were no significant differences between the genders (p > 0.05). The women consumed coffee significantly more frequently than the men (p < 0.05), but drank less alcohol (p < 0.05). The men were former smokers significantly more frequently (p < 0.05) than the women. CONCLUSION: These results indicate the role of certain personal habits in the development of type 2 diabetes. PMID- 20842893 TI - [Hypothermia as the cause of death in forensic pathology: autopsy study]. AB - INTRODUCTION: The body cooling process goes through few clinical phases. These are followed by some morphological thanatological changes such as frost erythema and Wischnewsky's spots, which are used in diagnosis of death due to hypothermia. In such cases there is no any specific autopsy finding. OBJECTIVE: To establish the frequency of hypothermia as the cause of death for a ten-year-period, and to analyze the sample according to gender and age, risk factors and autopsy findings of subjects. METHODS: A retrospective autopsy study was performed for a ten-year period (total of 12,765 forensic autopsies). The relevant data were collected from autopsy records, police reports and heteroanamnestic interviews. The sample was analyzed according to gender, age, scene of death, blood alcohol concentration, risk factors, and autopsy findings of all observed subjects. RESULTS: The sample included 67 subjects, 42 males and 25 females (chi2 = 4.31; p < 0.05), of average age 63.9 +/- 14.7 years (min=27, max=92; med=65, mod=55). Nineteen of subjects were found at in-door places. In 13 subjects blood alcohol concentration ranged from 0.50 to 3.32 promille (average 1.81 +/- 0.93). The younger the observed subject was, the higher the blood alcohol concentration (p = -0.251; p = 0.04). One third of the observed subjects were chronic alcohol abusers. Thirteen persons had psychiatric diseases. In 43 observed subjects the concomitant appearance of frost erythema and Wischniewsky's spots were established (chi2 = 49.59; df = 3; p < 0.001). CONCLUSION: In the analyzed ten year period hypothermia was not often the cause of death; it was disclosed only in 0.5% of the total number of the studied autopsies. The most of the deceased were older males with cardiovascular problems found in unprotected open-air places. The most frequent thanatological findings in the analyzed subjects were frost erythema and Wischnewsky's spots. PMID- 20842894 TI - [SWOT analysis: the analytical method in the process of planning and its application in the development of orthopaedic hospital department]. AB - INTRODUCTION: SWOT analysis is a managerial tool used to evaluate internal and external environment through strengths and weaknesses, opportunities and threats. OBJECTIVE: The aim was to demonstrate the application of the SWOT analysis on the example of the Department for Paediatric Orthopaedics and Traumatology at the Institute of Orthopaedic Surgery "Banjica" in Belgrade. METHODS: Qualitative research was conducted during December 2008 at the Department for Paediatric Orthopaedics and Traumatology of the Institute of Orthopaedic Surgery "Banjica" by applying the focus group technique. Participants were members of the medical staff and patients. In the first phase of the focus group brainstorming was applied to collect the factors of internal and external environment, and to identify strengths and weaknesses, opportunities and threats, respectively. In the second phase the nominal group technique was applied in order to reduce the list of factors. The factors were assessed according to their influence on the Department. Factors ranked by the three point Likert scale from 3 (highest impact) to 1 (lowest impact). RESULTS: The most important strengths of the Department are competent and skilled staff, high quality of services, average hospital bed utilization, the Department providing the educational basis of the School of Medicine, satisfied patients, pleasant setting, and additional working hours. The weaknesses are: poor spatial organization, personnel unmotivated to refresh knowledge, lack of specifically trained personnel, inadequate sanitary facilities, and uncovered services by the Insurance Fund, long average hospital stay, and low economic status of patients. The opportunities are: legislative regulations, formed paediatric traumatology service at the City level, good regional position of the Institute, and extension of referral areas. The threats are: absent Department autonomy in the personnel policy of the Institute, competitions within the Institute, impossibility to increase the Department capacities, inadequate nutrition, low opportunities for expert training of the personnel, outdated equipment, and presence of informal payments. CONCLUSION: SWOT analysis is a frequently used managerial instrument, which enables the systematic approach in decision making process. PMID- 20842895 TI - Improvement of teamwork in health care through interprofessional education. AB - INTRODUCTION: Collaboration, within and between healthcare teams, facilitates effective healthcare. Internationally, the development of interprofessional education, as a means to facilitate more effective teamwork in health care, has been recognized for over forty years. OBJECTIVE: The aim of this paper is to evaluate students' attitudes toward the influence of interprofessional education on improvement of collaboration and teamwork. METHODS: The research was conducted by interviewing students at the Medical Faculty in Novi Sad in the form of cross sectional study. The study sample included students from two undergraduate programmes: School of Nursing (n=52) and Integrated Studies of Medicine (n=53). Students admitted to the research had to be exposed to clinical experience. The instrument used in this study was the Readiness for Interprofessional Learning Scale (RIPLS). RESULTS: As many as 93.3% of students indicated that basics of teamwork skills should be obtained prior to graduation, whereas 96.2% considered that interprofessional education would enable them to improve mutual trust and respect. The majority of interviewees indicated that patients would ultimately benefit if healthcare students worked together to solve patient problems. Multivariate procedures MANOVA p < 0.05 and discriminative analysis p < 0.05 of students' attitudes toward teamwork and collaboration showed significant differences between the students of medicine and nursing. CONCLUSION: The students of the Integrated Studies of Medicine and School of Nursing had a positive attitude toward the influence of interprofessional education on the improvement of collaboration and teamwork. PMID- 20842896 TI - Spontaneous dislocation of a transparent lens to the anterior chamber--a case report. AB - INTRODUCTION: The causes leading to dislocation of the natural lenses are different involving injuries, hereditary diseases and spontaneous dislocation. Spontaneous dislocation of a transparent natural lens is extremely rare, especially dislocation of the anterior eye chamber. We report a case of spontaneous dislocation of the transparent natural lens to the anterior eye chamber in a patient who had no history of eye injuries. CASE OUTLINE: The patient was a 17-year-old boy. Lens dislocation was spontaneous, and the patient presented for ophthalmological consultation due to a sudden vision impairment of the left eye. Biomicroscopic examination verified that the transparent lens was in the anterior chamber, and it was spherophakia of lesser diameter; there were no signs of increased intraocular pressure, as typically expected in lens dislocation to the anterior chamber. The patient was operated on in general anaesthesia. Surgery involved intracapsular extraction of the dislocated lens through a corneoscleral incision. CONCLUSION: This case report shows that a spontaneous dislocation of the natural lens may occur in younger people. The dislocated spherophakic lens to the anterior eye chamber did not contribute to the rise of the intraocular pressure and development of acute glaucoma. The acute glaucoma resulted from the pilocarpine narrowing of the pupil due to pupillary block. The intracapsular instrumental extraction of the dislocated transparent lens from the anterior chamber was successfully completed through a corneoscleral incision. PMID- 20842897 TI - [Abdominal aorta coarctation: the first three case reports in our literature]. AB - INTRODUCTION: Congenital coarctation of the thoracic aorta at the ligamentum arteriosum or the aortic arch is well recognized. But a much less common variety (0.5-2.0%) of aortic coarctation is located in the distal thoracic aorta or abdominal aorta or both and is often called "middle aortic syndrome" or "mid aortic dysplastic syndrome". This represents serious pathological condition and indicates multidisciplinary therapy approach. OUTLINE OF CASES: From 1996 to 2007, at the Vascular Surgery Clinic of the Institute for Cardiovascular Diseases "Dedinje", Belgrade, three patients were treated due to abdominal aorta coarctation, two females aged 55 and 50 and a 4-year-old child. The patients were treated surgically (by-pass with a prosthetic graft and patch angioplasty) and endovascular- percutaneous transluminal angioplasty (PTA) with and without a stent. The follow-up period was 3-70 months. In the 50-year-old patient, angiography showed severe narrowing of the suprarenal segment of the abdominal aorta. Thoraco-abdominal bypass with a 16 mm dacronic tubular graft was performed. In the 4-year-old patient angiography also showed a suprarenal aorta narrowing. In the first act patch angioplasty was performed and after PTA of the visceral arteries was done on several occasions. In the 55-year-old patient, after diagnostic angiography, infrarenal aorta coarctation was registered. PTA was performed with stent placement. All patients were asymptomatic on control check-ups. CONCLUSION: Abdominal coarctation is a pathological disease which is seldom found in vascular surgery. Angiography is of major importance for setting the diagnosis and for the control of the results of surgical and nonsurgical treatment. The combination of surgical and endovascular treatment in our patients showed very good results in the studied period. PMID- 20842898 TI - [Diagnostic dilemmas of multislice CT angiography in the evaluation of the degree of common carotid artery stenosis]. AB - INTRODUCTION: Multislice CT angiography (CTA) is a noninvasive and quick technique to image carotid artery stenosis, as well as intracerebral vasculature. Modern multidetector CTA produces images with a high resolution of, not only the contrast-filled lumen, but also of the vessel wall and the surrounding soft tissues. Multiple studies have verified the ability of CTA to provide an accurate representation of the degree of carotid stenosis in comparison to digital subtraction angiography, both for moderate and high-grade stenosis. Because of its fast and accurate vessel imaging, CT angiography is increasingly used in the assessment of carotid artery stenosis. CASE OUTLINE: A 37-year-old female patient was admitted at the Vascular Surgery Clinic of the Institute for Cardiovascular Diseases "Dedinje", Belgrade, for angiography and endovascular procedure of a high-grade stenosis of the left common carotid artery based on Multislice CT findings brought by the patient. She complained of problems which we considered to be the result of cerebral circulation ischemia. After detailed diagnostic procedures, we concluded that no pathological lesions could be verified either on the left common carotid artery or other supraaortic branches.Therefore, the patient was discharged for further neurological examinations. CONCLUSION: Although Multislice CTA has many advantages over classical angiography, its validity should be taken with reserve, especially in younger patients. PMID- 20842899 TI - [Kiss-induced severe anaphylactic reactions]. AB - INTRODUCTION: Ingestion is the principal route for food allergens to trigger allergic reaction in atopic persons. However, in some highly sensitive patients severe symptoms may develop upon skin contact and by inhalation. The clinical spectrum ranges from mild facial urticaria and angioedema to life-threatening anaphylactic reactions. OUTLINE OF CASES: We describe cases of severe anaphylactic reactions by skin contact, induced by kissing in five children with prior history of severe anaphylaxis caused by food ingestion. These cases were found to have the medical history of IgE mediated food allergy, a very high total and specific serum IgE level and very strong family history of allergy. CONCLUSION: The presence of tiny particles of food on the kisser's lips was sufficient to trigger an anaphylactic reaction in sensitized children with prior history of severe allergic reaction caused by ingestion of food. Allergic reaction provoked with food allergens by skin contact can be a risk factor for generalized reactions. Therefore, extreme care has to be taken in avoiding kissing allergic children after eating foods to which they are highly allergic. Considering that kissing can be a cause of severe danger for the food allergic patient, such persons should inform their partners about the risk factor for causing their food hypersensitivity. PMID- 20842900 TI - Lesion of the femoral nerve caused by a hydatid cyst of the right psoas muscle. AB - INTRODUCTION: Hydatidosis is a human disease caused by the larval form of Echinococcus granulosus. All organs in the human body may be affected by hydatid disease, but excluding liver and lungs, all other organs are considered as uncommon locations. Hydatid disease located in the psoas muscle is uncommon. CASE OUTLINE: The authors present a 36-year-old male living in endemic areas of Serbia, admitted due to pain and weakness of the right thigh and weight loss. Duration of symptoms was one year. CT and MRI revealed a big cystic mass (20 cm long) in the right psoas muscle. Neurological investigation showed a loss of function of the right femoral nerve. Serology for Echinococcosis was negative. Surgery was indicated and performed by median laparotomy. Total excision of the cyst was done. Pathohystology confirmed the nature of the cyst. Three years after operation the patient was without any signs of disease relapse. CONCLUSION: Echinococcal disease of the psoas has been very rarely reported, sometimes associated with paraspinal disease and often with vertebral involvement. Cystic or complex retroperitoneal tumour, pyogenic abscess of the psoas and even tuberculosis should be considered in the differential diagnosis. Treatment of choice is surgery. The greatest danger for the patient is dissemination and anaphylactic reaction. Also, compression of adjacent organs may produce significant morbidity. PMID- 20842901 TI - [Acute intermittent porphyria in the puerperium]. AB - INTRODUCTION: Acute intermittent porphyria emerges as a result of partial defect of porphobilinogen deaminase and is manifested by repeated episodes of somatic, psychiatric and neurological disorders. The disease is conducted via the autosomal-dominant gene of variable penetration, so most of the carriers never experience seizures. Timely making of diagnosis, screening of blood relatives of the patient and education of patients on avoidance of provoking factors are the key to adequate treatment. CASE OUTLINE: A 23-year-old patient having born the third child was hospitalized due to pains in the abdomen and convulsive seizures nine days after the vaginal delivery. At admittance, she suffered a generalized convulsive seizure of clonic-tonic type. The patient immediately underwent a complete clinical, laboratory, bacteriological and ultrasound examination. Bearing in mind the fact that the patient had several convulsive seizures even after the given neurological therapy, haem-arginate was introduced into therapy during four days. The administration of haem-arginate led to the normalization of blood pressure, pulse and bowel function. The administration of haem-arginate led to the normalization of blood pressure, pulse and bowel function. The patient was treated by a team of doctors, in the intensive care ward, with the use of medicaments, which are allowed in the case of acute porphyria. Sixteen days after the admittance, with clean neurological status and gynaecological and ultra-sound findings, she was released for ambulatory treatment. CONCLUSION: The presented case exhibits the gravity of making a diagnosis of acute intermittent porphyria in puerperium and the necessity of multi-disciplinary approach in treating this disease. Acute intermittent porphyria should be considered in cases of ambiguous abdominal pain, as well as in patients having abdominal pains followed by neuro psychiatric disorders. PMID- 20842902 TI - Treatment of open tibial shaft fracture with soft tissue and bone defect caused by aircraft bomb--case report. AB - INTRODUCTION: Aircraft bombs can cause severe orthopaedic injuries. Tibia shaft fractures caused by aircraft bombs are mostly comminuted and followed by bone defects, which makes the healing process extremely difficult and prone to numerous complications. The goal of this paper is to present the method of treatment and the end results of treatment of a serious open tibial fracture with soft and bone tissue defects resulting from aircraft bomb shrapnel wounds. CASE OUTLINE: A 26-year-old patient presented with a tibial fracture as the result of a cluster bomb shrapnel wound. He was treated applying the method of external bone fixation done two days after wounding, as well as of early coverage of the lower leg soft tissue defects done on the tenth day after the external fixation of the fracture. The external fixator was removed after five months, whereas the treatment was continued by means of functional plaster cast for another two months. The final functional result was good. CONCLUSION: Radical wound debridement, external bone fixation of the fracture, and early reconstruction of any soft tissue and bone defects are the main elements of the treatment of serious fractures. PMID- 20842903 TI - [Immunological assays in the diagnosis of tuberculosis infection at the beginning of 21st century]. AB - A subject infected by tubercle bacilli may immediately develop the disease (primary tuberculosis), witch occurs in a few number of infected persons, or may overcome the primary infection (a latent carrier of the infection). Nowadays there are about two milliard people with a latent tubercular infection. About 10% of them will develop active tuberculosis during their lifetime. Detection of latent tuberculosis and its treatment decreases the risk of developing the active form of the disease. Until recently, the tuberculin test was a single screening method to identify the subjects with tubercular infection. In recent years, some novel in vitro tests to diagnose the tubercular infection have been designed. These tests measure the cell-mediated immune response quantifying the emission of interferon gamma by T cells in response to stimulation by Mycobacterium tuberculosis specific antigens. These tests are more sensitive and specific than the tuberculin skin test, but they are just an accessory tool, i.e., a link in the diagnostic chain of the tubercular infection. PMID- 20842904 TI - [Antimycotics susceptibility testing of dermatophytes]. AB - Dermatophytes are moulds that produce infections of the skin, hair and nails of humans and animals. The most common forms among these infections are onychomycosis and tinea pedis affecting 20% of world population. These infections are usually chronic. The treatment of dermatophytoses tends to be prolonged partly because available treatments are not very effective. Antifungal drug consumption and public health expenditure are high worldwide, as well as in Serbia. For adequate therapy, it is necessary to prove infection by isolation of dermatophytes and to test the antifungal susceptibility of isolates. Susceptibility testing is important for the resistance monitoring, epidemiological research and to compare in vitro activities of new antifungal agents. The diffusion and dilution methods of susceptibility tests are used, and technical issues of importance for the proper performance and interpretation of test results are published in the document E.DEF 9.1 (EUCAST) and M38-A2 (CLSI). The aim of our paper is to promptly inform the public about technical achievements in this area, as well as the new organization of laboratory for medical mycology in our country. The formation of laboratory networks coordinated by the National Reference Laboratory for the cause of mycosis need to enable interlaboratory studies and further standardization of methods for antifungal susceptibility testing of dermatophytes, reproducibility of tests and clinical correlation monitoring (MIK values and clinical outcome of dermatophytosis). The importance of the new organization is expected efficient improvement in the dermatophytosis therapy at home, better quality of patient's life and the reduction of the cost of treatment. PMID- 20842906 TI - [Science and medicine. Interview by I. Hulin]. PMID- 20842905 TI - [Mental hygiene: ideas and practice in Serbia]. AB - Mental health has great importance for the welfare both of individuals and society, because mental disorders cause reduced quality of life, suffering, alienation and discrimination of the diseased. The whole community also takes enormous burden of economic factors caused by mental health impairment (medical and social care and reduced productivity of patients). All societies and cultures throughout history had specific activities aimed at prevention and mental health improvement.The treatment of the diseased was under the influence of magic and empirical concepts, doctrine and religion, but also by the presence of scientific knowledge and progressive liberal streams. In Serbia the tradition of humanity is enriched with the cultural heritage of medieval history. Mental hygiene as a discipline that promoted mental health and the prevention of mental disorders was created a hundred years ago inspired by the work of Clifford Beers. Reforms of mental healthcare in the European countries, and Serbia as well, in the form of deinstitutionalisation (decreased number of beds in psychiatric institutions and increased social care), tends to develop into reinstitutionalization or transinstitutionalization (increased number of patients in isolated departments and forced hospitalizations). At the beginning of the new century the World Health Organization recognises again mental health as its priority. At the present moment, with new scientific knowledge and capabilities, but in the face of the struggle with multiple challenges of civilization (the experience of war conditions, social transition), as well as new harmful influences of polluted environment, we perceive the experience arising from the development of ideas and practices of mental hygiene in Serbia. PMID- 20842907 TI - [Hyperlipoproteinaemia and dyslipoproteinaemia II. Therapy: non-pharmacological and pharmacological approaches]. AB - At present, literally no one disputes hyperlipoproteinaemia and dyslipidemia (HLP and DLP) treatment as a rational therapeutic approach in the prevention of cardiovascular diseases (CVD). This approach is in line with the current principles of evidence-based medicine (EBM) and is sufficiently evidenced particularly by the results of large intervention studies. Nevertheless! When the results of the recent studies are critically appraised, these by no means are (mostly, there, obviously, are exceptions) as conclusive as the studies conducted in 1980s and 1990s. Consequently, positive results are being sought in subanalyses, subgroup evaluations and multiple-study metaanalyses. This paper is not intended as a critique of new drugs. These certainly are developed to be safe, effective and well-tolerated. However, the newer studies suffer from a range of issues: the populations studied are already very well managed, it is not possible to compare against placebo and sometimes, let us be honest, the trial design itself is problematic (often it is an uncritical effort to treat as wide as possible range of patients as well as new groups of patients who might not be suitable for the given treatment). Certainly, we should not start disputing the well-evidenced hypotheses and seek alternatives to the long-established arguments and approaches as a consequence to some less convincing studies. We must not overlook the most robust results of statin studies as well as 'positive' studies with other hypolipidemics. There is no doubt that the effect ofstatins on LDL cholesterol represents a significant move towards cardiovascular disease prevention. Despite this, we currently recognise with increased intensity that this very effective and well-evidenced treatment has its limits and that a high proportion of patients dies or are faced with cardiovascular diseases even though they are treated with a correct dose ofa statin and a target LDL-C level is achieved. This remaining risk (represents more than 50% ofevents) has been termed 'RESIDUAL RISK'. The issue of residual risk is crucial in patients with type 2 diabetes mellitus (DM2T) or in all patients with HDL-C-low DLP. As was repeatedly emphasised, a statin will be a cornerstone of pharmacological treatment of a DLP. However, a question arises what to combine it with. The most convincing data exist for niacin (combination of niacin with laropiprant minimising the incidence of unwanted flushes). We surely should not marginalize other hypolipidemics used mainly in combinations: resin and ezetimibe to treat LDL-C, niacin, fibrates and possibly omega-3-fatty acids to manage the residual risk (HDL and TG). Last but not least we should not forget non-pharmacological treatment as the pivotal treatment approach in all patients. PMID- 20842908 TI - [Chronic pancreatitis and the skeleton]. AB - The aim of our work was to determine the incidence of bone demineralization in patients with chronic pancreatitis, following the relation between the funcionality of the pancreatic tissue and etiological factors in the development of osteopathy and calciophosphate metabolism. Prospectivelly, during 1 year we followed 55 patients with chronic pancreatitis of different etiology verified by endoultrasound. Patients with other possible cause of osteopathy were not included in the group. In the following of calciophosphate metabolism we determined different biochemical parameters and we measured the bone mass with densitometry in standard locations. In the patients that we followed we managed to show high proportion (43.7%) of bone demineralization, however, no relation between the bone demineralization and the grade of chronic pancreatitis or the operation of pancreas was proved. Vitamin D deficiency has a significantly negative impact on bone metabolism, which is potentiated by pancreatic insufficiency and long-time alcohol abuse. PMID- 20842909 TI - [Necessity of continuous health system development]. AB - Increasing number of chronic diseases and accelerating costs of health care are important problems of health services system. Article presents four main methods of solving these difficulties: (a) more money to the system, (b) better effectiveness and efficiency of health services, (c) rationing, and (d) improvement of population health. The first three methods are limited, but increasing level of health is almost without any boundaries. The health education and professional training focused on better health literacy are important prerequisites of good health care system. PMID- 20842910 TI - [ECG markers in patients with hypertrophic cardiomyopathy]. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disease of the heart muscle whose main characteristic is unexplained hypertrophy of the left ventricle and/or right ventricle. It is considered to be the most common genetically determined cardiovascular disease with the prevalence in the population approximately 1 to 500 inhabitants. The disease is associated with severe complications such as heart failure, arrhythmias and sudden cardiac death (SCD). Nowadays the aim of intensive clinical research is to judge the contribution of noninvasive methods in the risk stratification of HCM patients. Abnormal electrocardiogram occurs in 75-95% and it often presents the first point for HCM suspicion although it is nonspecific. AIM: The aim of our study was to evaluate the electrocardiographic (standard 12-lead) and certain echocardiographic markers in patients with recurrent syncope of unknown origin in comparison with patients without these episodes. PATIENTS AND METHODS: 42 patients (17 men a 25 women) with verified HCM diagnosis underwent extensive clinical, standard 12-lead electrocardiographic and echocardiographic testing to compare these parameters in the subgroup of patients with syncope (n = 17) of unknown origin and patients without syncope (n = 23). RESULTS: As for the electrocardiographic signs we found that more than one half of patients had positive Sokolow-Lyon index (55.6%), prolonged QTc interval (63.2%). Depression of ST segment was present in 60.5%. We also found positive correlation between prolonged QTc interval and maximal left ventricle thickness. We observed that patients with syncope had statistically significantly left ventricle end diasotlic diameter in comparison with patients without syncope. CONCLUSION: Standard electrocardiography represents a "gold standard" in the diagnostics of HCM patients. We found positive correlation between prolonged QTc interval and maximal left ventricle thickness. Patients with syncope had statistically significantly smaller left ventricle end-diastolic diameter in comparison with patients without syncope. PMID- 20842911 TI - [NATO international advanced course on best way of training for mass casualty situations]. AB - NATO Advanced Training Course on Best Way of Training for Mass Casualty Situations was held in Haifa, Israel in November 16-18, 2009. In total, 22 participants from 8 countries of the Partnership for Peace and Mediterranean Dialogue Programmes attended the course. The participants, divided within three groups, discussed and practised the training methods for the preshospital aspect, the hospital aspect and the non-conventional aspect of the mass casualty management. An international team of experts, among others, used following teaching methods: general lectures, guided discussions, utilization of advanced multimedia tools, tabletop drills, and large scale drill as training tools. The trainees also learned about medical and clinical simulation as a training tool, and subsequently practiced it. A mass casualty drill was held in Rambam Health Care Campus at the end of the Course. The trainees of the course participated as observers and reviewers in the drill, and debriefed it together with Rambam medical staff. Realisation of the successful course was made possible by utilizing a grant of the NATO Science for Peace and Security Programme. PMID- 20842912 TI - Survival and quality of life in burns. AB - Advances in medical technology and practices have been associated with increasing medical specialization, but they have developed at a price. This price has included not only enormous financial costs, but the additional cost of dehumanized patient care, diminished confidence in the medical staff and, consequently, human suffering. Burn injuries are catastrophic in scope and require specialized, intensive and prolonged treatment from which ensure ethical and psychological problems often complicated by many individual factors. Some of them arising from the Code of Patients Rights not only in the Czech Republic and contribute to DNR decisions (do-not-resuscitate). Not only "Quantity" of life but also "Quality" of life should be considered, particularly in burns. Critical factor is age. In old patients more sophisticated medical knowledge and practice may actually contribute to suffering. At any age scarring represents a special type of disfigurement. The "burn image" is more likely to evoke public avoidance than sympathy. The non handicapped by their negative attitudes help create and perpetuate the handicap and the consequent burden of suffering in burn patients. PMID- 20842913 TI - [Twelve years of continuing medical education in Slovakia]. AB - Continuing medical education (CME) is an important part of the medical practice today. After the pregraduate and postgraduate education each general practitioner and specialist should follow the CME to maintain, develop or increase the knowledge and professional skills. In May of 2004 a Slovak accreditation council for continuing medical education (SACCME) was established on the base of mutual agreement among statutory representatives of Slovak Medical University, Association of Medical Schools, Slovak Medical Association, Slovak Medical Chamber, and Association of Private Physicians as non governmental non for profit organisations. During the period of 2004-2009, the number of accredited events (educational meetings, conferences and congresses) increased from 133 to 938 including the autodidactic tests in medical journals. From the beginning of 2009, SACCME credits obtained by physicians yearly are being transferred to the database of Slovak medical chamber which is responsible by law for control of CME process. PMID- 20842914 TI - [Pituitary adenomas--where is the treatment heading at the beginning of the 21st century?]. AB - To treat pituitary adenomas, three modes of treatment are usually combined: neurosurgery, radiation and pharmacological. Prolactinomas are an exception with predominantly pharmacological management. Patients with acromegaly are usually diagnosed late and thus many neurosurgeries fail to completely remove the adenoma. Any residual tumour tissue is usually irradiated with the Leksell Gamma Knife, and dopamine agonists, somatostatine analogues or growth hormone receptor antagonists are used to normalize the hormonal hypersecretion until the complete effect of the radiation. The same surgical and Gamma Knife procedures are used in patients with the Cushing's disease and TSH-secreting adenomas. Ketoconazole, metyrapone and cabergoline are used until the radiation effect in the Cushing's disease is complete, similarly, somatostatine analogues are used in TSH-secreting adenomas. Nonfunctional adenomas are less responsive to pharmacological treatment. Proautophagic cytostatic temozolamide has been used in aggressive pituitary adenomas and carcinomas. PMID- 20842915 TI - [Oxalic acid--important uremic toxin]. AB - INTRODUCTION: Oxalic acid is thought to be a significant uremic toxin that participates in the pathogenesis of uremic syndrome. AIM OF THE STUDY was to summarise results which we obtained during the study ofoxalic acid in biological fluids (plasma, saliva, urine and dialysate) in patients suffering from chronic kidney diseases (CKD), stage 3-5 and after renal transplantation. PATIENTS AND METHODS: In the retrospective study were investigated 28 healthy subjects, 112 CKD stage 1-4 patients, 39 haemodialysis patients and 27 CAPD patients. Besides 21 patients were investigated after renal transplantation. We used the following therapeutic methods: maximal water diuresis, diet with low (2g/day) and high (15g/day) sodium chloride intake, administration intravenous furosemide (20mg) and renal replacement therapy [CAPD, haemodialysis (HD), haemofiltration (HF) and postdilution haemodiafiltration (HDF)] and renal transplantation. Oxalic acid was determined by spectrophotometric method using oxalate oxidase which is free from vitamin C interference. Vitamin C was determined by spectrophotometric method. RESULTS: In CKD patients and those after renal transplantation direct relationships between plasma oxalic acid and serum creatinine were found (r = 0.904 and 0.943, respectively, P < 0.001). Despite of high plasma oxalic acid in uremic patients (23.1 +/- 10 micromol/l), there was no significant difference in salivary oxalic acid between control subjects (126.5 +/- 18 micromol/l) and CKD stage 3-4 patients (133.9 +/- 23.7 micromol/I). The urinary excretion of oxalic acid during maximal water diuresis in healthy subjects (n = 15) (from 37.5 +/- 17.4 to 110.2 +/- 49.3 micromol/4 hours) and after intravenous furosemide (CKD stage 3-4, n = 15) (from 34.5 +/- 5.5 to 66.7 +/- 8.1 micromol/3 hours) increased significantly, but was not affected by high intake of NaCI in diet (CKD stage 3 4, n = 12). One tablet of Sorbifer Durules containing 100 mg Fe2+ and 60 mg vitamin C did not lead to further increase of uremic hyperoxalemia in haemodialysis patients. Four-hour HD, H F and HDF led to the significant decrease of plasma oxalic acid, but the most significant decrease was observed during HDF (63.3%). CONCLUSION: The results of this study indicate, that renal replacement therapy is not effective for permanent reduction of elevated plasma levels of oxalic acid--important uremic toxin. PMID- 20842916 TI - [The influence of testosterone on cardiovascular disease in men]. AB - The influence of testosterone on cardiovascular disease is recently discussed question. Testosterone modulates vascular reactivity by genomic and nongenomic modes of action, it has an impact on endothelial function, production of proinflamatory cytokines and lipid profiles. The possible role of sex hormone binding globulin (SHBG) in androgen action by plasmatic membrane receptors breaks "the free hormone hypothesis", especially when clinical trials reveal strong association between SHBG and risk factors of cardiovascular disease. The results of last clinical trials mention that androgen deficiency is associated with obesity, insulin resistance and dyslipidaemia. Large clinical trials demonstrated that androgen deficiency predict mortality in elderly men. Testosterone substitution restores vasoreactivity and endothelial function and could potentially reduce cardiovascular disease in men but to confirm this theory more large clinical trials are needed. PMID- 20842917 TI - [Current options and principles of pathomorphology-based tumour diagnostics]. AB - Modern pathomorphology tumour diagnostics involve comprehensive cytology cell examination and, importantly, tissue biopsy examination using the most up-to-date assessment techniques. To correctly classify a tumour process, it is essential not only to define its histological typology and identify its biological character but, at the same time, using immunohistochemistry and diagnostic molecular pathology, to evaluate prognostic and predictive indicators. As regards the prognostic indicators, it is mainly grading and staging as part of the TNM system, the sentinel lymph node assessment, if it is assessed, and other nodes extracted in this context. Histological specimens of invasive carcinomas and skin melanomas are assessed with respect to the depth of the invasion. Endocrine oestrogen and progesterone receptors are assessed in endocrine-dependent breast carcinomas. Predictive pathology uses biomarkers; biomarkers confirm the presence of target molecules following their reaction with the administered small molecule like drugs, usually protein kinases or antibodies. HER2 gene amplification is estimated using the FISH method and predicts effectiveness of breast cancer therapies. In patients with a colon carcinoma, HER1 oncogene is identified immunohistochemically and the presence of a mutated K-ras is subsequently tested using the RT-PCR technique. CD 117 (c-kit) expression is determined in gastrointestinal stromal tumour and CD 20, 33 and 52 in malignant lymphomas and leukaemias. The most difficult task for a pathologist is defining the primary focus of the tumour in cases where only a fraction of a metastasis is available for examination. Nevertheless, at present, it is feasible to track the tumour differentiation down and, using an antibody battery, particularly against specific cytokeratines and vimentine and including organ-specific markers, to identify the primary source or at least to establish an assumption about the most likely organ affected by the tumour process. PMID- 20842918 TI - [Natriuretic peptides in patients with aortic stenosis]. AB - INTRODUCTION: The aim of this research was to, in patients with severe (tight) aortic stenosis (AoS), evaluate a) an association between clinical and some haemodynamic characteristics and natriuretic peptides (ANP, BNP) concentrations and b) usefulness of these hormones in the decision making on the next therapeutic steps. METHODS: Echocardiography and 6-minut exertion walking test were performed in 23 consecutive patients (12 men, 11 women; age 67 +/- 7 years) and 20 controls together with ANP and BNP measurements from three plasma samples before, immediately after and 20 minutes after the exertion test. RESULTS: There was high inter-individual variability in the ANP and BNP concentrations in patients with AoS. All ANP and BNP were significantly higher than in the controls (ANP 1, 2, 3, p < 0.001; BNP 1, 2, 3, p < 0.001). Only the ANP levels increased significantly after the exercise (ANP 1 vs. ANP 2 = 0.011; ANP 2 vs. ANP 3 p = 0.037). We identified significant correlations between aortic peak gradient and BNP 1, 2 (r = 0.821, p < 0.001) and ANP 1, with BNP correlations being stronger. We did not find any correlations with aortic valve area and the left ventricle mass. The hormone levels were non-significantly increased depending on NYHA classification. Exercise did not improve validity ofANP and BNP measurement. Their values had high sensitivity but low specificity in detecting critical AoS. CONCLUSION: ANP and mainly BNP helped to exclude severe AoS but they were not useful in detecting lower, orderline gradients. We did not prove ANP and BNP to be significant factors in decision making about the timing of AoS surgery. PMID- 20842919 TI - [Cardiovascular diseases in rheumatoid arthritis]. AB - Risk of cardiovascular diseases is significantly higher in patients with rheumatoid arthritis (RA) than in normal population, leading to higher mortality of these patients. An accelerated atherosclerosis has been considered a basis for the increased cardiovascular risk in RA. Besides classical atherosclerosis risk factors, systemic inflammation plays a substantial role. Indirect mechanisms such as insulin resistance and dyslipidemia may play a role, however, inflammation probably causes direct damage to blood vessels. Thus, systemic inflammation has a primary role and other factors accelerate this process. An adequate anti inflammatory therapy can have a positive effect also on cardiovascular diseases in RA. PMID- 20842920 TI - [The principles of care for patients with intermittent claudication]. AB - Patients with claudication have a high cardiovascular risk and, foremost, require an introduction of the appropriate procedures to stop the progression of the disease and to prevent cardiovascular events as if these were patients with a coronary or cerebrovascular disease. To manage the claudication-associated complaints, surgery and endovascular revascularization procedures, exercise therapy and vasoactive agents with proven clinical efficacy are used. PMID- 20842921 TI - [Distressful journey for the metabolic syndrome to its position in clinical practice]. AB - MS is a major atherogenic syndrome in our population. The concept of MS has had a very positive effect on our knowledge of the most serious civilization diseases, the genotypic constellation of MS, although monogenic defects explain only a very small part of pathological defects. It is certain, however, that a crucial role played is by interactions between genetic factors and risk factors of external environment. Undoubtedly, insulin resistance, central obesity and impaired metabolism of adipose tissue play an important role in the pathogenesis of MS, and there are other pathogenetic theories. The author discusses briefly the history of MS and presents the best-known definitions starting with the 90s ofthe last century, ADA and EASD reservations towards MS, as well as the new harmonized definition from 2009. This modified definition ofMS has been adopted in practice in the Czech Republic due to the Czech Institute ofmetabolic syndrome. The author discusses in greater detail the WHO expert report from 2010, which indicates some limitations of diagnostic criteria for MS. Despite all the objections the expert report provides reasons to support the use of the term metabolic syndrome, and metabolic syndrome is considered to be a recognized concept that focuses attention on the importance of comprehensive, multifactorial health problems. Finally, the author mentions sub-problems related to MS, which will have to be resolved in collaboration with diabetologists. PMID- 20842922 TI - [Diabetic osteopathy: previously disputed but most likely important ailment]. AB - Diabetic osteopathy is usually not mentioned in the list of diabetic complications. This osteopathy is very important in clinical medicine. In the pathogenesis many factors are involved--bone formation, hyperglycaemia, glycosuria, glycation of collagene etc. Clinically important is the high risk of fractures present in diabetic patients. This risk can be positively and negatively modified by antidiabetic drugs. It is important to find some markers for fracture risk in diabetes. Nowadays only bone densitometry can be used with some limitations to quantify this risk. PMID- 20842923 TI - [Will vaccines appear on the scene of oncology in the near future?]. AB - In parallel with the increasing knowledge of the role played by the immune system in the control oftumourgrowth, the efforts to develop anti-cancer vaccines intensify. In the present time two highly efficient prophylactic vaccines against the virus-induced cancers are in use, but a rapid progress in the development of anti-cancer therapeutic vaccines can also be seen. It is conditioned by an increasing understanding of the biology of the tumor cells and the rapid progress in the field of immunology. Nevertheless, these developments are associated with a number of difficulties, among which the immunosuppressive activities of the tumor cells and the tumor microenvironment are the most important. On the example of chronic myeloid leukemia the author proposes a strategy for the development ofa therapeutic cancer vaccine. PMID- 20842924 TI - [Current options for the treatment of osteoporosis]. AB - The primary aim of osteoporosis treatment is prevention of osteoporotic fractures. The main factors in the development of these fractures are mechanic resistance of the bone and the bone quality. The importance of risk factor identification increases and it is important to consider the structural analysis of the hip-bone when evaluating and deciding whether to prescribe antiresorptive or osteoanabolic drugs or whether to just modify calcium and vitamin D intake. Various options are currently available for the pharmacological treatment of osteoporosis: calcium and vitamin D supplementation together with aminobisphosphonates, or osteoanabolic treatment with parathormone derivatives; monoclonal antibody to RANKL denosumab will also soon become available. PMID- 20842925 TI - Biofeedback load technique in the rehabilitation of osteoporotic patients (biomechanical analysis). AB - Based on a simple biomechanical analysis, available to physicians, the article recommends carrying a backpack regularly as a part of the complex rehabilitation of osteoporotic patients. Carrying a backpack in front or on the back is recommended for patients with uncomplicated osteoporosis, carrying a backpack only on the back is recommended for patients with osteporotic vertebrae fractures. The importance of carrying a backpack is based upon remove the muscular dysbalance of the trunk muscles and upon increasing the bone strength by compressive force acting upon the vertebrae and proximal femur and activating osteoblasts to osteoformation. The backpack load magnitude is differentiated- patients with vertebrae fractures put a weight up to 1 kg into the backpack, patients without vertebrae fractures up to 2 kg. PMID- 20842926 TI - Femur strength index versus bone mineral density: new findings (slovak epidemiological etudy). AB - PATIENTS AND METHODS: We analysed the data in the sample (n = 3,215) of East Slovak women with a primary or secondary osteopenia, osteoporosis and with risk factors for osteoporosis, aged 20-89 years, median 59 years, 95% C. I. (59.31; 60.07) obtained from dual energy X-ray absorptiometry device (Prodigy-Primo, GE, USA). Measured variables: 1. left proximal femur: T-score total hip, FSI (femur strength index), 2. lumbarvertebrae L1-L4: BMD (bone mineral density). OBJECTIVES: 1. To estimate and to compare an expected frequency of pathological FSI < 1 and T-score total hip < or = -2.5 SD values in the East Slovak female population. 2. To estimate expected frequency of women with: FSI < 1 and T-score total hip < -2.5 SD (Group A), FSI < 1 and T-score total hip from interval from 1,0 till -2.5 SD (Group B), FSI < 1 and T-score total hip > -1.0 SD (Group C) in the East Slovak female population. 3. To determine, if FSI variable value is a significant predictor of BMD variable values in lumbar vertebrae. RESULTS: 1. In the East Slovak female population we can expect 14.54% ofwomen with FSI values < 1 and 6.25% ofwomen with osteoporosis in the total hip area according to T-score. 2. For the group A we can expect the mean value (mu) from interval (1.41; 2.36)%, for the group B from interval (4.50; 6.03)% and for the group C from interval (6.76; 8.55)%. 3. Between FSI and BMD L1-L4 variable values there is not a statistically significant dependence, because FSI variable is quantitative and qualitative different variable from BMD variable. CONCLUSION: The measurement of FSI variable values may discover a higher percentage of women with a probability of femoral neck fracture by fall than the measurement of BMD variable value in the total hip area. Patient with osteopenia or normal BMD measured in the total hip area may sustain a femoral neck fracture by fall, when she has pathological value of FSI, i.e. she has adverse values of geometric variables of proximal femur(biomechanically unfavourable proximal femur configuration). FSI variable value is not a significant predictor of BMD variable values in lumbar vertebrae L1-L4. PMID- 20842927 TI - [Laboratory diagnostics and endocrinology]. AB - Laboratory testing is among the most important diagnostic approaches in modern endocrinology; the presented overview summarizes diagnostic algorithms for the core endocrinopathies. PMID- 20842928 TI - [Parvovirus B19 infection--the cause of severe anaemia after renal transplantation]. AB - Anaemia belongs to the most frequent, mutlifactorial complications after kidney transplantation. Blood loss during surgery, iron deficiency, inflammation, bone marrow suppression by immunosuppressants and antiviral medication, use of angiotensin-converting enzyme and/or angiotensin receptor blockers, hyperparathyroidism, allograft dysfunction and at last viral infections participate in the development of posttransplant anaemia. Persistent aplastic anaemia after kidney transplantation could be caused by parvovirus 819 infection. PMID- 20842929 TI - Adsorption of chlorine dioxide gas on activated carbons. AB - Research and field experience with chlorine dioxide (ClO2) gas to decontaminate structures contaminated with Bacillus anthracis spores and other microorganisms have demonstrated the effectiveness of this sterilant technology. However, because of its hazardous properties, the unreacted ClO2, gas must be contained and captured during fumigation events. Although activated carbon has been used during some decontamination events to capture the ClO2 gas, no data are available to quantify the performance of the activated carbon in terms of adsorption capacity and other sorbent property operational features. Laboratory experiments were conducted to determine and compare the ClO2 adsorption capacities of five different types of activated carbon as a function of the challenge ClO2 concentration. Tests were also conducted to investigate other sorbent properties, including screening tests to determine gaseous species desorbed from the saturated sorbent upon warming (to provide an indication of how immobile the ClO2 gas and related compounds are once captured on the sorbent). In the adsorption tests, ClO2 gas was measured continuously using a photometric-based instrument, and these measurements were verified with a noncontinuous method utilizing wet chemistry analysis. The results show that the simple activated carbons (not impregnated or containing other activated sorbent materials) were the most effective, with maximum adsorption capacities of approximately 110 mg/g. In the desorption tests, there was minimal release of ClO(2) from all sorbents tested, but desorption levels of chlorine (Cl2) gas (detected as chloride) varied, with a maximum release of nearly 15% of the mass of ClO2 adsorbed. PMID- 20842930 TI - A feasibility study of a predictive emissions monitoring system applied to taipower's nanpu and hsinta power plants. AB - The Hsinta and Nanpu Power Stations are located in southern Taiwan. The Hsinta Power Station consists of five combined-cycle gas turbines (CCGT), whereas the Nanpu Power Station consists of four. A project was undertaken to develop and deploy a predictive emissions monitoring system (PEMS) on CCGT unit 3 of Hsinta Power Station (HT-3) and CCGT unit 1 of Nanpu Power Station (NP-1) with the long term goal of developing a universal model for this kind of power plant. After the first-year PEMS project at the Hsinta power plant, one goal of the second-year PEMS project was to set up a second PEMS at the Nanpu power plant and compare the PEM models applied the to two gas-fired combined cycle power generation units. Consequently, the second and third PEMS of Taiwan at CCGT HT-3 and NP-1 were finished. After comparing the differences among HT-1, HT-3, and NP-1 PEMS models, the pattern of model functionality indicated that this model could be applied to the other units of the same type and size. However, the PEMS function constant or parameter coefficients must be modified on a case-by-case basis. With regard to the PEMS model developed for HT-3, the relative accuracy (RA) of the 15-variable model with start-up mode is only 7.43% and met the criteria of draft PS-16. With regard to the PEMS model developed for NP-1, the RA of the 10-variable model with start-up mode was only 7.76% and also met the criteria of draft PS-16. PMID- 20842931 TI - Reactivity scales as comparative tools for chemical mechanisms. AB - Incremental ozone impacts or reactivities have been calculated for selected organic compounds using a Master Chemical Mechanism (MCMv3.1) and compared with those calculated elsewhere with the SAPRC-07 chemical mechanism. The comparison of incremental reactivities has been completed for 116 organic compounds representing the alkanes, alkenes, aldehydes, ketones, aromatics, oxygenates, and halocarbons. Both mechanisms have constructed a consistent and coherent description of reactivity within each class of organics. MCMv3.1 and SAPRC-07 have represented some features of the available body of understanding concerning the atmospheric oxidation of organic compounds in a consistent and quantitative manner, although significant differences were found for 14 organic compounds. These differences represent species-dependent facets of their atmospheric chemistry that have not been adequately resolved in the available literature experimental data. PMID- 20842932 TI - Carbon dioxide removal from flue gases by absorption/ desorption in aqueous diethanolamine solutions. AB - The carbon dioxide (CO2) desorption rate from CO2- loaded aqueous diethanolamine (DEA) solutions was measured using a stirred cell with a flat gas-liquid interface. The measurements were performed in the temperature range of 293.15 313.15 K and an amine concentration range of 10-20% mass DEA. Measurements were based on a semibatch isothermal absorption of the gas until the equilibrium state was reached, followed by desorption, which was initiated by the pressure release in the system. A simplified mass transfer model based on the film theory coupled with CO2, mass balance was developed to interpret the experimental data. On the basis of the proposed model, the initial mass transfer rates were calculated from the experimental results. The calculated initial desorption rates enabled estimation of the enhancement factor for CO2 mass transfer from aqueous DEA solutions. Analysis of the experimental data showed that desorption took place in the diffusive mass transfer regime. PMID- 20842933 TI - Electron beam technology for multipollutant emissions control from heavy fuel oil fired boiler. AB - The electron beam treatment technology for purification of exhaust gases from the burning of heavy fuel oil (HFO) mazout with sulfur content approximately 3 wt % was tested at the Institute of Nuclear Chemistry and Technology laboratory plant. The parametric study was conducted to determine the sulfur dioxide (SO2), oxides of nitrogen (NO(x)), and polycyclic aromatic hydrocarbon (PAH) removal efficiency as a function of temperature and humidity of irradiated gases, absorbed irradiation dose, and ammonia stoichiometry process parameters. In the test performed under optimal conditions with an irradiation dose of 12.4 kGy, simultaneous removal efficiencies of approximately 98% for SO2, and 80% for NO(x) were recorded. The simultaneous decrease of PAH and one-ringed aromatic hydrocarbon (benzene, toluene, and xylenes [BTX]) concentrations was observed in the irradiated flue gas. Overall removal efficiencies of approximately 42% for PAHs and 86% for BTXs were achieved with an irradiation dose 5.3 kGy. The decomposition ratio of these compounds increased with an increase of absorbed dose. The decrease of PAH and BTX concentrations was followed by the increase of oxygen-containing aromatic hydrocarbon concentrations. The PAH and BTX decomposition process was initialized through the reaction with hydroxyl radicals that formed in the electron beam irradiated flue gas. Their decomposition process is based on similar principles as the primary reaction concerning SO2 and NO(x) removal; that is, free radicals attack organic compound chains or rings, causing volatile organic compound decomposition. Thus, the electron beam flue gas treatment (EBFGT) technology ensures simultaneous removal of acid (SO2 and NO(x)) and organic (PAH and BTX) pollutants from flue gas emitted from burning of HFO. This technology is a multipollutant emission control technology that can be applied for treatment of flue gas emitted from coal-, lignite-, and HFO-fired boilers. Other thermal processes such as metallurgy and municipal waste incinerators are potential candidates for this technology application. PMID- 20842934 TI - Ammonia emissions from a U.S. broiler house--comparison of concurrent measurements using three different technologies. AB - There is a need for robust and accurate techniques for the measurement of ammonia (NH3) and other atmospheric pollutant emissions from poultry production facilities. Reasonable estimates of NH3 emission rate (ER) from poultry facilities are needed to guide discussions about the industry's impact on local and regional air quality. The design of these facilities features numerous emission points and results in emission characteristics of relatively low concentrations and exhaust flow rates that vary diurnally, seasonally, and with bird age over a considerable range. These factors combine to render conventional emissions monitoring approaches difficult to apply. Access to these facilities is also often restricted for biosecurity reasons. The three objectives of this study were (1) to compare three methods for measuring exhaust NH3 concentrations and thus ERs, (2) to compare ventilation rates using in situ measured fan characteristics versus using manufacturer sourced fan curves, and (3) to examine limitations of the alternative measurement technologies. In this study, two open path monitoring systems operating outside of the buildings were compared with a portable monitoring system sampling upstream of a primary exhaust fan. The position of the open-path systems relative to the exhaust fans, measurement strategy adopted, and weather conditions significantly influenced the quality of data collected when compared with the internally located, portable monitoring system. Calculation of exhaust airflow from the facility had a large effect on calculated emissions and assuming that the installed fans performed as per published performance characteristics potentially overestimated emissions by 13.6 26.8%. The open-path measurement systems showed promise for being able to obtain ER measurements with minimal access to the house, although the availability of individual fan characteristics markedly improved the calculated ER accuracy. However, substantial operator skill and experience and favorable weather conditions were required to obtain good quality results. PMID- 20842935 TI - Multicriteria aided design of integrated heating-cooling energy systems in buildings. AB - This paper presents an analysis of the possible application of integrated heating cooling systems in buildings. The general algorithm of integrated heating-cooling system design aid was formulated. The evaluation criteria of technically acceptable variants were defined. Fossil fuel energy consumption, carbon dioxide emission, investment, and total exploitation cost were identified as the most important factors describing the considered decision problem. The multicriteria decision aid method ELECTRE III was proposed as the decision tool for the choice of the most compromised variant. The proposed method was used for a case study calculation-the choice of an integrated heating-cooling system for an office building. PMID- 20842936 TI - Preliminary acclimation strategies for successful startup in conventional biofilters. AB - The question of how to obtain the best inocula for conventional biofilters arises when an acclimation/adaptation procedure is to be applied. Bearing in mind that no standardized procedure for acclimating inocula exists, certain preliminary strategies for obtaining an active inoculum from wastewater treatment sludge are proposed in this work. Toluene was the contaminant to be degraded. Concerning the prior separation of sludge phases, no obvious advantage was found in separating the supernatant phase of the sludge before acclimation. As far as a continuous or discontinuous acclimation mode is concerned, the latter is recommended for rapidly obtaining acclimated sludge samples by operating the system for no longer than 1 month. The continuous mode rendered similar degradation rates, although it required longer operating time. Nevertheless, the great advantage of the continuous system lay in the absence of daily maintenance and the ready availability of the activated sample. PMID- 20842937 TI - An analysis of field-aged diesel particulate filter performance: particle emissions before, during, and after regeneration. AB - A field-aged, passive diesel particulate filter (DPF) used in a school bus retrofit program was evaluated for emissions of particle mass and number concentration before, during, and after regeneration. For the particle mass measurements, filter samples were collected for gravimetric analysis with a partial flow sampling system, which sampled proportionally to the exhaust flow. A condensation particle counter and scanning mobility particle sizer measured total number concentration and number-size distributions, respectively. The results of the evaluation show that the number concentration emissions decreased as the DPF became loaded with soot. However, after soot removal by regeneration, the number concentration emissions were approximately 20 times greater, which suggests the importance of the soot layer in helping to trap particles. Contrary to the number concentration results, particle mass emissions decreased from 6 +/- 1 mg/hp-hr before regeneration to 3 +/- 2 mg/hp-hr after regeneration. This indicates that nanoparticles with diameters less than 50 nm may have been emitted after regeneration because these particles contribute little to the total mass. Overall, average particle emission reductions of 95% by mass and 10,000-fold by number concentration after 4 yr of use provided evidence of the durability of a field-aged DPF. In contrast to previous reports for new DPFs in which elevated number concentrations occurred during the first 200 sec of a transient cycle, the number concentration emissions were elevated during the second half of the heavy duty Federal Test Procedure (FTP) when high speed was sustained. This information is relevant for the analysis of mechanisms by which particles are emitted from field-aged DPFs. PMID- 20842938 TI - Potential ozone impacts of excess NO2 emissions from diesel particulate filters for on- and off-road diesel engines. AB - This study considers potential impacts of increased use of diesel oxidation catalysts (DOCs) and catalyzed diesel particulate filters (DPFs) on ozone formation in the Dallas/ Fort Worth (DFW) area. There is concern that excess nitrogen dioxide (NO2) emissions from vehicles equipped with these devices could increase ambient ozone levels. The approach involved developing two scenarios for use of these devices, quantifying excess NO2 emissions in each scenario, and using a photochemical model to estimate the resulting ozone changes. In the "maximum penetration" scenario, DOC/DPF devices in a 2009 fleet of heavy-duty on road trucks, school buses, and construction equipment were significantly increased by accelerating turnover of these vehicles and equipment to models that would require DOCs/DPFs. In the "realistic" scenario, current fractional usage of these devices was assessed for 2009. For both scenarios, excess NO2 emissions from DOCs/DPFs were estimated using U.S. Environmental Protection Agency's MOBILE6 and NONROAD emissions inventory modeling tools. The emissions analyses were used to adjust the DFW photochemical modeling emissions inventories and the Comprehensive Air Quality Model with extensions air quality model was rerun for the DFW area to determine the impact of these two scenarios on ozone formation. The maximum penetration scenario, which showed an overall reduction in oxides of nitrogen (NO(x)) because of the accelerated turnover of equipment to cleaner models, resulted in a net decrease in daily maximum 8-hr ozone of 4-5 parts per billion (ppb) despite the increase in NO2 emissions. The realistic scenario resulted in a small increase in daily maximum 8-hr ozone of less than 1 ppb for the DFW area. It was concluded that the excess NO2 emissions from DOC/DPF devices result in very small ozone impacts, particularly for the realistic scenario, in the DFW area. There are noticeable decreases in ozone for the maximum penetration scenario because NO(x) reductions associated with DOC/DPFs (i.e., accelerated fleet turnover) exert more influence than excess NO2. PMID- 20842939 TI - Mutagenicity of airborne particulates assessed by salmonella assay and the SOS chromotest in Wroclaw, Poland. AB - Ambient air particulate matter less than 2.5 microm in aerodynamic diameter (PM(2.5)) samples were collected during summer and autumn using a Staplex high volume air sampler. They were later extracted with dichloromethane in a Soxhlet apparatus. Polyaromatic hydrocarbon (PAH) content in extracts was determined by the high-performance liquid chromatography technique using fluorescence detection, whereas the nitro-PAH content was determined by gas chromatography using mass detection. Four Salmonella typhimurium strains (TA98, TA100, YG1041, and YG1042) were used in assays conducted with and without metabolic activation. The extracts were also tested with the SOS chromotest supplied by Environmental Biodetection Products Incorporated. The obtained results confirmed the Salmonella assay and the SOS chromotest usability for the purpose of atmospheric pollution monitoring within an urban agglomeration. The atmospheric pollution extracts under examination differed among each other regarding total content and percentage of individual compounds, depending on the season of sampling. The highest total PAH content and the highest nitro-PAH content in the tested samples as well as the most extensive range of detected compounds were found in the autumn season (heating season). The highest mutagenicity was noted for PM(2.5) samples collected in autumn. The high values of mutagenicity ratios and induction factors were obtained from assays carried out with and without metabolic activation, which is an argument for the presence of promutagens and direct mutagens. The YG1041 strain proved to be the most effective in detection of mutagenicity of the suspended dust extracts because of its notably high sensitivity to nitro-aromatic compounds. The SOS chromotest was very sensitive to a large spectrum of genotoxic air pollutants and showed a high degree of similarity with the results of the Salmonella assay. In comparison with the frequently used Ames test, the SOS chromotest enables quick analysis of the genotoxic effects of samples using only one tester strain. In addition, its miniaturized design decreases the consumption of tested samples. PMID- 20842940 TI - Novel catalytic process for flue gas conditioning in electrostatic precipitators of coal-fired power plants. AB - One of the most important environmental protection problems for coal-fired power plants is prevention of atmospheric pollution of flying ash. The ash particles are typically removed from flue gases by means of electrostatic precipitators, for which the efficiency may be significantly increased by lowering the resistance of fly ash, which may be achieved by controlled addition of microamounts of sulfur trioxide (SO3) into the flue gases. This paper describes the novel technology for production of SO3 by sulfur dioxide (SO2) oxidation using the combined catalytic system consisting of conventional vanadium catalyst and novel platinum catalyst on the base of silicazirconia glass-fiber supports. This combination provides highly efficient SO, oxidation in a wide temperature range with achievement of high SO, conversion. The performed pilot tests have demonstrated reliable and stable operation, excellent resistance of the novel catalytic system to deactivation, and high overall efficiency of the proposed process. The scale of the plant was equivalent to the commercial prototype; therefore, no further scale-up of the oxidation process is required. PMID- 20842941 TI - Technical description of parameters influencing the pH value of suspension absorbent used in flue gas desulfurization systems. AB - As a result of the large limestone deposits available in Poland, the low cost of reagent acquisition for the largescale technological use and relatively well documented processes of flue gas desulfurization (FGD) technologies based on limestone sorbent slurry, wet scrubbing desulfurization is a method of choice in Poland for flue gas treatment in energy production facilities, including power plants and industrial systems. The efficiency of FGD using the above method depends on several technological and kinetic parameters, particularly on the pH value of the sorbent (i.e., ground limestone suspended in water). Consequently, many studies in Poland and abroad address the impact of various parameters on the pH value of the sorbent suspension, such as the average diameter of sorbent particles (related to the limestone pulverization degree), sorbent quality (in terms of pure calcium carbonate [CaCO3] content of the sorbent material), stoichiometric surfeit of CaCO3 in relation to sulfur dioxide (SO2) absorbed from flue gas circulating in the absorption node, time of absorption slurry retention in the absorber tank, chlorine ion concentration in sorbent slurry, and concentration of dissolved metal salts (Na, K, Mg, Fe, Al, and others). This study discusses the results of laboratory-scale tests conducted to establish the effect of the above parameters on the pH value of limestone slurry circulating in the SO2 absorption node. On the basis of the test results, a correlation equation was postulated to help maintain the desirable pH value at the design phase of the wet FGD process. The postulated equation displays good coincidence between calculated pH values and those obtained using laboratory measurements. PMID- 20842942 TI - [High-resolution CT findings of inner ear malformations with cerebrospinal fluid leakage]. AB - OBJECTIVE: To describe the HRCT appearances of congenital inner ear malformations with cerebrospinal fluid leakage. METHOD: Conducted a retrospective case review. The subjects comprised 11 patients who were decisively confirmed by HRCT and exploratory tympanotomy. The result of temporal bone computed tomography scans (HRCT) were analyzed. RESULT: Inner ear malformations were classified into 4 types according to HRCT findings. There were 4 patients with cochlear aplasia, 2 patients with common cavity anomaly, 2 patients with IP-I anomaly, and 3 patients with IP- II anomaly. Eight patients had defects in the lamina cribrosa of the internal auditory canal. The development and aeration in the mastoid of involved ears was normal. Soft tissues were seen near the oval window in all involved ears. CONCLUSION: HRCT image has an important value in the diagnosis and treatment of inner ear malformations with cerebrospinal fluid leakage. PMID- 20842944 TI - [Discussion of cochlear implant indications in postlingually deaf adults]. AB - OBJECTIVE: To explore the indications of cochlear implantation in postlingually deaf adults. METHOD: Five postlingually deaf adults participated in our investigation, surgery age 19-58 (median age 26 years). All patients received 24R (Cochlear,Australia). Four weeks after operation, all the patients have started the program. Through one year follow-up, we used the categories of auditory performance (CAP) and speech intelligibility rating criteria (SIR) to assess their hearing ability and speech intelligibility. RESULT: Through testing for five patients who used cochlear implant continuously more than one year by Pure tone audiometry, CAP and SIR, we assessed and found that the five patients hearing threshold raise to 25-45 dB in 0.5 kHz, 1.0 kHz, 2.0 kHz, 4.0 kHz, CAP average of 3.4, SIR average of 2.4. Two patients' ability of speech recognition and emotional communication were not improved almost, while these ability in other three were improved in varying degrees. CONCLUSION: For postlingual deaf adults caused by different reasons, how to make patients benefit from cochlear implantation and increase their capacity for independent living and self confidence due to select surgical indications correctly. PMID- 20842943 TI - [Study of aural rehabilitation in post-lingual deafened patients with multi channel cochlear implant]. AB - OBJECTIVE: To seek a convenient and effective method through subjective psychophysical measurements and CAP/SIR assessment. To compare the discrimination of rehabilitation between post-lingual and pre-lingual deafened patients. METHOD: Thirty-one post-lingual cochlear implantees and 59 pre-lingual cochlear implantees, the warble tone and CAP/SIR were assessed. The discrimination of threshold levels, comfortable levels and dynamic range between post-lingual and pre-lingual deafened patients in same electrodes were compared. RESULT: There was no statistic difference in warble tone, T-levels, C-levels and dynamic range in same electrodes implant after 6 months implant (P>0.05). The score of CAP and SIR in post-lingual deafened patients were more prominent. CONCLUSION: CAP and SIR is a kind of convenient and effective method to assess the ability of aural and oral. There was no discrimination in warble tone, T-levels, C-levels and dynamic range in same electrodes implant, but the ability of aural and oral in post lingual deafened patients were more prominent. PMID- 20842946 TI - [Study for cochlear microphonic potential test in patients with profound sensorineural hearing loss]. AB - OBJECTIVE: To report intraoperative round window cochlear microphonic potential test (CM) in patients with profound sensorineural deafness. METHOD: Intraoperative round window CM test were performed on 40 cases with profound sensorineural deafness during cochlear implantation surgery under general anesthesia in the standard operating room. CM were compared with their reliable preoperation distortion product otoacoustic emission (DPOAE). RESULT: The CM were found in 40 patients. The rate at 0.5, 1.0, 2.0, 4.0. kHz was respectively 90%, 97.5%, 100%, 92.5%. The preoperation DPOAE were found in some frequency in 9 cases. The rate at 0.5, 1.0, 2.0, 4.0 kHz was respectively was 2.5%, 2.5%, 17.5%, 2.5%. CONCLUSION: The elicited rate of CM was obviously higher than the one of DPOAE in the same patient with profound sensorineural deafness. The intraoperative round window CM may objectively and accurately estimate the part of cochlear function in patients with profound sensorineural deafness. PMID- 20842945 TI - [An investigation of SLC26A4 gene mutation in nonsydromic hearing impairment in Hunan province of China]. AB - OBJECTIVE: To determinate the occurring frequency and mutational hot spot in Hunan province. METHOD: Blood samples was obtained from 96 patients with nonsydromic hearing impairment in Hunan province. PCR and DHPLC techniques were used to screening for all the 21exon of SLC26A4. PCR samples which were abnormal for DHPLC screening were analyzed with direct sequencing. Sequencing results were analyzed in DNASTAR software. RESULT: Fifteen of 96 patients were found to have SLC26A4 gene mutations, detection rate was 15 6 , for 3 examples were homozygous mutations, ten samples were complex heterozygous mutations and 2 were heterozygous mutations. Totally, sixteen base variations were found, including 10 types of known gene mutation were identified (S90L, S252P, IVS7-2A>G, T410M, N392Y, IVS10-12T>A, S448X, G497S, S517fs, H723R. Four types of novel gene mutation (S8X, A227P,C565fs, Y728H), one type of same sense mutation (c. 2182 T>C)and 1 type of polypeptide IVS11+47 T>C). IVS7-2A>G was the most common gene mutation , which 9 samples were identified with, and it's detection rate was 9.38% and 5.73% for all the mutant alleles. IVS11+47 T>C was the most common polypeptide, which 20 samples were detected. CONCLUSION: IVS7-2A>G was the most common gene mutation type for nonsyndromic hearing impairment in Hunan province; 4 novel mutations which were detected in the study enriched SLC26A4 gene mutation spectrum of Chinese. PMID- 20842947 TI - [The effect of intratympanic dexamethasone or methylprednisolone on treatment of sudden sensorineural hearing loss]. AB - OBJECTIVE: To investigate the effect of intratympanic dexamethasone or methylprednisolone on treatment of sudden sensorineural hearing loss. METHOD: Forty-seven subjects received an at least 7-day dexamethasone(5 g/L/d) or methylprednisolone (40 g/L/d) course. Pure-tone averages (PTA) of pre-injection and post-injection at 4-frequency (500, 1,000, 2,000, 4,000 Hz) were compared. More than 10 dB HL of improvement in PTA was considered to be clinically significant. RESULT: PTA of pre-injection and post-injection were (71.59 +/- 27.66) dB HL and (53.44 +/- 30.10) dB HL respectively in 24 patients with intratympanic dexamethasone. There was significant improvement in PTA (P<0.01), 1.67% of patients showed improvement in hearing. PTA of preinjection and post injection were (68.64 +/- 25.21) dB HL and (55.76 +/- 26.42) dB HL respectively in 23 patients with intratympanic methylprednisolone. There was significant improvement in PTA (P<0.01), 43% of patients showed improvement in hearing. There was no significant difference in PTA between intratympanic dexamethasone and methylprednisolone. After dexamethasone injection, evident improvement was accomplished in 11 cases who underwent treatment with other therapy (systemic steroids, vasodilator agent, or high-pressure-oxygen therapy) (P<0.05); PTA showed significant improvement in 13 cases with only intratympanic dexamethasone(P< 0.05). After methylprednisolone injection, evident improvement was accomplished in 17 cases who underwent treatment with other therapy (P<0.01); PTA decreased but had no significance in 6 cases with only intratympanic methyl prednisolone(P>0.05). No unexpected adverse events such as otitis media, perforated tympanic membrane and worsening in hearing occurred during the injection or follow-up period. CONCLUSION: Intratympanic dexamethasone or methylprednisolone can be beneficial in treatment on patient with sudden sensorineural hearing loss, however, there was no significant difference in the effect between dexamethasone and methylprednisolone. Dexamethasone is recommended to use as favorable drug for intratympanic application that could be primary therapy in treatment on sudden sensorineural hearing loss. PMID- 20842948 TI - [The clinical significance of ABR testing in the diagnosis of the large vestibular aqueduct syndrome]. AB - OBJECTIVE: To analyse the clinical audiological significance in the diagnosis of large vestibular aqueduct syndrome (LVAS) by the auditory brain stem response (ABR) testing. METHOD: Patients with sensorineural hearing loss were examined by temporal bone CT scanning from January, 2008 to September, 2009. The result of CT scanning of 70 cases inner ear malformation were analysed. Patients were divided into two groups, LVAS group including 38 cases (76 ears) and other inner ear malformation group including 32 cases (62 ears). All patient accepted clinical audiology analysis and auditory brainstem response (ABR) test. RESULT: Twenty four cases (41 ears) of LVAS group were detected with ASNR in 2 3 cm by the ABR testing, the positive rate was 54%, while ASNR was not detected in patients of other inner ear malformations group. There was significant differences (P=0.01) of the ASNR between two groups. CONCLUSION: There is high incidence of LVAS on the patients with non-syndromic deafness. ASNR by ABR testing could help diagnosing the LVAS. PMID- 20842949 TI - [Congenital middle ear cholesteatoma]. AB - OBJECTIVE: To investigate the location, clinical symptom, image features, treatment and prognosis of the congenital middle ear cholesteatoma. METHOD: Retrospective review of 9 patients treated at Department of Otolaryngology Head and Neck Surgery, the affiliated Hospital of the first Strasbourg University, France. RESULT: The mean age was 6.1 years. Including 7 boys and 2 girls with hearing loss, and 7 of them suffered conductive hearing loss. Typical cholesteatomas were found behind posterior tympanic membrane according the otoscopic examinations in 6 cases. CT were completed in 8 of 9 cases, spheroid or ovoid masses were found in the tympanic cavities, most of them located in the posterior region. All of the patients underwent the surgical treatment, 5 of 9 cases had the ossicular erosion. Four of 9 cases had the residual diseases. All of the cases were followed-up at the mean period of 5.3 years, the preoperative hearing threshold is 28 dB compared with 26 dB of postoperative hearing threshold. CONCLUSION: Congenital middle ear cholesteatoma is a rare and hiding lesion. The symptoms are more typical in children than that in adults, which is unilateral conductive hearing loss. Likewise,the preoperative CT scanning is important. The rate of residual lesions and prognosis of congenital cholesteatoma is mainly depended on the extension and the methods of the surgery, revision surgery as well. PMID- 20842950 TI - [Study on nonsyndromic hereditary hearing impairment mutations of GJB2 gene in Uyghur patients in Xinjiang]. AB - OBJECTIVE: To study mutations in the GJB2 gene in Uyghur patients with nonsyndromic hearing impairment from Xinjiang. METHOD: Forty-three cases with nonsyndromic hearing impairment and 46 adults with normal hearing were performed mutational analysis of the GJB2 coding region by PCR-direct sequencing. RESULT: Six kinds of mutation have been found in the encoding region of hearing impairment group: 380G>A, 109G>A, 235 delC, 233 delC, 7G0>A, 35 delG, of which one 235 delC case is heterozygotes mutation, two 233 delC are homozygotes mutation and two 35 delG are heterozygotes mutation. Six kinds of mutations have been found in the normal hearing group, of which 5 kinds are confirmed common polymorphic mutation. CONCLUSION: The GJB2 gene mutation detection rate in the Uyghur deaf population of Xinjiang Province is lower than other province, which has ethnic and regional characteristics. PMID- 20842951 TI - [Changes of filamentous-actin at different stages of apoptotic and necrotic hair cells in rat cochleas induced by noise exposure]. AB - OBJECTIVE: To observe the changes of filamentous-actin (F-actin) during process of apoptosis and necrosis in hair cells, and investigate the early mark for hair cells pathology following noise exposure. METHOD: Twenty young SD rats were used in present study. The animals were randomly assigned into two groups, 10 animals were exposed noise and the remaining without exposure to noise served as normal control. The animals were exposed to a narrow band noise at 110 dB SPL for 8 hours. Immediately after exposure to continuous nose, the animals were exposed to 75 pairs of impulse noise at 155 dB SPL. The auditory brainstem response (ABR) thrush olds of both ears elicited by tone bursts at 5, 10 and 20 kHz were measured before, immediately and 2-week after the noise exposure. Animals were sacrificed and cochleae were quickly removed from the skull. Following fixation, whole specimens comprising the basilar membrane with Corti organ were separated from the modiolus. The organs of Corti were double stained with propidium iodide (PI), a DNA intercalating fluorescent probe used to visualize the morphologic viability of hair cell nuclei, and FITC-labeled phalloidin, a F-actin intercalating fluorescent probe used to visualize the morphologic viability of cuticular plate and the stereocilia in the hair cells. Each organ of Corti was thoroughly examined using fluorescence microscopy. RESULT: The animals of test group exhibited a significant elevation of ABR threshold shifts at all tested frequencies after noise exposure immediately and 2-week. There was no detectable F-actin change in both the corresponding cuticular plates and the stereocilia in the OHCs undergoing necrosis. OHCs with slightly increased PI fluorescence and a relatively normal nuclear morphology exhibited normal level of F-actin activity. In the OHCs with mild nuclear condensation (about 3/4 of the normal size) exhibited normal or a slight increased F-actin fluorescence staining. In the OHCs with moderate or severe nuclear condensation (about 1/2 or 1/4 of the normal size), the reduction in F-actin staining was observed. Finally, in the areas where no detectable nuclear staining was present, the reduction in F-actin staining was more severely or absent. CONCLUSION: These results suggest that compare with the change of F-actin, nuclear morphology and staining is the early mark for necrotic and apoptotic hair cells pathology following noise exposure. A biphasic change in F-actin may exist during apoptosis, an initial polymerization and a subsequent depolymerization, but F-actin may be not a necessary component of the process of necrosis in the noise-damaged OHCs. PMID- 20842952 TI - [Diagnosis and classification of diabetes mellitus]. PMID- 20842953 TI - [Pharmacogenomics and chemotherapy]. AB - Genetic factors could alter drug metabolism and activity and could predict drug toxicity and/or efficacy. Several chemotherapy agents are administered in different schedules for the treatment of different cancer histotypes. The most used drug in the treatment of gastro-intestinal, head and neck and breast neoplasms is the 5-fluorouracil (5-FU). Capecitabine is a prodrug of 5-FU. Cisplatin based chemotherapy is administered in the treatment of lung, genitourinary tract, head and neck, occult neoplasms, mesothelioma and melanoma. Taxanes are used in lung, breast, head and neck, genitourinary tract neoplasms and sarcomas. Determination of polymorphisms in metabolizing enzymes before the administration of chemotherapy could offer new strategies for optimizing the treatment of individual patients. PMID- 20842954 TI - [Patients' satisfaction with pain management: the italian version of the Patient Outcome Questionnaire of the American Pain Society]. AB - According to American Pain Society (APS), assessment of quality of pain management must consider not only improvement of symptoms but also patients' satisfaction with care. To this purpose, Patient Outcome Questionnaire (APS-POQ) was made. Aim of the study was to analyze reliability and construct validity of the Italian version of the questionnaire. The tool was administered to 322 hospitalized adults. Results showed positive psychometric properties of the Italian version of APS-POQ, particularly for the sections assessing intensity and interference of pain, and satisfaction with pain management. PMID- 20842955 TI - [Echocardiographic evaluation of anti-tumor necrosis factor-alpha therapy with infliximab in patients without cardiac pathologies]. AB - In the course of heart failure, plasmatic levels of Tumor Necrosis Factor-alpha (TNF-alpha) are high and are related to prognosis and mortality. Infliximab, a recombinant chimeric antibody anti-TNF-alpha, was used in heart failure with disappointing results, similar to those obtained with other biological drugs.The aim of this study was the echocardiographic evaluation of infliximab infusion in nine patients without cardiac pathologies. The findings demonstrate a reduction of sistolic function and a modification of diastolic function after infliximab infusion in patients without cardiopathy. This study confirms the protective role played by TNFalpha on the myocardium, as suggested by previous experimental studies. PMID- 20842956 TI - [Takayasu arteritis with aortic coarctation and multiple stenosis of aortic branches]. AB - The authors discuss the diagnostic and therapeutic implication regarding the clinical case of a young woman with hypertension due to atypical coarctation type Takayasu arteritis with impressive stenosis of renal arteries, of the proximal segment of celiac tripod and of superior mesenteric artery. PMID- 20842957 TI - [The second opinion in oncology]. AB - The medical second opinion (MSO) means the process through which it is possible to consult any available medical institution or a single physician, to compare, confirm and/or review a first diagnosis and/or a proposed treatment. The MSO is of the utmost importance when patients are suffering serious and disabling diseases or when risking their lives. Oncology is a really complex discipline in which, daily, doctors and patients have to deal with new clinical, managerial and sociological problems. Most patients are now better informed-often having gathered information from the Web, newspapers, magazines.This information is often very mixed and confusing and the number of MSO is increasing. PMID- 20842958 TI - [For a new doctor: knowing how to cooperate, knowing how to learn, knowing how to know]. AB - The author considers the ten years experience of the Italian Program for Continuing Medical Education.The favorable shift in medical education is due to higher interest in this area and to the rising numbers of people involved in the debate.Today, the challenge is getting the emphasis on the"educational"approach rather than on didactics.The approach to CME should be comprehensive, focusing mainly on the objectives of the educational process. Considering the complexity of medical environment, doctors should: (1) knowing how to cooperate; (2) knowing how to learn; and (3) knowing how to know. PMID- 20842959 TI - [The workplace-based learning: a main paradigm of an effective continuing medical education]. AB - On the strength of the literature analysis and the Emilia-Romagna Region experience, we suggest a reflection on the workplace-based learning that goes beyond the analysis of the effectiveness of specific didactic methodologies and aspects related to Continuing Medical Education. Health education and training issue is viewed from a wider perspective, that integrates the three learning dimensions (formal, non formal and informal). In such a perspective the workplace based learning becomes an essential paradigm to reshape the explicit knowledge conveyed in formal context and to emphasize informal contexts where innovation is generated. PMID- 20842960 TI - [Encephalitis associated to novel influenza A virus infection (H1N1) in two young adults]. AB - At today, neurologic desorders associated with novel influenza A (H1N1) virus were reported only in children but not in adult. We report two cases of encephalitis associated to H1N1 virus infection occurred in females of age 28 and 37 years. In both cases disease was less severe without neurologic sequelae. In one case PCR analysis of CSF sample showed a positivity for HSV1. Novel influenza A (H1N1) viral RNA by real time PCR was detected in nasopharyngeal specimens. PMID- 20842961 TI - [Recent knowledges on chemosensitivity to hypoxia and hypercapnia in cardiovascular disease]. AB - The pathophysiologic role of enhanced chemosensitivity to carbon dioxide and/or hypoxia has been underscored in several cardiovascular diseases, including heart failure. In the early stages of this syndrome, the chemoreflex acts as a compensatory mechanism. Later on, however, it contributes to sustain the sympathetic activation, with detrimental effects on cardiovascular function and prognosis. PMID- 20842962 TI - [A new model of integrated care: Ospedale di Continuita]. AB - The "Continuity of Care Hospital", which is now realized in the Santa Verdiana Hospital, Castelfiorentino (Italy), is aimed at solving the existing gap between hospitalists and primary care physicians. This new model of care could represent an effective tool for solving the emerging medical and teaching needs of a population characterized by advanced age and comorbidities. PMID- 20842963 TI - [Medicine and literature: an anthology]. PMID- 20842964 TI - Art versus science. PMID- 20842965 TI - Phenomenal transparency at X-junctions. AB - Phenomenal transparency was studied in a stimulus geometry that differs markedly from the conventional Metelli configuration, namely four squares that abut at a common vertex. In case of subjective transparency one perceives either a bipartite square ground overlaid with a uniform transparent rectangle, or a uniform square background overlaid with a pair of mutually orthogonal, uniform, transparent rectangular regions. Thus, the generic interpretations are limited to "left", "right", "lower", or "upper" transparent rectangles or (when no subjective transparency occurs) "mosaic". All transparent cases are congruent, whereas the Metelli configuration allows distinct Gestalt interpretations. This avoids interactions between Gestalt factors and subjective transparency per se. Formal analysis reveals that as in Metelli's case a number of ambiguous cases (e.g., "left" or "lower") are to be expected. In the experiment we included these ambiguous cases as additional response categories. Observers who differ markedly on the Metelli configuration are virtually indistinguishable under the quad square configuration. Moreover, observers reliably categorise the ambiguous instances as such; thus, "multiple transparency" has to be reckoned with as a bona fide percept. PMID- 20842966 TI - Visual discomfort and natural image statistics. AB - Images with excessive energy at medium spatial frequencies (Fernandez and Wilkins, 2008 Perception 37 1098-1113), or that have high color contrast and little or no luminance contrast (Wilkins et al, 2008 Perception 37 Supplement, 144-145) appear uncomfortable or aversive and can induce headaches in hypersensitive observers. Such stimuli are uncharacteristic of natural images, and we examined whether visual discomfort more generally increases with deviations from the spatial and chromatic properties of natural scenes. Observers rated the level of discomfort or artistic merit in color images generated from noise or random overlapping rectangles (Mondrians). In one set, the slopes of the amplitude spectra for luminance or chromatic contrast were varied independently to create images ranging from strongly blurred to sharpened relative to a 'natural' 1/f spectrum. Perceived blur was dominated by the luminance slopes, with discomfort rated lowest for approximately 1/f spectra. In a second set of focused Mondrians, color was varied along different axes in the L-M versus S-LM chromatic plane. Discomfort ratings were lowest around bluish yellowish axes that are again typical of natural outdoor scenes. A final set varied in the levels of both luminance and chromatic contrast. Discomfort increased with increasing color contrast or decreasing luminance contrast, and tended toward lower ratings for images with balanced levels of luminance and color contrast. Notably, these ratings of discomfort were not related to judgments of artistic merit. Thus, for both spatial and chromatic content, the least aversive images corresponded to characteristic properties of the natural visual environment, and may reflect a normalization of visual coding to the natural world. PMID- 20842967 TI - Modulations of temporal perception by consciously and unconsciously perceived stimuli. AB - Temporal processing is of fundamental importance to the understanding of orders and durations of events in daily life. While recent research found that the perception of event durations is modulated by the visibility of perceived stimuli, it is still not known whether consciously and unconsciously perceived stimuli modulate temporal perception of a following stimulus in a similar vein. We investigated this using a temporal-comparison task that requires duration judgments of a standard stimulus and a probe. A prime prior to the standard stimulus reduced the subjective duration of the standard stimulus when observers were aware of the prime, and this effect changed with the temporal distance between the prime and standard. In contrast, a prime increased the subjective duration of the following standard stimulus when observers were unaware of the presence of the prime. Our findings indicate that a temporally neighbouring transient stimulus produces essentially different effects on temporal perception of following events when it is consciously and unconsciously perceived, leading to compression and expansion of subjective time, respectively. PMID- 20842968 TI - A dichoptic study of the oblique effect. AB - The oblique effect is a decreased sensitivity for oblique orientations compared with horizontal/vertical orientations. We investigated whether orientation matching acuity for binocularly presented stimuli is dependent on orientations of retinal projections or on the perceived orientation of the stimulus. Using a stereoscope, we constructed a stimulus, such that retinal orientations were oblique, while the perceived orientation was vertical. We then used this stimulus to test observers in an orientation-matching task. If orientation matching depends on the orientations of retinal projections, low matching performance would be expected, since retinal projections are oblique. However, if orientation matching depends on perceived orientation (vertical), high matching performance would be expected. We found that observers' performance can only be predicted from the perceived orientation, not the orientations of retinal projections, implying that in binocular viewing the oblique effect occurs after binocular fusion. PMID- 20842969 TI - Depth perception through circular movements of dots. AB - Elements that move with velocity gradients have been shown to give the impression of depth. In this study, it was found that dots in circular motion around a line of sight give a depth impression corresponding to the gradients of the angular velocities of circular motion on a screen. The results of two experiments show that depth perception through circular motion is as effective as that through expansion or spiral motion, but less effective than that through lateral motion parallax when the local speed distributions on the screen are matched. The present depth effect shows that expansion-contraction, spiral, and circular motions are a continuum in terms of producing depth effects; they differ from lateral motion parallax. PMID- 20842970 TI - Common neural mechanisms for the evaluation of facial trustworthiness and emotional expressions as revealed by behavioral adaptation. AB - People rapidly and automatically evaluate faces along many social dimensions. Here, we focus on judgments of trustworthiness, which approximate basic valence evaluation of faces, and test whether these judgments are an overgeneralization of the perception of emotional expressions. We used a behavioral adaptation paradigm to investigate whether the previously noted perceptual similarities between trustworthiness and emotional expressions of anger and happiness extend to their underlying neural representations. We found that adapting to angry or happy facial expressions causes trustworthiness evaluations of subsequently rated neutral faces to increase or decrease, respectively. Further, we found no such modulation of trustworthiness evaluations after participants were adapted to fearful expressions, suggesting that this effect is specific to angry and happy expressions. We conclude that, in line with the overgeneralization hypothesis, a common neural system is engaged during the evaluation of facial trustworthiness and expressions of anger and happiness. PMID- 20842971 TI - Analysis and explanation of the Thiery-Wundt illusion. AB - The midpoint of the axis of bisection in a triangle appears to be displaced toward the apex so that the apical extent seems to be shorter than the basal extent, an effect originally reported in 1895 by Thiery and later in 1898 by Wundt and, therefore, referred to here as the Thiery-Wundt illusion. Following a demonstration strongly suggesting that the illusion is yet another version of the Muller-Lyer effect in a stimulus figure with inward-directed angles, four exploratory experiments designed to throw more light on this group of illusions are reported. The first showed that the effect occurs in an open angle, between converging lines that do not meet to form an apex, between converging stepped lines, and when one of the converging lines is removed, leaving a single oblique line. The other three experiments showed that the illusion also occurs in an open semicircle and a rectangular bracket, is weakened by the addition of a complete or partial baseline to form a triangle, and weakly but reliably when the angle is minimally formed from dots marking the ends of oblique lines. On the basis of these data, Judd's version of the conventional Muller-Lyer figure, and informal but easily repeatable observations, it is concluded that the Thiery-Wundt illusion is, like other variants of the Muller-Lyer group of illusions, due to a process of directional biasing-an extension of the concept of biasing proposed originally by Morgan et al (1990, Vision Research 30 1793 1810). PMID- 20842972 TI - The role of visual experience in mental scanning of actual pathways: evidence from blind and sighted people. AB - In this research we compare blind and normally sighted people in mental scanning of spatial maps using locomotor or visual/locomotor exploration of a real 3-D environment. Different types of visual experience were tested: early (congenital) and late (adventitious) onset of blindness, short-term deprivation (blindfolded sighted), and full vision (sighted). Participants were asked to learn six positions in a large parking area with movement alone (congenital, adventitious, blindfolded-sighted) or with vision plus movement (sighted), and then to mentally scan between positions in the path. Finally, they had to describe how they imagined scanning the learned pathway. We found a significant linear relation between space and time, ie the classic mental scanning effect, in all tested groups. However, the linear component was lower in blind participants, especially congenital. Instead, short-term visual deprivation had minimal impact on mental scanning. Overall, blind participants had shorter scanning times than both sighted groups, and the effect was particularly evident with farther distances. These results suggest that there is a quantitative rather than a qualitative difference between the blind and the sighted. In addition, the mental scanning strategies reported by participants also affected mental scanning times. The theoretical implications of these findings are discussed. PMID- 20842973 TI - Does left-right orientation matter in the perceived expressiveness of pictures? A study of Bewick's animals (1753-1828). AB - Strong claims have been made about the importance of orientation in visual art. Although there have been a few studies whether left or right oriented pictures are more aesthetically pleasing, there have been no empirical studies whether the meaning and expressiveness of pictures depend on orientation. Thomas Bewick (1753 1828) made explicit decisions about whether the main protagonist in his pictures should face left or right and did so to express particular meaning. In three experiments we examined whether orientation changes the expressiveness of an image. In experiment 1 participants viewed eight of Bewick's animal wood engravings facing either in their original orientation or reversed, in a between subjects design. They rated each print on ten characteristics, for example: docile-wild, clumsy-agile, and weak-strong. The original received more extreme ratings, across characteristics, than the reversal. Experiment 2 confirmed this result with participants from Italy. In experiment 3, using a within-subjects design, participants viewed ten wood engravings of dogs and rated them on characteristics specifically identified by Bewick. Again, the ratings of the original orientation were more extreme. Thus, in agreement with Bewick, we conclude that orientation affects expressiveness. PMID- 20842974 TI - Effect of temporal separation on synchronization in rhythmic performance. AB - A variety of short time delays inserted between pairs of subjects were found to affect their ability to synchronize a musical task. The subjects performed a clapping rhythm together from separate sound-isolated rooms via headphones and without visual contact. One-way time delays between pairs were manipulated electronically in the range of 3 to 78 ms. We are interested in quantifying the envelope of time delay within which two individuals produce synchronous performances. The results indicate that there are distinct regimes of mutually coupled behavior, and that 'natural time delay'--delay within the narrow range associated with travel times across spatial arrangements of groups and ensembles- supports the most stable performance. Conditions outside of this envelope, with time delays both below and above it, create characteristic interaction dynamics in the mutually coupled actions of the duo. Trials at extremely short delays (corresponding to unnaturally close proximity) had a tendency to accelerate from anticipation. Synchronization lagged at longer delays (larger than usual physical distances) and produced an increasingly severe deceleration and then deterioration of performed rhythms. The study has implications for music collaboration over the Internet and suggests that stable rhythmic performance can be achieved by 'wired ensembles' across distances of thousands of kilometers. PMID- 20842975 TI - Raised-angle discrimination under passive finger movement. AB - The characteristics of raised-line drawing discrimination can be defined as the sum of the discriminability of the length, curvature, and angles of the edges. The size of the angle between two edges constitutes an important feature of these tactile stimuli. In the first experiment, five standard angles (30 degrees, 60 degrees, 90 degrees, 120 degrees, and 150 degrees) and twenty comparison angles for each standard angle were used to investigate the human capacity for tactile discrimination of raised angles by passive finger movement. The subjects in this study were asked to identify the larger angle of each pair by passive finger movement. We found that the threshold doubled when the standard angle was increased from 30 degrees to 90 degrees; however, the threshold remained unchanged when the standard angle was greater than 90 degrees. In the second experiment, to investigate the influence of the endpoints on angle discriminability, we used one standard angle (60 degrees) and seven comparison angles that changed in four bisector orientations. The results indicate that cutaneous feedback from the local apex and endpoints of the angle contributed to the discrimination of acute angles. Taken together, these results suggest that, when an acute angle is presented, both local apex and endpoint informations are used, while cutaneous mechanoreceptors rely more on apex information to discriminate the angle size when an obtuse angle is presented. PMID- 20842976 TI - Strange-face-in-the-mirror illusion. PMID- 20842977 TI - Best's Disease in a 20-Month-Old Child. AB - Best's disease is an autosomal dominant disorder characterized by bilateral vitelliform macular lesions that progress through several stages throughout life. The authors describe a 20-month-old child with hereditary Best's disease inherited from his father. To their knowledge, this is the youngest child to be diagnosed as having Best's disease using photographic documentation. PMID- 20842978 TI - Successful Treatment of Subretinal Neovascularization with Intravitreal Ranibizumab in a Child with Optic Nerve Head Drusen. AB - An 11-year-old boy presented with visual acuity reduced to 20/100 in his left eye. Investigations revealed optic disc drusen associated with a minimally classic choroidal neovascular membrane. The patient underwent a 3-month course of intravitreal ranibizumab. Six months of follow-up revealed remarkable visual acuity improvement to 20/20 and complete resolution of exudative maculopathy. PMID- 20842979 TI - Use of Anterior Segment OCT in the Evaluation and Management of Congenital Aphakia. AB - Anterior segment optical coherence tomography (AS-OCT) is a noninvasive technology capable of capturing high-resolution images of the anterior segment. With AS-OCT, a 7-year-old boy with nystagmus was diagnosed as having secondary congenital aphakia. The presence of lens capsules on the AS-OCT was of significant prognostic and management value and the child later benefited from bilateral sulcus-fixated intraocular lens implantation surgery. AS-OCT also required less cooperation from the patient compared to ultrasound biomicroscopy. To the authors' knowledge, this is the first reported case of congenital aphakia diagnosed by AS-OCT. PMID- 20842980 TI - Local anesthesia: A feasible option for pediatric frontalis sling surgery. AB - The purpose of this study was to demonstrate the suitability of local anesthesia in the pediatric age group for oculoplastic procedures. The authors present a case of frontalis sling surgery performed under local anesthesia in a 15-year-old boy with bilateral congenital ptosis. No significant technical difficulties were encountered during the procedure. Optimal intraoperative eyelid placement was facilitated by the patient's comfort and cooperation. For some selected children, local anesthesia is a good alternative to general anesthesia to obtain the best outcome. PMID- 20842982 TI - Interpreting and evaluating the details of the JUPITER study. PMID- 20842983 TI - Vitamin D supplementation in patients with tuberculosis. PMID- 20842984 TI - Malaria chemoprophylaxis and travel immunizations. PMID- 20842985 TI - Autism and childhood vaccinations: debunking the myth. PMID- 20842986 TI - Income disparities shape medical student specialty choice. AB - Currently, a gap of more than $135,000 separates the median annual subspecialist income from that of a primary care physician, yielding a $3.5 million difference in expected income over a lifetime. These income disparities dissuade medical students from selecting primary care and should be addressed to ensure sufficient patient access to primary care. PMID- 20842987 TI - Mammography screening for breast cancer: recommendation of the U.S. Preventive Services Task Force. PMID- 20842988 TI - Preventive health: time for change. PMID- 20842989 TI - Contraception choices in women with underlying medical conditions. AB - Primary care physicians often prescribe contraceptives to women of reproductive age with comorbidities. Novel delivery systems (e.g., contraceptive patch, contraceptive ring, single-rod implantable device) may change traditional risk and benefit profiles in women with comorbidities. Effective contraceptive counseling requires an understanding of a woman's preferences and medical history, as well as the risks, benefits, adverse effects, and contraindications of each method. Noncontraceptive benefits of combined hormonal contraceptives, such as oral contraceptive pills, include regulated menses, decreased dysmenorrhea, and diminished premenstrual dysphoric disorder. Oral contraceptive pills may be used safely in women with a range of medical conditions, including well-controlled hypertension, uncomplicated diabetes mellitus, depression, and uncomplicated valvular heart disease. However, women older than 35 years who smoke should avoid oral contraceptive pills. Contraceptives containing estrogen, which can increase thrombotic risk, should be avoided in women with a history of venous thromboembolism, stroke, cardiovascular disease, or peripheral vascular disease. Progestin-only contraceptives are recommended for women with contraindications to estrogen. Depo-Provera, a long-acting injectable contraceptive, may be preferred in women with sickle cell disease because it reduces the frequency of painful crises. Because of the interaction between antiepileptics and oral contraceptive pills, Depo-Provera may also be considered in women with epilepsy. Implanon, the single-rod implantable contraceptive device, may reduce symptoms of dysmenorrhea. Mirena, the levonorgestrel containing intrauterine contraceptive system, is an option for women with menorrhagia, endometriosis, or chronic pelvic pain. PMID- 20842990 TI - Weight loss maintenance. AB - Successful long-term weight loss maintenance can be achieved by various means. A combination of dietary and physical activity interventions, along with one or more behavioral approaches, has proven successful in some persons, as documented by the National Weight Control Registry, but is limited by adherence to a consistent weight loss regimen. Successful approaches to weight loss maintenance include consulting with a physician, nutritionist, or another support source; adhering to a stable diet with a limited variety of food; monitoring weight; eating breakfast; and exercising regularly. Long-term pharmacologic treatments for weight loss maintenance have been studied and were found to have modest success, with some weight regain typically reported. Sibutramine and orlistat are the two medications approved by the U.S. Food and Drug Administration with the potential to help patients achieve long-term weight loss maintenance. Bariatric surgery is another modality for accomplishing successful long-term weight loss maintenance in patients with morbid or complicated obesity. Its success is due in large part to better weight loss outcomes, more successful long-term weight loss maintenance, and remission of comorbid medical conditions. PMID- 20842991 TI - Tips on keeping weight off: successful weight loss maintenance. PMID- 20842992 TI - Recurrent urinary tract infections in women: diagnosis and management. AB - Recurrent urinary tract infections, presenting as dysuria or irritative voiding symptoms, are most commonly caused by reinfection with the original bacterial isolate in young, otherwise healthy women with no anatomic or functional abnormalities of the urinary tract. Frequency of sexual intercourse is the strongest predictor of recurrent urinary tract infections in patients presenting with recurrent dysuria. In those who have comorbid conditions or other predisposing factors, recurrent complicated urinary tract infections represent a risk for ascending infection or urosepsis. Escherichia coli is the most common organism in all patient groups, but Klebsiella, Pseudomonas, Proteus, and other organisms are more common in patients with certain risk factors for complicated urinary tract infections. A positive urine culture with greater than 102 colony forming units per mL is the standard for diagnosing urinary tract infections in symptomatic patients, although culture is often unnecessary for diagnosing typical symptomatic infection. Women with recurrent symptomatic urinary tract infections can be treated with continuous or postcoital prophylactic antibiotics; other treatment options include self-started antibiotics, cranberry products, and behavioral modification. Patients at risk of complicated urinary tract infections are best managed with broad-spectrum antibiotics initially, urine culture to guide subsequent therapy, and renal imaging studies if structural abnormalities are suspected. PMID- 20842993 TI - Proteinuria in children. AB - Proteinuria is common in children and may represent a benign condition or a serious underlying renal disease or systemic disorder. Proteinuria may occur secondary to glomerular or tubular dysfunction. Although a 24-hour urine protein excretion test is usually recommended, it may be impractical in children. A spot, first-morning urine test for protein/creatinine ratio can be useful in this situation. Proteinuria is usually benign, in the form of transient or orthostatic proteinuria. Persistent proteinuria may be associated with more serious renal diseases. Clinical features from the history, physical examination, and laboratory tests help determine the cause of proteinuria. Treatment should be directed at the underlying cause. Patients with active urinary sediments, persistent and gross hematuria, hypertension, hypocomplementemia, renal insufficiency with depressed glomerular filtration rate, or signs and symptoms suggestive of vasculitic disease may require a renal biopsy and referral to a pediatric nephrologist. PMID- 20842994 TI - Proteinuria in children. PMID- 20842995 TI - Pulmonary rehabilitation in the treatment of chronic obstructive pulmonary disease. AB - Pulmonary rehabilitation is a nonpharmacologic therapy that has emerged as a standard of care for patients with chronic obstructive pulmonary disease. It is a comprehensive, multidisciplinary, patient-centered intervention that includes patient assessment, exercise training, self-management education, and psychosocial support. In the United States, pulmonary rehabilitation is usually given in outpatient, hospital-based programs lasting six to 12 weeks. Positive outcomes from pulmonary rehabilitation include increased exercise tolerance, reduced dyspnea and anxiety, increased self-efficacy, and improvement in health related quality of life. Hospital admissions after exacerbations of chronic obstructive pulmonary disease are also reduced with this intervention. The positive outcomes associated with pulmonary rehabilitation are realized without demonstrable improvements in lung function. This paradox is explained by the fact that pulmonary rehabilitation identifies and treats the systemic effects of the disease. This intervention should be considered in patients who remain symptomatic or have decreased functional status despite optimal medical management. Medicare now covers up to 36 sessions of pulmonary rehabilitation in patients with moderate, severe, and very severe chronic obstructive pulmonary disease. PMID- 20842996 TI - Pulmonary rehabilitation in COPD. PMID- 20842998 TI - Enlarged tonsils and fatigue. PMID- 20843003 TI - Thermodynamic, structural and transport properties of tetramethyl ammonium fluoride: first principles molecular dynamics simulations of an unusual ionic liquid. AB - First principle molecular dynamics (FPMD) simulations in the isobaric-isothermal ensemble were carried out to investigate the liquid phase of pure tetramethyl ammonium fluoride (TMAF), its equimolar mixture with water, and its dilute solution in water. These simulations were performed using Born-Oppenheimer molecular dynamics with the quantum many-body potentials and forces obtained directly from on-the-fly electronic structure calculations at the Kohn-Sham density functional theory level. For the equimolar mixture, simulations were carried out using two different generalized gradient approximation functionals and two values of the charge density cutoff, and it is found that thermodynamic properties are rather sensitive to these details of the electronic structure calculations. The FPMD simulation for neat TMAF at a temperature of 600 K did not yield any indication for the decomposition of TMAF over the 50 ps production period, but trimethylamine and fluoromethane decomposition products were found during a short trajectory at 1200 K. At 400 K and 1 atm, the simulations indicate that significant structural rearrangement and changes in cohesive energy density and compressibility occur upon addition of water to TMAF. The hydration water is found to preferentially solvate the fluoride ions, and the distribution of F(-) H(2)O hydrogen bond lifetimes is broad. The simulations do not reveal any significant differences in the transport behavior of TMA(+), F(-), and H(2)O over the production periods. PMID- 20843004 TI - Mass-analyzed threshold ionization spectroscopy of ortho fluorinated 2 phenylethanol: identification of an additional gauche conformer. AB - The cationic ground state of the ortho fluorinated 2-phenylethanol has been investigated by combination of mass-analyzed threshold ionization (MATI) spectroscopy and quantum chemistry ab initio density functional theory (DFT) calculations employing the hybrid functional M05 with cc-pVDZ basis set. The MATI spectra measured via vibronic bands in the S1 intermediate state of the most stable gauche conformer stabilized by an intramolecular OH...pi hydrogen bond are structureless. The MATI spectrum recorded via a small band blueshifted by 3 cm-1 from the 0(0)(0) electronic origin of the gauche conformer features well-resolved peaks and is assigned to a cationic gauche structure without an OH...pi bond. The ab initio calculations are qualitatively consistent with the experimental observations and show that the presumable conformer giving rise to the observed MATI spectrum retains its structure during ionization, whereas the lowest-energy gauche conformer undergoes a significant structural change resulting in a break of the OH...pi bond, thus leading to unfavorable Franck-Condon factors for the threshold ionization. PMID- 20843006 TI - Simultaneous in-line monitoring of the conversion and the coating thickness in UV cured acrylate coatings by near-infrared reflection spectroscopy. AB - Near-infrared (NIR) reflection spectroscopy was used for in-line analysis of the conversion and the coating thickness (5-20 MUm) of UV-cured clear and pigmented acrylate coatings. The quantitative evaluation of the recorded spectra was carried out by partial least-squares (PLS) regression, in particular with the PLS2 algorithm, which allows simultaneous prediction of both parameters. The efficiency of this method was investigated in roll coating experiments at line speeds up to 100 m min(-1). It was shown that the method is able to compensate for the effect of accidental variations of the coating thickness, which inevitably occur upon changes of the line speed, on the prediction of the conversion. Accordingly, the conversion could be determined with a precision of +/-2...3%, whereas the error in the measurement of the thickness was found to be about 0.5-1 MUm. PMID- 20843005 TI - Probing the folding intermediate of Bacillus subtilis RNase P protein by nuclear magnetic resonance. AB - Protein folding intermediates are often imperative for overall folding processes and consequent biological functions. However, the low population and transient nature of the intermediate states often hinder their biochemical and biophysical characterization. Previous studies have demonstrated that Bacillus subtilis ribonuclease P protein (P protein) is conformationally heterogeneous and folds with multiphasic kinetics, indicating the presence of an equilibrium and kinetic intermediate in its folding mechanism. In this study, nuclear magnetic resonance (NMR) spectroscopy was used to study the ensemble corresponding to this intermediate (I). The results indicate that the N-terminal and C-terminal helical regions are mostly unfolded in I. 1H-15N heteronuclear single-quantum coherence NMR spectra collected as a function of pH suggest that the protonation of His 22 may play a major role in the energetics of the equilibria among the unfolded, intermediate, and folded state ensembles of P protein. NMR paramagnetic relaxation enhancement experiments were also used to locate the small anion binding sites in both the intermediate and folded ensembles. The results for the folded protein are consistent with the previously modeled binding regions. These structural insights suggest a possible role for I in the RNase P holoenzyme assembly process. PMID- 20843007 TI - Simultaneous detection of seven staphylococcal enterotoxins: development of hydrogel biochips for analytical and practical application. AB - A method of simultaneous analysis of staphylococcal enterotoxins using hydrogel based microarrays (biochips) has been developed. The method allows simultaneous quantitative detection of seven enterotoxins: A, B, C1, D, E, G, and I in a single sample. The development of the method included expression and purification of recombinant toxins, production of panels of monoclonal antibodies (mAbs) against the toxins, and design and manufacturing of an experimental biochip for the screening of mAbs and selection of optimal pairs of primary and secondary antibodies for each toxin. The selected mAbs have high affinity toward their targets and no cross-reactivity with unrelated enterotoxins. Finally, a diagnostic biochip was designed for quantitative analysis of the toxins, and the analytical protocols were optimized. The sensitivity of the detection reached 0.1 0.5 ng/mL, depending on the type of enterotoxin. The evaluation of the resulting biochip using spiked food samples demonstrated that the sensitivity, specificity, and reproducibility of the proposed test system fully satisfy the requirements for traditional immunoanalytical systems. The diagnostic biochips manufactured on reflecting metal-coated surfaces shortened the time of analysis from 17 to 2 h without loss of sensitivity. The method was successfully tested on samples of food and biological media. PMID- 20843008 TI - Evidence for the bioactivation of 4-nonylphenol to quinone methide and ortho benzoquinone metabolites in human liver microsomes. AB - 4-Nonylphenol (4-NP) is a well-known toxic environmental contaminant. The major objective of the present study was to identify reactive metabolites of 4-NP. Following incubations of 4-NP with NADPH- and GSH-supplemented human liver microsomes, 6 GSH conjugates, along with 19 oxidized metabolites, were detected by UPLC/Q-TOF mass spectrometry utilizing the mass defect filter method. Several authentic key metabolite standards were chemically synthesized for structural identification. Three GSH conjugates were found to derive from quinone methide intermediates, and the other three resulted from ortho-benzoquinone intermediates. Conjugation of the quinone methides with GSH produced benzylic orientated GSH conjugates by 1,6-addition, while the reaction of the ortho benzoquinone intermediates offered aromatic-orientated GSH conjugates. The conversion of 4-NP to the quinone methides and ortho-hydroquinones required cytochromes P450, specifically CYPs1A2, 2C19, 2D6, 2E1, and 3A4, while the oxidation of ortho-benzohydroquinones to the corresponding benzoquinones was apparently independent of microsomal enzymes. The ortho-benzoquinone derived from 4-NP was isomerized to the corresponding hydroxyquinone methide, and the former dominated the latter at a rate of approximately 20:1. The findings of the quinone methide and benzoquinone metabolites intensified the concern on the impact of 4 NP exposure on human health. PMID- 20843009 TI - Disulfide bond assignments by mass spectrometry of native natural peptides: cysteine pairing in disulfide bonded conotoxins. AB - The critical, and often most difficult, step in structure elucidation of diverse classes of natural peptides is the determination of correct disulfide pairing between multiple cysteine residues. Here, we present a direct mass spectrometric analytical methodology for the determination of disulfide pairing. Protonated peptides, having multiple disulfide bonds, fragmented under collision induced dissociation (CID) conditions and preferentially cleave along the peptide backbone, with occasional disulfide fragmentation either by C(beta)-S bond cleavage through H(alpha) abstraction to yield dehydroalanine and cysteinepersulfide, or by S-S bond cleavage through H(beta) abstraction to yield the thioaldehyde and cysteine. Further fragmentation of the initial set of product ions (MS(n)) yields third and fourth generation fragment ions, permitting a distinction between the various possible disulfide bonded structures. This approach is illustrated by establishing cysteine pairing patterns in five conotoxins containing two disulfide bonds. The methodology is extended to the Conus araneosus peptides Ar1446 and Ar1430, two 14 residue sequences containing 3 disulfide bonds. A distinction between 15 possible disulfide pairing schemes becomes possible using direct mass spectral fragmentation of the native peptides together with fragmentation of enzymatically nicked peptides. PMID- 20843011 TI - Stopped-flow kinetic analysis using Hadamard transform time-of-flight mass spectrometry. AB - A home-built stopped-flow apparatus is interfaced to a Hadamard transform time-of flight mass spectrometer, which permits study of reaction kinetics with a time between reaction initiation and observation as short as about 100 ms and a sampling rate of chemical change that can approach 1 ms. This technique is applied to the trypsin-catalyzed hydrolysis of several peptides and is validated by comparing the results with literature values as well as to optical data obtained with the present stopped-flow apparatus. In addition, we report a kinetic study of the action of trypsin on a peptide having more than one cleavage site. PMID- 20843010 TI - A microfluidic cell concentrator. AB - Cell concentration via centrifugation is a ubiquitous step in many cell culture procedures. At the macroscale, centrifugation suffers from a number of limitations, particularly when dealing with small numbers of cells (e.g., less than 50,000). On the other hand, typical microscale methods for cell concentration can affect cell physiology and bias readouts of cell behavior and function. In this paper, we present a microfluidic concentrator device that utilizes the effects of gravity to allow cells to gently settle out of a suspension into a collection region without the use of specific adhesion ligands. Dimensional analysis was performed to compare different device designs and was verified with flow modeling to optimize operational parameters. We are able to concentrate low-density cell suspensions in a microfluidic chamber, achieving a cell loss of only 1.1 +/- 0.6% (SD, n = 7) with no observed loss during a subsequent cell staining protocol which incorporates ~36 complete device volume replacements. This method provides a much needed interface between rare cell samples and microfluidic culture assays. PMID- 20843012 TI - Separation of peptide isomers with variant modified sites by high-resolution differential ion mobility spectrometry. AB - Many proteins and proteolytic peptides incorporate the same post-translational modification (PTM) at different sites, creating multiple localization variants with different functions or activities that may coexist in cells. Current analytical methods based on liquid chromatography (LC) followed by tandem mass spectrometry (MS/MS) are challenged by such isomers that often coelute in LC and/or produce nonunique fragment ions. The application of ion mobility spectrometry (IMS) was explored, but success has been limited by insufficient resolution. We show that high-resolution differential ion mobility spectrometry (FAIMS) employing helium-rich gases can readily separate phosphopeptides with variant modification sites. Use of He/N(2) mixtures containing up to 74% He has allowed separating to >95% three monophosphorylated peptides of identical sequence. Similar separation was achieved at 50% He, using an elevated electric field. Bisphosphorylated isomers that differ in only one modification site were separated to the same extent. We anticipate FAIMS capabilities for such separations to extend to other PTMs. PMID- 20843013 TI - Efficient synthesis of fullerenol in anion form for the preparation of electrodeposited films. AB - The first electrochemical characterization of the much-studied "fullerenols" has been carried out. The fullerenol was prepared by the reaction of C(60) in deoxygenated tetrahydrofuran with an aqueous NaOH solution using sodium zincate as an electrophilic reagent. The obtained fullerenol is not simply polyhydroxylated C(60) but is a structurally and electronically complex C(60) anion with a molecular formula of Na(+) (2)[C(60) (OH)(12)(O)(2)](2-). This negatively charged fullerenol is in the form of a spherical cluster of 50 nm in diameter, and it can migrate in the same solution to an anode surface and be oxidized into the less soluble fullerenol C(60)O(OH)(12), when 10 V is applied to the electroplating bath. A uniform film, with a particle of 50-250 nm in diameter and a thickness of a few 10-100s of nanometers, is obtained by drying the fullerenol covered anode. This is the first time that studies of water-soluble fullerenols acting as anions for electrodeposited film preparation have been reported. The deposition mechanism has been further demonstrated by electrochemical measurements and dissolved oxygen concentration testing to be an oxidation process consisting of two anodic oxygen evolution processes. PMID- 20843014 TI - New synthesis of fluorinated pyrazoles. AB - A new synthesis of fluorinated pyrazoles, a class of compounds with potential in medicinal chemistry, is described. The treatment of benzoylfluoroacetonitrile with hydrazine yielded the expected new 3-amino-4-fluoropyrazole, while the analogous reaction of alpha-cyano-alpha,alpha-difluoroketones with hydrazine in refluxing isopropanol surprisingly gave rise to 3-unsubstituted 4-fluoropyrazoles via an unprecedented mechanism. The isolation of intermediate hydrazine adducts led to a mechanistic rationale for this transformation. PMID- 20843015 TI - Mechanistic insights into nickel-catalyzed cycloisomerizations. AB - A nickel-catalyzed cycloisomerization coupling an allylic alcohol with an alkyne has been developed. Mechanistic insights gained through deuterium-labeling crossover studies and stereochemical probes illustrate that oxidation of the allylic alcohol to a metal-free enone is not involved in the cyclization pathway. The intermediacy of a metallacycle directly derived from oxidative cyclization of Ni(0) with the allylic alcohol and alkyne is consistent with the results obtained. The simple mechanistic probes employed could be useful in the study of many classes of cycloisomerization processes. PMID- 20843016 TI - Targeted discovery of polycyclic tetramate macrolactams from an environmental Streptomyces strain. AB - A targeted polymerase chain reaction (PCR)-based screening approach was used to identify candidate polycyclic tetramate macrolactam (PTM) biosynthetic gene clusters in environmental Streptomyces isolates. Isolation and characterization of the small molecules produced by one of the strains confirmed the production of two new PTMs (clifednamides A, 4, and B, 5) and, more generally, the utility of using a targeted approach for the discovery of new members of this interesting class. PMID- 20843018 TI - Tandem synthesis of 2,3-dihydro-4-iminoquinolines via three-component alkyne imine metathesis. AB - In the absence of any catalysts, ortho-alkynylanilines react with aldehydes and amines in HFIP to form trans-2,3-disubstituted 2,3-dihydro-4-iminoquinolines in a complete trans-selective manner via the three-component alkyne-imine metathesis. PMID- 20843017 TI - Anti-influenza virus compound from Streptomyces sp. RI18. AB - Screening for anti-influenza virus activity in compounds isolated from Streptomyces sp. RI18, which was isolated using the membrane filter method, uncovered a novel compound, JBIR-68 (1), which contains a unique skeleton. Its structure was established by extensive NMR and MS analyses. In addition, 1 was synthesized to confirm the configuration of its sugar moiety. Compound 1 inhibited influenza virus growth in plaque assays. PMID- 20843019 TI - Rhodium-catalyzed regioselective amination of secondary allylic trichloroacetimidates with unactivated aromatic amines. AB - The use of unactivated aromatic amines in the rhodium-catalyzed regioselective amination of secondary allylic trichloroacetimidates is explored. The desired N arylamines are obtained in high yields and regioselectivity, favoring the branched amination products. The presence of the trichloroacetimidate leaving group was found to be critical for successful regioselective amination reactions with unactivated aromatic amines. Control studies show that rhodium is not simply acting as a Lewis acid to activate the trichloroacetimidate leaving group. PMID- 20843020 TI - Synthesis of the tetracyclic core of tetrapetalone A enabled by a pyrrole reductive alkylation. AB - The tetracyclic framework of the tetrapetalone A aglycon has been secured through synthesis. A reductive pyrrole alkylation enables the formation of a key tetrasubstituted carbon stereocenter, and the tetramic acid portion of the molecule can be accessed through silicon or boronic ester conjugate addition to an ene-lactam. PMID- 20843021 TI - Diels-Alder reactions of cyclic isoimidium salts. AB - Diels-Alder reactions of cyclic isoimidium salts are described. The corresponding cycloadducts are obtained with high regio- and stereoselectivity. The use of homochiral cyclic isoimidium salts delivers cycloadducts with excellent diastereoselectivity (>99:1) that can be efficiently converted to enantiomerically pure lactones. PMID- 20843022 TI - Electrogenerated chemiluminescent anion sensing: selective recognition and sensing of pyrophosphate. AB - Recently, significant advances have been made independently in electrogenerated chemiluminescence (ECL) analysis and supramolecular anion sensing. Herein, we demonstrate a new proof of concept for ECL-based pyrophosphate (PPi) sensing, where the emission intensity is changed by electrochemical turn-on. The ECL PPi sensor (1-2Zn) consists of two orthogonally bonded moieties: boron dipyrromethene (ECL reporter) and a phenoxo-bridged bis(Zn(2+)-dipicolylamine) complex (PPi receptor). The presence of PPi is confirmed from the change in the intensity of green ECL generated from the former when PPi is selectively recognized by the latter. During PPi recognition, changes are caused in the electronic states of the receptor, and this stimulates the attenuation of ECL intensity. The electrochemical "on-off" triggering of light emission upon anion binding forms the basis of a new anion sensing strategy. We expect that green-colored ECL sensing would offer an advantage to current ECL analysis. PMID- 20843023 TI - Clay minerals mediate folding and regioselective interactions of RNA: a large scale atomistic simulation study. AB - Since a mineral-mediated origin of life was first hypothesized over 60 years ago, clays have played a significant role in origins of life studies. Such studies have hitherto rarely used computer simulation to understand the possible chemical pathways to the formation of biomolecules. We use molecular dynamics techniques, performed on supercomputing grids, to carry out large-scale simulations of various 25-mer sequences of ribonucleic acid (RNA), in bulk water and with aqueous montmorillonite clay over many tens of nanoseconds. Hitherto, there has only been limited experimental data reported for these systems. Our simulations are found to be in agreement with various experimental observations pertaining to the relative adsorption of RNA on montmorillonite in the presence of charge balancing cations. Over time scales of only a few nanoseconds, specific RNA sequences fold to characteristic secondary structural motifs, which do not form in the corresponding bulk water simulations. Our simulations also show that, in aqueous Ca(2+) environments, RNA can tether to the clay surface through a nucleotide base, leaving the 3'-end of the strand exposed, providing a mechanism for the regiospecific adsorption and elongation of RNA oligomers on clay surfaces. PMID- 20843024 TI - Influence of drying by convective air dryer or power ultrasound on the vitamin C and beta-carotene content of carrots. AB - Convective air drying and power ultrasound effects on vitamin C and beta-carotene contents in carrots were studied. For convective air drying, a central composite face-centered design fitting temperature between 40 and 65 degrees C and air flow rate between 2 and 6 * 10(-1) m/s were used; previously, carrots were blanched. Likewise, ultrasound drying was performed on both unblanched and blanched carrots at 20, 40, and 60 degrees C for 120, 90, and 75 min, respectively. Blanching had a sharp effect on vitamin C and beta-carotene degradation (80-92% retentions, respectively), and convective air drying led to further losses (32-50% and 73-90% retentions, respectively). According to the response surface model, a combination of 40 degrees C and 6 * 10(-1) m/s will maximize vitamin C retention in dried carrots, whereas 40 degrees C and 3.3 * 10(-1) m/s will ensure the highest beta-carotene content. Ultrasound drying caused higher vitamin C and beta-carotene retention (82-92% and 96-98%, respectively) than convective air drying. Blanched carrots dehydrated by ultrasound showed retentions of 55% and 88% of vitamin C and beta-carotene, respectively. Ultrasound drying at 20 degrees C for 120 min caused the maximum vitamin C and beta-carotene contents. Therefore, power ultrasound may be considered a valuable tool to obtain high nutritive dehydrated carrots. PMID- 20843025 TI - Formation of unusual seven-membered heterocycles incorporating nitrogen and sulfur by intramolecular conjugate displacement. AB - Baylis-Hillman alcohols derived from methyl acrylate or acrylonitrile and carrying an N-Boc group beta to the hydroxyl (CH(OH)CHNBoc) can be converted into unusual seven-membered heterocycles containing both nitrogen and sulfur by O acylation (AcCl or EtOCOCl), N-deprotection (CF(3)CO(2)H), and reaction with CS(2). In a modification of this process, when the original nitrogen is substituted in the form PhSCH(2)CON(Me), an azepine derivative is then generated. The ring closures occur by intramolecular conjugate displacement. PMID- 20843026 TI - Effects of cellulase from Aspergillus niger and solvent pretreatments on the extractability of organic green tea waste. AB - As green tea is being consumed in larger amounts, more green tea waste is being produced. Following extraction, several bioactive compounds may exist in the waste including polyphenols and amino acids. It was found that an Aspergillus niger cellulase treatment of green tea waste increased the extractability of various nutritional and functional components after pretreatments with various extraction solvents such as cold water (CW), hot water (HW), sulfuric acid (SA), hydrochloric acid (HA), and methanol (Me). After the residue was treated with cellulase from Aspergillus niger, the amounts of polyphenols, total catechins, and reducing sugars in the HW extract were increased by 64.6, 941.2, and 350.9%, respectively. In particular, levels of epigallocatechin, epicatechin, and gallic acid were significantly enhanced compared to those in the nontreated control. However, protein extraction was not significantly affected, and cellulase treatment was not more efficient for caffeine extraction compared to phenolic extraction. Among the four extraction solvents, HW and SA showed relatively higher extractabilities as compared to the other groups (CW, HA, and Me). These results indicate that cellulase from A. niger can increase the extractability of green tea waste when combined with certain solvent pretreatments. Consequently, the residual functional compounds and essential nutrients from cellulase-treated green tea waste have the potential to be applied in the production of new functional foods. PMID- 20843028 TI - Synthesis of a trans,syn,trans-dodecahydrophenanthrene via a bicyclic transannular Diels-Alder reaction: intermediate for the synthesis of fusidic acid. AB - While thermolysis of the macrobicyclic triene lactone 12 did not produce the expected bicyclic transannular Diels-Alder (BTADA) product 13, heating the corresponding ether 18 to 110 degrees C for 4 h afforded a quantitative yield of the desired cycloadduct 19, which could be easily reduced to the perhydrophenanthrene, an ABC ring analogue of fusidic acid 1. Theoretical calculations with hybrid density functional theory (B3LYP/6-31G(d)) help rationalize why the lactone does not cyclize whereas the ether does. PMID- 20843027 TI - Combinatorial selection of DNA thioaptamers targeted to the HA binding domain of human CD44. AB - CD44, the primary receptor for hyaluronic acid, plays an important role in tumor growth and metastasis. CD44-hyaluronic acid interactions can be exploited for targeted delivery of anticancer agents specifically to cancer cells. Although various splicing variants of CD44 are expressed on the plasma membrane of cancer cells, the hyaluronic acid binding domain (HABD) is highly conserved among the CD44 splicing variants. Using a novel two-step process, we have identified monothiophosphate-modified aptamers (thioaptamers) that specifically bind to the CD44's HABD with high affinities. Binding affinities of the selected thioaptamers for the HABD were in the range of 180-295 nM, an affinity significantly higher than that of hyaluronic acid (K(d) above the micromolar range). The selected thioaptamers bound to CD44 positive human ovarian cancer cell lines (SKOV3, IGROV, and A2780) but failed to bind the CD44 negative NIH3T3 cell line. Our results indicated that thio substitution at specific positions of the DNA phosphate backbone results in specific and high-affinity binding of thioaptamers to CD44. The selected thioaptamers will be of great interest for further development as a targeting or imaging agent for the delivery of therapeutic payloads for cancer tissues. PMID- 20843029 TI - Catalytic asymmetric synthesis of chiral propargylic alcohols for the intramolecular Pauson-Khand cycloaddition. AB - Several methods for the catalytic asymmetric alkyne addition to aldehydes are used to prepare the propargylic alcohol-based chiral en-ynes. Protection of the propargylic alcohols with either an acetyl or a methyl group allows the resulting en-ynes to undergo the intramolecular Pauson-Khand reaction to form the corresponding optically active 5,5- and 5,6-fused bicyclic products with high diastereoselectivity and high enantiomeric purity. In the major product, the propargylic substituent and the bridgehead hydrogen are cis with respect to each other on the fused bicyclic rings. The enantiomeric purity of the propargylic alcohols generated from the asymmetric alkyne addition is maintained in the cycloaddition products. The allylic ethers of the chiral propargylic alcohols are prepared which can also undergo the highly diastereoselective Pauson-Khand cycloaddition with retention of the high enantiomeric purity. This study has shown that the size of the substituents at the propargylic position as well as on the alkyne is important for the diastereoselectivity with the greater bulkiness of the substituents giving higher diastereoselectivity. PMID- 20843030 TI - Neutrophil targeting heterobivalent SPECT imaging probe: cFLFLF-PEG-TKPPR-99mTc. AB - A new heterobivalent peptide ligand specifically targeting polymorphonuclear leukocytes (PMNs) with favorable pharmacological parameters to monitor sites of inflammation for imaging is designed. The detailed synthesis, characterization, and pharmacological evaluation of the ligands are reported here. Two separate peptide binding ligands for formyl peptide and tuftsin receptors were chosen to link together based on the high expression levels of the two receptors on activated PMNs The heterobivalency and pegylated links were incorporated in the structural design to improve the sensitivity of the detection and to improve the bioavailability along with blood clearance profile, respectively. Two chemical constructs, cFLFLF-(PEG)(n)-TKPPR-(99m)Tc (n = 4, 12), were evaluated in vitro with human PMNs for binding affinity and bioavailability. As a result, cFLFLF (PEG)(12)-TKPPR-(99m)Tc was found to have more favorable pharmacological properties and was therefore used for further in vivo studies. Preliminary in vivo assessment of the agent was performed using single gamma emission computed tomography (SPECT) imaging of a mouse model of ear inflammation. The results of these studies indicate cFLFLF-(PEG)(12)-TKPPR-(99m)Tc may be a desirable imaging agent for binding to PMNs to identify sites of inflammation by SPECT. PMID- 20843033 TI - Zeolitic imidazolate framework-8 nanocrystal coated capillary for molecular sieving of branched alkanes from linear alkanes along with high-resolution chromatographic separation of linear alkanes. AB - A zeolitic imidazolate framework-8 (ZIF-8) nanocrystal coated capillary is shown not only to have a strong ability to sieve branched alkanes from linear alkane isomers owing to the narrow pore windows but also to offer excellent features for high-resolution gas chromatographic separation of linear alkanes due to van der Waals interaction between linear alkanes and the hydrophobic inner surfaces of the micropores. This makes the ZIF-8 coated capillary very promising for the specific adsorption and separation of alkanes in complicated matrices. PMID- 20843032 TI - ATP- and iron-protein-independent activation of nitrogenase catalysis by light. AB - We report here the light-driven activation of the molybdenum-iron-protein (MoFeP) of nitrogenase for substrate reduction independent of ATP hydrolysis and the iron protein (FeP), which have been believed to be essential for catalytic turnover. A MoFeP variant labeled on its surface with a Ru-photosensitizer is shown to photocatalytically reduce protons and acetylene, most likely at its active site, FeMoco. The uncoupling of nitrogenase catalysis from ATP hydrolysis should enable the study of redox dynamics within MoFeP and the population of discrete reaction intermediates for structural investigations. PMID- 20843034 TI - Limonoids from the Seeds of a Hainan Mangrove, Xylocarpus granatum. AB - Ten new limonoids, hainangranatumins A-J (1-10), and 25 known compounds were isolated from seeds of a Chinese mangrove, Xylocarpus granatum, collected on Hainan Island. Hainangranatumins A-E (1-5) and I and J (9 and 10) are 9,10-seco mexicanolides, whereas hainangranatumin F (6) is a limonoid possessing an 8alpha,30alpha-epoxy ring and a C1-C29 oxygen bridge. Hainangranatumin G (7) is a limonoid with a central pyridine ring, and hainangranatumin H (8) is a phragmalin 1,8,9-ortho ester. The relative configurations of hainangranatumins A and B were established by means of single-crystal X-ray diffraction analysis, and their absolute configurations were assigned on the basis of the specific rotation of the free acids obtained from alkaline hydrolysis. This is the first report of X ray crystallographic structures of 9,10-seco-mexicanolides with a flexible C2-C30 C8 linkage. Hainangranatumins I and J (9 and 10), unusual 9,10-seco-mexicanolides with a C9-C30 linkage, are proposed to be artifacts derived from hainangranatumin C and xylomexicanin A, respectively. PMID- 20843035 TI - Synthesis of P-stereogenic compounds via kinetic deprotonation and dynamic thermodynamic resolution of phosphine sulfides: opposite sense of induction using (-)-sparteine. AB - A systematic study of the asymmetric deprotonation of a dimethyl-substituted phosphine sulfide using organolithium bases in the presence of (-)-sparteine has been carried out. Use of nBuLi and (-)-sparteine in Et(2)O at -78 degrees C gave trapped adducts in ~88:12 er via a kinetically controlled process that was successfully predicted using a computational approach at the B3LYP/6-31+G(d) level. This initial kinetic enantioselectivity could be enhanced up to 97:3 er by trapping the lithiated intermediate with a prochiral electrophile (e.g., pivaldehyde or tBuPCl(2)). In addition, it was found that the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide could interconvert at temperatures above 0 degrees C. Such interconversion is unprecedented and differs from the configurational instability of organolithiums that are stereogenic at a lithiated carbon atom. The major, thermodynamically preferred diastereomeric (-)-sparteine-complexed lithated phosphine sulfide was investigated by X-ray crystallography and computational methods at the B3LYP/6 31+G(d) level. Through the interconversion of the R(P) and S(P) stereoisomers of the lithiated methylphosphine sulfide, a novel dynamic thermodynamic resolution of a racemic lithiated phosphine sulfide has been developed. Thus, the phosphine sulfide was lithiated with nBuLi, and then (-)-sparteine was added. After equilibration at 0 degrees C for 3 h, electrophilic trapping generated an adduct in 81:19 er with the configuration opposite to that obtained under kinetic control. Thus, the methodology provides access to P-stereogenic compounds with the opposite sense of induction using (-)-sparteine as the ligand simply by changing the reaction conditions (kinetic or thermodynamic control). PMID- 20843037 TI - Ni-catalyzed reduction of inert C-O bonds: a new strategy for using aryl ethers as easily removable directing groups. AB - An efficient Ni-catalyzed protocol for the reductive cleavage of inert C-O bonds has been developed. The method is characterized by its simplicity and wide scope, thereby allowing the use of aryl ethers as easily removable directing groups in organic synthesis. PMID- 20843036 TI - Total synthesis of plukenetione A. AB - We describe an alkylative dearomatization/acid-mediated adamantane annulation sequence that allows facile access to type A polyprenylated acylphloroglucinol natural products including plukenetione A. Introduction of the 2-methyl-1 propenyl moiety was achieved via stereodivergent S(N)2 and S(N)1 cyclizations of allylic alcohol substrates. PMID- 20843038 TI - Encapsulation of epigallocatechin-3-gallate (EGCG) using oil-in-water (O/W) submicrometer emulsions stabilized by iota-carrageenan and beta-lactoglobulin. AB - Oil-in-water (O/W) submicrometer emulsions stabilized by iota-carrageenan and beta-lactoglobulin were successfully prepared by high-pressure homogenization (HPH), with the goal to develop biocompatible carriers for the active component of green tea, epigallocatechin-3-gallate (EGCG). The effects of pressure and the number of cycles on the physical properties of emulsions, such as droplet sizes, microstructure, and rheological properties were investigated. The increase in both processing pressure and the number of HPH cycles resulted in a decrease in droplet sizes and viscosities. A submicrometer O/W emulsion with a droplet size of about 400 nm was used to encapsulate EGCG. The results showed that, when EGCG concentration was up to 0.5% in the emulsion, EGCG could be successfully encapsulated in the O/W emulsions stabilized by iota-carrageenan and beta lactoglobulin. Within 14 days, emulsion droplet sizes showed negligible changes. However, when EGCG concentration was >0.5%, significant instability of the O/W emulsions due to the binding between EGCG and beta-lactoglobulin was observed, as evidenced by the largely increased droplet sizes from light scattering and the appearance of large aggregates in the optical images. Moreover, EGCG encapsulated in an O/W submicrometer emulsion revealed an enhanced in vitro anticancer activity compared to the free EGCG. This study provides a novel encapsulation formulation to increase the biological efficacy of EGCG. PMID- 20843039 TI - Cathepsin D from the hepatopancreas of the cuttlefish (Sepia officinalis): purification and characterization. AB - Cathepsin D from the hepatopancreas of cuttlefish ( Sepia officinalis ) was purified to homogeneity by precipitation with ammonium sulfate (30-60%, w/v), Sephadex G-100 gel filtration, Mono-S cation-exchange chromatography, Sephadex G 75 gel filtration, and Mono-S FPLC with a 54-fold increase in specific activity and 17% recovery. The molecular weight of the purified cathepsin D was estimated to be 37.5 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS PAGE). On the basis of the native-PAGE and hemoglobin zymography, the purified protease appeared as a single band. The optimum pH and temperature for the cathepsin D activity were pH 3.0 and 50 degrees C, respectively, using hemoglobin as a substrate. The purified enzyme was completely inhibited by pepstatin A; however, no inhibition was observed with phenylmethylsulfonyl fluoride and ethylenediaminetetraacetic acid. Moreover, the activity was strongly inhibited by SDS and molybdate and enhanced by ATP. The purified cathepsin D was activated by Mg(2+), Ni(2+), Zn(2+), Cu(2+), Cd(2+), Sr(2+), and Co(2+) ions, whereas it was not affected by Na(+), K(+), and Ca(2+) ions. The N-terminal amino acid sequence of the first 13 amino acids of the purified cathepsin D was APTPEPLSNYMDA. S. officinalis cathepsin D, which showed high homology with cathepsin D from marine vertebrates and invertebrates, had a Pro residue at position 6 and a Ser residue at position 8, where Thr and Lys are common in all marine vertebrates cathepsins D. S. officinalis cathepsin D showed high efficiency for the hydrolysis of myofibrillar proteins extracted from cuttlefish muscle. PMID- 20843040 TI - Optimization of enzyme extractions for total folate in cereals using response surface methodology. AB - The trienzyme digestion including protease, alpha-amylase, and conjugase (gamma glutamyl hydrolase) for the extraction of total folate from cereal grain products used in AOAC Official Method 2004.05 was optimized using response surface methodology. Digestion times of alpha-amylase (p < 0.05) and conjugase (p < 0.01) showed significant effects on the response (total folate). Digestion time for Pronase digestion was not significant (p > 0.1). Ridge analysis showed that total times required for the trienzyme digestions ranged from 6.1 h for buckwheat to 8.7 h for CRM 121 (wholemeal flour). The predicted maximal value for CRM 121 (51 MUg/100 g) was close to the certified value (50 +/- 7 MUg/100 g). The optimized extractions for the four cereals suggest that a generalized trienzyme extraction for cereals of 1, 2.5, and 6 h for Pronase, alpha-amylase, and conjugase, respectively, could be used to approximate total folate in cereals and cereal products. These conditions provide data comparable to AOAC Official Method 2004.05 for the cereals included in this study and would be suitable to approximate total folate in most cereals and cereal products. Compared to the official method, the shortened digestion provides cost savings and minimizes the folate loss possible with prolonged digestions. PMID- 20843041 TI - Merging nucleophilic and hydrogen bonding catalysis: an anion binding approach to the kinetic resolution of propargylic amines. AB - An efficient kinetic resolution of primary propargylic amines with s-factors of up to 56 is reported. The strategy is based on a dual catalytic approach, namely the use of a newly developed and easy-to-make thiourea-amide anion binding catalyst in combination with 4-(dimethylamino)pyridine (DMAP), both employed at a 5 mol % catalyst loading. Benzylic amines are also resolved with s-factors of up to 38. PMID- 20843042 TI - Mn valence, magnetic, and electrical properties of LaMnO3+delta nanofibers by electrospinning. AB - LaMnO3+delta nanofibers have been prepared by electrospinning. The nearly 70% of Mn atoms is Mn4+, which is much higher than that in the nanoparticles. The average grain size of our fibers is approximately 20 nm, which is the critical size producing the nanoscale effect. The nanofibers exhibit a very broad magnetic transition with Tc~255 K, and the Tc onset is around 310 K. The blocking temperature TB is 180 K. The sample shows weak ferromagnetic property above the TB and below Tc and superparamagnetic property near the Tc onset. The resistivity measurements show a metal-insulator transition near 210 K and an upturn at about 45 K. PMID- 20843043 TI - Structure and bonding of isoleptic coinage metal (Cu, Ag, Au) dimethylaminonitrenes in the gas phase. AB - Dimethylaminonitrene complexes of IMesM(+) (IMes =1,3-bis(2,4,6 trimethylphenyl)imidazol-2-ylidene; M = Cu, Ag, Au) were prepared in the gas phase and structurally characterized by high-resolution infrared spectroscopy of the cold species, ion-molecule reactions, and DFT computations. We measured the binding energies of the nitrene fragment to the IMesM(+) moiety by energy resolved collision-induced dissociation experiments in the gas phase, affording a trend in bond strength of M = Cu ~ Au > Ag. This trend is explained in terms of a detailed metal-nitrogen bonding analysis, from which relativistic effects on the bonding were assessed. Various density functionals were evaluated for reproducing the observed thermochemical data and Truhlar's M06 functional was found to give the best agreement. PMID- 20843045 TI - The absolute configuration of palladium(II) and ruthenium(II) pseudochiral centers in either chiral or achiral environments. AB - The meso-dithioxamide H-((R)-1-(1-phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl)-H (H(2)-mesoDTO) bonds [(eta(6)-p-cymene)chlorido-ruthenium(II)](+) or [(eta(3) allyl)-palladium(II)](+) fragment and provides the C(s) symmetrical complexes [(eta(6)-p-cymene)ClRu(H-mesoDTO kappa-S,S Ru)] (1) and [(eta(3) allyl)palladium(H-mesoDTO kappa-S,S Pd)] (2). These complexes are pseudochiral, and each of them exists as a mixture of two symmetrical meso forms. The improper symmetry of [(eta(3)-allyl)palladium(H-mesoDTO kappa-S,S Pd)] has been broken in two different ways: (i) by changing the symmetrical allyl moiety with a eta(3) crotyl frame or (ii) by substituting the residual amidic hydrogen in the dithiooxamidate ligand with a M(PR(3))Cl(+) fragment (M = Pd or Pt and PR(3) = triorganophosphine). As a consequence, a chiral plane is added to the pseudochiral palladium center, and two pairs of enantiomers are formed in each case. Furthermore, [(eta(6)-p-cymene)chlorido-ruthenium(II)](+) and [(eta(3) allyl)-palladium(II)](+) fragments have been joined by means of the binucleating meso-dithiooxamidate ligand in a kappa-S,S Ru kappa-N,N Pd coordination mode. The resulting C(s)-symmetrical complex [(eta(6)-p-cymene)ClRu(MU-mesoDTO kappa-S,S Ru kappa-N,N Pd)Pd(eta(3)-allyl)] (8) possesses two pseudochiral metal centers, and it is therefore a mixture of four isomeric meso forms. All of these isomers in a chloroform solution interconvert in that both palladium and ruthenium invert their configurations. A mechanism of epimerization for both palladium and ruthenium is proposed. The absolute configurations of pseudochiral palladium in [(eta(3)-allyl)(c)-Pd(MU-((R)-1-(1-phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl) kappa-N,N (c)-Pd kappa-S,S (A,C)-Pd)(A,C)-Pd(tri(n)propyl-phosphine)Cl] (6) and of pseudochiral palladium and ruthenium in [(eta(3)-allyl)(c)-Pd(MU-((R)-1-(1 phenyl)ethyl)-NSC-CSN-((S)-1-(1-phenyl)ethyl) kappa-N,N (c)-Pd kappa-S,S(s) Ru)(s)-Ru(eta(6)-isopropyltoluene)Cl] (8) are provided. A suitable stereochemical notation is proposed for bimetallic complexes containing pseudochiral centers in either a chiral or an achiral environment. PMID- 20843044 TI - Going beyond the surface: revealing complex block copolymer morphologies with 3D scanning force microscopy. AB - We report on the quasi in situ scanning force microscopy nanotomography which proved to be a key method to effectively obtain a three-dimensional (3D) microdomain structure of a complex ABC triblock morphology. As an example, we studied polybutadiene-block-poly(2-vinyl pyridine)-block-poly(tert-butyl methacrylate) (BVT) thin triblock terpolymer films. We realized a controlled erosion of the material by using low-pressure plasma etching coupled to the scanning force microscope. The 3D reconstruction provides insights into the structural behavior in very thin volume elements revealing morphological details not accessible with other methods. PMID- 20843046 TI - Xe3OF3(+), a precursor to a noble-gas nitrate; syntheses and structural characterizations of FXeONO2, XeF2.HNO3, and XeF2.N2O4. AB - Xenon fluoride nitrate has been synthesized by reaction of NO(2)F with [FXeOXeFXeF][AsF(6)] at -50 degrees C. It was characterized in SO(2)ClF and CH(3)CN solutions by low-temperature (14)N, (19)F, and (129)Xe NMR spectroscopy and in the solid state by low-temperature Raman spectroscopy (-160 degrees C) and single-crystal X-ray diffraction (-173 degrees C). The reactions were carried out using natural abundance and (18)O-enriched [FXeOXeFXeF][AsF(6)] and (15)NO(2)F to aid in the vibrational assignments of FXeONO(2) and to establish the likely reaction pathway. Raman spectroscopy showed that FXe(16)ON((16)O(18)O) was formed, along with XeF(2) and [NO(2)][AsF(6)], when an excess of N(16)O(2)F reacted with [FXe(18)OXeFXeF][AsF(6)]. A reaction mechanism consistent with these findings is discussed. The crystal structure consists of well-separated FXeONO(2) molecules which display no significant intermolecular interactions, providing geometric parameters that are in good agreement with the gas-phase values determined from quantum-chemical calculations. Decomposition of solid FXeONO(2) is proposed to occur by three reaction pathways to give XeF(2), Xe, O(2), N(2)O(5), N(2)O(4), and NO(2)F. Attempts to synthesize FXeONO(2) and Xe(ONO(2))(2) by reaction of XeF(2) with HNO(3) in SO(2)ClF solution below -30 degrees C led to XeF(2).HNO(3). The structure of XeF(2).HNO(3) includes a hydrogen bond between HNO(3) and a fluorine atom of XeF(2), as well as an interaction between the xenon atom and an oxygen atom of HNO(3), leading to a crystal lattice comprised of layered sheets. A molecular addition compound between XeF(2) and N(2)O(4) crystallized from liquid N(2)O(4) below 0 degrees C. The crystal structure of XeF(2).N(2)O(4) displayed weak interactions between the xenon atom of XeF(2) and the oxygen atoms of N(2)O(4). Quantum-chemical calculations have been used to assign the vibrational spectra of FXeONO(2), XeF(2).HNO(3), and XeF(2).N(2)O(4) and to better understand the nature of the interactions of HNO(3) and N(2)O(4) with XeF(2). The synthesis of [XeONO(2)][AsF(6)] was attempted by the reaction of FXeONO(2) with excess liquid AsF(5) between -78 and -50 degrees C, but resulted in slow formation of [NO(2)][AsF(6)], Xe, and O(2). Thermodynamic calculations show that the pathways to [XeONO(2)][AsF(6)] formation and decomposition are exothermic and spontaneous under standard conditions and at -78 degrees C. PMID- 20843047 TI - Collisional energy transfer probability densities P(E, J; E', J') for monatomics colliding with large molecules. AB - Collisional energy transfer remains an important area of uncertainty in master equation simulations. Quasi-classical trajectory (QCT) calculations were used to examine the energy transfer probability density distribution (energy transfer kernel), which depends on translational temperature, on the nature of the collision partners, and on the initial and final total internal energies and angular momenta: P(E, J; E', J'). For this purpose, model potential energy functions were taken from the literature or were formulated for pyrazine + Ar and for ethane + Ar collisions. For each collision pair, batches of 10(5) trajectories were computed with three selected initial vibrational energies and five selected values for initial total angular momentum. Most trajectories were carried out with relative translational energy distributions at 300 K, but some were carried out at 1000 or 1200 K. In addition, some trajectories were computed for artificially "heavy" ethane, in which the H-atoms were assigned masses of 20 amu. The results were binned according to (DeltaE, DeltaJ), and a least-squares analysis was carried out by omitting the quasi-elastic trajectories from consideration. By trial-and-error, an empirical function was identified that fitted all 45 batches of trajectories with moderate accuracy. The results reveal significant correlations between initial and final energies and angular momenta. In particular, a strong correlation between DeltaE and DeltaJ depends on the smallest rotational constant in the excited polyatomic. These results show that the final rotational energy distribution is not independent of the initial distribution, showing that the plausible simplifying assumption described by Smith and Gilbert [Int. J. Chem. Kinet. 1988, 20, 307-329] and extended by Miller, Klippenstein, and Raffy [J. Phys. Chem. A 2002, 106, 4904-4913] is invalid for the systems studied. PMID- 20843048 TI - Phase transition analysis of 5-aminotetrazole from room temperature to the melting point. AB - The phase transition behavior of the 5-aminotetrazole (5-ATZ) crystal was studied in the range of room temperature to the melting point by the differential scanning calorimetry and powder X-ray diffraction techniques to investigate the dehydration phenomenon and to obtain the physical state of the high temperature phase. We found that 5-ATZ has one monohydrate crystal phase and three anhydrous crystal phases (I, II, and III) up to its melting point. The dehydration reaction of the monohydrate crystal occurred at about 50 degrees C. The dehydration enthalpy was 12.2 kcal/mol. The required activation energy was calculated using the Kissinger method, yielding the value of 27.1 kcal/mol. The phase transitions accompanying the sublimation from phase I to phase II and from phase II to phase III were observed during the prolonged heating at 175 degrees C. The dehydration phenomenon was also examined through quantum chemical calculations, and the calculated energy to eliminate a water molecule from the monohydrate crystal by the density functional theory at the M06/cc-pVTZ level basically agreed with the experimentally determined dehydration enthalpy. PMID- 20843049 TI - Theoretical study of the thermal decomposition of dimethyl disulfide. AB - Despite its use in a wide variety of industrially important thermochemical processes, little is known about the thermal decomposition mechanism of dimethyl disulfide (DMDS). To obtain more insight, the radical decomposition mechanism of DMDS is studied theoretically and a kinetic model is developed accounting for the formation of all the decomposition products observed in the experimental studies available in literature. Thermochemical data and rate coefficients are obtained using the high-level CBS-QB3 composite method. Among five methods tested (BMK/6 311G(2d,d,p), MPW1PW91/6-311G(2d,d,p), G3, G3B3, and CBS-QB3), the CBS-QB3 method was found to reproduce most accurately the experimental standard enthalpies of formation for a set of 17 small organosulfur compounds and the bond dissociation energies for a set of 10 sulfur bonds. Enthalpies of formation were predicted within 4 kJ mol(-1) while the mean absolute deviation on the bond dissociation enthalpies amounts to 7 kJ mol(-1). From the theoretical study, a new reaction path is identified for the formation of carbon disulfide via dithiirane (CH(2)S(2)). A reaction mechanism was constructed containing 36 reactions among 25 species accounting for the formation of all the decomposition products reported in literature. High-pressure limit rate coefficients for the 36 reactions in the reaction mechanism are presented. The kinetic model is able to grasp the experimental observations. With the recombination of thiyl radicals treated as being in the low-pressure limit, the experimentally reported first order rate coefficients for the decomposition of DMDS are reproduced within 1 order of magnitude, while the observed product selectivities of most compounds are reproduced satisfactory. Simulations indicate that at high conversions most of the carbon disulfide forms according to the newly identified reaction path involving the formation of dithiirane. PMID- 20843050 TI - Crystal-like growth of a metal oxide/CNT composite fiber with electroplated "seed" from a CNT-dispersed nonaqueous electrolyte. AB - A fabrication technique is developed for the preparation of metal oxide/CNT composites. An essential feature of the technique lies in the use of nonaqueous electrolyte in place of the usual aqueous electrolyte, which ensures well dispersed CNTs without surfactants. After a "seed" is formed by electroplating on the anode, the seed is simply pulled up at a certain speed to grow a 1D CNT composite structure. The technique leads to a uniform distribution of metal oxide and a high weight fraction of CNT in the composite structure. Moreover, the conductivity of the composite is much higher than that of the CNT fibers fabricated with polymer. PMID- 20843051 TI - Diffusiophoresis of a soft sphere normal to two parallel disks. AB - The diffusiophoresis of a soft spherical particle normal to two parallel disks subject to an applied ionic concentration gradient is modeled theoretically. The soft particle, which comprises a rigid core and a porous membrane layer, is capable of simulating a wide class of particles such as biocolloids and particles covered by an artificial membrane layer; a rigid particle can also be recovered as the limiting case where the membrane layer is infinitely thin. The problem considered simulates, for example, the chemotaxis of cells or microorganisms. We show that the presence of the membrane layer is capable of yielding complicated diffusiophoretic behavior when the sign of the charge carried by that layer is different from that on the surface of the rigid core of the particle. Both the sign and the magnitude of the diffusiophoretic velocity of a particle can be adjusted through varying the friction coefficient of its membrane layer. These results are of practical significance, for example, in the case where diffusiophoresis is adopted as a separation operation or as a tool to carry and/or control the rate of drug release. PMID- 20843052 TI - Superhydrophobicity on hairy surfaces. AB - We investigate the wetting properties of surfaces patterned with fine elastic hairs, with an emphasis on identifying superhydrophobic states on hydrophilic hairs. We formulate a 2D model of a large drop in contact with a row of equispaced elastic hairs and, by minimizing the free energy of the model, identify the stable and metastable states. In particular, we concentrate on partially suspended states, where the hairs bend to support the drop--singlet states, where all hairs bend in the same direction, and doublet states, where neighboring hairs bend in opposite directions--and find the limits of stability of these configurations in terms of the material contact angle, hair flexibility, and system geometry. The drop can remain suspended in a singlet state at hydrophilic contact angles, but doublets exist only when the hairs are hydrophobic. The system is more likely to evolve into a singlet state if the hairs are inclined at the root. We discuss how, under limited circumstances, the results can be modified to describe an array of hairs in three dimensions. We find that now both singlets and doublets can exhibit superhydrophobic behavior on hydrophilic hairs. We discuss the limitations of our approach and the directions for future work. PMID- 20843053 TI - Natural abundance 13C and 14C analysis of water-soluble organic carbon in atmospheric aerosols. AB - Water-soluble organic carbon (WSOC) constitutes a large fraction of climate forcing organic aerosols in the atmosphere, yet the sources of WSOC are poorly constrained. A method was developed to measure the stable carbon isotope (delta(13)C) and radiocarbon (Delta(14)C) composition of WSOC for apportionment between fossil fuel and different biogenic sources. Synthetic WSOC test substances and ambient aerosols were employed to investigate the effect of both modern and fossil carbon contamination and any method-induced isotope fractionation. The method includes extraction of aerosols collected on quartz filters followed by purification and preparation for off-line delta(13)C and Delta(14)C determination. The preparative freeze-drying step for isotope analysis yielded recoveries of only ~70% for ambient aerosols and WSOC probes. However, the delta(13)C of the WSOC isolates were in agreement with the delta(13)C of the unprocessed starting material, even for the volatile oxalic acid probe (6.59 +/- 0.370/00 vs 6.33 +/- 0.310/00; 2 sd). A (14)C-fossil phthalic acid WSOC probe returned a fraction modern biomass of <0.008 whereas a (14)C-modern sucrose standard yielded a fraction modern of >0.999, indicating the Delta(14)C-WSOC method to be free of both fossil and contemporary carbon contamination. Application of the delta(13)C/Delta(14)C-WSOC method to source apportion climate affecting aerosols was illustrated be constraining that WSOC in ambient Stockholm aerosols were 88% of contemporary biogenic C3 plant origin. PMID- 20843054 TI - Thermodynamic characterization of RNA triloops. AB - Relatively few thermodynamic parameters are available for RNA triloops. Therefore, 24 stem-loop sequences containing naturally occurring triloops were optically melted, and the thermodynamic parameters DeltaH degrees , DeltaS degrees , DeltaG degrees (37), and T(M) for each stem-loop were determined. These new experimental values, on average, are 0.5 kcal/mol different from the values predicted for these triloops using the model proposed by Mathews et al. [Mathews, D. H., Disney, M. D., Childs, J. L., Schroeder, S. J., Zuker, M., and Turner, D. H. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 7287-7292]. The data for the 24 triloops reported here were then combined with the data for five triloops that were published previously. A new model was derived to predict the free energy contribution of previously unmeasured triloops. The average absolute difference between the measured values and the values predicted using this proposed model is 0.3 kcal/mol. These new experimental data and updated predictive model allow for more accurate calculations of the free energy of RNA stem-loops containing triloops and, furthermore, should allow for improved prediction of secondary structure from sequence. PMID- 20843056 TI - Multicolor dye-doped silica nanoparticles independent of FRET. AB - Multicolor particles were prepared by incorporating two dyes, one fluorescent (fluorescein isothiocyanate) and one phosphorescent (tris(1,10-phenanathroline) ruthenium ion), into the silica matrix. Colors of the particles can be easily tuned by either varying the doping ratios of the two dyes or changing the excitation wavelength while fixing the ratios. The multicolor character of the particles is less sensitive to the location of the two dyes in the silica, since the luminescence of the particles is independent of Forster resonance energy transfer (FRET). PMID- 20843055 TI - Structural and functional analysis of cyclin D1 reveals p27 and substrate inhibitor binding requirements. AB - An alternative strategy for inhibition of the cyclin dependent kinases (CDKs) in antitumor drug discovery is afforded through the substrate recruitment site on the cyclin positive regulatory subunit. Critical CDK substrates such as the Rb and E2F families must undergo cyclin groove binding before phosphorylation, and hence inhibitors of this interaction also block substrate specific kinase activity. This approach offers the potential to generate highly selective and cell cycle specific CDK inhibitors and to reduce the inhibition of transcription mediated through CDK7 and 9, commonly observed with ATP competitive compounds. While highly potent peptide and small molecule inhibitors of CDK2/cyclin A, E substrate recruitment have been reported, little information has been generated on the determinants of inhibitor binding to the cyclin groove of the CDK4/cyclin D1 complex. CDK4/cyclin D is a validated anticancer drug target and continues to be widely pursued in the development of new therapeutics based on cell cycle blockade. We have therefore investigated the structural basis for peptide binding to its cyclin groove and have examined the features contributing to potency and selectivity of inhibitors. Peptidic inhibitors of CDK4/cyclin D of pRb phosphorylation have been synthesized, and their complexes with CDK4/cyclin D1 crystal structures have been generated. Based on available structural information, comparisons of the cyclin grooves of cyclin A2 and D1 are presented and provide insights into the determinants for peptide binding and the basis for differential binding and inhibition. In addition, a complex structure has been generated in order to model the interactions of the CDKI, p27(KIP)1, with cyclin D1. This information has been used to shed light onto the endogenous inhibition of CDK4 and also to identify unique aspects of cyclin D1 that can be exploited in the design of cyclin groove based CDK inhibitors. Peptidic and nonpeptidic compounds have been synthesized in order to explore structure-activity relationship for binding to the cyclin D1 groove, which to date has not been carried out in a systematic fashion. Collectively, the data presented provide new insights into how compounds can be developed that function as chemical biology probes to determine the cellular and antitumor effects of CDK inhibition. Furthermore, such compounds will serve as templates for structure-guided efforts to develop potential therapeutics based on selective inhibition of CDK4/cyclin D activity. PMID- 20843057 TI - EPR line-shape anisotropy and hyperfine shift of methyl radicals in solid Ne, Ar, Kr, and p-H2 gas matrices. AB - Earlier studies have shown that pure quantum mechanical effects on the "light" methyl radical at low temperature minimize the anisotropy of CW EPR spectra to a high resolution character, and new experiments under different conditions display a small additional electron paramagnetic resonance (EPR) line-shape anisotropy. In this work the effects of the solid H(2) quantum matrix and three other typical solid noble-gas matrices on the spectral anisotropy and the hyperfine interaction (hfi) constant of trapped methyl radicals presented as matrix shifts (deviation from the value in free space) are studied in some detail. Experimental EPR data at liquid-He temperatures were used to explore the dependence of the additional broadening and the spectral anisotropy of the hosted methyl radicals and to correlate the experimental spectral anisotropy to the matrix-radical interaction. Models correlating the spectral anisotropy and the matrix shift of the hyperfine (hf) coupling constant to the van der Waals (vdW) attraction and/or to the repulsive Pauli exclusion (RPE) forces between the host-matrix molecules and the methyl radical were constructed. It was shown that both vdW and RPE forces must be involved to explain these matrix effects, but while the RPE is the major source for the extra anisotropy, its contribution to the hf shift was also important but not dominant. PMID- 20843058 TI - Subeutectic synthesis of epitaxial Si-NWs with diverse catalysts using a novel Si precursor. AB - The applicability of a novel silicon precursor with respect to reasonable nanowire (NW) growth rates, feasibility of epitaxial NW growth and versatility with respect to diverse catalysts was investigated. Epitaxial growth of Si-NWs was achieved using octochlorotrisilane (OCTS) as Si precursor and Au as catalyst. In contrast to the synthesis approach with SiCl(4) as precursor, OCTS provides Si without the addition of H(2). By optimizing the growth conditions, effective NW synthesis is shown for alternative catalysts, in particular, Cu, Ag, Ni, and Pt with the latter two being compatible to complementary metal-oxide-semiconductor technology. As for these catalysts, the growth temperatures are lower than the lowest liquid eutectic; we suggest that the catalyst particle is in the solid state during NW growth and that a solid-phase diffusion process, either in the bulk, on the surface, or both, must be responsible for NW nucleation. PMID- 20843059 TI - Parametric amplification and back-action noise squeezing by a qubit-coupled nanoresonator. AB - We demonstrate the parametric amplification and noise squeezing of nanomechanical motion utilizing dispersive coupling to a Cooper-pair box qubit. By modulating the qubit bias and resulting mechanical resonance shift, we achieve gain of 30 dB and noise squeezing of 4 dB. This qubit-mediated effect is 3000 times more effective than that resulting from the weak nonlinearity of capacitance to a nearby electrode. This technique may be used to prepare nanomechanical squeezed states. PMID- 20843060 TI - Dynamic changes in dimensional structures of co-complex crystals. AB - A two-dimensional flexible porous coordination polymer (2D-PCP) that shows expansion/shrinkage structural transformation accompanied by molecular accommodation was synthesized by control of dimensionality in zero-dimensional and one-dimensional PCPs: The dynamic structural transformation cooperatively proceeds in the solid state with a drastic molecular rearrangement. Kinetics of the structural transformation was investigated. PMID- 20843061 TI - Subnanometer replica molding of molecular steps on ionic crystals. AB - Replica molding with elastomeric polymers has been used routinely to replicate features less than 10 nm in size. Because the theoretical limit of this technique is set by polymer-surface interactions, atomic radii, and accessible volumes, replication at subnanometer length scales should be possible. Using polydimethylsiloxane to create a mold and polyurethane to form the replica, we demonstrate replication of elementary steps 3-5 A in height that define the minimum separation between molecular layers in the lattices of the ionic crystals potassium dihydrogen phosphate and calcite. This work establishes the operation of replica molding at the molecular scale. PMID- 20843062 TI - Isolation and purification of medium chain length poly(3-hydroxyalkanoates) (mcl PHA) for medical applications using nonchlorinated solvents. AB - A novel process was developed to isolate poly([R]-3-hydroxyoctanoate-co-3 hydroxyhexanoate) (PHO) and poly([R]-3-hydroxy-omega-undecenoate-co-3-hydroxy omega-nonenoate-co-3-hydroxy-omega-heptenoate) (PHUE) from Pseudomonas putida species. Methyl tert-butyl ether (MTBE), ethyl acetate, acetone, and methylene chloride efficiently extracted PHO from freeze-dried biomass. The ratio of solvent to biomass was 15:1 (vol/wt). The nonchlorinated solvents required 18 h of extraction to achieve methylene chloride's yield of 15 wt % within 60 min. In the case of PHUE, the yield was 15-17 wt % after 60 min of extraction at room temperature, independently of the solvent used. MTBE performed best in life cycle assessment (LCA) if contamination of the environment is avoided. Filtration of the extract containing 8 wt % of raw polyhydroxyalkanoate (PHA) through activated charcoal revealed colorless polymers with less than one endotoxin unit/g. The ratio (v/v) of the solution to activated charcoal was 2:1. The loss (impurities and polymers) amounted up to 50 wt %. PMID- 20843064 TI - Highly efficient and mild electrochemical incineration: mechanism and kinetic process of refractory aromatic hydrocarbon pollutants on superhydrophobic PbO2 anode. AB - Aqueous aromatic hydrocarbons are chemically stable, high toxic refractory pollutants that can only be oxidized to phenols and quinone on either Pt or traditional PbO(2) electrodes. In this study, a novel method for the electrochemical incineration of benzene homologues on superhydrophobic PbO(2) electrode (hydrophobic-PbO(2)) was proposed under mild conditions. Hydrophobic PbO(2) can achieve the complete mineralization of aromatic hydrocarbons and exhibit high removal effect, rapid oxidation rate, and low energy consumption. The kinetics of the electrochemical incineration was also investigated, and the results revealed that the cleavage of the benzene ring is a key factor affecting the incineration efficiency. Moreover, on hydrophobic-PbO(2), the decay of intermediates was rapid, and low concentrations of aromatics were accumulated during the reaction. The removal of the initial pollutants and the effects of oxidative cleavage were related to the number of methyl groups on the benzene ring. Specifically, the results of physical experiments and quantum calculations revealed that the charge density of carbon atoms increases with an increase in the number of methyl groups, which promotes the electrophilic attack of .OH. PMID- 20843063 TI - Poly(N-isopropylacrylamide) brushes grafted from cellulose nanocrystals via surface-initiated single-electron transfer living radical polymerization. AB - Cellulose nanocrystals (CNCs) or nanowhiskers produced from sulfuric acid hydrolysis of ramie fibers were used as substrates for surface chemical functionalization with thermoresponsive macromolecules. The CNCs were grafted with poly(N-isopropylacrylamide) brushes via surface-initiated single-electron transfer living radical polymerization (SI-SET-LRP) under various conditions at room temperature. The grafting process was confirmed via Fourier transform IR spectroscopy and X-ray photoelectron spectroscopy and the different molecular masses of the grafts were quantified and found to depend on the initiator and monomer concentrations used. No observable damage occurred to the CNCs after grafting, as determined by X-ray diffraction. Size exclusion chromatography analyses of polymer chains cleaved from the cellulose nanocrystals indicated that a higher degree of polymerization was achieved by increasing initiator or monomer loading, most likely caused by local heterogeneities yielding higher rates of polymerization. It is expected that suspension stability, interfacial interactions, friction, and other properties of grafted CNCs can be controlled by changes in temperature and provide a unique platform for further development of stimuli-responsive nanomaterials. PMID- 20843065 TI - Ultrafine particles near a roadway intersection: origin and apportionment of fast changes in concentration. AB - A wavelet-based algorithm was implemented to separate the high frequency portion of ambient nanoparticle measurements taken during the summer and winter of 2009 in Wilmington, Delaware. These measurements included both number concentration and size distributions recorded once every second by a condensation particle counter (CPC) and a fast mobility particle sizer (FMPS). The high frequency portion of the signal, consisting of a series of abrupt spikes in number concentration that varied in length from a few seconds to tens of seconds, accounted for 6-35% of the daily ambient number concentration with hourly contributions sometimes greater than 50%. When the data were weighted by particle volume, this portion of the signal contributed an average of 20% to the daily PM(0.1) concentration. Particle concentration spikes were preferentially observed from locations surrounding the measurement site where motor vehicles accelerate after a red traffic light turns green. As the distance or transit time from emission to sampling increased, the size distribution shifted to larger particle diameters. PMID- 20843066 TI - Strategies for solid-state NMR studies of materials: from diamagnetic to paramagnetic porous solids. PMID- 20843067 TI - Structural chemistry of peptides containing backbone expanded amino acid residues: conformational features of beta, gamma, and hybrid peptides. PMID- 20843068 TI - cis-Dioxo- and cis-(hydroxo)oxo-Mo(V) complexes stabilized by intramolecular hydrogen-bonding. AB - The reactions of Tp(iPr)Mo(VI)O(2)Cl with salicylanilides and NEt(3) produce cis Tp(iPr)Mo(VI)O(2)(2-OC(6)H(4)CONHR) (Tp(iPr) = hydrotris(3-isopropylpyrazol-1 yl)borate, R = Ph, 4-C(6)H(4)Cl, 4-C(6)H(4)OMe). The N-methyl complex, Tp(iPr)MoO(2){2-OC(6)H(4)CON(Me)Ph}, is similarly prepared. Reduction of the amido complexes by cobaltocene produces green, EPR-active compounds, [CoCp(2)][Tp(iPr)Mo(V)O(2)(2-OC(6)H(4)CONHR)], that exhibit strong, low energy, nu(MoO(2)) IR bands at ~ 895 and 790 cm(-1) (cf. ~ 935 and 900 cm(-1) for the Mo(VI) analogues). The X-ray structures of all seven complexes have been determined. In each case, the Mo center exhibits a distorted octahedral coordination geometry defined by mutually cis oxo and phenolate ligands and a tridentate fac-Tp(iPr) ligand. The Mo(V) anions exhibit greater Mo?O distances (av. 1.738 A vs 1.695 A) and O?Mo?O angles (av. 112.4 degrees vs 102.9 degrees ) than their Mo(VI) counterparts, indicative of the presence of a three-center (MoO(2)), pi* semioccupied molecular orbital in these d(1) complexes. The amido Mo(VI) and Mo(V) complexes exhibit an intramolecular hydrogen-bond between the NH and O(phenolate) atoms. Protonation of [CoCp(2)][Tp(iPr)Mo(V)O(2)(2 OC(6)H(4)CONHR)] by lutidinium tetrafluoroborate is quantitative and produces EPR active, cis-(hydroxo)oxo-Mo(V) complexes, Tp(iPr)Mo(V)O(OH)(2-OC(6)H(4)CONHR), related to the low pH Mo(V) forms of sulfite oxidase. PMID- 20843069 TI - Low-coordinate germylene and stannylene heterocycles featuring sterically tunable bis(amido)silyl ligands. AB - A series of monomeric heterocyclic metallylenes [{(i)Pr(2)Si(NR)(2)}M:] (M = Ge and Sn; R = Dipp = 2,6-(i)Pr(2)C(6)H(3) or SiPh(3)) have been prepared. Preliminary atom-transfer chemistry involving the new low-valent germylenes with the chalcogen sources Me(3)NO and S(8) yielded the corresponding dimeric oxo- and sulfido complexes (e.g., [{(i)Pr(2)Si(NDipp)(2)}Ge(MU-E)](2); E = O and S). Structural analyses of the metallylenes and their oxidized products reveal that incorporation of the umbrella-shaped triarylsilyl groups (SiPh(3)) within the NSiN chelate confers additional steric protection about the group 14 centers relative to a Dipp group. The inclusion of sterically modifiable -SiAr(3) (Ar = aryl) units as part of a bis(amido) ligand array represents a new approach in this field and holds considerable promise with regard to attaining increasingly higher degrees of steric bulk. PMID- 20843070 TI - Formation of planar arrays of one-dimensional p-n heterojunctions using surface directed growth of nanowires and nanowalls. AB - We report a surface-directed vapor-liquid-solid process for planar growth of one dimensional heterojunctions of zinc oxide on single crystal gallium nitride (GaN) that enables their hierarchical assembly to light emitting diodes. An individual heterojunction is about 10 MUm in length and 80 nm in width and is formed by planar growth of an n-type ZnO nanowire or nanowall on p-type GaN surface using Au catalyst. Our results show that a ZnO nanocrystal at its nucleation site has six possible growth directions that can be engineered and controlled using an intentional blockade of the nanocrystal growth in certain directions owing to similarities in crystal structures of ZnO and GaN. The ZnO nanowalls are formed when nanowires during their planar growth slowly grow in direction normal to the substrate via a self-catalytic process. The crystal structure of these heterojunctions is examined from two different crystallographic perspectives using high resolution transmission electron microscopy. Results indicate abrupt and epitaxial formation of n-p heterojunctions, which are difficult to achieve in thin film growth of these heterojunctions. The collective light emission of micrometer- to millimeter-size arrays of the heterojunctions is demonstrated via a simple design that is scalable to literally any platform size. This technique allows in situ growth and combinations of II-VI and III-V semiconductors and offers their easier integration to photonic and lab-on-chip platforms with applications in energy generation and light detection. PMID- 20843071 TI - Modeling high-efficiency quantum dot sensitized solar cells. AB - With energy conversion efficiencies in continuous growth, quantum dot sensitized solar cells (QDSCs) are currently under an increasing interest, but there is an absence of a complete model for these devices. Here, we compile the latest developments in this kind of cells in order to attain high efficiency QDSCs, modeling the performance. CdSe QDs have been grown directly on a TiO(2) surface by successive ionic layer adsorption and reaction to ensure high QD loading. ZnS coating and previous growth of CdS were analyzed. Polysulfide electrolyte and Cu(2)S counterelectrodes were used to provide higher photocurrents and fill factors, FF. Incident photon-to-current efficiency peaks as high as 82%, under full 1 sun illumination, were obtained, which practically overcomes the photocurrent limitation commonly observed in QDSCs. High power conversion efficiency of up to 3.84% under full 1 sun illumination (V(oc) = 0.538 V, j(sc) = 13.9 mA/cm(2), FF = 0.51) and the characterization and modeling carried out indicate that recombination has to be overcome for further improvement of QDSC. PMID- 20843072 TI - Prepeak and first sharp diffraction peak in the structure factor of (Cs(2)O)(0.14)(B(2)O(3))(0.86) glass: influence of temperature. AB - Neutron diffraction measurements on (Cs(2)O)(0.14)(B(2)O(3))(0.86) glass were performed at varying temperature over an extended range from room temperature to 800 K. It was found that, in the same Q range where the first sharp diffraction peak (FSDP) is observed in the static structure factor of almost all glass forming systems, cesium borate glass shows two peaks. The intensities of these peaks increase with temperature, and their positions shift to lower Q values, in agreement with the peculiarities of the FSDP of network glasses. A description of this anomalous temperature dependence in terms of thermal relaxations of strained bonding arrangements of boron oxide units lying on the boundaries of cages present in the boron skeleton matrix is suggested. By comparing the diffraction patterns of a (Cs(2)O)(0.14)(B(2)O(3))(0.86) sample before and after a high temperature thermal treatment with the spectra of cesium crystals, a correspondence between the medium-range structure in the glass and the related crystalline phases has been inferred. PMID- 20843073 TI - Linear response of multiphoton reaction: three-photon cycloreversion of anthracene biplanemer in solution by intense femtosecond laser pulses. AB - The photocycloreversion of anthracene photodimers and biplanemer in solution was investigated by nonresonant intense femtosecond laser pulses. Cycloreversion of biplanemer showed a pseudolinear response to laser intensity whereas the formation of anthracene from photodimer was proportional to the cubic of laser intensity. The unusual intensity dependence of biplanemer was explained in terms of the sum of three-photon intramolecular cycloreversion and the recovery of reactant by a two-photon intramolecular cyclodimerization. The coexistence of high- and low-order multiphoton processes within the same laser pulse originated in the spatial distribution of the laser intensity. We observed white light emerging from the sample solution; however, the effect of solvated electrons was not observed in the present system. The saturation of both the photoreaction and white light due to a volume effect was observed at high intensity. PMID- 20843074 TI - Can lithium salts herald a new era for neutron capture therapy? PMID- 20843075 TI - Synthesis and structural studies of lithium and sodium complexes with OOO tridentate bis(phenolate) ligands: effective catalysts for the ring-opening polymerization of L-lactide. AB - A series of lithium and sodium complexes with OOO-tridentate bis(phenolate) ligands have been synthesized and fully characterized. The reaction of 2,2' dihydroxy-3,3',5,5'-tetrakis[(1-methyl-1-phenyl)ethyl]dibenzyl ether (L(1)-H(2)) with different ratios of (n)BuLi in toluene or tetrahydrofuran (THF) gave [Li(2)(L(1)-H)(2)] (1), [Li(4)L(1)(2)] (2), and [Li(2)L(1)(THF)(3)] (3), respectively. Similarly, [Na(L(1)-H)(THF)] (4), [Na(2)(L(1)-H)](2) (5), and [Na(4)L(1)(2)] (6) were prepared by the reaction of L(1)-H(2) and NaN[Si(CH(3))(3)](2) or sodium metal. In addition, the reaction of 2,2'-dihydroxy 3,3',5,5'-tetra-tert-butyldibenzyl ether (L(2)-H(2)) with (n)BuLi in toluene or THF yields Li(2)(L(2)-H)(2)] (7) and [Li(2)(L(2)-H)(2)(THF)(2)] (8), respectively. Further treatment of 7 with 2 mol equiv of benzyl alcohol provides [Li(2)(L(2)-H)(2)(BnOH)(2)] (9). Complexes 1-4 and 6-9 have been structurally characterized by single-crystal X-ray analysis. The dinuclear nature of complexes 1 and 3 was confirmed from their molecular structure. Complexes 2 and 6 illustrate tetranuclear species; however, complex 4 shows a mononuclear feature. A p-pi interaction exists from the phenyl ring of the 2-(methyl-1-phenylethyl) groups to the central metal in complexes 2, 4, and 6, which could effectively stabilize the metal center. Among them, complexes 1, 2, and 5-9 displayed efficient catalytic behavior for the ring-opening polymerization of L-lactide in the presence of benzyl alcohol. Experimental results indicate that among these alkali-metal complexes, the sodium compound 6 displays a rapid catalytic polymerization of L-lactide in "living" fashion, yielding poly(L-lactide) with a controlled molecular weight and narrow polydispersity indices for a wide range of monomer-to-initiator ratios. PMID- 20843076 TI - Unusual electronic effects imparted by bridging dinitrogen: an experimental and theoretical investigation. AB - We describe the preparation, structural and magnetic characterizations, and electronic structure calculations for a redox-related family of dinitrogen bridged chromium acetylide complexes containing the [RC(2)Cr(MU-N(2))CrC(2)R](n+) (R = Ph-, (i)Pr(3)Si-; n = 0, 1, 2) backbone: [(dmpe)(4)Cr(2)(C(2)Ph)(2)(MU N(2))] (1), [(dmpe)(4)Cr(2)(C(2)Si(i)Pr(3))(2)(MU-N(2))] (2), [(dmpe)(4)Cr(2)(C(2)Si(i)Pr(3))(2)(MU-N(2))]BAr(F)(4) (3), and [(dmpe)(4)Cr(2)(C(2)Si(i)Pr(3))(2)(MU-N(2))](BAr(F)(4))(2) (4). Compounds 3 and 4 are synthesized via chemical oxidation of 2 with [Cp(2)Co](+) and [Cp*(2)Fe](+), respectively. X-ray structural analyses show that the alteration of the formal Cr oxidation states does not appreciably change the Cr-N-N-Cr skeletal structures. Magnetic data collected for 2 and 4 are consistent with high-spin triplet and quintet ground states, respectively. The mixed-valent complex 3 exhibits temperature dependent magnetic behavior consistent with a quartet ? doublet two center spin equilibrium. Electronic structure calculations (B3LYP) performed on the full complexes in 2 and 4 suggest that the high-spin states arise from singly occupied orthogonal pi* orbitals coupled with a variable occupation of ddelta orbitals. Significant N-N and Cr-N pi-bonding pins the occupation of the pi manifold, leading to variable occupation of the ddelta space. In contrast, mixed valent 3 is not well described by a B3LYP hybrid density functional model. A [9,11] CAS-SORCI study on a simplified model of 3 reproduces the observed Hund's rule violation for the S = 1/2 ground state and places the lowest quartet 1.45 kcal/mol above the doublet ground state. PMID- 20843078 TI - Multilevel self-aligned microcontact printing system. AB - A multilevel microcontact printing (MUCP) system that avoids the use of optical alignment and precision manipulation equipment is demonstrated. Most of the complexity is transferred to the poly(dimethylsiloxane) (PDMS) stamp itself by forming the features, a mechanical self-alignment mechanism, and an elastic membrane by wafer scale replica molding on a Si master. Flexible 50-MUm-thick photoetched stainless steel sheets are bonded to PDMS prior to demolding to improve the mechanical stability. The Si master itself is made using conventional MEMS fabrication tools such as photolithography, reactive ion etching, and anisotropic wet etching. Self-alignment is achieved by introducing protrusions on the stamp that mate onto corresponding grooves on a machined substrate. Complete 10 mm * 10 mm prototypes are fabricated, and six-level MUCP is demonstrated with an average layer-to-layer misalignment of 5-10 MUm. PMID- 20843079 TI - Acid-induced aggregation of human monoclonal IgG1 and IgG2: molecular mechanism and the effect of solution composition. AB - The prevention of aggregation in therapeutic antibodies is of great importance to the biopharmaceutical industry. In our investigation, acid-induced aggregation of monoclonal IgG1 and IgG2 antibodies was studied at pH 3.5 as a function of salt concentration and buffer type. The extent of aggregation was estimated using a native cation-exchange chromatography (CEX) method based on the loss of soluble monomer. This approach allowed quantitative analysis of antibody aggregation kinetics for individual and mixed protein solutions. Information regarding the aggregation mechanism was gained by assessing stabilities of intact antibodies relative to their Fc and Fab fragments. The role of protein thermodynamic stability in aggregation was deduced from differential scanning calorimetry (DSC). The rate of aggregation under conditions mimicking the viral inactivation step during monoclonal antibody (mAb) processing was found to be strongly dependent on the antibody subclass (IgG1 vs IgG2). At 25 degrees C, IgG1s were resistant to low pH aggregation, but IgG2s aggregated readily in the presence of salt. The observed distinction between IgG1 and IgG2 aggregation resulted from differential stability of the corresponding C(H)2 domains. This was further confirmed by experimenting with an IgG1 molecule containing an aglycosylated C(H)2 domain. Interestingly, comparative analysis of two buffer systems (based on acetic acid vs citric acid) revealed differences in mAb aggregation under identical pH conditions. Evidence is provided for the importance of the total acid concentration for antibody aggregation at low pH. The effects of C(H)2 instability and solution composition on aggregation are significant and deserve careful consideration during the development of mAb- or Fc-based therapeutics. PMID- 20843080 TI - Formation mechanism of CaTiO3 hollow crystals with different microstructures. AB - The crystal growth of CaTiO(3) hollow crystals with different microstructures has been investigated. In a water-free poly(ethylene glycol) 200 (PEG-200) solution, CaTiO(3) nanocubes formed first. The nanocubes underwent an oriented self assembly into spherical particles, enhanced by the surface-adsorbed polymer molecules. Since the growth of nanocubes and their aggregation took place simultaneously, the nanocubes in the outer shells were larger than those in the cores. Disappearance of the small nanocubes in the cores of the spheres during an Ostwald ripening process led to spherical hollow crystals. Addition of a small amount of water (1.25 vol %) in the polymer solution enhanced surface recrystallization of the aggregated spheres, forming a cubic morphology. The orthorhombic distortion of the perovskite CaTiO(3) structure did not have a significant effect on the nanocube aggregation, resulting in a domain structure in the shells. Single-crystalline hollow cubes were produced with a slightly higher water content, e.g., 5 vol %. This process of (1) aggregation of nanocubes and (2) surface crystallization followed by (3) surface-to-core extension of recrystallization gives a good example of the reversed crystal growth route in ceramic materials. The proposed formation mechanism of the hollow CaTiO(3) crystals would enable us to control the microstructures of these materials and to explain the formation of many other hollow crystals. PMID- 20843081 TI - An N-heterocyclic carbene-disilyne complex and its reactivity toward ZnCl2. AB - The reaction of disilyne 1 with 1,3,4,5-tetramethylimidazol-2-ylidene (an N heterocyclic carbene, NHC) produced the disilyne-NHC complex 2, RLSi?SiR: (R = Si(i)Pr[CH(SiMe(3))(2)](2), L = NHC), with a trans geometry of the Si?Si moiety and lone-pair electrons residing on one of the double-bonded Si atoms. Upon complexation of 2 with ZnCl(2), the disilyne-NHC-ZnCl(2) complex 3 was produced, in which the Si?Si bond adopted the cis geometry. PMID- 20843083 TI - On the inhibitor effects of bergamot juice flavonoids binding to the 3-hydroxy-3 methylglutaryl-CoA reductase (HMGR) enzyme. AB - Density functional theory was applied to study the binding mode of new flavonoids as possible inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), an enzyme that catalyzes the four-electron reduction of HMGCoA to mevalonate, the committed step in the biosynthesis of sterols. The investigated flavonoid conjugates brutieridin and melitidin were recently quantified in the bergamot fruit extracts and identified to be structural analogues of statins, lipids concentration lowering drugs that inhibit HMGR. Computations allowed us to perform a detailed analysis of the geometrical and electronic features affecting the binding of these compounds, as well as that of the excellent simvastatin drug, to the active site of the enzyme and to give better insight into the inhibition process. PMID- 20843082 TI - Potent, highly selective, and orally bioavailable gem-difluorinated monocationic inhibitors of neuronal nitric oxide synthase. AB - In our efforts to discover neuronal isoform selective nitric oxide synthase (NOS) inhibitors, we have developed a series of compounds containing a pyrrolidine ring with two stereogenic centers. The enantiomerically pure compounds, (S,S) versus (R,R), exhibited two different binding orientations, with (R,R) inhibitors showing much better potency and selectivity. To improve the bioavailability of these inhibitors, we have introduced a CF(2) moiety geminal to an amino group in the long tail of one of these inhibitors, which reduced its basicity, resulting in compounds with monocationic character under physiological pH conditions. Biological evaluations have led to a nNOS inhibitor with a K(i) of 36 nM and high selectivity for nNOS over eNOS (3800-fold) and iNOS (1400-fold). MM-PBSA calculations indicated that the low pK(a) NH is, at least, partially protonated when bound to the active site. A comparison of rat oral bioavailability of the difluorinated compound to the parent molecule shows 22% for the difluorinated compound versus essentially no oral bioavailability for the parent compound. This indicates that the goal of this research to make compounds with only one protonated nitrogen atom at physiological pH to allow for membrane permeability, but which can become protonated when bound to NOS, has been accomplished. PMID- 20843084 TI - Enantioselective synthesis of indole-fused dihydropyranones via catalytic cycloaddition of ketenes and 3-alkylenyloxindoles. AB - Chiral N-heterocyclic carbenes were found to be efficient catalysts for the formal [4+2] cycloaddition reaction of alkyl(aryl)ketenes and 3 alkylenyloxindoles to give the corresponding 3,4-dihydropyrano[2,3-b]indol-2-ones in excellent yields with good diastereo- and enantioselectivities. PMID- 20843086 TI - Impact of fermentation, drying, roasting, and Dutch processing on epicatechin and catechin content of cacao beans and cocoa ingredients. AB - Low molecular weight flavan-3-ols are thought to be responsible, in part, for the cardiovascular benefits associated with cocoa powder and dark chocolate. The levels of epicatechin and catechin were determined in raw and conventionally fermented cacao beans and during conventional processing, which included drying, roasting, and Dutch (alkali) processing. Unripe cacao beans had 29% higher levels of epicatechin and the same level of catechin compared to fully ripe beans. Drying had minimal effect on the epicatechin and catechin levels. Substantial decreases (>80%) in catechin and epicatechin levels were observed in fermented versus unfermented beans. When both Ivory Coast and Papua New Guinea beans were subjected to roasting under controlled conditions, there was a distinct loss of epicatechin when bean temperatures exceeded 70 degrees C. When cacao beans were roasted to 120 degrees C, the catechin level in beans increased by 696% in unfermented beans, by 650% in Ivory Coast beans, and by 640% in Papua New Guinea fermented beans compared to the same unroasted beans. These results suggest that roasting in excess of 70 degrees C generates significant amounts of (-) catechin, probably due to epimerization of (-)-epicatechin. Compared to natural cocoa powders, Dutch processing caused a loss in both epicatechin (up to 98%) and catechin (up to 80%). The epicatechin/catechin ratio is proposed as a useful and sensitive indicator for the processing history of cacao beans. PMID- 20843085 TI - Palladium-catalyzed oxidative cross-coupling reaction of arylboronic acids with diazoesters for stereoselective synthesis of (E)-alpha,beta-diarylacrylates. AB - A Pd-catalyzed oxidative cross-coupling reaction of arylboronic acids with alpha diazoesters was achieved using molecular oxygen as the sole reoxidant, and E alpha,beta-diarylacrylates were obtained in good yields and >20:1 E-to-Z selectivity. PMID- 20843087 TI - U and P4 reaction products: a quantum chemical and matrix isolation spectroscopic investigation. AB - Reactions of laser-ablated U atoms with P(4) molecules upon codeposition in excess argon gave weak new infrared absorptions at 504, 483, and 426 cm(-1), which are best identified as binary uranium phosphide UP(4) species based on extensive B3LYP, BPW91, and PBE density functional and CASSCF/CASPT2 wave function based calculations. These UP(4) adducts may be considered as simple models for P(4) activation products by ligand-supported transition and main group metal complexes. The sought-after PUP molecule in the (3)Phi(u) ground state probably absorbs under the intense P(4) precursor band near 465 cm(-1). The triplet U(IV) molecule PUP is 7 kcal/mol lower in energy than the U(VI) analog, singlet PUP. The (3)Phi(u) ground state of PUP, with 2.54 effective bond order computed by CASPT2, may be compared to the (1)Sigma(g)(+) ground state of N=U=N with 2.87 effective bond order, where third row elements are less effective for pi bond formation than second row elements. PMID- 20843088 TI - Biomolecule-based nanomaterials and nanostructures. AB - Biomolecule-nanoparticle (or carbon nanotube) hybrid systems provide new materials that combine the unique optical, electronic, or catalytic properties of the nanoelements with the recognition or biocatalytic functions of biomolecules. This article summarizes recent applications of biomolecule-nanoparticle (or carbon nanotubes) hybrid systems for sensing, synthesis of nanostructures, and for the fabrication of nanoscale devices. The use of metallic nanoparticles for the electrical contacting of redox enzymes with electrodes, and as catalytic labels for the development of electrochemical biosensors is discussed. Similarly, biomolecule-quantum dot hybrid systems are implemented for optical biosensing, and for monitoring intracellular metabolic processes. Also, the self-assembly of biomolecule-metal nanoparticle hybrids into nanostructures and functional nanodevices is presented. The future perspectives of the field are addressed by discussing future challenges and highlighting different potential applications. PMID- 20843089 TI - Catalytic role of vicinal OH in ester aminolysis: proton shuttle versus hydrogen bond stabilization. AB - This computational study provoked by the process of peptide bond formation in the ribosome investigates the influence of the vicinal OH group in monoacylated diols on the elementary acts of ester aminolysis. Two alternative approaches for this influence on ester ammonolysis were considered: stabilization of the transition states by hydrogen bonds and participation of the vicinal hydroxyl in proton transfer (proton shuttle). The activation due to hydrogen bonds of the vicinal hydroxyl via tetragonal transition states was rather modest; the free energy of activation was reduced by only 5.2 kcal/mol compared to the noncatalyzed reaction. The catalytic activation via the proton shuttle mechanism with participation of the vicinal OH in the proton transfer via hexagonal transition states resulted in considerable reduction of the free energy of activation to 33.5 kcal/mol, i.e., 16.0 kcal/mol lower than in the referent process. Accounting for the influence of the environment on the reaction center by a continuum model (for epsilon from 5 to 80) resulted in further stabilization of the rate determining transition state by 4-5 kcal/mol. The overall reduction of the reaction barrier by about 16 kcal/mol as compared to the noncatalyzed process corresponds to about 10(9)-fold acceleration of the reaction, in agreement with the experimental estimate for acceleration of this process in the ribosome. PMID- 20843090 TI - Small band gap polymers synthesized via a modified nitration of 4,7-dibromo-2,1,3 benzothiadiazole. AB - The nitration of 4,7-dibromo-2,1,3-benzothiadiazole was modified by using CF(3)SO(3)H and HNO(3) as the nitrating agent, and the related yield was improved greatly. On the basis of this improvement, two new small band gap polymers, P1TPQ and P3TPQ, were developed. Bulk heterojunction solar cells based on P3TPQ and [6,6]-phenyl-C(71)-butyric acid methyl ester exhibit interesting results with a power conversion efficiency of 2.1% and photoresponse up to 1.1 MUm. PMID- 20843091 TI - Layer-by-layer transfer of multiple, large area sheets of graphene grown in multilayer stacks on a single SiC wafer. AB - Here we report a technique for transferring graphene layers, one by one, from a multilayer deposit formed by epitaxial growth on the Si-terminated face of a 6H SiC substrate. The procedure uses a bilayer film of palladium/polyimide deposited onto the graphene coated SiC, which is then mechanically peeled away and placed on a target substrate. Orthogonal etching of the palladium and polyimide leaves isolated sheets of graphene with sizes of square centimeters. Repeating these steps transfers additional sheets from the same SiC substrate. Raman spectroscopy, scanning tunneling spectroscopy, low-energy electron diffraction and X-ray photoelectron spectroscopy, together with scanning tunneling, atomic force, optical, and scanning electron microscopy reveal key properties of the materials. The sheet resistances determined from measurements of four point probe devices were found to be ~2 kOmega/square, close to expectation. Graphene crossbar structures fabricated in stacked configurations demonstrate the versatility of the procedures. PMID- 20843092 TI - Hofmann rearrangement of carboxamides mediated by hypervalent iodine species generated in situ from iodobenzene and oxone: reaction scope and limitations. AB - Alkylcarboxamides can be converted to the respective amines by Hofmann rearrangement using hypervalent iodine species generated in situ from PhI and Oxone in aqueous acetonitrile. On the basis of this reaction, a convenient experimental procedure for the preparation of alkylcarbamates using Oxone as the oxidant in the presence of iodobenzene in methanol has been developed. An efficient method for direct conversion of substituted benzamides to the respective quinone derivatives by treatment with Oxone and iodobenzene in aqueous acetonitrile has also been found. PMID- 20843093 TI - Synthesis of substituted indoles from 2-azidoacrylates and ortho-silyl aryltriflates. AB - 2-Azidoacrylates react with benzynes in the presence of PPh(3) and CsF to afford substituted indoles in good yields. The reaction involves the formation of iminophosphorane and benzyne and a subsequent double cyclization/hydrolysis/air oxidation cascade. This methodology was utilized to synthesize 10H-indolo[1,2 a]indol-10-ones. PMID- 20843094 TI - Gold-catalyzed cascade annulations of 2-(ynol)aryl aldehydes: facile synthesis of benzochromanes and benzobicyclo[n.3.1]acetals. AB - Gold-catalyzed reactions of 2-(ynol)aryl aldehydes were investigated. Benzochromanes were obtained from the reaction when AuCl(3) was employed as the catalyst, whereas benzobicyclo[n.3.1]acetals were produced when triazole-gold was employed as the catalyst. Plausible mechanisms are discussed. PMID- 20843095 TI - Constant-pH molecular dynamics simulations reveal a beta-rich form of the human prion protein. AB - The misfolding of the prion protein (PrP) into a pathogenic beta-rich form (PrP(Sc)) has been suggested to occur in the endocytic pathway, triggered by low pH. In this work we performed several constant-pH molecular dynamics simulations of human PrP 90-231 in the pH range 2-7, totaling more than 2 MUs. We observed a strong conformational pH dependence where on average the helix content decreased and the beta content increased toward acidic pH. Unlike some proposed models, the flexible N-terminus region did not gain stable structure at low pH. Rather, the main structural changes occurred on the helix-rich C-terminus core, as proposed in other models, namely, in the regions around 135-155 and 185-200. The protonation of His187 is found to be associated with a loss of interaction between two PrP subdomains, potentially playing a major role in the misfolding process. In one of the simulations at pH 2, a stable beta-rich structure was formed that may be an intermediate of PrP(Sc) formation, indicating that misfolding may precede dimerization. PMID- 20843096 TI - New insights into the effects of thermal treatment on the catalytic activity and conformational structure of glucose oxidase studied by electrochemistry, IR spectroscopy, and theoretical calculation. AB - Protein conformational changes may be associated with particular properties such as its function, transportation, assembly, tendency to aggregate, and potential cytotoxicity. In this study, the mechanism of the effects of thermal unfolding of proteins on their catalytic activities and conformational structures were studied by utilizing glucose oxidase (GOx) as a model protein. The characteristic kinetic constants for the enzymatic reaction were evaluated by the use of an electrochemical approach under a substrate-saturated condition. A combination of quantitative second-derivative infrared analysis, two-dimensional infrared correlation spectroscopy (2D IR), and theoretical calculation was used to elucidate the conformational structures that were responsible for inactivation and denaturation of GOx induced by heat. The IR analysis demonstrated that the conformational structures of GOx, especially the alpha-helix and unordered structures, were greatly dependent on the system temperature. Thermal treatment resulted in the increase of the unordered structure accompanied by the loss of the alpha-helical structure in GOx conformation. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations revealed that thermal treatment could significantly alter the electronic characteristics and the intramolecular electron transfer ability of FAD (flavin adenine dinucleotide), and hydrogen bond networks formed between FAD and the amino acid residues around the cofactor, leading to the change of the secondary structure and the catalytic activity of GOx. The study essentially paves an effective approach to investigation of the mechanism of protein unfolding. PMID- 20843097 TI - Asymmetric synthesis of (R)-antofine and (R)-cryptopleurine via proline-catalyzed sequential alpha-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde. AB - Naturally occurring phenanthroindolizidine alkaloids (R)-antofine and phenanthroquinolizidine alkaloids (R)-cryptopleurine have been synthesized in high optical purity via proline-catalyzed sequential alpha-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde. Both enantiopure forms of proline are commercially available, and thus, in principle, both isomers of antofine and cryptopleurine can be accessed with the new method. PMID- 20843098 TI - Structure of a prototypic ionic liquid: ethyl-methylimidazolium bromide. AB - High-energy X-ray diffraction measurements have been carried out on 1-ethyl-3 methylimidazolium bromide and complemented with molecular-dynamics simulations. Because the structure of the corresponding crystal is known, both the liquid and the crystal phases are simulated numerically. The liquid structure factor is dominated by an intense peak at 1.7 A(-1), associated mainly with the packing of the anions around the large cations. Analysis of the real-space correlations of the liquid shows that the Br(-) ions are distributed more symmetrically around the cation ring and move closer to the ring atoms compared with the crystal. Although the distribution of the anions around the cation in the first coordination shell of the liquid exhibits clear analogies with the crystal, the cation-cation partial distribution function of the liquid shows a significant component with lower distances between ring centers, with some pairs coming as close as 3.5 A in either parallel or antiparallel configurations. Finally, the presence of topological short-range order and charge ordering in the liquid is clearly demonstrated. PMID- 20843099 TI - Selective Na(+)/K(+) effects on the formation of alpha-cyclodextrin complexes with aromatic carboxylic acids: competition for the guest. AB - We investigated the effects of K(+) and Na(+) ions on the formation of alpha cyclodextrin complexes with ionized aromatic carboxylic acids. Using solution calorimetry and (1)H NMR, we performed the thermodynamic and structural investigation of alpha-cyclodextrin complex formation with benzoic and nicotinic acids in different aqueous solutions containing K(+) and Na(+) ions as well as in pure water. The experiments show that the addition of sodium ions to solution leads to a decrease in the binding constants of the carboxylic acids with alpha cyclodextrin as compared to pure water and solutions containing potassium ions. From another side, the effect of potassium ions on the binding constants is insignificant as compared to pure water solution. We suggest that the selectivity of cation pairing with carboxylates is the origin of the difference between the effects of sodium and potassium ions on complex formation. The strong counterion pairing between the sodium cation and the carboxylate group shifts the equilibrium toward dissociation of the binding complexes. In turn, the weak counterion pairing between the potassium cation and the carboxylate group has no effect on the complex formation. We complemented the experiments with molecular modeling, which shows the molecular scale details of the formation of cation pairs with the carboxylate groups of the carboxylic acids. The fully atomistic molecular simulations show that sodium ions mainly form direct contact pairs with the carboxylate group. At the same time, potassium ions practically do not form direct contact pairs with the carboxylate groups and usually stay in the second solvation shell of carboxylate groups. That confirms our hypotheses that the selective formation of ion pairs is the main cause of the difference in the observed effects of sodium and potassium salts on the guest-host complex formation of alpha-cyclodextrin with aromatic carboxylic acids. We propose a molecular mechanism explaining the effects of salts, based on competition between the cations and alpha-cyclodextrin for binding with the ionized carboxylic acids. PMID- 20843100 TI - Furan approach to vitamin D analogues. Synthesis of the A-ring of calcitriol and 1alpha-hydroxy-3-deoxyvitamin D(3). AB - The A-rings of calcitriol (1alpha,25-dihydroxyvitamin D(3)) and 1alpha-hydroxy-3 deoxyvitamin D(3) were synthesized using the furan approach. The critical steps in the synthesis of the A-ring of calcitriol involved an asymmetric carbonyl-ene reaction of 3-methylene-2,3-dihydrofuran with 3-(tert butyldimethylsiloxy)propanal, a diastereoselective Friedel-Crafts hydroxyalkylation, an oxidation of the 2,3-disubstituted furan to give a gamma hydroxybutenolide, and a Peterson olefination. The A-ring (Z)-dienol of calcitriol was synthesized in 12 steps from 3-(tert-butyldimethylsiloxy)propanal in 17% yield. PMID- 20843101 TI - Swords of cell death: caspase activation and regulation. AB - Apoptosis represents a crucial process in modulating organ development in the embryo, in organ homeostasis in the adult, and in fostering appropriate immunological function. Caspases represent two central classes of molecules that are either involved with the stimulation of the apoptotic cascade (initiator caspases), or the various sequential biological pathways required for its execution (effector caspases). With an eye towards therapeutic opportunities, this review discusses in detail the lineage of initiator and effector caspases, how they are each activated, their substrates, their regulation, and maps out how they interact throughout the process from initiation of the first apoptotic signal to the final consequential breakdown of cellular integrity. PMID- 20843102 TI - Effect modification of meat intake by genetic polymorphisms on colorectal neoplasia susceptibility. AB - Colorectal cancer incidences differ considerably between Western and non-Western countries. In recent years, a dramatic increase in colorectal cancer incidence has been reported in several Asian countries. Immigration studies have suggested that environmental rather than genetic factors are primarily responsible for the international variability and secular trends of colorectal cancer incidence rates. Therefore, not only the main effect of a gene but also the influence of gene-environment interactions on cancer risk are important from the public health perspective. This review encompasses the literature on gene-diet interactions, particularly focusing on meat intake and its association with the risk of colorectal carcinoma or adenomas. It is generally accepted that genotypes which are associated with the higher enzyme activity for metabolic activation or lower activity for detoxification would affect individual's susceptibility to meat carcinogens. The most intensively studied genes were those involved in xenobiotic metabolism, including N-acetyltransferase (NAT), cytochrome P450 (CYP) families, glutathione S-transferase (GST), and sulfotransferase (SULT). However, the associations were not consistent across studies. The role of genetic polymorphisms and their role in effect modification of environmental carcinogens should be assessed in well-designed large-scale epidemiological studies with comprehensive information for risk factors for better understanding the etiologic role of dietary factors and in developing a personalized cancer prevention strategy in the genome-wide association study era. PMID- 20843103 TI - Varicella outbreak in a pediatric oncology ward: the Manado experience. AB - BACKGROUND: Varicella is highly contagious and dangerous disease, especially in immunocompromised patients. Children with cancer are at increased risk of severe illness and fatal cases occur. OBJECTIVE: To describe an outbreak of varicella among in-patient cancer children, family members and staff. Estella Children Cancer Center in Manado, Indonesia with 14 beds and a 15 bed capacity guest house for family members. METHODS: A retrospective study of patients, family members and staff who were diagnosed with varicella based on clinical appearance was performed. Follow up was until 28 days from the last patient diagnosis' date. RESULTS: From late February to early May 2009, varicella was affecting 4 among 8 children with leukemia, 1 family member and 1 housekeeping staff. Measurers taken after the index case were oral acyclovir both for patients and contacts, patient isolation, ward disinfection and some chemotherapy interruption. Nevertheless, a second and third wave of varicella occurred. The index case died due to encephalitis. Other patients were non-severe and cured, but one child was lost to follow up. CONCLUSIONS: This outbreak highlights the importance of proper prevention and prompt management of varicella in immunocompromised patients. Simple and locally applicable guidelines are needed. PMID- 20843104 TI - Harm perception, attitudes and predictors of waterpipe (shisha) smoking among secondary school adolescents in Al-Hassa, Saudi Arabia. AB - OBJECTIVES: This study aimed to determine the prevalence and social determinants of waterpipe (WP) smoking among secondary school students in Al-Hassa, Saudi Arabia and to assess their health related knowledge and attitudes toward WP. SUBJECTS AND METHODS: A cross-sectional study was conducted with 1,652 Saudi secondary school students of both genders aged between 15-19 years selected by multistage sampling method. A self-administered anonymous Arabic version of Global Youth Tobacco Survey modified with items dedicated to WP smoking and to assess perception of health related hazards and attitudes towards WP was employed for data collection. RESULTS: Prevalence of current smokers 'all forms' was 30.3% among males (C.I= 27.5- 33.2%) and 8.5% in females (C.I= 6.6-10.9%). WP was used by 53.9% of the current tobacco users, significantly higher among older age students. Of the regular WP smokers, 20.7% smoked WP on daily basis, 23.8% weekly, 64.2% stated using flavored " Muassel " tobacco. Primary motives for WP smoking were outings with friends, company, boredom and wasting time. Of the total, 49.7% of students stated that WP smoking is less harmful than cigarettes, 60.5% believed that harmful substances were purified through water filtration, with non-addictive properties in 67.8%. Knowledge about health hazards of WP smoking was low, irrespective of student's smoking status. WP smoking is more socially acceptable than cigarettes (52.1%), represents a good opportunity for gathering of friends and family (33.8%), and smoking of WP can relieve stress and tensions (37.8%). Hierarchical regression analysis showed that socializing motives, cigarette smoking, smoking among close family and friends, male gender and increasing age were positive predictors for WP smoking. CONCLUSION: Social acceptability, poor knowledge of WP health related hazards and certain socio demographics are favoring the increasing current trend of WP use among adolescents in Al Hassa, Saudi Arabia. PMID- 20843105 TI - Response to neoadjuvant chemotherapy in patients with advanced breast cancer: a local hospital experience. AB - A large proportion of women present with advanced breast cancer in the developing countries with limited resources. Many of these patients have ulcerated, bleeding lesions or visually obvious masses in the breast. Neoadjuvant chemotherapy is well established as the standard of care and initial management of choice for these patients. Tumor shrinkage achieved with neoadjuvant chemotherapy has the advantage of converting an inoperable disease to an operable condition, with the option of breast conservation surgery where mastectomy is the only initial option for loco-regional control. Neoadjuvant chemotherapy also provides the earliest possible treatment of micrometastases and thus improves survival. In the present study, 165 advanced breast cancer female patients registered at the Institute of Nuclear Medicine and Oncology, Lahore, Pakistan, between 1st July 2005 and 30th June 2007 were evaluated for response to neoadjuvant chemotherapy. Tumor measurements were made and recorded prior to the first cycle of chemotherapy and 3 weeks after the third cycle. A clinical complete response was seen in 7.3%, a partial response in 60%, stable disease in 24% and progressive disease in 9%. A complete pathological response was only seen in 3.6% of evaluable patients. We conclude that breast cancer in patients presenting for neoadjuvant chemotherapy at our facility is more aggressive, generally presents as more advanced and bulky local disease, affects a younger population and features a low and unpredictable response to neoadjuvant chemotherapy. PMID- 20843106 TI - Correlation of mast cell density, tumor angiogenesis, and clinical outcomes in patients with endometrioid endometrial cancer. AB - BACKGROUND: Tumor angiogenesis has been demonstrated in several kinds of neoplasms. There is evidence that mast cells can produce many different chemical mediators with angiogenic properties. Since their specific role in female genital tract cancer has not been well understood, this study was conducted to determine correlations between among mast cell density, tumor angiogenesis, and clinical outcomes in patients with endometrioid adenocarcinoma of endometrium. METHODS: Histologically, four-micrometer-thick haematoxylin and eosin stained slides of hysterectomy specimens were evaluated. Microvessels were highlighted by CD31 immunostaining and mast cells were stained with 0.1% toluidine blue. All clinicopathological characteristics were reviewed to determine their possible correlation to microvessel density and number of mast cells. RESULTS: A total of 46 patients who underwent a complete staging surgery were eligible for this study. The median age was 55 years (range, 32-70 years) and the median follow-up was 27.0 months (range 3.6-83.8). Microvessels appeared to correlate to some extent with parity and the mean count was likely to be higher in women with non menopausal status (p=0.07), advanced FIGO stage (p=0.09), and lymph node metastasis (p=0.08). However, there was no significant correlation between microvessel counts, mast cell density, and disease recurrence. CONCLUSION: Our data suggest that the number of microvessel counts and mast cell density do not affect clinical progression or recurrence of endometrioid endometrial cancer. PMID- 20843107 TI - Smoking behavior and risk of helicobacter pylori infection, gastric atrophy and gastric cancer in Japanese. AB - Although many studies have shown that smoking is an established risk factor for gastric cancer, relatively few studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastric carcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastric cancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi Cancer Center Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency matched 1,742 cancer free controls were sampled, from whom those without serum samples or without information about smoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgG antibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smoking status was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as the OR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- and sex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62 (95% confidence interval (CI), 1.19 2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for current smokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased risk of gastric carcinogenesis from gastric atrophy, but had little influence on H. pylori infection or gastric atrophy development. PMID- 20843108 TI - Breast cancer: Awareness and risk factors in college-going younger age group women in Rajasthan. AB - OBJECTIVES: To determine awareness about breast cancer and its risk factors. STUDY DESIGN: Community based prospective cross sectional analysis. SETTING: College-going younger age group women of Rajasthan, with women's knowledge about breast cancer, risk factors, treatment, detection and preventive modalities as main outcome measures. RESULTS: All the respondents had heard of breast cancer. Awareness about breast mass/lump to be cardinal symptom of breast cancer was true for 65% of respondents. The main early diagnostic modality mammography was known by 19% of respondents while 49% aware about ultrasonography. Some 28% of the women were not aware about self breast examination. CONCLUSIONS: Women do have knowledge deficits about breast cancer and various related factors. PMID- 20843109 TI - Cervical cancer screening by visual inspection with acetic acid - interobserver variability between nurse and physician. AB - OBJECTIVES: The objective of the study was to evaluate and compare the test performance of visual inspection with acetic acid (VIA) by a physician and nurse so as to evaluate the feasibility and efficacy of training nurses in interpreting VIA. METHODS: This cross sectional study was conducted in the colposcopy clinic at the University teaching hospital. A total of 406 women who fulfilled the selection criteria underwent VIA done by both physician and nurse and the findings were interpreted independently. This was followed by colposcopy carried out by a gynecologist blinded to the results of VIA and a directed biopsy was taken if indicated. The diagnostic efficacy was calculated separately for physician and nurse using threshold of cervical intraepithelial neoplasia (CIN) 2 and above and concordance of results between the physician and nurse was determined by kappa statistics. RESULTS: VIA by physician had a higher sensitivity (88.9% versus 80.0%) and a higher specificity (69.8% versus 54.9%) with a disease threshold of CIN 2 and above. The concordance of results showed moderate agreement (kappa=0.366). CONCLUSION: Trained nurses can be an effective alternative human resource for cervical cancer screening using VIA as a preliminary screening method. Intensive training and periodic reinforcement sessions are needed so as to reduce false positive results. PMID- 20843110 TI - Anti-tumour, anti-mutagenic and chemomodulatory potential of Chlorophytum borivilianum. AB - In the present investigation anti-tumour, anti-mutagenic and chemomodulatory potential of Chlorophytum borivilianum were evaluated. Chlorophytum borivilianum root extract had no toxic effect up to a dose of 800 mg/kg body weight/day. Significant increase (p<0.05 to p<0.001) in the activity of reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) and a significant decrease in the hepatic MDA level were observed at 100, 400, and 800 mg/kg body weight of Chlorophytum borivilianum root extract when compared with the control value. Skin papillomagenesis studies demonstrated a significant (p<0.001) decrease in cumulative numbers of papilloma, tumour incidence, tumour burden, tumour size and tumour weight and significant (p<0.01) increase in average latent period when the animals received Chlorophytum borivilianum root extract at a dose level of 800 mg/kg body weight/day orally in double distilled water at pre, peri and post initiation stages of carcinogenesis. A significant reduction in the frequency of chromosomal aberration and micronuclei was observed in the treated animals as compared to carcinogen controls. The present investigation suggests that Chlorophytum borivilianum has anti-tumour, anti-mutagenic and chemomodulatory effects. PMID- 20843111 TI - Impact of age on prognosis in Iranian patients with gastric carcinoma: review of 742 cases. AB - BACKGROUND: Gastric carcinoma is one of the most common gastrointestinal malignancies worldwide. Some studies have suggested that it has a worse prognosis in non-elderly than in elderly patients. The aim of the present study was to clarify whether the patient's age is an independent prognostic factor. METHODS: A total of 742 patients with gastric carcinoma, who had registered in our cancer registry center between years 2001- 2006 were reviewed to investigate the prognostic significance of age. They were divided into the following two groups: non-elderly (under 70 years) and elderly (70 years or older). The clinicopathological features were reviewed retrospectively and a multivariate analysis was carried out. RESULTS: Lymph node metastasis and differentiated type were more frequently observed in non-elderly than in elderly patients (P<0.0001) and older patients diagnosed with more advanced stages compared with those younger than 70 years old (P=0.015). 5-year survival rates were 27.2 and 15.2% in non-elderly and elderly patients, respectively, the difference being statistically significant (P<0.001). Multivariate analysis showed that age and wall penetration were independent prognostic factors CONCLUSIONS: Age clinically serves as an important predictor of survival in patients with gastric carcinoma and elderly patients with gastric carcinoma have a worse prognosis than nonelderly patients. PMID- 20843112 TI - Lack of p16 gene mutations in gastric cancers in Kashmir. AB - BACKGROUND AND AIM: The focus of the study was to investigate the frequencies of homozygous deletions and mutations of p16 gene in gastric carcinomas in the Kashmiri population. METHODS: A total of 84 gastric carcinoma patients were screened by the single strand conformation polymorphism (SSCP) technique and later by DNA sequencing to detect mutations of the p16 gene. Also PCR was applied further to further detect any homozygous deletions. RESULTS: SSCP and DNA sequencing performed encompassing all the three exons of p16 gene could not detect any mutations in any ofl 84 cases. Though we could observe mobility shifts in SSCP of two samples, subsequent DNA sequencing did not show any mutation. Further PCR could not detect any homozygous deletion in P16 in any case. CONCLUSION: Though Kashmir is a high incidence area of gastric carcinomas, p16gene mutations /or deletions do not appear to be involved. PMID- 20843113 TI - Helicobacter bilis in human gallbladder cancer: results of a case-control study and a meta-analysis. AB - INTRODUCTION: Gallbladder cancer is an uncommon neoplasm of uncertain etiology and poor survival. Recently, interest has been generated in bacterial infections and cancers. Helicobacter is one such bacterium found to be associated with gastric MALToma, gastric adenocarcinoma and hepatobiliary neoplasms. PATIENTS AND METHODS: Fifty four gallbladder cancer and 55 controls with cholelithiasis were studied. Helicobacter bilis was identified using 16S rRNA PCR. Relative risk and odds ratio with 95% CI were estimated. A detailed search of literature was carried out and selected relevant articles were extracted. A meta analysis was carried out using a random effect model. RESULTS: Helicobacter bilis was identified in 32/54 patients and 32/55 controls, The relative risk of gallbladder cancer in H. bilis positive cases was 1.05 (95% CI 0.49 to 2.24). Of the 10 identified case control studies on Helicobacter in the hepatobiliary tract 3 each were on gallbladder cancer and H. bilis. In meta analysis a pooled odds ratio of 4.13 (95% CI 2.68-6.36) favoring Helicobacter was observed. Pooled analysis of published studies on gallbladder cancer showed an odds ratio of 1.24 (95% CI 0.63 2.44). CONCLUSIONS: The present study failed to demonstrate any increase in risk of gallbladder cancer in presence of Helicobacter bilis. It may be hypothesized that increased risk observed in earlier studies may be indirectly due to increase in the risk of gallstones, although lack of any study specifically looking at this aspect and absence of normal controls in the present study makes this assumption superfluous. PMID- 20843114 TI - Tobacco use by Indian medical students and the need for comprehensive intervention strategies. AB - BACKGROUND: Tobacco is one of the most important causes of pulmonary and cardiac diseases. Health professionals, including medical students, should ideally play an important role in the fight against tobacco use but several reports suggest that a good number of medical students are themselves addicted to tobacco. METHODS: This is a single institutional cross-sectional survey of preclinical medical students in Moti Lal Nehru Medical College, Allahabad over a five-year period from 2003-2007. Data was collected using the WHO Global Health Professionals Survey questionnaire. RESULTS: 560 students over a period of five years were included in this study. A total of 183 were tobacco users of which 83 were tobacco chewers, 59 cigarette smokers and 41 were addicted to both chewing and smoking. As health professionals, 88% knew that they should advise their patients to quit tobacco. CONCLUSION: This study showed rampant abuse of tobacco. Specific smoking cessation training is needed for medical students to develop appropriate skills and strategies. PMID- 20843115 TI - Comparison of three adjuvant chemotherapy regimes using an extended log-logistic model in women with operable breast cancer. AB - OBJECTIVE: The main objective of the present study was to compare the effects of three common chemotherapy regimes in terms of disease-free survival (DFS) of breast cancer (BC) patients; the three explored regimes were taxane-based, anthracycline-based and CMF (cyclophosphamide methotrexate and 5-fluorouracil). MATERIALS AND METHODS: In this historical-cohort study, we obtained the information of 62 patients with confirmed BC in non-metastatic stage and followed them for 8 years. All the patients had undergone modified radical mastectomy surgery and had received adjuvant chemotherapy in three medical centers in Tehran, Iran. DFS was considered as the end-point. Afterwards, an extended log logistic regression model was used to compare these regimes. RESULTS: The mean (SD) age of patients was 49.0 (10.3) years. The median time of follow-up was 20.0 months and the probability of 5-years DFS was 0.48. Survival analysis indicated that the type of chemotherapy (OR(CMF vs. taxane) = 0.33, OR(anthracycline vs. taxane) = 0.74), grade (OR(III vs. I or II) = 0.35), tumor size (OR(>5 cm vs. <5 cm)= 0.179) and nodal involvements (OR(Yes vs. No)= 0.36) affected DFS. CONCLUSION: The current study revealed that the efficacy of taxane-based, in terms of DFS, was more than CMF (p = 0.05). Moreover, taxane-based chemotherapy prolonged DFS more than anthracycline-based one although the difference was not significant (p= 0.63). Finally, considering the importance of tumor size, histological grade and number of involved lymph nodes in lengthening DFS, it is crucial to highlight the role of public education and screening programs in order to detect tumor in its early stages. PMID- 20843116 TI - Myofibroblast stromal presence and distribution in squamous epithelial carcinomas, oral dysplasia and hyperkeratosis. AB - PURPOSE: Stromal elements play a key role in growth and development of different neoplasms. Myofibroblasts are the major components and occur in stromal tissue during carcinogenesis processes. The purpose of this study was to review the frequency and the distribution pattern of myofibroblasts(alphaSMA-positive) in the stroma of squamous epithelial carcinoma and to compare values with those for with oral dysplasia and hyperkeratosis. METHODS: we evaluated alphaSMA protein frequency in hyperkeratosis (N =18), oral epithelial dysplasia (N=18) and oral squamous cell carcinoma (N=18) using immunohistochemistry. RESULTS: alphaSMA positive expression was observed in 67% of OSCC tissue samples with network and spindle patterns, whereas it was seen in 22% with a focal pattern in dysplasia and in 6% with a scanty pattern in hyperkeratosis cases. CONCLUSION: These findings suggest that an increase in number of myofibroblasts and change in their distribution pattern occurs during carcinogenesis which can be an expression of their role in tumor invasive characteristics. PMID- 20843117 TI - Glutathione S-transferase gene variants and risk of benign prostate hyperplasia in a North Indian population. AB - Glutagthione S-transferase (GST) is over-expressed in benign prostate hyperplasia (BPH) patients, but the significance of GST polymorphisms for susceptibility to diseases of the prostate is unclear. The objectives of this study were to determine relationships between polymorphisms in the GSTM1, T1 and P1 genes with risk of symptomatic BPH and influence on standard therapy. A gene polymorphism association study conducted with 160 symptomatic BPH patients with BPE (benign prostatic enlargement) and LUTS (lower urinary tract symptoms) and 200 age matched controls. Patient inclusion criteria are age > 50 years prostate size > 30 cm3, AUA (American urological association) score > 7 and PVR volume <= 200 ml. Patients were treated with alpha-adrenergic blockers and 5alpha-reductase inhibitors for 6 months and subdivided based on their significant improvement in parameters between pre and post 6 month combined therapy to study associations with the GST polymorphisms. The GSTT1 and GSTM1 variants genotyped with multiplex PCR, whereas GSTP1 polymorphisms were determined with PCR-RFLP (polymerase chain reaction- restriction fragment length polymorphism). We observed a lack of any association with the GSTT1 (p=0.45, OR=2.25, 95% CI=1.71-2.22) and GSTP1 (p=0.92 and 0.99) genes. However, there was a significant link with the null alleles of the GSTM1 (p=0.000, OR=2.24, 95%CI=1.46-3.42) gene. The combined analysis of the three genotypes demonstrated further increase in the risk of symptomatic BPH (p= 0.009, OR= 8.31 95%CI=1.71-40.37). Polymorphisms of GST genes were not associated with responders or non-responders. Thus the GSTM1 deletion polymorphism is significantly associated with increased risk of symptomatic BPH, but none of the genes appeared to influence response to standard BPH therapy. PMID- 20843118 TI - Chemopreventive and anticarcinogenic effects of Momordica charantia extract. AB - The aim of the study was to examine whether Momordica fruit extract (MFE) and Momordica leaves extract (MLE) might exert any chemopreventive effect in a two stage protocol in skin carcinogenesis with Swiss albino mice. The tumour incidence, tumour yield, tumour burden and cumulative no. of papillomas were found to be higher in the controls (without either extract) as compared to the MFE or MLE treated experimental groups. In a melanoma model, the mice which received fruit and leaf extracts of Momordica at the doses of 500 and 1000 mg/kg body weight for 30 days showed increase in life span of animals and tumour volume was significantly reduced as compared to control values. In cytogenetic studies, a single application of Momordica extracts at doses of 500, 1000 and 1500 mg/kg body weight, 24 hours prior the i.p. administration of cyclophosphamide, significantly prevented micronucleus formation and chromosomal aberrations in a dose dependent manner in bone marrow cells of mice. The present study demonstrate chemopreventive potential of Momordica fruit and leaf extracts on DMBA induced skin tumorigenesis, melanoma tumour and cytogenicity. PMID- 20843119 TI - Mammography utilization among Turkish women. AB - In Turkey, breast cancer is the leading type of cancer and cause of cancer related deaths among women, but information is limited on mammography practices. The objectives of the present study were to identify associations between attitudes and knowledge about mammography and socio-demographic indicators and having a mammogram. The participants of this cross-sectional and descriptive study were 1,208 women who attended the primary health care unit serving as a training unit of the medical faculty or the outpatient clinic for breast diseases of the same medical faculty's hospital between October and December 2007. A printed questionnaire covering socio-demographic variables, family history of breast cancer, mammography practices, and attitudes and knowledge of mammography was filled out in face-to-face interviews with the authors. Women with previously diagnosed breast cancer were excluded from the study. We performed chi square and logistic regression analyses. We found that 12.7% of the women had no knowledge of mammography, and 57.3 % had never had a mammogram. Fifty point six percent of our study group reported that they had had a clinical breast examination at least once, and 51.1% were aware of breast self examination (BSE). Need factors such as age and health-system-related factors such as awareness of BSE and having CBE were found to be more important than the socio-economic factors in mammography use. Mammography was accepted by 92.3% as a useful screening method for early detection of breast cancer and as a necessity for women of 50 years and over by the 90.6% of the study group. We found a positive attitude towards mammography and its importance but limited usage. PMID- 20843120 TI - Self examination for breast and testicular cancers: a community-based intervention study. AB - Prevalence of cancers is growing rapidly in all parts of the word with Pakistan being no exception. Prevention is the best option to tackle this rising epidemic. Screening, early detection and health awareness programs are the cornerstones in this regard. A community-based interventional study was therefore here conducted to assess the effect of health education intervention about knowledge and practice of self-breast examination (SBE) among women and self-testicular examination (STE) among men. A total of 127 (70 females and 57 males) adults (>= 18 years) from an urban community of Karachi, Pakistan were included after taking informed consent. Interventions were in the local language (Urdu) and included educational and awareness sessions by symposia, lectures and hand-on practice demonstrations about SBE and STE. Informative leaflets and brochures were also used in this regard. Pre-intervention assessment revealed that 57% women had knowledge of SBE and 4% men knew about STE and this proportion increased significantly (p<0.001) after the intervention both in women and in men, by 83% and 72%, respectively Similarly, significant post-intervention improvements were reported for SBE and STE practices (p<0.001). Our results suggest that educational interventions at the community level increase the knowledge and practices of women and men for SBE and STE. PMID- 20843121 TI - Cure models for estimating hospital-based breast cancer survival. AB - OBJECTIVE: Research on cancer survival is enriched by development and application of innovative analytical approaches in relation to standard methods. The aim of the present paper is to document the utility of a mixture model to estimate the cure fraction and compare it with other approaches. METHODS: The data were for 1,107 patients with locally advanced breast cancer, who completed the neo adjuvant treatment protocol during 1990-99 at the Cancer Institute (WIA), Chennai, India. Tumour stage, post-operative pathological node (PN) and tumour residue (TR) status were studied. Event free survival probability was estimated using the Kaplan-Meier method. Cure models under proportional and non proportional hazard assumptions following log normal distribution for survival time were used to estimate both the cure fraction and the survival function for the uncured. RESULTS: Event free survival at 5 and 10 years were 64.2% and 52.6% respectively and cure fraction was 47.5% for all cases together. Follow up ranged between 0-15 years and survival probabilities showed minimal changes after 7 years of follow up. TR and PN emerged as independent prognostic factors using Cox and proportional hazard (PH) cure models. Proportionality condition was violated when tumour stage was considered and it was statistically significant only under PH and not under non PH cure models. However, TR and PN continued to be independent prognostic factors after adjusting for tumour stage using the non PH cure model. A consistent ordering of cure fractions with respect to factors of PN and TR was forthcoming across tumour stages using PH and non PH cure models, but perceptible differences in survival were observed between the two. CONCLUSION: If PH conditions are violated, analysis using a non PH model is advocated and mixture cure models are useful in estimating the cure fraction and constructing survival curves for non-cures. PMID- 20843122 TI - Epidemiological data for common bone sarcomas. AB - Very little epidemiological data regarding bone sarcomas from South Asia in general and Pakistan in particular are available. At the largest center for histopathology in Pakistan, we looked at three common bone sarcomas in our practice i.e. osteosarcoma, Ewing's sarcoma and chondrosarcoma. Our aim was to compile epidemiological data regarding age, gender and site distribution, and to correlate our findings with published western data in order to determine whether there were any significant differences in our population compared to the west. An overwhelming majority of osteosarcomas in our study occurred in the second and third decades of life; they were common in males; and femur, tibia and hip bone were the commonest bones involved accounting for an overwhelming majority of cases. The large majority of Ewing's Sarcomas in our study occurred in the first three decades of life; they were more common in males; vertebrae, tibia, femur and hip bone were the commonest sites. In our study, chondrosarcomas showed a wide range of age distribution and occurred quite commonly in the young. Except for the greater occurrence of chondrosarcoma in young patients; and comparatively less frequent involvement of upper limb bones, most of the bone sarcoma trends in our population appear to be similar to published western data. PMID- 20843123 TI - A case control study on prostate cancer in Delhi. AB - Prostate cancer is one of the first five leading site of cancers in Delhi. The incidence rate is higher in North India compared to South India and it is rapidly increasing. A population based case-control study on prostate cases was therefore carried out in Delhi to identify potential risk factors. Cases were each matched with two controls. Past smoking and current alcohol consumption significantly increased the risk of prostate cancer. No statistically significant association was found with family history of cancer or prostate cancer. The risk of prostate cancer declined with increasing dietary consumption of tea, citrus fruits and melon. A statistically significant marginal increase in the odds ratio was observed with the consumption of eggs, fish and sunflower oil. Though an increased risk of prostate cancer was evident among vasectomised men, the association was not statistically significant. PMID- 20843124 TI - Population pharmacokinetics of methotrexate in Indian cancer patients. AB - AIMS: A population pharmacokinetic model was developed to describe dose-response Relationships of methotrexate (MTX) in adults with breast cancer; this is done in order to explore interindividual variability in relationships with different pathophysiological variables. METHODS: Forty-five patients receiving 122 courses of MTX (2-3 per patient) were included and data were analyzed using NONMEM software. A linear two-compartment model with linear elimination best described the data. The predictive performance was evaluated by comparing the predicted and observed concentrations and the population estimated parameters with the individual estimated parameters. RESULTS: The population pharmacokinetic parameters CL ,V1,Q, V2,K,K12 and K21 generated in NONMEM, using the FO method were 3.5 L/h,1.25 L,8.43 L/h,6.45 L, 2.8,6.74 and 1.30 h-1 respectively. No covariate had significant effects on CL and VD. CONCLUSIONS: The results of this study combine relationships between the pharmacokinetic parameters of MTX and patient covariates that may be useful for dose adjustment, with a convenient sampling procedure that may aid in optimizing cancer patient care. PMID- 20843125 TI - Analysis of the standardization and centralization for cancer treatment in Nagasaki prefecture. AB - In medical care systems for cancer, it is important to consider the issues of standardization and centralization. In this study, we employed the Nagasaki Cancer Registry, which has a high registry rate, to investigate standardization and centralization for five major cancers, in addition to childhood malignancies (which are often rare types). Subjects were patients diagnosed with cancer and registered in the Nagasaki Cancer Registry between 1985 and 2004. For standardization, we calculated a Preference Index and five-year survival rate, and for centralization we investigated Pareto curves and Gini coefficients as well as the annual average number of cases per hospital. Results suggested that patients migrate to medical service areas different from where they reside in order to receive treatment at facilities thought to have a better record of treatment. In addition, while the number of patients and treatment facilities for childhood cancer was decreasing due to a decline in the number of children, the centralized tendency differed for the 12 diagnoses assessed. By conducting analyses based on population-based cancer registries using the evaluation methods employed in this study, it should be possible to investigate patients' migrant patterns, as well as to develop systems for providing medical care in secondary medical service areas. PMID- 20843126 TI - Splenectomy during secondary cytoreductive surgery for epithelial ovarian cancer. AB - Splenic metastasis from ovarian cancer is unusual. Most splenic metastases are encountered in the setting of widespread visceral metastases. We present 6 cases of splenic metastasis of epithelial ovarian cancer. Three cases underwent a splenectomy as a part of interval debulking surgery, and the rest received a splenectomy as a surgery for recurrent disease. The splenectomies were well tolerated in all patients and no serious morbidity or mortality resulted. Only one patient experienced a transient elevation in platelet count. PMID- 20843127 TI - Does performance of breast self-exams increase the probability of using mammography: evidence from Malaysia. AB - OBJECTIVES: Breast self-examination (BSE) was evaluated to see if it is a significant predictor of mammography. METHODS: The decisions of females above age 40 in Malaysia to test for breast cancer using BSE and mammography are jointly modeled using a bivariate probit so that unobserved attributes affecting mammography usage are also allowed to affect BSE. Data come from the Malaysia Non Communicable Disease Surveillance-1, which was collected between September 2005 and February 2006. RESULTS: Having ever performed BSE is positively associated with having ever undergone mammography among Malay (adjusted OR=7.343, CI=2.686, 20.079) and Chinese (adjusted OR=3.466, CI=1.330, 9.031) females after adjusting for household income, education, marital status and residential location. Neither relationship is affected by jointly modelling the decision problem. Although the association is also positive for Indian females when mammography is modelled separately (adjusted OR=5.959, CI=1.546 - 22.970), the relationship is reversed when both decisions are modelled separately. CONCLUSIONS: De-emphasizing BSE in Malaysia may reduce mammography screening among a large proportion of the population. Previous work on the issue in developed countries may not apply to nations with limited resources. PMID- 20843128 TI - Living near overhead high voltage transmission power lines as a risk factor for childhood acute lymphoblastic leukemia: a case-control study. AB - This study aimed to investigate association of living near high voltage power lines with occurrence of childhood acute lymphoblastic leukemia (ALL). Through a case-control study 300 children aged 1-18 years with confirmed ALL were selected from all referral teaching centers for cancer. They interviewed for history of living near overhead high voltage power lines during at least past two years and compared with 300 controls which were individually matched for sex and approximate age. Logistic regression, chi square and paired t-tests were used for analysis when appropriate. The case group were living significantly closer to power lines (P<0.001). More than half of the cases were exposed to two or three types of power lines (P<0.02). Using logistic regression, odds ratio of 2.61 (95%CI: 1.73 to 3.94) calculated for less than 600 meters far from the nearest lines against more than 600 meters. This ratio estimated as 9.93 (95%CI: 3.47 to 28.5) for 123 KV, 10.78 (95%CI: 3.75 to 31) for 230 KV and 2.98 (95%CI: 0.93 to 9.54) for 400 KV lines. Odds of ALL decreased 0.61 for every 600 meters from the nearest power line. This study emphasizes that living close to high voltage power lines is a risk for ALL. PMID- 20843129 TI - Female hospital-based healthcare professionals' knowledge of cervical cancer, HPV and attitudes towards HPV vaccination. AB - OBJECTIVE: To find out female hospital-based healthcare professionals' knowledge of cervical cancer, HPV and attitudes towards HPV vaccination. DESIGN: A descriptive cross-sectional hospital-based study. SETTING: Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. SAMPLE: A total of 350 female hospital based healthcare professionals who had not been diagnosed as having any cancer and willing to participate in the study. METHODS: Participants completed written consent and an anonymous questionnaire and knowledge of cervical cancer, HPV and attitudes towards HPV vaccination were the main outcome measures. RESULTS: Among 300 responders, the mean age was 36.1 years. Most of them were married with children and had received university education. Nursing assistants accounted for 47.1%, and their income per month was about 5,001-15,000 baht. Most (56.3%) had only one lifetime sexual partner. Sixty-eight to 85.3% have a good knowledge of cervical cancer and Pap smear. However, only 12.0 to 58.3% have some knowledge of HPV, and less than fifty percent of them have knowledge of HPV vaccination. Nevertheless, 51.7 to 60.7% of them have good attitudes toward vaccination. Their age and income might influence their attitudes about having themselves vaccinated, and their career might be a factor which altered their attitudes about having their daughter vaccinated if they have one. CONCLUSIONS: Female hospital-based healthcare professionals have a good knowledge about cervical cancer and Pap smears, but they need motivation to have Pap tests regularly. More information regarding HPV and vaccination is needed to provide to them for cervical cancer prevention and best practices. PMID- 20843130 TI - Perception and opinion of medical students about Pap smear test: a qualitative study. AB - OBJECTIVE: the objective of this study is to explore the perceptions of medical students regarding the Pap smear test. METHODOLOGY: Focus group discussion was held with twenty three medical students. The students were divided into three focus groups; two groups of female participants consisting of 9 and 8 students; respectively. The third group consisted of 6 male students. Questions regarding Pap smear testing included barriers that prevented women from taking the test, gender preference for the physician to conduct the cervical screening test, willingness to suggest Pap smear test to the family or friends. The data obtained were classified into various categories and analyzed manually. RESULTS: Most of the study participants mentioned that the main barriers for women to not perform Pap smear test is lack of awareness 16 (70%), followed by shyness 12 (52%) and the cost of the test 12 (52%). Most agreed that the gender of the physician will affect the women decision to do Pap smear test. All mentioned that the advantage of a regular Pap smear test is to detect the abnormality at the early stage of cervical cancer. Some of the participants 9 (39%) mentioned that the disadvantages are expense, possible injury in the vagina due to the test procedures 8 (35%), associated infection 7(30.4%) and pain 7(30.4%) . The majority, 20 (87%) mentioned that the most effective prevention methods for cervical cancer are having sex only after getting married with the spouse only, HPV vaccination 15 (65%) and Pap smear 14 (61%). CONCLUSION: The main barriers for women to not perform Pap smear test is lack of awareness, shyness and the cost of the test. Gender of the physician will affect the women decision to do Pap smear test. PMID- 20843131 TI - Prediction of cancer cases for a hospital in Nepal: a statistical modelling. AB - OBJECTIVE: The aim of this study was to predict the number and trends of cancer cases for radiotherapy up to the year 2015 in Manipal Teaching Hospital, Pokhara, Nepal. METHODS: A retrospective study was carried out on data retrieved from the radiotherapy treatment records of patients treated at Manipal Teaching Hospital between 28 September 2000 and 31 December 2008. Different statistical programmes were used for statistical modelling and prediction. Using curve-fitting methods, Linear, Logarithmic, Inverse, Quadratic, Cubic, Compound, Power, Exponential, and Growth models were tested. RESULTS: Including constant term, none of the models were best fitted. However, excluding the constant term, the cubic model was best fitted; R2=0. 95, p=0.001 for total cancer cases, R2=0. 94, p=0.001 for female cancer cases and R2=0. 95, p=0.001 for male cancer cases. The cancer cases estimated using cubic model showed a steady increase in the total frequency of cancers (including male and female cancer cases) following the year 2010. The three most common cancers reported were head and neck 24.2% (CI 21.6 - 27.0), lung 20.9% (CI 18.4 -23.6), cervix 15.9% (CI 13.7-18.3) respectively. CONCLUSION: The cancer cases in need of radiotherapy will increase in future years. The curve fitting method could be an effective exploratory modelling technique for predicting cancer frequency and trends over the years. PMID- 20843132 TI - Effects of genetic polymorphisms in the ABCB1 gene on clinical outcomes in patients with gastric cancer treated by second-line chemotherapy. AB - OBJECTIVE: Tumor cells that overexpress P-glycoprotein (Pgp) may be resistant to several anticancer agents due to altered pharmacokinetics and reduced intracellular concentrations of the anticancer agents. Pgp is encoded by the ATP binding cassette gene B1 (ABCB1). To our knowledge, only one previous report has evaluated the effect of ABCB1 gene polymorphisms on clinical outcomes of gastric cancer. The purpose of this analysis was to evaluate the impact of genetic polymorphisms of the ABCB1 gene on clinical outcomes in patients with advanced gastric cancer (AGC) treated with second-line chemotherapy. METHODS: We retrospectively analyzed the impact of ABCB1 gene polymorphisms (ABCB1 3435C>T) on clinical outcomes in 100 patients with AGC who received second-line chemotherapy. RESULTS: Median overall survival (OS) since the initiation of second-line chemotherapy was 6.0 months (95% confidence interval [CI], 4.8 to 8.0 months), and median progression-free survival (PFS) was 2.7 months (95% CI, 2.1 to 3.4 months). In a multivariate analysis of PFS, a 3435 CC polymorphism (n=45) was significantly associated with longer PFS compared with the CT/TT type polymorphism (n=55), with borderline significance (PFS of 3.2 months vs. 2.2 months, respectively; HR 1.50; 95% CI, 0.98-2.30; P = 0.061). ABCB1 3435 C>T polymorphisms were not associated with OS. No interaction was seen between ABCB1 polymorphisms and treatment regimens. CONCLUSION: Genetic polymorphisms of ABCB1 3435C>T might have a possible impact on clinical outcomes of second-line chemotherapy in AGC. Further prospective evaluation using a larger sample size is required. PMID- 20843133 TI - Beliefs of Turkish female teaching staff regarding mammography scanning. AB - BACKGROUND: To our knowledge, there has hitherto been no research to determine the beliefs of female teaching staff, who are highly educated and form a special risk group regarding breast cancer, towards mammography scanning in Turkey. Definitive research was planned to determine the beliefs of the female teaching staff working in a university. METHODS: Data were collected by researchers via face-to-face interview using a sociodemographic questionnaire and " Health Belief Model ". RESULTS: The point average of the teaching staff in the mammography benefits sub-scale is 19.6 +/- 3.87, their average item score is 3.91. The point average of the teaching staff in the mammography obstacles sub-scale is 21.17 +/- 6.87, their average item score is 1.92. CONCLUSIONS: They agree on the benefits of the mammography, but they do not agree on the obstacles to mammography. PMID- 20843134 TI - Association of the GSTP1 gene (Ile105Val) polymorphism with chronic myeloid leukemia. AB - The GSTP1 enzyme plays a key role in biotransformation and bioactivation of certain environmental pollutants such as benzo[a]pyrene-7, 8-diol-9,10-epoxide (BPDE) and other diol epoxides of polycyclic aromatic hydrocarbons. It catalyses the detoxification of base propanols that arise from DNA oxidation thus offering cellular protection against oxidative stress. A single nucleotide polymorphism at codon 105 results in the substitution of isoleucine (Ile) to valine (Val) causing a metabolically less active variant of the enzyme. We here assessed the impact of the GSTP1 codon 105 polymorphism in chronic myeloid leukemia (CML) development and therapy response. The Ile105Val polymorphism was analyzed using a PCR-RFLP technique. Two hundred and sixty patients with CML and 248 healthy, age and sex matched controls were included in the study of associations with patient characteristics and treatment outcome. The GSTP1 Ile105Val polymorphism was significantly associated with CML development (?2 = 9.57; df = 2; p = 0.0084). With respect to clinical phase, CML patients in advanced phase (accelerated and blast crisis) had higher frequency of heterozygous (Ile/Val) genotype (47.62%) compared to chronic phase (36.5%). Further 54.5% of patients in blast crisis carried valine allele as compared to those in chronic phase (36.5%). The frequency of combined genotypes (Ile/Val, Val/Val) was elevated in cytogenetic poor (41.6%) and minor (53.57%) responders as compared to major (38.51%) responders. Hence the present study suggests that GSTP1 Ile105Val polymorphism with reduced GSTP1 enzyme activity might influence CML development, progression and response rates. PMID- 20843135 TI - Cisplatin combination chemotherapy induces oxidative stress in advance non small cell lung cancer patients. AB - BACKGROUND: This study determine oxidative stress and survival prospectively in advanced stage non small cell lung cancer (NSCLC) patients following cisplatin based combination chemotherapy. MATERIALS AND METHODS: The oxidative stress levels (LPO, NO, GSH and SOD) of 144 control subjects and 203 advanced stage (IIIA/IIIB/IV) newly diagnosed NSCLC patients were assessed at pre-treatment (day '0'), and after the 3rd and 6th cycles of chemotherapy. Groups were compared by repeated measures ANOVA while comparison of survival curves was conduced by Kaplan-Meier methods. RESULTS: The pre-treatment mean levels of LPO and NO in patients were significantly (P<0.01) higher while GSH and SOD were significantly (P<0.01) lower as compared to control. The oxidative stress was elevated more significantly (P<0.01) after the chemotherapy and was more evident in higher stage than lower stage patients. The two year overall survival (%) of stage IV patients was significantly lower (P<0.05) as compared to stage III A and III B. The proportional mortality was also maximal in stage IV patients (37.0%) followed by stage III B (31.7%) and III A (20.0%). CONCLUSION: Cisplatin based combination chemotherapy induces oxidative stress in NSCLC patients. PMID- 20843136 TI - Prevalence of prostate cancer among men aged 40+ living in Osman Gazi health care district. AB - BACKGROUND: Prostate cancer is a risk for men aged 40+ even if it is rarely seen among men under the age of 50. It is asymptomatic disease in its early period and if the person does not have an enlarged prostate it will be overlooked without screening. Consequently, the only way to diagnose prostate cancer in its early period is to determine the serum PSA (prostate-specific antigen) level of men aged 40+ and to do a digital rectal examination (DRE). OBJECTIVE: The aim of this study is to determine the prevalence of prostate cancer among men aged 40+, to mention the significance of DRE and PSA by means of a training to be done with the aid of a booklet about early diagnosis, and to encourage men to consult a doctor and get the right treatment at the right time. METHODS: The research was a descriptive field study. carried out among 660 men aged 40+ out of 3,285 men who live in Osman Gazi Health Care District, connected with the Presidency of Training and Research Health Group of Bornova. This group was selected as the smallest sample size by the systematic sampling method within the frame of setting the prevalence of prostate cancer at 10%, the confidence interval as 95%, the standard error as 2%. A total of 264 men of the sample group (participation rate 40%) agreed to a survey of International Prostate Symptom Score (I-PSS) projected by the study, and underwent DRE and PSA with a blood sample. RESULTS: Increase in the serum PSA level (4 ng/mL<) was determined in 10 men. Nodules were detected in 3 men together with the increase in PSA. One further nodule was detected only in DRE one examination of 12 participants. In the light of these data, it was decided to conduct a biopsy on 25 people, who had an increase in PSE and/or whose abnormalities were detected during DRE, in company with TRUS, and prostate cancer was detected in the biopsies of 5 people (1.89%). CONCLUSIONS: It can be thought that before a decision is made on routinizing prostate cancer screening, it may be more suitable to make randomized controlled screening trials for prostate cancer. PMID- 20843137 TI - Immunological profile of arsenic toxicity: a hint towards arsenic-induced carcinogenesis. AB - Arsenic (a Group I carcinogen in humans) contamination and poisoning of human populations in different parts of Southeast and Eastern Asia, including West Bengal and Bangladesh, has become a major environmental concern. Arsenic intoxication affects diverse human organs including the lungs, liver, skin, bladder and kidney. This metalloid acts as a promoter of carcinogenesis, exerting toxic effects on the immune system. The present study was aimed at investigating arsenic-induced carcinogenesis and effects on the immune system in an animal model. Tumors were induced using ethylnitrosourea (ENU) and arsenic was used as a promoter. To investigate specific effects on the immune system, cytokine (TNF alpha, IFNgamma, IL4, IL6, IL10, IL12) production of lymphocytes was evaluated by FACS. The damaging consequences of treatment were assessed by evaluating the specific programmed cell death cascade in lymphocytes, assessed by FACS readings. The results revealed that under arsenic influence, and more so with arsenic+ENU, marked neoplastic changes were noted, which were corroborated with histological changes, cytokine modulation and apoptosis hinted at marked neoplastic changes. PMID- 20843138 TI - High dose rate cobalt-60 afterloading intracavitary therapy of uterine cervical carcinomas in Srinagarind hospital - analysis of complications. AB - OBJECTIVES: To evaluate complications in uterine cervical cancer patients treated with teletherapy combined with high dose rate(HDR) cobalt-60 brachytherapy. MATERIALS AND METHODS: A retrospective study of uterine cervical cancer patients, stages IB-IVB (International Federation of Gynecologists and Obstetricians recommendations), treated by radiotherapy alone between April 1986 and December 1988 was conducted. The patients received teletherapy 50 Gy / 25 fractions, five fractions per week to the whole pelvis together with HDR Cobalt -60 afterloading brachytherapy of 850 cGy/ fraction weekly to point A for 2 fractions. RESULTS: The study subjects were 141 patients with uterine cervical cancer. The mean age was 49 years with a range of 30-78. The mean tumor size was 4.1 cms in diameter (range 1-8 cms ). Mean follow-up time was 2.9 years (range 1 month - 6.9 years). The treatments resulted in a 96.5% complete response rates but morbidity rates of grade 1 and grade 2 radiation proctitis of 27.0%, and 10.6 %. The grade 1 and grade 2 radiation cystitis were 1.4%, and 1.4 %. At the level of grade 3 radiation complications, 0.71% of radiation proctitis and 0.71% small bowel obstruction were observed. The mean onset time to develop radiation proctitis after complete treatment was 15 months with a range of 6-61 months, for radiation cystitis was 30 months (range 9 - 47 months) and for small bowel obstruction was 53 months in the one case it occurred. CONCLUSION: Combined teletherapy along with high dose rate Cobalt -60 brachytherapy of 850 cGy/ fraction, weekly to point A for 2 fractions for uterine cancer demonstrated a slightly higher incidence of grade 2 radiation proctitis. Therefore, treatment using HDR-60 brachytherapy less than 850 cGy per fractionation for decreasing the grade 2 and grade 3 radiation morbidity is recommended. PMID- 20843139 TI - Determination of the anxiety level of women who present for mammography. AB - OBJECTIVE: This paper was to examine the role of anxiety in mammography screening. Breast cancer screening with mammography has been shown to be effective for preventing breast cancer death. However mammography screening can be harmful to women. One of the major problems is anxiety or lack of peace of mind in mammography screening. METHODOLOGY: This study was conducted between November 3, 2007, and December 30, 2007, in Ordu Maternity and Childbirth Hospital. 93 women participated in the study. A 23-item questionnaire and the 20 item State Anxiety Inventory, developed by Spielberger et al. were completed by the participants. All numerical values were given as average +/- standard deviation; p<0.05 was accepted for level of significance. RESULTS: The average age of the participants was 47.83 +/- 7.50, the average age at marriage was 20.03 +/- 4.18, the average birth number 2.91 +/- 1.21, and the average age at menopause was 46.10 +/- 4.70. The average anxiety level was found to be 46.20 +/- 4.9. Significant differences (p<0.05) were found between education level, age at marriage, status of doing breast self examination, status of having a mammography for a breast-related complaint, and the number of mammograms done. CONCLUSION: It was determined that women who had mammography had a moderate level of anxiety. PMID- 20843140 TI - Recurrence patterns after radical hysterectomy in stage IB1-IIA cervical. AB - OBJECTIVES: The purpose of this study was to evaluate the patterns of recurrence and its associated factors in stage IB1-IIA cervical cancer cases after radical hysterectomy. METHODS: We retrospectively reviewed the 655 medical records of patients with cervical cancer who underwent radical surgery at Chiang Mai University Hospital between January 2003 and December 2006. All patients had a type III radical hysterectomy and complete systematic bilateral pelvic lymphadenectomy. Post-operative adjuvant pelvic radiation therapy was given concurrently with weekly cisplatin 40 mg/m2 for 6 cycles to patients with at least one major risk or two intermediate-risk factors. Sites of disease recurrence, time to relapse of disease, and postoperative overall survival were analyzed and all possible clinicopathological factors related to the risk of recurrence were determined. RESULTS: The median time to recurrence was 11.5 months (range, 2-45 months). There was no significant differences in the mean time to recurrence between local and distant recurrence groups (14.6 +/- 3.9 months vs. 16.2 +/- 5.3 months; p=0.632). The 3-year survival rates of patients with local and distant recurrences were 67.6% (95%CI=45.6 to 89.6%) and 39.8% (95%CI=11.8 to 67.8%), respectively (p=0.602). Tumor size was the only clinicopathological prognostic factor associated with overall survival. CONCLUSION: Patients with stage IB1-IIA cervical cancer should have close surveillance during the first two years of radical surgery. Tumor size of greater than 2 cm at the time of primary surgery appears to be significantly related to the prognosis of patients with recurrence. With an understanding of the natural history of cervical cancer recurrence, an optimal method of follow-up and prospective clinical trial for markers of metastatic potential to detect recurrence need to be conducted in the future. PMID- 20843141 TI - Clinical characteristics of renal cancer in Malaysia : a ten year review. AB - Renal cancer is rare and its incidence is 1.9 per 100,000 in the Malaysian population, which consists of three major ethnic groups (Malay, Chinese and Indians). A retrospective study was her conducted to identify clinical characteristics and ethnic background influences on presentation. The study included all renal cancer patients from a single medical institution over ten years, with a total of 75 cases. Seventy-three patients underwent surgery while 2 received only radiotherapy or chemotherapy. The male to female ratio was 2.75:1. Incidence was equal among the Malay (49.3%) and Chinese ethnic groups (45.3%). Mean age of patients were 57.1 (18-93) years old. There were 26 (37.4%) patients with Stage I disease, 14 (18.7%) at Stage II, 23 (30.7%) at Stage III and 12 (16%) at Stage IV. The Chinese race presented at mean older age (p= 0.02) and later stage of disease (p= 0.046). Patients above 40 years old had more advanced stage disease (p= 0.023). Tumour histology were clear cell (72%), urothelial cell (13.3%), sarcomatoid cell and nephroblastoma each contributed 2.7%. The mean tumour size was 8.1 (2-20) cm. There was substantial agreement between the pre and post operative staging (kappa 0.691). In conclusion we observed significant influences of age and race in the clinical presentation of renal cancer in our institution based population. There was larger male to female ratio and mean tumour size as compared to previous epidemiology studies. PMID- 20843142 TI - Five years cancer incidence in Aden Cancer Registry, Yemen (2002-2006). AB - The population-based Aden Cancer Registry (ACR) started its activities in 1997. The objective of the registry is to establish a reliable magnitude of cancer in the area covered and the first report was published in 2003. The present article describes data from the second report of cancer incidence over a five year period (2002-2006). Internationally accepted standardized cancer registration methodologies described by IACR and IARC were used. CanReg-4 using ICDO-3 and ICD 10 were applied in the data processing and analysis. Results showed no difference in the overall incidence between the males and females (ratio was 0.83:1) and age standardized rate s(ASR) per 100,000 inhabitants were 30.2 and 31.1. The five most common cancers were breast cancer, leukemia, non-Hodgkin's lymphomas (NH lymphoma), brain cancer and Hodgkin's disease (16.6%, 12.6%, 7.8%, 5.2% and 4.4%, respectively). Among males, leukemia was the first followed by NH lymphoma, Hodgkin's disease, brain and liver. In females, breast was the first, then leukemia, NH lymphoma, thyroid and brain cancer. The highest ASR for males (145 per 100,00 inhabitants) was observed at age 70-74 years whereas for females, two peaks (each 105 per 100,000 inhabitants) were equally noticed at age 60-64 and 70 74 years. Generally, females showed equal or higher incidence compared to males until age 55-59 where males reported higher incidence. The overall pattern of cancer incidence in this report is not much different from that in the previous report. Furthermore, the report generally indicates that the pattern of the most common registered cancer bears some similarities with the adjacent Gulf Cooperation Council States with which we share many characteristics, despite differences that warrant further investigation. PMID- 20843143 TI - Relations between radiotherapy resources and breast cancer patient survival rates. AB - In Japan, the number of patients that have been treated with radiotherapy (RT), particularly those with breast cancer, has increased in the past decade, and is expected to double in the next decade. There is, however, a shortage of RT resources, particularly personnel, which represents a social problem. The shortage of RT resources might cause a difference in survival rate among treated patients. This study analyzed the characteristics of RT resources in RT facilities from Osaka based on the Japanese Society for Therapeutic Radiology and Oncology (JASTRO) database with principle component analysis and cluster analysis. In addition, the relation between RT resources and treatment outcome of breast cancer patients was investigated by linking together Osaka Cancer Registry (OCR) and JASTRO data via a stratified key cord. By using the linked dataset it was shown that the prognosis of breast cancer patients was highly correlated with the scale of RT resources available at the RT facilities collaterally. From cluster analysis, four groups were identified based on RT facility information. The breast cancer survival rates for localized stage patients obtained in classified hospital groups showed a similar pattern, however, large differences (up to 20%) were seen in regional stage patients. Additional findings were: RT facilities with less than 1 radiation oncologist had the poorest outcome; RT was performed primarily at University hospitals; and differences in RT resources within the RT facilities had an effect on breast cancer patient prognosis in Osaka, Japan. PMID- 20843144 TI - Nutrient patterns and risk of breast cancer in Uruguay. AB - OBJECTIVES: To explore the role of nutrient patterns in the etiology of breast cancer (BC) among Uruguayan women. METHODS: A principal component analysis was conducted. The study included 442 newly diagnosed cases of BC and 442 hospitalized controls. RESULTS: Two dietary patterns derived from factor analysis and were labeled as high-meat and antioxidants patterns. Whereas the high-meat pattern was directly associated with BC risk (OR for the highest versus the lowest quartile = 3.50, 95 % CI 1.94-6.30, p-value for trend <0.0001), the antioxidants pattern displayed a protective effect (OR=0.44, 95 % CI 0.27-0.74). Its negative association was stronger for postmenopausal than for premenopausal women (OR=0.63, 95% CI 0.51-0.79 vs. OR=0.89, 95% CI 0.50-1.56, respectively). Both strata were heterogeneous (p=0.004). The high-meat pattern was more associated with BC risk among patients with family history of BC compared with participants without it, but results did not differ by histology. In contrast, the antioxidants pattern was more associated with non-ductal cancers (OR=0.50 [95 % CI 0.35-0.69]) than with ductal cancers (OR=0.72, 95 % CI 0.58-0.88, heterogeneity p-value=0.03). CONCLUSIONS: Results support an association between the high-meat and antioxidant dietary patterns and BC risk. Furthermore, findings suggest that gene-environmental interactions may be important in BC etiology. PMID- 20843145 TI - Cognitive and dynamic effects of training given to women at risk of breast cancer. AB - BACKGROUND: Breast cancer is an important public health problem. Although the disease is widespread, the prognosis is good, especially with early diagnosis. For this to occur, a consciousness of protection of breast health for all women is necessary, and risk groups need to be particularly targeted. AIM: This study was conducted to determine dynamic and cognitive effects of training given to women in a risk group. METHOD: This study that is planned as an intervention study has been carried out in a city that is on the eastern part of Turkey between February and June in 2009. The data were gathered through a question form aimed at diagnosing the knowledge and applications of women about breast cancer, and hospital reports of women and control lists of BSE skills. The women in the risk group were given five sessions of training split into groups of 12-13 persons. For the purpose of realizing the cognitive effects of the training, pre test and post test measures were assessed. The data were evaluated using number percentages and the McNemar test. RESULTS: At the end of the training program, compared to previous training period, women's knowledge, at the cognitive level, related with the risk factors, symptoms and the early diagnosis methods of the breast cancer was seen to have been expressively increased. As for effects at the dynamic level, one month after the training program had been completed, women re evaluated and 77.5% had conducted breast self-examination (BSE) at least one time, and 65.0% of them have passed through medical breast diagnosis and scanning tests by applying to hospital. CONCLUSION: In a study aimed to increase the conscious level and awareness related with breast health in women, variation at both cognitive and dynamic levels were evident at the end of the training program. PMID- 20843146 TI - Determining of prognostic factors in gastric cancer patients using artificial neural networks. AB - BACKGROUND AND OBJECTIVES: The aim of this study is to determine diagnostic factors for Iranian gastric cancer patients and their importance using artificial neural network and Weibull regression models. METHODS: This study was a historical cohort study with data gathered from 436 registered gastric cancer patients who underwent surgery between 2002 and 2007 at the Taleghani Hospital (a referral center for gastrointestinal cancers), Tehran, Iran. In order to determine risk factors and their importance, neural network and Weibull regression models were used. RESULTS: The Weibull regression analysis showed that lymph node metastasis and histopathology of tumor were selected as important variables. Based on the neural network model, staging, lymph node metastasis, histopathology of tumor, metastasis, and age at diagnosis were selected as important variables. The true prediction of neural network was 82.6%, and for the Weibull regression model, 75.7%. CONCLUSION: The present study showed that the neural network model is a more powerful tool in determining the important variables for gastric cancer patients compared to Weibull regression model. Therefore, this model is recommended for determining of risk factors of such patients. PMID- 20843148 TI - Insights into pictorial health warnings on tobacco product packages marketed in Uttar Pradesh, India. AB - BACKGROUND: The Government of India issued an undertaking in the Supreme Court mandating pictorial health warnings (PHWs) on packages of tobacco products from 31st May, 2009 under " Cigarettes and Other Tobacco Products Act " (COTPA) guidelines. This constitutes a key economic channel for educating people on devastating health impacts of deadly products within in a vivid and memorable way. Few studies have investigated PHWs on tobacco products marketed in India. OBJECTIVES: To assess met guidelines for pictorial health warnings under packaging and labeling rules on packages of collected tobacco products specified by COTPA. MATERIALS AND METHODS: Snowball/network sampling design was followed to obtain samples of 37 different tobacco brands, 18 in smoking form (12 cigarette, 6 bidi brands) and 19 in smokeless form (4 chewing tobacco, 11 Gutkha and 4 Khaini brands) marketed at retail outlets at Muradnagar. They were analyzed for their compliance with guidelines through checklist by one calibrated examiner. RESULTS: PHWs were absent on packages of 5 tobacco brands. Fifteen tobacco brands had PHWs smaller than stipulated 40% of principal display area; 6 brands of bidis had PHWs on deceptive backgrounds, 3 of which were placed on a curved axis. Misleading descriptors and promotional messages were also present. CONCLUSION: Locally marketed tobacco products were not compliant with packaging and labeling rules specified by COTPA. This highlights the need for more stringent implementation of COTPA guidelines to combat the ever-growing tobacco menace. PMID- 20843147 TI - Evaluation of cervical cancer risk-factors in women referred to Yazd-Iran hospitals from 2002 to 2009. AB - BACKGROUND: Although cervical cancer is a preventable disease, its prevalence is increasing in many developing countries. The aim of this study was to evaluate risk factors. MATERIALS AND METHODS: This cross-sectional study was conducted on 100 cervical cancer cases according to their pathology reports in Yazd city. The patients were referred to 4 gynecological centers. Demographic data (age, age at marriage, number of marriages and spouses, age at first pregnancy, frequency of pregnancies and term labors, positive history of smoking and Pap smear findings were documented by interview, questionnaire and reviewing patients documents. The data were analyzed with SPSS software. RESULTS: Mean age of the patients was 53.6 years. Mean age of marriage and first pregnancy was 15.2 and 16.6; respectively. Twenty percent (20%) of the cases married more than once and husbands of 38 patients (38%) had another wife too. Frequency of pregnancies and term labors was 7.4 and 6.4 in our patients. Some 17% of the patients had history of smoking; while 53% of them were passive smokers. Also only 2% of our patients have done Pap smear before diagnosis. DISCUSSION: The important risk factors of patients with cervical cancer were as follows: Marriage at young age (15.2%), high mean parity (7.4), low mean age at first pregnancy (16.2 year), smoking, and not doing Pap smear. CONCLUSION: There is important association between mass screening program with Pap smear and decreasing cervical cancer. Thus we should increase our women knowledge about all of risk-factors of cervical cancer and get them clues about regular pap smears. PMID- 20843149 TI - Anti-carcinogenic potentials of a plant extract (Hydrastis canadensis): I. Evidence from in vivo studies in mice (Mus musculus). AB - Ethanolic extract of Hydrastis canadensis has been tested for its possible anti cancer potentials against p-dimethylaminoazobenzene (p-DAB) induced hepatocarcinogenesis in mice. Mice were chronically fed p-dimethylaminoazobenzene (p-DAB) and phenobarbital (PB), two hepato-carcinogens for 1, 2, 3 and 4 months, respectively, and were divided into sub-groups: i) fed normal low protein diet (Gr. I, normal control); ii) fed diet mixed with 0.06% p-DAB at a daily dose of 165 mg/kg b.w. per mouse plus 0.05% PB plus 0.06 ml 90% alcohol (vehicle of the crude extract) (Gr. II, carcinogen treated); iii) fed diet mixed with p-DAB and PB at the same daily dose plus crude extract of Hydrastis canadensis (Gr. III, drug treated). Several biochemical parameters like acid and alkaline phosphatases, alanine amino-, aspartate amino-, and gamma glutamyl-transferases, lipid peroxidation, reduced glutathione content, lactate dehydrogenase, catalase and glucose-6-phosphate dehydrogenase activities and electron microscopy of liver in different groups of treated and control mice were studied. A critical analysis of results of these studies suggested anti-cancer potentials of the drug suitable for use as a supportive complementary medicine in liver cancer. PMID- 20843150 TI - Clinical observations on safety of fixed dose rate gemcitabine chemotherapy by intravenous infusion. AB - PURPOSE: To observe the safety of fixed dose rate gemcitabine by intravenous infusion (iv-FDR) for cancers. METHODS: From January 1, 2007 to December 31, 2009, four patients who were pathologically diagnosed with advanced pancreatic or breast cancer were recruited into this study. They were treated by gemcitabine 10mg/m2/min iv-FDR on days 1 and 8, and combined with other chemotherapeutics, repeated every four weeks. Toxicity was determined in line with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC). RESULTS: The main toxicity was reversible myelosuppression; other side effects included gastrointestinal toxicity and liver impairment. Cardiac or renal toxicity was not detected. CONCLUSION: The toxicity of iv-FDR gemcitabine combination chemotherapy was well tolerated, so that iv-FDR gemcitabine deserves to be further studied as a treatment option. PMID- 20843151 TI - Clinical and pathology characteristics of colorectal polyps in Iranian population. AB - BACKGROUND AND AIM: Colon polyps are important lesions and a concern because of the potential for colorectal cancer, one of the most common causes of cancer related deaths in Iran. The distribution of polyps in the colon may affect the efficacy of screening modalities. The aim of this study was to determine clinical and pathology characteristics of colorectal polyps in the Iranian population. METHODS: This cross sectional survey covered 856 polypectomies in 716 patients, with anatomical distribution, size and histopathology of the polyps described in 2004-2009 in the educational hospital of Taleghani in Tehran. RESULTS: Polyps were observed in 437 males and 279 females. The distribution was 3.12 percent located in the rectum, 19.6 percent in the sigmoid colon, 24.4 percent in the descending colon, 13.9 percent in the transverse colon, and 29.6 percent in the cecum and ascending colon. Some 77(9%) were non-neoplastic and 779 (91%) were neoplastic. Adenomas were present in 727 (85%) cases, of these 411 (56%) were left-sided and 316 (44% ) were right-sided. Carcinoma was observed in 52 cases, 18(34.5%) being left sided and 34(65.5% of carcinomas) right sided. Of the total, 354 were advance polyp (>1cm, villous type, high grade dysplasia), 87(34%) being found in patients under 50 years of age and 149 (58.6 %) being right sided. CONCLUSION: This study showed a significant number of adenomas and carcinomas to lie proximal to the splenic flexure. Thus, it is expected that examination of the colon limited to the splenic flexure would miss 44% of such lesions. The increasing right-sided prevalence of these lesions with age suggests that evaluation of the proximal bowel is particularly important in older people. In addition there were higher stages of dysplasia and malignancy in larger polyps. PMID- 20843152 TI - Evaluation of preventing chemotherapy induced oral mucositis project in patients with cancer of the female reproductive system at Maharaj Nakorn Chiang Mai Hospital, Thailand. AB - Oral mucositis is an important and common complication among female patients who have cancer of the reproductive system receiving chemotherapy. This study aimed to evaluate the prevention of chemotherapy-induced oral mucositis project in female reproductive system cancer patients at Maharaj Nakorn Chiang Mai Hospital. The clinical practice guidelines evaluation model of the Registered Nurses Association of Ontario (RNAO, 2002) was used as a framework. The subjects included 14 nurses and practical nurses, and 404 patient reports. Data were collected by using of two forms developed by the researcher; the nurses' opinion form about the project's implementation and a mucositis form. Data analysis was conducted using frequency, percentage, and mean. The findings showed that 92.9 % of the subjects reported that they could consistently follow the clinical practice guidelines. All of them (100.00 %) agreed that the clinical practice guidelines were easily to follow, convenient to use, had good outcome, reduced nursing time, and were satisfied with this project. After the project's implementation, it was found that mucositis was reduced from 22.0 % to 9.9 %. The results of this study confirm that with the prevention chemotherapy-induced oral mucositis project for female reproductive system cancer patients, care is more efficient. These results could be extended for use in other similar settings. PMID- 20843153 TI - Prevention of post-mole malignant trophoblastic disease with vitamin A. AB - OBJECTIVE: Around 15-28% of hydatidiform mole patients suffer from malignant degeneration following evacuation. Since retinoic acid can control cell proliferation and stimulate apoptosis, vitamin A could be used as a therapy for preventing such malignant transformation. The objective of this study was to demonstrate the use of vitamin A as a chemoprevention following hydatidiform mole development. MATERIALS AND METHODS: The study made use of a randomized clinical trial, double blind protocol. Subjects were patients with complete hydatidiform moles, not receiving cytostatics. The intervention was administration of placebo or vitamin A at 200,000 IU per day, performed until the patients were declared as having recovered or having malignant trophoblastic disease (MTD). The outcome variables were the incidence of regression and MTD, established based on WHO criteria. RESULTS: At clinical trial as many as 67 cases met the requirements for the study. Two cases were lost from observation and three experienced pregnancy. The incidence rate of malignant trophoblastic disease in the control group was 28.6%, and in the therapy group was 6.3%. No difference was found in the changes of SGOT and SGPT levels of the therapy group compared with the control group. CONCLUSION: The rate of malignant trophoblastic disease (MTD) was reduced in the group receiving vitamin A therapy. PMID- 20843154 TI - Helicobacter pylori screening to prevent gastric cancer: an economical analysis for a tropical developing country. AB - Gastric cancer is an important gastrointestinal carcinoma. Presently, it is accepted that the strongest etiological relationship is with Helicobacter pylori infection. Screening for the bacterium thus becomes an issue for discussion in gastric cancer prevention. Here, the author covers the use of H. pylori screening as a strategy based on an economical analysis in the scenario of a tropical developing country. PMID- 20843155 TI - Cost and financing issues limit access to the HPV vaccine. AB - Cervical cancer is a leading cause of death from cancer among women in low resource settings, affecting women at a time of life when they are critical to social and economic stability. Every year, about 500,000 women worldwide are diagnosed with cervical cancer and more than 250,000 die from the disease. It is the leading cancer in women in half the countries of the world and mostly affects relatively young poor women. But the vaccine cost is too high. With the availability of cost-effective, safe vaccine, there is real hope for reducing the global burden of cervical cancer. PMID- 20843156 TI - Point of care testing: can it be a solution for cervical cancer prevention? AB - In several Asian countries, such as Thailand, cervical cancer is the most common female malignancy. Early detection of cervical cancer by pap smear screening test is the classical method but there are problems with this, especially for loss of the following up.Therefore the feasibility of new alternative usage of point of care testing that might be a useful tool for cervical cancer prevention needs to be stressed. PMID- 20843157 TI - Effective management of pain in pediatric hematology and oncology. AB - In the last several decades, there have been major advances in the treatment of pediatric cancers. 5 year survival of children with acute lymphoblastic leukemia has increased from 25% to 80%. Early stages of non -Hodgkin's, Hodgkin's and Wilms tumors all have more than 90% long term survival. In addition to improving survival, the comprehensive care of children with cancer must offer total care including special emphasis on pain management and psychosocial support by a multidisciplinary team. Pain considerations in children are unique and differ from those in adults. For example, bone pain is often one of the presenting symptoms of leukemia in children, but can be mistaken for growing pain or labeled psychological. Bone pain is also a prominent symptom in late stage neuroblastoma, and of course in bone tumors. The American Medical Association and National Cancer Institute promote the absence of pain as a patient right and a marker of good clinical care and a quality of care issue. Pain due to disease burden responds dramatically to chemotherapy and the uninitiated are often surprised by the sudden increase in activity and playfulness of children undergoing induction chemotherapy. History and physical data, with special assessment of pain should be part of the medical record of all children. PMID- 20843158 TI - Breast cancer : True story of a doctor from India. PMID- 20843159 TI - Quality of care for hypertensive patients with type 2 diabetes in a rural area of Southern Italy: is the recording of patient data and the achievement of quality indicators targets satisfactory? AB - INTRODUCTION: Type 2 diabetes mellitus and hypertension are commonly associated chronic conditions which require regular structured treatment. In the UK many quality markers have been improved through an incentivisation scheme. The aim of this study was to discover if there is potential for improving the quality of care for patients with type 2 diabetes and hypertension in rural Italy, through a quality and outcome incentivisation scheme. METHODS: The study was conducted in a rural practice context in Southern Italy and seven family doctors were involved. The main outcome measures were glycated haemoglobin A1c (HbA1c), LDL cholesterol, and systolic and diastolic blood pressure. The patient characteristics examined were age, sex, educational level, behaviour-related factors such as smoking and BMI, and the presence of comorbidities. RESULTS: A poor level of registration was found for important variables such as HBA1c (61.4% compared with the UK Quality Indicator of 90%). An adequate level of registration and control was found only for blood pressure (95.7% and 82.1%, respectively), while an acceptable but not optimal level of control for HBA1c was also achieved (88.4% &#8804;10%). In comparison with levels in UK practices, the Italian district studied performed much less favorably, especially regarding process indicators. Intermediate outcome and treatment indicators were slightly better for blood pressure control but slightly worse for HBA1c and cholesterol control. CONCLUSION: The data confirm a poor registration level for important healthcare indicators in the study area, and that optimal levels are rarely reached for many quality indicators. A quality and outcome incentivisation scheme similar to the UK Quality and Outcomes Framework may offer a tool for achieving improvements. PMID- 20843160 TI - Effect of medium composition and light on root and rhinacanthin formation in Rhinacanthus nasutus cultures. AB - Rhinacanthus nasutus (L.) Kurz (Acanthaceae) has long been used in Thai traditional medicine for treatment of tinea versicolor, ringworm, pruritic rash, and abscess. The active constituents are known as a group of naphthoquinone esters, rhinacanthins. This work focused on establishment of R. nasutus root cultures and determination of rhinacanthin production. Induction of R. nasutus root formation was accomplished on solid Gamborg's B5 (B5) medium, supplied with 0.1 mg/L indole-3-butyric acid (IBA) and 20 g/L sucrose. The effects of explants (whole leaf explants and four-side excised leaf explants), light and medium composition on root and rhinacanthin formation were investigated. The root formation from the whole leaf explants was 10 times higher than that from the four-side excised leaf explants. In addition, light possessed an inhibitory effect on the root and rhinacanthin formation of R. nasutus. Medium manipulation found that Murashige and Skoog (MS) medium supplied with 3 mg/L IBA and 30 g/L sucrose was the most suitable for induction of the root formation. Unfortunately, the obtained root cultures produced only rhinacanthin-C in very low amount, 0.026 mg/g dry weight (DW), when they were transferred into the same MS liquid medium. With semisolid medium (4 g/L agar) of the same MS composition, however, the root cultures appeared to produce higher content of rhinacanthin-C, -D and -N (3.45, 0.07 and 0.07 mg/g DW, respectively). Our finding suggests that culturing in semisolid medium is capable of improving of rhinacanthin production in R. nasutus root cultures. PMID- 20843161 TI - Immunomodulatory activity of petroleum ether extract of Anacyclus pyrethrum. AB - CONTEXT: Anacyclus pyrethrum DC (Compositae) roots, commonly known as Pellitory root and locally as akarkara, are widely recognized in the Indian traditional systems of medicine, Ayurveda, as a 'rasayana', i.e. a plant with immunomodulatory properties. OBJECTIVE: Evaluation of A. pyrethrum extract for its effect on normal and chemically suppressed immune systems in vivo. MATERIALS: Petroleum ether extract (PEE) of roots was tested at 50 and 100 mg/kg dose. The effect of both doses on total and differential leukocyte count, cyclophosphamide induced immunosuppression, survival rate against Candida albicans infection, delayed type hypersensitivity reaction, percentage neutrophil adhesion, and phagocytic activity were tested. RESULTS: The PEE-treated rats were able to overcome cyclophosphamide-induced myelo-suppression as evidenced by the normalization of blood parameters. Survival rate of albino rats was improved in Candida albicans-infected animals by treatment with the extract (p <0.05). An increase in delayed type hypersensitivity response (DTH), percentage neutrophil adhesion, and in vivo phagocytosis by carbon clearance method was observed after treatment. Extract administration also increased the HA titer value and IgG antibodies. DISCUSSION: Immunostimulant activity increased two-fold upon doubling the dosage of extract administered. While a significant (p <0.05) improvement was observed in the humoral component, a highly significant (p <0.01) effect was observed in the cellular components of the immunity evaluated. The results thus provide a basis for the use of A. pyrethrum as an adaptogen and immunomodulator in the Ayurvedic system of medicine. PMID- 20843162 TI - Association of HLA Class II alleles and haplotypes with cervical dystonia: HLA DR13-DQ6 (DQB1*0604) homozygotes are at greatly increased risk of cervical dystonia in Caucasian Americans. AB - An unanticipated discovery was made while examining genetics of the immune response in patients treated with botulinum neurotoxin (BoNT), which included cervical dystonia (CD) patients. Initial examination of HLA DQA1:DQB1 frequencies revealed an unexpectedly high number of DQA1*0102:DQB1*0604 homozygotes (hz) in the CD patients. We typed the BoNT-treated CD Caucasian subset for HLA-DRB1, DQA1, and DQB1 and succeeded in typing HLA-DRB1, -DQA1, and -DQB1 for 75 of the patients. Two statistical methods found the DQB1 locus associated with CD and one method found a probable association of DQB1*0604. Examination of the allele and haplotype pairing indicated that DQB1*0604 hz comprised most to all of the positive association. Other than this genotype, one other allele, DQB1*0504 contributes to the association of the DQB1 locus. These findings indicate a probable infectious and/or autoimmune component in some CD patients. However, longer distance associations within an extended and conserved DQB1*0604 bearing haplotype leave a possibility that a locus proximal to DQB1 might be involved. PMID- 20843163 TI - Ezetimibe in diabetes: more than cholesterol lowering? AB - Ezetimibe, an inhibitor of cholesterol intestinal absorption, is a lipid lowering agent with potential pleiotropic actions. Ezetimibe in combination with a statin is effective in decreasing low density lipoprotein cholesterol(LDL-C), lowering triglyceride and raising high density lipoprotein cholesterol levels. Ezetimibe plus statin achieve LDL-C targets in a greater proportion of patients than statin monotherapy. Ezetimibe also seems to improve renal function, insulin resistance and inflammatory markers. These actions are useful in patients with diabetes. Ezetimibe is a well-tolerated and effective (in terms of achieving LDL-C targets) option inpatients with hyperlipidemia with or without diabetes. This editorial will discuss several properties of ezetimibe, with special reference to diabetes. PMID- 20843164 TI - Protective effects of Pergularia daemia roots against paracetamol and carbon tetrachloride-induced hepatotoxicity in rats. AB - CONTEXT: Pergularia daemia (Forsk) Chiov. (Asclepiadaceae) is a slender, hispid, fetid-smelling perennial climber and has been used for the treatment of inflammation, diabetes, malaria, asthma, and liver disorders. Ethnopharmacological surveys conducted among herbal practitioners of Western Ghats, Tamil Nadu, India, revealed that large numbers of laticiferous plant species are used as a source of herbal therapies, in which Pergularia daemia was commonly used to treat liver disease and jaundice. OBJECTIVE: The hepatoprotective effect of aqueous and ethanol extracts of Pergularia daemia roots by paracetamol and carbon tetrachloride (CCl(4))-induced liver damage in rats was studied. MATERIALS AND METHODS: The aqueous (PdAE) and ethanol (PdEE) extracts of Pergularia daemia were studied for their hepatoprotective effects on paracetamol and CCl(4)-induced liver damage on Wistar albino rats. The degree of protection was measured by physical changes (liver weight), biochemical (serum gultamic pyruvic transaminase, serum gultamic oxaloacetic transaminase, alkaline phosphatase, direct bilirubin, total bilirubin, cholesterol and decrease in protein), antioxidant enzymes (lipid peroxidation and glutathione levels), and histological changes. RESULTS: Pretreatment with PdAE and PdEE significantly prevented the physical, biochemical, antioxidant enzyme levels and histological changes induced by paracetamol and CCl(4) in the liver. The effects of PdAE and PdEE were comparable to that of the standard drug silymarin. The ethanol extract was found to exhibit greater hepatoprotective activity than the aqueous extract. DISCUSSION AND CONCLUSION: These results indicate that Pergularia daemia could be useful in preventing chemically induced acute liver injury. From this study it can be concluded that the aqueous and ethanol extracts of P. daemia possess significant hepatoprotective activity. PMID- 20843165 TI - Patient characteristics and utilization of breast cancer screening or diagnostic procedures prior to initiation of raloxifene, bisphosphonates and calcitonin. AB - OBJECTIVE: This study evaluated the characteristics of postmenopausal women who initiated on raloxifene, bisphosphonates, and calcitonin, specifically evaluating the use of breast cancer screening or diagnostic procedures prior to initiation of therapy. RESEARCH DESIGN AND METHODS: Women 50 years and older with at least one claim for raloxifene (RLX), bisphosphonates (BIS), or calcitonin (CT) in 2005 or 2006 and continuous enrollment (with consecutive gaps in enrollment of no more than 1 month) from January 2004 to December 2007 were identified in a large national commercial and Medicare claims database. Treatment-naive postmenopausal women initiating on raloxifene, bisphosphonates, and calcitonin were compared in terms of breast cancer screening or diagnostic procedures (i.e., mammogram, breast MRI, ultrasound, and biopsy) as well as age, provider specialty, fractures, bone mineral density screening, Chronic Disease Scores, and comorbidities. RESULTS: Treatment-naive patients initiated on raloxifene were younger than those initiated on bisphosphonates and calcitonin (mean age 63 years [RLX], 66 years [BIS], 72 years [CT]; p < 0.05). Treatment-naive patients initiated on raloxifene were more likely to have had breast cancer screening or diagnostic procedures in the 12 months prior to therapy initiation than treatment naive bisphosphonate or calcitonin patients (RLX 61%, BIS 57%, CT 41%; p < 0.05), and were more likely to have an increased frequency of mammograms in the 12 months after therapy initiation (RLX 18%, BIS 16%, CT 15%; p < 0.05). Calcitonin patients were the most likely to have had a fracture in the pre-period followed by bisphosphonates then raloxifene patients. CONCLUSION: These data suggest that there are differences in the clinical characteristics of postmenopausal women who initiate osteoporosis medications specifically in regards to age, pre-period fractures and breast cancer screening or diagnostic procedure use prior to initiation. Key limitations include general claims database limitations, lack of ability to assess behavior change, and lack of information on therapy initiation rationale. PMID- 20843166 TI - Characteristics of a capsule based dry powder inhaler for the delivery of indacaterol. AB - OBJECTIVE: To report performance characteristics and robustness of the Breezhaler device, a new capsule based dry powder inhaler (DPI) with low resistance (0.07 cm H(2)O(1/2)/L/min) facilitating high inspiratory flow rates. This device was developed to deliver the novel, inhaled once-daily ultra long-acting beta(2) agonist indacaterol, formulated as an inhalation powder in a capsule, and other investigational drugs including NVA237 and QVA149. RESEARCH DESIGN AND METHODS: Peak inspiratory flow rates via the DPI device were determined in patients with chronic obstructive pulmonary disease (COPD) using an Inhalation Profile Recorder. The flow-rate dependency of the in vitro performance (delivered dose and fine particle mass) of indacaterol in the DPI device was examined. Data on patient experience were captured throughout the indacaterol phase III registration program, and the robustness of the device was investigated after mechanical stress. RESULTS: Twenty-six patients with COPD that ranged from mild to very severe were recruited (aged 49-84 years); 25 patients were able to generate flow rates in excess of 60 L/min via the DPI device. The mean delivered dose of indacaterol (150 and 300 ug) remained within 15% of the target dose, with a consistent fine particle mass at flow rates of 50-100 L/min. In the indacaterol registration program, patients with mild to very severe COPD were able to use the device successfully, with a low device complaint rate (<0.03%) and no device failures from approximately 90,000 devices. In mechanical stress tests, drop testing resulted in, at most, only cosmetic damage, with no effect on the delivered dose. CONCLUSION: The capsule based DPI device is a low resistance device, suitable for use by patients with a wide range of COPD severities, delivering a consistent dose irrespective of disease severity and age. The device provided consistent delivery of indacaterol with no reported device failures in clinical trials. PMID- 20843167 TI - Protective effect of Clerodendron glandulosum extract against experimentally induced metabolic syndrome in rats. AB - CONTEXT: Metabolic syndrome (MetS) has become one of the major health burdens worldwide. To date, no single pharmacological agent has been developed to correct metabolic abnormalities associated with MetS. Use of indigenous medicinal plants as alternative medicines against MetS could be beneficial due to multiple therapeutic usage, easy availability, and relatively few side effects. OBJECTIVE: To investigate the protective effect of Clerodendron glandulosum Coleb. (Verbenaceae) aqueous leaf extract (CgE) against experimentally induced MetS in rats. METHODS: Changes in body weight, food and fluid intake, plasma glucose, insulin, fasting insulin resistance index (FIRI), plasma total lipid profile, free fatty acids (FFA), oral glucose tolerance test (OGTT), blood pressure and vascular reactivity have been investigated in various experimental groups. RESULTS: Fructose+CgE groups recorded significant decrement (P <0.05) in plasma glucose, insulin, FIRI, total cholesterol, triglycerides, LDL, VLDL and FFA, whereas plasma HDL level was significantly increased (P <0.05) along with an efficient clearance of glucose during OGTT and lowered area under curve values. FRU+CgE groups also showed significantly decreased (P <0.05) mean arterial blood pressure along with decreased vasoconstriction and increased vasorelaxation in response to administration of various pharmacological agents. These results were comparable with metformin treated rats. DISCUSSION: C. glandulosum leaf extract ameliorates experimentally induced MetS by improving dyslipidemia and insulin resistance. CONCLUSION: This study provides the first pharmacological evidence for the protective role of C. glandulosum leaves against experimentally induced MetS. Thus, therapeutic use of C. glandulosum in controlling MetS is indicated. PMID- 20843168 TI - Development of a new sensitive ELISA for the determination of uteroglobin-related protein 1, a new potential biomarker. AB - Uteroglobin-related protein 1 (UGRP-1) is a protein specifically secreted in airways, where it could play an anti-inflammatory role. We developed a sandwich enzyme-linked immunosorbent assay (ELISA) allowing the detection of UGRP-1 in serum, urine, and amniotic and pulmonary fluids. Concentrations of UGRP-1 determined by ELISA and latex immunoassay were correlated in sputum and bronchoalveolar lavage fluid (BALF). The pattern of UGRP-1 concentration resembled that of Clara cell protein, both proteins occurring in high concentrations in amniotic fluid, sputum and BALF and in much lower concentrations in serum and urine. These findings suggest that UGRP-1 might serve as a biomarker of respiratory epithelium integrity. PMID- 20843169 TI - Preparing for a U.S. National ALS Registry: Lessons from a pilot project in the State of Georgia. AB - Our objective was to investigate the utility of existing data sources for identifying cases of amyotrophic lateral sclerosis (ALS) and related motor neuron diseases (MND) in the State of Georgia. Data were acquired from Medicare, Medicaid, Veterans Administration, Emory Healthcare, community neurologists, the ALS Association, and mortality records for ALS/MND patients residing in Georgia during 2001-2005. A neurologist used abstracted medical records to verify the diagnosis of ALS/MND. The positive predictive value (PPV) of an ICD code for a verified diagnosis of ALS was estimated. Simple 'rules' were developed to improve PPV. Results showed that a total of 2413 unique potential cases were identified in existing data sources. Medical records of 579 cases were available for review; the diagnosis of ALS (or a related MND) was confirmed in 486 (PPV = 84%) cases. Predictive rules, which permitted classification of ~80% of the chart-reviewed population, improved PPV to 96-98%. In conclusion, existing data sources are useful for identifying cases of ALS/MND; most data sources contribute a substantial number of unique cases. Predictive algorithms may permit correct classification of a large proportion of cases without the need for verification based on medical record review. PMID- 20843170 TI - Toxicity manifesting as cosmetic hair alterations during erlotinib treatment. PMID- 20843171 TI - Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival. AB - INTRODUCTION: Matrix metalloproteinase 9 (MMP-9) is an endopeptidase involved in various cellular processes, such as tumour development and metastatic spread. In biological samples, MMP-9 can occur as pro-MMP-9 and active MMP-9, or these factors complexed with the inhibitor TIMP-1. An assay, which can measure active and total MMP-9 in biological samples, has been used on the urine from bladder cancer patients and demonstrated a significant correlation between MMP-9 and clinical parameters. The prognostic value of these measurements has never been investigated. Using this assay we have investigated the prognostic influence of total and active MMP-9 in urine from bladder cancer patients. MATERIAL AND METHODS: Fresh voided urines from 188 consecutive patients diagnosed with bladder cancer were collected and frozen at diagnosis. After 15 years follow-up 13 patients were still alive, and 175 patients had died. MMP-9 was measured with an immunocapture activity assay. RESULTS: Median MMP-9(total) was 173.7 units/10 g creatinine (range 0-34 792), and median MMP-9(active) was 14 units/10g creatinine (range, 0-294 757). The two factors were correlated (Spearman's rho 0.74, p<0.0001). High MMP-9(total) and MMP-9(active) were significantly correlated with large tumour size and poor malignancy grade. Increasing tertiles of MMP-9(total) and MMP-9(active) were associated with poor overall survival (p<0.0001 and p=0.003, respectively). A Cox multivariate analysis using death as endpoint identified high tertiles of MMP-9(total) as independent prognostic markers with a relative risk 2.25 (95% confidence interval, 1.53-3.30). CONCLUSION: MMP-9 measured in urine from bladder cancer patients was a strong independent prognostic marker of poor survival. This is the first time high levels of MMP-9 measured in urine from bladder cancer patients have been linked to poor prognosis. This may reflect MMP-9 playing a role in tumour invasion and metastasis. It may be possible to non-invasively measure tumour response to therapy and identify possible tumour recurrence in an early phase. PMID- 20843172 TI - New recommendation of doses in an ongoing phase II study of docetaxel, oxaliplatin and capecitabine as first line therapy in advanced gastro-oesophageal cancer. PMID- 20843173 TI - Distress, quality of life, neuroticism and psychological coping are related in head and neck cancer patients during follow-up. AB - The aim of the present study was to study the relation between distress, quality of life (QoL), personality and choice of coping in successfully treated head and neck squamous cell carcinoma (HNSCC) patients, and to study whether distress could be regarded as a QoL variable. MATERIAL AND METHODS: We determined present distress by the general health questionnaire (GHQ), QoL by the European Organization for Research and Treatment of Cancer Quality of life Questionnaire (EORTC-QLQ) C30/H&N35, personality by the Eysenck Personality Inventory and coping by the COPE questionnaire. All patients younger than 80 years who had been diagnosed with HNSCC in Western Norway in the period from 1992 to October 2001, and who had survived at least 12 months without evidence of disease were interviewed. In addition, treatment level, TNM stage, alcohol consumption level as well as smoking level were determined. One hundred and thirty-nine patients (96.5% response rate) were included. RESULTS: Distress and QoL indexes were scored with a common variance (CV) between 20% and 35%. The measured variables account for 40-48% of the variance of the QoL/GHQ scores. Between 3% and 10% of the GHQ/general QoL scores and 10% of the variance of the H&N35 QoL scores were predicted by the TNM stage. The measured psychological factors accounted for 20% of the H&N35 QoL scores and 40% of the measured variance of the general QoL and GHQ responses. High neuroticism (CV~20-35%), present avoidance coping (CV~10-30%) and coping by suppression of competing activity (CV~10-20%) were associated with low QoL and high distress. CONCLUSION: GHQ and QoL scores are scored similar, and are to some extent predicted by treatment related factors, but between 2.5 and 10 times more closely associated with psychological factors. Distress may possibly also be regarded as a QoL variable. PMID- 20843174 TI - From cell population models to tumor control probability: including cell cycle effects. AB - BACKGROUND: Classical expressions for the tumor control probability (TCP) are based on models for the survival fraction of cancer cells after radiation treatment. We focus on the derivation of expressions for TCP from dynamic cell population models. In particular, we derive a TCP formula for a generalized cell population model that includes the cell cycle by considering a compartment of actively proliferating cells and a compartment of quiescent cells, with the quiescent cells being less sensitive to radiation than the actively proliferating cells. METHODS: We generalize previously derived TCP formulas of Zaider and Minerbo and of Dawson and Hillen to derive a TCP formula from our cell population model. We then use six prostate cancer treatment protocols as a case study to show how our TCP formula works and how the cell cycle affects the tumor treatment. RESULTS: The TCP formulas of Zaider-Minerbo and of Dawson-Hillen are special cases of the TCP formula presented here. The former one represents the case with no quiescent cells while the latter one assumes that all newly born cells enter a quiescent cell phase before becoming active. From our case study, we observe that inclusion of the cell cycle lowers the TCP. CONCLUSION: The cell cycle can be understood as the sequestration of cells in the quiescent compartment, where they are less sensitive to radiation. We suggest that our model can be used in combination with synchronization methods to optimize treatment timing. PMID- 20843175 TI - Concurrent versus sequential radiotherapy and tamoxifen in breast cancer - The CONSET trial is launched. PMID- 20843176 TI - Mutational analysis of mononucleotide repeats in HDAC4, 5, 6, 7, 9 and 11 genes in gastric and colorectal carcinomas with microsatellite instability. PMID- 20843177 TI - A comparative study of cancer patients with short and long sick-leave after primary treatment. AB - BACKGROUND: Sick-leave after primary cancer treatment has hardly been studied. This study compares Norwegian cancer patients (CPs) with shorter (<=8 months) and longer (>=9 months) sick-leave after primary cancer treatment. Our aim was to characterize factors associated with these two types of sick-leave in order to identify possible factors for interventions by which long-term sick-leaves may be avoided. METHODS: A mailed questionnaire was completed by a sample of Norwegian CPs 15 to 39 months after primary treatment of the ten most common invasive types of cancer. The groups with shorter (n=359) and longer (n=481) sick-leaves (SSL vs LSL) were compared with each other by self-reported information as to socio demographic and cancer-related variables, health, quality of life, work ability, work situation and supportive interventions. RESULTS: The LSL consisted of 78% females, and 76% of them had breast or gynaecological cancer. A higher proportion of patients with low level of education, economical problems, treated with chemotherapy, hormones and multimodal treatment belonged to LSL compared to SSL. Significantly more LSL had recurrences of cancer, co-morbidity, regular use of medication, and poorer self-rated health, quality of life and work ability. Compared to SSL, more LSL reported needs for and offers of supportive care such as physiotherapy, physical activities and psychosocial support. A multivariate regression analysis showed that reduced work ability, changes in employment due to cancer, lack of support from supervisors at work, and having had combined treatment were significantly associated with being LSL. CONCLUSIONS: Longer sick leave after primary cancer treatment is associated with combined cancer treatment, lack of support from supervisors and reduced overall work ability. Interventions and counselling related to the work place and reduced work ability could be of value for prevention of long-term sick-leaves. PMID- 20843178 TI - Computer simulation of tumour control probabilities after irradiation for varying intrinsic radio-sensitivity using a single cell based model. AB - BACKGROUND: Currently, optimisation of the dose distribution and clinical acceptance are almost entirely based on the physical dose distribution and tumour control probability modelling is far from being routinely used as objective in treatment planning. For future individualised radiotherapeutic strategies, a reliable patient specific simulation model, taking into account customised tumour features, is needed to predict and improve treatment outcome. MATERIALS AND METHODS: To approach these demands, a single cell and Monte-Carlo based model was developed, which enables three-dimensional tumour growth and radiation response simulation. Tumour cells were characterised by cell-associated features such as age, intrinsic radio-sensitivity, proliferation ability, and oxygenation status, while capillary cells were considered as sources of a radial-dependent oxygen profile. Response to radiation was simulated by the linear-quadratic model, taking into account the lower radio-sensitivity of poorly oxygenated tumour cells. RESULTS: The present study shows the influence of the model components and demonstrates the impact of the intra- and inter-tumoural radio-sensitivity heterogeneity on the treatment response. CONCLUSION: The simulation model adequately delineates the importance of the above described selected parameters on tumour control probability, providing an insight into the interplay of different physical and biological parameters, and its relevance for an individual tumour response. PMID- 20843180 TI - Giant phyllodes tumor of the breast: Consequence of carelessness. PMID- 20843179 TI - Rectal cancer radiotherapy: towards European consensus. AB - BACKGROUND AND PURPOSE: During the first decade of the 21st century several important European randomized studies in rectal cancer have been published. In order to help shape clinical practice based on best scientific evidence, the International Conference on 'Multidisciplinary Rectal Cancer Treatment: Looking for an European Consensus' (EURECA-CC2) was organized. This article summarizes the consensus about imaging and radiotherapy of rectal cancer and gives an update until May 2010. METHODS: Consensus was achieved using the Delphi method. Eight chapters were identified: epidemiology, diagnostics, pathology, surgery, radiotherapy and chemotherapy, treatment toxicity and quality of life, follow-up, and research questions. Each chapter was subdivided by topic, and a series of statements were developed. Each committee member commented and voted, sentence by sentence three times. Sentences which did not reach agreement after voting round # 2 were openly debated during the Conference in Perugia (Italy) December 2008. The Executive Committee scored percentage consensus based on three categories: "large consensus", "moderate consensus", "minimum consensus". RESULTS: The total number of the voted sentences was 207. Of the 207, 86% achieved large consensus, 13% achieved moderate consensus, and only three (1%) resulted in minimum consensus. No statement was disagreed by more than 50% of members. All chapters were voted on by at least 75% of the members, and the majority was voted on by >85%. Considerable progress has been made in staging and treatment, including radiation treatment of rectal cancer. CONCLUSIONS: This Consensus Conference represents an expertise opinion process that may help shape future programs, investigational protocols, and guidelines for staging and treatment of rectal cancer throughout Europe. In spite of substantial progress, many research challenges remain. PMID- 20843181 TI - Cardiac and pulmonary dose reduction for tangentially irradiated breast cancer, utilizing deep inspiration breath-hold with audio-visual guidance, without compromising target coverage. AB - BACKGROUND AND PURPOSE: cardiac disease and pulmonary complications are documented risk factors in tangential breast irradiation. Respiratory gating radiotherapy provides a possibility to substantially reduce cardiopulmonary doses. This CT planning study quantifies the reduction of radiation doses to the heart and lung, using deep inspiration breath-hold (DIBH). PATIENTS AND METHODS: seventeen patients with early breast cancer, referred for adjuvant radiotherapy, were included. For each patient two CT scans were acquired; the first during free breathing (FB) and the second during DIBH. The scans were monitored by the Varian RPM respiratory gating system. Audio coaching and visual feedback (audio-visual guidance) were used. The treatment planning of the two CT studies was performed with conformal tangential fields, focusing on good coverage (V(95)>98%) of the planning target volume (PTV). Dose-volume histograms were calculated and compared. Doses to the heart, left anterior descending (LAD) coronary artery, ipsilateral lung and the contralateral breast were assessed. RESULTS: compared to FB, the DIBH-plans obtained lower cardiac and pulmonary doses, with equal coverage of PTV. The average mean heart dose was reduced from 3.7 to 1.7 Gy and the number of patients with >5% heart volume receiving 25 Gy or more was reduced from four to one of the 17 patients. With DIBH the heart was completely out of the beam portals for ten patients, with FB this could not be achieved for any of the 17 patients. The average mean dose to the LAD coronary artery was reduced from 18.1 to 6.4 Gy. The average ipsilateral lung volume receiving more than 20 Gy was reduced from 12.2 to 10.0%. CONCLUSION: respiratory gating with DIBH, utilizing audio-visual guidance, reduces cardiac and pulmonary doses for tangentially treated left sided breast cancer patients without compromising the target coverage. PMID- 20843183 TI - Task-dependent representation of moving objects within working memory in obstacle avoidance. AB - PURPOSE: The purpose of the study was the quantitative analysis of the working memory representation of dynamic objects related to gaze movement behavior. METHODS: Eighteen subjects participated in a virtual street-crossing paradigm. The primary task was collisions avoidance. To investigate the representation format, during a sub-task subjects were asked to reconstruct the traffic scene from memory. RESULTS: The distribution of cars positioned during the sub-task reveals a task-dependent (i.e., collision-relevant) representation of about four cars. In contrast, analysis of gaze behavior did not show a preference for collision-prone cars. CONCLUSION: Subjects avoided collisions efficiently by applying a gaze strategy adequate to create a representation that fulfills the demands of the task. Collision-prone cars are more likely to be represented in memory, but not more likely to be fixated. PMID- 20843184 TI - Trochlear palsies caused by isolated trochlear schwannomas. AB - PURPOSE: To describe clinical features and management of 4 patients suffering from unilateral superior oblique palsies due to MRI-documented trochlear nerve schwannomas. METHODS: Chart reviews of 4 patients seen at the departments of ophthalmogy and neurology at the University of Mainz. RESULTS: All four patients were male, aged 36 to 72 years at initial presentation. None suffered from neurofibromatosis. The history of double vision prior presentation was 9 months to 13 years, follow-up time was 9 to 156 months. Two patients didn't receive any intervention: one remained stable over the follow-up time of 9 months. In patient #2, fourth nerve palsy was diagnosed 13 years prior to confirmation of a trochlear schwannoma by high-resolution MRI. In the third patient disturbing diplopia and head tilt were sufficiently corrected by strabismus surgery (combined oblique muscle surgery). The fourth patient had received stereotactic radiotherapy of an 8 mm schwannoma. He remained unchanged in the orthoptic measurements for 3,5 years. None of these patients developed any additional symptoms or signs of further cranial nerve or central nervous system involvement. CONCLUSION: A trochlear nerve schwannoma is a possible cause of an isolated unilateral superior oblique palsy. MRI is a helpful tool for diagnosis and follow up. Conservative management seems to be justified as patients can remain unchanged over years. PMID- 20843185 TI - Predictive value of age, angle, and refraction on rate of reoperation and rate of spontaneous resolution in infantile esotropia. AB - In the Early vs. Late Infantile Strabismus Surgery Study (ELISSS), 13.5% of children operated at 20 months vs. 3.9% of those operated at age 4 had gross binocular vision (Titmus Housefly). Reoperation rates were 28.7% in the former vs. 24.6% in the latter group and, although all were eligible for surgery at baseline at 11 SD 3.7 months, 8% in the early group vs. 20% in the late group were never operated, mostly because their angle decreased spontaneously. We assessed the predictive value of age, angle, and refraction in these matters. METHODS: The ELISSS reoperation rates were first compared with those found in nine series of consecutive cases in nine university clinics operated during one particular year, between 6 and 23 years previously. Logistic regression was used to estimate the effect of postoperative angle and clinic on the chance of reoperation. Secondly, a meta-regression analysis was done of these and other reported reoperation rates. The mean age at operation and the mean duration of follow-up were regressed on the logistically transformed reported reoperation rates. Finally, to estimate the chance of spontaneous decrease of the angle without surgery, a random-effects model was fitted on the 6-monthly orthoptic measurements of angle and refraction in the ELISSS that antedated surgery, loss to follow-up, or final examination. In the random-effects model (see online-only supplement link or visit, www.simonsz.net), for ELISSS patients the random effect was defined as the deviation of the average angle, the fixed effect. A vector was defined based on age and spherical equivalent of the patient. The variance around the prediction consisted of uncertainty in the estimations, random effects, and residuals. RESULTS: In the retrospective study, 204 patients who had been first operated between 6 and 23 years previously were eligible. A reoperation had been performed in 32 (19.3%) of the remaining 166 children who were 4.33 SD 1.35 years old at first surgery. The reoperation rate was 7.3% for those with a postoperative angle of -4 degrees to +4 degrees (N = 82), 25% for postoperative divergence > 5 degrees , and 29% for postoperative convergence 10 degrees to 14 degrees . Strabismologists overestimated the reoperation rates at double. In the meta-regression analysis, 12 studies were included. Reoperation rates were between 60% and 80% for children first operated around age 1 and approximately 25% for children operated around age 4 (best fit: -0.221 Ln [age in months] + 1.1069; R(2) = 0.5725). Finally, in the predictions of random-effects model, a small angle at age 1 and hyperopia of approximately +4 increased the chance of spontaneous decrease of the angle into a microstrabismus. DISCUSSION: The benefit of early surgery for gross binocular vision is balanced by a higher reoperation rate and an occasional child being operated that would have had a spontaneous decrease into a microstrabismus without surgery. The fact that, in the ELISSS, hyperopia was associated with a decrease of the angle underscores the benefit of early refractive correction. PMID- 20843186 TI - A hypothetical mechanism for DVD: unbalanced cortical input to subcortical pathways. AB - Dissociated vertical divergence (DVD) is commonly encountered in the infantile strabismus syndrome. The movement is said to be dissociated since alignment differs between right and left eye fixation. It has been hypothesized that DVD is caused by a primitive reflex present in fish. Visual pathways in the fish brain indeed are dissociated with complete crossing at the optic chiasm and projection to the superior colliculus instead of a visual cortex. Neuroanatomical data and clinical characteristics of DVD, however, contradict this hypothesis. From these data a new hypothesis arises: corticotectal lateralization. The absence of binocular development in the cerebral cortex in infantile strabismus gives rise to dissociated activation of subcortical pathways through individual less tightly linked colliculi. PMID- 20843187 TI - The prevalence of anisometropia, amblyopia and strabismus in schoolchildren of Shiraz, Iran. AB - PURPOSE: To determine the prevalence of amblyopia, anisometropia, and strabismus in schoolchildren of Shiraz, Iran. MATERIALS AND METHODS: A random cluster sampling was used in a cross-sectional study on schoolchildren in Shiraz. Cycloplegic refraction was performed in elementary and middle school children and high school students had non-cylcoplegic refraction. Uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) were recorded for each participant. Anisometropia was defined as spherical equivalent (SE) refraction difference 1.00D or more between two eyes. Amblyopia was distinguished as a reduction of BCVA to 20/30 or less in one eye or 2-line interocular optotype acuity differences in the absence of pathological causes. Cover test was performed for investigating of strabismus. RESULTS: Mean age of 2638 schoolchildren was 12.5 years (response rate = 86.06%). Prevalence of anisometropia was 2.31% (95% confidence interval [CI], 1.45 to 3.16). 2.29% of schoolchildren (95% CI, 1.46 to 3.14) were amblyopic. The prevalence of amblyopia in boys and girls was 2.32% and 2.26%, respectively (p = 0.945). Anisometropic amblyopia was found in 58.1% of the amblyopic subjects. The strabismus prevalence was 2.02% (95% CI, 1.18 to 2.85). The prevalence of exotropia and esotropia was 1.30% and 0.59%, respectively. CONCLUSIONS: Results of this study showed that the prevalence of anisometropia, amblyopia, and strabismus are in the mid range. The etiology of amblyopia was often refractive, mostly astigmatic, and non strabismic. Exotropia prevalence increased with age and was the most common strabismus type. PMID- 20843188 TI - Superior oblique tucks for apparent inferior oblique overaction and V-pattern strabismus associated with craniosynostosis. AB - INTRODUCTION: Apparent inferior oblique overaction and apparent superior oblique underaction are common in strabismus associated with craniosynostosis, and in many cases are likely due to excyclotorsion of the globes, with the rectus muscles acting with oblique vectors. We present a patient with craniosynostosis who underwent bilateral superior oblique tucks to specifically address the excyclotorsion of the globes. METHODS: A 16-year-old male with Saethre-Chotzen syndrome presented with apparent bilateral inferior oblique overaction and apparent bilateral superior oblique underaction. He had 30 prism diopter (PD) esotropia and 5 PD left hypertropia by simultaneous prism and cover test (SPCT) at distance and near fixation. Fundus exam revealed marked excyclotorsion of both globes. The superior oblique tendons were tucked 10 mm bilaterally, using a 6-0 mersilene suture and the medial rectus muscles were recessed 5.5 mm on an adjustable suture with a 10-mm inferior displacement. Surgical results were reviewed at 6 weeks and 2 years postoperatively. RESULTS: At 6 weeks and 2 years postoperatively, apparent inferior oblique overaction, apparent superior oblique underaction, and V-pattern esotropia were markedly improved. At 2 years, SPCT measurements were 8 PD esotropia in primary position at distance and 4 PD esotropia and 3 PD left dissociated vertical deviation at near. CONCLUSIONS: Bilateral superior oblique tucks are useful in addressing the excyclotorsion that leads to apparent inferior oblique overaction and V-pattern strabismus associated with craniosynostosis. PMID- 20843189 TI - First description of anomalous retinal correspondence by Johannes Peter Muller in 1826. PMID- 20843190 TI - About the mutually alternating condition of the convergence of the visual axes and of clear vision at different distances, and about the various forms of strabismus. 1826. PMID- 20843192 TI - Recent progress in genetic variants associated with cancer and their implications in diagnostics development. PMID- 20843191 TI - The prevalence and outcome of hypertension in patients with acute coronary syndrome in six Middle-Eastern countries. AB - AIMS: The aim was to report the prevalence and significance of hypertension (HTN) in patients with acute coronary syndrome (ACS). METHODS AND MAJOR FINDINGS: Over a 6-month period in 2007, 8171 consecutive patients (49.4% hypertensive and 50.6% non-hypertensive) presenting with ACS were enrolled in a prospective, multicenter study from six Middle Eastern adjacent countries. Patients with HTN were older (59.2 vs 53.1 years, p<0.001), and more likely to be female (34% vs 14.4%, p<0.001) when compared with patients without HTN. Patients with HTN were also more likely to have diabetes mellitus, hyperlipidemia, cerebrovascular disease, prior history of coronary artery disease, peripheral artery disease but less likely to be cigarette smokers. At admission, HTN patients had higher Killip class, heart rate and GRACE risk scoring. In-hospital mortality was higher in hypertensive patients with ST-elevation myocardial infarction (STEMI) but not in patients with non-STEMI or unstable angina. The incidence of heart failure complications was significantly higher among patients with HTN in overall ACS type (OR = 1.2, 95% CI 1.001-1.338, p= 0.04). MAIN CONCLUSION: In this large cohort of patients with ACS, HTN was an independent predictor of heart failure and was associated with an increased rate of in-hospital mortality in STEMI only. PMID- 20843193 TI - Shed acute-phase antigen protein in an ELISA system for unequivocal diagnosis of congenital Chagas disease. PMID- 20843196 TI - Classification of pathogenic or benign status of CNVs detected by microarray analysis. AB - Multiple lines of evidence indicated that microarray analysis has a better diagnostic yield of clinically significant genetic changes than do conventional methods in patients with constitutional abnormalities. However, interpretation of microarray data is complicated by the presence of both novel and recurrent copy number variants (CNVs) of unknown significance. To address this issue, Hehir-Kwa et al. described a new computational method for determining the pathogenicity between benign and mental retardation (MR)-associated CNVs among patients with MR. This study demonstrated the value of objectively prioritizing MR-associated CNVs using structural and functional genomic features in diagnostics. In this regard, we discuss an evidence-based summary of how to classify pathogenic or benign status of a CNV in clinical genetics and advocate that there is a need for algorithmic adjustment between constitutional cytogenetic and prenatal diagnosis settings. PMID- 20843195 TI - Developments in real-time PCR research and molecular diagnostics. AB - This meeting was designed to highlight the wide range of new methods, instruments and applications that underlie the popularity of quantitative real-time PCR technology in all areas of life science research, as well as in clinical diagnostics. It provided a fascinating snapshot of current trends and novel approaches, as well as important issues concerning assay design, optimization and quality control issues. PMID- 20843197 TI - Automated genotyping of circulating tumor cells. AB - Cancer remains a prominent health concern in modern societies. Continuous innovations and introduction of new technologies are essential to level or reduce current healthcare spending. A diagnostic platform to detect circulating tumor cells (CTCs) in peripheral blood may be most promising in this respect. CTCs have been proposed as a minimally invasive, prognostic and predictive marker to reflect the biological characteristics of tumors and are implemented in an increasing number of clinical studies. Still, their detection remains a challenge as they may occur at concentrations below one single cell per ml of blood. To facilitate their detection, here we describe microfluidic modules to isolate and genotype CTCs directly from clinical blood samples. In a first cell isolation and detection module, the CTCs are immunomagnetically enriched, separated and counted. In a second module and after cell lysis, the mRNA is reversely transcripted to cDNA, followed by a multiplex ligation probe amplification of 20 specific genetic markers and two control fragments. Following the multiplex ligation probe amplification reaction, the amplified fragments are electrochemically detected in a third and final module. Besides the design of the modules, their functionality is described using control samples. Further testing using clinical samples and integration of all modules in a single, fully automated smart miniaturized system will enable minimal invasive testing for frequent detection and characterization of CTCs. PMID- 20843198 TI - Recombinant protein-based viral disease diagnostics in veterinary medicine. AB - Identification of pathogens or antibody response to pathogens in human and animals modulates the treatment strategies for naive population and subsequent infections. Diseases can be controlled and even eradicated based on the epidemiology and effective prophylaxis, which often depends on development of efficient diagnostics. In addition, combating newly emerging diseases in human as well as animal healthcare is challenging and is dependent on developing safe and efficient diagnostics. Detection of antibodies directed against specific antigens has been the method of choice for documenting prior infection. Other than zoonosis, development of inexpensive vaccines and diagnostics is a unique problem in animal healthcare. The advent of recombinant DNA technology and its application in the biotechnology industry has revolutionized animal healthcare. The use of recombinant DNA technology in animal disease diagnosis has improved the rapidity, specificity and sensitivity of various diagnostic assays. This is because of the absence of host cellular proteins in the recombinant derived antigen preparations that dramatically decrease the rate of false-positive reactions. Various recombinant products are used for disease diagnosis in veterinary medicine and this article discusses recombinant-based viral disease diagnostics currently used for detection of pathogens in livestock and poultry. PMID- 20843199 TI - Molecular diagnosis of genetic iron-overload disorders. AB - Genetic iron overload has long been confined to the picture of classical hemochromatosis related to the HFE C282Y mutation (type 1 hemochromatosis). C282Y homozygosity affects approximately three people out of 1000 of the Caucasian population, representing one of the most frequent genetic predispositions. It has, however, rapidly become clear that the HFE C282Y mutation is not the sole culprit in genetic iron overload. Several novel mutations in HFE and other genes have been discovered and related to various entities, which are now known as types 2, 3 and 4 hemochromatosis. These diseases are far less frequent than the classical type 1 hemochromatosis but, by contrast, are not limited to the Caucasian population. Molecular diagnosis obviously plays a key role in the diagnostic strategy. In the future, it will undoubtedly enable not only identification of new diagnostic markers, but also provide potential molecular targets for pathophysiologically based innovative therapeutic approaches. PMID- 20843200 TI - Klinefelter syndrome: clinical and molecular aspects. AB - Klinefelter syndrome is the most common chromosome abnormality in humans. The estimated prevalence is one in 500 to one in 1000 males but due to the widely variable and often aspecific features, only one in four cases are recognized. The most specific clinical features which can be observed at adult age are small testes, gynecomastia, female distribution of fat and body hair, slightly increased body length due to an increased leg length and azoospermia. Cognition is characterized by verbal deficits and psychosocial features include autistiform behavior. Structural brain abnormalities have been observed by MRI, such as decreased brain volumes and a decrease of asymmetry in areas corresponding to language performance. In the vast majority of cases a non-mosaic 47,XXY karyotype is observed. Parental imprinting of the extra X chromosome, variable inactivation of some X-chromosomal genes and CAG repeat length polymorphism of the androgen receptor may all be related to the variability of the phenotype. Surgical procedures of obtaining sperm in combination with repeated intracytoplasmic sperm injection/in vitro fertilization treatment may allow up to one in four men with Klinefelter syndrome to father children. PMID- 20843201 TI - Nanobodies(r): proficient tools in diagnostics. AB - With the advent of new antibody engineering technologies, conventional antibodies have been minimized into smaller antibody formats. Small size is an important advantage for current and future diagnostic development. Nanobodies(r) (Ablynx) are among the smallest known antigen-binding antibody fragments, and are derived from the heavy-chain only antibodies that occur naturally in the serum of Camelidae. Endowed by natural evolution, these Nanobodies inherently exhibit unique biophysical, biochemical and pharmacological characteristics. In addition to their excellent potential as molecules in drug development, Nanobodies possess very attractive functional properties that aid in their development for diagnostic tools. Here we present several examples of currently available applications of Nanobodies to the field of immunosensor for cancer, immunoaffinity chromatography, in vivo and intracellular imaging. PMID- 20843202 TI - Tumor markers for early detection of ovarian cancer. AB - The overall mortality rate for ovarian cancer is 75%, but when diagnosed at stage I, 90% of patients can be cured. Strategies for early detection require high sensitivity (>75%) and extremely high specificity (99.6%) to attain a positive predictive value of at least 10%. When functioning alone, conventional markers fall short of this required sensitivity or specificity. Greater specificity can be achieved by combining multiple markers. Meanwhile, technological developments offer the potential identification of new candidate markers. Panels of new markers have been discovered with improved sensitivity and specificity for early stage detection, but these require prospective validation. Through empirical development of: biotechnology (including monoclonal antibodies, gene expression, cloning of gene families and proteomics); statistical methods; and guidelines from specialized institutions, more candidate markers might be discovered and validated with systematic, efficient and cost-effective screenings. PMID- 20843203 TI - Early detection and screening of lung cancer. AB - Accounting for 28% of all cancer deaths and causing 1.3 million deaths worldwide every year, lung cancer is the most lethal cancer. Diagnosing and treating cancer at its early stages, ideally during precancerous stages, could increase the 5 year survival rate by three- to four-fold with a potential for cure. Thus far, no screening method has been shown to decrease disease-specific mortality rate. The present review describes the rationale and issues related to early lung cancer screening, the management of screen-detected primary cancers and different approaches that have been tested for screening. These include imaging techniques, bronchoscopies, molecular screenings from different noninvasive or invasive sources, such as blood, sputum, bronchoscopic samples and exhaled breath. PMID- 20843206 TI - Diet mixing: do animals integrate growth or resources across temporal heterogeneity? AB - Animals commonly experience spatial and temporal variation in resource quality, thus experiencing temporally variable diets. Methods for scaling up growth in component patches to long-term growth across heterogeneity are seldom explicitly considered. Long-term growth is sometimes considered to be a weighted average of growth rates on component diets (growth integration). However, if animals integrate resources across high- and low-quality diets, their long-term growth may be greater than predicted from diet-specific growth rates (resource integration). We measured biomass growth rates of seven Daphnia species exposed to different types of diet variation in algal phosphorus (P) content. Support for resource integration was found for four of the seven species, which achieved near maximal growth when high-P food was available for at least 12 h. In contrast, no support for resource integration was found for the other three species. These three species achieved only one-half maximal growth rate under the same conditions and could be considered growth integrators. The type of integration could be predicted from the degree of stoichiometric homeostasis. Species with weak homeostatic regulation exhibited a capacity for resource integration. Resource integrators should have an advantage in heterogeneous environments. PMID- 20843207 TI - Association between naturally acquired antibodies to erythrocyte-binding antigens of Plasmodium falciparum and protection from malaria and high-density parasitemia. AB - BACKGROUND: Antibodies targeting blood stage antigens are important in protection against malaria, but the principle targets remain unclear. Erythrocyte-binding antigens (EBAs) are important erythrocyte invasion ligands used by merozoites and may be targets of protective immunity, but there are limited data examining their potential importance. METHODS: We examined antibodies among 206 Papua New Guinean children who were treated with antimalarials at enrollment and observed prospectively for 6 months for reinfection and malaria. Immunoglobulin (Ig) G, IgG subclasses, and IgM to different regions of EBA175, EBA140, and EBA181 expressed as recombinant proteins were assessed in comparison with several other merozoite antigens. RESULTS: High levels of IgG to each of the EBAs were strongly associated with protection from symptomatic malaria and high density parasitemia, but not with risk of reinfection per se. The predominant IgG subclasses were either IgG1 or IgG3, depending on the antigen. The predominance of IgG1 versus IgG3 reflected structural features of specific regions of the proteins. IgG3 was most strongly associated with protection, even for those antigens that had an IgG1 predominant response. CONCLUSIONS: The EBAs appear important targets of acquired protective immunity. These findings support their further development as vaccine candidates. PMID- 20843204 TI - MicroRNA binding site polymorphisms as biomarkers of cancer risk. AB - MicroRNAs (miRNAs) are well established as global gene regulators and thus, slight alterations in miRNA levels as well as their ability to regulate their targets may cause important cellular changes leading to cancer risk. 3' untranslated region (UTR) miRNA binding site single nucleotide polymorphisms (SNPs) have added another layer of possible genetic variation involved in the complex process of oncogenesis. Identifying these key genetically inherited effectors of miRNA functioning has improved our understanding of the complexity of disease. Interest in the field has grown rapidly in only the last 5 years, with several studies reporting on the role of 3'UTR binding site SNPs as genetic markers of increased cancer susceptibility, as well as biomarkers of cancer type, outcome and response to therapy. Currently, there are numerous known miRNA binding site SNPs associated with multiple cancer subtypes. PMID- 20843211 TI - Notes on the life and work of Frieda Fromm-Reichmann. AB - It is now 25 years since Frieda Fromm-Reichmann died--over 30 years since she published her only book, Principles of Intensive Psychotherapy. Most of those who now attend the presentations of the annual research award of the Academy or the annual lectures of the Washington School of Psychiatry, both of which are named in her honor, never saw her. It seem appropriate to ask whether she still speaks to us today, whether in any significant way she influenced the development of what is now common practice in our field. PMID- 20843212 TI - Exposure to prolonged socio-political conflict and the risk of PTSD and depression among Palestinians. AB - Little is known about the impact of traumatic experiences and stressful life conditions on people in low-income countries who live in conditions of ongoing political violence. In order to determine the prevalence and predictors of post traumatic stress disorder (PTSD) and major depression (MD) among Palestinians subjected to chronic political violence and upheaval, we used a stratified multi stage cluster random sampling strategy to interview a representative sample of 1,200 Palestinian adults living in Gaza, the West Bank, and East Jerusalem. Prevalence of PTSD/MD for men living in the West Bank, Gaza, and East Jerusalem was 25.4%/29.9%, 22.6%/27.6%, and 16.1%/16.1%, respectively. For women, the prevalence of PTSD/MD was 23.8%/29.0%, 23.9%/28.9%, and 19.7%/27.6%. Among men, PTSD was significantly positively associated with age group, two or more incidences of political violence (compared to none), greater intrapersonal resource loss, and loss of faith in government. MD was positively associated with experiencing exposure to one, or two or more, incidences of political violence (compared to none), and greater interpersonal and intrapersonal resource loss. Among women, PTSD was positively associated with greater interpersonal and intrapersonal resource loss, and MD was positively associated with death of a loved one, two or more socio-political stressors (compared to none) previous to the past year, one or more socio-political stressors (compared to none) in the past year, and greater interpersonal and intrapersonal resource loss. Interpersonal and intrapersonal resource losses were consistently associated with PTSD and MD, suggesting potential targets for intervention and prevention efforts and thus provide important keys to treatment in areas of ongoing conflict. PMID- 20843213 TI - War, sociopolitical adversity and mental illness. PMID- 20843214 TI - PTSD and depression among Palestinians: reactions to a study. PMID- 20843215 TI - Painting by numbers: capturing the pathology of socio-political conflict. PMID- 20843216 TI - Bio-psychosocial foundations of contemporary terrorism. PMID- 20843217 TI - Application in Mexico of psychosocial rehabilitation with schizophrenia patients. AB - To determine whether evidence-based, psychosocial treatments developed in the United States and England are applicable to Mexican outpatients with schizophrenia, the present study was carried out to evaluate the relative effectiveness of family psycho-education and psychosocial skills training added to customary treatment vs. customary treatment alone. Clinically stable outpatients with schizophrenia participated in a 12-month randomized, controlled trial at the National Institute of Psychiatry in Mexico City. An experimental group (N = 47) received the combination of psychosocial skills training, family psycho-education and customary pharmacotherapy while the comparison group (N = 36) received customary treatment alone. Patients were assessed at baseline and one year after commencement of treatment. Significant differences favoring the group that received psychosocial rehabilitation were found in ratings of adherence to medication, attendance at appointments, symptoms, social functioning, relapse, and re-hospitalization. While some adaptations were made in the psychosocial treatments to resolve cultural differences, the results provide cross-national validation of evidence-based treatments for persons with schizophrenia. PMID- 20843218 TI - Effect of exposure to terrorism on sleep-related experiences in Israeli young adults. AB - General sleep-related experiences (Watson, 2001), including special dream states such as elevated dream recall, nightmares, hypnagogic hallucinations, flying dreams, and waking dreams, have been shown to be associated with life stress and psychopathological distress (Soffer-Dudek & Shahar, 2009). In this study, we attempted to examine these associations within the context of terror-related stress. In the week following operation Oferet Yetzuka in Israel, ninety-one participants filled out questionnaires concerning sleep experiences, psychopathological distress, and degree of exposure to terror. These participants were part of a larger study conducted three years earlier (Soffer-Dudek & Shahar, 2009). General sleep experiences (GSEs) were positively correlated to exposure to terror through media, a link that was mediated through psychopathological symptoms. Surprisingly, GSEs were negatively correlated with physical exposure variables. We suggest that GSEs may be related to a ruminative coping style (i.e., not "letting go," both by day and by night). PMID- 20843219 TI - Co-morbid intellectual disability and borderline personality disorder: a case series. AB - Borderline personality disorder (BPD) is characterized by a pervasive pattern of instability of interpersonal relationships, self-image, and affects, and marked impulsivity beginning by early adulthood and present in a variety of contexts. Researchers have proposed that BPD may be associated with neurocognitive dysfunction. However, the diagnosis of BPD in patients with intellectual disability, where developmental brain abnormality is inherent, has rarely been reported in the literature. Furthermore, it is uncommon to see the diagnosis of BPD made in individuals with intellectual disability in clinical practice. The cases of three patients diagnosed with BPD in the context of intellectual disability are presented. Challenges in making the diagnosis of BPD in this population are discussed, as is the importance of making an accurate diagnosis for guiding effective treatment. PMID- 20843222 TI - Why are there so many drug shortages? PMID- 20843223 TI - Assessing the need for anesthesia and sedation services in Kuwaiti dental practice. AB - The objective of this study was to examine the public health relevance of the prevalence of dental fear in Kuwait and the resultant barrier that it creates regarding access to dental care. The study analysis demonstrated a high prevalence of dental fear and anxiety in the Kuwaiti population and a perceived need for anesthesia services by dental care providers. The telephone survey of the general population showed nearly 35% of respondents reported being somewhat nervous, very nervous, or terrified about going to the dentist. In addition, about 36% of the population postponed their dental treatment because of fear. Respondents showed a preference to receive sedation and anesthesia services as a means of anxiety relief, and they were willing to go to the dentist more often when such services were available. People with high fear and anxiety preferred to receive some type of medication to relieve their anxiety. In conclusion, the significance and importance of the need for anesthesia services to enhance the public health of dental patients in Kuwait has been demonstrated, and improvements are needed in anesthesia and sedation training of Kuwaiti dental care providers. PMID- 20843224 TI - A comparison of intravenous sedation with two doses of dexmedetomidine: 0.2 ug/kg/hr Versus 0.4 ug/kg/hr. AB - The present study investigated the physiologic and sedative effects between two different continuous infusion doses of dexmedetomidine (DEX). Thirteen subjects were separately sedated with DEX at a continuous infusion dose of 0.2 ug/kg/hr for 25 minutes after a loading dose of 6 ug/kg/hr for 5 minutes (0.2 group) and a continuous infusion dose of 0.4 ug/kg/hr for 25 minutes after a loading dose of 6 ug/kg/hr for 5 minutes (0.4 group). The recovery process was then observed for 60 minutes post infusion. The tidal volume, mean arterial pressure, and heart rate in both groups decreased significantly during infusion, but they were within a clinically acceptable level. A Trieger dot test plot error ratio in the 0.4 group was significantly higher than that in the 0.2 group until 15 minutes post infusion. Sedation appears to be safe at the infusion doses of DEX studied. However, increasing maintenance infusion doses of DEX from 0.2 ug/kg/hr to 0.4 ug/kg/hr delays some recovery parameters. PMID- 20843225 TI - Effect of PaCO2 and PaO2 on lidocaine and articaine toxicity. AB - Alterations in arterial PaCO2 can influence local anesthetic toxicity. The objective of this study was to evaluate the effect of stress-induced changes in PaCO2 and PaO2 on the seizure threshold of lidocaine and articaine. Lidocaine (2% with 1 : 100,000 epinephrine) or articaine (4% with 1 : 100,000 epinephrine) was administered intravenously under rest or stress conditions to 36 rats separated into 4 groups. Propranolol and prazosin were administered preoperatively to minimize cardiovascular effects of epinephrine. Mean arterial pressure (MAP), heart rate (HR), and arterial pH, PaCO2, and PaO2 were measured. Results showed no differences in MAP, HR, or pH. Stress significantly increased the latency period for the first tonic-clonic seizure induced by a toxic dose of both lidocaine and articaine (P < .05). Seizures were brought on more rapidly by articaine. No significant difference between toxic doses of lidocaine and articaine was noted. Stress raised the seizure threshold dose for both drugs and significantly (P < .01) increased arterial PaO2 from 94.0 +/- 1.90 mm Hg to 113.0 +/- 2.20 mm Hg, and reduced PaCO2 from 36.0 +/- 0.77 mm Hg to 27.0 +/- 0.98 mm Hg. In conclusion, reduction in PaCO2 and/or increase in PaO2 raised the seizure threshold of lidocaine and articaine. This study also confirmed that lidocaine and articaine have equipotent central nervous system toxicity. PMID- 20843226 TI - General anesthesia for a child with Landau-Kleffner syndrome, a case report. AB - Landau-Kleffner syndrome is a rare, epileptiform disorder with a pathognomonic sudden aphasia, epilepsy, and electroencephalographic abnormalities. It was first described in 1957. No case reports are included in the anesthesia literature. This case report describes a 9-year-old male who was treated for dental caries while under intubated general anesthesia. The case was successful and uneventful, with multiple precautions taken to prevent seizures or other complications. The authors hope that this report will provoke communication and additional case reports. PMID- 20843227 TI - Application of gum elastic bougie to nasal intubation. AB - Gum elastic bougie (GEB), a useful device for difficult airway management, has seldom been used for nasotracheal intubation. Among 632 patients undergoing dental procedures or oral surgery, GEB was used successfully in 16 patients in whom conventional nasal intubation had failed because of anatomical problems or maldirection of the tip of the tracheal tube. We recommend that GEB should be applied from the first attempt for nasal intubation in patients with difficult airways. PMID- 20843228 TI - Pain management part II: pharmacologic management of chronic orofacial pain. AB - The pharmacologic management of chronic orofacial pain involves the use of medications not used routinely in dental practice. Additionally, many drugs are used for long periods of time necessitating careful monitoring for adverse effects and potential drug interactions. This article will review commonly used medications for chronic orofacial pain and highlight important areas of concern. PMID- 20843232 TI - Fusobacterium nucleatum binding to complement regulatory protein CD46 modulates the expression and secretion of cytokines and matrix metalloproteinases by oral epithelial cells. AB - BACKGROUND: Periodontitis is a chronic inflammatory disease that results in the destruction of the supporting tissues of the teeth. Gingival epithelial cells are an important mechanical barrier and participate in the host inflammatory response to periodontopathogens. The aim of the present study is to investigate the capacity of Fusobacterium nucleatum to bind to the complement regulatory protein CD46 expressed by oral epithelial cells and to determine the impact of the binding on the gene expression and protein secretion of interleukin (IL)-6, IL-8, and matrix metalloproteinase (MMP)-9 by oral epithelial cells. METHODS: Binding of recombinant human CD46 to the surface of F. nucleatum was demonstrated by immunologic assays. After stimulation of oral epithelial cells with F. nucleatum, gene expression was determined by real-time polymerase chain reaction analysis while protein secretion was monitored by enzyme-linked immunosorbent assays. RESULTS: Heat and protease treatments of bacterial cells reduced CD46 binding. F. nucleatum-bound CD46 mediated the cleavage of C3b in the presence of factor I. Stimulating oral epithelial cells with F. nucleatum at a multiplicity of infection of 50 resulted in a significant upregulation of the gene expression and protein secretion of IL-6, IL-8, and MMP-9 by oral epithelial cells. However, pretreating the epithelial cells with an anti-CD46 polyclonal antibody attenuated the production of IL-6, IL-8, and MMP-9 in response to F. nucleatum. Such an inhibitory effect was not observed with non-specific antibodies. CONCLUSIONS: The present study demonstrates that F. nucleatum can bind the complement regulatory protein CD46. The interaction of F. nucleatum with epithelial cell surface CD46 may contribute to increasing the levels of proinflammatory mediators and MMPs in periodontal sites and consequently modulate tissue destruction. PMID- 20843233 TI - Differential cytokine patterns in mouse macrophages and gingival fibroblasts after stimulation with porphyromonas gingivalis or Escherichia coli lipopolysaccharide. AB - BACKGROUND: A major cause of chronic inflammatory periodontal disease is Porphyromonas gingivalis, a non-motile, Gram-negative, rod-shaped, anaerobic bacterium. Within gingival tissue, both macrophages and fibroblasts participate in the immune response to foreign entities by releasing cytokines and expressing molecules to recruit and activate lymphocytes. However, the contribution of gingival macrophages and fibroblasts to the immune response to P. gingivalis infection is not fully known. METHODS: The AMJ2-C8 cell line (AM cells), a mouse alveolar macrophage cell line, and ESK-1 cells, a mouse gingival fibroblast cell line made in our laboratory, were treated with lipopolysaccharide (LPS) from either P. gingivalis or Escherichia coli. The expression of immune response molecules was quantified by real-time polymerase chain reaction and enzyme-linked immunoassay. RESULTS: AM and ESK-1 cells responded differently to P. gingivalis and E. coli LPS stimulation. The ESK-1 gingival fibroblast cell line was more responsive to E. coli LPS stimulation as seen by elevated levels of interleukin (IL)-6, inducible nitric oxide, and monocyte chemotactic protein-1 expression relative to stimulation by P. gingivalis LPS. Conversely, the AM macrophage cell line was more responsive to P. gingivalis LPS stimulation, particularly for interleukin IL-1beta, IL-6, and monocyte chemotactic protein-1, relative to stimulation by E. coli LPS. CONCLUSION: These findings demonstrate that E. coli LPS induces a stronger cytokine and chemokine response in gingival fibroblasts, whereas P. gingivalis LPS induces a stronger response in macrophages. PMID- 20843234 TI - Study of orthophosphate, pyrophosphate, and pyrophosphatase in saliva with reference to calculus formation and inhibition. AB - BACKGROUND: A large amount of calculus may hamper the efficacy of daily oral hygiene and thereby accelerate plaque formation. Salivary concentrations of orthophosphate and pyrophosphate are important in preventing calculus formation. Activity of orthophosphate, pyrophosphate, and pyrophosphatase was studied in whole saliva in calculus-forming groups and plaque-forming groups. METHODS: The material for this study consists of 60 healthy individuals (age range: 15 to 30 years; mean age: 22 years). Depending on calculus index score, individuals were divided into four groups, each of 15 patients: Group 1, calculus index score 0 to 0.6; Group 2, calculus index score 0.7 to 1.8; Group 3, calculus index score 1.9 to 3; and Group 4, plaque group where index varied from 0 to 3. The saliva was collected and biochemically analyzed for concentration of orthophosphate, pyrophosphate, and pyrophosphatase. RESULTS: The mean values of orthophosphate in Groups 1, 2, 3, and 4 were 0.2559, 1.3639, 1.7311, and 0.1868 mM, respectively. The mean values of pyrophosphate in Groups 1, 2, 3, and 4 were 0.3258, 0.1091, 0.0314, and 0.3860 mM, respectively. The mean values of pyrophosphatase in Groups 1, 2, 3, and 4 were 10.7937, 15.4249, 27.2900, and 7.5427 units/ml, respectively. CONCLUSIONS: A holistic approach toward the control of periodontal disease should include antiplaque and anticalculus agents. The results are conclusive that the components orthophosphate, pyrophosphate, and pyrophosphatase present in saliva have a very significant role to play in formation and inhibition of calculus. This study reinforces the idea of using pyrophosphate and newer bisphosphonates as potential anticalculus agents. PMID- 20843235 TI - Effects of enamel matrix derivative on vascular endothelial growth factor expression and microvessel density in gingival tissues of periodontal pocket: a comparative study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) stimulates proliferation and migration of endothelial cells, and correlates with inflammatory resolution and periodontal tissue healing. Enamel matrix derivative (EMD) seems to stimulate soft tissue healing. Our aim was to assess if topical EMD application in an instrumented periodontal pocket could affect angiogenesis at the gingival level. METHODS: A total of 56 periodontal sites in 28 patients were treated with a single session of comprehensive scaling and root planing under local anesthesia after recording the clinical attachment level (CAL). EMD gel in the test site or only the vehicle propylene glycol alginate in aqueous solution in the control site of the same mouth was applied onto the root surfaces and into the pocket and left in place for 3 minutes. After 48 hours, gingival biopsies were collected for histologic and immunohistochemical analysis for VEGF and CD34 (for microvessel density [MVD] count) antibodies. Statistical comparisons were performed by analysis of variance test. RESULTS: Endothelial VEGF expression and MVD were statistically different in the test site compared to the control site. VEGF expression and MVD of the control site were not correlated with CAL, whereas the test site showed high correlations among CAL and endothelial VEGF or MVD. CONCLUSIONS: EMD induces proliferation and viability and angiogenesis of human microvascular cells. Recent clinical and histologic studies found EMD to be useful as an adjunct to scaling and root planing in single-rooted teeth. Our findings may help to understand the mechanisms involved in soft tissue healing, through the ability of EMD to increase angiogenesis at periodontal pockets. PMID- 20843236 TI - Efficacy and safety of adjunctive local moxifloxacin delivery in the treatment of periodontitis. AB - BACKGROUND: Moxifloxacin exerts excellent antibacterial activity against most putative periodontal pathogens and has been shown to kill bacteria in biofilm and host cells. METHODS: Patients with chronic periodontitis were randomly assigned to receive a single subgingival application of a 0.125%, 0.4%, or 1.25% moxifloxacin gel or placebo gel immediately after full-mouth scaling and root planing (SRP). Clinical efficacy measurements were assessed in sites with baseline probing depth (PD) of >=5.4 mm at 6 weeks and 3 months and any adverse events were determined. In addition, putative periodontal pathogens and resistance of subgingival bacteria against moxifloxacin were assessed. RESULTS: Data of 57 patients were included in the statistical analysis. In all treatment groups, the PD decreased from baseline to 3 months, with the greatest reduction seen in patients treated with moxifloxacin 0.4% (1.5 +/- 0.6 mm; P = 0.023 compared to placebo), followed by patients receiving moxifloxacin 1.25% (1.2 +/- 0.4), moxifloxacin 0.125% (1.1 +/- 1.1), and placebo (1.0 +/- 0.6). No linear trend for PD reduction with increasing moxifloxacin concentrations was found. Porphyromonas gingivalis showed the greatest reduction in prevalence among the assessed pathogens, without any significant intergroup differences. No correlation or systematic relationship between adverse events, including bacterial resistance against moxifloxacin, and the investigational gels was found. CONCLUSIONS: In periodontal pockets with PD of >=5.4 mm, a single subgingival administration of a 0.4% moxifloxacin gel as an adjunct to SRP may result in additional PD reduction compared to SRP alone. In addition, the investigated moxifloxacin gels seem to be safe. PMID- 20843237 TI - Anemia of chronic disease and chronic periodontitis: does periodontal therapy have an effect on anemic status? AB - BACKGROUND: As the periodontal tissues mount an immune inflammatory response to bacteria and their products, the systemic challenge with these agents also induces a major vascular response. Certain inflammatory cytokines produced during periodontal inflammation can depress erythropoietin production leading to the development of anemia. The aim of this study is to investigate whether patients with chronic periodontitis have an anemic status, and subsequently, to analyze the effect of non-surgical periodontal therapy on the anemic status of subjects over a 6-month period. METHODS: A total of 187 patients with chronic periodontitis participated in the study. After red blood cell analyses, 60 patients with hemoglobin concentrations below reference ranges entered into the second part of the study in which patients were treated with non-surgical periodontal therapy. Clinical parameters and red blood cell analyses were repeated at 3 and 6 months. RESULTS: In the first part of the study, 33.6% of patients had hemoglobin concentrations below normal reference ranges. In the second part of the study, all red blood cell parameters and clinical parameters showed statistical improvements over a 6-month period. CONCLUSION: The present study strengthens the hypothesis that chronic periodontitis may lead to anemia and provides evidence that non-surgical periodontal therapy can improve the anemic status of patients with chronic periodontitis with greater improvement in females. PMID- 20843240 TI - The safety of tiotropium--the FDA's conclusions. PMID- 20843241 TI - Preparing for a consumer-driven genomic age. PMID- 20843242 TI - Risks of presymptomatic direct-to-consumer genetic testing. PMID- 20843243 TI - "Liberating the NHS"--another attempt to implement market forces in English health care. PMID- 20843245 TI - Neuromuscular blockers in early acute respiratory distress syndrome. AB - BACKGROUND: In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS. METHODS: In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. RESULTS: The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups. CONCLUSIONS: In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hopitaux de Marseille and the Programme Hospitalier de Recherche Clinique Regional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.) PMID- 20843246 TI - Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. AB - BACKGROUND: Myelofibrosis is a Philadelphia chromosome-negative myeloproliferative neoplasm associated with cytopenias, splenomegaly, poor quality of life, and shortened survival. About half of patients with myelofibrosis carry a gain-of-function mutation in the Janus kinase 2 gene (JAK2 V617F) that contributes to the pathophysiology of the disease. INCB018424 is a potent and selective Janus kinase 1 (JAK1) and JAK2 inhibitor. METHODS: We conducted a phase 1-2 trial of INCB018424 in patients with JAK2 V617F-positive or JAK2 V617F-negative primary myelofibrosis, post-essential thrombocythemia myelofibrosis, or post-polycythemia vera myelofibrosis. RESULTS: A total of 153 patients received INCB018424 for a median duration of more than 14.7 months. The initial dose-escalation phase established 25 mg twice daily or 100 mg once daily as maximum tolerated doses, on the basis of reversible thrombocytopenia. A dose dependent suppression of phosphorylated signal transducer and activator of transcription 3 (STAT3), a marker of JAK signaling, was demonstrated in patients with wild-type JAK2 and in patients with the JAK2 V617F mutation. We studied additional doses and established that a 15-mg twice-daily starting dose, followed by individualized dose titration, was the most effective and safest dosing regimen. At this dose, 17 of 33 patients (52%) had a rapid objective response (>=50% reduction of splenomegaly) lasting for 12 months or more, and this therapy was associated with grade 3 or grade 4 adverse events (mainly myelosuppression) in less than 10% of patients. Patients with debilitating symptoms, including weight loss, fatigue, night sweats, and pruritus, had rapid improvement. Clinical benefits were associated with a marked diminution of levels of circulating inflammatory cytokines that are commonly elevated in myelofibrosis. CONCLUSIONS: INCB018424 was associated with marked and durable clinical benefits in patients with myelofibrosis for whom no approved therapies existed. (Funded by Incyte; ClinicalTrials.gov number, NCT00509899.) PMID- 20843248 TI - Smoke-free legislation and hospitalizations for childhood asthma. AB - BACKGROUND: Previous studies have shown that after the adoption of comprehensive smoke-free legislation, there is a reduction in respiratory symptoms among workers in bars. However, it is not known whether respiratory disease is also reduced among people who do not have occupational exposure to environmental tobacco smoke. The aim of our study was to determine whether the ban on smoking in public places in Scotland, which was initiated in March 2006, influenced the rate of hospital admissions for childhood asthma. METHODS: Routine hospital administrative data were used to identify all hospital admissions for asthma in Scotland from January 2000 through October 2009 among children younger than 15 years of age. A negative binomial regression model was fitted, with adjustment for age group, sex, quintile of socioeconomic status, urban or rural residence, month, and year. Tests for interactions were also performed. RESULTS: Before the legislation was implemented, admissions for asthma were increasing at a mean rate of 5.2% per year (95% confidence interval [CI], 3.9 to 6.6). After implementation of the legislation, there was a mean reduction in the rate of admissions of 18.2% per year relative to the rate on March 26, 2006 (95% CI, 14.7 to 21.8; P<0.001). The reduction was apparent among both preschool and school-age children. There were no significant interactions between hospital admissions for asthma and age group, sex, urban or rural residence, region, or quintile of socioeconomic status. CONCLUSIONS: In Scotland, passage of smoke-free legislation in 2006 was associated with a subsequent reduction in the rate of respiratory disease in populations other than those with occupational exposure to environmental tobacco smoke. (Funded by NHS Health Scotland.) PMID- 20843247 TI - Susceptibility to exacerbation in chronic obstructive pulmonary disease. AB - BACKGROUND: Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. METHODS: We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. RESULTS: Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. CONCLUSIONS: Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.) PMID- 20843249 TI - Erythropoietic response and outcomes in kidney disease and type 2 diabetes. AB - BACKGROUND: Non-placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 MUg vs. 167 MUg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.) PMID- 20843250 TI - Clinical practice. Idiopathic urgency urinary incontinence. PMID- 20843251 TI - Images in clinical medicine. Radiation proctitis. PMID- 20843252 TI - Case records of the Massachusetts General Hospital. Case 28-2010. A 32-year-old woman, 3 weeks post partum, with substernal chest pain. PMID- 20843253 TI - The Journal from 1812 to 1989 at NEJM.org. PMID- 20843254 TI - Neuromuscular blocking agents in ARDS. PMID- 20843255 TI - From palliation to targeted therapy in myelofibrosis. PMID- 20843256 TI - Frequent exacerbations of chronic obstructive pulmonary disease--a distinct phenotype? PMID- 20843257 TI - Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. PMID- 20843258 TI - Pediatric mental health care dysfunction disorder? PMID- 20843259 TI - LNK mutations in JAK2 mutation-negative erythrocytosis. PMID- 20843263 TI - Floral mimicry enhances pollen export: the evolution of pollination by sexual deceit outside of the orchidaceae. AB - Although the majority of flowering plants achieve pollination by exploiting the food-seeking behavior of animals, some use alternative ploys that exploit their mate-seeking behavior. Sexual deception is currently known only from the Orchidaceae and almost always involves pollination by male hymenoptera. An outstanding problem has been to identify the selective factors in plants that favor exploitation of mating versus feeding behaviors in pollinators. Here we show that the insectlike petal ornaments on inflorescences of the daisy Gorteria diffusa elicit copulation attempts from male bombyliid flies and that the intensity of the mating response varies across geographical floral morphotypes, suggesting a continuum in reliance on feeding through mating responses for pollination. Using pollen analogues applied to a morphotype with prominent insectlike petal ornaments, we demonstrate that mate-seeking male flies are several-fold more active and export significantly more pollen than females. These results suggest that selection for traits that exploit insect mating behavior can occur through the male component of plant fitness and conclusively demonstrates pollination by sexual deception in Gorteria, making this the first confirmed report of sexual deception outside of the Orchidaceae. PMID- 20843264 TI - The International Classification of Functioning, Disability and Health and the version for children and youth as a tool in child habilitation/early childhood intervention--feasibility and usefulness as a common language and frame of reference for practice. AB - Early childhood intervention and habilitation services for children with disabilities operate on an interdisciplinary basis. It requires a common language between professionals, and a shared framework for intervention goals and intervention implementation. The International Classification of Functioning, Disability and Health (ICF) and the version for children and youth (ICF-CY) may serve as this common framework and language. This overview of studies implemented by our research group is based on three research questions: Do the ICF-CY conceptual model have a valid content and is it logically coherent when investigated empirically? Is the ICF-CY classification useful for documenting child characteristics in services? What difficulties and benefits are related to using ICF-CY model as a basis for intervention when it is implemented in services? A series of studies, undertaken by the CHILD researchers are analysed. The analysis is based on data sets from published studies or master theses. Results and conclusion show that the ICF-CY has a useful content and is logically coherent on model level. Professionals find it useful for documenting children's body functions and activities. Guidelines for separating activity and participation are needed. ICF-CY is a complex classification, implementing it in services is a long-term project. PMID- 20843265 TI - Comparison of XTT and Alamar blue assays in the assessment of the viability of various human cancer cell lines by AT-101 (-/- gossypol). AB - This study compared the two different commercially available in vitro viability assays: XTT and Alamar blue (AB), to detect anti-proliferative effects of AT-101, a cotton plant extract, on six different human carcinoma cell lines including: prostate (PC-3 and DU-145), breast (MCF-7 and MDA-MB-231), and ovary (OVCAR-3 and MDAH 2774) in a time- and dose-dependent manner. Cells were exposed to AT-101 in the concentration range of 2.5-40 uM for 24, 48, and 72 h. The AB assay was slightly more sensitive than the XTT assay in the evaluation of AT-101 at 24 h, suggesting that the AB assay might be used for detecting early changes in cell viability as compared to the XTT assay. Moreover, the AB assay showed less intra assay variability as compared to the XTT. The non-toxic, non-radioactive AB metabolism assay allows rapid assessment of large numbers of samples, with simple equipment and at reduced cost for continuous monitoring of cancer cell viability, and, thus, should be accepted as a suitable alternative viability method. PMID- 20843266 TI - Effect of glutathione combined with cisplatin and oxaliplatin on the proliferation and apoptosis of lung carcinoma cell line. AB - Reduced glutathione (GSH) is generally administered for patients with cancer to reduce the side-effects of anti-cancer drugs. However, whether its protective effects interfere with anti-carcinogenicity is still unclear. The aim of this study was to investigate the effect of exogenous GSH on effects of oxaliplatin (L OHP) or cisplatin (CDDP) by observing the proliferation and apoptosis of lung carcinoma cell line A549. Cell proliferation was evaluated by sulforhodamine-B assay and morphological changes were observed by an inverted microscope. Cell cycle distribution and apoptosis rate were observed by flow cytometry (FCM). Results showed that GSH did not change the inhibiting effects of L-OHP and CDDP on A549 proliferation, and did not reduce the apoptosis induced by CDDP. The FCM analysis showed the GSH combined with the CDDP group had fewer cells in the S phase and had an apoptotic peak, which was not significantly different from that of the CDDP alone group (p>0.05). These results indicated that GSH does not reduce the effects of L-OHP and CDDP to inhibit A549 growth in vitro, and doesn't affect the apoptosis induced by CDDP. PMID- 20843267 TI - Influence of extraneous supplementation of zinc on trace elemental profile leading to prevention of dimethylhydrazine-induced colon carcinogenesis. AB - Trace elemental analyses of cancerous tissue is a less explored field of inquiry in cancer research. If the deficiency or excess of a particular trace element can be linked to the cancer, studies can be initiated to see its controlled administration to check the growth of cancer. The present study explored the prophylactic potential of zinc in experimental colon carcinogenesis and also its interaction with other trace metals, which gets altered during the development of colon cancer. Rats were segregated into four groups viz., normal control, dimethylhydrazine (DMH) treated, zinc treated, DMH+zinc treated. Initiation and induction of colon carcinogenesis was achieved through weekly subcutaneous injections of DMH (30 mg/Kg body weight) dissolved in 1 mM EDTA-normal saline (pH 6.5), for 8 and 16 weeks, respectively. Zinc was supplemented at a dose level of 227 mg/L in drinking water, for 8 and 16 weeks. The elemental analyses of colonic samples were carried out using Energy Dispersive X-Ray Fluorescence technique (EDXRF). Zinc administration to DMH treated rats significantly decreased the tumor incidence, tumor multiplicity with simultaneous decrement in tumor size. EDXRF studies revealed that the concentrations of the elements zinc, chromium, manganese and copper were decreased, whereas the concentration levels of iron were found to be increased in the colon tissues following 8 and 16 weeks of DMH treatment. However, zinc supplementation to DMH-treated rats significantly improved the altered levels of elements when compared to DMH-treated animals indicating the chemopreventive role of zinc. In conclusion, DMH induced colon carcinogenesis is accompanied by altered trace element profile and zinc has a positive beneficial effect against chemically-induced colonic carcinogenesis. PMID- 20843268 TI - Protective effect of Phyllanthus niruri on alcohol and heated sunflower oil induced hyperlipidemia in Wistar rats. AB - The relationship between chronic alcohol consumption and various hepatic lesions are grouped under the term alcoholic liver disease. This is an extremely common disease with a high mortality. Alcoholics, along with alcohol, consume high fat diet and are susceptible to permanent liver damage. The current treatment modalities are inadequate and the need for effective treatment without side effects is increasing. The present work tested the protective role of Phyllanthus niruri aqueous leaf extract on alcohol and heated sunflower oil-induced hyperlipidemia. Male albino rats of Wistar strain were used for this study. This study analyzed the variation in lipid profiles; cholesterol, triglycerides, phospholipids, and free fatty acids in liver, histopathological changes, and the activities of liver marker enzymes in the plasma. The liver damage was apparent with the increase in the activities of AST and ALT in the rats treated with alcohol + heated sunflower oil (DeltaPUFA). Treatment with P.niruri protected the liver from damage, and prevented the release of the liver markers enzymes. The levels of cholesterol, triglycerides, and free fatty acids were increased significantly in the alcohol + DeltaPUFA group. Administration of P.niruri extract effectively reduced their levels. The phospholipid levels, which were decreased in the liver of the alcohol + DeltaPUFA group, were positively modulated by treatment with P.niruri. The histopathological observations were also in correlation with the biochemical parameters. From the results obtained, one could conclude that the P.niruri leaf extract effectively protects the system against alcohol and DeltaPUFA-induced hyperlipidemia and has a definite anti hyperlipidemic potential. PMID- 20843269 TI - Acute secretory cell toxicity and epithelial exfoliation after smoke inhalation injury in sheep: an electron and light microscopic study. AB - Smoke inhalation injury promotes exfoliation of the upper airway columnar epithelium. Tracheal tissues from sheep 30 min after smoke exposure show intact epithelial areas, areas of epithelial disruption with loss of columnar cells and areas denuded of columnar cells. In intact areas detaching ciliated cells can be seen raised above the apical surface. This study aims to assess cell-specific toxicity by examining intact epithelium after inhalation injury. The junctional adhesion integrity between columnar and basal cells and the type of cells initially being displaced were also studied using light (LM) and transmission electron microscopy (TEM). TEM assessment of intact areas of sheep tracheal tissue (n=3) 30 min after exposure showed secretory cell toxicity including extrusion of cytoplasmic contents. In cells with severe secretory cell cytoplasmic disruption, loss of desmosomal junctions between the secretory and adjacent ciliated cells was evident. The number of desmosomes visible between columnar cells and basal cells was reduced (2.8 +/- 1.8) in smoke-exposed animals compared to those in uninjured animals (5.0 +/- 2.7), p=0.008. Serial sections of intact regions found 52 cells being displaced from the epithelium. All detaching cells were identified as ciliated cells. These studies show that the acute effects of inhalation injury include selective secretory cell toxicity which is associated with loss of junctional adhesion mechanisms and displacement of ciliated cells. Improved understanding of acute hypersecretory responses and epithelial integrity after exposure to toxic agents may improve understanding of epithelial fragility in airway disease. PMID- 20843270 TI - Protective effects of Danshensu on liver injury induced by omethoate in rats. AB - This study was to evaluate the protective effects of Danshensu on liver injury induced by omethoate in Sprague Dawley rats. The acute omethoate poisoning model was established by administrating subcutaneously with omethoate at a single dose of 60 mg/kg. Danshensu treatment markedly inhibited the increases of aspartate aminotransferase, alanine aminotransferase, cyclooxygenase-2, tumor necrosis factor-alpha, thromboxane B(2), and thromboxane B(2)/6-keto-PGF1alpha ratio induced by omethoate. The histopathological examination further confirmed that administration with Denshensu ameliorated liver injury. The results demonstrated that Danshensu possesses protective action on hepatic injury induced by omethoate and the pharmacological mechanism was related to the anti-inflammatory effect and circulation improvement of Danshensu, at least in part. PMID- 20843271 TI - Dimerization of G protein-coupled purinergic receptors: increasing the diversity of purinergic receptor signal responses and receptor functions. AB - It is well accepted that G protein-coupled receptors (GPCRs) arrange into dimers or higher-order oligomers that may modify various functions of GPCRs. GPCR-type purinergic receptors (i.e. adenosine and P2Y receptors) tend to form heterodimers with GPCRs not only of the different families but also of the same purinergic receptor families, leading to alterations in functional properties. In the present review, we focus on current knowledge of the formation of heterodimers between metabotropic purinergic receptors that activate novel functions in response to extracellular nucleosides/nucleotides, revealing that the dimerization seems to be employed for 'fine-tuning' of purinergic signaling. Thus, the relationship between adenosine and adenosine triphosphate is likely to be more and more intimate than simply being a metabolite of the other. PMID- 20843273 TI - Non-coplanar polychlorinated biphenyl (PCB)-induced immunotoxicity is coincident with alterations in the serotonergic system. AB - Attention to non-coplanar polychlorinated biphenyl (PCB) congeners in immunotoxicological research is increasing. However, the exact mechanism by which these congeners may induce immune dysfunction is still undefined. Because the serotonergic nervous system has been shown to be involved in the regulation of some immune responses, and also serves as a sensitive target for PCBs, the relationship (if any) between non-coplanar PCB exposure, immune responsiveness and the neurotransmitter serotonin (5-HT) was examined. Using bluegill sunfish (Lepomis macrochirus) as a model, changes in brain 5-HT levels, 5-HT synthesis and metabolism, and innate and cell-mediated immune parameters were evaluated following a single intraperitoneal injection of PCB 153 (5.0 or 50 MUg/g body weight). Results revealed that 3 d following administration, PCB exposure decreased brain 5-HT levels (in the absence of effects on some enzymes involved in 5-HT synthesis and metabolism), increased oxyradical production by kidney phagocytes, and reduced splenic T- and B-lymphocyte proliferation. In vivo treatment of PCB-exposed fish with 5-hydroxy-L-tryptophan (the immediate precursor to 5-HT) ameliorated the observed PCB-induced immunotoxicity; in vitro treatment of immune cells from PCB-exposed fish with 5-HT failed to reverse the effects. Taken together, results from this study could suggest a link between PCB induced alterations of brain 5-HT levels and subsequent immune dysfunction. These studies highlight the importance of indirect mechanisms of immunotoxicity, and, specifically, suggest a role for the neuroimmune axis in non-coplanar PCB-induced immune alterations. PMID- 20843274 TI - Difference in growth hormone response to growth hormone-releasing hormone (GHRH) testing following GHRH subacute treatment in normal aging and growth hormone deficient adults: possible perspectives for therapeutic use of GHRH or its analogs in elderly subjects? AB - The somatotroph axis function shows a decline in the elderly (somatopause). In particular growth hormone (GH) response to GH-releasing hormone (GHRH) is reduced in aged man but less than that observed in GH-deficient adults (GHDAs). Plasma GH response to GHRH (1 ug/kg BW) was significantly lower in four GHDAs than in seven healthy aged men 30, 60, and 90 min after acute GHRH administration. To verify whether a priming regimen might be able to increase the reduced GH response to GHRH, both healthy aged men and GHDA patients underwent repetitive administration of GHRH (100 ug GHRH intravenously as a single morning dose, every 2 days for 12 days). After the GHRH-priming regimen, plasma GH values 30, 60, and 90 min after the acute GHRH test were significantly higher than values at the corresponding time points before priming regimen in healthy aged men but not in GHDA patients. These findings confirmed that somatotroph cells become less sensitive to GHRH with normal aging and demonstrate that repetitive administration of GHRH restores the attenuated response only in healthy aged men but not in GHDA patients. This could support the possible use of GHRH or its analogs instead of recombinant human GH in elderly patients with the advantage of preserving the endogenous pulses of GH with the secretion of the different isoforms of GH. However, concerns arise about the possible role of these molecules in tumorigenesis and tumor growth promotion. PMID- 20843272 TI - Protein tyrosine nitration in cellular signal transduction pathways. AB - How specificity and reversibility in tyrosine nitration are defined biologically in cellular systems is poorly understood. As more investigations identify proteins involved in cell regulatory pathways in which only a small fraction of that protein pool is modified by nitration to affect cell function, the mechanisms of biological specificity and reversal should come into focus. In this review experimental evidence has been summarized to suggest that tyrosine nitration is a highly selective modification and under certain physiological conditions fulfills the criteria of a physiologically relevant signal. It can be specific, reversible, occurs on a physiological time scale, and, depending on a target, can result in either activation or inhibition. PMID- 20843275 TI - Nodular fasciitis of the hand in a young athlete. A case report. AB - Nodular fasciitis is a rapidly growing mass, with high cellularity and mitotic activity, that can be both clinically and histologically misdiagnosed as a soft tissue sarcoma. Nodular fasciitis of the hand is an extremely rare condition. We report a 17-year-old male hand-ball player with nodular fasciitis in the dominant hand. The patient presented with a rapidly growing mass in his right hand and no history of major trauma. On physical examination, a painful mass measuring 2 cm in diameter was observed in the first web space. Magnetic resonance imaging (MRI) demonstrated a subcutaneous mass with isointensity on T1-weighted images and inhomogeneous high intensity on T2-weighted images. The lesion was inhomogeneously enhanced after intravenous administration of gadolinium. Moreover, thallium-201 scintigraphy showed high uptake at the early phase and no wash-out at the delayed phase. We performed an excisional biopsy. The mass was present subcutaneously and adhered to the interosseous muscle fascia. Although a pathological examination by frozen section during surgery showed a low-grade spindle cell sarcoma, the final histological diagnosis was nodular fasciitis. There was no evidence of local recurrence at the recent follow-up 2 years after the operation. We speculate that repeated small injuries as a result of sports activities played an important causative role in the nodular fasciitis. PMID- 20843276 TI - Apoptosis of gut-associated lymphoid tissue in rainbow trout Oncorhynchus mykiss after incubation with Candida albicans and bacterial lipopolysaccharide. AB - Until now a few studies have been carried out on the gut lymphoid system in fish despite its protective role in the host. Here, we have evaluated the effects of Candida albicans (Ca) and lipopolysaccaride (LPS) on the pyloric and terminal segments of gut in the rainbow trout Oncorhynchus mykiss. In particular, data show that both Ca and LPS are able to cause apoptosis of intestinal lymphoid cells as detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) procedure. These findings suggest a further modality of gut response in fish to environmental antigens. PMID- 20843277 TI - Oxidant generation capacity of source-apportioned PM2.5. AB - While many studies found associations between ambient particulate matter (PM) and morbidity or mortality outcomes, it is unclear whether these associations were dependent on the composition of PM, which varies with the source of that PM. We address this knowledge gap by conducting a time-series PM-health effects assessment that specifically investigates the role of source-apportioned fine PM (PM2.5) on the oxidant generation capacity that might be responsible for respiratory and cardiovascular health outcomes. Daily PM2.5 composition speciation and black carbon (BC) measurements, conducted in rural New York for 303 days between March 2003 and January 2005, were analyzed using factor analysis source-apportionment model, and five source categories (transported aerosol/secondary sulfate, resuspended soil, metals, residual oil combustion, and industrial/incineration) were identified. After the exposure of human epithelial cells (BEAS-2B) to these PM2.5 samples, cellular nuclear factor-kappaB (NF kappaB) activation showed a relatively significant association Ni (concentration averaging 38 ng/m(3)), and weaker but still significant correlations with Ba (13 ng/m(3)), Mn (9 ng/m(3)), and Fe (500 ng/m(3)). The single-source regression analysis of NF-kappaB signal showed significant association with metal source only. Our results showed that metals in PM2.5 were the important source for cellular oxidant generation and may be responsible for subsequent health effects associate with particle air pollution. PMID- 20843278 TI - The time-dependent protective effect of hyperbaric oxygen on neuronal cell apoptosis in carbon monoxide poisoning. AB - INTRODUCTION: The progressive clinical course with delayed neurological damage in carbon monoxide (CO) poisoning may be due to neuron apoptosis. The usefulness of hyperbaric oxygen (HBO) in different time periods after CO exposure in neuronal cell apoptosis reduction has not been evaluated thus far. The aim was to evaluate HBO efficacy in reducing neuronal apoptosis in different time periods after CO exposure. METHODS: Wistar rats were exposed to 3000 ppm CO in air for 60 min and 100% oxygen at a pressure of three bar for 30 min 0-12 h after CO exposure. The apoptosis was evaluated by immunohistochemical analysis with antibodies against activated caspase-3 and the percentage of caspase-3 positive hippocampal ganglionic cells was reported. RESULTS: It was shown that CO poisoning results in ganglionic cell apoptosis. The percentage of apoptotic cells in rats exposed to CO was the highest (32%), whereas the percentage of apoptotic cells in rats exposed to HBO 0 and 1 h after CO was similar with a lower percentage than rats exposed to CO. The percentage of apoptotic cells in rats exposed to HBO 3 and 5 h after CO was similar with a lower percentage than rats exposed to HBO 0 and 1 h after CO. The percentage of apoptotic cells in rats exposed to HBO 7-12 h after CO was similar with a higher percentage than rats exposed to HBO 5 h after CO. CONCLUSION: HBO has a time-dependent protective effect on CO-induced neuron apoptosis with the highest efficiency at 3 and 5 h after CO poisoning. PMID- 20843279 TI - ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. AB - IMPORTANCE OF THE FIELD: The identification of xenobiotic metabolizing enzymes (i.e., CYP) and transporters (i.e., ABC transporters) (XMET) in the human brain, including the BBB, raises the question whether these transporters and enzymes have specific functions in brain physiology, neuropharmacology and toxicology. AREAS COVERED IN THIS REVIEW: Relevant literature was identified using PubMed search articles published up to March 2010. Search terms included 'ABC transporters and P450 or CYP', 'drug metabolism, effect and toxicity' and 'neurodegenerative disease (Alzheimer and Parkinson diseases)' restricted to the field of 'brain or human brain'. WHAT THE READER WILL GAIN: This review aims to provide a better understanding of XMET functions in the human brain and show their pharmacological importance for improving drug delivery and efficacy and also for managing their side effects. Finally, the impact of brain XMET activity during neurodegenerative processes is discussed, giving an opportunity to identify new markers of human brain diseases. TAKE HOME MESSAGE: During the last 2 decades, much evidence concerning the specific distribution patterns of XMET, their induction by xenobiotics and endobiotics and their genetic variations have made cerebral ABC transporters and CYP enzymes key elements in the way individual patients respond to centrally acting drugs. PMID- 20843280 TI - Highlights of the XII International Congress on Toxicology, 19 - 23 July 2010, Barcelona, Spain. AB - IMPORTANCE OF THE FIELD: There are few true international meetings dedicated to covering multiple areas of toxicology. The XII International Congress of Toxicology (IUTOX) held from 19 to 23 July 2010 in Barcelona, Spain is one such meeting. The IUTOX is important as its emphasis is on chemical safety and integrating approaches and alternative possibilities to protecting public health. The meeting was an important forum with professional interactions in different subspecialties of toxicology addressing these current topics. AREAS COVERED IN THIS REVIEW: The basis of toxic effects including mechanistic, effects testing, monitoring and alternative methods are covered in this meeting highlights article. Coverage of industry, clinical toxicologists, environmentalists, regulators and technological developers is provided. WHAT THE READER WILL GAIN: Insight into the coverage of topics discussed at the XII IUTOX meeting. TAKE HOME MESSAGE: Current topics in toxicology with international impact are presently centered on new testing strategies, biomarkers and understanding mechanisms of toxicity to help address the safety and risk of substances relevant to public health. PMID- 20843281 TI - Synthesis, characterization, and molecular structure of a novel zinc (II) complex: assessment of impact of MDR1Pgp expression on its cytotoxic activity. AB - Zinc(II)complex (3) {bis(3-ethoxy-2-hydroxy-benzylidene)-N,N'-bis(2,2-dimethyl-3 aminopropyl)ethylenediamine}-zinc(II); [(3-OEt-ENBDMPI)Zn(II)] was obtained in situ by a ligand exchange reaction involving zinc(II) acetylacetonate and the Schiff-base ligand obtained in situ. For assessing ability of 3 to act as a transport substrate of multidrug resistance (MDR1) P-glycoprotein (Pgp), its cytotoxic activity was evaluated in human epidermal carcinoma drug-sensitive KB 3 1 (Pgp-) and drug resistant KB 8-5 (Pgp+) cells. Compared with its cationic gallium(III) counterpart 4 showing cytotoxicity profiles consistent with its recognition as a Pgp substrate, the neutral zinc(II) complex 3 did not display cytotoxicity profiles (at pharmacologically relevant concentrations <10 uM) modified by expression of Pgp. Further, 3 was found be slightly more toxic against KB 8-5 cells compared to KB 3-1 cells at higher concentration. The neutral zinc (II) complex 3 was also found to be considerably less toxic against Pgp-lacking cells compared to its cationic gallium(III) counterpart 4. Additionally, the neutral zinc(II) complex 3 demonstrated considerably more toxicity against Pgp expressing KB 8-5 cells (> 10 uM) compared with its cationic counterpart 4 displaying minimal effect at highest concentration. The results suggest that differential cytotoxic activity of 3 and 4 in drug-resistant human epidermal carcinoma KB 8-5 (Pgp+) cells could result from variation in the overall charge of the molecules. PMID- 20843282 TI - Phytosterols in physiological concentrations target multidrug resistant cancer cells. AB - Phytosterols have been proposed to act as potent anticancer agents. However the mechanism of their action has not been elucidated yet. Thus, the aim of our study was to determine whether plant sterols and their thermal processing products (in physiological concentration range) could influence the viability of cancer cells and thus could be considered as positive diet complements. Additionally we decided to study potential specificity of those natural compounds against cells showing high multidrug resistance. In this study we show that the cytotoxic effect of beta-sitosterol was observed in both, estrogen-dependent and estrogen independent cells. It was also shown that the beta-sitosterol was significantly more cytotoxic in cells with basal ABCB1 expression (MCF7) than in multidrug resistant NCI/ADR-RES. Surprisingly, 5a,6a-epoxysitosterol did not decrease the viability of any investigated cells but on the contrary, it provoked their increased proliferation. It was shown that oxyphytosterols blocked the cell cycle of MCF7 cells in G0/G1 phase while did not affect NCI/ADR-RES cell cycle in physiological concentration range. We also show that PgP activity (responsible for Multidrug Resistance phenomena) is inhibited by beta-sitosterol. Thus, the phytosterols are supposed to act at various mechanisms but, what is most interesting, can target cells showing high multidrug resistance potential. PMID- 20843283 TI - Polycationic polymers and drugs: investigations into interactions between acyclovir and polymers. AB - Interactions between pharmaceutical ingredients play an important role in the development of drug formulations. It was the aim of our present studies to investigate drug-polymer interactions. Interaction of the antiviral drug acyclovir with polyethylenimines, polyvinylamines and the non-ionic PVP was investigated using a modified equilibrium dialysis. The membrane was only permeable to free acyclovir, while polymers and acyclovir-polymer-associates did not pass through. Significant amounts of acyclovir were bound with the polyethylenimines. The formation of associates consisting of acyclovir and either PVP or polyvinylamine could not be demonstrated. In solutions of acyclovir and polyethylenimine (Mr=25,000) the amount of bound drug is increased with increasing concentration of acyclovir. Between 7.9 ug and 31.7 ug take part in the formation of associates. Differences in the osmotic pressure of the solutions do not play an important role in the permeation of acyclovir. In solutions containing acyclovir and high molecular weight polyethylenimine (Mr=750,000) the bound amount of drug increases with increasing acyclovir concentration up to c(0)=400 ug/100 ml. Further addition of free drug to the solution does not change the amount of bound drug significantly, due to possible limitations in the binding capacity. Molecular modeling investigations were performed. According to the calculations, about 85% of the interactions can be attributed to electrostatic interactions. PMID- 20843284 TI - Oseltamivir: a first line defense against swine flu. AB - Oseltamivir (has known by its brand name 'Tamiflu') is a prodrug, requiring ester hydrolysis for conversion to the active form, Oseltamivir carboxylate. Oseltamivir was the first orally active neuraminidase inhibitor commercially developed by US based Gilead Sciences and is currently marketed by F. Hoffmann-La Roche (Roche). Oseltamivir is an antiviral drug which works by blocking the function of the viral neuraminidase protein. US FDA approved Oseltamivir for prophylaxis of uncomplicated influenza A and B. Currently, Oseltamivir is the only first line defense drug available for the treatment of Swine Flu. Orally Oseltamivir is well tolerated and effective in treatment of influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease. Many of the pharmaceutical companies targeted Oseltamivir as a block buster molecule. In present review, we have tried to cover chemistry, mode of binding, total synthesis, current patent status, adverse effect and clinical status of Oseltamivir giving emphasis on medicinal chemistry aspect. PMID- 20843285 TI - 3D QSAR studies on 1, 3, 4-thiadiazole derivatives: an approach to design novel anticonvulsants. AB - A three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a series of 1, 3, 4-thiadiazole derivatives reported as anticonvulsant employing self-organizing molecular field analysis (SOMFA) techniques to investigate the structural requirements for the design of novel anticonvulsant. The training set composed of twenty two 1, 3, 4-thiadiazole derivatives that exhibit a potent activity in MMS test while predictive power was evaluated using a test set of 7 molecules. Physicochemical determinants of binding, such as steric and electrostatic properties, were mapped onto the molecular structures of 1, 3, 4-thiadiazole in order to interpret graphically the SOMFA results in terms of master grids showing various field contributions. The present 3D-QSAR studies yielded stable and statistically robust models indicated by the moderate cross correlation coefficients which may prove to be a guideline for design of novel anticonvulsants. PMID- 20843286 TI - Dehydroepiandrosterone modulates survival and immune functions during sepsis depending on the way of drug administration. AB - BACKGROUND: Administration of dehydroepiandrosterone (DHEA) has been demonstrated to improve survival and cellular immune functions during systemic inflammation. Although there is evidence that the route of drug application may profoundly affect the DHEA-induced effects the impact of this parameter remains to be established. MATERIALS AND METHODS: Male NMRI mice were subjected to sham operation (laparotomy) or sepsis (cecal ligation and puncture). Animals received saline or DHEA (20 mg/kg/day) given either subcutaneously, intravenously, or intraperitoneally. Termination of animals was performed 48 hrs after induction of sepsis in order to monitor splenocyte proliferation ((3)H-thymidine incorporation assay), splenocyte apoptosis (Annexin V binding capacity), and cytokine release (IL-1beta and IL-6, ELISA). RESULTS: Subcutaneous DHEA administration improved the survival rate of septic mice 48 hrs after induction of CLP (75% vs. 47%). This effect was paralleled by a restoration of splenocyte proliferation, a decreased cellular apoptosis rate of splenocytes, and an attenuation of pro inflammatory cytokine release. In contrast, no significant effects on the survival rate or cellular immune functions were observed following intravenous or intraperitoneal DHEA administration. CONCLUSIONS: Subcutaneous administration of DHEA induced an increased survival rate and improved cellular immune functions in septic mice. In contrast, no comparable effects were noticed following intravenous or intraperitoneal administration of DHEA. PMID- 20843287 TI - Synthesis and preliminary biological evaluation of capsaicin derivatives as potential analgesic drugs. AB - A series of capsaicin derivatives were designed and synthesized, including 10 compounds which are the combination of capsaicin and dihydro capsaicin with ibuprofen through bridge chain. Preliminary biological tests suggested that some compounds had both anti-inflammatory activity and analgesic activity. And their pungency was lower. Based on these results, some of these molecules can be considered as lead candidates for the further development of analgesic drugs. PMID- 20843288 TI - Synthesis and pharmacological evaluation of novel 1-(2-(benzoyl-substituted-2 phenyl-1H-indol-5-carbony) hydrazinyloxy) vinyl nitrate derivatives as potent non ulcerogenic, analgesic and anti-inflammatory agents. AB - Six derivatives of 1-(2-(benzoyl-(substituted)-2-phenyl-1H-indole-5-carbony) hydrazinyloxy) vinyl nitrate were synthesized and tested in vivo for anti inflammatory, analgesic, and ulcerogenic properties. Synthesized compounds shown significant anti-inflammatory activity comparable to that of Diclofenac sodium in the carrageenan-induced rat paw edema test and all of the compounds were found to be equipotent to Diclofenac sodium in the acetic acid induced writhing analgesic model. Out of six derivatives two derivatives found to produce no ulceration in stomach specimen of rats; nitric oxide seems to contribute to their excellent safety profile which supports several endogenous GIT defense mechanisms, including increase in mucus, bicarbonate secretions, increase in mucosal blood flow, and inhibition of the activation of pro-inflammatory cells by which NO Indomethacin protects GI mucosa. PMID- 20843289 TI - New synthesis of tic-hydantoins sigma-1 ligands and pharmacological evaluation on cocaine-induced stimulant effects. AB - Activation of the newly identified sigma1 chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the sigma1 protein may lead to putative potent anti-cocaine agents. We report here a new and more convergent synthetic pathway to amino side chain substituted hydantoins. Twenty new analogs of our lead compound were synthesized. None of them showed better in vitro affinity for sigma1 receptor than our lead compound. Nevertheless, three of them, obtained as racemates, showed high in vitro affinity and selectivity for sigma1 receptor. A preliminary in vivo evaluation of their pharmacological activity identified compound 22 as one that increases cocaine-induced locomotor stimulation and therefore acts as a potential efficient sigma1 agonist. PMID- 20843290 TI - Treatment of Graves' hyperthyroidism with thionamides-derived drugs: review. AB - Thionamide-derived antithyroid drugs (ATD) have been in use for over half a century and much is now known about their mechanism of action, pharmacokinetics and clinical pharmacology. Candidates for first option ATD therapy are young adults, without large goitre. The recommended initial dose for patients without big goitre and mild hyperthyroidism is 20 mg of MMI/CBZ. The recommended maintenance doses are 5-10 mg of MMI/CBZ. In cases of big goitre and/or severe hyperthyroidism the recommended initial dose is 30 to 40 mg/day. PTU use should be restricted to first trimester of pregnancy, doses should be as low as possible (150 to 200 mg/day) and then changing to MMI is recommended. Treatment Duration should be of 12-18 months. ATD plus thyroxine combination therapy have not advantage on ATD alone. ATD plus L-Thyroxine regimens should be used to avoid hypothyroidism when patients are with maintenance doses of ATD drugs in order to relax monitoring. In this case a low dose of T4 50-75 ug per day is used. Breast feeding women with hyperthyroidism can be treated with MMI/CBZ. ATD will not stop until serum stimulating TSH-receptors antibodies values are within the normal range. We are waiting for results of ongoing studies of biochemical and/or genetic markers that will permit us to predict the outcome of these patients after ATD treatment is stopped. PMID- 20843291 TI - Hydrophilic interaction liquid chromatography-tandem mass spectrometry for drug development. AB - Hydrophilic interaction chromatography (HILIC) offers a difference in selectivity as compared to traditional normal phase and reversed-phase liquid chromatography and therefore has great potential for the separation of a variety of pharmaceuticals. This review is devoted to summarizing HILIC coupled to tandem mass spectrometric (MS/MS) methods for the rapid, sensitive and accurate determinations of small molecules employed for supporting drug discovery. The perspectives and challenges on performing HILIC-MS/MS assays are also presented. PMID- 20843292 TI - Emerging in vitro tools to evaluate cytochrome P450 and transporter-mediated drug drug interactions. AB - Drug-drug interactions comprise a significant cause of morbidity and mortality worldwide as they may lead to adverse clinical events, result in decrease/inactivation of the therapeutic effect of a drug, may enhance drug toxicity and indirectly compromise treatment outcomes and adherence. Drug transporters and drug metabolism enzymes govern drug absorption, distribution, metabolism, and elimination (ADME). Inhibition or induction of transporter and drug metabolism enzymes can alter the ADME of a co-administered drug, which may lead to drug-induced toxicity or lack of efficacy. This review assesses our current understanding of the in vitro methods of evaluating CYPs and transporter mediated DDI. The DDI prediction models based on in vitro assays are also discussed in this review. The applications, advantages and limitations of each method are also addressed in this review. PMID- 20843293 TI - Hepatocytes as a tool in drug metabolism, transport and safety evaluations in drug discovery. AB - The liver is the primary site of metabolism for most drugs. Its major roles include detoxification of the systemic and portal blood, and production and secretion of critical blood and biliary components. A number of liver-derived in vitro systems, such as slices, primary and immortalized hepatocytes, microsomes and S9 fractions are used to assess the metabolism and potential toxicity of new chemical entities. Over the past decade, primary hepatocytes have become a standard in vitro tool to evaluate hepatic drug metabolism, cytochrome P450 (P450) induction, and drug interactions affecting hepatic metabolism. While earlier, hepatocytes were used in suspension for metabolic stability evaluations, more recent studies have demonstrated the added value of using these over longer terms in primary culture. Primary hepatocyte cultures are particularly useful in the evaluation of low turn-over compounds. Hepatic transporter studies are recommended for drug candidates that are predominantly eliminated through the bile. An appropriate strategy is to use primary hepatocytes to assess uptake, followed by singly transfected cell lines to identify the specific transporter(s) involved. Primary hepatocytes can also be used to assess biliary clearance to enable improved hepatic clearance predictions. Newer technologies such as siRNA can be used to knock out specific transporters for more predictive evaluations of potential clinically-based drug-drug interactions. In vitro safety (toxicology) studies have historically been conducted using cell lines. There is increasing evidence that co-cultures of primary hepatocytes and Kupffer cells would be more predictive of the in vivo outcome, as this system provides the complete complement of drug metabolizing enzymes, transcription factors and cytokines necessary to get a more in vivo-like toxicological response. In this review, we will discuss standard and novel in vitro approaches for using primary hepatocytes to extrapolate clinical hepatic metabolism, transport and toxicity. PMID- 20843294 TI - The in silico prediction of human-specific metabolites from hepatotoxic drugs. AB - In this study we employed the use of the Meteor computational software program to perform predictions in silico on 17 hepatotoxic drugs for determining human specific drug metabolites. Congruence of the in silico predictions from a qualitative standpoint of drug metabolite structures was established by comparison to human in vivo drug metabolic profiles characterized in publically available clinical studies. A total of 87 human-specific metabolites were identified from the 17 drugs. We found that Meteor's positive predictions included 4 out of the 9 reported major metabolites (detected in excreta at a level of >10% of the administered p.o. dose) and 10 out of the 15 major phase II metabolites giving a total of 14 correctly predicted drug metabolite structures out of 23 major metabolites. A significant level of unconfirmed positive predictions resulted and discussion on reasons for this is presented. An example is given whereby the in silico metabolism prediction succeeded to predict the putative toxic pathway of one of the drugs whilst conventional rodent liver microsomal assays failed to predict the pathway. Overall, we describe a reasonable simulation of human metabolic profiling using this in silico method with this data set of hepatotoxic drugs now withdrawn from the market. We provide an in-depth and objective discussion of this first of its kind validation test using clinical study data with interest in the prediction human-specific metabolism. Further research is discussed on what areas need to be investigated to improve upon the predictive data. The strong potential of this method to predict human-specific drug metabolites suggests the utility of this computational tool to help support not only the discovery development of therapeutics but also the safety assessment in identifying drug metabolites early to protect patients prior to initiating clinical studies. PMID- 20843296 TI - Integration of physicochemical and pharmacokinetic parameters in lead optimization: a physiological pharmacokinetic model based approach. AB - There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization. PMID- 20843295 TI - Glutathione modulation and oxidative stress in human liver slices. AB - Glutathione (GSH) levels are modulated in human liver slices to evaluate if drug induced liver injury is enhanced by a poor liver GSH status. Liver slice GSH levels were decreased by: 1) BSO (L-buthionine-S-sulfoximine) to inhibit GSH synthesis, and by 2) APAP (acetaminophen) which consumes GSH via conjugation to a metabolite. In this study, methimazole (MMI) liver injury was evaluated in the presence of a poor GSH status. MMI was selected because its structural thione moiety is linked with hepatotoxicity and during metabolism GSH is co-oxidized. MMI (500-1000 uM) affected oxidative stress pathways and mitochondrial function, resulting in lower liver slice GSH and ATP levels. Co-incubation of MMI with BSO or APAP led to further decreases of GSH and ATP levels in some human livers, at time points and concentrations not detected with MMI alone. Variation in human response was evident and demonstrated that some subjects with a poor liver GSH status could be further compromised with high MMI concentrations. MMI induced an up-regulation of gene expression linked with the GSH pathway, mitochondrial GSH and inflammation. Co-treatment of MMI with BSO induced a mixed response of oxidative stress related genes and an up-regulation of heat shock genes. The combination of MMI with APAP increased the expression of genes involved with oxidative stress and anti-oxidant defense, likely to protect the cells from mitochondrial injury. In summary, MMI induces oxidative stress at high concentrations, which can be augmented when liver GSH levels are decreased by the co-administration of some drugs or health status. PMID- 20843297 TI - Emerging technologies for the study of drug metabolism and pharmacokinetics. PMID- 20843298 TI - beta-Catenin and Rho GTPases as downstream targets of TGF-beta1 during pulp repair. AB - TGF-beta1 (transforming growth factor-beta1) plays a central role in regulating proliferation, migration and differentiation of dental pulp cells during the repair process after tooth injury. Our previous study showed that p38 mitogen activated protein kinase may act downstream of TGF-beta1 signalling to effect the differentiation of dental pulp cells. However, the molecular mechanisms that trigger and regulate the process remain to be elucidated. TGF-beta1 interacts with signalling pathways such as Wnt/beta-catenin and Rho to induce diverse biological effects. TGF-beta1 activates beta-catenin signalling, increases beta catenin nuclear translocation and interacts with LEF/TCF to regulate gene expression. Morphologic changes in response to TGF-beta1 are associated with activation of Rho GTPases, but are abrogated by inhibitors of Rho-associated kinase, a major downstream target of Rho. These results suggest that the Wnt/beta catenin and Rho pathways may mediate the downstream events of TGF-beta1 signalling. PMID- 20843299 TI - Effects and mechanisms of ghrelin on cardiac microvascular endothelial cells in rats. AB - Ghrelin is thought to directly exert a protective effect on the cardiovascular system, specifically by promoting vascular endothelial cell function. Our study demonstrates the ability of ghrelin to promote rat CMEC (cardiac microvascular endothelial cell) proliferation, migration and NO (nitric oxide) secretion. CMECs were isolated from left ventricle of adult male Sprague-Dawley rat by enzyme digestion and maintained in endothelial cell medium. Dil-ac-LDL (1,1'-dioctadecyl 3,3,3',3'- tetramethylindocarbocyanine-labelled acetylated low-density lipoprotein) intake assays were used to identify CMECs. Cells were split into five groups and treated with varying concentrations of ghrelin as follows: one control non-treated group; three ghrelin dosage groups (1*10-9, 1*10-8, 1*10-7 mol/l) and one ghrelin+PI3K inhibitor group (1*10-7 mol/l ghrelin+20 MUmol/l LY294002). After 24 h treatment, cell proliferation capability was measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and Western blot for PCNA (proliferating cell nuclear antigen) protein expression. Migration of CMECs was detected by transwell assays, and NO secretion of CMECs was measured via nitrate reduction. Protein expression of AKT and phosphorylated AKT in CMECs was measured by Western blot after exposure to various concentrations of ghrelin and the PI3K inhibitor LY294002. Our results indicate that ghrelin significantly enhanced cell growth at concentrations of 10-8 mol/l (0.271+/-0.041 compared with 0.199+/-0.021, P = 0.03) and 10-7 mol/l (0.296+/ 0.039 compared with 0.199+/-0.021, P<0.01). However, addition of the PI3K/AKT inhibitor LY294002 inhibited the ghrelin-mediated enhancement in cell proliferation (0.227+/-0.042 compared with 0.199+/-0.021, P = 0.15). At a concentration between 10-8 and 10-7 mol/l, ghrelin caused a significant increase in the number of migrated cells compared with the control group (126+/-9 compared with 98+/-7, P = 0.02; 142+/-6 compared with 98+/-7, P<0.01), whereas no such change could be observed in the presence of 20 MUmol/l of the PI3K/Akt inhibitor LY294002 (103+/-7 compared with 98+/-7, P = 0.32). Ghrelin treatment significantly enhanced NO production in a dose-dependent fashion compared with the untreated control group [(39.93+/-2.12) MUmol/l compared with (30.27+/-2.71) MUmol/l, P = 0.02; (56.80+/-1.98) MUmol/l compared with (30.27+/-2.71) MUmol/l, P<0.01]. However, pretreatment with 20 MUmol/l LY294002 inhibited the ghrelin stimulated increase in NO secretion [(28.97+/-1.64) MUmol/l compared with (30.27+/-2.71) MUmol/l, P = 0.37]. In summary, we have found that ghrelin treatment promotes the proliferation, migration and NO secretion of CMECs through activation of PI3K/AKT signalling pathway. PMID- 20843300 TI - A comparison of primary oesophageal squamous epithelial cells with HET-1A in organotypic culture. AB - BACKGROUND INFORMATION: Carcinoma of the oesophagus is the sixth leading cause of cancer death in the western world and is associated with a 5-year survival of less than 15%. Recent evidence suggests that stromal-epithelial interactions are fundamental in carcinogenesis. The advent of co-culture techniques permits the investigation of cross-talk between the stroma and epithelium in a physiological setting. We have characterized a histologically representative oesophageal organotypic model and have used it to compare the most commonly used squamous oesophageal cell line, HET-1A, with primary oesophageal squamous cells for use in studies of the oesophageal epithelium in vitro. RESULTS: When grown in an organotypic culture with normal fibroblasts, the oesophageal carcinoma cell lines OE21 (squamous) and OE19 (adenocarcinoma) morphologically resembled the tumour of origin with evidence of stromal invasion and mucus production, respectively. However, HET-1A cells, which were derived from normal squamous oesophageal cells, appeared dysplastic and failed to display evidence of squamous differentiation. By comparison with primary oesophageal epithelial cells, the HET-1A cells were highly proliferative and did not express the epithelial markers E-cadherin or CK5/6 (casein kinase 5/6), or the stratified epithelial marker DeltaNp63, but did express the mesenchymal markers vimentin and N-cadherin. CONCLUSION: Studies of epithelial carcinogenesis will benefit from culture systems which allow manipulation of the stromal and epithelial layers independently. We have developed an organotypic culture using primary oesophageal squamous cells and fibroblasts in which a stratified epithelium with a proliferative basal layer that stains strongly for DeltaNp63 develops. This model will be suitable for the study of the molecular events in the development of Barrett's oesophagus. The most commonly used normal oesophageal squamous cell line, HET-1A, does not have the characteristics of normal oesophageal squamous cells and should not be used in models of the normal oesophageal epithelium. Until more representative cell lines are available, future studies in oesophageal cancer will be reliant on the availability and manipulation of primary tissue. PMID- 20843301 TI - Assessing the efficacy of a modified assertive community-based treatment programme in a developing country. AB - BACKGROUND: A number of recently published randomized controlled trials conducted in developed countries have reported no advantage for assertive interventions over standard care models. One possible explanation could be that so-called "standard care" has become more comprehensive in recent years, incorporating some of the salient aspects of assertive models in its modus operandi. Our study represents the first randomised controlled trial assessing the effect of a modified assertive treatment service on readmission rates and other measures of outcome in a developing country. METHODS: High frequency service users were randomized into an intervention (n = 34) and a control (n = 26) group. The control group received standard community care and the active group an assertive intervention based on a modified version of the international model of assertive community treatment. Study visits were conducted at baseline and 12 months with demographic and illness information collected at visit 1 and readmission rates documented at study end. Symptomatology and functioning were measured at both visits using the PANSS, CDSS, ESRS, WHO-QOL and SOFAS. RESULTS: At 12 month follow-up subjects receiving the assertive intervention had significantly lower total PANSS (p = 0.02) as well as positive (p < 0.01) and general psychopathology (p = 0.01) subscales' scores. The mean SOFAS score was also significantly higher (p = 0.02) and the mean number of psychiatric admissions significantly lower (p < 0.01) in the intervention group. CONCLUSIONS: Our results indicate that assertive interventions in a developing setting where standard community mental services are often under resourced can produce significant outcomes. Furthermore, these interventions need not be as expensive and comprehensive as international, first world models in order to reduce inpatient days, improve psychopathology and overall levels of functioning in patients with severe mental illness. PMID- 20843302 TI - Role of Wnt canonical pathway in hematological malignancies. AB - Wnt canonical signaling pathway plays a diverse role in embryonic development and maintenance of organs and tissues in adults. It has been observed that Wnt/beta catenin signaling pathway is involved in the pathogenesis of many carcinomas. Moreover, Wnt/beta-catenin pathway has been revealed to be associated with angiogenesis. Wnt canonical pathway signaling has great potential as a therapeutic target. It has been disclosed that some hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, may occur partly due to the constitutive activation of Wnt canonical signaling pathway. This review will summarize the latest development in Wnt canonical signaling pathway and its roles in tumorigenesis and angiogenesis. PMID- 20843303 TI - Marital history, health and mortality among older men and women in England and Wales. AB - BACKGROUND: Health benefits of marriage have long been recognised and extensively studied but previous research has yielded inconsistent results for older people, particularly older women. At older ages accumulated benefits or disadvantages of past marital experience, as well as current marital status, may be relevant, but fewer studies have considered effects of marital history. Possible effects of parity, and the extent to which these may contribute to marital status differentials in health, have also been rarely considered. METHODS: We use data from the Office for National Statistics Longitudinal Study, a large record linkage study of 1% of the population of England & Wales, to analyse associations between marital history 1971-1991 and subsequent self-reported limiting long-term illness and mortality in a cohort of some 75,000 men and women aged 60-79 in 1991. We investigate whether prior marital status and time in current marital status influenced risks of mortality or long term illness using Poisson regression to analyse mortality differentials 1991-2001 and logistic regression to analyse differences in proportions reporting limiting long-term illness in 1991 and 2001. Co-variates included indicators of socio-economic status at two or three points of the adult life course and, for women, number of children borne (parity). RESULTS: Relative to men in long-term first marriages, never-married men, widowers with varying durations of widowerhood, men divorced for between 10 and twenty years, and men in long-term remarriages had raised mortality 1991 2001. Men in long-term remarriages and those divorced or widowed since 1971 had higher odds of long-term illness in 1991; in 2001 the long-term remarried were the only group with significantly raised odds of long-term illness. Among women, the long-term remarried also had higher odds of reporting long-term illness in 1991 and in 2001 and those remarried and previously divorced had raised odds of long-term illness and raised mortality 1991-2001; this latter effect was not significant in models including parity. All widows had raised mortality 1991-2001 but associations between widowhood of varying durations and long-term illness in 1991 or 2001 were not significant once socio-economic status was controlled. Some groups of divorced women had higher mortality risks 1991-2001 and raised odds of long-term illness in 1991. Results for never-married women showed a divergence between associations with mortality and with long-term illness. In models controlling for socio-economic status, mortality risk was raised but the association with 1991 long-term illness was not significant and in 2001 never married women had lower odds of reporting long-term illness than women in long term first marriages. Formally taking account of selective survival in the 20 years prior to entry to the study population had minor effects on results. CONCLUSIONS: Results were consistent with previous studies in showing that the relationship between marital experience and later life health and mortality is considerably modified by socio-economic factors, and additionally showed that taking women's parity into account further moderated associations. Considering marital history rather than simply current marital status provided some insights into differentials between, for example, remarried people according to prior marital status and time remarried, but these groups were relatively small and there were some disadvantages of the approach in terms of loss of statistical power. Consideration of past histories is likely to be more important for later born cohorts whose partnership experiences have been less stable and more heterogeneous. PMID- 20843304 TI - Determinants and prognostic implications of cardiac troponin T measured by a sensitive assay in type 2 diabetes mellitus. AB - BACKGROUND: The cardiac troponins are biomarkers used for diagnosis of myocardial injury. They are also powerful prognostic markers in many diseases and settings. Recently introduced high-sensitivity assays indicate that chronic cardiac troponin elevations are common in response to cardiovascular (CV) morbidity. Type 2 diabetes mellitus (T2DM) confers a high risk of CV disease, but little is known about chronic cardiac troponin elevations in diabetic subjects. Accordingly, we aimed to understand the prevalence, determinants, and prognostic implications of cardiac troponin T (cTnT) elevations measured with a high-sensitivity assay in patients with T2DM. METHODS: cTnT was measured in stored, frozen serum samples from 124 subjects enrolled in the Asker and Baerum Cardiovascular Diabetes trial at baseline and at 2-year follow-up, if available (96 samples available). Results were analyzed in relation to baseline variables, hospitalizations, and group assignment (multifactorial intensive versus conventional diabetes care for lowering CV risk). RESULTS: One-hundred thirteen (90%) had detectable cTnT at baseline and of those, 22 (18% of the total population) subjects had values above the 99th percentile for healthy controls (13.5 ng/L). Levels at baseline were associated with conventional CV risk factors (age, renal function, gender). There was a strong correlation between cTnT levels at the two time-points (r=0.92, p>0.001). Risk for hospitalizations during follow-up increased step-wise by quartiles of hscTnT measured at baseline (p=0.058). CONCLUSIONS: Elevations of cTnT above the 99th percentile measured by a highly sensitive assay were encountered frequently in a population of T2DM patients. cTnT levels appeared to be stable over time and associated with conventional CV risk factors. Although a clear trend was present, no statistically robust associations with adverse outcomes could be found. PMID- 20843305 TI - Gross genomic alterations and gene expression profiles of high- grade serous carcinoma of the ovary with and without BRCA1 inactivation. AB - BACKGROUND: BRCA1 gene inactivation causes chromosomal instability, leading to rapid accumulation of chromosomal rearrangements and mutations. The loss of BRCA1 function due to either germline/somatic mutation or epigenetic silencing is observed in most high-grade serous carcinomas of the ovary. METHODS: DNA ploidy and gene expression profile were used in order to compare gross genomic alteration and gene expression pattern between cases with BRCA1 loss through mutation, BRCA1 epigenetic loss, and no BRCA1 loss in cases of high-grade serous carcinoma with known BRCA1 and BRCA 2 status. RESULTS: Using image cytometry and oligonucleotide microarrays, we analyzed DNA ploidy, S-phase fraction and gene expression profile of 28 consecutive cases of ovarian high-grade serous adenocarcinomas, which included 8 tumor samples with BRCA1 somatic or germline mutation, 9 samples with promoter hypermethylation of BRCA1, and 11 samples with no BRCA1 loss. None had BRCA2 mutations. The prevalence of aneuploidy and tetraploidy was not statistically different in the three groups with different BRCA1 status. The gene expression profiles were also very similar between the groups, with only two genes showing significant differential expression when comparison was made between the group with BRCA1 mutation and the group with no demonstrable BRCA1 loss. There were no genes showing significant differences in expression when the group with BRCA1 loss through epigenetic silencing was compared to either of the other two groups. CONCLUSIONS: In this series of 28 high-grade serous carcinomas, gross genomic alteration characterized by aneuploidy did not correlate with BRCA1 status. In addition, the gene expression profiles of the tumors showed negligible differences between the three defined groups based on BRCA1 status. This suggests that all ovarian high-grade serous carcinomas arise through oncogenic mechanisms that result in chromosomal instability, irrespective of BRCA status; the molecular abnormalities underlying this in the BRCA intact tumors remains unknown. PMID- 20843306 TI - Low linkage disequilibrium in wild Anopheles gambiae s.l. populations. AB - BACKGROUND: In the malaria vector Anopheles gambiae, understanding diversity in natural populations and genetic components of important phenotypes such as resistance to malaria infection is crucial for developing new malaria transmission blocking strategies. The design and interpretation of many studies here depends critically on Linkage disequilibrium (LD). For example in association studies, LD determines the density of Single Nucleotide Polymorphisms (SNPs) to be genotyped to represent the majority of the genomic information. Here, we aim to determine LD in wild An. gambiae s.l. populations in 4 genes potentially involved in mosquito immune responses against pathogens (Gambicin, NOS, REL2 and FBN9) using previously published and newly generated sequences. RESULTS: The level of LD between SNP pairs in cloned sequences of each gene was determined for 7 species (or incipient species) of the An. gambiae complex. In all tested genes and species, LD between SNPs was low: even at short distances (< 200 bp), most SNP pairs gave an r2 < 0.3. Mean r2 ranged from 0.073 to 0.766. In most genes and species LD decayed very rapidly with increasing inter-marker distance. CONCLUSIONS: These results are of great interest for the development of large scale polymorphism studies, as LD generally falls below any useful limit. It indicates that very fine scale SNP detection will be required to give an overall view of genome-wide polymorphism. Perhaps a more feasible approach to genome wide association studies is to use targeted approaches using candidate gene selection to detect association to phenotypes of interest. PMID- 20843308 TI - Serological and molecular expression of Hepatitis B infection in patients with chronic Hepatitis C from Tunisia, North Africa. AB - BACKGROUND: This study reports the prevalence and the viral aspects of HBV infection in HCV-positive patients from Tunisia, a country with intermediate and low endemicity for hepatitis B and C, respectively. RESULTS: HBV infection was assessed in the serum samples of 361 HCV-positive patients and compared to a group of HCV negative individuals. Serological markers were determined by ELISA tests and HBV DNA by real-time PCR. HBV serological markers were found in 43% and 44% of patients and controls, respectively. However, the serological and molecular expression of HBV infection differed in the two groups: The group of patients included more individuals with ongoing HBV infection, as defined by the presence of detectable HBsAg and or HBV DNA (17% and 12%, respectively). Furthermore, while most of the controls with ongoing HBV infection expressed HBsAg, the majority of HCV and HBV positive patients were HBsAg negative and HBV DNA positive. Genotyping of HCV isolates showed large predominance of subtype 1b as previously reported in Tunisia. Comparison of the replicative status of the two viruses found low HBV viral load in all co-infected patients as compared to patients with single HBV infection. In contrast, high levels of HCV viremia levels were observed in most of cases with no difference between the group of co infected patients and the group with single HCV infection. CONCLUSIONS: This study adds to the knowledge on the prevalence and the virological presentation of HCV/HBV dual infection, providing data from the North African region. It shows that, given the local epidemiology of the two viruses, co-infected patients are likely to have low replication levels of HBV suggesting a suppressive effect of HCV on HBV. In contrast, high replication levels for HCV were fond in most cases which indicate that the presence of circulating HBV-DNA does not necessarily influence HCV replication. PMID- 20843307 TI - Epstein-Barr virus-encoded EBNA1 enhances RNA polymerase III-dependent EBER expression through induction of EBER-associated cellular transcription factors. AB - BACKGROUND: Epstein-Barr Virus (EBV)-encoded RNAs (EBERs) are non-polyadenylated RNA molecules transcribed from the EBV genome by RNA polymerase III (pol III). EBERs are the most abundant viral latent gene products, although the precise mechanisms by which EBV is able to achieve such high levels of EBER expression are not fully understood. Previously EBV has been demonstrated to induce transcription factors associated with EBER expression, including pol III transcription factors and ATF-2. We have recently demonstrated that EBV-encoded nuclear antigen-1 (EBNA1) induces cellular transcription factors, and given these findings, we investigated the role of EBNA1 in induction of EBER-associated transcription factors. RESULTS: Our data confirm that in epithelial cells EBNA1 can enhance cellular pol III transcription. Transient expression of EBNA1 in Ad/AH cells stably expressing the EBERs led to induction of both EBER1 and EBER2 and conversely, expression of a dominant negative EBNA1 led to reduced EBER expression in EBV-infected Ad/AH cells. EBNA1 can induce transcription factors used by EBER genes, including TFIIIC, ATF-2 and c-Myc. A variant chromatin precipitation procedure showed that EBNA1 is associated with the promoters of these genes but not with the promoters of pol III-transcribed genes, including the EBERs themselves. Using shRNA knock-down, we confirm the significance of both ATF-2 and c-Myc in EBER expression. Further, functional induction of a c-Myc fusion protein led to increased EBER expression, providing c-Myc binding sites upstream of EBER1 were intact. In vivo studies confirm elevated levels of the 102 kD subunit of TFIIIC in the tumour cells of EBV-positive nasopharyngeal carcinoma biopsies. CONCLUSIONS: Our findings reveal that EBNA1 is able to enhance EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1's transcription-regulatory properties. PMID- 20843309 TI - Formative evaluation of a telemedicine model for delivering clinical neurophysiology services part I: utility, technical performance and service provider perspective. AB - BACKGROUND: Formative evaluation is conducted in the early stages of system implementation to assess how it works in practice and to identify opportunities for improving technical and process performance. A formative evaluation of a teleneurophysiology service was conducted to examine its technical and sociological dimensions. METHODS: A teleneurophysiology service providing routine EEG investigation was established. Service use, technical performance and satisfaction of clinical neurophysiology personnel were assessed qualitatively and quantitatively. These were contrasted with a previously reported analysis of the need for teleneurophysiology, and examination of expectation and satisfaction with clinical neurophysiology services in Ireland. A preliminary cost-benefit analysis was also conducted. RESULTS: Over the course of 40 clinical sessions during 20 weeks, 142 EEG investigations were recorded and stored on a file server at a satellite centre which was 130 miles away from the host clinical neurophysiology department. Using a virtual private network, the EEGs were accessed by a consultant neurophysiologist at the host centre for interpretation. The model resulted in a 5-fold increase in access to EEG services as well as reducing average waiting times for investigation by a half. Technically the model worked well, although a temporary loss of virtual private network connectivity highlighted the need for clarity in terms of responsibility for troubleshooting and repair of equipment problems. Referral quality, communication between host and satellite centres, quality of EEG recordings, and ease of EEG review and reporting indicated that appropriate organisational processes were adopted by the service. Compared to traditional CN service delivery, the teleneurophysiology model resulted in a comparable unit cost per EEG. CONCLUSION: Observations suggest that when traditional organisational boundaries are crossed challenges associated with the social dimension of service delivery may be amplified. Teleneurophysiology requires a governance and management that recognises its socio-technical nature. PMID- 20843310 TI - Formative evaluation of a telemedicine model for delivering clinical neurophysiology services part II: the referring clinician and patient perspective. AB - BACKGROUND: Feedback from service users will provide insight into opportunities for improvement so that performance can be optimised. In the context of a formative evaluation referring clinician and patient satisfaction with a teleneurophysiology service was examined during a 20 week pilot period. METHODS: Questionnaire surveys of referring clinicians and patients were conducted. RESULTS: Fifteen (58%) clinicians responded to the first part of a postal survey which examined their satisfaction with traditional clinical neurophysiology services. Nine (35%) responded to a second part which assessed their experience with the teleneurophysiology service. Teleneurophysiology improved satisfaction with waiting times, availability of results and impact on patient management. There was unanimous support from the clinicians for the permanent development of a teleneurophysiology service, although 2 cautioned this could delay establishing a neurology service in their region.Eighty-two percent (116/142) of patients responded to a survey of their satisfaction with teleneurophysiology. This was compared to a previous report of 322 patients' experience with traditional CN services in Ireland. Waiting times for appointment were shorter for the former group who supported the telemedicine model recognising that it reduced the travel burden and need for overnight journeys. The two groups were equally anxious about the investigation although the teleneurophysiology patients received more prior information. CONCLUSION: This study illustrates that teleneurophysiology is an acceptable model of service delivery for its primary customers. Their feedback is important in informing appropriate design and governance of such innovative models of health service provision. PMID- 20843311 TI - Tiotropium's cost-effectiveness for the treatment of COPD: a cost-utility analysis under real-world conditions. AB - BACKGROUND: Tiotropium is reimbursed since March 2004 in Belgium for the treatment of Chronic Obstructive Pulmonary Disease (COPD). Questions however remain on this product's value for money. The purpose of this study is to calculate tiotropium's cost-effectiveness under real-world conditions. METHODS: Strengths of both observational and RCT data were combined in a model. A large longitudinal (2002-2006) observational dataset of regular tiotropium users (56,321 patients) was analysed to retrieve the baseline risk for exacerbations and exacerbation-related hospitalisations the year before the first delivery of tiotropium. The relative treatment effect from the UPLIFT (Understanding Potential Long-term Impacts on Function with Tiotropium) trial was then applied to this baseline risk to reflect the effect of tiotropium treatment and calculate the intervention's incremental cost-effectiveness ratio (ICER). RESULTS: After 1000 Latin Hypercube simulations, the incremental benefit expressed as quality adjusted life years (QALY) gained is on average 0.00048 (95% confidence interval (CI) 0.00009-0.00092). In combination with a substantial mean incremental cost of ?373 per patient (95% CI 279-475), this results in an unfavourable average ICER of ?1,244,023 (95% CI 328,571-4,712,704) per QALY gained. Results were most sensitive to the treatment effect on hospitalisations. Based on our large observational database, up to 89% of the patients were not hospitalised for COPD in the year before the first tiotropium delivery. CONCLUSIONS: The main cause for tiotropium's unfavourable cost-effectiveness ratio is a combination of a relative high price for tiotropium, a low number of hospitalisations without tiotropium treatment (on average 0.14/year) and a non-significant treatment effect (on average 0.94) with respect to avoiding exacerbation-related hospitalisations. From an economic point of view, a revision of reimbursement modalities (e.g. with a lower price) would be justified and would entail a more efficient use of resources. PMID- 20843312 TI - "Show me the money": a fair criticism of economic studies on inhaled bronchodilators for COPD. AB - Chronic obstructive pulmonary disease (COPD) represents a significant burden for healthcare systems that is expected to grow further in the future. Inhaled long acting bronchodilators, including tiotropium, represent the cornerstone of management of COPD patients. Economic studies evaluating the cost-effectiveness ratio of inhaled bronchodilators have to take into account several parameters, including the reduction of COPD exacerbations and related hospitalizations, as well as disease modification and improvement in quality of life and mortality. At an era when the healthcare resources are unlikely to grow as quickly as demand, economic analyses remain the cornerstone for the justification of the broad use of medication with an acceptable cost-effectiveness ratio. The greatest importance of such studies in COPD is the identification of subgroups of patients that will have the most benefit with an acceptable cost-effectiveness ratio for the healthcare providers. The development of models that will incorporate a global evaluation of the different aspects of this multi-component disease, in order to provide the best available care to each individual patient is urgently needed. PMID- 20843313 TI - Early detection and counselling intervention of asthma symptoms in preschool children: study design of a cluster randomised controlled trial. AB - BACKGROUND: Prevention of childhood asthma is an important public health objective. This study evaluates the effectiveness of early detection of preschool children with asthma symptoms, followed by a counselling intervention at preventive child health centres. Early detection and counselling is expected to reduce the prevalence of asthma symptoms and improve health-related quality of life at age 6 years. METHODS/DESIGN: This cluster randomised controlled trial was embedded within the Rotterdam population-based prospective cohort study Generation R in which 7893 children (born between April 2002 and January 2006) participated in the postnatal phase. Sixteen child health centres are involved, randomised into 8 intervention and 8 control centres. Since June 2005, an early detection tool has been applied at age 14, 24, 36 and 45 months at the intervention centres. Children who met the intervention criteria received counselling intervention (personal advice to parents to prevent smoke exposure of the child, and/or referral to the general practitioner or asthma nurse). The primary outcome was asthma diagnosis at age 6 years. Secondary outcomes included frequency and severity of asthma symptoms, health-related quality of life, fractional exhaled nitric oxide and airway resistance at age 6 years. Analysis was according to the intention-to-treat principle. Data collection will be completed end 2011. DISCUSSION: This study among preschool children provides insight into the effectiveness of early detection of asthma symptoms followed by a counselling intervention at preventive child health centres. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15790308. PMID- 20843314 TI - Chromogenic in situ hybridization to detect EGFR gene copy number in cell blocks from fine-needle aspirates of non small cell lung carcinomas and lung metastases from colo-rectal cancer. AB - BACKGROUND: Several studies demonstrated that epidermal growth factor receptor (EGFR) gene copy number (GCN) correlates to the response to tyrosine kinase inhibitors in non small cell lung cancer (NSCLC) and to anti-EGFR monoclonal antibodies (MoAbs) in metastatic colorectal cancer (CRC). In the presence of lung nodules, cytology is often the only possible diagnostic approach. Chromogenic in situ hybridization (CISH) is an alternative technique to fluorescence in situ hybridization (FISH), but its feasibility in detecting EGFR GCN in cell blocks from fine-needle aspiration cytology (FNAC) of lung nodules has not yet been established. METHODS: We evaluated the feasibility of CISH on 33 FNAC from 20 primary NSCLC (5 squamous carcinomas, 8 large cell carcinomas and 7 adenocarcinomas) and 13 lung metastases from CRC. RESULTS: Of the 33 FNAC analyzed by CISH, 27 (82%) presented a balanced increase in EGFR gene and chromosome 7 number: 10 cases (30%) showed a low polysomy, 15 (45%) a high polysomy and 2 (6%) NSCLC were amplified. No significant differences between NSCLC and CRC lung metastases were found in relation to disomic or polysomic status. In addition, no correlation between EGFR GCN and EGFR immunohistochemical overexpression was found. Furthermore, we compared CISH results with those obtained by FISH on the same samples and we found 97% overall agreement between the two assays (k = 0.78, p < 0.0001). Two cases were amplified with both assays, whereas 1 case of NSCLC was amplified by FISH only. CISH sensitivity was 67%, the specificity and positive predictive value (PPV) was 100%, and the negative predictive value (NPV) was 97%. CONCLUSIONS: Our study shows that CISH is a valid method to detect EGFR GCN in cell blocks from FNAC of primary NSCLC or metastatic CRC to the lung. PMID- 20843315 TI - In vivo imaging of zebrafish retinal cells using fluorescent coumarin derivatives. AB - BACKGROUND: The zebrafish visual system is a good research model because the zebrafish retina is very similar to that of humans in terms of the morphologies and functions. Studies of the retina have been facilitated by improvements in imaging techniques. In vitro techniques such as immunohistochemistry and in vivo imaging using transgenic zebrafish have been proven useful for visualizing specific subtypes of retinal cells. In contrast, in vivo imaging using organic fluorescent molecules such as fluorescent sphingolipids allows non-invasive staining and visualization of retinal cells en masse. However, these fluorescent molecules also localize to the interstitial fluid and stain whole larvae. RESULTS: We screened fluorescent coumarin derivatives that might preferentially stain neuronal cells including retinal cells. We identified four coumarin derivatives that could be used for in vivo imaging of zebrafish retinal cells. The retinas of living zebrafish could be stained by simply immersing larvae in water containing 1MUg/ml of a coumarin derivative for 30 min. By using confocal laser scanning microscopy, the lamination of the zebrafish retina was clearly visualized. Using these coumarin derivatives, we were able to assess the development of the zebrafish retina and the morphological abnormalities induced by genetic or chemical interventions. The coumarin derivatives were also suitable for counter-staining of transgenic zebrafish expressing fluorescent proteins in specific subtypes of retinal cells. CONCLUSIONS: The coumarin derivatives identified in this study can stain zebrafish retinal cells in a relatively short time and at low concentrations, making them suitable for in vivo imaging of the zebrafish retina. Therefore, they will be useful tools in genetic and chemical screenings using zebrafish to identify genes and chemicals that may have crucial functions in the retina. PMID- 20843316 TI - The WTX/AMER1 gene family: evolution, signature and function. AB - BACKGROUND: WTX is a novel gene mutated in a proportion of Wilms' tumors and in patients suffering from sclerosing bone dysplasia. On the molecular level WTX has been shown to act as an antagonist of canonical Wnt/beta-catenin signaling in fish and mammals thus linking it to an essential pathway involved in normal development and cancer formation. Interestingly, WTX seems to also localize to an intranuclear component called paraspeckles. In spite of the growing interest of molecular biologists in WTX, little is known about its paralogs and its phylogenetic history. RESULTS: Using the amino-acid sequence of WTX/AMER1 as a tool for the assignment of orthology and paralogy, we here identify two novel proteins, AMER2 and AMER3, as "WTX" related. This Amer gene family is present in all currently available vertebrate genome sequences, but not invertebrate genomes and is characterized by six conserved blocks of sequences. The phylogenetic analysis suggests that the protoAmer gene originated early in the vertebrate lineage and was then duplicated due to whole genome duplications (WGD) giving rise to the three different Amer genes. CONCLUSION: Our study represents the first phylogenetic analysis of Amer genes and reveals a new vertebrate specific gene family that is likely to have played an important role in the evolution of this subphylum. Divergent and conserved molecular functions of Wtx/Amer1, Amer2 and Amer3 are discussed. PMID- 20843317 TI - Candida albicans virulence and drug-resistance requires the O-acyltransferase Gup1p. AB - BACKGROUND: GUP1 gene was primarily identified in Saccharomyces cerevisiae being connected with glycerol uptake defects in association with osmotic stress response. Soon after, Gup1p was implicated in a complex and extensive series of phenotypes involving major cellular processes. These include membrane and wall maintenance, lipid composition, bud-site selection, cytoskeleton orientation, vacuole morphology, secretory/endocytic pathway, GPI anchors remodelling, and lipid-ordered domains assembly, which is compatible with their inclusion in the Membrane Bound O-acyl transferases (MBOAT) family. In mammals, it has been described as a negative regulator of the Sonic hedgehog pathway involved in morphogenesis, differentiation, proliferation, among other processes. RESULTS: We show that Candida albicans Gup1p strongly interferes with the capacity of cells to develop hyphae, to adhere, to invade, and to form a biofilm, all of which are significant virulence factors. Furthermore, the mutant colonies exhibited an aberrant morphology/differentiation pattern. Identically to S. cerevisiae, Cagup1Delta null mutant was more resistant to antifungals like fluconazole, ketoconazole, and clotrimazole, and displayed an abnormal even sterol distribution at the plasma membrane. CONCLUSIONS: This work is the first study in the opportunistic yeast Candida albicans, showing a role for the GUP1 gene in virulence as well as in the mechanisms underlying antifungal resistance. Moreover, its impact is even more significant since these results, taken together with all the knowledge about GUP1 gene (from S. cerevisiae and mammals) give consistence to the possibility that Gup1p may be part of a yeast morphogenic pathway parallel to the mammalian Hedgehog. PMID- 20843318 TI - Global transcriptional profiles of beating clusters derived from human induced pluripotent stem cells and embryonic stem cells are highly similar. AB - BACKGROUND: Functional and molecular integrity of cardiomyocytes (CMs) derived from induced pluripotent stem (iPS) cells is essential for their use in tissue repair, disease modelling and drug screening. In this study we compared global transcriptomes of beating clusters (BCs) microdissected from differentiating human iPS cells and embryonic stem (ES) cells. RESULTS: Hierarchical clustering and principal component analysis revealed that iPS-BCs and ES-BCs cluster together, are similarly enriched for cardiospecific genes and differ in expression of only 1.9% of present transcripts. Similarly, sarcomeric organization, electrophysiological properties and calcium handling of iPS-CMs were indistinguishable from those of ES-CMs. Gene ontology analysis revealed that among 204 genes that were upregulated in iPS-BCs vs ES-BCs the processes related to extracellular matrix, cell adhesion and tissue development were overrepresented. Interestingly, 47 of 106 genes that were upregulated in undifferentiated iPS vs ES cells remained enriched in iPS-BCs vs ES-BCs. Most of these genes were found to be highly expressed in fibroblasts used for reprogramming and 34% overlapped with the recently reported iPS cell-enriched genes. CONCLUSIONS: These data suggest that iPS-BCs are transcriptionally highly similar to ES-BCs. However, iPS-BCs appear to share some somatic cell signature with undifferentiated iPS cells. Thus, iPS-BCs may not be perfectly identical to ES-BCs. These minor differences in the expression profiles may occur due to differential cellular composition of iPS-BCs and ES-BCs, due to retention of some genetic profile of somatic cells in differentiated iPS cell-derivatives, or both. PMID- 20843319 TI - Longitudinal assessment of cyst-like lesions of the knee and their relation to radiographic osteoarthritis and MRI-detected effusion and synovitis in patients with knee pain. AB - INTRODUCTION: The purpose of the present study was to determine the prevalence of cystic lesions and cyst-like bursitides in subjects with frequent knee pain and to assess their relation to radiographic osteoarthritis (OA) severity; to describe bilaterality and size fluctuation of the lesions over 6 months; and to assess relations between the prevalence of synovium-lined lesions communicating with the joint capsule and severity of magnetic resonance imaging (MRI)-detected effusion and synovitis. METHODS: One hundred and sixty-three subjects (total 319 knees) aged 35 to 65 with chronic, frequent knee pain were included. Imaging with 3 Tesla MRI was performed at baseline and 6-month follow-up with the same protocols as those used in the Osteoarthritis Initiative. Severity of radiographic OA was assessed using the Kellgren-Lawrence grade (0 to 4). Severity of effusion and synovitis was graded 0 to 3 based on the Whole Organ Magnetic Resonance Imaging Score system. The associations of cysts and cyst-like bursitides and severity of radiographic OA, MRI-detected effusion and synovitis were analyzed using logistic regression controlling for clustering by person. The Wilcoxon signed-rank test was used to determine whether there was a significant change in the size of lesions between baseline and follow-up. RESULTS: At least one lesion (any type) was present in 222 (70%) knees. The most prevalent lesions were popliteal cysts (40%, 128/319), followed by subgastrocnemius bursitis (15%, 49/319) and proximal tibiofibular joint cysts (8%, 26/319). Bilateral lesions were seen in 49% of the subjects. Only popliteal cysts and subgastrocnemius bursitis showed a significant change in size (P < 0.001). No trend was observed between prevalence of any of the cyst-like lesions analyzed and the increasing radiographic OA severity. Increasing prevalence of subgastrocnemius bursitis was associated with increasing severity of effusion (P = 0.0072) and synovitis (P = 0.0033). CONCLUSIONS: None of the cyst-like lesions analyzed seems to be a marker of radiographic OA severity in knees with chronic frequent pain. Subgastrocnemius bursitis may be used as a marker of effusion/synovitis severity. Bilateral cyst like lesions are relatively commonly observed in people with chronic knee pain. PMID- 20843321 TI - The entomopathogenic fungus Beauveria bassiana reduces instantaneous blood feeding in wild multi-insecticide-resistant Culex quinquefasciatus mosquitoes in Benin, West Africa. AB - BACKGROUND: Mosquito-borne diseases are still a major health risk in many developing countries, and the emergence of multi-insecticide-resistant mosquitoes is threatening the future of vector control. Therefore, new tools that can manage resistant mosquitoes are required. Laboratory studies show that entomopathogenic fungi can kill insecticide-resistant malaria vectors but this needs to be verified in the field. METHODS: The present study investigated whether these fungi will be effective at infecting, killing and/or modifying the behaviour of wild multi-insecticide-resistant West African mosquitoes. The entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana were separately applied to white polyester window netting and used in combination with either a permethrin treated or untreated bednet in an experimental hut trial. Untreated nets were used because we wanted to test the effect of fungus alone and in combination with an insecticide to examine any potential additive or synergistic effects. RESULTS: In total, 1125 female mosquitoes were collected during the hut trial, mainly Culex quinquefasciatus Say. Unfortunately, not enough wild Anopheles gambiae Giles were collected to allow the effect the fungi may have on this malaria vector to be analysed. None of the treatment combinations caused significantly increased mortality of Cx. quinquefasciatus when compared to the control hut. The only significant behaviour modification found was a reduction in blood feeding by Cx. quinquefasciatus, caused by the permethrin and B. bassiana treatments, although no additive effect was seen in the B. bassiana and permethrin combination treatment. Beauveria bassiana did not repel blood foraging mosquitoes either in the laboratory or field. CONCLUSIONS: This is the first time that an entomopathogenic fungus has been shown to reduce blood feeding of wild mosquitoes. This behaviour modification indicates that B. bassiana could potentially be a new mosquito control tool effective at reducing disease transmission, although further field work in areas with filariasis transmission should be carried out to verify this. In addition, work targeting malaria vector mosquitoes should be carried out to see if these mosquitoes manifest the same behaviour modification after infection with B. bassiana conidia. PMID- 20843320 TI - A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12. AB - Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales. PMID- 20843322 TI - Seroprevalence of hepatitis B and C virus in HIV-1 and HIV-2 infected Gambians. AB - BACKGROUND: The prevalence of HIV/hepatitis co-infection in sub-Saharan Africa is not well documented, while both HIV and HBV are endemic in this area. OBJECTIVE: The aim of this study is to determine the seroprevalence of HBV and HCV virus in HIV-infected subjects in the Gambia. METHODS: Plasma samples from HIV infected patients (190 individuals with clinically defined AIDS and 382 individuals without AIDS) were tested retrospectively for the presence of HBV sero-markers and for serum HBV DNA, screened for HCV infection by testing for anti-HCV antibody and HCV RNA. RESULTS: HBsAg prevalence in HIV-positive individuals is 12.2%. HIV/HBV co-infected individuals with CD4 count of <200 cells uL-1 have a higher HBV DNA viral load than patients with higher CD4 count (log 4.0 vs. log 2.0 DNA copies/ml, p < 0.05). Males (OR = 1.8, 95% CI: 1.0, 3.2) were more likely to be HBsAg positive than female. HCV seroprevalence was 0.9% in HIV-positive individuals. CONCLUSION: The prevalence of HBsAg carriage in HIV- infected Gambians is similar to that obtained in the general population. However co infected individuals with reduced CD4 levels, indicative of AIDS had higher prevalence of HBeAg retention and elevated HBV DNA levels compared to non-AIDS patients with higher CD4 count. PMID- 20843323 TI - Patient evaluation of the use of follitropin alfa in a prefilled ready-to-use injection pen in assisted reproductive technology: an observational study. AB - BACKGROUND: Self-administration of recombinant human follicle-stimulating hormone (r-hFSH) can be performed using injection pen devices by women undergoing assisted reproductive technology procedures. The objective of this study was to explore the use of the prefilled follitropin alfa pen in routine assisted reproductive technology procedures in Germany. METHODS: This prospective, observational study was conducted across 43 German IVF centres over a period of 1.75 years. Patients who had used the prefilled follitropin alfa pen in the current or a previous cycle of controlled ovarian stimulation completed a questionnaire to assess their opinions of the device. RESULTS: A total of 5328 patients were included in the study. Of these, 2888 reported that they had previous experience of daily FSH injections. Significantly more patients reported that less training was required to use the prefilled follitropin alfa pen than a syringe and lyophilized powder (1997/3081 [64.8%]; p < 0.001 'less' versus 'more' training). Significantly more patients rated the prefilled follitropin alfa pen as easier in terms of use (2321/3206, 72.4%; p < 0.001 'much more easy' versus 'less easy') and daily injection (2384/3262, 73.1%; p < 0.001 'much more easy' versus 'less easy') than existing injection methods. Approximately one third of respondents rated the prefilled follitropin alfa pen as easier to use than the follitropin beta pen with reloadable cartridges. The majority (3378/4024, 83.9%) of patients had a general preference for the prefilled follitropin alfa pen over other injection methods. CONCLUSIONS: In this questionnaire-based survey, routine use of the prefilled follitropin alfa pen was well accepted and associated with favourable patient perceptions. Users of the pen found it easier to initially learn how to use, and subsequently use, than other injection methods. In general, the prefilled follitropin alfa pen was the preferred method for self administration of gonadotrophins. Together with previous findings, the results here indicate a high level of patient satisfaction among users of the prefilled follitropin alfa pen for daily self-administration of r-hFSH. PMID- 20843325 TI - Increased amyloidogenic processing of transgenic human APP in X11-like deficient mouse brain. AB - BACKGROUND: X11-family proteins, including X11, X11-like (X11L) and X11-like 2 (X11L2), bind to the cytoplasmic domain of amyloid beta-protein precursor (APP) and regulate APP metabolism. Both X11 and X11L are expressed specifically in brain, while X11L2 is expressed ubiquitously. X11L is predominantly expressed in excitatory neurons, in contrast to X11, which is strongly expressed in inhibitory neurons. In vivo gene-knockout studies targeting X11, X11L, or both, and studies of X11 or X11L transgenic mice have reported that X11-family proteins suppress the amyloidogenic processing of endogenous mouse APP and ectopic human APP with one exception: knockout of X11, X11L or X11L2 has been found to suppress amyloidogenic metabolism in transgenic mice overexpressing the human Swedish mutant APP (APPswe) and the mutant human PS1, which lacks exon 9 (PS1dE9). Therefore, the data on X11-family protein function in transgenic human APP metabolism in vivo are inconsistent. RESULTS: To confirm the interaction of X11L with human APP ectopically expressed in mouse brain, we examined the amyloidogenic metabolism of human APP in two lines of human APP transgenic mice generated to also lack X11L. In agreement with previous reports from our lab and others, we found that the amyloidogenic metabolism of human APP increased in the absence of X11L. CONCLUSION: X11L appears to aid in the suppression of amyloidogenic processing of human APP in brain in vivo, as has been demonstrated by previous studies using several human APP transgenic lines with various genetic backgrounds. X11L appears to regulate human APP in a manner similar to that seen in endogenous mouse APP metabolism. PMID- 20843324 TI - First-line single agent treatment with gefitinib in patients with advanced non small-cell lung cancer. AB - BACKGROUND: Lung cancer is a malignant carcinoma which has the highest morbidity and mortality in Chinese population. Gefitinib, a tyrosine kinase (TK) inhibitor of epidermal growth factor receptor (EGFR), displays anti-tumor activity. The present data regarding first-line treatment with single agent gefitinib against non-small-cell lung cancer (NSCLC) in Chinese population are not sufficient. PURPOSE: To assess the efficacy and toxicity of gefitinib in Chinese patients with advanced non-small-cell lung cancer (NSCLC), a study of single agent treatment with gefitinib in Chinese patients was conducted. METHODS: 45 patients with advanced NSCLC were treated with gefitinib (250 mg daily) until the disease progression or intolerable toxicity. RESULTS: Among the 45 patients, 15 patients achieved partial response (PR), 17 patients experienced stable disease (SD), and 13 patients developed progression disease (PD). None of the patients achieved complete response (CR). The tumor response rate and disease control rate was 33% and 71.1%, respectively. Symptom remission rate was 72.5%, and median remission time was 8 days. Median overall survival and median progression-free survival was 15.3 months and 6.0 months, respectively. The main induced toxicities by gefitinib were skin rash and diarrhea (53.3% and 33.3%, respectively). The minor induced toxicities included dehydration and pruritus of skin (26.7% and 22.2%, respectively). In addition, hepatic toxicity and oral ulceration occurred in few patients (6.7% and 4.4%2, respectively). CONCLUSIONS: Single agent treatment with gefitinib is effective and well tolerated in Chinese patients with advanced NSCLC. PMID- 20843326 TI - Environment-sensitive behavior of fluorescent molecular rotors. AB - Molecular rotors are a group of fluorescent molecules that form twisted intramolecular charge transfer (TICT) states upon photoexcitation. When intramolecular twisting occurs, the molecular rotor returns to the ground state either by emission of a red-shifted emission band or by nonradiative relaxation. The emission properties are strongly solvent-dependent, and the solvent viscosity is the primary determinant of the fluorescent quantum yield from the planar (non twisted) conformation. This viscosity-sensitive behavior gives rise to applications in, for example, fluid mechanics, polymer chemistry, cell physiology, and the food sciences. However, the relationship between bulk viscosity and the molecular-scale interaction of a molecular rotor with its environment are not fully understood. This review presents the pertinent theories of the rotor-solvent interaction on the molecular level and how this interaction leads to the viscosity-sensitive behavior. Furthermore, current applications of molecular rotors as microviscosity sensors are reviewed, and engineering aspects are presented on how measurement accuracy and precision can be improved. PMID- 20843327 TI - End-of-life discontinuation of destination therapy with cardiac and ventilatory support medical devices: physician-assisted death or allowing the patient to die? AB - BACKGROUND: Bioethics and law distinguish between the practices of "physician assisted death" and "allowing the patient to die." DISCUSSION: Advances in biotechnology have allowed medical devices to be used as destination therapy that are designed for the permanent support of cardiac function and/or respiration after irreversible loss of these spontaneous vital functions. For permanent support of cardiac function, single ventricle or biventricular mechanical assist devices and total artificial hearts are implanted in the body. Mechanical ventilators extrinsic to the body are used for permanent support of respiration. Clinical studies have shown that destination therapy with ventricular assist devices improves patient survival compared to medical management, but at the cost of a substantial alteration in end-of-life trajectories. The moral and legal assessment of the appropriateness and permissibility of complying with a patient's request to electively discontinue destination therapy in a life terminating act in non-futile situations has generated controversy. Some argue that complying with this request is ethically justified because patients have the right to request withdrawal of unwanted treatment and be allowed to die of preexisting disease. Other commentators reject the argument that acceding to an elective request for death by discontinuing destination therapy is 'allowing a patient to die' because of serious flaws in interpreting the intention, causation, and moral responsibility of the ensuing death. SUMMARY: Destination therapy with cardiac and/or ventilatory medical devices replaces native physiological functions and successfully treats a preexisting disease. We posit that discontinuing cardiac and/or ventilatory support at the request of a patient or surrogate can be viewed as allowing the patient to die if--and only if- concurrent lethal pathophysiological conditions are present that are unrelated to those functions already supported by medical devices in destination therapy. In all other cases, compliance with a patient's request constitutes physician assisted death because of the pathophysiology induced by the turning off of these medical devices, as well as the intention, causation, and moral responsibility of the ensuing death. The distinction between allowing the patient to die and physician-assisted death is pivotal to the moral and legal status of elective requests for death by discontinuing destination cardiac and/or ventilatory medical devices in patients who are not imminently dying. This distinction also represents essential information that must be disclosed to patients and surrogates in advance of consent to this type of therapy. PMID- 20843329 TI - Ferrets develop fatal influenza after inhaling small particle aerosols of highly pathogenic avian influenza virus A/Vietnam/1203/2004 (H5N1). AB - BACKGROUND: There is limited knowledge about the potential routes for H5N1 influenza virus transmission to and between humans, and it is not clear whether humans can be infected through inhalation of aerosolized H5N1 virus particles. Ferrets are often used as a animal model for humans in influenza pathogenicity and transmissibility studies. In this manuscript, a nose-only bioaerosol inhalation exposure system that was recently developed and validated was used in an inhalation exposure study of aerosolized A/Vietnam/1203/2004 (H5N1) virus in ferrets. The clinical spectrum of influenza resulting from exposure to A/Vietnam/1203/2004 (H5N1) through intranasal verses inhalation routes was analyzed. RESULTS: Ferrets were successfully infected through intranasal instillation or through inhalation of small particle aerosols with four different doses of Influenza virus A/Vietnam/1203/2004 (H5N1). The animals developed severe influenza encephalomyelitis following intranasal or inhalation exposure to 101, 102, 103, or 104 infectious virus particles per ferret. CONCLUSIONS: Aerosolized Influenza virus A/Vietnam/1203/2004 (H5N1) is highly infectious and lethal in ferrets. Clinical signs appeared earlier in animals infected through inhalation of aerosolized virus compared to those infected through intranasal instillation. PMID- 20843328 TI - Nuclear export regulation of COP1 by 14-3-3sigma in response to DNA damage. AB - Mammalian constitutive photomorphogenic 1 (COP1) is a p53 E3 ubiquitin ligase involved in regulating p53 protein level. In plants, the dynamic cytoplasm/nucleus distribution of COP1 is important for its function in terms of catalyzing the degradation of target proteins. In mammalian cells, the biological consequence of cytoplasmic distribution of COP1 is not well characterized. Here, we show that DNA damage leads to the redistribution of COP1 to the cytoplasm and that 14-3-3sigma, a p53 target gene product, controls COP1 subcellular localization. Investigation of the underlying mechanism suggests that COP1 S387 phosphorylation is required for COP1 to bind 14-3-3sigma. Significantly, upon DNA damage, 14-3-3sigma binds to phosphorylated COP1 at S387, resulting in COP1's accumulation in the cytoplasm. Cytoplasmic COP1 localization leads to its enhanced ubiquitination. We also show that N-terminal 14-3-3sigma interacts with COP1 and promotes COP1 nuclear export through its NES sequence. Further, we show that COP1 is important in causing p53 nuclear exclusion. Finally, we demonstrate that 14-3-3sigma targets COP1 for nuclear export, thereby preventing COP1 mediated p53 nuclear export. Together, these results define a novel, detailed mechanism for the subcellular localization and regulation of COP1 after DNA damage and provide a mechanistic explanation for the notion that 14-3-3sigma's impact on the inhibition of p53 E3 ligases is an important step for p53 stabilization after DNA damage. PMID- 20843330 TI - Techno-economic evaluation of stillage treatment with anaerobic digestion in a softwood-to-ethanol process. AB - BACKGROUND: Replacing the energy-intensive evaporation of stillage by anaerobic digestion is one way of decreasing the energy demand of the lignocellulosic biomass to the ethanol process. The biogas can be upgraded and sold as transportation fuel, injected directly into the gas grid or be incinerated on site for combined heat and power generation. A techno-economic evaluation of the spruce-to-ethanol process, based on SO2-catalysed steam pretreatment followed by simultaneous saccharification and fermentation, has been performed using the commercial flow-sheeting program Aspen PlusTM. Various process configurations of anaerobic digestion of the stillage, with different combinations of co-products, have been evaluated in terms of energy efficiency and ethanol production cost versus the reference case of evaporation. RESULTS: Anaerobic digestion of the stillage showed a significantly higher overall energy efficiency (87-92%), based on the lower heating values, than the reference case (81%). Although the amount of ethanol produced was the same in all scenarios, the production cost varied between 4.00 and 5.27 Swedish kronor per litre (0.38-0.50 euro/L), including the reference case. CONCLUSIONS: Higher energy efficiency options did not necessarily result in lower ethanol production costs. Anaerobic digestion of the stillage with biogas upgrading was demonstrated to be a favourable option for both energy efficiency and ethanol production cost. The difference in the production cost of ethanol between using the whole stillage or only the liquid fraction in anaerobic digestion was negligible for the combination of co-products including upgraded biogas, electricity and district heat. PMID- 20843332 TI - The anti-vaccination movement and resistance to allergen-immunotherapy: a guide for clinical allergists. AB - Despite over a century of clinical use and a well-documented record of efficacy and safety, a growing minority in society questions the validity of vaccination and fear that this common public health intervention is the root-cause of severe health problems. This article questions whether growing public anti-vaccine sentiments might have the potential to spill-over into other therapies distinct from vaccination, namely allergen-immunotherapy. Allergen-immunotherapy shares certain medical vernacular with vaccination (e.g., allergy shots, allergy vaccines), and thus may become "guilty by association" due to these similarities. Indeed, this article demonstrates that anti-vaccine websites have begun unduly discrediting this allergy treatment regimen. Following an explanation of the anti vaccine movement, the article aims to provide guidance on how clinicians can respond to patient fears towards allergen-immunotherapy in the clinical setting. This guide focuses on the provision of reliable information to patients in order to dispel misconceived associations between vaccination and allergen immunotherapy, and the discussion of the risks and benefits of both therapies in order to assist patients in making autonomous decisions about their choice of allergy treatment. PMID- 20843331 TI - Nitric oxide is negatively correlated to pain during acute inflammation. AB - BACKGROUND: The role that nitric oxide (NO) plays in modulating pain in the periphery is unclear. We show here, the results of two independent clinical studies (microdialysis and gene expression studies) and a pilot dose finding study (glyceryl trinitrate study), to study the role of NO in the early phase of acute inflammatory pain following oral surgery. The effect of ketorolac on NO production and nitric oxide synthase (NOS) gene expression was also studied. RESULTS: Microdialysis samples showed significantly higher levels of NO at the first 100 min compared to the last 80 minutes in the placebo treated group. In the ketorolac group, on the other hand, NO levels gradually decreased over the first 60 min but were similar to placebo over the later 100-180 min, with no significant change in NO level over time. The levels of NO were negatively correlated to pain intensity scores. Local infusion of the NO donor glyceryl trinitrate at the site of surgery, showed a small analgesic effect that did not reach statistical significance in the sample size used. While the gene expression of iNOS and eNOS were not up-regulated, 3 hours after surgery, nNOS was downregulated in both treatment groups and eNOS gene expression was significantly lower in the ketorolac group compared to the placebo group. Further, there was a positive correlation between the change in gene expression of nNOS and eNOS in the placebo group but not in the ketorolac group. CONCLUSION: We suggest that at this early stage of inflammatory pain in man, NO is analgesic in the periphery. Further, ketorolac down-regulates eNOS gene expression. PMID- 20843334 TI - Palliative care in urgent need of recognition and development in general practice: the example of Germany. AB - BACKGROUND: Specialist palliative care is being increasingly recognised and developed to improve end-of-life care in many developed countries. However, only a small proportion of the total number of patients with incurable, progressive diseases actually has direct contact with specialist palliative care practitioners. Using the German situation as an example, the main purpose of this paper is to argue that the emphasis on specialist palliative care services without a similar encouragement of primary palliative care will deliver a constrained service. DISCUSSION: For the vast majority of people with incurable, progressive diseases, good palliative care delivered by General Practitioners and community nurses, with access to specialist support when needed, is the optimal response. In Germany, specialist palliative care in the community was established in the 2007 health care reforms. However actual and potential delivery of palliative care by general practitioners and community based nurses has been sorely neglected. The time-consuming care of palliative patients and their families is currently far from accurately reflected in German, indeed most European primary care payment systems. However, it is not just a question of adequate financial compensation but also of the recognition of the fundamental value of this intense form of holistic family medicine. SUMMARY: It is imperative palliative care carried out by community nurses and general practitioners is better recognised by health professionals, health insurers, government and the scientific community as a central part of the delivery of health care for people in the last phase of life. Health systems should be arranged so that this critical role of general practice and primary care is intentionally fostered. Palliative care carried out by generalists needs an identity at an academic and practical level, developing in concert with specialist palliative care. PMID- 20843333 TI - Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages. AB - BACKGROUND: Investigations on pulmonary macrophages (MPhi) mostly focus on alveolar MPhi (AM) as a well-defined cell population. Characteristics of MPhi in the interstitium, referred to as lung interstitial MPhi (IM), are rather ill defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. METHODS: Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. RESULTS: IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both MPhi populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6. CONCLUSION: AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung MPhi in the inflammatory response. PMID- 20843335 TI - Suppression of LPS-induced matrix-metalloproteinase responses in macrophages exposed to phenytoin and its metabolite, 5-(p-hydroxyphenyl-), 5-phenylhydantoin. AB - BACKGROUND: Phenytoin (PHT) has been reported to induce gingival (gum) overgrowth (GO) in approximately 50% of patients taking this medication. While most studies have focused on the effects of PHT on the fibroblast in the pathophysiology underlying GO, few studies have investigated the potential regulatory role of macrophages in extracellular matrix (ECM) turnover and secretion of proinflammatory mediators. The aim of this study was to evaluate the effects of PHT and its metabolite, 5-(p-hydroxyphenyl-), 5-phenylhydantoin (HPPH) on LPS elicited MMP, TIMP, TNF-alpha and IL-6 levels in macrophages. METHODS: Human primary monocyte-derived macrophages (n = 6 independent donors) were pretreated with 15-50 MUg/mL PHT-Na+ or 15-50 MUg/mL HPPH for 1 hour. Cells were then challenged with 100 ng/ml purified LPS from the periodontal pathogen, Aggregatibacter actinomycetemcomitans. Supernatants were collected after 24 hours and levels of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TNF-alpha and IL-6 determined by multiplex analysis or enzyme-linked immunoadsorbent assay. RESULTS: A dose-dependent inhibition of MMP-1, MMP-3, MMP 9, TIMP-1 but not MMP-2 was noted in culture supernatants pretreated with PHT or HPPH prior to LPS challenge. MMP-12, TIMP-2, TIMP-3 and TIMP-2 were not detected in culture supernatants. High concentrations of PHT but not HPPH, blunted LPS induced TNF-alpha production although neither significantly affected IL-6 levels. CONCLUSION: The ability of macrophages to mediate turnover of ECM via the production of metalloproteinases is compromised not only by PHT, but its metabolite, HPPH in a dose-dependent fashion. Further, the preferential dysregulation of macrophage-derived TNF-alpha but not IL-6 in response to bacterial challenge may provide an inflammatory environment facilitating collagen accumulation without the counteracting production of MMPs. PMID- 20843336 TI - A rare mitochondrial disorder: Leigh syndrome--a case report. AB - Leigh syndrome is a rare progressive neurodegenerative, mitochondrial disorder of childhood with only a few cases documented from India. The clinical presentation of Leigh syndrome is highly variable. However, in most cases it presents as a progressive neurological disease with motor and intellectual developmental delay and signs and symptoms of brain stem and/or basal ganglia involvement. Raised lactate levels in blood and/or cerebrospinal fluid is noted. It is the neuroimaging, mainly the Magnetic Resonance Imaging showing characteristic symmetrical necrotic lesions in the basal ganglia and/or brain stem that leads to the diagnosis. Here, we report a case of 7 months old female child presenting to us with status epilepticus, delayed developmental milestones and regression of the achieved milestones suspected to be a case of neurodegenerative disorder, which on MRI was diagnosed as Leigh syndrome. PMID- 20843337 TI - Lubiprostone ameliorates the cystic fibrosis mouse intestinal phenotype. AB - BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the CFTR gene that impair the function of CFTR, a cAMP-regulated anion channel. In the small intestine loss of CFTR function creates a dehydrated, acidic luminal environment which is believed to cause an accumulation of mucus, a phenotype characteristic of CF. CF mice have small intestinal bacterial overgrowth, an altered innate immune response, and impaired intestinal transit. We investigated whether lubiprostone, which can activate the CLC2 Cl- channel, would improve the intestinal phenotype in CF mice. METHODS: Cftr(tm1UNC) (CF) and wildtype (WT) littermate mice on the C57BL/6J background were used. Lubiprostone (10 MUg/kg day) was administered by gavage for two weeks. Mucus accumulation was estimated from crypt lumen widths in periodic acid-Schiff base, Alcian blue stained sections. Luminal bacterial load was measured by qPCR for the bacterial 16S gene. Gastric emptying and small intestinal transit in fasted mice were assessed using gavaged rhodamine dextran. Gene expression was evaluated by Affymetrix Mouse430 2.0 microarray and qRT-PCR. RESULTS: Crypt width in control CF mice was 700% that of WT mice (P < 0.001). Lubiprostone did not affect WT crypt width but, unexpectedly, increased CF crypt width 22% (P = 0.001). Lubiprostone increased bacterial load in WT mice to 490% of WT control levels (P = 0.008). Conversely, lubiprostone decreased bacterial overgrowth in CF mice by 60% (P = 0.005). Lubiprostone increased gastric emptying at 20 min postgavage in both WT (P < 0.001) and CF mice (P < 0.001). Lubiprostone enhanced small intestinal transit in WT mice (P = 0.024) but not in CF mice (P = 0.377). Among other innate immune markers, expression of mast cell genes was elevated 4-to 40-fold in the CF intestine as compared to WT, and lubiprostone treatment of CF mice decreased expression to WT control levels. CONCLUSIONS: These results indicate that lubiprostone has some benefits for the CF intestinal phenotype, especially on bacterial overgrowth and the innate immune response. The unexpected observation of increased mucus accumulation in the crypts of lubiprostone-treated CF mice suggests the possibility that lubiprostone increases mucus secretion. PMID- 20843338 TI - Simultaneous bicompartmental bucket handle meniscal tears with a clinically competent Anterior Cruciate Ligament. AB - Bucket handle meniscal tears (BHMT) of the knee occur infrequently (approximately 10% of meniscal injuries). Simultaneous, bicompartmental BHMT are extremely rare. Previously, these have only been reported in association with a ruptured anterior cruciate ligament (ACL). The pathomechanism of this injury was thought to be due to the lack of knee stability following the ACL injury. We present a case of a 38 year old male patient with bicompartmental BHMT with a clinically competent ACL. This highlights the need for clinical and radiological suspicion of simultaneous BHMTs even in the presence of an intact ACL. PMID- 20843339 TI - Molecular evolution and the role of oxidative stress in the expansion and functional diversification of cytosolic glutathione transferases. AB - BACKGROUND: Cytosolic glutathione transferases (cGST) are a large group of ubiquitous enzymes involved in detoxification and are well known for their undesired side effects during chemotherapy. In this work we have performed thorough phylogenetic analyses to understand the various aspects of the evolution and functional diversification of cGSTs. Furthermore, we assessed plausible correlations between gene duplication and substrate specificity of gene paralogs in humans and selected species, notably in mammalian enzymes and their natural substrates. RESULTS: We present a molecular phylogeny of cytosolic GSTs that shows that several classes of cGSTs are more ubiquitous and thus have an older ancestry than previously thought. Furthermore, we found that positive selection is implicated in the diversification of cGSTs. The number of duplicate genes per class is generally higher for groups of enzymes that metabolize products of oxidative damage. CONCLUSIONS: 1) Protection against oxidative stress seems to be the major driver of positive selection in mammalian cGSTs, explaining the overall expansion pattern of this subfamily; 2) Given the functional redundancy of GSTs that metabolize xenobiotic chemicals, we would expect the loss of gene duplicates, but by contrast we observed a gene expansion of this family, which likely has been favored by: i) the diversification of endogenous substrates; ii) differential tissue expression; and iii) increased specificity for a particular molecule; 3) The increased availability of sequence data from diversified taxa is likely to continue to improve our understanding of the early origin of the different cGST classes. PMID- 20843340 TI - Eleven fetal echocardiographic planes using 4-dimensional ultrasound with spatio temporal image correlation (STIC): a logical approach to fetal heart volume analysis. AB - BACKGROUND: Theoretically, a cross-sectional image of any cardiac planes can be obtained from a STIC fetal heart volume dataset. We described a method to display 11 fetal echocardiographic planes from STIC volumes. METHODS: Fetal heart volume datasets were acquired by transverse acquisition from 200 normal fetuses at 15 to 40 weeks of gestation. Analysis of the volume datasets using the described technique to display 11 echocardiographic planes in the multiplanar display mode were performed offline. RESULTS: Volume datasets from 18 fetuses were excluded due to poor image resolution. The mean visualization rates for all echocardiographic planes at 15-17, 18-22, 23-27, 28-32 and 33-40 weeks of gestation fetuses were 85.6% (range 45.2-96.8%, N = 31), 92.9% (range 64.0-100%, N = 64), 93.4% (range 51.4-100%, N = 37), 88.7%(range 54.5-100%, N = 33) and 81.8% (range 23.5-100%, N = 17) respectively. CONCLUSIONS: Overall, the applied technique can favorably display the pertinent echocardiographic planes. Description of the presented method provides a logical approach to explore the fetal heart volumes. PMID- 20843341 TI - Left ventricular noncompaction and myocardial fibrosis: a case report. AB - BACKGROUND: Left ventricular noncompaction (LVNC) is a rare congenital abnormality. It is currently classified as a genetic cardiomyopathy and results from early arrest of endomyocardial morphogenesis. The pathophysiology of left ventricular dysfunction, which becomes apparent beyond the 4th decade of life, is unclear. CASE REPORT: We report a case of 60-year-old woman who presented with shortness of breath and showed noncompacted endocardium on echocardiography. Cardiac catheterization and viral studies were unremarkable. Histology revealed endomyocardial fibrosis without disarray. She was subsequently diagnosed with LVNC and treated with medications. DISCUSSION: Cardiologists and other physicians should be aware of LVNC due to its high likelihood of misdiagnosis and associated high complication rates. Early diagnosis, intervention and screening among family members can decrease the morbidity and mortality associated with LVNC. PMID- 20843342 TI - Dietary supplementation of soy germ phytoestrogens or estradiol improves spatial memory performance and increases gene expression of BDNF, TrkB receptor and synaptic factors in ovariectomized rats. AB - BACKGROUND: Estrogen or phytoestrogens treatment has been suggested to improve cognitive function of the brain in postmenopausal women. However, there is lack of information on the mechanism of such treatment on the central nervous system. The present study aimed to determine the effects of estradiol and soy germ phytoestrogens on spatial memory performance in ovariectomized rats and to explore the underlying mechanisms affecting the central nervous system. METHODS: Ovariectomized Sprague-Dawley rats were fed a basic diet supplemented with soy germ phytoestrogens (0.4 g/kg or 1.6 g/kg) or 17beta-estradiol (0.15 g/kg) for 12 weeks. At the end of the experiment, animals were evaluated for their spatial learning and memory performance by the Morris Water Maze task. The expressions of brain-derived neurotrophic factor (BDNF) and synaptic formation proteins in the hippocampal tissue were estimated using RT-PCR and ELISA. RESULTS: It was found that rats supplemented with soy germ phytoestrogens or estradiol performed significantly better in spatial memory acquisition and retention when compared to the rats fed on the control diet. Estradiol or the high dose of phytoestrogens treatment significantly increased BDNF concentration and the mRNA levels for BDNF and its TrkB receptors as well as the synaptic formation proteins, synaptophysin, spinophilin, synapsin 1 and PSD-95, in the hippocampal tissue of the experimental animals. It was also found that phytoestrogens, in contrast to estradiol, did not show any significant effect on the vaginal and uteri. CONCLUSION: Soy germ phytoestrogens, which may be a substitute of estradiol, improved spatial memory performance in ovariectomized rats without significant side-effects on the vaginal and uteri. The memory enhancement effect may relate to the increase in BDNF and the synaptic formation proteins expression in the hippocampus of the brain. PMID- 20843343 TI - Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation. AB - BACKGROUND: The Wnt/beta-catenin pathway is a major signaling cascade in bone biology, playing a key role in bone development and remodeling. The objectives of this study were firstly, to determine the effects of dexamethasone exposure on Wnt/beta-catenin signaling at an intracellular and transcriptional level, and secondly, to assess the phenotypic effects of silencing the Wnt antagonist, Dickkopf-1 (Dkk1) in the setting of dexamethasone exposure. METHODS: Primary human osteoblasts were exposed in vitro to 10-8 M dexamethasone over a 72 h time course. The phenotypic marker of osteoblast differentiation was analyzed was alkaline phosphatase activity. Intracellular beta-catenin trafficking was assessed using immunoflourescence staining and TCF/LEF mediated transcription was analyzed using a Wnt luciferase reporter assay. Dkk1 expression was silenced using small interfering RNA (siRNA). RESULTS: Primary human osteoblasts exposed to dexamethasone displayed a significant reductions in alkaline phosphatase activity over a 72 h time course. Immunoflourescence analaysis of beta-catenin localization demonstrated a significant reduction in intracytosolic and intranuclear beta-catenin in response to dexamethasone exposure. These changes were associated with a reduction of TCF/LEF mediated transcription. Silencing Dkk1 expression in primary human osteoblasts exposed to dexamethasone resulted in an increase in alkaline phosphatase activity when compared to scrambled control. CONCLUSIONS: Wnt/beta-catenin signaling plays a key role in regulating glucocorticoid-induced osteoporosis in vitro. Silencing Dkk1 expression rescues dexamethasone-induced suppression of primary human osteoblast differentiation. Targeting of the Wnt/beta-catenin signaling pathway offers an exciting opportunity to develop novel anabolic bone agents to treat osteoporosis and disorders of bone mass. PMID- 20843345 TI - The potential role of the educational system in addressing the effect of inadequate knowledge of mosquitoes on use of insecticide-treated nets in Ghana. AB - BACKGROUND: Since 2001, there has been a tremendous increase in number of households protected by ITN and IRS in Ghana. However, there has not been evidence of a reduction in malaria cases as expected and reported deaths have rather increased since 2007. As a result, this study was undertaken to get a better understanding of perceptions of malaria, knowledge on mosquitoes and the value attached to ITNs among secondary and tertiary students in Cape Coast. METHODS: Structured questionnaires were administered randomly to gather data on demographic characteristics of students, knowledge of mosquitoes and ITNs and attitude towards the use of ITN in seven public high schools and four tertiary institutions in Cape Coast metropolis. In addition, curriculums of science courses common to all students from junior high school to the university were carefully examined. RESULTS: A total of 492 students took part in this study and more than 90% of them had high knowledge of malaria transmission and ITN, but little knowledge of mosquito life history. Only 1% in secondary and 2.1% in tertiary institutions had seen or knew about all the development stages of mosquitoes. In high school and tertiary institutions, 24.2% and 10.8% of respondents, respectively, were able to mention other genera of mosquitoes, apart from Anopheles. Though 93.9% in senior high school and 86.7% in the tertiary institutions knew that ITNs are either used to protect oneself from mosquito bites or to prevent malaria, 32.7% of the respondents in secondary and 21.9% in tertiary institutions who owned ITN did not use them. CONCLUSIONS: The study reveals that respondents did not have adequate knowledge on the biology and behaviour of mosquitoes. This appears to weaken their knowledge of the link between the use of ITN and malaria control; the effect of this is that a significant number owned ITNs but did not use them. The implication is that if people will really accept and use ITN or other mosquito control interventions, then just creating awareness of those interventions is not enough but people should also be educated on the life history of mosquitoes and on the mechanism of the control strategies. This can be effectively done through the formal education system. PMID- 20843344 TI - Intensive care diaries reduce new onset post traumatic stress disorder following critical illness: a randomised, controlled trial. AB - INTRODUCTION: Patients recovering from critical illness have been shown to be at risk of developing Post Traumatic Stress disorder (PTSD). This study was to evaluate whether a prospectively collected diary of a patient's intensive care unit (ICU) stay when used during convalescence following critical illness will reduce the development of new onset PTSD. METHODS: Intensive care patients with an ICU stay of more than 72 hours were recruited to a randomised controlled trial examining the effect of a diary outlining the details of the patients ICU stay on the development of acute PTSD. The intervention patients received their ICU diary at 1 month following critical care discharge and the final assessment of the development of acute PTSD was made at 3 months. RESULTS: 352 patients were randomised to the study at 1 month. The incidence of new cases of PTSD was reduced in the intervention group compared to the control patients (5% versus 13%, P = 0.02). CONCLUSIONS: The provision of an ICU diary is effective in aiding psychological recovery and reducing the incidence of new PTSD. TRIAL REGISTRATION: NCT00912613. PMID- 20843346 TI - Prevalence of gastro-oesophageal reflux disease symptoms and reflux-associated respiratory symptoms in asthma. AB - BACKGROUND: Gastro-oesophageal reflux disease (GORD) symptoms are common in asthma and have been extensively studied, but less so in the Asian continent. Reflux-associated respiratory symptoms (RARS) have, in contrast, been little studied globally. We report the prevalence of GORD symptoms and RARS in adult asthmatics, and their association with asthma severity and medication use. METHODS: A cross-sectional analytical study. A validated interviewer-administered GORD scale was used to assess frequency and severity of seven GORD symptoms. Subjects were consecutive asthmatics attending medical clinics. Controls were matched subjects without respiratory symptoms. RESULTS: The mean (SD) composite GORD symptom score of asthmatics was significantly higher than controls (21.8 (17.2) versus 12.0 (7.6); P < 0.001) as was frequency of each symptom and RARS. Prevalence of GORD symptoms in asthmatics was 59.4% (95% CI, 59.1%-59.6%) versus 28.5% in controls (95% CI, 29.0% - 29.4%). 36% of asthmatics experienced respiratory symptoms in association with both typical and atypical GORD symptoms, compared to 10% of controls (P < 0.001). An asthmatic had a 3.5 times higher risk of experiencing a GORD symptom after adjusting for confounders (OR 3.5; 95% CI 2.5-5.3). Severity of asthma had a strong dose-response relationship with GORD symptoms. Asthma medication use did not significantly influence the presence of GORD symptoms. CONCLUSIONS: GORD symptoms and RARS were more prevalent in a cohort of Sri Lankan adult asthmatics compared to non-asthmatics. Increased prevalence of RARS is associated with both typical and atypical symptoms of GORD. Asthma disease and its severity, but not asthma medication, appear to influence presence of GORD symptoms. PMID- 20843347 TI - Identification of the full set of Listeria monocytogenes penicillin-binding proteins and characterization of PBPD2 (Lmo2812). AB - BACKGROUND: Bacterial penicillin-binding proteins (PBPs) can be visualized by their ability to bind radiolabeled or fluorescent beta-lactam derivatives both whole cells and membrane/cell enriched fractions. Analysis of the Listeria monocytogenes genome sequence predicted ten genes coding for putative PBPs, but not all of their products have been detected in studies using radiolabeled antibiotics, thus hindering their characterization. Here we report the positive identification of the full set of L. monocytogenes PBPs and the characteristics of the hitherto undescribed PBPD2 (Lmo2812). RESULTS: Eight L. monocytogenes PBPs were identified by the binding of fluorescent beta-lactam antibiotic derivatives Boc-FL, Boc-650 and Amp-Alexa430 to proteins in whole cells or membrane/cell wall extracts. The gene encoding a ninth PBP (Lmo2812) was cloned and expressed in Escherichia coli as a His-tagged protein. The affinity purified recombinant protein had DD-carboxypeptidase activity and preferentially degraded low molecular-weight substrates. L. monocytogenes mutants lacking the functional Lmo2812 enzyme were constructed and, compared to the wild-type, the cells were longer and slightly curved with bent ends.Protein Lmo1855, previously designated PBPD3, did not bind any of the antibiotic derivatives tested, similarly to the homologous enterococcal protein VanY. CONCLUSIONS: Nine out of the ten putative L. monocytogenes PBP genes were shown to encode proteins that bind derivatives of beta-lactam antibiotics, thus enabling their positive identification. PBPD2 (Lmo2812) was not visualized in whole cell extracts, most probably due to its low abundance, but it was shown to bind Boc-FL after recombinant overexpression and purification. Mutants lacking Lmo2812 and another low molecular mass (LMM) PBP, PBP5 (PBPD1)--both with DD-carboxypeptidase activity--displayed only slight morphological alterations, demonstrating that they are dispensable for cell survival and probably participate in the latter stages of peptidoglycan synthesis. Since Lmo2812 preferentially degrades low-molecular- mass substrates, this may indicate a role in cell wall turnover. PMID- 20843348 TI - Improved eradication of Clostridium difficile spores from toilets of hospitalized patients using an accelerated hydrogen peroxide as the cleaning agent. AB - BACKGROUND: C. difficle spores in the environment of patients with C. difficile associated disease (CDAD) are difficult to eliminate. Bleach (5000 ppm) has been advocated as an effective disinfectant for the environmental surfaces of patients with CDAD. Few alternatives to bleach for non-outbreak conditions have been evaluated in controlled healthcare studies. METHODS: This study was a prospective clinical comparison during non-outbreak conditions of the efficacy of an accelerated hydrogen peroxide cleaner (0.5% AHP) to the currently used stabilized hydrogen peroxide cleaner (0.05% SHP at manufacturer recommended use-dilution) with respect to spore removal from toilets in a tertiary care facility. The toilets used by patients who had diarrhea with and without C. difficile associated disease (CDAD) were cultured for C. difficile and were monitored using an ultraviolet mark (UVM) to assess cleaning compliance on a daily basis 5 days per week. A total of 243 patients and 714 samples were analysed. The culture results were included in the analysis only if the UVM audit from the same day confirmed that the toilet had been cleaned. RESULTS: Our data demonstrated that the efficacy of spore killing is formulation specific and cannot be generalized. The OxivirTB AHP formulation resulted in statistically significantly (p = 0.0023) lower levels of toxigenic C. difficile spores in toilets of patients with CDAD compared to the SHP formulation that was routinely being used (28% vs 45% culture positive). The background level of toxigenic C. difficile spores was 10% in toilets of patients with diarrhea not due to CDAD. The UVM audit indicated that despite the enhanced twice-daily cleaning protocol for CDAD patients cleaning was not achieved on approximately 30 - 40% of the days tested. CONCLUSION: Our data indicate that the AHP formulation evaluated that has some sporicidal activity was significantly better than the currently used SHP formulation. This AHP formulation provides a one-step process that significantly lowers the C. difficile spore level in toilets during non-outbreak conditions without the workplace safety concerns associated with 5000 ppm bleach. PMID- 20843349 TI - Sialic acid transport and catabolism are cooperatively regulated by SiaR and CRP in nontypeable Haemophilus influenzae. AB - BACKGROUND: The transport and catabolism of sialic acid, a critical virulence factor for nontypeable Haemophilus influenzae, is regulated by two transcription factors, SiaR and CRP. RESULTS: Using a mutagenesis approach, glucosamine-6 phosphate (GlcN-6P) was identified as a co-activator for SiaR. Evidence for the cooperative regulation of both the sialic acid catabolic and transport operons suggested that cooperativity between SiaR and CRP is required for regulation. cAMP was unable to influence the expression of the catabolic operon in the absence of SiaR but was able to induce catabolic operon expression when both SiaR and GlcN-6P were present. Alteration of helical phasing supported this observation by uncoupling SiaR and CRP regulation. The insertion of one half-turn of DNA between the SiaR and CRP operators resulted in the loss of SiaR-mediated repression of the transport operon while eliminating cAMP-dependent induction of the catabolic operon when GlcN-6P was present. SiaR and CRP were found to bind to their respective operators simultaneously and GlcN-6P altered the interaction of SiaR with its operator. CONCLUSIONS: These results suggest multiple novel features for the regulation of these two adjacent operons. SiaR functions as both a repressor and an activator and SiaR and CRP interact to regulate both operons from a single set of operators. PMID- 20843350 TI - Laparoscopic treatment of biliary peritonitis following nonoperative management of blunt liver trauma. AB - INTRODUCTION: Nonoperative management (NOM) of hemodynamically stable patients with blunt hepatic injuries is considered the current standard of care. However, it is associated with several in-hospital complications. In selected cases laparoscopy could be proposed as diagnostic and therapeutic means. CASE REPORT: A 28 years-old male was admitted in the Emergency Unit following a motor vehicle crash. CT-scan showed an isolated stade II hepatic injury at the level of the segment IV. Firstly a NOM was decided. Laparoscopic exploration was then performed at day 4 due to a biliary peritonitis. Intraoperative trans-cystic duct cholangiography showed a biliary leaks of left hepatic biliary tract, involving sectioral pedicle to segment III. Cholecystectomy, trans-cystic biliary drainage, application of surgical tissue sealing patch and abdominal drainage were performed. Postoperative outcome was uneventful, with fast patient recovery. CONCLUSION: Laparoscopy has gained a role as diagnostic and therapeutic means in treatment of complications following NOM of blunt liver trauma. This approach seems feasible and safety, with satisfactory postoperative outcome. PMID- 20843351 TI - Foodborne norovirus outbreak: the role of an asymptomatic food handler. AB - BACKGROUND: In July 2005 an outbreak of acute gastroenteritis occurred on a residential summer camp in the province of Barcelona (northeast of Spain). Forty four people were affected among residents and employees. All of them had in common a meal at lunch time on 13 July (paella, round of beef and fruit). The aim of this study was to investigate a foodborne norovirus outbreak that occurred in the residential summer camp and in which the implication of a food handler was demonstrated by laboratory tests. METHODS: A retrospective cohort study was designed. Personal or telephone interview was carried out to collect demographic, clinical and microbiological data of the exposed people, as well as food consumption in the suspected lunch. Food handlers of the mentioned summer camp were interviewed.Ten stool samples were requested from symptomatic exposed residents and the three food handlers that prepared the suspected food. Stools were tested for bacteries and noroviruses. Norovirus was detected using RT-PCR and sequence analysis.Attack rate, relative risks (RR) and its 95% confidence intervals (CI) were calculated to assess the association between food consumption and disease. RESULTS: The global attack rate of the outbreak was 55%. The main symptoms were abdominal pain (90%), nausea (85%), vomiting (70%) and diarrhoea (42.5%). The disease remitted in 24-48 hours. Norovirus was detected in seven faecal samples, one of them was from an asymptomatic food handler who had not eaten the suspected food (round of beef), but cooked and served the lunch. Analysis of the two suspected foods isolated no pathogenic bacteria and detected no viruses. Molecular analysis showed that the viral strain was the same in ill patients and in the asymptomatic food handler (genotype GII.2 Melksham-like). CONCLUSIONS: In outbreaks of foodborne disease, the search for viruses in affected patients and all food handlers, even in those that are asymptomatic, is essential. Health education of food handlers with respect to hand washing should be promoted. PMID- 20843352 TI - Adult growth hormone deficiency treatment with a combination of growth hormone and insulin-like growth factor-1 resulting in elevated sustainable insulin-like growth factor-1 and insulin-like growth factor binding protein 3 plasma levels: a case report. AB - INTRODUCTION: Adult Growth hormone Deficiency is a well known phenomenon effecting both males and females. Adult Growth Hormone Deficiency is marked by a number of neuropsychiatric, cognitive performance, cardiac, metabolic, muscular, and bone symptoms and clinical features. There is no known standardized acceptable therapeutic modality to treat this condition. A recent meta-analysis found that after 16 years of Growth Hormone replacement therapy a large proportion of the patients still had Growth Hormone associated symptoms especially related to executive functioning. A major goal is to increase plasma levels of both insulin-like growth factor (insulin-like growth factor-1) and insulin-like growth factor binding protein 3. CASE PRESENTATION: We report a case of a 45-year-old caucasian woman with early ovarian failure for 2 years and amenorrhea since the age of 43, who presented with Adult Growth Hormone Deficiency and an IGF-1 of 126 ng/mL. Since her insulin-like growth factor-1 was lowest at 81 ng/mL, she was started on insulin-like growth factor-1 Increlex at 0.2 mg at bedtime, which immediately raised her insulin-like growth factor-1 levels to 130 ng/mL within 1 month, and 193 ng/mL, 249 ng/mL, and 357 ng/mL, after 3, 4, and 5 months, respectively, thereafter. Her insulin-like growth factor binding protein 3 continued to decrease. It was at this point when we added back the Growth Hormone and increased her Increlex dosage to 1.3 - 1.5 mg that her insulin-like growth factor binding protein 3 began to increase. CONCLUSION: It appears that in some patients with Adult Growth Hormone Deficiency, insulin-like growth factor-1 elevation is resistant to direct Growth Hormone treatment. Furthermore, the binding protein may not rise with insulin like growth factor-1. However, a combination of Growth Hormone and insulin-like growth factor-1 treatment may be a solution. PMID- 20843353 TI - Increased expression of RXRalpha in dementia: an early harbinger for the cholesterol dyshomeostasis? AB - BACKGROUND: Cholesterol content of cerebral membranes is tightly regulated by elaborate mechanisms that balance the level of cholesterol synthesis, uptake and efflux. Among the conventional regulatory elements, a recent research focus has been nuclear receptors, a superfamily of ligand-activated transcription factors providing an indispensable regulatory framework in controlling cholesterol metabolism pathway genes. The mechanism of transcriptional regulation by nuclear receptors such as LXRs involves formation of heterodimers with RXRs. LXR/RXR functions as a sensor of cellular cholesterol concentration and mediates cholesterol efflux by inducing the transcription of key cholesterol shuffling vehicles namely, ATP-binding cassette transporter A1 (ABCA1) and ApoE. RESULTS: In the absence of quantitative data from humans, the relevance of expression of nuclear receptors and their involvement in cerebral cholesterol homeostasis has remained elusive. In this work, new evidence is provided from direct analysis of human postmortem brain gene and protein expression suggesting that RXRalpha, a key regulator of cholesterol metabolism is differentially expressed in individuals with dementia. Importantly, RXRalpha expression showed strong association with ABCA1 and ApoE gene expression, particularly in AD vulnerable regions. CONCLUSIONS: These findings suggest that LXR/RXR-induced upregulation of ABCA1 and ApoE levels may be the molecular determinants of cholesterol dyshomeostasis and of the accompanying dementia observed in AD. PMID- 20843354 TI - Effects of fetal bovine serum deprivation in cell cultures on the production of Anticarsia gemmatalis multinucleopolyhedrovirus. AB - BACKGROUND: Anticarsia gemmatalis is a pest in South America's soybean crops, which could be controlled by the Multinucleopolyhedrovirus of A. gemmatalis (AgMNPV). Currently, its commercial production is based on infected larvae. However, the possibility of using modified baculoviruses in Integrated Pest Management programs has stimulated an interest to develop alternative multiplication processes. This study evaluated the AgMNPV production in UFL-Ag 286 cells previously deprived Fetal Bovine Serum. RESULTS: Culture media containing 1% FBS during the previous 48 hours achieved a synchronized condition where 90% of cells were found in G0/G1 stage, showing the presence of non filamentous actin. All characteristics were estimated from cellular viability tests, cell actin detection trials and flow cytometer cell cycle analysis. AgMNPV production was tested by transcript studies and budded viruses (BVs) and occlusion bodies (OBs) yield quantitation. Results showed that the productivity in FBS deprived cells was 9.8 times more in BVs and 3.8 times more in OBs with respect to non-treated cells. CONCLUSIONS: UFL-Ag-286 cells previously deprived in FBS shown to be a better host for AgMNPV propagation, increasing the useful for both in vitro bioinsecticide production and applications such as recombinant protein expression or gene delivery. PMID- 20843355 TI - Improvement in medication education in a pediatric subspecialty practice. AB - BACKGROUND: The purpose of this study was to measure the impact of an educational intervention on parents of children taking methotrexate (MTX) for juvenile idiopathic arthritis (JIA). METHODS: This study was conducted using a pre- and postsurvey design. The parents of 100 children with JIA taking MTX for at least 2 months were surveyed during a routine office visit. The parents completed an initial questionnaire regarding the safe use, adverse effects, and guidelines for monitoring the toxicity of MTX. An educational intervention was then administered, and an identical follow-up questionnaire was given during the next office visit. Statistical analysis using a paired t-test (critical P value < 0.05) was performed on individuals who answered both questionnaires. RESULTS: There were 100 responses to the initial questionnaire and 67 responses to the follow-up questionnaire. The mean length of time between surveys was 2.9 +/- 0.9 months. In those who completed both questionnaires, the overall correct score increased significantly from 75.8% to 93.4%, respectively (P < 0.0001). Individuals scored the lowest (49%) on the question that addressed MTX's impact on pregnancy and fertility. CONCLUSIONS: MTX knowledge may be less than expected in the parents of children with JIA. Brief educational interventions in the pediatric subspecialty practice can significantly affect a family's understanding of their child's medications. PMID- 20843356 TI - Pan-genome sequence analysis using Panseq: an online tool for the rapid analysis of core and accessory genomic regions. AB - BACKGROUND: The pan-genome of a bacterial species consists of a core and an accessory gene pool. The accessory genome is thought to be an important source of genetic variability in bacterial populations and is gained through lateral gene transfer, allowing subpopulations of bacteria to better adapt to specific niches. Low-cost and high-throughput sequencing platforms have created an exponential increase in genome sequence data and an opportunity to study the pan-genomes of many bacterial species. In this study, we describe a new online pan-genome sequence analysis program, Panseq. RESULTS: Panseq was used to identify Escherichia coli O157:H7 and E. coli K-12 genomic islands. Within a population of 60 E. coli O157:H7 strains, the existence of 65 accessory genomic regions identified by Panseq analysis was confirmed by PCR. The accessory genome and binary presence/absence data, and core genome and single nucleotide polymorphisms (SNPs) of six L. monocytogenes strains were extracted with Panseq and hierarchically clustered and visualized. The nucleotide core and binary accessory data were also used to construct maximum parsimony (MP) trees, which were compared to the MP tree generated by multi-locus sequence typing (MLST). The topology of the accessory and core trees was identical but differed from the tree produced using seven MLST loci. The Loci Selector module found the most variable and discriminatory combinations of four loci within a 100 loci set among 10 strains in 1 s, compared to the 449 s required to exhaustively search for all possible combinations; it also found the most discriminatory 20 loci from a 96 loci E. coli O157:H7 SNP dataset. CONCLUSION: Panseq determines the core and accessory regions among a collection of genomic sequences based on user-defined parameters. It readily extracts regions unique to a genome or group of genomes, identifies SNPs within shared core genomic regions, constructs files for use in phylogeny programs based on both the presence/absence of accessory regions and SNPs within core regions and produces a graphical overview of the output. Panseq also includes a loci selector that calculates the most variable and discriminatory loci among sets of accessory loci or core gene SNPs. AVAILABILITY: Panseq is freely available online at http://76.70.11.198/panseq. Panseq is written in Perl. PMID- 20843357 TI - Preoperative evaluation of pulmonary artery morphology and pulmonary circulation in neonates with pulmonary atresia--usefulness of MR angiography in clinical routine. AB - BACKGROUND: To explore the role of contrast-enhanced magnetic resonance angiography (CE-MRA) in clinical routine for evaluating neonates with pulmonary atresia (PA) and to describe their pulmonary artery morphology and blood supply.CE-MRA studies of 15 neonates with PA (12 female; median weight: 2900 g) were retrospectively evaluated by two radiologists in consensus. Each study was judged to be either diagnostic or non-diagnostic depending on the potential to evaluate pulmonary artery morphology and pulmonary blood supply. In those cases where surgery or conventional angiocardiography was performed results were compared. RESULTS: CE-MRA was considered diagnostic in 87%. Pulmonary artery morphology was classified as "confluent with (n = 1) and without (n = 1) main pulmonary artery", "non-confluent" (n = 6) or "absent" (n = 7). Source of pulmonary blood supply was "a persistent arterial duct" (n = 12), "a direct" (n = 22) or "indirect (n = 9) aortopulmonary collateral artery (APCA)" or "an APCA from the ascending aorta" (n = 2). In no patient were there any additional findings at surgery or conventional angiocardiography which would have changed the therapeutic or surgical approach. CONCLUSIONS: CE-MRA is a useful diagnostic tool for the preoperative evaluation of the morphology of pulmonary arteries and blood supply in neonates with PA. In most cases diagnostic cardiac catheterization can be avoided. PMID- 20843358 TI - Patients presenting with somatic complaints in general practice: depression, anxiety and somatoform disorders are frequent and associated with psychosocial stressors. AB - BACKGROUND: Mental disorders in primary care patients are frequently associated with physical complaints that can mask the disorder. There is insufficient knowledge concerning the role of anxiety, depression, and somatoform disorders in patients presenting with physical symptoms. Our primary objective was to determine the prevalence of depression, anxiety, and somatoform disorders among primary care patients with a physical complaint. We also investigated the relationship between cumulated psychosocial stressors and mental disorders. METHODS: We conducted a multicentre cross-sectional study in twenty-one private practices and in one academic primary care centre in Western Switzerland. Randomly selected patients presenting with a spontaneous physical complaint were asked to complete the self-administered Patient Health Questionnaire (PHQ) between November 2004 and July 2005. The validated French version of the PHQ allowed the diagnosis of mental disorders (DSM-IV criteria) and the analyses of exposure to psychosocial stressors. RESULTS: There were 917 patients exhibiting at least one physical symptom included. The rate of depression, anxiety, and somatoform disorders was 20.0% (95% confidence interval [CI] = 17.4% to 22.7%), 15.5% (95% CI = 13.2% to 18.0%), and 15.1% (95% CI = 12.8% to 17.5%), respectively. Psychosocial stressors were significantly associated with mental disorders. Patients with an accumulation of psychosocial stressors were more likely to present anxiety, depression, or somatoform disorders, with an increase of 2.2 fold (95% CI = 2.0 to 2.5) for each additional stressor. CONCLUSIONS: The investigation of mental disorders and psychosocial stressors among patients with physical complaints is relevant in primary care. Psychosocial stressors should be explored as potential epidemiological causes of mental disorders. PMID- 20843359 TI - Gene cassette transcription in a large integron-associated array. AB - BACKGROUND: The integron/gene cassette system is a diverse and effective adaptive resource for prokaryotes. Short cassette arrays, with less than 10 cassettes adjacent to an integron, provide this resource through the expression of cassette associated genes by an integron-borne promoter. However, the advantage provided by large arrays containing hundreds of cassettes is less obvious. In this work, using the 116-cassette array of Vibrio sp. DAT722 as a model, we investigated the theory that the majority of genes contained within large cassette arrays are widely expressed by intra-array promoters in addition to the integron-borne promoter. RESULTS: We demonstrated that the majority of the cassette-associated genes in the subject array were expressed. We further showed that cassette expression was conditional and that the conditionality varied across the array. We finally showed that this expression was mediated by a diversity of cassette borne promoters within the array capable of responding to environmental stressors. CONCLUSIONS: Widespread expression within large gene cassette arrays could provide an adaptive advantage to the host in proportion to the size of the array. Our findings explained the existence and maintenance of large cassette arrays within many prokaryotes. Further, we suggested that repeated rearrangement of cassettes containing genes and/or promoters within large arrays could result in the assembly of operon-like groups of co-expressed cassettes within an array. These findings add to our understanding of the adaptive repertoire of the integron/gene cassette system in prokaryotes and consequently, the evolutionary impact of this system. PMID- 20843360 TI - Data-guide for brain deformation in surgery: comparison of linear and nonlinear models. AB - BACKGROUND: Pre-operative imaging devices generate high-resolution images but intra-operative imaging devices generate low-resolution images. To use high resolution pre-operative images during surgery, they must be deformed to reflect intra-operative geometry of brain. METHODS: We employ biomechanical models, guided by low resolution intra-operative images, to determine location of normal and abnormal regions of brain after craniotomy. We also employ finite element methods to discretize and solve the related differential equations. In the process, pre- and intra-operative images are utilized and corresponding points are determined and used to optimize parameters of the models. This paper develops a nonlinear model and compares it with linear models while our previous work developed and compared linear models (mechanical and elastic). RESULTS: Nonlinear model is evaluated and compared with linear models using simulated and real data. Partial validation using intra-operative images indicates that the proposed models reduce the localization error caused by brain deformation after craniotomy. CONCLUSIONS: The proposed nonlinear model generates more accurate results than the linear models. When guided by limited intra-operative surface data, it predicts deformation of entire brain. Its execution time is however considerably more than those of linear models. PMID- 20843361 TI - Evaluation of energy and dietary intake estimates from a food frequency questionnaire using independent energy expenditure measurement and weighed food records. AB - BACKGROUND: We have developed a food frequency questionnaire (FFQ) for the assessment of habitual diet, with special focus on the intake of fruit, vegetables and other antioxidant-rich foods and beverages. The aim of the present study was to evaluate the relative validity of the intakes of energy, food and nutrients from the FFQ. METHODS: Energy intake was evaluated against independent measures of energy expenditure using the ActiReg(r) system (motion detection), whereas 7-days weighed food records were used to study the relative validity of food and nutrient intake. The relationship between methods was investigated using correlation analyses and cross-classification of participants. The visual agreement between the methods was evaluated using Bland-Altman plots. RESULTS: We observed that the FFQ underestimated the energy intake by approximately 11% compared to the energy expenditure measured by the ActiReg(r). The correlation coefficient between energy intake and energy expenditure was 0.54 and 32% of the participants were defined as under-reporters. Compared to the weighed food records the percentages of energy from fat and added sugar from the FFQ were underestimated, whereas the percentage of energy from total carbohydrates and protein were slightly overestimated. The intake of foods rich in antioxidants did not vary significantly between the FFQ and weighed food records, with the exceptions of berries, coffee, tea and vegetables which were overestimated. Spearman's Rank Order Correlations between FFQ and weighed food records were 0.41 for berries, 0.58 for chocolate, 0.78 for coffee, 0.61 for fruit, 0.57 for fruit and berry juices, 0.40 for nuts, 0.74 for tea, 0.38 for vegetables and 0.70 for the intake of wine. CONCLUSIONS: Our new FFQ provides a good estimate of the average energy intake and it obtains valid data on average intake of most antioxidant-rich foods and beverages. Our study also showed that the FFQs ability to rank participants according to intake of total antioxidants and most of the antioxidant-rich foods was good. PMID- 20843362 TI - Extracellular Paracoccidioides brasiliensis phospholipase B involvement in alveolar macrophage interaction. AB - BACKGROUND: Phospholipase B (PLB) has been reported to be one of the virulence factors for human pathogenic fungi and has also been described as necessary for the early events in infection. Based on these data, we investigated the role of PLB in virulence and modulation of the alveolar pulmonary immune response during infection using an in-vitro model of host-pathogen interaction, i.e. Paracoccidioides brasiliensis yeast cells infecting alveolar macrophage (MH-S) cells. RESULTS: The effect of PLB was analyzed using the specific inhibitor alexidine dihydrochloride (0.25 MUM), and pulmonary surfactant (100 MUg mL-1), during 6 hours of co-cultivation of P. brasiliensis and MH-S cells. Alexidine dihydrochloride inhibited PLB activity by 66% and significantly decreased the adhesion and internalization of yeast cells by MH-S cells. Genes involved in phagocytosis (trl2, cd14) and the inflammatory response (nfkb, tnf-alpha, il 1beta) were down-regulated in the presence of this PLB inhibitor. In contrast, PLB activity and internalization of yeast cells significantly increased in the presence of pulmonary surfactant; under this condition, genes such as clec2 and the pro-inflammatory inhibitor (nkrf) were up-regulated. Also, the pulmonary surfactant did not alter cytokine production, while alexidine dihydrochloride decreased the levels of interleukin-10 (IL-10) and increased the levels of IL-12 and tumor necrosis factor-alpha (TNF-alpha). In addition, gene expression analysis of plb1, sod3 and icl1 suggests that P. brasiliensis gene re-programming is effective in facilitating adaptation to this inhospitable environment, which mimics the lung-environment interaction. CONCLUSION: P. brasiliensis PLB activity is involved in the process of adhesion and internalization of yeast cells at the MH-S cell surface and may enhance virulence and subsequent down-regulation of macrophage activation. PMID- 20843364 TI - Respiratory syncytial virus (RSV) RNA loads in peripheral blood correlates with disease severity in mice. AB - BACKGROUND: Respiratory Syncytial Virus (RSV) infection is usually restricted to the respiratory epithelium. Few studies have documented the presence of RSV in the systemic circulation, however there is no consistent information whether virus detection in the blood correlates with disease severity. METHODS: Balb/c mice were inoculated with live RSV, heat-inactivated RSV or medium. A subset of RSV-infected mice was treated with anti-RSV antibody 72 h post-inoculation. RSV RNA loads were measured by PCR in peripheral blood from day 1-21 post-inoculation and were correlated with upper and lower respiratory tract viral loads, the systemic cytokine response, lung inflammation and pulmonary function. Immunohistochemical staining was used to define the localization of RSV antigens in the respiratory tract and peripheral blood. RESULTS: RSV RNA loads were detected in peripheral blood from day 1 to 14 post-inoculation, peaked on day 5 and significantly correlated with nasal and lung RSV loads, airway obstruction, and blood CCL2 and CXCL1 expression. Treatment with anti-RSV antibody reduced blood RSV RNA loads and improved airway obstruction. Immunostaining identified RSV antigens in alveolar macrophages and peripheral blood monocytes. CONCLUSIONS: RSV RNA was detected in peripheral blood upon infection with live RSV, followed a time-course parallel to viral loads assessed in the respiratory tract and was significantly correlated with RSV-induced airway disease. PMID- 20843363 TI - Intracellular localization and interaction of mRNA binding proteins as detected by FRET. AB - BACKGROUND: A number of RNA binding proteins (BPs) bind to A+U rich elements (AREs), commonly present within 3'UTRs of highly regulated RNAs. Individual RNA BPs proteins can modulate RNA stability, RNA localization, and/or translational efficiency. Although biochemical studies have demonstrated selectivity of ARE-BPs for individual RNAs, less certain is the in vivo composition of RNA-BP multiprotein complexes and how their composition is affected by signaling events and intracellular localization. Using FRET, we previously demonstrated that two ARE-BPs, HuR and AUF1, form stable homomeric and heteromeric associations in the nucleus and cytoplasm. In the current study, we use immuno-FRET of endogenous proteins to examine the intracellular localization and interactions of HuR and AUF1 as well as KSRP, TIA-1, and Hedls. These results were compared to those obtained with their exogenously expressed, fluorescently labeled counterparts. RESULTS: All ARE-BPs examined were found to colocalize and to form stable associations with selected other RNA-BPs in one or more cellular locations variably including the nucleus, cytoplasm (in general), or in stress granules or P bodies. Interestingly, FRET based interaction of the translational suppressor, TIA-1, and the decapping protein, Hedls, was found to occur at the interface of stress granules and P bodies, dynamic sites of intracellular RNA storage and/or turnover. To explore the physical interactions of RNA-BPs with ARE containing RNAs, in vitro transcribed Cy3-labeled RNA was transfected into cells. Interestingly, Cy3-RNA was found to coalesce in P body like punctate structures and, by FRET, was found to interact with the RNA decapping proteins, Hedls and Dcp1. CONCLUSIONS: Biochemical methodologies, such as co-immunoprecipitation, and cell biological approaches such as standard confocal microscopy are useful in demonstrating the possibility of proteins and/or proteins and RNAs interacting. However, as demonstrated herein, colocalization of proteins and proteins and RNA is not always indicative of interaction. To this point, using FRET and immuno FRET, we have demonstrated that RNA-BPs can visually colocalize without producing a FRET signal. In contrast, proteins that appear to be delimited to one or another intracellular compartment can be shown to interact when those compartments are juxtaposed. PMID- 20843365 TI - Context dependent substitution biases vary within the human genome. AB - BACKGROUND: Models of sequence evolution typically assume that different nucleotide positions evolve independently. This assumption is widely appreciated to be an over-simplification. The best known violations involve biases due to adjacent nucleotides. There have also been suggestions that biases exist at larger scales, however this possibility has not been systematically explored. RESULTS: To address this we have developed a method which identifies over- and under-represented substitution patterns and assesses their overall impact on the evolution of genome composition. Our method is designed to account for biases at smaller pattern sizes, removing their effects. We used this method to investigate context bias in the human lineage after the divergence from chimpanzee. We examined bias effects in substitution patterns between 2 and 5 bp long and found significant effects at all sizes. This included some individual three and four base pair patterns with relatively large biases. We also found that bias effects vary across the genome, differing between transposons and non-transposons, between different classes of transposons, and also near and far from genes. CONCLUSIONS: We found that nucleotides beyond the immediately adjacent one are responsible for substantial context effects, and that these biases vary across the genome. PMID- 20843366 TI - Attitudes towards transfers of human tissue samples across borders: an international survey of researchers and policy makers in five countries. AB - BACKGROUND: Sharing of tissue samples for research and disease surveillance purposes has become increasingly important. While it is clear that this is an area of intense, international controversy, there is an absence of data about what researchers themselves and those involved in the transfer of samples think about these issues, particularly in developing countries. METHODS: A survey was carried out in a number of Asian countries and in Egypt to explore what researchers and others involved in research, storage and transfer of human tissue samples thought about some of the issues related to sharing of such samples. RESULTS: The results demonstrated broad agreement with the positions taken by developing countries in the current debate, favoring quite severe restrictions on the use of samples by developed countries. CONCLUSIONS: It is recommended that an international agreement is developed on what conditions should be attached to any sharing of human tissue samples across borders. PMID- 20843367 TI - Cognitive performance and leukocyte telomere length in two narrow age-range cohorts: a population study. AB - BACKGROUND: Cognitive function and telomere length both decline with age. A correlation between these two measures would suggest that they may be influenced by the same underlying age-related biological process. Several studies suggest telomere length may be positively correlated with cognitive performance but the evidence is equivocal. In this report, the relationships between telomere length and cognitive performance at Wave 2 and cognitive change from Wave 1 to Wave 2 are assessed in two narrow age-range population cohorts. METHODS: We tested the hypothesis that leukocyte telomere length correlates positively with cognitive performance and cognitive decline in two community cohorts of middle-aged (n = 351, 44-49 years) and older (n = 295, 64-70 years) adults, who participated in two waves of a longitudinal study undertaken in the Canberra-Queanbeyan region of Australia. Telomere length was estimated at Wave 2. Cognitive performance was measured using the Symbol Digit Modalities Test, the immediate recall test of the California Verbal Learning Test, reaction time (simple & choice) and the Trails Test Part B. RESULTS: Cross-sectionally at Wave 2, telomere length correlated with Symbol Digit Modalities Test scores (men) and simple reaction time (women) for the older cohort only, although the latter finding was in the opposite direction to that hypothesised. Telomere length measured at Wave 2 was not associated with cognitive change from Wave 1 to Wave 2 for either cohort, except for two associations of small magnitude (immediate recall in the older cohort, choice reaction time in older women), which were also in the contrary direction to that predicted. CONCLUSIONS: These results do not give strong support to the hypothesis that leukocyte telomere length is associated with either levels of cognitive performance or age-related cognitive change. PMID- 20843368 TI - FATS is a transcriptional target of p53 and associated with antitumor activity. AB - Frequent mutations of p53 in human cancers exemplify its crucial role as a tumor suppressor transcription factor, and p21, a transcriptional target of p53, plays a central role in surveillance of cell-cycle checkpoints. Our previous study has shown that FATS stabilize p21 to preserve genome integrity. In this study we identified a novel transcript variant of FATS (GenBank: GQ499374) through screening a cDNA library from mouse testis, which uncovered the promoter region of mouse FATS. Mouse FATS was highly expressed in testis. The p53-responsive elements existed in proximal region of both mouse and human FATS promoters. Functional study indicated that the transcription of FATS gene was activated by p53, whereas such effect was abolished by site-directed mutagenesis in the p53-RE of FATS promoter. Furthermore, the expression of FATS increased upon DNA damage in a p53-dependent manner. FATS expression was silent or downregulated in human cancers, and overexpression of FATS suppressed tumorigenicity in vivo independently of p53. Our results reveal FATS as a p53-regulated gene to monitor genomic stability. PMID- 20843369 TI - Protocol for population testing of an Internet-based Personalised Decision Support system for colorectal cancer screening. AB - BACKGROUND: Australia has a comparatively high incidence of colorectal (bowel) cancer; however, population screening uptake using faecal occult blood test (FOBT) remains low. This study will determine the impact on screening participation of a novel, Internet-based Personalised Decision Support (PDS) package. The PDS is designed to measure attitudes and cognitive concerns and provide people with individually tailored information, in real time, that will assist them with making a decision to screen. The hypothesis is that exposure to (tailored) PDS will result in greater participation in screening than participation following exposure to non-tailored PDS or resulting from the current non-tailored, paper-based approach. METHODS/DESIGN: A randomised parallel trial comprising three arms will be conducted. Men and women aged 50-74 years (N = 3240) will be recruited. They must have access to the Internet; have not had an FOBT within the previous 12 months, or sigmoidoscopy or colonoscopy within the previous 5 years; have had no clinical diagnosis of bowel cancer. Groups 1 and 2 (PDS arms) will access a website and complete a baseline survey measuring decision-to-screen stage, attitudes and cognitive concerns and will receive immediate feedback; Group 1 will receive information 'tailored' to their responses in the baseline survey and group 2 will received 'non-tailored' bowel cancer information. Respondents in both groups will subsequently receive an FOBT kit. Group 3 (usual practice arm) will complete a paper-based version of the baseline survey and respondents will subsequently receive 'non-tailored' paper based bowel cancer information with accompanying FOBT kit. Following despatch of FOBTs, all respondents will be requested to complete an endpoint survey. Main outcome measures are (1) completion of FOBT and (2) change in decision-to-screen stage. Secondary outcomes include satisfaction with decision and change in attitudinal scores from baseline to endpoint. Analyses will be performed using Chi-square tests, analysis of variance and log binomial generalized linear models as appropriate. DISCUSSION: It is necessary to restrict participants to Internet users to provide an appropriately controlled evaluation of PDS. Once efficacy of the approach has been established, it will be important to evaluate effectiveness in the wider at-risk population, and to identify barriers to its implementation in those settings. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000095066. PMID- 20843371 TI - The characterization of conserved binding motifs and potential target genes for M. tuberculosis MtrAB reveals a link between the two-component system and the drug resistance of M. smegmatis. AB - BACKGROUND: The two-component systems of Mycobacterium tuberculosis are apparently required for its growth and resistance in hostile host environments. In such environments, MtrAB has been reported to regulate the expression of the M. tuberculosis replication initiator gene, dnaA. However, the dnaA promoter binding sites and many potential target genes for MtrA have yet to be precisely characterized. RESULTS: In this study, a 7 bp sequence motif in the dnaA promoter region was identified for MtrA binding using DNaseI footprinting assays and surface plasmon resonance (SPR) analysis. Approximately 420 target genes potentially regulated by MtrA, including the isoniazid inducible gene iniB, were further characterized from M. tuberculosis and M. smegmatis genomes. When assayed using quantitative real-time PCR (qRT-PCR), many of the target genes demonstrated significant expression changes when the antisense mRNA of the mtrA gene was expressed in M. smegmatis. The recombinant mycobacteria grew in length and were more sensitive to two anti-tuberculosis drugs, isoniazid and streptomycin. CONCLUSIONS: These findings yield critical information about the regulatory mechanisms of the MtrAB two-component system and its role in the drug resistance of M. smegmatis. PMID- 20843370 TI - Reduction of lung metastasis, cell invasion, and adhesion in mouse melanoma by statin-induced blockade of the Rho/Rho-associated coiled-coil-containing protein kinase pathway. AB - BACKGROUND: Melanomas are highly malignant and have high metastatic potential; hence, there is a need for new therapeutic strategies to prevent cell metastasis. In the present study, we investigated whether statins inhibit tumor cell migration, invasion, adhesion, and metastasis in the B16BL6 mouse melanoma cell line. METHODS: The cytotoxicity of statins toward the B16BL6 cells were evaluated using a cell viability assay. As an experimental model, B16BL6 cells were intravenously injected into C57BL/6 mice. Cell migration and invasion were assessed using Boyden chamber assays. Cell adhesion analysis was performed using type I collagen-, type IV collagen-, fibronectin-, and laminin-coated plates. The mRNA levels, enzyme activities and protein levels of matrix metalloproteinases (MMPs) were determined using RT-PCR, activity assay kits, and Western blot analysis, respectively; the mRNA and protein levels of vary late antigens (VLAs) were also determined. The effects of statins on signal transduction molecules were determined by western blot analyses. RESULTS: We found that statins significantly inhibited lung metastasis, cell migration, invasion, and adhesion at concentrations that did not have cytotoxic effects on B16BL6 cells. Statins also inhibited the mRNA expressions and enzymatic activities of matrix metalloproteinases (MMPs). Moreover, they suppressed the mRNA and protein expressions of integrin alpha2, integrin alpha4, and integrin alpha5 and decreased the membrane localization of Rho, and phosphorylated LIM kinase (LIMK) and myosin light chain (MLC). CONCLUSIONS: The results indicated that statins suppressed the Rho/Rho-associated coiled-coil-containing protein kinase (ROCK) pathways, thereby inhibiting B16BL6 cell migration, invasion, adhesion, and metastasis. Furthermore, they markedly inhibited clinically evident metastasis. Thus, these findings suggest that statins have potential clinical applications for the treatment of tumor cell metastasis. PMID- 20843373 TI - Superhydrophilicity and antibacterial property of a Cu-dotted oxide coating surface. AB - BACKGROUND: Aluminum-made settings are widely used in healthcare, schools, public facilities and transit systems. Frequently-touched surfaces of those settings are likely to harbour bacteria and be a potential source of infection. One method to utilize the effectiveness of copper (Cu) in eliminating pathogens for these surfaces would be to coat the aluminum (Al) items with a Cu coating. However, such a combination of Cu and Al metals is susceptible to galvanic corrosion because of their different electrochemical potentials. METHODS: In this work, a new approach was proposed in which electrolytic plasma oxidation (EPO) of Al was used to form an oxide surface layer followed by electroplating of Cu metal on the top of the oxide layer. The oxide was designed to function as a corrosion protective and biocompatible layer, and the Cu in the form of dots was utilized as an antibacterial material. The antibacterial property enhanced by superhydrophilicity of the Cu-dotted oxide coating was evaluated. RESULTS: A superhydrophilic surface was successfully prepared using electrolytic plasma oxidation of aluminum (Al) followed by electroplating of copper (Cu) in a Cu dotted form. Both Cu plate and Cu-dotted oxide surfaces had excellent antimicrobial activities against E. coli ATCC 25922, methicillin-resistant Staphylococcus aureus (MRSA) ATCC 43300 and vancomycin-resistant Enterococcus faecium (VRE) ATCC 51299. However, its Cu-dotted surface morphology allowed the Cu-dotted oxide surface to be more antibacterial than the smooth Cu plate surface. The enhanced antibacterial property was attributed to the superhydrophilic behaviour of the Cu-dotted oxide surface that allowed the bacteria to have a more effective killing contact with Cu due to spreading of the bacterial suspension media. CONCLUSION: The superhydrophilic Cu-dotted oxide coating surface provided an effective method of controlling bacterial growth and survival on contact surfaces and thus reduces the risk of infection and spread of bacteria-related diseases particularly in moist or wet environments. PMID- 20843374 TI - Genetic characterization of 2008 reassortant influenza A virus (H5N1), Thailand. AB - In January and November 2008, outbreaks of avian influenza have been reported in 4 provinces of Thailand. Eight Influenza A H5N1 viruses were recovered from these 2008 AI outbreaks and comprehensively characterized and analyzed for nucleotide identity, genetic relatedness, virulence determinants, and possible sites of reassortment. The results show that the 2008 H5N1 viruses displayed genetic drift characteristics (less than 3% genetic differences), as commonly found in influenza A viruses. Based on phylogenetic analysis, clade 1 viruses in Thailand were divided into 3 distinct branches (subclades 1, 1.1 and 1.2). Six out of 8 H5N1 isolates have been identified as reassorted H5N1 viruses, while other isolates belong to an original H5N1 clade. These viruses have undergone inter lineage reassortment between subclades 1.1 and 1.2 and thus represent new reassorted 2008 H5N1 viruses. The reassorted viruses have acquired gene segments from H5N1, subclade 1.1 (PA, HA, NP and M) and subclade 1.2 (PB2, PB1, NA and NS) in Thailand. Bootscan analysis of concatenated whole genome sequences of the 2008 H5N1 viruses supported the reassortment sites between subclade 1.1 and 1.2 viruses. Based on estimating of the time of the most recent common ancestors of the 2008 H5N1 viruses, the potential point of genetic reassortment of the viruses could be traced back to 2006. Genetic analysis of the 2008 H5N1 viruses has shown that most virulence determinants in all 8 genes of the viruses have remained unchanged. In summary, two predominant H5N1 lineages were circulating in 2008. The original CUK2-like lineage mainly circulated in central Thailand and the reassorted lineage (subclades 1.1 and 1.2) predominantly circulated in lower north Thailand. To prevent new reassortment, emphasis should be put on prevention of H5N1 viruses circulating in high risk areas. In addition, surveillance and whole genome sequencing of H5N1 viruses should be routinely performed for monitoring the genetic drift of the virus and new reassorted strains, especially in light of potential reassortment between avian and mammalian H5N1 viruses. PMID- 20843372 TI - Transcription phase, protein characteristics of DEV UL45 and prokaryotic expression, antibody preparation of the UL45 des-transmembrane domain. AB - BACKGROUND: Some UL45 gene function of Herpesvirus was reported. While there was no any report of the duck enteritis virus (DEV) UL45 protein as yet. RESULTS: The UL45 gene and des-transmembrane domain of UL45 (named UL45Delta gene, 295-675bp of UL45) of DEV were amplified by PCR and subcloned into the prokaryotic expression vector pET-32a(+). The constructed recombinant plasmids were transformed into the host strain BL21(DE3) PLysS and induced by IPTG. SDS-PAGE analysis showed the UL45 gene couldn't express while UL45Delta gene was highly expressed. His Purify Kit or salting-out could purify the protein effectively. Using the purified protein to immunize New-Zealand rabbits and produce polyclonal antibody. The agar diffusion reaction showed the titer of antibody was 1:32. Western blot analysis indicated the purified rabbit anti-UL45Delta IgG had a high level of specificity and the UL45 gene was a part of DEV genome. The transcription phase study of UL45 gene showed that expression of UL45 mRNA was at a low level from 0 to 18 h post-infection (pi), then accumulated quickly at 24 h pi and peaked at 42 h pi. It can be detected till 72 h pi. Besides, western blot analysis of purified virion and different viral ingredients showed that the UL45 protein resided in the purified virion and the viral envelope. CONCLUSIONS: The rabbit anti-UL45Delta IgG was produced successfully and it can serve as a good tool for penetrating studies of the function of DEV UL45 protein. The transcription phase and protein characteristics analysis indicated that DEV UL45 gene was a late gene and UL45 protein may be a viral envelope protein. PMID- 20843375 TI - Rationale and design of the balANZ trial: a randomised controlled trial of low GDP, neutral pH versus standard peritoneal dialysis solution for the preservation of residual renal function. AB - BACKGROUND: The main hypothesis of this study is that neutral pH, low glucose degradation product (GDP) peritoneal dialysis (PD) fluid better preserves residual renal function in PD patients over time compared with conventional dialysate. METHODS/DESIGN: Inclusion criteria are adult PD patients (CAPD or APD) aged 18-81 years whose first dialysis was within 90 days prior to or following enrolment and who have a residual GFR >= 5 ml/min/1.73 m2, a urine output >= 400 ml/day and an ability to understand the nature and requirements of this trial. Pregnant or lactating patients or individuals with an active infection at the time of enrolment, a contra-indication to PD or participation in any other clinical trial where an intervention is designed to moderate rate of change of residual renal function are excluded. Patients will be randomized 1:1 to receive either neutral pH, low GDP dialysis solution (Balance) or conventional dialysis solution (Stay.safe) for a period of 2 years. During this 2 year study period, urinary urea and clearance measurements will be performed at 0, 3, 6, 9, 12, 18 and 24 months. The primary outcome measure will be the slope of residual renal function decline, adjusted for centre and presence of diabetic nephropathy. Secondary outcome measures will include time from initiation of peritoneal dialysis to anuria, peritoneal small solute clearance, peritoneal transport status, peritoneal ultrafiltration, technique survival, patient survival, peritonitis rates and adverse events. A total of 185 patients has been recruited into the trial. DISCUSSION: This investigator-initiated study has been designed to provide evidence to help nephrologists determine the optimal dialysis solution for preserving residual renal function in PD patients. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number: ACTRN12606000044527. PMID- 20843376 TI - Within a smoking-cessation program, what impact does genetic information on lung cancer need to have to demonstrate cost-effectiveness? AB - BACKGROUND: Many smoking-cessation programs and pharmaceutical aids demonstrate substantial health gains for a relatively low allocation of resources. Genetic information represents a type of individualized or personal feedback regarding the risk of developing lung cancer, and hence the potential benefits from stopping smoking, may motivate the person to remain smoke-free. The purpose of this study was to explore what the impact of a genetic test needs to have within a typical smoking-cessation program aimed at heavy smokers in order to be cost effective. METHODS: Two strategies were modelled for a hypothetical cohort of heavy smokers aged 50 years; individuals either received or did not receive a genetic test within the course of a usual smoking-cessation intervention comprising nicotine replacement therapy (NRT) and counselling. A Markov model was constructed using evidence from published randomized controlled trials and meta analyses for estimates on 12-month quit rates and long-term relapse rates. Epidemiological data were used for estimates on lung cancer risk stratified by time since quitting and smoking patterns. Extensive sensitivity analyses were used to explore parameter uncertainty. RESULTS: The discounted incremental cost per QALY was AU$34,687 (95% CI $12,483, $87,734) over 35 years. At a willingness to-pay of AU$20,000 per QALY gained, the genetic testing strategy needs to produce a 12-month quit rate of at least 12.4% or a relapse rate 12% lower than NRT and counselling alone for it to be equally cost-effective. The likelihood that adding a genetic test to the usual smoking-cessation intervention is cost effective was 20.6% however cost-effectiveness ratios were favourable in certain situations (e.g., applied to men only, a 60 year old cohort). CONCLUSIONS: The findings were sensitive to small changes in critical variables such as the 12 month quit rates and relapse rates. As such, the cost-effectiveness of the genetic testing smoking cessation program is uncertain. Further clinical research on smoking-cessation quit and relapse rates following genetic testing is needed to inform its cost-effectiveness. PMID- 20843377 TI - Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402. AB - BACKGROUND: The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma. METHODS: The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80 degrees C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-gamma- ELISPOT and MHC-Dextramer assays. RESULTS: No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+ gp100-in4+ CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4. CONCLUSION: Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications. PMID- 20843378 TI - Anti-angiogenic effects of differentiation-inducing factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/beta-catenin signaling pathway. AB - BACKGROUND: Differentiation-inducing factor-1 (DIF-1) is a putative morphogen that induces cell differentiation in Dictyostelium discoideum. DIF-1 inhibits proliferation of various mammalian tumor cells by suppressing the canonical Wnt/beta-catenin signaling pathway. To assess the potential of a novel cancer chemotherapy based on the pharmacological effect of DIF-1, we investigated whether DIF-1 exhibits anti-angiogenic effects in vitro and in vivo. RESULTS: DIF 1 not only inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) by restricting cell cycle in the G0/G1 phase and degrading cyclin D1, but also inhibited the ability of HUVECs to form capillaries and migrate. Moreover, DIF-1 suppressed VEGF- and cancer cell-induced neovascularization in Matrigel plugs injected subcutaneously to murine flank. Subsequently, we attempted to identify the mechanism behind the anti-angiogenic effects of DIF-1. We showed that DIF-1 strongly decreased vascular endothelial growth factor receptor-2 (VEGFR-2) expression in HUVECs by inhibiting the promoter activity of human VEGFR-2 gene, though it was not caused by inhibition of the Wnt/beta catenin signaling pathway. CONCLUSION: These results suggested that DIF-1 inhibits angiogenesis both in vitro and in vivo, and reduction of VEGFR-2 expression is involved in the mechanism. A novel anti-cancer drug that inhibits neovascularization and tumor growth may be developed by successful elucidation of the target molecules for DIF-1 in the future. PMID- 20843379 TI - Diabetes treatment patterns and goal achievement in primary diabetes care (DiaRegis) - study protocol and patient characteristics at baseline. AB - BACKGROUND: Patients with type 2 diabetes are at an increased risk for disease and treatment related complications after the initial approach of oral mono/dual antidiabetic therapy has failed. Data from clinical practice with respect to this patient group are however scarce. Therefore we set up a registry in primary care documenting the course and outcomes of this patient group. METHODS: Diabetes Treatment Patterns and Goal Achievement in Primary Diabetes Care (DiaRegis) is a prospective, observational, German, multicenter registry including patients with type-2 diabetes in which oral mono/dual antidiabetic therapy has failed. Data were recorded at baseline and will be prospectively documented during visits at 6 +/- 1, 12 +/- 2 and 24 +/- 2 months. The primary objective is to estimate the proportion of patients with at least 1 episode of severe hypoglycemia within one year. RESULTS: 313 primary care offices included 4,048 patients between June 2009 and March 2010 of which 3,810 patients fulfilled the in- and exclusion criteria. 46.7% of patients were female; patients had a median diabetes duration of 5.5 years and most were obese with respect to BMI or waist circumference. HbA1c at baseline was 7.4%, fasting plasma glucose 142 mg/dl and postprandial glucose 185 mg/dl. Co-morbidity in this patient population was substantial with 17.9% having coronary artery disease, 14.4% peripheral neuropathy, 9.9% heart failure and 6.0% peripheral arterial disease. 68.6% of patients received oral monotherapy, 31.4% dual oral combination therapy. The most frequent antidiabetic agent used as monotherapy was metformin (79.0%) followed by sulfonylureas (14.8%). CONCLUSIONS: DiaRegis is a large, prospective registry in primary diabetes care to document the course and outcomes of patients with type-2 diabetes in which the initial approach of oral mono/dual antidiabetic therapy has failed. The two year follow up will allow for a prospective evaluation of these patients during multiple adjustments of therapy. PMID- 20843380 TI - Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort study. AB - BACKGROUND: The optimum oral pharmacological treatment of diabetes mellitus to reduce cardiovascular disease and mortality following myocardial infarction has not been established. We therefore set out to investigate the association between individual oral glucose-lowering drugs and cardiovascular outcomes following myocardial infarction in patients with diabetes mellitus not treated with emergent percutaneous coronary intervention. MATERIALS AND METHODS: All patients aged 30 years or older receiving glucose-lowering drugs (GLDs) and admitted with myocardial infarction (MI) not treated with emergent percutaneous coronary intervention in Denmark during 1997-2006 were identified by individual-level linkage of nationwide registries of hospitalizations and drug dispensing from pharmacies. Multivariable Cox regression models adjusted for age, sex, calendar year, comorbidity, and concomitant pharmacotherapy were used to assess differences in the composite endpoint of non-fatal MI and cardiovascular mortality between individual GLDs, using metformin monotherapy as reference. RESULTS: The study comprised 9876 users of GLDs admitted with MI. The mean age was 72.3 years and 56.5% of patients were men. A total of 3649 received sulfonylureas and 711 received metformin at admission. The average length of follow-up was 2.2 (SD 2.6) years. A total of 6,171 patients experienced the composite study endpoint. The sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide were associated with increased risk of cardiovascular mortality and/or nonfatal MI with hazard ratios [HRs] of 1.31 (95% confidence interval [CI] 1.17-1.46), 1.19 (1.06-1.32), 1.25 (1.11-1.42), and 1.18 (1.03 1.34), respectively, compared with metformin. Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]). CONCLUSIONS: In patients with diabetes mellitus admitted with MI not treated with emergent percutaneous coronary intervention, monotherapy treatment with the sulfonylureas glibenclamide, glimepiride, glipizide, and tolbutamide was associated with increased cardiovascular risk compared with metformin monotherapy. PMID- 20843381 TI - The evolutionary trajectory of mitochondrial carrier family during metazoan evolution. AB - BACKGROUND: Exploring metabolic evolution is a way to understand metabolic complexity. The substrate transport of mitochondrial carrier family (MCF) influences direct metabolic activities, making it possible to understand indirectly metabolic evolution from the evolution of substrate transport of MCF. However, the evolutionary study of substrate transport of MCF does not mean that all the concrete structures of mitochondrial carriers (MCs) must first be gained. RESULTS: Here we studied the alternation of MCF structure and potential correlated functions of MCF during metazoan evolution. The data analysis indicates that the types of substrates transported by MCF as a whole were maintained during metazoan evolution. However, the size of the substrates transported by members of MCs continuously diminished during the evolutionary process. We have found that the ratio of hydrophobic amino acids at specific helix-helix interfaces increases significantly during vertebrate evolution. Amino acid's spatial positioning and the calculating of packing values both indicate the increase in the number of hydrophobic amino acids would lead to a more "tight" structure of the TR domain, which is in agreement with the trend of diminishing size of substrates transported by MCs. In addition, there was a significant increase in the number of carriers of MCF during vertebrate evolution. CONCLUSIONS: We propose that the more "tight" TR structure generated by the increase of the hydrophobic amino acids at specific helix-helix interfaces during vertebrate evolution enhances the substrate selectivity of MCF, reflecting the evolutionary trajectory of MCF during metazoan evolution. PMID- 20843382 TI - Temporal patterns of blood flow and nitric oxide synthase expression affect macrophage accumulation and proliferation during collateral growth. AB - BACKGROUND: The involvement of collateral blood flow/fluid shear stress, nitric oxide (NO), and macrophages during collateral growth (arteriogenesis) is established, but their interplay remains paradoxical. METHODS: In order to further elucidate the "fluid shear stress/NO/macrophage" paradox, we investigated the time course of collateral blood flow (using a Doppler flow probe) and NOS expression (immunohistochemistry, Western blot) in growing rat collateral vessels after femoral artery occlusion and their impact on macrophage recruitment and collateral proliferation (immunohistochemistry, angiographies). RESULTS: (values are given as mean +/- standard error of mean) Early after occlusion, collateral blood flow was significantly reduced (pre- 90.0 +/- 4.5 vs. post-occlusion 62.5 +/- 5.9 MUl/min; p < 0.01), and local inducible NOS (iNOS) and endothelial NOS (eNOS) expression were down-regulated (expression in % of non-occluded: eNOS 49.4 +/- 11.8% and iNOS 54.5 +/- 7.9% vs. non-occluded at 12 h after occlusion; p < 0.03). An artificial rise (induced by a peripheral vasodilatation) of the initially decreased collateral blood flow back to pre-occlusion levels reduced collateral macrophage recruitment (macrophages per collateral section: post- 42.5 +/- 4.4 vs. artificial pre-occlusion 27.8 +/- 2.0; p < 0.05) and diminished collateral proliferation (proliferative index: post- 0.54 +/- 0.02 vs. artificial pre-occlusion 0.19 +/- 0.04; p < 0.001) significantly 72 h after femoral artery occlusion. CONCLUSIONS: We propose the following resolution of the "fluid shear stress/NO/macrophage" paradox: Collateral blood flow and NOS expression are initially reduced during arteriogenesis allowing macrophages to accumulate and therewith enhancing collateral proliferation. After homing of macrophages (24 h after occlusion), collateral blood flow and NOS expression recover in order to join the effects of macrophages for restoring blood flow. PMID- 20843383 TI - Field evaluation of pyriproxyfen and spinosad mixture for the control of insecticide resistant Aedes aegypti in Martinique (French West Indies). AB - BACKGROUND: The resistance of Ae. aegypti to insecticides is already widespread and continues to develop. It represents a serious problem for programmes aimed at the control and prevention of dengue in tropical countries. In the light of this problem measures to control Ae. aegypti are being orientated towards how best to use existing insecticides, notably by combining those that have different modes of action. RESULTS: In this study we evaluated the operational efficiency of a mixture composed of pyriproxyfen (an insect growth regulator) and spinosad (a biopesticide) against a population of Ae. aegypti from Martinique resistant to pyrethroid and organophosphate insecticides. The first step consisted of evaluating the efficacy of pyriproxyfen and spinosad when used alone, or in combination, against Ae. aegypti larvae under simulated conditions. The results showed that the mixture of pyriproxyfen+spinosad remained active for at least 8 months, compared with 3 months for spinosad alone, and 5 months for pyriproxyfen alone. In a second step in containers experiencing natural conditions, pyriproxyfen and spinosad, maintained the rate of adult emergence at 20% for 3 weeks and 3.5 months, respectively. Following the same criteria of evaluation, the mixture pyriproxyfen+spinosad remained effective for 4.5 months, showing that the combination of the two larvicides with different modes of action acted to increase the residual activity of the treatment. CONCLUSION: The mixture of pyriproxyfen and spinosad kills larvae and pupae giving it a broader range of action than either insecticide. This mixture could preserve the utility of both insecticides in public health programs. PMID- 20843385 TI - Assessment of occupational exposure to leptospirosis in a sheep-only abattoir. AB - This study estimated the frequency of exposure of meat workers to carcasses infected with Leptospira serovars Hardjobovis or Pomona in a sheep-only abattoir in New Zealand. A stochastic spreadsheet model was developed to assess the daily risk of exposure of eviscerators, meat inspectors and offal handlers to live leptospires in sheep carcasses from May to November 2004 (high-risk period), and from December 2004 to June 2005 (low-risk period). The average sheep processed per day were 225 for an eviscerator, 374 for a meat inspector, and 1123 for an offal handler. The median daily exposures during high- and low-risk periods were 11 [95% distribution interval (DI) 5-19] and three (95% DI 1-8) infected carcasses/day for eviscerators, 18 (95% DI 9-29) and six (95% DI 2-12) for meat inspectors, and 54 (95% DI 32-83) and 18 (95% DI 8-31) for offal handlers, respectively. Stochastic risk modelling provided evidence that processing of sheep carcasses exposed meat workers regularly to live leptospires with substantial seasonal variation. PMID- 20843384 TI - Methicillin-resistant Staphylococcus aureus colonization in HIV-infected outpatients is common and detection is enhanced by groin culture. AB - SUMMARYAlthough high rates of clinical infection with methicillin-resistant Staphylococcus aureus (MRSA) have been reported in HIV-infected adults, data on MRSA colonization are limited. We enrolled HIV-infected adults receiving care at the Atlanta VA Medical Center. Swabs from each participant's nares and groin were cultured with broth enrichment for S. aureus. Of 600 HIV-infected adults, 79 (13%) were colonized with MRSA and 180 (30%) with methicillin-susceptible S. aureus. MRSA pulsed-field gel electrophoresis types USA300 (n=44, 54%) and USA500/Iberian (n=29, 35%) predominated. Inclusion of groin swabs increased MRSA detection by 24% and USA300 detection by 38%. In multivariate analysis, MRSA colonization compared to no MRSA colonization was associated with a history of MRSA clinical infection, rarely or never using condoms, and contact with prisons and jails. In summary, the prevalence of MRSA colonization was high in this study of HIV-infected adults and detection of USA300 was enhanced by groin culture. PMID- 20843386 TI - Microarray-based detection of virulence genes in verotoxigenic Escherichia coli O157:H7 strains from Swedish cattle. AB - Verotoxigenic Escherichia coli (VTEC) serotype O157:H7 strains from a Swedish cattle prevalence study (n=32), and livestock-derived strains linked to human disease (n=13), were characterized by microarray and PCR detection of virulence genes. The overall aim of the study was to investigate the distribution of known virulence determinants and determine which genes are linked to increased pathogenicity in humans. A core set of 18 genes or gene variants were found in all strains, while seven genes were variably present. This suggests that the majority of VTEC O157:H7 found in Swedish cattle carry a broad repertoire of virulence genes and should be considered potentially harmful to humans. A single virulence gene type was significantly associated with strains linked to human disease cases (P=0.012), but no genetic trait to explain the increased virulence of this genotype could be found. PMID- 20843388 TI - Salmonella prevalence in commercial raw shell eggs in Japan: a survey. AB - We examined 20 300 raw shell chicken eggs sold at retail stores in Japan for Salmonella outside and inside eggs. The eggs were purchased at 220 retail stores throughout Japan between August 2007 and January 2008. Of 2030 pooled egg samples (10 eggs/sample), Salmonella was isolated from five shell samples (0.25%), but not from any of egg-content samples. The serovars of the isolates were Salmonella Enteritidis (2), S. Derby, S. Livingstone and S. Cerro. The samples positive for Salmonella originated from five different egg grading and packaging (GP) centres. All the GP centres washed their egg shells according to government guidelines for hygienic practice in GP centres. Thus, practical control measures at GP centres need to be reviewed and implemented to diminish Salmonella prevalence of egg shells because Salmonella contamination on eggs is a potential hazard for foodborne salmonellosis in Japan. PMID- 20843387 TI - An extensive gastroenteritis outbreak after drinking-water contamination by sewage effluent, Finland. AB - An inappropriate cross-connection between sewage- and drinking-water pipelines contaminated tap water in a Finnish town, resulting in an extensive waterborne gastroenteritis outbreak in this developed country. According to a database and a line-list, altogether 1222 subjects sought medical care as a result of this exposure. Seven pathogens were found in patient samples of those who sought treatment. To establish the true disease burden from this exposure, we undertook a population-based questionnaire investigation with a control population, infrequently used to study waterborne outbreaks. The study covered three areas, contaminated and uncontaminated parts of the town and a control town. An estimated 8453 residents fell ill during the outbreak, the excess number of illnesses being 6501. Attack rates were 53% [95% confidence interval (CI) 49.5 56.4] in the contaminated area, 15.6% (95% CI 13.1-18.5) in the uncontaminated area and 6.5% (95% CI 4.8-8.8) in the control population. Using a control population allowed us to differentiate baseline morbidity from the observed morbidity caused by the water contamination, thus enabling a more accurate estimate of the disease burden of this outbreak. PMID- 20843389 TI - The epidemiology of rubella in Mexico: seasonality, stochasticity and regional variation. AB - The factors underlying the temporal dynamics of rubella outside of Europe and North America are not well known. Here we used 20 years of incidence reports from Mexico to identify variation in seasonal forcing and magnitude of transmission across the country and to explore determinants of inter-annual variability in epidemic magnitude in rubella. We found considerable regional variation in both magnitude of transmission and amplitude of seasonal variation in transmission. Several lines of evidence pointed to stochastic dynamics as an important driver of multi-annual cycles. Since average age of infection increased with the relative importance of stochastic dynamics, this conclusion has implications for the burden of congenital rubella syndrome. We discuss factors underlying regional variation, and implications of the importance of stochasticity for vaccination implementation. PMID- 20843390 TI - Comprehensive assessment of depression and behavioral problems in long-term care. AB - BACKGROUND: The IPA Taskforce on Mental Health Issues in Long-Term Care Homes seeks to improve mental health care in long-term care (LTC) homes. The aim of this paper is to provide recommendations on comprehensive assessment of depression and behavioral problems in order to further stimulate countries and professionals to enhance their quality of care. METHODS: Existing guidelines on comprehensive assessment of depression or behavioral problems in nursing home (NH) patients or patients residing in LTC homes were collected and a literature review was carried out to search for recent evidence. RESULTS: Five guidelines from several countries all over the world and two additional papers were included in this paper as a starting point for the recommendations. Comprehensive assessment of depression in LTC homes consists of a two-step screening procedure: an investigation to identify factors that influence the symptoms, followed by a formal diagnosis of depression according to DSM-IV-TR or the Provisional Diagnostic Criteria for Depression in Alzheimer Disease in cases of dementia. Comprehensive assessment of behavioral problems encompasses three steps: description and clarification of the behavior, additional investigation, and assessment of probable causes of the behavior. The procedure starts in the case of moderate behavioral problems. CONCLUSION: The recommendations given in this paper provide a useful guide to professional workers in the LTC sector, but clinical judgment and the consideration of the unique aspects of individual residents and their situations is necessary for an optimal assessment of depression and behavioral problems. The recommendations should not be rigidly applied and implementation will differ from country to country. PMID- 20843392 TI - Validation of the Literacy Independent Cognitive Assessment. AB - BACKGROUND: Low education and illiteracy are associated with an increased risk of dementia. This study aimed to develop a neuropsychological test battery applicable to both illiterate and literate elderly and to assess its reliability and validity for a diagnosis of dementia. METHODS: We developed the Literacy Independent Cognitive Assessment (LICA), which consists of 13 subtests assessing memory, language, visuoconstruction, executive function, attention and calculation. We investigated its reliability and validity on 152 patients with dementia, 66 with mild cognitive impairment and 639 normal controls. RESULTS: The subtests were found to be applicable to most of the illiterate normal controls (97.3%) and were found to have high inter-rater reliabilities (r = 0.85-1.00, p < 0.001) and moderate to high test-retest reliabilities (r = 0.50-0.86, p < 0.001). The LICA performed well in discriminating participants across Clinical Dementia Rating stages and showed excellent internal consistency and good concurrent validity with the Korean Mini-mental State Examination in both literate and illiterate participants. The area under the curve of the receiver operating characteristic was 0.985 in each of the two literacy groups. Sensitivity and specificity of the LICA to make a diagnosis of dementia was 91.9% and 91.8% at the cutoff point of 186.0 in the literate subjects and 96.2% and 91.1% at the cutoff point of 154.5 in the illiterate subjects. The battery was factored into two separate factors consisting of verbal memory tests and tests for other cognitive domains. CONCLUSION: The LICA is a valid and reliable instrument for a diagnosis of dementia in both illiterate and literate elderly. PMID- 20843391 TI - A comparison of the frequencies of risk factors for depression in older black and white participants in a study of indicated prevention. AB - BACKGROUND: To compare the frequencies of risk factors, we describe risks for depression as a function of race among consecutively admitted participants in a randomized clinical trial of indicated depression prevention in later life. METHODS: Seventy-two black and 143 white participants were screened for risk factors for depression. RESULTS: Black participants were more likely to have fewer years of education and lower household income. They were more likely to be obese, live alone, experience functional disability, have a history of alcohol and drug abuse, and have lower scores on the Mini-mental State Examination and the Executive Interview (EXIT). White participants were not found to have greater prevalence or higher mean score on any risk factor. On average, black participants experienced approximately one more risk factor than white participants (t(213) = 3.32, p = 0.0011). CONCLUSIONS: In our sample, black participants had higher frequencies of eight risk factors for depression and a greater mean number of risk factors compared to white participants. PMID- 20843393 TI - Attitudes, knowledge, and interest: preparing university students to work in an aging world. AB - BACKGROUND: The underlying goals of the present study were (i) to assess knowledge of and attitudes towards aging in a sample of Portuguese undergraduate students undertaking various degrees in health and welfare subjects, and (ii) to analyze the extent to which knowledge, attitudes and other factors were associated with interest in working with older adults. METHODS: The study was cross-sectional in design. The sample comprised 460 Portuguese undergraduate students enrolled in degrees in nursing, social work, and psychology. They were asked to complete questionnaires and quizzes, which were analyzed using contingency tables and one way analysis of variance for inter-group comparison, and then subjected to multivariate logistic regression analysis. RESULTS: Significant differences emerged between groups on knowledge, attitudes towards aging and interest in working with older adults, with both nursing and social work students displaying more positive attitudes, knowledge, and interest in working with older adults, when compared with psychology students. A regression analysis indicated that attitudes, knowledge, and previous formal contact were significant predictors of interest. CONCLUSION: Interest in working with older adults was significantly related to positive attitudes, more knowledge and formal previous contact. Positive attitudes towards older adults can be promoted through interaction with faculty members and experts, knowledge acquisition about normative changes with age, and contact with healthy and impaired older adults. PMID- 20843394 TI - The age-prospective memory-paradox: an exploration of possible mechanisms. AB - BACKGROUND: The age-prospective memory-paradox describes the general pattern of age-related deficits in laboratory-based prospective memory tasks and age-related benefits in naturalistic tasks that are carried out in participants' everyday lives. However, the mechanisms which are critical in determining the direction of age effects remain poorly delineated. METHOD: Twenty young and 20 old adults performed a laboratory and a naturalistic prospective memory task, which were similar in structure and demand. Several factors highlighted in recent theoretical models as potentially important to understanding the paradox (motivation, metacognitive awareness, activity absorption, control over the task) were assessed and their contribution to the age paradox empirically explored. RESULTS: First, analyzing mean level age differences, the paradox was confirmed. Second, exploring possible correlates of the paradox revealed that, while low levels of daily activity absorption, high motivation and good metacognitive awareness were associated with age benefits in prospective memory performance in the naturalistic task, high ongoing activity absorption and low control over the prospective memory cue seem important for understanding age deficits in lab-based tasks. CONCLUSION: The current study confirms the age-prospective memory-paradox within one sample and with carefully matched laboratory and naturalistic tasks. Additionally, it takes an important step forward in clarifying the role of different factors in understanding age effects across these different contexts. The results indicate that the relative importance of different factors vary as a function of assessment context, with conceptual as well as applied implications. PMID- 20843395 TI - The association between personality disorder and an act of deliberate self harm in the older person. AB - BACKGROUND: Suicide rates are higher in the over 65s than in younger adults and there is a strong link between deliberate self harm (DSH) and suicide in older people. The association between personality disorder (PD) and DSH in older adults remains uncertain. Our objective was to describe this association. METHODS: A case control study was conducted in which participants were: (i) those who had undertaken an act of DSH and (ii) a hospital-based control group drawn from a geographical contiguous population. PD was assessed using the Standardised Assessment of Personality (SAP). RESULTS: Seventy-seven cases of DSH were identified; 61 (79.2%) of these participants were interviewed. There were 171 potential controls identified of whom 140 (81.9%) were included. An SAP was completed in 45/61 (73.8%) of cases and 100/140 (71.4%) of controls. The mean age was 79.8 years (SD = 9, range 65-103). The crude odds ratio for the association between PD and DSH was 5.91 [(95% CI 2.3, 14.9) p<0.0001]. There was a strong interaction with age stratified at 80 years. There was no association between PD and DSH after age 80. The adjusted odds ratio for PD in the group <80 years was 20.5 [(95% CI 3, 141) p = 0.002]. Borderline and impulsive PD traits tended to be associated with an episode of DSH more than other personality types. CONCLUSIONS: PD appears to be a strong and independent risk for an act of DSH in people aged between 65 and 80 years and should be looked for as part of any risk assessment in this population. Access to specialist services may be required to optimally manage this problem and reduce the subsequent risk of suicide. PMID- 20843396 TI - Recommendations for staff education and training for older people with mental illness in long-term aged care. AB - BACKGROUND: This paper was written as a result of the International Psychogeriatric Association Task Force on Mental Health Services in Long-Term Care. The appraisal presented here aims to (1) identify the best available evidence that underpins best practice for geriatric mental health education and training of staff working in long-term care, and (2) summarize the appraisal of the literature to provide recommendations for practice. METHODS: An initial search of databases found 138 papers related to the search strategy. Selected papers were summarized and compared against set inclusion criteria. This resulted in 17 papers suitable for review. RESULTS: The majority of papers focused on behavior skills training. A number of key factors were identified that determine the success of geriatric mental health education and training and recommendations are outlined. CONCLUSIONS: Methodological weaknesses are common and highlight the need for further replication studies using strong research designs. PMID- 20843397 TI - A late form of neurosyphilis manifesting with psychotic symptoms in old age and good response to ceftriaxone therapy. AB - Neurosyphilis can present with psychiatric symptoms. The late form can occur in old age with psychosis, paranoid delusions, affective disorders or cognitive impairment. Here we present a case of neurosyphilis in an elderly woman who, over six months, progressively manifested personality changes and paranoid delusions which were initially suspected as Alzheimer's disease. Psychotic symptoms showed a good response to antibiotic treatment. We conclude that neurosyphilis is a relevant differential diagnosis in patients developing severe psychiatric symptoms in old age. As a causal antibiotic treatment is possible this infectious disease should be considered seriously in gerontopsychiatric patients. PMID- 20843398 TI - Iron deficiency in infants fully breastfed for 6 months may not be transitory: first observations during the second half of infancy. PMID- 20843399 TI - Impact of foods with health logo on saturated fat, sodium and sugar intake of young Dutch adults. AB - OBJECTIVE: Health logos are introduced to distinguish foods with 'healthier' nutrient composition from regular foods. In the present study, we evaluated the effects of changed food compositions according to health logo criteria on the intake of saturated fat, sugar and sodium in a Dutch population of young adults. DESIGN: Foods in the Dutch food composition table were evaluated against nutrient criteria for logo eligibility. Three replacement scenarios were compared with the nutrient intake 'as measured' in the Dutch consumption survey. The foods not complying with health logo criteria were replaced either by 'virtual' foods exactly complying with the health logo criteria, with real 2007 market shares (scenario I) and 100% market shares (scenario II), or by existing similar foods with a composition that already complied with the health logo criteria (scenario III). RESULTS: The percentage reduction in nutrient intake with the current 2007 market shares of 'health logo foods' was -2.5% for SFA, 0% for sodium and -1% for sugar. With a 100% market share these reductions would be -10% for SFA, -4% for sodium and -6% for sugar. This may lead to a reduction of -40% for SFA, -23% for sodium and -36% for sugar in the most optimal replacement scenario. CONCLUSIONS: With 'health logo foods', available in 2007 and current consumption patterns, small reductions can be achieved for SFA and sugar. For additional reductions, lowering the fat/sodium content of meat (products) towards health logo criteria and drinks without sugar towards limits far below health logo criteria would be the most effective reformulation strategy. PMID- 20843400 TI - Validation of a quantitative FFQ for the Barbados National Cancer Study. AB - OBJECTIVE: To assess the validity of a 148-item quantitative FFQ (QFFQ) that was developed for the Barbados National Cancer Study (BNCS) to determine dietary intake over 12 months and examine the dietary risk factors. DESIGN: A cross sectional validation study of the QFFQ against 4 d food diaries. Spearman's rank correlations (rho), intra-class correlation coefficients (ICC) and weighted kappa were computed as measures of concordance, adjusting for daily variations in the food diaries. Cross-classification tables and Bland-Altman plots were created for further assessment. SETTING: BNCS is a case-control study of environmental risk factors for breast and prostate cancer in a predominantly African-origin population in Barbados. SUBJECTS: Fifty-four individuals (21 years and older) were recruited among controls in the BNCS who were frequency-matched on sex and age group to breast and prostate cancer cases. RESULTS: Similar mean daily energy intake was derived from the food diary (8201 kJ (1960 kcal)) and QFFQ (7774 kJ (1858 kcal)). Rho for energy and macronutrients ranged from 0.66 (energy) to 0.17 (dietary fibre). The percentage of energy from carbohydrates and protein showed the highest and lowest ICC among macronutrients (0.63 and 0.27, respectively). The highest weighted kappa was observed for energy (0.45). When the nutrient intake was divided into quartiles, approximately 34 % of the observations were in the same quartile. CONCLUSIONS: This investigation supports the validity of the QFFQ as a method for assessing long-term dietary intake except for dietary fibre, folate, vitamins A, E and B12. The instrument will be a useful tool in the analysis of diet-cancer associations in the BNCS. PMID- 20843401 TI - Double burden of nutritional disorders in young Iranian children: findings of a nationwide screening survey. AB - OBJECTIVE: To assess the national prevalence of short stature, underweight, overweight and obesity in 6-year-old Iranian children before school entry. DESIGN: Cross-sectional nationwide survey. SETTING: Mandatory national screening programme before entrance to elementary school in 2008 in Iran. SUBJECTS: All Iranian children entering public and private elementary schools. RESULTS: The study population comprised 862,433 children (48.4% girls, 77.2% urban resident). Overall, 6.5% of children had short stature, 19.1% were underweight, 12.8% were overweight and 3.4% were obese. There was no significant difference in terms of gender, but considerably larger differences were documented among various provinces. CONCLUSIONS: The double burden of nutritional disorders among young children warrants a multi-faceted national policy with evidence-based local programmes. Such planning needs a comprehensive surveillance system and centralized data registry for children's growth. PMID- 20843402 TI - Impact of group-based dietary education on the dietary habits of female adolescents: a cluster randomized trial. AB - OBJECTIVE: The number of extremely thin young women has increased and education at school on maintaining an optimal weight has become important. The aim of the present study was to assess the effectiveness of a group-based home-collaborative dietary education (HCDE) programme to maintain appropriate dietary intake compared to conventional school classroom education. DESIGN: Two-arm cluster randomized controlled trial. Twelve classes were randomly assigned as clusters to either the HCDE group or the control group. Each participant in the HCDE group received twelve sessions of group counselling aimed at increasing energy intake at breakfast by modifying dietary intake and adopting appropriate habits. The hypothesis underlying the study was that after 6 months of HCDE the total energy intake would be increased by 627 kJ from baseline (primary endpoint). Secondary outcomes were differences in intake of various nutrients from baseline. Outcome measures after log transformation were examined by t tests and linear mixed models (crude and baseline-adjusted). SETTING: Young women among Japanese female adolescents in Tokyo. SUBJECTS: Four hundred and seventy-four participants aged 13-15 years. RESULTS: Students in twelve classes were used for analysis (n 459). Energy intake was decreased in many of the classes during the 6-month period, especially for those in the control group. After adjustment for the baseline value, significant increases in energy intake and protein, calcium, magnesium and iron intakes at breakfast were observed (P<0.05) CONCLUSIONS: Although energy intake was increased in the HCDE group compared to the control group, further study of the HCDE is warranted. PMID- 20843404 TI - Reliability and convergent validity of the past-week Modifiable Activity Questionnaire. AB - OBJECTIVE: To examine the reliability and convergent validity of physical activity (PA) and inactivity estimates obtained with the past-week Modifiable Activity Questionnaire (PWMAQ). DESIGN: The PWMAQ, an interviewer-administered questionnaire, was administered twice, one week apart, during visits 3 and 4 of six total visits. Intra-class correlation coefficients (ICC) between administrations of the PWMAQ were used to assess the reliability of summary estimates. Spearman rank-order correlation coefficients (rho) were used to examine the associations of PWMAQ summary estimates with temporally matched and averaged accelerometer data in all participants and then stratified by whether the data were reflective of usual PA. SETTING: Data were obtained from the Evaluation of Physical Activity Measures in Middle-Aged Women (PAW) study. SUBJECTS: Sixty-six women, mean age 52.6 (sd 5.4) years. RESULTS: The reliability of the PWMAQ physical inactivity estimate suggested substantial agreement over one week (ICC = 0.77, 95 % CI 0.57, 0.82; P < 0.0001). With the exception of light-intensity PA, the PWMAQ leisure PA estimate was significantly associated with averaged accelerometer data (rho = 0.33-0.76; P < 0.05). For both temporally matched and averaged accelerometer data, correlation coefficients were higher between the PWMAQ estimate and moderate-walk- to vigorous-intensity PA in those who indicated that reported activity was reflective of usual PA; however, the association with moderate-lifestyle-intensity PA was higher in those reporting that data were not reflective. CONCLUSIONS: The PWMAQ is a reliable and valid measure of leisure PA levels in middle-aged women and supports subsequent studies evaluating this questionnaire in other population subgroups. PMID- 20843405 TI - Vocal quality of patients treated for laryngeal tuberculosis, before and after speech therapy. AB - OBJECTIVES: To evaluate dysphonia in patients treated for laryngeal tuberculosis, and to assess the effect of speech therapy on patients' vocal quality. MATERIALS AND METHODS: Seven of 23 patients with a confirmed diagnosis of laryngeal tuberculosis, treated at the Evandro Chagas Institute of Clinical Research, Oswaldo Cruz Foundation, underwent speech therapy for six months. These seven patients were evaluated by videolaryngoscopy and vocal acoustic analysis, before, during and after a course of speech therapy. RESULTS: The 23 patients with laryngeal tuberculosis comprised five women and 18 men, with ages ranging from 25 to 83 years (mean 41.3 years). Dysphonia was present in 91.3 per cent of these laryngeal tuberculosis patients, being present as the first symptom in 82.6 per cent. In laryngeal tuberculosis patients with dysphonia, laryngeal tuberculosis treatment resulted in dysphonia resolution in only 15.8 per cent. After speech therapy, dysphonia patients had better vocal quality, as demonstrated by statistical analysis of jitter, shimmer, fundamental frequency variability, maximum phonation time, and the ratio between maximum phonation time for voiceless and voiced fricative sounds. CONCLUSIONS: Following treatment of laryngeal tuberculosis, the incidence of dysphonia was very high. Speech therapy improved patients' vocal quality. PMID- 20843403 TI - Socio-economic circumstances and food habits in Eastern, Central and Western European populations. AB - OBJECTIVE: To assess the relationship between several socio-economic indicators and frequency of consumption of seven predefined healthy foods (consumption of fruit, vegetables, wholegrain bread, vegetable-fat spread, vegetable cooking fat, low-fat milk and low-fat cheese) in populations from Eastern, Central and Western Europe. DESIGN: Analysis of baseline data collected in two cross-sectional cohort studies between 2000 and 2005: the Health, Alcohol and Psychosocial factors In Eastern Europe (HAPIEE) study and the Finnish Helsinki Health Study (HHS). SETTING: Urban populations in the Czech Republic, Russia, Poland and Finland. SUBJECTS: In the HAPIEE study, random samples of men and women aged 45-69 years were drawn from population registers and electoral lists of selected cities. In the HHS, men and women aged 40-60 years employed by the City of Helsinki were recruited. Data on 21,326 working subjects from both cohorts were analysed. RESULTS: Healthy food habits were, in general, positively associated with higher education, occupational position and fewer economic difficulties, but there were differences in the strength of the gradient by food and country. Fruit consumption showed the most consistent gradients, especially in relation to socio economic status among men (country-specific relative index of inequality (RII)=2.02-5.17) and women (RII=2.09-3.57). CONCLUSIONS: The associations between socio-economic indicators and healthy food habits showed heterogeneity between countries. Future studies of dietary behaviours should consider multiple measures of socio-economic position. PMID- 20843406 TI - Epistaxis in patients taking oral anticoagulant and antiplatelet medication: prospective cohort study. AB - OBJECTIVES: Epistaxis can be caused or exacerbated by anticoagulant and antiplatelet therapy. This prospective study assessed the prevalence of epistaxis in patients taking anticoagulant and antiplatelet medication, and monitored differences in patients' clinical courses. METHOD: Prospective data were collected for consecutive patients referred with epistaxis from the emergency department over a seven-month period. Emergency department records were used to investigate prevalence and referral rates. RESULTS: Over the study period, 290 patients presented to the emergency department with epistaxis; this represented 0.9 per cent of all emergency attendances. Of these patients, 119 (39 per cent) were referred on to the ENT department, 62 per cent of whom were currently taking anticoagulant or antiplatelet medication. Patients taking anticoagulant and antiplatelet medication were a significantly older group (relative risk 1.50 (1.08-2.28), p = 0.01) requiring longer in-patient stays (relative risk 2.50 (1.01-4.97), p = 0.01) and more aggressive local haemostasis measures. Most patients taking warfarin had an international normalised ratio outside the appropriate range for their disease. Hypertension was not a factor in these patients' clinical course. CONCLUSION: Increasingly, emergency and ENT departments are being presented with epistaxis in patients taking anticoagulant or antiplatelet medication. A better understanding of such medication and its effects may enable more effective management of these patients. PMID- 20843407 TI - Empirical foundations for the diagnosis of somatization: implications for DSM-5. AB - BACKGROUND: The aim of this study was to develop empirically validated criteria for the diagnoses of clinically relevant somatization. METHOD: This study was performed in a population-representative cohort consisting of 461 males (47.8%) and 503 females (52.2%), with an average age of 55.8 years (s.d.=11.1). Somatization, anxiety and depression were derived from the Composite International Diagnostic Interview. Mplus was used to perform confirmative factor analyses on the current DSM-IV symptom groups; on alternative symptom clusters previously suggested; and to perform latent class analysis in order to define an empirically derived cut-off for somatization. RESULTS: The existence of symptom groups as described in DSM-IV was not supported by our data, whereas a differentiation between cardiopulmonary, musculoskeletal, gastrointestinal and general somatic symptoms did fit our data. Latent class analysis revealed two classes characterized by few (n=859) and many (n=105) symptoms. The class of subjects could be approached by a simple cut-off of four functional symptoms (sensitivity 79%, specificity 98%, positive predictive value 82%, negative predictive value 97%) regardless of the number of organ systems involved. CONCLUSIONS: This study in a large population-representative cohort suggests that a simple symptom count can be used as a dimensional diagnosis of somatization. In those instances in which a categorical diagnosis is preferred, a simple cut-off of four out of 43 functional symptoms best fitted our data. We did not find any added value for incorporating the number of symptom clusters into the diagnostic criteria. PMID- 20843408 TI - Increased A-to-I RNA editing of the transcript for GABAA receptor subunit alpha3 during chick retinal development. AB - Adenosine-to-inosine (A-to-I) RNA editing is a cotranscriptional or posttranscriptional gene regulatory mechanism that increases the diversity of the proteome in the nervous system. Recently, the transcript for GABA type A receptor subunit alpha3 was found to be subjected to RNA editing. The aim of this study was to determine if editing of the chicken alpha3 subunit transcript occurs in the retina and if the editing is temporally regulated during development. We also raised the question if editing of the alpha3 transcript was temporally associated with the suggested developmental shift from excitation to inhibition in the GABA system. The editing frequency was studied by using Sanger and Pyrosequencing, and to monitor the temporal aspects, we studied the messenger RNA expression of the GABAA receptor subunits and chloride pumps, known to be involved in the switch. The results showed that the chick alpha3 subunit was subjected to RNA editing, and its expression was restricted to cells in the inner nuclear and ganglion cell layer in the retina. The extent of editing increased during development (after embryonic days 8-9) concomitantly with an increase of expression of the chloride pump KCC2. Expression of several GABAA receptor subunits known to mediate synaptic GABA actions was upregulated at this time. We conclude that editing of the chick GABAA subunit alpha3 transcript in chick retina gives rise to an amino acid change that may be of importance in the switch from excitatory to inhibitory receptors. PMID- 20843409 TI - Toxicity of acrylamide and evaluation of its exposure in baby foods. AB - Contaminants are a vast subject area of food safety and quality and can be present in our food chain from raw materials to finished products. Acrylamide, an alpha,beta-unsaturated (conjugated) reactive molecule, can be detected as a contaminant in several foodstuffs including baby foods and infant formulas. It is anticipated that children will generally have intakes that are two to three times those of adults when expressed on a body-weight basis. Though exposure to acrylamide is inevitable, it is necessary to protect infant and children from high exposure. The present review focuses on the several adverse health effects of acrylamide including mutagenicity, genotoxicity, carcinogenicity, neurotoxicity and reproductive toxicity, and the possible outcomes of childhood exposure from baby foods and infant formulas. PMID- 20843410 TI - Tuberculosis and poverty: what could (and should) be done? PMID- 20843411 TI - Time to put boots on the ground: making universal access to MDR-TB treatment a reality. PMID- 20843412 TI - Tuberculosis in humans and its epidemiology, diagnosis and treatment in the United States. AB - Tuberculosis (TB) is a pulmonary and systemic disease caused by Mycobacterium tuberculosis complex species. TB is spread from person to person by airborne transmission. Several factors determine the probability of transmission, including the infectiousness of the source patient and the nature of the environment where exposure occurs. This initial infection (primary TB) rapidly progresses to disease in some persons (especially children and immunocompromised persons), but resolves spontaneously in most individuals. This condition in which the organism lies dormant is known as latent TB infection (LTBI). In the United States, the diagnosis of LTBI is made with either the tuberculin skin test or an interferon-gamma release assay. LTBI is treated with isoniazid (INH; usually for 9 months) to prevent progression to TB disease. Up to 5% of immunocompetent persons will progress to TB disease at some time in the future, even decades after infection, if they are not treated for LTBI. Pulmonary TB disease is diagnosed using a combination of chest radiography and microscopic examination, culture and nucleic acid amplification testing of sputum. Treatment of drug susceptible TB consists of at least 6 months of an INH and rifampin-containing regimen (with ethambutol and pyrazinamide for the first 2 months). In the United States, drug-resistant TB is relatively rare (approximately 1% of all patients), and is treated with an 18-24 month individualized regimen based on drug susceptibility test results. PMID- 20843413 TI - Turning off the spigot: reducing drug-resistant tuberculosis transmission in resource-limited settings. AB - Ongoing transmission and re-infection, primarily in congregate settings, is a key factor fueling the global multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB) epidemic, especially in association with the human immunodeficiency virus. Even as efforts to broadly implement conventional TB transmission control measures begin, current strategies may be incompletely effective under the overcrowded conditions extant in high-burden, resource limited settings. Longstanding evidence suggesting that TB patients on effective therapy rapidly become non-infectious and that unsuspected, untreated TB cases account for the most transmission makes a strong case for the implementation of rapid point-of-care diagnostics coupled with fully supervised effective treatment. Among the most important decisions affecting transmission, the choice of an MDR-TB treatment model that includes community-based treatment may offer important advantages over hospital or clinic-based care, not only in cost and effectiveness, but also in transmission control. In the community, too, rapid identification of infectious cases, especially drug-resistant cases, followed by effective, fully supervised treatment, is critical to stopping transmission. Among the conventional interventions available, we present a simple triage and separation strategy, point out that separation is intimately linked to the design and engineering of clinical space and call attention to the pros and cons of natural ventilation, simple mechanical ventilation systems, germicidal ultraviolet air disinfection, fit-tested respirators on health care workers and short-term use of masks on patients before treatment is initiated. PMID- 20843415 TI - Mycobacterial genotype is associated with disease phenotype in children. AB - OBJECTIVE: To investigate the association between mycobacterial genotype and disease phenotype in children. METHODS: We describe hospitalised children diagnosed with culture-confirmed tuberculosis (TB) in South Africa, a high TB burden setting. Disease phenotype was classified as intrathoracic or extrathoracic based on mycobacterial culture site. Mycobacterial genotyping was completed using spoligotyping. RESULTS: We analysed 421 isolates from 392 children (median age 2 years, range 0.1-12). Intrathoracic disease was present in 294 (75%) children and extrathoracic disease in 98 (25%). The Beijing genotype was the most prevalent (32.9%), followed by the Latin American Mediterranean (LAM, 28.8%), and S genotypes (6.4%). Age was significantly associated with genotype. Children with the Beijing (OR = 2.36, 95%CI 1.21- 4.60) and S genotypes (OR = 3.47, 95%CI 1.26-9.56) were more likely to have extrathoracic disease compared to children infected with the LAM genotype, in analyses adjusted for age and drug resistance. CONCLUSIONS: TB genotype and disease phenotype in children were associated. Beijing and S genotypes were more frequently cultured from extrathoracic cultures, indicating potential improved ability to disseminate. Strain-related phenotypes could explain different disease spectra in geographic settings where certain strains are successful. Studies of mycobacterial human interaction should consider host immune responses, clinical and epidemiological factors. PMID- 20843414 TI - Extensively drug-resistant tuberculosis in children with human immunodeficiency virus in rural South Africa. AB - SETTING: Extensively drug-resistant tuberculosis (XDR-TB) has been documented worldwide, but reports of XDR-TB in children are extremely limited. OBJECTIVE: To report the characteristics of pediatric XDR-TB patients in rural South Africa. DESIGN: We retrospectively reviewed children with sputum culture-confirmed XDR-TB from Tugela Ferry, South Africa, from January 2006 to December 2007. Demographic, clinical and microbiologic data were abstracted from medical records. RESULTS: Four children aged 6-8 years with XDR-TB were reviewed. Two had previous histories of TB. All were human immunodeficiency virus (HIV) infected orphans; three received highly active antiretroviral therapy (HAART) before XDR-TB diagnosis. All had clinical and radiographic improvement and sputum culture conversion while on standardized XDR-TB treatment and HAART. Two tolerated concomitant XDR-TB and HIV treatment well. Two experienced neuropsychiatric side effects related to cycloserine. All have survived >24 months and all were cured. Prior to XDR-TB diagnosis, the children had resided in the hospital's pediatric ward for a median of 8 months (range 5-17), including a 3-month overlapping period. CONCLUSIONS: XDR-TB is a microbiologic diagnosis that, even with HIV co infection, can be successfully identified. Concurrent XDR-TB and HIV therapy is feasible and effective in children, although more research is needed into potential overlapping toxicities. Nosocomial transmission is suggested, calling for infection control policies in pediatric wards. PMID- 20843416 TI - Phenotypic and genotypic analysis of multidrug-resistant tuberculosis in Ethiopia. AB - SETTING: National Tuberculosis Reference Laboratory, Addis Ababa, Ethiopia. OBJECTIVES: To determine the drug susceptibility pattern of Mycobacterium tuberculosis isolates and to genetically characterise multidrug-resistant tuberculosis (MDR-TB) isolates. DESIGN: A total of 107 M. tuberculosis isolates recovered during the period December 2005-August 2006 were tested for drug susceptibility against streptomycin, isoniazid, rifampicin and ethambutol (SHRE) using the proportion method on Lowenstein-Jensen medium. The MDR-TB isolates were tested against kanamycin, ciprofloxacin, capreomycin, D-cycloserine and ethionamide. Genotyping was performed using spoligotyping. RESULTS: MDR-TB was observed in one of the 44 new cases (2.3%) and 45/63 previously treated patients (71.4%). Drug susceptibility testing against second-line drugs (SLDs) showed that 26.1% of all MDR-TB isolates were susceptible to all SLDs tested and 73.9% were resistant to one or more classes of SLD. Extensively drug-resistant (XDR) TB was detected in two isolates (4.4%). T3_ETH was the predominant spoligotype, followed by CAS_KILI. In this African setting, no Beijing spoligotype was identified. CONCLUSION: Both MDR- and XDR-TB are present in Ethiopian patients. MDR-TB was found to be associated with T3 and Central Asian genotypes. PMID- 20843417 TI - The tuberculin skin test: a comparison of ruler and calliper readings. AB - BACKGROUND: The Mantoux tuberculin skin test (TST) is widely used to diagnose latent infection with Mycobacterium tuberculosis. TST skin induration may be measured either by a transparent ruler or by a pair of callipers. We hypothesised that the type of instrument used may affect the reading. OBJECTIVE: To determine whether variability in Mantoux TST measurement is affected by the type of reading instrument. METHOD: A TST (Mantoux method) was performed among healthy adolescents. The indurations were read with among ruler and calliper by two independent readers. Limits of agreement and Kappa (kappa) scores at TST positivity cut-off points were calculated. A Bland-Altman graph was constructed. RESULTS: The 95% limits of agreement between instruments ranged from -5 mm to 3 mm. The limits of agreement between readers ranged from -5 mm to 4 mm. kappa scores between instruments were respectively 0.7 and 0.8 at 15 mm and 10 mm cut offs. CONCLUSION: The variability between readers of TST indurations is not influenced by changing the reading instrument. PMID- 20843418 TI - Tuberculin skin test reactivity of health care students in a country with a low prevalence of tuberculosis. AB - SETTING: Health care students in Sweden. OBJECTIVE: To analyse the distribution of tuberculin skin test (TST) reactions and epidemiological factors related to TST reactivity. DESIGN: TST reactivity was analysed in 1190 students. A linear regression model was created for the relative contribution of background factors of TST reactivity. A subgroup of 287 non-vaccinated subjects was comparatively skin-tested with Mycobacterium avium sensitin and tuberculin. RESULTS: Among non bacille Calmette-Guerin (BCG) vaccinated students, 91% had no TST reaction (0 mm induration) and reactions of >= 10 mm were found in 2.9%, whereas 34% of BCG vaccinated students had no TST reaction and 42% had reactions of >= 10 mm. The expected contribution to TST reactivity was 6.0 mm for a history of BCG vaccination, 3.0 mm for a country of birth with medium/high incidence of TB and 1.6 mm per 10 years of age. The sensitin reactions exceeded the TST reactions by >= 3 mm in 52% of the comparatively tested subjects with TST reactions of >= 1 mm. CONCLUSION: BCG vaccination, cross-reactivity with non-tuberculous mycobacteria, geographic origin and age had a decisive influence on TST reactivity. Most non-vaccinated health care students were non-reactive, which highlights the need to organise preventive measures in settings where TB exposure is expected. PMID- 20843419 TI - Children's role in enhanced case finding in Zambia. AB - OBJECTIVE: To evaluate information dissemination by children and attitudes among children towards a school-based tuberculosis (TB) reduction strategy that asked children to address TB symptoms, testing and stigma in their homes. SETTING AND DESIGN: Qualitative research was conducted with schoolchildren before, and 2 years into, an intervention to promote early detection of TB using sputum microscopy in Zambia. The baseline study in 2005 involved 38 children at five sites. The evaluation in 2008 included 209 children in schools at four sites. Research with schoolchildren included discussions, drawings, role plays and narratives. RESULTS: The baseline study revealed children's enthusiasm to learn about TB and the human immunodeficiency virus (HIV), but it also revealed children's anxieties about the possible conflicts related to discussing HIV and TB with adults. Children in the evaluation demonstrated more accurate knowledge about TB and HIV than in the baseline study. Children were enthusiastic about discussing TB and HIV at home. Their responses suggested that they did so with respect and adult approval, circumventing the intergenerational conflict expected during the baseline study. CONCLUSION: The present study demonstrates that schoolchildren have a role to play in enhanced case finding. Schoolchildren are already familiar with TB in areas of high burden, but they need more information about the link between TB and HIV and about antiretroviral treatment. PMID- 20843420 TI - Detection of human immunodeficiency virus infection in the sputum of tuberculosis patients in South India. AB - SETTING: A DOTS clinic in an academic tertiary referral hospital in South India. OBJECTIVE: To evaluate the performance of two rapid enzyme-linked immunoassays (EIAs) for the detection of human immunodeficiency virus (HIV) infection in sputum samples of patients with tuberculosis (TB). DESIGN: We prospectively recruited 522 consecutive out-patients presenting to the DOTS clinic with confirmed TB of any type to undergo HIV testing using reference serum EIA and index-blinded parallel sputum HIV testing with two rapid EIAs designed for oral mucosal transudate. RESULTS: HIV positivity was 14.9% (95%CI 12.1-18.4). Compared to reference serum EIA, the OraquickTM assay was 93.1% sensitive (95%CI 83.8 97.4) and 95.3% specific (95%CI 92.7-96.9), while the AwareTM assay was 92.3% sensitive (95%CI 83.4-96.8) and 96.6% specific (95%CI 94.4-98.0). The positive predictive values were respectively 77.0% and 82.7%. After freezing of sputum, the sensitivity of both assays declined, but the specificity significantly increased. Higher sputum volume reduced the odds of obtaining a true result with both assays. CONCLUSION: HIV testing of fresh sputum is not sufficiently accurate for anonymous HIV surveillance among TB patients in a setting of low (<10%) HIV prevalence. Freezing sputum samples and limiting sputum volume for HIV testing may improve assay specificity. PMID- 20843422 TI - Completeness and consistency in recording information in the tuberculosis case register, Cambodia, China and Viet Nam. AB - SETTING: Tuberculosis (TB) case registers in Cambodia, two provinces in China and in Viet Nam. OBJECTIVE: To determine completeness and consistency of information for quarterly reports on case finding and treatment outcome. METHODS: A representative sample of TB case registers was selected in Cambodia, in two provinces in China and in Viet Nam. Quarterly reports were reproduced from double entered, validated data to determine completeness and consistency. RESULTS: The dataset comprised 37,635 patient records in 2 calendar years. Only 0.2%, 3.6% and 1.1% of cases, respectively, in Cambodia, the two China provinces, and Viet Nam did not allow classification for the quarterly report on case finding. If the treatment outcome was reported as cured, it was correct in 99.9%, 85.7%, and 98.5% of the respective three jurisdictions: errors were mostly due to misclassification of completion as cure. Under-reporting of failures was more frequent than over-reporting in Cambodia and Viet Nam, while in the two provinces in China 84% of reported failures did not actually meet the bacteriological criterion. CONCLUSIONS: This evaluation demonstrates that recording essential information is exemplary in all three countries. It will be essential to carefully supervise the ability of staff to correctly define TB treatment outcome results in all three countries. PMID- 20843421 TI - Significant variation in presentation of pulmonary tuberculosis across a high resolution of CD4 strata. AB - BACKGROUND: The human immunodeficiency virus (HIV) alters the presentation of pulmonary tuberculosis (PTB), but it remains unclear whether alterations occur at a CD4 cell threshold or throughout HIV infection. OBJECTIVE: To better understand the relationship between CD4 count and clinical and radiographic presentation of PTB. SETTING AND DESIGN: Initial presentations of culture-confirmed PTB patients evaluated at a Ugandan national TB referral center and an affiliated research unit were compared by HIV status and across 11 CD4 cell count strata: 0-50 to >500 cells/MUl. RESULTS: A total of 873 HIV-infected PTB cases were identified. Among HIV-infected PTB cases with CD4 < 50, 21% had a normal chest X-ray (CXR) vs. 2% with CD4 > 500, with a continuous trend across CD4 strata (test for trend, P < 0.001). All radiographic manifestations of PTB displayed significant trends across CD4 strata. HIV-infected vs. non-HIV-infected patients had no significant difference in CXR findings of miliary patterns or pleural effusion at CD4 > 100, normal CXR or fibrosis at CD4 > 150, adenopathy at CD4 > 250, and cavitation or upper lung disease at CD4 > 300. Twenty-three per cent of co-infected cases with CD4 < 50 and 1% with CD4 > 500 had negative acid-fast bacilli (AFB) smears, with a significant trend between (P < 0.001). CONCLUSION: Variations in CXR appearance and AFB smear correlate with CD4 decline in significant, continuous trends. PMID- 20843423 TI - An evaluation of the completeness and accuracy of active tuberculosis reporting in the United States military. AB - SETTING: Despite the low incidence of tuberculosis (TB) in the United States military, there is uncertainty in the overall reporting and estimates of incidence. OBJECTIVE: To assess TB reporting in the active component US military. DESIGN: TB notification in the US military was compared with three other data sources: laboratory, hospitalization and pharmacy records. Sensitivity and positive predictive value were estimated for all data sources using a gold standard of either a reportable medical event (RME) reported as confirmed or a positive laboratory result for Mycobacterium tuberculosis. Uncorrected and capture-recapture (CR) methods were used to estimate underreporting and completeness of data sources. RESULTS: Completeness of reporting of pulmonary TB cases was estimated as 72.4% uncorrected or 58.3% with CR. Even after correction for possible underreporting, the incidence of active pulmonary TB was only 0.87 per 100,000 person-years between 2004 and 2006. CONCLUSION: The rate of active TB in the US military is low. Like civilian surveillance, US military RME surveillance may substantially underreport TB incidence rates. Expanding surveillance to include data sources such as hospitalizations and pharmacy records will increase the number of TB diagnoses at the cost of including many false-positives. PMID- 20843424 TI - Patient and family costs associated with tuberculosis, including multidrug resistant tuberculosis, in Ecuador. AB - BACKGROUND: There is little published information on the costs of multidrug resistant tuberculosis (MDR-TB) for patients and their families in low- or middle income countries. METHODS: Between February and July 2007, patients with microbiologically confirmed active TB who had received 2 months of treatment completed an interviewer-administered questionnaire on direct out-of-pocket expenditures and indirect costs from lost wages. Clinical data were abstracted from their medical records. RESULTS: Among 104 non-MDR-TB patients, total TB related patient costs averaged US$960 per patient, compared to an average total cost of US$6880 for 14 participating MDR-TB patients. This represents respectively 31% and 223% of the average Ecuadorian annual income. The high costs associated with MDR-TB were mainly due to the long duration of illness, which averaged 22 months up to the time of the interview. This resulted in very long periods of unemployment. Most patients experienced a significant drop in income, particularly the MDR-TB patients, all of whom were earning less than US$100/month at the time of the interview. CONCLUSION: Direct and indirect costs borne by patients with active TB and their families are very high in Ecuador, and are highest for patients with MDR-TB. These costs are important barriers to treatment completion. PMID- 20843425 TI - Fear, infection and compassion: social representations of tuberculosis in Medellin, Colombia, 2007. AB - OBJECTIVE: To identify and analyse the social representations (SRs) of tuberculosis (TB) among three groups of people in Medellin, Colombia, with the purpose of contributing to improvements in TB treatment and control programme activities. METHODS: Cross-sectional study using free word association and evocative analysis techniques in 1049 persons within a structural SR framework. RESULTS: The terms 'cough', 'contagion', 'illness' and 'fear' were found to be components of the central core in the three groups. In the peripheral system, 'rejection' and 'treatment' were considered modifiable factors. Text analysis showed that 'fear' and 'compassion' are associated with evocations among patients and their relatives, 'contagion' among lay people and 'isolation' among health care personnel. DISCUSSION: Fear of infection may have a negative effect on relationships with patients, health care activities, treatment surveillance and family support for patients. A better understanding of patient beliefs and their family environment can improve treatment quality and adherence in the city. PMID- 20843426 TI - Predictors of mortality in tuberculous meningitis: a multivariate analysis of 160 cases. AB - OBJECTIVE: To evaluate predictors of mortality in 160 patients with tuberculous meningitis (TBM). DESIGN: One hundred and sixty patients with TBM who had been followed for 11 years in a tertiary referral centre hospital were assessed retrospectively. Features considered as predictors of mortality in TBM were studied by multivariate logistic regression to develop a prognostic rule. RESULTS: Of 160 patients, 84% were in Stages II and III; 27 (17%) died. In univariate analysis, age, stage, altered sensorium, underlying comorbidities, pulmonary tuberculosis, leukocytosis and cerebrospinal fluid (CSF)/blood glucose < 0.30 and rise in CSF protein were associated with an increased risk of death. In multivariable analysis, age (OR 4.64, 95%CI 1.03-24.74, P = 0.046), altered sensorium (OR 8.62, 95%CI 1.25-110.0, P = 0.036), underlying comorbidity (OR 9.75, 95%CI 1.58-59.95, P = 0.014) and leukocytosis (OR 9.74, 95%CI 1.67-56.7, P = 0.011) were shown to be the best predictors of mortality in TBM. CONCLUSIONS: We observed that TBM patients who died were more likely to be older and have altered mental status on admission, underlying comorbidities and leukocytosis than TBM patients who survived. These factors were the most important predictors of mortality from TBM. PMID- 20843427 TI - Smoke-free homes: an intervention to reduce second-hand smoke exposure in households. AB - BACKGROUND: Second-hand tobacco smoke is a serious health hazard. We tested the fidelity and feasibility of the Smoke-Free Homes (SFH) intervention and looked for preliminary evidence of its effectiveness in imposing smoking restrictions in homes in Pakistan. METHODS: SFH was piloted and adapted for Pakistan. The adapted SFH intervention was then delivered to primary schoolchildren, community leaders and health professionals in a semi-rural Union Council. We carried out a survey before and after the intervention to assess adult smoking behaviour and restrictions at homes. We also carried out focus group discussions with stakeholders to determine the appropriateness and acceptability of the intervention. RESULTS: We found the adapted SFH intervention feasible and appropriate in a typical semi-rural setting in Pakistan. The proportion of smoke free homes increased from 43% (95%CI 37.4-48.2) to 85% (95%CI 80.9-89.2) after the intervention. The number of households with at least one smoker decreased from 57.5% (95%CI 52.1-62.9) to 38.4% (95%CI 32.7-44.1). There was a reduction in self-reported adult smoking prevalence from 44% (95%CI 39-48) to 28% (95%CI 24 33) in males. CONCLUSION: SFH has the potential to influence adult smoking behaviour in households. This approach needs to be further evaluated to establish its effectiveness and cost-effectiveness and to ascertain its long-term sustainability. PMID- 20843428 TI - Minocycline and talc slurry pleurodesis for patients with secondary spontaneous pneumothorax. AB - SETTING: Few studies have evaluated the sclerosing efficacy of minocycline, and none have specifically compared its sclerosing efficacy and safety profiles with talc slurry in secondary spontaneous pneumothorax (SSP). DESIGN: A retrospective analysis was conducted in patients with SSP who underwent chemical pleurodesis from January to December 2004 with minocycline or talc slurry in 12 public hospitals of Hong Kong. RESULT: There were 121 episodes of minocycline pleurodesis and 64 episodes of talc slurry pleurodesis. Immediate procedural failure were similar in the minocycline and talc slurry groups (21.5% vs. 28.1%, P = 0.31). Presence of interstitial lung disease, >= 2 previous episodes of pneumothorax, requiring mechanical ventilation during pleurodesis and persistent air leak before pleurodesis were independently associated with procedural failure. Pain was experienced in respectively 44.6% and 37.5% of the minocycline and the talc slurry groups. Pain was more common in patients receiving high doses of talc (>= 5 g; P = 0.03). Respiratory distress was found in respectively 1.7% and 1.6% of the minocycline and talc slurry groups. CONCLUSION: Minocycline and talc slurry had comparable sclerosing efficacy in SSP, with immediate success rates of >70%. Pain was the most common adverse effect and respiratory distress was uncommon. Both appeared to be effective and safe for chemical pleurodesis in SSP. PMID- 20843429 TI - South Carolina tuberculosis genotype cluster investigation: a tale of substance abuse and recurrent disease. AB - The South Carolina Tuberculosis (TB) Control Division ranked all the TB genotype clusters (two or more cases with matching genotypes) in the state based on the number of cases. The largest cluster, PCR00002, was investigated to determine if the cluster represented recent Mycobacterium tuberculosis transmission, and if so, to identify associated risk factors. The PCR0002 cluster, which included pediatric cases, clearly represented recent M. tuberculosis transmission. The two primary factors contributing to cluster growth were substance abuse and recurrent TB disease. Elimination of ongoing M. tuberculosis transmission in this population will require concurrent treatment for TB disease and substance abuse. PMID- 20843430 TI - Genotypic characterization of tuberculosis transmission within Toronto's under housed population, 1997-2008. AB - Toronto has been the site of a recent extended tuberculosis (TB) outbreak in the homeless or under-housed population. Genotyping has identified a unique strain that continues to circulate within this population, with spread to individuals with no links to the shelter system, and anecdotally appears to progress rapidly from infection to active disease in some cases. The recent appearance and transmission of another unique strain was also identified, indicating that TB transmission continues to be a problem within the under-housed population. Enhanced surveillance utilizing molecular epidemiology is a useful tool to assist in TB control in vulnerable populations. PMID- 20843431 TI - Evaluation of thin-layer agar 7H11 for the isolation of Mycobacterium tuberculosis complex. AB - We evaluated the thin-layer agar (TLA) method for the recovery of Mycobacterium tuberculosis complex and compared the results with the BACTEC Mycobacteria Growth Indicator Tube (MGIT) 960 system. A total of 53 mycobacterial isolates were isolated on both media. The recovery rates of mycobacteria on TLA and BACTEC MGIT 960 system were respectively 90.6% and 96.2%. Mean time to detection of mycobacteria on TLA was 12.5 compared to 11.2 days on BACTEC MGIT 960. TLA is a simple technique and can be used as an alternative to the Lowenstein-Jensen medium and BACTEC MGIT 960 for the isolation of mycobacteria in resource-poor settings. PMID- 20843432 TI - Proliferation of chondrocytes on a 3-d modelled macroporous poly(hydroxyethyl methacrylate)-gelatin cryogel. AB - Tissue-engineering constructs should be designed to mimic the native tissue environment for cells, the scaffold matching to stiffness and strength of the tissues while maintaining an interconnected porous network and a reasonable porosity. This study presents a new single-step protocol for synthesis of a poly(hydroxyethyl methacrylate)-poly(ethylene glycol) diacrylate-gelatin (HPG) macroporous polymeric scaffold with well-controlled porous structure and good mechanical strength. The pore size of these matrices lies in the range of 30 to 100 MUm with an average pore diameter of 80 MUm and with an interconnected pore structure as analyzed by scanning electron microscopy. Further, interconnectivity was also confirmed by high solvent uptake capacity, as the cryogel reached its equilibrium within 2 min. The gels also showed substantial mechanical integrity, i.e., the average compressive modulus was 32.73 +/- 2.36 kPa at 15% compression of their original length. The degree of weight loss of these cryogels was found to be approx. 88% within 8 weeks of incubation in PBS (pH 7.4) at 37 degrees C. Physio-chemically optimized cryogel was further evaluated for in vitro growth and proliferation of isolated primary goat chondrocytes up to 3 weeks. The cell adherence on cryogel was examined by SEM analysis, while cell-matrix interaction was examined by 4-6-diamidino-2-phenylindole and propidium iodide staining. Furthermore, the cell compatibility and proliferation was evaluated using the MTT assay. Increase in total cellular metabolic activity was observed as shown by continuous increase in glycosaminoglycan and collagen contents with time. Collagen type-I and type-II gene expression analysed for over 3 weeks by RT-PCR showed the prominent expression of collagen type-II. These results suggest the use of synthesised cryogel scaffold as a matrix for chondrocyte attachment and proliferation in 3-D environment and as a delivery system in cartilage-tissue engineering. PMID- 20843433 TI - Imidazole/poly(Ethylene glycol)-substituted poly(n-(8-aminooctyl)acrylamide) as biocompatible and efficient gene carrier. AB - A novel cationic polymer was developed by conjugating imidazole and poly(ethylene glycol) (PEG) on poly(N-(8-aminooctyl)acrylamide) (P8Am) for complexing with pDNA to exhibit high gene expression with low cytotoxicity and the resistance against erythrocyte agglutination and serum inhibition. Cytotoxicity results indicated that these P8Am derivatives with varying substitutions were more biocompatible than unmodified P8Am and PEI control. Moreover, the particle size and zeta potential experiment demonstrated that they were capable of complexing pDNA into sub-micrometer (135-625 nm) and positively charged (+10 to +43 mV) particles, while the high degree of substitution might impede their pDNA complexation ability that formed less positive and larger polyplexes. Flow cytometry analysis demonstrated that the cellular uptake efficiency was dependent on the degree of substitution; low degree of substitution would mediate high uptake efficiency. The gene-transfection ability, evaluated by luciferase assay, revealed low substitution in P8Am-IM11 (substituted with 11 mol% imidazole moieties) and P8Am PG7 (substituted with 7 mol% PEG moieties) in transfected cells more efficient than unmodified P8Am. Therefore, a multi-functional P8Am derivative, P8Am-IM11 PG7, containing both imidazole and PEG, was developed according to the optimized contents. In the presence of serum, P8Am-IM11-PG7 polyplexes significantly enhanced the gene-transfection efficiency relative to unmodified P8Am polyplexes. Moreover, they exhibited minimal cytotoxicity and the erythrocyte aggregation assay showed that P8Am-IM11-PG7 polyplexes had good blood compatibility as compared to P8Am and PEI polyplexes. This indicated that, by chemical modification, P8Am-IM11-PG7 could possess the required abilities to overcome the difficulties encountered in gene transfection and be a promising alternative of a gene carrier. PMID- 20843434 TI - An injectable oxidated hyaluronic acid/adipic acid dihydrazide hydrogel as a vitreous substitute. AB - Vitrectomy is a common procedure for treating ocular-related diseases. The surgery involves removing the vitreous humor from the center of the eye, and vitreous substitutes are needed to replace the vitreous humor after vitrectomy. In the present study, we developed a colorless, transparent and injectable hydrogel with appropriate refractive index as a vitreous substitute. The hydrogel is formed by oxidated hyaluronic acid (oxi-HA) cross-linked with adipic acid dihydrazide (ADH). Hyaluronic acid (HA) was oxidized by sodium periodate to create aldehyde functional groups, which could be cross-linked by ADH. The refractive index of this hydrogel ranged between 1.3420 and 1.3442, which is quite similar to human vitreous humor (1.3345). The degradation tests demonstrated that the hydrogel could maintain the gel matrix over 35 days, depending on the ADH concentration. In addition, the cytotoxicity was evaluated on retina pigmented epithelium (RPE) cells cultivated following the ISO standard (tests for in vitro cytotoxicity), and the hydrogel was found to be non-toxic. In a preliminary animal study, the oxi-HA/ADH hydrogel was injected into the vitreous cavity of rabbit eyes. The evaluations of slit-lamp observation, intraocular pressure, cornea thickness and histological examination showed no significant abnormal biological reactions for 3 weeks. This study suggests that the injectable oxi-HA/ADH hydrogel should be a potential vitreous substitute. PMID- 20843435 TI - In vivo evaluation of implant-host tissue interaction using morphology-controlled hydroxyapatite-based biomaterials. AB - In medicine, micro-electro-mechanical systems (MEMS) perform several specific functions. The design of bio-packages for MEMS to be implanted into the human body has been an increasing challenge in the last years. Mechanical, chemical and thermal resistance, as well as excellent bonding to silicon surfaces, are needed. Furthermore, ideal bio-packages should minimize post-operative complications and be well accepted by the host. To reach this goal, two different morphology controlled hydroxyapatite-based porous biomaterials were synthesized, implanted in rats and evaluated mechanically and histologically. The novel biomaterials were prepared at room temperature using synthetic hydroxyapatite micro-particles, silica nanoparticles and water-based resin and compared with a standard hydroxyapatite biomaterial. The morphology (porosity) was controlled to obtain interconnected pores with appropriated pore size and pore volume fraction. All biomaterials were implanted in rats at the dorsal area near the third thoracic vertebra. The rats were killed 2, 7 and 21 days after surgery. Histological analysis revealed that the implants were well accepted by the host and minimal local inflammation was observed. The acute inflammatory response disappeared 21 days after surgery for both novel biomaterials. Additionally, organic matter (collagen) was produced in the interior of the porous biomaterial, indicating that an incipient vascularization process was in progress after 21 days of implantation. Both new biomaterials showed high abrasion resistance, high Young modulus, the appropriate porosity to allow possible vascularization, and good bonding to silicon surfaces. PMID- 20843436 TI - [Oncological principles in minimally invasive surgery of the rectum]. PMID- 20843437 TI - [Comparison of plasma matrix metalloproteases 2, 3, 9 in breast carcinomas and fibroadenomas]. AB - Tumor cell infiltration causes the remodelling of peritumoral tissues, determined by an increased lytic activity of extracellular matrix exerted by the neoplastic invasive phenotype. Among the principal lytic enzymes produced by tumor cells and mainly involved in invasion process there are the matrix metalloproteases (MMPs). The Authors compared the plasmatic values of MMPs 2, 3, 9 from patients with breast carcinomas and fibroadenomas in order to evaluate whether there was a significant difference between the two groups of patients. MMPs 2, 3, 9 values were quantified by ELISA test from plasma collected 24 hours before surgery in 50 breast carcinomas and 30 fibroadenomas. MMP2 mean value from the patients with carcinomas resulted significantly higher as compared to that from the patients with fibroadenomas; while for MMP 3 and 9 mean values was not possible to find a significant difference between the two groups of malignant and benign breast tumors. These data confirm the main role played by MMPs during the tumor invasion process. Therefore, it is possible to propose the future inclusion of MMP2 test, together to other biological and clinical data, for prognostic evaluation of neoplastic breast lesions. PMID- 20843438 TI - Papillary glioneuronal tumor of the fourth ventricle: case report and review of the literature. AB - Rosette-forming glioneuronal tumour (RGNT) of the fourth ventricle is a relatively new entity recently described. Neuronal and mixed neuronal-glial tumours have been incorporated in the same category in the WHO Classification of Nervous System Tumours. This category comprises heterogeneous neoplasms composed of neuronal and glial cells with various grades of differentiation. We present a case of papillary glioneuronal tumor occurring in a 44-year-old man with an unusual hemorrhagic onset. The clinical, morphological and immunohistochemical features are discussed and the published literature is reviewed. PMID- 20843439 TI - Abdominal cerebrospinal fluid pseudocyst: a complication of ventriculoperitoneal shunt in a Brazilian Amazon woman. Case report. AB - Ventriculoperitoneal shunt (VPS) is the most common treatment for hydrocephalus, however it is not free of complications. Abdominal cerebrospinal fluid pseudocyst (ACP) is an uncommon, but potentially life-threatening, complication of VPS. It is characterized by a fluid filled collection of cerebrospinal fluid (CSF) in the peritoneal cavity containing the distal end of the VPS catheter and is surrounded by a wall composed of fibrous tissues without an epithelial lining. We report the case a Brazilian Amazon woman that presented ACP fifteen years after the placement of a VPS. Physicians should be aware of this possible complication once early diagnosis would improve outcome and reduce patient's suffering and distress. PMID- 20843440 TI - [Metastatic gastric cancer successfully treated with surgery and chemotherapy. Case report]. AB - A case of long-term survivor 50-year-old man treated for advanced gastric cancer with two liver metastases is described. Patient underwent a total gastrectomy with D2 lymphadenectomy and atipic liver resection. After surgery, chemotherapy with PELF achieved a complete clinical response; six month from the fourth cycle, Ca19.9 levels slowly increased until 185 U/mL and a retro-peritoneal lymphadenopathy was detected by US. Three different chemotherapeutic combinations (FOLFOX, FOLFIRI, FOLFOX4) was administrated but two new liver recurrences spread out. From November 2007 until now, patient received 8 CDF cycles and he obtained a complete clinical response supported by persistent negativity of TC-PET scans. The radiological investigations performed after last admission in our Department for jaundice, revealed multiple liver lesions with Ca 19.9 levels of 6.766 U/mL. The patient required placement of metallic biliary endoprosthesis. He is still alive 41 month after primary surgery. We consider this case a successful example of survival increasing by integrated surgery-chemotherapy treatment but also an expression of the failure of current available therapy in the definitive cure for gastric cancer. Metastatic gastric cancer should be considered a disease treatable but not curable. PMID- 20843441 TI - [Intestinal perforation by ingested foreign bodies in the digestive tract: an insidious pathology always of interest. Our experience]. AB - The authors want to present five cases (from May 1999 to May 2009) of acute abdomen from perforation of the foreign body introduced with food. They highlight how the accidental ingestion is very common but the perforation is rare. The preoperative diagnosis, in these cases, is always very difficult and the radiological examinations are not always able to resolve the diagnostic doubt with other acute intestinal diseases that are responsible of perforation. Then, the surgery procedure is, necessarily, the only possible diagnostic and therapeutic means. The mortality and the morbidity remain still high first of all for the delay in the diagnosis and the advanced age of patients. PMID- 20843442 TI - Invasive ductal carcinoma arising in ectopic breast tissue of the axilla. Case report and review of the literature. AB - Mammary carcinoma arising in ectopic breast tissue is an uncommon occurrence. Most reported cases have involved ductal carcinoma, but other types, such as medullary, papillary, and lobular carcinomas, have been described. For pathologists, the diagnosis of mammary carcinoma arising in ectopic breast tissue can be difficult, especially in the axilla, where carcinoma of adnexal origin must be excluded. We describe a 51-year-old woman who developed invasive secretory ductal carcinoma in ectopic left axillary breast tissue and micrometastatic carcinoma in an ipsilateral axillary lymph node. The carcinoma arose in a left axillary mass that had been present for several years, from which she had secreted fluid during prior menstrual periods. PMID- 20843443 TI - Acute respiratory distress following fine needle aspiration of thyroid nodule: case report and review of the literature. AB - BACKGROUND: Fine needle aspiration (FNA) is a widely used practice to assess thyroid lesions, with a low morbidity rate. Although neck hematomas following this procedure are quite common, only three cases of massive hemorrhage causing acute airways obstruction have been previously described. CASE REPORT: We report the case of a 74 years old female with acute respiratory distress following ultrasound-guided FNA for a right paraisthmic thyroid nodule. The patient was admitted to the Emergency Room (ER) 6 hours after the procedure with a large neck hematoma compressing the cervical trachea and requiring surgical decompression. Patient underwent endotracheal intubation followed by isthmectomy and evacuation of the hematoma. Extubation was made 24 hours later in the Intensive Care Unit and the patient was discharged after 48 hours uneventfully. CONCLUSIONS: Acute thyroid hemorrhage following FNA is very rare but still possible. Prompt intervention is mandatory for patients with rapidly evolving symptoms. PMID- 20843444 TI - Management of anaplastic thyroid carcinoma spread over the trachea with mediastinal extension. AB - INTRODUCTION: We report a case of treatment of anaplastic thyroid carcinoma spread over the trachea with mediastinal extension. METHODS: Case report and review of the world literature concerning the treatment of anaplastic thyroid carcinoma are presented. DISCUSSION: The role of surgery in treatment of anaplastic carcinoma remains controversial. Our case we underlined two questions: the appropriateness of the surgery options with extra-thyroid spread and the better surgery approach to anaplastic thyroid carcinoma interesting the mediastinum controlling the great vessels of the neck. Even if curative resection cannot be achieved, surgical resection can immediately reduce the tumor bulk to facilitate the efficacy of post-operative radiotherapy and/or chemotherapy and to achieve a good local control to avoid the need of a subsequent palliative tracheostomy. Tumor upper mediastinal involvement made mandatory to open the sternum in order to allow a more complete resection of the macroscopic mass. The mini-sternotomy represents a valuable alternative that allows reduction in surgical trauma increasing patient's comfort. CONCLUSION: The complete resection of the tumor mass without scarifying vital structures can lead to some prolonged survival. Even if complete resection cannot be achieved, surgical resection can immediately reduce the tumour bulk and achieve good local control of the disease to avoid the palliative tracheotomy. PMID- 20843446 TI - [A rare cause of acute abdomen: splenic infarction. Case report and review of the literature]. AB - INTRODUCTION: Splenic infarction is a rare cause of acute abdomen. It must be suspected in patient with hematologic diseases or thromboembolic conditions. The most common onset symptom is left-upper quadrant abdominal pain. Additional symptoms include fever and anemia. Laboratory may show elevated white blood cell and platelet counts. CASE REPORT: A 97-year-old female with a past history of atrial fibrillation presented with left-upper quadrant abdominal pain and fever since 20 days. Laboratory showed elevated white blood cell and platelet counts, increased C-reactive protein and lactate dehydrogenase. Both ultrasonographic and tomographic scans showed a large hypodense area of the spleen. The patient received intravenous antibiotic therapy, which led to significant clinical improvement with discharge 16 days after admission. DISCUSSION: The diagnosis of splenic infarction is based both on clinical presentation and imaging studies. Angio-computed tomography is the diagnostic procedure of choice. Ultrasonography and conventional radiology are useful in the differential diagnosis with other abdominal and thoracic diseases mimicking splenic infarction. In our case the management was conservative, because the patient was hemodynamically stable and antibiotic therapy could control the sepsis. Moreover, advanced age and poor cardiac and respiratory conditions contraindicated surgery. CONCLUSIONS: In our case splenic infarction was probably due to a thromboembolic event secondary to atrial fibrillation. In accordance with the literature, we suggest initial conservative therapy. Surgery is indicated only in the presence of complications. PMID- 20843448 TI - Fine-needle aspiration cytology for breast lesions and cytopathologic correlations. An Italian peripheral hospital experience with 440 cases (from 2000 to 2007). AB - Fine-needle aspiration cytology for breast lesions and cytopathologic correlations. An Italian peripheral hospital experience with 440 cases (from 2000 to 2007). S. Erra, D. Costamagna In the present study, we evaluate our experience with Fine-Needle Aspiration Cytology (FNAC) for the diagnosis of breast tumor. Our intent is to correlate the diagnostic accuracy of FNAC for breast lesions on the basis of their respective histopathologic results. We retrospectively examined 440 cases of breast lesions who underwent FNAC and subsequently had definitive histopathologic diagnosis. The patients were observed over a period of eight years (from January 2000 to December 2007) at the "Santo Spirito" Hospital of Casale Monferrato, a general peripheral hospital in the North-West Italy (Piemonte Region). The results of FNAC were expressed using the five diagnostic categories recommended by European Guidelines on breast tumors as follows: 159 C5 cases (36,1%), 88 C4 (20%), 51 C3 (11,6%), 42 C2 (9,5%), and 100 C1 (22,7%). The statistical analysis revealed these values: sensitivity 93.8% (C5+C4), specificity 79.6%, C5 positive predictive value 97.5%, C2 negative predictive value 83.3%, false positive fraction 2.5%, false negative fraction 16.6%, diagnostic accuracy 71.2%. In consideration to the low cost and the low disconfort for patients, we consider FNAC a safe and feasible procedure, in particular in the context of peripheral hospitals, where a sophisticated technology is not available. We remark the importance of a good selection of patients to obtain the best results from the procedure. PMID- 20843445 TI - [Splenic artery pseudoaneurysm: a rare case of gastrointestinal haemorrhage in a patient with chronic pancreatitis]. AB - A bleeding pseudoaneurysm in patients with chronic pancreatitis is a rare and potentially lethal complication. This diagnosis may be very difficult and the optimal treatment remains controversial. We report the case of 80 years old female with calcific pancreatitis and severe intestinal bleeding due to a pseudoaneurysm of the splenic artery treated with interventional radiographic embolization. PMID- 20843447 TI - [Traumatic rupture of hepatic hydatid cyst]. AB - Hydatid disease is endemic in some areas of the world. It is located mostly in the liver. The cysts rupture is possible after a trauma, or spontaneously by the increase of intracystic pressure. Rupture of the hydatid cyst requires urgent surgical intervention. We report our experience in treatment of traumatic rupture of hepatic hydatid cyst. PMID- 20843450 TI - [Bladder preservation with trimodality therapy. Is it really necessary?]. PMID- 20843449 TI - [Adrenal incidentaloma in elderly patients]. AB - The adrenal incidentaloma is a disease that, thanks to the progress of the modern diagnostic, means for the longer and more high quality of life, has given a progressive increase in its impact, which has become more apparent in the elderly population. The authors after a review of literature on the impact and diagnostic, troubleshooting data endocrinology and imaging, these adrenal gland silent tumor clinically poses, envisage a therapeutic for use in older patient protocol. PMID- 20843451 TI - [Does the pharmacological class effect between the different luteinizing hormone releasing hormone analogues used in the treatment of prostate cancer have to be assumed?]. AB - INTRODUCTION: Evidence-based medicine is transforming clinical practice because of its progressive implantation. OBJECTIVES: We considered studying whether LHRH analogues are agents of the same pharmacological class, i.e., whether they have the same clinical effect, using the approach to evidence-based medicine. MATERIAL AND METHODS: PubMed was used as the main source of search. We have reviewed the evidence on the alleged "drug class effect" between analogues and the existing bibliographic support for their use in various medical indications. An evidence level and degree of recommendation have been assigned to each conclusion based on the "Scottish Intercollegiate Guidelines Network". RESULTS: There are no studies designed to answer the question of a class effect between LHRH analogues or agonists. Reviews and meta-analyses have been performed on many other issues related to therapeutic management either with analogues, alone or in combination with surgery or radiation therapy. Direct comparisons do not allow for obtain definitive conclusions: Indirect evidence is obtained from randomized studies comparing the different LHRH analogues to other treatments used to obtain androgen deprivation. Other issues related to pharmacokinetics and pharmacodynamics supporting either the existence or non-existence of class effect were evaluated. CONCLUSIONS: The current available evidence is not enough to support a presumed "drug class effect" among the various analogues in the treatment of prostate carcinoma. PMID- 20843452 TI - [Postsurgical family information: an improvement area. Prospective study after urologic surgery]. AB - OBJECTIVES: Analyzing and quantifying the postoperative retention of information, checking if it could be improved been delivered in an organized way. MATERIAL AND METHODS: After the basic information to relatives of 50 post-surgical patients operated for bladder or prostate, we deliver a questionnaire about what has just been told. It must be completed by a family member. The information is distributed differently: group 1 (30 patients) reported to the family following a script designed by us, written in simple and natural language. In group 2 (20 patients) the doctor informed as usual, not knowing that he is participating in the research. Then the relative is interviewed by one of the researchers. RESULTS: Only 3 (6%) family members matched all the right answers, and 25 (50%) did not hit more than 70% of the issues. The best known concept was the organ involved: 46 (92%). 21(42%) of respondents did not know if the process is basically benign or malignant, getting better results in group 1 but without significance: 20/30 (66.7%) vs 9/20 (45%) (p>0.05). The only item in which there are differences in success rate depending on the group is if a catheter have been set: 29 (96.7%) of successes in group 1, 13(65%) in 2. We found no difference in success rate according to number of family members informed, education, age or number of previous interventions. CONCLUSIONS: Relatives do not retain everything that was said. Organizing the information provided may improve, but other factors have influence. We must improve issues such as personal identification. It may be useful to repeat the information later. PMID- 20843453 TI - [Intravenous urography is died. Long live the computerized tomography!]. AB - Very important changes have happened in the field of the genitourinary image during the last half of the 20th century, so that for most of the historical intravenous urography indications, nowadays the computerized tomography (CT) is technique of choice. The aim of this report is to perform an update in the correct use of the imaging techniques in the adult-related most frequent urological pathology, including: urolithiasis, haematuria, infections, tumours, surgery follow-up and pyelectasis, specially focused in CT. A brief historical review of the urological imaging techniques is performed, emphasizing the physical principles. In the second part, the role played by plain X-ray, ultrasound, CT and MR in the different urological pathologies are reviewed, discussing the sensibility and specificity of each technique. A brief reflection is finally carried out over of the radiation doses. PMID- 20843454 TI - [Response and progression-free survival in T2 to T4 bladder tumors treated with trimodality therapy with bladder preservation]. AB - OBJECTIVE: To evaluate the response and the free-survival progression in patients diagnosed of invasive bladder cancer who have been treated with transurethral resection, chemotherapy and radiotherapy. This multimodal treatment is compared with a not random serie of patients treated by radical cistectomy. MATERIAL AND METHODS: Retrospective analysis of 43 cases of invasive bladder cancer treated with two schemes of bladder preservation between 1994-2007. They are compared with 145 cases treated with radical cistectomy in the same period of time. Pronostic variables included in the study are clinical stage, grade of differentiation, presence of ureteral obstruction, chemotherapy modality, radiotherapy doses and p53 and ki-67 expression. RESULTS: Mean and median time are 51 and 39 months in patients with multimodal treatment. Complete response is achieved in 72% of cases treated with bladder preservation. Ureteral obstruction is a prognostic factor (OR: 7,3;p:0,02). 72% patients with complete response mantain it at the end of the study. None of analyzed variables are predictors of maintenance of the response. Survival rates with a intact bladder were 69+/-7% and 61+/-7% at three and five years. Radiotherapy doses greater than 60Gy (OR: 6,1; p<0,001) and the absence of ureteral obstruction (OR: 7,5; p<0,002) were pronostic variables. Free-survival in patients with complete response was 80+/-7% and 58+/-10% at three and five years. At the end of the study, 53,5% of patients had a intact bladder and free-disease.In the same period of time, 145 radical cistectomies were performed due to muscle invasive bladder cancer. Mean and median time in this group were 29 and 18 months respectively. Stadistical analysis reveals a worse clinical stage in the group of patients treated with multimodal treatment (p:0.01). Free-survival was 72+/-5% and 63+/-7% at 3 and 5 years in the group of radical cistectomies. There was not statistical significant differences between cistectomies and bladder preservation. CONCLUSIONS: Patients treated with bladder preservation have a free-survival similar to those treated with radical cistectomy. Radiotherapy doses greater than 60Gy and absence of ureteral obstruction were free-survival prognostic variables. PMID- 20843455 TI - [Utility of inhibin B in the management of male infertility]. AB - INTRODUCTION: Inhibin B (INHB) is an hormone produced by Sertoli's cells that exercises a negative feedback on FSH secretion. In this study we analyze its diagnostic value as a marker of spermatogenesis and its prognostic value for testicular sperm extraction in azoospermic patients. MATERIAL AND METHODS: Between June 2003 and April 2007 we studied 504 infertile males in our Fertility Department. Until May 2006 we determined INHB only in patients with a sperm count <10M/ml. Since then INHB was determined in every patient due to the present study. 158 determinations were finally performed using enzymoimmunoassay considering normal values between 80 and 300pg/ml. We correlated INHB values with other hormones, spermatic count and, in case of azoospermia (24 patients), with success/failure of surgical sperm retrieval from testes (TESE) to use for intracytoplasmatic sperm injection (ICSI). RESULTS: A significant correlation was observed between INHB and FSH (r=-0.469, p<0.001) and LH (r=-0.399, p<0.001) but not with testosterone, prolactin, estradiol and SHBG. Sperm count was better correlated with INHB (r=0.247; p<0.003) than with FSH (r: -0.157; p<0.052). INHB and FSH were altered in 57.6% and 42.1% of azoospermia respectively, 42.1% and 11.1% in severe oligospermia (0-2M/ml) and 5% and 3.3% in oligospermia (>2M/ml) and normozoospermia. In azoospemic patients PPV for success in testicular sperm extraction was 81.8 % for normal INHB and 76.6% for normal FSH. NPV for failure of sperm retrieval was 61.6% for low INHB and 63.6% for high FSH. CONCLUSIONS: An inverse correlation exists between INHB and FSH and LH levels. INHB correlates better than FSH with sperm count. In azoospermia and oligospermia (<2M/ml), low INHB is more sensitive to detect testicular damage than high FSH. Normal INHB level predicts better than FSH the success of testicular sperm extraction for ICSI, although the favourable outcome can never be assured. PMID- 20843456 TI - [The anatomical-functional characteristics of the pelvic floor and quality of life of women with stress urinary incontinence subjected to perineal exercises]. AB - OBJECTIVE: To determine the effects of exercise in anatomic abnormalities of the pelvic floor (SP) and the quality of life (QOL) of women with stress urinary incontinence (SUI). METHOD: An experimental study with 50 women with SUI, distributed randomly into two groups, experimental (GE, 49.24+/-7.37 years) and control group (CG; 45.25+/-5.60 years). The groups performed ultrasound evaluation of the SP, evidence of pelvic floor muscle strength by palpation bidigital, surface EMG motor activity and replied to the CV before and after treatment. The GE had 16 sessions of pelvic floor exercises twice a week for 30min. RESULTS: Comparison between the GE and GC revealed significant differences in favor of GE, namely: mobility of the bladder neck (Delta=-0.79mm, p=0.00), thickness of pelvic floor muscle (Delta=-0.04mm, p=0.00), EMG (Delta=0.05.V, p=0.00), muscle strength by the AFA (Delta=0.05 level, p=0.00), DOMI1 (Delta%=5.67%, p=0.00), DOMI2 (Delta%=18.00%, p=0.00), DOMI3 (Delta%=18.22%, p=0.00), DOMI4 (Delta%=4.45%, p=0.00), DOMI5 (Delta%=0.22%, p=0.00), DOMI6 (Delta%=2.00%, p=0.00), DOMI7 (Delta%=3.78%, p=0, 00), DOMI8 (Delta%=6.33%, p=0.00), DOMI9 (Delta%=4.03%, p=0.00). CONCLUSION: It was modified and improved anatomic features of the pelvic floor of women from GE through perineal exercises, which will positively influence the CV of these women. PMID- 20843457 TI - [Overactive bladder symptoms in pregnancy and puerperium: is there a relationship between the symptoms score and quality of life?]. AB - INTRODUCTION AND OBJECTIVE: During pregnancy, hormonal change, increase in the body mass index and the pressure caused by the enlarged uterus over the bladder and pelvic floor, are some factors involved in lower urinary tract symptoms (LUTS). This study was made to evaluate the correlation between pregnancy and delivery way with LUTS. MATERIAL AND METHOD: This open prospective study was carried out using the overactive bladder questionnaire short form (OABq-SF). A total of 60 patients enrolled this study. The mean age was 24 year, raging from 14 to 40 years. The patients were evaluated during the third trimester and 6 months after delivery. Statistical analysis of the OABq-SF scores was made using the Pearson method. RESULTS: Mean OABq-SF score during pregnancy was 35.2 and 6 months after delivery decreased to15. Quality of life was 82.9 during pregnancy and increased to 88.4 at 6 month after delivery. Patient's perception, that is correlation, was 55.02 (p=0.0001) during pregnancy and 36.1% (p=0.0046). Clinical correlation index was 6.7%. CONCLUSIONS: Our study demonstrated that in spite of LUTS being more important during pregnancy, there is no significant clinical correlation in patient's perception. PMID- 20843458 TI - [Laparoscopic partial nephrectomy. Analysis of first 30 cases of our series and review of the literature]. AB - OBJECTIVE: Our goal is to analyze the surgical and clinicopathological results of our first 30 laparoscopic partial nephrectomies (LPN) performed consecutively and correlate the results with the literature. MATERIAL AND METHODS: This is a cases series, with 30 patients (20 men and 10 women) operated between 2006 and 2008. We assessed the clinicopathological factors and complications. The mean and median follow-up was 25 and 5 months. RESULTS: Resected tumors had an average size of 2.4 cm. 60% of the tumors were malignant. The pathological stage was pT1 in 100% of cases (47% grade I, 53% Fuhrman grade II).Surgical margins were positive in 3 cases, switching to open surgery. Intraoperative bleeding was 74.66 cc (35.7+/ SD) and 70 cc of mean and median. The mean operative time was 214.4min (+/-69) and ischemia time of 31.3min (+/-13.8). CONCLUSIONS: Our results are similar to those reported in the literature, except for positive margins and conversion attributable to the learning curve. PMID- 20843459 TI - [REMEEX(r) system for the treatment of male urinary stress incontinence: our experience]. AB - INTRODUCTION: We evaluate the effectiveness of REMEEX(r) (readjustable sling) for the treatment of male urinary stress incontinence (SUI). MATERIALS AND METHOD: Between February 2007 and December 2009, 14 male patients with mild to severe SUI were operated with the use of REMEEX(r) system. The origin of incontinence was radical open prostatectomy (n=9), laparoscopic prostatectomy (n=4) and TUR (n=1). We evaluate postoperatively complications in three groups: intraoperatively, early complications (before 1 month) and late complications (after 1 month). Follow up was done at 1, 3, 6 and 12 months after intervention. RESULTS: The mean age was 68,5 years (range: 62-71). The average follow-up time was 18,6 months (range: 10,1-35,2). The mean of readjustment was 3,7 (range: 1-6). Twelve patients were readjusted during the early period (24-72h after intervention). The mesh was removed in 3 cases (21,4%) owing to infection in one and the others because patients didn't want more system readjustment. There were four (28,5%) intraoperative bladder perforations. The early complication more frequent was acute urinary retention with five cases (35,7%). To the year of follow-up 41,7% of the patients are totally continent (5/12) and 33,3% presents light urinary incontinence (4/12). CONCLUSIONS: The REMEEX(r) system for the treatment of male SUI presents (in our experience) a 75% of good results (continent patients or patients with light urinary incontinence) at the year of follow-up with a high rate of light complications. Readjustment are frequent at the first six months after intervention and it's necessary an intense follow-up. We need more studies that evaluate the long-term efficiency of this system. PMID- 20843460 TI - [Laparoscopic extraperitoneal adenomectomy: surgical technique and preliminary results]. AB - OBJECTIVE: We analyze the laparascopic adenomectomy preliminary results and describe the surgical technique, for benign prostatic hyperplasia (BPH), for glands greater than 60cc. MATERIALS AND METHODS: From January to April 2009 we have performed 10 laparoscopic adenomectomies. We performed a descriptive and retrospective study and early postoperative results were analyzed. Descriptive statistical analyses were performed using IPSS 17.0. The surgical technique is described step by step. RESULTS: Conversion to open surgery was not required, and none of the patients had serious peri-operative and post-operative complications. None of the ten patients required blood transfusions. Median operating time was 112,5min (80-135). Median hospital stay was 3,5 days (2-5) and median catheterization period was 7 days (3-21). The median prostate enucleated weight was 62gr. (40-93). The median postoperative Qmax was 18,8ml/seg and the median score of IPSS was 5. CONCLUSIONS: Laparoscopic adenomectomy is a low rate morbidity technique and reproducible in centers with laparoscopic skills. Prospective and comparative studies with open surgery will be necessary to choose the best technique for our patients. PMID- 20843461 TI - [Neprhon sparing surgery for renal tumours on kidney transplantation]. AB - INTRODUCTION: Nowadays, nephron sparing surgery for renal carcinoma achieves good oncological results, similar to radical surgery, with the advantage of preserving renal function. Renal cell carcinomas appear de novo in 4.6% of post-transplant patients compared with 3% of tumors in the general population, affecting less than 10% to renal allograft. OBJECTIVE: The purpose is to analyze our experience and make a literature review about the role of nephron sparing surgery to treat de novo renal tumours in renal grafts. MATERIAL AND METHODS: A retrospective and descriptive analysis has been realized, finding four patients who presented with de novo renal tumours over renal graft after kidney transplantation and treated by nephron sparing surgery. A Medline review is done to search similar series published. Oncological and functional results were reviewed and analyzed. We worked with SPSS 12.0 software. RESULTS: Medium age at diagnosis was 46.5 y (42 62). Medium size was 2.4cm. (1.5-3.5) and final histology showed medium tumours size of 3.0cm. (1.7-3.5). Medium hospital stay was 6.0d. Medium time from transplantation to diagnosis was 92 months (42-192). NSS was done in all cases, in 3 cases tumorectomy and one partial nephrectomy. Transfusion was only needed in one case. All cases had pT1aN0M0 RCC histology exam. Renal function did not change from preoperative. All patients are free of progression with a medium follow-up of 46.5 months (15-58). CONCLUSIONS: NSS could be an option to treat graft tumours in selected cases, preserving renal function. In our experience, is a safe and efficient treatment in patients with small de novo renal tumours over renal graft. PMID- 20843462 TI - [Retroperitoneal angiomyolipoma: review of the literature and report of a new case]. PMID- 20843463 TI - [Renal synchronous carcinoma of clear cells with non-hodgkin lymphoma of phenotype b of type MALT]. PMID- 20843464 TI - [Bladder amyloidosis: a lesion that simulates a tumor]. PMID- 20843465 TI - [Umbilical reconstruction in patients with vesical exstrophy]. PMID- 20843466 TI - [Double vena cava inferior]. PMID- 20843467 TI - [Recurrent of retroperitoneal cystic lymphangiomas with difficulty for surgical resection. Is there other therapeutic options?]. PMID- 20843469 TI - Characteristics of paediatric patients with 2009 pandemic influenza A(H1N1) and severe, oxygen-requiring pneumonia in the Tokyo region, 1 September-31 October 2009. AB - Few reports describe the features of 2009 pandemic influenza A(H1N1) pneumonia in children. We retrospectively reviewed 21 consecutive children admitted to hospital from September to October 2009 in the Tokyo region. The diagnosis of 2009 pandemic influenza A(H1N1) virus infection was based on positive results of real-time RT-PCR or rapid influenza antigen test. All patients were hospitalised for pneumonia with respiratory failure and severe hypoxia. The median interval from onset of influenza symptoms to admission was 14 hours (range: 5-72 hours) and the median interval from the onset of fever (>=38 degrees C) to hospitalisation was 8.5 hours (range: 0-36 hours). All patients required oxygen inhalation. Four patients required mechanical ventilation. Chest radiography revealed patchy infiltration or atelectasis in all patients. Antiviral agents and antibiotics were administrated to all patients. Antiviral agents were administered to 20 patients within 48 hours of influenza symptom onset. No deaths occurred during the study period. Paediatric patients with this pneumonia showed rapid aggravation of dyspnoea and hypoxia after the onset of influenza symptoms. PMID- 20843470 TI - Practical usage of computer-supported outbreak detection in five European countries. AB - This paper discusses computer-supported outbreak detection using routine surveillance data, as implemented at six institutes for infectious disease control in five European countries. We give an overview of the systems used at the Statens Serum Institut (Denmark), Health Protection Agency (England, Wales and Northern Ireland), Robert Koch Institute (Germany), Governmental Institute of Public Health of Lower Saxony (Germany), National Institute for Public Health and the Environment (the Netherlands) and Swedish Institute for Infectious Disease Control (Sweden). Despite the usefulness of the algorithms or the outbreak detection procedure itself, all institutes have experienced certain limitations of the systems. The paper therefore concludes with a list of recommendations for institutes planning to introduce computer-supported outbreak detection, based on experiences on the practical usage of the systems. This list--which concerns usability, standard operating procedures and evaluation--might also inspire improvements of systems in use today. PMID- 20843471 TI - Dengue virus infections in travellers returning from Benin to France, July-August 2010. AB - In July and August 2010, two cases of dengue fever were diagnosed in travellers returning from Benin to France. These two cases exemplify that dengue fever should be considered in febrile travellers, even those returning from areas where the infection is not usual. PMID- 20843472 TI - Spotlight on measles 2010: update on the ongoing measles outbreak in France, 2008 2010. AB - Since early 2008, France has been experiencing a measles outbreak with almost 5,000 notified cases as of 30 June 2010, including three measles-related deaths. The proportion of cases 20 years or older reached 38% during the first half of 2010. This situation is the consequence of insufficient vaccine coverage (90% at age 24 months in 2007) that led to the accumulation of susceptibles over the last years. It underlines the need for additional measures targeting susceptible children and young adults. PMID- 20843473 TI - Resistance to polymyxins: Mechanisms, frequency and treatment options. AB - Polymyxins act by binding to lipid A moiety of the bacterial lipopolysaccharide and subsequently disintegrating the bacterial membranes. The most important mechanism of resistance includes modifications of the bacterial outer membrane structure, including lipopolysaccharide. Lipopolysaccharide modification is mostly mediated by PmrA/PmrB and PhoP/PhoQ two-component regulatory systems. These mechanisms exist with some differences in many gram-negative bacterial species. Resistance to polymyxins is generally less than 10%. In specific regions, such as the Mediterranean basin, Korea and Singapore, they tend to be higher. Heteroresistance to polymyxins is associated with exposure to polymyxins and especially suboptimal therapeutic dosage. Polymyxin combination regimens, tigecycline and fosfomycin may be useful options for the treatment of polymyxin resistant gram-negative infections. PMID- 20843474 TI - The partial dopamine agonist pardoprunox (SLV308) administered in combination with l-dopa improves efficacy and decreases dyskinesia in MPTP treated common marmosets. AB - Dopamine agonist treatment in early Parkinson's disease (PD) induces less dyskinesia than l-dopa. However, once dyskinesia has developed, dopamine agonists administered with l-dopa exacerbate involuntary movements. The dopamine partial D2/D3 agonist pardoprunox reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine hydrochloride (MPTP)-treated primates without hyperactivity, indicating that pardoprunox may alleviate dyskinesia without compromising l dopa's beneficial actions. This study examines a clinical scenario in which pardoprunox was introduced, in an l-dopa sparing strategy, to existing l-dopa treatment in MPTP-treated marmosets previously primed to express dyskinesia. l Dopa (5-10 mg/kg) produced effects, which were stable over the 13 treatment days, of increased locomotor activity, reversed motor disability and marked dyskinesia. Pardoprunox (SLV308; 0.0125-0.025 mg/kg) plus l-dopa (3-10 mg/kg) administration increased locomotor activity over the same treatment period and initially produced an equivalent reversal of motor disability compared to l-dopa, however this effect was enhanced as treatment progressed. This reflected the prolonged duration of effect of pardoprunox compared to that of l-dopa. While pardoprunox plus l-dopa treatment initially produced dyskinesia to the same extent as l-dopa alone, the intensity diminished as treatment progressed and it was significantly different at the end of the study. On subsequent l-dopa challenge there was no difference in motor disability reversal between those animals previously treated with pardoprunox plus l-dopa compared to l-dopa alone but the combination treatment produced significantly less dyskinesia. These data suggest that pardoprunox may provide therapeutic benefit in mid to late stage PD by reducing dyskinesia while maintaining efficacy when used with concomitant l-dopa treatment. PMID- 20843475 TI - EBP50 inhibits the anti-mitogenic action of the parathyroid hormone type 1 receptor in vascular smooth muscle cells. AB - Parathyroid hormone-related protein (PTHrP) and the parathyroid hormone type 1 receptor (PTH1R) are important regulators of vascular remodeling. PTHrP expression is associated to increased proliferation of vascular smooth muscle cells (VSMC). In contrast, signaling via the PTH1R inhibits cell growth. The mechanisms regulating the dual effect of PTHrP and PTH1R on VSMC proliferation are only partially understood. In this study we examined the role of the adaptor protein ezrin-radixin-moesin-binding phosphoprotein (EBP50) on PTH1R expression, trafficking, signaling and control of A10 cell proliferation. In normal rat vascular tissues, EBP50 was restricted to the endothelium with little expression in VSMC. EBP50 expression significantly increased in VSMC following angioplasty in parallel with PTHrP. Interestingly, PTHrP was able to induce EBP50 expression. In the clonal rat aortic smooth muscle cell line A10, EBP50 increased the recruitment of PTH1R to the cell membrane and delayed its internalization in response to PTHrP(1-36). This effect required an intact C-terminal motif in the PTH1R. In naive A10 cells, PTHrP(1-36) stimulated cAMP production but not intracellular calcium release. In contrast, PTHrP(1-36) induced both cAMP and calcium signaling in A10 cells over-expressing EBP50. Finally, EBP50 attenuated the induction of p27(kip1) and the anti-proliferative effect of PTHrP(1-36). In summary, this study demonstrates the dynamic expression of EBP50 in vessels following injury and the effects of EBP50 on PTH1R function in VSMC. These findings highlight one of the mechanisms leading to increased VSMC proliferation and have important implication in the understanding of the molecular events leading to restenosis. PMID- 20843476 TI - Antinociceptive effects of morphine, fentanyl, tramadol and their combination, in morphine-tolerant mice. AB - The development of morphine-tolerance after chronic administration, reduces analgesic efficacy and is a significant clinical problem in some patients; may be managed clinically by increasing the doses of morphine and/or the administration of a second mu-opioid agonist. In morphine-tolerant mice, we investigated the presence of an interaction when two opioids are administered simultaneously. We determined the antinociceptive effects of morphine (M), fentanyl (FEN), and tramadol (TRM) individually and combined in a 1:1 proportion, based on their potency. Nociceptive thresholds were evaluated in CD1 mice using the hot plate test. Morphine tolerance was induced by the subcutaneous implantation of a 75mg morphine pellet, whereas control animals received a placebo pellet; the experiments were performed three days later. In both (placebo and morphine pellets), dose-response curves for M, FEN and TRM, individually and combined were obtained, and the doses that produced 50% inhibition (ED(50)) were determined. Sustained exposure to morphine induced a significant decrease in antinociceptive potency to acute M or FEN administration (tolerance), which was of a lesser magnitude after acute TRM; in these experiments the analysis of the interaction between chronic morphine and each opioid, demonstrated functional antagonism. The simultaneous administration of two opioids in morphine-tolerant mice, demonstrated antagonism for the M:FEN combination, whereas the effects of TRM combined with M or FEN, remained additive. The results suggest that during morphine-tolerance, TRM could be a useful drug to induce effective analgesia when combined with FEN or M. PMID- 20843477 TI - Ribonucleases of different origins with a wide spectrum of medicinal applications. AB - Ribonucleases (RNases) are a type of nucleases that catalyze the degradation of RNA into smaller components. They exist in a wide range of life forms from prokaryotes to eukaryotes. RNase-controlled RNA degradation is a determining factor in the control of gene expression, maturation and turnover, which are further associated with the progression of cancers and infectious diseases. Over the years, RNases purified from multiple origins have drawn increasing attention from medical scientists due to their remarkable antitumor properties. In this review, we present a brief summary of the representative RNases of fungal, bacterial, plant, and animal origins and outline their potential medicinal value in the treatment of tumor and AIDS. Among them, the most clinically promising RNases are mushroom RNases, Binase and Barnase from bacteria, ginseng RNases, and Onconase from frog (Rana pipiens). Fast developing protein engineering of RNases, which display more potent cytotoxic activity on and greater selectivity for malignant cells, has also aroused the interest of researchers. The multiple anti cancer mechanisms of RNases are also included. To sum up, these inspiring studies unveil a new perspective for RNases as potential therapeutic agents. PMID- 20843479 TI - Cerebellar abnormalities following hypoxia alone compared to hypoxic-ischemic forebrain injury in the developing rat brain. AB - Two-day-old (P2) rat pups were subjected to either a global hypoxia or to electrocoagulation of the right carotid artery followed by 2.5 h hypoxia. Cellular and regional injury in the cerebellum (CB) was studied at 1, 2 and 19 days using immunohistology. Following hypoxia and hypoxia-ischemia, all neuronal populations of the CB were damaged in a subset of Purkinje cells. The decrease in the number of interneurons, as well as the thickness of molecular and granular layers was significant following hypoxia. Diffuse white matter damage, with loss of preoligodendrocytes was more severe following hypoxia than hypoxia-ischemia. Global hypoxia in the rat at P2 produces extensive damage to many cell types in different areas of the CB. The addition of unilateral forebrain ischemia does not increase the severity of these changes. Our data provide insight into the mechanisms of the changes observed in the CB of premature newborns. PMID- 20843478 TI - The fragile X mental retardation protein developmentally regulates the strength and fidelity of calcium signaling in Drosophila mushroom body neurons. AB - Fragile X syndrome (FXS) is a broad-spectrum neurological disorder characterized by hypersensitivity to sensory stimuli, hyperactivity and severe cognitive impairment. FXS is caused by loss of the fragile X mental retardation 1 (FMR1) gene, whose FMRP product regulates mRNA translation downstream of synaptic activity to modulate changes in synaptic architecture, function and plasticity. Null Drosophila FMR1 (dfmr1) mutants exhibit reduced learning and loss of protein synthesis-dependent memory consolidation, which is dependent on the brain mushroom body (MB) learning and memory center. We targeted a transgenic GFP-based calcium reporter to the MB in order to analyze calcium dynamics downstream of neuronal activation. In the dfmr1 null MB, there was significant augmentation of the calcium transients induced by membrane depolarization, as well as elevated release of calcium from intracellular organelle stores. The severity of these calcium signaling defects increased with developmental age, although early stages were characterized by highly variable, low fidelity calcium regulation. At the single neuron level, both calcium transient and calcium store release defects were exhibited by dfmr1 null MB neurons in primary culture. Null dfmr1 mutants exhibit reduced brain mRNA expression of calcium-binding proteins, including calcium buffers calmodulin and calbindin, predicting that the inability to appropriately sequester cytosolic calcium may be the common mechanistic defect causing calcium accumulation following both influx and store release. Changes in the magnitude and fidelity of calcium signals in the absence of dFMRP likely contribute to defects in neuronal structure/function, leading to the hallmark learning and memory dysfunction of FXS. PMID- 20843481 TI - Foreword: Implementing cancer prevention in Europe. AB - The understanding of risk factors underpinning the aetiology of many common cancers is well established, yet the conversion of this knowledge into prevention lags considerably behind. The title of this Special Issue - Implementing cancer prevention in Europe - captures the central theme within; namely, the translation of cancer epidemiology into public health policy. The Special Issue is supported by focused evidence-based case studies of how these processes might be best taken forward. PMID- 20843480 TI - Effects of 17 beta-estradiol on lipopolysacharride-induced intracellular adhesion molecule-1 mRNA expression and Ca2+ homeostasis alteration in human endothelial cells. AB - Recent evidence showed that 17 beta-estradiol (E2) decreased cytokine-induced expression of cell adhesion molecules (CAM). Changes in intracellular Ca2+ concentration ([Ca2+](i)) has been shown to be associated with CAM expression in endothelial cells. Here, the effects of E2 (1 MUM, 24 h) on the expression of intracellular adhesion molecule-1 (ICAM-1) and [Ca2+](i) were investigated in a lipopolysaccharide (LPS) (100 ng/mL, 18 h)-stimulated human endothelial cell line, EA.hy926, using real-time PCR and spectrofluorometry, respectively. PCR analysis revealed a significant increase in ICAM-1 expression in calcium ionophore A23187 (1 nM)- or LPS-stimulated cells. Pretreatment of cells with E(2) significantly inhibited LPS-induced ICAM-1 mRNA expression. [Ca2+](i) was monitored in Fura-2AM-loaded cells in the presence and absence of extracellular Ca2+ with thapsigargin (TG, 1 MUM), a sarco/endoplasmic reticulum ATPase inhibitor or ATP (100 MUM). The extent of TG- or ATP-induced [Ca2+](i) increase was significantly higher in LPS-stimulated cells than in control cells. Pre treatment of LPS-stimulated cells with E2 limited the Ca2+ response to the same level as in control cells. Furthermore, ICI 182,780, an estrogen receptor antagonist, attenuated the inhibitory actions of E2 on ICAM-1 mRNA expression and Ca2+ responses, suggesting that estrogen receptors mediate, at least in part, the effects of estrogen. These data suggest a potential underlying mechanism for the protective effect of E2 against atherosclerosis. PMID- 20843482 TI - The effects of the financial crisis on primary prevention of cancer. AB - The present financial crisis will affect primary cancer prevention through several avenues: personal lifestyle choices, exposure to environmental risk factors, decisions made in the private sector and public policy on cancer prevention. Whilst it is clearly problematic to reach solid conclusions on a direct connection between economic crises and cancer mortality, we can identify trends that provide guidance for further action. For some lifestyle choices such as smoking or diet, we argue that public policy may channel existing tendencies during times of crisis for clear added value. In other areas, including research and health system investments, we will make the case that the resources not used now for cancer prevention efforts will lead to increased costs (both financial and human) down the road. Policy makers face a clear choice: they can follow a cost contention strategy, which may reduce expenditure in the short-term only to increase it in the long-term, or they can use the financial crisis as an opportunity to make difficult choices in terms of health service rationalisation, whilst at the same time strengthening evidence-based prevention policies. In short, we argue that despite the scarcity of funds and the governmental priorities on economic recovery, cancer prevention is more relevant now than ever. PMID- 20843483 TI - Prevalence of main cancer lifestyle risk factors in Europe in 2000. AB - BACKGROUND: Estimation of changes in cancer incidence possibly induced by primary prevention policies requires knowledge of the level of exposure to risk factors targeted by these policies. MATERIALS AND METHODS: We collected comparable exposure data from 30 European countries for five lifestyle cancer risk factors: tobacco smoking, alcohol drinking, overweight and obesity, physical activity and fruit and vegetable consumption. We obtained original reports for years 1995-2005 and the present manuscript reports results around year 2000. RESULTS: This work revealed the important heterogeneity in the quality and possibility to compare data between and within countries. Overall, we observed a clustering of lifestyle factors: highest tobacco consumption in Eastern Europe up to 61.6% in men in Latvia; high alcohol consumption in central Europe, particularly in Czech Republic in which the average daily consumption was 56.9 g/l in men and 14.6g/l in women; low fruit and vegetable consumption (less than 150 g/d) in Finland, Sweden, Norway and United Kingdom. Obesity was the most prevalent and exceeded 18% for men in United Kingdom, Malta and Greece; and for women in UK, Greece, Luxembourg and Hungary. CONCLUSION: We conclude that data on tobacco smoking and alcohol consumption are reasonably comparable and match the pattern of cancer incidence. Interpretation of data related to physical activity and fruit and vegetable consumption should be cautious because of considerable between-country variations in the way these data were collected. Recent efforts for harmonisation of health survey questionnaires and sampling methods across European countries should be pursued in order to increase comparability of results. PMID- 20843484 TI - Effects of occupation on risks of avoidable cancers in the Nordic countries. AB - Knowledge of cancer risk according to occupational affiliation is an essential part of formatting preventive actions aimed at the adult population. Herein, data on 10 major cancer sites amenable by life style exposures from the Nordic Occupational Cancer Study (NOCCA) are presented. All subjects aged 30-64 years participating in one or more national censuses in Denmark, Finland, Iceland, Norway, or Sweden between 1960 and 1990 were included in the cohort and followed up for cancer from inclusion until 2003/2005 via a linkage with the national cancer registries, and standardised incidence ratios (SIRs) were computed. Variation in risk across occupations was generally larger in men than in women. In men, the most consistent cluster with high risk of numerous cancer types included waiters, cooks and stewards, beverage workers, seamen, and chimney sweeps. Two clusters of occupations with generally low cancer risks were seen in both men and women. The first one comprised farmers, gardeners, and forestry workers, the second one included groups with high education, specifically those in health and pedagogical work. Although cancer risk varies by occupation, only a smaller part of the variation can be attributed to occupational exposures in the strict sense. Preventive measures at the work place are important to avoid established and new occupational health hazards. This study also indicates that the work place in addition should be seen as a useful arena for reaching groups of adults with more or less similar habits and attitudes for general health promotion. PMID- 20843485 TI - Diet and cancer prevention: Contributions from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. AB - We present the main findings observed to date from the European Prospective Investigation into Cancer and Nutrition (EPIC) on dietary factors associated with the most frequent cancer sites. METHODS: EPIC is a multicentre prospective study carried out in 23 centres in 10 European countries: Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden and the United Kingdom, including 519,978 participants (366,521 women and 153,457 men), most aged 35-70 years. RESULTS: We observed the following significant associations: gastric cancer risk was inversely associated with high plasma vitamin C, some carotenoids, retinol and alpha-tocopherol, high intake of cereal fibre and high adhesion to Mediterranean diet, while red and processed meat were associated with increased risk. High intake of dietary fibre, fish, calcium, and plasma vitamin D were associated with a decreased risk of colorectal cancer, while red and processed meat intake, alcohol intake, body mass index (BMI) and abdominal obesity were associated with an increased risk. High intake of fruit and vegetables in current smokers were associated with a decreased risk of lung cancer. An increased risk of breast cancer was associated with high saturated fat intake and alcohol intake. In postmenopausal women, BMI was positively and physical activity negatively associated with breast cancer risk. High intake of dairy protein and calcium from dairy products and high serum concentration of IGF I were associated with an increased risk of prostate cancer. These results contribute to scientific evidence for appropriate public health strategies and prevention activities aimed at reducing the global cancer burden. PMID- 20843486 TI - Increased consumption of fruit and vegetables and future cancer incidence in selected European countries. AB - Cancer is one of the major causes of death in western countries. Fruit and vegetable consumption may reduce the risk of cancers of the oropharynx, oesophagus, lung, stomach and colorectum. We investigated the potential effect of interventions aimed at increasing the intake of fruits and vegetables to the recommended level (500 g/d) on future cancer incidence in Europe. Data on cancer incidence and daily intake of fruit and vegetables were compiled for France, Germany, The Netherlands, Spain and Sweden. We also performed a meta-analysis of European observational studies to arrive at a quantitative estimate on the association between fruit and vegetable intake and cancer risk. Predictions on the future cancer incidence were modelled using PREVENT 3.01. Our study predicted 212,000 fruit- and vegetable-related cancer cases in these countries in 2050, out of which 398 (0.19%) might be prevented if the 500 g/d fruit and vegetable intake were achieved in the aforementioned countries. The largest absolute impact was observed for lung cancer with 257 (out of 136,517) preventable cases if the intervention was successfully implemented. Sweden would benefit the most from intervention to increase fruit and vegetable consumption with a 2% reduction in expected cases. Increasing fruit and vegetable consumption has a small impact on reducing the burden of cancer in Europe. Health impact assessment tools such as PREVENT can provide the basis for decision making in chronic disease prevention. PMID- 20843487 TI - Interpreting the epidemiological evidence linking obesity and cancer: A framework for population-attributable risk estimations in Europe. AB - Standard approaches to estimating population-attributable risk (PAR) include modelling estimates of exposure prevalence and relative risk. Here, we examine the associations between body mass index (BMI) and cancer risk and how effect modifications of these associations impact on PAR estimates. In 2008, sex- and population-specific risk estimates were determined for associations with BMI in a standardised meta-analysis for 20 cancer types. Since then, refinements of these estimates have emerged: (i) absence of menopausal hormonal therapy (MHT) is associated with elevated BMI associations in post-menopausal breast, endometrial and ovarian cancers; (ii) current smoking attenuates the BMI associations in oesophageal squamous cell carcinoma, lung and pancreatic cancers; (iii) prostate screening attenuates BMI associations when all prostate cancers are considered together; and (iv) BMI is differentially associated with different histological subtypes within the same cancer group. Using secondary analyses of the aforementioned meta-analysis, we show 2-3-fold shifts in PAR estimations for breast and endometrial cancers depending on the MHT usage in European countries. We also critically examine how to best handle exposures (in this example, BMI distributions) and relative risk estimates in PAR models, and argue in favour of a counterfactual approach based around BMI means. From these observations, we develop a research framework in which to optimally evaluate future trends in numbers of new cancers attributable to excess BMI. Overall, this framework gives conservative estimates for PAR - nonetheless, the numbers of avoidable cancers across Europe through avoidance of excess weight are substantial. PMID- 20843488 TI - State of the epidemiological evidence on physical activity and cancer prevention. AB - BACKGROUND: Physical activity is a modifiable lifestyle risk factor that has the potential to reduce the risk of most major cancer sites. METHODS: We examined the strength, consistency, dose-response and biological plausibility of an association between physical activity and risk of colon, breast, endometrium, lung, prostate, ovarian, gastric, rectal, pancreatic, bladder, testicular, kidney and haematological cancers. We also estimated the population-attributable risk (PAR) for physical inactivity and cancer in 15 European countries. RESULTS: There is convincing or probable evidence for a beneficial effect of physical activity on the risk of colon, breast and endometrial cancers. The evidence is weaker for ovarian, lung and prostate cancers and generally either null or insufficient for all remaining cancers. Several hypothesised biological mechanisms include a likely effect of physical activity on insulin resistance, body composition, sex steroid hormones and a possible effect on vitamin D, adipokines, inflammation and immune function. Somewhere between 165,000 and 330,000 cases of the six major cancers (breast, colon, lung, prostate, endometrium and ovarian) could have been prevented in 2008 in Europe alone if the population had maintained sufficient levels of physical activity. CONCLUSION: There is strong and consistent evidence that physical activity reduces the risk of several of the major cancer sites, and that between 9% and 19% of cancer cases could be attributed to lack of sufficient physical activity in Europe. Public health recommendations for physical activity and cancer prevention generally suggest 30-60 min of moderate or vigorous intensity activity done at least 5d per week. PMID- 20843489 TI - Lifestyle changes and reduction of colon cancer incidence in Europe: A scenario study of physical activity promotion and weight reduction. AB - BACKGROUND: Across Europe, there are over 300,000 new cases of colorectal cancer annually. Major risk factors include excess body weight (usually expressed by a high body mass index, BMI) and physical inactivity (PA). In this study we modelled the potential long-term effects on colon cancer incidence of changes in prevalence of excess body weight and physical inactivity in seven European countries across Europe with adequate data. METHODS: We addressed the impact of interventions aimed at preventing weight gain and increasing physical activity on colon cancer incidence using the Prevent model as refined in the FP-6 Eurocadet project. Relative risk (RR) estimates were derived from meta-analyses; sex- and country-specific prevalences of BMI and PA were determined from survey data. Models were made for Czech Republic, Denmark, France, Latvia, the Netherlands, Spain and the United Kingdom. RESULTS: In a hypothetical scenario in which a whole population had obtained an ideal weight distribution in the year 2009, up to 11 new cases per 100,000 person-years would be avoided by 2040. The population attributable fractions (PAF) for excess weight were much higher for males (between 13.5% and 18.2%) than for females (2.3-4.6%). In contrast, using the optimum scenario where everybody in Europe would adhere to the recommended guideline of at least 30 min of moderate PA 5d per week, the PAFs for PA in various countries were substantially greater in women (4.4-21.2%) than in men (3.2-11.6%). Sensitivity analyses were performed assuming underreporting of BMI by using self-reports (difference of 5 and 0.8 percent-points in males and females, respectively), using different risk estimates (between 5.8 and 11.5 percent-points difference for BMI for men and women, respectively, and up to 11.6 percent-points difference for PA for women). INTERPRETATION: Changes in lifestyle can indeed result in large health benefits, including for colon cancer. Two interesting patterns emerged: for colon cancer, achieving optimum BMI levels in the population appears to offer the greatest health benefits in population attributable fractions in males, while increased physical activity might offer the greatest fraction of avoidable cancers in females. These observations suggest a sex-specific strategy to colon cancer prevention. PMID- 20843490 TI - Impact of a smoking and alcohol intervention programme on lung and breast cancer incidence in Denmark: An example of dynamic modelling with Prevent. AB - PURPOSE: Among the known risk factors, smoking is clearly related to the incidence of lung cancer and alcohol consumption is to breast cancer. In this manuscript we modelled the potential benefits of reductions in smoking or alcohol prevalence for the burden of these cancers. METHOD: We used Prevent v.3.01 to assess the changes in incidence as a result of risk factor changes. Incidence of lung and breast cancer until 2050 was predicted under two scenarios: ideal (total elimination of smoking and reduction of alcohol intake to maximum 1 units/d for women) and optimistic (decreasing prevalence of risk factors because of a 10% increase in cigarette and alcohol beverage price, repeated every 5 years). Danish data from the household surveys, cancer registration and Eurostat were used. RESULTS: Up to 49% less new lung cancer cases can be expected in 2050 if smoking were to be completely eliminated. Five-yearly 10% price increases may prevent 521 new lung cancer cases in 2050 (21% less cases). An intervention that immediately reduces population alcohol consumption to the recommended level (below 12 g/d) may lower breast cancer by 7%, preventing 445 out of the 6060 expected new cases in 2050. Five-yearly 10% price increases in alcoholic beverages achieved a reduction of half as expected by the ideal scenario, i.e. 4% (262) preventable cases in 2050. CONCLUSIONS: The future burden of lung and breast cancer could be markedly reduced by intervening in their risk factors. Prevent illustrates the benefit of interventions and may serve as guidance in political decision-making. PMID- 20843491 TI - Scenarios of future lung cancer incidence by educational level: Modelling study in Denmark. AB - OBJECTIVE: To model future trends in lung cancer incidence in Denmark by education under different scenarios for cigarette smoking. METHODS: Lung cancer incidence until 2050 was modelled using Prevent software. We estimated lung cancer incidence under a baseline scenario and under four alternative scenarios for smoking reduction: decreasing initiation rates among the young, increasing cessation rates among smokers, a scenario combining both changes and a levelling up scenario in which people with low and medium levels of education acquired the smoking prevalence of the highly educated. Danish National Health Interview Surveys (1987-2005) and cancer registry data combined with individual education status from Statistics Denmark were used for empirical input. RESULTS: Under the baseline scenario, lung cancer rates are expected to decrease for most educational groups during the next few decades, but educational inequalities will increase further. Under the alternative scenarios, an additional decrease in lung cancer rates will be observed from 2030 onwards, but only from 2050 onwards it will be observed under the initiation scenario. The cessation and the combined scenarios show the largest decrease in lung cancer rates for all educational groups. However, in none of these scenarios would the relative differences between educational groups be reduced. A modest decrease in these inequalities will be observed under the levelling-up scenario. DISCUSSION: Our analyses show that relative inequalities in lung cancer incidence rates will tend to increase. They may be reduced to a small extent if the smoking prevalence of people with a low level of education was to converge towards those more highly educated people. An important decrease in lung cancer rates will be observed in all educational groups, however, especially when focusing on both initiation and cessation strategies. PMID- 20843492 TI - Reduction of socioeconomic inequality in cancer incidence in the South of the Netherlands during 1996-2008. AB - BACKGROUND: Cancer incidence varies according to socioeconomic status (SES) and time trends. SES category may thus point to differential effects of lifestyle changes but early detection may also affect this. PATIENTS AND METHODS: We studied patients diagnosed in 1996-2008 and registered in the South Netherlands Cancer registry. Incidence rates and estimated annual percentage changes were calculated according to SES category, age group (25-44, 45-64 and > or =65) and sex. RESULTS: People with a low SES exhibited elevated incidence rates of cancer of the head and neck, upper airways (both sexes), gastro-intestinal tract, squamous cell skin cancer, breast (> or =65) and all female genital, bladder, kidney and mature B-cells (all in females only), whereas prostate cancer, basal cell skin cancer (BCC) and melanoma (both except in older females) were most common among those with a high SES. Due to the greater increase in prostate cancer and melanoma in high SES males and the larger reduction of lung cancer in low SES males, incidence of all cancers combined became more elevated among males of > or =45 years with a high and intermediate SES, and approached rates for low SES men aged 45-64. In spite of more marked increases in the incidence of colon, rectal and lung cancer in high SES women, the incidence of all cancers combined remained highest for low SES women of > or =45 years. However, at age 25-44 years, the highest incidence of cancer of the breast and melanoma was observed among high SES females. During 1996-2008 inequalities increased unfavourably among higher SES people for prostate cancer, BCC (except in older women) and melanoma (at middle age), while decreasing favourably among low SES people for cancers of the oesophagus, stomach, pancreas and kidney (both in females only), breast (> or =65 years), corpus uteri and ovary. CONCLUSIONS: Although those with a low SES exhibited the highest incidence rates of the most common cancers, higher risks were observed among those with high SES for melanoma and BCC (both except older females) and for prostate and breast (young females) cancer. Altogether this might also have contributed to the recent higher cancer awareness in Dutch society which is usually promoted more by patients of high SES and those who know or surround them. PMID- 20843493 TI - Cancer risk diversity in non-western migrants to Europe: An overview of the literature. AB - BACKGROUND: Cancer risk varies geographically and across ethnic groups that can be monitored in cancer control to respond to observed trends as well as ensure appropriate health care. The study of cancer risk in immigrant populations has great potential to contribute new insights into aetiology, diagnosis and treatment of cancer. Disparities in cancer risk patterns between immigrant and autochthonous populations have been reported many times, but up to now studies have been heterogeneous and may be discordant in their findings. The aim of this overview was to compile and compare studies on cancer occurrence in migrant populations from non-western countries residing in Western Europe in order to reflect current knowledge in this field and to appeal for further research and culturally sensitive prevention strategies. METHODS: We included 37 studies published in the English language between 1990 and April 2010 focussing on cancer in adult migrants from non-western countries, living in the industrialised countries of the European Union. Migrants were defined based on their country of birth, ethnicity and name-based approaches. We conducted a between-country comparison of age-adjusted cancer incidence and mortality in immigrant populations with those in autochthonous populations. FINDINGS: Across the board migrants from non-western countries showed a more favourable all-cancer morbidity and mortality compared with native populations of European host countries, but with considerable site-specific risk diversity: Migrants from non-western countries were more prone to cancers that are related to infections experienced in early life, such as liver, cervical and stomach cancer. In contrast, migrants of non-western origin were less likely to suffer from cancers related to a western lifestyle, e.g. colorectal, breast and prostate cancer. DISCUSSION: Confirming the great cancer risk diversity in non-western migrants in and between different European countries, this overview reaffirms the importance of exposures experienced during life course (before, during and after migration) for carcinogenesis. Culturally sensitive cancer prevention programmes should focus on individual risk patterns and specific health care needs. Therefore, continuously changing environments and subsequently changing risks in both migrant and autochthonous populations need to be observed carefully in the future. PMID- 20843494 TI - The long road towards cancer prevention: 4 steps backward and 8 forward. PMID- 20843495 TI - ECG changes mimicking myocardial infarction. PMID- 20843496 TI - Improving influenza vaccination rates by targeting individuals not seeking early seasonal vaccination. AB - BACKGROUND: Influenza morbidity and mortality remain high in the United States although vaccination clearly improves health outcomes and reduces health expenditures. This study was designed to assess the effectiveness of mail and telephone reminder strategies on improving existing clinic influenza vaccination rates among those not seeking early seasonal vaccination. METHODS: In mid November, we randomized 1371 patients at a hypertension clinic into 1 of 2 intervention groups, a mail reminder group (letter plus the Centers for Disease Control [CDC] Influenza Vaccine Information Statement) or a phone reminder group (same information via a personal phone call), or a control group. The following spring, records were reviewed for vaccination documentation. Patients without documentation were contacted by phone to identify whether vaccination for the current season had been obtained. RESULTS: The final analysis included 884 patients (62% women, mean age 57.2 years old): 325 in the mail reminder group, 246 in the phone reminder group, and 313 represented the control group. Overall, 388 of these patients (44%) were vaccinated. Vaccination rates were significantly higher in the intervention groups, 46% for the mail reminder group (age and sex adjusted odds ratio [OR], 1.8, 95% confidence interval [CI], 1.3-2.5; P=.001) and 56% for the phone reminder group (OR, 2.8; 95% CI, 1.9-4.0; P<.0001), compared to 33% in the control group. Both interventions increased vaccination rates in all age/sex groups. CONCLUSION: In contrast to earlier studies, this intervention occurred later in the influenza vaccination period excluding those who seek early vaccination and allowing interventions to target those less likely to receive vaccination. Compared to previous studies demonstrating only trivial or modest benefits, both mail and phone reminders effectively increased clinic vaccination rates in our group of patients. PMID- 20843499 TI - Cold agglutinin syndrome associated with a 2009 influenza A H1N1 infection. PMID- 20843498 TI - Risk of suicide after long-term follow-up from bariatric surgery. AB - PURPOSE: Bariatric surgery is recognized as the treatment of choice for class III obesity (body mass index >=40) and has been increasingly recommended for obese patients. Prior research has suggested an excess of deaths due to suicide following bariatric surgery, but few large long-term follow-up studies exist. We examined postbariatric surgery suicides by time since operation, sex, age, and suicide death rates as compared with US suicide rates. METHODS: Medical data following bariatric operations performed on Pennsylvania residents between January 1, 1995 and December 31, 2004 were obtained from the Pennsylvania Health Care Cost and Containment Council. Matching mortality data from suicides between September 1, 1996 and December 28, 2006 were obtained from the Division of Vital Records, Pennsylvania State Department of Health. RESULTS: There were 31 suicides (16,683 operations), for an overall rate of 6.6/10,000; 13.7 per 10,000 among men and 5.2 per 10,000 among women. About 30% of suicides occurred within the first 2 years following surgery, with almost 70% occurring within 3 years. For every age category except the youngest, suicide rates were higher among men than women. Age and sex-matched suicide rates in the US population (ages 35-64 years) were 2.4/10,000 (men) and 0.7/10,000 (women). CONCLUSIONS: Compared with age and sex matched suicide rates in the US, there was a substantial excess of suicides among all patients who had bariatric surgery in Pennsylvania during a 10-year period. These data document a need to develop more comprehensive longer-term surveillance and follow-up methods in order to evaluate factors associated with postbariatric surgery suicide. PMID- 20843500 TI - The disappearing spleen. PMID- 20843501 TI - Drug rash with eosinophilia and systemic symptoms syndrome associated with clindamycin. PMID- 20843502 TI - Anticoagulation can reduce nonfatal myocardial infarction. PMID- 20843503 TI - Achieving hunter-gatherer fitness in the 21(st) century: back to the future. AB - The systematic displacement from a very physically active lifestyle in our natural outdoor environment to a sedentary, indoor lifestyle is at the root of many of the ubiquitous chronic diseases that are endemic in our culture. The intuitive solution is to simulate the indigenous human activity pattern to the extent that this is possible and practically achievable. Suggestions for exercise mode, duration, intensity, and frequency are outlined with a focus on realigning our daily physical activities with the archetype that is encoded within our genome. PMID- 20843504 TI - Effectiveness of delayed-release doxylamine and pyridoxine for nausea and vomiting of pregnancy: a randomized placebo controlled trial. AB - OBJECTIVE: To evaluate the effectiveness of Diclectin (doxylamine succinate 10 mg pyridoxine hydrochloride 10 mg, delayed-release preparation) as compared with placebo for nausea and vomiting of pregnancy. STUDY DESIGN: A randomized, double blind, multicenter placebo controlled trial studying pregnant women suffering from nausea and vomiting of pregnancy, analyzed by intention to treat. Women received Diclectin (n = 131) or placebo (n = 125) for 14 days. Nausea and vomiting of pregnancy symptoms were evaluated daily using the pregnancy unique quantification of emesis scale. RESULTS: Diclectin use resulted in a significantly larger improvement in symptoms of nausea and vomiting of pregnancy compared with placebo based on both the pregnancy unique quantification of emesis score (-4.8 +/- 2.7 vs -3.9 +/- 2.6; P = .006) and quality of life. After the trial, 64 (48.9%) women receiving Diclectin asked to continue compassionate use of their medication, as compared with 41 (32.8%) of placebo-treated women (P = .009). CONCLUSION: Diclectin delayed release formulation of doxylamine succinate and pyridoxine hydrochloride is effective and well tolerated in treating nausea and vomiting of pregnancy. PMID- 20843505 TI - Getting past first base: Going all the way with Cognitive Work Analysis. AB - This paper reports the application of Cognitive Work Analysis (CWA) to the problem of communications planning in military aviation. Applications of CWA rarely get beyond the first one or two phases; this paper presents an analysis in which all five phases have been completed. The method offers a formative description of the system, defining the set of boundaries and constraints that shape system activity in terms of work domain, recurring activities, decision making, social organisation and worker competency requirements. It is an analysis that is well suited to environments in which the occurrence of unanticipated events can have serious implications for both safety and productivity. Communications planning in military aviation is such an environment. The outputs of the analysis provided an extensive and exhaustive description of the system, highlighting the uneven spread of activity, across actors involved in communications planning and across the situations in which planning can occur. In addition, a new method for informing worker competency requirements based on abstract functions rather than specific decision steps is proposed and discussed in terms of job design, interface design, and person specification. PMID- 20843507 TI - Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability. AB - BACKGROUND: It was previously shown that antidepressants are associated with diminished vagal control over the heart. Longitudinal studies are needed to test the causality of this association further. METHODS: Longitudinal data were obtained in the Netherlands Study of Depression and Anxiety. At baseline and at 2 year follow-up, heart rate and cardiac vagal control as indexed by respiratory sinus arrhythmia were measured in 2114 subjects (mean age = 42.0 years; 66.2% female), who either used antidepressants at one or two time points (n = 603) or did not use antidepressants at any time point (n = 1511). Linear mixed-model analyses were conducted to compare changes in respiratory sinus arrhythmia and heart rate over time across antidepressant-naive subjects, subjects who started using an antidepressant during follow-up, subjects who stopped using an antidepressant, and persistent antidepressant users. Analyses were adjusted for demographics, health, and lifestyle factors. RESULTS: Compared with continuous nonusers, subjects who started the use of a tricyclic antidepressant or a serotonergic and noradrenergic antidepressant showed a significantly greater increase in heart rate and a decrease of respiratory sinus arrhythmia at 2 years. Subjects who started the use of selective serotonin reuptake inhibitors also showed a decrease in respiratory sinus arrhythmia, but their heart rate did not increase. Discontinuing antidepressants systematically caused opposite effects; levels returned in the direction of those observed among nonusers. CONCLUSIONS: These 2-year longitudinal results indicate that all antidepressants cause a decrease in cardiac vagal control. After discontinuing antidepressants, autonomic function recovers, suggesting that the unfavorable effects are (partly) reversible. PMID- 20843506 TI - Extreme thinking in clinically depressed adolescents: Results from the Treatment for Adolescents with Depression Study (TADS). AB - The purpose of this report is to examine relations between extreme thinking, as measured by the Dysfunctional Attitudes Scale, and the maintenance of gains among adolescents who participated in the Treatment for Adolescents with Depression Study (TADS). We examine extreme thinking among 327 adolescents (mean age=14.56, 57% female, 75% White) who received cognitive behavior therapy (CBT), fluoxetine (FLX), or a combination of CBT and FLX (COMB). Among those who met remission status on the Children's Depression Rating Scale - Revised (CDRS-R<=28; 56 at week 12, 79 at week 18) extreme thinking did not predict failure to maintain remission. This is in contrast to findings with depressed adults. Treatment influenced level of extreme thinking, and this appeared to be driven by greater endorsement of positively valenced beliefs as opposed to a decrease in negatively valenced beliefs. Developmental or investigation characteristics may account for the discrepancy in findings. PMID- 20843508 TI - Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing. AB - Delayed wound healing is a chronic problem in opioid drug abusers. We investigated the role chronic morphine plays on later stages of wound healing events using an angiogenesis model. Our results show that morphine treatment resulted in a significant decrease in inflammation induced angiogenesis. To delineate the mechanisms involved we investigate the role of hypoxia inducible factor 1 alpha (HIF-1 alpha), a potent inducer of angiogenic growth factor. Morphine treatment resulted in a significant decrease in the expression and nuclear translocation of HIF-1 alpha with a concurrent suppression in vascular endothelial growth factor (VEGF) synthesis. Cells of the innate immune system play a dominant role in the angiogenic process. Morphine treatment inhibited early recruitment of both neutrophils and monocytes towards an inflammatory signal with a significant decrease in the monocyte chemoattractant MCP-1. Taken together, our studies show that morphine regulates the wound repair process on multiple levels. Morphine acts both directly and indirectly in suppressing angiogenesis. PMID- 20843509 TI - Music, rhythm, rise time perception and developmental dyslexia: perception of musical meter predicts reading and phonology. AB - INTRODUCTION: Rhythm organises musical events into patterns and forms, and rhythm perception in music is usually studied by using metrical tasks. Metrical structure also plays an organisational function in the phonology of language, via speech prosody, and there is evidence for rhythmic perceptual difficulties in developmental dyslexia. Here we investigate the hypothesis that the accurate perception of musical metrical structure is related to basic auditory perception of rise time, and also to phonological and literacy development in children. METHODS: A battery of behavioural tasks was devised to explore relations between musical metrical perception, auditory perception of amplitude envelope structure, phonological awareness (PA) and reading in a sample of 64 typically-developing children and children with developmental dyslexia. RESULTS: We show that individual differences in the perception of amplitude envelope rise time are linked to musical metrical sensitivity, and that musical metrical sensitivity predicts PA and reading development, accounting for over 60% of variance in reading along with age and I.Q. Even the simplest metrical task, based on a duple metrical structure, was performed significantly more poorly by the children with dyslexia. CONCLUSIONS: The accurate perception of metrical structure may be critical for phonological development and consequently for the development of literacy. Difficulties in metrical processing are associated with basic auditory rise time processing difficulties, suggesting a primary sensory impairment in developmental dyslexia in tracking the lower-frequency modulations in the speech envelope. PMID- 20843510 TI - A quantitative assessment of the carcinogenicity of hexavalent chromium by the oral route and its relevance to human exposure. AB - BACKGROUND: Hexavalent chromium (Cr(6+)) has long been recognized as an inhalation carcinogen. Useful data on its carcinogenicity by ingestion have been slower to develop. The 2008 NTP chronic bioassay of sodium dichromate dihydrate in drinking water found clear evidence of carcinogenicity in rodents and allows a generalizable estimate of the human ingestion cancer potency of Cr(6+). OBJECTIVES: To estimate the human ingestion cancer potency of Cr(6+) and evaluate its relevance for human exposure. METHODS: Tumors of the small intestine in male mice were selected as the critical endpoint, for the derivation of cancer potency. Following the 2005 USEPA Cancer Risk Assessment Guidelines, the point of departure in the dose-response data was defined using benchmark-dose modeling. Linear extrapolation was carried out from the point of departure and interspecies dose conversion was based on allometric scaling of body weight. RESULTS: Small intestine tumor incidence in male mice provided a robust and nearly identical fit with most available dose-response models using benchmark-dose modeling. A human equivalent cancer slope factor of 0.5 (mg/kg/day)(-1) was derived based on linear extrapolation from the point of departure. Statistical and kinetic analysis carried out on the NTP data as well as data reported in other studies support that the carcinogenicity of Cr(6+) did not result from an exceedance of the reduction capacity of the mouse gastrointestinal tract at the doses in the NTP study. CONCLUSIONS: Mouse gastric emptying time and human Cr(6+) dosing studies strongly suggest that even at doses considerably lower than those in the NTP study, Cr(6+) escapes reduction in both the mouse and human stomachs due to kinetic competition from Cr(6+) absorption and gastric emptying. The cancer potency derived from the NTP data is, therefore, deemed to be relevant and applicable to human exposure. Cr(6+) is, therefore, identified as "likely to be carcinogenic to humans" in accordance with the USEPA's cancer characterization rubric. PMID- 20843511 TI - [Chronic obstructive pulmonary disease and type 2 diabetes mellitus]. PMID- 20843512 TI - Maintenance of normothermia during burn surgery with an intravascular temperature control system: a non-randomised controlled trial. AB - BACKGROUND: Hypothermia remains one of the major factors limiting surgery in extensively burned patients. We evaluated the effectiveness of an intravascular rewarming technique using CoolGard 3000TM system and IcyTM catheter to maintain normothermia during surgeries of severe burned patients and compared these findings to a historical control group. METHODS: This was a controlled non randomised trial conducted between March 2008 and August 2009. Patients with burns greater than or equal to 40% of the total body surface area were included. Before the first burn excision, the IcyTM catheter was placed in the inferior vena cava via the femoral vein. Warming was then initiated and maintained until the bladder temperature reached over 37.5 degrees C. The bladder temperature was recorded every 30min during surgery and for the first hour post-operatively and compared to a historical control group. RESULTS: We enrolled 4 patients and 11 surgeries in the CoolGardTM group and compared them to 3 patients and 10 surgeries in the historical cohort. All intraoperative bladder temperatures from T=30 were statistically different in the two groups. In the CoolGardTM group, no patient became hypothermic and no surgery was aborted because the patient's temperature had rapidly fallen below the threshold temperature (35.5 degrees C). No device-related complication was reported. CONCLUSION: The use of an intravenous warming catheter is a novel approach to maintain normothermia during surgery in burn victims and may be more effective than traditional methods. PMID- 20843513 TI - Myoglobin clearance by continuous venous-venous haemofiltration in rhabdomyolysis with acute kidney injury: a case series. AB - BACKGROUND: Clearance of circulating myoglobin is a critical measure to prevent further damage in patients with rhabdomyolysis (RM) and acute kidney injury (AKI). Continuous venous-venous haemofiltration has emerged to be a novel approach for this purpose. The objective of present study is to evaluate the efficacy and safety of CVVH in myoglobin clearance for patients with RM complicated with AKI. METHOD: We prospectively analysed 15 patients with acute RM and AKI due to crush syndrome (n=7), bee stings (n=5), polymyositis (n=2) and heroin poisoning (n=1). All of them presented oliguria with high serum myoglobin and creatine kinase concentration. They were treated by CVVH for at least 48h until the conditions turned to be stable, then replaced by intermittent renal replacement therapy (intermittent haemofiltration or haemodialysis). Meanwhile intravascular volume expansion, urinary alkalinisation, and forced diuresis were administered. During the procedure, serum and effluent concentrations of myoglobin and creatinine were measured simultaneously at 2, 6, 12 and 24h. RESULT: The mean sieving coefficients for myoglobin were 0.28+/-0.06, 0.21+/ 0.06, 0.15+/-0.02 and 0.11+/-0.02 during 2, 6, 12 and 24h of CVVH intervention, whilst mean clearance of myoglobin was 14.3+/-3.1ml/min during 2h and reduced to 11.5+/-3.2, 7.5+/-0.9, 5.6+/-1.0ml/min during 6, 12 and 24h. In contrast to myoglobin, the sieving coefficient for creatinine remained stable at 0.95+/-0.25, 1.02+/-0.12, 0.89+/-0.32, 0.98+/-0.27 during 24h of CVVH. In all of the 15 patients, serum myoglobin and creatine kinase were dramatically decreased in 24h (-56.2 and -32.1%), 3 days (-72.9 and -50.3%) and in 7 days (-97.6 and -96.7%). Seven patients (46.7%) complicated with hypophosphatemia during CVVH intervention improved in natural course after the cessation of CVVH. After 16+/-12 days, all of 15 patients came to polyuria stage and finally, discharged with normal renal function after 31+/-15 days. CONCLUSION: Our study showed CVVH can be employed to clear myoglobin effectively in patients with RM and AKI and presented oliguria. This indicate that CVVH would be better than other modes of renal replement treatment in acute RM with AKI because of the additional benefit of myoglobin removal, but large sample randomised controlled trials are still required to confirm it. PMID- 20843514 TI - Case report: Complications of using 'hinged' Kirschner wires for fixation of patellar tendon rupture. PMID- 20843515 TI - Inflammatory markers, lipoprotein components and risk of major cardiovascular events in 65,005 men and women in the Apolipoprotein MOrtality RISk study (AMORIS). AB - BACKGROUND AND AIMS: In contrast to lipoprotein components, few studies have analysed the importance of a combination of commonly available inflammatory markers as predictors of major cardiovascular events (MACE) in large healthy populations. We examined summary scores of inflammation and compared their predictive strength with that of lipoproteins in the Apolipoprotein MOrtality RISk (AMORIS) Study. METHOD AND RESULTS: Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 65,050 subjects with mean follow-up time of 11.8 years, we studied the association between lipoproteins, inflammatory markers and risk of acute myocardial infarction (AMI), stroke and heart failure. An inflammatory score was measured as the number of inflammatory variables (white blood cell count, haptoglobin and in a subgroup CRP) in their upper quartile or as a continuous summary score. All analyses were conducted with multivariate Cox proportional hazards analysis. The inflammatory scores added predictive information over and above classical lipids such as total cholesterol and triglycerides. Compared to the apolipoprotein B (apoB)/apolipoprotein A-1 (apoA-1) ratio, a stronger marker of CVD risk than conventional lipids, the inflammatory score added some discrimination value measured by net reclassification improvement, but added more within higher risk strata. No statistically significant biological interaction was found between lipoproteins and inflammatory markers. CONCLUSION: The inflammation score and lipoproteins, including apoB and apoA-I, carry important and at least additive predictive information for risk of MACE. Routinely used markers of inflammation could be used in daily medical practice to assess cardiovascular risk. PMID- 20843516 TI - Differences in the predictive value of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in advanced ischemic and non-ischemic heart failure. AB - OBJECTIVE: To assess the prognostic value of the pro-apoptotic, but also cell growth-inducing molecule soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) in heart failure (HF). METHODS: We assayed sTWEAK levels in 351 patients with advanced HF (non-ischemic: 130, ischemic: 221). During a median follow-up of 4.9 years, 195 patients (56%) died. RESULTS: sTWEAK concentrations were associated with extended survival in patients with non-ischemic (P=0.022), but not with ischemic HF (P=0.82). The inverse association in non-ischemic HF remained significant in a multivariable Cox regression model (P=0.025) with a hazard ratio of 0.40 (95% confidence interval: 0.21-0.77) comparing the third to the first tertile (P=0.007). CONCLUSION: Low sTWEAK levels independently predict mortality in advanced non-ischemic HF. sTWEAK-induced proliferation of cardiomyocytes may explain its impact on suvival. The different prognostic value of sTWEAK in ischemic and non-ischemic HF may point towards distinct pathogenic pathways determining the course of disease. PMID- 20843517 TI - A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice. AB - Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1) plays an essential role in macrophage foam cell formation and progression of atherosclerosis. We developed a potent and selective ACAT-1 inhibitor, K-604, and tested its effects in apoE-knockout mice. Administration of K-604 to 8-week-old apoE-knockout mice for 12 weeks at a dose of 60 mg/kg/day significantly reduced macrophage-positive area and increased collagen-positive area in atherosclerotic plaques in the aorta without affecting plasma cholesterol levels or lesion areas, indicating direct plaque-modulating effects of K-604 on vascular walls independent of plasma cholesterol levels. Pactimibe, a nonselective inhibitor of ACAT-1 and ACAT-2, reduced plasma cholesterol levels but did not affect macrophage- or collagen positive areas. The size of macrophages and cholesteryl ester contents in the aorta were reduced by K-604. Exposure of cultured human aortic smooth muscle cells to K-604 resulted in increased procollagen type 1 contents in the culture supernatant and increased procollagen type 1 mRNA levels. Procollagen production was unaffected by pactimibe even at a concentration that inhibited cholesterol esterification to the basal level. Thus, the plaque-modulating effects of K-604 can be explained by stimulation of procollagen production independent of ACAT inhibition in addition to potent inhibition of macrophage ACAT-1. PMID- 20843518 TI - DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK dependent MMP-1 expression by U937 histiocytes. AB - Dipeptidyl peptidase-4 (DPP-4)/CD26, a cell surface glycoprotein, is expressed by a variety of cells including T cells, B cells, NK cells, and macrophages. Although it has been shown that DPP-4/CD26 is involved in T cell activation, its role in biological functions in macrophages has not been well investigated. In this study, we used alogliptin, a specific inhibitor of DPP 4/CD26, to study the effect of DPP-4/CD26 on the activation of the extracellular signal-regulated kinase (ERK) that plays a critical role in the expression of proinflammatory cytokines and matrix metalloproteinases (MMPs) in U937 histiocytes. Results showed that 1nM of alogliptin inhibited ERK phosphorylation induced by lipopolysaccharide (LPS), a ligand for toll-like receptor (TLR)4, by 91%. Furthermore, results showed that alogliptin inhibited LPS-stimulated MMP-1 expression in a concentration-dependent manner and 1nM of alogliptin inhibited MMP-1 expression by 60%. To confirm the involvement of the ERK pathway in MMP-1 expression by U937 cells, we showed that PD98059, a specific inhibitor for the ERK pathway, blocked LPS-stimulated MMP-1 expression. In addition to MMP-1, our study showed that alogliptin also inhibited MMP-9, -12 and -15, but had no effect on TIMP-1 and -2 expression. Taken together, this study showed for the first time that the inhibition of DPP-4/CD26 by alogliptin suppressed TLR4-mediated ERK activation and ERK-dependent MMP expression by U937 cells, suggesting that DPP 4/CD26 may play an important role in macrophage-mediated inflammation response and tissue remodeling. PMID- 20843519 TI - Liquid-liquid microextraction methods based on ultrasound-assisted emulsification and single-drop coupled to gas chromatography-mass spectrometry for determining strobilurin and oxazole fungicides in juices and fruits. AB - Two procedures are proposed based on ultrasound-assisted emulsification and single-drop liquid-liquid microextraction for the sensitive determination of seven strobilurin and six oxazole fungicides in fruits and juice samples. Both miniaturized techniques are coupled to gas chromatography with mass spectrometry in the selected ion monitoring mode, GC-MS(SIM). The procedures use low density organic solvents, and several factors influencing the emulsification, extraction and collection efficiency are optimized. The detection limits obtained at a signal-to-noise ratio of 3 are below the MRLs set by the European Commission. Enrichment factors are between 140-1140 for the first technique used and 80-1600 for the latter. The recoveries obtained for spiked samples are satisfactory for all compounds. The methods are validated according to the Commission Decision 2002/657/EC. Different fruit and juices are analyzed by the proposed method and none of the samples contained fungicide residues above the detection limits. PMID- 20843520 TI - Impurity profiling of acetylspiramycin by liquid chromatography-ion trap mass spectrometry. AB - Investigation of acetylspiramycin (ASPM) and its related substances was carried out using a reversed-phase liquid chromatography/tandem mass spectrometry method. The identification of impurities in the ASPM complex was performed with a quadrupole ion trap mass spectrometer, with an electrospray ionization (ESI) source in the positive ion mode which provides MS(n) capability. A total of 83 compounds were characterized in commercial samples, among which 31 impurities that had never been reported and 31 partially characterized impurities were deduced using the collision-induced dissociation (CID) spectra of major ASPM components as templates. Most of the major impurities arise from the starting materials and the synthesis process. This work provides very useful information for quality control of ASPM and evaluation of its synthesis process. PMID- 20843521 TI - Current-dependent anisotropic conductivity of locally assembled silver nanoparticles in hybrid polymer films. AB - The electrical behaviour of hybrid poly(ethylene terephthalate) films containing localised, percolating networks of silver nanoparticles separated by pure polymer is studied. The films resemble an array of parallel wires in the submicron range and, thus, exhibit anisotropic conductivity. In the high-conductivity direction at low amplitudes, the films show Ohmic behaviour, while at moderate voltage, non linearity and a decreasing resistance is observed. The samples were found to heat up during the measurements and the deviation from Ohm's law coincides with the Tg of the polymer. Microstructural analysis of the samples revealed an irreversible agglomeration of the particles at moderate voltages leading to the formation of filaments with higher metallic character than the random particle network. PMID- 20843522 TI - Further advancements in predicting adsorption equilibria using excess formalism: calculation of adsorption excesses at the liquid/solid interface. AB - Prediction of adsorption equilibria for ternary liquid mixtures on solid surfaces by means of adsorption data for the corresponding three binary liquid mixtures can be improved by combining the thermodynamic excess formalism with geometrical models. This new strategy for the prediction of excess adsorption isotherms is examined for four ternary adsorption systems ranging from ideal to highly non ideal ternary mixtures. The predicted isotherms are discussed and compared with experimental ones as well as with those obtained for a model based on the absolute quantities. The results confirm: (i) superiority of predicting adsorption in terms of excess quantities, and (ii) utility of geometrical models for constructing ternary molar compositions on the basis of binary ones to predict equilibria not only for liquid mixtures alone but also for adsorption of liquid mixtures on solid surfaces. PMID- 20843523 TI - Impaired glucose absorption in children with severe malnutrition. AB - OBJECTIVE: To quantify intestinal glucose absorption in children with two types of severe malnutrition, kwashiorkor and marasmus, compared with healthy children. STUDY DESIGN: Children with kwashiorkor (n = 6) and marasmus (n = 9) and control subjects (n = 3) received a primed (13 mg/kg), constant infusion (0.15 mg/kg/min) of [6,6H2]glucose for 4.5 hours. Two hours after start of the infusion an oral bolus of glucose 1.75 g/kg labeled with [U-13C]glucose 10 mg/g was given and was followed by periodic blood sampling. Mathematical modeling was applied to determine oral glucose absorption. RESULTS: Median total glucose absorption was 5.9 mmol/kg, interquartile range (IQR) 4.5-6.7 mmol/kg and 4.4 (IQR 2.9-5.9) mmol/kg in children with kwashiorkor and marasmus compared with 7.7 (IQR 5.8-9.0) mmol/kg in control subjects; P = .03 compared with marasmus). Children with the lowest glucose absorption were found specifically in the kwashiorkor group and marasmic children with hypoalbuminemia. Severe impairment in absorption correlated with urinary 8-hydroxydeoxyguanosine secretion (r = -0.62, P = .01). CONCLUSIONS: Severe malnutrition is associated with an impaired glucose absorption and decreased glucose absorption correlates with oxidative stress in these children. PMID- 20843524 TI - Delayed wound healing in leukocyte adhesion deficiency type 1. PMID- 20843525 TI - Prevalence and distribution of the c.1436C->T sequence variant of carnitine palmitoyltransferase 1A among Alaska Native infants. AB - OBJECTIVES: To use genotype analysis to determine the prevalence of the c.1436C >T sequence variant in carnitine palmitoyltransferase 1A (CPT1A) among Alaskan infants, and evaluate the sensitivity of newborn screening by tandem mass spectrometry (MS/MS) to identify homozygous infants. STUDY DESIGN: We compared MS/MS and DNA analyses of 2409 newborn blood spots collected over 3 consecutive months. RESULTS: Of 2409 infants, 166 (6.9%) were homozygous for the variant, all but one of whom were of Alaska Native race. None of the homozygous infants was identified by MS/MS on the first newborn screen using a C0/C16 + C18 cutoff of 130. Among 633 Alaska Native infants, 165 (26.1%) were homozygous and 218 (34.4%) were heterozygous for the variant. The prevalence was highest in Alaska's northern/western regions (51.2% of 255 infants homozygous; allele frequency, 0.7). CONCLUSIONS: The CPT1A c.1436C->T variant is prevalent among some Alaska Native peoples, but newborn screening using current MS/MS cutoffs is not an effective means to identify homozygous infants. The clinical consequences of the partial CPT1A deficiency associated with this variant are unknown. If effects are substantial, revision of newborn screening, including Alaska-specific MS/MS cutoffs and confirmatory genotyping, may be needed. PMID- 20843526 TI - The need for quality improvement in sweat testing infants after newborn screening for cystic fibrosis. AB - The proportion of insufficient sweat tests after positive newborn screening for cystic fibrosis was determined. Infants <= 3 months old had a mean (+/- standard deviation) rate of 7.2% (+/- 7.6) (range, 0% to 40%). Collection methods did not affect the rates. The high and variable rates indicate a need for quality improvement. PMID- 20843527 TI - Neonatal lupus. PMID- 20843528 TI - Trypanosome infections of marine fish in the southern Barents Sea and the invasive red king crab Paralithodes camtschaticus. AB - The red king crab Paralithodes camtschaticus was introduced to the Barents Sea from the North Pacific in the 1960s. A previous study concluded that it may be indirectly responsible for increased transmission of Trypanosoma murmanense to cod Gadus morhua in the southern Barents Sea by promoting an increase in the population of the leech vector Johanssonia arctica. Eleven species of fish, totalling 681 individuals, caught in October 2002 along the coast of Finnmark, were examined for trypanosome infections. The aims were to investigate changes in levels of infection in cod since 1999-2001, and to extend the sampling to other fish species. Relatively high infection levels were found in cod, haddock Melanogrammus aeglefinus and long rough dab Hippoglossoides platessoides, while other species were lightly infected or uninfected. In cod, no significant geographical differences in levels of infection were found, but haddock were significantly more heavily infected in western Finnmark. PMID- 20843529 TI - Doubly linked, A-type proanthocyanidin trimer and other constituents of Ixora coccinea leaves and their antioxidant and antibacterial properties. AB - Phytochemical investigation of the ethyl acetate fraction of the methanol extract of the leaves of Ixora coccinea led to the isolation and identification of an A type trimeric proanthocyanidin epicatechin-(2beta->O->7, 4beta->8)-epicatechin-(5 >O->2beta, 6->4beta)-epicatechin named ixoratannin A-2 along with seven known compounds, epicatechin, procyanidin A2, cinnamtannin B-1, and four flavon-3-ol rhamnosides viz: kaempferol-7-O-alpha-L-rhamnnoside, kaempferol-3-O-alpha-L rhamnoside, quercetin-3-O-alpha-L-rhamnopyranoside, and kaempferol-3,7-O-alpha-L dirhamnoside. The structures were elucidated by the application of IR, UV, MS, 1D , and 2D-NMR spectroscopic analyses and by comparison with literature data. Antioxidant evaluation of isolated compounds revealed that ixoratannin A-2 and cinnamtannin B-1 were the most active compounds in DPPH, inhibition of lipid peroxidation and nitric oxide radical scavenging assays. Antibacterial activities were assessed by means of agar-diffusion assays using Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Bacillus subtilis. All tested compounds inhibited the growth of B. subtilis, while only epicatechin and quercetin-3-O-alpha-L-rhamnopyranoside inhibited the growth of E. coli. PMID- 20843530 TI - Sulfur-containing constituents and one 1H-pyrrole-2-carboxylic acid derivative from pineapple [Ananas comosus (L.) Merr.] fruit. AB - Two sulfur-containing compounds, (S)-2-amino-5-((R)-1-carboxy-2-((E)-3-(4-hydroxy 3-methoxyphenyl)allylthio)ethyl-amino)-5-oxopentanoic acid (1) and (S)-2-amino-5 ((R)-1-(carboxymethylamino)-3-((E)-3-(4-hydroxyphenyl)allylthio)-1-oxopropan-2 ylamino)-5-oxopentanoic acid (2), and one 1H-pyrrole-2-carboxylic acid derivative, 6-(3-(1H-pyrrole-2-carbonyloxy)-2-hydroxypropoxy)-3,4,5-trihydroxy tetrahydro-2H-pyran-2-carboxylic acid (3), together with eighteen known phenolic compounds, were isolated from the fruits of pineapple. Their structures were elucidated by a combination of spectroscopic analyses. Some of these compounds showed inhibitory activities against tyrosinase. The half maximal inhibitory concentration values of compounds 1, 4, 5, 6, 7 are lower than 1 mM. These compounds may contribute to the well-known anti-browning effect of pineapple juice and be potential skin whitening agents in cosmetic applications. PMID- 20843531 TI - Impact of environmental discourses on public health policy arrangements: a comparative study in the UK and Flanders, (Belgium). AB - OBJECTIVES: Theoretically inspired by discursive institutionalism and multi-level governance, this paper assesses the extent to which 'environmental health' has emerged as a new discourse at European level, the effects it has had on national public health governance in two European countries, and what mechanisms have triggered or hindered these effects. STUDY DESIGN: Comparison of the dynamics in public health policy arrangements in Flanders (Belgium) and the UK, nations influenced by both international and European environmental health discourses. METHODS: The Policy Arrangement Approach was the analytical framework used to structure the results of this textual analysis. RESULTS: Despite their shared focus on environmental health, Belgium and the UK display quite different approaches to environmental health governance. While Belgium works on environmental health in a predominantly top-down approach, the UK has developed a more inward-facing approach to environmental health policies. CONCLUSION: The cases of the UK and Belgium show that, although these countries respond similarly to internationally agreed charters and both are members of the European Union, national differences in environmental health policies persist, mainly due to pre existing national policy arrangements and the activities of national institutions. This leads to a divergent interplay between national and international institutions. PMID- 20843532 TI - Antiretroviral therapy abrogates association between arginase activity and HIV disease severity. AB - Arginase-induced L-arginine deprivation is emerging as a key mechanism for the downregulation of immune responses. We hypothesised that arginase activity increases with disease severity in HIV-seropositive patients. Our results show that peripheral blood mononuclear cells (PBMCs) from 23 HIV-seropositive patients with low CD4(+) T cell counts (<=350 cells/MUl) expressed significantly more arginase compared with 21 patients with high CD4(+) T cell counts. Furthermore, we found a significant association between the two principal prognostic markers used to monitor HIV disease (CD4(+) T cell count and plasma viral load) and PBMC arginase activity in antiretroviral therapy naive patients but not in patients undergoing therapy. PMID- 20843533 TI - Simultaneous evaluation of ultrasound velocity, attenuation and density of polymer solutions observed by multi-echo ultrasound spectroscopy. AB - Ultrasound spectroscopy is a powerful tool to investigate the viscoelastic properties of materials. The longitudinal elastic moduli M' and M("), or the adiabatic compressibility kappa(S) can be evaluated from ultrasound velocity v and attenuation coefficient alpha via the relation M'=rhov(2) and M(")=2rhoalphav(3)/omega, where rho is the density and omega is the angular frequency. So far, the density was independently measured by other equipments or its variation during the chemical reaction has been ignored in the previous literatures. Here we propose a multiple echo method to simultaneously evaluate alpha, v, rho, from a single acquisition, enabling us to monitor the polymerization process of acrylamide, where the three parameters vary independently during the reaction. This allows us to analyze the time evolution of the acoustic parameters for polymeric or gelling systems with the better understanding. PMID- 20843534 TI - Addressing uncertainty in fecal indicator bacteria dark inactivation rates. AB - Assessing the potential threat of fecal contamination in surface water often depends on model forecasts which assume that fecal indicator bacteria (FIB, a proxy for the concentration of pathogens found in fecal contamination from warm blooded animals) are lost or removed from the water column at a certain rate (often referred to as an "inactivation" rate). In efforts to reduce human health risks in these water bodies, regulators enforce limits on easily-measured FIB concentrations, commonly reported as most probable number (MPN) and colony forming unit (CFU) values. Accurate assessment of the potential threat of fecal contamination, therefore, depends on propagating uncertainty surrounding "true" FIB concentrations into MPN and CFU values, inactivation rates, model forecasts, and management decisions. Here, we explore how empirical relationships between FIB inactivation rates and extrinsic factors might vary depending on how uncertainty in MPN values is expressed. Using water samples collected from the Neuse River Estuary (NRE) in eastern North Carolina, we compare Escherichia coli (EC) and Enterococcus (ENT) dark inactivation rates derived from two statistical models of first-order loss; a conventional model employing ordinary least-squares (OLS) regression with MPN values, and a novel Bayesian model utilizing the pattern of positive wells in an IDEXX Quanti-Tray(r)/2000 test. While our results suggest that EC dark inactivation rates tend to decrease as initial EC concentrations decrease and that ENT dark inactivation rates are relatively consistent across different ENT concentrations, we find these relationships depend upon model selection and model calibration procedures. We also find that our proposed Bayesian model provides a more defensible approach to quantifying uncertainty in microbiological assessments of water quality than the conventional MPN-based model, and that our proposed model represents a new strategy for developing robust relationships between environmental factors and FIB inactivation rates, and for reducing uncertainty in water resource management decisions. PMID- 20843535 TI - Cellular and molecular osmoregulatory responses to cadmium exposure in Gammarus fossarum (Crustacea, Amphipoda). AB - Osmoregulation represents a reliable indicator of the physiological state of crustaceans. It is mainly effected in gills via Na(+)/K(+)-ATPase (NKA) providing the major driving force for ion transport. In the present study conducted in the freshwater amphipod Gammarus fossarum, the impact of an exposure to 15 MUg Cd L( 1) for 3 and 7d was investigated on the haemolymph osmolality (HO), gill structure, NKA localization in gills and its relative expression. In Cd-exposed G. fossarum, mean HO significantly decreased compared to controls. In animals exposed for 3 and 7d, high inter-individual variations in HO values were noted, resulting in their separation into unimpacted, slightly impacted and impacted animals. In unimpacted individuals, gills retained their organization, showing a thicker gill epithelium than in controls; NKA fluorescence was continuously observed along the gill epithelium and was distributed on a broader area than in controls. In slightly impacted individuals, a thinner epithelium, a slight collapse of the gill and a lower NKA fluorescence were observed compared to unimpacted specimens. In impacted individuals, dramatic alterations of the gill structure, including hyperplasia and alteration of the pillars, resulting in the collapse of the gill and the disappearance of the haemolymphatic canals were observed, as well as very limited NKA fluorescence. Therefore, the degree of gill alteration and the intensity of NKA fluorescence observed in the different groups were correlated with their respective HO levels. The relative amount of the NKA alpha-subunit mRNA significantly increased in specimens exposed to Cd for 3d compared to controls, and then returned to control level after 7d. The relationships between the changes in HO values, NKA immunostaining and mRNA relative expression are discussed. These results confirm that HO represents a valuable biomarker to evaluate crustacean health, and they underline the interest to assess individual responses to contaminants. PMID- 20843536 TI - Observation of an unusual electronically distorted semiquinone radical of PCB metabolites in the active site of prostaglandin H synthase-2. AB - The activation of the metabolites of airborne polychlorinated biphenyls (PCBs) into highly reactive radicals is of fundamental importance. We found that human recombinant prostaglandin H synthase-2 (hPGHS-2) biotransforms dihydroxy-PCBs, such as 4-chlorobiphenyl-2',5'-hydroquinone (4-CB-2',5'-H(2)Q), into semiquinone radicals via one-electron oxidation. Using electron paramagnetic resonance (EPR) spectroscopy, we observed the formation of the symmetric quartet spectrum (1:3:3:1 by area) of 4-chlorobiphenyl-2',5'-semiquinone radical (4-CB-2',5'-SQ()( )) from 4-CB-2',5'-H(2)Q. This spectrum changed to an asymmetric spectrum with time: the change can be explained as the overlap of two different semiquinone radical species. Hindered rotation of the 4-CB-2',5'-SQ()(-) appears not to be a major factor for the change in lineshape because increasing the viscosity of the medium with glycerol produced no significant change in lineshape. Introduction of a fluorine, which increases the steric hindrance for rotation of the dihydroxy PCB studied, also produced no significant changes. An in silico molecular docking model of 4-CB-2',5'-H(2)Q in the peroxidase site of hPGHS-2 together with ab initio quantum mechanical studies indicate that the close proximity of a negatively charged carboxylic acid in the peroxidase active site may be responsible for the observed perturbation in the spectrum. This study provides new insights into the formation of semiquinones from PCB metabolites and underscores the potential role of PGHS-2 in the metabolic activation of PCBs. PMID- 20843537 TI - Organochlorine pesticides (OCPs), dioxin-like polychlorinated biphenyls (dl PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo furans (PCDD/Fs) in edible fish from Lake Volta, Lake Bosumtwi and Weija Lake in Ghana. AB - Organochlorine pesticides (OCPs), dioxin-like polychlorinated biphenyls (dl PCBs), polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo furans (PCDD/Fs) were measured by a high resolution gas chromatograph-high resolution mass spectrometer (HRGC/HRMS) in selected edible fish from three freshwater bodies, Lake Volta, Lake Bosumtwi and Weija Lake in Ghana. The levels of organochlorine pesticides measured in this study were generally low. The highest concentration of OCPs was measured for dichlorodiphenyltrichloroethane compounds (DDTs) (p,p'-DDT, o,p'-DDT, p,p'-DDE, o,p'-DDE, p,p'-DDD and o,p'-DDD), followed by chlordane compounds (CHLs) (trans-chlordane, cis-chlordane, trans-nonachlor and cis-nonachlor), hexachlorobenzene (HCB) and gamma-hexachlorocyclohexane (gamma-HCH). The relatively high ratio of p,p'-DDT/p,p'-DDE in tilapia and catfish with an extremely high value in catfish purchased from a local market at Madina, a suburb of Accra, however, suggests the fresh contamination of technical DDT in Ghana. Although PCDD/Fs and dl-PCBs showed relatively low levels, the concentrations are, however, comparable with recent data of some developed countries. There is a potential health risk from DDTs, PCDD/Fs and dl-PCBs for the general population of Ghana because fish is one of their important protein sources. It is therefore necessary to estimate the total intake of DDTs, PCDD/Fs and dl-PCBs, and to assess the health risks for the general population of Ghana. PMID- 20843538 TI - A source mixing model to apportion PAHs from coal tar and asphalt binders in street pavements and urban aquatic sediments. AB - Present-day and more than 30 years old road and footpath pavements from Auckland, New Zealand were analysed for PAHs to test the hypothesis that coal tar based pavement binders contribute to unusually high PAH concentrations in adjacent stream and estuarine sediments. Total PAH (?(28)PAH) concentrations in the dichloromethane-soluble fraction ("binder"), comprising 5-10% of pavement mass, were as high as 200,000 mgkg(-1) (10,000 mgkg(-1) in binder+aggregate). Older and deeper pavement layers were strongly pyrogenic, whereas pavement layers from recently sealed roads had a more petrogenic composition and more than 1000 times lower ?(28)PAH concentrations. Source identification analysis using three PAH isomer ratio pairs (benz(a)anthracene/(benz(a)anthracene+chrysene); benzo(a)pyrene/(benzo(a)pyrene+benzo(e)pyrene); and indeno(1,2,3 cd)pyrene/(indeno(1,2,3-cd)pyrene+benzo(g,h,i)perylene) revealed low PAH (bitumen) pavements to have consistently lower isomer ratios than high PAH (coal tar) samples. Moreover, pavement data for one isomer ratio (e.g. benzo(a)pyrene/(benzo(a)pyrene+benzo(e)pyrene) were highly correlated with those of another isomer ratio (e.g. benz(a)anthracene/(benz(a)anthracene+chrysene) and were bounded at their lower and higher extremes by the characteristics of pure bitumen and coal tar, respectively, suggesting that PAH composition of a given pavement sample could be accounted for by conservative mixing between coal tar and bitumen as source materials. A concentration-weighted mixing model, with coal tar and bitumen as source materials, explained more than 80% of the variance in isomer ratios and enveloped the entire PAH compositional and concentration range encountered. PAH composition and concentrations in adjacent stream sediments (> 15 mgkg(-1) dry weight) were consistent with diluted coal tar material as a principal PAH source. Due to the very high PAH concentrations of coal tar, a coal tar content of as little as 0.01% of total sediment mass can account for more than 90% of PAH concentrations in adjacent stream sediments. PMID- 20843539 TI - Dynamic changes of alpha-hexachlorocyclohexane and its enantiomers in various tissues of Japanese Rabbits (Oyctolagus cuniculus) after oral or dermal exposure. AB - Japanese Rabbits (Oyctolagus cuniculus) were exposed to alpha hexachlorocyclohexane (alpha-HCH) either orally or dermally and concentrations of alpha-HCH and its two enantiomers were measured at different time intervals in the blood, intestine, liver, kidney, fat, brain, and muscle. The time trends were quantified using toxicokinetic models. It was found that absorption and elimination of alpha-HCH in blood were first-order processes which can be characterized by a single compartmental kinetic model. The absorption of dermally exposed alpha-HCH in blood was more than one order of magnitude faster than that of orally exposed alpha-HCH. The transport of alpha-HCH from the blood to other tissues was characterized using a two-compartment model. The accumulation rates were different among tissues depending on blood flow rate and fat content. Significant correlation was revealed between alpha-HCH concentration and fat content for various tissues either before or 1 d after the exposure. However, there was no such correlation at 10 min immediately after the exposure. The enantiomeric fraction (EF) of alpha-HCH in rabbit blood was nearly racemic before the exposure and increased to 0.73 and 0.82 after oral or dermal exposure, respectively. The result of a toxicokinetic modeling suggested that the strong enantioenrichment of (+)-alpha-HCH was primarily because the elimination rate of (-)-alpha-HCH was more than two times higher than that of (+)-alpha-HCH. The EFs for other tissues also increased dramatically after the exposure and the EFs in brain reached as high as 0.99 due to enantioselective transport across the blood brain barrier. PMID- 20843540 TI - Determination of anthropogenic and biogenic compounds on atmospheric aerosol collected in urban, biomass burning and forest areas in Sao Paulo, Brazil. AB - This study was conducted at three sites of different characteristics in Sao Paulo State: Sao Paulo (SPA), Piracicaba (PRB) and Mata Atlantica Forest (MAT). PM(10), n-alkanes, pristane and phytane, PAHs, water-soluble ions and biomass burning tracers like levoglucosan and retene, were determined in quartz fiber filters. Samplings occurred on May 8th to August 8th, 2007 at the MAT site; on August 15th to 29th in 2007 and November 10th to 29th in 2008 at the PRB site and, March 13th to April 4th in 2007 and August 7th to 29th in 2008 at the SPA site. Aliphatic compounds emitted biogenically were less abundant at the urban sites than at the forest site, and its distribution showed the influence of tropical vascular plants. Air mass transport from biomass burning regions is likely to impact the sites with specific molecular markers. The concentrations of all species were variable and dependent of seasonal changes. In the most dry and polluted seasons, n-alkane and cation total concentrations were similar between the megacity and the biomass burning site. PAHs and inorganic ion abundances were higher at Sao Paulo than Piracicaba, yet, the site influenced by biomass burning seems to be the most impacted by the organic anion abundance in the atmosphere. Pristane and phytane confirm the contamination by petroleum residues at urban sites; at the MAT site, biological activity and long range transport of pollutants might influence the levels of pristane. PMID- 20843542 TI - Sustained clinical response in psoriatic arthritis patients treated with anti-TNF agents: a 5-year open-label observational cohort study. AB - OBJECTIVE: To investigate the efficacy, toxicity, and drug discontinuation in patients with psoriatic arthritis treated with anti-tumor necrosis factor agents. METHODS: Sixty-five patients with active disease were included in this open-label study. They had tender or swollen joint count >=5, Psoriatic Arthritis Severity Index (PASI) score >=10, and erythrocyte sedimentation rate >=28 mm Hg/1st hour and/or C-reactive protein >=10 mg/L. All were refractory to at least 2 disease modifying antirheumatic drugs. Thirty were treated with infliximab, 25 with etanercept, and 10 with adalimumab. Infliximab (5 mg/kg body weight) was given intravenously at weeks 0, 2, 6, and every 8 weeks thereafter; etanercept was given subcutaneously (25 mg twice a week), while adalimumab was given subcutaneously (40 mg every other week) for a period of 5 years. Data concerning anti-tumor necrosis factor efficacy tolerability, adverse events, and drug discontinuation were recorded. The percentage of patients who achieved the Psoriatic Arthritis Response Criteria (PSARC), the improvement of PASI, the improvement according to the American College of Rheumatology (ACR) criteria, and the disease activity for 28 joint indices score (DAS-28) were recorded. RESULTS: After 5 years, PSARC was 60%, PASI 70 was 66.7%, PASI 90 was 63.3%, while ACR 50 was 56.7% for the patients treated with infliximab. Moreover, PsARC was 64%, PASI 70 and PASI 90 were 68%, while ACR 50 was 56% for those treated with etanercept. Furthermore, in the adalimumab group PsARC was 56%, PASI 70 and PASI 90 were 58% and 50%, respectively, while ACR 50 was 50%. Additionally, DAS-28 scores were significantly improved. Thirteen patients treated with infliximab, 6 with etanercept, and 5 patients with adalimumab were withdrawn. At the end of treatment, the survival of infliximab was 56.7%, for etanercept 76%, and for adalimumab 50%. CONCLUSION: All drugs were effective, safe, and well-tolerated. The clinical improvement was maintained through the 5 years with satisfying infliximab and adalimumab survival and high etanercept survival. PMID- 20843541 TI - Aspergillus fumigatus joint infection: a review. AB - OBJECTIVES: To describe a case of joint infection by Aspergillus fumigatus in a unusual site (sacroiliac) and perform a systematic review of such cases described in the literature. METHODS: We performed a Medline search of the cases of fungal joint of Aspergillus fumigatus in the period ranging from 1970 to 2009. RESULTS: Following PRISMA Guidelines, 15 cases including ours were reported during this period. Stem cell and solid organ transplantation, hematologic malignancy, and intra-articular steroids injection were the medical conditions found in such patients. The knee followed by the shoulder were the joints more affected. In the cases where synovial fluid analyses were reported, elevated cell count numbers could be found with a predominance of polymorphonuclear neutrophils. CONCLUSIONS: Fungal joint arthritis is a rare clinical disease most frequently present in immuno-incompetent patients. Rheumatologists should be aware of this condition, where early diagnosis can be associated with good prognosis. PMID- 20843543 TI - Monitoring platelet dependent thrombin generation in mice. AB - Calibrated automated thrombin generation assay was adapted to measure thrombin generation in platelet rich plasma from mice. Vena cava phlebotomy appeared the best technique for blood sampling. The concentration-effect curves of tissue factor and platelet count have been determined. Corn trypsin inhibitor 2MUM inhibits contact activation effectively. Recombinant human thrombomodulin does not inhibit thrombin generation in mouse plasma but activated protein C (20nM) does. Thrombin generation was dose dependently diminished by low molecular weight heparin and increased by high concentrations of exogenous factor VIII i.e. the assay can detect both hypo- and hypercoagulability. PMID- 20843544 TI - Receptor for activated C kinase (RACK) and protein kinase C (PKC) in egg activation. AB - In somatic cells, translocation of PKCs is facilitated by receptor for activated C kinase (RACK); however its involvement in egg activation is still elusive. We have followed the translocation pattern of conventional and novel PKCs (cPKCs and nPKCs, respectively) upon egg activation. Confocal microscopy indicated the expression and localization of RACK1, a specific receptor protein for cPKCs. Activation of MII eggs, led to translocation to the egg cortex of PKCalpha, betaII and delta and the co-translocation of RACK1, with both PKCalpha and PKCbetaII. The association of PKC and actin, both known to be involved in cortical granules exocytosis (CGE) with RACK1, was demonstrated by co immunoprecipitation. Egg activation resulted in an increased RACK1 level along with a decreased level of PKCbetaII. Based on these results, we suggest that upon egg activation, RACK1 shuttles activated cPKCs to the egg cortex, thus facilitating CGE. PMID- 20843545 TI - Positive and negative romantic relationship quality: age, familiarity, attachment and well-being as correlates of couple agreement and projection. AB - Capturing the multiple aspects of the romantic peer context is a significant challenge for research. One often recommended option is to use reports of multiple relationship features from both members of the romantic dyad. Using a new measure, we extended an existing model of dyadic perception (Kenny & Acitelli, 2001) to investigate associations between couples' (N = 148) reports about the positive and negative dimensions of their romantic relationships. Differences by participant age and relationship length were examined to test developmental hypotheses, and attachment and well-being were examined as correlates of participants' romantic perceptions. Agreement between partners was low, but associations of individuals' reports about themselves and their partners were high (projection). Agreement about negative romantic behaviors was higher in older compared to younger individuals and agreement about positive behaviors was higher in longer compared to shorter relationships. Partner similarity in negative behavior was higher than similarity in positive behavior. Individuals with better well-being reported more positive romantic behaviors, and attachment security was associated in some cases. Males were more negative about romantic behaviors than females, but there was no gender difference in agreement or projection. PMID- 20843546 TI - Self-reported internalization symptoms and family factors in indigenous Sami and non-Sami adolescents in North Norway. AB - Through differences in family socialization between indigenous and non-indigenous youth, there may be cultural differences in the impact of family factors on mental health outcome. Using structural equation modelling, this population-based study explored the relationship between symptoms of anxiety and depression and family factors in indigenous Sami and non-Sami boys and girls in North Norway. The findings show that family income was to a lesser degree related to internalization symptoms for Sami youth than non-Sami youth. For all groups except for Sami girls, family conflict and moving was associated with increasing symptoms. Sami boys differed from the other three groups with regard to the relationship between family connectedness and symptom level. These interaction effects were discussed in light of traditional Sami values and gender socialization. The present study has indicated that in the family socialization context, culture may be related to internalization symptoms in youth. PMID- 20843547 TI - Disabling gout. PMID- 20843548 TI - Brine-induced mortality of non-indigenous invertebrates in residual ballast water. AB - All transoceanic vessels entering the Great Lakes are required to manage ballast water and ballast tank residuals with ballast water exchange and tank flushing, respectively. While these management procedures effectively reduce the density and richness of biota in ballast waters and thereby reduce the risk of transferring non-indigenous species, some ships are unable to uniformly manage all tanks. Laboratory experiments were conducted to evaluate sodium chloride brine as an emergency treatment for ballast tanks with non-compliant residuals. Invertebrate communities collected from i) Detroit River, ii) exchanged ballast tanks arriving in the Great Lakes, and iii) North Sea ports, were exposed to a range of brine concentrations (15-1150/00) until complete mortality was reached. Results indicate that a 1-h exposure to 1150/00 brine is a broadly effective treatment (>99.9% mortality) regardless of treatment temperature, taxonomic group, or species' source habitat salinity. A median of 0.00% (range 0.00-5.33) of individuals are expected to survive treatment and the expected number of viable individuals released after treatment is within Canadian and proposed international discharge standards. Before implementation, validation with ship scale trials is recommended. PMID- 20843549 TI - Biochemical effects and polycyclic aromatic hydrocarbons (PAHs) in senegal sole (Solea senegalensis) from a Huelva estuary (SW Spain). AB - Relations between several stress oxidative biomarkers and aromatic polycyclic hydrocarbon (PAH) concentrations have been studied in wild sole, Solea senegalensis collected in the vicinity of a petrochemical industry. Antioxidant enzyme activities in eco-toxicological studies constitute excellent markers for exposure to a large variety of pollutants. The 16 PAHs in sediment as well as oxidative damage (LPO), activity of catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and PAHs type metabolites in sole liver were analysed. Significant correlations (p<0.05) were established between some biomarkers as GST, GPx and CAT and PAHs metabolites in liver (naphthalene, pyrene and phenanthrene) and PAHs concentrations in sediments (fluoranthene, acenaphthene, anthracene and chrysene). PAHs accumulated in the sediment and organisms are inducers of antioxidant defences. GST, GPx and CAT were robust biomarkers showing correlations with both PAHs in sediments and liver PAH metabolites showing different responses to low and high molecular weight PAHs. PMID- 20843550 TI - Evaluation of sugar-cane vinasse treated with Pleurotus sajor-caju utilizing aquatic organisms as toxicological indicators. AB - Toxicity tests with aquatic organisms constitute an effective tool in the evaluation, prediction and detection of the potential effect of pollutants from environmental samples in living organisms. Vinasse, a highly colored effluent, is a sub-product rich in nutrients, mainly organic matter, with high pollutant potential when disposed in the environment. Assays for vinasse decolorization were performed using the fungus Pleurotus sajor-caju CCB020 in vinasse biodegradation study, were occurred reductions of 82.8% in COD, 75.3% in BOD, 99.2% in the coloration and 99.7% in turbidity. The vinasse toxicity reduction was determined by the exposition to the following organisms: Pseudokirchneriella subcapitata, Daphnia magna, Daphnia similis and Hydra attenuata. This work concluded that the systematic combination of P. sajor-caju and vinasse can be applied in the bioprocess of color reduction and degradation of complex vinasse compounds, with reduction in the toxicity and improving its physical-chemical properties. PMID- 20843551 TI - Effects of binary mixtures on the life traits of Daphnia magna. AB - The environment is constantly exposed to a cocktail of contaminants mainly due to human activities. Because polluted ecosystems are characterized by an amalgam of chemical compounds, the objective of the present study was to assess the joint effect of chemical mixtures to the life--history traits of Daphnia magna Straus. For that a binary mixture of two neonicotinoid insecticides, imidacloprid and thiacloprid, and another one of imidacloprid with nickel chloride were tested. Theoretical models have been developed and applied in studies with chemical mixtures, predicting toxicity based on their modes of action: concentration addition (CA) and independent joint action (IA) models. Still there are cases where deviations are observed (e.g. synergistic or antagonistic behaviors, dose ratio or level dependency). In this study, the effects of the individual compounds and their mixtures were studied in a chronic test where reproduction, survival and body length were evaluated in D. magna. Regarding single compound effects, it was observed that the most toxic was nickel chloride followed by thiacloprid and imidacloprid. For the mixture exposure of imidacloprid and thiacloprid, a synergistic pattern was observed in the sublethal doses used for the number of neonates produced, while for the body length the best fit was shown with the CA model. In the mixture exposure of imidacloprid and nickel, no deviation from the IA was observed for the neonate production data; for the body length parameter, a synergistic pattern was observed in low doses of the chemicals while an antagonistic pattern was observed. PMID- 20843552 TI - Exposure to polyfluoroalkyl chemicals during pregnancy is not associated with offspring age at menarche in a contemporary British cohort. AB - INTRODUCTION: Polyfluoroalkyl chemicals (PFCs) are commercially synthesized chemicals used in consumer products. Exposure to certain PFCs is widespread, and some PFCs may act as endocrine disruptors. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) in the United Kingdom to conduct a nested case-control study examining the association between age at menarche, and exposure to PFCs during pregnancy. METHODS: Cases were selected from female offspring in the ALSPAC who reported menarche before the age of 11.5 years (n = 218), and controls were a random sample of remaining girls (n = 230). Serum samples taken from the girls' mothers during pregnancy (1991-1992) were analyzed using on-line solid-phase extraction coupled to isotope dilution high performance liquid chromatography-tandem mass spectrometry for 8 PFCs. Logistic regression was used to determine association between maternal serum PFC concentrations, and odds of earlier age at menarche. RESULTS: PFOS and PFOA were the predominant PFCs (median serum concentrations of 19.8 ng/mL and 3.7 ng/mL). All but one PFC were detectable in most samples. Total PFC concentration varied by number of births (inverse association with birth order; p-value < 0.0001) and race of the child (higher among whites; p-value = 0.03). The serum concentrations of carboxylates were associated with increased odds of earlier age at menarche; concentrations of perfluorooctane sulfonamide, the sulfonamide esters and sulfonates were all associated with decreased odds of earlier age at menarche. However, all confidence intervals included the null value of 1.0. CONCLUSIONS: ALSPAC study participants had nearly ubiquitous exposure to most PFCs examined, but PFC exposure did not appear to be associated with altered age at menarche of their offspring. PMID- 20843554 TI - Dithiocarbazate complexes with the [M(PPh3)]2+ (M = Pd or Pt) moiety: synthesis, characterization and anti-Trypanosoma cruzi activity. AB - New neutral Pd(II) and Pt(II) complexes of the type [M(L)(PPh(3))] (M = Pd or Pt) were prepared in crystalline form in high-yield synthesis with the S benzyldithiocarbazates and S-4-nitrobenzyldithiocarbazates derivatives from 2 hydroxyacetophenone, H(2)L(1a) and H(2)L(1b), and benzoylacetone, H(2)L(2a) and H(2)L(2b). The new complexes [Pt(L(1a))(PPh(3))] (1), [Pd(L(1a))(PPh(3))] (2), [Pt(L(1b))(PPh(3))] (3), [Pd(L(1b))(PPh(3))] (4), [Pt(L(2a))(PPh(3))] (5), [Pd(L(2a))(PPh(3))] (6), [Pt(L(2b))(PPh(3))] (7) and [Pd(L(2b))(PPh(3))] (8) were characterized on the basis of elemental analysis, conductivity measurements, UV visible, IR, electrospray ionization mass spectrometry (ESI-MS), NMR ((1)H and (31)P) and by X-ray diffraction studies. The studies showed that differently from what was observed for the H(2)L(1a) and H(2)L(1b) ligands, H(2)L(2a) and H(2)L(2b) assume cyclic forms as 5-hydroxypyrazolinic. Upon coordination, H(2)L(2a) and H(2)L(2b) suffer ring-opening reaction, coordinating in the same manner as H(2)L(1a) and H(2)L(1b), deprotonated and in O,N,S-tridentate mode to the (MPPh(3))(2+) moiety. All complexes show a quite similar planar fourfold environment around the M(II) center. Furthermore, these complexes exhibited biological activity on extra and intracellular forms of Trypanosoma cruzi in a time- and concentration-dependent manner with IC(50) values ranging from 7.8 to 18.7 MUM, while the ligand H(2)L(2a) presented a trypanocidal activity on trypomastigote form better than the standard drug benznidazole. PMID- 20843555 TI - Bi-directional effects of depressed mood in the postnatal period on mother-infant non-verbal engagement with picture books. AB - The purpose of the present study is to examine the bi-directional nature of maternal depressed mood in the postnatal period on maternal and infant non-verbal behaviors while looking at a picture book. Although, it is acknowledged that non verbal engagement with picture books in infancy plays an important role, the effect of maternal depressed mood on stimulating the interest of infants in books is not known. Sixty-one mothers and their infants, 38 boys and 23 girls, were observed twice approximately 3 months apart (first observation: mean age 6.8 months, range 3-11 months, 32 mothers with depressed mood; second observation: mean age 10.2 months, range 6-16 months, 17 mothers with depressed mood). There was a significant effect for depressed mood on negative behaviors: infants of mothers with depressed mood tended to push away and close books more often. The frequency of negative behaviors (pushing the book away/closing it on the part of the infant and withholding the book and restraining the infant on the part of the mother) were behaviors which if expressed during the first visit were more likely to be expressed during the second visit. Levels of negative behaviors by mother and infant were strongly related during each visit. Additionally, the pattern between visits suggests that maternal negative behavior may be the cause of her infant negative behavior. These results are discussed in terms of the effects of maternal depressed mood on the bi-directional relation of non-verbal engagement of mother and child. PMID- 20843553 TI - Suppression of complement activation by recombinant Crry inhibits experimental autoimmune anterior uveitis (EAAU). AB - This study was initiated to explore the effect of recombinant rat Crry linked to the Fc portion of rat IgG2a (Crry-Ig) on the induction of experimental autoimmune anterior uveitis (EAAU) and on established disease. EAAU was induced in Lewis rats by immunization with bovine melanin-associated antigen (MAA). MAA sensitized animals received Crry-Ig, rat IgG2a (isotype control) or PBS separately before the onset of EAAU or after the onset of clinical disease. Administration of Crry Ig suppressed the induction of EAAU while all animals injected with IgG2a or PBS developed the normal course of EAAU. Treatment with Crry-Ig resulted in the suppression of ocular complement activation as well as the functional activity of complement in the peripheral blood. At the peak of EAAU, levels of IFN-gamma, IP 10, ICAM-1 and LECAM-1 were significantly reduced within the eyes of Crry-Ig treated Lewis rats. Importantly, administration of Crry-Ig even after the onset of EAAU resulted in a sharp decline in the disease activity and early resolution of EAAU. Collectively, the evidence presented here demonstrate that inhibition of complement by Crry-Ig results in low levels of inflammatory molecules-C3 activation products, MAC, cytokines, chemokines and adhesion molecules in the eye. Down-regulation of these molecules affects the infiltration and recruitment of inflammatory cells to the eye resulting in the inhibition of EAAU. PMID- 20843556 TI - Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. AB - BACKGROUND: Considerable amount of biochemical data supports the potential involvement of protein kinase C in the pathophysiology and treatment of bipolar disorder. The aim of this double-blind, placebo-controlled study was to investigate the efficacy and tolerability of tamoxifen as an adjunct to lithium for the treatment of acute mania in hospitalized bipolar patients. METHODS: Eligible participants were 40 inpatients, between the ages of 19 and 49 years with current manic episode. Patients were randomly allocated to lithium (1-1.2 mEq/L) + tamoxifen 80 mg/day (group A) or lithium (1-1.2 mEq/L) + placebo (group B) for a 6-week, double-blind, placebo-controlled study. The principal measure of outcome was the Young Mania Rating Scale. The raters used standardized instructions for Young Mania Rating Scale. RESULTS: Young Mania Rating Scale scores improved with tamoxifen. The difference between the two protocols was significant as indicated by the effect of the group, the between-subjects factor (F=5.41, df=1, p=0.02). A significant difference was observed on the Positive and Negative Syndrome Scale total score at week 6 in the two groups. The difference between the two groups in the frequency of side effects was not significant except for fatigue that occurred more often in the tamoxifen group. LIMITATIONS: Tamoxifen is an antagonist of estrogen receptor as well. CONCLUSION: The results demonstrate that the combination of tamoxifen with lithium was superior to lithium alone for the rapid reduction of manic symptoms. The combined use of tamoxifen with lithium was well tolerated in these acutely manic patients. PMID- 20843557 TI - Validation of the Center for Epidemiologic Studies Depression Scale--Revised (CESD-R): pragmatic depression assessment in the general population. AB - Depression has a huge societal impact, making accurate measurement paramount. While there are several available measures, the Center for Epidemiological Studies Depression Scale (CESD) is a popular assessment tool that has wide applicability in the general population. In order to reflect modern diagnostic criteria and improve upon psychometric limitations of its predecessor, the Center for Epidemiologic Studies Depression Scale--Revised (CESD-R) was recently created, but has yet to be publicized. This study explored psychometric properties of the CESD-R across a large community sample (N=7389) and smaller student sample (N=245). A newly proposed algorithmic classification method yielded base-rates of depression consistent with epidemiological results. Factor analysis suggested a unidimensional factor structure, but important utility for two separate symptom clusters. The CESD-R exhibited good psychometric properties, including high internal consistency, strong factor loadings, and theoretically consistent convergent and divergent validity with anxiety, schizotypy, and positive and negative affect. Results suggest the CESD-R is an accurate and valid measure of depression in the general population with advantages such as free distribution and an atheoretical basis. PMID- 20843558 TI - Associations between substance use, neuropsychological functioning and treatment response in psychosis. AB - Relationships between substance use, severity of psychosis, and neuropsychological functioning were examined, together with their associations with treatment response and retention status. Participants included 477 people with psychosis (354 volunteers registered on a research database, and 123 enrolled in a treatment trial for substance misuse). Variables of primary interest included substance use history, course of psychotic disorder, and neuropsychological functioning on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Specific RBANS deficits were associated with a more chronic illness course. Compared to those with a stable or chronic course, younger people with a single episode of psychosis were more likely to have uncertain diagnoses, higher levels of substance use problems and variable neuropsychological functioning. History of substance use was not associated with additional overall neuropsychological deficits. Likewise, treatment retention and outcome were not associated with neuropsychological functioning. The findings suggest that, among people with co-existing psychotic and substance use disorders, response to cognitive-behaviour therapy is likely to be independent of neuropsychological functioning. Consideration should also be given to the potential use of neuropsychological assessments to assist differentiation of likely substance-associated psychosis from primary psychosis. PMID- 20843559 TI - Meaningful confusions and confusing meanings in communication in schizophrenia. AB - Unconventional discourse in schizophrenia has been speculated to be attributable to the mixing up of symbols and signs. We illustrate how a series of scientific images, cartoons, and prose are used by a patient to weave disparate-and objectively unrelated-concepts. The resulting prose is incoherent science. PMID- 20843561 TI - Acute otitis media: From diagnosis to prevention. Summary of the Italian guideline. AB - Acute otitis media (AOM) is the most common disease occurring in infants and children and has major medical, social and economic effects. If we consider the Italian pediatric population and the incidence rates in different age ranges it can be calculated that almost one million cases of AOM are diagnosed in Italy every year. Various attempts have been made internationally to clarify the most appropriate ways in which AOM should be managed. In Italy, this has been done at local or regional level but there have so far been no national initiatives. The objective of this guideline is to provide recommendations to pediatricians, general practitioners and otolaryngologists involved in the clinical management of acute otitis media in healthy children aged 2 months to 12 years. After a systematic review and grading of evidences from the literature, the document was drafted by a multidisciplinary panel with identified key clinical questions related to diagnosis, treatment of the acute episode, management of complications and prevention. PMID- 20843560 TI - Automatic stereotyping against people with schizophrenia, schizoaffective and affective disorders. AB - Similar to members of the public, people with mental illness may exhibit general negative automatic prejudice against their own group. However, it is unclear whether more specific negative stereotypes are automatically activated among diagnosed individuals and how such automatic stereotyping may be related to self reported attitudes and emotional reactions. We therefore studied automatically activated reactions toward mental illness among 85 people with schizophrenia, schizoaffective or affective disorders as well as among 50 members of the general public, using a Lexical Decision Task to measure automatic stereotyping. Deliberately endorsed attitudes and emotional reactions were assessed by self report. Independent of diagnosis, people with mental illness showed less negative automatic stereotyping than did members of the public. Among members of the public, stronger automatic stereotyping was associated with more self-reported shame about a potential mental illness and more anger toward stigmatized individuals. Reduced automatic stereotyping in the diagnosed group suggests that people with mental illness might not entirely internalize societal stigma. Among members of the public, automatic stereotyping predicted negative emotional reactions to people with mental illness. Initiatives to reduce the impact of public stigma and internalized stigma should take automatic stereotyping and related emotional aspects of stigma into account. PMID- 20843562 TI - The global need for effective antibiotics: challenges and recent advances. AB - The emerging problem of antibiotic resistance is a serious threat to global public health. The situation is aggravated by a substantial decline in the research and development of antibacterial agents. Hence, very few new antibacterial classes are brought to market when older classes lose their efficacy. There has been renewed and growing attention within policy groups to: (i) address the problem; (ii) discuss incentives for the development of urgently needed new treatments; (iii) preserve the efficacy of existing therapeutic options. We briefly review the basic principles of antibiotic resistance, and contrast the increasing resistance to the dwindling antibacterial 'pipeline'. We also highlight some recent policy initiatives aiming to secure the future need of effective antibiotics. PMID- 20843564 TI - Subcellular partitioning of cadmium in the freshwater bivalve, Pyganodon grandis, after separate short-term exposures to waterborne or diet-borne metal. AB - The dynamics of cadmium uptake and subcellular partitioning were studied in laboratory experiments conducted on Pyganodon grandis, a freshwater unionid bivalve that shows promise as a biomonitor for metal pollution. Bivalves were collected from an uncontaminated lake, allowed to acclimate to laboratory conditions (>=25 days), and then either exposed to a low, environmentally relevant, concentration of dissolved Cd (5nM; 6, 12 and 24h), or fed Cd contaminated algae (~70nmol Cdg-1 dry weight; 4*4h). In this latter case, the bivalves were allowed to depurate for up to 8 days after the end of the feeding phase. As anticipated, the gills were the main target organ during the aqueous Cd exposure whereas the intestine was the initial site of Cd accumulation during the dietary exposure; during the subsequent depuration period, the dietary Cd accumulated in both the digestive gland and in the gills. For the gills, the distribution of Cd among the subcellular fractions (i.e., granules>heat-denatured proteins (HDP)~heat-stable proteins (HSP)>mitochondria~lysosomes+microsomes) was insensitive to the exposure route; both waterborne and diet-borne Cd ended up largely bound to the granule fraction. The subcellular distribution of Cd in the digestive gland differed markedly from that in the gills (HDP>HSP~granules~mitochondria>lysosomes+microsomes), but as in the case of the gills, this distribution was relatively insensitive to the exposure route. For both the gills and the digestive gland, the subcellular distributions of Cd differed from those observed in native bivalves that are chronically exposed to Cd in the field - in the short-term experimental exposures of P. grandis, metal detoxification was less effective than in chronically exposed native bivalves. PMID- 20843563 TI - Protein modifications involved in neurotransmitter and gasotransmitter signaling. AB - Covalent modifications of intracellular proteins, such as phosphorylation, are generally thought to occur as secondary or tertiary responses to neurotransmitters, following the intermediation of membrane receptors and second messengers such as cyclic AMP. By contrast, the gasotransmitter nitric oxide directly S-nitrosylates cysteine residues in diverse intracellular proteins. Recently, hydrogen sulfide has been acknowledged as a gasotransmitter, which analogously sulfhydrates cysteine residues in proteins. Cysteine residues are also modified by palmitoylation in response to neurotransmitter signaling, possibly in reciprocity with S-nitrosylation. Neurotransmission also elicits sumoylation and acetylation of lysine residues within diverse proteins. This review addresses how these recently appreciated protein modifications impact our thinking about ways in which neurotransmission regulates intracellular protein disposition. PMID- 20843565 TI - NMR-based metabolomic studies on the toxicological effects of cadmium and copper on green mussels Perna viridis. AB - Traditional toxicology studies have focused on selected biomarkers to characterize the biological stress induced by metals in marine organisms. In this study, a system biology tool, metabolomics, was applied to the marine mussel Perna viridis to investigate changes in the metabolic profiles of soft tissue as a response to copper (Cu) and cadmium (Cd), both as single metal and as a mixture. The major metabolite changes corresponding to metal exposure are related to amino acids, osmolytes, and energy metabolites. Following metal exposure for 1 week, there was a significant increase in the levels of branched chain amino acids, histidine, glutamate, glutamine, hypotaurine, dimethylglycine, arginine and ATP/ADP. For the Cu+Cd co-exposed mussels, the levels of lactate, branched chain amino acid, succinate, and NAD increased, whereas the levels of glucose, glycogen, and ATP/ADP decreased, indicating a different metabolic profile for the single metal exposure groups. After 2 weeks of exposure, the mussels showed acclimatization to Cd exposure based on the recovery of some metabolites. However, the metabolic profile induced by the metal mixture was very similar to that from Cu exposure, suggesting that Cu dominantly induced the metabolic disturbances. Both Cu and Cd may lead to neurotoxicity, disturbances in energy metabolism, and osmoregulation changes. These results demonstrate the high applicability and reliability of NMR-based metabolomics in interpreting the toxicological mechanisms of metals using global metabolic biomarkers. PMID- 20843566 TI - Statins moderate coronary stenoses but not coronary calcification: results from meta-analyses. AB - INTRODUCTION: Coronary artery stenoses have been shown in various trials to be moderated by treatment with statins. A similar effect on coronary artery calcification has not been demonstrated. We therefore undertook meta-analyses of trials examining the effect of statin treatment on coronary artery stenoses and coronary artery calcification. METHODS: Literature searches identified five controlled trials suitable for inclusion in the analysis of the effect of statins (high dose versus either low dose or placebo) on coronary artery calcification and six trials suitable for inclusion in the analysis of the effect of statins on coronary artery stenoses. RESULTS: All trials reported substantial and significant reductions in LDL-C with statin treatment which results in net reductions of LDL-C in the CAC and coronary stenoses trials of 1.0 mmol/L and 0.9 mmol/L, respectively. Analysis of the CAC trials did not demonstrate any effect of statins on the progression of calcification. In contrast, in the coronary stenoses trials there was a consistent moderation of stenosis severity progression with statins (p<0.0001). CONCLUSIONS: Meta-analyses of the available trials have demonstrated a significant moderation of coronary stenoses associated with the statin-induced reduction in LDL-C. In contrast, there was no effect on coronary calcification despite a similar reduction in LDL-C levels. This suggests that the pathogenesis of the two conditions may be different, if not in aetiology, then certainly in their development. It further suggests that statin use to moderate arterial calcification is not effective. PMID- 20843567 TI - Safety and efficiency of chronic ACE inhibition in symptomatic heart failure patients with a systemic right ventricle. AB - BACKGROUND: ACE inhibition is an established treatment regimen in patients with congestive heart failure due to left ventricular dysfunction which improves morbidity and mortality. However, little is known about the beneficial effects of ACE inhibition in adult patients after Mustard procedure for transposition of the great arteries with heart failure symptoms. Therefore, we investigated the effects of ACE inhibition in these patients on heart failure symptoms, echocardiographic diameters, NT-proBNP and exercise capacity. METHODS: In 14 patients (age 25.2 +/- 3.5 years), after Mustard procedure for transposition of the great arteries (age at operation 1.1 +/- 1.3 years) with heart failure NYHA II (New York Heart Association class), an ACE inhibition was initiated. At baseline and 13.3 +/- 4.0 months after treatment with enalapril (10mg twice a day), echocardiography, exercise test and NT-proBNP measurements were performed and compared to an age- and sex-matched control group. RESULTS: Maximum oxygen uptake and echocardiographic parameters did not change significantly in both groups. However, NT-proBNP showed a significant decrease in the treatment group (242 +/- 105 vs. 151 +/- 93 ng/l, p=0.004), while in the control group a significant increase (120 +/- 89 vs. 173 +/- 149 ng/l, p<0.05) was observed. Furthermore, ACE inhibitor treatment did not result in a deterioration of heart failure symptoms or renal function. CONCLUSIONS: Thus, ACE inhibitor treatment of heart failure symptoms in patients with a systemic right ventricle is safe and reduces NT-proBNP levels significantly as a marker for ventricular overload. Nevertheless, larger scale trials are warranted to show effects on morbidity and mortality in this highly selected patient group. PMID- 20843568 TI - Comparison of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing an invasive strategy: a meta-analysis of randomized clinical trials. AB - OBJECTIVE: This meta-analysis was performed to assess the efficacy and safety of bivalirudin compared with unfractionated heparin or enoxaparin plus glycoprotein (GP) IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Pharmacotherapy for patients undergoing PCI includes bivalirudin, heparin, and GP IIb/IIIa inhibitors. We sought to compare ischemic and bleeding outcomes with bivalirudin versus heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI. METHODS: A literature search was conducted to identify fully published randomized trials that compared bivalirudin with heparin plus GP IIb/IIIa inhibitors in patients undergoing PCI. RESULTS: A total of 19,772 patients in 5 clinical trials were included in the analysis (9785 patients received bivalirudin and 9987 patients received heparin plus GP IIb/IIIa inhibitors during PCI). Anticoagulation with bivalirudin, as compared with heparin plus glycoprotein IIb/IIIa inhibitors, results in no difference in major adverse cardiovascular events (odds ratio [OR] 1.07, 95% confidence interval [CI] 0.96 to 1.19), death (OR 0.93, 95% CI 0.72 to 1.21), or urgent revascularization (OR 1.06, 95% CI 0.86 to 1.30). There is a trend towards a higher risk of myocardial infarction (OR 1.12, 95% CI 0.99 to 1.28) but a significantly lower risk of TIMI major bleeding with bivalirudin (OR 0.55, 95% CI 0.44 to 0.69). CONCLUSION: In patients who undergo PCI, anticoagulation with bivalirudin as compared with unfractionated heparin or enoxaparin plus GP IIb/IIIa inhibitors results in similar ischemic adverse events but a reduction in major bleeding. PMID- 20843570 TI - Global longitudinal speckle-tracking strain is predictive of left ventricular remodeling after coronary angioplasty in patients with recent non-ST elevation myocardial infarction. AB - AIMS: To test whether two-dimensional longitudinal strain (2DSE) performed after revascularization by percutaneous coronary intervention (PCI) could predict left ventricular (LV) remodeling in patients with recent non-ST elevation myocardial infarction (NSTEMI). METHODS: In 70 patients (62.7 +/- 8.7 years) with recent NSTEMI (between 72 hours and 14 days), undergoing coronary angiography for recurrent angina, myocardial deformation parameters were measured by 2DSE before and 24 hours after reperfusion therapy. Strain in all LV segments was averaged to obtain a global value (Global longitudinal Strain--GLS). Infarct size was estimated by clinical parameters and cardiac markers. After 6 months from intervention, LV negative remodeling was defined as lack of improvement of LV function, with increase in LV end-diastolic volume of greater than or equal than 15%. RESULTS: At follow-up, patients were subdivided into remodeled (n=32) and non-remodeled (n = 38) groups. Patients with negative LV remodeling had significantly lower baseline LV ejection fraction (44.8+/-6.9 vs. 48.7 +/- 5.5 %; p < 0.05), higher peak troponin I (p < 0.001) and reduced GLS (- 10.6+/-6.1 vs - 17.6 +/- 6.7 % p < 0.001) than those without LV remodeling. GLS showed a close correlation with peak troponin I after PCI (r = 0.64, P < 0.0001) and LV WMSI (r = 0.42, p < 0.01). By multivariable analysis, diabetes mellitus (P < 0.005), peak of Troponin I after PCI (P < 0.0005), GLS at baseline (OR: 4.3; p < 0.0001), and lack of improvement of GLS soon after PCI (OR: 1.45, P < 0.01) were powerful independent predictors of negative LV remodelling at follow-up. In particular, a GLS <= 12 % showed a sensitivity and a specificity respectively of 84.8% and 87.8% to predict negative LV remodelling at follow-up. CONCLUSIONS: in patients with recent NSTEMI, longitudinal LV global and regional speckle-tracking strain measurements are powerful independent predictors of LV remodeling after reperfusion therapy. PMID- 20843569 TI - Effect of enhanced external counterpulsation on circulating CD34+ progenitor cell subsets. AB - BACKGROUND: Enhanced external counterpulsation (EECP) is associated with improvement in endothelial function, angina and quality of life in patients with symptomatic coronary artery disease, although the mechanisms underlying the observed clinical benefits are not completely clear. The purpose of this study was to examine the effects of EECP on circulating haematopoietic progenitor cells (HPCs) and endothelial progenitor cells (EPCs) in patients with refractory angina. We compared HPC and EPC counts between patients scheduled for EECP and patients with normal angiographic coronary arteries, with and without coronary endothelial dysfunction. We hypothesized that an increase in circulating bone marrow derived progenitor cells in response to EECP may be part of the mechanism of action of EECP. METHODS: Thirteen consecutive patients scheduled to receive EECP treatment were prospectively enrolled. Clinical characteristics were recorded and venous blood (5 ml) was drawn on day 1, day 17, day 35 (final session) and one month post completion of EECP therapy. Buffy coat was extracted and HPCs and EPCs were counted by flow cytometry. RESULTS: Median Canadian Cardiovascular Society (CCS) angina class decreased and Duke Activity Status Index (DASI) functional score increased significantly (both, p < 0.05) in response to EECP, an effect that was maintained at one month after termination of treatment. Flow cytometric analysis revealed an accompanying significant increase in CD34+, CD133+ and CD34+, CD133+ CPC counts over the course of treatment (p < 0.05). DASI scores correlated significantly with CD34+ (R = 0.38 p = 0.02), CD133+ (R = 0.5, p = 0.006) and CD34+, CD133+ (R = 0.47, p = 0.01) CPC counts. CONCLUSION: This study shows that HPCs, but not EPCs are significantly increased in response to EECP treatment and correlate with reproducible measures of clinical improvement. These findings are the first to link the functional improvement observed with EECP treatment with increased circulating progenitor cells. PMID- 20843571 TI - Statintherapy in the primary and the secondary prevention of ischaemic cerebrovascular diseases. AB - INTRODUCTION: Stroke is a major public health problem. It is the third leading cause of death worldwide and results in hospital admissions, morbidity, and long term disability. Despite the inconsistent or weak association between cholesterol and stroke, statins can reduce the incidence of stroke in high-risk populations and in patients with a stroke or transient ischaemic attack. METHODS: The aim of our study was to review the efficacy of statin therapy in both primary and secondary stroke prevention. We also reviewed the effectiveness and cost effectiveness among different statins and we also reviewed the possible effect of treatment added to statin monotherapy. RESULTS: There is evidence that statin therapy in both primary and secondary prevention significantly reduces subsequent major coronary events but only marginally reduces the risk of stroke recurrence. There is no clear evidence of beneficial effect from statins in those with previous haemorrhagic stroke and it is unclear whether statins should be started immediately post stroke or later. There is a pressing need for direct evidence, from head-to-head trials, to determine whether individual statins provide differing protection from clinically important events in stroke prevention. It is possible that combinations of lipid-lowering agents did not improve clinical outcomes more than high-dose statin monotherapy, although clinical trials are still ongoing. PMID- 20843573 TI - Total and pathogenic Vibrio parahaemolyticus in shrimp: fast and reliable quantification by real-time PCR. AB - Vibrio parahaemolyticus is found in aquatic environments and is the leading cause of gastroenteritis due to seafood consumption worldwide. We evaluated a quantitative real-time PCR (Q-PCR) assay with hydrolysis probes, to determine whether this method could be used for the efficient counting of total, tdh and trh-positive V. parahaemolyticus in shrimps. We assessed the specificity of this assay, using 62 strains from 12 non target bacterial species of the Vibrio, Photobacterium, Shewanella and Aeromonas genera. Only V. parahaemolyticus with the appropriate target gene generated a fluorescent signal. We assessed the robustness of this assay, by analyzing spiked shrimps by Q-PCR and traditional culture methods, using most probable number (MPN)-PCR. After a 6h enrichment period, the assay successfully detected total and pathogenic V. parahaemolyticus in shrimps samples spiked with less than 5 V. parahaemolyticuscells/g of shrimp. The Q-PCR results obtained were compared with those obtained by most probable number (MPN)-PCR format. An excellent correlation between the two methods was observed in all cases (R2 > 0.9742). The application of this Q-PCR assay to 85 natural shrimp samples also resulted in the successful quantification of V. parahaemolyticus in this matrix, and the counts obtained were correlated with those obtained by (MPN)-PCR (P=0.2598). Thus, this rapid and sensitive Q-PCR can be used to quantify V. parahaemolyticus in natural shrimp samples. This assay could be proposed, in response to the demands of the European Commission, as a tool for testing for the presence of vibrios in crustaceans, making it possible to legislate in this domain. PMID- 20843572 TI - What is optimal revascularization strategy in patients with multivessel coronary artery disease in non-ST-elevation myocardial infarction? Multivessel or culprit only revascularization. AB - BACKGROUND: In patients with non-ST-elevation myocardial infarction (NSTEMI), current guidelines did not recommend optimal revascularization management in multivessel coronary artery disease. We compared clinical outcomes between multivessel revascularization and culprit-only revascularization in this setting. METHODS: A total of 1919 patients with multivessel disease (1011 patients; multivessel revascularization group, 908 patients; culprit-only revascularization group) diagnosed as NSTEMI was enrolled in a nationwide prospective Korea Acute Myocardial Infarction Registry (KAMIR) from November 2005 to January 2008. The primary end-points were major adverse cardiac events (MACE), all-causes of deaths, myocardial infarction (MI), and repeated percutaneous coronary intervention (PCI) during 1-year clinical follow-up. Also, subgroup analysis was performed in patients with high TIMI (Thrombolysis In Myocardial Infarction) risk score (>= 4) to find efficacy of multivessel PCI in high-risk patients. RESULTS: Baseline clinical characteristics and the risk factors of coronary artery disease were similar between both groups. In angiography, three-vessel lesion was more presented in the multivessel group (46.1% vs. 40.9%, p = 0.024) and rates of left anterior descending and left main stem coronary artery as culprit vessel were higher in the multivessel group (p = 0.003 and p = 0.001 respectively). In hospital mortality was higher in the culprit-only group (1.4% vs. 2.9%, p = 0.025). Primary end-points occurred in 241 patients (15.5%) during 1-year follow up. Multivessel revascularization reduced MACEs [hazard ratio (HR) 0.658, 95% confidence interval (CI) 0.45 to 0.96, p = 0.031], death or myocardial infarction (HR 0.58, 95% CI 0.35 to 0.97, p = 0.037) and non-target vessel revascularization (HR 0.44, 95% CI 0.24 to 0.81, p = 0.008). There were no significant differences in target lesion revascularization (TLR; HR 1.38, 95% CI 0.51 to 3.71, p = 0.529) and target vessel revascularization (TVR; HR 0.28, 95% CI 0.05 to 1.47, p = 0.131). In subgroup analysis in patients with a higher TIMI risk score, similar results were presented. CONCLUSION: Multivessel revascularization in multivessel coronary artery disease presenting with NSTEMI showed better clinical outcomes without significant in-stent restenosis and progression of diseased-vessel compared to culprit-only revascularization. PMID- 20843574 TI - Clinical characteristics of diabetic ketoacidosis in newly diagnosed adult patients. AB - A retrospective review was conducted of medical records of newly diagnosed diabetes in adults who presented with DKA between 2003 and 2007. The majority of DKA in Thailand could not be classified as classical type 1 diabetes. Some newly diagnosed people presenting with DKA could be safely withdrawn from insulin treatment. PMID- 20843575 TI - Individualized treatment with combination of Peg-interferon alpha 2b and ribavirin in patients infected with HCV genotype 3. AB - BACKGROUND & AIMS: The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly established. METHODS: Four hundred and fourteen patients received Peg-interferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg. Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36). In the variable treatment arm, patients with or without wk4-R were allocated to either 12 or 36 weeks duration. RESULTS: At treatment week 4, HCV RNA was undetectable in 262 patients (63.3%), 136 in the Std24, and 126 in the Var12/36 group (p=0.41). In patients with wk4-R, end-of-treatment (EOT) responses were 80.4% (CI 85.4-95.3) and 97.6% (CI 94.9-99.9) in the two arms, respectively (p=0.019). In patients without wk4 R, corresponding rates were 61.9% (50.6-73.2) and 75.3% (CI 65.9-84.6) (p=0.08). SVR was attained in 302 patients, 71.4% (CI 65.3-77.6) in the St24 group and 74.3% (CI 58.4-80.3) in the variable 12/36 arm. Among patients with wk4-R, SVR was 81.6% (CI 75.1-88.1) and 82.5% (75.9-89.1), respectively. In patients without wk4-R, SVR amounted to 52.1% (CI 40.4-63.7) and 61.7 (CI 51.1-72.3) in the two arms (p=0.25). CONCLUSIONS: HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy, provided that sufficiently high doses of ribavirin are administered. For patients still viremic at treatment week 4, SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks. PMID- 20843576 TI - Multiscaled combination of MR and SPECT images in neuroimaging: A simplex method based variable-weight fusion. AB - Single-photon emission computed tomography (SPECT) images alone are difficult to understand in diagnosis, since anatomical structures are absent from the data. Studies on combination attempt to locate functional changes of the SPECT image by the magnetic resonance (MR) image. Due to the low similarity between original images, fused results are always darkened, obscured or loss some crucial anatomical structures. This paper has solved these problems by the variable weight matrix which is estimated by minimizing the cost function using the simplex method. Under the generalized intensity-hue-saturation (GIHS) framework, the multiscaled analysis is presented for a better detail preservation. Besides, interactive approaches are discussed for the gradual variation between original images and the control of detail performance. The similarity assessment evaluates several different methods on a normal brain atlas. Two clips show the interactive property of the proposed method, while two medical cases demonstrate its clinical values. We conclude that the proposed method is superior to traditional methods, when considering the definition and the information capacity of fused results. PMID- 20843577 TI - Fovea center detection based on the retina anatomy and mathematical morphology. AB - In this work, we present a new fovea center detection method for color eye fundus images. This method is based on known anatomical constraints on the relative locations of retina structures, and mathematical morphology. The detection of this anatomical feature is a prerequisite for the computer aided diagnosis of several retinal diseases, such as Diabetic Macular Edema. The proposed method is adaptive to local illumination changes, and it is robust to local disturbances introduced by pathologies in digital color eye fundus images (e.g. exudates). Our experimental results using the DRIVE image database indicate that our method is able to detect the fovea center in 37 out of 37 images (i.e. with a success rate of 100%). Using the DIARETDB1 database, our method was able to detect the fovea center in 92.13% of all tested cases (i.e. in 82 out of 89 images). These results indicate that our approach potentially can achieve a better performance than comparable methods proposed in the literature. PMID- 20843579 TI - [Intracameral cefuroxime injections in prophylaxis of postoperative endophthalmitis after cataract surgery: implementation and results]. AB - INTRODUCTION: The European Society for Cataract and Refractive Surgery (ESCRS) endophthalmitis study demonstrated a significant decrease in the rates of postoperative endophthalmitis with the use of intracameral cefuroxime during cataract surgery. We report the organization of the implementation of this procedure in our departments and our results after 2 years. METHODOLOGY: All patients operated on for cataract between January 2007 and December 2008 in the ophthalmology departments of the Pellegrin University Hospital in Bordeaux and Lariboisiere University Hospital in Paris received an intracameral injection of cefuroxime at the end of the surgery. The cefuroxime was prepared in ready-for use syringes by the hospital's central pharmacy. RESULTS: A convenient method of preparation and conditioning cefuroxime with stable preservation lasting longer than 1 week was set up in our hospitals. Between January 2007 and December 2008, out of 3316 patients who had a cataract surgery, two presented an endophthalmitis (0.06%). CONCLUSION: The intracameral cefuroxime injection at the end of the cataract surgery is a means to consider to prevent endophthalmitis. It can be implemented as a part of regular practice with appropriate preparation rules. The major barrier to its further use appears to be the lack of a commercially available preformulated preparation. PMID- 20843580 TI - [Advantages of CT dacryocystography in exploration of lacrimonasal canal stenosis]. PMID- 20843581 TI - The peer review process: some gentle reminders for us all. PMID- 20843582 TI - [It was Wegener!]. PMID- 20843583 TI - [Incidence of permanent disability in a cohort of social security-affiliated workers (2004-2007)]. AB - OBJECTIVE: To describe the incidence of permanent disability, both work-related and non-work-related, by several socioeconomic and geographical variables. METHODS: We performed a retrospective study of a cohort of 768,454 workers covered by the General Social Security Regimen, followed-up from 2004 to 2007. This study was based on the Continuous Working Life Survey. In the 4 years of follow-up, 7,749 cases in 1,937,921 workers-years were identified. Incidence rates and crude and adjusted rate ratios were estimated by Poisson regression models. RESULTS: The incidence of non-work-related permanent disability was 10 times greater than that of work-related disability (36.3 versus 3.7 per 10,000 workers-years). The incidences for both non-work-related and work-related disability were higher in men and increased with age and lower education level. For non-work-related permanent disability, the region with the highest incidence was Asturias and that with the lowest was Madrid (56.7 vs. 23.3). For work related permanent disability, the highest incidence was found in Asturias and the lowest in Navarre (7.8 vs. 1.4). This differential was maintained for work related and non-work-related permanent disability for Asturias, after adjustment was made by sex, age, educational level, company size and economic activity. CONCLUSIONS: In this study, we observed substantial differences in the incidences of permanent disability by demographic, social and geographical characteristics, which should be analyzed in greater depth, especially the differences observed by regions. PMID- 20843584 TI - [Contributions to the development of a public health information system. SESPAS Report 2010]. AB - New public health laws are a conceptual and methodological adaptation of public health to current social needs, their common link being the incorporation of health in all policies. This represents a new strategic approach that will require different information systems, which should incorporate the rapid advances made in the field of information technology and communication. The aim of this article was to identify the most important aspects to be taken into account in information systems in public health from a technological perspective, both in their development and in the elements that compose them. To overcome the fragmentation of information systems in public health, these systems must be successfully integrated among themselves and with other health and non-health systems. To achieve this task, technical, semantic and organizational interoperability must be ensured. Emerging technologies should be considered to support these new strategies, especially Web 2.0 tools. This new strategic development will pose additional challenges because of its size and the diversity of the departments involved. It is proposed that information systems will include the elements of Web 2.0 and support systems for decision-making technologies in addition to the traditional operational systems. PMID- 20843585 TI - [Evaluation of public policies. SESPAS Report 2010]. AB - Public policy evaluation is not always a mandatory task for administrations. A priori, the instruments for government intervention are chosen and calculated to maximize the social welfare function that should be implicit in the policies undertaken, or in the government's electoral program. However, it is surprising how the government sometimes acts without questioning whether institutional functioning and the corresponding public policies can effectively and efficiently achieve this objective. The absence of evaluation drains the scarce available resources towards ineffective and inefficient programs, which could be otherwise used in other initiatives with a greater impact on the population's welfare. PMID- 20843586 TI - QSAR modeling, synthesis and bioassay of diverse leukemia RPMI-8226 cell line active agents. AB - A rigorous QSAR modeling procedure employing CODESSA PRO descriptors has been utilized for the prediction of more efficient anti-leukemia agents. Experimental data concerning the effect on leukemia RPMI-8226 cell line tumor growth of 34 compounds (treated at a dose of 10 MUM) was related to their chemical structures by a 4-descriptor QSAR model. Four bis(oxy)bis-urea and bis(sulfanediyl)bis-urea derivatives (4a, 4b, 8, 11a) predicted as active by this model, together with 11b predicted to be of low activity, were synthesized and screened for anti-tumor activity utilizing 55 different tumor cell lines. Compounds 8 and 11a showed anti tumor properties against most of the adopted cell lines with growth inhibition exceeding 50%. The highly promising preliminary anti-tumor properties of compounds 8 and 11a, were screened at serial dilutions (10(-4)-10(-8) MUM) for determination of their GI(50) and TGI against the screened human tumor cell lines. Compound 11a (GI(50) = 1.55, TGI = 8.68 MUM) is more effective than compound 8 (GI(50)=58.30, TGI = > 100 MUM) against the target leukemia RPMI-8226 cell line. Compound 11a also exhibits highly pronounced anti-tumor properties against NCI-H226, NCI-H23 (non-small cell lung cancer), COLO 205 (colon cancer), SNB-75 (CNS cancer), OVCAR-3, SK-OV-3 (ovarian cancer), A498 (renal cancer) MDA MB-231/ATCC and MDA-MB-468 (breast cancer) cell lines (GI(50) = 1.95, 1.61, 1.38, 1.56, 1.30, 1.98, 1.18, 1.85, 1.08, TGI = 8.35, 6.01, 2.67, 8.59, 4.01, 7.01, 5.62, 6.38, 5.63 MUM, respectively). Thus 11a could be a suitable lead towards the design of broad spectrum anti-tumor active agents targeting various human tumor cell lines. PMID- 20843587 TI - [Hemorrhagic [corrected] bullae]. PMID- 20843588 TI - [Most frequent drug-related events detected by pharmacists during prescription analysis in a university hospital]. AB - PURPOSE: In France, the analysis of the prescriptions by a pharmacist in hospital is mandatory since 1991. However, for various reasons, this activity remained poorly developed and little research has been performed. Consequently, this activity suffers of a lack of visibility to hospital decision-makers and others health care professionals. The aim of this paper is to describe drugs related problems identified by pharmacist prescriptions analysis on a large number of orders in a large teaching hospital. This was done in order to highlight recurrent and preventable problems. METHODS: During 1 year period, drug related problems detected by pharmacists when performing prescription analysis were registered prospectively. RESULTS: Among 70,849 orders, 7073 drug related problems were registered. Most frequently detected drug related problems were: over dosages, especially with three drugs (zopiclone, zolpidem and acetaminophen) representing more than 10% of the pharmacist's interventions; optimization of drug administration especially with tablets that should not be crushed and intravenous to oral step-down therapy (7.5%); lack of conformity with consensus recommendations and contra-indications (12.8%); drug-drug interactions (11.6%) with a high proportion of absorption inhibition of one drug by another along the digestive tract; problems related to computerized physicians order entry (5.1%) appeared as an emerging phenomenon. CONCLUSION: These results should be used to reexamine hospital drug prescription policy. They prompt health care professionals to be aware about new medications errors potentially related to computerized prescription order entry. Finally, they invite to modify initial and continuous education programs of health care professionals. PMID- 20843589 TI - The effects of plantar fasciitis and pain on plantar pressure distribution of recreational runners. AB - BACKGROUND: Plantar fasciitis is the third most frequent injury in runners. Despite its high prevalence, its pathogenesis remains inconclusive. The literature reports overload as the basic mechanism for its development. However, the way that these plantar loads are distributed on the foot surface of runners with plantar fasciitis and the effects of pain on this mechanical factor has not yet been investigated. Therefore, the aim of this study was to evaluate and compare the plantar pressure distributions during running in runners with symptom or history of plantar fasciitis and runners without the disease. METHODS: Forty five recreational runners with plantar fasciitis (30 symptomatic and 15 with previous history of the disease) and 60 runners without plantar fasciitis (control group) were evaluated. Pain was assessed by a visual analogue scale. All runners were evaluated by means of the Pedar system insoles during running forty meters at a speed of 12(5%) km/h, using standard sport footwear. Two-way ANOVAS were employed to investigate the main and interaction effects between groups and plantar areas. FINDINGS: No interaction effects were found for any of the investigated variables: peak pressure (P = 0.61), contact area (P = 0.38), contact time (P = 0.91), and the pressure-time integral (P = 0.50). INTERPRETATION: These findings indicated that the patterns of plantar pressure distribution were not affected in recreational runners with plantar fasciitis when compared to control runners. Pain also did not interfere with the dynamic patterns of the plantar pressure distributions. PMID- 20843590 TI - The spectrum of kidney involvement in lymphoma: a case report and review of the literature. AB - Kidney involvement is an under-recognized complication of both Hodgkin and non Hodgkin lymphoma. The diversity of lymphoma-related renal manifestations makes diagnosis difficult. Although abrupt worsening of kidney function may be the first sign of malignant disease, renal effects can be subtle or even silent. The causes of renal involvement similarly are varied. We discuss a case of non Hodgkin lymphoma and associated kidney failure from several distinct malignancy related mechanisms and review the spectrum of lymphoma-related kidney involvement. PMID- 20843591 TI - The role of endothelial cell injury in thrombotic microangiopathy. AB - Thrombotic microangiopathy (TMA) refers to a clinical and pathologic syndrome in which endothelial injury results in the manifestations of thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury. A host of causes may induce endothelial injury and TMA, including enteric bacterial toxins, deficiency or dysfunction of complement regulatory proteins, deficiency or inhibition of von Willebrand factor-cleaving proteases, and factors that inhibit endothelial cell proliferation and turnover. This has led specialists to concentrate on these specific inciting factors in terms of designing treatment and management. However, a key and less recognized factor is the underlying level of endothelial health. Many persons with hereditary causes may remain disease free for years or may never develop disease. Others with acute inciting events, such as Escherichia coli O157 enteritis, never manifest TMA. Experimental studies document the importance of specific factors, such as endothelial nitric oxide levels, in helping protect animals from TMA. This suggests that one might approach the management of TMA not simply with specific treatments aimed at the underlying hereditary cause or inciting event, but rather at general measures that may improve overall endothelial health. We propose studies to determine whether interventions that improve endothelial health, such as the administration of angiotensin-converting enzyme inhibitors, statins, vitamin C, allopurinol, or nitric oxide-producing drugs, may be able to prevent TMA, even in persons with underlying hereditary conditions that otherwise would predispose them to these diseases. PMID- 20843593 TI - A policy case study of blood in Australia. AB - In 2008 the Australian government decided to remove white blood cells from all blood products. This policy of universal leucodepletion was a change to the existing policy of supplying leucodepleted products to high risk patients only. The decision was made without strong information about the cost-effectiveness of universal leucodepletion. The aims for this policy analysis are to generate cost effectiveness data about universal leucodepletion, and to add to our understanding of the role of evidence and the political reality of healthcare decision-making in Australia. The cost-effectiveness analysis revealed universal leucodepletion costs $398,943 to save one year of life. This exceeds the normal maximum threshold for Australia. We discuss this result within the context of how policy decisions are made about blood, and how it relates to the theory and process of policy making. We conclude that the absence of a strong voice for cost effectiveness was an important omission in this decision. PMID- 20843592 TI - Wormwood (Artemisia absinthium) for poorly responsive early-stage IgA nephropathy: a pilot uncontrolled trial. AB - BACKGROUND: Inhibition of the renin-angiotensin system is a widely accepted approach to treat immunoglobulin A (IgA) nephropathy, whereas the role of fish oils as a supplement is controversial. Tumor necrosis factor alpha (TNF-alpha) is considered to be involved in the pathophysiologic process of this disorder. Recent in vitro and clinical observations that wormwood can decrease TNF-alpha levels has led us to investigate the effect of wormwood as a supplement in patients with IgA nephropathy. STUDY DESIGN: Pilot uncontrolled trial. SETTING & PARTICIPANTS: 10 patients with biopsy-proven IgA nephropathy, normal kidney function, and a history of at least 3 months of proteinuria with protein excretion > 500 mg/d and < 3,500 mg/d despite ongoing dual renin-angiotensin system blockade. INTERVENTION: The selected patients were given supplements of 1.8 g/d of thujone-free wormwood preparation for 6 months without discontinuing their renin-angiotensin system blockade. OUTCOMES: Proteinuria and blood pressure after intervention compared with baseline values. MEASUREMENTS: Monthly assessment of urine protein-creatinine ratio and blood pressure during the observation period. RESULTS: Urine protein-creatinine ratio decreased significantly from 2,340 +/- 530 to 315 +/- 200 mg/g at the end of the supplementation period (P < 0.001) and was stable during the supplement-free follow-up of another 6 months. Estimated glomerular filtration rate and endogenous creatinine clearance were unchanged during the entire study period. There was a moderate, but significant, decrease (P < 0.002) in mean arterial blood pressure. LIMITATIONS: Open uncontrolled trial including a small number of patients. CONCLUSIONS: Thujone-free wormwood with its favorable safety profile can be an alternative supplement to manage proteinuria in patients with IgA nephropathy. PMID- 20843594 TI - Passive leg raising during cardiopulmonary resuscitation in out-of-hospital cardiac arrest--does it improve circulation and outcome? AB - BACKGROUND: Passive leg raising (PLR), to augment the artificial circulation, was deleted from cardiopulmonary resuscitation (CPR) guidelines in 1992. Increases in end-tidal carbon dioxide (P(ET)CO(2)) during CPR have been associated with increased pulmonary blood flow reflecting cardiac output. Measurements of P(ET)CO(2) after PLR might therefore increase our understanding of its potential value in CPR. We also observed the alteration in P(ET)CO(2) in relation to the return of spontaneous circulation (ROSC) and no ROSC. METHODS AND RESULTS: The P(ET)CO(2) was measured, subsequent to intubation, in 126 patients suffering an out-of-hospital cardiac arrest (OHCA), during 15 min or until ROSC. Forty-four patients were selected by the study protocol to PLR 35 cm; 21 patients received manual chest compressions and 23 mechanical compressions. The PLR was initiated during uninterrupted CPR, 5 min from the start of P(ET)CO(2) measurements. During PLR, an increase in P(ET)CO(2) was found in all 44 patients within 15 s (p=0.003), 45 s (p=0.002) and 75 s (p=0.0001). Survival to hospital discharge was 7% among patients with PLR and 1% among those without PLR (p=0.12). Among patients experiencing ROSC (60 of 126), we found a marked increase in P(ET)CO(2) 1 min before the detection of a palpable pulse. CONCLUSION: Since PLR during CPR appears to increase P(ET)CO(2) after OHCA, larger studies are needed to evaluate its potential effects on survival. Further, the measurement of P(ET)CO(2) could help to minimise the hands-off periods and pulse checks. PMID- 20843595 TI - Conformational selection, dynamic restriction and the hydrophobic effect coupled to stabilization of the BIR3 domain of the human X-linked inhibitor of apoptosis protein by the tetrapeptide AVPI. AB - The XIAP-BIR3 domain blocks a substantial portion of the apoptosis pathway and is an attractive target for novel anticancer agents. The tetrapeptide AVPI, from the protein Smac/DIABLO, binds to the XIAP-BIR3 domain, allowing the cancer cells to die. Here we characterize the binding parameters of AVPI to XIAP-BIR3 and analyze its effects on the thermodynamic stability of this domain. XIAP-BIR3 was exceptionally stable against physical and chemical treatments and became even more stable by interaction with AVPI. Nuclear magnetic resonance experiments demonstrated that conformational selection is taking place upon AVPI interaction with XIAP-BIR3. Molecular dynamics simulations corroborate that the flexibility of XIAP-BIR3 is significantly reduced. The positive binding entropy associated with a loss of conformational entropy involved in the binding indicates that hydrophobic interactions play an important role in the interaction and domain stabilization. The mechanism of XIAP-BIR3 stabilization and its implications for drug affinity optimization are discussed. PMID- 20843596 TI - Simulation studies of ammonia removal from water in a membrane contactor under liquid-liquid extraction mode. AB - Simulation studies were carried out, in an unsteady state, for the removal of ammonia from water via a membrane contactor. The contactor had an aqueous solution of NH(3) in the lumen and sulphuric acid in the shell side. The model equations were developed considering radial and axial diffusion and convection in the lumen. The partial differential equations were converted by the finite difference technique into a series of stiff ordinary differential equations w.r.t. time and solved using MATLAB. Excellent agreement was observed between the simulation results and experimental data (from the literature) for a contactor of 75 fibres. Excellent agreement was also observed between the simulation results and laboratory-generated data from a contactor containing 10,200 fibres. Our model is more suitable than the plug-flow model for designing the operation of the membrane contactor. The plug-flow model over-predicts the fractional removal of ammonia and was observed to be limited when designing longer contactors. PMID- 20843597 TI - Drivers of illegal resource extraction: an analysis of Bardia National Park, Nepal. AB - While park-people conflicts have received worldwide attention, the extent of illegal resource extraction and the relationship with communities' livelihoods has gained little attention in the literature. Thus this paper investigates the impact of socio-economic factors involved in illegal fuel wood and fodder extraction at Bardia National Park in Nepal. Household questionnaires, key informant interviews and focus groups were conducted to identify different plant species used by households and explore the causes and mode of resource extraction in three buffer zone villages in the park. Altogether 50 different plants were identified by villagers that were used regularly for different livelihood purposes. Almost half of the respondents met their needs by illegally and regularly extracting resources from the park. Incentive schemes in the form of development projects were important but not sufficient in meeting the basic needs of households' especially for such daily items such as fuel wood and fodder. The results described in this paper showed that proximity and access to resources either in the national park, the buffer zone community forest or the government forest, and impact on the livelihoods significantly influenced the likelihood of illegal resource extraction activities. Villages that differed in terms of their location to the resource base, the provision of alternative resources and influence of these on their livelihoods showed significant differences in terms of their patterns of resource extraction and use of these resources. As resource use options, resource interest, and resource extraction patterns were different between villages and dependent on circumstances specific to villages, site specific management strategies were necessary and more influential than the enforcement of 'one-size fits all' policies. It is suggested that park management plans should be flexible and adaptive enough to meet site-specific contexts and to endear wider support from local communities. PMID- 20843598 TI - Repeat retrourethral transobturator sling in the management of recurrent postprostatectomy stress urinary incontinence after failed first male sling. AB - BACKGROUND: A failure rate between 20% and 45.5% after retrourethral transobturator sling (RTS) is reported. Recommendations for the management of persistent or recurrent postprostatectomy stress urinary incontinence (SUI) after failed male sling do not exist. OBJECTIVE: The aim of this study was the prospective evaluation of the efficacy of repeat RTS (RRTS) in patients after failed first RTS. DESIGN, SETTING, AND PARTICIPANTS: Between March 2007 and August 2009, 35 patients with mild to severe SUI after failed first RTS were treated with a second AdVance sling (American Medical Systems, Minnetonka, MN, USA). MEASUREMENTS: Preoperative and postoperative evaluation included daily pad use, 1-hr pad test, postvoiding residual (PVR) urine, uroflowmetry, and quality of-life (QoL) scores. RESULTS AND LIMITATIONS: After 6 mo, 45.5% (15 of 33 patients) showed no pad use; 30.3% (10 of 33 patients), one dry "security" pad; 3% (1 of 33 patients), one wet pad; 6.1% (2 of 33 patients), two pads; 3% (1 of 33 patients), pad reduction >=50%; and 12.1% (4 of 33 patients), treatment failure. After 16.6 mo, 34.5% (10 of 29 patients) showed no pad use; 37.9% (11 of 29 patients), one dry "security" pad; 3.4% (1 of 29 patients), one wet pad; 3.4% (1 of 29 patients), two pads; 10.3% (3 of 29 patients), pad reduction >=50%; and 10.4% (3 of 29 patients), treatment failure. Daily pad use and pad weight decreased significantly. PVR and uroflowmetry results showed no significant change. QoL improved significantly. Postoperative acute urinary retention was observed in 23.6% of patients. CONCLUSIONS: RRTS is an effective and safe treatment option for the management of SUI after failed first RTS. PMID- 20843599 TI - Use of steel slag as a granular material: volume expansion prediction and usability criteria. AB - The theoretical equation for predicting volume expansion of steel slag is deduced based on both chemical reaction and physical changes of free lime in steel slag during the hydration process. Laboratory volume expansion testing is conducted to compare the results with the theoretical volume expansion. It is proved that they correlated well. It is furthermore experimentally proved that certain volume expansion of steel slag can be absorbed internally by the void volume in bulk steel slag under external surcharge weight making the apparent volume expansion equal zero. The minimum (lowest) absorbable void volume is approximately 7.5%, which is unrelated to the free lime content. A usability criterion is then developed based on the volume expansion of steel slag (%) and the minimum percentage of the volume that can take the volume expansion of steel slag (%). Eventually the criterion (relationship) is established based on the free lime content, the specific gravity and bulk relative gravity of a specific steel slag sample. The criteria can be used as guidance and specification for the use of steel slag and other expansion-prone nonferrous slags, copper, nickel for instance as a granular material in highway construction. PMID- 20843600 TI - Ageing and structural effects on the sorption characteristics of Cd2+ by clinoptilolite and Y-type zeolite studied using isotope exchange technique. AB - This research investigates the long-term kinetics of Cd(2+) sorption and desorption by calcium-exchanged clinoptilolite (CaCpt) and Y-type (CaY) zeolite using isotopic exchange with (109)Cd while maintaining pH at circumneutral values. The effects of Si/Al ratio and crystal structure of these zeolitic materials on intracrystalline transport of Cd are discussed. A first-order kinetic model was developed to describe the progressive transfer of Cd(2+) to a less reactive form within the zeolite structure, following initial sorption and subsequent desorption of Cd subject to different initial contact times. The kinetic model differentiates between two forms of sorbed Cd(2+) designated 'labile' and 'non-labile' in which the labile form is in immediate equilibrium with the free Cd(2+) ion activity in solution. A model combining diffusion and first-order kinetics for cation exchange was also employed to determine Cd(2+) diffusivity and intracrystalline exchange rates in CaY and CaCpt. The efficiency of Permeable Reactive Barriers (PRBs) containing zeolitic materials in protecting water systems against lateral flow of metal-contaminated leachate was simulated for three contrasting zeolites. The slow transfer of Cd between labile and non labile forms was particularly important in moderating high concentration pulses of Cd traversing the PRB. In addition, the reversibility of Cd fixation effectively restored the sorption capability of the zeolite through slow leakage to drainage water. PMID- 20843601 TI - Degradation of nitroesters by plant tissue cultures. AB - Nitrate esters are widely used as effective explosives, important components of explosive ranges, and energetic plasticizers. The environmental problem arising from the production and use of these compounds can be solved using biotechnology. Phytoremediation appears as an efficient technology for this purpose. The uptake and transformation of nitroglycerine (NG) and ethylene glycol dinitrate (EGDN) from wastewater by plants using in vitro regenerants of Juncus inflexus and Phragmites australis were investigated. The plants were exposed to the NG, (600 mg l(-1)), the parent compound disappeared during 20 days and degradation products as dinitroglycerine (DNG) and mononitroglycerine (MNG) were identified in the medium. During 20 days the starting concentration of 100 mg l(-1) EGDN disappeared in the case of J. inflexus or decreased to 5% in the case of P. australis. Ethylene glycol mononitrate as the degradation product was identified. Using this approach directly to the wastewater from production of explosives, the starting concentration of nitroesters mixture (total concentration 270 mg l(-1)) was decreased by in vitro regenerants of reed (P. australis) during 6 weeks to the water contained only MNG (48 mg l(-1)). PMID- 20843602 TI - Identification of Calotropis procera L. as a potential phytoaccumulator of heavy metals from contaminated soils in Urban North Central India. AB - Lead and cadmium levels were monitored in soil at fifteen urban (riverbank, roadside, industrial and residential) sites in the north central part of India. Calotropis procera, a hardy xerophytic plant was identified and selected for remedial potential as it was seen growing well at all sites. Root and leaf samples were collected simultaneously with soil samples to assess the characteristics of accumulation and tolerance of Pb and Cd in C. procera. Chlorophyll and phenological studies were undertaken to investigate the health of plants. The overall trend of Pb and Cd content in soil and plant samples was in the order Industrial>Roadside>Riverbank>Residential. The highest uptake of both the metals was observed in plants from industrial sites. Sites with more anthropogenic disturbance like vehicular and machinery exhausts exhibited reduced chlorophyll levels, stunted growth as well as a delayed, shortened reproductive phase. The ratios of Pb in leaves to Pb in soil were in the range of 0.60-1.37; while similar ratios of Cd were in the range of 1.25-1.83. Highly significant correlation coefficients were determined between concentrations of Pb and Cd in the samples with R(2) values 0.839 for soil, 0.802 for leaf and 0.819 for root samples. The strong correlation between the degree of contamination and concentrations of Pb and Cd in plant samples identifies C. procera as an effective heavy metal remediator of contaminated lands coupled with environmental stress. PMID- 20843603 TI - Thermal decomposition studies of riot control agent omega-chloroacetophenone (CN) by pyrolysis-gas chromatography-mass spectrometry. AB - Pyrolysis-GC/MS system with on-line micro-furnace was used to make rapid evaluation of omega-chloroacetophenone (CN) decomposition under inert thermal atmospheres. The volatile products evolved during pyrolysis were analyzed by thermal gravimetric analysis (TGA) and Py-GC/MS to obtain specific thermogram and pyrogram. Thermal gravimetric analysis results showed that CN undergoes sublimation at 167 degrees C prior to its decomposition at 229 degrees C. Totally 45 degradation products were identified based on mass spectral library matching with the aid of correlation of the values of boiling point (bp) and retention time. A large number of mono-aromatics and polycyclic aromatic hydrocarbons were observed beyond 600 degrees C. In addition to the aromatic hydrocarbons, oxygenated compounds were also observed during the pyrolysis process. The pyrolysis mechanism was proposed based on the determined pyrolysates and their relative abundance with temperature. The investigation results can provide significant information for understanding the thermal behavior of CN and evaluation of the potential influence of the pyrolysates to living being and the environment. PMID- 20843604 TI - The measurement of pain in intensive care unit: comparison of 5 self-report intensity scales. AB - Unlike wards, where chronic and acute pain are regularly managed, comparisons of the most commonly used self-report pain tools have not been reported for the intensive care unit (ICU) setting. The objective of this study was to compare the feasibility, validity and performance of the Visual Analog Scale (horizontal (VAS H) and vertical (VAS-V) line orientation), the Verbal Descriptor Scale (VDS), the 0-10 oral Numeric Rating Scale (NRS-O) and the 0-10 visually enlarged laminated NRS (NRS-V) for pain assessment in critically ill patients. One hundred and eleven consecutive patients admitted into a medical-surgical ICU were included as soon as they became alert and were able to follow simple commands. Pain was measured using the 5 scales in a randomized order upon enrollment-(T1) and after (T2) administration of an analgesic or, in absence of pain upon enrollment, after a nociceptive procedure. The rate of any response obtained both at T1 and T2 (success rate) was significantly higher for NRS-V (91%) compared with NRS-O (83%), VDS (78%), VAS-H (68%) and VAS-V (66%). Pain intensity changed significantly between T1 and T2, showing a good validity and responsiveness for the 5 scales, which correlated well between each other. The negative predictive value calculated from true and false negatives defined by real and false absence of pain was highest for NRS-V (90%). In conclusion, the NRS-V should be the tool of choice for the ICU setting, because it is the most feasible and discriminative self-report scale for measuring critically ill patients' pain intensity. PMID- 20843605 TI - A suite of genes expressed during transition to parasitic lifestyle in the trichostrongylid nematode Haemonchus contortus encode potentially secreted proteins conserved in Teladorsagia circumcincta. AB - The control of gastro-intestinal nematodes remains largely based on anthelminthic treatments, however spreading of anthelmintic resistance has reduced their efficacy. The genes involved in the transition to parasitic lifestyle could constitute targets of interest to develop alternative control strategies. In the trichostrongylid nematode Haemonchus contortus, we have used a SSH (Suppressive Subtractive Hybridization) based approach to generate two distinct subtracted cDNA libraries specifically enriched in cDNA expressed during the early parasitic fourth stage larvae L4 (5 days post-infection). A total of 200 clones were subjected to dot-blot experiments and 46 clones were selected for further characterization. The 46 corresponding expressed sequence tags (EST) were found to cluster into nine contigs. The corresponding full-length cDNA was obtained for all candidates. The genes encoding potentially secreted proteins were investigated in more detail. RT-PCR experiments confirmed their specific expression or over expression from the early L4 larvae to the adult stages and search for homologs in the trichostrongylid species T. circumcincta was performed in order to investigate whether they may be novel cross-specific targets. PMID- 20843607 TI - Fixing the tube. PMID- 20843608 TI - The Trier Social Stress Test for Groups (TSST-G): A new research tool for controlled simultaneous social stress exposure in a group format. AB - Psychological stress is an ubiquitous challenge across human cultures affecting mental and physical health. Recent evidence indicates that performance tasks combining elements of socio-evaluative threat and uncontrollability elicit reliable stress responses. The Trier Social Stress Test (TSST) is the most frequently used psychological protocol in stress research; however, to date it has only been available in a single-subject version. In particular, there is an increasing need in several emerging research fields such as stress research or social neurosciences for a standardized research tool to expose relatively large groups of subjects to controlled simultaneous stress. In search of a laboratory stressor that allows simultaneous stress exposure in a group format, we exposed a total of 25 healthy male participants to the Trier Social Stress Test for Groups (TSST-G; public speaking and mental arithmetic tasks in front of a panel of two evaluators in groups of six participants) and a specific control condition. Results showed that the TSST-G induced significant increases in cortisol, heart rate, and psychological stress responses. The TSST-G provides a novel, effective, and economical protocol for experimental paradigms requiring simultaneous stress induction in multiple participants. PMID- 20843609 TI - Ethambutol-induced optic neuritis and multiple sclerosis: is there an association? PMID- 20843610 TI - Neuronal-immune interactions in mediating stress effects in the etiology and course of schizophrenia: role of the amygdala in developmental co-ordination. AB - Stress, in its many forms, is long associated with the etiology and course of schizophrenia. The mechanisms mediating the impacts of stress are not fully elucidated. Here it is proposed that stress induced cortisol alters kynurenic acid (KA) and quinolinic acid (QA) in the cortex and amygdala/striatum, respectively. These effects are significantly modulated by BAG-1 (bcl-2 associated anthanogene) and involve ROS, IL-18, and the induction of IDO (indoleamine 2,3-dioxygenase). The kynurenine pathway (KP) products response to stress seems to mediate both prenatal etiology and symptom course in adulthood. It is suggested that the effects of cortisol and quinolinic acid in the amygdala, coupled to an increase in dopamine efflux, mediate amygdala driven developmental changes in the cortex and VTA/N.Accumbens junction. This change in patterned brain activity co-ordinates alterations in motivated behaviour and thought outputs. Such developmental alterations determine changes in sensory-amygdala interactions, readily allowing developmental links to changes in lateral inhibition and pre-pulse inhibition. Decreases in vitamin D3 and melatonin further potentiate such stress induced changes. The likely involvement of glia in mediating increases in the KP products suggests that adaptation to stress is driven by neuronal activity as a form of glia to glia communication. PMID- 20843611 TI - Magnetic resonance imaging- versus computed tomography-based target volume delineation of the glandular breast tissue (clinical target volume breast) in breast-conserving therapy: an exploratory study. AB - PURPOSE: To examine MRI and CT for glandular breast tissue (GBT) volume delineation and to assess interobserver variability. METHODS AND MATERIALS: Fifteen breast cancer patients underwent a planning CT and MRI, consecutively, in the treatment position. Four observers (two radiation oncologists and two radiologists) delineated the GBT according to the CT and separately to the MR images. Volumes, centers of mass, maximum extensions with standard deviations (SD), and interobserver variability were quantified. Observers viewed delineation differences between MRI and CT and delineation differences among observers. RESULTS: In cranio-lateral and cranio-medial directions, GBT volumes were delineated larger using MRI when compared with those delineated with CT. Center of mass on MRI shifted a mean (SD) 17% (4%) into the cranial direction and a mean 3% (4%) into the dorsal direction when compared with that on the planning CT. Only small variations between observers were noted. The GBT volumes were approximately 4% larger on MRI (mean [SD] ratio MRI to CT GBT volumes, 1.04 [0.06]). Findings were concordant with viewed MRI and CT images and contours. Conformity indices were only slightly different; mean conformity index was 77% (3%) for MRI and 79% (4%) for CT. Delineation differences arising from personal preferences remained recognizable irrespective of the imaging modality used. CONCLUSIONS: Contoured GBT extends substantially further into the cranio-lateral and cranio-medial directions on MRI when compared with CT. Interobserver variability is comparable for both imaging modalities. Observers should be aware of existing personal delineation preferences. Institutions are recommended to review and discuss target volume delineations and to design supplementary guidelines if necessary. PMID- 20843612 TI - A new total distal radioulnar joint prosthesis: functional outcome. AB - PURPOSE: To present the evolution of design and the short-term functional outcome of our distal radioulnar joint (DRUJ) prosthesis. This total DRUJ prosthesis differs from others in that it consists of 2 parts and attains bony fixation by its hydroxyapatite coating. METHODS: Nineteen patients received a DRUJ prosthesis after a failed Darrach procedure (n = 10), Sauve-Kapandji procedure (n = 7), trauma (n = 1), or DRUJ synovitis (n = 1). Indications for the placement were decreased grip, decreased forearm motion, and pain due to ulnar impingement syndrome and instability of the distal ulna. Seven prostheses were removed, 5 due to loosening, 1 due to continuing pain, and 1 at the request of the patient. The 5 prostheses that loosened were an intermediate prototype no longer in use. In 12 remaining cases, range of motion, grip strength, and pinch strength were measured, and patients completed the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Pain was assessed with the visual analog scale (range, 0 10). A paired t-test was performed to assess the significance of the difference between preoperative and postoperative measurements. RESULTS: Statistically significant improvements were seen in forearm pronation, from an average of 79 degrees to 88 degrees ; grip strength, from an average of 10 kg to an average of 16 kg; and visual analog scale score, decreased from a mean of 5.3 to a mean of 3.5. The distal ulna was clinically stable in all 12 patients who retained the prosthesis. CONCLUSIONS: The intermediate prototype had a high failure rate, 5 out of 5. The early results for the current prosthesis prototype show clinical improvement. Based on these results, we conclude that this prosthesis offers a new treatment option for ulnar instability after distal ulnar resection. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20843613 TI - Multiple triggering in a girl with Ehlers-Danlos syndrome: case report. AB - We report a case of multiple triggering associated with Ehlers-Danlos syndrome. We postulate that the propensity for tendon degeneration in Ehlers-Danlos syndrome coupled with repetitive microtrauma might lead to fraying of the tendon fibers and, consequently, triggering. Indeed, in our case, debridement of the tendons rather than resection of A1 pulley resulted in a good long-term functional outcome 2 years after surgery. PMID- 20843614 TI - Experimental study of forearm compartmental pressures. AB - PURPOSE: Chronic compartment syndrome is well recognized, although it is rare in the forearm. Diagnosis is based on history, clinical examination, and compartment pressure readings. Existing normal pressure ranges for the forearm are based on lower limb measurements. This study aimed to establish normal pre- and post exercise forearm compartment pressures. METHODS: Using a Stryker intracompartmental pressure monitor (Stryker, Kalamazoo, MI), 41 volunteers had pressure measurements of the extensor and flexor forearm compartments before and after exercise. RESULTS: Normal ranges were established for pre-exercise extensor compartment (2-27 mm Hg; upper confidence interval [CI] 18.8-25.2 mm Hg), post exercise extensor compartment (2-24 mm Hg; upper CI 16.8-22.8 mm Hg), pre exercise flexor compartment (1-19 mm Hg; upper CI 13.3-17.4 mm Hg), and post exercise flexor compartment (0-19 mm Hg; upper CI 16-21.4 mm Hg) pressures. No significant difference was found between pressures before and after exercise. There was no correlation between whether pressures increased or decreased following exercise. There was a significant gender difference. Normal ranges were 0 to 25.2 mm Hg for the extensor compartment and 0 to 21.4 mm Hg for the flexor compartment. CONCLUSIONS: This study has shown a significant difference in normal forearm compartment pressures between genders. A normal reference range of flexor and extensor forearm compartment pressures to aid diagnosis of chronic compartment syndrome has been determined. This might also prove useful in aiding the diagnosis of acute forearm compartment syndrome. PMID- 20843615 TI - Reconstruction of complete palsies of the adult brachial plexus by root grafting using long grafts and nerve transfers to target nerves. AB - PURPOSE: We report on the results we obtained with reconstruction for total paralysis of the brachial plexus using long nerve grafts that connect nonavulsed roots to the musculocutaneous and radial nerve. Nerve transfers were performed to restore function of the suprascapular nerve, triceps long head, and pectoralis major muscle. METHODS: We studied 22 young adults with complete brachial plexus palsy who had surgical repair an average of 5 months after trauma. Nerve grafts connected the C5 root to the musculocutaneous nerve. The C6 root was connected by grafts to the radial nerve. When the C6 root was avulsed, the levator scapulae motor branch was connected by grafts to the triceps long head motor branch. In 13 patients, the platysma motor branch was transferred to the medial pectoralis nerve through a long nerve graft. The suprascapular nerve was repaired through transfer of the accessory nerve. Outcomes were assessed an average of 27 months after surgery, focusing on recovery of muscle strength, categorized using the Medical Research Council scale. RESULTS: All but one patient recovered some shoulder abduction, with a mean range of recovered shoulder abduction of 57 degrees . Pectoralis major reinnervation was observed in 9 of the 13. Twenty patients recovered full elbow flexion and achieved at least grade M3 strength. Among the 10 patients in whom the C6 root was grafted to the radial nerve, 4 patients recovered active elbow extension with biceps co-contraction. All patients in whom the levator scapulae nerve was connected to the triceps long head recovered active elbow extension, albeit weak. Double lesions of the musculocutaneous nerve were identified in 4 patients. CONCLUSIONS: Accessory to suprascapular nerve transfer, levator scapulae nerve transfer to the triceps long head and C5 root grafting to the musculocutaneous nerve is now our preferred method of reconstruction in total palsies of the brachial plexus. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 20843616 TI - Comparison of the Sensititre YeastOne(r) dilution method with the Clinical Laboratory Standards Institute (CLSI) M27-A3 microbroth dilution reference method for determining MIC of eight antifungal agents on 102 yeast strains. AB - The Clinical Laboratory Standards Institute ([CLSI] formerly NCCLS) reference broth microdilution testing method (protocol M27-A3) was compared with a commercially available methods (Sensititre YeastOne((r))) by testing two quality control strains and 102 isolates of Candida sp. and Cryptococcus sp. against fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole, flucytosin, amphotericin B and caspofungin. Minimal inhibitory concentrations (MIC) endpoints were determined after 24h of incubation for Sensititre YeastOne((r)) and after 24 and 48 h for CLSI microdilution method. Essential agreements between methods vary from 70.6 to 92.2%. Categorical agreements vary from 94.1% for 5FC to 72.6% for AMB. Sensititre YeastOne((r)) reading appears to be useful for avoiding very major errors and this confirms the interest of this method for evaluating new antifungals activity in vitro. PMID- 20843617 TI - [Results of a novel real-time PCR, sequence analysis, Inno-LiPA line probe assays in the detection of hepatitis B virus G1896A precore mutation in French blood donors]. AB - AIM: To screen hepatitis B virus (HBV) genotypes and associated basal core promoter (BCP; T1762A/A1764) and precore (PC; A1896) mutations among the 100 HBV surface antigen (HBsAg) positive voluntary blood donors in France. METHODS: HBV genotypes were determined by using direct sequence analysis. Three methods were used to detect G1896A mutation: non-commercial real-time PCR (PCRTR degrees , line probe assay (InnoLiPA HBV PreCore, INNOGENETICS((r))) and direct sequencing of precore gene. HBV viral load was quantified with two commercial real-time PCR (COBAS((r)) AmpliPrep/COBAS((r)) TaqMan((r)) HBV Test/Roche and Real Time HBV/M2000/Abbott). RESULTS: The mean age of donors was 30 (18-64). Patients were from Africa (42%), Europa (50%), and Asia (8%). HBV/D was the most predominant (37%) genotype followed by HBV/A (31%) and HBV/E (22%). PC and BCP mutants were found in 57% with Inno-LIPA HBV test and 59% with both PCRTR and sequencing methods. A significant difference in the viral load of blood donors with wild and PC mutants was observed with the Taqman Cobas real time PCR (3,19 Log(10) UI/ml versus 4,93 Log(10) UI/ml, p < 0.05). Precore phenotype determination was in agreement with the three PC mutation detection methods in 56% of cases. CONCLUSIONS: Non-Caucasian genotype E was present in the French blood donors. PC mutation was more common than BCP mutations in this study. As HBV infected blood donors were more often asymptomatic carriers, we could speculate that the G1896A mutation may favour the asymptomatic state, supporting previous observations. PMID- 20843618 TI - Antimicrobial susceptibility and tetracycline resistance determinant genotyping of Gallibacterium anatis. AB - The present investigation was undertaken to assess the antimicrobial susceptibility of a collection of 58 Gallibacterium isolates. All strains were tested by the broth dilution method using the veterinary fastidious medium. A total of 46 field strains were tested, whereof 23 were clinical isolates from 10 Mexican layer flocks and another 23 isolates originated from 13 clinically healthy poultry flocks in Denmark. In addition, 12 Gallibacterium reference strains that had been isolated some 30-40 years ago were included. The 58 strains were tested against 23 compounds of different classes. Multidrug resistance (resistance towards>=three drugs) was observed for 65% of the field strains and only two strains were susceptible to all compounds. Most prominently, resistance to tetracycline and sulfamethoxazole was observed in 92% and 97% of the field strains, respectively. For comparison these figures were 67% and 42%, respectively, for the reference strains. Genotyping of tetracycline resistance determinants was performed with primers specific for tet(A-E, H, K-M, O). Strains positive for tet(B), tet(H) and tet(L) were identified, however, in 20 out of 49 tetracycline resistant strains no determinant was identified. This is the first study to determine the antimicrobial susceptibility of Gallibacterium anatis by MIC revealing that multidrug resistance is very common among G. anatis field isolates. tet(B) was by far the most common determinant identified but future work should aim at identifying the tetracycline resistance determinants in the remaining 41% of strains where no determinant was assigned. PMID- 20843619 TI - Comparative evaluation of four competitive/blocking ELISAs for the detection of influenza A antibodies in horses. AB - New Zealand is free from equine influenza and has never experienced an incursion in its horse population. As part of New Zealand's preparedness to an incursion of an exotic animal disease, it was considered necessary to select the most accurate test for equine influenza (EI) from the array of those available. Four readily available blocking/competitive enzyme-linked immunosorbent assays (ELISA), originally developed and marketed for the detection of antibodies against the avian influenza virus, were evaluated using serum samples from New Zealand non infected, non-vaccinated horses (n=365), and Australian field infected (n=99) and experimentally infected horses (n=3). Diagnostic specificities (DSP) and diagnostic sensitivities (DSE) were determined as follows: ELISA-1=98.1%/99.0%; ELISA-2=90.1%/99.0%; ELISA-3=98.1%/96.0%; ELISA-4=95.3%/99.0%. For ELISA-1, DSP and DSE results were comparable to previously published data on a larger sample number from Australian horses (Sergeant et al., 2009). Receiver operating characteristics (ROC) and frequency histogram analysis were also performed. The area under the curve (AUC) ranged from 0.996 to 0.979, with ELISA-1 possessing the highest AUC, followed by ELISA-2, ELISA-4 and ELISA-3. Separation of the negative and the positive serum panel was best for ELISA-4, followed by ELISA-2, ELISA-1 and ELISA-3. In three experimentally infected horses, sero-positivity was detected between 7 and 9 days post-infection, with ELISA-4 being most sensitive, followed by ELISA-1, ELISA-2 and ELISA-3. Overall, the four ELISAs performed well in this evaluation but some differences were observed. PMID- 20843620 TI - Magnetic resonance imaging versus Acute Physiology And Chronic Healthy Evaluation II score in predicting the severity of acute pancreatitis. AB - OBJECTIVE: To study the correlation between established magnetic resonance (MR) imaging criteria of disease severity in acute pancreatitis and the Acute Physiology And Chronic Healthy Evaluation II (APACHE II) score, and to assess the utility of each prognostic indicators in acute pancreatitis. MATERIALS AND METHODS: In this study there were 94 patients with acute pancreatitis (AP), all had abdominal MR imaging. MR findings were categorized into edematous and necrotizing AP and graded according to the MR severity index (MRSI). The APACHE II score was calculated within 24h of admission, and local complications, death, duration of hospitalization and ICU were recorded. Statistical analysis was performed to determine their correlation. RESULTS: In patients with pancreatitis, no significant correlation can be found between the APACHE II score and the MRSI score (P=0.196). The MRSI score correlated well with morbidity (P=0.006) but not with mortality (P=0.137). The APACHE II score correlated well with mortality (P=0.002) but not with the morbidity (P=0.112). The MRSI score was superior to the APACHE II score as a predictor of the length of hospitalization (r=0.52 vs. r=0.35). A high MRSI and APACHE II score correlated with the need for being in the intensive care unit (ICU) (P=0.000 and P=0.000, respectively). CONCLUSION: In patients with pancreatitis, MRSI is superior to APACHE II in assessing local complications from pancreatitis but has a limited role in determining systemic complications in which the APACHE II score excels. PMID- 20843621 TI - Relevance of CONSORT reporting criteria for research on eHealth interventions. AB - OBJECTIVE: In 1996, 2001, and 2010, the Consolidated Standards of Reporting Trials (CONSORT) group released criteria for reporting critical information about randomized clinical trials [1,2]. These criteria were intended to improve the quality and completeness of reporting of RCTs in health care research. This paper discusses the relevance of the CONSORT recommendations for the reporting and design of eHealth research. METHODS: We reviewed the CONSORT recommendations and discussed their particular relevance to eHealth (electronic information, support and/or communication resources designed to promote health) research. This review focuses on such issues as recruitment and screening of participants, description of treatment elements, and reporting of outcome data and adverse events. RESULTS: eHealth research presents special challenges regarding the comprehensive and effective reporting of research information. However, the strategic application of CONSORT recommendations holds great promise for improving the quality and informativeness of eHealth research. CONCLUSION: Investigators need to consider CONSORT recommendations at all stages of the research enterprise, including planning, execution and reporting in order to increase the informativeness of their research efforts. PRACTICE IMPLICATIONS: The recommendations contained in this paper have the potential to enhance the public health and scientific value of eHealth research. PMID- 20843622 TI - Health care across a language divide. PMID- 20843624 TI - Radiation exposure of vascular surgery patients beyond endovascular procedures. AB - BACKGROUND: Medical imaging evaluations provide valuable information and are often imperative in the care of our patients. Radiation exposure in patients who undergo medical imaging procedures is not routinely monitored and the associated risks are often underestimated. METHODS: Radiation exposure associated with computed tomography (CT) angiography and coronary intervention is reviewed. RESULTS: Vascular surgeons are often involved in the decision-making process in roughly 30% of CT scans performed that are believed to be unnecessary. Society for Vascular Surgery (SVS) practice guidelines for patients with abdominal aortic aneurysms recommended eliminating a 6-month contrast surveillance CT if no endoleak was observed at 1 month after endovascular aneurysm repair (EVAR). Ultrasound and aortic duplex can help eliminate some of the CT scans. CONCLUSION: Vascular surgeons must remain vigilant in monitoring radiation exposure for their patients who have potential for coronary and vascular imaging with radiation. Judicious use of alternative imaging modalities when possible and maintaining the dose as low as reasonably achievable (ALARA) is the responsibility of vascular surgeons. PMID- 20843623 TI - Sodium 4-phenylbutyrate protects against spinal cord ischemia by inhibition of endoplasmic reticulum stress. AB - OBJECTIVE: Delayed paraplegia after operation on the thoracoabdominal aorta is considered to be related to vulnerability of motor neurons to ischemia. Previous studies have demonstrated the relationship between neuronal vulnerability and endoplasmic reticulum (ER) stress after transient ischemia in the spinal cord. The aim of this study was to investigate whether sodium 4-phenylbutyrate (PBA), a chemical chaperone that reduces the load of mutant or unfolded proteins retained in the ER during cellular stress, can protect against ischemic spinal cord damage. METHODS: Spinal cord ischemia was induced in rabbits by direct aortic cross-clamping (below the renal artery and above the bifurcation) for 15 minutes at normothermia. Group A (n = 6) was a sham operation control group. In group B (n = 6) and group C (n = 6), vehicle or 15 mg/kg/h of sodium 4-PBA was infused intravenously, respectively, from 30 minutes before the induction of ischemia until 30 minutes after reperfusion. Neurologic function was assessed at 8 hours, and 2 and 7 days after reperfusion with a Tarlov score. Histologic changes were studied with hematoxylin-eosin staining. Immunohistochemistry analysis for ER stress-related molecules, including caspase12 and GRP78 were examined. RESULTS: The mean Tarlov scores were 4.0 in every group at 8 hours, but were 4.0, 2.5, and 3.9 at 2 days; and 4.0, 0.7, and 4.0 at 7 days in groups A, B, and C, respectively. The numbers of intact motor neurons at 7 days after reperfusion were 47.4, 21.5, and 44.9 in groups A, B, and C, respectively. There was no significant difference in terms of viable neurons between groups A and C. Caspase12 and GRP78 immunoreactivities were induced in motor neurons in group B, whereas they were not observed in groups A and C. CONCLUSION: Reduction in ER stress-induced spinal cord injury was achieved by the administration of 4-PBA. 4 PBA may be a strong candidate for use as a therapeutic agent in the treatment of ischemic spinal cord injury. PMID- 20843625 TI - Prevention of radiation injury from medical imaging. AB - INTRODUCTION: Concerns over radiation safety are valid. Understanding and maintaining safe administration helps patients understand the potential risks during endovascular procedures. METHODS: X-ray production, units of radiation exposure, and forms of direct and indirect exposures are discussed. RESULTS: Positioning of the image intensifier as close to the patient as practical, moving the x-ray tube as far from the patient as possible, and using pulse fluoroscopy are all ways to help decrease the radiation dose. Collimation, achievable without the use of fluoroscopy, improves image quality while decreasing the radiation dose. Time, distance, and shielding are the three most productive means of reducing radiation exposure. CONCLUSION: The best defense against radiation injury to both patient and staff is to minimize the total fluoroscopy time, keep the image intensifier close to the patient, collimate to the region of interest, and use appropriate radiation shielding and monitoring. PMID- 20843626 TI - Tuberculosis should not be ignored in patients with peripheral gangrene. AB - Peripheral gangrene, characterized by distal ischemia of the extremities, is a rare complication in patients with tuberculosis (TB). We diagnosed a female patient with gangrene of her left toe caused by TB infection. She presented with fever, lymphadenectasis, and peripheral gangrene of the left toe. Lymph node biopsy confirmed tuberculous lymphadenitis and the computer tomography angiography showed vasculitis. The patient underwent antituberculous therapy and her condition was gradually improved. Although it is rare, TB should be considered as a possible cause of peripheral gangrene. PMID- 20843627 TI - The impact of body mass index on perioperative outcomes of open and endovascular abdominal aortic aneurysm repair from the National Surgical Quality Improvement Program, 2005-2007. AB - OBJECTIVES: Obesity and morbid obesity have been shown to increase wound infections and occasionally mortality after many surgical procedures. Little is known about the relative impact of body mass index (BMI) on these outcomes after open (OAR) and endovascular abdominal aortic aneurysm repair (EVAR). METHODS: The 2005-2007 National Surgical Quality Improvement Program (NSQIP), a multi institutional risk-adjusted database, was retrospectively queried to compare perioperative mortality (in-hospital or 30-day) and postoperative wound infections after OAR and EVAR. Patient demographics, comorbidities, and operative details were analyzed. Obesity was defined as a BMI >30 kg/m(2) and morbid obesity as a BMI >40 kg/m(2). Outcomes were compared with t test, Wilcoxon rank sum, chi(2), and multivariate logistic regression. RESULTS: There were 2097 OARs and 3358 EVARs. Compared with EVAR, OAR patients were younger, more likely to be women (26% vs 17%, P < .001), and less obese (27% vs 32%, P < .001). Mortality was 3.7% after OAR vs 1.2% after EVAR (risk ratio, 3.1; P < .001), and overall morbidity was 28% vs 12%, respectively (relative risk, 2.3; P < .001). Morbidly obese patients had a higher mortality for both OAR (7.3%) and EVAR (2.4%) than obese patients (3.9% OAR; 1.5% EVAR) or nonobese patients (3.7% OAR; 1.1% EVAR). Obese patients had a higher rate of wound infection vs nonobese after OAR (6.3% vs 2.4%, P < .001) and EVAR (3.3% vs 1.5%, P < .001). Morbid obesity predicted death after OAR but not after EVAR, and obesity was an independent predictor of wound infection after OAR and EVAR. CONCLUSIONS: Morbid obesity confers a worse outcome for death after abdominal aortic aneurysm repair. Obesity is also a risk factor for infectious complications after OAR and EVAR. Obese patients and, particularly, morbidly obese patients should be treated with EVAR when anatomically feasible. PMID- 20843628 TI - Success of arterial revascularization determined by contrast ultrasound muscle perfusion imaging. AB - BACKGROUND: In the early postoperative evaluation of the success of arterial revascularization, ankle-brachial index (ABI) and other noninvasive tests lack reliability, especially in patients with incompressible arteries or local edema. Contrast-enhanced ultrasound (CEUS) imaging of limb muscle perfusion may be an alternative to standard tests if it detects treatment success reliably. METHODS: We compared a simplified CEUS method with clinical staging, pulse volume recording (PVR), and ABI in patients with lifestyle-limiting peripheral arterial disease undergoing revascularization by percutaneous transluminal angioplasty (PTA) or bypass surgery. Patients underwent staging, PVR, ABI, and CEUS before, directly after, and 3 to 5 months after successful PTA (n = 20) or successful bypass grafting (n = 14). For CEUS, contrast agent was injected into an antecubital vein, and the time from beginning to peak intensity of contrast enhancement (TTP) in the calf muscle was measured. RESULTS: Successful revascularization by both PTA and bypass was associated with a significant improvement in staging, PVR, ABI, and TTP directly after intervention and at follow-up. Median ABI increased from 0.60 to 0.85 (P = .001) after PTA and from 0.36 to 0.76 (P = .003) after bypass surgery. Median TTP decreased from 45 seconds to 24 seconds (P = .015) and from 30 seconds to 27 seconds (P = .041), respectively. McNemar analysis revealed unidirectional changes in both ABI and TTP (P = .625 after PTA and P = 1.000 after bypass surgery), and equivalence analysis showed 95% confidence intervals within clinical indifference, indicating that TTP was equivalent to standard tests in detecting successful revascularization. CONCLUSIONS: Contrast ultrasound perfusion imaging of calf muscle after arterial revascularization may be a valuable alternative to standard noninvasive tests such as ABI or PVR to determine the success of an arterial revascularization. PMID- 20843629 TI - Early type III endoleak with an Endurant endograft. AB - We report the case of an 81-year-old man who presented with an intraoperative type III endoleak after treatment with an Endurant endograft for a 60-mm abdominal aortic aneurysm. To our knowledge, this is the first case of a type III endoleak reported with this new device. It was most likely due to a tear in the polyester graft, the cause of which remains speculative. The tear was demonstrated by postoperative angiography, which was more informative than computed tomography. The endoleak was successfully treated by relining with an aorto-uni-iliac device. PMID- 20843630 TI - Acute and chronic radiation injury. AB - INTRODUCTION: Although all areas of the body are susceptible to radiation injury, different tissues have varying tolerances for radiation exposure. The goal of this summary is to introduce basic concepts of radiation biology and discuss the effects of radiation on various tissues. METHODS: Reference texts and literature were reviewed to summarize key points in radiation biology and the direct and indirect cell damage caused by radiation. RESULTS: The most prevalent factor for injury is long exposure time, which can be an issue in lengthy peripheral vascular or aortic interventions. Several key maneuvers can help decrease exposure for both the patient and the physician. CONCLUSION: Radiation induces tissue injury at the cellular level. The use of good fluoroscopic technique is imperative for physician and patient protection. PMID- 20843631 TI - Cost-effectiveness of guidelines for insertion of inferior vena cava filters in high-risk trauma patients. AB - BACKGROUND: Inferior vena cava filters (IVCFs) can prevent pulmonary embolism (PE); however, indications for use vary. The Eastern Association for the Surgery of Trauma (EAST) 2002 guidelines suggest prophylactic IVCF use in high-risk patients, but the American College of Chest Physicians (ACCP) 2008 guidelines do not. This analysis compares cost-effectiveness of prophylactic vs therapeutic retrievable IVCF placement in high-risk trauma patients. METHODS: Markov modeling was used to determine incremental cost-effectiveness of these guidelines in dollars per quality-adjusted life-years (QALYs) during hospitalization and long term follow-up. Our population was 46-year-old trauma patients at high risk for venous thromboembolism (VTE) by EAST criteria to whom either the EAST (prophylactic IVCF) or ACCP (no prophylactic IVCF) guidelines were applied. The analysis assumed the societal perspective over a lifetime. For base case and sensitivity analyses, probabilities and utilities were obtained from published literature and costs calculated from Centers for Medicare & Medicaid Services fee schedules, the Healthcare Cost & Utilization Project database, and Red Book wholesale drug prices for 2007. For data unavailable from the literature, similarities to other populations were used to make assumptions. RESULTS: In base case analysis, prophylactic IVCFs were more costly ($37,700 vs $37,300) and less effective (by 0.139 QALYs) than therapeutic IVCFs. In sensitivity analysis, the EAST strategy of prophylactic filter placement would become the preferred strategy in individuals never having a filter, with either an annual probability of VTE of >= 9.6% (base case, 5.9%), or a very high annual probability of anticoagulation complications of >= 24.3% (base case, 2.5%). The EAST strategy would also be favored if the annual probability of venous insufficiency was <7.69% (base case, 13.9%) after filter removal or <1.90% with a retained filter (base case, 14.1%). In initial hospitalization only, EAST guidelines were more costly by $2988 and slightly more effective by .0008 QALY, resulting in an incremental cost-effectiveness ratio of $383,638/QALY. CONCLUSIONS: Analysis suggests prophylactic IVC filters are not cost-effective in high-risk trauma patients. The magnitude of this result is primarily dependent on probabilities of long-term sequelae (venous thromboembolism, bleeding complications). Even in the initial hospitalization, however, prophylactic IVCF costs for the additional quality-adjusted life years gained did not justify use. PMID- 20843632 TI - Bleomycin A5 sclerotherapy for cervicofacial lymphatic malformations. AB - OBJECTIVES: The purpose of this study was to document the results of bleomycin A5 sclerotherapy for cervicofacial lymphatic malformations (LMs), and the clinical data of 65 patients between October 2004 and October 2007 were reviewed. METHODS: Of the 65 patients in the study, 60 patients were given intralesional injection of bleomycin A5. Five patients underwent partial resection, and then an injection of bleomycin A5 for the remaining lesion. The outcomes were assessed by physical examination and Doppler ultrasonography scan. The follow-up time was from 6 months to 3 years after the last injection (mean, 16 months). RESULTS: Among the 65 patients, 41 were men and 24 were women (1.7:1 male:female ratio), the age range was 3 months to 45 years (mean, 12 years). Thirty-two lesions (49%) were macrocystic, 30 (46%) were microcystic, and 3 (5%) were combined. Each patient received 1 to 10 injections (mean, 3.0 injections) for the whole course of treatment, and the total dose of bleomycin A5 was from 8 to 80 milligrams (mean, 24.0 mg). Twenty-six of 32 macrocystic lesions (81%) showed greater than 90% reduction, whereas another 6 (19%) exhibited 50% to 90% reduction. Nineteen of 30 microcystic lesions (63%) showed greater than 90% reduction; 10 (33%) had 50% to 90% reduction; and 1 (4%) had less than 50% size reduction. Of the 3 combined lesions, 2 (67%) had greater than 90% shrinkage, and 1 (3%) had less than 50% reduction. The complications included ulceration of oral mucosa, minor soft tissue atrophy, mild fever, and hematoma. There was no recurrence throughout the follow-up period. CONCLUSION: These data suggest bleomycin A5 is a safe and effective intralesional agent for the treatment of macrocystic LMs, superficial oral mucosa LM, and localized deep microcystic lesions. For extensive macrocystic LMs involving contiguous anatomic areas and diffuse microcystic lesions involving deep tissues, bleomycin A5 injection combined with resection is necessary. PMID- 20843633 TI - ELISA assays and alcohol: increasing carbon chain length can interfere with detection of cytokines. AB - Enzyme-linked immunosorbent assays (ELISAs) are frequently used in studies on cytokine production in response to treatment of cell cultures or laboratory animals. When an ELISA assay is performed on cell culture supernatants, samples often contain the treatment agents. The purpose of the present study was to determine if some of the agents evaluated might inhibit cytokine detection by interfering with the ELISA, leaving the question of whether cytokine production was inhibited unanswered. Mouse and human cytokine ELISA kits from BD Biosciences were used according to the manufacturer's instructions. Cytokine proteins were subjected to one to five carbon alcohols at 86.8mM (methanol, ethanol, 1 propanol, 2-propanol, n-butanol, and n-pentanol). After treating cell cultures with alcohols of different carbon chain lengths, we found that some of the alcohols interfered with measurement of some cytokines by ELISA, thus making their effects on cytokine production by cells in culture unclear. Increasing carbon chain length of straight chain alcohols positively correlated with their ability to inhibit detection of tumor necrosis factor alpha (TNF-alpha) and interleukin 10 (IL-10), but not with the detection of interleukin 6 (IL-6), interleukin 8, (IL-8), and interleukin 12 (IL-12). To avoid misinterpretation of treatment effects, ELISA assays should be tested with the reference protein and the treatment agent first, before testing biological samples. These results along with other recent results we obtained using circular dichroism indicate that alcohols with two or more carbons can directly alter protein conformation enough to disrupt binding in an ELISA (shown in the present study) or to inhibit ligand induced conformational changes (results not shown). Such direct effects have not been given enough consideration as a mechanism of ethanol action in the immune system. PMID- 20843634 TI - Overexpression of 5-HT(1B) mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption. AB - Serotonin 1B (5-HT(1B)) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT(1B) receptors expressed on NAcSh projection neurons by means of virus-mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior. Animals received stereotaxic injections of viral vectors expressing either 5-HT(1B) receptor and green fluorescent protein (GFP) or GFP alone. Home cages equipped with a three bottle (water and 6 and 12% ethanol) lickometer system recorded animals' drinking behaviors continuously, capturing either initiation or maintenance of drinking behavior patterns. Overexpression of 5-HT(1B) receptors during initiation increased consumption of 12% ethanol during both forced-access and free-choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different. Finally, increased 5-HT(1B) expression induced more bouts with very high-frequency licking from the ethanol bottle sippers. During the maintenance phase of drinking, there were no differences between groups in total volume of ethanol consumed; however, there was a shift toward drinking bouts of longer duration, especially for 12% ethanol. This suggests that during maintenance drinking, increased 5-HT(1B) receptors facilitate longer drinking bouts of more modest volumes. Taken together, these results indicate that 5-HT(1B) receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol-drinking behavior. PMID- 20843635 TI - Assessment of GABA-B, metabotropic glutamate, and opioid receptor involvement in an animal model of binge drinking. AB - Drinking to intoxication or binge drinking is a hallmark characteristic of alcohol abuse. Although hard to model in rodents, the scheduled high alcohol consumption (SHAC) procedure generates high, stable ethanol intake and blood ethanol concentrations in mice to levels consistent with definitions of binge drinking. The purpose of the present studies was to determine the effects of pharmacological manipulation of the opioidergic, glutamatergic, and gamma aminobutyric acid (GABA)ergic systems on binge drinking with the SHAC procedure. Parallel manipulations were conducted in mice trained in operant self administration of either sucrose or ethanol. For the SHAC procedure, genetically heterogeneous Withdrawal Seizure Control mice were given varying periods of fluid access, with a 30-min ethanol session every third day (total of seven). Mice were pretreated intraperitoneally with naltrexone (0, 0.6, or 1.25 mg/kg), baclofen (0, 2.5, or 5.0 mg/kg), or 2-methyl-6-(phenylethynyl)-pyridine (MPEP; 0, 3.0, or 10.0 mg/kg) before each ethanol session. For the operant self-administration procedure, separate groups of C57BL/6 mice were trained to complete a single response requirement (16 presses on the active lever) to gain 30 min of access to an ethanol or a sucrose solution. Mice received pretreatments of the same doses of naltrexone, MPEP, or baclofen before the self-administration sessions, with saline injections on intervening days. Naltrexone produced a dose-dependent decrease in binge drinking, and the highest dose also significantly decreased operant self-administration of ethanol and sucrose. Both doses of baclofen significantly decreased binge alcohol consumption, but the higher dose also tended to decrease water intake. The highest dose of baclofen also significantly decreased operant self-administration of sucrose. MPEP (10 mg/kg) significantly decreased binge alcohol consumption and sucrose self-administration. These results indicate that manipulation of the opioidergic, glutamatergic, and GABAergic systems significantly decreased binge drinking. PMID- 20843636 TI - Elevated testosterone in females reveals a robust sex difference in altered androgen levels during chronic alcohol withdrawal. AB - The endocrine disruption associated with alcohol (ethanol) abuse in both males and females is widely recognized. Ethanol intoxication and withdrawal in males results in significant reductions in androgen levels. Less is known about female alcoholics, and because the changes in testosterone concentrations remain controversial, we systematically characterized changes in sex steroids after chronic ethanol exposure and withdrawal in both sexes. Testosterone and 17beta estradiol concentrations were determined during chronic high intoxication, over a withdrawal time course, and following a period of abstinence using a genetic model of withdrawal vulnerability, the Withdrawal Seizure-Resistant (WSR) and Prone (WSP) selected lines. In males, testosterone concentrations were significantly lower in intoxicated WSP mice after chronic ethanol exposure, and were dramatically and transiently reduced during the withdrawal period in both WSR and WSP lines. In contrast, testosterone levels were increased in intoxicated WSP females and in both WSR and WSP mice during withdrawal. Chronic ethanol exposure disrupted normal estrous cycling in WSP mice, associated with hyperandrogenemia while intoxicated. In abstinence, elevated testosterone was observed in both sexes but only in WSR mice. Estrogen levels were modestly reduced during withdrawal in both WSR and WSP lines, predominantly in males. These findings identify a mechanism based on altered androgen signaling that likely contributes to sex-specific responses during withdrawal. However, only WSR mice showed similar elevations in androgen long after withdrawal in both sexes, suggesting that genotype is an important determinant of steroid responses after abstinence. Increased androgen signaling in females as a consequence of chronic ethanol exposure may play an important and relatively uncharacterized role in sexually dimorphic responses to alcohol abuse. PMID- 20843637 TI - The alcohol use disorders identification test: reliability study of the Japanese version. AB - Alcohol abuse is recognized as a major health issue, and early detection of alcohol abuse is very important. The alcohol use disorders identification test (AUDIT) has been widely used as a specific tool for its detection. We conducted a cross-sectional survey of Japanese male workers to validate the Japanese version of this test. The Japanese version of AUDIT also contains 10 questions. A score greater than or equal to 11 was considered as indicative of serious alcohol abuse or dependence. A total of 168 subjects took part in the survey, and 145 of these subjects sent in their responses to the questionnaire. Among these 145 subjects, there were 136 men. The average age of these male subjects was 38.2 years (+/ 9.9). Among the 136 male subjects, 113 returned completely filled-in questionnaires. There were no significant differences in the mean values of the AUDIT score, short version of AUDIT (AUDIT-C) score, or age between the subjects who did or did not indicate their names in the questionnaire. The internal reliability (Cronbach alpha) of AUDIT was 0.67 for the total subject population and 0.45 for the subjects who indicated their names in the questionnaire (n=69). Cronbach's alpha of AUDIT-C was 0.51 for the total subject population and 0.43 for the subjects who indicated their names in the questionnaire. The Spearman's rho between AUDIT and AUDIT-C was 0.92 (P<.01), and the percentage of subjects with an AUDIT score greater than or equal to 11 was 8.0% (9/113). Thus, the Japanese version of AUDIT showed satisfactory internal reliability. AUDIT is easy to use and is useful for the detection of alcohol-related problems in occupational workers. PMID- 20843639 TI - Alcohol and multiple trauma: is there an influence on the outcome? AB - A relevant number of trauma patients are intoxicated with alcohol at admission in trauma centers. Meanwhile, some studies provide data suggesting a profound influence of ethanol on the posttraumatic clinical course; others could not confirm these findings. Knowledge of the influence of ethanol in a multiple trauma cohort is lacking. Therefore, we performed a retrospective outcome study of initially intoxicated multiple trauma patients in a German level-1 trauma center. Patients with an Injury Severity Score greater than or equal to 16 and aged 16-65 years were included in our study. Ventilation time, duration of intensive care unit treatment, the course of cytokines, and the incidence of systemic inflammatory response syndrome (SIRS), sepsis, and multiple organ dysfunction syndrome (MODS) were analyzed. Total in-patient time, mortality, and the requirement for blood products were evaluated. Logistic regression analyses were performed. Injury severity was comparable in both groups but there were more severe abdominal injuries in alcohol-intoxicated patients. The clinical course was comparable in both groups. Alcohol consumption was not an independent risk factor to sustain SIRS (odds ratio [OR], 1.00; 95% confidence interval [CI], 0.59 1.70), sepsis (OR, 0.84; 95% CI, 0.54-1.31), or for mortality (OR, 1.08; 95% CI, 0.53-2.13). There was a trend toward an increased incidence of MODS in alcohol intoxicated patients (OR, 2.74; 95% CI, 0.90-8.35). Blood alcohol level at the time of admission is not a valuable marker for worse or improved outcome in multiple trauma patients. There were no ethanol-related differences concerning overall injury severity; however, more severe abdominal injuries were found in alcohol-intoxicated patients. There was no increased risk for posttraumatic complications in primarily alcohol-intoxicated multiple trauma patients. PMID- 20843638 TI - Cultural and social network predictors of drinking among Korean American women. AB - This study estimated the association of cultural and social mechanisms with Korean American women's drinking behaviors. Data were drawn from telephone interviews with 591 Korean women selected from a random sample of households in California with Korean surnames during 2007. About 62% of eligible respondents completed the interview. Respondents reported any lifetime drinking (yes/no), drinking volume (typical number of drinks consumed on drinking days), level of acculturation, and described their social network by assessing who encouraged or discouraged drinking (drinking support) or drank (drinking models). Multivariable regressions were used for analyses. About 70% (95% confidence interval [95%CI]:, 67, 74) of Korean American women reported any lifetime drinking and current drinkers drank 1.18 (95%CI: 1.07, 1.28) drinks on drinking days. Acculturation was not significantly associated with any lifetime drinking or drinking volume, whereas models and support for drinking were statistically significantly associated with a higher probability of any lifetime drinking and drinking more on drinking days. Each additional encourager, or one or fewer discourager, for drinking in women's social networks was associated with a 2% (95%CI: 1, 3) higher probability of any lifetime drinking and drinking 0.25 (95%CI: -0.53, 1.18) more drinks on drinking days. Each additional drinker in women's networks was associated with a 4% (95%CI: 1, 8) higher probability of any lifetime drinking and drinking 0.26 (95%CI: -0.05, 0.60) more drinks on drinking days. Korean American women's drinking appears to be strongly related to their social networks, although how women take on traits of their new environment was not. PMID- 20843640 TI - Induction of blood lymphocyte cytochrome P450 2E1 in early stage alcoholic liver cirrhosis. AB - To validate the induction of blood lymphocyte cytochrome P450 2E1 (CYP2E1) expression in alcoholic liver cirrhosis and mRNA and protein expression of CYP2E1 in freshly prepared blood lymphocytes of alcoholic liver cirrhotic (ACP), nonalcoholic cirrhotic patients (NACP), alcoholic controls (ACs), and nonalcoholic controls (NACs) were investigated. Registered ACP and NACP patients at Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow, India along with NACs and ACs were included in the study. Real time polymerase chain reaction, enzyme-linked immunosorbent assay, and CYP2E1-dependent enzyme activity were determined in blood lymphocytes isolated from cases and controls. Significant increases in CYP2E1 mRNA and protein expression were observed in freshly prepared blood lymphocytes isolated from ACs and ACP patients as compared with respective NACs or NACP patients. A concomitant increase in N nitrosodimethyamine demethylase activity was evident in the blood lymphocytes of ACs and ACP patients. Interestingly, the comparative increase observed in CYP2E1 expression was of greater magnitude in the blood lymphocytes isolated from ACP patients, although they abstained from alcohol drinking. Findings suggest that significant increase in the CYP2E1 mRNA and protein expression in the blood lymphocytes, isolated from early stage ACP patients, can be used to predict alcohol-induced toxicity. PMID- 20843641 TI - Continuous versus discontinuous drinking of an ethanol liquid diet in peripubertal rats: effect on 24-h variation of lymph node and splenic mitogenic responses and lymphocyte subset populations. AB - Excessive alcohol consumption continues to be a major public health problem, particularly in the adolescent and young adult populations. Generally, such a behavior tends to be confined to the weekends, to attain frequently binge drinking. This study in peripubertal male rats compares the effect of the discontinuous feeding of a liquid diet containing a moderate amount of ethanol (6.2% wt/vol) to that of continuous ethanol administration or a control diet, taking as end points the 24-h variations of plasma prolactin levels and mitogenic responses and lymphocyte subset populations in submaxillary lymph nodes and spleen. Animals received the ethanol liquid diet starting on day 35 of life, the diet being similar to that given to controls except for that maltose was isocalorically replaced by ethanol. Ethanol provided 36% of the total caloric content. Every week, the discontinuous ethanol group received the ethanol diet for 3 days and the control liquid diet for the remaining 4 days. After 4 weeks, rats were killed at six time intervals, beginning at 0900 h. A significant decrease of splenic cells' response to concanavalin A, and of lymph node and splenic cells' response to lipopolysaccharide was found in rats under the discontinuous ethanol regime, when compared with control- or ethanol-chronic rats. Under discontinuous ethanol feeding, mean values of lymph node and splenic CD8(+) and CD4(+)-CD8(+) cells decreased, whereas those of lymph node and splenic T cells, and splenic B cells, augmented. In rats chronically fed with ethanol, splenic mean levels of CD8(+) and CD4(+)-CD8(+) cells augmented. Both modalities of ethanol administration disrupted the 24 h variation in immune function seen in controls. Mean plasma prolactin levels increased by 3.6-fold and 8.5-fold in rats chronically or discontinuously fed with alcohol, respectively. The immune parameters examined in an additional group of rats fed regular chow and water ad libitum did not differ significantly from control liquid diet. The results support the view that the discontinuous drinking of a moderate amount of ethanol can be more harmful for the immune system than a continuous ethanol intake, presumably by inducing a greater stress as indicated by the augmented plasma prolactin levels observed. PMID- 20843642 TI - Temporal and spatial patterns in the rate of alcohol withdrawal syndrome in a defined community. AB - There is a paucity of data about the epidemiology of alcohol withdrawal syndrome (AWS) and, particularly, with regard to temporal trends and sociodemographic factors. This study included 7,195 episodes of AWS in a defined community (Galicia, Spain) over a 11-year period. We looked for geographical correlations between AWS rate and sociodemographic factors (education and socioeconomic levels and rates of occupational activity and unemployment) within respective districts. We also investigated the inter- and intra-annual time trends for AWS. The median age of the participants was 49 years (interquartile range, 41-60 years), and 85% were men. The annual frequency of AWS episodes remained stable during the study period, with a consistent peak in episodes during the summer months and lowest frequency of episodes in winter months (P<.001). The age- and sex-adjusted geographical distribution of the AWS rate was uneven; districts with high rate tended to cluster. The mean education level was negatively correlated with AWS rate within a given district after adjusting for socioeconomic level, occupational activity rate, and unemployment rate (P<.001). In conclusion, we identified characteristic temporospatial patterns of AWS rate in this defined community. The rate of AWS tended to be higher in the summer months and lower in the winter months. The rate of AWS was higher in districts with low education levels. PMID- 20843643 TI - Immunoglobulin-E reactivity to wine glycoproteins in heavy drinkers. AB - N-glycans from plant and invertebrate allergens can induce extensive immunoglobulin-E (IgE) cross-reactivity in vitro. IgE antibodies against these N glycans, also termed cross-reactive carbohydrate determinants or CCDs, are prevalent in alcohol drinkers. This study investigated the prevalence and biological significance of IgE antibodies to N-glycans from wine glycoproteins in heavy drinkers. A structured questionnaire, skin prick tests, serum IgE levels, IgE-immunoblotting to wine extracts, and basophil activation tests were used to characterize 20 heavy drinkers and 10 control subjects. Eleven heavy drinkers (55%) showed IgE binding to proteins in wine extracts. The proteins were identified by mass spectrometry as grape-derived vacuolar invertase and thaumatin like protein. Immunoblot reactivity was closely associated with the presence of IgE to CCDs and was inhibited by preincubation with a glycoconjugate containing bromelain-type N-glycans. The same conjugate, CCD-bearing allergens, and wine extracts activated basophils in patients with high-titer CCD-specific IgE but not in healthy controls. There was no relationship between immunoblot reactivity and consumption of any specific type of wine. No patient reported symptoms of hypersensitivity to Hymenoptera venom, food, or wine. In conclusion, heavy drinkers frequently show IgE reactivity to the N-glycans of wine glycoproteins. Glycans and wine glycoprotein extracts can induce basophil activation in sensitized alcoholics. The clinical significance of these findings remains to be elucidated. PMID- 20843645 TI - [Temporomandibular joint dislocation occurring by removing an LMA]. PMID- 20843644 TI - The infracolic approach to pancreatoduodenectomy for large pancreatic head tumours invading the colon. AB - BACKGROUND: Tumours arising from the head of the pancreas can invade both the proximal transverse colon and its mesocolon. At laparoscopy, this may be considered a contraindication to proceeding to pancreatoduodenectomy. However, in some patients, pancreatoduodenectomy can still be performed with an R0 resection using an en-bloc resection technique by an infracolic approach. METHODS: This technique relies on the infracolic control of the superior mesenteric vein (SMV) and is based on the presence of a normal fat cuff around the superior mesenteric artery (SMA) on pre-operative imaging. The dissection is maintained along the adventitial plane of the SMA. Pancreatoduodenectomy is performed in conjunction with en-bloc resection of the transverse colon. In the event of tumour invading the SMV, this is also resected en-bloc with the pancreatic head and transverse colon. We reviewed all such cases performed at our institution between April 2004 and April 2009. RESULTS: This technique was attempted in eleven patients. In two patients, the procedure had to be abandoned because of unexpected SMA encasement by tumour. In the remaining nine patients this procedure was carried out successfully. In this paper, the infracolic approach to pancreatoduodenectomy, and the associated limitations, are described in detail. CONCLUSION: The infracolic technique may be used to deal with large pancreatic head tumours and all pancreatic surgeons should be familiar with this technique. In the absence of metastatic disease, large pancreatic head tumours involving the colon can be resected en-bloc with the pancreatic head, as long as the SMA is not encased by the tumour. PMID- 20843646 TI - [Evolution of the pharmacological management of osteoarthritis: the biologics]. AB - Proinflammatory cytokines such as IL-1 beta et TNF alpha are implicated in osteoarthritis where they contribute to the local synovitis. Blocking IL-1 beta is a promising tool in experimental animal's model of osteoarthritis (OA). So far in human clinical trials using IL-1 blockers, the results are inconclusive. The blockade of TNF alpha seems more appropriated for inflammatory forms of hand OA with some encouraging results. Intra-articular administration of biologics is hampered by their short resident time into the joint. Gene therapy is one of the possible way to prolong the local intra-articular delivery of biologics. PMID- 20843647 TI - [The discovery of anesthesia]. PMID- 20843648 TI - [Endovascular treatment of ruptured gastroduodenal aneurysm]. PMID- 20843649 TI - [Physiologic skin changes in pregnancy]. AB - INTRODUCTION: Pregnancy is a period of hormonal, immunological, metabolic and vascular changes. Some of them are considered to be physiologic, but others are real diseases specific or not of pregnancy. The aim of our study is to present the epidemiological and clinical physiologic dermatological changes of pregnancy. METHODS: We present a transversal monocentric study. One hundred pregnant women attending the department of dermatology of the La Rabta hospital were enrolled. Systematic detailed cutaneous examination was performed by a dermatologist to look for a physiologic skin changes. RESULTS: The mean age was 29 years [20-46 years]. Pigmentary changes were the most preponderant (93%), dominated by the areolar region pigmentation (77%). The glandular changes were noted in 75% of cases. The vascular modifications were observed in 77% of pregnant women. Of these, gingival hyperemia was the most common (46%). Others cutaneous changes were less frequent (stria distensae 45%, nevi changes 35%, molluscum gravidarum 10%). DISCUSSION: The physiologic cutaneous changes during pregnancy are numerous. Our study confirms the frequency and the variability of these modifications. The pigmentary changes were the most common finding. PMID- 20843650 TI - [Patient education for osteoarthritis]. AB - Therapeutic education is part of the nonpharmacological management of osteoarthritis (OA) both at the medical and surgical phase. The aim of education at an early stage of OA is to change patients' lifestyle, especially the regular practice of physical activity and weight reduction. When a surgical option is considered, the aim of education is to hasten patient recovery, improve autonomy after surgery, facilitate the return home and reduce the rate of transfer to a rehabilitation unit. Like other nonpharmacological treatment, therapeutic education implementation seems insufficient for OA management. One way to improve therapeutic education in the management of OA could be to propose dedicated continuing medical education programs supported by specific economic sources for health care professionals. PMID- 20843651 TI - [Nonpharmacological and nonsurgical therapies for osteoarthritis: orthosis, exercises]. AB - Unloading valgus knee braces may be more effective than knee sleeves, to improve pain and disability for medial knee osteoarthritis, but have more adverse effects. A lateral-wedge insole could reduce pain in medial knee osteoarthritis. Cushioning insoles and footwear with shock absorbance could be proposed for hip osteoarthritis by authors' recommendations. Nocturnal splints for base-of-thumb osteoarthritis are recommended to reduce pain and disability. Aerobic, strengthening, range-of-motion and proprioceptive exercise are recommended to decrease pain and improve function and quality of life in knee and hip osteoarthritis. Strengthening and range-of-motion exercise is recommended for hand osteoarthritis. PMID- 20843652 TI - [Letter on the article "Consequences of critical appraisal of medical literature on 2009 national ranking in France"]. PMID- 20843654 TI - [Guidelines for the management of knee and hip osteoarthritis: For whom? Why? To do what?]. AB - This paper summarizes the guidelines published by the Osteoarthritis research society International (OARSI) and compares these guidelines with others. The OARSI guidelines are based on a systematic review of the literature, a meta analysis and an expert consensus. The OARSI has developed 25 guidelines including 8 for pharmacology modalities, 12 for non-pharmacology modalities and 5 for surgery modalities. The usefulness of the guidelines in the daily practice is very low. The barriers for the guidelines implementation are the lack of interest of the practitioners, the lack of scientific advances in the OA diagnosis and treatments and the low applicability of these guidelines in the daily practice. PMID- 20843655 TI - [Platypnea-orthodeoxia syndrome by phrenic nerve paralysis responsible for vascular dementia]. PMID- 20843657 TI - [Letter on the article "Medical writing for publication in France: the benefits of language assistants"]. PMID- 20843659 TI - Congenital accessory mitral valve tissue anomaly in a patient with genetically confirmed hypertrophic cardiomyopathy. AB - Accessory mitral valve tissue is a rare congenital cardiac anomaly that was initially described in children in association with other cardiac congenital abnormalities and, more recently, has also been reported in adults. The authors report a patient with genetically confirmed hypertrophic cardiomyopathy who also had a highly mobile, free-floating membrane-like structure in contiguity with the ventricular side of the anterior mitral valve leaflet, a feature consistent with the diagnosis of accessory mitral valve tissue. PMID- 20843658 TI - Development and initial validation of the Preschooler Gross Motor Quality Scale. AB - Motor skills have great impact on children in adapting to an environment and developing interpersonal interaction, cognition, and social behavior. Understanding what children can do and how they perform it is essential. Most motor tests seldom contain quality evaluation in the items or criteria. The purpose of this study was to develop and construct validity of the Preschooler Gross Motor Quality Scale (PGMQ) that included 17 items in three subscales to evaluate the quality of fundamental motor skills for the preschooler. The study designed PGMQ items and subscales according to well-described procedures, and recruited 174 children, aged 3-6 (89 boys and 85 girls) from 17 kindergartens. Two independent evaluators who were unaware of each other's results evaluated all the children separately in their kindergartens using PGMQ standardized setting and procedures and Gross Motor Scales of Peabody Developmental Motor Scales II (PDMS-II). Results of this study found significant differences between different ages and genders (Wilks'Lambda=0.221, p<.001 and Wilks'Lambda=0.690, p<.001 respectively). Total scores and raw scores in three subscales of PGMQ increased as age increased. Confirmatory factor analysis revealed three factors, including locomotion, manipulative ability and balance to explain 51.06% of the variance. The correlations between PGMQ and PDMS-II subscales were moderate to high (r=0.544-0.868, p<.01). The results showed satisfactory validity of PGMQ. PGMQ is useful to evaluate the development and quality of fundamental motor skills for the preschoolers. PMID- 20843660 TI - Characterization of regulatory T cells in patients with dermatomyositis. AB - The purpose of this study was to characterize regulatory T cells (T(reg)) in skin lesions and peripheral blood from patients with dermatomyositis (DM) and to determine the serum levels of regulatory cytokines in the disease. In skin biopsy specimens from patients with DM, immunohistochemistry was performed for CD4(+), CD25(+), forkhead/winged helix transcription factor (FoxP3)(+), transforming growth factor (TGF)-beta(+) and interleukin (IL)-10(+) cells. Additionally, we defined the number of T(reg) subpopulations in peripheral blood by flow cytometry using monoclonal antibodies against CD4, CD25, FoxP3, CD45RO, CD95, CCR4 and CLA. The levels of TGF-beta and IL-10 were also determined in serum samples from patients with DM by enzyme-linked immunosorbent assays. Controls included patients with cutaneous lupus erythematosus, psoriasis and atopic dermatitis (AD) as well as healthy donors. The frequency of FoxP3(+) cells was significantly reduced in skin lesions from patients with DM (p < 0.001) compared to psoriasis and AD. Moreover, the number of cells positive for TGF-beta was lower in DM than in psoriasis and AD, while IL-10(+) cells were significantly reduced only compared to psoriasis. The number of CD4(+)CD25(++)FoxP3(+) T(reg) in the peripheral blood of patients with DM was significantly reduced compared to healthy controls (p < 0.05), whereas other cell populations showed no significant differences. Finally, TGF-beta and IL-10 serum levels were significantly lower in patients with DM compared to healthy controls (p < 0.05). These data suggest that the depletion of T(reg) and their main effector cytokines in the skin and the serum of patients with DM may be an important factor in the pathogenesis of the disease. PMID- 20843661 TI - The prolonged and enhanced immune response in the non-obese diabetic mouse is dependent on genes in the Idd1/24, Idd12 and Idd18 regions. AB - In non-obese diabetic (NOD) mice B cells are an absolute requirement for T1D development. NOD mice display various B cell related immune deviations when compared to normal mice such as an enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. We hypothesized that this trait contributes to diabetes pathogenesis, and investigated the genetic factor(s) governing the altered immune response. A (NODxC57BL/6)F(2) cohort (n = 214) were analyzed for its primary immune response against a BALB/c derived monoclonal antibody, and a genome wide linkage analysis was performed. Significant linkage to the Idd1/Idd24, Idd12 and Idd18.1 regions as well as to a proximal region (marker D2Mit367, 33.5 Mb) on chromosome 2 was detected. We verified the observed linkage by analyzing a set of H2 congenic NOD and C57BL/6 mice and narrowed down the region to 8 Mb. Interaction between Idd1/24 and Idd12, as well as the novel locus on chromosome 2 was observed. However, the action by Idd18.1 was not influenced by any of the other loci. In addition to the known H2 I-Abeta(g7) allelic variant of Idd1 in NOD, candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. We hypothesize that multiple mechanisms contribute to the loss of immune response control, including that peptide loading on MHC class II in B cells of NOD is altered. PMID- 20843662 TI - Waon therapy mobilizes CD34+ cells and improves peripheral arterial disease. AB - BACKGROUND: We previously reported that Waon therapy upregulates endothelial nitric oxide synthase protein, and augments ischemia-induced angiogenesis in mice with hindlimb ischemia, and it improves limb ischemia in patients with peripheral arterial disease (PAD). The aim of this study was to investigate the underlying mechanism of Waon therapy for the treatment of patients with PAD, and to determine whether Waon therapy can mobilize blood-derived progenitor cells. METHODS: 21 consecutive PAD patients received standard medications, and were randomly divided into control (n=10) and Waon therapy groups (n=11). The Waon therapy group received Waon therapy daily for 6 weeks. The control group continued conventional therapy for 6 weeks. Leg pain was scored using a visual analogue scale. The ankle-brachial pressure index (ABPI) and the 6-min walking distance were measured at baseline and 6 weeks after therapy. Frequency of circulating CD34+ progenitor cell numbers was measured by quantitative real-time polymerase chain reaction, and the serum nitrate and nitrite levels were also measured at baseline and 6 weeks after therapy. RESULTS: The leg pain score, ABPI and the 6-min walking distance improved significantly after 6 weeks in the Waon therapy group, but not in the control group. Frequency of circulating CD34+ cells increased after 6 weeks of Waon therapy [2.0 +/- 1.2 (*10(-4)) at baseline to 3.9 +/- 1.9 (*10(-4)), p=0.015], while it remained unchanged in the control group [1.8 +/- 1.8 (*10(-4)) at baseline to 1.2 +/- 0.9 (*10(-4))]. Serum nitrate and nitrite levels increased significantly after Waon therapy (29.6 +/- 17.6 to 36.0 +/- 17.7 MUmol/ml, p<0.05), but not in the control group (34.4 +/- 9.4 to 38.3 +/ 8.8 MUmol/ml). CONCLUSION: Waon therapy mobilized circulating endothelial progenitor cells and improved limb ischemia in patients with PAD. Waon therapy is a highly promising therapy for patients with PAD. PMID- 20843663 TI - Detection and characterisation of AmpC beta-lactamase-producing isolates of Acinetobacter spp. in North India. PMID- 20843664 TI - Allele-specific polymerase chain reaction (PCR) for rapid detection of the aac(6')-Ib-cr quinolone resistance gene. PMID- 20843665 TI - Investigation of lectinized liposomes as M-cell targeted carrier-adjuvant for mucosal immunization. AB - In the present investigation hepatitis B surface antigen (HBsAg) encapsulated liposomes were developed and coupled with Ulex europaeus agglutinin 1 (UEA-1) to increase transmucosal uptake by M-cells of the Peyer's patches. The liposomes were characterized for shape, size, polydispersity and encapsulation efficiency. Bovine submaxillary mucin (BSM) was used as a biological model for the in vitro determination of lectin activity and specificity. Dual staining technique was used to investigate targeting of lectinized liposomes to the M-cells. Anti-HBsAg IgG response in serum and anti-HBsAg sIgA level in various mucosal fluids was estimated by using ELISA, following oral immunization with lectinized and non lectinized liposomes in Balb/c mice. Additionally, interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) level in the spleen homogenates was determined. The results suggest that lectinized liposomes were successfully developed, exhibited increased activity with BSM as compared to non-lectinized liposomes and alpha-l fucose specificity of the lectinized liposomes was also maintained. The lectinized liposomes were predominantly targeted to the M-cells. The serum anti HBsAg IgG titre obtained after 3 consecutive days oral immunizations with HBsAg encapsulated lectinized liposomes and boosting after third week was comparable with the titre recorded after single intramuscular prime and third week boosting with alum-HBsAg. Moreover, lectinized liposomes induced higher sIgA level in mucosal secretions and cytokines level in the spleen homogenates. The results showed that the developed surface modified liposomes could be a potential module for the development of effective mucosal vaccines. PMID- 20843666 TI - Improved glucose electrochemical biosensor by appropriate immobilization of nano ZnO. AB - We constructed the transferred ZnO biosensor and the grown ZnO biosensor by two different nano-ZnO immobilization approaches. And the influence of different assembly processes on the biosensor performance has been systematically investigated and compared. An enhanced sensitivity of the grown ZnO biosensor is found to be 52% higher than that of the transferred ZnO biosensor. Correspondingly, the other properties are also better in the grown ZnO biosensor, including the response time, the detection limit and the linear range. These results are well consistent with the fact that more glucose oxidase is immobilized on the well-aligned ZnO arrays, which have higher specific surface area and more direct electron communication path, in the grown sensor than the randomly distributed and stacked ZnO nanorods in the transferred sensor. The nano ZnO grown directly has been demonstrated more desirable for enzymatic immobilization and signal transduction in the high performance biosensors. PMID- 20843667 TI - Existence of hybrid structures in cationic liposome/DNA complexes revealed by their interaction with plasma proteins. AB - The self-assembling of cationic liposomes (CLs) and DNA can give rise to a variety of nanostructures and morphologies. Multilamellar complexes are made of DNA intercalated between opposing lipid bilayers, while clusters formed by intact vesicles may exist as 'beads-on-a-string' (i.e. CLs attached to a string of DNA). Precise knowledge of the structure and morphology of complexes is relevant in many biological important processes such as gene delivery. Here dynamic light scattering, zeta potential, synchrotron small angle X-ray scattering and one dimensional polyacrylamide gel electrophoresis were performed to investigate the equilibrium structure, morphology and interactions with plasma proteins of lipoplexes made of the cationic lipid (3beta-[N-(N',N'-dimethylaminoethane) carbamoyl])-cholesterol (DC-Chol), the zwitterionic lipid dioleoylphosphatidylethanolamine (DOPE) and DNA. Results show that DC-Chol DOPE/DNA complexes are multilamellar systems with DNA protected by cationic lipids. On the other hand, the 'protein corona' associated to lipoplexes after interaction with human plasma was found to be much richer in basic immunoglobulins gamma proteins (Ig-Gs) than that of pure lipid vesicles in the absence of DNA. According to the most recent evidences reported in the literature, this finding would suggest the existence of hybrid structures made of multilamellar complexes either stuck together by DNA or coexisting with DNA loaded intact vesicles. Because surface properties of lipoplexes may determine their interaction with cells and tissues, these results may be important for predicting biological responses in vivo. PMID- 20843668 TI - Phage Langmuir monolayers and Langmuir-Blodgett films. AB - Stable, insoluble Langmuir monolayer films composed of Staphylococcus aureus specific lytic bacteriophage were formed at an air-water interface and characterized. The phage monolayer was very strong, withstanding a surface pressure of ~40 mN/m at 20 degrees C. The surface pressure-area (Pi-A) isotherm possessed a shoulder at ~7 * 10(4)nm(2)/phage particle, attributed to a change in phage orientation at the air-water interface from horizontal to vertical capsid down/tail-up orientation as surface pressure was increased. The Pi-A-dependence was accurately described using the Volmer equation of state, assuming horizontal orientation to an air-water interface at low surface pressures with an excluded area per phage particle of 4.6 * 10(4)nm(2). At high pressures phage particles followed the space-filling densely packed disks model with a specific area of 8.5 * 10(3)nm(2)/phage particle. Lytic phage monolayers were transferred onto gold coated silica substrates from the air-water interface at a constant surface pressure of 18 mN/m by Langmuir-Blodgett method, then dried and analyzed by scanning electron microscopy (SEM) and ellipsometry. Phage specific adsorption (Gamma) in Langmuir-Blodgett (LB) films measured by SEM was consistent with that calculated independently from Pi-A isotherms at the transfer surface pressure of 18 mN/m (Gamma=23 phage particles/MUm(2)). The 50 nm-thickness of phage monolayer measured by ellipsometer agreed well with the horizontal phage average size estimated by SEM. Surface properties of phage Langmuir monolayer compare well with other monolayers formed from nano- and micro-particles at the air-water interface and similar to that of classic amphiphiles 1,2-diphytanoyl-sn-glycero-3 phosphocholine (phospholipid) and stearic acid. PMID- 20843669 TI - Effects of low-molecular-weight organic ligands and phosphate on adsorption of Pseudomonas putida by clay minerals and iron oxide. AB - Adsorption of Pseudomonas putida on kaolinite, montmorillonite and goethite was studied in the presence of organic ligands and phosphate. Citrate, tartrate, oxalate and phosphate showed inhibitive effect on P. putida adsorption by three minerals in a broad range of anion concentrations. The highest efficiencies of the four ligands in blocking the adsorption of P. putida on goethite, kaolinite and montmorillonite were 58-90%, 35-76% and 20-48%, respectively. The ability of organic ligands in prohibiting the binding of P. putida cells to the minerals followed the sequence of citrate>tartrate>oxalate>acetate. The significant suppressive effects on P. putida adsorption were ascribed to the increased negative charges by adsorbed ligands and the competition of ligands with bacterial surface groups for binding sites. The inhibitive effects on P. putida adsorption by organic ligands were also dependent on the steric hindrance of the molecules. Acetate presented promotive effect on P. putida adsorption by kaolinite and goethite at low anion concentrations. The results obtained in this study suggested that the adsorption of bacteria in soils especially in the rhizosphere can significantly be impacted by various organic and inorganic anions. PMID- 20843671 TI - [Heel lance versus venepuncture in blood sampling for newborn screening]. PMID- 20843670 TI - [Morgagni hernia causing cardiac tamponade]. AB - Morgagni hernia is a rare malformation (3% of diaphragmatic hernias). This hernia is usually asymptomatic in children. We report on a case revealed by an unusual complication. Severe cyanosis was due to right-to-left atrial shunt through the foramen ovale assessed by 2D echocardiography. Diagnosis of the Morgagni hernia was made with CT scan. The intrathoracic liver compressed the right chambers of the heart causing tamponade. Cardiac compression was reversed after surgery and replacement of the liver in the abdomen. Six months after the surgery, the infant was symptom-free with normal size right chambers of the heart. PMID- 20843672 TI - [New technologies for the human genome exploration]. AB - Human genome consists of 23 pairs of chromosomes, bearing our genetic information. Basically, there are two main approaches to analyse our genome: molecular genetics with direct sequencing, which detects genic mutations, and cytogenetics with the karyotype, which detects number and structural chromosomal anomalies. The main limitation of the karyotype is its level of resolution: it cannot detect abnormalities smaller than five megabases. The combined use of cytogenetics and molecular genetics has allowed the development of several new techniques that provide a comprehensive analysis of the genome with a very high level of resolution. Currently, the most efficient of those techniques is comparative genomic hybridization on microarray (array CGH), which already has diagnostic applications. However, those new methods are challenging to interpret and they raise ethical problems. Therefore they must be cautiously supervised. PMID- 20843673 TI - A practical method of Ludox density gradient centrifugation combined with protargol staining for extracting and estimating ciliates in marine sediments. AB - Methodological impediments have long been the main problem in estimating the ecological role of marine benthic ciliates. Percoll density centrifugation is currently the most efficient technique for extracting ciliates from fine-grained sediments, while the high cost and low density of Percoll limit its wide application. We developed a protocol of density gradient centrifugation using the cheap sol Ludox HS 40 in combination with the quantitative protargol stain (QPS) to enumerate and identify marine benthic ciliates. The combined Ludox-QPS method involves sample collection and salt reduction, extraction with Ludox centrifugation, and preparation with the QPS technique. The recovery efficiency of Ludox was first tested with azoic sandy and muddy sediments. A 94-100% recovery rate of ciliates was reached. The method was further tested with natural sandy, muddy-sand and muddy sediments. Excellent extraction efficiencies were consistently obtained: an average of 97.6% for ciliates in sand, and 96.9-97.8% for nematodes in the three types of sediments. The high efficiencies indicate that the method allows for simultaneous enumeration of micro- and meiobenthos. Advantages of the new method include: (i) reliable and cost-efficient operation; (ii) appropriate centrifugation for both micro- and meiobenthos; and (iii) applicability to large samples and routine ecological surveys. PMID- 20843674 TI - Ectopic thyroid tissue in the periaortic area, cardiac cavity and aortic valve in a Beagle dog - a case report. AB - Microscopic examination of the heart of a clinically normal 14-month-old female Beagle dog revealed the presence of ectopic thyroid tissue at the base of the heart, around the aorta, and intracardially at the level of the left ventricle and the aortic valve. The tissue was composed of well-differentiated follicles lined by a cuboidal epithelium and containing colloid. Follicular cells and colloid exhibited strong thyroglobulin immunoreactivity, while no parafollicular cells were noted and the immunoreactions for calcitonin remained consistently negative. Although in the dog ectopic thyroid tumors represent 1-10% of all heart base neoplasms (Capen, 1978; Bracha et al., 2009), to the best of our knowledge, nonneoplastic ectopic thyroid tissue has not been reported in the heart of the dog itself or within the dog aortic valve. PMID- 20843675 TI - Facile characterization of polymer fractions from waste electrical and electronic equipment (WEEE) for mechanical recycling. AB - In view of the environmental problem involved in the management of WEEE, and then in the recycling of post-consumer plastic of WEEE there is a pressing need for rapid measurement technologies for simple identification of the various commercial plastic materials and of the several contaminants, to improve the recycling of such wastes. This research is focused on the characterization and recycling of two types of plastics, namely plastic from personal computer (grey plastic) and plastic from television (black plastic). Various analytical techniques were used to monitor the compositions of WEEE. Initially, the chemical structure of each plastic material was identified by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). Polymeric contaminants of these plastics, in particular brominated flame retardants (BFRs) were detected in grey plastics only using different techniques. These techniques are useful for a rapid, correct and economics identification of a large volumes of WEEE plastics. PMID- 20843676 TI - Integration of microfluidic and cantilever technology for biosensing application in liquid environment. AB - Microcantilever based oscillators have shown the possibility of highly sensitive label-free detection by allowing the transduction of a target mass into a resonant frequency shift. Most of such measurements were performed in air or vacuum environment, since immersion in liquid dramatically deteriorates the mechanical response of the sensor. Besides, the integration of microcantilever detection in a microfluidic platform appears a highly performing technological solution to exploit real time monitoring of biomolecular interactions, while limiting sample handling and promoting portability and automation of routine diagnostic tests (Point-Of-Care devices). In the present paper, we report on the realization and optimization of a microcantilever-based Lab-on-Chip, showing that microplates rather than microbeams exhibit largest mass sensitivity in liquid, while pirex rather than polymers represents the best choice for microfluidic channels. Maximum Q factor achieved was 140 (for fifth resonance mode of Pirex prototype), as our knowledge the highest value reported in literature for cantilever biosensors resonating in liquid environment without electronic feedback. Then, we proved the successfully detection of Angiopoietin-1 (a putative marker in tumor progression), showing that the related frequency shifts coming from non-specific interactions (negative controls) are roughly one order of magnitude lower than typical variations due to specific protein binding. Furthermore, we monitored the formation of antibody-antigen complex on MC surface in real-time. The proposed tool could be extremely useful for the comprehension of complex biological systems such as angiogenic machinery and cancer progression. PMID- 20843677 TI - Activators generated electron transfer for atom transfer radical polymerization for immunosensing. AB - A novel and ultrasensitive immunosensing strategy based on activators generated electron transfer for atom transfer radical polymerization (AGET ATRP) in combination with flow injection chemiluminescent (CL) and electrochemical detection was proposed. The initiator-conjugated polyclone PSA antibodies (Ab2*), prepared by coupling of N-hydroxysuccinmidyl bromoisobutyrate (initiator) with polyclone PSA antibodies (Ab2), were immobilized on the substrate surface through sandwiched immunoreactions to trigger polymerization. AGET ATRP is used for local accumulation of glycidyl methacrylate (GMA) monomers. Horseradish peroxidase (HRP) was chosen as signal species for its well-characterized chemiluminescent and electrochemical behavior, strong enzyme activity, good solubility and ease in coupling. Growth of long chain polymeric materials provided excess epoxy groups for HRP coupling, which in turn significantly increased the loading of signal molecules and enhanced the chemiluminescent and electrochemical readouts. With the proposed strategy, a detection limit of 4.0 and 1.3 pg mL(-1) was obtained for flow injection chemiluminescent and electrocatalytic measurements, respectively. A more than 13- and 14-fold enhancement in the chemiluminescent intensity and electrocatalytic current was achieved comparing to the traditional sandwiched immunoassays using HRP-conjugated antibody directly. The proposed method exhibited an efficient amplification performance for immunosensing. This paved a new way for ultrasensitive detection of cancer biomarkers. PMID- 20843679 TI - Can we reduce burnout amongst cancer health professionals? PMID- 20843678 TI - Apicomplexan parasite adhesins: novel strategies for targeting host cell carbohydrates. AB - Apicomplexan parasites such as Plasmodium spp. (malaria) and Toxoplasma gondii (toxoplasmosis) are significant global pathogens of humans and animals. Unlike many intracellular bacterial and viral pathogens that rely on host cell uptake machinery to gain entry, apicomplexan parasites promote recognition, attachment and ultimately invasion of host cells through an orchestrated delivery of adhesins. While several of these adhesins are now known to target host cell glycans, only recently have atomic level insights been forthcoming. Here we review recent developments in defining detailed molecular blueprints used by these widespread pathogens to drive host cell adhesion and promote infectivity. PMID- 20843680 TI - The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single institution study. AB - BACKGROUND: To evaluate the skin and heart toxicity of a concurrent adjuvant trastuzumab-radiotherapy for breast cancer (BC), especially in the case of internal mammary chain (IMC) irradiation. MATERIAL AND METHODS: Prospective study of 106 patients treated between 06/2003 and 03/2007 by concurrent trastuzumab radiotherapy for non-metastatic BC. Left ventricular ejection fractions (LVEF) was assessed at baseline, before and after radiotherapy and then every 4-6 months. All toxicities were evaluated using CTCAEV3. RESULTS: Median age was 52 years (25-76). Chemotherapy with anthracycline was administered in 92% of patients. All patients received trastuzumab every three weeks (8 mg/kg followed by 6 mg/kg) for a median duration of 12 months (3-40). The IMC was irradiated in 83% of patients. There were: 87 grade 1, 14 grade 2 and 2 grade 3 skin reactions. There were 13 oesophagitis: 9 grade 1; 3 grade 2, and 1 grade 3. Out of 101 patients with assessments after 6 months, late telangiectasia grade 1 occurred in 5 patients, local pain grade 1 in 19 patients and grade 2 in 3 patients, fibrosis grade 1 in 16 patients. A reversible grade >=2 left ventricular systolic dysfunction occurred in 6 patients. CONCLUSION: In this prospective study of breast cancer patients treated with trastuzumab-radiotherapy with, in most cases, anthracycline-based chemotherapy and IMC irradiation, both the rate of abnormal LVEF after concurrent trastuzumab-radiotherapy and the skin toxicity were deemed acceptable. Further follow-up is needed. PMID- 20843681 TI - Anaerobic digestion of whole stillage from dry-grind corn ethanol plant under mesophilic and thermophilic conditions. AB - Anaerobic digestion of whole stillage from a dry-grind corn-based ethanol plant was evaluated by batch and continuous-flow digesters under thermophilic and mesophilic conditions. At whole corn stillage concentrations of 6348 to 50,786 mg total chemical oxygen demand (TCOD)/L, at standard temperature (0 degrees C) and pressure (1 atm), preliminary biochemical methane potential assays produced 88+/ 8 L (49+/-5 L CH4) and 96+/-19 L (65+/-14 L CH4) biogas per L stillage from mesophilic and thermophilic digesters, respectively. Continuous-flow studies for the full-strength stillage (TCOD=254 g/L) at organic loadings of 4.25, 6.30 and 9.05 g TCOD/L days indicated unstable performance for the thermophilic digester. Among the sludge retention times (SRTs) of 60, 45 and 30 days tested, the mesophilic digestion was successful only at 60 days-SRT which does not represent a practical operation time for a large scale bioethanol plant. Future laboratory studies will focus on different reactor configurations to reduce the SRT needed in the digesters. PMID- 20843682 TI - Characterization of a copper-resistant symbiotic bacterium isolated from Medicago lupulina growing in mine tailings. AB - A root nodule bacterium, Sinorhizobium meliloti CCNWSX0020, resistant to 1.4 mM Cu2+ was isolated from Medicago lupulina growing in mine tailings. In medium supplied with copper, this bacterium showed cell deformation and aggregation due to precipitation of copper on the cell surface. Genes similar to the copper resistant genes, pcoR and pcoA from Escherichia coli, were amplified by PCR from a 1.4-Mb megaplasmid. Inoculation with S. meliloti CCNWSX0020 increased the biomass of M. lupulina grown in medium added 0 and 100 mg Cu2+ kg(-1) by 45.8% and 78.2%, respectively, and increased the copper concentration inside the plant tissues grown in medium supplied with 100 MUM Cu2+ by 39.3%, demonstrating that it is a prospective symbiotic system for bioremediation purposes. PMID- 20843683 TI - An analysis of net energy production and feedstock availability for biobutanol and bioethanol. AB - In this study, the potential of biobutanol was evaluated as an alternative to bioethanol which is currently the predominant liquid biofuel in the US. Life cycle assessments (LCAs) suggest that the net energy generated during corn-to biobutanol conversion is 6.53 MJ/L, which is greater than that of the corn derived bioethanol (0.40 MJ/L). Additionally, replacing corn with lignocellulosic materials in bioethanol production can further increase the net energy to 15.90 MJ/L. Therefore, it was interesting to study the possibility of using domestically produced switchgrass, hybrid poplar, corn stover, and wheat straw as feedstocks to produce liquid biofuels in the US. By sustainable harvest based on current yields, these materials can be converted to 8.27 billion gallons of biobutanol replacing 7.55 billion gallons of gasoline annually. To further expand the scale, significant crop yield increases and appropriate land use changes are considered two major requirements. PMID- 20843685 TI - Co-deoxy-liquefaction of biomass and vegetable oil to hydrocarbon oil: Influence of temperature, residence time, and catalyst. AB - Co-deoxy-liquefaction of biomass and vegetable oil was investigated under the conditions of different temperatures (350-500 degrees C) and residence time as well as catalyst using HZSM-5. Results suggested low temperature was favorable for the formation of diesel-like products, while high temperature caused more gasoline-like products. By the addition of HZSM-5, at 450 degrees C alkanes content of the obtained oil with low oxygen content of 2.28%, reached a maximum of 56.27%, resulting in the highest HHV of 43.8 MJ kg(-1). High temperature favored cracking activity of HZSM-5 which reduced the char formation and contributed to the removal of carbonyl. Compared to temperature, the effect of residence time on products was relatively less; experiments indicated the optimum residence time was 15 min at which obtained oil with the highest yield of 17.78%, had better properties. Preliminary analysis of mechanisms showed biomass provided hydrogen for vegetable oil, facilitating hydrogenation of CC bonds of vegetable oil. PMID- 20843684 TI - Stable and efficient immobilization technique of aldolase under consecutive microwave irradiation at low temperature. AB - To establish a stable and efficient immobilization technique under microwave irradiation, a focused microwave reaction system was used, where the temperature was set appropriately in the microwave system and cooling module to produce consecutive microwave irradiation. 2-Deoxy-D-ribose-5-phosphate aldolase (DERA) was rapidly and efficiently immobilized in mesocellular siliceous foams (MCFs) under microwave irradiation. When the output power in the microwave system was set to 30 W, after 3 min, 88.4% of the enzyme protein was coupled to the wall of the support pores and the specific activity of the immobilized enzyme was 2.24 U mg(-1), 149.2% higher than that of the free enzyme and 157.0% higher than that of the non-microwave-assisted immobilized enzyme. In catalysis, microwave-assisted immobilized DERA tolerated a wider range of both pH and temperature than other DERA preparations. The thermal and storage stabilities were also significantly improved. This focused; microwave-assisted immobilization technique has proven to be simple, stable and highly efficient. This technique could also be applied to other enzyme immobilizations. PMID- 20843686 TI - Design and optimization of new piperidines as renin inhibitors. AB - The discovery of a new series of piperidine-based renin inhibitors is described herein. SAR optimization upon the P3 renin sub-pocket is described, leading to the discovery of 9 and 41, two bioavailable renin inhibitors orally active at low doses in a transgenic rat model of hypertension. PMID- 20843688 TI - 'Click' assembly of selective inhibitors for MAO-A. AB - In this Letter, an efficient strategy for the fast construction of 108 compounds library was developed using click chemistry. The fingerprint of inhibitory activity toward MAO-A/B against this library was obtained, and four hit compounds were identified as selective inhibitors toward MAO-A. Docking study was carried out to demonstrate the binding mode between a9 and MAO-A/B, and the result reveals that a9 localized in the 'aromatic cage' and oriented to establish pi-pi stacking interactions with Tyr407, Tyr444 and FAD in MAO-A rather than in MAO-B. PMID- 20843687 TI - Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG. AB - Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile. PMID- 20843689 TI - A retro-inverso TAT-like peptide designed to deliver cysteamine to cells. AB - A retro-inverso, TAT-like peptide wherein lysine residues are replaced with cysteine residues bearing a disulfide-linked cysteamine group is found to engage in thiol-disulfide exchange with cysteine. These peptides are transported into cells and localize to lysosomes. Cellular uptake is enhanced in peptides bearing two cysteamine groups over those with one or none, by factors of approximately 1.5 and 12, respectively. PMID- 20843690 TI - Piperidine-based renin inhibitors: upper chain optimization. AB - The optimization of the 4-position of recently described new 3,4-disubstituted piperidine-based renin inhibitors is reported herein. The synthesis and characterization of compounds leading to the discovery of 11 (ACT-178882, MK 1597), a renin inhibitor with a suitable profile for development is described. PMID- 20843691 TI - Indole- and benzothiophene-based histamine H3 antagonists. AB - Previous research on histamine H(3) antagonists has led to the development of a pharmacophore model consisting of a central phenyl core flanked by two alkylamine groups. Recent investigation of the replacement of the central phenyl core with heteroaromatic fragments resulted in the preparation of novel 3,5-, 3,6- and 3,7 substituted indole and 3,5-substituted benzothiophene analogs that demonstrate good to excellent hH(3) affinities. Select analogs were profiled in a rat pharmacokinetic model. PMID- 20843693 TI - Surgical treatment of intracranial Erdheim-Chester disease. AB - We review the clinical presentation, radiological and histological characteristics, and the natural history, of intracranial Erdheim-Chester disease (ECD). ECD is a rare form of non-Langerhans histiocytosis that affects multiple organs. It is clinically characterized by leg pain, exophthalmos and diabetes insipidus (DI). Central nervous system involvement is rare, with only 27 patients reported in the international literature. DI and cerebellar signs represent the most common neurological symptoms. Its treatment is controversial. Intracranial surgical procedures for ECD have been reported in 11 patients with a complete surgical resection performed in six, and an intracerebral biopsy performed in five patients. In seven patients the cranial procedures represented the initial diagnostic method. Surgical resection and radiation therapy have been used in the further management of these cerebral lesions. PMID- 20843694 TI - Design, synthesis, biological evaluation, and modeling of a non-carbohydrate antagonist of the myelin-associated glycoprotein. AB - Broad modifications of various positions of the minimal natural epitope recognized by the myelin-associated glycoprotein (MAG), a blocker of regeneration of neurite injuries, produced sialosides with nanomolar affinities. However, important pharmacokinetic issues, for example, the metabolic stability of these sialosides, remain to be addressed. For this reason, the novel non-carbohydrate mimic 3 was designed and synthesized from (-)-quinic acid. For the design of 3, previously identified beneficial modifications of side chains of Neu5Ac were combined with the replacement of the ring oxygen by a methylene group and the substitution of the C(4)-OH by an acetamide. Although docking experiments to a homology model of MAG revealed that mimic 3 forms all but one of the essential hydrogen bonds identified for the earlier reported lead 2, its affinity was substantially reduced. Extensive molecular-dynamics simulation disclosed that the missing hydrogen bond of the former C(8)-OH leads to a change of the orientation of the side chain. As a consequence, an important hydrophobic contact is compromised leading to a loss of affinity. PMID- 20843692 TI - Cell cholesterol homeostasis: mediation by active cholesterol. AB - Recent evidence suggests that the major pathways mediating cell cholesterol homeostasis respond to a common signal: active membrane cholesterol. Active cholesterol is the fraction that exceeds the complexing capacity of the polar bilayer lipids. Increments in plasma membrane cholesterol exceeding this threshold have an elevated chemical activity (escape tendency) and redistribute via diverse transport proteins to both circulating plasma lipoproteins and intracellular organelles. Active cholesterol thereby prompts several feedback responses. It is the substrate for its own esterification and for the synthesis of regulatory side-chain oxysterols. It also stimulates manifold pathways that down-regulate the biosynthesis, curtail the ingestion and increase the export of cholesterol. Thus, the abundance of cell cholesterol is tightly coupled to that of its polar lipid partners through active cholesterol. PMID- 20843695 TI - Synthesis of a BSA-Le(x) glycoconjugate and recognition of Le(x) analogues by the anti-Le(x) monoclonal antibody SH1: the identification of a non-cross reactive analogue. AB - A Le(x) trisaccharide functionalized with a cysteamine arm was prepared and this synthesis provided additional information on the reactivity of N acetylglucosamine O-4 acceptors when they are glycosylated with trichloroacetimidate donors activated with excess BF(3).OEt(2). In turn, this trisaccharide was conjugated to BSA lysine side chains through a squarate mediated coupling. This BSA-Le(x) glycoconjugate displayed 35 Le(x) haptens per BSA molecule. The relative affinity of the anti-Le(x) monoclonal antibody SH1 for the Le(x) antigen and analogues of Le(x) in which the D-glucosamine, L-fucose or D-galactose residues were replaced with D-glucose, L-rhamnose and D-glucose, respectively, was measured by competitive ELISA experiments. While all analogues were weaker inhibitors than the Le(x) antigen, only the analogue of Le(x) in which the galactose residue was replaced by a glucose unit showed no binding to the SH1 mAb. To confirm that the reduced or loss of recognition of the Le(x) analogues by the anti-Le(x) mAb SH1 did not result from different conformations adopted by the analogues when compared to the native Le(x) antigen, we assessed the conformational behavior of all trisaccharides by a combination of stochastic searches and NMR experiments. Our results showed that, indeed, the analogues adopted the same stacked conformation as that identified for the Le(x) antigen. The identification of a trisaccharide analogue that does not cross-react with Le(x) but still retains the same conformation as Le(x) constitutes the first step to the design of a safe anti-cancer vaccine based on the dimeric Le(x) tumor associated carbohydrate antigen. PMID- 20843696 TI - Improvement of water-solubility of biarylcarboxylic acid peroxisome proliferator activated receptor (PPAR) delta-selective partial agonists by disruption of molecular planarity/symmetry. AB - To elucidate the molecular basis of peroxisome proliferator-activated receptor (PPAR) delta partial agonism, X-ray crystal structures of complexes of the PPARdelta ligand-binding site with partial agonists are required. Unfortunately, reported PPARdelta partial agonists, biphenylcarboxylic acids 1 and 2, possess insufficient aqueous solubility to allow such crystals to be obtained. To improve the aqueous solubility of 1 and 2, substituents were introduced at the 2-position of the biaryl moiety, focusing on disruption of molecular planarity and symmetry. All 2-substituted biphenyl analogs examined showed more potent PPARdelta agonistic activity with greater aqueous solubility than 1 or 2. Among these biphenyls, 25 showed potent and selective PPARdelta partial agonistic activity (EC(50): 5.7 nM), with adequate solubility in phosphate buffer (0.022 mg/mL). The 2-substituted pyridyl analog 27 showed weaker PPARdelta partial agonistic activity (EC(50): 76 nM) with excellent solubility in phosphate buffer (2.7 mg/mL; at least 2700 times more soluble than 2). Our results indicate that two strategies to improve aqueous solubility, that is, introduction of substituent(s) to modify the dihedral angle and to disrupt molecular symmetry, may be generally applicable to bicyclic molecules. Combination of these approaches with the traditional approach of reducing the molecular hydrophobicity may be particularly effective. PMID- 20843697 TI - Preliminary evaluation of two radioiodinated maleimide derivatives targeting peripheral and membrane sulfhydryl groups for in vitro cell labeling. AB - A factor impeding the advancement of cell mediated therapy is the inability to track these cells in vivo by noninvasive techniques. It has been shown that cells express high levels of sulfhydryl groups. We sought to explore these groups to covalently label cells with radiolabeled maleimide derivatives. Two maleimide derivatives; N-[2-(2,5-dioxoazolinyl)ethyl](5-iodo(3-pyridyl))carboxamide and N [2-(2,5-dioxoazolinyl)ethyl](3-iodophenyl)carboxamide ([(125)I]-4 and [(125)I]-8) were synthesized and radioiodinated. These compounds were evaluated for in vitro binding to neutrophils, endothelial and mesenchymal stem cells, and biodistribution of the radiolabeled stem cells in nude mice. These radiotracers were obtained in moderate to high radiochemical yields. Binding to cells were moderate (20-60%/10(6) cells) and the label was retained, although washout (an average of 18-55%) was observed depending on the cell type and the tracer used. The labeled cells initially localized in well perfused organs and at a later time showed a general distribution as expected. The novel tracers labeled several cell types and shown that the stability of the label and viability of the cells were maintained in vitro and in vivo for a reasonable period and warrant further in vivo investigation. PMID- 20843698 TI - Changes of cytosolic Ca(2+) fluorescence intensity and plasma membrane calcium channels of maize root tip cells under osmotic stress. AB - The changes of cytosolic Ca(2+) fluorescence intensity and the activities of calcium channel of primary maize root tip cells induced by PEG6000 or abscisic acid (ABA) were studied by both confocal techniques and the whole-cell patch clamping in this study. The Ca(2+) fluorescence intensity increased while treated with PEG or ABA within 10 min, illuminating that Ca(2+) participated in the process of ABA signal transduction. For further proving the mechanism and origin of cytosolic Ca(2+) increase induced by PEG treatments, N,N,N',N'-tetraacetic acid (EGTA), Verapamil (VP) and Trifluoperazine (TFP) were added to the PEG solution in the experiments separately. The results showed that Ca(2+) fluorescence intensity induced by PEG was suppressed by both EGTA and VP obviously in the root tip cells. The Ca(2+) fluorescence intensity of plants changed after the addition of CaM inhibitor TFP while subjected to osmotic stress, which seemed to show that CaM participated in the process of signal transduction of osmotic stress too. The mechanism about it is unknown today. Further, a hyperpolarization-activated calcium permeable channel was recorded in plasma membrane of maize root tip cells. The Ca(2+) current (I(Ca)) intensity increased remarkably after PEG treatment, and the open voltage of the calcium conductance increased. Similar changes could be observed after ABA treatment, but the channel opened earlier and the current intensity was stronger than that of PEG treatment. The activation of calcium channel initiated by PEG strongly was inhibited by EGTA, VP or TFP respectively. The results revealed that Ca(2+) participated in the signals transduction process of osmotic stress, and the cytosolic free Ca(2+) increase by osmotic stress mainly came from the extracellular, and some came from the release of cytoplasmic calcium pool. PMID- 20843699 TI - Surgical strategy for acquired tracheomalacia due to innominate artery compression of the trachea. AB - We reviewed six cases demonstrating acquired tracheomalacia due to innominate artery compression of the trachea and investigated the benefit and effectiveness of a technique for correcting tracheomalacia. All the patients developed scoliosis and the innominate artery run over the trachea. Four cases had permanent neurologic impairment, whereas two patients developed acquired neurologic impairment. The surgical strategy for acquired tracheomalacia due to innominate artery compression of the trachea involved superior mediastinal exposure, external reinforcement with autologous cartilage graft, anterior sling of the innominate artery with a muscle sling, and tracheopexy. Our surgical procedure has been effective in maintaining the patency of the tracheal lumen in all cases but one. This patient suffered from straight back syndrome and developed recurrence of tracheomalacia owing to mucosal infolding secondary to the deformed spine in a supine position. The authors believe our surgical procedure is effective to relieve the symptoms of tracheomalacia, but it is important to select surgical interventions in accordance with the specific patient's condition. PMID- 20843701 TI - Native electrospray and electron-capture dissociation in FTICR mass spectrometry provide top-down sequencing of a protein component in an intact protein assembly. AB - The intact yeast alcohol dehydrogenase (ADH) tetramer of 147 kDa was introduced into a FTICR mass spectrometer by native electrospray. Electron capture dissociation of the entire 23+ to 27+ charge state distribution produced the expected charge-reduced ions and, more unexpectedly, 39 c-type peptide fragments that identified N-terminus acetylation and the first 55 amino acids. The results are in accord with the crystal structure of yeast ADH, which shows that the C terminus is buried at the assembly interface, whereas the N-terminus is exposed, allowing ECD to occur. This remarkable observation shows promise that a top-down approach for intact protein assemblies will be effective for characterizing their components, inferring their interfaces, and obtaining both proteomics and structural biology information in one experiment. PMID- 20843702 TI - A window of vulnerability: health insurance coverage among women 55 to 64 years of age. AB - INTRODUCTION: largely a consequence of historical gender differences in labor force attachment in the United States, many women rely on their spouse for health insurance coverage, particularly during late middle age. Prior research finds that this creates a window of vulnerability for women during late middle age who may lose their (older) spouse's employment-based coverage when he retires from the labor force and enrolls in Medicare. However, the few studies that have examined this window of vulnerability have been based primarily on white adults. METHODS: we used the 2004 and 2006 Annual Social and Economic Supplements to the Current Population Survey to examine whether the window of vulnerability exists among non-Hispanic Black, Mexican-origin, and non-Hispanic White women 55 to 64 years of age, and whether similar factors contribute to the vulnerability across these race/ethnic groups. RESULTS: women 55 to 64 years of age married to men 65 years or older had an elevated risk of lacking coverage at a time of life when health problems are common and expensive. Among non-Hispanic White women, their husband's exit from full-time employment accounted for the higher risk, whereas a more complex and systemic set of social factors contributed to the higher risk among non-Hispanic Black and Mexican-origin women. CONCLUSION: ensuring adequate and affordable health insurance coverage among women during late middle age may require additional health care reforms such as extending Medicare eligibility to younger adults or basing Medicare age eligibility on the age of the older partner within a married couple. PMID- 20843703 TI - Effect of pressure intensity of graduated elastic compression stocking on muscle fatigue following calf-raise exercise. AB - The purpose of the present study was to examine the effects of wearing a graduated elastic compression (EC) stocking, with different pressure profiles during a fatiguing calf-raise exercise session, on the torque generating capacity after exercise. Fourteen subjects performed 15 sets of 10 repetitions of calf raise exercise, wearing one of three stockings of different compression pressure profiles: two kinds of EC stockings (one (EC30) with 30mmHg at the ankle, 21 25mmHg at the calf, and 10mmHg below the knee, and the other (EC18) with 18, 12 14, and 7mmHg at the same regions, respectively) and a non-EC sport stocking as a control (CON). Before and after the exercise, torque and electromyographic (EMG) signals of medial gastrocnemius and soleus muscles were recorded during an evoked triplet contraction and the maximal voluntary contraction (MVC). All stockings had no effect on the decline of the MVC torque whereas the reduction of the evoke triplet torque in EC30 stocking condition was significantly smaller compared with that in CON (-6.4+/-8.5% for EC30 and -16.5+/-9.0% for CON, P<0.05). The reduction of the mean power frequency of EMG during MVC in the EC30 condition was significantly smaller than that in CON (-4.4+/-10.9Hz for EC30 and -18.7+/-7.9Hz for CON, P<0.05). These results suggest that the EC stocking with adequate pressure at the calf region relieves muscle fatigue of the triceps surae induced by calf-raise exercise. PMID- 20843705 TI - Results of long-term follow-up of patients with superficial bladder carcinoma treated with intravesically applied bacillus Calmette-Guerin vaccine according to the schedule of 6 weekly + 6 monthly instillations. AB - BACKGROUND: The efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in the prevention of local recurrence and disease progression in patients with superficial bladder cancer is very well documented. This study reports the effect of BCG on disease-specific and overall survival. PATIENTS AND METHODS: In this retrospective trial, we have analyzed 170 patients with stage Ta and T1 superficial bladder cancer. Patients in the control group (87 patients) we followed-up only (median follow-up of 119 months) and treated surgically or with other oncologic modalities when progression of disease was diagnosed. The BCG group consisted of 83 patients treated with 6 weekly followed by 6 monthly instillations, and they have been followed-up of median 124 months. RESULTS: Patients receiving BCG had statistically significant better 10-year disease specific survival (83% vs. 69%, P = 0.03). At the same time point, the local recurrence rate was 48 % and the progression rate 19% for patients treated with BCG, while 77% (P < 0.001) and 38% (P = 0.007) were results in control group. Despite numerically better in the BCG group, overall survival is not significantly different in the 2 groups (P = 0.14). CONCLUSION: BCG immunotherapy significantly increases the disease-specific survival in patients with superficial bladder carcinoma. PMID- 20843704 TI - Conscious awareness is necessary for processing race and gender information from faces. AB - Previous studies suggested that emotions can be correctly interpreted from facial expressions in the absence of conscious awareness of the face. Our goal was to explore whether subordinate information about a face's gender and race could also become available without awareness of the face. Participants classified the race or the gender of unfamiliar faces that were ambiguous with regard to these dimensions. The ambiguous faces were preceded by face-images that unequivocally represented gender and race, rendered consciously invisible by simultaneous continuous-flash-suppression. The classification of ambiguous faces was biased away from the category of the adaptor only when it was consciously visible. The duration of subjective visibility correlated with the aftereffect strength. Moreover, face identity was consequential only if consciously perceived. These results suggest that while conscious awareness is not needed for basic level categorization, it is needed for subordinate categorization. Emotional information might be unique in this respect. PMID- 20843706 TI - High matrix metalloproteinase-to-E-cadherin ratio measured by bicolor fluorescent in situ hybridization is associated with lymphangiogenesis and lymph node metastasis in prostate cancer. AB - OBJECTIVE: The colorimetric in situ hybridization (CISH)-based matrix metalloproteinase (MMP)-to-E-cadherin (ECD) ratio (MER) has been revealed as an excellent marker for the disease stage in prostate cancer. The one aim of this study was investigating a new method for estimation of MER by bicolor fluorescent ISH (bicolor FISH) with a computerized fluorescence detector-based system. Another aim was examination of relation of MER by bicolor FISH with expression of vascular endothelial growth factor-C (VEGF-C). METHODS: The bicolor FISH technique used cyanin 5 (cy5)-labeled MMP-2 and -9 probes, and a cyanin 3 (cy3) labeled ECD probe on needle biopsy specimens from 67 prostate cancer cases. The ISH was followed by computerized detection of the signal intensities and cy5-to cy3 ratios using a fluorescence detector. VEGF-C expression was examined using cy5-labeled VEGF-C by computerized detection. RESULTS: The bicolor FISH-based MER was well correlated with CISH-based MER (P < 0.0001). The bicolor FISH-based MER correlated with Gleason score and pathologic stage of the cases. VEGF-C mRNA expression was associated with the pathologic stage and maximum lymph vessel density (LVD). The LVD was associated with VEGF-C expression at the tumor area where the maximum MER was detected (P < 0.0001). CONCLUSION: The MER was correlated with the VEGF-C expression and LVD, indicating lymph node metastasis of prostate cancer. Therefore, this computer-assisted MER is a useful marker for preoperative prediction of disease stage, especially lymph node metastasis, of prostate cancer. PMID- 20843707 TI - Effective enrichment of prostate cancer stem cells from spheres in a suspension culture system. AB - BACKGROUND: Stem-like prostate cancer cells are also called prostate cancer stem cells (PrCSCs). These rare cells are supposed to be highly tumorigenic and to be involved in maintenance of tumor homeostasis and mediation of tumor metastasis. Methods for sorting PrCSCs are mainly based on sorting cells with the marker (CD133(+)/CD44(+)) or side population cells. However, CD133(+)/CD44(+) cells or side population cells are very rare or even undetectable. The scarcity of approaches for isolation and purification of PrCSCs is the main obstacle to studying PrCSCs. METHODS: In the present study, suspension culture was used for enrichment of PrCSCs. And PrCSCs were verified by side population technology, drug sensitivity assays, and the molecular marker analysis of prostate cancer stem cell. RESULTS: PC3 cells survived and formed spheres in nonadherent suspension culture. The percentage of CD44(+)/CD133(+) cells was 18-fold higher in the nonadherent sphere-forming cell population than in the adherent PC3 cell population (13.94% vs. 0.77%, respectively). This side population was increased to 3.1% in the nonadherent population but undetectable in adherent population. Resistance to cisplatin was higher in the nonadherent cells than adherent cells. CONCLUSION: Suspension culture can be used to enrich for PrCSCs. This approach will aid prostate stem cell biology research and facilitate identification of novel therapeutic agents for prostate cancer. PMID- 20843708 TI - Current chemotherapeutic options for the treatment of advanced bladder cancer: a review. AB - Advanced bladder cancer is a disease with a high recurrence rate and metastatic capacity exhibiting a poor outcome. The pathologic stage and nodal involvement are independent prognostic factors for survival after cystectomy, and in locally advanced or metastatic disease, the performance status and the presence of visceral metastases have been correlated with treatment outcome. The regimen methotrexate-vinblastine-adriamycin-cisplatin (MVAC) has been the treatment of choice for decades and later the combination of cisplatin with gemcitabine became also the new standard of care, by demonstrating a more favorable toxicity profile. Also, carboplatin-gemcitabine and taxanes have been useful alternatives for patients unfit for cisplatin-based treatment. Additionally, the evaluation of certain chemotherapeutic agents has produced promising results in the second-line setting. Lastly, the past decade has provided information on the molecular mechanism of bladder cancer offering a personalized approach and optimizing the management of the disease. PMID- 20843709 TI - Up-regulation of glucosylceramide synthase in urinary bladder neoplasms. AB - OBJECTIVE: To investigate the relationships between the clinicopathologic features and the expression of GCS in bladder cancer. METHODS AND MATERIALS: Using immunohistochemistry and Western blotting method, 75 bladder cancer specimens were tested for expression of GCS. The correlation of GCS with clinicopathologic features of the patients was analyzed in combination with clinical data. Statistics analyses were done with SPSS 13.0 software, chi(2) test, Fisher's exact test, Kaplan-Meier method, Log-rank test. RESULTS: High and low level expression of GCS explored by immunohistochemistry were 61.3 (46/75) and 39.6 (29/75), respectively. The high expression group (n = 46) showed a significant correlation with high histologic grade (P = 0.021) and tended to show (P = 0.045) that up-expression of GCS was positive related to BNs with lymph node metastasis among the various clinicopathologic characteristics. The overall 5 year survival and disease-free survival rates were 39.5% and 18.4%, respectively. Mean overall survival time was 60.3 months for the low expression group and 45.1 months for the high expression group. Mean disease-free survival was 36.2 months for the low-expression group and 27.3 months for the high-expression group. CONCLUSION: Our study suggested that up-regulation of GCS might make an aggressive choice of surgical therapy. A high expression of GCS seemed to be an indicator of poor prognosis. PMID- 20843710 TI - Clinical features and prognosis of patients with renal cancer and a second malignancy. AB - OBJECTIVE: To evaluate the epidemiologic aspects, the clinical features, and the prognosis of patients with renal cancer affected by a second malignancy. MATERIALS AND METHODS: Since 1983, at our institution, a database concerning all the patients who underwent surgery for renal neoplasia has been prospectively compiled. In the present study, we compared patients with renal cancer and a second primary malignancy, diagnosed before, at the same time, or after the renal cancer, to those affected only by a renal malignancy. RESULTS: Out of 1,673 patients with renal cancer, 285 (17%) were diagnosed with a second malignancy. The follow-up lasted on average 71 months after the treatment of renal neoplasia. The second neoplasia was antecedent in 115 patients (average latency period 8.5 years), synchronous in 97 patients, and subsequent in 103 patients (average latency period 4.4 years). The sites of associated neoplasia were, in descending order of frequency, prostate, bladder, and bowel for men and breast, gynecologic organs, thyroid, and bladder for women. Compared with the patients not affected by a second neoplasm, those with multiple malignancies generally were older and had a smaller, low-grade, low-stage, and asymptomatic renal tumor. Comparing patients with associated neoplasia with a group without associated neoplasia matched for gender, mode of diagnosis, dimension, grade, stage, and histologic subtype of renal cancer, at survival analysis, no significant differences were noticed in renal cancer-related survival. However, among patients with multiple malignancies, the contemporaneous diagnosis of renal and associated cancer had an independent negative impact on survival. CONCLUSIONS: The association between renal cancer and other malignancies is a frequent event with an unremarkable impact on prognosis, and it shall not limit surgical indication to treat renal cancer, even if the negative prognostic impact of synchronous occurrence of multiple neoplasias should be regarded, especially in older or unhealthy patients, since ablative therapies or active surveillance could be considered as viable alternative options. PMID- 20843711 TI - 13-Methyltetradecanoic acid induces mitochondrial-mediated apoptosis in human bladder cancer cells. AB - OBJECTIVE: 13-Methyltetradecanoic acid (13-MTD), a saturated branched-chain fatty acid purified from soy fermentation products, is known to induce apoptosis in many types of human cancer cells. This study was designed to investigate the molecular mechanisms involved in 13-MTD-induced apoptosis in human bladder cancer cells. METHODS AND MATERIALS: MTT assay was used to investigate the potential effects of 13-MTD on the growth and viability of human bladder cancer cells. To find out whether anti-proliferation and cell death were associated with apoptosis, we used flow cytometry to quantify the extent of apoptosis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay to measures DNA degradation of apoptotic cells. The proteins involved in the 13-MTD induced apoptosis were examined using Western blot. RESULTS: We show that 13-MTD inhibits cellular proliferation and viability in human bladder cancer cells, which has been attributed to apoptosis. 13-MTD down-regulates Bcl-2 and up regulates Bax. This promotes mitochondrial dysfunction, leading to the release of cytochrome c from the mitochondria to the cytoplasm, as well as the proteolytic activation of caspases. Moreover, 13-MTD down-regulates AKT phosphorylation and activates phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Up-regulating AKT phosphorylation and down-regulating JNK and P38 phosphorylation could attenuate the13-MTD-induced apoptosis. CONCLUSION: Taken together, these data indicate that 13-MTD induces mitochondrial-mediated apoptosis through regulation of the AKT and MAPK pathways, suggesting 13-MTD is a potential candidate for treatment of human bladder cancer. PMID- 20843712 TI - Functional role of LASP1 in cell viability and its regulation by microRNAs in bladder cancer. AB - OBJECTIVE: Our previous study demonstrated that fascin homolog 1 (FSCN1) might have an oncogenic function in bladder cancer (BC) and that its expression was regulated by specific microRNAs (miRNAs). Recently, LIM and SH3 protein 1 (LASP1) as well as FSCN1 have been reported as actin filament bundling proteins in the same complexes attached to the inner surfaces of cell membranes. We hypothesize that LASP1 as well as FSCN1 have an oncogenic function and that is regulated by miRNAs targeting LASP1 mRNA. METHODS: The expression levels of LASP1 mRNA in 86 clinical samples were evaluated by real-time RT-PCR. LASP1-knockdown BC cell lines were transfected by siRNA in order to examine cellular viability by XTT assay, wound healing assay, and matrigel invasion assay. We employed web-based software in order to search for candidate miRNAs targeting LASP1 mRNA, and we focused on miR-1, miR-133a, miR-145, and miR-218. The luciferase reporter assay was used to confirm the actual binding sites between the miRNAs and LASP1 mRNA. RESULTS: Real-time RT-PCR showed that LASP1 mRNA expression was higher in 76 clinical BC specimens than in 10 normal bladder epitheliums (P < 0.05). Loss-of function studies using si-LASP1-transfected BC cell lines demonstrated significant cell viability inhibition (P < 0.0005), cell migration inhibition (P < 0.0001), and a decrease in the number of invading cells (P < 0.005) in the transfectants compared with the controls. Transient transfection of three miRNAs (miR-1, miR-133a, and miR-218), which were predicted as the miRNAs targeting LASP1 mRNA, repressed the expression levels of mRNA and protein levels of LASP1. The luciferase reporter assay demonstrated that the luminescence intensity was significantly decreased in miR-1, miR-133a, and miR-218 transfectants (P < 0.05), suggesting that these miRNAs have actual target sites in the 3' untranslated region of LASP1 mRNA. Furthermore, significant cell viability inhibitions occurred in miR-218, miR-1, and miR-133a transfectants (P < 0.001). CONCLUSION: Our data indicate that LASP1 may have an oncogenic function and that it might be regulated by miR-1, miR-133a, and miR-218, which may function as tumor suppressive miRNAs in BC. PMID- 20843713 TI - New bacteriological patterns in primary infected aorto-iliac aneurysms: a single centre experience. AB - OBJECTIVES: To assess causative pathogens and surgical outcomes in patients with primary infected aorto-iliac aneurysms at our institution. DESIGN: Retrospective study of patients treated at a university hospital between 1992 and 2009. RESULTS: We identified 26 patients (median age, 63 years) with primary infected aneurysms on the aorta (descending thoracic, n = 2; thoraco-abdominal, n = 3; suprarenal, n = 2; infrarenal, n = 15) or iliac arteries (n = 4). Among them, 22 were symptomatic, including 13 with ruptured aneurysms. The causative organisms, identified in 25/26 patients, were Campylobacter fetus, n = 6; Streptococcus pneumoniae, n = 4; Listeria, n = 3; Salmonella, n = 2; Mycobacterium tuberculosis, n = 2; Staphylococcus aureus, n = 1; and other, n = 7. Immune suppression was a feature in 10 (38.4%) patients. Revascularisation was performed in situ in 23 patients (10 allografts, eight grafts, three superficial femoral veins, and 2 stentgrafts) and by extra-anatomic bypass in three patients. Hospital mortality was 23% (in situ group, 17.4%; extra-anatomic group, 66.7%; chi(2)(Yates), P = 0.24). During follow-up in the 20 survivors (median, 48.5 months), there were two non-infection-related deaths (five and 24 months) and six (30%) vascular complications. CONCLUSIONS: The bacteriological spectrum of primary infected aorto-iliac aneurysms was wider than previously reported. The availability of new diagnostic tests and increased prevalence of immunosuppression may explain this finding. PMID- 20843714 TI - HFE gene mutations in patients with primary iron overload: is there a significant improvement in molecular diagnosis yield with HFE sequencing? AB - Rare HFE variants have been shown to be associated with hereditary hemochromatosis (HH), an iron overload disease. The low frequency of the HFE p.C282Y mutation in HH-affected Brazilian patients may suggest that other HFE related mutations may also be implicated in the pathogenesis of HH in this population. The main aim was to screen for new HFE mutations in Brazilian individuals with primary iron overload and to investigate their relationship with HH. Fifty Brazilian patients with primary iron overload (transferrin saturation>50% in females and 60% in males) were selected. Subsequent bidirectional sequencing for each HFE exon was performed. The effect of HFE mutations on protein structure were analyzed by molecular dynamics simulation and free binding energy calculations. p.C282Y in homozygosis or in heterozygosis with p.H63D were the most frequent genotypic combinations associated with HH in our sample population (present in 17 individuals, 34%). Thirty-six (72.0%) out of the 50 individuals presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n=11, 22.0%). One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior indicated that the p.V256I mutation does not reduce the binding affinity between HFE and beta2-microglobulin (beta2M) in the same way the p.C282Y mutation does compared with the native HFE protein. In conclusion, screening of HFE through direct sequencing, as compared to p.C282Y/p.H63D genotyping, was not able to increase the molecular diagnosis yield of HH. The novel p.V256I mutation could not be implicated in the molecular basis of the HH phenotype, although its role cannot be completely excluded in HH phenotype development. Our molecular modeling analysis can help in the analysis of novel, previously undescribed, HFE mutations. PMID- 20843716 TI - SD-CAS: Spin Dynamics by Computer Algebra System. AB - A computer algebra tool for describing the Liouville-space quantum evolution of nuclear 1/2-spins is introduced and implemented within a computational framework named Spin Dynamics by Computer Algebra System (SD-CAS). A distinctive feature compared with numerical and previous computer algebra approaches to solving spin dynamics problems results from the fact that no matrix representation for spin operators is used in SD-CAS, which determines a full symbolic character to the performed computations. Spin correlations are stored in SD-CAS as four-entry nested lists of which size increases linearly with the number of spins into the system and are easily mapped into analytical expressions in terms of spin operator products. For the so defined SD-CAS spin correlations a set of specialized functions and procedures is introduced that are essential for implementing basic spin algebra operations, such as the spin operator products, commutators, and scalar products. They provide results in an abstract algebraic form: specific procedures to quantitatively evaluate such symbolic expressions with respect to the involved spin interaction parameters and experimental conditions are also discussed. Although the main focus in the present work is on laying the foundation for spin dynamics symbolic computation in NMR based on a non-matrix formalism, practical aspects are also considered throughout the theoretical development process. In particular, specific SD-CAS routines have been implemented using the YACAS computer algebra package (http://yacas.sourceforge.net), and their functionality was demonstrated on a few illustrative examples. PMID- 20843715 TI - Microtesla MRI with dynamic nuclear polarization. AB - Magnetic resonance imaging at microtesla fields is a promising imaging method that combines the pre-polarization technique and broadband signal reception by superconducting quantum interference device (SQUID) sensors to enable in vivo MRI at microtesla-range magnetic fields similar in strength to the Earth magnetic field. Despite significant advances in recent years, the potential of microtesla MRI for biomedical imaging is limited by its insufficient signal-to-noise ratio due to a relatively low sample polarization. Dynamic nuclear polarization (DNP) is a widely used approach that allows polarization enhancement by 2-4 orders of magnitude without an increase in the polarizing field strength. In this work, the first implementation of microtesla MRI with Overhauser DNP and SQUID signal detection is described. The first measurements of carbon-13 NMR spectra at microtesla fields are also reported. The experiments were performed at the measurement field of 96 MUT, corresponding to Larmor frequency of 4 kHz for protons and 1 kHz for carbon-13. The Overhauser DNP was carried out at 3.5-5.7 mT fields using rf irradiation at 120 MHz. Objects for imaging included water phantoms and a cactus plant. Aqueous solutions of metabolically relevant sodium bicarbonate, pyruvate, alanine, and lactate, labeled with carbon-13, were used for NMR studies. All the samples were doped with TEMPO free radicals. The Overhauser DNP enabled nuclear polarization enhancement by factor as large as -95 for protons and as large as -200 for carbon-13, corresponding to thermal polarizations at 0.33 T and 1.1 T fields, respectively. These results demonstrate that SQUID-based microtesla MRI can be naturally combined with Overhauser DNP in one system, and that its signal-to-noise performance is greatly improved in this case. They also suggest that microtesla MRI can become an efficient tool for in vivo imaging of hyperpolarized carbon-13, produced by low-temperature dissolution DNP. PMID- 20843717 TI - [Evaluation of the teamwork in six intensive care units of two university hospitals]. AB - INTRODUCTION: It has been demonstrated that teamwork has a direct positive effect on the quality and the efficiency of patient's care and consequently on hospital costs. OBJECTIVES: 1.To assess attitudes toward the teamwork of nurses and physicians of 6 ICUs in two teaching hospitals. 2.To analyze if there are any relationships between attitudes toward teamwork and socio-demographic variables. 3.To study if there are differences in the attitudes toward teamwork among professionals of the different units. METHOD: This prospective study evaluated the attitudes of teamwork of 136 professionals with the scale development by Heinemann et al. in 1999. This scale is made up of three subscales that measure the value of being in a team, the efficiency of the team and the function of collaboration of the physician within the team. RESULTS: The majority of professionals had a positive attitude towards teamwork. They obtained a mean score of 97.01 for a maximum of 120 points. In regards to sociodemographic variables, statistically significant differences were only found in gender and professional category, as women and female nurses had better attitudes toward teamwork. There were no differences in attitudes towards teamwork in the different units studied. CONCLUSION: Attitude toward teamwork by physicians and nurses of the 6 ICUs studied was good. No differences were found between attitudes toward teamwork among the professionals of the different units. PMID- 20843718 TI - Toxoplasma gondii infection in first-episode and inpatient individuals with schizophrenia. AB - BACKGROUND: A high seroprevalence of Toxoplasma gondii infection has been detected in psychiatric patients, particularly in schizophrenia cases. METHODS: In the present study 98 patients suffering from schizophrenia (58 inpatients and 40 first-episode patients) and 96 control patients (50 healthy volunteers and 46 with a depressive disorder) were examined for the presence of both IgG and IgM antibodies against T. gondii by enzyme-linked immunosorbent assay (ELISA). We applied the Bradford Hill criteria to identify the weight of causal inference. RESULTS: The positivity rate of anti-T. gondii IgG antibodies among individuals with schizophrenia (57.1%) was significantly higher than in healthy controls (29.2%). There were no associations between immune status ratio (ISR) values and the risk of schizophrenia. The weight of evidence approach using the Bradford Hill criteria revealed a 92% probability of a causal association. CONCLUSION: Our results show that exposure to T. gondii may lead to schizophrenia. PMID- 20843719 TI - Outbreak of acute gastroenteritis in young children with death due to rotavirus genotype G9 in Rio Branco, Brazilian Amazon region, 2005. AB - BACKGROUND: An epidemic of acute gastroenteritis occurred in Rio Branco City, Acre State, in Brazil's Amazon region in 2005. An investigation was conducted to confirm the etiology and identify possible risk factors for death. METHODS: Rio Branco municipality surveillance data for the period May to October 2005 were reviewed. In a case-control study, children who died following acute gastroenteritis were compared to age-matched controls with acute gastroenteritis who survived. Rotavirus A (RV-A) was investigated in 799 stool samples and genotyped by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The cumulative incidence of diarrhea in children aged <5 years was 21%. A fatal outcome was significantly associated with uncovered household water storage containers. RV-A was identified in 88% of samples and G9 was the prevalent genotype (71%). CONCLUSIONS: Oral rehydration solution and boiling or chlorinating drinking water likely limited mortality. This epidemic was caused by RV-A genotype G9. After the outbreak, a rotavirus vaccine was introduced into the official childhood immunization schedule in Brazil. PMID- 20843720 TI - Resistant and multi-resistant Gram-positive severe infections: the GISIG working methodology. AB - BACKGROUND: Five thematic working groups composed of Italian infectious disease experts and a group coordinator, supported by a scientific secretary, identified controversial issues in the field of severe healthcare-associated infections caused by multidrug-resistant organisms. The five group coordinators received training courses on data sources and electronic databases, literature search strategies, the scientific revision methods of quality assessment, and the construction of an evidence matrix. WORKING PLAN AND METHODS: The working plan identified the following step: definition of the controversial issues and identification of documents for a systematic literature review. A specific methodology to classify the selected evidence was used that required the evaluation of the quality of review documents and statement documents and evaluation of the quality of original research. An original method to assess review documents and statement documents was proposed. A matrix model to extract and evaluate the evidence from original studies was designed using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, cohorts, and retrospective studies. QUALITY OF EVIDENCE: A modified GRADE working group method was applied for grading quality of evidence and strength of recommendations. The working groups reviewed the available studies and formulated recommendations to be voted on at the national consensus conference held in Rome in June 2009. PMID- 20843722 TI - Methicillin-resistant Staphylococcus aureus: related infections and antibiotic resistance. AB - Staphylococcus aureus is a well adapted human pathogen, capable of living freely in the inanimate environment and spreading from person to person, existing as a colonizer or commensal, hiding in intracellular compartments and, most importantly, inducing various forms of human disease. Infections caused by S. aureus, above all by antibiotic-resistant strains, have reached epidemic proportions globally. The overall burden of staphylococcal disease caused by antibiotic-resistant S. aureus, particularly by the methicillin-resistant strains, is increasing in many countries, including Italy, in both healthcare and community settings. The widespread use of antibiotics has undoubtedly accelerated the evolution of S. aureus, which, acquiring multiple resistance genes, has become able to survive almost all antibiotic families; this evolution versus more resistant phenotypes has continued among the newer agents, including linezolid and daptomycin. The diminished clinical usefulness of vancomycin is seen as one of the most worrisome problems in many clinical settings and in many countries. In fact, the increasing spread of heteroresistant vancomycin-intermediate S. aureus (hVISA) and vancomycin intermediate (VISA) strains adds new problems, not only in terms of the treatment of severe infections sustained by these microorganisms, but also in the microbiological definition of susceptibility. PMID- 20843721 TI - Consensus document on controversial issues in the diagnosis and treatment of prosthetic joint infections. AB - BACKGROUND: Joint replacement surgery has been on the increase in recent decades and prosthesis infection remains the most critical complication. Many aspects of the primary prevention and clinical management of such prosthesis infections still need to be clarified. CONTROVERSIAL ISSUES: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for the following controversial issues: (1) Is a conservative surgical approach for the management of prosthetic joint infections effective? (2) Is the one-stage or the two-stage revision for the management of prosthetic joint infections more effective? (3) What is the most effective treatment for the management of prosthetic joint infections due to methicillin-resistant staphylococci? Results are presented and discussed in detail. METHODS: A systematic literature search using the MEDLINE database for the period 1988 to 2008 of randomized controlled trials and/or non randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence and strength of recommendation was applied. PMID- 20843723 TI - Consensus document on controversial issues in the diagnosis and treatment of bloodstream infections and endocarditis. AB - BACKGROUND: The treatment of severe bloodstream infections (sepsis, endocarditis, and infections of vascular prostheses) caused by Gram-positive microorganisms is made even more difficult by the emergence of resistant strains. The introduction of new antibiotics with activity against these strains has created new opportunities, but many controversial issues remain. CONTROVERSIAL ISSUES: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues concerned the duration of therapy and role of aminoglycosides and teicoplanin in the treatment of Gram-positive bacterial endocarditis, the optimal use of the new antibiotics in the treatment of bloodstream infections caused by resistant Gram-positive strains, and the use of microbiological techniques (i.e., bactericidal serum testing and synergy testing) and of pharmacokinetic data (e.g., monitoring of plasma levels of antibiotics) in the treatment of difficult-to-treat Gram-positive bloodstream infections. METHODS: A systematic literature search of randomized controlled trials and/or non-randomized studies was performed mainly using the MEDLINE database. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for non-randomized studies. The GRADE method for grading the quality of evidence and strength of recommendation was applied. PMID- 20843725 TI - Feedback loop process to control acoustic cavitation. AB - Applications involving acoustic cavitation mechanisms, such as sonoporation, are often poorly reproducible because of the unstationary behavior of cavitation. For this purpose, this study proposes to work at a fixed cavitation level instead of a fixed acoustic intensity. A regulated cavitation generator has been developed in an in vitro configuration of standing wave field. This system implements the regulation of the cavitation level during sonication by modulating the applied acoustic intensity with a feedback loop based on acoustic measurements. The experimental setup consists of a plane piezoelectric transducer for sonication (continuous wave, frequency 445 kHz) and a hydrophone pointing to the sonicated medium. The cavitation level is quantified every 5 ms from a spectral analysis of the acoustic signal. The results show that the regulation device generates reproducible mean cavitation levels with a standard deviation lower than 1.6% in the applied intensity range (from 0.12 to 3.44 W/cm(2)), while this standard deviation can reach 76% without regulation. The feedback loop process imposes precise cavitation level even in low applied acoustic intensity. PMID- 20843724 TI - Expression of C-fos, Fos-B, Fosl-1, Fosl-2, Dusp-1 and C-jun in the mouse heart after single and repeated chlorpromazine administrations. AB - Many cases of sudden chlorpromazine (Chl)-related deaths have been identified in forensic autopsies. Because Chl concentration detected in such cases is often low, identifying the cause of death can be difficult. Patients on Chl therapy exhibit arrhythmia and cardiomyopathy. Thus, Chl may affect the heart, particularly, gene expression there. Immediate early genes (IEGs) are expressed following stimulation. Using real-time quantitative-PCR, we investigated the mRNA expression of IEGs, including C-fos, Fos-B, Fosl-1, Fosl-2, Dusp-1 and C-jun, in the mouse heart after once-daily high-dose (7.5 mg/kg) or low-dose (0.75 mg/kg) of Chl single and repeated (1-4 weeks) injections. We showed that single high dose Chl administration induced IEGs except C-jun. This induction was not observed after the repeated administration, and thus; suggested that the transcriptome is altered after repeated administration and tolerance is developed to Chl. Moreover, C-jun expression decreases after repeated administration. These results reflect that C-jun is down-regulated to avoid cardiomyopathy caused by the over stimulation of C-jun. In future, we intend to clarify the Chl-induced IEG cascade via IEGs in the mouse heart. Chl treatment can result in cardiovascular diseases. Investigation of the transcriptome in the heart after repeated Chl administration will aid in elucidating the patho-physiology of Chl related cardiovascular diseases. PMID- 20843726 TI - Efficient and green sonochemical synthesis of 3,3-bis(4 (dimethylamino)phenyl)indolin-2-ones. AB - A simple, green sonochemical synthesis of 3,3-bis(4-(dimethylamino)phenyl)indolin 2-ones, 2,2-bis(4-(dimethylamino)phenyl)-1H-indene-1,3(2H)-dione, 2,2-bis(4 (dimethylamino)phenyl)acenaphthylen-1(2H)-one and 5-(4-(dimethylamino)phenyl)-5 hydroxypyrimidine-2,4,6(1H,3H,5H)-triones using indium(III) chloride catalyst in aqueous media at room temperature is reported. Good yields, easy workup, short reaction time and the use of water as a solvent that is considered to be relatively environmentally benign are advantages of this new method. PMID- 20843727 TI - Site and neighborhood environments for walking among older adults. AB - Walking has significant health and mobility benefits for older adults. Previous environment-walking studies have focused on neighborhood environments, overlooking proximate site-level characteristics. This study examines both the neighborhood and site-level environments. A survey was conducted with 114 older adults from five assisted-living facilities in Houston, TX. A subset of 61 participants' environments was examined using Geographic Information Systems (GIS). Multivariate analyses identified positive correlates of walking at the site level including yard landscaping and corner-lots, and neighborhood-level correlates including walking destinations, safety from crime, and sidewalks. Both site-level and neighborhood environmental supports appear important in promoting walking among older adults. PMID- 20843728 TI - Paradigm shifts in the management of osteoradionecrosis of the mandible. AB - Osteoradionecrosis (ORN) of the mandible is a significant complication of radiation therapy for head and neck cancer. In this condition, bone within the radiation field becomes devitalized and exposed through the overlying skin or mucosa, persisting as a non-healing wound for three months or more. In 1926, Ewing first recognized the bone changes associated with radiation therapy and described them as "radiation osteitis". In 1983, Marx proposed the first staging system for ORN that also served as a treatment protocol. This protocol advocated that patients whose disease progressed following conservative therapy (hyperbaric oxygen (HBO), local wound care, debridement) were advanced to a radical resection with a staged reconstruction utilizing a non-vascularized bone graft. Since the introduction of Marx's protocol, there have been advances in surgical techniques (i.e. microvascular surgery), as well as in imaging techniques, which have significantly impacted on the diagnosis and management of ORN. High resolution CT scans and orthopantamograms have become a key component in evaluating and staging ORN, prior to formulating a treatment plan. Patients can now be stratified based on imaging and clinical findings, and treatment can be determined based on the stage of disease, rather than determining the stage of disease based on a patient's response to a standardized treatment protocol. Reconstructions are now routinely performed immediately after resection of the diseased tissue rather than in a staged fashion. Furthermore, the transfer of well-vascularized hard and soft tissue using microvascular surgery have brought the utility of HBO treatment in advanced ORN into question. PMID- 20843729 TI - The use of the pectoralis major flap for advanced and recurrent head and neck malignancy in the medically compromised patient. AB - A retrospective review of seventy-one PPM flaps used between 1996 and 2010 primarily for oral and oropharyngeal squamous cell carcinoma presenting as either advanced stage IV primary disease (41/43), extensive recurrent (10) or metastatic (9) neck disease. The PPM flap was most commonly used following resection of the mandible (23) or the tongue/oropharynx (19). When the PPM flap was the preferred reconstruction option (54) the main indication, in addition to advanced disease, was significant medical co-morbidity (23). The majority of PPM flaps (75%) were used in the latter half of the series for an increasing number of patients in poor health with advanced disease. There was no evidence of an increase in age, ASA grade or extent of disease during this period. Approximately one quarter (17) of the flaps were used after failure of a free flap, most commonly a DCIA (7) or radial (6) flap. The 30day mortality in this group of compromised patients undergoing major surgery for advanced disease was 7% (5/71). The overwhelming majority had significant co-morbidity (94% grade 2 or higher with 63% ASA grade 3) and 90% had already undergone previous major surgery and/or radiotherapy. The 1-year, 3-year and 5-year overall survival rates were 65.5%, 39.1% and 11.0% respectively with cancer-specific survival rates of 82.0%, 65.5% and 65.5%. The majority died of disease related to the underlying co-morbidity. We recommend an aggressive approach to the surgical resection of advanced and recurrent disease but a pragmatic approach to reconstruction. The PPM major flap is reliable for reconstruction of defects of the mandible, tongue and oropharynx with a complete flap failure rate of 2.8%. Lateral defects of the mandible were managed without a plate and with an acceptable outcome in the context of limited life expectancy. This is the largest study of the use of the PPM flap for this type of patient group. The flap retains a major role in the management of advanced primary or recurrent disease, extensive metastatic neck disease and after failure of a free flap when in conjunction with significant co-morbidity. PMID- 20843730 TI - A novel indole-3-carbinol derivative inhibits the growth of human oral squamous cell carcinoma in vitro. AB - Indole-3-carbinol (I3C), a naturally occurring phytochemical found in cruciferous vegetables, has received much attention due to its translational potential in cancer prevention and therapy. In this study, we investigated the antitumor effects of OSU-A9, a structurally optimized I3C derivative, in a panel of oral squamous cell carcinoma cell lines, SCC4, SCC15, and SCC2095. The antiproliferative effect of OSU-A9 was approximately two-orders-of-magnitude higher than that of I3C. Importantly, normal human oral keratinocytes were less sensitive to OSU-A9 than oral cancer cells. This antiproliferative effect of OSU A9 was attributable to the induction of mitochondrial-dependent apoptosis as evidenced by sub-G1 accumulation of cells, poly ADP-ribose polymerase cleavage, and cytochrome c release from the mitochondria. OSU-A9 down regulates Akt and NF kappaB signaling pathways, leading to changes in many downstream effectors involved in regulating cell cycle and apoptosis. Moreover, the observed down regulation of IKKalpha and IKKbeta expression by OSU-A9 is not reported for I3C. OSU-A9 also induces both the production of reactive oxygen species and the endoplasmic reticulum stress. Taken together, these results suggest the translational value of OSU-A9 in oral squamous cell cancer therapy in the future. PMID- 20843731 TI - Primary oncocytic carcinoma of the salivary glands: a clinicopathologic and immunohistochemical study of 12 cases. AB - Oncocytic carcinoma (OC) of salivary gland origin is an extremely rare proliferation of malignant oncocytes with adenocarcinomatous architectural phenotypes, including infiltrative qualities. To help clarify the clinicopathologic and prognostic features of this tumor group, herein, we report 12 OC cases arising from the salivary glands, together with follow-up data and immunohistochemical observations. There were 10 males and 2 females with an age range of 41 to 86 years (median age: 61.3 years). Most occurred in the parotid gland (10/12) with one in the palate and one in the retromolar gland. The tumors were unencapsulated and often invaded into the nearby gland, lymphatic tissues and nerves. The neoplastic cells had eosinophilic granular cytoplasm and round vesicular nuclei with prominent red nucleoli. Ultrastructural study, PTAH, and immunohistochemistry staining confirmed the presence of numerous mitochondria in the cytoplasm of oncocytes. Cellular atypia and pleomorphism varied in the current series. Double nuclei and mitoses were observed in some cases, while one case that showed mild cellular pleomorphism but had local invasion following local recurrence was also identified as an OC. Of the 11 cases with follow-up information, 7 cases had local recurrence. Regional or distant metastases were found in 6 and 4 cases, respectively. Five-year disease-specific survivals were 54.9%. In summary, OC of salivary gland origin is a high-grade tumor, often with local recurrence, regional or distant metastasis, diagnosis of which based on a combination of clinical and histopathological features. Immunohistochemistry for mitochondria is considered as a practical and helpful adjuvant diagnosis. Complete surgical excision is the treatment of choice while the role of radiotherapy or chemotherapy is controversial, and careful follow-up is necessary. PMID- 20843732 TI - Human papilloma virus in locally advanced stage III/IV squamous cell cancer of the oropharynx and impact on choice of therapy. AB - Oropharyngeal cancers (OPCs) are now believed to arise from two distinct pathways: one influenced by alcohol and tobacco use and the other a result of genomic instability induced by the human papilloma virus (HPV). The incidence of HPV-associated OPC is increasing, particularly among younger males. Case series and clinical trials suggest that patients with HPV-positive OPC have better clinical outcomes than those with HPV-negative tumors. We evaluated efficacy data in published articles and meeting abstracts from clinical studies comparing response rates and survival outcomes in patients with HPV-positive and -negative locally advanced OPC. Eight clinical studies were identified: half were prospective analyses of outcome according to HPV status; the remaining four reports were retrospective analyses. The majority of these analyses showed that patients with HPV-positive tumors had significantly better responses to treatment than those with HPV-negative tumors. In the two studies in which the effect of treatment was also evaluated, patients with HPV-positive tumors did not benefit significantly from intensive therapy, unlike those with HPV-negative tumors. HPV positive tumor status is an important prognostic factor associated with a favorable outcome in patients with locally advanced OPC. The HPV status of patients with locally advanced OPC should be established before treatment commences. Surgery is well accepted in the treatment of OPC, but the place of chemoradiotherapy has yet to be confirmed. Prospective, well-controlled clinical studies are required to establish whether chemoradiotherapy provides an acceptable risk-benefit balance versus high-quality radiotherapy alone in patients with HPV-positive OPC, in whom the goal is to maximize progression-free and overall survival, while preserving function and maintaining quality of life. PMID- 20843733 TI - High-throughput sequencing and clinical microbiology: progress, opportunities and challenges. AB - High-throughput sequencing is sweeping through clinical microbiology, transforming our discipline in its wake. It is already providing an enhanced view of pathogen biology through rapid and inexpensive whole-genome sequencing and more sophisticated applications such as RNA-seq. It also promises to deliver high resolution genomic epidemiology as the ultimate typing method for bacteria. However, the most revolutionary effect of this 'disruptive technology' is likely to be creation of a novel sequence-based, culture-independent diagnostic microbiology that incorporates microbial community profiling, metagenomics and single-cell genomics. We should prepare for the coming 'technological singularity' in sequencing, when this technology becomes so fast and so cheap that it threatens to out-compete existing diagnostic and typing methods in microbiology. PMID- 20843734 TI - Fabrication of Eu(III) complex doped nanofibrous membranes and their oxygen sensing properties. AB - In this paper, we report the synthesis, characterization, and photophysical properties of Eu(TTA)3ECIP, where TTA=2-thenoyltrifluoroacetonate, and ECIP=1 ethyl-2-(N-ethyl-carbazole-yl-4-)imidazo[4,5-f]1,10-phenanthroline. Its elementary application for oxygen-sensing application is also investigated by doping it into a polymer matrix of polystyrene (PS). Experimental data suggest that the 2.5 wt% doped Eu(TTA)3ECIP/PS nanofibrous membrane exhibits a high sensitivity of 3.4 towards oxygen with a good linear relationship of R2 = 0.9962. In addition, the 2.5 wt% doped Eu(TTA)3ECIP/PS nanofibrous membrane owns a quick response of 8s towards oxygen, along with its excellent atmosphere insensitivity and photobleaching resistance. All these results suggest that both Eu(TTA)3ECIP and Eu(TTA)3CIP/PS system are promising candidates for oxygen-sensing optical sensors. PMID- 20843735 TI - Frequency dependent study of the correlation functions in EPR spectroscopy--The Cole-Davidson approach. II. 2,N-(4-n-Butyl benzilidene) 4-amino 2,2,6,6 tetramethyl piperidine 1-oxide in toluene. AB - EPR linewidth measurements of 2,N-(4-n-butyl benzilidene) 4-amino 2,2,6,6 tetramethyl piperidine 1-oxide (BBTMPO) in toluene at 1 GHz (L-Band), 4 GHz (S Band), 9 GHz (X-Band) and 34 GHz (Q-Band) microwave frequencies indicate the presence of a distribution of relaxation times. The empirical response parameter introduced by Cole-Davidson for the analysis of dielectric relaxation in liquids has been used for the analysis of EPR relaxation data in the L-Band and S-Band frequency regions. The Cole-Davidson parameter can assume values in the range 0 < beta <= 1. When beta = 1, one obtains the Debye-type spectral density. The calculated linewidth data at 1 GHz and 4 GHz agree with a Cole-Davidson parameter of 0.7 for the spherocone shaped BBMTPO solute. beta < 1 at the L- and S-bands suggests the presence of an asymmetrical distribution of relaxation times associated with different modes of relaxation mechanisms or internal molecular motions. This study shows EPR experiments at low microwave frequencies are more sensitive to the shape of the correlation function. Differences between this study and an earlier study [6] on perdeuterated 2,2,6,6-tetramethly-4-piperidone N oxide (PD-Tempone) in toluene are attributed to the size of and absence of deuteration in the BBTMPO probe. PMID- 20843736 TI - Contrasting effects on ganciclovir susceptibility and replicative capacity of two mutations at codon 466 of the human cytomegalovirus UL97 gene. AB - BACKGROUND: Human cytomegalovirus (HCMV) infections cause significant morbidity in immunocompromised hosts. Resistance to ganciclovir is predominantly associated with alterations in the HCMV UL97 kinase and, more occasionally, with mutations in the HCMV DNA polymerase gene. OBJECTIVES: The aim of this study was to investigate the impact of two different mutations found at the same UL97 codon on drug susceptibility and viral replicative capacity. Mutation V466G was observed in a solid organ transplant recipient whereas mutation V466M was observed in a patient with AIDS. STUDY DESIGN: Two HCMV UL97 mutations, V466M and V466G, were transferred to recombinant viruses using a bacterial artificial chromosome system. Susceptibility testing of the recombinant wild-type and mutant viruses was performed using a standard plaque reduction assay. Replication kinetics of recombinant viruses was investigated using a yield assay. RESULTS: Mutant V466G was resistant to ganciclovir and had significant replicative defect whereas mutant V466M was drug susceptible and had unaltered replication kinetics. Furthermore, mutant V466G formed small viral plaques with intracellular inclusions. CONCLUSIONS: To our knowledge, this is the first report of such contrasting phenotypes for drug susceptibility and replicative capacity for HCMV mutations found at the same codon of the UL97 gene. PMID- 20843737 TI - Neurofeedback in children with ADHD: specific event-related potential findings of a randomized controlled trial. AB - OBJECTIVE: In a randomized controlled trial, we could demonstrate clinical efficacy of neurofeedback (NF) training for children with ADHD (Gevensleben et al., 2009a). The present investigation aimed at learning more about the neuronal mechanisms of NF training. METHODS: Children with ADHD either completed a NF training or a computerized attention skills training (ratio 3:2). NF training consisted of one block of theta/beta training and one block of slow cortical potential (SCP) training, each comprising 18 training units. At three times (pre training, between the two training blocks and at post-training), event-related potentials (ERP) were recorded during the Attention Network Test. ERP analysis focused on the P3, reflecting inter alia attentional resources for stimulus evaluation, and the contingent negative variation (CNV), primarily related to cognitive preparation. RESULTS: After NF training, an increase of the CNV in cue trials could be observed, which was specific for the SCP training. A larger pre training CNV was associated with a larger reduction of ADHD symptomatology for SCP training. CONCLUSIONS: CNV effects reflect neuronal circuits underlying resource allocation during cognitive preparation. These distinct ERP effects are closely related to a successful NF training in children with ADHD. In future studies, neurophysiological recordings could help to optimize and individualize NF training. SIGNIFICANCE: The findings contribute to a better understanding of the mechanisms underlying NF training in children with ADHD. PMID- 20843738 TI - Immunoproteomics of Helicobacter pylori infection in patients with atrophic body gastritis, a predisposing condition for gastric cancer. AB - Atrophic body gastritis is considered an outcome of H. pylori infection at high risk for gastric cancer. Immunoproteomics has been used to detect H. pylori antigens, which may act as potential markers for neoplastic disease and may be used in specific serological tests. We used immunoproteome technology to identify H. pylori antigens, recognized by sera from patients with atrophic body gastritis. Here, we performed 2DE protein maps of H. pylori strain 10K, probed against single sera from 3 groups of H. pylori-positive patients (atrophic body gastritis; intestinal-type gastric cancer; peptic ulcer) and negative controls. Immunoreactive spots were identified by MALDI-TOF-MS. A total of 155 immunoreactive spots were detected corresponding to 14.1% of total spots detected in our reference map of H. pylori strain 10K. Sera from atrophic body gastritis (40.5+/-2%) and gastric cancer patients (25.9+/-1.8%) showed a significantly higher and stronger mean immunoreactivity versus H. pylori antigens compared to peptic ulcer patients (11.2+/-1.3%). The average intensity of immunoreactivity of sera from atrophic body gastritis and gastric cancer patients was significantly stronger compared to peptic ulcer patients. Sera from atrophic body gastritis and gastric cancer patients differentially recognized 17 H. pylori spots. Immunoproteome technology may discriminate between different H. pylori-related disease phenotypes showing a serological immunorecognition pattern common to patients with gastric cancer and atrophic body gastritis, its precursor condition. This tool may be promising for developing specific serological tests to identify patients with gastritis at high risk for gastric cancer, to be evaluated in prospective investigations. PMID- 20843739 TI - Impact of Staphylococcus aureus on the pathogenesis of chronic cystic fibrosis lung disease. AB - One of the first pathogens which can be isolated from the airways of cystic fibrosis (CF) patients is Staphylococcus aureus, which often persists in this hostile environment for many months or even years. The increase in infections due to the methicillin-resistant S. aureus (MRSA) worldwide and even more the emergence of community-acquired MRSA, which differ from nosocomial MRSA by lack of multiresistance and carriage of a phage-encoded toxin, Panton-Valentine leukocidin, attracts new attention to the epidemiology, pathogenesis, and impact of S. aureus in the background of CF. In this review, recent data and studies will be reported and discussed to give an overview of the latest research. PMID- 20843740 TI - Adaptation of Staphylococcus aureus to the cystic fibrosis lung. AB - Staphylococcus aureus colonizes the lungs of cystic fibrosis (CF) patients and despite treatment with antibiotics results in recurrent and relapsing infections. With increasing duration of the infection, the bacterial population is exposed more and more to changing selective pressures exerted by the host immune system, to frequent therapeutic interventions, and to interference with other microorganisms. S. aureus has evolved a variety of strategies to adapt to these challenges: Recombination and mutation provide the population with a preselected heterogeneity, resulting in an inheritable shift of phenotypic traits. This includes the emergence of isolates with mutations in metabolic (e.g. small-colony variants) and regulatory (e.g. agr mutants) genes. Additionally, phages become mobilized with a higher frequency during infection, raising the propensity for recombination. On the other hand, S. aureus can also adapt to the CF lung using regulatory mechanisms which are not well understood in this context. The quorum sensing system agr is not activated during lung infection in CF, which is consistent with a proposed biofilm mode of growth in the lungs and also with the observation that in CF patients the organism usually remains localized in the lungs without systemic manifestation. Altogether, adaptive processes result in the generation of a heterogeneous S. aureus population in the CF lung which is highly protected against antibiotic therapy, expressing factors necessary for persistence rather than virulence. PMID- 20843741 TI - Sleep apnoeas and neurobehavioral effects in solvent exposed workers. AB - BACKGROUND: Exposure to organic solvents may cause an increase of sleep apnoeas, which may explain the excess of fatigue, concentration and memory problems reported in exposed workers. METHODS: Polysomnography was performed in 21 long term exposed printers and 27 controls. In addition, a questionnaire regarding sleep related complaints, Q16 questionnaire and computerized neurobehavioral tests were administered. The groups matched well regarding age, weight, neck circumference and schooling level. A semi-quantitative cumulative exposure index was calculated. RESULTS: Excessive sleepiness while watching TV (p<0.01) and diminished sexual interest (p=0.03) was found in the organic solvent-workers. The sleep complaints score correlated positively with the exposure index and duration (both p=0.01). The polysomnography results showed an increase of central apnoeas in the exposed workers (67%) compared to the referents (30%). The presence of central apnoeas was positively correlated with the exposure index (p<0.05) in regression models. Of the neurobehavioral test only hand-eye coordination was dose-related impaired in the exposed workers. The co-existence of abnormal values on at least one neurobehavioral test and the presence of central apnoeas was observed in the exposed workers, but did not reach significance. CONCLUSIONS: Workers chronically exposed to low organic solvent levels may experience mild sleeping problems, however, our data do not support the hypothesis that the clinical picture of chronic toxic encephalopathy can be primarily caused by the induction of sleep apnoea syndrome. It seems thus that the risk to experience central apnoeas rather accompanies the risk of impaired neurobehavioral performance with increasing exposure in a working population. PMID- 20843742 TI - Determination of operator exposure levels to insecticide during bait applications in olive trees: study of coverall performance and duration of application. AB - In this study the operator exposure levels during bait applications of an insecticide in olive groves were determined using a whole body dosimetry method for dermal exposure. The study design allowed the roles of application task duration and coverall type to be evaluated as factors influencing operator exposure. Twenty applications were carried out with knapsack sprayers in the Tanagra region of Viotia, Greece, ten of which were for a 1h and ten for a 3h duration. An in-house GC-NPD analytical method was developed and validated for the determination of malathion, the active substance (a.s.) of the insecticide formulation used in field trials. The mean recovery of field-fortified samples was 84% (%RSD=3.0). Field trial results generally indicated lower operator exposure levels than indicated by the most relevant operator exposure predictive model. Residues of malathion on internal dosimeters were compared to those measured on the respective outer coveralls (potential dermal exposure) to evaluate the protective factor of each one of the two coverall types used. Both coverall types provided satisfactory levels of protection and can be considered as suitable protection for the conditions of the application scenario studied. Furthermore, the results indicated that there is not a strong correlation between exposure levels and duration of application. PMID- 20843743 TI - Assessment of perchlorate-reducing bacteria in a highly polluted river. AB - A 1-year monitoring experiment of the Sarno River basin was conducted during 2008 to evaluate the overall quality of the water over time and to compare the results with those obtained previously. The physico-chemical and microbiological characteristics of the water course had not changed appreciably with respect to previous determinations, thus emphasizing the major contribution of untreated urban wastewater to the overall pollution of the river. Moreover, attention was paid to the perchlorate ion, one of the so-called emerging contaminants, which is widespread in natural environments and is known to have adverse effects on the human thyroid gland. Over the entire monitoring program, we did not find appreciable levels of perchlorate, although the particular environmental condition could support its development. Thus, a dedicated study was designed to assess the presence of bacteria that can reasonably reduce perchlorate levels. By enrichment and molecular procedures, we identified alpha- and beta-Proteobacteria strains, classified by 16S rDNA sequences as Dechlorospirillum sp. and Dechlorosoma sp., respectively. Further physiologic characterization and the presence of the alpha subunit gene (pcrA) of the perchlorate reductase in both strains confirmed the presence in the river of viable and active perchlorate dissimilatory bacteria. PMID- 20843744 TI - Dorsiflexion range of motion significantly influences dynamic balance. AB - The purpose of this study was to examine the relationships between dorsiflexion range of motion on the weight-bearing lunge test (WBLT) and normalized reach distance in three directions on the Star Excursion Balance Test (SEBT). Thirty five healthy adults (14 males, 21 females, age: 25.9+/-6.7 years, height: 166.7+/ 22.9 cm, weight: 76.7+/-22.8 kg) participated. All subjects performed three trials of maximum lower extremity reach in the anterior, posteromedial, and posterolateral directions of the SEBT on each limb to assess dynamic balance. Subjects performed three trials of the WBLT to measure maximum dorsiflexion range of motion. Dependent variables included the means of the SEBT normalized reach distances in the anterior, posteromedial, and posterolateral directions and the mean of the WBLT. Only the anterior direction (mean: 79.0+/-5.8%) of the SEBT was significantly related to the WBLT (mean: 11.9+/-2.7 cm), r=0.53 (p=0.001). The r2 for this simple linear regression was 0.28, indicating that the WBLT explained 28% of the variance in the anterior normalized reach distance. The WBLT explained a significant proportion of the variance within the anterior reach distance signifying this direction of the SEBT may be a good clinical test to assess the effects of dorsiflexion range of motion restrictions on dynamic balance. PMID- 20843745 TI - Pyrethroid resistance in African anopheline mosquitoes: what are the implications for malaria control? AB - The use of pyrethroid insecticides in malaria vector control has increased dramatically in the past decade through the scale up of insecticide treated net distribution programmes and indoor residual spraying campaigns. Inevitably, the major malaria vectors have developed resistance to these insecticides and the resistance alleles are spreading at an exceptionally rapid rate throughout Africa. Although substantial progress has been made on understanding the causes of pyrethroid resistance, remarkably few studies have focused on the epidemiological impact of resistance on current malaria control activities. As we move into the malaria eradication era, it is vital that the implications of insecticide resistance are understood and strategies to mitigate these effects are implemented. PMID- 20843746 TI - Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF. AB - A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150MUg corifollitropin alfa versus daily 200IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ?11mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5-1.8; P<0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4-2.8; P<0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar. A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150MUg corifollitropin alfa or to daily injections of 200IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar. PMID- 20843747 TI - A simple method for dose fusion from multimodality treatment of prostate cancer: brachytherapy to external beam therapy. AB - PURPOSE: Suboptimal dosage evaluated from postimplant dosimetry of prostate brachytherapy creates conundrum that needs resolution. This pilot study was undertaken to explore the feasibility of summing and visualizing radiation dosage from multimodality treatment. METHODS AND MATERIALS: Four weeks after (125)I permanent prostate seed implant, CT scans were performed on the whole pelvis of patients using our standard protocol for prostate planning. The acquired CT data sets were reconstructed using different sizes of field of view (FOV). The images with limited FOV focusing on prostate were imported into Variseed (Varian Medical Systems, Inc., Palo Alto, CA) for postimplant evaluation, whereas images with full FOV were imported to Eclipse (Varian Medical Systems, Inc., Palo Alto, CA) treatment planning system (TPS) for future managements, that is, for external beam salvage. RESULTS: The dose matrix resulted from the postimplant dosimetry was exported from Variseed in standard DICOM format and imported into Eclipse TPS. The brachytherapy dose matrix was registered with the patient images with full FOV in Eclipse TPS. Targets for dose boost were defined based on the isodose curves generated from brachytherapy. An external photon beam plan was successfully generated to deliver dose for selected underdose regions. CONCLUSION: Accurate external beam radiation treatment planning can be accomplished using our planning protocols when inadequate brachytherapy dose delivery occurs. The proposed technique can be used to safely deliver additional external radiation dose using intensity-modulated radiation therapy technique after suboptimal brachytherapy procedure. PMID- 20843748 TI - An unusual case of radioactive seed migration to the vertebral venous plexus and renal artery with nerve root compromise. AB - PURPOSE: We report a case of prostate brachytherapy seed migration to the vertebral venous plexus and subsequently to the renal artery with corresponding dosimetry analysis describing nerve doses. METHODS AND MATERIALS: A 52-year-old male with low-risk prostate carcinoma (clinical stage T1c; Gleason score=6; prostate-specific antigen level of 5.5) underwent transperineal permanent prostate seed implant. Postimplantation routine imaging had failed to locate the missing seed, but he subsequently presented with back pain and parathesia with radiation down the leg. RESULTS: CT with bony windows and MRI had located the seed in the left L5 vertebral venous plexus. Neurosurgical intervention failed to locate and remove the migrated seed. Postsurgery, the left lower limb parathesia persisted but had normal nerve conduction studies. Dose to the spinal nerve roots and nearby structures were estimated using a GEANT4 Monte Carlo simulation. Serial X-ray imaging and CT had found that the seed had further migrated to left renal hilum. CONCLUSIONS: Seed migration to vertebral venous plexus is uncommon and to our knowledge this is the third reported case. Its subsequent migration to the renal hilum is most unusual. CT with bony windows or MRI are required if this is suspected. There is risk of spinal or nerve root damage and dose to these structures has to be estimated using GEANT4, although the tissue tolerance in the setting of low-dose rates are unknown and long-term followup of this patient is required. PMID- 20843749 TI - Quantification of cyanuric acid residue in human urine using high performance liquid chromatography-tandem mass spectrometry. AB - Concern has increased about the resulting health effects of exposure to melamine and its metabolic contaminant, cyanuric acid, after infants in China were fed baby formula milk products contaminated with these compounds. We have developed a selective and sensitive analytical method to quantify the amount of cyanuric acid in human urine. The sample preparation involved extracting free-form cyanuric acid in human urine using anion exchange solid phase extraction. Cyanuric acid was separated from its urinary matrix components on the polymeric strong anion exchange analytical column; the analysis was performed by high performance liquid chromatography-tandem mass spectrometry using negative mode electrospray ionization interface. Quantification was performed using isotope dilution calibration covering the concentration range of 1.00-200ng/mL. The limit of detection was 0.60ng/mL and the relative standard deviations were 2.8-10.5% across the calibration range. The relative recovery of cyanuric acid was 100 104%. Our method is suitable to detect urinary concentrations of cyanuric acid caused by either environmental exposures or emerging poisoning events. PMID- 20843750 TI - Determination of 3,4-methylenedioxymethamphetamine and its five main metabolites in rat urine by solid-phase extraction and high performance liquid chromatography with on line mass spectrometry. AB - The consumption of psychostimulant amphetamine-like drugs has increased significantly in recent years. Some MDMA metabolites are probably involved in the neurotoxicity and neurodegeneration caused by prolonged use rather than MDMA itself. We recently developed a method to analyze MDMA and its five main metabolites in rat plasma [7]. We have now fully validated this method to the quantification of these drugs in rat urine. We extracted MDMA and its metabolites with Oasis WCX cartridges, separated them on a Nucleodur C18 analytical column and quantified them by ion-trap mass spectrometry. Linearity was excellent: 12.5 1250ng/mL urine for HMA, HMMA, MDA and MDMA, 25-2500ng/mL for HHMA, and 150 7500ng/mL for HHA (r(2)>0.993 for all analytes). The lower limits of quantification were 12.5ng/mL urine for MDMA, MDA, HMA and HMMA, 25ng/mL for HHMA and 150ng/mL for HHA. Reproducibility was good (intra-assay precision=1.7-6.1%; inter-assay precision=0.6-5.7%), as was accuracy (intra-assay deviation=0.1-4.8%; inter-assay deviation=0.7-7.9%). Average recoveries were around 85.0%, except for HHMA (66.2%) and HHA (53.0%) (CV<8.3%). We also checked the stability of stock solutions and the internal standards after freeze-thawing and in the autosampler. Lastly, we measured the MDMA, MDA, HHMA, HHA, HMMA and HMA in urine samples taken over 24h from rats given subcutaneous MDMA. PMID- 20843751 TI - [Comparative study of historical series of differentiated thyroid carcinoma in two tertiary hospitals in Spain versus North American series]. AB - BACKGROUND AND OBJECTIVE: There is little national literature on descriptive series of patients with differentiated thyroid carcinoma (DTC) and long-term monitoring in Spain. The aim of our study was to describe the DTC series in two tertiary hospitals [Hospital Clinic de Barcelona (HC) and Hospital Germans Trias i Pujol (HGTiP)] and compare these series with those described in the National Cancer Data Base (NCDB) and the Mayo Clinic, the leading international series by number of patients and length of follow-up. MATERIAL AND METHODS: We performed a retrospective review of the medical records of patients diagnosed with DTC in two tertiary hospitals in the Barcelona area. The results were compared with those published by the NCDB and the Mayo Clinic. RESULTS: We reviewed 480 medical records of patients with DTC diagnosed between 1973 and 2006, with a mean follow up of 16+/-8 years. No significant differences were observed in clinical characteristics, risk factors or the most frequent form of presentation between the joint HC/HGTiP group and the NCDB series. The most commonly used diagnostic methods were ultrasound and cytology in all series and the main type of surgery was total or nearly total thyroidectomy, with no differences between groups. Postoperative I-131 was administered more often in the HC/HGTiP series (83.9%) than in the NCDB series (55.1%) and in the Mayo Clinic (46%). In the HC/HGTiP group tumor recurrence was 9.3% and mortality 1.8%. CONCLUSIONS: The HC and HGTiP series were comparable and the various diagnostic and therapeutic techniques used were similar. This study highlights historical trends in the use of imaging techniques, as well as differences with large American series in some procedures (such as laryngoscopy) and the use of radioiodine therapy. PMID- 20843752 TI - [Diffuse sclerosing variant of papillary thyroid carcinoma]. PMID- 20843753 TI - Ileal biopsy: Clinical indications, endoscopic and histopathologic findings in 10,000 patients. AB - BACKGROUND: Ileal biopsies are often reported as having a low yield. Data from endoscopy practices in the private setting are lacking. AIMS: To correlate the frequency of histologic abnormalities in ileal biopsies with clinical indications and ileoscopic appearances. METHODS: Retrospective analysis of clinical, endoscopic, and histopathologic data from a large database. RESULTS: We studied 9785 unique adult patients (median age 46 years, 61.4% women) with ileal biopsies. The most common symptoms were diarrhoea (52.2%) and abdominal pain (37.1%). Ileoscopy was reported as being normal in 75.1% patients. Subjects screened for cancer had the highest prevalence of abnormal endoscopic findings (63.3%); patients with known or suspected Crohn's had the highest prevalence abnormal ileal histology (36.4%). Overall, 5.0% of ileal biopsies obtained from patients with normal endoscopy and 47.4% of biopsies from patients with an endoscopically abnormal ileum had significant histopathologic findings. CONCLUSIONS: In adults, biopsies from the endoscopically normal ileum rarely provide clinically relevant information and cannot be recommended. In contrast, half of the adult patients with an endoscopically abnormal ileum have significant histopathologic findings in ileal biopsies. Therefore, ileoscopy associated with a sensible use of the ileal biopsy is a valuable complement to the colonoscopy. PMID- 20843754 TI - Three consecutive pregnancies in a woman with Crigler-Najjar syndrome type II with good maternal and neonatal outcomes. PMID- 20843755 TI - Prevalence of eosinophilic esophagitis in patients with refractory gastroesophageal reflux disease symptoms: A prospective study. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is not routinely considered in the differential diagnosis of refractory gastroesophageal reflux disease (GERD). AIMS: To prospectively evaluate the prevalence of EoE and describe the clinical features and predictors of EoE in patients with refractory symptoms of GERD. METHODS: Esophageal biopsies were obtained in patients with symptoms of GERD refractory to 8 weeks of conventional antisecretory therapy. Diagnosis of EoE was defined as at least 20 eosinophils * high power field and clinical unresponsiveness to proton pump inhibitors. Clinical and manometric features were compared. Independent risk factors predicting EoE were identified. RESULTS: Six out of 150 included patients (4%) met the diagnostic criteria for EoE. Patients with EoE were significantly younger, had significantly more dysphagia, atopy, ineffective esophageal peristalsis, esophageal rings and esophageal strictures than patients without EoE. Independent predictors of EoE were: age under 45 years (OR 4.8, 95% CI 2.4-8.6), dysphagia (OR 12.2, 95% CI 4.3-19.4), and atopy (OR 3.4, 95% CI 1.5-7.4). CONCLUSIONS: EoE is an uncommon condition (4%) in patients with refractory symptoms of GERD. Age under 45 years, atopy or dysphagia may warrant suspicion of EoE in this subset of patients. PMID- 20843756 TI - The Italian Society of Gastroenterology (SIGE) and the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) Clinical Practice Guidelines: The use of tumor necrosis factor-alpha antagonist therapy in inflammatory bowel disease. AB - Biological therapies are an important step in the management of Inflammatory Bowel Diseases. In consideration of high cost and safety issues there is the need to have clear recommendations for their use. Despite the American Gastroenterological Association and the European Crohn's and Colitis Organisation have published exhaustive Inflammatory Bowel Disease guidelines, national guidelines may be necessary as cultural values, economical and legal issues may differ between countries. For these reasons the Italian Society of Gastroenterology and the Italian Group for the study of Inflammatory Bowel Disease have decided to elaborate the Italian guidelines on the use of biologics in Inflammatory Bowel Disease. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-tumor necrosis factor alpha therapy use in active steroid dependent and refractory luminal Crohn's Disease, in fistulising Crohn's Disease, in steroid dependent and resistant active Ulcerative Colitis; risk of cancer; risk of infections during anti-tumor necrosis factor alpha therapy; special situations. These guidelines are based on evidence from relevant medical literature and clinical experience of a national working group. PMID- 20843757 TI - Assessing body image issues and body satisfaction/dissatisfaction among Hmong American children 9-18 years of age using mixed methodology. AB - This study investigated body image issues and the usefulness of self-reported measurements among Hmong American children, 9-18 years using mixed methodology. Twelve focus groups were conducted (n=68) and a silhouette drawing instrument and six questions pertaining to body image were administered (n=335). About 50% of the children were either overweight or obese and 23% were short statured relative to US norms. About 70% of the girls and 53% of the boys selected smaller body ideals than their perceived body sizes. Further, 21% of the girls and 31% of the boys were satisfied with their bodies. Children underestimated their weights and overestimated their heights. During focus groups children reported that parents, peers, and media influenced their body image perceptions. Our results indicate that the majority of Hmong children are dissatisfied with their bodies and tend to endorse American ideals of beauty and attractiveness rather than the heavier, traditional Hmong body ideals supported by their parents. PMID- 20843758 TI - Foetal monitoring: a woman-centred decision-making pathway. AB - PROBLEM: Many midwives continue to use continuous foetal monitoring on low risk women in labour, despite evidence based clinical guidelines to the contrary. Continuous foetal monitoring has been linked to increased rates of medical intervention during labour and birth with no improvement in long term neonatal outcomes. PARTICIPANTS: Midwives who used continuous foetal monitoring on low risk women in labour at two regional Queensland hospitals. METHODS: This Grounded Theory study explored midwives' decision-making processes related to the use of continuous electronic foetal monitoring on low risk labouring women. Primary data were gathered in semi-structured interviews with five purposively selected midwives and concurrently analysed using Grounded Theory techniques of theoretical sampling and constant comparison. FINDINGS: The midwives made the decision that led to continuous electronic foetal monitoring on low risk women at two key decision points during labour care; the first during the midwives' initial assessment of the woman and foetus, and the second when the midwives categorised the women as high or low risk. However, various factors impacted on these decisions including trust and staff workloads within a context of risk management and medical dominance. There was limited opportunity for women to be involved in the decision-making process about foetal monitoring and only partial information was provided prior to cardiotocography. CONCLUSIONS: Consistent with current clinical guidelines which recommend open, consultative discussion with the woman about foetal monitoring and a partnership approach towards decision making following informed choice, a woman-centred foetal monitoring decision making pathway is proposed. This pathway is applicable in midwifery education, research and clinical practice to promote both evidence based practice and woman centred decision-making. PMID- 20843759 TI - Working for socially disadvantaged women. PMID- 20843760 TI - Y-chromosomal STRs in two populations from Israel and the Palestinian Authority Area: Christian and Muslim Arabs. PMID- 20843761 TI - Ureteropelvic junction obstruction and calyceal diverticulum in a child with Turner syndrome and horseshoe kidney. AB - Laparoscopic dismembered pyeloplasty for ureteropelvic junction (UPJ) obstruction is considered to be a routine procedure in many pediatric surgical centers. UPJ obstruction is known to be associated with horseshoe kidney and several reports on successful laparoscopic repair in such cases exist. The case of a 9-month-old girl with Turner syndrome is reported. A horseshoe kidney with grade 4 hydronephrosis on the left side was diagnosed by ultrasound during the neonatal period. MAG3 diuretic renography and dynamic magnetic resonance imaging nephrography revealed a differential renal function of 31% and 69% on the left and right side, respectively. No drainage from the left renal pelvis could be demonstrated. Laparoscopy showed a combined UPJ obstruction and a calyceal diverticulum with a narrow infundibulum of the upper pole calices on the left side of the horseshoe kidney. Laparoscopic dismembered pyeloplasty and an additional infundibulopelvic anastomosis was performed. No intraoperative complications occurred. The immediate postoperative course was uneventful. Unobstructed drainage and stable differential renal function on the left side could be demonstrated on MAG3 diuretic renography 6 weeks postoperatively. In conclusion, laparoscopic repair of complex malformations of the upper urinary tract is feasible and leads to good functional outcome in selected cases. PMID- 20843763 TI - Implications of oxidative stress mechanisms in toxicity of nanoparticles (review). AB - Nanosized particles (NPs) have recently been proposed for extensive use, including into the biomedical field. As a result, research on toxicity and oxidative stress concerning the interaction of nanoparticle and the living organism has attracted increasing interest among specialists. Two different targets have been the motor of this type of research: 1) the safety concern regarding such NPs large-scale use along with the need to generate antidote solutions to possible adverse effects, 2) the idea of influencing oxidative damage and of using them for elaborating anticancer/antimicrobial therapies. Present study reviews recent research achievements within the proposed theme taking into account the nature and particularities of each type of nanoparticle. PMID- 20843764 TI - Vitamin K and vascular calcifications. AB - The role of vitamin K in the synthesis of some coagulation factors is well known. The implication of vitamin K in vascular health was demonstrated in many surveys and studies conducted over the past years on the vitamin K-dependent proteins non involved in coagulation processes. The vitamin K-dependent matrix Gla protein is a potent inhibitor of the arterial calcification, and may become a non-invasive biochemical marker for vascular calcification. Vitamin K(2) is considered to be more important for vascular system, if compared to vitamin K(1). This paper is reviewing the data from recent literature on the involvement of vitamin K and vitamin K-dependent proteins in cardiovascular health. PMID- 20843765 TI - Development of a virtual reality guided diagnostic tool based on magnetic resonance imaging. AB - Computed tomography (CT) and virtual reality (VR) made it possible to create internal views of the human body without actual penetration. During the last two decades, several endoscopic diagnosis procedures have received virtual counter candidates. This paper presents an own concept of a virtual reality guided diagnostic tool, based on magnetic resonance images representing parallel cross sections of the investigated organ. A series of image processing methods are proposed for image quality enhancement, accurate segmentation in two dimensions, and three-dimensional reconstruction of detected surfaces. These techniques provide improved accuracy in image segmentation, and thus they represent excellent support for three dimensional imaging. The implemented software system allows interactive navigation within the investigated volume, and provides several facilities to quantify important physical properties including distances, areas, and volumes. PMID- 20843766 TI - Effect of the two new calcium channel blockers mebudipine and dibudipine in comparison to amlodipine on vascular flow of isolated kidney of diabetic rat. AB - Calcium channel blockers are clinically useful vasodilators, used widely in the treatment of hypertension. These agents are reported to preserve or improve renal function in patients with essential hypertensive renal disease or diabetic renal disease. Among the classes of calcium channel blockers, dihydropyridine derivatives are widely used because of their potent vasodilating activity and weak cardiodepressant action. Mebudipine and dibudipine are two new 1,4 dihydropyridine calcium channel blockers that recently have been synthesized. In previous research mebudipine and dibudipine showed considerable relaxant effects on vascular and ileal smooth muscle cells. In this study we investigated the effects of these new drugs on vascular flow of isolated kidney of diabetic rat and compare their potencies to amlodipine. It is concluded that mebudipine and dibudipine (1-10 MUM) are at least as potent as amlodipine in inhibiting PE induced perfusion pressure in isolated kidney of diabetic rats. These new dihydropyridines improve kidney perfusion of diabetic rat in the setting of PE infusion. Similarly, amlodipine. PMID- 20843767 TI - Osteocalcin and specific markers of bone resorption in sickle cell disease. AB - Sickle cell disease commonly causes avascular necrosis of bone. Plain radiographs are not useful if obtained early in the disease. Radionuclide scans do not appear to increase the sensitivity of the diagnosis. Magnetic resonance imaging can detect disease but this is expensive and hard to employ on a routine or regular basis. The determination of the following new biochemical markers of bone metabolism has not been previously performed in sickle cell disease: serum osteocalcin (S-BGP), urinary cross-linked aminoterminal telopeptide of type I collagen (INTP or NTx) and urinary deoxypyridinoline (U~DPD). As a first step or preliminary study we evaluate the usefulness of these biochemical markers of bone metabolism, by measuring the plasma or serum and urine levels of these markers in 20 adult patients with sickle cell disease. There was no change in S-BGP (p<0.9) a biochemical marker of bone formation. The two markers of bone resorption, urinary NTx (p<0.002) and U-DPD (p<0.001) increased highly significantly. Although the mean values of urinary NTx and U-DPD were significantly elevated in five patients with clinical evidence of bone complications, only two of these subjects had values above mean +2 SD of normal (control) mean values. Hence the sensitivity and specificity of these measures need to be further investigated with a larger sample size. There was significant correlation (P < 0.001) between NTx and U-DPD. These preliminary findings indicate that urinary NTx and U-DPD should be further investigated as possible biochemical markers of skeletal changes in SCD. PMID- 20843768 TI - Effects of chronic stress on cognitive functions and anxiety related behaviors in rats. AB - The effects of 100 dB prenatal and chronic postnatal white noise stress (WNS) on some cognitive functions and behaviors in rats were investigated. For this purpose, 60 female Sprague-Dawley rats and their 90 male offspring were used. Pregnant rats were divided into Prenatal Stress (PS) and Prenatal Control (PC) groups. WNS was applied to PS group between the 14th and 21st days of their pregnancy, while PC rats were left undisturbed. After weaning, 40 male pups of PS dams were assigned to prenatal + chronic postnatal stress (PSCS) and prenatal stress + non-stress (PSN) groups. Pups of PC dams were divided into Control (CON) and Corticosterone (CORT) groups. During the postnatal 30th and 51st days, WNS was applied to PSCS and CORT rats everyday for 45 minutes, while PSN and CON groups were left undisturbed. The effects of stress on adult male offspring were investigated using Morris water maze and defensive withdrawal tests. Blood samples were collected after each test for serum corticosterone measurements. Blood samples of CORT rats were collected before the stress application and at the 1st, 7th, 14th, and 21st days of the stress period, immediately after cessation of the stress application. There were no significant differences among groups for learning and behavior tests. Corticosterone levels of CORT rats were significantly higher after the stress period than before stress application. These results indicate that although chronic 100 dB WNS induces a stress response by increasing corticosterone levels, it does not affect cognitive functions and anxiety related behaviors of adult male offspring. PMID- 20843769 TI - The assessment of rat ureteral pressure generation in vitro: regional heterogeneity and influence of distending pressure. AB - Contraction of ureteral smooth muscle drives the urine bolus to the urinary bladder for storage prior to micturition. This study describes a novel approach to the measurement of ureteral pressure generation in vitro and the influence of distending pressure on acetylcholine-stimulated ureteral lumenal pressure generation. Isolated segments of ureters obtained from Wistar rats were pressurised in a blind-ended sac arrangement and contractile responses were recorded as phasic oscillations in ureteral luminal pressure. Distal segments generated greater luminal pressures than proximal segments (p<0.001) in response to acetylcholine. Increasing baseline distending pressures in the range 2-10 mmHg in proximal segments was associated with greater frequency of contraction (p<0.001) and decreased magnitude of contraction (p<0.001) when expressed as % maximum response. Nifedipine (10(-5) M) or removal of extracellular Ca(2+) abolished the contractions. Isometric contractile responses of ureteral ring preparations were not significantly influenced by pretensions equivalent to distending pressures in the range 2-10 mmHg. This is the first study to fully establish the influence of baseline ureteral distending pressure upon ureteral luminal pressure generation in vitro and demonstrates regional heterogeneity of ureteral contractile responses. It is suggested that this experimental approach may be a useful methodology for the investigation of ureteral function during urinary outflow obstruction. PMID- 20843770 TI - Exercise and suspension hypokinesia-induced alterations in mechanical properties of rat fast and slow-twitch skeletal muscles. AB - Physical activity has a modulatory role on regulatory steps of excitation contraction coupling (ECC) determining skeletal muscle contractility. We evaluated and compared the contractile responsiveness and caffeine-induced contractures of fast (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) muscles in suspension hypokinesia (SH) and exercised rats. After SH or low intensity exercise, EDL and SOL were isolated, twitch and tetanic contractions and caffeine (10 mM) contractures were recorded. Twitch and tetanic contractions of EDL increased by 60% in exercised rats (p <0.05) while no alteration was observed after SH. Exercise did not alter twitch and tetanic contractions of SOL, while SH depressed contractions (p <0.05). Caffeine contractures were diminished in exercised rat EDL (P <0.05). In SH-rat EDL, contractures increased in amplitude (p <0.01) with a rapid time course (p <0.05). Contractures did not change in SOL after exercise or SH. We concluded that SH and exercise exerted diverse modulatory effects on skeletal muscle contractility. Contractile improvement due to exercise was prominent in EDL. Our results suggest that the muscle-type specific adaptations are related to a change in ECC due to the differences in the regulatory steps, particularly in the intracellular Ca(2+) handling mechanisms. PMID- 20843771 TI - Interocular amplitude differences of multifocal electroretinograms obtained under monocular and binocular stimulation conditions. AB - PURPOSE: To compare the interocular amplitude differences of the multifocal electroretinograms (mfERGs) evoked by either monocular or binocular stimulation in healthy subjects with good vision. METHODS: Thirty-five subjects were included in the study. A Roland Consult RETIscan system was used. DTL electrodes were employed. First, the right and left eyes were stimulated separately, then, binocular stimulation was applied. The amplitudes of the scalar products were averaged over five concentric retinal regions (rings). RESULTS: The interocular amplitude differences were 21.55% (SD: +/-12.72) under monocular conditions and 18.69% (SD: +/-11.64) under binocular conditions. No significant differences were found between the amplitudes and variability values obtained under either monocular or binocular stimulation. CONCLUSIONS: Our results provided no evidence for the advantage of either binocular or monocular stimulating conditions in obtaining mfERGs. A considerable side difference was found between the mfERGs of the two eyes in almost all individual cases. PMID- 20843773 TI - Amyl nitrite induced cerebral and coronary vasospasm. PMID- 20843774 TI - How should we best manage patients with immune-mediated inflammatory disease on immunosuppressant therapy during the 'swine flu' pandemic? PMID- 20843775 TI - Brain tumor stem cells maintain overall phenotype and tumorigenicity after in vitro culturing in serum-free conditions. AB - Traditional in vitro culturing of tumor cells has been shown to induce changes so that cultures no longer represent the tumor of origin. Serum-free culturing conditions are used in a variety of cancers to propagate stem-like cells in vitro. Limited reports, however, exist on the effects of such propagation. We have compared cells from brain tumor biopsies cultivated under serum-free conditions at passages 2 and 10 to describe the effects of in vitro culturing. We were able to establish cell lines from 7 of 10 biopsies from patients with glioblastoma. The cell lines adapted to conditions and had 2.2 times increased population doubling rate at later passages. Karyotyping and comparative genomic hybridization analysis revealed that all examined cell lines had cytogenetic aberrations commonly found in glioblastomas, and there were only minor differences between tumor and early and late passages in the same culture. Whole transcriptome analysis shows that tumors had interindividual differences. Changes in the overall expression patterns through passaging were modest, with a significant change in only 14 genes; the variation among cultures was, however, reduced through passages. The ability to differentiate differed among tumors but was maintained throughout passaging. The cells initiated tumors upon transplantation to immunodeficient mice with differing phenotypes, but a given cell culture maintained tumor phenotype after serial cultivation. The cultures established maintained individual characteristics specific to culture identity. Thus, each cell culture reflects an image of the tumor--or a personalized model- from which it was derived and remains representative after moderate expansion. PMID- 20843776 TI - Zona pellucida-induced acrosome reaction in human spermatozoa is potentiated by glycodelin-A via down-regulation of extracellular signal-regulated kinases and up regulation of zona pellucida-induced calcium influx. AB - BACKGROUND: Glycodelin-A interacts with spermatozoa before fertilization, but its role in modulating sperm functions is not known. Zona pellucida-induced acrosome reaction is crucial to fertilization and its dysfunction is a cause of male infertility. We hypothesized that glycodelin-A, a glycoprotein found in the female reproductive tract, potentiates human spermatozoa for zona pellucida induced acrosome reaction. METHODS: Glycodelin isoforms were immunoaffinity purified. The sperm intracellular cAMP concentration, protein kinase-A (PKA) and extracellular signal-regulated kinase (ERK) activities, and intracellular calcium were measured by ELISA, kinase activity assay kits and Fluo-4AM technique, respectively. The phosphorylation of inositol 1,4,5-trisphosphate type-1 receptor (IP3R1) mediated by ERK was determined by western blotting. Zona pellucida induced acrosome reaction was detected by Pisum sativum staining. RESULTS: Pretreatment of spermatozoa with glycodelin-A significantly up-regulated adenylyl cyclase/PKA activity and down-regulated the activity of ERK and its phosphorylation of IP3R1, thereby enhancing zona pellucida-induced calcium influx and zona pellucida-induced acrosome reaction. Glycodelin-F or deglycosylated glycodelin-A did not have these actions. Treatment of spermatozoa with a protein kinase inhibitor abolished the priming activity of glycodelin-A, whilst ERK pathway inhibitors mimic the stimulatory effect of glycodelin-A on zona pellucida induced acrosome reaction. CONCLUSIONS: Glycodelin-A in the female reproductive tract sensitizes spermatozoa for zona pellucida-induced acrosome reaction in a glycosylation-specific manner through activation of the adenylyl cyclase/PKA pathway, suppression of extracellular signal-regulated kinase activation and up regulation of zona pellucida-induced calcium influx. The action of glycodelin-A may be important in vivo to ensure full responsiveness of human spermatozoa to the zona pellucida. PMID- 20843777 TI - Levels of Rabs and WAVE family proteins associated with translocation of GLUT4 to the cell surface in endometria from hyperinsulinemic PCOS women. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine-metabolic disorder highly associated with insulin resistance and compensatory hyperinsulinemia. It is known that the insulin signaling pathway is impaired in endometria from PCOS hyperinsulinemic women, but no information is available about molecules associated with cell surface GLUT4 translocation. We therefore evaluated the protein levels of AS160 target molecules, Rab8A and Rab10, and the WAVE family proteins involved in the cortical-actin remodeling, Neural Wiskott-Aldrich Syndrome Protein (N-WASP) and WASP, in endometria from hyperinsulinemic PCOS women and controls. METHODS: Protein levels were assessed by western blot, immunohistochemistry and immunofluorescence in proliferative (PE = 7) and secretory (SE = 7) phase endometria from control women and in endometria from hyperinsulinemic PCOS women (PCOS h-INS = 7). RESULTS: Similar levels were detected for Rab10 in the three studied groups; however, Rab8A levels decreased in SE (P < 0.05) while higher levels were obtained in PCOSE h-INS compared with PE (P < 0.05). In the normal menstrual cycle, Neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP levels were increased in SE versus PE (P < 0.05), but in PCOSE h-INS, the levels were diminished compared with PE (P < 0.05). CONCLUSIONS: SE is characterized by protein expression changes associated with glucose uptake. In endometria from PCOS women with hyperinsulinemia, reduced levels of WAVE family proteins could compromise the cell surface GLUT4 exposure and the consequent glucose uptake in this tissue. PMID- 20843778 TI - Improving the accuracy of predicting secondary structure for aligned RNA sequences. AB - Considerable attention has been focused on predicting the secondary structure for aligned RNA sequences since it is useful not only for improving the limiting accuracy of conventional secondary structure prediction but also for finding non coding RNAs in genomic sequences. Although there exist many algorithms of predicting secondary structure for aligned RNA sequences, further improvement of the accuracy is still awaited. In this article, toward improving the accuracy, a theoretical classification of state-of-the-art algorithms of predicting secondary structure for aligned RNA sequences is presented. The classification is based on the viewpoint of maximum expected accuracy (MEA), which has been successfully applied in various problems in bioinformatics. The classification reveals several disadvantages of the current algorithms but we propose an improvement of a previously introduced algorithm (CentroidAlifold). Finally, computational experiments strongly support the theoretical classification and indicate that the improved CentroidAlifold substantially outperforms other algorithms. PMID- 20843779 TI - Design, construction and characterization of a set of insulated bacterial promoters. AB - We have generated a series of variable-strength, constitutive, bacterial promoters that act predictably in different sequence contexts, span two orders of magnitude in strength and contain convenient sites for cloning and the introduction of downstream open-reading frames. Importantly, their design insulates these promoters from the stimulatory or repressive effects of many 5'- or 3'-sequence elements. We show that different promoters from our library produce constant relative levels of two different proteins in multiple genetic contexts. This set of promoters should be a useful resource for the synthetic biology community. PMID- 20843781 TI - Zinc finger protein-dependent and -independent contributions to the in vivo off target activity of zinc finger nucleases. AB - Zinc finger nucleases (ZFNs) facilitate tailor-made genomic modifications in vivo through the creation of targeted double-stranded breaks. They have been employed to modify the genomes of plants and animals, and cell-based therapies utilizing ZFNs are undergoing clinical trials. However, many ZFNs display dose-dependent toxicity presumably due to the generation of undesired double-stranded breaks at off-target sites. To evaluate the parameters influencing the functional specificity of ZFNs, we compared the in vivo activity of ZFN variants targeting the zebrafish kdrl locus, which display both high on-target activity and dose dependent toxicity. We evaluated their functional specificity by assessing lesion frequency at 141 potential off-target sites using Illumina sequencing. Only a minority of these off-target sites accumulated lesions, where the thermodynamics of zinc finger-DNA recognition appear to be a defining feature of active sites. Surprisingly, we observed that both the specificity of the incorporated zinc fingers and the choice of the engineered nuclease domain could independently influence the fidelity of these ZFNs. The results of this study have implications for the assessment of likely off-target sites within a genome and point to both zinc finger-dependent and -independent characteristics that can be tailored to create ZFNs with greater precision. PMID- 20843782 TI - Role of transcript and interplay between transcription and replication in triplet repeat instability in mammalian cells. AB - Triplet-repeat expansions cause several inherited human diseases. Expanded triplet-repeats are unstable in somatic cells, and tissue-specific somatic instability contributes to disease pathogenesis. In mammalian cells instability of triplet-repeats is dependent on the location of the origin of replication relative to the repeat tract, supporting the 'fork-shift' model of repeat instability. Disease-causing triplet-repeats are transcribed, but how this influences instability remains unclear. We examined instability of the expanded (GAA*TTC)(n) sequence in mammalian cells by analyzing individual replication events directed by the SV40 origin from five different locations, in the presence and absence of doxycycline-induced transcription. Depending on the location of the SV40 origin, either no instability was observed, instability was caused by replication with no further increase due to transcription, or instability required transcription. Whereas contractions accounted for most of the observed instability, one construct showed expansions upon induction of transcription. These expansions disappeared when transcript stability was reduced via removal or mutation of a spliceable intron. These results reveal a complex interrelationship of transcription and replication in the etiology of repeat instability. While both processes may not be sufficient for the initiation of instability, transcription and/or transcript stability seem to further modulate the fork-shift model of triplet-repeat instability. PMID- 20843783 TI - Genome-wide mapping of RNA Pol-II promoter usage in mouse tissues by ChIP-seq. AB - Alternative promoters that are differentially used in various cellular contexts and tissue types add to the transcriptional complexity in mammalian genome. Identification of alternative promoters and the annotation of their activity in different tissues is one of the major challenges in understanding the transcriptional regulation of the mammalian genes and their isoforms. To determine the use of alternative promoters in different tissues, we performed ChIP-seq experiments using antibody against RNA Pol-II, in five adult mouse tissues (brain, liver, lung, spleen and kidney). Our analysis identified 38 639 Pol-II promoters, including 12 270 novel promoters, for both protein coding and non-coding mouse genes. Of these, 6384 promoters are tissue specific which are CpG poor and we find that only 34% of the novel promoters are located in CpG-rich regions, suggesting that novel promoters are mostly tissue specific. By identifying the Pol-II bound promoter(s) of each annotated gene in a given tissue, we found that 37% of the protein coding genes use alternative promoters in the five mouse tissues. The promoter annotations and ChIP-seq data presented here will aid ongoing efforts of characterizing gene regulatory regions in mammalian genomes. PMID- 20843784 TI - Tissue-specific regulation of mouse microRNA genes in endoderm-derived tissues. AB - MicroRNAs fine-tune the activity of hundreds of protein-coding genes. The identification of tissue-specific microRNAs and their promoters has been constrained by the limited sensitivity of prior microRNA quantification methods. Here, we determine the entire microRNAome of three endoderm-derived tissues, liver, jejunum and pancreas, using ultra-high throughput sequencing. Although many microRNA genes are expressed at comparable levels, 162 microRNAs exhibited striking tissue-specificity. After mapping the putative promoters for these microRNA genes using H3K4me3 histone occupancy, we analyzed the regulatory modules of 63 microRNAs differentially expressed between liver and jejunum or pancreas. We determined that the same transcriptional regulatory mechanisms govern tissue-specific gene expression of both mRNA and microRNA encoding genes in mammals. PMID- 20843785 TI - Analysis of subgroup C of fungal chitinases containing chitin-binding and LysM modules in the mycoparasite Trichoderma atroviride. AB - Fungi have a plethora of chitinases, which can be phylogenetically divided into three subgroups (A, B and C). Subgroup C (sgC) chitinases are especially interesting due to their multiple carbohydrate-binding modules, but they have not been investigated in detail yet. In this study, we analyzed sgC chitinases in the mycoparasites Trichoderma atroviride and Trichoderma virens. The expression of sgC chitinase genes in T. atroviride was induced during mycoparasitism of the fungal prey Botrytis cinerea, but not Rhizoctonia solani and correspondingly only by fungal cell walls of the former. Interestingly, only few sgC chitinase genes were inducible by chitin, suggesting that non-chitinous cell wall components can act as inducers. In contrast, the transcriptional profile of the most abundantly expressed sgC chitinase gene tac6 indicated a role of the protein in hyphal network formation. This shows that sgC chitinases have diverse functions and are not only involved in the mycoparasitic attack. However, sequence analysis and 3D modelling revealed that TAC6 and also its ortholog in T. virens have potentially detrimental deletions in the substrate-binding site and are thus probably not catalytically active enzymes. Genomic analysis showed that the genes neighboring sgC chitinases often encode proteins that are solely composed of multiple LysM modules, which were induced by similar stimuli as their neighboring sgC chitinase genes. This study provides first insights into fungal sgC chitinases and their associated LysM proteins. PMID- 20843780 TI - Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing. AB - A common goal in the discovery of rare functional DNA variants via medical resequencing is to incur a relatively lower proportion of false positive base calls. We developed a novel statistical method for resequencing arrays (SRMA, sequence robust multi-array analysis) to increase the accuracy of detecting rare variants and reduce the costs in subsequent sequence verifications required in medical applications. SRMA includes single and multi-array analysis and accounts for technical variables as well as the possibility of both low- and high frequency genomic variation. The confidence of each base-call was ranked using two quality measures. In comparison to Sanger capillary sequencing, we achieved a false discovery rate of 2% (false positive rate 1.2 * 10-5, false negative rate 5%), which is similar to automated second-generation sequencing technologies. Applied to the analysis of 39 nuclear candidate genes in disorders of mitochondrial DNA (mtDNA) maintenance, we confirmed mutations in the DNA polymerase gamma POLG in positive control cases, and identified novel rare variants in previously undiagnosed cases in the mitochondrial topoisomerase TOP1MT, the mismatch repair enzyme MUTYH, and the apurinic-apyrimidinic endonuclease APEX2. Some patients carried rare heterozygous variants in several functionally interacting genes, which could indicate synergistic genetic effects in these clinically similar disorders. PMID- 20843786 TI - Protein-disulfide isomerase-associated 3 (Pdia3) mediates the membrane response to 1,25-dihydroxyvitamin D3 in osteoblasts. AB - Protein-disulfide isomerase-associated 3 (Pdia3) is a multifunctional protein hypothesized to be a membrane receptor for 1,25(OH)(2)D(3). In intestinal epithelium and chondrocytes, 1,25(OH)(2)D(3) stimulates rapid membrane responses that are different from genomic effects via the vitamin D receptor (VDR). In this study, we show that 1,25(OH)(2)D(3) stimulates phospholipase A(2) (PLA(2)) dependent rapid release of prostaglandin E(2) (PGE(2)), activation of protein kinase C (PKC), and regulation of bone-related gene transcription and mineralization in osteoblast-like MC3T3-E1 cells (WT) via a mechanism involving Pdia3. Pdia3 was present in caveolae based on co-localization with lipid rafts and caveolin-1. In Pdia3-silenced (Sh-Pdia3) cells, 1,25(OH)(2)D(3) failed to stimulate PKC and PGE(2) responses; in Pdia3-overexpressing cells (Ov-Pdia3), responses to 1,25(OH)(2)D(3) were augmented. Downstream mediators of Pdia3, PLA(2)-activating protein (PLAA) and arachidonic acid, stimulated similar PKC activation in wild-type, Sh-Pdia3, and Ov-Pdia3 cells supporting the hypothesis that Pdia3 mediates the membrane action of 1,25(OH)(2)D(3). Treatment of MC3T3-E1 cells with 1,25(OH)(2)D(3) for 9 min stimulated rapid phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and increased expression of alkaline phosphatase, MMP-13, and osteopontin but decreased expression of osteocalcin, osteoprotegerin (mRNA and protein), and smad2. These effects were attenuated in Sh-Pdia3 cells. Sh-Pdia3 cells produced higher numbers of von Kossa positive nodules and alizarin red-positive nodules compared with WT cells with or without 1,25(OH)(2)D(3) treatment whereas Ov-Pdia3 did not show any mineralization. Our data suggest Pdia3 is an important initiator of 1,25(OH)(2)D(3)-stimulated membrane signaling pathways, which have both genomic and non genomic effects during osteoblast maturation. PMID- 20843787 TI - Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to Rho-kinase-associated cytoskeleton activation and breast tumor cell invasion. AB - Dysregulation of microRNAs is observed in many cancers, including breast cancer. In particular, miR-10b appears to play an important role in tumor cell invasion and breast cancer progression. In this study, we investigated hyaluronan (HA) induced CD44 (a primary HA receptor) interaction with c-Src kinase and the transcriptional factor, Twist, in breast tumor cells (MDA-MB-231 cells). Our results indicate that HA binding to CD44 promotes c-Src kinase activation, which, in turn, increases Twist phosphorylation, leading to the nuclear translocation of Twist and transcriptional activation. Further analyses reveal that miR-10b is controlled by an upstream promoter containing the Twist binding site(s), whereas ChIP assays demonstrate that stimulation of miR-10b expression by HA/CD44 activated c-Src is Twist-dependent in breast tumor cells. This process results in the reduction of a tumor suppressor protein (HOXD10), RhoA/RhoC up-regulation, Rho-kinase (ROK) activation, and breast tumor cell invasion. Treatment of MDA-MB 231 cells with PP2 (a c-Src inhibitor) or Twist-specific siRNAs effectively blocks HA-mediated Twist signaling events, abrogates miR-10b production, and increases HOXD10 expression. Subsequently, this c-Src/Twist signaling inhibition causes down-regulation of RhoA/RhoC expression and impairment of ROK-regulated cytoskeleton function (e.g. tumor cell invasion). To further evaluate the role of miR-10b in RhoGTPase signaling, MDA-MB-231 cells were also transfected with a specific anti-miR-10b inhibitor in order to silence miR-10b expression and block its target functions. Our results demonstrate that anti-miR-10b inhibitor not only enhances HOXD10 expression but also abrogates HA/CD44-mediated tumor cell behaviors in breast tumor cells. Taken together, these findings indicate that the HA-induced CD44 interaction with c-Src-activated Twist plays a pivotal role in miR-10b production, leading to the down-regulation of tumor suppressor protein (HOXD10), RhoGTPase-ROK activation, and tumor cell invasion. All of these events are critical prerequisite steps for the acquisition of metastatic properties by human breast cancer cells. PMID- 20843788 TI - Activin A binds to perlecan through its pro-region that has heparin/heparan sulfate binding activity. AB - Activin A, a member of the transforming growth factor-beta family, plays important roles in hormonal homeostasis and embryogenesis. In this study, we produced recombinant human activin A and examined its abilities to bind to extracellular matrix proteins. Recombinant activin A expressed in 293-F cells was purified as complexes of mature dimeric activin A with its pro-region. Among a panel of extracellular matrix proteins tested, recombinant activin A bound to perlecan and agrin, but not to laminins, nidogens, collagens I and IV, fibronectin, and nephronectin. The binding of recombinant activin A to perlecan was inhibited by heparin and high concentrations of NaCl and abolished by heparitinase treatment of perlecan, suggesting that activin A binds to the heparan sulfate chains of perlecan. In support of this possibility, recombinant activin A was capable of directly binding to heparin and heparan sulfate chains. Site-directed mutagenesis of recombinant activin A revealed that clusters of basic amino acid residues, Lys(259)-Lys(263) and Lys(270)-Lys(272), in the pro region were required for binding to perlecan. Interestingly, deletion of the peptide segment Lys(259)-Gly(277) containing both basic amino acid clusters from the pro-region did not impair the activity of activin A to stimulate Smad dependent gene expressions, although it completely ablated the perlecan-binding activity. The binding of activin A to basement membrane heparan sulfate proteoglycans through the basic residues in the pro-region was further confirmed by in situ activin A overlay assays using frozen tissue sections. Taken together, the present results indicate that activin A binds to heparan sulfate proteoglycans through its pro-region and thereby regulates its localization within tissues. PMID- 20843789 TI - Against the rules: human keratin K80: two functional alternative splice variants, K80 and K80.1, with special cellular localization in a wide range of epithelia. AB - Of the 54 human keratins, five members have, at present, only been characterized at the gene level. In this study we have investigated the expression patterns of keratin K80, whose gene is located at the centromeric end of the type II keratin gene domain. K80 possesses a number of highly unusual properties. Structurally, it is distinctly closer to type II hair keratins than to type II epithelial keratins. Nonetheless, it is found in virtually all types of epithelia (stratified keratinizing/non-keratinizing, hard-keratinizing, as well as non stratified tissues, and cell cultures thereof). This conspicuously broad expression range implies an unprecedented in vivo promiscuity of K80, which involves more than 20 different type I partners for intermediate filament (IF) formation. Throughout, K80 expression is related to advanced tissue or cell differentiation. However, instead of being part of the cytoplasmic IF network, K80 containing IFs are located at the cell margins close to the desmosomal plaques, where they are tightly interlaced with the cytoplasmic IF bundles abutting there. In contrast, in cells entering terminal differentiation, K80 adopts the "conventional" cytoplasmic distribution. In evolutionary terms, K80 is one of the oldest keratins, demonstrable down to fish. In addition, KRT80 mRNA is subject to alternative splicing. Besides K80, we describe a smaller but fully functional splice variant K80.1, which arose only during mammalian evolution. Remarkably, unlike the widely expressed K80, the expression of K80.1 is restricted to soft and hard keratinizing epithelial structures of the hair follicle and the filiform tongue papilla. PMID- 20843790 TI - The canonical BMP signaling pathway plays a crucial part in stimulation of dentin sialophosphoprotein expression by BMP-2. AB - Dentin sialophosphoprotein (DSPP), a typical dentin-specific protein, is mainly expressed in the dentin extracellular matrix and plays a role in dentin mineralization. BMP-2 provides a strong signal for differentiation and mineralization of odontoblasts and osteoblasts. Previously, BMP-2 treatment is reported to stimulate Dspp expression in the MD10-F2 pre-odontoblast cells through activation of the heterotrimeric transcription factor Y (NF-Y). The canonical BMP signaling pathway is known to contribute greatly to biomineralization, however, it is not known whether it is involved in Dspp expression. Here, we investigated this question. Activation of the canonical BMP 2 signaling pathway in MDPC-23, preodontoblast cell, by overexpression of constitutively active Smad1/5 or downstream transcription factors Dlx5 and Runx2 stimulated Dspp expression. Conversely, knockdown of each element with siRNA significantly blocked the BMP-2-induced Dspp expression. To test whether these transcription factors downstream of BMP-2 are directly involved in regulating Dspp, we analyzed the mouse Dspp promoter. There are 5 well conserved homeodomain binding elements, H1 to H5, in Dspp proximal promoter regions (-791 to +54). A serial deletion of H1 and H2 greatly changed basal promoter activity and responsiveness to Dlx5 or Msx2. However, further deletions did not change the responsiveness to Dlx5 or Msx2. H1 and H2 sites can be suggested as specific response elements of Dlx5 and Msx2, respectively, based on their promoter activity modulation. Thus, the canonical BMP-2 signaling pathway plays a crucial part in the regulation of Dspp expression through the action of Smads, Dlx5, Runx2, and Msx2. PMID- 20843791 TI - PAMP (pathogen-associated molecular pattern)-induced changes in plasma membrane compartmentalization reveal novel components of plant immunity. AB - Plasma membrane compartmentalization spatiotemporally regulates cell-autonomous immune signaling in animal cells. To elucidate immediate early protein dynamics at the plant plasma membrane in response to the bacterial pathogen-associated molecular pattern (PAMP) flagellin (flg22) we employed quantitative mass spectrometric analysis on detergent-resistant membranes (DRMs) of Arabidopsis thaliana suspension cells. This approach revealed rapid and profound changes in DRM protein composition following PAMP treatment, prominently affecting proton ATPases and receptor-like kinases, including the flagellin receptor FLS2. We employed reverse genetics to address a potential contribution of a subset of these proteins in flg22-triggered cellular responses. Mutants of three candidates (DET3, AHA1, FER) exhibited a conspicuous defect in the PAMP-triggered accumulation of reactive oxygen species. In addition, these mutants showed altered mitogen-activated protein kinase (MAPK) activation, a defect in PAMP triggered stomatal closure as well as altered bacterial infection phenotypes, which revealed three novel players in elicitor-dependent oxidative burst control and innate immunity. Our data provide evidence for dynamic elicitor-induced changes in the membrane compartmentalization of PAMP signaling components. PMID- 20843792 TI - ASK1 negatively regulates the 26 S proteasome. AB - The 26 S proteasome, composed of the 20 S core and 19 S regulatory particle, plays a central role in ubiquitin-dependent proteolysis. Disruption of this process contributes to the pathogenesis of the various diseases; however, the mechanisms underlying the regulation of 26 S proteasome activity remain elusive. Here, cell culture experiments and in vitro assays demonstrated that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase family, negatively regulated 26 S proteasome activity. Immunoprecipitation/Western blot analyses revealed that ASK1 did not interact with 20 S catalytic core but did interact with ATPases making up the 19 S particle, which is responsible for recognizing polyubiquitinated proteins, unfolding them, and translocating them into the 20 S catalytic core in an ATP-dependent process. Importantly, ASK1 phosphorylated Rpt5, an AAA ATPase of the 19 S proteasome, and inhibited its ATPase activity, an effect that may underlie the ability of ASK1 to inhibit 26 S proteasome activity. The current findings point to a novel role for ASK1 in the regulation of 26 S proteasome and offer new strategies for treating human diseases caused by proteasome malfunction. PMID- 20843793 TI - Thiazolidinediones up-regulate insulin-like growth factor-1 receptor via a peroxisome proliferator-activated receptor gamma-independent pathway. AB - There is increasing evidence that thiazolidinediones (TZDs), antidiabetic compounds that are synthetic ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma), have cardiovascular effects through as yet poorly defined mechanisms. We tested the effect of two TZD class drugs, rosiglitazone and pioglitazone, on human aortic smooth muscle cell (SMC) expression of insulin like growth factor-1 receptor (IGF-1R). Both TZDs dose dependently up-regulated IGF-1R protein levels (rosiglitazone, 10 MUmol/liter, 67% increase, n = 4, p < 0.01; pioglitazone, 10 MUmol/liter, 41% increase, n = 4, p < 0.01) and increased IGF-1R signaling activity (36% increase in Akt phosphorylation). However, the endogenous PPARgamma ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2), dose dependently reduced IGF-1R (10 MUmol/liter, 80% decrease, n = 4, p < 0.01), and overexpression of PPARgamma using an adenovirus likewise reduced IGF-1R (50% decrease versus SMC infected with control adenovirus), suggesting a PPARgamma independent action of TZDs. All three PPARgamma ligands (rosiglitazone, pioglitazone, and 15-deoxy-Delta(12,14)-prostaglandin J(2)), however, did not change IGF-1R mRNA levels, indicating that their effects were posttranscriptional. Use of bicistronic constructs revealed that TZD induction of IGF-1R translation occurred via internal ribosomal entry. To examine the potential physiological relevance of TZD up-regulation of IGF-1R, we determined the effect of rosiglitazone on oxidized LDL (oxLDL)-induced apoptosis. 20 MUmol/liter of rosiglitazone reduced oxidized LDL-induced apoptosis by 40% and neutralizing antibody to IGF-1R (alphaIR3) counteracted this rescue, suggesting the rosiglitazone survival effect was, at least in part, mediated by IGF-1R. In conclusion, TZDs markedly up-regulate SMC IGF-1R expression and signaling, likely via a PPARgamma-independent mechanism. This novel action of TZDs may play an important role in their cardiovascular effects. PMID- 20843794 TI - Functional redundancy of steroid C26-monooxygenase activity in Mycobacterium tuberculosis revealed by biochemical and genetic analyses. AB - One challenge to the development of new antitubercular drugs is the existence of multiple virulent strains that differ genetically. We and others have recently demonstrated that CYP125A1 is a steroid C(26)-monooxygenase that plays a key role in cholesterol catabolism in Mycobacterium tuberculosis CDC1551 but, unexpectedly, not in the M. tuberculosis H37Rv strain. This discrepancy suggests that the H37Rv strain possesses compensatory activities. Here, we examined the roles in cholesterol metabolism of two other cytochrome P450 enzymes, CYP124A1 and CYP142A1. In vitro analysis, including comparisons of the binding affinities and catalytic efficiencies, demonstrated that CYP142A1, but not CYP124A1, can support the growth of H37Rv cells on cholesterol in the absence of cyp125A1. All three enzymes can oxidize the sterol side chain to the carboxylic acid state by sequential oxidation to the alcohol, aldehyde, and acid. Interestingly, CYP125A1 generates oxidized sterols of the (25S)-26-hydroxy configuration, whereas the opposite 25R stereochemistry is obtained with CYP124A1 and CYP142A1. Western blot analysis indicated that CYP124A1 was not detectably expressed in either the H37Rv or CDC1551 strains, whereas CYP142A1 was found in H37Rv but not CDC1551. Genetic complementation of CDC1551 Deltacyp125A1 cells with the cyp124A1 or cyp142A1 genes revealed that the latter can fully rescue the growth defect on cholesterol, whereas cells overexpressing CYP124A1 grow poorly and accumulate cholest-4-en-3 one. Our data clearly establish a functional redundancy in the essential C(26) monooxygenase activity of M. tuberculosis and validate CYP125A1 and CYP142A1 as possible drug targets. PMID- 20843795 TI - NMR structure of the first extracellular domain of corticotropin-releasing factor receptor 1 (ECD1-CRF-R1) complexed with a high affinity agonist. AB - The corticotropin-releasing factor (CRF) peptide hormone family members coordinate endocrine, behavioral, autonomic, and metabolic responses to stress and play important roles within the cardiovascular, gastrointestinal, and central nervous systems, among others. The actions of the peptides are mediated by activation of two G-protein-coupled receptors of the B1 family, CRF receptors 1 and 2 (CRF-R1 and CRF-R2alpha,beta). The recently reported three-dimensional structures of the first extracellular domain (ECD1) of both CRF-R1 and CRF-R2beta (Pioszak, A. A., Parker, N. R., Suino-Powell, K., and Xu, H. E. (2008) J. Biol. Chem. 283, 32900-32912; Grace, C. R., Perrin, M. H., Gulyas, J., Digruccio, M. R., Cantle, J. P., Rivier, J. E., Vale, W. W., and Riek, R. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 4858-4863) complexed with peptide antagonists provided a starting point in understanding the binding between CRF ligands and receptors at a molecular level. We now report the three-dimensional NMR structure of the ECD1 of human CRF-R1 complexed with a high affinity agonist, alpha-helical cyclic CRF. In the structure of the complex, the C-terminal residues (23-41) of alpha-helical cyclic CRF bind to the ECD1 of CRF-R1 in a helical conformation mainly along the hydrophobic face of the peptide in a manner similar to that of the antagonists in their corresponding ECD1 complex structures. Unique to this study is the observation that complex formation between an agonist and the ECD1-CRF-R1 promotes the helical conformation of the N terminus of the former, important for receptor activation (Gulyas, J., Rivier, C., Perrin, M., Koerber, S. C., Sutton, S., Corrigan, A., Lahrichi, S. L., Craig, A. G., Vale, W., and Rivier, J. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10575-10579). PMID- 20843796 TI - Internalization of aggrecan G1 domain neoepitope ITEGE in chondrocytes requires CD44. AB - Degradation of the cartilage proteoglycan aggrecan is one of the earliest events that occurs in association with osteoarthritis. Little is known concerning the fate of the residual N-terminal G1 domains of cleaved aggrecan; domains that remain bound to hyaluronan. In this study, 68-72-kDa bands representative of aggrecan G1 domains containing ITEGE(373) neoepitope were detected within a hyaluronidase-sensitive pool at the cell surface of bovine articular chondrocytes and within a hyaluronidase-insensitive, intracellular pool. To determine the mechanisms that contribute to this distribution, CD44 expression was knocked down by siRNA or function by CD44-DN. Both approaches prevented the retention and internalization of G1-ITEGE. Inhibition of CD44 transit into lipid rafts blocked the endocytosis of G1-ITEGE but not the retention at the cell surface. Chondrocytes derived from CD44 null mice also exhibited limited potential for retention and internalization of G1-VTEGE. The consequence of a lack of chondrocyte-mediated endocytosis of these domains in cartilage of the CD44 null mice was the accumulation of the degradation fragments within the tissue. Additionally, chondrocytes or fibroblasts derived from CD44 null mice exhibited little capacity for retention and internalization of exogenous G1-ITEGE derived from bovine cartilage explants. Bovine or wild type mouse fibroblasts were able to bind and internalize bovine-derived G1-ITEGE. Although several pathways are available for the clearance of these domains, CD44-mediated cellular internalization is the most prominent. PMID- 20843797 TI - Structural and functional analysis of transmembrane segment VI of the NHE1 isoform of the Na+/H+ exchanger. AB - The Na(+)/H(+) exchanger isoform 1 is a ubiquitously expressed integral membrane protein. It resides on the plasma membrane of cells and regulates intracellular pH in mammals by extruding an intracellular H(+) in exchange for one extracellular Na(+). We characterized structural and functional aspects of the transmembrane segment (TM) VI (residues 227-249) by using cysteine scanning mutagenesis and high resolution NMR. Each residue of TM VI was mutated to cysteine in the background of the cysteineless NHE1 protein, and the sensitivity to water-soluble sulfhydryl-reactive compounds (2 (trimethylammonium)ethyl)methanethiosulfonate (MTSET) and (2 sulfonatoethyl)methanethiosulfonate (MTSES) was determined for those residues with significant activity remaining. Three residues were essentially inactive when mutated to Cys: Asp(238), Pro(239), and Glu(247). Of the remaining residues, proteins with the mutations N227C, I233C, and L243C were strongly inhibited by MTSET, whereas amino acids Phe(230), Gly(231), Ala(236), Val(237), Ala(244), Val(245), and Glu(248) were partially inhibited by MTSET. MTSES did not affect the activity of the mutant NHE1 proteins. The structure of a peptide representing TM VI was determined using high resolution NMR spectroscopy in dodecylphosphocholine micelles. TM VI contains two helical regions oriented at an approximate right angle to each other (residues 229-236 and 239-250) surrounding a central unwound region. This structure bears a resemblance to TM IV of the Escherichia coli protein NhaA. The results demonstrate that TM VI of NHE1 is a discontinuous pore-lining helix with residues Asn(227), Ile(233), and Leu(243) lining the translocation pore. PMID- 20843798 TI - Nucleolar follistatin promotes cancer cell survival under glucose-deprived conditions through inhibiting cellular rRNA synthesis. AB - Solid tumor development is frequently accompanied by energy-deficient conditions such as glucose deprivation and hypoxia. Follistatin (FST), a secretory protein originally identified from ovarian follicular fluid, has been suggested to be involved in tumor development. However, whether it plays a role in cancer cell survival under energy-deprived conditions remains elusive. In this study, we demonstrated that glucose deprivation markedly enhanced the expression and nucleolar localization of FST in HeLa cells. The nucleolar localization of FST relied on its nuclear localization signal (NLS) comprising the residues 64-87. Localization of FST to the nucleolus attenuated rRNA synthesis, a key process for cellular energy homeostasis and cell survival. Overexpression of FST delayed glucose deprivation-induced apoptosis, whereas down-regulation of FST exerted the opposite effect. These functions depended on the presence of an intact NLS because the NLS-deleted mutant of FST lost the rRNA inhibition effect and the cell protective effect. Altogether, we identified a novel nucleolar function of FST, which is of importance in the modulation of cancer cell survival in response to glucose deprivation. PMID- 20843799 TI - Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating. AB - The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP(3)R) exhibit distinct IP(3) sensitivities and cooperativities in calcium (Ca(2+)) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP(3)R. We determined the 1.9 A crystal structure of the suppressor domain from type 3 IP(3)R (IP(3)R3(SUP), amino acids 1-224) and revealed structural features contributing to isoform-specific functionality of IP(3)R by comparing it with our previously determined structure of the type 1 suppressor domain (IP(3)R1(SUP)). The molecular surface known to associate with the ligand binding domain (amino acids 224-604) showed marked differences between IP(3)R3(SUP) and IP(3)R1(SUP). Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP(3)R1 and Glu-19, Trp-168, and Ser-218 in IP(3)R3) within the N-terminal suppressor domains of IP(3)R1(SUP) and IP(3)R3(SUP) interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081-36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP(3)R1 and Trp-168 in IP(3)R3) plays a critical role in the coupling between ligand binding and channel gating. PMID- 20843800 TI - Structural and kinetic characterization of 4-hydroxy-4-methyl-2-oxoglutarate/4 carboxy-4-hydroxy-2-oxoadipate aldolase, a protocatechuate degradation enzyme evolutionarily convergent with the HpaI and DmpG pyruvate aldolases. AB - 4-Hydroxy-4-methyl-2-oxoglutarate/4-carboxy-4-hydroxy-2-oxoadipate (HMG/CHA) aldolase from Pseudomonas putida F1 catalyzes the last step of the bacterial protocatechuate 4,5-cleavage pathway. The preferred substrates of the enzyme are 2-keto-4-hydroxy acids with a 4-carboxylate substitution. The enzyme also exhibits oxaloacetate decarboxylation and pyruvate alpha-proton exchange activity. Sodium oxalate is a competitive inhibitor of the aldolase reaction. The pH dependence of k(cat)/K(m) and k(cat) for the enzyme is consistent with a single deprotonation with pK(a) values of 8.0 +/- 0.1 and 7.0 +/- 0.1 for free enzyme and enzyme substrate complex, respectively. The 1.8 A x-ray structure shows a four-layered alpha-beta-beta-alpha sandwich structure with the active site at the interface of two adjacent subunits of a hexamer; this fold resembles the RNase E inhibitor, RraA, but is novel for an aldolase. The catalytic site contains a magnesium ion ligated by Asp-124 as well as three water molecules bound by Asp-102 and Glu-199'. A pyruvate molecule binds the magnesium ion through both carboxylate and keto oxygen atoms, completing the octahedral geometry. The carbonyl oxygen also forms hydrogen bonds with the guanadinium group of Arg-123, which site-directed mutagenesis confirms is essential for catalysis. A mechanism for HMG/CHA aldolase is proposed on the basis of the structure, kinetics, and previously established features of other aldolase mechanisms. PMID- 20843801 TI - Acceptor substrate discrimination in phosphatidyl-myo-inositol mannoside synthesis: structural and mutational analysis of mannosyltransferase Corynebacterium glutamicum PimB'. AB - Long term survival of the pathogen Mycobacterium tuberculosis in humans is linked to the immunomodulatory potential of its complex cell wall glycolipids, which include the phosphatidylinositol mannoside (PIM) series as well as the related lipomannan and lipoarabinomannan glycoconjugates. PIM biosynthesis is initiated by a set of cytosolic alpha-mannosyltransferases, catalyzing glycosyl transfer from the activated saccharide donor GDP-alpha-D-mannopyranose to the acceptor phosphatidyl-myo-inositol (PI) in an ordered and regio-specific fashion. Herein, we report the crystal structure of mannosyltransferase Corynebacterium glutamicum PimB' in complex with nucleotide to a resolution of 2.0 A. PimB' attaches mannosyl selectively to the 6-OH of the inositol moiety of PI. Two crystal forms and GDP- versus GDP-alpha-d-mannopyranose-bound complexes reveal flexibility of the nucleotide conformation as well as of the structural framework of the active site. Structural comparison, docking of the saccharide acceptor, and site directed mutagenesis pin regio-selectivity to a conserved Asp residue in the N terminal domain that forces presentation of the correct inositol hydroxyl to the saccharide donor. PMID- 20843802 TI - Crystal structure of bacteriophage SPP1 distal tail protein (gp19.1): a baseplate hub paradigm in gram-positive infecting phages. AB - Siphophage SPP1 infects the gram-positive bacterium Bacillus subtilis using its long non-contractile tail and tail-tip. Electron microscopy (EM) previously allowed a low resolution assignment of most orf products belonging to these regions. We report here the structure of the SPP1 distal tail protein (Dit, gp19.1). The combination of x-ray crystallography, EM, and light scattering established that Dit is a back-to-back dimer of hexamers. However, Dit fitting in the virion EM maps was only possible with a hexamer located between the tail-tube and the tail-tip. Structure comparison revealed high similarity between Dit and a central component of lactophage baseplates. Sequence similarity search expanded its relatedness to several phage proteins, suggesting that Dit is a docking platform for the tail adsorption apparatus in Siphoviridae infecting gram positive bacteria and that its architecture is a paradigm for these hub proteins. Dit structural similarity extends also to non-contractile and contractile phage tail proteins (gpV(N) and XkdM) as well as to components of the bacterial type 6 secretion system, supporting an evolutionary connection between all these devices. PMID- 20843803 TI - Structure of Escherichia coli AlkA in complex with undamaged DNA. AB - Because DNA damage is so rare, DNA glycosylases interact for the most part with undamaged DNA. Whereas the structural basis for recognition of DNA lesions by glycosylases has been studied extensively, less is known about the nature of the interaction between these proteins and undamaged DNA. Here we report the crystal structures of the DNA glycosylase AlkA in complex with undamaged DNA. The structures revealed a recognition mode in which the DNA is nearly straight, with no amino acid side chains inserted into the duplex, and the target base pair is fully intrahelical. A comparison of the present structures with that of AlkA recognizing an extrahelical lesion revealed conformational changes in both the DNA and protein as the glycosylase transitions from the interrogation of undamaged DNA to catalysis of nucleobase excision. Modeling studies with the cytotoxic lesion 3-methyladenine and accompanying biochemical experiments suggested that AlkA actively interrogates the minor groove of the DNA while probing for the presence of lesions. PMID- 20843804 TI - The streptococcal binding site in the gelatin-binding domain of fibronectin is consistent with a non-linear arrangement of modules. AB - Fibronectin-binding proteins (FnBPs) of Staphylococcus aureus and Streptococcus pyogenes mediate invasion of human endothelial and epithelial cells in a process likely to aid the persistence and/or dissemination of infection. In addition to binding sites for the N-terminal domain (NTD) of fibronectin (Fn), a number of streptococcal FnBPs also contain an upstream region (UR) that is closely associated with an NTD-binding region; UR binds to the adjacent gelatin-binding domain (GBD) of Fn. Previously, UR was shown to be required for efficient streptococcal invasion of epithelial cells. Here we show, using a Streptococcus zooepidemicus FnBP, that the UR-binding site in GBD resides largely in the (8)F1(9)F1 module pair. We also show that UR inhibits binding of a peptide from the alpha1 chain of type I collagen to (8)F1(9)F1 and that UR binding to (8)F1 is likely to occur through anti-parallel beta-zipper formation. Thus, we propose that streptococcal proteins that contain adjacent NTD- and GBD-binding sites form a highly unusual extended tandem beta-zipper that spans the two domains and mediates high affinity binding to Fn through a large intermolecular interface. The proximity of the UR- and NTD-binding sequences in streptococcal FnBPs is consistent with a non-linear arrangement of modules in the tertiary structure of the GBD of Fn. PMID- 20843805 TI - Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2. AB - Nedd4-2 is an archetypal HECT ubiquitin E3 ligase that disposes target proteins for degradation. Because of the proven roles of Nedd4-2 in degradation of membrane proteins, such as epithelial Na(+) channel, we examined the effect of Nedd4-2 on the apical Ca(2+) channel TRPV6, which is involved in transcellular Ca(2+) transport in the intestine using the Xenopus laevis oocyte system. We demonstrated that a significant amount of Nedd4-2 protein was distributed to the absorptive epithelial cells in ileum, cecum, and colon along with TRPV6. When co expressed in oocytes, Nedd4-2 and, to a lesser extent, Nedd4 down-regulated the protein abundance and Ca(2+) influx of TRPV6 and TRPV5, respectively. TRPV6 ubiquitination was increased, and its stability was decreased by Nedd4-2. The Nedd4-2 inhibitory effects on TRPV6 were partially blocked by proteasome inhibitor MG132 but not by the lysosome inhibitor chloroquine. The rate of TRPV6 internalization was not significantly altered by Nedd4-2. The HECT domain was essential to the inhibitory effect of Nedd4-2 on TRPV6 and to their association. The WW1 and WW2 domains interacted with TRPV6 terminal regions, and a disruption of the interactions by D204H and D376H mutations in the WW1 and WW2 domains increased TRPV6 ubiquitination and degradation. Thus, WW1 and WW2 may serve as a molecular switch to limit the ubiquitination of TRPV6 by the HECT domain. In conclusion, Nedd4-2 may regulate TRPV6 protein abundance in intestinal epithelia by controlling TRPV6 ubiquitination. PMID- 20843806 TI - Crystal structures of mutant forms of the yeast F1 ATPase reveal two modes of uncoupling. AB - The mitochondrial ATP synthase couples the flow of protons with the phosphorylation of ADP. A class of mutations, the mitochondrial genome integrity (mgi) mutations, has been shown to uncouple this process in the yeast mitochondrial ATP synthase. Four mutant forms of the yeast F(1) ATPase with mgi mutations were crystallized; the structures were solved and analyzed. The analysis identifies two mechanisms of structural uncoupling: one in which the empty catalytic site is altered and in doing so, apparently disrupts substrate (phosphate) binding, and a second where the steric hindrance predicted between gammaLeu83 and beta(DP) residues, Leu-391 and Glu-395, located in Catch 2 region, is reduced allowing rotation of the gamma-subunit with less impedance. Overall, the structures provide key insights into the critical interactions in the yeast ATP synthase involved in the coupling process. PMID- 20843807 TI - Endogenous retinoids in mammalian growth plate cartilage: analysis and roles in matrix homeostasis and turnover. AB - The growth plate contains resting and proliferating chondrocytes in its upper zones (UGP) and maturing and hypertrophic chondrocytes in its lower zones (LGP), but the mechanisms by which it operates to sustain skeletal growth are not fully clear. Retinoid signaling was previously found to be nearly absent in UGP, but to be much stronger in LGP coincident with hypertrophy, extracellular matrix turnover and endochondral bone formation. To determine whether such distinct signaling levels and phenotypic events reflect different endogenous retinoid levels, the upper two-thirds and lower one-third of rabbit rib growth plates were microsurgically isolated and processed for ultrasensitive retinoid LC-tandem MS quantification. Indeed, the UGP samples contained only about a 0.6 nm concentration of all-trans-retinoic acid (atRA) that is the most active natural retinoid in tissues, whereas LGP samples contained nearly 3-fold higher atRA levels (about 1.8 nM). Perichondrium was quite rich in atRA (about 4.9 nM). Interestingly, the levels of retinol, the major but inactive atRA precursor, were similar in all tissues (1.1-1.6 MUM), suggesting that the distinct atRA levels in UGP and LGP reflect different retinoid anabolic capacity. Indeed, RALDH2 and CRABP1 transcript levels were much higher in LGP than UGP samples. To determine the minimum effective atRA concentration, chondrogenic cells transfected with a retinoic acid response element (RARE)-luc reporter plasmid were treated with different concentrations of exogenous atRA (0-100 nM). About 3 nm atRA was needed to elicit appreciable RARE-luc reporter activity and to decrease proteoglycan synthesis and activity of an aggrecan enhancer reporter plasmid. In sum, the data indicate that (i) the endogenous levels of atRA are significantly higher in hypertrophic than upper zones of growth plate; (ii) such difference likely reflects distinct retinoid anabolic capacity; and (iii) importantly, atRA levels in hypertrophic portion are within effective ranges to elicit retinoid signaling and action, but those in upper zones are not. PMID- 20843808 TI - BRAF drives synovial fibroblast transformation in rheumatoid arthritis. AB - Synovial fibroblasts destroy articular cartilage and bone in rheumatoid arthritis, but the mechanism of fibroblast transformation remains elusive. Because gain-of-function mutations of BRAF can transform fibroblasts, we examined BRAF in rheumatoid synovial fibroblasts. The strong gain-of-function mutation, V600R, of BRAF found in melanomas and other cancers was identified in first passage synovial fibroblasts from two of nine rheumatoid arthritis patients and confirmed by restriction site mapping. BRAF-specific siRNA inhibited proliferation of synovial fibroblasts with V600R mutations. A BRAF aberrant splice variant with an intact kinase domain and partial loss of the N-terminal autoinhibitory domain was identified in fibroblasts from an additional patient, and fibroblast proliferation was inhibited by BRAF-specific siRNA. Our finding is the first to establish mechanisms for fibroblast transformation responsible for destruction of articular cartilage and bone in rheumatoid arthritis and establishes a new target for therapeutic intervention. PMID- 20843809 TI - Histidine residues in the Na+-coupled ascorbic acid transporter-2 (SVCT2) are central regulators of SVCT2 function, modulating pH sensitivity, transporter kinetics, Na+ cooperativity, conformational stability, and subcellular localization. AB - Na(+)-coupled ascorbic acid transporter-2 (SVCT2) activity is impaired at acid pH, but little is known about the molecular determinants that define the transporter pH sensitivity. SVCT2 contains six histidine residues in its primary sequence, three of which are exofacial in the transporter secondary structure model. We used site-directed mutagenesis and treatment with diethylpyrocarbonate to identify histidine residues responsible for SVCT2 pH sensitivity. We conclude that five histidine residues, His(109), His(203), His(206), His(269), and His(413), are central regulators of SVCT2 function, participating to different degrees in modulating pH sensitivity, transporter kinetics, Na(+) cooperativity, conformational stability, and subcellular localization. Our results are compatible with a model in which (i) a single exofacial histidine residue, His(413), localized in the exofacial loop IV that connects transmembrane helices VII-VIII defines the pH sensitivity of SVCT2 through a mechanism involving a marked attenuation of the activation by Na(+) and loss of Na(+) cooperativity, which leads to a decreased V(max) without altering the transport K(m); (ii) exofacial histidine residues His(203), His(206), and His(413) may be involved in maintaining a functional interaction between exofacial loops II and IV and influence the general folding of the transporter; (iii) histidines 203, 206, 269, and 413 affect the transporter kinetics by modulating the apparent transport K(m); and (iv) histidine 109, localized at the center of transmembrane helix I, might be fundamental for the interaction of SVCT2 with the transported substrate ascorbic acid. Thus, histidine residues are central regulators of SVCT2 function. PMID- 20843810 TI - Functional rescue of a misfolded eukaryotic ATP-binding cassette transporter by domain replacement. AB - ATP-binding cassette (ABC) transporters are integral membrane proteins that couple ATP binding/hydrolysis with the transport of hydrophilic substrates across lipid barriers. Deletion of Phe-670 in the first nucleotide-binding domain (NBD1) of the yeast ABC transporter, Yor1p, perturbs interdomain associations, reduces functionality, and hinders proper transport to the plasma membrane. Functionality of Yor1p-DeltaF was restored upon co-expression of a peptide containing wild-type NBD1. To gain insight into the biogenesis of this important class of proteins, we defined the requirements for this rescue. We show that a misfolding lesion in NBD1 of the full-length protein is a prerequisite for functional rescue by exogenous NBD1, which is mediated by physical replacement of the dysfunctional domain by the soluble NBD1. This association does not restore trafficking of Yor1p-DeltaF but instead confers catalytic activity to the small population of Yor1p-DeltaF that escapes to the plasma membrane. An important coupling between the exogenous NBD1 and ICL4 within full-length aberrant Yor1p-DeltaF is required for functional rescue but not for the physical interaction between the two polypeptides. Together, our genetic and biochemical data reveal that it is possible to modulate activity of ABC transporters by physically replacing dysfunctional domains. PMID- 20843811 TI - CCK1 and CCK2 receptors are expressed on pancreatic stellate cells and induce collagen production. AB - The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-beta-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-beta, both CCK and gastrin inhibit proliferation in PSC. PMID- 20843812 TI - Identification of acidic pH-dependent ligands of pentameric C-reactive protein. AB - C-reactive protein (CRP) is a phylogenetically conserved protein; in humans, it is present in the plasma and at sites of inflammation. At physiological pH, native pentameric CRP exhibits calcium-dependent binding specificity for phosphocholine. In this study, we determined the binding specificities of CRP at acidic pH, a characteristic of inflammatory sites. We investigated the binding of fluid-phase CRP to six immobilized proteins: complement factor H, oxidized low density lipoprotein, complement C3b, IgG, amyloid beta, and BSA immobilized on microtiter plates. At pH 7.0, CRP did not bind to any of these proteins, but, at pH ranging from 5.2 to 4.6, CRP bound to all six proteins. Acidic pH did not monomerize CRP but modified the pentameric structure, as determined by gel filtration, 1-anilinonaphthalene-8-sulfonic acid-binding fluorescence, and phosphocholine-binding assays. Some modifications in CRP were reversible at pH 7.0, for example, the phosphocholine-binding activity of CRP, which was reduced at acidic pH, was restored after pH neutralization. For efficient binding of acidic pH-treated CRP to immobilized proteins, it was necessary that the immobilized proteins, except factor H, were also exposed to acidic pH. Because immobilization of proteins on microtiter plates and exposure of immobilized proteins to acidic pH alter the conformation of immobilized proteins, our findings suggest that conformationally altered proteins form a CRP-ligand in acidic environment, regardless of the identity of the protein. This ligand binding specificity of CRP in its acidic pH-induced pentameric state has implications for toxic conditions involving protein misfolding in acidic environments and favors the conservation of CRP throughout evolution. PMID- 20843813 TI - Identification of key functional residues in the active site of human {beta}1,4 galactosyltransferase 7: a major enzyme in the glycosaminoglycan synthesis pathway. AB - Glycosaminoglycans (GAGs) play a central role in many pathophysiological events, and exogenous xyloside substrates of beta1,4-galactosyltransferase 7 (beta4GalT7), a major enzyme of GAG biosynthesis, have interesting biomedical applications. To predict functional peptide regions important for substrate binding and activity of human beta4GalT7, we conducted a phylogenetic analysis of the beta1,4-galactosyltransferase family and generated a molecular model using the x-ray structure of Drosophila beta4GalT7-UDP as template. Two evolutionary conserved motifs, (163)DVD(165) and (221)FWGWGREDDE(230), are central in the organization of the enzyme active site. This model was challenged by systematic engineering of point mutations, combined with in vitro and ex vivo functional assays. Investigation of the kinetic properties of purified recombinant wild-type beta4GalT7 and selected mutants identified Trp(224) as a key residue governing both donor and acceptor substrate binding. Our results also suggested the involvement of the canonical carboxylate residue Asp(228) acting as general base in the reaction catalyzed by human beta4GalT7. Importantly, ex vivo functional tests demonstrated that regulation of GAG synthesis is highly responsive to modification of these key active site amino acids. Interestingly, engineering mutants at position 224 allowed us to modify the affinity and to modulate the specificity of human beta4GalT7 toward UDP-sugars and xyloside acceptors. Furthermore, the W224H mutant was able to sustain decorin GAG chain substitution but not GAG synthesis from exogenously added xyloside. Altogether, this study provides novel insight into human beta4GalT7 active site functional domains, allowing manipulation of this enzyme critical for the regulation of GAG synthesis. A better understanding of the mechanism underlying GAG assembly paves the way toward GAG-based therapeutics. PMID- 20843815 TI - Characterization of alternatively spliced transcript variants of CLEC2D gene. AB - Lectin-like transcript 1 (LLT1) encoded by CLEC2D gene is a C-type lectin-like molecule interacting with human CD161 (NKR-P1A) receptor expressed by natural killer cells and subsets of T cells. Using RT-PCR and sequencing, we identified several CLEC2D alternatively spliced transcript variants generated by exon skipping. In addition to the reported transcript variants 1 (LLT1) and 2, we identified a novel splice variant 4 and transcripts coding for putative soluble proteins. CLEC2D transcripts were detected primarily in hematopoietic cell lines and were found to be co-induced by the same activation signals. Although very low amounts of putative soluble CLEC2D protein isoforms could be produced by transfectants, CLEC2D isoforms 2 and 4 were efficiently expressed. By contrast to LLT1, which was detected on the cell surface, isoform 2 and 4 remained in the endoplasmic reticulum where they formed homodimers or heterodimers with LLT1. They failed to interact with CD161, leaving LLT1 as the sole ligand for this receptor. CLEC2D therefore uses gene splicing to generate protein isoforms that are structurally distinct and that have different biological activities. PMID- 20843814 TI - A naturally occurring variant in human TLR9, P99L, is associated with loss of CpG oligonucleotide responsiveness. AB - The innate immune system employs Toll-like receptors (TLRs) for the detection of invading microorganisms based on distinct molecular patterns. For example, TLR9 is activated by microbial DNA and also by short therapeutic CpG-containing oligonucleotides (CpG-ODN). TLR9 activation leads to the production of interferons and the priming of humoral adaptive immune responses. Unfortunately, the principles of ligand recognition by TLR9 are poorly understood, and genetic variants of TLR9, which may affect its function, have not been characterized systematically on the molecular level. We therefore sought to functionally characterize reported single nucleotide polymorphisms of TLR9 in the HEK293 model system. We discovered that two variants, P99L and M400I, are associated with altered receptor function regarding NF-kappaB activation and cytokine induction. Our investigations show that for the most functionally impaired variant, P99L, the ability to respond to physiological and therapeutic TLR9 ligands is severely compromised. However, CpG-ODN binding is normal. CpG-ODN recognition by TLR9 thus appears to involve two separate events, CpG-ODN binding and sensing. Our studies highlight Pro-99 as a residue important for the latter process. In genotyping studies, we confirmed that both M400I (rs41308230) and P99L (rs5743844) are relatively rare variants of TLR9. Our data add rs41308230 and rs5743844 to the list of functionally important TLR variants and warrant further research into their relevance for infectious disease susceptibility or responsiveness to CpG ODN-based therapies. PMID- 20843816 TI - Duplicated gephyrin genes showing distinct tissue distribution and alternative splicing patterns mediate molybdenum cofactor biosynthesis, glycine receptor clustering, and escape behavior in zebrafish. AB - Gephyrin mediates the postsynaptic clustering of glycine receptors (GlyRs) and GABA(A) receptors at inhibitory synapses and molybdenum-dependent enzyme (molybdoenzyme) activity in non-neuronal tissues. Gephyrin knock-out mice show a phenotype resembling both defective glycinergic transmission and molybdenum cofactor (Moco) deficiency and die within 1 day of birth due to starvation and dyspnea resulting from deficits in motor and respiratory networks, respectively. To address whether gephyrin function is conserved among vertebrates and whether gephyrin deficiency affects molybdoenzyme activity and motor development, we cloned and characterized zebrafish gephyrin genes. We report here that zebrafish have two gephyrin genes, gphna and gphnb. The former is expressed in all tissues and has both C3 and C4 cassette exons, and the latter is expressed predominantly in the brain and spinal cord and harbors only C4 cassette exons. We confirmed that all of the gphna and gphnb splicing isoforms have Moco synthetic activity. Antisense morpholino knockdown of either gphna or gphnb alone did not disturb synaptic clusters of GlyRs in the spinal cord and did not affect touch-evoked escape behaviors. However, on knockdown of both gphna and gphnb, embryos showed impairments in GlyR clustering in the spinal cord and, as a consequence, demonstrated touch-evoked startle response behavior by contracting antagonistic muscles simultaneously, instead of displaying early coiling and late swimming behaviors, which are executed by side-to-side muscle contractions. These data indicate that duplicated gephyrin genes mediate Moco biosynthesis and control postsynaptic clustering of GlyRs, thereby mediating key escape behaviors in zebrafish. PMID- 20843817 TI - Leptin promotes the myofibroblastic phenotype in hepatic stellate cells by activating the hedgehog pathway. AB - Trans-differentiation of quiescent hepatic stellate cells (Q-HSCs), which exhibit epithelial and adipocytic features, into myofibroblastic-HSC (MF-HSCs) is a key event in liver fibrosis. Culture models demonstrated that Hedgehog (Hh) pathway activation is required for transition of epithelioid/adipocytic Q-HSCs into MF HSCs. Hh signaling inhibits adiposity and promotes epithelial-to-mesenchymal transitions (EMTs). Leptin (anti-adipogenic, pro-EMT factor) promotes HSC trans differentiation and liver fibrosis, suggesting that the pathways may interact to modulate cell fate. This study aimed to determine whether leptin activates Hh signaling and whether this is required for the fibrogenic effects of leptin. Cultures of primary HSCs from lean and fa/fa rats with an inherited ObRb defect were examined. Inhibitors of PI3K/Akt, JAK/STAT, and Hh signaling were used to delineate how ObRb activation influenced Hh signaling and HSC trans differentiation. Fibrogenesis was compared in wild type and db/db mice (impaired ObRb function) to assess the profibrotic role of leptin. The results demonstrate that leptin-ObR interactions activate Hh signaling with the latter necessary to promote trans-differentiation. Leptin-related increases in Hh signaling required ObR induction of PI3K/Akt, which was sufficient for leptin to repress the epithelioid/adipocytic program. Leptin-mediated induction of JAK/STAT was required for mesenchymal gene expression. Leptin-ObRb interactions were not necessary for HSC trans-differentiation to occur in vitro or in vivo but are important because liver fibrogenesis was attenuated in db/db mice. These findings reveal that leptin activates Hh signaling to alter gene expression programs that control cell fate and have important implications for liver fibrosis and other leptin-regulated processes involving EMTs, including development, obesity, and cancer metastasis. PMID- 20843820 TI - Relationship between radiation exposure and risk of second primary cancers among atomic bomb survivors. AB - Radiation exposure is related to risk of numerous types of cancer, but relatively little is known about its effect on risk of multiple primary cancers. Using follow-up data through 2002 from 77,752 Japanese atomic bomb survivors, we identified 14,048 participants diagnosed with a first primary cancer, of whom 1,088 were diagnosed with a second primary cancer. Relationships between radiation exposure and risks of first and second primary cancers were quantified using Poisson regression. There was a similar linear dose-response relationship between radiation exposure and risks of both first and second primary solid tumors [excess relative risk (ERR)/Gy = 0.65; 95% confidence interval (CI), 0.57 0.74 and ERR/Gy = 0.56; 95% CI, 0.33-0.80, respectively] and risk of both first and second primary leukemias (ERR/Gy = 2.65; 95% CI, 1.78-3.78 and ERR/Gy = 3.65; 95% CI, 0.96-10.70, respectively). Background incidence rates were higher for second solid cancers, compared with first solid cancers, until about age 70 years for men and 80 years for women (P < 0.0001), but radiation-related ERRs did not differ between first and second primary solid cancers (P = 0.70). Radiation dose was most strongly related to risk of solid tumors that are radiation-sensitive including second primary lung, colon, female breast, thyroid, and bladder cancers. Radiation exposure confers equally high relative risks of second primary cancers as first primary cancers. Radiation is a potent carcinogen and those with substantial exposures who are diagnosed with a first primary cancer should be carefully screened for second primary cancers, particularly for cancers that are radiation-sensitive. PMID- 20843821 TI - In human granulosa cells from small antral follicles, androgen receptor mRNA and androgen levels in follicular fluid correlate with FSH receptor mRNA. AB - Human small antral follicles (diameter 3-9 mm) were obtained from ovaries surgically removed for fertility preservation. From the individual aspirated follicles, granulosa cells and the corresponding follicular fluid were isolated in 64 follicles, of which 55 were available for mRNA analysis (24 women). Expressions of androgen receptor (AR) mRNA levels in granulosa cells, and of androstenedione and testosterone in follicular fluid, were correlated to the expression of the FSH receptor (FSHR), LH receptor (LHR), CYP19 and anti Mullerian Hormone-receptor II (AMHRII) mRNA in the granulosa cells and to the follicular fluid concentrations of AMH, inhibin-B, progesterone and estradiol. AR mRNA expression in granulosa cells and the follicular fluid content of androgens both showed a highly significant positive association with the expression of FSHR mRNA in granulosa cells. AR mRNA expression also correlated significantly with the expression of AMHRII, but did not correlate with any of the hormones in the follicular fluid. These data demonstrate an intimate association between AR expression in immature granulosa cells, and the expression of FSHR in normal small human antral follicles and between the follicular fluid levels of androgen and FSHR expression. This suggests that follicular sensitivity towards FSH stimulation may be augmented by stimulation of androgens via the AR. PMID- 20843819 TI - MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. AB - Radical radiotherapy and surgery achieve similar cure rates in muscle-invasive bladder cancer, but the choice of which treatment would be most beneficial cannot currently be predicted for individual patients. The primary aim of this study was to assess whether expression of any of a panel of DNA damage signaling proteins in tumor samples taken before irradiation could be used as a predictive marker of radiotherapy response, or rather was prognostic. Protein expression of MRE11, RAD50, NBS1, ATM, and H2AX was studied by immunohistochemistry in pretreatment tumor specimens from two cohorts of bladder cancer patients (validation cohort prospectively acquired) treated with radical radiotherapy and one cohort of cystectomy patients. In the radiotherapy test cohort (n = 86), low tumor MRE11 expression was associated with worse cancer-specific survival compared with high expression [43.1% versus 68.7% 3-year cause-specific survival (CSS), P = 0.012] by Kaplan-Meier analysis. This was confirmed in the radiotherapy validation cohort (n = 93; 43.0% versus 71.2%, P = 0.020). However, in the cystectomy cohort (n = 88), MRE11 expression was not associated with cancer-specific survival, commensurate with MRE11 being a predictive marker. High MRE11 expression in the combined radiotherapy cohort had a significantly better cancer-specific survival compared with the high-expression cystectomy cohort (69.9% versus 53.8% 3-year CSS, P = 0.021). In this validated immunohistochemistry study, MRE11 protein expression was shown and confirmed as a predictive factor associated with survival following bladder cancer radiotherapy, justifying its inclusion in subsequent trial designs. MRE11 expression may ultimately allow patient selection for radiotherapy or cystectomy, thus improving overall cure rates. PMID- 20843822 TI - Purification, characterization and amino acid sequence of a novel enzyme, D-threo 3-hydroxyaspartate dehydratase, from Delftia sp. HT23. AB - D-threo-3-hydroxyaspartate dehydratase (D-THA DH) was purified from the cell-free extract of the soil-isolated bacterium Delftia sp. HT23. The enzyme exhibited dehydratase activity towards D-threo-3-hydroxyaspartate, l-threo-3 hydroxyaspartate, l-erythro-3-hydroxyaspartate and d-serine. Absorption of the purified enzyme at 412 nm suggests that it contains pyridoxal 5'-phosphate (PLP) as a cofactor. The NH(2)-terminal and internal amino acid sequences showed significant similarity to hypothetical alanine racemase of genome-sequenced Delftia acidovorans SPH-1; however, the purified enzyme showed no alanine racemase activity. Using the sequence information of D. acidovorans SPH-1, the gene encoding d-THA DH was cloned. The deduced amino acid sequence, which belongs to the alanine racemase family, shows significant (26-36%) similarity to d-serine dehydratase of both Saccharomyces cerevisiae and chicken. In order to obtain purified d-THA DH efficiently, the gene was expressed in Escherichia coli. The recombinant enzyme was highly activated by divalent cations, such as Mn(2+), Co(2+) and Ni(2+). Site-directed mutagenesis experiment revealed that lysine 43 is an important residue involved in PLP binding and catalysis. This is the first reported enzyme that acts on d-THA. In addition, this enzyme is the first example of a prokaryotic dehydratase belonging to the fold-type III PLP-dependent enzyme family. PMID- 20843823 TI - Quantitative image analysis reveals that phosphorylation of liver-type isozyme of fructose-6-phosphate 2-kinase/fructose-2,6-bisphosphatase does not affect nuclear translocation of glucokinase in rat primary hepatocytes. AB - We have developed a new quantification method to measure translocation of glucokinase between nucleus and cytoplasm in primary hepatocytes. The method is robust, reliable and sensitive with the use of a high content fluorescence microscope, which can analyse more than 20,000 hepatocytes under each experimental condition. Frequency distributions of the nuclear and cytoplasmic contents of glucokinase did not exhibit a Gaussian distribution. Moreover, the distributions have large standard deviation values compared with their average values. These results indicate that a large number of cells must be analysed for the accurate quantification. Glucose and sorbitol promoted the translocation of glucokinase from nucleus to cytoplasm. These results show good agreement with previous reports. However, glucagon did not affect the localization of glucokinase. Under the same conditions, liver-type isozyme of fructose-6 phosphate 2-kinase/fructose-2,6-bisphosphatase (F6P2K), whose dephosphorylated form has been proposed as a cytoplasmic binding protein with glucokinase, was completely phosphorylated. These results indicate that the phosphorylation and dephosphorylation of F6P2K does not have any appreciable effect on the intracellular localization of glucokinase. PMID- 20843824 TI - Genetic diversity at endoplasmic reticulum aminopeptidases is maintained by balancing selection and is associated with natural resistance to HIV-1 infection. AB - Human ERAP1 and ERAP2 encode two endoplasmic reticulum aminopeptidases. These enzymes trim peptides to optimal size for loading onto major histocompatibility complex class I molecules and shape the antigenic repertoire presented to CD8(+) T cells. Therefore, ERAP1 and ERAP2 may be considered potential selection targets and modulators of infection susceptibility. We resequenced two genic regions in ERAP1 and ERAP2 in three HapMap populations. In both cases, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and reduced population genetic differentiation. The genealogy of ERAP1 and ERAP2 haplotypes was split into two major branches with deep coalescence times. These features suggest that long-standing balancing selection has acted on these genes. Analysis of the Lys528Arg (rs30187 in ERAP1) and Asn392Lys (rs2549782 in ERAP2) variants in an Italian population of HIV-1-exposed seronegative (ESN) individuals and a larger number of Italian controls indicated that rs2549782 significantly deviates from Hardy-Weinberg equilibrium (HWE) in ESN but not in controls. Technical errors were excluded and a goodness-of-fit test indicated that a recessive model with only genetic effects adequately explains HWE deviation. The genotype distribution of rs2549782 is significantly different in the two cohorts (P = 0.004), mainly as the result of an over-representation of Lys/Lys genotypes in the ESN sample (P-value for a recessive model: 0.00097). Our data suggest that genetic diversity in ERAP1 and ERAP2 has been maintained by balancing selection and that variants in ERAP2 confer resistance to HIV-1 infection possibly via the presentation of a distinctive peptide repertoire to CD8(+) T cells. PMID- 20843825 TI - An imbalance of human complement regulatory proteins CFHR1, CFHR3 and factor H influences risk for age-related macular degeneration (AMD). AB - A frequent deletion of complement factor H (CFH)-related genes CFHR3 and CFHR1 (DeltaCFHR3/CFHR1) is considered to have a protective effect against age-related macular degeneration (AMD), although the underlying mechanism remains elusive. The deletion seems to be linked to one of the two protective CFH haplotypes which are both tagged by the protective allele of single nucleotide polymorphism rs2274700 (CFH:A473A). In a German cohort of 530 AMD patients, we now show that protection against AMD conferred by DeltaCFHR3/CFHR1 is independent of the effects of rs2274700 and rs1061170 (CFH:Y402H). This suggests a functional role of CFHR1 and/or CFHR3 in disease pathogenesis. We therefore characterized the CFHR3 function and identified CFHR3 as a novel human complement regulator that inhibits C3 convertase activity. CFHR3 displays anti-inflammatory effects by blocking C5a generation and C5a-mediated chemoattraction of neutrophils. In addition, CFHR3 and CFHR1 compete with factor H for binding to the central complement component C3. Thus, deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H. Our findings allude to a critical balance between the complement regulators CFHR3, CFHR1 and factor H and further emphasize the central role of complement regulation in AMD pathology. PMID- 20843826 TI - Analysis of next-generation genomic data in cancer: accomplishments and challenges. AB - The application of next-generation sequencing technology has produced a transformation in cancer genomics, generating large data sets that can be analyzed in different ways to answer a multitude of questions about the genomic alterations associated with the disease. Analytical approaches can discover focused mutations such as substitutions and small insertion/deletions, large structural alterations and copy number events. As our capacity to produce such data for multiple cancers of the same type is improving, so are the demands to analyze multiple tumor genomes simultaneously growing. For example, pathway-based analyses that provide the full mutational impact on cellular protein networks and correlation analyses aimed at revealing causal relationships between genomic alterations and clinical presentations are both enabled. As the repertoire of data grows to include mRNA-seq, non-coding RNA-seq and methylation for multiple genomes, our challenge will be to intelligently integrate data types and genomes to produce a coherent picture of the genetic basis of cancer. PMID- 20843828 TI - HSPB7 is the most potent polyQ aggregation suppressor within the HSPB family of molecular chaperones. AB - A small number of heat-shock proteins have previously been shown to act protectively on aggregation of several proteins containing an extended polyglutamine (polyQ) stretch, which are linked to a variety of neurodegenerative diseases. A specific subfamily of heat-shock proteins is formed by the HSPB family of molecular chaperones, which comprises 10 members (HSPB1-10, also called small HSP). Several of them are known to act as anti-aggregation proteins in vitro. Whether they also act protectively in cells against polyQ aggregation has so far only been studied for few of them (e.g. HSPB1, HSPB5 and HSPB8). Here, we compared the 10 members of the human HSPB family for their ability to prevent aggregation of disease-associated proteins with an expanded polyQ stretch. HSPB7 was identified as the most active member within the HSPB family. It not only suppressed polyQ aggregation but also prevented polyQ-induced toxicity in cells and its expression reduces eye degeneration in a Drosophila polyQ model. Upon overexpression in cells, HSPB7 was not found in larger oligomeric species when expressed in cells and-unlike HSPB1-it did not improve the refolding of heat denatured luciferase. The action of HSPB7 was also not dependent on the Hsp70 machine or on proteasomal activity, and HSPB7 overexpression alone did not increase autophagy. However, in ATG5-/- cells that are defective in macroautophagy, the anti-aggregation activity of HSPB7 was substantially reduced. Hence, HSPB7 prevents toxicity of polyQ proteins at an early stage of aggregate formation by a non-canonical mechanism that requires an active autophagy machinery. PMID- 20843827 TI - Functional interactions between the LRP6 WNT co-receptor and folate supplementation. AB - Crooked tail (Cd) mice bear a gain-of-function mutation in Lrp6, a co-receptor for canonical WNT signaling, and are a model of neural tube defects (NTDs), preventable with dietary folic acid (FA) supplementation. Whether the FA response reflects a direct influence of FA on LRP6 function was tested with prenatal supplementation in LRP6-deficient embryos. The enriched FA (10 ppm) diet reduced the occurrence of birth defects among all litters compared with the control (2 ppm FA) diet, but did so by increasing early lethality of Lrp6(-/-) embryos while actually increasing NTDs among nulls alive at embryonic days 10-13 (E10-13). Proliferation in cranial neural folds was reduced in homozygous Lrp6(-/-) mutants versus wild-type embryos at E10, and FA supplementation increased proliferation in wild-type but not mutant neuroepithelia. Canonical WNT activity was reduced in LRP6-deficient midbrain-hindbrain at E9.5, demonstrated in vivo by a TCF/LEF reporter transgene. FA levels in media modulated the canonical WNT response in NIH3T3 cells, suggesting that although FA was required for optimal WNT signaling, even modest FA elevations attenuated LRP5/6-dependent canonical WNT responses. Gene expression analysis in embryos and adults showed striking interactions between targeted Lrp6 deficiency and FA supplementation, especially for mitochondrial function, folate and methionine metabolism, WNT signaling and cytoskeletal regulation that together implicate relevant signaling and metabolic pathways supporting cell proliferation, morphology and differentiation. We propose that FA supplementation rescues Lrp6(Cd/Cd) fetuses by normalizing hyperactive WNT activity, whereas in LRP6-deficient embryos, added FA further attenuates reduced WNT activity, thereby compromising development. PMID- 20843829 TI - Discovery of the BMPR1A promoter and germline mutations that cause juvenile polyposis. AB - Juvenile polyposis (JP) is an autosomal dominant hamartomatous polyposis syndrome where affected individuals are predisposed to colorectal and upper gastrointestinal cancer. Forty-five percent of JP patients have mutations or deletions involving the coding regions of SMAD4 and BMPR1A, but the genetic basis of other cases is unknown. We set out to identify the JP gene in a large kindred having 10 affected members without SMAD4 or BMPR1A coding sequence mutations or deletions. We found a germline deletion segregating in all affected members, mapping 119 kb upstream of the coding region of BMPR1A by multiplex ligation dependent probe amplification and comparative genomic hybridization. To further understand the genomic structure of BMPR1A, we performed 5' RACE from lymphoblastoid cell lines and normal colon tissue, which revealed four non-coding (NC) exons and two putative promoters. Further analysis of this deletion showed that it encompassed 12 433 bp, including one promoter and NC exon. The activities of each promoter and deletion constructs were evaluated by luciferase assays, and the stronger promoter sequence analyzed for changes in JP patients without SMAD4 or BMPR1A alterations. A total of 6 of 65 JP probands were found to have mutations affecting this promoter. All probands examined had diminished BMPR1A protein by ELISA, and all promoter mutations but one led to significantly reduced luciferase activity relative to the wild-type promoter reporter. We conclude that we have identified the promoter for BMPR1A, in which mutations may be responsible for as many as 10% of JP cases with unknown mutations. PMID- 20843830 TI - The planar cell polarity gene Vangl2 is required for mammalian kidney-branching morphogenesis and glomerular maturation. AB - The planar cell polarity (PCP) pathway, incorporating non-canonical Wnt signalling, controls embryonic convergent (CE) extension, polarized cell division and ciliary orientation. It also limits diameters of differentiating renal tubules, with mutation of certain components of the pathway causing cystic kidneys. Mutations in mouse Vangl genes encoding core PCP proteins cause neural tube defects (NTDs) and Vangl2 mutations also impair branching of embryonic mouse lung airways. Embryonic metanephric kidneys also undergo branching morphogenesis and Vangl2 is known to be expressed in ureteric bud/collecting duct and metanephric mesenchymal/nephron lineages. These observations led us to investigate metanephroi in Vangl2 mutant mice, Loop-tail (Lp). Although ureteric bud formation is normal in Vangl2(Lp/Lp) embryos, subsequent in vivo and in vitro branching morphogenesis is impaired. Null mutant kidneys are short, consistent with a CE defect. Differentiating glomerular epithelia express several PCP genes (Vangl1/2, Celsr1, Scrib, Mpk1/2 and Fat4) and glomeruli in Vangl2(Lp/Lp) fetuses are smaller and contain less prominent capillary loops than wild-type littermates. Furthermore, Vangl2(Lp/+) kidneys had modest reduction in glomerular numbers postnatally. Vangl2(Lp/Lp) metanephroi contained occasional dilated tubules but no overt cystic phenotype. These data show for the first time that a PCP gene is required for normal morphogenesis of both the ureteric bud and metanephric mesenchyme-derived structures. It has long been recognized that certain individuals with NTDs are born with malformed kidneys, and recent studies have discovered VANGL mutations in some NTD patients. On the basis of our mutant mouse study, we suggest that PCP pathway mutations should be sought when NTD and renal malformation co-exist. PMID- 20843831 TI - The distribution of repressive histone modifications on silenced FMR1 alleles provides clues to the mechanism of gene silencing in fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and the most common known cause of autism. Most cases of FXS result from the expansion of a CGG.CCG repeat in the 5' UTR of the FMR1 gene that leads to gene silencing. It has previously been shown that silenced alleles are associated with histone H3 dimethylated at lysine 9 (H3K9Me2) and H3 trimethylated at lysine 27 (H3K27Me3), modified histones typical of developmentally repressed genes. We show here that these alleles are also associated with elevated levels of histone H3 trimethylated at lysine 9 (H3K9Me3) and histone H4 trimethylated at lysine 20 (H4K20Me3). All four of these modified histones are present on exon 1 of silenced alleles at levels comparable to that seen on pericentric heterochromatin. The two groups of histone modifications show a different distribution on fragile X alleles: H3K9Me2 and H3K27Me3 have a broad distribution, whereas H3K9Me3 and H4K20Me3 have a more focal distribution with the highest level of these marks being present in the vicinity of the repeat. This suggests that the trigger for gene silencing may be local to the repeat itself and perhaps involves a mechanism similar to that involved in the formation of pericentric heterochromatin. PMID- 20843832 TI - Just HIT it! A time-efficient exercise strategy to improve muscle insulin sensitivity. PMID- 20843833 TI - Colon lengthening slows transit: is this the mechanism underlying redundant colon or slow transit constipation? PMID- 20843834 TI - Like breathing out and breathing in.... PMID- 20843835 TI - Regulation of neuronal cell volume: from activation to inhibition to degeneration. PMID- 20843836 TI - Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value. AB - PURPOSE: Sunitinib--a multitargeted tyrosine kinase inhibitor--can modulate circulating inflammatory factors in cancer patients that may be relevant for hepatocellular carcinoma (HCC) progression. However, a recent phase III study of sunitinib in HCC was halted due to its toxicity. Here, we studied the early kinetics of adverse events after sunitinib, and explored their association with circulating proteins and clinical outcome in advanced HCC in a single-arm phase II study. EXPERIMENTAL DESIGN: Toxicity was evaluated every two weeks during the first cycle of therapy. Biomarker changes from baseline were tested after adjusting for multiple comparisons. Correlation between toxicities and overall survival (OS) or time-to-tumor progression (TTP) was evaluated in a Cox model using log-transformed levels or change in biomarkers, after stratifying by stage and adjusting for baseline level. RESULTS: Myeloid and lymphoid blood cell counts decreased by 20% to 50% after sunitinib treatment (P < 0.05 for all). The extent of the early decrease in neutrophils and monocytes, and the development of nonhematologic toxicities (i.e., skin toxicities), were significantly associated with both OS and TTP (P < 0.05). Changes in circulating cells significantly associated with specific changes in plasma biomarkers (i.e., changes in platelets with changes in VEGF-C and soluble-VEGFR3; changes in neutrophils with changes in IL-8, TNF-alpha, and soluble-VEGFR2). CONCLUSIONS: The adverse effects of sunitinib, particularly on the hematopoietic system, may be rapid and appear directly related to its activity in HCC. This exploratory study suggests that early hematopoietic toxicities may potentially predict outcome in advanced HCC after sunitinib treatment. PMID- 20843837 TI - A proteasome inhibitor, bortezomib, inhibits breast cancer growth and reduces osteolysis by downregulating metastatic genes. AB - PURPOSE: The incidence of bone metastasis in advanced breast cancer (BrCa) exceeds 70%. Bortezomib, a proteasome inhibitor used for the treatment of multiple myeloma, also promotes bone formation. We tested the hypothesis that proteasome inhibitors can ameliorate BrCa osteolytic disease. EXPERIMENTAL DESIGN: To address the potentially beneficial effect of bortezomib in reducing tumor growth in the skeleton and counteracting bone osteolysis, human MDA-MB-231 BrCa cells were injected into the tibia of mice to model bone tumor growth for in vivo assessment of treatment regimens before and after tumor growth. RESULTS: Controls exhibited tumor growth, destroying trabecular and cortical bone and invading muscle. Bortezomib treatment initiated following inoculation of tumor cells strikingly reduced tumor growth, restricted tumor cells mainly to the marrow cavity, and almost completely inhibited osteolysis in the bone microenvironment over a 3- to 4-week period as shown by [(18)F]fluorodeoxyglucose positron emission tomography, micro-computed tomography scanning, radiography, and histology. Thus, proteasome inhibition is effective in killing tumor cells within the bone. Pretreatment with bortezomib for 3 weeks before inoculation of tumor cells was also effective in reducing osteolysis. Our in vitro and in vivo studies indicate that mechanisms by which bortezomib inhibits tumor growth and reduces osteolysis result from inhibited cell proliferation, necrosis, and decreased expression of factors that promote BrCa tumor progression in bone. CONCLUSION: These findings provide a basis for a novel strategy to treat patients with BrCa osteolytic lesions, and represent an approach for protecting the entire skeleton from metastatic bone disease. PMID- 20843840 TI - Regenerative medicine: the emergence of an industry. AB - Over the last quarter of a century there has been an emergence of a tissue engineering industry, one that has now evolved into the broader area of regenerative medicine. There have been 'ups and downs' in this industry; however, it now appears to be on a track that may be described as 'back to the future'. The latest data indicate that for 2007 the private sector activity in the world for this industry is approaching $2.5 billion, with 167 companies/business units and more than 6000 employee full time equivalents. Although small compared with the medical device and also the pharmaceutical industries, these numbers are not insignificant. Thus, there is the indication that this industry, and the related technology, may still achieve its potential and address the needs of millions of patients worldwide, in particular those with needs that currently are unmet. PMID- 20843841 TI - Observational learning in orangutan cultural transmission chains. AB - Field reports suggest that orangutans acquire local traditions by observing neighbouring conspecifics. However, there is little direct evidence of social learning to support this conclusion. The present study investigated whether orangutans would learn a novel foraging method through observation of a conspecific in a diffusion-chain paradigm testing for the spread of the behaviour. A foraging box with two possible methods for extracting food was used to investigate the transmission of a foraging tradition among zoo-living subjects. In a socially housed group of five orangutans, the dominant male was trained to use one technique exclusively to retrieve food. He then performed this technique in the presence of another group member, who was then allowed to forage. After several trials, the observer became the model for the next individual. A second experimental group of six individuals was introduced to the alternative method. The model-seeded technique was successfully transmitted along both experimental chains, with significant preferences for the model method. These results are consistent with claims for social transmission of foraging methods in wild orangutans. PMID- 20843842 TI - Effects of bacterial secondary symbionts on host plant use in pea aphids. AB - Aphids possess several facultative bacterial symbionts that have important effects on their hosts' biology. These have been most closely studied in the pea aphid (Acyrthosiphon pisum), a species that feeds on multiple host plants. Whether secondary symbionts influence host plant utilization is unclear. We report the fitness consequences of introducing different strains of the symbiont Hamiltonella defensa into three aphid clones collected on Lathyrus pratensis that naturally lack symbionts, and of removing symbionts from 20 natural aphid bacterial associations. Infection decreased fitness on Lathyrus but not on Vicia faba, a plant on which most pea aphids readily feed. This may explain the unusually low prevalence of symbionts in aphids collected on Lathyrus. There was no effect of presence of symbiont on performance of the aphids on the host plants of the clones from which the H. defensa strains were isolated. Removing the symbiont from natural aphid-bacterial associations led to an average approximate 20 per cent reduction in fecundity, both on the natural host plant and on V. faba, suggesting general rather than plant-species-specific effects of the symbiont. Throughout, we find significant genetic variation among aphid clones. The results provide no evidence that secondary symbionts have a major direct role in facilitating aphid utilization of particular host plant species. PMID- 20843843 TI - Selective pressures for accurate altruism targeting: evidence from digital evolution for difficult-to-test aspects of inclusive fitness theory. AB - Inclusive fitness theory predicts that natural selection will favour altruist genes that are more accurate in targeting altruism only to copies of themselves. In this paper, we provide evidence from digital evolution in support of this prediction by competing multiple altruist-targeting mechanisms that vary in their accuracy in determining whether a potential target for altruism carries a copy of the altruist gene. We compete altruism-targeting mechanisms based on (i) kinship (kin targeting), (ii) genetic similarity at a level greater than that expected of kin (similarity targeting), and (iii) perfect knowledge of the presence of an altruist gene (green beard targeting). Natural selection always favoured the most accurate targeting mechanism available. Our investigations also revealed that evolution did not increase the altruism level when all green beard altruists used the same phenotypic marker. The green beard altruism levels stably increased only when mutations that changed the altruism level also changed the marker (e.g. beard colour), such that beard colour reliably indicated the altruism level. For kin- and similarity-targeting mechanisms, we found that evolution was able to stably adjust altruism levels. Our results confirm that natural selection favours altruist genes that are increasingly accurate in targeting altruism to only their copies. Our work also emphasizes that the concept of targeting accuracy must include both the presence of an altruist gene and the level of altruism it produces. PMID- 20843839 TI - Human endothelial stem/progenitor cells, angiogenic factors and vascular repair. AB - Neovascularization or new blood vessel formation is of utmost importance not only for tissue and organ development and for tissue repair and regeneration, but also for pathological processes, such as tumour development. Despite this, the endothelial lineage, its origin, and the regulation of endothelial development and function either intrinsically from stem cells or extrinsically by proangiogenic supporting cells and other elements within local and specific microenvironmental niches are still not fully understood. There can be no doubt that for most tissues and organs, revascularization represents the holy grail for tissue repair, with autologous endothelial stem/progenitor cells, their proangiogenic counterparts and the products of these cells all being attractive targets for therapeutic intervention. Historically, a great deal of controversy has surrounded the identification and origin of cells and factors that contribute to revascularization, the use of such cells or their products as biomarkers to predict and monitor tissue damage and repair or tumour progression and therapeutic responses, and indeed their efficacy in revascularizing and repairing damaged tissues. Here, we will review the role of endothelial progenitor cells and of supporting proangiogenic cells and their products, principally in humans, as diagnostic and therapeutic agents for wound repair and tissue regeneration. PMID- 20843844 TI - Leaving home ain't easy: non-local seed dispersal is only evolutionarily stable in highly unpredictable environments. AB - It is widely understood that in the presence of asynchronous environmental variation, seeds disperse to escape disturbances, avoid crowding or colonize newly favourable habitat before a superior competitor can arrive. If seeds are dispersing for any of these reasons, it seems intuitive that they should travel far enough to reach conditions uncorrelated with their natal environment: why 'escape in space' only to land somewhere more or less like where they started? However, in this paper, I present a series of mathematical experiments which show that the evolutionarily stable mean dispersal distance remains well short of the spatial correlation length of the environmental variation, regardless of disturbance severity, coevolution with a superior competitor or the presence of a small fraction of seeds which travel well beyond the mean distance. Non-local dispersal arises only as part of a polymorphism that evolves when favourable conditions are fleeting. To the degree that non-local dispersal is a response to environmental variation, it appears to be a response to environmental unpredictability. PMID- 20843845 TI - Missing and forbidden links in mutualistic networks. AB - Ecological networks are complexes of interacting species, but not all potential links among species are realized. Unobserved links are either missing or forbidden. Missing links exist, but require more sampling or alternative ways of detection to be verified. Forbidden links remain unobservable, irrespective of sampling effort. They are caused by linkage constraints. We studied one Arctic pollination network and two Mediterranean seed-dispersal networks. In the first, for example, we recorded flower-visit links for one full season, arranged data in an interaction matrix and got a connectance C of 15 per cent. Interaction accumulation curves documented our sampling of interactions through observation of visits to be robust. Then, we included data on pollen from the body surface of flower visitors as an additional link 'currency'. This resulted in 98 new links, missing from the visitation data. Thus, the combined visit-pollen matrix got an increased C of 20 per cent. For the three networks, C ranged from 20 to 52 per cent, and thus the percentage of unobserved links (100 - C) was 48 to 80 per cent; these were assumed forbidden because of linkage constraints and not missing because of under-sampling. Phenological uncoupling (i.e. non-overlapping phenophases between interacting mutualists) is one kind of constraint, and it explained 22 to 28 per cent of all possible, but unobserved links. Increasing phenophase overlap between species increased link probability, but extensive overlaps were required to achieve a high probability. Other kinds of constraint, such as size mismatch and accessibility limitations, are briefly addressed. PMID- 20843846 TI - Evidence of parasitic Oomycetes (Peronosporomycetes) infecting the stem cortex of the Carboniferous seed fern Lyginopteris oldhamia. AB - Thin sections of petrified fossils made during the latter part of the nineteenth and early twentieth centuries to investigate the internal tissue systems of plants now provide an important new source of information on associated micro organisms. We report a new heterokont eukaryote (Combresomyces williamsonii sp. nov.) based on exquisitely preserved fossil oogonia, antheridia and hyphae from the Carboniferous (Pennsylvanian: Bashkirian stage) of UK. The structure of the oogonia and antheridia and features observed within the hyphae demonstrate a relationship with Oomycetes (Peronosporomycetes). The fossil micro-organism was documented in situ in petrified stem cortex and rootlets of the extinct seed fern Lyginopteris oldhamia (Pteridospermales). The main observed features point towards a pythiaceous Oomycete but links to biotrophic Albuginales or Peronosporaceae cannot be ruled out owing to the observation of a possible haustorium. Our study provides the earliest evidence for parasitism in Oomycetes. PMID- 20843847 TI - Plant nutrient supply determines competition between phytophagous insects. AB - Indirect competition is often mediated by plant responses to herbivore feeding damage and is common among phytophagous insect species. Plant-mediated responses may be altered by abiotic conditions such as nutrient supply, which can affect plant growth, morphology, and the concentration of primary and secondary metabolites. Nutrient supply can be manipulated by the type and amount of fertilizer applied to a plant. Brassica oleracea plants were grown in several types of fertilizer, including those commonly used in sustainable and conventional agricultural systems. The occurrence of indirect competition between two phytophagous species from different feeding guilds (a phloem-feeder and leaf chewer) was assessed. The leaf-chewer reduced aphid populations on plants growing in most fertilizer treatments, but not on those in the ammonium nitrate fertilizer treatment, which caused the highest concentration of foliar nitrogen. The potential consequences of our findings are discussed for phytophagous species in conventional and sustainable agricultural systems. PMID- 20843848 TI - Rapid change in host use of the common cuckoo Cuculus canorus linked to climate change. AB - Parasites require synchrony with their hosts so if host timing changes with climate change, some parasites may decline and eventually go extinct. Residents and short-distance migrant hosts of the brood parasitic common cuckoo, Cuculus canorus, have advanced their phenology in response to climate change more than long-distance migrants, including the cuckoo itself. Because different parts of Europe show different degrees of climate change, we predicted that use of residents or short-distance migrants as hosts should have declined in areas with greater increase in spring temperature. Comparing relative frequency of parasitism of the two host categories in 23 European countries before and after 1990, when spring temperatures in many areas had started to increase, we found that relative parasitism of residents and short-distance migrants decreased. This change in host use was positively related to increase in spring temperature, consistent with the prediction that relative change in phenology for different migrant classes drives host-use patterns. These findings are consistent with the hypothesis that climate change affects the relative abundance of different host races of the common cuckoo. PMID- 20843849 TI - Genetic variation in resistance, but not tolerance, to a protozoan parasite in the monarch butterfly. AB - Natural selection should strongly favour hosts that can protect themselves against parasites. Most studies on animals so far have focused on resistance, a series of mechanisms through which hosts prevent infection, reduce parasite growth or clear infection. However, animals may instead evolve tolerance, a defence mechanism by which hosts do not reduce parasite infection or growth, but instead alleviate the negative fitness consequences of such infection and growth. Here, we studied genetic variation in resistance and tolerance in the monarch butterfly (Danaus plexippus) to its naturally occurring protozoan parasite, Ophryocystis elektroscirrha. We exposed 560 monarch larvae of 19 different family lines to one of five different parasite inoculation doses (0, 1, 5, 10 and 100 infective spores) to create a range of parasite loads in infected butterflies. We then used two proxies of host fitness (adult lifespan and body mass) to quantify: (i) qualitative resistance (the ability to prevent infection; also known as avoidance or anti-infection resistance); (ii) quantitative resistance (the ability to limit parasite growth upon infection; also known as control or anti growth resistance); and (iii) tolerance (the ability to maintain fitness with increasing parasite infection intensity). We found significant differences among host families in qualitative and quantitative resistance, indicating genetic variation in resistance. However, we found no genetic variation in tolerance. This may indicate that all butterflies in our studied population have evolved maximum tolerance, as predicted by some theoretical models. PMID- 20843850 TI - Oceanic rafting by a coastal community. AB - Oceanic rafting is thought to play a fundamental role in assembling the biological communities of isolated coastal ecosystems. Direct observations of this key ecological and evolutionary process are, however, critically lacking. The importance of macroalgal rafting as a dispersal mechanism has remained uncertain, largely owing to lack of knowledge about the capacity of fauna to survive long voyages at sea and successfully make landfall and establish. Here, we directly document the rafting of a diverse assemblage of intertidal organisms across several hundred kilometres of open ocean, from the subantarctic to mainland New Zealand. Multispecies analyses using phylogeographic and ecological data indicate that 10 epifaunal invertebrate species rafted on six large bull kelp specimens for several weeks from the subantarctic Auckland and/or Snares Islands to the Otago coast of New Zealand, a minimum distance of some 400-600 km. These genetic data are the first to demonstrate that passive rafting can enable simultaneous trans-oceanic transport and landfall of numerous coastal taxa. PMID- 20843851 TI - Maternal investment of female mallards is influenced by male carotenoid-based coloration. AB - The differential allocation hypothesis predicts that females modify their investment in a breeding attempt according to its reproductive value. One prediction of this hypothesis is that females will increase reproductive investment when mated to high-quality males. In birds, it was shown that females can modulate pre-hatch reproductive investment by manipulating egg and clutch sizes and/or the concentrations of egg internal compounds according to paternal attractiveness. However, the differential allocation of immune factors has seldom been considered, particularly with an experimental approach. The carotenoid-based ornaments can function as reliable signals of quality, indicating better immunity or ability to resist parasites. Thus, numerous studies show that females use the expression of carotenoid-based colour when choosing mates; but the influence of this paternal coloration on maternal investment decisions has seldom been considered and has only been experimentally studied with artificial manipulation of male coloration. Here, we used dietary carotenoid provisioning to manipulate male mallard (Anas platyrhynchos) bill coloration, a sexually selected trait, and followed female investment. We show that an increase of male bill coloration positively influenced egg mass and albumen lysozyme concentration. By contrast, yolk carotenoid concentration was not affected by paternal ornamentation. Maternal decisions highlighted in this study may influence chick survival and compel males to maintain carotenoid-based coloration from the mate-choice period until egg-laying has been finished. PMID- 20843852 TI - Sharks that pass in the night: using Geographical Information Systems to investigate competition in the Cretaceous Western Interior Seaway. AB - One way the effects of both ecology and environment on species can be observed in the fossil record is as changes in geographical distribution and range size. The prevalence of competitive interactions and species replacements in the fossil record has long been investigated and many evolutionary perspectives, including those of Darwin, have emphasized the importance of competitive interactions that ultimately lead one species to replace another. However, evidence for such phenomena in the fossil record is not always manifest. Here we use new quantitative analytical techniques based on Geographical Information Systems and PaleoGIS tectonic reconstructions to consider this issue in greater detail. The abundant, well-preserved fossil marine vertebrates of the Late Cretaceous Western Interior Seaway of North America provide the component data for this study. Statistical analysis of distributional and range size changes in taxa confirms earlier ideas that the relative frequency of competitive replacement in the fossil record is limited to non-existent. It appears that typically, environmental gradients played the primary role in determining species distributions, with competitive interactions playing a more minor role. PMID- 20843853 TI - Sometimes slower is better: slow-exploring birds are more sensitive to changes in a vocal discrimination task. AB - Animal personality, defined as consistent individual differences across context and time, has attracted much recent research interest in the study of animal behaviour. More recently, this field has begun to examine how such variation arose and is maintained within populations. The habitat-dependent selection hypothesis, which posits that animals with differing personality types may fare better (i.e. have a fitness advantage) in different habitats, suggests one possible mechanism. In the current experiment, we tested whether slow- and fast exploring black-capped chickadees (Poecile atricapillus), determined by performance in a novel environment exploration task, perform differentially when the demands of an acoustic operant discrimination (cognitive) task were altered following successful task acquisition. We found that slow-exploring birds learn to reverse previously learned natural category rules more quickly than faster exploring conspecifics. In accordance with the habitat-dependent selection hypothesis, and previous work with great tits (Parus major), a close relative of the black-capped chickadee, our results suggest that fast-exploring birds may perform better in stable, predictable environments where forming a routine is advantageous, while slow-exploring birds are favoured in unstable, unpredictable environments, where task demands often change. Our results also support a hypothesis derived from previous work with great tits; slow-exploring birds may be generally more flexible (i.e. able to modify their behaviour in accordance with changes in environmental stimuli) in some learning tasks. PMID- 20843854 TI - Evidence for the stress-linked immunocompetence handicap hypothesis in human male faces. AB - The stress-linked immunocompetence handicap hypothesis (SL-ICHH) of sexual selection incorporates a role of the stress hormone corticosterone (C; cortisol in humans) in relationships between testosterone (T), immunity and secondary sexual trait expression. In support of this, C has been shown to mediate and moderate relationships between T and immune response and to be inversely related to attractiveness in some avian species. We predicted that female preferences for cues to T in human male faces would be contingent upon co-occurring cortisol levels. In study 1, we tested relationships between T and cortisol and attractiveness, masculinity and health ratings of raw male faces. We found cortisol to be inversely related to attractiveness. In study 2, we tested female preferences for male faces that were parametrically manipulated on the basis of cues to naturally co-occurring levels of T and cortisol across the menstrual cycle. Women preferred cues to low cortisol in general and in the fertile phase of the cycle, and there was an interaction between T and cortisol in general and in the non-fertile phase. Results were consistent with the SL-ICHH but not the original immunocompetence handicap model: females expressed preferences for cues to cortisol but not for cues to T, except in interaction with the stress hormone. Results inform the SL-ICHH by demonstrating female preferences for low cortisol and the nature of its interaction with T in humans, as well as indicating the traits that may be signalled by different combinations of the hormones including immune response, current health and resource acquisition characteristics. PMID- 20843855 TI - Inhibition of viral replication in vitro by antiviral-treated amniotic membrane. Possible use of amniotic membrane as drug-delivering tool. AB - PURPOSE: To investigate if amniotic membrane (AM) incubated with antivirals can inhibit viral growth in vitro. METHODS: AM samples were incubated with a solution of acyclovir or trifluridine. The treated AM was placed onto monolayers of Vero cells, a continuous cell line from monkey kidney, infected with herpes simplex virus. Viral growth was assessed in comparison to control infected cells by direct examination with an inverted microscope at low magnification for the presence and extension of the typical cytopathic effect, or by estimation of viral genomes. RESULTS: AM soaked in acyclovir or trifluridine inhibited significantly the development of herpes simplex virus in cell cultures, based on the viral growth compared with controls. Non-treated AM did not significantly affect viral replication. CONCLUSIONS: Our preliminary in vitro data show that antiviral-treated amniotic membrane can inhibit viral replication. Therefore, the possibility to combine the previously published anti-inflammatory properties of AM with the capability to absorb antivirals and sustain drug release could be taken into consideration. PMID- 20843856 TI - Integrin alphaV is necessary for gastrulation movements that regulate vertebrate body asymmetry. AB - Integrin alphaV can form heterodimers with several beta subunits to mediate cell cell and cell-extracellular matrix interactions. During zebrafish gastrulation, alphaV is expressed maternally and zygotically. Here, we used a morpholino mediated alphaV knockdown strategy to study alphaV function. Although alphaV morphants displayed vascular defects, they also exhibited left-right body asymmetry defects affecting multiple visceral organs. This was preceded by mislocalization of dorsal forerunner cells (DFCs) and malformation of the Kupffer's vesicle (KV) laterality organ. These defects were rescued with morpholino-resistant alphaV mRNA. Like alphaV, integrin beta1b was expressed in DFCs, and beta1b knockdown largely recapitulated the laterality phenotype of alphaV morphants. When tracked in real-time, individual DFCs of both morphants showed defects in DFC migration, preventing them from organizing into a KV of normal shape and size. Thus, we propose that alphaVbeta1b mediates cellular interactions that are necessary for DFC clustering and movements necessary for Kupffer's vesicle formation, uncovering an early contribution of integrins to the regulation of vertebrate laterality. PMID- 20843857 TI - Planar cell polarity signalling regulates cell adhesion properties in progenitors of the zebrafish laterality organ. AB - Organ formation requires the precise assembly of progenitor cells into a functional multicellular structure. Mechanical forces probably participate in this process but how they influence organ morphogenesis is still unclear. Here, we show that Wnt11- and Prickle1a-mediated planar cell polarity (PCP) signalling coordinates the formation of the zebrafish ciliated laterality organ (Kupffer's vesicle) by regulating adhesion properties between organ progenitor cells (the dorsal forerunner cells, DFCs). Combined inhibition of Wnt11 and Prickle1a reduces DFC cell-cell adhesion and impairs their compaction and arrangement during vesicle lumen formation. This leads to the formation of a mis-shapen vesicle with small fragmented lumina and shortened cilia, resulting in severely impaired organ function and, as a consequence, randomised laterality of both molecular and visceral asymmetries. Our results reveal a novel role for PCP dependent cell adhesion in coordinating the supracellular organisation of progenitor cells during vertebrate laterality organ formation. PMID- 20843858 TI - Developmental role for ACF1-containing nucleosome remodellers in chromatin organisation. AB - The nucleosome remodelling complexes CHRAC and ACF of Drosophila are thought to play global roles in chromatin assembly and nucleosome dynamics. Disruption of the gene encoding the common ACF1 subunit compromises fly viability. Survivors show defects in chromatin assembly and chromatin-mediated gene repression at all developmental stages. We now show that ACF1 expression is under strict developmental control. The expression is strongly diminished during embryonic development and persists at high levels only in undifferentiated cells, including the germ cell precursors and larval neuroblasts. Constitutive expression of ACF1 is lethal. Cell-specific ectopic expression perturbs chromatin organisation and nuclear programmes. By monitoring heterochromatin formation during development, we have found that ACF1-containing factors are involved in the initial establishment of diversified chromatin structures, such as heterochromatin. Altering the levels of ACF1 leads to global and variegated deviations from normal chromatin organisation with pleiotropic defects. PMID- 20843859 TI - FGF8 acts as a classic diffusible morphogen to pattern the neocortex. AB - Gain- and loss-of-function experiments have demonstrated that a source of fibroblast growth factor (FGF) 8 regulates anterior to posterior (A/P) patterning in the neocortical area map. Whether FGF8 controls patterning as a classic diffusible morphogen has not been directly tested. We report evidence that FGF8 diffuses through the mouse neocortical primordium from a discrete source in the anterior telencephalon, forms a protein gradient across the entire A/P extent of the primordium, and acts directly at a distance from its source to determine area identity. FGF8 immunofluorescence revealed FGF8 protein distributed in an A/P gradient. Fate-mapping experiments showed that outside the most anterior telencephalon, neocortical progenitor cells did not express Fgf8, nor were they derived from Fgf8-expressing cells, suggesting that graded distribution of FGF8 results from protein diffusion from the anterior source. Supporting this conclusion, a dominant-negative high-affinity FGF8 receptor captured endogenous FGF8 at a distance from the FGF8 source. New FGF8 sources introduced by electroporation showed haloes of FGF8 immunofluorescence indicative of FGF8 diffusion, and surrounding cells reacted to a new source of FGF8 by upregulating different FGF8-responsive genes in concentric domains around the source. Reducing endogenous FGF8 with the dominant-negative receptor in the central neocortical primordium induced cells to adopt a more posterior area identity, demonstrating long-range area patterning by FGF8. These observations support FGF8 as a classic diffusible morphogen in neocortex, thereby guiding future studies of neocortical pattern formation. PMID- 20843860 TI - A prominent requirement for single-minded and the ventral midline in patterning the dorsoventral axis of the crustacean Parhyale hawaiensis. AB - In bilaterians, establishing the correct spatial positioning of structures along the dorsoventral (DV) axis is essential for proper embryonic development. Insects such as Drosophila rely on the Dorsal activity gradient and Bone morphogenetic protein (BMP) signaling to establish cell fates along the DV axis, leading to the distinction between tissues such as mesoderm, neurogenic ectoderm and dorsal ectoderm in the developing embryo. Subsequently, the ventral midline plays a more restricted role in DV patterning by establishing differential cell fates in adjacent regions of the neurogenic ectoderm. In this study, we examine the function of the ventral midline and the midline-associated gene single-minded (Ph sim) in the amphipod crustacean Parhyale hawaiensis. Remarkably, we found that Ph sim and the ventral midline play a central role in establishing proper fates along the entire DV axis in this animal; laser ablation of midline cells causes a failure to form neurogenic ectoderm and Ph-sim RNAi results in severely dorsalized embryos lacking both neurogenic ectoderm and the appendage-bearing lateral ectoderm. Furthermore, we hypothesize that this role of midline cells was present in the last common ancestor of crustaceans and insects. We predict that the transition to a Dorsal-dependent DV patterning system in the phylogenetically derived insect lineage leading to Drosophila has led to a more restricted role of the ventral midline in patterning the DV axis of these insects. PMID- 20843861 TI - Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons. AB - Mammalian limb and trunk skeletal muscles are composed of muscle fibers that differ in contractile and molecular properties. They are commonly divided into four categories according to the myosin heavy chain that they express: I, IIA, IIX and IIB, ranging from slowest to fastest. Individual motor axons innervate tens of muscle fibers, nearly all of which are of the same type. The mechanisms accounting for this striking specificity, termed motor unit homogeneity, remain incompletely understood, in part because there have been no markers for motoneuron types. Here we show in mice that the synaptic vesicle protein SV2A is selectively localized in motor nerve terminals on slow (type I and small type IIA) muscle fibers; its close relatives, SV2B and SV2C, are present in all motor nerve terminals. SV2A is broadly expressed at birth; fast motoneurons downregulate its expression during the first postnatal week. An inducible transgene incorporating regulatory elements from the Sv2a gene permits selective labeling of slow motor units and reveals their composition. Overexpression of the transcriptional co-regulator PGC1alpha in muscle fibers, which converts them to a slow phenotype, leads to an increased frequency of SV2A-positive motor nerve terminals, indicating a fiber type-specific retrograde influence of muscle fibers on their innervation. This retrograde influence must be integrated with known anterograde influences in order to understand how motor units become homogeneous. PMID- 20843863 TI - The health status of nonparticipants in a population-based health study: the Hordaland Health Study. AB - The authors aimed to examine whether nonparticipation in a population-based health study was associated with poorer health status; to determine whether specific health problems were overrepresented among nonparticipants; and to explore potential consequences of participation bias on associations between exposures and outcomes. They used data from the Hordaland Health Study (HUSK), conducted in western Norway in 1997-1999. Of 29,400 persons invited, 63.1% participated in the study. Information from HUSK was linked with the Norwegian national registry of disability pensions (DPs), including information about DP diagnosis. The risk of DP receipt was almost twice as high among nonparticipants as participants (relative risk = 1.88, 95% confidence interval: 1.81, 1.95). The association was strongest for DPs received for mental disorders, with a 3-fold increased risk for nonparticipation. Substance abuse, psychotic disorders, and personality disorders were especially overrepresented among nonparticipants. The authors simulated the impact of nonparticipation on associations between exposures and outcomes by excluding HUSK participants with higher symptoms of common mental disorders (exposure) and examining the impact on DP (outcome). This selective exclusion modestly reduced associations between common mental disorders and DP. The authors conclude that nonparticipants have poorer health, but this is disorder-dependent. Participation bias is probably a greater threat to the validity of prevalence studies than to studies of associations between exposures and outcomes. PMID- 20843862 TI - The C. elegans developmental timing protein LIN-42 regulates diapause in response to environmental cues. AB - Environmental conditions can have a major impact on developmental progression in animals. For example, when C. elegans larvae encounter harsh conditions they can reversibly halt the passage of developmental time by forming a long-lived dauer larva at the end of the second larval stage. Here, we show that the period homolog lin-42, known to control developmental time, also acts as a component of a switch that mediates dauer entry. Loss of lin-42 function renders animals hypersensitive to dauer formation under stressful conditions, whereas misexpression of lin-42 in the pre-dauer stage inhibits dauer formation, indicating that lin-42 acts as a negative regulator of this life history decision. These phenotypes place LIN-42 in opposition to the ligand-free form of the nuclear receptor DAF-12, which indirectly senses environmental conditions and helps to integrate external cues into developmental decisions. Mutations that impair DAF-12 ligand binding are exquisitely sensitive to the absence of lin-42, whereas overexpression of LIN-42 can suppress the dauer constitutive phenotype of a ligand-insensitive daf-12 mutant, suggesting that LIN-42 and DAF-12 are intimate partners in controlling the decision to become a dauer larva. The functional outputs of Period family proteins and nuclear receptors also converge in other organisms, suggesting that the relationship between lin-42 and daf-12 represents an ancient genetic framework for responding to environmental stimuli. PMID- 20843865 TI - Recurrence of stillbirth in sibships: Population-based cohort study. AB - Knowledge of stillbirth recurrence risk is of clinical interest and may give etiological insight. The authors studied "gestational age-" and "weight-by gestation-specific" stillbirth recurrence, and evaluated time trends in a population-based cohort study from the Medical Birth Registry of Norway, from 1967 to 2004. Singleton births, including stillbirths from 20 weeks' gestation, were linked to their mothers by national identification numbers. Stillbirth rates in second pregnancies among mothers with (N = 5,091) and without (N = 562,057; the reference group) a stillbirth in first pregnancies were compared across 4 gestational age and 3 weight-by-gestation groups. A remarkable symmetric pattern of gestational age-specific recurrence of stillbirth was found, with highest odds of stillbirth in the same age group. The adjusted odds ratio values associated with preterm stillbirth recurrence were high, for example, 25.7 (95% confidence interval: 19.8, 33.3) for stillbirth at 20-27 weeks' gestation (73/1,511 vs. 1,021/562,057), while lower for term stillbirth: adjusted odds ratio = 2.3 (95% confidence interval: 1.2, 4.7) (9/1,844 vs. 1,021/538,499). The proportion of second early stillbirths in the population attributable to previous early stillbirth was 6.4%, compared with 0.5% for second term stillbirth. Over time, recurrence of early stillbirth decreased, whereas that of mid/late stillbirth did not change significantly. A symmetric pattern of recurring stillbirth in similar weight-by-gestation groups was not found. PMID- 20843866 TI - Academic family medicine--redefining academic. PMID- 20843864 TI - Objective light-intensity physical activity associations with rated health in older adults. AB - The extent to which light-intensity physical activity contributes to health in older adults is not well known. The authors examined associations between physical activity across the intensity spectrum (sedentary to vigorous) and health and well-being variables in older adults. Two 7-day assessments of accelerometry from 2005 to 2007 were collected 6 months apart in the observational Senior Neighborhood Quality of Life Study of adults aged >65 years in Baltimore, Maryland, and Seattle, Washington. Self-reported health and psychosocial variables (e.g., lower-extremity function, body weight, rated stress) were also collected. Physical activity based on existing accelerometer thresholds for moderate/vigorous, high-light, low-light, and sedentary categories were examined as correlates of physical health and psychosocial well-being in mixed-effects regression models. Participants (N = 862) were 75.4 (standard deviation, 6.8) years of age, 56% female, 71% white, and 58% overweight/obese. After adjustment for study covariates and time spent in moderate/vigorous physical activity and sedentary behavior, low-light and high-light physical activity were positively related to physical health (all P < 0.0001) and well being (all P < 0.001). Additionally, replacing 30 minutes/day of sedentary time with equal amounts of low-light or high-light physical activity was associated with better physical health (all P < 0.0001). Objectively measured light intensity physical activity is associated with physical health and well-being variables in older adults. PMID- 20843867 TI - IGVBrowser--a genomic variation resource from diverse Indian populations. AB - The Indian Genome Variation Consortium (IGVC) project, an initiative of the Council for Scientific and Industrial Research, has been the first large-scale comprehensive study of the Indian population. One of the major aims of the project is to study and catalog the variations in nearly thousand candidate genes related to diseases and drug response for predictive marker discovery, founder identification and also to address questions related to ethnic diversity, migrations, extent and relatedness with other world population. The Phase I of the project aimed at providing a set of reference populations that would represent the entire genetic spectrum of India in terms of language, ethnicity and geography and Phase II in providing variation data on candidate genes and genome wide neutral markers on these reference set of populations. We report here development of the IGVBrowser that provides allele and genotype frequency data generated in the IGVC project. The database harbors 4229 SNPs from more than 900 candidate genes in contrasting Indian populations. Analysis shows that most of the markers are from genic regions. Further, a large fraction of genes are implicated in cardiovascular, metabolic, cancer and immune system-related diseases. Thus, the IGVC data provide a basal level variation data in Indian population to study genetic diseases and pharmacology. Additionally, it also houses data on ~50,000 (Affy 50 K array) genome wide neutral markers in these reference populations. In IGVBrowser one can analyze and compare genomic variations in Indian population with those reported in HapMap along with annotation information from various primary data sources. Database URL: http://igvbrowser.igib.res.in. PMID- 20843868 TI - A quality-based review of randomized controlled trials of psychodynamic psychotherapy. AB - OBJECTIVE: The Ad Hoc Subcommittee for Evaluation of the Evidence Base for Psychodynamic Psychotherapy of the APA Committee on Research on Psychiatric Treatments developed the Randomized Controlled Trial Psychotherapy Quality Rating Scale (RCT-PQRS). The authors report results from application of the RCT-PQRS to 94 randomized controlled trials of psychodynamic psycho-therapy published between 1974 and May 2010. METHOD: Five psychotherapy researchers from a range of therapeutic orientations rated a single published paper from each study. RESULTS: The RCT-PQRS had good interrater reliability and internal consistency. The mean total quality score was 25.1 (SD=8.8). More recent studies had higher total quality scores. Sixty-three of 103 comparisons between psychodynamic psychotherapy and a nondynamic comparator were of "adequate" quality. Of 39 comparisons of a psychodynamic treatment and an "active" comparator, six showed dynamic treatment to be superior, five showed dynamic treatment to be inferior, and 28 showed no difference (few of which were powered for equivalence). Of 24 adequate comparisons of psychodynamic psychotherapy with an "inactive" comparator, 18 found dynamic treatment to be superior. CONCLUSIONS: Existing randomized controlled trials of psychodynamic psychotherapy are promising but mostly show superiority of psychodynamic psychotherapy to an inactive comparator. This would be sufficient to make psychodynamic psychotherapy an "empirically validated" treatment (per American Psychological Association Division 12 standards) only if further randomized controlled trials of adequate quality and sample size replicated findings of existing positive trials for specific disorders. We do not yet know what will emerge when other psychotherapies are subjected to this form of quality-based review. PMID- 20843869 TI - Altitude, gun ownership, rural areas, and suicide. AB - OBJECTIVE: The authors recently observed a correlation between state altitude and suicide rate in the United States, which could be explained by higher rates of gun ownership and lower population density in the intermountain West. The present study evaluated the relationship between mean county and state altitude in the United States and total age-adjusted suicide rates, firearm-related suicide rates, and non-firearm-related suicide rates. The authors hypothesized that altitude would be significantly associated with suicide rate. METHOD: Elevation data were calculated with an approximate spatial resolution of 0.5 km, using zonal statistics on data sets compiled from the National Geospatial-Intelligence Agency and the National Aeronautics and Space Administration. Suicide and population density data were obtained through the Centers for Disease Control and Prevention (CDC) WONDER database. Gun ownership data were obtained through the CDC's Behavioral Risk Factor Surveillance System. RESULTS: A significant positive correlation was observed between age-adjusted suicide rate and county elevation (r=0.51). Firearm (r=0.41) and non-firearm suicide rates (r=0.32) were also positively correlated with mean county elevation. CONCLUSIONS: When altitude, gun ownership, and population density are considered as predictor variables for suicide rates on a state basis, altitude appears to be a significant independent risk factor. This association may be related to the effects of metabolic stress associated with mild hypoxia in individuals with mood disorders. PMID- 20843870 TI - Children of parents with affective and nonaffective psychoses: a longitudinal study of behavior problems. AB - OBJECTIVE: It is generally accepted that children of parents with schizophrenia or other forms of psychosis are at heightened risk for a range of behavioral problems. However, it remains unclear whether offspring of parents with different forms of psychosis (e.g., schizophrenia, other nonaffective psychoses, and affective psychoses) have distinct forms of behavioral problems (i.e., internalizing and externalizing). METHOD: Behavioral observations of children of parents with psychosis (N=281) and parents without psychosis (N=185) were conducted at ages 4 and 7 years. RESULTS: There were no significant differences between groups in behavior observed at age 4 years. At age 7 years, compared with children of unaffected parents, children of parents with psychosis had an adjusted odds ratio of 2.8 (95% CI=1.5-5.6) for externalizing problems, in particular for children of parents with schizophrenia (adjusted odds ratio=4.4; 95% CI=1.7-12.5). This increase in risk for externalizing problems was observed for female children only (adjusted odds ratio=8.1; 95% CI=2.5-26.3). In contrast, male children were at increased risk for internalizing problems (adjusted odds ratio=3.6; 95% CI=1.6-8.3). CONCLUSIONS: Children of parents with various forms of psychosis are at risk for internalizing and externalizing problems by age 7 years. This risk varies by gender of the offspring. Implications for treatment of parents with psychotic disorders and high-risk children are discussed. PMID- 20843871 TI - High-field magnetic resonance imaging of suicidality in patients with major depressive disorder. AB - OBJECTIVE: Suicide is a major social and public health problem, but its neurobiology in major depressive disorder is poorly understood. The purpose of this study was to use magnetic resonance diffusion tensor imaging to characterize abnormalities of white matter integrity in major depressive disorder patients with and without a history of suicide attempts. METHOD: Participants were 52 patients with major depressive disorder, with (N=16) and without (N=36) a history of suicide attempts, and 52 healthy comparison subjects matched for age, gender, education, and ethnicity. Diffusion tensor imaging in a 3.0 Tesla magnetic resonance scanner was performed. Whole-brain voxel-based analysis was used to compare fractional anisotropy across the three groups and analyze the correlation with symptom severity. A region-of-interest analysis was applied to the bilateral hippocampus, thalamus, and lentiform nucleus RESULTS: Fractional anisotropy was decreased in the left anterior limb of the internal capsule in suicide attempters relative to both nonattempters and healthy comparison subjects, in the right frontal lobe relative to comparison subjects only, and in the right lentiform nucleus relative to nonattempters only. There was no significant correlation with symptom severity. CONCLUSIONS: Decreased fractional anisotropy in the left anterior limb of the internal capsule appears to characterize patients with major depressive disorder who have a history of attempting suicide. Longitudinal studies are required to validate this as a potential marker that may inform the development of strategies for reducing suicide. PMID- 20843872 TI - "A disease like any other"? A decade of change in public reactions to schizophrenia, depression, and alcohol dependence. AB - OBJECTIVE: Clinicians, advocates, and policy makers have presented mental illnesses as medical diseases in efforts to overcome low service use, poor adherence rates, and stigma. The authors examined the impact of this approach with a 10-year comparison of public endorsement of treatment and prejudice. METHOD: The authors analyzed responses to vignettes in the mental health modules of the 1996 and 2006 General Social Survey describing individuals meeting DSM-IV criteria for schizophrenia, major depression, and alcohol dependence to explore whether more of the public 1) embraces neurobiological understandings of mental illness; 2) endorses treatment from providers, including psychiatrists; and 3) reports community acceptance or rejection of people with these disorders. Multivariate analyses examined whether acceptance of neurobiological causes increased treatment support and lessened stigma. RESULTS: In 2006, 67% of the public attributed major depression to neurobiological causes, compared with 54% in 1996. High proportions of respondents endorsed treatment, with general increases in the proportion endorsing treatment from doctors and specific increases in the proportions endorsing psychiatrists for treatment of alcohol dependence (from 61% in 1996 to 79% in 2006) and major depression (from 75% in 1996 to 85% in 2006). Social distance and perceived danger associated with people with these disorders did not decrease significantly. Holding a neurobiological conception of these disorders increased the likelihood of support for treatment but was generally unrelated to stigma. Where associated, the effect was to increase, not decrease, community rejection. CONCLUSIONS: More of the public embraces a neurobiological understanding of mental illness. This view translates into support for services but not into a decrease in stigma. Reconfiguring stigma reduction strategies may require providers and advocates to shift to an emphasis on competence and inclusion. PMID- 20843873 TI - Personalized medicine for depression: can we match patients with treatments? AB - OBJECTIVE: Response to specific depression treatments varies widely among individuals. Understanding and predicting that variation could have great benefits for people living with depression. METHOD: The authors describe a conceptual model for identifying and evaluating evidence relevant to personalizing treatment for depression. They review evidence related to three specific treatment decisions: choice between antidepressant medication and psychotherapy, selection of a specific antidepressant medication, and selection of a specific psychotherapy. They then discuss potential explanations for negative findings as well as implications for research and clinical practice. RESULTS: Many previous studies have examined general predictors of outcome, but few have examined true moderators (predictors of differential response to alternative treatments). The limited evidence indicates that some specific clinical characteristics may inform the choice between antidepressant medication and psychotherapy and the choice of specific antidepressant medication. Research to date does not identify any biologic or genetic predictors of sufficient clinical utility to inform the choice between medication and psychotherapy, the selection of specific medication, or the selection of a specific psychotherapy. CONCLUSIONS: While individuals vary widely in response to specific depression treatments, the variability remains largely unpredictable. Future research should focus on identifying true moderator effects and should consider how response to treatments varies across episodes. At this time, our inability to match patients with treatments implies that systematic follow-up assessment and adjustment of treatment are more important than initial treatment selection. PMID- 20843877 TI - Assessing psychological well-being in mothers of children with disability: evaluation of the Parenting Morale Index and Family Impact of Childhood Disability scale. AB - OBJECTIVE: Process model of stress and coping guided psychometric assessment of two brief measures of psychological well-being: Parenting Morale Index (PMI); Family Impact of Childhood Disability (FICD) scale. METHODS: Canadian mothers (N=195) of children with disability (CWD) completed PMI, FICD, and validation measures (Brief Family Assessment Measure [FAM], Personal Well-Being Index, Positive and Negative Affect Schedule, General Self-Efficacy Scale, Social Desirability Scale) via computer-assisted telephone interview. Of these, 154 completed additional validation measures (Center for Epidemiological Studies Depression Scale, Parenting Stress Index, Family Hardiness Index, Brief FAM) 1 year later. RESULTS: Factor structures of PMI and FICD were supported; both demonstrated internal consistency, temporal stability, and convergent and discriminant validity. After 1 year, PMI and FICD jointly predicted depressive symptoms, parenting stress, family hardiness, and family adjustment. CONCLUSION: PMI and FICD can identify mothers of CWD at risk for poor psychological well being to increase the specificity of supports. PMID- 20843875 TI - Abnormally reduced dorsomedial prefrontal cortical activity and effective connectivity with amygdala in response to negative emotional faces in postpartum depression. AB - OBJECTIVE: Postpartum major depression is a significant public health problem that strikes 15% of new mothers and confers adverse consequences for mothers, children, and families. The neural mechanisms involved in postpartum depression remain unknown, but brain processing of affective stimuli appears to be involved in other affective disorders. The authors examined activity in response to negative emotional faces in the dorsomedial pre-frontal cortex and amygdala, key emotion regulatory neural regions of importance to both mothering and depression. METHOD: Postpartum healthy mothers (N=16) and unmedicated depressed mothers (N=14) underwent functional magnetic resonance imaging blood-oxygen-level dependent acquisition during a block-designed face versus shape matching task. A two-way analysis of variance was performed examining main effects of condition and group and group-by-condition interaction on activity in bilateral dorsomedial prefrontal cortical and amygdala regions of interest. RESULTS: Depressed mothers relative to healthy mothers had significantly reduced left dorsomedial prefrontal cortical face-related activity. In depressed mothers, there was also a significant negative correlation between left amygdala activity and postpartum depression severity and a significant positive correlation between right amygdala activity and absence of infant-related hostility. There was reliable top-down connectivity from the left dorsomedial prefrontal cortex to the left amygdala in healthy, but not depressed, mothers. CONCLUSIONS: Significantly diminished dorsomedial prefrontal cortex activity and dorsomedial prefrontal cortical amygdala effective connectivity in response to negative emotional faces may represent an important neural mechanism, or effect, of postpartum depression. Reduced amygdala activity in response to negative emotional faces is associated with greater postpartum depression severity and more impaired maternal attachment processes in postpartum depressed mothers. PMID- 20843878 TI - Cost-effectiveness analysis of interventions to prevent cardiovascular disease in Vietnam. AB - BACKGROUND: Vietnam is in the process of an epidemiological transition, with cardiovascular disease (CVD) now ranked as the leading cause of death. The burden of CVD will continue to rise unless effective interventions for addressing its underlying risk factors are put in place. OBJECTIVES: To assess the costs, health effects and cost-effectiveness of a set of personal and non-personal prevention strategies to reduce CVD in Vietnam, including mass media campaigns for reducing consumption of salt and tobacco, drugs for lowering blood pressure or cholesterol, and combined pharmacotherapy for people at varying levels of absolute risk of a cardiovascular event. METHODS: WHO-CHOICE methods and analytical models were employed, using local data to estimate the costs, effects and cost-effectiveness of 12 population and individual interventions implemented singly or in combination. Costs were measured in Vietnamese Dong for the year 2007 (discounted at a rate of 3% per year), while health effects were expressed in age-weighted and discounted disability-adjusted life years (DALYs) averted. RESULTS: A health education programme to reduce salt intake (VND 1 945 002 or US$118 per DALY averted) and individual treatment of systolic blood pressure above 160 mmHg (VND 1 281 596 or US$78 per DALY averted) were found to be the most cost-effective measures for population- and individual-based approaches, respectively. Where budget is very limited, a mass media education programme on salt intake and a combination mass media programme addressing salt intake, cholesterol and tobacco should be selected first. If more resources become available, greatest population health gains can be achieved via individual treatment of systolic blood pressure and the absolute risk approach to CVD prevention. CONCLUSIONS: Contextualization of WHO-CHOICE using local data provides health decision-makers with more sound economic evidence for policy debates on prioritizing health interventions to reduce cardiovascular diseases in Vietnam. When used, cost-effectiveness analysis could increase efficiency in allocating scare resources. PMID- 20843874 TI - Linking molecules to mood: new insight into the biology of depression. AB - Major depressive disorder is a heritable psychiatric syndrome that appears to be associated with subtle cellular and molecular alterations in a complex neural network. The affected brain regions display dynamic neuroplastic adaptations to endocrine and immunologic stimuli arising from within and outside the CNS. Depression's clinical and etiological heterogeneity adds a third level of complexity, implicating different pathophysiological mechanisms in different patients with the same DSM diagnosis. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are themselves incompletely understood. This review summarizes the current knowledge of the neurobiology of depression by combining insights from human clinical studies and molecular explanations from animal models. The authors provide recommendations for future research, with a focus on translating today's discoveries into improved diagnostic tests and treatments. PMID- 20843876 TI - Thalamic dysfunction in schizophrenia suggested by whole-night deficits in slow and fast spindles. AB - OBJECTIVE: Slow waves and sleep spindles are the two main oscillations occurring during non-REM sleep. While slow oscillations are primarily generated and modulated by the cortex, sleep spindles are initiated by the thalamic reticular nucleus and regulated by thalamo-reticular and thalamo-cortical circuits. In a recent high-density EEG study, the authors found that 18 medicated schizophrenia patients had reduced sleep spindles, compared with healthy and depressed subjects, during the first non-REM episode. In the present study, the authors investigated whether spindle deficits were present in a larger sample of schizophrenia patients, were consistent across the night, were related to antipsychotic medications, and were suggestive of impairments in specific neuronal circuits. METHOD: Whole-night high-density EEG recordings were performed in 49 schizophrenia patients, 20 nonschizophrenia patients receiving antipsychotic medication, and 44 healthy subjects. In addition to sleep spindles, several parameters of slow waves were assessed. RESULTS: Schizophrenia patients had whole-night deficits in spindle power (12-16 Hz) and in slow (12-14 Hz) and fast (14-16 Hz) spindle amplitude, duration, number, and integrated activity in the prefrontal, centroparietal, and temporal regions. Integrated spindle activity and spindle number had the largest effect sizes (effect size: >= 2.21). In contrast, no slow wave deficits were found in schizophrenia patients. CONCLUSIONS: These results indicate that spindle deficits can be reliably established in schizophrenia, are stable across the night, are unlikely to be due to antipsychotic medications, and point to deficits in the thalamic reticular nucleus and thalamo-reticular circuits. PMID- 20843879 TI - Long-term clinical outcomes of care management for chronically depressed primary care patients: a report from the depression in primary care project. AB - PURPOSE: Recent studies examining depression disease management report improvements in short-term outcomes, but less is known about whether improvements are sustainable over time. This study evaluated the sustained clinical effectiveness of low-intensity depression disease management in chronically depressed patients. METHODS: The Depression in Primary Care (DPC) intervention was introduced in 5 primary care practices in the University of Michigan Health System, with 5 matched practices selected as control sites. Clinicians were free to refer none, some, or all of their depressed patients at their discretion. Core clinical outcomes of remission and serial change in Patient Health Questionnaire (PHQ-8) scores for 728 DPC enrollees observed for up to 18 months after enrollment were compared with those for 78 patients receiving usual care who completed mailed questionnaires at baseline, 6, 12, and 18 months. RESULTS: DPC enrollees had sustained improvement in remission rates and reduced-function days over the full 18 months. Mean change in the PHQ-8 score over each 6-month interval was more favorable for DPC enrollees than for usual care patients, and the proportion of DPC enrollees in remission was higher at 6 months (43.4% vs 33.3%; P = .11), 12 months (52.0% vs 33.9%; P = .012), and 18 months (49.2% vs 27.3%; P = .004). Multivariate analysis controlling for age, sex, ethnicity, baseline severity, and comorbid medical illness confirmed that DPC enrollees had significantly more reduction in depressive symptom burden over 18 months. CONCLUSIONS: The DPC intervention produced sustained improvement in clinical outcomes over 18 months in a cohort of chronically depressed patients with persistent symptoms despite active treatment. PMID- 20843880 TI - Longitudinal adherence with fecal occult blood test screening in community practice. AB - PURPOSE: Although screening with fecal occult blood testing (FOBT) reduces colorectal cancer (CRC) mortality, its effectiveness may diminish if patients do not adhere with repeated screenings. Among patients who had previously engaged in FOBT screening, we assessed subsequent adherence with FOBT screening. METHODS: We assessed longitudinal adherence with biennial FOBT screening (every other year) within a cohort of patients enrolled in an integrated Washington State health plan. Among 11,110 patients who participated in FOBT screening during a 2-year baseline period (2000-2001), we ascertained CRC screening use during a subsequent 2-year observation period (2002-2003). We used multinomial logistic regression to identify patient characteristics associated with higher incidence of repeat CRC screening (with or without FOBT) relative to patients who received no CRC screening. RESULTS: Despite prior participation in FOBT screening, less than one half of patients (44.4%; 95% CI, 42.9%-45.8%) completed FOBT screening during the 2-year observation period. Although 8.8% of patients (95% CI, 8.0%-9.7%) received other CRC tests without FOBT during the observation period, nearly one-half, 46.8% (95% CI, 45.3%-48.4%), received no CRC screening. After adjustment for other patient characteristics, receipt of a preventive health examination was strongly associated with FOBT adherence relative to no CRC screening (adjusted relative rate ratio = 11.16; 95% CI, 9.61-12.96). CONCLUSIONS: Longitudinal adherence with FOBT screening was low in this insured population, potentially compromising its effectiveness in population CRC mortality reduction. Interventions to promote adherence may be necessary to achieve high effectiveness in population-based FOBT screening programs. PMID- 20843882 TI - Participatory decision making, patient activation, medication adherence, and intermediate clinical outcomes in type 2 diabetes: a STARNet study. AB - PURPOSE: Participatory decision making (PDM) is associated with improved diabetes control. We examine a causal model linking PDM to improved clinical outcomes that included patient activation and medication adherence. METHODS: This observational study was conducted in 5 family physician offices. Diabetic patients were recruited by mail and by completing a study interest card at the conclusion of their office visit. Two survey questionnaires, administered 12 months apart, elicited patients' ratings of their physician's PDM style at baseline and their level of activation and medication adherence both at baseline and at follow-up. Measures of glycated hemoglobin (hemoglobin A(1c)), systolic blood pressure, and low-density lipoprotein (LDL) cholesterol were abstracted from the medical record starting 12 months before the baseline survey to 12 months after the follow-up survey. A path analysis using a structural equation model was used to test hypotheses. RESULTS: We mailed questionnaires to 236 participants; 166 (70%) returned the baseline questionnaire, and 141 (80%) returned the follow-up questionnaire. Hemoglobin A(1c) levels, systolic blood pressure, and LDL cholesterol values all declined significantly, and patient activation and medication adherence improved. PDM at baseline was associated with patient activation at follow-up. Patient activation at follow-up was associated with medication adherence at follow-up, and medication adherence at follow-up was associated with change in hemoglobin A(1c) levels and LDL cholesterol values but not with systolic blood pressure. CONCLUSIONS: Participatory decision making during primary care encounters by patients with type 2 diabetes resulted in improvements in hemoglobin A(1c) levels and LDL cholesterol values by improving patient activation, which in turn improved medication adherence. PMID- 20843881 TI - Effect of drug sample removal on prescribing in a family practice clinic. AB - PURPOSE: Little is known about the impact of recent restrictions on pharmaceutical industry detailing and sampling on prescribing behavior, particularly within smaller, independent practices. The objective of this study was to evaluate the effect of a policy prohibiting prescription drug samples and pharmaceutical industry interaction on prescribing patterns in a rural family practice clinic in central Oregon. METHODS: Segmented linear regression models were used to evaluate trends in prescribing using locally obtained pharmacy claims. Oregon Medicaid pharmacy claims were used to control for secular prescribing changes. Total and class-specific monthly trends in branded, promoted, and average prescription drug costs were analyzed 18 months before and after policy implementation. RESULTS: Aggregate trends of brand name drug use did not change significantly after policy implementation. In aggregate, use of promoted agents decreased by 1.43% while nonpromoted branded agents increased by 3.04%. Branded drugs prescribed for respiratory disease declined significantly by 11.34% compared with a control group of prescribers. Relative to the control group, prescriptions of promoted cholesterol-lowering drugs and antidepressants were reduced by approximately 9.98% and 11.34%, respectively. The trend in average cost per prescription for lipid-lowering drugs was significantly reduced by $0.70 per prescription per month. Overall, average prescription drug costs increased by $5.18 immediately after policy implementation. CONCLUSIONS: Restriction of pharmaceutical industry representatives and samples from a rural family practice clinic produced modest reductions in branded drug use that varied by class. Although aggregate average costs increased, prescriptions for branded and promoted lipid-lowering agents and antidepressants were reduced. PMID- 20843883 TI - Quality of care for chronic diseases in a British cohort of long-term cancer survivors. AB - PURPOSE: Previous research has shown that long-term cancer survivors with other chronic diseases may receive poorer care for those diseases compared with the general population. We sought to establish the quality of care for chronic diseases among cancer survivors in the United Kingdom. METHODS: From the UK General Practice Research Database, we identified 21,366 adult patients who had survived 5 or more years after a diagnosis of breast, colorectal, or prostate cancer with a diagnosis of hypertension, coronary artery disease, diabetes, or cerebrovascular disease. For each patient, an age-sex matched noncancer control patient was selected from the same general practice and with the same chronic disease. We compared the chronic disease care in cancer survivors and their matched controls. RESULTS: The proportion of patients meeting quality standards for chronic disease care was high in both cancer survivors and control patients. Although cancer survivors were slightly less likely to receive blood pressure monitoring and cholesterol tests, this difference was no longer apparent if patients who died during the study period were excluded. For instance, 93% of breast cancer survivors received blood pressure monitoring compared with 94% of matched control patients. Similarly, control of disease was comparable among all patients, with the exception of diabetic prostate cancer survivors, who had fewer cholesterol readings under the control limit (17% reduction, 95% CI, 7%-26%) and diabetic colorectal survivors, who had fewer calendar quarters of glycated hemoglobin control (12% reduction, 95% CI, 2%-23%). CONCLUSIONS: Care of comorbidities is not neglected in the United Kingdom because people have had a previous diagnosis of cancer. One explanation is that in the United Kingdom, such care is provided through a robust primary care system. PMID- 20843884 TI - Using Learning Teams for Reflective Adaptation (ULTRA): insights from a team based change management strategy in primary care. AB - PURPOSE: The Using Learning Teams for Reflective Adaptation (ULTRA) study used facilitated reflective adaptive process (RAP) teams to enhance communication and decision making in hopes of improving adherence to multiple clinical guidelines; however, the study failed to show significant clinical improvements. The purpose of this study was to examine qualitative data from 25 intervention practices to understand how they engaged in a team-based collaborative change management strategy and the types of issues they addressed. METHODS: We analyzed field notes and interviews from a multimethod practice assessment, as well as field notes and audio-taped recordings from RAP meetings, using an iterative group process and an immersion-crystallization approach. RESULTS: Despite a history of not meeting regularly, 18 of 25 practices successfully convened improvement teams. There was evidence of improved practice-wide communication in 12 of these practices. At follow-up, 8 practices continued RAP meetings and found the process valuable in problem solving and decision making. Seven practices failed to engage in RAP primarily because of key leaders dominating the meeting agenda or staff members hesitating to speak up in meetings. Although the number of improvement targets varied considerably, most RAP teams targeted patient care-related issues or practice-level organizational improvement issues. Not a single practice focused on adherence to clinical care guidelines. CONCLUSION: Primary care practices can successfully engage in facilitated team meetings; however, leaders must be engaged in the process. Additional strategies are needed to engage practice leaders, particularly physicians, and to target issues related to guideline adherence. PMID- 20843885 TI - Ethics of health research in communities: perspectives from the southwestern United States. AB - PURPOSE: The increasing attention paid to community-based research highlights the question of whether human research protections focused on the individual are adequate to safeguard communities. We conducted a study to explore how community members perceive low-risk health research, the adequacy of human research protection processes, and the ethical conduct of community-based research. METHODS: Eighteen focus groups were conducted among rural and urban Hispanic and Native American communities in New Mexico using a semistructured guide. Group transcriptions were analyzed using iterative readings and coding, with review of the analytic summary by group members. RESULTS: Although participants recognized the value of health research, many also identified several adverse effects of research in their communities, including social (community and individual labeling, stigmatization, and discrimination) and economic (community job losses, increased insurance rates, and loss of community income). A lack of community beneficence was emphasized by participants who spoke of researchers who fail to communicate results adequately or assist with follow-through. Many group members did not believe current human research and data privacy processes were adequate to protect or assist communities. CONCLUSIONS: Ethical review of community-based health research should apply the Belmont principles to communities. Researchers should adopt additional approaches to community-based research by engaging communities as active partners throughout the research process, focusing on community priorities, and taking extra precautions to assure individual and community privacy. Plans for meaningful dissemination of results to communities should be part of the research design. PMID- 20843886 TI - Continuity and trust in primary care: a qualitative study informed by game theory. AB - PURPOSE: The relationship between continuity of care and patient trust in primary care is not fully understood. We report an empirical investigation, informed by game theory, of patients' accounts of their trust in general practitioners (GPs). METHODS: We conducted an analysis based on the constant comparative method of 20 semistructured interviews with patients about trust in GPs in the United Kingdom. RESULTS: People use institutional trust, derived from expectations of medicine as an institution and doctors as professionals, as a starting point for their transactions with unfamiliar doctors. This expectation may be enough to allow patients the minimum of what they want from doctors and is often sufficient for single-episode encounters, where patients have specific goals. Repeated interactions with the same doctor can allow patients to develop more secure expectations, based on a history of other interactions and anticipation of future interactions. Secure trust can develop over time, especially if patients are convinced that the doctor has their interests at heart. CONCLUSIONS: This work identifies dynamics inherent in repeated interactions that enable secure trust to develop. These findings have important implications for the design of services, which in the United Kingdom and elsewhere are increasingly focused on enhancing access rather than continuity. They suggest that patients do not see GPs as interchangeable and that the move toward organizing services around single encounters may disrupt the development of secure trust. PMID- 20843887 TI - Including socioeconomic status in coronary heart disease risk estimation. AB - PURPOSE: Socioeconomic status (SES) predicts coronary heart disease independently of the Framingham risk-scoring factors included in cholesterol treatment guidelines, possibly resulting in undertreatment of lower SES persons. We examined whether hybrid SES measures (based on area measures of income and individual education) address this bias and derived an approach to incorporating SES information into treatment guidelines. METHODS: The Atherosclerosis Risk in Communities study data (initiated in 1987 with a 10-year follow-up of 15,495 adults aged 45 to 64 years in 4 southern and midwestern communities) were used to assess the calibration bias of 4 Cox models predicting 10-year coronary heart disease risk: Framingham risk score alone, and Framingham risk score plus SES using an individual-based measure (income less than 150% federal poverty level or less then 12 years of schooling), and 2 hybrid SES measures substituting area based income measures (block group or zip code median incomes of less than 25th national percentiles) for the individual income component. Revised cholesterol treatment thresholds based on SES risk were also derived. RESULTS: Use of either the block group hybrid or individual-based SES measures eliminated the significant SES bias observed using Framingham risk score alone. Cholesterol treatment guideline thresholds of 10% and 20% coronary heart disease risk (based on the Framingham risk score) were reduced to 6% and 13% for those with low SES. CONCLUSIONS: Using patient income based on block group and individual education minimizes the SES bias in Framingham risk scoring and suggests more aggressive cholesterol treatment thresholds for low-SES persons. PMID- 20843888 TI - Capability and clinical success. AB - Better outcomes for chronic diseases remain elusive because success depends on events outside the control of the health care system: patients' ability to mange their health behaviors and chronic diseases. Among the most powerful influences on self-management are the social and environmental constraints on healthy living, yet the clinical response to these environmental determinants is poorly developed. A potential approach for addressing social determinants in practice, as well as planning and evaluating community responses, is the capability framework. Defined as the real opportunity to achieve a desired lifestyle, capability focuses attention on the material conditions that constrain real opportunity and how opportunity emerges from the interaction between personal resources and the social environment. Using examples relevant to chronic disease and behavior change, we discuss the clinical application of the capability framework. PMID- 20843889 TI - Losing touch in the era of superbugs? AB - Nosocomial infections are increasingly multidrug resistant and at times more virulent. As such, they pose real threats to patients and clinicians. In this essay the author discusses his own methacillin-resistant staphylococcus infection and how it has affected his work in the hospital. In so doing, he reflects on the value of touch in the doctor-patient relationship. In particular, he discusses how gloves serve as a barrier to infection but also create a small distance between the doctors and their patients. The implications of contact precautions must be considered as we reflect on balancing patient-centered care with infection control. PMID- 20843890 TI - ABFM announces further enhancements to MC-FP. PMID- 20843891 TI - The evolution of the STFM Foundation--an improved synergy between STFM and the STFM Foundation. PMID- 20843892 TI - Family medicine clerkship, tracks, and faculty support for family medicine education in Departments of Family Medicine: an update. PMID- 20843893 TI - Residency "dashboard": family medicine GME's step towards transparency and accountability? PMID- 20843894 TI - Involving community residency programs in research: the Residency Research Network of Texas. PMID- 20843895 TI - Final definition of 'meaningful use' of EHRs modified based on AAFP comments. PMID- 20843896 TI - Viability of equine embryos after puncture of the capsule and biopsy for preimplantation genetic diagnosis. AB - The equine embryo possesses a capsule that is considered essential for its survival. We assessed viability after breaching the capsule of early (Day 6) and expanded (Day 7 and 8) equine blastocysts by micromanipulation. The capsule was penetrated using a Piezo drill, and trophoblast biopsy samples were obtained for genetic analysis. Pregnancy rates for Day-6 embryos, which had intact zonae pellucidae at the time of recovery, were 3/3 for those biopsied immediately after recovery and 2/3 for those biopsied after being shipped overnight under warm (~28 degrees C) conditions. The pregnancy rates for encapsulated Day-7 expanded blastocysts were 5/6 for those biopsied immediately and 5/6 for those biopsied after being shipped overnight warm. Two of four encapsulated Day-8 blastocysts, 790 and 1350 MUm in diameter, established normal pregnancies after biopsy. Nine mares were allowed to maintain pregnancy, and they gave birth to nine normal foals. Biopsied cells from eight embryos that produced foals were subjected to whole-genome amplification. Sex was successfully determined from amplified DNA in 8/8 embryos. Identification of disease-causing mutations matched in the analyses of 6/6 samples for the sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) gene and in 6/7 samples for the peptidylprolyl isomerase B (PPIB) gene, in embryo-foal pairs. Thus, the capsule of the equine embryo can be breached without impairing viability. Further work is needed to determine whether this breach is transient or permanent. These findings are relevant to the understanding of equine embryo development and to the establishment of methods for micromanipulation and embryo cryopreservation in this species. PMID- 20843897 TI - Exposure to hexavalent chromium resulted in significantly higher tissue chromium burden compared with trivalent chromium following similar oral doses to male F344/N rats and female B6C3F1 mice. AB - In National Toxicology Program 2-year studies, hexavalent chromium [Cr(VI)] administered in drinking water was clearly carcinogenic in male and female rats and mice, resulting in small intestine epithelial neoplasms in mice at a dose equivalent to or within an order of magnitude of human doses that could result from consumption of chromium-contaminated drinking water, assuming that dose scales by body weight(3/4) (body weight raised to the 3/4 power). In contrast, exposure to trivalent chromium [Cr(III)] at much higher concentrations may have been carcinogenic in male rats but was not carcinogenic in mice or female rats. As part of these studies, total chromium was measured in tissues and excreta of additional groups of male rats and female mice. These data were used to infer the uptake and distribution of Cr(VI) because Cr(VI) is reduced to Cr(III) in vivo, and no methods are available to speciate tissue chromium. Comparable external doses resulted in much higher tissue chromium concentrations following exposure to Cr(VI) compared with Cr(III), indicating that a portion of the Cr(VI) escaped gastric reduction and was distributed systemically. Linear or supralinear dose responses of total chromium in tissues were observed following exposure to Cr(VI), indicating that these exposures did not saturate gastric reduction capacity. When Cr(VI) exposure was normalized to ingested dose, chromium concentrations in the liver and glandular stomach were higher in mice, whereas kidney concentrations were higher in rats. In vitro studies demonstrated that Cr(VI), but not Cr(III), is a substrate of the sodium/sulfate cotransporter, providing a partial explanation for the greater absorption of Cr(VI). PMID- 20843898 TI - The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed in a subpopulation of mature cortical interneurons characterized by reduced structural features and connectivity. AB - Principal neurons in the adult cerebral cortex undergo synaptic, dendritic, and spine remodeling in response to different stimuli, and several reports have demonstrated that the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) participates in these plastic processes. However, there is only limited information on the expression of this molecule on interneurons and on its role in the structural plasticity of these cells. We have found that PSA-NCAM is expressed in mature interneurons widely distributed in all the extension of the cerebral cortex and have excluded the expression of this molecule in most principal cells. Although PSA-NCAM expression is generally considered a marker of immature neurons, birth-dating analyses reveal that these interneurons do not have an adult or perinatal origin and that they are generated during embryonic development. PSA-NCAM expressing interneurons show reduced density of perisomatic and peridendritic puncta expressing different synaptic markers and receive less perisomatic synapses, when compared with interneurons lacking this molecule. Moreover, they have reduced dendritic arborization and spine density. These data indicate that PSA-NCAM expression is important for the connectivity of interneurons in the adult cerebral cortex and that its regulation may play an important role in the structural plasticity of inhibitory networks. PMID- 20843899 TI - Attentional load asymmetrically affects early electrophysiological indices of visual orienting. AB - Recent behavioral studies suggest that asymmetries in visuospatial orienting are modulated by changes in the demand on nonspatial components of attention, but the brain correlates of this modulation are unknown. We used scalp-recorded event related potentials to examine the influence of central attentional load on neural responses to lateralized visual targets. Forty-five participants were required to detect transient, unilateral visual targets while monitoring a stream of alphanumeric stimuli at fixation, in which the target was defined either by a unique feature (low load) or by a conjunction of features (high load). The earliest effect of load on spatial orienting was seen at the latency of the posterior N1 (190-240 ms). The commonly observed N1 enhancement with contralateral visual stimulation was attenuated over the right hemisphere under high load. Source analysis localized this effect to occipital and inferior parietal regions of the right hemisphere. In addition, we observed perceptual enhancement with increasing load within the focus of attention (fixation) at an earlier stage (P1, 90-140 ms) than has previously been reported. These data support the view that spatial asymmetries in visual orienting are modulated by nonspatial attention due to overlapping neural circuits within the right hemisphere. PMID- 20843901 TI - Determinants of early radiographic progression in ankylosing spondylitis. AB - OBJECTIVE: To investigate the demographic and clinical characteristics associated with early, extensive radiographic changes in ankylosing spondylitis (AS). METHODS: Radiographic severity was assessed cross-sectionally in 235 patients with AS using the Bath AS Radiological Index spine score (BASRI-s). Patients with extensive radiographic changes on the lumbar portion of BASRI-s were defined as the early axial ankylosis (EAA) Group. ANCOVA and logistic regression analyses were used to identify factors affecting EAA. RESULTS: Most study patients were men (139/235, 59.0%). Mean disease duration was 12.4 +/- 9.3 years. Fifteen percent of women and 34.8% of men with AS were in the EAA group. HLA-B27-positive men with AS had significantly higher BASRI-lumbar scores, while HLA-B27 had no effect on radiographic progression of axial disease in women with AS. Peripheral joint involvement was associated with slow radiographic progression. Hip involvement had no effect on axial progression but uveitis was more frequent in the male EAA group. The odds for an HLA-B27-positive male patient with AS who did not have peripheral arthritis of having a BASRI-lumbar score of 3 or higher were 3.4 (77% chance to have axially progressive disease). Presence of uveitis increased these odds to 93%. Only 15% of female patients with AS had EAA, and the absence of peripheral arthritis was the only clinical measure associated with EAA in this group. CONCLUSION: EAA was more frequent in men with AS than in women. Absence of peripheral arthritis, HLA-B27 positivity, and uveitis were associated with multiple syndesmophytes or fusion of multiple vertebrae of the lumbar vertebrae. PMID- 20843900 TI - Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia. AB - Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic gamma-aminobutyric acid (GABA(A)) receptors containing different alpha subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of alpha1, alpha2, alpha3, and alpha5 subunit, and of beta1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA(A) alpha1 mRNA expression was 17% lower in layers 3 and 4, alpha2 expression was 14% higher in layer 2, alpha5 expression was 15% lower in layer 4, and alpha3 expression did not differ relative to comparison subjects. The mRNA expression of beta2, which preferentially assembles with alpha1 subunits, was also 20% lower in layers 3 and 4, whereas beta1 and beta3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits. PMID- 20843902 TI - The Hawthorne effect, sponsored trials, and the overestimation of treatment effectiveness. AB - OBJECTIVE: To determine if the results of rheumatoid arthritis (RA) clinical trials are upwardly biased by the Hawthorne effect. METHODS: We studied 264 patients with RA who completed a commercially sponsored 3-month, open-label, phase 4 trial of a US Food and Drug Administration approved RA treatment. We evaluated changes in the Health Assessment Questionnaire disability index (HAQ) and visual analog scales for pain, patient global, and fatigue during 3 periods: pretreatment in the trial, on treatment at the close of the trial, and by a trial unrelated survey 8 months after the close of the trial, but while the patients were receiving the same treatment. RESULTS: The HAQ score (0-3) improved by 41.3% during the trial, but only by 16.5% when the endpoint was the post-trial result. Similar results for the other variables were patient global (0-10) 51.9% and 34.6%, pain (0-10) 51.7% and 39.7%, fatigue (0-10) 45.6% and 24.6%. Worsening between the trial end and the first survey assessment was HAQ 0.29 units, pain 0.8 units, patient global 0.8 units, and fatigue 1.1 units. CONCLUSION: Almost half the improvement noted in the clinical trial HAQ score disappeared on entry to a non-sponsored followup study, and from 23% to 44% of improvements in pain, patient global, and fatigue also disappeared. These changes can be attributed to the Hawthorne effect. Based on these data, we hypothesize that the absolute values of RA outcome variables in clinical trials are upwardly biased, and that the treatment effect is less than observed. PMID- 20843903 TI - Temporal association of Streptococcus, Staphylococcus, and parainfluenza pediatric hospitalizations and hospitalized cases of Henoch-Schonlein purpura. AB - OBJECTIVE: To determine if hospitalizations for specific infectious exposures are associated with hospital admissions for Henoch-Schonlein purpura (HSP). METHODS: We conducted a retrospective cohort study using administrative data of children admitted to 40 children's hospitals between January 1, 2002, and December 31, 2008. We examined the association of standardized rates of group A beta-hemolytic Streptococcus (GABS), Staphylococcus aureus, parainfluenza, influenza, adenovirus, and respiratory syncytial virus (RSV)-associated hospital admissions with standardized rates of HSP hospital admissions on a month by month basis using autoregressive moving average process models to account for temporal autocorrelation and clustering by hospital. RESULTS: Among the 3,132 admissions for HSP observed over the 7-year study period, hospital admissions were most frequent September through April, but with substantial variability between hospitals for each month. Accounting for these month by month differences within each hospital, the rate of HSP admissions in a given month increased significantly as the standardized rates of GABS (p = 0.01), S. aureus (p < 0.01), and parainfluenza (p = 0.03) admissions increased. CONCLUSION: Our results demonstrate a local month by month temporal association between hospitalization for GABS, S. aureus, and parainfluenza and hospitalization for HSP. Future investigations will be required to determine causality. PMID- 20843904 TI - Prospective evaluation of clinical and ultrasound findings in ankle disease in juvenile idiopathic arthritis: importance of ankle ultrasound. AB - OBJECTIVE: To prospectively compare clinical examination of the ankle structures with ultrasound (US) findings. METHODS: In 42 children with juvenile idiopathic arthritis (JIA; 25 girls, 17 boys, mean age 11.3 yrs, range 2.3-22.3 yrs), a total of 61 swollen/painful ankles were assessed clinically and ultrasonographically. Accurate clinical examination of the entire ankle joint was performed, focusing especially on 3 regions - tibiotalar joint and medial and lateral tendons. Clinical and US findings were both scored 0-3 (normal-severe). RESULTS: US demonstrated no signs of tibiotalar joint effusion in 14 out of 43 ankles considered clinically involved. For the medial tendons, US showed tenosynovitis in 13 ankles out of 31 thought to be clinically normal; and for the lateral tendons, of the 19 deemed to be clinically involved, less than 50% had involvement on US. Very poor agreement was observed comparing the clinical and US scores for the 3 regions: tibiotalar joint, kappa = 0.3; medial tendons, kappa = 0.24; lateral tendons, kappa = 0.25. With regard to other ankle structures, only 39% of the subtalar (talocalcaneal) joints considered clinically involved were deemed abnormal on US. Finally, of the 10 ankles with talonavicular US effusion, only 2 were considered clinically involved. CONCLUSION: Using US findings as the "gold standard," clinical examination of the ankle in children with JIA was found to be inadequate in identifying the structures involved. US assessment prior to any glucocorticoid injection should be considered to improve the outcome. A prospective study comparing the outcome following clinical- versus US-guided ankle joint injection should be undertaken, to confirm our findings. PMID- 20843905 TI - Characteristics of patients with juvenile onset systemic sclerosis in an adult single-center cohort. AB - OBJECTIVE: Systemic sclerosis (SSc) is a rare connective tissue disease in childhood. We compared the characteristics of adult patients with juvenile-onset SSc (jSSc) from a single-center cohort to an adult-onset group. METHODS: Patients with disease onset before the age of 17 years were included in the jSSc cohort, while subjects with SSc onset after age 17 formed the adult-onset cohort. RESULTS: We identified 52 adult subjects with jSSc and compared them to 954 patients with adult-onset SSc. The mean +/- SD age at disease onset of the patients with jSSc was 14 +/- 2 years, 39 (75%) of them were women, and 24 (46%) had the diffuse cutaneous subset of SSc (dcSSc). There were no differences between the 2 cohorts in terms of sex and disease subset. Overlaps were significantly more frequent among the jSSc cohort (37%) compared to the adult onset group (18%; p = 0.002). Autoantibody analysis demonstrated significantly more antitopoisomerase I antibody-positive subjects (33% vs 20%; p = 0.034) and significantly fewer anticentromere antibody-positive subjects (2% vs 25%; p < 0.001) in the jSSc cohort. Compared to the adult-onset group at 10 years from disease onset, survival was significantly higher among the subjects with jSSc (98% vs 75%; p = 0.001), pulmonary arterial hypertension had a significantly lower incidence (2% vs 14%; p = 0.032), and there was no difference in terms of pulmonary fibrosis (22% vs 21%) and cardiac scleroderma (3% vs 2%) between the 2 groups. CONCLUSION: The high survival rates and lower proportion of dcSSc in the adult jSSc cohort may represent a survival bias. PMID- 20843906 TI - High DNA oxidative damage in systemic sclerosis. AB - OBJECTIVE: Several lines of evidence suggest that the generation of reactive oxygen species (ROS) is of major importance in the pathogenesis of SSc. Protein and lipid damage have previously been demonstrated, but scarce data are available on oxidative damage to DNA. In patients with SSc, we evaluated levels of 8 hydroxy-2'-deoxyguanosine (8-oxodG), the main validated biomarker of endogenous oxidative damage to DNA, compared to levels of F2-isoprostane, a product of free radical-mediated peroxidation of arachidonic acid. METHODS: Urinary levels of 8 oxodG and 8-isoprostaglandin-F(2alpha) (8-iso-PGF(2alpha)) were determined by competitive ELISA method in consecutive SSc patients and controls matched for age and sex. RESULTS: We included 80 unrelated SSc patients (72 women, mean age 56 +/ 11 yrs) and 39 controls (33 women, mean age 64 +/- 8 yrs). Urinary levels of 8 oxodG/creat and 8-iso-PGF(2alpha)/creat in SSc patients were found to be higher than in controls (6.5 ng/mg vs 3.7 ng/mg, p = 0.0001; and 11.4 ng/mg vs 4.2 ng/mg, p < 0.0001). In multivariate analysis, 8-oxodG levels were associated with the presence of pulmonary fibrosis on computerized tomography scan, decreased forced vital capacity, and decreased DLCO/alveolar volume. In patients with the diffuse cutaneous subset, a modified Rodnan skin score > 14 was independently associated with 8-oxodG levels. In SSc, 8-oxodG and 8-iso-PGF(2alpha) values were correlated (r = 0.32; p = 0.005). CONCLUSION: Our study confirmed marked oxidative stress in SSc. We also found increased values of 8-oxodG in SSc patients and a relevant association with a fibrotic phenotype. The predictive value of this marker and its potential influence on fibrotic disturbances remain to be determined. PMID- 20843907 TI - Discordance between patient and physician assessments of disease severity in systemic sclerosis. AB - OBJECTIVE: To describe the magnitude and correlates of discordance between patient and physician assessments of disease severity in patients with systemic sclerosis (SSc). METHODS: Subjects were patients enrolled in the Canadian Scleroderma Research Group Registry. The outcomes of interest were patient and physician global assessments of disease severity (scales ranging from 0-10). Predictors of disease severity represented the spectrum of disease in SSc (skin involvement, severity of Raynaud's phenomenon, shortness of breath, gastrointestinal symptoms and pain, number of fingertip ulcers, tender and swollen joints, creatinine, and fatigue). The results of the analysis were validated in an independent sample of patients with SSc from the United States. RESULTS: Patients perceived greater disease severity than physicians (mean difference 0.78 +/- 2.65). The agreement between patient and physician assessments of disease severity was, at best, modest (intraclass correlation 0.3774; weighted kappa 0.3771). Although both patients and physicians were influenced by skin scores, breathlessness, and pain, the relative importance of these predictors differed. Patients were also influenced by other subjective symptoms, while physicians were also influenced by disease duration and creatinine. The predictors explained 56% of the deviance in the patient global assessments and 29% in the physician assessments. These findings were confirmed in the US dataset. CONCLUSION: Patients and physicians rate SSc disease severity differently in magnitude and are influenced by different factors. Patient assessed and physician-assessed measures of severity should be considered as complementary and used together in future studies of SSc. PMID- 20843908 TI - Comparative analysis of disease activity measures, use of biologic agents, body mass index, radiographic features, and bone density in psoriatic arthritis and rheumatoid arthritis patients followed in a large U.S. disease registry. AB - OBJECTIVE: To compare disease activity, radiographic features, and bone density in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) matched cohorts. METHODS: Disease activity and radiographic data in the Consortium of Rheumatology Researchers of North America database from 2001 to 2008 were compared for 2481 patients with PsA and 17,107 patients with RA subsequently matched for age, gender, and disease duration. Radiographic outcomes included presence of erosions, and joint deformity. In addition, bone mineral density (BMD) scores for lumbar spine (L-spine) and femoral neck were compared using the same matching criteria plus weight and smoking status. RESULTS: Tender (4.5 vs 3.4, p < 0.001) and swollen (4.4 vs 2.9, p < 0.012) joint counts, and modified Health Assessment Questionnaire scores were significantly higher (0.4 vs 0.3, p < 0.001) in patients with RA compared with patients with PsA. Patient general health and pain scores were also higher in patients with RA vs patients with PsA. Joint erosions (47.4% vs 37.6%, p = 0.020) and deformity (25.2% vs 21.6%, p = 0.021) were more prevalent in RA than PsA. In multivariate analysis, a reduced prevalence of erosions in PsA vs RA was noted (OR 0.609, p < 0.001). After matching, T-scores for L-spine (-0.54 vs -0.36, p = 0.077) and femoral neck (-0.88 vs -0.93, p = 0.643) were similar in patients with RA and patients with PsA, although body weight was a major confounder. CONCLUSION: The level of disease activity and radiographic damage was significantly higher for RA vs PsA subjects, although the magnitude of differences was relatively small. BMD levels were comparable between cohorts. Outcomes in patients with PsA and patients with RA may be more similar than previously reported. PMID- 20843909 TI - En coup de sabre scleroderma and Parry-Romberg syndrome in adolescents: surgical options and patient-related outcomes. AB - OBJECTIVE: There is little information regarding surgical options and outcomes in patients with facial localized scleroderma. We evaluated the surgical outcomes of procedures performed for linear scleroderma of the face in the pediatric age group; and assessed psychosocial effects of surgical interventions on the affected children. METHODS: A retrospective chart review was performed of children with en coup de sabre scleroderma (ECDS) and Parry-Romberg syndrome (PRS) who underwent surgical intervention; this included demographic data, clinical features, and type of surgical interventions. A questionnaire of 13 questions covering 4 domains (physical, emotional, social, and symptoms) was sent to patients who consented to take part in the survey. Surgical treatments and outcomes were analyzed retrospectively. RESULTS: Seventeen patients underwent surgical intervention (autologous fat injections, Medpor implants, bone paste cranioplasty, and free groin flap) to correct facial asymmetry. Ten patients answered the questionnaire (58.8% response rate). Unhappiness with their appearance, loss of confidence, and bullying were cited as reasons for surgery. The appearance subscale of the survey demonstrated the lowest standardized scores and greatest negative effect on the patients' quality of life compared to the 3 other subscales. All subjects would consider another surgery and would recommend surgery to other patients with ECDS and PRS. CONCLUSION: Surgical treatment is a potential useful intervention in children with facial disfigurement. Prospective data are needed. PMID- 20843910 TI - Canadian variation by province in rheumatoid arthritis initiating anti-tumor necrosis factor therapy: results from the optimization of adalimumab trial. AB - OBJECTIVE: We compared variations among Canadian provinces in rheumatoid arthritis (RA) initiating anti-tumor necrosis factor (TNF) therapy. METHODS: Data were obtained from the Optimization of Humira trial (OH) and from the Ontario Biologics Research Initiative (OBRI). Baseline characteristics were compared between regions: Ontario (ON), Quebec (QC), and other provinces (OTH). We compared Ontario OH to OBRI patients who were initiating anti-TNF therapy. RESULTS: In 300 OH patients, mean age was 54.8 years (13.3). There were 151 (50.3%) ON patients, 57 from QC (19%), and 92 from OTH (30.7%). Regional differences were seen in the number of disease-modifying antirheumatic drugs (DMARD) ever taken (ON: 3.8 +/- 1.4, QC: 3.1 +/- 1.1, OTH: 3.3 +/- 1.4; p < 0.001); swollen joint count (SJC; ON: 10.9 +/- 5.9, QC: 9.0 +/- 4.4, OTH: 11.3 +/ 5.6; p = 0.033); tender joint count (TJC; ON: 12.2 +/- 7.5, QC: 10.3 +/- 5.7, OTH: 14.4 +/- 7.6; p = 0.003); 28-joint Disease Activity Score (DAS28; ON: 5.8 +/ 1.2, QC: 5.6 +/- 1.0, OTH: 6.0 +/- 1.1; p = 0.076); and Health Assessment Questionnaire (ON: 1.4 +/- 0.7, QC: 1.7 +/- 0.7, OTH: 1.5 +/- 0.7; p = 0.060). DMARD-ever use differed: methotrexate (ON: 94.7%, QC: 93%, OTH: 84.8%; p = 0.025); leflunomide (ON: 74.8%, QC: 21.1%, OTH: 51.1%; p < 0.001); sulfasalazine (ON: 51%, QC: 38.6%, OTH: 25%; p < 0.001); myochrysine (ON: 9.3%, QC: 0%, OTH: 15.2%; p = 0.008); and hydroxychloroquine (ON: 67.5%, QC: 86%, OTH: 66.3%; p = 0.018). In comparison to ON OH patients, 95 OBRI patients initiating first anti TNF had lower SJC (p = 0.017), TJC (p = 0.008), and DAS28 (p = 0.05). CONCLUSION: In Quebec, where access to anti-TNF is less restrictive, patients had lower SJC and TJC. ON used more DMARD, especially leflunomide, as mandated by the provincial government. Both provincial funding criteria and prescribing habits may contribute to differences. Canadian rheumatologists may vary in treatment decisions, but patients generally have similar DAS28 when initiating anti-TNF therapy. PMID- 20843911 TI - Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double blind, placebo-controlled trial. AB - OBJECTIVE: To investigate the efficacy of flexible dose duloxetine 60-120 mg/day on changes in fibromyalgia (FM) symptoms assessed by the Patient Global Impression of Improvement (PGI-I) scale. METHODS: Outpatients >= 18 years of age who met American College of Rheumatology criteria for FM, and had >= 4 score on the Brief Pain Inventory (BPI) average pain item, were randomized to duloxetine (n = 263) or placebo (n = 267) for 24 week double-blind treatment (primary endpoint at Week 12). Key secondary measures included BPI average pain severity, patient-rated scales assessing mood, anxiety, pain, sleep, and stiffness, Clinical Global Impression of Severity (CGI-S), Multidimensional Fatigue Inventory, Cognitive and Physical Functioning Questionnaire, Beck Depression Inventory (BDI), Beck Anxiety Inventory, and Medical Outcome Study Short-Form Health Survey (SF-36). RESULTS: At Week 12, duloxetine-treated patients reported significantly greater global improvement with mean PGI-I scores of 2.8 compared to 3.4 in the placebo group (p < 0.001). Significantly more duloxetine- versus placebo-treated patients (57% vs 32%; p < 0.001) reported feeling "much" or "very much better" (PGI-I score <= 2). There was significantly greater improvement with duloxetine versus placebo treatment in BPI average pain severity, mood (including BDI total), anxiety (patient-rated only), stiffness, CGI-S, fatigue, all SF-36 domains (except role-physical and physical component summary), and being less bothered by pain or sleep difficulties. Treatment-emergent adverse events occurring significantly more frequently with duloxetine included: nausea, headache, constipation, dry mouth, dizziness, diarrhea, and hyperhidrosis. CONCLUSION: Treatment with duloxetine 60, 90, and 120 mg/day was associated with feeling much better, pain reduction, being less bothered by sleep difficulties, and improvement in mood, stiffness, fatigue and functioning. (Clinical trial registry NCT00673452). PMID- 20843912 TI - Interleukin 6 gene polymorphisms are associated with systemic lupus erythematosus in Koreans. AB - OBJECTIVE: Interleukin 6 (IL-6) gene polymorphisms are known to play a role in chronic inflammatory disorders. We searched for polymorphisms in the IL-6 gene and described their pathogenic role in Korean patients with systemic lupus erythematosus (SLE). METHODS: Genomic DNA was extracted from 151 patients with SLE and 151 controls, and about 1.4 kb-sized IL-6 genes located between promoter region and exon 2 region were amplified by polymerase chain reaction. The promoter activity was analyzed by luciferase reporter assay in Hep3B cells and HeLa cells. RESULTS: We identified 4 single-nucleotide polymorphisms (SNP; -572 C > G, -278 A > C in the promoter, and 330 T > G, and 334 A > T in exon 2) and a 373 A(n)T(n) tract polymorphism in the IL-6 gene. The genotype frequency, -373 A(10)T(11), -278 C, and 334 T allele were significantly associated with SLE (p < 0.001, p = 0.03 and p = 0.005, respectively). Patients with SLE carrying the -572 G allele had anti-dsDNA more frequently (p = 0.007). In addition, thrombocytopenia was significantly more common in patients carrying the -278 C allele (p = 0.006). In the haplotype analysis, patients with SLE had more frequently haplotype HT3 (CA(10)T(11)ATA, dominant model, p = 0.012) that was associated with arthritis, leukopenia, anti-dsDNA, and hypocomplementemia. Promoter reporter structures carrying the -278 C allele displayed significantly higher promoter activity than the -278 A allele in Hep3B cells (p < 0.001) and HeLa cells (p < 0.001). CONCLUSION: These data suggest that IL-6 gene polymorphisms are associated with disease susceptibility and phenotype of SLE. In addition, promoter polymorphisms may be involved in regulation of IL-6 expression. PMID- 20843913 TI - Incident comorbidity among patients with rheumatoid arthritis treated or not with low-dose glucocorticoids: a retrospective study. AB - OBJECTIVE: To assess the prevalence of comorbidity in a cohort of patients with rheumatoid arthritis (RA), treated or not with low-dose glucocorticoids (GC) and who have been followed for at least 10 years. METHODS: This was a retrospective study by review of medical records. RESULTS: We identified 365 patients: 297 (81.3%) were GC users (4-6 mg methylprednisolone daily) and 68 (18.7%) were nonusers. We found that fragility fractures occurred in 18.2% of GC users and in 6.0% of GC nonusers (p < 0.02); arterial hypertension in 32.3% of GC users and in 10.4% of GC nonusers (p < 0.0005); acute myocardial infarction in 13.1% of GC users and in 1.5% of the nonusers (p < 0.01). Prevalence of diabetes mellitus, cataract, and infections was comparable. We divided GC users into groups of different duration of GC therapy: < 2, 2-5, and > 5 years; the mean duration of GC treatment was 1.3 +/- 0.5, 3.6 +/- 1.1, and 12.1 +/- 5.1 years, respectively. GC treatment for > 5 years was associated with significantly higher prevalence of fragility fractures (26.6%; p < 0.001 vs the other groups), arterial hypertension (36.7%; p < 0.0002 vs nonusers and GC users < 2 years), myocardial infarction (16.1%; p < 0.01 vs nonusers), and infections (9.7%; p < 0.005 vs the other groups). GC treatment for 2-5 years was associated with a significantly higher prevalence of arterial hypertension (30.0%; p < 0.01) compared to nonusers. CONCLUSION: Patients with RA treated with low-dose GC compared to patients never treated with GC show a higher prevalence of fractures, arterial hypertension, myocardial infarction, and serious infections, especially after 5 years of GC treatment. The high prevalence of myocardial infarction and fractures in patients with RA suggests that a more accurate identification of risk factors and prevention measures should be adopted when longterm GC treatment is needed. PMID- 20843915 TI - Calcium and heart attacks. Editorial was confusing. PMID- 20843917 TI - Calcium and heart attacks. The heart of the matter. PMID- 20843918 TI - Calcium and heart attacks. No evidence for increased risk. PMID- 20843914 TI - Paracetamol use in early life and asthma: prospective birth cohort study. AB - OBJECTIVE: To determine if use of paracetamol in early life is an independent risk factor for childhood asthma. DESIGN: Prospective birth cohort study. SETTING: Melbourne Atopy Cohort Study. PARTICIPANTS: 620 children with a family history of allergic disease, with paracetamol use prospectively documented on 18 occasions from birth to 2 years of age, followed until age 7 years. MAIN OUTCOME MEASURES: The primary outcome was childhood asthma, ascertained by questionnaire at 6 and 7 years. Secondary outcomes were infantile wheeze, allergic rhinitis, eczema, and skin prick test positivity. RESULTS: Paracetamol had been used in 51% (295/575) of children by 12 weeks of age and in 97% (556/575) by 2 years. Between 6 and 7 years, 80% (495/620) were followed up; 30% (148) had current asthma. Increasing frequency of paracetamol use was weakly associated with increased risk of childhood asthma (crude odds ratio 1.18, 95% confidence interval 1.00 to 1.39, per doubling of days of use). However, after adjustment for frequency of respiratory infections, this association essentially disappeared (odds ratio 1.08, 0.91 to 1.29). Paracetamol use for non-respiratory causes was not associated with asthma (crude odds ratio 0.95, 0.81 to 1.12). CONCLUSIONS: In children with a family history of allergic diseases, no association was found between early paracetamol use and risk of subsequent allergic disease after adjustment for respiratory infections or when paracetamol use was restricted to non-respiratory tract infections. These findings suggest that early paracetamol use does not increase the risk of asthma. PMID- 20843919 TI - Calcium and heart attacks. Making too much of a weak case. PMID- 20843920 TI - Calcium and heart attacks. Doesn't apply to most calcium prescriptions. PMID- 20843921 TI - "Cherry picking" did not occur in studied example. PMID- 20843922 TI - Length of treatment. Three questions for prescribers. PMID- 20843923 TI - Access to artificial hips. Using PROMs to improve equity. PMID- 20843924 TI - Access to artificial hips. Is still inequitable. PMID- 20843925 TI - Health in Developing Countries. Toiling for toilets. PMID- 20843926 TI - WHO calls for better access to medical devices in poor nations. PMID- 20843927 TI - Maternal mortality fell by a third over 18 years, says UN. PMID- 20843928 TI - New GP consortiums should cover 500,000 patients, says RCGP. PMID- 20843929 TI - An agitated man with earache. PMID- 20843932 TI - Is there a role for revascularisation in asymptomatic carotid stenosis? Yes. PMID- 20843933 TI - Is there a role for revascularisation in asymptomatic carotid stenosis? No. PMID- 20843934 TI - NICE approves liraglutide for diabetic patients not achieving glucose control. PMID- 20843935 TI - Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. AB - OBJECTIVE: To determine the relation between concentrations of prostate specific antigen at age 60 and subsequent diagnosis of clinically relevant prostate cancer in an unscreened population to evaluate whether screening for prostate cancer and chemoprevention could be stratified by risk. DESIGN: Case-control study with 1:3 matching nested within a highly representative population based cohort study. SETTING: General population of Sweden taking part in the Malmo Preventive Project. Cancer registry at the National Board of Health and Welfare. PARTICIPANTS: 1167 men aged 60 who provided blood samples in 1981 and were followed up to age 85. MAIN OUTCOME MEASURES: Metastasis or death from prostate cancer. RESULTS: The rate of screening during the course of the study was low. There were 43 cases of metastasis and 35 deaths from prostate cancer. Concentration of prostate specific antigen at age 60 was associated with prostate cancer metastasis (area under the curve 0.86, 95% confidence interval 0.79 to 0.92; P<0.001) and death from prostate cancer (0.90, 0.84 to 0.96; P<0.001). The greater the number for the area under the curve (values from 0 to 1) the better the test. Although only a minority of the men with concentrations in the top quarter (>2 ng/ml) develop fatal prostate cancer, 90% (78% to 100%) of deaths from prostate cancer occurred in these men. Conversely, men aged 60 with concentrations at the median or lower (<=1 ng/ml) were unlikely to have clinically relevant prostate cancer (0.5% risk of metastasis by age 85 and 0.2% risk of death from prostate cancer). CONCLUSIONS: The concentration of prostate specific antigen at age 60 predicts lifetime risk of metastasis and death from prostate cancer. Though men aged 60 with concentrations below the median (<=1 ng/ml) might harbour prostate cancer, it is unlikely to become life threatening. Such men could be exempted from further screening, which should instead focus on men with higher concentrations. PMID- 20843936 TI - Screening for prostate cancer. PMID- 20843937 TI - Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVE: To examine the evidence on the benefits and harms of screening for prostate cancer. DESIGN: Systematic review and meta-analysis of randomised controlled trials. DATA SOURCES: Electronic databases including Medline, Embase, CENTRAL, abstract proceedings, and reference lists up to July 2010. Review methods Included studies were randomised controlled trials comparing screening by prostate specific antigen with or without digital rectal examination versus no screening. Data abstraction and assessment of methodological quality with the GRADE approach was assessed by two independent reviewers and verified by the primary investigator. Mantel-Haenszel and inverse variance estimates were calculated and pooled under a random effects model expressing data as relative risks and 95% confidence intervals. RESULTS: Six randomised controlled trials with a total of 387 286 participants that met inclusion criteria were analysed. Screening was associated with an increased probability of receiving a diagnosis of prostate cancer (relative risk 1.46, 95% confidence interval 1.21 to 1.77; P<0.001) and stage I prostate cancer (1.95, 1.22 to 3.13; P=0.005). There was no significant effect of screening on death from prostate cancer (0.88, 0.71 to 1.09; P=0.25) or overall mortality (0.99, 0.97 to 1.01; P=0.44). All trials had one or more substantial methodological limitations. None provided data on the effects of screening on participants' quality of life. Little information was provided about potential harms associated with screening. CONCLUSIONS: The existing evidence from randomised controlled trials does not support the routine use of screening for prostate cancer with prostate specific antigen with or without digital rectal examination. PMID- 20843939 TI - A predictive ligand-based Bayesian model for human drug-induced liver injury. AB - Drug-induced liver injury (DILI) is one of the most important reasons for drug development failure at both preapproval and postapproval stages. There has been increased interest in developing predictive in vivo, in vitro, and in silico models to identify compounds that cause idiosyncratic hepatotoxicity. In the current study, we applied machine learning, a Bayesian modeling method with extended connectivity fingerprints and other interpretable descriptors. The model that was developed and internally validated (using a training set of 295 compounds) was then applied to a large test set relative to the training set (237 compounds) for external validation. The resulting concordance of 60%, sensitivity of 56%, and specificity of 67% were comparable to results for internal validation. The Bayesian model with extended connectivity functional class fingerprints of maximum diameter 6 (ECFC_6) and interpretable descriptors suggested several substructures that are chemically reactive and may also be important for DILI-causing compounds, e.g., ketones, diols, and alpha-methyl styrene type structures. Using Smiles Arbitrary Target Specification (SMARTS) filters published by several pharmaceutical companies, we evaluated whether such reactive substructures could be readily detected by any of the published filters. It was apparent that the most stringent filters used in this study, such as the Abbott alerts, which captures thiol traps and other compounds, may be of use in identifying DILI-causing compounds (sensitivity 67%). A significant outcome of the present study is that we provide predictions for many compounds that cause DILI by using the knowledge we have available from previous studies. These computational models may represent cost-effective selection criteria before in vitro or in vivo experimental studies. PMID- 20843938 TI - Obesity, inflammatory markers, and endometrial cancer risk: a prospective case control study. AB - Obesity, a major risk factor for endometrial cancer, is a low-grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first to investigate the associations of C-reactive protein (CRP), interleukin 6 (IL6), and IL1 receptor antagonist (IL1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case-control study, nested within the European Prospective Investigation into Cancer and Nutrition, which comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL6, and IL1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided, and P values <0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio (OR) for top versus bottom quartile: 1.58, 95% confidence interval (CI): 1.03 2.41, P(trend)=0.02), IL6 (OR for top versus bottom quartile: 1.66, 95% CI: 1.08 2.54, P(trend)=0.008), and IL1Ra (OR for top versus bottom quartile: 1.82, 95% CI: 1.22-2.73, P(trend)=0.004). After adjustment for body mass index (BMI), the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated (~10-20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provided epidemiological evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu. PMID- 20843940 TI - A mechanism-based mathematical model of aryl hydrocarbon receptor-mediated CYP1A induction in rats using beta-naphthoflavone as a tool compound. AB - beta-Naphthoflavone (BNF) is a synthetic flavone that selectively and potently induces CYP1A enzymes via aryl hydrocarbon receptor activation. Mechanism-based mathematical models of CYP1A enzyme induction were developed to predict the time course of enzyme induction and quantitatively evaluate the interrelationship between BNF plasma concentrations, hepatic CYP1A1 and CYP1A2 mRNA levels, and CYP1A enzyme activity in rats in vivo. Male Sprague-Dawley rats received a continuous intravenous infusion of vehicle or 1.5 or 6 mg . kg(-1) . h(-1) BNF for 6 h, with blood and liver sampling. Plasma BNF concentrations were determined by liquid chromatography-tandem mass spectrometry. Hepatic mRNA levels of CYP1A1 and CYP1A2 were determined by TaqMan. Ethoxyresorufin O-deethylation was used to measure the increase in CYP1A enzyme activity as a result of induction. The induction of hepatic CYP1A1/CYP1A2 mRNA and CYP1A activity occurred within 2 h after BNF administration. This caused a rapid increase in metabolic clearance of BNF, resulting in plasma concentrations declining during the infusion. Overall, the enzyme induction models developed in this study adequately captured the time course of BNF pharmacokinetics, CYP1A1/CYP1A2 mRNA levels, and increases in CYP1A enzyme activity data for both dose groups simultaneously. The model-predicted degradation half-life of CYP1A enzyme activity is comparable with previously reported values. The present results also confirm a previous in vitro finding that CYP1A1 is the predominant contributor to CYP1A induction. These physiologically based models provide a basis for predicting drug-induced toxicity in humans from in vitro and preclinical data and can be a valuable tool in drug development. PMID- 20843941 TI - A novel domain mediates insulin-induced proteasomal degradation of insulin receptor substrate 1 (IRS-1). AB - Insulin receptor substrate-1 (IRS-1) plays a pivotal role in insulin signaling, therefore its degradation is exquisitely regulated. Here, we show that insulin stimulated degradation of IRS-1 requires the presence of a highly conserved Ser/Thr-rich domain that we named domain involved in degradation of IRS-1 (DIDI). DIDI (amino acids 386-430 of IRS-1) was identified by comparing the intracellular degradation rate of several truncated forms of IRS-1 transfected into CHO cells. The isolated DIDI domain underwent insulin-stimulated Ser/Thr phosphorylation, suggesting that it serves as a target for IRS-1 kinases. The effects of deletion of DIDI were studied in Fao rat hepatoma and in CHO cells expressing Myc-IRS 1(WT) or Myc-IRS-1(Delta386-430). Deletion of DIDI maintained the ability of IRS 1(Delta386-434) to undergo ubiquitination while rendering it insensitive to insulin-induced proteasomal degradation, which affected IRS-1(WT) (80% at 8 h). Consequently, IRS-1(Delta386-434) mediated insulin signaling (activation of Akt and glycogen synthesis) better than IRS-1(WT). IRS-1(Delta386-434) exhibited a significant greater preference for nuclear localization, compared with IRS-1(WT). Higher nuclear localization was also observed when cells expressing IRS-1(WT) were incubated with the proteasome inhibitor MG-132. The sequence of DIDI is conserved more than 93% across species, from fish to mammals, as opposed to approximately 40% homology of the entire IRS-1. These findings implicate DIDI as a novel, highly conserved domain of IRS-1, which mediates its cellular localization, rate of degradation, and biological activity, with a direct impact on insulin signal transduction. PMID- 20843942 TI - Inflammatory mediators and glucose in pregnancy: results from a subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. AB - CONTEXT: Inflammatory mediators are associated with type 2 and gestational diabetes. It is unknown whether there are associations with glucose in pregnant women with lesser degrees of hyperglycemia. OBJECTIVE: The objective of the study was to examine associations of inflammatory mediators with maternal glucose levels and neonatal size in a subset of participants in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. DESIGN: Eligible pregnant women underwent a 75-g oral glucose tolerance test between 24 and 32 wk gestation, and levels of C-peptide, adiponectin, plasminogen activator inhibitor type 1 (PAI-1), C reactive protein (CRP), and resistin were measured in fasting serum samples. Associations of inflammatory mediators with maternal glucose and with birth size were assessed using multiple linear regression analyses, adjusting for maternal body mass index (BMI), fasting C-peptide, and other potential confounders. RESULTS: Mean levels of adiponectin declined, and PAI-1 and CRP increased across increasing levels of maternal glucose, BMI, and C-peptide. For example, for fasting plasma glucose less than 75 mg/dl and fasting plasma glucose of 90 mg/dl or greater, adiponectin was 22.5 and 17.4 MUg/ml and PAI-1 was 30.9 and 34.2 ng/ml, respectively. Associations with 1- and 2-h plasma glucose remained significant for adiponectin (P<0.001), PAI-1 (P<0.05), and CRP (P<0.01) after adjustment for BMI and C-peptide. Adiponectin and CRP were inversely associated with birth weight, sum of skinfolds and percent body fat, and PAI-1 with sum of skinfolds (all P<0.05) after adjustment for confounders. Resistin was not associated with 1- or 2-h glucose or birth size. CONCLUSION: Levels of inflammatory mediators are associated with levels of maternal glucose in pregnant women without overt diabetes. PMID- 20843943 TI - Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. AB - CONTEXT: Bisphosphonates are the mainstay of anti-osteoporotic treatment and are commonly used for a longer duration than in the placebo-controlled trials. A link to development of atypical subtrochanteric or diaphyseal fragility fractures of the femur has been proposed, and these fractures are currently the subject of a U.S. Food and Drug Administration review. OBJECTIVE: Our objective was to examine the risk of subtrochanteric/diaphyseal femur fractures in long term users of alendronate. DESIGN: We conducted an age- and gender-matched cohort study using national healthcare data. PATIENTS: Patients were alendronate users, without previous hip fracture, who began treatment between January 1, 1996, and December 31, 2005 (n=39,567) and untreated controls, (n=158,268). MAIN OUTCOME MEASURES: Subtrochanteric or diaphyseal femur fractures were evaluated. RESULTS: Subtrochanteric and diaphyseal fractures occurred at a rate of 13 per 10,000 patient-years in untreated women and 31 per 10,000 patient-years in women receiving alendronate [adjusted hazard ratio (HR)=1.88; 95% confidence interval (CI)=1.62-2.17]. Rates for men were six and 31 per 10,000 patient-years, respectively (HR=3.98; 95% CI=2.62-6.05). The HR for hip fracture was 1.37 (95% CI=1.30-1.46)) in women and 2.47 (95% CI=2.07-2.95) in men. Risks of subtrochanteric/diaphyseal fracture were similar in patients who had received 9 yr of treatment (highest quartile) and patients who had stopped therapy after the equivalent of 3 months of treatment (lowest quartile). CONCLUSIONS: Alendronate treated patients are at higher risk of hip and subtrochanteric/diaphyseal fracture than matched control subjects. However, large cumulative doses of alendronate were not associated with a greater absolute risk of subtrochanteric/diaphyseal fractures than small cumulative doses, suggesting that these fractures could be due to osteoporosis rather than to alendronate. PMID- 20843944 TI - Effects of medroxyprogesterone acetate on gene expression in myometrial explants from pregnant women. AB - CONTEXT: Progesterone is important physiologically and therapeutically to maintain uterine quiescence during pregnancy, in part through controlling myometrial gene expression. OBJECTIVE: The objective of the study was to use expression microarray and quantitative reverse transcriptase-PCR (qRT-PCR) validation to determine the changes in gene expression induced by prolonged exposure of human myometrium to a synthetic progestogen. DESIGN: Myometrial explants, obtained at elective cesarean section (n=9), were maintained in culture, under 0.6 g tension, for 65 h in the presence of medroxyprogesterone acetate (100 nm) or vehicle. Expression array was performed using Illumina beadchip arrays. Approximately 30% of differentially expressed transcripts were validated in biological replicates (n=10) by qRT-PCR. RESULTS: The 114 significantly regulated transcripts were significantly enriched in inflammatory response (P=0.00001), growth factor activity (P=0.0004), and cytokine activity genes (P=0.008). Thirty-four transcripts were validated using qRT-PCR in explants obtained from 10 further women. There was very close agreement in the fold changes obtained by array and qRT-PCR (r2=0.9, P<0.0001). We confirmed significant down-regulation of a number of genes that have been well characterized as progesterone sensitive (IL-1B, IL-6, PTGS2, and GJA1). However, the top and sixth most down-regulated transcripts encoded two cytokines, IL-11 and IL-24, respectively, not previously implicated in mediating the effects of progesterone in myometrium. Both were validated by qRT-PCR (4.3- and 2.2-fold down-regulated, both P<0.001). CONCLUSIONS: Medroxyprogesterone acetate controls expression of multiple genes in myometrium, including many that have not previously been characterized as progestogen regulated in this tissue, including IL-11 and IL-24. It is plausible that proteins encoded by some of these genes may have important but as yet uncharacterized effects in controlling human parturition. PMID- 20843945 TI - Thyroid cancer recurrence in patients clinically free of disease with undetectable or very low serum thyroglobulin values. AB - DESIGN: This was a retrospective clinical study. SETTING: The study was conducted at a university-based tertiary cancer hospital. PATIENTS: One hundred seven patients had initial thyroid cancer surgery and subsequent remnant radioiodine ablation. Patients underwent recombinant human TSH (rhTSH)-mediated diagnostic whole-body scan and rhTSH-stimulated thyroglobulin (Tg) measurement before April 2001 if they had no antithyroglobulin antibodies, were clinically free of disease, and had one or more undetectable (<=0.5 ng/ml) or low (0.6-1 ng/ml) basal Tg measurements on levothyroxine. Patients were stratified according to their rhTSH-Tg responses: group 1, Tg 0.5 ng/ml or less (68 patients); group 2, Tg from 0.6 to 2.0 ng/ml (19 patients); and group 3, Tg greater than 2 ng/ml (20 patients). MAIN OUTCOME MEASURES: Tumor recurrence was measured. RESULTS: In group 1, two of 62 patients (3%) with follow-up recurred. In group 2, 63% converted to group 1, whereas two of 19 (11%) converted to group 3 and then recurred. Sixteen of the initial 20 group 3 patients (80%) recurred, including recurrence rates of 69 and 100% for those with an initial rhTSH-Tg greater than 2.0 ng/ml but 5.0 ng/ml or less, and 4.6 ng/ml or greater, respectively. One group 3 patient died of distant metastases. rhTSH-Tg more accurately predicted tumor recurrence than basal Tg. An rhTSH-Tg threshold of 2.5 ng/ml or greater optimally predicted future recurrence with sensitivity, specificity, and negative and positive predictive values of 80, 97, 95, and 84%, respectively. CONCLUSIONS: The prevalence of postablation thyroid cancer recurrence is predicted by the rhTSH-Tg response with an optimal Tg threshold of 2.5 ng/ml. Still, recurrent disease occurs in some patients with an initial rhTSH-Tg of 0.5 ng/ml or less. PMID- 20843946 TI - Basal alpha-cell up-regulation in obese insulin-resistant adolescents. AB - CONTEXT: The aim of this analysis was to evaluate glucagon and c-peptide concentrations in two scenarios: euglycemic hyperinsulinemia and hyperglycemic hyperinsulinemia. We postulated that worsening obesity and insulin resistance will be reflected as an up-regulated (less suppressible) islet secretion profile. METHODS: Eighty-two [34 obese with normal glucose tolerance (NGT), 30 obese with impaired glucose tolerance (IGT), and 18 nonobese with NGT] subjects underwent a euglycemic-hyperinsulinemic clamp (EHC) and a hyperglycemic clamp. C-peptide and glucagon were evaluated at basal and steady-state (SS) conditions. RESULTS: Basal glucagon was significantly elevated in obese insulin-resistant and obese IGT subjects as was basal c-peptide. SS glucagon and c-peptide levels during the EHC were lower in the lean and obese insulin-sensitive subjects compared with the obese insulin-resistant subjects with NGT or IGT. Fasting glucagon was the only significant determinant (beta = 0.66, P < 0.001) of SS glucagon during the EHC (R(2) = 0.57). In a longitudinal follow-up of a subsample, those who converted from normal to IGT significantly increased their fasting glucagon concentration in comparison with those who remained with NGT. CONCLUSIONS: Islet up-regulation manifesting as basal elevated glucagon and c-peptide secretion that determines the suppressive effects of hyperinsulinemia appears early in the course of deteriorating glucose tolerance. PMID- 20843947 TI - Increased psychopathology and maladaptive personality traits, but normal cognitive functioning, in patients after long-term cure of acromegaly. AB - OBJECTIVE: Active acromegaly is associated with psychopathology, personality changes, and cognitive dysfunction. It is unknown whether, and to what extent, these effects are present after long-term cure of acromegaly. AIM: The aim of the study was to assess psychopathology, personality traits, and cognitive function in patients after long-term cure of acromegaly. DESIGN: This was a cross sectional study. PATIENTS AND METHODS: We studied 68 patients after long-term cure (13+/-1 yr) of acromegaly and 68 matched controls. We compared these data with 60 patients treated for nonfunctioning pituitary macroadenomas (NFMAs) and 60 matched controls. Psychopathology was assessed using the Apathy Scale, Irritability Scale, Hospital Anxiety and Depression Scale, and Mood and Anxiety Symptoms Questionnaire short-form, and personality was assessed by the Dimensional Assessment of Personality Pathology short-form (DAPPs). Cognitive function was assessed by 11 tests. RESULTS: Compared with matched controls, patients cured from acromegaly scored significantly worse on virtually all psychopathology questionnaires and on several subscales of the DAPPs. Compared with NFMA patients, patients cured from acromegaly scored worse on negative affect (P=0.050) and somatic arousal (P=0.009) and seven of 18 subscales of the DAPPs (P<0.05). Cognitive function in patients cured from acromegaly did not differ from matched controls or patients treated for NFMA. CONCLUSION: Patients with long-term cure of acromegaly show a higher prevalence of psychopathology and maladaptive personality traits but not cognitive dysfunction, compared with matched controls and patients treated for NFMA. These results suggest irreversible effects of previous GH excess, rather than effects of pituitary adenomas per se and/or their treatment, on the central nervous system. PMID- 20843948 TI - Changes in anti-Mullerian hormone (AMH) throughout the life span: a population based study of 1027 healthy males from birth (cord blood) to the age of 69 years. AB - CONTEXT: Anti-Mullerian hormone (AMH), which is secreted by immature Sertoli cells, triggers the involution of the fetal Mullerian ducts. AMH is a testis specific marker used for diagnosis in infants with ambiguous genitalia or bilateral cryptorchidism. AIM: The aim of the study was to describe the ontogeny of AMH secretion through life in healthy males. SETTING: This was a population based study of healthy volunteers. PARTICIPANTS: PARTICIPANTS included 1027 healthy males from birth (cord blood) to 69 yr. A subgroup was followed up longitudinally through the infantile minipuberty [(in cord blood, and at 3 and 12 months), n=55] and another group through puberty [(biannual measurements), n=83]. MAIN OUTCOME MEASURES: Serum AMH was determined by a sensitive immunoassay. Serum testosterone, LH, and FSH were measured, and pubertal staging was performed in boys aged 6 to 20 yr (n=616). RESULTS: Serum AMH was above the detection limit in all samples with a marked variation according to age and pubertal status. The median AMH level in cord blood was 148 pmol/liter and increased significantly to the highest observed levels at 3 months (P<0.0001). AMH declined at 12 months (P<0.0001) and remained at a relatively stable level throughout childhood until puberty, when AMH declined progressively with adults exhibiting 3-4% of infant levels. CONCLUSION: Based on this extensive data set, we found detectable AMH serum levels at all ages, with the highest measured levels during infancy. At the time of puberty, AMH concentrations declined and remained relatively stable throughout adulthood. The potential physiological role of AMH and clinical applicability of AMH measurements remain to be determined. PMID- 20843949 TI - Skeletal muscle lipase content and activity in obesity and type 2 diabetes. AB - CONTEXT: The obese insulin-resistant state is characterized by elevated lipid storage in skeletal muscle tissue. OBJECTIVE: We tested whether differences in muscle triacylglycerol (TAG) and diacylglycerol (DAG) lipase content and activity are associated with incomplete in vivo lipolysis and lipid accumulation. DESIGN AND PATIENTS: Two case-control studies were conducted on skeletal muscle biopsies from lean (n=13) and obese (n=10) men (study 1) and from 11 nonobese type 2 diabetic (T2D), obese T2D, and healthy normoglycemic men (study 2). MAIN OUTCOME MEASURES: Skeletal muscle lipase protein content and activity and muscle lipid content (TAG and DAG) were determined. RESULTS: Skeletal muscle hormone-sensitive lipase protein content was lower (0.39+/-0.07 vs. 1.00+/-0.19 arbitrary units; P=0.004) and adipose triglyceride lipase protein content was higher in obese men compared with lean controls (2.17+/-0.40 vs. 0.42+/-0.23 arbitrary units; P=0.008). This apparent difference in lipase content was accompanied by a 60% lower ratio of DAG to TAG hydrolase activity in the obese men (11.4+/-2.3 vs. 26.5+/-7.3 nmol/h.mg; P=0.045), implying incomplete lipolysis. Lower hormone sensitive lipase and higher adipose triglyceride lipase content was confined to obesity per se, because it was observed solely in obese T2D men but not in healthy normoglycemic controls and nonobese T2D men. Muscle total DAG content was not higher in obese men but was even lower (6.2+/-0.7 vs. 9.4+/-0.9 MUmol/mg dry weight; P=0.017). TAG content did not differ between groups (84.7+/-18.9 vs. 70.4+/-12.4 MUmol/mg dry weight; P=0.543). CONCLUSIONS: Our data do not support an important role of total muscle DAG content in the development of insulin resistance in obese men. PMID- 20843950 TI - Longitudinal study of insulin resistance and sex hormones over the menstrual cycle: the BioCycle Study. AB - CONTEXT: Conflicting findings have been reported regarding the effect of menstrual cycle phase and sex hormones on insulin sensitivity. OBJECTIVE: The aim was to determine the pattern of insulin resistance over the menstrual cycle and whether variations in sex hormones explain these patterns. DESIGN: The BioCycle study is a longitudinal study that measured hormones at different phases of the menstrual cycle. Participants had up to eight visits per cycle; each visit was timed using fertility monitors to capture sensitive windows of hormonal changes. SETTING: The study was conducted in the general community of the University at Buffalo (Buffalo, NY). PARTICIPANTS: A total of 257 healthy, premenopausal women (age, 27+/-8 yr; body mass index, 24+/-4 kg/m2) participated in the study. MAIN OUTCOME MEASURES: We measured fasting insulin, glucose, and insulin resistance by the homeostasis model of insulin resistance (HOMA-IR). RESULTS: Significant changes in HOMA-IR were observed over the menstrual cycle; from a midfollicular phase level of 1.35, levels rose to 1.59 during the early luteal phase and decreased to 1.55 in the late-luteal phase. HOMA-IR levels primarily reflected changes in insulin and not glucose. After adjustment for age, race, cycle, and other sex hormones, HOMA-IR was positively associated with estradiol (beta=0.082; P<0.001) and progesterone (beta=0.025; P<0.001), and inversely associated with FSH (adjusted beta=-0.040; P<0.001) and SHBG (beta=-0.085; P<0.001). LH was not associated with HOMA-IR. Further adjustment for BMI weakened the association with SHBG (beta=-0.057; P=0.06) but did not affect other associations. CONCLUSION: Insulin exhibited minor menstrual cycle variability. Estradiol and progesterone were positively associated with insulin resistance and should be considered in studies of insulin resistance among premenopausal women. PMID- 20843951 TI - Neuroendocrine regulation of growth hormone and androgen axes by selective estrogen receptor modulators in healthy men. AB - CONTEXT: In men, the stimulation of GH and inhibition of LH secretion by testosterone requires aromatization to estradiol. Tamoxifen, a selective estrogen receptor modulator (SERM), possesses central estrogen antagonistic effect but peripheral hepatic agonist effect, lowering IGF-I. Thus, tamoxifen is likely to perturb the neuroendocrine regulation of GH and gonadal axes. Raloxifene, a SERM, is used for therapy of osteoporosis in both sexes. Its neuroendocrine effects in men are poorly understood. OBJECTIVE: The aim was to compare the impact of raloxifene and tamoxifen on GH-IGF-I and gonadal axes in healthy men. DESIGN: We conducted a randomized, open-label crossover study. PATIENTS AND INTERVENTION: Ten healthy men were randomized to 2-wk sequential treatment with tamoxifen (10 and 20 mg/d) and raloxifene (60 and 120 mg/d), with a 2-wk intervening washout period. MAIN OUTCOME MEASURES: We measured the GH response to arginine and circulating levels of IGF-I, LH, FSH, testosterone, and SHBG. RESULTS: Tamoxifen, but not raloxifene, significantly reduced IGF-I levels by 25+/-6% (P<0.01) and increased SHBG levels by 20+/-7% (P<0.05) at the higher therapeutic dose. There was a nonstatistically significant trend toward a reduction in the GH response to arginine with both SERMs. Both drugs significantly increased LH, FSH, and testosterone concentrations. The mean increase in testosterone (40 vs. 25%; P<0.05) and LH (70 vs. 30%; P<0.01) was significantly greater with tamoxifen than with raloxifene treatment. CONCLUSIONS: Tamoxifen, but not raloxifene, reduces IGF-I levels. Both SERMs stimulate the gonadal axis, with tamoxifen imparting a greater effect. We conclude that in therapeutic doses, raloxifene perturbs the GH and gonadal axes to a lesser degree than tamoxifen. PMID- 20843952 TI - Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. AB - OBJECTIVE: Obesity is a major driver of cardiometabolic risk. Abdominal visceral adipose tissue (VAT) and sc adipose tissue (SAT) may confer differential metabolic risk profiles. We investigated the relations of VAT and SAT with cardiometabolic risk factors in the Jackson Heart Study cohort. METHODS: Participants from the Jackson Heart Study (n=2477; 64% women; mean age, 58 yr) underwent multidetector computed tomography, and the volumetric amounts of VAT and SAT were assessed between 2007 and 2009. Cardiometabolic risk factors were examined by sex in relation to VAT and SAT. RESULTS: Men had a higher mean volume of VAT (873 vs. 793 cm3) and a lower mean volume of SAT (1730 vs. 2659 cm3) than women (P=0.0001). Per 1-sd increment in either VAT or SAT, we observed elevated levels of fasting plasma glucose and triglyceride, lower levels of high-density lipoprotein-cholesterol, and increased odds ratios for hypertension, diabetes, and metabolic syndrome. The effect size of VAT in women was larger than that of SAT [fasting plasma glucose, 5.51+/-1.0 vs. 3.36+/-0.9; triglyceride, 0.17+/-0.01 vs. 0.05+/-0.01; high-density lipoprotein-cholesterol, -5.36+/-0.4 vs. -2.85+/ 0.4; and odds ratio for hypertension, 1.62 (1.4-1.9) vs. 1.40 (1.2-1.6); diabetes, 1.82 (1.6-2.1) vs. 1.58 (1.4-1.8); and metabolic syndrome, 3.34 (2.8 4.0) vs. 2.06 (1.8-2.4), respectively; P<0.0001 for difference between VAT and SAT]. Similar patterns were also observed in men. Furthermore, VAT remained associated with most risk factors even after accounting for body mass index (P ranging from 0.006-0.0001). The relationship of VAT to most risk factors was significantly different between women and men. CONCLUSIONS: Abdominal VAT and SAT are both associated with adverse cardiometabolic risk factors, but VAT remains more strongly associated with these risk factors. The results from this study suggest that relations with cardiometabolic risk factors are consistent with a pathogenic role of abdominal adiposity in participants of African ancestry. PMID- 20843953 TI - During rapid weight loss in obese children, reductions in TSH predict improvements in insulin sensitivity independent of changes in body weight or fat. AB - BACKGROUND: Although serum TSH is often elevated in obesity and may be linked to disorders of lipid and glucose metabolism, the clinical relevance of these relationships remains unclear. SUBJECTS: Subjects were obese children and adolescents (n=206; mean age 14 yr) undergoing rapid weight and fat loss in a standardized, multidisciplinary, 2-month, in-patient weight loss program. DESIGN: This was a prospective study that determined thyroid function, glucose and lipid parameters, leptin, anthropometric measures, and body composition measured by dual-energy x-ray absorption at baseline and at the end of the intervention. RESULTS: At baseline, 52% of children had TSH concentrations in the high normal range (>2.5 mU/liter), but TSH was not correlated with body weight, body mass index sd scores, lean body mass, or body fat percentage. At baseline, independent of adiposity, TSH significantly correlated with total cholesterol (P=0.008), low density lipoprotein cholesterol (P=0.013), fasting insulin (P=0.010), homeostatic model assessment (HOMA) (P=0.004), and leptin (P=0.006). During the intervention, mean body fat, TSH, HOMA, and fasting insulin decreased by 21, 11, 53, and 54%, respectively. Change (Delta) in TSH did not correlate with Deltabody weight or Deltabody composition, but DeltaTSH significantly correlated with, Deltafasting insulin and DeltaHOMA, independent of Deltabody weight or Deltabody composition (P<0.05). CONCLUSION: TSH concentrations are elevated in obese children but are not correlated with the amount of excess body weight or fat. During weight loss, independent of changes in body weight or composition, decreases in elevated serum TSH predict decreases in fasting insulin and HOMA. These findings suggest interventions that target high TSH concentrations during weight loss in obese subjects may improve insulin sensitivity. PMID- 20843954 TI - Oligoovulatory and anovulatory cycles in women with polycystic ovary syndrome (PCOS): what's the difference? AB - CONTEXT: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. The phenotype may differ between patients who exhibit signs of recent ovulation and anovulatory PCOS patients. OBJECTIVE: Our objective was to study differences in clinical and endocrine characteristics and response to ovulation induction (OI) treatment comparing oligoovulatory and anovulatory PCOS patients. DESIGN AND SETTING: We conducted a retrospective cohort study at a tertiary hospital. PATIENTS: PCOS patients (n=1750) presenting with oligo- or amenorrhea were diagnosed according to the Rotterdam 2003 consensus criteria. Arbitrarily, oligoovulatory PCOS was defined by a single random serum progesterone level of 10 nmol/liter or higher. MAIN OUTCOME MEASURES: We evaluated the incidence of oligo- or amenorrhea, menstrual cycle length, serum androgen levels, follicle count, and OI outcome parameters. RESULTS: Anovulatory women (n=1541 of 1750, 88.1%) were more often amenorrheic (P<0.001) and presented with a longer cycle duration (P<0.001) compared with oligoovulatory women (n=209 of 1750, 11.9%). Serum levels of testosterone (P<0.001), the free androgen index (P<0.001), and total follicle count (P<0.005) were higher in anovulatory compared with oligoovulatory patients. During clomiphene citrate OI, more oligoovulatory women gained regular menstrual cycles (P<0.05), whereas after second-line treatment with recombinant FSH, more anovulatory women became pregnant (P<0.05). CONCLUSIONS: Oligoovulatory women with PCOS exhibit a milder phenotype of ovarian dysfunction and have a more favorable response to OI treatment using clomiphene citrate compared with anovulatory PCOS patients. However, during second-line treatment with recombinant FSH, anovulatory PCOS patients presented with a higher chance of pregnancy compared with oligoovulatory patients. PMID- 20843955 TI - The specific slow afterhyperpolarization inhibitor UCL2077 is a subtype-selective blocker of the epilepsy associated KCNQ channels. AB - Mutations in members of the KCNQ channel family underlie multiple diseases affecting the nervous and cardiovascular systems. Despite their clinical relevance, research into these channels is limited by the lack of subtype selective inhibitors, making it difficult to differentiate the physiological function of each family member in vivo. We have proposed that KCNQ channels might partially underlie the calcium-activated slow afterhyperpolarization (sAHP), a neuronal conductance whose molecular components are uncertain. Here, we investigated whether 3-(triphenylmethylaminomethyl)pyridine (UCL2077), identified previously as an inhibitor of the sAHP in neurons, acts on members of the KCNQ family expressed in heterologous cells. We found that 3 MUM UCL2077 strongly inhibits KCNQ1 and KCNQ2 channels and weakly blocks KCNQ4 channels in a voltage independent manner. In contrast, UCL2077 potentiates KCNQ5 channels at more positive membrane potentials, with little effect at negative membrane potentials. We found that the effect of UCL2077 on KCNQ3 is bimodal: currents are enhanced at negative membrane potentials and inhibited at positive potentials. We found that UCL2077 facilitates KCNQ3 currents by inducing a leftward shift in the KCNQ3 voltage-dependence, a shift dependent on tryptophan 265. Finally, we show that UCL2077 has intermediate effects on KCNQ2/3 heteromeric channels compared with KCNQ2 and KCNQ3 homomers. Together, our data demonstrate that UCL2077 acts on KCNQ channels in a subtype-selective manner. This feature should make UCL2077 a useful tool for distinguishing KCNQ1 and KCNQ2 from less-sensitive KCNQ family members in neurons and cardiac cells in future studies. PMID- 20843957 TI - Sequencing delivers diminishing returns for homology detection: implications for mapping the protein universe. AB - MOTIVATION: Databases of sequenced genomes are widely used to characterize the structure, function and evolutionary relationships of proteins. The ability to discern such relationships is widely expected to grow as sequencing projects provide novel information, bridging gaps in our map of the protein universe. RESULTS: We have plotted our progress in protein sequencing over the last two decades and found that the rate of novel sequence discovery is in a sustained period of decline. Consequently, PSI-BLAST, the most widely used method to detect remote evolutionary relationships, which relies upon the accumulation of novel sequence data, is now showing a plateau in performance. We interpret this trend as signalling our approach to a representative map of the protein universe and discuss its implications. PMID- 20843956 TI - Stimulation of alpha7 nicotinic acetylcholine receptor by nicotine increases suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. AB - alpha7 Nicotinic acetylcholine receptor (alpha7 nAChR) has been found in several non-neuronal cells and is described as an important regulator of cellular function. Naturally occurring CD4(+)CD25(+) regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study investigated whether naturally occurring Tregs expressed alpha7 nAChR and investigated the functionary role of this receptor in controlling suppressive activity of these cells. We found that CD4(+)CD25(+) Tregs from naive C57BL/6J mice positively expressed alpha7 nAChR, and its activation by nicotine enhanced the suppressive capacity of Tregs. Nicotine stimulation up-regulated the expression of cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on Tregs but had no effect on the production of interleukin (IL)-10 and transforming growth factor-beta1 by Tregs. In the supernatants of CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell cocultures, we observed a decrease in the concentration of IL-2 in nicotine stimulated groups, but nicotine stimulation had no effect on the ratio of IL 4/interferon (IFN)-gamma, which partially represented T-cell polarization. The above-mentioned effects of nicotine were reversed by a selective alpha7 nAChR antagonist, alpha-bungarotoxin. In addition, the ratio of IL-4/IFN-gamma was increased by treatment with alpha-bungarotoxin. We conclude that nicotine might increase Treg-mediated immune suppression of lymphocytes via alpha7 nAChR. The effect is related to the up-regulation of CTLA-4 as well as Foxp3 expression and decreased IL-2 secretion in CD4(+)CD25(+) Tregs/CD4(+)CD25(-) T-cell coculture supernatants. alpha7 nAChR seems to be a critical regulator for immunosuppressive function of CD4(+)CD25(+) Tregs. PMID- 20843958 TI - PedMerge: merging pedigrees to facilitate family-based genetic statistical analyses. AB - SUMMARY: PedMerge allows users to accurately and efficiently merge separately ascertained pedigrees that belong to the same extended family. In addition to validation checks of pedigree structure, the software provides files in LINKAGE or PEDSYS format that easily allow to be used by a variety of genetic statistical software packages including LINKAGE, SOLAR, SLINK or can be further manipulated with Mega2. AVAILABILITY: http://sites.google.com/site/rosemarieplaetke/home/s/pedmerge PMID- 20843960 TI - Sudden death in hypertrophic cardiomyopathy: old risk factors re-assessed in a new model of maximalized follow-up. AB - AIMS: in hypertrophic cardiomyopathy (HCM), the following five risk factors have a major role in the primary prevention of sudden death (SD): family history of SD (FHSD), syncope, massive wall thickness (MWTh) >30 mm, non-sustained ventricular tachycardia (nsVT) in Holter monitoring of electrocardiography, and abnormal blood pressure response to exercise (aBPRE). In HCM, as a genetic cardiac disease, the risk for SD may also exist from birth. The aim of the study was to compare the survival curves constructed for each of the five risk factors in a traditional follow-up model (started at the first presentation of a patient at the institution) and in a novel follow-up model (started at the date of birth). In an additional analysis, we compared the survival rate in three subgroups (without FHSD, with one SD, and with two or more SDs in a family). METHODS AND RESULTS: a total of 1306 consecutive HCM patients (705 males, 601 females, mean age of 47 years, and 193 patients were <18 years) evaluated at 15 referral centres in Poland were enrolled in the study. In a novel method of follow-up, all the five risk factors confirmed its prognostic power (FHSD: P = 0.0007; nsVT: P < 0.0001; aBPRE: P = 0.0081; syncope: P < 0.0001; MWTh P> 0.0001), whereas in a traditional method, only four factors predicted SD (except aBPRE). In a novel model of follow-up, FHSD in a single episode starts to influence the prognosis with a delay to the fifth decade of life (P = 0.0007). Multiple FHSD appears to be a very powerful risk factor (P < 0.0001), predicting frequent SDs in childhood and adolescence. CONCLUSION: the proposed concept of a lifelong calculated follow up is a useful strategy in the risk stratification of SD. Multiple FHSD is a very ominous risk factor with strong impact, predicting frequent SD episodes in the early period of life. PMID- 20843959 TI - Transcatheter aortic valve implantation: early results of the FRANCE (FRench Aortic National CoreValve and Edwards) registry. AB - AIMS: Transcatheter aortic valve implantation is a therapeutic alternative for high-surgical-risk patients with severe symptomatic aortic stenosis. Two models of prosthesis are currently commercialized in France, which can be implanted either via a transarterial or a transapical approach. The aim of the study was to evaluate in a national French registry the early safety and efficacy of transcatheter aortic valve replacement (AVR) using either the Edwards SAPIENTM or CoreValveTM in high-surgical-risk patients with severe aortic stenosis. METHODS AND RESULTS: The multicentre national registry was conducted in 16 centres between February 2009 and June 2009, under the authority of the French Societies of Cardiology and Thoracic and Cardio-Vascular Surgery. The primary endpoint was mortality at 1 month. Two hundred and forty-four high-surgical-risk patients (logistic EuroSCORE >=20%, STS >=10%, or contra-indication to AVR) were enrolled. Mean age was 82 +/- 7 years and 43.9% were female. Edwards SAPIEN and CoreValve were implanted in 68 and 32% of patients, respectively. The approaches used were transarterial (transfemoral: 66%; subclavian: 5%) or transapical in 29%. Device success rate was 98.3% and 30-day mortality was 12.7%. Severe complications included stroke (3.6%), tamponade (2%), acute coronary occlusion (1.2%), and vascular complications (7.3%). Pacemaker was required in 11.8%. At 1 month, 88% of patients were in NYHA class II or less. CONCLUSION: This prospective registry reflects the real-life experience of transcatheter aortic valve implantation in high-risk elderly patients in France. The early results are satisfactory in terms of feasibility, short-term haemodynamic and functional improvement, and safety. Longer term follow-up will be further assessed. PMID- 20843961 TI - Age and outcome in acute emergency medical admissions. AB - BACKGROUND: there is a lack of outcome information with respect to older health service users. The purpose of this study was to examine 30-day in-hospital mortality and its predictors in all elderly patients admitted as a medical emergency to our hospital. METHODS: all patients admitted between 2002 and 2008 were studied, linking anonymised clinical, administrative, laboratory and mortality data. Significant univariate predictors of outcome, including co morbidity and illness severity score, were entered into a multivariate logistic regression model, adjusting the univariate estimates of the effect of age on in hospital mortality. RESULTS: we admitted 23,114 consecutive acute medical admissions between 2002 and 2008; 30-day in-hospital mortality was 20.7% in the over 75 age category versus 4.5% in those younger. The unadjusted OR for a 30-day in-hospital mortality in the over 75 category of 5.21 (95% CI 4.73, 5.73) fell to 4.69 (95% CI 4.04, 5.44) when adjusted for outcome predictors excluding acute illness severity and 2.93 (95% CI 2.50, 3.42) when acute illness severity was added as a covariate. When the interaction between age and co-morbidity is examined, the odds ratio adjusts to 3.22 (95% CI 2.63, 3.6). CONCLUSION: acute illness severity is more important than co-morbidity in explaining the outcome in older patients admitted as medical emergencies. Service planning for acute elderly care should be based on effective disease management programmes but recognise the contribution of acute illness severity to outcome when conditions deteriorate. PMID- 20843962 TI - Frailty measures, inflammatory biomarkers and post-operative complications in older surgical patients. PMID- 20843963 TI - A cross-section analysis of FT3 age-related changes in a group of old and oldest old subjects, including centenarians' relatives, shows that a down-regulated thyroid function has a familial component and is related to longevity. AB - BACKGROUND: several studies suggest that a decreased thyroid activity might be favourable in oldest-old subjects and that subclinical thyroid hyperfunction may be detrimental. OBJECTIVES: to verify whether declining levels of circulating thyroid hormones may contribute to longevity. DESIGN: cross-sectional observational study. SETTING: all subjects were born in Calabria (southern Italy) and their ancestry in the region was ascertained up to the grandparents. SUBJECTS: six hundred and four home-dwelling subjects (301 females, 303 males), divided into three groups: 278 individuals 60-85 years old; 179 children or nieces/nephews of centenarians who are 60-85 years old; 147 individuals older than 85 years. METHODS: thyroid function parameters were measured in the frame of a comprehensive geriatric assessment. RESULTS: FT3 and FT4 levels were negatively associated with age. Lower levels of FT3, FT4 and TSH were found in centenarians' children and nieces/nephews with respect to age-matched controls. Indeed, being a relative of centenarians qualified as an independent correlate of thyroid parameters. CONCLUSIONS: age-related subtle thyroid hypofunction (either due to a familial component or due to a reset of the thyroid function occurring between the sixth and the eighth decade of life) appears to be related to longevity. PMID- 20843964 TI - Objective measures of physical capability and subsequent health: a systematic review. AB - BACKGROUND: measures of physical capability may be predictive of subsequent health, but existing published studies have not been systematically reviewed. We hypothesised that weaker grip strength, slower walking speed and chair rising and shorter standing balance time, in community-dwelling populations, would be associated with higher subsequent risk of fracture, cognitive outcomes, cardiovascular disease, hospitalisation and institutionalisation. METHODS: studies were identified through systematic searches of the electronic databases MEDLINE and EMBASE (to May 2009). Reference lists of eligible papers were also manually searched. RESULTS: twenty-four papers had examined the associations between at least one physical capability measure and one of the outcomes. As the physical capability measures and outcomes had been assessed and categorised in different ways in different studies, and there were differences in the potential confounding factors taken into account, this made it impossible to pool results. There were more studies examining fractures than other outcomes, and grip strength and walking speed were the most commonly examined capability measures. Most studies found that weaker grip strength and slower walking speed were associated with increased risk of future fractures and cognitive decline, but residual confounding may explain results in some studies. Associations between physical capability levels and the other specified outcomes have not been tested widely. CONCLUSIONS: there is some evidence to suggest that objective measures of physical capability may be predictors of subsequent health in older community dwelling populations. Most hypothesised associations have not been studied sufficiently to draw definitive conclusions suggesting the need for further research. PMID- 20843966 TI - The influence of diabetes on degree of abdominal aortic aneurysm tissue inflammation. AB - Abdominal aortic aneurysm (AAA) progression and disease resistance are related to transmural degenerative processes and an inflammatory infiltration (INF). Diabetes is associated with low prevalence and growth rate of AAA. We sought to characterize INF in established AAA (INFAAA), in diabetic patients. From 89 male patients aged 52 to 83 years, aneurysm specimens obtained at open asymptomatic nonruptured AAA repair were graded for INF and immunostained using antibodies against T-lymphocytes (CD3) and macrophages (CD68). Diabetic patients had an odds ratio (OR) 3.8, 95% confidence interval ([CI] 1.14-12.96), P = .03, of experiencing above-median INFAAA. These associations were affected by serum glucose (SG) levels (OR 3.6, 95% CI [0.72-18.77]; P = .1). Macrophage subpopulations higher in diabetic patients (1.44 +/- 0.78 versus 0.98 +/- 0.76; P = .02) were correlated with SG (r = .21, P = .044). Abdominal aortic aneurysms in diabetic patients are associated with higher INF. Macrophage densities are correlated with SG. PMID- 20843965 TI - Clinical outcomes in relation to the daily dose of recombinant follicle stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis. AB - BACKGROUND: The optimal ovarian stimulation dose to obtain the best balance between the probability of pregnancy and the risk of complications, while maximizing cost-effectiveness of in vitro fertilization (IVF) treatment, is yet to be established. METHODS: A systematic search of the electronic databases PubMed, EMBASE and Cochrane library, from 1984 until October 2009 for randomized controlled trials comparing different doses of recombinant FSH in IVF, was performed. RESULTS: Ten studies (totaling 1952 IVF cycles) were included in the present meta-analysis, comprising patients younger than 39 years with regular menstrual cycle, normal basal FSH levels and two normal ovaries. Comparison was made between studies using a daily dose of 100 versus 200 IU recFSH, and between 150 versus 200 IU recFSH or higher. Although oocyte yield was greater in the >200 IU/day dose group, pregnancy rates were similar compared with lower dose groups. The risk of insufficient response to ovarian stimulation was greatest in the 100 IU/day dose group. The risk of developing ovarian hyperstimulation syndrome was greater in the >200 IU/day dose group. The number of embryos available for cryopreservation was lowest in the 100 IU/day group, but similar comparing the 150 IU/day and the >200 IU/day dose groups. CONCLUSIONS: This meta-analysis suggests that the optimal daily recFSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy and embryo cryopreservation rates. Furthermore, the wide spread adherence to this optimal dose will allow for a considerable reduction in IVF costs and complications. PMID- 20843967 TI - Importance of validation of accuracy of duplex ultrasonography in identifying moderate and severe carotid artery stenosis. AB - BACKGROUND AND PURPOSE: The accuracy of carotid duplex ultrasonography (CDU) in detecting moderate and severe carotid artery disease was evaluated in comparison with arteriography. METHODS: Accuracy of CDU was correlated with arteriographic findings using North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria in 147 internal carotid arteries. The duplex measurements consisted of peak systolic velocities (PSVs), end diastolic velocities (EDVs), and internal carotid PSV to common carotid artery PSV ratios (ICA/CCA). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy (OA) using the 3 parameters were determined. Receiver operating characteristic (ROC) curves were constructed from the ultrasonographic data for detection of 50% or greater stenosis (moderate disease) and 70% or greater stenosis (severe disease). RESULTS: CDU for detecting >= 50% stenosis had a sensitivity of 100%, specificity of 87.8%, and accuracy of 96.6%. The area under the ROC curves for PSV was 0.86 (95% confidence interval [CI] 0.80-0.93), for EDV was 0.86 (95% CI 0.80-0.92), and for ICA:CCA ratio was 0.95 (CI 0.91 0.99). CDU for detecting >= 70% stenosis had a sensitivity of 100%, specificity of 87.1%, and accuracy of 94.5%. The area under the ROC curves for PSV was 0.76 (95% CI 0.68-0.84), for EDV was 0.74 (95% CI of 0.65-0.82), and for ICA/CCA ratio was 0.89 (0.84-0.94). CONCLUSIONS: We conclude that >= 50% stenosis and >= 70% stenosis can be reliably determined by CDU in our vascular laboratory. Each vascular laboratory must validate their own criteria against the current gold standard of carotid arteriography. A high degree of confidence in CDU is critical before any institution uses the test as the sole diagnostic method prior to carotid intervention. PMID- 20843968 TI - Endovascular treatment for chronic arteriovenous fistula between renal artery and inferior vena cava: image in vascular surgery. AB - Arteriovenous fistula involving renal artery and inferior vena cava are rare. We report the case of a 47-year-old woman with a chronic arteriovenous fistula between right renal artery and inferior vena cava due to a penetrating trauma. Another finding was a vena cava aneurysm caused by the fistula. The patient was successfully treated with a covered stent in the renal artery. Diagnosis and postoperative control have been documented with CT scan. Endovascular techniques may be effective and minimally invasive option for treatment and renal preservation in renal-cava arteriovenous fistulae. PMID- 20843969 TI - Surgical management of inferior vena cava strut penetration causing hydronephrosis: case report. AB - We present a case of penetration of inferior vena cava (IVC) by primary struts of Cook Celect filter and impingement on right ureter, causing symptomatic hydronephrosis and hydroureter, which was managed surgically by ureterolysis, mobilization of the ureter by retroperitoneal approach, excision of the filter strut, and omental wrap around the ureter. PMID- 20843970 TI - The measurements of thoron, radon and their decay products thanks to Pinocchio, Tengu and Trolls. AB - In the present paper, the long noses of Pinocchio, Tengu and Trolls are used to measure, respectively, radon, thoron, and their decay products both by track-etch detectors and by Geiger-Muller (G-M) counters. Just recently, four new passive samplers (termed quatrefoil) have been developed which greatly simplify the detection of all airborne radionuclides by using either passive or real-time detectors. In particular, surface-deposited radon (thoron) decay products are sampled by films with large area and small surface density (0.1-1 mg cm(-2)). Once exposed, these films are stacked together for their detection by a pancake G M counter. For the measurements of radon and thoron in soil, 25-cm-long tubes with sampling films along their internal surfaces can be successfully used. Once exposed, these films can be counted by a pancake G-M for the selective measurement of radon and thoron. PMID- 20843971 TI - Medical expenditures associated with diabetes acute complications in privately insured U.S. youth. AB - OBJECTIVE: To estimate medical expenditures attributable to diabetes ketoacidosis (DKA) and severe hypoglycemia among privately insured insulin-treated U.S. youth with diabetes. RESEARCH DESIGN AND METHODS: We analyzed the insurance claims of 7,556 youth, age <= 19 years, with insulin-treated diabetes. The youth were continuously enrolled in fee-for-service health plans, and claims were obtained from the 2007 U.S. MarketScan Commercial Claims and Encounter database. We used regression models to estimate total medical expenditures and their subcomponents: outpatient, inpatient, and drug expenditures. The excess expenditures associated with DKA and severe hypoglycemia were estimated as the difference between predicted medical expenditures for youth who did/did not experience either DKA or severe hypoglycemia. RESULTS: For youth with and without DKA, respectively, predicted mean annual total medical expenditures were $14,236 and $8,398 (an excess of $5,837 for those with DKA). The excess was statistically greater for those with one or more episodes of DKA ($8,455) than among those with only one episode ($3,554). Predicted mean annual total medical expenditures were $12,850 and $8,970 for youth with and without severe hypoglycemia, respectively (an excess of $3,880 for those with severe hypoglycemia). The excess was greater among those with one or more episodes ($5,929) than among those with only one ($2,888). CONCLUSIONS: Medical expenditures for potentially preventable DKA and severe hypoglycemia in U.S. youth with insulin-treated diabetes are substantial. Improving the quality of care for these youth to prevent the development of these two complications could avert substantial U.S. health care expenditures. PMID- 20843972 TI - Diabetes preventive services and policy implications in the U.S. AB - OBJECTIVE: To investigate whether the patient or physician practice characteristics predict the use of diabetes preventive care services. RESEARCH DESIGN AND METHODS: This was a cross-sectional study of a nationally representative sample of 27,169 adult ambulatory care visits, using the 2007 National Ambulatory Medical Care Survey data. The outcome variable is whether any preventive care services, defined as diagnostic tests (glucose, urinalysis, A1C, and blood pressure) or patient education (diet/nutrition, exercise, and stress management), were ordered/provided. Multivariate analysis was performed to identify independent predictors of diabetes preventive care services, controlling for patient and physician practice characteristics. All analyses were adjusted for the complex survey design and analytic weights. RESULTS: Compared with people without diabetes, diabetic patients were older (63 vs. 53 years; P < 0.01) and were more likely to be nonwhite and covered by Medicare insurance. In multivariate analyses, younger patients and the availability of primary care physicians, electronic medical records, and on-site laboratory tests were associated with more effective preventive care services (P < 0.05). If physician compensation relied on productivity, preventive care services were less likely (odds ratio 0.4 [95% CI 0.27-0.82 for men and 0.26-0.81 for women]). Although the patterns of patient education and diagnostic testing were similar, the provision of patient education was less likely than that of diagnostic testing. CONCLUSIONS: Primary care physicians and practice features seem to steer diabetes preventive services. Given the time constraints of physicians, strategies to strengthen structural capabilities of primary care practices and enhance partnerships with public health systems on diabetic patient education are recommended. PMID- 20843973 TI - Clinical outcomes of pregnancies complicated by mild gestational diabetes mellitus differ by combinations of abnormal oral glucose tolerance test values. AB - OBJECTIVE: To examine the association between levels of hyperglycemia, determined by each prenatal oral glucose tolerance test (OGTT) value (fasting, 1 and 2 h), and maternal and perinatal outcomes and to determine whether the risk for these outcomes differs for women whose value(s) equaled or exceeded the thresholds for gestational diabetes mellitus (GDM) established by the International Association of Diabetes in Pregnancy Study Groups (IADPSG). RESEARCH DESIGN AND METHODS: This article discusses a retrospective study of 8,711 women, delivering at >= 20 weeks' gestation, who had a prenatal 2-h 75-g OGTT without a prior 50-g challenge and were not treated with insulin, glyburide, diet, and/or exercise during pregnancy. Associations between adverse outcomes and elevated OGTT values are reported. RESULTS: After excluding treated women, 19.4% of the remaining women had IADPSG-defined GDM. Continuous fasting, 1- and 2-h OGTT measures, and GDM (yes/no) were significantly associated with most adverse outcomes. However, the magnitude and significance of risk for these outcomes differed by various combinations of abnormal glucose values. Women with normal fasting and elevated postload values were at higher risk for preterm delivery, gestational hypertension, and having an infant with hyperbilirubinema, whereas women with elevated fasting and normal postload values were at higher risk of having a large for-gestational-age infant, compared with women without GDM. CONCLUSIONS: Risks for different adverse outcomes vary depending on which single or combined IADPSG defined OGTT thresholds are equaled or exceeded. Prospective studies are needed to determine whether changing pre- and postprandial glucose targets during pregnancy will more uniformly reduce adverse outcomes. PMID- 20843974 TI - The influence of glycemic control on the prognosis of Japanese patients undergoing percutaneous transluminal angioplasty for critical limb ischemia. AB - OBJECTIVE: To reveal the influence of preoperative factors on the prognosis of patients undergoing percutaneous transluminal angioplasty (PTA) for critical limb ischemia (CLI). RESEARCH DESIGN AND METHODS: We recruited 278 Japanese patients who underwent PTA for CLI between 2003 and 2009. The outcome measures were mortality and major amputation. Cox proportional hazards regression analyses were performed. RESULTS: The prevalence of diabetes was 71%, and A1C was 7.0 +/- 1.4%. The follow-up period was 90 +/- 72 weeks, and 48 patients underwent major amputations and 89 died. The presence of diabetes in the whole population and A1C level in the diabetic population had no influence on morality; rather, mortality was associated with age (P = 0.007), impaired activities of daily living (P < 0.001), hemodialysis (P < 0.001), and albumin level (P = 0.010). In contrast, the presence of diabetes and A1C level had significant association with major amputation (P = 0.012 and P = 0.007, respectively). The quartile analysis showed that diabetic subjects with an A1C >= 6.8%, but not <6.8%, had a significantly higher risk of major amputation than nondiabetic subjects. The adjusted hazard ratio of diabetes with A1C >= 6.8% was 2.907 (95% CI 1.606-5.264) (P < 0.001). CONCLUSIONS: Diabetes with poor glycemic control is associated with major amputation, but not mortality, in CLI patients undergoing PTA. Prognostic indicators seem somewhat different between survival and limb salvage in the population. PMID- 20843975 TI - Menarchal timing in type 1 diabetes through the last 4 decades. AB - OBJECTIVE: We sought to examine whether age at menarche has changed over the past 4 decades by comparing age at menarche by year of diagnosis with type 1 diabetes. RESEARCH DESIGN AND METHODS: This work consisted of a cross-sectional study of age at menarche in two cohorts: adolescents (ages 11-24 years, n = 228) and adults (ages 19-55 years, n = 290, enrolled in the Coronary Artery Calcification in Type 1 Diabetes study). RESULTS: The adolescent cohort reported a younger age of menarche than the adult women with type 1 diabetes (12.69 +/- 0.08 vs. 13.22 +/- 0.12 years, mean +/- SE, P < 0.001). Age at menarche was later in both adolescent girls and adult women with type 1 diabetes diagnosed before menarche (12.82 +/- 1.16 and 13.7 +/- 2.23 years) than for individuals diagnosed after menarche (12.12 +/- 1.25 and 12.65 +/- 1.38 years, P < 0.001 for both). Age at menarche was then examined by decade of type 1 diabetes diagnosis (1970-1979, 1980-1989, 1990-1999, and 2000-2009). Age at menarche significantly declined over the 4 decades (P = 0.0002). However, the delay in menarche among girls diagnosed with type 1 diabetes before menarche compared with those diagnosed after menarche was also significant across all decades (P < 0.0001) and did not change significantly over time (P = 0.41 for interaction of cohort and diagnosis premenarche). CONCLUSIONS: Age at menarche has declined over the past 4 decades among girls with type 1 diabetes, but a delay in age at menarche remains among individuals diagnosed before menarche compared with individuals diagnosed after menarche. PMID- 20843976 TI - Sagittal abdominal diameter is a strong anthropometric measure of visceral adipose tissue in the Asian general population. AB - OBJECTIVE: Finding the anthropometric measure of visceral obesity is essential to clinical practice, because it predicts cardiovascular and metabolic risks. Sagittal abdominal diameter (SAD) has been proposed as an estimate of visceral adipose tissue (VAT). The aim of the present study was to evaluate the usefulness of SAD in predicting visceral obesity by comparing SAD to other anthropometric measures. RESEARCH DESIGN AND METHODS: Estimation of subcutaneous and visceral adipose tissue and measurement of SAD and transverse abdominal diameter using computed tomography at the umbilical level were obtained in 5,257 men and women who were enrolled in a health checkup program in Korea. To compare SAD to other anthropometric measures, linear regression analyses were used to determine correlations between anthropometrics and visceral obesity. RESULTS: SAD showed a stronger correlation to VAT than waist circumference, BMI, and transverse abdominal diameter in the both sexes (men: r = 0.804, women: r = 0.724). Waist circumference showed generally stronger associations to subcutaneous adipose tissue (SAT) than to VAT (men: r = 0.789 vs. 0.705, women: r = 0.820 vs. 0.636). Even after subdividing according to age or BMI in both sexes and analyzing multiple regressions, SAD showed the strongest correlation to VAT. CONCLUSIONS: SAD showed the strongest correlation to VAT irrespective of age, sex, and the degree of obesity compared with other anthropometric measures, whereas waist circumference may have a stronger correlation to SAT than to VAT. The clinical use of SAD has advantages over other anthropometric measures in predicting VAT. PMID- 20843977 TI - Comparison of outcomes following thrombolytic therapy among patients with prior stroke and diabetes in the Virtual International Stroke Trials Archive (VISTA). AB - OBJECTIVE: The use of alteplase in patients who have had a prior stroke and concomitant diabetes is not approved in Europe. To examine the influence of diabetes and prior stroke on outcomes, we compared data on thrombolysed patients with nonthrombolysed comparators. RESEARCH DESIGN AND METHODS: We selected patients with ischemic stroke on whom we had data on age, pretreatment baseline National Institutes of Health Stroke Scale (b-NIHSS), and 90-day outcome measures (functional modified Rankin score [mRS]) and neurological measures [NIHSS]) in the Virtual International Stroke Trials Archive. We compared outcomes between thrombolysed patients and nonthrombolysed comparators in those with and without diabetes, those who have had a prior stroke, or both and report findings using the Cochran-Mantel-Haenszel (CMH) test and proportional odds logistic regression analyses. We report an age-adjusted and b-NIHSS-adjusted CMH P value and odds ratio (OR). RESULTS: Rankin data were available for 5,817 patients: 1,585 thrombolysed patients and 4,232 nonthrombolysed comparators. A total 1,334 (24.1%) patients had diabetes, 1,898 (33.7%) patients have had a prior stroke, and 491 (8%) patients had both. Diabetes and nondiabetes had equal b-NIHSS (median 13; P = 0.3), but patients who have had a prior stroke had higher b-NIHSS than patients who have not had a prior stroke (median 13 vs. 12; P < 0.0001). Functional outcomes were better for thrombolysed patients versus nonthrombolysed comparators among both nondiabetic (P < 0.0001; OR 1.4 [95% CI 1.3-1.6]) and diabetic (P = 0.1; 1.3 [1.05-1.6 ]) subjects. Similarly, outcomes were better for thrombolysed patients versus nonthrombolysed comparators among who have not had a prior stroke (P < 0.0001; 1.4 [1.2-1.6 ]) and those who have (P = 0.02; 1.3 [1.04 1.6 ]). There was no interaction of diabetes and prior stroke with treatment (P = 0.8). Neurological outcomes were consistent with the mRS. CONCLUSIONS: Outcomes from thrombolysis are better among patients with diabetes and/or those who have had a prior stroke than in control subjects. Withholding thrombolytic treatment from otherwise-eligible patients may not be justified. PMID- 20843978 TI - Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: a randomized crossover clinical trial. AB - OBJECTIVE: To determine the effects of the Dietary Approaches to Stop Hypertension (DASH) eating pattern on cardiometabolic risks in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: A randomized crossover clinical trial was undertaken in 31 type 2 diabetic patients. For 8 weeks, participants were randomly assigned to a control diet or the DASH eating pattern. RESULTS: After following the DASH eating pattern, body weight (P = 0.007) and waist circumference (P = 0.002) reduced significantly. Fasting blood glucose levels and A1C decreased after adoption of the DASH diet (-29.4 +/- 6.3 mg/dl; P = 0.04 and 1.7 +/- 0.1%; P = 0.04, respectively). After the DASH diet, the mean change for HDL cholesterol levels was higher (4.3 +/- 0.9 mg/dl; P = 0.001) and LDL cholesterol was reduced (-17.2 +/- 3.5 mg/dl; P = 0.02). Additionally, DASH had beneficial effects on systolic (-13.6 +/- 3.5 vs. -3.1 +/- 2.7 mmHg; P = 0.02) and diastolic blood pressure (-9.5 +/- 2.6 vs. -0.7 +/- 3.3 mmHg; P = 0.04). CONCLUSIONS: Among diabetic patients, the DASH diet had beneficial effects on cardiometabolic risks. PMID- 20843979 TI - Small self-cleaving ribozymes. AB - The hammerhead, hairpin, hepatitis delta virus (HDV), Varkud Satellite (VS), and glmS ribozymes catalyze sequence-specific intramolecular cleavage of RNA. They range between 50 and 150 nucleotides in length, and are known as the "small self cleaving ribozymes." Except for the glmS ribozyme that functions as a riboswitch in Gram-positive bacteria, they were originally discovered as domains of satellite RNAs. However, recent studies show that several of them are broadly distributed in genomes of organisms from many phyla. Each of these ribozymes has a unique overall architecture and active site organization. Crystal structures have revealed how RNA active sites can bind preferentially to the transition state of a reaction, whereas mechanistic studies have shown that nucleobases can efficiently perform general acid-base and electrostatic catalysis. This versatility explains the abundance of ribozymes in contemporary organisms and also supports a role for catalytic RNAs early in evolution. PMID- 20843980 TI - Understanding the structure and function of the immunological synapse. AB - The immunological synapse has been an area of very active scientific interest over the last decade. Surprisingly, much about the synapse remains unknown or is controversial. Here we review some of these current issues in the field: how the synapse is defined, its potential role in T-cell function, and our current understanding about how the synapse is formed. PMID- 20843981 TI - Associations of six single nucleotide polymorphisms in obesity-related genes with BMI and risk of obesity in Chinese children. AB - OBJECTIVE: Childhood obesity strongly predisposes to some adult diseases. Recently, genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with BMI and obesity. The associations of those SNPs with BMI and obesity among other ethnicities are not fully described, especially in children. Among those previously identified SNPs, we selected six (rs7138803, rs1805081, rs6499640, rs17782313, rs6265, and rs10938397, in or near obesity-related genes FAIM2, NPC1, FTO, MC4R, BDNF, and GNPDA2, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with BMI and obesity in Chinese children. RESEARCH DESIGN AND METHODS: We investigated the associations of these SNPs with BMI and obesity in school-aged children. A total of 3,503 children participated in the study, including 1,229 obese, 655 overweight, and 1,619 normal-weight children (diagnosed by the Chinese age- and sex-specific BMI cutoffs). RESULTS: After age and sex adjustment and correction for multiple testing, the SNPs rs17782313, rs6265, and rs10938397 were associated with BMI (P = 1.0 * 10-5, 0.038, and 0.00093, respectively) and also obesity (P = 5.0 * 10-6, 0.043, and 0.00085, respectively) in the Chinese children. The SNPs rs17782313 and rs10938397 were also significantly associated with waist circumference, waist-to-height ratio, and fat mass percentage. CONCLUSIONS: Results of this study support obesity-related genes in adults as important genes for BMI variation in children and suggest that some SNPs identified by GWA studies in Caucasians also confer risk for obesity in Chinese children. PMID- 20843982 TI - Perspectives on withdrawing pacemaker and implantable cardioverter-defibrillator therapies at end of life: results of a survey of medical and legal professionals and patients. AB - OBJECTIVE: To determine the opinions of medical professionals, legal professionals, and patients regarding the withdrawal of implantable cardioverter defibrillator (ICD) and pacemaker therapy at the end of life. PARTICIPANTS AND METHODS: A survey regarding 5 cases that focused on withdrawal of ICD or pacemaker therapy at the end of life was constructed and sent to 5270 medical professionals, legal professionals, and patients. The survey was administered from March 1, 2008, to March 1, 2009. RESULTS: Of the 5270 recipients of the survey, 658 (12%) responded. In a terminally ill patient requesting that his ICD be turned off, most legal professionals (90% [63/70]), medical professionals (98% [330/336]), and patients (85% [200/236]) agreed the ICD should be turned off. Most legal professionals (89%), medical professionals (87%), and patients (79%) also considered withdrawal of pacemaker therapy in a non-pacemaker-dependent patient appropriate. However, significantly more legal (81%) than medical professionals (58%; P<.001) or patients (68%, P=.02) agreed with turning off a pacemaker in the pacemaker-dependent patient. A similar number of legal professionals thought turning off a device was legal regardless of whether it was an ICD or pacemaker (45% vs 38%; P=.50). However, medical professionals were more likely to perceive turning off an ICD as legal than turning off a pacemaker (85% vs 41%; P<.001). CONCLUSION: Most respondents thought device therapy should be withdrawn if the patient requested its withdrawal at the end of life. However, opinions of medical professionals and patients tended to be dependent on the type of device, with turning off ICDs being perceived as more acceptable than turning off pacemakers, whereas legal professionals tended to perceive all devices as similar. Thus, education and discussion regarding managing devices at the end of life are important when having end-of-life discussions and making end-of-life decisions to better understand patients' perceptions and expectations. PMID- 20843983 TI - Low allergenic potential with fondaparinux: results of a prospective investigation. AB - OBJECTIVE: To determine the incidence and causes of skin reactions to the synthetic pentasaccharide fondaparinux. PATIENTS AND METHODS: Patients who received prophylactic/therapeutic subcutaneous fondaparinux treatment for more than 7 days were prospectively examined for cutaneous adverse effects between September 1, 2008, and April 30, 2009. When indicated, other procedures, such as skin biopsy, allergy testing, and clinical/laboratory assessment for thrombosis and heparin-induced thrombocytopenia, were performed. RESULTS: Overall, 231 patients were enrolled. No patient developed typical delayed type IV hypersensitivity (DTH) erythematous skin lesions. However, one female patient experienced abdominal pruritus at sites of injection. Histology revealed a mild lymphohistiocytic infiltrate, confirming a DTH reaction. Heparin-induced thrombocytopenia, as another possible underlying pathomechanism for cutaneous lesions, was ruled out clinically and serologically. Hence, the overall incidence of fondaparinux-induced allergic skin lesions was 0.4% (95% confidence interval, 0.01%-2.4%). No cross-allergies were observed in patients with DTH reaction to heparins. CONCLUSION: Fondaparinux has a low allergenic potential. The incidence of allergic cutaneous DTH reactions is almost 20 times lower compared to that with commonly used heparins. These results, together with the known low prevalence of secondary thrombotic events or heparin-induced thrombocytopenia during fondaparinux therapy, suggest that in selected patients fondaparinux might substantially improve patient care, therapeutic safety, and cost-effectiveness of anticoagulant therapy. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00510432. PMID- 20843984 TI - Addition of cetuximab to first-line chemotherapy in patients with advanced non small-cell lung cancer: a cost-utility analysis. AB - BACKGROUND: Adding cetuximab to standard chemotherapy results in a moderate increase of overall survival in patients with advanced non-small-cell lung cancer (NSCLC), but the cost-effectiveness is unknown. MATERIALS AND METHODS: A Markov model was constructed based on the results of the First-Line ErbituX in lung cancer randomized trial, adding cetuximab to cisplatin-vinorelbine first-line chemotherapy in patients with advanced NSCLC. The primary outcome was the incremental cost-effectiveness ratio (ICER) of adding cetuximab, expressed as cost per quality-adjusted life year (QALY) gained, and relative to a willingness to-pay threshold of ?60 000/QALY. The impact of cetuximab intermittent dosing schedules on the ICER was also evaluated. RESULTS: Adding cetuximab to standard chemotherapy leads to a gain of 0.07 QALYs per patient at an additional cost of ?26 088. The ICER for adding cetuximab to chemotherapy was ?376 205 per QALY gained. Intermittent cetuximab dosing schedules resulted in ICERs per QALY gained between ?31 300 and ?83 100, under the assumption of equal efficacy. CONCLUSIONS: From a health economic perspective, the addition of cetuximab to standard first line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high ICER compared with other health care interventions. Treatment schedules resulting in more favorable cost-utility ratios should be evaluated. PMID- 20843986 TI - Epistle. PMID- 20843985 TI - sRNATarBase: a comprehensive database of bacterial sRNA targets verified by experiments. AB - Bacterial sRNAs are an emerging class of small regulatory RNAs, 40-500 nt in length, which play a variety of important roles in many biological processes through binding to their mRNA or protein targets. A comprehensive database of experimentally confirmed sRNA targets would be helpful in understanding sRNA functions systematically and provide support for developing prediction models. Here we report on such a database--sRNATarBase. The database holds 138 sRNA target interactions and 252 noninteraction entries, which were manually collected from peer-reviewed papers. The detailed information for each entry, such as supporting experimental protocols, BLAST-based phylogenetic analysis of sRNA-mRNA target interaction in closely related bacteria, predicted secondary structures for both sRNAs and their targets, and available binding regions, is provided as accurately as possible. This database also provides hyperlinks to other databases including GenBank, SWISS-PROT, and MPIDB. The database is available from the web page http://ccb.bmi.ac.cn/srnatarbase/. PMID- 20843987 TI - Review: acute serum procalcitonin levels may indicate pyelonephritis in children with febrile UTIs. PMID- 20843988 TI - Nebulised hypertonic saline reduced the severity of illness in infants with bronchiolitis. PMID- 20843989 TI - Health services research: rethinking the quest to be useful. AB - Health services research (HSR) is conceived as an applied discipline and studies are expected to be useful. Yet some of the most justly famous and important HSR has no tangible short-term impact. This raises the question of what constitutes 'useful' and whether it is possible to predict which studies will influence policy or practice. Attribution is also a constant issue: elements of health care systems change all the time and changes consistent with research findings may not signal causation but mere correlation. It is possible to make good changes in the absence of solid research evidence and it is also possible to make good changes while unaware of supportive research. Given these contingencies, it is worthwhile reflecting on the extent to which it is reasonable to expect HSR to affect policy or practice. Herein lies a paradox: the easier it is to act on research evidence, the more likely the change may have taken place regardless, while the more original and potentially game-changing the research, the greater the challenge of responding to it. It is nonetheless possible to design health services research more effectively to increase the likelihood of applicability (usually by broadening its scope and examining contextual issues that decision-makers must take into account). For their part, funders of HSR should take note of the historical fact that uptake of the most important work may take decades and may manifest in unforeseeable ways. PMID- 20843990 TI - Lopinavir/ritonavir monotherapy versus current treatment continuation for maintenance therapy of HIV-1 infection: the KALESOLO trial. AB - OBJECTIVES: We evaluated a monotherapy maintenance regimen with lopinavir/ritonavir versus continuing current combined antiretroviral treatment (cART) in HIV patients with suppressed plasma HIV-1 RNA. PATIENTS AND METHODS: This was an open-label, non-inferiority, multicentre trial in 23 sites in France. Adults were randomized if they had no history of virological failure while receiving a protease inhibitor, maintained HIV-1 RNA <50 copies/mL for at least 6 months and did not change cART during the last 3 months. The primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 (non inferiority margin set at -12%) with missing data and treatment modification considered as failure. The trial has been registered in ClinicalTrials.gov under the identifier NCT00140751. RESULTS: At Week 48, 84% (73/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group [difference, -4.0%, lower limit of 90% two-sided confidence interval (CI) for difference, -12.4%]. In secondary analysis with success defined as plasma HIV-1 RNA <400 copies/mL, 87% (76/87) of patients in the lopinavir/ritonavir monotherapy group were virologically suppressed compared with 88% (87/99) in the cART group (difference, -0.5%, lower limit of 90% two sided CI for difference, -8.5%). If antiretroviral treatment intensification was taken into account, 91% (79/87) of patients in the lopinavir/ritonavir monotherapy group met the primary endpoint compared with 88% (87/99) in the cART group (difference, +2.9%, lower limit of 90% two-sided CI for difference, -4.5%). Failures of lopinavir/ritonavir monotherapy did not show acquired resistance mutations in the protease gene. CONCLUSIONS: Lopinavir/ritonavir monotherapy did not achieve non-inferiority versus cART for maintaining plasma HIV-1 RNA <50 copies/mL. Nevertheless, the incidence of virological failure was low (mostly with HIV-1 RNA <400 copies/mL) and easily managed by treatment intensification. PMID- 20843991 TI - Quantitative MR imaging of brain iron: a postmortem validation study. AB - PURPOSE: To investigate the relationship between transverse relaxation rates R2 and R2*, the most frequently used surrogate markers for iron in brain tissue, and chemically determined iron concentrations. MATERIALS AND METHODS: This study was approved by the local ethics committee, and informed consent was obtained from each individual's next of kin. Quantitative magnetic resonance (MR) imaging was performed at 3.0 T in seven human postmortem brains in situ (age range at death, 38-81 years). Following brain extraction, iron concentrations were determined with inductively coupled plasma mass spectrometry in prespecified gray and white matter regions and correlated with R2 and R2* by using linear regression analysis. Hemispheric differences were tested with paired t tests. RESULTS: The highest iron concentrations were found in the globus pallidus (mean +/- standard deviation, 205 mg/kg wet mass +/- 32), followed by the putamen (mean, 153 mg/kg wet mass +/- 29), caudate nucleus (mean, 92 mg/kg wet mass +/- 15), thalamus (mean, 49 mg/kg wet mass +/- 11), and white matter regions. When all tissue samples were considered, transverse relaxation rates showed a strong linear correlation with iron concentration throughout the brain (r2 = 0.67 for R2, r2 = 0.90 for R2*; P < .001). In white matter structures, only R2* showed a linear correlation with iron concentration. Chemical analysis revealed significantly higher iron concentrations in the left hemisphere than in the right hemisphere, a finding that was not reflected in the relaxation rates. CONCLUSION: Because of their strong linear correlation with iron concentration, both R2 and R2* can be used to measure iron deposition in the brain. Because R2* is more sensitive than R2 to variations in brain iron concentration and can detect differences in white matter, it is the preferred parameter for the assessment of iron concentration in vivo. PMID- 20843992 TI - Prostate cancer: differentiation of central gland cancer from benign prostatic hyperplasia by using diffusion-weighted and dynamic contrast-enhanced MR imaging. AB - PURPOSE: To analyze the diffusion and perfusion parameters of central gland (CG) prostate cancer, stromal hyperplasia (SH), and glandular hyperplasia (GH) and to determine the role of these parameters in the differentiation of CG cancer from benign CG hyperplasia. MATERIALS AND METHODS: In this institutional review board approved (with waiver of informed consent), HIPAA-compliant study, 38 foci of carcinoma, 38 SH nodules, and 38 GH nodules in the CG were analyzed in 49 patients (26 with CG carcinoma) who underwent preoperative endorectal magnetic resonance (MR) imaging and radical prostatectomy. All carcinomas and hyperplastic foci on MR images were localized on the basis of histopathologic correlation. The apparent diffusion coefficient (ADC), the contrast agent transfer rate between blood and tissue (K(trans)), and extravascular extracellular fractional volume values for all carcinoma, SH, and GH foci were calculated. The mean, standard deviation, 95% confidence interval (CI), and range of each parameter were calculated. Receiver operating characteristic (ROC) and multivariate logistic regression analyses were performed for differentiation of CG cancer from SH and GH foci. RESULTS: The average ADCs (* 10(-3) mm(2)/sec) were 1.05 (95% CI: 0.97, 1.11), 1.27 (95% CI: 1.20, 1.33), and 1.73 (95% CI: 1.64, 1.83), respectively, in CG carcinoma, SH foci, and GH foci and differed significantly, yielding areas under the ROC curve (AUCs) of 0.99 and 0.78, respectively, for differentiation of carcinoma from GH and SH. Perfusion parameters were similar in CG carcinomas and SH foci, with K(trans) yielding the greatest AUCs (0.75 and 0.58, respectively). Adding K(trans) to ADC in ROC analysis to differentiate CG carcinoma from SH increased sensitivity from 38% to 57% at 90% specificity without noticeably increasing the AUC (0.79). CONCLUSION: ADCs differ significantly between CG carcinoma, SH, and GH, and the use of them can improve the differentiation of CG cancer from SH and GH. Combining K(trans) with ADC can potentially improve the detection of CG cancer. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100021/-/DC1. PMID- 20843993 TI - Assessment of non-small cell lung cancer perfusion: pathologic-CT correlation in 15 patients. AB - PURPOSE: To assess tumor perfusion with multi-detector row computed tomography (CT) in patients with non-small cell lung carcinoma and to correlate CT findings with pathologic results. MATERIALS AND METHODS: This study was approved by the local Ethics Committee, and all patients provided written informed consent, which included information on the radiation exposure at the CT examinations. Fifteen consecutive patients (mean age, 60.5 years +/- 7.7 [standard deviation]), including 14 men (mean age, 59.9 years +/- 7.5) and one woman (age, 70 years) with histologically proved non-small cell lung carcinoma were prospectively enrolled. Overall, pathologic-CT correlations were examined in 31 focal tumoral zones. Comparative analysis was performed by using the chi(2) or the Fisher exact test for categoric data. For numeric data, group comparisons were performed by using the Mann-Whitney test. RESULTS: Whole-tumor coverage (mean height, 4.3 cm +/- 2.1) was possible in all patients with generation of colored parametric maps of volume transfer constant (K(trans)) and blood volume (BV) by using Patlak analysis. Of the 12 areas that showed high BV, 10 (83%) had a high K(trans); in all 12 cases, the vascular score was high, confirming the presence of numerous tumoral vessels. Nineteen areas showed low BV; when observed concurrently with a high K(trans) (seven of 19), the mean vessel number per area was significantly higher than that seen in areas with low BV and low K(trans) (12 of 19) (P = .038), suggestive of tumoral vessels associated with high interstitial pressure. CONCLUSION: Whole-tumor perfusion analysis is technically feasible with 64 detector row CT, with two patterns suggestive of high tumoral vascularity. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100181/-/DC1. PMID- 20843994 TI - Selective atrophy of the middle hepatic venous drainage area in hepatitis C related cirrhotic liver: morphometric study by using multidetector CT. AB - PURPOSE: To retrospectively analyze the morphologic changes of hepatitis C related cirrhosis, which commonly show macronodular cirrhosis, in relation to the portal venous supply and hepatic venous drainage, by using multidetector computed tomographic volumetry. MATERIALS AND METHODS: Institutional ethics committee approval and informed consent were obtained. The volume of the entire liver, each portal segment, and hepatic venous drainage area with the respective proportion relative to the entire liver and the volume of hepatic area with the respective proportion relative to the anterior segment of the right lobe were measured in 74 patients without cirrhosis and with normal liver function and in 64 patients with cirrhosis classified as Child-Pugh class A and in 68 with that classified as Child-Pugh class B. The diameter and length of each hepatic vein were measured in normal liver. All measurements were statistically analyzed by using the Kruskal Wallis test, and multiple comparisons were made by using a Bonferroni correction (P < .05). RESULTS: The entire liver volume was significantly smaller in patients with Child-Pugh class B cirrhosis (P = .002), whereas there was no significant difference in volume between the normal liver and the liver with Child-Pugh class A cirrhosis (P > .99). Middle hepatic venous (MHV) drainage area revealed significant atrophy in cirrhosis (P < .0001), more markedly in Child-Pugh class B. The right hepatic venous (RHV) and left hepatic venous drainage areas showed significant hypertrophy in cirrhosis (P < .0001). The anterior and medial segments showed significant atrophy (P < .0001), and the lateral and posterior segments and caudate lobe showed significant hypertrophy in cirrhosis (P < .05). In the anterior segment, the MHV drainage area showed significant atrophy (P < .0001), and the RHV drainage area demonstrated relative hypertrophy in cirrhosis, more definitely in Child-Pugh class B. The diameter of MHV was significantly the smallest (P < .0001), and the length of MHV was relatively longer in normal livers. CONCLUSION: The morphologic changes in hepatitis C-related cirrhosis (mainly macronodular cirrhosis) were attributed to a selective volume reduction of the MHV drainage area and relative enlargement of the other areas. PMID- 20843995 TI - Apelin mediates the induction of profibrogenic genes in human hepatic stellate cells. AB - Apelin is a peptide with relevant functions in angiogenesis and inflammation. Recent studies have demonstrated that apelin is overexpressed in hepatic stellate cells (HSCs) of cirrhotic rats. Moreover, patients with cirrhosis show high circulating levels of this peptide. We evaluated the role of endogenous apelin system in fibrogenesis-related gene induction in human HSCs. Messenger expression and immunolocalization of apelin were analyzed in human cirrhotic liver and in control samples. Apelin expression was analyzed in a human HSC line (LX-2) under hypoxic conditions or in the presence of proinflammatory or profibrogenic stimuli. LX-2 cells were stimulated with apelin, and a selected profile of fibrogenesis-related genes was quantified. In vivo inactivation of apelin was analyzed in the liver of fibrotic rats after administrating specific blockers of the molecules triggering apelin induction. Apelin was overexpressed in HSCs from human cirrhotic liver. Neither hypoxia nor proinflammatory substances induced the expression of apelin in LX-2. By contrast, both profibrogenic molecules angiotensin II (AII) and endothelin-1 (ET-1) enhanced apelin expression in these cells. Apelin increased the synthesis of collagen-I and platelet-derived growth factor receptor beta (PDGFRbeta) in LX-2. AII and ET-1 stimulated collagen-I and PDGFRbeta expression, and this induction was drastically reduced when apelin receptor was blocked in these cells. In accordance, AII or ET-1 receptor antagonists reduced the hepatic synthesis of apelin, collagen-I, and PDGFRbeta in fibrotic rats. CONCLUSIONS: apelin mediates some of the fibrogenic effects triggered by AII and ET-1, thus suggesting that apelin could be an important mediator of fibrogenesis in human liver disease. PMID- 20843996 TI - Corticosterone regulates synaptic input organization of POMC and NPY/AgRP neurons in adult mice. AB - Changes in circulating hormones, such as leptin and ghrelin, induce alterations in synaptic input organization and electrophysiological properties of neurons of the arcuate nucleus of the hypothalamus. To assess whether changes in circulating glucocorticoids also alter synaptic arrangement and membrane potential properties, we studied the effect of adrenalectomy (ADX) and corticosterone replacement in mice on the proopiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus. ADX reduced the number of symmetric, putative inhibitory synapses onto POMC neurons and the number of asymmetric, putative excitatory synapses onto NPY/AgRP neurons. Corticosterone replacement in ADX mice to levels similar to sham operated animals restored the number of synapses onto POMC and NPY/AgRP neurons to that seen in sham-operated controls. The alterations in the synaptic arrangement in ADX mice were not due to their decrease in food intake as evidenced by the synaptic analysis of the pair-fed control animals. In line with the altered synaptic input organization, a depolarization of POMC membrane potential and a hyperpolarization of NPY/AgRP membrane potential were observed in ADX mice compared with their sham-operated controls. All of these changes reverted upon corticosterone replacement. These results reveal that the known orexigenic action of corticosteroids is mediated, at least in part, by synaptic changes and altered excitability of the melanocortin system. PMID- 20843998 TI - Development and hormonal regulation of the ovarian lymphatic vasculature. AB - The lymphatic vasculature plays a number of essential physiological roles including maintaining fluid homeostasis, providing a network for the transport of immune cells, and facilitating the uptake of fat-soluble nutrients from the gastrointestinal tract. Although the critical importance and remodeling capacity of the blood vasculature has been well described within the ovary, just a few reports describe the lymphatic vasculature. Using histological and molecular techniques, we report the kinetics of ovarian lymphangiogenesis and the hormonal regulation of lymphangiogenic growth factors associated with key stages of ovarian follicle growth. We exploited the Adamts1-null mouse model, a model with a previously characterized lymphatic defect to further interrogate the mechanisms controlling ovarian lymphangiogenesis. The establishment and development of the ovarian lymphatic vascular network in postnatal developing ovaries was associated with the presence and hormonal regulation of the lymphangiogenic growth factors and their receptors, including Vegfc, Vegfd, and Vegfr3. We characterized the hormonally regulated remodeling of the ovarian lymphatic vasculature in response to FSH and estradiol. The lymphatic network was defective in the Adamts1-null ovary, clearly demonstrating both the involvement of FSH/estradiol and the Adamts1 (a disintegrin and metalloproteinase with thrombospondin motifs 1) protease in ovarian lymphangiogenesis. This study provides the first evidence of a malleable lymphatic system responsive to hormonal changes of the female reproductive cycle, at least in the mouse ovary, suggesting a role for lymphatic vessel functions in normal folliculogenesis. PMID- 20843997 TI - Developmental programming: differential effects of prenatal testosterone excess on insulin target tissues. AB - Polycystic ovarian syndrome (PCOS) is the leading cause of infertility in reproductive-aged women with the majority manifesting insulin resistance. To delineate the causes of insulin resistance in women with PCOS, we determined changes in the mRNA expression of insulin receptor (IR) isoforms and members of its signaling pathway in tissues of adult control (n = 7) and prenatal testosterone (T)-treated (n = 6) sheep (100 mg/kg twice a week from d 30-90 of gestation), the reproductive/metabolic characteristics of which are similar to women with PCOS. Findings revealed that prenatal T excess reduced (P < 0.05) expression of IR-B isoform (only isoform detected), insulin receptor substrate-2 (IRS-2), protein kinase B (AKt), peroxisome proliferator-activated receptor-gamma (PPARgamma), hormone-sensitive lipase (HSL), and mammalian target of rapamycin (mTOR) but increased expression of rapamycin-insensitive companion of mTOR (rictor), and eukaryotic initiation factor 4E (eIF4E) in the liver. Prenatal T excess increased (P < 0.05) the IR-A to IR-B isoform ratio and expression of IRS 1, glycogen synthase kinase-3alpha and -beta (GSK-3alpha and -beta), and rictor while reducing ERK1 in muscle. In the adipose tissue, prenatal T excess increased the expression of IRS-2, phosphatidylinositol 3-kinase (PI3K), PPARgamma, and mTOR mRNAs. These findings provide evidence that prenatal T excess modulates in a tissue-specific manner the expression levels of several genes involved in mediating insulin action. These changes are consistent with the hypothesis that prenatal T excess disrupts the insulin sensitivity of peripheral tissues, with liver and muscle being insulin resistant and adipose tissue insulin sensitive. PMID- 20844000 TI - Phenotypic plasticity of the ovarian surface epithelium: TGF-beta 1 induction of epithelial to mesenchymal transition (EMT) in vitro. AB - Ovarian surface epithelium (OSE) is the most conceivable cell origin of epithelial ovarian carcinomas. Unlike many other epithelial tumors, the precancerous lesion acquires expression of epithelial markers, e.g. E-cadherin and claudins, suggesting that OSE cells undergo mesenchymal to epithelial transition (MET) during transformation. Recent findings indicate that TGF-beta1, a prototypic stimulus of epithelial to mesenchymal transition (EMT), i.e. reverse to MET, is produced at significant amounts in the intact ovary. In the present study, we therefore investigated whether TGF-beta1 changes the OSE phenotype accordingly, focusing on epithelial junction proteins and transcriptional EMT regulators quantified by real-time RT-PCR and Western blotting in cultured normal human OSE. Early OSE passages were found to paradoxically express de novo E cadherin and also establish tight junctions exhibiting claudin-1 (but not claudin 3 and -4) and occludin. Stimulation with TGF-beta1 (100 ng/ml) for 3-5 d down regulated all these epithelial markers including Crumbs3 and also prevented the formation of an epithelial barrier This was accompanied by sustained expression of Snail and N-cadherin and transient expression of Slug, whereas Zeb1 (zinc finger E-box binding homeobox 1) and Twist mRNA levels were not significantly changed. In conclusion, TGF-beta1 enforces the mesenchymal phenotype of OSE cells in vitro by an EMT-like process, leading to an altered molecular composition of the epithelial junction complex that partly coincides with the expression pattern of the native OSE. This suggests a potential role of TGF-beta1-induced EMT in OSE under physiological conditions and possibly also in epithelial ovarian tumorigenesis. PMID- 20843999 TI - Beneficial metabolic effects caused by persistent activation of beta-cell M3 muscarinic acetylcholine receptors in transgenic mice. AB - Previous studies have shown that beta-cell M(3) muscarinic acetylcholine receptors (M3Rs) play a key role in maintaining blood glucose homeostasis by enhancing glucose-dependent insulin release. In this study, we tested the hypothesis that long-term, persistent activation of beta-cell M3Rs can improve glucose tolerance and ameliorate the metabolic deficits associated with the consumption of a high-fat diet. To achieve the selective and persistent activation of beta-cell M3Rs in vivo, we generated transgenic mice that expressed the Q490L mutant M3R in their pancreatic beta-cells (beta-M3-Q490L Tg mice). The Q490L point mutation is known to render the M3R constitutively active. The metabolic phenotypes of the transgenic mice were examined in several in vitro and in vivo metabolic tests. In the presence of 15 mm glucose and the absence of M3R ligands, isolated perifused islets prepared from beta-M3-Q490L Tg mice released considerably more insulin than wild-type control islets. This effect could be completely blocked by incubation of the transgenic islets with atropine (10 MUm), an inverse muscarinic agonist, indicating that the Q490L mutant M3R exhibited ligand-independent signaling (constitutive activity) in mouse beta-cells. In vivo studies showed that beta-M3-Q490L Tg mice displayed greatly improved glucose tolerance and increased serum insulin levels as well as resistance to diet induced glucose intolerance and hyperglycemia. These results suggest that chronic activation of beta-cell M3Rs may represent a useful approach to boost insulin output in the long-term treatment of type 2 diabetes. PMID- 20844001 TI - Tumor suppressor action of liganded thyroid hormone receptor beta by direct repression of beta-catenin gene expression. AB - The abundance of beta-catenin, which plays a critical role in oncogenesis, is tightly controlled by proteasomal pathways. Its aberrant accumulation is associated with the overactivation of its oncogenic signaling and tumorigenesis in cancers, including thyroid cancer. Our previous studies have suggested that beta-catenin abundance could also be regulated at the transcriptional level by thyroid hormone (T(3)) and thyroid hormone receptor beta (TRbeta). By using hypothyroid mice supplemented or not with T(3), we showed that T(3) significantly repressed Ctnnb1 expression in vivo in the thyroid. By using two human cell lines, i.e., the thyroid HTori and the cervical cancer HeLa cell lines, each stably expressing TRbeta, we observed that T(3) induced the down-regulation of CTNNB1 transcript levels. Luciferase reporter assays with various constructs harboring 5' deletion of the CTNNB1 promoter or with mutated thyroid hormone response element (TRE) binding sites, and EMSAs showed that this transrepression was mediated through an interaction between TRbeta-retinoid X receptor beta complexes and TREs located in the human CTNNB1 promoter between -807 and -772 and consisting of two hexamers separated by 14 nucleotides. The direct regulation of CTNNB1 expression by TRbeta was further confirmed by chromatin immunoprecipitation assays showing TRbeta recruitment to the CTNNB1 promoter in thyroid cells. This is the first report demonstrating a direct repression of the beta-catenin gene by liganded TRbeta through interaction with negative TREs located in CTNNB1 promoter. Importantly, this study uncovers a new molecular mechanism whereby liganded TRbeta acts as a tumor suppressor via inhibition of the expression of a potent tumor promoter, the CTNNB1 gene. PMID- 20844002 TI - Cyclin G2 regulates adipogenesis through PPAR gamma coactivation. AB - Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor gamma (PPARgamma), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARgamma coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARgamma-responsive element of the promoter of aP2, which is a PPARgamma target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARgamma. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis. PMID- 20844003 TI - Progesterone increases systemic and local uterine proportions of CD4+CD25+ Treg cells during midterm pregnancy in mice. AB - Mechanisms maintaining the growth of a "semi-foreign" fetus within the maternal uterus via immune tolerance remain unclear. CD4(+)CD25(+) regulatory T (Treg) cells have been implicated in the maintenance of maternal-fetal immune tolerance. Additionally, 17beta-estradiol (E2) is able to initiate immune suppression through CD4(+)CD25(+) Treg cells during early pregnancy. Little is known, however, regarding the relationship between progesterone (P4) and immune tolerance during midterm pregnancy, an important period, characterized by higher levels of P4 but lower levels of E2 in the serum. Here, we examined the effects of P4 on the expansion and function of systemic and local uterine CD4(+)CD25(+) Treg cells during midterm pregnancy in mice. Using in vivo and in vitro models, we provide the first evidence that P4 not only increases the proportion of CD4(+)CD25(+) Treg cells and IL-10 expression but also enhances their suppressive function. Moreover, at physiological doses relevant to midterm pregnancy, P4, but not E2, converts CD4(+)CD25(-) T cells into CD4(+)CD25(+) Treg cells. This conversion was inhibited in vitro by the nuclear P4 receptors antagonist RU 486 and in vivo in P4-treated ovariectomized and pseudopregnant mice models, suggesting that P4 expands Treg populations via nuclear P4 receptors. Furthermore, RU 486 significantly reduced the quantity and function of Treg cells in the fetal-maternal interface before the onset of induced abortion. Interestingly, with decreasing Foxp3, proinflammatory factors increased. Together, the present results demonstrate that P4 is an important regulator of systemic and local CD4(+)CD25(+) Treg cells, which are involved in maintaining maternal-fetal immune tolerance during midterm pregnancy. PMID- 20844004 TI - Neutral antibodies to the TSH receptor are present in Graves' disease and regulate selective signaling cascades. AB - TSH receptor (TSHR) antibodies (Abs) may be stimulating, blocking, or neutral in their functional influences and are found in patients with autoimmune thyroid disease, especially Graves' disease (GD). Stimulators are known to activate the thyroid epithelial cells via both Gs- and Gq-coupled signaling pathways, whereas blockers inhibit the action of TSH and may act as weak agonists. However, TSHR neutral Abs do not block TSH binding and are unable to induce cAMP via Gsalpha. The importance of such neutral Abs in GD remains unclear because their functional consequence has been assumed to be zero. We hypothesized that: 1) neutral TSHR Abs are more common to GD than generally recognized; 2) they may induce distinct signaling imprints at the TSHR not seen with TSH itself; and 3) these signaling events may alter cellular function. To evaluate these hypotheses, we first confirmed the presence of neutral TSHR Abs in sera from patients with GD and then, using mouse and hamster neutral TSHR monoclonal Abs (N-mAbs) performed detailed signaling studies, including a proteomic Ab array, with rat thyrocytes (FRTL-5) as targets. This allowed us to examine a battery of signaling cascades and their downstream effectors. Neutral TSHR Abs were indeed frequently present in sera from patients with GD. Sixteen of 27 patients (59%) had detectable neutral TSHR Abs by competition assay with N-mAbs. On examining signaling cascades, we found that N-mAbs induced signal transduction, primarily via the protein kinase A II cascade. In addition to the activation of phosphatidylinositol 3K/Akt, N-mAbs, unlike TSH, had the ability to exclusively activate the mammalian target of rapamycin/p70 S6K, nuclear factor-kappaB, and MAPK-ERK1/2/p38alpha signaling cascades and their downstream effectors p90 ribosomal kinase/MAPK-interacting kinase-1/mitogen and stress-activated kinase-1 and N-mAbs activated all forms of protein kinase C isozymes. To define the downstream effector mechanisms produced by these signaling cascades, cytokine production, proliferation, and apoptosis in thyrocytes were investigated. Although N-mAbs produced less cytokines and proliferation compared with TSH, they had the distinction of inducing thyroid cell apoptosis under the experimental conditions used. When dissecting out possible mechanisms of apoptosis, we found that activation of multiple oxidative stress markers was the primary mechanism orchestrating the death signals. Therefore, using oxidative stress-induced apoptosis, N-mAbs may be capable of exacerbating the autoimmune response in GD via apoptotic cells inducing antigen-driven mechanisms. This may help explain the inflammatory nature of this common disorder. PMID- 20844006 TI - Decreased expression of natriuretic peptides associated with lipid accumulation in cardiac ventricle of obese mice. AB - Plasma B-type natriuretic peptide (BNP) and proBNP are established markers of cardiac dysfunction. Even though obesity increases the risk of cardiovascular disease, obese individuals have reduced plasma concentrations of natriuretic peptides. The underlying mechanism is not established. We used cultured cardiomyocytes and three different mouse models to examine the impact of obesity and cardiac lipid accumulation on cardiac natriuretic peptide expression. The cardiac ventricular expression of atrial natriuretic peptide (ANP) and BNP mRNA and ANP peptide was decreased 36-72% in obese ob/ob, db/db, and fat-fed C57BL/6 mice as compared with their respective controls. The db/db and ob/ob mice displayed impaired cardiac function, whereas the fat-fed mice had almost normal cardiac function. Moreover, the ventricular expression of hypertrophic genes (alpha- and beta-myosin heavy chain and alpha-actin) and natriuretic peptide receptor genes were not consistently altered by obesity across the three mouse models. In contrast, cardiac ventricular triglycerides were similarly increased by 60-115% in all three obese mouse models and incubation with oleic acid caused triglyceride accumulation and an approximately 35% (P < 0.005) depression of ANP mRNA expression in cultured HL-1 atrial myocytes. The data suggest that obesity and altered cardiac lipid metabolism are associated with reduced production of ANP and BNP in the cardiac ventricles in the setting of normal as well as impaired cardiac function. PMID- 20844005 TI - Liver-specific overexpression of pancreatic-derived factor (PANDER) induces fasting hyperglycemia in mice. AB - The pancreas-derived hormones, insulin and glucagon, are the two main regulators of glucose homeostasis. However, their actions can be modulated by the presence of other circulating factors including cytokines. Pancreatic-derived factor (PANDER) is a novel cytokine-like molecule secreted from the endocrine pancreas, but its biological function is currently unknown. To address this, we employed adenoviral gene delivery to develop a novel murine model of PANDER overexpression, which we used to study PANDER's effect on glucose homeostasis. Although serum metabolites in fed mice were unaffected by PANDER overexpression, fasting glucose, insulin, and corticosterone levels were significantly elevated. Additionally, PANDER-overexpressing mice displayed elevated glucose and insulin levels during a glucose tolerance test, indicating that glucose tolerance was impaired. However, there were no defects in glucose-stimulated insulin secretion or peripheral insulin sensitivity. Elevated transcription of hepatic gluconeogenic genes, PEPCK and G6Pase accompanied the fasting hyperglycemia observed in PANDER-overexpressing animals. Similarly, treatment of primary hepatocytes with PANDER-expressing adenovirus or PANDER-enriched conditioned medium elevated gluconeogenic gene expression and glucose output. PANDER treatment also resulted in higher levels of Ser133-phosphorylated cAMP-response element-binding protein in hepatocytes stimulated with 8-bromo-cAMP and dexamethasone and higher levels of intracellular cAMP upon stimulation with forskolin. In summary, we provide the first report that identifies PANDER as a regulator of hepatic glucose metabolism, where it serves as a novel factor that amplifies hepatic cAMP and cAMP-response element-binding protein signaling to induce gluconeogenic gene expression and glucose output. PMID- 20844007 TI - Deficiency of scavenger receptor class B type I negatively affects progesterone secretion in human granulosa cells. AB - Our goal was to examine the effect of deficiency of the lipoprotein receptor, scavenger receptor class B type I (SR-BI), on progesterone secretion in human granulosa cells (HGL5). Scrambled or SR-BI small interfering RNA [knockdown (KD)] cells were exposed to dimethylsulfoxide [DMSO, vehicle for forskolin (Fo)], Fo, serum, high-density lipoprotein, low-density lipoprotein (LDL), or Fo plus lipoproteins or serum for 24 h. Progesterone secretion was lower in all of the SR BI KD cells regardless of treatment. We examined progesterone secretion in SR-BI KD, LDL receptor KD, and double KD cells incubated with DMSO, Fo, LDL, or Fo + LDL for 6-24 h. As compared with scrambled cells, progesterone secretion was lower in SR-BI and double KD cells regardless of treatment; whereas progesterone secretion was only lower in LDL receptor KD cells incubated with LDL and Fo + LDL. We measured phosphorylation of hormone-sensitive lipase (pHSL) expression, intracellular total cholesterol (TC) mass, and progesterone secretion in scrambled and SR-BI KD cells incubated with DMSO or Fo for 2-24 h. The expression of pHSL was similar between the cells and conditions. The mean change in TC mass and progesterone secretion was lower in SR-BI KD cells exposed to DMSO and Fo. Incubating SR-BI KD cells with 22-hydroxy cholesterol did not overcome the reduction in progesterone secretion. At different time points, RNA expression of steroidogenic acute regulatory protein, side-chain cleavage, and 3beta hydroxysteroid dehydrogenase was significantly lower in SR-BI KD cells incubated with Fo. In conclusion, SR-BI protein deficiency, in part, might explain progesterone deficiency in some infertile women. PMID- 20844008 TI - Rac1-dependent intracellular superoxide formation mediates vascular endothelial growth factor-induced placental angiogenesis in vitro. AB - Vascular endothelial growth factor (VEGF) is one of the best characterized angiogenic factors controlling placental angiogenesis; however, how VEGF regulates placental angiogenesis has not yet completely understood. In this study, we found that all the components of assembling a functional NADPH oxidase (NOX2, p22(phox), p47(phox), p67(phox), and Rac1) are expressed in ovine fetoplacental artery endothelial cells (oFPAECs) in vitro and ex vivo. Treatment with VEGF (10 ng/ml) rapidly and transiently activated Rac1 in oFPAECs in vitro and increased Rac1 association with p67(phox) in 5 min. Intracellular superoxide formation began to significantly increase after 25-30 min of VEGF stimulation, which was mediated by both VEGFR1 and VEGFR2. VEGF also stimulated oFPAE cell proliferation and migration and enhanced the formation of tube-like structures on Matrigel matrix. In oFAPEC transfected with specific Rac1 small interfering RNA (siRNA, 40 nm), VEGF-induced intracellular superoxide formation was completely abrogated in association with a 78% reduction of endogenous Rac1. In oFPAE cells transfected with the specific Rac1 siRNA, but not with transfection reagent alone or scrambled control siRNA, VEGF-induced cell proliferation, migration, and tube like structure formation were dramatically inhibited. Pretreatment of an NADPH oxidase inhibitor apocynin also abrogates the VEGF-stimulated intracellular superoxide production and DNA synthesis in oFPAECs. Taken together, our results demonstrated that a Rac1/Nox2-based NADPH oxidase system is present in placental endothelial cells. This NADPH oxidase system appears to generate the second messenger superoxide that plays a critical role in the signaling control of the VEGF-induced placental angiogenesis. PMID- 20844009 TI - Mice lacking bone sialoprotein (BSP) lose bone after ovariectomy and display skeletal site-specific response to intermittent PTH treatment. AB - Bone sialoprotein (BSP) belongs to the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, whose members play multiple and distinct roles in the development, turnover, and mineralization of bone and dentin. The functions of BSP in bone remodeling are not yet well established. We previously showed that BSP knockout (BSP(-/-)) mice exhibit a higher trabecular bone volume, concomitant with lower bone remodeling, than wild-type (BSP(+/+)) mice. To determine whether bone turnover can be stimulated in the absence of BSP, we subjected BSP(+/+) and BSP(-/-) mice to catabolic [ovariectomy (OVX)] or anabolic (intermittent PTH administration) hormonal challenges. BSP(-/-) mice progressively develop hypocalcemia and high serum PTH between 2 and 4 months of age. Fifteen and 30 d after OVX, microtomography analysis showed a significant decrease of trabecular bone volume in tibiae of both genotypes. Histomorphometric parameters of bone formation and resorption were significantly increased by OVX. PTH treatment resulted in an increase of trabecular thickness and both bone formation and resorption parameters at all skeletal sites in both genotypes and a decrease of trabecular bone volume in tibiae of BSP(+/+) but not BSP(-/-) mice. PTH increased cortical thickness and bone area in BSP(+/+) but not BSP(-/-) mice and stimulated the bone formation rate specifically in the endosteum of BSP(+/+) mice and the periosteum of BSP(-/-) mice. PTH enhanced the expression of RANKL, MEPE, and DMP1 in both genotypes but increased OPG and OPN expression only in BSP(-/-) mice. In conclusion, despite the low basal turnover, both catabolic and anabolic challenges increase bone formation and resorption in BSP(-/-) mice, suggesting that compensatory pathways are operative in the skeleton of BSP-deficient mice. Although up-regulation of one or several other SIBLINGs is a possible mechanism, further studies are needed to analyze the interplay and cross-regulation involved in compensating for the absence of BSP. PMID- 20844010 TI - Effect of chronic hCG administration on Alzheimer's-related cognition and A beta accumulation in PS1KI mice. AB - Age-associated changes in the reproductive hormones-the gonadal steroid hormones and the gonadotropins-have been identified as potential risk factors for Alzheimer's disease (AD). However, levels of gonadotropins and estrogens are closely linked in vivo, and it has proven difficult to separate the effects of gonadotropins from the well-documented estrogenic effects on AD-related neuropathology in experimental models of menopause. To assess the effects of gonadotropins on cognition and AD biochemical markers independent of estrogenic effects, a potent analog of luteinizing hormone [human chorionic gonadotropin (hCG)] was administered to ovariectomized presenilin1 knock-in mice (PS1KI). Gonadotropin administration was found to induce hyperactivity and anxiety (Open Field Maze and Taste Neophobia Task) and working memory dysfunction, without altering reference memory (Morris Water Maze). Although gonadotropin administration modestly altered beta amyloid (Abeta40) levels, levels of the longer more toxic form (Abeta42) were unaffected. Furthermore, altered Abeta40 levels were not associated with observed behavioral and cognitive impairments. These findings provide proof, in principle, that the gonadotropin hormones play a role in the modulation of AD-related behavior, cognition, and neuropathology. PMID- 20844011 TI - Elective affinities: a Tudor-Aubergine tale of germline partnership. AB - In Drosophila melanogaster and many other metazoans, the specification of germ cells requires cytoplasmic inheritance of maternally synthesized RNA and protein determinants, which are assembled in electron-dense cytoplasmic structures known as germ or polar granules, found at the posterior end of the oocytes. Recent studies have shown that the formation of germ granules is dependent on the interaction of proteins containing tudor domains with the piwi-interacting RNA (piRNA)-binding Piwi proteins, and such interactions are dependent on symmetrically dimethylated arginines (sDMAs) of Piwi proteins. Tudor-Piwi interactions are crucial and are conserved in the germ cells of sexually reproducing animals, including mammals. In the September 1, 2010, issue of Genes & Development, Liu and colleagues (pp. 1876-1881) use a combination of genetics, biochemistry, and crystallography to uncover the molecular and structural details of how Tudor recognizes and binds the sDMAs of the Piwi protein Aubergine. PMID- 20844013 TI - Interactions between Hedgehog proteins and their binding partners come into view. AB - Hedgehog (Hh) proteins are secreted signaling molecules that mediate essential tissue-patterning events during embryonic development and function in tissue homeostasis and regeneration throughout life. Hh signaling is regulated by multiple mechanisms, including covalent lipid modification of the Hh protein and interactions with multiple protein and glycan partners. Unraveling the nature and effects of these interactions has proven challenging, but recent structural and biophysical studies of Hh proteins and active fragments of heparin, Ihog, Cdo, Boc, Hedgehog-interacting protein (Hhip), Patched (Ptc), and the monoclonal antibody 5E1 have added a new level of molecular detail to our understanding of how Hh signal response and distribution are regulated within tissues. We review these results and discuss their implications for understanding Hh signaling in normal and disease states. PMID- 20844014 TI - Chromatin-dependent binding of the S. cerevisiae HMGB protein Nhp6A affects nucleosome dynamics and transcription. AB - The Saccharomyces cerevisiae protein Nhp6A is a model for the abundant and multifunctional high-mobility group B (HMGB) family of chromatin-associated proteins. Nhp6A binds DNA in vitro without sequence specificity and bends DNA sharply, but its role in chromosome biology is poorly understood. We show by whole-genome chromatin immunoprecipitation (ChIP) and high-resolution whole genome tiling arrays (ChIP-chip) that Nhp6A is localized to specific regions of chromosomes that include ~23% of RNA polymerase II promoters. Nhp6A binding functions to stabilize nucleosomes, particularly at the transcription start site of these genes. Both genomic binding and transcript expression studies point to functionally related groups of genes that are bound specifically by Nhp6A and whose transcription is altered by the absence of Nhp6. Genomic analyses of Nhp6A mutants specifically defective in DNA bending reveal a critical role of DNA bending for stabilizing chromatin and coregulation of transcription but not for targeted binding by Nhp6A. We conclude that the chromatin environment, not DNA sequence recognition, localizes Nhp6A binding, and that Nhp6A stabilizes chromatin structure and coregulates transcription. PMID- 20844015 TI - ATP is required for interactions between UAP56 and two conserved mRNA export proteins, Aly and CIP29, to assemble the TREX complex. AB - The conserved TREX mRNA export complex is known to contain UAP56, Aly, Tex1, and the THO complex. Here, we carried out proteomic analysis of immunopurified human TREX complex and identified the protein CIP29 as the only new component with a clear yeast relative (known as Tho1). Tho1 is known to function in mRNA export, and we provide evidence that CIP29 likewise functions in this process. Like the known TREX components, a portion of CIP29 localizes in nuclear speckle domains, and its efficient recruitment to mRNA is both splicing- and cap-dependent. We show that UAP56 mediates an ATP-dependent interaction between the THO complex and both CIP29 and Aly, indicating that TREX assembly is ATP-dependent. Using recombinant proteins expressed in Escherichia coli, we show that UAP56, Aly, and CIP29 form an ATP-dependent trimeric complex, and UAP56 bridges the interaction between CIP29 and Aly. We conclude that the interaction of two conserved export proteins, CIP29 and Aly, with UAP56 is strictly regulated by ATP during assembly of the TREX complex. PMID- 20844016 TI - G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase independent mechanisms in Drosophila. AB - G protein-coupled receptor kinase 2 (Gprk2/GRK2) plays a conserved role in modulating Hedgehog (Hh) pathway activity, but its mechanism of action remains unknown. Here we provide evidence that Gprk2 promotes high-level Hh signaling by regulating Smoothened (Smo) conformation through both kinase-dependent and kinase independent mechanisms. Gprk2 promotes Smo activation by phosphorylating Smo C terminal tail (C-tail) at Ser741/Thr742, which is facilitated by PKA and CK1 phosphorylation at adjacent Ser residues. In addition, Gprk2 forms a dimer/oligomer and binds Smo C-tail in a kinase activity-independent manner to stabilize the active Smo conformation, and promotes dimerization/oligomerization of Smo C-tail. Gprk2 expression is induced by Hh signaling, and Gprk2/Smo interaction is facilitated by PKA/CK1-mediated phosphorylation of Smo C-tail. Thus, Gprk2 forms a positive feedback loop and acts downstream from PKA and CK1 to facilitate high-level Hh signaling by promoting the active state of Smo through direct phosphorylation and molecular scaffolding. PMID- 20844017 TI - Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. AB - Mutations in the X-linked human EPHRIN-B1 gene result in cleft palate and other craniofacial anomalies as part of craniofrontonasal syndrome (CFNS), but the molecular and developmental mechanisms by which ephrin-B1 controls the underlying developmental processes are not clear. Here we demonstrate that ephrin-B1 plays an intrinsic role in palatal shelf outgrowth in the mouse by regulating cell proliferation in the anterior palatal shelf mesenchyme. In ephrin-B1 heterozygous mutants, X inactivation generates ephrin-B1-expressing and -nonexpressing cells that sort out, resulting in mosaic ephrin-B1 expression. We now show that this process leads to mosaic disruption of cell proliferation and post-transcriptional up-regulation of EphB receptor expression through relief of endocytosis and degradation. The alteration in proliferation rates resulting from ectopic Eph ephrin expression boundaries correlates with the more severe dysmorphogenesis of ephrin-B1(+/-) heterozygotes that is a hallmark of CFNS. Finally, by integrating phosphoproteomic and transcriptomic approaches, we show that ephrin-B1 controls proliferation in the palate by regulating the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signal transduction pathway. PMID- 20844012 TI - Molecular genetics of prostate cancer: new prospects for old challenges. AB - Despite much recent progress, prostate cancer continues to represent a major cause of cancer-related mortality and morbidity in men. Since early studies on the role of the androgen receptor that led to the advent of androgen deprivation therapy in the 1940s, there has long been intensive interest in the basic mechanisms underlying prostate cancer initiation and progression, as well as the potential to target these processes for therapeutic intervention. Here, we present an overview of major themes in prostate cancer research, focusing on current knowledge of principal events in cancer initiation and progression. We discuss recent advances, including new insights into the mechanisms of castration resistance, identification of stem cells and tumor-initiating cells, and development of mouse models for preclinical evaluation of novel therapuetics. Overall, we highlight the tremendous research progress made in recent years, and underscore the challenges that lie ahead. PMID- 20844020 TI - Cooperative role of ETA and ETB receptors in mediating the diuretic response to intramedullary hyperosmotic NaCl infusion. AB - Acute intramedullary infusion of hyperosmotic NaCl, used to simulate a high-salt diet-induced increase of medullary osmolality, increases urine production and endothelin release from the kidney. To determine whether endothelin mediates this diuretic and natriuretic response, urine flow and Na(+) excretion rate were measured during acute intramedullary infusion of hyperosmotic NaCl in anesthetized rats, with or without endothelin receptor antagonism. Isosmotic NaCl was infused into the left renal medulla during an equilibration period and 30-min baseline period, followed by hyperosmotic NaCl for two additional 30-min periods. Hyperosmotic NaCl infusion significantly increased urine flow of vehicle-treated rats (from 5.9 +/- 0.9 to 11.1 +/- 1.8 MUl/min). Systemic ET(B) receptor blockade enhanced this effect (A-192621; from 7.7 +/- 1.1 to 18.7 +/- 2.9 MUl/min; P < 0.05), ET(A) receptor blockade (ABT-627) had no significant effect alone, but the diuresis was markedly attenuated by combined ABT-627 and A-192621 administration (from 4.4 +/- 0.7 to 5.4 +/- 0.9 MUl/min). Mean arterial pressures overall were not significantly different between groups. Surprisingly, the natriuretic response to hyperosmotic NaCl infusion was not significantly altered by systemic endothelin receptor blockade, and furthermore, intramedullary ET(B) receptor blockade enhanced the diuretic and natriuretic response to hyperosmotic NaCl infusion. ET(A) receptor blockade significantly attenuated both the diuretic and natriuretic responses to hyperosmotic NaCl infusion in ET(B) receptor-deficient sl/sl rats. These results demonstrate an important role of endothelin in mediating diuretic responses to intramedullary infusion of hyperosmotic NaCl. Moreover, these data suggest ET(A) and ET(B) receptors are both required for the full diuretic and natriuretic actions of endothelin. PMID- 20844019 TI - The GATA-type transcription factors GNC and GNL/CGA1 repress gibberellin signaling downstream from DELLA proteins and PHYTOCHROME-INTERACTING FACTORS. AB - The phytohormone gibberellin (GA) regulates various developmental processes in plants such as germination, greening, elongation growth, and flowering time. DELLA proteins, which are degraded in response to GA, repress GA signaling by inhibitory interactions with PHYTOCHROME-INTERACTING FACTOR (PIF) family transcription factors. How GA signaling is controlled downstream from the DELLA and PIF regulators is, at present, unclear. Here, we characterize GNC (GATA, NITRATE-INDUCIBLE, CARBON-METABOLISM INVOLVED) and GNL/CGA1 (GNC-LIKE/CYTOKININ RESPONSIVE GATA FACTOR1), two homologous GATA-type transcription factors from Arabidopsis thaliana that we initially identified as GA-regulated genes. Our genetic analyses of loss-of-function mutants and overexpression lines establish that GNC and GNL are functionally redundant regulators of germination, greening, elongation growth and flowering time. We further show by chromatin immunoprecipitation that both genes are potentially direct transcription targets of PIF transcription factors, and that their expression is up-regulated in pif mutant backgrounds. In line with a key role of GNC or GNL downstream from DELLA and PIF signaling, we find that their overexpression leads to gene expression changes that largely resemble those observed in a ga1 biosynthesis mutant or a pif quadruple mutant. These findings, together with the fact that gnc and gnl loss-of-function mutations suppress ga1 phenotypes, support the hypothesis that GNC and GNL are important repressors of GA signaling downstream from the DELLA and PIF regulators. PMID- 20844018 TI - A functional genomic screen in planarians identifies novel regulators of germ cell development. AB - Germ cells serve as intriguing examples of differentiated cells that retain the capacity to generate all cell types of an organism. Here we used functional genomic approaches in planarians to identify genes required for proper germ cell development. We conducted microarray analyses and in situ hybridization to discover and validate germ cell-enriched transcripts, and then used RNAi to screen for genes required for discrete stages of germ cell development. The majority of genes we identified encode conserved RNA-binding proteins, several of which have not been implicated previously in germ cell development. We also show that a germ cell-specific subunit of the conserved transcription factor CCAAT binding protein/nuclear factor-Y is required for maintaining spermatogonial stem cells. Our results demonstrate that conserved transcriptional and post transcriptional mechanisms regulate germ cell development in planarians. These findings suggest that studies of planarians will inform our understanding of germ cell biology in higher organisms. PMID- 20844021 TI - Eicosapentaenoic acid restores diabetic tubular injury through regulating oxidative stress and mitochondrial apoptosis. AB - The present study was designed to elucidate a possible mechanism of hyperglycemia induced tubular injury and to examine a therapeutic potential of dietary eicosapentaenoic acid (EPA) for the prevention of diabetic kidney disease. Utilizing streptozotocin-induced diabetic mice, the extents of albuminuria and histological injuries were monitored at 2 wk after diabetic induction. Reactive oxygen species (ROS) production, apoptosis, and hypoxia in the kidney were evaluated by immunohistochemistry and Western blotting. An in vitro study was performed using rat proximal tubular cells (NRK-52E) to confirm the protective effect of EPA for methylglyoxal (MG)-induced ROS generation and staurosporine (STS)-induced mitochondrial apoptosis. The extents of albuminuria and histological tubular injuries were significantly lower in EPA-treated diabetic mice compared with untreated diabetic mice. The levels of lipid peroxidation product (4-hydroxy-2-nonenal), oxidative DNA damage (8-hydoxy-deoxyguanosine), and mitochondrial apoptosis (TUNEL, caspase-9, cleaved caspase-3, and cytochrome c release) in the tubular cells were also significantly lower in EPA-treated diabetic mice. Furthermore, hypoxia-inducible factor (HIF)-1alpha expression was significantly upregulated in the kidney tissues from EPA-treated mice compared with untreated diabetic mice. MG-induced ROS overproduction and STS-induced mitochondrial apoptosis in NRK-52E cells were significantly reduced by EPA treatment in vitro. These results indicated that the ROS generation and mitochondrial apoptosis were involved in hyperglycemia-induced tubular injury and EPA had a beneficial effect by suppressing ROS generation and mitochondrial apoptosis partly through augmentation of an HIF-1alpha response in diabetic kidney disease. PMID- 20844022 TI - Mice lacking the matrix metalloproteinase-9 gene reduce renal interstitial fibrosis in obstructive nephropathy. AB - Matrix metalloproteinase-9 (MMP-9) is one of the major components of the matrix proteolytic network, and its role in the pathogenesis of renal interstitial fibrosis remains largely unknown. Here, we demonstrate that ablation of MMP-9 attenuated renal interstitial fibrotic lesions in obstructive nephropathy. Mice lacking MMP-9 were less likely to develop morphological injury, which was characterized by a reduced disruption of tubular basement membrane (TBM) and expression of fibronectin as well as deposition of total tissue collagen in the kidneys after sustained ureteral obstruction compared with their wild-type counterparts. Deficiency of MMP-9 blocked tubular epithelial-to-myofibroblast transition (EMT) but did not alter the induction of transforming growth factor (TGF)-beta1 axis expression in the obstructed kidneys. In vitro, TBM, which was digested by MMP-9 instead of MMP-9 itself, induces EMT and enhances migration of transformed cells. Thus increased MMP-9 is detrimental in renal interstitial fibrogenesis through a cascade of events that leads to TBM destruction and in turn to promotion of EMT. Our findings establish a crucial and definite importance of MMP-9 in the pathogenesis of renal interstitial fibrosis at the whole-animal level. PMID- 20844023 TI - Human marrow-derived mesenchymal stromal cells decrease cisplatin renotoxicity in vitro and in vivo and enhance survival of mice post-intraperitoneal injection. AB - Acute kidney injury (AKI) can occur from the toxic side-effects of chemotherapeutic agents such as cisplatin. Bone marrow-derived mesenchymal stromal cells (MSCs) have demonstrated wide therapeutic potential often due to beneficial factors they secrete. The goal of this investigation was to evaluate in vitro the effect of human MSCs (hMSCs) secretome on cisplatin-treated human kidney cells, and in vivo the consequence of hMSCs intraperitoneal (ip) implantation in mice with AKI. Our results revealed that hMSCs-conditioned media improved survival of HK-2 human proximal tubular cells exposed to cisplatin in vitro. This enhanced survival was linked to increased expression of phosphorylated Akt (Ser473) and was reduced by a VEGF-neutralizing antibody. In vivo testing of these hMSCs established that ip administration in NOD-SCID mice decreased cisplatin-induced kidney function impairment, as demonstrated by lower blood urea nitrogen levels and higher survival. In addition, blood phosphorous and amylase levels were also significantly decreased. Moreover, hMSCs reduced the plasma levels of several inflammatory cytokines/chemokines. Immunohistochemical examination of kidneys showed less apoptotic and more proliferating cells. Furthermore, PCR indicated the presence of hMSCs in mouse kidneys, which also showed enhanced expression of phosphorylated Akt. In conclusion, our study reveals that hMSCs can exert prosurvival effects on renal cells in vitro and in vivo, suggests a paracrine contribution for kidney protective abilities of hMSCs delivered ip, and supports their clinical potential in AKI. PMID- 20844024 TI - Serum and urinary markers of early impairment of GFR in chronic kidney disease patients: diagnostic accuracy of urinary beta-trace protein. AB - The screening for chronic kidney diseases (CKD) patients with impaired GFR needs the measurement of serum creatinine (SCr) or cystatin C (SCys). GFR can also be predicted from SCr or SCys with different formulas. The aim of this study, performed in a group of CKD patients with different levels of GFR, was to evaluate the possibility to select the patients with a GFR <90 ml.min(-1).1.73 m( 2) by means of serum levels and urinary excretion of different low-molecular weight proteins (LMWP), cystatin C (Cys), beta2-microglobulin (beta2M), retinol binding protein (RBP), beta-trace protein (BTP), and derived prediction equations for GFR. In the 295 CKD patients (137 women), at all stages of GFR impairment a very high correlation was found between GFR ((99m)Tc-DTPA) and serum Cr, Cys, beta2M, and BTP. All these serum markers showed a similar accuracy as indicators of different GFR impairments. RBP had the lowest correlation with GFR and was also significantly less accurate. The different prediction formulas derived from gender, anthropometric data and SCr or S-LMWP had a diagnostic accuracy similar to that of serum Cr, Cys, beta2M, and BTP. Urinary albumin was inadequate as an indicator of any level of GFR impairment. Urinary excretion of Cys and beta2M increased significantly only in patients with a GFR <30 ml.min(-1).1.73 m(-2), while urinary BTP increased already at GFR <90 ml.min(-1).1.73 m(-2). In this selected group of CKD patients, the positive predictive value of urinary BTP for a GFR <90 ml.min(-1).1.73 m(-2) was 85%, indicating that, in CKD patients, a urine-based test can predict a slight GFR impairment. PMID- 20844025 TI - Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. AB - OBJECTIVE: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug-metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. DESIGN: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. METHODS: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes. We also performed genotyping for variant CYP alleles known to affect drug metabolism. RESULTS: Though CYP enzyme genotyping predicted normal or high enzymatic activities in both subjects, in vivo assessment showed subnormal activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in the patient and of CYP1A2 and CYP2C9 in her mother. CONCLUSIONS: Our results provide in vivo evidence for an important role of POR in regulating drug metabolism and detoxification. In patients with ORD, in vivo assessment of drug metabolizing activities with subsequent tailoring of drug therapy and steroid replacement should be considered. PMID- 20844026 TI - Interaction of hantavirus nucleocapsid protein with ribosomal protein S19. AB - Hantaviruses, members of the Bunyaviridae family, are emerging category A pathogens that initiate the translation of their capped mRNAs by a novel mechanism mediated by viral nucleocapsid protein (N). N specifically binds to the mRNA 5' m7G cap and 40S ribosomal subunit, a complex of 18S rRNA and multiple ribosomal proteins. Here, we show that N specifically interacts with the ribosomal protein S19 (RPS19), located at the head region of the 40S subunit. We suggest that this N-RPS19 interaction facilitates ribosome loading on capped mRNAs during N-mediated translation initiation. PMID- 20844027 TI - Respiratory syncytial virus induces host RNA stress granules to facilitate viral replication. AB - Mammalian cell cytoplasmic RNA stress granules are induced during various conditions of stress and are strongly associated with regulation of host mRNA translation. Several viruses induce stress granules during the course of infection, but the exact function of these structures during virus replication is not well understood. In this study, we showed that respiratory syncytial virus (RSV) induced host stress granules in epithelial cells during the course of infection. We also showed that stress granules are distinct from cytoplasmic viral inclusion bodies and that the RNA binding protein HuR, normally found in stress granules, also localized to viral inclusion bodies during infection. Interestingly, we demonstrated that infected cells containing stress granules also contained more RSV protein than infected cells that did not form inclusion bodies. To address the role of stress granule formation in RSV infection, we generated a stable epithelial cell line with reduced expression of the Ras-GAP SH3 domain-binding protein (G3BP) that displayed an inhibited stress granule response. Surprisingly, RSV replication was impaired in these cells compared to its replication in cells with intact G3BP expression. In contrast, knockdown of HuR by RNA interference did not affect stress granule formation or RSV replication. Finally, using RNA probes specific for RSV genomic RNA, we found that viral RNA predominantly localized to viral inclusion bodies but a small percentage also interacted with stress granules during infection. These results suggest that RSV induces a host stress granule response and preferentially replicates in host cells that have committed to a stress response. PMID- 20844028 TI - Novel immunodominant peptide presentation strategy: a featured HLA-A*2402 restricted cytotoxic T-lymphocyte epitope stabilized by intrachain hydrogen bonds from severe acute respiratory syndrome coronavirus nucleocapsid protein. AB - Antigenic peptides recognized by virus-specific cytotoxic T lymphocytes (CTLs) are presented by major histocompatibility complex (MHC; or human leukocyte antigen [HLA] in humans) molecules, and the peptide selection and presentation strategy of the host has been studied to guide our understanding of cellular immunity and vaccine development. Here, a severe acute respiratory syndrome coronavirus (SARS-CoV) nucleocapsid (N) protein-derived CTL epitope, N1 (QFKDNVILL), restricted by HLA-A*2402 was identified by a series of in vitro studies, including a computer-assisted algorithm for prediction, stabilization of the peptide by co-refolding with HLA-A*2402 heavy chain and beta(2)-microglobulin (beta(2)m), and T2-A24 cell binding. Consequently, the antigenicity of the peptide was confirmed by enzyme-linked immunospot (ELISPOT), proliferation assays, and HLA-peptide complex tetramer staining using peripheral blood mononuclear cells (PBMCs) from donors who had recovered from SARS donors. Furthermore, the crystal structure of HLA-A*2402 complexed with peptide N1 was determined, and the featured peptide was characterized with two unexpected intrachain hydrogen bonds which augment the central residues to bulge out of the binding groove. This may contribute to the T-cell receptor (TCR) interaction, showing a host immunodominant peptide presentation strategy. Meanwhile, a rapid and efficient strategy is presented for the determination of naturally presented CTL epitopes in the context of given HLA alleles of interest from long immunogenic overlapping peptides. PMID- 20844029 TI - Potent and broadly reactive HIV-2 neutralizing antibodies elicited by a vaccinia virus vector prime-C2V3C3 polypeptide boost immunization strategy. AB - Human immunodeficiency virus type 2 (HIV-2) infection affects about 1 to 2 million individuals, the majority living in West Africa, Europe, and India. As for HIV-1, new strategies for the prevention of HIV-2 infection are needed. Our aim was to produce new vaccine immunogens that elicit the production of broadly reactive HIV-2 neutralizing antibodies (NAbs). Native and truncated envelope proteins from the reference HIV-2ALI isolate were expressed in vaccinia virus or in bacteria. This source isolate was used due to its unique phenotype combining CD4 independence and CCR5 usage. NAbs were not elicited in BALB/c mice by single immunization with a truncated and fully glycosylated envelope gp125 (gp125t) or a recombinant polypeptide comprising the C2, V3, and C3 envelope regions (rpC2-C3). A strong and broad NAb response was, however, elicited in mice primed with gp125t expressed in vaccinia virus and boosted with rpC2-C3. Serum from these animals potently neutralized (median 50% neutralizing titer, 3,200) six of six highly divergent primary HIV-2 isolates. Coreceptor usage and the V3 sequence of NAb sensitive isolates were similar to that of the vaccinating immunogen (HIV-2ALI). In contrast, NAbs were not reactive on three X4 isolates that displayed major changes in V3 loop sequence and structure. Collectively, our findings demonstrate that broadly reactive HIV-2 NAbs can be elicited by using a vaccinia virus vector prime/rpC2-C3-boost immunization strategy and suggest a potential relationship between escape to neutralization and cell tropism. PMID- 20844030 TI - Dendritic cell activation by recombinant hemagglutinin proteins of H1N1 and H5N1 influenza A viruses. AB - Since dendritic cells may play a key role in defense against influenza virus infection, we examined the effects of recombinant hemagglutinin (HA) proteins derived from mouse-adapted H1N1 (A/WSN/1933), swine-origin 2009 pandemic H1N1 (A/Texas/05/2009), and highly pathogenic avian influenza H5N1 (A/Thailand/KAN 1/2004) viruses on mouse myeloid dendritic cells (mDCs). The results reveal that tumor necrosis factor alpha (TNF-alpha), interleukin-12 (IL-12) p70, and major histocompatibility complex class II (MHC-II) expression was increased in mDCs after treatment with recombinant HA proteins of H1N1 and H5N1. The specificity of recombinant HA treatments for mDC activation was diminished after proteinase K digestion. HA apparently promotes mDC maturation by enhancing CD40 and CD86 expression and suppressing endocytosis. No significant differences in mDC activation were observed among recombinant proteins of H1N1 and H5N1. The stimulation of mDCs by HA proteins of H1N1 and H5N1 was completely MyD88 dependent. These findings may provide useful information for the development of more-effective influenza vaccines. PMID- 20844031 TI - Antagonism of type I interferon responses by new world hantaviruses. AB - Evasion of interferon (IFN)-mediated antiviral signaling is a common defense strategy for pathogenic RNA viruses. To date, research on IFN antagonism by hantaviruses is limited and has focused on only a subset of the numerous recognized hantavirus species. The host IFN response has two phases, an initiation phase, resulting in the induction of alpha/beta IFN (IFN-alpha/beta), and an amplification phase, whereby IFN-alpha/beta signals through the Jak/STAT pathway, resulting in the establishment of the cellular antiviral state. We examined interactions between these critical host responses and the New World hantaviruses. We observed delayed cellular responses in both Andes virus (ANDV)- and Sin Nombre virus (SNV)-infected A549 and Huh7-TLR3 cells. We found that IFN beta induction is inhibited by coexpression of ANDV nucleocapsid protein (NP) and glycoprotein precursor (GPC) and is robustly inhibited by SNV GPC alone. Downstream amplification by Jak/STAT signaling is also inhibited by SNV GPC and by either NP or GPC of ANDV. Therefore, ANDV- and SNV-encoded proteins have the potential for inhibiting both IFN-beta induction and signaling, with SNV exhibiting the more potent antagonism ability. Herein we identify ANDV NP, a previously unrecognized inhibitor of Jak/STAT signaling, and show that IFN antagonism by ANDV relies on expression of both the glycoproteins and NP, whereas the glycoproteins appear to be sufficient for antagonism by SNV. These data suggest that IFN antagonism strategies by hantaviruses are quite variable, even between species with similar disease phenotypes, and may help to better elucidate species-specific pathogenesis. PMID- 20844032 TI - Macaque proteome response to highly pathogenic avian influenza and 1918 reassortant influenza virus infections. AB - The host proteome response and molecular mechanisms that drive disease in vivo during infection by a human isolate of the highly pathogenic avian influenza virus (HPAI) and 1918 pandemic influenza virus remain poorly understood. This study presents a comprehensive characterization of the proteome response in cynomolgus macaque (Macaca fascicularis) lung tissue over 7 days of infection with HPAI (the most virulent), a reassortant virus containing 1918 hemagglutinin and neuraminidase surface proteins (intermediate virulence), or a human seasonal strain (least virulent). A high-sensitivity two-dimensional liquid chromatography tandem mass spectroscopy strategy and functional network analysis were implemented to gain insight into response pathways activated in macaques during influenza virus infection. A macaque protein database was assembled and used in the identification of 35,239 unique peptide sequences corresponding to approximately 4,259 proteins. Quantitative analysis identified an increase in expression of 400 proteins during viral infection. The abundance levels of a subset of these 400 proteins produced strong correlations with disease progression observed in the macaques, distinguishing a "core" response to viral infection from a "high" response specific to severe disease. Proteome expression profiles revealed distinct temporal response kinetics between viral strains, with HPAI inducing the most rapid response. While proteins involved in the immune response, metabolism, and transport were increased rapidly in the lung by HPAI, the other viruses produced a delayed response, characterized by an increase in proteins involved in oxidative phosphorylation, RNA processing, and translation. Proteomic results were integrated with previous genomic and pathological analysis to characterize the dynamic nature of the influenza virus infection process. PMID- 20844033 TI - Andes virus regulation of cellular microRNAs contributes to hantavirus-induced endothelial cell permeability. AB - Hantaviruses infect human endothelial cells (ECs) and cause two diseases marked by vascular permeability defects, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Vascular permeability occurs in the absence of EC lysis, suggesting that hantaviruses alter normal EC fluid barrier functions. ECs infected by pathogenic hantaviruses are hyperresponsive to vascular endothelial growth factor (VEGF), and this alters the fluid barrier function of EC adherens junctions, resulting in enhanced paracellular permeability. Vascular permeability and VEGF-directed responses are determined by EC-specific microRNAs (miRNAs), which regulate cellular mRNA transcriptional responses. miRNAs mature within cytoplasmic processing bodies (P bodies), and the hantavirus nucleocapsid (N) protein binds RNA and localizes to P bodies, suggesting that hantaviruses may modify miRNA functions within infected ECs. Here we assessed changes in EC miRNAs following infection by the HPS-causing Andes hantavirus (ANDV). We analyzed 352 human miRNAs within ANDV-infected ECs using quantitative real-time (RT)-PCR arrays. Fourteen miRNAs, including six miRNAs that are associated with regulating vascular integrity, were upregulated >4-fold following infection by ANDV. Nine miRNAs were downregulated 3- to 3,400-fold following ANDV infection; these included miR-410, involved in regulating secretion, and miR-218, which is linked to the regulation of EC migration and vascular permeability. We further analyzed changes in miR-126, an EC-specific miRNA that regulates vascular integrity by suppressing SPRED1 and PIK3R2 mRNAs. While miR-126 levels were only slightly altered, we found that SPRED1 and PIK3R2 mRNA levels were increased 10- and 7-fold, respectively, in ANDV-infected ECs but were unaltered in ECs infected by the nonpathogenic Tula hantavirus (TULV). Consistent with increased SPRED1 expression, we found that the level of phospho cofilin was decreased within ANDV-infected ECs. Moreover, small interfering RNA (siRNA) knockdown of SPRED1 dramatically decreased the permeability of ANDV infected ECs in response to VEGF, suggesting that increased SPRED1 contributes to EC permeability following ANDV infection. These findings suggest that interference with normal miRNA functions contributes to the enhanced paracellular permeability of ANDV-infected ECs and that hantavirus regulation of miRNA functions is an additional determinant of hantavirus pathogenesis. PMID- 20844034 TI - Role of N-linked glycans in the functions of hepatitis C virus envelope proteins incorporated into infectious virions. AB - Hepatitis C virus (HCV) envelope glycoproteins are highly glycosylated, with generally 4 and 11 N-linked glycans on E1 and E2, respectively. Studies using mutated recombinant HCV envelope glycoproteins incorporated into retroviral pseudoparticles (HCVpp) suggest that some glycans play a role in protein folding, virus entry, and protection against neutralization. The development of a cell culture system producing infectious particles (HCVcc) in hepatoma cells provides an opportunity to characterize the role of these glycans in the context of authentic infectious virions. Here, we used HCVcc in which point mutations were engineered at N-linked glycosylation sites to determine the role of these glycans in the functions of HCV envelope proteins. The mutants were characterized for their effects on virus replication and envelope protein expression as well as on viral particle secretion, infectivity, and sensitivity to neutralizing antibodies. Our results indicate that several glycans play an important role in HCVcc assembly and/or infectivity. Furthermore, our data demonstrate that at least five glycans on E2 (denoted E2N1, E2N2, E2N4, E2N6, and E2N11) strongly reduce the sensitivity of HCVcc to antibody neutralization, with four of them surrounding the CD81 binding site. Altogether, these data indicate that the glycans associated with HCV envelope glycoproteins play roles at different steps of the viral life cycle. They also highlight differences in the effects of glycosylation mutations between the HCVpp and HCVcc systems. Furthermore, these carbohydrates form a "glycan shield" at the surface of the virion, which contributes to the evasion of HCV from the humoral immune response. PMID- 20844035 TI - Extracellular 2'-5' oligoadenylate synthetase stimulates RNase L-independent antiviral activity: a novel mechanism of virus-induced innate immunity. AB - The 2'-5' oligoadenylate synthetase (OAS) proteins are traditionally considered intracellular antiviral proteins. However, several studies demonstrate a correlation between the concentration of freely circulating OAS protein in sera from hepatitis C patients and their clinical prognosis. Here we demonstrate that extracellular OAS1 enters into cells and possesses a strong antiviral activity, both in vitro and in vivo, which is independent of RNase L. The OAS protein directly inhibits viral proliferation and does not require the activation of known antiviral signaling pathways. We propose that OAS produced by cells infected with viruses is released to the extracellular space, where it acts as a paracrine antiviral agent. Thus, the OAS protein represents the first direct antiviral compound released by virus-infected cells. PMID- 20844036 TI - Regulation of tumor necrosis factor-like weak inducer of apoptosis receptor protein (TWEAKR) expression by Kaposi's sarcoma-associated herpesvirus microRNA prevents TWEAK-induced apoptosis and inflammatory cytokine expression. AB - Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is the causative agent of KS, the second most common AIDS-associated malignancy. KSHV expresses at least 18 different mature microRNAs (miRNAs) during latency. To identify cellular targets of KSHV miRNAs, we have analyzed a previously reported series of microarrays examining changes in cellular gene expression in the presence of KSHV miRNAs. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) receptor (TWEAKR) was among the most consistently and robustly downregulated genes in the presence of KSHV miR-K12-10a (miR-K10a). Results from luciferase assays with reporter plasmids containing the 3' untranslated region (UTR) of TWEAKR suggest a targeting of TWEAKR by miR-K10a. The mutation of two predicted miR-K10a recognition sites within the 3' UTR of TWEAKR completely disrupts inhibition by miR-K10a. The expression of TWEAKR was downregulated in cells transfected with miR-K10a as well as during de novo KSHV infection. In a KS tumor-derived endothelial cell line, the downregulation of TWEAKR by miR-K10a resulted in reduced levels of TWEAK-induced caspase activation. In addition, cells transfected with miR-K10a showed less induction of apoptosis by annexin V staining and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays. Finally, the downregulation of TWEAKR by miR-K10a in primary human endothelial cells resulted in a decrease in levels of expression of the proinflammatory cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) in response to TWEAK. These results identify and validate an important cellular target of KSHV miRNAs. Furthermore, we demonstrate that a viral miRNA protects cells from apoptosis and suppresses a proinflammatory response, which may have significant implications in the complex context of KS lesions. PMID- 20844037 TI - Whole-genome characterization of human and simian immunodeficiency virus intrahost diversity by ultradeep pyrosequencing. AB - Rapid evolution and high intrahost sequence diversity are hallmarks of human and simian immunodeficiency virus (HIV/SIV) infection. Minor viral variants have important implications for drug resistance, receptor tropism, and immune evasion. Here, we used ultradeep pyrosequencing to sequence complete HIV/SIV genomes, detecting variants present at a frequency as low as 1%. This approach provides a more complete characterization of the viral population than is possible with conventional methods, revealing low-level drug resistance and detecting previously hidden changes in the viral population. While this work applies pyrosequencing to immunodeficiency viruses, this approach could be applied to virtually any viral pathogen. PMID- 20844038 TI - Reevaluating herpes simplex virus hemifusion. AB - Membrane fusion induced by enveloped viruses proceeds through the actions of viral fusion proteins. Once activated, viral fusion proteins undergo large protein conformational changes to execute membrane fusion. Fusion is thought to proceed through a "hemifusion" intermediate in which the outer membrane leaflets of target and viral membranes mix (lipid mixing) prior to fusion pore formation, enlargement, and completion of fusion. Herpes simplex virus type 1 (HSV-1) requires four glycoproteins-glycoprotein D (gD), glycoprotein B (gB), and a heterodimer of glycoprotein H and L (gH/gL)-to accomplish fusion. gD is primarily thought of as a receptor-binding protein and gB as a fusion protein. The role of gH/gL in fusion has remained enigmatic. Despite experimental evidence that gH/gL may be a fusion protein capable of inducing hemifusion in the absence of gB, the recently solved crystal structure of HSV-2 gH/gL has no structural homology to any known viral fusion protein. We found that in our hands, all HSV entry proteins-gD, gB, and gH/gL-were required to observe lipid mixing in both cell cell- and virus-cell-based hemifusion assays. To verify that our hemifusion assay was capable of detecting hemifusion, we used glycosylphosphatidylinositol (GPI) linked hemagglutinin (HA), a variant of the influenza virus fusion protein, HA, known to stall the fusion process before productive fusion pores are formed. Additionally, we found that a mutant carrying an insertion within the short gH cytoplasmic tail, 824L gH, is incapable of executing hemifusion despite normal cell surface expression. Collectively, our findings suggest that HSV gH/gL may not function as a fusion protein and that all HSV entry glycoproteins are required for both hemifusion and fusion. The previously described gH 824L mutation blocks gH/gL function prior to HSV-induced lipid mixing. PMID- 20844039 TI - The varicella-zoster virus ORFS/L (ORF0) gene is required for efficient viral replication and contains an element involved in DNA cleavage. AB - The genome of varicella-zoster virus (VZV), a human alphaherpesvirus, consists of two unique regions, unique long (U(L)) and unique short (U(S)), each of which is flanked by inverted repeats. During replication, four isomers of the viral DNA are generated which are distinguished by the relative orientations of U(L) and U(S). VZV virions predominantly package two isomeric forms of the genome that have a fixed orientation of U(L). An open reading frame (ORF) of unknown function, ORFS/L, also referred to as ORF0, is located at the extreme terminus of U(L), directly adjacent to the a-like sequences, which are known to be involved in cleavage and packaging of viral DNA. We demonstrate here that the ORFS/L protein localizes to the Golgi network in infected and transfected cells. Furthermore, we were able to demonstrate that deletion of the predicted ORFS/L gene is lethal, while retention of the N-terminal 28 amino acid residues resulted in viable yet replication-impaired virus. The growth defect was only partially attributable to the expression of the ORFS/L product, suggesting that the 5' region of ORFS/L contains a sequence element crucial for cleavage/packaging of viral DNA. Consequently, mutations introduced into the extreme 5' terminus of ORFS/L resulted in a defect in DNA cleavage, indicating that the region is indeed involved in the processing of viral DNA. Since the sequence element has no counterpart at the other end of U(L), we concluded that our results can provide an explanation for the almost exclusive orientation of the U(L) seen in packaged VZV DNA. PMID- 20844041 TI - Sphingomyelin activates hepatitis C virus RNA polymerase in a genotype-specific manner. AB - Hepatitis C virus (HCV) replication and infection depend on the lipid components of the cell, and replication is inhibited by inhibitors of sphingomyelin biosynthesis. We found that sphingomyelin bound to and activated genotype 1b RNA dependent RNA polymerase (RdRp) by enhancing its template binding activity. Sphingomyelin also bound to 1a and JFH1 (genotype 2a) RdRps but did not activate them. Sphingomyelin did not bind to or activate J6CF (2a) RdRp. The sphingomyelin binding domain (SBD) of HCV RdRp was mapped to the helix-turn-helix structure (residues 231 to 260), which was essential for sphingomyelin binding and activation. Helix structures (residues 231 to 241 and 247 to 260) are important for RdRp activation, and 238S and 248E are important for maintaining the helix structures for template binding and RdRp activation by sphingomyelin. 241Q in helix 1 and the negatively charged 244D at the apex of the turn are important for sphingomyelin binding. Both amino acids are on the surface of the RdRp molecule. The polarity of the phosphocholine of sphingomyelin is important for HCV RdRp activation. However, phosphocholine did not activate RdRp. Twenty sphingomyelin molecules activated one RdRp molecule. The biochemical effect of sphingomyelin on HCV RdRp activity was virologically confirmed by the HCV replicon system. We also found that the SBD was the lipid raft membrane localization domain of HCV NS5B because JFH1 (2a) replicon cells harboring NS5B with the mutation A242C/S244D moved to the lipid raft while the wild type did not localize there. This agreed with the myriocin sensitivity of the mutant replicon. This sphingomyelin interaction is a target for HCV infection because most HCV RdRps have 241Q. PMID- 20844040 TI - Herpesviruses and chromosomal integration. AB - Herpesviruses are members of a diverse family of viruses that colonize all vertebrates from fish to mammals. Although more than one hundred herpesviruses exist, all are nearly identical architecturally, with a genome consisting of a linear double-stranded DNA molecule (100 to 225 kbp) protected by an icosahedral capsid made up of 162 hollow-centered capsomeres, a tegument surrounding the nucleocapsid, and a viral envelope derived from host membranes. Upon infection, the linear viral DNA is delivered to the nucleus, where it circularizes to form the viral episome. Depending on several factors, the viral cycle can proceed either to a productive infection or to a state of latency. In either case, the viral genetic information is maintained as extrachromosomal circular DNA. Interestingly, however, certain oncogenic herpesviruses such as Marek's disease virus and Epstein-Barr virus can be found integrated at low frequencies in the host's chromosomes. These findings have mostly been viewed as anecdotal and considered exceptions rather than properties of herpesviruses. In recent years, the consistent and rather frequent detection (in approximately 1% of the human population) of human herpesvirus 6 (HHV-6) viral DNA integrated into human chromosomes has spurred renewed interest in our understanding of how these viruses infect, replicate, and propagate themselves. In this review, we provide a historical perspective on chromosomal integration by herpesviruses and present the current state of knowledge on integration by HHV-6 with the possible clinical implications associated with viral integration. PMID- 20844042 TI - The HIV-1 central polypurine tract functions as a second line of defense against APOBEC3G/F. AB - HIV-1 and certain other retroviruses initiate plus-strand synthesis in the center of the genome as well as at the standard retroviral 3' polypurine tract. This peculiarity of reverse transcription results in a central DNA "flap" structure that has been of controversial functional significance. We mutated both HIV-1 flap-generating elements, the central polypurine tract (cPPT) and the central termination sequence (CTS). To avoid an ambiguity of previous studies, we did so without affecting integrase coding. DNA flap formation was disrupted but single cycle infection was unaffected in all target cells tested, regardless of cell cycle status. Spreading HIV-1 infection was also normal in most T cell lines, and flap mutant viruses replicated equivalently to the wild type in nondividing cells, including macrophages. However, spreading infection of flap mutant HIV-1 was impaired in non-vif-permissive cells (HuT78, H9, and primary human peripheral blood mononuclear cells [PBMCs]), suggesting APOBEC3G (A3G) restriction. Single cycle infections confirmed that vif-intact flap mutant HIV-1 is restricted by producer cell A3G/F. Combining the Deltavif and cPPT-CTS mutations increased A3G restriction synergistically. Moreover, RNA interference knockdown of A3G in HuT78 cells released the block to flap mutant HIV-1 replication. Flap mutant HIV-1 also accrued markedly increased A3G-mediated G->A hypermutation compared to that of wild-type HIV-1 (a full log(10) in the 0.36 kb downstream of the mutant cPPT). We suggest that the triple-stranded DNA structure, the flap, is not the consequential outcome. The salient functional feature is central plus-strand initiation, which functions as a second line of defense against single-stranded DNA editing by A3 proteins that survive producer cell degradation by Vif. PMID- 20844043 TI - Virally induced cellular microRNA miR-155 plays a key role in B-cell immortalization by Epstein-Barr virus. AB - Infection of resting primary human B cells by Epstein-Barr virus (EBV) results in their transformation into indefinitely proliferating lymphoblastoid cell lines (LCLs). LCL formation serves as a model for lymphomagenesis, and LCLs are phenotypically similar to EBV-positive diffuse large B-cell lymphomas (DLBCLs), which represent a common AIDS-associated malignancy. B-cell infection by EBV induces the expression of several cellular microRNAs (miRNAs), most notably miR 155, which is overexpressed in many tumors and can induce B-cell lymphomas when overexpressed in animals. Here, we demonstrate that miR-155 is the most highly expressed miRNA in LCLs and that the selective inhibition of miR-155 function specifically inhibits the growth of both LCLs and the DLBCL cell line IBL-1. Cells lacking miR-155 are inefficient in progressing through S phase and spontaneously undergo apoptosis. In contrast, three other B-cell lymphoma lines, including two EBV-positive Burkitt's lymphoma cell lines, grew normally in the absence of miR-155 function. These data identify the induction of cellular miR 155 expression by EBV as critical for the growth of both laboratory-generated LCLs and naturally occurring DLBCLs and suggest that targeted inhibition of miR 155 function could represent a novel approach to the treatment of DLBCL in vivo. PMID- 20844045 TI - Stimulation of human dendritic cells by wild-type and M protein mutant vesicular stomatitis viruses engineered to express bacterial flagellin. AB - Vesicular stomatitis viruses (VSVs) containing wild-type (wt) or mutant matrix (M) proteins are being developed as candidate vaccine vectors due to their ability to induce innate and adaptive immunity. Viruses with wt M protein, such as recombinant wild-type (rwt) virus, stimulate maturation of dendritic cells (DC) through Toll-like receptor 7 (TLR7) and its adaptor molecule MyD88. However, M protein mutant viruses, such as rM51R-M virus, stimulate both TLR7-positive and TLR7-negative DC subsets. The goal of this study was to determine whether the ability of rwt and rM51R-M viruses to induce maturation of human DC can be enhanced by engineering these vectors to express bacterial flagellin. Flagellin expressed from the rwt virus genome partially protected human DC from VSV-induced shutoff of host protein synthesis and promoted the production of interleukin 6 (IL-6) and IL-1beta. In addition, DC infected with rwt virus expressing flagellin were more effective at stimulating gamma interferon (IFN-gamma) production from CD8(+) allogeneic T cells than DC infected with rwt virus. Although rM51R-M virus effectively stimulated human DC, flagellin expressed from the rM51R-M virus genome enhanced the production of cytokines. Furthermore, mice immunized with both rwt and rM51R-M viruses expressing flagellin had enhanced anti-VSV antibody responses in vivo. Therefore, rwt and rM51R-M viruses expressing flagellin may be promising vectors for the delivery of foreign antigen due to their potential to stimulate DC function. PMID- 20844044 TI - Virulence-associated substitution D222G in the hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding. AB - The clinical impact of the 2009 pandemic influenza A(H1N1) virus (pdmH1N1) has been relatively low. However, amino acid substitution D222G in the hemagglutinin of pdmH1N1 has been associated with cases of severe disease and fatalities. D222G was introduced in a prototype pdmH1N1 by reverse genetics, and the effect on virus receptor binding, replication, antigenic properties, and pathogenesis and transmission in animal models was investigated. pdmH1N1 with D222G caused ocular disease in mice without further indications of enhanced virulence in mice and ferrets. pdmH1N1 with D222G retained transmissibility via aerosols or respiratory droplets in ferrets and guinea pigs. The virus displayed changes in attachment to human respiratory tissues in vitro, in particular increased binding to macrophages and type II pneumocytes in the alveoli and to tracheal and bronchial submucosal glands. Virus attachment studies further indicated that pdmH1N1 with D222G acquired dual receptor specificity for complex alpha2,3- and alpha2,6 linked sialic acids. Molecular dynamics modeling of the hemagglutinin structure provided an explanation for the retention of alpha2,6 binding. Altered receptor specificity of the virus with D222G thus affected interaction with cells of the human lower respiratory tract, possibly explaining the observed association with enhanced disease in humans. PMID- 20844046 TI - Distinct stability states of disease-associated human prion protein identified by conformation-dependent immunoassay. AB - The phenotypic and strain-related properties of human prion diseases are, according to the prion hypothesis, proposed to reside in the physicochemical properties of the conformationally altered, disease-associated isoform of the prion protein (PrP(Sc)), which accumulates in the brains of patients suffering from Creutzfeldt-Jakob disease and related conditions, such as Gerstmann Straussler-Scheinker disease. Molecular strain typing of human prion diseases has focused extensively on differences in the fragment size and glycosylation site occupancy of the protease-resistant prion protein (PrP(res)) in conjunction with the presence of mutations and polymorphisms in the prion protein gene (PRNP). Here we report the results of employing an alternative strategy that specifically addresses the conformational stability of PrP(Sc) and that has been used previously to characterize animal prion strains transmitted to rodents. The results show that there are at least two distinct conformation stability states in human prion diseases, neither of which appears to correlate fully with the PrP(res) type, as judged by fragment size or glycosylation, the PRNP codon 129 status, or the presence or absence of mutations in PRNP. These results suggest that conformational stability represents a further dimension to a complete description of potentially phenotype-related properties of PrP(Sc) in human prion diseases. PMID- 20844047 TI - Nuclear export of human papillomavirus type 31 E1 is regulated by Cdk2 phosphorylation and required for viral genome maintenance. AB - The initiator protein E1 from human papillomavirus (HPV) is a helicase essential for replication of the viral genome. E1 contains three functional domains: a C terminal enzymatic domain that has ATPase/helicase activity, a central DNA binding domain that recognizes specific sequences in the origin of replication, and a N-terminal region necessary for viral DNA replication in vivo but dispensable in vitro. This N-terminal portion of E1 contains a conserved nuclear export signal (NES) whose function in the viral life cycle remains unclear. In this study, we provide evidence that nuclear export of HPV31 E1 is inhibited by cyclin E/A-Cdk2 phosphorylation of two serines residues, S92 and S106, located near and within the E1 NES, respectively. Using E1 mutant proteins that are confined to the nucleus, we determined that nuclear export of E1 is not essential for transient viral DNA replication but is important for the long-term maintenance of the HPV episome in undifferentiated keratinocytes. The findings that E1 nuclear export is not required for viral DNA replication but needed for genome maintenance over multiple cell divisions raised the possibility that continuous nuclear accumulation of E1 is detrimental to cellular growth. In support of this possibility, we observed that nuclear accumulation of E1 dramatically reduces cellular proliferation by delaying cell cycle progression in S phase. On the basis of these results, we propose that nuclear export of E1 is required, at least in part, to limit accumulation of this viral helicase in the nucleus in order to prevent its detrimental effect on cellular proliferation. PMID- 20844048 TI - Species-specific regions of occludin required by hepatitis C virus for cell entry. AB - Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. As HCV infects only human and chimpanzee cells, antiviral therapy and vaccine development have been hampered by the lack of a convenient small-animal model. In this study we further investigate how the species tropism of HCV is modulated at the level of cell entry. It has been previously determined that the tight junction protein occludin (OCLN) is essential for HCV host cell entry and that human OCLN is more efficient than the mouse ortholog at mediating HCV cell entry. To further investigate the relationship between OCLN sequence and HCV species tropism, we compared OCLN proteins from a range of species for their ability to mediate infection of naturally OCLN-deficient 786-O cells with lentiviral pseudoparticles bearing the HCV glycoproteins. While primate sequences function equivalently to human OCLN, canine, hamster, and rat OCLN had intermediate activities, and guinea pig OCLN was completely nonfunctional. Through analysis of chimeras between these OCLN proteins and alanine scanning mutagenesis of the extracellular domains of OCLN, we identified the second half of the second extracellular loop (EC2) and specific amino acids within this domain to be critical for modulating the HCV cell entry factor activity of this protein. Furthermore, this critical region of EC2 is flanked by two conserved cysteine residues that are essential for HCV cell entry, suggesting that a subdomain of EC2 may be defined by a disulfide bond. PMID- 20844049 TI - Reduction of immune activation with chloroquine therapy during chronic HIV infection. AB - Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38(+) HLA-DR(+) CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals. PMID- 20844050 TI - Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV. AB - Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic or polytropic mouse leukemia viruses (X-MLVs or P-MLVs, respectively) of the gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV (xenotropic murine leukemia virus-related virus), an X-MLV-like virus isolated from humans with prostate cancer and chronic fatigue syndrome. We identified multiple distinct susceptibility phenotypes; these include the four known Xpr1 variants in Mus and a novel fifth Xpr1 gene found in Mus molossinus and Mus musculus. We describe the geographic and species distribution of the Mus Xpr1 variants but failed to find the X-MLV-restrictive laboratory mouse allele in any wild mouse. We used mutagenesis and phylogenetic analysis to evaluate the functional contributions made by constrained, variable, and deleted residues. Rodent Xpr1 is under positive selection, indicating a history of host-pathogen conflicts; several codons under selection have known roles in virus entry. All non-Mus mammals are susceptible to mouse X-MLVs, but some restrict other members of the X/P-MLV family, and the resistance of hamster and gerbil cells to XMRV indicates that XMRV has unique receptor requirements. We show that the hypervariable fourth extracellular XPR1 loop (ECL4) contains three evolutionarily constrained residues that do not contribute to receptor function, we identify two novel residues important for virus entry (I579 and T583), and we describe a unique pattern of ECL4 variation in the three virus-restrictive Xpr1 variants found in MLV-infected house mice; these mice carry different deletions in ECL4, suggesting either that these sites or loop size affects receptor function. PMID- 20844051 TI - Neutralizing epitopes of influenza virus hemagglutinin: target for the development of a universal vaccine against H5N1 lineages. AB - The nature of influenza virus to randomly mutate and evolve into new types with diverse antigenic determinants is an important challenge in the control of influenza infection. Particularly, variations within the amino acid sequences of major neutralizing epitopes of influenza virus hemagglutinin (HA) hindered the development of universal vaccines against H5N1 lineages. Based on distribution analyses of the identified major neutralizing epitopes of hemagglutinin, we selected three vaccine strains that cover the entire variants in the neutralizing epitopes among the H5N1 lineages. HA proteins of selected vaccine strains were expressed on the baculovirus surface (BacHA), and the preclinical efficacy of the vaccine formulations was evaluated in a mouse model. The combination of three selected vaccine strains could effectively neutralize viruses from clades 1, 2.1, 2.2, 4, 7, and 8 of influenza H5N1 viruses. In contrast, a vaccine formulation containing only adjuvanted monovalent BacHA (mono-BacHA) or a single strain of inactivated whole viral vaccine was able to neutralize only clade 1 (homologous), clade 2.1, and clade 8.0 viruses. Also, the trivalent BacHA vaccine was able to protect 100% of the mice against challenge with three different clades (clade 1.0, clade 2.1, and clade 7.0) of H5N1 strains compared to mono-BacHA or inactivated whole viral vaccine. The present findings provide a rationale for the development of a universal vaccine against H5N1 lineages. Furthermore, baculoviruses displaying HA will serve as an ideal choice for a vaccine in prepandemic or pandemic situations and expedite vaccine technology without the requirement of high-level-biocontainment facilities or tedious protein purification processes. PMID- 20844052 TI - Intracellular distribution of NS1 correlates with the infectivity and interferon antagonism of an avian influenza virus (H7N1). AB - Highly pathogenic avian influenza viruses of subtype H7N1 that emerged during an outbreak in 1999 and 2000 in Italy differ from their low-pathogenicity precursor viruses by changes in several genes, including three mutations in the NS1 protein. Two of them involve amino acid exchanges located within or closely adjacent to the nuclear export signal of NS1. The third mutation resulted in a new stop codon and thereby a C-terminal truncation of the NS1 protein of the highly pathogenic viruses. To find out whether these mutations contribute to the phenotypic differences between the highly pathogenic and low pathogenic viruses, we generated recombinants of the highly pathogenic A/ostrich/Italy/984/00 strain that contained the nuclear export signal and/or the extended C terminus of NS1 of a low pathogenic virus (A/chicken/Italy/1082/99). Using these recombinants we could demonstrate that replication rate and spread of infection in chicken fibroblast cultures, as well as infectivity for chicken embryos is reduced, whereas the mean death time for chicken embryos is increased, when the highly pathogenic virus acquires the NS1 motifs of the low pathogenic virus. Analysis of beta interferon transcription in chicken fibroblasts infected with the recombinants revealed that the mutations observed in the nuclear export signal of the highly pathogenic viruses were responsible for the enhanced interferon antagonism of these viruses. Cell fractionation and immunofluorescence studies in chicken fibroblasts showed that the nuclear export signal of the highly pathogenic viruses is responsible for cytoplasmic accumulation of NS1, whereas the C-terminal truncation promotes transport into the nucleoli. Comparative analysis in human A549 cells indicated that intracellular distribution of NS1 is host specific. Taken together, these observations support the concept that compartmentalization of NS1 within the cell contributes to the pathogenicity of avian influenza viruses. PMID- 20844053 TI - High-throughput, sensitive quantification of repopulating hematopoietic stem cell clones. AB - Retroviral vector-mediated gene therapy has been successfully used to correct genetic diseases. However, a number of studies have shown a subsequent risk of cancer development or aberrant clonal growths due to vector insertion near or within proto-oncogenes. Recent advances in the sequencing technology enable high throughput clonality analysis via vector integration site (VIS) sequencing, which is particularly useful for studying complex polyclonal hematopoietic progenitor/stem cell (HPSC) repopulation. However, clonal repopulation analysis using the current methods is typically semiquantitative. Here, we present a novel system and standards for accurate clonality analysis using 454 pyrosequencing. We developed a bidirectional VIS PCR method to improve VIS detection by concurrently analyzing both the 5' and the 3' vector-host junctions and optimized the conditions for the quantitative VIS sequencing. The assay was validated by quantifying the relative frequencies of hundreds of repopulating HPSC clones in a nonhuman primate. The reliability and sensitivity of the assay were assessed using clone-specific real-time PCR. The majority of tested clones showed a strong correlation between the two methods. This assay permits high-throughput and sensitive assessment of clonal populations and hence will be useful for a broad range of gene therapy, stem cell, and cancer research applications. PMID- 20844054 TI - Bovine foamy virus transactivator BTas interacts with cellular RelB to enhance viral transcription. AB - Viruses are obligate intracellular parasites that depend on cellular machinery for their efficient transcription and replication. In a previous study we reported that bovine foamy virus (BFV) is able to activate the nuclear factor kappaB (NF-kappaB) pathway through the action of its transactivator BTas to enhance viral transcription. However, the mechanism used by NF-kappaB to enhance BFV transcription remains elusive. To address this question, we employed a yeast two-hybrid assay to screen for BTas-interacting proteins. We found that RelB, a member of NF-kappaB protein family, interacts with BTas. We confirmed the putative RelB-BTas interaction in vitro and in vivo and identified the protein regions responsible for the RelB-BTas interaction. Using a luciferase reporter assay, we next showed that RelB enhances BFV transcription (BTas-induced long terminal repeat [LTR] transactivation) and that this process requires both the localization of the RelB-BTas interaction in the nucleus and the Rel homology domain of RelB. The knockdown of the cellular endogenous RelB protein using small interfering RNA (siRNA) significantly attenuated BTas-induced LTR transcription. The results of chromatin immunoprecipitation (ChIP) analysis showed that endogenous RelB binds to the viral LTR in BFV-infected cells. Together, these results suggest that BFV engages the RelB protein as a cotransactivator of BTas to enhance viral transcription. In addition, our findings indicate that BFV infection upregulates cellular RelB expression through BTas-induced NF-kappaB activation. Thus, this study demonstrates the existence of a positive-feedback circuit in which BFV utilizes the host's NF-kappaB pathway through the RelB protein for efficient viral transcription. PMID- 20844055 TI - Comparison of various airflow measurements in symptomatic textile workers. AB - AIMS: To investigate the poorly understood relationship between work-related respiratory symptoms, airway reactivity, across working shift change in forced expiratory volume in 1 s (FEV(1)) and work-related changes in serial peak expiratory flow (sPEF) measures in a group of textile workers. METHODS: Fifty three workers, 34 exposed to cotton dust and 19 to man-made fibre (MMF), were investigated using a standard respiratory questionnaire, sPEF, across-shift FEV(1) measurement and airway responsiveness. RESULTS: Thirty-four workers (64%) were male, and 9 workers (17%) had a >5% across-shift fall in FEV(1), and these falls were associated with the presence of work-related symptoms. Seven workers had a positive sPEF chart as judged by the software analysis (OASYS), although there was no relationship between work-related symptoms and sPEF. Six cotton workers (18%) and one MMF worker (5%) had airway hyperreactivity, which was associated strongly with work-related symptoms. Five of the 7 subjects with a positive sPEF had airway hyperreactivity compared with 12 of 46 with a negative sPEF. CONCLUSIONS: In this worker group, the presence of work-related respiratory symptoms was best associated with airway hyperresponsiveness and across-shift changes in FEV(1). While a positive sPEF chart was associated with increased airway responsiveness, it was not associated with work-related symptoms. sPEF measurements may not be the initial investigation of choice for such workers. As these findings also have relevance to developing evidence-based approaches to health surveillance, further work is needed to better define these relationships in other workers complaining of work-related respiratory symptoms. PMID- 20844056 TI - Musculoskeletal disorders among Irish farmers. AB - BACKGROUND: Farming is an occupation that predisposes individuals to health problems including musculoskeletal disorders (MSDs). There is limited research regarding MSDs among farmers especially in Ireland. AIMS: To establish the prevalence of MSDs, identify the most commonly affected body regions and to explore what factors may influence the development of the most common MSDs among farmers in Ireland. METHODS: A questionnaire survey of Irish farmers was conducted. The study sample comprised 600 farmers (100 farmers from each of the six main farm enterprise systems in Ireland). RESULTS: Of the 600 farmers, 56% had experienced a MSD in the previous year. The most commonly experienced MSDs were back pain (37%) and neck/shoulder pain (25%). Other MSDs experienced in the previous year included knee pain (9%), hand-wrist-elbow pain (9%), ankle/foot pain (9%) and hip pain (8%). Overall, MSDs were more common in farmers working longer hours (P < 0.05). Back pain was more prevalent in full-time farmers (P < 0.05), while prevalence of hip pain was greater in farmers who were older (P < 0.01), full time (P < 0.05), farming for longer (P < 0.01) and working for longer hours (P < 0.01). Farm enterprise was not a factor in influencing the development of MSDs. CONCLUSIONS: These findings suggest that the number of hours worked by farmers, rather than enterprise specific tasks render farmers more susceptible to MSDs. Further investigation is needed to explore risk factors in the development of MSDs. PMID- 20844057 TI - The work environment, stress and well-being. AB - BACKGROUND: Much recent work extending the field of job characteristics to include positive aspects of work makes the implicit assumption that the absence of negative work characteristics is equivalent to the presence of positive work characteristics. AIMS: To consider the effect sizes seen at different ends of job characteristic dimensions and to compare the impact of the presence and absence of job characteristics in association with mental health and well-being outcomes. METHODS: Data from 8755 workers were analysed to compare the impacts of the presence or absence of job characteristics (job demand, extrinsic effort and social support) in associations with both positive (job satisfaction) and negative (work-related stress) outcome measures. RESULTS: Comparable presence and absence impacts were apparent for extrinsic effort in association with work related stress. However, in the association between job demand and work-related stress, the presence of high levels of job demand had a significantly greater impact than the absence of high levels of job demand; while in the association between social support and job satisfaction, the absence of high levels of social support had a significantly greater impact than the presence of high levels of social support. CONCLUSIONS: It is not always appropriate to assume that the absence of negative aspects of the work environment is equivalent to the presence of positive aspects. PMID- 20844058 TI - Allergic contact dermatitis due to a PVC table cover. AB - BACKGROUND: Plastics are a common cause of occupational skin disorders such as irritant or allergic contact dermatitis (ACD). CASE REPORT: We report a case of occupational ACD due to a polyvinyl chloride (PVC) plastic table cover used as a mouse pad for which we performed patch tests and obtained positive patch tests for the PVC table cover. Composition testing revealed the presence of phthalates and phosphites, which may represent the specific allergens. CONCLUSIONS: Contact with some of the chemical components of the PVC table cover, together with a combination of sweating and friction, may have enhanced the allergenicity of these components. Workplace adjustment resulted in disappearance of the dermatitis. PMID- 20844059 TI - How do we find the best biomarkers for cardiovascular disease? PMID- 20844060 TI - Specificity of serum and urine protein electrophoresis for the diagnosis of monoclonal gammopathies. PMID- 20844061 TI - Hemoglobin A1c to diagnose diabetes: why the controversy over adding a new tool? PMID- 20844062 TI - Diagnostic accuracy and user-friendliness of 5 point-of-care D-dimer tests for the exclusion of deep vein thrombosis. AB - BACKGROUND: Point-of-care D-dimer tests have recently been introduced to enable rapid exclusion of deep venous thrombosis (DVT) without the need to refer a patient for conventional laboratory-based D-dimer testing. Before implementation in practice, however, the diagnostic accuracy of each test should be validated. METHODS: We analyzed data of 577 prospectively identified consecutive primary care patients suspected to have DVT, who underwent 5 point-of-care D-dimer tests 4 quantitative (Vidas(r), PathfastTM, Cardiac(r), and Triage(r)) and 1 qualitative (Clearview Simplify(r))-and ultrasonography as the reference method. We evaluated the tests for the accuracy of their measurements and submitted a questionnaire to 20 users to assess the user-friendliness of each test. RESULTS: All D-dimer tests showed negative predictive values higher than 98%. Sensitivity was high for all point-of-care tests, with a range of 0.91 (Clearview Simplify) to 0.99 (Vidas). Specificity varied between 0.39 (Pathfast) and 0.64 (Clearview Simplify). The quantitative point-of-care tests showed similar and high discriminative power for DVT, according to calculated areas under the ROC curves (range 0.88-0.89). The quantitative Vidas and Pathfast devices showed limited user-friendliness for primary care, owing to a laborious calibration process and long analyzer warm-up time compared to the Cardiac and Triage. For the qualitative Clearview Simplify assay, no analyzer or calibration was needed, but interpretation of a test result was sometimes difficult because of poor color contrast. CONCLUSIONS: Point-of-care D-dimer assays show good and similar diagnostic accuracy. The quantitative Cardiac and Triage and the qualitative Clearview Simplify D-dimer seem most user-friendly for excluding DVT in the doctor's office. PMID- 20844063 TI - Prognostic assessment of elderly patients with symptoms of heart failure by combining high-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide measurements. AB - BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful biomarker in heart failure assessment, whereas measurement of cardiac troponin is central in the diagnosis of patients with acute coronary syndromes. This report examined the prognostic use of combining high-sensitivity cardiac troponin T (hs cTnT) and NT-proBNP measurements in elderly patients presenting to a primary care center with symptoms associated with heart failure. METHODS: A total of 470 elderly patients (age range 65-86 years) presenting with symptoms of heart failure were recruited from primary healthcare. In addition to clinical examination and echocardiography, hs-cTnT and NT-proBNP plasma concentrations were measured. All patients were followed for 10 years, and cardiovascular mortality was registered. RESULTS: By use of the hs-cTnT assay, 80.4% of the population had plasma concentrations above the lower detection limit of the assay. Of those displaying a plasma concentration of hs-cTnT >99th percentile of a healthy population, 43% also had an NT-proBNP concentration in the fourth quartile (>507 ng/L). In the multivariate analysis, we observed a 2.5-fold increased risk for cardiovascular mortality in individuals with a plasma NT proBNP concentration >507 ng/L (P < 0.0001). Conversely, patients with hs-cTnT >99th percentile displayed an approximately 2-fold increased risk for cardiovascular mortality (P = 0.0002). Combining the 2 biomarkers, NT-proBNP concentrations >507 ng/L with hs-cTnT >99th percentile increased the risk 3-fold, even after adjustment for clinical variables such as age, sex, impaired estimated glomerular filtration rate, and anemia (P < 0.0001). CONCLUSIONS: hs-cTnT and NT proBNP measurements combined provide better prognostic information than using either biomarker separately in elderly patients with symptoms associated with heart failure. PMID- 20844064 TI - Meat intake's influence on body fatness cannot be assessed without measurement of body fat. PMID- 20844065 TI - Effect of mother's weight on infant's microbiota acquisition, composition, and activity during early infancy: a prospective follow-up study initiated in early pregnancy. AB - BACKGROUND: It has been reported that deviations in gut microbiota composition may predispose toward obesity, and specific groups of commensal gut bacteria may harvest energy from food more efficiently than others. Alterations in microbiota compositions of mothers may be transferred to infants and lead to an increased risk of overweight. OBJECTIVE: We analyzed the fecal microbiota composition of infants of overweight and normal-weight mothers and assessed the relations of weight and excessive weight gain of mothers during pregnancy on the microbiota of infants. DESIGN: Mothers (n = 16) whose prepregnancy body mass index (BMI; in kg/m2) was >=25 were selected with their infants from a prospective follow-up study of 256 women. Women with a BMI <25 (n = 26) and their infants served as control subjects. At the ages of 1 and 6 mo, infant stool samples were available for the analysis of microbiota composition by fluorescence in situ hybridization combined with flow cytometry and quantitative real-time polymerase chain reaction. RESULTS: Infants' fecal microbial composition was related to the weight and weight gain of their mothers during pregnancy. Fecal Bacteroides and Staphylococcus concentrations were significantly higher in infants of overweight mothers during the first 6 mo. Higher weights and BMIs of mothers were related to higher concentrations of Bacteroides, Clostridium, and Staphylococcus and lower concentrations of the Bifidobacterium group. Prevalences of Akkermansia muciniphila, Staphylococcus, and Clostridium difficile groups were lower in infants of normal-weight mothers and of mothers with normal weight gains during pregnancy. CONCLUSION: The composition and development of infant gut microbiota are influenced by BMI, weight, and weight gain of mothers during pregnancy. PMID- 20844066 TI - Intake of artificially sweetened soft drinks and risk of preterm delivery. PMID- 20844067 TI - Differential effects of omega-6 and omega-3 fatty acids on telomere length. PMID- 20844068 TI - Random serial sampling to evaluate efficacy of iron fortification: a randomized controlled trial of margarine fortification with ferric pyrophosphate or sodium iron edetate. AB - BACKGROUND: Random serial sampling is widely used in population pharmacokinetic studies and may have advantages compared with conventional fixed time-point evaluation of iron fortification. OBJECTIVE: Our objective was to validate random serial sampling to judge the efficacy of iron fortification of a low-fat margarine. DESIGN: We conducted a 32-wk placebo-controlled, double-blind, iron intervention trial in 18-40-y-old Swiss women (n = 142) with serum ferritin (SF) concentrations <25 MUg/L. Women were randomly assigned to 3 groups to receive 20 g margarine, with 14 mg added iron as either micronized ground ferric pyrophosphate (MGFePP) or sodium iron edetate (NaFeEDTA), or placebo daily. We measured hemoglobin and iron status of subjects at 2 fixed time points (at baseline and the endpoint) plus 3 randomly assigned time points between 4 and 28 wk. With the use of bootstrapping, the number of observations per individual was reduced to 3 and then compared with the 5-time-point data. Mixed-effects models were used to estimate iron repletion over time for random sampling, and analysis of covariance was used for fixed time-point sampling. RESULTS: Body iron stores increased in women who received MGFePP or NaFeEDTA compared with women who received placebo (P < 0.05). The increase in body iron stores with NaFeEDTA fortification was 2-3 times the increase with MGFePP fortification (P < 0.05); the difference was more marked in women with baseline SF concentrations <15 MUg/L (P < 0.05). Random serial sampling reduced the required sample size per group to one-tenth of that for 2 fixed time points. Compared with the 5-time-point analysis, the 3-time-point sparse sampling generated comparable estimates of efficacy. CONCLUSIONS: When used to evaluate the efficacy of iron fortificants, random serial sampling can reduce the sample size, invasiveness, and costs while increasing sensitivity. Random serial sampling more clearly describes the pattern of iron repletion and may prove useful in evaluating other micronutrient interventions. PMID- 20844069 TI - Fish consumption and prostate cancer risk: a review and meta-analysis. AB - BACKGROUND: Prostate cancer incidence varies 60-fold globally, which suggests the roles of lifestyle and dietary factors in its cause. To our knowledge, a comprehensive assessment of the association between fish consumption and prostate cancer incidence and mortality has not been reported. OBJECTIVE: We conducted a meta-analysis of fish intake and prostate cancer by focusing on the incidence of prostate cancer and prostate cancer-specific mortality and included subgroup analyses based on race, fish type, method of fish preparation, and high-grade and high-stage cancer. DESIGN: We searched MEDLINE and EMBASE databases (May 2009) for case-control and cohort studies that assessed fish intake and prostate cancer risk. Two authors independently assessed eligibility and extracted data. RESULTS: There was no association between fish consumption and a significant reduction in prostate cancer incidence [12 case-control studies (n = 5777 cases and 9805 control subjects), odds ratio (OR): 0.85; 95% CI: 0.72, 1.00; and 12 cohort studies (n = 445,820), relative risk (RR): 1.01; 95% CI: 0.90, 1.14]. It was not possible to perform a meta-analysis for high-grade disease (one case-control study, OR: 1.44; 95% CI: 0.58, 3.03), locally advanced disease (one cohort study, RR: 0.80; 95% CI: 0.61, 1.13), or metastatic disease (one cohort study, RR: 0.56; 95% CI: 0.37, 0.86). There was an association between fish consumption and a significant 63% reduction in prostate cancer-specific mortality [4 cohort studies (n = 49,661), RR: 0.37; 95% CI: 0.18, 0.74]. CONCLUSION: Our analyses provide no strong evidence of a protective association of fish consumption with prostate cancer incidence but showed a significant 63% reduction in prostate cancer specific mortality. PMID- 20844070 TI - Trends in food availability, 1909-2007. PMID- 20844071 TI - A qualitative study of fish consumption during pregnancy. AB - BACKGROUND: Many pregnant women in the United States do not consume enough docosahexaenoic acid (DHA)--an essential nutrient found in fish. Apparently conflicting findings that fish consumption is beneficial for the developing fetus, yet potentially toxic because of mercury contamination, have created uncertainty about the appropriate fish-consumption advice to provide to pregnant women. OBJECTIVE: Our objective was to determine knowledge, behaviors, and received advice regarding fish consumption among pregnant women who are infrequent consumers of fish. DESIGN: In 2009-2010 we conducted 5 focus groups with 22 pregnant women from the Boston area who ate <2 fish servings/wk. We analyzed transcripts by using immersion-crystallization. RESULTS: Many women knew that fish might contain mercury, a neurotoxin, and had received advice to limit fish intake. Fewer women knew that fish contains DHA or what the function of DHA is. None of the women had received advice to eat fish, and most had not received information about which fish types contain more DHA or less mercury. Because of advice to limit fish intake, as well as a lack of information about which fish types they should be eating, many of the women said that they would rather avoid fish than possibly harm themselves or their infants. The participants thought that a physician's advice to eat fish and a readily available reference regarding which fish are safe to consume during pregnancy would likely have encouraged them to eat more fish. CONCLUSION: Pregnant women might be willing to eat more fish if this were advised by their obstetricians or if they had an accessible reference regarding which types are safe. PMID- 20844072 TI - Concentrations of unmetabolized folic acid and primary folate forms in pregnant women at delivery and in umbilical cord blood. AB - BACKGROUND: The importance of unmetabolized folic acid in maternal and fetal blood is not known. OBJECTIVE: We investigated total folate, tetrahydrofolate (THF), 5-methyltetrahydrofolate (5-MTHF), formyl-THF, 5,10-methenylTHF, and folic acid concentrations in women and in umbilical cord blood at delivery. DESIGN: The study included 87 pregnant women and 29 cord blood samples, including 24 mother infant pairs. We measured serum concentrations of folate forms by using ultraperformance liquid chromatography-tandem mass spectrometry. RESULTS: Pregnant women who received 400 MUg folic acid daily (n = 25) had higher total folate (P = 0.041), 5-MTHF (P = 0.049), and formyl-THF (P < 0.001) concentrations and slightly higher THF (P = 0.093) concentrations than did nonsupplemented pregnant women (n = 61). We measured folic acid concentrations >0.20 nmol/L in 38 (44%) pregnant women and in 55% of the cord serum samples, but these measurements were not explained by maternal supplement use. Concentrations of folic acid were nonsignificantly higher in cord blood from supplemented women than in cord blood from nonsupplemented women (P = 0.154). Proportions of folic acid to total folate in cord serum did not differ according to maternal supplement usage (0.54% compared with 0.43% in supplemented and nonsupplemented women, respectively). Concentrations of folic acid did not differ between maternal and cord serum. However, folic acid constituted a significantly lower proportion of total folate in cord serum than in maternal serum. CONCLUSIONS: We detected unmetabolized folic acid in more than one-half of cord blood samples. Folic acid (400 MUg/d) supplied during pregnancy is not likely to accumulate in the fetus, in contrast to 5-MTHF and THF, which accumulate in the fetus. PMID- 20844073 TI - Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. AB - BACKGROUND: We previously showed that human muscle protein synthesis (MPS) increased during infusion of amino acids (AAs) and peaked at ~120 min before returning to baseline rates, despite elevated plasma AA concentrations. OBJECTIVE: We tested whether a protein meal elicited a similar response and whether signaling responses that regulate messenger RNA translation matched MPS changes. DESIGN: Eight postabsorptive healthy men (~21 y of age) were studied during 8.5 h of primed continuous infusion of [1,2-13C2]leucine with intermittent quadriceps biopsies for determination of MPS and anabolic signaling. After 2.5 h, subjects consumed 48 g whey protein. RESULTS: At 45-90 min after oral protein bolus, mean (+/- SEM) myofibrillar protein synthesis increased from 0.03 +/- 0.003% to 0.10 +/- 0.01%/h; thereafter, myofibrillar protein synthesis returned to baseline rates even though plasma essential AA (EAA) concentrations remained elevated (+130% at 120 min, +80% at 180 min). The activity of protein kinase B (PKB) and phosphorylation of eukaryotic initiation factor 4G preceded the rise of MPS and increases in phosphorylation of ribosomal protein kinase S6 (S6K1), and 4E-binding protein 1 (4EBP1) was superimposable with MPS responses until 90 min. However, although MPS decreased thereafter, all signals, with the exception of PKB activity (which mirrored insulin responses), remained elevated, which echoed the slowly declining plasma EAA profile. The phosphorylation of eukaryotic initiation factor 2alpha increased only at 180 min. Thus, discordance existed between MPS and the mammalian target of rapamycin complex 1 (mTORC1) and signaling (ie, S6K1 and 4EBP1 phosphorylation). CONCLUSIONS: We confirm our previous findings that MPS responses to AAs are transient, even with oral protein bolus. However, changes in MPS only reflect elevated mTORC1 signaling during the upswing in MPS. PMID- 20844074 TI - Coffee and tea intake and risk of brain tumors in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. AB - BACKGROUND: In a recent US cohort study, total coffee and tea consumption was inversely associated with risk of glioma, and experimental studies showed that caffeine can slow the invasive growth of glioblastoma. OBJECTIVE: The objective was to examine the relation between coffee and tea intake and the risk of glioma and meningioma in a large European cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). DESIGN: Data on coffee and tea intake were collected from men and women recruited into the EPIC cohort study. Over an average of 8.5 y of follow-up, 343 cases of glioma and 245 cases of meningioma were newly diagnosed in 9 countries. We used Cox proportional hazards models to examine the relation between coffee and tea and brain tumors. RESULTS: We observed no associations between coffee, tea, or combined coffee and tea consumption and risk of either type of brain tumor when using quantiles based on country-specific distributions of intake. However, a significant inverse association was observed for glioma risk among those consuming >=100 mL coffee and tea per day compared with those consuming <100 mL/d (hazard ratio: 0.66; 95% CI: 0.44, 0.97; P = 0.03). The association was slightly stronger in men (hazard ratio: 0.59; 95% CI: 0.34, 1.01) than in women (hazard ratio: 0.74; 95% CI: 0.42, 1.31), although neither was statistically significant. CONCLUSIONS: In this large cohort study, we observed an inverse association between total coffee and tea consumption and risk of glioma that was consistent with the findings of a recent study. These findings, if further replicated in other studies, may provide new avenues of research on gliomas. PMID- 20844075 TI - Effects of Concord grape juice on ambulatory blood pressure in prehypertension and stage 1 hypertension. AB - BACKGROUND: Consumption of flavonoid-containing foods may be useful for the management of hypertension. OBJECTIVE: We investigated whether 100% Concord grape juice lowers blood pressure in patients with prehypertension and stage 1 hypertension. DESIGN: We conducted a double-blind crossover study to compare the effects of grape juice (7 mL . kg-1 . d-1) and matched placebo beverage on 24-h ambulatory blood pressure, stress-induced changes in blood pressure, and biochemical profile. Participants consumed each beverage for 8 wk with a 4-wk rest period between beverages. They ceased consumption of grapes and other flavonoid-containing beverages throughout the study. RESULTS: We enrolled 64 otherwise healthy patients taking no antihypertensive medications (31% women, 42% black, age 43 +/- 12 y). Baseline mean (+/- SD) cuff blood pressure was 138 +/- 7 (systolic)/82 +/- 7 (diastolic) mm Hg. No effects on the primary endpoint of 24-h mean systolic blood pressure, diastolic blood pressure, or stress-induced changes in blood pressure were observed. A secondary endpoint was nocturnal dip in systolic pressure. At baseline, nocturnal pressure was 8.3 +/- 7.1% lower at night than during daytime. The mean nocturnal dip increased 1.4 percentage points after grape juice and decreased 2.3 percentage points after placebo (P = 0.005). Fasting blood glucose was 91 +/- 10 mg/dL at baseline for the entire cohort. Glucose decreased 2 mg/dL after consumption of grape juice and increased 1 mg/dL after consuming the placebo (P = 0.03). CONCLUSIONS: We observed no effect of grape juice on ambulatory blood pressure in this cohort of relatively healthy individuals with modestly elevated blood pressure. Secondary analyses suggested favorable effects on nocturnal dip and glucose homeostasis that may merit further investigation. This trial was registered at clinicaltrials.gov as NCT00302809. PMID- 20844076 TI - Survival predictability of lean and fat mass in men and women undergoing maintenance hemodialysis. AB - BACKGROUND: Larger body size is associated with greater survival in maintenance hemodialysis (MHD) patients. It is not clear how lean body mass (LBM) and fat mass (FM) compare in their associations with survival across sex in these patients. OBJECTIVE: We examined the hypothesis that higher FM and LBM are associated with greater survival in MHD patents irrespective of sex. DESIGN: In 742 MHD patients, including 31% African Americans with a mean (+/- SD) age of 54 +/- 15 y, we categorized men (n = 391) and women (n = 351) separately into 4 quartiles of near-infrared interactance-measured LBM and FM. Cox proportional hazards models estimated death hazard ratios (HRs) (and 95% CIs), and cubic spline models were used to examine associations with mortality over 5 y (2001 2006). RESULTS: After adjustment for case-mix and inflammatory markers, the highest quartiles of FM and LBM were associated with greater survival in women: HRs of 0.38 (95% CI: 0.20, 0.71) and 0.34 (95% CI: 0.17, 0.67), respectively (reference: first quartile). In men, the highest quartiles of FM and percentage FM (FM%) but not of LBM were associated with greater survival: HRs of 0.51 (95% CI: 0.27, 0.96), 0.45 (95% CI: 0.23, 0.88), and 1.17 (95% CI: 0.60, 2.27), respectively. Cubic spline analyses showed greater survival with higher FM% and higher "FM minus LBM percentiles" in both sexes, whereas a higher LBM was protective in women. CONCLUSIONS: In MHD patients, higher FM in both sexes and higher LBM in women appear to be protective. The survival advantage of FM appears to be superior to that of LBM. Clinical trials to examine the outcomes of interventions that modify body composition in MHD patients are indicated. PMID- 20844077 TI - Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis. AB - BACKGROUND: The effect of caffeine intake during pregnancy on the risk of preterm delivery has been studied for the past 3 decades with inconsistent results. OBJECTIVE: We performed a meta-analysis examining the association between caffeine consumption during pregnancy and risk of preterm birth. DESIGN: We searched MEDLINE and EMBASE articles published between 1966 and July 2010, cross referenced reference lists of the retrieved articles, and identified 15 cohort and 7 case-control studies that met inclusion criteria for this meta-analysis. RESULTS: The combined odds ratios (ORs) obtained by using fixed-effects models for cohort studies were 1.11 (95% CI: 0.96, 1.28), 1.10 (95% CI: 1.01, 1.19), and 1.08 (95% CI: 0.93, 1.27) for risk of preterm birth comparing the highest with the lowest level of caffeine intake (or no intake) (mg/d) during the first, second, and third trimesters, respectively. Results for the case-control studies yielded no associations for the first (OR: 1.07; 95% CI: 0.84, 1.37), second (OR: 1.17; 95% CI: 0.94, 1.45), or third (OR: 0.94; 95% CI: 0.79, 1.12) trimesters. No overall heterogeneity was found by region, publication decade, exposure and outcome assessment, caffeine sources, or adjustment for confounding, which was largely driven by individual studies. CONCLUSION: In this meta-analysis, we observed no important association between caffeine intake during pregnancy and the risk of preterm birth for cohort and case-control studies. PMID- 20844078 TI - Dual functions of yeast tRNA ligase in the unfolded protein response: unconventional cytoplasmic splicing of HAC1 pre-mRNA is not sufficient to release translational attenuation. AB - The unfolded protein response (UPR) is an essential signal transduction to cope with protein-folding stress in the endoplasmic reticulum. In the yeast UPR, the unconventional splicing of HAC1 mRNA is a key step. Translation of HAC1 pre-mRNA (HAC1(u) mRNA) is attenuated on polysomes and restarted only after splicing upon the UPR. However, the precise mechanism of this restart remained unclear. Here we show that yeast tRNA ligase (Rlg1p/Trl1p) acting on HAC1 ligation has an unexpected role in HAC1 translation. An RLG1 homologue from Arabidopsis thaliana (AtRLG1) substitutes for yeast RLG1 in tRNA splicing but not in the UPR. Surprisingly, AtRlg1p ligates HAC1 exons, but the spliced mRNA (HAC1(i) mRNA) is not translated efficiently. In the AtRLG1 cells, the HAC1 intron is circularized after splicing and remains associated on polysomes, impairing relief of the translational repression of HAC1(i) mRNA. Furthermore, the HAC1 5' UTR itself enables yeast Rlg1p to regulate translation of the following ORF. RNA IP revealed that yeast Rlg1p is integrated in HAC1 mRNP, before Ire1p cleaves HAC1(u) mRNA. These results indicate that the splicing and the release of translational attenuation of HAC1 mRNA are separable steps and that Rlg1p has pivotal roles in both of these steps. PMID- 20844079 TI - Dynamics of multiple nuclei in Ashbya gossypii hyphae depend on the control of cytoplasmic microtubules length by Bik1, Kip2, Kip3, and not on a capture/shrinkage mechanism. AB - Ashbya gossypii has a budding yeast-like genome but grows exclusively as multinucleated hyphae. In contrast to budding yeast where positioning of nuclei at the bud neck is a major function of cytoplasmic microtubules (cMTs), A. gossypii nuclei are constantly in motion and positioning is not an issue. To investigate the role of cMTs in nuclear oscillation and bypassing, we constructed mutants potentially affecting cMT lengths. Hyphae lacking the plus (+)end marker Bik1 or the kinesin Kip2 cannot polymerize long cMTs and lose wild-type nuclear movements. Interestingly, hyphae lacking the kinesin Kip3 display longer cMTs concomitant with increased nuclear oscillation and bypassing. Polymerization and depolymerization rates of cMTs are 3 times higher in A. gossypii than in budding yeast and cMT catastrophes are rare. Growing cMTs slide along the hyphal cortex and exert pulling forces on nuclei. Surprisingly, a capture/shrinkage mechanism seems to be absent in A. gossypii. cMTs reaching a hyphal tip do not shrink, and cMT +ends accumulate in hyphal tips. Thus, differences in cMT dynamics and length control between budding yeast and A. gossypii are key elements in the adaptation of the cMT cytoskeleton to much longer cells and much higher degrees of nuclear mobilities. PMID- 20844080 TI - Autocrine transforming growth factor-{beta}1 activation mediated by integrin {alpha}V{beta}3 regulates transcriptional expression of laminin-332 in Madin Darby canine kidney epithelial cells. AB - Laminin (LM)-332 is an extracellular matrix protein that plays a structural role in normal tissues and is also important in facilitating recovery of epithelia from injury. We have shown that expression of LM-332 is up-regulated during renal epithelial regeneration after ischemic injury, but the molecular signals that control expression are unknown. Here, we demonstrate that in Madin-Darby canine kidney (MDCK) epithelial cells LM-332 expression occurs only in subconfluent cultures and is turned-off after a polarized epithelium has formed. Addition of active transforming growth factor (TGF)-beta1 to confluent MDCK monolayers is sufficient to induce transcription of the LM alpha3 gene and LM-332 protein expression via the TGF-beta type I receptor (TbetaR-I) and the Smad2-Smad4 complex. Significantly, we show that expression of LM-332 in MDCK cells is an autocrine response to endogenous TGF-beta1 secretion and activation mediated by integrin alphaVbeta3 because neutralizing antibodies block LM-332 production in subconfluent cells. In confluent cells, latent TGF-beta1 is secreted apically, whereas TbetaR-I and integrin alphaVbeta3 are localized basolaterally. Disruption of the epithelial barrier by mechanical injury activates TGF-beta1, leading to LM 332 expression. Together, our data suggest a novel mechanism for triggering the production of LM-332 after epithelial injury. PMID- 20844081 TI - An outer arm Dynein conformational switch is required for metachronal synchrony of motile cilia in planaria. AB - Motile cilia mediate the flow of mucus and other fluids across the surface of specialized epithelia in metazoans. Efficient clearance of peri-ciliary fluids depends on the precise coordination of ciliary beating to produce metachronal waves. The role of individual dynein motors and the mechanical feedback mechanisms required for this process are not well understood. Here we used the ciliated epithelium of the planarian Schmidtea mediterranea to dissect the role of outer arm dynein motors in the metachronal synchrony of motile cilia. We demonstrate that animals that completely lack outer dynein arms display a significant decline in beat frequency and an inability of cilia to coordinate their oscillations and form metachronal waves. Furthermore, lack of a key mechanosensitive regulatory component (LC1) yields a similar phenotype even though outer arms still assemble in the axoneme. The lack of metachrony was not due simply to a decrease in ciliary beat frequency, as reducing this parameter by altering medium viscosity did not affect ciliary coordination. In addition, we did not observe a significant temporal variability in the beat cycle of impaired cilia. We propose that this conformational switch provides a mechanical feedback system within outer arm dynein that is necessary to entrain metachronal synchrony. PMID- 20844082 TI - Adenomatous polyposis coli and hypoxia-inducible factor-1{alpha} have an antagonistic connection. AB - The tumor suppressor adenomatous polyposis coli (APC) is mutated in the majority of colorectal cancers and is best known for its role as a scaffold in a Wnt regulated protein complex that determines the availability of beta-catenin. Another common feature of solid tumors is the presence of hypoxia as indicated by the up-regulation of hypoxia-inducible factors (HIFs) such as HIF-1alpha. Here, we demonstrate a novel link between APC and hypoxia and show that APC and HIF 1alpha antagonize each other. Hypoxia results in reduced levels of APC mRNA and protein via a HIF-1alpha-dependent mechanism. HIF-1alpha represses the APC gene via a functional hypoxia-responsive element on the APC promoter. In contrast, APC mediated repression of HIF-1alpha requires wild-type APC, low levels of beta catenin, and nuclear factor-kappaB activity. These results reveal down-regulation of APC as a new mechanism that contributes to the survival advantage induced by hypoxia and also show that loss of APC mutations produces a survival advantage by mimicking hypoxic conditions. PMID- 20844085 TI - P4 peptide therapy rescues aged mice from fatal pneumococcal sepsis. PMID- 20844083 TI - Centriolar association of ALMS1 and likely centrosomal functions of the ALMS motif-containing proteins C10orf90 and KIAA1731. AB - Mutations in the human gene ALMS1 cause Alstrom syndrome, a rare progressive condition characterized by neurosensory degeneration and metabolic defects. ALMS1 protein localizes to the centrosome and has been implicated in the assembly and/or maintenance of primary cilia; however its precise function, distribution within the centrosome, and mechanism of centrosomal recruitment are unknown. The C-terminus of ALMS1 contains a region with similarity to the uncharacterized human protein C10orf90, termed the ALMS motif. Here, we show that a third human protein, the candidate centrosomal protein KIAA1731, contains an ALMS motif and that exogenously expressed KIAA1731 and C10orf90 localize to the centrosome. However, based on deletion analysis of ALMS1, the ALMS motif appears unlikely to be critical for centrosomal targeting. RNAi analyses suggest that C10orf90 and KIAA1731 have roles in primary cilium assembly and centriole formation/stability, respectively. We also show that ALMS1 localizes specifically to the proximal ends of centrioles and basal bodies, where it colocalizes with the centrosome cohesion protein C-Nap1. RNAi analysis reveals markedly diminished centrosomal levels of C Nap1 and compromised cohesion of parental centrioles in ALMS1-depleted cells. In summary, these data suggest centrosomal functions for C10orf90 and KIAA1731 and new centriole-related functions for ALMS1. PMID- 20844084 TI - Golgi partitioning controls mitotic entry through Aurora-A kinase. AB - At the onset of mitosis, the Golgi complex undergoes a multistep fragmentation process that is required for its correct partitioning into the daughter cells. Inhibition of this Golgi fragmentation results in cell cycle arrest at the G2 stage, suggesting that correct inheritance of the Golgi complex is monitored by a "Golgi mitotic checkpoint." However, the molecular basis of this G2 block is not known. Here, we show that the G2-specific Golgi fragmentation stage is concomitant with centrosome recruitment and activation of the mitotic kinase Aurora-A, an essential regulator for entry into mitosis. We show that a block of Golgi partitioning impairs centrosome recruitment and activation of Aurora-A, which results in the G2 block of cell cycle progression. Overexpression of Aurora A overrides this cell cycle block, indicating that Aurora-A is a major effector of the Golgi checkpoint. Our findings provide the basis for further understanding of the signaling pathways that coordinate organelle inheritance and cell duplication. PMID- 20844087 TI - Characterization of Treponema pallidum particle agglutination assay-negative sera following screening by treponemal total antibody enzyme immunoassays. AB - Following a laboratory audit, a significant number of Treponema pallidum particle agglutination assay (TPPA)-negative sera were identified when TPPA was used as a confirmatory assay of syphilis enzyme immunoassay (EIA) screening-reactive sera (SSRS). Sera giving such discrepant results were further characterized to assess their significance. A panel of 226 sera was tested by the Abbott Murex ICE Syphilis EIA and then by the Newmarket Syphilis EIA II. TPPA testing was performed on 223 sera. Further testing by the Venereal Disease Research Laboratory (VDRL) test, the Mercia Syphilis IgM EIA, the fluorescent treponemal antibody (FTA-ABS) assay, and INNO-LIA immunoblotting was undertaken in discrepant cases. One hundred eighty-seven of 223 (83.8%) SSRS were TPPA reactive, while 26 (11.6%) sera which were reactive in both the ICE and Newmarket EIAs were nonreactive by TPPA. The majority (68%) of the TPPA-discrepant sera were from HIV-positive patients and did not represent early acute cases, based on previous or follow-up samples, which were available for 22/26 samples. FTA-ABS testing was performed on 24 of these sera; 14 (58.3%) were FTA-ABS positive, and 10 (41.7%) were FTA-ABS negative. Twenty-one of these 26 sera were tested by INNO LIA, and an additional 4 FTA-ABS-negative samples were positive. In this study, significant numbers (18/26) of SSRS- and TPPA-negative sera were shown by further FTA-ABS and LIA (line immunoblot assay) testing to be positive. The reason why certain sera are negative by TPPA but reactive by treponemal EIA and other syphilis confirmatory assays is not clear, and these initial findings should be further explored. PMID- 20844086 TI - Evaluating the orthopoxvirus type I interferon-binding molecule as a vaccine target in the vaccinia virus intranasal murine challenge model. AB - The biological threat imposed by orthopoxviruses warrants the development of safe and effective vaccines. We developed a candidate orthopoxvirus DNA-based vaccine, termed 4pox, which targets four viral structural components, A33, B5, A27, and L1. While this vaccine protects mice and nonhuman primates from lethal infections, we are interested in further enhancing its potency. One approach to enhance potency is to include additional orthopoxvirus immunogens. Here, we investigated whether vaccination with the vaccinia virus (VACV) interferon (IFN) binding molecule (IBM) could protect BALB/c mice against lethal VACV challenge. We found that vaccination with this molecule failed to significantly protect mice from VACV when delivered alone. IBM modestly augmented protection when delivered together with the 4pox vaccine. All animals receiving the 4pox vaccine plus IBM lived, whereas only 70% of those receiving a single dose of 4pox vaccine survived. Mapping studies using truncated mutants revealed that vaccine-generated antibodies spanned the immunoglobulin superfamily domains 1 and 2 and, to a lesser extent, 3 of the IBM. These antibodies inhibited IBM cell binding and IFN neutralization activity, indicating that they were functionally active. This study shows that DNA vaccination with the VACV IBM results in a robust immune response but that this response does not significantly enhance protection in a high-dose challenge model. PMID- 20844089 TI - Global distribution of peste des petits ruminants virus and prospects for improved diagnosis and control. AB - Viral diseases of farm animals, rather than being a diminishing problem across the world, are now appearing with regularity in areas where they have never been seen before. Across the developing world, viral pathogens such as peste des petits ruminants virus (PPRV) place a huge disease burden on agriculture, in particular affecting small ruminant production and in turn increasing poverty in some of the poorest parts of the world. PPRV is currently considered as one of the main animal transboundary diseases that constitutes a threat to livestock production in many developing countries, particularly in western Africa and south Asia. Infection of small ruminants with PPRV causes a devastating plague and as well as being endemic across much of the developing world, in recent years outbreaks of PPRV have occurred in the European part of Turkey. Indeed, the relevance of many once considered 'exotic' viruses is now also high across the European Union and may threaten further regions across the globe in the future. Here, we review the spread of PPRV across Africa, Asia and into Europe through submissions made to the OIE Regional Reference Laboratories. Further, we discuss current control methods and the development of further tools to aid both diagnosis of the disease and prevention. PMID- 20844088 TI - Generation of Fab fragment-like molecular recognition proteins against staphylococcal enterotoxin B by phage display technology. AB - Antigen-binding fragments (Fab fragments) and single-chain variable fragments (scFv) against staphylococcal enterotoxin B (SEB) were produced by phage display technology. SEB epitopes were first identified by phage display approach using the commercial anti-SEB monoclonal antibody ab53981 as the target. Heptamer and dodecamer mimotope peptides recognized by ab53981 were screened from Ph.D-7 or Ph.D-12 random peptide phage libraries expressed in Escherichia coli. The isolated 7-mer and 12-mer mimotopes were shown to share a sequence homologous to 8PDELHK14S in the amino acid sequence of SEB. The N-terminal 15-mer peptide of SEB was determined to be an epitope of ab53981. After immunization of mice with maltose-binding protein-tagged N-terminal 15-mer peptide, a phage display Fab library was constructed using cDNA prepared from the mRNAs of spleen cells. Three phage clones displaying the Fab molecule which recognized SEB were isolated through three rounds of panning. Only one of them produced a soluble Fab fragment from the transformed cells, and the fragment fused with a histidine tag sequence was produced in E. coli cells and converted into scFv. Surface plasmon resonance analysis showed that the dissociation constants of these proteins with SEB were (4.1 +/- 1.1) * 10-9 M and (8.4 +/- 2.3) * 10-10 M, respectively. The produced molecule was applied to the determination of SEB by enzyme-linked immunosorbent assay and Western blot analysis. PMID- 20844091 TI - Acute abdominal pain in systemic lupus erythematosus. PMID- 20844090 TI - Lysine residues of interferon regulatory factor 7 affect the replication and transcription activator-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) infection goes through latent and lytic phases, which are controlled by the viral replication and transcription activator (RTA). Upon KSHV infection, the host responds by suppressing RTA activated lytic gene expression through interferon regulatory factor 7 (IRF-7), a key regulator of host innate immune response. Lysine residues are potential sites for post-translational modification of IRF-7, and were suggested to be critical for its activity. In this study, we analysed the 15 lysine residues for their effects on IRF-7 function by site-directed mutagenesis. We found that some mutations affect the ability of IRF-7 to activate interferon (IFN)-alpha1 and IFN beta promoters, to suppress RTA-mediated lytic gene expression and to repress KSHV reactivation and lytic replication. However, other mutations affect only a subset of these four functions. These findings demonstrate that the lysine residues of IRF-7 play important roles in mediating IFN synthesis and modulating viral lytic replication. PMID- 20844092 TI - Doctor on board? What is the optimal skill-mix in military pre-hospital care? AB - BACKGROUND: In a military setting, pre-hospital times may be extended due to geographical or operational issues. Helicopter casevac enables patients to be transported expediently across all terrains. The skill-mix of the pre-hospital team can vary. AIM: To quantify the doctors' contribution to the Medical Emergency Response Team-Enhanced (MERT-E). METHODS: A prospective log of missions recorded urgency category, patient nationality, mechanism of injury, medical interventions and whether, in the crew's opinion, the presence of the doctor made a positive contribution. RESULTS: Between July and November 2008, MERT-E flew 324 missions for 429 patients. 56% of patients carried were local nationals, 35% were UK forces. 22% of patients were T1, 52% were T2, 21.5% were T3 and 4% were dead. 48% patients had blast injuries, 25% had gunshot wounds, 6 patients had been exposed to blast and gunshot wounds. Median time from take-off to ED arrival was 44 min. A doctor flew on 88% of missions. It was thought that a doctor's presence was not clinically beneficial in 77% of missions. There were 62 recorded physician's INTERVENTIONS: the most common intervention was rapid sequence induction (45%); other interventions included provision of analgesia, sedation or blood products (34%), chest drain or thoracostomy (5%), and pronouncing life extinct (6%). CONCLUSION: MERT-E is a high value asset which makes an important contribution to patient care. A relatively small proportion of missions require interventions beyond the capability of well-trained military paramedics; the indirect benefits of a physician are more difficult to quantify. PMID- 20844093 TI - Full text publication rates of studies presented at an international emergency medicine scientific meeting. AB - The publication rate of full text papers following an abstract presentation at a medical conference is variable, and few studies have examined the situation with respect to international emergency medicine conferences. This retrospective study aimed to identify the publication rate of abstracts presented at the 2006 International Conference on Emergency Medicine (ICEM) held in Halifax, Canada. The full text publication rate was 33.2%, similar to previous emergency medicine meetings. English language barriers may play a role in the low publication rate seen. PMID- 20844094 TI - Establishing a successful pre-hospital emergency service in a developing country: experience from Rescue 1122 service in Pakistan. AB - As in many other developing countries, emergency medical services, especially pre hospital emergency care, has long been neglected in Pakistan. Consequently, patients are brought to the emergency departments by relatives or bystanders in private cars, taxis or any other readily available mode of transportation. Ambulances, where they exist, have barely a stretcher and arrangements for oxygen supply. Modern emergency services are considered too costly for many countries. A model of pre-hospital emergency services, called Rescue 1122 and established in Punjab province of Pakistan, is presented. The system is supported by government funding and provides a quality service. The article describes the process of establishment of the service, the organisational structure, the scope of services and the role it is currently playing in the healthcare of the region it serves. PMID- 20844095 TI - Early prehospital use of non-invasive ventilation improves acute respiratory failure in acute exacerbation of chronic obstructive pulmonary disease. AB - AIM: To evaluate the use of prehospital non-invasive ventilation (NIV) in patients with acute exacerbation of chronic obstructive pulmonary disease. METHODS: 36 adult patients were treated by prehospital NIV or standard oxygen therapy. RESULTS: Prehospital NIV was described as feasible by the paramedics. Prehospital improvement of respiratory rate and dyspnoea was significantly better and the length of intensive care was significantly lower in NIV patients. CONCLUSION: Prehospital NIV can be managed by a trained emergency team with high but sustainable workload. Dyspnoea and length of intensive care may be significantly reduced. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN47620321. PMID- 20844096 TI - Traumatic abdominal wall hernia secondary to handlebar injury: a case report. AB - A traumatic abdominal wall hernia (TAWH) caused by a handlebar collision is very rare. It is difficult for the emergency physician to exclude the possibility of mesenteric or intestinal injuries when viewing handlebar trauma. Because TAWH may have no other clinical symptoms, early recognition and differentiation from haematoma is important. An unusual case of TAWH caused by a handlebar injury is reported, where a multi-layer muscular defect was found along with a segment of incarcerated jejunum and omentum. The latest literature is reviewed, and valuable ideas on the management of blunt abdominal trauma with TAWH are shared. PMID- 20844097 TI - Training and competency in rapid sequence intubation: the perspective from a Scottish teaching hospital emergency department. AB - BACKGROUND: Rapid sequence intubation (RSI) is an established core competency for emergency medicine trainees. The training and experience required to achieve competency is unclear. AIMS: To illustrate the RSI training and experience attained as a specialist registrar in a Scottish teaching hospital emergency department (ED) and establish whether it is sufficient to progress to independent practice. METHODS: Single centre observational study in the ED of Ninewells Hospital, Dundee. RSI data were collected over a 51-month period (April 2005-July 2009) specifically for: patient population; case-mix; operator; and pre-hospital RSI. Competency was assessed by a postal survey questionnaire. RESULTS: 329 RSIs were performed. Trauma was the most common reason for RSI, in 134 (41%) patients. Emergency physicians were the primary operator in 288 (88%) cases. ED registrars were the predominant operator in 206 (63%) RSI. ED registrars perform approximately 6.5 RSI/year. Pre-hospital RSI occurred in 45 (14%) patients. An ED registrar was the operator in 15 (33%) vs an ED consultant in 30 (66%). 12 (71%) of the 17 questionnaires were completed. All trainees (100%) were confident to perform RSI independently at the end of registrar training. 7 (60%) were confident to practice RSI in the pre-hospital environment. CONCLUSION: ED trainees in this department achieve a relatively broad experience and exposure to RSI. Trainees appear to be satisfied with the training they have obtained in order to continue with ED RSI as a new consultant. Additional training is likely to be necessary to confidently perform pre-hospital RSI. PMID- 20844098 TI - Comparative quality analysis of hands-off time in simulated basic and advanced life support following European Resuscitation Council 2000 and 2005 guidelines. AB - AIM: To compare hands-off time (HOT) in simulated advanced life support (ALS) following European Resuscitation Council (ERC) 2005 guidelines and ERC 2000 and to provide quantitative data on workflow. SUBJECTS AND METHODS: Observations with 18 professional paramedics, performing 39 megacodes (mega-code training; MCT) were videotaped during ALS re-certification. Teams were randomly assigned to train according to ERC 2000 or ERC 2005. HOT, hands-off intervals (HOI) and other variables describing interventions and workflow were analysed. RESULTS: In group ERC 2000 17+/-3 HOI appeared with a mean duration of 17.5+/-10.8 s (mean+/-SD). Overall HOT was 382+/-47 s, equivalent to a mean hands-off fraction (HOF) of 0.45+/-0.05. 15+/-5 ventilation-free intervals (VFI) were observed, with a mean duration of 21+/-10 s. In contrast after ERC 2005 variables resulted in 18+/-3 HOI with a mean duration of 10.0+/-4.0 s (p<0.001 vs ERC 2000), overall HOT 196+/ 33 s (HOF 0.23+/-0.04; p<0.001), 24+/-12 VFI with a duration of 24+/-7 s (p<0.05). The first HOI lasted for 60.4+/-33.1 s in ERC 2000 and 17.6+/-4.3 s in ERC 2005 (p<0.001). In ERC 2000 6.1+/-2.6 interruptions for two bag/mask ventilations (BMV) lasted for 5.4+/-0.8 s, whereas in ERC 2005 9.6+/-3.1 interruptions for two BMV took 6.5+/-2.2 s (p<0.001). In both groups HOI were used thoroughly for basic life support/ALS-based interventions. CONCLUSION: The application of ERC guidelines of 2005 markedly reduced the first HOI and mean duration of HOI at the cost of delayed secure airway management and ECG analysis in this MCT model. PMID- 20844099 TI - Flying doctor emergency airway registry: a 3-year, prospective, observational study of endotracheal intubation by the Queensland section of the Royal Flying Doctor Service of Australia. AB - OBJECTIVE: To describe the profile and success rates of emergency endotracheal intubation conducted by the Queensland Royal Flying Doctor Service aeromedical retrieval team comprising a doctor and flight nurse. METHOD: Each intubator completed a study questionnaire at the time of each intubation for indications, complications, overall success, drugs utilised and deployment of rescue airway devices/adjuncts. RESULTS: 76 patients were intubated; 72 intubations were successful. None required surgical airway and three were managed with laryngeal mask airways; the remaining failure was managed with simple airway positioning for transport. There were two cardiac arrests during intubation. Thiopentone and suxamethonium were the predominant drugs used to facilitate intubation. CONCLUSION: Despite a low rate of endotracheal intubation, the high success rate was similar to other aeromedical organisations' published airway data. This study demonstrates the utility of the laryngeal mask airway device in the retrieval and transport setting, in particular for managing a failed intubation. PMID- 20844100 TI - Adolescents in mental health crisis: the role of routine follow-up calls after emergency department visits. AB - To improve care of adolescents in mental health crisis, the role of routine follow-up calls in discharged patients with referral plans after emergency department (ED) presentation to a children's hospital was explored. Main outcome measure was patient attendance at referral sites. In 113 mental health patients with follow-up appointments, either patient/carers or corresponding referral services could be contacted. Median age was 14 years, 77% were girls, and most presentations were after self-harm/depression (61%). Eighty-three per cent (95% CI 75% to 90%) were compliant with the discharge plan without prompting from the ED staff. Fourteen per cent (95% CI 8% to 22%) did not comply after being called by ED staff, and only 3% (95% CI 1% to 7%) were persuaded to attend their outpatient care after being prompted by ED staff. Routine follow-up calls for adolescent mental health patients after ED care are not warranted in all settings. PMID- 20844101 TI - Traumatic testicular injury: a fracture not to miss! PMID- 20844102 TI - Exploratory study of factors associated with adverse clinical features in patients presenting with non-fatal drug overdose/self-poisoning to the ambulance service. AB - AIM: To investigate the factors associated with adverse clinical features presented by drug overdose/self-poisoning patients and the treatments provided. METHODS: Historical patient records collected over 3 months from ambulance crews attending non-fatal overdoses/self-poisoning incidents were reviewed. Logistic regression was used to investigate predictors of adverse clinical features (reduced consciousness, obstructed airway, hypotension or bradycardia, hypoglycaemia) and treatment. RESULTS: Of 22,728 calls attended to over 3 months, 585 (rate 26/1000 calls) were classified as overdose or self-poisoning. In the 585 patients identified, paracetamol-containing drugs were most commonly involved (31.5%). At least one adverse clinical feature occurred in 103 (17.7%) patients, with higher odds in men and opiate overdose or illegal drugs. Older patients and patients with reduced consciousness were more likely to receive oxygen. The latter also had a greater chance of receiving saline. CONCLUSION: Non-fatal overdose/self-poisoning accounted for 2.6% of patients attended by an ambulance. Gender, illegal drugs or opiates were important predictors of adverse clinical features. The treatments most often provided to patients were oxygen and saline. PMID- 20844103 TI - Usefulness of pain presentation characteristics for predicting outcome in patients presenting to the hospital with chest pain of uncertain origin. AB - BACKGROUND: Decision making in chest pain of uncertain origin is challenging. OBJECTIVES: To evaluate the predictive value of simple characteristics of pain presentation in patients coming to the emergency department with chest pain and without electrocardiogram ischaemia or raised troponin. METHODS: 789 patients were studied. The following categorical pain characteristics were collected: effort related pain, pressing character, radiation, associated symptoms, and >= 2 episodes in 24 h. Additionally, a predefined semi-quantitative pain score including seven items (Geleijnse score) was completed. Risk factors and co morbidities were also recorded. The primary and secondary endpoints were cardiac events at 30 days and at 1 year. RESULTS: After adjusting for risk factors and co morbidites, the pain characteristics associated with the primary and secondary endpoints were effort related pain (HR=2.1, 95% CI 1.5 to 3.0, p=0.0001; HR=1.8, 95% CI 1.3 to 2.5, p=0.0003) and >= 2 episodes in 24 h (HR=2.4, 95% CI 1.7 to 3.5, p=0.0001; HR=2.3, 95% CI 1.7 to 3.2, p=0.0001). Both variables retained their predictive value in women, diabetics and elderly (>70 years) patients. The discriminatory capacity of the predictive models including these two pain characteristics for the primary and secondary endpoints (C-statistic 0.76 and 0.76) was better than using the complex semi-quantitative pain score (C-statistic 0.69 and 0.71). CONCLUSION: In patients presenting to the emergency department with chest pain and without electrocardiogram ischaemia or raised troponin, effort related pain and >= 2 episodes in 24 h are the main characteristics to be considered for decision making. PMID- 20844106 TI - Rapid online correction is selectively suppressed during movement with a visuomotor transformation. AB - Reaching movements to visual targets are under fast feedback control, which can rapidly correct an ongoing movement for errors. This study investigates how this online correction is affected by the application of a new visuomotor transformation. Thirty-two subjects made planar pointing movements to visual targets. Vision of the arm was prevented, and hand position was represented by a cursor displayed in the movement plane. In some trials, the target abruptly changed location at the onset of arm movement, which required a rapid correction of movement direction. After performing baseline trials, some subjects were required to adapt to a mirror-image transformation that inverted the visual feedback of their hand position across the body midline, whereas others were not familiarized with the transformation. Afterward, subjects' online correction was tested with target jumps in the presence of the mirror transformation. Results show that after short-term motor adaptation to the mirror transformation there was a selective suppression of the rapid non-mirror correction in the direction of visual target displacement but no mirror reversal. The suppression occurred within the first few trials after the introduction of the mirror transformation, and it was strongest for the movements in which the transformation caused the largest dissociation between the target location and hand movement. Finally, whether or not the short-latency non-mirror correction was suppressed in a given trial, the mirror correction occurred at the same latency as the onset time of voluntary correction in subjects who had not experienced the mirror transformation. PMID- 20844105 TI - Cannabinoids reveal separate controls for whisking amplitude and timing in rats. AB - Whisking is controlled by multiple, possibly functionally segregated, motor sensory-motor loops. While testing for effects of endocannabinoids on whisking, we uncovered the first known functional segregation of channels controlling whisking amplitude and timing. Channels controlling amplitude, but not timing, were modulated by cannabinoid receptor type 1 (CB1R). Systemic administration of CB1R agonist Delta(9)-tetrahydrocannabinol (Delta(9)-THC) reduced whisking spectral power across all tested doses (1.25-5 mg/kg), whereas whisking frequency was affected at only very high doses (5 mg/kg). Concomitantly, whisking amplitude and velocity were significantly reduced in a dose-dependent manner (25-43 and 26 50%, respectively), whereas cycle duration and bilateral synchrony were hardly affected (3-16 and 3-9%, respectively). Preadministration of CB1R antagonist SR141716A blocked Delta(9)-THC-induced kinematic alterations of whisking, and when administered alone, increased whisking amplitude and velocity but affected neither cycle duration nor synchrony. These findings indicate that whisking amplitude and timing are controlled by separate channels and that endocannabinoids modulate amplitude control channels. PMID- 20844104 TI - Neural representation during visually guided reaching in macaque posterior parietal cortex. AB - Visually guided hand movements in primates require an interconnected network of various cortical areas. Single unit firing rate from area 7a and dorsal prelunate (DP) neurons of macaque posterior parietal cortex (PPC) was recorded during reaching movements to targets at variable locations and under different eye position conditions. In the eye position-varied task, the reach target was always foveated; thus eye position varied with reach target location. In the retinal varied task, the monkey reached to targets at variable retinotopic locations while eye position was kept constant in the center. Spatial tuning was examined with respect to temporal (task epoch) and contextual (task condition) aspects, and response fields were compared. The analysis showed distinct tuning types. The majority of neurons changed their gain field tuning and retinotopic tuning between different phases of the task. Between the onset of visual stimulation and the preparatory phase (before the go signal), about one half the neurons altered their firing rate significantly. Spatial response fields during preparation and initiation epochs were strongly influenced by the task condition (eye position varied vs. retinal varied), supporting a strong role of eye position during visually guided reaching. DP neurons, classically considered visual, showed reach related modulation similar to 7a neurons. This study shows that both area 7a and DP are modulated during reaching behavior in primates. The various tuning types in both areas suggest distinct populations recruiting different circuits during visually guided reaching. PMID- 20844108 TI - Interacting noise sources shape patterns of arm movement variability in three dimensional space. AB - Reaching movements are subject to noise in both the planning and execution phases of movement production. The interaction of these noise sources during natural movements is not well understood, despite its importance for understanding movement variability in neurologically intact and impaired individuals. Here we examined the interaction of planning and execution related noise during the production of unconstrained reaching movements. Subjects performed sequences of two movements to targets arranged in three vertical planes separated in depth. The starting position for each sequence was also varied in depth with the target plane; thus required movement sequences were largely contained within the vertical plane of the targets. Each final target in a sequence was approached from two different directions, and these movements were made with or without visual feedback of the moving hand. These combined aspects of the design allowed us to probe the interaction of execution and planning related noise with respect to reach endpoint variability. In agreement with previous studies, we found that reach endpoint distributions were highly anisotropic. The principal axes of movement variability were largely aligned with the depth axis, i.e., the axis along which visual planning related noise would be expected to dominate, and were not generally well aligned with the direction of the movement vector. Our results suggest that visual planning-related noise plays a dominant role in determining anisotropic patterns of endpoint variability in three-dimensional space, with execution noise adding to this variability in a movement direction-dependent manner. PMID- 20844107 TI - The sphingosine 1-phosphate receptor, S1PR1, plays a prominent but not exclusive role in enhancing the excitability of sensory neurons. AB - Sphingosine 1-phosphate (S1P) through its interaction with a family of G protein coupled receptors (S1PR) is proving to have a significant impact on the activation of a variety of cell types, most notably those cells mediating the inflammatory response. Previously, we showed that S1P enhanced the excitability of small diameter sensory neurons, and mRNA for S1PR(1-4) was expressed in sensory neurons. These initial findings did not determine which S1PR subtype(s) mediated the increased excitability. Here, we report that exposure to the selective S1PR(1) agonist, SEW2871, produced a significant increase in excitability of some, but not all, sensory neurons. To further examine the role of S1PR(1), neurons were treated with siRNA targeted to S1PR(1). siRNA reduced S1PR(1) protein expression by 75% and blocked the sensitization produced by SEW2871, although some neurons remained responsive to subsequent exposure to S1P. Treatment with scramble siRNA did not alter S1PR(1) expression. Recordings from siRNA- and scramble-treated neurons suggested three distinct populations based on their sensitivities to SEW2871 and S1P. Approximately 50% of the neurons exhibited a significant increase in excitability after exposure to SEW2871 and subsequent S1P produced no additional increase; ~25% were not affected by SEW2871 but S1P significantly increased excitability; and ~25% of the neurons were not sensitized by either SEW2871 or S1P. RT-PCR measurements obtained from single neurons showed that 50% of the small diameter neurons expressed the mRNA for S1PR(1). These results indicate that S1PR(1) plays a prominent, although not exclusive, role in mediating the enhancement of excitability produced by S1P. PMID- 20844109 TI - Theta burst stimulation of human primary motor cortex degrades selective muscle activation in the ipsilateral arm. AB - This study investigated whether repetitive transcranial magnetic stimulation (TMS) delivered as continuous theta burst stimulation (cTBS) to left M1 degraded selective muscle activation in the contralateral and ipsilateral upper limb in healthy participants. Contralateral motor-evoked potentials (cMEPs) were elicited in left and right biceps brachii (BB) before either elbow flexion or forearm pronation. A neurophysiological index, the excitability ratio (ER), was computed from the relative size of BB cMEPs before each type of movement. Short interval intracortical inhibition (SICI) was assessed in cMEPs of right BB with paired pulse TMS of left M1. Ipsilateral MEPs (iMEPs) and silent periods (iSPs) were measured in left BB with single-pulse TMS of left M1. Low-intensity cTBS was expected to suppress corticospinal output from left M1. A sham condition was also included. Real but not sham cTBS caused increases in BB ER bilaterally. In the right arm, ER increased because BB cMEPs before flexion were less facilitated, whereas cMEPs in the pronation task were unaffected. This was accompanied by an increase in left M1 SICI. In the left arm, ER increased because BB cMEPs before pronation were facilitated but were unaffected in the flexion task. There was also facilitation of left BB iMEPs. These changes in the left arm are consistent with inappropriate facilitation of left BB alpha-motoneurons (alphaMNs) before pronation. This is the first demonstration that cTBS of M1 can alter excitability of neurons controlling ipsilateral proximal musculature and degrade ipsilateral upper limb motor control, providing evidence that ipsilateral and contralateral M1 shape the spatial and temporal characteristics of proximal muscle activation appropriate for the task at hand. PMID- 20844111 TI - Inhibition of steady-state smooth pursuit and catch-up saccades by abrupt visual and auditory onsets. AB - It is known that visual transients prolong saccadic latency and reduce saccadic frequency. The latter effect was attributed to subcortical structures because it occurred only 60-70 ms after stimulus onset. We examined the effects of large task-irrelevant transients on steady-state pursuit and the generation of catch-up saccades. Two screen-wide stripes of equal contrast (4, 20, or 100%) were briefly flashed at equal eccentricities (3, 6, or 12 degrees ) from the pursuit target. About 100 ms after flash onset, we observed that pursuit gain dropped by 6-12% and catch-up saccades were entirely suppressed. The relatively long latency of the inhibition suggests that it results from cortical mechanisms that may act by promoting fixation or the deployment of attention over the visual field. In addition, we show that a loud irrelevant sound is able to generate the same inhibition of saccades as visual transients, whereas it only induces a weak modulation of pursuit gain, indicating a privileged access of acoustic information to the saccadic system. Finally, irrelevant changes in motion direction orthogonal to pursuit had a smaller and later inhibitory effect. PMID- 20844110 TI - Stiffness control of balance during quiet standing and dual task in older adults: the MOBILIZE Boston Study. AB - Distractions affect postural control, but this mechanism is not well understood. Diversion of resources during cognitive stress may lead to decreased motor drive and postural muscle tone. This may appear as decreased postural stiffness and increased postural sway amplitude. We hypothesized that dual tasking leads to decreased stiffness and increased sway amplitude. Postural sway (center of pressure; COP) data were used from 724 participants aged 77.9 +/- 5.3 yr, a representative sample of community-dwelling older adults, the MOBILIZE Boston Study cohort. Subjects stood barefoot with eyes open for 30 s per trial on a force plate. Five trials were performed each with and without a serial subtractions-by-3 task. Sway data were fit to a damped oscillator inverted pendulum model. Amplitudes (COP and center of mass), mechanical stiffness, and damping of the sway behavior were determined. Sway amplitudes and damping increased with the dual task (P < 0.001); stiffness decreased only mediolaterally (P < 0.001). Those with difficulty doing the dual task exhibited larger sway and less damping mediolaterally (P <= 0.001) and an increased stiffness with dual task anteroposteriorly (interaction P = 0.004). Dual task could still independently explain increases in sway (P < 0.001) after accounting for stiffness changes. Thus the hypothesis was supported only in mediolateral sway. The simple model helped to explain the dual task related increase of sway only mediolaterally. It also elucidated the differential influence of cognitive function on the mechanics of anteroposterior and mediolateral sway behaviors. Dual task may divert the resources necessary for mediolateral postural control, thus leading to falls. PMID- 20844112 TI - Depolarization-induced Ca2+ entry preferentially evokes release of large quanta in the developing Xenopus neuromuscular junction. AB - The amplitude histogram of spontaneously occurring miniature synaptic currents (mSCs) is skewed positively at developing Xenopus neuromuscular synapses formed in culture. To test whether the quantal size of nerve-evoked quanta (eSCs) distributes similarly, we compared the amplitude histogram of single quantum eSCs in low external Ca(2+) with that of mSCs and found that nerve stimulation preferentially released large quanta. Depolarization of presynaptic terminals by elevating [K(+)] in the external solution or by direct injection of current through a patch pipette increased the mSC frequency and preferentially, but not exclusively, evoked the release of large quanta, resulting in a second broad peak in the amplitude histogram. Formation of the second peak under these conditions was blocked by the N-type Ca(2+) channel blocker, omega-conotoxin GVIA. In contrast, when the mSC frequency was elevated by thapsigargin- or caffeine induced mobilization of internal Ca(2+), formation of the second peak did not occur. We conclude that the second peak in the amplitude histogram is generated by Ca(2+) influx through N-type Ca(2+) channels, causing a local elevation of internal Ca(2+). The mSC amplitude in the positively skewed portion of the histogram varied over a wide range. A competitive blocker of acetylcholine (ACh) receptors, d-tubocurarine, reduced the amplitude of smaller mSCs in this range relatively more than that of larger mSCs, suggesting that this variation in the mSC amplitude is due to variable amounts of ACh released from synaptic vesicles. We suggest that Ca(2+) influx through N-type Ca(2+) channels preferentially induces release of vesicles with large ACh content. PMID- 20844114 TI - Irritancy expectancy alters odor perception: evidence from olfactory event related potential research. AB - The aim of the present research was to investigate the influences of cognition on temporal processing of olfactory information in a health-relevant context. We investigated whether expecting an odor to cause adverse health effects alters perception of that odor. An irritation-free odor (Study 1: H(2)S; Study 2: phenyl ethyl alcohol [PEA]) was presented after which participants expected to experience either adverse sensory irritation (caused by intranasal CO(2) presentation) in one condition or no adverse effects in another condition, depending on a previously presented visual cue. Olfactory event-related potentials (OERPs) were measured to assess effects of expectations on the temporal course of olfactory processing. When participants expected irritancy after perceiving the odor of H(2)S, N1 and P3 peak amplitude and N1 latency were increased and shortened, respectively, suggesting more intense and faster processing of the odor as well as effects on salience and anticipation of sensory irritation. When the odor was PEA, only the N1 amplitude was increased. These results, obtained with OERP, provide converging evidence for comparable conclusions regarding the influence of cognition on odor perception reached with functional magnetic resonance imaging. Furthermore, the results suggest that a priori hedonic valence of an odor affects how susceptible the olfactory percept is to modulation via expectations. PMID- 20844115 TI - Contribution of the premotor cortex to consolidation of motor sequence learning in humans during sleep. AB - Motor learning and memory consolidation require the contribution of different cortices. For motor sequence learning, the primary motor cortex is involved primarily in its acquisition. Premotor areas might be important for consolidation. In accordance, modulation of cortical excitability via transcranial DC stimulation (tDCS) during learning affects performance when applied to the primary motor cortex, but not premotor cortex. We aimed to explore whether premotor tDCS influences task performance during motor memory consolidation. The impact of excitability-enhancing, -diminishing, or placebo premotor tDCS during rapid eye movement (REM) sleep on recall in the serial reaction time task (SRTT) was explored in healthy humans. The motor task was learned in the evening. Recall was performed immediately after tDCS or the following morning. In two separate control experiments, excitability-enhancing premotor tDCS was performed 4 h after task learning during daytime or immediately before conduction of a simple reaction time task. Excitability-enhancing tDCS performed during REM sleep increased recall of the learned movement sequences, when tested immediately after stimulation. REM density was enhanced by excitability-increasing tDCS and reduced by inhibitory tDCS, but did not correlate with task performance. In the control experiments, tDCS did not improve performance. We conclude that the premotor cortex is involved in motor memory consolidation during REM sleep. PMID- 20844113 TI - Spatially distributed encoding of covert attentional shifts in human thalamus. AB - Spatial attention modulates signal processing within visual nuclei of the thalamus--but do other nuclei govern the locus of attention in top-down mode? We examined functional MRI (fMRI) data from three subjects performing a task requiring covert attention to 1 of 16 positions in a circular array. Target position was cued after stimulus offset, requiring subjects to perform target detection from iconic visual memory. We found positionally specific responses at multiple thalamic sites, with individual voxels activating at more than one direction of attentional shift. Voxel clusters at anatomically equivalent sites across subjects revealed a broad range of directional tuning at each site, with little sign of contralateral bias. By reference to a thalamic atlas, we identified the nuclear correspondence of the four most reliably activated sites across subjects: mediodorsal/central-intralaminar (oculomotor thalamus), caudal intralaminar/parafascicular, suprageniculate/limitans, and medial pulvinar/lateral posterior. Hence, the cortical network generating a top-down control signal for relocating attention acts in concert with a spatially selective thalamic apparatus-the set of active nuclei mirroring the thalamic territory of cortical "eye-field" areas, thus supporting theories which propose the visuomotor origins of covert attentional selection. PMID- 20844116 TI - Brain noise is task dependent and region specific. AB - The emerging organization of anatomical and functional connections during human brain development is thought to facilitate global integration of information. Recent empirical and computational studies have shown that this enhanced capacity for information processing enables a diversified dynamic repertoire that manifests in neural activity as irregularity and noise. However, transient functional networks unfold over multiple time, scales and the embedding of a particular region depends not only on development, but also on the manner in which sensory and cognitive systems are engaged. Here we show that noise is a facet of neural activity that is also sensitive to the task context and is highly region specific. Children (6-16 yr) and adults (20-41 yr) performed a one-back face recognition task with inverted and upright faces. Neuromagnetic activity was estimated at several hundred sources in the brain by applying a beamforming technique to the magnetoencephalogram (MEG). During development, neural activity became more variable across the whole brain, with most robust increases in medial parietal regions, such as the precuneus and posterior cingulate cortex. For young children and adults, activity evoked by upright faces was more variable and noisy compared with inverted faces, and this effect was reliable only in the right fusiform gyrus. These results are consistent with the notion that upright faces engender a variety of integrative neural computations, such as the relations among facial features and their holistic constitution. This study shows that transient changes in functional integration modulated by task demand are evident in the variability of regional neural activity. PMID- 20844118 TI - Honey bee thermal/chemical sensor, AmHsTRPA, reveals neofunctionalization and loss of transient receptor potential channel genes. AB - Insects are relatively small heterothermic animals, thus they are highly susceptible to changes in ambient temperature. However, a group of honey bees is able to maintain the brood nest temperature between 32 degrees C and 36 degrees C by either cooling or heating the nest. Nevertheless, how honey bees sense the ambient temperature is not known. We identified a honey bee Hymenoptera-specific transient receptor potential A (HsTRPA) channel (AmHsTRPA), which is activated by heat with an apparent threshold temperature of 34 degrees C and insect antifeedants such as camphor in vitro. AmHsTRPA is expressed in the antennal flagellum, and ablation of the antennal flagella and injection of AmHsTRPA inhibitors impair warmth avoidance of honey bees. Gustatory responses of honey bees to sucrose are suppressed by noxious heat and insect antifeedants, but are relieved in the presence of AmHsTRPA inhibitors. These results suggest that AmHsTRPA may function as a thermal/chemical sensor in vivo. As shown previously, Hymenoptera has lost the ancient chemical sensor TRPA1; however, AmHsTRPA is able to complement the function of Drosophila melanogaster TRPA1. These results demonstrate that HsTRPA, originally arisen by the duplication of Water witch, has acquired thermal- and chemical-responsive properties, which has resulted in the loss of ancient TRPA1. Thus, this is an example of neofunctionalization of the duplicated ion channel gene followed by the loss of the functionally equivalent ancient gene. PMID- 20844117 TI - Loss of leptin receptors on hypothalamic POMC neurons alters synaptic inhibition. AB - Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr(-/-) GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr(-/-) GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr(-/-) GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr(-/-) GFP mice. Moreover, POMC neurons receive greater total ionic flux per GABAergic event in the absence of leptin receptor signaling. In addition, treatment with the alpha 3 subunit-containing GABA(A) receptor modulator SB-205384 enhances GABAergic transmission only onto POMC neurons in POMC: Lepr(-/-) GFP mice. Single cell RT-PCR analysis further supports the expression of the alpha 3 subunit of the GABA(A) receptor on POMC neurons in POMC: Lepr(-/-) GFP mice. Finally, the responses to the GABA(A) receptor agonist isoguvacine of POMC neurons are significantly smaller in POMC: Lepr(-/-) GFP than in control animals. Therefore our present work demonstrates that loss of leptin signaling in POMC neurons induces synaptic alterations at POMC synapses that may play an essential role in energy homeostasis. PMID- 20844119 TI - Muscle-derived collagen XIII regulates maturation of the skeletal neuromuscular junction. AB - Formation, maturation, stabilization, and functional efficacy of the neuromuscular junction (NMJ) are orchestrated by transsynaptic and autocrine signals embedded within the synaptic cleft. Here, we demonstrate that collagen XIII, a nonfibrillar transmembrane collagen, is another such signal. We show that collagen XIII is expressed by muscle and its ectodomain can be proteolytically shed into the extracellular matrix. The collagen XIII protein was found present in the postsynaptic membrane and synaptic basement membrane. To identify a role for collagen XIII at the NMJ, mice were generated lacking this collagen. Morphological and ultrastructural analysis of the NMJ revealed incomplete adhesion of presynaptic and postsynaptic specializations in collagen XIII deficient mice of both genders. Strikingly, Schwann cells erroneously enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Consistent with morphological findings, electrophysiological studies indicated both postsynaptic and presynaptic defects in Col13a1(-/-) mice, such as decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release and reduced readily releasable neurotransmitter pool. To identify the role of collagen XIII at the NMJ, shed ectodomain of collagen XIII was applied to cultured myotubes, and it was found to advance acetylcholine receptor (AChR) cluster maturation. Together with the delay in AChR cluster development observed in collagen XIII-deficient mutants in vivo, these results suggest that collagen XIII plays an autocrine role in postsynaptic maturation of the NMJ. Altogether, the results presented here reveal that collagen XIII is a novel muscle-derived cue necessary for the maturation and function of the vertebrate NMJ. PMID- 20844120 TI - Mitochondrial protection attenuates inflammation-induced impairment of neurogenesis in vitro and in vivo. AB - The impairment of hippocampal neurogenesis has been linked to the pathogenesis of neurological disorders from chronic neurodegenerative disease to the progressive cognitive impairment of children who receive brain irradiation. Numerous studies provide evidence that inflammation downregulates neurogenesis, with multiple factors contributing to this impairment. Although mitochondria are one of the primary targets of inflammatory injury, the role of mitochondrial function in the modulation of neurogenesis remains relatively unstudied. In this study, we used neurosphere-derived cells to show that immature doublecortin (Dcx)-positive neurons are uniquely sensitive to mitochondrial inhibition, demonstrating rapid loss of mitochondrial potential and cell viability compared with glial cells and more mature neurons. Mitochondrial inhibition for 24 h produced no significant changes in astrocyte or oligodendrocyte viability, but reduced viability of mature neurons by 30%, and reduced survival of Dcx(+) cells by 60%. We demonstrate that protection of mitochondrial function with mitochondrial metabolites or the mitochondrial chaperone mtHsp75/mortalin partially reverses the inflammation-associated impairment of neurogenesis in vitro and in irradiated mice in vivo. Our findings highlight mitochondrial mechanisms involved in neurogenesis and indicate mitochondria as a potential target for protective strategies to prevent the impairment of neurogenesis by inflammation. PMID- 20844121 TI - Increased BMP6 levels in the brains of Alzheimer's disease patients and APP transgenic mice are accompanied by impaired neurogenesis. AB - During aging and in the progression of Alzheimer's disease (AD), synaptic plasticity and neuronal integrity are disturbed. In addition to the alterations in plasticity in mature neurons, the neurodegenerative process in AD has been shown to be accompanied by alterations in neurogenesis. Members of the bone morphogenetic protein (BMP) family of growth factors have been implicated as important regulators of neurogenesis and neuronal cell fate determination during development; however, their role in adult neurogenesis and in AD is less clear. We show here by qRT-PCR analysis that BMP6 mRNA levels were significantly increased in the hippocampus of human patients with AD and in APP transgenic mice compared to controls. Immunoblot and immunohistochemical analyses confirmed that BMP6 protein levels were increased in human AD brains and APP transgenic mouse brains compared to controls and accumulated around hippocampal plaques. The increased levels of BMP6 were accompanied by defects in hippocampal neurogenesis in AD patients and APP transgenic mice. In support of a role for BMP6 in defective neurogenesis in AD, we show in an in vitro model of adult neurogenesis that treatment with amyloid-beta(1-42) protein (Abeta) resulted in increased expression of BMP6, and that exposure to recombinant BMP6 resulted in reduced proliferation with no toxic effects. Together, these results suggest that Abeta associated increases in BMP6 expression in AD may have deleterious effects on neurogenesis in the hippocampus, and therapeutic approaches could focus on normalization of BMP6 levels to protect against AD-related neurogenic deficits. PMID- 20844123 TI - Sox1 is required for the specification of a novel p2-derived interneuron subtype in the mouse ventral spinal cord. AB - During mouse development, the ventral spinal cord becomes organized into five progenitor domains that express different combinations of transcription factors and generate different subsets of neurons and glia. One of these domains, known as the p2 domain, generates two subtypes of interneurons, V2a and V2b. Here we have used genetic fate mapping and loss-of-function analysis to show that the transcription factor Sox1 is expressed in, and is required for, a third type of p2-derived interneuron, which we named V2c. These are close relatives of V2b interneurons, and, in the absence of Sox1, they switch to the V2b fate. In addition, we show that late-born V2a and V2b interneurons are heterogeneous, and subsets of these cells express the transcription factor Pax6. Our data demonstrate that interneuron diversification in the p2 domain is more complex than previously thought and directly implicate Sox1 in this process. PMID- 20844124 TI - Atypical reflexive gaze patterns on emotional faces in autism spectrum disorders. AB - Atypical scan paths on emotional faces and reduced eye contact represent a prominent feature of autism symptomatology, yet the reason for these abnormalities remains a puzzle. Do individuals with autism spectrum disorders (ASDs) fail to orient toward the eyes or do they actively avoid direct eye contact? Here, we used a new task to investigate reflexive eye movements on fearful, happy, and neutral faces. Participants (ASDs: 12; controls: 11) initially fixated either on the eyes or on the mouth. By analyzing the frequency of participants' eye movements away from the eyes and toward the eyes, respectively, we explored both avoidance and orientation reactions. The ASD group showed a reduced preference for the eyes relative to the control group, primarily characterized by more frequent eye movements away from the eyes. Eye-tracking data revealed a pronounced influence of active avoidance of direct eye contact on atypical gaze in ASDs. The combination of avoidance and reduced orientation into an individual index predicted emotional recognition performance. Crucially, this result provides evidence for a direct link between individual gaze patterns and associated social symptomatology. These findings thereby give important insights into the social pathology of ASD, with implications for future research and interventions. PMID- 20844122 TI - Protein kinase A in the pedunculopontine tegmental nucleus of rat contributes to regulation of rapid eye movement sleep. AB - Intracellular signaling mechanisms within the pedunculopontine tegmental (PPT) nucleus for the regulation of recovery rapid eye movement (REM) sleep following REM sleep deprivation remain unknown. This study was designed to determine the role of PPT intracellular cAMP-dependent protein kinase A (cAMP-PKA) in the regulation of recovery REM sleep in freely moving rats. The results show that a brief period (3 h) of selective REM sleep deprivation caused REM sleep rebound associated with increased PKA activity and expression of the PKA catalytic subunit protein (PKA-CU) in the PPT. Local application of a cAMP-PKA-activation selective inhibitor, RpCAMPS (0.55, 1.1, and 2.2 nmol/100 nl; n = 8 rats/group), bilaterally into the PPT, reduced PKA activity and PKA-CU expression in the PPT, and suppressed the recovery REM sleep, in a dose-dependent manner. Regression analyses revealed significant positive relationships between: PPT levels of PKA activity and the total percentages of REM sleep recovery (Rsqr = 0.944; n = 40 rats); PPT levels of PKA-CU expression and the total percentages of REM sleep recovery (Rsqr = 0.937; n = 40 rats); PPT levels of PKA-CU expression and PKA activity (Rsqr = 0.945; n = 40 rats). Collectively, these results provide evidence that activation of intracellular PKA in the PPT contributes to REM sleep recovery following REM sleep deprivation. PMID- 20844125 TI - Associative learning and CA3-CA1 synaptic plasticity are impaired in D1R null, Drd1a-/- mice and in hippocampal siRNA silenced Drd1a mice. AB - Associative learning depends on multiple cortical and subcortical structures, including striatum, hippocampus, and amygdala. Both glutamatergic and dopaminergic neurotransmitter systems have been implicated in learning and memory consolidation. While the role of glutamate is well established, the role of dopamine and its receptors in these processes is less clear. In this study, we used two models of dopamine D(1) receptor (D(1)R, Drd1a) loss, D(1)R knock-out mice (Drd1a(-/-)) and mice with intrahippocampal injections of Drd1a-siRNA (small interfering RNA), to study the role of D(1)R in different models of learning, hippocampal long-term potentiation (LTP) and associated gene expression. D(1)R loss markedly reduced spatial learning, fear learning, and classical conditioning of the eyelid response, as well as the associated activity-dependent synaptic plasticity in the hippocampal CA1-CA3 synapse. These results provide the first experimental demonstration that D(1)R is required for trace eyeblink conditioning and associated changes in synaptic strength in hippocampus of behaving mice. Drd1a-siRNA mice were indistinguishable from Drd1a(-/-) mice in all experiments, indicating that hippocampal knockdown was as effective as global inactivation and that the observed effects are caused by loss of D(1)R and not by indirect developmental effects of Drd1a(-/-). Finally, in vivo LTP and LTP-induced expression of Egr1 in the hippocampus were significantly reduced in Drd1a(-/-) and Drd1a-siRNA, indicating an important role for D(1)R in these processes. Our data reveal a functional relationship between acquisition of associative learning, increase in synaptic strength at the CA3-CA1 synapse, and Egr1 induction in the hippocampus by demonstrating that all three are dramatically impaired when D(1)R is eliminated or reduced. PMID- 20844126 TI - GABA(A) receptors in the pontine reticular formation of C57BL/6J mouse modulate neurochemical, electrographic, and behavioral phenotypes of wakefulness. AB - Drugs that potentiate transmission at GABA(A) receptors are widely used to enhance sleep and to cause general anesthesia. The mechanisms underlying these effects are unknown. This study tested the hypothesis that GABA(A) receptors in the pontine reticular nucleus, oral part (PnO) of mouse modulate five phenotypes of arousal: sleep and wakefulness, cortical electroencephalogram (EEG) activity, acetylcholine (ACh) release in the PnO, breathing, and recovery time from general anesthesia. Microinjections into the PnO of saline (vehicle control), the GABA(A) receptor agonist muscimol, muscimol with the GABA(A) receptor antagonist bicuculline, and bicuculline alone were performed in male C57BL/6J mice (n = 33) implanted with EEG recording electrodes. Muscimol caused a significant increase in wakefulness and decrease in rapid eye movement (REM) and non-REM (NREM) sleep. These effects were reversed by coadministration of bicuculline. Bicuculline administered alone caused a significant decrease in wakefulness and increase in NREM sleep and REM sleep. Muscimol significantly increased EEG power in the delta range (0.5-4 Hz) during wakefulness and in the theta range (4-9 Hz) during REM sleep. Dialysis delivery of bicuculline to the PnO of male mice (n = 18) anesthetized with isoflurane significantly increased ACh release in the PnO, decreased breathing rate, and increased anesthesia recovery time. All drug effects were concentration dependent. The effects on phenotypes of arousal support the conclusion that GABA(A) receptors in the PnO promote wakefulness and suggest that increasing GABAergic transmission in the PnO may be one mechanism underlying the phenomenon of paradoxical behavioral activation by some benzodiazepines. PMID- 20844128 TI - Rule-based learning explains visual perceptual learning and its specificity and transfer. AB - Visual perceptual learning models, as constrained by orientation and location specificities, propose that learning either reflects changes in V1 neuronal tuning or reweighting specific V1 inputs in either the visual cortex or higher areas. Here we demonstrate that, with a training-plus-exposure procedure, in which observers are trained at one orientation and either simultaneously or subsequently passively exposed to a second transfer orientation, perceptual learning can completely transfer to the second orientation in tasks known to be orientation-specific. However, transfer fails if exposure precedes the training. These results challenge the existing specific perceptual learning models by suggesting a more general perceptual learning process. We propose a rule-based learning model to explain perceptual learning and its specificity and transfer. In this model, a decision unit in high-level brain areas learns the rules of reweighting the V1 inputs through training. However, these rules cannot be applied to a new orientation/location because the decision unit cannot functionally connect to the new V1 inputs that are unattended or even suppressed after training at a different orientation/location, which leads to specificity. Repeated orientation exposure or location training reactivates these inputs to establish the functional connections and enable the transfer of learning. PMID- 20844127 TI - Regulatory mechanisms that mediate tenascin C-dependent inhibition of oligodendrocyte precursor differentiation. AB - Here, we present mechanisms for the inhibition of oligodendendrocyte precursor cell (OPC) differentiation, a biological function of neural extracellular matrix (ECM). The differentiation of oligodendrocytes is orchestrated by a complex set of stimuli. In the present study, we investigated the signaling pathway elicited by the ECM glycoprotein tenascin C (Tnc). Tnc substrates inhibit myelin basic protein (MBP) expression of cultured rat oligodendrocytes, and, conversely, we found that the emergence of MBP expression is accelerated in forebrains of Tnc deficient mice. Mechanistically, Tnc interfered with phosphorylation of Akt, which in turn reduced MBP expression. At the cell surface, Tnc associates with lipid rafts in oligodendrocyte membranes, together with the cell adhesion molecule contactin (Cntn1) and the Src family kinase (SFK) Fyn. Depletion of Cntn1 in OPCs by small interfering RNAs (siRNAs) abolished the Tnc-dependent inhibition of oligodendrocyte differentiation, while Tnc exposure impeded the activation of the tyrosine kinase Fyn by Cntn1. Concomitant with oligodendrocyte differentiation, Tnc antagonized the expression of the signaling adaptor and RNA binding molecule Sam68. siRNA-mediated knockdown or overexpression of Sam68 delayed or accelerated oligodendrocyte differentiation, respectively. Inhibition of oligodendrocyte differentiation with the SFK inhibitor PP2 could be rescued by Sam68 overexpression, which may indicate a regulatory role for Sam68 downstream of Fyn. Our study therefore uncovers the first signaling pathways that underlie Tnc-induced, ECM-dependent maintenance of the immature state of OPCs. PMID- 20844129 TI - Audiovisual synchrony improves motion discrimination via enhanced connectivity between early visual and auditory areas. AB - Audiovisual synchrony enables integration of dynamic visual and auditory signals into a more robust and reliable multisensory percept. In this fMRI study, we investigated the neural mechanisms by which audiovisual synchrony facilitates shape and motion discrimination under degraded visual conditions. Subjects were presented with visual patterns that were rotated by discrete increments at irregular and unpredictable intervals while partially obscured by a dynamic noise mask. On synchronous trials, each rotation coincided with an auditory click. On asynchronous trials, clicks were noncoincident with the rotational movements (but with identical temporal statistics). Subjects discriminated shape or rotational motion profile of the partially hidden visual stimuli. Regardless of task context, synchronous signals increased activations bilaterally in (1) calcarine sulcus (CaS) extending into ventral occipitotemporal cortex and (2) Heschl's gyrus extending into planum temporale (HG/PT) compared with asynchronous signals. Adjacent to these automatic synchrony effects, synchrony-induced activations in lateral occipital (LO) regions were amplified bilaterally during shape discrimination and in the right posterior superior temporal sulcus (pSTS) during motion discrimination. Subjects' synchrony-induced benefits in motion discrimination significantly predicted blood oxygenation level-dependent synchrony effects in V5/hMT+. According to dynamic causal modeling, audiovisual synchrony increased connectivity between CaS and HG/PT bidirectionally, whereas shape and motion tasks increased forwards connectivity from CaS to LO or to pSTS, respectively. To increase the salience of partially obscured moving objects, audiovisual synchrony may amplify visual activations by increasing the connectivity between low level visual and auditory areas. These automatic synchrony-induced response amplifications may then be gated to higher order areas according to behavioral relevance and task context. PMID- 20844130 TI - Conditions for the generation of beta oscillations in the subthalamic nucleus globus pallidus network. AB - The advance of Parkinson's disease is associated with the existence of abnormal oscillations within the basal ganglia with frequencies in the beta band (13-30 Hz). While the origin of these oscillations remains unknown, there is some evidence suggesting that oscillations observed in the basal ganglia arise due to interactions of two nuclei: the subthalamic nucleus (STN) and the globus pallidus pars externa (GPe). To investigate this hypothesis, we develop a computational model of the STN-GPe network based upon anatomical and electrophysiological studies. Significantly, our study shows that for certain parameter regimes, the model intrinsically oscillates in the beta range. Through an analytical study of the model, we identify a simple set of necessary conditions on model parameters that guarantees the existence of beta oscillations. These conditions for generation of oscillations are described by a set of simple inequalities and can be summarized as follows: (1) The excitatory connections from STN to GPe and the inhibitory connections from GPe to STN need to be sufficiently strong. (2) The time required by neurons to react to their inputs needs to be short relative to synaptic transmission delays. (3) The excitatory input from the cortex to STN needs to be high relative to the inhibition from striatum to GPe. We confirmed the validity of these conditions via numerical simulation. These conditions describe changes in parameters that are consistent with those expected as a result of the development of Parkinson's disease, and predict manipulations that could inhibit the pathological oscillations. PMID- 20844131 TI - The role of the primary visual cortex in perceptual suppression of salient visual stimuli. AB - The role of primary visual cortex (area V1) in subjective perception has intrigued students of vision for decades. Specifically, the extent to which the activity of different types of cells (monocular versus binocular) and electrophysiological signals (i.e., local field potentials versus spiking activity) reflect perception is still debated. To address these questions we recorded from area V1 of the macaque using tetrodes during the paradigm of binocular flash suppression, where incongruent images presented dichoptically compete for perceptual dominance. We found that the activity of a minority (20%) of neurons reflect the perceived visual stimulus and these cells exhibited perceptual modulations substantially weaker compared with their sensory modulation induced by congruent stimuli. Importantly, perceptual modulations were found equally often for monocular and binocular cells, demonstrating that perceptual competition in V1 involves mechanisms across both types of neurons. The power of the local field potential (LFP) also showed moderate perceptual modulations with similar percentages of sites showing significant effects across frequency bands (18-22%). The possibility remains that perception may be strongly reflected in more elaborate aspects of activity in V1 circuits (e.g., specific neuronal subtypes) or perceptual states might have a modulatory role on more intricate aspects of V1 firing patterns (e.g., synchronization), not necessarily altering the firing rates of single cells or the LFP power dramatically. PMID- 20844132 TI - An approximately Bayesian delta-rule model explains the dynamics of belief updating in a changing environment. AB - Maintaining appropriate beliefs about variables needed for effective decision making can be difficult in a dynamic environment. One key issue is the amount of influence that unexpected outcomes should have on existing beliefs. In general, outcomes that are unexpected because of a fundamental change in the environment should carry more influence than outcomes that are unexpected because of persistent environmental stochasticity. Here we use a novel task to characterize how well human subjects follow these principles under a range of conditions. We show that the influence of an outcome depends on both the error made in predicting that outcome and the number of similar outcomes experienced previously. We also show that the exact nature of these tendencies varies considerably across subjects. Finally, we show that these patterns of behavior are consistent with a computationally simple reduction of an ideal-observer model. The model adjusts the influence of newly experienced outcomes according to ongoing estimates of uncertainty and the probability of a fundamental change in the process by which outcomes are generated. A prior that quantifies the expected frequency of such environmental changes accounts for individual variability, including a positive relationship between subjective certainty and the degree to which new information influences existing beliefs. The results suggest that the brain adaptively regulates the influence of decision outcomes on existing beliefs using straightforward updating rules that take into account both recent outcomes and prior expectations about higher-order environmental structure. PMID- 20844135 TI - Functional role of the interaction between polysialic acid and extracellular histone H1. AB - Polysialic acid (PSA) is a large and highly negatively charged glycan that plays crucial roles in nervous system development and function in the adult. It has been suggested to facilitate cell migration, neurite outgrowth, and synaptic plasticity because its hydration volume could enhance flexibility of cell interactions. Evidence for receptors of PSA has so far been elusive. We now identified histone H1 as binding partner of PSA via a single-chain variable fragment antibody using an anti-idiotypic approach. Histone H1 directly binds to PSA as shown by ELISA. Surface biotinylation of cultured cerebellar neurons indicated an extracellular localization of histone H1. Immunostaining of live cerebellar neurons and Schwann cells confirmed that an extracellular pool of histone H1 colocalizes with PSA at the cell surface. Histone H1 was also detected in detergent-insoluble synaptosomal membrane subfractions and postsynaptic densities. When applied in vitro, histone H1 stimulated neuritogenesis, process formation and proliferation of Schwann cells, and migration of neural precursor cells via a PSA-dependent mechanism, further indicating that histone H1 is active extracellularly. These in vitro observations suggested an important functional role for the interaction between histone H1 and PSA not only for nervous system development but also for regeneration in the adult. Indeed, histone H1 improved functional recovery, axon regrowth, and precision of reinnervation of the motor branch in adult mice with femoral nerve injury. Our findings encourage investigations on the therapeutic potential of histone H1 in humans. PMID- 20844134 TI - Molecular anatomy of the hair cell's ribbon synapse. AB - Hearing depends on reliable and temporally precise neurotransmission by cochlear hair cells. The wide dynamic range and high sensitivity with which these cells encode acoustic stimuli are associated with a presynaptic specialization termed the presynaptic dense body or synaptic ribbon. Apposed to the presynaptic density, this spherical or flattened structure tethers a layer of synaptic vesicles and is thought to facilitate their exocytotic fusion. Although defining the molecular constituents of the hair cell's synaptic ribbon should contribute to our understanding of neurotransmitter release at this synapse, accomplishing this task has been slowed by the difficulty of obtaining sufficient amounts of starting material for protein analysis from hair cells. We isolated synaptic material from chicken cochleas, purified synaptic ribbons with specific immunological reagents, and identified the associated proteins by tandem mass spectrometry. Purification of the ribbons revealed a predominant composition of C terminal-binding proteins, especially ribeye, in association with the small GTPase Rab3, which is possibly involved in attaching vesicles to the ribbon. In comparison with the components of conventional synapses and of retinal ribbon synapses, we observed that certain regulatory proteins are excluded from the hair cell's synapse. Using antisera against several of the novel proteins and membrane trafficking components that we had identified, we documented their localization in isolated hair cells. Our results indicate that the ribbon synapses of hair cells display modifications to the presynaptic machinery that are associated with the high-fidelity transmission of acoustic signals to the brain. PMID- 20844133 TI - M-type potassium channels modulate the intrinsic excitability of infralimbic neurons and regulate fear expression and extinction. AB - Growing evidence indicates that the activity of infralimbic prefrontal cortex (IL) is critical for inhibiting inappropriate fear responses following extinction learning. Recently, we showed that fear conditioning and extinction alter the intrinsic excitability and bursting of IL pyramidal neurons in brain slices. IL neurons from Sprague Dawley rats expressing high fear had lower intrinsic excitability and bursting than those from rats expressing low fear, suggesting that regulating the intrinsic excitability and bursting of IL neurons would modulate fear expression. To test this, we combined patch-clamp electrophysiology, auditory fear conditioning, and IL infusions of M-type K(+) channel modulators. Patch-clamp recordings from IL neurons showed that the M-type K(+) channel blocker, XE-991, increased the number of spikes evoked by a depolarizing pulse and reduced the first interspike interval indicating enhanced bursting. To test whether pharmacological enhancement of IL excitability and bursting reduces fear expression and facilitates extinction, fear-conditioned rats were infused with XE-991 into IL before extinction training. XE-infused rats showed reduced freezing and facilitated extinction compared to vehicle-infused rats. The following day, recall of extinction memory was enhanced. Reducing IL excitability and bursting with the M-type K(+) channel agonist, flupirtine, had the opposite effect. Flupirtine reduced IL spike count and bursting in brain slices. Fear-conditioned rats infused with flupirtine into IL before extinction showed significantly higher levels of freezing, indicating that stimulation of M channels enhanced fear expression. Our findings suggest that the intrinsic excitability and bursting of IL neurons regulate fear expression even before extinction. PMID- 20844136 TI - Hepatocyte growth factor-Met signaling is required for Runx1 extinction and peptidergic differentiation in primary nociceptive neurons. AB - Nociceptors in peripheral ganglia display a remarkable functional heterogeneity. They can be divided into the following two major classes: peptidergic and nonpeptidergic neurons. Although RUNX1 has been shown to play a pivotal role in the specification of nonpeptidergic neurons, the mechanisms driving peptidergic differentiation remain elusive. Here, we show that hepatocyte growth factor (HGF) Met signaling acts synergistically with nerve growth factor-tyrosine kinase receptor A to promote peptidergic identity in a subset of prospective nociceptors. We provide in vivo evidence that a population of peptidergic neurons, derived from the RUNX1 lineage, require Met activity for the proper extinction of Runx1 and optimal activation of CGRP (calcitonin gene-related peptide). Moreover, we show that RUNX1 in turn represses Met expression in nonpeptidergic neurons, revealing a bidirectional cross talk between Met and RUNX1. Together, our novel findings support a model in which peptidergic versus nonpeptidergic specification depends on a balance between HGF-Met signaling and Runx1 extinction/maintenance. PMID- 20844137 TI - Abnormal long-range neural synchrony in a maternal immune activation animal model of schizophrenia. AB - The synchrony of neural firing is believed to underlie the integration of information between and within neural networks in the brain. Abnormal synchronization of neural activity between distal brain regions has been proposed to underlie the core symptomatology in schizophrenia. This study investigated whether abnormal synchronization occurs between the medial prefrontal cortex (mPFC) and the hippocampus (HPC), two brain regions implicated in schizophrenia pathophysiology, using the maternal immune activation (MIA) animal model in rats. This neurodevelopmental model of schizophrenia is induced through a single injection of the synthetic immune system activator polyriboinosinic polyribocytidylic acid, a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection, in pregnant rat dams. It is based on epidemiological evidence of increased risk of schizophrenia in adulthood after prenatal exposure to infection. In the present study, EEG coherence and neuronal phase-locking to underlying EEG were measured in freely moving MIA and control offspring. The MIA intervention produced significant reductions in mPFC-HPC EEG coherence that correlated with decreased prepulse inhibition of startle, a measure of sensory gating and a hallmark schizotypal behavioral measure. Furthermore, changes in the synchronization of neuronal firing to the underlying EEG were evident in the theta and low-gamma frequencies. Firing within a putative population of theta-modulated, gamma-entrained mPFC neurons was also reduced in MIA animals. Thus, MIA in rats produces a fundamental disruption in long-range neuronal synchrony in the brains of the adult offspring that models the disruption of synchrony observed in schizophrenia. PMID- 20844139 TI - beta-adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth. AB - beta-Adrenoceptor antagonists are used widely to reduce cardiovascular sympathetic tone, but withdrawal is accompanied by sympathetic hyperactivity. Receptor supersensitivity accounts for some but not all aspects of this withdrawal syndrome. Therefore, we investigated effects of beta-blockers on sympathetic innervation. Rats received infusions of adrenergic receptor blockers or saline for 1 week. The nonselective beta-blocker propranolol and the beta(1) antagonist metoprolol both increased myocardial sympathetic axon density. At 2 d after propranolol discontinuation, beta-receptor sensitivity and responsiveness to isoproterenol were similar to controls. However, tyramine-induced mobilization of norepinephrine stores produced elevated ventricular contractility consistent with enhanced sympathetic neuroeffector properties. In addition, rats undergoing discontinuation showed exaggerated increases in mean arterial pressure in response to air puff or noise startle. In sympathetic neuronal cell cultures, both propranolol and metoprolol increased axon outgrowth but the beta(2)-blocker ICI 118551 did not. Norepinephrine synthesis suppression by alpha-methyl-p tyrosine also increased sprouting and concurrent dobutamine administration reduced it, confirming that locally synthesized norepinephrine inhibits outgrowth via beta(1)-adrenoceptors. Immunohistochemistry revealed beta(1)-adrenoceptor protein on sympathetic axon terminations. In rats with coronary artery ligation, propranolol reversed heart failure-induced ventricular myocardial sympathetic axon depletion, but did not affect infarct-associated sympathetic hyperinnervation. We conclude that sympathetic neurons possess beta(1) autoreceptors that negatively regulate axon outgrowth. Chronic beta-adrenoceptor blockade disrupts this feedback system, leading to ventricular sympathetic axon proliferation and increased neuroeffector gain, which are likely to contribute to beta-blocker withdrawal syndrome. PMID- 20844138 TI - Oligodendrocyte-myelin glycoprotein and Nogo negatively regulate activity dependent synaptic plasticity. AB - In the adult mammalian CNS, the growth inhibitors oligodendrocyte-myelin glycoprotein (OMgp) and the reticulon RTN4 (Nogo) are broadly expressed in oligodendrocytes and neurons. Nogo and OMgp complex with the neuronal cell surface receptors Nogo receptor-1 (NgR1) and paired Ig-like receptor-B (PirB) to regulate neuronal morphology. In the healthy CNS, NgR1 regulates dendritic spine shape and attenuates activity-driven synaptic plasticity at Schaffer collateral CA1 synapses. Here, we examine whether Nogo and OMgp influence functional synaptic plasticity, the efficacy by which synaptic transmission occurs. In acute hippocampal slices of adult mice, Nogo-66 and OMgp suppress NMDA receptor dependent long-term potentiation (LTP) when locally applied to Schaffer collateral-CA1 synapses. Neither Nogo-66 nor OMgp influences basal synaptic transmission or paired-pulse facilitation, a form of short-term synaptic plasticity. PirB(-/-) and NgR1(-/-) single mutants and NgR1(-/-);PirB(-/-) double mutants show normal LTP, indistinguishable from wild-type controls. In juvenile mice, LTD in NgR1(-/-), but not PirB(-/-), slices is absent. Mechanistic studies revealed that Nogo-66 and OMgp suppress LTP in an NgR1-dependent manner. OMgp inhibits LTP in part through PirB but independently of p75. This suggests that NgR1 and PirB participate in ligand-dependent inhibition of synaptic plasticity. Loss of NgR1 leads to increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), signaling intermediates known to regulate neuronal growth and synaptic function. In primary cortical neurons, BDNF elicited phosphorylation of AKT and p70S6 kinase is attenuated in the presence of myelin inhibitors. Collectively, we provide evidence that mechanisms of neuronal growth inhibition and inhibition of synaptic strength are related. Thus, myelin inhibitors and their receptors may coordinate structural and functional neuronal plasticity in CNS health and disease. PMID- 20844141 TI - Essential role of Phox2b-expressing ventrolateral brainstem neurons in the chemosensory control of inspiration and expiration. AB - Phox2b-expressing neurons of the retrotrapezoid nucleus (RTN), located in the ventrolateral brainstem, are sensitive to changes in PCO(2)/pH, have excitatory projections to the central respiratory rhythm/pattern generator, and their activation enhances central respiratory drive. Using in vivo (conscious and anesthetized rats) and in situ (arterially perfused rat brainstem-spinal cord preparations) models, we evaluated the functional significance of this neuronal population for both resting respiratory activity and the CO(2)-evoked respiratory responses by reversibly inhibiting these neurons using the insect peptide allatostatin following transduction with a lentiviral construct to express the G protein-coupled Drosophila allatostatin receptor. Selective inhibition of the Phox2b-expressing neurons in the ventrolateral brainstem, including the RTN, using allatostatin was without effect on resting respiratory activity in conscious rats, but decreased the amplitude of the phrenic nerve discharge in anesthetized rats and the in situ rat preparations. Postinspiratory activity was also reduced in situ. In the absence or presence of the peripheral chemoreceptor input, inhibiting the Phox2b-expressing neurons during hypercapnia abolished the CO(2)-evoked abdominal expiratory activity in anesthetized rats and in situ preparations. Inspiratory responses evoked by rising levels of CO(2) in the breathing air were also reduced in anesthetized rats with denervated carotid bodies and conscious rats with peripheral chemoreceptors intact (by 28% and 60%, respectively). These data indicate a crucial dependence of central expiratory drive upon Phox2b-expressing neurons of the ventrolateral brainstem and support the hypothesis that these neurons contribute in a significant manner to CO(2) evoked increases of inspiratory activity. PMID- 20844140 TI - Calcium/calmodulin kinase II-dependent acetylcholine receptor cycling at the mammalian neuromuscular junction in vivo. AB - At the mammalian skeletal neuromuscular junction, cycling of nicotinic ACh receptors (nAChRs) is critical for the maintenance of a high postsynaptic receptor density. However, the mechanisms that regulate nAChRs recycling in living animals remain unknown. Using in vivo time-lapse imaging, fluorescence recovery after photobleaching, and biochemical pull down assays, we demonstrated that recycling of internalized nAChRs into fully functional and denervated synapses was promoted by both direct muscle stimulation and pharmacologically induced intracellular calcium elevations. Most of internalized nAChRs are recycled directly into synaptic sites. Chelating of intracellular calcium below resting level drastically decreased cycling of nAChRs. Furthermore we found that calcium-dependent AChR recycling is mediated by Ca(2+)/calmodulin-dependent kinase II (CaMKII). Inhibition of CaMKII selectively blocked recycling and caused intracellular accumulation of internalized nAChRs, whereas internalization of surface receptors remained unaffected. Electroporation of CaMKII-GFP isoforms into the sternomastoid muscle showed that muscle-specific CaMKIIbetam isoform is highly expressed at the neuromuscular junction (NMJ) and precisely colocalized with nAChRs at crests of synaptic folds while the CaMKIIgamma and delta isoforms are poorly expressed in synaptic sites. These results indicate that Ca(2+) along with CaMKII activity are critical for receptor recycling and may provide a mechanism by which the postsynaptic AChR density is maintained at the NMJ in vivo. PMID- 20844142 TI - NMDA receptors with locked glutamate-binding clefts open with high efficacy. AB - Glutamate-gated channels mediate fundamental brain processes, yet the mechanisms by which the neurotransmitter controls channel activation are incompletely understood. Structural studies revealed that the agonist has the critical role of bridging the divide between two flexible extracellular lobes and solidified the view that agonist-induced cleft-closure drives further isomerizations, which eventually open the channel. Within the glutamate receptor family, NMDA-sensitive channels are unique in their requirement that both glycine and glutamate bind to homologous regions on GluN1 and GluN2 subunits, respectively, before the channel can open. To study the gating reaction in separation from agonist binding and dissociation, we characterized the kinetic mechanism of individual NMDA receptors whose ligand-binding clefts were locked shut by disulfide bridges engineered across lobes. We found that locking GluN1 domains had no observable consequences on receptor activity, whereas locking GluN2A domains increased channel activity without reducing the number of resolvable kinetic states. Based on these results, we suggest that glutamate but not glycine activates NMDA receptors with submaximal efficacy. Low glutamate efficacy may represent a mechanism by which the neurotransmitter maintains control over receptor kinetics despite sharing with glycine the task of activation. PMID- 20844143 TI - Neural correlates of auditory scene analysis based on inharmonicity in monkey primary auditory cortex. AB - Segregation of concurrent sounds in complex acoustic environments is a fundamental feature of auditory scene analysis. A powerful cue used by the auditory system to segregate concurrent sounds, such as speakers' voices at a cocktail party, is inharmonicity. This can be demonstrated when a component of a harmonic complex tone is perceived as a separate tone "popping out" from the complex as a whole when it is sufficiently mistuned from its harmonic value. The neural bases of perceptual "pop out" of mistuned harmonics are unclear. We recorded multiunit activity from primary auditory cortex (A1) of behaving monkeys elicited by harmonic complex tones that were either "in tune" or that contained a mistuned third harmonic set at the best frequency of the neural populations. Responses to mistuned sounds were enhanced relative to responses to "in-tune" sounds, thus correlating with the enhanced perceptual salience of the mistuned component. Consistent with human psychophysics of "pop out," response enhancements increased with the degree of mistuning, were maximal for neural populations tuned to the frequency of the mistuned component, and were not observed under comparable stimulus conditions that do not elicit perceptual "pop out." Mistuning was also associated with changes in neuronal temporal response patterns phase locked to "beats" in the stimuli. Intracortical auditory evoked potentials paralleled noninvasive neurophysiological correlates of perceptual "pop out" in humans, further augmenting the translational relevance of the results. Findings suggest two complementary neural mechanisms for "pop out," based on the detection of local differences in activation level or coherence of temporal response patterns across A1. PMID- 20844144 TI - Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision. AB - Visual thresholds of mice for the detection of small, brief targets were measured with a novel behavioral methodology in the dark and in the presence of adapting lights spanning ~8 log(10) units of intensity. To help dissect the contributions of rod and cone pathways, both wild-type mice and mice lacking rod (Gnat1(-/-)) or cone (Gnat2(cpfl3)) function were studied. Overall, the visual sensitivity of mice was found to be remarkably similar to that of the human peripheral retina. Rod absolute threshold corresponded to 12-15 isomerized pigment molecules (R*) in image fields of 800 to 3000 rods. Rod "dark light" (intrinsic retinal noise in darkness) corresponded to that estimated previously from single-cell recordings, 0.012 R* s(-1) rod(-1), indicating that spontaneous thermal isomerizations are responsible. Psychophysical rod saturation was measured for the first time in a nonhuman species and found to be very similar to that of the human rod monochromat. Cone threshold corresponded to ~5 R* cone(-1) in an image field of 280 cones. Cone dark light was equivalent to ~5000 R* s(-1) cone(-1), consistent with primate single-cell data but 100-fold higher than predicted by recent measurements of the rate of thermal isomerization of mouse cone opsins, indicating that nonopsin sources of noise determine cone threshold. The new, fully automated behavioral method is based on the ability of mice to learn to interrupt spontaneous wheel running on the presentation of a visual cue and provides an efficient and highly reliable means of examining visual function in naturally behaving normal and mutant mice. PMID- 20844145 TI - A role for protein kinase C-dependent upregulation of adrenomedullin in the development of morphine tolerance in male rats. AB - Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and is a pronociceptive mediator. This study investigated whether AM plays a role in the development of tolerance to morphine-induced analgesia. Repetitive intrathecal injection of morphine increased the expression of AM-like immunoreactivity (AM-IR) in the spinal dorsal horn and dorsal root ganglion (DRG) neurons. Ganglion explant culture study showed that this upregulation of AM-IR was MU-opioid receptor dependent through the use of another agonist, fentanyl, and a selective antagonist, CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2)). The coadministration of the selective AM receptor antagonist AM(22-52) markedly attenuated the development of morphine tolerance, associated thermal hyperalgesia, and increase in AM-IR. A likely autocrine mechanism is supported by the finding that AM-IR is colocalized with AM receptor components in DRG neurons. Furthermore, opiate-induced increase in AM content was blocked by protein kinase C (PKC) inhibitors, whereas a PKC activator increased AM synthesis and release. A treatment with AM(22-52) also inhibited increases in the expression of CGRP-IR in the spinal cord and DRGs as well as in culture ganglion explants, whereas exposure to CGRP failed to alter AM content. Together, these results reveal that a sustained opiate treatment induces an upregulation of AM through the activation of MU-opioid receptors and the PKC signaling pathway. This phenomenon contributes to the development of tolerance to the antinociceptive effects of opiates at least partially via the upregulation of CGRP. Targeting AM and its receptors should be considered as a novel approach to preserve the analgesic potency of opiates during their chronic use. PMID- 20844146 TI - Molecular dynamics and social regulation of context-dependent plasticity in the circadian clockwork of the honey bee. AB - The social environment influences the circadian clock of diverse animals, but little is known about the functional significance, the specifics of the social signals, or the dynamics of socially mediated changes in the clock. Honey bees switch between activities with and without circadian rhythms according to their social task. Forager bees have strong circadian rhythms, whereas "nurse" bees typically care for the brood around-the-clock with no circadian rhythms in behavior or clock gene expression. Here we show that nurse-age bees that were restricted to a broodless comb inside or outside the hive showed robust behavioral and molecular circadian rhythms. By contrast, young nurses tended brood with no circadian rhythms in behavior or clock gene expression, even under a light-dark illumination regime or when placed with brood--but no queen--in a small cage outside the hive. This behavior is context-dependent because nurses showed circadian rhythms in locomotor activity shortly after removal from the hive, and in clock gene expression after ~16 h. These findings suggest that direct interaction with the brood modulates the circadian system of honey bees. The dynamics of rhythm development best fit models positing that at least some pacemakers continue to oscillate and be entrained by the environment in nurses that are active around the clock. These cells set the phase to the clock network when the nurse is removed from the hive. These findings suggest that despite its robustness, the circadian system exhibits profound plasticity, enabling adjustment to rapid changes in the social environment. PMID- 20844148 TI - Pathogenic lysosomal depletion in Parkinson's disease. AB - Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including alpha synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrial-derived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4 phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD. PMID- 20844147 TI - Gating of transient receptor potential melastatin 8 (TRPM8) channels activated by cold and chemical agonists in planar lipid bilayers. AB - The transient receptor potential melastatin 8 (TRPM8) ion channel is a major sensor of environmental cold temperatures. It is activated by cold and chemical agonists, such as menthol and icilin. The activation of these channels both by cold and cooling agents requires the presence of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)]. The mechanism of TRPM8 activation by physical and chemical factors is unknown, and the involvement of cellular signaling pathways has been considered. Here we have characterized the gating mechanism of the rat TRPM8 reconstituted in planar lipid bilayers and its activation by different stimuli. In this system, the influence of cellular signaling pathways can be excluded. We found that TRPM8 activated by cold exhibits steep temperature dependence [temperature coefficient (Q(10)) of ~40], and the channel openings are accompanied by large changes in entropy and enthalpy, suggesting a substantial conformation change. TRPM8 channel behavior upon menthol and icilin activation was distinguishable, and the effect of icilin depended on the presence of calcium on the intracellular side of the protein. Here we also demonstrate that PI(4,5)P(2) is the prime factor that impacts the gating of TRPM8 and that other phosphoinositides are less efficient in supporting channel activity. Menthol increases the potency of PI(4,5)P(2) to activate the channels and increases binding of phosphoinositides to the full-length channel protein. Our data demonstrate conclusively that TRPM8 is gated by cold and its chemical agonists directly, and that dependence of its gating on PI(4,5)P(2) is a result of direct specific interactions with the lipid. PMID- 20844149 TI - Supporting cells eliminate dying sensory hair cells to maintain epithelial integrity in the avian inner ear. AB - Epithelial homeostasis is essential for sensory transduction in the auditory and vestibular organs of the inner ear, but how it is maintained during trauma is poorly understood. To examine potential repair mechanisms, we expressed beta actin-enhanced green fluorescent protein (EGFP) in the chick inner ear and used live-cell imaging to study how sensory epithelia responded during aminoglycoside induced hair cell trauma. We found that glial-like supporting cells used two independent mechanisms to rapidly eliminate dying hair cells. Supporting cells assembled an actin cable at the luminal surface that extended around the pericuticular junction and constricted to excise the stereocilia bundle and cuticular plate from the hair cell soma. Hair bundle excision could occur within 3 min of actin-cable formation. After bundle excision, typically with a delay of up to 2-3 h, supporting cells engulfed and phagocytosed the remaining bundle-less hair cell. Dual-channel recordings with beta-actin-EGFP and vital dyes revealed phagocytosis was concurrent with loss of hair cell integrity. We conclude that supporting cells repaired the epithelial barrier before hair cell plasmalemmal integrity was lost and that supporting cell activity was closely linked to hair cell death. Treatment with the Rho-kinase inhibitor Y-27632 did not prevent bundle excision but prolonged phagocytic engulfment and resulted in hair cell corpses accumulating within the epithelium. Our data show that supporting cells not only maintain epithelial integrity during trauma but suggest they may also be an integral part of the hair cell death process itself. PMID- 20844152 TI - Testosterone-induced permanent changes of hepatic gene expression in female mice sustained during Plasmodium chabaudi malaria infection. AB - Testosterone has been previously shown to induce persistent susceptibility to Plasmodium chabaudi malaria in otherwise resistant female C57BL/6 mice. Here, we investigate as to whether this conversion coincides with permanent changes of hepatic gene expression profiles. Female mice aged 10-12 weeks were treated with testosterone for 3 weeks; then, testosterone treatment was discontinued for 12 weeks before challenging with 106 P. chabaudi-infected erythrocytes. Hepatic gene expression was examined after 12 weeks of testosterone withdrawal and after subsequent infection with P. chabaudi at peak parasitemia, using Affymetrix microarrays with 22 ,690 probe sets representing 14, 000 genes. The expression of 54 genes was found to be permanently changed by testosterone, which remained changed during malaria infection. Most genes were involved in liver metabolism: the female-prevalent genes Cyp2b9, Cyp2b13, Cyp3a41, Cyp3a44, Fmo3, Sult2a2, Sult3a1, and BC014805 were repressed, while the male-prevalent genes Cyp2d9, Cyp7b1, Cyp4a10, Ugt2b1, Ugt2b38, Hsd3b5, and Slco1a1 were upregulated. Genes encoding different nuclear receptors were not persistently changed. Moreover, testosterone induced persistent upregulation of genes involved in hepatocellular carcinoma such as Lama3 and Nox4, whereas genes involved in immune response such as Ifngamma and Igk-C were significantly decreased. Our data provide evidence that testosterone is able to induce specific and robust long-term changes of gene expression profiles in the female mouse liver. In particular, those changes, which presumably indicate masculinized liver metabolism and impaired immune response, may be critical for the testosterone-induced persistent susceptibility of mice to P. chabaudi malaria. PMID- 20844151 TI - PKCzeta regulates cell polarisation and proliferation restriction during mammary acinus formation. AB - Mammary epithelial cells organize in three dimensions and generate acini when supported on laminin-rich extracellular matrix. Acinus formation begins with the apicobasal polarisation of the outer cells of the assembly and the withdrawal of these cells from the cell cycle. Internal cells then clear out to form a hollow lumen. Here, we show that PKCzeta is phosphorylated (at T410) and activated in the early stages of acinus formation in both primary cells and MCF10A cells, and during mammary tree maturation in vivo. Phospho-PKCzeta colocalised with tight junction components and bound to the Par polarising complex in developing acini. To further investigate the importance of PKCzeta phosphorylation in this context, acinus formation was studied in MCF10A cells overexpressing non-phosphorylatable (T410A) or 'constitutively phosphorylated' (T410E) PKCzeta. In both cell types, acinus-associated cell polarisation and lumen clearance were compromised, emphasising the importance of regulated phosphorylation of PKCzeta at T410 for successful acinus formation. PKCzeta can be activated in a phosphorylation (at T410)-dependent and a phosphorylation-independent manner. Cells overexpressing a complete kinase-deficient PKCzeta (K281W) displayed a cell polarising deficit, but also generated large 'multi-acinar' structures with associated early lumenal cell hyperproliferation. Therefore our data shows, for the first time, that two separable PKCzeta activities (one phosphorylation-dependent, the other not) are required to support the cell polarisation and proliferation restriction that underpins successful acinus formation. Paralleling these contributions, we found that low levels of PKCzeta mRNA expression are associated with more 'poorly differentiated' tumours and a poor outcome in a cohort of 295 breast cancer patients. PMID- 20844150 TI - Regulation of the Apaf-1-caspase-9 apoptosome. PMID- 20844153 TI - Commentary on an article by Sebastien Parratte, MD, PhD, et al.: "Effect of postoperative mechanical axis alignment on the fifteen-year survival of modern, cemented total knee replacements". PMID- 20844154 TI - Commentary on an Article by Marybeth Ezaki, MD, et al.: "OnabotulinumtoxinA injection as an adjunct in the treatment of posterior shoulder subluxation in neonatal brachial plexus palsy". PMID- 20844155 TI - Effect of postoperative mechanical axis alignment on the fifteen-year survival of modern, cemented total knee replacements. AB - BACKGROUND: One long-held tenet of total knee arthroplasty is that implant durability is maximized when postoperative limb alignment is corrected to 0 degrees +/- 3 degrees relative to the mechanical axis. Recently, substantial health-care resources have been devoted to computer navigation systems that allow surgeons to more often achieve that alignment. We hypothesized that a postoperative mechanical axis of 0 degrees +/- 3 degrees would result in better long-term survival of total knee arthroplasty implants as compared with that in a group of outliers. METHODS: Clinical and radiographic data were reviewed retrospectively to determine the fifteen-year Kaplan-Meier survival rate following 398 primary total knee arthroplasties performed with cement in 280 patients from 1985 to 1990. Preoperatively, most knees were in varus mechanical alignment (mean and standard deviation, 6 degrees +/- 8.8 degrees of varus [range, 30 degrees of varus to 22 degrees of valgus]), whereas postoperatively most knees were corrected to neutral (mean and standard deviation, 0 degrees +/- 2.8 degrees [range, 8 degrees of varus to 9 degrees of valgus]). Postoperatively, we defined a mechanically aligned group of 292 knees (with a mechanical axis of 0 degrees +/- 3 degrees ) and an outlier group of 106 knees (with a mechanical axis of beyond 0 degrees +/- 3 degrees ). RESULTS: At the time of the latest follow-up, forty-five (15.4%) of the 292 implants in the mechanically aligned group had been revised for any reason, compared with fourteen (13%) of the 106 implants in the outlier group (p = 0.88); twenty-seven (9.2%) of the 292 implants in the mechanically aligned group had been revised because of aseptic loosening, mechanical failure, wear, or patellar problems, compared with eight (7.5%) of the 106 implants in the outlier group (p = 0.88); and seventeen (5.8%) of the 292 implants in the mechanically aligned group had been revised because of aseptic loosening, mechanical failure, or wear, compared with four (3.8%) of the 106 implants in the outlier group (p = 0.49). CONCLUSIONS: A postoperative mechanical axis of 0 degrees +/- 3 degrees did not improve the fifteen-year implant survival rate following these 398 modern total knee arthroplasties. We believe that describing alignment as a dichotomous variable (aligned versus malaligned) on the basis of a mechanical axis goal of 0 degrees +/- 3 degrees is of little practical value for predicting the durability of modern total knee arthroplasty implants. PMID- 20844156 TI - Risk factors for incision-healing complications following total ankle arthroplasty. AB - BACKGROUND: The anterior incision used for the insertion of total ankle arthroplasty systems is at high risk for wound complications, and little has been documented regarding who is at risk for the development of these complications. METHODS: We conducted a retrospective chart review of 106 total ankle arthroplasties. Independent risk variables, including age, sex, body-mass index, diabetes, smoking, medications, preoperative diagnosis, implant size, tourniquet time, closure method, and anticoagulation status, were recorded. Postoperative office notes were reviewed for wound-related complications. Outcomes were divided into three categories: no complications (uncomplicated wound-healing), minor complications (wounds requiring only local care/oral antibiotics), and major complications (requiring a return to the operating room for treatment). Simultaneously, categorical variables were compared with use of chi-square analysis. Multivariate logistic regression and odds ratio assessment were performed as well. RESULTS: When patients who had no complications were compared with those who had minor complications, a history of diabetes was the only variable that was identified as resulting in a significant risk increase (p = 0.04). When patients who had no wound complications or minor wound complications were compared with those who had major wound complications, female sex, a history of corticosteroid use, and underlying inflammatory arthritis were all associated with increased risk. Multivariate logistic regression demonstrated underlying inflammatory arthritis (p = 0.004) to be the only significant risk factor for major wound complications, with an odds ratio demonstrating a 14.03 times increased risk of requiring reoperation. CONCLUSIONS: We recommend that caution be used when selecting and educating patients with inflammatory arthritic conditions who are potential candidates for total ankle arthroplasty. PMID- 20844157 TI - Risk factors for venous thromboembolism in patients undergoing total hip replacement and receiving routine thromboprophylaxis. AB - BACKGROUND: Data on the risk factors for venous thromboembolism among patients undergoing total hip replacement and receiving pharmacological thromboprophylaxis are limited. The purpose of this study was to examine potential patient-related risk factors for venous thromboembolism following total hip replacement in a nationwide follow-up study. METHODS: Using medical databases, we identified all patients who underwent primary total hip replacement and received pharmacological thromboprophylaxis in Denmark from 1995 to 2006. The outcome measure was hospitalization with venous thromboembolism within ninety days of surgery. We considered age, sex, indication for primary total hip replacement, calendar year of surgery, and comorbidity history as potential risk factors. RESULTS: The overall rate of hospitalization for venous thromboembolism within ninety days following a primary total hip replacement was 1.02% (686 hospitalizations after 67,469 procedures) at a median of twenty-two days. The incidence of symptomatic deep venous thrombosis and of nonfatal pulmonary embolism was 0.7% (499 of 67,469) and 0.3% (205 of 67,469), respectively. The incidence of death due to venous thromboembolism or from all causes was 0.05% (thirty-eight patients) and 1.0% (678 patients), respectively. Patients with rheumatoid arthritis had a reduced relative risk for venous thromboembolism compared with patients with primary osteoarthritis (adjusted relative risk = 0.47; 95% confidence interval, 0.25 to 0.90). Patients with a high score on the Charlson comorbidity index had an increased relative risk for venous thromboembolism compared with patients with a low score (adjusted relative risk = 1.45; 95% confidence interval, 1.02 to 2.05). Patients with a history of cardiovascular disease (relative risk = 1.40; 95% confidence interval, 1.15 to 1.70) or prior venous thromboembolism (relative risk = 8.09; 95% confidence interval, 6.07 to 10.77) had an increased risk for venous thromboembolism compared with patients without that history. CONCLUSIONS: The cumulative incidence of a venous thromboembolism within ninety days of surgery among patients with total hip replacement receiving pharmacological thromboprophylaxis was 1%. This information on the associated risk factors could be used to better anticipate the risk of venous thromboembolism for an individual patient. PMID- 20844158 TI - The natural history of untreated asymptomatic osteonecrosis of the femoral head: a systematic literature review. AB - BACKGROUND: An asymptomatic hip with osteonecrosis is typically discovered as the contralateral hip of a patient with one symptomatic joint. Treatment of the asymptomatic hip is controversial. While some authors claim a benign natural history, others have reported a rate of femoral head collapse exceeding 50%. The purpose of this report was to systematically review the published literature regarding asymptomatic osteonecrosis of the femoral head to evaluate the overall prevalence of progression to symptomatic disease and/or femoral head collapse as well as to determine whether various radiographic and demographic factors influence progression of the disorder. METHODS: A comprehensive literature search was performed to identify prognostic studies evaluating asymptomatic hip osteonecrosis. Demographic, radiographic, and outcome data were extracted from all relevant studies. The prevalence of progression to symptomatic disease and/or femoral head collapse was determined. Next, outcomes were stratified by lesion size, lesion location, radiographic stage, associated risk factors and/or disease, and the level of evidence of the study. RESULTS: Sixteen studies that included a total of 664 hips were available for an analysis of outcomes. Overall, 394 hips (59%) had progression to symptoms or collapse. Differences in outcomes based on lesion size, lesion location, and radiographic stage at the time of diagnosis were seen. Small, medially located lesions had the best prognosis, with a prevalence of collapse of <10%. Patients with sickle cell disease had the highest frequency of progression, and those with a history of systemic lupus erythematosus had the most benign course. CONCLUSIONS: Data extracted from previously published studies suggest that asymptomatic osteonecrosis has a high prevalence of progression to symptomatic disease and femoral head collapse. While small, medially located lesions have a low rate of progression, the natural history of asymptomatic medium-sized, and especially large, osteonecrotic lesions is progression in a substantial number of patients. For this reason, it may be beneficial to consider joint-preserving surgical treatment in asymptomatic patients with a medium-sized or large, and/or laterally located, lesion. PMID- 20844159 TI - Onabotulinum toxinA injection as an adjunct in the treatment of posterior shoulder subluxation in neonatal brachial plexus palsy. AB - BACKGROUND: Botulinum toxin A is used to treat contractures in children with spasticity by temporarily interfering with neural transmission at the motor end plate. In infants with brachial plexus palsy, posterior shoulder subluxation and dislocation are the result of muscle imbalance, in which neurologic recovery is evolving, and spasticity is not a deforming force. We postulated that temporary weakening of the shoulder internal rotator muscles with botulinum toxin A would facilitate reduction of the glenohumeral joint in such infants with early posterior shoulder subluxation or dislocation. METHODS: Thirty-five infants with posterior subluxation or dislocation of the shoulder due to brachial plexus palsy were treated with botulinum toxin A between January 1999 and December 2006, and were followed for a minimum period of one year. Records were reviewed for the severity of the palsy, age at time of treatment, recurrence of subluxation or dislocation, and the subsequent need for further treatment to reduce the glenohumeral joint. RESULTS: The average age at the time of shoulder reduction and botulinum toxin-A injection was 5.7 months. Six patients had a second injection. Reduction of the shoulder was maintained in twenty-four (69%) of the thirty-five patients. There were no complications related to the use of botulinum toxin A. CONCLUSIONS: Although there may be specific risks associated with its use, botulinum toxin-A injection into the internal rotator muscles is a useful adjunct to the treatment of early posterior subluxation or dislocation of the shoulder in infants with neonatal brachial plexus palsy, and may help to avoid the need for open surgical procedures to restore or maintain shoulder reduction. PMID- 20844160 TI - The impact of response shift on perceived disability two years following rotator cuff surgery. AB - BACKGROUND: Understanding how patients appraise their health-related problems is important for an accurate assessment of recovery over time. It has been proposed that the response shift phenomenon has an impact on self-report measures, and this may subsequently affect measurement of true treatment effects. The objective of the present study was to explore the impact of response shift on the subjective perception of disability following rotator cuff surgery. METHODS: We conducted a repeated-measures study of the outcome following surgical decompression or repair of the rotator cuff. The American Shoulder and Elbow Surgeons (ASES) questionnaire was used in a thentest design to measure recalibration response shift two years following surgery. Disability was measured with a disease-specific measure. Objective findings consisting of the range of motion and strength were recorded preoperatively and postoperatively. Parametric and nonparametric univariate and multivariate analyses were performed. The contribution of recall bias was estimated by assessing agreement between pretest and thentest scores on the basis of the percentage of agreement and the Spearman correlation coefficient. RESULTS: One hundred and seven patients (forty-one women and sixty-six men; mean age, fifty-seven years) participated in the study. Seventy-two patients had decompression surgery and forty-four underwent a rotator cuff repair; nine patients had both procedures. A significant response shift was observed in the pain domain (p < 0.0001) and not in the functional ability domain of the ASES (p = 0.58). Three distinct patterns of response shift were observed. Univariate analyses showed that satisfaction with the result of the surgery, the range of motion, strength, age, and response shift were associated with disability. The final multivariate analysis showed that disability at two years following the surgery was affected by the range of motion (p < 0.0001), satisfaction (p = 0.006), age (p = 0.02), and response shift (p = 0.03). CONCLUSIONS: The response shift phenomenon exists in patients who have undergone surgery for rotator cuff disorders and has different patterns related to overrating or underrating of preoperative pain. A recalibration response shift characterized by overrating of preoperative pain was associated with lower levels of residual disability at two years following the surgery. PMID- 20844161 TI - Health status after open elbow contracture release. AB - BACKGROUND: Operative contracture release may improve motion of a posttraumatic stiff elbow. In this study, we tested the hypothesis that improvement in ulnohumeral motion after elbow contracture release leads to improvement in general health status and decreases upper-extremity-specific disability. METHODS: Twenty-three patients with posttraumatic loss of >=30 degrees of elbow flexion or extension who elected to have an open elbow capsulectomy completed the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) and the Short Form-36 (SF-36) preoperatively and at least one year postoperatively. Pain was measured with use of the American Shoulder and Elbow Surgeons (ASES) Elbow Evaluation instrument. Four patients underwent additional, subsequent procedures to address residual elbow stiffness. RESULTS: One patient who needed several additional procedures, including a total elbow arthroplasty, was considered to have had a failure of the operative contracture release and was excluded from the analysis; this left twenty-two patients in the study. On the average, the arc of flexion and extension improved from 51 degrees preoperatively to 106 degrees postoperatively; the DASH score, from 38 points to 18 points; the SF-36 Physical Component Summary (PCS) score, from 39 points to 49 points (all p < 0.05); and the SF-36 Mental Component Summary (MCS) score, from 49 points to 54 points (p < 0.05). There was no significant correlation between the improvement in the arc of flexion and extension and the improvement in the DASH (p = 0.53), PCS (p = 0.73), or MCS (p = 0.41) score. There also was no correlation between the final arc of flexion and extension and the final DASH score (p = 0.39 for the total score, p = 0.52 for the PCS score, and p = 0.42 for the MCS score). CONCLUSIONS: Health status and disability scores improve after open elbow contracture release, but the improvements do not correlate with the improvement in elbow motion. Among multiple objective and subjective factors, pain was a strong predictor of the final general health status and arm-specific disability. PMID- 20844162 TI - Orthopaedic sequelae of childhood meningococcemia: management considerations and outcome. AB - BACKGROUND: Patients who survive the initial acute phase of fulminant meningococcemia are at increased risk for serious orthopaedic complications. This report describes our experience with purpura fulminans related to meningococcemia, with emphasis on musculoskeletal sequelae and their treatment. METHODS: We retrospectively reviewed the cases of forty-eight patients (twenty two boys and twenty-six girls) who survived the acute phase of meningococcal septicemia and developed musculoskeletal sequelae. Early sequelae required surgical treatment within six months after the onset of sepsis and were primarily amputations. Late sequelae required surgical management six months or more following the initial infection and included growth disturbances, stump overgrowth, scar contractures, and soft-tissue and bone infections. RESULTS: The mean age at the onset of sepsis (and standard deviation) was 2.6 +/- 3.0 years, and the mean duration of follow-up was 11.7 +/- 5.1 years. The mean number of surgical procedures required was 4.4 +/- 2.9 per patient. Early sequelae included amputations at a variety of levels. Upper-extremity amputations were less frequent than lower-extremity amputations. Growth disturbances in the upper extremities were less frequent than growth disturbances in the lower extremities. Stump overgrowth occurred in only eleven patients (23%) with a lower-extremity amputation. The prevalence of scar contractures in the upper extremities was similar to that in the lower extremities. Eight patients (17%) acquired soft tissue and bone infections at the distal portion of the amputation stump, at a mean of 7.2 +/- 5.4 years after the initial sepsis. Thirteen patients (27%) were found to have developmental delay at the time of follow-up, and it was severe in seven of them. CONCLUSIONS: All patients who survive meningococcal septicemia should be followed by an orthopaedic surgeon who is experienced in pediatric limb deformities and amputations. Children requiring surgery for purpura fulminans are often limited by physical disability due to amputation, scarring, and abnormal bone growth. Despite advances in orthopaedic management, children are still at risk of developing physical and developmental limitations. PMID- 20844163 TI - Physician tiering by health plans in Massachusetts. AB - BACKGROUND: Physician tiering is an emerging health-care strategy that purports to grade physicians on the basis of cost-efficiency and quality-performance measures. We investigated the consistency of tiering of orthopaedic surgeons by examining tier agreement between health plans and physician factors associated with top-tier ranking. METHODS: Health plan tier, demographic, and training data were collected on 615 licensed orthopaedic surgeons who accepted one or more of three health plans and practiced in Massachusetts. We then computed the concordance of physician tier rankings between the health plans. We further examined the factors associated with top-tier ranking, such as malpractice claims and socioeconomic conditions of the practice area. RESULTS: The concordance of physician tiering between health plans was poor to fair (range, 8% to 28%, kappa = 0.06 to 0.25). The percentage of physicians ranked as top-tier varied widely among the health plans, from 21% to 62%. Thirty-eight percent of physicians were not rated top-tier by any of the health plans, whereas only 5.2% of physicians were rated top-tier by all three health plans. Multivariate analysis showed that board certification, accepting Medicaid, and practicing in a suburban location were the independent factors associated with being ranked in the top tier. More years in practice or fewer malpractice claims were not related to tier. CONCLUSIONS: Current methods of physician tiering have low consistency and manifest evidence of geographic and demographic biases. PMID- 20844164 TI - Treatment of Gibbus deformity associated with myelomeningocele in the young child with use of the vertical expandable prosthetic titanium rib (VEPTR): a case report. PMID- 20844165 TI - Childhood obesity and low-velocity knee dislocation in a fifteen-year-old girl: a case report. PMID- 20844166 TI - Autologous chondrocyte implantation: a systematic review. AB - BACKGROUND: The purpose of the present study was to determine (1) whether the current literature supports the choice of using autologous chondrocyte implantation over other cartilage procedures with regard to clinical outcome, magnetic resonance imaging, arthroscopic assessment, and durability of treatment, (2) whether the current literature supports the use of a specific generation of autologous chondrocyte implantation, and (3) whether there are patient-specific and defect-specific factors that influence outcomes after autologous chondrocyte implantation in comparison with other cartilage repair or restoration procedures. METHODS: We conducted a systematic review of multiple databases in which we evaluated Level-I and II studies comparing autologous chondrocyte implantation with another cartilage repair or restoration technique as well as comparative intergenerational studies of autologous chondrocyte implantation. The methodological quality of studies was evaluated with use of Delphi list and modified Coleman methodology scores. Effect size analysis was performed for all outcome measures. RESULTS: Thirteen studies (917 subjects) were included. Study methodological quality improved with later publication dates. The mean modified Coleman methodology score was 54 (of 100). Patients underwent autologous chondrocyte implantation (n = 604), microfracture (n = 271), or osteochondral autograft (n = 42). All surgical techniques demonstrated improvement in comparison with the preoperative status. Three of seven studies showed better clinical outcomes after autologous chondrocyte implantation in comparison with microfracture after one to three years of follow-up, whereas one study showed better outcomes two years after microfracture and three other studies showed no difference in these treatments after one to five years. Clinical outcomes after microfracture deteriorated after eighteen to twenty-four months (in three of seven studies). Autologous chondrocyte implantation and osteochondral autograft demonstrated equivalent short-term clinical outcomes, although there was more rapid improvement after osteochondral autograft (two studies). Although outcomes were equivalent between first and second-generation autologous chondrocyte implantation and between open and arthroscopic autologous chondrocyte implantation, complication rates were higher with open, periosteal-cover, first generation autologous chondrocyte implantation (four studies). Younger patients with a shorter preoperative duration of symptoms and fewer prior surgical procedures had the best outcomes after both autologous chondrocyte implantation and microfracture. A defect size of >4 cm(2) was the only factor predictive of better outcomes when autologous chondrocyte implantation was compared with a non autologous chondrocyte implantation surgical technique. CONCLUSIONS: Cartilage repair or restoration in the knee provides short-term success with microfracture, autologous chondrocyte implantation, or osteochondral autograft. There are patient-specific and defect-specific factors that influence clinical outcomes. PMID- 20844167 TI - Management of complex knee ligament injuries. PMID- 20844169 TI - Intermediate to long-term results following the bernese periacetabular osteotomy and predictors of clinical outcome: surgical technique. AB - BACKGROUND: The Bernese periacetabular osteotomy is a commonly used non arthroplasty option to treat developmental hip dysplasia in symptomatic younger patients. Predicting which hips will remain preserved and which hips will go on to require arthroplasty following periacetabular osteotomy is a major challenge. In the present study, we assessed the intermediate to long-term results following periacetabular osteotomy to demonstrate the clinical outcomes for patients with varying amounts of dysplasia and arthritis. From these results, a probability-of failure analysis was conducted to predict the likelihood of hip preservation and to improve surgical decision-making. METHODS: Of the 189 hips (in 157 patients) that were treated with periacetabular osteotomy by a single surgeon from May 1991 to September 1998, thirty-one had diagnoses other than developmental hip dysplasia and twenty-three were lost to follow-up. The remaining 135 hips (in 109 patients) were retrospectively reviewed at an average of nine years. Hips were evaluated with use of the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis Index postoperatively as well as with radiographs that were made preoperatively and at one and more than five years postoperatively. Osteotomy failure was defined as a pain score of >=10 or the need for total hip arthroplasty. RESULTS: One hundred and two hips (76%) remained preserved at an average of nine years, with an average Western Ontario and McMaster Universities pain score of 2.4 of 20. Thirty-three hips (24%) met the failure criteria: seventeen underwent arthroplasty at an average of 6.1 years after the osteotomy, and sixteen had a postoperative pain score of >=10. Kaplan Meier analysis with arthroplasty as the end point revealed a survival rate of 96% (95% confidence interval, 93% to 99%) at five years and 84% (95% confidence interval, 77% to 90%) at ten years. Complications occurred in twenty hips. Fifteen hips (11%) were treated with a subsequent arthroscopy because of chondral and/or labral lesions at an average of 6.8 years after the osteotomy. Two independent predictors of failure (defined as arthroplasty or a high pain score) were identified: (1) an age of more than thirty-five years and (2) poor or fair preoperative joint congruency. The probability of failure requiring arthroplasty was 14% for hips with no predictors of failure, 36% for those with one predictor (either an age of more than thirty-five years or poor or fair joint congruency), and 95% for those with both predictors. CONCLUSIONS: The Bernese periacetabular osteotomy can be effective for the treatment of painful hip dysplasia, but complications may be expected in as many as 15% of cases. The ideal candidate is the patient who is less than thirty-five years of age and who has good or excellent hip joint congruency. PMID- 20844170 TI - Arthroscopic repair of circumferential lesions of the glenoid labrum: surgical technique. AB - BACKGROUND: Symptomatic pan-labral or circumferential (360 degrees ) tears of the glenohumeral labrum are an uncommon injury. The purpose of the present study was to report the results of surgical treatment of circumferential lesions of the glenoid labrum with use of validated outcome instruments. METHODS: From July 2003 to May 2006, forty-one shoulders in thirty-nine patients (thirty-four men and five women) with a mean age of 25.1 years were prospectively enrolled in a multicenter study and were managed for a circumferential (360 degrees ) lesion of the glenoid labrum. All patients had a primary diagnosis of pain and recurrent shoulder instability, and all underwent arthroscopic repair of the circumferential labral tear with a mean of 7.1 suture anchors. The outcomes for thirty-nine of the forty-one shoulders were assessed after a mean duration of follow-up of 31.8 months on the basis of the rating of pain and instability on a scale of 0 to 10, a physical examination, and three outcome instruments (the Single Assessment Numeric Evaluation score, the modified American Shoulder and Elbow Surgeons score, and the Short Form-12 score). RESULTS: Significant improvement was noted in terms of the mean pain score (from 4.3 to 1.1), the mean instability score (from 7.3 to 0.2), the mean modified American Shoulder and Elbow Surgeons score (from 55.5 to 89.6), the mean Short Form-12 score (from 75.7 to 90.0), and the mean Single Assessment Numeric Evaluation score (from 36.7 to 88.5). Six shoulders required revision surgery because of recurrent instability (two), recalcitrant biceps tendinitis (two), or postoperative tightness (two). All patients returned to their preinjury activity level. CONCLUSIONS: Pan-labral or circumferential lesions are an uncommon yet extensive injury of the glenohumeral joint that may result in recurrent instability and pain. The present study demonstrates that arthroscopic capsulolabral repair with suture anchor fixation can restore the stability of the glenohumeral joint and can provide a reliable improvement in subjective and objective outcome measures. PMID- 20844171 TI - Comparison of the clinical results of three posterior cruciate ligament reconstruction techniques: surgical technique. AB - BACKGROUND: Despite its technical complexity, arthroscopic tibial inlay reconstruction of the posterior cruciate ligament has biomechanical advantages over transtibial procedures. The purpose of this study was to compare the clinical results of arthroscopic tibial inlay single-bundle and double-bundle techniques with those of the conventional transtibial single-bundle technique. METHODS: We evaluated twenty-nine patients treated with primary posterior cruciate ligament reconstruction and followed for longer than two years. Eight patients were treated with a transtibial single-bundle procedure; eleven, with an arthroscopic inlay single-bundle procedure; and ten, with an arthroscopic inlay double-bundle procedure. An Achilles tendon allograft was used in all cases. Each patient was evaluated on the basis of the Lysholm knee score, the mean side-to side difference in tibial translation as measured on Telos stress radiographs, and the side-to-side difference in the range of motion of the knee. RESULTS: The mean side-to-side difference (and standard deviation) in posterior tibial translation differed significantly between the arthroscopic tibial inlay double bundle group (3.6 +/- 1.43 mm) and the transtibial single-bundle group (5.6 +/- 2.0 mm) (p = 0.023), although there was no significant difference between the arthroscopic inlay single-bundle group (4.7 +/- 1.62 mm) and the transtibial group (p = 0.374). The mean range of motion and Lysholm scores were similar among the three groups. CONCLUSIONS: Despite its technical difficulty, the arthroscopic tibial inlay double-bundle technique is our preferred method of reconstruction of the posterior cruciate ligament because it stabilizes posterior tibial translation better than do the other two methods. PMID- 20844172 TI - The clamshell osteotomy: a new technique to correct complex diaphyseal malunions: surgical technique. AB - BACKGROUND: The treatment of complex diaphyseal malunions is challenging, requiring extensive preoperative planning and precise operative technique. We have developed a simpler method to treat some of these deformities. METHODS: Ten patients with complex diaphyseal malunions (including four femoral and six tibial malunions) underwent a clamshell osteotomy. The indications for surgery included pain at adjacent joints and deformity. After surgical exposure, the malunited segment was transected perpendicular to the normal diaphysis proximally and distally. The transected segment was again osteotomized along its long axis and was wedged open, similar to opening a clamshell. The proximal and distal segments of the diaphysis were then aligned with use of an intramedullary rod as an anatomic axis template and with use of the contralateral extremity as a length and rotation template. The patients were assessed clinically and radiographically at a mean of thirty-one months (range, six to fifty-two months) after the osteotomy. RESULTS: Complete angular correction was achieved in each case; the amount of correction ranged from 2 degrees to 20 degrees in the coronal plane, from 0 degrees to 32 degrees in the sagittal plane, and from 0 degrees to 25 degrees in the axial plane (rotation). Correction of length ranged from 0 to 5 cm, and limb length was restored to within 2 cm in all patients. All osteotomy sites were healed clinically by six months. While no deep infections occurred, superficial wound dehiscence occurred in two patients along the approach for the longitudinal portion of the osteotomy, emphasizing the importance of careful soft tissue handling and patient selection. CONCLUSIONS: The clamshell osteotomy provides a useful way to correct many forms of diaphyseal malunion by realigning the anatomic axis of the long bone with use of a reamed intramedullary rod as a template. This technique provides an alternative that could decrease preoperative planning time and complexity as well as decrease the need for intraoperative osteotomy precision in a correctly chosen subset of patients with diaphyseal deformities. PMID- 20844173 TI - Total hip arthroplasty with shortening subtrochanteric osteotomy in Crowe type-IV developmental dysplasia: surgical technique. AB - BACKGROUND: When surgeons perform total hip arthroplasty for hips with a high dislocation related to developmental dysplasia of the hip, obtaining long-term stable implant fixation and optimizing patient function remain challenges. The purpose of this paper was to evaluate the results of cementless arthroplasty with a simultaneous subtrochanteric shortening osteotomy in a group of patients with Crowe type-IV developmental dysplasia of the hip. METHODS: In a retrospective study, we evaluated the results and complications of twenty-eight consecutive primary cementless total hip arthroplasties in twenty-four patients (twenty women and four men), all of whom had Crowe type-IV developmental dysplasia of the hip. The arthroplasty was performed in combination with a subtrochanteric shortening osteotomy and with placement of the acetabular component at the level of the anatomic hip center. The patients were evaluated at a mean of 4.8 years postoperatively. RESULTS: The mean Harris hip score increased from 43 points preoperatively to 89 points at the time of final follow-up (p < 0.01). Twelve (43%) of the twenty-eight hips had an early or late complication or a reoperation. Two (7%) of the twenty-eight subtrochanteric osteotomies were followed by nonunion. There was one instance of isolated loosening of the femoral stem. One acetabular component loosened, and one acetabular liner disengaged. Four hips dislocated postoperatively. All remaining components were well-fixed at the time of the last radiographic follow-up. No sciatic neurapraxic injuries were identified. CONCLUSIONS: Cementless total hip arthroplasty combined with a subtrochanteric femoral shortening osteotomy in patients with a high hip dislocation secondary to developmental dysplasia was associated with high rates of successful fixation of the implants and healing of the osteotomy site and a mean postoperative Harris hip score of 89 points. The complication rate, however, was substantially higher than that associated with primary total hip arthroplasty in patients with degenerative arthritis. PMID- 20844174 TI - Allograft-prosthesis composite reconstruction of the proximal part of the humerus: surgical technique. AB - BACKGROUND: Limb salvage following resection of a tumor in the proximal part of the humerus poses many challenges. Reconstructive options are limited because of the loss of periarticular soft-tissue stabilizers of the glenohumeral joint in addition to the loss of bone and articular cartilage. The purpose of this study was to evaluate the functional outcome and survival of the reconstruction following use of a humeral allograft-prosthesis composite for limb salvage. METHODS: An allograft-prosthesis composite was used to reconstruct a proximal humeral defect following tumor resection in thirty-six consecutive patients at one institution over a sixteen-year period. The reconstruction was performed at the time of a primary tumor resection in thirty cases, after a failure of a reconstruction following a previous tumor resection in five patients, and following excision of a local recurrence in one patient. The mean duration of follow-up of the living patients was five years. Glenohumeral stability, function, implant survival, fracture rate, and union rate following the reconstructions were measured. Functional outcome and implant survival were analyzed on the basis of the amount of deltoid resection, whether the glenohumeral resection had been extra-articular or intra-articular, and the length of the humerus that had been resected. RESULTS: One patient sustained a glenohumeral dislocation. Deltoid resection (partial or complete) resulted in a reduced postoperative range of motion in flexion and abduction but had no effect on the mean Musculoskeletal Tumor Society score. Extra-articular resections were associated with lower Musculoskeletal Tumor Society scores. All patients had either mild or no pain and normal hand function at the time of final follow-up. The overall estimated rate of survival of the construct, with revision as the end point, was 88% at ten years. There were three failures due to progressive prosthetic loosening that necessitated removal of the construct. Four patients required an additional bone-grafting procedure to treat a delayed union of the osteosynthesis site. CONCLUSIONS: An allograft-prosthesis composite used for limb salvage following tumor resection in the proximal part of the humerus is a durable construct associated with an acceptable complication rate. Deltoid preservation and intra-articular resection are associated with a greater range of shoulder motion and a superior functional outcome, respectively. PMID- 20844175 TI - Opening-wedge high tibial osteotomy with a locked low-profile plate: surgical technique. AB - BACKGROUND: High tibial osteotomy has been recognized as a beneficial treatment for osteoarthritis of the medial compartment of the knee. The purpose of this prospective study was to assess the short-term results of opening-wedge high tibial osteotomies with locked plate fixation. METHODS: From September 2002 to November 2005, fifty-one consecutive medial opening-wedge high tibial osteotomies were performed. The mean age of the patients at the time of the index operation was forty-nine years. The preoperative and postoperative factors analyzed included the grade of arthritis of the tibiofemoral compartment (the Ahlback radiographic grade), the anatomic tibiofemoral angle, patellar height, the Hospital for Special Surgery rating system score, and the Lysholm and Gillquist knee score. RESULTS: Postoperatively, one superficial wound infection occurred. Fifty of the fifty-one osteotomies healed after an average period of 12.9 weeks (range, eight to sixteen weeks) without bone grafts. A nonunion developed in a sixty-two-year-old patient who was a cigarette smoker. The average postoperative tibiofemoral angle was 9 degrees of valgus. Forty-nine patients were followed for a mean of fifty-two months. The average score on the Hospital for Special Surgery rating system was 86 points at the time of the most recent follow-up. The rating was excellent in twenty-eight patients (57%), good in twelve (24%), fair in four (8%), and poor in five (10%). The average score on the Lysholm and Gillquist knee-scoring scale was 83 points. According to these scores, the outcome was excellent in nine patients (18%), good in thirty-one (63%), fair in three (6%), and poor in six (12%). Four knees failed after an average of thirty six months. CONCLUSIONS: Our results suggest that an opening-wedge high tibial osteotomy with locked plate fixation allows a correct valgus angle to be achieved with good short-term results. PMID- 20844177 TI - Clamp-assisted reduction of high subtrochanteric fractures of the femur: surgical technique. AB - BACKGROUND: Subtrochanteric fractures can be a treatment challenge. The substantial forces that this region experiences and the fact that the proximal fragment is frequently displaced make accurate reduction and internal fixation difficult. The purpose of this study was to evaluate a series of patients who had undergone clamp-assisted reduction and intramedullary nail fixation to determine the impact of this technique on fracture union rates and reduction quality. METHODS: Between December 2003 and January 2007, fifty-five consecutive patients with a displaced high subtrochanteric femoral fracture were treated with clamp assisted reduction and intramedullary nail fixation at two level-I trauma centers. Two patients died, and nine were lost to follow-up. The remaining forty four patients were followed until union or a minimum of six months. There were twenty-seven male and seventeen female patients with a mean age of fifty-five years. All were treated with an antegrade statically locked nail implanted with a reaming technique as well as the assistance of a reduction clamp placed through a small lateral incision. Nine patients were treated with a single supplemental cerclage cable. Radiographs were evaluated for the quality of the reduction and fracture union. RESULTS: Forty-three of the forty-four fractures united. All reductions were within 5 degrees of the anatomic position in both the frontal and the sagittal plane. Thirty-eight (86%) of the forty-four reductions were anatomic. Six fractures had a minor varus deformity of the proximal fragment (between 2 degrees and 5 degrees ). There were no complications. DISCUSSION: Surgical treatment of subtrochanteric femoral fractures with clamp-assisted reduction and intramedullary nail fixation techniques with judicious use of a cerclage cable can result in excellent reductions and a high union rate. Careful attention to detail is important to perform these maneuvers with minimal additional soft-tissue disruption. PMID- 20844176 TI - Autologous osteochondral mosaicplasty for osteochondritis dissecans of the elbow in teenage athletes: surgical technique. AB - BACKGROUND: Although autologous osteochondral mosaicplasty is widely used as a procedure for osteochondritis dissecans lesions, the effectiveness of this procedure in elbow lesions remains unclear. Our aim was to clarify the surgical efficacy of mosaicplasty for teenage athletes with advanced lesions of capitellar osteochondritis dissecans. METHODS: From 2001 to 2006, nineteen teenage male patients who were competitive athletes and had advanced lesions of capitellar osteochondritis dissecans underwent mosaicplasties. The mean age of the patients was 14.2 years. The surgical technique involved obtaining small-sized cylindrical osteochondral grafts with a mean diameter of 3.5 mm from the lateral periphery of the femoral condyle at the level of the patellofemoral joint and transplanting the grafts (mean, 3.3 grafts) to prepared osteochondral defects. The patients were evaluated clinically and radiographically at a mean of forty-five months after surgery. RESULTS: Eighteen patients were free from elbow pain, and one had mild pain occasionally. The mean total arc of elbow motion and standard deviation increased significantly from 112 degrees +/- 17 degrees preoperatively to 128 degrees +/- 12 degrees postoperatively (p < 0.005). The mean clinical score described by Timmerman and Andrews (with a maximum of 200 points) improved significantly from 131 +/- 23 points preoperatively to 191 +/- 15 points postoperatively (p < 0.0001). All patients except one had an excellent or good clinical result. All donor knees were graded as excellent on the basis of the Lysholm knee scoring system. All patients except two returned to a competitive level of the sport they had previously played. Neither loose-body formation nor secondary osteoarthritic changes were found in any patient. CONCLUSIONS: The current midterm results indicate that mosaicplasty can provide satisfactory clinical outcomes for teenage athletes with advanced capitellar osteochondritis dissecans lesions. PMID- 20844178 TI - Latissimus dorsi tendon transfer for irreparable rotator cuff tears: a modified technique to improve tendon transfer integrity: surgical technique. AB - BACKGROUND: Latissimus dorsi tendon transfer is a well-established method for the treatment of massive irreparable posterosuperior defects of the rotator cuff. Subsequent rupture of the transferred tendon may contribute to the rate of failure of the index procedure. We hypothesized that modification of our technique of tendon harvesting would lead to greater fixation stability and a reduced failure rate. METHODS: Forty-two patients (mean age, fifty-eight years) with a massive irreparable posterosuperior tear of the rotator cuff were managed with a latissimus dorsi tendon transfer. Sharp separation of the latissimus tendon from the humerus was performed in twenty-two patients (Group A), whereas the tendon harvest was carried out with a modified technique that involved removal of some bone along with the tendon at the humeral insertion in a subsequent group of twenty patients (Group B). The mean duration of follow-up was forty-seven months. Outcome measures included the Constant and American Shoulder and Elbow Surgeons (ASES) scores and a patient subjective satisfaction scale. Standard radiographs were made to determine the stage of osteoarthritis and proximal migration of the humeral head, and magnetic resonance imaging was performed to assess the integrity of the transferred muscle. RESULTS: In Group A, the mean Constant score improved from 43.4 preoperatively to 64.8 points at the time of follow-up and the mean ASES score improved from 49.3 to 69.6 points (p < 0.05). In Group B, the mean Constant score increased from 40.2 to 74.2 points and the mean ASES score, from 47.2 to 77.1 points (p < 0.05). The Constant pain score improved from 5.6 to 11.9 points in Group A and from 5.2 to 13.8 points in Group B. The results in Group B were significantly superior to those in Group A (p < 0.05). Magnetic resonance imaging revealed complete rupture at the tendon insertion with tendon retraction in four patients in Group A and none in Group B. The final outcome was rated as poor in 27% of the patients in Group A and in 10% in Group B. CONCLUSIONS: Latissimus dorsi tendon transfer achieves satisfactory clinical results in most patients who have a massive irreparable posterosuperior tear of the rotator cuff. Harvesting the tendon along with a small piece of bone enables direct bone-to-bone transosseous fixation, resulting in better tendon integrity and clinical results. PMID- 20844179 TI - Mobile and fixed-bearing (all-polyethylene tibial component) total knee arthroplasty designs: surgical technique. AB - BACKGROUND: Proponents of mobile-bearing total knee arthroplasty believe that it has potential advantages over a fixed-bearing design in terms of diminished wear and improved motion and/or function, but these advantages have not been demonstrated in a randomized clinical comparison to our knowledge. We conducted a patient-blinded, prospective, randomized clinical trial to compare mobile-bearing and fixed-bearing cruciate-substituting total knee arthroplasties of the same design. METHODS: Patients between the ages of sixty and eighty-five years were prospectively randomized to receive a cruciate-substituting rotating-platform design or a fixed-bearing design with an all-polyethylene tibial component. There were no significant differences in the demographic characteristics (mean age, 72.2 years; mean American Society of Anesthesiologists score, 2.7; mean body mass index, 31.8 kg/m2) or preoperative clinical or radiographic measures between the groups. Routine clinical and radiographic follow-up measures included the Knee Society score (KSS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Short Form-36 (SF-36) outcome measures. RESULTS: The results of 312 arthroplasties (136 with an all-polyethylene tibial component and 176 rotating-platform designs) in 273 patients were analyzed at a minimum of two years (mean, forty-two months) postoperatively. Although there was significant improvement in both groups, there was no significant difference between the groups with regard to the mean postoperative range of motion (110.9 degrees and 109.1 degrees , respectively; p = 0.21), the mean KSS clinical score (90.4 and 88.2 points; p = 0.168), or the mean KSS pain score (44.9 and 43.1 points; p = 0.108) at this follow-up point. There were ten revisions: seven because of infection, one because of patellar fracture, one because of instability, and one because of aseptic loosening. CONCLUSIONS: The two designs functioned equivalently at the time of early follow-up in this low-to-moderate-demand patient group. The rotating-platform design had no significant clinical advantage over the design with the all-polyethylene tibial component. PMID- 20844180 TI - Determination of correct implant size in radial head arthroplasty to avoid overlengthening: surgical technique. AB - BACKGROUND: Insertion of a radial head implant that results in radial overlengthening has been associated with altered elbow kinematics, increased radiocapitellar joint forces, capitellar erosions, early-onset arthritis, and loss of elbow flexion. The purpose of this study was to identify clinical and radiographic features that may be used to diagnose overlengthening of the radius intraoperatively and on postoperative radiographs. METHODS: Radial head implants of varying thicknesses were inserted into seven cadaver specimens, which were then assessed clinically and radiographically. Eight stages were examined: the intact specimen (stage 1); repair of the lateral collateral ligament (stage 2); radial head resection with repair of the lateral collateral ligament (stage 3); insertion of an implant of the correct thickness (stage 4); and insertion of an implant that resulted in radial overlengthening of 2 mm (stage 5), 4 mm (stage 6), 6 mm (stage 7), or 8 mm (stage 8). The specimens were tested with and without muscle loading to simulate resting muscle tone and surgical paralysis, respectively. At each stage, radiographs were made to measure the ulnohumeral joint space and the lateral ulnohumeral joint was visually assessed. RESULTS: We identified no difference, with regard to medial ulnohumeral joint incongruity as seen radiographically, among stages 1 through 6 during the tests with muscle loading. A significant difference in medial ulnohumeral joint incongruity was found in stages 7 (p = 0.003) and 8 (p < 0.001). The clinical (visually assessed) lateral ulnohumeral joint space gap was negligible in stages 1 through 4 but increased significantly at all stages involving overlengthening (gross gap, 0.9 mm with 2 mm of erlengthening [p = 0.005], 2.3 mm with 4 mm of overlengthening [p < 0.001], 3.4 mm with 6 mm [p < 0.001], and 4.7 mm with 8 mm [p < 0.001]). CONCLUSIONS: Incongruity of the medial ulnohumeral joint becomes apparent radiographically only after overlengthening of the radius by >=6 mm. Intraoperative visualization of a gap in the lateral ulnohumeral joint is a reliable indicator of overlengthening following the insertion of a radial head prosthesis. PMID- 20844181 TI - Long-term outcome after surgical treatment of unresolved osgood-schlatter disease in young men: surgical technique. AB - BACKGROUND: Surgical treatment of Osgood-Schlatter disease is occasionally warranted, but its long-term prognosis remains poorly investigated. We studied the rate of occurrence of surgical treatment of unresolved Osgood-Schlatter disease as well as the clinical course, radiographic characteristics, and long term outcomes after that treatment in a large population of military recruits. METHODS: During a thirteen-year period, 178 consecutive recruits underwent surgery for unresolved Osgood-Schlatter disease, and 107 of them (117 knees) who met the inclusion criteria participated in a follow-up examination. We obtained data from the original medical records and radiographs as well as follow-up information from physical and radiographic examinations, interviews, and questionnaires to determine functional outcomes. RESULTS: The rate of occurrence of surgically treated unresolved Osgood-Schlatter disease was forty-two per 100,000 military recruits. The median age at the onset of symptoms was fifteen years. After a median duration of follow-up of ten years after the surgery, ninety-three patients (87%) reported no restrictions in everyday activities or at work and eighty (75%) had returned to their preoperative level of sports activity. The median modified Kujala score was 95 points, and the median visual analog score for pain was 7 mm. Forty-one patients (38%) reported a complete absence of pain when kneeling. Six patients had experienced minor postoperative complications, and two had undergone a reoperation for the treatment of the Osgood-Schlatter disease. After resection, the mean tibial tuberosity thickness decreased by 47%. The mean Insall-Salvati index was 1.0 preoperatively and 1.09 postoperatively (p = 0.003), and the corresponding mean Blackburne-Peel indexes were 0.85 and 0.95 (p = 0.003). With the numbers studied, the symptom duration, surgical methods, and radiographic indexes were not found to have an effect on the outcome of surgery. CONCLUSIONS: In the great majority of young adults, the functional outcome of surgical treatment of unresolved Osgood-Schlatter disease is excellent or good, the residual pain intensity is low, and postoperative complications or subsequent reoperations are rare. PMID- 20844182 TI - Dialysis modality-dependent changes in serum metabolites: accumulation of inosine and hypoxanthine in patients on haemodialysis. AB - BACKGROUND: The body metabolism of patients with end-stage renal disease may be altered in response to long-term dialysis treatment. Moreover, the pattern of serum metabolites could change depending on the type of dialysis modality used. However, dialysis modality-dependent changes in serum metabolites are poorly understood. Our aim was to profile comprehensively serum metabolites by exploiting a novel method of (1)H-NMR-based metabonomics and identify the differences in metabolite patterns in subjects receiving haemodialysis (HD) and peritoneal dialysis (PD). METHODS: Anuric and non-diabetic HD patients were matched to PD patients for age, sex and dialysis duration. Accurate concentrations of serum metabolites were determined using the target-profiling procedure, and differences in the levels of metabolites were compared using multivariate analysis. RESULTS: Principal Components Analysis score plots showed that the metabolic patterns could be discriminated by dialysis modalities. Hypoxanthine and inosine were present only with HD, whereas serum xanthine oxidase activity and uric acid levels were not different. In contrast, PD was associated with higher levels of lactate, glucose, maltose, pyruvate, succinate, alanine, and glutamate linked to glucose metabolism and the tri-carboxylic acid cycle. Maltose appeared only in patients using icodextrin solution for PD. Known uraemic retention solutes such as urea, creatinine, myo-inositol and trimethylamine-N-oxide were increased in both dialysis groups. CONCLUSIONS: Metabonomics shows apparent differences in the profiles of serum metabolites between HD and PD, which were influenced by dialysis-related processes. Inosine and hypoxanthine are present only in HD patients, which is likely to represent more hypoxic and oxidative stress. PMID- 20844183 TI - Expression of the chemokine receptor CCR6 in human renal inflammation. AB - BACKGROUND: Nodular inflammatory cell infiltrates with defined microarchitecture, i.e. tertiary lymphoid organs, develop in the tubulointerstitium during chronic renal inflammation. CCR6 and the corresponding ligand CCL20 are involved in the formation of gut-associated lymphatic tissue. We hypothesized that CCR6 might be involved in the formation of nodular infiltrates in the kidney. METHODS: CCR6- and CD20-positive B cells were localized in renal biopsies with IgA nephropathy (n = 13), membranous nephropathy (n = 12), crescentic glomerulonephritis (cGN, n = 11) and chronic interstitial nephritis (n = 13), and in pre-implantation biopsies as controls (n = 8). The mRNA expression of CCR6 and the ligand CCL20 was quantified by real-time RT-PCR in 51 renal biopsies of the same disease entities. RESULTS: In the pre-transplant biopsies, CCR6 was expressed by endothelial cells of peritubular and glomerular capillaries. In patients with glomerulonephritis, infiltrating cells were positive particularly in areas of nodular inflammatory cell accumulations. A major part of the CCR6-positive cells were CD20-positive B cells, but a part of the CD3-positive T cells were also found to be positive. The constitutive expression of CCR6 on the endothelium of glomerular capillaries was lost in biopsies with progressive injury. Tubular epithelial cells expressed CCR6 in inflamed kidneys, most commonly on the basolateral side. CONCLUSIONS: CCR6 and the corresponding ligand CCL20 might therefore be involved in the recruitment of T and B cells to organized nodular infiltrates in chronic renal inflammation. The functional role of endothelial CCR6 needs to be evaluated in further studies. PMID- 20844184 TI - The angiotensin II receptor type 2 polymorphism influences haemodynamic function and circulating RAS mediators in normotensive humans. AB - BACKGROUND: The haemodynamic responses to angiotensin II type 1 (AT1) receptor blockade may be mediated in part by interactions between angiotensin II and the angiotensin II type 2 receptor (AT2R). An AT2R G1675A gene polymorphism has been described, but the functional effects of this polymorphism are unknown. METHODS: Haemodynamic function, circulating renin-angiotensin system mediators and norepinephrine were measured in young healthy subjects at baseline and at 2 and 4 weeks after treatment with irbesartan. Subjects were divided into two groups on the basis of the AT2R G1675A gene polymorphism: GG subjects (n = 12) and AA/GA subjects (n = 22). RESULTS: AA/AG subjects exhibited hypotensive and renal vasodilatory responses to irbesartan at 4 weeks, but GG subjects did not. In accord with haemodynamic effects, circulating aldosterone levels were suppressed in AA/AG, while circulating norepinephrine levels were augmented only in GG subjects. In contrast, increases in circulating renin, angiotensin II and plasma renin activity after irbesartan were exaggerated in AA/AG subjects. CONCLUSIONS: The AT2R G1675A polymorphism is a determinant of haemodynamic responses to AT1 receptor blockade, an effect that may be due to influences on aldosterone escape. PMID- 20844185 TI - C4d staining in post-reperfusion renal biopsy is not useful for the early detection of antibody-mediated rejection when CDC crossmatching is negative. AB - BACKGROUND: Sensitized patients (pts) may develop acute antibody-mediated rejection (AMR) due to preformed donor-specific antibodies, undetected by pre transplant complement-dependent cytotoxicity (CDC) crossmatch (XM). We hypothesized that C4d staining in 1-h post-reperfusion biopsies (1-h Bx) could detect early complement activation in the renal allograft due to preformed donor specific antibodies. METHODS: To test this hypothesis, renal transplants (n = 229) performed between June 2005 and December 2007 were entered into a prospective study of 1-h Bx and stained for C4d by immunofluorescence. Transplants were performed against a negative T-cell CDC-XM with the exception of three cases with a positive B-cell XM. RESULTS: All 229 1-h Bx stained negative for C4d. Fourteen pts (6%) developed AMR. None of the 14 protocol 1-h Bx stained positive for C4d in peritubular capillaries (PTC). However, all indication biopsies-that diagnosed AMR-performed at a median of 8 days after transplantation stained for C4d in PTC. CONCLUSIONS: These data show that C4d staining in 1-h Bx is, in general, not useful for the early detection of AMR when CDC-XM is negative. PMID- 20844188 TI - Children who recover from early stunting and children who are not stunted demonstrate similar levels of cognition. AB - Stunting is associated with adverse cognitive development in childhood and adolescence, fewer years of schooling, decreased productivity, and reduced adult stature. Recovery from early stunting is possible; however, few studies explore whether those who demonstrate linear catch-up growth experience long-term cognitive deficits. Using longitudinal data on 1674 Peruvian children from the Young Lives study, we identified factors associated with catch-up growth and assessed whether children who displayed catch-up growth have significantly lower cognition than children who were not stunted during infancy and childhood. Based on anthropometric data for children 6-18 mo of age and again for the same children when they were 4.5-6 y of age, we categorized participants as not stunted, stunted in infancy but not childhood (catch-up), stunted in childhood, and stunted in infancy and childhood. Children who had grandparents in the home, had less severe stunting in infancy, and had taller mothers were more likely to demonstrate catch-up growth by round 2. Children who experienced catch-up growth had verbal vocabulary and quantitative test scores that did not differ from children who were not stunted (P = 0.6 and P = 0.7, respectively). Those stunted in childhood as well as those stunted in infancy and childhood scored significantly lower on both assessments than children who were not stunted. Based on findings from this study, policy makers and program planners should consider redoubling efforts to prevent stunting and promote catch-up growth over the first few years of life as a way of improving children's physical and intellectual development. PMID- 20844187 TI - Maternal dietary counseling in the first year of life is associated with a higher healthy eating index in childhood. AB - Food preferences are established in early childhood and track later in life. Therefore, it is important to promote healthy feeding practices as early as possible. A randomized field trial was conducted with 500 mother-child pairs from a low-income area of Sao Leopoldo, State of Rio Grande do Sul, Brazil, to evaluate the impact of a nutritional intervention in the first year of life on the dietary quality of 3- to 4-y-old children. Mother-child pairs were randomized either to intervention and control groups and dietary counseling was provided for mothers in the intervention group during 10 home visits in the course of the first year of life. These visits were carried out by fieldworkers who counseled the mothers about the Ten Steps for Healthy Feeding from Birth to Two Years of Age, based on the WHO guidelines. Dietary intake was assessed at 3-4 y of age for 345 children using two 24-h food recalls. Overall diet quality was determined by the Healthy Eating Index. The prevalence of poor diet in the intervention group was lower compared with the control group [relative risk (RR) = 0.30; 95% CI = 0.13-0.71). The number of children who achieved the 75th percentile for the vegetable and fruit component score was higher in the intervention than in control group (RR = 1.95; 95% CI = 1.31-2.89 and RR = 1.49; 95% CI = 1.07-2.07, respectively). Such data provide evidence that dietary counseling for mothers during the first year of life improves the overall dietary quality of children in a low-income population. PMID- 20844186 TI - Excess leucine intake enhances muscle anabolic signaling but not net protein anabolism in young men and women. AB - Essential amino acids (EAA) stimulate skeletal muscle protein synthesis (MPS) in humans. Leucine may have a greater stimulatory effect on MPS than other EAA and/or decrease muscle protein breakdown (MPB). To determine the effect of 2 different leucine concentrations on muscle protein turnover and associated signaling, young men (n = 6) and women (n = 8) ingested 10 g EAA in 1 of 2 groups: composition typical of high quality proteins (CTRL; 1.8 g leucine) or increased leucine concentration (LEU; 3.5 g leucine). Participants were studied for 180 min postingestion. Fractional synthetic rate and leg phenylalanine and leucine kinetics were assessed on muscle biopsies using stable isotopic techniques. Signaling was determined by immunoblotting. Arterial leucine concentration and delivery to the leg increased in both groups and was significantly higher in LEU than in CTRL; however, transport into the muscle and intracellular availability did not differ between groups. MPS increased similarly in both groups 60 min postingestion. MPB decreased at 60 min only in LEU, but net muscle protein balance improved similarly. Components of mammalian target of rapamycin (mTOR) signaling were improved in LEU, but no changes were observed in ubiquitin-proteasome system signaling. Changes in light chain 3 and mTOR association with Unc-51-like kinase 1 indicate autophagy decreased more in LEU. We conclude that in 10 g of EAA, the leucine content typical of high quality proteins (~1.8 g) is sufficient to induce a maximal skeletal muscle protein anabolic response in young adults, but leucine may play a role in autophagy regulation. PMID- 20844189 TI - OX40 ligand regulates inflammation and mortality in the innate immune response to sepsis. AB - The initial phase of sepsis is characterized by massive inflammatory cytokine production that contributes to multisystem organ failure and death. Costimulatory molecules are a class of receptors capable of regulating cytokine production in adaptive immunity. Recent studies described their presence on neutrophils and monocytes, suggesting a potential role in the regulation of cytokine production in innate immunity. The purpose of this study was to determine the role for OX40 OX40 ligand (OX40L) interaction in the innate immune response to polymicrobial sepsis. Humans with sepsis demonstrated upregulation of OX40L on monocytes and neutrophils, with mortality and intensive care unit stay correlating with expression levels. In an animal model of polymicrobial sepsis, a direct role for OX40L in regulating inflammation was indicated by improved survival, decreased cytokine production, and a decrease in remote organ damage in OX40L(-/-) mice. The finding of similar results with an OX40L Ab suggests a potential therapeutic role for OX40L blockade in sepsis. The inability of anti-OX40L to provide significant protection in macrophage-depleted mice establishes macrophages as an indispensable cell type within the OX40/OX40L axis that helps to mediate the clinical signs of disease in sepsis. Conversely, the protective effect of anti OX40L Ab in RAG1(-/-) mice further confirms a T cell-independent role for OX40L stimulation in sepsis. In conclusion, our data provide an in vivo role for the OX40/OX40L system in the innate immune response during polymicrobial sepsis and suggests a potential beneficial role for therapeutic blockade of OX40L in this devastating disorder. PMID- 20844190 TI - TLR agonists that induce IFN-beta abrogate resident macrophage suppression of T cells. AB - Resident tissue macrophages (Mphis) continually survey the microenvironment, ingesting Ags and presenting them on their surface for recognition by T cells. Because these Ags can be either host cell- or pathogen-derived, Mphis must be able to distinguish whether a particular Ag should provoke an immune response or be tolerated. However, the mechanisms that determine whether Mphis promote or inhibit T cell activation are not well understood. To investigate this, we first determined the mechanism by which murine resident peritoneal Mphis suppress in vitro T cell proliferation in the absence of pathogens and then explored the effects of different pathogen-derived molecules on Mphi immunosuppression. Our results suggest that, in response to IFN-gamma, which is secreted by TCR activated T cells, resident peritoneal Mphis acquire immunosuppressive properties that are mediated by NO. However, pretreatment of Mphis with LPS or dsRNA, but not CpG or peptidoglycan, eliminates their suppressive properties, in part via the induction of autocrine-acting IFN-beta. These results suggest TLR agonists that activate TRIF, and consequently induce IFN-beta, but not those that exclusively signal through MyD88, abrogate the immunosuppressive properties of Mphis, and thus promote T cell expansion and elimination of invading microorganisms. PMID- 20844191 TI - Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells. AB - The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8(+) T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-beta gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-beta expression that is dependent on NF-kappaB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-beta expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-beta expression and found that PB1-F2-mediated IFN-beta induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection. PMID- 20844192 TI - Development of a nascent galectin-1 chimeric molecule for studying the role of leukocyte galectin-1 ligands and immune disease modulation. AB - Galectin-1 (Gal-1), a beta-galactoside-binding lectin, plays a profound role in modulating adaptive immune responses by altering the phenotype and fate of T cells. Experimental data showing recombinant Gal-1 (rGal-1) efficacy on T cell viability and cytokine production, nevertheless, is controversial due to the necessity of using stabilizing chemicals to help retain Gal-1 structure and function. To address this drawback, we developed a mouse Gal-1 human Ig chimera (Gal-1hFc) that did not need chemical stabilization for Gal-1 ligand recognition, apoptosis induction, and cytokine modulation in a variety of leukocyte models. At high concentrations, Gal-1hFc induced apoptosis in Gal-1 ligand(+) Th1 and Th17 cells, leukemic cells, and granulocytes from synovial fluids of patients with rheumatoid arthritis. Importantly, at low, more physiologic concentrations, Gal 1hFc retained its homodimeric form without losing functionality. Not only did Gal 1hFc-binding trigger IL-10 and Th2 cytokine expression in activated T cells, but members of the CD28 family and several other immunomodulatory molecules were upregulated. In a mouse model of contact hypersensitivity, we found that a non-Fc receptor-binding isoform of Gal-1hFc, Gal-1hFc2, alleviated T cell-dependent inflammation by increasing IL-4(+), IL-10(+), TGF-beta(+), and CD25(high)/FoxP3(+) T cells, and by decreasing IFN-gamma(+) and IL-17(+) T cells. Moreover, in human skin-resident T cell cultures, Gal-1hFc diminished IL-17(+) T cells and increased IL-4(+) and IL-10(+) T cells. Gal-1hFc will not only be a useful new tool for investigating the role of Gal-1 ligands in leukocyte death and cytokine stimulation, but for studying how Gal-1-Gal-1 ligand binding shapes the intensity of immune responses. PMID- 20844193 TI - C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes. AB - Almost all humans with homozygous deficiency of C1q develop systemic lupus erythematosus (SLE). The precise cellular mechanism(s) by which C1q prevents the development of SLE remains unclear. In this study, we tested the role of C1q in the regulation of IFN-alpha induced by immune complexes (ICs) in vitro, as well as the consequences of lack of C1q in vivo. Our experiments revealed that C1q preferentially promotes the binding of SLE ICs to monocytes rather than plasmacytoid dendritic cells, but this inhibition was not due to the induction of inhibitory soluble factors. The presence of C1q also altered the trafficking of ICs within monocytes such that ICs persisted in early endosomes. In patients with C1q deficiency, serum and cerebrospinal fluid levels of IFN-alpha and IFN-gamma inducible protein-10 levels were elevated and strongly correlated with Ro autoantibodies, demonstrating the clinical significance of these observations. These studies therefore associate C1q deficiency with defective regulation of IFN alpha and provide a better understanding of the cellular mechanisms by which C1q prevents the development of IC-stimulated autoimmunity. PMID- 20844194 TI - Combined administration of a mutant TGF-beta1/Fc and rapamycin promotes induction of regulatory T cells and islet allograft tolerance. AB - The critical roles of TGF-beta in the reciprocal differentiation of tolerance promoting CD4(+)Foxp3(+) regulatory T cells (Tregs) and proinflammatory Th17 effector cells affect alloimmune reactivity and transplant outcome. We reasoned that a strategy to harness TGF-beta and block proinflammatory cytokines would inhibit the differentiation of Th17 cells and strengthen the cadre of Tregs to promote tolerance induction and long-term allograft survival. In this study, we report the development of a long-lasting autoactive human mutant TGF-beta1/Fc fusion protein that acts in conjunction with rapamycin to inhibit T cell proliferation and induce the de novo generation of Foxp3(+) Treg in the periphery, while at the same time inhibiting IL-6-mediated Th17 cell differentiation. Short-term combined treatment with TGF-beta1/Fc and rapamycin achieved long-term pancreatic islet allograft survival and donor-specific tolerance in a mouse model. This effect was accompanied by expansion of Foxp3(+) Tregs, enhanced alloantigen-specific Treg function, and modulation of transcript levels of Foxp3, IL-6, and IL-17. Our strategy of combined TGF-beta1/Fc and rapamycin to target the IL-6-related Tregs and Th17 signaling pathways provides a promising approach for inducing transplant tolerance and its clinical application. PMID- 20844195 TI - Lunatic fringe enhances competition for delta-like Notch ligands but does not overcome defective pre-TCR signaling during thymocyte beta-selection in vivo. AB - Notch1 activation by Delta-like (DL) Notch ligands is essential to induce T cell commitment and to suppress B cell development from thymus-seeding progenitors. Thymus-seeding progenitor competition for DL4 is critically regulated by Lunatic Fringe (Lfng), which glycosylates epidermal growth factor repeats in the Notch1 extracellular domain to enhance binding avidity for DL ligands. Notch1 activation is also essential for the process of beta-selection, which drives TCRbeta(+) CD4/CD8 double-negative 3 (DN3) precursors to proliferate and generate a large pool of CD4/CD8 double-positive thymocytes. We have used several genetic approaches to determine the importance of Lfng-Notch1 interactions in regulating competition of preselection and postselection DN3 thymocytes for DL ligands in vivo. Surprisingly, although Lfng overexpression enhanced DL4 binding by preselection DN3a thymocytes, it did not confer them with a competitive advantage in mixed chimeras. In contrast, Lfng overexpression enhanced competition of post beta-selection DN3b precursors for DL ligands. Lfng modification of O-fucose in the Notch1 ligand-binding domain contributed to but was not solely responsible for the developmental effects of Lfng overexpression. Although previous studies have suggested that pre-TCR-deficient DN3 thymocytes compete poorly for DL ligands, Lfng overexpression did not fully restore double-positive thymocyte pools from DN3b cells with pre-TCR signaling defects. Thus, pre-TCR and Notch signaling have largely nonoverlapping functions in beta-selection. Collectively, our data reveal that Lfng enhances DN3b precursor competition for intrathymic DL ligands to maximize Notch-induced clonal expansion during the earliest stage of beta-selection. PMID- 20844196 TI - Endogenous IL-10 attenuates cisplatin nephrotoxicity: role of dendritic cells. AB - Sterile inflammation is associated with tissue injury and organ failure. Recent studies indicate that certain endogenous cytokines and immune cells may limit tissue injury by reducing immune-mediated inflammatory responses. Cisplatin is a commonly used anticancer chemotherapeutic agent but causes acute kidney injury and dysfunction. In a recent study, we showed that renal dendritic cells attenuate cisplatin-induced kidney injury by reducing inflammation. In this study, we investigated the effect of endogenous IL-10 and dendritic cell IL-10 in cisplatin-mediated kidney injury. Cisplatin treatment caused increases in renal IL-10R1 expression and STAT3 phosphorylation. In response to cisplatin treatment, IL-10 knockout mice showed more rapid and greater increases in blood urea nitrogen and serum creatinine compared with wild-type mice, indicating that endogenous IL-10 ameliorates kidney injury in cisplatin nephrotoxicity. Renal infiltration of IFN-gamma-producing neutrophils was markedly increased in IL-10 knockout mice compared with wild-type mice. However, IFN-gamma neutralization had no impact on renal dysfunction, suggesting IFN-gamma-independent mechanisms of tissue injury in cisplatin nephrotoxicity. Renal dendritic cells showed high expression of IL-10 in response to cisplatin treatment. We further investigated the effect of dendritic cell-derived IL-10 in cisplatin nephrotoxicity using a conditional cell ablation approach. Mixed bone marrow chimeric mice lacking IL-10 in dendritic cells showed moderately greater renal dysfunction than chimeric mice positive for IL-10 in dendritic cells. These data demonstrate that endogenous IL 10 reduces cisplatin nephrotoxicity and associated inflammation. Moreover, IL-10 produced by dendritic cells themselves accounts for a portion of the protective effect of dendritic cells in cisplatin nephrotoxicity. PMID- 20844197 TI - IL-17 promotes immune privilege of corneal allografts. AB - Corneal allograft rejection has been described as a Th1-mediated process involving IFN-gamma production. However, it has been reported that corneal allograft rejection soars in IFN-gamma(-/-) mice or mice treated with anti-IFN gamma mAb. Th17 is a recently described IL-17A-producing Th cell population that has been linked to renal and cardiac graft rejection, which was originally thought to be Th1-mediated. We tested the hypothesis that Th17 cells mediate corneal allograft rejection in an IL-17A-dependent fashion and unexpectedly found that depletion of IL-17A increased the incidence of rejection to 90%. We demonstrate that the exacerbated rejection following depletion of IL-17A did not result from a loss of cross-regulation of Th1 cells or exaggerated delayed-type hypersensitivity responses. Instead, inhibition of the Th1 or Th17 cell lineages promoted the emergence of a Th2 cell subset that independently mediated allograft rejection. These findings demonstrate that IL-17A is not required for corneal allograft rejection and may instead contribute to the immune privilege of corneal allografts. PMID- 20844198 TI - Bim dictates naive CD4 T cell lifespan and the development of age-associated functional defects. AB - With age, peripheral naive CD4 T cells become both longer lived and functionally impaired and they express reduced levels of Bim, a proapoptotic Bcl family member. In this study, we show that reduced Bim expression by naive CD4 T cells intrinsically mediates their longer lifespan in the periphery. Moreover, using mixed bone marrow chimeras reconstituted with Bim(+/+) and Bim(+/-) bone marrow cells, Bim(+/-) naive CD4 T cells exhibit accelerated development of age associated dysfunctions, including reduced proliferation and IL-2 production and defective helper function for B cells, without any increase in their turnover. However, newly generated Bim(+/-) naive CD4 T cells in middle-aged mice are not defective, indicating an additional requirement for their persistence in the periphery. These age-associated immune defects develop independently of the "aged" host environment and without extensive division, distinguishing them from classic "senescence." We suggest that the reduction of Bim levels with age in naive CD4 T cell is the initiating step that leads to increased cellular lifespan and development of age-associated functional defects. PMID- 20844199 TI - Differential modulation of TLR3- and TLR4-mediated dendritic cell maturation and function by progesterone. AB - The role of progesterone in modulating dendritic cell (DC) function following stimulation of different TLRs is relatively unknown. We compared the ability of progesterone to modulate murine bone marrow-derived DC cytokine production (IL-6 and IL-12) and costimulatory molecule expression (CD40, CD80, and CD86) induced by either TLR3 or TLR4 ligation and determined whether activity was via the progesterone receptor (PR) or glucocorticoid receptor (GR) by comparative studies with the PR-specific agonist norgestrel and the GR agonist dexamethasone. Progesterone was found to downregulate, albeit with different sensitivities, both TLR3- and TLR4-induced IL-6 production entirely via the GR, but IL-12p40 production via either the GR or PR. Of particular significance was that progesterone was able to significantly inhibit TLR3- but not TLR4-induced CD40 expression in bone marrow-derived DCs. Stimulation of the PR (with progesterone and norgestrel) by pretreatment of DCs was found to sustain IFN regulatory factor 3 phosphorylation following TLR3 ligation, but not TLR4 ligation. Overall, these studies demonstrate that progesterone can differentially regulate the signaling pathways employed by TLR3 and TLR4 agonists to affect costimulatory molecule expression and cytokine production. PMID- 20844200 TI - Thrombospondin-1 derived from APCs regulates their capacity for allosensitization. AB - Thrombospondin (TSP)-1 is a matricellular glycoprotein with immunoregulatory properties, which include inhibition of APC function. We show in transplantation that TSP-1 inhibits T cell allosensitization and consequently suppresses immune rejection. This was revealed by comparing wild-type (WT) versus TSP-1 null allografts in corneal transplantation, as the cornea is a rich source of TSP-1. Compared with only 50% of rejected WT allografts, nearly all TSP-1 null allografts succumbed to rejection. This effect was reflected by donor-derived APCs, which exhibited a distinctively greater capacity for allosensitization in transplanted hosts. Corroborated in MLRs, greater proliferation levels and robust IFN-gamma (but not IL-10)-positive T cells resulted from stimulation by TSP-1 null APCs relative to WT ones. Moreover, enhanced expression of MHC class II and B7 maturation markers were detected on TSP-1 null APCs during inflammation. Increased expression of CCR7 was further matched by enhanced lymph node migration of TSP-1 null APCs posttransplantation. We therefore conclude that APC-derived TSP-1 suppresses their capacity to allosensitize T cells, and this regulation stems from their resistance to taking on a mature form. Future strategies targeting APCs for TSP-1 upregulation may thus be effective in promoting allograft survival. PMID- 20844201 TI - IL-21 deficiency influences CD8 T cell quality and recall responses following an acute viral infection. AB - CD4 T cells are principal producers of IL-21 and are often required for optimal CD8 T cell responses. Therefore, we investigated the importance of IL-21 in determining the phenotypic attributes, functional quality, and maintenance of antiviral CD8 T cells following acute infection with the prototypic mouse pathogen lymphocytic choriomeningitis virus. Previous reports have documented an obligatory role for IL-21 in sustaining CD8 T cell responses during chronic infections. Here we show that the requirements for IL-21 are less stringent following acute infections; however, in the absence of IL-21, the capacity of CD8 T cells to attain the polyfunctional trait of IL-2 production is consistently reduced during both the effector and memory phases. This is further supported by in vitro studies showing that the addition of IL-21 promotes the differentiation of IL-2-producing CD8 T cells. Although the generation of memory CD8 T cells, which are capable of mounting protective recall responses, proceeds independently of IL-21, we demonstrate that IL-21 does function to support secondary responses, especially under competitive conditions. Collectively, these studies highlight the potential roles of IL-21 in determining the quality of CD8 T cell responses postinfection. PMID- 20844202 TI - Ability of IDO to attenuate liver injury in alpha-galactosylceramide-induced hepatitis model. AB - IDO converts tryptophan to l-kynurenine, and it is noted as a relevant molecule in promoting tolerance and suppressing adaptive immunity. In this study, we examined the effect of IDO in alpha-galactosylceramide (alpha-GalCer)-induced hepatitis. The increase in IDO expression in the liver of wild-type (WT) mice administered alpha-GalCer was confirmed by real-time PCR, Western blotting, and IDO immunohistochemical analysis. The serum alanine aminotransferase levels in IDO-knockout (KO) mice after alpha-GalCer injection significantly increased compared with those in WT mice. 1-Methyl-D-tryptophan also exacerbated liver injury in this murine hepatitis model. In alpha-GalCer-induced hepatitis models, TNF-alpha is critical in the development of liver injury. The mRNA expression and protein level of TNF-alpha in the liver from IDO-KO mice were more enhanced compared with those in WT mice. The phenotypes of intrahepatic lymphocytes from WT mice and IDO-KO mice treated with alpha-GalCer were analyzed by flow cytometry, and the numbers of CD49b(+) and CD11b(+) cells were found to have increased in IDO-KO mice. Moreover, as a result of the increase in the number of NK cells and macrophages in the liver of IDO-KO mice injected with alpha-GalCer, TNF-alpha secretion in these mice was greater than that in WT mice. Deficiency of IDO exacerbated liver injury in alpha-GalCer-induced hepatitis. IDO induced by proinflammatory cytokines may decrease the number of TNF-alpha-producing immune cells in the liver. Thus, IDO may suppress overactive immune response in the alpha-GalCer-induced hepatitis model. PMID- 20844203 TI - Langerhans cells serve as immunoregulatory cells by activating NKT cells. AB - Ultraviolet exposure alters the morphology and function of epidermal Langerhans cells (LCs), which play a role in UV-induced immune suppression. It is generally believed that UV exposure triggers the migration of immature LCs from the skin to the draining lymph nodes (LNs), where they induce tolerance. However, because most of the previous studies employed in vitro UV-irradiated LCs, the data generated may not adequately reflect what is happening in vivo. In this study, we isolated migrating LCs from the LNs of UV-irradiated mice and studied their function. We found prolonged LC survival in the LNs of UV-irradiated mice. LCs were necessary for UV-induced immune suppression because no immune suppression was observed in LC-deficient mice. Transferring LCs from UV-irradiated mice into normal recipient animals transferred immune suppression and induced tolerance. We found that LCs colocalized with LN NKT cells. No immune suppression was observed when LCs were transferred from UV-irradiated mice into NKT cell-deficient mice. NKT cells isolated from the LNs of UV-irradiated mice secreted significantly more IL-4 than NKT cells isolated from nonirradiated controls. Injecting the wild-type mice with anti-IL-4 blocked the induction of immune suppression. Our findings indicate that UV exposure activates the migration of mature LC to the skin draining LNs, where they induce immune regulation in vivo by activating NKT cells. PMID- 20844204 TI - CD8 controls T cell cross-reactivity. AB - Estimates of human alphabeta TCR diversity suggest that there are <10(8) different Ag receptors in the naive T cell pool, a number that is dwarfed by the potential number of different antigenic peptide-MHC (pMHC) molecules that could be encountered. Consequently, an extremely high degree of cross-reactivity is essential for effective T cell immunity. Ag recognition by T cells is unique in that it involves a coreceptor that binds at a site distinct from the TCR to facilitate productive engagement of the pMHC. In this study, we show that the CD8 coreceptor controls T cell cross-reactivity for pMHCI Ags, thereby ensuring that the peripheral T cell repertoire is optimally poised to negotiate the competing demands of responsiveness in the face of danger and quiescence in the presence of self. PMID- 20844205 TI - The capacity to induce cross-presentation dictates the success of a TLR7 agonist conjugate vaccine for eliciting cellular immunity. AB - Covalent conjugation of TLR agonists to protein Ags often facilitates the generation of a CD8(+) T cell response. However, mechanisms underlying the efficacy of the conjugate over its unconjugated counterpart have been largely uninvestigated. In this study, we show that conjugation of a TLR7 agonist enhances CD8(+) T cell responses without affecting Ag persistence and with minimal impact on cellular uptake of the Ag in vivo. Instead, the conjugated form induced a robust accumulation of dendritic cells (DCs) in regional lymph nodes. Perhaps more importantly, cross-presentation in DCs was detected only when the Ag was delivered in the conjugated form with the TLR7 agonist. Collectively, these data represent the first demonstration that a TLR agonist-Ag conjugate elicits CD8(+) T cell responses based not on its capacity to induce DC maturation or Ag persistence and uptake, but on the engagement of DC cross-presentation pathways. PMID- 20844206 TI - WASP is activated by phosphatidylinositol-4,5-bisphosphate to restrict synapse growth in a pathway parallel to bone morphogenetic protein signaling. AB - Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P(2)] is a membrane lipid involved in several signaling pathways. However, the role of this lipid in the regulation of synapse growth is ill-defined. Here we identify PI(4,5)P(2) as a gatekeeper of neuromuscular junction (NMJ) size. We show that PI(4,5)P(2) levels in neurons are critical in restricting synaptic growth by localizing and activating presynaptic Wiscott-Aldrich syndrome protein/WASP (WSP). This function of WSP is independent of bone morphogenetic protein (BMP) signaling but is dependent on Tweek, a neuronally expressed protein. Loss of PI(4,5)P(2)-mediated WSP activation results in increased formation of membrane-organizing extension spike protein (Moesin) GFP patches that concentrate at sites of bouton growth. Based on pharmacological and genetic studies, Moesin patches mark polymerized actin accumulations and correlate well with NMJ size. We propose a model in which PI(4,5)P(2)- and WSP mediated signaling at presynaptic termini controls actin-dependent synapse growth in a pathway at least in part in parallel to synaptic BMP signaling. PMID- 20844207 TI - Evolving migration. PMID- 20844209 TI - In vitro susceptibility of the yeast pathogen cryptococcus to fluconazole and other azoles varies with molecular genotype. AB - Cryptococcosis is primarily caused by Cryptococcus neoformans and Cryptococcus gattii. These two pathogenic species each divide into four distinct molecular genotypes. In this study, we examined whether genotype influenced susceptibility to antifungal drugs used to treat cryptococcosis using the broth microdilution method described by the Clinical and Laboratory Standards Institute. C. gattii isolates belonging to molecular genotype VGII had significantly higher MIC values for flucytosine and all azole antifungal agents tested, particularly fluconazole, than isolates of other C. gattii genotypes. In an extended analysis of fluconazole susceptibility, VGII isolates from the north and west of Australia required higher drug levels for inhibition than those from Vancouver Island, Canada. Within C. neoformans, genotype VNII had significantly lower geometric mean MICs for fluconazole than genotype VNI. These results indicate that cryptococcal species, molecular genotype, and region of origin may be important when deciding treatment options for cryptococcosis. PMID- 20844211 TI - Distribution of non-locus of enterocyte effacement pathogenic island-related genes in Escherichia coli carrying eae from patients with diarrhea and healthy individuals in Japan. AB - The relationship to diarrhea of genes located on the pathogenicity islands (PAI) other than the locus of enterocyte effacement (LEE) was investigated. Enteropathogenic Escherichia coli (EPEC), the retention of espC on the EspC PAI, the OI-122 genes (efa1/lifA, nleB), the phylogenetic marker gene yjaA, and the bundle-forming pilus gene bfpA on the EPEC adherence factor (EAF) plasmid were studied. E. coli strains carrying the intimin gene (eae) without the Shiga toxin gene, isolated from patients with diarrhea (n = 83) and healthy individuals (n = 38) in Japan, were evaluated using PCR. The genotypes of eae and espC were identified by heteroduplex mobility assay (HMA). The proportions of strains isolated from individuals with and without diarrhea that carried these genes were as follows: bfpA, 13.3 and 7.9%, respectively; espC, 25.3 and 36.8%; efa1/lifA, 32.5 and 13.2%; nleB, 63.9 and 60.5%; yjaA, 42.2 and 55.3%. Statistical significance (P < 0.05) was achieved only for efa1/lifA. The proportion of strains lacking espC and carrying efa1/lifA was higher for patient-derived strains (30.1%) than for strains from healthy individuals (13.2%), but the difference was not significant. Strains carrying both espC and efa1/lifA were rare (2 strains from patients). Statistical analyses revealed significant relationships between espC and yjaA and between efa1/lifA and nleB, as well as significant inverse relationships between espC and efa1/lifA and between efa1/lifA and yjaA. espC was found in eae HMA types a1, a2, and c2, whereas efa1/lifA was found in types b1, b2, and c1. In addition, 6 polymorphisms of espC were found. The espC, yjaA, efa1/lifA, and nleB genes were mutually dependent, and their distributions were related to eae type, findings that should be considered in future epidemiological studies. PMID- 20844210 TI - Real-time quantitative PCR detection of four human bocaviruses. AB - Human bocavirus (HBoV) was discovered in 2005 and is associated with respiratory tract symptoms in young children. Three additional members of the genus Bocavirus, HBoV2, -3, and -4, were discovered recently from fecal specimens, and early results indicate an association between HBoV2 and gastrointestinal disease. In this study, we present an undifferentiating multiplex real-time quantitative PCR assay for the detection of these novel viruses. Differentiation of the individual bocavirus species can be subsequently achieved with corresponding singleplex PCRs or by sequencing. Both multiplex and singleplex assays were consistently able to detect <=10 copies of HBoV1 to -4 plasmid templates/reaction, with dynamic quantification ranges of 8 logs and 97% to 102% average reaction efficiencies. These new assays were used to screen stool samples from 250 Finnish patients (median age, 40 years) that had been sent for diagnosis of gastrointestinal infection. Four patients (1.6%; median age, 1.1 years) were reproducibly positive for HBoV2, and one patient (0.4%; 18 years of age) was reproducibly positive for HBoV3. The viral DNA loads varied from <10(3) to 10(9) copies/ml of stool extract. None of the stool samples harbored HBoV1 or HBoV4. The highly conserved sequence of the hydrolysis probe used in this assay may provide a flexible future platform for the quantification of additional, hitherto unknown human bocaviruses that might later be discovered. Our results support earlier findings that HBoV2 is a relatively common pathogen in the stools of diarrheic young children, yet does not often occur in the stools of adults. PMID- 20844212 TI - Albendazole stimulates the excretion of strongyloides stercoralis Larvae in stool specimens and enhances sensitivity for diagnosis of strongyloidiasis. AB - We succeeded in stimulation of excretion of Strongyloides stercoralis larvae in stool by oral administration of a single dose of 400 mg albendazole to strongyloidiasis patients. This result overcame the false-negative results of stool examination due to low larval numbers. Stool samples were collected from 152 asymptomatic strongyloidiasis patients in the morning, prior to eating. After breakfast, they were given a dose of 400 mg albendazole, and stool samples were collected the following morning. Agar plate culture (APC), modified formalin ether concentration technique (MFECT), and direct-smear (DS) methods were used to examine stool specimens within 3 h after defecation. The results before and after albendazole was taken were compared. All APCs that were positive became negative after albendazole administration, while MFECT showed a 1.4- to 18.0-fold increase in larval numbers in 97.4% (148/152) of the samples. The DSs were positive in 3 out of 3 smears at a larval number of >=45 larvae per g (lpg) of stool, and in 1or 2 out of 3 smears at a larval number between 35 and 44 lpg. At a larval number of <35 lpg, the DS became negative. Interestingly 90.5% (19/21) of the samples that were negative by all methods before albendazole administration became positive by MFECT after the treatment. Thus, MFECT can be effectively used for diagnosis of strongyloidiasis with prior administration of albendazole to the subject. PMID- 20844213 TI - Carbapenem Heteroresistance in VIM-1-producing Klebsiella pneumoniae isolates belonging to the same clone: consequences for routine susceptibility testing. AB - Susceptibility results with low reproducibility by the same or different methods have been observed for metallo-beta-lactamase (MBL)-producing Enterobacteriaceae. Eighteen VIM-1-producing Klebsiella pneumoniae isolates (one per patient) belonging to a single epidemic clone in our hospital (2005 to 2008) but with different susceptibilities to carbapenems were studied. Imipenem MICs ranged from 8 to >128 mg/liter by standard CLSI microdilution, from <=1 to >8 mg/liter by the semiautomatic Wider system, and from 0.75 to >32 mg/liter by Etest. Meropenem MICs ranged from 0.5 to 128, <=1 to >8, and 0.38 to >32 mg/liter, respectively. Ertapenem MICs by CLSI microdilution and Etest ranged from 1 to 64 and 0.75 to >32 mg/liter, respectively. The rates of essential agreement (+/-1 log(2) dilution) for imipenem and meropenem MICs between the Wider system and the reference microdilution method were 45% and 49%, respectively. Those between Etest and the reference microdilution method for imipenem, meropenem, and ertapenem MICs were 33%, 67%, and 84%. The rates of very major errors for the Wider system and Etest were 33% and 28% for imipenem and 25% and 75% for meropenem, respectively. Low MIC reproducibility was observed even when the same inoculum was used (differences up to 4-fold dilutions). Heteroresistance was suspected due to the presence of colonies in the Etest inhibition zone. It was confirmed by population analysis profiles of 4 isolates displaying different imipenem MICs, with the exception of an OmpK36-porin-deficient isolate that homogeneously expressed carbapenem resistance (MIC, >128 mg/liter). Low carbapenem MIC reproducibility could be due to the presence of resistant subpopulations and variable expression of the resistance mechanisms. Since carbapenem MICs are not good markers of MBL production, reliable and reproducible phenotypic methods are needed to detect the presence of this mechanism. PMID- 20844214 TI - Hepatitis C virus genotyping using an oligonucleotide microarray based on the NS5B sequence. AB - The genotype of the hepatitis C virus (HCV) is essential for determining treatment duration in clinical practice and for epidemiological and clinical studies. Currently, few genotyping assays that determine the HCV subtype are available. This report describes a microarray-based molecular technique for identifying the HCV genotype and subtype. It uses low-density hydrogel-based biochips containing genotype- and subtype-specific oligonucleotides based on the sequences of the NS5B region of the HCV genome. The biochip contains 120 oligonucleotides that identify genotypes 1 to 6 and 36 (1a, 1b, 1c, 1d, 1e, 2a, 2b, 2c, 2d, 2i, 2j, 2k, 2l, 2m, 3a, 3b, 3k, 4a, 4c, 4d, 4f, 4h, 4i, 4k, 4n, 4o, 4p, 4r, 4t, 5a, 6a, 6b, 6d, 6g, 6h, and 6k) subtypes. The procedure included amplification of a 380-nucleotide (nt) fragment of NS5B and its hybridization on the biochip. Tests on 345 HCV-positive samples showed that the assay agreed with NS5B sequencing 100% for the genotype and 99.7% for the subtype. The hybridization on the microarray and the NS5B sequence were in 100% agreement for identifying the most common subtypes, 1a, 1b, 4a, 4d, and 3a. This approach is a promising tool for HCV genotyping, especially for implementing the new anti-HCV drugs that require accurate identification of clinically relevant subtypes. PMID- 20844215 TI - Fast duplex one-step reverse transcriptase PCR for rapid differential detection of West Nile and Japanese encephalitis viruses. AB - The aim of this study was to develop a highly sensitive and specific one-step duplex reverse transcriptase PCR (RT-PCR) assay for the simultaneous and differential detection of West Nile (WNV) and Japanese encephalitis (JEV) viruses. The bioinformatic analysis of published sequences of WNV and JEV revealed conserved regions not targeted by previously reported primers. A total of 13 primers were designed based on these regions to detect all of the WNV and JEV lineages and to discriminate between the two viruses by the generation of 482 and 241-bp cDNA products, respectively. The results indicate that single-tube duplex PCR using these primers is a useful technique for the detection and differentiation of WNV and JEV in plasma or brain tissue. The novel duplex RT-PCR described in this study enables the early diagnosis of these two encephalitic flaviviruses. In addition, this technique may be useful as part of a testing regimen for human patients, horses, and other susceptible animal species, as it is rapid (less than 3.5 h from RNA extraction), sensitive, and specific, and it may enable the differential diagnosis of clinical samples. PMID- 20844216 TI - Specific detection of Rinderpest virus by real-time reverse transcription-PCR in preclinical and clinical samples from experimentally infected cattle. AB - A highly sensitive detection test for Rinderpest virus (RPV), based on a real time reverse transcription-PCR (rRT-PCR)system, was developed. Five different RPV genomic targets were examined, and one was selected and optimized to detect viral RNA in infected tissue culture fluid with a level of detection ranging from 0.59 to 87.5 50% tissue culture infectious doses (TCID(50)) per reaction depending on the viral isolate. The strain sensitivity of the test was validated on 16 RPV strains belonging to all three phylogenetic branches described for RPV. No cross reactivity was detected with closely related peste des petit ruminants or with symptomatically similar viruses, including all seven serotypes of foot-and-mouth disease virus, two serotypes of vesicular stomatitis virus, bluetongue virus, and bovine herpes virus type 2. In samples from experimentally infected cattle, our real-time RT-PCR test was significantly more sensitive than the gold standard test of virus isolation, allowing the detection of the disease 2 to 4 days prior to the appearance of clinical signs. The comparison of clinical samples with putative diagnostic value from live animals showed that conjunctival swabs and blood buffy coat were the samples of choice for epidemiological surveillance, while lymph nodes performed the best as postmortem specimens. This portable and rapid real-time RT-PCR has the capability of the preclinical detection of RPV and provides differential diagnosis from look-alike diseases of cattle. As RPV is declared globally eradicated, this test provides an important rapid virus detection tool that does not require the use of infectious virus and allows the processing of a large number of samples. PMID- 20844217 TI - Multilocus sequence typing identifies evidence for recombination and two distinct lineages of Corynebacterium diphtheriae. AB - We describe the development of a multilocus sequence typing (MLST) scheme for Corynebacterium diphtheriae, the causative agent of the potentially fatal upper respiratory disease diphtheria. Global changes in diphtheria epidemiology are highlighted by the recent epidemic in the former Soviet Union (FSU) and also by the emergence of nontoxigenic strains causing atypical disease. Although numerous techniques have been developed to characterize C. diphtheriae, their use is hindered by limited portability and, in some instances, poor reproducibility. One hundred fifty isolates from 18 countries and encompassing a period of 50 years were analyzed by multilocus sequence typing (MLST). Strain discrimination was in accordance with previous ribotyping data, and clonal complexes associated with disease outbreaks were clearly identified by MLST. The data produced are portable, reproducible, and unambiguous. The MLST scheme described provides a valuable tool for monitoring and characterizing endemic and epidemic C. diphtheriae strains. Furthermore, multilocus sequence analysis of the nucleotide data reveals two distinct lineages within the population of C. diphtheriae examined, one of which is composed exclusively of biotype belfanti isolates and the other of multiple biotypes. PMID- 20844218 TI - Phylogeny and identification of Nocardia species on the basis of multilocus sequence analysis. AB - Nocardia species identification is difficult due to a complex and rapidly changing taxonomy, the failure of 16S rRNA and cellular fatty acid analysis to discriminate many species, and the unreliability of biochemical testing. Here, Nocardia species identification was achieved through multilocus sequence analysis (MLSA) of gyrase B of the beta subunit of DNA topoisomerase (gyrB), 16S rRNA (16S), subunit A of SecA preprotein translocase (secA1), the 65-kDa heat shock protein (hsp65), and RNA polymerase (rpoB) applied to 190 clinical, 36 type, and 11 reference strains. Phylogenetic analysis resolved 30 sequence clusters with high (>85%) bootstrap support. Since most clusters contained a single type strain and the analysis corroborated current knowledge of Nocardia taxonomy, the sequence clusters were equated with species clusters and MLSA was deemed appropriate for species identification. By comparison, single-locus analysis was inadequate because it failed to resolve species clusters, partly due to the presence of foreign alleles in 22.1% of isolates. While MLSA identified the species of the majority (71.3%) of strains, it also identified clusters that may correspond to new species. The correlation of the identities by MLSA with those determined on the basis of microscopic examination, biochemical testing, and fatty acid analysis was 95%; however, MLSA was more discriminatory. Nocardia cyriacigeorgica (21.58%) and N. farcinica (14.74%) were the most frequently encountered species among clinical isolates. In summary, five-locus MLSA is a reliable method of elucidating taxonomic data to inform Nocardia species identification; however, three-locus (gyrB-16S-secA1) or four-locus (gyrB-16S secA1-hsp65) MLSA was nearly as reliable, correctly identifying 98.5% and 99.5% of isolates, respectively, and would be more feasible for routine use in a clinical reference microbiology laboratory. PMID- 20844219 TI - Rapid differentiation of Mycobacterium tuberculosis and M. bovis by high resolution melt curve analysis. AB - Identification and characterization of the Mycobacterium tuberculosis strains are important for clinical and therapeutic management of tuberculosis. Real-time PCR with a high-resolution melt assay was found to improve the diagnostic process. The assay includes differentiation between M. tuberculosis and Mycobacterium bovis based on one single-nucleotide polymorphism (SNP) in the narGHJI and oxyR genes and determination of M. bovis based on the region of differences 1 (RD1). This assay correctly identified the 7 tested Mycobacterium reference strains and 52 clinical samples with a sensitivity of 2 pg DNA. This assay will help in prescribing adequate treatment and monitoring disease dynamics. PMID- 20844220 TI - Intercontinental dissemination of IMP-13-producing Pseudomonas aeruginosa belonging in sequence type 621. PMID- 20844221 TI - Multilocus microsatellite markers for molecular typing of Candida glabrata: application to analysis of genetic relationships between bloodstream and digestive system isolates. AB - Candida glabrata has emerged as the second most common etiologic agent, after Candida albicans, of superficial and invasive candidiasis in adults. Strain typing is essential for epidemiological investigation, but easy-to-use and reliable typing methods are still lacking. We report the use of a multilocus microsatellite typing method with a set of eight markers on a panel of 180 strains, including 136 blood isolates from hospitalized patients and 34 digestive tract isolates from nonhospitalized patients. A total of 44 different alleles were observed, generating 87 distinct genotypes. In addition to perfect reproducibility, typing ability, and stability, the method had a discriminatory power calculated at 0.97 when all 8 markers were associated, making it suitable for tracing strains. In addition, it is shown that digestive tract isolates differed from blood culture isolates by exhibiting a higher genotypic diversity associated with different allelic frequencies and preferentially did not group in clonal complexes (CCs). The demonstration of the occurrence of microevolution in digestive strains supports the idea that C. glabrata can be a persistent commensal of the human gut. PMID- 20844222 TI - Global proficiency study of human papillomavirus genotyping. AB - Internationally comparable quality assurance of Human Papillomavirus (HPV) DNA detection and typing methods is essential for evaluation of HPV vaccines and effective monitoring and implementation of HPV vaccination programs. Therefore, the World Health Organization (WHO) HPV Laboratory Network (LabNet) designed an international proficiency study. Following announcement at the WHO website, the responding laboratories performed HPV typing using one or more of their usual assays on 43 coded samples composed of titration series of purified plasmids of 16 HPV types (HPV6, -11, -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, 59, -66, and -68). Detection of at least 50 IU of HPV16 or HPV18 DNA and of 500 genome equivalents (GE) of the other 14 HPV types (in samples with single and multiple HPV types) was considered proficient. Fifty-four laboratories worldwide submitted a total of 84 data sets. More than 21 HPV-genotyping assays were used. Commonly used methods were Linear Array, Lineblot, InnoLiPa, Clinical Array, type specific real-time PCR, PCR-Luminex and microarray assays. The major oncogenic HPV types (HPV16 and -18) were detected in 89.7% (70/78) and 92.2% (71/77) of the data sets, respectively. HPV types 56, 59, and 68 were the least commonly detected types (in less than 80% of the data sets). Twenty-eight data sets reported multiple false-positive results and were considered nonproficient. In conclusion, we found that international proficiency studies, traceable to international standards, allow standardized quality assurance for different HPV typing assays and enable the comparison of data generated from different laboratories worldwide. PMID- 20844223 TI - Prevalence and diversity of Borrelia species in ticks that have bitten humans in Sweden. AB - Members of the genus Borrelia are among the most common infectious agents causing tick-borne disease in humans worldwide. Here, we developed a Light Upon eXtension (LUX) real-time PCR assay that can detect and quantify Borrelia species in ticks that have fed on humans, and we applied the assay to 399 such ticks. Borrelia PCR positive ticks were identified to species level by sequencing the products of conventional PCR performed using Borrelia group-specific primers. There was a 19% prevalence of Borrelia spp. in the detached ticks, and the number of spirochetes per Borrelia PCR-positive tick ranged from 2.0 * 10(2) to 4.9 * 10(5), with a median of 7.8 * 10(3) spirochetes. Adult ticks had a significantly larger number of spirochetes, with a median of 8.4 * 10(3) compared to the median of nymphs of 4.4 * 10(3). [corrected] Adult ticks also exhibited a higher prevalence of Borrelia (33%) than nymphs (14%). Among the identified species, Borrelia afzelii was found to predominate (61%) and was followed by B. garinii (23%), B. valaisiana (13%), B. burgdorferi sensu stricto (1%), B. lusitaniae (1%), and B. miyamotoi-like (1%). Also, 3% of the ticks were coinfected with multiple strains of B. afzelii. Notably, this is the first report of B. lusitaniae being detected in ticks in Sweden. Our LUX real-time PCR assay proved to be more sensitive than a corresponding TaqMan assay. In conclusion, the novel LUX real-time PCR method is a rapid and sensitive tool for detection and quantification of Borrelia spp. in ticks. PMID- 20844224 TI - Changing epidemiology of methicillin-resistant Staphylococcus aureus in Iceland from 2000 to 2008: a challenge to current guidelines. AB - The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) is continuously changing. Iceland has a low incidence of MRSA. A "search and destroy" policy (screening patients with defined risk factors and attempting eradication in carriers) has been implemented since 1991. Clinical and microbiological data of all MRSA patients from the years 2000 to 2008 were collected prospectively. Isolates were characterized by pulsed-field gel electrophoresis (PFGE), sequencing of the repeat region of the Staphylococcus protein A gene (spa typing), staphylococcal cassette chromosome mec (SCCmec) typing, and screening for the Panton-Valentine leukocidin (PVL) gene. Two hundred twenty-six infected (60%) or colonized (40%) individuals were detected (annual incidence 2.5 to 16/100,000). From 2000 to 2003, two health care-associated outbreaks dominated (spa types t037 and t2802), which were successfully controlled with extensive infection control measures. After 2004, an increasing number of community-associated (CA) cases without relation to the health care system occurred. A great variety of clones (40 PFGE types and 49 spa types) were found, reflecting an influx of MRSA from abroad. The USA300 and Southwest Pacific (SWP) clones were common. SCCmec type IV was most common (72%), and 38% of the isolates were PVL positive. The incidence of MRSA in Iceland has increased since 1999 but remains low and has been stable in the last years. The search and destroy policy was effective to control MRSA in the health care setting. However, MRSA in Iceland is now shifting into the community, challenging the current Icelandic guidelines, which are tailored to the health care system. PMID- 20844225 TI - Lactobacillus rhamnosus meningitis following recurrent episodes of bacteremia in a child undergoing allogeneic hematopoietic stem cell transplantation. AB - We report a case of meningitis due to Lactobacillus rhamnosus in a child undergoing allogeneic hematopoietic stem cell transplantation for acute leukemia. Four episodes of bacteremia involving strains with pulsotypes identical to that of the cerebrospinal fluid isolate preceded meningitis. After several courses of clindamycin, no relapse occurred during the patient follow-up. PMID- 20844226 TI - Mass spectrometry biotyper system identifies enteric bacterial pathogens directly from colonies grown on selective stool culture media. AB - We evaluated the performance and cost-effectiveness of a matrix-assisted laser desorption ionization time-of-flight mass spectrometry-based Biotyper system for the routine identification of common enteric bacterial pathogens seen in middle Tennessee from suspicious colonies grown on selective stool culture media. A total of 304 suspicious colonies were selected and further identified from 605 stool specimens. The suspicious colonies were analyzed by the Biotyper system, and the results were compared to those from routine phenotypic methods, which identified 22 Salmonella species, 39 Shigella species, 3 enterohemorrhagic Escherichia coli (EHEC) isolates, 2 Yersinia enterocolitica isolates, 2 Campylobacter species, and 236 gastrointestinal normal flora isolates. The Biotyper system correctly identified the Salmonella species, Yersinia enterocolitica, and Campylobacter species but failed to distinguish the Shigella species and EHEC isolates from E. coli. Among the 236 normal flora isolates, 233 (98.7%) and 228 (96.6%) agreed at the genus and species levels, respectively, between the phenotypic and Biotyper methods. Organism identification scores were insignificantly different between colonies directly from selective media and subsequently from pure subculture. The entire Biotyper identification procedure, from smear preparation to final result reporting, can be completed within 30 min. The Biotyper system provides a rapid and simple screening tool for identifying many, but not all, suspicious colonies grown on selective media within 24 h after inoculation, which shortens test turnaround time by 2 to 3 days. PMID- 20844227 TI - Snapshot of Mycobacterium bovis and Mycobacterium caprae infections in livestock in an area with a low incidence of bovine tuberculosis. PMID- 20844228 TI - Unique hepatitis B virus subgenotype in a primitive tribal community in eastern India. AB - Hepatitis B virus (HBV) strains isolated from members of the primitive Paharia ethnic community of Eastern India were studied to gain insight into the genetic diversity and evolution of the virus. The Paharia tribe has remained quite separate from the rest of the Indians and differs culturally, genetically, and linguistically from the mainstream East Indian population, whose HBV strains were previously characterized. Full-length HBV DNA was PCR amplified, cloned, and sequenced. Phylogenetic relationships between the tribal sequences and reference sequences from the mainstream population were assessed, and divergence times of subgenotypes of HBV genotype D were estimated. HBV was found in 2% of the Paharias participating in the study. A predominance of hepatitis B e antigen negative infection (73%) was observed among the Paharias, and the genome sequences of the HBV strains exhibited relative homogeneity, with a very low prevalence of mutations. The novel feature of Paharia HBV was the exclusive presence of the D5 subgenotype, which was recently identified in Eastern India. Analysis of the four open reading frames (ORFs) of these tribal HBV D5 sequences and comparison with previously reported D1 to D7 sequences enabled the identification of 27 specific amino acid residues, including 6 unique ones, that could be considered D5 signatures. The estimated divergence times among subgenotypes D1 to D5 suggest that D5 was the first to diverge and hence is the most ancient of the D subgenotypes. The presence of a specific, ancient subgenotype of HBV within an ethnically primitive, endogamous population highlights the importance of studies of HBV genetics in well-separated human populations to understand viral transmission between communities and genome evolution. PMID- 20844229 TI - Detection of oseltamivir resistance during treatment of 2009 H1N1 influenza virus infection in immunocompromised patients: utility of cycle threshold values of qualitative real-time reverse transcriptase PCR. AB - Two immunocompromised patients with 2009 H1N1 influenza pneumonia had viral shedding for over 5 weeks despite therapy with oseltamivir. Declining or persistently low cycle threshold values noted on serial qualitative real-time reverse transcriptase PCR (rRT-PCR) of respiratory specimens implied increasing viral load and probable drug resistance. Oseltamivir resistance was later confirmed by pyrosequencing. PMID- 20844230 TI - Evaluation of three influenza A and B real-time reverse transcription-PCR assays and a new 2009 H1N1 assay for detection of influenza viruses. AB - The performance characteristics of three real-time influenza A/B virus reverse transcription-PCR (RT-PCR) assays and two real-time 2009 H1N1 RT-PCR assays were evaluated using previously characterized clinical specimens. A total of 150 respiratory specimens from children (30 influenza A/H1 virus-, 30 influenza A/H3 virus-, 30 2009 H1N1-, and 30 influenza B virus-positive specimens and 30 influenza virus-negative specimens) were tested with the CDC influenza A/B PCR (CDC), ProFlu(+) multiplex real-time RT-PCR assay (ProFlu(+)), and MGB Alert Influenza A/B & RSV RUO (MGB) assays. A second set of 157 respiratory specimens (100 2009 H1N1-, 22 seasonal influenza A/H1-, and 15 seasonal influenza A/H3 positive specimens and 20 influenza-negative specimens) were tested with a new laboratory-developed 2009 H1N1 RT-PCR and the CDC 2009 H1N1 assay. The overall sensitivities of the CDC, ProFlu(+), and MGB assays for detection of influenza A and B viruses were 100%, 98.3%, and 94%, respectively. The ProFlu(+) assay failed to detect one influenza A/H1 virus-positive specimen and yielded one unresolved result with another influenza A/H1 virus-positive specimen. The MGB assay detected 84/87 (96.5%) of influenza A and B viruses and 26/30 (86.6%) of 2009 H1N1 viruses. The new laboratory-developed 2009 H1N1 RT-PCR assay detected 100/100 (100%) 2009 H1N1 virus-positive specimens, while the CDC SW Inf A and SW H1 PCR assays failed to detect one and three low-positive 2009 H1N1-positive specimens, respectively. The CDC influenza A/B virus assay and the newly developed 2009 H1N1 RT-PCR assay with an internal control can be set up in two separate reactions in the same assay for routine clinical testing to detect influenza A and B viruses and to specifically identify the 2009 H1N1 influenza virus. PMID- 20844231 TI - High-resolution melting curve analysis for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis clinical isolates. AB - We evaluated high-resolution melting (HRM) curve analysis as a tool for detecting rifampin (RIF) and isoniazid (INH) resistance in Mycobacterium tuberculosis in an accurate, affordable, and rapid manner. Two hundred seventeen M. tuberculosis clinical isolates of known resistance phenotype were used. Twenty-nine known rpoB mutant DNAs, including rare mutations, were also included. Four pairs of primers were designed: rpoB-F/R (for codons 516 to 539 of rpoB), rpoB-516F/R (for codons 508 to 536 of rpoB), katG-F/R (for the codon 315 region of katG), and inhA-F/R (for the nucleotide substitution of C to T at position -15 of inhA). An HRM curve was generated for each isolate after real-time PCR differentiated the mutant from the wild-type strains. DNA sequencing of the target regions was performed to confirm the results of the HRM curve analysis. All but one of the 73 RIF resistant (RIF-R) strains and all 124 RIF-susceptible (RIF-S) isolates were correctly identified by HRM curve analysis of rpoB. Twenty-seven of 29 known rpoB mutants were detected. In HRM curve analysis of katG and inhA, 90 INH-R strains that harbored katG or inhA mutations, or both, and all INH-S strains were correctly identified. Ten phenotypically INH-R strains not harboring katG or inhA mutations were not detected. The HRM curve analysis will be a useful method for detection of RIF and INH resistance in M. tuberculosis in a rapid, accurate, simple, and cost-effective manner. PMID- 20844232 TI - Better detection of Staphylococcus aureus nasal carriage by use of nylon flocked swabs. AB - Flocked swabs (Copan) were compared to rayon swabs (Copan) for the nasal detection of Staphylococcus aureus in 90 healthy volunteers sampled sequentially during a 5-week period. The use of flocked swabs improved the number of nasal carriers (P = 0.026), the number of positive specimens (P = 0.01), and the quantity of bacteria in positive samples (P = 0.004). PMID- 20844233 TI - Eltrombopag for the treatment of the inherited thrombocytopenia deriving from MYH9 mutations. AB - Platelet transfusion is currently the primary medical treatment for reducing thrombocytopenia in patients with inherited thrombocytopenias. To evaluate whether stimulating megakaryopoiesis could increase platelet count in these conditions, we treated patients with a severe thrombocytopenia induced by MYH9 mutations (MYH9-related disease) with a nonpeptide thrombopoietin receptor agonist, eltrombopag. Twelve adult patients with MYH9-RD and platelet counts of less than 50 * 10(9)/L received 50 mg of eltrombopag orally per day for 3 weeks. Patients who achieved a platelet count higher than 150 * 10(9)/L stopped therapy, those with 100 to 150 platelets * 10(9)/L continued treatment at the same eltrombopag dose for 3 additional weeks, while those with less than 100 platelets * 10(9)/L increased the eltrombopag dose to 75 mg for 3 weeks. Major responses (platelet count of at least 100 * 10(9)/L or 3 times the baseline value) were obtained in 8 patients, minor responses (platelet counts at least twice the baseline value) in 3. One patient did not respond. Bleeding tendency disappeared in 8 of 10 patients with bleeding symptoms at baseline. Mild adverse events were reported in 2 patients. The availability of thrombopoietin mimetics opened new prospects in the treatment of inherited thrombocytopenias. This study is registered at www.clinicaltrials.gov as NCT01133860 (European Union Drug Regulating Authorities Clinical Trials number 2008-001903-42). PMID- 20844234 TI - Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes. AB - In this report, we investigated the mechanism responsible for synergistic induction of myeloma cell apoptosis induced by the combination of tipifarnib and bortezomib. Immunofluorescence studies revealed that bortezomib alone resulted in an accumulation of puncta of ubiquitinated proteins that was further enhanced by the addition of tipifarnib. These data suggest inhibition of the degradation of bortezomib-induced aggresomes; and consistent with this possibility, we also observed an increase in p62SQSTM1 in cells treated with the combination. However, autophagy in these cells appears to be normal as LC3BII is present, and autophagic flux appears to be unaffected as demonstrated by the addition of bafilomycin A1. Together, these data demonstrate that tipifarnib synergizes with bortezomib by inducing protein accumulation as a result of the uncoupling of the aggresome and autophagy pathways. PMID- 20844235 TI - Erythropoietin stimulates spleen BMP4-dependent stress erythropoiesis and partially corrects anemia in a mouse model of generalized inflammation. AB - Mouse bone marrow erythropoiesis is homeostatic, whereas after acute anemia, bone morphogenetic protein 4 (BMP4)-dependent stress erythropoiesis develops in the spleen. The aim of this work was to compare spleen stress erythropoiesis and bone marrow erythropoiesis in a mouse model of zymosan-induced generalized inflammation, which induces long-lasting anemia and to evaluate the ability of erythropoietin (Epo) injections to correct anemia in this setting. The effects of zymosan and/or Epo injections on erythroid precursor maturation and apoptosis, serum interferon-gamma levels, hematologic parameters, and spleen BMP4 expression were analyzed, as well as the effect of zymosan on red blood cell half-life. We found that bone marrow erythropoiesis is suppressed by inflammation and does not respond to Epo administration, despite repression of erythroblast apoptosis. On the contrary, a robust erythropoietic response takes place in the spleen after Epo injections in both control and zymosan-induced generalized inflammation mice. This specific response implies Epo-mediated induction of BMP4 expression by F4/80(+) spleen macrophages, proliferation of stress burst-forming units erythroid, and increased number of spleen erythroblasts. It allows only partial recovery of anemia, probably because of peripheral destruction of mature red cells. It is not clear whether similar BMP4-dependent stress erythropoiesis can occur in human bone marrow after Epo injections. PMID- 20844236 TI - HGAL, a germinal center specific protein, decreases lymphoma cell motility by modulation of the RhoA signaling pathway. AB - HGAL is a germinal center (GC)-specific gene that negatively regulates lymphocyte motility and whose expression predicts improved survival of patients with diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). We demonstrate that HGAL serves as a regulator of the RhoA signaling pathway. HGAL enhances activation of RhoA and its down-stream effectors by a novel mechanism - direct binding to the catalytic DH-domain of the RhoA-specific guanine nucleotide exchange factors (RhoGEFs) PDZ-RhoGEF and LARG that stimulate the GDP-GTP exchange rate of RhoA. We delineate the structural domain of HGAL that mediates its interaction with the PDZ-RhoGEF protein. These observations reveal a novel molecular mechanism underlying the inhibitory effects of GC-specific HGAL protein on the motility of GC-derived lymphoma cells. This mechanism may underlie the limited dissemination and better outcome of patients with HGAL-expressing DLBCL and cHL. PMID- 20844237 TI - 8-Aminoadenosine inhibits Akt/mTOR and Erk signaling in mantle cell lymphoma. AB - 8-Aminoadenosine (8-NH(2)-Ado), a ribosyl nucleoside analog, in preclinical models of multiple myeloma inhibits phosphorylation of proteins in multiple growth and survival pathways, including Akt. Given that Akt controls the activity of mammalian target of rapamycin (mTOR), we hypothesized that 8-NH(2)-Ado would be active in mantle cell lymphoma (MCL), a hematological malignancy clinically responsive to mTOR inhibitors. In the current study, the preclinical efficacy of 8-NH(2)-Ado and its resulting effects on Akt/mTOR and extracellular-signal regulated kinase signaling were evaluated using 4 MCL cell lines, primary MCL cells, and normal lymphocytes from healthy donors. For all MCL cell lines, 8 NH(2)-Ado inhibited growth and promoted cell death as shown by reduction of thymidine incorporation, loss of mitochondrial membrane potential, and poly (adenosine diphosphate-ribose) polymerase cleavage. The efficacy of 8-NH(2)-Ado was highly associated with intracellular accumulation of 8-NH(2)-adenosine triphosphate (ATP) and loss of endogenous ATP. Formation of 8-NH(2)-ATP was also associated with inhibition of transcription and translation accompanied by loss of phosphorylated (p-)Akt, p-mTOR, p-Erk1/2, p-phosphoprotein (p)38, p-S6, and p 4E-binding protein 1. While normal lymphocytes accumulated 8-NH(2)-ATP but maintained their viability with 8-NH(2)-Ado treatment, primary lymphoma cells accumulated higher concentrations of 8-NH(2)-ATP, had increased loss of ATP, and underwent apoptosis. We conclude that 8-NH(2)-Ado is efficacious in preclinical models of MCL and inhibits signaling of Akt/mTOR and Erk pathways. PMID- 20844239 TI - A mechanistic rationale for combining alemtuzumab and rituximab in the treatment of ALL. AB - B-lineage acute lymphoblastic leukemia (ALL) may express CD52 and CD20. Alemtuzumab (ALM) and rituximab (RTX) are therapeutic antibodies directed against CD52 and CD20, respectively, but showed limited activity against ALL in clinical trials. The mechanisms for the impaired responses remained unclear. We studied expression of CD52 and CD20 on ALL cells and found that most cases coexpressed CD52 and CD20. However, distinct CD52-negative (CD52(-)) subpopulations were detected in most cases as the result of defective glycophosphatidyl-inositol anchoring. Although ALM efficiently eradicated CD52-positive (CD52(+)) cells in NOD/scid mice engrafted with primary human ALL, CD52(-) subclones escaped therapy. In the same model, RTX showed limited activity resulting from occurrence of CD20 down-modulation. However, CD52(-) cells concurrently lacked the glycophosphatidyl-inositol-anchored complement regulators CD55 and CD59 and showed increased susceptibility to RTX-mediated complement-dependent cytotoxicity in vitro. At the same time, ALM was shown to inhibit down-modulation of CD20 in response to RTX by depleting the trogocytic capacity of phagocytic cells. Probably because of these complementary mechanisms, combined administration of ALM and RTX induced complete responses in vivo. Based on these data, we propose a mechanistic rationale for combined application of RTX and ALM in ALL. PMID- 20844238 TI - Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution. AB - To better understand the tissue iron overload and anemia previously reported in a human patient and mice that lack heme oxygenase-1 (HO-1), we studied iron distribution and pathology in HO-1(Hmox1)(-/-) mice. We found that resident splenic and liver macrophages were mostly absent in HO-1(-/-) mice. Erythrophagocytosis caused the death of HO-1(-/-) macrophages in in vitro experiments, supporting the hypothesis that HO-1(-/-) macrophages died of exposure to heme released on erythrophagocytosis. Rupture of HO-1(-/-) macrophages in vivo and release of nonmetabolized heme probably caused tissue inflammation. In the spleen, initial splenic enlargement progressed to red pulp fibrosis, atrophy, and functional hyposplenism in older mice, recapitulating the asplenia of an HO-1-deficient patient. We postulate that the failure of tissue macrophages to remove senescent erythrocytes led to intravascular hemolysis and increased expression of the heme and hemoglobin scavenger proteins, hemopexin and haptoglobin. Lack of macrophages expressing the haptoglobin receptor, CD163, diminished the ability of haptoglobin to neutralize circulating hemoglobin, and iron overload occurred in kidney proximal tubules, which were able to catabolize heme with HO-2. Thus, in HO-1(-/-) mammals, the reduced function and viability of erythrophagocytosing macrophages are the main causes of tissue damage and iron redistribution. PMID- 20844240 TI - Expression and signaling of the tyrosine kinase FGFR2b/KGFR regulates phagocytosis and melanosome uptake in human keratinocytes. AB - Membrane and actin cytoskeleton dynamics during phagocytosis can be triggered and amplified by the signal transduction of receptor tyrosine kinases. The epidermal keratinocytes appear to use the phagocytic mechanism of uptake to ingest melanosomes released by the melanocytes and play a pivotal role in the transfer process. We have previously demonstrated that the keratinocyte growth factor KGF/FGF7 promotes the melanosome uptake through activation of its receptor tyrosine kinase FGFR2b/KGFR. The aim of the present study was to investigate the contribution of KGFR expression, activation, and signaling in regulating the phagocytic process and the melanosome transfer. Phagocytosis was analyzed in vitro using fluorescent latex beads on human keratinocytes induced to differentiate. Melanosome transfer was investigated in keratinocyte-melanocyte cocultures. KGFR depletion by small interfering RNA microinjection and overexpression by transfection of wild type or defective mutant KGFR were performed to demonstrate the direct effect of the receptor on phagocytosis and melanosome transfer. Colocalization of the phagocytosed beads with the internalized receptors in phagolysosomes was analyzed by optical sectioning and 3 dimensional reconstruction. KGFR ligands triggered phagocytosis and melanosome transfer in differentiated keratinocytes, and receptor kinase activity and signaling were required for these effects, suggesting that FGFR2b/KGFR expression/activity and PLCgamma signaling pathway play crucial roles in phagocytosis. PMID- 20844241 TI - Effects of NOD-like receptors in human B lymphocytes and crosstalk between NOD1/NOD2 and Toll-like receptors. AB - NLRs are recently discovered PRRs detecting substructures of peptidoglycans and triggering innate immunity. NLRs are expressed in several cell types, but the presence in human B lymphocytes is still unknown. This study aimed to investigate expression and function of NLRs in human B lymphocytes. B cells were isolated and analyzed for mRNA and protein expression. The functional responsiveness of NOD1 and NOD2 was investigated upon stimulation with the cognate ligands, with or without stimulation via IgM/IgD/CD40 and/or selected TLR agonists. A differential expression of NLRs was demonstrated in blood-derived and tonsillar B cells, whereas no variations were found among naive, germinal center, or memory B cells. Stimulation with the ligands alone did not induce B cell activation. However, upon concomitant BCR triggering, an increase in proliferation was seen, together with an induction of cell surface markers (CD27, CD69, CD71, CD80, CD86, and CD95) and prolonged survival. Peripheral B cells were activated by NOD1 and NOD2 ligands, whereas tonsil-derived B cells responded solely to NOD1. In contrast, costimulation with CD40L failed to induce activation. Additionally, it was found that NLR ligands could enhance TLR-induced proliferation of B cells. The present study demonstrates expression of functional NLRs in human B cells. We show that NOD1 and NOD2 have the ability to augment the BCR-induced activation independently of physical T cell help. Hence, NLRs represent a new pathway for B cell activation and a potentially important host defense system against bacterial infections. PMID- 20844242 TI - Does antiplatelet therapy at the time of intracerebral hemorrhage bode poor outcome? PMID- 20844243 TI - Neurodegenerative basis of age-related cognitive decline. AB - OBJECTIVE: To assess the contribution of dementia-related neuropathologic lesions to age-related and disease-related change in cognitive function. METHODS: A total of 354 Catholic nuns, priests, and brothers had annual clinical evaluations for up to 13 years, died, and underwent brain autopsy. The clinical evaluations included detailed testing of cognitive function from which previously established composite measures of global cognition and specific cognitive functions were derived. As part of a uniform neuropathologic evaluation, the density of neurofibrillary tangles was summarized in a composite measure and the presence of Lewy bodies and gross and microscopic cerebral infarction was noted. RESULTS: During follow-up, rate of global cognitive decline was gradual at first and then more than quadrupled in the last 4 to 5 years of life consistent with the onset of progressive dementia. Neurofibrillary tangles, cerebral infarction, and neocortical Lewy bodies all contributed to gradual age-related cognitive decline and little age-related decline was evident in the absence of these lesions. Neurofibrillary tangles and neocortical Lewy bodies contributed to precipitous disease-related cognitive decline, but substantial disease-related decline was evident even in the absence of these lesions. CONCLUSION: Mild age-related decline in cognitive function is mainly due to the neuropathologic lesions traditionally associated with dementia. PMID- 20844244 TI - Role of epoxyeicosatrienoic acids as autocrine metabolites in glutamate-mediated K+ signaling in perivascular astrocytes. AB - Epoxyeicosatrienoic acids (EETs), synthesized and released by astrocytes in response to glutamate, are known to play a pivotal role in neurovascular coupling. In vascular smooth muscle cells (VSMC), EETs activate large conductance, Ca(2+)-activated K(+) (BK) channels resulting in hyperpolarization and vasodilation. However, the functional role and mechanism of action for glial derived EETs are still to be determined. In this study, we evaluated the effect of the synthetic EET analog 11-nonyloxy-undec-8(Z)-enoic acid (NUD-GA) on outward K(+) currents mediated by calcium-activated K(+) channels. Addition of NUD-GA significantly increased intracellular Ca(2+) and outward K(+) currents in perivascular astrocytes. NUD-GA-induced currents were significantly inhibited by BK channel blockers paxilline and tetraethylammonium (TEA) (23.4 +/- 2.4%; P < 0.0005). Similarly, NUD-GA-induced currents were also significantly inhibited in the presence of the small-conductance Ca(2+)-activated K(+) channel inhibitor apamin along with a combination of blockers against glutamate receptors (12.8 +/- 2.70%; P < 0.05). No changes in outward currents were observed in the presence of the channel blocker for intermediate-conductance K(+) channels TRAM-34. Blockade of the endogenous production of EETs with N-methylsulfonyl-6-(2 propargyloxyphenyl)hexanamide (MS-PPOH) significantly blunted (dl)-1 aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD)-induced outward K(+) currents (P < 0.05; n = 6). Both NUD-GA and t-ACPD significantly increased BK channel single open probability; the later was blocked following MS-PPOH incubation. Our data supports the idea that EETs are potent K(+) channel modulators in cortical perivascular astrocytes and further suggest that these metabolites may participate in NVC by modulating the levels of K(+) released at the gliovascular space. PMID- 20844245 TI - Ion transporters in secretory and cyclically modulating ameloblasts: a new hypothesis for cellular control of preeruptive enamel maturation. AB - Mature enamel consists of densely packed and highly organized large hydroxyapatite crystals. The molecular machinery responsible for the formation of fully matured enamel is poorly described but appears to involve oscillative pH changes at the enamel surface. We conducted an immunohistochemical investigation of selected transporters and related proteins in the multilayered rat incisor enamel organ. Connexin 43 (Cx-43) is found in papillary cells and ameloblasts, whereas Na(+)-K(+)-ATPase is heavily expressed during maturation in the papillary cell layer only. Given the distribution of Cx-43 channels and Na(+)-K(+)-ATPase, we suggest that ameloblasts and the papillary cell layer act as a functional syncytium. During enamel maturation ameloblasts undergo repetitive cycles of modulation between ruffle-ended (RA) and smooth-ended (SA) ameloblast morphologies. Carbonic anhydrase II and vacuolar H(+)-ATPase are expressed simultaneously at the beginning of the maturation stage in RA cells. The proton pumps are present in the ruffled border of RA and appear to be internalized during the SA stage. Both papillary cells and ameloblasts express plasma membrane acid/base transporters (AE2, NBC, and NHE1). AE2 and NHE1 change position relative to the enamel surface as localization of the tight junctions changes during ameloblast modulation cycles. We suggest that the concerted action of the papillary cell layer and the modulating ameloblasts regulates the enamel microenvironment, resulting in oscillating pH fluctuations. The pH fluctuations at the enamel surface may be required to keep intercrystalline spaces open in the surface layers of the enamel, enabling degraded enamel matrix proteins to be removed while hydroxyapatite crystals grow as a result of influx of calcium and phosphate ions. PMID- 20844246 TI - Bone morphogenetic protein 4 enhances canonical transient receptor potential expression, store-operated Ca2+ entry, and basal [Ca2+]i in rat distal pulmonary arterial smooth muscle cells. AB - Recent advances have identified an important role of bone morphogenetic protein 4 (BMP4) in pulmonary vascular remodeling, yet the underlying mechanisms remain largely unexplored. We have previously found that Ca(2+) influx through store operated calcium channels (SOCC), which are mainly thought to be composed of canonical transient receptor potential (TRPC) proteins, likely contribute to the pathogenic development of chronic hypoxic pulmonary hypertension. In this study, we investigated the effect of BMP4 on expression of TRPC and store-operated Ca(2+) entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs). Real-time quantitative PCR and Western blotting revealed that treatment with BMP4 (50 ng/ml, 60 h) increased TRPC1, TRPC4, and TRPC6 mRNA and protein expression in growth-arrested rat distal PASMCs. Moreover, in comparison to vehicle control, cells treated with BMP4 also exhibited enhanced SOCE, and elevated basal intracellular calcium concentration ([Ca(2+)](i)) as determined by fluorescent microscopy using the Ca(2+) indicator Fura-2 AM. Perfusing cells with Ca(2+)-free Krebs-Ringer bicarbonate solution (KRBS) or KRBS containing SOCC antagonists SKF 96365 or NiCl(2) attenuated the increases in basal [Ca(2+)](i) caused by BMP4. Specific knockdown of BMP4 by small interference RNA significantly decreased the mRNA and protein expression of TRPC1, TRPC4, and TRPC6 and reduced SOCE and basal [Ca(2+)](i) in serum-stimulated PASMCs. We conclude that BMP4 regulates calcium signaling in PASMCs likely via upregulation of TRPC expression, leading to enhanced SOCE and basal [Ca(2+)](i) in PASMCs, and by this mechanism contributes to pulmonary vascular remodeling during pulmonary arterial hypertension. PMID- 20844247 TI - Soleus muscle in glycosylation-deficient muscular dystrophy is protected from contraction-induced injury. AB - The glycosylation of dystroglycan is required for its function as a high-affinity laminin receptor, and loss of dystroglycan glycosylation results in congenital muscular dystrophy. The purpose of this study was to investigate the functional defects in slow- and fast-twitch muscles of glycosylation-deficient Large(myd) mice. While a partial alteration in glycosylation of dystroglycan in heterozygous Large(myd/+) mice was not sufficient to alter muscle function, homozygous Large(myd/myd) mice demonstrated a marked reduction in specific force in both soleus and extensor digitorum longus (EDL) muscles. Although EDL muscles from Large(myd/myd) mice were highly susceptible to lengthening contraction-induced injury, Large(myd/myd) soleus muscles surprisingly showed no greater force deficit compared with wild-type soleus muscles even after five lengthening contractions. Despite no increased susceptibility to injury, Large(myd/myd) soleus muscles showed loss of dystroglycan glycosylation and laminin binding activity and dystrophic pathology. Interestingly, we show that soleus muscles have a markedly higher sarcolemma expression of beta(1)-containing integrins compared with EDL and gastrocnemius muscles. Therefore, we conclude that beta(1) containing integrins play an important role as matrix receptors in protecting muscles containing slow-twitch fibers from contraction-induced injury in the absence of dystroglycan function, and that contraction-induced injury appears to be a separable phenotype from the dystrophic pathology of muscular dystrophy. PMID- 20844249 TI - Imaging of oxygen gradients in monolayer cultured cells using green fluorescent protein. AB - Gradients of Po(2) between capillary blood and mitochondria are the driving force for diffusional O(2) delivery in tissues. Hypoxic microenvironments in tissues that result from diffusional O(2) gradients are especially relevant in solid tumors because they have been related to a poor prognosis. To address the impact of tissue O(2) gradients, we developed a novel technique that permits imaging of intracellular O(2) levels in cultured cells at a subcellular spatial resolution. This was done, with the sensitivity to O(2) <=3%, by the O(2)-dependent red shift of green fluorescent protein (AcGFP1) fluorescence. Measurements were carried out in a confluent monolayer of Hep3B cells expressing AcGFP1 in the cytoplasm. To establish a two-dimensional O(2) diffusion model, a thin quartz glass slip was placed onto the monolayer cells to prevent O(2) diffusion from the top surface of the cell layer. The magnitude of the red shift progressively increased as the distance from the gas coverslip interface increased. It reached an anoxic level in cells located at ~220 MUm and ~690 MUm from the gas coverslip boundary at 1% and 3% gas phase O(2), respectively. Thus the average O(2) gradient was 0.03 mmHg/MUm in the present tissue model. Abolition of mitochondrial respiration significantly dampened the gradients. Furthermore, intracellular gradients of the red shift in mitochondria-targeted AcGFP1 in single Hep3B cells suggest that the origin of tissue O(2) gradients is intracellular. Findings in the present two dimensional O(2) diffusion model support the crucial role of tissue O(2) diffusion in defining the O(2) microenvironment in individual cells. PMID- 20844248 TI - Syntaxin 3 is necessary for cAMP- and cGMP-regulated exocytosis of CFTR: implications for enterotoxigenic diarrhea. AB - Enterotoxins elaborated by Vibrio cholerae and Escherichia coli cannot elicit fluid secretion in the absence of functional cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels. After enterotoxin exposure, CFTR channels are rapidly recruited from endosomes and undergo exocytic insertion into the apical plasma membrane of enterocytes to increase the number of channels on the cell surface by at least fourfold. However, the molecular machinery that orchestrates exocytic insertion of CFTR into the plasma membrane is largely unknown. The present study used immunofluorescence, immunoblotting, surface biotinylation, glutathione S-transferase (GST) pulldown assays, and immunoprecipitation to identify components of the exocytic soluble N ethylmaleimide (NEM)-sensitive factor attachment receptor (SNARE) vesicle fusion machinery in cyclic nucleotide-activated exocytosis of CFTR in rat jejunum and polarized intestinal Caco-2(BB)e cells. Syntaxin 3, an intestine-specific SNARE, colocalized with CFTR on the apical domain of enterocytes in rat jejunum and polarized Caco-2(BB)e cells. Coimmunoprecipitation and GST binding studies confirmed that syntaxin 3 interacts with CFTR in vivo. Moreover, heat-stable enterotoxin (STa) activated exocytosis of both CFTR and syntaxin 3 to the surface of rat jejunum. Silencing of syntaxin 3 by short hairpin RNA (shRNA) interference abrogated cyclic nucleotide-stimulated exocytosis of CFTR in cells. These observations reveal a new and important role for syntaxin 3 in the pathophysiology of enterotoxin-elicited diarrhea. PMID- 20844250 TI - Genetic downregulation of AMPK-alpha isoforms uncovers the mechanism by which metformin decreases FA uptake and oxidation in skeletal muscle cells. AB - Metformin is known to improve insulin sensitivity in part via a rise in AMP activated protein kinase (AMPK) activity and alterations in muscle metabolism. However, a full understanding of how metformin alters AMPK-alpha(1) vs. AMPK alpha(2) activation remains unknown. To study this question, L6 skeletal muscle cells were treated with or without RNAi oligonucleotide sequences to downregulate AMPK-alpha(1) or AMPK-alpha(2) protein expression and incubated with or without 5 aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) or metformin and/or insulin. In contrast to AICAR, which preferentially activated AMPK-alpha(2), metformin preferentially activated AMPK-alpha(1) in a dose- and time-dependent manner. Metformin increased (P < 0.05) glucose uptake and plasma membrane (PM) Glut4 in a dose- and time-dependent manner. Metformin significantly reduced palmitate uptake (P < 0.05) and oxidation (P < 0.05), and this was accompanied by a similar decrease (P < 0.05) in PM CD36 content but with no change in acetyl-CoA carboxylase (ACC) phosphorylation (P > 0.05). AICAR and metformin similarly increased (P < 0.05) nuclear silent mating-type information regulator 2 homolog 1 (SIRT1) activity. Downregulation of AMPK-alpha(1) completely prevented the metformin-induced reduction in palmitate uptake and oxidation but only partially reduced the metformin-induced increase in glucose uptake. Downregulation of AMPK alpha(2) had no effect on metformin-induced glucose uptake, palmitate uptake, and oxidation. The increase in SIRT1 activity induced by metformin was not affected by downregulation of either AMPK-alpha(1) or AMPK-alpha(2). Our data indicate that, in muscle cells, the inhibitory effects of metformin on fatty acid metabolism occur via preferential phosphorylation of AMPK-alpha(1), and the data indicate that cross talk between AMPK and SIRT1 does not favor either AMPK isozyme. PMID- 20844251 TI - Force enhancement following stretch in a single sarcomere. AB - It has been accepted for half a century that, for a given level of activation, the steady-state isometric force of a muscle sarcomere depends exclusively on the amount of overlap between the contractile filaments actin and myosin, or equivalently sarcomere length (Gordon AM et al., J Physiol 184: 170-192, 1966). Moreover, according to the generally accepted paradigm of muscle contraction, the cross-bridge theory (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957), this steady-state isometric sarcomere force is independent of the muscle's contractile history (Huxley AF, Prog Biophys Biophys Chem 7: 255-318, 1957; Walcott S and Herzog W, Math Biosci 216: 172-186, 2008); i.e., it is independent of whether a muscle is held at a constant length before and during the contraction or whether the muscle is shortened or lengthened to the same constant length. This, however, is not the case, as muscles and single fibers that are stretched show greatly increased steady-state isometric forces compared with preparations that are held at a constant length (Abbott BC and Aubert XM, J Physiol 117: 77-86, 1952; De Ruiter CJ et al., J Physiol 526.3: 671-681, 2000; Edman KAP et al., J Physiol 281: 139-155, 1978; Edman KAP et al., J Gen Physiol 80: 769-784, 1982; Edman KAP and Tsuchiya T, J Physiol 490.1: 191-205, 1996). This so-called "residual force enhancement" (Edman KAP et al., J Gen Physiol 80: 769-784, 1982) offers a perplexing puzzle for muscle physiologists. Many theories have been advanced to address the discrepancy between prediction and observation with the most popular and accepted being the sarcomere length nonuniformity theory (Morgan DL, Biophys J 57: 209-221, 1990), which explains the residual force enhancement with the development of large nonuniformities in sarcomere lengths during muscle stretching. Here, we performed experiments in mechanically isolated sarcomeres and observed that the residual force enhancement following active stretching is preserved. Since our preparation utilizes a single sarcomere, a redistribution of the length of neighboring sarcomeres to produce the higher force following stretch is, by design, precluded. Furthermore, the enhanced forces in the single sarcomeres always exceed the isometric forces on the plateau of the force-length relationship, thereby eliminating the possibility that our result might have been obtained because of a redistribution of half-sarcomere lengths. Since force enhancement in single myofibrils has been associated with actin-titin interactions (Kulke M et al., Circ Res 89: 874-881, 2001; Li Q et al., Biophys J 69: 1508-1518, 1995) and calcium binding to titin (Joumaa V et al., Am J Physiol Cell Physiol 294: C74-C78, 2008; Labeit D et al., Proc Natl Acad Sci USA 100: 13716-13721, 2003), titin may regulate the sarcomeric force enhancement observed here. PMID- 20844252 TI - Differential gene expressions in atrial and ventricular myocytes: insights into the road of applying embryonic stem cell-derived cardiomyocytes for future therapies. AB - Myocardial infarction has been the leading cause of morbidity and mortality in developed countries over the past few decades. The transplantation of cardiomyocytes offers a potential method of treatment. However, cardiomyocytes are in high demand and their supply is extremely limited. Embryonic stem cells (ESCs), which have been isolated from the inner cell mass of blastocysts, can self-renew and are pluripotent, meaning they have the ability to develop into any type of cell, including cardiomyocytes. This suggests that ESCs could be a good source of genuine cardiomyocytes for future therapeutic purposes. However, problems with the yield and purity of ESC-derived cardiomyocytes, among other hurdles for the therapeutic application of ESC-derived cardiomyocytes (e.g., potential immunorejection and tumor formation problems), need to be overcome before these cells can be used effectively for cell replacement therapy. ESC derived cardiomyocytes consist of nodal, atrial, and ventricular cardiomyocytes. Specifically, for treatment of myocardial infarction, transplantation of a sufficient quantity of ventricular cardiomyocytes, rather than nodal or atrial cardiomyocytes, is preferred. Hence, it is important to find ways of increasing the yield and purity of specific types of cardiomyocytes. Atrial and ventricular cardiomyocytes have differential expression of genes (transcription factors, structural proteins, ion channels, etc.) and are functionally distinct. This paper presents a thorough review of differential gene expression in atrial and ventricular myocytes, their expression throughout development, and their regulation. An understanding of the molecular and functional differences between atrial and ventricular myocytes allows discussion of potential strategies for preferentially directing ESCs to differentiate into chamber-specific cells, or for fine tuning the ESC-derived cardiomyocytes into specific electrical and contractile phenotypes resembling chamber-specific cells. PMID- 20844253 TI - Reducing the effects of background noise during auditory functional magnetic resonance imaging of speech processing: qualitative and quantitative comparisons between two image acquisition schemes and noise cancellation. AB - PURPOSE: The intense sound generated during functional magnetic resonance imaging (fMRI) complicates studies of speech and hearing. This experiment evaluated the benefits of using active noise cancellation (ANC), which attenuates the level of the scanner sound at the participant's ear by up to 35 dB around the peak at 600 Hz. METHOD: Speech and narrowband noise were presented at a low sound level to 8 listeners during fMRI using 2 common scanning protocols: short ("continuous") and long ("sparse") temporal schemes. Three outcome measures were acquired simultaneously during fMRI: ratings of listening quality, discrimination performance, and brain activity. RESULTS: Subjective ratings and discrimination performance were significantly improved by ANC and sparse acquisition. Sparse acquisition was the more robust method for detecting auditory cortical activity. ANC reduced some of the "extra-auditory" activity that might be associated with the effort required for perceptual discrimination in a noisy environment and also offered small improvements for detecting activity within Heschl's gyrus and planum polare. CONCLUSIONS: For the scanning protocols evaluated here, the sparse temporal scheme was the more preferable for detecting sound-evoked activity. In addition, ANC ensures that listening difficulty is determined more by the chosen stimulus parameters and less by the adverse testing environment. PMID- 20844254 TI - Perception of suprasegmental speech features via bimodal stimulation: cochlear implant on one ear and hearing aid on the other. AB - PURPOSE: The purpose of the study was to evaluate the contribution of acoustic hearing to the perception of suprasegmental features by adults who use a cochlear implant (CI) and a hearing aid (HA) in opposite ears. METHOD: 23 adults participated in this study. Perception of suprasegmental features-intonation, syllable stress, and word emphasis-was assessed. All tests were administered in 2 conditions: CI alone and CI + HA (bimodal). RESULTS: Scores were significantly higher in the bimodal condition in comparison to scores in CI alone for all 3 tests. In both conditions, there was great variability among the individual participants. Significant negative correlations emerged between perception of suprasegmental features and the unaided pure-tone average of the contralateral ear to the CI. CONCLUSIONS: This study found a significant bimodal advantage for perception of all suprasegmental features, most probably due to the better low frequency acoustic hearing that is provided by the HA. Outcomes suggest that in cases of residual hearing in the contralateral ear to the implanted ear, HA use should be encouraged. PMID- 20844255 TI - Are false-positive rates leading to an overestimation of noise-induced hearing loss? AB - PURPOSE: To estimate false-positive rates for rules proposed to identify early noise-induced hearing loss (NIHL) using the presence of notches in audiograms. METHOD: Audiograms collected from school-age children in a national survey of health and nutrition (the Third National Health and Nutrition Examination Survey [NHANES III]; National Center for Health Statistics, 1994) were examined using published rules for identifying noise notches at various pass-fail criteria. These results were compared with computer-simulated "flat" audiograms. The proportion of these identified as having a noise notch is an estimate of the false-positive rate for a particular rule. RESULTS: Audiograms from the NHANES III for children 6-11 years of age yielded notched audiograms at rates consistent with simulations, suggesting that this group does not have significant NIHL. Further, pass-fail criteria for rules suggested by expert clinicians, applied to NHANES III audiometric data, yielded unacceptably high false-positive rates. CONCLUSIONS: Computer simulations provide an effective method for estimating false-positive rates for protocols used to identify notched audiograms. Audiometric precision could possibly be improved by (a) eliminating systematic calibration errors, including a possible problem with reference levels for TDH style earphones; (b) repeating and averaging threshold measurements; and (c) using earphones that yield lower variability for 6.0 and 8.0 kHz--2 frequencies critical for identifying noise notches. PMID- 20844256 TI - Effect of Parkinson's disease on the production of structured and unstructured speaking tasks: respiratory physiologic and linguistic considerations. AB - PURPOSE: To examine the effects of cognitive-linguistic deficits and respiratory physiologic changes on respiratory support for speech in individuals with Parkinson's disease (PD) using two speech tasks: reading and extemporaneous speech. METHOD: Five women with PD, 9 men with PD, and 14 age- and sex-matched control participants read a passage and spoke extemporaneously on a topic of their choice at comfortable loudness. Sound pressure level, syllables per breath group, speech rate, and lung volume parameters were measured. Number of formulation errors, disfluencies, and filled pauses were counted. RESULTS: Individuals with PD produced shorter utterances compared with control participants. The relationships between utterance length and lung volume initiation and inspiratory duration were weaker for individuals with PD than for control participants, particularly for the extemporaneous speech task. These results suggest less consistent planning for utterance length by individuals with PD in extemporaneous speech. Individuals with PD produced more formulation errors in both tasks and significantly fewer filled pauses in extemporaneous speech. CONCLUSION: Both respiratory physiologic and cognitive-linguistic issues affected speech production by individuals with PD. Overall, individuals with PD had difficulty planning or coordinating language formulation and respiratory support, particularly during extemporaneous speech. PMID- 20844257 TI - Modified spectral tilt affects older, but not younger, infants' native-language fricative discrimination. AB - PURPOSE: It is important to ensure that hearing aid fitting strategies for infants take into account the infant's developing speech perception system. As a way of exploring this issue, this study examined how 6- and 9-month-olds with normal hearing perceive native-language speech in which the natural spectral shape was altered to emphasize either high-frequency (positive spectral tilt) or low-frequency (negative spectral tilt) information. METHOD: Discrimination was tested using a visual habituation procedure. Forty-eight 6-month-olds and forty eight 9-month-olds were presented with a fricative contrast, /f/-/s/, in 1 of 3 conditions: (a) as unmodified speech; (b) with a -6 dB/octave tilt; or (c) with a +6 dB/octave tilt. RESULTS: Six-month-olds showed evidence of discriminating /f/ /s/ in all 3 conditions, but 9-month-olds showed such evidence only in the unmodified condition. CONCLUSIONS: The findings suggest that the perceptual reorganization that emerges for consonants at the end of the first year affects 9 month-olds' discrimination of native speech sounds. Perceptual reorganization is usually indexed by a decline in the ability to discriminate nonnative speech sounds. In this study, 6-month-olds demonstrated an acoustic-based sensitivity to both modified and unmodified native speech sounds, but 9-month-olds were most sensitive to the unmodified speech sounds that adhered to the native spectral profile. PMID- 20844258 TI - Circulation and metabolic rates in a natural hibernator: an integrative physiological model. AB - Small hibernating mammals show regular oscillations in their heart rate and body temperature throughout the winter. Long periods of torpor are abruptly interrupted by arousals with heart rates that rapidly increase from 5 beats/min to over 400 beats/min and body temperatures that increase by ~30 degrees C only to drop back into the hypothermic torpid state within hours. Surgically implanted transmitters were used to obtain high-resolution electrocardiogram and body temperature data from hibernating thirteen-lined ground squirrels (Spermophilus tridecemlineatus). These data were used to construct a model of the circulatory system to gain greater understanding of these rapid and extreme changes in physiology. Our model provides estimates of metabolic rates during the torpor arousal cycles in different model compartments that would be difficult to measure directly. In the compartment that models the more metabolically active tissues and organs (heart, brain, liver, and brown adipose tissue) the peak metabolic rate occurs at a core body temperature of 19 degrees C approximately midway through an arousal. The peak metabolic rate of the active tissues is nine times the normothermic rate after the arousal is complete. For the overall metabolic rate in all tissues, the peak-to-resting ratio is five. This value is high for a rodent, which provides evidence for the hypothesis that the arousal from torpor is limited by the capabilities of the cardiovascular system. PMID- 20844259 TI - Leupeptin-based inhibitors do not improve the mdx phenotype. AB - Calpain activation has been implicated in the disease pathology of Duchenne muscular dystrophy. Inhibition of calpain has been proposed as a promising therapeutic target, which could lessen the protein degradation and prevent progressive fibrosis. At the same time, there are conflicting reports as to whether elevation of calpastatin, an endogenous calpain inhibitor, alters pathology. We compared the effects of pharmacological calpain inhibition in the mdx mouse using leupeptin and a proprietary compound (C101) that linked the inhibitory portion of leupeptin to carnitine (to increase uptake into muscle). Administration of C101 for 4 wk did not improve muscle histology, function, or serum creatine kinase levels in mdx mice. Mdx mice injected daily with leupeptin (36 mg/kg) for 6 mo also failed to show improved muscle function, histology, or creatine kinase levels. Biochemical analysis revealed that leupeptin administration caused an increase in m-calpain autolysis and proteasome activity, yet calpastatin levels were similar between treated and untreated mdx mice. These data demonstrate that pharmacological inhibition of calpain is not a promising intervention for the treatment of Duchenne muscular dystrophy due to the ability of skeletal muscle to counter calpain inhibitors by increasing multiple degradative pathways. PMID- 20844260 TI - Maternal obesity markedly increases placental fatty acid transporter expression and fetal blood triglycerides at midgestation in the ewe. AB - Obesity of women at conception is increasing, a condition associated with offspring obesity. We hypothesized that maternal obesity increases placental fatty acid transporter (FATP) expression, enhancing delivery of fatty acids to their fetuses. Sheep are a commonly utilized biomedical model for pregnancy studies. Nonpregnant ewes were randomly assigned to a control group [100% of National Research Council (NRC) recommendations] or obese group (OB, 150% of NRC) from 60 days before conception to 75 or 135 days of gestation (dG; term = 150 dG), when placental cotyledonary tissue was collected for analysis. Fetuses of OB ewes were markedly heavier (P < 0.05) on 75 dG than fetuses from control ewes, but this difference disappeared by 135 dG. Maternal obesity markedly increased (P < 0.05) cholesterol and triglyceride concentrations of both maternal and fetal blood. There is no difference in lipoprotein lipase mRNA expression between control and OB group at either gestational age. On 75 dG, the mRNA expression of FATP1 (P < 0.05), FATP4 (P = 0.08), and fatty acid translocase CD (cluster of differentiation) 36 (P < 0.05) proteins were more enhanced in cotyledonary tissue from OB than control ewes; consistently, protein expression of FATP1 and FATP4 was increased (P < 0.05). Similarly, on 135 dG, the mRNA levels of FATP1, FATP4, and CD36 were all higher (P < 0.05), but only FATP4 protein content was enhanced (P < 0.05) in OB cotyledonary tissue. Peroxisome proliferator-activated receptor (PPAR)-gamma regulates the expression of FATPs. Both the mRNA expression and protein content of PPARgamma were increased in OB cotyledonary in the midgestation. In conclusion, maternal obesity enhances the mRNA expression and protein content of FATPs in cotyledonary in the midgestation, which is associated with higher PPARgamma content in cotyledonary. PMID- 20844261 TI - Top-down control analysis of the cadmium effects on molluscan mitochondria and the mechanisms of cadmium-induced mitochondrial dysfunction. AB - Cadmium (Cd) is a toxic metal and an important environmental pollutant that can strongly affect mitochondrial function and bioenergetics in animals. We investigated the mechanisms of Cd action on mitochondrial function of a marine mollusk (the eastern oyster Crassostrea virginica) by performing a top-down control analysis of the three major mitochondrial subsystems (substrate oxidation, proton leak, and phosphorylation). Our results showed that the substrate oxidation and proton leak subsystems are the main targets for Cd toxicity in oyster mitochondria. Exposure to 12.5 MUM Cd strongly inhibited the substrate oxidation subsystem and stimulated the proton conductance across the inner mitochondrial membrane. Proton conductance was also elevated and substrate oxidation inhibited by Cd in the presence of a mitochondrially targeted antioxidant, MitoVitE, indicating that Cd effects on these subsystems were to a large extent ROS independent. Cd did not affect the kinetics of the phosphorylation system, indicating that it has negligible effects on F1, F(O) ATP synthase and/or the adenine nucleotide transporter in oyster mitochondria. Cd exposure altered the patterns of control over mitochondrial respiration, increasing the degree of control conferred by the substrate oxidation subsystem, especially in resting (state 4) mitochondria. Taken together, these data suggest that Cd-induced decrease of mitochondrial efficiency and ATP production are predominantly driven by the high sensitivity of substrate oxidation and proton leak subsystems to this metal. PMID- 20844262 TI - CCAAT/enhancer binding protein-delta expression is increased in fast skeletal muscle by food deprivation and regulates myostatin transcription in vitro. AB - We recently demonstrated that mRNA levels of three members of the CCAAT/enhancer binding factor (C/EBP) family of transcription factors are increased in skeletal muscle following 12 days of spaceflight. In the present study, we further explored the expression of C/EBP-delta in atrophying fast skeletal muscle by examining its expression in muscle from food-deprived (FD) mice, and investigated its role in regulating the expression of the secreted antigrowth factor myostatin. C/EBP-delta mRNA and protein levels were significantly increased by 2 days of food deprivation in the tibialis anterior (TA) muscle, and expression of both myostatin and C/EBP-delta mRNA during food deprivation was attenuated by injection with the glucocorticoid inhibitor RU486. The increase in myostatin mRNA levels with food deprivation appears to be at least partially transcriptionally driven, since levels of myostatin pre-mRNA were significantly increased in the TA muscle. C/EBP-delta mRNA levels and promoter activity were significantly increased by transfection of C(2)C(12) myotubes with a glucocorticoid receptor construct and 24 h of treatment with the synthetic glucocorticoid dexamethasone. Furthermore, activity of the C/EBP-delta promoter was significantly increased with as little as 1 h of dexamethasone treatment, while activity of the mouse myostatin promoter was only significantly increased with longer treatment periods of 24 h or more. Activity of the myostatin promoter-reporter construct was significantly increased in C(2)C(12) myotubes by cotransfection with expression constructs for C/EBP-alpha, -beta, and -delta, with C/EBP-delta having the greatest effect. The myostatin promoter contains two potential C/EBP binding sequences, a CCAAT box, and a C/EBP binding element (CBE). Mutation of the CCAAT box attenuated basal myostatin promoter activity but potentiated C/EBP-delta activated myostatin promoter activity in C(2)C(12) myotubes in vitro, while mutation of the CBE abolished glucocorticoid receptor and C/EBP-delta responsiveness. The present results support a model in which glucocorticoid induced increases in C/EBP-delta expression may contribute to myostatin transcription during atrophic states. PMID- 20844263 TI - t10,c12-CLA decreases adiposity in peripubertal mice without dose-related detrimental effects on mammary development, inflammation status, and metabolism. AB - The trans 10, cis 12-conjugated linoleic acid (10,12-CLA) isomer reduces adiposity in several animal models. In the mouse, however, this effect is associated with adipose tissue inflammation, hyperinsulinemia and hepatic lipid accumulation. Moreover, 10,12-CLA was recently shown to promote mammary ductal hyperplasia and ErbB2/Her2-driven mammary cancer in the mouse. Reasons for detrimental effects of 10,12-CLA on the mouse mammary gland could relate to its effect on the mammary fat pad (MFP), which is essential for normal development. Accordingly, we hypothesized that mammary effects of 10,12-CLA were mediated through the MFP in a dose-dependent manner. Female FVB mice were fed 10,12-CLA at doses of 0%, 0.1%, 0.2%, or 0.5% of the diet from day 24 of age, and effects on mammary development and metabolism were measured on day 49. The 0.5% dose reduced ductal elongation and caused premature alveolar budding. These effects were associated with increased expression of inflammatory markers and genes shown to alter epithelial growth (IGF binding protein-5) and alveolar budding (TNF-alpha and receptor of activated NF-kappaB ligand). The 0.5% dose also caused hyperinsulinemia and hepatic lipid accumulation. In contrast, the 0.1% 10,12-CLA dose had no adverse effects on mammary development, metabolic events, and inflammatory responses, but remained effective in decreasing adipose weights and lipogenic gene expression. These results show that a low dose of 10,12-CLA reduces adiposity in the mouse without negative effects on mammary development, inflammation, and metabolism, and suggest that previously reported detrimental effects relate to the use of excessive doses. PMID- 20844264 TI - AICAR treatment for 14 days normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle. AB - The aim of this study was to determine the effect of 14 days of 5-aminoimidazole 4-carboxamide-1beta-4-ribofuranoside (AICAR) treatment on mammalian target of rapamycin (mTOR) signaling and mTOR-regulated processes (i.e., translation initiation) in obese mouse skeletal muscle. Our hypothesis was that daily treatment (14 days) with AICAR would normalize obesity-induced alterations in skeletal muscle mTOR signaling and mTOR-regulated processes to lean levels and positively affect muscle mass. Fourteen-week-old male, lean (L; 31.3 g body wt) wild-type and ob/ob (O; 59.6 g body wt) mice were injected with the AMP-activated kinase (AMPK) activator AICAR (A) at 0.5 mg.g body wt(-1).day(-1) or saline control (C) for 14 days. At 24 h after the last injection (including a 12-h fast), all mice were killed, and the plantar flexor complex muscle (gastrocnemius, soleus, and plantaris) was excised for analysis. Muscle mass was lower in OC (159 +/- 12 mg) than LC, LA, and OA (176 +/- 10, 178 +/- 9, and 166 +/- 16 mg, respectively) mice, independent of a body weight change. A decrease in obese muscle mass corresponded with higher muscle cross section staining intensity for lipid and glycogen, higher blood glucose and insulin levels, and lower nuclear-enriched fractions for peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expression in OC skeletal muscle, which was normalized with AICAR treatment. AMPK and acetyl-cocarboxylase phosphorylation was reduced in OC mice and augmented by AICAR treatment in OA mice. Conversely, OC mice displayed higher activation of downstream targets (S6 kinase-1 and ribosomal protein S6) of mTOR and lower raptor-associated mTOR than LC mice, which were reciprocally altered after 14 days of AICAR treatment. Dysregulation of translational capacity was improved in OA mice, as assessed by sucrose density gradient fractionation of ribosomes, total and ribosome-associated RNA content, eukaryotic initiation factor 4F complex formation, and eukaryotic initiation factor 4G phosphorylation. These data show that short-term (14 days) AMPK agonist treatment augments regulatory processes in atrophic obese mouse skeletal muscle through the normalization of mTOR signaling and mRNA translation closer to lean levels. PMID- 20844265 TI - Effects of combined aging and heart failure on visceral sympathetic nerve and cardiovascular responses to progressive hyperthermia in F344 rats. AB - Sympathetic nerve discharge (SND) responses to hyperthermia are attenuated in aged rats without heart failure (HF) and in young HF (Y(HF)) rats, demonstrating that individually aging and HF alter SND regulation. However, the combined effects of aging and HF on SND regulation to heat stress are unknown, despite the high prevalence of HF in aged individuals. We hypothesized that SND responses to heating would be additive when aging and HF are combined, demonstrated by marked reductions in SND and mean arterial pressure (MAP) responses to heating in aged HF (A(HF)) compared with aged sham HF (A(SHAM)) rats, and in A(HF) compared with Y(HF) rats. Renal and splenic SND responses to hyperthermia (colonic temperature increased to 41.5 degrees C) were determined in anesthetized Y(HF), young sham (Y(SHAM)), A(HF), and A(SHAM) Fischer rats. HF was induced by myocardial infarction and documented using echocardiographic, invasive, and postmortem measures. The severity of HF was similar in Y(HF) and A(HF) rats. SND responses to heating were attenuated in Y(HF) compared with Y(SHAM) rats, demonstrating an effect of HF on SND regulation in young rats. In contrast, A(HF) and A(SHAM) rats demonstrated similar SND responses to heating, suggesting a prominent influence of age on SND regulation in A(HF) rats. Splenic SND and MAP responses to heating were similar in Y(HF), A(HF), and A(SHAM) rats, indicating that the imposition of HF in young rats changes the regulatory status of these variables to one consistent with aged rats. These data suggest that the effect of HF on SND regulation to hyperthermia is age dependent. PMID- 20844267 TI - Neointima formation: a local affair. PMID- 20844268 TI - Closer to fine: fewer steps to endothelial stemness. PMID- 20844266 TI - Dehydration followed by sham rehydration contributes to reduced neuronal activation in vasopressinergic supraoptic neurons after water deprivation. AB - This experiment tested the role of oropharyngeal and gastric afferents on hypothalamic activation in dehydrated rats instrumented with gastric fistulas and allowed to drink water or isotonic saline compared with euhydrated controls (CON). Rats were water-deprived for 48 h (48 WD) or 46 h WD with 2 h rehydration with water (46+W) or isotonic saline (46+S). 46+W and 46+S rats were given water with fistulas open (46+WO/46+SO, sham) or closed (46+WC/46+SC). Compared with CON, water deprivation increased and water rehydration decreased plasma osmolality, while sham rehydration had no effect. Water deprivation increased c Fos staining in the lamina terminalis. However, none of the sham or rehydration treatments normalized c-Fos staining in the lamina terminalis. Analysis of AVP and c-Fos-positive neurons in the supraoptic nucleus (SON) revealed reduced colocalization in 46+WO and 46+SC rats compared with 48 WD and 46+SO rats. However, 46+WO and 46+SC rats had higher c-Fos staining in the SON than 46+WC or CON rats. Examination of c-Fos in the perinuclear zone (PNZ) revealed that sham and rehydrated rats had increased c-Fos staining to CON, while 48 WD and 46+SO rats had little or no c-Fos staining in this region. Thus, preabsorptive reflexes contribute to the regulation of AVP neurons in a manner independent of c-Fos expression in the lamina terminalis. Further, this reflex pathway may include inhibitory interneurons in the PNZ region surrounding the SON. PMID- 20844269 TI - Platelet/von Willebrand factor inhibitors to the rescue of ischemic stroke. PMID- 20844271 TI - Evidence-based practice for children with speech sound disorders: part 2 application to clinical practice. AB - PURPOSE: This article provides both a tutorial and a clinical example of how speech-language pathologists (SLPs) can conduct evidence-based practice (EBP) when working with children with speech sound disorders (SSDs). It is a companion paper to the narrative review of 134 intervention studies for children who have an SSD (Baker & McLeod, 2011). METHOD: A seven-step EBP decision-making process is presented for managing SSDs in children (drawing on the work of Dollaghan, 2007, and Gillam & Gillam, 2006). We describe how SLPs can integrate externally published evidence with evidence from clinical practice as well as client factors, values, and preferences, to make clinical decisions. An organized EBP network is described as a clinical example of the application of the EBP decision making process. RESULTS: Compared with a matched and national sample, SLPs in the EBP network were more likely to read relevant articles and tended to have more confidence in research evidence and in their own ability to select intervention targets based on published research. CONCLUSION: SLPs need to use their clinical expertise to integrate research findings with the constraints and complexities of everyday clinical practice and client factors, values, and preferences in their management of SSDs in children. PMID- 20844272 TI - What speech-language pathologists need to know about auditory processing disorder. AB - PURPOSE: To consider whether auditory processing disorder (APD) is truly a distinct clinical entity or whether auditory problems are more appropriately viewed as a processing deficit that may occur with various developmental disorders. METHOD: Theoretical and clinical factors associated with APD are critically evaluated. RESULTS: There are compelling theoretical and clinical reasons to question whether APD is in fact a distinct clinical entity. Not only is there little evidence that auditory perceptual impairments are a significant risk factor for language and academic performance (e.g., Hazan, Messaoud-Galusi, Rosan, Nouwens, & Shakespeare, 2009; Watson & Kidd, 2009), there is also no evidence that auditory interventions provide any unique benefit to auditory, language, or academic outcomes (Fey et al., 2011). CONCLUSION: Because there is no evidence that auditory interventions provide any unique therapeutic benefit (Fey et al., 2011), clinicians should treat children who have been diagnosed with APD the same way they treat children who have been diagnosed with language and learning disabilities. The theoretical and clinical problems associated with APD should encourage clinicians to consider viewing auditory deficits as a processing deficit that may occur with common developmental language and reading disabilities rather than as a distinct clinical entity. PMID- 20844270 TI - Group X secretory phospholipase A2 negatively regulates ABCA1 and ABCG1 expression and cholesterol efflux in macrophages. AB - OBJECTIVE: GX sPLA(2) potently hydrolyzes plasma membranes to generate lysophospholipids and free fatty acids; it has been implicated in inflammatory diseases, including atherosclerosis. To identify a novel role for group X (GX) secretory phospholipase A(2) (sPLA(2)) in modulating ATP binding casette transporter A1 (ABCA1) and ATP binding casette transporter G1 (ABCG1) expression and, therefore, macrophage cholesterol efflux. METHODS AND RESULTS: The overexpression or exogenous addition of GX sPLA(2) significantly reduced ABCA1 and ABCG1 expression in J774 macrophage-like cells, whereas GX sPLA(2) deficiency in mouse peritoneal macrophages was associated with enhanced expression. Altered ABC transporter expression led to reduced cholesterol efflux in GX sPLA(2) overexpressing J774 cells and increased efflux in GX sPLA(2)-deficient mouse peritoneal macrophages. Gene regulation was dependent on GX sPLA(2) catalytic activity, mimicked by arachidonic acid and abrogated when liver X receptor (LXR)alpha/beta expression was suppressed, and partially reversed by the LXR agonist T0901317. Reporter assays indicated that GX sPLA(2) suppresses the ability of LXR to transactivate its promoters through a mechanism involving the C terminal portion of LXR spanning the ligand-binding domain. CONCLUSIONS: GX sPLA(2) modulates gene expression in macrophages by generating lipolytic products that suppress LXR activation. GX sPLA(2) may play a previously unrecognized role in atherosclerotic lipid accumulation by negatively regulating the genes critical for cellular cholesterol efflux. PMID- 20844273 TI - Functional seating for school-age children with cerebral palsy: an evidence-based tutorial. AB - PURPOSE: This tutorial is designed to teach speech-language pathologists (SLPs) best practices to support functional seating of children with cerebral palsy (CP) in the classroom and in school-based therapy sessions. This tutorial teaches SLPs to (a) recognize the positive effects of seating intervention, (b) identify the characteristics of functional seating that may produce these positive effects, and (c) realize their role in supporting functional seating for school-age children with CP. METHOD: The research reporting positive effects of seating intervention for school-age children with CP is presented according to the International Classification of Functioning, Disability and Health (World Health Organization, 2001). Recommended guidelines for functional seating for school-age children with CP are gleaned from the research evidence. The specific role of the SLP in providing functional seating for children with CP is then discussed. CONCLUSION: Seating intervention may produce positive body structure and function, activities, and participation effects for school-age children with CP when appropriate equipment is provided for weight bearing, the pelvis is positioned for stability and mobility, and the body is properly aligned. SLPs can support functional seating for school-age children with CP by communicating with professionals with seating expertise and by invoking and monitoring recommended guidelines for children with basic and complex seating needs, respectively. PMID- 20844274 TI - Evidence-based practice for children with speech sound disorders: part 1 narrative review. AB - PURPOSE: This article provides a comprehensive narrative review of intervention studies for children with speech sound disorders (SSD). Its companion paper (Baker & McLeod, 2011) provides a tutorial and clinical example of how speech language pathologists (SLPs) can engage in evidence-based practice (EBP) for this clinical population. METHOD: Studies reporting speech sound intervention for children with SSDs published from 1979 to 2009 were identified and coded. RESULTS: One hundred thirty-four intervention studies were identified. Intervention typically was conducted by an SLP in a one-to-one individual format for 30- to 60-min sessions 2 to 3 times per week. Total duration of intervention (from assessment to discharge) was reported for 10 studies and ranged from 3 to 46 months. Most studies were either Level IIb (quasi-experimental studies, 41.5%) or Level III (nonexperimental case studies, 32.6%). Single-case experimental design (29.6%) was the most frequently used experimental research design. There were 7 distinct approaches to target selection and 46 distinct intervention approaches, with 23 described in more than 1 publication. Each approach was associated with varying quantities and levels of evidence, according to research design. CONCLUSION: Collaborative research reflecting higher levels of evidence using rigorous experimental designs is needed to compare the relative benefits of different intervention approaches. PMID- 20844275 TI - Auditory processing disorder and auditory/language interventions: an evidence based systematic review. AB - PURPOSE: In this systematic review, the peer-reviewed literature on the efficacy of interventions for school-age children with auditory processing disorder (APD) is critically evaluated. METHOD: Searches of 28 electronic databases yielded 25 studies for analysis. These studies were categorized by research phase (e.g., exploratory, efficacy) and ranked on a standard set of quality features related to methodology and reporting. RESULTS: Some support exists for the claim that auditory and language interventions can improve auditory functioning in children with APD and those with primary spoken language disorder. There is little indication, however, that observed improvements are due to the auditory features of these programs. Similarly, evidence supporting the effects of these programs on spoken and written language functioning is limited. CONCLUSION: The evidence base is too small and weak to provide clear guidance to speech-language pathologists faced with treating children with diagnosed APD, but some cautious skepticism is warranted until the record of evidence is more complete. Clinicians who decide to use auditory interventions should be aware of the limitations in the evidence and take special care to monitor the spoken and written language status of their young clients. PMID- 20844276 TI - Antioxidants induce apoptosis of rat ovarian theca-interstitial cells. AB - Regulation of growth of ovarian theca-interstitial tissues is essential for normal ovarian development and function. Reactive oxygen species are involved in modulation of signal transduction pathways, including regulation of tissue growth and apoptosis. Previously, we have demonstrated that antioxidants inhibit proliferation of theca-interstitial cells. This report evaluates the effects of antioxidants on apoptosis of rat theca-interstitial cells. The cells were cultured in chemically defined media without or with vitamin E succinate and ebselen. Apoptosis was evaluated by cytochemical assessment of nuclear morphology, activity of executioner caspases 3 and 7, and determination of staining with annexin V in combination with propidium iodide. Both tested antioxidants induced significant morphological changes consistent with apoptosis, including chromatin condensation, nuclear shrinkage, and pyknosis. Antioxidants also induced other hallmarks of apoptosis including increased activity of caspases 3/7 as well as increased staining with annexin V. The present findings demonstrate that antioxidants with distinctly different mechanisms of action induce a series of events consistent with the process of apoptosis in ovarian mesenchyme. These observations may be of translational-clinical relevance, providing mechanistic support for the use of antioxidants in the treatment of PCOS, a condition associated with excessive growth and activity of theca interstitial cells. PMID- 20844277 TI - SIRT1 is a novel regulator of key pathways of human labor. AB - Human sirtuin (SIRT) 1 and SIRT2, which possess nicotinamide adenosine dinucleotide (NAD(+))-dependent deacetylase activity, exhibit anti-inflammatory actions. However, there are no data available on SIRT1 and SIRT2 expression and regulation in human intrauterine tissues. Thus, the aim of this study was to characterize the localization and expression of SIRT1 and SIRT2 in 1) placenta and fetal membranes before and after term spontaneous labor onset, 2) prelabor fetal membranes from the supracervical site (SCS) and a distal site (DS), and 3) in response to proinflammatory stimuli. Further, the effect of SIRT activation using resveratrol and SRT1720 on prolabor mediators was also assessed. SIRT1 and SIRT2 were localized in the syncytiotrophoblast layer and the cytotrophoblasts of the placenta, amnion epithelium, trophoblast layer of the chorion, and decidual cells. Additionally, SIRT2 was found within the endothelial walls of placental vessels. SIRT2, but not SIRT1, staining was significantly lower in amnion and chorion obtained from the SCS compared to a DS. On the other hand, SIRT1, but not SIRT2, gene and/or protein expression was significantly lower in placenta, amnion, and chorion obtained after labor compared to prelabor. SIRT1 expression, but not SIRT2, was down-regulated by lipopolysaccharide (LPS) and proinflammatory cytokines TNF and IL1B. The SIRT1 activators resveratrol and SRT1720 significantly decreased LPS-induced TNF, IL6, and IL8 gene expression and release and PTGS2 mRNA expression and resultant prostaglandin (PG) E(2) and PGF(2alpha) release from human gestational tissues. In conclusion, SIRT1 possesses anti inflammatory actions and thus may play a role in regulating pregnancy and parturition. PMID- 20844278 TI - Resveratrol inhibits development of experimental endometriosis in vivo and reduces endometrial stromal cell invasiveness in vitro. AB - Endometriosis is a common gynecologic disorder characterized by ectopic attachment and growth of endometrial tissues. Resveratrol is a natural polyphenol with antiproliferative and anti-inflammatory properties. Our objective was to study the effects of resveratrol on human endometriotic implants in a nude mouse model and to examine its impact on human endometrial stromal (HES) cell invasiveness in vitro. Human endometrial tissues were obtained from healthy donors. Endometriosis was established in oophorectomized nude mice by intraperitoneal injection of endometrial tissues. Mice were treated with 17beta estradiol (8 mg, silastic capsule implants) alone (n = 16) or with resveratrol (6 mg/mouse; n = 20) for 10-12 and 18-20 days beginning 1 day after tissue injection. Mice were killed and endometrial implants were evaluated. A Matrigel invasion assay was used to examine the effects of resveratrol on HES cells. We assessed number and size of endometriotic implants in vivo and Matrigel invasion in vitro. Resveratrol decreased the number of endometrial implants per mouse by 60% (P < 0.001) and the total volume of lesions per mouse by 80% (P < 0.001). Resveratrol (10-30 MUM) also induced a concentration-dependent reduction of invasiveness of HES by up to 78% (P < 0.0001). Resveratrol inhibits development of endometriosis in the nude mouse and reduces invasiveness of HES cells. These observations may aid in the development of novel treatments of endometriosis. PMID- 20844279 TI - Serum- and feeder-free culture of mouse germline stem cells. AB - Spermatogonial stem cells (SSCs) undergo self-renewal divisions to support spermatogenesis. Although several in vitro SSC culture systems have been developed, these systems include serum or fibroblast feeders, which complicate SSC self-renewal analyses. Here, we developed a serum- and feeder-free culture system for long-term propagation of SSCs. In addition to the SSC self-renewal factors, including glial cell line-derived neurotrophic factor, supplementation with fetuin and lipid-associated molecules was required to drive SSC proliferation in vitro. Cultured cells proliferated for at least 6 mo at a rate comparable to that of serum-supplemented cultured cells. However, germline potential was reduced under serum- and feeder-free conditions, as indicated by a lower SSC frequency after germ cell transplantation. Nevertheless, the cultured cells completed spermatogenesis and produced offspring following spermatogonial transplantation into seminiferous tubules of infertile mice. This culture system provides a basic platform for understanding the regulation of SSC fate commitment in vitro and for improving SSC culture medium. PMID- 20844280 TI - New insights into the regulation of gametogenesis by retinoic acid. PMID- 20844281 TI - Select nutrients in the ovine uterine lumen. VIII. Arginine stimulates proliferation of ovine trophectoderm cells through MTOR-RPS6K-RPS6 signaling cascade and synthesis of nitric oxide and polyamines. AB - During the peri-implantation period in sheep, L-arginine (L-Arg) in the uterine lumen is an essential substrate for the synthesis of nitric oxide (NO), by nitric oxide synthase (NOS), and polyamines, via arginase and ornithine decarboxylase, that are required for survival and development of ovine conceptuses (embryo and its extraembryonic membranes). L-Arginine can stimulate hypertrophy, hyperplasia, and differentiation of the ovine conceptus trophectoderm; however, the responsible signal transduction cascade has not been determined. Therefore, this study examined possible signaling pathways mediated by L-Arg, as well as the effects of two NO donors (S-nitroso-N-acetyl-DL-penicillamine and diethylenetriamine) and putrescine (precursor for spermidine and spermine) on oTr cell proliferation. Further, the inhibition of these effects by L-NAME (L-nitro arginine methyl ester, an inhibitor of NOS) and nor-NOHA (N-omega-hydroxy-nor arginine, an inhibitor of arginase) was assessed. L-Arginine treatment increased the abundance of phosphorylated MTOR, RPS6K, and EIF4EBP1 in oTr cells. Consistent with activation of these cell-signaling molecules, L-Arg increased protein synthesis and reduced protein degradation in oTr cells. Both NO and polyamines enhanced cell proliferation in a dose-dependent manner. The effects of L-Arg were partially inhibited by both L-NAME and nor-NOHA. These results indicate that L-Arg enhances production of polyamines and NO and activates the MTOR/FRAP1-RPS6K-RPS6 signaling pathway to stimulate proliferation and migration of oTr cells. PMID- 20844282 TI - Select nutrients in the ovine uterine lumen. VII. Effects of arginine, leucine, glutamine, and glucose on trophectoderm cell signaling, proliferation, and migration. AB - Histotroph is required for survival and development of ovine conceptuses (embryo and extraembryonic membranes). Results from our laboratory indicate that arginine (Arg), leucine (Leu), glutamine (Gln), and glucose increase in the uterine lumen between Days 10 and 15 of pregnancy, coincident with increases in expression of amino acid and glucose transporters by uterine epithelia as well as trophectoderm and yolk sac of conceptuses and elongation of the conceptus trophectoderm. Therefore, we hypothesized that Arg, Leu, Gln, and glucose have differential effects on hypertrophy, hyperplasia, and differentiated functions of trophectoderm cells that are critical to conceptus development. Primary ovine trophectoderm (oTr) cells isolated from Day 15 conceptuses were serum-starved for 24 h in a customized medium, deprived of select nutrients, and then treated with either Arg, Leu, Gln, or glucose. Western blot analyses of whole oTr cell extracts revealed that Arg, Leu, and glucose, but not Gln, increased phosphorylated AKT1 by 2.8-, 2.5-, and 1.8-fold, respectively, within 15 min, and the increase was maintained to 60 min. Arg, Leu, and glucose also stimulated increases in phosphorylated ribosomal protein S6K (pRPS6K) by 4.2-, 4.7-, and 2.3 fold, respectively, within 15 min, as well as increases in phosphorylated ribosomal protein S6 (pRPS6) between 0 and 30 min posttreatment, that were sustained to 60 min. When oTr cells were treated with Arg, pRPS6K protein increased in nuclei, but this was not observed in nuclei of oTr cells treated with Leu and glucose. Immunocytochemical analyses also revealed abundant amounts of pRPS6 protein in the cytoplasm of oTr cells treated with Arg, Leu, and glucose. Furthermore, Arg and Leu increased proliferation and migration of oTr cells. Collectively, these results indicate that Arg, Leu, and glucose, but not Gln, in histotroph coordinately activate AKT1-mechanistic target of rapamycin and RPS6K-RPS6 cell signaling pathways to stimulate hypertrophy, hyperplasia, and migration of oTr cells. PMID- 20844283 TI - A multi-level systems perspective for the science of team science. AB - This Commentary describes recent research progress and professional developments in the study of scientific teamwork, an area of inquiry termed the "science of team science" (SciTS, pronounced "sahyts"). It proposes a systems perspective that incorporates a mixed-methods approach to SciTS that is commensurate with the conceptual, methodological, and translational complexities addressed within the SciTS field. The theoretically grounded and practically useful framework is intended to integrate existing and future lines of SciTS research to facilitate the field's evolution as it addresses key challenges spanning macro, meso, and micro levels of analysis. PMID- 20844284 TI - GIP: no longer the neglected incretin twin? AB - In the design of therapeutics to treat type 2 diabetes, researchers have exploited the observation that oral ingestion of nutrients leads to the secretion of glucose homeostasis-regulating incretin hormones (for example, glucagon-like peptide-1) from the gut. Here, we discuss two recent papers that suggest that the "other" incretin hormone, gastric inhibitory polypeptide (GIP), also is important in the regulation of glucose homeostasis. These findings warrant further studies to unravel the mechanism of action of GIP in beta-cells of the endocrine pancreas and to evaluate the possibility of designing novel therapeutics that target both incretin hormones. PMID- 20844285 TI - Personalized epigenomic signatures that are stable over time and covary with body mass index. AB - The epigenome consists of non-sequence-based modifications, such as DNA methylation, that are heritable during cell division and that may affect normal phenotypes and predisposition to disease. Here, we have performed an unbiased genome-scale analysis of ~4 million CpG sites in 74 individuals with comprehensive array-based relative methylation (CHARM) analysis. We found 227 regions that showed extreme interindividual variability [variably methylated regions (VMRs)] across the genome, which are enriched for developmental genes based on Gene Ontology analysis. Furthermore, half of these VMRs were stable within individuals over an average of 11 years, and these VMRs defined a personalized epigenomic signature. Four of these VMRs showed covariation with body mass index consistently at two study visits and were located in or near genes previously implicated in regulating body weight or diabetes. This work suggests an epigenetic strategy for identifying patients at risk of common disease. PMID- 20844287 TI - Clinical year in review I: interstitial lung disease, pulmonary vascular disease and venous thromboembolism, diagnostic imaging, and lung cancer. PMID- 20844288 TI - Clinical year in review II: bronchiectasis, mycobacterial infections of the lung, sleep-disordered breathing, and lung transplantation. PMID- 20844289 TI - Clinical year in review III: pulmonary rehabilitation, respiratory health effects of smoking, genetics of lung disease, and chronic obstructive pulmonary disease. PMID- 20844290 TI - Clinical year in review IV: advances in critical care medicine, end-of-life care of the critically ill patient, asthma, and mechanical ventilation. PMID- 20844286 TI - Disruption at the PTCHD1 Locus on Xp22.11 in Autism spectrum disorder and intellectual disability. AB - Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability. PMID- 20844291 TI - An official American Thoracic Society Workshop report: obesity and asthma. AB - RATIONALE: The developed world is currently facing an epidemic of obesity. With the increased prevalence of obesity has come the recognition that obesity is a risk factor for asthma. OBJECTIVES: The purpose of this workshop was to bring together experts in the field of asthma, with experts in the field of obesity to review the current state-of-the-art knowledge regarding obesity and asthma, with the goal of furthering our understanding of the link between these two disease entities to help define important future directions for research. METHODS: Speakers were invited to give presentations highlighting recent developments in their area of expertise that were related to obesity and lung disease. These presentations were followed by interactive discussion. A writing committee from among the participants produced a document summarizing the proceedings. MEASUREMENTS AND MAIN RESULTS: The participants found that obesity was a risk factor for asthma in all demographic groups studied. Asthma in the obese may represent a unique phenotype of asthma, with more severe disease that does not respond as well to conventional therapy. Factors that could contribute to the pathogenesis of asthma in the obese include both mechanical factors and altered inflammation and immune responses related to the obese state. CONCLUSIONS: There is an urgent need for research to better understand the mechanisms of asthma in the obese, and to develop new therapies specifically targeted to this unique patient population. PMID- 20844292 TI - Maternal smoking during pregnancy and physical control and coordination among offspring. AB - BACKGROUND: To examine if smoking during pregnancy is associated with poorer motor competence among offspring, indicating impaired neurological function. The measures may be less susceptible to socioeconomic confounding than cognition tests. METHODS: Data were from 13,207 members of the National Child Development Study, born in Great Britain in 1958. Maternal smoking during pregnancy was recorded prospectively. Tests of physical control and coordination administered by a school doctor at age 11 years were: time to pick up 20 matches (PUM), number of squares marked (NSM) and copying designs (CD). PUM and NSM were tested for left and right hand. Test scores were dependent variables in linear regression analysis, with adjustment for maternal smoking during pregnancy, sex, birth weight standardised for gestational age, breast-feeding, social class, parental education, mother's age, laterality and pubertal development. RESULTS: After adjustment, heavy smoking during pregnancy was statistically significantly associated with PUM (non-dominant hand) and CD, but not NSM; particularly among boys. The regression coefficients (and 95% CI) for PUM (non-dominant hand) are 1.474 (0.47 to 2.48, p=0.004) and 1.203 (0.15 to 2.26, p=0.026) for boys and girls, respectively: higher scores indicate poorer performance. The coefficients for CD are -0.185 (-0.32 to -0.05, p=0.006) for boys and 0.020 (-0.11 to 0.15, p=0.753) for girls: lower scores indicate poorer performance. CONCLUSIONS: Smoking during pregnancy is associated with subtly reduced motor competence, particularly on the non-dominant side. Statistically significant effect modification by sex was observed for only one test, providing equivocal evidence of a sex difference. PMID- 20844293 TI - Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. AB - BACKGROUND: Previous studies have shown that aspirin and other non-steroidal anti inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are not defined. In a large population-based case-control study, we have explored the relationship between NSAID dose and duration, CRC risk and overall CRC-specific survival. METHODS: The relationship between NSAID use and CRC risk was examined in 2279 cases and 2907 controls. Subjects completed food-frequency and lifestyle questionnaires. NSAID categories were low-dose aspirin (75 mg), non-aspirin NSAIDs (NA-NSAIDs) and any NSAID. Users were defined as taking >4 tablets/week for >1 month. ORs were calculated by logistic regression models and adjusted for potential confounding factors. Effect of NSAID use on all-cause and CRC-specific mortality was estimated using Logrank tests and Cox's hazard models. RESULTS: In all, 354 cases (15.5%) were taking low-dose aspirin compared to 526 controls (18.1%). Low-dose aspirin use was associated with decreased CRC risk (OR 0.78 95% CI 0.65 to 0.92, p=0.004), evident after 1 year and increasing with duration of use (p(trend)=0.004). NA-NSAID and any NSAID use were also inversely associated with CRC. There was no demonstrable effect of NSAIDS on all-cause (HR 1.11, p=0.22, 0.94-1.33) or CRC-specific survival (HR 1.01, p=0.93, 0.83-1.23). CONCLUSION: This is the first study to demonstrate a protective effect against CRC associated with the lowest dose of aspirin (75 mg per day) after only 5 years use in the general population. NSAID use prior to CRC diagnosis does not influence survival from the disease. PMID- 20844295 TI - Discuss injectable shaping agents within the context of the established and emerging concepts of facial aging. Introduction. PMID- 20844296 TI - Update on facial aging. AB - Facial aging was once thought to be the result of the relentless downward pull of gravity on skin and underlying fat. In turn, facial fat was believed to be a contiguous sheet of tissue. However, over the past four decades, a number of investigators have examined more closely the causes of facial aging, leading to a better understanding of age-related changes, and have confirmed and further explored the proposal by Gonzalez-Ulloa and Flores in 1965 that facial aging involves changes in muscle and bone, as well as skin and fat. Further, the recent work of Rohrich and Pessa (and other authors) has demonstrated that facial fat is not a sheet of tissue, but rather is compartmentalized throughout the face. This discovery has allowed the evolution of improved techniques for facial rejuvenation. PMID- 20844294 TI - Effects of depressive symptoms and coronary heart disease and their interactive associations on mortality in middle-aged adults: the Whitehall II cohort study. AB - BACKGROUND: Depression and mortality have been studied separately in patients with coronary heart disease (CHD) and in populations healthy at study inception. This does not allow comparisons across risk-factor groups based on the cross classification of depression and CHD status. OBJECTIVE: To examine effects of depressive symptoms and CHD and their interactive associations on mortality in middle-aged adults followed over 5.6years. DESIGN AND SETTING: A prospective population-based cohort study of 5936 middle-aged men and women from the British Whitehall II study. We created four risk-factor groups based on the cross classification of depressive symptoms and CHD status. RESULTS: The age-adjusted and sex-adjusted hazard ratios for death from all causes were 1.67 (p<0.05) for participants with only CHD, 2.10 (p<0.001) for those with only depressive symptoms and 4.99 (p<0.001) for those with both CHD and depressive symptoms when compared to participants without either condition. The two latter risk-factor groups remained at increased risk after adjustments for relevant confounders. The relative excess risk due to the interaction between depressive symptoms and CHD for all-cause mortality was 3.58 (95% CI -0.09 to 7.26), showing some evidence of an additive interaction. A similar pattern was also observed for cardiovascular death. CONCLUSIONS: This study provides evidence that depressive symptoms are associated with an increased risk of all-cause and cardiovascular death and that this risk is particularly marked in depressive participants with co-morbid CHD. PMID- 20844297 TI - Facial aesthetic analysis. AB - Consideration of the individual patient's appearance based on systematic mapping and a three-dimensional evaluation of the four levels of facial structure (bone, muscle, fat, and skin) will help the clinician choose the most appropriate modalities for facial rejuvenation. This article addresses these concepts and also discusses universal perceptions of attractiveness. PMID- 20844298 TI - Surgical versus nonsurgical rejuvenation. AB - The number of cosmetic procedures for facial rejuvenation has increased steadily over the past decade. The increase in the application of nonsurgical modalities, particularly injectable shaping agents, has been remarkable. As knowledge and experience about facial aging has increased, techniques and tools have improved, and it is increasingly apparent that surgical and nonsurgical/injectable modalities are complementary. PMID- 20844299 TI - Nonsurgical modalities to treat the aging face. AB - Injectable shaping agents include neurotoxins (botulinum toxin type A products), replacement fillers (hyaluronic acid [HA] agents), and biostimulatory fillers (calcium hydroxylapatite [CaHA], polymethylmethacrylate [PMMA], and poly-L-lactic acid [PLLA]). This article presents an overview of the agents currently available for use in facial rejuvenation in the United States. PMID- 20844300 TI - Appropriate selection and application of nonsurgical facial rejuvenation agents and procedures: panel consensus recommendations. AB - As injectable products have been introduced and as clinicians have gained experience with them, applications and techniques for injection have evolved, with better cosmetic results, enhanced patient safety, and greatly improved patient satisfaction. Within the past four years, several consensus recommendation panels have been convened to summarize the accumulated clinical experience and knowledge about the application of these products. The guidelines that already exist in the literature are referred to, and suggested guidelines for the administration of poly-L-lactic acid-for which no consensus guidelines have previously been published-are included in this article. PMID- 20844302 TI - [A concept of neuromyelitis optica in Japan]. AB - Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by relapses of optic neuritis and acute myelitis. The disease was referred to as the optic-spinal form of multiple sclerosis (OSMS) in Japan for a long period. A specific auto-antibody, NMO-IgG, was detected in the serum of NMO patients, and aquaporin-4 water channel protein was detected as its target antigen; aquaporin-4 water channel protein is localized at the end-feet of astrocytes. Because of the presence of this specific serum auto-antibody, most OSMS patients in Japan were found to exhibit a disease that was identical to NMO that affects individuals of the Western countries. Since the discovery of NMO IgG, various clinical and histopathological features of this condition have been recognized; in addition the concept of NMO has been established in Japan as well as in many other countries. PMID- 20844303 TI - [New insights into the pathogenesis of neuromyelitis optica]. AB - Recently, the disease-specific antibody was found in the sera from neuromyelitis optica (NMO) patients, and its target was identified as aquaporin-4 (AQP4), mainly expressed in astroglial foot processes. In our immunohistochemical studies, loss of AQP4 and glial fibrillary acidic protein (GFAP) was evident in about 90% of NMO lesions, especially in perivascular areas of acute inflammatory lesions where immunoglobulins and complements were deposited. In contrast, myelin basic protein (MBP)-stained myelinated fibers were relatively preserved in those lesions, which probably suggested the secondary damage of myelin sheaths following astrocytic damage. Recently, there are developing evidences of the effect of AQP4 antibody in vitro or in vivo. In HEK293 cells transfected with AQP4, AQP4 antibody could bind to the membrane AQP4, and induced the degradation and endocytosis of AQP4 in complement-dependent manner. In vitro experiments by primary cultured astrocytes, AQP4 antibody had cytotoxic effects with complement, and also could impair the astrocytic function such as the maintenance of the blood brain barrier or glutamate homeostasis. In vivo study, the lesions lacking AQP4 and GFAP was appeared by passive-transferred Lewis rats with human purified IgG from NMO patients. Furthermore, in cerebrospinal fluid (CSF) biomarker study, astrocytic damage reflected by marked increase of CSF-GFAP, far severe than demyelination (CSF-MBP), was evident in NMO but not in classical multiple sclerosis (MS). These evidences suggested the pathogenic role of AQP4 antibody with astrocytopathy in NMO. Now it is indispensable to check the AQP4 antibody,and is important to reconsider the role of astrocyte in demyelinating disorders. PMID- 20844304 TI - [Clinical features of NMO according to brain MRI findings]. AB - Neuromyelitis optica (NMO) is a severe inflammatory, demyelinating disease, and its clinical characteristics include recurrent optic neuritis and longitudinally extensive transverse myelitis. The NMO-immunoglobulin (Ig) G auto-antibody (Ab), which binds to the aquaporin-4 (AQP4) water channel protein, is a marker for NMO. These clinical and immunological features have been used to distinguish NMO from multiple sclerosis (MS). In 1999, Wingerchuk et al. broadened the clinical criteria for diagnosing NMO to include "negative brain magnetic resonance imaging (MRI) at onset." However, after NMO-IgG/AQP4-Ab became a supportive criterion for diagnosing NMO, patients with NMO were frequently found to have symptomatic or asymptomatic brain lesions. In 2006, Pittock et al. reported that asymptomatic brain lesions were common in NMO, and that NMO brain lesions characteristically occurred in the hypothalamus and periventricular areas, which correspond to brain regions with high levels of AQP4 expression. Furthermore, Nakashima et al. detected abnormalities on brain MRI in 71% of NMO-IgG-positive Japanese patients. Patients with NMO have unique brain lesions that are clearly different from the lesions of patients with MS. In patients with NMO, involvement of the dorsal portion of the medulla oblongata causes intractable hiccups and nausea. Some studies described a hypothalamic lesion, and hypothalamic dysfunction could cause symptomatic hypersomnia, narcolepsy, and endocrinopathies. In some patients with NMO and NMO spectrum disorder who experience blood pressure fluctuations, vasogenic edema, manifesting as posterior reversible encephalopathy syndrome, may occur. In a recent report highlighting brain MRI with contrast enhancement, the most prominent feature that appeared to be a specific finding in NMO was "cloud like enhancement" with multiple patchy enhancing lesions with a blurred margin. Another report showed that acute, large, edematous callosal lesions with heterogeneous intensity ("marbled pattern") occasionally occur in NMO. This review presents the characteristic clinical features of NMO according to the brain MRI findings and the features that can be used to distinguish NMO from MS. PMID- 20844305 TI - [Treatment and clinical management of patients with neuromyelitis optica and anti aquaporin 4 antibody]. AB - Neuromyelitis optica (NMO) is a unique inflammatory condition characterized by selective involvement of the optic nerves and spinal cord. The cardinal features of NMO and a tendency of recurrence led to the classification of NMO as a subtype of multiple sclerosis (MS); however, it can be distinguished from MS on the basis of clinicoradiological and serological findings. In particular, NMO is characterized by the presence of spinal cord lesions that are longer than the total length of 3 vertebral segments and presence of anti-aquaporin 4 antibodies. Secondary progression of this condition is usually not observed, and therapy for NMO patients is designed to prevent acute exacerbations and limit irreversible neurological disability. Intravenous administration of a high dose of methylprednisolone is a standard treatment for patients with acute exacerbations of this condition, and patients with refractory cases are often responsive to plasmapheresis. To reduce the frequency of relapses and severity, standard therapies for MS, such as interferon-beta therapy, are not effective; further, a long-term immunosuppressive therapy is required for NMO patients. Immunosuppressive therapies often involve oral administration of prednisolone with or without azathioprine; patients who are refractory to the oral therapy may be treated by parental administration of cyclophosphamide, mitoxantrone, or rituximab. At present, there is no cure for NMO; early and precise diagnosis is critical to initiate immunosuppressive therapy for prevention of relapse. PMID- 20844306 TI - [Differential diagnosis of neuromyelitis optica spectrum disorders]. AB - Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system that preferentially affects the optic nerves and spinal cord. NMO-IgG/anti aquaporin 4 antibody (AQP4-Ab) is considered as a specific diagnostic marker for NMO. A previous study using animal models passively transferred with AQP4-Ab has partially proven that NMO-IgG/AQP4-Ab has an effector function in the pathogenesis of NMO, exemplifying the diagnostic significance of this antibody. Further, this marker can be used to differentiate the limited forms of NMO, such as recurrent myelitis or optic neuritis or NMO with isolated cerebral/brainstem lesions during the early course of the disease, from other diseases with a different etiology. NMO spectrum disorders (NMOSD) comprise these clinically heterogeneous conditions, all of which are positive for AQP4-Ab. However, few patients show clinical characteristic features of NMO, without AQP4-Ab positivity. We should be careful to introduce interferon beta for the prevention of relapse to these seronegative but suspicious for NMO patients. A few NMOSD patients have also been diagnosed with systemic lupus erythematosus (SLE) or Sjogren syndrome (SjS). However, there have been no reported cases of patients with SLE/SjS who do not exhibit any neurological symptoms and AQP4-Ab-positivity, and it is likely that these 2 autoimmune diseases incidentally overlap. NMO might follow myasthenia gravis (MG), after thymectomy for the treatment of MG. Taken together,as in the case of other systemic autoimmune diseases,an antibody mediated pathomechanism of NMO is suggested. PMID- 20844307 TI - [AQP4 immunohistochemistry in neuromyelitis optica and multiple sclerosis: a neuropathological review]. AB - We retrospectively analyzed and compared patterns of anti-aquaporin-4 (AQP4) immunoreactivity of autopsied brains of 2 patients with classical multiple sclerosis (MS) and 2 patients with neuromyelitis optica (NMO). Serological examination for NMO-IgG was not performed in all the cases. We confirmed that the expression of AQP4 is strongly inhibited in demyelinating lesions of NMO, accompanied by the loss of grial fibrillary acidic protein (GFAP) expression. The expression of AQP4 is preserved in MS lesions losing myelin basic protein (MBP) positivity. Therefore, AQP4 immunoreactivity may distinguish NMO from MS neuropathologically. NMO preferentially exhibited central lesions of the spinal cord with strongly necrotizing features and axonal injury. One NMO patient with oligoclonal band in the cerebrospinal fluid presented severe necrotizing lesions of the corpus callosum, cerebral white matter in addition to optic nerves and longitudinally extensive spinal cord lesions. Another patient with MS presented longitudinally extensive spinal cord lesions and a lesion in the medullary tegmentum in the floor of the fourth ventricle, which is reported to be one of the vulnerable lesions of NMO. We also reported a patient with NMO accompanied with Sjogren syndrome. These findings suggest that longitudinally extensive spinal cord lesions and medullary tegmentum lesion may be found in MS,and cerebral white matter lesion may be found in NMO. The distribution of lesions may overlap in MS and NMO although the immunoreactivity of AQP4 differs in these 2 conditions. PMID- 20844309 TI - [Isolated trigeminal neuropathy involved with motor dysfunction due to small infarction in the pontine tegmentum]. AB - We present a case of isolated trigeminal neuropathy involved with motor dysfunction due to a small infarction in the pontine tegmentum. A 70-year-old man presented with sudden numbness around the left mouth accompanied by maxillary pain. Neurological examinations revealed jaw deviation to the left when opening the mouth, but no other abnormal findings including those of the cranial nerves were detected. X-rays indicated hypomobility of the left temporomandibular joint, and diffusion-weighted magnetic resonance imaging (MRI) revealed a small infarction in the left pontine tegmentum. Unilateral limitation of the temporomandibular joint movement, numbness, and pain in the territory of the left trigeminal nerve resolved within 2 months. This case suggests that a small infarction in the pontine tegmentum can simultaneously cause trigeminal neuralgia and masticatory muscle weakness with no other symptoms and signs. MRI, especially diffusion-weighted imaging, should be considered for patients with isolated trigeminal neuropathy. PMID- 20844308 TI - [Autism spectrum disorders--recent advances in the research on the impairment in social communication]. AB - Since the discovery of early infantile autism (1943), the etiology of the disease has for long been a matter of dispute-from a form of innate schizophrenia, maltreatment by 'refrigerator mother', to dysfunction of speech development. After the re-discovery of Asperger syndrome by Wing (1981), the concept of this diverse syndrome complex has merged to pervasive developmental disorders (PDD) or autism spectrum disorders (ASD). People suffering from Asperger syndrome do not show impairments in speech development, in fact, they have good linguistic abilities. They can explain their own psychopathology, which helps in the understanding of classical autism with profound mental retardation. Currently, ASD is prevalent in 1 of 150 births with strong genetic inheritance. ASD is therefore thought a psychiatric common disease. Asperger syndrome has frequently been the subject of neuroimaging studies,since social communication is an important characteristic of human behavior. This review encompasses a historical and clinical overview of ASD and puts force the current perspectives on the researches in animal models,genetic studies of animal and human samples,and neuroimaging studies. Our current focus is the possible role of oxytocin,which was recently found to have an effect on empathy,in the etiology of ASD. PMID- 20844310 TI - [Meaning, phonological, orthography and kinestic route of reading and writing: a case with alexia and agraphia due to the left parietal lesion]. AB - Abstract A 69-year-old right-handed man developed alexia with agraphia after resection of a brain tumor in the left parietal lobe. After the operation, neurological examination revealed right lower quadrantanopia, mild paresis and sensory disturbance on the right side. He showed marked alexia with agraphia, very mild aphasia, acalculia, and constructional disability. In reading tasks, he was able to read kanji word and kana words but not a single kana character or nonword. After he traced a single kana character or kana nonword, he was able to read it. In writing tasks, he could write kana but not kanji characters, except simple kanji characters that involved less than 4 strokes. These findings indicated that kinesthetic traces may enable such patients to read and write. We propose that processes of reading and writing may include kinesthetic route in addition to the meaning, phonological, and orthographical routes. PMID- 20844311 TI - [A case of cerebral venous angioma associated with a varix in great vein of Galen]. PMID- 20844312 TI - [One hundred books which built up neurology (45)--Louis Florentin Calmeil "De la Paralysie consideree chez les Alienes" (1826)]. PMID- 20844313 TI - CeKlotho opens a new road for investigation in worm aging. PMID- 20844314 TI - The ASK1-Signalosome regulates p38 MAPK activity in response to levels of endogenous oxidative stress in the Klotho mouse models of aging. AB - Reactive oxygen species (ROS) and elevated levels of p38 MAPK activity accelerate physiological aging. This emphasizes the importance of understanding the molecular mechanism(s) that link ROS production to activation of the p38 mediated promotion of aging, longevity, and resistance to oxidative stress. We examined Klotho(-/-) (elevated ROS) and Klotho overexpressing mice (low ROS and resistance to ROS) to determine whether the ROS-sensitive apoptosis signal-regulating kinase (ASK1)-signalosome -> p38 MAPK pathway plays a role in the accelerated aging of Klotho(-/-), and resistance to oxidative stress and extended lifespan in the Klotho overexpressing models. Our results suggest that increased endogenous ROS generated by Klotho(-/-) and resistance to oxidative stress in Klotho overexpression are linked to the regulation of ASK1-signalosome -> p38 activity. We propose that (a) the ASK1-signalosome -> p38 MAPK pathway is activated by oxidative stress due to ablation of the Klotho gene; (b) increased longevity by Klotho overexpression is linked to suppression of the ASK1-signalosome-p38 MAPK activity; (c) the ROS-responsive ASK1-signalosome regulates physiological aging via its regulation of p38 MAPK, through a mechanism that balances the levels of inhibitory vs. activating ASK1-signalosomes. We conclude that the Klotho suppressor-of-aging activity is linked to the ASK1-signalsome, a physiological ROS-sensitive signaling center. PMID- 20844315 TI - Klotho interferes with a novel FGF-signalling pathway and insulin/Igf-like signalling to improve longevity and stress resistance in Caenorhabditis elegans. AB - Klotho exerts anti-aging properties in mammals in two different ways. While membrane-bound Klotho, which is primarily expressed in the kidney, acts as an obligate co-receptor of FGF23 to regulate phosphate homeostasis, secreted Klotho, resulting from the shedding of the KL1-KL2 ectodomain into the bloodstream, inhibits Insulin/IGF1 signalling. However, the underlying molecular mechanisms are not fully understood. Here, we investigated the biological role of Klotho in Caenorhabditis elegans. Two redundant homologues of the klotho gene exist in C. elegans and encode predicted proteins homologous to the ? glucosidase-like KL1 domain of mammalian Klotho. We have used a genetic approach to investigate the functional activity of Klotho in C. elegans. Here, we report that whereas Klotho requires EGL-15 (FGFR) and EGL-17 to promote longevity and oxidative stress resistance, it is not involved in the regulation of fluid homeostasis, controlled by LET-756. Besides revealing a new post-developmental role for EGL-17, our data suggest that the KL1 form of Klotho is involved in FGF23-independent FGF signalling. We also report a genetic interaction between Klotho and the DAF-2 (Ins/IGF1R)/DAF-16 (FOXO) pathway. While the regulation of longevity requires functional DAF-2/DAF-16 signalling, the control of oxidative stress resistance involves a DAF-2- independent, DAF-16-dependent pathway, suggesting that Klotho may target either DAF-2 or DAF-16, depending of environmental conditions. Thus, the predictive KL1 form of Klotho appears to crosstalk with both FGF and Insulin/IGF1/FOXO pathways to exert anti-aging properties in C. elegans. PMID- 20844316 TI - Adult-onset, short-term dietary restriction reduces cell senescence in mice. AB - Dietary restriction (DR) extends the lifespan of a wide variety of species and reduces the incidence of major age-related diseases. Cell senescence has been proposed as one causal mechanism for tissue and organism ageing. We show for the first time that adult-onset, short-term DR reduced frequencies of senescent cells in the small intestinal epithelium and liver of mice, which are tissues known to accumulate increased numbers of senescent cells with advancing age. This reduction was associated with improved telomere maintenance without increased telomerase activity. We also found a decrease in cumulative oxidative stress markers in the same compartments despite absence of significant changes in steady state oxidative stress markers at the whole tissue level. The data suggest the possibility that reduction of cell senescence may be a primary consequence of DR which in turn may explain known effects of DR such as improved mitochondrial function and reduced production of reactive oxygen species. PMID- 20844319 TI - Development of a novel AMX-loaded PLGA/zein microsphere for root canal disinfection. AB - The aim of this study was to develop polymeric biodegradable microspheres (MSs) of poly(D-L lactide-co-glycolide) (PLGA) and zein capable of delivering amoxicillin (AMX) at significant levels for root canal disinfection. PLGA/zein MSs were prepared using a spray-drying technique. The systems were characterized in terms of particle size, morphology, drug loading and in vitro release. Drug levels were reached to be effective during the intracanal dressing in between visits during the endodontic treatment. In vitro release studies were carried out to understand the release profile of the MSs. Antimicrobial activity of AMX was performed by antibiograms. Enterococcus faecalis was the bacteria selected due to its prevalence in endodontic failure. Drug microencapsulation yielded MSs with spherical morphology and an average particle size of between 5 and 38 um. Different drug-release patterns were obtained among the formulations. Release features related to the MSs were strongly dependent on drug nature as it was demonstrated by using a hydrophobic drug (indomethacin). Finally, AMX-loaded MSs were efficient against E faecalis as demonstrated by the antibiogram results. In conclusion, PLGA/zein MSs prepared by spray drying may be a useful drug delivery system for root canal disinfection. PMID- 20844318 TI - In vitro biocompatibility of plasma-aided surface-modified 316L stainless steel for intracoronary stents. AB - 316L-type stainless steel is a raw material mostly used for manufacturing metallic coronary stents. The purpose of this study was to examine the chemical, wettability, cytotoxic and haemocompatibility properties of 316L stainless steel stents which were modified by plasma polymerization. Six different polymeric compounds, polyethylene glycol, 2-hydroxyethyl methacrylate, ethylenediamine, acrylic acid, hexamethyldisilane and hexamethyldisiloxane, were used in a radio frequency glow discharge plasma polymerization system. As a model antiproliferative drug, mitomycin-C was chosen for covalent coupling onto the stent surface. Modified SS 316L stents were characterized by water contact angle measurements (goniometer) and x-ray photoelectron spectroscopy. C1s binding energies showed a good correlation with the literature. Haemocompatibility tests of coated SS 316L stents showed significant latency (t-test, p < 0.05) with respect to SS 316L and control groups in each test. PMID- 20844320 TI - Effects of functional groups and soluble matrices in fish otolith on calcium carbonate mineralization. AB - Calcium carbonate mineralization is significantly influenced by organic matrices in vivo. The effect mainly relies on functional groups in proteins. In order to study the influence of functional groups on calcium carbonate mineralization, OH, -NH2 and -COOH groups were grafted onto single crystal silicon chips, and such modified chips were used as substrates in in vitro mineralization experiments. An x-ray photoelectron spectroscopy (XPS) test was conducted to examine the grafting efficiency, and the three groups were successfully grafted. Calcium carbonate mineralization on a modified silicon substrate was examined by a scanning electron microscope (SEM) and x-ray diffraction (XRD), and the results showed that the effects of -OH, -NH2 and -COOH groups were quite different. Furthermore, a water-soluble protein matrix (WSM) and an acid-soluble protein matrix (ASM) extracted from fish otolith were adsorbed onto the -COOH-modified silicon substrate, and the effects of the protein matrices on calcium carbonate mineralization were studied. The results showed that both WSM and ASM of lapillus could mediate aragonite crystallization, but the size and morphology of the formed crystals were different. The WSM and ASM of asteriscus adsorbed on the silicon substrate had little effect on calcium carbonate mineralization; almost all the crystals were calcite, while both asteriscus WSM and ASM in solution could mediate vaterite crystals, and the morphologies of vaterite crystal aggregates were different. PMID- 20844317 TI - ATM-independent, high-fidelity nonhomologous end joining predominates in human embryonic stem cells. AB - We recently demonstrated that human embryonic stem cells (hESCs) utilize homologous recombination repair (HRR) as primary means of double-strand break (DSB) repair. We now show that hESCs also use nonhomologous end joining (NHEJ). NHEJ kinetics were several-fold slower in hESCs and neural progenitors (NPs) than in astrocytes derived from hESCs. ATM and DNA-PKcs inhibitors were ineffective or partially effective, respectively, at inhibiting NHEJ in hESCs, whereas progressively more inhibition was seen in NPs and astrocytes. The lack of any major involvement of DNA-PKcs in NHEJ in hESCs was supported by siRNA-mediated DNA-PKcs knockdown. Expression of a truncated XRCC4 decoy or XRCC4 knock-down reduced NHEJ by more than half suggesting that repair is primarily canonical NHEJ. Poly(ADP-ribose) polymerase (PARP) was dispensable for NHEJ suggesting that repair is largely independent of backup NHEJ. Furthermore, as hESCs differentiated a progressive decrease in the accuracy of NHEJ was observed. Altogether, we conclude that NHEJ in hESCs is largely independent of ATM, DNA PKcs, and PARP but dependent on XRCC4 with repair fidelity several-fold greater than in astrocytes. PMID- 20844321 TI - Fabrication and mechanical characterization of 3D electrospun scaffolds for tissue engineering. AB - Electrospinning is a polymer processing technique that produces fibrous structures comparable to the extracellular matrix of many tissues. Electrospinning, however, has been severely limited in its tissue engineering capabilities because this technique has produced few three-dimensional structures. Sintering of electrospun materials provides a method to fabricate unique architectures and allow much larger structures to be made. Electrospun mats were sintered into strips and cylinders, and their tensile and compressive mechanical properties were measured. In addition, electrospun materials with salt pores (salt embedded within the material and then leached out) were fabricated to improve porosity of the electrospun materials for tissue engineering scaffolds. Sintered electrospun poly(D,L-lactide) and poly(L-lactide) (PDLA/PLLA) materials have higher tensile mechanical properties (modulus: 72.3 MPa, yield: 960 kPa) compared to unsintered PLLA (modulus: 40.36 MPa, yield: 675.5 kPa). Electrospun PDLA/PLLA cylinders with and without salt-leached pores had compressive moduli of 6.69 and 26.86 MPa, respectively, and compressive yields of 1.36 and 0.56 MPa, respectively. Sintering of electrospun materials is a novel technique that improves electrospinning application in tissue engineering by increasing the size and types of electrospun structures that can be fabricated. PMID- 20844322 TI - Controlled photoluminescence from self-assembled semiconductor-metal quantum dot hybrid array films. AB - Thin films of hybrid arrays of cadmium selenide quantum dots and polymer grafted gold nanoparticles have been prepared using a BCP template. Controlling the dispersion and location of the respective nanoparticles allows us to tune the exciton-plasmon interaction in such hybrid arrays and hence control their optical properties. The observed photoluminescence of the hybrid array films is interpreted in terms of the dispersion and location of the gold nanoparticles and quantum dots in the block copolymer matrix. PMID- 20844323 TI - The structure and growth mechanism of Si nanoneedles prepared by plasma-enhanced chemical vapor deposition. AB - Silicon nanowires and nanoneedles show promise for many device applications in nanoelectronics and nanophotonics, but the remaining challenge is to grow them at low temperatures on low-cost materials. Here we present plasma-enhanced chemical vapor deposition of crystalline/amorphous Si nanoneedles on glass at temperatures as low as 250 degrees C. High resolution electron microscopy and micro-Raman spectroscopy have been used to study the crystal structure and the growth mechanism of individual Si nanoneedles. The H(2) dilution of the SiH(4) plasma working gas has caused the formation of extremely sharp nanoneedle tips that in some cases do not contain a catalytic particle at the end. PMID- 20844324 TI - Au-nanoprobes for detection of SNPs associated with antibiotic resistance in Mycobacterium tuberculosis. AB - Tuberculosis (TB) is one of the leading causes of infection in humans, causing high morbility and mortality all over the world. The rate of new cases of multidrug resistant tuberculosis (MDRTB) continues to increase, and since these infections are very difficult to manage, they constitute a serious health problem. In most cases, drug resistance in Mycobacterium tuberculosis has been related to mutations in several loci within the pathogen's genome. The development of fast, cheap and simple screening methodologies would be of paramount relevance for the early detection of these mutations, essential for the timely and effective diagnosis and management of MDRTB patients. The use of gold nanoparticles derivatized with thiol-modified oligonucleotides (Au-nanoprobes) has led to new approaches in molecular diagnostics. Based on the differential non cross-linking aggregation of Au-nanoprobes, we were able to develop a colorimetric method for the detection of specific sequences and to apply this approach to pathogen identification and single base mutations/single nucleotide polymorphisms (SNP) discrimination. Here we report on the development of Au nanoprobes for the specific identification of SNPs within the beta subunit of the RNA polymerase (rpoB locus), responsible for resistance to rifampicin in over 95% of rifampicin resistant M. tuberculosis strains. PMID- 20844325 TI - Continuous flow synthesis of nanoparticles using ceramic microfluidic devices. AB - A microfluidic system based on the low-temperature co-fired ceramics technology (LTCC) is proposed to reproducibly carry out a simple one-phase synthesis and functionalization of monodispersed gold nanoparticles. It takes advantage of the LTCC technology, offering a fast prototyping without the need to use sophisticated facilities, reducing significantly the cost and production time of microfluidic systems. Some other interesting advantages of the ceramic materials compared to glass, silicon or polymers are their versatility and chemical resistivity. The technology enables the construction of multilayered systems, which can integrate other mechanical, electronic and fluidic components in a single substrate. This approach allows rapid, easy, low cost and automated synthesis of the gold colloidal, thus it becomes a useful approach in the progression from laboratory scale to pilot-line scale processes, which is currently demanded. PMID- 20844326 TI - The structural properties of GaN/AlN core-shell nanocolumn heterostructures. AB - The growth and structural properties of GaN/AlN core-shell nanowire heterostructures have been studied using a combination of resonant x-ray diffraction, Raman spectroscopy and high resolution transmission electron microscopy experiments. For a GaN core of 20 nm diameter on average surrounded by a homogeneous AlN shell, the built-in strain in GaN is found to agree with theoretical calculations performed using a valence force field model. It is then concluded that for an AlN thickness up to at least 12 nm both core and shell are in elastic equilibrium. However, in the case of an inhomogeneous growth of the AlN shell caused by the presence of steps on the sides of the GaN core, plastic relaxation is found to occur. Consistent with the presence of dislocations at the GaN/AlN interface, it is proposed that this plastic relaxation, especially efficient for AlN shell thickness above 3 nm, is promoted by the shear strain induced by the AlN inhomogeneity. PMID- 20844327 TI - Enhancing the photoelectrical performance of dye-sensitized solar cells using TiO2:Eu3+ nanorods. AB - TiO(2):Eu(3+) nanorods are hydrothermally grown and used to fabricate a bilayer film electrode in a dye-sensitized solar cell. A light-to-electrical energy conversion efficiency of 8.0% and a quantum efficiency of 93.7% (at 575 nm) is achieved in this solar cell. The high efficiency is due to the improvement of ultraviolet light harvesting via a down-conversion luminescence process by the Eu(3+) ion and the increase of light scattering by one-dimensional TiO(2). PMID- 20844328 TI - A phenomenological kV beam model for cone-beam imaging. AB - A phenomenological kV beam model was developed to address attenuation and scatter in radiographic images for the purpose of cone-beam imaging. Characterization of a kV beam in terms of the minimal number of parameters and calculation of attenuation and scatter in radiographs of scanned objects are the main applications of this model. Model parameters are derived from radiographs of homogeneous solid water phantoms for various depths and field sizes. The response of the cone-beam detector to kV beams is factorized into different contributions such as output factor, tissue-air ratio and off-axis ratio, with each contribution having an analytical representation. The formulas which are used to characterize the beam model in uniform phantoms are then extended to arbitrary objects using the concept of the water-equivalent pathlength. A weighted sum of three Gaussians in each direction models the dose deposition kernel. Detector response arising from the first Gaussian term can be interpreted as the primary signal while the second and third Gaussians constitute short- and long-range scatter. The model is then applied to predict the primary and scatter signals for arbitrary objects. A technique of scatter removal from the measured radiographs is investigated. The model accurately predicts detector response of varying thickness phantoms such as multi-step and cylindrical phantoms. The scatter contributes over 90% to the total signal for 20 cm thick phantoms. The calculated scatter-to-primary ratio as a function of spatial coordinates agrees with Monte Carlo studies reported in the literature. Water-equivalent thickness related to primary and scatter contributions calculated from an analysis of radiographs results in an improved calibration technique suitable for CB-CT reconstruction. The kV beam model and the associated theoretical formulations can be utilized to characterize any kV beam line; however, for the specific study the OBI system (Varian) was used to obtain experimental radiographs. PMID- 20844329 TI - Temperature changes associated with radiofrequency exposure near authentic metallic implants in the head phantom--a near field simulation study with 900, 1800 and 2450 MHz dipole. AB - Along with increased use of wireless communication devices operating in the radiofrequency (RF) range, concern has been raised about the related possible health risks. Among other concerns, the interaction of medical implants and RF devices has been studied in order to assure the safety of implant carriers under various exposure conditions. In the RF range, the main established quantitative effect of electromagnetic (EM) fields on biological tissues is heating due to vibrational movements of water molecules. The temperature changes induced in tissues also constitute the basis for the setting of RF exposure limits and recommendations. In this study, temperature changes induced by electromagnetic field enhancements near passive metallic implants have been simulated in the head region. Furthermore, the effect of the implant material on the induced temperature change was evaluated using clinically used metals with the highest and the lowest thermal conductivities. In some cases, remarkable increases in maximum temperatures of tissues (as much as 8 degrees C) were seen in the near field with 1 W power level whereas at lower power levels significant temperature increases were not observed. PMID- 20844330 TI - Development of a Si-PM-based high-resolution PET system for small animals. AB - A Geiger-mode avalanche photodiode (Si-PM) is a promising photodetector for PET, especially for use in a magnetic resonance imaging (MRI) system, because it has high gain and is less sensitive to a static magnetic field. We developed a Si-PM based depth-of-interaction (DOI) PET system for small animals. Hamamatsu 4 * 4 Si PM arrays (S11065-025P) were used for its detector blocks. Two types of LGSO scintillator of 0.75 mol% Ce (decay time: ~45 ns; 1.1 mm * 1.2 mm * 5 mm) and 0.025 mol% Ce (decay time: ~31 ns; 1.1 mm * 1.2 mm * 6 mm) were optically coupled in the DOI direction to form a DOI detector, arranged in a 11 * 9 matrix, and optically coupled to the Si-PM array. Pulse shape analysis was used for the DOI detection of these two types of LGSOs. Sixteen detector blocks were arranged in a 68 mm diameter ring to form the PET system. Spatial resolution was 1.6 mm FWHM and sensitivity was 0.6% at the center of the field of view. High-resolution mouse and rat images were successfully obtained using the PET system. We confirmed that the developed Si-PM-based PET system is promising for molecular imaging research. PMID- 20844331 TI - A dynamic model for ALA-PDT of skin: simulation of temporal and spatial distributions of ground-state oxygen, photosensitizer and singlet oxygen. AB - Singlet oxygen (1O2) direct dosimetry and photosensitizer fluorescence photobleaching are being investigated and applied as dosimetric tools during 5 aminolevulinic acid (ALA)-induced protophorphyrin IX (PpIX) photodynamic therapy (PDT) of normal skin and skin cancers. The correlations of photosensitizer fluorescence and singlet oxygen luminescence (SOL) emission signals to 1O2 distribution and cumulative 1O2dose are difficult to interpret because of the temporal and spatial variations of three essential components (light fluence rate, photosensitizer concentration and oxygen concentration) in PDT. A one dimensional model is proposed in this paper to simulate the dynamic process of ALA-PDT of normal human skin in order to investigate the time-resolved evolution of PpIX, ground-state oxygen (3O2and 1O2 distributions. The model incorporates a simplified three-layer semi-infinite skin tissue, Monte Carlo simulations of excitation light fluence and both PpIX fluorescence and SOL emission signals reaching the skin surface, 1O2-mediated photobleaching mechanism for updating PpIX, 3O2 and 1O2 distributions after the delivery of each light dose increment, ground-state oxygen supply by diffusion from the atmosphere and perfusion from blood vessels, a cumulative 1O2-dependent threshold vascular response, and the initial non-uniform distribution of PpIX. The PpIX fluorescence simulated using this model is compared with clinical data reported by Cottrell et al (2008 Clin. Cancer Res. 14 4475-83) for a range of irradiances (10-150 mW cm-2). Except for the vascular response, one set of parameters is used to fit data at all irradiances. The time-resolved depth-dependent distributions of PpIX, 3O2 and 1O2 at representative irradiances are presented and discussed in this paper, as well as the PDT-induced vascular response at different depths. Tissue hypoxia and shutdown of oxygen supply occur in the upper dermis, where PpIX is also preserved at the end of treatment. PMID- 20844332 TI - Performance characterization of a new high resolution PET scintillation detector. AB - Performance of a new high resolution PET detection concept is presented. In this new concept, annihilation radiation enters the scintillator detectors edge-on. Each detector module comprises two 8 * 8 LYSO scintillator arrays of 0.91 * 0.91 * 1 mm(3) crystals coupled to two position-sensitive avalanche photodiodes (PSAPDs) mounted on a flex circuit. Appropriate crystal segmentation allows the recording of all three spatial coordinates of the interaction(s) simultaneously with submillimeter resolution. We report an average energy resolution of 14.6 +/- 1.7% for 511 keV photons at FWHM. Coincident time resolution was determined to be 2.98 +/- 0.13 ns FWHM on average. The coincidence point spread function (PSF) has an average FWHM of 0.837 +/- 0.049 mm (using a 500 MUm spherical source) and is uniform across the arrays. Both PSF and coincident time resolution degrade when Compton interactions are included in the data. Different blurring factors were evaluated theoretically, resulting in a calculated PSF of 0.793 mm, in good agreement with the measured value. PMID- 20844333 TI - High-frequency attenuation and backscatter measurements of rat blood between 30 and 60 MHz. AB - There has recently been a great deal of interest in noninvasive high-frequency ultrasound imaging of small animals such as rats due to their being the preferred animal model for gene therapy and cancer research. Improving the interpretation of the obtained images and furthering the development of the imaging devices require a detailed knowledge of the ultrasound attenuation and backscattering of biological tissue (e.g. blood) at high frequencies. In the present study, the attenuation and backscattering coefficients of the rat red blood cell (RBC) suspensions and whole blood with hematocrits ranging from 6% to 40% were measured between 30 and 60 MHz using a modified substitution approach. The acoustic parameters of porcine blood under the same conditions were also measured in order to compare differences in the blood properties between these two animals. For porcine blood, both whole blood and RBC suspension were stirred at a rotation speed of 200 rpm. Three different rotation speeds of 100, 200 and 300 rpm were carried out for rat blood experiments. The attenuation coefficients of both rat and porcine blood were found to increase linearly with frequency and hematocrit (the values of coefficients of determination (r(2)) are around 0.82-0.97 for all cases). The average attenuation coefficient of rat whole blood with a hematocrit of 40% increased from 0.26 Nepers mm(-1) at 30 MHz to 0.47 Nepers mm(-1) at 60 MHz. The maximum backscattering coefficients of both rat and porcine RBC suspensions were between 10% and 15% hematocrits at all frequencies. The fourth power dependence of backscatter on frequency was approximately valid for rat RBC suspensions with hematocrits between 6% and 40%. However, the frequency dependence of the backscatter estimate deviates from a fourth-power law for porcine RBC suspension with hematocrit higher than 20%. The backscattering coefficient plateaued for hematocrits higher than 15% in porcine blood, but for rat blood it was maximal around a hematocrit of 20% at the same rotation speed, and shifted to a hematocrit of 10% at a higher speed. The backscattering properties of rat RBCs in plasma are similar to those of RBCs in saline at a higher rotation speed. The differences in attenuation and backscattering between rat and porcine blood may be attributed to RBCs' being smaller and the RBC aggregation level being lower for rat blood than for porcine blood. PMID- 20844335 TI - In vitro and in vivo MR evaluation of internal gradient to assess trabecular bone density. AB - Here we propose a new magnetic resonance (MR) strategy based on the evaluation of internal gradient (G(i)) to assess the trabecular bone (TB) density in spongy bone. Spongy bone is a porous system characterized by a solid trabecular network immersed in bone marrow and characterized by a different relative percentage of water and fats. Using a 9.4 T MR micro-imaging system, we first evaluated the relative water and fat G(i) as extracted from the Spin-Echo decay function in vitro of femoral head samples from calves. Indeed, the differential effects of fat and water diffusion result in different types of G(i) behavior. Using a clinical MR 3T scanner, we then investigated in vivo the calcanei of individuals characterized by different known TB densities. We demonstrate, on these samples, that water is more prevalent in the boundary zone, while fats are rearranged primarily in the central zone of each pore. In vitro experiments showed that water G(i) magnitude from the samples was directly proportional to their TB density. Similar behavior was also observed in the clinical measures. Conversely, fat G(i) did not provide any information on spongy-bone density. Our results suggest that water G(i) may be a reliable marker to assess the status of spongy bone. PMID- 20844334 TI - Efficient implementation of the rank correlation merit function for 2D/3D registration. AB - A growing number of clinical applications using 2D/3D registration have been presented recently. Usually, a digitally reconstructed radiograph is compared iteratively to an x-ray image of the known projection geometry until a match is achieved, thus providing six degrees of freedom of rigid motion which can be used for patient setup in image-guided radiation therapy or computer-assisted interventions. Recently, stochastic rank correlation, a merit function based on Spearman's rank correlation coefficient, was presented as a merit function especially suitable for 2D/3D registration. The advantage of this measure is its robustness against variations in image histogram content and its wide convergence range. The considerable computational expense of computing an ordered rank list is avoided here by comparing randomly chosen subsets of the DRR and reference x ray. In this work, we show that it is possible to omit the sorting step and to compute the rank correlation coefficient of the full image content as fast as conventional merit functions. Our evaluation of a well-calibrated cadaver phantom also confirms that rank correlation-type merit functions give the most accurate results if large differences in the histogram content for the DRR and the x-ray image are present. PMID- 20844336 TI - Evaluation of an MR-compatible blood sampler for PET. AB - The integration of magnetic resonance imaging (MRI) and positron emission tomography (PET) is an upcoming hybrid imaging technique. Prototype scanners for pre-clinical and clinical research have been built and tested. However, the potential of the PET part can be better exploited if the arterial input function (AIF) of the administered tracer is known. This work presents a dedicated MR compatible blood sampling system for precise measurement of the AIF in an MR-PET study. The device basically consists of an LSO/APD-detector assembly which performs a coincidence measurement of the annihilation photons resulting from positron decays. During the measurement, arterial blood is drawn continuously from an artery and lead through the detector unit. Besides successful tests of the MR compatibility and the detector performance, measurements of the AIF of rats have been carried out. The results show that the developed blood sampling system is a practical and reliable tool for measuring the AIF in MR-PET studies. PMID- 20844337 TI - Benchmarking nuclear models of FLUKA and GEANT4 for carbon ion therapy. AB - As carbon ions, at therapeutic energies, penetrate tissue, they undergo inelastic nuclear reactions and give rise to significant yields of secondary fragment fluences. Therefore, an accurate prediction of these fluences resulting from the primary carbon interactions is necessary in the patient's body in order to precisely simulate the spatial dose distribution and the resulting biological effect. In this paper, the performance of nuclear fragmentation models of the Monte Carlo transport codes, FLUKA and GEANT4, in tissue-like media and for an energy regime relevant for therapeutic carbon ions is investigated. The ability of these Monte Carlo codes to reproduce experimental data of charge-changing cross sections and integral and differential yields of secondary charged fragments is evaluated. For the fragment yields, the main focus is on the consideration of experimental approximations and uncertainties such as the energy measurement by time-of-flight. For GEANT4, the hadronic models G4BinaryLightIonReaction and G4QMD are benchmarked together with some recently enhanced de-excitation models. For non-differential quantities, discrepancies of some tens of percent are found for both codes. For differential quantities, even larger deviations are found. Implications of these findings for the therapeutic use of carbon ions are discussed. PMID- 20844338 TI - Three-dimensional ultrasonic Nakagami imaging for tissue characterization. AB - The two-dimensional (2D) Nakagami image complements the ultrasound B-scan image when attempting to visualize the scatterer properties of tissues. The resolution of the Nakagami image is lower than that of the B-scan image, since the former is produced by processing the raw envelope data using a 2D sliding window with side lengths typically corresponding to three times the pulse length of the incident ultrasound. This paper proposes using three-dimensional (3D) Nakagami imaging for improving the resolution of the obtained Nakagami image and providing more complete information of scatterers for a better tissue characterization. The 3D Nakagami image is based on a voxel array composed of the Nakagami parameters constructed using a 3D sliding cube to process the 3D backscattered raw data. Experiments on phantoms with different scatterer concentrations were carried out to determine the optimal size of the sliding cube for a stable estimation of the Nakagami parameter. Tissue measurements on rat livers without and with fibrosis formation were further used to explore the practical feasibility of 3D Nakagami imaging. The results indicated that the side length of the cube used to construct the 3D Nakagami image must be at least two times the pulse length, which improved the resolution for each Nakagami image frame in the 3D Nakagami image. The results further demonstrated that the 3D Nakagami image is better than the conventional 2D Nakagami image for complementing the B-scan in detecting spatial variations in the scatterer concentration and classifying normal and fibrotic livers. This study suggests that 3D Nakagami imaging has the potential to become a new 3D quantitative imaging approach. PMID- 20844340 TI - Alzheimer's prevention initiative. PMID- 20844341 TI - WITHDRAWN: In vitro ubiquitination of small heterodimer partner and effects of K122/123R double point mutation on transcriptional modulation. AB - Ahead of Print article withdrawn by publisher. PMID- 20844342 TI - Bone marrow suppression: a side effect of ciprofloxacin therapy. AB - Ciprofloxacin is a commonly used antibiotic for gastrointestinal and genitourinary tract infections with a considerably good safety profile. However, occasionally it may cause life-threatening complications. Two case reports of bone marrow depression and 1 case of thrombocytopenia due to ciprofloxacin therapy have been reported in literature. We report a case of bone marrow depression due to ciprofloxacin therapy for urinary tract infection in an otherwise healthy woman. PMID- 20844343 TI - The midodrine withdrawal. PMID- 20844344 TI - Adherence to aldosterone-blocking agents in patients with heart failure. AB - The use of aldosterone blockers in the pharmacologic therapy for heart failure (HF) in patients with left ventricular systolic dysfunction has been shown to significantly reduce overall mortality, sudden cardiac death, and hospitalization. Patient adherence to polypharmaceutical regimens including aldosterone blockade and other key medication components is a concern for clinicians and their patients. A retrospective cohort study was conducted using integrated US pharmacy/medical claims covering 44.5 million lives. Inclusion criteria included the following: age at least 50 years, newly prescribed spironolactone or eplerenone from 2002 to 2006, with HF diagnosis within 12 months of prescription initiation and follow-up of at least 6 months to assess outcomes (12 months for adherence). Compliance was measured as the proportion of days covered (prescription days supply in the first year postindex for 365 days), and persistence was measured as days from the first to the last prescription. Of 388,523 patients with HF, 60,183 patients (15.5%) received an aldosterone blocker (n = 2024 for eplerenone, n = 58,159 for spironolactone), from which a newly treated subset was studied (n = 568 eplerenone, n = 11,982 spironolactone). Proportion of days covered was significantly greater for eplerenone (79% +/- 42%) than for spironolactone (66% +/- 42%, P < 0.01). Persistence was significantly higher for eplerenone than for spironolactone (P < 0.01) with discontinuation before 1 year at 49.5% and 73.7%, respectively. This analysis shows that a majority of patients did not receive an aldosterone blocker after HF diagnosis despite cardiovascular event risks and raises the hypothesis that eplerenone is associated with higher compliance and persistence as compared with spironolactone. PMID- 20844345 TI - A review of granisetron, 5-hydroxytryptamine3 receptor antagonists, and other antiemetics. AB - Nausea and vomiting are 2 of the most upsetting adverse reactions of chemotherapy. Current guidelines propose 5-hydroxytryptamine3 (5-HT3) receptor antagonists as a pharmacologic intervention for acute and delayed nausea and vomiting [chemotherapy-induced nausea and vomiting (CINV)] associated with moderately and highly emetogenic chemotherapy. Meanwhile, both postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting are challenging situations after surgeries and procedures. Prophylactic and therapeutic combinations of antiemetics are recommended in patients at high risk of suffering from PONV and postdischarge nausea and vomiting. Granisetron (Kytril) is a selective 5-HT3 receptor antagonist that does not induce or inhibit the hepatic cytochrome P-450 system in vitro. There are also 4 other antagonists of 5-HT3 receptor (dolasetron, ondansetron, palonosetron, and tropisetron) being metabolized via the CYP2D6 and are subject to potential genetic polymorphism. The launch of a new class of antiemetics, the substance P/neurokinin1 receptor antagonists, was attributed to the scientific update on the central generator responsible for emesis and role of substance P. There has been mounting interest in exploring integrative medicine, either acupuncture or acustimulation of P6 (Nei-Kuwan), to complement the western medicine for prevention and management of nausea and vomiting. The potential application of cannabinoids, either alone or in combination with other agents of different mechanism, could contribute further to improve outcome in CINV. Implementation of future treatment guidelines for more effective management of CINV and PONV could certainly improve the efficacy and outcome of cancer and postoperative care. PMID- 20844346 TI - Propofol infusion syndrome. AB - A review of the history, incidence, presentation, pathophysiology, and treatment of propofol infusion syndrome. PMID- 20844347 TI - Less is more: the recent history of neuraxial labor analgesia. AB - Labor analgesia researchers have pursued better and safer ways to provide pain relief in labor. Although some pharmacologic investigations have focused on alternative mechanisms to target and medications to employ, a large part of the recent obstetric anesthesiology literature has contributed toward the safety and efficacy of techniques dependent on traditional therapeutics, specifically local anesthetics given through a neuraxial anesthetic technique. Investigators have worked to demonstrate and remove doubts that neuraxial anesthesia can be a safe method of labor analgesia. Pharmacodynamic studies during the last 3 decades have revealed ways to achieve adequate analgesia with minimal doses and correspondingly minimal risks. Dose-sparing opiate adjuncts to local anesthetics are now commonplace. To avoid excessive dosages, clinical up-down sequential allocation experiments identified the minimum amounts of local analgesia needed. Modifications to the administration of drug allowed total doses to be further reduced. This historical overview highlights some of these important advances in the present and recent past of neuraxial labor analgesia, and it traces how desired outcomes are being achieved with less and less total drug. PMID- 20844348 TI - Opioid-induced hyperalgesia and tolerance. AB - We have all encountered the following postanesthesia care unit dilemma a myriad of times. As the attending covering the postanesthesia care unit, the anesthesiologist will be confronted not infrequently with the following clinical scenario: "He needed 500 MUg fentanyl in the operating room for a toe amputation and has received 20 mg morphine, and he's still complaining of severe pain.... Do you think he may need more morphine?" Opiates do prevail as first-line therapy for moderate to severe surgical and chronic pain states. However, their use may actually confound the clinical picture postoperatively, because opiate exposure counterintuitively may actually trigger exaggerated pain sensation. When assessing a patient experiencing exaggerated postoperative or chronic pain, several questions should come to mind. First, is this patient experiencing tolerance or hyperalgesia induced by opiate therapy? Second, does the management differ for the two etiologies? Third, what underlying mechanisms, both at the neuroanatomic and molecular/chemical levels, underlie the two processes? Fourth, how does the recent literature on opiate-induced hyperalgesia influence previously accepted views of pre-emptive analgesia? Fifth, what treatment modalities exist for opiate-induced hyperalgesia? Most importantly, sixth, how can opiate-induced hyperalgesia be prevented? In this literature review, we aim to address these questions and to hopefully change the current perception and management of perioperative and chronic pain states with opiates. PMID- 20844351 TI - The challenge of childhood maltreatment and trauma. PMID- 20844350 TI - Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics. AB - PURPOSE OF REVIEW: Environmental factors, such as drugs, chemicals, or abnormal concentrations of natural metabolites, induce birth defects. Environmental effects on cardiogenesis have been little studied in contrast to neurogenesis. This review presents evidence on three environmental factors: alcohol, the drug lithium, and the metabolite homocysteine, impacting the Wnt/beta-catenin pathway during cardiac development and folate protection. RECENT FINDINGS: Animal and epidemiological studies have shown that folate protects the embryo from birth defects. New animal studies demonstrate that folate prevents cardiovascular defects induced by the drug lithium, homocysteine, or alcohol, but protection occurs at a higher concentration than currently used in vitamin supplements. The data indicate that folate in combination with myo-inositol may further reduce the risk of birth defects. Discussion is presented of the cell specification stages that are impacted resulting in cardiac defects, how Wnt/beta-catenin signaling is involved, and how folate and myo-inositol additively may protect embryonic pathways. The possible epigenetic role of folate in Wnt/beta-catenin signaling is described. SUMMARY: This review will enable better counseling of women by defining, during early pregnancy, a susceptible window of embryonic exposure leading to a high risk of cardiac defects, and provides a therapeutic means and the necessary timing for prevention of environmentally induced birth defects. PMID- 20844352 TI - Bibliography. Cardiovascular medicine. Current world literature. PMID- 20844353 TI - Use of temporary nurses and nurse and patient safety outcomes in acute care hospital units. AB - BACKGROUND: To deal with nursing shortages and inadequate hospital nurse staffing, many solutions have been tried, including utilizing temporary nurses. Relatively little attention has been given to use of temporary nurses and its association with both nurse and patients outcomes. PURPOSE: : The purpose of this study is to investigate the association between use of temporary nurses and nurse (needlesticks and back injuries) and patient (patient falls and medication errors) safety outcomes at the nursing unit level. METHODOLOGY/APPROACH: Data came from a large organizational study which investigated the relationship between registered nurse (RN) staffing adequacy, work environments, organizational, and patient outcomes. The sample for this study was 4,954 RNs on 277 nursing units in 142 hospitals. FINDINGS: Nurses working on nursing units with high levels (more than 15%) of external temporary RN hours were more likely to report back injuries than nurses working on nursing units that did not use external temporary RNs. Nurses working on these nursing units also reported greater levels of patient falls compared with those who did not use temporary RNs. This study found that nurses working on nursing units with moderate levels (5-15%) of external temporary RN hours reported fewer medication errors than those without using any external temporary RNs. PRACTICE IMPLICATIONS: Hospitals need to monitor the levels of temporary nurse use and maintain a level of approximately 15% to ensure both nurse and patient safety outcomes. The temporary nurse use to manage nursing shortfall may provide both benefit and harm to nurse and patient safety depending on the level of the use. PMID- 20844354 TI - Keys for successful implementation of total quality management in hospitals. AB - Editor's Note: This article reports the findings of an analysis of the implementation of continuous quality improvement (CQI) or total quality management (TQM) programs in 10 hospitals. This analysis is the result of a 2 year study designed to identify and assess the ingredients that lead to the successful implementation of CQI programs in acute care hospitals. This article first appeared in Health Care Management Review 21(1), 48-60. Copyright (c) 1996 Aspen Publishers, Inc. (Lippincott Williams & Wilkins). PMID- 20844355 TI - Specialty hospital market proliferation: Strategic implications for general hospitals. AB - BACKGROUND: Since the early 1990s, specialty hospitals have been continuously increasing in number. A moratorium was passed in 2003 that prohibited physicians' referrals of Medicare patients to newly established specialty hospitals if the physician has ownership stakes in the hospital. Although this moratorium expired in effect in 2007, many are still demanding that the government pass new policies to discourage the proliferation of specialty hospitals. PURPOSE: This study aimed at examining the regulatory and environmental forces that influence specialty hospitals founding rate. Specifically, we use the resource partitioning theory to investigate the relationship between general hospitals closure rates and the market entry of specialty hospitals. This study will help managers of general hospitals in their strategic thinking and planning. METHODOLOGY: We rely on secondary data resources, which include the American Hospital Association, Area Resource file, census, and Center for Medicare and Medicaid Services data, to perform a longitudinal analysis of the founding rate of specialty hospital in the 48 states. Specifically, we use the negative binomial generalized estimating equation approach available through Stata 9.0 to study the effect of general hospitals closure rate and environmental variables on the proliferation of specialty hospitals. FINDINGS: Specialty hospitals founding rate seems to be significantly related to general hospitals closure rates. Moreover, results indicate that economic, supply, regulatory, and financial conditions determine the founding rate of specialty hospitals in different states. PRACTICE IMPLICATIONS: The results from this study indicate that the closure of general hospitals creates market conditions that encourage the market entry of specialized health care delivery forms such as specialty hospitals. Managers of surviving general hospitals have to view the closure of other general hospitals not just as an opportunity to increase market share but also as a threat of competition from new forms of health care organizations. PMID- 20844356 TI - Predictors of perceived health care quality for registered nurses during and after health care reform. AB - BACKGROUND: Limited research has focused on the predictive nature of organizational culture and trust on registered nurses' perceived health care quality in reformed health care systems. PURPOSES: The purpose of this article was to investigate nurses' perceptions of organizational culture factors, trust in employer, and perceived health care quality during and 5 years after major organizational reform in the acute care setting and to test a model linking culture to perceived health care quality. METHODOLOGY: Survey data collected from two samples of nurses (N = 222,343) during and 5 years after major organizational reform in the acute care setting of one Canadian province were analyzed, and an exploratory model linking aspects of culture, trust, and quality was tested. FINDINGS: For both periods, most variable scores were in the low range and depicted moderately positive intercorrelations with each other. Support for the proposed model was mixed. Select culture variables predicted health care quality at both periods, but trust emerged as a significant predictor in 2000 only. The findings support the negative impact of system transformation on nurses and the link between culture and health care quality. PRACTICE IMPLICATIONS: The study findings suggest that managers and policy makers must develop and implement supportive and nurturing strategies that will enhance the organizational culture (emotional climate, collaborative relations), which should result in more positive perceptions of health care quality. However, further research is required to gain a better understanding of the relationships among trust, organizational culture, and perceptions of health care quality and what implications this may or may not have for nursing practice. PMID- 20844357 TI - Exploring the impact of customer relational benefit on relationship commitment in health service sectors. AB - BACKGROUND: An increasing number of health service sectors have begun to implement relationship marketing to try to establish long-term relationship with customers. PURPOSE: Customer relational benefit has been an important subject for relationship marketing researchers. This study was conducted to investigate how customer relational benefit might influence relationship commitment in health service sectors. METHODOLOGY: The research used a questionnaire survey that retrieved a total number of 403 valid questionnaires. The data were collected by way of personal visits and investigations of outpatients in three regional hospitals in Taiwan. After the reliability and the validity of the questionnaire sample were examined, the data were verified by using hierarchical regression analysis. FINDINGS: Results showed that confidence benefit constituted the most pronounced factor for hospital customers. Confidence benefit, social benefit, and special treatment benefit were perceived by customers as the key factors that have a positive influence on relationship commitment. In particular, customers placing greater emphasis on confidence benefit tended to be less willing to establish relationship commitment. PRACTICE IMPLICATIONS: When health service managers develop marketing strategies using customer relational benefit, they will still need to enhance customer confidence benefit as one of the main ways of achieving future improvements. In the event where health service managers seek to install resources for establishing and maintaining a good relationship commitment with customers, the crucial factors of social and special treatment benefits should not be ignored when seeking to enhance the customers' perception of confidence benefit. PMID- 20844358 TI - The association between organizational characteristics and benefits offered to nursing assistants: Results from the National Nursing Home Survey. AB - BACKGROUND: Previous research has demonstrated that employment-based benefits are important for the recruitment and retention of nursing assistants (NAs). PURPOSE: The objectives of this study were to describe the availability of benefits offered to NAs and to explore the association between nursing home organizational characteristics and NA benefits using the political economy of aging framework. METHODOLOGY: Cross-sectional data on 944 nationally representative nursing homes were derived from the 2004 National Nursing Home Survey. Benefits were measured as a composite variable of five NA benefits weighted by cost. A linear regression model was used to examine the relationship between nursing home organizational characteristics and NA benefits. FINDINGS: For-profit/nonchain ownership and Medicaid occupancy were negatively associated with NA benefits. Facility size, not-for-profit ownership (chain or nonchain), occupancy level, nurse staffing level, union involvement, and education of the nursing home administrator were positively associated with NA benefits. PRACTICE IMPLICATIONS: Nursing home organizational characteristics may explain some of the variations in the availability of benefits and may be informative for policy and practice to improve benefits as a potential strategy to recruit and retain NAs. In particular, for-profit, freestanding facilities and facilities with high proportions of Medicaid residents should consider cost-effective initiatives to enhance the benefit package offered to NAs. PMID- 20844359 TI - A typology for health care teams. AB - BACKGROUND: Effective interdisciplinary health care teamwork improves clinical and financial outcomes, and training and assessment of team competencies are central to establishing high-functioning health care teams. The roles that team members assume in the provision of patient care are important contributors to effective health care team performance; however, variability among health care practitioners can lead to philosophical, political, social, and clinical differences in perceptions and recommendations for patient care as well as expected communication patterns and protocols. PURPOSE: The purpose of this study was to describe the roles and behaviors within variable health care teams in the provision of patient care across multiple clinical practice areas to inform a model for team development strategies. METHODOLOGY: Interdisciplinary health care teams were observed in vivo during the routine course of their work in multiple patient care contexts. Data were collected and analyzed using qualitative methods of observation and categorization, with supplemental interviews to substantiate, to clarify, and to verify observations. The constant comparative method of data analyses was used to derive a compositional typology for health care teams. FINDINGS: A compositional typology for health care teams emerged from the data specifying four types of health care teams: stable role, stable personnel (Type SRSP); stable role, variable personnel (Type SRVP); variable role, stable personnel (Type VRSP); and variable role, variable personnel (Type VRVP). IMPLICATIONS: Results suggest that health care teams may be more complicated than non-health care teams, and team models with associated derived competencies from other professions may not wholly transfer to health care. A singular model to inform best practices for health care team development may not adequately address the specific performance challenges of each team type. Adaptable development strategies for each type of team and its associated role membership may be required to optimize team performance. The health care team typology derived from this study may help inform the selection of appropriate team development strategies and define associated team competencies. PMID- 20844360 TI - Nurse perceptions of the quality of patient care: Confirming the importance of empowerment and job satisfaction. AB - AIM: This aim of this study was to investigate the interactive effects of psychological empowerment and job satisfaction on the relationship between high performance work systems (HPWS) and nurses' perceptions of the quality of patient care they provide. BACKGROUND: Studies of high-performing organizations in a variety of industries have consistently reported a positive relationship between HPWS and performance outcomes. Although many of these studies have been conducted in manufacturing, similar findings of a positive correlation between aspects of HPWS and improved patient outcomes have been reported in international health care studies. METHOD: We used regression analysis with tests of mediation and moderation to analyze survey responses collected in March 2008 of 201 nurses in a large regional Australian health service. FINDINGS: Psychological empowerment fully mediated the relationship between HPWS and perceptions of quality of patient care. Job satisfaction moderated the relationship between HPWS and perceptions of quality of patient care. CONCLUSION: Hospital managers should focus on promoting HPWS and ensuring that nurse unit managers have the competencies to empower and to enhance the job satisfaction of their staff. PMID- 20844361 TI - Organizational culture predicts job satisfaction and perceived clinical effectiveness in pediatric primary care practices. AB - BACKGROUND: In recent years, there has been a growing understanding that organizational culture is related to an organization's performance. However, few studies have examined organizational culture in medical group practices. OBJECTIVES: The purpose of this study was to examine the relationship of organizational culture on provider job satisfaction and perceived clinical effectiveness in primary care pediatric practices. RESEARCH DESIGN: This cross sectional study included 36 primary care pediatric practices located in Connecticut. PARTICIPANTS: There were 374 participants in this study, which included 127 clinicians and 247 nonclinicians. MEASURES: Office managers completed a questionnaire that recorded staff and practice characteristics; all participants completed the Organizational Culture Scale, a questionnaire that assessed the practice on four cultural domains (i.e., group, developmental, rational, and hierarchical), and the Primary Care Organizational Questionnaire that evaluated perceived effectiveness and job satisfaction. RESULTS: Hierarchical linear models using a restricted maximum likelihood estimation method were used to evaluate whether the practice culture types predicted job satisfaction and perceived effectiveness. Group culture was positively associated with both satisfaction and perceived effectiveness. In contrast, hierarchical and rational culture were negatively associated with both job satisfaction and perceived effectiveness. These relationships were true for clinicians, nonclinicians, and the practice as a whole. CONCLUSIONS: Our study demonstrates that practice culture is associated with job satisfaction and perceived clinical effectiveness and that a group culture was associated with high job satisfaction and perceived effectiveness. PMID- 20844363 TI - Outcomes of endoscopic submucosal dissection versus endoscopic mucosal resection in management of superficial squamous esophageal neoplasms outside Japan. AB - GOALS: This study aims to evaluate the outcomes of endoscopic submucosal dissection (ESD) versus endoscopic mucosal resection (EMR) in management of superficial squamous esophageal neoplasms. BACKGROUND: Endoscopic resection is a potential alternative in treatment of superficial squamous esophageal neoplasms. However, there have been limited reports comparing the outcomes of ESD versus EMR in the treatment of these lesions outside Japan. STUDY: A retrospective analysis of all patients with high-grade superficial neoplasms (moderate to severe dysplasia and noninvasive carcinoma) or intramucosal carcinoma resected endoscopically between January 2002 and December 2007 was carried out. Clinical and pathologic outcomes were compared. RESULTS: ESD was done in 22 lesions (18 patients) and cap-EMR in 13 lesions (10 patients). ESD allowed resection of larger lesions indicated by a significantly longer endoscopic length (P=0.015), larger specimen size (P<0.001), and more lesions extending for more than half the circumference of the esophagus (P=0.005) when compared with cap-EMR. ESD also achieved with a higher en bloc resection rate (P=0.052) and lower piecemeal resection rate (P=0.015). Procedure-related morbidities were not significantly different (P=1.0). There was no procedure-related mortality in the entire series. CONCLUSIONS: ESD allows en bloc resection of larger mucosal lesions of the esophagus, earlier not possible by cap-EMR. This is achievable without significantly increasing the risks to the patient even in low-volume centers outside Japan. Whether ESD decreases the local recurrence and improves survival when compared with cap-EMR will require further long-term follow-up studies. PMID- 20844362 TI - Novel drugs targeting hypertension revisited. PMID- 20844365 TI - Ultrasound-based hepatic elastography: origins, limitations, and applications. AB - A reliable, noninvasive marker to help clinicians evaluate hepatic fibrosis is urgently needed. The liver biopsy, an imperfect gold standard, has recognized limitations including sampling error and interobserver variability. Hepatic elastography (HE) is a novel sonographic method for assessing liver stiffness and has excellent accuracy in making the diagnosis of minimal fibrosis and cirrhosis. Several conditions intrinsic to the pathology of the liver compromise the positive predictive value of HE for fibrosis alone including acute hepatitis, obstructive cholestasis, and passive congestion. Technical considerations that hinder the performance of elastography include an advanced body mass index, the presence of ascites and narrow intercostal spaces. Despite these limitations, elastography has a role in staging fibrosis, prognosis of disease outcome, surveillance, and treatment decisions. HE is now being used in lieu of liver biopsy to investigate the natural history of chronic liver diseases. Additional studies are required to better define the appropriate role of HE in clinical practice. PMID- 20844366 TI - Ambulatory blood pressure monitoring: its time to move on! PMID- 20844367 TI - Evaluating aortic stiffness through an arm cuff oscillometric device: is validation against invasive measurements enough? PMID- 20844368 TI - Antihypertensive pharmacogenetics: missed opportunity. PMID- 20844369 TI - Oxidative stress and inflammation in the endothelial dysfunction of obesity: a role for nuclear factor kappa B? PMID- 20844370 TI - Effects of continuous positive airway pressure therapy on hypertension control in patients with sleep-related breathing disorders: available evidence and unresolved issues. PMID- 20844371 TI - Arterial stiffness as determinant of increased amino terminal pro-B-type natriuretic peptide levels in individuals with and without cardiovascular disease -the Rotterdam Study. AB - OBJECTIVE: Large artery stiffening has adverse effects on cardiac structure and function and, therefore, may be associated with elevated circulating levels of amino-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: In a large community-dwelling older population (n = 6211, mean age 69.2 years), serum NT proBNP, brachial pulse pressure (PP) and carotid-femoral pulse wave velocity (cfPWV) were measured. RESULTS: In individuals without cardiovascular disease (CVD), median NT-proBNP was 6.7 pmol/l in men (n = 2073) and 10.1 pmol/l in women (n = 3085) (P < 0.001). In these individuals, indices of arterial stiffness correlated with NT-proBNP with beta-coefficients for brachial PP and cfPWV of 0.315 and 0.255 in men and 0.233 and 0.232 in women (all P < 0.001). After multivariable adjustment (age, weight, height, mean arterial pressure, heart rate, smoking, diabetes, estimated glomerular filtration rate, total and high density lipoprotein-cholesterol and use of lipid-lowering and antihypertensive medication), these associations remained significant for brachial PP and cfPWV in men and for brachial PP in women. In multivariable-adjusted models, brachial PP explained 20.3% and cfPWV 10.7% of the variation of NT-proBNP in men and, respectively, 10.8 and 9.4% in women. In patients with prevalent CVD, indices of arterial stiffness and NT-proBNP were unrelated in multivariable-adjusted models. CONCLUSION: Our findings show that arterial stiffness is independently associated with elevated NT-proBNP levels in individuals without prevalent CVD. The association between vascular stiffness and NT-proBNP is stronger in men than in women and absent in individuals with prevalent CVD. PMID- 20844372 TI - Number and function of circulating endothelial progenitor cells and calcitonin gene-related peptide in hypertension: support from and opportunities in Bartter's and Gitelman's syndromes patients. PMID- 20844373 TI - Does Bartter's syndrome/Gitelman's syndrome provide a clinical model for investigating the association between calcitonin gene-related peptide and angiotensin II-mediated senescence of endothelial progenitor cells? PMID- 20844374 TI - Discrepancy between European Society of Hypertension and SCORE risk assessment methods in hypertensive patients: still a matter of concern--answer to Sehestedt et al. PMID- 20844379 TI - Where should patients with severe traumatic brain injury be managed?: Patients can be safely managed in a nonspecialist center. PMID- 20844378 TI - Does nitrous oxide affect bispectral index and state entropy when added to a propofol versus sevoflurane anesthetic? AB - BACKGROUND: In earlier studies, nitrous oxide (N2O) did not affect bispectral index (BIS) or state entropy (SE) when administered as the sole anesthetic agent. We investigated the effect of adding N2O to sevoflurane or propofol anesthesia on BIS and SE. METHODS: A total of 28 patients were randomized to receive general anesthesia using either 2% sevoflurane or 120 mcg/kg/min propofol during surgery. After 20 minutes of stable anesthetic and surgical conditions (baseline), 60% N2O was added for 20 minutes. Another 20 minutes was allowed for washout after N2O was discontinued. Sevoflurane concentration was closely monitored using the standard end-tidal gas analysis and vaporizer output was constantly adjusted to offset the second-gas effect caused by the addition and discontinuation of N2O. Mean values for BIS and SE were calculated for the last 5 minutes of the baseline, nitrous oxide, and washout periods. RESULTS: In the propofol group, BIS and SE values in baseline versus N2O periods were 40+/-10 versus 39+/-10 and 43+/ 11 versus 43+/-12, respectively (mean+/-SD, P>0.05). In the sevoflurane group, addition of N2O decreased both BIS (36+/-7 to 32+/-7, P<0.001) and SE (37+/-10 to 31+/-11, P=0.001). The magnitude of change from the baseline in BIS and SE in the sevoflurane group was 3.6+/-3.8 (95% CI: 0.8-6.5) and 6.1+/-5.5 (95% CI: 3.7 8.6), respectively. Average baseline and washout values of BIS and SE were not different in both groups (P>0.05). CONCLUSIONS: N2O decreased both BIS and SE when added to sevoflurane, but not propofol. The observed changes in the sevoflurane group were not clinically significant. Decreases in BIS and SE in the sevoflurane group could result from a true additive effect and second-gas effect of N2O that was unaccounted for despite a meticulous titration of sevoflurane using end-tidal gas monitoring. PMID- 20844380 TI - Where should patients with severe traumatic brain injury be managed? All patient should be managed in a neurocritical care unit. PMID- 20844386 TI - Unleashing animal-assisted therapy. PMID- 20844392 TI - Bringing Achilles tendinopathy to heel. PMID- 20844394 TI - Journal clubs enlighten nurses, improve practice. PMID- 20844395 TI - Jonathan defied expectations. PMID- 20844396 TI - Patient education series. Pneumonia. PMID- 20844398 TI - Caring for a patient's vascular access for hemodialysis. PMID- 20844397 TI - Culture change through patient engagement. PMID- 20844399 TI - Standards of care for diabetes: what's new? AB - Each year, the American Diabetes Association (ADA) publishes standards of medical care for people with diabetes. The ADA updates these standards based on the latest evidence so that healthcare professional scan incorporate this evidence into their care. The standards also summarize and rate the levels of evidence on which the recommendations are based. This article describes new recommendations in the 2010 Standards of Medical Care in Diabetes (the 2010 Standards). PMID- 20844400 TI - Is continuous subcutaneous infusion a good route for pain medication? PMID- 20844401 TI - An update on meningococcal meningitis. PMID- 20844402 TI - Caring for adults with congenital heart disease. PMID- 20844404 TI - Hypernatremia. PMID- 20844405 TI - Hypotension and shock: the truth about blood pressure. PMID- 20844406 TI - Clinical pharmacists: coming soon to an ED near you. PMID- 20844407 TI - Keeping your cool when heatstroke strikes. PMID- 20844408 TI - Getting to the root of testicular cancer. PMID- 20844409 TI - What's new in Shock, October 2010? PMID- 20844410 TI - Early elevation in random plasma IL-6 after severe injury is associated with development of organ failure. AB - Excessive proinflammatory activation after trauma plays a role in late morbidity and mortality, including the development of multiple organ dysfunction syndrome (MODS). To date, identification of patients at risk has been challenging. Results from animal and human studies suggest that circulating interleukin 6 (IL-6) may serve as a biomarker for excessive inflammation. The purpose of this analysis was to determine the association of IL-6 with outcome in a multicenter developmental cohort and in a single-center validation cohort. Severely injured patients with shock caused by hemorrhage were evaluated within a multicenter developmental cohort (n = 79). All had blood drawn within 12 h of injury. Plasma IL-6 was determined by multiplex proteomic analysis. Clinical and outcome data were prospectively obtained. Within this developmental cohort, a plasma IL-6 level was determined for the subsequent development of MODS by developing a receiver operating curve and defining the optimal IL-6 level using the Youden Index. This IL-6 level was then evaluated within a separate validation cohort (n = 56). A receiver operating curve was generated for IL-6 and MODS development, with an IL 6 level of 350 pg/mL having the highest sensitivity and specificity within the developmental cohort. IL-6 was associated with MODS after adjusting for Acute Physiology and Chronic Health Evaluation, Injury Severity Score, male sex, and blood transfusions with an odds ratio of 3.9 (95% confidence interval, 1.33 - 11.19). An IL-6 level greater than 350 pg/mL within the validation cohort was associated with an increase in MODS score, MODS development, ventilator days, intensive care unit length of stay, and hospital length of stay. However, this IL 6 level was not associated with either the development of nosocomial infection or mortality. Elevation in plasma IL-6 seems to correlate with a poor prognosis. This measurement may be useful as a biomarker for prognosis and serve to identify patients at higher risk of adverse outcome that would benefit from novel therapeutic interventions. PMID- 20844411 TI - Outcome scoring systems for acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is commonly diagnosed in intensive care units (ICUs), often in association with acute kidney injury. In this study, we compared the predictive value of outcome scoring systems: Acute Physiology and Chronic Health Evaluation IV (APACHE IV), earlier APACHE models, Sequential Organ Failure Assessment (SOFA), the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure (RIFLE) classification, and Acute Lung Injury score in critically ill patients with ARDS. We retrospectively abstracted data from the medical records of 135 critically ill ARDS patients in two medical ICUs of a tertiary care hospital from December 1999 to June 2006. Overall mortality rate was 65% (88/135). Forward conditional logistic regression identified APACHE IV, alveolar-arterial O2 tension difference, age, sepsis, and maximum RIFLE (RIFLEmax) score on ICU days 1 and 3 to be independent predictors of hospital mortality. The area under the receiver operating characteristic curve for the APACHE IV score revealed good fit (Hosmer and Lemeshow goodness-of-fit test results) and discriminative power (area under the receiver operating characteristic curve, 0.792 +/- 0.038; P < 0.001). The cumulative survival rates at 6-month follow-up after hospital discharge were significantly (P < 0.001) different among ARDS patients with APACHE IV mortality rate 35% or less and APACHE IV mortality rate higher than 35%. The APACHE IV score and RIFLEmax score are predictors of hospital mortality in ARDS patients, with APACHE IV demonstrating desirable properties of prognostic accuracy. PMID- 20844412 TI - Rons formation under restrictive reperfusion does not affect organ dysfunction early after hemorrhage and trauma. AB - Reactive oxygen species have been implicated in the pathophysiology of early reperfusion. We aimed to determine 1) reactive oxygen and nitrogen species (RONS) formation in organs of rats and 2) its pathophysiological relevance during a phase of restrictive reperfusion after hemorrhagic/traumatic shock (HTS). Fifty seven male Sprague-Dawley rats were subjected to a clinically relevant HTS model, featuring laparotomy, bleeding, and a phase of restrictive reperfusion. The RONS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (continuous i.v. infusion) and electron paramagnetic resonance spectroscopy were applied for RONS (primarily superoxide and peroxynitrite) detection. Compared with sham-operated animals, the organ-specific distribution of RONS changed during restrictive reperfusion after HTS. Reactive oxygen and nitrogen species formation increased during restrictive reperfusion in red blood cells and ileum only but decreased in the kidney and remained unchanged in other organs. Hemorrhagic traumatic shock followed by restrictive reperfusion resulted in metabolic acidosis, dysfunction of liver and kidney, and increased oxidative burst capacity in circulating cells. Plasma RONS correlated with shock severity and organ dysfunction. However, RONS scavenging neither affected organ dysfunction nor oxidative burst capacity nor myeloperoxidase activity in lung when compared with the shock controls. In summary, a phase of restrictive reperfusion does not increase RONS formation in most organs except in intestine and red blood cells. Moreover, scavenging of RONS does not affect the early organ dysfunction manifested at the end of a phase of restrictive reperfusion. PMID- 20844413 TI - Anesthesia aggravates lung damage and precipitates hypotension in endotoxemic sheep. AB - Beneficial anti-inflammatory properties have been ascribed to volatile anesthetics in septic conditions, but no studies have compared anesthesia to the conscious state in a large-animal model. The aim of this study was to investigate the effect of isoflurane anesthesia on cardiovascular and respiratory function, leukocyte activation, and lung damage in a model of endotoxemia in sheep. Conscious (n = 6) and anesthetized (n = 6) sheep were made endotoxemic by continuous infusion of LPS for 48 h. Central hemodynamics were monitored continuously, and blood samples were collected regularly. Activation of leukocytes was assessed by surface expression of CD11b and plasma myeloperoxidase concentration. Lung damage was determined by electron microscopy, cell count in bronchoalveolar lavage fluid, and analysis of lung vascular permeability. Four additional animals (two conscious and two anesthetized) went through the same protocol but did not receive LPS. LPS infusion induced a hyperdynamic sepsis. The drop in total peripheral resistance was compensated by an increase in heart rate and cardiac output in the conscious group, whereas anesthetized sheep failed to compensate in this way. Endotoxemic isoflurane-anesthetized sheep also showed signs of aggravated lung edema formation and tissue damage together with enhanced neutrophil activation and lung tissue accumulation. Our data suggest that isoflurane in conjunction with mechanical ventilation blunts cardiovascular compensatory mechanisms in sepsis and enhances leukocyte activation, which may contribute to lung edema formation and tissue damage. PMID- 20844414 TI - Re: Boden SD, Zdeblick TA, Sandhu HS, et al. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine 2000; 25:376-81. PMID- 20844415 TI - Re: Mroz TE, Wang JC, Hashimoto R, et al.Complications related to osteobiologics use in spine surgery: a systematic review. Spine (Phila Pa 1976) 2010;35:S86-104. PMID- 20844416 TI - Re: Bakker EW, Verhagen AP, van Trijffel E, et al. Spinal mechanical load as a risk factor for low back pain: a systematic review of prospective cohort studies. Spine 2009; 34:E281-93. PMID- 20844419 TI - Re: Kleeman TJ, Ahn UM, Talbot-Kleeman A. Laparoscopic anterior lumbar interbody fusion with rhBMP-2: a prospective study of clinical and radiographic outcomes. Spine 2001;26:2751-6. PMID- 20844420 TI - Clinical experience using Cortoss for treating vertebral compression fractures with vertebroplasty and kyphoplasty: twenty four-month follow-up. AB - STUDY DESIGN: Forty patients were enrolled in 2 FDA-approved pilot Investigational Device Exemption (IDE) studies using Cortoss for the treatment of vertebral compression fractures (VCF). Twenty patients were treated at 3 centers, using vertebroplasty (VP) and 20 patients were treated at 5 centers, using kyphoplasty (KP). OBJECTIVE: To assess the feasibility and clinical outcomes using Cortoss to treat osteoporotic VCF. SUMMARY OF BACKGROUND DATA: Cortoss is an injectable bioactive, self-setting, radiopaque composite shown to stabilize and provide immediate weight bearing support to fractured vertebrae. Cortoss is approved for use in Europe for both screw and vertebral augmentation. METHODS.: Patient assessments were conducted before surgery and after surgery through 24 months using Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and quality-of-life assessment (SF-12) questionnaires. Extravasations were evaluated using radiographs and CT scans. RESULTS: Immediate pain improvement was seen in VP patients with VAS scores decreasing from 75.7 before surgery to 35.9 at 72 hours. Continued improvement from baseline was seen out to 2 years (average VAS of 48.9). Disability improved with average ODI scores decreasing from 52.2% preoperative to 38.3% at 2 years for VP patients. Immediate pain improvement was also seen in KP patients with VAS scores decreasing from 78.1 before surgery to 42.7 at 72 hours. Continued improvement from baseline was seen out to 2 years (average VAS of 25.4). ODI scores improved from 60.5% preoperative to 34.5% at 2 years for KP patients. Average material volumes injected were 1.85 mL for VP and 4.13 mL for KP. Extravasations from both techniques were minor, anatomically close to the treated vertebrae and asymptomatic. No cardiac irregularities or pulmonary emboli were observed. CONCLUSION: These studies indicate Cortoss is safe and effective in treating osteoporotic VCF using vertebroplasty or kyphoplasty. Pain relief and restoration of function with Cortoss is comparable to results found in the literature for polymethylmethacrylate. PMID- 20844421 TI - The impact of intermittent retraction on paraspinal muscle function during lumbar surgery. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To study the effect of surgical retraction on paraspinal muscle function and investigate the effect of intermittent muscle retraction. SUMMARY OF BACKGROUND DATA: Paraspinal muscle retraction leads to increased intramuscular pressure with a reduction in local blood flow resulting in ischemic damage. This may lead to muscle dysfunction and increased back pain after surgery. METHODS: Two groups of 20 patients underwent one-level decompressive lumbar surgery. Group A underwent continuous muscle retraction, group B underwent intermittent muscle retraction. All patients completed pain questionnaires and underwent spinal strength assessment, paraspinal needle electromyography (EMG) before and after surgery, and had intraoperative muscle biopsy analysis using the technique of birefringence. RESULTS: Pain questionnaires revealed a reduction in back pain in all patients following surgery; patients with shorter retraction times had less pain (P < 0.05). Paraspinal muscle histochemistry revealed patients with shorter muscle retraction times and patients who underwent intermittent muscle retraction has less damage (P < 0.05). Isometric strength testing revealed patients in the intermittent retraction group had a less profound reduction in strength after surgery (P < 0.05). Needle EMG data and pain questionnaires showed no differences between the continuous and intermittent groups, although EMG data did show that muscle shows evidence of reinnervation after surgery. CONCLUSION: Although histologically there was a reduction in muscle damage in patients that underwent intermittent retraction, there was no benefit on clinical outcome. Paraspinal muscle shows evidence of reinnervation after surgery. PMID- 20844423 TI - Preoperative bracing affects postoperative outcome of posterior spine fusion with instrumentation for adolescent idiopathic scoliosis. AB - STUDY DESIGN.: Multicenter, prospective clinical series. OBJECTIVE.: To investigate the effect of preoperative bracing on postoperative outcome of posterior spine fusion with instrumentation for adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA.: Bracing is the standard of care for adolescent idiopathic scoliosis between 25 degrees and 45 degrees , yet the efficacy of bracing is questionable. It is important to evaluate the effect of bracing on outcomes in the adolescent idiopathic scoliosis population. METHODS.: We reviewed the outcomes of 281 before surgery braced and 328 before surgery nonbraced patients who underwent posterior spine fusion with instrumentation for adolescent idiopathic scoliosis before operation and at 2 years after operation using the Scoliosis Research Society instrument (SRS-30) and the Spinal Appearance Questionnaire. RESULTS.: At 2 years after operation, nonbraced patients demonstrated a greater improvement in the SRS-30 Pain domain score (0.23 vs. 0.08, P < 0.001), more improvement in back pain at rest (26.7% vs. 20.5%, P = 0.0009), and more improvement in back pain in the past 6 months (42.4% vs. 32.6%, P = 0.039) compared to braced patients. Also at 2 years after operation, nonbraced patients reported higher SRS-30 Activity domain scores (4.38 vs. 4.32, P = 0.031), Satisfaction domain scores (4.53 vs. 4.42, P = 0.007), and Total scores (4.27 vs. 4.35, P = 0.036) compared with braced patients. The 2-year Spinal Appearance Questionnaire scores showed that nonbraced patients reported a greater "decrease in importance" than braced patients in having "more even shoulders" (79.4% vs. 70.5%, P = 0.03), "more even hips" (74.6% vs. 71.6%, P = 0.042), and "more even ribs in back" (78.4% vs. 69.5%, P = 0.05). CONCLUSION.: Before surgery braced patients have more pain, lower activity levels, lower satisfaction, and lower total SRS-30 scores at 2 years after operation. Braced patients also have more "spine-specific" appearance concerns compared to nonbraced patients. These results suggest a negative impact of preoperative bracing on outcomes after posterior spinal fusion for adolescent idiopathic scoliosis. This "brace signature" should be taken into account when brace treatment is being considered. PMID- 20844424 TI - Commentary: Personalized health planning and the Patient Protection and Affordable Care Act: an opportunity for academic medicine to lead health care reform. AB - The Patient Protection and Affordable Care Act of 2010 (PPACA) mandates the exploration of new approaches to coordinated health care delivery--such as patient-centered medical homes, accountable care organizations, and disease management programs--in which reimbursement is aligned with desired outcomes. PPACA does not, however, delineate a standardized approach to improve the delivery process or a specific means to quantify performance for value-based reimbursement; these details are left to administrative agencies to develop and implement. The authors propose that coordinated care can be implemented more effectively and performance quantified more accurately by using personalized health planning, which employs individualized strategic health planning and care relevant to the patient's specific needs. Personalized health plans, developed by providers in collaboration with their patients, quantify patients' health and health risks over time, identify strategies to mitigate risks and/or treat disease, deliver personalized care, engage patients in their care, and measure outcomes. Personalized health planning is a core clinical process that can standardize coordinated care approaches while providing the data needed for performance-based reimbursement. The authors argue that academic health centers have a significant opportunity to lead true health care reform by adopting personalized health planning to coordinate care delivery while conducting the research and education necessary to enable its broad clinical application. PMID- 20844425 TI - Diagnosis and management of foreign bodies in the skin. AB - PURPOSE: To enhance the learner's competence in the diagnosis and management of foreign bodies in the skin. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: 1. Accurately assess clinical presentation of foreign bodies in skin wounds. 2. Demonstrate use of diagnostic tests and injury management. PMID- 20844426 TI - Super bugs: survival of the fittest. PMID- 20844427 TI - HIV-1 infection and antiretroviral therapies: risk factors for osteoporosis and bone fracture. AB - PURPOSE OF REVIEW: Patients with HIV-1 infection/AIDS are living longer due to the success of highly active antiretroviral therapy (HAART). However, serious metabolic complications including bone loss and fractures are becoming common. Understanding the root causes of bone loss and its potential implications for aging AIDS patients will be critical to the design of effective interventions to stem a tidal wave of fractures in a population chronically exposed to HAART. RECENT FINDINGS: Paradoxically, bone loss may occur not only due to HIV/AIDS but also as a consequence of HAART. The cause and mechanisms driving these distinct forms of bone loss, however, are complex and controversial. This review examines our current understanding of the underlying causes of HIV-1 and HAART-associated bone loss, and recent findings pertaining to the relevance of the immuno-skeletal interface in this process. SUMMARY: It is projected that by 2015 more than half of the HIV/AIDS population in the USA will be over the age of 50 and the synergy between HIV and/or HAART-related bone loss with age-associated bone loss could lead to a significant health threat. Aggressive antiresorptive therapy may be warranted in high-risk patients. PMID- 20844428 TI - Potential new drugs for human African trypanosomiasis: some progress at last. AB - PURPOSE OF REVIEW: This review covers recent developments towards novel treatments for human African trypanosomiasis (HAT). RECENT FINDINGS: Within the past decade, some important advances in the treatment of HAT have been made. One old drug, melarsoprol, previously administered over a period of a month or more, is now given in a 10-day regimen greatly reducing hospital costs. A combination chemotherapy, eflornithine alongside nifurtimox, has been introduced to decrease the time frame and overall dosing of eflornithine and reducing the risk of drug resistance emerging. One new, orally available diamidine prodrug, pafuramidine, that recently completed phase III clinical trials, disappointingly was halted in its progress to clinic when unforeseen toxicity issues emerged. The diamidine series, however, has recently yielded representatives that cure second-stage central nervous system (CNS)-involved infections in experimental animals while showing less tissue accumulation in mammals and thus offer considerable promise. A nitroheterocycle, fexinidazole, whose trypanocidal activity was first shown nearly 30 years ago, has entered clinical trials. Another approach, grounded in the use of pharmacokinetic data, has brought another new class of compound based on the oxaborole scaffold forward for clinical candidacy. Furthermore, several target-based and whole organism-based chemical compound screening campaigns have identified promising hits for lead development. SUMMARY: The new developments in trypanocidal drug discovery mean that new compounds could become available within the next 5 years to support the WHO declared campaign to eliminate HAT. PMID- 20844429 TI - Skin autofluorescence as a measure of advanced glycation endproduct deposition: a novel risk marker in chronic kidney disease. AB - PURPOSE OF REVIEW: Skin autofluorescence (SAF) is a new method to noninvasively assess accumulation of advanced glycation endproducts (AGEs) in a tissue with low turnover. Recent progress in the clinical application of SAF as a risk marker for diabetic nephropathy as well as cardiovascular disease in nondiabetic end-stage kidney disease, less advanced chronic kidney disease, and renal transplant recipients is reviewed. RECENT FINDINGS: Experimental studies highlight the fundamental role of the interaction of AGEs with the receptor for AGEs (RAGEs), also called the AGE-RAGE axis, in the pathogenesis of vascular and chronic kidney disease. SAF predicts (cardiovascular) mortality in renal failure and also chronic renal transplant dysfunction. Long-term follow-up results from the Diabetes Control and Complications Trial and UK Prospective Diabetes Study suggest that AGE accumulation is a key carrier of metabolic memory and oxidative stress. Short-term intervention studies in diabetic nephropathy with thiamine, benfotiamine and angiotensin-receptor blockers aimed at reducing AGE formation have reported mixed results. SUMMARY: SAF is a noninvasive marker of AGE accumulation in a tissue with low turnover, and thereby of metabolic memory and oxidative stress. SAF independently predicts cardiovascular and renal risk in diabetes, as well as in chronic kidney disease. Further long-term studies are required to assess the potential benefits of interventions to reduce AGE accumulation. PMID- 20844432 TI - Current world literature. PMID- 20844431 TI - The role of ischemia in postlung transplantation complications. PMID- 20844433 TI - Treating uncomplicated malaria in children: comparing artemisinin-based combination therapies. AB - PURPOSE OF REVIEW: In response to increased resistance to conventional drugs, the WHO is promoting artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. The objective of this report is to review the available evidence on the efficacy and effectiveness, acceptability, and deployment of ACT in resource-limited settings with a focus on sub-Saharan Africa. RECENT FINDINGS: ACTs are very effective in the treatment of uncomplicated Plasmodium falciparum malaria in children. ACTs are relatively safe and tolerable with no reported resistance in sub-Saharan Africa despite indications of delayed clearance of infections in south-east Asia. The major challenges to the widespread use of ACT include its high cost, availability, and inefficient delivery due to, among other things, weak healthcare systems. SUMMARY: ACTs are an essential tool in the fight to control and eliminate malaria. They are currently the most effective drugs against P. falciparum malaria. They should be deployed through programs that address availability, cost, adherence, and quality assurance. Initiatives including home-based management of malaria, improving public sector procurement and supply chains, and reducing private sector pricing should make ACTs more accessible for sub-Saharan African children who bear the brunt of the burden of malarial disease. PMID- 20844434 TI - After the fire: the mental health consequences of fire disasters. AB - PURPOSE OF REVIEW: This article aims to summarize recent findings relating to the impact of fire disasters on the mental health of victims, responders, families and communities within the context of the existing literature. RECENT FINDINGS: Recent studies support previous findings that fire disasters are associated with a negative impact on the mental and physical health of victims, their families and professional and voluntary responders to the disasters. These effects can be delayed in onset and can persist over at least several years, although long-term follow-up studies over 20 years or more indicate that the psychological effects on victims are minimal relative to controls by this stage. SUMMARY: Fire disasters, like other natural or man-made disasters, can have significant mental health impact on individuals directly and indirectly affected and on communities caught up in the events. PMID- 20844435 TI - Therapeutic strategies for advanced penile carcinoma. AB - PURPOSE OF REVIEW: The article will review the treatment of regionally advanced squamous cell carcinoma (SCC) of the penis and will highlight contemporary therapeutic strategies in advanced penile carcinoma. RECENT FINDINGS: Advanced penile cancer as defined by bulky inguinal or pelvic metastasis is treated in a systematic fashion by integrating systemic and local therapies. Contemporary series show the morbidity from consolidative surgery has been reduced, whereas the integration of neoadjuvant and adjuvant therapies may provide improved cancer specific outcomes over single modality treatment. Multiple clinical and pathologic features guide the treatment of advanced disease and aid in determining the appropriate use of neoadjuvant or adjuvant therapies. SUMMARY: The current treatment of advanced SCC of the penis has evolved to include multimodal treatments for patients with advanced locoregional disease. PMID- 20844437 TI - Male circumcision: Africa and beyond? AB - PURPOSE OF REVIEW: Male circumcision has become an important component of HIV prevention strategies in Africa. Results of recent trials have renewed interest in this ancient procedure and its potential application in the reduction of sexually transmitted infections (STIs). With renewed interest comes controversy, which has always been a close companion to circumcision. RECENT FINDINGS: Following the three randomized trials in Africa demonstrating the protective effects of male circumcision on HIV infection, studies have reported other benefits of circumcision including protection from certain STIs, including human papillomavirus and herpes simplex virus 2. With data accumulating on the public health benefits of circumcision and the endorsement of circumcision from WHO, investigators have begun to evaluate the feasibility, safety and cost of implementation of large-scale circumcision programs. Limitations of circumcision have also been explored. SUMMARY: Male circumcision will likely play an important role in HIV/STI prevention programs in Africa; the inclusion of circumcision in the health policy of developed countries will require further investigation. PMID- 20844436 TI - New advances on the expansion and storage of human spermatogonial stem cells. AB - PURPOSE OF REVIEW: Fertility in adult life can be severely impaired by gonadotoxic therapies and with remarkable advancements in the treatment of childhood cancers there is a growing population of adult survivors of childhood malignancies. The aim of the study is to review the developments that have been made in spermatogonial stem cell research and potential future utility in fertility preservation. RECENT FINDINGS: Whereas intense interest and subsequent research surrounds the regenerative potential of spermatogonial stem cells, a recent article highlights the in-vitro propagation of human spermatogonial stem cells from testicular biopsies for future transplantation and restoration of fertility. Whereas in-vitro propagation of spermatogonial stem cells has been established in animal models this is the first study in humans. SUMMARY: Spermatogonial stem cell transplantation began as a theoretical approach that currently is studied ardently by several research groups to make this a valid clinical option. Restoration of fertility following spermatogonial stem cell transplantation in animals suggests therapeutic potential for the technique in humans, and further research is proceeding to address the safety and efficacy of this technique. PMID- 20844438 TI - Estimation of risk ratios in cohort studies with common outcomes: a Bayesian approach. AB - In cohort studies with common outcomes, the odds ratio estimated from a logistic regression analysis is often interpreted as an indirect estimate of the risk ratio. In such settings, the odds ratio will be farther from the null than the risk ratio. Direct and unbiased estimates of the risk ratio may be obtained from a log binomial model fit by maximum likelihood. When the maximum likelihood log binomial model fails to converge (as is common) or provides predicted probability estimates or upper confidence limits greater than 1.0, various approaches have been suggested, but each has drawbacks, as we describe. We propose a novel Bayesian approach for the estimation of the risk ratio from the log binomial model that addresses drawbacks of existing approaches. Posterior computation can be accomplished easily using the WinBUGs code provided. PMID- 20844439 TI - Peripheral nerve excitability measures at different target levels: the effects of aging and diabetic neuropathy. AB - Threshold tracking testing has provided novel insights of peripheral nerve excitability in normal and pathologic conditions. However, little has been known on the nerve excitability properties of axons with different stimulation thresholds and the effects of aging and peripheral neuropathy to those. We performed multiple nerve excitability tests in normal controls divided into three age groups and in patients with diabetic neuropathy, which were recorded at three target levels (10%, 40%, and 60% of the maximum motor response amplitudes). In all the control groups, tracking at low target level shows smaller threshold change by hyperpolarizing stimuli and greater threshold change by depolarizing stimuli, suggestive of greater transient Na current. Normal elderly showed greater threshold change by hyperpolarizing pulse than younger subjects at high target level, likely reflecting decrease of axon diameters. Patients with diabetic neuropathy showed smaller threshold changes by both depolarizing and hyperpolarizing pulses ("fanning-in"), more noticeably at the lower target level, suggestive of the combined effects of membrane depolarization and greater decrease of axonal diameters in smaller fibers. Given the reported unpredictable electrical recruitment order in the diseased conditions and difference of nerve excitability measures in threshold electrotonus at different target levels, comparing threshold electrotonus values between normal and diseased axons may be problematic by comparing axons with different nerve excitability characteristics. PMID- 20844440 TI - Automatic removal of various artifacts from EEG signals using combined methods. AB - In this article, a novel and robust method is proposed to automatically remove various artifacts from EEG signals. First, canonical correlation analysis method is adopted to separate electromyography (EMG) artifacts from EEG signals. EMG free EEG signals are obtained by subtracting the contribution of the components with autocorrelation value less than a threshold determined by the statistical analysis. For the removal of ocular artifacts, independent component analysis is applied to decompose the EMG-free signals. For the identification of eye movement artifact components, spectral and topographic features are extracted, and the classifier of support vector machine is used. Specifically, a peak detection algorithm of independent component is proposed to identify eye blink artifact components for the first time. The proposed artifact removal method is evaluated by the comparisons of EEG data before and after artifacts removal. The results show that the proposed method provides a promising method for complete artifact removal from EEG. PMID- 20844441 TI - Channel selection for optimizing feature extraction in an electrocorticogram based brain-computer interface. AB - Feature extractor and classifier are two major components in a brain-computer interface system, in which the feature extractor plays a critical role. To increase the discriminability of features or feature vectors used for classification, it is necessary to select a suitable number of task-related data recording channels. In this article, a machine-learning algorithm is proposed for optimizing feature extraction in an electrocorticogram-based brain-computer interface. Common spatial pattern was used for feature extraction, and channel selection was performed by genetic algorithm for optimizing the feature extraction. Fisher discriminant analysis was used as classifier, and the channel subset chosen at each generation was evaluated by classification accuracy. The algorithm was applied to three electrocorticogram datasets that were recorded during two kinds of motor imagery tasks. The results suggest that the channel number used for building a brain-computer interface system could be significantly decreased without losing classification accuracy, and the accuracy rate could be noticeably improved by using the optimal channel subsets chosen by genetic algorithm. PMID- 20844442 TI - Effect of memantine in Alzheimer's disease evaluated by visual-evoked potentials to pattern-reversal, motion-onset, and cognitive stimuli. AB - The authors tested visual-evoked potentials to pattern-reversal, motion-onset, and visual cognitive event-related potentials in 17 patients with mild-to moderate Alzheimer's disease treated with Memantine (noncompetitive N-methyl-D aspartic acid antagonist) to verify whether these objective methods can evaluate its therapeutic effect. The patients were examined before Memantine administration and after 3 and 6 months from the treatment onset. Besides electrophysiology, psychologic Alzheimer Disease Assessment Scale-cognitive part (ADAS-cog) test was also performed. Neither ADAS-cog nor any of the electrophysiological tests were able to prove a significant beneficial effect of Memantine therapy in our group of patients. The results of psychologic and electrophysiological tests did not correlate. An individual improvement of ADAS cog score (decrease of score by 4 and more points) was present in only 29% of patients, improvement of event-related potentials (shortening of P300 peak latency by at least 20 milliseconds) occurred in 42% of patients. Conversely, in 52% of patients, Memantine therapy led to transitory decline of motion processing (delay of N2 peak latency of the motion-onset visual-evoked potentials by at least 10 milliseconds after the first 3 months of therapy, followed by return to pretherapy values in next 3 months). PMID- 20844443 TI - Fractality and a wavelet-chaos-neural network methodology for EEG-based diagnosis of autistic spectrum disorder. AB - A method is presented for investigation of EEG of children with autistic spectrum disorder using complexity and chaos theory with the goal of discovering a nonlinear feature space. Fractal Dimension is proposed for investigation of complexity and dynamical changes in autistic spectrum disorder in brain. Two methods are investigated for computation of fractal dimension: Higuchi's Fractal Dimension and Katz's Fractal Dimension. A wavelet-chaos-neural network methodology is presented for automated EEG-based diagnosis of autistic spectrum disorder. The model is tested on a database of eyes-closed EEG data obtained from two groups: nine autistic spectrum disorder children, 6 to 13 years old, and eight non-autistic spectrum disorder children, 7 to 13 years old. Using a radial basis function classifier, an accuracy of 90% was achieved based on the most significant features discovered via analysis of variation statistical test, which are three Katz's Fractal Dimensions in delta (of loci Fp2 and C3) and gamma (of locus T6) EEG sub-bands with P < 0.001. PMID- 20844444 TI - Lower tibial than peroneal compound muscle action potential amplitude in neuromuscular diseases. AB - The pattern of findings on nerve conduction studies is an important component of an electrodiagnostic evaluation to assess for peripheral neuromuscular disorders. The aim of this study was to determine the extent to which a lower tibial compound muscle action potential (CMAP) amplitude compared with the peroneal CMAP amplitude is more indicative of specific neuromuscular disorders such as S1 radiculopathies, sciatic neuropathies, or peripheral neuropathies. The electromyographic (EMG) findings of 921 patients who had undergone an EMG of the lower extremity and in whom the EMG study was interpreted as normal or a single neuromuscular diagnosis was identified were retrospectively reviewed to determine the frequency of an absolutely lower tibial than peroneal CMAP amplitude. Thirty five (7%) healthy subjects had a lower tibial than peroneal CMAP amplitude (i.e., the absolute value of the tibial CMAP was lower than the absolute value of the peroneal CMAP), despite both values being in normal range. The finding on nerve conduction study of an absolutely lower tibial than peroneal CMAP occurred in a significantly higher proportion of patients with a diffuse polyneuropathy (24%) and S1 radiculopathies (21%) compared with controls. The findings suggest that in subjects in whom lower extremity nerve conduction study demonstrates an absolutely lower tibial than peroneal CMAP amplitude, neuromuscular disorders such as a polyneuropathy or S1 radiculopathy should be considered. PMID- 20844446 TI - Extent of EEG epileptiform pattern distribution in "focal" cortical dysplasia. AB - To assess the pathophysiological complexity of cortical dysplasia-related intractable focal epilepsy among surgical candidates, using our data-based EEG classification system, we reviewed preresection scalp awake and sleep EEGs (median, 8) in 46 consecutive patients whose resected pathology disclosed cortical dysplasia. Epileptiform phenomena occurred on at least one EEG in 42 (91%) patients. Twenty-three (50%) of the 46 patients displayed at least one type of independently occurring abnormality (spikes, excess delta, or theta) in each hemisphere. Nineteen of these 23 (83%), thus 41% of all 46 patients, showed independently occurring epileptiform abnormalities (spikes) in each hemisphere, i.e., the multiple independent spike foci phenomenon. In an additional 13 of the 46 (28%) patients, spike foci involving more than one lobe appeared within a single hemisphere. Thus, spike foci involving more than one lobe appeared in 32 of the 46 (70%) patients. Generalized bilaterally synchronous epileptiform features (spike waves, slow spike waves, or fast rhythmic waves) appeared in 10 (22%) of the 46 patients. Two findings suggest more widespread dysfunction among extratemporal patients than temporal patients: (1) a significantly higher number of lobes containing focal interictal epileptiform activity in extra temporal patients (mean = 3.14) than among temporal patients (mean = 2.14) (P = 0.02), (2) a higher percentage of bisynchronous epileptiform abnormalities: 8 of 23 (35%) versus 2 of 23 (9%). Among 34 patients with a Principal Spike Lobe (more active spiking over more EEGs), those of 32 (94%) arose from the ultimately resected lobe. Of the 30 patients with scalp-recorded seizures, relationship between seizure origin and ultimately resected lobe were same lobe (16 patients), same and adjacent lobes (12), adjacent lobe only (1), and distant lobe (1). Thus, despite the multifocality of several EEG features, Principal Spike Lobe and scalp recorded seizure origin correlate well with epileptogenesis. PMID- 20844445 TI - Thenar motor neuropathy electrophysiological study of 28 cases. AB - PURPOSE: To report an electrophysiological study on thenar motor neuropathy of the median nerve. METHODS: Twenty-eight consecutive patients (mean age, 48.8 years; 17 men) with dominant hand thenar muscle weakness without sensory symptoms were enrolled in this study. Electromyography of hand and forearm muscles and neurography of median, ulnar, radial, and palmar nerves, including distal motor latency recording from the second interosseous-lumbrical muscles, were performed. RESULTS: Complete denervation of the abductor pollicis brevis muscle was observed in one case and delayed median abductor pollicis brevis-distal motor latency was observed in the others. Other neurographic findings were normal. CONCLUSIONS: Thenar motor neuropathy may have different pathogeneses. It may be considered a variant of carpal tunnel syndrome involving the motor branch only or more likely due to chronic direct compression of the branch, because it preferentially affects males, dominant hand, and persons doing manual work. In both cases, anatomic origin and variations in the course of the branch may favor thenar motor neuropathy. PMID- 20844447 TI - Treatment of Enneking stage 3 aggressive vertebral hemangiomas with intralesional spondylectomy: report of 10 cases and review of the literature. AB - STUDY DESIGN: A retrospective review of consecutive series of Enneking stage 3 vertebral hemangiomas surgically treated at a major tertiary spine tumor center. OBJECTIVE: To determine the short-term recurrence rates, pain improvement, and operative morbidity of intralesional spondylectomy combined with preoperative embolization for Enneking stage 3 vertebral hemangiomas. SUMMARY OF BACKGROUND DATA: Aggressive vertebral hemangiomas (Enneking stage 3) often involve both the anterior and posterior columns with spinal canal and local soft tissue extension and may present with dramatic bony destruction, spinal instability, and pain accompanied with neurologic compromise. Although the current treatment paradigm for most vertebral hemangiomas is conservative management directed toward symptomatic relief, the subset of patients presenting with this rare variant requires more extensive surgical treatment. METHODS: A retrospective clinical review of patients diagnosed with Enneking stage 3 vertebral hemangiomas was conducted at the University of California at San Francisco. RESULTS: We identified 10 consecutive cases of Enneking stage 3 hemangiomas. Average follow up was 2.42 years. The most common presentation was pain with or without myelopathy. Three of the 10 cases were recurrences after prior partial resection and reconstruction or cement augmentation. All patients underwent preoperative embolization. Average blood loss despite embolization was 2.1 L (range: 0.8 to 5 L). Average preoperative back pain visual analog scale was 7.2 and postoperative visual analog scale was 3.1 at 6 months. On postoperative imaging, all patients had gross total resection. Six patients had staged posterior/anterior transcavitary approach and 4 patients underwent single stage posterior transpedicular spondylectomy. To date, no patient has required adjuvant radiation therapy for tumor recurrence. CONCLUSIONS: Our results suggest that complete wide resection of aggressive Enneking stage 3 lesions can be safely accomplished with acceptable morbidity and blood loss and significant improvement in pain and neurological status. Partial resection of stage 3 lesions, even with stabilization or vertebroplasty, may lead to early recurrence. PMID- 20844448 TI - Radiation exposure to the surgeon during percutaneous pedicle screw placement. AB - STUDY DESIGN: In-vitro radiation exposure study. OBJECTIVE: To determine the radiation exposure to the eyes, extremities, and deep tissue during percutaneous pedicle screw placement. SUMMARY OF BACKGROUND DATA: Image-guided minimally invasive spinal surgery is typically performed with the use of fluoroscopy, exposing the surgeon and patient to ionizing radiation. The radiation dose to the surgeon has not been reported and risk to the surgeon performing this procedure over the long term is uncertain. METHODS: Percutaneous pedicle screws were placed in a cadaveric specimen from L2-S1 bilaterally using a cannulated pedicle screw system. Two fluoroscopes were used in the anteroposterior and lateral planes. The surgeon wore a thermolucent dosimeter ring on the right hand and badge over the left chest beneath the lead apron. Complete surgical time was recorded and a computed tomography scan was performed to assess screw placement. Radiation exposure was measured for total time of fluoroscopy use; average exposure per screw, surgical level, and dose to the eyes was calculated. This data was used to define the safety of percutaneous pedicle screw placement. RESULTS: Total fluoroscope time for placement of 10 percutaneous pedicle screws was 4 minutes 56 seconds (29 s per screw). The protected dosimeter recorded less than the reportable dose. The ring dosimeter recorded 103 mREM, or 10.3 mREM per screw placed. All screws were within the bone confines with acceptable trajectory. Exposure to the eyes was 2.35 mREM per screw. CONCLUSIONS: On the basis of this data, percutaneous pedicle screw placement seems to be safe. A surgeon would exceed occupational exposure limit for the eyes and extremities by placing 4854 and 6396 screws percutaneously, respectively. Lead protected against radiation exposure during screw placement. The "hands-off" technique used in this study is recommended to minimize radiation exposure. Lead aprons, thyroid shields, and leaded glasses are recommended for this procedure. PMID- 20844449 TI - Biomechanical evaluation of transfacet screw fixation for stabilization of multilevel cervical corpectomies. AB - STUDY DESIGN: Cadaveric biomechanical investigation. OBJECTIVES: To test the feasibility of transfacet screws as a minimally invasive posterior fixation device for the cervical spine by comparing the biomechanical stability of transfacet screws to lateral mass screws and rods in a multilevel cervical corpectomy model. SUMMARY OF BACKGROUND DATA: Minimally invasive surgery (MIS) of the spine has gained increasing acceptance and popularity. However, a minimally invasive means of instrumenting the posterior cervical spine has yet to be discovered. Posterior transfacet screws have been described as a means of posterior fixation. In addition, they have the potential of being placed percutaneously through stab incisions. However, validation of transfacet screws in an unstable cervical model in which posterior instrumentation may be necessary has not been carried out till date. METHODS: Sixteen cadaveric cervical spines were randomized to transfacet or lateral mass instrumentation groups. The spines were tested in the following conditions: (a) intact, (b) after multilevel corpectomies with strut graft placement with stand-alone posterior fixation, and (c) with an additional anterior plate over the strut graft. Corpectomy site loading was measured with a custom-designed strut graft. Data were collected for spinal stiffness, range of motion, and strut graft loading, and was analyzed using 2-way analysis of variance (P<0.05). RESULTS: Stand-alone transfacet screw fixation was found to provide inferior spinal stability and resulted in increased spinal motion and graft loading compared with the other constructs (P<0.05 for all). CONCLUSIONS: It is unclear what kind of mechanical stiffness is necessary to stabilize the cervical spine and obtain solid fusion. However, decreased stability and increased graft loading suggest that transfacet screws may not be the ideal method of posterior fixation to supplement multilevel anterior cervical corpectomies and fusions despite their potential as a minimally invasive method for posterior cervical instrumentation. PMID- 20844450 TI - Apical vertebral rotation in adolescent idiopathic scoliosis: comparison of uniplanar and polyaxial pedicle screws. AB - STUDY DESIGN: Retrospective radiographic outcome analysis. OBJECTIVE: To compare residual postoperative apical vertebral rotation between uniplanar versus polyaxial bilateral pedicle screw constructs in thoracic adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Vertebral rotation is a component of the 3-dimensional deformity of AIS. The correction of vertebral rotation is an important goal of surgery. A comparison of uniplanar versus polyaxial screws has yet to be studied. METHODS: A review of a multicenter database of Lenke type 1 to 3 AIS patients who underwent surgical correction of thoracic AIS by posterior segmental pedicle screw instrumentation and fusion with either uniplanar or polyaxial pedicle screws and 5.5-mm steel rod constructs was performed. Curves greater than 100 degrees were excluded to control for the propensity to use polyaxial screws to correct larger curves. Postoperative apical vertebral rotation of thoracic curves was graded as 0, 1, or 2 based on a computed tomography scan-validated radiographic method that uses the relative position of the screw tips to grade apical vertebral rotation at the 6-week and 1-year postoperative visits. By this grading method, higher grades correspond to greater residual apical vertebral rotation. RESULTS: Two hundred and ten patients met the inclusion criteria. The uniplanar screw group included 95 patients whereas the polyaxial screw group had 115 patients. The respective mean preoperative thoracic Cobb angle of 58+/-12 and 60+/-13 degrees (P=0.1), first erect postoperative coronal correction of 72% and 74% (P=0.38), and 1-year correction of 70% and 76% (P=0.07) were not significantly different between the uniplanar and polyaxial groups. At 6 weeks postoperation, the uniplanar group had 34% of patients with grade 0 rotation, 52% with grade 1, and only 14% with grade 2 thoracic apical vertebral rotation. In the polyaxial group, only 14% of patients were grade 0, 35% were grade 1, and 51% were the most rotated grade 2. This was a significant difference in the distribution of the axial rotation grades (P<0.001), with less residual apical vertebral rotation with the use of uniplanar screws. The same pattern of results was found at 1-year postoperative evaluation (P<0.001). CONCLUSIONS: There was little difference in the coronal plane correction of thoracic curves between the 2 types of screws. However, the uniplanar pedicle screw group had a larger proportion of patients with greater thoracic apical vertebral derotation (less residual apical vertebral rotation) compared with the polyaxial screw group. This can be attributed to the increase in rotational leverage afforded by uniplanar screws during intraoperative bilateral direct apical vertebral derotation maneuvers. PMID- 20844451 TI - Lateral lumbar interbody fusion: clinical and radiographic outcomes at 1 year: a preliminary report. AB - STUDY DESIGN: A retrospective review of patients' radiographs and charts. BACKGROUND: The various methods of lumbar interbody fusion have been described in the literature. With the development of the lateral lumbar interbody fusion (LLIF) approach, a wider cage can be inserted in the intervertebral space without disrupting the anterior-posterior annulus or longitudinal ligament, with minimal danger to the retroperitoneal structures and the great vessels. There is a paucity of the literature on the radiographic and clinical outcome of this approach. OBJECTIVE: The purpose of this study is to assess the radiographic change in the coronal and sagittal plane alignment of the lumbar spine after the LLIF approach using XLIF cages (Nuvasive, Inc, San Diego, CA). Radiographic and clinical outcomes, and complications associated with the approach are also described. METHODS: A retrospective review of 43 consecutive patients' preoperative, immediate postoperative, and 1-year follow-up radiographs was done. All patients had LLIF procedure performed for lumbar degenerative disc disease, spondylolisthesis, or de novo scoliosis. The radiographic measurements were taken to assess change in the sagittal and coronal plane alignment of the individual instrumented disc level, overall lumbar spine, and lumbar scoliotic curves. The radiographs were also analyzed for fusion at 1 year, end-plate fracture, and other complications. The patients' hospital and clinic charts were reviewed to identify the complications and patient outcomes. RESULTS: There was a mean correction of 3.7 degrees (P<=0.001) at each instrumented disc level in coronal plane in 87 instrumented levels. Similarly, there was a mean gain of 2.8 degrees (P<=0.001) of lordosis at each level. In 25 patients with lumbar scoliosis (>10 degrees), mean scoliosis angle correction was 10.4 degrees (P=0.001, 43%). There was no significant change in the overall coronal or sagittal plane alignment of the lumbar spine. The most common postoperative complication (25%) was anterior thigh pain, which was transitory in the majority of cases. End-plate breach was common at the instrumented disc levels; however, it was nonprogressive in most of the cases, and did not affect the fusion or alignment at the instrumented levels. The outcome scores were improved significantly at the final follow-up. CONCLUSION: The LLIF approach is effective in correcting the coronal plane deformity and in gaining lordosis at individual instrumented levels. They parallelize adjacent end plates to correct the lumbar scoliotic curves. The complications are mostly approach-related and transitory. A larger cohort with long-term follow-up is required to establish the advantages and shortcomings of the procedure. PMID- 20844452 TI - Augmentation of pedicle screw stability with calcium sulfate cement in osteoporotic sheep: biomechanical and screw-bone interfacial evaluation. AB - STUDY DESIGN: Augmentation of pedicle screws with calcium sulfate cement (CSC) was performed in osteoporotic sheep. Biomechanical tests, micro-computed tomography (CT) analysis, and histological observation were performed. OBJECTIVE: To investigate the long-term biomechanical performance of pedicle screws augmented with CSC in vivo and evaluated the screw-bone interfacial bonding with micro-CT and histological techniques. SUMMARY OF BACKGROUND DATA: There is little information on the long-term biomechanical performance and screw-bone interfacial bonding of pedicle screws augmented with CSC in osteoporosis in vivo. METHODS: Twelve months after ovariectomy, bilateral pedicles of lumbar vertebrae (L1 to L5) of 6 female sheep were fixed with pedicle screws. One pedicle of each vertebral body was treated with a screw augmented with CSC (CSC group) and the contralateral pedicle was treated with a screw without any augmentation (control group). Three months later, the sheep were killed and biomechanical tests, micro CT analysis, and histological observation were conducted on the isolated specimen vertebrae. RESULTS: Twelve months after ovariectomy, animal model of osteoporosis was established successfully. Both the axial and vertical stabilities of the pedicle screws in CSC group were significantly enhanced compared with those in the control group (P<0.05). Micro-CT reconstruction and analysis showed that there were more bone trabeculae around the screws in CSC group compared with those in control group (P<0.05), and the bone trabeculae were significantly denser than those in control group (P<0.05). Histological observation showed that CSC was completely degradated and bone trabeculae around the screws in CSC group were more and denser than that in the control group. Bone trabeculae held the screws tightly without any interspaces between screw and bone, which formed strong bonding between bone and screw. CONCLUSIONS: CSC can significantly improve screw-bone interfacial bonding and strengthen the long-term stability of pedicle screws in osteoporotic sheep. Augmentation with CSC may be a potentially useful method to increase the stability of pedicle screws in patients with osteoporosis. PMID- 20844453 TI - Foot drop caused by a lesion in the thoracolumbar spine. AB - STUDY DESIGN: Fifteen patients with foot drop caused by a thoracolumbar spine lesion were retrospectively investigated. OBJECTIVE: To clarify surgical outcomes and prognostic factors for foot drop owing to thoracolumbar disease. SUMMARY OF BACKGROUND DATA: Although the literature contains some reports of the surgical outcome for foot drop because of lumbar degenerative disease, to the best of our knowledge, little is known about foot drop resulting from thoracolumbar lesions. METHODS: Thoracolumbar lesions were classified into 2 groups (ossification of the ligamentum flavum; OLF, and osteoporotic vertebral collapse; OVC). Mean age at surgery was 73.7 years (range, 62 to 84 y) and the average follow-up period was 50 months (range, 19 to 85 mo). We measured the muscle strength of the tibialis anterior (TA) before operation and at the last follow-up. Diagnosis (OLF or OVC), age, sex, preoperative TA strength, and palsy duration were compared according to surgical outcome. RESULTS: Excellent or good surgical outcomes were seen in 87% of patients with foot drop. Of the 8 patients who were chairbound or bedridden preoperatively, 5 (62.5%) were able to walk with the aid of a cane at the last follow-up. OVC patients, those with palsy duration shorter than 3 months, and those with good TA muscle contraction in response to peroneal nerve stimulation had a better surgical outcome. CONCLUSIONS: Prognosis of foot drop was much better when the causative lesion was at the thoracolumbar spine than when it was at the lumbar spine. Severe paralysis was not a poor prognostic factor. PMID- 20844454 TI - Significance of angular mismatch between vertebral endplate and prosthetic endplate in lumbar total disc replacement. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To determine whether angular mismatch between the vertebral endplate and prosthetic endplate during lumbar total disc replacement (L-TDR) affects the radiological and clinical outcomes. SUMMARY OF BACKGROUND DATA: A prosthesis anchored to the vertebral body by using a large central keel carries an inherent risk of angular mismatch between the vertebral endplate and prosthetic endplate at a segment with a greater degree of lordosis, such as L5-S1. Theoretically, this angular mismatch can cause several problems, such as segmental hyperlordosis, anterior positioning of the upper prosthesis, posterior prosthetic edge subsidence, decreased range of motion (ROM), and a poor clinical outcome. METHODS: This study evaluated 64 prosthetic levels of 56 patients who were implanted with L-TDR between June 2002 and February 2006. There were 38 and 26 prosthetic levels at the L4-5 and L5-S1, respectively. The mean follow-up period was 25.6 (12 to 49) months. The angle of mismatch between the lower endplate of the upper vertebral body and the upper prosthetic plate, segmental flexion/extension ROM, segmental lordosis angle at extension, distance from the posterior wall of the vertebral body to the posterior prosthetic edge were measured by obtaining radiographs. Clinically, the Visual Analogue Scale and Oswestry Disability Index were also evaluated. RESULTS: The angular mismatches between the upper vertebra and prosthesis at L4-5 and L5 S1 were 1.6 degree and 5.6 degree, respectively (P <0.001), at the final follow up; these angles were not significantly different from those measured on radiographs obtained postoperatively (2.3 degree and 4.9 degree in L4-5 and L5 S1, respectively, P=0.324 in L4-5 and P=0.620 in L5-S1). The mean segmental ROM of the operated levels was 10.6 degree (4 to 22) and 6.1 degree (2 to 13) in the L4-5 and L5-S1, respectively (P <0.001). The mean segmental ROM, mean segmental lordosis angle, and mean distance from the posterior margin of the vertebral body to the posterior edge of the prosthesis in L5-S1 were 6.8 degree (4 to 13), 12.8 degree (8 to 17), and 3.8 mm (1 to 6 mm) in patients with an angular mismatch of <10 degree, and were 4.6 degree (2 to 7), 21.3 degree (19 to 25), and 6.0 mm (2 to 8 mm) in patients with an angular mismatch of more than 10 degree (P=0.024, <0.001, and 0.039), respectively. In L4-5, there were only 2 cases with an angular mismatch of more than 5 degree, which had no statistical significance. There were no significant differences in the clinical outcomes, Visual Analogue Scale, and Oswestry Disability Index between patients with an angular mismatch of <10 degree and those with an angular mismatch of more than 10 degree (P >0.05). CONCLUSIONS: Angular mismatch was more common in L5-S1 than in L4-5. L-TDR at the most lordotic level, L5-S1, and implantation of an upper prosthesis with a mismatched angle seem to be the causes of a reduced segmental ROM, increased segmental lordosis, and anterior malpositioning of the prosthesis. However, these changes do not affect the clinical outcomes of patients. PMID- 20844455 TI - Comparison of speed and agility performance of college football players on field turf and natural grass. AB - The purpose of this study was to determine the difference in 40-yd dash and proagility times performed on field turf (FT) and natural grass (NG). Red-shirt freshmen National Collegiate Athletic Association Division II college football players (n = 24) performed 2 trials each of a 40-yd dash and proagility run on each surface. Sprints were timed by an electronic timing system (ET) and by 2 hand timers (HTs). Agility was timed on each surface by 2 HTs. There was no significant difference in 40-yd dash times between FT and NG using ET (FT: 5.34 +/- 0.30 seconds, NG: 5.33 +/- 0.33 seconds) or HT (FT: 5.06 +/- 0.31 seconds, NG: 5.11 +/- 0.29 seconds). Hand timer 40-yd dashes were significantly faster than ET 40-yd dashes on both surfaces, with the difference between HT and ET on FT (-0.28 +/- 0.11 seconds) significantly greater than the difference on NG ( 0.22 +/- 0.06 seconds). The time differences between surfaces were significantly correlated (r = 0.12, p = 0.56). Proagility times were significantly faster on FT (4.49 +/- 0.28 seconds) than on grass (4.64 +/- 0.33 seconds). Thus, it appears that straight-ahead sprint speed is similar between FT and NG, but change-of direction speed may be significantly faster on FT. PMID- 20844456 TI - Game activity and blood lactate in men's elite water-polo players. AB - The purpose of this study was to examine game demands during highly competitive men's water-polo games after the introduction of the new Federation International Natation Association (FINA) rules. Participants of this study were 77 outfield international level men's water-polo players (age 25.9 +/- 4.5 years, height 188 +/- 4.5 cm, body mass 93 +/- 10.9 kg). Game earlobe blood lactate, speed, and distance covered (semiautomatic image recognition system) were measured during 6 highly competitive matches (FINA International Tournament). In the game, players covered 1,613 +/- 150 m (n = 68). This corresponds to a mean coverage rate of 54 +/- 5.8 m.min (n = 68). At speeds faster than 1.4 m.s-1 (high-intensity swimming), players covered 44% of the total distance. A significant decrease in coverage rate was detected during the final stage of the game. Mean blood-lactate concentration was 7.7 +/- 1.0 mmol.L-1 (range 2.2-14.3). Center Defenders (1,816 +/- 496 m) covered significantly (p < 0.05) more distance swimming compared to Field (1,676 +/- 348 m) and Center-Forward (1,317 +/- 281 m) players. Mean match blood-lactate concentrations for Center Forwards, Center Defenders, and Field Players were 11.2 +/- 1.0 (3-14.3), 6.7 +/- 0.9 (1.4-8), and 5.3 +/- 0.9 mmol.L-1 (2.2-11.9), respectively. This study confirmed the high-intensity nature of male elite level water polo showing remarkable role-dependent game demands. As a result, strength and conditioning interventions should be individualized and mainly address intermittent high-intensity endurance and anaerobic fitness. PMID- 20844457 TI - Using additional eccentric loads to increase concentric performance in the bench throw. AB - The purpose of this study was to determine whether superior concentric performance could be achieved in the bench throw with the use of additional eccentric loads. Fourteen male subjects performed bench throws in a smith machine with an eccentric-concentric load of 40-kg (40-40), and 40-kg concentric with additional eccentric loads of 20 (60-40), 30 (70-40), and 40 kg (80-40). A linear position transducer was used to record displacement-time characteristics, allowing for determination of maximum displacement of the barbell. Differences between the conditions were accepted when p < 0.05. Barbell displacements in the 60- to 40-, 70- to 40-, and 80- to 40-kg eccentric-concentric conditions were all significantly greater than for the 40- to 40-kg eccentric-concentric equated load condition, but no significant difference was observed between each eccentric concentric load condition. Superior concentric peak barbell displacement can be achieved with additional eccentric loads in the 40-kg bench throw when compared to an equated eccentric-concentric 40- to 40-kg condition, possibly because of greater muscle tension and crossbridging during the eccentric action. Strength and conditioning coaches can use accentuated eccentric load bench throws to elicit greater concentric bench throw performance in athletes. PMID- 20844458 TI - Effects of in-season short-term plyometric training program on leg power, jump- and sprint performance of soccer players. AB - Our hypothesis was that the addition of an 8-week lower limb plyometric training program (hurdle and depth jumping) to normal in-season conditioning would enhance measures of competitive potential (peak power output [PP], jump force, jump height, and lower limb muscle volume) in junior soccer players. The subjects (23 men, age 19 +/- 0.7 years, body mass 70.5 +/- 4.7 kg, height 1.75 +/- 0.06 m, body fat 14.7 +/- 2.6%) were randomly assigned to a control (normal training) group (Gc; n = 11) and an experimental group (Gex, n = 12) that also performed biweekly plyometric training. A force-velocity ergometer test determined PP. Characteristics of the squat jump (SJ) and the countermovement jump (CMJ) (jump height, maximal force and velocity before take-off, and average power) were determined by force platform. Video-camera kinematic analyses over a 40-m sprint yielded running velocities for the first step (VS), the first 5 m (V5m) and between 35 and 40 m (Vmax). Leg muscle volume was estimated using a standard anthropometric kit. Gex showed gains relative to controls in PP (p < 0.01); SJ (height p < 0.01; velocity p < 0.001), CMJ (height p < 0.001; velocity p < 0.001, average power p < 0.01) and all sprint velocities (p < 0.001 for V5m and Vmax, p < 0.01 for VS). There was also a significant increase (p < 0.05) in thigh muscle volume, but leg muscle volume and mean thigh cross-sectional area remain unchanged. We conclude that biweekly plyometric training of junior soccer players (including adapted hurdle and depth jumps) improved important components of athletic performance relative to standard in-season training. Accordingly, such exercises are highly recommended as part of an annual soccer training program. PMID- 20844459 TI - Persistence of immunity following a booster dose of Haemophilus influenzae type B Meningococcal serogroup C glycoconjugate vaccine: follow-up of a randomized controlled trial. AB - BACKGROUND: Antibodies against Haemophilus influenzae type b (Hib) and serogroup C Neisseria meningitidis (MenC) wane after early infant immunization. METHODS: Children previously immunized in a randomized controlled trial at ages 2, 3, and 4 months with DTPa-IPV-Hib and MenC-CRM197 (MenC-CRM group) or DTPa-IPV and Hib MenC-TT (Hib-MenC-TT group) had blood samples drawn at 1 and 2 years following a booster dose of Hib-MenC-TT at 12 to 15 months of age. A blood sample was also drawn at the year 2 follow-up from a separately recruited age-matched control group who had not received a booster. RESULTS: In 271 children at year 1, mean 14.6 months (range: 12-18 months) following the Hib-MenC-TT booster, MenC bactericidal titers above the protective threshold (rSBA >= 1:8) was demonstrated in 89.0% of the Hib-MenC-TT group and 69.5% of MenC-CRM participants. Antipolyribosylribitol phosphate Ig >= 1.0 MUg/mL (Hib correlate for long-term protection) was seen in 94.9% and 82.5%, respectively.In 379 participants (including 72 control children) at year 2 (age: 39-43 months, 25-31 months post Hib-MenC-TT) persistence of MenC antibodies was demonstrated in 67.1% of the Hib MenC-TT group and 40.5% of the MenC-CRM group, compared with 44.1% of control group participants. Antipolyribosylribitol phosphate Ig >= 1.0 MUg/mL was seen in 89.0%, 74.7%, and 38.9%, respectively. CONCLUSIONS: A toddler Hib-MenC-TT booster helps sustain immunity against Hib to 31/2 years of age. Persistence of MenC antibody is similar in children primed with MenC-CRM197 in infancy who receive a booster Hib-MenC-TT, to those who receive no booster. Persistence of MenC antibody is better when primed and boosted with Hib-MenC-TT. PMID- 20844460 TI - Effectiveness of measles vaccination for control of exposed children. AB - The effectiveness of measles vaccine for postexposure prophylaxis at educational centers was investigated. A total of 166 children who shared the classroom with 10 confirmed cases during the infectious period of cases were studied. Of total susceptible exposed children, 72% (54/75) were vaccinated and 25 contracted measles. Vaccine effectiveness in children vaccinated within 72 hours of exposure was 90.5% (95% confidence interval, 34%-99%). PMID- 20844461 TI - Herpes zoster and meningitis due to reactivation of varicella vaccine virus in an immunocompetent child. AB - Neurologic complications from varicella zoster virus (VZV) reactivation are rare. In this article, we describe a previously immunized child who developed herpes zoster with meningitis. Vaccine strain of VZV was recovered from a skin swab and the cerebrospinal fluid. Reactivation of the vaccine strain of VZV should be recognized as a potential cause of meningitis in children. PMID- 20844462 TI - Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial. AB - BACKGROUND: An investigational vaccine against serogroup B meningococcal (MenB) disease containing 3 main recombinant proteins (factor H-binding protein, Neisserial adhesion A, and Neisserial heparin-binding antigen) has been developed. We evaluated the immunogenicity and reactogenicity of a 3-dose course of this vaccine administered alone (recombinant MenB [rMenB]) or combined with the outer membrane vesicle (OMV) component of the vaccine used in New Zealand (rMenB+OMV). METHODS: A randomized, single-blind, comparative study of 60 healthy infants enrolled at 6 to 8 months of age and immunized with rMenB or rMenB+OMV at day 0, day 60, and at age 12 months. Blood samples obtained at baseline and 1 month following the second and third doses of vaccine were analyzed for serum bactericidal antibody (SBA) using human complement (hSBA) against 7 MenB strains. The putative correlate of protection was an hSBA titer of >=4. RESULTS: The per protocol analysis included 24 of 30 participants randomized to each group. After 3 doses of rMenB+OMV, 90% or more of participants had an hSBA titer >=4 for 5 MenB strains, with 70% of participants having an hSBA titer >=4 for a sixth strain. rMenB alone was immunogenic for only 3 strains. Both vaccines were well tolerated. CONCLUSIONS: Three doses of rMenB+OMV in the second half of infancy induce bactericidal antibodies against strains expressing vaccine antigens, demonstrating the potential for broader vaccine prevention of MenB disease. This vaccine is now in phase III clinical trials. PMID- 20844463 TI - Streptococcus pneumoniae nasopharyngeal colonization in children in Brasov, Central Romania: high antibiotic resistance and coverage by conjugate vaccines. AB - We report high colonization rates among 400 healthy infants and children, and moderate (66%) coverage by PCV7 and PCV10, with a superior (80%) PCV13 coverage. Most frequent serotypes were 23F, 6B, 19F, and 14. Resistance to penicillin, ceftriaxone, erythromycin, and trimethoprim/sulfamethoxazole was 83%, 18%, 62%, and 66%, respectively. 67% isolates were multidrug resistant. Pneumococcal conjugate vaccines covered 80% to 93% of multidrug resistant isolates. PMID- 20844464 TI - Assays for measuring rivaroxaban: their suitability and limitations. AB - Several new oral anticoagulants such as rivaroxaban (which targets Factor Xa) and dabigatran etexilate (which targets thrombin) are in advanced stages of clinical development and are already available for clinical use in some countries. Although these agents do not require routine coagulation monitoring, assays to assess the level of anticoagulation may be of assistance in certain circumstances such as in case of overdose, in patients with a hemorrhagic or thromboembolic event during treatment, or to assess compliance. Moreover, the influence of the new oral anticoagulants on routine coagulation tests must be recognized. The prothrombin time is not suitable for rivaroxaban measurement for several reasons, and the routinely used international normalized ratio for monitoring the vitamin K antagonists cannot be applied to rivaroxaban. Development of universal assays is challenging because the new oral anticoagulants have different targets, and even those with the same target have variable effects on routine coagulation assays. Focusing on rivaroxaban, there is emerging evidence that an anti-Factor Xa assay that uses rivaroxaban-containing plasma calibrators may provide the optimal method for determining plasma rivaroxaban concentrations. PMID- 20844465 TI - Stevens-Johnson syndrome and toxic epidermal necrolysis: what do we know? AB - Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare but severe cutaneous adverse reactions related to a variety of medications. Although rare, SJS and TEN have a significant impact on public health because of high mortality. Also, if the SJS/TEN physiopathology is still unclear, a specific immune response to one or more drugs is involved, constituting a form of delayed type hypersensitivity. Patients with SJS/TEN are often critically ill; therefore, they must be admitted to hospitals capable of delivering critical care. Currently, no treatment modality has been established as standard for these patients; therefore, therapy is primarily supportive and symptomatic and involves a multidisciplinary approach. PMID- 20844466 TI - A novel role of innate immune responses (toll-like receptor-4) in triggering graft-versus-host disease. PMID- 20844467 TI - Assessing and comparing rival definitions of delayed renal allograft function for predicting subsequent graft failure. AB - BACKGROUND: The traditional definition of delayed graft function (DGF) rests on dialysis requirement during the first postoperative week. Subsequently, a more objective and "functional" definition of DGF (fDGF) has been proposed as an alternative to this dialysis-based definition of DGF (dDGF) and defined as a failure of the serum creatinine to decrease by at least 10% daily on 3 successive days during the first week posttransplantation, irrespective of dialysis requirement. However, an association between fDGF and long-term graft failure has not been fully established, and it is unknown whether fDGF is a better marker of subsequent outcomes than dDGF. METHODS: We studied 750 adult deceased donor kidney transplant recipients (1996-2006) and analyzed the association between these two DGF definitions and long-term graft outcome. RESULTS: Univariable associations with death-censored graft failure were seen for both dDGF and fDGF (hazard ratio [HR] 1.59; 95% confidence interval [CI] 1.16-2.18; P=0.004 and HR 1.72; 95% CI 1.26-2.36; P=0.001, respectively). On bivariable analysis (dDGF vs. fDGF), dDGF lost significance, whereas the effect of fDGF persisted (HR 1.52; 95%CI 1.03-2.25; P=0.04). This was also the case in a multivariable model, where fDGF but not dDGF was significantly associated with graft failure (HR 1.47; 95%CI 1.06-2.03; P=0.02). Results were similar for overall graft failure. CONCLUSIONS: This study confirms the utility of fDGF as an early marker of subsequent inferior allograft outcomes, suggesting superiority over the traditional (often subjective) dialysis-based definition. Wider adoption of the fDGF definition should be considered, both as a risk-stratification tool in clinical practice and a clinical trial endpoint. PMID- 20844468 TI - A study of renal outcomes in obese living kidney donors. AB - BACKGROUND: Little is known about the long-term outcomes of obese living kidney donors (OLKDs). We undertook this study to describe renal outcomes of OLKDs several years after donation. METHODS: We invited 101 OLKDs for follow-up health evaluation. RESULTS: Thirty-six subjects (35.6%) completed evaluation at 6.8+/ 1.5 years postdonation. The mean estimated glomerular filtration rate (eGFR) using the abbreviated modification of diet in renal disease (MDRD) equation (MDRD eGFR) at follow-up was 72.1+/-16.3 (range: 42-106) mL/min per 1.73 m, and 47.2% of subjects had an MDRD-eGFR of 30 to 59. The absolute decrease in MDRD-eGFR from the time of donation to follow-up was 27.2 +/- 13.1 mL/min per 1.73 m (P<0.001 on paired t test), which represents a 29.2% drop in the serial MDRD-eGFRs. Seven subjects (19.4%) had microalbuminuria (30-300 MUg/mg creatinine). Subjects with microabuminuria were more likely to have MDRD-eGFR of less than 60 mL/min per 1.73 m (P=0.021). Subjects whose body mass index was greater than or equal to 35 kg/m (n=14) were found to have an absolute decrement in MDRD-eGFR similar to those with body mass index less than 35 kg/m (31.5 +/- 15.6 and 24.7 +/- 11.0 mL/min/1.73 m, respectively; P=not significant). Fifteen (41.6%) were hypertensive at follow-up. CONCLUSIONS: On medium-term follow-up, a large proportion of OLKDs will have a MDRD-eGFR of less than 60 mL/min per 1.73 m, and the likelihood increases markedly among those who develop microalbuninuria. This raises concern for hyperfiltration injury. Furthermore, OLKDs experience a substantial incidence of hypertension. Caution is advised in selecting OLKDs pending further data on long-term outcomes. PMID- 20844469 TI - Distinct immunohistochemical phenotype of nonmelanoma skin cancers between renal transplant and immunocompetent populations. AB - BACKGROUND: Nonmelanoma skin cancers (NMSCs), the most common malignancy in kidney transplant recipients (KTRs), are more frequent and aggressive in KTR than in the general population. These phenomena could be caused by immunosuppressive treatments, both by decreasing immunosurveillance and by a direct oncogenic potential. METHODS: To assess the possible mechanisms involved in the clinical behavior of NMSC in KTR, we compared the tumoral expression of several molecule markers between 106 NMSC (basal cell carcinoma [BCC]; n=55, squamous cell carcinoma [SCC]; n=51) collected from 37 KTR and 51 control patients (CPs) from the general population. Immunohistochemical expression of transforming growth factor beta 1, epidermal growth factor receptor, protein 53 (p53), phospho-p70-S6 kinase, mammalian target of rapamycin (mTOR), and phospho-mTOR (Ser2448) were compared between KTR and CP and were also correlated with immunosuppressive therapy. RESULTS: p53 expression and transforming growth factor beta intensity were greater in SCC from KTR than from CP. In contrast, phospho-mTOR and phospho p70S6K (Thr421Ser424) expressions were higher in SCC from CP. p53 and phospho p70S6K (Thr389) expression were higher in BCC from KTR than from CP. Expression of the other biological markers showed no statistically significant differences between SCC and BCC from KTR treated with or without calcineurin inhibitors. CONCLUSIONS: Several prooncogenic markers showed distinct patterns of expression in NMSC from KTR. These differential characteristics could be responsible for the clinical behavior of posttransplantation NMSC. Furthermore, these markers may constitute possible targets for future therapeutic approaches to NMSC in KTR and could help to guide immunosuppressive therapy. PMID- 20844470 TI - Cystatin C is not a better estimator of GFR than plasma creatinine in the general population. AB - Accurate measurement of glomerular filtration rate (GFR) is complicated and costly; therefore, GFR is commonly estimated by assessing creatinine or cystatin C concentrations. Because estimates based on cystatin C predict cardiovascular disease better than creatinine, these estimates have been hypothesized to be superior to those based on creatinine, when the GFR is near the normal range. To test this, we measured GFR by iohexol clearance in a representative sample of middle-aged (50-62 years) individuals in the general population, excluding those with coronary heart or kidney disease, stroke or diabetes mellitus. Bias, precision (median and interquartile range of estimated minus measured GFR (mGFR)), and accuracy (percentage of estimates within 30% of mGFR) of published cystatin C and creatinine-based GFR equations were compared in a total of 1621 patients. The cystatin C-based equation with the highest accuracy (94%) had a bias of 3.5 and precision of 18 ml/min per 1.73 m2, whereas the most accurate (95%) creatinine-based equation had a bias of 2.9 and precision of 15 ml/min per 1.73 m2 The best equation, based on both cystatin C and creatinine, had a bias of 7.6 ml/min per 1.73 m2, precision of 15 ml/min per 1.73 m2, and accuracy of 92%. Thus, estimates of GFR based on cystatin C were not superior to those based on creatinine in the general population. Hence, the better prediction of cardiovascular disease by cystatin C than creatinine measurements, found by others, may be due to factors other than GFR. PMID- 20844471 TI - Amelioration of cisplatin nephrotoxicity by genetic or pharmacologic blockade of prostaglandin synthesis. AB - Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use. Here, we determined whether arachidonic acid metabolism has a role in the pathogenesis of cisplatin nephrotoxicity in mice. Three days following cisplatin injection, wild-type mice displayed renal functional and structural abnormalities consistent with nephrotoxicity accompanied by elevated circulating and renal levels of TNF-alpha and renal levels of IL-1beta, subunits of NADPH oxidase, thiobarbituric acid-reactive substances, and PGE(2). These indices of kidney injury, inflammation, oxidative stress, and arachidonate metabolism were all diminished in microsomal prostaglandin E synthase-1 (mPGES-1) null mice; a phenotype recapitulated by treatment of wild-type mice with the COX-2 inhibitor celecoxib. Following cisplatin administration, there was paralleled induction of COX-2 and mPGES-1 in renal parenchymal cells. Interestingly, mPGES-1 null mice were not protected from acute kidney injury caused by ischemia-reperfusion or endotoxin. Hence, our results suggest the activation of COX-2/mPGES-1 pathway in renal parenchymal cells may selectively mediate cisplatin-induced renal injury. This may offer a novel therapeutic target for management of the adverse effect of cisplatin chemotherapy. PMID- 20844472 TI - Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. AB - Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of injury in experimental models, as disease does not occur in their absence and injury is enhanced by lipopolysaccharide (LPS). In this study, highly purified LPS (a pure TLR4 ligand) acted with antimyeloperoxidase antibodies to synergistically increase kidney and lung neutrophil recruitment and functional injury; effects abrogated in TLR4-deficient mice. Increased kidney TLR4 expression after stimulation predominantly occurred in glomerular endothelial cells. Enhanced glomerular neutrophil recruitment correlated with increased kidney mRNA expression of CXCL1 and CXCL2 (homologs of human CXCL8), whereas their preemptive neutralization decreased neutrophil recruitment. Disease induction in bone marrow chimeric mice showed that TLR4 in both bone marrow and renal parenchymal cells is required for maximal neutrophil recruitment and glomerular injury. Further studies in human glomerular cell lines stimulated with LPS found that glomerular endothelial cells were the prominent sources of CXCL8. Thus, our results define a role for TLR4 expression in bone marrow-derived and glomerular endothelial cells in neutrophil recruitment and subsequent functional and histological renal injury in experimental antimyeloperoxidase glomerulonephritis. PMID- 20844473 TI - Direct evidence for a causative role of FGF23 in the abnormal renal phosphate handling and vitamin D metabolism in rats with early-stage chronic kidney disease. AB - Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with early chronic kidney disease (CKD) and are postulated to cause low blood levels of 1,25-dihydroxyvitamin D, as well as normal phosphate levels. In order to provide more direct evidence for the pathophysiological role of FGF23 in the settings of mineral ion homeostasis typically seen in early CKD, we studied rats with progressive CKD treated with anti-FGF23 neutralizing antibody. Without antibody treatment, rats with CKD exhibited high circulating levels of FGF23 and parathyroid hormone, low 1,25-dihydroxyvitamin D, and normal serum phosphate levels, accompanied by increased fractional excretion of phosphate. Antibody treatment, however, lessened fractional excretion of phosphate, thus increasing serum phosphate levels, and normalized serum 1,25-dihydroxyvitamin D by increased 1alpha-OHase and decreased 24-OHase expressions in the kidney. These antibody induced changes were followed by increased serum calcium levels, leading to decreased serum parathyroid hormone. Hence, our study shows that FGF23 normalizes serum phosphate and decreases 1,25-dihydroxyvitamin D levels in early-stage CKD, and suggests a pathological sequence of events for the development of secondary hyperparathyroidism triggered by increased FGF23, followed by a reduction of 1,25 dihydroxyvitamin D and calcium levels, thereby increasing parathyroid hormone secretion. PMID- 20844474 TI - Serum levels of matrix metalloproteinase-10 are associated with the severity of atherosclerosis in patients with chronic kidney disease. AB - Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). As matrix metalloproteinases have a major role in atherosclerosis, we hypothesized that alterations in metalloproteinases-8, -10 and their tissue inhibitor-1 can be associated with the severity of atherosclerosis in patients with kidney disease. This was evaluated in a cross-sectional, observational study of 111 patients with stages I-V kidney disease, 217 patients on dialysis and 50 healthy controls. The severity of atherosclerosis was estimated with the atherosclerosis score (AS), combining the results of ankle-brachial index and carotid ultrasound. Serum levels of the two metalloproteinases and tissue inhibitor-1 were measured by enzyme-linked immunosorbent assay and were significantly increased in patients with kidney disease compared with the healthy controls, and higher in patients on dialysis than in earlier stages of CKD. The severity of the AS was also more prevalent in the dialysis group, in which serum levels of both metalloproteinases and tissue inhibitor-1 were significantly higher. After multivariate analysis, metalloproteinase-10, dialysis, C-reactive protein, age, and male gender were associated with increased risk of atherosclerosis. Thus, patients with CKD exhibit elevated levels of circulating metalloproteinase-10, and this was independently associated with the severity of atherosclerosis and may represent a new biomarker of atherosclerotic diseases. PMID- 20844475 TI - Oxytocin decreases aversion to angry faces in an associative learning task. AB - Social and financial considerations are often integrated when real life decisions are made, and recent studies have provided evidence that similar brain networks are engaged when either social or financial information is integrated. Other studies, however, have suggested that the neuropeptide oxytocin can specifically affect social behaviors, which would suggest separable mechanisms at the pharmacological level. Thus, we examined the hypothesis that oxytocin would specifically affect social and not financial information in a decision making task, in which participants learned which of the two faces, one smiling and the other angry or sad, was most often being rewarded. We found that oxytocin specifically decreased aversion to angry faces, without affecting integration of positive or negative financial feedback or choices related to happy vs sad faces. PMID- 20844476 TI - Oxytocin reduces background anxiety in a fear-potentiated startle paradigm. AB - Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 MUg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hyper-vigilance and exaggerated startle typically seen in PTSD patients. PMID- 20844479 TI - TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage. AB - Toll-like receptor-5 (TLR5)-mediated detection of flagellin induces nuclear factor (NF)-kappaB-mediated transcription of host defense gene expression, whereas recognition of intracellular flagellin by interleukin (IL)-1-converting enzyme protease-activation factor (IPAF) results in maturation/secretion of the inflammasome cytokine IL-1beta. The potent effects of IL-1beta are counter regulated by secretory IL-1 receptor antagonist (sIL-1Ra). We studied the roles of flagellin receptors in regulating the expression of IL-1beta and sIL-1Ra and their subsequent roles in inflammation. Flagellin induced sIL-1Ra in intestinal epithelia and macrophages in a dose- and time-dependent manner, whereas IL-1beta was only induced in macrophages. In vivo, flagellin-induced sIL-1Ra, but not IL 1beta, was absolutely dependent upon TLR5 expressed on non-hemopioetic cells. Thus, loss of TLR5 increased the IL-1beta/sIL-1Ra ratio on flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for the induction of sIL-1Ra and limiting inflammatory pathology on Salmonella infection. Finally, reduced sIL-1Ra levels in TLR5KO mice correlated with spontaneous colitis. Taken together, we demonstrate that intestinal epithelia, despite not expressing IL-1beta, secrete sIL-1Ra in a TLR5-dependent manner suggesting that loss of TLR5 may promote inflammation by increasing IL-1beta activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders. PMID- 20844480 TI - Mucosal adjuvants and long-term memory development with special focus on CTA1-DD and other ADP-ribosylating toxins. AB - The ultimate goal for vaccination is to stimulate protective immunological memory. Protection against infectious diseases not only relies on the magnitude of the humoral immune response, but more importantly on the quality and longevity of it. Adjuvants are critical components of most non-living vaccines. Although little attention has been given to qualitative aspects of the choice of vaccine adjuvant, emerging data demonstrate that this function may be central to vaccine efficacy. In this review we describe efforts to understand more about how adjuvants influence qualitative aspects of memory development. We describe recent advances in understanding how vaccines induce long-lived plasma and memory B cells, and focus our presentation on the germinal center reaction. As mucosal vaccination requires powerful adjuvants, we have devoted much attention to the adenosine diphosphate (ADP)-ribosylating cholera toxin and the CTA1-DD adjuvants as examples of how mucosal adjuvants can influence induction of long-term memory. PMID- 20844482 TI - Transcriptional regulation of the mucosal immune system mediated by T-bet. AB - The immune system faces the arduous task of defending the mucosal surfaces from invading pathogens, but must simultaneously repress responses against commensal organisms and other inert antigens that are abundant in the external environment, as inappropriate immune activation might expose the host to increased risk of autoimmunity. The behavior of individual immune cells is governed by the expression of transcription factors that are responsible for switching immune response genes on and off. T-bet (T-box expressed in T cells) has emerged as one of the key transcription factors responsible for controlling the fate of both innate and adaptive immune cells, and its expression in different immune cells found at mucosal surfaces is capable of dictating the critical balance between permitting robust host immunity and limiting susceptibility to autoimmunity and allergy. PMID- 20844481 TI - CXCR3 and CCR5 are both required for T cell-mediated protection against C. trachomatis infection in the murine genital mucosa. AB - Chemokine receptors direct T lymphocytes to the site of an infection by following coordinated chemokine gradients, which allow their recruitment to specific tissues. Although identification of receptors needed for homing to some mucosal sites, such as skin and gut, have been elucidated, the receptors that direct lymphocytes to the genital mucosa remain relatively uncharacterized. In this study we identify that the chemokine receptors CXCR3 (chemokine (C-X-C motif) receptor 3) and CCR5 (chemokine (C-C motif) receptor 5) are pivotal for T lymphocyte access to the genital tract during Chlamydia trachomatis infection. Chlamydia-specific CD4(+) transgenic T cells that lack CXCR3 or CCR5 do not accumulate in the genital mucosa following infection. Loss of either CXCR3 or CCR5 impairs the protective capacity of Chlamydia-specific T cells, whereas T cells lacking both receptors are completely nonprotective. These results show that CXCR3 and CCR5 are the predominant chemokine receptors that act cooperatively to promote homing to the genital mucosa during Chlamydia infection. PMID- 20844477 TI - Pharmacological enhancement of memory and executive functioning in laboratory animals. AB - Investigating how different pharmacological compounds may enhance learning, memory, and higher-order cognitive functions in laboratory animals is the first critical step toward the development of cognitive enhancers that may be used to ameliorate impairments in these functions in patients suffering from neuropsychiatric disorders. Rather than focus on one aspect of cognition, or class of drug, in this review we provide a broad overview of how distinct classes of pharmacological compounds may enhance different types of memory and executive functioning, particularly those mediated by the prefrontal cortex. These include recognition memory, attention, working memory, and different components of behavioral flexibility. A key emphasis is placed on comparing and contrasting the effects of certain drugs on different cognitive and mnemonic functions, highlighting methodological issues associated with this type of research, tasks used to investigate these functions, and avenues for future research. Viewed collectively, studies of the neuropharmacological basis of cognition in rodents and non-human primates have identified targets that will hopefully open new avenues for the treatment of cognitive disabilities in persons affected by mental disorders. PMID- 20844484 TI - The impact of thyroid disease on the regulation, expression, and function of ABCB1 (MDR1/P glycoprotein) and consequences for the disposition of digoxin. AB - The impact of thyroid dysfunction on the regulation, expression, and function of ABCB1 remains unclear. We therefore investigated ABCB1 mRNA expression and function in patients with thyroid dysfunction and studied the disposition of the ABCB1 substrate digoxin before and after treatment for thyroid disease. In patients with hypothyroidism, normalization of thyroid function was associated with a 1.8-fold increase in mRNA expression and a 26% increase in rhodamine efflux from CD56(+) cells. In hypothyroidism, digoxin clearance was significantly decreased, whereas bioavailability, volume of distribution, half-life time, and protein binding were unaltered. In hyperthyroidism, ABCB1 mRNA expression, rhodamine efflux, and disposition of digoxin were not significantly affected other than in relation to renal clearance. Experiments using the LS174T cell line indicated that the gene is a direct target of thyroid hormone receptors. In conclusion, thyroid abnormalities can exert significant effects on the expression of P-glycoprotein, thereby altering the disposition and action of drugs that are substrates of P-glycoprotein. PMID- 20844485 TI - Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo controlled, crossover comparison studies. AB - Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P <= 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P <= 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole. PMID- 20844486 TI - Genome-wide analysis of a long-term evolution experiment with Drosophila. AB - Experimental evolution systems allow the genomic study of adaptation, and so far this has been done primarily in asexual systems with small genomes, such as bacteria and yeast. Here we present whole-genome resequencing data from Drosophila melanogaster populations that have experienced over 600 generations of laboratory selection for accelerated development. Flies in these selected populations develop from egg to adult ~20% faster than flies of ancestral control populations, and have evolved a number of other correlated phenotypes. On the basis of 688,520 intermediate-frequency, high-quality single nucleotide polymorphisms, we identify several dozen genomic regions that show strong allele frequency differentiation between a pooled sample of five replicate populations selected for accelerated development and pooled controls. On the basis of resequencing data from a single replicate population with accelerated development, as well as single nucleotide polymorphism data from individual flies from each replicate population, we infer little allele frequency differentiation between replicate populations within a selection treatment. Signatures of selection are qualitatively different than what has been observed in asexual species; in our sexual populations, adaptation is not associated with 'classic' sweeps whereby newly arising, unconditionally advantageous mutations become fixed. More parsimonious explanations include 'incomplete' sweep models, in which mutations have not had enough time to fix, and 'soft' sweep models, in which selection acts on pre-existing, common genetic variants. We conclude that, at least for life history characters such as development time, unconditionally advantageous alleles rarely arise, are associated with small net fitness gains or cannot fix because selection coefficients change over time. PMID- 20844487 TI - Direct visualization of secondary structures of F-actin by electron cryomicroscopy. AB - F-actin is a helical assembly of actin, which is a component of muscle fibres essential for contraction and has a crucial role in numerous cellular processes, such as the formation of lamellipodia and filopodia, as the most abundant component and regulator of cytoskeletons by dynamic assembly and disassembly (from G-actin to F-actin and vice versa). Actin is a ubiquitous protein and is involved in important biological functions, but the definitive high-resolution structure of F-actin remains unknown. Although a recent atomic model well reproduced X-ray fibre diffraction intensity data from a highly oriented liquid crystalline sol specimen, its refinement without experimental phase information has certain limitations. Direct visualization of the structure by electron cryomicroscopy, however, has been difficult because it is relatively thin and flexible. Here we report the F-actin structure at 6.6 A resolution, made obtainable by recent advances in electron cryomicroscopy. The density map clearly resolves all the secondary structures of G-actin, such as alpha-helices, beta structures and loops, and makes unambiguous modelling and refinement possible. Complex domain motions that open the nucleotide-binding pocket on F-actin formation, specific D-loop and terminal conformations, and relatively tight axial but markedly loose interprotofilament interactions hydrophilic in nature are revealed in the F-actin model, and all seem to be important for dynamic functions of actin. PMID- 20844478 TI - Cognitive control deficits in schizophrenia: mechanisms and meaning. AB - Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia. PMID- 20844488 TI - In vivo imaging of labelled endogenous beta-actin mRNA during nucleocytoplasmic transport. AB - Export of messenger RNA occurs via nuclear pores, which are large nanomachines with diameters of roughly 120 nm that are the only link between the nucleus and cytoplasm. Hence, mRNA export occurs over distances smaller than the optical resolution of conventional light microscopes. There is extensive knowledge on the physical structure and composition of the nuclear pore complex, but transport selectivity and the dynamics of mRNA export at nuclear pores remain unknown. Here we developed a super-registration approach using fluorescence microscopy that can overcome the current limitations of co-localization by means of measuring intermolecular distances of chromatically different fluorescent molecules with nanometre precision. With this method we achieve 20-ms time-precision and at least 26-nm spatial precision, enabling the capture of highly transient interactions in living cells. Using this approach we were able to spatially resolve the kinetics of mRNA transport in mammalian cells and present a three step model consisting of docking (80 ms), transport (5-20 ms) and release (80 ms), totalling 180 +/- 10 ms. Notably, the translocation through the channel was not the rate-limiting step, mRNAs can move bi-directionally in the pore complex and not all pores are equally active. PMID- 20844489 TI - The role of toxin A and toxin B in Clostridium difficile infection. AB - Clostridium difficile infection is the leading cause of healthcare-associated diarrhoea in Europe and North America. During infection, C. difficile produces two key virulence determinants, toxin A and toxin B. Experiments with purified toxins have indicated that toxin A alone is able to evoke the symptoms of C. difficile infection, but toxin B is unable to do so unless it is mixed with toxin A or there is prior damage to the gut mucosa. However, a recent study indicated that toxin B is essential for C. difficile virulence and that a strain producing toxin A alone was avirulent. This creates a paradox over the individual importance of toxin A and toxin B. Here we show that isogenic mutants of C. difficile producing either toxin A or toxin B alone can cause fulminant disease in the hamster model of infection. By using a gene knockout system to inactivate the toxin genes permanently, we found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo. Furthermore, by constructing the first ever double-mutant strain of C. difficile, in which both toxin genes were inactivated, we were able to completely attenuate virulence. Our findings re-establish the importance of both toxin A and toxin B and highlight the need to continue to consider both toxins in the development of diagnostic tests and effective countermeasures against C. difficile. PMID- 20844490 TI - Seizing the moment. PMID- 20844491 TI - An alternative route. PMID- 20844492 TI - Publish or perish. PMID- 20844503 TI - Journal club. A genomic systems biologist muses on how shared DNA mistakes reveal shared cellular ancestry. PMID- 20844505 TI - Temporary reprieve for stem cells. PMID- 20844506 TI - Transgenic fish go large. PMID- 20844507 TI - Statistics spark dismissal suit. PMID- 20844508 TI - Strong medicine for China's journals. PMID- 20844509 TI - 'Sound science' code draws fire. PMID- 20844510 TI - Tiny traits cause big headaches. PMID- 20844511 TI - Can conservation cut poverty? PMID- 20844512 TI - Education: Ten weeks to save the world. PMID- 20844513 TI - World view: Save British science, again. PMID- 20844514 TI - Low repopulation of poor districts in New Orleans proves little. PMID- 20844515 TI - Embryonic stem cells: court decision a threat to science itself. PMID- 20844516 TI - How nanotechnology captured the public imagination. PMID- 20844517 TI - Embryonic stem cells: don't let litigation put research off limits. PMID- 20844518 TI - Commodities for export still threaten rainforests in Brazil. PMID- 20844523 TI - Gene therapy: Targeting beta-thalassaemia. PMID- 20844519 TI - Road will ruin Serengeti. PMID- 20844524 TI - Quantum physics: Quantum leaps in the solid state. PMID- 20844526 TI - Stem cells: Troublesome memories. PMID- 20844527 TI - Earth science: Glaciers shield mountain tops. PMID- 20844528 TI - Origins of life: Shock synthesis. PMID- 20844529 TI - Cell biology: A sensor for calcium uptake. PMID- 20844530 TI - Obituary: Nicola Cabibbo (1935-2010). PMID- 20844531 TI - Observation of spin-dependent quantum jumps via quantum dot resonance fluorescence. AB - Reliable preparation, manipulation and measurement protocols are necessary to exploit a physical system as a quantum bit. Spins in optically active quantum dots offer one potential realization and recent demonstrations have shown high fidelity preparation and ultrafast coherent manipulation. The final challenge that is, single-shot measurement of the electron spin-has proved to be the most difficult of the three and so far only time-averaged optical measurements have been reported. The main obstacle to optical spin readout in single quantum dots is that the same laser that probes the spin state also flips the spin being measured. Here, by using a gate-controlled quantum dot molecule, we present the ability to measure the spin state of a single electron in real time via the intermittency of quantum dot resonance fluorescence. The quantum dot molecule, unlike its single quantum dot counterpart, allows separate and independent optical transitions for state preparation, manipulation and measurement, avoiding the dilemma of relying on the same transition to address the spin state of an electron. PMID- 20844532 TI - Production and application of electron vortex beams. AB - Vortex beams (also known as beams with a phase singularity) consist of spiralling wavefronts that give rise to angular momentum around the propagation direction. Vortex photon beams are widely used in applications such as optical tweezers to manipulate micrometre-sized particles and in micro-motors to provide angular momentum, improving channel capacity in optical and radio-wave information transfer, astrophysics and so on. Very recently, an experimental realization of vortex beams formed of electrons was demonstrated. Here we describe the creation of vortex electron beams, making use of a versatile holographic reconstruction technique in a transmission electron microscope. This technique is a reproducible method of creating vortex electron beams in a conventional electron microscope. We demonstrate how they may be used in electron energy-loss spectroscopy to detect the magnetic state of materials and describe their properties. Our results show that electron vortex beams hold promise for new applications, in particular for analysing and manipulating nanomaterials, and can be easily produced. PMID- 20844533 TI - Decreased frequency of North Atlantic polar lows associated with future climate warming. AB - Every winter, the high-latitude oceans are struck by severe storms that are considerably smaller than the weather-dominating synoptic depressions. Accompanied by strong winds and heavy precipitation, these often explosively developing mesoscale cyclones-termed polar lows-constitute a threat to offshore activities such as shipping or oil and gas exploitation. Yet owing to their small scale, polar lows are poorly represented in the observational and global reanalysis data often used for climatological investigations of atmospheric features and cannot be assessed in coarse-resolution global simulations of possible future climates. Here we show that in a future anthropogenically warmed climate, the frequency of polar lows is projected to decline. We used a series of regional climate model simulations to downscale a set of global climate change scenarios from the Intergovernmental Panel of Climate Change. In this process, we first simulated the formation of polar low systems in the North Atlantic and then counted the individual cases. A previous study using NCEP/NCAR re-analysis data revealed that polar low frequency from 1948 to 2005 did not systematically change. Now, in projections for the end of the twenty-first century, we found a significantly lower number of polar lows and a northward shift of their mean genesis region in response to elevated atmospheric greenhouse gas concentration. This change can be related to changes in the North Atlantic sea surface temperature and mid-troposphere temperature; the latter is found to rise faster than the former so that the resulting stability is increased, hindering the formation or intensification of polar lows. Our results provide a rare example of a climate change effect in which a type of extreme weather is likely to decrease, rather than increase. PMID- 20844534 TI - Glaciation as a destructive and constructive control on mountain building. AB - Theoretical analysis predicts that enhanced erosion related to late Cenozoic global cooling can act as a first-order influence on the internal dynamics of mountain building, leading to a reduction in orogen width and height. The strongest response is predicted in orogens dominated by highly efficient alpine glacial erosion, producing a characteristic pattern of enhanced erosion on the windward flank of the orogen and maximum elevation controlled by glacier equilibrium line altitude, where long-term glacier mass gain equals mass loss. However, acquiring definitive field evidence of an active tectonic response to global climate cooling has been elusive. Here we present an extensive new low temperature thermochronologic data set from the Patagonian Andes, a high-latitude active orogen with a well-documented late Cenozoic tectonic, climatic and glacial history. Data from 38 degrees S to 49 degrees S record a marked acceleration in erosion 7 to 5 Myr ago coeval with the onset of major Patagonian glaciation and retreat of deformation from the easternmost thrust front. The highest rates and magnitudes of erosion are restricted to the glacial equilibrium line altitude on the windward western flank of the orogen, as predicted in models of glaciated critical taper orogens where erosion rate is a function of ice sliding velocity. In contrast, towards higher latitudes (49 degrees S to 56 degrees S) a transition to older bedrock cooling ages signifies much reduced late Cenozoic erosion despite dominantly glacial conditions here since the latest Miocene. The increased height of the orogenic divide at these latitudes (well above the equilibrium line altitude) leads us to conclude that the southernmost Patagonian Andes represent the first recognized example of regional glacial protection of an active orogen from erosion, leading to constructive growth in orogen height and width. PMID- 20844535 TI - Transfusion independence and HMGA2 activation after gene therapy of human beta thalassaemia. AB - The beta-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of beta-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound beta(E)/beta(0)-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. The beta(E)-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated beta(E)-globin with partial instability. When this is compounded with a non-functional beta(0) allele, a profound decrease in beta-globin synthesis results, and approximately half of beta(E)/beta(0)-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral beta-globin gene transfer, an adult patient with severe beta(E)/beta(0)-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl(-1), of which one-third contains vector-encoded beta-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells. PMID- 20844536 TI - Notch and EGFR pathway interaction regulates neural stem cell number and self renewal. AB - Specialized cellular microenvironments, or 'niches', modulate stem cell properties, including cell number, self-renewal and fate decisions. In the adult brain, niches that maintain a source of neural stem cells (NSCs) and neural progenitor cells (NPCs) are the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus. The size of the NSC population of the SVZ at any time is the result of several ongoing processes, including self-renewal, cell differentiation, and cell death. Maintaining the balance between NSCs and NPCs in the SVZ niche is critical to supply the brain with specific neural populations, both under normal conditions or after injury. A fundamental question relevant to both normal development and to cell-based repair strategies in the central nervous system is how the balance of different NSC and NPC populations is maintained in the niche. EGFR (epidermal growth factor receptor) and Notch signalling pathways have fundamental roles during development of multicellular organisms. In Drosophila and in Caenorhabditis elegans these pathways may have either cooperative or antagonistic functions. In the SVZ, Notch regulates NSC identity and self-renewal, whereas EGFR specifically affects NPC proliferation and migration. This suggests that interplay of these two pathways may maintain the balance between NSC and NPC numbers. Here we show that functional cell-cell interaction between NPCs and NSCs through EGFR and Notch signalling has a crucial role in maintaining the balance between these cell populations in the SVZ. Enhanced EGFR signalling in vivo results in the expansion of the NPC pool, and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signalling. Our findings define a novel interaction between EGFR and Notch pathways in the adult SVZ, and thus provide a mechanism for NSC and NPC pool maintenance. PMID- 20844537 TI - Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. AB - The ability to produce vigorous immune responses that spare self tissues and organs depends on the elimination of autoreactive T and B cells. However, purging of immature and mature self-reactive T and B cells is incomplete and may also require the involvement of cells programmed to suppress immune responses. Regulatory T cells (T(reg)) belonging to the CD4(+) T-cell subset may have a role in preventing untoward inflammatory responses, but T-cell subsets programmed to inhibit the development of autoantibody formation and systemic-lupus erythematosus-like disease have not yet been defined. Here we delineate a CD8(+) regulatory T-cell lineage that is essential for the maintenance of self tolerance and prevention of murine autoimmune disease. Genetic disruption of the inhibitory interaction between these CD8(+) T cells and their target Qa-1(+) follicular T helper cells results in the development of a lethal systemic-lupus-erythematosus like autoimmune disease. These findings define a sublineage of CD8 T cells programmed to suppress rather than activate immunity that represents an essential regulatory element of the immune response and a guarantor of self tolerance. PMID- 20844538 TI - Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo. AB - Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells. Here we report the generation of ELMO1-deficient mice, which we found to be unexpectedly viable and grossly normal. However, they had a striking testicular pathology, with disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells and decreased sperm output. Subsequent in vitro and in vivo analyses revealed a crucial role for ELMO1 in the phagocytic clearance of apoptotic germ cells by Sertoli cells lining the seminiferous epithelium. The engulfment receptor BAI1 and RAC1 (upstream and downstream of ELMO1, respectively) were also important for Sertoli-cell-mediated engulfment. Collectively, these findings uncover a selective requirement for ELMO1 in Sertoli-cell-mediated removal of apoptotic germ cells and make a compelling case for a relationship between engulfment and tissue homeostasis in vivo. PMID- 20844539 TI - Formate-driven growth coupled with H(2) production. AB - Although a common reaction in anaerobic environments, the conversion of formate and water to bicarbonate and H(2) (with a change in Gibbs free energy of DeltaG degrees = +1.3 kJ mol(-1)) has not been considered energetic enough to support growth of microorganisms. Recently, experimental evidence for growth on formate was reported for syntrophic communities of Moorella sp. strain AMP and a hydrogen consuming Methanothermobacter species and of Desulfovibrio sp. strain G11 and Methanobrevibacter arboriphilus strain AZ. The basis of the sustainable growth of the formate-users is explained by H(2) consumption by the methanogens, which lowers the H(2) partial pressure, thus making the pathway exergonic. However, it has not been shown that a single strain can grow on formate by catalysing its conversion to bicarbonate and H(2). Here we report that several hyperthermophilic archaea belonging to the Thermococcus genus are capable of formate-oxidizing, H(2)-producing growth. The actual DeltaG values for the formate metabolism are calculated to range between -8 and -20 kJ mol(-1) under the physiological conditions where Thermococcus onnurineus strain NA1 are grown. Furthermore, we detected ATP synthesis in the presence of formate as a sole energy source. Gene expression profiling and disruption identified the gene cluster encoding formate hydrogen lyase, cation/proton antiporter and formate transporter, which were responsible for the growth of T. onnurineus NA1 on formate. This work shows formate-driven growth by a single microorganism with protons as the electron acceptor, and reports the biochemical basis of this ability. PMID- 20844542 TI - Smoking wears away happiness: new concept, 'smoking creates thunderclouds'. PMID- 20844543 TI - Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine. AB - This study evaluated the impact of renal function on cardiovascular outcomes in elderly hypertensive patients enrolled in the Japanese Trial to Assess Optimal Systolic Blood Pressure in Elderly Hypertensive patients. The patients were randomly assigned to either a strict-treatment group (target systolic blood pressure (BP) <140 mm Hg, n=2212) or a mild-treatment group (target systolic BP, 140 to <160 mm Hg, n=2206), each with efonidipine (a T/L-type Ca channel blocker) based regimens. Cardiovascular events (stroke, cardiovascular disease and renal disease) were evaluated during the 2-year follow-up period following the prospective randomized open-blinded end-point method. Estimated glomerular filtration rate (eGFR) was elevated throughout the trial period in both the strict-treatment (59.4-62 ml min-1 per 1.73 m2) and the mild-treatment group (58.8-61.4 ml min-1 per 1.73 m2). This tendency was also observed in diabetic patients and patients aged >=75 years, with baseline eGFR<60 ml min-1 per 1.73 m2. Baseline eGFR (<60 vs. >=60 ml min-1 per 1.73 m2) had no definite relationship with the incidence of cardiovascular events, nor did the level of BP control. Proteinuria at the time of entry into the study, however, was significantly correlated with cardiovascular event rates (7.1%), an association that was more apparent in patients with eGFR<60 ml min-1 per 1.73 m2 (8.2%). Furthermore, the event rate was more elevated in patients with greater declines in eGFR and was amplified when the baseline eGFR was <60 ml min-1 per 1.73 m2. In conclusion, the rates of decline of renal function and proteinuria constitute critical risk factors for cardiovascular events in elderly hypertensive patients, trends that are enhanced when baseline eGFR is diminished. Furthermore, the fact that efonidipine-based regimens ameliorate renal function in elderly hypertensive patients with chronic kidney disease may offer novel information on the mechanisms of cardiovascular protection. PMID- 20844544 TI - Mutation analysis of the MYO7A and CDH23 genes in Japanese patients with Usher syndrome type 1. AB - Usher syndrome (USH) is an autosomal recessive disorder characterized by retinitis pigmentosa and hearing loss. USH type 1 (USH1), the second common type of USH, is frequently caused by MYO7A and CDH23 mutations, accounting for 70-80% of the cases among various ethnicities, including Caucasians, Africans and Asians. However, there have been no reports of mutation analysis for any responsible genes for USH1 in Japanese patients. This study describes the first mutation analysis of MYO7A and CDH23 in Japanese USH1 patients. Five mutations (three in MYO7A and two in CDH23) were identified in four of five unrelated patients. Of these mutations, two were novel. One of them, p.Tyr1942SerfsX23 in CDH23, was a large deletion causing the loss of 3 exons. This is the first large deletion to be found in CDH23. The incidence of the MYO7A and CDH23 mutations in the study population was 80%, which is consistent with previous findings. Therefore, mutation screening for these genes is expected to be a highly sensitive method for diagnosing USH1 among the Japanese. PMID- 20844545 TI - FLNA p.V528M substitution is neither associated with bilateral periventricular nodular heterotopia nor with macrothrombocytopenia. AB - Filamin A is encoded by the FLNA gene on chromosome Xq28 and functions in cross linking actin filaments into orthogonal networks in the cortical cytoplasm. FLNA p.V528M was initially detected in a female autopsy case of X-linked bilateral periventricular nodular heterotopia (BPNH), a neuronal migration disorder characterized by subependymal nodules of gray matter. During our mutation analysis of FLNA in a boy with apparent X-linked thrombocytopenia, we detected the p.V528M variant. The patient, mother and sister, who were heterozygous for the substitution, did not have BPNH. We observed an allele frequency of 4.8% in healthy control Japanese, but did not observe the variant in Caucasian subjects. Hemizygous controls had a normal platelet count and size. We suggest that p.V528M is neither associated with BPNH nor with thrombocytopenia and giant platelets, and represents a functional polymorphism. PMID- 20844547 TI - Mutation analysis of the gene encoding the PALB2-binding protein MRG15 in BRCA1/2 negative breast cancer families. AB - MRG15 is a recently identified member of the BRCA multiprotein complex, essential for the maintenance of the genome integrity and DNA repair. The functional relationship between PALB2 and MRG15 makes MRG15 a strong candidate breast cancer susceptibility gene. We screened affected probands from 232 BRCA1/2-negative breast cancer families for mutations in MRG15. We identified seven previously unreported variants but in silico analyses revealed that none of these variants appears to modify the function of MRG15. Thus, it seems unlikely that any constitutional changes in MRG15 confer an increased risk for breast cancer. PMID- 20844546 TI - Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. AB - To identify susceptibility genes for endometriosis in Japanese women, genome-wide association (GWA) analysis was performed using two case-control cohorts genotyped with the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. In each of the two array cohorts, stringent quality control (QC) filters were applied to newly obtained genotype data, together with previously analyzed data from the Japanese Integrated Database Project. After QC-based filtering of samples and single nucleotide polymorphisms (SNPs) in each cohort, 282 838 SNPs in both genotyping platforms were tested for association with endometriosis using a meta-analysis of the two GWA studies with 696 patients with endometriosis and 825 controls. The meta-analysis revealed that a common susceptibility locus conferring a large effect on the disease risk was unlikely. On the other hand, an excess of SNPs with P-values <10(-4) (36 vs 28 SNPs expected by chance) was observed in the meta-analysis. Of note, four of the top five SNPs with P-values <10(-5) were located in and around IL1A (interleukin 1alpha), which might be a functional candidate gene for endometriosis. Further studies with larger case control cohorts will be necessary to elucidate the genetic risk factors. PMID- 20844548 TI - The novel and independent association between single-point SNP of NPHP4 gene and renal function in non-diabetic Japanese population: the Takahata study. AB - Nephronophthisis (NPHP) 4 gene coding nephrocystin-4 is involved in the development of renal tubules and its congenital mutations cause juvenile end stage renal disease, NPHP. To investigate the association between single-point single-nucleotide polymorphism (SNP) of NPHP4 gene and renal function, we conducted a cross-sectional study in Japanese population. The subjects of this study were non-diabetic general population consisting of 2604 individuals >40 years in Takahata town, Japan. We genotyped 11 SNPs within NPHP4 gene that displayed frequent minor allele frequencies (>0.1) in Japanese general population. Among 11 SNPs in NPHP4 gene, only rs1287637 that induces amino acid substitution (A (Gln)/T (Leu)), located in the acceptor site of exon 21, showed a significant association with estimated glomerular filtration rate (eGFR; T/T: 81.3+/-15.6 (n=1886), A/T: 82.0+/-15.5 (n=652) and A/A: 87.4+/-21.4 ml min(-1) per 1.73m(2) (n=66); mean+/-s.d., P=0.006). This SNP was not in linkage disequilibrium with the surrounding SNPs. The multivariate analysis adjusted with possible confounders showed that the A/T+T/T genotype of rs1287637 was independently associated with reduced renal function (eGFR <90 ml min(-1) per 1.73m(2); odds ratio (OR) 1.75, 95% confidence interval (CI) 1.05-2.94, P=0.033). These results indicate the novel and independent association between single-point SNP rs1287637 in NPHP4 gene and renal function in non-diabetic Japanese population. PMID- 20844550 TI - Elevated epidermal ornithine decarboxylase activity suppresses contact hypersensitivity. AB - Previous reports have shown that elevated polyamine biosynthesis is sufficient to promote skin tumorigenesis in susceptible mouse strains. We hypothesized that increased activity of epidermal ornithine decarboxylase (ODC), a key regulatory enzyme in polyamine biosynthesis, may suppress the cutaneous immune response in addition to stimulating proliferation. Using an ODCER transgenic mouse model in which ODC is targeted to the epidermis, we examined the effect of ODC overexpression in keratinocytes on a classic contact hypersensitivity (CHS) response. Compared with normal littermate mice, ODCER transgenic mice showed reduced ear swelling, reduced neutrophil infiltration, and decreased migration of fluorescein isothiocyanate-loaded dendritic cells (DCs) to draining lymph nodes following hapten elicitation of CHS. In addition, elevated epidermal ODC activity suppressed the levels of cytokines keratinocyte-derived chemokine, monocyte chemoattractant protein-1, interleukin-6 (IL-6), and IL-10. Adoptive transfer of lymphocytes from sensitized ODCER transgenic or normal littermate mice to naive ODCER transgenic or wild-type mice indicated that elevated epidermal ODC activity suppresses both the sensitization and elicitation phases of CHS. The specific ODC inhibitor, alpha-difluoromethylornithine, abrogated all suppressive effects of ODC in CHS reactions. Collectively, these data suggest that the immunosuppression promoted by increased epidermal ODC is mediated by a reduction in cytokine levels, which suppresses DC migration and reduces immune cell infiltration to the site of hapten application. PMID- 20844551 TI - Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. AB - We performed a cross-sectional, questionnaire-based study to explore the relationship of suicidal ideation, mental health problems, and social functioning to acne severity among adolescents aged 18-19 years. A total of 4,744 youth were invited and 3,775 (80%) participated. In all, 14% reported having substantial acne (a lot and very much). Among those with very much acne, as compared those with no/little acne, suicidal ideation was twice as frequently reported among girls (25.5 vs. 11.9%) and three times more frequently reported among boys (22.6 vs. 6.3%). Suicidal ideation remained significantly associated with substantial acne (odds ratio 1.80, 95% confidence interval 1.30-2.50) in a multivariate model including adjustments of symptoms of depression, ethnicity, and family income. Mental health problems, as assessed by the Strengths and Difficulties Questionnaire (2.25, 1.69-3.00), low attachment to friends (1.52, 1.21-1.91), not thriving at school (1.41, 1.12-1.78), never having had a romantic relationship (1.35, 1.05-1.70), and never having had sexual intercourse (1.51, 1.21-1.89) were all associated with substantial acne in a multivariate model. Acne is frequently found in late adolescence and is associated with social and psychological problems. Adverse events including suicidal ideation and depression that have been associated with therapies for acne may reflect the burden of substantial acne rather than the effects of medication. PMID- 20844552 TI - Primary cutaneous CD30+ anaplastic large-cell lymphomas show a heterogeneous genomic profile: an oligonucleotide arrayCGH approach. PMID- 20844553 TI - Harnessing transposons for cancer gene discovery. AB - Recently, it has become possible to mobilize the Tc1/mariner transposon, Sleeping Beauty (SB), in mouse somatic cells at frequencies high enough to induce cancer. Tumours result from SB insertional mutagenesis of cancer genes, thus facilitating the identification of the genes and signalling pathways that drive tumour formation. A conditional SB transposition system has also been developed that makes it possible to limit where SB mutagenesis occurs, providing a means to selectively model many types of human cancer. SB mutagenesis has already identified a large collection of known cancer genes in addition to a plethora of new candidate cancer genes and potential drug targets. PMID- 20844555 TI - Seeking perfection. PMID- 20844554 TI - Licensed to elongate: a molecular mechanism for MLL-based leukaemogenesis. AB - The RNA polymerase II (Pol II) elongation factor (ELL) was the first translocation partner of mixed lineage leukaemia (MLL) for which a biochemical function was determined. It was therefore proposed that the regulation of the elongation stage of transcription could be fundamental to MLL-based leukaemogenesis. Recent studies have identified ELL complexed with several of the translocation partners of MLL in a transcriptional super elongation complex (SEC). These studies provide evidence for the importance of the regulation of Pol II elongation in disease pathogenesis and suggest that MLL chimaeras function by licensing Pol II transcription elongation without the appropriate checkpoints. PMID- 20844556 TI - The ParMRC system: molecular mechanisms of plasmid segregation by actin-like filaments. AB - The ParMRC plasmid partitioning apparatus is one of the best characterized systems for bacterial DNA segregation. Bundles of actin-like filaments are used to push plasmids to opposite poles of the cell, whereupon they are stably inherited on cell division. This plasmid-encoded system comprises just three components: an actin-like protein, ParM, a DNA-binding adaptor protein, ParR, and a centromere-like region, parC. The properties and interactions of these components have been finely tuned to enable ParM filaments to search the cell space for plasmids and then move ParR-parC-bound DNA molecules apart. In this Review, we look at some of the most exciting questions in the field concerning the exact molecular mechanisms by which the components of this self-contained system modulate one another's activity to achieve bipolar DNA segregation. PMID- 20844557 TI - Microbial electrosynthesis - revisiting the electrical route for microbial production. AB - Microbial electrocatalysis relies on microorganisms as catalysts for reactions occurring at electrodes. Microbial fuel cells and microbial electrolysis cells are well known in this context; both use microorganisms to oxidize organic or inorganic matter at an anode to generate electrical power or H(2), respectively. The discovery that electrical current can also drive microbial metabolism has recently lead to a plethora of other applications in bioremediation and in the production of fuels and chemicals. Notably, the microbial production of chemicals, called microbial electrosynthesis, provides a highly attractive, novel route for the generation of valuable products from electricity or even wastewater. This Review addresses the principles, challenges and opportunities of microbial electrosynthesis, an exciting new discipline at the nexus of microbiology and electrochemistry. PMID- 20844559 TI - History of science is good for you. PMID- 20844558 TI - The origin of eukaryotes and their relationship with the Archaea: are we at a phylogenomic impasse? AB - The origin of eukaryotes and their evolutionary relationship with the Archaea is a major biological question and the subject of intense debate. In the context of the classical view of the universal tree of life, the Archaea and the Eukarya have a common ancestor, the nature of which remains undetermined. Alternative views propose instead that the Eukarya evolved directly from a bona fide archaeal lineage. Several recent large-scale phylogenomic studies using an array of approaches are divided in supporting either one or the other scenario, despite analysing largely overlapping data sets of universal genes. We examine the reasons for such a lack of consensus and consider how alternative approaches may enable progress in answering this fascinating and as-yet-unresolved question. PMID- 20844560 TI - Insulin is a potent myeloma cell growth factor through insulin/IGF-1 hybrid receptor activation. AB - Insulin and insulin growth factor type 1 (IGF-1) and their receptors are closely related molecules, but both factors bind to the receptor of the other one with a weak affinity. No study has presently documented a role of insulin as a myeloma growth factor (MGF) for human multiple myeloma cells (MMCs), whereas many studies have concluded that IGF-1 is a major MGF. IGF-1 receptor (IGF-1R) is aberrantly expressed by MMCs in association with a poor prognosis. In this study we show that insulin receptor (INSR) is increased throughout normal plasma cell differentiation. INSR gene is also expressed by MMCs of 203/206 newly diagnosed patients. Insulin is an MGF as potent as IGF-1 at physiological concentrations and requires the presence of insulin/IGF-1 hybrid receptors, stimulating INSR(+)IGF-1R(+) MMCs, unlike INSR(+)IGF-1R(-) or INSR(-)IGF-1R(-) MMCs. Immunoprecipitation experiments indicate that INSR is linked with IGF-1R in MMCs and that insulin induces both IGF-1R and INSR phosphorylations and vice versa. In conclusion, we demonstrate for the first time that insulin is an MGF as potent as IGF-1 at physiological concentrations and its activity necessitates insulin/IGF-1 hybrid receptor activation. Further therapeutic strategies targeting the IGF/IGF 1R pathway have to take into account neutralizing the IGF-1R-mediated insulin MGF activity. PMID- 20844561 TI - Smac mimetics: implications for enhancement of targeted therapies in leukemia. AB - Drug resistance is a growing concern with clinical use of tyrosine kinase inhibitors. Utilizing in vitro models of intrinsic drug resistance and stromal mediated chemoresistance, as well as functional mouse models of progressive and residual disease, we attempted to develop a potential therapeutic approach designed to suppress leukemia recurrence following treatment with selective kinase inhibitors. The novel IAP inhibitor, LCL161, [corrected] was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal-protected [corrected] environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of drug inhibition. These results support the idea of using IAP inhibitors in conjunction with targeted tyrosine kinase inhibition to override drug resistance and suppress or eradicate residual disease. PMID- 20844562 TI - Automated pattern-guided principal component analysis vs expert-based immunophenotypic classification of B-cell chronic lymphoproliferative disorders: a step forward in the standardization of clinical immunophenotyping. AB - Immunophenotypic characterization of B-cell chronic lymphoproliferative disorders (B-CLPD) is becoming increasingly complex due to usage of progressively larger panels of reagents and a high number of World Health Organization (WHO) entities. Typically, data analysis is performed separately for each stained aliquot of a sample; subsequently, an expert interprets the overall immunophenotypic profile (IP) of neoplastic B-cells and assigns it to specific diagnostic categories. We constructed a principal component analysis (PCA)-based tool to guide immunophenotypic classification of B-CLPD. Three reference groups of immunophenotypic data files-B-cell chronic lymphocytic leukemias (B-CLL; n = 10), mantle cell (MCL; n = 10) and follicular lymphomas (FL; n = 10)--were built. Subsequently, each of the 175 cases studied was evaluated and assigned to either one of the three reference groups or to none of them (other B-CLPD). Most cases (89%) were correctly assigned to their corresponding WHO diagnostic group with overall positive and negative predictive values of 89 and 96%, respectively. The efficiency of the PCA-based approach was particularly high among typical B-CLL, MCL and FL vs other B-CLPD cases. In summary, PCA-guided immunophenotypic classification of B-CLPD is a promising tool for standardized interpretation of tumor IP, their classification into well-defined entities and comprehensive evaluation of antibody panels. PMID- 20844563 TI - Do we have to kill the last CML cell? AB - Previous experience in the treatment of chronic myeloid leukaemia (CML) has shown that the achievement of clinical, morphological and cytogenetic remission does not indicate eradication of the disease. A complete molecular response (CMR; no detectable BCR-ABL mRNA) represents a deeper level of response, but even CMR is not a guarantee of elimination of the leukaemia, because the significance of CMR is determined by the detection limit of the assay that is used. Two studies of imatinib cessation in CMR are underway, cumulatively involving over 100 patients. The current estimated rate of stable CMR after stopping imatinib is approximately 40%, but the duration of follow-up is relatively short. The factors that determine relapse risk are yet to be identified. The intrinsic capacity of any residual leukaemia [corrected] cells to proliferate following the withdrawal of treatment may be important, but there may also be a role for immunological suppression of the leukaemia [corrected] clone. No currently available test can formally prove that the leukaemic clone is eradicated. Here we discuss the sensitive measurement of minimal residual disease, and speculate on the biology of BCR-ABL-positive cells that may persist after effective therapy of CML. PMID- 20844564 TI - Targeting B cell leukemia with highly specific allogeneic T cells with a public recognition motif. AB - The possibility that allogeneic T cells may be targeted to leukemia has important therapeutic implications. As most tumor antigens represent self-proteins, high avidity tumor-specific T cells are largely deleted from the repertoire of the patient. In contrast, T cells from major histocompatibility complex (MHC) mismatched donors provide naive repertoires wherein such cells have not been systematically eliminated. Yet, evidence for peptide degeneracy or poly specificity warrants caution in the use of foreign human leukocyte antigen (HLA) or peptide complexes as therapeutic targets. Here, we cocultured HLA-A(*)0201 negative T cells with autologous dendritic cells engineered to present HLA A(*)0201 complexed with a peptide from the B cell antigen CD20 (CD20p). HLA A(*)0201/CD20p pentamer-reactive CD8(+) T cells were readily obtained from all donors. The polyclonal cells showed exquisite peptide and MHC specificity, and efficiently killed HLA-A(*)0201-positive B cells, including primary chronic lymphocytic leukemia cells. The T cell receptor (TCR) sequences displayed a novel type of conservation, with extensive homology in the TCR beta chain complementarity-determining region 3 and in J, but not V, region. This is surprising, as the donors were HLA disparate and their TCR repertoires are expected to show little overlap. The results demonstrate the first public recognition motif for an allogeneic HLA/peptide complex. The allo-restricted T cells or TCRs could provide graft-versus-leukemia in the absence of graft-versus host disease. PMID- 20844565 TI - A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. PMID- 20844566 TI - Mixed-phenotype acute leukemia: historical overview and a new definition. AB - Acute leukemia with a mixed phenotype is a rare disease and comprises 2-5% of all acute leukemias. These disorders have been known historically by a variety of names, such as mixed lineage leukemia, bilineal leukemia and biphenotypic leukemia, and the criteria for diagnosis have often been arbitrary. The scoring criteria proposed by the European Group for the Immunological Characterization of Leukemias represented a major attempt to define this disorder. However, the relative weight given to some markers and the lack of lineage specificity of most markers have raised questions regarding the significance of this approach. In 2008, the World Health Organization classification of hematopoietic and lymphoid tumors proposed a simpler diagnostic algorithm, which relies on fewer and more lineage-specific markers to define mixed-phenotype acute leukemia (MPAL). MPAL with t(9;22) and MLL rearrangement have been separated. Several studies have suggested that patients with acute leukemia of mixed phenotype have a worse clinical outcome when compared with matched controls with acute myeloid leukemia or acute lymphoblastic leukemia. Further studies are needed to confirm the significance of MPAL as currently defined, to determine a standardized treatment approach and to better understand the biological and clinical aspects of this disease. PMID- 20844567 TI - Celastrol enhances AAV1-mediated gene expression in mice adipose tissues. AB - The transduction of adeno-associated virus (AAV) in adipose tissues was not well characterized and appeared to be insufficient as compared with other targeted tissues in gene therapy. We have found that celastrol, a chemical from a traditional Chinese herb known to inhibit the proteasome activity, was able to enhance the transgene expression mediated by AAV1 in 3T3-L1 preadipocytes both before and after induced differentiation. A synergism of celastrol and nonionic surfactant pluronic F68 cotreatment on AAV1 transduction was observed in the experiments with rat primary preadipocyte cultures and in adipose tissues in vivo. By fluorescent microscopy using Alexa Fluor 647-labeled AAV and quantitative PCR assays, we found that celastrol treatments increased the nuclear distribution of AAV genomic DNAs, but not the total amount of viral cellular uptake in preadipocytes, which was different from the effect of pluronic F68 treatment to significantly promote the AAV internalization. Our data suggested that bioactive monomeric compounds extracted from herbal medicines might be used to facilitate AAV-mediated gene transfer applications. PMID- 20844568 TI - AAV-P125A-endostatin and paclitaxel treatment increases endoreduplication in endothelial cells and inhibits metastasis of breast cancer. AB - Endostatin potentiates the antimitotic effects of paclitaxel (taxol) on endothelial cells (ECs). P125A-endostatin and taxol-treated ECs showed multipolar spindles and nuclear lobulation, leading to mitotic catastrophe and cell death. Induction of nuclear abnormalities was found to be dependent on beta-catenin levels as wnt-mediated overexpression of beta-catenin reversed the changes in nuclear morphology. These results prompted us to investigate whether antiangiogenic gene therapy and paclitaxel chemotherapy can synergistically inhibit angiogenesis and tumor growth. We first determined the effect of combination treatment in a transgenic mouse model of breast cancer. Intramuscular injection of recombinant adeno-associated virus type-2 virus induced sustained expression of P125A-endostatin. In vivo studies showed that combination therapy inhibited mammary cancer growth, delayed the onset of multifocal mammary adenocarcinomas, decreased tumor angiogenesis and increased survival in treated mice. In a second model, female athymic mice were orthotopically transplanted with a metastatic human breast cancer cell line. Antiangiogenic gene therapy in combination with paclitaxel inhibited tumor angiogenesis and lung/lymph-node metastasis in this model. These studies demonstrate cooperation between endostatin gene therapy and chemotherapy to inhibit tumor initiation, growth and metastasis. PMID- 20844570 TI - Myeloid Sarcoma of the Uterine Cervix as Presentation of Acute Myeloid Leukaemia after Treatment with Low-Dose Radioiodine for Thyroid Cancer: A Case Report and Review of the Literature. AB - The development of acute myeloid leukaemia after low-dose radioiodine therapy and its presentation as a myeloid sarcoma of the uterine cervix are both rare events. We report a case of acute myeloid leukaemia revealed by a myeloid sarcoma of the uterine cervix in a 48-year-old woman, 17 months after receiving a total dose of 100 mCi (131)I for papillary thyroid cancer. A strict hematological follow-up of patients treated with any dose of (131)I is recommended to accurately detect any hematological complications which might have been underestimated. Unusual presentations, such as chloroma of the uterine cervix, may reveal myeloid malignancy and should be kept in mind. PMID- 20844569 TI - Quantitative analysis of a deeply sequenced marine microbial metatranscriptome. AB - The potential of metatranscriptomic sequencing to provide insights into the environmental factors that regulate microbial activities depends on how fully the sequence libraries capture community expression (that is, sample-sequencing depth and coverage depth), and the sensitivity with which expression differences between communities can be detected (that is, statistical power for hypothesis testing). In this study, we use an internal standard approach to make absolute (per liter) estimates of transcript numbers, a significant advantage over proportional estimates that can be biased by expression changes in unrelated genes. Coastal waters of the southeastern United States contain 1 * 10(12) bacterioplankton mRNA molecules per liter of seawater (~200 mRNA molecules per bacterial cell). Even for the large bacterioplankton libraries obtained in this study (~500,000 possible protein-encoding sequences in each of two libraries after discarding rRNAs and small RNAs from >1 million 454 FLX pyrosequencing reads), sample-sequencing depth was only 0.00001%. Expression levels of 82 genes diagnostic for transformations in the marine nitrogen, phosphorus and sulfur cycles ranged from below detection (<1 * 10(6) transcripts per liter) for 36 genes (for example, phosphonate metabolism gene phnH, dissimilatory nitrate reductase subunit napA) to >2.7 * 10(9) transcripts per liter (ammonia transporter amt and ammonia monooxygenase subunit amoC). Half of the categories for which expression was detected, however, had too few copy numbers for robust statistical resolution, as would be required for comparative (experimental or time-series) expression studies. By representing whole community gene abundance and expression in absolute units (per volume or mass of environment), 'omics' data can be better leveraged to improve understanding of microbially mediated processes in the ocean. PMID- 20844571 TI - Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer. AB - BACKGROUND: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. METHODS: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). RESULTS: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1-25 months). In particular, the group with a good postoperative performance status score (0-2) was shown to have a better median postoperative survival of 13 months. CONCLUSIONS: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor. PMID- 20844572 TI - Gene and noncoding RNA regulation underlying photoreceptor protection: microarray study of dietary antioxidant saffron and photobiomodulation in rat retina. AB - PURPOSE: To identify the genes and noncoding RNAs (ncRNAs) involved in the neuroprotective actions of a dietary antioxidant (saffron) and of photobiomodulation (PBM). METHODS: We used a previously published assay of photoreceptor damage, in which albino Sprague Dawley rats raised in dim cyclic illumination (12 h 5 lux, 12 h darkness) were challenged by 24 h exposure to bright (1,000 lux) light. Experimental groups were protected against light damage by pretreatment with dietary saffron (1 mg/kg/day for 21 days) or PBM (9 J/cm(2) at the eye, daily for 5 days). RNA from one eye of four animals in each of the six experimental groups (control, light damage [LD], saffron, PBM, saffronLD, and PBMLD) was hybridized to Affymetrix rat genome ST arrays. Quantitative real-time PCR analysis of 14 selected genes was used to validate the microarray results. RESULTS: LD caused the regulation of 175 entities (genes and ncRNAs) beyond criterion levels (p<0.05 in comparison with controls, fold-change >2). PBM pretreatment reduced the expression of 126 of these 175 LD-regulated entities below criterion; saffron pretreatment reduced the expression of 53 entities (50 in common with PBM). In addition, PBM pretreatment regulated the expression of 67 entities not regulated by LD, while saffron pretreatment regulated 122 entities not regulated by LD (48 in common with PBM). PBM and saffron, given without LD, regulated genes and ncRNAs beyond criterion levels, but in lesser numbers than during their protective action. A high proportion of the entities regulated by LD (>90%) were known genes. By contrast, ncRNAs were prominent among the entities regulated by PBM and saffron in their neuroprotective roles (73% and 62%, respectively). CONCLUSIONS: Given alone, saffron and (more prominently) PBM both regulated significant numbers of genes and ncRNAs. Given before retinal exposure to damaging light, thus while exerting their neuroprotective action, they regulated much larger numbers of entities, among which ncRNAs were prominent. Further, the downregulation of known genes and of ncRNAs was prominent in the protective actions of both neuroprotectants. These comparisons provide an overview of gene expression induced by two neuroprotectants and provide a basis for the more focused study of their mechanisms. PMID- 20844573 TI - The OmpL37 surface-exposed protein is expressed by pathogenic Leptospira during infection and binds skin and vascular elastin. AB - Pathogenic Leptospira spp. shed in the urine of reservoir hosts into freshwater can be transmitted to a susceptible host through skin abrasions or mucous membranes causing leptospirosis. The infection process involves the ability of leptospires to adhere to cell surface and extracellular matrix components, a crucial step for dissemination and colonization of host tissues. Therefore, the elucidation of novel mediators of host-pathogen interaction is important in the discovery of virulence factors involved in the pathogenesis of leptospirosis. In this study, we assess the functional roles of transmembrane outer membrane proteins OmpL36 (LIC13166), OmpL37 (LIC12263), and OmpL47 (LIC13050), which we recently identified on the leptospiral surface. We determine the capacity of these proteins to bind to host tissue components by enzyme-linked immunosorbent assay. OmpL37 binds elastin preferentially, exhibiting dose-dependent, saturating binding to human skin (K(d), 104+/-19 nM) and aortic elastin (K(d), 152+/-27 nM). It also binds fibrinogen (K(d), 244+/-15 nM), fibrinogen fragment D (K(d), 132+/ 30 nM), plasma fibronectin (K(d), 359+/-68 nM), and murine laminin (K(d), 410+/ 81 nM). The binding to human skin elastin by both recombinant OmpL37 and live Leptospira interrogans is specifically enhanced by rabbit antiserum for OmpL37, suggesting the involvement of OmpL37 in leptospiral binding to elastin and also the possibility that host-generated antibodies may promote rather than inhibit the adherence of leptospires to elastin-rich tissues. Further, we demonstrate that OmpL37 is recognized by acute and convalescent leptospirosis patient sera and also by Leptospira-infected hamster sera. Finally, OmpL37 protein is detected in pathogenic Leptospira serovars and not in saprophytic Leptospira. Thus, OmpL37 is a novel elastin-binding protein of pathogenic Leptospira that may be promoting attachment of Leptospira to host tissues. PMID- 20844574 TI - An immune response network associated with blood lipid levels. AB - While recent scans for genetic variation associated with human disease have been immensely successful in uncovering large numbers of loci, far fewer studies have focused on the underlying pathways of disease pathogenesis. Many loci which are associated with disease and complex phenotypes map to non-coding, regulatory regions of the genome, indicating that modulation of gene transcription plays a key role. Thus, this study generated genome-wide profiles of both genetic and transcriptional variation from the total blood extracts of over 500 randomly selected, unrelated individuals. Using measurements of blood lipids, key players in the progression of atherosclerosis, three levels of biological information are integrated in order to investigate the interactions between circulating leukocytes and proximal lipid compounds. Pair-wise correlations between gene expression and lipid concentration indicate a prominent role for basophil granulocytes and mast cells, cell types central to powerful allergic and inflammatory responses. Network analysis of gene co-expression showed that the top associations function as part of a single, previously unknown gene module, the Lipid Leukocyte (LL) module. This module replicated in T cells from an independent cohort while also displaying potential tissue specificity. Further, genetic variation driving LL module expression included the single nucleotide polymorphism (SNP) most strongly associated with serum immunoglobulin E (IgE) levels, a key antibody in allergy. Structural Equation Modeling (SEM) indicated that LL module is at least partially reactive to blood lipid levels. Taken together, this study uncovers a gene network linking blood lipids and circulating cell types and offers insight into the hypothesis that the inflammatory response plays a prominent role in metabolism and the potential control of atherogenesis. PMID- 20844575 TI - Chromatin landscape dictates HSF binding to target DNA elements. AB - Sequence-specific transcription factors (TFs) are critical for specifying patterns and levels of gene expression, but target DNA elements are not sufficient to specify TF binding in vivo. In eukaryotes, the binding of a TF is in competition with a constellation of other proteins, including histones, which package DNA into nucleosomes. We used the ChIP-seq assay to examine the genome wide distribution of Drosophila Heat Shock Factor (HSF), a TF whose binding activity is mediated by heat shock-induced trimerization. HSF binds to 464 sites after heat shock, the vast majority of which contain HSF Sequence-binding Elements (HSEs). HSF-bound sequence motifs represent only a small fraction of the total HSEs present in the genome. ModENCODE ChIP-chip datasets, generated during non-heat shock conditions, were used to show that inducibly bound HSE motifs are associated with histone acetylation, H3K4 trimethylation, RNA Polymerase II, and coactivators, compared to HSE motifs that remain HSF-free. Furthermore, directly changing the chromatin landscape, from an inactive to an active state, permits inducible HSF binding. There is a strong correlation of bound HSEs to active chromatin marks present prior to induced HSF binding, indicating that an HSE's residence in "active" chromatin is a primary determinant of whether HSF can bind following heat shock. PMID- 20844576 TI - Cyclin-dependent kinase activity controls the onset of the HCMV lytic cycle. AB - The onset of human cytomegalovirus (HCMV) lytic infection is strictly synchronized with the host cell cycle. Infected G0/G1 cells support viral immediate early (IE) gene expression and proceed to the G1/S boundary where they finally arrest. In contrast, S/G2 cells can be infected but effectively block IE gene expression and this inhibition is not relieved until host cells have divided and reentered G1. During latent infection IE gene expression is also inhibited, and for reactivation to occur this block to IE gene expression must be overcome. It is only poorly understood which viral and/or cellular activities maintain the block to cell cycle or latency-associated viral IE gene repression and whether the two mechanisms may be linked. Here, we show that the block to IE gene expression during S and G2 phase can be overcome by both genotoxic stress and chemical inhibitors of cellular DNA replication, pointing to the involvement of checkpoint-dependent signaling pathways in controlling IE gene repression. Checkpoint-dependent rescue of IE expression strictly requires p53 and in the absence of checkpoint activation is mimicked by proteasomal inhibition in a p53 dependent manner. Requirement for the cyclin dependent kinase (CDK) inhibitor p21 downstream of p53 suggests a pivotal role for CDKs in controlling IE gene repression in S/G2 and treatment of S/G2 cells with the CDK inhibitor roscovitine alleviates IE repression independently of p53. Importantly, CDK inhibiton also overcomes the block to IE expression during quiescent infection of NTera2 (NT2) cells. Thus, a timely block to CDK activity not only secures phase specificity of the cell cycle dependent HCMV IE gene expression program, but in addition plays a hitherto unrecognized role in preventing the establishment of a latent-like state. PMID- 20844577 TI - The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. AB - Influenza A viruses (IAV) bind to sialic-acids at cellular surfaces and enter cells by using endocytotic routes. There is evidence that this process does not occur constitutively but requires induction of specific cellular signals, including activation of PI3K that promotes virus internalization. This implies engagement of cellular signaling receptors during viral entry. Here, we present first indications for an interplay of IAV with receptor tyrosine kinases (RTKs). As representative RTK family-members the epidermal growth factor receptor (EGFR) and the c-Met receptor were studied. Modulation of expression or activity of both RTKs resulted in altered uptake of IAV, showing that these receptors transmit entry relevant signals upon virus binding. More detailed studies on EGFR function revealed that virus binding lead to clustering of lipid-rafts, suggesting that multivalent binding of IAV to cells induces a signaling platform leading to activation of EGFR and other RTKs that in turn facilitates IAV uptake. PMID- 20844578 TI - The microbiota mediates pathogen clearance from the gut lumen after non-typhoidal Salmonella diarrhea. AB - Many enteropathogenic bacteria target the mammalian gut. The mechanisms protecting the host from infection are poorly understood. We have studied the protective functions of secretory antibodies (sIgA) and the microbiota, using a mouse model for S. typhimurium diarrhea. This pathogen is a common cause of diarrhea in humans world-wide. S. typhimurium (S. tm(att), sseD) causes a self limiting gut infection in streptomycin-treated mice. After 40 days, all animals had overcome the disease, developed a sIgA response, and most had cleared the pathogen from the gut lumen. sIgA limited pathogen access to the mucosal surface and protected from gut inflammation in challenge infections. This protection was O-antigen specific, as demonstrated with pathogens lacking the S. typhimurium O antigen (wbaP, S. enteritidis) and sIgA-deficient mice (TCRbeta(-/-)delta(-/-), J(H) (-/-), IgA(-/-), pIgR(-/-)). Surprisingly, sIgA-deficiency did not affect the kinetics of pathogen clearance from the gut lumen. Instead, this was mediated by the microbiota. This was confirmed using 'L-mice' which harbor a low complexity gut flora, lack colonization resistance and develop a normal sIgA response, but fail to clear S. tm(att) from the gut lumen. In these mice, pathogen clearance was achieved by transferring a normal complex microbiota. Thus, besides colonization resistance ( = pathogen blockage by an intact microbiota), the microbiota mediates a second, novel protective function, i.e. pathogen clearance. Here, the normal microbiota re-grows from a state of depletion and disturbed composition and gradually clears even very high pathogen loads from the gut lumen, a site inaccessible to most "classical" immune effector mechanisms. In conclusion, sIgA and microbiota serve complementary protective functions. The microbiota confers colonization resistance and mediates pathogen clearance in primary infections, while sIgA protects from disease if the host re encounters the same pathogen. This has implications for curing S. typhimurium diarrhea and for preventing transmission. PMID- 20844579 TI - Steric shielding of surface epitopes and impaired immune recognition induced by the ebola virus glycoprotein. AB - Many viruses alter expression of proteins on the surface of infected cells including molecules important for immune recognition, such as the major histocompatibility complex (MHC) class I and II molecules. Virus-induced downregulation of surface proteins has been observed to occur by a variety of mechanisms including impaired transcription, blocks to synthesis, and increased turnover. Viral infection or transient expression of the Ebola virus (EBOV) glycoprotein (GP) was previously shown to result in loss of staining of various host cell surface proteins including MHC1 and beta1 integrin; however, the mechanism responsible for this effect has not been delineated. In the present study we demonstrate that EBOV GP does not decrease surface levels of beta1 integrin or MHC1, but rather impedes recognition by steric occlusion of these proteins on the cell surface. Furthermore, steric occlusion also occurs for epitopes on the EBOV glycoprotein itself. The occluded epitopes in host proteins and EBOV GP can be revealed by removal of the surface subunit of GP or by removal of surface N- and O- linked glycans, resulting in increased surface staining by flow cytometry. Importantly, expression of EBOV GP impairs CD8 T-cell recognition of MHC1 on antigen presenting cells. Glycan-mediated steric shielding of host cell surface proteins by EBOV GP represents a novel mechanism for a virus to affect host cell function, thereby escaping immune detection. PMID- 20844580 TI - High content phenotypic cell-based visual screen identifies Mycobacterium tuberculosis acyltrehalose-containing glycolipids involved in phagosome remodeling. AB - The ability of the tubercle bacillus to arrest phagosome maturation is considered one major mechanism that allows its survival within host macrophages. To identify mycobacterial genes involved in this process, we developed a high throughput phenotypic cell-based assay enabling individual sub-cellular analysis of over 11,000 Mycobacterium tuberculosis mutants. This very stringent assay makes use of fluorescent staining for intracellular acidic compartments, and automated confocal microscopy to quantitatively determine the intracellular localization of M. tuberculosis. We characterised the ten mutants that traffic most frequently into acidified compartments early after phagocytosis, suggesting that they had lost their ability to arrest phagosomal maturation. Molecular analysis of these mutants revealed mainly disruptions in genes involved in cell envelope biogenesis (fadD28), the ESX-1 secretion system (espL/Rv3880), molybdopterin biosynthesis (moaC1 and moaD1), as well as in genes from a novel locus, Rv1503c-Rv1506c. Most interestingly, the mutants in Rv1503c and Rv1506c were perturbed in the biosynthesis of acyltrehalose-containing glycolipids. Our results suggest that such glycolipids indeed play a critical role in the early intracellular fate of the tubercle bacillus. The unbiased approach developed here can be easily adapted for functional genomics study of intracellular pathogens, together with focused discovery of new anti-microbials. PMID- 20844581 TI - A novel family of Toxoplasma IMC proteins displays a hierarchical organization and functions in coordinating parasite division. AB - Apicomplexans employ a peripheral membrane system called the inner membrane complex (IMC) for critical processes such as host cell invasion and daughter cell formation. We have identified a family of proteins that define novel sub compartments of the Toxoplasma gondii IMC. These IMC Sub-compartment Proteins, ISP1, 2 and 3, are conserved throughout the Apicomplexa, but do not appear to be present outside the phylum. ISP1 localizes to the apical cap portion of the IMC, while ISP2 localizes to a central IMC region and ISP3 localizes to a central plus basal region of the complex. Targeting of all three ISPs is dependent upon N terminal residues predicted for coordinated myristoylation and palmitoylation. Surprisingly, we show that disruption of ISP1 results in a dramatic relocalization of ISP2 and ISP3 to the apical cap. Although the N-terminal region of ISP1 is necessary and sufficient for apical cap targeting, exclusion of other family members requires the remaining C-terminal region of the protein. This gate keeping function of ISP1 reveals an unprecedented mechanism of interactive and hierarchical targeting of proteins to establish these unique sub-compartments in the Toxoplasma IMC. Finally, we show that loss of ISP2 results in severe defects in daughter cell formation during endodyogeny, indicating a role for the ISP proteins in coordinating this unique process of Toxoplasma replication. PMID- 20844582 TI - Ubiquitin/SUMO modification regulates VHL protein stability and nucleocytoplasmic localization. AB - Functional inactivation of the von Hippel-Lindau (VHL) tumor suppressor protein is linked to the development of several forms of cancer as well as oncogenic progression like sporadic renal clear-cell carcinomas (RCC). Despite the critical role played by VHL in destruction of hypoxia-inducible factor alpha (HIFalpha) via ubiquitin-mediated proteolysis, very little is known about the post translational modification which regulates VHL activity. Our previous study showed that the SUMO E3 ligase PIASy interacts with VHL and induces VHL SUMOylation on lysine residue 171 (Cai et al, PLoS ONE, 2010, 5(3):e9720). Here we further report that VHL also undergoes ubiquitylation on both lysine residues 171 and 196, which is blocked by PIASy. Moreover, using a VHL-SUMO1 or ubiquitin fusion protein, we found that ubiquitylated VHL is localized predominantly in the cytoplasm, while SUMOylated VHL results in increased VHL protein stability and nuclear redistribution. Interestingly, substitution of lysine 171 and 196 to arginine of VHL abrogates its inhibitory function on the transcriptional activity of HIFalpha, and tube formation in vitro. This demonstrates that post translational modifications like ubiquitylation and SUMOylation contributes to VHL protein stability and nucleocytoplasmic shuttling, and that the overall function of VHL in tumor suppression may require a precise and dynamically regulated process which involves protein modification. PMID- 20844583 TI - Naturally occurring triggers that induce apoptosis-like programmed cell death in Plasmodium berghei ookinetes. AB - Several protozoan parasites have been shown to undergo a form of programmed cell death that exhibits morphological features associated with metazoan apoptosis. These include the rodent malaria parasite, Plasmodium berghei. Malaria zygotes develop in the mosquito midgut lumen, forming motile ookinetes. Up to 50% of these exhibit phenotypic markers of apoptosis; as do those grown in culture. We hypothesised that naturally occurring signals induce many ookinetes to undergo apoptosis before midgut traversal. To determine whether nitric oxide and reactive oxygen species act as such triggers, ookinetes were cultured with donors of these molecules. Exposure to the nitric oxide donor SNP induced a significant increase in ookinetes with condensed nuclear chromatin, activated caspase-like molecules and translocation of phosphatidylserine that was dose and time related. Results from an assay that detects the potential-dependent accumulation of aggregates of JC-1 in mitochondria suggested that nitric oxide does not operate via loss of mitochondrial membrane potential. L-DOPA (reactive oxygen species donor) also caused apoptosis in a dose and time dependent manner. Removal of white blood cells significantly decreased ookinetes exhibiting a marker of apoptosis in vitro. Inhibition of the activity of nitric oxide synthase in the mosquito midgut epithelium using L-NAME significantly decreased the proportion of apoptotic ookinetes and increased the number of oocysts that developed. Introduction of a nitric oxide donor into the blood meal had no effect on mosquito longevity but did reduce prevalence and intensity of infection. Thus, nitric oxide and reactive oxygen species are triggers of apoptosis in Plasmodium ookinetes. They occur naturally in the mosquito midgut lumen, sourced from infected blood and mosquito tissue. Up regulation of mosquito nitric oxide synthase activity has potential as a transmission blocking strategy. PMID- 20844584 TI - Functional dichotomy between NKG2D and CD28-mediated co-stimulation in human CD8+ T cells. AB - Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC derived naive (CD45RA+CD27+) and memory (CD45RA-CD27+) CD8+ T cells (CD28Hi), while its expression was significantly lower in effector (CD45RA+CD27-) CD8+ T cells (CD28Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2 pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-gamma and TNF-alpha levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-gamma and TNF-alpha production in CD28Hi naive/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naive/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate naive CD8+ T cells would require CD28-mediated co-stimulation. PMID- 20844585 TI - Connexin mediated cataract prevention in mice. AB - Cataracts, named for any opacity in the ocular lens, remain the leading cause of vision loss in the world. Non-surgical methods for cataract prevention are still elusive. We have genetically tested whether enhanced lens gap junction communication, provided by increased alpha3 connexin (Cx46) proteins expressed from alpha8(Kialpha3) knock-in alleles in Gja8tm1(Gja3)Tww mice, could prevent nuclear cataracts caused by the gammaB-crystallin S11R mutation in CrygbS11R/S11R mice. Remarkably, homozygous knock-in alpha8(Kialpha3/Kialpha3) mice fully prevented nuclear cataracts, while single knock-in alpha8(Kialpha3/-) allele mice showed variable suppression of nuclear opacities in CrygbS11R/S11R mutant mice. Cataract prevention was correlated with the suppression of many pathological processes, including crystallin degradation and fiber cell degeneration, as well as preservation of normal calcium levels and stable actin filaments in the lens. This work demonstrates that enhanced intercellular gap junction communication can effectively prevent or delay nuclear cataract formation and suggests that small metabolites transported through gap junction channels protect the stability of crystallin proteins and the cytoskeletal structures in the lens core. Thus, the use of an array of small molecules to promote lens homeostasis may become a feasible non-surgical approach for nuclear cataract prevention in the future. PMID- 20844586 TI - A candidate subspecies discrimination system involving a vomeronasal receptor gene with different alleles fixed in M. m. domesticus and M. m. musculus. AB - Assortative mating, a potentially efficient prezygotic reproductive barrier, may prevent loss of genetic potential by avoiding the production of unfit hybrids (i.e., because of hybrid infertility or hybrid breakdown) that occur at regions of secondary contact between incipient species. In the case of the mouse hybrid zone, where two subspecies of Mus musculus (M. m. domesticus and M. m. musculus) meet and exchange genes to a limited extent, assortative mating requires a means of subspecies recognition. We based the work reported here on the hypothesis that, if there is a pheromone sufficiently diverged between M. m. domesticus and M. m. musculus to mediate subspecies recognition, then that process must also require a specific receptor(s), also sufficiently diverged between the subspecies, to receive the signal and elicit an assortative mating response. We studied the mouse V1R genes, which encode a large family of receptors in the vomeronasal organ (VNO), by screening Perlegen SNP data and identified one, Vmn1r67, with 24 fixed SNP differences most of which (15/24) are nonsynonymous nucleotide substitutions between M. m. domesticus and M. m. musculus. We observed substantial linkage disequilibrium (LD) between Vmn1r67 and Abpa27, a mouse salivary androgen-binding protein gene that encodes a proteinaceous pheromone (ABP) capable of mediating assortative mating, perhaps in conjunction with its bound small lipophilic ligand. The LD we observed is likely a case of association rather than residual physical linkage from a very recent selective sweep, because an intervening gene, Vmn1r71, shows significant intra(sub)specific polymorphism but no inter(sub)specific divergence in its nucleotide sequence. We discuss alternative explanations of these observations, for example that Abpa27 and Vmn1r67 are coevolving as signal and receptor to reinforce subspecies hybridization barriers or that the unusually divergent Vmn1r67 allele was not a product of fast positive selection, but was derived from an introgressed allele, possibly from Mus spretus. PMID- 20844587 TI - The antipsychotic thioridazine shows promising therapeutic activity in a mouse model of multidrug-resistant tuberculosis. AB - Multidrug- and extensively drug-resistant tuberculosis have emerged as grave threats to public health worldwide. Very few active drugs are available or likely to become available soon. To address these problems we revisited a classical observation, the applicability of phenothiazines as antimicrobial drugs. Within this pharmacological class we selected thioridazine, which is most efficacious and least toxic, when used as an antipsychotic drug. We tested thioridazine monotherapy in the Balb/c mouse model for its activity to treat both susceptible and multidrug-resistant tuberculosis by a two months daily oral administration of 32 and 70 mg/kg. In addition, we tested its additive value when combined with a standard first-line regimen for susceptible tuberculosis. Thioridazine treatment resulted in a significant reduction of colony-forming-units of the susceptible ( 4.4 log CFU, p<0.05) and multidrug-resistant tuberculosis bacilli (-2.4 log CFU, p<0.009) in the lung both at one and two months after infection, compared to controls. Moreover, when thioridazine was added to a regimen containing rifampicin, isoniazid and pyrazinamide for susceptible tuberculosis, a significant synergistic effect was achieved (-6.2 vs -5.9 log CFU, p<0.01). Thioridazine may represent an effective compound for treatment of susceptible and multidrug-resistant tuberculosis. The phenothiazines and their targets represent interesting novel opportunities in the search for antituberculosis drugs. PMID- 20844588 TI - Nucleo-cytoplasmic localization domains regulate Kruppel-like factor 6 (KLF6) protein stability and tumor suppressor function. AB - BACKGROUND: The tumor suppressor KLF6 and its oncogenic cytoplasmic splice variant KLF6-SV1 represent a paradigm in cancer biology in that their antagonistic cancer functions are encoded within the same gene. As a consequence of splicing, KLF6-SV1 loses both the C-terminus C2H2 three zinc finger (ZF) domain, which characterizes all KLF proteins, as well as the adjacent 5' basic region (5BR), a putative nuclear localization signal (NLS). It has been hypothesized that this NLS is a functional domain critical to direct the distinct subcellular localization of the tumor suppressor and its splice variant. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate using EGFP fusion constructs that KLF6/KLF6-SV1 nucleo-cytoplasmic transport is not regulated by the 5' basic region but activated by a novel NLS encoded within the ZF domain, and a nuclear export signal (NES) located in the first 16 amino acids of the shared N-terminus sequence. We demonstrate KLF6 nuclear export to be Crm1 dependent. The dysregulation of nucleo-cytoplasmic transport when disrupting the KLF6 NLS using site-directed mutagenesis showed that its integrity is necessary for appropriate protein stability. Moreover, these mutations impaired transcriptional induction of two KLF6 well-characterized target genes, E-cadherin and p21, as shown by RT-PCR and luciferase promoter assays. The addition of the ZF domain to KLF6-SV1 results in its nuclear localization and a markedly decreased half-life similar to wild type KLF6. CONCLUSIONS/SIGNIFICANCE: We describe the domains that control KLF6 nucleo-cytoplasmic shuttling and how these domains play a role in KLF6 protein half-life and tumor suppressor function. The results begin to mechanistically explain, at least in part, the opposing functions of KLF6 and KLF6-SV1 in cancer. PMID- 20844589 TI - High viral fitness during acute HIV-1 infection. AB - Several clinical studies have shown that, relative to disease progression, HIV-1 isolates that are less fit are also less pathogenic. The aim of the present study was to investigate the relationship between viral fitness and control of viral load (VL) in acute and early HIV-1 infection. Samples were obtained from subjects participating in two clinical studies. In the PULSE study, antiretroviral therapy (ART) was initiated before, or no later than six months following seroconversion. Subjects then underwent multiple structured treatment interruptions (STIs). The PHAEDRA study enrolled and monitored a cohort of individuals with documented evidence of primary infection. The subset chosen were individuals identified no later than 12 months following seroconversion to HIV-1, who were not receiving ART. The relative fitness of primary isolates obtained from study participants was investigated ex vivo. Viral DNA production was quantified using a novel real time PCR assay. Following intermittent ART, the fitness of isolates obtained from 5 of 6 PULSE subjects decreased over time. In contrast, in the absence of ART the fitness of paired isolates obtained from 7 of 9 PHAEDRA subjects increased over time. However, viral fitness did not correlate with plasma VL. Most unexpected was the high relative fitness of isolates obtained at Baseline from PULSE subjects, before initiating ART. It is widely thought that the fitness of strains present during the acute phase is low relative to strains present during chronic HIV-1 infection, due to the bottleneck imposed upon transmission. The results of this study provide evidence that the relative fitness of strains present during acute HIV-1 infection may be higher than previously thought. Furthermore, that viral fitness may represent an important clinical parameter to be considered when deciding whether to initiate ART during early HIV-1 infection. PMID- 20844590 TI - Metabolomic analysis in severe childhood pneumonia in the Gambia, West Africa: findings from a pilot study. AB - BACKGROUND: Pneumonia remains the leading cause of death in young children globally and improved diagnostics are needed to better identify cases and reduce case fatality. Metabolomics, a rapidly evolving field aimed at characterizing metabolites in biofluids, has the potential to improve diagnostics in a range of diseases. The objective of this pilot study is to apply metabolomic analysis to childhood pneumonia to explore its potential to improve pneumonia diagnosis in a high-burden setting. METHODOLOGY/PRINCIPAL FINDINGS: Eleven children with World Health Organization (WHO)-defined severe pneumonia of non-homogeneous aetiology were selected in The Gambia, West Africa, along with community controls. Metabolomic analysis of matched plasma and urine samples was undertaken using Ultra Performance Liquid Chromatography (UPLC) coupled to Time-of-Flight Mass Spectrometry (TOFMS). Biomarker extraction was done using SIMCA-P+ and Random Forests (RF). 'Unsupervised' (blinded) data were analyzed by Principal Component Analysis (PCA), while 'supervised' (unblinded) analysis was by Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Projection to Latent Structures (OPLS). Potential markers were extracted from S-plots constructed following analysis with OPLS, and markers were chosen based on their contribution to the variation and correlation within the data set. The dataset was additionally analyzed with the machine-learning algorithm RF in order to address issues of model overfitting and markers were selected based on their variable importance ranking. Unsupervised PCA analysis revealed good separation of pneumonia and control groups, with even clearer separation of the groups with PLS DA and OPLS analysis. Statistically significant differences (p<0.05) between groups were seen with the following metabolites: uric acid, hypoxanthine and glutamic acid were higher in plasma from cases, while L-tryptophan and adenosine 5'-diphosphate (ADP) were lower; uric acid and L-histidine were lower in urine from cases. The key limitation of this study is its small size. CONCLUSIONS/SIGNIFICANCE: Metabolomic analysis clearly distinguished severe pneumonia patients from community controls. The metabolites identified are important for the host response to infection through antioxidant, inflammatory and antimicrobial pathways, and energy metabolism. Larger studies are needed to determine whether these findings are pneumonia-specific and to distinguish organism-specific responses. Metabolomics has considerable potential to improve diagnostics for childhood pneumonia. PMID- 20844591 TI - Does early mismatched nutrition predispose to hypertension and atherosclerosis, in male mice? AB - BACKGROUND: A link between early mismatched nutritional environment and development of components of the metabolic syndrome later in life has been shown in epidemiological and animal data. The aim of this study was to investigate whether an early mismatched nutrition produced by catch-up growth after fetal protein restriction could induce the appearance of hypertension and/or atherosclerosis in adult male mice. METHODOLOGY/PRINCIPAL FINDINGS: Wild-type C57BL6/J or LDLr-/- dams were fed a low protein (LP) or a control (C) diet during gestation. Catch-up growth was induced in LP offspring by feeding dams with a control diet and by culling the litter to 4 pups against 8 in controls. At weaning, male mice were fed either standard chow or an obesogenic diet (OB), leading to 4 experimental groups. Blood pressure (BP) and heart rate (HR) were assessed in conscious unrestrained wild-type mice by telemetry. Atherosclerosis plaque area was measured in aortic root sections of LDLr-/- mice. We found that: (1) postnatal OB diet increased significantly BP (P<0.0001) and HR (P<0.008) in 3 month old OB-C and OB-LP offspring, respectively; (2) that maternal LP diet induced a significant higher BP (P<0.009) and HR (P<0.004) and (3) an altered circadian rhythm in addition to higher plasma corticosterone concentration in 9 months-old LP offspring; (4) that, although LP offspring showed higher plasma total cholesterol than control offspring, atherosclerosis assessed in aortic roots of 6-mo old mice featured increased plaque area due to OB feeding but not due to early mismatched nutrition. CONCLUSIONS/SIGNIFICANCE: These results indicate a long-term effect of early mismatched nutrition on the appearance of hypertension independently of obesity, while no effect on atherosclerosis was noticed at this age. PMID- 20844593 TI - Best linear unbiased prediction of genomic breeding values using a trait-specific marker-derived relationship matrix. AB - BACKGROUND: With the availability of high density whole-genome single nucleotide polymorphism chips, genomic selection has become a promising method to estimate genetic merit with potentially high accuracy for animal, plant and aquaculture species of economic importance. With markers covering the entire genome, genetic merit of genotyped individuals can be predicted directly within the framework of mixed model equations, by using a matrix of relationships among individuals that is derived from the markers. Here we extend that approach by deriving a marker based relationship matrix specifically for the trait of interest. METHODOLOGY/PRINCIPAL FINDINGS: In the framework of mixed model equations, a new best linear unbiased prediction (BLUP) method including a trait-specific relationship matrix (TA) was presented and termed TABLUP. The TA matrix was constructed on the basis of marker genotypes and their weights in relation to the trait of interest. A simulation study with 1,000 individuals as the training population and five successive generations as candidate population was carried out to validate the proposed method. The proposed TABLUP method outperformed the ridge regression BLUP (RRBLUP) and BLUP with realized relationship matrix (GBLUP). It performed slightly worse than BayesB with an accuracy of 0.79 in the standard scenario. CONCLUSIONS/SIGNIFICANCE: The proposed TABLUP method is an improvement of the RRBLUP and GBLUP method. It might be equivalent to the BayesB method but it has additional benefits like the calculation of accuracies for individual breeding values. The results also showed that the TA-matrix performs better in predicting ability than the classical numerator relationship matrix and the realized relationship matrix which are derived solely from pedigree or markers without regard to the trait. This is because the TA-matrix not only accounts for the Mendelian sampling term, but also puts the greater emphasis on those markers that explain more of the genetic variance in the trait. PMID- 20844592 TI - Signs of the 2009 influenza pandemic in the New York-Presbyterian Hospital electronic health records. AB - BACKGROUND: In June of 2009, the World Health Organization declared the first influenza pandemic of the 21(st) century, and by July, New York City's New York Presbyterian Hospital (NYPH) experienced a heavy burden of cases, attributable to a novel strain of the virus (H1N1pdm). METHODS AND RESULTS: We present the signs in the NYPH electronic health records (EHR) that distinguished the 2009 pandemic from previous seasonal influenza outbreaks via various statistical analyses. These signs include (1) an increase in the number of patients diagnosed with influenza, (2) a preponderance of influenza diagnoses outside of the normal flu season, and (3) marked vaccine failure. The NYPH EHR also reveals distinct age distributions of patients affected by seasonal influenza and the pandemic strain, and via available longitudinal data, suggests that the two may be associated with distinct sets of comorbid conditions as well. In particular, we find significantly more pandemic flu patients with diagnoses associated with asthma and underlying lung disease. We further observe that the NYPH EHR is capable of tracking diseases at a resolution as high as particular zip codes in New York City. CONCLUSION: The NYPH EHR permits early detection of pandemic influenza and hypothesis generation via identification of those significantly associated illnesses. As data standards develop and databases expand, EHRs will contribute more and more to disease detection and the discovery of novel disease associations. PMID- 20844594 TI - Tailored graph ensembles as proxies or null models for real networks I: tools for quantifying structure. AB - We study the tailoring of structured random graph ensembles to real networks, with the objective of generating precise and practical mathematical tools for quantifying and comparing network topologies macroscopically, beyond the level of degree statistics. Our family of ensembles can produce graphs with any prescribed degree distribution and any degree-degree correlation function, its control parameters can be calculated fully analytically, and as a result we can calculate (asymptotically) formulae for entropies and complexities, and for information theoretic distances between networks, expressed directly and explicitly in terms of their measured degree distribution and degree correlations. PMID- 20844595 TI - Soluble biomarkers of cartilage and bone metabolism in early proof of concept trials in psoriatic arthritis: effects of adalimumab versus placebo. AB - BACKGROUND: There is growing interest in soluble biomarkers that could be used on the group level for screening purposes in small proof of principle studies during early drug development. We investigated early changes in serum levels of several candidate biomarkers involved in cartilage and bone metabolism following the initiation of adalimumab as a prototypic active treatment in psoriatic arthritis (PsA) compared to placebo. MATERIALS AND METHODS: Twenty-four PsA patients were randomized to receive either adalimumab 40 mg s.c. every other week or placebo for 4 weeks, followed by an open label extension phase. Serum samples were obtained at baseline and after 4 and 12 weeks of treatment and analyzed for levels of CPII and PINP (synthesis of type II and type I procollagen), melanoma inhibitory activity (MIA) (chondrocyte anabolism), matrix metalloproteinase (MMP) 3, C2C and cartilage oligomeric matrix protein (COMP) (type II collagen degradation), osteocalcin (OC) (bone formation), NTX-I and ICTP (both type I collagen degradation). RESULTS: After 4 weeks, there was a significant decrease in serum MMP-3 levels in adalimumab-treated patients (P<0.005), while no change was observed in the placebo group. A significant increase in serum MIA was noted after adalimumab therapy (P<0.005) but not after placebo treatment. After 12 weeks, there was a marked reduction in serum MMP-3 in both groups (P<0.005), whereas other markers did not show significant changes compared to baseline. CONCLUSION: MMP-3 and MIA could serve as soluble biomarkers associated with inflammation as well as joint remodelling and destruction and may, together with clinical evaluation and in combination with other biomarkers, assist in distinguishing between effective and ineffective therapy in small, proof-of principle studies of short duration in PsA. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23328456. PMID- 20844596 TI - AMBIENT DOSE EQUIVALENT VERSUS EFFECTIVE DOSE FOR QUANTIFYING STRAY RADIATION EXPOSURES TO A PATIENT RECEIVING PROTON THERAPY FOR PROSTATE CANCER. AB - The purpose of this study was to evaluate the suitability of the quantity ambient dose equivalent H*(10) as a conservative estimate of effective dose E for estimating stray radiation exposures to patients receiving passively scattered proton radiotherapy for cancer of the prostate. H*(10), which is determined from fluence free-in-air, is potentially useful because it is simpler to measure or calculate because it avoids the complexities associated with phantoms or patient anatomy. However, the suitability of H*(10) as a surrogate for E has not been demonstrated for exposures to high-energy neutrons emanating from radiation treatments with proton beams. The suitability was tested by calculating H*(10) and E for a proton treatment using a Monte Carlo model of a double-scattering treatment machine and a computerized anthropomorphic phantom. The calculated E for the simulated treatment was 5.5 mSv/Gy, while the calculated H*(10) at the isocenter was 10 mSv/Gy. A sensitivity analysis revealed that H*(10) conservatively estimated E for the interval of treatment parameters common in proton therapy for prostate cancer. However, sensitivity analysis of a broader interval of parameters suggested that H*(10) may underestimate E for treatments of other sites, particularly those that require large field sizes. Simulations revealed that while E was predominated by neutrons generated in the nozzle, neutrons produced in the patient contributed up to 40% to dose equivalent in near field organs. PMID- 20844597 TI - Role for PKC delta in Fenretinide-Mediated Apoptosis in Lymphoid Leukemia Cells. AB - The synthetic Vitamin A analog fenretinide is a promising chemotherapeutic agent. In the current paper, the role of PKC delta was examined in fenretinide-induced apoptosis in lymphoid leukemia cells. Levels of proapoptotic cleaved PKC delta positively correlated with drug sensitivity. Fenretinide promoted reactive oxygen species (ROS) generation. The antioxidant Vitamin C prevented fenretinide-induced PKC delta cleavage and protected cells from fenretinide. Suppression of PKC delta expression by shRNA sensitized cells to fenretinide-induced apoptosis possibly by a mechanism involving ROS production. A previous study demonstrated that fenretinide promotes degradation of antiapoptotic MCL-1 in ALL cells via JNK. Now we have found that fenretinide-induced MCL-1 degradation may involve PKC delta as cleavage of the kinase correlated with loss of MCL-1 even in cells when JNK was not activated. These results suggest that PKC delta may play a complex role in fenretinide-induced apoptosis and may be targeted in antileukemia strategies that utilize fenretinide. PMID- 20844598 TI - Overview of Community Collaborative Partnerships and Empirical Findings: The Foundation for Youth HIV Prevention. AB - This article presents a summary history and context of the CHAMP Family Program. Primarily, CHAMP was created and developed in response to rising levels of HIV and AIDS in inner-city communities of color. Concurrently, major changes in the field of psychology were underway during the late 1980s and early 1990s including new perceptions of the effect of culture and context on development; the birth of development psychopathology as a field; and increasing interest in-and recognition of-adolescent psychology. It is within the context of these transformations that this article places the design and implementation of CHAMP. The evolution of the CHAMP Family Program a relatively small, cyclical study in Chicago, to a major, multi-site project is discussed, with particular emphasis on the role of community collaboration in the transitions that CHAMP has experienced thus far. PMID- 20844599 TI - How Can Hydrophobic Association Be Enthalpy Driven? AB - Hydrophobic association is often recognized as being driven by favorable entropic contributions. Here, using explicit solvent molecular dynamics simulations we investigate binding in a model hydrophobic receptor-ligand system which appears, instead, to be driven by enthalpy and opposed by entropy. We use the temperature dependence of the potential of mean force to analyze the thermodynamic contributions along the association coordinate. Relating such contributions to the ongoing changes in system hydration allows us to demonstrate that the overall binding thermodynamics is determined by the expulsion of disorganized water from the receptor cavity. Our model study sheds light on the solvent-induced driving forces for receptor-ligand association of general, transferable relevance for biological systems with poorly hydrated binding sites. PMID- 20844600 TI - Detection of Neural Action Potentials Using Optical Coherence Tomography: Intensity and Phase Measurements with and without Dyes. AB - We review the use of optical coherence tomography (OCT) for detection of neural activity, and present a new approach for depth-localization of neural action potentials (APs) using voltage-sensitive dyes as contrast agents in OCT. A stained squid giant axon is imaged by spectral-domain OCT. Changes in the intensity and phase of back-scattered light coming from regions around the membrane are measured during AP propagation. The depth-resolved change in back scattered intensity coincides with the arrival of AP at the measurement area, and is synchronous with the changes in transmitted light intensity and reflection mode cross-polarized light intensity measured independently. The system also provides depth-resolved phase changes as an additional indication of activity. With further investigation our results could open a new era in functional imaging technology to localize neural activity at different depths in situ. PMID- 20844601 TI - Glutamatergic mechanisms for speed control and network operation in the rodent locomotor CpG. AB - Locomotion is a fundamental motor act that, to a large degree, is controlled by central pattern-generating (CPG) networks in the spinal cord. Glutamate is thought to be responsible for most of the excitatory input to and the excitatory activity within the locomotor CPG. However, previous studies in mammals have produced conflicting results regarding the necessity and role of the different ionotropic glutamate receptors (GluRs) in the CPG function. Here, we use electrophysiological and pharmacological techniques in the in vitro neonatal mouse lumbar spinal cord to investigate the role of a broad range of ionotropic GluRs in the control of locomotor speed and intrinsic locomotor network function. We show that non-NMDA (non-NMDARs) and NMDA receptor (NMDAR) systems may independently mediate locomotor-like activity and that these receptors set different speeds of locomotor-like activity through mechanisms acting at various network levels. AMPA and kainate receptors are necessary for generating the highest locomotor frequencies. For coordination, NMDARs are more important than non-NMDARs for conveying the rhythmic signal from the network to the motor neurons during long-lasting and steady locomotor activity. This study reveals that a diversity of ionotropic GluRs tunes the network to perform at different locomotor speeds and provides multiple levels for potential regulation and plasticity. PMID- 20844602 TI - Linear superposition of sensory-evoked and ongoing cortical hemodynamics. AB - Modern non-invasive brain imaging techniques utilize changes in cerebral blood flow, volume and oxygenation that accompany brain activation. However, stimulus evoked hemodynamic responses display considerable inter-trial variability even when identical stimuli are presented and the sources of this variability are poorly understood. One of the sources of this response variation could be ongoing spontaneous hemodynamic fluctuations. To investigate this issue, 2-dimensional optical imaging spectroscopy was used to measure cortical hemodynamics in response to sensory stimuli in anesthetized rodents. Pre-stimulus cortical hemodynamics displayed spontaneous periodic fluctuations and as such, data from individual stimulus presentation trials were assigned to one of four groups depending on the phase angle of pre-stimulus hemodynamic fluctuations and averaged. This analysis revealed that sensory evoked cortical hemodynamics displayed distinctive response characteristics and magnitudes depending on the phase angle of ongoing fluctuations at stimulus onset. To investigate the origin of this phenomenon, "null-trials" were collected without stimulus presentation. Subtraction of phase averaged "null trials" from their phase averaged stimulus evoked counterparts resulted in four similar time series that resembled the mean stimulus-evoked response. These analyses suggest that linear superposition of evoked and ongoing cortical hemodynamic changes may be a property of the structure of inter-trial variability. PMID- 20844603 TI - Adolescent resting state networks and their associations with schizotypal trait expression. AB - The rising interest in temporally coherent brain networks during baseline adult cerebral activity finds convergent evidence for an identifiable set of resting state networks (RSNs). To date, little is know concerning the earlier developmental stages of functional connectivity in RSNs. This study's main objective is to characterize the RSNs in a sample of adolescents. We further examine our data from a developmental psychopathology perspective of psychosis proneness, by testing the hypothesis that early schizotypal symptoms are linked to disconnection in RSNs. In this perspective, this study examines the expression of adolescent schizotypal traits and their potential associations to dysfunctional RSNs. Thirty-nine adolescents aged between 12 and 20 years old underwent an 8-min functional magnetic resonance imaging (fMRI) "resting state" session. In order to explore schizotypal trait manifestations, the entire population was assessed by the Schizotypal Personality Questionnaire (SPQ). After conventional processing of the fMRI data, we applied group-level independent component analysis (ICA). Twenty ICA maps and associated time courses were obtained, among which there were RSNs that are consistent with findings in the literature. We applied a regression analysis at group level between the energy of RSN-associated time courses in different temporal frequency bins and the clinical measures (3 in total). Our results highlight the engagement of six relevant RSNs; (1) a default-mode network (DMN); (2) a dorso-lateral attention network; (3) a visual network (VN); (4) an auditory network (AN); (5) a sensory motor network (SMN); (6) a self-referential network (SRN). The regression analysis reveals a statistically significant correlation between the clinical measures and some of the RSNs, specifically the visual and the AN. In particular, a positive correlation is obtained for the VN in the low frequency range (0.05 Hz) with SPQ measures, while the AN correlates negatively in the high frequency range (0.16 0.19 Hz). Trend-like significance for the SRN may hint to its implication in disorganized thoughts and behaviors during adolescence. Unlike DMN activity in schizophrenic patients, adolescent DMN was unrelated to schizotypal trait expression. This suggests that relationships between the DMN and schizotypy may be modified in later developmental stages of both functional connectivity and psychotic expression. These results are discussed in light of RSNs literature involving children, adults, and individuals with schizophrenia. PMID- 20844604 TI - Deficits in analogical reasoning in adolescents with traumatic brain injury. AB - Individuals with traumatic brain injury (TBI) exhibit deficits in executive control, which may impact their reasoning abilities. Analogical reasoning requires working memory and inhibitory abilities. In this study, we tested adolescents with moderate to severe TBI and typically developing (TD) controls on a set of picture analogy problems. Three factors were varied: complexity (number of relations in the problems), distraction (distractor item present or absent), and animacy (living or non-living items in the problems). We found that TD adolescents performed significantly better overall than TBI adolescents. There was also an age effect present in the TBI group where older participants performed better than younger ones. This age effect was not observed in the TD group. Performance was affected by complexity and distraction. Further, TBI participants exhibited lower performance with distractors present than TD participants. The reasoning deficits exhibited by the TBI participants were correlated with measures of executive function that required working memory updating, attention, and attentional screening. Using MRI-derived measures of cortical thickness, correlations were carried out between task accuracy and cortical thickness. The TD adolescents showed negative correlations between thickness and task accuracy in frontal and temporal regions consistent with cortical maturation in these regions. This study demonstrates that adolescent TBI results in impairments in analogical reasoning ability. Further, TBI youth have difficulty effectively screening out distraction, which may lead to failures in comprehension of the relations among items in visual scenes. Lastly, TBI youth fail to show robust cortical-behavior correlations as observed in TD individuals. PMID- 20844605 TI - Hierarchy and dynamics of neural networks. PMID- 20844607 TI - Contemporary Proton Therapy Systems Adequately Protect Patients from Exposure to Stray Radiation. AB - Proton beam therapy has provided safe and effective treatments for a variety of adult cancers. In recent years, there has been increasing interest in utilizing proton therapy for pediatric cancers because it allows better sparing of healthy tissues. Minimizing exposures of normal tissues is especially important in children because they are highly susceptible to consequential late effects, including the development of a radiogenic second cancer, which may occur years or even decades after treatment of the first cancer. While the dosimetric advantage of therapeutic proton beams is well understood, relatively little attention has been paid to the whole-body exposure to stray neutron radiation that is inherent in proton therapy. In this report, we review the physical processes that lead to neutron exposures, discuss the potential for mitigating these exposures using advanced proton beam delivery systems, and present a comparative analysis of predicted second cancer incidence following various external beam therapies. In addition, we discuss uncertainties in the relative biological effectiveness of neutrons for carcinogenesis and the impact that these uncertainties have on second-cancer risk predictions for survivors of adult and childhood cancer who receive proton therapy. PMID- 20844606 TI - The Benefits of Calorie Restriction and Calorie Restriction Mimetics as Related to the Eye. AB - The effects of calorie restriction without malnutrition seem to possess many beneficial effects in numerous disease states. Recently, studies related to calorie restriction mimetics that biochemically mimic the effects of calorie restriction are also becoming increasingly popular. Both calorie restriction and calorie restriction mimetics trigger an adaptive response reminiscent of mild stress or low-dose toxic response, which is frequently referred to as hormesis in the toxicology literature. Although some benefits of calorie restriction and calorie restriction mimetics have been studied, the role of hormesis-related pathways in the eye has not been given a special attention. This review will present the current literature on calorie restriction and calorie restriction mimetics as related to most prominent eye diseases and provide insights on the therapeutic role of hormesis in eye diseases. PMID- 20844608 TI - Undergraduate medical research: the student perspective. AB - BACKGROUND: Research training is essential in a modern undergraduate medical curriculum. Our evaluation aimed to (a) gauge students' awareness of research activities, (b) compare students' perceptions of their transferable and research specific skills competencies, (c) determine students' motivation for research and (d) obtain students' personal views on doing research. METHODS: Undergraduate medical students (N = 317) completed a research skills questionnaire developed by the Centre for Excellence in Teaching and Learning in Applied Undergraduate Research Skills (CETL-AURS) at Reading University. The questionnaire assessed students' transferable skills, research-specific skills (e.g., study design, data collection and data analysis), research experience and attitude and motivation towards doing research. RESULTS: The majority of students are motivated to pursue research. Graduate entrants and male students appear to be the most confident regarding their research skills competencies. Although all students recognise the role of research in medical practice, many are unaware of the medical research activities or successes within their university. Of those who report no interest in a career incorporating research, a common perception was that researchers are isolated from patients and clinical practice. DISCUSSION: Students have a narrow definition of research and what it entails. An explanation for why research competence does not align more closely with research motivation is derived from students' lack of understanding of the concept of translational research, as well as a lack of awareness of the research activity being undertaken by their teachers and mentors. We plan to address this with specific research awareness initiatives. PMID- 20844609 TI - Dendritic cell-specific antigen delivery by coronavirus vaccine vectors induces long-lasting protective antiviral and antitumor immunity. AB - Efficient vaccination against infectious agents and tumors depends on specific antigen targeting to dendritic cells (DCs). We report here that biosafe coronavirus-based vaccine vectors facilitate delivery of multiple antigens and immunostimulatory cytokines to professional antigen-presenting cells in vitro and in vivo. Vaccine vectors based on heavily attenuated murine coronavirus genomes were generated to express epitopes from the lymphocytic choriomeningitis virus glycoprotein, or human Melan-A, in combination with the immunostimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). These vectors selectively targeted DCs in vitro and in vivo resulting in vector-mediated antigen expression and efficient maturation of DCs. Single application of only low vector doses elicited strong and long-lasting cytotoxic T-cell responses, providing protective antiviral and antitumor immunity. Furthermore, human DCs transduced with Melan-A-recombinant human coronavirus 229E efficiently activated tumor-specific CD8(+) T cells. Taken together, this novel vaccine platform is well suited to deliver antigens and immunostimulatory cytokines to DCs and to initiate and maintain protective immunity. PMID- 20844610 TI - Prostacyclin therapy for pulmonary arterial hypertension. AB - In pulmonary arterial hypertension, the blood vessels that carry blood between the heart and lungs are constricted, making it difficult for the heart to pump blood through the lungs. Prostacyclin, a prostanoid metabolized from endogenous arachidonic acid through the cyclooxygenase (COX) pathway, is a potent vasodilator that has been identified as one of the most effective drugs for the treatment of pulmonary arterial hypertension. Currently, prostacyclin and its analogues are widely used in the clinical management of pulmonary arterial hypertension patients. However, the mortality rate associated with pulmonary arterial hypertension has not been significantly reduced within the past 5 years. More powerful therapeutic approaches are needed. This article briefly reviews the current management of pulmonary arterial hypertension to identify the problems associated with present therapies; then it focuses on the emerging technology of prostacyclin synthase gene therapy and cell-based therapy using native stem cells and engineered stem cells with enhanced prostacyclin production capacity. By using the recent advances in technology and the molecular understanding of prostacyclin synthesis, researchers are prepared to make significant advances in the treatment of pulmonary arterial hypertension. PMID- 20844611 TI - Comparison of antimicrobial agents as therapy for experimental endocarditis: caused by methicillin-resistant Staphylococcus aureus. AB - We used an experimental rat model to compare the therapeutic efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin with that of vancomycin as standard therapy for infective endocarditis.Aortic endocarditis was induced in rats by insertion of a polyethylene catheter into the left ventricle, followed by intravenous inoculation of 106 colony-forming units of methicillin-resistant Staphylococcus aureus 24 hours later. Forty-eight hours after bacterial challenge, intravenous antibiotic therapies were initiated. There were 6 groups of 8 rats each: uninfected control; infected, untreated control; vancomycin treated (40 mg/kg twice daily); teicoplanin-treated (20 mg/kg twice daily after a loading dose of 40 mg/kg); linezolid-treated (75 mg/kg 3 times daily for 1 day, then 75 mg/kg twice daily); and quinupristin/dalfopristin-treated (30 mg/kg twice daily and an additional 10 mg/kg dalfopristin infusion over 6 to 12 hr daily). At the end of therapy, the aortic valve vegetations in the drug-treated rats were evaluated microbiologically.Compared with the infected, untreated group, all drug treated groups had significantly reduced bacterial titers in the vegetations. Vancomycin, teicoplanin, and quinupristin/dalfopristin all effectively reduced the quantitative bacterial cultures of aortic valve vegetations. In addition, there was no significant difference in the comparative efficacy of teicoplanin, linezolid, and quinupristin/dalfopristin. Vancomycin significantly reduced bacterial counts in comparison with linezolid, which was nonetheless also effective.Our experimental model showed that each of the investigated antimicrobial agents was effective in the treatment of infective endocarditis. PMID- 20844612 TI - Epsilon waves detected by various electrocardiographic recording methods: in patients with arrhythmogenic right ventricular cardiomyopathy. AB - We analyzed the shape and distribution of epsilon waves by 3 various methods of electrocardiographic recording in patients with arrhythmogenic right ventricular cardiomyopathy.Thirty-two patients who met recognized diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy were included in this study (24 men and 8 women; mean age, 42.3 +/- 12.9 yr). Epsilon waves were detected by standard 12-lead electrocardiography (S-ECG), right-sided precordial lead electrocardiography (R-ECG), and Fontaine bipolar precordial lead electrocardiography (F-ECG). We found 3 types of epsilon waves: wiggle waves, small spike waves, and smooth potential waves that formed an atypical prolonged R' wave. The most common configuration was small spiked waves. In some circumstances, epsilon waves were evident in some leads (especially in leads V(1) through V(3)), but notches were recorded in the other leads during the corresponding phase. These waves could be detected only by S-ECG in 1 patient, R ECG in 3 patients, and F-ECG in 5 patients; the rates of epsilon-wave detection by these 3 methods were 38% (12/32), 38% (12/32), and 50% (16/32), respectively. However, the detection rate using combined methods was significantly higher than that by S-ECG alone (SF-ECG 56% vs S-ECG 38%, P = 0.0312; and SRF-ECG 66% vs S ECG 38%, P = 0.0039). In addition, the rate of widespread T-wave inversion (exceeding V(3)) was significantly higher in patients with epsilon waves than in those without (48% vs 9%, P = 0.029), as was ventricular tachycardia (95% vs 64%, P = 0.019).These 3 electrocardiographic recording methods should be used in combination to improve the detection rate of epsilon waves. PMID- 20844614 TI - Statins do not decrease small, dense low-density lipoprotein. AB - In an observational study, we examined the effect of statins on low-density lipoprotein (LDL) subfractions.Using density-gradient ultracentrifugation, we measured small, dense LDL density in 612 patients (mean age, 61.7 +/- 12.6 yr), some with and some without coronary artery disease, who were placed in a statin treated group (n=172) or a control group (n=440) and subdivided on the basis of coronary artery disease status.Total cholesterol, LDL cholesterol, apolipoprotein B, and the LDL cholesterol/apolipoprotein B ratio were significantly lower in the statin group. However, the proportion of small, dense LDL was higher in the statin group (42.9% +/- 9.5% vs 41.3% +/- 8.5%; P=0.046) and the proportion of large, buoyant LDL was lower (23.6% +/- 7.5% vs 25.4% +/- 7.9%; P=0.011). In the statin group, persons without coronary artery disease had higher proportions of small, dense LDL, and persons with coronary artery disease tended to have higher proportions of small, dense LDL.Our study suggests that statin therapy--whether or not recipients have coronary artery disease--does not decrease the proportion of small, dense LDL among total LDL particles, but in fact increases it, while predictably reducing total LDL cholesterol, absolute amounts of small, dense LDL, and absolute amounts of large, buoyant LDL. If and when our observation proves to be reproducible in subsequent large-scale studies, it should provide new insights into small, dense LDL and its actual role in atherogenesis or the progression of atherosclerosis. PMID- 20844613 TI - LateTIME: a phase-II, randomized, double-blinded, placebo-controlled, pilot trial evaluating the safety and effect of administration of bone marrow mononuclear cells 2 to 3 weeks after acute myocardial infarction. AB - A realistic goal for cardiac cell therapy may be to attenuate left ventricular remodeling following acute myocardial infarction to prevent the development of congestive heart failure. Initial clinical trials of cell therapy have delivered cells 1 to 7 days after acute myocardial infarction. However, many patients at risk of developing congestive heart failure may not be ready for cell delivery at that time-point because of clinical instability or hospitalization at facilities without access to cell therapy. Experience with cell delivery 2 to 3 weeks after acute myocardial infarction has not to date been explored in a clinical trial. The objective of the LateTIME study is to evaluate by cardiac magnetic resonance the effect on global and regional left ventricular function, between baseline and 6 months, of a single intracoronary infusion of 150 * 106 autologous bone marrow mononuclear cells (compared with placebo) when that infusion is administered 2 to 3 weeks after moderate-to-large acute myocardial infarction. The 5 clinical sites of the Cardiovascular Cell Therapy Research Network (CCTRN) will enroll a total of 87 eligible patients in a 2:1 bone marrow mononuclear cells-to-placebo patient ratio; these 87 will have undergone successful percutaneous coronary intervention of a major coronary artery and have left ventricular ejection fractions <=0.45 by echocardiography. When the results become available, this study should provide insight into the clinical feasibility and appropriate timing of autologous cell therapy in high-risk patients after acute myocardial infarction and percutaneous coronary intervention. PMID- 20844615 TI - Surgical management of pulmonary hydatid cysts: is size an important prognostic indicator? AB - Giant hydatid cysts of the lung (diameter, >=10 cm) are considered more difficult to treat surgically than are smaller cysts. We reviewed our experience with giant pulmonary hydatid cysts, focusing on clinical symptoms, cystic location, extent of surgery, and postoperative complications, according to age, long-term results, and comparison with non-giant cysts. From January 1988 to January 2008, 537 patients underwent surgery for pulmonary hydatid cysts. We separated patients into 2 groups: patients who had cysts <10 cm (group A) and those who had giant cysts (group B). Group B comprised 75 patients (14%). Giant cysts were more common in younger patients (mean age, 30 vs 32 yr; P=0.014). The most frequent complaints were cough, chest pain, and dyspnea. Patients with giant cysts were more often symptomatic at presentation (96% vs 88%; P=0.04). In both groups, lower-lobe locations predominated. Parenchyma-saving operations were almost uniformly performed for each group; however, a higher percentage of patients in group B required anatomic resection (4% vs 1%; P=0.038). Fifty-seven patients (10%) also underwent resection of concomitant liver cysts. Cystic rupture occurred more frequently in group B than in group A (27% vs 15%; P=0.01). There were no deaths in either group, nor were there significant differences in morbidity between groups.In summary, giant hydatid cysts of the lung occurred more often in younger patients and were more often symptomatic at presentation. Regardless of size, the cysts could usually be surgically treated without lung resection, and size did not appear to influence short-term perioperative outcomes. PMID- 20844616 TI - Intracorporeal knot-tying for the thoracoscopic surgeon: a novel and simplified technique. AB - Thoracoscopic surgery has usually been limited by 2-dimensional vision and the limited space between ribs--problems that have been only partially overcome by the use of robotics. One of the technical challenges of any minimally invasive surgical approach is tying an intracorporeal knot. For the thoracoscopic surgeon, we describe an easier technique of knot-tying that involves using a right-angled dissector. The technique enables ambidextrous performance and is particularly useful for ligating major pulmonary vessels that might be too small to be stapled or too confined for the admission and maneuvering of a stapling device. Rotating the thumb-dials accordingly enables one to vary the configuration of the knots to create slip or reef knots.The technique is easy to learn and does not require any complicated devices. It is easily adapted to create even more complex constructs, such as a double surgeon's knot. This technique has special advantages in areas of limited domain and in situations that require very narrow angles of instrument manipulation, particularly in thoracoscopic-assisted procedures. PMID- 20844617 TI - On redefining hypertension. PMID- 20844618 TI - Left ventricle on top versus right ventricle on top in superoinferior ventricles: what are we talking about? PMID- 20844619 TI - Superior left ventricle in combination with inferior right ventricle: presenting with balanced hemodynamics and mild symptoms in a late adolescent. AB - We describe a case of superoinferior ventricles with an unusual superior location of the left ventricle and inferior location of the right ventricle. The patient was a 17-year-old boy who had been admitted for paroxysmal supraventricular tachycardia with pre-excitation syndrome. The cardiac anomaly was first recognized after admission, and the pre-excitation syndrome, eventually, was treated successfully by radiofrequency catheter ablation. This case featured a segmental set notation {S, D, S} with concordant atrioventricular and ventriculoarterial alignments. Persistent left superior vena cava was the only associated defect. To the best of our knowledge, there has been only 1 other reported case of superoinferior ventricles in which the left ventricle was in the superior position. In our case, the patient's hemodynamics were sufficiently normal that he had reached adolescence with only minor adverse events. PMID- 20844621 TI - Alternative approach for aortic valve replacement: in mediastinal deviation after right lobectomy. AB - A 71-year-old man on hemodialysis and with a history of right lobectomy was referred for aortic valve replacement. Chest computed tomography revealed counterclockwise rotation of the heart through its longitudinal axis.We approached the aortic valve through median sternotomy. Accordingly, we transected the sternum at the level of the 3rd intercostal space and extended the skin incision approximately 2 inches perpendicular to the midline. After partial transection of the sternum, 3 spreaders were placed: the 1st, in the upper sternum; the 2nd, in the lower sternum; and the 3rd, between the ribs. These devices yielded excellent exposure of the ascending aorta. In addition, the relatively central shift of the ascending aorta contributed to the exposure of the right atrium and the right upper pulmonary vein. Subsequently, aortic valve replacement was performed in the usual fashion, and the patient experienced no postoperative respiratory complications. Aortic valve surgery with T-shaped sternotomy and without thoracotomy is an alternative technique in a patient who has a secondary deviation after lobectomy. PMID- 20844620 TI - Covered-stent treatment of coronary aneurysm after drug-eluting stent placement: case report and literature review. AB - Most commonly, coronary artery aneurysms are secondary to atherosclerosis, but cases have been reported in patients who have vasculitis or tissue disorders, and in patients who have undergone interventional procedures. However, over the past few years, an increasing number of cases of coronary artery aneurysms after drug eluting stent implantation have been reported. The exact mechanism is unknown. Experimental animal studies have shown that both the active drug and the polymer coating, under certain circumstances, might cause progressive luminal dilation, positive vascular remodeling, and aneurysmal formation. Complications like rupture, thrombosis, embolization, myocardial infarction, and even sudden death have been reported. Treatment options vary from aggressive surgical ligation of the aneurysm, in union with distal bypass surgery, to percutaneous implantation of a covered stent or conservative medical management with continued antiplatelet therapy. Currently, there is no consensus on an ideal approach to treating coronary artery aneurysm after drug-eluting stent implantation. Polytetrafluoroethylene-covered stents, easy and rapid to deploy, have emerged as a newer option. We report a case of coronary artery aneurysm at the site of a previous drug-eluting stent. The lesion was successfully treated with a polytetrafluoroethylene-covered stent. PMID- 20844622 TI - Left ventricular rupture due to HIV-associated T-cell lymphoma. AB - Patients with lymphoma can develop cardiac involvement that includes malignant pericardial effusions and myocardial infiltration, but extensive myocardial invasion by tumor with resultant rupture has been reported only rarely. We report a case of a patient with human immunodeficiency virus and T-cell lymphoma who presented with signs and symptoms that were suggestive of a non-ST-elevation myocardial infarction. Plans were made for cardiac catheterization, but the patient developed thrombocytopenia after the initiation of heparin and eptifibatide. Cardiac catheterization was deferred, and shortly afterwards he had a witnessed cardiac arrest in the hospital and could not be resuscitated. Autopsy revealed transmural infiltration of the myocardium with lymphoma and resultant rupture of the left ventricular free wall. To our knowledge, this is the 1st reported case of left ventricular free-wall rupture due to transmural infiltration by human-immunodeficiency-virus-associated peripheral T-cell lymphoma.We conclude that noncoronary causes of chest pain, including direct myocardial infiltration, should be considered in immunocompromised patients with lymphoma. PMID- 20844623 TI - Percutaneous closure of mitral paravalvular leak via retrograde approach: with use of the Amplatzer duct occluder II and without a wire loop. AB - The gold-standard treatment for prosthetic-valve paravalvular leakage is surgery to repair or replace the valve; however, the morbidity and mortality rates cannot be ignored, and some patients are poor surgical candidates. The percutaneous closure of such defects is possible, and different devices are being used for this purpose. In almost all instances, a femorofemoral or femorojugular wire loop is constructed to deliver the closure device. Herein, we present the case of a 61 year-old man in whom a mitral paravalvular leak was successfully closed with use of the Amplatzer Duct Occluder II, via retrograde approach under 3-dimensional transesophageal echocardiographic guidance, without the use of a wire loop. To the best of our knowledge, this is the 1st report of retrograde device deployment without the construction of an arteriovenous wire loop, and the 1st case in which the Amplatzer Duct Occluder II was used for the percutaneous closure of a mitral paravalvular leak. PMID- 20844624 TI - Coronary ostial stenosis after aortic valve replacement: successful treatment of 2 patients with drug-eluting stents. AB - Coronary ostial stenosis is a rare but potentially serious sequela after aortic valve replacement. It occurs in the left main or right coronary artery after 1% to 5% of aortic valve replacement procedures. The clinical symptoms are usually severe and may appear from 1 to 6 months postoperatively. Although the typical treatment is coronary artery bypass grafting, patients have been successfully treated by means of percutaneous coronary intervention.Herein, we present the cases of 2 patients in whom coronary ostial stenosis developed after aortic valve replacement. In the 1st case, a 72-year-old man underwent aortic valve replacement and bypass grafting of the saphenous vein to the left anterior descending coronary artery. Six months later, he experienced a non-ST-segment elevation myocardial infarction. Coronary angiography revealed a critical stenosis of the right coronary artery ostium. In the 2nd case, a 78-year-old woman underwent aortic valve replacement and grafting of the saphenous vein to an occluded right coronary artery. Four months later, she experienced unstable angina. Coronary angiography showed a critical left main coronary artery ostial stenosis and occlusion of the right coronary artery venous graft. In each patient, we performed percutaneous coronary intervention and deployed a drug eluting stent. Both patients were asymptomatic on 6-to 12-month follow-up. We attribute the coronary ostial stenosis to the selective ostial administration of cardioplegic solution during surgery. We conclude that retrograde administration of cardioplegic solution through the coronary sinus may reduce the incidence of postoperative coronary ostial stenosis, and that stenting may be an efficient treatment option. PMID- 20844625 TI - Coronary artery spasm during angiography in a pediatric heart transplant recipient: subsequent prevention by intracoronary nitroglycerin administration. AB - Coronary artery spasm can occur during coronary angiography in pediatric heart transplant recipients. The angiographic appearance can suggest allograft vasculopathy. We report coronary artery spasm in a pediatric heart transplant recipient in whom intracoronary nitroglycerin administration prevented a repetition of spasm upon subsequent diagnostic coronary angiography. Additional studies of dose response, particularly in cardiac transplant recipients, may help determine whether lower doses of intracoronary nitrates, such as that administered to our patient, can be effective in preventing coronary artery vasospasm in pediatric heart transplant recipients. PMID- 20844626 TI - Monophasic synovial sarcoma presenting as mitral valve obstruction. AB - We report the case of a 26-year-old man who experienced progressive left-sided chest pain and 2 episodes of near-syncope. Studies revealed a 15-cm mass in the upper left lung, a 10-cm mass in the medial base of the left lung, and a 5-cm left atrial mass that involved the left lung, infiltrated the left pulmonary vein, and prolapsed into the mitral valve, causing intermittent obstruction. The patient underwent surgical excision of the left atrial tumor. Pathologic evaluation confirmed the diagnosis of monophasic synovial sarcoma.To our knowledge, this is only the 3rd report of left atrial invasion and resultant mitral valve obstruction from a synovial sarcoma that infiltrated the pulmonary vein. We believe that this is the 1st documented case of a metastatic left atrial synovial sarcoma in monophasic form. PMID- 20844627 TI - Syncope, widened QRS interval, and left ventricular systolic depression: coincident with propafenone therapy for atrial fibrillation. AB - We report the case of a 46-year-old man who developed syncope, a widened QRS interval, and depressed left ventricular systolic function during propafenone therapy for atrial fibrillation. These acute findings may have been consequent to an increased dosage of propafenone combined with heavy alcohol consumption that led to decreased metabolism of propafenone. In addition, propafenone is known to interfere with liver function, although this patient's test results showed scant evidence of liver abnormalities. Yet another possible factor is the genetic spectrum in the metabolism of propafenone and other class I antiarrhythmic agents. When propafenone is prescribed, we recommend advising patients that alcohol consumption and interactions with other drugs can lead to increased levels of the antiarrhythmic agent, with resultant toxicity that can lead to adverse cardiovascular effects. Patients taking propafenone should also undergo periodic liver function testing. Finally, attention should be paid to voluntary or official recalls of specific antiarrhythmic medications that are of unreliable quality or potency. PMID- 20844628 TI - Aorta-right atrial tunnel. AB - Aorta-right atrial tunnel is a vascular channel that originates from one of the sinuses of Valsalva and terminates in either the superior vena cava or the right atrium. The tunnel is classified as anterior or posterior, depending upon its course in relation to the ascending aorta. An origin above the sinotubular ridge differentiates the tunnel from an aneurysm of the sinus of Valsalva, and the absence of myocardial branches differentiates it from a coronary-cameral fistula. Clinical presentation ranges from an asymptomatic precordial murmur to congestive heart failure. The embryologic background and pathogenesis of this lesion are attributable either to an aneurysmal dilation of the sinus nodal artery or to a congenital weakness of the aortic media. In either circumstance, progressive enlargement of the tunnel and ultimate rupture into the low-pressure right atrium could occur under the influence of the systemic pressure.The lesion is diagnosed by use of 2-dimensional echocardiography and cardiac catheterization. Computed tomographic angiography is an additional noninvasive diagnostic tool. The possibility of complications necessitates early therapy, even in asymptomatic patients or those with a hemodynamically insignificant shunt. Available treatments are catheter-based intervention, external ligation under controlled hypotension, or surgical closure with the patient under cardiopulmonary bypass.Herein, we discuss the cases of 2 patients who had this unusual anomaly. We highlight the outcome on follow-up imaging (patient 1) and the identification and safe reimplantation of the coronary artery (patient 2). PMID- 20844629 TI - Reversion of left ventricular systolic dysfunction and abnormal stress test: by catheter ablation, in a patient with Wolff-Parkinson-White syndrome from Para Hisian Kent bundle. AB - The diagnosis of Wolff-Parkinson-White syndrome is typically reserved for patients who experience ventricular pre-excitation and symptoms that are related to paroxysmal supraventricular tachycardia, such as chest pain, dyspnea, dizziness, palpitations, or syncope. Herein, we report the case of a 38-year-old woman who presented at our outpatient department because of exercise intolerance. Cardiac auscultation revealed a grade 2/6 pansystolic murmur over the left lower sternal border. Twelve-lead electrocardiography showed sinus rhythm at a rate of 76 beats/min, with a significant delta wave. Transthoracic echocardiography revealed abnormal left ventricular systolic function. The results of a thallium stress test were also abnormal. Coronary artery disease was suspected; however, coronary angiography yielded normal results. Electrophysiologic study revealed a para-Hisian Kent bundle and a dual atrioventricular nodal pathway. After radiofrequency catheter ablation was performed, the patient's left ventricular function improved and her symptoms disappeared. In Wolff-Parkinson-White syndrome, left ventricular systolic dyssynchrony can yield abnormal findings on echocardiography and thallium scanning--even in persons who have no cardiovascular risk factors. Physicians who are armed with this knowledge can avoid performing coronary angiography unnecessarily. Catheter ablation can reverse the dyssynchrony of the ventricle and improve the patient's symptoms. PMID- 20844630 TI - Resection of intercostal hemangioma with involved chest wall and ribs: in an 11 year-old girl. AB - We report a case of an 11-year-old girl who presented with a slowly enlarging mass in the right posterolateral chest wall. Computed tomography showed a soft tissue mass 8.5 * 7.5 * 5.5 cm in size, arising from the right posterolateral 9th, 10th, and 11th intercostal spaces. Magnetic resonance imaging confirmed a vascular mass. The patient underwent complete resection of the tumor, together with the right 8th, 9th, 10th, 11th, and 12th ribs and their intercostal muscles. Reconstruction of the chest wall was performed with methyl methacrylate and Marlex mesh. Histopathologic examination of the tumor confirmed an intercostal cavernous hemangioma. At last examination, 6 months after the operation, the child was doing well, with no evidence of recurrence. PMID- 20844631 TI - Single coronary artery originating from the right coronary sinus. PMID- 20844633 TI - Functional pulmonary atresia: in a critically ill premature infant. PMID- 20844632 TI - Diffuse large B-cell lymphoma in an aortic valve allograft. PMID- 20844634 TI - Intravascular ultrasound guidance in treating May-Thurner syndrome. PMID- 20844635 TI - Acute massive pulmonary embolism after radiofrequency catheter ablation: a rare but devastating complication. PMID- 20844636 TI - Fulminant Coxsackie B myocarditis mimicking acute coronary artery occlusion. PMID- 20844638 TI - Biventricular repair of right atrial isomerism with complex congenital anomalies. PMID- 20844640 TI - Isolated cleft of the mitral valve: its pathogenic relationship with endocardial cushion defects. PMID- 20844641 TI - Public mental health: An evolving imperative. PMID- 20844642 TI - A biomedical educational intervention to change explanatory models of psychosis among community health workers in South India. AB - BACKGROUND: Community health workers in developing countries commonly hold indigenous beliefs about mental illness which differ markedly from biomedical models. AIM: To test the effect of a biomedical intervention on explanatory models (EMs) of community health workers. METHODS: Indigenous beliefs about chronic psychosis were elicited from community health workers. The Short Explanatory Model Interview formed the basis of the interview. Half the workers were taught about the biomedical model after discussing their EMs of chronic psychosis. The others did not receive education. The beliefs of all community health workers were reassessed 2 weeks after the initial assessment. RESULTS: A variety of indigenous beliefs, which contradicted the biomedical model, were elicited at the baseline evaluation. Seeking biomedical help at follow up was significantly related to receiving education about the biomedical aspects of chronic psychosis (OR 17.2; 95% CI: 18.75, 15.65; p<0.001). This remained statistically significant (OR 9.7; 95% CI: 82.28, 1.14; p<0.04) after using logistic regression to adjust for baseline variables. CONCLUSION: The high prevalence of non-medical beliefs among community health workers suggests the need to elicit and discuss beliefs before imparting knowledge about biomedical models of mental disorders. Biomedical educational intervention can change EMs of mental illness among health workers. PMID- 20844643 TI - An estimate of the monthly cost of two major mental disorders in an Indian metropolis. AB - BACKGROUND: THE COMPONENTS OF HIGH COST OF TREATING A CHRONIC PSYCHIATRIC ILLNESS ARE: long-term continuous treatment consisting of consultation and medication costs, traveling to the treatment centre and taking time off from work for both patient and caregiver. Apart from direct treatment costs, expenditure of time in care-giving results in indirect costs. All these costs are borne by families as the sufferer may be unable to work. AIM: To estimate the cost of treatment of chronically ill patients at home, in terms of the above parameters. METHODS: The sample consisted of 117 subjects of either sex in the age range of 18 to 60 years, ill for at least one year, diagnosed as schizophrenia (n=95) or bipolar disorder (n=22, a comparison group) who agreed to participate in the study along with at least one caregiver. The tools used were the Diagnostic Interview of Genetic Studies and Economic Burden Questionnaire administered to both the subject and the caregiver. RESULTS AND CONCLUSIONS: The costs of treatment were found to be high but with wide variations in the range. Costs for bipolar disorder were somewhat higher than those for schizophrenia at least for the period of study. Demographic differences between subjects and caregivers were present. PMID- 20844644 TI - Regional brain metabolism in schizophrenia: An FDG-PET study. AB - BACKGROUND: Recent technological advances have established beyond any doubt the biological nature of schizophrenia. Functional neuroimaging using FDG-PET forms an important technique in understanding the biological underpinnings of psychopathology of schizophrenia. METHODS: Eighteen male patients diagnosed as having schizophrenia and having active psychosis as determined by PANSS were subjected to FDG-PET scanning under resting conditions. The glucose uptake in selected regions of interest was studied across the spectrum of schizophrenia. RESULTS: Chronicity and severity of illness did not influence cerebral glucose metabolism. Participants with negative schizophrenia had significantly decreased metabolism in all regions of the brain as compared to the positive type. The positive syndrome of schizophrenia was associated with significantly increased glucose metabolism in the medial temporal regions, basal ganglia and left thalamic regions. Hypometabolism was also noted in the cerebellum. CONCLUSION: While a number of brain areas can be identified as potential causative regions and hypotheses regarding putative mechanisms can be formed, the considerable heterogeneity of schizophrenia poses a great challenge in the precise delineation of the disease process. PMID- 20844645 TI - Deficiencies in social relationships of individuals with neurosis. AB - BACKGROUND: Social interaction and network of individuals with neurosis have been reported to be inadequate. AIM: To measure deficiencies in the social network of individuals with neurosis. METHODS: Fifty consecutive patients with neurosis attending the OPD of the Department of Psychiatry, King George's Medical College, Lucknow, who were diagnosed as per the criteria of ICD-9, were included in the study. A control group of 40 healthy persons matched for age, sex, education and marital status was also taken. Interaction with the primary group (defined as consisting of all kin, nominated friends, work associates and neighbours) was measured by the Social Interaction Schedule of Henderson et al. as modified for the Indian population. RESULTS: Patients reported significantly higher mean duration of unpleasant but affectively intense interaction with one person within or outside the primary group and affectively unpleasant and intense interaction with more than one person within or outside the primary group or affectively superficial but unpleasant interaction with one or more person of the primary group. Healthy subjects reported more of pleasant interaction with one person within or outside the primary group and affectively intense and pleasant interaction with more than one person within or outside the primary group or affectively superficial but pleasant interaction with one or more persons of the primary group; the difference was statistically significant as compared to patients with neurosis. CONCLUSION: The primary group of patients with neurosis was significantly smaller in numerical size as compared with that of controls and in terms of the total time spent with members of the primary group, patients with neurosis reported more interactions of unpleasant type and less of pleasant type as compared with healthy controls. PMID- 20844648 TI - 'Joke's A Part': In defence of humour. PMID- 20844647 TI - A Life Events Scale for Armed Forces personnel. AB - BACKGROUND: Armed Forces personnel are routinely exposed to a number of unique stressful life events. None of the available scales are relevant to service personnel. AIM: To construct a scale to measure life events in service personnel. METHODS: In the first stage of the study open-ended questions along with items generated by the expert group by consensus method were administered to 50 soldiers. During the second stage a scale comprising 59 items and open-ended questions was administered to 165 service personnel. The final scale of 52 items was administered to 200 service personnel in group setting. Weightage was assigned on a 0 to 100 range. For normative study the Armed Forces Medical College Life Events Scale (AFMC LES) was administered to 1200 Army, 100 Air Force and 100 Navy personnel. RESULTS: Service personnel experience an average of 4 life events in past one year and 13 events in a life-time. On an average service personnel experience 115 life change unit scores in past one year and 577 life change unit scores in life-time on the AFMC LES. The scale has concurrent validity when compared with the Presumptive Stressful Life Events Scale (PSLES). There is internal consistency in the scale with the routine items being rated very low. There is a pattern of uniformity with the civilian counterparts along with differences in the items specific to service personnel. CONCLUSIONS: The AFMC LES includes the unique stresses of service personnel that are not included in any life events scale available in India or in the west and should be used to assess stressful life events in service personnel. PMID- 20844646 TI - Prevalence of conduct disorder in schoolchildren of Kanke. AB - BACKGROUND: Prevalence estimates of conduct disorder, one of the most frequently diagnosed psychiatric conditions in children, vary widely from 0.2% to 8.7%. AIM: To find out the prevalence of conduct disorder and its DSM-IV subtypes and comorbid attention deficit hyperactivity disorder (ADHD) in 4 schools of Kanke block among students of classes V to X. METHODS: A total of 240 students, selected by stratified random sampling, were subjected to the Schedule for Affective Disorders and Schizophrenia for School Age Children: Present and Lifetime Version (K-SADS-PL) screening interview. Nineteen students who qualified were subjected to conduct disorder and ADHD supplement of K-SADS-PL with additional information from parents. RESULTS: Conduct disorder was found in 4.58%; the ratio of boys to girls being 4.5:1. Childhood onset was found in 73% and adolescent onset in 27%. Mild conduct disorder was found in 36%, moderate in 64% and severe conduct disorder in none. Comorbid ADHD was found in 36%, hyperactive-impulsive being predominant. Significant difference was found in temperament between students with and without conduct disorder with difficult temperament predominating in the former and easy in the latter (p=0.004). Lying, bullying and cruelty to animals were most frequent symptoms. CONCLUSION: The prevalence of conduct disorder was 4.58%, more common in boys, the majority had childhood onset, and one-third had comorbid ADHD. PMID- 20844649 TI - Wisconsin Card Sorting Test: Normative data and experience. AB - BACKGROUND: The Wisconsin Card Sorting Test (WCST) has been increasingly employed as a clinical neuropsychological instrument. However, in India the use of WCST is still in a relatively preliminary stage. AIM: To analyse the utility of WCST in the Indian population. METHODS: Fifty-three subjects in the age group of 20-50 years, comprising both men and women, were recruited for the study. The normality was established by administering the General Health Questionnaire as a screening instrument to evaluate their health status. The WCST was administered and the norms for various dimensions were established; these were compared with those of normal healthy individuals from the West as per the WCST manual. RESULTS AND CONCLUSION: The significance of differences and the experience of administration have been described. The present study found highly significant differences between the means on almost all WCST scores among the Western and the Indian sample, except for the number of correct responses. PMID- 20844650 TI - Psychiatric comorbidity of headache in a medical relief camp in a rural area. AB - BACKGROUND: Headache is one of the most common complaints seen by primary care physicians, but very few well-planned studies have been conducted to know its prevalence. AIM: To study the prevalence of headache and associated psychiatric morbidity. METHODS: A medical relief camp was held in village Mavta (near Ratlam in Madhya Pradesh) in 2002. Of a total of 1350 registered subjects, 80 with primary complaints of headache were referred to our expert team of psychiatrists. RESULTS: Sixty-nine subjects (86.25%) had psychiatric morbidity-mainly affective disorders (depression) and panic disorder, dysthymia, alcohol and nicotine dependence. Subjects with migraine and depression were mostly women with onset of symptoms at an early age. Subjects with less education; who were unmarried or had lost a spouse; those with a nuclear family; who were unemployed and those with a family history and past history of mental illness, were all susceptible to headache and depression. CONCLUSION: Disturbed sleep, free floating anxiety, sad mood, lack of pleasure, body ache and fatigue were the main presenting complaints along with headache. PMID- 20844651 TI - An analysis of six cases of acute intermittent porphyria (AIP). AB - This analysis describes the diagnosis and psychiatric treatment modalities of 6 patients (5 women, 1 man; mean age 28.5 years) of acute intermittent porphyria (AIP), who presented to the Psychiatry OPD over a period of one year. The mean number of episodes was 2.83. Premorbid personality traits, clinical presentation, urine colour and urinary porphobilinogen titre were recorded. Among the 6 patients, 4 had abdominal pain, 5 had autonomic instability, all 6 had mental symptoms, 3 had depression, 2 came in delirium, and 3 had an episode of seizure. PMID- 20844652 TI - Neurocognitive deficits in HIV-positive patients-two case reports: Revising current AANTF guidelines in view of recent revelation of new neurocognitive symptoms. AB - Certain organic antecedents such as fever, weight loss, diarrhoea and systemic infections often present with neurocognitive deficits (NCDs). However, routine HIV screening is not done in such cases. HIV can present with psychiatric and neurocognitive symptoms as highlighted in the two cases given below.Case 1, a housewife, had been exhibiting altered behaviour following a low-grade fever over the past 3 weeks, associated with muttering to self, talking irrelevantly, would wander away from home, had decreased sleep, loss of appetite, and neglected self care. She had displayed impulsivity by jumping into a well. On admission, the patient was mute, lethargic and the cerebrospinal fluid (CSF) tested positive for cryptococcus. Her human immunodeficiency virus (HIV) status was positive.Case 2, a housewife, presented with one-month history of muttering to self, increased irritability, aggressive on minimal provocation, decreased sleep, loss of appetite, and suspiciousness towards family members. On provisional diagnosis of schizophrenia, the patient was started on low-dose antipsychotic drugs, which showed minimal improvement. There was a distinct slowness in her movements and she progressively lost weight. Routine investigations were normal but her HIV status was positive.It has recently come to light that HIV infection also presents with subtle manifestations of the central nervous system (CNS), which are distinct from NCD and, if harnessed, could enhance diagnostic sensitivity and reduce the 'asymptomatic period'. Hence HIV testing is recommended in such cases. PMID- 20844653 TI - Clozapine in pregnancy. AB - This report describes the case of a woman with treatment-resistant schizophrenia who became pregnant while being treated successfully with clozapine. Possible risks associated with continuation of clozapine during pregnancy are discussed. PMID- 20844654 TI - Compulsive symptoms in dissociative (conversion) disorder. AB - According to Mayer-Gross, Slater and Roth's classical textbook Clinical psychiatry, obsessive-compulsive symptoms are rarely seen in hysteria. The release of obsessive-compulsive symptoms is said to occur only in those who are constitutionally predisposed. In this context, the case of a young woman with dissociative (conversion) disorder, who presented with compulsive symptoms, is reported. In her case, the dissociative phenomena manifested as compulsive symptoms without concomitant predisposing factors. Management on the line of treatment for hysteria promptly achieved lasting resolution of symptoms without recourse to pharmacological or non-pharmacological treatment strategies used for obsession(s) or compulsion(s). The underlying mechanism(s) are discussed. PMID- 20844655 TI - Is olfactory reference syndrome an OCD? PMID- 20844656 TI - Reply to 'Critical appraisal of an article on factitious schizophrenia'. PMID- 20844657 TI - My inner experience. PMID- 20844658 TI - A new beginning.... PMID- 20844659 TI - Message from SNM President. PMID- 20844660 TI - PET-MRI: Challenges and new directions. PMID- 20844661 TI - Sestamibi (99mTc) scan as a single localization modality in primary hyperparathyroidism and factors impacting its accuracy. AB - BACKGROUND: The proper localization of a hypersecreting parathyroid gland is of vital importance for successful unilateral neck exploration (UNE) and parathyroidectomy. AIM: In this study we aim to evaluate the (99mTc) sestamibi parathyroid scan as a single localizing modality, and we also assess its relation to the weight of the gland and to the preoperative parathyroid hormone (PTH) levels. PATIENTS AND METHODS: We reviewed 170 patients from our hospital (Notre Dame hospital) from 2005 to 2008, with a mean age of 56.6 years and a female to male ratio of 3.3:1. With primary hyperparathyroidism, all of them had (99mTc) sestamibi parathyroid scan for the localization of the parathyroid adenoma. Preoperative and postoperative PTH levels were recorded. The histopathology reports confirmed the diagnosis and weight of the diseased gland, which were recorded every time. The results were analyzed and correlated with the sestamibi results, to evaluate its accuracy. RESULTS: Seventy-eight patients (41%) of the 170 had an exact match (EM) sestamibi results, 81 (51.6%) had a partial match, and only 11 patients were reported as mismatch. Analyzing the mean weight of the gland in each group between matching (EM, PM) versus mismatch resulted in a mean difference of 0.823 g (1.05 and 0.247 g, respectively) P = 0.045. Hyperplasia to adenoma ratio was more in the partial matching group (18.5%) versus the exact matching group (7.6%). Finally the mean PTH level was higher in the EM group (28.8 pmol/L) compared to the mismatch group (10.1 pmol/L) P = 0.02. Overall sensitivity and specificity for the (99 mTc) sestamibi in our data was 98.1 and 97%, respectively. CONCLUSION: (99mTc) sestamibi is a highly accurate test that can be employed as a single localizing modality for identifying a hypersecreting parathyroid, a UNE, or a parathyroidectomy. The weight of the gland plays an important role in the accuracy of the test, as also the preoperative PTH levels. PMID- 20844662 TI - Physical dosimetry and mathematical dose calculation in nuclear medicine: A comparative study. AB - OBJECTIVES: This paper addresses a comparison between physical dosimetry and mathematical dose calculation in nuclear medicine. MATERIALS AND METHODS: Dose rate was calculated by mathematical external dose calculation formula and by physical dosimetry from the surface of 38 adult patients' body referred to nuclear medicine department. Results of the methods were compared and correlation and regression tests were also performed. RESULTS: Although the physical dosimetry data in this study are in good consistency with other researches, they are much lower than the results of mathematical dose calculation formula. The correlation coefficient between measured dose rate with calculated values derived by mathematical formula was found to be 0.852 (P value=0.148). CONCLUSION: It seems that physical dosimetry data are more accurate than the results of mathematical dose calculation. In case of using mathematical dose calculation formula, other correction factors should be considered and applied for getting reliable data. PMID- 20844663 TI - Tc-99m radio-guided completion thyroidectomy for differentiated thyroid carcinoma. AB - BACKGROUND: The purpose of this study is to investigate whether or not radio guided surgery has any beneficial effects on completion thyroidectomy (CT) and the associated complication rates. PATIENTS AND METHODS: Twenty-seven patients were scheduled for CT, for thyroid carcinoma, from December 2004 to June 2005, and were included in the study. All the patients had had initial thyroid surgery in other centers and been referred to our clinic for CT. Operation findings and the effectiveness of Tc-99m radio-guided CT were analyzed. RESULTS: The intraoperative mean ratio of thyroid activity to background activity counted with a gamma probe was 1.3 +/- 0.3. Average operation timing was 74 +/- 9 minutes. Postoperatively, no residual tissue was detected in any of the patients with ultrasonography and thyroid scintigraphy. In the first postoperative month, serum TSH level was 61 +/- 16.4 mIU / L, when preoperatively it was 7.3 +/- 3.1 mIU / L (P < 0.001). In the postoperative period, one patient experienced temporary hypoparathyroidism (3.9%). Permanent hypoparathyroidism or recurrent laryngeal nerve damage was not detected in any patient. CONCLUSION: Tc-99 radio-guided CT is a reliable surgical method, which provides the detection and removal of residual thyroid tissues with minimal complications. PMID- 20844664 TI - Nidus localization in osteod osteoma by SPECT skeletal scintigraphy: Aid to diagnosis and surgical approach. AB - Osteod osteoma, although not a common clinical occurrence, does pose problems both in diagnosis and surgical management. Initial plain radiographic diagnosis is sometimes fraught with the limitation of not being able to differentiate from chronic osteomyelitis and stress fracture. CT-aided localization of the nidus is also often inconclusive. Radionuclide single photon emission computed tomography (SPECT) scintigraphy is highly sensitive in localizing the active nidus and also orients the lesion in a three-dimensional plane well, for effective surgical removal. PMID- 20844665 TI - Scintigraphic and radiological correlative and confirmative features obviating invasive biopsy in Caffey's disease. AB - Caffey's disease is not a common clinical occurrence; it often poses problems in diagnosis due to its close resemblance to osteomyelitis. Initial plain radiographic diagnosis is sometimes fraught with the limitation of not being able to differentiate it from chronic osteomyelitis. Skeletal scintigraphy is sensitive in localizing the disease activity to the radiological features of the affected regions and the characteristic location of the lesions helps make the diagnosis without resorting to biopsy and further workup. PMID- 20844666 TI - Absent right iliac bone on Tc99m MDP bone scan in a patient with Gorham's vanishing bone disease. AB - Gorham's (vanishing bone) disease is an extremely rare condition of the bone. The diagnosis is usually made on the basis of the characteristic history of osteolysis and failure of bone healing in conjunction with the histological findings of marrow fibrosis and increased vascularity. When the disease is established, an X-ray and magnetic resonance imaging show complete loss of affected bone. There are very few reports found in literature on bone scan appearance of the disease. A bone scan of a 24-year-old female patient with known Gorham's disease revealed absence of tracer uptake in the right iliac bone, right sacroiliac joint, and part of the right ischial pubic rami, which matched the radiographic abnormalities. Consequently this disease should be added to the gamut of cold defects seen on bone scan. PMID- 20844667 TI - Tc99m MDP bone SPECT in a case of osteomyelitis of the skull. AB - A seven-year-old male child presented with swelling at the left temporal region. His skull X-ray was normal. A three-phase bone scan showed increased blood flow, soft tissue activity, and increased tracer concentration in the left temporal region. Single photon emission computed tomography (SPECT) imaging of the skull revealed full thickness involvement of the left temporal bone. Our case report shows that, in osteomyelitis of the skull, SPECT imaging provides significantly more information for identifying the extent and thickness of bone involvement. PMID- 20844668 TI - Tc-MDP bone scintigraphy in a case with sporodical tumoral calcinosis. AB - Tumoral calcinosis is an uncommon and benign condition characterized by the presence of large calcific soft tissue deposits occurring predominantly in a periarticular location. It generally occurs as a complication of renal dialysis or trauma, and is rarely seen in familial and sporadic cases. Bone scintigraphy is a sensitive method for diagnosing tumoral calcinosis. A 28-year-old female patient with a history of operation due to tumoral calcinosis located bilateral hips, referred to our department. She had a tender palpable mass in the right knee and a fistulized incisional scar overlying the bilateral hip joints. A sporadic case of tumoral calcinosis with relapses was presented. PMID- 20844669 TI - Utility of Iodine-131 hybrid SPECT-CT fusion imaging before high-dose radioiodine therapy in papillary thyroid carcinoma. AB - The management protocol for differentiated thyroid cancer includes whole body iodine-131 imaging, to detect residual thyroid tissue and distant metastasis, after thyroidectomy. However, the diagnostic dose of radioiodine may fail to detect the non-functioning or poorly functioning metastasis. We present a case where hybrid single photon-emission computed tomographic and computed tomographic (SPECT-CT) fusion imaging, using a diagnostic dose of iodine-131, was able to detect both functioning as well as non-functioning pulmonary metastases, prior to high-dose radioiodine therapy. PMID- 20844670 TI - Utility of hybrid SPECT-CT in the detection of unsuspected single lytic vertebral metastases in renal cell carcinoma. AB - Authors describe the incremental value of hybrid SPECT-CT in upstaging disease and changing the management strategy of a case of renal cell carcinoma. PMID- 20844671 TI - Closed system vacuum assisted administration of high dose radio iodine to cancer thyroid patients: NIMS techniqe. PMID- 20844672 TI - Oncology update. PMID- 20844675 TI - Spontaneously Resolving Periocular Erythema and Ciliary Madarosis Following Intra arterial Chemotherapy for Retinoblastoma. AB - PURPOSE AND DESIGN: To describe an unusual clinical finding seen in children undergoing intra-arterial chemotherapy for retinoblastoma. MATERIALS AND METHODS: A retrospective review of 69 eyes of 63 patients receiving intra-arterial chemotherapy over a 3-year period. Charts and photographs of 69 consecutive cases were reviewed, and data were collected on patients with clinical evidence of a hyperemic cutaneous periocular abnormality following the procedure. RESULTS: A blanching erythematous and edematous patch was noted in the periocular region in 16% (11 of 69) of the children who received intraarterial chemotherapy. The plaque extended into the region of the supertrochlear and medial marginal artery distribution on the ipsilateral side of the intra-arterial chemotherapy. All patches of erythema spontaneously resolved within 3 months following completion of the intra-arterial chemotherapy. CONCLUSION: Periocular erythema and swelling is a self-limited clinical finding associated with intra-arterial chemotherapy in a small number of patients. PMID- 20844674 TI - Fundus autofluorescence and optical coherence tomography findings in choroidal melanocytic lesions. AB - PURPOSE: To establish the characteristics of secondary retinal and retinal pigment epithelial (RPE) changes associated with the presence of choroidal melanoma and choroidal nevus as documented by optical coherence tomography (OCT) and fundus autofluorescence (FAF). MATERIALS AND METHODS: PubMed review of major English publications examining the correlation between clinical characteristics of choroidal melanoma and nevus with OCT and FAF findings. RESULTS: The intrinsic properties of choroidal melanoma, as well as overlying RPE changes, drusen, and lipofuscin are best characterized by FAF, while OCT is more sensitive for the identification of subretinal and intraretinal fluid as well as atrophy, degeneration, and photoreceptor loss in the neurosensory retina. CONCLUSIONS: Secondary retinal changes associated with choroidal melanocytic lesions can be documented by OCT and FAF. OCT-evident changes are observed more often with choroidal melanoma than choroidal nevus. OCT is better suited to identify the overlying retinal detachment and edema, even before these findings are clinically apparent. FAF is most useful in documenting the presence of lipofuscin, a finding that represents one of the important criteria in differentiating small choroidal melanoma from benign choroidal nevus. PMID- 20844673 TI - Vascular tumors of the retina and choroid: diagnosis and treatment. AB - The vascular tumors of the retina and choroid comprise a diverse group of congenital and acquired lesions. The major vascular tumors of the retina include retinal capillary hemangioma, cavernous hemangioma of the retina, retinal vasoproliferative tumor, and racemose hemangiomatosis of the retina or Wyburn Mason syndrome. Choroidal vascular tumors include circumscribed choroidal hemangioma and diffuse choroidal hemangioma. While classified as benign, visual symptoms secondary to exudative retinal detachment and a variety of other mechanisms are common and are a major source of long-term visual disability. While many therapeutic modalities exist, treatment of symptomatic cases can be challenging. Of particular importance, many of the vascular tumors of the retina and choroid have significant associations with systemic disease. As ocular symptoms are often the most common presenting disease manifestation, the ophthalmologist plays an important role in accurate and early diagnosis. The ability to initiate prompt screening and treatment in appropriate cases is critical. In the following article, the key clinical and diagnostic features of the major retinal and choroidal vascular tumors, their systemic associations, and the literature pertaining to the most currently available treatment strategies are reviewed. PMID- 20844676 TI - Exoresection and endoresection for uveal melanoma. AB - Surgical resection of uveal melanomas is an alternative eye-salvaging approach to the more commonly used irradiation techniques. There are two surgical resection techniques: Transscleral resection or "Exoresection" via a partial lamellar sclerouvectomy and "Endoresection" via a pars plana vitrectomy. While exoresection is more applicable to anteriorly located tumors with ciliary body and/or iris involvement, endoresection is more suitable for posteriorly located tumor without ciliary body involvement. Both approaches are suitable for large tumors with >8 mm in thickness. In general, eyes containing these large tumors have a very dismal prognosis regarding long-term visual function, eye retention, and irradiation-induced side effects. By removing the tumor burden from the eye, histopathologic and cytogenetic information of the tumor is available and complications associated with the so-called toxic tumor syndrome are avoided. However, both types of surgical resection are challenging surgical procedures, bearing the risk of early and late postoperative complications. PMID- 20844679 TI - Characteristics of optic disc melanocytomas presenting with visual dysfunction. AB - OBJECTIVE AND DESIGN: A retrospective review study was designed to describe five cases of optic disc melanocytomas with tumor-related visual impairment. PARTICIPANTS: Five patients with optic disc melanocytoma presented with visual complaints to a tertiary eye hospital in Saudi Arabia. MATERIALS AND METHODS: Demographic and clinical data were analyzed, including the results of ocular examination, lesion laterality, best-corrected Snellen visual acuity, pupillary reflex, visual field testing, color fundus photography, fundus fluorescein angiography, and ophthalmic ultrasound. RESULTS: Visual dysfunction secondary to optic disc melanocytoma was identified. Case 1 had macular star edema with mild tumor enlargement, Case 2 had optic atrophy, Case 3 had juxtapapillary choroidal neovascular membrane with macular involvement, Case 4 had optic disc swelling with an enlarged blind spot, and Case 5 had a large altitudinal visual field defect. CONCLUSION: Although melanocytomas of the optic disc tend to have a benign behavior with slow evolution and stable vision, they may adversely affect visual function through a variety of mechanisms. PMID- 20844680 TI - The burden and spectrum of vitreo-retinal diseases among ophthalmic outpatients in a resource-deficient tertiary eye care setting in South-eastern Nigeria. AB - PURPOSE: This study was designed to determine the rate and pattern of vitreo retinal diseases at a tertiary eye care center in South-eastern Nigeria. MATERIALS AND METHODS: The outpatient register at the Eye Clinic of the University of Nigeria Teaching Hospital, Enugu, was retrospectively examined to identify all new patients registered between January 2004 and December 2008. A chart review of subjects with vitreo-retinal disease was conducted to record relevant demographic and clinical data including the needs for vitreo-retinal care. Descriptive and analytical statistics were performed. A P-value <0.001 (one degree of freedom) was considered statistically significant. RESULTS: Of the 8,239 new patients reported during the period, 326 subjects (males- 59.3%; females- 40.7%; sex ratio = 1.1:1) aged 49.3 +/- 16.8 years (range 3-82 years) had vitreo-retinal disease. The rate of vitreo-retinal disease was 3.9%. The rate was higher in subjects above 40 years old (P < 0.001), but did not differ between sexes (P = 0.469). Diabetic retinopathy (24.9%), hypertensive retinopathy (13.3%), and age-related macular degeneration (10.7%) were the leading vitreo retinal diseases. Blindness from vitreo-retinal disease was bilateral in 6.1% of subjects and unilateral in 17.5% of subjects. The common co-morbidities were ocular conditions such as refractive error (19.8%), cataract (14.2%), and glaucoma (10.4%); and systemic conditions such as diabetes mellitus (14.6%) and hypertension (13.2%). CONCLUSIONS: The rate of vitreo-retinal diseases among new ophthalmic outpatients at UNTH, Enugu, is 3.9%. Retinal vascular disorders and age-related maculopathy are the leading retinal diseases. At UNTH, resource needs for vitreo-retinal care are urgent including retinal photography/angiography, laser photocoagulation, intra-vitreal pharmacotherapy, and vitreo-retinal surgery. PMID- 20844677 TI - Molecular pathology of retinoblastoma. AB - Retinoblastoma (RB) is an embryonic neoplasm of retinal origin. For many years, scientists have sought the fundamental origins of tumorigenesis, with the ultimate hope of discovering a cure. Indeed, these efforts have led to a significant understanding that multiple molecular and genetic aberrations, such as uncontrolled proliferation and the inhibition of apoptosis that contribute to the canonical characteristics of tumor biology. Despite these advances, a thorough understanding, such as the precise cells, which are the targets of neoplastic transformation, especially in solid tumors, is currently lacking. The focus of this review is to emphasize the molecular defects involved in the RB tumor progression and mechanisms associated with inhibition of tumor cell apoptotic processes. This review also discusses the importance of target molecules characterization and their potential therapeutic or prognostic use in RB disease. PMID- 20844678 TI - Idiopathic juxtafoveolar retinal telangiectasis: a current review. AB - Idiopathic juxtafoveolar retinal telangiectasis (IJFT), also known as parafoveal telangiectasis or idiopathic macular telangiectasia, refers to a heterogeneous group of well-recognized clinical entities characterized by telangiectatic alterations of the juxtafoveolar capillary network of one or both eyes, but which differ in appearance, presumed pathogenesis, and management strategies. Classically, three groups of IJFT are identified. Group I is unilateral easily visible telangiectasis occurring predominantly in males, and causing visual loss as a result of macular edema. Group II, the most common, is bilateral occurring in both middle-aged men and women, and presenting with telangiectasis that is more difficult to detect on biomicroscopy, but with characteristic and diagnostic angiographic and optical coherence tomography features. Vision loss is due to retinal atrophy, not exudation, and subretinal neovascularization is common. Group III is very rare characterized predominantly by progressive obliteration of the perifoveal capillary network, occurring usually in association with a medical or neurologic disease. This paper presents a current review of juxtafoveolar retinal telangiectasis, reviewing the classification of these entities and focusing primarily on the two most common types encountered in clinical practice, i.e., groups I and II, describing their clinical features, histopathology, natural history, complications, latest results from imaging modalities and functional studies, differential diagnosis, and treatment modalities. PMID- 20844681 TI - A prospective, randomized comparison of intravitreal triamcinolone acetonide versus intravitreal bevacizumab (avastin) in diffuse diabetic macular edema. AB - PURPOSE: To compare the functional and anatomical outcomes following intravitreal triamcinolone acetonide vs. intravitreal bevacizumab (Avastin) treatment for diffuse diabetic macular edema. MATERIALS AND METHODS: IN THIS PROSPECTIVE, RANDOMIZED STUDY, SUBJECTS WERE DIVIDED INTO TWO GROUPS: 24 eyes that received intravitreal injection of 4 mg/0.1 mL triamcinolone acetonide (IVTA group) and 24 eyes received intravitreal injection of 1.25 mg/0.05 mL bevacizumab (IVB group). Changes in best corrected visual acuity (BCVA), intraocular pressure (IOP), baseline fluorescein angiography and optical coherence tomography measurements were evaluated in both groups. Follow-up visits out to three months from baseline are reported. RESULTS: One month after treatment, baseline foveal thickness decreased from 452 u to 299 u in the IVTA group and from 292 u to 270 u in the IVB group. BCVA increased by two or more lines in 58.3% of eyes in the IVTA group and there was no similar improvement in the IVB group. In the IVTA group, a transient increase in IOP (27-43 mmHg) occurred in four cases (16.7%), which was successfully controlled with topical medications. There were no complications in the IVB group. CONCLUSION: Short term outcomes indicate that intravitreal injection of bevacizumab was not associated with surgical complications compared to triamcinolone acetonide. Triamcinolone acetonide appears to be more effective treatment for diabetic macular edema than bevacizumab. PMID- 20844682 TI - Non-Foveal Macular Holes After PPV for Macular Pucker. AB - PURPOSE: To describe six patients (six eyes) who developed an eccentric macular hole after surgery for idiopathic epimacular proliferation. MATERIALS AND METHODS: Review of records from six patients who developed eccentric macular holes postoperatively following vitrectomy in 107 consecutive cases with peeling of the epimacular proliferation and internal limiting membrane (ILM) from June 2004 to January 2009 RESULTS: Eccentric macular holes were developed from nine days to eight months (mean, 3.1 months) after epimacular proliferation peeling. The ILM was peeled in addition to the epimacular proliferation in five of the six cases. Of the six eccentric macular holes, four were located temporal to the fovea, one was located superior to the fovea, and one was located nasal to the fovea. Final visual acuities after a mean follow-up period of 17.3 months were 20/20 in two eyes, 20/25 in one eye, 20/40 in two eyes, and 5/200 in one eye. The eye with the eccentric macular hole nasal to the fovea had the poorest final visual acuity of 5/200. CONCLUSION: Eccentric macular holes occurring after vitrectomy to remove epimacular proliferation is an uncommon postoperative finding. Various explanations have been suggested for the etiology of these holes, but there is no consensus. We suggested that the ILM tear should be initiated with a diamond dusted knife to reduce the likelihood of injury to the underlying Muller cells that may contribute to the formation of eccentric macular holes. PMID- 20844683 TI - Prevalence and determinants of diabetic retinopathy in Al hasa region of saudi arabia: primary health care centre based cross-sectional survey, 2007-2009. AB - PURPOSE: To evaluate the prevalence of diabetic retinopathy (DR) in the urban and rural areas of Al Hasa region of Saudi Arabia and to determine risk factors related to DR. MATERIALS AND METHODS: This study was conducted on patient attending primary health care centers between July 2007 and June 2009. A retrospective chart review was conducted on subjects with diabetes mellitus greater than 18 years old. Ophthalmologists examined DR status through dilated pupils by using direct, indirect, and slit lamp bio-microscopy. Frequencies, percentage, and their 95% confidence intervals (CIs) were calculated. Odd's ratio was used to associate DR with possible risk factors. A P value less than 0.05 was considered statistically significant. RESULTS: The prevalence of DR among 473 diabetic subjects was 30% (95% CI: 25.80-34.20). The odd ratios (ORs) of DR among diabetic residing in an urban area was significantly higher than diabetics residing in rural areas [OR = 1.94 (95% CI of OR 0.82-2.89)]. DR was associated to the duration of diabetes (adjusted OR = 1.70), uncontrolled blood sugar level (adjusted OR = 1.96), hyperlipidemia (adjusted OR = 2.04), and hypercholesterolemia (adjusted OR = 2.80). CONCLUSIONS: DR appears to be a public health problem in the Al Hasa district of Saudi Arabia, and a planned approach is required to avoid severe visual impairment in patients with diabetes mellitus. Primary prevention and early detection could be implemented through primary health centers and non-ophthalmologists. PMID- 20844685 TI - Small choroidal melanoma with monosomy 3. AB - PURPOSE: To report a patient with small juxtapapillary choroidal melanoma with chromosome 3 monosomy treated with I(125) plaque and transpupillary thermotherapy (TTT). A 64-year-old Caucasian male presented with painless blurred vision of the left eye. Ocular examination disclosed a small juxtapapillary choroidal melanocytic tumor with overlying subretinal fluid and orange pigment. Ultrasound showed an elevated choroidal mass of 2 mm thickness with low reflectivity on A scan and hollowness on B scan, consistent with a small choroidal melanoma. The patient was treated with plaque I(125) radiotherapy combined with one session of TTT. Genetic testing of the tumor cells obtained by fine needle aspiration biopsy showed chromosome 3 monosomy. At 1 year after treatment, the tumor was regressed with resolution of subretinal fluid and 20/40 visual acuity. A small choroidal melanoma can manifest monosomy of chromosome 3, a known predictive factor for the development of systemic metastasis. PMID- 20844684 TI - Early experience with intravitreal bevacizumab combined with laser treatment for retinopathy of prematurity. AB - OBJECTIVE: This study was designed to present our early experience with intravitreal bevacizumab combined with laser treatment for retinopathy of prematurity (ROP) at a single institution over a 13-month-period. METHODS: A retrospective case series of eight children with ROP who received intravitreal bevacizumab combined with laser treatment between June 2007 and July 2008 were reported. A chart review was conducted to evaluate if stability of the ROP lesion had been achieved. Main information collected included data on demographics, gestational age, birth weight, length of stay in neonatal intensive care unit, and stage of ROP. RESULTS: Fifteen eyes of eight subjects were treated. One eye did not receive any treatment due to complete retinal detachment. The median age at treatment was 8 weeks (range, 6 weeks to 1 year). The most common stage of ROP was 3+. All eyes remained stable at 1 year or later after treatment. CONCLUSION: Intravitreal bevacizumab in conjunction with laser treatment had promising results at our institution. We recommend prospective, randomized, controlled clinical trials to compare the effect of laser treatment alone, of bevacizumab treatment alone (at different doses), and of combined bevacizumab and laser treatment. PMID- 20844686 TI - Idiopathic choroidal neovascularisation as the inaugural sign of multiple evanescent white dot syndrome. AB - We report a case of multiple evanescent white dot syndrome (MEWDS) that presented with putative idiopathic choroidal neovascularisation (ICNV) before showing angiographic signs typical of MEWDS. A 16-year-old male presented with unilateral metamorphopsias and visual loss in his left eye. ICNV with subretinal hemorrhage was diagnosed and treated with intravitreal Avastin((r)). Fifteen days later, regression of choriodal neovascularization (CNV) was documented together with the appearance of fluorescein angiography (FA) and indocyanine green angiography (ICGA) signs typical for MEWDS, that included faint mottled FA hyperfluorescence in the mid-peripheral fundus, irregularly shaped mid-peripheral ICGA dark areas in the intermediate angiographic phase that were clearly delineated in the late phase as well as peripapillary hypofluorescence. Fundus examination appeared completely normal during the follow-up except for the CNV hemorrhage noted at the initial visit. This case demonstrates the need to consider ICNV as a diagnosis of exclusion until inflammatory causes have been eliminated. In this case, the underlying occult inflammatory condition would have been missed without the ICGA data that clearly showed signs of MEWDS that was supported by FA findings. PMID- 20844687 TI - Isolated cilioretinal artery occlusion as an initial manifestation of polycythemia vera. AB - Isolated cilioretinal artery occlusion is a rarely reported initial manifestation of polycythemia vera. In this study, we reported a case of a 65-year-old man with polycythemia vera with cilioretinal artery occlusion as an initial manifestation. PMID- 20844688 TI - Successful surgical management of optic disc pit maculopathy without internal membrane peeling. AB - Optic disc pit is an excavation of the optic nerve head usually seen in association with other abnormalities of the optic nerve, peripapillary retina, or posterior vitreous detachment. In 50% the cases, it might be associated with serous macular detachment. The prevailing theory that explains this disorder is that subretinal fluid which is derived from liquefied vitreous passes through the optic disc pit and elevates the macula. In this study, we report a case of serous macular detachment complicating optic disc pit in a young male patient treated surgically without internal limiting membrane peeling and showed dramatic improvement of vision after 1 year. PMID- 20844690 TI - How healthy is your county? PMID- 20844689 TI - Erectile dysfunction following intravitreal bevacizumab. AB - Despite initial concerns regarding systemic complications, the use of intravitreal antivascular endothelial growth factor (anti-VEGF) agents for ocular disease is rapidly expanding worldwide, in terms of both the number of patients injected and its indications. To our knowledge, there are no cases in the literature reporting erectile dysfunction following the use of intravitreal bevacizumab. We postulate an organic mechanism for impaired erectile function due to systemically absorbed intravitreal bevacizumab. We describe a case of erectile dysfunction following intravitreal bevacizumab administration. Color fundus photos, fluorescein angiogram and optical coherence tomography images are presented. A 40-year-old male underwent intravitreal bevacizumab therapy for macular edema secondary to a branch retinal vein occlusion. He subsequently developed transient erectile dysfunction after each of his two bevacizumab injections. His only comorbidity was mild hypertension. Erectile dysfunction may be a side effect of intravitreal bevacizumab. The erectile dysfunction could be organic and/or psychogenic in etiology. PMID- 20844691 TI - Reducing errors with injectable medications: unlabeled syringes are surprisingly common. PMID- 20844692 TI - New mandate for covering mental health and substance abuse may force employers to reduce hospital and drug benefits. PMID- 20844693 TI - New drugs/drug news. PMID- 20844694 TI - Guanfacine Extended-Release Tablets (Intuniv), a Nonstimulant Selective Alpha(2A) Adrenergic Receptor Agonist For Attention-Deficit/Hyperactivity Disorder. PMID- 20844696 TI - Current Issues Regarding Complementary and Alternative Medicine (CAM) in the United States: Part 1: The Widespread Use of CAM and the Need for Better-Informed Health Care Professionals to Provide Patient Counseling. PMID- 20844695 TI - Expenditures associated with dose titration at initiation of therapy in patients with major depressive disorder: a retrospective analysis of a large managed care claims database. AB - OBJECTIVE.: Although selective serotonin reuptake inhibitors (SSRIs) are considered cost-effective medications for patients with major depressive disorder (MDD), significant dosage adjustments are often necessary when treatment is initiated. Our study was conducted to examine whether dose titration for SSRIs at initiation of therapy was associated with a greater use of health care resources and higher costs. STUDY DESIGN.: A retrospective database analysis was conducted. METHODS.: A nationally representative cohort of individuals with MDD was identified in a large managed care claims database between January 1, 2004, and December 31, 2006. A study-specific titration algorithm was used to identify patients who underwent dose titration, compared with those who did not, within the first eight weeks of initiating SSRI therapy. We calculated propensity scores and identified a 1:1 matched cohort of titration versus non-titration patients. We used univariate and multivariate statistical tests to compare the mean number of therapeutic days, health care service utilization, and expenditures between the two groups during the first eight weeks (56 days) of treatment and six months (180 days) after treatment began. RESULTS.: Over the first eight weeks, the titration cohort had a 32% decrease in the adjusted mean number of therapeutic days (38 vs. 56, respectively; P < 0.001), a 50% increase in depression-related outpatient visits (1.8 vs. 1.2; P < 0.001), a 38% increase in depression-related outpatient costs ($137 vs. $81; P <= 0.001), an increase in antidepressant pharmacy costs ($139 vs. $61; P < 0.001), and a 64% increase in psychiatric visits (0.69 vs. 0.42; P = 0.001), compared with the matched non-titration cohort. These differences were consistent among individual SSRI groups as well as during the six-month period. CONCLUSION.: Patients undergoing dose titration of SSRIs at the beginning of therapy consumed more medical resources and spent more days receiving a subtherapeutic dose than a comparable control group without dose titration. Differences in the utilization of resources were consistent with increased patient monitoring in the titration group; however, the added benefit of titration could not be assessed with this database. PMID- 20844698 TI - Pharmaceutical approval update. PMID- 20844697 TI - American society of clinical oncology, 2010 annual meeting and rose bengal: from a wool dye to a cancer therapy. PMID- 20844699 TI - Factors Contributing to Door-to-Balloon Times of <=90 Minutes in 97% of Patients with ST-Elevation Myocardial Infarction: Our One-Year Experience with a Heart Alert Protocol. AB - CONTEXT: Prompt percutaneous coronary intervention (PCI) for patients with ST segment elevation myocardial infarction (STEMI) can significantly reduce mortality and morbidity, although its effectiveness may be limited by delays in delivery. In March 2008, our hospital implemented a Heart Alert protocol to rapidly identify and treat patients with STEMI presenting to our Emergency Department (ED) with PCI, using strategies previously described to reduce door-to balloon times. Before the Heart Alert protocol start date, patients with STEMI presenting to our ED were treated with thrombolysis. OBJECTIVE: We evaluated data from patients with STEMI after one year of use of our Heart Alert protocol to determine protocol success on the basis of the percentage of patients for whom the recommended door-to-balloon times of <=90 minutes were met. We examined factors involved in implementation of the protocol that contributed to these results. DESIGN: We conducted a retrospective data and chart review for patients in the ED with STEMI who underwent PCI after a Heart Alert protocol activation between March 17, 2008, and March 17, 2009. RESULTS: During the study period, our staff met the recommended door-to-balloon time of <=90 minutes (mean door-to balloon time, 57.3 +/- 17.6 minutes) for 70 of 72 patients (97%) presenting to our ED with STEMI. Sixty-five of the 72 patients (90.3%) survived to hospital discharge. CONCLUSION: Initiation of a Heart Alert protocol at our hospital resulted in achievement of door-to-balloon times of <=90 minutes for 97% of patients with STEMI. This achievement was obtained through careful preparation, training, and interdepartmental collaboration and occurred despite immediate conversion from a previous thrombolytic protocol. PMID- 20844700 TI - Reasons for not meeting coronary artery disease targets of care in ambulatory practice. AB - INTRODUCTION: Four targets of care: control of blood pressure, control of low density lipoprotein cholesterol level, taking aspirin daily, and not using tobacco improve outcomes for patients with coronary artery disease (CAD). We sought to identify why, in a large multispecialty group, these targets were not being met in patients with CAD. METHODS: We thus conducted a retrospective review of patient records in the group practice's CAD registry, which is updated quarterly. RESULTS: Of a random selection of 14,973 patients in the CAD registry, 353 charts were consecutively reviewed until theoretic saturation was achieved that is, until no new information was found. We could not find any evidence of CAD in 14 patients, and we considered that all four targets had been met for 169 patients. The most frequent reasons for not meeting all targets of care among the 170 remaining patients were 1) the patient was in for a visit and the care team failed to address an unmet target of care (n = 98), 2) the patient was asked to come back for follow-up care but did not (n = 28), and 3) the patient declined an intervention that was offered (n = 14). Blood pressure and low-density lipoprotein cholesterol levels were the targets that were most frequently out of range. CONCLUSION: Giving the health care team access to tools with which they can identify the concurrent care needs of their patients could significantly increase the proportion of patients with CAD for whom care targets are met. Lists generated by these tools would also be significantly more accurate than lists generated from quarterly reports. PMID- 20844701 TI - The Protective Effect of Family Strengths in Childhood against Adolescent Pregnancy and Its Long-Term Psychosocial Consequences. AB - BACKGROUND: Few reports have addressed associations between family strengths during childhood and adolescent pregnancy and its consequences. We examined relationships among a number of childhood family strengths and adolescent pregnancy, risk behavior, and psychosocial consequences after adolescent pregnancy. METHODS: Our retrospective cohort of 4648 women older than 18 years (mean age, 56 years) received primary care in San Diego, CA. Outcomes included adolescent pregnancy and psychosocial consequences compared with number of the following childhood family strengths: family closeness, support, loyalty, protection, love, importance, and responsiveness to health needs. RESULTS: Of the cohort, 3082 participants (66%) reported 6 or 7 categories of childhood family strengths. Teen pregnancy occurred in 39%, 33%, 30%, 25%, 24%, 21%, and 19% of those with 0 or 1, 2, 3, 4, 5, 6, and 7 childhood family strengths, respectively (p for trend < 0.00001). When childhood abuse and household dysfunction were present, adjusted odds ratios (ORs) for adolescent pregnancy demonstrated an increasingly protective effect as numbers of childhood family strengths increased from 0 or 1 to 2 or 3, 4 or 5, and 6 or 7 (1.0 to 0.80), (1.0 to 0.80, 0.60, and 0.54, respectively). These findings were partly explained by progressive delays in initiation of sexual activity as the number of childhood family strengths increased. Adjusted ORs for psychosocial problem occurring decades later decreased as the number of childhood family strengths increased from 0 or 1 to 2 or 3, 4 or 5, and 6 or 7 (job problems, 1.0, 0.8, 0.6, 0.4; family problems, 1.0, 1.1, 0.7, 0.6; financial problems, 1.0, 0.9, 0.9, 0.6; high stress, 1.0, 1.1, 0.9, 0.8; uncontrollable anger, 1.0, 0.7, 0.7, 0.4). CONCLUSIONS: Childhood family strengths are strongly protective against adolescent pregnancy, early initiation of sexual activity, and long-term psychosocial consequences. PMID- 20844702 TI - Effects of 12- and 24-week multimodal interventions on physical activity, nutritional behaviors, and body mass index and its psychological predictors in severely obese adolescents at risk for diabetes. AB - BACKGROUND: Although 7% of US adolescents have impaired fasting glucose, a precursor of type 2 diabetes, research has suggested that few interventions for obese adolescents at risk for diabetes have been effective. Therefore, pediatricians seek effective behavioral treatments for referral for this age group. OBJECTIVE: We wanted to determine the effects of two different durations of nutritional and exercise treatments on changes in nutrition, physical activity, body mass index (BMI), and psychological predictors of BMI change in overweight and obese adolescents at risk for type 2 diabetes. METHODS: We obtained data from 64 pediatrician-referred patients with diabetes risk factors (mean age, 14.1 years; BMI, >=99th percentile.) Study participants were assigned to nutrition and exercise treatments for 12 weeks (n = 35) or 24 weeks (n = 29). A specific weight-loss goal was given only for the 24-week group. RESULTS: Both treatments demonstrated significant within-group changes over 12 weeks in days per week of physical activity of at least 60 minutes, physical self-concept, general self, and overall mood. However, they failed to demonstrate significant 12-week increases in fruit and vegetable intake, decreases in sweetened-beverage consumption, or decreases in BMI. Between-group differences were found only in mood changes in favor of the 12-week treatment. In the 24-week treatment, BMI change from week 12 to week 24 was significantly better than corresponding normative data (d = 0.37). Physical self-concept, general self, and mood scores at week 12 explained a significant portion of the variance in BMI change (R2 = 0.13, p = 0.04). CONCLUSION: Nutrition education alone may be insufficient for nutrition behavior change. Behavioral treatment lasting longer than 12 weeks and having a specific weight-loss goal may be useful for BMI improvements, and attention to participants' self-concept and mood may be important treatment considerations. PMID- 20844703 TI - Proactive office encounter: a systematic approach to preventive and chronic care at every patient encounter. AB - In 2007, Kaiser Permanente's (KP) Southern California Region designed and implemented a systematic in-reach program, the Proactive Office Encounter (POE), to address the growing needs of its three million patients for preventive care and management of chronic disease. The program sought staff from both primary and specialty care departments to proactively identify gaps in care and to assist physicians in closing those gaps. The POE engaged the entire health team in a proactive patient-care experience, creating standard work flows and using information technology to identify gaps in patient care. The goals were to improve consistency of preventive care and improve quality of care for chronic conditions and to improve reliability of staff support for physicians. The POE has been implemented in all outpatient settings in KP's Southern California Region's 13 medical centers and 148 medical office buildings. The program has contributed to significant improvements in key clinical quality metrics, including cancer screenings, blood pressure control, and tobacco cessation. It is now being extended into the inpatient setting and is being shared with other KP Regions. PMID- 20844704 TI - An alternate model for medical education: longitudinal medical education within an integrated health care organization- a vision of a model for the future? PMID- 20844705 TI - The northern california perinatal research unit: a hybrid model bridging research, quality improvement and clinical practice. AB - Kaiser Permanente (KP) has a long-standing commitment to conduct research and report publicly. Simultaneously, it faces a different imperative: harnessing information systems to leverage internal improvements in outcomes, efficiency, and costs. Now that KP HealthConnect, the KP electronic health record, is fully implemented, research challenges at KP are moving away from issues of data access and toward the mechanisms through which raw data create meaningful clinical knowledge that is based on rigorous research. In this report we describe a model for research-the Northern California Division of Research Perinatal Research Unit that leverages internal and external resources to fulfill these twin missions. PMID- 20844707 TI - Thiazolidinediones: a 2010 perspective. AB - A large number of cardiology clinical trials have mortality as an endpoint unless adequate surrogate endpoints are available. Although there are nine classes of agents used in the treatment of diabetes mellitus, none have shown a mortality benefit in clinical trials. The United Kingdom Prospective Diabetic Study was the first to suggest that metformin given for diabetes mellitus had a trend toward lowering mortality. The accidental discovery of peroxisome proliferator-activated receptors (PPARs) led to the introduction of the thiazolidinediones (TZD), a PPAR agent with a suggestion of a promise for the future. As the incidence of cardiovascular complications related to diabetes mellitus increases, there is a sense of urgency to produce antidiabetic medications that achieve not only nontoxic glycemic control but also improved cardiovascular outcomes. The goal of this review is to aid the clinician to appropriately assess the benefits and risks of TZD use when prescribing for patients. PMID- 20844706 TI - Overview of emerging concepts in metabolic surgery. PMID- 20844708 TI - ECG Diagnosis: Hypothermia. PMID- 20844709 TI - Image diagnosis: interesting chest radiographs from the emergency department. PMID- 20844710 TI - Tribute. PMID- 20844711 TI - HAITI: The Kaiser Permanente Experience-Part 1. PMID- 20844712 TI - From tragedy, opportunity-a new beginning for haiti and the dominican republic. PMID- 20844713 TI - Haiti-forgotten already? PMID- 20844714 TI - Mes quatre fils (my four sons). PMID- 20844715 TI - Disaster medical relief- haiti earthquake january 12, 2010. PMID- 20844716 TI - Mentoring About Vector-borne Disease Control. PMID- 20844717 TI - First Responders: The DMAT Team. PMID- 20844718 TI - Disaster readiness tips steeped in my time in haiti. PMID- 20844719 TI - Dear editors and readers. PMID- 20844720 TI - Dear editor. PMID- 20844723 TI - The iris - a window into the genetics of common and rare eye diseases. AB - Visual examination, without instruments, of the eye allows inspection of the iris, sclera, cornea and, through the iris, some abnormalities of the lens and retina. Several hereditary disorders can easily be recognised by characteristic iris changes. This review discusses changes in the iris, visible lens anomalies, and changes in the cornea surrounding the iris. A genetic diagnosis can help with management of diseases. Some conditions are single gene disorders, some are chromosomal rearrangements, and some are abnormalities of fetal development. PMID- 20844724 TI - Are alcohol-related acute surgical admission rates falling? AB - BACKGROUND: Alcohol-related admissions (ARA) represent a significant burden on hospital resources. The study objectives were to assess alcohol-related acute surgical admissions to a District General Hospital over a 5-year period, to determine the cost of these admissions and to consider strategies to affect future admission rates. METHODS: A prospective observational study was completed from October 2007 to March 2008. A daily review of acute surgical admissions determined whether alcohol was a factor for patients admitted. Data recorded included patient demographics, clinical presentation, investigations and final outcomes. This data was then compared with a previously completed prospective study between November 2002 and March 2003. RESULTS: Overall emergency surgical admissions during the study period were 1,125 (10.4%) compared to 838 (11.02%) in 2002. There was a 1.1% reduction in ARA from 9.5% (80/838) in 2002 to 8.4% (94/1,125) in 2007. The majority of ARA were male (82.8%) and 59.8% of ARA were under 40 years of age. ARA secondary to road traffic collisions (RTC) were reduced in 2007 compared to 2002 (12.5% to 8.5%). However, head injuries (30.0% to 48.9%) and pancreatitis (3.8% to 19.1%) secondary to alcohol had increased (p=0.27). 79.3% of admissions occurred out of hours. Although use of plain x-rays had decreased (70% to 54.3%, p=0.018), CT imaging (11.3% to 20.2%, p=0.67) and upper GI endoscopy had increased (2.5% to 7.4%, p=0.82). Blood alcohol levels increased with 83.0% of patients in 2007 compared to 60.9% in 2002 admitted with a level greater than 151mg/100mls (p=0.10). The overall cost of ARA over one year was calculated at L341,796. CONCLUSION: Alcohol-related admissions have reduced at this District General Hospital. However, despite recent government initiatives it still remains unclear how these factors affected ARA, as blood alcohol levels, alcohol-related head injuries and pancreatitis admissions all increased. Our findings highlight the relevance of the implementation of an inpatient alcohol policy combined with the availability of an alcohol liaison nurse in all acute surgical units. PMID- 20844725 TI - Current trends in Antenatal Screening Services: Results from a regional survey. AB - OBJECTIVE: To identify variations in current antenatal screening programmes across one region and compare results with a previous survey. DESIGN: A cross section descriptive survey. SETTING: All maternity units within the region of Northern Ireland. SAMPLE: Eleven maternity units were invited and ten agreed to participate. MAIN OUTCOME MEASURES: The number of written policies for individual screening tests; the range of screening tests offered; the frequency of training opportunities for health professionals; and the information systems in place to record data. RESULTS: There is variation in service provision across maternity units and, in particular, inconsistency in the offer of serum screening tests for Down syndrome. A lack of training opportunities for health professionals involved in offering screening was highlighted, and no common information system employed. CONCLUSION: While improvements have been made since 2002, variations persist. This is leading to inequalities in the provision of antenatal screening services across Northern Ireland. PMID- 20844726 TI - Laparoscopic cardiomyotomy for achalasia: A single unit study. AB - AIMS: Achalasia is a rare incurable neuromuscular disorder of the oesophagus. A number of treatment options are available. We reviewed our results of laparoscopic cardiomyotomy over a 30 month period. METHODS: 18 patients with manometric features of achalasia underwent surgery between 2004 and 2006. Pre and postoperative weight and dysphagia scores were recorded (maximum score 45=normal, 0=complete dysphagia). Change in the Body Mass Index (BMI) was measured. Other symptoms (heartburn, epigastric pain, regurgitation, odynophagia and sleep disturbance) were scored on a 0-4 scale of increasing severity. RESULTS: At mean follow up of 16.2 months the mean dysphagia score was significantly improved from 7.5 to 33.9 (p<0.005). BMI was significantly increased from 22.3 to 25.8 kg/m(2) (p<0.05). Scores for heartburn, epigastric pain, regurgitation, odynophagia and sleep disturbance were also significantly improved. The average inpatient stay was 3.1 days and average operating time 111 minutes. One mucosal perforation occurred which was repaired intraoperatively. No patients required secondary operative intervention. CONCLUSIONS: Laparoscopic cardiomyotomy is a safe, highly effective, minimally invasive treatment for achalasia. PMID- 20844727 TI - Baffling perforation of the colon. PMID- 20844728 TI - Paraneoplastic limbic encephalitis in an elderly patient with small cell lung carcinoma. AB - We report a case of paraneoplastic limbic encephalitis (PLE) in an elderly lady with small-cell lung carcinoma (SCLC) and positive anti-RI neuronal auto antibody. PLE is a relatively rare clinical entity associated with cancer patients, but is probably under-diagnosed. PLE typically presents clinically with affective changes in personality, cognitive dysfunction and seizures in a patient with malignancy, particularly SCLC. Although diagnosis does not rely upon definitive investigation results, serum paraneoplastic antibodies, abnormal CSF, and characteristic MRI and EEG findings may support the diagnosis. As PLE often presents prior to the discovery of a primary tumour, knowledge of the disease may assist in identifying underlying malignancy. PMID- 20844729 TI - Sir Hans Sloane (1660-1735): his life and legacy. AB - Sir Hans Sloane was born in Killyleagh, Co Down, the seventh and last son of Alexander Sloane. His father, who was of Scottish ancestry, had a long association with James Hamilton, Earl of Clanbrassil who had acquired the castle in Killyleagh and extensive estates in east Down. The Hamilton family took an interest in the education of the Sloane children, and much of the early tuition of Hans was conducted within the library of Killyleagh Castle. In 1679 he moved to London to study medicine and botany. In 1683, he continued his studies in Paris and Montpellier, and graduated from the University of Orange. On his return to London, he became a protege of Thomas Sydenham. In 1687 he was appointed physician to the Duke of Albemarle and surgeon to the West Indies fleet. While in Jamaica he added countless specimens to his collections, continuing a lifetime passion. He also invented milk chocolate there. Following the untimely death of the duke, he returned to London and built up a fashionable medical practice. He married Elizabeth Langley, heiress of a wealthy city alderman, and widow of a sugar planter in Jamaica. They set up house in Great Russell Street. The family home accommodated his burgeoning collections of books, specimens and curiosities. In 1685 he was elected a Fellow of the Royal Society, later becoming the honorary secretary and president. Following his death, his collections were bought for the nation and formed the foundation of the British Museum. PMID- 20844730 TI - Embolic stroke as a late complication of inferior vena cava thrombosis. PMID- 20844731 TI - Sir William Whitla's family name. PMID- 20844732 TI - Comparison of public perceptions associated with healthcare-associated infections (HCAIS) in Northern Ireland following the 2007/2008 outbreak of Clostridium difficile in the Northern Trust. PMID- 20844733 TI - A third status. PMID- 20844734 TI - Role of th17 cell and autoimmunity in chronic obstructive pulmonary disease. AB - The molecular mechanisms involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) are poorly defined. Accumulating evidences indicate that chronic inflammatory responses and adaptive immunity play important roles in the development and progression of the disease. Recently, it has been shown that IL 17 producing CD4 T cells, named Th17 cells, which have been implicated in the pathogenesis of several inflammatory and autoimmune diseases, are involved in airway inflammation and COPD. In addition, we and others suggest that autoimmunity may play a critical role in the pathogenesis of COPD. Here, we will review the current understanding of roles of Th17 cells and autoimmune responses in COPD. PMID- 20844735 TI - Heterogeneity of IL-22-producing Lymphoid Tissue Inducer-like Cells in Human and Mouse. AB - Lymphoid tissue inducer (LTi) cells have been characterized in mouse as a key cell when secondary lymphoid tissues are organized during development and memory T cells are formed after birth. In addition to their involvement in adaptive immune responses, recent studies show that they contribute to innate immune responses by producing large amount of interleukin (IL)-22 against microbial attack. Here, we compare IL-22-producing LTi and LTi-like cells in human and mouse and discuss their heterogeneity in different tissues. PMID- 20844736 TI - T-cell dysfunction and inhibitory receptors in hepatitis C virus infection. AB - Dysfunction of the virus-specific T cells is a cardinal feature in chronic persistent viral infections such as one caused by hepatitis C virus (HCV). In chronic HCV infection, virus-specific dysfunctional CD8 T cells often overexpress various inhibitory receptors. Programmed cell death 1 (PD-1) was the first among these inhibitory receptors that were identified to be overexpressed in functionally impaired T cells. The roles of other inhibitory receptors such as cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and T cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) have also been demonstrated in T cell dysfunctions that occur in chronic HCV patients. Blocking these inhibitory receptors in vitro restores the functions of HCV-specific CD8 T cells and allows enhanced proliferation, cytolytic activity and cytokine production. Therefore, the blockade of the inhibitory receptors is considered as a novel strategy for the treatment of chronic HCV infection. PMID- 20844738 TI - Cordyceps militaris Enhances MHC-restricted Antigen Presentation via the Induced Expression of MHC Molecules and Production of Cytokines. AB - BACKGROUND: Cordyceps militarys water extract (CME) has been reported to exert antitumor and immunomodulatory activities in vivo and in vitro. However, the therapeutic mechanism has not yet been elucidated. In this study, we examined the effects of CME on the antigen presenting function of antigen presenting cells (APCs). METHODS: Dendritic cells (DCs) were cultured in the presence of CME, and then allowed to phagocytose microspheres containing ovalbumin (OVA). After washing and fixing the efficacy of OVA, peptide presentation by DCs were evaluated using CD8 and CD4 T cells. Also, we confirmed the protein levels of proinflammatory cytokines through western blot analysis. RESULTS: CME enhanced both MHC class I and class II-restricted presentation of OVA in DCs. In addition, the expression of both MHC class I and II molecules was enhanced, but there was no changes in the phagocytic activity of exogenous OVA. Furthermore, CME induced the protein levels of iNOS, COX-2, proinflammatory cytokines, and nuclear p65 in a concentration-dependent manner, as determined by western blot. CONCLUSION: These results provide an understanding of the mechanism of the immuno-enhancing activity of CME on the induction of MHC-restricted antigen presentation in relation to their actions on APCs. PMID- 20844737 TI - Expression of hepatitis B virus x protein in hepatocytes suppresses CD8 T cell activity. AB - BACKGROUND: CD8(+) T cells contribute to the clearance of Hepatitis B virus (HBV) infection and an insufficient CD8(+) T cell response may be one of the major factors leading to chronic HBV infection. Since the HBx antigen of HBV can up regulate cellular expression of several immunomodulatory molecules, we hypothesized that HBx expression in hepatocytes might affect CD8(+) T cell activity. METHODS: We analyzed the activation and apoptosis of CD8(+) T cells co cultured with primary hepatocytes rendered capable of expressing HBx by recombinant baculovirus infection. RESULTS: Expression of HBx in hepatocytes induced low production of interferon-gamma and apoptosis of CD8(+) T cells, with no effect on CD8 T cell proliferation. However, transcriptional levels of H-2K, ICAM-1 and PD-1 ligand did not correlate with HBx expression in hepatocytes. CONCLUSION: Our results suggest that HBx may inhibit CD8(+) T cell response by regulation of interferon-gamma production and apoptosis. PMID- 20844739 TI - A comprehensive and universal method for assessing the performance of differential gene expression analyses. AB - The number of methods for pre-processing and analysis of gene expression data continues to increase, often making it difficult to select the most appropriate approach. We present a simple procedure for comparative estimation of a variety of methods for microarray data pre-processing and analysis. Our approach is based on the use of real microarray data in which controlled fold changes are introduced into 20% of the data to provide a metric for comparison with the unmodified data. The data modifications can be easily applied to raw data measured with any technological platform and retains all the complex structures and statistical characteristics of the real-world data. The power of the method is illustrated by its application to the quantitative comparison of different methods of normalization and analysis of microarray data. Our results demonstrate that the method of controlled modifications of real experimental data provides a simple tool for assessing the performance of data preprocessing and analysis methods. PMID- 20844740 TI - Reduced expression of IFIH1 is protective for type 1 diabetes. AB - IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response. IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function. Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala. This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala(946), may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles. We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-beta stimulated peripheral blood mononuclear cells (overall p = 0.012). In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1). We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1. These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D. PMID- 20844742 TI - Cpd-1 null mice display a subtle neurological phenotype. AB - BACKGROUND: CPD1 (also known as ANP32-E) belongs to a family of evolutionarily conserved acidic proteins with leucine rich repeats implicated in a variety of cellular processes regulating gene expression, vesicular trafficking, intracellular signaling and apoptosis. Because of its spatiotemporal expression pattern, CPD1 has been proposed to play an important role in brain morphogenesis and synaptic development. METHODOLOGY/PRINCIPAL FINDINGS: We have generated CPD1 knock-out mice that we have subsequently characterized. These mice are viable and fertile. However, they display a subtle neurological clasping phenotype and mild motor deficits. CONCLUSIONS/SIGNIFICANCE: CPD1 is not essential for normal development; however, it appears to play a role in the regulation of fine motor functions. The minimal phenotype suggests compensatory biological mechanisms. PMID- 20844741 TI - Assessing the performance of a computer-based policy model of HIV and AIDS. AB - BACKGROUND: Model-based analyses, conducted within a decision analytic framework, provide a systematic way to combine information about the natural history of disease and effectiveness of clinical management strategies with demographic and epidemiological characteristics of the population. Among the challenges with disease-specific modeling include the need to identify influential assumptions and to assess the face validity and internal consistency of the model. METHODS AND FINDINGS: We describe a series of exercises involved in adapting a computer based simulation model of HIV disease to the Women's Interagency HIV Study (WIHS) cohort and assess model performance as we re-parameterized the model to address policy questions in the U.S. relevant to HIV-infected women using data from the WIHS. Empiric calibration targets included 24-month survival curves stratified by treatment status and CD4 cell count. The most influential assumptions in untreated women included chronic HIV-associated mortality following an opportunistic infection, and in treated women, the 'clinical effectiveness' of HAART and the ability of HAART to prevent HIV complications independent of virologic suppression. Good-fitting parameter sets required reductions in the clinical effectiveness of 1st and 2nd line HAART and improvements in 3rd and 4th line regimens. Projected rates of treatment regimen switching using the calibrated cohort-specific model closely approximated independent analyses published using data from the WIHS. CONCLUSIONS: The model demonstrated good internal consistency and face validity, and supported cohort heterogeneities that have been reported in the literature. Iterative assessment of model performance can provide information about the relative influence of uncertain assumptions and provide insight into heterogeneities within and between cohorts. Description of calibration exercises can enhance the transparency of disease-specific models. PMID- 20844744 TI - Serosorting is associated with a decreased risk of HIV seroconversion in the EXPLORE Study Cohort. AB - BACKGROUND: Seroadaptation strategies such as serosorting and seropositioning originated within communities of men who have sex with men (MSM), but there are limited data about their effectiveness in preventing HIV transmission when utilized by HIV-negative men. METHODOLOGY/PRINCIPAL FINDINGS: Data from the EXPLORE cohort of HIV-negative MSM who reported both seroconcordant and serodiscordant partners were used to evaluate serosorting and seropositioning. The association of serosorting and seropositioning with HIV seroconversion was evaluated in this cohort of high risk MSM from six U.S. cities. Serosorting was independently associated with a small decrease in risk of HIV seroconversion (OR=0.88; 95%CI, 0.81-0.95), even among participants reporting >=10 partners. Those who more consistently practiced serosorting were more likely to be white (p=0.01), have completed college (p=<0.0002) and to have had 10 or more partners in the six months before the baseline visit (p=0.01) but did not differ in age, reporting HIV-infected partners, or drug use. There was no evidence of a seroconversion effect with seropositioning (OR 1.02, 95%CI, 0.92-1.14). SIGNIFICANCE: In high risk HIV uninfected MSM who report unprotected anal intercourse with both seroconcordant and serodiscordant partners, serosorting was associated with a modest decreased risk of HIV infection. To maximize any potential benefit, it will be important to increase accurate knowledge of HIV status, through increased testing frequency, improved test technology, and continued development of strategies to increase disclosure. PMID- 20844743 TI - Single nucleotide polymorphisms in the Wnt and BMP pathways and colorectal cancer risk in a Spanish cohort. AB - BACKGROUND: Colorectal cancer (CRC) is considered a complex disease, and thus the majority of the genetic susceptibility is thought to lie in the form of low penetrance variants following a polygenic model of inheritance. Candidate-gene studies have so far been one of the basic approaches taken to identify these susceptibility variants. The consistent involvement of some signaling routes in carcinogenesis provided support for pathway-based studies as a natural strategy to select genes that could potentially harbour new susceptibility loci. METHODOLOGY/PRINCIPAL FINDINGS: We selected two main carcinogenesis-related pathways: Wnt and BMP, in order to screen the implicated genes for new risk variants. We then conducted a case-control association study in 933 CRC cases and 969 controls based on coding and regulatory SNPs. We also included rs4444235 and rs9929218, which did not fulfill our selection criteria but belonged to two genes in the BMP pathway and had consistently been linked to CRC in previous studies. Neither allelic, nor genotypic or haplotypic analyses showed any signs of association between the 37 screened variants and CRC risk. Adjustments for sex and age, and stratified analysis between sporadic and control groups did not yield any positive results either. CONCLUSIONS/SIGNIFICANCE: Despite the relevance of both pathways in the pathogenesis of the disease, and the fact that this is indeed the first study that considers these pathways as a candidate-gene selection approach, our study does not present any evidence of the presence of low-penetrance variants for the selected markers in any of the considered genes in our cohort. PMID- 20844745 TI - Skewed distribution of circulating activated natural killer T (NKT) cells in patients with common variable immunodeficiency disorders (CVID). AB - Common variable immunodeficiency disorder (CVID) is the commonest cause of primary antibody failure in adults and children, and characterized clinically by recurrent bacterial infections and autoimmune manifestations. Several innate immune defects have been described in CVID, but no study has yet investigated the frequency, phenotype or function of the key regulatory cell population, natural killer T (NKT) cells. We measured the frequencies and subsets of NKT cells in patients with CVID and compared these to healthy controls. Our results show a skewing of NKT cell subsets, with CD4+ NKT cells at higher frequencies, and CD8+ NKT cells at lower frequencies. However, these cells were highly activated and expression CD161. The NKT cells had a higher expression of CCR5 and concomitantly expression of CCR5+CD69+CXCR6 suggesting a compensation of the remaining population of NKT cells for rapid effector action. PMID- 20844747 TI - Evidence for a novel marine harmful algal bloom: cyanotoxin (microcystin) transfer from land to sea otters. AB - "Super-blooms" of cyanobacteria that produce potent and environmentally persistent biotoxins (microcystins) are an emerging global health issue in freshwater habitats. Monitoring of the marine environment for secondary impacts has been minimal, although microcystin-contaminated freshwater is known to be entering marine ecosystems. Here we confirm deaths of marine mammals from microcystin intoxication and provide evidence implicating land-sea flow with trophic transfer through marine invertebrates as the most likely route of exposure. This hypothesis was evaluated through environmental detection of potential freshwater and marine microcystin sources, sea otter necropsy with biochemical analysis of tissues and evaluation of bioaccumulation of freshwater microcystins by marine invertebrates. Ocean discharge of freshwater microcystins was confirmed for three nutrient-impaired rivers flowing into the Monterey Bay National Marine Sanctuary, and microcystin concentrations up to 2,900 ppm (2.9 million ppb) were detected in a freshwater lake and downstream tributaries to within 1 km of the ocean. Deaths of 21 southern sea otters, a federally listed threatened species, were linked to microcystin intoxication. Finally, farmed and free-living marine clams, mussels and oysters of species that are often consumed by sea otters and humans exhibited significant biomagnification (to 107 times ambient water levels) and slow depuration of freshwater cyanotoxins, suggesting a potentially serious environmental and public health threat that extends from the lowest trophic levels of nutrient-impaired freshwater habitat to apex marine predators. Microcystin-poisoned sea otters were commonly recovered near river mouths and harbors and contaminated marine bivalves were implicated as the most likely source of this potent hepatotoxin for wild otters. This is the first report of deaths of marine mammals due to cyanotoxins and confirms the existence of a novel class of marine "harmful algal bloom" in the Pacific coastal environment; that of hepatotoxic shellfish poisoning (HSP), suggesting that animals and humans are at risk from microcystin poisoning when consuming shellfish harvested at the land-sea interface. PMID- 20844746 TI - Electron tomography of cryofixed, isometrically contracting insect flight muscle reveals novel actin-myosin interactions. AB - BACKGROUND: Isometric muscle contraction, where force is generated without muscle shortening, is a molecular traffic jam in which the number of actin-attached motors is maximized and all states of motor action are trapped with consequently high heterogeneity. This heterogeneity is a major limitation to deciphering myosin conformational changes in situ. METHODOLOGY: We used multivariate data analysis to group repeat segments in electron tomograms of isometrically contracting insect flight muscle, mechanically monitored, rapidly frozen, freeze substituted, and thin sectioned. Improved resolution reveals the helical arrangement of F-actin subunits in the thin filament enabling an atomic model to be built into the thin filament density independent of the myosin. Actin-myosin attachments can now be assigned as weak or strong by their motor domain orientation relative to actin. Myosin attachments were quantified everywhere along the thin filament including troponin. Strong binding myosin attachments are found on only four F-actin subunits, the "target zone", situated exactly midway between successive troponin complexes. They show an axial lever arm range of 77 degrees /12.9 nm. The lever arm azimuthal range of strong binding attachments has a highly skewed, 127 degrees range compared with X-ray crystallographic structures. Two types of weak actin attachments are described. One type, found exclusively in the target zone, appears to represent pre-working-stroke intermediates. The other, which contacts tropomyosin rather than actin, is positioned M-ward of the target zone, i.e. the position toward which thin filaments slide during shortening. CONCLUSION: We present a model for the weak to strong transition in the myosin ATPase cycle that incorporates azimuthal movements of the motor domain on actin. Stress/strain in the S2 domain may explain azimuthal lever arm changes in the strong binding attachments. The results support previous conclusions that the weak attachments preceding force generation are very different from strong binding attachments. PMID- 20844748 TI - Copy number analysis identifies novel interactions between genomic loci in ovarian cancer. AB - Ovarian cancer is a heterogeneous disease displaying complex genomic alterations, and consequently, it has been difficult to determine the most relevant copy number alterations with the scale of studies to date. We obtained genome-wide copy number alteration (CNA) data from four different SNP array platforms, with a final data set of 398 ovarian tumours, mostly of the serous histological subtype. Frequent CNA aberrations targeted many thousands of genes. However, high-level amplicons and homozygous deletions enabled filtering of this list to the most relevant. The large data set enabled refinement of minimal regions and identification of rare amplicons such as at 1p34 and 20q11. We performed a novel co-occurrence analysis to assess cooperation and exclusivity of CNAs and analysed their relationship to patient outcome. Positive associations were identified between gains on 19 and 20q, gain of 20q and loss of X, and between several regions of loss, particularly 17q. We found weak correlations of CNA at genomic loci such as 19q12 with clinical outcome. We also assessed genomic instability measures and found a correlation of the number of higher amplitude gains with poorer overall survival. By assembling the largest collection of ovarian copy number data to date, we have been able to identify the most frequent aberrations and their interactions. PMID- 20844749 TI - Possession and usage of insecticidal bed nets among the people of Uganda: is BRAC Uganda Health Programme pursuing a pro-poor path? AB - BACKGROUND: The use of insecticidal bed nets is found to be an effective public health tool for control of malaria, especially for under-five children and pregnant women. BRAC, an indigenous Bangladeshi non-governmental development organization, started working in the East African state of Uganda in June 2006. As part of its efforts to improve the health and well-being of its participants, BRAC Uganda has been distributing long lasting insecticide-treated bed nets (LLIN) at a subsidized price through health volunteers since February 2008. This study was conducted in March-April 2009 to examine how equitable the programme had been in consistence with BRAC Uganda's pro-poor policy. METHODOLOGY/PRINCIPAL FINDINGS: Information on possession of LLINs and relevant knowledge on its proper use and maintenance was collected from households either with an under-five child and/or a pregnant woman. The sample included three villages from each of the 10 branch offices where BRAC Uganda's community-based health programme was operating. Data were collected by trained enumerators through face-to-face interviews using a hand-held personal digital assistant (PDA). Findings reveal that the study population had superficial knowledge on malaria and its transmission, including the use and maintenance of LLINs. The households' rate of possession of bed nets (41-59%), and the proportion of under-five children (17 19%) and pregnant women (25-27%) who reported sleeping under an LLIN were not encouraging. Inequity was observed in the number of LLINs possessed by the households, in the knowledge on its use and maintenance, and between the two programme areas. CONCLUSIONS/SIGNIFICANCE: The BRAC Uganda's LLINs distribution at a subsidized price appeared to be inadequate and inequitable, and BRAC's knowledge dissemination is insufficient for initiating preventive actions such as proper use of LLINs to interrupt malaria transmission. Findings contribute to the on-going debate on LLINs distribution in Africa and make a strong case for its free distribution. PMID- 20844750 TI - High-density expression of Ca2+-permeable ASIC1a channels in NG2 glia of rat hippocampus. AB - NG2 cells, a fourth type of glial cell in the mammalian CNS, undergo reactive changes in response to a wide variety of brain insults. Recent studies have demonstrated that neuronally expressed acid-sensing ion channels (ASICs) are implicated in various neurological disorders including brain ischemia and seizures. Acidosis is a common feature of acute neurological conditions. It is postulated that a drop in pH may be the link between the pathological process and activation of NG2 cells. Such postulate immediately prompts the following questions: Do NG2 cells express ASICs? If so, what are their functional properties and subunit composition? Here, using a combination of electrophysiology, Ca2+ imaging and immunocytochemistry, we present evidence to demonstrate that NG2 cells of the rat hippocampus express high density of Ca2+ permeable ASIC1a channels compared with several types of hippocampal neurons. First, nucleated patch recordings from NG2 cells revealed high density of proton activated currents. The magnitude of proton-activated current was pH dependent, with a pH for half-maximal activation of 6.3. Second, the current-voltage relationship showed a reversal close to the equilibrium potential for Na+. Third, psalmotoxin 1, a blocker specific for the ASIC1a channel, largely inhibited proton-activated currents. Fourth, Ca2+ imaging showed that activation of proton activated channels led to an increase of [Ca2+]i. Finally, immunocytochemistry showed co-localization of ASIC1a and NG2 proteins in the hippocampus. Thus the acid chemosensor, the ASIC1a channel, may serve for inducing membrane depolarization and Ca2+ influx, thereby playing a crucial role in the NG2 cell response to injury following ischemia. PMID- 20844751 TI - Comparative studies of the pyrolytic and kinetic characteristics of maize straw and the seaweed Ulva pertusa. AB - Seaweed has attracted considerable attention as a potential biofuel feedstock. The pyrolytic and kinetic characteristics of maize straw and the seaweed Ulva pertusa were studied and compared using heating rates of 10, 30 and 50 degrees C min(-1) under an inert atmosphere. The activation energy, and pre-exponential factors were calculated by the Flynn-Wall-Ozawa (FWO), Kissinger-Akahira-Sunose (KAS) and Popescu methods. The kinetic mechanism was deduced by the Popescu method. The results indicate that there are three stages to the pyrolysis; dehydration, primary devolatilization and residual decomposition. There were significant differences in average activation energy, thermal stability, final residuals and reaction rates between the two materials. The primary devolatilization stage of U. pertusa can be described by the Avramic-Erofeev equation (n=3), whereas that of maize straw can be described by the Mampel Power Law (n=2). The average activation energy of maize straw and U. pertusa were 153.0 and 148.7 KJ mol(-1), respectively. The pyrolysis process of U.pertusa would be easier than maize straw. And co-firing of the two biomass may be require less external heat input and improve process stability. There were minor kinetic compensation effects between the pre-exponential factors and the activation energy. PMID- 20844752 TI - The CC-NB-LRR-type Rdg2a resistance gene confers immunity to the seed-borne barley leaf stripe pathogen in the absence of hypersensitive cell death. AB - BACKGROUND: Leaf stripe disease on barley (Hordeum vulgare) is caused by the seed transmitted hemi-biotrophic fungus Pyrenophora graminea. Race-specific resistance to leaf stripe is controlled by two known Rdg (Resistance to Drechslera graminea) genes: the H. spontaneum-derived Rdg1a and Rdg2a, identified in H. vulgare. The aim of the present work was to isolate the Rdg2a leaf stripe resistance gene, to characterize the Rdg2a locus organization and evolution and to elucidate the histological bases of Rdg2a-based leaf stripe resistance. PRINCIPAL FINDINGS: We describe here the positional cloning and functional characterization of the leaf stripe resistance gene Rdg2a. At the Rdg2a locus, three sequence-related coiled coil, nucleotide-binding site, and leucine-rich repeat (CC-NB-LRR) encoding genes were identified. Sequence comparisons suggested that paralogs of this resistance locus evolved through recent gene duplication, and were subjected to frequent sequence exchange. Transformation of the leaf stripe susceptible cv. Golden Promise with two Rdg2a-candidates under the control of their native 5' regulatory sequences identified a member of the CC-NB-LRR gene family that conferred resistance against the Dg2 leaf stripe isolate, against which the Rdg2a-gene is effective. Histological analysis demonstrated that Rdg2a-mediated leaf stripe resistance involves autofluorescing cells and prevents pathogen colonization in the embryos without any detectable hypersensitive cell death response, supporting a cell wall reinforcement-based resistance mechanism. CONCLUSIONS: This work reports about the cloning of a resistance gene effective against a seed borne disease. We observed that Rdg2a was subjected to diversifying selection which is consistent with a model in which the R gene co-evolves with a pathogen effector(s) gene. We propose that inducible responses giving rise to physical and chemical barriers to infection in the cell walls and intercellular spaces of the barley embryo tissues represent mechanisms by which the CC-NB-LRR-encoding Rdg2a gene mediates resistance to leaf stripe in the absence of hypersensitive cell death. PMID- 20844753 TI - Molecular decoy to the Y-box binding protein-1 suppresses the growth of breast and prostate cancer cells whilst sparing normal cell viability. AB - The Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor that is activated by phosphorylation at S102 whereby it induces the expression of growth promoting genes such as EGFR and HER-2. We recently illustrated by an in vitro kinase assay that a novel peptide to YB-1 was highly phosphorylated by the serine/threonine p90 S6 kinases RSK-1 and RSK-2, and to a lesser degree PKCalpha and AKT. Herein, we sought to develop this decoy cell permeable peptide (CPP) as a cancer therapeutic. This 9-mer was designed as an interference peptide that would prevent endogenous YB-1(S102) phosphorylation based on molecular docking. In cancer cells, the CPP blocked P-YB-1(S102) and down-regulated both HER-2 and EGFR transcript level and protein expression. Further, the CPP prevented YB-1 from binding to the EGFR promoter in a gel shift assay. Notably, the growth of breast (SUM149, MDA-MB-453, AU565) and prostate (PC3, LNCap) cancer cells was inhibited by ~90% with the CPP. Further, treatment with this peptide enhanced sensitivity and overcame resistance to trastuzumab in cells expressing amplified HER-2. By contrast, the CPP had no inhibitory effect on the growth of normal immortalized breast epithelial (184htert) cells, primary breast epithelial cells, nor did it inhibit differentiation of hematopoietic progenitors. These data collectively suggest that the CPP is a novel approach to suppressing the growth of cancer cells while sparing normal cells and thereby establishes a proof-of-concept that blocking YB-1 activation is a new course of cancer therapeutics. PMID- 20844754 TI - Diagnosis of tuberculosis in the wild boar (Sus scrofa): a comparison of methods applicable to hunter-harvested animals. AB - BACKGROUND: To obtain robust epidemiological information regarding tuberculosis (TB) in wildlife species, appropriate diagnostic methods need to be used. Wild boar (Sus scrofa) recently emerged as a major maintenance host for TB in some European countries. Nevertheless, no data is available to evaluate TB post-mortem diagnostic methods in hunter-harvested wild boar. METHODOLOGY/PRINCIPAL FINDINGS: Six different diagnostic methods for TB were evaluated in parallel in 167 hunter harvested wild boar. Compared to bacteriological culture, estimates of sensitivity of histopathology was 77.8%, gross pathology 72.2%, PCR for the MPB70 gene 66.7%, detection of acid-fast bacilli (AFB) in tissue contact smears 55.6% and in histopathology slides 16.7% (estimated specificity was 96.7%, 100%, 100%, 94.4% and 100%, respectively). Combining gross pathology with stained smears in parallel increased estimated sensitivity to 94.4% (94.4% specificity). Four probable bacteriological culture false-negative animals were identified by Discriminant Function Analysis. Recalculating the parameters considering these animals as infected generated estimated values for sensitivity of bacteriology and histopathology of 81.8%, gross pathology 72.7%, PCR for the MPB70 gene 63.6%, detection of AFB in tissue contact smears 54.5% and in histopathology slides 13.6% (estimated specificity was 100% for gross pathology, PCR, bacteriology and detection of AFB in histopathology slides, 96.7% for histopathology and 94.4% for stained smears). CONCLUSIONS/SIGNIFICANCE: These results show that surveys for TB in wild boar based exclusively on gross pathology considerably underestimate prevalence, while combination of tests in parallel much improves sensitivity and negative predictive values. This finding should thus be considered when planning future surveys and game meat inspection schemes. Although bacteriological culture is the reference test for TB diagnosis, it can generate false-negative results and this should be considered when interpreting data. PMID- 20844755 TI - Serum free cultured bone marrow mesenchymal stem cells as a platform to characterize the effects of specific molecules. AB - Human mesenchymal stem cells (hMSC) are easily isolated from the bone marrow by adherence to plastic surfaces. These cells show self-renewal capacity and multipotency. A unique feature of hMSC is their capacity to survive without serum. Under this condition hMSC neither proliferate nor differentiate but maintain their biological properties unaffected. Therefore, this should be a perfect platform to study the biological effects of defined molecules on these human stem cells. We show that hMSC treated for five days with retinoic acid (RA) in the absence of serum undergo several transcriptional changes causing an inhibition of ERK related pathways. We found that RA induces the loss of hMSC properties such as differentiation potential to either osteoblasts or adipocytes. We also found that RA inhibits cell cycle progression in the presence of proliferating signals such as epidermal growth factor (EGF) combined with basic fibroblast growth factor (bFGF). In the same manner, RA showed to cause a reduction in cell adhesion and cell migration. In contrast to these results, the addition of EGF+bFGF to serum free cultures was enough to upregulate ERK activity and induce hMSC proliferation and cell migration. Furthermore, the addition of these factors to differentiation specific media instead of serum was enough to induce either osteogenesis or adipogenesis. Altogether, our results show that hMSC's ability to survive without serum enables the identification of signaling factors and pathways that are involved in their stem cell biological characteristics without possible serum interferences. PMID- 20844756 TI - Genome scan for locus involved in mandibular prognathism in pedigrees from China. AB - BACKGROUND: It is well known that genetic components play an important role in the etiology of mandibular prognathism, but few susceptibility loci have been mapped. METHODOLOGY: In order to identify linkage regions for mandibular prognathism, we analyzed two Chinese pedigrees with 6,090 genome-wide single nucleotide polymorphism (SNP) markers from Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM). Multipoint parametric and non-parametric (model-free) linkage analyses were used for the pedigrees. PRINCIPAL FINDING: The most statistically significant linkage results were with markers on chromosome 4 (LOD=3.166 and NPL=3.65 with rs 875864, 4p16.1, 8.38 cM). Candidate genes within the 4p16.1 include EVC, EVC2. CONCLUSION: We detected a novel suggestive linkage locus for mandibular prognathism in two Chinese pedigrees, and this linkage region provides target for susceptibility gene identification, a process that will provide important insights into the molecular and cellular basis of mandibular prognathism. PMID- 20844757 TI - Extracranial sources of S100B do not affect serum levels. AB - S100B, established as prevalent protein of the central nervous system, is a peripheral biomarker for blood-brain barrier disruption and often also a marker of brain injury. However, reports of extracranial sources of S100B, especially from adipose tissue, may confound its interpretation in the clinical setting. The objective of this study was to characterize the tissue specificity of S100B and assess how extracranial sources of S100B affect serum levels. The extracranial sources of S100B were determined by analyzing nine different types of human tissues by ELISA and Western blot. In addition, brain and adipose tissue were further analyzed by mass spectrometry. A study of 200 subjects was undertaken to determine the relationship between body mass index (BMI) and S100B serum levels. We also measured the levels of S100B homo- and heterodimers in serum quantitatively after blood-brain barrier disruption. Analysis of human tissues by ELISA and Western blot revealed variable levels of S100B expression. By ELISA, brain tissue expressed the highest S100B levels. Similarly, Western blot measurements revealed that brain tissue expressed high levels of S100B but comparable levels were found in skeletal muscle. Mass spectrometry of brain and adipose tissue confirmed the presence of S100B but also revealed the presence of S100A1. The analysis of 200 subjects revealed no statistically significant relationship between BMI and S100B levels. The main species of S100B released from the brain was the B-B homodimer. Our results show that extracranial sources of S100B do not affect serum levels. Thus, the diagnostic value of S100B and its negative predictive value in neurological diseases in intact subjects (without traumatic brain or bodily injury from accident or surgery) are not compromised in the clinical setting. PMID- 20844758 TI - Claudin 13, a member of the claudin family regulated in mouse stress induced erythropoiesis. AB - Mammals are able to rapidly produce red blood cells in response to stress. The molecular pathways used in this process are important in understanding responses to anaemia in multiple biological settings. Here we characterise the novel gene Claudin 13 (Cldn13), a member of the Claudin family of tight junction proteins using RNA expression, microarray and phylogenetic analysis. We present evidence that Cldn13 appears to be co-ordinately regulated as part of a stress induced erythropoiesis pathway and is a mouse-specific gene mainly expressed in tissues associated with haematopoietic function. CLDN13 phylogenetically groups with its genomic neighbour CLDN4, a conserved tight junction protein with a putative role in epithelial to mesenchymal transition, suggesting a recent duplication event. Mechanisms of mammalian stress erythropoiesis are of importance in anaemic responses and expression microarray analyses demonstrate that Cldn13 is the most abundant Claudin in spleen from mice infected with Trypanosoma congolense. In mice prone to anaemia (C57BL/6), its expression is reduced compared to strains which display a less severe anaemic response (A/J and BALB/c) and is differentially regulated in spleen during disease progression. Genes clustering with Cldn13 on microarrays are key regulators of erythropoiesis (Tal1, Trim10, E2f2), erythrocyte membrane proteins (Rhd and Gypa), associated with red cell volume (Tmcc2) and indirectly associated with erythropoietic pathways (Cdca8, Cdkn2d, Cenpk). Relationships between genes appearing co-ordinately regulated with Cldn13 post-infection suggest new insights into the molecular regulation and pathways involved in stress induced erythropoiesis and suggest a novel, previously unreported role for claudins in correct cell polarisation and protein partitioning prior to erythroblast enucleation. PMID- 20844759 TI - Functional characterization of the incomplete phosphotransferase system (PTS) of the intracellular pathogen Brucella melitensis. AB - BACKGROUND: In many bacteria, the phosphotransferase system (PTS) is a key player in the regulation of the assimilation of alternative carbon sources notably through catabolic repression. The intracellular pathogens Brucella spp. possess four PTS proteins (EINtr, NPr, EIIANtr and an EIIA of the mannose family) but no PTS permease suggesting that this PTS might serve only regulatory functions. METHODOLOGY/PRINCIPAL FINDINGS: In vitro biochemical analyses and in vivo detection of two forms of EIIANtr (phosphorylated or not) established that the four PTS proteins of Brucella melitensis form a functional phosphorelay. Moreover, in vitro the protein kinase HprK/P phosphorylates NPr on a conserved serine residue, providing an additional level of regulation to the B. melitensis PTS. This kinase activity was inhibited by inorganic phosphate and stimulated by fructose-1,6 bisphosphate. The genes encoding HprK/P, an EIIAMan-like protein and NPr are clustered in a locus conserved among alpha-proteobacteria and also contain the genes for the crucial two-component system BvrR-BvrS. RT-PCR revealed a transcriptional link between these genes suggesting an interaction between PTS and BvrR-BvrS. Mutations leading to the inactivation of EINtr or NPr significantly lowered the synthesis of VirB proteins, which form a type IV secretion system. These two mutants also exhibit a small colony phenotype on solid media. Finally, interaction partners of PTS proteins were identified using a yeast two hybrid screen against the whole B. melitensis ORFeome. Both NPr and HprK/P were shown to interact with an inorganic pyrophosphatase and the EIIAMan like protein with the E1 component (SucA) of 2-oxoglutarate dehydrogenase. CONCLUSIONS/SIGNIFICANCE: The B. melitensis can transfer the phosphoryl group from PEP to the EIIAs and a link between the PTS and the virulence of this organism could be established. Based on the protein interaction data a preliminary model is proposed in which this regulatory PTS coordinates also C and N metabolism. PMID- 20844760 TI - Monoculture of leafcutter ant gardens. AB - BACKGROUND: Leafcutter ants depend on the cultivation of symbiotic Attamyces fungi for food, which are thought to be grown by the ants in single-strain, clonal monoculture throughout the hundreds to thousands of gardens within a leafcutter nest. Monoculture eliminates cultivar-cultivar competition that would select for competitive fungal traits that are detrimental to the ants, whereas polyculture of several fungi could increase nutritional diversity and disease resistance of genetically variable gardens. METHODOLOGY/PRINCIPAL FINDINGS: Using three experimental approaches, we assessed cultivar diversity within nests of Atta leafcutter ants, which are most likely among all fungus-growing ants to cultivate distinct cultivar genotypes per nest because of the nests' enormous sizes (up to 5000 gardens) and extended lifespans (10-20 years). In Atta texana and in A. cephalotes, we resampled nests over a 5-year period to test for persistence of resident cultivar genotypes within each nest, and we tested for genetic differences between fungi from different nest sectors accessed through excavation. In A. texana, we also determined the number of Attamyces cells carried as a starter inoculum by a dispersing queens (minimally several thousand Attamyces cells), and we tested for genetic differences between Attamyces carried by sister queens dispersing from the same nest. Except for mutational variation arising during clonal Attamyces propagation, DNA fingerprinting revealed no evidence for fungal polyculture and no genotype turnover during the 5-year surveys. CONCLUSIONS/SIGNIFICANCE: Atta leafcutter ants can achieve stable, fungal monoculture over many years. Mutational variation emerging within an Attamyces monoculture could provide genetic diversity for symbiont choice (gardening biases of the ants favoring specific mutational variants), an analog of artificial selection. PMID- 20844761 TI - LYL1 degradation by the proteasome is directed by a N-terminal PEST rich site in a phosphorylation-independent manner. AB - BACKGROUND: The Lymphoblastic leukemia 1 (LYL1) gene is a proto-oncogenic transcription factor found upregulated in patients with T-cell acute lymphoblastic leukemia (T-cell ALL). Initially, the upregulation was described to be as a result of a translocation. However, further studies revealed that transcriptional upregulation of LYL1could also occur without translocations. In addition, post-translational mechanisms, such as protein degradation could influence LYL1 expression as well. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we considered possible post-translational regulation of Lyl1, and investigated fundamental mechanisms governing LYL1 degradation in cell-based culture assays. We identify a PEST sequence motif located in the N-terminus of LYL1, which determines the efficiency of LYL1 degradation by the proteasome. The absence of the PEST degradation site leads to accumulation or upregulation of LYL1. We also show that LYL1 is phosphorylated by MAPK at S36, and determined that proteasomal degradation of LYL1 occurs in a phosphorylation-independent manner. CONCLUSIONS/SIGNIFICANCE: Understanding LYL1 degradation is a step forward not only towards deciphering the normal function and regulation of LYL1, but could suggest post-translational mechanisms for upregulation of LYL1 that may contribute to its oncogenic role. PMID- 20844762 TI - Mucoidy, quorum sensing, mismatch repair and antibiotic resistance in Pseudomonas aeruginosa from cystic fibrosis chronic airways infections. AB - Survival of Pseudomonas aeruginosa in cystic fibrosis (CF) chronic infections is based on a genetic adaptation process consisting of mutations in specific genes, which can produce advantageous phenotypic switches and ensure its persistence in the lung. Among these, mutations inactivating the regulators MucA (alginate biosynthesis), LasR (quorum sensing) and MexZ (multidrug-efflux pump MexXY) are the most frequently observed, with those inactivating the DNA mismatch repair system (MRS) being also highly prevalent in P. aeruginosa CF isolates, leading to hypermutator phenotypes that could contribute to this adaptive mutagenesis by virtue of an increased mutation rate. Here, we characterized the mutations found in the mucA, lasR, mexZ and MRS genes in P. aeruginosa isolates obtained from Argentinean CF patients, and analyzed the potential association of mucA, lasR and mexZ mutagenesis with MRS-deficiency and antibiotic resistance. Thus, 38 isolates from 26 chronically infected CF patients were characterized for their phenotypic traits, PFGE genotypic patterns, mutations in the mucA, lasR, mexZ, mutS and mutL gene coding sequences and antibiotic resistance profiles. The most frequently mutated gene was mexZ (79%), followed by mucA (63%) and lasR (39%) as well as a high prevalence (42%) of hypermutators being observed due to loss-of-function mutations in mutL (60%) followed by mutS (40%). Interestingly, mutational spectra were particular to each gene, suggesting that several mechanisms are responsible for mutations during chronic infection. However, no link could be established between hypermutability and mutagenesis in mucA, lasR and mexZ, indicating that MRS-deficiency was not involved in the acquisition of these mutations. Finally, although inactivation of mucA, lasR and mexZ has been previously shown to confer resistance/tolerance to antibiotics, only mutations in MRS genes could be related to an antibiotic resistance increase. These results help to unravel the mutational dynamics that lead to the adaptation of P. aeruginosa to the CF lung. PMID- 20844763 TI - Alphavirus replicon particles expressing TRP-2 provide potent therapeutic effect on melanoma through activation of humoral and cellular immunity. AB - BACKGROUND: Malignant melanoma is the deadliest form of skin cancer and is refractory to conventional chemotherapy and radiotherapy. Therefore alternative approaches to treat this disease, such as immunotherapy, are needed. Melanoma vaccine design has mainly focused on targeting CD8+ T cells. Activation of effector CD8+ T cells has been achieved in patients, but provided limited clinical benefit, due to immune-escape mechanisms established by advanced tumors. We have previously shown that alphavirus-based virus-like replicon particles (VRP) simultaneously activate strong cellular and humoral immunity against the weakly immunogenic melanoma differentiation antigen (MDA) tyrosinase. Here we further investigate the antitumor effect and the immune mechanisms of VRP encoding different MDAs. METHODOLOGY/PRINCIPAL FINDINGS: VRP encoding different MDAs were screened for their ability to prevent the growth of the B16 mouse transplantable melanoma. The immunologic mechanisms of efficacy were investigated for the most effective vaccine identified, focusing on CD8+ T cells and humoral responses. To this end, ex vivo immune assays and transgenic mice lacking specific immune effector functions were used. The studies identified a potent therapeutic VRP vaccine, encoding tyrosinase related protein 2 (TRP-2), which provided a durable anti-tumor effect. The efficacy of VRP-TRP2 relies on a novel immune mechanism of action requiring the activation of both IgG and CD8+ T cell effector responses, and depends on signaling through activating Fcgamma receptors. CONCLUSIONS/SIGNIFICANCE: This study identifies a VRP-based vaccine able to elicit humoral immunity against TRP-2, which plays a role in melanoma immunotherapy and synergizes with tumor-specific CD8+ T cell responses. These findings will aid in the rational design of future immunotherapy clinical trials. PMID- 20844764 TI - Proteome-wide search reveals unexpected RNA-binding proteins in Saccharomyces cerevisiae. AB - The vast landscape of RNA-protein interactions at the heart of post transcriptional regulation remains largely unexplored. Indeed it is likely that, even in yeast, a substantial fraction of the regulatory RNA-binding proteins (RBPs) remain to be discovered. Systematic experimental methods can play a key role in discovering these RBPs--most of the known yeast RBPs lack RNA-binding domains that might enable this activity to be predicted. We describe here a proteome-wide approach to identify RNA-protein interactions based on in vitro binding of RNA samples to yeast protein microarrays that represent over 80% of the yeast proteome. We used this procedure to screen for novel RBPs and RNA protein interactions. A complementary mass spectrometry technique also identified proteins that associate with yeast mRNAs. Both the protein microarray and mass spectrometry methods successfully identify previously annotated RBPs, suggesting that other proteins identified in these assays might be novel RBPs. Of 35 putative novel RBPs identified by either or both of these methods, 12, including 75% of the eight most highly-ranked candidates, reproducibly associated with specific cellular RNAs. Surprisingly, most of the 12 newly discovered RBPs were enzymes. Functional characteristics of the RNA targets of some of the novel RBPs suggest coordinated post-transcriptional regulation of subunits of protein complexes and a possible link between mRNA trafficking and vesicle transport. Our results suggest that many more RBPs still remain to be identified and provide a set of candidates for further investigation. PMID- 20844766 TI - Learning priors for Bayesian computations in the nervous system. AB - Our nervous system continuously combines new information from our senses with information it has acquired throughout life. Numerous studies have found that human subjects manage this by integrating their observations with their previous experience (priors) in a way that is close to the statistical optimum. However, little is known about the way the nervous system acquires or learns priors. Here we present results from experiments where the underlying distribution of target locations in an estimation task was switched, manipulating the prior subjects should use. Our experimental design allowed us to measure a subject's evolving prior while they learned. We confirm that through extensive practice subjects learn the correct prior for the task. We found that subjects can rapidly learn the mean of a new prior while the variance is learned more slowly and with a variable learning rate. In addition, we found that a Bayesian inference model could predict the time course of the observed learning while offering an intuitive explanation for the findings. The evidence suggests the nervous system continuously updates its priors to enable efficient behavior. PMID- 20844765 TI - Serum stabilities of short tryptophan- and arginine-rich antimicrobial peptide analogs. AB - BACKGROUND: Several short antimicrobial peptides that are rich in tryptophan and arginine residues were designed with a series of simple modifications such as end capping and cyclization. The two sets of hexapeptides are based on the Trp- and Arg-rich primary sequences from the "antimicrobial centre" of bovine lactoferricin as well as an antimicrobial sequence obtained through the screening of a hexapeptide combinatorial library. METHODOLOGY/PRINCIPAL FINDINGS: HPLC, mass spectrometry and antimicrobial assays were carried out to explore the consequences of the modifications on the serum stability and microbicidal activity of the peptides. The results show that C-terminal amidation increases the antimicrobial activity but that it makes little difference to its proteolytic degradation in human serum. On the other hand, N-terminal acetylation decreases the peptide activities but significantly increases their protease resistance. Peptide cyclization of the hexameric peptides was found to be highly effective for both serum stability and antimicrobial activity. However the two cyclization strategies employed have different effects, with disulfide cyclization resulting in more active peptides while backbone cyclization results in more proteolytically stable peptides. However, the benefit of backbone cyclization did not extend to longer 11-mer peptides derived from the same region of lactoferricin. Mass spectrometry data support the serum stability assay results and allowed us to determine preferred proteolysis sites in the peptides. Furthermore, isothermal titration calorimetry experiments showed that the peptides all had weak interactions with albumin, the most abundant protein in human serum. CONCLUSIONS/SIGNIFICANCE: Taken together, the results provide insight into the behavior of the peptides in human serum and will therefore aid in advancing antimicrobial peptide design towards systemic applications. PMID- 20844767 TI - Population genetics of a trochid gastropod broadens picture of Caribbean Sea connectivity. AB - BACKGROUND: Regional genetic connectivity models are critical for successful conservation and management of marine species. Even though rocky shore invertebrates have been used as model systems to understand genetic structure in some marine environments, our understanding of connectivity in Caribbean communities is based overwhelmingly on studies of tropical fishes and corals. In this study, we investigate population connectivity and diversity of Cittarium pica, an abundant rocky shore trochid gastropod that is commercially harvested across its natural range, from the Bahamas to Venezuela. METHODOLOGY/PRINCIPAL FINDINGS: We tested for genetic structure using DNA sequence variation at the mitochondrial COI and 16S loci, AMOVA and distance-based methods. We found substantial differentiation among Caribbean sites. Yet, genetic differentiation was associated only with larger geographic scales within the Caribbean, and the pattern of differentiation only partially matched previous assessments of Caribbean connectivity, including those based on larval dispersal from hydrodynamic models. For instance, the Bahamas, considered an independent region by previous hydrodynamic studies, showed strong association with Eastern Caribbean sites in our study. Further, Bonaire (located in the east and close to the meridional division of the Caribbean basin) seems to be isolated from other Eastern sites. CONCLUSIONS/SIGNIFICANCE: The significant genetic structure and observed in C. pica has some commonalities in pattern with more commonly sampled taxa, but presents features, such as the differentiation of Bonaire, that appear unique. Further, the level of differentiation, together with regional patterns of diversity, has important implications for the application of conservation and management strategies in this commercially harvested species. PMID- 20844770 TI - Resurfacing of isolated articular cartilage defects in the glenohumeral joint with microfracture: a surgical technique & case report. AB - Isolated, full-thickness chondral lesions of the glenohumeral joint remain significant problems for athletes, workers, and the elderly. Microfracture has been established as an effective therapeutic solution for such cartilage defects of the knee, because of its low surgical morbidity and ease as a first-line treatment with good clinical outcomes. Although the indications for microfracture and the surgical techniques are similar for cartilage injuries of the shoulder and knee joints, the literature includes no reviews of the use of microfracture in the humeral head or glenoid surface. Overall, microfracture is a minimally invasive, technically simple surgical procedure that provides an excellent option for patients with isolated full-thickness chondral defects. In this article, we describe the subtleties of microfracture in the glenohumeral joint and outline the clinical course of a typical patient. PMID- 20844771 TI - Incidence of early development of radiolucent lines in keeled polyethylene glenoid components after total shoulder arthroplasty. AB - Glenoid loosening after total shoulder arthroplasty (TSA) remains a major concern. The purpose of this study was to determine the incidence of radiolucent lines (RLLs) after TSA performed with modern glenoid bone preparation and cement techniques for keeled-back glenoid components. One hundred ten consecutive patients with osteoarthritis were included in this study. Patients had undergone primary TSA with a keeled-back glenoid component. Mean age was 64.0 years (SD, 10.6 years; range, 27-91 years). Two independent, blinded observers assessed the initial postoperative radiographs for RLLs using the Mole, Torchia, and Franklin classification systems. On 93 (84.5%) of the 110 radiographs, there was no evidence of RLLs; on the other 17 radiographs (15.5%), there was evidence of RLLs. Mean Torchia score was 0.02 (SD, 0.13) on the anteroposterior view and 0.14 (SD, 0.34) on the axillary lateral view. Mean Franklin score was 0.02 (SD, 0.13) on the anteroposterior view and 0.21 (SD, 0.62) on the axillary lateral view. Incidence of early RLLs in keeled-back glenoid components prepared with modern cement and bone compaction techniques was 15.5%, similar to what other investigators have reported for pegged-back glenoid components. PMID- 20844768 TI - Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. AB - Although lactic acidosis is a prominent feature of solid tumors, we still have limited understanding of the mechanisms by which lactic acidosis influences metabolic phenotypes of cancer cells. We compared global transcriptional responses of breast cancer cells in response to three distinct tumor microenvironmental stresses: lactic acidosis, glucose deprivation, and hypoxia. We found that lactic acidosis and glucose deprivation trigger highly similar transcriptional responses, each inducing features of starvation response. In contrast to their comparable effects on gene expression, lactic acidosis and glucose deprivation have opposing effects on glucose uptake. This divergence of metabolic responses in the context of highly similar transcriptional responses allows the identification of a small subset of genes that are regulated in opposite directions by these two conditions. Among these selected genes, TXNIP and its paralogue ARRDC4 are both induced under lactic acidosis and repressed with glucose deprivation. This induction of TXNIP under lactic acidosis is caused by the activation of the glucose-sensing helix-loop-helix transcriptional complex MondoA:Mlx, which is usually triggered upon glucose exposure. Therefore, the upregulation of TXNIP significantly contributes to inhibition of tumor glycolytic phenotypes under lactic acidosis. Expression levels of TXNIP and ARRDC4 in human cancers are also highly correlated with predicted lactic acidosis pathway activities and associated with favorable clinical outcomes. Lactic acidosis triggers features of starvation response while activating the glucose-sensing MondoA-TXNIP pathways and contributing to the "anti-Warburg" metabolic effects and anti-tumor properties of cancer cells. These results stem from integrative analysis of transcriptome and metabolic response data under various tumor microenvironmental stresses and open new paths to explore how these stresses influence phenotypic and metabolic adaptations in human cancers. PMID- 20844772 TI - Effective glenoid version in professional baseball players. AB - The pathomechanics of the throwing shoulder have yet to be fully elucidated. The focus of this study reported here was to further characterize the morphology of the glenoid in a population of elite throwing athletes. We obtained magnetic resonance imaging scans of 38 professional baseball players (dominant shoulders) and of 35 age matched nonthrowing control patients (17 dominant and 18 nondominant shoulders). Seven measurements were made by 3 blinded reviewers on 3 axial images per patient: version of superior glenoid, middle glenoid, inferior glenoid, superior capsulolabral junction, middle capsulolabral junction, inferior capsulolabral junction, and depth of concavity of glenoid in a middle slice. Mean age of the 38 players (24 pitchers, 14 fielders) was 26.8 years, and mean age of the 35 control patients was 27.6 years. Intraclass correlation coefficients ranged from .55 to .84 for the version measurements. There were no statistically significant differences between the pitchers and the fielders on any of the 7 measurements, but such differences were found between the throwers and the dominant-shoulder control patients on all 7 measurements. There were only 2 differences (version of superior glenoid, depth of concavity of glenoid in a middle slice) between dominant- and nondominant- shoulder control patients. There was significantly more retroversion in the osseous and soft tissues of the elite throwing athletes than in the nonthrowing control patients. This increased retroversion may play a role in development of internal impingement in the overhead athlete. PMID- 20844773 TI - From entrepreneur to employee: Part 2. The Devil's in the details, so don't forget to ask about them. PMID- 20844774 TI - Arthroscopic management of a chronic primary anterior shoulder dislocation. AB - Chronic anterior dislocation of the glenohumeral joint often leads to functional impairment and pain. Duration of dislocation is correlated with complications, and this injury is traditionally treated with an open procedure. A right-hand - dominant woman in her late 70s presented with traumatic chronic anterior dislocation of the glenohumeral joint. Her physical exam and imaging studies were consistent with anterior shoulder dislocation, a large Hill-Sachs deformity, and rotator cuff and anterior labral tears. A shoulder reduction under anesthesia was performed followed by an arthroscopic double-row rotator cuff repair. In addition, a labral repair was performed via percutaneously inserted suture anchors. Following this treatment, stability was restored to the glenohumeral joint. The patient progressed well with physical therapy and, at 1-year follow up, the patient had returned to all routine activities pain-free. Arthroscopic repair of chronic primary traumatic anterior shoulder dislocations requiring surgical treatment is a valuable alternative to open procedures and should be considered in higher-functioning elderly patients. Percutaneous suture anchor placement minimizes trauma to an already pathologic rotator cuff and joint capsule. PMID- 20844775 TI - Proximal humerus fracture after keyhole biceps tenodesis. AB - A biceps tenodesis is a common surgical procedure that is often carried out in conjunction with other surgical shoulder repairs to relieve biceps tendonitis. This case presents a 50-year-old woman who suffered a humerus fracture following an open keyhole biceps tenodesis. The potential reasons for the fracture as well as a brief analysis of the technique itself are presented. To our knowledge, this is the first case report of a humerus fracture following keyhole biceps tenodesis in the English-language literature. PMID- 20844776 TI - A vascular complication of trochanteric-entry femoral nailing on a fracture table. AB - In this case report, we describe a complication of occlusion of a low-flow artery related to traction and compression against the center post of a fracture table during trochanteric femoral nailing. The ischemic limb subsequently underwent urgent revascularization by the vascular surgery team. The patient was placed on anticoagulation and recovered. Radiographically visible vascular plaques should alert the surgeon to potential vascular complications of traction and center-post compression. PMID- 20844777 TI - Heterotopic ossification of the deltoid muscle after arthroscopic rotator cuff repair. AB - Heterotopic ossification (HO), a well-known sequela of trauma, burns, head injury, and certain congenital or acquired metabolic conditions, has a predilection for the hip and the elbow. This disease has uncommonly been found after elective open shoulder surgery but extremely seldom after minimally invasive surgery. In our search of the peer-reviewed literature, we found no reports of HO after arthroscopic rotator cuff repair. The clinical importance of heterotopic bone after shoulder surgery remains unclear because of inconsistent definitions, varying correlations of symptom severity and radiographic findings, and lack of treatment efficacy data. Here we report a case of severely symptomatic HO after arthroscopic rotator cuff repair - successfully treated with excision of the heterotopic bone, interval release, and manipulation. PMID- 20844778 TI - A simple PDMS-based microfluidic channel design that removes bubbles for long term on-chip culture of mammalian cells. AB - This report shows methods to fabricate polydimethylsiloxane (PDMS) microfluidic systems for long-term (up to 10 day) cell culture. Undesired bubble accumulation in microfluidic channels abruptly changes the microenvironment of adherent cells and leads to the damage and death of cells. Existing bubble trapping approaches have drawbacks such as the need to pause fluid flow, requirement for external vacuum or pressure source, and possible cytotoxicity. This study reports two kinds of integrated bubble trap (IBT) which have excellent properties, including simplicity in structure, ease in fabrication, no interference with the flow, and long-term stability. IBT-A provides the simplest solution to prevent bubbles from entering microfluidic channels. In situ time-lapse imaging experiments indicate that IBT-B is an excellent device both for bubble trapping and debubbling in cell loaded microfluidics. MC 3T3 E1 cells, cultured in a long and curved microfluidic channel equipped with IBT-B, showed high viability and active proliferation after 10 days of continuous fluid flow. The comprehensive measures taken in our experiments have led to successful long-term, bubble-free, on-chip culture of cells. PMID- 20844779 TI - DNA hybridization induced selective encapsulation of small dye molecules in dendrimer based microcapsules. AB - A novel approach for selectively encapsulating Cy5 dye molecules via DNA hybridization in cationic phosphorus dendrimers (G(4)(+))/polystyrenesulfonate (PSS) microcapsules has been developed. The hybridization between Cy5 labeled single strand DNA (ssDNA) targets and complementary ssDNA probes was performed in the microcapsules. During hybridization, the ssDNA targets acted as 'vehicles' and Cy5 dye molecules as 'cargos', which led to the selective encapsulation of the Cy5 molecules inside the capsules. The approach may be applied for many small molecules, which are usually difficult to be encapsulated due to their diffusion properties in microcapsules. PMID- 20844780 TI - Anisotropic hybrid particles based on electrohydrodynamic co-jetting of nanoparticle suspensions. AB - Electrohydrodynamic co-jetting of two different nanocrystal suspensions can result in anisotropic nanocomposite particles. Using this approach, we are able to prepare submicron-sized, spherical Janus particles (464 +/- 242 nm), which are not only comprised of two chemically distinct compartments, but are also morphologically anisotropic. Specifically, multifunctional hybrid particles have been derived, which are composed of a crosslinked copolymer, poly(acrylamide-co acrylic acid) (p(AAm-co-AA)), and compartmentalized with respect to two metal oxides, i.e. titanium dioxide (TiO(2)) and magnetite (Fe(3)O(4)). Due to size as well as optical color differences between the Fe(3)O(4) (~10 nm) and TiO(2) (<100 nm) loadings, the surface morphology of the two compartments are significantly different and the particles display magnetic, optical, and interfacial anisotropy. Magnetic anisotropy of the particles has been utilized to control the particles' positioning in an external magnetic field, which--with further work- may lead to magnetically switchable surfaces for display applications. PMID- 20844781 TI - Fine tuning of emission through the engineering of colloidal crystals. AB - We describe the preparation and characterization of photonic colloidal crystals from silica spheres with incorporated luminescent [Mo(6)Br(14)](2-) cluster units. These structures exhibit strong angle-dependent luminescent properties. The incorporation of one or several planar defects in the periodic structures gives rise to the creation of a passband in the stopband. In the energy range of this passband, an increase of the emission intensity has been found. PMID- 20844782 TI - Molecular balances for quantifying non-covalent interactions. AB - Molecular interactions underlie the whole of chemistry and biology. This tutorial review illustrates the use of rotameric folding molecules, topoisomers, atropoisomers, and tautomers as molecular balances for quantifying non-covalent interactions. This intramolecular approach enables a wide variety of interactions to be examined with a degree of geometric control that is difficult to achieve in supramolecular complexes. Synthetic variation of molecular balances allows the fundamental physicochemical origins of molecular recognition to be systematically examined by providing insights into the interplay of geometry and solvation on non-covalent interactions. PMID- 20844783 TI - The unusual surface chemistry of alpha-Al(2)O(3) (0001). AB - We report on the influence of heat treatment on the surface chemistry of an alpha alumina crystal. We compare its electrical double layer behaviour with that of 150 nm diameter alpha-Al(2)O(3) particles. Surface spectroscopy and zeta potential studies are used to understand the changes in surface chemistry. The pH(pzc) of an alpha-Al(2)O(3) (0001) single crystal (~4) is more acidic than that of alpha-Al(2)O(3) particles (8.5), a difference explained by the dominance of [triple bond, length as m-dash]Al(2)OH surface groups on the single crystals and their charging behaviour. Heat treatment of the alumina surface causes a substantial decrease in the number of surface OH groups. Heating at 500 degrees C decreases the surface density of hydroxyl groups. Heating at 1050 degrees C also affects surface morphology and surface chemistry. The increased magnitude of the zeta potential and the pH(pzc) shift to lower pH suggest a surface reconstruction and the appearance of more acidic aluminium sites. PMID- 20844784 TI - Integration of single oocyte trapping, in vitro fertilization and embryo culture in a microwell-structured microfluidic device. AB - In vitro fertilization (IVF) therapy is an important treatment for human infertility. However, the methods for clinical IVF have only changed slightly over decades: culture medium is held in oil-covered drops in Petri dishes and manipulation occurs by manual pipetting. Here we report a novel microwell structured microfluidic device that integrates single oocyte trapping, fertilization and subsequent embryo culture. A microwell array was used to capture and hold individual oocytes during the flow-through process of oocyte and sperm loading, medium substitution and debris cleaning. Different microwell depths were compared by computational modeling and flow washing experiments for their effectiveness in oocyte trapping and debris removal. Fertilization was achieved in the microfluidic devices with similar fertilization rates to standard oil-covered drops in Petri dishes. Embryos could be cultured to blastocyst stages in our devices with developmental status individually monitored and tracked. The results suggest that the microfluidic device may bring several advantages to IVF practices by simplifying oocyte handling and manipulation, allowing rapid and convenient medium changing, and enabling automated tracking of any single embryo development. PMID- 20844785 TI - Turn on fluorescence sensing of vapor phase electron donating amines via tetraphenylporphyrin or metallophenylporphrin doped polyfluorene. AB - A sensitive, selective, reversible, and easy performance way of detecting electron donating volatile amines such as abused drug methamphetamine (MAPA) has been developed. PMID- 20844786 TI - Switching of functionalized azobenzene suspended between gold tips by mechanochemical, photochemical, and opto-mechanical means. AB - Optical, purely mechanical, and combined opto-mechanical switching cycles of a molecular switch embedded in a metal junction are investigated using density functional theory and (excited state) ab initio molecular dynamics. The nanomechanical simulations are done on realistic models of gold electrode tips bridged by a single dithioazobenzene molecule. Comparison of different tip models shows that the nature of the tips affects switching processes both qualitatively and quantitatively. The study predicts that purely photochemical cis?trans switching cycles of suspended azobenzene bridges are mechanically hindered; combined opto-mechanical as well as purely mechanochemical forward and backward switching is, however, feasible. PMID- 20844787 TI - Is the planar hexacoordinate nitrogen molecule NB(6)(-) viable? AB - Molecules with hypercoordinate planar centers have continued to receive enthusiastic attention due to their violation of the traditional models of three dimensional chemical bonding and maximum tetracoordination. These electronic exotic but structurally aesthetic species have been optimistically conceived as building blocks in cluster-assembly for bulky materials. Recently, the planar hexacoordinate nitrogen (phN) unit, NB(6)(-), has been theoretically incorporated into a series of sandwich-like transition-metal compounds. However, the intrinsic stability of NB(6)(-) in both gas-phase and assembly has not been tackled, though it is the key factor for predicting the viability of any molecules. In this paper, at the CCSD(T)/6-311+G(2df)//B3LYP/6-311+G(d)+ZPVE level, we investigate for the first time the thermodynamic and kinetic stability of the phN unit, NB(6)(-), in both free and assembled ([NB(6)](2)Fe) forms. The calculated least barrier height of phN towards conversion is 9.2 and 4.4 kcal mol(-1) in free and assembled forms, respectively. Most importantly, the phN structure is thermodynamically rather unstable, by 102.8 and 162.1 kcal mol(-1) higher than the respective lower-lying conversion isomers. Therefore, in view of the combined thermodynamic and kinetic consideration, we propose that isolation of the phN structure of NB(6)(-) in either gas phase or assembly is unlikely. The present results manifest that for predicting any viable molecule with exotic structures, investigation of its "intrinsic stability" is highly necessary. The maintenance of the phN-NB(6)(-) is discussed at the 6-311+G(d)-B3LYP, MP2, CCSD and CCSD(T) optimization levels in comparison with the isoelectronic and milestone phC CB(6)(2-). PMID- 20844788 TI - Pathways affected by 3,5-diiodo-l-thyronine in liver of high fat-fed rats: evidence from two-dimensional electrophoresis, blue-native PAGE, and mass spectrometry. AB - 3,5-Diiodo-l-thyronine (T2) powerfully reduces adiposity in rats fed a high-fat diet (HFD), stimulating (in the liver) fatty acid oxidation and mitochondrial uncoupling, and strongly counteracting steatosis, a condition commonly associated with diet-induced obesity. Proteomics offer unique possibilities for the investigation of changes in the levels and modifications of proteins. Here, combining 2D-E, mass spectrometry, and blue native (BN) PAGE, we studied how the subcellular hepatic phenotype responds to HFD and T2-treatment. By identifying differentially expressed proteins and analyzing their interrelation [using the Ingenuity Pathway Analysis (IPA) platform], we obtained an integrated view of the phenotypic/metabolic adaptations occurring in the liver proteome during HFD with or without T2-treatment. Interestingly, T2 counteracted several HFD-induced changes, mostly in mitochondria. BN-PAGE and subsequent in-gel activity analysis of OXPHOS complexes revealed a modified profile of individual complexes in HFD mitochondria vs. normal ones. This pattern was re-normalized in mitochondria from T2-treated HFD animals. These data indicate that in HFD rats, the effects of T2 on the liver proteome cause it to resemble that associated with a non-steatotic condition. The identified metabolic pathways (mainly at the mitochondrial level) may be responsible for the beneficial effects of T2 on liver adiposity and metabolism. PMID- 20844789 TI - Sub-10 nm strontium titanate nanocubes highly dispersed in non-polar organic solvents. AB - Strontium titanate (SrTiO(3)) nanoparticles with well defined cubic shape and sub 10 nm size that are highly dispersible in non-polar organic solvents were successfully synthesized by hydrothermal (HT) processing. Water-soluble titanium complexes and strontium hydroxide were employed as precursors. When the HT process was carried out without oleic acid, the SrTiO(3) particles obtained were relatively large and aggregated. However, SrTiO(3) nanocubes that are highly dispersible in hexane were obtained via the HT process using oleic acid and hydrazine. PMID- 20844791 TI - A general and concise asymmetric synthesis of sphingosine, safingol and phytosphingosines via tethered aminohydroxylation. AB - A novel, practical and efficient enantioselective synthesis of sphingoid bases, l threo-[2S,3S]-sphinganine (safingol), l-threo-[2S,3S]-sphingosine, l-arabino [2R,3S,4R] and l-xylo-[2R,3S,4S]-C(18)-phytosphingosine is described. The synthetic strategy features the Sharpless kinetic resolution and tethered aminohydroxylation (TA) as the key steps. PMID- 20844790 TI - The reaction of primary aromatic amines with alkylene carbonates for the selective synthesis of bis-N-(2-hydroxy)alkylanilines: the catalytic effect of phosphonium-based ionic liquids. AB - At T>= 140 degrees C, different primary aromatic amines (pX-C(6)H(4)NH(2); X = H, OCH(3), CH(3), Cl) react with both ethylene- and propylene-carbonates to yield a chemoselective N-alkylation process: bis-N-(2-hydroxyalkyl)anilines [pX C(6)H(4)N(CH(2)CH(R)OH)(2); R = H, CH(3)] are the major products and the competitive formation of carbamates is substantially ruled out. At 140 degrees C, under solventless conditions, the model reaction of aniline with ethylene carbonate goes to completion by simply mixing stoichiometric amounts of the reagents. However, a class of phosphonium ionic liquids (PILs) such as tetraalkylphosphonium halides and tosylates turn out to be active organocatalysts for both aniline and other primary aromatic amines. A kinetic analysis monitored by (13)C NMR spectroscopy, shows that bromide exchanged PILs are the most efficient systems, able to impart a more than 8-fold acceleration to the reaction. The reactions of propylene carbonate take place at a higher temperature than those of ethylene carbonate, and only in the presence of PIL catalysts. A mechanism based on the Lewis acidity of tetraalkylphosphonium cations and the nucleophilicity of halide anions has been proposed to account for both the reaction chemoselectivity and the function of the catalysts. PMID- 20844792 TI - Stereoselective synthesis of epi-jasmonic acid, tuberonic acid, and 12-oxo-PDA. AB - epi-Jasmonic acid (epi-JA) and tuberonic acid (TA) were synthesized from the key aldehyde, all cis-2-(2-hydroxy-5-vinylcyclopentyl)acetaldehyde (14), which was in turn prepared stereoselectively from the (1R)-acetate of 4-cyclopentene-1,3-diol (10) through S(N)2-type allylic substitution with CH(2)[double bond, length as m dash]CHMgBr followed by Mitsunobu inversion, Eschenmoser-Claisen rearrangement, and regioselective Swern oxidation of the corresponding bis-TES ether (13). Wittig reaction of the aldehyde 14 with [Ph(3)P(CH(2))Me](+)Br(-) followed by oxidation afforded epi-JA (3) stereoselectivity over the trans isomer. Similarly, TA (5) was synthesized. Furthermore, the above findings were applied successfully to improve the total efficiency of the previous synthesis of 12-oxo-PDA (1). PMID- 20844794 TI - A comparative study of F-DPPC/DPPC mixed monolayers. Influence of subphase temperature on F-DPPC and DPPC monolayers. AB - The surface behavior of two zwitterionic phospholipids: 1,2-dipalmitoyl-sn glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-[16-fluoropalmitoyl phosphatidylcholine] (F-DPPC), has been investigated at the air-water interface at the temperature range from 10 to 30 degrees C. Surface pressure-area isotherms, BAM images and thickness-time curves were obtained for monolayers made from these pure phospholipids and from their mixtures.The comparative study of the behavior of both phospholipid monolayers with temperature showed some differences as the disappearance of the liquid expanded (LE)-liquid condensed (LC) phase transition at low temperatures for the DPPC but not for F-DPPC, because the F-DPPC monolayer is more expanded and more resistant to changes of temperature. On the other hand, film elasticity (C(s)(-1)) values calculated for both phospholipids show that the film condensation diminishes when the temperature increases, in accordance with the results obtained from surface pressure measurements.BAM images for F-DPPC monolayers recorded at different surface pressures and temperatures show the existence of numerous ovoid-like domains when the LE-LC phase transition is reached. However, in the LE and LC phases, homogeneous images were obtained. Time evolution of relative thickness along the compression of F-DPPC and DPPC monolayers shows similar behavior of both phospholipids, except at low temperatures.For DPPC/F-DPPC mixed systems, the plots of the mean molecular area as a function of F-DPPC mole fraction (X(F DPPC)) indicated that, whatever the surface pressure, the experimental results match the theoretical values calculated from the additivity rule, a typical behavior for ideal mixed monolayers made of miscible components. This conclusion is confirmed from the values calculated for the free energy of excess (DeltaG(exc)) of this system, which are practically zero, whatever the composition of the mixtures and the surface pressure at which DeltaG(exc) values were calculated. PMID- 20844793 TI - Optical imaging: new tools for arthritis. AB - Conventional radiography, ultrasound, CT, MRI, and nuclear imaging are the current imaging modalities used for clinical evaluation of arthritis which is highly prevalent and a leading cause of disability. Some of these types of imaging are also used for monitoring disease progression and treatment response of arthritis. However, their disadvantages limit their utilities, such as ionizing radiation for radiography, CT, and nuclear imaging; suboptimal tissue contrast resolution for radiography, CT, ultrasound, and nuclear imaging; high cost for CT and MRI and nuclear imaging; and long data-acquisition time with ensuing patient discomfort for MRI. Recently, there have been considerable advances in nonionizing noninvasive optical imaging which has demonstrated promise for early diagnosis, monitoring therapeutic interventions and disease progression of arthritis. Optical based molecular imaging modalities such as fluorescence imaging have shown high sensitivity in detection of optical contrast agents and can aid early diagnosis and ongoing evaluation of chronic inflammatory arthritis. Optical transillumination imaging or diffuse optical tomography may differentiate normal joint clear synovial fluid from turbid and pink medium early in the inflammatory process. Fourier transform infrared spectroscopy has been used to evaluate fluid composition from joints affected by arthritis. Hemodynamic changes such as angiogenesis, hypervascularization, and hypoxia in arthritic articular tissue can potentially be observed by diffuse optical tomography and photoacoustic tomography. Optical measurements could also facilitate quantification of hemodynamic properties such as blood volume and oxygenation levels at early stages of inflammatory arthritis. Optical imaging provides methodologies which should contribute to detection of early changes and monitoring of progression in pathological characteristics of arthritis, with relatively simple instrumentation. PMID- 20844795 TI - Synthetic studies on the mycolactone core. AB - Two approaches are presented for the synthesis of the macrolide core of the mycolactone polyketides. The first intertwines ring closing metathesis (RCM) within a two-step Julia olefination protocol, while the second intercepts the optimized routes of Kishi, thereby providing formal access to the mycolactones. PMID- 20844796 TI - Gas-phase complexes of cyclic and linear polyethers with alkali cations. AB - The flexibility of polymer backbones constitutes one key aspect in their molecular recognition properties. This investigation characterizes the structure of the gas-phase complexes formed by the cyclic and linear polyethers with the heavier alkali metal cations. In particular, the cyclic 15-crown-5 ether (15c5), (OCH(2)CH(2))(5), and the polyethylene glycol linear chains PEG4 and PEG9, H(OCH(2)CH(2))(n=4,9)OH, are considered. Infrared multiple photon dissociation spectroscopy is applied to probe the polymer vibrational modes within the spectral range 800-1500 cm(-1), in combination with Density Functional Theory calculations. The experimental spectra of the 15c5-M(+) (M = K, Rb, Cs) complexes correlate with distorted asymmetric backbone structures in which the cation lies above the ether ring, and four oxygens are oriented toward the cation. In contrast, the PEG4-K(+) complex features an inclusion-like fivefold coordination structure in which the cation and four oxygens are quasi-coplanar and one terminal oxygen lies out of plane. For the PEG9-K(+) complex, the ether chain builds stable cages involving a coordination of eight oxygens with the cation, sustained by hydrogen bonds between the terminal hydroxyl groups. PMID- 20844797 TI - 2D materials: to graphene and beyond. AB - This review is an attempt to illustrate the different alternatives in the field of 2D materials. Graphene seems to be just the tip of the iceberg and we show how the discovery of alternative 2D materials is starting to show the rest of this iceberg. The review comprises the current state-of-the-art of the vast literature in concepts and methods already known for isolation and characterization of graphene, and rationalizes the quite disperse literature in other 2D materials such as metal oxides, hydroxides and chalcogenides, and metal-organic frameworks. PMID- 20844798 TI - Ensembles of uncertain mathematical models can identify network response to therapeutic interventions. AB - The role of mechanistic modeling and systems biology in molecular medicine remains unclear. In this study, we explored whether uncertain models could be used to understand how a network responds to a therapeutic intervention. As a proof of concept, we modeled and analyzed the response of the human coagulation cascade to recombinant factor VIIa (rFVIIa) and prothrombin (fII) addition in normal and hemophilic plasma. An ensemble of parametrically uncertain human coagulation models was developed (N = 437). Each model described the time evolution of 193 proteins and protein complexes interconnected by 301 interactions under quiescent flow. The 467 unknown model parameters were estimated, using multiobjective optimization, from published in vitro coagulation studies. The model ensemble was validated using published in vitro thrombin measurements and thrombin measurements taken from coronary artery disease patients. Sensitivity analysis was then used to rank-order the importance of model parameters as a function of experimental or physiological conditions. A novel strategy for the systematic comparison of ranks identified a family of fX/FXa and fII/FIIa interactions that became more sensitive with decreasing fVIII/fIX. The fragility of these interactions was preserved following the addition of exogenous rFVIIa and fII. This suggested that exogenous rFVIIa did not alter the qualitative operation of the cascade. Rather, exogenous rFVIIa and fII took advantage of existing fluid and interfacial fX/FXa and fII/FIIa sensitivity to restore normal coagulation in low fVIII/fIX conditions. The proposed rFVIIa mechanism of action was consistent with experimental literature not used in model training. Thus, we demonstrated that an ensemble of uncertain models could unravel key facets of the mechanism of action of a focused intervention. Whereas the current study was limited to coagulation, perhaps the general strategy used could be extended to other molecular networks relevant to human health. PMID- 20844799 TI - Stereoselective synthesis of enynones via base-catalyzed isomerization of 1,5 disubstituted-2,4-pentadiynyl silyl ethers or their alcohol derivatives. AB - 1,5-Disubstituted-2,4-pentadiynyl silyl ethers undergo smooth desilylative isomerization to afford cis-enynones as major products with moderate stereoselectivities in the presence of a catalytic amount of KO(t)Bu or DBU. While the isomerization reactions of their alcohol derivatives catalyzed by KOH, KO(t)Bu or NaH take place efficiently to produce trans-enynones with high stereoselectivities. These reactions provide convenient and practical routes for the synthesis of enynones with a wide range of substitution groups. PMID- 20844800 TI - Synthesis of new pentacyclic chromophores through a highly regio- and diastereoselective cascade process. AB - A new family of pentacyclic compounds incorporating a central 1,2-dihydropyridine core is obtained through a pseudo three-component reaction. Four new bonds and two stereocenters with trans relationship are produced during the cascade process under palladium catalysis. PMID- 20844801 TI - Self-assembled dicopper(II) diethanolaminate cores for mild aerobic and peroxidative oxidation of alcohols. AB - The new dicopper(ii) complexes [Cu(2)(MU-Hmdea)(2)(NCS)(2)] (1) and [Cu(2)(MU Hedea)(2)(N(3))(2)].(H(2)O)(0.25) (2) with the {Cu(2)(MU-O)(2)} diethanolaminate cores have been easily generated by aqueous medium self-assembly reactions of copper(ii) nitrate with N-methyl- or N-ethyldiethanolamine (H(2)mdea or H(2)edea, respectively), in the presence of sodium thiocyanate (for 1) or sodium azide (for 2) as ancillary ligands sources. They have been isolated as air-stable crystalline solids and fully characterized by IR and UV-vis spectroscopies, ESI MS(+), elemental and single-crystal X-ray diffraction analyses. The latter complex also features a fourfold linkage of neighbouring dimeric units via strong intermolecular O-HO hydrogen bonds, giving rise to the formation of tetracopper aggregates. The catalytic activity of compounds 1 and 2 has been studied for the mild (50-80 degrees C) and selective oxidations of alcohols, namely for (i) the aerobic aqueous medium oxidation of benzyl alcohols to benzaldehydes, mediated by TEMPO radical, and for (ii) the solvent-free oxidation of secondary alcohols to ketones by t-BuOOH under microwave (MW) irradiation. Complex 2 shows the highest efficiency in both oxidation systems, resulting in up to 99% molar yields (based on the alcohol substrate) of products. In addition, remarkably high values of TON (1020) and TOF (4080 h(-1)) have been achieved in the MW-assisted peroxidative oxidation of 1-phenylethanol to acetophenone (model reaction). Attractive green features of these catalytic systems include the operation in aqueous or solvent free reaction medium, under mild conditions and with high yields and selectivities, using Cu catalyst precursors that are readily available by self assembly in water of simple chemicals. PMID- 20844802 TI - Fluorous diastereomeric mixture synthesis (FDMS) of hydantoin-fused hexahydrochromeno[4,3-b]pyrroles. AB - Fluorous diastereomeric mixture synthesis (FDMS) is introduced and demonstrated in the synthesis of six diastereomers of hydantoin-fused hexahydrochromeno[4,3 b]pyrroles. PMID- 20844803 TI - Low-temperature mass production of superconducting MgB2 nanofibers from Mg(BH4)2 decomposition and recombination. AB - Massive superconducting MgB(2) nanofibers are obtained for the first time from Mg(BH(4))(2). The technique optimizes reaction conditions to only 1 h at 460 degrees C and provides nanofibers which exhibited satisfying superconducting properties. The morphology transformation according to temperature changes and the special mechanism of precursor inductive synthesis are discussed. PMID- 20844805 TI - A new building block for anion supramolecular chemistry. Study of carbazolocarbazole as anion receptor. AB - A novel carbazolocarbazole system has been evaluated as an anion receptor in DMF solution. A good affinity has been detected for oxoanions. The anion binding studies have been contrasted by different experimental techniques. PMID- 20844806 TI - Artificial bowel sphincters for severe fecal incontinence. Are they a solution? AB - Fecal incontinence is a debilitating and common problem with a profound effect on a patient's well being medically, socially, and economically. Non-operative management of this condition includes dietary modification, antidiarrheal medications, and biofeedback. Patients with severe incontinence can be divided into 2 categories. The first group includes patients with an identifiable and isolated anatomic sphincter defect who can expect 80% short-term surgical success using overlapping sphincteroplasty. The second group is patients who will not benefit from sphincteroplasty; fortunately, they are not obligated to permanent stomas. Artificial bowel sphincter (ABS) implantation is a well-established surgical technique, offers a chance for continence, restoration, and improved quality of life with significant functional success rate. The surgeon needs to understand how they function. They should be proficient in different procedure types and match these with the patient's need. Post-operative long-term follow-up continues to help surgeons better serve this type of patient population. PMID- 20844807 TI - Cordyceps sinensis extract suppresses hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells. AB - OBJECTIVE: To investigate the effects of a Chinese herb Cordyceps sinensis (C. sinensis) extract on hypoxia-induced proliferation and the underlying mechanisms involved. METHODS: This prospective study was carried out at the Central Laboratory of Yichang Central People's Hospital, Yichang, China from March 2008 to April 2010. The C. sinensis was extracted from the Chinese herb C. sinensis using aqueous alcohol extraction techniques. Forty healthy adult male Sprague Dawley rats were used in the study. The proliferation of pulmonary artery smooth muscle cells (PASMCs) was measured using 3-(4,5-dimethylthiazol-2-Yl)-2,5 diphenyltetrazolium bromide (MTT) assay, and cell viability was determined by trypan blue exclusion. Cell cycles were analyzed using FACSort flow cytometric analysis. The expression of proliferating cell nuclear antigen (PCNA), c-jun, and c-fos in rat PASMCs was determined by immunohistochemistry. RESULTS: We found an increased proliferation of PASMCs and increased expression of transcription factors, c-jun and c-fos in PASMCs cultured under hypoxic conditions. The C. sinensis extract significantly inhibited hypoxia-induced cell proliferation in a dose-dependent manner. In addition, C. sinensis extract also significantly inhibited the expression of PCNA, c-jun, and c-fos in these PASMCs. CONCLUSION: Our results indicated that C. sinensis extract inhibits hypoxia-induced proliferation of rat PASMCs, probably by suppressing the expression of PCNA, c fos, c-jun, and decreasing the percentage of cells in synthesis phase, second gap phase, and mitotic phase in cell cycle (S+G2/M) phase. Our results therefore, provided novel evidence that C. sinensis extract may be used as a therapeutic reagent in the treatment of hypoxic pulmonary hypertension. PMID- 20844808 TI - B7-H3 and CD133 expression in non-small cell lung cancer and correlation with clinicopathologic factors and prognosis. AB - OBJECTIVE: To detect the expression of B7-H3 and CD133 in human non-small cell lung cancer (NSCLC) specimens and lung benign lesions, and to evaluate the correlation between the 2 biomarkers and clinicopathologic features. METHODS: This is a case-control study of 102 tissue specimens collected from NSCLC participants undergoing thoracic surgery in the Second Affiliated Hospital of Soochow University, Suzhou, China, between January 2006 and December 2008. From the 102 patients, 25 adjacent non-cancer samples were verified pathologically as normal tissue (positive group), and 24 benign inflammatory lesion tissues were used as control (negative group). Specimens from 126 participants were stained immunohistochemically using Image-Pro Plus software, and the cell number was measured in each section. RESULTS: Of the 102 specimens, 71 expressed B7-H3, and 51 expressed CD133, higher than that in benign lesions (p<0.001) or non-cancer tissues (p<0.001). B7-H3 expression in squamous cell carcinoma (SCC) was significantly higher than those in adenocarcinoma (p=0.048), while CD133 expression in large cell lung carcinoma was higher than that in SCC (p=0.023). The mean number of tumor-infiltrating lymphocytes (TILs) in the B7-H3-positive group was lower than that in the B7-H3-negative group (p=0.026). The mean TILs in the CD133-positive group was significantly lower than that in CD133-negative group (p=0.029). We found that CD133 was related to tumor cell differentiation degree and CD133 expression was negatively correlated with B7-H3 expression. The CD133 positive or B7-H3 negative was associated with poor prognosis of NSCLC patients by Cox regression analysis. CONCLUSION: Both CD133 and B7-H3 might induce apoptosis of TILs in NSCLC and tumor evading host immune surveillance. Either CD133 or B7-H3 might be an independent risk factor of NSCLC participants. PMID- 20844809 TI - Genotype and antiretroviral drug resistance of human immunodeficiency virus-1 in Saudi Arabia. AB - OBJECTIVE: To analyze antiretroviral drug resistance and determine the genotype of human immunodeficiency virus (HIV)-1 in Saudi patients by sequencing an amplified region of the viral pol gene. METHODS: This retrospective study analyzed data from plasma samples submitted for genotypic drug sensitivity monitoring. Samples were analyzed at the Special Infectious Agent Unit, King Fahd Medical Research Center of King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia from August 2004 to June 2009. The Viroseq2.5 kit (Celera/Abbott) was used with ABI Prism 3100 sequencer. All patients were Saudi nationals and were on antiretroviral therapy, some experiencing treatment failure. RESULTS: Based on protease region (PR), genotypes of 63 samples were as follows: C:22, G:21, B:9, CRF02_AG:5, D:3, A:1, F:1, and J:1. Based on reverse transcriptase region (RT), genotypes were as follows: C:23, G:24, B:9, CRF02_AG: 2, D:2, A:1, and F:1. Antiretroviral susceptibility testing results were as follows: 52% of the isolates were susceptible to all 3 major classes of antiretroviral drugs used, 41% had mutations known to confer high level resistance to one or more of the nucleoside analogue reverse transcriptase inhibitors, 16% had mutations known to confer high level resistance to non-nucleoside analogues reverse transcriptase inhibitors, 13% had mutations known to confer high level resistance to one or more of the protease inhibitors (PI). Most isolates were susceptible to 2 or at least one class of antiretroviral, and only 3% of the isolates had resistance to several members of all 3 classes. CONCLUSION: Antiretroviral resistance is not uncommon in Saudi patients on antiretroviral therapy. PMID- 20844811 TI - Effects of prostate manipulation on serum total and free prostate specific antigen, and free-to-total prostate specific antigen ratio. AB - OBJECTIVE: To evaluate the effects of the different types of manipulation on prostate total specific antigen (tPSA), free prostate specific antigen (fPSA), and free-to-total prostate specific antigen (f/tPSA). METHODS: A total of 160 males were enrolled from January 2006 to December 2009 in the Urology Department, Beijing Anzhen Hospital affiliated to the Capital Medical University, Beijing, China. Of these patients, 23 had digital rectal examination (DRE), 21 had urethral catheterization, 28 had rigid cystoscopy, 35 had prostate biopsy, 35 underwent transurethral resection of the prostate (TURP), and 18 underwent suprapubic prostatectomy. Blood samples were taken before, at 24 hours, and 4 weeks after the manipulation for PSA tests. RESULTS: The DRE had no significant effect on PSA. Catheterization and cystoscopy exerted significant increases in tPSA at 24 hours. However, these small increases may not be clinically significant. The fPSA and f/tPSA were not significantly changed. There was a marked increase in tPSA and fPSA, associated with a decrease in f/tPSA at 24 hours after biopsy. No significant alterations were found in tPSA, fPSA, and f/tPSA at 4 weeks after catheterization, cystoscopy, and biopsy. The TURP and prostatectomy caused significant increases in tPSA and fPSA at 24 hours, associated with decreases in f/tPSA. The tPSA and fPSA values were below the baseline levels at 4 weeks after TURP and prostatectomy, however, f/tPSA remained constant. CONCLUSION: The DRE, catheterization, and cystoscopy had no crucial effect on PSA. Prostatic biopsy, TURP and prostatectomy significantly affected the PSA levels, and their longitudinal courses should be considered while evaluating different forms of PSA levels. PMID- 20844810 TI - Clinical characteristics of 74 pandemic H1N1 influenza patients from Turkey. Risk factors for fatality. AB - OBJECTIVE: To evaluate the clinical characteristics and certain risk factors that may be associated with fatal outcome in patients with H1N1 influenza. METHODS: This retrospective study was conducted between October and December 2009 in the Department of Infectious Diseases and Clinical Microbiology, SB Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey. Data regarding the epidemiological and clinical characteristics of 74 hospitalized cases of confirmed pandemic H1N1 influenza were reviewed. RESULTS: The median age was 49 (18-83) years, and 34 (46%) were males. The most common symptom and signs on admission were cough (91.9%) and fever more than 38 degrees Centigrade (71.7%). More than two-thirds of patients (68.9%) had at least one underlying condition; most frequently chronic respiratory disease, including asthma and diabetes. Seventy-seven percent had evidence of pneumonia on their chest x-rays at presentation. Of the 74 cases, 16 (21.6%) were followed up in the Intensive Care Unit, and 10 (13.5%) died. Obesity and oxygen saturation below 92% at the time of admission were found to be significantly related with fatal outcome. In addition, fatal patients had significantly higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), urea, creatinine, d-dimer on admission and prothrombin time (PT), activated partial thromboplastin time, and the international normalized ratio (INR) was longer. CONCLUSION: Timely identification and management of patients with higher risk for fatality may improve outcomes. PMID- 20844812 TI - Gunshot wound injuries to the male external genitalia. AB - OBJECTIVE: To identify the patterns of civilian gunshot wound (GSW) injuries to the male external genitalia, and to present our experience in the management of such injuries. METHODS: This descriptive study was carried out in the Urology and Nephrology Center, Al-Thawra Modern General and Teaching Hospital, Sanaa, Yemen from June 2005 to April 2008, and included 20 men that presented with GSW injuries to the external genitalia. After clinical and radiological evaluation with retrograde urethrography when indicated, early surgical repair was undertaken for all patients with evident, or suspected deep genito-urinary wounds. RESULTS: The mean age of the patients was 33.2 years. In 15 (75%) patients, injuries were inflicted by high-velocity weapons, and in 5 by low velocity pistols, and 18 (90%) patients had other associated injuries. The penis was involved alone in 10 (50%), scrotum in 4 (20%), and the penis and scrotum in combination in 6 (30%) patients. In 5 patients, the lesions were superficial. Corporeal injuries were detected in 13 patients, and urethral injuries were detected in 6 patients. In post-repair, mild curvature during erection was experienced by 5 patients, severe angulation by one, and sexual dysfunction by 2 patients. We encountered 9 testicular ruptures, and our testicular salvage rate was 45.5%. CONCLUSION: Although the dominant inflicting weapons were high velocity automatic rifles, the severity of injuries and their related outcomes were almost comparable to other low-velocity series. This is possibly due to the primary involvement of nearby bulky muscles in 90% of cases, which may absorb the blasts effect of the projectiles on the genitalia. PMID- 20844813 TI - Breast diseases in Southern Yemen. AB - OBJECTIVE: To investigate the magnitude of breast diseases, and its frequency distribution in different age groups in Hadramout, Yemen. METHODS: This is a prospective study conducted at the Central Laboratory of Ibn-Sinna Hospital, Hadramout, Yemen from January 2006 to December 2009. Patients attending surgical units for breast problems were eligible. Patients were assessed clinically and referred to the laboratory center to confirm the diagnosis by histopathology. The data were collected from the patients and referral sheets. RESULTS: A total of 635 cases of breast disease were diagnosed. This includes 604 female and 31 male patients. Benign breast diseases (BBD) was the most common lesion found in this study comprising 493 cases (77.6%), and 142 (22.4%) comprised malignant cases. Among BBD, the most common lesion was fibroadenoma (40.5%) followed by fibrocystic changes (16%), other benign breast lesions (10%), and inflammatory lesion (8%). The age groups affected by BBD were: 20-29 years for fibroadenoma; 30-39 years for fibrocystic change; 20-29 years for other benign breast lesions; and 30-39 for inflammatory lesions, and carcinoma of the breast was common in the 40-49 age group. The left breast was affected in 331 (52%) cases, the right in 283 (45%), while in 3%, both breasts were affected. CONCLUSION: Fibroadenoma was the most frequently diagnosed benign breast lesion in Hadramout. An educational program is needed to alert patients of the significance of breast masses. PMID- 20844814 TI - Serum beta human chorionic gonadotropin levels at 16 days following embryo transfer in intra cytoplasmic sperm injection cycles to predict pregnancy outcome. AB - OBJECTIVE: To determine the prognostic value of beta human chorionic gonadotropin (B-hCG) concentration on the sixteenth day after embryo transfer to predict pregnancy outcome. METHODS: In this retrospective cohort study, B-hCG levels were measured in 97 pregnant women that underwent intra-cytoplasmic sperm injection (ICSI) in Fatemeh-Zahra Infertility and Reproductive Health Research Center, Babol University of Medical Sciences, Babol, Iran from January 2008 to December 2009. Type, duration, causes of infertility, and age of patients, B-hCG levels on the sixteenth day after embryo transfer, the number of embryos, and pregnancy outcome were assessed. RESULTS: Incidence of viable pregnancies in B-hCG levels less than 100 IU/L (n=18) was 38.9%, and in B-hCG levels more than or equal to 100 IU/L (n=79) was 84.4%. Correlation of B-hCG with pregnancy outcome was significant (p less than 0.001). Cut-off value of B-hCG to predict viable pregnancy was 100 IU/L (sensitivity - 91%, specificity - 48%, PPV - 85%, and NPV 61%). The B-hCG levels less than or equal to 200 IU/L with a sensitivity of 88%, specificity of 45%, PPV - 37%, and NPV = 91% had predicted twin pregnancy. CONCLUSION: Serum B-hCG level on the sixteenth day after embryo transfer can be useful to predict the pregnancy outcome in ICSI cycles. PMID- 20844815 TI - Association of consanguinity with congenital heart diseases in a teaching hospital in Western Iraq. AB - OBJECTIVE: To study the association of consanguinity as a risk factor for congenital heart diseases (CHDs). METHODS: Patients with suggestive signs of CHD admitted to the Al-Ramadi Maternity and Children Hospital, Al-Anbar Governorate, Iraq from January 2009 to January 2010 were subject to diagnostic investigations. Case data includes: name, age, gender, and cause of admission. Parents data includes: age, residence, degree of consanguinity, and history of family recurrent CHDs. Three controls to one case (3:1) were selected to compare their consanguinity with the CHD cases. Odds ratio was used for the measurement of consanguinity and other variable risks on CHD occurrence. RESULTS: The CHD cases were 86. Selected controls were 258 non-CHD cases. The most recorded subtypes were ventricular septal defect (VSD), atrial septal defect (ASD), and tetralogy of fallot (ToF). Consanguinity was found in 78% of cases and 43.3% in controls. First cousin consanguinity comprised 66.2% in cases and 35.6% in controls from all their marriages. Consanguinity was found a significant risk factor, more affecting the VSD and ASD than ToF subtypes, while parental age and infant gender were not found as risk factors. CONCLUSION: Consanguinity proved to be a risk factor for CHD. Further social education of the risks of consanguineous marriages in this tribal population is needed to reduce the prevalence of these morbid and mortal anomalies. PMID- 20844816 TI - Assessment of major risk factors among stroke patients. AB - OBJECTIVE: To evaluate the major modifiable risk factors of stroke among stroke patients in Al-Anbar Province, western Iraq. METHODS: A cross-sectional study was carried out on stroke patients admitted in the Internal Medical Department, Al Ramadi Teaching Hospital from January to August 2009. Informative and detailed history was obtained concerning the presence of risk factor(s) and essential demographic data. General and neurological examinations, biochemical and laboratory investigations, in addition to brain CT-scanning were performed. RESULTS: In a total of 200 patients, 97 (48.5%) were males, and 103 patients (51.5%) were females. One hundred and sixty-six patients (83%) were more than 50 years old with a mean age of 63.66 years. Ischemic stroke was found in 171 patients (85.5%), and hemorrhagic stroke was found in 29 patients (14.5%). Hypertension was found in 138 patients (69%). Sixty-one (44.2%) of them were males, and 77 (55.8%) of them were females. Diabetes was found in 82 patients (41%), and 37 (45.1%) of them were males, and 45 (54.9%) of them were females. Smokers was found in 66 patients (33%), and 50 (75.5%) of them were males, and 16 (24.2%) of them were females. Multiple risk factors (more than 1) were found in 146 patients (73%). CONCLUSION: Hypertension, diabetes, and smoking were the major risk factors for stroke. People with multiple risk factors are more susceptible to develop stroke. PMID- 20844817 TI - Effect of a 6-week rehabilitation program on gait parameters after total knee arthroplasty. AB - OBJECTIVE: To investigate early changes in gait parameters following total knee arthroplasty (TKA). METHODS: Fifteen patients scheduled to undergo unilateral TKA at King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia, between March 2009 and February 2010, were included in the study. This study was a prospective pretest-posttest experimental design; all patients underwent unilateral TKA, and were subjected to a 6-week standard postoperative rehabilitation program. Pain intensity and gait variables were evaluated before surgery and 6-weeks postoperatively using the Visual Analogue Scale and simple footprint method. RESULTS: Statistical analysis showed improvement in pain intensity and reduction in gait velocity, cadence, and stride length following the 6-week postoperative exercise intervention compared with preoperatively. CONCLUSION: A 6-week postoperative exercise program is not a long enough time period to restore walking abilities to their pre-surgery values in patients undergoing TKA. A longer period of rehabilitation is needed to improve the quality of the patient's gait. PMID- 20844818 TI - The Global Youth Tobacco Survey - 2007. Comparison with the Global Youth Tobacco Survey 2001-2002 in Saudi Arabia. AB - OBJECTIVE: To primarily describe both smoking pattern in the youth population and a comparison with the Global Youth Tobacco Survey (GYTS) in 2001-2002. METHODS: The standard 2-stage methodology and a cross-sectional design were used to select randomly a representative sample of intermediate schools, classes, and students from all regions in the Kingdom of Saudi Arabia from January to June 2007. RESULTS: Comparing results with the 2001 GYTS, the prevalence of ever and current smoking, use of other tobacco products, and initiation of smoking by never smokers in the next year increased among males, but with improvement in the students' knowledge and attitudes towards smokers. The second-hand tobacco smoke items were not distinguished, however, one or both parent smokers increased by 6% over 6 years. Media anti-smoking messages and awareness improved, however, the widespread display and proliferation of items with a cigarette brand logo on it, encourages participants to buy more cigarettes. Teaching hazards of smoking to students improved, however, the reasons why people of their age smoke were not discussed interactively. Females less than 18 years of age (minors) were not denied cigarette purchase compared to male participants of the same age. CONCLUSION: The National Tobacco Control Programs is apparently working effectively but differentially against smoking. The program needs to be evaluated systematically and accordingly and intensified further to reduce smoking among youths in the Kingdom of Saudi Arabia. PMID- 20844819 TI - Determinants of periodontopathogens in microbiological monitoring of diabetic patients with periodontitis. AB - OBJECTIVE: To determine and analyze the frequency of periodontopathogens in microbiological monitoring of diabetic patients with periodontitis. METHODS: This cross-sectional study included 352 diabetic patients with periodontitis who were registered at Riyadh Armed Forces Hospital, King Faisal Specialist Hospital and Research Centre, King Abdul Aziz Medical City, Naval Base Hospital, and Sultan Bin Adulaziz Humanitarian City, Riyadh, Kingdom of Saudi Arabia from July 2004 to August 2008. Microbiological analysis comprised the detection of Bacteroides forsythus (Bf), Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), and Prevotella intermedia (Pi) by polymerase chain reaction method. RESULTS: The mean age of patients was 54.4 +/- 0.67 (range: 21-80 years). There were 214 (61%) males and 138 (39%) females. Among the study population, 36 (10%) had type 1, and 316 (90%) patients had type 2 diabetes. The results showed that 55.6% of patients had Bf, 51.7% had Aa, 63.7% had Pg, and 6.1% had Pi. The frequencies of periodontopathogens were higher in males than females in all age groups. The risk of periodontopathogens Bf were found higher level in 41-50 age group, Aa in 51-60, Pg in 51-60, and Pi in 31-40 age groups. CONCLUSION: This study found that the frequencies of periodontal pathogens Bf, Aa, and Pg were higher than Pi in diabetic patients with periodontitis. PMID- 20844820 TI - Primary health care physicians' knowledge, use, and attitude towards online continuous medical education in Saudi Arabia. AB - OBJECTIVE: To determine the knowledge, attitude, and use of primary health care (PHC) physicians of online continuous medical education (OCME) in the regions of Riyadh, Kingdom of Saudi Arabia. METHODS: This is a cross-sectional analysis using a self administered questionnaire. The physician sample was selected to cover all Riyadh regions (city of Riyadh, and all accessible clinics in the villages, and cities outside of Riyadh). The study was conducted from April until May 2007. The data were analyzed using the Statistical Package for Social Sciences software version 12. RESULTS: Out of the 613 questionnaires distributed, 483 was completed and returned. Approximately two-thirds of the participants are aware of OCME. Almost all were interested to learn more regarding OCME. Although 80% of the participants are currently using the internet to obtain medical knowledge, only one-third are using OCME. Ninety percent of those who are using OCME think that it will improve their patient's care. The use of OCME is significantly related to the level of computer skills the physicians have. There was no statistical significant difference on the use of OCME on one hand, and age, gender, level of education, years of experience, and location on the other hand. CONCLUSION: The PHC physicians have favorable attitude towards OCME, however, their use is quite minimal. More effort is needed to encourage our physicians to utilize this promising method of continuous education, and to understand the challenges and obstacles against using it. PMID- 20844821 TI - Psoriasis induced by infliximab in a Saudi patient with ankylosing spondylitis. AB - Although the therapeutic uses of tumor necrosis factor alpha antagonists have added a highly effective treatment of ankylosing spondylitis and associated spondyloarthropathies, they are associated with many untoward effects. We describe a Saudi patient with ankylosing spondylitis who developed severe psoriatic lesions in treatment with infliximab. He had no personal, or family history of psoriasis, and no other triggering factors known to induce psoriasis. PMID- 20844822 TI - Congenital unilateral nasal aperture stenosis. AB - Congenital nasal aperture stenosis is an unusual cause of upper airway obstruction among neonates, and rarely presents as unilateral. Most commonly presents as choanal atresia. A CT evaluation is essential to confirm the diagnosis. Both surgical and conservative management can be applied, based on the severity of the associated clinical presentation; however, the very rare unilateral condition is usually treated conservatively. We present a case of a 30 day-old male baby (second twin, preterm 29 weeks pregnancy, and birth weight 1.070 kg) with difficult breathing since birth. The baby was referred for an ENT consultation. He was on a nasal cannula, not in respiratory distress, with no stridor, nor tachypnea. There were decreased breathing sounds in the left nostril. Nasogastric tubes size 8 French (Fr) and 6 Fr could not be introduced through the left nostril, which looked obstructed more anteriorly. PMID- 20844823 TI - Myocardial infarction in a patient with mirror-image dextrocardia. PMID- 20844824 TI - Quality of life in females with spinal cord injury in Saudi Arabia. PMID- 20844825 TI - Vasocontractile effect of SeraSeal in rat thoracic aorta. PMID- 20844826 TI - Bennett's fracture dislocation. PMID- 20844827 TI - Breastfeeding knowledge and attitude among Saudi women in Central Saudi Arabia. PMID- 20844828 TI - Central nervous system anomalies diagnosed antenatally and post-delivery management. PMID- 20844829 TI - Comparison between traditional yogurt and probiotic yogurt in non-inflammatory acute gastroenteritis. PMID- 20844830 TI - Effects of education of the head of the household on the prevalence of malnutrition in children. PMID- 20844831 TI - Incidence trends of childhood type 1 diabetes in eastern Saudi Arabia. PMID- 20844832 TI - Gastrointestinal stromal tumors in Saudi Arabia. PMID- 20844833 TI - High-mobility group box-1 protein (HMGB1) is increased in antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis with renal manifestations. AB - High-mobility group box 1 (HMGB1) is a nuclear and cytosolic protein that is increasingly recognized as an important proinflammatory mediator actively secreted from monocytes and macrophages and passively released from necrotic cells. In antineutrophilic cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), the kidneys are commonly affected vital organs, characterized by focal necrotizing and/or crescentic pauci-immune glomerulonephritis. The aim of the study was to determine whether HMGB1 serum levels are elevated in AAV with renal manifestations. A total of 30 AAV patients (16 female and 14 male; median age 59 years, range 17-82) with Wegener granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome with available renal biopsies and serum samples were included. In seven cases, serum was also obtained at rebiopsy in remission. HMGB1 was analyzed with Western blot. Birmingham Vasculitis Activity Score (BVAS, version 2003), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinanalysis, creatinine, estimated glomerular filtration rate, sex and age were included in the analysis. Twenty-five episodes of biopsy-proven active disease with BVAS 17.9 +/- 4.6 and 13 cases with inactive biopsies and BVAS 2.3 +/- 3.7 (P = 0.0001) were identified. CRP, ESR, hematuria and proteinuria were significantly higher in active cases. HMGB1 was significantly elevated (P = 0.01) comparing active with inactive cases (120 +/- 48 versus 78 +/- 46 ng/mL) and significantly lower in the seven control patients (P = 0.03) at rebiopsy in remission. HMGB1 remained higher in inactive cases compared with historic healthy controls (10.9 +/- 10.5 ng/mL). HMGB1 levels did not differ significantly between AAV subgroups. CRP and ESR did not correlate with HMGB1. HMGB1 is significantly increased in AAV with renal involvement. Residual HMGB1 elevation in remission could possibly reflect low-grade inflammatory activity or tissue damage. Future studies may further reveal whether HMGB1 is useful as a marker of disease activity and a predictor of outcome in AAV. PMID- 20844834 TI - Insulinlike growth factor-1Ec (MGF) expression in eutopic and ectopic endometrium: characterization of the MGF E-peptide actions in vitro. AB - The transcription of the insulinlike growth factor 1 (igf-1) gene generates three mRNA isoforms, namely IGF-1Ea, IGF-1Eb and IGF-1Ec (or MGF [mechano growth factor]). Herein, we analyzed the expression of IGF-1 isoforms in eutopic and ectopic endometrium (red lesions and endometriotic cysts) of women with endometriosis, and we characterized the actions of a synthetic MGF E-peptide on KLE cells. Our data documented that all three igf-1 gene transcripts are expressed in the stromal cells of the eutopic and ectopic endometrium; however, endometriotic cysts contained significantly lower IGF-1 isoform expression, both at the mRNA and protein level, as was shown using semiquantitative PCR and immunohistochemical methods. In addition, the glandular cells of the eutopic endometrium did not express any of the IGF-1 isoforms; however, the glandular cells of the ectopic endometrium (red lesions) did express the IGF-1Ec at mRNA and protein level. Furthermore, synthetic MGF E-peptide, which comprised the last 24 amino acids of the MGF, stimulated the growth of the KLE cells. Experimental silencing of the type 1 IGF receptor (IGF-1R) and insulin receptor expression of KLE cells (siRNA knock-out methods) did not alter the mitogenic action of the synthetic MGF E-peptide, revealing that MGF E-peptide stimulates the growth of KLE cells via an IGF-1R-independent and insulin receptor-independent mechanism. These data suggest that the IGF-1Ec transcript might generate, apart from mature IGF-1 peptide, another posttranslational bioactive product that may have an important role in endometriosis pathophysiology. PMID- 20844835 TI - Angiotensin-converting enzyme (ACE) 2 overexpression ameliorates glomerular injury in a rat model of diabetic nephropathy: a comparison with ACE inhibition. AB - The reduced expression of angiotensin-converting enzyme (ACE) 2 in the kidneys of animal models and patients with diabetes suggests ACE2 involvement in diabetic nephrology. To explore the renoprotective effects of ACE2 overexpression, ACE inhibition (ACEI) or both on diabetic nephropathy and the potential mechanisms involved, 50 Wistar rats were randomly divided into a normal group that received an injection of sodium citrate buffer and a diabetic model group that received an injection of 60 mg/kg streptozotocin. Eight wks after streptozotocin injection, the diabetic rats were divided into no treatment group, adenoviral (Ad)-ACE2 group, Ad-green flurescent protein (GFP) group, ACEI group receiving benazepril and Ad-ACE2 + ACEI group. Four wks after treatment, physical, biochemical, and renal functional and morphological parameters were measured. An experiment in cultured glomerular mesangial cells was performed to examine the effects of ACE2 on cellular proliferation, oxidative stress and collagen IV synthesis. In comparison with the Ad-GFP group, the Ad-ACE2 group exhibited reduced systolic blood pressure, urinary albumin excretion, creatinine clearance, glomeruli sclerosis index and renal malondialdehyde level; downregulated transforming growth factor (TGF)-beta1, vascular endothelial growth factor (VEGF) and collagen IV protein expression; and increased renal superoxide dismutase activity. Ad-ACE2 and ACEI had similar effects, whereas combined use of Ad-ACE2 and ACEI offered no additional benefits. ACE2 transfection attenuated angiotensin (Ang) II-induced glomerular mesangial cell proliferation, oxidative stress and collagen IV protein synthesis. In conclusion, ACE2 exerts a renoprotective effect similar to that of ACEI treatment. Decreased renal Ang II, increased renal Ang-(1-7) levels, and inhibited oxidative stress were the possible mechanisms involved. PMID- 20844836 TI - Identification of genes potentially involved in the increased risk of malignancy in NF1-microdeleted patients. AB - Patients with NF1 microdeletion develop more neurofibromas at a younger age, and have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs). We postulated that the increased risk of malignancy could be due to inactivation, in addition to NF1, of a second tumor suppressor gene located in the typical 1.4-Mb microdeletion found in most of the microdeleted patients. We investigated the expression of NF1, the other 16 protein-coding genes and the 2 microRNAs located in the 1.4-Mb microdeletion by means of real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in a large series of human dermal and plexiform neurofibromas and MPNSTs. Five genes were significantly upregulated: OMG and SUZ12 in plexiform neurofibromas and ATAD5, EVI2A and C17orf79 in MPNSTs. More interestingly, two genes were significantly downregulated (RNF135 and CENTA2) in tumor Schwann cells from MPNST biopsies and in MPNST cell lines. This study points to the involvement of several genes (particularly RNF135 and CENTA2) in the increased risk of malignancy observed in NF1-microdeleted patients. PMID- 20844837 TI - Modulation of insulin sensitivity and caveolin-1 expression by orchidectomy in a nonobese type 2 diabetes animal model. AB - Previously, we found that male JYD mice developed type 2 diabetes but female mice did not, and that decreased expression levels of caveolin-1 were correlated with the development of a diabetic phenotype in these mice. Therefore, we hypothesized that sex hormones affect the expression of caveolin-1 and contribute to the development of insulin resistance and hyperglycemia in JYD mice. We used glucose and insulin tolerance tests to examine insulin sensitivity in male, female and orchidectomized male JYD mice. Glucose uptake was analyzed by using (18)F fluorodeoxyglucose positron emission tomography. We also examined insulin signaling molecules and caveolin proteins in various tissues in these mice by Western blotting. In addition, we examined changes of caveolin-1 expression in L6 skeletal muscle cells treated with 17-beta estradiol or dihydroxytestosterone. We found that glucose and insulin tolerance were impaired and hyperglycemia developed in male, but not female, JYD mice. Expression of insulin-signaling molecules such as insulin receptor, protein kinase B, and glucose transporter-4 were decreased in male JYD mice compared with female mice. Orchidectomized JYD male mice showed improved glucose and insulin tolerance with a concomitant increase in the expression of insulin-signaling molecules and caveolin-1 in adipose tissue and skeletal muscle. Moreover, 17-beta-estradiol treatment increased the expression of caveolin-1 in differentiated skeletal muscle cells. We conclude that sex hormones modulate the expression of caveolin-1 and insulin signaling molecules, subsequently affecting insulin sensitivity and the development of type 2 diabetes in JYD mice. PMID- 20844838 TI - High expression of H3K27me3 in human hepatocellular carcinomas correlates closely with vascular invasion and predicts worse prognosis in patients. AB - It has been suggested that trimethylation of lysine 27 on histone H3 (H3K27me3) is a crucial epigenetic process in tumorigenesis. However, the expression dynamics of H3K27me3 and its clinicopathological/prognostic significance in hepatocellular carcinoma (HCC) are unclear. In this study, immunohistochemical analysis (IHC) was used to examine protein expression of H3K27me3 in HCC tissues from two independent cohorts and corresponding nontumorous hepatocellular tissues by tissue microarray. The optimal cutpoint of H3K27me3 expression was assessed by the X-tile program. Our results showed that the cutpoint for high expression of H3K27me3 in HCCs was determined when more than 70% of the tumor cells showed positive staining. High expression of H3K27me3 was observed in 134 of 212 (63.2%) and 76 of 126 (60.4%) of HCCs in the testing and validation cohorts, respectively. Correlation analysis demonstrated that high expression of H3K27me3 in HCCs was significantly correlated with large tumor size, multiplicity, poor differentiation, advanced clinical stage and vascular invasion (P < 0.05). In addition, high expression of H3K27me3 in HCC patients was associated closely with shortened survival time, independent of serum alpha-fetoprotein levels, tumor size and multiplicity, clinical stage, vascular invasion and relapse as evidenced by univariate and multivariate analysis in both cohorts (P < 0.05). In different subsets of HCC patients, H3K27me3 expression was also a prognostic indicator in patients with stage II tumors (P < 0.05). Thus, these findings provide evidence that a high expression of H3K27me3, as detected by IHC, correlates closely with vascular invasion of HCCs and is an independent molecular marker for poor prognosis in patients with HCC. PMID- 20844839 TI - Interleukin-18 delays neutrophil apoptosis following alcohol intoxication and burn injury. AB - Studies have shown that burn patients who are intoxicated at the time of injury are more susceptible to infection and have a higher incidence of mortality. A major cause of death in burn and trauma patients regardless of their alcohol (EtOH) exposure is multiple organ dysfunction, which is driven in part by the systemic inflammatory response and activated neutrophils. Neutrophils are short lived and undergo apoptosis to maintain homeostasis and resolution of inflammation. A delay in apoptosis of neutrophils is one important mechanism which allows for their prolonged presence and the release of potentially harmful enzymes. The purpose of this study was to examine whether EtOH intoxication combined with burn injury influences neutrophil apoptosis and whether IL-18 plays any role in this setting. To accomplish this investigation, rats were gavaged with EtOH (3.2 g/kg) 4 h before being subjected to sham or burn injury of ~12.5% of the total body surface area, and then killed on d 1 after injury. Peripheral blood neutrophils were isolated and lysed. The lysates were analyzed for pro- and antiapoptotic proteins. We found that EtOH combined with burn injury prolonged neutrophil survival. This prolonged neutrophil survival was accompanied by a decrease in the levels of the neutrophil proapoptotic protein Bax, and an increase in antiapoptotic proteins Mcl-1 and Bcl-xl. Administration of IL-18 antibody following burn injury normalized the levels of Bax, Mcl-1 and Bcl-xl. The decrease in caspase-3 and DNA fragmentation observed following EtOH and burn injury was also normalized in rats treated with anti-IL-18 antibody. These findings suggest that IL-18 delays neutrophil apoptosis following EtOH and burn injury by modulating the pro- and antiapoptotic proteins. PMID- 20844840 TI - [Treatment of human infections caused by Bartonella spp.]. AB - Infections by Bartonella spp. include a wide spectrum of emerging and re-emerging infectious diseases. There is not a universal therapy for this infection, therefore treatment should be chosen individually. The aim of this review is to update the therapeutics aspects of this kind of infections. PMID- 20844841 TI - [Endotoxin adsortion as adjuvant therapy in gram negative severe sepsis]. AB - The mortality rate of severe sepsis and septic shock remains still high. Within the last years a better knowledge of its physiopathology and the implementation of a group of measures addressed to a fast identification and early treatment of the septic patients have proved to reduce mortality rate. Likewise, it continues being investigated in modulating the inflammatory response and limiting the harmful action of the bacterial products on the immune system. As a result of this research some endotoxin adsorber devices have been designed to control one of the most important targets that start the inflammatory cascade when gram negative microorganisms are involved.The usefulness that these endotoxin removal devices might have as adjuvant treatment in the Septic Syndrome and its applicability are reviewed in this paper. Likewise a profile of patient that might be to the benefit of this therapy is suggested according to the current knowledge. PMID- 20844842 TI - Antifungal activity of posaconazole against Candida spp. and non-Candida clinical yeasts isolates. AB - The in vitro antifungal activity of posaconazole was tested against 315 yeast clinical isolates and 11 ATCC reference strains by means an agar diffusion method (Neosensitabs, Rosco,Denmark) based in CLSI M44-A2 document. Posaconazole activity was excellent against Cryptococcus and Rhodotorula species studied and showed very good activity against most species of Candida tested. A total of 13 clinical isolates (4.1%) were resistant: Candida albicans (n=5), Candida glabrata (n=5), Candida tropicalis (n=1), Geotrichum australiensis (n=1) and Geotrichum capitatum (n=1). Our results suggest posaconazole is an effective antifungal agent against the most clinically important yeasts species (92.7% of susceptibility). Agar diffusion method provides good conditions for the posaconazole susceptibility study in the routine laboratory. PMID- 20844843 TI - [Critical study of spanish adult consumer profile of antibiotics on the basis of National Surveys of Health in 1993, 1995, 1997, 2001 and 2003]. AB - OBJECTIVE: The objective of this study has been to examine antibiotic consumption in Spain through the use of the National Surveys of Health (NSH) . MATERIAL AND METHODS: Taking the NSH, between 1993 and 2003, certain variables regarding the consumption of antibiotics have been analyzed; putting these into groups according to their typology, habits, comorbidity and the utilization of health resources. This information has been compared with published data by other authors. RESULTS: The consumption of antibiotics was approximately 3%, and 9-19% of this was not prescribed. Significant statistical associations have been observed between the consumption of antibiotics and other aspects such as academic and income levels, habits such as smoking, general health, certain chronic diseases, being bed-ridden due to disease; and also the use of certain medicines and the anti-influenza vaccine. CONCLUSIONS: Consumption of antibiotics coincides with described data by other authors, and this was always higher than prescribed. The association with other variables may be limited by the inadequate NSH design in order to know the exact consumption of antibiotics. PMID- 20844844 TI - [Impact factor and quality of scientific publications on Microbiology: the example of the Spanish Journal of Chemotherapy]. AB - INTRODUCTION: The impact factor of a journal is the quantitative analysis of the number of citations obtained during a specific period of time. This currently is the standard tool to measure the quality of the publication and a way to evaluate the research trajectory of a scientist. METHODS: Search for bibliometric indicators: Journal Citation Reports, SCImago Journal Rank and Potencial Impact Factor for the Spanish Medical Journals of the Instituto de Historia de la Ciencia y Documentacion Lopez Pinero (IHCD). To identify criteria of editorial quality, of visibility and of spreading by reviewing databases such as the Online Regional Information System for Scholarly Journals from Latin America, the Caribbean, Spain and Portugal (LATINDEX), SciELO (Scientific Electronic Library Online), DIALNET and the Collective Periodical Publications Catalogue of Spanish Healthcare Science Libraries, known as C17. RESULTS: For the first time, the Spanish Journal of Chemotherapy appears in the 2009 edition of JCR, previously by joined the two spanish journals Clinical Microbiology and Infectious Diseases and International Microbiology, both ranked at a lower position. While calculating factors of national and international impact of the five publications included in the category of Pharmacology and Pharmacy as part of theproject initiated by the IHCD, the Spanish Journal of Chemotherapy showed the best results. CONCLUSIONS: The Spanish Journal of Chemotherapy obtained good results in analysed bibliometric indicators, positioning it at the top of the ranking of Spanish medical journals. A good spreading helped to maintain visibility on the publication in the editorial field. PMID- 20844845 TI - [Comparative activity of doripenem, meropenem, and imipenem in recent clinical isolates obtained during the COMPACT-Spain epidemiological surveillance study]. AB - INTRODUCTION: Doripenem is a new carbapenem with broad spectrum antibacterial activity indicated for the treatment of nosocomial pneumonia and complicated urinary and intraabdominal infections. METHODS: Isolates of Pseudomonas aeruginosa, Acinetobacter and Enterobacteriaceae from patients with nosocomial pneumonia, bacteremia and complicated intraabdominal infections attended in 16 Spanish hospitals were included (October 2008-May 2009). Susceptibility to imipenem, meropenem and doripenem was studied with the Etest method, and the results were interpreted according to the EUCAST criteria. RESULTS: Considering all the isolates, doripenem (MIC(50) 0.12 mg/L) was 2- to 8-fold more active than meropenem (0.25 mg/L) and imipenem (1 mg/L). In relation to Enterobacteriaceae, the MIC(50) and MIC(90) values of doripenem and meropenem were similar (0.03 and 0.12 mg/L, respectively) and clearly superior to those of imipenem (0.25 and 1 mg/L). In the case of P. aeruginosa, MIC(50) and MIC(90) were more favorable to doripenem (0.25 and 16 mg/L) than to meropenem (0.5 and >=64 mg/L) or imipenem (2 and >=64 mg/L). In this species, the percentage of strains with lower MIC values for doripenem among those exhibiting intermediate susceptibility and resistance to meropenem was 63.0% (29/46) and 61.7% (63/102), respectively, versus only 4.3% (2/46) and 1.9% (2/102) with higher MIC values for doripenem. CONCLUSIONS: The results obtained in this study are similar to those reported in other countries, and reinforce the superior in vitro activity of doripenem versus the other carbapenems and its position in the treatment guidelines regarding the nosocomial infections for which it is indicated. PMID- 20844846 TI - [Child with injuries in eyelashes in rural environment]. PMID- 20844847 TI - [Antibiotic prophylaxis for transesophageal echocardiography]. PMID- 20844848 TI - Nanodermatology: a bright glimpse just beyond the horizon - part I. AB - Nanotechnology is a relatively new branch of engineering that is making rapid inroads in medicine and dermatology. Nanotechnology applies the unique properties of matter on the nanoscale (1000 nm and smaller) for the purposeful design of new materials. Dermatology is already one of the leading beneficiaries of nanotechnology. Among US patent holders in nanotechnology, the sixth largest is a cosmetics company. Nanotechnology applications have been realized in sunscreens and are being developed for the maintenance of skin health, as well as for the diagnosis and management of skin disease. This article summarizes some of the recent and anticipated advances in nanotechnology for dermatology. In part II, the author addresses the chief concerns of nanotechnology. PMID- 20844849 TI - The management of chronic pruritus in the elderly. AB - The elderly in North America represent the fastest growing segment of the population and the most common skin complaint in this age group is pruritus. The multitude of variables that come with advanced age means that the management of pruritus in the elderly poses a particular therapeutic challenge. Pruritus in advanced age may result from a variety of etiologies, although xerosis is the most common. In addition, certain cutaneous and systemic diseases that are associated with pruritus are more prevalent in the elderly. At present, there is no universally accepted therapy for pruritus. Currently, management of pruritus in the elderly must take an individualistically tailored approach with consideration of the patient's general health, the severity of symptoms, and the adverse effects of treatment. Physical and cognitive limitations, multiple comorbid conditions, and polypharmacy are some aspects that can influence the choice of treatment in this age group. PMID- 20844850 TI - DTI findings of brainstem involvement in Langerhans' cell histiocytosis. PMID- 20844851 TI - [Oncological pelvic surgery under urological aspects: bladder carcinoma]. AB - The aim of the treatment of invasive bladder cancer with radical cystectomy and subsequent urinary diversion is to combine a safe oncological procedure with a satisfactory quality of life. Radical cystectomy is the treatment of choice for all patients with recurrent or multifocal high grade T1 bladder cancer, T1 tumors with high risk of progression, failure of Bacillus Calmette-Guerin treatment and muscle-invasive bladder cancer. Radical cystectomy offers excellent recurrence free and cancer-specific survival rates as well as local tumor control in patients with organ-confined and node-negative diseases. Tumor control in non organ-confined tumors is still satisfactory with long term recurrence-free survival (RFS) rates of about 50%. Nerve-sparing cystectomy is of importance for lower urinary tract function, including continence rates after orthotopic urinary diversion and for sexual function in males and females. Orthotopic urinary reconstruction using a neobladder achieves good continence rates. Overall quality of life after radical cystectomy remains good in most patients irrespective of the type of urinary diversion. PMID- 20844852 TI - [Locally recurrent rectal cancer]. AB - Over the last decades the therapy of rectal carcinoma has shown continuous improvement. Due to improvements in operative techniques, such as the establishment of total mesorectal excision (TME) and the combination of surgery and (neo-) adjuvant radiochemotherapy, the incidence of locally recurrent rectal cancer could be improved from nearly 50% to less then 10%. Nevertheless recurrent rectal carcinoma remains a severe problem. Predictive factors relating to locally recurrent rectal cancer are surgical experience, localization of the tumor, circumferential resection margins, stage-oriented multimodal therapy and a suitable oncological procedure for the primary tumor. In addition the tumor specific biology also seems to be a relevant risk factor for recurrence. Operative treatment of locally recurrent rectal cancer was seen for a long time as a palliative procedure. Newer data show that resection of locally recurrent rectal cancer can be carried out with a curative intention in experienced institutions with a long-term 5 year survival of about 30% and mortality around 5%. The composite sacropelvic resection technique is a reasonable option in the curative treatment of locally recurrent rectal cancer. For the future the focus must be on improvements in the primary therapy of rectal carcinoma to avoid local recurrence. In addition early diagnosis of local recurrence and multimodal therapies will be of decisive importance. PMID- 20844853 TI - [Posterior atlantoaxial transarticular screw fixation. Surgery according to Magerl]. PMID- 20844854 TI - [Surgical procedures to stabilize the upper cervical spine]. AB - The options for surgical treatment of injuries to the upper cervical spine have increased considerably in recent years. A distinction can be made between two forms of surgical stabilization. Techniques of osteosynthesis serve to reconstruct the injured structure with the goal of maintaining mobility of the upper cervical spine. A spondylodesis, that can be performed at the atlantoaxial or occipitoatlantoaxial joint, aims to stabilize the upper cervical spine by fusion techniques. This article describes the surgical procedures for both treatment principles with regard to the indications, techniques, and complications. PMID- 20844856 TI - [Not every form of breast cancer can be demarcated with MRI]. PMID- 20844855 TI - [Nuclear medicine imaging in patients with Parkinson's syndrome: an update]. AB - Nuclear medicine imaging using positron emission tomography (PET) or single photon emission computed tomography (SPECT) has enabled to study not only the metabolism and blood flow in specific brain areas but also the quantification of the function of distinct molecules. With respect to Parkinson's disease PET and later SPECT allowed the number of dopaminergic neurons to be assessed in vivo. These quantifications are relevant to establishing a clinical diagnosis, assessing the progression of the disease or the survival of transplanted dopaminergic neurons. In addition both techniques have markedly contributed to our understanding of the pathophysiology of this disorder. More recently, molecular imaging has been directed towards understanding the pathophysiology of non-motor symptoms in this disorder. PMID- 20844857 TI - [What is new in breast imaging? From bench to bedside]. PMID- 20844858 TI - [Strategies for reducing the CT radiation dose]. AB - The rapid technical advances in computed tomography have led to an increased number of clinical indications. Unfortunately, at the same time the radiation exposure to the population has also increased due to the increased total number of CT examinations. In the last few years various publications have demonstrated the feasibility of radiation dose reduction for CT examinations with no compromise in image quality and loss in interpretation accuracy. The majority of the proposed methods for dose optimization are easy to apply and are independent of the detector array configuration. This article reviews indication-dependent principles (e.g. application of reduced tube voltage for CT angiography, selection of the collimation and the pitch, reducing the total number of imaging series, lowering the tube voltage and tube current for non-contrast CT scans), manufacturer-dependent principles (e.g. accurate application of automatic modulation of tube current, use of adaptive image noise filter and use of iterative image reconstruction) and general principles (e.g. appropriate patient centering in the gantry, avoiding over-ranging of the CT scan, lowering the tube voltage and tube current for survey CT scans) which lead to radiation dose reduction. PMID- 20844859 TI - [Node-positive prostate cancer. Value of radical prostatectomy]. AB - The current review article critically discusses the potential advantages and disadvantages of radical prostatectomy in patients with locally advanced lymph node-positive prostate cancer. It is the purpose of the manuscript to develop a therapeutic algorithm for management of these patients to achieve optimal oncological and functional results. Based on the data in the literature radical prostatectomy as part of a multimodality approach seems to be indicated in the following clinical scenario: limited intrapelvic lymph node metastasis without bulky disease; complete resectability of the primary cancer and metastases by extended radical prostatectomy and extended pelvic lymphadenectomy; inclusion of the patient in a multimodality approach; life expectancy > 10 years. In patients with extensive locally advanced PCA or large pelvic metastases, radical prostatectomy might be indicated to improve local cancer control and to prevent significant local and supravesical complications. In these cases, the indication for extensive surgery includes radical cystoprostatectomy and should be discussed in an interdisciplinary tumour board. PMID- 20844860 TI - [Haematuria, lymphadenopathy and splenomegaly: case report in a 22-year-old man and review of the literature]. AB - A 22-year-old patient attended the urological office with unclear bladder symptoms, haemorrhoids and haematuria. Splenomegaly was detected by ultrasound together with the suspicion of a bladder cyst. Computed tomography revealed mesenteric, retroperitoneal and inguinal lymph node swelling. The laboratory diagnostics produced the diagnosis of syphilis. The patient was successfully treated with ceftriaxone and benzylpenicillin benzathine. PMID- 20844861 TI - [Diagnostic procedure for bladder cancer. Standards and current developments]. AB - Urinary cytology and white light endoscopy have been the gold standard for initial diagnosis of bladder cancer for decades. Furthermore the use of imaging techniques, such as ultrasound or CT scanning can be necessary in certain cases. This article gives an overview on standard diagnostic techniques and introduces new optical diagnostic technologies, such as Raman spectroscopy, optical coherence tomography, narrow band imaging and confocal laser microscopy, which could play a role in the diagnosis of bladder cancer in the future. Furthermore the current indications for photodynamic diagnoses are discussed. PMID- 20844862 TI - Short-term hyperglycaemia causes non-reversible changes in arterial gene expression in a fully 'switchable' in vivo mouse model of diabetes. AB - AIMS/HYPOTHESIS: Irreversible arterial damage due to early effects of hypo- or hyperglycaemia could account for the limited success of glucose-lowering treatments in preventing cardiovascular disease (CVD) events. We hypothesised that even brief hypo- or hyperglycaemia could adversely affect arterial gene expression and that these changes, moreover, might not be fully reversible. METHODS: By controlled activation of a 'switchable' c-Myc transgene in beta cells, adult pIns-c-MycER(TAM) mice were rendered transiently hypo- and then hyperglycaemic, after which they were allowed to recover for up to 3 months. Immediate and sequential changes in aortic global gene expression from normal glycaemia through hypo- and hyperglycaemia to recovery were assessed. RESULTS: Gene expression was compared with that of normoglycaemic transgenic and tamoxifen treated wild-type controls. Overall, expression of 95 genes was significantly affected by moderate hypoglycaemia (glucose down to 2.5 mmol/l), whereas over 769 genes were affected by hyperglycaemia. Genes and pathways activated included several involved in atherogenic processes, such as inflammation and arterial calcification. Although expression of many genes recovered to initial pre exposure levels when hyperglycaemia was corrected (74.9%), in one in four genes this did not occur. Quantitative reverse transcriptase PCR and immunohistochemistry verified the gene expression patterns of key molecules, as shown by global gene arrays. CONCLUSIONS/INTERPRETATION: Short-term exposure to hyperglycaemia can cause deleterious and persistent changes in arterial gene expression in vivo. Brief hypoglycaemia also adversely affects gene expression, although less substantially. Together, these results suggest that early correction of hyperglycaemia and avoidance of hypoglycaemia may both be necessary to avoid excess CVD risk in diabetes. PMID- 20844863 TI - [Reconstruction of the proximal femur with the MUTARS(r) system]. AB - In the proximal femur a modular tumor prosthesis can be used today for reconstruction after resection of primary malignant bone tumors, metastatic lesions, and in revision surgery. The MUTARS(r) Munster system offers a high modularity and the possibility of combining it with the hip and knee revision system. Technical innovations, like hexagonal press fit bone anchorage, fine adjustment of rotation, silver coating of the surface of the prosthesis, and functional reconstruction with the help of a Trevira tube, guarantee a very good long-term survival of the prostheses and protection against the main complications such as aseptic loosening, deep infection, and instability. PMID- 20844865 TI - The sensitivity of Bacillus subtilis to diverse antimicrobial compounds is influenced by Abh. AB - Abh is a transition state regulator of Bacillus subtilis that controls biofilm formation and the production of several diverse antimicrobial compounds. Using a high-throughput non-biased technique, we show for the first time that Abh influences the sensitivity of B. subtilis to diverse antimicrobial compounds. Following up on these findings with a combination of classical genetics and antibiotic susceptibility assays, we demonstrate that Abh influences cellular processes such as the remodelling of the cell wall. We present data demonstrating that the extracytoplasmic function sigma factor sigma(X) controls resistance to beta-lactam antibiotics by activating abh transcription. Downstream from Abh, activation of slrR expression by Abh is responsible for controlling the sensitivity of B. subtilis to such antibiotics due to the role that SlrR plays in regulating autolysin biosynthesis. The abh mutant additionally exhibits increased resistance to aminoglycoside antimicrobials. We confirm that aminoglycoside killing of B. subtilis is likely to be caused by oxidative damage but rule out the possibility that the increased resistance of the abh mutant to aminoglycosides is due to a general increase in resistance to oxidative stress. PMID- 20844866 TI - Assessment of the modulating effects of fructo-oligosaccharides on fecal microbiota using human flora-associated piglets. AB - We first used human flora-associated (HFA) piglets, a significantly improved model for research on human gut microbiota, to study the effects of short-chain fructo-oligosaccharides (scFOS) on the gut bacterial populations. Ten neonatal HFA piglets were assigned to receive basal diets alone or supplemented with scFOS (0.5 g/kg body weight/day) from 1 to 37 days after birth (DAB). The impact of scFOS on the fecal bacterial populations of the piglets before (12 DAB), during (17 DAB), and after (25 and 37 DAB) weaning were monitored by PCR-denaturing gradient gel electrophoresis and real-time quantitative PCR. The Bifidobacterium genus was stimulated consistently, except during weaning, confirming the bifidogenic property of scFOS. At 12 DAB, the Clostridium leptum subgroup was decreased and two unknown Bacteroides-related species were increased; at 25 DAB, the C. leptum subgroup and Subdoligranulum variabile-like species were elevated, whereas one unknown Faecalibacterium-related species was suppressed; and at 37 DAB, the Bacteroides genus was decreased. The results showed that effects of scFOS on non-bifidobacteria varied at different developmental stages of the animals, warranting further investigation into the host-development-related effects of prebiotics on the gut microbiota and the host physiology using the HFA piglets as a model for humans. PMID- 20844867 TI - Effects of the antibiotic growth promoters flavomycin and florfenicol on the autochthonous intestinal microbiota of hybrid tilapia (Oreochromis niloticus ? * O. aureus ?). AB - The 16S rDNA PCR-DGGE and rpoB quantitative PCR (RQ-PCR) techniques were used to evaluate the effects of dietary flavomycin and florfenicol on the autochthonous intestinal microbiota of hybrid tilapia. The fish were fed four diets: control, dietary flavomycin, florfenicol and their combination. After 8 weeks of feeding, 6 fish from each cage were randomly chosen for the analysis. The total number of intestinal bacteria was determined by RQ-PCR. The results showed that dietary antibiotics significantly influenced the intestinal microbiota and dramatically reduced the intensity of total intestinal bacterial counts. The intensity of some phylotypes (EU563257, EU563262 and EU563255) were reduced to non-detectable levels by both dietary antibiotics, while supplementation of florfenicol to the diet also reduced the intensity of the phylotypes EU563242 and EU563262, uncultured Mycobacterium sp.-like, uncultured Cyanobacterium-like and uncultured Cyanobacterium (EU563246). Dietary flavomycin only reduced the OTU intensity of one phylotype, identified as a member of the phylum Fusobacteria. The antibiotic combination only reduced the phylotypes EU563242 and EU563262. Based on our results, we conclude that the reduced effect of florfenicol on intestinal microbiota was stronger than that of flavomycin, and when flavomycin and florfenicol were added in combination, the effect of florfenicol overshadowed that of flavomycin. PMID- 20844868 TI - Shotgun proteomics of Xanthobacter autotrophicus Py2 reveals proteins specific to growth on propylene. AB - Coenzyme M (CoM, 2-mercaptoethanesulfonate), once thought to be exclusively produced by methanogens, is now known to be the central cofactor in the metabolism of short-chain alkenes by a variety of aerobic bacteria. There is little evidence to suggest how, and under what conditions, CoM is biosynthesized by these organisms. A shotgun proteomics approach was used to investigate CoM dependent propylene metabolism in the Gram-negative bacterium Xanthobacter autotrophicus Py2. Cells were grown on either glucose or propylene, and the soluble proteomes were analyzed. An average of 395 proteins was identified from glucose-grown replicates, with an average of 419 identified from propylene-grown replicates. A number of linear megaplasmid (pXAUT01)-encoded proteins were found to be specifically produced by growth on propylene. These included all known to be crucial to propylene metabolism, in addition to an aldehyde dehydrogenase, a DNA-binding protein, and five putative CoM biosynthetic enzymes. This work has provided fresh insight into bacterial alkene metabolism and has generated new targets for future studies in X. autotrophicus Py2 and related CoM-dependent alkene-oxidizing bacteria. PMID- 20844869 TI - Are results from pharmaceutical-company-sponsored studies available to the public? AB - PURPOSE: Only 53% and 63% of studies and clinical trials results presented at congresses are published. Company-sponsored trial results are being posted on publicly accessible Web sites. We analyzed the public availability (publication or posting on a Web site) rate, time to publication, and factors predicting public availability of results of studies sponsored by a pharmaceutical company. METHODS: This was a retrospective cohort study analyzing all studies conducted by GlaxoSmithKline in Spain between 2001 and 2006. Initiation and completion were defined as first participant/first visit and last participant/last visit (or their equivalents). Papers published up to 31 March 2009 were considered. Logistic regression models were used to identify factors predicting public availability of results. RESULTS: The cohort comprised 143 studies (94 clinical trials; of these, 87 were included in international products clinical development plans). Public availability rate was 80% (114/143) for all studies and 78% (73/94) for clinical trials; publication rates were 68% and 61%, respectively. The median time to publication for all studies and trials was 27.3 and 28.4 months, respectively. Study associated to a cancelled project was the only significant factor associated with lower publication rate for all studies [odds ratio (OR) 0.069; 95% confidence interval (CI) 0.02-024; p < 0.001) and trials (OR 0.075; 95% CI 0.016-0.343; p = 0.001) and a lower public availability rate (OR 0.052; 95% CI 0.007-0.382; p = 0.004) for trial results. Therapy area, sample size, positive trial results, duration of experimental phase, and being a clinical trial did not predict publication or public availability. CONCLUSIONS: Eighty percent of studies included in this analysis are publicly available. Web site posting increases public availability rate of clinical trial results from 61% to 78%. Cancellation of projects is the single factor negatively influencing publication and public availability rates. PMID- 20844870 TI - Selection, trans-species polymorphism, and locus identification of major histocompatibility complex class IIbeta alleles of New World ranid frogs. AB - Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II beta1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class IIbeta exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class IIbeta loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the beta1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations. PMID- 20844874 TI - Bird mortality in oil field wastewater disposal facilities. AB - Commercial and centralized oilfield wastewater disposal facilities (COWDFs) are used in the Western United States for the disposal of formation water produced from oil and natural gas wells. In Colorado, New Mexico, Utah, and Wyoming, COWDFs use large evaporation ponds to dispose of the wastewater. Birds are attracted to these large evaporation ponds which, if not managed properly, can cause wildlife mortality. The U.S. Fish and Wildlife Service (USFWS) and the U.S. Environmental Protection Agency (EPA) conducted 154 field inspections of 28 COWDFs in Wyoming from March 1998 through September 2008 and documented mortality of birds and other wildlife in 9 COWDFs. Of 269 bird carcasses recovered from COWDFs, grebes (Family Podicipedidae) and waterfowl (Anatidae) were the most frequent casualties. Most mortalities were attributed to oil on evaporation ponds, but sodium toxicity and surfactants were the suspected causes of mortality at three COWDFs. Although the oil industry and state and federal regulators have made much progress in reducing bird mortality in oil and gas production facilities, significant mortality incidents continue in COWDFs, particularly older facilities permitted in the early 1980's. Inadequate operation and management of these COWDFs generally results in the discharge of oil into the large evaporation ponds which poses a risk for birds and other wildlife. PMID- 20844871 TI - In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer's disease. AB - PURPOSE: Amyloid beta protein (Abeta) is known as a pathological substance in Alzheimer's disease (AD) and is assumed to coexist with a degree of activated microglia in the brain. However, it remains unclear whether these two events occur in parallel with characteristic hypometabolism in AD in vivo. The purpose of the present study was to clarify the in vivo relationship between Abeta accumulation and neuroinflammation in those specific brain regions in early AD. METHODS: Eleven nootropic drug-naive AD patients underwent a series of positron emission tomography (PET) measurements with [(11)C](R)PK11195, [(11)C]PIB and [(18)F]FDG and a battery of cognitive tests within the same day. The binding potentials (BPs) of [(11)C](R)PK11195 were directly compared with those of [(11)C]PIB in the brain regions with reduced glucose metabolism. RESULTS: BPs of [(11)C](R)PK11195 and [(11)C]PIB were significantly higher in the parietotemporal regions of AD patients than in ten healthy controls. In AD patients, there was a negative correlation between dementia score and [(11)C](R)PK11195 BPs, but not [(11)C]PIB, in the limbic, precuneus and prefrontal regions. Direct comparisons showed a significant negative correlation between [(11)C](R)PK11195 and [(11)C]PIB BPs in the posterior cingulate cortex (PCC) (p < 0.05, corrected) that manifested the most severe reduction in [(18)F]FDG uptake. CONCLUSION: A lack of coupling between microglial activation and amyloid deposits may indicate that Abeta accumulation shown by [(11)C]PIB is not always the primary cause of microglial activation, but rather the negative correlation present in the PCC suggests that microglia can show higher activation during the production of Abeta in early AD. PMID- 20844875 TI - [To the delivery of the editorship]. PMID- 20844876 TI - [Changes in the TNM classification of gynecological tumors]. AB - Based on the results of clinical and histomorphological studies in recent years, a revision of the TNM classification of malignant tumours of the female genital organs became necessary. Vulvar cancer saw the most significant changes. In the T1 category the new system recognises tumour size and its relation to the infiltration of adjacent structures by the tumour. The number of positive regional lymph nodes has also been included in the new staging system. For cervical cancer, there is a new subdivision of the category T2a depending on tumour size with a breakpoint of <= 4 cm versus > 4 cm and a subdivision into T2a1 und T2a2. In endometrial cancer, the previous pT1a and pT1b were merged to pT1a. The former category T1c has changed into T1b. The category pT1c is no longer used. For the first time, there is a TNM classification system for uterine sarcomas. PMID- 20844878 TI - Kinase activation profile associated with TGF-beta-dependent migration of HCC cells: a preclinical study. AB - PURPOSE: To identify the molecular mechanisms responsible for tumor cell migration is essential for developing agents that can prevent the relapse or the metastatic spread of hepatocellular carcinoma (HCC). METHODS: In this study, we investigated the effects of the transforming growth factor-beta receptor I inhibitor LY2109761 on two different human HCC cell lines, in vitro and in vivo. RESULTS: LY2109761 inhibits HCC migration in a dose-dependent manner. This inhibition is associated with the decreased phosphorylation of SMAD-2, FAK and beta1-integrin, and with increased levels of E-cadherin. By contrast, LY2109761 did not alter the phosphorylation pattern of p38MAPkinase. In a two- and a three day time-course and in dose-titration experiments, LY2109761 inhibited HCC migration as well as phospho-SMAD-2 and the adhesion proteins. LY2109761 showed the best effect on day 2 at 1 nM and for 3 days at 100 nM concentration. This suggests that maximum effects were sustained for several days and were not dependent on excess concentrations. Finally, in a xenograft model of HCC, LY2109761 strongly inhibits tumor growth, intravasation and metastasis at the aforementioned lower concentrations. CONCLUSIONS: In conclusion, inhibition of transforming growth factor-beta (TGF-beta) appears to occur at low concentrations of LY2109761 that displays multiple effects on kinases that control HCC cell migration. These findings may help the design of future clinical trials with inhibitors of TGF-beta. PMID- 20844879 TI - Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868. AB - PURPOSE: The need for new treatment options for acute myeloid leukemia (AML) is increasing. AS602868 is a novel investigational drug with reported activity on AML cells. METHODS: We studied gene expression profiles in AML blasts exposed to AS602868 in order to better understand its mechanism of action. We analyzed the in vitro cytotoxicity of AS602868 alone or in combination with daunorubicin, etoposide or cytarabine. To document AS602868-induced IKK2 inhibition in fresh AML cells, a flow cytometry analysis of IkappaB was performed. Finally, the effect of AS602868 on gene expression in fresh AML cells was analyzed. RESULTS: The results show that AML cells are globally as sensitive to AS602868 as they are to cytarabine, with large interindividual variations. Combinations with conventional antileukemic agents showed enhanced cytotoxic activity in subsets of patients. IKK2 appeared to be effectively inhibited by 100 MUM AS602868 in fresh leukemic cells. Gene expression profiling and gene ontology analyses identified several groups of genes induced/inhibited by exposure to AS602868 and/or exhibiting a correlation with sensitivity to this agent in vitro. Of note, the expression of several genes related to immune function was found to be significantly altered after exposure to AS602868. CONCLUSION: These data suggest that AS602868 is cytotoxic against fresh human AML blasts and provide insights regarding the mechanisms of cytotoxicity. PMID- 20844880 TI - Interleukin-1 receptor antagonist reduced apoptosis and attenuated intestinal mucositis in a 5-fluorouracil chemotherapy model in mice. AB - PURPOSE: The aim of this study was to investigate the relationship between changes in IL-1beta expression and intestinal apoptosis after chemotherapy. And we further determine whether interleukin-1 receptor antagonist (IL-1Ra) reduces apoptosis in vivo after 5-fluorouracil (5-FU) chemotherapy in the small intestine. METHODS: Intestinal mucositis was induced in mice by intraperitoneal injection of a single dose of 5-FU (200 mg/kg). IL-1Ra (1 mg/kg) was injected subcutaneously twice daily after 5-FU injection. 5-FU-induced intestinal apoptosis was detected by TUNEL assay. The expression of IL-1beta induced by 5-FU in local intestinal tissue was examined by RT-PCR and immunohistochemistry. Assessment of 5-FU-induced mucositis (histology, diarrhea scores, bowel weight) was performed. The apoptosis-related proteins were investigated by western blotting analysis. The proliferation of intestine was examined by immunohistological staining of PCNA. Viability of IEC-6 cells was determined using the CCK-8 assay. The apoptosis of IEC-6 cells was examined by Hoechst 33342 staining. RESULTS: The variation of IL-1beta expression induced by 5-FU was in accordance with the changes in intestinal apoptosis. Administration of IL-1Ra could block the destructive effect of IL-1beta and reduce apoptosis in the small intestinal crypt after chemotherapy. The protection against apoptosis was in accordance with the reduction of the up-regulation of Bax and caspase 3 and the elimination of the down-regulation of Bcl-2 and Bcl-xL. Moreover, IL-1Ra attenuated the severity of intestinal mucositis induced by 5-FU and enhanced intestinal crypt proliferation. In vitro experiments showed that IL-1Ra suppressed apoptosis and increased cell viability in enterocyte IEC-6 cells treated with 5-FU. Additionally, IL-1Ra did not affect the chemotherapeutic effect of 5-FU in tumor CT-26 xenograft mice. CONCLUSIONS: Our studies elucidate that IL-1beta is quite possibly involved in and mediated the course of intestinal apoptosis after 5-FU chemotherapy. Administered with IL-1Ra protects mice against intestinal apoptosis induced by 5-FU, relieves mucosal impairment of the small intestine, and facilitates the recovery of the intestinal mucosa. IL-1Ra treatment offers a novel promising strategy for the prevention and cure of chemotherapy-induced intestinal mucositis in clinical practice. PMID- 20844881 TI - Clinical effect of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer. AB - PURPOSE: To evaluate the efficacy and toxicities of erlotinib as first-line treatment for Asian elderly patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Untreated patients with advanced NSCLC were included in this study; erlotinib was orally administered at a dose of 150 mg daily until disease progression or intolerable toxicity or for other reasons. RESULTS: A total of 35 patients were enrolled. Patient characteristics were as follows: mean age 75.6 years (ranged 70-81 years), 24 (68.6%) male, 16 (45.7%) former or current smokers, 13 (37.1%) adenocarcinoma, 18 (51.4%) squamous cell carcinoma and 4 (11.4%) bronchioloalveolar carcinoma. Out of 35 patients, 1 CR, 16 PR and 10 SD, resulting in an overall response rate (CR + PR) of 48.6% and disease control rate (DCR = CR + PR + SD) of 77.1%. The median TTP was 6.4 months, and the median OS was 12.7 months. The CBR was 80%, and the 1-year survival rate was 48.6%. The most common adverse event (AE) was mild skin rash and diarrhea (CTC AE 1/2). Among them, the female never smokers with a non squamous cell carcinoma histology was superior to the male smokers with a squamous cell carcinoma in disease control rate, with significant differences (P < 0.05). CONCLUSION: The results suggest that erlotinib monotherapy is an effective and well-tolerated treatment option for Asian elderly patients with advanced NSCLC. PMID- 20844882 TI - [Hereditary head and neck tumors]. AB - Hereditary paraganglioma, Gorlin-Goltz syndrome and Fanconi anemia are among the rare hereditary tumor syndromes of the head and neck. Patients with hereditary paraganglioma often develop multiple tumors of the glomus caroticum and glomus jugulotympanicum. The corresponding genetic defects of the mitochondrial succinate dehydrogenase complex induce autonomous tumor cell growth. In patients with Gorlin-Goltz syndrome basal cell carcinomas and keratocystic odontogenic tumors usually occur much earlier than in patients with sporadic tumors. The associated germline mutations are located in the patched gene which is a modulator of the cell cycle. Fanconi anemia represents a chromosomal instability syndrome which is characterized by early onset of pancytopenia, i.e. bone marrow failure and subsequent development of acute myeloid leukemia and/or squamous cell carcinomas, especially of the head and neck. A total of 13 different gene clusters have been identified in 2 DNA associated complexes which play an important role in DNA repair mechanisms. PMID- 20844883 TI - IgG4-related meningeal disease: clinico-pathological features and proposal for diagnostic criteria. AB - IgG4-related disease has evolved from originally being recognized as a form of pancreatitis to encompass diseases of numerous organs including the hypophysis and one reported case of dural involvement. A search of the University of Virginia, Division of Neuropathology files for 10 years identified ten cases of unexplained lymphoplasmacytic meningeal inflammation that we then evaluated using immunohistochemical stains for IgG4 and IgG. Ten control cases including sarcoidosis (4), tuberculosis (1), bacterial abscess (2), Langerhans cell histiocytosis (2), and foreign body reaction (1) were also examined. The number of IgG4-positive plasma cells was counted in five high power fields (HPFs) and an average per HPF was calculated. Cases that contained greater than ten IgG4 positive cells/HPF were considered to be IgG4-related. Five of the study cases met these criteria, including one case of leptomeningeal inflammation. All cases exhibited the typical histological features of IgG4-related disease including lymphoplasmacytic inflammation, fibrosis, and phlebitis. The dural-based lesions appear to represent a subset of the cases historically diagnosed as idiopathic hypertrophic pachymeningitis. While the leptomeningeal process most closely resembles non-vasculitic autoimmune inflammatory meningoencephalitis. Given these findings, IgG4-related meningitis should be considered in the differential diagnosis of meningeal inflammatory lesions after stringent clinical and histologic criteria are used to rule out other possible diagnoses. PMID- 20844884 TI - Abdominal, vaginal and total laparoscopic hysterectomy: perioperative morbidity. AB - PURPOSE: The aim of our retrospective study was to assess and to compare the surgical complications of hysterectomy regarding the choice of procedure [abdominal (AH), vaginal (VH), and total laparoscopic hysterectomy (TLH)]. METHODS: A total of 6,480 patient charts undergone hysterectomy were retrospectively analyzed. Data including transfusion, bladder, ureteral and bowel injury, cuff dehiscence, pulmoner embolus, febrile morbidity, hematoma, reoperation, pelvic wall problems were gathered. The Chi-square test and Student's t test were used in the statistical analysis. RESULTS: The most common perioperative complication was blood transfusion which occurred in 114 patients (2.6%). VH patients required significantly less blood transfusion than AH (2.1, 2.6%, respectively). AH had significantly more bladder injury than VH (0.7, 0.4%, respectively). AH had significantly more ureteral injury than VH (0.2, 0.1%, respectively). AH had the same bowel injury as VH (0.1%). AH and VH necessitated significantly more reoperation than TLH (0.4, 0.2, 0.0%, respectively). CONCLUSION: To our study, VH ensures less complication rates than AH. In experienced centers, VH can be a reliable alternative to AH. Controlled prospective studies with large patient volumes are required to compare TLH and VH according to complication rates. PMID- 20844885 TI - Chorioamnionitis and neonatal sepsis due to Candida tropicalis. PMID- 20844886 TI - Electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas assessed by antral follicle count: preliminary results of randomized clinical trial. AB - PURPOSE: The assessment of ovarian reserve by antral follicle count (AFC) following electrocoagulation versus suture after laparoscopic stripping of ovarian endometriomas. METHODS: Forty-five patients between 18 and 35 years, with unilateral endometriomas were randomly analyzed. Laparoscopic cystectomy was performed by the stripping method. Ovarian hemostasis was obtained either by suturing (group A, n = 23) or by bipolar electrocoagulation (group B, n = 22). AFC was performed by ultrasound on the third day of the three postoperative menstrual cycles. The sum of AFC was compared between sutured (A1) and electrocoagulated (B1) ovaries, as well as between intact ovaries of both groups (A0: intact ovaries in sutured group, B0: intact ovaries in electrocoagulated group). RESULTS: The median of AFC was significantly lower in operated ovaries than in intact ovaries in both groups of patients, regardless of suturing [A1 median: 12 (range 9-19) vs. A0 median: 21.0 (range 15-27), p < 0.05] or electrocoagulation [B1: 5.0 (2-10) vs. B0: 18.5 (8-29), p < 0.05]. The median AFC was significantly higher in sutured ovaries than in electrocoagulated ovaries [A1: 12 (9-19) vs. B1: 5.0 (2-10), p < 0.05]. CONCLUSION: Our preliminary data show that operation on ovarian endometriomas could reduce ovarian reserve. The AFC value suggests that the ovarian reserve was less reduced in sutured ovaries than in those electrocoagulated. Suturing as a method of hemostasis could be a better choice after stripping ovarian endometriomas. PMID- 20844887 TI - Hypotension in normotensive pregnant women treated with nifedipine as a tocolytic drug. AB - OBJECTIVE: To determine hypotensive effect of nifedipine in the treatment of preterm labor. METHODS: A descriptive analytic study was conducted on pregnant women treated with nifedipine as tocolytic drug for preterm labor. Maternal blood pressure before and at 15, 30, 45 and 60 min after administration of nifedipine was evaluated and analyzed. Hypotension was defined as a decrease in systolic or diastolic blood pressure of 15 mmHg or more. RESULTS: A total of 157 pregnant women met the inclusion criteria. The mean systolic and diastolic blood pressure before treatment was 109.4 and 72.5 mmHg, respectively. The blood pressure following treatment with nifedipine was significantly decreased both systolic and diastolic blood pressure (p < 0.05) at 30, 45 and 60 min. Of 157 patients, 28 (17.8%) and 27 (17.2%) had systolic and diastolic hypotension, respectively. Of the patients with decreased blood pressure, the mean decrease of systolic and diastolic blood pressure was 16.3 and 14.5 mmHg, respectively. CONCLUSION: Nifedipine was associated with a minimal but significant decrease in blood pressure. 17% of cases have hypotension. However, hypotension secondary to nifedipine was not associated with significant clinical symptoms, suggesting that nifedipine is relatively safe in terms of hypotensive effect. PMID- 20844888 TI - Pharmacotherapy: lithium and ALS, levodopa and neuropathy, antiepileptic drugs and suicide. PMID- 20844890 TI - The auxin-signaling pathway is required for the lateral root response of Arabidopsis to the rhizobacterium Phyllobacterium brassicacearum. AB - Plant root development is highly responsive both to changes in nitrate availability and beneficial microorganisms in the rhizosphere. We previously showed that Phyllobacterium brassicacearum STM196, a plant growth-promoting rhizobacteria strain isolated from rapeseed roots, alleviates the inhibition exerted by high nitrate supply on lateral root growth. Since soil-borne bacteria can produce IAA and since this plant hormone may be implicated in the high nitrate-dependent control of lateral root development, we investigated its role in the root development response of Arabidopsis thaliana to STM196. Inoculation with STM196 resulted in a 50% increase of lateral root growth in Arabidopsis wild type seedlings. This effect was completely abolished in aux1 and axr1 mutants, altered in IAA transport and signaling, respectively, indicating that these pathways are required. The STM196 strain, however, appeared to be a very low IAA producer when compared with the high-IAA-producing Azospirillum brasilense sp245 strain and its low-IAA-producing ipdc mutant. Consistent with the hypothesis that STM196 does not release significant amounts of IAA to the host roots, inoculation with this strain failed to increase root IAA content. Inoculation with STM196 led to increased expression levels of several IAA biosynthesis genes in shoots, increased Trp concentration in shoots, and increased auxin-dependent GUS staining in the root apices of DR5::GUS transgenic plants. All together, our results suggest that STM196 inoculation triggers changes in IAA distribution and homeostasis independently from IAA release by the bacteria. PMID- 20844891 TI - Comparison of six immunohistochemical markers for the histologic diagnosis of neoplasia in Barrett's esophagus. AB - In esophageal neoplasms, the histopathologic differentiation between Barrett's esophagus with or without intraepithelial neoplasia and adenocarcinoma is often challenging. Immunohistochemistry might help to differentiate between these lesions. The expression of CDX2, LI-cadherin, mucin 2 (MUC2), blood group 8 (BG8, Lewis(y)), claudin-2, and villin was investigated in normal gastroesophageal (n = 23) and in Barrett's (n = 17) mucosa, in low-grade (n = 12) and high-grade (n = 9) intraepithelial neoplasia (IEN) as well as in esophageal adenocarcinoma (n = 16), using immunohistochemistry. For CDX2 and LI-cadherin, the immunoreactivity score was highest in IEN while for MUC2, BG8, and villin, it dropped gradually from Barrett's via IEN to adenocarcinoma, and expression of Claudin-2 was only weak and focal in all lesions. The expression of MUC2 and LI-cadherin differed significantly between all examined lesions except between low-grade and high grade IEN. MUC2 and LI-cadherin are useful immunohistochemical markers for the differentiation between normal glandular mucosa, Barrett's mucosa, IEN, and invasive carcinoma of the esophagus; however, none of the examined markers was helpful for the differentiation between low-grade and high-grade IEN. PMID- 20844892 TI - Antiplasmodial activity of two marine polyherbal preparations from Chaetomorpha antennina and Aegiceras corniculatum against Plasmodium falciparum. AB - The ocean covers more than 70% of earth surface and hosts most 300,000 described species of plants and animals to use, which have been virtually unexploited for the development of medicines. Marine plants are the good source of biologically active entities which exhibit therapeutic properties, when applied single or in combination of different plant extracts (polyherbal). Polyherbal preparations are always a complex mixture of different forms and thus different compounds, which might act as agonistic, synergistic, complementary, antagonistic or toxic way. The present study was initially carried out to test the antiplasmodial activity of 13 mangrove plants and eight seaweeds species distributed along the coast of south India. Of these, mangrove species Aegiceras corniculatum and the seaweed species Chaetomorpha antennina have shown maximum antiplasmodial activity. Hence, the present study was mooted out to increase the percentage of antiplasmodial activity when applied as polyherbal preparations. The effect of marine polyherbal preparations from the methanolic extracts of two marine plants A. corniculatum and C. antennina for their antiplasmodial activity was tested. It shows that the polyherbal extract showed 63.50 +/- 0.408% suppression of parasitaemia against Plasmodium falciparum at 1.5 mg ml-1 concentration. In vivo test was carried out with rat animal model to find out the effectiveness of the polyherbal extracts in the live system, which reveals that polyherbal extracts have exhibited remarkable antiplasmodial activity (50.57 +/- 0.465%) against Plasmodium berghei at 120 mg kg-1 bw. This study shows that combinations of mangrove plants and seaweeds extracts had a source of lead compounds for the development of new drugs for the treatment of malaria. PMID- 20844893 TI - Preoperative versus intraoperative endoscopic sphincterotomy for management of common bile duct stones. AB - BACKGROUND: ERCP remains the prevailing method of treating CBDS; however, its ideal timing in respect to laparoscopic cholecystectomy (LC) is not defined. LC combined with intraoperative endoscopic sphincterotomy (IOES) was compared with preoperative endoscopic sphincterotomy (PES) followed by LC for management of preoperatively known cholecystocholedocholithiasis. METHODS: Between June 2006 and September 2009, 198 patients diagnosed preoperatively by clinical assessment, liver chemistry, ultrasonography, and magnetic resonance cholangiopancreatography (MRCP) to have combined choledochocystolithiasis were eligible. They were randomly divided into two groups: PES/LC group (n = 100) and LC/IOES group (n = 98). The surgical times, surgical success rates, number of stone extractions, postoperative complications, retained common bile duct stones, and postoperative lengths of stay were compared prospectively. RESULTS: There were no statistically significant differences in surgical time, surgical success rate, CBD diameter, stone size, or stone number between the two groups. The success rate was 95.3% and 97.8% for PES/LC and LC/IOES, respectively. There were no significant difference in postoperative retained stones, surgical time, and complications, but the total hospital stay was significantly shorter in the LC/IOES group. CONCLUSIONS: PES/LC and LC/IOES are both good options for dealing with preoperatively diagnosed CBDS, but when there is enough experience and facilities, LC/IOES, as a single-stage treatment, would be preferable. PMID- 20844894 TI - Extracervical approaches to endoscopic thyroid surgery. AB - There is increasing demand for surgical procedures which avoid visible scars while maintaining optimal functional and ideal cosmetic results, without compromising the safety or effectiveness of the procedure. Endoscopic techniques have been adapted to abdominal and pelvic surgery and increasingly employed over the past three decades. Although hampered by the absence of a natural cavity, endoscopic techniques have been adapted to surgery in the neck for the past 15 years, particularly for the thyroid gland. While earlier attempts at endoscopic thyroid surgery were performed through incisions in or near the midline of the neck, recent techniques have been developed to place the incisions and endoscopic ports extracervically, or at least away from the midline region of the neck, rendering the cosmetic result more acceptable. Most of these approaches are through the axilla, breast, chest wall or a combination of approaches. Visualization of the thyroid and rate of complications with these approaches are equal to those attained with older endoscopic approaches. Careful patient selection is important for endoscopic surgery. Complications unique to the endoscopic approach are mostly related to insufflation of cervical tissues with pressurized CO(2). PMID- 20844895 TI - Long-term outcome and survival with laparoscopy-assisted pylorus-preserving gastrectomy for early gastric cancer. AB - BACKGROUND: Laparoscopically assisted pylorus-preserving gastrectomy (LAPPG) is introduced as a function-preserving operation with minimal invasion for early gastric cancer (EGC). This study aimed to investigate the long-term outcome and survival with LAPPG. METHODS: From January 2005 to July 2008, 188 patients with EGC underwent LAPPG. The surgical and long-term outcomes and survival were assessed retrospectively. RESULTS: The accuracy of the preoperative EGC diagnosis was 92.6%. The median follow-up period was 38 months (range, 2-63 months). Two patients experienced gallstones, and three patients experienced a second primary EGC. One patient with T3N0 gastric cancer died of peritoneal metastasis, and four patients died of other causes. The overall 3-year survival rate was 97.8%, and the disease-specific 3-year survival rate was 99.3%. CONCLUSIONS: The LAPPG procedure is safe in terms of satisfactory long-term outcome and survival for patients with EGC in the middle third of the stomach. PMID- 20844896 TI - Decrease in sweet taste in rats after gastric bypass surgery. AB - BACKGROUND: The literature contains evidence that Roux-en-Y gastric bypass (RYGB) surgery has an effect in humans on taste and preference for carbohydrate-rich foods. This study tested the hypothesis that RYGB affects sweet taste behavior using a rat model. METHODS: Male Sprague-Dawley rats underwent either RYGB or sham surgery. Then 4 weeks after surgery, the rats were given taste-salient, brief-access lick tests with a series of sucrose concentrations. RESULTS: The RYGB rats, but not the sham rats, lost weight over the 5-week postoperative period. The RYGB rats showed a significant decrease in mean licks for the highest concentration of sucrose (0.25-1.0 mol/l) but not for the low concentrations of sucrose or water. CONCLUSIONS: The findings showed that RYGB surgery affected sweet taste behavior in rats, with postsurgical rats having lower sensitivity or avidity for sucrose than sham-treated control rats. This finding is similar to human reports that sweet taste and preferences for high-caloric foods are altered after bypass surgery. PMID- 20844897 TI - Techniques of radiofrequency-assisted precoagulation in laparoscopic liver resection. AB - BACKGROUND: Although radiofrequency-assisted (RF) precoagulation has been described for open resections, there is little data evaluating precoagulation options in laparoscopic liver resection. The purpose of this study is to provide an algorithm for the use of monopolar and bipolar RF devices in laparoscopic liver resection. METHODS: Patients undergoing laparoscopic liver resection utilizing precoagulation during the period 2007-2009 were identified from a prospectively maintained, institutional review board-approved database. RF assisted precoagulation was performed using a second-generation monopolar RF ablation catheter (Starburst XL, AngioDynamics) or bipolar RF device (Habib 4X, AngioDynamics). RESULTS: Precoagulation was utilized in 31cases (monopolar, n = 19, and bipolar, n = 12). Procedures performed included segmentectomy/wedge resection in 19 patients and bisegmentectomy in 12 patients. The bipolar RF device was used for left lateral sectionectomies (90%) in which there was linear transaction, whereas the monopolar RF catheter was used for nonlinear segmental and wedge resections involving the right lobe (95%). Time required for precoagulation was 22.5 +/- 7.2 min for the bipolar and 33.6 +/- 15.9 min for the monopolar device. No patient developed postoperative bleeding, bile duct injury, or liver abscess. At follow-up, one patient in the monopolar group developed a suspected local recurrence. CONCLUSIONS: We have suggested an algorithm to select a given device based on tumor location and type of resection. With approximately 30 min of time spent for precoagulation, the blood loss and rate of local recurrence were favorable. There also could be an oncologic benefit due to additional functional margin obtained with the RF effect. PMID- 20844898 TI - Randomized study of natural orifice transluminal endoscopic surgery and endoscopy shows similar hemodynamic impact in a porcine model. AB - BACKGROUND: A previous porcine study showed a significant difference in heart rate and diastolic blood pressure (DBP) between natural orifice transluminal endoscopic surgery (NOTES) and laparoscopy. This study evaluated the hemodynamics during endoscopy, laparoscopy, and transluminal access. METHODS: For this study, 37 female swine were randomized and invasively monitored in terms of blood and abdominal pressure, heart rate, and arterial blood gas (ABG) during 90-min procedures. Group 1 (n = 11) underwent NOTES peritoneoscopy; group 2 (n = 14) underwent 45-min diagnostic endoscopy, a 10-min washout period, and 35-min laparoscopy with mesh placement; and group 3 (n = 12) NOTES had transgastric mesh placement. The groups were compared using a mixed model and a Spearman trend test. This study was approved by Institutional Animal Care and Use Committee (IACUC). RESULTS: No difference in the systolic blood pressure (SBP) was noted. During the initial 30 min, DBP increased significantly from baseline in groups 1 (p < 0.001) and 2 (p = 0.01), but not in group 3 (p = 0.08). The mean DBP did not differ between the groups. During laparoscopy, the average end-tidal carbon dioxide (CO(2)) level was 6.6 mmHg higher in group 2 than in group 1 (p = 0.01). The heart rate and ABG values did not differ between the groups (p >= 0.10). CONCLUSION: Heart rate and DBP were similar for NOTES and endoscopy. The differences seen in a previous trial comparing NOTES and laparoscopy were not duplicated. The initial DBP increased for the endoscopy and diagnostic NOTES animals. Differences in end-tidal CO(2) were encountered again during the shortened laparoscopy segment. PMID- 20844899 TI - How effective is extracorporeal shock wave lithotripsy of ureteral stones with Dornier Lithotripter S EMSE 220F-XXP? A prospective and preliminary assessment. AB - AIM: To report our preliminary series with the Doli S EMSE 220F-XXP, the upgraded version of the previous Dornier Lithotripter S EMSE 220, for treatment of ureteral stones. METHODS: Since July 2006, a total of 200 patients with ureteral stones were submitted to shock wave lithotripsy (SWL) with Doli S EMSE 220F-XXP. Mean stone size was 9.3 mm (range 6-18 mm). Ureteral stone location was proximal in 75, middle in 34, and distal in 91. Follow-up was carried out at 6 weeks after the treatment, by means of kidney-ureter-bladder (KUB) film and ultrasound, or helical computed tomography (CT). RESULTS: The overall stone-free rate was 89.5%, and the effectiveness quotient was 80. Stratifying by stone site, the stone-free rate was 93.3, 67.6, and 94.5% for proximal, middle, and distal location, respectively. Mean number of sessions per patient was 1.14. Analgesia with intravenous ketorolac or tramadol was required in 42.5% of cases. No significant side-effects were recorded. CONCLUSIONS: The new Doli S EMSE 220F-XXP provides similar characteristics to the Doli S EMSE 220 in terms of safety and lack of major complications, when dealing with ureteral stones; the improvement in stone disintegration is particularly evident for distal location, for which the number of pulses and the intensity of treatment can be greatly increased and the upgraded power of the device can be widely applied. PMID- 20844900 TI - Video: transcervical videoscopic esophageal dissection in minimally invasive esophagectomy. AB - BACKGROUND: Minimally invasive esophagectomy (MIE) may involve video-assisted thoracoscopic surgery (VATS) for mediastinal esophageal dissection. Usually, VATS requires single-lung ventilation and has associated cardiopulmonary morbidity [1 3]. Alternatively, transhiatal dissection can be performed, although its complications include vocal cord palsy [4], cardiac arrythmias [5], and increased bleeding [5, 6], the latter associated with mortality after esophagectomy [2]. Therefore, the feasibility of MIE using transcervical videoscopic esophageal dissection (TVED) in swine was investigated. A simultaneous laparoscopic and TVED approach may decrease operative time and blood loss while improving visualization and avoiding single-lung ventilation. METHODS: Two pigs (Sus domesticus) underwent two similar procedures. The methods were approved by the authors' Institutional Animal Care and Use Committee (no. A24209) under United States Department of Agriculture guidelines. Steps included a cervical incision to accommodate a modified hand-assist access device. The cervical esophagus was dissected. Trocars were placed through the modified access device, and pneumomediastinum was established. The tracheoesophageal plane was dissected into the thorax and beyond the mid esophagus, on which the pleura of the separate mediastinal compartment inserts itself. Vagal nerves were identified and divided distal to recurrent branches. Standard laparoscopic techniques were used for esophagogastric dissection. After specimen extraction, the animals were euthanized. RESULTS: A full circumferential dissection of the mediastinal esophagus was successfully accomplished in two animals using a single-incision TVED for MIE. CONCLUSIONS: A novel technique for mediastinal esophageal dissection using a TVED approach performed with instruments designed for single port surgery is described. Fortunately, the human lacks the swine's separate mediastinal compartment, and this unique difference should facilitate the human version of this dissection. This approach may avoid the potential morbidity of VATS while providing better visualization and facilitating dissection of the upper mediastinal esophagus compared with either the transhiatal approach or the previously attempted rigid mediastinoscopic approaches [7-9]. PMID- 20844901 TI - Factors that influence the efficacy of bereavement life review therapy for spiritual well-being: a qualitative analysis. AB - PURPOSE: We have previously shown that bereavement life review therapy improves the spiritual well-being of a bereaved family, but the factors that influence the efficacy of this therapy have not been determined. Therefore, this study was performed to identify factors associated with improvement of spiritual well-being of bereaved families. METHODS: The participants were 21 bereaved family members who lost a relative who had been treated in a palliative care unit in Japan. The family members received the Bereavement Life Review over two sessions of about 60 min each. In the first session, the bereaved family member reviewed their memories of the deceased relative with a clinical psychologist and answered several questions. After the first session, the psychologist made an album. In the second session, the family member and the psychologist confirmed the accuracy of the contents of the album. Assessment was performed using the Functional Assessment Chronic Illness Therapy-Spiritual score, based on which the participants were separated into effective and non-effective groups. Factors were extracted from the narrative of the therapy using a text-mining software. RESULTS: Factors such as "good memories of family," "loss and reconstruction," and "pleasant memories of last days" were commonly found in the effective group, whereas factors such as "suffering with memories," "regret and sense of guilt," and "disagreement on funeral arrangements" were more common in the non-effective group. CONCLUSIONS: Factors like "good memories of families," "loss and reconstruction," and "pleasant memories of last days" were associated with the improvement of spiritual well-being of bereaved families. PMID- 20844902 TI - Malnutrition in patients treated for oral or oropharyngeal cancer--prevalence and relationship with oral symptoms: an explorative study. AB - PURPOSE: This study aimed to assess prevalence of malnutrition after treatment for oral/oropharyngeal cancer and to explore how oral symptoms relate to malnutrition after treatment. METHODS: In this cross-sectional study, malnutrition (weight loss >= 10% in 6 months or >= 5% in 1 month), oral symptoms (EORTC QLQ-H&N35 questionnaire and additional questions to assess chewing problems), dental status, trismus and dietary intake were assessed in 116 adult patients treated for oral/oropharyngeal cancer. RESULTS: Prevalence of malnutrition was 16% (95%CI: 10% to 23%). Prevalence of malnutrition in the period 0-3 months after treatment was significantly higher (25%) than in the periods >3-12 months (13%) and >12-36 months after treatment (3%, p = 0.008). Logistic multivariate regression analysis revealed that swallowing problems (p = 0.021) and insufficient protein intake were significantly related to malnutrition (p = 0.016). CONCLUSIONS: In conclusion, malnutrition is a considerable problem in patients treated for oral/oropharyngeal cancer, shortly after treatment. Of all oral symptoms, only swallowing problems were significantly related to malnutrition in the period after treatment for oral/oropharyngeal cancer. PMID- 20844903 TI - Prevalence, gender, ethnic variations, and prognosis of NASH. AB - We provide an update review on the prevalence, gender, ethnic variations, and prognosis of nonalcoholic steatohepatitis (NASH). According to annual health checks, 9-30% of Japanese adults have nonalcoholic fatty liver disease (NAFLD) by ultrasonography (US) and prevalence of NASH is estimated to be 1-3%. These conditions are strongly associated with the presence of obesity and lifestyle related diseases. NAFLD and NASH exhibit age and gender differences in both prevalence and severity. Among younger patients, these conditions are more common in men (2-3 times); however, after 60 years of age, the prevalence of NASH is higher in women. According to a systemic analysis of histological findings for NASH, 37.6% of patients had progressive fibrosis, 20.8% improved, and 41.6% remained stable over a mean duration of follow-up of 5.3 years. Age and presence of inflammation on initial biopsy were independent predictors of progression to advanced fibrosis. The frequencies of development of cirrhosis in NASH are 5-25% during around 7-year follow-up periods. Survival in NASH is lower than the expected survival of the matched general population due to the higher prevalence of cardiovascular and liver-related death. In patients with cirrhotic NASH, hepatocellular carcinoma (HCC) and liver failure are the main causes of morbidity and mortality (5-year cumulative HCC development rate 11.3%, 5-year survival rate 75.2%, respectively). The cumulative rate of recurrence of HCC at 5 years was 72.5%. Regular screening for complications of liver cirrhosis and HCC is extremely important for cirrhotic NASH patients. PMID- 20844904 TI - Long-term predictive power of heart rate variability on all-cause mortality in the diabetic population. AB - To examine the long-term predictive power of heart rate variability (HRV) on all cause mortality in randomly selected diabetic individuals. A total of 240 diabetic persons were randomly selected from the diabetic population. A 24-h ECG was obtained for each person included and analysed on the Pathfinder 700. In the RR Tools Program time (SDNN, SDANN, SDNN index, RMSSD, NN50, Triangular index) and frequency domain parameters (total power, VLF, LF, LFnorm, HF, HFnorm, HF/LF) were computed. After 151/2 years vital statistics were obtained. The analysis included 165 persons with acceptable ECG recordings. 81 individuals (49%) died during follow-up. Correcting for age and gender we found that in time domain, only the SDNN index was a significant mortality predictor but in the frequency domain, all parameters were significantly associated with death. In multivariate analysis only the power in the low frequency band was an independent predictor. During the period following the first 5 years, the baseline LF continued to be a significant predictor of mortality. This long-term follow-up study indicates that the LF power is the strongest HRV predictor with regard to mortality. A reduced HRV at baseline still holds prognostic information after 5 years. PMID- 20844906 TI - Whole-genome sequencing and gene mapping of a newly isolated lytic enterococcal bacteriophage EFRM31. AB - Bacteriophages contribute greatly to bacterial evolution. There has been limited investigation of enterococcal bacteriophages, and only two enterococcal bacteriophages have been sequenced completely. In this study, a novel enterococcal bacteriophage, EFRM31, was isolated from a piggery effluent sample and then characterized. The complete bacteriophage genome was determined by shotgun sequencing. EFRM31 belongs to the family Siphoviridae (order Caudovirales) and has a circular double-stranded DNA genome. The putative EFRM31 genome consists of 16945 nucleotides with a low GC content (34.5%) and does not contain CpG islands. The EFRM31 genome contains 82 putative open reading frames, including 17 with identities to genes required for the assembly of a head-tail bacteriophage and 6 hypothetical proteins of unknown function. In general, the sequencing results from EFRM31 revealed considerable similarity to another enterococcal bacteriophage, EFAP-1. This identity and the order of shared genes suggest a close relationship or a common ancestor for these two bacteriophages. PMID- 20844905 TI - theta power responses in mild Alzheimer's disease during an auditory oddball paradigm: lack of theta enhancement during stimulus processing. AB - There is evidence that theta responses reflect cognitive performance: good performances are associated with a decrease in tonic theta power as well as an increase in phasic theta power. In the present study, both tonic and phasic theta activity were analysed in 22 patients with mild Alzheimer's disease (AD), and 16 healthy elderly controls. Single-trial theta power responses were evaluated by an active auditory oddball paradigm along an early poststimulus window (0-250 ms) and a late time window (250-500 ms), and then compared to prestimulus theta power during both target tone and standard tone processing. The main findings were: (1) in AD patients, there was an increased prestimulus theta power, as well as no significant poststimulus theta power increase upon both target and non-target stimulus processing; (2) in healthy aged controls, only during target tone processing, an enhancement of both early and late theta responses relative to the prestimulus baseline was found. Moreover, healthy controls had a frontal dominance of theta power. The results might indicate that, during target processing, theta response is not functionally sensitive in AD and cannot be involved in processing demands as efficiently as in healthy controls. From a psychophysiological point of view, this might suggest an impairment of attentional allocation resources. The psychological implications might be related to selective attention/working-memory impairment from the early stage of the disease. Our data confirm that both tonic and phasic theta are relevant indicators of cognitive performance: the lack of a phasic theta and an increase in tonic theta are congruous findings in cognitive decline. Another factor worth noting is that in AD patients theta response is not dominant at the frontal site (as observed in healthy controls), indicating a weaker frontal lobe network reactivity during stimulus processing. PMID- 20844907 TI - Determination of trace amino acids in human serum by a selective and sensitive pre-column derivatization method using HPLC-FLD-MS/MS and derivatization optimization by response surface methodology. AB - Analysis of trace amino acids (AA) in physiological fluids has received more attention, because the analysis of these compounds could provide fundamental and important information for medical, biological, and clinical researches. More accurate method for the determination of those compounds is highly desirable and valuable. In the present study, we developed a selective and sensitive method for trace AA determination in biological samples using 2-[2-(7H-dibenzo [a,g]carbazol 7-yl)-ethoxy] ethyl chloroformate (DBCEC) as labeling reagent by HPLC-FLD-MS/MS. Response surface methodology (RSM) was first employed to optimize the derivatization reaction between DBCEC and AA. Compared with traditional single factor design, RSM was capable of lessening laborious, time and reagents consumption. The complete derivatization can be achieved within 6.3 min at room temperature. In conjunction with a gradient elution, a baseline resolution of 20 AA containing acidic, neutral, and basic AA was achieved on a reversed-phase Hypersil BDS C(18) column. This method showed excellent reproducibility and correlation coefficient, and offered the exciting detection limits of 0.19-1.17 fmol/MUL. The developed method was successfully applied to determinate AA in human serum. The sensitive and prognostic index of serum AA for liver diseases has also been discussed. PMID- 20844908 TI - Cytotoxicity of denture adhesives. AB - Ten commercially available denture adhesives, nine soluble formulations (six creams, three powders) and one insoluble product (pad), were analyzed regarding the cytotoxicity profile in direct and indirect assays using L929 fibroblast cells. In the direct assay, fibroblasts were seeded over the surface of a thick adhesive gel (5%, creams; 2.5%, powders and pad). In the indirect assay, cells were cultured in the presence of adhesive extracts prepared in static and dynamic conditions (0.5-2%, creams; 0.25-1%, powders and pad). Cell toxicity was assessed for cell viability/proliferation (MTT assay) and cell morphology (observation of the F-actin cytoskeleton organization by confocal laser scanning microscopy). Direct contact of the L929 fibroblasts with the thick adhesive gels caused no, or only a slight, decrease in cell viability/proliferation. The adhesive extracts (especially those prepared in dynamic conditions) caused significantly higher growth inhibition of fibroblasts and, in addition, caused dose- and time dependent effects, throughout the 6-72 h exposure time. Also, dose-dependent effects on cell morphology, with evident disruption of the F-actin cytoskeleton organization, were seen in the presence of most adhesives. In conclusion, the adhesives possessed different degrees of cytotoxicity, but similar dose- and time dependent biological profiles. PMID- 20844909 TI - Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer's disease. AB - Pharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode between GSP and AChE, in which GSP functional groups may perform specific interactions with residues in the enzyme active site, according to the ligand-protein contacts detected by the LPC/CSU server. Four hydrogen bonds were detected between GSP and Tyr121, Ser122, Ser200, and His440, in which the last two residues belong to the catalytic triad (Ser200...His440...Glu327). Hydrophobic and pi-pi stacking interactions were also detected between GSP and Phe330 and Trp84, respectively; these are involved in substrate stabilization at the active site. This study provides the basis to propose structural changes to the GSP structure, such as molecular simplification and isosteric replacement, in order to aid the design of new potential AChE inhibitors that are relevant to the treatment of Alzheimer's disease. PMID- 20844910 TI - A comparative study of one- and two-photon absorption properties of pyrene and perylene diimide derivatives. AB - Two important classes of organic molecules, perylene diimide (PDI) and pyrene derivatives have been found to possess relatively excellent photophysical and photochemical properties and especially high two-photon absorption cross sections (delta(T)(max)). Herein, one-photon absorption (OPA) and two-photon absorption (TPA) properties of some novel PDI and pyrene derivatives were comparatively investigated by the density functional theory (DFT) and Zerner's intermediate neglect of differential overlap (ZINDO) methods. The calculated results indicate that with respect to PDI derivatives, the maximum TPA cross-sections for pyrene compounds increase obviously, the maximum peaks of OPA and TPA spectra are blue shifted, the DeltaE(H-L) (energy gaps between the highest occupied orbital and the lowest unoccupied orbital) increase. The different pi-conjugated bridges (fluorene and pyrene) and terminal groups have slight effect on the OPA properties. Nevertheless, the molecules bearing 1,6-disubstituted pyrene as the pi-conjugated bridge display the largest delta(T)(max) in both series of compounds 3 and 4. Moreover, the delta(T)(max) values of molecules with benzothiazole-substituted terminal groups are larger than those of the molecules with diphenylamine, which is attributed to benzothiazole groups stabilizing the planarity of the branch parts, extending the conjugated length and increasing the pi-electron delocalized extent. Furthermore, the molecular size has marked effect on OPA and TPA properties. It is worthy to mention that cruciform 8 displays the largest delta(T)(max) among all the studied molecules in the range of 600-1100 nm. This research could provide a better understanding for the origin of the linear and nonlinear optical properties, and it would be helpful to gain more information about designing two-photon absorption materials with large delta(T)(max). PMID- 20844911 TI - Methylprednisolone pulse plus mizoribine in children with Henoch-Schoenlein purpura nephritis. AB - We evaluated whether methylprednisolone and urokinase pulse therapy combined with mizoribine (MUPM) was effective in children with severe Henoch-Schoenlein purpura nephritis (HSPN). We studied 12 patients who had been diagnosed with HSPN of at least ISKDC type III. All patients were treated with MUPM. Clinical features, pathological findings, and prognosis were prospectively investigated. Ten patients (responders; nine with ISKDC grade IIIb and one with grade IVb) were treated with MUPM, whereas MUPM was discontinued due to the lack of response in two patients (non-responders; two with grade IVb). Among responders, urinary protein excretion had decreased significantly from 99.7 +/- 37.8 to 25.9 +/- 33.4 mg/m(2) per hour after 3 months of therapy. The acute index and tubulointerstitial scores decreased significantly from 5.8 +/- 1.5 and 3.8 +/- 0.6 at the first biopsy to 2.3 +/- 1.3 and 1.0 +/- 0.8 at the second biopsy, respectively. At the most recent follow-up, eight of the responders had normal urine, and two had minor urinary abnormalities. Non-responders demonstrated continued high levels of urinary protein excretion after 3 months of therapy, and MUPM was discontinued. Our study suggests that MUPM is effective in ameliorating the proteinuria and the histological severity of HSPN in patients with <50% crescents but is not so effective for HSPN in patients with >50% crescents. PMID- 20844912 TI - Contribution of serotype and genetic background to biofilm formation by Streptococcus pneumoniae. AB - Streptococcus pneumoniae is the main cause of a variety of infections in children and the elderly ranging from otitis media to pneumonia. In recent years, biofilm formed by S. pneumoniae has begun to attract attention for a possible role in strains fitness and/or virulence. We evaluated the ability to form biofilm in a collection of clinical isolates, including antibiotic-resistant isolates whose genetic background had been previously ascertained. It appears that biofilm formation is a rather common feature among pneumococci, an observation which would fit with some types of infections caused by this microorganism (i.e. otitis, meningitis), which have often been associated with the ability to form biofilm. Antibiotic-susceptible isolates were able to form thicker biofilms compared to resistant strains, although no specific association could be observed with either serotypes or clones. This lack of association between the ability to form biofilm and any of the characters examined, while being a very common feature of pneumococci, may be suggestive of an important role for biofilm in pneumococcal ecology. PMID- 20844913 TI - Efficacy of fosfomycin and its combination with linezolid, vancomycin and imipenem in an experimental peritonitis model caused by a Staphylococcus aureus strain with reduced susceptibility to vancomycin. AB - The objective of this study was to evaluate the in vitro and in vivo efficacies of therapies including fosfomycin against clinical Staphylococcus aureus isolates with reduced susceptibility to vancomycin (hGISA). Time-kill curves were performed over 24 h. Peritonitis in C57BL/6 mice was induced by intraperitoneal inoculation of 10(8) CFU/ml. Four hours later (0 h), therapy was started and the treatment groups were: control (not treated), fosfomycin (100 mg/kg/5 h), vancomycin (60 mg/kg/5 h), imipenem (30 mg/kg/5 h), fosfomycin plus linezolid, fosfomycin plus vancomycin and fosfomycin plus imipenem, receiving subcutaneous therapy over 25 h. Bacterial counts in peritoneal fluid, bacteraemia and mortality rates were determined. In vitro, fosfomycin showed a synergistic effect when combined with the other antimicrobials tested. In the animal model, fosfomycin combinations were effective and significantly reduced the bacteraemia rates achieved in the control, imipenem and vancomycin groups (p < 0.05). The best combination in vivo was fosfomycin plus imipenem. Also, fosfomycin plus linezolid was significantly better than vancomycin alone, reducing the bacterial concentration in the peritoneal fluid. In conclusion, in vitro and in vivo, fosfomycin in combination with linezolid, vancomycin or imipenem exerted a good activity. Fosfomycin plus imipenem was the most active combination, decreasing 3 log CFU/ml, and appears to be a promising combination for clinical practice. PMID- 20844914 TI - Transferase activity function and system development process are critical in cattle embryo development. AB - Microarray gene expression experiments often consider specific developmental stages, tissue sources, or reproductive technologies. This focus hinders the understanding of the cattle embryo transcriptome. To address this, four microarray experiments encompassing three developmental stages (7, 25, 280 days), two tissue sources (embryonic or extra-embryonic), and two reproductive technologies (artificial insemination or AI and somatic cell nuclear transfer or NT) were combined using two sets of meta-analyses. The first set of meta-analyses uncovered 434 genes differentially expressed between AI and NT (regardless of stage or source) that were not detected by the individual-experiment analyses. The molecular function of transferase activity was enriched among these genes that included ECE2, SLC22A1, and a gene similar to CAMK2D. Gene POLG2 was over expressed in AI versus NT 7-day embryos and was under-expressed in AI versus NT 25-day embryos. Gene HAND2 was over-expressed in AI versus NT extra-embryonic samples at 280 days yet under-expressed in AI versus NT embryonic samples at 7 days. The second set of meta-analyses uncovered enrichment of system, organ, and anatomical structure development among the genes differentially expressed between 7- and 25-day embryos from either reproductive technology. Genes PRDX1and SLC16A1 were over-expressed in 7- versus 25-day AI embryos and under-expressed in 7- versus 25-day NT embryos. Changes in stage were associated with high number of differentially expressed genes, followed by technology and source. Genes with transferase activity may hold a clue to the differences in efficiency between reproductive technologies. PMID- 20844915 TI - Effects of renal dysfunction on cardiovascular events in diabetic patients with hypertension: challenge-DM Study subgroup analysis. AB - BACKGROUND: This study investigated the relation between renal dysfunction and cardiovascular events in patients from the Challenge-DM Study (a large-scale investigation of Japanese diabetic patients with hypertension on candesartan therapy). METHODS: The subjects were 4706 patients in whom renal function could be assessed at the time of registration among 16860 patients analyzed in the Challenge-DM Study. The definition of renal dysfunction (low GFR) was an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) calculated by the formula for Japanese. RESULTS: The low GFR group was older, and had a high proportion of females and a high prevalence of cerebrovascular or cardiovascular disease (CVD) compared to the normal GFR group (eGFR >= 60 ml/min/1.73 m(2)). Univariate Cox regression analysis of cardiovascular events showed a significant increase in the incidence of primary events and total events in the low GFR group. Among patients <65 years old, the same results were obtained, but no differences were found between the low GFR and normal GFR groups aged over 65 years. Multivariate Cox regression analysis was done with patient characteristics at registration and the presence/absence of achieving the target blood pressure and HbA(1c) before the event as explanatory variables. As a result, low GFR was not the main cause of cardiovascular events, but it had a significant influence on primary events and total events among patients <65 years old. CONCLUSIONS: Low GFR may be an independent risk factor for cerebrovascular and CVD among young and middle-aged Japanese diabetic patients with hypertension on candesartan therapy. PMID- 20844916 TI - Orbital pseudotumor in a child: diagnostic implications and treatment strategies. AB - Orbital pseudotumor is a benign, idiopathic, non-infectious and non-neoplastic clinical syndrome characterized by the presence of an inflammatory mass at orbital level with no identifiable cause. The disease is rarely observed in the pediatric population. This article describes a relapsing bilateral orbital pseudotumor in a young girl. The diagnostic implications and treatment strategies are discussed. PMID- 20844917 TI - Managing biomedical image metadata for search and retrieval of similar images. AB - Radiology images are generally disconnected from the metadata describing their contents, such as imaging observations ("semantic" metadata), which are usually described in text reports that are not directly linked to the images. We developed a system, the Biomedical Image Metadata Manager (BIMM) to (1) address the problem of managing biomedical image metadata and (2) facilitate the retrieval of similar images using semantic feature metadata. Our approach allows radiologists, researchers, and students to take advantage of the vast and growing repositories of medical image data by explicitly linking images to their associated metadata in a relational database that is globally accessible through a Web application. BIMM receives input in the form of standard-based metadata files using Web service and parses and stores the metadata in a relational database allowing efficient data query and maintenance capabilities. Upon querying BIMM for images, 2D regions of interest (ROIs) stored as metadata are automatically rendered onto preview images included in search results. The system's "match observations" function retrieves images with similar ROIs based on specific semantic features describing imaging observation characteristics (IOCs). We demonstrate that the system, using IOCs alone, can accurately retrieve images with diagnoses matching the query images, and we evaluate its performance on a set of annotated liver lesion images. BIMM has several potential applications, e.g., computer-aided detection and diagnosis, content-based image retrieval, automating medical analysis protocols, and gathering population statistics like disease prevalences. The system provides a framework for decision support systems, potentially improving their diagnostic accuracy and selection of appropriate therapies. PMID- 20844918 TI - Post varicella disseminated intravascular coagulation and transient protein S deficiency in an otherwise healthy 6-year-old boy: a case report. PMID- 20844919 TI - Plant ribosome-inactivating proteins type II induce the unfolded protein response in human cancer cells. AB - Cytotoxic ribosome-inactivating proteins (RIPs) of type II such as ricin were investigated as anti-cancer agents, but also pose a threat as biological weapons. The molecular mechanism leading to their toxic effects is, however, not yet clear. The current paradigm, which states that the irreversible depurination of 28S rRNA results in a general translational arrest eventually leading to cell death, has been questioned. Using micro-array, qRT-PCR and Western blot, we identified the unfolded protein response (UPR), a cellular mechanism activated in response to endoplasmic reticulum stress, that is induced in HCT116 and MDA-MB 231 cells exposed to the plant type II RIPs ricin, riproximin and volkensin. Apoptosis was induced by concentrations at which translation of UPR-related genes still occurred, despite concomitant ribosomal depurination. We conclude that UPR induction represents a model that better describes the cellular effects of RIP exposure at concentrations at which selected proteins are translated despite ribosomal depurination. PMID- 20844921 TI - Twinning frequency of Japanese Macaques (Macaca fuscata) at Takasakiyama. AB - In a wild-living, artificially provisioned population of Japanese macaques at Takasakiyama in southern Japan, nine sets of twins were recorded from 12,392 known deliveries over a 56-year study period. Recorded twinning frequency was 0.073%. During the first 28-year period, artificial food was given until macaques were satiated and population size increased rapidly. In the second 28-year period, provisioned food was restricted to about half of the former period's calorific content. Seven sets of twins were born in the first period and two sets in the second. Twining frequency in the two periods was 0.137 and 0.027%, respectively. In comparing studies of other Catarrhine primate samples, we hypothesize that twinning frequency is influenced by living conditions, and we suggest that living conditions should be carefully evaluated in studies of twinning frequency. PMID- 20844920 TI - Base excision repair and design of small molecule inhibitors of human DNA polymerase beta. AB - Base excision repair (BER) can protect a cell after endogenous or exogenous genotoxic stress, and a deficiency in BER can render a cell hypersensitive to stress-induced apoptotic and necrotic cell death, mutagenesis, and chromosomal rearrangements. However, understanding of the mammalian BER system is not yet complete as it is extraordinarily complex and has many back-up processes that complement a deficiency in any one step. Due of this lack of information, we are unable to make accurate predictions on therapeutic approaches targeting BER. A deeper understanding of BER will eventually allow us to conduct more meaningful clinical interventions. In this review, we will cover historical and recent information on mammalian BER and DNA polymerase beta and discuss approaches toward development and use of small molecule inhibitors to manipulate BER. With apologies to others, we will emphasize results obtained in our laboratory and those of our collaborators. PMID- 20844922 TI - Three-dimensional orientations of talar articular surfaces in humans and great apes. AB - The morphology of the talus prescribes relative positions and movements of the calcaneus and navicular with respect to the tibia, hence determining the overall geometry, mobility and function of the foot that mechanically interacts with environments. Clarifying the variations of the articular surface orientations of the talus in humans and extant great apes is therefore of importance in understanding the evolution of bipedal locomotion in the human lineage. The aim of this study is to clarify the three-dimensional orientations of three articular surfaces of the talus (superior, posterior calcaneal and navicular articular surfaces) by means of the newly proposed surface approximation method. Thirty-two tali in humans, chimpanzees, gorillas and orangutans were scanned using a three dimensional noncontact digitizer, and the articular surfaces were then approximated using a paraboloid or a plane to calculate the orientations of the surfaces with respect to the body of the talus. The results quantitatively demonstrated that the superior articular surfaces in humans were relatively more parallel with the horizontal plane of the talar body, while those in apes were more medially oriented. Furthermore, the cylindrical axis defined by the shape of the posterior calcaneal articular surface was directed less anteroposteriorly in humans than in apes, in contrast to the fact that the subtalar axis is more anteroposteriorly oriented in humans. It was also demonstrated that the navicular articular surface in humans was more plantarly oriented and axially twisted. These specialized features of the human talus seem to be functionally linked to obligate bipedal locomotion. The talar morphological differences among the great apes were prominent in the mediolateral and rotational orientations of the navicular articular surfaces, possibly reflecting the degree of arboreality among the great apes. PMID- 20844923 TI - Adding value to a toxic residue from the biodiesel industry: production of two distinct pool of lipases from Penicillium simplicissimum in castor bean waste. AB - In countries with a strong agricultural base, such as Brazil, the generation of solid residues is very high. In some cases, these wastes present no utility due to their toxic and allergenic compounds, and so are an environmental concern. The castor bean (Ricinus communis) is a promising candidate for biodiesel production. From the biodiesel production process developed in the Petrobras Research Center using castor bean seeds, a toxic and alkaline waste is produced. The use of agroindustrial wastes in solid-state fermentation (SSF) is a very interesting alternative for obtaining enzymes at low cost. Therefore, in this work, castor bean waste was used, without any treatment, as a culture medium for fungal growth and lipase production. The fungus Penicillium simplicissimum was able to grow and produce an enzyme in this waste. In order to maximize the enzyme production, two sequential designs-Plackett-Burman (variable screening) followed by central composite rotatable design (CCRD)-were carried out, attaining a considerable increase in lipase production, reaching an activity of 155.0 U/g after 96 h of fermentation. The use of experimental design strategy was efficient, leading to an increase of 340% in the lipase production. Zymography showed the presence of different lipases in the crude extract. The partial characterization of such extract showed the occurrence of two lipase pools with distinct characteristics of pH and temperature of action: one group with optimal action at pH 6.5 and 45 degrees C and another one at pH 9.0 and 25 degrees C. These results demonstrate how to add value to a toxic and worthless residue through the production of lipases with distinct characteristics. This pool of enzymes, produced through a low cost methodology, can be applied in different areas of biotechnology. PMID- 20844924 TI - Sugarcane bagasse enzymatic hydrolysis: rheological data as criteria for impeller selection. AB - The aim of this work was to select an efficient impeller to be used in a stirred reactor for the enzymatic hydrolysis of sugar cane bagasse. All experiments utilized 100 g (dry weight)/l of steam-pretreated bagasse, which is utilized in Brazil for cattle feed. The process was studied with respect to the rheological behavior of the biomass hydrolysate and the enzymatic conversion of the bagasse polysaccharides. These parameters were applied to model the power required for an impeller to operate at pilot scale (100 l) using empirical correlations according to Nagata [16]. Hydrolysis experiments were carried out using a blend of cellulases, beta-glucosidase, and xylanases produced in our laboratory by Trichoderma reesei RUT C30 and Aspergillus awamori. Hydrolyses were performed with an enzyme load of 10 FPU/g (dry weight) of bagasse over 36 h with periodic sampling for the measurement of viscosity and the concentration of glucose and reducing sugars. The mixture presented pseudoplastic behavior. This rheological model allowed for a performance comparison to be made between flat-blade disk (Rushton turbine) and pitched-blade (45 degrees ) impellers. The simulation showed that the pitched blade consumed tenfold less energy than the flat-blade disk turbine. The resulting sugar syrups contained 22 g/l of glucose, which corresponded to 45% cellulose conversion. PMID- 20844925 TI - Biological detoxification of different hemicellulosic hydrolysates using Issatchenkia occidentalis CCTCC M 206097 yeast. AB - This work had as its main objective to contribute to the development of a biological detoxification of hemicellulose hydrolysates obtained from different biomass plants using Issatchenkia occidentalis CCTCC M 206097 yeast. Tests with hemicellulosic hydrolysate of sugarcane bagasse in different concentrations were carried out to evaluate the influence of the hydrolysate concentration on the inhibitory compounds removal from the sugarcane bagasse hydrolysate, without reduction of sugar concentration. The highest reduction values of inhibitors concentration and less sugar losses were observed when the fivefold concentrated hydrolysate was treated by the evaluated yeast. In these experiments it was found that the high sugar concentrations favored lower sugar consumption by the yeast. The highest concentration reduction of syringaldehyde (66.67%), ferulic acid (73.33%), furfural (62%), and 5-HMF (85%) was observed when the concentrated hydrolysate was detoxified by using this yeast strain after 24 h of experimentation. The results obtained in this work showed the potential of the yeast Issatchenkia occidentalis CCTCC M 206097 as detoxification agent of hemicellulosic hydrolysate of different biomass plants. PMID- 20844926 TI - Methylphenidate in the management of asthenia in breast cancer patients treated with docetaxel: results of a pilot study. AB - BACKGROUND: The objectives of this pilot study were to evaluate the safety and efficacy of the central nervous system stimulant methylphenidate in the management of asthenia in breast cancer patients treated with docetaxel. PATIENTS AND METHODS: Patients with early breast cancer who presented asthenia >3 on the Visual Analogue Scale (VAS) after the first cycle of docetaxel-based chemotherapy were included. Patients received two additional cycles of chemotherapy, one with methylphenidate (10 mg bid) and the other without methylphenidate. Asthenia was evaluated using VAS and the Functional Assessment of Cancer Therapy-Fatigue (FACT F) scale. Distress was assessed using the Hospital Anxiety and Depression Scale (HADS), and quality of life using FACT-F. RESULTS: Ten patients were included and evaluated for efficacy and safety. Overall, cycles with methylphenidate were better tolerated than those without methylphenidate in terms of asthenia (VAS, p = 0.004; FACT-F, p = 0.027) and quality of life (FACT-F, p = 0.047). No significant differences were observed in terms of distress (HADS, p = 0.297). Six (60%) patients continued with methylphenidate after study end. Main adverse events during study were palpitations and insomnia (30% of patients each). CONCLUSIONS: This pilot study suggests that methylphenidate may reduce asthenia and improve quality of life in breast cancer patients treated with docetaxel. PMID- 20844927 TI - Efficient protein production method for NMR using soluble protein tags with cold shock expression vector. AB - The E. coli protein expression system is one of the most useful methods employed for NMR sample preparation. However, the production of some recombinant proteins in E. coli is often hampered by difficulties such as low expression level and low solubility. To address these problems, a modified cold-shock expression system containing a glutathione S-transferase (GST) tag, the pCold-GST system, was investigated. The pCold-GST system successfully expressed 9 out of 10 proteins that otherwise could not be expressed using a conventional E. coli expression system. Here, we applied the pCold-GST system to 84 proteins and 78 proteins were successfully expressed in the soluble fraction. Three other cold-shock expression systems containing a maltose binding protein tag (pCold-MBP), protein G B1 domain tag (pCold-GB1) or thioredoxin tag (pCold-Trx) were also developed to improve the yield. Additionally, we show that a C-terminal proline tag, which is invisible in 1H-15N HSQC spectra, inhibits protein degradation and increases the final yield of unstable proteins. The purified proteins were amenable to NMR analyses. These data suggest that pCold expression systems combined with soluble protein tags can be utilized to improve the expression and purification of various proteins for NMR analysis. PMID- 20844928 TI - Cadmium-induced heme oxygenase-1 gene expression is associated with the depletion of glutathione in the roots of Medicago sativa. AB - Following previous findings that cadmium (Cd) induces heme oxygenase-1 (HO1) gene expression in alfalfa seedling roots, we now show that the decreased glutathione (GSH) and ascorbic acid (AsA) contents, induction of HO-1 gene expression and its protein level by Cd was mimicked by a GSH depletor diethylmaleate (DEM). Meanwhile, above Cd- or DEM-induced decreased GSH content followed by HO-1 up regulation could be strengthened or reversed differentially by the application of a selective inhibitor of GSH biosynthesis L: -buthionine-sulfoximine (BSO), or exogenous GSH and AsA, respectively. The antioxidative behavior of HO-1 induction was further confirmed by histochemical staining for the detection of loss of membrane integrity in a short period of treatment time. Additionally, the induction of HO-1 transcript was inhibited by the transcriptional inhibitor actinomycin D (ActD) or protein synthesis inhibitor cycloheximide (CX, especially). In contrast, the level of HO-2 transcript did not change upon various treatments. Together, above results suggested that Cd-induced up regulation of HO-1 gene expression is associated with GSH depletion, which is at least existing transcriptional regulation level, thus leading to enhanced antioxidative capability transiently. PMID- 20844929 TI - Suitability of the predatory mites Iphiseiodes zuluagai and Euseius concordis in controlling Polyphagotarsonemus latus and Tetranychus bastosi on Jatropha curcas plants in Brazil. AB - One of the most promising plant species for biofuel production in Brazil is the physic nut Jatropha curcas. Major phytosanitary problems include the attack of two pest mite species, the broad mite Polyphagotarsonemus latus and the spider mite Tetranychus bastosi. Owing to pesticide-related problems, there is an increasing demand for sustainable environmental-friendly control methods such as biological control. In this study we evaluated the suitability of the predatory mite species Iphiseiodes zuluagai and Euseius concordis in controlling P. latus and T. bastosi on J. curcas. The number of T. bastosi killed by I. zuluagai was lower than the number of P. latus consumed. Euseius concordis preyed upon both T. bastosi and P. latus but the number of prey killed was always lower in comparison with I. zuluagai. However, P. latus and T. bastosi are suitable for the development of I. zuluagai and E. concordis as oviposition of both predators did not differ in relation to prey species. The preference of I. zuluagai for leaves of plants infested by either P. latus or T. bastosi, combined with the higher values for predation obtained by this predatory mite when fed on P. latus, compared to those values obtained by E. concordis, suggests that I. zuluagai can be more efficient than E. concordis in reducing populations of P. latus and T. bastosi under field conditions. Furthermore, we report here on the first record of predatory mites associated with P. latus and T. bastosi on native J. curcas plants in Brazil. In conclusion, we emphasize the crucial importance of predatory mites as agents of natural biological control of mite pests on J. curcas in small farms. PMID- 20844930 TI - The presence of Tetranychus urticae (Acari: Tetranychidae) and its predators on plants in the ground cover in commercially treated vineyards. AB - The presence of Tetranychus urticae and its predators on plants in the ground cover in commercially treated vineyards in the Hex River Valley, Western Cape Province, South Africa was investigated. Six Barlinka and six Dauphine vineyards were surveyed. Leaf samples from the plants on the vineyard floor were taken at monthly intervals and microscopically examined for spider mites and their predators. The coverage of the plants was determined using a co-ordinate sampling system. A wide variety of plant species was found on the vineyard floor. Most of the spider mites found on these plants were T. urticae. The phytoseiid mites on the plants were Euseius rubicolus, Neoseiulus californicus and an undescribed Typhlodromus species. The presence of these plants made it possible for T. urticae and phytoseiid mites to occur throughout the year, with a similar pattern in their seasonal activity on the vineyard floor and the vine leaves. PMID- 20844931 TI - p-AKT overexpression in primary renal cell carcinomas and their metastases. AB - In cancer therapy novel concepts focus on phosphoinositide 3-kinase (PI3K)/activated protein kinase B (p-AKT)/mammalian target of rapamycin (mTOR) inhibitors. In this context, p-AKT overexpression was previously shown to be associated with sensitivity to inhibitors of mTOR. The present study evaluated p AKT expression in a tissue microarray of primary renal cell carcinomas (PRCCs) (n = 45), their metastases (primary onset n = 45, secondary onset n = 5), and normal renal parenchyma (n = 45) by means of immunohistochemistry. Total p-AKT overexpression was found in 24/45 (53.3%) PRCCs, in 32/45 (71.1%) primary and in 3/5 (60%) secondary onset metastases. Membranous p-AKT overexpression was seen more frequently in PRCCs, namely 11/45 (24.4%), than in primary onset metastases 1/45 (2.2%). Overexpression of total p-AKT solely in metastases without overexpression in PRCC was exclusively demonstrated in primary onset metastases, namely in 28.9%. Patients with total p-AKT overexpression in primary carcinomas showed a trend to longer, and those with total p-AKT overexpression in metastases a tendency to shorter survival. In conclusion, the present study shows total p AKT overexpression to be more frequent in metastases than in PRCCs. Total p-AKT overexpression in metastases without concomitant overexpression in their primary tumors was found in approximately one-third of primary onset metastases, which is interesting with regard to the association between high p-AKT expression and sensitivity to mTOR inhibitor therapy. PMID- 20844933 TI - Analysis of infant cry through weighted linear prediction cepstral coefficients and Probabilistic Neural Network. AB - Acoustic analysis of infant cry signals has been proven to be an excellent tool in the area of automatic detection of pathological status of an infant. This paper investigates the application of parameter weighting for linear prediction cepstral coefficients (LPCCs) to provide the robust representation of infant cry signals. Three classes of infant cry signals were considered such as normal cry signals, cry signals from deaf babies and babies with asphyxia. A Probabilistic Neural Network (PNN) is suggested to classify the infant cry signals into normal and pathological cries. PNN is trained with different spread factor or smoothing parameter to obtain better classification accuracy. The experimental results demonstrate that the suggested features and classification algorithms give very promising classification accuracy of above 98% and it expounds that the suggested method can be used to help medical professionals for diagnosing pathological status of an infant from cry signals. PMID- 20844932 TI - KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model. AB - Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-expression of KISS1 would reduce metastases. Highly metastatic S2VP10 cells expressing luciferase (S2VP10L) were transfected with a FLAG-tagged version of KISS1 (KFM), KFMDeltaSS (with deleted secretion signal sequence), or pcDNA3 control plasmid (CP) and expression was confirmed by RTQ-PCR. SCID mice were implanted orthotopically with S2VP10L cells or transfectants and tumor growth and metastases were monitored using bioluminescence imaging. Mice with S2VP10L-KISS1 tumors developed fewer liver (98%) and lung (99%) metastases than S2VP10L. Unexpectedly, mice with S2VP10L-KFMDeltaSS tumors also had reduced liver and lung metastases, but had more metastases than mice with S2VP10L-KISS. KISS1 protein was found in the cytoplasm of both KFMDeltaSS and KISS1-expressing orthotopic tumors by immunohistochemistry. Metastases were not found in lungs of mice with S2VP10L KISS1 tumors; whereas, KFMDeltaSS lung sections had regions of concentrated KISS1 staining, suggesting that secretion of KISS1 is needed to reduce metastasis significantly. These data suggest induction of KISS1 expression has potential as an adjuvant treatment for pancreatic cancer. PMID- 20844934 TI - After the waters receded: a qualitative study of university officials' disaster experiences during the Great Iowa Flood of 2008. AB - When the Great Flood of 2008 hit towns across Eastern Iowa, officials from the University of Iowa shut its operations for a week, relocated and evacuated students and community residents, and suffered damage to over a dozen buildings. This study is a qualitative assessment of the experiences and perceptions of twelve university officials involved in the response and management of the disaster. Major themes are presented according to phases of the Disaster Management Cycle. During the preparedness phase, an established all-hazards plan as well as specific annexes for flooding and pandemic influenza proved to enhance community response to the flood. However, training university clientele across a large organization to execute these plans and respond to future disasters is not an easy task. The content and effective means for delivering these trainings are areas for further research. During the response phase of the flood, officials swiftly expedited a business continuity plan to assure that personnel were paid during the university closure. However, enforcing a policy to avoid coming to work during the closure was challenging. Thus, future work must be done to determine and implement effective disaster communications that relay clear messages about roles and responsibilities. Now, in recovery, the university must rebuild its infrastructure and consider potential mental health issues. Lessons learned from the Great Flood of 2008 provide the opportunity to self-assess and prepare universities for disasters in the future. PMID- 20844936 TI - Comparative analysis of microbial diversity in Longitarsus flea beetles (Coleoptera: Chrysomelidae). AB - Herbivorous beetles comprise a significant fraction of eukaryotic biodiversity and their plant-feeding adaptations make them notorious agricultural pests. Despite more than a century of research on their ecology and evolution, we know little about the diversity and function of their symbiotic microbial communities. Recent culture-independent molecular studies have shown that insects possess diverse gut microbial communities that appear critical for their survival. In this study, we combined culture-independent methods and high-throughput sequencing strategies to perform a comparative analysis of Longitarsus flea beetles microbial community diversity (MCD). This genus of beetle herbivores contains host plant specialists and generalists that feed on a diverse array of toxic plants. Using a deep-sequencing approach, we characterized the MCD of eleven Longitarsus species across the genus, several of which represented independent shifts to the same host plant families. Database comparisons found that Longitarsus-associated microbes came from two habitat types: insect guts and the soil rhizosphere. Statistical clustering of the Longitarsus microbial communities found little correlation with the beetle phylogeny, and uncovered discrepancies between bacterial communities extracted directly from beetles and those from frass. A Principal Coordinates Analysis also found some correspondence between beetle MCD and host plant family. Collectively, our data suggest that environmental factors play a dominant role in shaping Longitarsus MCD and that the root-feeding beetle larvae of these insects are inoculated by soil rhizosphere microbes. Future studies will investigate MCD of select Longitarsus species across their geographic ranges and explore the connection between the soil rhizosphere and the beetle MCD. PMID- 20844935 TI - Ovate family protein 1 as a plant Ku70 interacting protein involving in DNA double-strand break repair. AB - The Ku heterodimer, a DNA repair protein complex consisting of 70- and 80-kDa subunits, is involved in the non-homologous end-joining (NHEJ) pathway. Plants are thought to use the NHEJ pathway primarily for the repair of DNA double-strand breaks (DSBs). The Ku70/80 protein has been identified in many plants and been shown to possess several similar functions to its counter protein complex in mammals. In the present study, ovate family protein 1 (AtOFP1) was demonstrated to be a plant Ku-interacting protein by yeast two-hybrid screening and the GST pull-down assay. Truncation analysis revealed that the C-terminal domain of AtKu70 contains interacting sites for AtOFP1. The electrophoretic mobility shift assay (EMSA) indicated that AtOFP1 is also a DNA binding protein with its binding domain at the N-terminus. In 3-week-old seedlings, expression of the AtOFP1 gene increased after exposure to DNA-damaging agents (such as methyl methanesulfonate (MMS) and menadione) in a time dependent manner. Seedlings lacking the AtOFP1 protein were more sensitive to MMS and menadione as compared with wild-type. Furthermore, similar to AtKu70(-/-) and AtKu80(-/-), the AtOFP1(-/-) mutant showed relatively lower NHEJ activity in vivo. Taken together, these results suggest that AtOFP1 may play a role in DNA repair through the NHEJ pathway accompanying with the AtKu protein. PMID- 20844937 TI - Mitotic and polytene chromosomes analysis of the oriental fruit fly, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). AB - The Oriental fruit fly, Batrocera dorsalis s.s. (Hendel) is one of the most destructive agricultural pests, belonging to a large group of difficult to distinguish morphologically species, referred as the B. dorsalis complex. We report here a cytogenetic analysis of two laboratory strains of the species and provide a photographic polytene chromosome map from larval salivary glands. The mitotic complement consists of six chromosome pairs including a heteromorphic sex (XX/XY) chromosome pair. Analysis of the polytene complement has shown a total of five polytene chromosomes (10 polytene arms) that correspond to the five autosomes. The most important landmarks of each polytene chromosome and characteristic asynapsis at a specific chromosomal region are presented and discussed. Chromosomal homology between B. dorsalis and Ceratitis capitata has been determined by comparing chromosome banding patterns. The detection of chromosome inversions in both B. dorsalis strains is shown and discussed. Our results show that the polytene maps presented here are suitable for cytogenetic analysis of this species and can be used for comparative studies among species of the Tephritidae family. They also provide a diagnostic tool that could accelerate species identification within the B. dorsalis complex and could shed light on the ongoing speciation in this complex. Polytene chromosome maps can facilitate the development of biological control methods and support the genome mapping project of the species that is currently in progress. PMID- 20844938 TI - Recombination technologies for enhanced transgene stability in bioengineered insects. AB - Transposon-based vectors currently provide the most suitable gene transfer systems for insect germ-line transformation and are used for molecular improvement of the Sterile Insect Technique. However, the long time stability of genome-integrated transposon constructs depends on the absence of transposase activity that could remobilize the transposon-embedded transgenes. To achieve transgene stability transposon vectors are usually non-autonomous, lacking a functional transposase gene, and chosen so that endogenous or related transposon activities are not present in the host. Nevertheless, the non-autonomous transposon-embedded transgenes could become unstable by the unintended presence of a mobilizing transposase that may have been undetected or subsequently entered the host species by horizontal gene transfer. Since the field release of transgenic insects will present environmental concerns relating to large populations and high mobility, it will be important to ensure that transgene constructs are stably integrated for maintaining strain integrity and eliminating the possibility for unintentional transfer into the genome of another organism. Here we review efficient methods to delete or rearrange terminal repeat sequences of transposons necessary for their mobility, subsequent to their initial genomic integration. These procedures should prevent transposase-mediated remobilization of the transgenes, ensuring their genomic stability. PMID- 20844939 TI - Organisation and expression of a cluster of yolk protein genes in the Australian sheep blowfly, Lucilia cuprina. AB - The Australian sheep blowfly Lucilia cuprina is a major pest for the Australian and New Zealand sheep industries. With the long-term aim of making a strain of L. cuprina suitable for a genetic control program, we previously developed a tetracycline-repressible female lethal genetic system in Drosophila. A key part of this system is a female-specific promoter from a yolk protein (yp) gene controlling expression of the tetracycline-dependent transactivator (tTA). Here we report the sequence of a 14.2 kb genomic clone from L. cuprina that contains a cluster of three complete yp genes and one partial yp gene. The Lcyp genes are specifically expressed in females that have received a protein meal. A bioinformatic analysis of the promoter of one of the yp genes (LcypA) identified several putative binding sites for DSX, a known regulator of yp gene expression in other Diptera. A transgenic strain of L. cuprina was made that contained the LcypA promoter driving the expression of the Escherichia coli lacZ reporter gene. Transgenic females express high levels of beta-galactosidase after a protein meal. Thus the LcypA promoter could be used to obtain female-specific expression of tTA in transgenic L. cuprina. PMID- 20844940 TI - Training the Millennial learner through experiential evolutionary scaffolding: implications for clinical supervision in graduate education programs. AB - They are the Millennials--Generation Y. Over the next few decades, they will be entering genetic counseling graduate training programs and the workforce. As a group, they are unlike previous youth generations in many ways, including the way they learn. Therefore, genetic counselors who teach and supervise need to understand the Millennials and explore new ways of teaching to ensure that the next cohort of genetic counselors has both skills and knowledge to represent our profession well. This paper will summarize the distinguishing traits of the Millennial generation as well as authentic learning and evolutionary scaffolding theories of learning that can enhance teaching and supervision. We will then use specific aspects of case preparation during clinical rotations to demonstrate how incorporating authentic learning theory into evolutionary scaffolding results in experiential evolutionary scaffolding, a method that potentially offers a more effective approach when teaching Millennials. We conclude with suggestions for future research. PMID- 20844941 TI - Women's challenges with postpartum weight loss. AB - This study was designed to examine women's experiences of weight loss during the postpartum period. Understanding women's positive and negative experiences can assist health care providers to successfully intervene in helping women lose weight following pregnancy and avoid long-term weight gain and obesity development. DESIGN: Phenomenology, according to Husserl's perspective. SETTING: Private location of the women's choosing. PARTICIPANTS: Twenty-six women, who ranged in age from 25 to 35 years, and had given birth within the last 5 years, were interviewed regarding their experiences with postpartum weight loss. The majority of the sample was Caucasian. Interviews were transcribed and themes were identified from each of the interviews. Comparisons were made between interviews to identify common experiences between women. Data were analyzed according to the Giorgi method. The women in the study had a wide range of experiences. Themes that emerged from the interviews related to women's challenges with return to prepregnancy weight. These included: time and motivation issues, the need for support, and weight and other struggles. This study provides a look inside the lives of women faced with the reality of losing weight after childbirth. Losing weight after delivery is multi-faceted and influenced by many factors. Interventions to assist women with weight loss should target the challenges described in this paper. When effective strategies are developed, education can be done during pregnancy to prepare for the postpartum period. Ultimately, future research efforts can help us to eliminate pregnancy as a risk factor for obesity in women. PMID- 20844942 TI - Pragmatic language and school related linguistic abilities in siblings of children with autism. AB - Siblings of probands with autism spectrum disorders are at higher risk for developing the broad autism phenotype (BAP). We compared the linguistic abilities (i.e., pragmatic language, school achievements, and underling reading processes) of 35 school-age siblings of children with autism (SIBS-A) to those of 42 siblings of children with typical development. Results indicated lower pragmatic abilities in a subgroup of SIBS-A identified with BAP related difficulties (SIBS A-BAP) whereas school achievements and reading processes were intact. Furthermore, among SIBS-A-BAP, significant negative correlations emerged between the severity scores on the Autism Diagnostic Observation Schedule and full and verbal IQ scores. These results are discussed in the context of the developmental trajectories of SIBS-A and in relation to the BAP. PMID- 20844943 TI - A mutant of infectious Asia 1 serotype foot-and-mouth disease virus with the deletion of 10-amino-acid in the 3A protein. AB - Foot-and-mouth disease virus (FMDV) serotype Asia 1 is one of the most predominant endemic serotypes in China. Our previous study has generated a full length cDNA clone (pBSAs) of an Asia 1 serotype FMDV (As1/CHA/05) isolated from bovine. To further study the properties of this virus, a mutant in the 3A region of the cDNA clone (pBSAs-3A10D), containing the deletion at position 93-102 of the 3A protein of As1/CHA/05, was generated by PCR and cloning. After synthesis of RNA in vitro and transfection, the recombinant rvAs-3A10D virus was recovered from BHK-21 cells. Characterization of the rvAs-3A10D revealed that the infectivity, immunoreactivity, and replication kinetics in BHK-21 and PK-15 cells and virulence in mice of the rvAs-3A10D were similar to that of its parent virus. Notably, while wild-type and recombinant viruses containing full-length sequence of the 3A replicated well in primary calf kidney cells, the mutant rvAs-3A10D failed to replicate in primary calf kidney cells in vitro. Apparently, the full length sequence of 3A in As1/CHA/05 is a necessary component for its replication in calf kidney cells. The availability of this 3A deletion infectious cDNA clone may help in further investigating the virulent determinants of FMDV and potentially developing FMDV vaccines. PMID- 20844944 TI - Molecular analysis of infectious bronchitis viruses isolated in Slovenia between 1990 and 2005: a retrospective study. AB - Fifteen infectious bronchitis viruses (IBV) isolated from broiler and broiler breeder flocks in Slovenia between 1990 and 2005 were molecularly characterised. IBV strains were divided into four genotypes by the analysis of the S1 gene region. Four strains belonged to the Massachusetts genotype, one strain was placed into the QX genotype, one strain formed a cluster together with the B1648 strain and nine strains were classified into the 624/I genotype. Nine Slovenian strains of the 624/I genotype formed two subgroups independently of the time of isolation and the geographical origin. Phylogenetic analysis of the partial N gene sequences revealed lower sequence variability and different clustering of the Slovenian IBV. Fourteen strains were grouped together with the strains H120 and D1466. One strain formed a cluster with the strain 793/B. PMID- 20844945 TI - "And let me see them damn papers!" The role of STI/AIDS screening among urban African American and Puerto Rican youth in the transition to sex without a condom. AB - Common strategies employed in preventing STI/AIDS transmission among young adults in America include abstinence, monogamy and safer sex. These strategies require a high level of vigilance and responsibility and, according to inner city participants in Project PHRESH.comm, neither option is always desirable, available, or rational in the context of their lived experiences. This article reports findings from Project PHRESH.comm, a mixed-method, ethnographic study incorporating data from focus group discussions, semi-structured interviews, coital diaries, systematic cultural assessments and a structured survey designed to explore concepts of risk and decision making about condom use among at risk African American and Puerto Rican young adults aged 18-25 years in Hartford, CT. We found that many young adults from our study population rely on a strategy of using clinic-sponsored STI/AIDS screening when wanting to discontinue condom use with a partner. While our data suggest that screening is a common strategy used by many couples to transition to having sex without a condom, the data also show that most youth do not maintain monogamy even in long-term, serious relationships. Thus, sharing test results may provide a false sense of security in the sexual culture of inner city, minority youth. PMID- 20844946 TI - The importance of male partner involvement for women's acceptability and adherence to female-initiated HIV prevention methods in Zimbabwe. AB - Enlisting male partner involvement is perceived as an important component of women's successful uptake of female-initiated HIV prevention methods. We conducted a longitudinal study among a cohort of 955 Zimbabwean women participating in a clinical trial of the effectiveness of a female-initiated HIV prevention method (the diaphragm and lubricant gel) to: (a) describe the extent to which women involved their male partners in the decision to use the study products, and (b) measure the effect perceived male partner support had on their acceptability and consistent use of these methods. Reported levels of male partner involvement in discussions and decisions regarding: joining the study, study activities, the outcome of HIV/STI test results, and product use were very high. In multivariate analyses, regular disclosure of study product use and partner approval for the diaphragm and gel were significantly associated with women's acceptability and consistent use of the products; an essential component for determining efficacy of investigational prevention methods. These results support the need for more sophisticated measurement of how couples interact to make decisions that impact study participation and investigational product use as well as more rigorous adaptations and evaluations of existing strategies to involve male partners in female-initiated HIV prevention trials. PMID- 20844948 TI - Use of tree bark for comparing environmental pollution in different sites from Buenos Aires and Montevideo. AB - Multi-elemental profiles in bark of green ash trees collected in three representative areas of Buenos Aires, Argentina and Montevideo, Uruguay, were assessed as potential air pollution indicators. Ten elements: Al, Ba, Cr, Cu, Fe, Mg, Mn, Ni, Pb, and Zn, were measured using inductively coupled plasma optical emissions spectrometry from 70 samples collected in different environments: central, residential and rural (reference site), in order to compare spatial patterns of metal concentration. The samples used as a control were collected from a nature reserve situated far away from any significant influences, not even a nearby road. The reference site (RF) exhibited the lowest concentrations of Al, Cr, Fe, Ni, Pb, and Zn. However, Ba and Mn showed similar concentrations in all measured sites. Magnesium is the only element that had a greater concentration in RF than at the other sites. Copper did not show any clear pattern. The Centre of Montevideo (MVD) showed higher concentrations of Al, Ba, Cr, Fe, Pb and Zn than the Centre of Buenos Aires (BA). In the A sectors, Montevideo (SAMVD) showed higher concentrations of Al, Cu, Mg, Ni, and Zn and lower concentrations of Ba, Cr, Fe, Mn, and Pb than Buenos Aires (SABA). In the B sectors, Montevideo (SBMVD) showed higher concentrations of Al, Ba, Cu, Fe, Pb, and Zn and lower concentrations of Cr and Mg than Buenos Aires (SBBA), but similar concentrations of Mn and Ni. The use of bark for biomonitoring metals allowed us to detect concentration differences related to the urban fabric and the different kinds of vehicles and their fuels. In the cities, the differences in metal concentrations detected in bark were more striking between the sectors than between centers, despite CBA being much larger than CMVD in population, extension and vehicular traffic. PMID- 20844947 TI - Continuous expression of HIF-1alpha in neural stem/progenitor cells. AB - Hypoxia-inducible factor-1 alpha subunit (HIF-1alpha) is a transcriptional activator mediating adaptive cellular response to hypoxia. Normally degraded in most cell types and tissues, HIF-1alpha becomes stable and transcriptionally active under conditions of hypoxia. In contrast, we found that HIF-1alpha is continuously expressed in adult brain neurogenic zones, as well as in neural stem/progenitor cells (NSPCs) from the embryonic and post-natal mouse brain. Our in vitro studies suggest that HIF-1alpha does not undergo typical hydroxylation, ubiquitination, and degradation within NSPCs under normoxic conditions. Based on immunofluorescence and cell fractionation, HIF-1alpha is primarily sequestered in membranous cytoplasmic structures, identified by immuno-electron microscopy as HIF-1alpha-bearing vesicles (HBV), which may prevent HIF-1alpha from degradation within the cytoplasm. HIF-1alpha shRNAi-mediated knockdown reduced the resistance of NSPCs to hypoxia, and markedly altered the expression levels of Notch-1 and beta-catenin, which influence NSPC differentiation. These findings indicate a unique regulation of HIF-1alpha protein stability in NSPCs, which may have importance in NSPCs properties and function. PMID- 20844949 TI - Elimination of erythromycin in milk after intramammary administration in cows with specific mastitis: relation to dose, milking frequency and udder health. AB - Elimination of erythromycin in milk following intramammary therapy of specific mastitis in cows was studied. Five cows received therapy in one quarter (G1), and eight in two quarters with five milked twice (G2) and three thrice a day (G3). Dose infused was 300 mg/quarter 12 h * 5 times. The drug concentrations in milk were determined using microbial assay technique with Micrococcus luteus as the test organism. Considerable variations occurred in the excretion of drug; levels for treated quarters being 8.25 to 37.61 MUg/ml at first milking that declined rapidly at 24 h and no drug activity was observed beyond 36 h post treatment. In total, about 6-25% of the last infused dose appeared in the milk. Drug crossed to 1/15 quarter (G1), 6/10 quarters (G2) and all the six untreated quarters (G3). Crossover levels were significantly higher in mastitic quarters and for G3 cows, but duration of excretion remained same in all cases. It seems that crossover of erythromycin to untreated quarters is related to the udder health and dose infused. PMID- 20844950 TI - Ascorbic acid status of female camels during different phases of reproduction. AB - There is suggestive evidence that a low status of ascorbic acid in camels enhances their risk for infectious diseases. This study was carried out to disclose the role of reproduction, if any, in affecting ascorbic acid status. The associations between the reproductive cycle and ascorbic acid contents in plasma and leukocytes were studied in Sudanese camels browsing on local vegetation. Ascorbic acid status was found to be lowest during pregnancy and highest during lactation. Estrus versus non-estrus was associated with high vitamin C status. Brucellosis-positive camels showed decreased levels of ascorbic acid in plasma and leukocytes. Possibly, the phases of non-estrus and pregnancy in camels invoke an increased susceptibility to infectious diseases due to a lower ascorbic acid status. PMID- 20844952 TI - An accurate, objective test for minimal hepatic encephalopathy may provide a medical basis to prevent driving while encephalopathic. PMID- 20844951 TI - Pediatric feeding disorders: a quantitative synthesis of treatment outcomes. AB - A systematic review of the literature regarding treatment of pediatric feeding disorders was conducted. Articles in peer-reviewed scientific journals (1970 2010) evaluating treatment of severe food refusal or selectivity were identified. Studies demonstrating strict experimental control were selected and analyzed. Forty-eight single-case research studies reporting outcomes for 96 participants were included in the review. Most children presented with complex medical and developmental concerns and were treated at multidisciplinary feeding disorders programs. All studies involved behavioral intervention; no well-controlled studies evaluating feeding interventions by other theoretical perspectives or clinical disciplines met inclusion criteria. Results indicated that behavioral intervention was associated with significant improvements in feeding behavior. Clinical and research implications are discussed, including movement toward the identification of key behavioral antecedents and consequences that promote appropriate mealtime performance, as well as the need to better document outcomes beyond behavioral improvements, such as changes in anthropometric parameters, generalization of treatment gains to caregivers, and improvements in nutritional status. PMID- 20844953 TI - Increasing incidence of inflammatory bowel disease among young men in Korea between 2003 and 2008. AB - BACKGROUND AND AIMS: Temporal trends in incidence rates of Crohn's disease (CD) and ulcerative colitis (UC) can provide valuable clues about etiology. Korea has a draft system, and every male must fulfill his military service. However, according to military rules, patients with CD and UC are not conscripted into the army, and when the disease is diagnosed during military service, patients are relieved from military duties. Such policies provide a unique opportunity to determine the incidence of CD and UC among young men in Korea. We studied the incidence of CD and UC over time in Korea, a rapidly developing country. METHODS: The Armed Forces Medical Command of the Republic of Korea Army provided lists of members who were relieved from military duties due to diagnoses of CD and UC between 2003 and 2008. RESULTS: During this 6-year period, there were 96 incident cases of CD and 104 incident cases of UC. For the 6-year period, the adjusted mean annual incidence rates of CD and UC per 100,000 persons were 3.2 and 3.5, respectively. When analyzed by 2-year intervals, the mean annual incidence of CD and UC increased, from 1.8 and 1.7 per 100,000 persons in 2003-2004, to 2.7 and 3.3 per 100,000 persons in 2005-2006, and to 5.1 and 5.4 per 100,000 persons in 2007-2008, respectively. CONCLUSIONS: Incidence of CD and UC among young men is rapidly increasing in Korea, which strongly suggests an environmental contribution to the disease. PMID- 20844954 TI - Biologic agent use varies inversely with age at diagnosis in Crohn's disease. AB - BACKGROUND: For patients with Crohn's disease, age at onset is known to influence the clinical course of the illness. AIMS: The aim of this study is to seek an association between age at onset of Crohn's disease and use of biologic agents for its treatment. METHODS: We reviewed the medical records of 127 veteran patients with Crohn's disease treated at our hospital, and compared differences in age at disease onset between patients who had received biologics and those who had not. RESULTS: The mean age of our patients was 54.9 +/- 15.4 years, and 34% were currently receiving or had previously received treatment with a biologic agent. For those with biologic use, average age at time of diagnosis of Crohn's disease was 32.3 +/- 12.2 years, compared with 43.7 +/- 16.3 years for those who had not received biologics (P = 0.005). This relationship remained significant even after controlling for disease severity. The frequency of use of biologic agents varied inversely with age at diagnosis. For patients diagnosed before age 21 years, 55.5% had used biologics, whereas no patient >70 years of age at time of diagnosis had used biologics. We found no significant correlation between biologic use and duration of disease, smoking or ethnicity. Perianal disease and concomitant arthritis were both significantly associated with use of biologics. CONCLUSIONS: In our veteran patients with Crohn's disease, frequency of treatment with a biologic agent varied inversely with age at disease onset. PMID- 20844955 TI - A role for intestinal alkaline phosphatase in the maintenance of local gut immunity. AB - BACKGROUND AND AIMS: Intestinal alkaline phosphatase (IAP) is a gut mucosal defense factor known to dephosphorylate lipopolysaccharide (LPS); however, the role of IAP in the gut response to luminal bacteria remains poorly defined. We investigated immune responses of wild-type (WT) and IAP-knockout (IAP-KO) mice to LPS and Salmonella typhimurium challenges. METHODS: Cryostat sectioning and standard indirect immunohistochemical staining for major histocompatibility complex (MHC) class II molecules were performed on liver tissue from WT and IAP KO mice. WT and IAP-KO mice were orally gavaged with S. typhimurium; bacterial translocation to mesenteric nodes, liver, and spleen was determined by tissue homogenization and plating. In other experiments, WT and IAP-KO mice received intraperitoneal injections of LPS, with subsequent quantification of complete blood counts and serum interleukin (IL)-6 by enzyme-linked immunosorbent assay (ELISA). WT and IAP-KO whole blood were plated and stimulated with LPS and Pam-3 Cys, followed by cytokine assays. RESULTS: Immunohistologic liver examinations showed increased expression of MHC class II molecules in IAP-KO mice. Following S. typhimurium challenge, WT mice appeared moribund compared with IAP-KO mice, with increased bacterial translocation. WT mice had >50% decrease (P<.005) in platelets and 1.8-fold (P<.05) increased serum IL-6 compared with IAP-KO mice in response to LPS injections. IAP-KO whole-blood stimulation with LPS and Pam-3-Cys resulted in increased IL-6 and tumor necrosis factor (TNF)-alpha secretion compared with WT. CONCLUSIONS: IAP-KO mice exhibit characteristics consistent with local LPS tolerance. Whole-blood response of IAP-KO mice did not reflect systemic tolerance. These data suggest that IAP is a local immunomodulating factor, perhaps regulating LPS-toll-like receptor 4 (TLR4) interaction between commensal microflora and intestinal epithelium. PMID- 20844956 TI - Accuracy of MELD scores in predicting mortality in decompensated cirrhosis from variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, or acute liver failure as well as mortality after non-transplant surgery or TIPS. AB - BACKGROUND: To systematically review literature on use of model for end-stage liver disease (MELD) score to determine severity and prognosis of liver disease in various clinical situations and to evaluate its use in decisions regarding therapeutic interventions. METHODS: Computerized literature searches using key medical terms; review of authors' extensive files on this subject; and personal clinical experience. RESULTS: The MELD score, a prospectively developed and validated scale for severity of end-stage liver disease, utilizes serum bilirubin, serum creatinine, and international normalized ratio to predict mortality in cirrhotic patients. It has proven clinically useful in increasingly varied clinical situations. The United Network for Organ Sharing uses MELD scores, with bonus points assigned for hepatocellular cancer, to prioritize allocation of deceased donor livers for liver transplantation. This work reviews recent data demonstrating that MELD scores relatively accurately predict mortality in patients with variceal bleeding, hepatorenal syndrome, alcoholic hepatitis, and acute liver failure, as well as assess risks of non-liver transplantation surgery or transjugular intrahepatic portosystemic shunts in cirrhotic patients. MELD scores fail to predict mortality in about 15% of patients with end-stage liver disease. Incorporation of additional parameters, including serum sodium level, serum albumin level, glucose intolerance, or APACHE II score, may potentially improve prognostic accuracy. CONCLUSIONS: MELD scores relatively accurately assess severity of liver disease and prognosis in patients with advanced liver disease in general, and in patients with individual complications of liver disease. It is useful in making decisions on potential therapies. Incorporating additional parameters may further improve its prognostic accuracy. PMID- 20844957 TI - Surveillance for hepatocellular carcinoma: development and validation of an algorithm to classify tests in administrative and laboratory data. AB - BACKGROUND: The purpose of alpha-fetoprotein (AFP) and abdominal ultrasound (US) cannot be discerned in administrative data. AIM: We developed an algorithm to identify AFP and US used as surveillance tests for hepatocellular carcinoma (HCC). METHODS: We evaluated 300 AFP and 301 US tests from a VA database. Surveillance predictors in the administrative files (diagnoses, labs) were examined in logistic regression models. We calculated model-based probabilities of HCC surveillance status, and developed classification procedures using single and multiple imputation methods. RESULTS: The predictors of surveillance intent for AFP were absence of alcoholism, abdominal pain, ascites, diabetes and high AST levels. For US, the predictors of surveillance were prior AFP testing and HIV status and absence of abdominal pain, ascites, or drug dependence. For AFP classification, single imputation compared favorably with multiple imputation, both showing robustness in discrimination and calibration. For US both approaches were less robust in discrimination and calibration which was more moderate in multiple imputation than single imputation. CONCLUSIONS: Predictive algorithms in administrative files can be used to identify AFP performed for HCC surveillance, however, the intent of US is more difficult to identify. PMID- 20844958 TI - The expression of PTHLH in human gastric mucosa enterochromaffin-like cells. AB - BACKGROUND: Gastrectomy may disturb the body's mineral homeostasis, with osteopenia and osteoporosis being among the late outcomes. Parathyroid hormone like hormone (PTHLH) was detected in rat gastric enterochromaffin-like (ECL) cells in 2005, and some researchers suggested that it was the hypothetical hormone gastrocalcin that is believed to lead to osteoporosis. AIMS: Our objective was to learn whether PTHLH is expressed in human gastric ECL cells and to form a basic understanding about the relationship between PTHLH and gastrin. METHODS: We collected normal human gastric mucosa specimens and serum samples from 28 patients. RESULTS: RT-PCR and immunohistochemical analysis demonstrated weak expression of PTHLH in ECL cells at the RNA and protein levels. A low level of PTHLH expression was also found in the serum. Serum gastrin did have a significant positive correlation with the relative ratio of PTHLH mRNA to beta actin levels in gastric mucosa (rs=0.569, p=0.002). CONCLUSIONS: This indicates that PTHLH has a low signal expression in human gastric ECL cells and that serum gastrin levels correlate with PTHLH RNA levels in gastric mucosa. Further work is needed to evaluate the functional role of PTHLH in ECL cells and to determine whether PTHLH is gastrocalcin. PMID- 20844959 TI - Quantitative assessment of endoscopic images for degree of villous atrophy in celiac disease. AB - BACKGROUND: The degree of villous atrophy in celiac disease is difficult to assess at endoscopy. We sought to develop a quantitative technique for the evaluation of villous atrophy in endoscopic images. METHOD: In ten celiac patients as identified by standard endoscopy with biopsy, and ten control patients, standard and videocapsule endoscopic images of the duodenum were digitized. Subimages 7.5 * 7.5 mm(2) in area from random locations within each image were assessed by measuring the length of mucosal fissures per unit area (L), and correlating L with the histologic grade of villous atrophy as determined by modified Marsh criteria. RESULTS: Mean L values for standard endoscopic images were 37.8, 43.3, 64.1, and 83.5 mm for Marsh grades II, IIIa, IIIb, and IIIc, respectively. Mean L values for videocapsule images were 49.1, 50.0, 64.7, and 72.4 mm for Marsh grades II, IIIa, IIIb, and IIIc, respectively. Significant differences in the means existed between celiac images (Marsh scores II-IIIc) versus controls (p < 0.001) for both endoscopic and videocapsule images. There were no significant differences between measurements obtained from endoscopic versus videocapsule images. CONCLUSIONS: Quantified image analysis correlates with the histologic grade of villous atrophy, is automated, and lacks observer bias, thus lending itself to standardization. PMID- 20844960 TI - Small intestinal bacterial overgrowth in patients with morbid obesity. PMID- 20844961 TI - Hepatic arteriovenous malformations from hereditary hemorrhagic telangiectasia: treatment with liver transplantation. PMID- 20844962 TI - Uncovering multiple pathways to substance use: a comparison of methods for identifying population subgroups. AB - This paper describes and compares a selection of available modeling techniques for identifying homogeneous population subgroups in the interest of informing targeted substance use intervention. We present a nontechnical review of the common and unique features of three methods: (a) trajectory analysis, (b) functional hierarchical linear modeling (FHLM), and (c) decision tree methods. Differences among the techniques are described, including required data features, strengths and limitations in terms of the flexibility with which outcomes and predictors can be modeled, and the potential of each technique for helping to inform the selection of targets and timing of substance intervention programs. PMID- 20844963 TI - Changes in skeletal muscle qualities during enzyme replacement therapy in late onset type II glycogenosis: temporal and spatial pattern of mass vs. strength response. AB - Muscle quality is defined as muscle strength generated per unit muscle mass. If enzyme replacement therapy (ERT) has some effects on type II glycogenosis (GSDII) skeletal muscle pathology, we should be able to measure a change in strength and mass. We conducted a prospective study including 11 patients aged 54.2 +/- 11.2 years, referring to a single institution and receiving ERT for >=2 years. Median Walton score was 3 (2.5-6). Lower limb skeletal muscles were assessed by dynamometry and quantitative muscle MRI. Three segments (anterior thigh, posterior thigh, leg) were analysed separately. Clinical-MRI correlations were searched for at T0, T6/T8, and T18/24. Changes in lean and fat body composition were assessed by bioelectrical impedance analysis. We found that the anterior thigh showed the best therapeutic response, with an improvement in muscle quality (muscle mass: +7.5%, p = 0.035; strength: +45%, p = 0.002). BMI and lean body mass increased (p = 0.007). Patients with low BMI showed a better outcome. Intramuscular fat accumulation significantly progressed in spite of ERT (+3.7%, p = 0.001), especially in the poorly responsive posterior thigh muscles. Both clinical assessment and MRI revealed a definite improvement in the anterior thigh muscles. However, progression of intramuscular fat accumulation during ERT, as well as the limited responsiveness of posterior thigh muscles, suggests the necessity for early treatment intervention. The better outcome of patients with low BMI, if confirmed, may indicate that dietary protocols could be adopted as adjuvant measures to ERT in adult GSDII. PMID- 20844964 TI - Dietary modifications in patients receiving miglustat. AB - Weight loss and gastrointestinal disturbances are often seen during miglustat therapy for lysosomal storage diseases. A retrospective analysis of data from a mixed group of patients treated with miglustat at two UK centres was performed to evaluate the effect of two different dietary interventions on body weight and gastrointestinal tolerability during the initial 6 months of miglustat therapy. Neurological outcomes in these patients are not discussed herein. Data were analysed from a total of 29 patients with varied neurolipidoses (21 children/adolescents; 8 adults). Negative mean changes in body weight were seen in children/adolescents on an unmodified diet (-8.1%), and in adults (-4.1%) and children/adolescents (-5.2%) on a low-lactose diet. Patients on the low disaccharide diet showed a positive mean change in body weight (+2.0%), although there was high variability in this group. Non-parametric sub-analysis of median body-weight change in children/adolescents also showed high variability both within and between diet groups, with no statistically significant difference between the effects of different diets on body weight (p = 0.062). The low lactose diet reduced gastrointestinal disturbances; single small doses of loperamide were required in some patients. Patients on the low-disaccharide diet showed the lowest frequency of gastrointestinal effects. In conclusion, simple dietary modifications allowed the maintenance of body-weight gain in line with normal growth potential during miglustat therapy in young patients with lysosomal storage diseases, and reduced gastrointestinal disturbances. PMID- 20844966 TI - 2010 SSO John Wayne clinical research lecture: rectal cancer outcome improvements in Europe: population-based outcome registrations will conquer the world. AB - During the past two decades, rectal cancer treatment has improved considerably in Europe. Clinical trials played a crucial role in improving surgical techniques, (neo)adjuvant treatment schedules, imaging, and pathology. However, there is still a wide variation in outcome after rectal cancer. In most western health care systems, efforts are made to reduce hospital variation by focusing on selective referral and encouraging patients to seek care in high-volume hospitals. On the other hand, the expertise for diagnosis and treatment of common types of cancer should be preferably widespread and easily accessible for all patients. As an alternative to volume-based referral, hospitals and surgeons can improve their results by learning from their own outcome statistics and those from colleagues treating a similar patient group. Several European surgical (colo)rectal audits have led to improvements with a greater impact than any of the adjuvant therapies currently under study. However, differences remain between European countries, which cannot be easily explained. To generate the best care for colorectal cancer in the whole of Europe and to meet political and public demands for transparency, the European CanCer Organisation (ECCO) initiated an international, multidisciplinary, outcome-based quality improvement program: European Registration of Cancer Care (EURECCA). The goal is to create a multidisciplinary European registration structure for patient, tumor, and treatment characteristics linked to outcome registration. Clinical trials will always play a major role in improving rectal cancer treatment. To further improve outcomes and diminish variation, EURECCA will establish the basis for a strong, multidisciplinary, international audit structure that can be used as a template for similar projects worldwide. PMID- 20844965 TI - Life satisfaction in adult survivors of cancer during adolescence: what contributes to the latter satisfaction with life? AB - PURPOSE: To compare the general and health-related life satisfaction (LS) in long term survivors of adolescent cancer with a community sample and to identify medical and psychosocial factors associated with LS. METHODS: LS of 820 survivors (age M = 30.4 +/- 6.0 years; time since diagnosis M = 13.7 +/- 6.0 years) was assessed with the Questions on Life Satisfaction (FLZ(M)) and compared to an age- and sex-matched community sample. The effects of medical, psychological, and socio-demographical factors on the survivors' general and health-related LS were investigated by means of multiple regression analyses. RESULTS: Survivors were significantly less satisfied than the comparison group in terms of both their general (P < .001, d = -.35) and health-related (P < .001, d = -.47) life. Somatic late effects, symptoms of depression and anxiety, and less posttraumatic growth were associated with impaired general and health-related LS. Moreover, being married contributed significantly to higher general LS. CONCLUSION: Adult survivors of cancer with onset during adolescence are experiencing less LS than the general population. Long-term routine follow-up visits are recommended to identify persisting effects of cancer survival on LS and to provide support for those with special needs. Physicians need to pay special attention to potential risk factors such as psychological distress, somatic late effects, persistent psychological distress, and a lack of posttraumatic growth, which are negatively correlated with LS. PMID- 20844967 TI - The fibroblast growth factor receptor-4 Arg388 allele is associated with gastric cancer progression. AB - BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism, located in the FGFR4 gene exon 9, was reported to be associated with malignant tumors prognosis; however, there has been no relevant research for gastric cancer. The purpose of this study was to investigate the clinical significance of FGFR4 Gly388Arg polymorphism as well as the mRNA expression of FGFR4 in patients with gastric cancer. METHODS: The mRNA expression of FGFR4 in 103 gastric cancer tissues and corresponding normal tissues were measured by reverse transcription polymerase chain reaction (PCR) and real-time quantitative PCR. PCR-restriction fragment length polymorphism analysis was performed to detect the FGFR4 Gly388Arg in 103 gastric cancer tissues. RESULTS: In 57.3% of patients, homozygous or heterozygous Arg388 allele was present. FGFR4 expressions in mRNA levels were higher in gastric cancer tissues compared with those in relevant normal tissues. However, there is no significantly statistical difference compared with mRNA expression of FGFR4 in different genotypes. Associations between FGFR4 Gly388Arg polymorphism and overall survival exist in patients with gastric cancer (P = 0.046).The FGFR4 Arg allele (hazard risk (HR), 2.324; 95% confidence interval (CI), 1.054-4.125; P = 0.037) and TNM stage (HR, 5.516; 95% CI 3.658-7.409; P = 0.005) were independent prognostic factors in patients with gastric cancer. CONCLUSIONS: Based on this study, FGFR4 Arg388 genotype-a marker for gastric cancer progression-may predict prognosis of gastric cancer. PMID- 20844968 TI - Sinusoidal obstruction syndrome impairs long-term outcome of colorectal liver metastases treated with resection after neoadjuvant chemotherapy. AB - BACKGROUND: Chemotherapy-induced liver injury is a considerable problem in patients undergoing surgery for colorectal liver metastases, since an increase in postoperative morbidity and mortality has been observed. We investigated whether liver damage had further implications on long-term outcome in these patients. MATERIALS AND METHODS: Liver specimens from 196 patients resected for colorectal liver metastases were evaluated for chemotherapy-associated hepatic damage in the nontumorous liver. Injury patterns were correlated with recurrence free (RFS) and overall survival (OS). Factors leading to sinusoidal injury were identified. RESULTS: Patients who developed grade 2 or 3 sinusoidal dilatation had a significantly shorter RFS (hazard ratio [HR] 2.05; 95% confidence interval [95% CI] 1.23-3.39, P = .005) and OS (HR 2.90; 95% CI 1.61-6.19, P < .001), compared to patients without this alteration. Those patients also had significantly more intrahepatic recurrences (66.7% vs 30.5%, P = .003). Other patterns of chemotherapy-associated liver damage (nonalcoholic steatohepatitis, fibrosis) were not associated with impaired survival. Factors indicating sinusoidal injury were oxaliplatin-based chemotherapy, tumor size >5 cm, and elevated alkaline phosphatase or gamma glutamyltransferase. CONCLUSIONS: Sinusoidal obstruction syndrome due to oxaliplatin-based chemotherapy may not only compromise perioperative outcome, but can lead to early recurrence and decreased survival in the long term. Strategies to prevent this condition are clearly needed. PMID- 20844969 TI - Dermatofibrosarcoma protuberans (DFSP): predictors of recurrence and the use of systemic therapy. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft tissue malignancy that typically presents with local invasion but rarely metastasizes. We examine clinicopathologic factors associated with disease-free survival (DFS) in patients with primary and recurrent DFSP and evaluate responses to multimodality therapy. MATERIALS AND METHODS: Patients treated for DFSP were identified in a prospectively maintained database. Clinicopathologic factors associated with DFS were analyzed using univariate and multivariate analysis. RESULTS: A total of 244 patients with DFSP were identified. Median follow-up was 50 months. A total of 14 patients had local recurrence (LR), and 2 patients had distant recurrence (DR), with a median time to recurrence of 35 months. At time of last follow-up, 70% and 47% of patients showed no evidence of disease (NED) in the primary (n = 197) and recurrent groups (n = 47), respectively. On univariate analysis, tumor location and depth were associated with DFS in the primary group, while margin status (R1 vs. R0) was associated with DFS in the LR group. On multivariate analysis, only depth (primary group) and margin status (LR group), remained significant. Also, 22 patients had therapy other than surgical resection: 14 radiotherapy, 4 tyrosine kinase inhibitor (TKI) only, 2 conventional chemotherapy only, and 2 chemotherapy plus TKI. Responses to other therapies were variable. CONCLUSIONS: DFS after treatment for DFSP is strongly predicted by tumor depth in the primary setting and margin status in recurrent tumors. The treatment for DFSP in the primary or recurrent setting is excision with negative margins, resulting in low recurrence rates and infrequent metastatic spread. Multimodality treatment, especially TKI use, can be effective, but is not curative. PMID- 20844971 TI - Self-efficacy contributes to individual differences in subjective improvements using CPAP. AB - PURPOSE: Continuous positive airway pressure (CPAP) improves depressive symptoms and daytime sleepiness in patients with obstructive sleep apnea (OSA). However, there is variability in response to CPAP. This study examined individual differences in the daily associations between CPAP use and improvements in affect and sleepiness patients beginning CPAP. METHODS: This observational repeated measures study involved 31 CPAP-naive patients diagnosed with obstructive sleep apnea at an academic sleep disorders center. Patients completed pre-treatment assessments of OSA knowledge, expectations for CPAP, and treatment self-efficacy as well as a repeated daily assessment of positive affect and negative affect, sleepiness/fatigue, and CPAP adherence for 10 days beginning the first week of treatment. Data were analyzed using multilevel modeling. RESULTS: Nightly CPAP adherence predicted improvements in next-day positive affect, negative affect, and sleepiness/fatigue. The apnea-hypopnea index (AHI), treatment self-efficacy, and outcome expectancies were significant moderators of day-to-day improvement. Higher self-efficacy and lower AHI were associated with a stronger relationship between adherence and next-day improvements in positive affect and sleepiness. Very high-outcome expectances were associated with a weaker relationship between adherence and next-day improvements in sleepiness. Subjective sleepiness at pre treatment did not give moderate improvements in next-day affect. CONCLUSIONS: Although CPAP use predicted daily improvements in affect and sleepiness for the majority of patients, patients with lower AHI, greater treatment self-efficacy, and moderate outcome expectancies reported stronger daily benefits from CPAP. For patients with high-treatment efficacy, adherence may be reinforced by a stronger link between adherence and daily improvements. PMID- 20844972 TI - Novel targeted agents for platelet-derived growth factor receptor and c-KIT in malignant gliomas. AB - Malignant gliomas are a heterogeneous group of tumors with a varying natural history and response to treatment. Despite current therapeutic strategies, these tumors almost universally recur after excision and are associated with a poor survival. Increasingly, the true heterogeneity of these tumors is being correlated with distinct molecular subgroups. Platelet-derived growth factor receptor (PDGFR) alpha is almost universally expressed on glioma cells; expression of the proto-oncogene c-KIT has also been reported. These findings have led to the clinical investigation of inhibitors of this pathway, such as imatinib and dasatinib, for the treatment of recurrent malignant glioma. To date, this approach in unselected patients has been disappointing. However, isolated responses have been seen, which may correlate with constitutive activation of one or more of the corresponding tyrosine kinases. In the future, it is hoped that an increasing knowledge of glioma biology will translate into the more judicious use of these and other targeted therapies, resulting in improvements in patient outcomes. This review describes the preclinical science behind PDGFR and c-KIT, the clinical importance of these molecular pathways and the available data from translational clinical trials. PMID- 20844973 TI - Micro and nanotechnology for biological and biomedical applications. AB - This special issue contains some of the current state-of-the-art development and use of micro and nanotechnological tools, devices and techniques for both biological and biomedical research and applications. These include nanoparticles for bioimaging and biosensing, optical and biophotonic techniques for probing diseases at the nanoscale, micro and nano-fabricated tools for elucidating molecular mechanisms of mechanotransduction in cell and molecular biology and cell separation microdevices and techniques for isolating and enriching targeted cells for disease detection and diagnosis. Although some of these works are still at the research stage, there is no doubt that some of the important outcomes will eventually see actual biomedical applications in the not too distant future. PMID- 20844974 TI - A context-sensitive mechanism in hippocampal CA1 networks. AB - This paper presents a possible context-sensitive mechanism in a neural network and at single neuron levels based on the experiments of hippocampal CA1 and their theoretical models. First, the spatiotemporal learning rule (STLR, non-Hebbian) and the Hebbian rule (HEBB) are experimentally shown to coexist in dendrite-soma interactions in single hippocampal pyramidal cells of CA1. Second, the functional differences between STLR and HEBB are theoretically shown in pattern separation and pattern completion. Third, the interaction between STLR and HEBB in neural levels is proposed to play an important role in forming a selective context determined by value information, which is related to expected reward and behavioral estimation. PMID- 20844975 TI - Dietary t10,c12-CLA but not c9,t11 CLA reduces adipocyte size in the absence of changes in the adipose renin-angiotensin system in fa/fa Zucker rats. AB - In obesity, increased activity of the local renin-angiotensin system (RAS) and enlarged adipocytes with altered adipokine production are linked to the development of obesity-related health problems and cardiovascular disease. Mixtures of conjugated linoleic acid (CLA) isomers have been shown to reduce adipocyte size and alter the production of adipokines. The objective of this study was to investigate the effects of feeding individual CLA isomers on adipocyte size and adipokines associated with the local adipose RAS. Male fa/fa Zucker rats received either (a) control, (b) cis(c)9,trans(t)11-CLA, or (c) t10,c12-CLA diet for 8 weeks. The t10,c12-CLA isomer reduced adipocyte size and increased cell number in epididymal adipose tissue. RT-PCR and Western blot analysis revealed that neither CLA isomer altered mRNA or protein levels of angiotensinogen or AngII receptors in adipose tissue. Likewise, levels of the pro inflammatory cytokines TNF-alpha and IL-6 or the anti-inflammatory cytokine IL-10 were unchanged in adipose tissue. Similarly, neither CLA isomer had any effect on phosphorylation nor DNA binding of NF-kappaB. Our results suggest that although the t10,c12-CLA isomer had beneficial effects on reducing adipocyte size in obese rats, this did not translate into changes in the local adipose RAS or associated adipokines. PMID- 20844976 TI - Relationship of EMAST and microsatellite instability among patients with rectal cancer. AB - BACKGROUND: Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature identified in 60% of sporadic colon cancers and may be linked with heterogeneous expression of the DNA mismatch repair (MMR) protein hMSH3. Unlike microsatellite instability-high (MSI-H) in which hypermethylation of hMLH1 occurs followed by multiple susceptible gene mutations, EMAST may be associated with inflammation and subsequent relaxation of MMR function with the biological consequences not known. We evaluated the prevalence of EMAST and MSI in a population-based cohort of rectal cancers, as EMAST has not been previously determined in rectal cancers. METHODS: We analyzed 147 sporadic cases of rectal cancer using five tetranucleotide microsatellite markers and National-Cancer-Institute-recommended MSI (mononucleotide and dinucleotide) markers. EMAST and MSI determinations were made on analysis of DNA sequences of the polymerase chain reaction products and determined positive if at least two loci were found to have frame-shifted repeats upon comparison between normal and cancer samples from the same patient. We correlated EMAST data with race, gender, and tumor stage and examined the samples for lymphocyte infiltration. RESULTS: Among this cohort of patients with rectal cancer (mean age 62.2 +/- 10.3 years, 36% female, 24% African American), 3/147 (2%) showed MSI (three males, two African American) and 49/147 (33%) demonstrated EMAST. Rectal tumors from African Americans were more likely to show EMAST than Caucasians (18/37, 49% vs. 27/104, 26%, p = 0.014) and were associated with advanced stage (18/29, 62% EMAST vs. 18/53, 37%, non-EMAST p = 0.02). There was no association between EMAST and gender. EMAST was more prevalent in rectal tumors that showed peri-tumoral infiltration compared to those without (30/49, 60% EMAST vs. 24/98, 25% non-EMAST, p = 0.0001). CONCLUSIONS: EMAST in rectal cancer is common and MSI is rare. EMAST is associated with African-American race and may be more commonly seen with metastatic disease. The etiology and consequences of EMAST are under investigation, but its association with immune cell infiltration suggests that inflammation may play a role for its development. PMID- 20844977 TI - Redefining mortality after pancreatic cancer resection. AB - INTRODUCTION: Distinct outcome measures such as in-hospital and 30-day mortality have been used to evaluate pancreatectomy results. We posited that these measures could be compared using national data, providing more precision for evaluating published outcomes after pancreatectomy. METHODS: Patients undergoing resection for pancreatic cancer were identified from the linked SEER-Medicare databases (1991-2002). Mortality was analyzed and trend tests were utilized to evaluate risk of death within <=60 days of resection and from 60 days to 2 years post resection. Univariate analysis assessed patient characteristics such as race, gender, marital status, socioeconomic status, hospital teaching status, and complications. RESULTS: One thousand eight hundred forty-seven resected patients were identified: 7.7% (n = 142) died within the first 30 days, 83.6% of whom died during the same hospitalization. Postoperative in-hospital mortality was 8.1% (n = 150), 79% of which was within 30 days, greater than 90% of which was within 60 days. Risk of death decreased significantly over the first 60 days (P < 0.0001). After 60 days, the risk did not decrease through 2 years (P = 0.8533). Univariate analysis showed no difference between the two groups in terms of race, gender, marital status, and socioeconomic status, but patients dying within 60 days were more likely to have experienced a complication (41.1% vs. 17.0%, P < 0.0001). CONCLUSIONS: In-hospital and 30-day mortality after resection for cancer are similar nationally; thus, comparing mortality utilizing these measures is acceptable. After a 60-day post-resection window of increased mortality, mortality risk then continues at a constant rate over 2 years, suggesting that mortality after pancreatectomy is not limited to early ("complication") and late ("cancer") phases. Determining ways to decrease perioperative mortality in the 60 day interval will be critical to improving overall survival. PMID- 20844978 TI - Modified "liver-sparing" multivisceral transplant with preserved native spleen, pancreas, and duodenum: technique and long-term outcome. AB - BACKGROUND: Modification of the originally described multivisceral transplant operation was introduced at our institution 17 years ago. Donor liver was spared, and native spleen along with pancreaticoduodenal complex was preserved. METHODS: Thirty-six modified multivisceral grafts that include stomach, duodenum, pancreas, and intestine were given to 30 adults and six children. Leading causes of intestinal failure were pseudo-obstruction and Gardner's syndrome. Native spleen was preserved in 24 (67%) recipients along with pancreaticoduodenal complex in 18 (50%). Immunosuppression was tacrolimus-based, and recipient preconditioning was utilized in 80% of patients. RESULTS: Patient survival was 94% at 1 year and 75% at 5 years with graft survival of 91% and 51%; respectively. With mean follow-up of 51 +/- 35 months, full nutritional autonomy was achieved in 89% of current survivors with no single example of disease recurrence. Preservation of native spleen was associated with increased survival and reduced risk of PTLD, life-threatening infections, and GVHD with no significant impact on graft loss due to rejection. Concomitant preservation of pancreaticoduodenal complex eliminated risks of biliary complications and glucose intolerance. CONCLUSION: Modified multivisceral transplantation with and without preservation of native spleen, pancreas, and duodenum is a valid therapeutic option for patients with diffuse gastrointestinal disorders and preserved hepatic functions. PMID- 20844979 TI - The Nazi engineers: reflections on technological ethics in hell. AB - Engineers, architects, and other technological professionals designed the genocidal death machines of the Third Reich. The death camp operations were highly efficient, so these technological professionals knew what they were doing: they were, so to speak, good engineers. As an educator at a technological university, I need to explain to my students-future engineers and architects-the motivations and ethical reasoning of the technological professionals of the Third Reich. I need to educate my students in the ethical practices of this hellish regime so that they can avoid the kind of ethical justifications used by the Nazi engineers. In their own professional lives, my former students should not only be good engineers in a technical sense, but good engineers in a moral sense. In this essay, I examine several arguments about the ethical judgments of professionals in Nazi Germany, and attempt a synthesis that can provide a lesson for contemporary engineers and other technological professionals. How does an engineer avoid the error of the Nazi engineers in their embrace of an evil ideology underlying their technological creations? How does an engineer know that the values he embodies through his technological products are good values that will lead to a better world? This last question, I believe, is the fundamental issue for the understanding of engineering ethics. PMID- 20844980 TI - Morphological and biological characterization of cell line developed from bovine Echinococcus granulosus. AB - The taeniid tapeworm Echinococcus granulosus is the causative agent of echinococcal disease, a major zoonosis with worldwide distribution. Several efforts to establish an in vitro model of E. granulosus have been undertaken; however, many of them have been designed for Echinococcus multilocularis. In the present study, we have described and characterized a stable cell line obtained from E. granulosus bovine protoscoleces maintained 3 yr in vitro. Growth characterization, morphology by light, fluorescent and electronic microscopy, and karyotyping were carried out. Cell culture origin was confirmed by immunofluorescent detection of AgB4 antigen and by PCR for the mitochondrial cytochrome c-oxidase subunit 1 (DCO1) gene. Cells seeded in agarose biphasic culture resembled a cystic structure, similar to the one formed in secondary hosts. This cell line could be a useful tool to research equinococcal behavior, allowing additional physiological and pharmacological studies, such as the effect of growth factors, nutrients, and antiparasitic drugs on cell viability and growth and on cyst formation. PMID- 20844981 TI - Cultured human corneal epithelial stem/progenitor cells derived from the corneal limbus. AB - Stem/progenitor cells of the human corneal epithelium are present in the human corneal limbus, and several corneal epithelial stem/progenitor cell markers have been reported. Recently, the neurotrophin family receptors were reported to be useful markers of corneal epithelial stem/progenitor cells. Therefore, we examined an enzymatic separation method for obtaining corneal epithelial stem/progenitor cells and measuring the change in the expression of low-affinity neurotrophin receptor p75 (p75(NTR)), a receptor belonging to the neurotrophin family. As a result, it was found that our separation method preserved cell viability. Furthermore, p75(NTR) was mainly observed in epithelial basal cells as were the corneal epithelial stem/progenitor markers p63 and integrin beta1. p75(NTR) was also observed in the cultured cells, but its frequency decreased with passage. In conclusion, we propose that our culture method will enable the culture of corneal stem cells and that it is a useful tool for elucidating the molecular basis of the niche that is necessary for the maintenance of epithelial stem cells in the corneal limbus. Furthermore, we conclude that p75(NTR) is a useful cell marker for evaluating the characteristics of stem/progenitor cells in culture. PMID- 20844982 TI - Retrograde intussusception 5 years after Roux-en-Y gastric bypass for morbid obesity. AB - INTRODUCTION: Small bowel obstruction secondary to intussusception is a rare but important consequence of Roux-en-Y gastric bypass (RYGB). CASE REPORT: A 37-year old female presented to the emergency department with abdominal pain. She had undergone RYGB 5-years previously for obesity. CT revealed a retrograde jejuno jejunal intussusception. The intussusceptum was the common jejunal channel and the intussuscepiens was the jejunojejunostomy resulting in obstruction of both the alimentary and biliary limbs. The patient underwent laparotomy, small bowel resection and refashioning of the jejunojejunal anastamosis. CONCLUSION: We report this case as it highlights both how a delay in diagnosis can occur and the importance of including this complication early in the differential diagnoses of any patient presenting with acute or chronic abdominal pain with a history of bariatric surgery. Retrograde intussusception is more common than previously thought and the incidence may increase as bariatric surgery is performed more frequently worldwide. PMID- 20844983 TI - Theoretical investigation of interaction of sorbitol molecules with alcohol dehydrogenase in aqueous solution using molecular dynamics simulation. AB - The nature of protein-sorbitol-water interaction in solution at the molecular level, has been investigated using molecular dynamics simulations. In order to do this task, two molecular dynamics simulations of the protein ADH in solution at room temperature have been carried out, one in the presence (about 0.9 M) and another in the absence of sorbitol. The results show that the sorbitol molecules cluster and move toward the protein, and form hydrogen bonds with protein. Also, coating by sorbitol reduces the conformational fluctuations of the protein compared to the sorbitol-free system. Thus, it is concluded that at moderate concentration of sorbitol solution, sorbitol molecules interact with ADH via many H-bonds that prevent the protein folding. In fact, at more concentrated sorbitol solution, water and sorbitol molecules accumulate around the protein surface and form a continuous space-filling network to reduce the protein flexibility. Namely, in such solution, sorbitol molecules can stabilize a misfolded state of ADH, and prevent the protein from folding to its native structure. PMID- 20844984 TI - Applications of loop-mediated isothermal DNA amplification. AB - During the last 10 years, with the development of loop-mediated isothermal amplification (LAMP) method, it has been widely applied in nucleic acid analysis because of its simplicity, rapidity, high efficiency, and outstanding specificity. This method employs a DNA polymerase and a set of four specially designed primers that recognize a total of six distinct sequences on the target DNA. Expensive equipment are not necessary to acquire a high level of precision, and there are fewer preparation steps compared to conventional PCR and real-time PCR assays. This paper briefly summarized the applications of LAMP method in pathogenic microorganisms, genetically modified ingredients, tumor detection, and embryo sex identification. PMID- 20844985 TI - Identification of microRNA target genes in vivo. AB - MicroRNAs (miRNAs) are short non-coding RNAs transcribed from intergenic or intronic sequences as long precursors that are sequentially processed by the endonucleases Drosha and Dicer into short double-stranded sequences. It is clear that miRNAs play essential roles in gene expression, development, and cell fate specification in animals. However, one of the barriers of miRNA research is how to find the target genes. In this study, we have developed a rapid and effective method to isolate miRNA target genes in vivo. MicroRNA was synthesized in vitro and labeled by biotin. After transfected into cells, the miRNA/mRNA complexes were isolated by streptavidin-coated magnetic beads. hsa-miR155 was taken as model to validate this method, which is a very important modulator in tumor development. It is useful for validation of targets predicted in silico, and, potentially, for discovery of previously uncharacterized targets. PMID- 20844986 TI - Evaluation of ER, PgR, HER-2, Ki-67, cyclin D1, and nm23-H1 as predictors of pathological complete response to neoadjuvant chemotherapy for locally advanced breast cancer. AB - The purpose of this study was to evaluate the importance of biological markers to predict pathologic complete response (pCR) to neoadjuvant docetaxel plus epirubicin combination chemotherapy in patients with locally advanced breast cancer (LABC). Two hundred and twenty consecutive patients with LABC who had received neoadjuvant chemotherapy (NCT) with docetaxel and epirubicin from March 2006 to March 2009 were included in this retrospective study. The pre- and post neoadjuvant chemotherapy (NCT) treatment expression levels and changes of Ki-67 proliferation index, estrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor 2 (HER-2), cyclin D1, and nm23-H1 were detected by immunohistochemistry (IHC). The pCR rate was 9.1% (95% CI, 5.3-12.9%). In univariate analysis, poor tumor differentiation, OR after 2 cycles of NCT, both negative of ER/PgR, negative HER-2, positive cyclin D1, and positive nm23-H1 were found to be significantly predictive of a pCR. Histological grade and ER/PgR status were significant for pCR on multivariate analysis (P = 0.023 and 0.003, respectively). The expression levels of cyclin D1 (median, 8% vs. 9%; P = 0.016) after NCT treatment increased significantly, while the median Ki-67 proliferation index was dramatically decreased after NCT treatment from 35 to 15% (P = 0.036). However, after a Bonferroni adjustment, only the difference of Ki-67 proliferation index was still significant (P = 0.026). Histological grade and ER/PgR status are independent predictive factors of pCR to neoadjuvant docetaxel plus epirubicin combination chemotherapy in locally advanced breast cancer. Expression of HER-2, Ki-67, cyclin D1, and nm23-H1 were not predictive for pCR. PMID- 20844987 TI - Frequency variations in the methylated pattern of p73/p21 genes and chromosomal aberrations correlating with different grades of glioma among south Indian population. AB - Gliomas are the most common primary brain tumors in India. The main epigenetic modification in glioma is aberrant DNA methylation that is now renowned to be a common hallmark of brain tumors. This study was designed to determine the frequency of aberrant CpG island methylation in the promoter regions of p21 and p73 in different grades of glioma and to explore their respective chromosomal aberrations. Total of 160 patients with histologically confirmed grades of glioma (I, II, III, and IV) were included in the study. DNA samples from blood and brain tissues, including benign lesions were subjected to sodium bisulfite conversion and hypermethylation detection using methylation-specific PCR followed by RT-PCR. Western blotting was also carried out for p21 and its related protein, p53. A total of 124 of 160 glioma samples (77.5%) displayed CpG island hypermethylation of both p73, p21 genes associated with the loss of mRNA expression (P < 0.001) and the loss of protein expressions (p53 independent p21 expression). p73 gene showed increased methylation frequency in all grades, 40 of 60 (66%) glioblastomas and 16 of 30 (53.3%) anaplastic astrocytoma, 10 of 20(50%) oligodendrogliomas, 8 of 20 (40%) ependymoma, and low-grade glioma 6 of 20 (30%). The percentage of methylation significantly well correlated with the overall survival and also with chromosomal loss. Thus, the studied glioma patients among south Indians showed a high frequency of aberrant methylation with varied chromosomal signatures in different grades, playing a role in aggressiveness and characterization of a particular grade, the appreciation of which might help for designing a specific therapy. PMID- 20844988 TI - The sequence of drug administration influences the antitumor effects of bevacizumab and cyclophosphamide in a neuroblastoma model. AB - Currently, the prognosis of neuroblastoma is poor, and new therapeutic strategies are needed. This study aimed at evaluating whether the administration sequence of bevacizumab and cyclophosphamide influenced the antitumor effects in a neuroblastoma model. Bevacizumab was administered at 5 mg/kg body weight weekly, alone or combined with cyclophosphamide, to treat a neuroblastoma xenograft in nude mice, and the tumor inhibition rates were compared. The functions of tumor vessels at different time points after bevacizumab administration were detected by Hoechst 33342 labeling. The antitumor effects of cyclophosphamide, administered concomitantly with bevacizumab or when vessel function was most improved post-bevacizumab administration, were compared. The tumor inhibition rates of the neuroblastoma xenograft treated with bevacizumab, cyclophosphamide, or both were 38.1, 44.0, and 56.0%, respectively (P < 0.05). Bevacizumab reduced 64% of angiogenesis. Tumor vessel function was most improved 6 days after bevacizumab administration. The tumor inhibition rates in mice treated with cyclophosphamide, concomitantly with bevacizumab or 6 days after bevacizumab administration, were 55.9 and 66.8%, respectively (P < 0.05). Bevacizumab can reduce neuroblastoma growth and has a synergistic effect when combined with cyclophosphamide in vivo. This synergistic effect is further enhanced when cyclophosphamide is administered after bevacizumab, when tumor vessel function is most improved. PMID- 20844990 TI - Influenza A (H1N1) virus infection associated with hemiplegia. PMID- 20844989 TI - Childhood pneumococcal diseases and serotypes: can vaccines protect? AB - OBJECTIVES: To describe pneumococcal diseases in pediatric intensive care unit (PICU) and non-PICU patients. METHODS: The clinical, serotypes, and antibacterial sensitivity patterns of all children admitted to the pediatric wards (including PICU) of a university-affiliated teaching hospital from 2007 through 2009 with pneumococcal isolates were reviewed. RESULTS: Twelve cases of pneumococcal disease in children from 2007 through 2009 were reported. Five patients were admitted to PICU and 7 were general pediatric admissions. Four patients (2 PICU and 2 general pediatric) had received full or partial 7-valent pneumococcal vaccinations. All four patients recovered following systemic antibiotic treatment without sequelae. The serotypes of all PICU and some general pediatric cases were available and included 3, 6B, 19A and 19F. All isolates were sensitive to vancomycin. 50% were intermediate resistant/resistant to penicillin and 17% resistant to cefotaxime. PICU cases required longer total hospital stay (23 days vs 5 days, p=0.013). Three patients were ventilated and one received inotropic support. There was no death in this series. CONCLUSIONS: Pneumococcal disease may develop despite prior vaccination. The expanded coverage of newer polyvalent pneumococcal vaccines might have prevented some, but not all, of these admissions. PMID- 20844991 TI - Syndromic management of common illnesses in hospitalized children and neonates: a cost identification study. AB - OBJECTIVE: To find out drug treatment cost per illness per patient admitted to pediatric ward. METHODS: Patients admitted to pediatric ward over a period of 1 year were studied without exclusions. Following presentations were studied: fever, rapid breathing, diarrhea, severe malnutrition and neurological problems such as altered conscious level or convulsion. In this prospective observational study, patients with other problems were excluded. The subjects were also categorized as critically sick, sick and stable. Expenditure on medicines was calculated individually for each patient. Total expenditure, average cost and illness-wise cost were subsequently derived. Management of illnesses was on the lines of existing guidelines of our center. Sick newborns or newborns referred for special care were separately studied. Following outcome variables were studied: death or discharge, length of hospital stay and the day on which symptomatic relief was noted. RESULTS: 774 children and 141 newborns were studied. 25(3.2%) died. Presenting features were as follows: fever-568 (73.4%), rapid breathing-175 (22.6%), diarrhea-145 (18.7%), mild-moderate malnutrition-278 (35.8%), severe malnutrition-111 (14.3%) and neurological problems-41 (5.3%). Category-wise distribution was as follows: critically sick-89 (11.3%), sick-188 (24.3%) and stable-497 (46.2%). Average hospital stay was 7.1 days and symptomatic relief was experienced by day three in 77.7% cases. Average cost of medicines per patient was INR-167.8 (USD-4.2), 173 patients required oxygen and mean expenditure on oxygen was INR-310 (USD-8) and 68 patients required inotropes with a mean expenditure of INR-198 (USD-5). Of the 141 newborns admitted, 20(14.1%) died. Mean hospital stay was 9.8 days and average cost of drug treatment was INR-790 (USD-20) in newborns. CONCLUSIONS: This cost analysis study presents drug treatment costs for common illnesses at a referral centre in a developing country. It gives an option to choose drugs for an optimum mix of cost and effectiveness. PMID- 20844992 TI - Non invasive urodynamic assessment in children--are they reliable? Validation of non-invasive urodynamics in children with functional voiding disorders. AB - OBJECTIVES: To validate the non-invasive tests that can predict the type of bladder dysfunction normally diagnosed by invasive urodynamics. METHODS: Children below 12 yrs of age were evaluated prospectively. Non-invasive urodynamic evaluation included history, clinical examination, frequency volume charting, ultrasonographic scan, urine analysis and renal function tests. Micturating cystourethrogram was carried out in children with recurrent urinary tract infections. All children underwent invasive urodynamic studies and the significance of association of the parameters of noninvasive assessment with invasive urodynamics was determined. Chi square test using Epi 6 software was used for statistical analysis of data. RESULTS: 41 children underwent invasive urodynamic studies. The commonest disorder was detrusor instability in 28 (68.2%). Dysynergic voiding was noted in 8 (19.5%). The study was normal in 5 (12.1%). Nocturnal enuresis with day time symptoms, holding maneuvers, small frequent voiding pattern (p<0.05) and a small capacity bladder with insignificant residue (p=0.0003) predicts detrusor instability. Straining (p=0.0006), large capacity bladder with significant post void residue in the absence of vesicouretric reflux (p<0.05) predicts dysyneric voiding. On combining the various non-invasive tests and validating them against invasive urodynamics in diagnosing detrusor instability and dysnergic voiding, they have a sensitivity of 88.4% and 87.5%, specificity of 72.7% and 69.2%, positive predictive value of 0.88 and 0.63 and positive likelihood ratio of 3.1 & 2.2 respectively. CONCLUSIONS: Functional voiding disorders can be diagnosed with reasonable accuracy by minimally invasive methods. PMID- 20844993 TI - The Journey of the Gold Anklet from the foot into the gut. PMID- 20844994 TI - Familial occurrence of peripartum cardiomyopathy presages a genetic rather than an environmental cause. AB - Peripartum cardiomyopathy (PPCM) is an uncommon form of left ventricular dysfunction associated with pregnancy and triggered by a number of obstetric factors including pre-eclampsia, plural gestations and multiparity. PPCM is the most frequent cause of pregnancy-related maternal death. Although the clinical outcome of PPCM has been determined, its patho-etiology has not been elucidated. Two recent studies have demonstrated for the first time in a small proportion of patients, convincing evidence of a genetic predisposition for PPCM, activated by modifier genes responding to biochemical and hemodynamic signals during mid to late pregnancy. PMID- 20844995 TI - Is rituximab superior to cyclophosphamide for ANCA-associated vasculitis for induction of remission, and with a better safety profile? PMID- 20844996 TI - Continued improved wear with an annealed highly cross-linked polyethylene. AB - BACKGROUND: Highly cross-linked polyethylene (HXLPE), created by disrupting the molecular structure of polyethylene, then through the application of heat, encourages creation of new cross-links in the process, resulting in a material with improved wear resistance. The impetuses for this new technology were the unsatisfactory wear properties and subsequent osteolysis of noncross-linked polyethylene. A 72% reduction in wear using highly cross-linked polyethylenes (HXLPE) compared with conventional polyethylene at 5 years was described previously. The longest term followup studies on HXLPE range from 2 to 6 years. QUESTIONS/PURPOSES: We therefore addressed the following questions: (1) Does the improvement in wear observed at the earlier followup continue to 7 to 10 years? (2) What is the incidence of osteolysis in this group of patients and in the control group? METHODS: We retrospectively reviewed 38 prospectively followed patients who had 42 hips with an annealed HXLPE who were followed a minimum of 7 years (average, 8.6 years; SD=1; range, 7-10.3 years). Wear and osteolysis were compared with those of a control group of 39 patients (40 hips) from a US Investigational Device Exemption (IDE) prospective, randomized study begun in 1996 with conventional polyethylene and followed for a minimum of 6 years (average, 7.5 years; SD=1.1; range, 6-10.2 years). Linear head penetration was measured from AP radiographs at early, 1-year, 5-year, and most recent followups. RESULTS: At the average followup, annual linear wear was 0.031 mm (SD=0.014) for the HXLPE and 0.141 mm (SD=0.080) for the control group, a 78% reduction. No mechanical failure of the polyethylene was noted in either group. Incidence of osteolysis was 50% in the control group (all lesions confined to proximal Gruen Zones 1 and 7) compared with no cases in the investigational group. CONCLUSIONS: We observed an improvement in wear and no mechanical failures with this annealed material. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20844997 TI - Hip offset in total hip arthroplasty: quantitative measurement with navigation. AB - BACKGROUND: Offset in THA correlates to abductor muscle function, wear, and impingement. Femoral offset after THA is not independent of the cup center of rotation (COR) so hip offset, a combination of femoral offset and change in hip COR, becomes the important measurement. QUESTIONS/PURPOSES: We therefore asked whether hip offset in arthritic hips would correlate with cup COR; whether offset could always be balanced within 6 mm of contralateral normal hips; and whether hip length could also be kept within 6 mm. METHODS: We compared hip offset of arthritic and contralateral normal hips on radiographs in 82 patients (82 hips) who had THA. We used computer navigation in all patients with the aim of reconstructing the hip offset and to compare hip offset change to the quantitative change of the hip COR. RESULTS: The preoperative radiographic change to equalize the offset ranged from -12 to +21 mm (mean, 1.5); postoperatively the change was 1.4 +/- 6.4 mm and was within +/- 6 mm in 78 of 82 hips. As COR displaced superiorly from 3 to 6+ mm the offset had to be substantially increased. Only with COR 0-3 mm superior and 0-5 mm medial was offset always within 5 mm. CONCLUSIONS: Hip offset reconstruction was directly related to the position of the hip COR, and navigation allowed quantitative control of offset and hip length. PMID- 20844998 TI - Retrieved highly crosslinked UHMWPE acetabular liners have similar wear damage as conventional UHMWPE. AB - BACKGROUND: Highly crosslinked UHMWPE is associated with increased wear resistance in hip simulator and clinical studies. Laboratory and case studies, however, have described rim fracture in crosslinked acetabular liners. Controversy exists, therefore, on the relative merits of crosslinked liners over conventional liners in terms of wear performance versus resistance to fatigue cracking. QUESTIONS/PURPOSES: We asked whether crosslinked liners would show less surface damage than conventional liners but would be more susceptible to fatigue damage. METHODS: We examined 36 conventional UHMWPE and 39 crosslinked UHMWPE retrieved implants with similar patient demographics and identical design for evidence of wear damage, including articular surface damage, impingement, screw hole creep, and rim cracks. RESULTS: We observed no difference in wear damage scores for the two liners. Conventional liners more frequently impinged but were more often elevated with smaller head sizes. We observed creep in approximately 70% of both types of liners. Incipient rim cracks were found in five crosslinked liners, and one liner had a rim fracture. Only one conventional liner had an incipient rim crack. CONCLUSIONS: Contrary to our expectation, damage was similar between crosslinked and conventional UHMWPE liners. Moreover, the 15% occurrence (six of 39) of incipient or complete fractures in crosslinked liners as compared with a 3% occurrence (one of 36) in conventional liners may have implications for the long-term performance of crosslinked liners. Longer-term studies will be necessary to establish the fate of rim cracks and thus the overall clinical fatigue performance of crosslinked liners. PMID- 20844999 TI - Engaging and empowering patients to manage their type 2 diabetes, Part II: Initiatives for success. AB - Type 2 diabetes (T2D) has reached pandemic proportions. The impact of it and its long-term sequelae represent a significant burden for many healthcare systems around the world, and a significant number of patients struggle to achieve the internationally recommended targets for the modifiable risk factors that optimize healthy outcomes. In the first part of this two-part review, the scene was set showing that there seems to be a knowledge, attitude, and practice (KAP) gap hindering successful management of T2D. Although theoretical knowledge about how T2D should be managed exists, the attitude of patients and healthcare professionals seems to influence the practicalities of implementing life enhancing changes for patients living with diabetes. Following the chronic care model, macro-level initiatives such as Finland's national diabetes program, "The Development Programme for the Prevention and Care of Diabetes" (DEHKO), encourage a coordinated, supportive policy and financial environment for healthcare system change, and are advocated by the International Diabetes Federation. Over a 10 year period, the DEHKO program aims to demonstrate that a top-down population approach to prevention, focusing on reducing obesity, increasing physical activity, and encouraging healthier eating habits, may improve the overall health of the nation. However, the patient is the focus of day-to-day management of T2D, and innovative strategies that use a community (meso-level) approach to encourage self-management, or that embrace new technologies to access diabetes self management education or support networks, are likely to be the way forward. Such measures may close the apparent KAP gap and bring about real and measurable benefits in quality of life and life expectancy. The second part of this review describes some of the many and varied initiatives designed to engage and empower patients to self-manage their T2D, with the aim of increasing the proportion of patients reaching health-related targets. This will ultimately impact on national health systems and the quality of life of the nation. PMID- 20845001 TI - Efficacy and safety of bromfenac for the treatment of corneal ulcer pain. AB - PURPOSE: To evaluate the efficacy and safety of bromfenac ophthalmic solution 0.09% (XibromTM, ISTA Pharmaceuticals Inc., Irvine, CA, USA) for treating pain associated with corneal ulcers. METHODS: Twenty-five eyes of 24 patients with corneal infiltrates (bacterial or fungal) were treated with appropriate anti infective agents along with bromfenac twice daily for up to 102 days to treat the pain caused by the infection. Follow-up visits were frequent in the first 2 weeks upon initiation of treatment, then at least weekly until infections were resolved. The best corrected visual acuity, location, size, and density of corneal infiltrates, the size and presence of a corneal epithelial defect, subjective eye pain (scale of 0-4) and time to pain resolution, the ability to conduct daily activities, and adverse events were recorded at each follow-up visit. The results of these treated patients were compared with those of 10 control eyes with corneal infiltrates (bacterial or fungal) where appropriate anti-infectives were used without adjunct medications. RESULTS: Fifty-two percent of bromfenac-treated patients reported no pain by day 3, compared with 0% of untreated controls (P=0.023). Most of the treated patients' epithelium healed by day 20 (68%) compared with only 10% of controls (P=0.040). Most bromfenac-treated patients (71%) returned to normal activities within 2 days of starting treatment with bromfenac, compared with 0% of controls (P=0.018). No adverse events were recorded. CONCLUSION: Bromfenac was effective in treating pain associated with infectious keratitis and did not delay corneal epithelialization nor cause any corneal adverse events in this group of 25 eyes. PMID- 20845002 TI - Efficacy and safety of flavocoxid, a novel therapeutic, compared with naproxen: a randomized multicenter controlled trial in subjects with osteoarthritis of the knee. AB - INTRODUCTION: Flavocoxid is a novel flavonoid-based "dual inhibitor" of the 5 lipoxygenase (5-LOX) enzyme and the cyclooxygenase (COX) enzymes. This study was designed to compare the effectiveness and safety of flavocoxid to naproxen in subjects with moderate to severe osteoarthritis (OA) of the knee. METHODS: In this randomized, multicenter, double-blind study, 220 subjects were assigned to receive either flavocoxid (500 mg twice daily) or naproxen (500 mg twice daily) for 12 weeks. The trial was structured to show noninferiority of flavocoxid to naproxen. Primary outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and subscales and a timed walk. RESULTS: More than 90% of the subjects in both groups noted significant reduction in the signs and symptoms of knee OA. There were no statistically significant differences in efficacy between the flavocoxid and naproxen groups when the entire intent-to-treat population was analyzed. The flavocoxid group had significantly fewer upper gastrointestinal (UGI) and renal (edema) adverse events (AEs) as well as a strong trend toward fewer respiratory AEs. CONCLUSION: Flavocoxid, a first-in-class flavonoid-based therapeutic that inhibits COX-1 and COX-2 as well as 5-LOX, was as effective as naproxen in managing the signs and symptoms of OA of the knee. Flavocoxid demonstrated better UGI, renal (edema), and respiratory safety profiles than naproxen. PMID- 20845005 TI - Vascular resections in pancreatic cancer. PMID- 20845003 TI - Enhanced synaptic inhibition disrupts the efferent code of cerebellar Purkinje neurons in leaner Cav2.1 Ca 2+ channel mutant mice. AB - Cerebellar Purkinje cells (PCs) encode afferent information in the rate and temporal structure of their spike trains. Both spontaneous firing in these neurons and its modulation by synaptic inputs depend on Ca(2+) current carried by Ca(v)2.1 (P/Q) type channels. Previous studies have described how loss-of function Ca(v)2.1 mutations affect intrinsic excitability and excitatory transmission in PCs. This study examines the effects of the leaner mutation on fast GABAergic transmission and its modulation of spontaneous firing in PCs. The leaner mutation enhances spontaneous synaptic inhibition of PCs, leading to transitory reductions in PC firing rate and increased spike rate variability. Enhanced inhibition is paralleled by an increase in the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) measured under voltage clamp. These differences are abolished by tetrodotoxin, implicating effects of the mutation on spike-induced GABA release. Elevated sIPSC frequency in leaner PCs is not accompanied by increased mean firing rate in molecular layer interneurons, but IPSCs evoked in PCs by direct stimulation of these neurons exhibit larger amplitude, slower decay rate, and a higher burst probability compared to wild-type PCs. Ca(2+) release from internal stores appears to be required for enhanced inhibition since differences in sIPSC frequency and amplitude in leaner and wild-type PCs are abolished by thapsigargin, an ER Ca(2+) pump inhibitor. These findings represent the first account of the functional consequences of a loss-of-function P/Q channel mutation on PC firing properties through altered GABAergic transmission. Gain in synaptic inhibition shown here would compromise the fidelity of information coding in these neurons and may contribute to impaired cerebellar function resulting from loss-of function mutations in the Ca(V)2.1 channel gene. PMID- 20845007 TI - Plasma cholesterol level after hepatopancreatobiliary surgery provides information on the postoperative clinical course. PMID- 20845004 TI - Expressions of hypoxia-inducible factor-1alpha and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. AB - The impact of hypoxia-inducible factor (HIF)-1alpha and hexokinase-II (HK-II) expression on prognosis of gastric adenocarcinoma patients has not been clearly established. We identified all patients in Cancer Center of Sun Yat-Sen University who were diagnosed as gastric adenocarcinoma and underwent radical gastrectomy between January 1999 and December 2001. We used immunohistochemistry to determine the expressions of HIF-1alpha protein and HK-II in the surgical sections. We identified 188 patients with gastric adenocarcinoma for the final analysis. The positive rate of HIF-1alpha and HK-II were 110/188 (54.6%) and 40/188 (21.3%), respectively. Both HIF-1alpha and HK-II were all positively correlated with tumor size, lower differentiation, and tumor stage. Univariate analysis showed that advanced tumor stages (P < 0.001), tumor size (P = 0.003), HIF-1alpha expression (P < 0.001), and HK-II expression (P < 0.001) were all significantly associated with shorter survival. The multivariate Cox analysis revealed that tumor stage (P < 0.001), HIF-1alpha expression (P < 0.001), and HK II expression (P = 0.002) remained independent prognostic variables for survival. In addition, there was a positive correlation of HIF-1alpha protein expression and HK-II (P = 0.022). Both HIF-1alpha and HK-II were overexpressed in gastric adenocarcinoma. The multivariate Cox analysis revealed that both of them were independent factors on survival of gastric adenocarcinoma patients. PMID- 20845008 TI - Necrotizing fasciitis: a surgical emergency. AB - Accurate assessment and timely interventions are critical in the treatment of patients affected with necrotizing fasciitis, a rare, fulminating, potentially life-threatening, infectious process of the soft tissues. Understanding the natural history and unique characteristics of this disease is crucial to achieve early recognition, effective management and a favorable patient outcome. Classic symptoms include severe pain, erythema, mottling, crepitus, skin anesthesia, warmth, tenderness, bullous formations and edema in the affected area and fever. This article aims at reviewing the information known about this disease, collected from various sources. Radical surgical debridement, broad-spectrum antibiotics, negative pressure wound therapy and hyperbaric oxygen therapy are considered to be the cornerstones of treatment. PMID- 20845009 TI - Experience on surgical treatment of gastrointestinal stromal tumor of the stomach. AB - In spite of their rarity, gastrointestinal stromal tumors (GISTs) represent a complex clinical problem, mainly diagnostic and therapeutic, for their unpredictable biological course and their long-term prognosis, the most involved site being the stomach. Although a great number of tyrosine-kinase inhibitors has been developed for blocking their proliferative pathways (constitutive CD117 and PDGFRa activation), surgical treatment still remains the only curative one. Nevertheless, their particular non-lymphatic spread and their tendency to peritoneal seeding have emphasized technical issues that are still greatly debated. The definition of the best surgical procedure aiming at the complete R0 resection of the tumor has changed in the recent years and, with the improvement of laparoscopic techniques, the minimally invasive approach of gastric GIST has become feasible in most cases. In this paper we present our experience on surgical treatment of 43 gastric GISTs observed from 2001 to 2008 taken from our case study (75 patients from 1994). The risk class, treatment and long-term follow-up (mean 36 months) has been analyzed. All patients underwent a surgical procedure; 10 of them were also treated with molecular tyrosine-kinase inhibitors as adjuvant treatment. Overall survival at 60 months was 89.3%, with a disease free survival of 87.68%. PMID- 20845010 TI - Lymph node retrieval and examination during the implementation of extended lymph node dissection for gastric cancer in a non-specialized western institution. AB - The optimal degree of lymph node dissection for gastric cancer is still matter of debate. Particularly, there are serious doubts about the reproducibility of extended lymph node dissection in western surgical units, and no studies to date have investigated factors influencing lymph node retrieval and examination during the learning curve. Univariate and multivariate retrospective analysis of 21 variables were carried out on a prospective series of 313 consecutive resections for gastric cancer performed by ten different surgeons, with lymph node retrieval and analysis performed by ten different pathologists. Endpoints were number of examined lymph nodes per patient, number of cases with inadequate nodal staging (<15 examined lymph nodes) and lymph node ratio (calculated as the absolute ratio between the number of metastatic and the number of examined lymph nodes). The number of examined lymph nodes per patient (mean +/- SD 28.3 +/- 14.1, median 26, range 2-78) was independently influenced by age, pN status, the type of gastric resection, the degree of lymph node dissection and single pathologist. There were 47 cases (15.0%) with incomplete nodal staging that was independently determined by the degree of lymph node dissection and by the pathologist. Lymph node ratio was independently influenced by the number of metastatic lymph nodes, the disease stage and by the histological subtype of the tumor. The role of an experienced or dedicated pathologist should not be underevaluated in western series when dealing with lymph node retrieval and examination. Lymph node ratio appeared not to be significantly influenced by the number of examined lymph nodes, being independently influenced only by the number of metastatic lymph nodes, the disease stage and by the histological subtype of the tumor. It could be therefore tested as a prognostic factor limiting the stage-migration phenomenon induced by extended lymph node dissection. PMID- 20845011 TI - Ectopic hepatic tissue misdiagnosed as a tumor of lung. AB - The ectopic or accessory liver lobe is an uncommon congenital anatomic abnormality. It is considered to be the outcome of an abnormal development of liver tissue during embryologic period. In some cases, it may be secondary to a trauma or a surgical operation. Literature reports only anecdotal cases; there are not series. The most common localization is the abdominal cavity, but very rarely it can also be found in the thoracic cavity. In most cases, preoperative correct diagnosis is very difficult because it is unlikely to consider this rare condition in course of differential diagnosis. Most cases are misdiagnosed, and patients undergo surgical intervention with suspect of lung lesion. Some times the intrathoracic accessory lobe is an intraoperative incidental finding. In this report, we present the case of a young female patient who underwent surgical treatment for a suspect pulmonary lesion that at histological examination resulted to be an intrathoracic accessory hepatic lobe. PMID- 20845012 TI - Pancreaticoduodenectomy with unusual artery reconstruction in a patient with celiac axis occlusion: report of a case. AB - Celiac axis stenosis is a relatively common finding that may require major revascularization during pancreaticoduodenectomy. We present a patient that underwent pancreaticoduodenectomy for intraductal papillary mucinous neoplasm of the pancreatic head associated with celiac axis obstruction. To secure arterial blood flow to the upper abdominal organs, the superior posterior pancreaticoduodenal artery and the posterior-inferior pancreatic-duodenal artery were carefully preserved, and anastomosed. The postoperative course was complicated by a pseudoaneurysm of the splenic artery that was successfully treated with angiographic embolization through the vascular bypass. This may be a valid alternative procedure for revascularization of the common hepatic artery during pancreaticoduodenectomy in a patient with celiac axis stenosis. PMID- 20845013 TI - The TNM classification of breast cancer: need for change. PMID- 20845014 TI - Sevoflurane does not alter norepinephrine-induced intracellular Ca2(+) changes in the diabetic rat aorta. AB - PURPOSE: The effect of volatile anesthetics on the mechanism(s) of vascular contraction in diabetes mellitus (DM) has not been fully understood. The current study was designed to determine the effects of sevoflurane on the norepinephrine (NE)-induced changes in contractile state and intracellular Ca2(+) concentrations ([Ca2(+)](i)) in the spontaneously developing type 2 DM rat. METHODS: The effects of sevoflurane on NE (10-6M)-induced vasoconstriction and increase in [Ca2(+)](i) in the aortas from Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 DM model, and from age-matched control Long-Evans Tokushima Otsuka (LETO) rats were investigated using an isometric force transducer and fluorometer with fura-2 as an indicator of [Ca2(+)](i). RESULTS: Norepinephrine-induced increases in tension and [Ca2(+)](i) in OLETF rats were 54.8%, 95% confidence interval (CI) 36.9-72.6% and 58.8%, 95% CI 51.5-66.1%, respectively, and in LETO rats they were 46.4%, 95% CI 39.0-53.7% and 53.8%, 95% CI 46.9-60.7%, respectively, when expressed as the percentage relative to that induced by KCl 30 mM. In LETO rats, sevoflurane at a concentration of 3.4% inhibited the vascular contraction (9.4%, 95% CI 6.3-12.6%; P < 0.001) and the increase in [Ca2(+)](i) (33.3%, 95% CI 27.4-39.2%; P = 0.002). In OLETF rats, however, sevoflurane failed to affect either the NE-induced contraction (43.6%, 95% CI 28.3-58.9%; P = 0.68) or the elevation in [Ca2(+)](i) (60.5%, 95% CI 56.3-64.8%; P = 0.93). CONCLUSION: Sevoflurane at clinically relevant concentrations inhibited the NE-induced increase in [Ca2(+)](i) in the aortic smooth muscle from normal rats but not in that from type 2 DM rats. Thus, a Ca2(+)- signalling pathway resistant to sevoflurane appears to exist in the type 2 DM rat aorta. PMID- 20845015 TI - Evidence-based clinical update: Which local anesthetic drug for pediatric caudal block provides optimal efficacy with the fewest side effects? AB - PURPOSE: The purpose of this evidence-based clinical update is to identify the best evidence when selecting a long-acting local anesthetic agent for single-shot pediatric caudal anesthesia in children. METHODS: A structured literature search was conducted using PubMed and Medline (OVID) using the terms "caudal" and combinations of at least two of "bupivacaine", "ropivacaine", and "levobupivacaine". The search limits included "randomized controlled trials" (RCTs), "meta-analysis", "evidence-based reviews" or "reviews", "human", and "all child: 0-18 yr". Seventeen RCTs were identified that concerned single-shot pediatric caudal anesthesia with at least two of the three drugs in question. Data were extracted for the areas of clinical efficacy and side effects. Study findings were assigned levels of evidence, and grades of recommendation were made according to Centre for Evidence-Based Medicine criteria. RESULTS: The three drugs investigated were found to be equivalent in terms of efficacy. Evidence showed bupivacaine with the highest incidence of motor block and ropivacaine with the lowest. Adverse effects were rare and unrelated to the choice of drug. There were no serious adverse events. CONCLUSION: None of the three agents was shown to be superior in terms of efficacy. Bupivacaine is preferred if motor block is desired, ropivacaine is preferred if motor block is to be minimized. Adverse effects in human studies are rare, mild, and unrelated to the choice of drug. Despite encountering the absence of serious adverse events in each of the studies reviewed, it is noted that animal studies suggest a safer profile with ropivacaine or levobupivacaine than with bupivacaine. PMID- 20845016 TI - [Protection of the airway in obstetrics: a study of clinical practices in an academic centre hospital in Benin]. PMID- 20845017 TI - Raising the bar. PMID- 20845020 TI - Elderly patient with acute, left lower abdominal pain: perforated jejunal diverticulitis (2010:7b). AB - An elderly patient with acute, left, lower abdominal pain is described, for whom the diagnosis of perforated jejunal diverticulitis was established by computed tomography (CT). The presence of a jejunal segmental inflammatory process, with or without abscess or perforation, in the setting of jejunal diverticulosis, is very suggestive of jejunal diverticulitis. PMID- 20845022 TI - Understanding mental disorders from neuronal networks to glial cells and proteomics. PMID- 20845024 TI - Identification of QTL regions and SSR markers associated with resistance to reniform nematode in Gossypium barbadense L. accession GB713. AB - The identification of molecular markers that are closely linked to gene(s) in Gossypium barbadense L. accession GB713 that confer a high level of resistance to reniform nematode (RN), Rotylenchulus reniformis Linford & Oliveira, would be very useful in cotton breeding programs. Our objectives were to determine the inheritance of RN resistance in the accession GB713, to identify SSR markers linked with RN resistance QTLs, and to map these linked markers to specific chromosomes. We grew and scored plants for RN reproduction in the P(1), P(2), F(1), F(2), BC(1)P(1), and BC(1)P(2) generations from the cross of GB713 * Acala Nem-X. The generation means analysis using the six generations indicated that one or more genes were involved in the RN resistance of GB713. The interspecific F(2) population of 300 plants was genotyped with SSR molecular markers that covered most of the chromosomes of Upland cotton (G. hirsutum L.). Results showed two QTLs on chromosome 21 and one QTL on chromosome 18. One QTL on chromosome 21 was at map position 168.6 (LOD 28.0) flanked by SSR markers, BNL 1551_162 and GH 132_199 at positions 154.2 and 177.3, respectively. A second QTL on chromosome 21 was at map position 182.7 (LOD 24.6) flanked by SSR markers BNL 4011_155 and BNL 3279_106 at positions 180.6 and 184.5, respectively. Our chromosome 21 map had 61 SSR markers covering 219 cM. One QTL with smaller genetic effects was localized to chromosome 18 at map position 39.6 (LOD 4.0) and flanked by SSR markers BNL 1721_178 and BNL 569_131 at positions 27.6 and 42.9, respectively. The two QTLs on chromosome 21 had significant additive and dominance effects, which were about equal for each QTL. The QTL on chromosome 18 showed larger additive than dominance effects. Following the precedent set by the naming of the G. longicalyx Hutchinson & Lee and G. aridum [(Rose & Standley) Skovsted] sources of resistance, we suggest the usage of Ren (barb1) and Ren (barb2) to designate these QTLs on chromosome 21 and Ren (barb3) on chromosome 18. PMID- 20845023 TI - Carotenoid-based bill colour is an integrative signal of multiple parasite infection in blackbird. AB - In the study of parasite-mediated sexual selection, there has been controversial evidence for the prediction that brighter males should have fewer parasites. Most of these studies have focused on one parasite species. Our aim was to investigate the expression of carotenoid-based coloured signals in relation to patterns of multiple parasite infections, to determine whether colour reflects parasite load of all parasite species, or whether different relationships might be found when looking at each parasite species independently. We investigated the relationship between bill colour, body mass and plasma carotenoids and parasite load (feather chewing lice, blood parasite Plasmodium sp., intestinal parasites cestodes and coccidia) in the blackbird (Turdus merula). Bill colour on its own appeared to be a poor predictor of parasite load when investigating its relationships with individual parasite species. Variation in parasite intensities at the community level was summarised using principal component analysis to derive synthetic indexes of relative parasite species abundance and absolute parasite load. The relative abundance of parasite species was strongly related to bill colour, plasma carotenoid levels and body mass: birds with relatively more cestodes and chewing lice and relatively less Plasmodium and coccidia had a more colourful bill, circulated more carotenoids and were heavier. These results suggest that bill colour more accurately reflects the relative intensities of parasite infection, rather than one-by-one relationships with parasites or absolute parasite burden. Investigating patterns of multiple parasite infection would thus improve our understanding of the information conveyed by coloured signals on parasite load. PMID- 20845025 TI - Endothelin receptor antagonist attenuates inflammatory response and prolongs the survival time in a neonatal sepsis model. AB - PURPOSE: To evaluate effects of endothelin receptor antagonist ETR-P1/fl in a neonatal sepsis model. METHOD: Eighteen anesthetized and mechanically ventilated 3-day-old piglets were divided into three groups. Six piglets received cecal ligation and perforation (CLP group). Six piglets were administrated a continuous infusion of ETR-P1/fl (0.05 mg/kg/h), an antisense homology box-derived peptide with an endothelin A receptor antagonist effect, starting 30 min after CLP (ETR P1/fl group). Six piglets acted as the sham group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, body temp (BT), serum nitrite and nitrate (NOx), tumor necrosis factor (TNF)-alpha, and high-mobility group box 1 (HMGB-1) were measured before CLP and at 1, 3, 6, and 9 h after CLP. RESULTS: Cecal ligation and perforation exposure evoked a state of shock and showed deteriorated cardiac output, pulmonary hypertension, decreased MAP, low oxygen saturation, and base excess (BE) with elevated TNF-alpha, NOx, and HMGB1. ETR P1/fl administration resulted in higher MAP at 6 and 9 h after CLP, less negative BE, lower mean pulmonary arterial pressure (mPAP)/MAP ratio at 9 h after CLP, and lower TNF-alpha, NOx, and HMGB-1 compared to the CLP group. BT showed no differences between the groups. Survival time in the ETR-P1/fl group was longer than in the CLP group (18.9 +/- 2.3 h vs. 9.0 +/- 0.8 h, p < 0.01). CONCLUSIONS: ETR-P1/fl treatment significantly attenuated the elevation of NOx, TNF-alpha, and HMGB-1, which improved the systemic hypotension, pulmonary hypertension, and blood gases, thereby causing improvement of survival time in a progressive neonatal sepsis CLP model. PMID- 20845026 TI - Could nephrotoxicity due to colistin be ameliorated with the use of N acetylcysteine? AB - PURPOSE: The protective effect of N-acetylcysteine (NAC) on nephrotoxicity due to contrast nephropathy and reperfusion-induced ischemia has been reported in experimental models. However, its efficacy on colistin-induced nephrotoxicity has not been elucidated yet. The primary aim of this study was to evaluate the nephrotoxic effect of colistin and to investigate the possible protective effect of NAC on colistin-induced nephrotoxicity. The secondary aim was to research the systemic effects of nephrotoxicity-induced oxidative stress on the lung. METHODS: Eighteen female Sprague-Dawley rats were randomly assigned and were given (a) 1 ml/kg sterile saline, (b) 300,000 IU/kg/day colistin, and (c) 300,000 IU/kg/day colistin and 150 mg/kg NAC for six consecutive days. RESULTS: Plasma blood urea nitrogen (BUN), creatinine, urinary creatinine, urinary protein, plasma TNF-alpha levels, renal tissue superoxide dismutase (SOD) and malondialdehyde (MDA) activity and immunocytochemical findings were evaluated. Colistin exerted nephrotoxicity and achieved a significant increase in plasma BUN and creatinine levels and renal tissue SOD levels. NAC exhibited no significant effect on biochemical parameters but reduced renal tissue SOD level and reversed immunocytochemical staining of inducible nitric oxide synthase (i-NOS) and neurotrophin-3. Increased oxidative stress in the lung tissue of the rats treated with colistin has also been documented. Additionally, NAC significantly reduced the immunostaining of endothelial NOS (e-NOS) and i-NOS in the lung tissue. CONCLUSIONS: Colistin-induced renal toxicity may be attributable to oxidative damage. The combined treatment of colistin plus NAC seems to have a beneficial role in restoration of the oxidant injury which may be related to its antioxidant effect. PMID- 20845027 TI - Imminent brain death and brain death are not the same: reply to Verheijde and Rady. PMID- 20845028 TI - Successful use of neurally adjusted ventilatory assist in a patient with extremely low respiratory system compliance undergoing ECMO. PMID- 20845029 TI - An unusual cause of severe lactic acidosis: cyanide poisoning after bitter almond ingestion. PMID- 20845030 TI - Malalignment and cartilage lesions in the patellofemoral joint treated with autologous chondrocyte implantation. AB - PURPOSE: The aim of our current study is to present the 12.6 years' follow-up results in patients with cartilage lesions of the patellofemoral joint, treated with autologous chondrocyte implantation (ACI) with the use of periosteum. METHODS: Ninety-two patients having patella or trochlea lesion participated in this study. Lysholm and Tegner questionnaires were completed 12.6 years (SD 2.3 years) after the surgery. The patients were asked whether they feel better, worse or had not experienced any difference compared to previous years and whether they would undergo the operation again. Complications or subsequent surgeries were also assessed. RESULTS: Median Tegner score was three, improved by one level compared with preoperative values (P = 0.02). Median Lysholm score was 70, improved by nine points (n.s.). Seventy-two percent of the patients were better or unchanged while 93% would undergo the operation again. Patients with no kissing lesions appeared to have a better prognosis. Patients with malalignment or instability that had undergone a realignment procedure had comparable outcomes to the patients that did not need any additional surgery. Realignment procedures increased the incidence of serious complications but they were associated with decreased incidence of periosteal hypertrophy. No association was found between the age of the patients at the time of the ACI or the size per lesion and any of the clinical outcomes. CONCLUSION: ACI provides a satisfactory outcome for the treatment of cartilage lesions of the patellofemoral joint, even for the cases with concomitant patellar instability. It seems that correcting the coexisting background factors with realignment, stabilizing or unloading procedures, along with the treatment of cartilage lesions, is improving the clinical outcomes over time and decreases the incidence of periosteal hypertrophies although increasing the incidence of serious complications. Our study reveals the good results and the high level of patients' activities (as shown by Tegner score), were preserved 12.6 years after the implantation, in both isolated trochlea and patella lesions and also in multiple and in kissing lesions where an intervention could be considered as a salvage procedure. PMID- 20845032 TI - Physicochemical characterisation of different welding aerosols. AB - Physicochemical properties important in exposure characterisation of four different welding aerosols were investigated. Particle number size distributions were determined by scanning mobility particle sizer (SMPS), mass size distributions by separation and weighing the individual size fractions of an 11 stage cascade impactor. The size distribution of the primary particles of agglomerates, chemical composition and morphology of the particles were examined by TEM. There were significant differences in the particle number size distributions of the different welding aerosols according to the SMPS determinations. The particle mass size distributions determined gravimetrically were, however, not really different. The dominant range with respect to mass was between 0.1 and 1 MUm, regardless of the welding technique. Most of the primary particles in all different welding aerosols had diameters between 5 and 40 nm. All types of primary particles had a tendency to form chainlike agglomerates. A clear size dependence of the particle chemical composition was encountered in the case of manual metal arc welding aerosol. Small particles with diameters below 50 nm were mostly metal oxides in contrast to larger particles which also contained more volatile elements (e.g. potassium, fluorine, sodium, sulphur). PMID- 20845031 TI - In vivo kinematics of mobile-bearing total knee arthroplasty during deep knee bending under weight-bearing conditions. AB - PURPOSE: Little is known about the in vivo kinematics of mobile-bearing total knee arthroplasty, especially at deep knee flexion under weight-bearing conditions. METHODS: In vivo knee kinematics was analyzed for 12 patients (13 knees) implanted with PFC-Sigma Rotating Platform-Flex (RP-F) prostheses. Under fluoroscopic surveillance, each patient performed weight-bearing deep knee bending. Motion between each component was analyzed using a two- to three dimensional registration technique, which uses computer-assisted design models to reproduce the spatial positions of the femoral and tibial components and a polyethylene insert (implanted with four tantalum beads) from single-view fluoroscopic images. RESULTS: External rotation of the femoral component on the tibial tray was mostly caused by rotation of the polyethylene insert on the tibial tray. The femoral component typically exhibited a central pivot pattern from extension to 80 degrees relative to the tibial component. From 80 degrees to 120 degrees , bilateral condyles moved backward. In an upright standing position, the femoral component had already rotated externally relative to the tibial component by 7.8+/-7.5 degrees , and the polyethylene insert had also rotated 8.2 degrees +/-6.2 degrees externally on the tibial tray. CONCLUSION: The present results demonstrated that mobile-bearing mechanisms with this prosthesis might reduce articular contact stress in vivo. PMID- 20845033 TI - Functional Fe3O4@ZnO magnetic nanoparticle-assisted enrichment and enzymatic digestion of phosphoproteins from saliva. AB - Saliva contains various proteins, particularly abundant are phosphoproteins, that may be related to disease occurrences and that play significant roles in a biological system. Thus, medical diagnostics will benefit tremendously if disease related protein biomarkers are discovered from saliva. In this paper, we propose and demonstrate an approach using functional zinc oxide coated iron oxide magnetic nanoparticles (Fe(3)O(4)@ZnO MNPs) as affinity probes to selectively enrich phosphoproteins from complex saliva samples and as microwave absorbers to assist the enrichment and subsequent tryptic digestion of trapped proteins under microwave heating. The target species trapped by MNPs were characterized by matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) combined with protein database search. Entire analysis time was shortened to less than 20 min. The detection limit of this approach for a monophosphopeptide was as low as 250 pM (10 MUL). PMID- 20845034 TI - Molecularly imprinted polymers: synthetic receptors in bioanalysis. AB - Molecularly imprinted polymers (MIPs) are tailor-made synthetic materials possessing specific cavities designed for a target molecule. Since they recognise their target analyte with affinities and selectivities comparable to those of antibody-antigen, enzyme-substrate and ligand-receptor interactions, they are often referred to as synthetic receptors or plastic antibodies. In this review, we describe the great potential and recent developments of MIPs in affinity separations, with emphasis on their application to the solid-phase extraction (SPE) of analytes from complex matrices. Research efforts made in this field to obtain water-compatible polymers for their applicability in aqueous environments are described. We particularly discuss problems encountered in the use of MIPs in SPE and the attempts carried out to improve their efficiency. PMID- 20845035 TI - Arthroscopically assisted anatomical coracoclavicular ligament reconstruction using tendon graft. AB - We describe a method of arthroscopically assisted, mini-open, anatomical reconstruction of the coracoclavicular ligament. This method restores both components of the native ligament with the aim of achieving maximum stability with minimal disruption of the normal anatomy. Using the same principles of ligament reconstruction that are employed in other joints, transosseous tunnels are created following the native footprints of the conoid and trapezoid ligaments and an autologous graft is fixed using a PEEK screw. Adequate healing of the ligament occurs within the bone, to prevent stress risers with an appropriate working length. This procedure is unique, as it replaces the torn ligament with a natural substitute, in the appropriate location, through a minimally invasive procedure. This technique would be suitable for treatment of patients with either grade III or V acute acromioclavicular dislocations. Clinical outcomes for the first 13 consecutive patients treated with this procedure are reported, revealing excellent satisfaction rates with a Constant score of 96.6 at final follow-up. PMID- 20845036 TI - Choledochoduodenostomy is a safe alternative to Roux-en-Y choledochojejunostomy for biliary reconstruction in liver transplantation. PMID- 20845037 TI - A nomogram for predicting the probability of carcinoma in patients with intraductal papillary-mucinous neoplasm. AB - BACKGROUND: The objective of the present study was to use clinical and laboratory data to develop a model for predicting the presence of carcinoma in patients with intraductal papillary mucinous neoplasm (IPMN). METHODS: Data were collected on 81 patients with IPMN who underwent a pancreatic resection between 1989 and 2008 at Aichi Cancer Center Hospital. Variables analyzed included age, gender, laboratory findings (serum amylase, carcinoembryonic antigen, and carbohydrate antigen 19-9 level), pancreatic juice cytology grade, and imaging studies. Factors associated with the presence of carcinoma were evaluated by univariate and multivariate logistic regression analysis. RESULTS: Among the 81 patients with IPMN, 34 (42%) had malignant tumors (noninvasive carcinoma in 22 and invasive carcinoma in 12), and 47 (58%) had adenoma. On multivariate analysis, existing carcinoma was associated with female gender, main pancreatic duct IPMN, nodule size, and pancreatic juice cytology grade. Based on these variables, a predictive nomogram was developed. The area under the receiver operating characteristic curve (AUC) for the model was 0.903. The sensitivity and specificity of the model were 97.1 and 68.1%, respectively, in the validation study, for which the predictive probability of >10% was used to indicate the presence of carcinoma. CONCLUSIONS: The nomogram has high diagnostic predictability for carcinoma in patients with IPMN and for individual cancer probability. This instrument may help to identify patients who need a surgical procedure. PMID- 20845038 TI - Management of penetrating abdominal trauma in the conflict environment: the role of computed tomography scanning. AB - BACKGROUND: Computed tomography (CT) scanning is a vital imaging technique in selecting patients for nonoperative management of civilian penetrating abdominal trauma. This has reduced the rate of nontherapeutic laparotomies and associated complications. Battlefield abdominal injuries conventionally mandate laparotomy, and with the advent of field deployable CT scanners it is unclear whether some ballistic injuries can be managed conservatively. METHODS: A retrospective 12 month cohort of patients admitted to a forward surgical facility in Afghanistan who sustained penetrating abdominal injury severe enough to warrant laparotomy or CT scan were studied. Patient details were retrieved from a prospectively maintained operative log and CT logs. Case notes were then reviewed and data pertaining to injury pattern, operative intervention, and survival were collected. RESULTS: A total of 133 patients were studied: 73 underwent immediate laparotomy (Lap group) and 60 underwent CT scanning (CT group). Of those undergoing CT scanning 17 underwent laparotomy and 43 were selected for nonoperative management. There were 15 deaths in the Lap group and none in the CT group. The median New Injury Severity and Revised Trauma Score was 29 and 7.55 in the Lap group and 9 and 7.8408 in the CT group, which is statistically significantly different (p < 0.001). Five patients in the CT-Lap group had nontherapeutic laparotomies and 1 patient failed nonoperative management. CONCLUSIONS: Computed tomography scanning can be used in stable patients who have sustained penetrating battlefield abdominal injury to exclude peritoneal breach and identify solid abdominal organ injury that can be safely managed nonoperatively. PMID- 20845040 TI - Nanotechnology and its relationship to interventional radiology. Part II: Drug Delivery, Thermotherapy, and Vascular Intervention. AB - Nanotechnology can be defined as the design, creation, and manipulation of structures on the nanometer scale. This two-part review is intended to acquaint the interventionalist with the field of nanotechnology, and provide an overview of potential applications, while highlighting advances relevant to interventional radiology. Part 2 of the article concentrates on drug delivery, thermotherapy, and vascular intervention. In oncology, advances in drug delivery allow for improved efficacy, decreased toxicity, and greater potential for targeted therapy. Magnetic nanoparticles show potential for use in thermotherapy treatments of various tumours, and the effectiveness of radiofrequency ablation can be enhanced with nanoparticle chemotherapy agents. In vascular intervention, much work is focused on prevention of restenosis through developments in stent technology and systems for localised drug delivery to vessel walls. Further areas of interest include applications for thrombolysis and haemostasis. PMID- 20845039 TI - Clinical evaluation of spatial accuracy of a fusion imaging technique combining previously acquired computed tomography and real-time ultrasound for imaging of liver metastases. AB - PURPOSE: This study was designed to evaluate the spatial accuracy of matching volumetric computed tomography (CT) data of hepatic metastases with real-time ultrasound (US) using a fusion imaging system (VNav) according to different clinical settings. METHODS: Twenty-four patients with one hepatic tumor identified on enhanced CT and US were prospectively enrolled. A set of three landmarks markers was chosen on CT and US for image registration. US and CT images were then superimposed using the fusion imaging display mode. The difference in spatial location between the tumor visible on the CT and the US on the overlay images (reviewer #1, comment #2) was measured in the lateral, anterior-posterior, and vertical axis. The maximum difference (Dmax) was evaluated for different predictive factors. CT performed 1-30 days before registration versus immediately before. Use of general anesthesia for CT and US versus no anesthesia. Anatomic landmarks versus landmarks that include at least one nonanatomic structure, such as a cyst or a calcification RESULTS: Overall, Dmax was 11.53 +/- 8.38 mm. Dmax was 6.55 +/- 7.31 mm with CT performed immediately before VNav versus 17.4 +/- 5.18 with CT performed 1-30 days before (p < 0.0001). Dmax was 7.05 +/- 6.95 under general anesthesia and 16.81 +/- 6.77 without anesthesia (p < 0.0015). Landmarks including at least one nonanatomic structure increase Dmax of 5.2 mm (p < 0.0001). The lowest Dmax (1.9 +/- 1.4 mm) was obtained when CT and VNav were performed under general anesthesia, one immediately after the other. CONCLUSIONS: VNav is accurate when adequate clinical setup is carefully selected. Only under these conditions (reviewer #2), liver tumors not identified on US can be accurately targeted for biopsy or radiofrequency ablation using fusion imaging. PMID- 20845041 TI - Nanotechnology and its relationship to interventional radiology. Part I: imaging. AB - Nanotechnology refers to the design, creation, and manipulation of structures on the nanometer scale. Interventional radiology stands to benefit greatly from advances in nanotechnology because much of the ongoing research is focused toward novel methods of imaging and delivery of therapy through minimally invasive means. Through the development of new techniques and therapies, nanotechnology has the potential to broaden the horizon of interventional radiology and ensure its continued success. This two-part review is intended to acquaint the interventionalist with the field of nanotechnology, and provide an overview of potential applications, while highlighting advances relevant to interventional radiology. Part I of the article deals with an introduction to some of the basic concepts of nanotechnology and outlines some of the potential imaging applications, concentrating mainly on advances in oncological and vascular imaging. PMID- 20845042 TI - A case of cystic biliary atresia with an antenatally detected cyst: the possibility of changing from a correctable type with a cystic lesion (I cyst) to an uncorrectable one (IIId). AB - This report presents the case of a 6-day-old male with cystic biliary atresia (CBA), and the cyst was detected antenatally. Antenatal ultrasonography suggested the possibility of CBA or a choledochal cyst at 16 weeks' gestation. However, the cyst disappeared during the later gestational period. The cyst was detected again by preoperative imaging. Surgical cholangiography at 30 days of age confirmed CBA, but the common hepatic duct (CHD) was extremely narrow. The histopathological findings revealed the partial obstruction of CHD. These findings suggest that correctable CBA (I cyst) may change into uncorrectable CBA (IIId). PMID- 20845043 TI - Laryngotracheal separation using skin flap formation: a novel surgical procedure. AB - Laryngotracheal separation is often performed to prevent intractable aspiration for children with severe mental and physical disabilities. However, tracheo innominate artery fistula after surgery can occur as a severe complication and cause fatal hemorrhage. We have therefore developed a novel procedure to prevent tracheo-innominate artery fistula. Surgery was performed by making an H-shaped incision and creating skin flaps. The trachea was not raised anteriorly and the skin flaps were sutured to the trachea. We performed this procedure on nine patients, and no major complications occurred in any case. This procedure can be expected to reduce the occurrence of tracheo-innominate artery fistula. PMID- 20845044 TI - Management and outcome of low anorectal malformations. AB - Low anorectal malformation comprises about half of all anorectal anomalies. Most of the literature concerning management of anorectal anomalies is centred around the treatment and outcome of high anomalies. The management of low anomalies has been considered significantly less challenging than high anomalies. Also, the outcome of low anomalies has traditionally been considered good. However, recent more critical long-term follow-up reports show a different picture. Many patients with low anomalies suffer from long-term anorectal functional problems, especially constipation but also soiling that occurs in a significant percentage of patients. In this review, we compile the recent views on the diagnosis, surgical treatment and outcome of low anorectal anomalies. We also present an algorithm for the management of these anomalies. The emphasis on the surgical management of low anorectal anomalies is to use as minimally invasive operative methods as possible and preserve the native mechanisms of continence that usually are much better preserved than in more severe high anomalies. PMID- 20845045 TI - Botox, dilation, or myotomy? Clinical outcome of interventional and surgical therapies for achalasia. AB - PURPOSE: Achalasia is a rare, but well-defined primary esophageal motor disorder. Classic therapeutic approaches include botulinum toxin injection, balloon dilation, and surgical myotomy of the lower esophageal sphincter. This report summarizes our experience with different treatment modalities for achalasia. METHODS: Forty-three patients with achalasia treated in our hospital were subdivided according to therapeutic strategy: endoscopic botulinum toxin injection into the lower esophageal sphincter (EBTI; n = 7), endoscopic esophageal balloon dilation (EBD; n = 16), surgical myotomy after failed esophageal balloon dilation (EBD-HM; n = 14), and first-line surgical myotomy (HM; n = 6). Therapeutic efficiency was evaluated comparing standardized symptom scores preoperatively and at follow-up. RESULTS: There was no mortality and no significant difference between the groups for age, sex, or morbidity. The mean follow-up was at 9, 35, 38, and 17 months. At follow-up, recurrent or persistent symptoms were found in 71.4%, 6.3%, 35.7%, and 16.7% in EBTI, EBD, EBD-HM, and HM, respectively. Considering EBD-HM patients as failures of esophageal dilation, the total rate of recurrent or persistent symptoms after EBD was 50%. Poor symptomatic outcome was correlated to a low esophageal sphincter pressure during pretherapeutic manometry (p = 0.03) and to sigmoid-shaped esophageal dilatation (p = 0.06). CONCLUSION: Surgical myotomy is the most reliable first-line therapy for achalasia, particularly in patients with a high sphincter pressure and moderate esophageal dilatation. Botox injection has a high failure rate and should be reserved for exceptional cases. Endoscopic dilation provides about 50% of patients with long-term symptomatic relief; in most cases, failure can be successfully treated surgically. PMID- 20845046 TI - Idiopathic severe constriction of the fetal ductus arteriosus: a possible underestimated pathophysiology. AB - Idiopathic intrauterine constriction/closure of the ductus arteriosus, which is distinct from that secondary to maternal exposure to non-steroidal anti inflammatory drugs, such as indomethacin, or structural cardiac defect, is an uncommon event that often results in severe fetal-neonatal morbidity and mortality. We reported a case of idiopathic fetal ductal constriction, in which the diagnosis was confirmed by documentation of an abnormal four-chamber view of the fetal heart at 38 weeks of gestation on obstetric ultrasound examination. A female infant weighing 2,816 g was born by Cesarean section, and her postnatal course was mild; transient tachypnea requiring only several days of supplemental oxygen with spontaneous regression of the abnormal echocardiographic findings by 3 months of age. The incidence of idiopathic constriction/closure of the fetal ductus arteriosus may be underestimated, particularly with a negative history of maternal drug exposure and mild postnatal clinical presentation. PMID- 20845047 TI - IRF6 mutations may not be a major cause of Van der Woude syndrome in India. PMID- 20845048 TI - Cost analysis of adult-adult living donor liver transplantation in Tokyo University Hospital. AB - BACKGROUND AND PURPOSE: Living donor liver transplantation (LDLT) is now a well established treatment modality for end-stage liver diseases, but the financial aspects of LDLT have not yet been fully investigated. The purpose of this study was to determine the overall direct cost of adult-adult LDLT in Japan and to identify the factors associated with the high cost. MATERIALS AND METHODS: The direct cost of initial admission for LDLT was determined in a retrospective analysis of data from hospital charts and databases. The records for 100 consecutive adults who underwent LDLT from January 2004 to February 2006 at our center were reviewed, and clinical and financial data of all recipients and donors were analyzed. RESULTS: The median direct total cost for LDLT was $82,017 (range $51,189-438,295). Of this, the median cost for donors was $15,011 (range $12,354-23,251). A multivariate stepwise logistic regression model for overall cost of transplantation revealed that donor age [odds ratio (OR) = 1.1, p = 0.02], acute renal failure (OR = 24, p = 0.007), and posttransplant plasma exchange (OR = 72, p = 0.01) were associated with higher cost. When the models were repeated with preoperative patient and donor factors alone, donor age (OR 1.1, p = 0.008) and model for end stage liver disease score (OR 1.2, p = 0.003) were associated with higher cost. CONCLUSIONS: Donor age, acute renal failure, and posttransplant plasma exchange were independent risk factors for the high cost of LDLT in Japan. PMID- 20845049 TI - Cerebellopontine angle tumors causing hemifacial spasm: types, incidence, and mechanism in nine reported cases and literature review. AB - OBJECTIVE: Although hemifacial spasm is usually caused by vascular compression around the root exit zone of the facial nerve, it is sometimes brought on by a cerebellopontine angle tumor. We reviewed and analyzed data from past experience with hemifacial spasm induced by cerebellopontine angle tumors. METHODS: Nine patients of a total 2,050, who had presented with hemifacial spasms associated with cerebellopontine angle tumors between 1986 and 2009, were reviewed. RESULTS: Two vestibular schwannomas, five meningiomas, and two epidermoid tumors were included in this study. Hemifacial spasm occurred on the same side of the lesion in eight patients whereas it occurred on the opposite side of the lesion in one patient. With respect to the pathogenesis of hemifacial spasms, offending vessels were found in six patients, tumor encasement of the facial nerve in one patient, hypervascular tumor compression of the facial nerve without offending vessels in one patient, and a huge tumor compressing the brain stem and, thus, contralateral facial nerve compression in one patient. Hemifacial spasm was resolved in seven patients, whereas in two patients with a vestibular schwannoma and an epidermoid tumor, it improved transiently and then recurred in a month. CONCLUSIONS: Each type of tumor had different characteristics with respect to the induction of hemifacial spasm; therefore, it is suggested that neurosurgeons, who are planning surgeries both for the purposes of relieving hemifacial spasm and removal of cerebellopontine angle tumor, should thoroughly prepare appropriate approaches and specific dissecting strategies according to each causative lesion. PMID- 20845050 TI - The common consensus criteria have high predictive values for long-term postoperative acromegaly remission. AB - OBJECTIVE: The aim of this work was to retrospectively study the long-term reliability of the common consensus endocrinological criteria for the assessment of postoperative remission of acromegaly. PATIENTS AND METHODS: In 96 consecutive patients, surgical remission of acromegaly following transsphenoidal surgery was considered to be present when, without adjuvant treatment, 3 months postoperatively there was no clinical evidence of persisting disease, and, according to the common consensus criteria for acromegaly remission, GH was suppressed to < 1 MUg/l during the oral glucose tolerance test (OGTT) and insulin like growth factor-1 (IGF-1) was within normal limits. The results of the second postoperative week, 3 months postoperative, and the most recent follow-up OGTT and IGF-1 measurements were used to calculate the positive and negative predictive values of the following endocrinological criteria of acromegaly remission: the common consensus criteria for acromegaly remission, GH suppression to < 1 MUg/l during OGTT and IGF-1 within normal limits. Sensitive IRMA (<= 0.3 MUg/l) and RIA (<= 32 MUg/l) assays for GH and IGF-1 were used. RESULTS: The surgical remission rate of acromegaly was 72.9%. At a median follow-up of 5.06 years, the recurrence rate of acromegaly was 2.08%. Overall, the common consensus criteria for acromegaly remission were the most reliable tests, with the following positive and negative predictive values at 2 weeks postoperatively, 3 months postoperatively and at the most recent follow-up: 68%, 100% and 100%, and 98%, 100% and 100%, respectively. The negative likelihood ratio confirmed that the test qualities of the common consensus criteria for acromegaly remission were superior to the other tests. CONCLUSIONS: The common consensus criteria were the most reliable tests for the diagnosis of postoperative acromegaly remission. The positive and negative predictive values of the common consensus criteria for acromegaly remission increased from the second postoperative week to 3 months postoperatively, thereafter reliably indicating the long-term results of transsphenoidal surgery. PMID- 20845051 TI - Comparative study of quantitative ultrasonography and dual-energy X-ray absorptiometry for evaluating renal osteodystrophy in children with chronic kidney disease. AB - Our aim was to assess bone parameters in children with chronic kidney disease (CKD) with both dual-energy X-ray absorptiometry (DXA) and quantitative ultrasonography (QUS) and additionally with biochemical markers of bone turnover. Twenty children (12 boys and 8 girls) with CKD and a mean decimal age of 9.47 +/- 4.44 years were included in the study where anthropometric parameters (height and weight), pubertal status, bone mineral density (BMD) at lumbar spine, speed of sound (SOS) measured by QUS at radius and at tibia, and biochemical markers of bone metabolism were measured. Six patients (30%) had tibial SOS Z score <-1, and 52.7% had radial SOS Z score <-1, whereas only 16.67% had BMD Z score <-1. Patients had significantly increased levels of serum intact parathormone (p < 0.001), serum bone alkaline phosphatase (BAP) (p < 0.001) and serum N-terminal mid fragment (aminoacids 1-43) of osteocalcin (p < 0.001) compared to controls, whereas serum osteoprotegerin was significantly decreased in patients compared to controls (p = 0.001). SOS was significantly correlated to BAP (r = -0.586, p = 0.013 and r = -0.709, p = 0.001, respectively, for radius and tibia). In conclusion no association between DXA and QUS measurements was documented in our study, whereas QUS was better correlated to biochemical indices of ROD. PMID- 20845052 TI - Horses (Equus caballus) use human local enhancement cues and adjust to human attention. AB - This study evaluates the horse (Equus caballus) use of human local enhancement cues and reaction to human attention when making feeding decisions. The superior performance of dogs in observing human states of attention suggests this ability evolved with domestication. However, some species show an improved ability to read human cues through socialization and training. We observed 60 horses approach a bucket with feed in a three-way object-choice task when confronted with (a) an unfamiliar or (b) a familiar person in 4 different situations: (1) squatting behind the bucket, facing the horse (2) standing behind the bucket, facing the horse (3) standing behind the bucket in a back-turned position, gazing away from the horse and (4) standing a few meters from the bucket in a distant, back-turned position, again gazing away from the horse. Additionally, postures 1 and 2 were tested both with the person looking permanently at the horse and with the person alternating their gaze between the horse and the bucket. When the person remained behind the correct bucket, it was chosen significantly above chance. However, when the test person was turned and distant from the buckets, the horses' performance deteriorated. In the turned person situations, the horses approached a familiar person and walked towards their focus of attention significantly more often than with an unfamiliar person. Additionally, in the squatting and standing person situations, some horses approached the person before approaching the correct bucket. This happened more with a familiar person. We therefore conclude that horses can use humans as a local enhancement cue independently of their body posture or gaze consistency when the persons remain close to the food source and that horses seem to orientate on the attention of familiar more than of unfamiliar persons. We suggest that socialization and training improve the ability of horses to read human cues. PMID- 20845053 TI - Free-ranging dogs assess the quantity of opponents in intergroup conflicts. AB - In conflicts between social groups, the decision of competitors whether to attack/retreat should be based on the assessment of the quantity of individuals in their own and the opposing group. Experimental studies on numerical cognition in animals suggest that they may represent both large and small numbers as noisy mental magnitudes subject to scalar variability, and small numbers (<=4) also as discrete object-files. Consequently, discriminating between large quantities, but not between smaller ones, should become easier as the asymmetry between quantities increases. Here, we tested these hypotheses by recording naturally occurring conflicts in a population of free-ranging dogs, Canis lupus familiaris, living in a suburban environment. The overall probability of at least one pack member approaching opponents aggressively increased with a decreasing ratio of the number of rivals to that of companions. Moreover, the probability that more than half of the pack members withdrew from a conflict increased when this ratio increased. The skill of dogs in correctly assessing relative group size appeared to improve with increasing the asymmetry in size when at least one pack comprised more than four individuals, and appeared affected to a lesser extent by group size asymmetries when dogs had to compare only small numbers. These results provide the first indications that a representation of quantity based on noisy mental magnitudes may be involved in the assessment of opponents in intergroup conflicts and leave open the possibility that an additional, more precise mechanism may operate with small numbers. PMID- 20845054 TI - Combination therapy with sorafenib and S-1 for renal cell carcinoma producing granulocyte colony-stimulating factor. AB - We present the first case report of the use of sorafenib and S-1 for the treatment of renal cell carcinoma (RCC) producing granulocyte colony-stimulating factor (G-CSF). This entity is clinically rare and has a poor outcome. A 78-year old Japanese man presented with macrohematuria, left flank pain, and a palpable mass. Laboratory data showed marked leukocytosis with increased serum and urinary G-CSF. The histopathological diagnosis was unclassified RCC. New combination therapy with sorafenib and S-1 exerted a therapeutic effect and apparently decreased serum and urinary G-CSF levels, although the patient died of gastrointestinal perforation. The use of combined sorafenib and S-1 may be worthy of consideration in the treatment of RCC producing G-CSF. PMID- 20845055 TI - Measures of autonomic nervous system activity and lower urinary tract symptoms. AB - Autonomic nervous system (ANS) activity may play an important role in the development of lower urinary tract symptoms (LUTS). Men with severe LUTS and men with mild or no LUTS completed the Valsalva maneuver, quantitative sudomotor axon reflex test, tilt-table, and deep breathing tests. There were no differences between men with severe LUTS compared to men with mild or no LUTS (all P values > 0.05). Systemic ANS tests may not be useful in detecting the underlying physiologic changes that lead to LUTS in aging men. PMID- 20845056 TI - Transient orthostatic hypertension after partial cerebellar resection. AB - An effective baroreflex and autonomic pathways normally ensure that blood pressure (BP) is satisfactorily maintained, despite various stimuli in daily life that include postural changes. We describe a 20-year-old man with a cerebellar hematoma and acute hydrocephalus, who had a vermian and partial right cerebellar hemisphere resection followed by orthostatic hypertension (OHT) and mutism. On standing his systolic BP rose over 60 mmHg with a fivefold increase in plasma noradrenaline. After a period of 8 weeks, postural BP regulation improved along with his ability to communicate. We conclude that transient impairment of cerebellar autonomic modulation or dysfunction of the baroreflex medullary circuit, may have resulted in OHT. PMID- 20845057 TI - Holmes-Adie syndrome associated with high altitude pulmonary edema and low chemo responsiveness to hypoxia. AB - A 63-year-old patient with Holmes-Adie syndrome presented an altered peripheral chemoreflex and suffered from high altitude pulmonary edema, suggesting an alteration of sensitive afferent fibers from the peripheral chemoreceptors. Chemo responsiveness to hypoxia should be explored before any exposure to moderate altitude in Holmes-Adie patients. PMID- 20845058 TI - Gingival crevicular fluid IL-6, tPA, PAI-2, albumin levels following initial periodontal treatment in chronic periodontitis patients with or without type 2 diabetes. AB - OBJECTIVES: To evaluate initial periodontal treatment effects on gingival crevicular fluid (GCF) interleukin-6 (IL-6), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-2 (PAI-2), albumin levels in type 2 diabetic patients. DESIGN AND METHODS: GCF samples were collected from 20 type 2 diabetic, 22 non-diabetic non-smokers all with chronic periodontitis at baseline, 1-, 3-months following initial periodontal treatment. Biochemical analysis was performed by ELISA. Data were tested by Mann-Whitney U, Wilcoxon tests. RESULTS: The total amounts of albumin, IL-6, tPA, PAI-2 decreased significantly in diabetics after treatment (1- and 3-months) whereas, only PAI-2 decreased in non diabetic group at 3-months (p < 0.05). There were statistically significant differences between the diabetics and non-diabetics at all time points for albumin, PAI-2 and at 1-, 3-months for GCF volume (p < 0.050) but only at baseline for IL-6 (p < 0.050). CONCLUSION: Present data suggest clinical improvements are less apparent in diabetic chronic periodontitis patients as reflected by disease markers in GCF and by an increase in concentrations of inflammatory proteins IL-6, tPA, and PAI-2 in GCF of this patient group following initial periodontal treatment. PMID- 20845060 TI - Downregulation of uPARAP mediates cytoskeletal rearrangements and decreases invasion and migration properties in glioma cells. AB - To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA (cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen. In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills other functions in addition to collagenolysis. Quantitative PCR analysis using a cDNA panel revealed higher expression levels of uPARAP in glioma tissue compared with normal brain tissue. Western blot analysis revealed that the uPARAP protein was expressed in glioma samples and two glioma cell lines, KNS42 and KNS81, but not expressed in control tissue from the normal brain. Introduction of small interfering RNA-targeted uPARAP into the two different glioma cell lines, KNS42 and KNS81, resulted in downregulation of uPARAP expression, and it significantly suppressed glioma cell migration and invasion in vitro. Control glioma cells showed small cell bodies, whereas uPARAP siRNA-treated glioma cells exhibited large and flat morphology. Most of the polymeric actin in the control glioma cells was concentrated in the lamellipodia that are observed in mobile cells. In contrast, in the uPARAP siRNA-treated glioma cells, polymeric actin became organized in stress fibers and the lamellipodia disappeared, characteristic of immobile cells. Our present study suggests that uPARAP may be involved in glioma cell invasiveness through actin cytoskeletal rearrangement. downregulation of uPARAP may be a novel anti-invasion therapeutic strategy for malignant gliomas. PMID- 20845059 TI - Inflammation as death or life signal in diabetic fracture healing. AB - Increased apoptosis of chondrocytes and osteoblasts and prolonged survival of osteoclasts lead to early destruction of callus tissue and impair bone remodeling in fracture healing of diabetic patients. Diabetes is accompanied by an increased inflammatory state, reactive oxygen species (ROS) generation and accumulation of advanced glycation end products (AGEs), a heterogenous group of toxic metabolites that can induce inflammation. Prolonged hyperglycemia and insulin resistance correlate with increased apoptosis rate and, accordingly, the proapoptotic role of several inflammatory mediators, ROS and AGEs has been also documented. In this review we summarize the most recent reports supporting the idea that inflammatory signaling increases chondrocyte and osteoblast death and prolongs osteoclast survival, resulting in impaired bone regeneration in diabetes. Antagonising inflammatory signal pathways and solution of inflammation may deserve greater attention in the management of diabetic fracture healing. PMID- 20845061 TI - Efficacy and safety of intratumoral thermotherapy using magnetic iron-oxide nanoparticles combined with external beam radiotherapy on patients with recurrent glioblastoma multiforme. AB - Therapy options at the time of recurrence of glioblastoma multiforme are often limited. We investigated whether treatment with a new intratumoral thermotherapy procedure using magnetic nanoparticles improves survival outcome. In a single-arm study in two centers, 66 patients (59 with recurrent glioblastoma) received neuronavigationally controlled intratumoral instillation of an aqueous dispersion of iron-oxide (magnetite) nanoparticles and subsequent heating of the particles in an alternating magnetic field. Treatment was combined with fractionated stereotactic radiotherapy. A median dose of 30 Gy using a fractionation of 5 * 2 Gy/week was applied. The primary study endpoint was overall survival following diagnosis of first tumor recurrence (OS-2), while the secondary endpoint was overall survival after primary tumor diagnosis (OS-1). Survival times were calculated using the Kaplan-Meier method. Analyses were by intention to treat. The median overall survival from diagnosis of the first tumor recurrence among the 59 patients with recurrent glioblastoma was 13.4 months (95% CI: 10.6-16.2 months). Median OS-1 was 23.2 months while the median time interval between primary diagnosis and first tumor recurrence was 8.0 months. Only tumor volume at study entry was significantly correlated with ensuing survival (P < 0.01). No other variables predicting longer survival could be determined. The side effects of the new therapeutic approach were moderate, and no serious complications were observed. Thermotherapy using magnetic nanoparticles in conjunction with a reduced radiation dose is safe and effective and leads to longer OS-2 compared to conventional therapies in the treatment of recurrent glioblastoma. PMID- 20845062 TI - Primary central nervous system extranodal NK/T-cell lymphoma, nasal type: case report and review of the literature. AB - Primary central nervous system (CNS) extranodal NK/T-cell lymphoma, nasal type (NKTCL), is an extremely rare tumor. To the best of our knowledge, only four cases have been described previously. Here, we report a case of primary CNS NKTCL in a 25-year-old immunocompetent Chinese male. The patient presented with worsening dizziness, headaches, and vomiting for approximately 2 weeks. Magnetic resonance imaging demonstrated three masses with solid components entirely in the parenchyma of the right hemisphere, and no sinonasal/nasopharyngeal lesions were found. The patient underwent a partial resection of the right temporal mass. Histological examination revealed that intermediate-sized, pleomorphic lymphocytes were arranged in an angiocentric distribution with large geographic necroses. The tumor cells expressed CD3epsilon, CD56, TIA-1, granzyme B, and Epstein-Barr virus-encoded RNAs. A rearrangement study showed T-cell receptor gamma-chain gene rearrangement with monoclonal appearance. Postoperative chemotherapy and radiotherapy were also given, but the lymphoma failed to respond to therapy and the patient died 18 months later. Our observation and the four others found in the literature indicate that primary CNS NKTCL occurs predominantly in adult males. This is the youngest patient with primary CNS NKTCL reported. PMID- 20845063 TI - Occupational and behavioural factors in the explanation of social inequalities in premature and total mortality: a 12.5-year follow-up in the Lorhandicap study. AB - The respective contribution of occupational and behavioural factors to social disparities in all-cause mortality has been studied very seldom. The objective of this study was to evaluate the role of occupational and behavioural factors in explaining social inequalities in premature and total mortality in the French working population. The study population consisted of a sample of 2,189 and 1,929 French working men and women, who responded to a self-administered questionnaire in mid-1996, and were followed up until the end of 2008. Mortality was derived from register-based information and linked to the baseline data. Socioeconomic status was measured using occupation. Occupational factors included biomechanical and physical exposures, temporary contract, psychological demands, and social support, and behavioural factors, smoking, alcohol abuse, and body mass index. Significant social differences were observed for premature and total mortality. Occupational factors reduced the hazard ratios of mortality for manual workers compared to managers/professionals by 72 and 41%, from 1.88 (95% CI: 1.17-3.01) to 1.25 (95% CI: 0.74-2.12) for premature mortality, and from 1.71 (95% CI: 1.18 2.47) to 1.42 (95% CI: 0.95-2.13) for total mortality. The biggest contributions were found for biomechanical and physical exposures, and job insecurity. The role of behavioural factors was very low. Occupational factors played a substantial role in explaining social disparities in mortality, especially for premature mortality and men. Improving working conditions amongst the lowest social groups may help to reduce social inequalities in mortality. PMID- 20845064 TI - Multifunctional polymeric carriers for gene and drug delivery. PMID- 20845065 TI - HPMA copolymer-aminohexylgeldanamycin conjugates targeting cell surface expressed GRP78 in prostate cancer. AB - PURPOSE: This study focused on the synthesis and in vitro characterization of N (2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates for the delivery of geldanamycin to prostate cancer tumors. Conjugates were modified to incorporate WIFPWIQL peptide, which binds to cell-surface-expressed Glucose-regulated protein 78. METHODS: HPMA copolymers containing aminohexylgeldanamycin with and without WIFPWIQL peptide were synthesized and characterized, and stability in pH 7.4 and pH 5.0 buffers, complete cell culture medium, and fetal bovine serum was evaluated. The comparative cell surface expression of GRP78 in DU145 and PC3 cell lines was assessed and competitive binding to cell surface expressed GRP78 evaluated. The ability of the conjugates to inhibit cell growth was also evaluated in vitro. RESULTS: HPMA copolymer-aminohexylgeldanamycin conjugates were stable with maximal release observed in fetal bovine serum at 37 degrees C of approximately 10% in 72 h. HPMA copolymers bearing WIFPWIQL peptide bound to cell surface expressed GRP78 with affinities comparable to free WIFPWIQL peptide and demonstrated increased cytotoxicity as compared to untargeted conjugates. CONCLUSION: HPMA copolymer aminohexylgeldanamycin conjugates bearing WIFPWIQL peptide have the ability to bind to cell-surface-expressed GRP78 and inhibit the growth of human prostate cancer cells, suggesting that the conjugates have the potential to target solid prostate cancer tumors. PMID- 20845066 TI - Nanomedicine for cancer therapy. PMID- 20845067 TI - PEG-functionalized magnetic nanoparticles for drug delivery and magnetic resonance imaging applications. AB - PURPOSE: Polyethylene glycol (PEG) functionalized magnetic nanoparticles (MNPs) were tested as a drug carrier system, as a magnetic resonance imaging (MRI) agent, and for their ability to conjugate to an antibody. METHODS: An iron oxide core coated with oleic acid (OA) and then with OA-PEG forms a water-dispersible MNP formulation. Hydrophobic doxorubicin partitions into the OA layer for sustained drug delivery. The T(1) and T(2) MRI contrast properties were determined in vitro and the circulation of the MNPs was measured in mouse carotid arteries. An N-hydroxysuccinimide group (NHS) on the OA-PEG-80 was used to conjugate the amine functional group on antibodies for active targeting in the human MCF-7 breast cancer cell line. RESULTS: The optimized formulation had a mean hydrodynamic diameter of 184 nm with an ~8 nm iron-oxide core. The MNPs enhance the T(2) MRI contrast and have a long circulation time in vivo with 30% relative concentration 50 min post-injection. Doxorubicin-loaded MNPs showed sustained drug release and dose-dependent antiproliferative effects in vitro; the drug effect was enhanced with transferrin antibody-conjugated MNPs. CONCLUSION: PEG-functionalized MNPs could be developed as a targeted drug delivery system and MRI contrast agent. PMID- 20845068 TI - Purification of BmR1 recombinant protein. AB - This paper describes a refinement in the purification step that facilitated the downstream recovery of high purity BmR1 recombinant protein, which is a protein used as a test reagent in the commercialized rapid tests for detection of lymphac filariasis i.e. Brugia RapidTM and panLF rapidTM. Purification was performed by immobilized metal affinity chromatography (IMAC), followed by ion exchange chromatography (IEX). Results showed that a total of 10.27 mg of BmR1 was obtained when IMAC was performed using 20 mM of imidazole and 5 column volume of wash buffer containing 500 mM of NaCl. Purity of the target protein was enhanced when buffer at pH 5.8 was used during the IEX. Two proteins that recurrently appeared below the BmR1 recombinant protein were identified by mass-spectrometry analysis as the same protein, thus they were probably degradation products of BmR1. These strategies improve purity of the target protein to be used in applications such as production of aptamers and monoclonal antibodies. PMID- 20845069 TI - Synergistic effect of tumor necrosis factor-alpha and hydrogen peroxide on the induction of IL-8 production in human intestinal Caco-2 cells. AB - Oxidative stress and inflammatory cytokines such as TNF-alpha are thought to be involved in mucosal inflammation. The intestinal epithelium may be concurrently stimulated by both oxidative stress and inflammatory cytokines during the inflammation process in the intestines. However, experimental models for intestinal inflammation still employ single stimulation, either by an oxidative stress or inflammatory cytokine. We therefore examined an in vitro inflammation study using human intestinal epithelial Caco-2 cells, in which the cells were stimulated both by hydrogen peroxide and TNF-alpha, and measured the IL-8 production as an index of inflammation. The IL-8 production (secretion, mRNA expression, and transcriptional activity) induced by both TNF-alpha and H(2)O(2) was significantly higher than that by single stimulation. The synergistic effect of TNF-alpha and H(2)O(2) on the NF-kappaB signaling pathway (transcriptional activity and p65 nuclear translocation) was also observed. Oxidative stress and TNF-alpha may cooperatively enhance IL-8 production via NF-kappaB in Caco-2 cells. PMID- 20845070 TI - Utility of NucleoCounter for the chondrocyte count in the collagenase digest of human native cartilage. AB - In cartilage tissue engineering, viable cell numbers should be correctly counted in the collagenase digest of the biopsied cartilage. However, this is a difficult task due to the presence of matrix debris, cell ghosts and their aggregates. To search for the correct cell counting method in this situation, we evaluated the utility of an automatic cell counting device, the NucleoCounter, and compared it with conventional staining using the LIVE/DEAD(r) kit. We first measured the cell numbers of a standard chondrocyte sample by the NucleoCounter, which showed a high accuracy (R(2) = 0.9999) and reproducibility (%CV: 2.00-8.66). We then calculated the cell numbers and viability in some collagenase digests of native cartilage using either the NucleoCounter or LIVE/DEAD(r) kit, revealing that the total cell numbers, viable ones and viability were highly correlated between them (R(2) = 0.9601, 0.9638 and 0.917, respectively). However, both the intrapersonal and interpersonal variabilities in the NucleoCounter was significantly decreased to about 1/20-1/5, compared to that of the LIVE/DEAD(r) kit. The NucleoCounter was regarded as a useful tool for simple, rapid, and highly reproducible cell counts, which may not only provide constant experimental data in a certain laboratory, but also contribute to the high reproducibility of the clinical results of cartilage tissue engineering among multiple institutions. PMID- 20845071 TI - Femoral head bone mineral density patterns may identify hips at risk of degeneration. AB - Developmental dysplasia of the hip (DDH) is a common abnormality that causes elevated contact stress and early onset osteoarthritis (OA). We hypothesized that adaptation of femoral head bone mineral density (BMD) patterns to focal loading during postnatal development could be used to identify hips at risk of degeneration. Evolving BMD patterns of the femoral head secondary center of ossification (SCO) were quantified and tested for differences with hip subluxation and degeneration. BMD was measured using quantitative computed tomography of hips in a canine model of DDH from 4 weeks to early skeletal maturity at 32 weeks. During body weight and SCO volumetric growth deceleration, SCO mean BMD increased rapidly and local regions of high BMD formed. Greater subluxation was associated with a lower mean BMD up to 14 weeks. At 32 weeks, greater subluxation was associated with a larger area of high BMD that was more laterally located and had a greater maximum BMD. BMD differences were associated with a higher probability of cartilage degeneration. Measurement and visualization of BMD pattern changes due to altered mechanical loading provide a basis for identifying hips at risk of early onset OA and a tool for surgical planning of contact stress reduction procedures. PMID- 20845072 TI - Arthritis patterns in familial Mediterranean fever patients and association with M694V mutation. AB - Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of febrile peritonitis, pleuritis and synovitis. Arthritis is a common and important feature of FMF. The clinical spectrum of arthritis in 71 FMF patients was retrospectively investigated. Mutations in the familial Mediterranean (MEFV) gene were screened. Unlike the previous reports on arthritis of FMF, most of the FMF patients (59%) in this study had symmetric two-joint arthritis whereas monoarticular, oligoarticular and polyarticular arthritis was presented in 20, 8 and 10% of the patients, respectively. Knees were affected in 45 (63%) patients, ankles in 30 (42%), elbows in 11 (15%), wrists in 12 (17%), hips in 12 (17%), small joints of the hands 7 (10%), small joints of the feet 2 (3%) and sacroiliac in 1 (1%). Destruction of the hip was observed in 2 (3%) patients and required hip replacement. Amyloidosis developed in 2 (3%) of our patients. Mutations in the MEFV gene were identified in 50 (71%) patients and the most dominant mutation detected was M694V (64%). Since FMF can be diagnosed by a simple DNA mutation analysis, all arthritis patients of certain origins (Arabs, Turks, Armenians and Jews) should be tested for FMF in order to prevent the complications (amyloidosis and protracted arthritis) by introducing colchicine which is the treatment of choice for FMF. PMID- 20845073 TI - Effect of dietary betaine supplementation on lipogenesis gene expression and CpG methylation of lipoprotein lipase gene in broilers. AB - Experiments were conducted to investigate the effect of betaine supplementation on mRNA expression levels of lipogenesis genes and CpG methylation of lipoprotein lipase gene (LPL) in broilers. From 22 days of age, 78 broilers were feed basal diet without betaine and basal diet supplemented with 0.1% betaine, respectively, and at 56 and 66 days of age, the traits of 15 chickens (7 males and 8 females) of each group were recorded and abdominal fat pads were collected. The mRNA expression levels of several lipogenesis gene were analyzed by semi-quantitative RT-PCR and real-time quantitative RT-PCR (qPCR), respectively. The CpG methylation profile at the promoter region of LPL gene in 66-day-old broilers was determined by bisulfite sequencing. The average daily gain and percent abdominal fat traits were slightly improved in 56-day-old and 66-day-old broilers after dietary supplementation of betaine to diet. After adding 0.1% betaine to diet, the mRNA levels of fatty acid synthase (FAS) and adipocyte-type fatty acid binding protein genes in abdominal adipose were significantly decreased in 56-day old broilers, and those of LPL and FAS genes in abdominal adipose were significantly decreased in 66-day-old broilers comparing with the control group (P < 0.05 and P < 0.001). Moreover, in 66-day-old broilers fed 0.1% betaine diet, a different CpG methylation pattern was observed: the CpG dinucleotides of 1st, 6th, 7th, 8th and from 10th to 50th were less methylated; however, those of 2nd, 5th and 9th were more heavily methylated. The results suggest that transcription of some lipogenesis genes was decreased by betaine supplementation and betaine may decrease LPL mRNA expression by altering CpG methylation pattern on LPL promoter region. PMID- 20845074 TI - Effect of penehyclidine hydrochloride on expressions of MAPK in mice with CLP induced acute lung injury. AB - Penehyclidine hydrochloride (PHC) is a new anticholinergic drug. PHC has been shown to have a good curative effect for sepsis. Mitogen-activated protein kinase (MAPK) has recently been considered to play an important role in sepsis. In this study, the role of MAPK signal pathways in protective effects of PHC preconditioning on acute lung injury in cecal ligation and puncture (CLP)-induced sepsis was investigated. Healthy female mice were randomly divided into 4 groups: sham control, CLP, and 0.3 or 0.45 mg/kg PHC. At 12 h after surgery, arterial blood was drawn for blood gas analysis, and lung tissue samples were collected to examine pulmonary microvascular permeability, IL-6 levels and myeloperoxidase (MPO) activity. MAPK protein expressions were measured using western blot technique. Compared with sham control mice, acute lung injury was induced in CLP group, which was indicated by decreased PaO(2)/FiO(2), increased pulmonary microvascular permeability, IL-6 levels and MPO activity. Furthermore, mice' exposure to CLP induced the increased protein levels of MAPK. Treatment of 0.45 mg/kg PHC markedly improved PaO(2)/FiO(2), decreased pulmonary microvascular permeability, IL-6 levels and MPO activity, and inhibited expressions of extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. Taken together, these results suggest that PHC ameliorated acute lung injury through the inhibition of extracellular signal-regulated kinase (ERK1/2) and p38 MAPK activation in septic mice. PMID- 20845075 TI - The characterization of transaldolase gene tal from Pichia stipitis and its heterologous expression in Fusarium oxysporum. AB - The 972 bp length of transaldolase gene tal was cloned from Pichia stipitis CICC1960, encoding a 323 amino acid protein with a calculated molecular mass of 35.36 kDa and isoelectric point of 5.20. Real time PCR analysis demonstrated that the mRNA transcript level of constitutive tal gene rise on xylose, glucose, fructose, mannose, galactose and sucrose as carbon source, respectively. Furthermore, the transcription of tal gene in P. stipitis on xylose was higher than on other carbon source, indicating that transaldolase plays a part in xylose utilization. To deeply study the tal gene biological function, it was expressed in Fusarium oxysporum CCTCC M209040. Recombinant transaldolase activity of transformant F. oxysporum M209040-Tal2 was about 0.52 U mg(-1) protein and was 1.57 times higher than that of the wild type F. oxysporum CCTCC M209040, indicating that the improvement of transaldolase activity in transformant was due to expression of the exogenous tal gene. Growth of transformant F. oxysporum M209040-Tal2 without selection pressure did not affect the level of hygromycin resistance of the transformants, suggesting that integrated tal gene was stable in mitosis. Fermentation trials of F. oxysporum M209040-Tal2 showed that the ethanol yield improved by 8.39 and 11.71% on glucose and xylose substrates, respectively, demonstrating that the expression of tal gene from P. stipitis CICC1960 in F. oxysporum CCTCC M209040 could improve ethanol production. PMID- 20845076 TI - DD genotype of ace gene I/D polymorphism is associated in a Turkish study population with osteoarthritis. AB - This study was conducted in Turkish osteoarthritis patients to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene, and to examine the role of this polymorphism in osteoarthritis development. Genomic DNA obtained from 200 persons (135 patients with osteoarthritis and 65 healthy controls) was used in the study. DNA was multiplied by polymerase chain reaction using I and D allele-specific primers. Polymerase chain reaction products were assessed with CCD camera by being exposed to 2% agarose gel electrophoresis. There was statistically significant difference between the groups with respect to genotype distribution (P < 0.001). The D allele frequency was indicated as 69% and I allele was as 31% in the patients, whereas it was 55 45% in the control group. Consequently, in this study, we may assert that ACE gene I/D polymorphism DD genotype determination is significant criteria for identifying patients who are likely to develop osteoarthritis in east population of Turkey. PMID- 20845077 TI - Cytochrome P450 2C19 polymorphism is associated with poor clinical outcomes in coronary artery disease patients treated with clopidogrel. AB - Patients with lesser degrees of platelet inhibition in response to clopidogrel appear to be at increased risk for recurrent ischemic events. Cytochrome P450 (CYP) polymorphisms have been proposed as possible mechanisms for nonresponsiveness to clopidogrel. Published data on the association between CYP2C19*2 polymorphism and atherothrombotic events are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of eight prospective cohort studies including 2,345 patients carrying CYP2C19*2 variant allele and 5,935 cases with the wild-type genotype were included in this meta-analysis. Overall, borderline statistically significantly elevated risk of adverse clinical events was associated with genotyping 681G>A polymorphism (for AA + GA vs. GG: OR, 1.46; 95% CI, 1.01 to 2.13; P = 0.05). The summary odds ratio showed a significant association between the CYP2C19*2 polymorphism and an increased risk of cardiac mortality in the follow-up period (OR, 2.07; 95% CI, 1.22 to 3.52; P = 0.007). When studies evaluating myocardial infarction, stent thrombosis, and ischemic stroke, the presence of the variant allele was associated with significantly increased risks of recurrent atherothrombotic events. In summary, this meta-analysis indicated that CYP2C19*2 carrier status is significantly associated with an increased risk of adverse cardiovascular events. PMID- 20845078 TI - Expression and identification of a thermostable malate dehydrogenase from multicellular prokaryote Streptomyces avermitilis MA-4680. AB - A malate dehydrogenase (MDH) from Streptomyces avermitilis MA-4680 (SaMDH) has been expressed and purified as a fusion protein. The molecular mass of SaMDH is about 35 kDa determined by SDS-PAGE. The recombinant SaMDH has a maximum activity at pH 8.0. The enzyme shows the optimal temperature around 42 degrees C and displays a half-life (t(1/2)) of 160 min at 50 degrees C which is more thermostable than reported MDHs from most bacteria and fungi. The k(cat) value of SaMDH is about 240-fold of that for malate oxidation. In addition, the k(cat)/K(m) ratio shows that SaMDH has about 1,246-fold preference for oxaloacetate (OAA) reduction over L-malate oxidation. The recombinant SaMDH may also use NADPH as a cofactor although it is a highly NAD(H)-specific enzyme. There was no activity detected when malate and NADP(+) were used as substrates. Substrate inhibition studies show that SaMDH activity is strongly inhibited by excess OAA with NADH, but is not sensitive to excess L-malate. Enzymatic activity is enhanced by the addition of Na(+), NH(4)(+), Ca(2+), Cu(2+) and Mg(2+) and inhibited by addition of Hg(2+) and Zn(2+). MDH is widely used in coenzyme regeneration, antigen immunoassays and bioreactors. The enzymatic analysis could provide the important basic knowledge for its utilizations. PMID- 20845079 TI - Is a single nucleotide polymorphism a risk factor for lung cancer in the matrix metalloproteinase-2 promoter? AB - We aimed to investigate the association of polymorphism frequencies of MMP-2 C1306T and MMP-2 plasma enzyme activity in lung cancer patients. In this study 300 genomic DNA (200 lung cancer patients + 100 no lung cancer) were analyzed. Polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism (RFLP) and electrophoresis. Plasma MMP-2 enzyme activity levels were measured by using ELISA. Sex, asbestos expose and smoking might be risk factors for lung cancer. The frequencies of C1306T genotypes in controls CC 65%, CT 32%, TT 3% and in patients CC 61%, CT 37%, TT2 % were found. It was determined that CC genotype frequency increase significantly in patients and controls. Plasma MMP-2 enzyme activity levels were increased in lung cancer patients according to controls. Finally, we claimed that determining of MMP-2 enzyme level can be used as a marker in lung cancer. PMID- 20845080 TI - Association of pre-microRNAs genetic variants with susceptibility in systemic lupus erythematosus. AB - MicroRNAs (miRNAs) may play important roles in SLE, but genetic polymorphisms of miRNAs and their relationships with various autoantibodies present in SLE patients remain unclear. Here, we report that 213 SLE patients and 209 healthy individuals of Chinese had been taken into this case-control studies, which had been performed by selecting two miRNAs (hsa-mir-146a rs2910164 G>C, and hsa-mir 499 rs3746444 T>C) to analyze the genetic polymorphisms. The single nucleotide polymorphism (SNP) variants had been analyzed by PCR-RFLP and serum anti ribonucleoprotein (anti-RNP), anti-Sm nuclear antigen (anti-Sm) antibodies had been determined by an anti-ENA kit and serum anti-double-stranded DNA (anti dsDNA) antibodies had been assessed by indirect immunofluorescence. We found that hsa-mir-146a rs2910164 and hsa-mir-499 rs3746444 polymorphisms had no significant relationship with SLE susceptibility. The genotype frequencies of rs2910164 (GG, CC, and GC) were 16, 37, and 47% in SLE patients, but 11, 39, and 50% in healthy group (P = 0.397), respectively; The genotype frequencies of rs3746444 (CC, TT, and TC) were 3, 74, and 23% in SLE patients, but 3, 76, and 22% in healthy group (P = 0.892), respectively. The G and C allele frequencies of rs2910164 were 39 and 61% in SLE patients, but 36 and 64% in healthy group (P = 0.990), respectively. The C and T allele frequencies of rs3746444 were 15 and 85% in SLE patients, but 14 and 86% in healthy group (P = 0.702), respectively. In addition, we also showed no significant difference in the distribution of rs2910164 and rs3746444 genotypes in each of the three antibodies (anti-RNP, anti-Sm, and anti dsDNA). PMID- 20845081 TI - The effects of TGF-beta1 on the expression of type IV collagenases in mouse peritoneal macrophages. AB - Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine that plays a critical role in modulating immune response and inflammation. We have investigated the effects of TGF-beta1 on the expression of type IV collagenases, matrix metalloproteinase (MMP)-2 and MMP-9, in mouse peritoneal macrophages. TGF beta1 alone enhanced the secretion of MMP-9, while it blocked lipopolysaccharide (LPS)-stimulated MMP-9 production. We have shown that this biphasic effect of TGF beta1 is exerted at the mRNA level of the MMP-9 gene. Although TGF-beta1 increased both basal and LPS-induced MMP-2 production at the protein and mRNA levels, the extent of the increase was smaller in LPS-activated macrophages than in control macrophages. The expression of type I and type II receptors for TGF beta was significantly decreased upon activation, suggesting that the lesser effect of TGF-beta1 in activated macrophages may result from the decreased expression of TGF-beta receptors. In addition, the expression of endogenous TGF beta1 mRNA was decreased significantly in activated macrophages. These findings suggest that activated macrophages not only produce less TGF-beta1, but also respond less well to TGF-beta to provide for inflammatory response. PMID- 20845083 TI - Age relationships of postmortem observations in Portuguese Water Dogs. AB - A dog model has been used to evaluate histological changes arising from senescence. Autopsies of 145 Portuguese Water Dogs have been used to evaluate the individual and group "state of health" at time of death. For each dog, weights or dimensions of organs or tissues were obtained, together with histological evaluation of tissues. Twenty-three morphological metrics correlated significantly to age at death. Many of these involved muscles; others were associated with derivatives of embryonic foregut. The latter included lengths of the small intestine and trachea as well as weights of the stomach and some lung lobes. Nearly all of the dogs examined had histological changes in multiple tissues, ranging from two to 12 per dog. Associations among pathologies included inflammatory bowel disease with osteoporosis and dental calculus/periodontitis with atherosclerosis and amyloidosis. In addition, two clusters of histological changes were correlated to aging: hyperplasia, frequency of adenomas, and hemosiderosis constituted one group; inflammation, plasmacytic and lymphocytic infiltration, fibrosis, and atrophy, another. Heritability analysis indicated that many of the changes in tissue/organ morphology or histology could be heritable and possibly associated with IGF1, but more autopsies will be required to substantiate these genetic relationships. PMID- 20845084 TI - Aortic valve prosthesis tracking for transapical aortic valve implantation. AB - PURPOSE: Transapical aortic valve implantation (TA-AVI) is a new minimally invasive surgical treatment of aortic stenosis for high-risk patients. The placement of aortic valve prosthesis (AVP) is performed under 2D X-ray fluoroscopic guidance. Difficult clinical complications can arise if the implanted valve is misplaced. Therefore, we present a method to track the AVP in 2D X-ray fluoroscopic images in order to improve the accuracy of the TA-AVI. METHODS: The proposed tracking method includes the template matching approach to estimate the position of AVP and a shape model of the prosthesis to extract the corner points of the AVP in each image of sequence. To start the AVP tracking procedure, an initialization step is performed by manually defining the corner points of the prosthesis in the first image of sequence to provide the required algorithm parameters such as the AVP model parameters. RESULTS: We evaluated the AVP tracking method on six 2D intra-operative fluoroscopic image sequences. The results of automatic AVP localization agree well with manually defined AVP positions. The maximum localization errors of tracked prosthesis are less than 1 mm and within the clinical accepted range. CONCLUSIONS: For assisting the TA-AVI, a method for tracking the AVP in 2D X-ray fluoroscopic image sequences has been developed. Our AVP tracking method is a first step toward automatic optimal placement of the AVP during the TA-AVI. PMID- 20845085 TI - Kinetics of tissue iron in experimental autoimmune encephalomyelitis in rats. AB - To elucidate the role of iron in the pathomechanisms of autoimmune CNS disorders, we estimated the tissue concentrations of Fe(2+) in the brain, spinal cord, and liver in the chronic relapsing form of experimental autoimmune encephalomyelitis (EAE). The disease was induced in Dark Agouti (DA) strain of rats, by subcutaneous injection of bovine brain homogenate in complete Freund's adjuvant (CFA). Control rats consisted of unsensitized rats and of rats treated with CFA or saline. The data obtained by clinical assessment and by inductively coupled plasma spectrometry have shown that the attacks of disease (on the 12th and 22nd post-immunization day) were followed by high accumulation of iron in the liver. Additionally, during the second attack of disease, the decreased concentration of Fe(2+) was found in cervical spinal cord. The data point to regulatory effects of iron and hepatic trace elements regulating mechanisms in the pathogenesis of EAE. PMID- 20845082 TI - Neurobiology of the aging dog. AB - Aged canines naturally accumulate several types of neuropathology that may have links to cognitive decline. On a gross level, significant cortical atrophy occurs with age along with an increase in ventricular volume based on magnetic resonance imaging studies. Microscopically, there is evidence of select neuron loss and reduced neurogenesis in the hippocampus of aged dogs, an area critical for intact learning and memory. The cause of neuronal loss and dysfunction may be related to the progressive accumulation of toxic proteins, oxidative damage, cerebrovascular pathology, and changes in gene expression. For example, aged dogs naturally accumulate human-type beta-amyloid peptide, a protein critically involved with the development of Alzheimer's disease in humans. Further, oxidative damage to proteins, DNA/RNA and lipids occurs with age in dogs. Although less well explored in the aged canine brain, neuron loss, and cerebrovascular pathology observed with age are similar to human brain aging and may also be linked to cognitive decline. Interestingly, the prefrontal cortex appears to be particularly vulnerable early in the aging process in dogs and this may be reflected in dysfunction in specific cognitive domains with age. PMID- 20845086 TI - Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation. AB - Autism is a neurodevelopmental disorder of childhood with poorly understood etiology and pathology. This pilot study aims to evaluate the levels of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH Px), and levels of malondialdehyde (MDA), a marker of lipid peroxidation, in Egyptian autistic children. Autism is a neurodevelopmental disorder of childhood with poorly understood etiology and pathology. The present study included 20 children with autism diagnosed by DSM-IV-TR criteria and Childhood Autism Rating Scale. Controls included 25 age-matched healthy children. Cases were referred to Outpatient Clinic of Children with Special Needs Department, National Research Center, Cairo, Egypt. We compared levels of SOD, GSH-Px, and MDA in children with autism and controls. In children less than 6 years of age, levels of SOD, and GSH Px were significantly lower in autistic children compared with their controls, while MDA was significantly higher among patients than controls. In children older than 6 years, there was no significant difference in any of these values between cases and controls. We concluded that children with autism are more vulnerable to oxidative stress in the form of increased lipid peroxidation and deficient antioxidant defense mechanism especially at younger children. We highlight that autistic children might benefit from antioxidants supplementation coupled with polyunsaturated fatty acids. Moreover, early assessment of antioxidant status would have better prognosis as it may decrease the oxidative stress before inducing more irreversible brain damage. PMID- 20845087 TI - Anti-tumor necrosis factor-alpha therapy and changes of flow-mediated vasodilatation in psoriatic and rheumatoid arthritis patients. AB - For a long time, the endothelial covering of the vessels has been considered an inert surface. On the contrary, the endothelial cells are active and dynamic elements in the interaction between blood and tissues. The control of the vessel basal tone is obtained by the complex balance between the relaxing and contracting endothelial factors. Previous clinical studies show that patients suffering from rheumatoid arthritis and other autoimmune rheumatologic pathologies are at high risk of death being prematurely affected by atherosclerosis and cardiovascular diseases. Blocking tumor necrosis factor (TNF) alpha by biological drugs improves the endothelial function. The aim of our study was to evaluate the effects of two anti-TNF-alpha drugs (infliximab and etanercept) on the endothelial function by evaluating the flow-mediated dilatation (FMD), which was measured in the brachial artery before and after treatment and after 8-12 weeks. We enrolled 36 patients (average age 52 +/- 9.8 years, 12 men and 24 women), 25 of them were affected by rheumatoid arthritis (RA) and 11 were affected by psoriatic arthritis (PsA) and they were divided into three groups: 10 patients were treated with etanercept, 13 patients were treated with infliximab, 13 patients were treated with DMARDs. We measured the common carotid intimal-medial thickness (ccIMT) and the endothelial function was evaluated by FMD measurement in the brachial artery, before treatment, 1 h after the beginning of treatment and after 8-12 weeks. No statistically significant difference between the three groups was found for the ultrasonographic evaluation of the carotid IMT. On the contrary, the differences between FMD values before and after the treatment in the patients treated with etanercept (13.1 +/- 0.01 vs. 18.8 +/- 0.01%, p < 0.01) and in the patients treated with infliximab (11.8 +/- 0.09 vs. 16.7 +/- 0.09%, p < 0.01) were statistically significant. Long-term evaluation for infliximab and etanercept was performed by comparing the FMD values, respectively, 8 and 12 weeks after the first treatment. After 8 weeks, FMD value was similar to the value recorded at enrollment in the infliximab group (11.9 +/- 0.03 vs. 13.54 +/- 0.04%, p = 0.236) and the FMD values in the etanercept group after 12 weeks showed a not statistically significant reduction of vasodilatating effect (13.01 +/- 0.03 vs. 15.67 +/- 0.02%, p = 0.197). In conclusion, the use of biological drugs in patients affected by autoimmune arthritis can modify the endothelial function, as indicated by the induced FMD changes, but the long-term effect tends to be considerably reduced. PMID- 20845088 TI - Strategies in stable ischemic heart disease: lessons from the COURAGE and BARI-2D trials. AB - There is a continuing debate regarding the most effective strategy for treating stable ischemic heart disease (SIHD). Conflicting data have emerged from several small, randomized controlled trials and meta-analyses regarding the benefits of early revascularization in SIHD. Two recent multicenter, randomized trials, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial and the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI-2D) trial, compared two management strategies in SIHD-an initial conservative approach with optimal medical therapy (OMT) versus a strategy of early revascularization in combination with OMT. COURAGE randomized SIHD patients who were candidates for percutaneous coronary intervention (PCI) to either a strategy of early PCI in combination with OMT or OMT alone, whereas BARI 2D randomized diabetic patients with coronary artery disease to either early revascularization (PCI or coronary artery bypass surgery [CABG]) versus OMT. This review examines the principal findings of these trials, with discussion of their strengths, limitations, and applicability to the general population. The results support the hypothesis that in patients with SIHD, early revascularization with PCI in combination with OMT is not superior to OMT alone in reducing mortality and other major cardiovascular events. Subset analysis from BARI-2D did suggest that early CABG, although it did not reduce mortality, significantly reduced the rate of nonfatal myocardial infarction compared with an initial OMT approach. Based on these data, the majority of patients with SIHD should be managed initially with medical therapy, a strategy that is also the most cost effective. Revascularization can be considered for patients with severe or refractory symptoms despite a trial of medical therapy. For diabetic patients who have extensive coronary artery disease, early revascularization with CABG may be reasonable. PMID- 20845089 TI - Formulation development of morphine sulfate sustained-release tablets and its bioequivalence study in healthy Thai volunteers. AB - The objectives of this study were to develop morphine sulfate sustained-release tablet formulations and to evaluate the bioequivalence compared with a commercial brand. The physicochemical properties of the formulated and commercial tablets were determined and compared. The bioequivalence investigation was carried out in 15 healthy male volunteers who received a single dose in a randomized two-way crossover design. After dosing, serial blood samples were collected for a period of 24 h. Morphine concentration was assayed by high-performance liquid chromatography with electrochemical detector. The log-transformed C(max) and AUC(s) were statistically compared by analysis of variance, and the 90% confidence intervals (CIs) of the ratio of the log-transformed C(max) and AUC(s) between the most promising developed formulation and the commercial product were determined. It was found that the dissolution rate profile of a developed formulation was similar to the commercial brand. Their similarity and difference factors were well within limits. In the bioequivalence study, the AUC(last) and AUC(inf) between the test and the reference products were not statistically different (p = 0.227 and p = 0.468, respectively), with the 90% CIs of 83.4 102.6% and 87.7-139.4%, respectively. However, the C(max) of the two formulations was significantly different (p = 0.019). The 90% CI of the developed formulation was 72.0-93.0% compared to the commercial product. In vitro dissolution of locally prepared morphine sulfate sustained-release tablets was comparable to commercial brand. However, the results justified the conclusion of lack of bioequivalence of the developed product to the commercial one. PMID- 20845090 TI - A new approach for increasing ascorbyl palmitate stability by addition of non irritant co-antioxidant. AB - The aim of this work was to test innovative approach for enhancing ascorbyl palmitate stability in microemulsions for topical application by addition of newly synthesized co-antioxidant 4-(tridecyloxy)benzaldehyde oxime (TDBO) and to investigate its antioxidant activity and finally to evaluate cytotoxicity of TDBO loaded microemulsions on keratinocyte cells. TDBO significantly increased ascorbyl palmitate stability in oil-dispersed-in-water (o/w) microemulsions, most presumably due to reduction of ascorbyl palmitate radical back to ascorbyl palmitate, since TDBO free-radical scavenging activity was confirmed. Cytotoxicity experiments demonstrated no significant change in cell viability or morphology in the presence of TDBO-loaded microemulsions regarding unloaded microemulsions, although greater cytotoxicity was observed with increased microemulsion concentrations. Therefore, the incorporation of TDBO as non cytotoxic co-antioxidant in o/w microemulsions is a promising new strategy for enhancing ascorbyl palmitate stability that could be used to support antioxidant network in the skin. PMID- 20845091 TI - Sterile products: advances and challenges in formulation, manufacturing and regulatory aspects--a regulatory review perspective. AB - For several decades, the FDA has undertaken many initiatives to improve the quality and safety of sterile drug products. In recent years, efforts have also been undertaken to accelerate the rate for application approval by adding earlier involvement of microbiology reviewers in drug development. Product and manufacturing process development, as well as safe use and product design, are among the elements of enhanced technical involvement. An overview of the product quality microbiology aspects for sterile drugs is provided. PMID- 20845094 TI - Breaking news for our journal. PMID- 20845092 TI - The ANKK1 protein associated with addictions has nuclear and cytoplasmic localization and shows a differential response of Ala239Thr to apomorphine. AB - The TaqIA single-nucleotide polymorphism (SNP), which is the most widely studied genetic polymorphism in addictions, is located at the gene that encodes the RIP kinase ANKK1 near the gene for dopamine receptor D2. The TaqIA SNP is in strong linkage disequilibrium with the SNP rs7118900, which changes the alanine at position 239 to threonine in the ANKK1 protein (Ala239/A2; Thr239/A1). In silico analysis has predicted that this polymorphic substitution creates an additional phosphorylation site in the kinase domain of ANKK1. To investigate the contribution of ANKK1 to the pathophysiology of TaqIA-associated phenotypes, we analyzed transfected HEK293T cells with the human ANKK1-kinase(Ala239) and ANKK1 kinase(Thr239) variants tagged with GFP. We observed that the ANKK1-kinase is located in both the nucleus and the cytoplasm, suggesting that there is nucleocytoplasmic shuttling of this putative signal transducer. In addition, we found that the Ala239Thr ANKK1-kinase polymorphism exhibited strong expression differences in both the nucleus and the cytoplasm at basal level and when stimulated with the dopamine agonist apomorphine. Specifically, the ANKK1 kinase(Thr239) variant showed the highest level of basal protein expression, while ANKK1-kinase(Ala239) was 0.64-fold lower. After treatment with apomorphine, ANKK1-kinase(Ala239) showed a 2.4-fold increment in protein levels, whereas a 0.67-fold reduction was observed in ANKK1-kinase(Thr239). Thus, here we provide the first evidence of functional ANKK1 differences that are marked by TaqIA and could be associated with vulnerability to addiction. PMID- 20845093 TI - Chirurgia Italiana. PMID- 20845095 TI - Primary liver cancer: intrahepatic cholangiocarcinoma emerges from the shadows. PMID- 20845096 TI - Intrahepatic cholangiocarcinoma: prognostic factors after liver resection. AB - Liver resection may represent the only hope of cure for patients with intrahepatic cholangiocarcinoma (IHC) but long-term results are still far from satisfactory and the impact of prognostic factors is still controversial. Fifty five patients underwent hepatectomy for IHC between 1997 and 2008 in our unit. Features of the patients and the tumors, operations, postoperative and long-term results were retrospectively assessed. Twenty-one patients had HBV/HCV infection, four had congenital biliary dilatation. Thirty-two patients had increased CA 19 9; 12 had multiple (>= 4) tumors. Operations included 43 major resections, with 9 resections of biliary confluence, 40 regional lymphadenectomies. Operative mortality and morbidity were 0 and 27.3%, respectively. There were 44 R0 resections (80.0%). Lymphadenectomy yielded lymph node metastases in 14 cases (14/40; 35.0%). Five-year overall and disease-free survival rates were 30.2 and 27.5%, respectively. At multivariate analysis the strongest poor prognostic factor for overall survival was tumor stage. This factor, with multiplicity of lesions (>= 4) and tumor grading > 2, was significant predictor of recurrence. CA19-9 > 100 IU/mL and tumor grading > 2 were found to be significantly related with early multinodular hepatic recurrence. Patients with lymph node metastases had significantly lower overall and disease-free survival but patients who underwent lymph node dissection with negative lymph nodes at final pathology showed significantly higher 5-year disease-free survival than patients who did not underwent lymphadenectomy. In conclusion, these results support the role of hepatectomy with regional lymphadenectomy as the best available treatment for IHC. Prognosis after liver resection correlates with clinical stage and multiplicity of lesions. PMID- 20845097 TI - Radiological estimation of size in colorectal liver metastases: is it reliable? Comparison with post-resectional measurements. AB - Since the efficiency of percutaneous ablation techniques in treating colorectal liver metastases is dependent on tumor size, the aim of this study was to verify the accuracy of computed tomography or magnetic resonance in estimating the maximum diameter of colorectal liver metastases by comparing these findings with those of pathology in a series of patients who underwent liver resection. Radiological and pathological tumor measurements in 39 patients operated for 69 colorectal liver metastasis were recorded. The radiological measurement was performed by magnetic resonance in 40 tumors (23 cases) and by computed tomography in 29 tumors (16 patients). The mean difference between pathological and radiological sizes was 0.4 cm (p < 0.001). Radiological size was smaller than pathological size in 60.9% of tumors, equal in 16% and bigger in 23% of tumors. The results indicated that radiology significantly underestimates the diameter of liver metastasis. To avoid on-site recurrence after percutaneous ablation therapies due to inaccurate radiological measurement, a radiological size of colorectal metastasis up to 2.5 cm should be considered as selection criteria for this treatment. PMID- 20845098 TI - Safety and prognostic role of regional lymphadenectomy for primary and metastatic liver tumors. AB - Routine regional lymphadenectomy for colorectal liver metastases and primary liver tumors is still a subject for debate. During 2001-2005, we performed a prospective study of cases in which regional lymphadenectomy around the hepato duodenal ligament and common hepatic artery was applied (group R+ LN) or not (group R- LN). Pre-operative clinical features of patients were comparable among groups as well as the operative data. There were 108 (67%) males; the median age was 66 years; 124 cases had a single lesion (77%), and the median diameter was 4 cm. The type of lesion was: 77 (48%) colorectal liver metastases (M-CR), 75 (46%) hepatocellular carcinomas (HCC) and 10 (6%) cholangiocellular carcinomas. In the R+ LN group, the mean number of lymph nodes removed was 6.7 +/- 4.8 (range 4-26), and seven cases (8.6%) presented lymph node metastasis. The median follow-up was 3.5 years. M-CR patients showed comparable hospital mortality (R+ LN 0% vs. R- LN 2.6%) and morbidity (R+ LN 17.9% vs. R- LN 21.1%), but R+ LN had higher 5-year disease-free survival (31 vs. 16%, p < 0.05). HCC cases in the R+ LN group presented higher hospital mortality (13.5 vs. 0%, p < 0.05) without any improvement in disease-free survival (it was at 5-year disease-free survival 34 vs. 33%, respectively, p = n.s.). Routine regional lymphadenectomy should be performed for colorectal liver metastases, and avoided in patients with hepatocellular carcinoma. PMID- 20845099 TI - Video-assisted versus open ileocolic resection in primary Crohn's disease: a comparative case-matched study. AB - Despite the technical difficulties, laparoscopic ileocolic resection for Crohn's disease (CD) has become widely accepted in recent years, due to its potential benefits. There are numerous reports concerning the use of laparoscopy in successfully treating CD, including two randomized trials and few comparative studies. For the most part, these reports outline use of laparoscopic approach in primary distal ileal or ileocolic disease, with a careful selection of the patients. The purpose of this comparative case-control study was to point out potential advantages and disadvantages in short- and long-term outcomes of the laparoscopic approach compared with the open one. From January 1999 to January 2004, 200 patients were admitted in our Surgical Unit for complicated primary CD. 100 patients (group 1) underwent a laparoscopic ileocolic resection, 100 patients (group 2), with alike demographic and clinical characteristics, underwent the same procedure using a traditional approach. The incidence of perforative disease was 32 and 40% in groups 1 and 2, respectively. Average operative time was 140 min (range 90-245 min) in the video-assisted group and 98 min (range 65-255 min) in group 2 (P < 0.05). Postoperative morbidity was 6 and 8% in groups 1 and 2, respectively (P = NS). Recovery of peristalsis occurred within 2-3 days in group 1 and 3-4 days in group 2 (P = NS). Median postoperative hospitalization was 7 days (range 5-18 days) in group 1 and 9 days (range 7-22 days) in control group (P < 0.05). The overall rate of surgical relapse of CD was 8 and 13% in groups 1 and 2, respectively (P = NS), at a mean follow-up of 52 and 60 months, respectively. The 1-year surgical recurrence rate was similar (3%) for the two groups. In conclusions, in spite of the technical difficulties, video-assisted surgery for CD offers advantages over laparotomy, including less postoperative pain, reduced postoperative hospital stay, less disability of the patient, and better cosmetic results. Potential advantages are: easier approach for re resection, lower rate of postoperative adhesions and bowel obstruction, and lower rate of wound complications. PMID- 20845100 TI - Total pancreatectomy: indications, operative technique, and results: a single centre experience and review of literature. AB - The aims of this study were to identify the indications to perform a total pancreatectomy and to evaluate the outcome and quality of life of the patient who underwent this operation. A retrospective analysis of a prospective database, regarding all the patients who underwent total pancreatectomy from January 2006 to June 2009, was carried out. Perioperative and outcome data were analyzed in two different groups: ductal adenocarcinoma (group 1) and non-ductal adenocarcinoma (group 2). Twenty (16.9%) total pancreatectomies out of 118 pancreatic resections were performed. Seven (35.0%) patients were affected by ductal adenocarcinoma (group 1) and the remaining 13 (65.0%) by pancreatic diseases different from ductal adenocarcinoma (group 2) [8 (61.5%) intraductal pancreatic mucinous neoplasms, 2 (15.4%) well-differentiated neuroendocrine carcinomas, 2 (15.4%) pancreatic metastases from renal cell cancer and, finally, 1 (7.7%) chronic pancreatitis]. Eleven patients (55%) underwent primary elective total pancreatectomy; nine (45%) had a completion pancreatectomy previous pancreaticoduodenectomy. Primary elective total pancreatectomy was significantly more frequent in group 2 than in group 1. Early and long-term postoperative results were good without significant difference between the two groups except for the disease-free survival that was significantly better in group 2. The follow-up examinations showed a good control of the apancreatic diabetes and of the exocrine insufficiency without differences between the two groups. In conclusion, currently, total pancreatectomy is a standardized and safe procedure that allows good early and late results. Its indications are increasing because of the more frequent diagnose of pancreatic disease that involved the whole gland as well as intraductal pancreatic mucinous neoplasm, neuroendocrine tumors and pancreatic metastases from renal cell cancer. PMID- 20845101 TI - How does dexamethasone influence surgical outcome after laparoscopic Nissen fundoplication? A randomized double-blind placebo-controlled trial. AB - Laparoscopic floppy Nissen fundoplication (LFNF) is an effective treatment for gastroesophageal reflux disease. The duration of convalescence, after noncomplicated LFNF, may depend on several factors of which pain, fatigue and sociocultural factors are the most important. Nausea and vomiting occur mainly on the day of operation. Glucocorticoids are well known for their analgesic, anti inflammatory, immune-modulating and antiemetic effects. We therefore undertook the present study to investigate whether preoperative dexamethasone could improve surgical outcome in patients undergoing uncomplicated laparoscopic floppy Nissen fundoplication. From March 2005 to April 2008, 82 patients were randomized to receive dexamethasone (8 mg) intravenously, 90 min before skin incision or saline (placebo). Patients received a similar standardized anesthetic, surgical and multimodal analgesic treatment. The primary end points were pain and fatigue. Preoperatively and at several times during the first 24 postoperative hours, we measured C-reactive protein (CRP), interleukin-6 and 1 (IL-6, IL-1), pain scores and nausea, and the number of vomiting episodes were registered. Dexamethasone significantly reduced postoperative levels of CRP (p = 0.01), IL-6 and IL-1 (p < 0.05), fatigue (p = 0.01) and overall pain during the first 24 postoperative hours (p < 0.05) and the total requirement of analgesic (ketorolac) (p < 0.05). Dexamethasone also reduced nausea and vomiting on the day of operation (p < 0.05). Preoperative dexamethasone (8 mg) reduced pain, fatigue, nausea and vomiting in patients undergoing uncomplicated LNF when compared with placebo. PMID- 20845102 TI - Outcomes of the open mesh repair of large incisional hernias using an intraperitoneal composite mesh: our experience with 100 cases. AB - Incisional hernia repair sometimes requires intraperitoneal implantation of a mesh. This becomes necessary when the hernia opening is large, in particular, in patients with a low abdominal wall surface/wall defect surface (AWS/WDS) ratio, in large boundary incisional hernias where the proximity to bone structures or cartilage often complicates retromuscular mesh implantation and in multi recurrent incisional hernias that are sometimes characterised by an actual loss of abdominal wall tissue. The authors report on the results of a series of 100 incisional hernias treated between 1999 and 2006 using the open technique to implant an intraperitoneal mesh (Parietex Composite). Mean follow-up time was 42 months (range 12-96 months). The mean wall defect surface was 95 cm(2) (range 60 210 cm(2)). Twelve percent of patients suffered minor complications: 5 seromas (5%), 3 haematomas (3%) and 4 parietal suppurations (4%). No mesh had to be removed. The recurrence rate was 6%. At 6 months after surgery, no patient lamented pain or discomfort due to foreign body sensation. None of these patients presented intestinal occlusion or enterocutaneous fistulae. In conclusion, it is our opinion that the mesh should be implanted in direct contact with the viscera only where absolutely necessary, i.e., when it cannot be implanted in the retromuscular area without creating excessive parietal tension. Our experience with PC mesh, over the short-to-medium term, was positive. Naturally, further studies are required to evaluate long-term biocompatibility. PMID- 20845103 TI - Adrenal metastases from adenocarcinoma of the esophagogastric junction: adrenalectomy and long-term survival. AB - Treatment of adrenal metastases from cancer of the esophagogastric junction (EGJ) is not defined. The aim of the present work is to analyze retrospectively our experience in treating patients with adrenal metastases from EGJ adenocarcinoma. 102 patients with Siewert 1 or 2 EGJ adenocarcinoma underwent esophagectomy between May 2001 and Jan 2009. Five patients were diagnosed an adrenal metastases from EGJ adenocarcinoma, synchronous (s) in one and metachronous (m) in four, in the latter 11 months (mean) after esophagectomy. At diagnosis, three patients had synchronous metastases to mediastinal nodes (1 s and 2 m), 1 (m) had synchronous metastases to bone, and 1 (m) had an isolated adrenal metastasis. Three patients with synchronous node metastasis received chemotherapy followed by adrenalectomy 3, 8 and 16 months (mean 9) after diagnosis; one patient also received postoperative mediastinal radiotherapy. These patients are alive with no evidence of disease 16, 40 and 50 months after diagnosis of adrenal metastasis. The patient with bone metastasis received chemotherapy only and died 12 months after diagnosis of metastatic disease. The patient with isolated metastasis underwent laparoscopic adrenalectomy only, developed early bone metastases and died 15 months after surgery. In conclusion, our experience indicates that patients with adrenal metastases from adenocarcinoma of the EGJ may benefit from adrenalectomy if the gland is the only site of metastasis beyond lymphnodal disease. Chemotherapy should be considered before adrenalectomy to achieve better disease control and identify aggressive disease that would contraindicate adrenalectomy. PMID- 20845104 TI - Solid pseudopapillary tumor of the pancreas in children: report of a case and review of the literature. AB - Solid pseudopapillary tumor (SPT) of the pancreas is an infrequent neoplasm of low malignant potential, first described by Frantz in 1933 and representing less than 3% of all exocrine tumors. SPT is rare in children, accounting for 6% of all cases and shows different clinical features compared with adults. Here, a pediatric case is reported and a review of the Literature is provided. A 15-year old girl with a 12 * 14 * 10 cm solid mass growing from the tail and the body of the pancreas, involving spleen, left adrenal gland and kidney, stomach and some bowel loops, was referred for surgical treatment. A distal pancreasectomy with splenectomy was performed. Histopathological examination revealed that the tumor was a 14-cm well-circumscribed solid mass, with pseudopapillary cell architecture, showing strong cellular immunoreactivity for alpha-1 antitrypsin, vimentin, neurone-specific enolase, progesterone receptors and in part to CD10 and CAM 5.2, but not to sinaptofisin and chromogranin. A 24-month post-surgical follow-up after successful surgical resection showed no evidence of recurrent disease. SPT shows different clinical features in childhood. High survival rates can be achieved in most cases, warranting aggressive treatments even in metastatic disease. PMID- 20845105 TI - [Continuing education through the European Heart Rhythm Association (EHRA): chance for European standardization?]. AB - Standardization of training with an examination in cardiac electrophysiology represents a milestone in the unification and improvement in the quality of electrophysiological therapy within the member countries of the European Society of Cardiology (ESC). Since 2004 the European Heart Rhythm Association (EHRA) has established an Educational Committee with the mission of improving training in device therapy and electrophysiology in the ESC with accredited materials and educational initiatives. The Educational Committee established Europe-wide courses for continuous medical education in 1. invasive electrophysiology and catheter ablation, 2. pacemaker, ICD and cardiac resynchronization therapy and 3. case-based tutorials to prepare for the EHRA examinations for electrophysiology/ablation and device therapy. Independent from participation in EHRA examinations these courses represent a useful aid for daily practice in cardiac electrophysiology and help to bring young and advanced European cardiologists with an interest in electrophysiology together. PMID- 20845107 TI - Understanding the logic of IkappaB:NF-kappaB regulation in structural terms. AB - NF-kappaB is an inducible transcription factor that controls expression of diverse stress response genes. The entire mammalian NF-kappaB family is generated from a small cadre of five gene products that assemble with one another in various combinations to form active homo- and heterodimers. The ability of NF kappaB to alter target gene expression is regulated at many levels. Chief among these regulatory mechanisms is the noncovalent association in the cell cytoplasm of NF-kappaB dimers with IkappaB inhibitor proteins. Removal of IkappaB leads to accumulation of active NF-kappaB within the cell nucleus where it binds to specific DNA sequences contained within the promoter regions of target genes and initiates recruitment of general transcription factors and assembly of the basal transcription machinery. Here we provide a detailed description of these fundamental NF-kappaB regulatory events using as a basis macromolecular structures and experimental data derived from structure-based biochemistry. PMID- 20845106 TI - TGF-beta1 29T/C polymorphism and breast cancer risk: a meta-analysis involving 25,996 subjects. AB - Transforming growth factor beta1 (TGF-beta1) is a cytokine, playing an important role in controlling cell proliferation and differentiation involved in breast cancer. It was reported the 29T/C polymorphism in TGF-beta1 has been implicated in breast cancer risk. However, studies on the association between this polymorphism and breast cancer remain conflicting. To derive a more precise estimation of the relationship, a meta-analysis of 10,341 cases and 15,655 controls from fifty published case-control studies was performed. Our analysis suggested that 29T/C has no association with a trend of breast cancer risk when using both dominant [odds ratio (OR) = 1.01, 95% confidence intervals (CI) 0.96 1.07] and recessive models (OR = 0.98, 95% CI 0.89-1.08) to analyze the data. In ethnic subgroups analysis, 29T/C also did not appear to be risk factors for breast cancer. However, larger scale primary studies are required to further evaluate the interaction of TGF-beta1 29T/C polymorphism and breast cancer risk in specific populations. PMID- 20845108 TI - IKK regulation and human genetics. AB - The IKK kinase complex is the core element of the NF-kappaB cascade. It is essentially made of two kinases (IKKalpha and IKKbeta) and a regulatory subunit, NEMO/IKKgamma. Additional components may exist, transiently or permanently, but their characterization is still uncertain. In this review, we will focus on the NEMO molecule, and describe the results which have been obtained, and the hypotheses which have been proposed, to explain how NEMO controls the activation of the IKK complex. NEMO is one of the very few non-redundant components of the NF-kappaB cascade, and the localization of the gene that encodes it on the X chromosome suggests it is likely to be the target of mutations leading to pathologies: this is indeed the case, and we will also present the current status of our knowledge regarding NEMO-associated pathologies. PMID- 20845109 TI - IKK- and NF-kappaB-mediated functions in carcinogenesis. AB - Since the initial cloning of RelA and its close relationship to c-Rel, the cellular homolog of the viral oncoprotein v-Rel, the nuclear factor kappaB (NF kappaB) signaling pathway and its upstream activating kinase complex (IkappaB kinase) have been suspected to play a major role in tumorigenesis. This was further corroborated by the discovery of oncogenic mutations in NF-kappaB proteins in certain lymphoid malignancies and the notion that NF-kappaB is persistently activated in a large variety of solid tumors. With the advent of conditional knockout mice allowing tissue-specific targeting of the various components of the NF-kappaB signaling pathway, it was possible to genetically test the cell autonomous and non-autonomous functions of NF-kappaB in inflammation-associated cancer as well as sporadic cancers. Here, we review molecular evidence that demonstrates the various functions of NF-kappaB during different tumor stages and that supports the rationale to target NF-kappaB in cancer prevention and therapy. PMID- 20845111 TI - Reflections on the Swiss Consensus Statement in the context of qualitative interviews with heterosexuals living with HIV. AB - In 2008, the Swiss Federal AIDS Commission released a statement concluding that people with HIV who are on treatment and have an undetectable viral load are non infectious and can safely practice unprotected sex with their HIV-negative partner under certain conditions. Contradicting over 25 years of HIV prevention messages, the so called Swiss Consensus Statement sparked a polarised international debate. One key concern is that the Statement will be misinterpreted to imply that everybody on treatment can have unprotected sex. Therefore, critics warn against any departure from the emphasis on condoms as the most effective prevention method. Given this concern, it is useful to reflect on what relevance the Swiss Statement may have for those concerned. This paper draws on qualitative interviews with HIV-positive heterosexuals and HIV-negative partners in Australia. Conducted both before and after the release of the Statement, these interviews revealed that sexual decision-making was not based solely on calculations of risk, but shaped by complex emotions and relationship priorities. The interviews also revealed that participants were sceptical towards the Statement's prevention message. These findings call into question the central concerns that drive this debate. PMID- 20845112 TI - Self-efficacy and distress in women with AIDS: the SMART/EST women's project. AB - Though African American and Hispanic women accounted for 14% of the female population in the USA, they represented 66% of the total HIV/AIDS diagnoses among women in 2007. Among men living with HIV, increased coping self-efficacy (SE) following a cognitive behavioral intervention has been related to decreased distress, anxiety, anger, and confusion, but comparable studies had not been carried out with HIV+ women. The purpose of this study was to examine the impact of changes in SE following a cognitive behavioral stress management plus expressive supportive therapy (CBSM+) intervention on depression and anxiety in low-income urban predominantly minority women living with AIDS. Women (n=451) were randomized to a group CBSM+ or individual informational intervention condition and completed baseline, post-intervention and long-term follow-up (12 months) assessments of depression, anxiety and SE. Women who were assigned to the CBSM+ group condition and increased their level of cognitive behavioral SE reported significant decreases in anxiety and depression at post-intervention and long-term follow-up in comparison with controls who did not improve. Results suggest that both cognitive behavioral skills and a concomitant increase in the perceived level of SE in the use of those skills are predictive of distress reduction. PMID- 20845113 TI - Prevalence and correlates of lifetime suicidal ideation among HIV-infected male inmates in Taiwan. AB - The purpose of this study was to explore the prevalence and correlates of lifetime suicidal ideation (SI) among HIV-infected male inmates. All participants in seven prisons, comprising roughly 20% of all HIV-infected male inmates in Taiwan, were stratified by geographic location and surveyed using a self administered, anonymous questionnaire. The five-item Brief Symptom Rating Scale (BSRS-5) was used on 535 participants to measure various dimensions of psychological distress. Seven questions regarding lifetime psychiatric symptoms were also added to the questionnaire. Questionnaire results in this sample revealed that 23.7% had suffered depressive symptoms for at least two weeks, 20.6% experienced serious anxiety or tension symptoms, 12.5% had serious thoughts of suicide symptoms, and 4.1% had made a suicide attempt. Results of multiple logistic regression analysis indicated that SI was significantly related to (1) recent psychological distress, and (2) lifetime experience of depression for two weeks or more, serious anxiety or tension, or hallucinations. Since nearly 70% of the respondents reported at least one psychiatric symptom in their lifetime, it would seem important to target HIV-infected male inmates with mental health interventions and suicide prevention. PMID- 20845114 TI - Mechanics of the maxillary central incisor. Influence of the periodontal ligament represented by beam elements. AB - This study aimed to evaluate the influence of loading on a maxillary central incisor with the periodontal ligament (PDL) represented by 2D elastic beam elements using a 2D finite element analysis. Two models (M) were built varying the PDL representation: Mh (homogeneous PDL) and Mht (heterogeneous PDL with beam3 elements). Stress and displacements were determined for three loading conditions (L): Ll, lingual face loading at 45 degrees with the tooth long axis; Li, perpendicular to the incisal edge; and Lip, on the incisal edge, parallel to the tooth long axis. Evaluation was performed on ANSYS software. Lip provided lower stress variation on the tooth and support structures when compared to Ll and Li. PDL's influence on stress values was lower for Lip. Oblique loading showed stress and displacement not observed in parallel loading condition through PDL's heterogeneous representation and it is probably incompatible with the in vivo condition. PMID- 20845115 TI - Finite element analysis for the evaluation of protective functions of helmets against ballistic impact. AB - The ballistic impact of a human head model protected by a Personnel Armor System Ground Troops Kevlar(r) helmet is analysed using the finite element method. The emphasis is to examine the effect of the interior cushioning system as a shock absorber in mitigating ballistic impact to the head. The simulations of the frontal and side impacts of the full metal jacket (FMJ) and fragment-simulating projectile (FSP) were carried out using LS-DYNA. It was found that the Kevlar(r) helmet with its interior nylon and leather strap was able to defeat both the FMJ and FSP without the projectiles penetrating the helmet. However, the head injuries caused by the FMJ impact can be fatal due to the high stiffness of the interior strap. The bulge section at the side of the Kevlar(r) helmet had more room for deformation that resulted in less serious head injuries. PMID- 20845110 TI - NF-kappaB as a target for oncogenic viruses. AB - NF-kappaB is a pivotal transcription factor that controls cell survival and proliferation in diverse physiological processes. The activity of NF-kappaB is tightly controlled through its cytoplasmic sequestration by specific inhibitors, IkappaBs. Various cellular stimuli induce the activation of an IkappaB kinase, which phosphorylates IkappaBs and triggers their proteasomal degradation, causing nuclear translocation of activated NF-kappaB. Under normal conditions, the activation of NF-kappaB occurs transiently, thus ensuring rapid but temporary induction of target genes. Deregulated NF-kappaB activation contributes to the development of various diseases, including cancers and immunological disorders. Accumulated studies demonstrate that the NF-kappaB signaling pathway is a target of several human oncogenic viruses, including the human T cell leukemia virus type 1, the Kaposi sarcoma-associated herpesvirus, and the Epstein-Bar virus. These viruses encode specific oncoproteins that target different signaling components of the NF-kappaB pathway, leading to persistent activation of NF kappaB. This chapter will discuss the molecular mechanisms by which NF-kappaB is activated by the viral oncoproteins. PMID- 20845117 TI - Validation of an Arab name algorithm in the determination of Arab ancestry for use in health research. AB - OBJECTIVE: Data about Arab-Americans, a growing ethnic minority, are not routinely collected in vital statistics, registry, or administrative data in the USA. The difficulty in identifying Arab-Americans using publicly available data sources is a barrier to health research about this group. Here, we validate an empirically based probabilistic Arab name algorithm (ANA) for identifying Arab Americans in health research. DESIGN: We used data from all Michigan birth certificates between 2000 and 2005. Fathers' surnames and mothers' maiden names were coded as Arab or non-Arab according to the ANA. We calculated sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of Arab ethnicity inferred using the ANA as compared to self-reported Arab ancestry. RESULTS: Statewide, the ANA had a specificity of 98.9%, a sensitivity of 50.3%, a PPV of 57.0%, and an NPV of 98.6%. Both the false-positive and false-negative rates were higher among men than among women. As the concentration of Arab Americans in a study locality increased, the ANA false-positive rate increased and false-negative rate decreased. CONCLUSION: The ANA is highly specific but only moderately sensitive as a means of detecting Arab ancestry. Future research should compare health characteristics among Arab-American populations defined by Arab ancestry and those defined by the ANA. PMID- 20845118 TI - Age differences in outdated information processing during news reports reading. AB - In two experiments, the authors explored whether there are any age differences associated with the ability to process outdated information during news reports comprehension. Younger and older participants (mean age: 70 years old) read passages in which a cause was first said to be responsible for the occurrence of a news event. New elements emerged from the investigation in progress and revealed that the original cause was incorrect. Inference response times indicated that older adults more than younger ones took advantage of an alternative cause mentioned in the text to put the outdated information in the background, whereas younger readers probably kept both causes activated. The research tested the concepts involved with age differences in updating situation model. PMID- 20845119 TI - Experimental aging research. PMID- 20845122 TI - Aging performance for masters records in athletics, swimming, rowing, cycling, triathlon, and weightlifting. AB - Record performances for Masters sporting events for swimming, cycling, triathlon, rowing, and weightlifting were analyzed and then compared with the authors' previously published results for Masters running, walking, and jumping sports events. Records were normalized using the 30s age records as a baseline, and studied through the various age ranges to the 90s. A curvilinear mathematical model [y = 1 - exp((T - T(0))/tau)] was again used for the major comparisons, along with slope changes using a linear model [y = alpha(T -T'0)] across the age groupings. All sports declined with increasing age, with rowing showing the least deterioration. Performances in running, swimming, and walking were reasonably well maintained, followed by greater decline with age for cycling, triathlon, and jumping events. Weightlifting showed the fastest and greatest decline with increasing age. The relative performances for women, when compared with men's performances for these Masters events, was approximately 80% to 85%, with jumping at 73% and weightlifting at 52%. These relative performances compared with World Record comparisons of approximately 90% (with weightlifting at approximately 75%). All these results show no greater decline with age for endurance events over the sprint events, though there was a greater decline for the strength events of weightlifting and jumping. There may be real physiological differences for these strength events, or there may be other explanations such as training or competitive considerations or smaller numbers participating. PMID- 20845120 TI - Cognitive function, physical performance, health, and disease: norms from the georgia centenarian study. AB - This study provides, for the first time, normative data on cognitive functioning and physical performance, health and health behaviors, and diseases from a population-based sample of 244 centenarians and near-centenarians (M age = 100.5 years, range 98-108, 84.8% women, 21.3% African American) from the Georgia Centenarian Study. Data are presented by the four key dimensions of gender, race, residence, and educational attainment. Results illustrate the profound range of functioning in this age group and indicate considerable differences as a function of each dimension. Bivariate models generally suggest that cognitive functioning and physical performance is higher for men than women; whites than African Americans; community than facility residents; and those with more than high school education than those with less than high school education. Multivariate models elaborate that differences in educational attainment generally account for the largest proportion of variance in cognitive functioning and residential status generally accounts for the largest proportion of variance in physical performance measures. Addition of health variables seldom increases variance accounted for in each domain beyond these four dimensions. PMID- 20845121 TI - Race-related cognitive test bias in the active study: a mimic model approach. AB - The present study investigated evidence for race-related test bias in cognitive measures used in the baseline assessment of the ACTIVE clinical trial. Test bias against African Americans has been documented in both cognitive aging and early life span studies. Despite significant mean performance differences, Multiple Indicators Multiple Causes (MIMIC) models suggested most differences were at the construct level. There was little evidence that specific measures put either group at particular advantage or disadvantage and little evidence of cognitive test bias in this sample. Small group differences in education, cognitive status, and health suggest positive selection may have attenuated possible biases. PMID- 20845125 TI - Welcome to the 100th issue of Health Communication! PMID- 20845123 TI - Assessment of hypertension control in a district of Mombasa, Kenya. AB - As populations move to urban centres across East Africa, lifestyle habits that affect cardiovascular disease have changed, affecting non-communicable disease risk. In particular, the prevalence of hypertension, and associated awareness of this life-threatening condition, has not been studied in Mombasa, Kenya. This paper assesses the rates of prevalence, awareness, treatment and control of hypertension in Old Town, an urban district of the coastal city. We surveyed 469 subjects, gathered via a clustered sampling technique. Age-adjusted prevalence of hypertension was measured at 32.6% (+/- 2.2) for adults over 18 and was linearly related to age. Results indicate that hypertension awareness was associated with age and sex, as women were substantially more likely to be aware of and to control their hypertension. Only 23.2% (+/- 2.0) of subjects had knowledge of both the causes of and practical solutions to hypertension, and practical hypertension knowledge was associated with hypertension awareness and gender (women had higher rates of knowledge than men). These results indicate that hypertension is a real public health concern in Old Town, and that younger individuals, particularly males, are least likely to be aware of the dangers of hypertension. Public health measures should focus on this population. PMID- 20845126 TI - Mapping health communication scholarship: breadth, depth, and agenda of published research in Health Communication. AB - This study analyzed trends and patterns in the 22 years of research published in Health Communication. A content analysis of 642 articles examined the breadth and depth that Health Communication has achieved since its inception. Readers of Health Communication can thus see the history and scope of health communication as defined in the pages of this journal, and juxtapose this historical overview in the backdrop of the current scholarship that appears in the journal. We also identified some notable trends in research for the future development of the journal Health Communication specifically and the health communication discipline in general. PMID- 20845127 TI - Kindness, gentility, and rejection: an analysis of 99 manuscript reviews. PMID- 20845128 TI - The nuts and bolts of publication in Health Communication. PMID- 20845129 TI - A journal-level analysis of Health Communication. AB - Citation data from 2006 through 2008 were used to examine the journal citation network of Health Communication in comparison to 26 related journals indexed by Journal Citation Reports, a database published by the Institute for Scientific Information (ISI) Web of Knowledge. A recently advanced journal relatedness factor based on out-degree (i.e., cited journals) and in-degree (i.e., citing journals) citations was used to determine the network of peer journals. Results indicate Health Communication serves to link communication and health-related journals. Data were also reported on journal impact and 5-year journal impact factors. When compared to ISI-indexed communication journals, Health Communication is consistently ranked in the top 25% across impact factors and citations to the journal are consistent over the 7 years of analysis from 2002 through 2008. Methods of increasing the impact of Health Communication among journals in social sciences are discussed. PMID- 20845130 TI - 100th issue of Health Communication. PMID- 20845131 TI - What the numbers don't tell us. PMID- 20845133 TI - Past as prologue or there from here. PMID- 20845132 TI - On the need for a life-span approach to health campaign evaluation. AB - Campaign evaluation researchers should investigate age not just as an audience segmentation variable but also as a potentially valuable moderator of measure validity and campaign effects. Although researchers interested in physician patient interaction and family communication have long considered aging dynamics, media campaign evaluation research has insufficiently addressed changes over the life span. In this article, I summarize some examples illustrating the importance of such work and propose additional theoretical possibilities. PMID- 20845134 TI - Accomplishing the goals of health communication research: predictions, accomplishments, and continued efforts. PMID- 20845135 TI - The critical cultural turn in health communication: reflexivity, solidarity, and praxis. PMID- 20845136 TI - A few thoughts about the trends in 100 issues of Health Communication. PMID- 20845138 TI - What is normative in health communication research on norms? A review and recommendations for future scholarship. PMID- 20845137 TI - Commentary on "Mapping health communication scholarship: breadth, depth, and agenda of published research in Health Communication": implications for reaching practitioners with communication research. PMID- 20845139 TI - Health communication research in Europe: an emerging field. PMID- 20845140 TI - The emerging landscape of health communication in Asia: theoretical contributions, methodological questions, and applied collaborations. PMID- 20845141 TI - Why is it so difficult to talk about impact? PMID- 20845142 TI - Accrediting and licensing standards as evidence of impact. PMID- 20845143 TI - The impact of Health Communication research on cancer survivorship. PMID- 20845144 TI - The impact of interdisciplinary collaboration. PMID- 20845145 TI - Engaging ethnic media to expand the reach and effectiveness of communication strategies to reduce health disparities. PMID- 20845146 TI - Health Communication as applied social science: what is applied? PMID- 20845147 TI - DTC advertising's programmatic research and its effect on health communication. PMID- 20845148 TI - Suicide in the news: informing strategies to improve the reporting of suicide. PMID- 20845149 TI - Smoking in movies. PMID- 20845150 TI - Fear appeals and public service advertising: applications to influenza in Hong Kong. PMID- 20845151 TI - Interactive media for childhood obesity prevention. PMID- 20845152 TI - Pink ribbons, blue moons, and silver linings: communicating, coping, and caring. PMID- 20845153 TI - The dissemination of keepin' it REAL Through D.A.R.E. America: a lesson in disseminating health messages. PMID- 20845154 TI - Improving communication practices to reduce breast cancer environmental risks. PMID- 20845155 TI - The impact of health communication research on organ donation outcomes in the United States. PMID- 20845156 TI - The contributions of health communication research to campaign practice. PMID- 20845157 TI - Media research contributes to the battle against childhood obesity. PMID- 20845158 TI - Patient-provider interaction and the regulation of diabetes mellitus. PMID- 20845159 TI - Communicating about cancer in families and clinics. PMID- 20845160 TI - Parasocial interaction and identification: social change processes for effective health interventions. PMID- 20845161 TI - The impact of health communication on the culture of college drinking. PMID- 20845162 TI - Communicating what works! Applying the positive deviance approach in health communication. PMID- 20845163 TI - Diabetic foot health education and amputation prevention. PMID- 20845164 TI - Impact of SENTAR on Prevention Campaign Policy and Practice. PMID- 20845165 TI - Applications of communication infrastructure theory. PMID- 20845166 TI - Using communication research to advance the goals of the national health insurance law in Israel: deliberative methods to elicit public value priorities. PMID- 20845167 TI - Social norms marketing campaigns to reduce campus alcohol problems. PMID- 20845168 TI - Impacting behavior by integrating health communication and marketing. PMID- 20845169 TI - The impact of direct-to-consumer prescription drug advertising research-a diffusion of policy analysis. PMID- 20845170 TI - Health advocacy by accident and discipline. PMID- 20845171 TI - The impact of the work of Martin Fishbein on health issues in the world. PMID- 20845172 TI - The day Patrick Swayze died. PMID- 20845173 TI - Older adults coping with vision loss. AB - Age-related vision loss is one of the most commonly cited disabling impairments of adult life. Stressors presented by vision loss can create barriers, threatening the well-being of the individual. This qualitative study of 30 older adults (65 to 95 years of age) investigated vision loss and coping strategies. All participants experienced unexpected sight loss during their adult years. The Adaptation to Age-Related Vision Loss (AVL) Scale was used in this study to examine psychosocial adaptation to vision impairment. The coping strategies of vision impairment were assessed by collecting self-reported reflections toward vision loss and how the change impacted the participant's life. Given the correct balance of support, confidence, and acceptance, older adults can confront the existing barriers and focus on the ability to optimize function with vision loss. Health care service providers and practitioners can provide needed assistance and a helpful guide to assist older adults in successfully coping with vision impairment. PMID- 20845174 TI - Depressive symptoms and use of home-based respite time in family caregivers. AB - This study investigated the relationship between activities during respite time and depressive symptoms in family caregivers (N = 74) of older adults receiving in-home respite services. Contrary to prior research, demographic contextual variables (caregiver gender, household income, and dyad relationship) and care recipient problems (behavioral dysfunction and functional impairment) were not associated with caregiver depressive symptoms, nor was total minutes engaged in discretionary activities during respite. Self-reported depressive symptomatology in family caregivers was significantly and inversely related to both past service usage and total minutes of chore time completed on a typical home-based respite day. Implications for research in this area and service delivery are discussed. PMID- 20845175 TI - Home- and community-based services utilization and aging in place. AB - This study examines the relationship between home- and community-based service (HCBS) utilization and perceived service needs for aging in place versus relocation, using the data from the Community Partnership for Older Adults Survey. Among the vulnerable, community-dwelling older adult sample (N = 2,001), users of adult day programs, housekeeping, senior lunch, helpline, or personal assistance services were more likely to indicate they would need regular help to remain living on their own. By contrast, users of senior centers, personal assistance, or visiting nurse services were more likely to indicate they would move out due to health problems. Home repair service users were less likely to perceive the need for relocation. Findings have implications for improving long term care and supportive service systems to meet the current and future needs of community-dwelling older adults. PMID- 20845176 TI - Preface. Selected papers from the International Workshop G-DAT 2008: Groundwater Dating Using Environmental Tracers, 5-7 March 2008, Leipzig, Germany. PMID- 20845177 TI - Dating of 'young' groundwaters using environmental tracers: advantages, applications, and research needs. AB - Many problems related to groundwater supply and quality, as well as groundwater dependent ecosystems require some understanding of the timescales of flow and transport. For example, increased concern about the vulnerabilities of 'young' groundwaters (less than ~1000 years) to overexploitation, contamination, and land use/climate change effects are driving the need to understand flow and transport processes that occur over decadal, annual, or shorter timescales. Over the last few decades, a powerful suite of environmental tracers has emerged that can be used to interrogate a wide variety of young groundwater systems and provide information about groundwater ages/residence times appropriate to the timescales over which these systems respond. These tracer methods have distinct advantages over traditional approaches providing information about groundwater systems that would likely not be obtainable otherwise. The objective of this paper is to discuss how environmental tracers are used to characterise young groundwater systems so that more researchers, water managers, and policy-makers are aware of the value of environmental tracer approaches and can apply them in appropriate ways. We also discuss areas where additional research is required to improve ease of use and extend quantitative interpretations of tracer results. PMID- 20845178 TI - Obituary for Jacob Bigeleisen. PMID- 20845180 TI - Estimation of plant protection product application dates for environmental fate modeling based on phenological stages of crops. AB - According to the EU directive 91/414/EEC potential environmental concentrations of pesticides have to be assessed with environmental fate models. For the calculation of pesticide concentrations it is necessary to provide an application date which has to match the specific Biologische Bundesanstalt, Bundesamt, Chemische Industrie (BBCH) stage at which the pesticide shall be applied. If these application dates are not available for a specific stage, crop and country they must be estimated, which adds an additional uncertainty to the predicted concentrations. In the present study, we therefore evaluate to which extent application dates can be derived from phenological data. For this analysis phenological data, converted to BBCH stages, of two field crops provided by the German Weather Service (DWD) were analyzed. We found a linear correlation between BBCH stages and the respective appearance dates, which can be used for interpolation of appearance dates of specific BBCH stages. Remarkably, when comparing BBCH stages from Germany and the Czech Republic almost identical correlations of appearance dates and BBCH stages were found. In the next step, soil and climate data from Joint Research Centre (JRC) were analyzed together with phenological data in order to evaluate if BBCH stages can be estimated for countries with other climate or soil conditions. This analysis revealed that temperature, global radiation and evaporation were the parameters with the strongest impact. These parameters were used for estimating appearance dates of BBCH stages for other countries. Exemplarily, appearance dates for maize BBCH were calculated for Italy. Estimated and observed appearance dates showed a high concordance (on average six days difference). Finally, the political of impact a variation of a few days on calculated pesticide concentration was analyzed. Exemplarily, the pesticide fate model FOCUS PEARL was used to estimate pesticide groundwater concentrations. When calculating concentrations for application dates varying by +/- two weeks, concentrations in groundwater usually varied very little. The highest variation was found for application at BBCH 30 in maize (6.6 % variation over all scenarios). These results showed that the uncertainty included in the estimation of appearance dates of BBCH stages for other countries has a relatively small effect on the results of PEARL and consequentially on the decision of the pesticide risk assessment by changing only the application date. PMID- 20845181 TI - A simple HPLC method for determination of permethrin residues in wine. AB - An isocratic High Performance Liquid Chromatographic (HPLC) method was optimized for 3-phenoxybenzyl (1RS)-cis-trans-3-(2,2-dichlorovinyl)-2,2-dimethyl cyclopropanecarboxylate (permethrin) residues identification and quantification in wine matrix. Analytical reverse phase (RP) C-18 column was used (25 cm * 4 mm i.d., 5 MU m) with mobile phase consisting of acetonitrile and water in ratio 70 %/30 % (v v(-1)), flow-rate 2.0 mL min(-1), UV-detection at 215 nm and controlled oven temperature at 25 degrees C. The peaks of isomers were identified with the retention times as compared to standard cis-/trans- mixture and confirmed with characteristic spectra using photodiode array detector. Under these conditions, permethrin isomers were well separated with resolution 2.8 and no interference with the naturally present wine compounds was observed. The method was validated for linearity, precision, accuracy, limit of detection (LOD) and limit of quantification (LOQ). Linear regression analysis data proved a good linear relationship (correlation coefficients, r(2), for cis- and trans-isomer are: 0.9995 and 0.9997, respectively) between response of the detector and concentration of permethrin isomers over a wide concentration range for both isomers (0.55 mg L(-1) -4.40 mg L(-1)). Experimental data showed mean recoveries between 93.95% and 96.58% with RSD values in range: 0.89% -3.69%. The effect of ethanol content in the solvent on permethrin isomers peak areas was also studied and 60% v v(-1) ethanol was found to be optimal for sample preparation. The method was successfully tested on 20 commercial wine samples from the market in which no permethrin was detected. Thus, it was proved that it is suitable for routine permethrin residues analysis. The proposed method is suitable for routine analysis because of the simple sample preparation, acceptable run-time, low cost and its applicability with conventional instruments. PMID- 20845182 TI - Bacterial diversity in paclobutrazol applied agricultural soils. AB - The aim of this study was to investigate the bacterial communities on paclobutrazol [(2RS, 3RS)-1-(4-Chlorophenyl)-4, 4-dimethyl-2-(1H-1,2,4-triazol-1 yl) pentan-3-ol]-applied agricultural soils by denaturing gradient gel electrophoresis (DGGE) of polymerase chain reaction (PCR) amplified 16S rDNA gene fragments. Three different agricultural soil samples were collected from paclobutrazol applied mango and waxapple orchards, peanut fields and untreated rice fields as a control for DGGE analysis. The DGGE pattern of PCR- generated 16S rDNA gene fragments indicated that the bacterial populations from four paclobutrazol-applied soils of peanut fields were closely related to each other and two paclobutrazol-applied soils of mango and waxapple orchards harbored closely related bacterial communities. But, paclobutrazol-free agricultural soils comprised relatively a different bacterial group. However, the bacterial populations of mango and waxapple orchard are completely different from the bacterial communities of peanut field. Further purification and sequence analysis of 40 DGGE bands followed by phylogenetic tree assay showed similar results that soil bacteria from paclobutrazol applied mango and waxapple orchard are phylogenetically related. Based on the phylogenetic analysis, the clone M-4 was clad 100 % (bootstrap value) with Mycobacterium sp. The Mycobacterium sp. has been proved to degrade the phenolic compounds such as phenol, 4-chlorphenol, 2,4 dichlorophenol and paclobutrazol molecule containing chlorobenzene ring. PMID- 20845183 TI - Alterations in the rabbit lymphoid tissue after bendiocarb administration. AB - Various pesticides have immuno-suppressive effects, and thus the organisms become responsive to viral, bacterial and parasitic diseases and neoplasm. The aim of the study was to observe the structure of the small intestine (height of enterocytes and crypts), mucosal lymphoid tissue (Payer's patches, lymphocytes in lamina propria) and a lymph node after administration of bendiocarb (2,2-dimethyl 1,3-benzodioxol-4-yl-methylcarbamate) on days 3, 10, 20, 30 and 60 of the experiment. The height of the observed enterocytes showed an increasing tendency. On days 20, 30 and 60 we also observed an increase in diameter of crypts located in intestinal epithelium. The number of cells in lamina propria mucosae was significantly reduced on days 20 and 30 after administration of bendiocarb. Observations of the lymph node showed that on days 10 and 20 there was a significant increase in relative volume of medulla at the expense of the relative volume of the cortex and a decrease in the number of lymphocytes. However, we recorded an increase in diameter of lymphocytes. The intracellular parasite Toxoplasma gondii (T. gondii) belongs to the most common pathogenic parasites in the world and it can cause serious health complications in pregnant and immunodeficient individuals. DNA isolation, standard polymerase chain reaction (PCR) and visualization in a 2.5 % agarose gel, the presence of DNA T. gondii was detected in no examined rabbit brain samples. Using real time PCR T. gondii DNA was detected and quantified in the three rabbit brain samples (10 %). PMID- 20845184 TI - Metolachlor and chlorothalonil dissipation in gypsum-amended soil. AB - This work focused on the interactive effects of the fungicide chlorothalonil (2,3,4,6-tetrachloro-1,3-benzendicarbonitrile) and gypsum on the persistence of the soil-residual herbicide metolachlor (2-chloro-N-(6-ethyl-o-tolyl)-N-[(1RS)-2 methoxy-1-methylethyl]acetamide). Gypsum application was included due to its widespread use on peanut (Arachis hypogaea). Both agricultural grade gypsum and reagent CaSO(4)-2H(2)O were tested. A laboratory soil incubation was conducted to evaluate interactive effects. Results indicated 1.5X greater metolachlor half life (DT(50)) in soil amended with chlorothalonil (37 d) as compared to control soil (25 d). The two gypsum sources alone increased metolachlor DT(50) to about 32 d and with the combination of chlorothalonil and gypsum, DT50 was 50 d, 2-fold greater than the control. Chlorothalonil dissipation was rapid (DT(50) < 4d). A possible explanation for metolachlor dissipation kinetics is a build-up of the chlorothalonil intermediate (4-hydroxychlorothalonil) which limited soil microbial activity and depleted glutathione S-transferase (GST) from chlorothalonil detoxification. Further information related to gypsum impacts is needed. Results confirm previous reports of chlorothalonil impeding metolachlor dissipation and showed the gypsum application extended persistence even longer. Farming practices, such as reducing metolachlor application rates, may need to be adjusted for peanut cropping systems where chlorothalonil and gypsum are used. PMID- 20845186 TI - Health literacy improvement as a national priority. PMID- 20845187 TI - Improve health literacy. PMID- 20845188 TI - The evolving field of health literacy research. PMID- 20845189 TI - Health literacy: what is it? AB - The concept of health literacy evolved from a history of defining, redefining, and quantifying the functional literacy needs of the adult population. Along with these changes has come the recognition that sophisticated literacy skills are increasingly needed to function in society and that low literacy may have an effect on health and health care. We present a brief history of literacy in the United States, followed by a discussion of the origins and conceptualization of health literacy. Increased attention to this important issue suggests the need to review existing definitions of the term "health literacy," because despite the growing interest in this field, one question that persists is, "What is health literacy?" PMID- 20845190 TI - Health literacy: a second decade of distinction for Americans. AB - Efforts to describe health literacy in the last decade have helped us define the issue and recognize that our public's skills and abilities are not adequate for successfully navigating the growing demands and complexity of healthcare. There have been significant developments in health literacy over the last decade, with milestones of progress. Much of the work done in the 1990s focused on defining health literacy, initially measuring its prevalence and subsequently looking at its associations. Since then, health literacy has grown from an issue of an under recognized "silent epidemic" to an issue of health policy and reform. Ideas and objectives proposed have actually been adopted in recent years, with significant policy developments. This article recognizes many achievements and milestones while developing recommendations for implementation in the decade ahead. PMID- 20845191 TI - Promoting health literacy research to reduce health disparities. AB - Limited health literacy has been linked to worse health outcomes for a range of medical conditions. In addition, limited health literacy is more prevalent among specific racial and ethnic minorities. Although these findings have been widely acknowledged, little systematic research has been conducted to elucidate the role of health literacy in the creation of health disparities or to evaluate the possibility that interventions relating to health literacy may help eliminate health disparities. This paper presents recommendations for a research agenda that is focused on advancing the science for how health literacy research can promote the effort to eliminate health disparities. PMID- 20845192 TI - New directions in research on public health and health literacy. AB - Numerous calls for a public health approach to health literacy and visions of a health literate society have appeared in recent years. Yet, many gaps in what we know about and do to improve health literacy remain. Major developments at the national level in the last decade help define the role of health literacy in creating better public health and have set the stage for new investigations in public health and health literacy. Four frameworks are examined for their usefulness in posing new questions about public health and health literacy: Healthy People, the Ten Essential Public Health Functions, health promotion, and health disparities. Each of the frameworks generates questions and uses methods that can produce new findings about health literacy. Using the frameworks will open new investigations into population health and health literacy improvement at multiple levels. PMID- 20845193 TI - Measuring health literacy: a pilot study of a new skills-based instrument. AB - Although a number of instruments have been used to measure health literacy, a key limitation of the leading instruments is that they only measure reading ability or print literacy and, to a limited extent, numeracy. Consequently, the present study aimed to develop a new instrument to measure an individual's health literacy using a more comprehensive and skills-based approach. First, we identified a set of skills to demonstrate and tasks to perform. Next, we selected real-world health-related stimuli to enable measurement of these skills, and then we developed survey items. After a series of cognitive interviews, the survey items were revised, developed into a 38-item instrument, and pilot tested using a Web-based panel. Based on the psychometric properties, we removed items that did not perform as well, resulting in a 25-item instrument named the Health Literacy Skills Instrument. Based on confirmatory factor analysis, the items were grouped into five subscales representing prose, document, quantitative, oral, and Internet-based information seeking skills. Construct validity was supported by correlations with the short form of the Test of Functional Health Literacy in Adults and self-reported skills. The overall instrument demonstrated good internal consistency, with a Cronbach's alpha of 0.86. Additional analyses are planned, with the goal of creating a short form of the instrument. PMID- 20845194 TI - Ask, understand, remember: a brief measure of patient communication self-efficacy within clinical encounters. AB - Patients' ability to effectively communicate with their health care providers is an essential aspect of proper self-care, especially for those with chronic conditions. We wanted to develop and validate a brief, reliable measure of patient communication self-efficacy within clinical encounters. Consecutively recruited patients (n = 330) with diagnosed hypertension from seven primary care clinics in Chicago, Illinois, Grand Rapids, Michigan, and Shreveport, Louisiana completed an in-person interview including chronic disease self-efficacy, hypertension knowledge, health literacy assessments, and items modified from the Communication and Attitudinal Self-Efficacy (CASE) - Cancer scale. Six items from the CASE were candidates for a new scale due to their focus on the patient provider relationship. Using principal components analysis with varimax rotation, four items strongly loaded onto one factor (Eigenvalue = 2.33; proportion of variance explained = 58%) with a Cronbach's alpha coefficient of 0.75. The measure, referred to as the Ask, Understand, Remember Assessment, (AURA) was moderately correlated with the total score from an existing chronic disease management self-efficacy scale (r = 0.31) and disease knowledge (beta coefficient = 0.2, 95% Confidence Interval 0.04 - 0.3, p = .03). Patients with low health literacy had lower scores on the AURA than those with marginal or adequate health literacy (p < .05). The AURA demonstrated high internal consistency and was correlated with both hypertension knowledge and a chronic disease self-efficacy scale. The AURA is brief, valid, has low reading demands, and is an appropriate tool for use among patients with chronic illness. It may also be useful in identifying and assisting patients who are at risk for errors or non-adherence with self-care behaviors. PMID- 20845195 TI - Acceptability of the talking touchscreen for health literacy assessment. AB - Self-administration of a multimedia health literacy measure in clinic settings is a novel concept. Demonstrated ease of use and acceptability will help predicate the future value of this strategy. We previously demonstrated the acceptability of a "Talking Touchscreen" for health status assessment. For this study, we adapted the touchscreen for self-administration of a new health literacy measure. Primary care patients (n = 610) in clinics for underserved populations completed health status and health literacy questions on the Talking Touchscreen and participated in an interview. Participants were 51% women, 10% age 60+, 67% African American, 18% without a high school education, and 14% without any prior computer experience. The majority (93%) had no difficulty using the touchscreen, including those who were computer-naive (87%). Most rated the screen design as very good or excellent (72%), including computer-naive patients (71%) and older patients (75%). Acceptability of the touchscreen did not differ by health literacy level. The Talking Touchscreen was easy to use and acceptable for self administration of a new health literacy measure. Self-administration should reduce staff burden and costs, interview bias, and feelings of embarrassment by those with lower literacy. Tools like the Talking Touchscreen may increase exposure of underserved populations to new technologies. PMID- 20845196 TI - The development of a health literacy assessment tool for health plans. AB - Despite growing information on the magnitude and consequences of low health literacy, there is little information about the role health plans are playing and the activities they undertake to address this problem. Our goal was to develop a health literacy organizational assessment tool for health plans that could be used as a benchmark and encourage further work. The existing tool consists of six evaluation areas: (1) information for members/navigation; (2) member services/communication; (3) web navigation; (4) forms; (5) nurse call line; and (6) nurse case/disease management. During May and June, 2009, a pilot was conducted with eight diverse health plans, including national, regional, and local plans serving commercial, Medicare, and/or Medicaid members. After incorporating feedback from the pilot, the full assessment was launched in June 2009. Feedback from the participating plans has been very positive about using this tool as a benchmark and using the results to help strengthen health literacy efforts within their health plans. The variety of health plans that have utilized this assessment tool suggests that widespread use is possible. Evaluation of health literacy efforts using this comprehensive tool can help bring attention to areas in need of improvement and help plans better engage consumers in their own health. PMID- 20845197 TI - Health literacy and communication quality in health care organizations. AB - The relationship between limited health literacy and poor health may be due, in part, to poor communication quality within health care delivery organizations. We explored the relationship between health literacy status and receiving patient centered communication in clinics and hospitals serving communication-vulnerable patient populations. Thirteen health care organizations nationwide distributed a survey to 5929 patients. All patients completed seven items assessing patient centered communication. One third also completed three items assessing health literacy. The majority of patients had self-reported health literacy challenges, reporting problems learning about their medical condition because of difficulty understanding written information (53%), a lack of confidence in completing medical forms by themselves (61%), and needing someone to help them read hospital/clinic materials (57%). Logistic regression models showed that, after adjustment for patient demographic characteristics and health care organization type, patients with limited health literacy were 28% to 79% less likely than those with adequate health literacy to report their health care organization "always" provides patient-centered communication across seven communication items. Using a scaled composite of these items, limited health literacy remained associated with lower reported communication quality. These results suggest that improving communication quality in health care organizations might help to address the challenges facing patients with limited health literacy. They also highlight that efforts to address the needs of patients with limited health literacy should be sensitive to the range of communication challenges confronting these patients and their caregivers. PMID- 20845198 TI - Literacy, cognitive ability, and the retention of health-related information about colorectal cancer screening. AB - Interventions to mitigate the impact of low literacy on patients' recall of information by simplifying language have had limited success. The current study examines the extent to which cognition explains the relationship between literacy and retention of health information. Primary care patients aged 40 to 85 years watched a video about colorectal cancer (CRC) screening and then answered knowledge-based questions about the video's content as well as a literacy assessment and cognitive assessments measuring processing speed, working memory, and-long term memory. A week later, available participants completed the knowledge assessment a second time. In regression models for immediate knowledge, literacy significantly predicted knowledge. However, once cognition (i.e., processing speed, working memory, and long-term memory) was added to the model, it explained 70.7% of the relationship between literacy and performance. A week later, literacy again significantly predicted knowledge, but entering cognition into the model explained 45.9% of the relationship between literacy and performance. These results suggest that cognition explains much of the association between literacy and both immediate and delayed recall of health information. Design and intervention strategies for educational tools should consider cognitive factors such as working memory demands in addition to focusing on the readability of materials. PMID- 20845199 TI - Media messages about cancer: what do people understand? AB - Health messages on television and other mass media have the potential to significantly influence the public's health-related knowledge and behaviors, but little is known about people's ability to comprehend such messages. To investigate whether people understood the spoken information in media messages about cancer prevention and screening, we recruited 44 adults from 3 sites to view 6 messages aired on television and the internet. Participants were asked to paraphrase main points and selected phrases. Qualitative analysis methods were used to identify what content was correctly and accurately recalled and paraphrased, and to describe misunderstandings and misconceptions. While most participants accurately recalled and paraphrased the gist of the messages used here, overgeneralization (e.g., believing preventative behaviors to be more protective than stated), loss of details (e.g., misremembering the recommended age for screening), and confusion or misunderstandings around specific concepts (e.g., interpreting "early stage" as the stage in one's life rather than cancer stage) were common. Variability in the public's ability to understand spoken media messages may limit the effectiveness of both pubic health campaigns and provider-patient communication. Additional research is needed to identify message characteristics that enhance understandability and improve comprehension of spoken media messages about cancer. PMID- 20845200 TI - Self-efficacy links health literacy and numeracy to glycemic control. AB - The mechanisms underlying the relationship between health literacy, numeracy, and glycemic control are unclear. We explored the role of diabetes self-efficacy in the predicted pathway linking health literacy and numeracy to glycemic control (A1C). Adults with type 1 or type 2 diabetes mellitus (N = 383) were enrolled in a cross-sectional study at primary care and diabetes clinics at three medical centers. Data collected included demographic information, health literacy, general numeracy, and A1C. Path models estimated relations among health literacy, numeracy, and diabetes self-efficacy as predictors of A1C. Health literacy (r = 0.14, p < .01) and numeracy (r = 0.17, p < .001) were each associated with greater diabetes self-efficacy, and greater diabetes self-efficacy was associated with lower A1C levels (r = -0.25, p < .001). When considered in combination, numeracy was related to diabetes self-efficacy (r = 0.13, p < .05), and the effect of health literacy on diabetes self-efficacy was reduced to non significance (r = 0.06, p = .30). Health literacy and numeracy are each associated with greater diabetes self-efficacy, and greater diabetes self efficacy is associated with lower A1C levels. Diabetes self-efficacy may be an important target of interventions to improve diabetes control and promote health equity related to health literacy and general numeracy skills needed for diabetes management. PMID- 20845201 TI - Uncertainty about advance care planning treatment preferences among diverse older adults. AB - The complexities associated with advance treatment decisions may result in decisional uncertainty and poorly informed choices, particularly among vulnerable populations such as minorities and patients with limited health literacy. Using a hypothetical scenario, we assessed uncertainty about treatment preferences among 205 chronically ill, English/Spanish-speaking older adults from a county outpatient clinic in San Francisco. Participants were read a scenrio that described a very poor health state and poor outcome of life support treatment. Participants were asked to imagine that they were in this scenario and to choose either: all life support treatments; try life support with an option of stopping; or no life support. They were then asked how certain they were about this decision. Forty-five percent of participants were uncertain about their decision. In adjusted multivariate analysis, Latinos and Asian/Pacific Islanders were more likely than Whites to be uncertain about their treatment decisions, as were participants with limited versus adequate literacy and poor versus good self rated health. Many patients may be uncertain about advance treatment preferences. Culturally sensitive, literacy-appropriate tools are needed to address decisional uncertainty and to help patients prepare for decision making about their future health care. PMID- 20845202 TI - How to achieve informed consent for research from Spanish-speaking individuals with low literacy: a qualitative report. AB - Investigators have the responsibility to ensure that prospective participants are fully informed about a research protocol prior to consenting to participate, yet many researchers face challenges when obtaining consent, since the majority of the general population has limited or no familiarity with research studies. These challenges are further magnified when obtaining consent from individuals with low literacy levels and who speak languages other than English. In this article we present findings from a qualitative study conducted with Spanish-speaking individuals with low-literacy designed to refine the Agency for Healthcare Research and Quality's Informed Consent and Authorization Toolkit for Minimal Risk Research. Findings from this study indicate that familiarity with providing informed consent and authorization for research or the experience of being a research participant appear to play key roles in an individual's ability to understand the consent and authorization process. While the text of the consent and authorization documents can be simplified using plain language principles, comprehension of several fundamental ideas such as risk and privacy need to be safeguarded with a consent process that confirms comprehension. Recommendations are provided to address the informational needs of individuals with low literacy levels and limited or no experience with research participation. PMID- 20845203 TI - The literacy divide: health literacy and the use of an internet-based patient portal in an integrated health system-results from the diabetes study of northern California (DISTANCE). AB - Internet-based patient portals are intended to improve access and quality, and will play an increasingly important role in health care, especially for diabetes and other chronic diseases. Diabetes patients with limited health literacy have worse health outcomes, and limited health literacy may be a barrier to effectively utilizing internet-based health access services. We investigated use of an internet-based patient portal among a well characterized population of adults with diabetes. We estimated health literacy using three validated self report items. We explored the independent association between health literacy and use of the internet-based patient portal, adjusted for age, gender, race/ethnicity, educational attainment, and income. Among 14,102 participants (28% non-Hispanic White, 14% Latino, 21% African-American, 9% Asian, 12% Filipino, and 17% multiracial or other ethnicity), 6099 (62%) reported some limitation in health literacy, and 5671 (40%) respondents completed registration for the patient portal registration. In adjusted analyses, those with limited health literacy had higher odds of never signing on to the patient portal (OR 1.7, 1.4 to 1.9) compared with those who did not report any health literacy limitation. Even among those with internet access, the relationship between health literacy and patient portal use persisted (OR 1.4, 95% CI 1.2 to 1.8). Diabetes patients reporting limited health literacy were less likely to both access and navigate an internet-based patient portal than those with adequate health literacy. Although the internet has potential to greatly expand the capacity and reach of health care systems, current use patterns suggest that, in the absence of participatory design efforts involving those with limited health literacy, those most at risk for poor diabetes health outcomes will fall further behind if health systems increasingly rely on internet-based services. PMID- 20845205 TI - Health literacy and the Millennium Development Goals: United Nations Economic and Social Council (ECOSOC) regional meeting background paper (abstracted). AB - This paper uses a health literacy "lens" to look at key global health challenges, including the achievement of health-related Millennium Development Goals (MDGs) and the reduction of disease burden due to non-communicable diseases (NCDs). Available global evidence is summarized related to: assessment of the impact of health literacy on health and development; identification of measures for reporting progress; exploring ways to strengthen multisectoral collaboration at the national, regional, and international levels to undertake joint actions for increasing health literacy; finding ways to promote better access and use of information through information and communication technology and empowerment; and building capacity for sustained action to increase health literacy. Key action messages are identified. Findings presented informed the 2009 ECOSOC Ministerial Declaration on Health Literacy. PMID- 20845204 TI - Usability of conversational agents by patients with inadequate health literacy: evidence from two clinical trials. AB - Embodied Conversational Agents (ECA) are computer-animated characters that simulate face-to-face conversation with patients. These agents can be programmed with best practices in human-human health communication and used for automated health education and behavior change counseling interventions. Evidence is presented from two ongoing clinical trials demonstrating that patients at different levels of health literacy find these agents acceptable and easy to use for automated health communication interventions. Innovative computer interface systems can be used to ensure that inadequate health literacy not serve as a barrier to interventions using health information technology. PMID- 20845207 TI - Hexavalent chromium exposure and control in welding tasks. AB - Studies of exposure to the lung carcinogen hexavalent chromium (CrVI) from welding tasks are limited, especially within the construction industry where overexposure may be common. In addition, despite the OSHA requirement that the use of engineering controls such as local exhaust ventilation (LEV) first be considered before relying on other strategies to reduce worker exposure to CrVI, data on the effectiveness of LEV to reduce CrVI exposures from welding are lacking. The goal of the present study was to characterize breathing zone air concentrations of CrVI during welding tasks and primary contributing factors in four datasets: (1) OSHA compliance data; (2) a publicly available database from The Welding Institute (TWI); (3) field survey data of construction welders collected by the Center for Construction Research and Training (CPWR); and (4) controlled welding trials conducted by CPWR to assess the effectiveness of a portable LEV unit to reduce CrVI exposure. In the OSHA (n = 181) and TWI (n = 124) datasets, which included very few samples from the construction industry, the OSHA permissible exposure level (PEL) for CrVI (5 MUg/m(3)) was exceeded in 9% and 13% of samples, respectively. CrVI concentrations measured in the CPWR field surveys (n = 43) were considerably higher, and 25% of samples exceeded the PEL. In the TWI and CPWR datasets, base metal, welding process, and LEV use were important predictors of CrVI concentrations. Only weak-to-moderate correlations were found between total particulate matter and CrVI, suggesting that total particulate matter concentrations are not a good surrogate for CrVI exposure in retrospective studies. Finally, in the controlled welding trials, LEV reduced median CrVI concentrations by 68% (p = 0.02). In conclusion, overexposure to CrVI in stainless steel welding is likely widespread, especially in certain operations such as shielded metal arc welding, which is commonly used in construction. However, exposure could be substantially reduced with proper use of LEV. PMID- 20845208 TI - Early age of first sexual intercourse and depressive symptomatology among adolescents. AB - Past literature has provided conflicting evidence for the association between adolescent sexual intercourse and depressive symptomatology. Whereas some studies conclude that sexually active youth may be at risk for depression, others provide contrary results. Thus, it is unclear as to whether depression results directly from coitus or if this relationship is explained by other factors-that is, there may be biological, psychological, or sociological predictors of both depressive symptomatology and early sexual intercourse. Using the National Longitudinal Study of Adolescent Health dataset, depressive symptomatology in adolescents over a seven-year time period was analyzed. The final sample (n = 6,510) was comprised of 49.35% male (n = 3,213) and 50.65% female (n = 3,297) participants. Although an earlier age of first coitus was predictive of future depressive symptoms, both variables appear to be concomitant outcomes of the biopsychosocial process. Thus, although one may be able to use early coitus as a marker for subsequent depressive symptomatology, it does not appear to occur because of early sexual intercourse. Furthermore, the reverse relationship was not found to be significant in this study-that is, higher levels of previous depressive symptomatology did not predict an earlier age of first sexual intercourse in adolescents. PMID- 20845209 TI - It's his right, it's her duty: benevolent sexism and the justification of traditional sexual roles. AB - This study tested the effects on social perceptions of sexual marital rights and duties of ambivalent sexist ideology and information about the benevolent sexist ideology of a husband, portrayed in a hypothetical marital vignette. In addition, the perception of whether hypothetical forced sex between husband and wife is considered rape was explored. For one half of the participants (college students), the husband was presented as high in benevolent sexism (BS); and for the other half, no information about his ideology was given. Results showed that participants in the first group ranked sexual marital rights (for him) and duties (for her) more highly, and regarded forced sex as rape to a lesser extent. Positive relationships were also found between participants' BS and these ratings. Moreover, participants' perceptions of marital rights and duties played a mediating role in the relationship between their BS and their perception of forced penetration as rape. Finally, an interaction was found between participants' and husbands' BS in the perception of marital rights and duties: The influence of participants' BS was higher when the husband was presented as a benevolent sexist man. Results highlight the role of sexist attitudes in the interpretation of marital rape. PMID- 20845210 TI - No effect of acute ingestion of Thai ginseng (Kaempferia parviflora) on sprint and endurance exercise performance in humans. AB - Thai ginseng, Kaempferia parviflora, is widely believed among the Mong hill tribe to reduce perceived effort and improve physical work capacity. Kaempferia parviflora is consumed before their daily work. Therefore, we conducted an acute study on the effects of K. parviflora on repeated bouts of sprint exercise and on endurance exercise time to exhaustion. Two studies were conducted in college males using a randomized, double-blind, crossover design. Ninety minutes after consumption of K. parviflora or a starch placebo, participants in study 1 (n = 19) completed three consecutive maximum 30-s sprint cycling Wingate tests, separated by 3 min recovery, while participants in study 2 (n = 16) performed submaximal cycling exercise to exhaustion. Peak and mean power output decreased with successive Wingate tests, while percent fatigue and blood lactate concentration increased after the third Wingate test (P < 0.05). There were no detectable differences in any measures with or without K. parviflora. There was also no effect of K. parviflora on time to exhaustion, rating of perceived exertion or heart rate during submaximal exercise. Our results indicate that acute ingestion of K. parviflora failed to improve exercise performance during repeated sprint exercise or submaximal exercise to exhaustion. However, chronic effects or actions in other populations cannot be excluded. PMID- 20845211 TI - Exercise, music, and the brain: is there a central pattern generator? AB - The frequency for movements along the longitudinal axis during running peaks at approximately 3 Hz. Other physiological systems (e.g. heart rate and brain cortical activity) are known to show a dominant frequency of ~3 Hz connected to exercise. As recent studies have proposed a clear correlation between musical tempo, mood, and performance output, we wished to ascertain whether peak locomotion frequency of ~3 Hz during running is synchronized with different intrinsic and extrinsic frequencies. Eighteen healthy regular runners performed three outdoor running sessions at different intensities. Oscillations along the longitudinal axis were recorded using an accelerometer (ActiBelt). Electrocortical activity was recorded using electroencephalography before and after exercise and analysed in the delta frequency range (2-4 Hz). In addition, the frequency spectra of the participants' favourite musical pieces were analysed. Data revealed a peak frequency at around 2.7 to 2.8 Hz for the vertical acceleration during running. Similar oscillation patterns were found for heart rate and musical pieces. Electroencephalographic delta activity increased after running. Results of this study give reason to speculate that a strong relationship exists between intrinsic and extrinsic oscillation patterns during exercise. A frequency of approximately 3 Hz seems to be dominant in different physiological systems and seems to be rated as pleasurable when choosing the appropriate music for exercising. This is in line with previous research showing that an adequate choice of music during exercise enhances performance output and mood. PMID- 20845212 TI - Could a vegetarian diet reduce exercise-induced oxidative stress? A review of the literature. AB - Oxidative stress is a natural physiological process that describes an imbalance between free radical production and the ability of the antioxidant defence system of the body to neutralize free radicals. Free radicals can be beneficial as they may promote wound healing and contribute to a healthy immune response. However, free radicals can have a detrimental impact when they interfere with the regulation of apoptosis and thus play a role in the promotion of some cancers and conditions such as cardiovascular disease. Antioxidants are molecules that reduce the damage associated with oxidative stress by counteracting free radicals. Regular exercise is a vital component of a healthy lifestyle, although it can increase oxidative stress. As a typical vegetarian diet comprises a wide range of antioxidant-rich foods, it is plausible that the consumption of these foods will result in an enhanced antioxidant system capable of reducing exercise-induced oxidative stress. In addition, a relationship between a vegetarian diet and lower risks of cardiovascular disease and some cancers has been established. This review explores the current available evidence linking exercise, vegetarians, antioxidants, and oxidative stress. PMID- 20845213 TI - Three-dimensional kinematics and ground reaction forces during the instep and outstep soccer kicks in pubertal players. AB - The purpose of the present study was to compare the three-dimensional kinematics of the lower extremities and ground reaction forces between the instep kick and the kick with the outside area of the foot (outstep kick) in pubertal soccer players. Ten pubertal soccer players performed consecutive kicking trials in random order after a two-step angled approach with the instep and the outstep portion of the foot. Three-dimensional data and ground reaction forces were measured during kicking. Paired t-tests indicated significantly higher (P < 0.05) ball speeds and ball/foot speed ratios for the instep kick compared with the outstep kick. Non-significant differences in angular and linear sagittal plane kinematic parameters, temporal characteristics, and ground reaction forces between the instep and outstep soccer kicks were observed (P > 0.05). In contrast, analysis of variance indicated that the outstep kick displayed higher hip internal rotation and abduction, knee internal rotation, and ankle inversion than the instep kick (P < 0.05). Our results suggest that the instep kick is more powerful than the outstep kick and that different types of kick require different types of skill training. PMID- 20845214 TI - Children's self-perceived bodily competencies and associations with motor skills, body mass index, teachers' evaluations, and parents' concerns. AB - The associations between physical competence, self-perceived bodily competence, parental concern for their children's motor skill development, and teachers' evaluation of their bodily competence were assessed in 646 six- to seven-year olds. Physical competence was assessed by the German motor ability test "Korperkoordinationstest fur Kinder", while the children's, their parents', and their teachers' evaluations were obtained through questionnaires. Parental concern, teacher evaluation, and a high body mass index were the strongest predictors of low physical competence (motor skill quotient < 85). Teachers' evaluation of bodily competence was associated with low self-perceived bodily competence in the children even after adjustment for motor skill quotient, with an odds ratio of 2.3 (P < 0.05) between the lowest and highest of the three levels after correction for motor skill competence. Results indicate that teachers' evaluation of children's motor skills should be considered a key factor when tracking and assessing physical competencies among youth. PMID- 20845215 TI - The relationship between biomechanical variables and driving performance during the golf swing. AB - Swing kinematic and ground reaction force data from 308 golfers were analysed to identify the variables important to driving ball velocity. Regression models were applied at four selected events in the swing. The models accounted for 44-74% of variance in ball velocity. Based on the regression analyses, upper torso-pelvis separation (the X-Factor), delayed release (i.e. the initiation of movement) of the arms and wrists, trunk forward and lateral tilting, and weight-shifting during the swing were significantly related to ball velocity. Our results also verify several general coaching ideas that were considered important to increased ball velocity. The results of this study may serve as both skill and strength training guidelines for golfers. PMID- 20845216 TI - Effects of different cooling treatments on water diffusion, microcirculation, and water content within exercised muscles: evaluation by magnetic resonance T2 weighted and diffusion-weighted imaging. AB - In this study, we determined the effects of different cooling treatments on exercised muscles. Seven adults underwent four post-exercise treatments (20-min ice-bag application, 60-min gel-pack application at 10 degrees C and 17 degrees C, and non-cooling treatment) with at least 1 week between treatments. Magnetic resonance diffusion- and T2-weighted images were obtained to calculate the apparent diffusion coefficients (apparent diffusion coefficient 1, which reflects intramuscular water diffusion and microcirculation, and apparent diffusion coefficient 2, which is approximately equal to the true diffusion coefficient that excludes as much of the effect of intramuscular microcirculation as possible) and the T2 values (intramuscular water content level) of the ankle dorsiflexors, respectively, before and after ankle dorsiflexion exercise and after post-exercise treatment. The T2 values increased significantly after exercise and returned to pre-exercise values after each treatment; no significant differences were observed among the four post-exercise treatments. Both apparent diffusion coefficients also increased significantly after exercise and decreased significantly after the three cooling treatments; no significant difference was detected among the three cooling treatments. Local cooling suppresses both water diffusion and microcirculation within exercised muscles. Moreover, although the treatment time was longer, adequate cooling effects could be achieved using the gel-pack applications at relatively mild cooling temperatures. PMID- 20845217 TI - Kinematic characteristics of the stroke and orientation of the hand during front crawl resisted swimming. AB - The aim of this study was to examine the acute effect of front crawl sprint resisted swimming with different added resistances on the kinematic characteristics of the stroke and the orientation of the hand. Ten female swimmers swam four maximal trials (25 m) with small, moderate, large, and no added resistance respectively. Four camcorders were used to record the underwater motion of the right hand and digitizing was undertaken using the Ariel Performance Analysis System. Stroke rate, the stroke length, and mean swimming velocity were significantly decreased, whereas the total duration of the stroke and the relative duration of the pull and push phases were significantly increased during resisted swimming. The increase in the total duration of the stroke was accompanied by an increase in absolute pull length, while no alterations were observed in relative pull length or medial-lateral displacements of the hand. Moreover, the mean resultant velocity of the hand, as well as the pitch and the sweepback angles of the hand were not modified. In conclusion, resisted swimming appears to be a specific form of training, at least regarding its acute effect, although long-term effects should be investigated further. PMID- 20845218 TI - Post-prandial capillary triacylglycerol responses to moderate exercise in centrally obese middle-aged men. AB - In this study, we wished to determine whether 30 min of moderate-intensity exercise, corresponding to minimal recommended guidelines, attenuates post prandial capillary triacylglycerol concentrations in obese men. Ten middle-aged, centrally obese men (age 46 +/- 2 years, body mass index 31.6 +/- 1.0 kg . m(-2), waist circumference 104.6 +/- 2.2 cm) completed two 2-day trials (exercise and control) at least one week apart in a randomized, repeated-measures design. On day 1, participants either cycled for 30 min at approximately 60% of maximal heart rate in the afternoon or rested (no exercise). On day 2 of both trials, after a 10-h overnight fast, participants consumed a test meal of moderate fat content (35%) for breakfast. Capillary blood samples were collected in the fasted state (0 h) and at 2, 4, and 6 h post-prandially on day 2. Total area under the capillary triacylglycerol concentration versus time curve was significantly lower on the exercise than control trial (P = 0.023). One 30-min session of moderate intensity cycling is effective in lowering post-prandial capillary triacylglycerol concentration in obese middle-aged men. These findings may have important implications for exercise recommendations as a means to reduce the risk of cardiovascular disease if such exercise is performed for an extended period. PMID- 20845219 TI - Systematically increasing contextual interference is beneficial for learning sport skills. AB - To better understand the contextual interference effect, in two experiments we investigated a form of practice schedule that provided novices with systematic increases in contextual interference. This new type of practice schedule was compared with traditional blocked and random scheduling for two types of sports skills. In Experiment 1, we tested the hypothesis that practising variations of the same task with systematic increases in contextual interference would lead to superior performance compared with blocked or random scheduling. Participants practised golf putting tasks following a blocked, random or increasing schedule, which involved initial blocked trials, followed by serial practice trials, and ended with random scheduling. Participants who followed the increasing schedule had superior retention test performance. In Experiment 2, we tested if these learning benefits were observed when learning tasks controlled by different generalized motor programs. Participants practised three different basketball passes (chest, overhead, single arm) in a blocked, random or increasing schedule. Participants practising with gradual increases in contextual interference performed better on retention and transfer tests than participants practising with blocked or random scheduling. The results of these two expe PMID- 20845220 TI - A cross-sectional examination of the physical fitness and selected health attributes of recreational all-terrain vehicle riders and off-road motorcyclists. AB - The aims of this study were: (1) to characterize selected fitness and health attributes of two types of habitual recreational off-road vehicle riders - off road motorcyclists and all-terrain vehicle riders; (2) to explore differences among riders in terms of vehicle type, age, and gender; and (3) to compare the fitness and health of riders to population norms and clinical health standards. Canadian off-road riders (n = 141) of both sexes aged 16 years and over were recruited through local and national off-road riding organizations. Anthropometry, fitness, and health measures of off-road motorcycle and all terrain vehicle riders were compared with population norms, health standards, and physical activity guidelines. Off-road motorcycle riders had above average aerobic fitness (79th percentile), while all-terrain vehicle riders were lower than average (40th percentile). All riders had a healthy blood lipid profile and a low incidence of the metabolic syndrome (12.9%) compared with members of the general population. Off-road motorcycle riders had healthier body composition and fitness than all-terrain vehicle riders; however, the body composition of off road motorcycle riders was no healthier than that of the general population and all-terrain vehicle riders were worse than the general population. Off-road motorcycle riders had healthier anthropometry and fitness than all-terrain vehicle riders and thus fewer health risk factors for future disease, demonstrating that the physiological profiles of off-road riders are dependent on vehicle type. PMID- 20845221 TI - ACTN3 R577X and other polymorphisms are not associated with elite endurance athlete status in the Genathlete study. AB - Homozygosity for a premature stop codon at amino acid position 577 in the alpha actinin-3 (ACTN3) gene leads to alpha-actinin-3 deficiency. This genotype is observed in approximately 18% of Caucasians. The ACTN3 R577X polymorphism has been previously associated with indicators of physical performance in several, but not all, studies. We examined the prevalence of R577X (rs1815739) and two additional haplotype tagging single nucleotide polymorphisms (htSNPs) of the ACTN3 gene (rs1791690 and rs2275998) in the Genathlete study comprising 316 male elite endurance athletes (VO2max 79.0+3.5 ml . kg(-1) . min(-1); mean +/- s) from North America, Finland, and Germany and 304 sedentary controls (VO2max 40.1+7.0 ml . kg(-1) . min(-1) matched by country of origin. The distribution of genotype and allele frequencies between the two groups was tested by Pearson chi-square and/or Fischer exact test. The prevalence of the 577X homozygote genotype was similar in endurance athletes and controls (20% and 17.5%, respectively). The resulting odds ratio for endurance performance in 577X homozygotes compared with 577R-allele carriers was 1.24 (95%CI 0.82-1.87, P = 0.3). The genotype distribution of the two htSNPs and haplotype frequencies did not differ significantly between athletes and controls. In conclusion, our findings indicate that ACTN3 R577X and other SNPs in ACTN3 are not genetic determinants of endurance performance in Caucasian males. PMID- 20845222 TI - Relationships among peak power output, peak bar velocity, and mechanomyographic amplitude during the free-weight bench press exercise. AB - The purpose of this study was to examine the relationships among mechanomyographic (MMG) amplitude, power output, and bar velocity during the free weight bench press exercise. Twenty-one resistance-trained men [one-repetition maximum (1-RM) bench press = 125.4+18.4 kg] performed bench press muscle actions as explosively as possible from 10% to 90% of the 1-RM while peak power output and peak bar velocity were assessed with a TENDO Weightlifting Analyzer. During each muscle action, surface MMG signals were detected from the right and left pectoralis major and triceps brachii, and the concentric portion of the range of motion was selected for analysis. Results indicated that power output increased from 10% to 50% 1-RM, followed by decreases from 50% to 90% 1-RM, but MMG amplitude for each of the muscles increased from 10 to 80% 1-RM. The results of this study indicate that during the free-weight bench press exercise, MMG amplitude was not related to power output, but was inversely related to bar velocity and directly related to the external load being lifted. In future research, coaches and sport scientists may be able to estimate force/torque production from individual muscles during multi-joint, dynamic constant external resistance muscle actions. PMID- 20845223 TI - Automatically assisting human memory: a SenseCam browser. AB - SenseCams have many potential applications as tools for lifelogging, including the possibility of use as a memory rehabilitation tool. Given that a SenseCam can log hundreds of thousands of images per year, it is critical that these be presented to the viewer in a manner that supports the aims of memory rehabilitation. In this article we report a software browser constructed with the aim of using the characteristics of memory to organise SenseCam images into a form that makes the wealth of information stored on SenseCam more accessible. To enable a large amount of visual information to be easily and quickly assimilated by a user, we apply a series of automatic content analysis techniques to structure the images into "events", suggest their relative importance, and select representative images for each. This minimises effort when browsing and searching. We provide anecdotes on use of such a system and emphasise the need for SenseCam images to be meaningfully sorted using such a browser. PMID- 20845224 TI - Childbearing history, later-life health, and mortality in Germany. AB - Using data from the German Socio-Economic Panel, we investigated the role of childbearing history in later-life health and mortality, paying particular attention to possible differences by sex and region. Higher parity is associated with better self-rated health in West German mothers and fathers aged 50+, but its relationship with East German women's physical health and survival is negative. Early motherhood is paralleled by poorer physical health in West Germany, whereas late motherhood is associated with lower psychological well being in Eastern Germany. Moreover, among West German women, having had a non marital first birth is weakly correlated with poorer physical health. Our findings support the notion of biosocial pathways playing an important role in shaping the fertility-health nexus. Specifically, the West German 'male breadwinner' model of specialization appears to have buffered the stresses associated with childrearing, whereas fertility off the 'normative' life-course track appears to have had adverse effects on women's health in West Germany. PMID- 20845225 TI - Narrative evolution and assimilation of problematic experiences in a case of pharmacotherapy for schizophrenia. AB - This case study applied the assimilation model to examine the changing narrative of an outpatient with schizophrenia and symptoms of depression across a successful pharmacotherapy. The assimilation model describes how clients assimilate painful, problematic experiences. Therapeutic progress is understood to reflect increasing assimilation, measured by the Assimilation of Problematic Experiences Scale (APES). The authors used a 15-min semistructured interview (Problematic Experiences Questionnaire) to elicit narrative descriptions of the patient's problems and coping across five interviews throughout his 12-week treatment. They describe how the patient's narrative and APES ratings of his main problems by two clinicians changed in concert through treatment, explain these developments using assimilation concepts, and interpret the results in relation to assimilation and insight in schizophrenia. PMID- 20845226 TI - Searching for recognition: the professional development of psychodynamic psychotherapists during training and the first few years after it. AB - The aim of the present study was to investigate the development of psychotherapists' professional self during training and the first few years after it. Constant comparison analysis was conducted on interviews with former students (N = 18) at a training institute for psychoanalytic psychotherapy. The resulting core category "searching for recognition" indicated that participants' ambition during the studied time period was to reach high status by becoming psychotherapists. During training, this was expressed by the category "attachment to preformed professional self," meaning that students wanted their preconceptions about therapy to be acknowledged by teachers. After training, participants experienced achieved recognition and, as a result, a sense of freedom to use their own judgment. PMID- 20845227 TI - The process of change in brief psychotherapy: effects of psychodynamic and cognitive-behavioral prototypes. AB - A brief psychodynamic psychotherapy was assessed using the Brazilian Portuguese version of the Psychotherapy Process Q-Set (PQS). Each session was scored for its adherence to expert psychodynamic therapy (PDT) and cognitive-behavioral therapy (CBT) prototypes derived from the PQS. Results revealed that the therapy process adhered more closely to prototypical CBT than prototypical PDT. Bivariate time series analyses showed that prototype components capturing the client's adherence to ideal CBT behaviors and collaboration between therapist and client on ideal PDT and CBT behaviors predicted therapy progress. In addition, specific client symptoms influenced whether the therapist adhered to prototypical PDT or CBT behaviors. PMID- 20845228 TI - Brain connectivity in listening to affective stimuli: a functional magnetic resonance imaging (fMRI) study and implications for psychotherapy. AB - To investigate the functional connectivity among amygdala, insula, and auditory cortex during affective auditory stimulation and its relevance for psychotherapy, the authors recorded, using functional magnetic resonance imaging (fMRI), the blood oxygenation level-dependent (BOLD) responses of these brain regions in 20 healthy adults while listening to affective sounds (laughing and crying). Their connectivity was analyzed by time-series panel analysis. The authors found significant positive associations among brain regions, with time-lagged associations generally directed from the right to the left hemisphere. Associations between amygdalar and cortical regions, however, were negative; specifically, activations of the left auditory cortex preceded decreases of the right amygdala. This suggested that affect regulation using cognitive control may have been achieved through active inhibition of amygdalar structures by the cortex. The authors discuss the implications of the findings for the change mechanisms inherent in psychotherapy. PMID- 20845229 TI - Therapist and client perceptions of therapeutic presence: the development of a measure. AB - The authors developed two versions of a therapeutic presence measure, based on an earlier model of presence (Geller & Greenberg, 2002)-Therapeutic Presence Inventory-therapist (TPI-T) and client (TPI-C) versions-to measure in-session therapeutic presence. They explored their reliability and validity in two studies. In the first, items generated from the previously established model were subjected to analyses and expert ratings. In the second study, therapists and clients rated therapists' presence postsession. Therapists also completed the Relationship Inventory, and clients assessed two additional factors: session outcome, using the Client Task Specific Measure-Revised, and therapeutic alliance, using the Working Alliance Inventory. Findings revealed that both versions of the TPI had good reliability and construct validity. However, TPI-T had low predictive validity and the TPI-C showed good predictive validity. In particular, clients reported positive therapeutic alliance and change following sessions when they felt their therapist was present with them. PMID- 20845230 TI - Utility of measuring remoralization in addition to symptoms in efficacy research: a preliminary study. AB - Remoralization as an outcome measure for psychological treatments was compared with symptom reduction (agoraphobic avoidance and cognitions). Twenty-four patients with panic disorder and agoraphobia received empirically supported treatment and were monitored across multiple time points for 28 weeks. Treatment resulted in reduced symptoms and enhanced remoralization (Cohen's d=1.19-1.45). Slopes of symptoms and remoralization were obtained from latent growth model analyses. The slopes correlated highly (r=- .50 to -.55), which indicates similar patterns of change over time. The slope of remoralization also correlated with a number of aspects of health-related quality of life, while the slope of symptom reduction did not. Although strongly related to symptom reduction, the measurement of remoralization is expected to provide unique information for treatment efficacy research. PMID- 20845231 TI - Effectiveness of symptom validity measures in identifying cognitive and behavioral symptom exaggeration in adult attention deficit hyperactivity disorder. AB - This study examines the effectiveness of symptom validity measures to detect suspect effort in cognitive testing and invalid completion of ADHD behavior rating scales in 268 adults referred for ADHD assessment. Patients were diagnosed with ADHD based on cognitive testing, behavior rating scales, and clinical interview. Suspect effort was diagnosed by at least two of the following: failure on embedded and free-standing SVT measures, a score > 2 SD below the ADD population average on tests, failure on an ADHD behavior rating scale validity scale, or a major discrepancy between reported and observed ADHD behaviors. A total of 22% of patients engaged in symptom exaggeration. The Word Memory test immediate recall and consistency score (both 64%), TOVA omission errors (63%) and reaction time variability (54%), CAT-A infrequency scale (58%), and b Test (47%) had good sensitivity as well as at least 90% specificity. Clearly, such measures should be used to help avoid making false positive diagnoses of ADHD. PMID- 20845232 TI - Readers routinely represent implied object rotation: the role of visual experience. AB - We conducted an eye tracking experiment to investigate whether prior visual experience affects later language processing. We assessed the effects of previously encountered pictures of objects with a vertical or horizontal orientation on the later reading of sentences that implied an object's orientation. First-pass reading times were longer when participants read about an implied orientation that did not match the orientation of the previously seen picture than when the orientation matched. This suggests that a picture encountered 20 min earlier and incidental to the reading task influenced reading. These results have implications for theories of reading comprehension and embodied cognition. PMID- 20845234 TI - Menopause: demystifying management of common clinical challenges. PMID- 20845235 TI - Emerging facade of menopausal hormone therapy. AB - Menopausal hormone therapy (HT) has been around for 70 years, and in the 1980s and 1990s was considered a universal panacea for women's problems from midlife onward. However, this concept was challenged by the results of the Women's Health Initiative (WHI) and the Million Women Study (MWS) that were first published in 2002 and 2003. Since the publication of these studies, prescriptions of HT have markedly declined and there have been many media scares. An unfortunate sequel was an extrapolation of the observations from women in their 50s and older to those with early ovarian failure. This article discusses the WHI and the MWS with a focus on differences between HT regimens including doses, formulations, and routes, timing, and duration of HT. It addresses practical issues such as strategies for stopping HT, and discusses bioidentical hormones. The specialist knowledge now required to deliver post-reproductive health service has led to considerations that menopause management should be now the responsibility of a specialist and not a general gynecologist. PMID- 20845236 TI - Early menopause: primary ovarian insufficiency and surgical menopause. AB - Early menopause, whether a consequence of primary ovarian insufficiency or resulting from surgical removal of gonads in a premenopausal woman, offers unique health-related challenges. Premature deprivation of sex steroids sets into motion a cascade of events that preferentially target urogenital, skeletal, cardiovascular, and neurocognitive systems, and culminate in global health deterioration in a chronologically younger population of women compared with those undergoing age-appropriate, NATURAL menopause. Overtly, menopausal symptoms may be shared between those experiencing early menopause versus those undergoing a natural attrition of their reproductive physiology. Extrapolation of concerns emanating from recent randomized trials of menopausal hormone therapy may not be applicable to young women experiencing early menopause, however, and estrogen replacement remains a mainstay in the clinical management of this population. PMID- 20845237 TI - Determinants of female reproductive senescence: differential roles for the ovary and the neuroendocrine axis. AB - Aging in women is a complex process that begins with the transition into reproductive senescence and evolves to impact not just women's procreative potential but also multiple health-related parameters including longevity. Although somatic aging is an equal opportunity nemesis, certain disease states correlate highly with ovarian failure and the menopause, such as osteoporosis, diabetes, cardiovascular disease, and compromised cognitive function. Epidemiological studies suggest that a delayed natural menopause confers longevity and decelerates the appearance of many of the debilitating morbidities associated with the menopause. However, recent randomized clinical trials assessing the benefits of menopausal hormone therapy during the postmenopause clearly suggest that attenuation of the negative consequences of reproductive aging involves much more than a simple add back of ovarian steroids in the postmenopause. Conflicts between observations in epidemiological studies and in randomized clinical trials give good reason for continued innovative research focused on identifying the mechanisms that bring about the transition from peak reproductive potential to female reproductive quiescence. This article provides a brief update on our current understanding of the physiological and cellular mechanisms that precipitate and/or commit women to transit into reproductive senescence. PMID- 20845238 TI - Menopause perspectives and treatment of Asian women. AB - This review summarizes the published literature on menopausal symptoms and concerns from the perspective of Asian menopausal women, compares and contrasts common menopausal symptoms between the Asian and the Western postmenopausal populations, and highlights considerations from the perspective of clinical practice. In contrast to menopausal symptomatology described in the Western populations, musculoskeletal symptoms and sleeplessness, rather than vasomotor symptoms, dominate the clinical presentation in menopausal Asian women; decreased sexual function, although an important issue, is not commonly brought up for discussion in the context of bothersome menopausal symptoms by Asian women. The epidemiology of the common disorders of aging, such as osteoporosis, breast cancer, and cardiovascular disease, differs between the Asian and Western populations. Awareness and the use of hormone replacement therapy (HRT) are generally low and noted to vary significantly among populations from different Asian countries. The perspectives, and the spectrum of symptom burden relating to reproductive aging in the Asian menopausal women are unique; an appreciation of these distinctions will allow for better tailoring of management paradigms to accommodate the diversified cultural, customary, and religious backgrounds and the socioeconomic disparities that exist among the various Asian populations. PMID- 20845240 TI - [Femoroacetabular impingement of the hip in sports - a review for sports physicians]. AB - Recently the relevance of femoroacetabular impingement as a cause of hip and groin pain in sportsmen has been recognized. The entity often poses diagnostic and therapeutic problems to the sports physician. The patients go through an odyssey of different diagnostic and therapeutic modalities before the correct diagnosis is made and an adequate therapy is implemented. Not seldom, patients get even operated at another site which is thought to cause the problems. The present review analyzes the current literature concerning diagnostic standards and therapy of femoroacetabular impingement focussing on their relevance for sports medicine. It is aimed to help the sports physician to recognise this entity as a cause for groin and hip pain in the athlete and realise its importance for the short term performance of the athlete and its long term significance in terms of development of early hip osteoarthrosis. PMID- 20845241 TI - [Improved performance in endurance sports through acupuncture]. AB - In many years of experience in treating athletes with acupuncture, I often had the impression that athletes in endurance sports showed improved performances after such treatments. In order to scientifically verify these impressions, I performed a field test with three groups of runners of different performance levels preparing for a marathon. The first group was given acupuncture, the second a placebo, with the third being the control group. After their maximum pulse rates were recorded, the runners were asked to run 5000m four times in 4 weeks at 75 % of their maximum pulse rate. Their pulse rates were measured for each runner at the finish of the run, and subsequently, one, two and five minutes after the run. Based on these data, the complexity factor (running time multiplied by the respective pulse rate) was calculated for all four recorded pulse rates for each run and each runner. All groups showed statistically significant enhancements in their running times and their complexity factors, but in the case of the runners treated with acupuncture, the improvements were highly significant. Therefore, the field test proves that acupuncture has a significant impact on the performance of the athletes in endurance sports. PMID- 20845242 TI - [Relation between pelvis malposition and functional knee pain by long distance running]. AB - PURPOSE: During endurance run knee problems often appear. This study wants to show the connection between a one- sided malposition of the pelvis and knee joint pain during endurance running. METHOD: We tested endurance runners which had pelvis malposition and knee pain. Therefore 100 athletes were tested, 50 with knee pain and 50 without knee pain. Manual examination and clinical instruments were used for examination of sacroiliac joints for measurement of vertical distances between spinae iliacae anteriores superiores. Collected data were analyzed by appropriate statistical methods. RESULTS: The results show that there is a connection between a one- sided pelvic malposition and knee pain during endurance running. These relations are probably realized by changes in lower extremity dysfunction as a result of pathological chains. The one sided pelvis malposition was in the control group significant higher (0.9 +/- 0.4 cm) than in the control group (0.3 +/- 0.2 cm). CONCLUSION: There is a correlation between knee pain and os coxae malposition. (It is necessary in examine and treat the the cause- and effect chain to prevent injuries). PMID- 20845243 TI - [Mean speed of winter sport participants depending on various factors]. AB - Objective of this study was to evaluate speeds on ski slopes depending on various factors as gender, age, height, weight, and nationality, helmet use, used type of gear, skiing ability, risk taking behaviour and weather conditions. The average speed measured with a radar speed gun was 44 km/h for all observations. A multivariate logistic regression model revealed five independent factors for higher speeds on slopes: younger age, male gender, skier, higher skill level, and riskier behaviour. Helmet use is not associated with higher speeds on slopes. Therefore, ski helmets have been recommended because helmet use is associated with a considerable reduction of head injury risk. In general, to avoid speed related injuries, preventive recommendations include skiing under speed control consistent with the individual skiing ability, and slope and weather conditions. PMID- 20845239 TI - Evaluation and management of sleep disturbance during the menopause transition. AB - Sleep disturbances in midlife women are common and have been associated with the menopause transition itself, symptoms of hot flashes, anxiety and depressive disorders, aging, primary sleep disorders (i.e., obstructive sleep apnea, periodic limb movement disorder), comorbid medical conditions and medications, as well as with psychosocial and behavioral factors. Because there are several common sources of sleep problems in midlife women, the cause of an individual woman's sleep disturbance may be multifactorial. Effective behavioral and pharmacological therapies are available to treat sleep disturbances of different etiologies. This review provides an overview of different types of sleep disturbance occurring in midlife women and presents data supporting the use of hormone therapy, hypnotic agents, and behavioral strategies to treat sleep problems in this population. The review aims to equip clinicians evaluating menopause-age women with the knowledge and evaluation tools to diagnose, engage sleep experts where appropriate, and treat sleep disturbance in this population. Sleep disorders in midlife women should be treated because substantial improvements in quality of life and health outcomes are achievable. PMID- 20845244 TI - [Risks in sport riding - a critical survey of safety standards in sport riding]. AB - INTRODUCTION: Equitation is associated with a high rate of injuries and lethal accidents. The head is the most frequently concerned body part. Hence in the majority of the cases deaths results from head injuries. In this study injuries as well as causes of deaths were analyzed in 21 cases. Actual safety standards in equitation were appraised and suggestions for improvement were formulated. MATERIAL AND METHODS: Between 1996 and 2008 21 equestrians suffered from a fatal accident in the greater area of Hamburg. In a retrospective analysis, equestrians' records which bases on the documentation of the institute of forensic medicine as well as the insurance company ARAG were reviewed. Details of the accidents were reconstructed and pattern of injuries of those wearing a riding helmet were analyzed. RESULTS: The 21 equestrians had 29 injuries. Therefrom 86 % (18 / 21) suffered from head injuries which consequences were the causes for death. In 5 cases (24 %) equestrians wore riding helmets on the date of accident. Therefrom 80 % (4 / 5) suffered from head injuries which results in death. DISCUSSION: Actual safety standards in equitation are disappointing. The implementation of the obligation wearing a helmet as well as the improvement of the efficiency of protective clothing for equestrians is essential. Prospective studies in order to broad the state of knowledge in this context are necessary. PMID- 20845245 TI - [The operative treatment of the dorsal distal phalanx near to the base (osseous pull out of the extensor tendon) with extreme exposure of the hand by athletic activities - is the hook plate a option for treatment?]. AB - AIM: Aim of the presented investigation was to work out the short- and mid-term outcomes after operative treatment of distal phalanx fractures near to the base of type Doyle IVb and IVc (osseous pull out of the extensor tendon) by means of a hook plate in patients with extreme exposure of the hand by athletic activities. PATIENTS AND METHODS: Between February 2002 and September 2009 77 patients were treated by operation in our hospital by means of a hook plate due to a traumatic fracture of the dorsal distal phalanx near to the base of type Doyle IVb and IVc (osseous pull out of the extensor tendon) by means of a hook plate (Aerni plate/S2-Prong-Plate) of Stryker Leibinger. 64 of these 77 patients incur the fracture while exercising sport. 46 of these 64 patients were clinically and radiologically followed up within a retrospective study. To assess the therapy's outcome a specific scoring scheme containing subjective and objective parameters was elaborated in order to gain a transparent result of the treatment. RESULTS: According to this scoring scheme 84.79 % of the patients reached a very good or good result. Nail growth defects by an intraoperative injury of nail matrix represents an essential complication of the presented surgical method. CONCLUSION: By means of the presented method in the majority of the cases good or very good results could be achieved. That method represents a simple, safe and less complicate possibility to treat the distal phalanx fractures near to the base type IVb and IVc according to Doyle and it is considered as a useful alternative to other procedures. PMID- 20845246 TI - [Hand disinfection - simple but not trivial]. PMID- 20845247 TI - [Diseases of the retinal vessels: dedicated to Prof. L. Hansen on the occasion of his 65th birthday]. PMID- 20845248 TI - [Intravitreal drug therapy for retinal vein occlusion--pathophysiological mechanisms and routinely used drugs]. AB - The novel therapeutic principle of intravitreal drug therapy for retinal vein occlusion has become an integrated constituent of clinical practice over the last years. The two substance classes that have been evaluated in large randomised clinical trials so far are corticosteroids and inhibitors of vascular endothelial growth factor (VEGF). The reported treatment success of these intravitreally administered substances has lead not only to a paradigm shift in clinical care but has also advanced our understanding of the underlying pathophysiological principles of retinal vein occlusions. In this review the different substances are discussed, their mechanisms of action are analysed and the results of the large clinical trials available to date are critically evaluated. Furthermore, an approach to integrate these novel treatment options into the existing treatment regimes for retinal vein occlusions is suggested. PMID- 20845249 TI - [VEGF antibodies as therapy for retinopathy of prematurity]. AB - Retinopathy of prematurity (ROP) is one of the three leading causes of legal blindness in childhood in the developed countries. Improved neonatal care has resulted in the increased survival of extremely immature infants at high risk to develop ROP. Current treatment for ROP with laser may prevent blindness by causing involution of pathological vessels and thus inhibit the development of retinal detachment. But this coagulation of the avascular retina is a destructive therapy and does not otherwise ameliorate retinal development. Recent reports have described vascular endothelial growth factor antibodies as therapy for ROP. This article reports our own experience with this new therapy and gives an overview of the recent literature. PMID- 20845250 TI - [Anti-VEGF inhibitors and their role in the treatment of diabetic macular oedema]. AB - Diabetic macular edema (DME) and proliferative retinopathy are common causes for blindness in middle-aged patients. The gold standard for treatment has been laser coagulation. Limitations of this therapy are refractive DME, ischaemic diabetic maculopathy and complications after laser application. The need for a non destructive and effective strategy has led to investigations regarding vascular endothelial growth factor (VEGF) inhibitors for reduction of vessel leakage and oedema formation. VEGF antibody fragments have been approved for age-associated macular degeneration (AMD) in different countries and have proved to be safe and effective. Trials for different anti-VEGF compounds are nearing completion or are completed. Published data show a superiority of anti-VEGF therapy compared to laser coagulation. In the present article, data regarding dose, injection scheme and practicable application form are reviewed. PMID- 20845251 TI - [Clinical diagnostics and therapy for non-arteritic central retinal artery occlusion]. AB - Central retinal artery occlusion (CRAO) is an ophthalmological emergency situation. Known risk factors are arterial hypertension, cardial arrhythmia, arteriosclerosis, hypercholesterolemia and diabetes. Elderly patients should be examined for an arteritic genesis. Young patients (< 45 years) without typical risk factors may suffer from thrombophilia. There is no uniform recommendation on how to treat non-arteritic CRAO. Many different interventions have been suggested in the literature, i. e., massaging the eye, systemic or local reduction of intraocular pressure, anticoagulation, either systemically administered venous thrombolysis or supraselective intra-arterial thrombolysis. In this review we present the causes of CRAO and diagnostic means to detect causes; we also critically discuss previously described therapeutic options. It is our aim to provide a guide through the necessary interdisciplinary diagnostics in co operation with internal medicine and neurology and to recommend a multimodal therapy in patients with non-arteritic CRAO. PMID- 20845253 TI - [Parapapillary orange-pigment--lipofuscin autofluorescence]. PMID- 20845254 TI - [Medicine, humanity and competition--what about ophthalmology?]. PMID- 20845255 TI - [The Affect Experience and Affect Regulation Q-Sort Test (AREQ): validation and short version]. AB - Affect experience and affect regulation are based on varying concepts and the integration of this constructs is discussed controversy. The AREQ - Affect Experience and Affect Regulation Q-sort Test, an expert rating, covers the need of an integrated method to explore the emotional functioning of patients. This is the validation of the german version of the AREQ. Based on statistical considerations and in order to create a practicable and time efficient instrument, which is necessary to display the course and process of a therapy, we created a short version of the AREQ. In this short version only significant items are included, and therefore the time for the implementation is much shorter. The results of the statistical calculations show better psychometric properties for the short version. Especially the scales, which are defined by the original version, show better reliability and account in different samples for 60-73% of the variance. PMID- 20845256 TI - [Psychophysiology as a predictor for treatment outcome: a pilot-study]. AB - To test the possibility of predicting psychotherapy outcome by measures of cardiovascular adaptability to stress at the beginning of treatment we used a prospective, within-subject design with experimental induction of short-term stress. Cardiovascular data during induced stress (mental arithmetic, anger recall) and relaxation were assessed in 21 patients with a main diagnosis of depression at the beginning of their 12-week inpatient psychotherapy treatment. Lower change scores in blood pressure during induced stress at the beginning of therapy were significantly related to better treatment outcome, accounting for 41% of variance, even after controlling for several covariates. Furthermore, there was evidence for the impact of negative affect. Using cardiovascular stress testing as an additional area of information seems a feasible method of incorporating biological parameters in psychotherapy evaluation. PMID- 20845257 TI - [Pharmacological vitreolysis]. AB - BACKGROUND: The vitreous plays an important role in the development and progression of vitreoretinal diseases. Vitrectomy is the treatment modality of choice in these cases. However, mechanical vitrectomy is incomplete. Therefore, alternative strategies have been pursued including pharmacological means such as enzymes. The goal of pharmacological vitreolysis is to make the surgical intervention easier and less traumatic. METHODS: Different substances have been investigated, including chondroitinase, dispase, hyaluronidase, plasmin, and microplasmin. Besides preclinical investigations, hyaluronidase and microplasmin (ThromboGenics Ltd., Dublin, Leuven) have been tested clinically. Results from the literature are reported herein. RESULTS: Plasmin and microplasmin are both capable of inducing posterior vitreous detachment (PVD) in a dose- and time dependent manner. There are no morphological or functional changes of the retina at therapeutic doses. Two phase II studies published to date demonstrate both efficacy and safety. Phase III studies are ongoing, and results are expected during 2010. Other enzymes tested show limitations in that retinal damage may occur (dispase) or liquefaction (hyaluronidase) occurs without cleavage of the vitreous cortex from the retina. CONCLUSIONS: Microplasmin induces PVD. Results from clinical trials show that microplasmin helps to detach the vitreous cortex from the retina. This may be advantageous in terms of complete vitreous removal and less traumatic intervention compared to mechanical techniques, such as vitrectomy and peeling of the internal limiting membrane. PMID- 20845258 TI - [Else Steinert (1879 - 1948): One of Germany's first female ophthalmologists]. PMID- 20845259 TI - [Clinical experience with brilliant blue G staining of the retinal surface]. AB - BACKGROUND: Staining of the retinal surface has improved the intraoperative removal of semitransparent membranes during macular surgery. The purpose of this study was to evaluate the clinical experiences with brilliant blue G (BBG) staining of the retinal surface. METHODS: BBG (Brilliant peel, Fluoron) was applied during vitrectomy and macular surgery in 43 patients. In 47 % there was a macular hole (MH), whereas 53 % had epiretinal membranes (ERM). Intraoperatively BBG was applied on the retinal surface under infusion or air conditions for 30 - 60 s. In MH the internal limiting membrane (ILM) and in ERM the membrane was removed. Postoperatively all patients were examined on average after 9 weeks. RESULTS: Although intraoperative BBG staining was less intensive compared to ICG staining, the staining was sufficient to safely remove the semitransparent membranes in all cases. In all patients with MH hole closure was achieved, and in 96 % with ERM the metamorphopsiae decreased. The mean decimal visual acuity increased from 0.25 +/- 0.13 to 0.37 +/- 0.20 (p < 0.05) and improved in 63 % of the patients. Clinically, there were no toxic side-effects from BBG staining. CONCLUSIONS: BBG allowed a complete and selective staining of the retinal surface. Thus, ILM and ERM could be removed safely during macular surgery. No clinical retinal toxicity was observed. PMID- 20845260 TI - [Anatomic and subjective success of structured surgical treatment strategy in the management of chronic epiphora - a postoperative analysis of contentment]. AB - BACKGROUND: Epiphora is the result of hypersecretion or reduced tear outflow because of relative or absolute obstruction of the lacrimal system. For the treatment a specific surgical procedure is usually required. Herein we present the subjective and objective findings of 243 consecutive patients with non irritative induced epiphora, who underwent an operation in a standardised therapy scheme, which is used at the eye departments of the Universities of Lubeck and Wurzburg. PATIENTS AND METHODS: In a retrospective cohort study 243 patients were included who underwent lateral tarsal strip (n = 72), external dacryocystorhinostomy (DCR) in the case of an absolute nasolacrimal duct obstruction (NLDO) (n = 116) and relative NLDO (n = 25), DCR with canalicular surgery (n = 18) and simple canalicular surgery (n = 12) with a follow-up of at least 6 month. Common patient and cosmetical satisfaction, intensity of symptoms and further symptoms of 168 patients were evaluated by sending a questionnaire with subsequent telephone survey. Objective findings were recorded from hospital charts. RESULTS: 59.5% of the patients were free of complaints, 19.6% had an absolute decrease of symptoms (epiphora outside and in windy weather) and 20.8 % persistent epiphora (symptoms both in- and outside persisted). 81% of patients with absolute NLDO and 57% with relative NLDO were graded as being free of symptoms, 7% (24%) as a relative decrease and 12% (19%) as a persistence of symptoms. There was a significant difference in success between these indications (p = 0.018). Patency of the lacrimal system assessed by irrigation was found in 95% (absolute NLDO). Commonly, 73.8% were satisfied, 7.7% indifferent and 18.4 % not satisfied. 4 patients were cosmetically not satisfied. CONCLUSIONS: Use of a standardised therapy scheme reduces the symptoms in 79.1% of the patients. In patients with absolute NLDO external DCR achieves an anatomic success rate of 95% and a subjective improvement in 88% with excellent cosmetic results. In comparison with absolute NLDO the success rate of relative NLDO is lower, but still with a subjective improvement in 81%. Our results show that postoperative success depends on the preoperative cause of the epiphora. PMID- 20845262 TI - Limonoids and quinoline alkaloids from Dictamnus dasycarpus. AB - Phytochemical investigation on Dictamnus dasycarpus (Rutaceae) has led to the isolation of four new secondary metabolites (2, 6, 9, and 10) along with twelve known phytochemicals (1, 3- 5, 7, 8, 11-16). Compound 4 was isolated as a natural product for the first time. The structures of compounds 1-16 were elucidated by extensive spectroscopic analyses and comparison with previously reported spectroscopic data. The structures of 8 and 13 were further confirmed based on X ray data analyses. The absolute configuration of compounds 8-12 were studied based on the CD spectra analyses. PMID- 20845263 TI - Anxiolytic effects of a semipurified constituent of guarana seeds on rats in the elevated T-maze test. AB - The objective of this study was to investigate the effects of chronic administration of a semi-purified extract (Purified Extract A--PEA; 4, 8, or 16 mg/kg) of PAULLINIA CUPANA (guarana) seeds on rats submitted to the elevated T maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine (PAR; 3 mg/kg), was used as a positive control. To evaluate possible serotonergic and dopaminergic neurotransmission involvement in the action of PEA during the ETM test, ineffective doses of metergoline (MET; 5-HT (2A/2C) antagonist receptor) or sulpiride (SUL; dopaminergic receptor antagonist) were acutely administered together with the PEA. The locomotion of the rats was assessed in a circular arena following each drug treatment. Both PEA (8 and 16 mg/kg) and PAR (3 mg/kg) increased one-way escape latencies from the open arm of the ETM, indicating a panicolytic effect compared to the control group. MET, in higher doses (1, 2 or 3 mg/kg), produced a panicolytic effect in the ETM test, whereas SUL did not (10, 20 or 40 mg/kg). The panicolytic effect produced by PEA (8 mg/kg) was blocked by both MET (2 mg/kg) and SUL (20 mg/kg), whereas the panicolytic effect produced by PAR (3 mg/kg) was blocked only by MET (2 mg/kg). These results show that chronic treatment with PEA produces a panicolytic effect during the ETM test, and that the dopaminergic and the serotonergic neurotransmission systems are involved in this effect. PMID- 20845264 TI - Metabolic alterations in different developmental stages of Pilocarpus microphyllus. AB - Pilocarpine is an imidazole alkaloid that has been used for more than a century in glaucoma treatment. It is present in several species of the Pilocarpus genus (jaborandi), with its highest concentrations in P. microphyllus. In addition to pilocarpine, pilosine--an imidazole alkaloid without pharmacological use--is produced in high concentrations in mature plants. A metabolomic study was carried out on juvenile and mature plants to obtain information about pilocarpine metabolism at different developmental stages. Methanol-water and alkaloid extracts were analyzed by 1H NMR and ESI-MS. Metabolic profiles from both techniques showed clear differences between various developmental stages. Intense signals in the aromatic region of the 1H NMR spectrum and ions from pilosine and related alkaloids by ESI/MS were found only in extracts from mature plant. Two new imidazole alkaloids were identified by MS(n). Our results suggest that pilosine is produced exclusively in mature developmental stage, and juvenile plant material seems to be appropriate for further studies on pilocarpine biosynthesis. PMID- 20845261 TI - Uterotonic plants and their bioactive constituents. AB - Abnormalities in the process of uterine muscle contractility during pregnancy and birth can have major clinical implications, including preterm labour, which is the single largest cause of maternal and prenatal mortality in the Western world and a major contributor to childhood developmental problems. In contrast, induction of labour may be necessary in certain conditions. Currently used interventional therapies to suppress (tocolytic agents) or to induce (uterotonic agents) uterine contractions lack potency and/or selectivity and can have harmful side effects for mother and baby. Nature's diversity has always been, and still is, one of the biggest resources of therapeutic lead compounds. Many natural products exhibit biological activity against unrelated targets, thus providing researchers with starting points for drug development. In this review we will provide an overview of uterine muscle physiology, describe currently available biological screening procedures for testing of uterotonic plant compounds and will summarise traditionally-used uterotonic plants, their active components and their mechanisms, primarily focusing on uterotonic active circular plant peptides called cyclotides. Finally we will comment on the discovery of novel cyclotide producing plant species and the possibility for the development of novel plant derived uterotonic and tocolytic drugs. PMID- 20845265 TI - [Influence of natural fluoride concentration in drinking water on dental health of first class pupils in an area with enhanced fluoride content at the beginning of the 21st century]. AB - BACKGROUND: Since the end of the first half of the 20 (th) century it is well known that fluoride concentrations in drinking water of about 1 ppm reduce the prevalence of dental caries by about 40-60%. This knowledge led to the fluoridation of drinking water during the second half of the 20 (th) century in many countries, including East Germany. Although the natural F (-) content in drinking water in Germany is usually very low, the eastern Eifel is one of the few larger areas in Germany with (nearly) optimal (0.7-1.0 ppm) or moderately enhanced (0.3-0.7 ppm) natural fluoride concentrations in drinking water. 30 years ago, in 1977, the caries prevalence of children of various age groups in the fluoride-rich areas of the eastern Eifel was established by Einwag to be about 40% lower than in adjacent fluoride-poor regions (0.1 ppm). Meanwhile fluoride has become available from many different sources for children of any age: e. g., toothpaste (with 500 ppm fluoride even for very young children who just got the first tooth), fluoridated salt, professional fluoride applications (paid by health insurances), the rising consumption of mineral waters (many of which have a fluoride content >0.3 ppm). This poses the question of the current influence of enhanced natural drinking water fluoride concentrations on caries prevalence in children. METHOD AND RESULTS: The results of the dental examinations of 9 555 pupils (6 or 7 years old) of the first classes of all 63 primary schools in the Landkreis Mayen-Koblenz from 5 years (2004/2005-2008/2009) are compared to the fluoride content of the drinking water. The data show no obvious correlation between dental health and fluoride concentration for any of the dental health parameters investigated. However, in spite of the low geographic resolution of social parameters, there was a notable connection between dental health status and sociodemographic indicators for the respective region. DISCUSSION: 30 years after the study by Einwag in the same region, the natural fluoride content of drinking water either had no influence on dental health at all, or this influence is so diminutive that it is exceeded by far by sociodemographic factors. Obviously there is much more fluoride available from other sources nowadays compared to 30 years ago. The results may also have implications for the administration of fluoride tablets and support the recommendations of the DGZMK (Deutsche Gesellschaft fur Zahn-, Mund- und Kieferheilkunde) from the year 2000, restricting the administration of fluoride tablets to special situations following an individual anamnesis of fluoride uptake. PMID- 20845266 TI - [Improvement strategy to increase vaccination rates in adolescents]. AB - BACKGROUND: Vaccination rates in adolescents in Germany are not sufficient. An intervention programme, which has been launched by the community health centre in Essen, should significantly increase vaccination coverage. METHODS: In 2001 the Children and Youth Health Service at the Community Health Centre in Essen implemented a specific strategy to improve vaccination rates in adolescents. Vaccination rates were determined by control of vaccination certificates of all 6 (th) graders in Essen (n=5 589). After control of vaccination records the parents got a written, individual vaccination counselling for their child as well as a referral to the paediatrician to get the missing vaccinations. After 6 months the vaccination certificates were looked at again and vaccination coverage was determined. RESULTS: At the initial vaccination record control of 6 (th) graders in 2001 only 15% of the students, who presented their vaccination certificate, had an appropriate age related immunisation status. 84% of the students had had the tetanus/diphtheria and polio booster. But only 43% had been given a second measles, mumps and rubella (MMR) immunisation and only 24% had a complete hepatitis B coverage. The intervention programme (e. g., individual vaccination counselling) improved vaccination rates for hepatitis B and MMR by 16%. From 2001 to 2008 vaccination coverage in this age group could be improved from 43% to 87% for the second MMR vaccination and from 24% to 85% for hepatitis B. CONCLUSIONS: A remarkable improvement in vaccination coverage in children and adolescents could be achieved by a single, individual, written vaccination reminder. As a prerequisite a good cooperation between schools/paediatricians and the health authorities is needed. PMID- 20845267 TI - Deep enteroscopy in patients with left ventricular assist devices: practical and technical considerations. PMID- 20845268 TI - Giant atypical lymphoid hyperplasia of the colon. PMID- 20845269 TI - Over-the-scope clip to close a fistula after removing a percutaneous endoscopic gastrostomy tube. PMID- 20845270 TI - Capsule endoscopic detection of bleeding Meckel's diverticulum, with capsule retention in the diverticulum. PMID- 20845271 TI - Placement of covered self-expanding metal stent to treat razor blade-induced esophageal hemorrhage. PMID- 20845272 TI - Toothpick impaction in the sigmoid colon as a cause of chronic abdominal pain. PMID- 20845273 TI - Acute obstructive cholangitis caused by an enterolith in a duodenal diverticulum. PMID- 20845274 TI - Gallbladder perforation with formation of hepatic subcapsular biloma, treated with endoscopic nasobiliary drainage. PMID- 20845275 TI - Ingested pin penetrating stomach wall and liver. PMID- 20845276 TI - An unusual finding during screening colonoscopy: a cockroach! PMID- 20845277 TI - Life-threatening bleeding following Barrett's surveillance biopsies. PMID- 20845278 TI - Combined colonoscopy and laparoscopy to close a colonic perforation. PMID- 20845279 TI - Gastric outlet obstruction due to impacted gallstone. PMID- 20845280 TI - A case of recurrent infective endocarditis following colonoscopy. PMID- 20845281 TI - Gastric actinomycosis: an rare endoscopic diagnosis. PMID- 20845283 TI - Hydroxycut((r)) (herbal weight loss supplement) induced hepatotoxicity: a case report and review of literature. AB - Use of supplement and alternative drugs continues to thrive and is becoming an increasing cause of concern since many of these substances may have unexpected or unexplained medical consequences. We present below the first reported case of hepatotoxicity from Hydroxycut((r)) in Hawaii. PMID- 20845284 TI - Diffuse plexiform neurofibroma of the back: report of a case. AB - Neurofibromatosis type 1 is an autosomal dominant disorder affecting the ras proto-oncogene. It is characterized by the overgrowth of nervous tissue and skin discoloration. While it is associated with a variety of phenotypic presentations, it is the plexiform variant that is particular concerning, as it can become extremely disfiguring and has a propensity for malignant degeneration. A case of a Pacific Islander with a large plexiform type 1 neurofibroma is presented. The patient was ultimately treated with surgical resection, negative pressure wound therapy, and split-thickness skin grafting with good results. A review of the literature concerning the diagnosis and treatment of neurofibromatosis is included. PMID- 20845285 TI - Racial/ethnic differences in the incidence of Kawasaki syndrome among children in Hawaii. AB - OBJECTIVE: To describe the occurrence of Kawasaki syndrome (KS) among different racial/ethnic groups in Hawaii. METHODS: Retrospective analysis of children <18 years of age, with a focus on children <5 years of age, living in Hawaii who were hospitalized with KS using the 1996-2006 Hawaii State Inpatient Data. RESULTS: Children <5 years of age accounted for 84% of the 528 patients <18 years of age with KS. The average annual incidence among this age group was 50.4 per 100,000 children <5 years of age, ranging from 45.5 to 56.5. Asian and Pacific Islander children accounted for 92% of the children <5 years of age with KS during the study period; the average annual incidence was 62.9 per 100,000. Within this group, Japanese children had the highest incidence (210.5), followed by Native Hawaiian children (86.9), other Asian children (84.9), and Chinese children (83.2). The incidence for white children (13.7) was lower than for these racial/ethnic groups. The median age of KS admission for children <5 years of age was 21 months overall, 24 months for Japanese children, 14.5 months for Native Hawaiian children and 26.5 months for white children. CONCLUSIONS: The high average annual KS incidence for children <5 years of age in Hawaii compared to the rest of the United States population reflects an increased KS incidence among Asian and Pacific Islander children, especially Japanese children. The incidence for white children was slightly higher than or similar to that generally reported nationwide. PMID- 20845286 TI - Induction of breast cancer in wild type p53 cells by BRCA1-IRIS overexpression. AB - Cells ability to evade cell death and to proliferate post geno-/cell-toxic stresses, likely leads to formation of cancer. Activation of p38MAPK and p53 following these stresses help protect cells against cancer development by initiating apoptosis. The duration of p38MAPK and p53 activation is regulated by the WIP1 phosphatase. BRCA1-IRIS triggers WIP1 expression in p53-dependent and independent manner. BRCA1-IRIS triggers the expression and cytoplasmic localization of the mRNA stabilization and translation inducer, HuR that binds p53 and PPM1D mRNA. Hence, BRCA1-IRIS overexpression inactivates p38MAPK and/or p53 by upregulating WIP1 expression. BRCA1-IRIS abrogation of the homeostatic balance maintained by p38MAPK-p53-WIP1 pathway suppressed cell death induced by a lethal dose of UVC, high dosages of etoposide or H2O2, and allowed cells to survive and proliferate post geno-/cell-toxic stresses. This mechanism represents a new link between geno-/cell-toxic stress and aggressive breast cancer formation in p53 wild-type cells. PMID- 20845287 TI - Mixed epithelial and stromal tumor of the kidney or adult mesoblastic nephroma: an update. AB - PURPOSE: Our aim was to review the spectrum of usual and unusual clinical and morphologic findings observed in mixed epithelial and stromal tumor of the kidney (MEST). MATERIALS AND METHODS: On the basis of MEDLINE database searches, we assessed all aspects of MEST or adult mesoblastic nephroma since the first report in 1997 till the end of 2009. RESULTS: Mixed epithelial and stromal tumor is a relatively rare and distinct neoplasm of the kidney that should be distinguished from other renal neoplasms. Although the overall prognosis is favorable, recurrence and malignant transformation of MEST can occur CONCLUSION: It is difficult to distinguish benign or malignant nature on imaging studies. PMID- 20845288 TI - Comparison of intranasal desmopressin and intramuscular tramadol versus pethidine in patients with renal colic. AB - PURPOSE: To study the safety and efficacy of intranasal desmopressin and intramuscular tramadol versus pethidine for treatment of renal colic. MATERIALS AND METHODS: A total of 90 adult patients who presented with renal colic to the emergency wards were recruited in this study. The patients were randomly assigned to receive 100 mg intramuscular tramadol, 40u g intranasal desmopressin, or 40u g intranasal desmopressin plus 100 mg intramuscular tramadol. The severity of the pain was assessed using Visual Analogue Scale. RESULTS: The studied patients consisted of 49 men and 41 women with the mean age of 35.20 +/- 13.26 years (range, 16 to 82 years). There was no statistically significant difference regarding the mean age (F [2, 89] = 2.98, P = .056) and gender differences (X2 = 3.3, df = 2, P = .19) in three groups. There was also no statistically significant difference considering pain relief in 3 studied groups (P = .2). CONCLUSION: We concluded that narcotics such as pethidine cannot be replaced by tramadol in patients with renal colic, but tramadol, desmopressin, or both in combination can reduce pethidine requirement. PMID- 20845289 TI - Primary left upper quadrant (Palmer's point) access for laparoscopic radical prostatectomy. AB - PURPOSE: Although Palmer's point approach is described for upper urinary tract laparoscopy, we use this technique routinely for robotic and standard laparoscopic radical prostatectomy and we describe our experience with this approach. MATERIALS AND METHODS: Since 2004, Palmer's point Veress entry has been used to create pneumoperitoneum in 126 robotic and 21 standard laparoscopic radical prostatectomies. On the left side, a 2-mm transverse skin incision was made 3 cm below the left costal margin on the midclavicular line. Through this incision, a Veress needle was inserted to create pneumoperitoneum. RESULTS: The mean patient's age and body mass index were 59.7 years (range, 37 to 73 years) and 27.92 kg/m2 (range, 22 to 39 kg/m2), respectively.Thirty-eight patients had prior abdominal operations. The mean number of punctures performed was 1.08 per case. In 93% of the subjects, Veress needle was inserted during the first attempt. The mean time to establish pneumoperitoneum was 5.63 minutes (range, 4 to 8 minutes). No major entrance injuries occurred. CONCLUSION: Palmer's point upper quadrant Veress needle access may be a safe and effective method of establishing pneumoperitoneum in patients subjected to robotic and standard laparoscopic radical prostatectomy. PMID- 20845290 TI - Laparoscopic bilateral retroperitoneal lymph node dissection in stage II testis cancer. AB - PURPOSE: We report our experience with laparoscopic bilateral retroperitoneal lymph node dissection (RPLND) in 4 patients with stage II testis cancer. MATERIALS AND METHODS: Between January 2002 and January 2009, 4 patients with stage II testis cancer underwent laparoscopic bilateral RPLND. In 2 patients, laparoscopic bilateral RPLND was performed for residual mass post-chemotherapy. We performed classic bilateral RPLND without patient repositioning. RESULTS: The procedure was done uneventfully without any major perioperative complication. The demanding part was contralateral, depending side dissection, which was accomplished with the help of a bowel retractor. Patient repositioning was not necessary. CONCLUSION: Laparoscopic bilateral RPLND can be performed efficiently and safely in stage II testis cancer, without need to repositioning and placement of trocar in contralateral side. PMID- 20845291 TI - Ultrasonographic screening of newborns for congenital anomalies of the kidney and the urinary tracts. AB - PURPOSE: To search for the efficiency of scanning the newborns with routine urinary system ultrasonography. MATERIALS AND METHODS: Urinary ultrasonography has been carried out on 721 infants born in or brought to our hospital. During the study, name, sex, week of birth, presence of antenatal diagnosis or urinary tract infections, and pathologies in examinations of the babies were recorded. Ultrasonography analysis was done with a scanner by a radiologist. Patients identified to have pathology, were watched closely in pediatric nephrology clinic, and advanced visualizations and treatments were carried out. RESULTS: Seventy-six infants (10.5%) had congenital anomalies of the kidney and the urinary tracts that prompted medical and/or surgical intervention. Of whom, 32 were diagnosed with antenatal ultrasonography and 44 during their initial postnatal ultrasonography screening. The most frequent identified pathology was hydronephrosis, in particular physiologic hydronephrosis (35.8%). The most frequent congenital urinary anomaly which caused hydronephrosis was ureteropelvic obstruction. CONCLUSION: It is suggested to apply the urinary ultrasonography scanning to all the infants that are born or brought to the university hospital. If possible, it is to be considered to include urinary ultrasonography scanning in newborn scanning programs. PMID- 20845292 TI - Genetic aberrations of the K-ras proto-oncogene in bladder cancer in Kashmiri population. AB - PURPOSE: To assess the frequency of specific point mutations in the K-ras gene in a group of Kashmiri patients with bladder cancer. MATERIALS AND METHODS: We analyzed the incidence of K-ras exon 1 gene mutations in tumors and surgical margins in 60 patients with transitional cell carcinoma of varied clinical stages and histological grades using the polymerase chain reaction-single strand conformation polymorphism and DNA sequencing. RESULTS: A significant correlation was found between the K-ras, the lymph node status, and tumor recurrence (P < 0.05). Also, smokers and patients with higher tumor grade showed a significantly higher relative risk of developing K-ras mutations than the normal ones. CONCLUSION: K-ras exon 1 gene mutations were found with low frequency in the bladder cancer tumors from Kashmir valley, which suggests that K-ras gene might be involved in a sub-set of bladder tumors, but it needs further investigation on a larger cohort sample to authenticate the current findings. PMID- 20845293 TI - Erectile function and dysfunction following low flow priapism: a comparison of distal and proximal shunts. AB - PURPOSE: To compare erectile function following low flow priapism in patients undergoing distal and proximal shunts. MATERIALS AND METHODS: From January 1995 to December 2005, we retrospectively studied 16 patients who presented to our medical center with refractory priapism. Of 16 patients, 5 underwent Winter shunt, while El-Ghorab procedure was performed for 7 patients and the remaining 4 underwent Grayhack shunt. Erectile function was assessed in a minimum follow-up of 2 years (range, 2 to 10 years) using erectile dysfunction (ED) intensity scale [Total score: 5 to 10 (severe ED); 11 to 15 (moderate ED); 16 to 20 (mild ED); and 21 to 25 (no ED)]. RESULTS: The mean patient's age was 40.62 +/- 15.27 years. Mean duration of priapism was 51.12 +/- 37.99 hours. Of 4 patients (25%) who underwent proximal shunt (Grayhack procedure), 2 (50%) were impotent, 1 had potency, and the other one achieved some penile erection with administration of oral sildenafil. Of 5 patients (31.25%) who underwent Winter procedure, 1 died because of metastatic bladder cancer and of 4 remainders, 2 (50%) had normal erectile function, but 1 patient suffered from recurrent priapism. Of 7 patients (43.75%) who underwent El-Ghorab procedure, 1 was lost for follow-up and of remaining 6 patients, 2 (33.3%) had normal erectile function and 4 (66.6%) were impotent. No surgical complication was seen. Median lag time from priapism till surgery for patients with and without ED was 48 and 26 hours, respectively (P = .22). CONCLUSION: Grayhack shunt is a safe surgical procedure without any major complications and with lower ED rate. Grayhack shunt might be considered as treatment of choice for refractory low flow priapism. PMID- 20845294 TI - Complications of transverse distal penile island flap: urethroplasty of complex anterior urethral stricture. AB - PURPOSE: To report the complications of transverse distal penile island flap urethroplasty for urethral reconstruction in adult patients with long/multiple segments anterior urethral stricture. MATERIALS AND METHODS: This prospective study was carried out on 55 patients with complex anterior urethral stricture to study complications of transverse distal penile island flap urethroplasty in two teaching hospitals between June 2002 and December 2008. Pre-, intra- and postoperative information were collected on a pro forma to generate data, which was analyzed. RESULTS: The patient's mean age was 43.83 years (range, 19 to 73 years). The leading etiology of the stricture was urethral inflammation (76.4%) with the commonest complication being infection: wound infection in 9.1%, urosepsis in 3.6%, and epididymo-orchitis in 1.8% of the subjects. CONCLUSION: Transverse distal penile island flap urethroplasty has a remarkable outcome in treatment of a long/multiple segment urethral stricture with few manageable complications. PMID- 20845295 TI - Effects of isosorbide dinitrate on the urinary flow rate in patients with benign prostatic hyperplasia. AB - PURPOSE: To compare the immediate effects of a systemic nitric oxide (NO) donor with placebo on the uroflowmetric parameters in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Eighty patients with the mean age of 61.5 years (range, 49 to 74 years) who suffered from BPH were enrolled in the study. We examined peak flow rate, average flow rate, and residual urine in all the patients. Then, patients were randomized to receive either 20 mg sublingual isosorbide dinitrate (ISDN) (n = 40) or placebo (n = 40) 20 minutes prior to the second uroflowmetry, which was performed one day after the first test. RESULTS: The mean peak flow rate increased from 7.6 +/- 0.41 mL/s to 10.2 +/- 0.54 mL/s (P = .013) in the ISDN group, while it increased +0.40 mL/s in the placebo group (P > .05). Mean residual urine volume decreased significantly from 51 +/- 3.1 mL to 29 +/- 2.9 mL and from 56 +/- 4.1 to 51 +/- 2.6 in the ISDN (P = .02) and the placebo groups (P > .05), respectively. At baseline, the mean arterial pressure was 95 +/- 2.1 mmHg and under the influence of the NO-donor, it decreased to 83 +/- 1.9 mmHg, which was significant (P < .001). No significant changes of micturition parameters were found in the placebo group. CONCLUSION: Organic nitrates influence micturition parameters in patients with BPH. This new approach could offer a potential pharmacological option to treat obstructive lower urinary tract symptoms. PMID- 20845296 TI - Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: a comparative study. AB - PURPOSE: To compare the effects of L-carnitine with clomiphene citrate in idiopathic infertile men. MATERIALS AND METHODS: Fifty-two men with idiopathic infertility were recruited in this randomized controlled trial. They were randomly assigned into 2 treatment groups, group 1 (n = 20) and group 2 (n = 32), who received L-carnitine 25 mg/day and clomiphene citrate 2 gr/day, respectively, for a period of 3 months. RESULTS: Comparing the effect of L-carnitine and clomiphene on sperm parameters before and after the treatment, both medications had influence on sperm count and motility (P = .01). L-carnitine significantly increased the semen volume (P = .001), while clomiphene citrate was significantly associated with the motility percentage and normal morphology (P = .008). CONCLUSION: It seems that the use of clomiphene citrate and L-carnitine, either individually or in combination, as the first step of idiopathic male infertility treatment is reasonable, safe, and effective. PMID- 20845297 TI - Laparoscopically assisted percutaneous pyelolithotomy in pelvic kidneys: a different approach. PMID- 20845298 TI - A complication after percutaneous nephrolithotomy. PMID- 20845299 TI - Fungating anorectal carcinoma causing urinary retention. PMID- 20845300 TI - Filarial labial chylorrhoea: an uncommon problem in an endemic region. PMID- 20845301 TI - Laparoscopic removal of retained surgical gauze. PMID- 20845302 TI - Four cases of entero pouch fistula after orthotopic neobladder. PMID- 20845303 TI - Bilateral simple orthotopic ureteroceles with bilateral stones in an adult: a case report and review of literature. PMID- 20845304 TI - Diffuse aerodermectasia: floating body sign. PMID- 20845306 TI - Performance of human immunostimulating agents in the improvement of fish cytogenetic preparations. AB - Inoculation with bacterial or fungal antigens that stimulate cell proliferation has been widely used to obtain metaphases for cytogenetic studies of fish. We evaluated the potential of new pharmaceutical compounds as mitogenic agents in fish, testing the efficacy of Aminovac (mixed antigens and epsilon acetamidocaproic acid), Broncho-Vaxom (bacterial lysate) and Estimoral (bacterial lysate) to increase the mitotic index in fingerlings of the Neotropical fish Prochilodus brevis (Prochilodontidae) and Hoplias malabaricus (Erythrinidae), which were obtained from an aquaculture facility. The animals were treated with intramuscular or intraperitoneal injections of 1 mL/50 g body weight of each compound. After 24 h, cytogenetic analyses were performed. All immunostimulants tested significantly stimulated cell division, although Aminovac proved to be the most efficient, leading to a 5-fold increase in the number of metaphase cells compared to the control group and to a 2-fold increase compared to conventional yeast inoculation. This compound facilitates fish cytogenetics analyses as it stimulates the proliferation of defense cells and reduces loss of samples. It will be especially useful for the study of specimens that either have a high commercial value or are fragile, small and/or rare. PMID- 20845307 TI - Molecular characterisation of a der(Y)t(Xp;Yp) with Xp functional disomy and sex reversal. AB - Sex reversal due to duplication of the Xp21 dosage-sensitive sex reversal locus results in XY females with gonadal dysgenesis. Pure Xp disomy (without a concurrent loss of genetic material) can occur by translocation or interstitial duplication. The case reported here is the rare form with a t(Xp;Yp). The combination of conventional clinical cytogenetic techniques, microsatellite analysis and high-density microarrays identified the X-chromosome breakpoint as centromeric of the NR0B1 gene and its control elements. Cytogenetics and array technology complemented each other in characterizing the translocation event and the extent of the dosage-sensitive sex reversal critical region on the derivative Y-chromosome. The implications of this analysis also lie in genetic counseling that highlight the likely de novo nature of a paternal meiotic event. PMID- 20845308 TI - Variation characteristics of the nitrate reductase gene of key inbred maize lines and derived lines in China. AB - Key inbred lines have played a fundamental role in maize genetics and breeding. Research on variation characteristics of key genes from key inbred lines and from derived lines is important for early identification and evaluation of inbred maize lines. The nitrate reductase (NR) gene, which plays a central role in nitrate acquisition, was the target gene for this research. Forty-one inbred maize lines were investigated, including four key inbred lines: Huangzaosi, Mo17, Dan340, and Ye478. Through multiple sequence alignment with the NR gene from B73, used as a control, we found that: 1) the NR gene of most inbred lines from Huangzaosi and from derived lines had two insertion fragments and two replacement fragments; 2) the NR gene of most inbred lines from Mo17 and derived lines had one insertion fragment and one replacement fragment; 3) there were two common variations and eight common SNPs in the NR gene of the four key lines. Huangzaosi and Mo17 also had three common variations compared with the other key lines. Moreover, Mo17 had some unique variations; there were no unique variations in the other key lines, even for SNPs, and 4) phylogenetic tree analysis showed that the NR gene of the derived lines from the same key line had higher sequence homology. Based on the above NR gene variation characteristics and sequence homology of key inbred lines and derived lines, a candidate inbred line can be preliminarily selected and evaluated by marker development and/or sequence alignment of the NR gene. PMID- 20845309 TI - Remarkably low genetic variation but high population differentiation in the climbing perch, Anabas testudineus (Anabantidae), based on the mtDNA control region. AB - Anabas testudineus (Anabantidae) is an important food fish in Southeast Asia. We analyzed the mitochondrial DNA control region sequence data to evaluate the genetic variability and population structure of this species. Sixty specimens were collected from four populations in Sumatra and two populations in Peninsular Malaysia. We found a very low level of genetic variability, with five of the six populations exhibiting total absence of genetic variation. Based on analysis of molecular variance, 84.72% of the total variation was among populations and 15.28% within populations. A geographical division based on FST values indicated highly significant genetic differentiation among populations from the four drainage systems: Aceh, Sumatra Utara, Pulau Pinang, and Terengganu (FST ranging from 0.633 to 1.000). No phylogeographic relationships among populations were detected, despite the generation of four distinct clades in a neighbor-joining phylogenetic tree. PMID- 20845310 TI - Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Mongolian population in China. AB - We examined the distribution of major allelic variants of CYP2C9 and CYP2C19 in the Mongolian population of China and compared it with that of other populations. The polymorphisms of CYP2C9 (including the CYP2C9*1, CYP2C9*2 and CYP2C9*3 alleles) and CYP2C19 (including the CYP2C19*1, CYP2C19*2 and CYP2C19*3 alleles) were analyzed in 280 healthy unrelated Chinese Mongolian subjects, using a PCR RFLP assay. The frequencies of CYP2C9*1, *2 and *3 alleles were 0.97, 0.00 and 0.03, respectively. The frequencies of CYP2C19*1, *2 and *3 alleles were 0.72, 0.24 and 0.04, respectively. We did not find any differences in the allelic distribution of these two genes between age groups. However, the genotype frequency of CYP2C9 *1/*3 was significantly higher in males than in females. Compared with other populations, we found that the allele frequencies of the CYP2C9*2 and CYP2C9*3 allelic variants in this Mongolian population of China were similar to those reported for other Asian populations, with significant differences compared to Caucasians and African-Americans. PMID- 20845311 TI - Building together. PMID- 20845312 TI - Prior exposure to major flooding increases individual preparedness in high-risk populations. AB - INTRODUCTION: July 2007 brought unprecedented levels of flooding to the United Kingdom. Health and financial implications were vast and still are emerging. Hydrological disasters will increase in frequency. Therefore, individual preparedness is paramount, as it may mitigate some of the devastating impacts of flooding. Literature on individual preparedness for flooding is scarce, so it is key that current levels of awareness, information gathering, and protective behaviors are investigated. It also is not clear whether being in a high-risk area or having recent exposure to flooding are motivational factors for preparedness. OBJECTIVES: The objectives of this study were to: (1) ascertain whether prior experience with flooding is a strong motivational factor for preparedness for future flooding episodes; and (2) assess preparedness in populations at high risk for flooding. METHODS: A prospective questionnaire survey was sent to individuals living in two towns in the United Kingdom, Monmouth and Tewkesbury. Both towns are deemed to be at significant risk for flooding, and Tewkesbury was severely affected by the July 2007 flooding disaster. Data were obtained from these two populations and analyzed. RESULTS: A total of 125 responses (of 200) were returned, and demographic data indicated no major differences between the two populations. The number of protective behaviors was higher from participants from Tewksbury (flood risk and exposure; p=0.004). Participants from Tewkesbury were more likely to be aware of living in a flood risk area and of the emergency systems present in the area, and feel prepared for future episodes of major flooding (p=0.03, p=0.005). Awareness of living in a flood risk-area increased the likelihood of being knowledgeable about emergency systems and adopting protective behaviors (p=0.0053, p=0.043). However, feeling prepared for future episodes of flooding was not associated with a strong increase in knowledge gained to prepare for flooding or having an increased number of protective behaviors. CONCLUSIONS: Awareness of being at-risk for flooding is vital for self-protective behavior. Both awareness of risk and recent exposure are motivational for flood preparedness. Recent exposure to flooding increases awareness, but it is unknown how long this effect will last. Recent exposure increases the preparedness of individuals for major flooding 18 months after major flooding and, if it continues, will help mitigate the devastating health, financial, and social effects of major flooding. PMID- 20845313 TI - H1N1: communication patterns among emergency department staff during the H1N1 outbreak, April 2009. AB - INTRODUCTION: The H1N1 influenza virus has been described by the World Health Organization (WHO) and the media as a disease that could rival the 1918 Spanish Influenza epidemic in deaths. During the spring of 2009, emergency departments across the world saw a spike in the number of influenza cases and by June 2009, the WHO had declared H1N1 a pandemic. In order to prevent emergency department staff from becoming ill and to provide up-to-date medical care to patients, information had to be disseminated quickly to emergency department staff. METHODS: An anonymous Internet survey was utilized to query emergency department staff regarding communication methods and overall attitudes regarding safety and treatment during the spring of 2009. RESULTS: The majority of emergency department staff (263; 88.3%) used multiple sources to obtain information about the H1N1 virus. There were 258 respondents (88.9%) that felt that the hospital was supplying them with the necessary information to protect themselves and their families and 280 (98.5%) felt confident that their emergency department was treating patients by the government-recommended guidelines. Statistically significant differences were noted in communication patterns between direct and indirect patient care providers. CONCLUSIONS: In general, H1N1 communication to emergency department staff was perceived as good during the initial H1N1 outbreak. However, because of the limitations associated with an online survey, these results do not allow for generalization to the total emergency department staff population. Hospital administrators may need to consider the differences in communication preferences of direct patient care providers and indirect patient care providers when distributing important information to emergency department staff during crisis and emergency situations. PMID- 20845314 TI - Association between patient unconscious or not alert conditions and cardiac arrest or high-acuity outcomes within the Medical Priority Dispatch System "Falls" protocol. AB - INTRODUCTION: Falls are one of the most common types of complaints received by 9 1-1 emergency medical dispatch centers. They can be accidental or may be caused by underlying medical problems. Though "not alert" falls patients with severe outcomes mostly are "hot" transported to the hospital, some of these cases may be due to other acute medical events (cardiac, respiratory, circulatory, or neurological), which may not always be apparent to the emergency medical dispatcher (EMD) during call processing. OBJECTIVES: The objective of this study was to characterize the risk of cardiac arrest and "hot-transport" outcomes in patients with "not alert" condition, within the Medical Priority Dispatch System (MPDS(r)) Falls protocol descriptors. METHODS: This retrospective study used 129 months of de-identified, aggregate, dispatch datasets from three US emergency communication centers. The communication centers used the Medical Priority Dispatch System version 11.3-OMEGA type (released in 2006) to interrogate Emergency Medical System callers, select dispatch codes assigned to various response configurations, and provide pre-arrival instructions. The distribution of cases and percentages of cardiac arrest and hot-transport outcomes, categorized by MPDS(r) code, was profiled. Assessment of the association between MPDS(r) Delta-level 3 (D-3) "not alert" condition and cardiac arrest and hot transport outcomes then followed. RESULTS: Overall, patients within the D-3 and D 2 "long fall" conditions had the highest proportions (compared to the other determinants in the "falls" protocol) of cardiac arrest and hot-transport outcomes, respectively. "Not alert" condition was associated significantly with cardiac arrest and hot-transport outcomes (p<0.001). CONCLUSIONS: The "not alert" determinant within the MPDS(r) "fall" protocol was associated significantly with severe outcomes for short falls (<6 feet; 2 meters) and ground-level falls. As reported to 9-1-1, the complaint of a "fall" may include the presence of underlying conditions that go beyond the obvious traumatic injuries caused by the fall itself. PMID- 20845316 TI - Predictive ability of emergency medical priority dispatch system protocols should be assessed at the atomic level of the determinant code. PMID- 20845315 TI - Does emergency medical dispatch priority predict delphi process-derived levels of prehospital intervention? AB - OBJECTIVE: The Medical Priority Dispatch System (MPDS) is an emergency medical dispatch system widely used to prioritize 9-1-1 calls and optimize resource allocation. This study evaluates whether the assigned priority predicts a Delphi process-derived level of prehospital intervention in each emergency medical dispatch category. METHODS: All patients given a MPDS priority in a suburban California county from 2004-2006 were included. A Delphi process of emergency medical services (EMS) professionals in another system developed the following categories of prehospital treatment representing increasing acuity, which were adapted for this study: advanced life support (ALS) intervention, ALS-Stat, and ALS-Critical. The sensitivities and specificities of MPDS priority for level of prehospital intervention were determined for each MPDS category. Likelihood ratios of low and high priority dispatch codes for the level of prehospital intervention also were calculated for each MPDS category. RESULTS: A total of 65,268 patients met inclusion criteria, representing 61% of EMS calls during the study period. The overall sensitivities of high-priority dispatch codes for ALS, ALS-Stat, and ALS-Critical interventions were 83% (95% confidence interval 83 84%), 83% (82-84%), and 94% (92-96%). Overall specificities were: ALS, 32% (31 32%); ALS-Stat, 31% (30-31%); and ALS-Critical 28% (28-29%). Compared to calls assigned to a low priority, calls with high-priority dispatch codes were more likely to receive ALS interventions by 22%, ALS-Stat by 20%, and ALS-Critical by 32%. A low priority dispatch code decreased the likelihood of ALS interventions by 48%, ALS-Stat by 45%, and ALS-Critical by 80%. Among high-priority dispatch codes, the rates of interventions were: ALS 26%, ALS-Stat 22%, and ALS-Critical 1.5%, all of which were significantly greater than low-priority calls (p<0.05) [ALS 13%, ALS-Stat 11%, and ALS-Critical 0.2%]. Major MPDS were categories with high sensitivities (>95%) for ALS interventions included breathing problems, cardiac or respiratory arrest/death, chest pain, stroke, and unconscious/fainting; these categories had an average specificity of 3%. Medical Priority Dispatch System categories such as back pain, unknown problem, and traumatic injury had sensitivities for ALS interventions<15%. CONCLUSIONS: The MPDS is moderately sensitive for the Delphi process derived ALS, ALS-Stat, and ALS-Critical intervention levels, but nonspecific. A low MPDS priority is predictive of no prehospital intervention. A high priority, however, is of little predictive value for ALS, ALS-Stat, or ALS-Critical interventions. PMID- 20845317 TI - Physiological scoring: an aid to emergency medical services transport decisions? AB - INTRODUCTION: Attendance at UK emergency departments is rising steadily despite the proliferation of alternative unscheduled care providers. Evidence is mixed on the willingness of emergency medical services (EMS) providers to decline to transport patients and the safety of incorporating such an option into EMS provision. Physiologically based Early Warning Scores are in use in many hospitals and emergency departments, but not yet have been proven to be of benefit in the prehospital arena. HYPOTHESIS: The use of a physiological-social scoring system could safely identify patients calling EMS who might be diverted from the emergency department to an alternative, unscheduled, care provider. METHODS: This was a retrospective, cohort study of patients with a presenting complaint of "shortness of breath" or "difficulty breathing" transported to the emergency department by EMS. Retrospective calculation of a physiological social score (PMEWS) based on first recorded data from EMS records was performed. Outcome measures of hospital admission and need for physiologically stabilizing treatment in the emergency department also were performed. RESULTS: A total of 215 records were analyzed. One hundred thirty-nine (65%) patients were admitted from the emergency department or received physiologically stabilizing treatment in the emergency department. Area Under the Receiver Operating Characteristic Curve (AUROC) for hospital admission was 0.697 and for admission or physiologically stabilizing treatment was 0.710. No patient scoring<2 was admitted or received stabilizing treatment. CONCLUSIONS: Despite significant over triage, this system could have diverted 79 patients safely from the emergency department to alternative, unscheduled, care providers. PMID- 20845318 TI - Editorial comments--physiological scoring: an aid to emergency medical services transport decisions? PMID- 20845319 TI - Geographical maldistribution of pediatric medical resources in Seattle-King County. AB - OBJECTIVE: Seattle-King County (SKC) Washington is at risk for regional disasters, especially earthquakes. Of 1.8 million residents, >400,000 (22%) are children, a proportion similar to that of the population of the State of Washington (24%) and of the United States (24%). The county's large area of 2,134 square miles (5,527 km2) is connected through major transportation routes that cross numerous waterways; sub-county zones may become isolated in the wake of a major earthquake. Therefore, each of SKC's three subcounty emergency response zones must have ample pediatric medical response capabilities. To date, total quantities and distribution of crucial hospital resources (available in SKC) to manage pediatric victims of a medical disaster are unknown. This study assessed whether geographical distribution of hospital pediatric resources corresponds to the pediatric population distribution in SKC. METHODS: Surveys were delivered electronically to all eight acute care hospitals in SKC that admit pediatric patients. Quantities and categories of pediatric resources, including inpatient treatment space, staff, and equipment, were queried and verified via site visits. RESULTS: Within the seven responding hospitals of eight queried, the following were identified: 477 formal pediatric bed spaces (pediatric intensive care unit, neo-natal intensive care unit, general wards, and emergency department), 43 informal pediatric bed spaces (operating room and post-anesthesia care unit), 1,217 pediatric nurses, 554 pediatric physicians, and 252 infant/pediatric adaptable ventilators. The City of Seattle emergency response zone contains 82.1% of bed spaces, 83.5% of nurses, and 95.8% of physicians, yet only 22.8% of all SKC children live in that zone. CONCLUSIONS: The majority of hospital pediatric resources are located in the SKC sub-region with the fewest children. These resources are potentially inaccessible and unable to be redistributed by ground transportation in the event of a significant regional disaster. Future planning for pediatric care in the event of a medical disaster in SKC must address this vulnerability. PMID- 20845320 TI - Editorial comments--surge capacity implications and geographic mal-distribution of pediatric medical resources in Seattle-King County. PMID- 20845321 TI - Utilization of warning lights and siren based on hospital time-critical interventions. AB - OBJECTIVE: The objective of this study was to evaluate the time saved by usage of lights and siren (L&S) during emergency medical transport and measure the total number of time-critical hospital interventions gained by this time difference. METHODS: A retrospective study was performed of all advanced life support (ALS) transports using lights and siren to this university emergency department during a three-week period. Consecutive times were measured for 112 transports and compared with measured transport times for a personal vehicle traveling the same day of the week and time of day without lights and siren. The time-critical hospital interventions are defined as procedures or treatments that could not be performed in the prehospital setting requiring a physician. The project assessed whether the patients received the hospital interventions within the average time saved using lights and siren transport. RESULTS: The average difference in time with versus without L&S was -2.62 minutes (95% CI: -2.60- -2.63, paired t-test p<0.0001). The average transport time with L&S was 14.5+/-7.9 minutes (min) (1 standard deviation/minute (min), range=1-36 min.). The average transport time without L&S was 17.1+/-8.3 min (range=1-40 min). Of the 112 charts evaluated, five patients (4.5%) received time-critical hospital interventions. No patients received time-critical interventions within the time saved by utilizing lights and siren. Longer distances did not result in time saved with lights and siren. CONCLUSIONS: Limiting lights and siren use to the patients requiring hospital interventions will decrease the risks of injury and death, while adding the benefit of time saved in these critical patients. PMID- 20845322 TI - Prehospital rapid sequence intubation in an emergency medical services system with two advanced life support providers. AB - OBJECTIVE: A rapid sequence intubation (RSI) method was introduced to a university-based emergency medical services (EMS) system. This is a report of the initial experience with the first 50 patients in a unique, two-tiered, two advanced life support (ALS) providers system. METHODS: The data were evaluated prospectively after an extensive RSI training period, consisting of didactic information and skills performance. Fifty consecutive patient records that documented the procedure were abstracted. Data abstracted included end-tidal CO2, heart rate, blood pressure, and pulse oximetry at various time intervals. Intubation success rates and number of attempts were documented. The consistency of proper documentation also was noted on patient care records. RESULTS: No differences were noted in heart rate prior to RSI and one and five minutes after the RSI procedure was begun. No differences in blood pressure at one and five minutes were noted. Statistically significant improvements were found in pulse oximetry comparing prior to RSI and one minute after (p<0.001; 95% CI: 3.15 11.41) as well as prior to RSI and five minutes after RSI was started (p<0.0002; 95% CI=4.60-13.33). No differences were observed in end-tidal CO2 at one and five minutes. Overall intubation success rate was 96%, with 82% on first attempt and 92% on two or less attempts. Documentation for individual vitals was consistently <75%. CONCLUSIONS: Patients had no significant worsening of vital signs during the RSI procedure and mild improvement in pulse oximetry. Intubation success rates were consistent with national averages. Proper documentation was lacking in more than one quarter of the charts. These data add to a body of literature that raises further concerns regarding prehospital RSI. PMID- 20845323 TI - Tactical medical skill requirements for law enforcement officers: a 10-year analysis of line-of-duty deaths. AB - INTRODUCTION: In the absence of other data, military Tactical Combat Casualty Care (TCCC) precepts are increasingly being adapted to law enforcement needs. The purpose of this study is to better describe the nature of potentially preventable law enforcement Line-of-Duty Deaths (LODDs) occurring as a result of felonious assaults. METHODS: A retrospective analysis was performed of open source data available through the US Federal Bureau of Investigation Uniform Crime Reporting (UCR) Law Enforcement Officers Killed and Assaulted (LEOKA) program for the years 1998-2007 inclusive. RESULTS: After applying exclusion criteria, 341 victim officers were included in the study. The most common cause of death was head trauma (n=198), followed by chest trauma (n=90). There were 123 victim officers that suffered potentially preventable deaths; the majority of these injuries involved the chest. Over the 10-year study period, only two officers (0.6%) died from isolated extremity hemorrhage. CONCLUSIONS: The current emphasis of TCCC on control of exsanguinating extremity hemorrhage may not meet the needs of law enforcement personnel in an environment with expedited access to well-developed trauma systems. Further study is needed to better examine the causes of preventable deaths in law enforcement officers, as well as the most appropriate law enforcement tactical medical skill set and treatment priorities. PMID- 20845324 TI - Editorial comments: tactical medical skill requirements for law enforcement officers: a 10-year analysis of line-of-duty deaths. PMID- 20845325 TI - Development of disaster pamphlets based on health needs of patients with chronic illnesses. AB - The aim of this research was to develop a pamphlet that would enable patients with diabetes, rheumatic diseases, chronic respiratory disease, and dialysis treatment to be aware of changes in their physical conditions at an early stage of a disaster, cope with these changes, maintain self-care measures, and recover their health. Illness-specific pamphlets were produced based on disaster-related literature, news articles, surveys of victims of the Great Hanshin-Awaji Earthquake Disaster and Typhoon Tokage, and other sources. Each pamphlet consisted of seven sections-each section includes items common to all illnesses as well as items specific to each illness. The first section, "Physical Self Care", contains a checklist of 18 common physical symptoms as well as symptoms specific to each illness, and goes on to explain what the symptoms may indicate and what should be done about them. The main aim of the "Changes in Mental Health Conditions" section is to detect posttraumatic stress disorder (PTSD) at an early stage. The section "Preventing the Deterioration of Chronic Illnesses" is designed to prevent the worsening of each illness through the provision of information on cold prevention, adjustment to the living environment, and ways of coping with stress. In the sections, "Medication Control" and "Importance of Having Medical Examinations", spaces are provided to list medications currently being used and details of the hospital address, in order to ensure the continued use of medications. The section, "Preparing for Evacuations" gives a list of everyday items and medical items needed to be prepared for a disaster. Finally, the "Methods of Contact in an Emergency" section provides details of how to use the voicemail service. The following content-specific to each illness also was explained in detail: (1) for diabetes, complications arising from the deterioration of the illness, attention to nutrition, and insulin management; (2) for rheumatic diseases, a checklist of factors indicating the worsening of the illness and methods of coping with stress; (3) for chronic respiratory disease, prevention of respiratory infections and management of supplemental oxygen; and (4) for patients requiring dialysis, conditions of dialysis (such as dry weight, dialyzer, number of dialysis treatments, and dialysis hours) and what to do if a disaster occurs during dialysis. It is expected that these pamphlets will be useful to patients with chronic illnesses, and will be used to prepare for disasters, thereby helping the patients cope with the unusual situation that during a disaster and recover as soon as possible. PMID- 20845326 TI - Pakistan earthquake: experiences of a multidisciplinary surgical team. AB - INTRODUCTION: Four weeks after the earthquake in Kashmir, Pakistan, multidisciplinary surgical teams were organized within the United Kingdom to help treat disaster victims who had been transferred to Rawalpindi. The work of these teams between 05-17 November 2005 is reviewed, and experiences and lessons learned are presented. METHODS: Two self-sufficient teams consisting of orthopedic, plastic surgical, anesthetic, and theatre staff were deployed consecutively over a two-week period. A trauma unit was set up in a donated ward within a private ophthalmological hospital in Rawalpindi. RESULTS: Seventy-eight patients with a mean age of 23 years were treated: more than half (40) were <16 years of age. Fifty-two patients only had lower limb injuries, 18 upper limb injuries, and eight combined lower and upper limb. The most common types of injuries were: (1) tibial fractures (n=24), with the majority being open grade 3B injuries (n=22); (2) femoral fractures (n=11); and (3) forearm fractures (n=9). Almost half (n=34) of the fractures were open injuries requiring soft tissue cover. Over 12 days, 293 operations were performed (average 24.4 per day). A total of 202 examinations under anesthesia, washouts, and debridements were performed. The majority of wounds required multiple washouts prior to definitive procedures. Thirty-four definitive orthopedic procedures (fixations) and 57 definitive plastic procedures were performed. Definitive orthopedic procedures included 15 circular frame fixations of long bones, nine of which required acute shortening and five open reduction and internal fixation of long bones. Definitive plastic procedures included 21 skin grafts, four amputations, 11 revisions of amputations, 20 regional flaps, and one free flap. CONCLUSIONS: A joint ortho-plastic approach was key to the treatment of the spectrum of injuries encountered. Only four patients required fresh amputations. Twenty patients may have required amputation without the use of ring fixators and soft tissue reconstruction. Having self-sufficient teams along with their own equipment and supplies also was mandatory in order not to put further demand on already scarce resources. However, mobilizing such teams logistically was difficult, and therefore, an organization consisting of willing volunteers for future efforts has been established. PMID- 20845327 TI - Editorial comments--Pakistan earthquake: experiences of a multidisciplinary surgical team. PMID- 20845328 TI - Training novice users in bag-valve-mask technique. PMID- 20845329 TI - Disaster coordination needs more than the "health cluster". PMID- 20845330 TI - Global Health Cluster position paper: removing user fees for primary healthcare services during humanitarian crises. PMID- 20845331 TI - Guidelines for reports on health crises and critical health events. PMID- 20845332 TI - Phyloproteomic classification of unsequenced organisms by top-down identification of bacterial proteins using capLC-MS/MS on an Orbitrap. AB - Currently, most MS-based proteomic studies of bacteria and archea match experimental data to known amino acid sequences from the target organism. Top down studies use a protein's molecular weight along with data gathered from MS/MS experiments to identify proteins by database matching. For Erwinia herbicola and Enterobacter cloacae, studied here, the necessary protein sequences are not available in protein sequence repositories. We apply top-down protein fragmentation, but match the experimental data with homologous proteins from related organisms with sequenced genomes, demonstrating considerable shared protein sequence between closely related bacteria. Using this homology-based approach, we are not only able to identify representative proteins, but are also able to place the two target bacteria in their correct phylogeny. Furthermore, we show that the unexpected mass delta between the experimental precursor and matched protein sequence can often be localized and characterized using accurate mass precursor and fragment ion measurements. Finally, we demonstrate that proteins identified by top-down workflows provide strong experimental evidence for correct, missing, and misannotated bacterial protein sequences, not only in the analyzed organism, but also for homologous proteins in closely related species. PMID- 20845333 TI - Data-directed top-down Fourier-transform mass spectrometry of a large integral membrane protein complex: photosystem II from Galdieria sulphuraria. AB - High-resolution top-down MS was used to characterize eleven integral and five peripheral subunits of the 750 kDa photosystem II complex from the eukaryotic red alga, Galdieria sulphuraria. The primary separation used LC MS with concomitant fraction collection (LC-MS+), yielding around 40 intact mass tags at 100 ppm mass accuracy on a low-resolution ESI mass spectrometer, whose retention and mass were used to guide subsequent high-resolution top-down nano-electrospray FT ion cyclotron resonance MS experiments (FT-MS). Both collisionally activated and electron capture dissociation were used to confirm the presence of eleven small subunits to mass accuracy within 5 ppm; PsbE, PsbF, PsbH, PsbI, PsbJ, PsbK, PsbL, PsbM, PsbT, PsbX and PsbZ. All subunits showed covalent modifications that fall into three classes including retention of initiating formyl-methionine, removal of methionine at the N-terminus with or without acetylation, and removal of a longer N-terminal peptide. Peripheral subunits identified by top-down analysis included oxygen-evolving complex subunits PsbO, PsbU, PsbV, as well as Psb28 (PsbW) and Psb27 ("PsbZ-like"). Top-down high-resolution MS provides the necessary precision, typically less than 5 ppm, for identification and characterization of polypeptide composition of these important membrane protein complexes. PMID- 20845335 TI - Nucleic acid/organic polymer hybrid materials: synthesis, superstructures, and applications. AB - Extensive efforts have been devoted to the development of hybrid structures consisting of biomacromolecules and organic polymers connected through covalent bonds. While the combination of proteins and peptides with synthetic macromolecules has been explored in depth, far fewer examples of nucleic acid/polymer hybrids are known. In this Review we give selected examples of this exciting class of materials which can be arranged as linear block copolymer architectures, as side-chain polymers, or as cross-linked networks. Emphasis is placed on the fabrication of these materials as well as on their potential applications in nanoscience, diagnostics, and biomedicine. PMID- 20845334 TI - Identification of osteocyte-selective proteins. AB - Since little is known regarding osteocytes, cells embedded within the mineralized bone matrix, a proteomics approach was used to discover proteins more highly expressed in osteocytes than in osteoblasts to determine osteocyte-specific function. Two proteomic profiles obtained by two different proteomic approaches using total cell lysates from the osteocyte cell line MLO-Y4 and the osteoblast cell line MC3T3 revealed unique differences. Three protein clusters, one related to glycolysis (Phosphoglycerate kinase 1, fructose-bisphosphate aldolase A, hypoxia up-regulated 1 [ORP150], triosephosphate isomerase), one to protein folding (Mitochondrial Stress-70 protein, ORP150, Endoplasmin), and one to actin cytoskeleton regulation (Macrophage-capping protein [CapG], destrin, forms of lamin A and vimentin) were identified. Higher protein expression of ORP-150, Cap G, and destrin in MLO-Y4 cells compared with MC3T3 cells was validated by gene expression, Western blotting, and in vivo expression. These proteins were shown to be selective in osteocytes in vivo using immuno-staining of mouse ulnae. Destrin was most highly expressed in embedding osteoid osteocytes, GapG in embedded osteocytes, and ORP150 in deeply embedded osteocytes. In summary, the proteomic approach has yielded important information regarding molecular mechanisms used by osteocytes for embedding in matrix, the formation of dendritic processes, and protection within a hypoxic environment. PMID- 20845336 TI - Anomalous surface compositions of stoichiometric mixed oxide compounds. PMID- 20845337 TI - Neutral Lewis base adducts of silicon tetraazide. PMID- 20845338 TI - Dressing in layers: layering surface functionalities in nanoporous aluminum oxide membranes. PMID- 20845339 TI - A general approach to the construction of structure-switching reporters from RNA aptamers. PMID- 20845341 TI - Anomalous diffusion of electrically neutral molecules in charged nanochannels. PMID- 20845340 TI - Noncovalent and site-directed spin labeling of nucleic acids. PMID- 20845342 TI - Catalytic hydrogen evolution from mononuclear iron(II) carbonyl complexes as minimal functional models of the [FeFe] hydrogenase active site. PMID- 20845343 TI - Asymmetric nanocatalysis: N-heterocyclic carbenes as chiral modifiers of Fe3O4/Pd nanoparticles. PMID- 20845344 TI - Direct visualization of protein association in living cells with complex-edited electron microscopy. PMID- 20845346 TI - Catalytic C-H amination with unactivated amines through copper(II) amides. PMID- 20845345 TI - cat-ELCCA: a robust method to monitor the fatty acid acyltransferase activity of ghrelin O-acyltransferase (GOAT). PMID- 20845347 TI - The modular assembly of clusters is the natural synthetic strategy for the active site of [FeFe] hydrogenase. PMID- 20845348 TI - Multiple routes to characterize the folding of a small DNA hairpin. PMID- 20845349 TI - Circular dichroism of amino acids in the vacuum-ultraviolet region. PMID- 20845350 TI - Controlling contact electrification with photochromic polymers. PMID- 20845351 TI - Stereoselective synthesis of alpha-diazo oxime ethers and their application in the synthesis of highly substituted pyrroles through a [3+2] cycloaddition. PMID- 20845358 TI - Structural and functional analysis of human liver-expressed antimicrobial peptide 2. AB - Human liver-expressed antimicrobial peptide 2 (LEAP-2) is a cationic antimicrobial peptide (CAMP) believed to have a protective role against bacterial infection. Little is known about the structure-activity relationships of LEAP-2 or its mechanism of action. In this study we describe the structure of LEAP-2, analyze its interaction with model membranes, and relate them to the antimicrobial activity of the peptide. The structure of LEAP-2, determined by NMR spectroscopy, reveals a compact central core with disorder at the N and C termini. The core comprises a beta-hairpin and a 3(10)- helix that are braced by disulfide bonds between Cys17-28 and Cys23-33 and further stabilized by a network of hydrogen bonds. Membrane-affinity studies show that LEAP-2 membrane binding is governed by electrostatic attractions, which are sensitive to ionic strength. Truncation studies show that the C-terminal region of LEAP-2 is irrelevant for membrane binding, whereas the N-terminal (hydrophobic domain) and core regions (cationic domain) are essential. Bacterial-growth-inhibition assays reveal that the antimicrobial activity of LEAP-2 correlates with membrane affinity. Interestingly, the native and reduced forms of LEAP-2 have similar membrane affinity and antimicrobial activities; this suggests that disulfide bonds are not essential for the bactericidal activity. This study reveals that LEAP-2 has a novel fold for a CAMP and suggests that although LEAP-2 exhibits antimicrobial activity under low-salt conditions, there is likely to be another physiological role for the peptide. PMID- 20845359 TI - Potent inhibition of HIV-1 entry with a chemically programmed antibody aided by an efficient organocatalytic synthesis. PMID- 20845360 TI - Development of peptide and small-molecule HIV-1 fusion inhibitors that target gp41. AB - It has been 25 years since the development of the first efficient HIV-1/AIDS treatment. Scientists now know more about the HIV-1 infection life cycle, and more than 30 antiretroviral drugs have been developed, including HIV-1 fusion inhibitors. Fundamental work was begun in the early 1990s and led to the development of a novel class of anti-HIV-1 drugs, culminating in a peptide known as T20, which is currently the only HIV-1 fusion inhibitor approved by the US Food and Drug Administration. However, more work needs to be done to perfect the development of peptide and small-molecule HIV fusion inhibitors, particularly those that target gp41. Herein we present a brief overview of the development of this class of anti-HIV-1 drug by focusing on the achievements, challenges, and lessons learned. We cite hallmark studies of the past and comment on future drug development. PMID- 20845361 TI - Inhibition of HIV-1 entry: multiple keys to close the door. PMID- 20845363 TI - P4 activation with Pt(0) metal centers: selective formation of a dinuclear {Pt2(MU,eta(2:2)-P2)} complex. PMID- 20845362 TI - Synthesis of benzofuran, benzothiophene, and benzothiazole-based thioamides and their evaluation as K(ATP) channel openers. AB - Several series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel K(ATP) channel openers in artificial cell systems: CHO cells transfected with SUR1/Kir6.2, and HEK 293 cells transfected with SUR2B/Kir6.1; these served as model systems for insulin secreting pancreatic beta cells and smooth muscle cells, respectively. All compounds were investigated with respect to their binding affinity for the SUR2B type K(ATP) channels using [(3)H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC(4)(3) and DyeB (R7260) as membrane potential dyes. Remarkable affinity for SUR2B/Kir6.1 channels in the single-digit micromolar range was observed. In addition, benzothiazole-derived thioamides with sterically demanding, lipophilic substituents showed >100-fold selectivity in favor of SUR2B/Kir6.1. A one-carbon spacer between the heterocyclic skeleton and the thioamide moiety was observed to be crucial for affinity and selectivity. Two of the most potent and selective compounds were studied by crystal structure analyses. PMID- 20845364 TI - Hydrogen bonds and local symmetry in the crystal structure of gibbsite. AB - First-principles quantum mechanical calculations of NMR chemical shifts and quadrupolar parameters have been carried out to assign the (27)Al MAS NMR resonances in gibbsite. The (27)Al NMR spectrum shows two signals for octahedral aluminum revealing two aluminum sites coordinated by six hydroxyl groups each, although the crystallographic positions of the two Al sites show little difference. The presence of two distinguished (27)Al NMR resonances characterized by rather similar chemical shifts but quadrupolar coupling constants differing by roughly a factor of two is explained by different character of the hydrogen bonds, in which the hydroxyls forming the corresponding octahedron around each aluminum site, are involved. The Al-I site characterized by a C(Q) = 4.6 MHz is surrounded by OH-groups participating in four intralayer and two interlayer hydrogen bonds, while the Al-II site with the smaller quadrupolar constant (2.2 MHz) is coordinated by hydroxides, of which two point toward the intralayer cavities and four OH-bonds are aligned toward the interlayer gallery. In high resolution solid-state (1)H CRAMPS (combination of rotation and multiple-pulse spectroscopy) four signals with an intensity ratio of 1:2:2:1 are resolved which allow to distinguish six nonequivalent hydrogen sites reported in the gibbsite crystal structure and to ascribe them to two types of structural OH groups associated with intralayer and interlayer hydrogen bonds. This study can be applied to characterize the gibbsite-like layer-intergallery interactions associated with hydrogen bonding in the more complex systems, such as synthetic aluminum layered double hydroxides. PMID- 20845365 TI - Development and validation of a high-throughput and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of oseltamivir phosphate and its oseltamivir carboxylate metabolite in human plasma for pharmacokinetic studies. AB - A rapid, sensitive and rugged solid-phase extraction ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for determination of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) in human plasma. The procedure for sample preparation includes a simple SPE extraction procedure coupled with a Chromatopack C(18) column (50 * 3.0 mm, i.d., 3.0 um) with isocratic elution at a flow-rate of 0.600 mL /min and acyclovir was used as the internal standard. The analysis was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization. Using 500 uL plasma, the methods were validated over the concentration ranges 0.92-745.98 and 5.22-497.49 ng/mL for OP and OC, with a lower limit of quantification of 0.92 and 5.22 ng/mL. The intra- and inter-day precision and accuracy of the quality control samples were within 10.1%. The recovery was 68.72, 70.66 and 71.59% for OP, OC and IS, respectively. Total run time was only 1.0 min. The method was highly reproducible with excellent chromatography properties. PMID- 20845366 TI - Stability-indicating validation of acitretin and isoacitretin in human plasma by LC-ESI-MS/MS bioanalytical method and its application to pharmacokinetic analysis. AB - LC- ESI- MS/MS simultaneous bioanalytical method was developed to determine acitretin and its metabolite isoacitretin in human plasma using acitretin-d3 used as the internal standard for both analytes. The compounds were extracted using protein precipitation coupled with liquid-liquid extraction with flash freezing technique. Negative mass transitions (m/z) of acitretin, isoacitretin and acitretin-d3 were detected in multiple reactions monitoring (MRM) mode at 325.4 > 266.3, 325.2 -> 266.1 and 328.3 -> 266.3, respectively, with a turbo ion spray interface. The chromatographic separation was achieved on an Ascentis-RP amide column (4.6 * 150 mm, 5 um) with mobile phase delivered in isocratic mode. The method was validated over a concentration range of 1.025-753.217 ng/mL for acitretin and 0.394-289.234 ng/mL for isoacitretin with a limit of quantification of 1.025 and 0.394 ng/mL. The intra-day and inter-day precisions were below 8.1% for acitretin and below 13.8% for isoacitretin, while accuracy was within +/-7.0 and +/-10.6% respectively. For the first time, the best possible conditions for plasma stability of acitretin and isoacitretin are presented and discussed with application to clinical samples. PMID- 20845367 TI - Flow cytometric detection of degranulated basophils in chronic myeloid leukemia in accelerated phase. AB - We report a rare case of chronic myeloid leukemia in accelerated phase with basophilic transformation, in which basophils exceeding 70%, were detectable only by flow cytometry because of their morphologic atypicality and degranulation. PMID- 20845369 TI - The use of IL-3 in basophil activation tests is the real pitfall. PMID- 20845370 TI - Relationship of protein tyrosine phosphorylation state with tolerance to frozen storage and the potential to undergo cyclic AMP-dependent hyperactivation in the spermatozoa of Japanese Black bulls. AB - The aim of this study was to elucidate the relationship between protein tyrosine phosphorylation state and sperm characteristics in frozen-stored spermatozoa of Japanese Black bulls. The spermatozoa were washed with PBS containing polyvinyl alcohol and then incubated with cell-permeable cAMP analog cBiMPS to induce flagellar hyperactivation. Before and after incubation, the spermatozoa were used for immunodetection of tyrosine-phosphorylated proteins, assessment of morphological acrosome condition and evaluation of motility. In bulls whose frozen-stored spermatozoa were classified as having a high-grade acrosome condition before incubation, sperm tyrosine-phosphorylated proteins, including the 33-kDa tyrosine-phosphorylated SPACA1 protein, were localized in the anterior region of the acrosome and equatorial subsegment. The immunodetection level of the 41- and 33-kDa sperm tyrosine-phosphorylated proteins in the Western blots and the immunofluorescence of tyrosine-phosphorylated proteins and SPACA1 proteins in the anterior region of the sperm acrosome were lower in bulls whose frozen-stored sperm were classified as having a low-grade acrosome condition. On the other hand, after incubation with cBiMPS, immunodetection levels of at least 10 tyrosine-phosphorylated proteins increased in the connecting and principal pieces of spermatozoa, coincident with the induction of flagellar hyperactivation. Many of the spermatozoa also exhibited detection patterns similar to those of boar hyperactivated spermatozoa. These results are consistent with the suggestion that immunodetection levels of tyrosine-phosphorylated proteins are valid markers that can predict the level of tolerance to frozen storage and the potential to undergo cAMP-dependent hyperactivation for the spermatozoa of individual Japanese Black bulls. PMID- 20845371 TI - Quantitative determination of cefetamet in human plasma by liquid chromatography mass spectrometry. AB - Cefetamet is a potent antibiotic to treat respiratory and urinary tract infections. To improve oral bioavailability, it is administered as a prodrug, cefetamet pivoxyl hydrolyzed by esterase following absorption. A quantification method using a mass spectrometry was developed for the determination of cefetamet in human plasma. After a protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase C18 column and detected by a tandem mass spectrometer with electrospray ionization. The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of the cefetamet in plasma after a single oral administration of 500 mg cefetamet pivoxyl. PMID- 20845373 TI - Solid-state processing of organic semiconductors. PMID- 20845374 TI - Development and validation of an HPLC method for quantitation of BA-TPQ, a novel iminoquinone anticancer agent, and an initial pharmacokinetic study in mice. AB - We herein describe the development and validation of an HPLC method for the quantitation of 7-(benzylamino)-1,3,4,8-tetrahydropyrrolo [4,3,2-de]quinolin 8(1H)-one (BA-TPQ), a newly synthesized iminoquinone anticancer agent. BA-TPQ was extracted from plasma and tissue samples by first precipitating proteins with acetonitrile followed by a liquid-liquid extraction with ethyl acetate. Chromatographic separation was carried out using a gradient flow rate on a Zorbax SB C(18) column, and the effluent was monitored by UV detection at 346 nm. The method was found to be precise, accurate, and specific, with a linear range of 3.91-1955.0 ng/mL in plasma, 19.55-1955.0 ng/mL in spleen, brain, and liver homogenates and 19.55-3910.0 ng/mL in heart, lung and kidney homogenates. The method was stable under all relevant conditions. Using this method, we also carried out an initial study determining plasma pharmacokinetics and tissue distribution of BA-TPQ in mice following intravenous administration. In summary, this simple and sensitive HPLC method can be used in future preclinical and clinical studies of BA-TPQ. PMID- 20845375 TI - Influence of Moringa oleifera on pharmacokinetic disposition of rifampicin using HPLC-PDA method: a pre-clinical study. AB - The influence of active fraction isolated from pods of an indigenous plant, Moringa oleifera (MoAF) was studied on the pharmacokinetic profile of the orally administered frontline anti-tuberculosis drug rifampicin (20 mg/kg b.w.) in Swiss albino mice. The antibiotic rifampicin alone and in combination with MoAF (0.1 mg/kg b.w.) was administered orally and heparanized blood samples were collected from the orbital plexus of mice for plasma separation at 0, 1, 2, 3, 4 and 5 h, post treatment. Plasma rifampicin concentration, pharmacokinetic parameters and drug metabolizing enzyme (cytochrome P-450) activity were determined. The pharmacokinetic data revealed that MoAF-treated animals had significantly increased rifampicin plasma concentration, C(max), K(el), t(1/2(a)), t(1/2(el)), K(a) and AUC as well as inhibited rifampicin-induced cytochrome P-450 activity. In conclusion, the result of this study suggested that the bioavailability enhancing property of MoAF may help to lower the dosage level and shorten the treatment course of rifampicin. PMID- 20845376 TI - Differential interactions of plasmid DNA, RNA and genomic DNA with amino acid based affinity matrices. AB - The development of a strategy to plasmid DNA (pDNA) purification has become necessary for the development of gene therapy and DNA vaccine production processes in recent years, since this nucleic acid and most of contaminants, such as RNA, genomic DNA and endotoxins, are negatively charged. An ideal separation methodology may be achieved with the use of affinity interactions between immobilized amino acids and nucleic acids. In this study, the binding behaviour of nucleic acids under the influence of different environmental conditions, such as the composition and ionic strength of elution buffer, and the temperature, is compared with various amino acids immobilized on chromatography resins. Supercoiled (sc) plasmid isoform was isolated with all matrices used, but in some cases preferential interactions with other nucleic acids were found. Particularly, lysine chromatography showed to be an ideal technology mainly on RNA purification using low salt concentration. On the other hand, arginine ligands have shown a greater ability to retain the sc isoform comparatively to the other nucleic acids retention, becoming this support more adequate to sc pDNA purification. The temperature variation, competitive elution and oligonucleotides affinity studies also allowed to recognize the dominant interactions inherent to biorecognition of pDNA molecule and the affinity matrices. PMID- 20845377 TI - Effects on the dynamic utilization of the adsorptive capacity of chromatographic columns induced by non-uniform ligand density distributions. AB - The dynamic behavior of the breakthrough curves of a single adsorbate obtained from columns employing adsorbent media which differ from one another only on the spatial distribution of the immobilized ligands in the porous particles is examined. The spatial distributions of the immobilized ligands considered in this study are uniform and non-uniform, but the total number of immobilized ligands in the particles has the same value whether the spatial distribution is uniform or non-uniform. The results clearly show that the columns employing adsorbent particles in which the spatial distribution of the immobilized ligands is non uniform and such that the concentration of the immobilized ligands increases monotonically from the center of the particle to the outer particle surface, exhibit (i) larger breakthrough times, (ii) steeper breakthrough curves, and (iii) higher dynamic utilization of the adsorptive capacity of the column as the superficial velocity of the flowing fluid stream in the column increases (throughput increase) than the columns using adsorbent particles in which the spatial distribution of the immobilized ligands is uniform. The importance of employing in the columns adsorbent media whose spatial ligand density distributions satisfy the mathematical property of monotonically increasing ligand concentration with increasing from the particle center radial position, will be significantly enhanced when (i) the size of the particle radius is increased, and (ii) continuous counter-current and periodic counter-current (simulated moving beds) operations are employed. PMID- 20845380 TI - Nutrigenomics--uncovering dietary signatures in obesity and metabolic diseases. PMID- 20845378 TI - Determination of triclosan and methyl triclosan in environmental solid samples by matrix solid-phase dispersion and gas chromatography-mass spectrometry. AB - In this study, a method for the determination of triclosan (TCS) and methyl triclosan (MTCS) in soil and sewage sludge samples from municipal wastewater treatment plants was developed based on the extraction by matrix solid-phase dispersion. After extraction, the analytes were derivatized with N-(tert butyldimethylsilyl)-N-methyl-trifluoroacetamide for their determination by isotope dilution GC with electron impact MS detection in the SIM mode, using (13)C(12)-labeled compounds as internal standards. Recoveries of MTCS and TCS from laboratory spiked sludge samples were in the range from 95.7 to 101.0% and 97.4 to 101.3%, respectively. In the case of soil samples, the recoveries of MTCS and TCS ranged from 98.4 to 101.0% and 98.7 to 99.0%, respectively. The limits of detection (S/N=3) varied from 0.10 to 0.12 ng/g for sewage sludge samples and from 0.05 to 0.08 ng/g for soil samples. The validated method was used to assess the levels of TCS and MTCS in sewage sludge collected from 19 wastewater treatment plants located in Madrid (Spain) and in soil samples collected from agricultural fields in Madrid. Both compounds were detected in all the sludge samples at concentrations ranging from 54 to 2987 ng/g dry weight for TCS and from 4 to 311 ng/g dry weight for MTCS. The levels encountered in soil were much lower, 0.8 to 4.7 ng/g dry weight for TCS and 0.3 to 3.8 ng/g dry weight for MTCS. PMID- 20845382 TI - Nutrigenomics and the stewardship of scientific promises. AB - Here we analyze the rise and establishment of nutrigenomics versus nutrition science from a political perspective. We argue that the exceptionalist status of nutrigenomics has been brought about by a carefully orchestrated economy of expectation, enabling the nutrigenomics community to develop its own research agenda that differs significantly from that of nutrition science. Nutrigenomics promotes research specifically directed towards the heterogeneity of dietary guidelines, while nutrition science pursues a public health goal dominated by homogeneous health messages. Through the development of genomic technology and the protective niche created by large global funding initiatives, this heterogeneity-research agenda has been able to develop itself. Those pursuing and supporting it have, through nutrigenomics' economy of expectation, influenced public opinion, and regulatory and political structures dealing with food and health. With many big global nutrigenomics initiatives slowly approaching their end, this article hints at some of the possible political consequences of its economy of expectation and suggests that a "stewardship" of promises and expectations is in order PMID- 20845383 TI - Meeting report: fourth Asia-Pacific nutrigenomics conference: gene-diet interactions in gut health, Auckland, New Zealand, February 21-25, 2010. PMID- 20845384 TI - Carbohydrate metabolic pathway genes associated with quantitative trait loci (QTL) for obesity and type 2 diabetes: identification by data mining. AB - Increasing consumption of refined carbohydrates is now being recognized as a primary contributor to the development of nutritionally related chronic diseases such as obesity and type 2 diabetes mellitus (T2DM). A data mining approach was used to evaluate the role of carbohydrate metabolic pathway genes in the development of obesity and T2DM. Data from public databases were used to map the position of the carbohydrate metabolic pathway genes to known quantitative trait loci (QTL) for obesity and T2DM and for examining the pathway genes for the presence of sequence and structural genetic variants such as single nucleotide polymorphisms (SNPs) and copy number variants (CNS), respectively. The results demonstrated that a majority of the genes of the carbohydrate metabolic pathways are associated with QTL for obesity and many for T2DM. In addition, some key genes of the pathways also encode non-synonymous SNPs that exhibit significant differences in population frequencies. This study emphasizes the significance of the metabolic pathways genes in the development of disease phenotypes, its differential occurrence across populations and between individuals, and a strategy for interpreting an individuals' risk for disease. PMID- 20845385 TI - Hepatoprotective effect of oleuropein in mice: mechanisms uncovered by gene expression profiling. AB - Oleuropein, an active constituent of olive leaf, has a variety of pharmacological activities associated with its capacity to scavenge reactive oxygen species. Oleuropein is also reported to have protective effects against non-alcoholic fatty liver disease (NAFLD) in vivo. In this study, gene expression profiling of hepatic tissues was examined, and transcription factors (TFs) with target genes that were modulated by oleuropein were identified to gain insights into the molecular mechanisms for the hepatoprotective action of this compound. C57BL/6N mice were fed either a high-fat diet (HFD) or 0.03% oleuropein-supplemented HFD for 10 weeks, after which their livers were subjected to oligo DNA microarray analysis. The oleuropein with which the HFD was supplemented reduced the hepatic mRNA level of the genes that encoded the key regulators of the hepatic fatty acid uptake and transport. In addition, the oleuropein reduced the expression of a number of hepatic genes involved in the oxidative stress responses and detoxification of lipid peroxidation products and proinflammatory cytokine genes. The (putative) candidate TFs that bound to the promoters of the genes regulated at least threefold (both up and down) by oleuropein were implicated in the lipogenesis, inflammation, insulin resistance, fibrosis, and cell proliferation and differentiation, which implies that the mechanisms that underlie the beneficial effects of oleuropein on NAFLD may be multifactorial. PMID- 20845387 TI - Large scale purification of linear plasmid DNA for efficient high throughput cloning. AB - In this report we describe a rapid, simple, and efficient method for large-scale purification of linear plasmid DNA to answer demand from high-throughput gene cloning. The process is based on the separation of the linear vector from small DNA fragments by anion exchange chromatography. Gene cloning experiments by restriction/ligation or the In-Fusion technique confirmed the high quality of the linearized vector as 100% of the genes were successfully cloned. PMID- 20845386 TI - Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice. AB - An ethanol extract of fucoxanthin-rich seaweed was examined for its effectiveness as a nutraceutical for body fat-lowering agent and for an antiobese effect based on mode of actions in C57BL/6J mice. Animals were randomized to receive a semi purified high-fat diet (20% dietary fat, 10% corn oil and 10% lard) supplemented with 0.2% conjugated linoleic acid (CLA) as the positive control, 1.43% or 5.72% fucoxanthin-rich seaweed ethanol extract (Fx-SEE), equivalent to 0.05% or 0.2% dietary fucoxanthin for six weeks. Results showed that supplementation with both doses of Fx-SEE significantly reduced body and abdominal white adipose tissue (WAT) weights, plasma and hepatic triglyceride (TG), and/or cholesterol concentrations compared to the high-fat control group. Activities of adipocytic fatty acid (FA) synthesis, hepatic FA and TG synthesis, and cholesterol regulating enzyme were also lowered by Fx-SEE supplement. Concentrations of plasma high-density lipoprotein-cholesterol, fecal TG and cholesterol, as well as FA oxidation enzyme activity and UCP1 mRNA expression in epididymal WAT were significantly higher in the Fx-SEE groups than in the high-fat control group. CLA treatment reduced the body weight gain and plasma TG concentration. Overall, these results indicate that Fx-SEE affects the plasma and hepatic lipid profile, fecal lipids and body fat mass, and alters hepatic cholesterol metabolism, FA synthesis and lipid absorption. PMID- 20845390 TI - Electroanalysis of trimethoprim on metalloporphyrin incorporated glassy carbon electrode. AB - Trimethoprim (TMP) is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Its use is associated with idiosyncratic reactions, including liver toxicity and agranulocytosis. In order to determine TMP electrochemically, a metalloporphyrin modified glassy carbon electrode was prepared by coating [5,10,15,20- tetrakis(4 methoxyphenyl) porphyrinato]Mn (III)chloride (TMOPPMn(III)Cl) solution on the surface of the electrode. The electrochemical behaviour of TMP in Phosphate buffer solution (PBS) on TMOPPMn(III)Cl modified glassy carbon electrode (TMOPPMn(III)Cl/GCE) was explored using differential pulse voltammetry (DPV). The voltammograms showed enhanced oxidation response at the TMOPPMn (III)Cl/GCE with respect to the bare GCE for TMP, attributable to the electrocatalytic activity of TMOPPMn(III)Cl. Electrochemical parameters of the oxidation of TMP on the modified electrode were analyzed. The electro-oxidation of TMP was found to be irreversible, pH dependent and adsorption controlled on the modified electrode. It is found that the oxidation peak current is proportional to the concentration of TMP over the range 6 * 10-8 - 1 * 10-6 M with a very low detection limit of 3 * 10-9 M at 2 min open circuit accumulation. The repeatability expressed as relative standard deviation (RSD) for n = 9 was 3.2% and the operational stability was found to be 20 days. Another striking feature is that equimolar concentration of sulfamethoxazole did not interfere in the determination of TMP. Applicability to assay the drug in urine and tablet samples has also been studied. PMID- 20845391 TI - Melatonin decreases delirium in elderly patients: a randomized, placebo controlled trial. AB - BACKGROUND: Disturbance in the metabolism of tryptophan and tryptophan-derived compounds (e.g., melatonin) may have a role in the pathogenesis of delirium. OBJECTIVE: To evaluate the efficacy of low dose exogenous melatonin in decreasing delirium. DESIGN: A randomized, double-blinded, placebo-controlled study. SETTING: An Internal Medicine service in a tertiary care centre in London, Ontario, Canada. PARTICIPANTS: 145 individuals aged 65 years or over admitted through the emergency department to a medical unit in a tertiary care hospital. INTERVENTION: Patients were randomized to receive either 0.5 mg of melatonin or placebo every night for 14 days or until discharge. MEASUREMENTS: The primary outcome was the occurrence of delirium as determined by Confusion Assessment Method (CAM) criteria. RESULTS: Of a total of 145 individuals (mean age (standard deviation): 84.5 (6.1) years) 72 were randomly assigned to the melatonin group and 73 to the placebo group. Melatonin was associated with a lower risk of delirium (12.0% vs. 31.0%, p = 0.014), with an odds ratio (OR), adjusted for dementia and co-morbidities of 0.19 (95% confidence intervals (CI): 0.06-0.62). Results were not different when patients with prevalent delirium were excluded. LIMITATION: An intention to treat analysis was not possible due to loss to follow up. CONCLUSION: Exogenous low dose melatonin administered nightly to elderly patients admitted to acute care may represent a potential protective agent against delirium. PMID- 20845392 TI - Within-limb somatotopic representation of acute muscle pain in the human contralateral dorsal posterior insula. AB - It is well established that the insular cortex processes noxious information. We have previously shown that noxious inputs from the arm and leg are coarsely organized somatotopically within the dorsal posterior insula. The same has been shown for inputs from C tactile afferents, which mediate affective touch, and it has been suggested that the insula may be responsible for the localization of some somatosensory stimuli. Knowing the degree of spatial detail may have significant implications for the potential role of the dorsal posterior insula in the processing of noxious stimuli. Using high-resolution functional magnetic resonance imaging (fMRI), we compared insula activation patterns in 13 subjects during muscle pain induced by injection of hypertonic saline (5%) into three muscles within the same limb: shoulder (deltoid), forearm (flexor carpi radialis), and hand (first dorsal interosseous). Mapping the maximally activated voxels within the contralateral dorsal posterior insula in each individual subject during each pain stimulus revealed a clear somatotopy of activation within the contralateral dorsal posterior insula. Shoulder pain was represented anterior to forearm pain and medial to hand pain. This fine somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on stimulation site. PMID- 20845394 TI - Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype. AB - The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission. PMID- 20845393 TI - Electrocorticographic correlates of cognitive control in a Stroop task intracranial recording in epileptic patients. AB - The human brain executes cognitive control, such as selection of relevant information in the presence of competing irrelevant information, and cognitive control is essential for us to yield a series of optimal behaviors in our daily life. This study assessed electrocorticographic gamma-oscillations elicited by cognitive control in the context of the Stroop color-naming paradigm, with a temporal resolution of 10 msec and spatial resolution of 1 cm. Subjects were instructed to overtly read a color word printed in an incongruent color in the reading task, and to overtly name the ink color of a color word printed in an incongruent color in the Stroop color-naming task. The latter task specifically elicited larger gamma-augmentations in the dorsolateral-premotor, dorsolateral prefrontal and supplementary motor areas with considerable inter-subject spatial variability. Such Stroop color-naming-specific gamma-augmentations occurred 500 to 200 msec prior to overt responses. Electrical stimulation of the sites showing Stroop color-naming-specific gamma-augmentations resulted in temporary naming impairment more frequently than that of the remaining sites. This study has provided direct evidence that a critical process of cognitive control in the context of Stroop color-naming paradigm consists of recruitment of neurons essential for naming located in variable portions of the dorsolateral premotor and prefrontal areas. PMID- 20845395 TI - Assessing the cost-effectiveness of the rivastigmine transdermal patch for Alzheimer's disease in the UK using MMSE- and ADL-based models. AB - OBJECTIVE: Assess long-term cost-effectiveness of rivastigmine patch in Alzheimer's disease (AD) management in the UK, using cognitive and functional models based on clinical trial efficacy data. METHODS: Incremental costs and Quality Adjusted Life Years (QALYs) associated with rivastigmine patch and capsule treatment versus best supportive care (BSC) were calculated using two economic models, one based solely on Mini-Mental State Examination (MMSE) scores, and one also incorporating activities of daily living (ADL) scores. The clinical pathway was populated with data from a clinical trial of rivastigmine patch (9.5 mg/24 h) and capsules (12 mg/day) versus placebo. Costs were based on the UK health and social care costs and basic UK National Health Service (NHS) prices. Disease progression was modelled beyond the trial period over 5 years using published equations to predict natural decline in AD patients. Base case costing variables included drugs, clinical monitoring, and institutionalization. RESULTS: The MMSE model estimated incremental costs per QALY of L10 579 for rivastigmine patch and L15 154 for capsule versus BSC. The MMSE-ADL model estimated incremental costs per QALY of L9114 for rivastigmine patch and L13 758 for capsules. The main difference between the models was a greater number of institutionalized days avoided for rivastigmine versus BSC estimated by the MMSE ADL model. CONCLUSIONS: Both the MMSE and MMSE-ADL models suggest that rivastigmine patch and capsules are cost-effective treatments versus BSC. Incorporating ADL evidence makes a marginal but important difference to estimates in this case. Future economic evaluations of AD treatment should include measures of both cognition and functioning. PMID- 20845396 TI - Network interactions explain effective encoding in the context of medial temporal damage in MCI. AB - Selective dysfunction in the medial temporal lobe (MTL) in amnestic mild cognitive impairment (MCI) results in a relatively circumscribed impairment in episodic memory. Previously, we found that activation extent in MTL during encoding correlated with subsequent recognition (hit rate) in controls but not in MCI patients (Mandzia et al. [2009]: Neurobiol Aging 30:717-730). Here, we examined whether functional connectivity amongst MTL and cortical regions might better explain differences in subsequent recognition success. Participants underwent fMRI scanning during picture encoding, and multivariate analysis was used to characterize the relationship between network activations and recognition. Both patients and controls activated a canonical MTL encoding network. However, this network correlated with hit rate only for controls. In MCI patients, recognition variability was best explained by the engagement of an additional network including BA 20. We propose that this pattern represents functional reorganization caused by reduced efficiency in the MTL network. Our findings suggest that understanding brain-behavior relationships in neurological disorders requires examination of large-scale networks, even when dysfunction is relatively focal as in MCI. PMID- 20845397 TI - Evaluation of Qualidem: a dementia-specific quality of life instrument for persons with dementia in residential settings; scalability and reliability of subscales in four Dutch field surveys. AB - OBJECTIVE: To evaluate the scalability and reliability of Qualidem, a quality of life observation instrument rated by professional caregivers of persons with mild to very severe dementia living in residential settings. METHOD: Data from four field surveys in the Netherlands were used. The instrument consists of nine subscales for mild to severe dementia; of which six can be applied in very severe dementia. The Mokken scaling model was used to compute scalability and reliability coefficients for each subscale and dementia group. RESULTS: Seven hundred fifty nine persons with mild to severe dementia and 214 persons with very severe dementia residing in 36 nursing homes and 4 homes for the elderly were included. In general, the subscales for the mild to severely demented group were scalable and (moderate) sufficiently reliable; the results confirmed the results of previous research to develop Qualidem. For the very severe demented group, four out of six subscales were scalable (Care relationship, H = 0.56; Positive affect, H = 0.55; Restless tense behavior, H = 0.42; and Social isolation, H = 0.34); they were also sufficiently reliable to measure quality of life (0.57 <= rho <= 0.82). From the other two measured subscales, Social relations was considered not scalable (H = 0.26) and Negative affect was scalable (H = 0.36), but insufficiently reliable (rho = 0.40). CONCLUSION: Qualidem is an easy to administer and overall moderately sufficient reliable rating scale that provides a quality of life profile of persons with mild to even very severe dementia living in residential settings. PMID- 20845398 TI - Acceptability of dementia screening in primary care patients. AB - OBJECTIVES: To determine the acceptability of dementia screening in two populations of older adults in different primary care settings. METHODS: Cross sectional study of consecutive patients presenting for primary care appointments in the Duke University Health System (n = 152) or Durham VA Medical Center (n = 193) were evaluated face to face using the Dementia Screening and Perceived Harms (SAPH) questionnaire. RESULTS: Overall, 81% of primary care patients indicated that they would want to be screened to determine if they are developing dementia. After exposure to possible risks and benefits of screening, 86% of patients indicated they would like to be screened. The SAPH was easy to use and contained five relevant and cohesive domains. The items most associated with a desire for dementia screening were male gender, acceptance of other types of screening, and a belief that a treatment for dementia exists. CONCLUSIONS: Primary care patients in two different health care systems indicated they would like to be screened for dementia. The SAPH was easy to use and contains cohesive domains. PMID- 20845399 TI - Clinical and radiologic correlates of insomnia symptoms in ischemic stroke patients. AB - OBJECTIVES: Insomnia is a common complaint in stroke survivors. The purpose of this study was to investigate the clinical and magnetic resonance imaging (MRI) correlates of insomnia symptoms in Chinese ischemic stroke survivors. METHODS: A comprehensive psychiatric assessment was performed involving 508 ischemic stroke patients 3 months after their first-ever or recurrent acute stroke. Insomnia symptoms were evaluated with a standard insomnia questionnaire. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS).The evaluation of the MRI scans focused on infarctions, white matter lesions, and microbleeds. RESULTS: One hundred and eight-six patients (36.6% of the sample) had insomnia symptoms. Sixty-four patients (12.6%) had insomnia symptoms with daytime consequences. In the multivariate logistic regression analysis, GDS score (OR = 1.157, p < 0.001) and acute frontal lobe infarction (OR = 1.933, p = 0.039) were significant predictors of insomnia symptoms, while the GDS score (OR = 1.251, p < 0.001) and diabetes mellitus (OR = 1.959, p = 0.017) were significant predictors of insomnia symptoms with daytime consequences. CONCLUSIONS: Insomnia symptoms have a multi-factorial origin in stroke. Besides depressive symptoms, frontal lobe infarction and diabetes mellitus predict insomnia symptoms. PMID- 20845400 TI - Rectum-conserving surgery in the era of chemoradiotherapy. AB - BACKGROUND: A complete pathological response occurs in 10-30 per cent of patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiotherapy (CRT). The standard of care has been radical surgery with high morbidity risks and the challenges of stomata despite the favourable prognosis. This review assessed minimalist approaches (transanal excision or observation alone) to tumours with a response to CRT. METHODS: A systematic review was performed using PubMed and Embase databases. Keywords included: 'rectal', 'cancer', 'transanal', 'conservative', 'complete pathological response', 'radiotherapy' and 'neoadjuvant'. Original articles from all relevant listings were sourced. These were hand searched for further articles of relevance. Main outcome measures assessed were rates of local recurrence and overall survival, and equivalence to radical surgery. RESULTS: Purely conservative 'watch and wait' strategies after CRT are still controversial. Originally used for elderly patients or those who refused surgery, the data support transanal excision of rectal tumours showing a good response to CRT. A complete pathological response in the T stage (ypT0) indicates < 5 per cent risk of nodal metastases. CONCLUSION: Rectal tumours showing an excellent response to CRT may be suitable for local excision, with equivalent outcomes to radical surgery. This approach should be the subject of prospective clinical trials in specialist centres. PMID- 20845401 TI - Perceptions of depression among dementia caregivers: findings from the CATIE-AD trial. AB - OBJECTIVE: For patients with Alzheimer's disease complicated by behavioral disturbances, to use single questions about perceived depression and assess patient and caregiver accuracy in recognizing patient depression. METHODS: Cross sectional interviews from the Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD). Patients were asked 'Do you believe you are depressed?' Caregivers were asked 'Do you believe the patient is depressed?' and 'Do you believe you (caregiver) are depressed?' These responses were compared to the patient's score on the Cornell Scale for Depression in Dementia (CSDD), and to the caregiver's score on the Beck Depression Inventory (BDI) using screening test characteristics. RESULTS: Two hundred fifty-seven total patient/caregiver pairs were evaluated. Patients had a mean age of 78 years, were mainly female, white, and had a mean Mini-Mental State Examination Score of 15. Caregivers were on average 63 years old, and were mostly spouses or children. 37% of patients had depression (CSDD >= 12). Patients recognized their own depression with a sensitivity of 0.26 (CI: 0.18, 0.37) and specificity of 0.85 (0.79, 0.90). Caregivers' accuracy in recognizing depression in the patient revealed a sensitivity of 0.65 (C.I.: 0.55, 0.75) and specificity of 0.58 (CI: 0.50, 0.66). Twelve per cent of caregivers were depressed, and caregiver burden was associated with patient depression. CONCLUSION: Clinically significant depression was common, and asking a single question to the patient about depression failed to detect most cases. Caregivers identified two-thirds of patient depression when asked this one question. Caregiver depression and perceived burden were associated with patient depression. PMID- 20845403 TI - The influence of ApoE4 on clinical progression of dementia: a meta-analysis. AB - OBJECTIVE: ApoE4 is a risk factor for the development of Alzheimer's disease, and has a functional role suggesting its importance in the neuropathology of dementia. We present a meta-analysis to investigate whether ApoE4 also affects the clinical progression of dementia in terms of cognitive decline or mortality. METHODS: We searched Medline, Embase and PsychINFO from 1990 until April 2009, for case control or cohort studies which investigated the effect of ApoE4 on progression of dementia. We identified 427 studies; 17 were suitable for inclusion. In total, there were 1733 participants with dementia at baseline, of whom 975 were heterozygous or homozygous for ApoE4. RESULTS: There was no significant difference in cognitive decline (random-model effect size = 0.02; 95% C.-I.: -0.09 to 0.14; p = 0.67) or mortality (random-model pooled odds ratio = 0.74; 95% C.-I.: 0.36 to 1.53; p = 0.41) based on the presence of ApoE4. There was no significant heterogeneity between studies using cognitive decline as an outcome. In meta-regressions of cognitive decline, duration of symptoms, age, gender and frequency of participants with ApoE4 in the samples did not contribute to outcome. CONCLUSION: Different ApoE alleles do not modify the speed of clinical progression of dementia in a way that would be detectable in a sample of 1700 patients. PMID- 20845402 TI - Neuropsychiatric symptoms in MCI subtypes: the importance of executive dysfunction. AB - OBJECTIVE: Mild cognitive impairment (MCI) is a syndrome thought to be a prodrome of dementia for some patients. One subtype, amnestic MCI (aMCI), may be specifically predispose patients to develop Alzheimer's dementia (AD). Since dementia has been associated with a range of neuropsychiatric symptoms (NPS), we sought to examine the prevalence of NPS in MCI and its subtypes. METHODS: One thousand seven hundred seventy-nine participants in the National Alzheimer's Coordinating Center (NACC) with MCI were included in this study. All participants were evaluated systematically with a thorough cognitive battery, clinical interview, and consensus diagnoses, and subtyped as: (1) amnestic (aMCI) (single- or multiple-domain) versus non-amnestic (non-aMCI); (2) executive dysfunction-MCI (exMCI) (single- or multiple-domain) versus no executive dysfunction-MCI (non exMCI); (3) both aMCI and exMCI; and (4) neither aMCI nor exMCI. Additionally, aMCI versus non-aMCI and exMCI versus non-exMCI dichotomies were explored. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS). RESULTS: 1379 participants (77.5%) met criteria for aMCI and 616 (34.6%) for exMCI. No differences were observed in the prevalence of NPS between aMCI versus non-aMCI. However, exMCI was associated with greater severity of depression, anxiety, agitation, disinhibition, irritability, and sleep problems, although these differences do not persist after adjustment for multiple comparisons. CONCLUSIONS: While there were few associations between aMCI and NPS, the presence of executive dysfunction in MCI was associated with greater severity of symptoms and specifically with depression (evidenced by GDS score) and anxiety. These findings may have implications for MCI prognosis and need to be explored in longitudinal studies. PMID- 20845405 TI - Low serum BDNF may indicate the development of PSD in patients with acute ischemic stroke. AB - OBJECTIVE: This study was to test whether serum BDNF or tissue plasminogen activator (tPA) is correlated with the development of depression at the acute stage of stroke. METHODS: Hundred ischemic stroke patients admitted to the hospital within the first 24 h of stroke onset were consecutively recruited and followed up for 14 days. The 17-item HDRS and MADRS were used to assess the severity of major depressive symptoms on day 3, day 7, and day 14 after admission. The diagnoses of depression were made in accordance with DSM-IV criteria for post-stroke depression (PSD). Serum BDNF and tPA of all the patients were determined by ELISA both on day 1 and day 7 after admission. Meanwhile, 50 healthy control subjects were also recruited and underwent measurement of serum BDNF and tPA once. RESULTS: We found that 37 patients (37.0%) were diagnosed of major depression at the end of the follow-up. Serum BDNF on day 1 was significantly higher in non-PSD stroke patients than in normal controls, while PSD patients had significantly lower BDNF than non-PSD patients. There was a significant negative correlation between serum BDNF and tPA on day 1 only in PSD patients (r = -0.440, p = 0.006). Serum BDNF < 5.86 ng/ml on day 1 was independently associated with incident PSD at the acute stage of stroke (OR = 28.992; 95% CI, 8.014-104.891; p < 0.001 after adjustment). CONCLUSION: There was a significant elevation of BDNF early after ischemic stroke. Serum BDNF on day 1 after admission may predict the risk of subsequent PSD. Moreover, tPA may be involved in the change of BDNF. PMID- 20845407 TI - Relief of angina pectoris when carrying heavy loads with the left hand in a patient with previous coronary artery bypass graft operation who has severe exercise angina: a case report. AB - In patients with known coronary artery disease and/or a history of revascularization, angina pectoris or unstable coronary syndromes are usually attributed to the progression of atherosclerotic lesions rather than an unrecognized great vessel disease. However, for patients with a previous coronary artery bypass graft operation (CABG), during which a left internal mammary artery (LIMA) conduit has been used, great vessel disease, especially subclavian artery stenosis should also be suspected. We present a case of a patient with a LIMA conduit who has angina pectoris on exertion, but interestingly the pain is relieved when he carries heavy loads with his left hand, which can be due to increased blood flow to the LIMA conduit during heavy lifting because of increased peripheral resistance. PMID- 20845408 TI - Is antibiotic use a risk factor for breast cancer? A meta-analysis. AB - PURPOSE: Breast cancer is a disease integrating hormonal and non-hormonal factors. Given the widespread antibiotic use, attention has been recently drawn upon the association between antibiotic use and breast cancer; however, the published studies have yielded contradictory results. In addition, various types of quantification in antibiotic use have been adopted. This meta-analysis aims to examine whether antibiotic use is associated with breast cancer risk presenting two analyses: one on antibiotic ever-use and one on the number of antibiotic prescriptions. METHODS: Eligible studies were retrieved by a search in MEDLINE, Cochrane, and EMBASE databases till July 2009. Odds ratios (OR) pertaining to antibiotic ever-use were appropriately calculated. The random effects model was used to estimate the pooled OR. Publication bias was assessed through Begg's and Egger's tests. Meta-regression with the number of antibiotic prescriptions was performed. RESULTS: Five case-control studies were eligible at the ever-use versus never-use analysis (13 069 cases and 73 920 controls). Antibiotic ever-use was associated with slightly elevated breast cancer risk (pooled OR = 1.175, 95%CI: 0.994-1.387). No publication bias became apparent. Meta-regression showed a borderline dose-response effect implicating the number of antibiotic prescriptions. CONCLUSIONS: Antibiotic use seems associated with slightly elevated breast cancer risk. The underlying nature of the association remains elusive, as it may be direct or due to secondary associations, that is, causal or confounding. At any case, this is a finding with potentially important public health implications, which should be further examined in the literature. PMID- 20845409 TI - Quality check of spontaneous adverse drug reaction reporting forms of different countries. AB - Adverse drug reactions (ADRs) are considered as one of the leading causes of death among hospitalized patients. Thus reporting of adverse drug reactions become an important phenomenon. Spontaneous adverse drug reaction reporting form is an essential component and a major tool of the pharmacovigilance system of any country. This form is a tool to collect information of ADRs which helps in establishing the causal relationship between the suspected drug and the reaction. As different countries have different forms, our aim was to study, analyze the suspected adverse drug reaction reporting form of different countries, and assess if these forms can capture all the data regarding the adverse drug reaction. For this analysis we identified 18 points which are essential to make a good adverse drug reaction report, enabling proper causality assessment of adverse reaction to generate a safety signal. Adverse drug reaction reporting forms of 10 different countries were collected from the internet and compared for 18 points like patient information, information about dechallenge-rechallenge, adequacy of space and columns to capture necessary information required for its causality assessment, etc. Of the ADR forms that we analyzed, Malaysia was the highest scorer with 16 out of 18 points. This study reveals that there is a need to harmonize the ADR reporting forms of all the countries because there is a lot of discrepancy in data captured by the existing ADR reporting forms as the design of these forms is different for different countries. These incomplete data obtained result in inappropriate causality assessment. PMID- 20845410 TI - The knowledge, perceptions and practice of pharmacovigilance amongst community pharmacists in Lagos state, south west Nigeria. AB - PURPOSE: Community Pharmacists both have an important responsibility in monitoring the ongoing safety of medicines and are widely accessible to do it. This study aims to investigate the knowledge, perceptions and practice of Pharmacovigilance amongst community pharmacists in Lagos State, South West Nigeria METHODS: A cross-sectional observational survey was used in this study. A multistage random sampling technique was employed in the selection of 420 community pharmacies in Lagos. RESULTS: About 55% of respondents have ever heard of the word 'Pharmacovigilance' out of which less than half (representing only 18% of all respondents) could define the term 'Pharmacovigilance'. Forty percent of the respondents stated that patients reported ADRs to them at least once a month, and 20% reported to the relevant authorities. However only 3% of respondents actually reported an ADR to the National Pharmacovigilance Centre. The most important reason for poor reporting was lack of knowledge about how to report ADRs (44.6%).Meanwhile, 90% of respondents believed that the role of the pharmacists in ADR reporting was important. Most community pharmacists were willing to practice pharmacovigilance if they were trained. CONCLUSION: Community pharmacists in Lagos had poor knowledge about pharmacovigilance. Reporting rate was also poor. There is an urgent need for educational programs to train pharmacists about pharmacovigilance and ADR reporting. PMID- 20845411 TI - Asymmetric dimethylarginine (ADMA) induces chronic kidney disease through a mechanism involving collagen and TGF-beta1 synthesis. AB - Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, is accumulated in plasma during chronic kidney disease (CKD). It is considered an independent mortality and cardiovascular risk factor in CKD patients. To test the involvement of ADMA in CKD progression, we investigated the effects of chronic ADMA administration on renal structure and compared these effects with NG-nitro-L-arginine methyl ester (L-NAME) treatment, a widely used exogenous inhibitor of NOS that induces CKD. Three groups of uninephrectomized mice were studied: ADMA (60 mg/kg per day), L-NAME (60 mg/kg per day), and isotonic saline (control) were infused through osmotic mini-pumps for 8 weeks. ADMA and L-NAME induced hypertension (PAS 167 +/- 16 and 168 +/- 10 versus 100 +/ 4 mmHg, p < 0.01, respectively). High level of ADMA was associated with increased renal oxidative stress. ADMA treatment induced glomerular and vascular fibrosis as evidenced by the elevated deposits of collagen I, III, and fibronectin (p < 0.01). A similar profile was observed in the L-NAME group. Mice treated with ADMA had reduced peritubular capillaries versus controls (p < 0.01). Collagen I mRNA expression and renal TGF-beta1 concentrations were higher in the ADMA and L-NAME groups. Increased level of TGF-beta1 was associated with a significant rise of HIF-1alpha and endothelin-1 expression. These results demonstrate for the first time that elevated concentrations of ADMA are associated with the development of renal fibrosis. These data suggest that in pathophysiological conditions of endothelial dysfunction, the exaggerated endogenous synthesis of ADMA could contribute to CKD progression by favouring hypertension, extracellular matrix synthesis, and rarefaction of peritubular capillaries. PMID- 20845413 TI - Improved catalysts for the iridium-catalyzed asymmetric isomerization of primary allylic alcohols based on Charton analysis. AB - An improved generation of chiral cationic iridium catalysts for the asymmetric isomerization of primary allylic alcohols is disclosed. The design of these air stable complexes relied on the preliminary mechanistic information available, and on Charton analyses using two preceding generations of iridium catalysts developed for this highly challenging transformation. Sterically unbiased chiral aldehydes that were not accessible previously have been obtained with high levels of enantioselectivity, thus validating the initial hypothesis regarding the selected ligand-design elements. A rationale for the high enantioselectivities achieved in most cases is also presented. PMID- 20845414 TI - A useful, reliable and safer protocol for hydrogenation and the hydrogenolysis of O-benzyl groups: the in situ preparation of an active Pd(0)/C catalyst with well defined properties. AB - A simple, highly reproducible protocol for the hydrogenation of alkenes and alkynes and for the hydrogenolysis of O-benzyl ethers has been developed. The method features the in situ preparation of an active Pd(0)/C catalyst from Pd(OAc)(2) and charcoal, in methanol. The mild reaction conditions (25 degrees C) and low catalyst loading required (0.025 mol%), as well as the absence of contamination of the product by palladium residues (<4 ppb), make this a sustainable, useful process for organic chemists. Alternatively, the protocol can be carried out under microwave activation, to shorten the reaction times, with cyclohexene as the hydrogen source. PMID- 20845415 TI - Atomic-level elucidation of the initial stages of self-assembled monolayer metallization and nanoparticle formation. AB - The development of high-performance molecular electronics and nanotech applications requires deep understanding of atomic level structural, electronic, and magnetic properties of electrode/molecular interfaces. Recent electrochemical experiments on self-assembled monolayers (SAMs) have identified highly practical means to generate nanoparticles and metal monolayers suspended above substrate surfaces through SAM metallizations. A rational basis why this process is even possible is not yet well-understood. To clarify the initial stages of interface formation during SAM metallization, we used first-principles spin-polarized density functional theory (DFT) calculations to study Pd diffusion on top of 4 mercaptopyridine (4MP) SAMs on Au(111). After distinguishing potential-energy surfaces (PESs) for different spin configurations for transition metal atoms on the SAM, we find adatom diffusion is not possible over the clean 4MP-SAM surface. Pre-adsorption of transition-metal atoms, however, facilitates atomic diffusion that appears to explain multiple reports on experimentally observed island and monolayer formation on top of SAMs. Furthermore, these diffusions most likely occur by moving across low-lying and intersecting PESs of different spin states, opening the possibility of magnetic control over these systems. Vertical diffusion processes were also investigated, and the electrolyte was found to play a key role in preventing metal permeation through the SAM to the substrate. PMID- 20845412 TI - Antibacterials from the sea. AB - The ocean contains a host of macroscopic life in a great microbial soup. Unlike the terrestrial environment, an aqueous environment provides perpetual propinquity and blurs spatial distinctions. Marine organisms are under a persistent threat of infection by resident pathogenic microbes including bacteria, and in response they have engineered complex organic compounds with antibacterial activity from a diverse set of biological precursors. The diluting effect of the ocean drives the construction of potent molecules that are stable to harsh salty conditions. Members of each class of metabolite-ribosomal and non ribosomal peptides, alkaloids, polyketides, and terpenes-have been shown to exhibit antibacterial activity. The sophistication and diversity of these metabolites points to the ingenuity and flexibility of biosynthetic processes in Nature. Compared with their terrestrial counterparts, antibacterial marine natural products have received much less attention. Thus, a concerted effort to discover new antibacterials from marine sources has the potential to contribute significantly to the treatment of the ever increasing drug-resistant infectious diseases. PMID- 20845416 TI - Anion-pi interactions in salts with polyhalide anions: trapping of I4(2-). AB - The directionality of interaction of electron-deficient pi systems with spherical anions (e.g,. halides) can be controlled by secondary effects like NH or CH hydrogen bonding. In this study a series of pentafluorophenyl-substituted salts with polyhalide anions is investigated. The compounds are obtained by aerobic oxidation of the corresponding halide upon crystallization. Solid-state structures reveal that in bromide 2, directing NH-anion interactions position the bromide ion in an eta(1)-type fashion over but not in the center of the aromatic ring. The same directing forces are effective in corresponding tribromide salt 3. In the crystal, the bromide ion is paneled by four electron-deficient aromatic ring systems. In addition, compounds 4 and 6, which have triiodide and the rare tetraiodide dianion as anions, are described. Computational studies reveal that the latter is highly unstable. In the present case it is stabilized by the crystal lattice, for example, by interaction with electron-deficient pi systems. PMID- 20845417 TI - Efficient multicomponent reaction synthesis of the schistosomiasis drug praziquantel. PMID- 20845418 TI - Sintered silicon carbide: a new ceramic vessel material for microwave chemistry in single-mode reactors. AB - Silicon carbide (SiC) is a strongly microwave absorbing chemically inert ceramic material that can be utilized at extremely high temperatures due to its high melting point and very low thermal expansion coefficient. Microwave irradiation induces a flow of electrons in the semiconducting ceramic that heats the material very efficiently through resistance heating mechanisms. The use of SiC carbide reaction vessels in combination with a single-mode microwave reactor provides an almost complete shielding of the contents inside from the electromagnetic field. Therefore, such experiments do not involve electromagnetic field effects on the chemistry, since the semiconducting ceramic vial effectively prevents microwave irradiation from penetrating the reaction mixture. The involvement of electromagnetic field effects (specific/nonthermal microwave effects) on 21 selected chemical transformations was evaluated by comparing the results obtained in microwave-transparent Pyrex vials with experiments performed in SiC vials at the same reaction temperature. For most of the 21 reactions, the outcome in terms of conversion/purity/product yields using the two different vial types was virtually identical, indicating that the electromagnetic field had no direct influence on the reaction pathway. Due to the high chemical resistance of SiC, reactions involving corrosive reagents can be performed without degradation of the vessel material. Examples include high-temperature fluorine-chlorine exchange reactions using triethylamine trihydrofluoride, and the hydrolysis of nitriles with aqueous potassium hydroxide. The unique combination of high microwave absorptivity, thermal conductivity, and effusivity on the one hand, and excellent temperature, pressure and corrosion resistance on the other hand, makes this material ideal for the fabrication of reaction vessels for use in microwave reactors. PMID- 20845419 TI - Synthesis and comparative characterization of 9-boraanthracene, 5 boranaphthacene, and 6-borapentacene stabilized by the H2IMes carbene. AB - A general procedure for the preparation of three N-heterocyclic carbene stabilized, boron-containing acenes (9-boraanthracene, 5-boranaphthacene, and 6 borapentacene) is presented. The key steps involve a transmetallation reaction between BCl(3) and an appropriate stannacyclic precursor, and the dehydrochlorination of the H(2)IMes adduct of the chloroborane product. Comparative structural, photophysical, and redox properties reveal narrow HOMO LUMO gaps relative to the all-carbon acene analogues. PMID- 20845421 TI - Thermochemical stabilities, electronic structures, and optical properties of C56X10 (X = H, F, and Cl) fullerene compounds. AB - Stimulated by the recent isolation and characterization of C56Cl10 chlorofullerene (Tan et al., J Am Chem Soc 2008, 130, 15240), we perform a systematic study on the geometrical structures, thermochemistry, and electronic and optical properties of C56X10 (X = H, F, and Cl) on the basis of density functional theory (DFT). Compared with pristine C56, the equatorial carbon atoms in C56X10 are saturated by X atoms and change to sp3 hybridization to release the large local strains. The addition reactions C56 + 5X2 --> C56X10 are highly exothermic, and the optimal temperature for synthesizing C56X10 should be ranged between 500 and 1000 K. By combining 10 X atoms at the abutting pentagon vertexes and active sites, C56Cl10 molecules exhibit large energy gaps between the highest occupied and lowest unoccupied molecular orbitals (from 2.84 to 3.00 eV), showing high chemical stabilities. The C56F10 and C56Cl10 could be excellent electron acceptors for potential photonic/photovoltaic applications in consequence of their large vertical electron affinities. The density of states is also calculated, which suggest that the frontier molecular orbitals of C56X10 are mainly from the carbon orbitals of two separate annulene subunits, and the contributions derived from X atoms are secondary. In addition, the ultraviolet visible spectra and second-order hyperpolarizabilities of C56X10 are calculated by means of time-dependent DFT and finite field approach, respectively. Both the average static linear polarizability and second-order hyperpolarizability of these compounds are larger than those of C60 due to lower symmetric structures and high delocalization of pi electron density on the two separate annulene subunits. PMID- 20845420 TI - MIBPB: a software package for electrostatic analysis. AB - The Poisson-Boltzmann equation (PBE) is an established model for the electrostatic analysis of biomolecules. The development of advanced computational techniques for the solution of the PBE has been an important topic in the past two decades. This article presents a matched interface and boundary (MIB)-based PBE software package, the MIBPB solver, for electrostatic analysis. The MIBPB has a unique feature that it is the first interface technique-based PBE solver that rigorously enforces the solution and flux continuity conditions at the dielectric interface between the biomolecule and the solvent. For protein molecular surfaces, which may possess troublesome geometrical singularities, the MIB scheme makes the MIBPB by far the only existing PBE solver that is able to deliver the second-order convergence, that is, the accuracy increases four times when the mesh size is halved. The MIBPB method is also equipped with a Dirichlet-to Neumann mapping technique that builds a Green's function approach to analytically resolve the singular charge distribution in biomolecules in order to obtain reliable solutions at meshes as coarse as 1 A--whereas it usually takes other traditional PB solvers 0.25 A to reach similar level of reliability. This work further accelerates the rate of convergence of linear equation systems resulting from the MIBPB by using the Krylov subspace (KS) techniques. Condition numbers of the MIBPB matrices are significantly reduced by using appropriate KS solver and preconditioner combinations. Both linear and nonlinear PBE solvers in the MIBPB package are tested by protein-solvent solvation energy calculations and analysis of salt effects on protein-protein binding energies, respectively. PMID- 20845422 TI - A TD-DFT study on the cyanide-chemosensing mechanism of 8-formyl-7 hydroxycoumarin. AB - Proton transfer (PT) and excited-state PT process are proposed to account for the fluorescent sensing mechanism of a cyanide chemosensor, 8-formyl-7 hydroxycoumarin. The time-dependent density functional theory method has been applied to investigate the ground and the first singlet excited electronic states of this chemosensor as well as its nucleophilic addition product with cyanide, with a view to monitoring their geometries and spectrophotometrical properties. The present theoretical study indicates that phenol proton of the chemosensor transfers to the formyl group along the intramolecular hydrogen bond in the first singlet excited state. Correspondingly, the nucleophilic addition product undergoes a PT process in the ground state, and shows a similar structure in the first singlet excited state. This could explain the observed strong fluorescence upon the addition of the cyanide anion in the relevant fluorescent sensing mechanism. PMID- 20845424 TI - Stereodynamics of tetramezine. AB - The antidepressant drug tetramezine [1,2-bis-(3,3-dimethyldiaziridin-1-yl)ethane] consists of two bridged diaziridine moieties with four stereogenic nitrogen centers, which are stereolabile and, therefore, are prone to interconversion. The adjacent substituents at the nitrogen atoms of the diaziridines moieties exist only in an antiperiplanar conformation, which results in a coupled interconversion. Therefore, three stereoisomers exist (meso form and two enantiomeric forms), which epimerize when the diaziridine moieties are regarded as stereogenic units due to the coupled interconversion. Here, we have investigated the epimerization between the meso and enantiomeric forms by dynamic gas chromatography. Temperature-dependent measurements were performed, and reaction rate constants were determined using the unified equation of chromatography implemented in the software DCXplorer. The activation barriers of the epimerization were found to be DeltaG(?) = 100.7 kJ mol(-1) at 25 degrees C and DeltaG(?) = 104.5 kJ mol(-1) at 37 degrees C, respectively. The activation enthalpy and entropy were determined to be DeltaH(?) = 70.3 +/- 0.4 kJ mol(-1) and DeltaS(?) = -102 +/- 2 J mol(-1) K(-1) . PMID- 20845423 TI - Awake at 4 AM: treatment of insomnia with early morning awakenings among older adults. AB - Insomnia is a common problem among older adults. In particular, older adults experience insomnia coupled with early morning awakenings due to an interaction between age-related changes in circadian rhythm timing coupled with behavior changes that contribute to sustained poor sleep. Cognitive-behavioral therapy for insomnia (CBT-I), at times coupled with circadian interventions (e.g., timed light exposure), are likely to be most successful in optimizing sleep quality. In delivering CBT-I to older adults, modifications are sometimes necessary to accommodate for medical problems, lifestyle, social factors, and patient preferences. Addition of circadian interventions can ameliorate the negative effects of inappropriately timed sleep as well. These treatment methods can be highly effective and benefits can be long-standing. A case example is used to illustrate these points. PMID- 20845425 TI - Distinct microbiome in pouchitis compared to healthy pouches in ulcerative colitis and familial adenomatous polyposis. AB - BACKGROUND: Pouchitis occurs in up to 50% of patients with ulcerative colitis (UC) undergoing ileal pouch anal anastomosis (IPAA). Pouchitis rarely occurs in patients with familial adenomatous polyposis (FAP) who undergo IPAA. Our aim was to compare mucosal and luminal flora in patients with UC-associated pouchitis (UCP), healthy UC pouches (HUC), and healthy FAP pouches (FAP). METHODS: Nineteen patients were enrolled in this cross-sectional study (nine UCP, three HUC, seven FAP). Patients with active pouchitis were identified using the Pouchitis Disease Activity Index (PDAI). Ileal pouch mucosal biopsies and fecal samples were analyzed with a 16S rDNA-based terminal restriction fragment length polymorphism (TRFLP) approach. Pooled fecal DNA from four UCP and four FAP pouches were sequenced for further speciation. RESULTS: TRFLP data revealed statistically significant differences in the mucosal and fecal microbiota between each group of patients. UCP samples exhibited significantly more TRFLP peaks matching Clostridium and Eubacterium genera compared to HUC and FAP pouches and fewer peaks matching Lactobacillus and Streptococcus genera compared to FAP. DNA Sanger sequencing of a subset of luminal samples revealed UCP having more identifiable sequences of Firmicutes (51.2% versus 21.2%) and Verrucomicrobia (20.2% versus 3.2%), and fewer Bacteroidetes (17.9% versus 60.5%) and Proteobacteria (9.8% versus 14.7%) compared to FAP. CONCLUSIONS: The pouch microbial environment appears to be distinctly different in the settings of UC pouchitis, healthy UC, and FAP. These findings suggest that a dysbiosis may exist in pouchitis which may be central to understanding the disease. PMID- 20845426 TI - Regulation of Tbx22 during facial and palatal development. AB - Mutations in the gene encoding the T-box transcription factor TBX22 cause X linked cleft palate and ankyloglossia in humans. Here we show that Tbx22 expression during facial and palatal development is regulated by FGF and BMP signaling. Our results demonstrate that FGF8 induces Tbx22 in the early face while BMP4 represses and thus restricts its expression. This regulation is conserved between chicken and mouse, although the Tbx22-expression patterns differ considerably between these two species. We suggest that these species specific differences may result at least in part from differences in the spatiotemporal patterns of BMP activity, but we exclude a direct repression of Tbx22 by the BMP-inducible transcriptional repressor MSX1. Together these findings help to integrate Tbx22 into the molecular network of factors regulating facial development. PMID- 20845427 TI - A direct role for Wnt8 in ventrolateral mesoderm patterning. AB - Vertebrate dorsoventral patterning requires both Wnt8 and BMP signaling. Because of their multiple interactions, discerning roles attributable specifically to Wnt8 independent of BMP has been a challenge. For example, Wnt8 represses the dorsal organizer that negatively regulates ventral BMP signals, thus Wnt8 loss-of function phenotypes may reflect the combined effects of reduced Wnt8 and BMP signaling. We have taken a loss-of-function approach in the zebrafish to generate embryos lacking expression of both Wnt8 and the BMP antagonist Chordin. wnt8;chordin loss-of-function embryos show rescued BMP signaling, thereby allowing us to identify Wnt8-specific requirements. Our analysis shows that Wnt8 is uniquely required to repress prechordal plate specification but not notochord, and that Wnt8 signaling is not essential for specification of tailbud progenitors but is required for normal expansion of posterior mesoderm cell populations. Thus, Wnt8 and BMP signaling have independent roles during vertebrate ventrolateral mesoderm development that can be identified through loss-of function analysis. PMID- 20845429 TI - Preparation of enantiomerically enriched alpha-aminoorganostannanes and their applications in stereoselective synthesis. AB - This review deals with the preparation of chiral, nonracemic alpha aminoorganostannanes and their applications in asymmetric synthesis. The pioneering works in this field date back almost 20 years ago and since then extensive research has been carried out to develop efficient and selective routes to highly enantioenriched alpha-aminoorganostannanes. The facile Sn/Li transmetalation of these compounds by n-BuLi has led to various applications in stereoselective synthesis. Selected examples using chiral alpha aminoorganostannanes as starting materials will be reported. PMID- 20845428 TI - A hybrid process for chiral separation of compound-forming systems. AB - The resolution of chiral compound-forming systems using hybrid processes was discussed recently. The concept is of large relevance as these systems form the majority of chiral substances. In this study, a novel hybrid process is presented, which combines pertraction and subsequent preferential crystallization and is applicable for the resolution of such systems. A supported liquid membrane applied in a pertraction process provides enantiomeric enrichment. This membrane contains a solution of a chiral compound acting as a selective carrier for one of the enantiomers. Screening of a large number of liquid membranes and potential carriers using the conductor-like screening model for realistic solvation method led to the identification of several promising carriers, which were tested experimentally in several pertraction runs aiming to yield enriched (+)-(S) mandelic acid (MA) solutions from racemic feed solutions. The most promising system consisted of tetrahydronaphthalene as liquid membrane and hydroquinine-4 methyl-2-quinolylether (HMQ) as chiral carrier achieving enantiomeric excesses of 15% in average. The successful production of (+)-(S)-MA with a purity above 96% from enriched solutions by subsequent preferential crystallization proved the applicability of the hybrid process. PMID- 20845430 TI - Loss of Lhx1 activity impacts on the localization of primordial germ cells in the mouse. AB - Mouse embryos lacking Lhx1 (Lim1) activity display defective gastrulation and are deficient of primordial germ cells (PGCs) (Tsang et al. [2001] International Journal of Developmental Biology 45:549-555). To dissect the specific role of Lhx1 in germ cell development, we studied embryos with conditional inactivation of Lhx1 activity in epiblast derivatives, which, in contrast to completely null embryos, develop normally through gastrulation before manifesting a head truncation phenotype. Initially, PGCs are localized properly to the definitive endoderm of the posterior gut in the conditional mutant embryos, but they depart from the embryonic gut prematurely. The early exit of PGCs from the gut is accompanied by the failure to maintain a strong expression of Ifitm1 in the mesoderm enveloping the gut, which may mediate the repulsive activity that facilitates the retention of PGCs in the hindgut during early organogenesis. Lhx1 therefore may influence the localization of PGCs by modulating Ifitm1-mediated repulsive activity. PMID- 20845431 TI - Enantioselective sigma1 receptor binding and biotransformation of the spirocyclic PET tracer 1'-benzyl-3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidine]. AB - It was shown that racemic (+/-)-2 [1'-benzyl-3-(3-fluoropropyl)-3H spiro[[2]benzofuran-1,4'-piperidine], WMS-1813] represents a promising positron emission tomography (PET) tracer for the investigation of centrally located sigma(1) receptors. To study the pharmacological activity of the enantiomers of 2, a preparative HPLC separation of (R)-2 and (S)-2 was performed. The absolute configuration of the enantiomers was determined by CD-spectroscopy together with theoretical calculations of the CD-spectrum of a model compound. In receptor binding studies with the radioligand [(3)H]-(+)-pentazocine, (S)-2 was thrice more potent than its (R)-configured enantiomer (R)-2. The metabolic degradation of the more potent (S)-enantiomer was considerably slower than the metabolism of (R)-2. The structures of the main metabolites of both enantiomers were elucidated by determination of the exact mass using an Orbitrap-LC-MS system. These experiments showed a stereoselective biotransformation of the enantiomers of 2. PMID- 20845432 TI - Vortex-induced chiral bifurcation in aggregating insulin. AB - Chiral symmetry breaking occurs during vortex-assisted crystallization of several simple compounds leading to a stochastically determined emergence of an enantiomeric excess of one chiral isomer. This article summarizes recent developments in studies of a similar phenomenon observed in agitated solutions of aggregating insulin, when a phase transition-precipitation of insoluble amyloid fibrils from solutions of the native protein-is coupled to a conformational transition of the native alpha-helical structure into aggregated beta-sheets. In contrast to the previously known cases of chiral bifurcation, the substrate is built of L-amino acids and, therefore, chirally biased. However, under certain conditions, insulin forms fibrils with superstructural chiral features that are independent of the left-handedness of amino acid residues, as revealed by the sign of extrinsic Cotton effect induced in amyloid-bound achiral dye-thioflavin T. The inherent chiral bias of the protein results in a diastereomeric relationship between the two optical isomers of amyloid superstructures and the fact that relative probability of formation of either isomer is temperature dependent. As the formation of amyloid fibrils in vivo is associated with several degenerative disorders such as Alzheimer's disease, this newly observed phenomenon may have important implications in the context of structural basis of biological activity of misfolded proteins. PMID- 20845434 TI - A theoretical study on the exciton circular dichroism of propeller-like metal complexes of bipyridine and tripodal tris(2-pyridylmethyl)amine derivatives. AB - Time-dependent density functional theory (TD-DFT) has been employed to simulate the circular dichroism (CD) spectra of bipyridyl ruthenium(II) complexes as well as zinc(II) and copper(II) complexes containing tris(2-pyridylmethyl)amine (TPA) derivatives. A qualitative model is used to account for the mechanism by which the bis- and tris-bipyridine complexes (or analogous systems) exhibit exciton CD. The model is further used to predict the sign of the exciton CD bands. The predictions are in agreement with experiment and DFT calculations. A comprehensive analysis is presented of the subtle differences in the CD spectra of this series of related complexes. PMID- 20845435 TI - Scrofula. PMID- 20845437 TI - Improving care transitions: hospitalists partnering with primary care. PMID- 20845436 TI - Pott's puffy tumor in a six-year-old female. PMID- 20845438 TI - The independent association of provider and information continuity on outcomes after hospital discharge: implications for hospitalists. AB - BACKGROUND: Since hospitalist physicians do not frequently see patients in follow up after discharge from the hospital, patient continuity of care will decrease. To determine how this influenced patient outcomes, we examined the independent association of several physician continuity and information continuity measures on death or urgent readmission after discharge from hospital. DESIGN: Multicenter, prospective cohort study of patients discharged to the community after elective or emergency hospitalization. We measured three physician continuity scores (preadmission; hospital; and postdischarge) and two information continuity scores (discharge summary; postdischarge visit information) as time dependent covariates. Continuity scores ranged from 0 (perfect discontinuity) to 1 (perfect continuity). The primary outcomes were time to all-cause death or urgent readmission. RESULTS: A total of 3876 people were followed for a median of 175 days. Death rate was 2.6 events per 100 patient-years observation (pys) (95% confidence interval [CI], 2.0-3.4) and urgent readmission rate was 19.6 events per 100 pys (95% CI, 15.9-24.3). After adjusting for important covariates and other continuity scores, increased preadmission physician continuity was independently associated with a decreased risk of urgent readmission (adjusted hazard ratio 0.94 [95% CI, 0.91-0.98] for each absolute increase in continuity of 0.1). Other continuity measures-including hospital physician continuity-were not associated with either outcome. CONCLUSIONS: After discharge from the hospital, increased continuity with physicians who routinely treated the patient prior to the admission was significantly and independently associated with a decreased risk of urgent readmission. These data suggest that continuity with the hospital physician after discharge did not independently influence the risk of patient death or urgent readmission. PMID- 20845440 TI - Sensitivity of superficial cultures in lower extremity wounds. AB - BACKGROUND: Superficial wound cultures are routinely used to guide therapy, despite a lack of clear supporting evidence. PURPOSE: To conduct a systematic review of the correlation between superficial wound cultures and the etiology of skin and soft tissue infections. DATA SOURCES: Medline, EMBASE, CINAHL, Scopus. STUDY SELECTION: Articles published between January 1960 and August 2009 involving superficial wound cultures and deeper comparison cultures. DATA EXTRACTION: Two reviewers independently searched for abstracted information pertaining to the microbiology of lower extremity wounds sufficient to calculate the sensitivity and specificity of superficial wound cultures versus comparison cultures. DATA SYNTHESIS: Data pooled using a random-effects meta-analysis model. RESULTS: Of 9032 unique citations, 8 studies met all inclusion criteria. Inter rater reliability was substantial (Kappa = 0.78). Pooled test sensitivity for superficial wound swabs was 49% (95% confidence interval [CI], 37-61%], and specificity was 62% (95% CI, 51-74%). The pooled positive and negative likelihood ratios (LRs) were 1.1 (95% CI, 0.71-1.5) and 0.67 (95% CI, 0.52-0.82). The median number of isolates for surface cultures (2.7, interquartile range [IQR] 1.8-3.2) was not significantly different than that for comparison cultures, (2.2, IQR 1.7 2.9) (P = 0.75). CONCLUSION: Few studies show a strong relationship between superficial wound swabs and deep tissue cultures, and the current data demonstrate poor overall sensitivity and specificity. The positive and negative LRs were found to provide minimal utility in influencing pretest probabilities. Results of this analysis show that wound cultures should not be used in lieu of local antibiograms to guide initial antibiotic therapies. PMID- 20845441 TI - Pot shots-Cannabis arteritis of the digits. PMID- 20845442 TI - Package selection for moisture protection for solid, oral drug products. AB - This review describes how best to select the appropriate packaging options for solid, oral drug products based on both chemical and physical stability, with respect to moisture protection. This process combines an accounting for the initial moisture content of dosage form components, moisture transfer into (out of) packaging based on a moisture vapor transfer rate (MVTR), and equilibration between drug products and desiccants based on their moisture sorption isotherms to provide an estimate of the instantaneous relative humidity (RH) within the packaging. This time-based RH is calculationally combined with a moisture sensitive Arrhenius equation (determined using the accelerated stability assessment program, ASAP) to predict the drug product's chemical stability over time as a function of storage conditions and packaging options. While physical stability of dosage forms with respect to moisture has been less well documented, a process is recommended based on the threshold RH at which changes (e.g., dosage form dissolution, tablet hardness, drug form) become problematic. The overall process described allows packaging to be determined for a drug product scientifically, with the effect of any changes to storage conditions or packaging to be explicitly accounted for. PMID- 20845443 TI - Salt or co-crystal? Determination of protonation state by X-ray photoelectron spectroscopy (XPS). AB - Combined (15)N ssNMR and X-ray photoelectron spectroscopy (XPS) investigations for theophylline, a theophylline co-crystal, and a theophyllinium salt demonstrate that XPS allows direct observation of the degree of proton transfer, and thus identification of whether a salt or a co-crystal has been formed. The presence of a strongly binding-energy-shifted N 1s XPS peak with protonation indicates a salt (C==NH(+)), while this peak is unmistakably absent in the co crystal. XPS should be considered as an alternative and complementary technique to single crystal X-ray diffraction and solid-state nuclear magnetic resonance spectroscopy (ssNMR). PMID- 20845444 TI - Transforming powder mechanical properties by core/shell structure: compressible sand. AB - Some active pharmaceutical ingredients possess poor mechanical properties and are not suitable for tableting. Using fine sand (silicon dioxide), we show that a core/shell structure, where a core particle (sand) is coated with a thin layer of polyvinylpyrrolidone (PVP), can profoundly improve powder compaction properties. Sand coated with 5% PVP could be compressed into intact tablets. Under a given compaction pressure, tablet tensile strength increases dramatically with the amount of coating. This is in sharp contrast to poor compaction properties of physical mixtures, where intact tablets cannot be made when PVP content is 20% or less. The profoundly improved tabletability of core/shell particles is attributed to the formation of a continuous three-dimensional bonding network in the tablet. PMID- 20845445 TI - Interstrain differences of in vitro metabolic stability and impact on early drug discovery. AB - With the extensive use of different strains of mice and rats in in vivo efficacy models, lack of relevant metabolic clearance data among strains has been a concern. Metabolic clearance is an important parameter impacting drug discovery, and it is often used as a compound selection filter. Metabolically stable compounds are often preferred, and will have a better chance to achieve the desired exposure in vivo. The present study examined strain differences in mouse and rat, using 96 compounds which spanned a wide range of intrinsic clearances. The in vitro clearances were determined using liver microsomes from commonly used strains of mouse (BALB/c, C57BL/6J, and CD-1) and of rat (Sprague-Dawley, Fischer, and Wistar Han). There were few discrepancies in the interpretation of the in vitro intrinsic clearance results within species for the 96 compounds tested in mouse and rat liver microsomes. This data gives us confidence that the phase I hepatic clearance can be determined using only one strain of mouse or rat liver microsomes. PMID- 20845446 TI - Middle-down fragmentation for the identification and quantitation of site specific methionine oxidation in an IgG1 molecule. AB - A middle-down LC/MS approach, for the rapid quantitation and characterization of site-specific methionine oxidation in a recombinant monoclonal IgG1 molecule, is described. An IgG1 antibody was digested with endoprotease LysC under limited proteolytic conditions to produce two major components; an antigen binding fragment (Fab) and a crystallizable fraction (Fc). These fractions were then reduced to produce three major species; light chain (LC), Fc/2 which is the C terminal region of the heavy chain (HC) and the N-terminal heavy chain region (Fd). These three fragments were separated by reversed-phase HPLC using a diphenyl column. The diphenyl column resolved site-specific methionine oxidation in all three subunits. Middle-down N-terminal sequencing with a LCT premier mass spectrometer was used to identify the sites of oxidation in the LC. Sites of oxidation in the Fc/2 were identified using middle-down collision-induced dissociation (CID) on a Qtof premier. This method allowed for the rapid quantitation and identification of oxidation on each methionine residue in an IgG1 molecule. PMID- 20845447 TI - Theoretical prediction of induction period from transient pore evolvement in polyester-based microparticles. AB - A model was developed and compared to experimental results for prediction of the induction period during drug delivery from various compositions of biodegradable copolymer PLGA microparticles. The uniqueness of this model is that it considers transient pore evolvement and uses the kinetic parameters of polymer degradation, which are independent of experimental measurements of microparticle erosion, in its analysis. Delivery data from PLGA microparticles (50:50, 75:25, and 85:15) releasing ovalbumin (OVA, 46 kDa) and bovine serum albumin (BSA, 66 kDa) were determined and used as the model systems. Experimental measurements were carried out from 85 to 150 days depending on the PLGA characteristics. The predicted induction periods were approximately 45, 70, and 105 days for the release of both OVA and BSA from 50:50, 75:25, and 85:15 PLGA microparticles, respectively. Overall, these values were in very good agreement with experimentally estimated results. PMID- 20845448 TI - Formulation and immunogenicity studies of type III secretion system needle antigens as vaccine candidates. AB - Bacterial infections caused by Shigella flexneri, Salmonella typhimurium, and Burkholderia pseudomallei are currently difficult to prevent due to the lack of a licensed vaccine. Here we present formulation and immunogenicity studies for the three type III secretion system (TTSS) needle proteins MxiH(Delta5), PrgI(Delta5), and BsaL(Delta5) (each truncated by five residues at its C terminus) as potential candidates for vaccine development. These antigens are found to be thermally stabilized by the presence of carbohydrates and polyols. Additionally, all adsorb readily to aluminum hydroxide apparently through a combination of hydrogen bonds and/or Van der Waals forces. The interaction of these proteins with the aluminum-based adjuvant changes with time resulting in varying degrees of irreversible binding. Peptide maps of desorbed protein, however, suggest that chemical changes are not responsible for this irreversible association. The ability of MxiH(Delta5) and PrgI(Delta5) to elicit strong humoral immune responses was tested in a murine model. When administered intramuscularly as monomers, the needle components exhibited dose dependent immunogenic behavior. The polymerized version of MxiH was exceptionally immunogenic even at low doses. The responses of both monomeric and polymerized forms were boosted by adsorption to an aluminum salt adjuvant. PMID- 20845450 TI - Investigation of PEG crystallization in frozen PEG-sucrose-water solutions: II. Characterization of the equilibrium behavior during freeze-thawing. AB - Our objective was to characterize, by DSC and XRD, the equilibrium thermal behavior of frozen aqueous solutions containing polyethylene glycol (PEG) and sucrose. Aqueous solutions of (i) PEG (2.5-50% w/w), (ii) sucrose (10% w/v) with different concentrations of PEG (1-20% w/v), and (iii) PEG (2% or 10% w/v) with different concentrations of sucrose (2-20% w/v), were cooled to -70 degrees C at 5 degrees C/min and heated to 25 degrees C at 2 degrees C/min in a DSC. Annealing was performed for 2 or 6 h at temperatures, ranging from -50 to -20 degrees C. Experiments under similar conditions, on select compositions, were also performed in a powder X-ray diffractometer. Two endotherms, observed during heating of a frozen PEG solution (10% w/v), were attributed to PEG-ice eutectic melting and ice melting, and were confirmed by XRD. At higher PEG concentrations (>= 37.5% w/w), only the endotherm attributed to the PEG-ice eutectic melting was observed. Inclusion of sucrose decreased both PEG-ice melting and ice melting temperatures. In unannealed systems with a fixed sucrose concentration (10% w/v), the PEG-ice melting event was not observed at PEG concentration <= 5% w/v. Annealing for 2-6 h facilitated PEG crystallization. In unannealed systems with a fixed PEG concentration (10% w/v), an increase in the sucrose concentration increased the devitrification but decreased the PEG-ice melting temperature. The PEG-ice melting temperatures obtained by DSC and XRD were in good agreement. In ternary systems at a fixed PEG to sucrose ratio, the T' g as well as the PEG-ice melting temperature were unaffected by the total solute concentration. XRD confirmed the absence of a PEG-sucrose-ice ternary eutectic. When the PEG to sucrose ratio was systematically varied, the PEG-ice and ice melting temperatures decreased with an increase in the sucrose concentration. However, at a fixed PEG to sucrose ratio, the PEG-ice melting temperature, was unaffected by the total solute concentration. PMID- 20845449 TI - Formulation and immunogenicity of a potential multivalent type III secretion system-based protein vaccine. AB - The virulence of many pathogenic Gram-negative bacteria is dependent upon their type III secretion (TTS) systems. Here, we discuss initial formulation studies of five TTS needle tip proteins IpaD (Shigella flexneri), BipD (Burkholderia pseudomallei), SipD (Salmonella spp.), LcrV (Yersinia spp.), and PcrV (Pseudomonas aeruginosa) as targets for subunit vaccines. Excipient screening and subsequent assays lead to the selection of 10% sucrose and 5% dextrose as an optimal stabilizer combination for all five proteins. All of the proteins adsorb to aluminum hydroxide adjuvant, although the mechanisms of adsorption may vary. The proteins are physically stable when adsorbed to the adjuvant for at least 3 months at room temperature and chemical stability is enhanced in the presence of excipients. The ability of the IpaD and SipD proteins to elicit strong humoral immune responses was also tested in a murine model in the presence and absence of their needle counterparts MxiH and PrgI (see previous paper in this issue). Both proteins produce high antibody titers regardless of dose. While the IpaD titer is boosted slightly in the presence of its needle protein, MxiH, SipD titers appear to be reduced when administered in the presence of its needle counterpart, PrgI. PMID- 20845451 TI - Drug supersaturation in simulated and human intestinal fluids representing different nutritional states. AB - It was the purpose of this study to explore supersaturation of poorly soluble drugs in human intestinal fluids (HIF), and to assess potential food effects on the creation and maintenance of supersaturation. Duodenal fluids were collected from healthy volunteers and pooled according to three nutritional states (fasted , fed-, and fat-enriched fed state). Supersaturation was created at a fixed degree of supersaturation (DS=20) using the solvent-shift method. Fasted- and fed state simulated intestinal fluids (FaSSIF and FeSSIF) were used as intestinal simulation media. Supersaturation in HIF showed to be stable up to a certain degree for different poorly soluble drugs. In HIF as well as in FaSSIF and FeSSIF, supersaturation appeared to be compound and medium specific. Supersaturation stability was found to be inversely proportional to the solubility in the corresponding media. Food intake affected itraconazole supersaturation positively. On the contrary, etravirine and loviride supersaturation decreased upon food intake. Supersaturation experiments in FaSSIF and FeSSIF showed similar results as in HIF for etravirine and loviride, whereas itraconazole supersaturation behaved differently in HIF versus simulation media. The present study illustrates, for the first time, that supersaturation can be created and maintained in HIF, even in the absence of excipients. PMID- 20845452 TI - Self-organizing map analysis using multivariate data from theophylline powders predicted by a thin-plate spline interpolation. AB - The quality by design concept in pharmaceutical formulation development requires establishment of a science-based rationale and a design space. We integrated thin plate spline (TPS) interpolation and Kohonen's self-organizing map (SOM) to visualize the latent structure underlying causal factors and pharmaceutical responses. As a model pharmaceutical product, theophylline powders were prepared based on the standard formulation. The angle of repose, compressibility, cohesion, and dispersibility were measured as the response variables. These responses were predicted quantitatively on the basis of a nonlinear TPS. A large amount of data on these powders was generated and classified into several clusters using an SOM. The experimental values of the responses were predicted with high accuracy, and the data generated for the powders could be classified into several distinctive clusters. The SOM feature map allowed us to analyze the global and local correlations between causal factors and powder characteristics. For instance, the quantities of microcrystalline cellulose (MCC) and magnesium stearate (Mg-St) were classified distinctly into each cluster, indicating that the quantities of MCC and Mg-St were crucial for determining the powder characteristics. This technique provides a better understanding of the relationships between causal factors and pharmaceutical responses in theophylline powder formulations. PMID- 20845453 TI - Enhanced oral absorption of paclitaxel in N-deoxycholic acid-N, O-hydroxyethyl chitosan micellar system. AB - The overall goal of this study was to develop a micellar system of paclitaxel (PTX) to enhance its oral absorption. An amphiphilic chitosan derivative, N deoxycholic acid-N, O-hydroxyethyl chitosan (DHC), was synthesized and characterized by FTIR, (1)H NMR, elemental analysis, and X-ray diffraction (XRD) techniques. The degree of substitution (DS) of hydroxyethyl group and deoxycholic acid group ranged from 89.5-114.5% and 1.11-8.17%, respectively. The critical micelle concentration (CMC) values of DHC decreased from 0.26 to 0.16 mg/mL as the DS of deoxycholic acid group increased. PTX was successfully loaded in DHC micelles with a high drug loading (31.68 +/- 0.14%) and entrapment efficiency (77.57 +/- 0.51%). The particle size of PTX-loaded DHC micelles ranged from 203.35 +/- 2.19 to 236.70 +/- 3.40 nm as the DS of deoxycholic acid group increased. After orally administration of PTX-loaded DHC micelles, the bioavailability was threefold compared with that of an orally dosed Taxol(r). The single-pass intestinal perfusion studies (SPIP) showed that the intestinal absorption of micelles was via endocytosis involving a saturable process and a p glycoprotein (P-gp)-independent way. All these indicated that the DHC micelles might be a promising tool for oral delivery of poorly water-soluble drugs. PMID- 20845454 TI - Inhalable liposomes of low molecular weight heparin for the treatment of venous thromboembolism. AB - This study tests the feasibility of inhalable pegylated liposomal formulations of low molecular weight heparin (LMWH) for treatment of two clinical manifestations of vascular thromboembolism: deep vein thrombosis (DVT) and pulmonary embolism (PE). Conventional distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) and long circulating pegylated (DSPE-PEG-2000 and DSPE-PEG-5000) liposomes were prepared by hydration method. Formulations were evaluated for particle size, entrapment efficiency, stability, pulmonary absorption, anticoagulant, and thrombolytic effects in rats. Pulmonary absorption was monitored by measuring plasma antifactor Xa activity; anticoagulant and thrombolytic effects were studied by measuring reduction in thrombus weight and amount of dissolved radioactive clot in the blood, respectively. Pegylated liposomal were smaller and showed greater drug entrapment efficiency than conventional liposomes. All formulations produced an increase in pulmonary absorption and circulation time of LMWH upon first dosing. Three repeated dosings of conventional liposomes resulted in decreased half-life and bioavailability; no changes in these parameters were observed with pegylated liposomes. PEG-2000 liposomes were effective in reducing thrombus weight when administered every 48 h over 8 days. In terms of thrombolytic effects and dosing frequency, PEG-2000 liposomes administered via the pulmonary route at a dose of 100 U/kg were as effective as 50 U/kg LMWH administered subcutaneously. This paper suggests that inhalable pegylated liposomes of LMWH could be a potential noninvasive approach for DVT and PE treatment. PMID- 20845455 TI - In vitro and in vivo evaluation of a novel water-soluble N-glycyl prodrug (N-GLY CBZ) of carbamazepine. AB - The synthesis and characterization of N-glycyl-carbamazepine (N-Gly-CBZ), an N acyl urea derivative of carbamazepine (CBZ) designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the glycyl-urea bond was recently reported. The rate and extent of conversion of N-Gly-CBZ to CBZ in a whole animal model is reported here along with supporting in vitro data. Pharmacokinetic parameters were determined for N-Gly-CBZ and CBZ following IV and oral administration of N-Gly-CBZ and CBZ control to rats using a crossover design. The in vivo elimination of N-Gly-CBZ following IV administration in rats was biphasic in nature with a t(1/2) of about 1.1 min, which was very similar to the t(1/2) for appearance of CBZ. The mean value for the relative AUC ratio for CBZ from N-Gly-CBZ and CBZ from a cyclodextrin solution showed that N-Gly-CBZ delivered a (+/- SD) 98 +/- 16% (+/- SD) equivalent dose of CBZ in six rats. The results of the IV dosing pharmacokinetics investigation were consistent with N Gly-CBZ acting as a prodrug with rapid and complete conversion to CBZ in vivo. The overall absolute oral bioavailability of CBZ from N-Gly-CBZ was determined to be 41 +/- 14% in three rats. The relative oral bioavailability of CBZ from N-Gly CBZ compared to an oral CBZ control was 1.72 +/- 0.54. That is, the prodrug, N Gly-CBZ, demonstrated superior oral bioavailability of CBZ over the CBZ control, which was likely due to its greater aqueous solubility. PMID- 20845456 TI - Inhibiting the gastric burst release of drugs from enteric microparticles: the influence of drug molecular mass and solubility. AB - Undesired drug release in acid medium from enteric microparticles has been widely reported. In this paper, we investigate the relative contribution of microparticle and drug properties, specifically microsphere size and drug's molecular weight and acid solubility, on the extent of such undesired release. A series of nine drugs with different physicochemical properties were successfully encapsulated into Eudragit S and Eudragit L microparticles using a novel emulsion solvent evaporation process. The process yielded spherical microparticles with a narrow size distribution (27-60 and 36-56 um for Eudragit L and Eudragit S microparticles, respectively). Upon incubation in acid medium (pH 1.2) for 2 h, the release of dipyridamole, cinnarizine, amprenavir, bendroflumethiazide, budesonide and prednisolone from both Eudragit microparticles was less than 10% of drug load and conformed with the USP specifications for enteric dosage forms. In contrast, more than 10% of the entrapped paracetamol, salicylic acid and ketoprofen were released. Multiple regression revealed that the drug's molecular weight was the most important factor that determined its extent of release in the acid medium, while its acid solubility and microsphere's size had minor influences. PMID- 20845457 TI - The buccal mucosa as an alternative route for the systemic delivery of risperidone. AB - The purpose of this study was to investigate the potential of the buccal mucosa for the systemic delivery of risperidone (RISP), and to determine the impact of Azone(r) (AZ) on the transport of RISP via this route. The permeability of RISP through porcine buccal mucosa was assessed in modified Ussing chambers at various concentrations to determine the mechanisms involved in transport across the tissue. The effect of AZ was assessed by administering AZ 5% (w/w) to the tissue as a pretreatment or together with RISP in solution or in a mucoadhesive gel formulation. RISP permeated the buccal mucosa via a passive diffusion mechanism and pretreatment or coadministration of AZ 5% did not significantly modify the permeation of RISP. Application of a RISP mucoadhesive gel resulted in a steady state flux of 64.65 +/- 8.0 ug/cm(2)/h, which when extrapolated to the in vivo setting, is predicted to result in RISP plasma concentrations of 11.2-56.1 ug/L for mucosal application areas between 2 and 10 cm(2). Given that these predicted concentrations are within the therapeutic range of RISP required in humans, delivery of RISP via the buccal mucosa has the potential to result in therapeutically relevant plasma concentrations for the treatment of schizophrenia. PMID- 20845458 TI - Interaction of Amphotericin B with cholesteryl palmityl carbonate ester. AB - A cholesteryl carbonate ester was prepared and evaluated as a possible thermotropic liquid crystal excipient for dry powder inhalers. Cholesteryl palmityl carbonate (CPC) was synthesized, and the phase behavior was characterized by differential scanning calorimetry, transmission electron microscopy, polarized light microscope, small angle X-ray diffraction, and solid state nuclear magnetic resonance spectroscopy. Amphotericin B (AmB) was incorporated into CPC at various mole% (7.7, 14.3, 25, 33.3, and 50) using a solvent evaporation method. The amount of AmB loaded into liquid crystal was limited. The mixture of AmB in liquid crystal did not produce a new complex; rather, the addition of AmB affected the orientational order and the motional aspects of liquid crystal molecules. PMID- 20845459 TI - Partial least squares analysis and mixture design for the study of the influence of composition variables on lipidic nanoparticle characteristics. AB - Lipidic nanoparticles (NP), formulated from a phase inversion temperature process, have been studied with chemometric techniques to emphasize the influence of the four major components (Solutol(r), Labrasol(r), Labrafac(r), water) on their average diameter and their distribution in size. Typically, these NP present a monodisperse size lower than 200 nm, as determined by dynamic light scattering measurements. From the application of the partial least squares (PLS) regression technique to the experimental data collected during definition of the feasibility zone, it was established that NP present a core-shell structure where Labrasol(r) is well encapsulated and contributes to the structuring of the NP. Even if this solubility enhancer is regarded as a pure surfactant in the literature, it appears that the oil moieties of this macrogolglyceride mixture significantly influence its properties. Furthermore, results have shown that PLS technique can be also used for predictions of sizes for given relative proportions of components and it was established that from a mixture design, the quantitative mixture composition to use in order to reach a targeted size and a targeted polydispersity index (PDI) can be easily predicted. Hence, statistical models can be a useful tool to control and optimize the characteristics in size of NP. PMID- 20845460 TI - Determination of the influence of primary drying rates on the microscale structural attributes and physicochemical properties of protein containing lyophilized products. AB - This work investigated the impact of primary drying conditions on the microstructure and protein stability of bovine serum albumin (BSA) containing lyophilized cakes. Two primary drying conditions were employed (termed 'conservative', slower drying rate and 'aggressive', higher drying rate) at two protein loadings (5 and 50 mg mL(-1)). The cake attributes were characterized using micro-X-ray computed tomography (micro-CT), scanning electron microscopy, manometric temperature measurements, Fourier transform infrared spectroscopy (FTIR) and size exclusion chromatography (SEC). The combination of analytical techniques revealed that although the aggressive drying conditions produced intact cakes which retained their macrostructure, they had undergone various degrees of microcollapse. The study demonstrates the applicability of micro-CT for resolving microstructural attributes of the freeze-dried cakes such as residual porosity, pore size distribution and connectivity. Micro-CT data showed significant differences in residual porosity and matrix connectivity between aggressively and conservatively dried cakes. The FTIR data show that at each protein loading, there is no observable difference in the secondary structure of the protein and the SEC data show comparable stability in the cakes produced under different primary drying conditions. Good content uniformity was observed with respect to BSA and sucrose distribution in the cakes. PMID- 20845461 TI - Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation. AB - The aim of this study was to evaluate the effect of curcumin (CUR) in oral bioavailability and therapeutic efficacy of paclitaxel (PTX) administered in nanoemulsion to SKOV3 tumor-bearing nu/nu mice. Oral administration of the mice with CUR at 50 mg/kg for 3 consecutive days resulted in a down regulation of intestinal P-glycoprotein (Pgp) and cytochrome P450 3A2 (CYP3A2) protein levels. PTX, a Pgp and CYP3A2 substrate, was administered orally at 20 mg/kg in solution or nanoemulsion either as single agent or upon pretreatment with CUR at 50 mg/kg in tumor-bearing mice. Plasma AUC(0-infinity) of PTX administered in nanoemulsion to CUR pretreated mice showed 4.1-fold increase relative to controls. Similarly, relative PTX bioavailability was increased by 5.2-fold, resulting in a 3.2-fold higher PTX accumulation in the tumor tissue. PTX administered in nanoemulsion to CUR pretreated mice also showed significantly enhanced anti-tumor activity. Preliminary safety evaluation showed that CUR + PTX combination did not induce any acute toxicity as measured by body weight changes, blood cell counts, liver enzyme levels, and liver histopathology. The results of this study suggest that combination of PTX and CUR, administered in nanoemulsions, could improve oral bioavailability and therapeutic efficacy in ovarian adenocarcinoma. PMID- 20845462 TI - Polyamine aza-cyclic compounds demonstrate anti-proliferative activity in vitro but fail to control tumour growth in vivo. AB - Cationic polyamines such as the poly(propylenimine) dendrimers (DAB16) are anti tumour agents (Dufes et al., 2005, Cancer Res 65:8079-8084). Their mechanism of action is poorly understood, but the lack of in vivo toxicity suggests cancer specificity. To explore this polyamine pharmacophore we cross-linked the aza cyclic compound, hexacyclen, with 1,4-dibromobutane or 1,8-dibromooctane to yield the polyamines [poly(butylhexacyclen)--CL4] or [poly(octylhexacyclen)--CL8] respectively, both free of primary amines. We characterised the compounds and their respective nanoparticles and examined their interaction with the putative targets of the cationic polyamines: the cell membrane and DNA. Like DAB 16, CL4 and CL8 bind plasmid DNA and all three compounds interrupted the cell cycle of A431 epidermoid carcinoma cells in the S-phase. Additionally all three compounds disrupted erythrocyte membranes, with CL8 and DAB 16 being more active, in this respect, than CL4. CL4 (IC(50) =775.1 ug mL(-1)) and CL8 (IC(50) =8.4 ug mL(-1)), in a similar manner to DAB 16, were anti-proliferative against A431 cells; although unlike DAB 16, CL4 and CL8 were not tumouricidal against A431 xenografts in mice, indicating that primary amines may play an important role in the in vivo activity of DAB 16. PMID- 20845463 TI - In vitro and in vivo lung deposition of coated magnetic aerosol particles. AB - The magnetic induced deposition of polydispersed aerosols composed of agglomerated superparamagnetic particles was measured with an in vitro model system and in the mouse trachea and deep lung for the purpose of investigating the potential of site specific respiratory drug delivery. Oleic acid coated superparamagnetic particles were prepared and characterized by TEM, induced magnetic moment, and iron content. The particles were dispersed in cyclohexane, aerosolized with an ultrasonic atomizer and dried by sequential reflux and charcoal columns. The fraction of iron deposited on glass tubes increased with particle size and decreasing flow rate. High deposition occurred with a small diameter tube, but the deposition fraction was largely independent of tube size at larger diameters. Results from computational fluid dynamics qualitatively agreed with the experimental results. Enhanced deposition was observed in the mouse lung but not in the trachea consistent with the analysis of the aerodynamic time allowed for deposition and required magnetic deposition time. PMID- 20845464 TI - Water sorption, glass transition, and protein-stabilizing behavior of an amorphous sucrose matrix combined with various materials. AB - The effects of various additives on the physical properties of an amorphous sugar matrix were compared. Amorphous, sugar-additive mixtures were prepared by freeze drying and then rehumidified at given RHs. Sucrose and eighteen types of substances were used as the sugar and the additive, respectively, and water sorption, glass-to-rubber transition, and protein stabilization during freeze drying for the various sucrose-additive mixtures were examined. The additives were categorized into two groups according to their effects on T(g) and water sorption. Presence of polysaccharides, cyclodextrins, and polymers (large-sized additives) resulted in a decrease in equilibrium water content from the ideal value calculated from individual water contents for sucrose and additive, and in contrast, low MW substances containing ionizable groups (small-ionized additives) resulted in an increase. The increase in T(g) by the addition of large-sized additives was significant at the additive contents >50 wt.% whereas the T(g) was markedly increased in the lower additive content by the addition of small-ionized additives. The addition of small-ionized additives enhanced the decrease in T(g) with increasing water content. The protein stabilizing effect was decreased with increasing additive content in the cases of the both groups of the additives. PMID- 20845465 TI - Design and in vitro evaluation of a film-controlled dosage form self-converted from monolithic tablet in gastrointestinal environment. AB - The purpose of this study is to design an easily manufactured sustained drug delivery system, which can be converted to a film coated system during the dissolution process and then control the drug release according to near zero order kinetics. Two kinds of pH-sensitive and oppositely charged hydrophilic polymers, chitosan and alginate, were physically mixed as the matrix. Slightly water-soluble drugs such as theophylline, aspirin, and acetaminophen were utilized as model drugs. In vitro drug release and swelling tests were undertaken in simulated gastrointestinal environments. The formation and properties of the film formed during the dissolution process were identified using different techniques. It was demonstrated that formation of the film was based on the interaction of the polymers on tablet surface with the change of system pH. In 0 4 h drug release depended on the intrinsic properties of the polymers, however, characteristics of the film played a leading role in controlling drug release after 4 h. By studying the ratio of relaxation over Fickian diffusion and relationship between tablets swelling and drug release, it was revealed that the film probably modified drug release behavior by limiting polymer erosion. The in vivo behavior of this hydrophilic matrix system will be investigated. PMID- 20845466 TI - In-line optimization and control of an industrial freeze-drying process for pharmaceuticals. AB - This paper deals with the in-line optimization and control of the freeze-drying process of pharmaceuticals in vials. The proposed control system, named LyoDriver, uses a mathematical model of the process to calculate the values of the temperature of the heating fluid: the goal is to minimize the time required to get the desired amount of residual water in the dried product, and to maintain product temperature below the maximum allowed value, thus preserving product quality. The values of product temperature and residual ice content, as well as other parameters, are required to perform the calculations: these variables are estimated in-line by means of the Dynamic Parameters Estimation algorithm, an advanced tool based on the pressure rise test, but also other monitoring systems can be used. Two different control algorithms are presented and investigated by means of mathematical simulation and experiments carried out in a small industrial-type apparatus (LyoBeta 25 by Telstar). Results show the effectiveness of LyoDriver in a wide range of operating conditions, even when the process becomes mass-transfer controlled, or when the operating pressure is changed. PMID- 20845467 TI - Effects of solute miscibility on the micro- and macroscopic structural integrity of freeze-dried solids. AB - The purpose of this study was to elucidate the effect of solute miscibility in frozen solutions on their micro- and macroscopic structural integrity during freeze-drying. Thermal analysis of frozen solutions containing poly(vinylpyrrolidone) (PVP) and dextran showed single or multiple thermal transitions (T'g: glass transition temperature of maximally freeze-concentrated solutes) depending on their composition, which indicated varied miscibility of the concentrated noncrystalline polymers. Freeze-drying of the miscible solute systems (e.g., PVP 10,000 and dextran 1060, single T'g induced physical collapse during primary drying above the transition temperatures T'g). Phase-separating PVP 29,000 and dextran 35,000 mixtures (two T'g s) maintained their cylindrical structure following freeze-drying below both of the T'g s (<-24 degrees C). Primary drying of the dextran-rich systems at temperatures between the two T'g s (-20 to -14 degrees C) resulted in microscopically disordered "microcollapsed" cake-structure solids. Freeze-drying microscopy (FDM) analysis of the microcollapsing polymer system showed locally disordered solid region at temperatures between the collapse onset (T(c1)) and severe structural change (T(c2)). The rigid dextran-rich matrix phase should allow microscopic structural change of the higher fluidity PVP-rich phase without loss of the macroscopic cake structure at the temperature range. The results indicated the relevance of physical characterization and process control for appropriate freeze-drying of multicomponent formulations. PMID- 20845468 TI - Albumin/gentamicin microspheres produced by supercritical assisted atomization: optimization of size, drug loading and release. AB - In this work, the supercritical assisted atomization (SAA) is proposed, for the first time, not only as a micronization technology but also as a thermal coagulation process for the production of bovine serum albumin (BSA) microspheres charged with Gentamicin sulfate (GS). Particularly, different water solutions of BSA/GS were processed by SAA to produce protein microspheres with different size and antibiotic content. SAA precipitation temperature was selected in the range 100-130 degrees C to generate protein coagulation and to recover micronized BSA in form of hydrophobic aggregates; GS loading was varied between 10% and 50% (w/w) with an encapsulation efficiency which often reached 100%. In all cases, spherical and noncoalescing particles were successfully produced with a mean particle size of 2 um and with a standard deviation of about +/-1 um. The microspheres also showed a good stability and constant water content after 60 days of storage. The release profiles of the entrapped drug were monitored using Franz cells to evaluate the possible application of the produced microspheres in wound dressing formulations. Particularly, the microspheres with a BSA/GS ratio of 4:1 after the first burst effect (of 40% of GS loaded) were able to release the GS continuously over 10 days. PMID- 20845469 TI - Solid lipid microparticles for the stability enhancement of a dopamine prodrug. AB - The oral or peripheral administration of dopamine for the treatment of Parkinson's disease is hampered by its extensive metabolism and inability to cross the blood-brain barrier. Consequently, the enhancement of dopamine stability in physiologic environments and its brain targeting appear useful in formulation development. We propose the preparation and characterization of solid lipid microparticles based on tristearin as a sustained delivery system for dopamine. The microparticles were produced by conventional hot emulsion techniques. The synthesis of a new valeroyl ester of dopamine (3,4-O-divaleroyl dopamine, DVD) was necessary to obtain its encapsulation in the microparticles. DVD appeared totally hydrolyzed to dopamine in human plasma within 40 s. The amount of encapsulated DVD in microparticles was 2.67 +/- 1.2%. The mean diameter of particles was 14.2 +/- 4.8 um. The DVD release from microparticles was characterized by an initial burst of 20% of incorporated prodrug and a continuous slow release thereafter. The microparticles were able to stabilize DVD in its solid form. In human plasma, DVD encapsulated in microparticles hydrolyzed with a markedly reduced rate in comparison with free prodrug: after 15 min, 35.8% of DVD was still detectable. The DVD-loaded microparticles could represent a potential system for dopamine uptake in the brain, following nasal administration. PMID- 20845470 TI - Econazole nitrate-loaded MCM-41 for an antifungal topical powder formulation. AB - The aim of this article was to prepare a topical powder for the treatment of fungal infections, such as Candida intertrigo and tinea pedis. Thus, an econazole nitrate (ECO) formulation with improved drug dissolution and proper moisture adsorption was designed. ECO was melt with the mesoporous silicate MCM-41 (drug/MCM-41 1/3) and the resulting inclusion compound was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The drug loading was confirmed by the decrease of specific surface area and pore volume between MCM-41 and the inclusion compound. Formulations containing the inclusion compound were prepared and submitted to in vitro dissolution test and in vitro antifungal activity. A remarkable dissolution rate improvement as well as a higher antifungal activity was observed for the inclusion compound if compared to a commercial product. Moisture sorption properties for MCM-41 and formulations were evaluated as well. PMID- 20845473 TI - Law, ethics, religion, and clinical translation in the 21st century--a discussion with Andrew Webster. PMID- 20845471 TI - Clinical pharmacokinetics of paclitaxel liposome with a new route of administration in human based on the analysis with ultra performance liquid chromatography. AB - We investigated the clinical pharmacokinetics of paclitaxel liposome with a new route of administration, which was intrapleural infusion, in nine advanced nonsmall-cell lung cancer (NSCLC) patients with malignant pleural effusions after a single administration. Paclitaxel concentrations were measured in pleural fluid and plasma using a simple and rapid ultra performance liquid chromatography (UPLC) method following intra- and inter-day validations. In subjects, AUC(0-96 h) values in pleural fluid and plasma were 17831 +/- 6439 ug h/mL and 778 +/- 328 ug h/mL, respectively, and T(max) values were initial time and 6.67 h after administration and the corresponding C(max) values were 558 +/- 44 ug/mL and 12.89 +/- 6.86 ug/mL, respectively. The T(1/2,IP), CL(IP) and Vd(IP) values in pleural fluid were 76 +/- 48 h, 0.005 +/- 0.002 L/h m(2) and 0.53 +/- 0.23 L/m(2), respectively. The T(1/2,pla), CL(pla), and Vd(pla) values in plasma were 68.34 +/- 56.74 h, 0.184 +/- 0.080 L/h m(2), and 17.53 +/- 16.57 L/m(2), respectively. However, some paclitaxel concentrations from several patients in plasma could not be detected at some designed time-points. Our results might offer new opportunities to design and determine individually appropriate therapeutic dosage regimens based on a pharmacokinetic profile. PMID- 20845474 TI - Bidirectional regulation of neurogenesis by neuronal nitric oxide synthase derived from neurons and neural stem cells. AB - It has been demonstrated that neuronal nitric oxide synthase (nNOS) negatively regulates adult neurogenesis. However, the cellular and molecular mechanisms underlying are poorly understood. Here, we show that nNOS from neural stem cells (NSCs) and from neurons play opposite role in regulating neurogenesis. The NSCs treated with nNOS inhibitor N(5)-(1-imino-3-butenyl)-L- ornithine (L-VNIO) or nNOS gene deletion exhibited significantly decreased proliferation and neuronal differentiation, indicating that NSCs-derived nNOS is essential for neurogenesis. The NSCs cocultured with neurons displayed a significantly decreased proliferation, and deleting nNOS gene in neurons or scavenging extracellular nitric oxide (NO) abolished the effects of coculture, suggesting that neurons derived nNOS, a source of exogenous NO for NSCs, exerts a negative control on neurogenesis. Indeed, the NSCs exposed to NO donor DETA/NONOate displayed decreased proliferation and neuronal differentiation. The bidirectional regulation of neurogenesis by NSCs- and neurons-derived nNOS is probably related to their distinct subcellular localizations, mainly in nuclei for NSCs and in cytoplasm for neurons. Both L-VNIO and DETA/NONOate inhibited telomerase activity and proliferation in wild-type (WT) but not in nNOS(-/-) NSCs, suggesting a nNOS telomerase signaling in neurogenesis. The NSCs exposed to DETA/NONOate exhibited reduced cAMP response element binding protein (CREB) phosphorylation, nNOS expression, and proliferation. The effects of DETA/NONOate were reversed by forskolin, an activator of CREB signaling. Moreover, disrupting CREB phosphorylation by H-89 or LV-CREB133-GFP simulated the effects of DETA/NONOate, and inhibited telomerase activity. Thus, we conclude that NSCs-derived nNOS stimulates neurogenesis via activating telomerase, whereas neurons-derived nNOS represses neurogenesis by supplying exogenous NO that hinders CREB activation, in turn, reduces nNOS expression in NSCs. PMID- 20845475 TI - Adipose tissue as a dedicated reservoir of functional mast cell progenitors. AB - White adipose tissue (WAT) is a heterogeneous tissue, found in various locations throughout the body, containing mature adipocytes and the stroma-vascular fraction (SVF). The SVF includes a large proportion of immune hematopoietic cells, among which, mast cells that contribute to diet-induced obesity. In this study, we asked whether mast cells present in mice adipose tissue could derive from hematopoietic stem/progenitor cells (HSPC) identified in the tissue. We therefore performed both in vitro and in vivo experiments dedicated to monitoring the progeny of WAT-derived HSPC. The entire study was conducted in parallel with bone marrow-derived cells, considered the gold standard for hematopoietic-lineage studies. Here, we demonstrate that adipose-derived HSPC contain a precursor-cell population committed to the mast cell lineage, and able to efficiently home to peripheral organs such as intestine and skin, where it acquires properties of functional tissue mast cells. Additionally, WAT contains a significant mast cell progenitor population, suggesting that the entire mast cell lineage process take place in WAT. Considering the quantitative importance of WAT in the adult organism and the increasing roles recently assigned to mast cells in physiopathology, WAT may represent an important source of mast cells in physiological and pathological situations. PMID- 20845476 TI - Local control after craniospinal irradiation, intensity-modulated radiotherapy boost, and chemotherapy in childhood medulloblastoma. AB - BACKGROUND: The current study was conducted to determine whether the use of cochlear-sparing intensity-modulated radiotherapy (IMRT) boost results in excess local failures in children with medulloblastoma. METHODS: Fifty children with a median age of 7.8 years underwent resection, craniospinal irradiation (CSI), IMRT posterior fossa (PF) and/or tumor bed (TB) boost, and cisplatin-based chemotherapy for medulloblastoma. For standard-risk patients, the CSI dose was 18 to 23.4 grays (Gy) and was followed either by an IMRT PF boost to 36 Gy and a TB boost of 54 to 55.8 Gy (n = 29) or by an IMRT TB boost to 55.8 Gy (n = 4). For high-risk patients, the CSI dose was 36 to 39.6 Gy followed by an IMRT PF boost to 54 to 55.8 Gy (n = 8), an IMRT PF boost to 45 Gy and a TB boost to 55.8 Gy (n = 2), or an IMRT TB boost to 55.8 Gy (n = 7). For the TB boost, a 2-cm margin around the surgical bed was treated in most patients. RESULTS: The 5-year overall and progression-free survival rates (+/-standard deviation) were 72% +/- 6.6% and 68.3% +/- 6.8%, respectively, for all patients; 77.8% +/- 7.4% and 75.1% +/- 7.6%, respectively, for standard-risk patients; and 60.8% +/- 12.8% and 55.4% +/- 12.8%, respectively, for high-risk patients. The 5-year PF control rate was 90.5% +/- 4.6%. TB failures occurred in 3 patients (including 2 patients who had distant failure), whereas an isolated non-TB PF failure occurred in 1 patient. CONCLUSIONS: The use of IMRT was associated with excellent local control and did not result in excess PF failures outside of the TB. PMID- 20845477 TI - Glucose metabolism gene polymorphisms and clinical outcome in pancreatic cancer. AB - BACKGROUND: Altered glucose metabolism is the most common metabolic hallmark of malignancies. The authors tested the hypothesis that glucose metabolism gene variations affect clinical outcome in pancreatic cancer. METHODS: The authors retrospectively genotyped 26 single nucleotide polymorphisms from 5 glucose metabolism genes in 154 patients with localized disease and validated the findings in 552 patients with different stages of pancreatic adenocarcinoma. Association between genotypes and overall survival (OS) was evaluated using multivariate Cox proportional hazard regression models with adjustment for clinical predictors. RESULTS: Glucokinase (GCK) IVS1 + 9652C > T and hexokinase 2 (HK2) N692N homozygous variants were significantly associated with reduced OS in the training set of 154 patients (P < .001). These associations were confirmed in the validation set of 552 patients and in the combined dataset of all 706 patients (P <= .001). In addition, HK2 R844K variant K allele was associated with a better survival in the validation set and the combined dataset (P <= .001). When data were further analyzed by disease stage, glutamine-fructose-6-phosphate transaminase (GFPT1) IVS14-3094T>C, HK2 N692N and R844K in patients with localized disease and GCK IVS1 + 9652C>T in patients with advanced disease were significant independent predictors for OS (P <= .001). Haplotype CGG of GPI and GCTATGG of HK2 were associated with better OS, respectively, with P values of .004 and .007. CONCLUSIONS: The authors demonstrated that glucose metabolism gene polymorphisms affect clinical outcome in pancreatic cancer. These observations support a role of abnormal glucose metabolism in pancreatic carcinogenesis. PMID- 20845478 TI - Current event-free survival after sequential tyrosine kinase inhibitor therapy for chronic myeloid leukemia. AB - BACKGROUND: Imatinib is an effective tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML) in chronic phase (CP). Although some patients may fail on therapy with imatinib, effective salvage therapy is available with second-generation TKIs. Current measurement of efficacy for each therapy is judged by its individual impact on overall survival and event-free survival (EFS). METHODS: In total, 586 patients with CML in CP who received imatinib were included in this analysis in 2 cohorts: imatinib as front-line therapy (n = 281) or after failure on interferon-alpha (IFN-alpha) (n = 305). By accounting for successful salvage treatment (ie, regain of complete cytogenetic response), the current EFS (CEFS) rate was calculated to obtain a more accurate impression of the outcome of patients with CML who received treatment with sequential TKIs. RESULTS: For patients who received imatinib after failing on IFN-alpha, the 7 year EFS rate was 61%, whereas the CEFS rate was 69%. The 7-year EFS rate for patients who received imatinib as initial therapy was 81% compared with a 7-year CEFS rate of 88%. CONCLUSIONS: CEFS provided a more accurate representation of the outcome of patients with CML in CP. These patients may frequently be treated successfully with subsequent TKIs after experiencing failure on the first TKI. PMID- 20845479 TI - Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine: from US Military Cancer Institute Clinical Trials Group Study I 01 and I-02. AB - BACKGROUND: The authors are conducting clinical trials of the HER-2/neu E75 peptide vaccine in clinically disease-free breast cancer (BC) patients. Their phase 1-2 trials revealed that the E75 + granulocyte-macrophage colony stimulating factor (GM-CSF) vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8(+) T cells. They assessed the need for and response to a booster after completion of primary vaccination series. METHODS: BC patients enrolled in the E75 vaccine trials who were >=6 months from completion of their primary vaccination series were offered boosters with E75 + GM-CSF. Patients were monitored for toxicity. E75-specific CD8(+) T cells were quantified using the human leukocyte antigen-A2:immunoglobulin G dimer before and after boosting. RESULTS: Fifty-three patients received the vaccine booster. Median time from primary vaccination series was 9 months (range, 6-35 months), and median residual E75-specific immunity was 0.70% (range, 0-3.49%) CD8(+) lymphocytes. Elevated residual immunity (ERI) (CD8(+) E75-specific T cells >0.5%) was seen in 94.4% of patients at 6 months from primary vaccination series versus 48% of patients at >6 months (P = .002). The booster was well tolerated, with only grade 1 and 2 toxicity observed. Local reactions were more robust in patients receiving the booster at 6 months from primary vaccination series compared with those at >6 months (99.4 +/- 6.1 mm vs 81.8 +/- 4.1 mm, P = .01). In patients lacking ERI, 85% had increased ERI after vaccination (P = .0014). CONCLUSIONS: The HER-2/neu E75 peptide vaccine E75 stimulates specific immunity in disease-free BC patients. However, immunity wanes with time. A vaccine booster is safe and effective in stimulating E75-specific immunity in those patients without ERI. These results suggest that the booster may be most effective at 6 months after completion of the primary vaccination series. PMID- 20845480 TI - Mucinous ovarian carcinoma: slippery business. PMID- 20845482 TI - Hypothyroidism in patients with renal cell carcinoma: blessing or curse? AB - BACKGROUND: Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC. METHODS: Eighty-seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid-stimulating hormone (TSH), tri-iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 MUM/mL) with normal T3 and T4 levels. RESULTS: Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14-0.85; P = .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P = .014). CONCLUSIONS: The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered. PMID- 20845481 TI - Evidence for an hMSH3 defect in familial hamartomatous polyps. AB - BACKGROUND: Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN, a gene inactivated in the germline of some hamartomatous polyposis syndrome patients. METHODS: Ten hamartomatous polyposis syndrome patients were genotyped for germline mutations. Epithelial and nonepithelial polyp DNA were assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. In addition, 99 MSI-high sporadic CRCs and 50 each of hMLH1(-/-) and hMSH3(-/-) cell clones were examined for PTEN frameshifts. RESULTS: Twenty-five (58%) of 43 hamartomatous polyposis syndrome polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3 deficiency. MSI domains lost hMSH3 expression, and PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wild type exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however, MSI-high sporadic CRC showed 11 (11%) of 99 frameshifts within PTEN, with 4 tumors having complete loss of PTEN expression. Subcloning hMLH1(-/-) and hMSH3(-/-) cells revealed somatic PTEN frameshifts in 4% and 12% of clones, respectively. CONCLUSIONS: Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN(+/-) patients lose PTEN expression, but loss is not a universal early feature of all hamartomatous polyposis syndrome. However, PTEN frameshifts can occur in hMSH3-deficient cells, suggesting that hMSH3 deficiency could drive hamartomatous polyposis syndrome tumorigenesis. PMID- 20845483 TI - Evaluation of PML immunofluorescence, flow cytometric immunophenotypic analysis, and reverse transcriptase polymerase chain reaction for PML/RARa for rapid diagnosis of acute promyelocytic leukemia. PMID- 20845484 TI - Enhancement of the blood compatibility of dialyzer membranes by the physical adsorption of human thrombomodulin (ART-123). AB - ART-123 is a recombinant soluble human thrombomodulin (hTM) with excellent anticoagulant activity. We focused on improving the blood compatibility of the polysulfone-polyvinylpyrrolidone dialyzer surface by the physical adsorption of ART-123 onto the surface. The blood compatibility of the dialyzer with the hTM adsorbed membrane was evaluated by measuring the differential pressure between the arterial and the venous pressures and by blood parameters during blood circulation. The hTM adsorbed dialyzer membrane inhibited blood clot formation without heparin administration due to the anticoagulant activity of hTM for over 4 h. The physically adsorbed hTM was stable during blood circulation, and it did not affect activated clotting time, which is significant drawback of heparin administration, and blood cell counts of RBC, WBC, or platelets. The physical adsorption of hTM onto the dialyzer membrane will be a simple and safe method to prevent blood coagulation during dialysis instead of heparin administration. PMID- 20845485 TI - Treatment of pituitary neoplasms with temozolomide: a review. AB - Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had high-level MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. PMID- 20845487 TI - Evaluating the suitability of highly cross-linked and remelted materials for use in posterior stabilized knees. AB - Posterior stabilized (PS) knee designs are a popular choice for cruciate sacrificing knee arthroplasty procedures. The introduction of PS inserts fabricated from highly cross-linked and remelted Ultra High Molecular Weight Polyethylene (UHMWPE) has recently generated concern as these materials have been shown to possess reduced mechanical properties. This study investigated whether highly cross-linked and remelted UHMWPE material (referred to as XRP) can be expected to perform similarly to historical gamma-air polyethylene, which has suffered few reported incidences of tibial post failure. Never-implanted gamma air PS tibial inserts shelf-aged 14 years were examined and compared to XRP materials. Evaluation of oxidation levels, impact toughness, and fatigue strength demonstrated never-implanted gamma-air PS tibial inserts to possess nonuniform mechanical properties. Despite severe oxidation along the exterior of gamma-air tibial posts, comparatively low oxidation levels at the center of the tibial posts corresponded to sufficiently high mechanical properties. XRP material (75 kGy) showed superior impact toughness over shelf aged gamma-air material; however, tibial post fatigue testing demonstrated XRP material (100 kGy) to be less resistant to fatigue failure than historical gamma-air material. Results from this study indicate that XRP materials (100 kGy) may demonstrate an inferior resistance to tibial post failure than historical polyethylene. PMID- 20845488 TI - Photochemical crosslinking of soluble wool keratins produces a mechanically stable biomaterial that supports cell adhesion and proliferation. AB - Keratins extracted from various "hard tissues" such as wool, hair, and nails are increasingly being investigated as a source of abundant, biocompatible materials. In this study we explored a recent photochemical method to crosslink solubilized wool keratoses, with the aim of producing a mechanically favorable biomaterial. Wool proteins were isolated by oxidizing the disulfides and extracting the resulting soluble keratoses. The alpha- and gamma-keratose fractions were analyzed by liquid chromatography-mass spectrometry to identify their constituent proteins. Hydrogels were produced by covalent crosslinking of the alpha-keratoses via a photo-oxidative process catalyzed by blue light, a ruthenium complex, and persulfate. The presence of dityrosine crosslinks was demonstrated by high performance liquid chromatography and mass spectrometry analyses. The crosslinked alpha-keratose material had moderate tensile strength and elasticity, and high adhesive strength. The material displayed modest shrinking after crosslinking, however the shrinking could be prevented by crosslinking in the presence of 2.5% glycerol, resulting in gels that did not shrink or swell. Small solutes such as Tris and glycerol influenced the crosslink density and elastic modulus of the crosslinked material. The alpha-keratose was able to support adhesion and growth of NIH/3T3 fibroblasts in vitro. The fabrication of mechanically stable keratin biomaterials by this facile photo-crosslinking method may be useful for various tissue engineering applications. PMID- 20845489 TI - Effects of exogenous phosphorus and silicon on osteoblast differentiation at the interface with bioactive ceramics. AB - In this study, we have investigated the effects of dissolved phosphorus and silicon on osteoblast differentiation in vitro. Neonatal rat calvarial osteoblasts were seeded on silica-calcium phosphate composites (SCPCS), hydroxyapatite (HA-200), and tissue culture polystyrene (TCPS) and incubated over 4 days in media containing 0 {minimal essential medium [MEM] (-)} or 3 mM beta glycerophosphate [MEM (+)]. Inductively coupled plasma analysis showed that P content in original MEM (+) was 225% higher than that in MEM (-). Moreover, P content in MEM (+) significantly increased to 3.4-4.4 mM and 3.6-4.7 mM after 2 and 4 days incubation with SCPC, respectively, owing to material dissolution and exogenous phosphate supplementation. In contrast, P-content in MEM (+) showed no change upon incubation with HA or TCPS. The P-content in MEM (-) incubated with SCPC was considerably lower than that in MEM (+). SCPC exhibited controlled Si release in cell culture media [MEM (-) or MEM (+)], with Si-rich SCPC showing a significantly greater dissolution than Si-poor SCPC. Moreover, SCPC, unlike HA, demonstrated a cell- and solution-mediated dissolution over 4 days. Quantitative real-time PCR showed that in MEM (-), osteocalcin and osteopontin mRNA expression on Si-rich SCPC was significantly greater than that on HA, suggesting that Si plays an important role in enhancing bone-cell differentiation. However, osteoblast phenotypic expression on SCPC was significantly decreased after 4 days incubation in MEM (+), indicating that sustained exposure to elevated P-levels in the media can downregulate osteoblast function. Our results demonstrate that the controlled dissolution of SCPC provides a natural stimulus for bone-cell differentiation in vitro and could obviate the need of exogenous phosphate supplementation. PMID- 20845490 TI - Innovative macroporous granules of nanostructured-hydroxyapatite agglomerates: bioactivity and osteoblast-like cell behaviour. AB - To modulate the biological response of implantable granules, two types of bioactive porous granules composed of nanostructured-hydroxyapatite (HA) agglomerates and microstructured-HA, respectively, were prepared using a polyurethane sponge impregnation and burnout method. The resulting granules presented a highly porous structure with interconnected porosity. Both types of granules were characterized using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and mercury intrusion porosimetry. Results showed that nanostructed-HA granules presented higher surface area and porosity than microstructured-HA granules. In vitro testing using MG63 human osteoblast-like cells showed that on both types of surfaces cells were able to adhere, proliferate, and migrate through the macropores, and a higher growth rate was achieved on nanostructured-HA granules than on microstructured-HA granules (76 and 40%, respectively). In addition, these cells maintained similar expression levels of osteoblastic-associated markers namely collagen type I, alkaline phosphatase, bone morphogenetic protein 2, macrophage colony-stimulating factor, and osteoprotegerin. These innovative nanostructured-HA granules may be considered as promising bioceramic alternative matrixes for bone regeneration and drug release application. PMID- 20845491 TI - Effect of three-dimensional expansion and cell seeding density on the cartilage forming capacity of human articular chondrocytes in type II collagen sponges. AB - Chondrocytes for tissue engineering strategies are typically expanded in monolayer (2D), leading to cell dedifferentiation but allowing to generate large cell numbers for seeding into scaffolds. Direct chondrocyte culture in scaffolds, instead, may support better maintenance of the differentiated phenotype but reduce the extent of proliferation and thus the resulting cell density. This study investigates whether the quality of cartilaginous tissues generated in vitro by human articular chondrocytes (HAC) on type II collagen sponges is enhanced (1) by direct expansion on the scaffolds (3D), as compared with standard 2D, or (2) by increasing cell seeding density, which in turn requires extensive 2D expansion. Three-dimensional expansion of HAC on the scaffolds, as compared with 2D expansion for the same number of doublings, better maintained the chondrocytic phenotype of the expanded cells (13.7-fold higher levels of type II collagen mRNA) but did not enhance their accumulation of glycosaminoglycan (GAG) following chondrogenic culture. Instead, increasing the HAC seeding density in the scaffolds (from 25 * 10(3) to 66 * 10(3) cells/mm(3)) significantly improved chondrogenesis (up to 3.3-fold higher GAG accumulation and up to 9.3-fold higher type II collagen mRNA), even if seeded cells had to be expanded and dedifferentiated more extensively in 2D to reach the required cell numbers. This study indicates that, under the specific conditions tested, a high-seeding density of HAC in 3D scaffolds is more critical for the generation of cartilaginous constructs than the stage of cell differentiation reached following expansion. PMID- 20845492 TI - Latex use as an occlusive membrane for guided bone regeneration. AB - Latex extracted from Hevea brasiliensis was used as an occlusive membrane for guided bone regeneration. Twenty-four rabbits were divided in two groups: treated and control group. Critical size bone defects (2 cm * 1 cm) were surgically made in the rabbit calvarium. Two latex membranes were implanted in each animal of the treated group, whereas the control defect was filled only with autogenous blood clot. After 15, 30, 60, and 120 days, animals from each group were euthanized, and the samples with regenerated bone were removed. No signs of allergy or rejection were noticed around the calvarial bone defect of the treated group. In the histological analysis, no foreign body inflammatory reaction was observed in the adjacent tissues in contact with the membranes demonstrating that latex can be used at injured sites as an aid in the healing process. Histological analysis, digital radiography, and electron spin resonance were used to evaluate the progress of bone repair. The results show significant differences between groups (p < 0.05) suggesting that latex membranes accelerates healing in critical bone defects. PMID- 20845493 TI - Modifications of a calcium phosphate cement with biomolecules--influence on nanostructure, material, and biological properties. AB - Calcium phosphate cements (CPC), forming hydroxyapatite during the setting reaction, are characterized by good biocompatibility and osteoconductivity, however, their remodeling into native bone tissue is slow. One strategy to improve remodeling and bone regeneration is the directed modification of their nanostructure. In this study, a CPC was set in the presence of cocarboxylase, glucuronic acid, tartaric acid, alpha-glucose-1-phosphate, L-arginine, L-aspartic acid, and L-lysine, respectively, with the aim to influence formation and growth of hydroxyapatite crystals through the functional groups of these biomolecules. Except for glucuronic acid, all these modifications resulted in the formation of smaller and more agglomerated hydroxyapatite particles which had a positive impact on the biological performance indicated by first experiments with the human osteoblast cell line hFOB 1.19. Moreover, adhesion, proliferation, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSC) as well as binding of the growth factors BMP-2 and VEGF was investigated on CPC modified with cocarboxylase, arginine, and aspartic acid. Initial adhesion of hBMSC was improved on these three modifications and proliferation was enhanced on CPC modified with cocarboxylase and arginine whereas osteogenic differentiation remained unaffected. Modification of the CPC with arginine and aspartic acid, but not with cocarboxylase, led to a higher BMP-2 binding. PMID- 20845494 TI - Cytoskeletal dynamics in response to tensile loading of mammalian axons. AB - In response to an applied tensile load, axons of cultured neurons exhibit a number of morphological responses. We designed and implemented a cell stretching device to study the cellular mechanisms governing these responses. Rat sensory neurons were seeded onto a flexible silicone substrate and imaged during substrate stretch. The positions of stationary mitochondria, docked to the axonal cytoskeleton, were determined before and after 10% stretch, and used to calculate the resulting "instantaneous" strain in regions of the axon. There was dramatic heterogeneity in strain along the length of the stretched axons, particularly in regions shorter than 20 MUm. The substrate was then held at 10% strain and the axons imaged for 20 min during "relaxation." Both strain magnitude and variability were larger at small lengths in stretched axons during the initial phase of relaxation, but after 14 min, decreased to levels smaller than those seen in unstretched axons. Mitochondrial pairs in stretched axons showed uncoordinated movement with each other at all lengths, suggesting that cytoskeletal cohesion is reduced after stretch. Collectively, these data present the axonal cytoskeleton as a dynamic structure, which responds to stretch rapidly and locally. Globally, the axon behaves as a viscoelastic continuum. Below a characteristic length, though, it appears to behave as a series of independent linked elements, each with unique mechanical properties which suggests a length scale within which cytoskeletal structural elements may be altered to modulate the biomechanical response of the axon. Finally, testable hypotheses of strain accomodation in the axon are suggested. PMID- 20845495 TI - Binding of proteins to ultra high molecular weight polyethylene wear particles as a possible mechanism of macrophage and lymphocyte activation. AB - Binding of five human plasma proteins (IgG, serum albumin, alpha(1)-acid glycoprotein, holo-transferrin, alpha(1)-antitrypsin) to ultra high molecular weight polyethylene wear particles (0.1-10 MUm) isolated from hip periprosthetic tissues was studied in vitro. All tested plasma proteins were bound to wear particles in a similar way indicating irreversible binding. Analogous interaction was found also between GUR 4120 particles (diameter ~250 MUm) and two tested plasma proteins (human serum albumin and alpha(1)-acid glycoprotein). The binding was not affected by pH of a buffer or the isoelectric point of bound proteins; thus it was apparently of clearly hydrophobic nature. We hypothesize that the binding causes some unfolding of the bound proteins, thus exposing new determinants with which sensitive cells may react. This could be a mechanism by which polyethylene wear particles trigger, for example, macrophages activity and thence initiate aseptic inflammation and cause the failure of total joint replacements. Results can contribute to the choice of a convenient construction type of prostheses. PMID- 20845496 TI - In vivo behavior of trimethylene carbonate and epsilon-caprolactone-based (co)polymer networks: degradation and tissue response. AB - The in vivo erosion behavior of crosslinked (co)polymers based on trimethylene carbonate (TMC) and epsilon-caprolactone (CL) was investigated. High molecular weight poly(trimethylene carbonate) (PTMC) homopolymer- and copolymer films were crosslinked by gamma irradiation. To adjust the in vivo erosion rate of the (co)polymer films, both the irradiation dose (25, 50, or 100 kGy) for PTMC and composition (100-70 mol % TMC) at a constant irradiation dose of 25 kGy were varied. After subcutaneous implantation of irradiated films in rats, their in vivo behavior was evaluated qualitatively and quantitatively. When the irradiation dose for PTMC was increased from 25 to 100 kGy, the erosion rate of nonextracted PTMC films (determined at day 5) decreased from 39.7 +/- 16.0 MUm day(-1) to 15.1 +/- 2.5 MUm day(-1), and the number of lymphocytes in the tissue surrounding the films decreased from 235 +/- 114 cells mm(-2) to 64 +/- 33 cells mm(-2). The number of macrophages and giant cells at the tissue-polymer interface also decreased with increasing irradiation dose. All (co)polymer films eroded completely within 28 days of implantation. Variation of the TMC content of gamma irradiated (co)polymer films did not affect the tissue response to the gamma irradiated (co)polymer films and their in vivo erosion behavior much. PMID- 20845497 TI - Enhancement of bone formation by BMP-7 transduced MSCs on biomimetic nano hydroxyapatite/polyamide composite scaffolds in repair of mandibular defects. AB - This study was to evaluate enhanced bone formation by bone morphogenetic protein 7 (BMP-7) transduced MSCs on nano-hydroxyapatite/polyamide (n-HA/PA) composite scaffolds for bone tissue engineering in repair of mandibular defect. n-HA/PA scaffolds were prepared and rabbit MSCs were separated and expanded; and then infected with adenoviral-mediated BMP-7 in vitro. The MSCs-BMP-7 and MSCs were seeded on the porous scaffolds. Scaffold/MSCs-BMP-7 constructs and scaffold/MSCs constructs were implanted in the defects of rabbits' mandible as the experimental groups A (n = 18) and groups B (n = 18), respectively, the pure scaffolds were implanted as controls (group C, n = 18). Six animals were sacrificed at 4-, 8-, and 16-week postimplantation, respectively. Their mandibles were removed and processed for radiographic, biomechanical tests, histological, and histomorphometric analysis. Group A animals showed greater bone formation and earlier mineralization than group B at 4- and 8-week postimplantation and similarly group B more than group C. However, no difference was found among three groups at 16-week postimplantation. The results of this study suggest that BMP-7 transduced MSCs-n-HA/PA composite could significantly accelerate bone formation in the implant at early stage. BMP-7 mediated ex vivo gene transfer based on MSCs as seed cells, combined with porous n-HA/PA as scaffolds for bone tissue engineering might be an alternative or supplemental approach to repair the mandibular defects. PMID- 20845498 TI - Particulate gold as an anti-inflammatory mediator in bone allograft---an animal study. AB - Morselized allograft is widely used when increased bone stock is needed in implant surgery. Gold ions liberated from metallic gold surfaces act in an anti inflammatory manner by inhibiting cellular NF-kappaB-DNA binding and suppressing I-kappa B-kinase activation. This study investigated the effect of 45-63 MUm sized gold particles mixed in morselized allograft. It was hypothesized that bio released gold ions would influence allograft reabsorption, increase mechanical stability, and further stimulate osseointegration. A pair of 10 mm long implants surrounded by a 2.5-mm gap was inserted in proximal part of each humerus in 10 sheep. Each gap was filled with morselized allograft with 1.29 mg gold particles or nothing. Observation time was 12 weeks. The gold ion liberation was visualized by autometallographic tracing and showed liberation of gold ions. Biomechanical push-out tests and stereological histomorphometric analyses showed no statistically significant differences in the two groups. Although particulate gold was primarily observed surrounded by bone marrow tissue, no obvious clinically relevant short-term effects could be measured using gold as an anti inflammatory mediator. These findings show that the released gold ions have only influenced cells adjacent to the particles without influencing the fixation and illustrates gold ions' limited field of effect. We suggest a new design for orthopedic implants by introducing gold dots on the prosthesis surface. This aims at suppressing the inflammatory foci along the implant-bone zone and reduces the risk of chronic inflammation before aseptic loosening without affecting bone remodeling. This implant model will be investigated in further studies. PMID- 20845499 TI - Pulmonary outcome prediction for cystic fibrosis patients. PMID- 20845500 TI - The relationship of neuropsychological function to instrumental activities of daily living in mild cognitive impairment. AB - OBJECTIVE: While activities of daily living are by definition preserved in mild cognitive impairment (MCI), there is evidence of poorer instrumental activities of daily living (IADL) functioning in MCI compared to normal ageing. The aims of the present study were to examine differences in IADL between individuals with MCI and cognitively normal elderly, and to examine the relationships of IADL with cognitive functions. METHODS: The sample of 762 community-living participants aged 70-90 were assessed with a comprehensive neuropsychological test battery and with the informant-completed Bayer-Activities of Daily Living Scale (B-ADL). RESULTS: Compared to cognitively normal individuals, the MCI group was rated as having more difficulties on the B-ADL and performed worse on cognitive tests. Factor analysis of the B-ADL items yielded two factors, which were labelled 'high cognitive demand' (HCD) and 'low cognitive demand' (LCD). Individuals with MCI scored worse than cognitively normal participants on the HCD factor but similarly on the LCD factor. Men were rated as having more difficulties on the HCD, but not the LCD, factor compared to women. The HCD factor score correlated significantly with all five cognitive domains measured, but the LCD factor correlated significantly only with attention/processing speed and to a lesser extent with executive function. CONCLUSIONS: Having more difficulties in IADL, especially those with higher demand on cognitive capacities, was found to be associated with MCI and overall cognitive functioning. This has implications for the definition of MCI, as lack of functional impairment is generally used as a criterion for diagnosis. PMID- 20845501 TI - Probing the stereo-electronic properties of cationic rhodium complexes bearing chiral diphosphine ligands by 103Rh NMR. AB - (103)Rh NMR represents a powerful tool to assess the global electronic and steric contribution of diphosphine ligands on [Rh(COD)(diphosphine)](+) complexes. In the case of DIOP, BINAP and MeDUPHOS, this approach proved to be more informative than classical CO-stretching frequency measurements. After validation, this method has been extended to a set of seven diphosphines. (103)Rh NMR measurements on [Rh(COD)(diphosphine)]PF(6) lead to the following order of donor properties: dppe > MeBPE > MeDUPHOS > dppb > DIOP > BINAP > Tol-BINAP. This trend has been validated by DFT in the case of DIOP, BINAP and MeDUPHOS. In conjunction, (31)P NMR chemical shift has been shown to reflect the ring constraints of the Rh diphosphine scaffold. This contribution is a step towards a mechanistic investigation of the catalytic hydrogenation of unsaturated substrates by (103)Rh NMR and DFT. PMID- 20845502 TI - Natural orifice transluminal endoscopic surgery: where are we going? AB - The foundation for natural orifice transluminal endoscopic surgery (NOTES) is to access the peritoneal and other body cavities through the wall of the alimentary tract via natural orifices, with the goal of performing procedures within the peritoneum and other cavities, without the need to make incisions in the abdominal wall. We have made great progress in the field of NOTES since the publication of the White Paper in 2006. There are still major fundamental goals as outlined by the Society of American Gastrointestinal and Endoscopic Surgeons/American Society for Gastrointestinal Endoscopy joint committee that need to be evaluated and answered before NOTES is ready for widespread clinical use. These include prevention of infection, instrument development, creation of a multitasking platform, and the ability to recognize and treat intraperitoneal complications such as hemorrhage and other physiological adverse events. In response to this need, recent abstracts and papers have focused on the management of intraoperative complications. The next phase is to focus on controlled prospective multicenter clinical trials that compare defined NOTES procedure to standard laparoscopy. The goal is to produce reliable and convincing data for the United States Food and Drug Administration, insurance companies, the physician community and the general public. At the present time, we still have many important milestones that still need to be met. Most investigators agree that a hybrid technique and not a pure NOTES practice should be advocated until devices can meet the current and new challenges in this field. PMID- 20845503 TI - Esophagogastric junction gastrointestinal stromal tumor: resection vs enucleation. AB - Esophageal gastrointestinal stromal tumors (GISTs) are extremely uncommon, representing approximately 5% of GISTs with the majority of esophageal GISTs occurring at the esophagogastric junction (EGJ). The treatment options available for these GISTs are fairly controversial. Many different options are nowadays at our disposal. From surgery to the target therapies we have the possibility to treat the majority of GISTs, including those which are defined as unresectable. The EGJ GISTs represent a stimulating challenge for the surgeon. The anatomical location increases the possibility of post-operative complications. As the role of negative margins in GIST surgery is still controversial and the efficacy of target therapy has been demonstrated, why not treat EGJ GISTs with enucleation and, where indicated, adjuvant target therapy? PMID- 20845505 TI - Diagnosis and management of interstitial pneumonitis associated with interferon therapy for chronic hepatitis C. AB - Interstitial pneumonitis (IP) is an uncommon pulmonary complication associated with interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection. Pneumonitis can occur at any stage of HCV treatment, ranging from 2 to 48 wk, usually in the first 12 wk. Its most common symptoms are dyspnoea, dry cough, fever, fatigue, arthralgia or myalgia, and anorexia, which are reversible in most cases after cessation of IFN therapy with a mean subsequent recovery time of 7.5 wk. Bronchoalveolar lavage in combination with chest high resolution computed tomography has a high diagnostic value. Prompt discontinuation of medication is the cornerstone, and corticosteroid therapy may not be essential for patients with mild-moderate pulmonary functional impairment. The severity of pulmonary injury is associated with the rapid development of IP. We suggest that methylprednisolone pulse therapy followed by low dose prednisolone for a short term is necessary to minimize the risk of fatal pulmonary damage if signs of significant pulmonary toxicity occur in earlier stage. Clinicians should be aware of the potential pulmonary complication related to the drug, so that an early and opportune diagnosis can be made. PMID- 20845504 TI - Liver transplantation for alcoholic liver disease. AB - Alcoholic liver disease (ALD) is the second commonest indication for liver transplantation after viral hepatitis in the United States and Europe. Controversies surround the indications and allocation of scarce and expensive resource for this so called self inflicted disease. Controversies stem from the apprehension that alcoholic recipients are likely to relapse and cause damage to the graft. There is a need to select those candidates with lower risk for relapse with the available predictive factors and scores. Substance abuse specialist and psychiatrists are mandatory in the pre-transplant evaluation and in the post transplant follow-up. There is conflicting evidence to support a fixed period of pretransplant abstinence, although most units do follow this. Alcoholic hepatitis (AH) continues to be a contraindication for transplantation, however there is a need for further research in this field as a subset of patients with AH who do not respond to medical treatment, have high early mortality and could benefit from transplantation. One year, 3-year, and 5-year survival post-transplant is similar for both ALD and non-ALD recipients. The incidence of post-transplant rejection and retransplantation is also similar to other recipients. ALD with viral hepatitis especially hepatitis C virus leads to a more aggressive liver disease with early presentation for transplantation. ALD patients are more prone to develop de-novo malignancy; this is attributed to the long term effect of alcohol, tobacco combined with immunosuppression. Post-transplant surveillance is important to detect early relapse to alcoholism, presence of de-novo malignancy and treat the same adequately. PMID- 20845506 TI - Pegylated interferon alpha-2b plus ribavirin for older patients with chronic hepatitis C. AB - AIM: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) alpha-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV). METHODS: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 MUg/kg per week PEG-IFN alpha-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk. RESULTS: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN alpha-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%). CONCLUSION: PEG-IFN alpha-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage. PMID- 20845507 TI - Diagnostic value of glypican-3 in serum and liver for primary hepatocellular carcinoma. AB - AIM: To evaluate the diagnostic value of glypican-3 (GPC3) in serum and liver for primary hepatocellular carcinoma (HCC). METHODS: Serum levels of GPC3 and alpha fetoprotein (AFP) were measured in 75 patients with primary HCC and 32 patients with liver cirrhosis. Expression of GPC3 and AFP in 58 HCC and 12 cirrhotic specimens was detected with immunohistochemical staining. RESULTS: When the cut off value of serum GPC3 was set at 300 ng/L, its sensitivity and specificity for HCC were 47.0% and 93.5%, respectively. Among the 14 patients with HCC at stage according to the Barcelona Clinic Liver Cancer staging system, the serum GPC3 level was higher than 300 ng/L in 50% (7/14) patients, the serum AFP level was not >= 400 MUg/L in any patient. Combined serum AFP and GPC3 significantly increased the sensitivity to the diagnosis of HCC. The GPC3 expression was detected in cytoplasm of HCC cells but not in hepatocytes and bile ducts of benign tumors. Among the 58 HCC patients, the GPC3 was expressed in 100% (28/28) patients with their serum AFP level >= 400 MUg/L, and in 90% (27/30) patients with their AFP level < 400 MUg/L, respectively. The GPC3 was weakly or negatively expressed in all paracarcinomatous and cirrhotic tissue samples. AFP positive HCC cells were only found in 1 out of the 58 HCC patients. CONCLUSION: GPC3 protein is a sensitive and specific serum marker for diagnosis of early HCC. Its expression in liver tissues can be used to discriminate tumor cells from benign hepatic cells. PMID- 20845508 TI - Measuring episodic abdominal pain and disability in suspected sphincter of Oddi dysfunction. AB - AIM: To evaluate the reliability of an instrument that measures disability arising from episodic abdominal pain in patients with suspected sphincter of Oddi dysfunction (SOD). METHODS: Although several treatments have been utilized to reduce pain and associated disability, measurement tools have not been developed to reliably track outcomes. Two pilot studies were conducted to assess test retest reliability of a newly developed instrument, the recurrent abdominal pain intensity and disability (RAPID) instrument. The RAPID score is a 90-d summation of days where productivity for various daily activities is reduced as a result of abdominal pain episodes, and is modeled after the migraine disability assessment instrument used to measure headache-related disability. RAPID was administered by telephone on 2 consecutive occasions in 2 consenting populations with suspected SOD: a pre-sphincterotomy population (Pilot I, n = 55) and a post-sphincterotomy population (Pilot II, n = 70). RESULTS: The average RAPID scores for Pilots I and II were: 82 d (median: 81.5 d, SD: 64 d) and 48 d (median: 0 d, SD: 91 d), respectively. The concordance between the 2 assessments for both populations was very good: 0.81 for the pre-sphincterotomy population and 0.95 for the post sphincterotomy population. CONCLUSION: The described pilot studies suggest that RAPID is a reliable instrument for measuring disability resulting from abdominal pain in suspected SOD patients. PMID- 20845509 TI - Decreased serum essential and aromatic amino acids in patients with chronic pancreatitis. AB - AIM: To investigate the influence of chronic pancreatitis (CP) on serum concentrations of amino acids. METHODS: Thirty-five male patients with alcoholic CP and 21 healthy male subjects were examined. Serum concentrations of amino acids were assayed by ion-pair high-performance liquid chromatography with mass detection. RESULTS: Serum glutamate concentration was increased in CP patients as compared to controls. In contrast, serum concentrations of glutamine, histidine, tyrosine, proline, tryptophan and threonine were significantly decreased in CP patients. A trend towards decreasing concentrations of serum lysine, alanine, methionine and valine as well as for total serum amino acids was observed. The sum of aromatic and the sum of essential amino acid concentrations were significantly lower in CP patients than in controls. CONCLUSION: CP leads to decreased serum concentrations of several amino acids, such as essential and aromatic serum amino acids, most likely due to decreased exocrine function. PMID- 20845510 TI - Exercise-provoked esophageal motility disorder in patients with recurrent chest pain. AB - AIM: To investigate the relationship between exercise-provoked esophageal motility disorders and the prognosis for patients with chest pain. METHODS: The study involved 63 subjects with recurrent angina-like chest pain non-responsive to empirical therapy with proton pump inhibitor (PPI). In all, a coronary artery angiography, panendoscopy, 24-h esophageal pH-metry and manometry, as well as a treadmill stress test with simultaneous esophageal pH-metry and manometry monitoring, were performed. Thirty-five subjects had no significant coronary artery lesions, and 28 had more than 50% coronary artery narrowing. In patients with hypertensive esophageal motility disorders, a calcium antagonist was recommended. The average follow-up period was 977 +/- 249 d. RESULTS: The prevalence of esophageal disorders, such as gastroesophageal reflux or diffuse esophageal spasm, was similar in patients both with and without significant coronary artery narrowing. Exercise prompted esophageal motility disorders, such as a decrease in the percentage of peristaltic and effective contractions and their amplitude, as well as an increase in the percentage of simultaneous and non effective contractions. In 14 (22%) patients the percentage of simultaneous contractions during the treadmill stress test exceeded the value of 55%. Using Kaplan-Meier analysis and the proportional hazard Cox regression model, it was shown that the administration of a calcium channel antagonist in patients with such an esophageal motility disorder significantly decreased the risk of hospitalization as a result of a suspicion of acute coronary syndrome after the 2.7-year follow-up period. CONCLUSION: In patients with chest pain non-responsive to PPIs, a diagnosis of exercise-provoked esophageal spasm may have the effect of lowering the risk of the next hospitalization. PMID- 20845512 TI - Clinical significance of Helicobacter pylori cagA and iceA genotype status. AB - AIM: To study the presence of Helicobacter pylori (H. pylori) virulence factors and clinical outcome in H. pylori infected patients. METHODS: A prospective analysis of ninety nine H. pylori-positive patients who underwent endoscopy in our Endoscopy suite were included in this study. DNA was isolated from antral biopsy samples and the presence of cagA, iceA, and iceA2 genotypes were determined by polymerase chain reaction and a reverse hybridization technique. Screening for H. pylori infection was performed in all patients using the rapid urease test (CLO-Test). RESULTS: From a total of 326 patients who underwent endoscopy for upper gastrointestinal symptoms, 99 patients were determined to be H. pylori-positive. Peptic ulceration was seen in 33 patients (33%). The main virulence strain observed in this cohort was the cagA gene isolated in 43 patients. cagA was associated with peptic ulcer pathology in 39.5% (17/43) and in 28% (16/56) of non-ulcer patients. IceA1 was present in 29 patients (29%) and iceA2 in 15 patients (15%). Ulcer pathology was seen in 39% (11/29) of patients with iceA1, while 31% (22/70) had normal findings. The corresponding values for iceA2 were 33% (5/15) and 33% (28/84), respectively. CONCLUSION: Virulence factors were not common in our cohort. The incidence of factors cagA, iceA1 and iceA2 were very low although variations were noted in different ethnic groups. PMID- 20845511 TI - High-dose-rate intraluminal brachytherapy during preoperative chemoradiation for locally advanced rectal cancers. AB - AIM: To determine the feasibility and safety of high dose rate intraluminal brachytherapy (HDR-ILBT) boost during preoperative chemoradiation for rectal cancer. METHODS: Between 2008 and 2009, thirty-six patients with locally advanced rectal cancer (>= T3 or N+), were treated initially with concurrent capecitabine (825 mg/m(2) oral twice daily) and pelvic external beam radiotherapy (EBRT) (45 Gy in 25 fractions), then were randomized to group A; HDR-ILBT group (n = 17) to receive 5.5-7 Gy * 2 to gross tumor volume (GTV) and group B; EBRT group (n = 19) to receive 5.4 Gy * 3 fractions to GTV with EBRT. All patients underwent total mesorectal excision. RESULTS: Grade 3 acute toxicities were registered in 12 patients (70.6%) in group A and in 8 (42.1%) in group B. Complete pathologic response of T stage (ypT0) in group A was registered in 10 patients (58.8%) and in group B, 3 patients (15.8%) had ypT0 (P < 0.0001). Sphincter preservation was reported in 6/9 patients (66.7%) in group A and in 5/10 patients (50%) in group B (P < 0.01). Overall radiological response was 68.15% and 66.04% in Group A and B, respectively. During a median follow up of 18 mo, late grade 1 and 2 sequelae were registered in 3 patients (17.6%) and 4 patients (21.1%) in the groups A and B, respectively. CONCLUSION: HDR-ILBT was found to be effective dose escalation technique in preoperative chemoradiation for rectal cancers, with higher response rates, downstaging and with manageable acute toxicities. PMID- 20845513 TI - p73 G4C14 to A4T14 polymorphism is associated with colorectal cancer risk and survival. AB - AIM: To analyze the association between the p73 G4C14-to-A4T14 polymorphism (a.k.a., the GC/AT variation) and colorectal cancer risk and survival in the Korean population, and to evaluate the relationships between p73 polymorphism and the p73 protein expression or clinicopathological characteristics of colorectal cancer. METHODS: Three hundred and eighty-three histologically confirmed cases and 469 healthy controls, recruited at one teaching hospital in Pusan, Korea from 2001 and 2007, were genotyped for p73 G4C14-to-A4T14 by PCR with confronting two pair primers (PCR-CTPP) and the expression profile of p73 in cancer tissues (n = 383) was analyzed by immunohistochemistry. RESULTS: Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression model adjusted for age and gender. Compared with the GC/GC genotypes, the GC/AT and AT/AT genotypes were significantly associated with colorectal cancer risk (GC/AT vs GC/GC: OR = 1.46, 95% CI: 1.10-1.94; AT/AT vs GC/GC: 1.72, 0.98-3.03; P(trend) = 0.01). When stratified by age and gender, the association was restricted to those less than 60 years of age (GC/AT or AT/AT vs GC/GC: 2.22, 1.39-3.55) and male (GC/AT or AT/AT vs GC/GC: 1.91, 1.31-2.77). The expression of p73 was associated with invasion depth (P = 0.003) and advanced Duke's stage (P = 0.06) of colorectal cancer. The patients with the GC/GC genotype were associated with worse survival compared with those with the other genotypes (P = 0.02). However, no significant relationship was observed between the p73 G4C14-to-A4T14 polymorphism and p73 protein expression in cancer tissues. CONCLUSION: Our results suggest that the p73 GC/AT polymorphism is associated with an increased colorectal cancer risk and survival in the Korean population. PMID- 20845514 TI - Antacid effects of Chinese herbal prescriptions assessed by a modified artificial stomach model. AB - AIM: To assess the antacid effects of the tonic Chinese herbal prescriptions, si jun-zi-tang (SJZT) and shen-ling-bai-zhu-san (SLBZS). METHODS: Decoctions of the tonic Chinese herbal prescriptions, SJZT and SLBZS, were prepared according to Chinese original documents. The pH of the prescription decoctions and their neutralizing effects on artificial gastric acids were determined and compared with water and the active controls, sodium bicarbonate and colloidal aluminum phosphate. A modified model of Vatier's artificial stomach was used to determine the duration of consistent neutralization effect on artificial gastric acids. The neutralization capacity in vitro was determined with the titration method of Fordtran's model. RESULTS: The results showed that both SJZT and SLBZS have antacid effects in vitro. Compared with the water group, SJZT and SLBZS were found to possess significant gastric acid neutralizing effects. The duration for consistent neutralization of SLBZS was significantly longer than that of water. Also, SLBZS and SJZT exhibited significant antacid capacities compared to water. CONCLUSION: SJZT and SLBZS were consistently active in the artificial stomach model and are suggested to have antacid effects similar to the active control drugs. PMID- 20845515 TI - Evaluation of cross-reactive antibody response to HVR1 in chronic hepatitis C. AB - AIM: To evaluate the presence and cross-reactive antibodies against hypervariable region 1 (HVR1) in hepatitis C virus (HCV) infected patients and its relationship with the progression of the disease. METHODS: Sixteen representative HVR1 proteins selected from a unique set of 1600 natural sequences were used to semiquantitate the cross-reactivity of HVR1 antibodies in the sera of HCV patients. Fifty-five chronic HCV patients including 23 with asymptomatic mild hepatitis, 18 with chronic hepatitis and 16 with liver cirrhosis patients were studied. RESULTS: The degree of the cross-reactivity of anti-HVR1 antibodies in 23 patients with mild asymptomatic hepatitis was 3.09 +/- 2.68, which was significantly lower than in those with chronic hepatitis (5.44 +/- 3.93, P < 0.05) and liver cirrhosis (7.44 +/- 3.90, P < 0.01). No correlation was observed between the broadness of the cross-reactivity anti-HVR1 antibodies and patient's age, infection time, serum alanine aminotransferase activity, or serum HCV-RNA concentration. It was the breath of cross-reactivity rather than the presence of anti-HVR1 antibody in HCV sera that was associated with the progression of liver disease. CONCLUSION: The broadly cross-reactive HVR1 antibodies generated in natural HCV patients can not neutralize the virus, which results in persistent infection in patients with chronic hepatitis. PMID- 20845516 TI - Diabetes mellitus and hepatocellular carcinoma: comparison of Chinese patients with and without HBV-related cirrhosis. AB - AIM: To determine the role of diabetes mellitus (DM) and other associated factors in Chinese hepatocellular carcinoma (HCC) patients with cirrhosis, compared with those HCC patients without cirrhosis, in the single setting of hepatitis B virus (HBV) infection, after other known concomitant diseases were excluded. METHODS: A total of 482 patients, treated at the China-Japan Friendship Hospital, Ministry of Health (Beijing, China), in the period January 2003 to June 2009, and with a hospital discharge diagnosis of HCC, were included. Demographic, clinical, laboratory, metabolic and instrumental features were analyzed. RESULTS: Of the total, 310 patients were diagnosed with HBV infection and, following the inclusion and exclusion criteria, 224 were analyzed, including 122 patients (54.5%) with cirrhosis (the case group) and 102 patients without cirrhosis (the control group). Twenty-seven patients (12.1%) were diabetic, including 19 in the case group and 8 in the control group (19/122 = 15.6% vs 8/102 = 7.8%, P = 0.077). Thirty-one possible relevant parameters were compared by univariate analysis, and 9 variables were selected for multivariable analysis, including DM (P = 0.077), past history of HBV infection (P = 0.005), total bilirubin (P < 0.001), albumin level (P < 0.001), international normalized ratio (INR) (P < 0.001), alanine aminotransferase (P = 0.050), platelet (P < 0.001), total cholesterol (P = 0.047), and LDL cholesterol (P = 0.002) levels. Diabetes showed a statistical difference by multivariable analysis [odds ratio (OR) 4.88, 95% confidence interval (CI): 1.08-21.99, P = 0.039], although no significant difference was found in univariate analysis. In addition, three cirrhosis-related parameters remained statistically different, including INR (OR 117.14, 95% CI: 4.19-3272.28, P = 0.005), albumin (OR 0.89, 95% CI: 0.80-0.99, P = 0.027), and platelet count (OR 0.992, 95% CI: 0.987-0.999, P = 0.002). CONCLUSION: Besides the three cirrhosis-related parameters, DM was found to be the sole independent factor associated with HCC in patients with HBV-related cirrhosis, compared with those without cirrhosis. PMID- 20845517 TI - HOGG1 polymorphism in atrophic gastritis and gastric cancer after Helicobacter pylori eradication. AB - AIM: To investigate the association between Ser326Cys human oxoguanine glycosylase 1 (hOGG1) polymorphism and atrophic gastritis and gastric cancer after Helicobacter pylori (H. pylori) eradication. METHODS: A total of 488 subjects (73 patients with gastric cancer, 160 with atrophic gastritis after H. pylori eradication and 255 controls) were prospectively collected. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to distinguish hOGG1 Ser326Cys polymorphism. Statistical analysis was conducted by two-sample t test for continuous variables and chi(2) test for categorical variables. Logistic regression models were used to find the risk factors for gastric cancer and atrophic gastritis. RESULTS: Neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with gastric cancer. Compared with the Ser/Ser genotype, odds ratio (OR) for Ser/Cys was 0.96, (95% CI: 0.51-1.84) and OR for Cys/Cys was 1.1 (95% CI: 0.48-2.1). No association was detected between hOGG1 polymorphism and Lauren type of gastric cancer (P = 0.61) either. However, Ser/Cys and Cys/Cys were significantly associated with atrophic gastritis with OR: 1.76 for Ser/Cys (95% CI: 1.03-3.0) and 2.38 for Cys/Cys (95% CI: 1.34-4.23). After controlling for age, gender, smoking and alcohol, there were still significant associations with OR: 2.05 for Ser/Cys (95% CI: 1.14-3.68) and 2.76 for Cys/Cys (95% CI: 1.47-5.18). CONCLUSION: HOGG1 polymorphisms (Cys/Cys and Ser/Cys) are associated with atrophic gastritis. No significant association is detected between hOGG1 polymorphisms (Cys/Cys or Ser/Cys) and gastric cancer. PMID- 20845518 TI - Paeonol inhibits tumor growth in gastric cancer in vitro and in vivo. AB - AIM: To investigate the anti-tumor effects of paeonol in gastric cancer cell proliferation and apoptosis in vitro and in vivo. METHODS: Murine gastric cancer cell line mouse forestomach carcinoma (MFC) or human gastric cancer cell line SGC 7901 was cultured in the presence or absence of paeonol. Cell proliferation was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and cell cycle and apoptosis by flow cytometry and TUNEL staining. Tumor growth after subcutaneous implantation of MFC cells in mice was monitored, and the effects of treatment with paeonol were determined. RESULTS: In vitro, paeonol caused dose-dependent inhibition on cell proliferation and induced apoptosis. Cell cycle analysis revealed a decreased proportion of cells in G0/G1 phase, with arrest at S. Paeonol treatment in gastric cancer cell line MFC and SGC-790 cells significantly reduced the expression of Bcl-2 and increased the expression of Bax in a concentration-related manner. Administration of paeonol to MFC tumor-bearing mice significantly lowered the tumor growth and caused tumor regression. CONCLUSION: Paeonol has significantly growth-inhibitory and apoptosis-inducing effects in gastric cancer cells both in vitro and in vivo. PMID- 20845519 TI - Febrile cholestatic disease as an initial presentation of nodular lymphocyte predominant Hodgkin lymphoma. AB - Febrile cholestatic liver disease is an extremely unusual presentation of Hodgkin lymphoma (HL). The liver biopsy of a 40-year-old man with febrile episodes and cholestatic laboratory pattern disclosed an uncommon subtype of HL, a nodular lymphocyte-predominant HL (NLPHL). Liver involvement in the early stage of the usually indolent NLPHL's clinical course suggests an aggressiveness and unfavorable outcome. Emphasizing a liver biopsy early in the diagnostic algorithm enables accurate diagnosis and appropriate treatment. Although rare, HL should be considered in the differential diagnosis of cholestasis. PMID- 20845520 TI - Delayed internal pancreatic fistula with pancreatic pleural effusion postsplenectomy. AB - The occurrence of pancreatic pleural effusion, secondary to an internal pancreatic fistula, is a rare clinical syndrome and diagnosis is often missed. The key to the diagnosis is a dramatically elevated pleural fluid amylase. This pancreatic pleural effusion is also called a pancreatic pleural fistula. It is characterized by profuse pleural fluid and has a tendency to recur. Here we report a case of delayed internal pancreatic fistula with pancreatic pleural effusion emerging after splenectomy. From the treatment of this case, we conclude that the symptoms and signs of a subphrenic effusion are often obscure; abdominal computed tomography may be required to look for occult, intra-abdominal infection; and active conservative treatment should be carried out in the early period of this complication to reduce the need for endoscopy or surgery. PMID- 20845521 TI - Walled-off pancreatic necrosis: wishing our pancreatitis nomenclature was correct. AB - The ultimate reason why pancreatologists have strived to establish definitions for inflammatory pathologies of the pancreas is to improve patient care. Although the Atlanta Classification has been used for around for 17 years, considerable misunderstanding of the key elements of the nomenclature still persists. While a recent article by Stamatakos et al aimed to deal with an entity not clearly defined in the 1993 document, it is replete with factual and conceptual errors as well as contradictory statements. PMID- 20845522 TI - Abstract of the 46th Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology. September 12-15, 2010. Perth, Western Australia, Australia. PMID- 20845523 TI - Abstracts of the First Eastern Asia Dermatology Congress. Fukuoka, Japan. September 30-October 3, 2010. PMID- 20845524 TI - Microwave chemistry for inorganic nanomaterials synthesis. AB - This Feature Article gives an overview of microwave-assisted liquid phase routes to inorganic nanomaterials. Whereas microwave chemistry is a well-established technique in organic synthesis, its use in inorganic nanomaterials' synthesis is still at the beginning and far away from having reached its full potential. However, the rapidly growing number of publications in this field suggests that microwave chemistry will play an outstanding role in the broad field of Nanoscience and Nanotechnology. This article is not meant to give an exhaustive overview of all nanomaterials synthesized by the microwave technique, but to discuss the new opportunities that arise as a result of the unique features of microwave chemistry. Principles, advantages and limitations of microwave chemistry are introduced, its application in the synthesis of different classes of functional nanomaterials is discussed, and finally expected benefits for nanomaterials' synthesis are elaborated. PMID- 20845525 TI - [Friedreich ataxia]. PMID- 20845526 TI - A journey shared; a task fulfilled. PMID- 20845527 TI - Mitral valve prolapse as a new finding in branchio-oto-renal syndrome. AB - We report a patient and his family, who have branchio-oto-renal (BOR) syndrome and coexisting mitral valve prolapse. A literature review of BOR syndrome failed to identify any similar families and we report this as a new observation. During the preoperative assessment of a patient with BOR syndrome, tachycardia was noted and a cardiologic examination including echocardiography revealed mitral valve prolapse. Members of his extended family were investigated, including carrying out cardiology and otolaryngology examinations to determine whether they had signs of either BOR syndrome or cardiac problems. Mitral valve prolapse was identified in five (71.4%) of the seven BOR syndrome patients in the family. Deafness was present in all patients. Distribution of the other clinical findings of the BOR syndrome patients were as follows: branchial fistula in five (71.4%), preauricular pits in four (57.1%), ear deformity in two (28.5%), renal anomalies in three (42.8%), lacrimal duct anomaly in two (28.5%) and orbital anterior compartment anomaly in one (14.2%). We conclude that mitral valve prolapse can be associated with BOR syndrome. Further large studies are needed to clarify this association. PMID- 20845528 TI - Words of wisdom. Re: Increased risk of high-grade prostate cancer among infertile men. Walsh TJ, Shembri M, Turek PJ, et al. PMID- 20845529 TI - Words of wisdom. Re: Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Scher HI, Beer TM, Higano CS, et al. Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. PMID- 20845531 TI - Quadriceps fatigue alters human muscle performance during a novel weight-bearing task. PMID- 20845530 TI - Words of wisdom. Re: Overall survival analysis of a phase II randomized controlled trial of a poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. PMID- 20845532 TI - Management of hepatocellular carcinoma: from prevention to molecular targeted therapy. Proceedings of the 3rd International Kobe Liver Symposium on HCC with an International Liver Cancer Association (ILCA) Scientific Session. Hyogo, Japan, June 6-7, 2009. PMID- 20845533 TI - Words of wisdom. Re: Effect of dutasteride on the risk of prostate cancer. Andriole GL, Bostwick DG, Brawley OW, et al. REDUCE Study Group. N Engl J Med 2010;362:1192-202. AB - In this 4-yr, multicenter, randomized, double-blind, placebo-controlled study (REDUCE), the authors compared dutasteride 0.5 mg daily to determine the risk reduction of biopsy-detectable prostate cancer (PCa). Eligible men were 50-75 yr old, had a PSA between 2.5 and 10 ng/ml, and had one negative prostate biopsy (6 12 cores) within 6 mo before inclusion.Subjects underwent a 10-core transrectal biopsy at 2 yr and 4 yr. Dutasteride resulted in an absolute risk reduction of 5.1%and a 23% relative risk reduction with no increased risk for high-grade tumors. Men on dutasteride had a 77% risk reduction for acute urinary retention and a 73% risk reduction for benign prostatic hyperplasia (BPH)-related surgery but had higher rates for erectile dysfunction (3.3%), decreased libido (1.7%), and loss of libido (0.6%) and compared to placebo. PMID- 20845534 TI - Words of wisdom. Re: Does oral antiandrogen use before leuteinizing hormone releasing therapy in patients with metastatic prostate cancer prevent clinical consequences of a testosterone flare? Oh WK, Landrum MB, Lamont EB, et al. Urology 2010;75:642-7. AB - Oh et al report their experience with 1566 metastatic prostate cancer patients treated with luteinising hormone-releasing hormone (LHRH) agonists in the area of Boston, Massachusetts, USA. Of these patients, 79.5% were given antiandrogens (bicalutamide, flutamide, or nilutamide) before the first LHRH agonist dose. The remaining patients (20.5%) did not receive antiandrogens. In all patients, complications appearing within 30 d and attributable to a flare phenomenon (fractures, spinal cord compression, bladder outlet obstruction, exacerbation of pain) were assessed retrospectively. Such complications were extremely rare (<1%) in both groups. There was no difference whether or not antiandrogens were administered. The timing of antiandrogen prescription(0-6 vs > or =7 d before starting the LHRH analogues) made no difference.The authors concluded that no evidence supports a generalised use of antiandrogens in addition to the LHRH agonists. The risks of antiandrogen therapy (hepatic,gastrointestinal, ocular, and pulmonary complications)may counterbalance the benefits of the combined therapy,which is much more expensive. PMID- 20845535 TI - Words of wisdom. Re: Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. Stillebroer AB, Mulders PFA, Boerman DC, Oyen WJG, Oosterwijk. E Eur Urol. In press. DOI: 10.1016/j.eururo.2010.03.015. AB - The authors analysed the potential use and limitations of carbonic anhydrase IX (CAIX) antigen as a marker with diagnostic and prognostic value in cases of clear cell renal cell carcinoma (ccRCC). The study reports that >95% of ccRCCs show high and homogeneous levels of CAIX expression by reverse transcription polymerase chain reaction and immunohistochemistry. Monoclonal antibody (MAb) G250 has a high affinity for the CAIX antigen. Using MAb G250 in iodine 131-G250 radioimmunoscintigraphy (RIS) and fluorodeoxyglucose F 18 positron emission tomography (PET) can detect primary ccRCC and metastatic sites through the affinity with CAIX antigen. CAIX expression in ccRCC is also presented as a significant and independent adverse predictor of survival. Finally, CAIX has a potential role as a predictor of response to immunotherapy. Seventy-eight percent of renal cell carcinomas(RCCs) responding to interleukin-2 therapy showed high CAIX-expressing primary tumours. Similarly, CAIX expression was associated with a significantly higher treatment response rate in patients with metastatic RCC who received sorafenib. PMID- 20845536 TI - Questions study on the use of pheromones in dogs and cats. PMID- 20845537 TI - Potential consequences of inhaling intranasal and aerosolized vaccines. PMID- 20845539 TI - Proceedings of the 9th Cooley's Anemia Symposium, October 21-24, 2009. PMID- 20845538 TI - Requests more information on hyperphosphatasemia study. PMID- 20845540 TI - Words of wisdom. Re: Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumours in patients who are candidates for nephron-sparing surgery. Ficarra V, Novara G, Secco S, et al. PMID- 20845541 TI - Words of wisdom. Re: Post-prostatectomy urinary incontinence: a confluence of 3 factors. Loughlin KR, Prasad MM. PMID- 20845542 TI - Words of wisdom. Re: Effect of dutasteride on the risk of prostate cancer. Andriole GL, Bostwick DG, Brawley OW, et al. PMID- 20845543 TI - Words of wisdom. Re: Phase 1 trial of high-dose exogenous testosterone in patients with castration-resistant metastatic prostate cancer. Morris MJ, Huang D, Kelly WK, et al. Eur Urol 2009;56:237-44. AB - Laboratory studies suggest that castration-resistant prostate cancer (CRPC) cell growth is suppressed by supraphysiologic doses of testosterone (T). In this study, 12 men received high doses of T transdermally for 7 d, for 4 mo, or until progression.The approach was safe and toxicity was mild, but responses were modest. Because serum T did not reach intended supraphysiologic levels, the authors urged more clinical testing. PMID- 20845544 TI - Words of wisdom. Re: Effect of dutasteride on the risk of prostate cancer. Andriole G, Bostwick D, Brawley O, et al. N Engl J Med 2010;362:1192-202. AB - This is the first published report of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial, a 4-yr, multicenter, randomized, double-blind, placebo-controlled study involving 6729 men and comparing dutasteride 0.5 mg daily to placebo. The study was similar to the Prostate Cancer Prevention Trial (PCPT) [1] with some key differences. To be eligible, men had to have a prostate specific antigen (PSA) level between 2.5 and 10 ng/ml, and a prior negative prostate biopsy (6-12 cores) within 6 mo before enrollment (vs a PSA <3.0 in PCPT); and the biopsies were at 2 and 4 yr (vs 7 yr). The primary end point was the presence of cancer on 10-core biopsy at 2 and 4 yr. Eighty-three percent of participants were biopsied(vs < 50% in PCPT). Less than 7% of cancers were diagnosed on protocol-independent biopsies (vs 52% of cancers diagnosed on for cause biopsies in PCPT). Of the 3305 men in the dutasteride group and the 3424 men in the placebo group, 659 (20%) and 858 (25%), respectively, had cancer on the follow-up biopsies-an absolute reduction of 5.1% and a relative risk reduction of 23% ( p < 0.001). There was no difference between the groups in Gleason 7-10 cancers overall. Twenty-nine patients on dutasteride had Gleason 8 10,compared with 19 on placebo ( p = 0.15). The most likely explanation for this difference was the removal of 141 more men from the trial with Gleason 5-7 cancers. Based on surveillance studies, about 7% would be upgraded to Gleason 8 10 on rebiopsy [2]. Dutasteride also decreased the rate of urinary retention (1.6% vs 6.7%: a 77.3% relative reduction). PMID- 20845545 TI - Words of wisdom. Re: Retrospective analysis of prostate cancer recurrence potential with tissue metabolomic profiles. Maxeiner A, Adkins CB, Zhang Y, et al. Prostate 2010;70:710-7. AB - The authors analysed the value of metabolomic profiles to predict biochemical progression (BP) risk in patients with prostate cancer (PCa) submitted to radical prostatectomy(RP). They retrospectively analysed 183 PCa cases submitted to RP, using an intact-tissue magnetic resonance spectroscopy(MRS) method. A high resolution, magic-angle, spinning proton MRS was used to investigate a metabolomic analysis of still-intact prostate tissue. This method allows study of chemical metabolites in their native state and control of intact tissue spectra, preserving the tissue for pathologic analysis. In this study, metabolomic profiles analysed by MRS could differentiate cases of PCa with BP after RP from clinical and pathologic-stage matched cases without BP.The major contributing factors to the observed metabolomic profiles were changes in spermine polyamines,phosphoryl choline, glutamine, inositol, and glutamate. The overall accuracy for predicting BP based on metabolomic profiles ranged from 71% to 78%. The suggestion is that PCa metabolic profiles studied at RP with MRS may provide available adjunct parameter to predict the risk of progression after surgery. PMID- 20845566 TI - [Indication for particle radiotherapy in the treatment of head and neck cancer- based on the experience at Hyogo Prefectural Particle Radiotherapy Center]. PMID- 20845567 TI - The wheels of misfortune: the street and cycles of displacement in Surabaya, Indonesia. AB - This focus of this paper is not Surabaya's increasingly free-flowing streets, but the people those streets displace. Based on research in a low-income neighbourhood, or kampung, of Indonesia's second largest city, this paper shows how the street facilitates displacement and exacerbates the marginalisation of underemployed kampung men. This argument is set against the struggles over the use of public space between Surabaya's kampung residents and the municipality since independence and is grounded through the biographical detail of seven kampung men over the ten years since the economic crisis of 1998. PMID- 20845568 TI - Sweat or no sweat: foreign workers in the garment industry in Malaysia. AB - In the last decade factory owners, in response to brand-name Corporate Social Responsibility (CSR) parameters, have joined associations that verify (through a monitoring and audit system) that management does not exploit labour. There have been no reports of violations of codes of conduct concerning Malaysian workers but for foreign workers on contract there are certain areas that have been reported. These areas, including trade union membership, the withholding of workers' passports and unsuitable accommodation, generally escape notice because auditors who monitor factory compliance do not question the terms of contracts as long as they comply with national labour standards. This paper is based on research with foreign workers in Malaysia and argues that despite the success of the anti-sweatshop movement in a global context, the neo-liberal state in Malaysia continues to place certain restrictions on transnational labour migrants which breach garment industry codes of conduct. Available evidence does not support the assumption that CSR practices provide sufficient protection for both citizen and foreign workers on contract in the garment industry. PMID- 20845570 TI - [Health service research (1): At the start of the series]. PMID- 20845569 TI - [Social factors determining health (3) "Behavioral problems of children"]. PMID- 20845571 TI - How sex became gender. AB - This article argues that "sex" which had been commonly assumed in the West to refer to a permanent set of biological and behavioural traits particular to men and women, is gradually being replaced in general usage by "gender." Though feminist theorists attempted to attach a constructivist meaning to gender, a generation of developmental theorists, clinicians and analysts has imbued the term with the determinism and biological qualities formerly ascribed to "sex." The triumph of this materialist conception of gender is not assured, but it threatens our ability to think about gender identity as a historically constructed category. PMID- 20845572 TI - Introduction to William Stephenson's quest for a science of subjectivity. AB - In this introduction to the life and work of William Stephenson my aim is to provide a general overview of the development of his thinking and, more specifically, to highlight the importance he attached to the study of single cases. I also attempt to provide a context for an understanding of the significance of his "Tribute to Melanie Klein." Some of the principal reasons for Stephenson's marginal status in the discipline of psychology will also emerge in the course of the article. I begin by outlining some of the central notions in Q methodology. The early sections of the article trace his roots in the north of England - the setting for his schooling and university training in physics - and then outline his encounters with Charles Spearman and Cyril Burt at University College London. The subsequent section deals with his time at the University of Oxford Institute of Experimental Psychology and the wartime interruption to his career. The next few sections take us across the Atlantic and describe some of the most significant features of his work on Q-methodology. these sections also record the difficulties Stephenson experienced before he eventually secured a tenured position at the University of Missouri School of Journalism in Columbia. In the final section I attempt to situate Q-methodology in relation to some of the principal theoretical orientations in the human sciences. PMID- 20845573 TI - The equally wonderful field: Ernst Mayr and organismic biology. AB - Biologists in the 1960s witnessed a period of intense intra-disciplinary negotiations, especially the positioning of organismic biologists relative to molecular biologists. The perceived valorization of the physical sciences by "molecular" biologists became a catalyst creating a unified front of "organismic" biology that incorporated not just evolutionary biologists, but also students of animal behavior, ecology, systematics, botany - in short, almost any biological community that predominantly conducted their research in the field or museum and whose practitioners felt the pinch of the prestige and funding accruing to molecular biologists and biochemists. Ernst Mayr, Theodosius Dobzhansky, and George Gaylord Simpson took leading roles in defending alternatives to what they categorized as the mechanistic approach of chemistry and physics applied to living systems - the "equally wonderful field of organismic biology." Thus, it was through increasingly tense relations with molecular biology that organismic biologists cohered into a distinct community, with their own philosophical grounding, institutional security, and historical identity. Because this identity was based in large part on a fundamental rejection of the physical sciences as a desirable model within biology, organismic biologists succeeded in protecting the future of their field by emphasizing deep divisions that ran through the biological sciences as a whole. PMID- 20845574 TI - Cementing the enemy category: arrest and imprisonment of German Jews in Nazi concentration camps, 1933-8/9. AB - Understandably, research has focused overwhelmingly on Jews in the camps of the Holocaust. But the nazis had been detaining Jews in concentration camps ever since 1933, at times in large numbers. Who were these prisoners? This article analyzes nazi policies that brought Jews into the concentration camps. It ventures into the inner structure and dynamics of one of the most heterogeneous groups of concentration camp inmates. By contrasting the perpetrators' objectives with the victims' experiences, this article will illuminate the role of the concentration camp as the ultimate means of pressure in the fatal process of turning a minority group into an outsider group: that is, the act of defining and marking the enemy which was the critical stage before the destruction of European Jewry. Furthermore, it will examine Jewish reactions to SS terror inside the camps. PMID- 20845575 TI - Cultural behaviour and the invention of traditions: music and musical practices in the early concentration camps, 1933-6/7. AB - This article investigates music in the concentration camps before the second world war. For the camp authorities, ordering prisoners to sing songs or play in orchestras was an instrument of domination. But for the prisoners, music could also be an expression of solidarity and survival: inmates could retain a degree of their own agency in the pre-war camps, despite the often unbearable living conditions and harsh treatment by guards. The present article emphasizes this ambiguity of music in the early camps. It illustrates the emergence of musical traditions in the pre-war camps which came to have a significant impact on everyday life in the camps. It helps to overcome the view that concentration camp prisoners were simply passive victims. PMID- 20845576 TI - Suicide in Nazi concentration camps, 1933-9. AB - Too often histories of the concentration camps tend to be ignorant of the wider political context of nazi repression and control. This article tries to overcome this problem. Combining legal, social and political history, it contributes to a more thorough understanding of the changing relationship between the camps as places of extra-legal terror and the judiciary, between nazi terror and the law. It argues that the conflict between the judiciary and the SS was not a conflict between "good" and "evil," as existing accounts claim. Rather, it was a power struggle for jurisdiction over the camps. Concentration camp authorities covered up the murders of prisoners as suicides to prevent judicial investigations. This article also looks at actual suicides in the pre-war camps, to highlight individual inmates' reactions to life within the camps. The article concludes that the history of the concentration camps needs to be firmly integrated into the history of nazi terror and the Third Reich. PMID- 20845577 TI - The role of the concentration camps in the Nazi repression of prostitutes, 1933 9. AB - This article uses prostitutes as a case study in order to investigate the role of the early concentration camps as centres of detention for social deviants. In contrasting the intensification of repressive policies towards prostitutes against narratives which demonstrate the unexpectedly lax treatment of these women, it explores what the reasons behind these contradictions might have been, and what this demonstrates about the development of these institutions. It asks the following questions. How and why were prostitutes interned? Which bureaucrats were responsible for incarcerating these women and what did they view the role of the camp to be? Were such policies centrally directed or the product of local decision-making? Through asking these questions, the article explores to what extent these camps were unique as mechanisms for the repression and marginalization of prostitutes. PMID- 20845578 TI - Football in inter-war Northern Ireland: Ballymena Football and Athletic Club Limited - religious and political exclusivity or civic inclusivity? AB - Historians have almost universally seen association football in the north of Ireland as a divisive influence. The impacts of sectarian and political tensions on the game have been stressed, alongside the extent to which this sport supposedly feeds into existing divisions. Much of the work carried out has concentrated on the last four decades, though even studies outside this period of widespread civil disorder have highlighted these problems. This paper uses the surviving records of the Ballymena Football and Athletic Club, the local press, census returns and other records to consider aspects of one particular Northern Irish club in the 1920s and 1930s. This short consideration of the players, supporters and shareholders suggests that at least in this case football was successful in bringing together and developing cooperation between men of widely differing political and religious views. While the club was a not a financial success, it was a social and sporting one. The evidence available suggests there was little exhibition of sectarian tension at any level. PMID- 20845579 TI - The pan-cardiovascular syndrome - venous thromboembolism and atherothrombotic vascular disease. PMID- 20845580 TI - Trinity mysteries: university, elite schooling and sport in Ireland. AB - The development of sport in Ireland was, contrary to some arguments, highly influenced by English examples and Anglo-Irish institutions. Trinity College and prestigious Irish schools did have an impact, as did the number of Irish students sent to England for public school or university education. Athleticism was evident in Ireland as it was in England. Although the development of soccer did follow a slightly different trajectory from other sports, as was also the case in both England and Scotland, this does not mean that it departed from this broad evolutionary model of Irish sport. Yet this was Ireland: and Ireland was different. As opposition to British rule intensified, forms of sporting participation took on more and more of a national symbolism. The outcome was the emergence of a very potent form of athleticism: an Irish athleticism for an Irish people. PMID- 20845581 TI - The cultural bond? Cricket and the imperial mission. AB - Cricket tours provide an excellent insight into the relationship between the colonies and England during the Imperial era. New Zealand has never had much of a cricketing legacy, but the game was still cherished and English tours were enthusiastically followed because they provided a link with 'home'. Two English cricket teams visited New Zealand in the Edwardian age, the Lord Hawke XI in 1902 03 and the MCC in 1906-07. These tours were intended to be a panacea for a struggling local game while providing an extension of the cultural bonds of Empire. Both tours were rich in Imperial code and ceremony but their impact was lost in translation. The Lord Hawke XI, although all conquering, failed to win the hearts and minds of the New Zealand public because of a series of on-field moments of poor sportsmanship, and the public response to the treatment of the professionals in the team. The MCC team provided a fair challenge to New Zealand team, but lacked the star appeal of the Lord Hawke team, leaving the public somewhat underwhelmed. Both tours exemplify the difficulty in balancing the ideals inherent in the game with the realities of colonial sporting expectation. PMID- 20845582 TI - Activist emotions: gay radicalism and melancholic attachments. AB - It has been argued recently that Australian historians have overlooked histories of emotion. In this article, through the life-history analysis of two long standing Sydney gay activists, I trace the emotional currents of radical gay activism and suggest these histories point to a wider story of Left melancholy in the closing decades of the twentieth century. I argue that their melancholia is not a trauma-like despair but surprisingly is tinged with a sustaining hope. PMID- 20845583 TI - Colonial judiciaries, Aboriginal protection and South Australia's policy of punishing "with exemplary severity". AB - The ways in which Europeans experienced the legal system for crimes against Aboriginal people needs more systematic research. Although for the first fifty years of Australian settlement Aboriginal legal status was protractedly ambiguous, the foundational principle of later-established South Australia was that Aboriginal people were British subjects and settler crimes against them would be punished 'with exemplary severity'. This paper puts this foundational principle to the test by examining the working of the legal system where Europeans were investigated for the deaths of Aboriginal people. Ultimately, we argue, the principle of protecting Aboriginal people as British subjects not only failed, but became inverted into a principle of Aboriginal punishment. PMID- 20845584 TI - Pathologising white male sexuality in late nineteenth-century Australia through the medical prism of excess and constraint. AB - This paper will explore the constructions of white male sexuality in late nineteenth-century Australia by the medical profession. In a period where female sexuality was always suspect, male sexuality, too, was brought into question, and the male body was increasingly constructed as vulnerable to sexual excess and sexual pathology. If male sexuality was to be active and dynamic, this could readily go too far, rendering men merely a slip away from deviance. Here, I will consider these notions of excess and constraint through an examination of sexual norms and perceived perversions, including sexual excess, sodomy and masturbation. PMID- 20845585 TI - Welfare impact of a ban on child labor. AB - This article presents a new rationale for imposing restrictions on child labor. In a standard overlapping generation model where parental altruism results in transfers that children allocate to consumption and education, the Nash-Cournot equilibrium results in suboptimal levels of parental transfers and does not maximize the average level of utility of currently living agents. A ban on child labor decreases children's income and generates an increase in parental transfers bringing their levels closer to the optimum, raising children's welfare as well as average welfare in the short run and in the long run. Moreover, the inability to work allows children to allocate more time to education, and it leads to an increase in human capital. Besides, to increase transfers, parents decrease savings and hence physical capital accumulation. When prices are flexible, these effects diminish the positive welfare impact of the ban on child labor. PMID- 20845588 TI - "That was then, but this is now": historical perspectives on intercountry adoption and domestic child adoption in Australian public policy. AB - This paper brings historical perspectives to bear on the ambivalent and contradictory position of adoption in Australian public policy. It examines the divergent histories of Australian domestic and intercountry adoption (ICA) since the mid-1970s and the impact of these histories on adoption policy in Australia. It identifies tendencies in contemporary ICA to repeat elements of pre-reform era domestic adoption. In particular, it is argued that the resistance of ICA to the move to openness in local adoption has been an unacknowledged driver of ICA for many Australian families. We offer corrective readings of the rise of ICA in relation to domestic adoption and conclude by offering alternatives for adoption policy which better align the two kinds of adoption, focusing on the needs of children, as distinct from the desires of adults. PMID- 20845589 TI - Local municipalities and progress with the delivery of basic services in South Africa. AB - In 1994, South Africa adopted the Reconstruction and Development Programme (RDP) and emphasised the delivery of services to meet basic needs. Since then great strides have been made to redress past social inequalities. However, analysis of these successes have been limited to national or provincial aggregates, when much of the responsibility for meeting the RDP commitment lies at the local government level. The need for closer investigation is nonetheless clear from continuing protests over poor service delivery. This paper aims to shed more light on delivery at a local level by using data from the 2001 Census and 2007 Community Survey. The analysis involves the construction of a service delivery index for each municipality and analysis of variance to explain the changes in service delivery over the period 2001-2007. The results show that improved service provision may require further urbanisation and densification. Also, local economic growth in itself may not be important, but it would contribute to the ability to pay for services and in that way aid delivery. PMID- 20845590 TI - Class transformation and work-life balance in urban Britain: the case of Manchester. AB - Recent years have seen an expansion in the work on the attitudes, beliefs and preferences of those middle-class groups that have accompanied the return of capital to many North American and western European city centres and their surrounding urban suburbs. Yet despite this, it is argued that there is little research linking gentrification to wider processes of social transformation, particularly debates over housing market decision-making, the balancing of work and life, and the gender division of labour within the household. It is to examining the interaction of these aspects of everyday life in a gentrifying area that this paper turns, using the example of Chorlton, a southern urban suburb of Manchester. PMID- 20845591 TI - Job accessibility, residential segregation and risk of long-term unemployment in the Paris region. AB - The research presented in this paper explores, in the French context, the hypothesis that employment problems experienced by low-skilled jobseekers are partially caused by spatial urban factors. Many low-skilled workers live in poor neighbourhoods where they are exposed to a distressed social environment and/or weak job accessibility. For reasons discussed in this article, living in such neighbourhoods may increase the duration of unemployment for jobseekers. On the basis of an empirical study, this hypothesis is tested in the Paris-Ile-de-France metropolitan area and addresses the question: all other things being equal, are low-skilled workers living in high-poverty neighbourhoods and/or neighbourhoods with low job accessibility exposed to a greater risk of long-term unemployment? PMID- 20845592 TI - Living in a mixed-income development: resident perceptions of the benefits and disadvantages of two developments in Chicago. AB - Policy-makers in several countries are turning to income- and tenure-mixing strategies in an attempt to reverse decades of social and economic isolation in impoverished urban areas. In the US city of Chicago, all high-rise public housing developments across the city are being demolished, public housing residents are being dispersed throughout the metropolitan area and 10 new mixed-income developments are being created on the footprint of former public housing complexes. Findings are presented from in-depth interviews with residents across income levels and tenures at two mixed-income developments and the paper explores residents' perceptions of the physical, psychological and social impacts of the mixed-income setting on their lives. PMID- 20845593 TI - Children's bicycle safety education does not reduce injuries. PMID- 20845594 TI - Encouraging community cycling and physical activity: a user survey of a community bicycle loan scheme. PMID- 20845595 TI - Unravelling medical locums. PMID- 20845596 TI - Is there a genetic component to hyperemesis gravidarum? PMID- 20845597 TI - A closer look at cervical smear uptake and results pre- and post- introduction of the national screening programme. AB - Prior to the introduction of a national cervical screening programme, death rates from cervical cancer in the Republic of Ireland were greater than the death rates in all other regions in Britain and Northern Ireland. The following audit compares the impact of the national cervical screening programme, established on 1 September '08, on uptake and results per age group screened before and after its implementation. This retrospective audit was carried out in a four-doctor practice with approximately 1554 GMS and 5000 private patients. Data over a ten month period in '08/'09 was collected from the practice record of cervical smears and compared to the same period in '07/'08. A cohort of 534 Irish urban women was included. A total number of 148 women were screened between October 2007 and July 2008 compared with 386 women screened over the same months in 2008/2009. Increase in uptake was most marked in the 25-44 years age group, 100 ('07-'08) vs. 303 ('08-'09). The majority of results for both time periods were negative (85% 07/08, 81% 08/09). There was a higher number of HSIL in '08-'09 (an increase from 1% to 3.37% of the total screened). This audit clearly supports the introduction of the national cervical screening programme showing both an increase in uptake and a increased pick-up of high grade lesions. PMID- 20845598 TI - The role of thyrotropin suppression in patients with differentiated thyroid carcinoma. AB - Thyroid carcinoma is the commonest endocrine malignancy. The majority of these are differentiated thyroid carcinomas, which have a good overall prognosis. Treatment includes surgical excision, radio-iodine ablation and long-term thyrotropin suppression. The degree and length of suppression required, as well as the potential side-effect remain controversial. Therefore, the aim of this study was to establish the degree of thyrotropin suppression achieved in a cohort of patients with differentiated thyroid carcinoma. A retrospective review was performed of a prospectively maintained database. All patients with a diagnosis of differentiated thyroid carcinoma between January 1998 and January 2008 were identified. Demographic data, pathological stage and the treatment that the patient received was documented. TSH and free T4 levels were identified at specific time points post-operatively. Eighty-eight patients with differentiated thyroid carcinoma were identified. Seventy patients (79.5%) were female. The mean age was 55, with a range of 18 to 79 years. The majority of patients underwent a total thyroidectomy (n=79; 89.7%) and of those 29 (32.9%) had an associated modified neck dissection. Accurate follow-up was available on forty-nine patients. TSH and free T4 were measured at 3 and 6 months, as well as at 1 and 2 years post-operatively. Adequate TSH suppression was taken at a level < 0.1 mU/L. The majority of patients (69.5%) had achieved adequate TSH suppression at 2 years. However, 65% of these same patients had a high free T4 at 2 years indicating a degree of hyperthyroidism. This study has demonstrated that TSH suppression is being adequately achieved in the majority of patients with differentiated thyroid carcinoma. However, this must be carefully weighed against the potential detrimental side-effects of long-term sub-clinical hyperthyroidism. PMID- 20845599 TI - An investigation into the use of complementary and alternative medicine in an urban general practice. AB - Several International studies have shown the substantial growth in the use of complementary and alternative medicine (CAM). However, no study in the Republic of Ireland to date has looked at its use among the population. A cross-sectional survey of 328 patients attending an urban general practice was conducted. A high number of respondents reported having visited a CAM practitioner within the past 12 months (89 patients; 27%). A significant positive association was found between CAM use and female gender (p = 0.006), middle-aged (p = 0.013), private health insurance (p = 0.016) and full time employment (p = 0.031). Massage was the most common modality used (35 patients; 39.8%), the most common reason for use was 'to treat an illness for which conventional medicine was already sought' (31 patients; 42%), a high rate of non-disclosure to GPs was found (34 patients; 41%) and personal recommendation was the most important source of information (42 patients; 53.2%). This study demonstrates the current popularity of an alternative healthcare system. PMID- 20845600 TI - Nephrogenic systemic fibrosis. AB - Nephroaenic systemic fibrosis (NSF) is a potentiallv fatal dermatiological condition found exclusively in patients with advanced renal I failure. There is minimal literature regarding the epidemiology and outcomes of patients with NSF in Ireland. A retrospective chart review was performed for all patients with NSF in Ireland. Ireland's experience with the disease was examined in light of international reports. There have been three cases of NSF in Ireland; an area which serves 1915 dialysis patients--giving a point prevalence among Irish end stage kidney disease patients of 0.002. There was a large variation in disease severity between the three patients. All three patients had significant exposure to gadolinium chelate. Caution with gadolinium administration must be exercised in patients with advanced renal failure. PMID- 20845601 TI - An outcome analysis of seventeen patients treated surgically for intractable extratemporal epilepsy. AB - We studied the outcomes of seventeen patients treated surgically for extratemporal lobe epilepsy. A retrospective case review of medical charts was performed. Seizure freedom post surgery was appraised using the Engel classification system. Post-operatively seven patients (41%) were seizure free (Engel class I), four patients were class II (23.5%), two in class III (11.76%) and four in class IV (23.5%). Three patients (17.6%) suffered traumatic injuries due to seizures. The mean duration of epilepsy prior to surgery was 12.2 years and the mean number of anti-epileptic medications given was 6.5. Seizure freedom rates for surgical treatment of extratemporal epilepsy in this centre are similar to those of other centres. Post-operative morbidity in this centre was similar to other centres. Any complications resolved with no lasting impairment. PMID- 20845602 TI - Hairball--a case of mistaken identity. AB - We report a classical presentation of trichobezoar in an 8 year old girl who was referred for consultation querying a probable abdominal neoplasm in the left upper quadrant. A large mobile mass was palpable in the left upper quadrant extending toward the umbilicus. Of note, she also had symptoms of recurrent abdominal pain, nausea, vomiting and halitosis. Although a rare occurrence, trichobezoar must be considered as a differential diagnosis in a patient who had a history of pica, presenting with an abdominal mass. PMID- 20845603 TI - Recent onset neck pain with associated neurological deficit--Pott's disease remains an important differential diagnosis. AB - The incidence of spinal tuberculosis is increasing in developed nations. In Ireland, half of all cases seen in the most recent decade for which figures are available were diagnosed in 2005-2007, the three most recent years for which there is complete data. We discuss a patient who presented with neurological complications due to destructive spinal tuberculous disease affecting the sixth cervical vertebra. PMID- 20845604 TI - Lap belt injuries in children. AB - The use of adult seat belts without booster seats in young children may lead to severe abdominal, lumbar or cervical spine and head and neck injuries. We describe four characteristic cases of lap belt injuries presenting to a tertiary children's hospital over the past year in addition to a review of the current literature. These four cases of spinal cord injury, resulting in significant long term morbidity in the two survivors and death in one child, arose as a result of lap belt injury. These complex injuries are caused by rapid deceleration characteristic of high impact crashes, resulting in sudden flexion of the upper body around the fixed lap belt, and consequent compression of the abdominal viscera between the lap belt and spine. This report highlights the dangers of using lap belts only without shoulder straps. Age-appropriate child restraint in cars will prevent these injuries. PMID- 20845605 TI - Herbal medicine--sets the heart racing! AB - The potential for pharmaceuticals to produce side effects and drug interactions is well known to medical practitioners and the lay public alike. However, the potential for alternative medicines to produce such effects is less widely known. We describe a potentially dangerous interaction between a herbal medicine and concomitant selective serotonin re-uptake inhibitor (SSRI) ingestion. PMID- 20845606 TI - Re: Using electronic mail to improve MMR uptake amongst third level students. PMID- 20845608 TI - [How and why have the old drugs changed the prognosis of patients with the primary CNS lymphoma?]. PMID- 20845607 TI - RE: Pregnant until proven otherwise. PMID- 20845609 TI - [The issue of the primary central nervous system lymphomas]. PMID- 20845610 TI - [Changes in NT-proBNP levels in patients with atrial fibrillation related to heart failure]. AB - INTRODUCTION: NT-proBNP, a well-established diagnostic and prognostic marker in clinical practice, is significantly elevated in individuals with atrial fibrillation (AF), even in absence of heart failure or major structural heart disease. OBJECTIVES: The aim of this study was to determine the cut-off value of NT-proBNP for diagnosis of heart failure in individuals with atrial fibrillation. METHODS: We compared 44 patients (25 male/19 female) with AF and concomitant overt heart failure [age 76 (62-82) years; median (interquartile range - IQR)] versus 29 patients (16 male/13 female) with AF with no signs of heart failure [age 59 (50-67) years; median (IQR)]. We considered the underlying causes of heart failure and its severity, comorbidities, echocardiographic and selected laboratory parameters, the body mass index as well as the treatment at discharge. We determined the cut-off value for heart failure and major structural heart disease using ROC curve analysis. RESULTS: Median NT-proBNP in the group of patients with AF and concomitant heart failure was 3 218 ng/l (IQR 1 758-7 480 ng/l) vs 981 ng/l (IQR 431-1 685 ng/l) in the group of patients with AF with no signs of heart failure; this difference was statistically significant (p < 0.001). The level of NT-proBNP higher than 1 524 ng/l in patients with AF was diagnostic of major structural heart disease and pointed towards a possible heart failure (sensitivity 80%, specificity of 76%, accuracy 78%, positive predictive value 83%, negative predictive value 71%). The NT-proBNP levels significantly correlated with age (p < 0.001), left atrial diameter (p < 0.01) and furosemide dose at discharge (p < 0.05). The NT-proBNP levels significantly negatively correlated with left ventricular ejection fraction (p < 0.001) and body mass index (p < 0.05). CONCLUSION: We found out that NT-proBNP is significantly elevated in patients with AF with preserved left ventricular function and in absence of heart failure and significantly correlates with age, left ventricular ejection fraction, left atrial diameter, body mass index and the furosemide dose necessary to achieve cardiac compensation. Furthermore, we determined the NT proBNP cut-offvalue predictive of a possible heart failure in patients with AF. PMID- 20845611 TI - [Primary central nervous system lymphomas]. AB - Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal lymphoma (nearly always non-Hodgkin's) and accounts for approximately 3 to 4% of primary brain tumors. PCNSL typically affects patients older than 60 years. Clinical features are variable and reflect the location of central nervous system lesion. Magnetic resonance imaging and stereotactic biopsy are the most important tools for diagnostic assessment. Chemotherapy based on high-dose of methotrexate (HD-MTX) and whole brain radiotherapy are the cornerstones of treatment. Radiotherapy is usually omitted in individuals older than 60 years because of high risk of unacceptable delayed neurotoxicity. Treatment of PCNSL should be started as soon as possible after diagnosis because delay in treatment may shorten the patients' survival. PMID- 20845612 TI - [Care for patients on mechanical ventilation from the perspective of an internal medicine physician]. AB - At times of respiratory insufficiency, mechanical ventilation (MV) provides support for or a substitution ofcertain components of the respiratory system. The aim of ventilation therapy is to achieve appropriate ventilation and oxygenation parameters and to minimize adverse events of MV. The main examples of non invasive ventilation (NIV) are Continuous Positive Airway Pressure (CPAP) and Bi level Positive Airway Pressure (BiPAP). The main benefit of NIV is a minimal need for tracheal intubation. To perform invasive mechanical ventilation, it is necessary to secure the airways with intubation or tracheotomy. We aim for the shortest possible duration of mechanical ventilation and intubation; their duration is a risk factor in development of ventilator-associated pneumonia. PMID- 20845613 TI - [Successful treatment of angiomatosis with thalidomide and interferon alpha. A description of five cases and overview of treatment of angiomatosis and proliferating hemangiomas]. AB - Our paper describes 5 patients with a vascular malformation - angiomatosis. In the first patient, a young man, angiomatosis affected the stomach, intestine, the area of mesenterium and retroperitoneum as well as mediastinum. Angiomatous mass had invaded pelvic bones and vertebrae. Treatment was initiated with interferon alpha in a maximum tolerated dose of 3 million units 3 times a week. Because of low efficacy of interferon alpha, thalidomide was added at a dose of 100 mg per day. Bone pain disappeared following a few applications of zoledronate administered in regular monthly intervals. After 3 years of concomitant administration of interferon alpha and thalidomide, we changed the regimen due to adverse effects and are administering thalidomide and interferon alternatively in 4-monthly intervals. Treatment has resulted in 50% reduction, according to imaging, of angiomatous mass, reduced intensity of disseminated intravascular coagulation and disappearance of clinical signs. The second was a case of multiple angiomatosis affecting the intestine only (multiple intestinal angiodysplasias) where we used thalidomide monotherapy. This treatment reduced blood losses and haemoglobin concentrations rose to normal levels. This male patient had consumed 120 transfusion units per year before the initiation of thalidomide. The third case was a slowly progressing vascular malformation of the face. This vascular malformation troubled its sufferer by spontaneous shortening that could not be resolved surgically because of its fragility. Two years of combined treatment with interferon a 6 million unites 3 times a week and thalidomide 100 mg daily led to a reduction and flattening of the malformation, paling of its colour and ceasing of spontaneous bleeding. This development enabled minor surgery--partial excision of this large vascular malformation. Histology examination confirmed that there was no evidence of new capillary formation. Histological examination thus confirmed efficacy of the treatment. The fourth case involved a patient with large vascular malformations affecting supraclavicular region of the neck and nape in whom radiotherapy was applied (54 Gy) leading to a reduction of the malformation mass by a at least 50%. The fifth is a case of an extensive periorbital lymphangioma that diminished following treatment with interferon alpha. These cases illustrate the benefits of combined treatment including thalidomide and interferon alpha in patients with multiple angiomatosis or large proliferating hemangioma (vascular malformation). If combined treatment with thalidomide and interferon a is not possible, it is beneficial to use thalidomide monotherapy. Radiotherapy is another alternative, although it is necessary to apply doses exceeding 50 Gy which may not be always possible. PMID- 20845614 TI - [Immunoglobulin G4-associated cholangitis]. AB - Autoimmune LgG4- associated cholangitis is a new entity among the liver and biliary tree disorders, classified among the so-called IgG4-related diseases. Even though prognosis of this disease is unclear, this type of sclerosing cholangitis is not being linked to a carcinoma. Clinical and laboratory data differ slightly from the findings associated with the usual primary sclerosing cholangitis and it is mainly the high IgG4 level and hyperbilirubinaemia that supports the diagnosis ofautoimmune disease. Unlike primary sclerosing cholangitis, this disease is not associated with a malignant prognosis and steroids represent an effective treatment. Combination of steroids with azathioprin is a possible alternative in case of a relapse. Patient's response to steroid therapy is a diagnosis-supporting criterion. This disease should always be considered as part of differential diagnosis of primary sclerosing cholangitis, especially when autoimmune aberrations or other autoimmune diseases are present. Long-term evaluations of these patients are so far lacking and thus studies on larger patient samples are required. PMID- 20845615 TI - [Risk profile of hypertensive patients]. AB - INTRODUCTION: Arterial hypertension is an important component of global cardiovascular risk profile of an individual patient. Estimation of global cardiovascular risk besides the blood pressure level incorporates all risk factors (RF), preclinical cardiovascular diseases (hypertension--induced target organ disease--TOD) and associated clinical conditions, and it should influence the therapy and long-term patient management. A group of metabolic risk factors comprizes several modifyable risk factors, detection of which influences the antihypertensive drug selection. The main goal of antihypertensive therapy is to achieve maximum reduction in the long-term total risk of cardiovascular disease, treating all modifyable risk factors in hypertensive patients. PATIENTS AND METHODS: In this work we present the results of group of 60 hypertensive patients examined for different risk factors detection and subsequent total cardiovascular risk estimation. RESULTS: The mean number of risk factors per patient was 4,1 (3% of patients had two RF, 22% of patients had three RF, 37% patients had four factors and 38% patients had five RF present). The ischaemic heart disease was found more frequently among hypertensives with higher number of RF. Metabolic syndrom (MS) was present in 53% of patients. Hypertensives with MS have higher rate of RF (4.9 per person) comparing to thouse without MS (3.6 RF per person). CONCLUSION: We found a quite high number of RF per individual hypertensive patient; the serious unfavourable consequence of this finding was the increased rate of coronary heart disease with the increasing number of risk factors found. PMID- 20845616 TI - [Comprehensive management of cardiovascular risk. Focusing on telmisartan]. AB - Cardiovascular diseases (CVD) represent a significant health problem in all countries world-wide and in the developed world, including the Czech Republic, in particular. The underlying cause in the majority of CVD patients is atherosclerosis and its complications, respectively. The present paper focuses on prevention and timely treatment of atherosclerosis. Management should be comprehensive and should target the risk factors (RF). Hypertension, hyperlipoproteinaemia and dyslipidemia (HLP and DLP), type 2 diabetes mellitus (T2DM), visceral fat obesity and cigarette smoking are the dominating RFs. Even though all RFs have to be managed simultaneously and it is not possible to focus on just one of them, for the sake of clarity, this paper discusses hypertension and the use of telmisartan, a representative of one the most up-to-date group of antihypertensives. There is a growing evidence that it is not always just a reduction of a specific risk that is important but also the mode of treatment. For example, to reduce a CV risk in a patient with hypertension but also, for example, with metabolic syndrome, it is more beneficial to treat the patient with rennin-angiotensin system (RAS) blocking agents, possibly in a combination with calcium channels antagonists, than to use "traditional" (older) treatment approach with a combination of a beta/blocker and diuretic. Among the RAS modifying agents, ACE inhibitors and sartans are the most widely used. Among sartans, telmisartan is very well-tolerated and has evidence from a large interventional study for its effect on reducing the CV risk. PMID- 20845617 TI - [Characteristics and the prognosis of patients with acute heart failure in current clinical practice]. AB - PURPOSE: Analysis of predefined characteristics and outcomes in a non-selected population of patients hospitalized for acute heart failure (AHF) in Slovakia. METHODS: We conducted a nationwide prospective multicenter survey with 860 consecutive patients enrolled in 11 hospitals throughout Slovakia--two centres with a non-stop catheterization service, two central and 7 regional hospitals. Relevant data of 78 characteristics in 9 categories were collected during 3 months (between 1 May 2009 and 31 July 2009). There was a specific form designed for this survey. Collected data were then transferred into the electronic database and statistically analysed. RESULTS: Mean age was 72 years, 81% of patients were in NYHA class III/IV (52% male). The majority of patients were admitted with decompensated heart failure (68.4%), frequency of cardiogenic shock was 0.3%. New-onset AHF (AHF de novo) was diagnosed in 31.1%, of which 20.8% was due to acute coronary syndromes. Coronary heart disease was the predominant primary aetiology of AHF (67%), followed by almost equally represented hypertension (10.5%), valvular disease (10%) and dilated cardiomyopathy (9%). Hypertension was referred as the most frequent comorbidity (82%), followed by atrial fibrillation (48%), diabetes mellitus (42%), history of renal failure (31%) and with anaemia at admission (38%). Rales were the dominant physical sign (69.9%). Systolic blood pressure greater than 140 mm Hg was present in 37.8% and QRS length > 120 ms in 21.4% of patients. Preserved left ventricular ejection fraction (> or = 40%) was observed in 57% out of 70% documented cases in the whole survey. 23.3% of patients had a history of coronary angiography. 84.3% of patients received intravenous treatment, diuretics, nitrates and inotropes were given to 82.2%, 18% and 6%, respectively. The number of patients with cardiac resynchronization therapy (CRT), with or without defibrillator function, was 0.9%. Mean length of stay was 9.2 days and in-hospital mortality was 9.1%. At discharge, 76% of patients were on angiotensin-converting enzyme inhibitors (ACE I) or angiotensin receptor blockers (ARB), 62% were using beta-blockers (BB), however the doses of drugs were lower then recommended values. CONCLUSIONS: Results of the survey are comparable with other observational studies, surveys and large registries. Although the percentage of patients with ACE-I/ARB and BB at discharge seems promising, there is still area for improvement in AHF patients health care. PMID- 20845618 TI - [Anaemia in chronic heart failure]. AB - Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study. PMID- 20845619 TI - [Therapy with implantable cardioverter-defibrillators (ICD) in the early of third millenium]. AB - The patients without ventricular arrhythmias with markers of high risk of sudden cardiac death are indicated for ICD implantation today. Last generation of ICD systems are equipped with high capacity batteries, with many automatic functions, capabilities of data sending and possibilities of prediction of worsening of heart failure. Nowadays ICD systems offers not only elimination of the risk of sudden cardiac death but reduction of symptoms of chronic heart failure through the resynchronization therapy, too. PMID- 20845620 TI - [The significance of fenofibrate in the therapy of atherogenic dyslipoproteinaemia]. AB - There are accepted the lipid levels goals in all world, which are needed to achievement in primary and secondary prevention. Despite efficacy of current standards of care (including achievement of LDL-C, blood pressure and blood sugar goals), patients with atherogenic dyslipidemia (DLP) (high TG levels, low HDL-C, high apolipoprotein B and small dense LDL-particles), which is common in patients with diabetes melitus (DM), metabolic syndrome or cardiovascular diseases (KVD), remain exposed to a high residual risk of major cardiovascular events and microvascular complications. Statin therapy does not adequately address vascular risk asociated with elevated triglycerides (TG) and low HDL-C levels. As ACCORD lipid trial last time shows, the addition of lipid-modifying activity of fenofibrate to statin therapy benefited only certain subgroups of patients at increased cardiometabolic risk. PMID- 20845621 TI - [Atrial fibrillation in the era of catheter ablation]. AB - Atrial fibrillation is the most frequent heart rhythm abnormality and is associated with increased morbidity and mortality. Trigerring ectopias and arrhythmogenic substrate that enable arrhythmia to sustain are both influenced by many modulating factors. Which risk factor is the most significant one remains unknown. Understanding pathophysiology of atrial fibrillation including molecular and genetic aspects is necessary to assign the most effective preventive measures as well as treatment of atrial fibrillation. Pharmacological treatment is the method of choice but "upstream therapy" that counteracts atrial remodelling has been more and more discussed. Presently the most effective treatment of atrial fibrillation is catheter ablation. Successful ablation prevents from the progression of electrical, structural and mechanical myocardial remodelling, improves left ventricle function and the risk oftrombembolism drops to the level of healthy population. The restitution of sinus rhythm triggers a reversal remodelling. We present results of catheter ablations performed at Internal Cardiology Department of the MU Medical Faculty and Faculty Hospital Brno. PMID- 20845622 TI - [Aortic pulse wave velocity in patients with metabolic syndrome and hypertension treated with sartans]. AB - INTRODUCTION: The incidence of subclinical organ damage is higher in patients with hypertension (HT) and metabolic syndrome (MS). Increased aortic pulse wave velocity (PWV) is one the markers reflecting subclinical arterial damage. Treatment with sartans leads not only to a reduction of blood pressure but may also bring regression of the subclinical damage. Long-acting sartans (telmisartan) may be more effective than sartans with medium duration of action (losartan); the aim of this research was to compare the impact of hypertension therapy with losartan and telmisartan on aortic pulse wave velocity (Ao-PWV). METHODS: We examined 32 patients with HT and MS, 15 patients were treated with losartan 50 mg (group A) and 17 patients were treated with telmisartan 80 mg (group B). At the beginning and the end of the study, PWV was measured using the Complior method and 24-hour BP monitoring and biochemistry testing were carried out. RESULTS: Treatment with sartans led to a reduction in BP in both groups, daytime BPs/BPd declined by 11.5/9.0 mm Hg in group A and by 13.8/8.1 mm Hg in group B, respectively, and night time BP declined by 5.7/5.1 mm Hg in group A compared to 7.4/3.89 mm Hg in group B. Aortal pulse wave velocity declined by 1.94 m/s in group A (p < 0.001) and by 0.46 m/s in group B (p < 0.001), respectively. CONCLUSION: Treatment with losartan as well as telmisartan resulted in reduced values of BP and Ao-PWV. We did not prove a more significant effect of a long-acting sartan (telmisartan) compared to a sartan with a medium duration of action (losartan) on Ao-PWV reduction after 1 year of treatment. PMID- 20845623 TI - [Heart transplantations--the past, the present and outlook into the future]. AB - We provide an overview of the history, current status and future perspectives of heart transplantations. We describe indication criteria and possible post transplantation complications. Finally, we list the options that could, as an alternative, complement transplantations in the future. This is mainly the use of mechanical heart support devices. PMID- 20845624 TI - Decentralization: the scary change. PMID- 20845625 TI - The epidemiological transition: policy and planning implications for developing countries. AB - BACKGROUND: Medical Scientists are beginning to understand better some of the trends in the changing disease and mortality patterns but policymakers need to know how to use this information to make decisions about the priorities for the health sector. This Paper is aimed at x-raying this shift in morbidity and mortality patterns and make recommendations for possible shift in planning and policies. METHOD: Relevant literatures were reviewed from medical journals, library search and internet source using Google search engine as well as international, national and local journals. The key words employed were: Epidemiological Transition with particular emphasis on policy and planning implications in developing countries. RESULT: Several studies have outlined definitions, stages and historical perspectives of epidemiological transition, as well as the scenarios in developed and developing countries. The impending challenges and policy and planning implications in the developing countries were suggested and outlined in this paper. CONCLUSION: It is very obvious that epidemiological transition is here with us as there are transformations in the age, cause, and sex structure of death in developing world. Yet not much progress has been made towards averting the dire consequences. A fundamental policy shift therefore needs to be put in place. PMID- 20845626 TI - Polymorphism of cytochrome p450, glutathione-s-transferase and N acetyltransferases: influence on lung cancer susceptibility. AB - Lung cancer remains a major health challenge in the world. It is the commonest cause of cancer mortality in men, it has been suggested that genetic susceptibility may contribute to the major risk factor, with increasing prevalence of smoking. Lung cancer has reached epidemic proportions in India. Recently indoor air pollution and dietary factors have been implicated in the causation of lung Cancer development. Accumulating evidences have highlighted that several polymorphisms involve the metabolic activation or detoxification of carcinogens derived from cigarette smoke have been found to be associated with lung cancer risk. Many studies have focused on the relation between the distribution of polymorphic variants of different forms of the metabolic enzymes and lung cancer susceptibility, Few of human biotransformating enzymes (Phase I enzyme: Cytochrome p450 enzymes, and Phase II enzymes: Glutathione-s transferases, N-acetyltransferases) have been implicated in the formation and scavenging of ultimate reactive metabolites. These enzyme families are known to catalyze detoxification of electrophilic compounds including carcinogens. The treatment and prevention of lung cancer are major unmet needs that can probably be improved by a better understanding of the molecular origins and evolution of the disease. This review will focus on major recent advances in the molecular study of the origins and biology of lung cancer. PMID- 20845627 TI - The pattern of cut throat injuries in the University of Port-Harcourt Teaching Hospital, Portharcourt. AB - BACKGROUND: The incidence of cut throat injuries irrespective of the cause is on the increase worldwide but they are underreported in Nigeria. The neck contains a lot of vital organs and great vessels which make the patients with injuries to the neck to present most times as emergency. The management of cut throat injuries is bedeviled with complications which can be reduced to the barest minimum if managed by the specialists. Our aim and objectives are to determine the pattern of cut throat injuries as seen in University of Port-Harcourt Teaching Hospital (UPTH) and to highlight the factors responsible for the morbidity and the mortality associated with this condition. METHODOLOGY: The study is a retrospective review of cut throat injuries that presented to the Ear Nose and Throat (E.N.T.) department of University of Port-Harcourt Teaching Hospital (U.P.T.H.) over a 10 yr period (1995 to 2010). The accident and emergency department records; ward records and theatre registers were the main source of the information. Twenty four cases were recorded and analyzed. The data extracted for analysis were age, sex, occupation, clinical presentation, treatment, duration of stay and complications. RESULTS: All the patients were males; age range was 26-45 years. The commonest age group affected was 31-35 years, suicide accounted for 60% of cases. Majority (62.5%) of patients were unemployed. Lacerations of the anterior aspect of the neck, aphonia with exposure of the thyroid cartilage were the commonest clinical features. Majority (58.3%) of the patients had complications following treatment while two patients had mortality. CONCLUSION: Cut throat injuries require a multidisciplinary approach and could be managed with better prognosis if the patients present early to the hospital and are given prompt attention. Poor socioeconomic status and poverty have been associated with a high incidence of cut throat injuries. PMID- 20845628 TI - Prophylactic ketamine reduces incidence of postanaesthetic shivering. AB - BACKGROUND: General anesthesia influences the thermoregulatory process. The aim of this study was to compare the efficacy of low-dose prophylactic ketamine with that of placebo in preventing postoperative shivering. METHODS: A prospective randomized double-blind study involved 76 ASA I and II patients undergoing general anesthesia that was expected to last no more than 2 hours. Patients were randomly allocated to receive normal saline (Group P, n = 33) or ketamine 0.5 mg kg1 (Group K, n = 33) intravenously 20 min before completion of surgery. The anesthesia was induced with propofol 2.5-3.0 mg kg(-1) and fentanyl (2-3 microg kg(-1)), atracurium 0.5 mg kg(-1) was given to facilitate orotracheal intubation. It was maintained with propofol (510 mg kg(-1) hr(-1)), fentanyl up to (5 microg x kg1 x h1) and a mixture of nitrous oxide/oxygen (2:1). Ambient temperature was maintained at 20 degrees-22 degrees C with constant humidity. Postoperative shivering in the recovery room was evaluated according to 5 point scale of Wrench. RESULTS: The two groups did not differ significantly regarding patient characteristics. The number of patients shivering on arrival in the recovery room, and at 10 and 20 min after operation was significantly less in Groups K than in Group P. In group P 36% have had shivering in TO whereas in group K 6%, in T10 45% in group P whereas 18% in group K. In T20 24% in group P have had shivering compared with 6% in group K, whereas in T30 9% in group P compared with 0% in group K. The incidence of free Postanaesthetic shivering (no shivering) on arrival in the recovery room T0 was: 63.6% in group P compared with 90.9 % in group K. The postoperative hemodynamic parameters were similar in the two groups. Active warming was not required in group K but was needed in 8 cases in group P. None of patients had episodes of O2 desaturation or respiratory depression during the study period. No hallucinations, delirium, nausea, vomiting, hypertension, tachycardia, and feeling like walking in the space or nystagmus were seen in any of the patients. CONCLUSION: Prophylactic low-dose ketamine was found to be effective in preventing postoperative shivering. PMID- 20845629 TI - Domestic water sourcing and the risk of diarrhoea: a cross-sectional survey of a peri-urban community in Jos, Nigeria. AB - BACKGROUND: Water and sanitation has been identified as an important component of Primary Health Care (PHC) necessitating the World Health Organization to declare 1981-1990 as the international water years. Nigeria is the largest single country in sub Saharan Africa worst hit with about three quarters of its population unable to access safe water. The study aims to examine the association between domestic water sourcing practice and the risk of developing diarrhea. METHODOLOGY: A total of 200 households were studied over an eight week period from 4th June to 31st July 2005 using an interviewer administered questionnaire. Data was analyzed using Epi Info version 3.5.1. RESULTS: Most of the household (80%) were seen to source domestic water from the municipal pipe-borne water supply while only 5% source water from their own dug-in well only. 27% of the households reported diarrhea in their household in the last six month. The diarrhea was found to have bivariate association with the number of children in the household, the educational level of the household head, and income of household head. No association was found between diarrhea and age of household head. CONCLUSION: The study showed that there is association between domestic water sourcing practice and the risk of developing diarrhea. It is therefore recommended that high premium be placed on improving access to water and improved household hygiene as a way of helping to curb diarrhea. PMID- 20845630 TI - Factors influencing the onset of cigarette smoking among adolescents in Konduga local government area. AB - BACKGROUND: Tobacco is the leading preventable cause of death in the United States; responsible for more than 400,000 deaths annually. There have been few reports in the literature about the association between these diseases and cigarette smoking from African countries, which may indicate that these diseases are not common in Africans. There is a dearth of knowledge about the smoking habit among adolescents and factors influencing it in Africa. This is a survey of the factors influencing the onset of cigarette smoking among adolescents in Konduga local government area. METHODS: A cross-sectional study involving 400 randomly selected subjects from the four districts of the local government who responded to a modified version of the standard WHO questionnaire (WHO/SMO, 1984) for surveying smoking habit. RESULTS: The study showed that friends/peers (57%) as the major factor for initiating the smoking habit in adolescents. Others were pleasure (24%), stress (13%), family members (4%) and cigarette adverts (1%). The study also revealed that the adolescents continued to smoke even though they were aware of the health consequences of smoking. The majority of the respondents (70%) advocated outright ban on tobacco sales by the government as the most effective way to check this world's major preventable health hazard. CONCLUSION: The study showed that friends/peer groups were the dominant factor influencing the onset of cigarette smoking among adolescents. This underscores the need for targeting the group in behaviour change communication. PMID- 20845631 TI - A prospective cohort study of immunologic and virologic outcomes in patients with HIV/AIDS and hepatitis virus co-infection in Jos, Nigeria. AB - BACKGROUND: In this era of highly active antiretroviral therapy (HAART), hepatitis B and C virus (HBV and HCV) co-infection have emerged as significant co morbid conditions. Local reports indicate that co-infection is not uncommon in Nigeria as in other sub-Saharan African countries. Whether treatment outcomes of HIV mono-infected patients differ from those with co-infection remains largely unknown. We hypothesised that co-infected patients will have lower CD4+ count recovery and viralload reduction following HAART. METHODS: A cohort study in antiretroviral therapy-naive HIV-infected adults involving 150 cases (HIV and co infection) and 150 controls (HIV infection only). Patients' care was according to the National guidelines and patients received first line therapy mostly comprising Lamivudine, Stavudine and Nevirapine. Medication adherence was monitored using pharmacy computerised system, and CD4+ cell counts and HIV viral load (VL) were compared at baseline, 3 and 6 months of therapy RESULTS: There were 98 (65.3%) and 96 (64%) female cases and controls (p = 0.79) respectively. The mean ages of cases and controls were 38 +/- 8.4 and 37 +/- 8.9 years (p = 0.20) respectively. Cases comprised 73 (48%) HBV, 70 (47%) HCV and 7 (5%) with both HBV and HCV infection. Medication adherence was > 95% in both arms. Attrition rate was 2.7% (8); seven of them were co-infected. Five cases (3.3%) compared to zero controls developed clinical hepatitis. The proportions of patients with CD4+ count < 200 cells/microl among cases and controls were 111 (74%) and 109 (72%), p = 0.36 at baseline; 66 (45.5%) and 64 (42.7%), p = 0.21 at 3 months; 60 (42%) and 56 (37.6%), p = 0.40 at 6 months respectively. Significantly more controls (60.7%) had CD4+ increases 50 cells/microl at 3 months compared to 37 (54.5%) HCV+ cases (p = 0.03). No significant difference in CD4+ counts between controls and cases at 6 months. The baseline median VL for cases and controls were log(10)4.95 and log(10)4.83 (p = 0.17) respectively. The proportions of cases and controls with undetectable VL at 3 and 6 months were 96 (66.2%) and 97 (65.5%); p = 0.74, and 116 (81.1%) and 97 (79.3%); p = 0.010 respectively. CONCLUSION: Co-infection has limited impact on immunologic and virologic outcomes, but may be an important cause of hepatotoxicity. PMID- 20845633 TI - Physician use of updated anti-virus software in a tertiary Nigerian hospital. AB - BACKGROUND: While physicians are becoming increasingly dependent on computers and the internet, highly lethal malware continue to be loaded into cyberspace. We sought to assess the proportion of physicians with updated anti-virus software in Jos University Teaching Hospital Nigeria and to determine perceived barriers to getting updates. METHODS: We used a pre-tested semi-structured self-administered questionnaire to conduct a cross-sectional survey among 118 physicians. RESULTS: The mean age (+/- SD) of subjects was 34 (+/- 4) years, with 94 male and 24 female physicians. Forty-two (36.5%) of 115 physicians with anti-virus software used an updated program (95% Cl: 27, 45). The top-three antivirus software were: McAfee 40 (33.9%), AVG 37 (31.4%) and Norton 17 (14.4%). Common infections were: Trojan horse 22 (29.7%), Brontok worm 8 (10.8%), and Ravmonlog.exe 5 (6.8%). Internet browsing with a firewall was an independent determinant for use of updated anti-virus software [OR 4.3, 95% CI, 1.86, 10.02; P < 0.001]. Busy schedule, 40 (33.9%) and lack of credit card 39 (33.1%) were perceived barriers to updating antivirus software. CONCLUSION: The use of regularly updated anti virus software is sub-optimal among physicians implying vulnerability to computer viruses. Physicians should be careful with flash drives and should avoid being victims of the raging arms race between malware producers and anti-virus software developers. PMID- 20845632 TI - Pattern of semen fluid abnormalities in male partners of infertile couples in southeastern, Nigeria. AB - BACKGROUND: The incidence of male infertility is increasing in our environment. There is a need to evaluate the pattern of abnormality with a view to recommending appropriate interventions. We aimed to to analyze the seminal fluid parameters of the male partners of the infertile couples managed in the hospital over a 12 month period and to identify the pattern of abnormalities. METHODS: A retrospective study of all the semen samples of male partners of infertile couples submitted for analysis to the microbiology laboratory of Nnamdi Azikiwe University Teaching Hospital, Nnewi Nigeria between 1st January 2006 and 31st December 2006 The reports of the semen fluid analysis were retrieved from the records department and supplemented with the laboratory register. RESULT: Out of the 348 semen sample reports evaluated, 237 (68.0%) had semen fluid abnormalities. 104 (30.0%) had single factor abnormalities while 133 (38.0%) had combined factor anomalies. Asthenozoospermia 58 (16.7%) was the main single abnormality, while Astheno-oligozoospermia 51 (14.7%) and Astheno oligoteratozoospermia (13.2%) were the major combined factor abnormalities detected. Very few 5 (1.4%) of the patients had azospermia. CONCLUSION: The study showed a high rate of semen fluid abnormalities among the male partners of infertile women in our environment. The high preponderance of poor motility emphasizes the need to include men in programmes aimed at reducing sexually transmitted infections in Nigeria. PMID- 20845634 TI - HIV prevalence amongst clients attending antenatal clinic at the Federal Medical Centre, Makurdi. AB - BACKGROUND: Evidence from the 2005 National HIV Seroprevalence Sentinel Survey showed that Benue state has the highest seroprevalence rate of HIV infection in the country. Seroprevalence rate amongst antenatal women is a reflection of what is happening in the larger society. Knowledge of seroprevalence rate amongst pregnant women would help in targeting intervention strategies for prevention of mother to child transmission (PMTCT) of HIV. OBJECTIVE: The objective of the study is to determine the seroprevalence rate of HIV infection amongst clients attending antenatal clinic at the Federal Medical Centre Makurdi. METHODS: Cross sectional study of 262 randomly selected women that booked for antenatal care at the Federal Medical Centre Makurdi between 1st January 2007 to 30th April, 2007 was carried out. Information regarding age, parity, gestational age at booking, educational status and HIV sero-status of the clients were looked into. RESULTS: A total of 50 women out of the 262 women studied were positive, giving a seroprevalence rate of 19.1%. The highest seroprevalence rate was amongst 25-29 years age group (40.8%). Women of parity 1-4 constituted the highest group (53.4%). Majority of them (45.5%) had secondary school education while 60 (22.9%) had tertiary education. One hundred and ten (42%) booked in the 3rd trimester while only 34 (13%) booked in the 1st trimester. CONCLUSION: HIV seroprevalence is high amongst antenatal women in Makurdi and intervention strategies should be scaled up for prevention of vertical transmission of the virus. PMID- 20845635 TI - Microalbuminuria in children with human immunodeficiency virus (HIV) infection in Port Harcourt, Nigeria. AB - BACKGROUND: Microalbuminuria is an early manifestation of HIV associated nephropathy (HIVAN). This study was to determine the prevalence and risk factors for microalbuminuria in children with HIV infection in Port Harcourt, Nigeria. METHODS: Urine specimen of 50 children with HIV infection seen over a 4 months period (October 2007-February 2008) was assayed for albumin and creatinine to determine urinary albumin to creatinine ratio (ACR). Microalbuminuria was defined as urinary albumin to creatinine ratio (ACR) of greater than 2.5-25 mg/mmol. The glomerular filtration rate (GFR) was calculated using the Schwartz formula. RESULTS: There were 28 (56%) males and 22 (44%) females with a male to female ratio of 1.3:1. They aged 1 month to 18 years with a mean age of 4.07 +/- 3.61 years. Microalbuminuria occurred in 6 (12%) patients; 3 males and 3 females, mean age of 5.5 +/- 4.6 years. Five (83.3%) of the patients with microalbuminuria had clinical AIDS and CD4+ cell count less than 200 cells/microL. All the patients with microalbuminuria were not receiving highly active antiretroviral therapy (HAART) at the time of study. One (16.7%) patient had overt HIV-associated nephropathy (HIVAN) with ACR greater than 2.5 mg/mmol, elevated serum creatinine 400 micrommo/L, urea of 20 mmol/L and a GFR of 69 ml/min/1.73m2. CONCLUSION: The prevalence of microalbuminuria in Nigerian children with HIV infection is high, and it occurs mainly in older children with clinical AIDS who are not on HARRT. PMID- 20845636 TI - Antiretroviral drug resistance--implications for HIV/AIDS reduction in sub Saharan Africa and other developing countries. AB - BACKGROUND: The introduction of the highly active antiretroviral therapy in the mid-1990s has significantly reduced morbidities and prolonged the lifespan of people living with HIV However, the emergence of resistance to the antiretroviral drugs is becoming a major cause of treatment failure. While the problem of drug resistance is being tackled in developed countries, not much seem to be done in this regard in developing countries of Africa, Asia and Latin America. This review looked at the regional distribution of HIV groups and subtypes and how this has affected the pattern of antiretroviral resistance. METHODS: The review was sourced from papers presented at international conferences on HIV/AIDS and rational drug use, relevant journals and Medline search using the keywords Antiretroviral drugs, drug resistance, HIV subtypes and resistance testing. RESULTS: The types, groups, subtypes, sub-subtypes and recombinant forms of HIV-1 have been identified according to their geographical distributions. The evolution of HIV viral mutations, process (es) involved in development of primary and secondary antiretroviral drug resistance, including the role of HIV genetic polymorphisms, and transmitted resistance have been discussed. CONCLUSION: The pitfalls in the current resistance testing based on HIV-1 subtype B have been highlighted. The design of resistance testing algorithm based on HIV-1 subtype non-B has been suggested for the developing world. PMID- 20845637 TI - Awareness, perception and practice of female genital mutilation among expectant mothers in Jos University Teaching Hospital Jos, north-central Nigeria. AB - BACKGROUND: WHO estimates that some 130 million women worldwide are affected, and every year another 2 million girls and young women are at risk of undergoing the practice of FGM. Although Nigeria has a prevalence of 19% in 2003,a reduction from 25% prevalence of 1999 national survey, it still has high absolute number of cases with wide regional variation. The awareness and perception of expectant mothers may give an insight as to what awaits their unborn daughters and have a bearing on the future of the practice. METHODOLOGY: Semi-structured questionnaires were administered to 260 expectant mothers at the antenatal clinic of Jos University Teaching Hospital between 1st and 31st July 2007. RESULTS: Majority of the respondents (94.6%) were aware of FGM. Mass media was the main source of information. Majority (83.8%) wanted the practice to be discontinued, 31.3% reported having had FGM, most done by traditional healers. About 14.6% have a plan to circumcise their daughters citing tradition, marriage prospects, and faithfulness to husband as their reasons. Only 16.2% wanted the practice to continue. CONCLUSION: There is high level of awareness of the FGM among respondents who also have negative attitude to the practice, even as the practice is still prevalent. More health education is needed to illustrate the dangers of the practice in order to safeguard the health of the girl-child. PMID- 20845638 TI - Immunologic factors in patients with chronic polypoid sinusitis. AB - BACKGROUND: Nasal polyposis is the benign protrusion of soft tissue into the nasal cavity, with multifactorial origin. This study is designed to examine the suggested role of IgE and CD4 and CD8 lymphocytes in the pathogenesis of nasalpolyposis. METHODOLOGY: Blood samples were taken from 32 patients with chronic polypoid sinusitis and 32 controls. CD4 and CD8 total lymphocyte count were determined by flow cytometry and the level of serum IgE was measured by ELISA. Nasal discharge samples were also collected for determining IgE level in both patients and controls during surgery. RESULTS: In 68.8% of patients a history of allergy was present. The level of nasal discharge IgE was significantly higher (p < 0.001) in patients compared to controls, but the difference between serum IgE levels was not significant (p > 0.05). CD8 concentration and blood lymphocytes were significantly higher (p < 0.001) in the patients group, while CD4 concentration was significantly lower (p < .OO01) in them. Finally, CD4/CD8 ratio was significantly lower(p < 0. 001) in the patients group. CONCLUSION: This study suggests that a change in the amount of CD4 and CD8 lymphocytes and an increased level of local IgE contribute to nasal polyposis, but the results should be confirmed in more extensive studies including cytokine analyses. Such increasing insights in the pathophysiology of nasal polyposis open perspectives for new pharmacological treatment options, with immunologic factors as potential targets. PMID- 20845639 TI - Pattern of ototoxicity in a Nigerian teaching hospital. AB - INTRODUCTION: Ototoxicity is a preventable cause of irreversible sensorineural hearing loss. This paper aims to highlight the pattern of ototoxicity seen in a tertiary health institution. METHOD: A retrospective study of patients with ototoxicity seen over a seven year period at ENT department of Aminu Kano Teaching Hospital, Kano. Case notes were retrieved and studied. RESULTS: Fifty nine patients made up 37 males and 22 females were seen with 86% in the age group 20-60 years. The commonest ototoxic drugs were aminoglycosides (37.3%), loop diuretics (27.1%), antimalarials (23.7%) and traditional concoctions (11.9%). The commonest presentation from most drugs was permanent sensorineural hearing loss (50-85%). Associated comorbid conditions included "febrile illness" (475%), hypertension (30.5%), diabetes mellitus (13.6%), renal disease (5%). Follow-up was poor. Only 18 patients presented for review beyond a second hospital visit, only those with ototoxicity from antimalarials recovered hearing. There were no effective audiometric and serum drug monitoring mechanism in place before, during or after therapy with ototoxic medications. CONCLUSION: Ototoxicity is not uncommon and attempts at prevention are feeble. Increased awareness of this condition is advised. High frequency audiometric assessment, otoacoustic emission and serum drug monitoring facilities should be provided at health institutions. Caution should be exercised when prescribing ototoxic drugs in the presence of other risk factors. PMID- 20845640 TI - Vaginal hysterectomy in a Nigerian tertiary health facility. AB - BACKGROUND: Despite evidence that vaginal hysterectomy offers advantages in regard to operative time, complication rates and return to normal activities, gynaecologists remain reluctant to change their practice patterns because of concerns about safety and feasibility of the vaginal approach. We reviewed cases of vaginal hysterectomies done in Nnamdi Azikiwe University Teaching Hospital Nnewi, Nigeria over a ten year period. METHOD: This is a retrospective analysis of cases of vaginal hysterectomy that were done in the hospital between 1st January 1998 and 31st December 2007. Data was analyzed with Epi info version 3.3.2. Outcome measures include duration of hospital stay, indication for the surgery, postoperative morbidity and mortality and the need for blood transfusion. RESULT: Hysterectomy accounted for 224 of 1,370 gynaecological surgeries (16.4%). Vaginal hysterectomy was responsible for 47 (21.0%) of these 224 cases and accounted for 3.7% of all gynaecological surgeries. Majority of the patients were in the 7th decade of life with a mean age of 65.2 +/- 6.8. Most (87.5%) patients were retired farmers and grandmultiparous with a mean parity 6.5 +/- 2.4). Utero-vaginal prolapse was the only indication for the surgery. The only postoperative complication accounted was febrile morbidity which was reported in 5 (10.6%) of the patients had febrile morbidity. There were no cases of conversion to abdominal procedure. All the surgeries were done by the consultants. CONCLUSION: Vaginal hysterectomy was safe and associated with minimal morbidity to the patient. The only indication was uterovaginal prolapse and all the procedures were done by the consultants. There is need to transfer the skill to the Residents. PMID- 20845641 TI - Tuberous sclerosis: a rare cause of seizure in Nigeria. AB - BACKGROUND: Tuberous sclerosis is a rare genetic multisystem disorder that is typically apparent shortly after birth. Dermatologic manifestations may be the only clues to the diagnosis of the disorder, which is also marked by childhood seizures and mental retardation. The aim of this report is to present a twelve year old boy with tuberous sclerosis. METHODS: A review of the case records of a child with angiofibromas of the face and neck and the relevant literature. RESULTS: An eleven year old primary two pupil of Ijaw tribe, southern Nigeria, presented with recurrent afebrile, generalized tonic--clonic seizures from nine months of age, hyperpigmented papulonodular eruptions on the face and neck with some hypo pigmented patches at the back for six years. He also had a growth on the right index finger of six years duration. There was associated learning disabilities and poor school performance, with sudden outburst of mood swings ranging from laughter to anger. Speech was delayed. He has been on Carbamazepine for the past two years and is seizure free. There was no history of similar illness in the family. Physical examination showed that he had labile mood with presence of hyperpigmented papulonodular (angiofibromas) eruptions on the malar area of the face and neck. There were also associated hypomelanotic macules on the back, bony cyst on the right index finger. He also had bilateral undescended testis. All other systems were essentially normal. Cranial computed tomography showed multiple hyperdense non enhancing nodules in the walls of the lateral ventricles with a hyperdense nodule in the subcortical area of the parietal lobe of the left cerebrum. Multiple areas of nonenhancing hypodensities were also seen in the cortical white matter of the frontal and parietal lobes bilaterally with associated thickening of the adjacent gyri. He is being managed by a team of a paediatric neurologist, surgeon, speech therapist and a dermatologist. He is regular at follow up clinic. CONCLUSION: Tuberous Sclerosis though a rare condition, once diagnosed needs multidisciplinary management to improve the quality of life of the patient. PMID- 20845642 TI - Inevitable caesarean myomectomy; a case report. AB - The standard teaching is to avoid caesarean myomectomy as much as possible for the fear of the attendant severe haemorrhage. Classical caesarean section in spite of its risk of uterine rupture in subsequent pregnancies had been prescribed in its place. We report a case of a 32 year old nullipara who had an inevitable removal of a huge intramural fibroid in order to assess the baby. A high dose oxytocin infusion, and skillful surgery ensured minimal intra operative and post operative blood loss. PMID- 20845643 TI - Exsanguinating blunt breast trauma: a report of a rare injury. AB - We report a rare case of blunt trauma in a non-augmented multiparous breast of a young Nigeria woman with exsanguinating haemorrhage who had no clotting disorder. She had no seatbelt on at the time of injury and the car was not fitted with air bag device. Prompt surgical intervention to control haemorrhage from the breast was essential in saving her life. Reasons are advanced why this injury is uncommon. PMID- 20845644 TI - Breast-axillary complex in HIV/AIDS patients. AB - BACKGROUND: HIV/AIDS have not only increased the health care burden especially in developing countries, it equally complicates the presentation of many diseases. Some well known disease entities now occur in fulminant complexities not previously described or known as such. The objective of this article is to report an unusual presentation of HIV/AIDS patients to the surgeon with Axillary and ipsilateral breast swelling. METHOD: This is a report of three cases seen and managed by the authors. RESULTS: Three adult female patients presented with progressively increasing axillary and ipsilateral breast swellings. They also had associated fevers and weight loss. Their main concern had been development of breast cancer. One of the patients was a known retroviral positive on Highly Active Anti-Retroviral Therapy (HAART). Examination revealed axillary abscess and ipsilateral breast oedema in two cases. The patient on HAART had a hard breast axillary mass complex. Biopsy (FNAB) revealed inflammatory cells and no malignancy in all three cases. HIV screening was positive in all cases. One of the patients had excision of breast-axillary mass complex, and the histology showed features of chronic inflammation, with no malignant cells. The other two had incision and drainage of their axillary abscess. CONCLUSION: This shows the ubiquitous presentation of HIV/AIDS in our environment and surgeons should be aware of the breast axillary complex in HIV/AIDS. Medical practitioners should be careful to obtain accurate diagnosis before embarking on treatment especially mutilating surgical procedures. PMID- 20845645 TI - Ultrasound scan in Nigeria--the urgent need for standardized training/certification for operators and regulation of its practice. PMID- 20845646 TI - Pneumococcal disease: swinging away at a dangerous killer. PMID- 20845647 TI - Meperidine versus morphine, and PPIs with clopidogrel. PMID- 20845648 TI - Round, pitting lesions on the lower leg. Necrobiosis lipoidica. PMID- 20845649 TI - Hypertension. Is BP out of control or uncontrolled? PMID- 20845650 TI - Stress management: helping patients to find effective coping strategies. PMID- 20845651 TI - Hyperglycemia management in the urgent surgical patient. PMID- 20845652 TI - New-onset status epilepticus develops after a motor vehicle collision. PMID- 20845653 TI - Buprenorphine: a more accessible treatment for opioid dependence. PMID- 20845654 TI - Hip resurfacing: a fresh look at an alternative to total joint arthroplasty. PMID- 20845655 TI - Pleural effusion. PMID- 20845656 TI - Cirrhosis. PMID- 20845657 TI - What is MRSA? PMID- 20845658 TI - Patient information. What is MRSA? PMID- 20845659 TI - A cracking sensation is the onset of severe ankle pain. PMID- 20845660 TI - Case of the month. Renal infarction. PMID- 20845661 TI - [Sunbathing or health--choice is yours]. PMID- 20845662 TI - [Maternal autoimmune thyroid disease and pregnancy complication]. AB - BACKGROUND/AIM: Thyroid disorders exert a great impact on pregnancy course and outcome. The aim of the study was to investigate impact of autoimmune thyroid disorders on pregnancy course and outcome, frequency of pregnancy complications and pregnancy loss. METHODS: We followed 63 pregnancies prospectively during the period 1985-2007, 28 with hyperthyroid and 15 with hypothyroid autoimmune disorders, and 20 healthy pregnancies. Follow up included clinical, sonographic and laboratory investigations, including OGTT and postprandial glicemia. RESULTS: There was no difference between previous preterm and term labor in the observed groups (chi2 = 2.309; p > 0.05). Analysis of previous early pregnancy loss showed no significance (chi2 = 4.918; p > 0.05), including varieties of spontaneous and missed abortion (Fisher, p < 0.05). The hypothyroid patients developed gestational diabetes more frequently than the controls (chi2 = 7.638; p = 0.022), which is not the case with hyperthyroid patients (chi2 = 1.078; p > 0.05), or between the groups with thyroid disorders (chi2 = 3.619; p > 0.05). There was no difference among the groups in developing pregnancy-induced hypertension (chi2 = 1.953; p > 0.05). CONCLUSIONS: Controlling thyroid diseases reduces pregnancy complications. Development of gestational diabetes in hypothyroid patients requires controlling glycoregulation in all pregnant women with hypothyroidism. PMID- 20845663 TI - [Role of natriuretic peptides in the assessment of aortic stenosis severity]. AB - BACKGROUND/AIM: Symptom onset is a critical point in natural course of aortic stenosis and the most important indication for aortic valve replacement. The aim of the study was to evaluate the role of natriuretic peptides level in the assessment of symtomatic status of patients with severe aortic stenosis and the preserved left ventricular systolic function. METHODS: In 67 patients with isolated severe aortic stenosis symptomatic status, transthoracic echocardiography, and BNP and NT-proBNP plasma level were assesed. Natriuretic peptides levels were also measured in 36 healthy controls. RESULTS: BNP and NT proBNP levels were significantly higher in the patients with aortic stenosis compared with the healthy controls. The symptomatic patients had a higher level of natriuretic peptides than the asymptomatic ones (BNP 118 [29-266] vs. 79 [44 90] pg/mL, p < 0.001; NT-proBNP 258 [67-520], vs. 79 [77-112] pmol/L, p < 0.0001). Natriuretic peptides levels increased with the severity of NYHA class. NT-proBNP level higher than 122 pmol/L was a cutoff value for detection of symptoms in the patients with severe aortic stenosis. CONCLUSION: The levels of natriuretic peptides were significantly higher in the patients with symptomatic aortic stenosis, and increased with NYHA class. Measurement of natriuretic peptides levels could be important addition to clinical and echocardiographic assesment in determing optimal timing for valve replacement in aortic stenosis. PMID- 20845664 TI - How a routine checking of Escherichia coli in retailed food of animal origin can protect consumers against exposition to Campylobacter spp. and Listeria monocytogenes? AB - BACKGROUND/AIM: According to the literature that has been published over the last two decades Campylobacter spp i Listeria monocitogens can be identified as causes of numerous diseases derived by consuming food of animal origin. The purpose of this paper was to find out how established national microbiological criteria of the Republic of Serbia on food safety in retailed food of animal origin could contribute to consumer's protection against exposition to foodborne pathogens such as Campylobacter spp. and Listeria monocytogenes. METHODS: During a routine microbiological safety control of randomly selected 60 samples of fresh poultry meat, 30 samples of other fresh meat readymade for grilling, 30 samples of sausage products, 37 samples of heat-treated meat, 39 samples of toppings for fast food of animal origin and 31 samples of dairy products a national food safety criteria (Escherichia coli, aerobic plate count, Salmonella spp., coagulasa positive Staphylococcus, Proteus spp., sulphito-reducting Clostridia) were applied and, as well as, testing to Campylobacter spp. and Listeria monocitogens. In determination of Campylobacter spp. and Listeria monocytogenes, food quality control methods of the Food and Agriculture Organization (FAO) were applied, while in determination of the other above motioned bacteria, national provisions on microbiological methods were applied who are adjusted to the FAO ones. RESULTS: Related to the national criteria on microbiological food safety, 88 (38.8%) samples, out of the total 227 tested, were rejected. When to these results, the results of laboratory tests on Listeria monocytogens were added, a terminal number of rejected samples were not changed. When to these results, the results of Campylobacter spp. testing were added, 91 (40.1%) out of the 227 samples were unsatisfied. Results of logistic regression model with occurrence of Escherichia coli as dependent variable indicated that Escherichia coli was 4.5 times likely to occur among samples with Campylobacter spp. than among samples without Campylobacter spp. (OR = 4.515, 95% CI: 1.019-20.002). Sensitivity of the fitted model (Hosmer-Lemeshowp = 0.268) was 76.8% and its specificity was 75.0%. At the same time Escherichia coli was confound in all (100%) food samples that were contaminated by Listeria monocytogenes. CONCLUSION: Statistical analysis indicated that Escherichia coli was completely sensitive to identify all samples contaminated with Listeria monocytogenas and highly sensitive to identify samples contaminated with Campylobacter spp. Nevertheless, 3 (1.3%) of the tested samples were not covered with Escherichia coli. PMID- 20845665 TI - The first outbreak of brucellosis in the region of Sabac. AB - BACKGROUND/AIM: In Serbia brucellosis is a primary disease of the animals in the southern parts of the country. The aim of this study was to describe the first outbreak of human and animal brucellosis in the region of Sabac, Serbia. METHODS: An epidemiological investigation was conducted to identify a source of outbreak and the ways of transmission of brucellosis infection in human population. A descriptive and analytical epidemiological methods (cohort study) were used. Additional data included monthly reports of the infectious diseases from the Institutes of Public Health and data from the Veterinary Specialistic Institute in Sabac. The serological tests for human brucellosis cases were performed in the Laboratory of the Military Medical Academy; laboratory confirmation of animal brucellosis cases was obtained from the reference laboratory of the Faculty of Veterinary Medicine, Belgrade. RESULTS: Twelve cases of brucellosis were recorded from February 9 to September 1, 2004. Total attack rate was 8.1% (7.5% of males, 14.2% of females). Relative risk (RR) of milk consumption was 8.9 (95% confidence interval: 1.63-13.38), and RR for direct contact with animals was 14 (95% confidence interval: 3.5-55.6). The prevalence of seropositive animals in 33 villages of the Macva region accounted for 0.8%. Regarding animal species, sheep were predominant--264 (95.7%). Out of a total number of seropositive animals, ELISA results were positive in 228 (88.7%) of them. CONCLUSION: As contact epidemics generally last longer, it is probable that the implemented measures of outbreak control did reduce the length of their duration. PMID- 20845666 TI - [Histopathological finding as a prognostic factor of the surgical treatment outcome in colorectal cancer]. AB - BACKGROUND/AIM: Adenocarcinomas of the colon are the most common malignant colorectal tumors. Macroscopic and histopahtological features of colorectal cancer significantly affect its outcome. The aim of this study was to analyze the impact of histopahological finding as a prognostic factor on the surgical treatment outcome and the course of the disease. METHODS: In the first part of this study the distribution (numerical and proportional) of certain histopathological parameters in the examined groups of patients were reviewed; in the second part of the study the statistical significance of the impact of the certain elements of a histopahtological finding on the surgical treratment outcome was analyzed. The histopathological elements analyzed included: the hsitological tumor type grading according to Duke, ie Astler-Coller, and tumor, nodes, metastases (TNM) staging in the examined sample of 100 patients. RESULTS: Statistically significant prognostic factors of the outcome of surgical treatment were selected after multivariant analysis. These factors comprise Astler-Coller Dukes stage D (revealed in 77.78% patients died), stage IV according TNM classification (T1-4, N0-2, M1), histological structure (poorly diferentiated adenocarcinoma in 85.2% patents died) and type of tumor (mucynous adenocarcinoma was more often present in died, 77.78%). Since phi = 0.000 for four risk factors were formed using discriminant analysus, it was proved their significant influence on the outcome of surgical treatment Discriminant coefficient showed that the greatest influence on surgical treatment were registred in patients with tumor of Astler-Coller-Dukes stage D (0.255), poorly differentiated adenocarcinoma (histological structure) (0.139), mucynous adenocarcinoma (type of tumor) (0.074) and stage IV according to the TNM classification (T1-4, N0-2, M1) (0.39). CONCLUSION: The prognostic factors influencing the outcome of surgery for colorectal carcinoma were defined. Patients with pathohistological finding of Astler-Coller-Dukes stage D, stage IV according to the TNM classification (T1-4, N0-2, M1) and poorly differentiated adenocarcioma have statistically highly significant mortality during the perioperative course of the disease. PMID- 20845667 TI - [Evaluation of using Alvarado score and C-reactive protein in diagnosing acute appendicitis in children]. AB - BACKGROUND/AIMS: Acute appendicitis (AA) remains a diagnostic challenge in children, despite ongoing researches. With an aim to facilitate making diagnosis of AA many scoring systems have been created; among them Alvarado score is the most popular. C-reactive protein (CRP) has proven significance for diagnosing AA in adults, but not in children. The aim of this study was to evaluate significance of Alvarado score, as well as CRP values, in making diagnosis of AA in children. METHODS: This prospective six-month study was performed on 257 patients under the age of 15, admitted for acute abdominal pain in the Clinic of Pediatric Surgery and Orthopedics in the Clinical Centre of Nis. Alvarado score and CRP values were determined on admission and compared with final diagnosis on discharge. The patients were divided into two groups: group I--non operated patients with abdominal pain (n=184) and group II--operated on patients for appendectomy (n=73). RESULTS: Values of Alvardo score were statistically significantly different between groups (group I: 4.9 +/- 1.21, group II: 8.55 +/- 1.32). Also, our results showed significantly high values of CRP measured in operated children (group I: 8.17 +/- 4.7 mg/L, group II: 38 +/- 26 mg/L). Values of validity parameters for Alvarado score were: sensitivity 90%, specifity 80%, positive predictive values 87%; for CRP 95%, 70% and 80%, respectively. CONCLUSION: Alvarado score and CRP are very useful adjuvant diagnostic tool for AA to a less experienced surgeon. High values of Alvarado score and CRP cannot be ignored neither at the same time, used as the sole diagnostic method for discriminating children with AA. PMID- 20845668 TI - [Radical cystectomy--analysis of postoperative course]. AB - BACKGROUND/AIM: Radical cystectomy is a method of choice in the therapy of infiltrative bladder cancer. The aim of this research was to analyze postoperative course after radical cystectomy (length of hospitalization, most frequent complications and utilization of antibiotics and transfusions). METHODS: We analyzed the records of 82 patients operated on in the Department of Urology, Clinical Center of Vojvodina, in a three-year period. In order to aquire data World Health Organization (WHO) has developed Anatomical Therapeutic Chemical/Defined Daily Dose (ATC/DDD) methodology. Defined daily dose (DDD) is the assumed average maintenance dose per day for a drug use for its main indication. RESULTS: Continent urinary derivation was preformed in 23.15% cases. Postoperative complications occurred in 18.29% of patients. Average blood utilization was 2.19 units. Blood utilization for continent derivations (n=48) was 4.6 units, and incontinent ones 3.36 units. Totally 159.33 DDD/100 bed days were used. CONCLUSION: When preforming continent derivation there is a significant increase in blood utilization. Frequency of postoperative complications correlates to those reported in the literature. PMID- 20845669 TI - [Correlation of adverse childhood experiences with psychiatric disorders and aggressiveness in adulthood]. AB - BACKGROUND/AIM: Consequences of individual adverse childhood experiences for adult mental health have been precisely studied during past decades. The focus of past research was mainly on childhood maltreatment and neglect. The aim of this paper was to determine association between multiple adverse childhood experiences and psychiatric disorders, as well as their correlation to the degree and type of aggressiveness in adult psychiatric patients. METHODS: One hundred and thirteen psychiatric outpatients were divided into three diagnostic groups: psychotics, non-psychotics and alcoholics and compared with fourty healthy individuals. Adverse childhood experiences data were gathered retrospectively, using the Adverse childhood experiences questionnaire and explanatory interview. Aggressiveness was assessed using Buss-Perry Aggression Questionnaire. The Student's t test, ANOVA and correlational analysis were used for evaluation of statistical significance of differences among the groups. A value p < 0.05 was considered statistically significant. RESULTS: Our results showed that the mean number of adverse childhood experiences in each group of psychiatric patients, as well as in the whole group of patients, was statistically significantly higher than in the group of healthy individuals (p < 0.001); there was a statistically significant difference in score of physical aggressiveness between the patients exposed to adverse childhood experiences and those who were not exposed to them (p < 0.05); scores of physical aggressiveness were in positive correlation with the number of adverse childhood experiences (p < 0.05). The highest mean score of adverse childhood experiences was evidenced in the group of patients with psychotic disorders. CONCLUSION: Multiple adverse childhood experiences are significantly associated with psychotic disorders, nonpsychotic disorders and alcohol dependence in adulthood and their presence is important morbidity risk factor for psychiatric disorders. They are in positive correlation with physical aggressiveness of the patients from these diagnostic groups. PMID- 20845670 TI - The effects of different anesthesia techniques on free radical production after tourniquet-induced ischemia-reperfusion injury at children's age. AB - BACKGROUND/AIM: Reperfusion of previously ischemic tissue leads to injuries mediated by reactive oxygen species. The aim of the study was to investigate the effects of different anesthesia techniques on oxidative stress caused by tourniquet-induced ischemia-reperfusion (IR) injury during extremity operations at children's age. METHODS: The study included 45 patients American Society of Anesthesiologists (ASA) classification I or II, 8 to 17 years of age, undergoing orthopedic procedures that required bloodless limb surgery. The children were randomized into three groups of 15 patients each: general inhalational anesthesia with sevoflurane (group S), total intravenous anesthesia with propofol (group T) and regional anesthesia (group R). Venous blood samples were obtained at four time points: before peripheral nerve block and induction of general anesthesia (baseline), 1 min before tourniquet release (BTR), 5 and 20 min after tourniquet release (ATR). Postischemic reperfusion injury was estimated by measurement of concentration of malondialdehyde (MDA) in plasma and erythrocytes as well as catalase (CAT) activity. RESULTS: Plasma MDA concentration in the group S was significantly higher at 20 min ATR in comparison with the groups T and R (6.78 +/ 0.33 micromolL-1(-1) vs. 4.07 +/- 1.53 and 3.22 +/- 0.9. micromolL-1(-1), respectively). There was a significant difference in MDA concentration in erytrocythes between the groups S and T after 5 min of reperfusion (5.88 +/- 0.88 vs. 4.27 +/- 1.04 nmol/mlEr, p < 0.05). Although not statistically significant, CAT activity was slightly increased as compared to baseline in both groups S and R. In the group T, CAT activity decreased at all time points when compared with baseline, but the observed decrease was only statistically significant at BTR (34.70 +/- 9.27 vs. 39.69 +/- 12.91 UL-1, p < 0.05). CONCLUSION: Continuous propofol infusion and regional anesthesia techniques attenuate lipid peroxidation and IR injury connected with tourniquet application in pediatric extremity surgery. PMID- 20845671 TI - [Morbidity and mortality in the early postoperative course following elective reconstruction of abdominal aorta aneurysm using endovascular and open surgical techniques]. AB - BACKGROUND/AIM: Surgical treatment is the only method of abdominal aorta aneurysm (AAA) treatment. According to data of the available literature, elective open, i.e., conservative, reconstruction (OR) is followed by 3%-5% mortality, as well as by numerous comorbide conditions inside the early postoperative course (the first 30 days after the surgery) that occur in 20%-30% of the operated on. The aim of the study was to present preliminar results of a comparative clinical retrospective study of early postoperative morbidity and mortality in AAA reconstruction using endovascular (EVAR) and open surgical techniques. METHOD: This comparative clinical retrospective study included 59 patients, electively operated on for AAA within the period January 2008-March 2009, divided into two groups. The group I counted 29 (49%) of the patients who had been submitted to EVAR by the use of Excluder stent. The group II consisted of 30 (51%) of the patients operated on using OR. All of the patients were males, 50-87 years old (mean 67.6 year in the group I, and 54-86 years (mean 68.3 years) in the group II. All tha patients had AAA larger than 50 mm, in the group I 50-105 mm (mean 68 mm), and in the group II 50-84 mm (mean 65 mm). Preoperative comorbide conditions of any patients were similar (coronary disease, obstructive lung disease, chronical renal insufficiency). Patients operated on as emergency cases due to rupture or due to symptomatic aneurysm (threthening rupture) were excluded. The analysed parameters were the duration of surgical operation, intraoperative and operative blood substitution, postoperative morbidity, the duration of postoperative hospitalization, and hospital mortality. RESULTS: The obtained results showed a statistically significantly shorter time taken by EVAR surgery (average 95 min, ranging 70-180 min) as compared to OR surgery (average 167 min, ranging 90-300 min). They also showed statistically significantly less blood loss in the patients operated on by the use of EVAR surgery (average blood compensation 130 mL, ranging 0-1050 mL) as compared to OR surgery (average blood compensation 570 mL, ranging 0-2.000 mL). Also, general complications as wound infection, no restoration of intestines peristalsis, febrility, proteinic and electolytic disbalance, lung and heart decompensation were statistically significantly less following EVAR than OR surgery. Postoperative hospitalization was also statistically significantly shorter after EVAR than after OR surgery (average 4.2 days, ranging 3-7 days; 10.6 days, ranging 8-35 days, respectively). Finally, within this 13-month study there was no mortality following EVAR surgery, while two patients died after OR surgery. CONCLUSION: In the patients with elective AAA reconstruction endovascular reconstruction is shown to be far more safer and minimally invasive procedure than open conventional aorta reconstruction. PMID- 20845672 TI - [Intra-abdominal hypertension and abdominal compartment syndrome]. PMID- 20845673 TI - A young soldier with syncope, shortness of breath and palpitations. AB - INTRODUCTION: Coronary artery disease in people under 30 years is relatively uncommon, but once a disease occurs it brings a significant morbidity and psychological effects. CASE REPORT: We reported a 28-year-old patient presenting atypical symptoms after sincopa and non-specific changes on electrocardiogram at admission. After noninvasive and invasive cardiology diagnostic procedures were made, we concluded that he had a subtotal tubular stenosis in proximal segment of the left anterior descending coronary artery. Myocardial revascularization was successfully performed 24-hour after coronarography with the left internal mammary thoracic artery graft on the left anterior descending coronary artery and the patient had a prompt and satisfactory postoperative recovery. CONCLUSION: This case indicates the importance of a careful evaluation of young adults even if they do not experience typical anginal symptoms or do not have multiple risk factors for cardiovascular diseases. PMID- 20845674 TI - Triple Bjork-Shiley valve--more than 30 years of asymptomatic functioning: to the memory of late academic prof. Isidor Papo and the 45th anniversary of the first valve implantation in Yugoslavia. AB - INTRODUCTION: The Bjork-Shiley Delrin (BSD) tilting disc heart valve was first clinically used in 1969. A triple BSD valve replacement has not been quite common, because of high postoperative risk and complications, but there have been several cases with different postoperative course. The first implantation of artificial valve in Yugoslavia was done by Prof. Isidor Papo, in 1965. CASE REPORT: We presented patient with more than 30 years of successful triple (aortic, mitral and tricuspid) BSD valve functioning. This is a rare case of a triple BSD valve long-term functioning and, as far as we know, the case of the longest period of successful functioning of the triple BSD valves. In March 1977, a 34-year-old female with severe congestive heart failure of the New York Heart Association (NYHA) functional class IV was admitted to the Military Medical Academy, Belgrade, for triple valve (aortic, mitral and tricuspid) surgery with BSD mechanical valves. Complicated surgery was done well. Sixteen months later the patient was diagnosed with infective endocarditis caused by Enterobacter spp. that was isolated from blood cultures. The patient was successfully cured. After that the patient had no cardiovascular symptoms and regular physical and echocardiographic examinations used to reveal satisfactory cardiovascular function. The patient died more than 30 years after the surgery due to a terminal phase of uterine carcinoma. CONCLUSION: Although BSD valves were withdrawn from clinical use long time ago, there are still some rare cases of their successful functioning, mostly due to the precise surgical technique and regular follow-up by the cardiologists. PMID- 20845675 TI - [Penetrating injury of the lungs and multiple injuries of lower extremities caused by aircraft bombs splinters]. AB - INTRODUCTION: Injuries caused by aircraft bombs cause severe damages to the human body. They are characterized by massive destruction of injured tissues and organs, primary contamination by polymorph bacterial flora and modified reactivity of the body. Upon being wounded by aircraft bombs projectiles a victim simultaneously sustains severe damages of many organs and organ systems due to the fact that a large number of projectiles at the same time injure the chest, stomach, head and extremities. CASE REPORT: We presented a patient, 41 years of age, injured by aircraft bomb with hemo-pneumothorax and destruction of the bone and soft tissue structures of the foot, as well as the treatment result of such heavy injuries. After receiving thoracocentesis and short reanimation, the patient underwent surgical procedure. The team performed thoracotomy, primary treatment of the wound and atypical resection of the left lung. Thoracic drains were placed. The wounds on the lower leg and feet were treated primarily. Due to massive destruction of bone tissue of the right foot by cluster bomb splinters, and impossibility of reconstruction of the foot, guillotine amputation of the right lower leg was performed. Twelve days after the wounding caused by cluster bomb splinters, soft tissue of the left lower leg was covered by Tirsch free transplant and the defect in the area of the left foot was covered by dorsalis pedis flap. The transplant and flap were accepted and the donor sites were epithelized. Twenty-six days following the wounding reamputation was performed and amputation stump of the right lower leg was closed. The patient was given a lower leg prosthesis with which he could move. CONCLUSION: Upon being wounded by aircraft bomb splinters, the injured person sustains severe wounds of multiple organs and organ systems due to simultaneous injuries caused by a large number of projectiles. It is necessary to take care of the vital organs first because they directly threaten the life of the wounded patient. Despite adequate surgical treatment of war wounds of the feet, because of massive defect of bone and soft tissue, amputation may be the only rational solution of the treatment. The resection of the lung may be succesfull method for the severe destruction of the lung. PMID- 20845676 TI - Collaborating clinicians. PMID- 20845677 TI - A social network analysis of healthcare professional relationships in a French hospital. AB - PURPOSE: This paper aims to describe relationships among healthcare professionals in a French public hospital using social network analysis (SNA) and to improve health service quality by strengthening health service management and leadership. DESIGN/METHODOLOGY/APPROACH: This study was based on a questionnaire sent to randomly selected French public hospital professionals and administrators. Network composition measures were obtained using a name generator. Analysis focused on three main indicators: "centrality", "prestige", and "clique participants". The SNA was carried out using UCINET and statistical analyses were performed with SPSS version 15.0. FINDINGS: A total of 104 questionnaires were returned and analysed. Centrality, prestige and clique indicators were highly correlated (all p-value were less than 0.01). Physicians had the highest scores for the three indicators. Older age (> or = 45 years) was associated with higher centrality and clique numbers scores. Transversal activity was associated with higher scores than other specific activities (hospitalisation, ambulatory care), except for emergency care. ORIGINALITY/VALUE: The paper shows how networks and SNA techniques provide novel and useful means to understand communication and collaboration between hospital professionals. PMID- 20845678 TI - Healthcare reforms and cost reduction strategies in Europe: the cases of Germany, UK, Switzerland, Italy and France. AB - PURPOSE: This paper aims to analyse health reforms carried out in a sample of European countries. DESIGN/METHODOLOGY/APPROACH: Using a country-specific approach, outstanding health reform features such as: greater competition between sickness funds in Germany; fund-holding practices in the UK; managed care models in Switzerland; health networks in France; and healthcare system decentralisation in Italy are analysed. FINDING: There have been different approaches to controlling healthcare costs. Some states relied on public sector competition by creating quasi-markets (UK), insurance sector competition, particularly in Switzerland and Germany, organisational reforms in France by creating health networks and decentralisation in Italy. RESEARCH LIMITATIONS/IMPLICATIONS: Societal and legal aspects are not discussed. ORIGINALITY/VALUE: The paper compares healthcare reform effectiveness in a number of western European countries. PMID- 20845679 TI - Improving patient safety culture. AB - PURPOSE: Improving hospital patient safety means an open and stimulating culture is needed. This article aims to describe a patient safety culture improvement approach in five Belgian hospitals. DESIGN/METHODOLOGY/APPROACH: Patient safety culture was measured using a validated Belgian adaptation of the Hospital Survey on Patient Safety Culture (HSOPSC) questionnaire. Studies before (autumn 2005) and after (spring 2007) the improvement approach was implemented were completed. Using HSOPSC, safety culture was measured using 12 dimensions. Results are presented as evolving dimension scores. FINDINGS: Overall, 3,940 and 3,626 individuals responded respectively to the first and second surveys (overall response rate was 77 and 68 percent respectively). After an 18 to 26 month period, significant improvement was observed for the "hospital management support for patient safety" dimension--all main effects were found to be significant. Regression analysis suggests there is a significant difference between professional subgroups. In one hospital the "supervisor expectations and actions promoting safety" improved. The dimension "teamwork within hospital units" received the highest scores in both surveys. There was no improvement and sometimes declining scores in the lowest scoring dimensions: "hospital transfers and transitions", "non-punitive response to error", and "staffing". RESEARCH LIMITATIONS/IMPLICATIONS: The five participating hospitals were not randomly selected and therefore no representative conclusions can be made for the Belgian hospital sector as a whole. Only a quantitative approach to measuring safety culture was used. Qualitative approaches, focussing on specific safety cultures in specific parts of the participating hospitals, were not used. PRACTICAL IMPLICATIONS: Although much needs to be done on the road towards better hospital patient safety, the study presents lessons from various perspectives. It illustrates that hospital staff are highly motivated to participate in measuring patient safety culture. Safety domains that urgently need improvement in these hospitals are identified: hospital transfers and transitions; non-punitive response to error; and staffing. It confirms that realising progress in patient safety culture, demonstrating at the same time that it is possible to improve management support, is complex. ORIGINALITY/VALUE: Safety is an important service quality aspect. By measuring safety culture in hospitals, with a validated questionnaire, dimensions that need improvement were revealed thereby contributing to an enhancement plan. PMID- 20845680 TI - Quality control and quality assurance of medical committee performance in the Israel Defense Forces. AB - PURPOSE: The paper aims to focus on a unique quality control system that was set up ten years ago to evaluate Medical Classification Committee decision-making processes at the Israel Defense Forces (IDF) conscription center. DESIGN/METHODOLOGY/APPROACH: Two main approaches were deployed by the control system to assess medical classification committees' performance. The first was direct assessment of the medical committees' clinical work and decision-making processes. The second applied data mining procedures to the computerized medical databases. The functional classification codes (FCCs)--codes for the most common medical disorders assigned to male recruits from the central computerized central IDF database, the sub-districts comprising the recruitment centers, and the chairmen assigning the FCCs to recruits--were all analyzed. FINDINGS: A total of 26 FCCs, each indicating a common medical problem and its severity, constituted approximately 90 percent of all FCCs assigned at recruitment centers between 2001 and 2006. Major contributors to medical profiling outcomes were underweight, asthma, chronic headache, mental illness, symptomatic scoliosis, hypnosis, chronic back pain, knee joint disorders, allergic rhinitis and sinusitis. Evaluating the computerized medical database revealed significant differences in: medical profile prevalence; recruitment center FCCs; different sub-districts in a given recruitment center; and profiling by medical committee chairmen. PRACTICAL IMPLICATIONS: Findings indicate disparities between recruitment centers and their chairmen in the medical profiling process owing to variations in recruitment center working methods and medical history taking, physical examinations, interpreting medical information and individual differences in the chairmen's decision-making process. Other reasons include technician and laboratory staff inaccuracies. These significant discrepancies highlighted the need for an intervention program. To minimize variations and create a uniform work platform, an orderly instruction system and training programs for the committee chairmen, technicians and laboratory staff were established. These actions resulted in improved performance in 2007 as confirmed by a decreased variability in the assignment of medical FCCs. ORIGINALITY/VALUE: The paper highlights methods that can be used to assess disability screening, sports medicine committees and primary care setting procedures. PMID- 20845682 TI - Reducing unnecessary outpatient attendances. AB - PURPOSE: The purpose of this paper is to explore unnecessary outpatient department attendances and to improve efficiency by actively pre-assessing patient charts and pre-specifying management plans before scheduled outpatient visits. DESIGN/METHODOLOGY/APPROACH: All charts were reviewed by a senior clinician two weeks before the clinic and a brief, written management plan made. FINDINGS: A significant reduction in clinic sizes by about 40 per cent can be expected. There was a non-significant increase in the ratio of new to review patients and no significant reduction in waiting lists. RESEARCH LIMITATIONS/IMPLICATIONS: Pre-assessing patient charts leads to cancelling unnecessary outpatient reviews, which can increase outpatient department effectiveness. ORIGINALITY/VALUE: Clinical efficiency is becoming increasingly important. This work describes a simple strategy to improve outpatient department productivity. PMID- 20845681 TI - DOC questionnaire: measuring how GPs and medical specialists rate collaboration. AB - PURPOSE: This paper aims to assess the validity of a questionnaire aimed at assessing how general practitioners (GPs) and specialists rate collaboration. DESIGN/METHODOLOGY/APPROACH: Primary data were collected in The Netherlands during March to September 2006. A cross-sectional study was conducted among 259 GPs and 232 specialists. Participants were randomly selected from The Netherlands Medical Address Book. Specialists rarely contacting a GP were not invited to participate. FINDINGS: Exploratory factor analysis indicated that the questionnaire, consisting of 20 items, measured five domains: organisation; communication; professional expertise; image; and knowing each other. Cronbach's alpha coefficients ranged from 0.64 to 0.83 indicating sufficient internal consistency. Correlation coefficients between domains were all < 0.4. All but "communication" clearly produced distinguishing scores for different respondent groups. RESEARCH LIMITATIONS/IMPLICATIONS: This study shows that the doctors' opinions on collaboration (DOC) questionnaire is valid and that it may have the potential to give feedback to both medical professionals and policy makers. Such feedback creates an opportunity to improve collaboration. ORIGINALITY/VALUE: The DOC questionnaire is a useful instrument for assessing collaboration among GPs and specialists. It can provide feedback to both medical professionals and policy makers. Such feedback creates an opportunity to improve collaboration. PMID- 20845683 TI - [Review of pulmonary Mycobacterium xenopi infection cases: 11 cases of our own and 18 other cases reported in Japan]. AB - OBJECTIVE: To investigate clinical features of patients with pulmonary Mycobacterium xenopi infection treated at our hospital. SUBJECTS AND METHODS: We diagnosed 11 cases of M. xenopi infection at Tokyo National Hospital between 2000 and 2008 and recorded the drug susceptibility, patient characteristics, radiographic findings, treatments given and clinical courses. Eighteen other Japanese cases from the literature were discussed along with our findings. RESULTS AND METHODS: The cases of M. xenopi infection at our hospital consisted of 10 men and 1 woman with a mean age (+/- SD) of 55.1 +/- 19.4 years. Among the patients, 10 were smokers, 4 were heavy drinkers, and 6 had sequelae of pulmonary tuberculosis as an underlying disorder. Four patients had chronic obstructive pulmonary disease and 2 had diabetes mellitus, while there were 2 patients who had no underlying disease. All cases had radiographic opacities, predominantly found in the upper lung region, and cavernous lesions. These findings were demonstrated in both lungs in 5 patients, in the right lung only in 5 patients and in the left lung only in 1 patient. Concurrent aspergillosis was observed in 8 patients. The bacterial isolates from 7 cases were tested for drug sensitivity to levofloxacin (LVFX) and were found to be susceptible. M. xenopi disease was treated in 5 cases with INH+RFP+EB, in 2 cases with INH+RFP+Clarithromycin (CAM), and in 1 case with RFP+EB+CAM. Concurrent aspergillosis was treated with itraconazole in 2 cases. One patient underwent surgery for lung cancer. The duration of treatment was 16.4 +/- 12.8 months (range, 4-36 months). The radiographic findings were improved in 4 cases, deteriorated in 2 and unchanged in 5. M. xenopi was eradicated bacteriologically in 6 cases. The combination of radiographic and bacteriological findings indicated improvement in 3 cases, no change in 6 and deterioration in 2. DISCUSSION: The review of our cases disclosed that medical treatment alone was not sufficient in most cases for the control of clinical M. xenopi infection as reported overseas. Although we did not use LVFX for treatment, LVFX might be recommended for the treatment since all isolates tested proved to be susceptible to LVFX. PMID- 20845684 TI - [Clinical investigation among elderly patients with tuberculosis]. AB - OBJECTIVES: We discussed the factors which may confuse diagnosis and treatment of tuberculosis (TB) in elderly patients, in order to improve the situation. SUBJECTS AND METHODS: 414 patients who were hospitalized for active tuberculosis in Tokyo National Hospital were divided into three groups according to their ages (in years): less than 65, 65 to 74, and greater than 75. The three groups were compared in terms of performance status (PS), serum albumin level (whether over 3 g/dl or not), underlying diseases, symptoms at onset, sputum smear findings for acid-fast bacilli, presence or absence of cavitary lesion, regimen of treatment, adverse reaction to medications, and treatment outcome. RESULT: The older group had significantly poorer PS (3 or 4), lower albumin level, more complications, a larger proportion of non-respiratory to respiratory symptoms, less cavity formation, less likelihood of continuing to take drugs regularly and higher mortality. It is supposed that these characteristics are mostly due to the aging itself. CONCLUSION: Diagnosing and treating active tuberculosis among elderly people is difficult because of nonspecific and thus confusing findings due to other diseases or aging. Delay in diagnosis and start of treatment makes prognosis of their TB poorer. To improve this situation we should keep a high index to TB and make better use of novel diagnostic technologies. For satisfactory treatment that allows maintenance of a high level of activity of daily life, it is necessary to pay more attention to such aspects as nutrition and rehabilitation and to offer appropriate supports. PMID- 20845685 TI - [Control of cattle TB in Japan]. AB - Traditional food custom of Japan changed after the opening of the country in late 19th century, and habit of eating beef and of drinking milk was introduced, and the control of cattle TB had become one of major topics of veterinary medicine in Japan. Old tuberculin (OT) prepared by Koch R in 1890 initially intended to cure TB, however, it was found ineffective against TB, while local and general reactions after the introduction of OT were found to be useful to detect TB infection, and OT was first applied in veterinary medicine to detect TB infection in cattle. Cattle TB Control Law was legislated in Japan in 1901, and cattle was subjected to health checking including tuberculin test, and TB cattle had to be slaughtered, and TB suspects had to be isolated. Several trials had been done to improve the implementation of the Law by increasing the number of experts in health checking of cattle including tuberculin test and compensation for cattle slaughtered during isolation, and they were partly achieved in the revision of the Law in 1933. However, no marked progress was achieved up to 1945 because of war conditions. In 1948 during the occupation period by the US, tuberculin test method was changed to intradermal skin test method by the strong recommendation of the GHQ, and some lawsuits were raised to slaughter cattle based on tuberculin positive reaction by the newly introduced intradermal method. Autopsy was done for slaughtered cattle due to tuberculin positive test results, and as shown in Table 1, TB lesions were found in the majority of autopsied cattle, and thereafter, no more lawsuits were raised. Annual examination including tuberculin test has been continued hard thereafter, and as shown in Fig. 3, the prevalence of TB cattle has dropped down rapidly, and only one or few TB cattle were found by the annual examination, and TB has been nearly eliminated from cattle in Japan. The efforts made by those engaged in the fight against TB in cattle in Japan were highly appreciated. PMID- 20845686 TI - [A case of tuberculous pleurisy with transient new intra-pulmonary lesions during anti-tuberculosis therapy]. AB - A 24-year-old man who had been treated 3 months for tuberculous pleurisy presented with thoracic back pain. Chest CT showed a new lesion abutting the pleura, despite the disappearance of pleural effusion. Two weeks later, the mass abutting the pleura progressed to form a new intrapulmonary infiltrative shadow. A transbronchial lung biopsy was performed and the histopathologic examination of the specimen from this lesion revealed granulomatous inflammation without caseous necrosis or acid-fast bacilli. No acid-fast bacilli were cultured from the bronchoalveolar lavage fluid. Anti-tuberculosis medication was continued without change, and the lesions finally resolved. More than 3 years have passed since the completion of anti-tuberculosis chemotherapy, and no recurrence has been observed. We believe that these lesions were pulmonary tuberculomas and transient intra-pulmonary infiltration due to non-specific inflammation, caused secondarily by an excessive immune response, as in paradoxical worsening. PMID- 20845687 TI - [A case of cold abscess of the chest wall due to thoracic drainage for tuberculous pleuritis]. AB - A 56-year-old man underwent thoracic drainage for two weeks for tuberculous pleuritis. He was put on antituberculosis chemotherapy with INH (400 mg), RFP (450 mg), and EB (750 mg). Two months later, he developed an elastic hard subcutaneous mass in the area of the previous thoracic drainage. The mass was 10 cm in diameter, warm, reddish and painful. Chest computed tomography (CT) revealed localized and encapsulated empyema in the left thoracic space and a subcutaneous abscess with rim enhancement in the left lateral chest wall. Magnetic resonance imaging (MRI) demonstrated a dumbbell abscess in the subcutaneous tissue communicating with the empyema through the chest wall. A needle aspiration of the subcutaneous abscess had acid-fast bacilli smears of 2+ and tested positive by polymerase chain reaction (PCR) for Mycobacterium tuberculosis. Thus, he was diagnosed with a cold abscess of the chest, with the empyema in the thoracic space draining into the chest wall through the cut for artificial drainage. Continuation of the anti-tuberculosis treatment and the drainage of the empyema with repeated aspiration reduced the subcutaneous mass, and the clinical and radiological course was favorable. Both the smear and culture for acid-fast test became negative. After completion of chemotherapy, there has been no disease recurrence. PMID- 20845688 TI - [A case of multidrug-resistant tuberculosis who acquired additional resistance to ethambutol before the result of the initial drug sensitivity test was reported]. AB - On December 6, 2008, a 52-year-old man presented to a clinic with chronic cough, sputum, and chest discomfort, which had lasted since mid-November. Since the chest radiograph showed a small cavity with small nodules and granular shadows, he was referred to another hospital. On TB-PCR, the gastric juice was positive. Therefore, on December 16, 2008, treatment for pulmonary tuberculosis was initiated with isoniazid, rifampicin, ethambutol, and pyrazinamide. However, on February 4, 2009, a drug susceptibility test revealed that the bacilli were resistant to isoniazid and rifampicin. Therefore, he was referred to our hospital. At that time, he had no symptoms and his sputum smear was negative. We performed a right upper lobectomy. The smear result of the surgical specimen was heavily positive (equivalent to Gaffky 6), and the drug susceptibility test showed resistance to ethambutol in addition to isoniazid and rifampicin. After surgery, we treated him with pyrazinamide, streptomycin, para-aminosalicylate, ethionamide, and levofloxacin. We report this case of multidrug-resistant tuberculosis without past treatment who acquired additional resistance to ethambutol during the first 2 months of chemotherapy. When treating multidrug resistant tuberculosis, very careful consideration of susceptibility to other drugs is warranted. PMID- 20845689 TI - [Tuberculosis annual report 2008--series 10. Treatment outcome and TB deaths]. AB - Evaluation of the outcome of treatment by the cohort analysis method is an important aspect of TB control. In the Japanese tuberculosis (TB) surveillance system, the outcome of treatment is automatically classified by computer according to the order of pre-set algorithm, so the treatment outcome is evaluated very rigidly. Although treatment outcomes are classified roughly into the eight categories of "cured", "completed", "died", "failed", "defaulted", "transferred", "still on treatment" and "not evaluated", there are actually 15 categories in our surveillance system; each category of "completed", "defaulted", and "still on treatment" has two subcategories and "not evaluated" has five subcategories. In the case of new sputum smear positive pulmonary cases (n=9,421) newly notified in 2007, their treatment outcome was as follows; "success" which combined "cured" and "completed" was 45.5%, "died" was 18.4%, "failed" was 1.0%, "defaulted" was 5.0%, "transferred" was 3.2%, "still on treatment" was 12.0% and "not evaluated" was 14.9%. Among the 5.0% who were classified as "defaulted", 0.7% was due to treatment interruption for more than consecutive 60 days or 2 months, and 4.3% was due to premature treatment cessation of any causes. The category "not evaluated" includes those who died before beginning treatment, those whose initial treatment regimen is unknown, those whose treatment is other than standard treatment, those who stopped INH and/or RFP before treatment completion, and those whose information is insufficient for classifying treatment outcome. In addition to evaluation of treatment outcome by the cohort method, the proportion of deaths was observed among all forms of TB patients (n = 25,184) and new sputum smear positive pulmonary patients (n=9421) who were newly registered in 2007. 16.4% of all forms of TB cases and 22.5% of new sputum smear positive pulmonary cases died within one year after beginning of treatment. Among new sputum smear positive pulmonary patients died within one year after beginning of treatment (n=2124), 36.2% of them died within one month after beginning of treatment, 52.4% within two months, 61.9% within three months. PMID- 20845690 TI - [Application of partial median sternotomy in cardiac surgery in patients with tracheostoma]. AB - Median full-sternotomy carries a risk of sternal infection and lethal mediastinitis in cardiac surgery. We performed open-heart surgery through partial median sternotomy in 5 patients with tracheostomy. Coronary artery bypass grafting (CABG) was performed in 3 patients, aortic valve replacement in 1, and mitral valve replacement in 1. No operative deaths or complications related to wound infection occurred. Partial sternotomy represents a safe alternative in cardiac surgery in patients with tracheostoma. PMID- 20845691 TI - [A phase II study of gemcitabine and carboplatin bi-weekly combination chemotherapy for complete resected non-small-cell lung cancer patients]. AB - Recently, postoperative adjuvant chemotherapy is very popular for completely resected non-small-cell lung cancer patients, but cisplatin-based regimens are not safety and tolerable for outpatients. In this study, gemcitabine plus carboplatin regimen is selected as more safety and feasible for outpatient chemotherapy, and scheduled bi-weekly administration to reduce hematological toxity, especially thrombocytopenia. Twenty patients with completely resected non small-cell lung cancer (pStage IA - IIIB) administered gemcitabine 1,000 mg/m2 and carboplatin area under the curve (AUC) 3 bi-weekly for 8 times at outpatient chemotherapy center except that 1st treatment was done with short stay in hospital. Of 20 patients, 13 (65%) completed the 8 times bi-weekly treatment and 7 patients incompleted because of neutropenia in 2, anemia in 1, liver dysfunction in 3, interstitial pneumonia suspected in 1. Relative dose intensity was 79%. Seven patients had grade 3/4 neutropenia, 2 had grade 3 thrombocytopenia, 2 had grade 3 anemia, and 2 had grade 3 liver dysfunction. Hematological toxity, especially thorombocytopenia are less than standard administration of gemcitabine and carboplatin regimen, so we conclude that this regimen is feasible in outpatient adjuvant chemotherapy for completely resected non-small-cell lung cancer. PMID- 20845692 TI - [Refractory pulmonary hypertension following mitral valve repair necessitating percutaneous cardiopulmonary support]. AB - A 37-year-old woman underwent semi-emergency mitral valve plasty for severe mitral regurgitation and congestive heart failure. Although repair was successfully performed and the left ventricular function was maintained, refractory pulmonary hypertension precluded cessation of cardiopulmonary bypass. Inhalation of nitric oxide was ineffective, and assist circulation was required. All data obtained from the Swan-Ganz catheter and other routine monitors were devastating, and the patient showed no clinical recovery in the early postoperative period. However, transesophageal echocardiography (TEE) performed on the 2nd postoperative day (POD) revealed much better filling of the left heart and the patient was weaned from assist circulation on the 4th POD. Pulmonary vascular disease was denied histologically. Late cardiac catheterization disclosed normal pulmonary artery pressure and resistance. TEE played a key role during very complicated postoperative management. Monitoring of the left atrial pressure might be necessary in cases that require assist circulation due to pulmonary vasoconstriction. PMID- 20845693 TI - [Thymic basaloid carcinoma]. AB - This is a case of a 72-year-old male whose chest computed tomography (CT) revealed a 2.0 x 1.6 cm anterior mediastinal solid tumor during follow-up of an abnormal shadow of the lung. The tumor increased its size during preoperative follow-up, and multilocular cyst was also observed. Radical thymectomy was performed, and histopathologically the tumor was diagnosed as thymic basaloid carcinoma. Thymic basaloid carcinoma is a rare tumor and is often associated with multilocular thymic cyst. There are only 32 cases reported both locally and internationally. Surgical resection is the general treatment for this disease. Adjuvant radiotherapy can be considered in cases of incomplete resection and invasive tumor. In our case, no recurrence of the tumor was noted 12 months post operative. Generally, the malignancy of thymic basaloid carcinomas are regarded as low-grade compared with other thymic carcinomas, however, since mortality and recurrence have been reported, careful follow-up is required. PMID- 20845694 TI - [Surgical repair of a total-defect aortopulmonary window in a neonate]. AB - Aortopulmonary window (APW) is a rare congenital heart defect that requires urgent repair, as it can lead to rapid development of pulmonary hypertension. A 6 day-old boy with a total-defect APW was transferred to our hospital and underwent definitive repair on the 15th day after birth. The ascending aorta and pulmonary trunk were divided to create a larger tissue margin on the aortic side for the next seam. Then, the aortic window was sutured and closed directly, while the large pulmonary defect was reconstructed with a fresh autologous pericardial patch. Although peritoneal dialysis was briefly required for acute renal failure due to low output syndrome, his condition improved and he was discharged 22 days after surgery. Six years later, he remains well, without complications or need for medication. PMID- 20845695 TI - [An approach to vacuum-assisted closure therapy using the S-B Vac]. AB - Vacuum-assisted closure (VAC) therapy is increasingly applied for patients with wound dehiscence or mediastinitis caused by surgical site infection (SSI) after open-heart surgery. We have used wall suction for such cases in the past. But this method was an obstacle for improvement of the quality of life (QOL) of the patient. Since the S-B Vac is portable, this equipment may allow wound healing without decreasing QOL. Here, we report a case in which VAC therapy was performed using the S-B Vac. PMID- 20845696 TI - [Resection and reconstruction of intimal sarcoma of the pulmonary artery with autologous pericardial roll]. AB - Tumors of the pulmonary artery (PA) are rare and their prognosis is poor. Proper diagnosis is often delayed or made post mortem despite diagnostic advances. Although the only treatment of choice is radical surgical resection, local recurrences are soon recognized after the operation. There is no standard regimen of perioperative additional therapy, and its effectiveness is still unknown. We report a case of an 80-year-old male whose PA was almost completely obstructed by the intimal sarcoma. It was resected and reconstructed with autologous pericardial roll. His postoperative course was uneventful. PMID- 20845697 TI - [Pulmonary hamartoma associated with lung cancer]. AB - Pulmonary hamartoma is most common benign tumor of the lung and is not recognised as having a character of malignant transformation. So, longtime radiological observation is not uncommon for patients with diagnosis of pulmonary hamartoma from computed tomography (CT) finding. Although pulmonary hamartoma does not transform to malignancy, high frequency of coexistence hamartoma and lung cancer has been reported. We experienced 14 cases of resected pulmonary hamartoma, and 3 of them had lung cancer, showing that 21.4% of pulmonary hamartoma coexisted with lung cancer. Patients with pulmonary hamartoma should undergo sufficient evaluations for malignancy. PMID- 20845698 TI - [Plasmacytoma of chest wall]. AB - We report a 70-year-old man who suffered from right anterior chest wall tumor. Physical examination revealed an elastic hard mass at the right 4th rib measured 6 cm in diameter. Chest X-ray and computed tomography (CT) revealed enhanced mass and destruction of the 4th rib. As needle aspiration cytology did not define the diagnosis, we performed a chest wall resection and reconstruction. Histological diagnosis of the tumor was plasmacytoma (IgG lambda type). Five months after the operation, the tumor recurred at the right anterior chest wall. Radiotherapy was performed with dose of 50 Gy. Fourteen months after the operation, the tumor recurred at the lower sternum, and the chemotherapy was performed using ranimustine, vincristine, melpharan and dexamethasone. He is doing well 2 years and 9 months after surgery without signs of progressive disease or conversion to myeloma PMID- 20845699 TI - [Delayed massive hemothorax due to diaphragmatic injury by lower rib fracture]. AB - We report a case of delayed massive hemothorax, a 72-year-old women, due to diaphragmatic injury by multiple lower rib fracture on 4th day aftrer traffic injury. We tried to stop bleeding by transcatheter arterial embolization, but the control of bleeding was difficult, necessitating the emergency surgery. The diaphragmatic injury about 3 cm diameter was found, and was sutured with absorption thread. The post operative course was uncomplicated. Patient was discharged on 51th day after injury. Careful observation is important for delayed hemothorax after lower rib fracture. PMID- 20845700 TI - [Organizing printed copies from on-line scientific journals]. AB - With recent advances in reference management software, bibliographic data can be down-loaded directly from PubMed and other databases. And then, the down-loaded full text of an article is immediately printed out. However, it is still a hassle to store, organize and search hard copies accumulated in piles. PMID- 20845701 TI - [Total aortic arch replacement for aortic aneurysm in a 91-year-old man: report of a case]. AB - A 91-year-old man was transferred to our hospital because of severe chest pain. Chest computed tomography (CT) scan showed impending rupture of the true aneurysm of the aortic arch. The patient underwent emergent graft replacement of the total aortic arch. He was extubated on the 1st postoperative day, and received continuous hemodiafiltration (CHDF) for oliguria. However, he recovered from oliguria and renal dysfunction. He discharged at the 67th postoperative day. PMID- 20845702 TI - [Successful treatment of a 97-year-old female with acute aortic dissection (DeBakey type II); report of a case]. AB - We operated on an advanced aged patient who presented with acute aortic dissection (DeBakey type II). The patient was a 97-year-old female who was admitted to our hospital due to chest pain. We initially administered conservative medical therapy as far as possible. However, due to the continuing chest pain and the fact that the diameter of the aneurysm was quite large and the risk of a rupture was high, we therefore decided to operate on the ascending graft replacement using retrograde cerebral perfusion on the 8th day from onset. Sufficiently controlling the bleeding proved to be difficult because the site of cannulation on the right atrium was fragile and it therefore tended to split easily. The postoperative course was uneventful except for the fact that it took the patient longer than usual to wake up from anesthesia. As far as could be determined based on an extensive search of the pertinent literature, this appears to be the most advanced aged case of an operation for acute aortic dissection ever reported in Japan. PMID- 20845703 TI - [Aortic regurgitation due to quadricuspid aortic valve; report of a case]. AB - A 66-year-old man was referred to our hospital for surgical treatment for aortic regurgitation. Transthoracic echocardiography revealed the diagnosis of aortic regurgitation due to quadricuspid aortic valve. During operation, we confirmed that the aortic valve consisted of 4 leaflets with almost same size (Hurwitz and Roberts classification type A). We performed valve replacement because each leaflet has degenerative change. The patient's postoperative course was uneventful and discharged the hospital without complications. Congenital quadricuspid aortic valves are rare, and patients with this disease are frequently operated because of aortic regurgitation. Presently, common operative procedure is aortic valve replacement, although in the future valvuloplasty should be investigated. PMID- 20845704 TI - [Bronchial carcinoid discovered due to repeated pneumonia in the lingular division of the left lung; report of a case]. AB - Bronchial carcinoids are relatively rare, low-grade malignancies. Here we report a case of a bronchial carcinoid found by repeated pneumonia in the lingular division of the left lung. A 34-year-old man was referred to our hospital because of an abnormal shadow detected in an annual checkup. A chest computed tomography (CT) showed an infiltrative shadow in the lingular division. Two months later, a follow-up CT showed the shadow had remarkably improved. Two years after the 1st detection, an annual checkup revealed an abnormal shadow in the same lesion again. A chest CT showed not only an infiltrative shadow in the lingular division, but also a solid mass with calcification in the lingular bronchus. A bronchoscopy revealed an obstruction of the left upper lobe bronchus by a vascularized polypoid tumor. A transbronchial biopsy indicated a presence of a carcinoid, and a resection of the left upper lobe was performed. A histopathological examination showed that it was a typical carcinoid. The patient has been free of recurrence for 2 years since surgery. This is a case with repeated pneumonia and atelectasis caused by a bronchial carcinoid. PMID- 20845705 TI - [Lung cancer in patient with a common trunk of left pulmonary veins; report of two cases]. AB - A 69-year-old man and a 53-year-old man with lung cancer of left upper lobe underwent pulmonary resection. A preoperative chest computed tomography (CT) scan showed the left superior and inferior pulmonary veins forming a common trunk. In the former case, the common trunk was misidentified as the superior pulmonary vein. The latter was recognized preoperatively by using 3-dimensional CT, and successfully performed left superior segmentectomy. This variation type is surgically important because of a potential risk of intraoperative bleeding and damage to pulmonary circulation during pulmonary resection. PMID- 20845706 TI - [Incidental detection of thymic mucoepidermoid carcinoma with massive calcification; report of a case]. AB - 31-year-old man who complained of chest pain due to chest wall wound caused by tumble. He took chest X-ray examination and suggested of having mediastinal tumor. Computed tomography (CT) scan revealed 3.0 cm mass in diameter with irregular shaped calcification and lobulated cystic lesion (size : 21 x 17 x 41 mm). The mediastinal tumor was totaly removed by surgical operation. No invasive portion was observed between mediastinal pleura and solid tumor. Pathological examination revealed that tumor was composed of mucoepidermoid carcinoma of the thymus and postoperative adjuvant radiotherapy was performed. The patient have survived without disease for 3 years after surgery. PMID- 20845707 TI - [Surgery for the chest wall tuberculous abscess; report of a case]. AB - The patient was a 70-year-old woman who visited our hospital due to right chest pain. Chest computed tomography (CT) and magnetic resonance imaging (MRI) revealed an abscess in the chest wall which was diagnosed as tuberculous abscess by a bacterial examination of needle aspiration. In spite of anti-tuberculosis chemotherapy, the abscess was ruptured on day 15 after starting treatment, and a radical resection of the abscess was performed after 10-days conservative treatment. Skin over the abscess and a part of right 7th and 8th rib were also resected. Postoperative anti-tuberculosis chemotherapy was added and no relapse was seen for 40 months postsurgery. PMID- 20845708 TI - [Relationship between IgE antibodies to recombinant allergens rBet v 1 and rBet v 2 and food causing oral allergy syndrome in cases of birch-pollen allergy]. AB - BACKGROUND: Persons allergic to birch pollen often report oral and pharyngeal hypersensitivity to fruit and vegetables, such as apples and peaches due to immunological cross-reactivity, or oral allergy syndrome (OAS) sometimes accompanied by systemic reaction. Such cross-reactive antigen reactions involve Bet v 1, the main birch-pollen allergen, and Bet v 2, birch-pollen profilin. We evaluated the food/antigen relationship. METHODS: Subjects interviewed numbered 60-40 women and 20 men aged 12 to 70 (mean age: 35 years)-suffering OAS episodes and having IgE birch-pollen antibodies. Using CAP scoring we examined IgE antibodies to recombinant Bet v 1 (rBet v 1), recombinant Bet v 2 (rBet v 2), and recombinant Pru p 3 (rPru p 3) a peach lipid transfer protein (LTP). A CAP score of 0.35 or more was considered positive. We evaluated the relationship between recombinant allergens and 9 fruit often involving OAS--apple, peach, cherry, kiwi, pear, melon, plum, strawberry, and watermelon-based on subjects' reports. RESULTS: Of the 60, all (100%) were rBet v 1-positive, 9 (15%) rBet v 2-positive, and none (0%) rPru p 3-positive. Rose-family fruit-apples, peaches, cherries, pears, plums, and strawberries-often caused OAS regardless of positive or negative rBet v 2 CAP and were associated with rBet v 1. In contrast, more of those who were rBet v 2 CAP-positive had OAS to non-rose-family fruit-melon and watermelon-than those rBet v 2-negative. In rose-family and non-rose-family classification of the 9 fruit, cluster analysis and kappa statistics showed non rose-family melon, watermelon, and kiwi to be associated with rBet v 2, as were grass and mugwort pollen allergies. CONCLUSION: Bet v 1 is associated with OAS due to rose-family fruit and Bet v 2 with OAS due to non-rose-family fruit. PMID- 20845709 TI - [New scoring proposed for endoscopic swallowing evaluation and clinical significance]. AB - Dysphagia is becoming a critical medical and social issue with aging population. Appropriate treatment requires that swallowing be assessed objectively. The simple, clinic-based scoring we developed for flexible endoscopic evaluation of swallowing (FEES) uses four parameters--(1) the salivary pooling degree at the vallecula and piriform sinuses, (2) the glottal closure reflex induced by touching the epiglottis or arytenoid with the endoscope, (3) swallowing reflex initiation assessed by "white-out" timing, and (4) pharyngeal clearance after blue-dyed water is swallowed-categorized as 0 for normal, 1 for mildly impaired, 2 for moderate, or 3 for severe. Scores given by experienced otolaryngologists expert in treating dysphagic subjects correlated significantly with those of nonexpert otolaryngologists and speech-language-hearing therapists. Pharyngeal clearance evaluated by videofluorography correlated with FEES clearance scores, as did aspiration severity with total scores statistically significantly. Feeding procedures related significantly to total scores for the four parameters, indicating its usefulness in deciding oral food intake. Our new scoring is thus simple and reliable in evaluating dysphagia severity and features, and potentially clinically advantageous. PMID- 20845710 TI - [A clinical study of traumatic tympanic membrane perforation]. AB - We reviewed 165 cases of traumatic tympanic membrane perforation treated in the last 9 years (2000-2008). Of these, 103 sustained direct injury and 62 indirect injury. Ear picking accounted for 90.3% of direct injuries. Perforation size followed the classification of Yoshikawa, with Grade I perforation the most common, according for 129 (78.2%). The anteroinferior quadrant perforation site was the most common, with 98 (59.4%). Of the 165, 66 were lost during followup. Of the remaining 99, perforations closed spontaneously in 85 (85.9%), within a mean 25.9 days. Tympanoplasty was done in 14, in whom postoperative hearing improved in 12. The remaining 2 had ossicular fractures associated with perilymph fistula. In the 14 undergoing surgery, tympanic membrane perforation relapsed in 4 and 2 developed cholesteatoma as tympanoplasty sequelae. PMID- 20845711 TI - [A new scoring system for assessing the severity of adult acute rhinosinusitis]. AB - Treating acute rhinosinusitis requires assessing severity and selecting appropriate antimicrobial agents. In 2006, we developed clinical scoring system for diagnosing and treating acute rhinosinusitis based on three clinical symptoms of rhinorrhea, fever, and facial pain and three nasal findings of characteristics and nasal discharge amount, nasal mucosal swelling and nasal mucosal redness. To verify and update scoring, we studied score-based diagnosis of adult acute rhinosinusitis severity. Prevalence of symptoms such as fever and serous nasal discharge in 95 subjects was low as 8.4% and 3% indicating less useful as evaluation items on the diagnosis. Mucopurulent nasal discharge (r = 0.67), facial pain (r = 0.51), rhinorrhea (r = 0.47), and swelling (r = 0.45) correlated significantly with severity evaluated by attending otolaryngological specialists. Nasal mucosal swelling caused discrepancy between clinical scoring and specialists' assess- ment. Evaluated by multivaliate analysis, factors affecting severity assessment were mucopurulent nasal discharge, facial pain, and rhinorrhea (p < 0.0001), but not swelling (p = 0.49). We concluded that mucopurulent nasal discharge scored 0, 2, or 4, facial pain scored 0, 1, or 2, and rhinorrhea scored 0, 1, or 2 should be used in evaluation in new clinical scoring, classified by severity as mild scored 1-3, moderate scored 4-6, and severe scored 7-8 by evaluating consistency with specialist assessment. PMID- 20845712 TI - [Pricing and uptake rate of public funded pneumococcal vaccination for the elderly in Japan]. AB - PURPOSE: The number of municipalities that offer a pneumococcal pneumonia vaccine (PPV) to their aged inhabitants has been increasing. In this study, a complete count survey of the practice of municipality-organized PPV vaccination programs was carried out to explore co-payment/subsidy levels and uptake rates. METHOD: A questionnaire inquiring into the price charged to the vaccinee, the subsidy provided by the municipality, the size of the target population, and the numbers of individuals vaccinated from 2001 to 2007 was sent to 63 municipal authorities which had organized PPV vaccination programs. Annual changes of co payment/subsidy and uptake rates are examined with analysis of variance (excluding the year with n < or = 2). RESULTS: The number of municipalities that provided a subsidy was 1 in 2001, 2 in 2002, 18 in both 2003 and 2004, 24 in 2005, 41 in 2006, and 56 in 2007. Average levels of subsidy were 3233 yen in 2003, 3225 yen in 2004, 3168 yen in 2005, 3158 yen in 2006, and 3351 yen in 2007. Average levels of co-payment are 3899 yen in 2003, 3928 yen in 2004, 3979 yen in 2005, 3891 yen in 2006 and 3672 yen in 2007. No significant differences were found among average levels of subsidy/co-payment between consecutive years (F = 0.195, p = 0.964/F = 0.271, p = 0.949). Average uptake rates by number of years since the beginning of the program (response rate 68.1%, 109/160) were 17.7% for the 1st-year, and 5.4%, 3.7%, 3.4%, 4.6% for the 2nd- to 5th-years, respectively. Statistically significant differences were observed between the 1st- and each of the following years (Dunnett T3, p < 0.001). Average uptake rates in the first year of the program (response rate 80.9%, 51/63) were 32.1% in 2003, 8.5% in 2005, 13.6% in 2006 and 16.5% in 2007. Significant differences were observed between 2003 and 2005 (Tukey's HSD, p = 0.03), and 2003 and 2006 (Tukey's HSD, P = 0.015). CONCLUSION: Our results revealed levels of co-payment/subsidy and uptake rates of municipality-organized PPV vaccination programs for the first time. PMID- 20845713 TI - [Development of social activities-related daily life satisfaction scale for the elderly and evaluation of its reliability and validity]. AB - PURPOSE: The purpose of this study was to develop a Social Activities-Related Daily Life Satisfaction Scale specifically applicable to elderly people in communities and to evaluate its reliability and validity. METHODS: Sixteen items were extracted from an initial pool and assessed for inclusion in the scale by correlation and exploratory factor analyses. To confirm validity, confirmatory factor analysis was conducted and correlation coefficients were calculated. In addition, t-tests were performed in order to generate scores of the subscale related to activity. To prove reliability, Cronbach's coefficient alpha values were calculated. Data for 755 older adults aged 65 to 84 years were obtained from a mail survey in Ichikawa City, Chiba Prefecture. RESULTS: Exploratory factor analyses indicated that four factors, "satisfaction with learning" (four items), "satisfaction with usefulness to others and society" (four items), "satisfaction with health and physical strength" (three items), and "satisfaction with friends" (three items) should be extracted. Confirmatory factor analysis for assessing the 14-item four-factor model showed high goodness of fit indices (GFI = 0.943, AGFI = 0.915, RMSEA = 0.068). Concurrent validity was established by comparing the score of the scale with five external variables (Activity and Daily Life Satisfaction Scale for the Elderly, Life Satisfaction Index K, etc). Student's t tests revealed that each score of the subscale was positively associated with activity variable. The overall Cronbach's coefficient alpha for the scale was 0.919 and for its four subscales values ranged from 0.814 to 0.887. CONCLUSION: A Social Activities-Related Daily Life Satisfaction Scale was derived consisting of four subscales, "satisfaction with learning", "satisfaction with usefulness to others and society", "satisfaction with health and physical strength", and "satisfaction with friends". The results of the present study suggested that the Social Activities-Related Daily Life Satisfaction Scale has adequate reliability and validity. PMID- 20845714 TI - [Life-space of community-dwelling older adults using preventive health care services in Japan and the validity of composite scoring methods for assessment]. AB - OBJECTIVE: Life-space is a spatial measure of mobility defined by the distance a person routinely travels to perform activities over a specific time period. Life space assessment (LSA) has been widely applied, but measurement properties have not been investigated in a Japanese population. The purpose of this cross sectional study was to describe distributions of maximal life-space and to clarify the validity of composite scores of an LSA scale among community-dwelling older adults using preventive health care services in Japan. METHODS: Surveys were conducted between November 2007 and February 2008 with a specially prepared Japanese LSA version. The sample was composed of 2,147 participants using preventive health care services provided by the Japanese long-term care insurance system, all being aged 65 and over, with adequate cognitive functions and living at home in the community (29.5% men, mean age +/- [SD] 79.4 +/- 6.9 years). First, the levels of life-space, based on how far a person had travelled on leaving his or her place of residence during the month preceding the assessment, were investigated. Second, LSA scores were calculated considering the degree of independence as well as frequencies for individuals at each level, then descriptive statistics were checked. Finally, it was tested whether the scores could be related to external criteria and functional or socio-psychological variables stated in previous studies. RESULTS: Sixty-four percent of individuals attained the highest level of life-space (i.e. outside town). The average of the composite scores was 51.4 +/- 25.2 points and the distribution was almost normal. The dispersion of the scores tended to be large. Values correlated with the hierarchical mobility level classification as an external criterion (0.539). As hypothesized, the scores were correlated with age (-0.296), functional mobility (time up and go test) (-0.387), and instrumental activities of daily living (0.533), and were discriminated by sex, depressive mood, and perceived health status, in the expected directions. CONCLUSIONS: The present study described the extent of life-space in older adults using preventive health care services in Japan, and provided preliminary support for criterion-related (concurrent) and construct validity of scores with the LSA Japanese version. The LSA composite scoring method may have advantages for detecting differences in life-space among individuals, as compared to simply using the maximal level attained. PMID- 20845715 TI - [Depression and the risk of long-term care insurance certification: the Tsurugaya project]. AB - OBJECTIVE: The purpose of this study was to examine the relationship between depressive status and subsequent certification of long-term care insurance use, and to investigate sex differences in this relationship in an elderly Japanese population. METHODS: The Tsurugaya Project was a comprehensive geriatric assessment conducted for community-dwelling elderly persons aged 70 years or older in the Tsurugaya area, Sendai, Japan (N = 2,925). Of those who participated (N = 958), the 841 who gave informed consent and were not qualified for certification of long-term care insurance use at the baseline survey were analyzed. Depression was asessed using the 30-item Geriatric Depression Scale (GDS). We classified the subjects into three categories: normal (GDS less than 10), mild depression (GDS between 10 and 13), and moderate to severe depression (GDS more than 13 and/or taking antidepressive medication). The hazard ratio of incident certification of long-term care insurance use by depressive status was calculated using the Cox proportional hazards model. RESULTS: During 4 years of follow-up, a total of 151 subjects were certificated for long-term care insurance and 46 subjects died. Particularly in men, the depressive status was related to subsequent incident certification of long-term care insurance use. In men, the age-adjusted hazard ratios (HRs) were 1.77 (95% confidence interval (CI): 0.91 3.48) for mild depression, and 2.26 (1.11-4.64) for moderate to severe depression (P for trend = 0.023). The relationship between depressive status and subsequent certification of long-term care insurance use in men was significant even after adjustment for age, comorbid conditions, social factors and lifestyle (multivariate-adjusted HR: 1.31 (95% CI: 0.65-2.65); mild depression 2.19 (1.06 4.54); moderate to severe depression: P for trend= 0.034). In women, there was no significant association between depressive status and certification of long-term care insurance use. In both sexes, there was no significant association between depressive status and death. CONCLUSION: The relationship between depressive status and subsequent certification of long-term care insurance use was significant only in men. In men, the relationship was significant even after adjustment for age, comorbid conditions, social factors and lifestyle. These results suggest a sex difference in the relationship between depressive status and subsequent certification of long-term care insurance use in elderly Japanese. PMID- 20845716 TI - [Psychosocial classification of suicide completers by employment situation: a psychological autopsy study]. AB - OBJECTIVE: This study sought to clarify psychosocial and psychiatric differences of suicide-completers dependent on their employment situation. METHODS: Since December 2007, we have been conducting a Japan-wide study on suicide-completers using a psychological autopsy method, a semi-structured interview by a psychiatrist and a mental health professional including a public health nurse with the closest bereaved. Items questioned included family environment, suicide situation, life history f, labor situation, economic problems, and psychiatric diagnosis according to DSM-IV criteria at the time of death. As of July 2009, we had collected psychosocial and psychiatric information for 46 Japanese suicide cases. RESULTS: More than half of 31 suicide-completers with a job at the time of their death were married men aged 40-59 (mean age 48.1 +/- 12.6). Many had social difficulties such as alcohol-related problems or debt (38.7% and 41.9%, respectively). More than sixty percent of the 15 unemployed suicide-completers were unmarried and aged 20-39 (mean age 43.4 +/- 19.9). The percentage of women in the unemployed suicide-completers was significantly higher than that for women with a job. Although social problems were not confirmed in the unemployed, the prevalence of alcohol use disorders was significantly higher in suicide completers with ajob than in those who were unemployed. However, the prevalence of schizophrenia was significantly higher in the unemployed. CONCLUSIONS: Our findings suggest that to prevent suicide of those with ajob, enhanced mental health support in the workplace and a better understanding of the association between alcohol use disorders and suicide are required. To prevent suicide of those who are unemployed, mental health support for the younger generation, particularly in cases with schizophrenia, is recommended. PMID- 20845718 TI - [Survey of educational practice to understand mental illness in public junior high schools of the metropolitan area]. PMID- 20845717 TI - [Numbers and activities of public health centers]. PMID- 20845719 TI - [Cell therapy for spinal cord injury]. PMID- 20845720 TI - [Etiology of overactive bladder and its therapeutic perspective--focusing on a myogenic basis for the overactive bladder]. PMID- 20845721 TI - Alcohol consumption and lung cancer risk among Japanese: a meta-analysis. AB - t is unknown what biologic mechanism may be responsible for the harmful effects of alcohol, though several have been suggested. Alcohol consumption is an established risk factor for cancers of the oral cavity, pharynx, larynx, esophagus and liver. However, epidemiologic studies have not provided consistent evidence on the effect of alcohol consumption on the risk of lung cancer. To evaluate the role of alcohol consumption in the risk of lung cancer among Japanese, the authors performed a meta-analysis of existing epidemiological studies. The authors first examined whether current alcohol consumption could potentially increase the risk of lung cancer without considering confounding factors. The summary risk estimate based on then random effects model for current consumption was 0.65 (95% confidence interval (CI) = 0.53 - 0.77). This risk estimate might be biased due to uncontrolled confounders, especially smoking cigarettes which is highly correlated with alcohol consumption. After adjustment for cigarette smoking, the summary risk estimate based on the random effects model for current alcohol consumption was no longer statistically significant (summary risk = 1.00, 95% CI = 0.73 - 1.26). Our results do not indicate that alcohol consumption serves as a major risk factor for lung cancer among Japanese. Additional studies with detailed assessments of alcohol consumption and potential confounding factors will undoubtedly lead to a better understanding of the role of alcohol consumption in lung cancer development. PMID- 20845722 TI - [Neuropathy is associated with depression independently of health-related quality of life in Japanese patients with diabetes]. PMID- 20845723 TI - [Social phobia is not Shako-Kyofu in Japanese, is it?]. PMID- 20845724 TI - [Process of coping with work-family conflicts in dual-income couples with children]. AB - This study elucidates processes of coping with work-family conflicts in double income couples with children. Eight stories of dilemmas concerning work-family conflicts were constructed. Regular employees (N=20) were instructed to narrate the parts of the story in which they thought about how to cope with work-family conflict situations. The protocol analyses revealed the following: (a) most people prioritized their home over their jobs when their families encountered difficult situations, and (b) in cases where either spouse had a demanding or difficult job, there were gender differences with regard to the process of coping with work-family conflicts. The implications of these results are discussed. PMID- 20845725 TI - [Influences on the amount of the reward: how five-year-old children distribute rewards]. AB - Five-year-old children were presented two stories in which each of two characters made different numbers of Origami stars; the total number of stars was 16 in one story and 12 in the other. The children allocated rewards to the characters and justified their allocations. There were three conditions in which the total number of rewards was equal to (Middle-N), less than (Small-N), or more than (Large-N) the total number of stars in each story. Most children allocated the rewards equally to the two characters in the Small-N condition, while almost half of the children did not employ an equal allocation in the Middle-N and Large-N conditions. This suggests that in the Small-N condition, if an equity-like allocation were employed, children would feel sorry for the character given very few rewards, and therefore they distributed the rewards equally. On the other hand, in the Middle-N and Large-N conditions, even when one character received fewer rewards than the other, the children did not feel that the fewer rewards were too few. PMID- 20845726 TI - [Visual representation of natural scenes in flicker changes]. AB - Coherence theory in scene perception (Rensink, 2002) assumes the retention of volatile object representations on which attention is not focused. On the other hand, visual memory theory in scene perception (Hollingworth & Henderson, 2002) assumes that robust object representations are retained. In this study, we hypothesized that the difference between these two theories is derived from the difference of the experimental tasks that they are based on. In order to verify this hypothesis, we examined the properties of visual representation by using a change detection and memory task in a flicker paradigm. We measured the representations when participants were instructed to search for a change in a scene, and compared them with the intentional memory representations. The visual representations were retained in visual long-term memory even in the flicker paradigm, and were as robust as the intentional memory representations. However, the results indicate that the representations are unavailable for explicitly localizing a scene change, but are available for answering the recognition test. This suggests that coherence theory and visual memory theory are compatible. PMID- 20845727 TI - [The effect of prison crowding on prisoners' violence in Japan: testing with cointegration regressions and error correction models]. AB - This research examined the effect of prison population densities (PPD) on inmate inmate prison violence rates (PVR) in Japan using one-year-interval time-series data (1972-2006). Cointegration regressions revealed a long-run equilibrium relationship between PPD and PVR. PPD had a significant and increasing effect on PVR in the long-term. Error correction models showed that in the short-term, the effect of PPD was significant and positive on PVR, even after controlling for the effects of the proportions of males, age younger than 30 years, less than one year incarceration, and prisoner/staff ratio. The results were discussed in regard to (a) differences between Japanese prisons and prisons in the United States, and (b) methodological problems found in previous research. PMID- 20845728 TI - [Hemispheric difference in the time course of semantic activation: evidence from event-related potentials]. AB - To investigate hemispheric differences of semantic activation, event-related potentials were recorded when two pairs of words were successively presented with a SOA of 200 ms or 800 ms. Each word pair was simultaneously exposed to the left (LVF) and right (RVF) visual fields. Participants were required to attend one visual field and make a judgment whether the words (prime-target) presented at the attended visual field were semantically related or not. A priming effect on reaction time was observed for RVF targets with SOA 200 ms, and for both LVF and RVF targets with SOA 800 ms, consistent with the idea that semantic activation is faster in the left than the right hemisphere. In contrast, the priming effect on N400 amplitude was not affected by the SOA and visual field, and the onset latency was shorter for RVF than for LVF targets, irrespective of SOA. The N400 priming effects were interpreted to be associated with task-induced semantic processing. PMID- 20845729 TI - [Relationship between embarrassment and stages of change in purchasing or using of condoms]. AB - This research focused on (a) embarrassment at the time of condom purchase or use, and (b) stages of change (Prochaska & DiClemente, 1983) as psychological factors related to the use of condoms. A written questionnaire was completed by 376 university students. For condom purchases, ANOVAs revealed that scores for "intent of behavior" increased as participants moved from the "precontemplation" stage to the "action" stage. The scores for embarrassment, and many factors of embarrassment, were lower in the "action" stage than in the other stages. However, the patterns of condom use scores were unclear. These results indicate that with regard to condom purchases, persons who are in the "preparation" or earlier stages (i.e., persons who are not purchasing condoms) are particularly susceptible to embarrassment. PMID- 20845730 TI - [Circular relation between children's social power cognition and daily use of influence tactics]. AB - This study examines how children's social power cognitions about themselves and the collective efficacy of their classrooms affect their selection and use of influence tactics toward their classmates. The effect of daily usage of influence tactics by children on agents' perception of social power is also examined. The results of linear regression analysis indicate that children who see themselves as friendly holders of power deriving from the perception of affable friendships use both collaborative and coercive influence tactics. While the use of collaborative tactics encourages agents' friendly social power cognition, the use of coercive tactics only reinforces their coercive power cognition. In addition, it is suggested that the effect of social power over agents' use of influence tactics is moderated by the collective efficacy of their classroom. PMID- 20845731 TI - [Distinguishing the voice of self from others: the self-monitoring hypothesis of auditory hallucination]. AB - Auditory hallucinations (AH), a psychopathological phenomenon where a person hears non-existent voices, commonly occur in schizophrenia. Recent cognitive and neuroscience studies suggest that AH may be the misattribution of one's own inner speech. Self-monitoring through neural feedback mechanisms allows individuals to distinguish between their own and others' actions, including speech. AH maybe the results of an individual's inability to discriminate between their own speech and that of others. The present paper tries to integrate the three theories (behavioral, brain, and model approaches) proposed to explain the self-monitoring hypothesis of AH. In addition, we investigate the lateralization of self-other representation in the brain, as suggested by recent studies, and discuss future research directions. PMID- 20845732 TI - [Genetic and molecular characteristics of the 2009 H1N1 pandemic influenza A virus]. PMID- 20845733 TI - [History of pandemic influenza in Japan]. AB - In Japan, influenza like epidemics were described many times since Heian era. However, Spanish flu as the modern medicine invaded Japan in 1918, thus almost infected 390,000 patients died with associated pneumonia. After the discovery of influenza virus in 1933, Japan experienced pandemic influenza--Asian flu(H2N2) in 1957. After about 10 years, Hong Kong flu (H3N2) came to Japan at 1968. However, we had many reliable antibiotics but had not any antiviral drug at the early time. After year 2000, we fortunately obtained reliable three antiviral drugs such as amantadine, oseltamivir and zanamivir. Moreover, very useful rapid test kits for influenza A and B viruses were developed and used in Japan. 2009 H1N1 influenza epidemic occured in Japan after the great epidemic in Mexico and North America but elderly patient was few. With together, host conditions regarding with high risk are changing. Lessons from past several pandemic influenza are those that many issues for changing high risk conditions, viral genetic changes, developing antiviral agents, developing new useful vaccins and determinating bacterial secondary pathogens are important. PMID- 20845734 TI - [Novel influenza H1N1 pandemic: lesson learned]. AB - The efforts made by the government of Japan and its people to prevent and control the spread of the disease and to limit its health impact had three major characteristics: (1) Suspension of schools in wide geographical areas particularly at the early stage of the outbreak. (2) High proportion of the infected persons who were given antiviral drugs. (3) High level of public awareness and personal hygiene such as regular hand washing. Although more research needs to be done, it seems fair to say that the three characteristics mentioned above contributed to Japan's globally one of the lowest mortality rate associated with the 2009 H1N1 influenza pandemic. Nonetheless, in the process of implementing prevention and control measures, the following four major lessons have been learned: (1) At the early stage of the outbreak, when the epidemiological information by definition is limited, control measures have to be based upon the worst case scenario. And as more information becomes available, measures have to be adjusted accordingly. (2) Risk communication is certainly one of the areas where more improvement have to be made, because some key messages did not reach the general public in a timely and accurate manner. (3) Essential is the development of "situation-based" intervention strategies, which take into consideration both infectivity and health impact such as mortality rate. (4) Decision making process is another area where there is more room for improvement, for example, clarification has to be made as to who are responsible for what. PMID- 20845735 TI - [Lessons learned from pandemic (H1N1) 2009: Japan and global prospective]. AB - Currently there have reported pandemic (H1N1) 2009 over 200 countries and areas globally with more than 16,813 victims according to World Health Organization. Demographic characterization of those cases seemed to be consistent around the world that is higher incidence among school age children and higher mortality rate among elderly. Uniquely Japan has lower mortality rate compared with other countries. Based upon pandemic preparedness plan, several interventions such as personal hygiene and social distancing as well as clinical management were implemented since the beginning of pandemic. Of particular, school closure was continuously implemented during pandemic and medical access for influenza like illness cases was sustained with administration of antivirals in Japan. It is important to identify some gaps in the implementation of interventions for further preparedness. PMID- 20845736 TI - [Mechanisms of influenza virus replication]. AB - The influenza A virus genome consists of eight, single-stranded, negative-sense RNA segments. Unlike most negative-sense RNA viruses, transcription and replication of the influenza A virus genome occurs in the nucleus of cells. Once synthesized, the genomic RNA is exported to the cytoplasm and then to the apical plasma membrane, where a complete set of the eight viral RNA segments is packaged into progeny virions. Here, we discuss the influenza A virion structure and its replication steps in host cells. PMID- 20845737 TI - [Transmissibility and pathogenicity of influenza viruses]. AB - In the spring of 2009, a novel swine-origin H1N1 virus, whose antigenicity is quite different from those of seasonal human H1N1 strains, emerged in Mexico and readily transmitted and spread among humans, resulting in the first influenza pandemic in the 21st century. Molecular analyses of the pandemic H1N1 2009 viruses indicate low-pathogenic features for humans, although worldwide transmission of the virus and a considerable numbers of lethal cases with acute pneumonia have been observed in the first wave of the current pandemic. Here, we review our current molecular knowledge of transmissibility and pathogenicity of influenza viruses and discuss the future aspects of the pandemic virus. PMID- 20845738 TI - [Immunity against influenza virus infection]. AB - Influenza A viruses of 16 serologically different hemagglutinin (HA) subtypes have been identified in waterfowl reservoirs, and the introduction of a novel HA subtype of avian viruses into the human population has the potential to generate the next pandemic strains. Both humoral and cellular immunity play important roles against influenza virus infection. Currently available inactivated influenza vaccines primarily induce subtype-specific serum neutralizing antibodies, but not cross-reactive cytotoxic T-cell response. Thus, vaccine induced immunity is not fully effective against strains with serologically distinct HA. Our long-term goal is to develop a vaccine/therapy to induce highly crossreactive anti-influenza immunity, which may lead to the establishment of an ultimate strategy for the control of influenza. PMID- 20845739 TI - [Influenza virus infection: clinical diagnosis and current considerations]. AB - Point-of-care diagnosis of influenza requires sound recognition of the prevalence of the signs and symptoms of the patients, which would help to define the pattern of clinical presentation of this infection. In severely ill patients, however, clinical features of influenza could be erroneously modified by the exacerbation of co-morbid conditions, resulting in a delay of the diagnosis. Enzymatic rapid diagnostic tests, although establishing the diagnosis with positive result especially when the virus is in high circulation, has relatively poor sensitivity for the 2009 A/H1N1 virus and it varies among the different age groups. Given the likelihood of long-term circulation of the novel H1N1 virus, patients' clinical features and the performance of the rapid tests should continuously be monitored. PMID- 20845740 TI - [Clinical characteristics of pandemic (H1N1) 2009 influenza and preventive/therapeutic strategies]. AB - Majority of cases of pandemic (H1N1) 2009 influenza were observed in young generation, but the severe cases were more frequently observed in elder generation in Japan during 2009-10 period. The people with certain underlying medical conditions appear to be at higher risk of severe illness, but over 60% of patients had healthy background. Signs of the influenza are seasonal-flu-like. The virus is spread from person to person, similar to seasonal influenza viruses. It is transmitted to other people by exposure to infected droplets or contaminated hands. To prevent spread, certain infection control measures should be performed. We also mentioned the treatment guidelines of IDSA, WHO and the Japanese association for infectious diseases. PMID- 20845741 TI - [Pandemic (H1N1) 2009 in children]. AB - In Japan, about 20 million people were infected with pandemic (H1N1) 2009 virus between July 2009 and March 2010. About 60% of them were under 15 years, but only 38 pediatric deaths were reported. The reasons for hospitalization were respiratory and neurological complications. Children with pneumonia or encephalopathy were older than those with seasonal influenza. The time from onset to appear dyspnea in patients with lower respiratory complications was very short, and encephalopathy also appears very rapidly. It is very important to observe clinical course closely and to start neuraminidase inhibitor within 48 hours. PMID- 20845742 TI - [Change of strategies for novel and seasonal flu during pregnancy]. AB - In 2009/10 season pandemic (H1N1) 2009 epidemic, pregnant women were recognized as high risk group, and taken different measures from non-pregnant adults. This new recommendations for pregnant women was also different from Japanese conventional management for pregnant women suffering from seasonal flu. The policy of these recommendations of novel flu for pregnant women was highlighted to aggressive preventions and treatments. To put it concretely, 1) pregnant women will be preferably accepted influenza virus vaccines during all the period of pregnancy, 2) early administration of oseltamivir/zanamivir to pregnant women will not be hesitated. This new recommendation for pregnancy will be probably applied in this 2010/11 season too. PMID- 20845743 TI - [Clinical features of, treatments and preventions for newborns with pandemic influenza A (H1N1) 2009]. AB - Newborns should be considered to be at high risk of developing complications of novel influenza like pandemic influenza A (H1N1) 2009, because maternal antibodies are not transferred via crossing the placenta. In Japan, some newborns with pandemic influenza A (H1N1) 2009 appeared non-specific symptoms, such as fever, poor activity and sucking, and apnea. A Japanese newborn infected with pandemic influenza A (H1N1) 2009 combined with S. pneumoniae, developed severe pneumonia by which a mechanical ventilation was initiated. Orally oseltamivir(3-4 mg/kg/dose twice a day for 5 days) was used for treatments of flu-infected newborns. Contact and droplet precautions were very important measures to prevent transmission of pandemic influenza A (H1N1) 2009 virus to newborns. PMID- 20845744 TI - [Influenza-associated encephalopathy]. AB - Acute encephalopathy is one of the most serious complications of pediatrics viral infections including influenza. It is characterized clinically by rapidly progressive brain damage following viral infection, and pathologically by brain edema in the absence of direct invasion of the virus and inflammatory cells. Recently, it has been classified into several categories according to the clinical characteristics and pathogenesis. In 2009, an outbreak of AH1N1 (swine) influenza was discovered in North America and quickly spread worldwide. During this pandemic, a number of patients with acute encephalopathy have been reported from all over the world. This article reviews the pathogenesis and classification of acute encephalopathy in general and the epidemiological, clinical and pathological features of pandemic flu-associated encephalopathy in comparison with those of seasonal flu-associated encephalopathy. PMID- 20845745 TI - [Pneumonia and acute respiratory distress syndrome due to pandemic influenza H1N1 2009]. AB - Pandemic influenza H1N1 2009 caused more severe diseases in children and young adults than seasonal influenza. The typical manifestation of severe diseases was diffuse viral pneumonia complicated with acute respiratory distress syndrome. Over half of the severe cases had underlying conditions, in which pregnancy and morbid obesity were regarded as major risk factors. Pathological findings revealed that the virus efficiently replicated in alveolar cells and caused diffuse alveolar damage as well as bronchiolitis. The level of plasma cytokines was also elevated in the severe cases. Antiviral use was generally recommended for the severe cases and might improve the outcomes. Further studies are needed for better clinical management of the severe cases of the latest pandemic influenza. PMID- 20845746 TI - [Drug-resistant influenza viruses: an overview]. AB - Amantadine resistance has become increasingly common among recent seasonal influenza viruses. In addition, almost all pandemic (H1N1) 2009 viruses are resistant to this drug. Between 2007 and early 2009, the prevalence of oseltamivir-resistant seasonal H1N1 variants that possess the His274Tyr neuraminidase mutation had dramatically increased, raising concerns regarding the utility of oseltamivir. Fortunately, most of the pandemic (H1N1) 2009 viruses were sensitive to neuraminidase inhibitors. In this paper, drug resistance among recent influenza virus isolates is comprehensively reviewed, especially from the standpoint of the molecular basis of drug resistance. PMID- 20845747 TI - [Current anti-influenza virus chemotherapy]. AB - The environment surrounding influenza is changing in recent years. In the spring of 2009, pandemic (H1N1) 2009 occurred in Mexico, and became epidemic on a global scale thereafter. Therefore, control of influenza is very important all over the world. Now in Japan, four specific anti-influenza antiviral drugs are available: amantadine, oseltamivir, zanamivir and peramivir. Pandemic (H1N1) 2009 are amantadine-resistant viruses, thus is not recommended for use. Oseltamivir is most commonly used in Japan, however, we have to pay attention to oseltamivir resistant influenza virus. Almost no zanamivir-resistant influenza virus has been so far reported. In Japan, peramivir is the first drip infusion medicine and is expected to be used in severe cases. PMID- 20845748 TI - [Present and future in development of new anti-influenza drugs]. AB - Against pandemic influenza A (H1N1) 2009, anti-influenza drugs were useful to save the disease aggravation and reduce the mortality. In addition to the existing anti-influenza drugs, novel drugs, including neuraminidase inhibitors (peramivir and laninamivir) and RNA polymerase inhibitors (favipiravir), also have clinical potentials to suppress pandemic influenza A (H1N1) 2009 virus as well as seasonal influenza virus. PMID- 20845749 TI - [Influenza vaccination: recommendations and remarks]. AB - Several types of influenza vaccine have been developed in the world. Split vaccine has been used as seasonal influenza vaccine and 2009 pandemic monovalent vaccine in Japan. Seasonal influenza vaccine should be administered annually to the health-care personnels, the higher risk persons who had suffered from influenza, and household contacts and caregivers of higher risk persons. Since 2009 pregnant women could be administered with split vaccine in Japan. Since the split vaccine in Japan contains 1-10 ng/mL of ovalbumin, children with egg allergy could be administered safely. PMID- 20845750 TI - [Trends and perspectives in development of influenza vaccines]. AB - Currently licensed influenza vaccines in Japan are split-virus vaccine for seasonal influenza and alum-adjuvanted whole-virion vaccine for higly pathogenic avian H5N1 influenza, respectively. There are many challenges to improve the efficacy, safety and productivity of influenza vaccine. Prompt supply of vaccine is required for pandemic use and cell culture-based vaccine provides a useful production system because of the flexibility of scale-up production. Development of potent adjuvants for parenteral and intranasal administration enhances the immunogenicity and efficacy of influenza vaccine. Vaccines inducing nasal antibody have a potency to elicit broad protective immune response against different subtypes and antigenically distinguishable viruses. More effective and safer influenza vaccine in a single formulation is desirable for both seasonal and pandemic use. PMID- 20845751 TI - [Local administrative measures for outbreak of H1N1 influenza--Chiba prefecture]. AB - Since the onset of 2009 H1N1 influenza outbreak, Chiba prefecture had been taking several measures to mitigate its impact, including phone counseling, supporting outpatient clinics, and coordinating hospitals to prevent the overflow of patients. These measures seem to contribute to the very low mortality caused by pandemic (H1N1) 2009 virus infection during the pandemic in Chiba prefecture. At the same time, it gave us several lessons to prepare for the next--possibly more serious--pandemic. Here, we describe those lessons learnt as well as steps to be taken in the future. PMID- 20845752 TI - [Measures taken by a university hospital for the prevention and control of the 2009 H1N1 influenza]. AB - After extensive discussion with the Fukuoka City government of measures for the prevention and control of the 2009 H1N1 influenza pandemic, Kyushu University Hospital organized the infection control teams of 39 hospitals in the Fukuoka City area in preparation for a possible outbreak. A facility was set up at Kyushu University Hospital for the screening of outpatients with fever, and those with influenza and an underlying disease or severe symptoms were admitted to the hospital. 37 (22%) of the 171 outpatients with fever were infected with the new strain of influenza, confirmed by rapid influenza antigen test and PCR: Of these 37 patients, 17 (45.9%) were negative by influenza antigen test. Other 37 patients (5 adults, 32 children) were admitted, all of whom were successfully treated with neuraminidase inhibitors and discharged with no aftereffects. PMID- 20845753 TI - [How have we understood and responded clinically to pandemic H1N1 2009?]. AB - Pandemic H1N1 2009 (pdmH1) has a broad clinical spectrum. Although many cases are mild, its pathogenesis is not necessarily low as it often causes serious respiratory disorder in children, and thus early treatment is necessary. As the positive rate as determined by rapid diagnostic kit is low, and false negative results can occur when the test is conducted too early following symptomatic onset, patients suspected of pdmH1 influenza warrant initiation of treatment even before establishment of a definite diagnosis. For therapeutic drugs, oseltamivir, zanamivir, and peramivir can be similarly efficacious, but intravenous administration is required in patients suffering symptoms of respiratory disorder and/or vomiting. As for the infectiousness, based on higher household transmission from parents to children in comparison to seasonal influenza A (FluA), as well as a high prevalence among primary school children, pdmH1 appears more likely to affect children, especially school children. In addition, since pdmH1 has a long incubation period, which can facilitate latent viral transmission, wearing a mask is useful during the epidemic period. A judgment of recovery should be carefully made especially in children, because the virus remains for a long time even after resolution of fever. PMID- 20845754 TI - [Measures taken for Influenza by organizing a relief unit in the nursing department]. AB - Nurses have the most frequent contact with patients, and it makes their risk of infection very high. At the same time, they have a lot of opportunities to control patient's behavior to prevent infection. So it takes important part of precaution that all nurses sufficiently acknowledge their roles and responsibilities. Also, it's necessary to establish organization which can arrange competent nurses for influenza (A/H1N1) epidemic so that they can perform efficiently. PMID- 20845755 TI - [Evidence-based public health for pandemic flu]. AB - Various public health interventions for mitigating the effect of pandemic flu such as quarantine, school closures, and social distancing have been implemented in Japan for influenza A (H1N1) 2009. However, there has been arguments on the effectiveness of these interventions. Evidence for the effectiveness of public health interventions often does not meet the criteria used in evidence-based medicine (EBM) because of the study design used in evidence-based public health (EBPH). Public health experts in various fields try to find better solutions as a team, even though there is not always sufficient evidence for effectiveness of these strategies. In cases of the occurrence of emerging infectious diseases, prompt decision making is required. Thus, continuous efforts to review evidence and to establish the systems for decision making are necessary. PMID- 20845757 TI - [Trends in and challenges for highly pathogenic avian influenza A (H5N1)]. AB - A new pandemic influenza A (H1N1) virus had emerged and rapidly spread throughout the world. The clinical pathological observations associated with severe cases of pandemic (H1N1) 2009 are similar to that of high pathogenic avian influenza (H5N1). In order to find the most effective treatment methods for this pandemic influenza (H1N1), we describe our experiences, investigations and collaboration studies of avian influenza (H5N1) in Vietnam in association of our cooperative study of pandemic (H1N1) 2009 in Mexico. Effective treatment methods for critical illness due to influenza will be discussed from medical, regional and global points of view, which may be applied for the treatment of any type of influenza virus. PMID- 20845756 TI - [Current situation in human infections with highly pathogenic avian influenza viruses]. AB - Highly pathogenic avian influenza (HPA1) virus of H5N1 subtype has spread worldwide and continues to cause outbreaks in poultry and sporadic human infections since 2003. As of 9 April 2010, 493 confirmed human cases including 292 fatal cases were reported from 15 countries. Despite emergence of the pandemic A (H1N1)2009 virus, pandemic threats posed by H5N1 subtype virus still remain. H7 subtype avian influenza viruses also pose a similar threat to humans as H5N1 subtype virus. We provide here an updated overview on the human infections of HPA1 viruses in the world. PMID- 20845758 TI - [Global surveillance and the disease pandemics]. AB - Humans experienced various disease pandemics in the history of the world. Disease can spread over the world more rapidly and in larger scale than in any other time in the past as the world is getting smaller. The World Health Organization established its innovative event-based surveillance system in close collaboration with many partners at global scale for early detection and rapid response to the public health events (PHE) of international importance in 1997. It has been being strengthened to respond effectively to PHEs in harmony with the International Health Regulations which were revised in 2005. PMID- 20845759 TI - [Per-oral endoscopic myotomy (POEM) for 43 consecutive cases of esophageal achalasia]. AB - INTRODUCTION: To establish less invasive permanent treatment for esophageal achalasia, per-oral endoscopic myotomy (POEM) was addressed. PATIENTS: POEM was performed in 43 consecutive cases of achalasia. Among them, nine cases of sigmoidal achalasia were involved. POEM got IRB approval from our hospital. Written informed consent was given to all patients. PROCEDURE: After creating submucosal tunnel, endoscopic myotomy of circular muscle bundles was carried out at approximately 12cm in total length (10 cm in distal esophagus and 2 cm cardia). Smooth passing of endoscope through GE junction was confirmed at the end of the procedure. RESULTS: In all cases symptoms of achalasia were dramaticaly reduced or disappeared. Resting pressure was 52.1 mmHg before POEM, and reduced to 18.8 mmHg after procedure. No specific complications related to POEM were experienced. During follow-up period, no additional treatment and no medication were necessary. CONCLUSION: Short-term outcome of POEM was excellent with no serious complications. Long-term follow up is scheduled. PMID- 20845760 TI - [Most recommended timing to start medication for hypertensive patients]. AB - Hypertension is a major risk factor for cardiovascular disease. About forty million people are estimated to have hypertension. But, only 50% of hypertensive patients achieve well control of blood pressure. To prevent cardiovascular disease, more careful attention to hypertension is needed. Diagnostic level for hypertension in clinic is > or = 140/90mmHg. On the other hand, home blood pressure and 24-h ambulatory blood pressure are necessary for distinguish masked hypertension, white coat hypertension and sustained hypertension. Blood pressure is classified into optimal, normal and high-normal, and the corresponding levels are classified into grade I, grade II and grade III hypertension, respectively. Hypertensive patients are stratified into low-, moderate- and high-risk groups according to the presence or absence of risk factors other than blood pressure, hypertensive target organ damage and cardiovascular disease. In particular, the presence of diabetes mellitus and chronic kidney disease increases the risk. Attention to metabolic syndrome including a high-normal pressure as a component is also necessary. The treatment program should be prepared according to stratification of the risk; all patients must be guided to modify their lifestyle, and hypertensive medication should be started if necessary to achieve the target blood pressure level. In this paper most recommended timing to start medication for hypertensive patients is discussed. PMID- 20845761 TI - ["The authentic leadership"]. PMID- 20845762 TI - [A thirteen-year-old boy presenting with slowly progressive ataxia]. PMID- 20845763 TI - [Topics of brain malformation and epilepsy--age-dependent epileptic encephalopathies and interneuronopathies]. AB - The ARX gene is involved in the development of GABAergic interneurons in the forebrain. Loss-of-function mutations, such as nonsense or frameshifts mutation, of ARX cause a group of brain malformations, such as hydranencephaly, lissencephaly, and agenesis of the corpus callosum, while expansion mutations of the polyalanine tracts of ARX, supposed to be gain-of-function mutations, result in a non-malformation group, such as non-syndromic mental retardation, mental retardation with dystonia, West syndrome, and Ohtahara syndrome. A variety of phenotypes caused by pleiotropic mutations of the ARX gene are considered to share a common pathological mechanism connected with the structural and functional disturbance of interneurons, designated as 'interneuronopathies'. We identified the second gene responsible for Ohtahara syndrome, STXBP1, which is essential for synaptic vesicle release. Molecular studies of the diseases will reveal the relationships between the structure and function of the brain. It is indispensable to clarify the etiology of hereditary diseases and identify new approaches to treatment. PMID- 20845764 TI - [Development of human visual cognitive function in childhood: evaluation by exploratory eye movements to a picture of a smiling face]. AB - To evaluate the development of human visual cognitive function in childhood, we examined exploratory eye movements in 78 healthy subjects using affective pictures. We divided them into six groups, each of which comprised 14 subjects (7 boys or men, 7 girls or women) at the indicated ages. Exploratory eye movements were recorded via gazing points using an eye-mark recorder. The total eye scanning length (TESL) of gaze points increased significantly with age, and the mean eye scanning length, in 4-6-year-olds was significantly shorter than in the others groups. The total number of gaze points (TNGP) on the left half of the screen increased significantly with age. The left TNGP in 4-6-year-olds was significantly smaller than in the other groups. The response search score (RSS) measured in 8 areas of the screen increased significantly with age. It was concluded that exploratory eye movements are useful markers to estimate the development of human visual cognitive function in childhood. PMID- 20845765 TI - [Status of the medical management of convulsive seizures at regular schools]. AB - The nurse-teachers have important roles in health care of the students in Japanese schools. Usually one nurse-teacher works in each regular primary and junior high school in order to manage health care of the students. We surveyed the medical care of the students who had a history of convulsions by the questionnaires to 319 nurse-teachers. One hundred thirty nine nurse-teachers (93%) of 150 responders replied that they were taking care of at least one student with a history of convulsion. In 26 (17.4%) of the schools surveyed, more than one convulsion occurred between the first of April 2006 and the 31st of March 2007. More than 65% of nurse-teachers had witnessed convulsions at school. Results of the present study show 59 nurse-teachers were asked by parents to keep the rectal diazepam to administer to their children in the event of a convulsion. However, only 16 nurse-teachers received the instructions from a doctor on the indication of rectal diazepam. Sixty eight per cent of nurse-teachers felt that they had no or little support from doctors. Although most of the nurse-teachers felt reluctant to administer rectal diazepam at school, they considered the administration was unavoidable for student's safety and comfort. Clear instructions and detailed consultation by the doctors and prompt response in case of emergency were desired by the nurse-teachers. The establishment of the support system for the students with a history of convulsions is required to maintain safe and comfortable school life. PMID- 20845766 TI - [Intervention to reduce the difficulty in kanji copying related to the visuo spatial dysfunction in patients with Williams syndrome]. AB - Williams syndrome (WS) is known for its uneven cognitive abilities. Visuo-spatial cognition is more disturbed, whereas cognition of colors or shapes of objects is relatively preserved. This tendency is attributed to the greater deficits of functions in the dorsalpathway compared to those in the ventral pathway in the visual system. When patients with WS are asked to copy two dimensional figures, they often show difficulty in locating components of the figures to make global shapes. Similar findings are observed in copying kanji, Japanese semantic characters. Patients with WS often can copy only the components of a kanji character but can not locate the components properly and fail to make appropriate global shapes of the character even though they can read it. In order to ameliorate this difficulty, we rely on the preserved cognitive function, that is, the cognition of colors. Four participants with WS, who have difficulty copying two dimensional figures, joined the study. A kanji written on a square which is divided into four sections was used as a copy model. Each divided part of the square was colored red, green, yellow and blue, respectively. A similarly colored square was given to copy the kanji. This method was successful and made it easier for the participants with WS to copy a given kanji as it became easier to realize where to locate each component. Intervention using similar squares without colors or only with gray scaled back ground did not work. In addition, kanji with differently colored components was also presented to one of the participants as a model but it was not copied successfully. The similar difficulty in copying two dimensional objects and kanji was observed in a patient with Kabuki syndrome and the same interventional method with colored squares was effective for copying kanji. PMID- 20845767 TI - [Efficacy of topiramate in childhood epilepsies]. AB - To evaluate the efficacy of topiramate (TPM) for the treatment of children with epilepsies, we introduced TPM to 45 patients whose epilepsy began in childhood and whose ages ranged from 4 months to 30 years old (mean age: 11 years 7 months). Thirteen of these patients had been diagnosed with generalized epilepsy (GE) (1 cryptogenic, 12 symptomatic), 30 with localization-related epilepsy (LRE) (7 idiopathic, 23 symptomatic), and 2 with unclassified epilepsy [1 case of severe myoclonic epilepsy in infancy (SMEI), 1 case of epilepsy with continuous spikes and waves during slow sleep (CSWS)]. The initial dose of TPM was 1.97 +/- 0.45 mg/kg/day, followed by a slow titration to the maximum dose of 7.32 +/- 1.32 mg/kg/day. After a mean treatment period of 13.5 months (range 4-20 months), the rate of reduction in seizure frequency by more than 50% [50% responder rate (50% RR)] and the rate of complete remission (seizure-free) were 53.8% and 23.1%, respectively, in patients with GE, and 73.3% and 23.3%, respectively, in patients with LRE. TPM was significantly effective against many seizure types including tonic, clonic, complex partial, myoclonic, and atypical absence seizures. Adverse effects included sleepiness in 13 cases (28.9%), weight loss in 6 cases (13.3%), and metabolic acidosis in 2 cases (4.4%); all of these effects were both mild and transient. In conclusion, TPM is effective and safe for the treatment of pediatric epilepsies. PMID- 20845768 TI - [Autopsy case of child with severe motor and intellectual disabilities showing hyper IgE subsequent to food allergy]. AB - We presented an autopsy case with severe motor and intellectual disabilities (SMID) who showed a severe increase in the serum level of IgE. Although the patient had rarely been exposed to food allergens, the serum level of IgE continued increasing. He developed a high titer of serum IgE against specific antigens to which he had never been exposed. There was no mutation of the STAT3 gene, and no abnormalities in immunological functions including serum levels of cytokines. Death was from a hemorrhage caused by a tracheoinnominate artery fistula. At autopsy, the submucosal area of the colon presented with an increase in the number of mast cells immunoreactive for tryptase, which could have been involved with hyper IgE. Since SMID patients tend to be sensitized by food allergens subsequent to recurrent gastroesophageal reflux, we should pay attention to complications of food allergy even when using an elemental diet. PMID- 20845769 TI - [Acute idiopathic autonomic neuropathy with local autonomic failure in a child]. AB - A 5-year-old girl presented with flushing and sweating on the left arm with coldness on the left palm that had persisted for approximately 24 hours. She had a fever and chicken pox-like exanthemas on her skin. She had no weakness, sensory disturbance or other autonomic dysfunction, such as orthostatic hypotension. Physical, neurological, blood and cerebrospinal fluid findings, including those of a viral study, were normal. A spinal MRI revealed no abnormal signals. Motor nerve conduction velocity, compound muscle action potential and sensory nerve conduction velocity in both medial nerves were normal, although compound sensory nerve action potential was low in the left medial nerve. F waves were absent in both medial nerves. The amplitude of the sympathetic skin response was low in the left palm. The cold-induced vasodilatation test showed bilateral sympathetic nerve dysfunction, especially on the left side. The coefficient of variation of RR intervals was low. Aciclovir was administered until chicken pox was ruled out. Subsequently, her symptoms improved. However, a sympathetic skin response and cold-induced vasodilatation findings 9 months later revealed sympathetic nerve dysfunction. These findings suggested autonomic neuropathy with local sympathetic dysfunction and a mild sensory nerve disturbance. PMID- 20845770 TI - [Case of novel influenza A (H1N1) encephalopathy with transient low TSH level]. PMID- 20845771 TI - [Evaluation of the accumulation of dry substance and active componentsevaluation of the accumulation of dry substance and active components of Radix Aconiti Lateralis Praeparata]. AB - OBJECTIVE: To study the accumulation rules of dry substance and active components in the Radix Aconiti Lateralis Praeparata for providing the basic evidences to collection time. METHODS: The Roots were collected periodically and their fresh weight and dry weight were measured. The contents of total alkaloids and three diester aconitum alkaloids aconitine, hypaconitine and mesaconitine were determined by titration and HPLC respectively. RESULTS: During the stage of root inflation, the content of total alkaloids was at a certain level, while the content of diester aconitum alkaloids were increased gradually. The total amount of alkaloid and diester aconitom alkaloids were increased rapidly from the last third of April to the middle third of June, and then maintained at relative constant levels and were decreased from the first third of July. CONCLUSION: It is more preferable to collect the Radix Aconiti Lateralis Praeparata during the period from the last third of June to first third of July. PMID- 20845772 TI - [Correlation and path analysis of artemisininum content and related factor on Artemisiae annie in Three Gorges reservoir area]. AB - OBJECTIVE: Study on the correlation and path analysis of artemisininum comtent and related factor on Artemisiae annie. In order to obtain high artemisininum content Artemisiae annie. METHODS: On the natural condition, choose 36 area where Artemisiae annie growth in three gorges reservoir area. The related factor on artemisininum content are studies through correlation and path analysis. RESULTS: The artemisininum content had significant correlations with biomass, over cover degree, K, P, and N in soil. P in soil had the nost positive influence on the artemisininum content with the direct path coefficinent 0.3439, over cover degree had the nost negative in fluence on the artemisininum content with the direct path coefficient -0.1421. The influence order of other factor was N in soil (0.3180), K in soil (0.2352), biomass ( -0.0084), and plant height (-0.0347). CONCLUSION: Artemisininum content in Artemisiae annie leaves are correlated with biomass, over cover degree, K in soil, P in soil, N in soil. PMID- 20845773 TI - [Effects of centipede extracts on normal mouse and S180, H22 bearing mouse]. AB - OBJECTIVE: To study the effects of centipede extracts on H22 tumor-bearing mouse, sarcoma S180 mouse and normal mouse. METHODS: Normal and tumor-bearing mouse were orally administrated by centipede extracts. Rate of restraining tumor, index of thymus and spleen were calculated after 12 days treatment. Acute toxicity testing tried to figure out In LD50 of centipede extracts. RESULTS: The restraining tumor rates of centipede ethanol extracts at low and medium doses were 22.2% and 17. 88%. There was no tumor restraining effect by the high dose treatment. The tumor growth of the H22 model mouse was not restrained by the centipede water extracts. There were no significant differences among the treatments in their spleen weight and spleen index. In LD50 test, the administrating dosages of centipede extracts given to the mouse were 48 times those given to patients on clinic. The result showed no mouse dead in centipede group. CONCLUSION: Centipede water extracts had no anti-tumor effect on tumor-bearing mouse. There is certain toxicity in ethanol extracts of centipede, suggesting that centipede alone for treatment of cancer needs further study. PMID- 20845774 TI - [Analysis odor of Rhizoma Aatractylodis Macrocephalae based on electronic nose]. AB - OBJECTIVE: To appraise rationally the quality between wild and cultivated Rhizoma Atractylodis Macrocephalae. METHODS: Evaporability composition of Rhizoma Atractylodis Macrocephalae was sampled from headspace of emanating, and then response values was obtained. Principal component analysis (PCA) and discriminant factor analysis (DFA) are used to combine the optimum feature parameters, and statistical quality control analysis (SQC). RESULTS: The odor of wild Atractylodis Macrocephalae Rhizoma was diffenrent from that of the cultivated. The odor of Atractylodis Macrocephalae Rhizoma cultivated in Zhejiang was similar to the cultivated in Anhui which transplanted from Zhejiang and wild Atractylodis Macrocephalae Rhizoma which cultivated in the environment with full of sunlight. The odor of Atractylodis Macrocephalae Rhizoma cultivated in Hubei and Jiangxi were diffenrent to the odor of others. CONCLUSION: The quality of semiwild cultivated Atractylodis Macrocephalae Rhizoma was the similarest to the wild. The electronic nose combined with PCA, DFA and SQC can be applied to identify the quality of Traditional Chinese Medicine. PMID- 20845775 TI - [Anatomy and adaptation to environment study of endangered alpine medical plant Neopicrorhiza scrophulariiflora]. AB - OBJECTIVE: To study the anatomical structure of endangered alpine medical plant Neopicrorhiza scrophulariiflora and the high altitude adaptability. METHODS: The leaf epidermis character as well as section structure of leaf, aerial stem and rhizome were observed by light microscopical technique. RESULTS: The leaf surface of Neopicrorhiza scrophulariiflora was covered with two kinds of glandular hair, and the stommata was anomocytic type. Moreover, the leaf was isolateral and differed from most of alpine plant. The aerial stem had well-developed mechanical tissue. The rhizome was distributed by well-developed cork layers and collenchyma. Large numbers of aerenchymas distributed widely in leaf, aerial stem and rhizome. CONCLUSION: There existed characteristic traits in Neopicrorhiza scrophulariiflora that adapted the alpine environment, however, there still had some particular character different from other alpine plant. Thus, the adaptive style of alpine plant to high altitude environment was diversity. PMID- 20845776 TI - [Analysis on adaptive area of Curcuma wenyujin based on GIS]. AB - OBJECTIVE: This stdudy was to determine the suitable area for Curcuma wenyujin in Wenzhou, and expand its growing region, based the growth characteristic of Curcuma wenyujin. METHODS: The 13 main factors including climate, soil and other environmental conditions were selected. The best genuine production area was regarded as the goal area in similar calculation. The grid data was calculated from the station and sampling sites by Inverse Distance Interpolation on GIS. After normolizing to the grid data, the dimension effect was removed. on this basis, calculating the absolute distance of every cell to the the goal cell. Wenzhou region was divided into best suitable area, suitable area, second suitable area and unsuitable area by clustering analyzing. RESULT: Most of area in Wenzhou are suit for Curcuma wenyujin, best suitable area, suitable area, second suitable area and unsuitable area reach 98% area of Wenzhou. CONCLUSION: This result give important reference value of Curcuma wenyujin breeding in Wenzhou. PMID- 20845777 TI - [Studies of preparing procedures of Yuhuangliang]. AB - OBJECTIVE: To optimize preparing procedures of Yuhuangliang. METHODS: The single factor experimets and the L9 (3(4)) orthogonal design were used to optimize the preparing procedures of Yuhuangliang with contents of berberine and total alkaloids as evalustion index. RESULTS: The optimal preparing method was Rhizoma Coptidis adding amount of 10 mL (0.2 g/mL) juice of wuzhuyu mixed thoroughly, baking at 100 degrees C, for 15 min. CONCLUSION: The preparing procedure is effective, stable and reliable. PMID- 20845778 TI - [Studies on the chemical constituents from the stems of Acanthopanax gracilistylus]. AB - OBJECTIVE: To study the chemical constituents from the stems of Acanthopanax gracilistylus. METHODS: The chemical constituents of the plant were isolated and puried by column chromatography and their structures were elucidated on the basis of physico-chemical properties and spectral data. RESULTS: Sixteen compounds were isolated and identified as (2S,3S, 4R, 8E)-2-[(2'R)-2'-hydroxy pentadecanoylamino]-heptacosane-1,3,4-triol-8-ene(1a),(2S,3S,4R,8E)-2-[(2'R)-2' hydroxy-octadecanoylamino]-lignocer-ane-1,3,4-triol-8-ene(1b), (2S, 3S, 4R, 8E) 2-[(2'R) -2'-hydroxy-heneicosanoylamino]-heneicosane-1,3,4-triol-8-ene (1c), (2S, 3S,4R, 8E)-2-[(2'R) -2'-hydroxy-docosanoylamino] -eicosane-1,3,4-triol-8-ene (1d), (2S, 3S, 4R, 8E)-2-[(2'R)-2'-hydroxy-trico-sanoylamino]-nonadecane-1,3,4 triol-8-ene (1e), (2S,3S,4R,8E)-2-[(2'R)-2'-hydroxy-lignocera-noylamino] cctadecane-1,3,4-tri-ol-8-ene(1f), 1-O-beta-D-glucopyranosyl-(2S, 3S, 4R, 8E)-2 [(2'R)-2'-hydroxy-pentadecanoylamino]-nonadecane-1, 3, 4-triol-8-ene (2), 16alpha hydroxy-ent-kauran-19-ocid (3), 16alphaH, 17-isovaleryloxy-ent-kauran-19-oic acid (4), coniferin (5), syringin (6), eleutheroside D (7), stigmasterol (8), beta sitosterol (9), daucosterol (10), pentacosanoic acid (11). CONCLUSION: Compounds 1a - f, 2 are isolated from this genus for the first time, and compounds 4, 5, 11 are firstly obtained from Acanthopanax gracilistylus. PMID- 20845779 TI - [Studies on the phenolic acids from Sarcopyramis bodinieri var. delicata]. AB - OBJECTIVE: To study the chemical constituents from Sarcopyramis bodinieri var. delicata. METHODS: These compounds were isolated and purified by chromatography with silica gel column combined with Sephadex LH-20 column from high polar extracts. The structures were identified on the basis of extensive spectroscopic data analysis, and by comparison of their spectral data with those reported. RESULTS: Seven compounds were isolated as 3, 3'-di-O-methylellagic acid-4'-O alpha-L-rhamnopyranoside (I), ellagic acid (II), ferulic acid (III), isoferulic acid (IV), caffeic acid (V), 3, 4-di-hydroxybenzoic acid (VI), p-hydroxycinnamic acid (VII). CONCLUSION: Compound I, III, VI, VII are isolated from the genus for the first time. PMID- 20845780 TI - [Studies on the chemical constituents of marine sponge Iotrochota sp]. AB - OBJECTIVE: To study the chemical constituents from the marine sponge Iotrochota sp. METHODS: The compounds were isolated and purified by various column chromatography methods, and their structure wer identified cholesterol (1), nonadecyl ethers of glycerol (2), p-hydroxybenzaldehyde (3), (E)-4-(3,4 dihydroxyphenyl) but-3-en-2-one (4), 3,4-dihydroxybenzaldehyde (5), ethyl vanillin (6), hendecanoic acid (7), tricosane (8). CONCLUSION: All compounds are isolated from marine sponge Iotrochota sp. for the first time. PMID- 20845781 TI - [Study on the chemical constituents from Sarcopyramis nepalensis]. AB - OBJECTIVE: To study the chemical constituents from Sarcopyramis nepalensis. METHODS: Compounds were isolated by D101 macroporous adsorption resin column and purified by repeatedly chromatographic techniques on Sephadex LH-20, silica gel and ODS columnl chromatograph. Their structures were elucidated by chemical and spectral methods. RESULTS: Six compounds were isolated from Sarcopyramis nepalensis, and identified as kaempferol (1), myricetic (2), dihydroquercetin (3), egllagic acid (4), isoferulic acid (5) and caffeic acid (6). CONCLUSION: All compounds are isolated from the genus for the first time. PMID- 20845782 TI - [Studies on the chemical constituents of Lithocarpus polystachyus]. AB - OBJECTIVE: To study the chemical constituents from Lithocarpus polystachyus. METHODS: Compounds were isolated and purified with silica gel, and there structures were identified by chemical property and spectral data. RESULTS: Nine compounds were isolated as phloridzin (I), phloretin (II), dihydrochalcone-2' beta-D-glucopyranoside (III), daucossterol (IV), beta-sitosterol (V), quercetin (VI), luteolin (VII), quercitrin (VI), oleanolic acid (IX). CONCLUSION: Compounds II, IV - IX are isolated from this plant for the first time. PMID- 20845783 TI - [Studies on the chemical constituents of Kalimeris indica]. AB - OBJECTIVE: To study the chemical constituents from Kalimeris indica. METHODS: Compounds were isolated and purified with silica gel and Sephadex LH-20 column chromatography, their structures were determined by using spectroscopic analysis including MS and NMR. RESULTS: Nine compounds were isolated and identified as tritriacontane (I), hexadecanol (II), chrysophanol (III), vanillin (IV), physcion (V), beta-sitosterol (VI), stigmasterol (VII), leinoleic acid (VII), emodin (IX). CONCLUSION: All of them, except compound IV, VI, are isolated from this genus for the first time. Compound III, IV had the protective effects with the toxicity of CCl4 on primary cultered hepatocytes. PMID- 20845784 TI - [Studies on the chemical constituents of Solanum nigrum]. AB - OBJECTIVE: To study the chemical constituents from Solanum nigrum. METHODS: Compounds were isolated and purified by silica gel, Sephadex LH-20 and preparative HPLC. Their structures were identified by physicochemical properties and spectral analysis. RESULTS: Six compounds were isolated and identified as (+) pinoresinol (I), (+)-syringaresinol (II), (+)-medioresinol (III), scopoletin (IV), tetracosanoic acid (V) and beta-sitosterol (VI). CONCLUSION: Compounds I - III are isolated from this genus for the first time, while compounds IV and V are isolated from this plant for the first time. PMID- 20845785 TI - [Studies on the chemical constituents of rhizoma of Coniogramme japonica]. AB - OBJECTIVE: To study the chemical constituents of Rhizoma of Coniogramme japonica. METHODS: The Rhizome of C. japonica were extracted with ethanol and the chemical constituents were separated by chromatography technique, and their structures were determined by spectral analysis. RESULTS: Six compounds were isolated and identified as butyl 2-formyl-5-butoxymethyl-1 H-pyrrole-1-butanoate (1), pterolactam (2), 5-hydroxymethylfurfural (3), methyl linoleate (4), trilinolein (5), dehydrovomifoliol (6). CONCLUSION: All compounds are isolated from the genus for the first time, and the compound 1 is a new compound. PMID- 20845786 TI - [Effects of Rhein on the hypertrophy of renal proximal tubular epithelial cells induced by high glucose and angiotensin II in rats]. AB - OBJECTIVE: To explore the effect of Rhein on the hypertrophy of renal proximal tubular epithelial cells induced by high glucose and angiotensin II in rats. METHODS: Studies were performed on anesthetized SD rats. Renal proximal tubular were gained by microdissection and cultured in RPMI-1640 medium. The cell types were identified by immunocytochemistry. The renal proximal tubular epithelial cells were incubated with high glucose (30 mmol/L) and angiotensin II (10(-7) mol/L) to induce the hypertrophy of cells. To observe the effect of Rhein on hypertrophy induced by high glucose and angiotensin II, renal proximal tubular epithelial cells were cultured with different concentrations of Rhein (30, 15, 5 mg/L) for 72 h, then cell size, 3H-leucine incorporation, and cellular protein content were detected to observe the changes. RESULTS: High glucose (30 mmol/L) and Ang II (10(-7) mol/L) induced hypertrophy of renal proximal tubular epithelial cells result in, cell size, 3H-leucine incorporation and cellular protein content increased significantly. On the contrary, Rhein inhibited the hypertrophy of renal proximal tubular epithelial cells induced by high glucose and Angiotensin II. Rhein 30 mg/L significantly decreased cell size, 3H-leucine incorporation and cellular protein content. Rhein 15 mg/L decreased 3H-leucine incorporation and cellular protein content. Rhein 5 mg/L decreased cellular protein content. CONCLUSIONS: Rhein can inhibit the hypertrophy of renal proximal tubular epithelial cells induced by high glucose and Angiotensin II in rats. PMID- 20845787 TI - [Effect of cold property Chinese medicine radix scutellariae on energy metabolism of rats]. AB - OBJECTIVE: To observe the effect on energy metabolism of rats with cold property Chinese medicine Radix Scutellariae. METHODS: The body weight gain, temperature, hydroposia content were determined before administration and every five days after administration. The activities of Na4(+)-K(+)-ATPase, Ca(2+)-ATPase and SDH, LPL, HP, the contents of NEAF, T3, T4, TSH were measured after having been administrated with water extracts of Radix Scutullaxiae at the dose of 6.0, 3.0 g/kg for 43 days. RESULTS: The body weight gains were raised and the hydroposia contents have been decreased. The activities of SDH were increased significantly while Na(+)-K(+)-ATPase, Ca(2+)-ATPase of liver had little change. The content of NEAF, the activity of LPL, HP were decreased significantly, and the contents of T3, T4, TSH and the body weight, temperature had no significant change. CONCLUSION: Radix Scutellariae can inhibit the energy metabolism of rat. The mechanism may not be related to thyroxine pathway. PMID- 20845788 TI - [Effects of Ginkgolide B on inflammation induced by cerebral ischemia-reperfusion in rats]. AB - OBJECTIVE: To investigate the protective effects of Ginkgolide B on inflammation induced by cerebral ischemia-reperfusion in rats. METHODS: Rats were pretreated with Ginkgolide B at the dose of 2. 5, 5, 10 mg/kg for 3 days and then subjected to cerebral ischemia/reperfusion induced by a middle cerebral artery occlusion (MCAO). The infarct volume and the neurological deficit were determined by the method of TTC (2,3,5-triphenylterazolium chloride) staining and Longa's score. The permeability of blood-brain barrier (BBB) was evaluated by measurement of the evans blue (EB) content in the brain with spectrophotometer. The content of interleukin-1beta, interleukin-6 (IL-6, IL-1beta) in serum and tumor necrosis factor-alpha (TNF-alpha), The content of E-selectin and ICAM 1 in brain were determined by radio-immunoassay and ELISA assay. RESULTS: Ginkgolide B reduced infarct volume, ameliorated the neurological deficit and the permeability of BBB, the content of IL-6, IL-1beta in serum and TNF-alpha, expressions of E-selectin and ICAM 1 in brain tissue also were significantly decreased. CONCLUSION: Ginkgolide B has protective effects on cerebral injury by inhibiting the inflammation induced by ischemia/reperfusion injury. PMID- 20845789 TI - [Effects of Valeriana amurensis on the expressions of iNOS, COX-2 and IkappaCB alpha in Alzheimer's disease model rat's brain]. AB - OBJECTIVE: To investigate effects of Valeriana amurensis Smir. ex Kom. on the inflammation reaction of cortical neurons and hippocampus neuronsin in Alzheimer's disease model rat's brain. METHODS: The model of Alzheimer's disease was established with multiple factors and the expressions of iNOS, COX-2, IkappaB alpha of cortical neurons and hippocampus neuronsin in Alzheimer's disease model rats' brain were observed by electron lens using immunohistochemistry method. RESULTS: The extracts of Valeriana amurensis could reduce the expressions of iNOS, COX-2 and IkappaB-alpha of cortical neurons and hippocampus neuronsin in a dose-dependent manner. The effects of 50% ethanol extracts of macroporous resin group were more significant than other groups. CONCLUSION: The 50% ethanol extract of macroporous resin group from Valeriana amurensis can improve the ability of spatial exploratory and effectively control the inflammation reaction, the mechanism maybe relevant to it's effect of decreasing the expressions of iNOS, COX-2 and IkappaB-alpha of cortical neurons and hippocampus neuronsin to inhibit the activity of glia cell and inflammatory injury of cortical neurons and hippocampus neuronsin in Alzheimer's disease model rat's brain. PMID- 20845790 TI - [Reactive oxygen species and mitochondrial membrane potential changes in leukemia cells during 6-gingerol induced apoptosis]. AB - OBJECTIVE: To observe the effects of 6-gingerol on reactive oxygen species (ROS) and mitochondrial membrane potential(deltapsim) of chronic myeloid leukemia K562 cells and human acute T lymphoblastic leukemia MOLT4 cells, to investigate the role of mitochondrial pathway in the signal transduction of leukemia cell. METHODS: With different concentrations of 6-gingerol treatment, using 2,7 dichloro fluoresceinciactate (DCFH-DA) as ROS probe, rhodamine-123 as deltapsim probe, the levels of ROS and deltapsim of K562 cells and MOLT4 cells were tested by flow cytomentry. RESULTS: After treated with 6-gingerol, the ROS levels of K562 cells were significantly higher than control group (P < 0.01), while the deltapsim were significantly lower than control group (P < 0.01), and the ROS levels of MOLT4 cells were significantly higher than control group (P < 0.05). CONCLUSIONS: 6-gingerol can significantly increase ROS levels of K562 cells and MOLT4 cells, decrease deltapsim of K562 cells,induce apoptosis of leukemia cells by mitochondrial pathway. PMID- 20845791 TI - [Study on the chemical stability of tanshinone IIA]. AB - OBJECTIVE: To investigate the chemical kinetics of tanshinone IIA in different conditions quantitatively and calculate the chemical kinetic parameters and equations in order to find out the major factors affecting the stability of tanshinone IIA. METHODS: The kinetic line was obtained by setting the ln (C(t)/C0) as ordinate and making time as abscissa. The slope of the kinetic line was the reaction constant of tanshinone IIA in such condition. The t1/2 was calculated by the equation t1/2 = 0. 692/K. RESULTS: The influences of initial concentration, pH value, temperature and light on stability of tanshinone IIA in solutions were carried out, respectively. The results suggested the degradation of tanshinone IIA in solutions fitted the pseudo-first-order reaction. The chemical kinetics parameters including rates constant and half time of degradation in different conditions were obtained by the means of ln (C(t)/C0) versus reaction time. The activation energy of tanshinone IIA in solutions were also available from the calculation of rate constants under different temperature according to the Arrhenius equation and was 82. 74 kJ/mol. CONCLUSION: Tanshinone IIA is unstable in the high temperature and light conditions, and is prone to degradation, this may be the main reason for its decrease in the whole process of extraction, concentration, granulation, drying and ending product of Danshen prescription. PMID- 20845792 TI - [Preparation and in vitro drug release study of long-circulating hydroxycamptothecin nanoparticles]. AB - OBJECTIVE: To prepare long-circulating hydroxycamptothecin nanoparticles and study its in vitro drug release characteristics. METHODS: The HCPT-PEG-PCL-NPs were prepared by solvent-diffusion method using PEG-PCL block copolymer synthesized as a matrix and HCPT as an antitumor agent. Then the obtained NPs were evaluated and its in vitro drug release characteristics were investigated. RESULTS: When using PEG4000-PCL2000, PEG4000-PCL1250, PEG2000-PCL2000, PEG2000 PCL1250 as the carrier material to prepare NPs, the average particle size of NPs in turn were 116.1, 110.0, 119.9, 99.1 nm; the zeta potential were -22.4, - 16. 9, -33.5, - 28.8 mV; the entrapment efficiency were 88.29%, 83.10%, 80.67%, 77.46%; and the drug loading were 2.96%, 2.56%, 2.31%, 2.14%, respectively. HCPT PEG-PCL-NPs all showed a certain degree of sustained-release characteristics and their release mechanisms were fitted to Weibull modle, which showed that the drug release process included passive diffusion and matrix-eroded procedure. CONCLUSION: The HCPT-PEG-PCL-NPs has high entrapment efficiency, drug loading, uniform particle size, and can retard drug release in vitro, so it provides an extensive prospect for clinical application of HCPT. PMID- 20845793 TI - [Liposomal encapsulation of free anthraquinones in rhizoma et radix rhei and its quality control]. AB - OBJECTIVE: To encapsulate the free anthraquiones in Rhizoma et Radix Rhei (rhein, chrysophanol, physcione, emodin and aloeemodin) in liposomes and characterize the liposomes. METHODS: The liposomes were separated from free drug with sephadex G 50 with HPLC determination of the free anthraquinones in liposomes, then its entrapment efficiency was calculated. Ethanol injection method was used to prepare the liposomes with the addition of a suitable amount Ca2+ in the medium. The influence of Ca2+ on the entrapment efficiency of free anthraquinones in Rhizoma et Radix Rhei in liposomes has been studied. Dynamic laser scatterometer and transmission electron microscopy were used to study the sizes and morphology of the liposomes. RESULTS: The entrapment efficiency of rhein, chrysophanol, physcione, emodin and aloeemodin in liposomes were 27.63%, 85.16%,100.14%, 99.77% and 66.16%, respectively. The total entrapment efficiency of free anthraquinones in Rhizoma et Radix Rhei was 80.67%. Ca2+ could greatly promote the liposomal encapsulation of free anthraquinones in Rhizoma et Radix Rhei from 13.98% - 23.78% to 81.42% - 89.43%. The liposomes were white spheres and its average size was mainly concentrated on 340 nm. CONCLUSION: The entrapment efficiency of the liposomal encapsulation of free anthraquinones in Rhizoma et Radix Rhei is high. The quality control method is simple and rapid with good repeatability. PMID- 20845794 TI - [Optimization of extraction technics of total saponins from Pulsatilla cernua]. AB - OBJECTIVE: The extraction condition of total saponins from Pulsatilla cenua by ultrasonic wave was optimized by single factor and orthogonal experiments. METHODS: The largest absorbency of saponin was intended to be 470 nm by wavelength scan method with the pulchinenoside B4 as control sample, the linear relationship was observed between the absorbency and the content of saponin in the range of 0 - 0.040 mg/mL. RESULTS: The optimal conditions of extraction was as following: 80% of alcohol concentration, 40 min of ultrasonic time, 1: 20 of solid to liquid ratio, 80 W of ultrasonic power and one time for extraction. Among them, alcohol had the most significant effect on the extraction of total saponins. CONCLUSION: The content of total saponins in Pulsatilla cernua was 4. 32% under the optimal condition. The method developed here is efficient, stable, accurate and repeatable. PMID- 20845795 TI - [Optimization of the extraction technology of total flavonoids from Mulgedium tataricum using response surface analysis]. AB - OBJECTIVE: Response surface analysis methodology (RSM) was used to optimize the extraction technology of total flavonoids from Mulgedium tataricum. METHODS: Ethanol concentration, solvent-solid ratio, extraction temperature and extraction time were selected as influencing factors during extraction. The experiment mathematical model was arranged according to Box-Behnken central composite experiment design. RESULTS: The optimal extraction conditions were as following: ethanol concentration 63.78%, solvent-solid ratio 40: 1, extraction temperature 90 degrees C, and extraction time 1.07 h, the predicted value of extraction rate of total flavonoids was 14.04% under the optimum conditions, and the experimental value was 13.79%. CONCLUSION: The combination of Box-Behnken design and response surface analysis can well optimize the extraction technology of total flavonoids from Mulgedium tataricum. PMID- 20845796 TI - Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer? AB - AIMS AND BACKGROUND: The aim of the study was to investigate the growth rate of inherited breast cancer, to analyze its T2 signal intensity besides kinetic and morphologic aspects, and to verify whether there is any correlation between magnetic resonance imaging phenotype and BRCA status. METHODS: Between June 2000 and September 2009, we enrolled 227 women at high genetic risk for breast cancer in a surveillance program, within a multicenter project of the Istituto Superiore di Sanita (Rome). RESULTS: Thirty-four cancers were detected among 31 subjects. One patient refused magnetic resonance imaging because of claustrophobia. Compared with sporadic disease, hereditary cancer showed some differences, in terms of biologic attitude and semeiotic patterns. These differences were mainly registered for magnetic resonance imaging, where the most frequent radiological variant was represented by the very high T2 signal intensity (73%). Moreover, the size of 8 of the neoplasms showed a significant increase in less than one year, 5 of them in less than 6 months. Six lesions were in BRCA1 patients and the remaining in BRCA2. Furthermore, cancers with a high growth rate also demonstrated a significant increment in T2 signal intensity. CONCLUSIONS: Our results confirmed the high growth rate within BRCA-related breast cancers, especially for BRCA1 mutation carriers. In our experience, we found a specific imaging phenotype, represented by the high T2 signal intensity of hereditary breast cancer. To our knowledge, this is the first report that points out this new semeiotic parameter, which is usually typical of benign lesions. Considering the correlation between high growth rate and high T2 signal intensity, the former seems to be related to the absence of induction of a desmoplastic reaction that could somehow restrict cancer growth. PMID- 20845797 TI - Use of trastuzumab in HER2-positive metastatic breast cancer beyond disease progression: a systematic review of published studies. AB - AIMS AND BACKGROUND: Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB, has determined clinical benefit for women affected by metastatic or early stage HER2-positive breast cancer and never previously treated with trastuzumab. Trastuzumab is generally used as first-line treatment of HER2+ metastatic breast cancer and is currently administered beyond progression even without clear evidence supporting such clinical practice. In fact, HER2-positive metastatic breast cancer has a high risk of progressing after first-line therapy, and second-line treatments vary. The aim of the study was to investigate by a systematic review the efficacy of trastuzumab-based treatments beyond progression in HER2-positive metastatic breast cancer. MATERIALS AND METHODS: We performed a systematic review using Medline, Embase and Cochrane Library data bases and publications in principal meetings or congresses of oncology in Europe and America until September 2008. The main selection criterium was the reporting of time to progression, calculated from the start of each trastuzumab-based therapy to the date of progressive disease or death. RESULTS: Twelve studies were selected that included a total of 516 patients. The weighted mean time to progression was 23.66 weeks (standard deviation, 4.37) and the median was 26 weeks (range, 13-39). Interestingly, combined trastuzumab plus vinorelbine treatment showed a lower mean and median time to progression (20.59 and 19.57 weeks, respectively), whereas trastuzumab plus capecitabine yielded a mean time to progression of 30.33 weeks. CONCLUSIONS: The added value of the present study has been to provide a quantitative summary measure of time to progression which can be used for comparisons between current and future available regimens. PMID- 20845798 TI - Efficacy of surgery and imatinib mesylate in the treatment of advanced gastrointestinal stromal tumor: a systematic review. AB - AIMS AND BACKGROUND: In patients with localized gastrointestinal stromal tumors, surgery remains the elective treatment. Nowadays, imatinib therapy has been standardized in advanced gastrointestinal stromal tumors, showing continuous improvements in progression-free and overall survival. A combination of imatinib therapy and surgery may also be effective in a subset of patients with metastatic or unresectable gastrointestinal stromal tumors. In this review, the authors analyzed the role of imatinib mesylate associated to surgery in unresectable and/or metastatic gastrointestinal stromal tumors. METHODS AND STUDY DESIGN: We searched for all published and unpublished randomized controlled clinical trials and controlled clinical trials. We conducted the review according to the recommendations of The Cochrane Collaboration. We used Review Manager 5 software for the statistical analysis. RESULTS: There are currently no randomized controlled clinical trials or controlled clinical trials on this issue. We performed a subgroup analysis in the patients preoperatively treated with imatinib mesylate. This subgroup revealed a minor incidence of recurrent or metastatic gastrointestinal stromal tumors and a greater incidence of locally unresectable gastrointestinal stromal tumors in the responsive disease group (P = 0.001). In this patient group, more complete resections were observed (P = 0.00001). Furthermore, in the same patient group we observed a more significant 12 and 24-month disease-free survival after imatinib treatment and complete resection (respectively P= 0.06 and P= 0.003) and also a better 24-month overall survival (P = 0.004). CONCLUSIONS: There is actually only one ongoing European randomized study evaluating surgery of residual disease in patients with metastatic gastrointestinal stromal tumors responding to imatinib mesylate. Imatinib mesylate represents the standard treatment as preoperative supplement for locally unresectable and/or metastatic gastrointestinal stromal tumors, and a trial to compare the approach versus surgery alone is not necessary. For patients responding to imatinib or patients with prolonged stable disease, resection of residual disease should be considered. A phase III randomized study evaluating surgery of residual disease in patients with metastatic gastrointestinal stromal tumor responding to imatinib mesylate, EORTC 62063, has been opened. Moreover, surgery should be considered for patients at higher risk of complications during pharmacological debulking. In advanced gastrointestinal stromal tumors, the advantages of the integrated treatment are significant in the complete or partial response disease group in terms of more complete resections and better disease free and overall survival. PMID- 20845799 TI - Cisplatin plus docetaxel combination in the first-line treatment of metastatic non-small cell lung cancer. AB - AIMS: To evaluate activity and toxicity of cisplatin plus docetaxel combination in the first-line treatment of chemotherapy-naive patients with metastatic non small cell lung cancer. PATIENTS AND METHODS: Between October 2004 and July 2008, 186 patients with metastatic non-small cell lung cancer treated with first-line cisplatin plus docetaxel were retrospectively evaluated in 7 centers. The chemotherapy schedule consisted of cisplatin, 75 mg/m(2) iv infusion, and docetaxel, 75 mg/m(2) iv infusion on day 1, every 3 weeks. RESULTS: Median age was 56 years (range, 28-75). Eighteen patients (9.7%) were females and 168 (90.3%) were males, with a median ECOG performance status of 1 (range, 0-2). A total of 833 cycles of chemotherapy was administered (median, 4 cycles; range, 1 6). Two patients (1.1%) achieved clinical complete response, 77 patients (41.4%) partial response, and 66 patients (35.5%) stable disease. Median time to disease progression was 6 months (95% CI, 5.54-6.46). Median overall survival was 14.6 months (95% CI, 11.47-17.73). One- and 2-year overall survival was 55.2% and 19.7%, respectively. The most common grade 3-4 hematological toxicities were neutropenia (n = 32, 17.2%) and anemia (n = 4, 2.2%). CONCLUSIONS: The cisplatin plus docetaxel combination was effective and safe in the first-line treatment of patients with metastatic non-small cell lung cancer. PMID- 20845801 TI - Cytoreductive surgery and perioperative intraperitoneal chemotherapy in recurrent ovarian cancer. AB - BACKGROUND AND AIMS: Cytoreductive surgery with perioperative intraperitoneal chemotherapy is another approach for recurrent ovarian cancer. The purpose of the study was to assess the feasibility and the effect of cytoreduction and perioperative intraperitoneal chemotherapy in recurrent ovarian cancer. PATIENTS AND METHODS: Twenty-nine women with recurrent ovarian cancer underwent cytoreductive surgery. Clinical variables were correlated to morbidity, hospital mortality, recurrences, and survival. RESULTS: Complete cytoreduction was possible in 58.6%. Extensive seeding of the small bowel and distant metastases excluded the possibility of performing complete cytoreduction. Perioperative intraperitoneal chemotherapy was given in 75.9%. Morbidity and hospital mortality rates were subsequently 24.1% and 3.4%. Recurrence was recorded in 48.3%. The extent of peritoneal dissemination was an independent variable of recurrence (P= 0.014). The 5-year survival rate was 30%. The extent of peritoneal dissemination and the completeness of cytoreduction were related to survival (P <0.05). The completeness of cytoreduction independently influenced survival (P= 0.013). CONCLUSIONS: Secondary cytoreduction with intraperitoneal chemotherapy is feasible in most women with recurrent ovarian cancer with acceptable morbidity and mortality. Complete cytoreduction is not possible if distant and unresectable metastases are present or if the small bowel is extensively seeded. Long-term survivors are patients with limited peritoneal dissemination who may undergo complete cytoreduction. PMID- 20845800 TI - Fixed-dose-rate gemcitabine infusion in patients with advanced pancreatic or biliary tree adenocarcinoma. AB - AIMS AND BACKGROUND: Gemcitabine is an effective agent in pancreatic adenocarcinoma. Fixed-dose-rate gemcitabine has an interesting biological and clinical rationale, with successful results in previous studies. We conducted a trial to confirm efficacy and toxicity of fixed-dose-rate gemcitabine in patients with pancreatic or biliary tree adenocarcinoma. METHODS: Eligible patients with locally advanced or metastatic pancreatic or biliary tree adenocarcinoma received fixed-dose-rate gemcitabine at a dose of 1500 mg/m(2) at a rate of 10 mg/m(2)/min weekly for 3 weeks every 28 days. Efficacy measures were overall survival, response rate and progression-free survival. RESULTS: Sixty-two patients were enrolled, and 59 were assessable for response. Seven patients (11.3%) had a partial response, 26 stable disease (41.9%) and 26 progressive disease (41.9%). Median time to progression was 21 weeks and median overall survival, 37.71 weeks. Main toxicities were grade 3-4 neutropenia (45.2%) and grade 2-3 asthenia (54.8%). No toxic deaths were documented. CONCLUSIONS: Fixed-dose-rate gemcitabine has a relevant antitumor activity but with significant toxicity. It represents an interesting schedule and could be combined with other biological or chemotherapeutic agents. PMID- 20845803 TI - Metastatic breast cancer shows different immunohistochemical phenotype according to metastatic site. AB - AIMS AND BACKGROUND: The study was performed to assess the status of immunohistochemical markers in primary and metastatic breast cancer and to determine the organ-specific characteristics of metastatic breast cancer. METHODS: Samples from 13 cases of paired primary and metastatic breast cancer and 34 cases of metastatic breast cancer were included. RESULTS: In the analysis of 13 cases of paired primary and metastatic breast cancer, estrogen receptor and progesterone receptor loss were noted in 1 (7.7%) case each. Androgen receptor loss and gain was noted in 2 (15.4%) cases, respectively. HER-2 showed 100% concordance with primary and metastatic tumors. C-kit was demonstrated in only 2 (15.4%) cases of metastatic breast cancer. In the analysis of 34 cases of metastatic breast cancer, when classified into triple-negative type (ER-, PR-, and HER-2-), HER-2+ type, and ER+ or PR+/HER-2- type according to immunohistochemical stain results, HER-2 type (66.7%) in brain metastasis and ER+ or PR+/HER-2- type (75.0%) in liver metastasis were predominant. Bone metastasis was composed of triple negative type (44.4%) and ER+ or PR+/HER-2- type (55.6%), and lung metastasis showed all of three subtypes in similar proportions. CONCLUSIONS: Metastatic breast cancer shows different immunohistochemical phenotypes according to metastatic site (P = 0.048). PMID- 20845802 TI - Active Breathing Coordinator in adjuvant three-dimensional conformal radiotherapy of early stage breast cancer: a feasibility study. AB - AIMS: To investigate the technical feasibility of utilizing the Active Breathing Coordinator for planning of postoperative three-dimensional conformal radiation therapy in patients with early stage breast cancer undergoing breast conservation therapy. METHODS: Patients with early stage breast cancer for whom adjuvant radiotherapy after breast-conserving surgery was planned were consecutively enrolled. Five sessions of simulation with the Active Breathing Coordinator were planned for each patient. Computed tomography for simulation was not acquired until a good level of compliance with the procedure was achieved by the patient. Patients who did not show a satisfactory level of compliance after the planned fifth session were defined as noncompliant. Two simulation computed tomography scans were acquired: the first without the Active Breathing Coordinator during free breathing, the second with the Active Breathing Coordinator. Forward intensity-modulated treatment plans were calculated. Mean lung dose (MLDipsilateral) and V30 (V30lung) for the ipsilateral lung and V30 for the heart (V30heart), were evaluated. RESULTS: Twenty consecutive patients were enrolled (6 with left-sided breast cancer and 14 with right-sided breast cancer). Eighteen of the patients completed the simulation computed tomography with the Active Breathing Coordinator after 1-5 sessions (median, 3). In 16 of the 18 patients, a reduction of V301ung was observed with the Active Breathing Coordinator. In 15 of the 18 patients, a reduction of MLDipsiateral was also observed. In 5 of the 6 patients with left-sided breast cancer, a reduction of V30heart was noted. CONCLUSIONS: Routine application of the Active Breathing Coordinator in clinical practice is feasible, even though it requires an increased workload. Dosimetric results are encouraging in terms of a better sparing of the ipsilateral lung and the heart. PMID- 20845804 TI - Parametric model to analyse the survival of gastric cancer in the presence of interval censoring. AB - AIMS AND BACKGROUND: The objective of the study was to assess the impact of prognostic factors on survival of patients with gastric cancer in the presence of interval censoring using parametric models. METHODS AND STUDY DESIGN: In a retrospective cohort study, 178 patients with gastric cancer were studied from February 2003 to January 2008. Gender, age at diagnosis, distant metastasis, tumor size, histology type, tumor grade, lymph node metastasis and pathologic stage were selected as prognostic and entered in the models. Weibull, exponential, log-logistic and log-normal analyses with interval censoring were performed as parametric models, and Akaike Information Criterion (AIC) was used to compare the efficiency of models. RESULTS: The risk of death for patients at an older age, with tumor size greater than 35 mm, distant metastasis and advanced stage of disease was statistically higher. Other clinical and demographic factors were not significant. According to AIC, the log logistic model is the most efficient of all the models in multivariable analysis. CONCLUSIONS: The results indicated that the early detection of a cancer at a young patient age and in primary stages is important to increase survival from gastric cancer. According to statistical criteria, a parametric model can also be a useful statistical model to find prognostic factors in the presence of interval censoring. Although it seems that all models in this analysis fit well, AIC supported the log logistic regression as the best option. PMID- 20845805 TI - Pharmacoeconomic aspects of FOLFIRI or FOLFOX regimens administered with a fully ambulatory pump compared to the day hospital setting. AB - AIMS AND BACKGROUND: The social cost of management of patients suffering from colorectal cancer has been growing dramatically in the last decade due to the high number of active antitumor agents and to the increased incidence of the tumor in western countries. The aim of the study was to explore from a pharmacoeconomic point of view a different way to administer the two most common regimens in this patient setting. STUDY DESIGN: This was a cost-minimization study. Data were extracted from hospital registries and dedicated offices. The traditional setting (day hospital inpatient setting) and a fully ambulatory setting (CIP pump) were considered and compared. RESULTS: The CIP system resulted in higher direct costs than the day hospital setting (444.70 versus 159.00 euro/cycle). However, traditional infusion resulted in longer nursing care, with an increase in nursing costs of more than 100.00 euro/cycle. Moreover, the inpatient setting obliged patients to stay in the hospital as much as ten times longer than with the CIP system. This meant that with the same time span and the same resources, the CIP pump permitted treatment of at least five times more patients than the traditional setting. Thus, a threshold of 52.00 euro per patient for general hospital costs (ordinary and extraordinary maintenance of buildings, power supply, and housekeeping) was identified to discriminate whether the CIP pump is cost-saving or not. CONCLUSIONS: Administration of the FOLFIRI or FOLFOX regimen in a traditional day hospital setting was less costly when considering the direct costs. However, a fully ambulatory pump permitted to better employ hospital resources and could permit cost-saving in those units in which more than five patients per day are treated and global costs are higher than 52.00 euro per patient. PMID- 20845806 TI - Clinical governance benchmarking issues in oncology: aggressiveness of cancer care and consumption of strong opioids. A single-center experience on measurement of quality of care. AB - AIMS AND BACKGROUND: The aggressiveness of cancer care near the end of life and the consumption of opioids are potential indicators of quality of care in palliative and end-of-life settings. The purpose of this article is to present a retrospective analysis regarding these themes and the adopted procedures to improve quality of care. METHODS: We evaluated all cancer patients treated and deceased during 2008 and considered those who died and received any antiblastic therapy within 14 and 30 days prior to death. Moreover, we evaluated the annual consumption of pure opioids during 2007 and 2008 in our inpatient clinic. We found that 5% and 9% of all treated patients were still receiving antiblastic treatment near the end of life within respectively 14 and 30 days prior to death (respectively 29.6% and 51.5% of deceased patients). All but 2 patients died from progressive disease, one patient died from acute myocardial infarction during chemotherapy, and one of severe sepsis after chemotherapy for non-Hodgkin lymphoma. As regards the annual consumption of strong opioids, there was a 179% increase in the use of morphine-equivalent doses of oral long-acting opioids (+228% for oxycodone) after the introduction of daily pain measurement through a numerical rating scale. CONCLUSIONS: To reduce the administration of chemotherapy near the end of life, we introduced the palliative prognostic score, to be administered to all advanced cancer patients with performance status of at least 2. To evaluate the effectiveness of analgesics and to reduce the cases of undertreatment of cancer pain, we adopted, in addition to the numerical rating scale, Cleeland's Pain Management Index. We are convinced that attempts to improve the quality of care can be achieved by the collaboration of all health professionals, patients and care givers. PMID- 20845807 TI - The effects of growth inhibitory peptide on follicular thyroid cancer cell growth, migration, and invasion. AB - AIMS AND BACKGROUND: Thyroid cancer is the most common endocrine neoplasm worldwide. Although differentiated thyroid cancers are associated with a favorable survival, the prognosis worsens dramatically for patients with distant metastasis. Metastases from follicular thyroid carcinoma (FTC) occur earlier and are more aggressive than those from papillary thyroid carcinoma. For FTC that is resistant to radioactive iodine, new treatments are urgently needed. Human alpha fetoprotein (HAFP) is a tumor-associated fetal protein that has been demonstrated to regulate tumorigenesis. Growth inhibitory peptide (GIP), a synthetic 34-mer peptide isolated from the third domain of HAFP, has been shown to have antitumor growth ability in various human cancers. However, the effects of GIP in FTC have not yet been studied. The aim of this study was to investigate the antitumor ability of GIP in FTC. METHODS AND STUDY DESIGN: Using both PBS and GIP control peptide as a negative control, the antiproliferative activity of GIP in the WRO human FTC cell line was determined using a tetrazolium-based colorimetric assay. In addition, cell migration and invasion assays were used to measure tumor metastasis inhibition effects in vitro. RESULTS: GIP did not inhibit WRO cell proliferation in a time- or dose-dependent manner. However, in WRO cells treated with GIP for 4 days, migration was significantly inhibited at concentrations of 50 and 100 microM (33.3% and 19.5%, respectively; both P <0.05). Cell invasion was also significantly inhibited at 50 and 100 microM (67.1% and 39.0%, respectively; both P<0.05). CONCLUSIONS: Although GIP failed to suppress FTC cell growth, it effectively interrupted both FTC cell migration and invasion abilities in vitro. Further validation in an animal model and elucidation of the underlying mechanisms will be required. GIP may potentially serve as an anti-FTC metastasis agent aiding current chemotherapy regimens. PMID- 20845808 TI - Glycosyl-phosphatidylinositol-anchored interleukin-2 expressed on tumor-derived exosomes induces antitumor immune response in vitro. AB - AIMS AND BACKGROUND: Tumor-derived exosomes (TEXs) have been considered as a new kind of cancer vaccine, but the antitumor effects are not satisfactory. In order to improve the efficacy of TEXs, we investigated whether exosomes derived from glycosyl-phosphatidylinositol-anchored interleukin 2 (GPI-IL-2) gene-modified bladder cancer cells can increase the antitumor effects. METHODS AND STUDY DESIGN: We transfected melanoma antigen-1 (MAGE-1)-expressing T24 tumor cells with a plasmid encoding GPI-IL-2 and prepared the TEXs. Exosomes expressing GPI IL-2 were characterized by electron microscope and Western blot analysis. RESULTS: IL-2 was present on the cell surface in the GPI-anchored form as demonstrated by fluorescent microscope and ELISA analyses. Exosomes expressing GPI-IL-2 naturally contained bioactive GPI-IL-2 and tumor-associated antigen MAGE 1. Moreover, exosomes expressing GPI-IL-2-pulsed dendritic cells could induce the proliferation of T cells and the antigen-specific cytotoxic T-lymphocyte immune response more efficiently. CONCLUSIONS: GPI-IL-2 gene-modified tumor cells can make the TEXs contain GPI-IL-2, resulting in increased antitumor effects. Our study provided a feasible approach for exosome-based tumor immunotherapy. PMID- 20845809 TI - Protective effect of tetrandrine on doxorubicin-induced cardiotoxicity in rats. AB - AIMS AND BACKGROUND: Doxorubicin (Dox) is effective in curative and adjuvant chemotherapy of malignant tumors. Cardiotoxicity is the chief toxic effect that limits the clinical use of Dox. We studied the effects of tetrandrine (Tet) on doxorubicin-induced cardiotoxicity in rats and its protective activity. MATERIALS AND METHODS: Sprague-Dawley rats were randomly divided into the following 4 groups: a control group (received only saline), Dox group (received only Dox), Tet/Dox group (received Tet plus Dox), and Tet group (received only Tet). Rats were injected intravenously with 2 mg/kg Dox once a week for 7 weeks and 50 mg/kg Tet was administered intraperitoneally weekly for 7 weeks. Measurements of cardiac contractile parameters including LSVP +dP/dt max and -dP/dt max, and assessment of electrocardiograms were carried out. Mitochondrial oxidation and phosphorylation state 3 (S3) and state 4 (S4) respiration were measured. Respiration control rate (RCR) and the ADP/O ratio were calculated. Cardiac ultrastructure was examined by electron microscopy. RESULTS: Dox induced significant cardiotoxicity in this rat model. The values of LSVP, +dP/dt max, and -dP/dt max in the Tet/Dox group increased as compared to the Dox group (P <0.05). The cardiac contraction and relaxation improved on Tet administration. Tet inhibited the prolonged QT interval on the electrocardiogram in Dox-treated rats. Compared to the Dox group, the values of S3, RCR, and ADP/O increased by more than 28%, 48%, and 27%, respectively, in the Tet/Dox group. Significant cardiac morphological protection was observed in the Tet/Dox-treated rats. CONCLUSION: Tet can improve the reduced cardiac function caused by Dox treatment and prevent Dox-induced mitochondrial impairment in rat cardiotoxicity. PMID- 20845810 TI - Gene analysis of Epstein-Barr virus-associated lymphomas in Hu-Pbl/SCID chimeras. AB - AIMS AND BACKGROUND: The mechanisms of Epstein-Barr virus (EBV)-associated tumor development are incompletely understood. The aim of this study was to investigate the gene expression of EBV-associated lymphomas in hu-PBL/SCID mice. METHODS: Human peripheral blood lymphocytes (hu-PBL) from EBV-seropositive donors were transplanted into severe combined immunodeficiency (SCID) mice. In situ hybridization was used to detect EBV-encoded small RNA- 1 (EBER1) in tumor tissues. Mutation of TP53 exons 5-8 in EBV-induced lymphomas was analyzed by PCR SSCP. Immunohistochemical staining was used to examine EBV gene products and cellular oncoproteins. RESULTS: Twenty-one of 29 mice developed tumors. EBER1 was positive in the nuclei of almost all tumor cells. Immunohistochemistry showed positive staining of LMP1, EBNA2 and ZEBRA in a small number of tumor cells. Immunohistochemically detectable p53 protein expression was common (85.7%), but TP53 gene mutations were identified in only four cases (19.1%) of EBV-associated lymphomas. Positivity rates of C-myc, Bcl-2 and Bax expression were 100%, 95.2%, and 90.5%, respectively, in the 21 cases of EBV-associated lymphomas. CONCLUSIONS: Our preliminary findings suggest that EBV-associated lymphomas in hu PBL/SCID chimeras show EBV infection, expression of oncogenic viral genes, and overexpression of cellular oncogenes. TP53 gene mutations are rare but p53 protein is commonly expressed in EBV-associated lymphomas. PMID- 20845811 TI - Successful treatment with the fully human antibody panitumumab after a severe infusion reaction with cetuximab. AB - AIMS AND BACKGROUND: There are only limited data on the safety and efficacy of panitumumab in patients who experienced severe infusion reactions during cetuximab antibody therapy. CASE REPORT: We report the case of a 69-year-old woman with chemotherapy-refractory metastatic colorectal cancer who received single-agent cetuximab treatment but experienced a severe reaction during the first infusion, despite premedication with corticosteroids/antihistamines. Cetuximab was discontinued and treatment with panitumumab initiated approximately 14 days later (without premedication); no infusion reactions occurred and there was a rapid improvement in her general condition. She experienced a partial response that was sustained for 7 months before progression. CONCLUSIONS: This case supports the use of panitumumab in patients with chemotherapy-refractory metastatic colorectal cancer and suggests that panitumumab may be used in some patients with prior infusion reactions to cetuximab. PMID- 20845812 TI - Prolonged response to cytoreductive surgery and sunitinib in an elderly patient with synchronous multiple metastases from renal cell carcinoma. AB - One third of patients with renal cell cancer have metastatic disease at diagnosis. Until now the outcome of these patients has been poor due to the variable natural history of the disease and the lack of effective therapy. Multitargeted therapy of advanced renal cell cancer appears to be a better option than immunotherapy. We report the case of an elderly patient with skin, lung, bone and brain metastases and widespread intraabdominal disease treated with cytoreductive surgery and sunitinib, resulting in a prolonged response. PMID- 20845813 TI - Metastatic colorectal carcinoma and kidney tumors: a report of four cases. AB - AIMS AND BACKGROUND: The prognosis of patients with metastatic colorectal carcinoma (CRC) has improved substantially over the last two decades. Longer patient survival comes at a price of more complications, including second primary neoplasms and metastases at unusual sites. METHOD: Retrospective chart review. RESULTS: We present 4 patients with metastatic CRC who developed kidney tumors. In 2 cases, partial nephrectomy or nephrectomy was performed for second primary renal cell carcinoma. The patients survived 2.5 and more than 6 years after kidney surgery. In the other 2 patients the kidney tumors were diagnosed as CRC metastases, histologically verified in one case; these two patients died within two years of diagnosis of kidney involvement. CONCLUSION: The diagnostic approach to kidney tumors in CRC patients should include a biopsy because only patients with primary renal cell carcinoma and selected patients with metastatic CRC benefit from nephrectomy. PMID- 20845814 TI - B-cell lymphofollicular infiltrates in mycosis fungoides. AB - AIMS AND BACKGROUND: The histopathological picture of mycosis fungoides can be characterized by heavy reactive infiltrates. These are rarely composed of B lymphocytes with formation of reactive follicles. METHODS AND STUDY DESIGN: We collected three cases of mycosis fungoides with a reactive B-cell lymphofollicular reaction at the bottom of the epidermotropic infiltrate. RESULTS: Case 1 showed flat lesions (patches) with a CD4+ neoplastic phenotype; case 2 presented infiltrated lesions (plaques) with a CD8+ immonophenotype; case 3 was characterized by nodular lesions (tumors) with a CD4+ neoplastic component. In all three cases, no clonal gene rearrangement was found with the polymerase chain reaction technique. CONCLUSIONS: Among the protean clinicopathological features which mycosis fungoides can show, we underline that a B-cell lymphofollicular component can be encountered at the base of the epidermotropic infiltrate even in clinically flat ("patchy") lesions. PMID- 20845815 TI - Inflammatory myofibroblastic tumor of the stomach in an adult woman: a rare intermittent cause of gastric outlet obstruction. AB - BACKGROUND: Inflammatory myofibroblastic tumor is a neoplasm of intermediate biological potential that frequently recurs and rarely metastasizes. CASE REPORT: We report a rare case of intermittent gastric outlet obstruction by an inflammatory myofibroblastic tumor of the cardia. RESULTS: A 56-year-old woman presented at the gastroenterology department with a two-day history of hematemesis and melena. She had intermittent nausea and vomiting complaints, which had manifested periodically for about five months. Upper gastrointestinal endoscopy demonstrated a mass of 6 cm in diameter, which was resected. Histological examination revealed ulcerated mucosal granulation-like tissue with myofibroblastic spindle cell proliferation in a storiform pattern. CONCLUSIONS: In order to avoid unnecessary aggressive therapy, gastric IMT should be taken into account when a gastric mass accompanied by the various clinical manifestations of IMT is found in an adult. PMID- 20845816 TI - Metastatic gastric melanoma: a challenging diagnosis. AB - BACKGROUND: The stomach is regarded as a rare site for metastasis. When a gastric mass is observed macroscopically, the presumed diagnosis is usually a primary gastric carcinoma. However, the stomach may be involved in metastatic malignant melanoma. Besides a possible macroscopical misdiagnosis, metastatic gastric melanoma may also be misdiagnosed microscopically as adenocarcinoma due to its protean histological characteristics. These features make metastatic gastric melanoma a challenging diagnosis in some cases. CASE REPORT: We report a patient with metastatic gastric melanoma referred to us with an initial macroscopic and histopathological diagnosis of primary gastric adenocarcinoma. He was diagnosed as having metastatic gastric melanoma by further examination because of the peculiar metastatic involvement and normal gastrointestinal tumor marker levels. CONCLUSIONS: The stomach may be involved in melanoma and melanoma metastasis to the stomach is a diagnosis that should be taken into account while evaluating any gastric mass lesion. It is likely to be encountered more commonly nowadays due to the significant increase in the melanoma incidence. A history of melanoma, an atypical metastatic pattern, and normal gastrointestinal tumor marker levels may contribute to its diagnosis. PMID- 20845817 TI - Consolidation radiotherapy for a rare case of extranodal mucosa-associated lymphoid tissue non-Hodgkin's lymphoma synchronous with prostate adenocarcinoma. AB - Nongastric primary extranodal mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon, with around 0.1% occurring in the prostate. Even less frequent is the presence of MALT lymphoma synchronous with another type of neoplasm in the same organ, especially the prostate. Only a single case of concurrent adenocarcinoma and MALT lymphoma of the prostate has been reported in the literature. We report a rare case of primary extranodal marginal zone MALT lymphoma incidentally diagnosed during radical prostatectomy for an adenocarcinoma of the prostate in a 53-year-old patient. Fourteen months later a recurrence of the MALT lymphoma involving both sides of the diaphragm was found and was treated with chemoimmunotherapy. High-dose radiotherapy was delivered to residual bulky disease in the pelvic region. At 18 months from the end of radiation treatment the patient was without signs of relapse of MALT lymphoma. This preliminary result confirms that rare cases of MALT lymphoma of the prostate should be discussed and treated under the collaborative supervision of hematologists and medical and radiation oncologists. In fact, at an advanced stage of the disease, a chemotherapy regimen with additional consolidation radiotherapy could be an effective strategy, as in all other lymphomas. PMID- 20845818 TI - EGFR polysomy in squamous cell carcinoma of the thyroid. Report of two cases and review of the literature. AB - AIMS AND BACKGROUND: Primary squamous cell carcinoma of the thyroid gland (PSCCT) is an uncommon malignancy characterized by a poor prognosis. A radical surgical approach combined with radiotherapy or chemotherapy is the generally accepted treatment for this tumor. The epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor modulating the cell proliferation and biological progression of many human epithelial tumors. The EGFR overexpression in PSCCT suggests an additional therapeutic option for the treatment of this tumor. METHODS AND STUDY DESIGN: The clinicopathological features and immunohistochemical profiles of two cases of primary squamous cell carcinoma of the thyroid in a 66-year-old and an 83-year-old woman are presented. EGFR status was valued in both cases. RESULTS: Overexpression of EGFR protein was detected in 50% and 75% of the tumor cell membranes. EGRF gene polysomy was detected in both tumors. CONCLUSIONS: Pharmaceuticals targeting EGFR may help to provide the rationale for an additional, novel therapeutic option for this rare tumor, especially when other therapeutic options have been exhausted. PMID- 20845819 TI - Treatment of Merkel cell carcinoma with radiotherapy and imiquimod (Aldara): a case report. AB - AIMS AND BACKGROUND: Merkel cell carcinoma (MCC) is a rare skin tumor occurring mostly in older people. Postoperative radiotherapy is strongly recommended to improve local control. A case of a MCC treated by radiotherapy associated with imiquimod (Aldara) is presented. A possible physiopathological rationale for this concomitant treatment is also given. MATERIALS AND METHODS: We treated a diabetic 82-year-old man presenting with a MCC of the right zygomatic area. Despite surgery, postoperative ultrasonography showed a firm, painless residual mass of about 11 x 10 cm, fixed to the deep tissues. Parotid and zygomatic areas were treated along with the ipsilateral laterocervical lymph nodes. The total dose to the planning target volume was 50.4 Gy (1.8 Gy/day). Imiquimod was applied once a day to the zygomatic area with macroscopic infiltration and to the surrounding erythema. RESULTS: During the combination treatment, the patient showed acute G3 skin toxicity (RTOG) and a scab that resolved after a 3-week interruption of the radiotherapy and imiquimod treatment. When the scab was removed, the underlying skin appeared completely re-epithelialized. Imiquimod was suspended and treatment was continued only with irradiation. During this second phase of the treatment, the patient developed G2 dermatitis and G2 stomatitis. Clinical and instrumental re-evaluation showed a complete response 7 months after the end of radiotherapy, with very good local tropism. CONCLUSION: This case report suggests the possible effective use of immunomodulators, in this case imiquimod, combined with radiation therapy for cutaneous malignancies such as MCC. Skin tolerance should be an important issue to consider. PMID- 20845820 TI - Dose per fraction and dose rate effect. PMID- 20845821 TI - How healthy is the annual health check? AB - PURPOSE: This paper aims to provide an assessment of organisational implementation of the healthcare standards focusing on the annual health check (AHC) in the UK NHS. DESIGN/METHODOLOGY/APPROACH: Using a postal questionnaire a national survey of all acute and specialist NHS Trusts in England was undertaken. The survey yielded a total of 102 responses, which equates to a 59 per cent response rate. FINDINGS: The findings suggest considerable variation and diversity in the rate of progress individual Trusts made towards implementing the AHC in its first year. However, across many of the organisations surveyed, there was good evidence of some progress towards ensuring that basic operational and strategic components of the framework were in place. RESEARCH LIMITATIONS/IMPLICATIONS: The research appears to reflect the findings of earlier work on the implementation of clinical governance, suggesting that few lessons have been learnt from previous policy initiatives and raising important questions for the future of health care standards. PRACTICAL IMPLICATIONS: The findings could be used to support future national health care initiatives by giving an insight into how organisations respond to and manage the process of standards. ORIGINALITY/VALUE: This study makes a number of recommendations to facilitate smooth implementation of standards in health care. These include the introduction of a national IT solution; development of regional/national networks; more timely, relevant and consistent national guidance and, the definition of minimum information requirements needed for organisational assurance. PMID- 20845822 TI - Psychometric properties of the instrument quality in psychiatric care and descriptions of quality of care among in-patients. AB - PURPOSE: The purpose of this paper is to test the psychometric properties and dimensionality of a new instrument, quality in psychiatric care (QPC), and to describe and compare quality of care among in-patients as measured by this instrument. DESIGN/METHODOLOGY/APPROACH: The instrument quality in psychiatric care measures patients' experiences regarding quality of care. The instrument is based on a definition of quality of care from the patients' perspective. A sample of 265 in-patients at eight general psychiatric wards in Sweden was assessed. FINDINGS: Exploratory factor analysis revealed that the original five-dimensional 69-item QPC was better with six dimensions and reduced to 30 items, hereinafter denoted quality in psychiatric care-in-patients (QPC-IP) with retained internal consistency. The patients' ratings of quality of care were generally high; the highest rating was for quality of encounter and the lowest for participation. RESEARCH LIMITATIONS/IMPLICATIONS: Analysis of the dropouts was not possible because of incomplete registrations at the wards. PRACTICAL IMPLICATIONS: QPC-IP is a simple, inexpensive and quick way to evaluate quality of care and thus contributes to health care improvement in the field of psychiatry. ORIGINALITY/VALUE: The new 30 items instrument, QPC-IP includes important aspects of patients' perceptions of quality of care. The QPC-IP is psychometrically adequate and thus recommended for evaluating patients' experiences of the quality of psychiatric care. PMID- 20845823 TI - Medication reviews with computerised expert support: evaluation of a method to improve the quality of drug utilisation in the elderly. AB - PURPOSE: This paper aims to examine whether a computerised system for medication reviews can support physicians' decisions and improve the quality of drug treatment in the elderly. DESIGN/METHODOLOGY/APPROACH: This is a descriptive intervention study. The study included 275 patients living in community settings and nursing homes in Stockholm, Sweden. Patient data were analysed using computer software and scrutinised by a clinical pharmacologist. Pharmaco-therapeutic advice was sent to the physician responsible for each patient. The main outcome measures were initiation and discontinuation of drugs, changes of doses and rates of identified drug-related problems. FINDINGS: Expert opinions were given by the clinical pharmacologist, for 275 patients, mean age 85 years; 70 per cent female. An average of 3.3 remarks was given concerning unsuitable drugs, unclear indication, dosing when the kidney function was decreased, drug-drug interactions and quality indicators. On average 1.5 drug-related problems (DRP) per patient were attended to by the responsible physician at each unit. The most common action taken was withdrawal of a drug (n = 208). On average the drug use decreased from 10.4 to 9.5 drugs per patient, and several quality indicators were met. The drug costs decreased, and resulted in a more cost-effective drug therapy. ORIGINALITY/VALUE: The paper develops and tests a method for intervention in the care of elderly patients. The method is based on a computerised expert support system for medication reviews at a distance and on education of the staff. A safer drug therapy with improved quality and cost effectiveness is thus provided. PMID- 20845824 TI - Sanosil, a more effective agent for preventing the hospital-acquired ventilator associated pneumonia. AB - PURPOSE: The aim of this study is to compare the effects of Sanosil and glutaraldehyde 2 percent in disinfecting ventilator connecting tubes in an intensive care unit (ICU) environment. DESIGN/METHODOLOGY/APPROACH: The 12-week open-labelled clinical trial was conducted in the surgical ICU of a teaching hospital from March to May 2005. In the first phase of the study, high level disinfection was performed using glutaraldehyde 2 percent, whereas Sanosil was used as the disinfectant agent of the second phase. Samples for microbial culture were obtained from the Y piece, the expiratory limb proximal to the ventilator and the humidifier in different stages; the results were then compared. FINDINGS: Positive culture was more frequently reported in Y pieces, humidifiers and expiratory end of ventilators. Comparing the two groups, there were more positive cultures in the glutaraldehyde group (p value = 0.005); multiple organism growths, gram negative, gram positive and fungi were also more frequent in this group (p value = 0.01; 0. 007; 0. 062; 0.144, respectively). ORIGINALITY/VALUE: The paper shows that Sanosil is an effective agent in reducing the contamination risk in the tubes used in ICUs. PMID- 20845825 TI - Service experiences in hospitals in Bangladesh: are there gender inequities? AB - PURPOSE: The disparities faced by women, especially in Bangladesh, have a long and contentious history. From education and employment to health care and other social products, the marginalization of women has been stark. This paper aims to examine whether women experience poorer services than men in the hospitals in Bangladesh. DESIGN/METHODOLOGY/APPROACH: A survey was conducted in both public and private hospitals in Dhaka City, Bangladesh. The sample comprised 305 randomly selected respondents. Using statistical and data mining techniques, the authors test the hypothesis and identify interesting data patterns. FINDINGS: Surprisingly, very few differences were found between the service experiences of male and female patients. While the literature would predict differently, given the disparities that women generally experience, on most service quality attributes female patients were at least as well-served as male patients. RESEARCH LIMITATIONS/IMPLICATIONS: The findings may be unique to the sample from the capital city where hospital users may be more affluent and are provided better service without gender inequity. PRACTICAL IMPLICATIONS: The findings raise intriguing questions. Among the various possibilities the authors surmise the following: there may be deeper systemic changes underway that are reflected in service providers' attitudes toward women. It is possible that women have lower expectations from the service providers; thus, their ratings are at par with those of men even if they actually received poorer services. ORIGINALITY/VALUE: This is probably a unique study in that it focuses on gender effects on perceived service quality in a hospital setting in Bangladesh. PMID- 20845826 TI - Design and analysis of a health care clinic for homeless people using simulations. AB - PURPOSE: Improving quality of care is important in health care management. For health care clinics, reducing patient waiting time and improving throughput with efficient utilization of the workforce are important issues to achieve better quality of care. This paper seeks to introduce a simulation study on design and analysis of a health clinic for homeless patients in Lexington, Kentucky, USA. DESIGN/METHODOLOGY/APPROACH: Using the simulation model, the patient flow of the clinic and analyze quality of care for different staffing levels is simulated. In addition, the dependence of distributions on service times is investigated. Moreover, the impact of service time variability on quality of care (e.g. patient waiting time) is analyzed. FINDINGS: The necessary staffing level and utilizations to reduce patient waiting times and improve throughput to achieve better quality of care are obtained. In addition, it is shown that the system performance is primarily dependent on the mean and coefficients of variation, rather than a complete distribution, of service times. In addition, a piece-wise linear approximation formula is proposed so that patient waiting time in the clinic can be estimated for any variability with only two simulations. RESEARCH LIMITATIONS/IMPLICATIONS: The simulation method may need long model development time and long simulation executing time for complex systems. PRACTICAL IMPLICATIONS: The quality of care delivery in a health care clinic can be evaluated using simulations. The results presented in the paper provide an easier approach for medical practitioners to evaluate different scenarios, examine needed resources, and carry out what-if analysis to predictthe impact of any changes in the system, to determine an optimal system configuration. ORIGINALITY/VALUE: The paper shows that such models provide a quantitative tool for clinic operations and management to achieve better care quality. Moreover, it can be easily adapted to model other health care facilities, such as hospitals, emergency rooms, operating rooms, supply chain in health care industry. PMID- 20845827 TI - Challenging orthodoxies: the road ahead for health and human rights. AB - Two decades of work delivering health care in poor communities provide a standpoint from which to challenge conventional doctrines in human rights and public health. These orthodoxies include the priority often assigned to civil and political rights over economic and social rights and a narrow concept of cost effectiveness in public health policy. An analysis based on economic and social rights underscores, for example, that effectively treating infectious diseases in poor communities requires ensuring that people receive adequate food The challenge of maternal mortality in low-income settings similarly shows the need for an approach to rights that is simultaneously comprehensive and pragmatic. In many settings, paying community health workers for their efforts on behalf of their neighbors can also be seen as a critical strategy to realize right. Across contexts, the yield on the expanded and pragmatic view of health and human rights adumbrated here may be considerable. In forthcoming issues, Health and Human Rights will continue to investigate the conceptual, but above all the practical aspects of such issues, seeking to shift the health and rights agenda in a way that may make sense to the world's poor and marginalized, the chief victims of contemporary human rights violations. PMID- 20845828 TI - Excluding the poor from accessing biomedical literature: a rights violation that impedes global health. AB - Most biomedical journals charge readers a hefty access toll to read the full text version of a published research article. These tolls bring enormous profits to the traditional corporate publishing industry, but they make it impossible for most people worldwide--particularly in low and middle income countries--to access the biomedical literature. Traditional publishers also insist on owning the copyright on these articles, making it illegal for readers to freely distribute and photocopy papers, translate them, or create derivative educational works. This article argues that excluding the poor from accessing and freely using the biomedical research literature is harming global public health. Health care workers, for example, are prevented from accessing the information they need to practice effective medicine, while policymakers are prevented from accessing the essential knowledge they require to build better health care systems. The author proposes that the biomedical literature should be considered a global public good, basing his arguments upon longstanding and recent international declarations that enshrine access to scientific and medical knowledge as a human right. He presents an emerging alternative publishing model, called open access, and argues that this model is a more socially responsive and equitable approach to knowledge dissemination. PMID- 20845829 TI - Will we take suffering seriously? Reflections on what applying a human rights framework to health means and why we should care. AB - Since this journal was first published, rights-based approaches to health have prolferated in the health and development communities. At the same time, human rights advocacy organizations, courts, and UN actors have increasingly been engaged in applying rights norms in health contexts. Together with others in this issue, this article is a call not to lose sight of the radical potential of using a human rightsparadigm to promote health--even as we go about the pragmatic work of translating rights frameworks into practice in our research, advocacy, litigation strategies, program planning, and service delivery. Drawing together points made in other pieces in this issue, the article describes certain conceptual and practical implications of a transformative engagement between health and human rights. It argues that an appropriate starting point is to take suffering seriously; in so doing, approaches in both health and rights will necessarily shift. A human rights approach challenges biological individualism in both clinical medicine and public health, and builds on work in social epidemiology by providing frameworks for accountability. At the same time, using rights to advance the health of marginalized peoples around the world requires critiquing and expanding limited approaches to human rights, in theory and practice. PMID- 20845830 TI - What is a human-rights based approach to health and does it matter? AB - A human rights approach to health is critical to address growing global health inequalities. Three aspects of the nature of health as a right are relevant to shaping a human rights approach to health: (1) the indivisibility of civil and political rights, and socio-economic rights; (2) active agency by those vulnerable to human rights violations; and (3) the powerful normative role of human rights in establishing accountabiliy for protections and freedoms. Health professionals' practice, tpically governed by ethical codes, may benefit from human rights guidelines, particularly in situations of dual loyalty where clients' or communities' human rights are threatened Moreover, institutional accountability for protecting human rights is essential to avoid shifting responsibility solely onto the health professional Human rights approaches can include holding states and other parties accountable, developing policies and programs consistent with human rights, and facilitating redress for victims of violations of the right to health. However, underlying all models is the need to enable active social mobilization, without which legal approaches to rights lack sustainability and power. Evidence from South and Southern Africa has shown that different conceptions of what is meant by human rights impact substantially on state willingness and abiliy to meet constitutional obligations with regard to the right to health. New approaches to health polity development, which draw on the agency of vulnerable groups, link local struggles with their global context, and explicitly incorporate rights frameworks into public health planning are needed. Models that move away from individualizing conflict over rights between health professionals as disempowered duty bearers and patients as frustrated rights holders, toward more mutual approaches to shared rights objectives may be possible and are being actively pursued through the development of a learning network to realize the right to health in South Africa. PMID- 20845831 TI - Health systems and the right to the highest attainable standard of health. AB - The right to the highest attainable standard of health should be the cornerstone of any consideration of health and human rights. The content of this fundamental human right is now sufficiently well understood to be applied in an operational, systematic, and sustained manner. At the heart of the right to the highest attainable standard of health lies an effective and integrated health system, encompassing medical care and the underlying determinants of health, which is responsive to national and local priorities and accessible to all. Yet in many countries, health systems are failing and collapsing, giving rise to an extremely grave human rights problem. This article outlines the general approach of the right to the highest attainable standard of health toward the strengthening of health systems. It identifies some of the key right-to-health features of a health system, such as transparency, participation, equity and equality, a comprehensive national health plan, a minimum "basket" of health-related services and facilities, disaggregated data, monitoring and accountability, and so on. This general approach has to be consistently and systematically applied across the "building blocks" that together constitute a functioning health system. By way of illustration, the article applies this approach to one of these "building blocks:" leadership, governance, and stewardship. There are numerous health movements and approaches, including health equity, primary health care, social determinants, and so on. All are very important. But it is misconceived to regard human rights as yet another approach with the same status as the others. Like ethics, the right to the highest attainable standard of health is not optional- and, like ethics, it recurs throughout all other approaches. The right to the highest attainable standard of health is the only perspective that is both underpinned by universally recognized moral values and reinforced by legal obligations. PMID- 20845832 TI - A human rights approach to quality of life and health: applications to public health programming. AB - Approaching health as a basic human right has a profound impact on the way we treat it politically. Viewing health as a public good--with both individual and collective dimensions--shapes the nature of health policies. The concept of a right to health can be used to formulate policies, organize systems and services, and develop actions that promote better health outcomes. Building on experiences in Latin America, this article discusses lessons learned for achieving policies and health systems that contribute to building democracy into a system that guarantees sodcial justice. Drawing on work in Latin American Social Medicine, it specifically proposes new ways of thinking about social fragility (instead of risks) and developing inter-sectoral programming to improve care, as well as to reduce inequalities among population groups. The article argues that a right based approach can be a concrete tool for restructuring both public policies and action. PMID- 20845833 TI - Notes on the rights of a poor woman in a poor country. PMID- 20845834 TI - "Nationals" and "expatriates": challenges of fulfilling "sans frontieres" ("without borders") ideals in international humanitarian action. AB - The international humanitarian organization, Medecins Sans Frontieres (MSF), is strongly committed to principles of universalism, egalitarianism, and equity, in both its internal and external relations. Nevertheless, the organization distinguishes between so-called "national" staff members (those who are indigenous to the countries where MSF projects are located), and "expatriate" staff (those who are involved in projects outside their countries of residence), in certain ways that it has self-critically termed "discriminatory", "colonialist", and even "racist". It has resolved to remedy such practices. Through a first-hand case study of MSF activities in Russia, this article demonstrates that the dynamics of the "nationals"/ "expatriates" divide is a more complex phenomenon than MSF's self-accusatory diagnosis implies; that a fuller recognition and utilization of nationals' local knowledge would mitigate some of the conditions of inequality and inequity that they experience; but that it would not necessarily be desirable to expunge all differences between the two groups of staff Furthermore, because they are intrinsic to the structure and conditions of international humanitarian action, some of these differences could not easily be elminated by MSF, or by any other organization engaged in this kind of action. PMID- 20845835 TI - From market competition to solidarity? Assessing the prospects of U.S. health care reform plans from a human rights perspective. AB - Although the crisis of health care in the United States is widely acknowledged- marked by poor health outcomes, high costs, unequal access, and widening health inequities--its structural underpinnings have not been adequately addressed and reformers have settled on promoting piecemeal measures to avoid disruption. The human right to health care offers an analytical and advocacy framework for shifting the health care reform debate from individualist, market-based approaches to the collective responsibility for health care as a public good based on an assessment of the health care reform proposals put foward during the U.S. 2008 presidential primaries, the article argues that the emerging consensus among Democrats and health care advocacy organizations on incremental, market based reforms ignores issues of equity, participation, and accountability. Alternately, the newly popularized concept of shared responsibility would reconnect rights to responsibilities and thus reinforce the public obligation to protect and provide health care. The article concludes by introducing the Human Right to Health Program, run by the National Economic and Social Rights Initiative (NESRI) and the National Health Law Program (NHeLP), which seeks to advance the recognition of health care as a human right in the US by supporting grassroots partners and allies in their struggle for universal and equitable health care. PMID- 20845836 TI - The catalytic synergy of health and human rights: the People's Health Movement and the right to health and health care campaign. AB - The Peoples Health Movement (PHM) is a global network at the intersection of many health and human rights organizations that has articulated and attempted to put into practice a human rights-based approach to improving health, organizing particularly in the area of economic, social, and cultural rights. PHM's approach to human rights and its Right to Health and Health Care Campaign (RTHHCC), the focus of this article, are responses influenced by several concerns: the failure to implement the primary health care strategy defined in the Alma Ata declaration, the discipline of social medicine, and the application of human rights methods to local health problems and to organiZational practice. Through PHM, a global network of activists is renewing the concept of citizenship and creating new forms of direct democratic social organization. PMID- 20845837 TI - The right of children in developing countries to be born and live HIV-free. PMID- 20845838 TI - Shades of dignity: exploring the demands of equality in applying human rights frameworks to health. AB - The foundational princple of human rights is that all human beings are equal in rights, dignity, and worth. Yet we live in a world ravaged by social inequalities both within and between countries, which have profound implications for the distribution of population health as well as the unequal enjoyment of economic and social rights and of human rights generally. It is far from clear that we have a consensus in the human rights community about which inequalities in health constitute inequities or how egalitarian a society must be to conform to the requirements of a social order in which all human rights can be realized. Further, the conversations in the world of human rights have largely been divorced from those in the worlds of development and public health. In this article, I attempt to bring those two conversations together. I first set out how concepts of formal and substantive equality and non-discrimination are defined under international law and might be applied in practice to questions we face in public health today. I argue that the application of these concepts is far from formulaic; interpretations of equality and non-discrimination necessarily reflect deeply held understandings about justice, power, and how we are the same and different from one another. I then explore how far a human rights framework can guide us in terms of some of these underlying questions in health and development polity, particularly in relation to how much priority should be given to the worst off in society, what kind of equality we should be seeking from a human rights perspective, and how we should evaluate who is worst off in terms of health. In conclusion, I argue that the great power of applying a human rights framework to health lies in denaturalizing the inequalities that pervade our societies and our world and in establishing that all people--by virtue of being human--have both a claim for redress when they are treated unfairly and a right to participate in determining what equity and equality require in a given context. PMID- 20845839 TI - Mental health and inequity: a human rights approach to inequality, discrimination, and mental disability. AB - Mental disability and mental health care have been neglected in the discourse around health, human rights, and equality. This is perplexing as mental disabilities are pervasive, affecting approximately 8% of the world population. Furthermore, the experience of persons with mental disability is one characterized by multiple interlinked levels of inequality and discrimination within society. Efforts directed toward achieving formal equality should not stand alone without similar efforts to achieve substantive equality for persons with mental disabilities. Structural factors such as poverty, inequality, homelessness, and discrimination contribute to risk for mental disability and impact negatively on the course and outcome of such disabilities. A human rights approach to mental disability means affirming the full personhood of those with mental disabilities by respecting their inherent dignity, their individual autonomy and independence, and their freedom to make their own choices. A rights based approach requires us to examine and transform the language, terminology, and models of mental disability that have previously prevailed especially within health discourse. Such an approach also requires us to examine the multiple ways in which inequality and discrimination characterize the lives of persons with mental disabilities and to formulate a response based on a human rights framework. In this article, I examine issues of terminology, models of understanding mental disability, and the implications of international treaties such as the United Nations Convention on the Rights of Persons with Disabilities for our response to the inequalities and discrimination that exist within society -both within and outside the health care system. Finally, while acknowledging that health care professionals have a role to play as advocates for equality, non discrimination, and justice, I argue that it is persons with mental disabilities themselves who have the right to exercise agency in their own lives and who, consequently, should be at the center of advocacy movements and the setting of the advocacy agenda. PMID- 20845840 TI - The right to health in the courts of Brazil: worsening health inequities? AB - This article analyzes the recent and growing phenomenon of right-to-health litigation in Brazil from the perspective of health equity. It argues that the prevailing model of litigation is likely worsening the country's already pronounced health inequities. The model is characterized by a prevalence of individualized claims demanding curative medical treatment (most often drugs) and by a high success rate for the litigant. Both elements are largely a consequence of the way Brazilian judges have interpreted the scope of the right to health recognized in Article 6 and Article 196 of the Brazilian constitution, that is, as an entitlement of individuals to the satiSfaction of all their health needs with the most advanced treatment available, irrespective of its costs. Given that resources are always scarce in relation to the health needs of the population as a whole, this interpretation can only be sustained at the expense of universality, that is, so long as only a part of the population is granted this unlimited right at any given time. The individuals and (less often) groups who manage to access the judiciary and realize this right are therefore privileged over the rest of the population. This is potentially detrimental to health equity because the criterion for privileging litigants over the rest of the population is not based on any conception of need or justice but purely on their ability to access the judiciary, something that only a minority of citizens possess. This paper examines studies that are beginning to confirm that a majority of right-to health litigants come from social groups that are already considerably advantaged in terms of all socioeconomic indicators, including health conditions. It is a plausible assumption that the model of right-to-health litigation currently prevalent in Brazil is likely worsening health inequities. PMID- 20845841 TI - Untangling equality and non-discrimination to promote the right to health care for all. AB - Equality and non-discrimination are core principles in international human rights law, and all members of the United Nations have legal obligations to promote these principles. Although widely adopted into law, interpretations of the rights to equality and non-discrimination, as well as their relationship to each other, vary considerably across jurisdictions. At the international level, there are separate provisions on equality and non-discrimination in the human rights treaties, yet legal scholars tend to treat the two concepts as one. This article examines the equality and non-discrimination provisions in the International Bill of Human Rights to consider their potential for addressing economic and social inequalities. The article proposes a legal framework that recognizes positive equality as distinct from status-based non-discrimination. Finally, it argues that both of these distinct rights have important roles in contributing to realizing social rights, in particular, a right to health care. PMID- 20845842 TI - Kenya's cash transfer program: protecting the health and human rights of orphans and vulnerable children. AB - In Kenya, as in other countries of sub-Saharan Africa heavily burdened by HIV/ AIDS, orphans and vulnerable children (OV/C) face poverty and despair. There is an urgent need to provide a comprehensive response that supports families and communities in their efforts to care for children and safeguard their rights. The government of Kenya has established a cash transfer program that delivers financial and social support directly to the poorest households containing OV/C, with special concern for those children with or affected by HIV/AIDS. The Kenyan effort builds on lessons drawn from research and program development on cash transfers in Latin America, Asia, and Africa, and the Kenyan program offers an opportunity to examine the challenges faced by Kenya, and its responses in the context of international experiences. This paper-based on observation of and interviews with key actors involved in the origins, development, evaluation, and continued strengthening of Kenyas cash transfer program and on the analysis of technical program documents obtained from those key actors--describes the Kenyan cash transfer program in light of human rights issues as they relate to childrens health. It offers one example of how caring for society's most vulnerable members is a collective responsibility to be shared by a country's government, local citizens, and the international community. PMID- 20845843 TI - Reproductive rights violations reported by Mexican women with HIV. AB - Demand for reproductive health services by people with HIV is increasing, as is the urgency of protecting and promoting their reproductive rights. The reproductive rights of Mexicans with HIV are formally protected by the constitution and by health and anti-discrimination legislation, as well as by international conventions. However, the reproductive rights of women with HIV continue to be violated in public clinics and hospitals. This paper discusses three violations identified as priority problems by Mexican women with HIV, illustrating these problems with cases identified during a participatory skills building workshop. The violations cover the following rights: the right to non discrimination, the right to adequate information and informed consent to medical procedures, and the right to choose the number and spacing of children. Physicians can either violate or promote reproductive rights. Unfortunately, in many instances Mexican physicians continue to perpetrate reproductive rights abuses against women with HIV. Collaborations between women with HIV, civil society, government, and international organizations are needed to educate and sanction health care providers and to support women with HIV in their pursuit of reproductive rights. Demanding accountability from health care practitioners and the State to guarantee reproductive rights in countries where these rights are formally protected will improve the quality of life of people with HIV and can demonstrate that rights-based approaches are compatible with and indeed, crucial for public health. PMID- 20845844 TI - HIV screening and care for immigration detainees. AB - The detention of immigrants in the United States is a rapidly expanding endeavor with serious health consequences for the detainees. This detainee population represents non-criminal immigrants who are detained because of a visa violation or other immigration issue but who are not charged with any crime and do not enter the criminal justice system. HIV-positive detainees are especially vulnerable to lapses in proper medical care, and press reports have highlighted deaths and adverse medical outcomes among HIV-positive detainees. We have examined reports on detainee health issues published by numerous groups and conducted our own analysis of the health plan used to govern much of the specialty care for detainees who are HIV positive. We conclude that the system of immigration detention in the US fails to adequately screen detainees for HIV and delivers a substandard level of medical care to those with HIV. We provide several specific recommendations for improving screening and medical care among this highly vulnerable population. PMID- 20845846 TI - The power of community in advancing the right to health: a conversation with Anand Grover. Interview by Alec Irwin. PMID- 20845845 TI - No shelter from the storm: reclaiming the right to housing and protecting the health of vulnerable communities in post-Katrina New Orleans. AB - This article explores human rights- and health-related aspects of the rebuilding process in New Orleans, Louisiana, USA, following the August 2005 assault of Hurricane Katrina. We look at the health and social impacts of post-Katrina redevelopment policies on New Orleans'poor Black communities. We describe systematic violations of poor Black residents' human right to housing, and we explore associations between these rights violations and documented negative trends in community health. The article describes some of the ways that poor constituencies in New Orleans have organized to resist the destruction of their communities and to reclaim their rights to adequate housing, health, and dignity. Post-Katrina violations of the right to housing in New Orleans should be seen as part of a broader pattern in social policy and the control of urban habitats in the United States. Poor Black residents' struggle to assert their human right to housing has implications for the health of local communities and the credibility of democratic processes. PMID- 20845847 TI - Suffering and powerlessness: the significance of promoting participation in rights-based approaches to health. AB - In a rights framework, participation is inextricably related to power. Through effective participation, we can challenge political and other forms of exclusion that prevent people from having power over the decisions and processes that affect their lives and health. Yet concepts of power are as contested as notions of participation. Thus, I argue here that, far from there being a formula for what participation means in a rights-based approach to health, the way in which we conceptualize the role of participation is closely linked to how we understand power and, in turn, the purpose and meaning of human rights themselves. I outline three ways of thinking about domination and participation-as-empowerment. In a liberal understanding of how power operates, there is an overarching concern for ensuring processes of participation that enable competing groups to express their voices on the proverbial level playing field, so that no one group may impose its will on the others. Critics of this approach assert that it ignores the power relations in which participatory processes are embedded, which determine which of the issues that affect health get decided--and which issues are never brought to the table because they are systematically blocked. If a second dimension of power entails deciding what gets decided, participatory approaches need to challenge the definition of what is "up for contention," or they risk merely legitimating social control. A third dimension of power entails securing compliance from oppressed groups by shaping their perceptions of their own interests. A human rights-based approach concerned with the effects of this form of domination on people's health calls for developing critical consciousness before there can be any truly "empowering" participation. I conclude by arguing that much is at stake in defining participation in a human rights framework to health, because in defining what we are calling for, we will determine how relevant human rights are to the daily struggles of people around the world for well-being. PMID- 20845848 TI - Health through people's empowerment: a rights-based approach to participation. AB - Analysis of the academic discourse on participation, empowerment, and the right to health since the 1978 Alma-Ata International Conference on Primary Health Care and the subsequent Alma-Ata Declaration shows that each phase of the evolution of these concepts added important new aspects to the discussion. This article focuses on three crucial issues that relate to these additions: the importance of social class when analyzing the essentials of community participation, the pivotal role of power highlighted in the discussion on empowerment, and the role of the state, which refers to the concepts of claim holders and duty bearers included in a rights-based approach to health. The authors compare these literature findings with their own experiences over the past 20 years in the Philippines, Palestine, and Cuba, and they offer some lessons learned. The concept of "health through people's empowerment" is proposed to identify and describe the core aspects of participation and empowerment from a human rights perspective and to put forward common strategies. If marginalized groups and classes organize, they can influence power relations and pressure the state into action. Such popular pressure through organized communities and people's organizations can play an essential role in ensuring adequate government policies to address health inequities and in asserting the tright to health. PMID- 20845849 TI - Social participation within a context of political violence: implications for the promotion and exercise of the right to health in Guatemala. AB - Social participation has been understood in many different ways, and there are even typologies classifying participation by the degree of a population's control in decision making. Participation can vary from a symbolic act, which does not involve decision making, to processes in which it constitutes the principal tool for redistributing power within a population. This article argues that analyzing social participation from a perspective of power relations requires knowledge of the historical, social, and economic processes that have characterized the social relations in a specific context. Applying such an analysis to Guatemala reveals asymmetrical power relations characterized by a long history of repression and political violence. The armed conflict during the second half of the 20th century had devastating consequences for a large portion of the population as well as the country's social leadership. The ongoing violence resulted in negative psychosocial effects among the population, including mistrust toward institutions and low levels of social and political participation. Although Guatemala made progress in creating spaces for social participation in public policy after signing the Peace Accords in 1996, the country still faces after-effects of the conflict. One important task for the organizations that work in the field of health and the right to health is to help regenerate the social fabric and to rebuild trust between the state and its citizens. Such regeneration involves helping the population gain the skills, knowledge, and information needed in order to participate in and affect formal political processes that are decided and promoted by various public entities, such as the legislative and executive branches, municipal governments, and political parties. This process also applies to other groups that build citizenship through participation, such as neighborhood organizations and school and health committees. PMID- 20845850 TI - Participation and the right to health: lessons from Indonesia. AB - The right to participation is the "the right of rights"--the basic right of people to have a say in how decisions that affect their lives are made. All legally binding international human rights treaties explicitly recognize the essential role of participation in realizing fundamental human rights. While the substance of the human right to health has been extensively developed, the right to participation as one of its components has remained largely unexplored. Should rights-based health advocacy focus on participation because there is a relationship between an individual's or a community's active involvement in health care decision-making and the highest attainable standard of health? In the context of the human right to health, does participation mean primarily political participation, or should we take the right to participation to mean more specifically the right of persons, individually and as a group, to shape health care policy for society and for themselves as patients? Decentralization of health care decision-making promises greater participation through citizen involvement in setting priorities, monitoring service provision, and finding new and creative ways to finance public health programs. Between 1999 and 2008, Indonesia decentralized health care funding and delivery to regional governments, resulting in substantial exclusion of its poor and uneducated citizens from the health care system while simultaneously expanding the opportunities for political participation for educated elites. This article explores the tension between the right to participation as an underlying determinant of health and as a political right by reviewing the experience of Indonesia ten years after its decision to decentralize health care provision. It is ultimately argued that rights-based advocates must be vigilant in retaining a unified perspective on human rights, resisting the persistent tendency to separate and prioritize the civil and political aspects of participation over its social component. PMID- 20845851 TI - A card before you leave: participation and mental health in Northern Ireland. AB - Due to a recent and dramatic rise in suicide and self-harm rates, mental health services have received a high level of attention in the politics of Northern Ireland, resulting in the implementation of numerous policies and the publication of many public reviews on the subject. Critically, these policies have also emphasized and required the participation of mental health service users in decision making about service design, implementation, and monitoring. This paper analyzes the experience of a group of mental health service users in north and west Belfast, the Public Initiative for the Prevention of Suicide-Greater Shankill Bereaved Families Rights Group supported by the Particpation and the Practice of Rights Project, as they campaigned for policy change using a human rights-based approach. It considers, first, the group's use of a participatory, "bottom-up" approach to set human rights indicators and benchmarks defined by group members themselves as an example of meaningful participation from an affected group. The paper then looks specifically at one of the group's issues- follow-up care--and reveals how the group was able to bring about policy change on this issue across Northern Ireland. Finally, it discusses how the group's experience in this campaign has revealed problems with the way that the government currently engages with mental health service users in Northern Ireland. The article closes by identifying key next steps to be taken as the focus of the campaign shifts to ensuring that active, free, and meaningful participation takes place in accordance with international human rights standards. PMID- 20845852 TI - Witnesses to hunger: participation through photovoice to ensure the right to food. AB - Currently 30.2% of female-headed households with children in the United States experience food insecurity, defined as the lack of access to enough food for an active and healthy life. In 2007, approximately 12.4 million children were at risk for hunger. When female-headed households and households with children have the highest prevalence of food insecurity and hunger in the US, the participation of low-income mothers in the development and administration of policies and programs related to nutrition and poverty are fundamental to the process of ending hunger and improving child well-being. In this article, we describe the Witnesses to Hunger program, a participatory advocacy project that uses the "photovoice" technique to engage mothers to take photos and record their stories about poverty and hunger with the intent to inform social welfare policy in the US. Witnesses to Hunger is grounded in the human rights framework that is supported by international conventions on the rights of women, the rights of the child, and economic, social, and cultural rights. The Witnesses to Hunger program works to increase civic participation of low-income women and to maintain a strategic public awareness campaign. After introducing the Witnesses to Hunger program, this article describes the past decade of unchanging food insecurity disparities, demonstrates the lack of participatory dialogue in health and welfare programs, and provides examples of how Witnesses to Hunger counters the conventional dialogue about welfare. Throughout, this paper demonstrates how the participatory approach of the Witnesses to Hunger program improves our understanding of basic human needs and the social determinants of health, and informs legislators on how to improve health and welfare policy. PMID- 20845853 TI - Unexpected agency: participation as a bargaining chip for the poor. AB - Populations in the developing world that are targeted for disease eradication programs are commonly seen as passive recipients of international aid. Poor people can, however, "participate" in these interventions in unexpected ways. In the absence of traditional sources of leverage, some marginalized people have used their one remaining form of influence--their noncompliance in public health initiatives--to articulate a higher priority need and to assert their basic human rights to food and primary health care. Vertical international health initiatives whose goals are to eradicate and control diseases may be forced to contend with this phenomenon. The success of these interventions will hinge upon ensuring that the basic human rights of the target populations are addressed. PMID- 20845854 TI - HIV/AIDS in Cuba: a rights-based analysis. AB - The common assertion that Cuba's achievements in HIV/AIDS control have come at a cost in human rights is reinforced by US hostility toward its small neighbor. Nevertheless, a rights-based analysis may be one useful way of examining the actual Cuban experience. By reference to the United Nation's Guidelines on HIV/AIDS and Human Rights, this paper examines the Cuban experience as it relates to the themes of quarantine and personal freedom; privacy in testing and tracing; education, participation, and non-discrimination; and the availability of AIDS treatment. The paper concludes that Cuba's quarantine period was unnecessarily prolonged in the late 1980s but that this prolonged quarantine did not target men who have sex with men. Testing and tracing procedures in Cuba follow a standard protocol, but they are more thorough than elsewhere. Cuba has strengthened participation in education programs, and treatment is now the best in the Caribbean region. The human rights implications of HIV programs must be considered in an integrated way. Selective criticisms of the Cuban program have not improved international understanding of HIV/AIDS treatment in Cuba. PMID- 20845855 TI - Global goes local: integrating human rights principles into a county health care reform project. AB - In the United States, city and county governments are often responsible for implementing health policies and programs on behalf of state and federal governments. However, local jurisdictions have generally not capitalized on their own expertise or on local knowledge to advocate rights-based health care reform. Working with local public health officials to develop a rights-based health care reform advocacy plan is a way to integrate human rights principles into local government policy and practice at the grassroots level. The concrete policy objectives found in human rights princples can also be the basis of local government advocacy efforts toward state and federal government for reform that addresses local and regional health needs. This article presents a first-person, "hands-on" account of efforts to operationalize a human rights framework in public health advocacy and action in a local setting, King County, a jurisdiction of Washington, USA, that includes the city of Seattle. PMID- 20845856 TI - Beyond compassion: the central role of accountability in applying a human rights framework to health. AB - Accountability is a central feature of any rights-based approach to health because it converts passive beneficiaries into claims-holders and identifies states and other actors as duty-bearers that can be held responsible for their discharge of legal, and not merely moral, obligations. This article reviews what we mean by accountability, how courts and other mechanisms are being engaged to promote accountability, and what we should understand as the central obligations of states and other actors if we are concerned with obligations of progressive realization relating to health and development goals. The first part of the article sets out a number of mutually-reinforcing dimensions of accountability, examines different duty-bearers, and discusses mechanisms for enforcement, with a focus on courts. The second part of the article explores how we might define the obligations of progressive realization for which we seek accountability. I argue that there are three aspects of accountability with which a human rights approach to health as a social policy and development issue should be concerned: (1) what the state is doing; (2) how much effort the state is expending; and (3) how the state is going about the process. Although the focus is on national obligations, I argue that donor states and other actors have parallel obligations. PMID- 20845857 TI - Litigation as a strategy to hold governments accountable for implementing the right to health. AB - This article offers a framework for exploring litigation as a strategy to advance the right to health by holding governments accountable to human rights norms. Since the 1990s, cases in which people go to court to claim their right to health have increased dramatically in resource-poor countries. With issues ranging from access to health services and medication, to discriminatory labor practices, to public health, to the basic determinants of health (such as food, water, shelter, and a healthy environment), these cases potentially have huge financial and social implications. Little is known, however, about the success of such attempts to hold governments accountable for their obligations with respect to the right to health--or about who benefits. Is litigation primarily used by marginalized persons to gain fair access to medical services, or is it more often a means by which those patients with more financial resources or creativity in seeking assistance pursue access to treatment that is not otherwise provided due to expense? To what extent does litigation affect health policy and service delivery? What little is known about these cases is fragmented and anecdotal The theoretical framework outlined here facilitates the systematic comparative and interdisciplinary studies needed to advance knowledge in this field, taking account of the entire litigation and implementation process. PMID- 20845858 TI - "Rights" and wrongs: what utility for the right to health in reforming trade rules on medicines? AB - This paper explores the legal and normativepotential of the right to health to mitigate the restrictive impact of trade-related intellectual property rules on access to medicines, as evidenced by the global outcomes of the seminal pharmaceutical company litigation in South Africa in 2001. I argue that the litigation and resulting public furor provoked a paradigm shift in global approaches to AIDS treatment in sub-Saharan Africa. I argue further that this outcome illustrates how human rights in concert with social action were able to effectively challenge dominant claims about the necessity of stringent trade related intellectual property rights in poor countries, and ergo, to raise the priority of public health needs in related decision-making. I explore the causal role of rights in achieving these outcomes through the analytical lens provided by international legal compliance theories, and in particular, the model of normative emergence proposed by Martha Finnemore and Kathryn Sikkink. I suggest that the AIDS medicines experience offers strategic guidance for realizing the right to health's transformative potential with regard to essential medicines more generally. PMID- 20845859 TI - Judicial activism in the Argentine health system: recent trends. AB - This article explores judicial activism in Argentina as it relates to health, as evidenced by courts' willingness to address health issues and to monitor public policies. It examines the strategic use of the courts to channel claims against the government or companies providing health care services both by organizations devoted to litigation in the public interest and by individuals. In addition, the article looks closely at conflicts that have been adjudicated in the courts and various court responses. Special focus is given to the possible effects of certain court decisions on the Argentine health system following its reform during the 1990s, which included transfer and decentralization of functions and services. PMID- 20845860 TI - Woch nan Soley: the denial of the right to water in Haiti. AB - This article combines health and water research results, evidence from confidential documents released under the Freedom of Information Act, legal analysis, and discussion of historical context to demonstrate that actions taken by the international community through the Inter-American Development Bank are directly related to a lack of access to clean water in Haiti. The article demonstrates that these actions constitute a clear violation of Haitians' right to water under both domestic and international law. The article exposes the United States governments role in blocking the disbursal of millions of dollars in international bank loans that would have had life-saving consequences for the Haitian people. The loans were derailed in 2001 by politically-motivated interventions on behalf of the US and other members of the international community in direct violation of the Inter-American Development Bank charter. To demonstrate the impact of these interventions, the article presents data gathered in a study that employed human rights and public health methodologies to assess the right to water in Haiti. The data reveal that Haitians experience obstacles concerning every aspect of the right to water: diffculties with water availability, limited physical and economic accessibility, and poor water quality. The article provides a framework of concrete duties and obligations that should be followed by all actors involved in Haiti in order to realize Haitians' human right to water. In response to the undeniable link between the international community's political interference and the intolerably poor state of potable water in Haiti, the article concludes with a recommendation that all actors in Haiti follow a rights-based approach to the development and implementation of water projects in Haiti. The full report of Woch nan Soley: The Denial of the Right to Water in Haiti is available online at http://www.pih.org/inforesources/Reports/Hait_Report_FINAL.pdf. PMID- 20845861 TI - Women's reproductive rights in the Amazon basin of Ecuador: challenges for transforming policy into practice. AB - Despite advances made by Ecuador in developing policies on reproductive and sexual rights, implementation, and oversight remain a challenge, affecting in particular those living in the Amazon basin. This paper reports on an evaluation of sexual and reproductive health and rights (SRHR) in Orellana, Ecuador, the basis of which was the Health Rights of Women Assessment Instrument, which was altered to focus on government obligations, the reality of access and utilization of services, and the inequities and implementation challenges between the two. A community-based cross-sectional survey conducted in 2006 served to document the current status of SRHR Local female field workers interviewed 2025 women on three areas of womens reproductive health: delivery care, family planning, and pregnancy among adolescent girls age 10-19. The results suggest a reality more dismal than that of the official information for the area. Skilled delivery care, modern contraceptive use, and wanted pregnancies were conspicuously lower among indigenous women living in rural areas. Access to reproductive health services varied between rural and urban women. These significant differences in care- amongst others documented--raise concerns over the utility of national-level data for addressing inequities. The gaps evident in the validity of available information for monitoring policies and programs, and between national policy and action reveal that much still needs to be done to realize SRHR for women in the Amazon basin, and that current accountability mechanisms are inadequate. PMID- 20845862 TI - Relative response: ranking country responses to HIV and AIDS. AB - The aim of this article is to support efforts to hold governments accountable for their commitments to respond to HIV and AIDS. It describes a new approach to ranking countries' responses in order to facilitate cross-country comparisons. The method uses the United Nations General/Assembly Speecial Session on HIV/AIDS (UNGASS) Declaration of Commitment as its point of departure and was designed to rank countries in terms of their efforts to fight HIV and AIDS. Three indicators of the country response were analyzed. (1) prevention of mother-to-child transmission (PMTCT) coverage; (2) antiretroviral (ARV) coverage; and (3) the ratio of orphans to non-orphans attending school An assessment of this nature must acknowledge the unique situation of each country, depending on its infrastructure and access to resources. To account for these differences, a regression analysis with contextual control variables was carried out to identify the variation resulting from controllable factors. It is this variation which is used to examine countries' relative response to HIV as it considers what was actually achieved relative to what was expected given the context. The results highlight the efforts of not only some well-reputed, strong actors but also some unexpected front-runners. The results also point to a group of countries which are lagging behind in all regards. Comparisons between the three indicators show great variations in the focus of countries' efforts. Rating countries' relative response to HIV highlghts countries that do well in spite of diffcult circumstances. The article argues that these "relative overachievers" should be examined more closely so that lessons may be learnt from their efforts. The rating also draws attention to countries where the response is comparatively weak, and where governments, as lead actors in the AIDS partnership, bear the greatest responsibility. PMID- 20845863 TI - Limitations on human rights: are they justifiable to reduce the burden of TB in the era of MDR- and XDR-TB? AB - Tuberculosis, in all its forms, poses a serious, demonstrable threat to the health of countless individuals as well as to health as a public good. MDR-TB and, in particular, the emergence of XDR-TB, have re-opened the debate on the importance, and nature, of treatment supervision for basic TB control and the management of drug-resistant TB. Enforcing compulsory measures regarding TB patients raises questions of respect for human rights. Yet, international law provides for rights-limiting principles, which would justify enforcing compulsory measures against TB patients who refuse to have diagnostic procedures or who refuse to be monitored and treated once disease is confirmed. This article analyzes under what circumstances compulsory measures for TB patients may be enforced under international law. Compulsory measures for TB patients may, in fact, be justified on legal grounds provided that these measures are foreseen in the law, that they are used as a last resort, and that safeguards are in place to protect affected individuals. The deadly nature of the disease, its epidemiology, the high case fatality rate, and the speed at which the disease leads to death when associated with HIV are proven. PMID- 20845864 TI - Sex and the global fund: how sex workers, lesbians, gays, bisexuals, transgender people, and men who have sex with men are benefiting from the Global Fund, or not. AB - The Global Fund to Fight AIDS, Tuberculosis and Malaria has allowed countries to bring their response to HIV/AIDS to an unprecedented scale, resulting in innovative projects that reach otherwise underserved communities with HIV prevention, treatment, and care. But in regions and countries where sex workers, men who have sex with men, or lesbian, gay, bisexual, and transgender persons are criminalized or stigmatized, organizations that are led by or work with these groups face challenges participating in Global Fund processes and accessing funding. This article explores the potential of the Global Fund to create space for the participation of these groups in decision-making and to increase their access to resources; examines barriers that hinder their participation; and proposes measures to overcome them. PMID- 20845865 TI - [Working principle and accuracy of infrared thermometers]. PMID- 20845866 TI - [Control mechanisms and the variation of normal human body temperature]. PMID- 20845867 TI - [Assessment of falsehood fever and effective intervention]. PMID- 20845868 TI - [Fever patterns and differential diagnosis]. PMID- 20845869 TI - [Importance of meticulous history-taking]. PMID- 20845870 TI - [Diagnostic approach for the patient with respiratory infection]. PMID- 20845871 TI - [Diagnosis of gastroenterological diseases with fever]. PMID- 20845872 TI - [Differential diagnosis for high fever of unknown origin; tuberculosis and non tuberculosis mycobacterial infections]. PMID- 20845873 TI - [Fever associated with pets, wild and domestic animals]. PMID- 20845874 TI - [Post-travel care--fever in a returned traveler]. PMID- 20845875 TI - [Gynecological disorder--pelvic inflammatory disease: PID]. PMID- 20845876 TI - [Differential diagnosis in nephro-urological infectious diseases]. PMID- 20845877 TI - [Sepsis and severe sepsis]. PMID- 20845878 TI - [Oral diseases and fever]. PMID- 20845879 TI - [Fever in collagen vascular disease]. PMID- 20845880 TI - [Fever in patients with cancer]. PMID- 20845881 TI - [Fever induced by various drugs]. PMID- 20845882 TI - [Endocrine disorders (adrenal crisis and thyrotoxic crisis)]. PMID- 20845883 TI - [High body temperature in childhood]. PMID- 20845884 TI - [Difference points of fever genesis with postoperative period in digestive surgery]. PMID- 20845885 TI - Is early antithrombotic therapy necessary after tissue mitral valve replacement? AB - BACKGROUND AND AIM OF THE STUDY: Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy during the early postoperative period after biologic mitral valve replacement (MVR) is controversial. Hence, a retrospective study was conducted to investigate the efficacy of different antithrombotic therapies in patients after MVR with bioprostheses. METHODS: Between January 2000 and January 2006, a total of 99 patients presenting with preoperative sinus rhythm underwent isolated bioprosthetic MVR. Of these patients, 59 (58%) received a bovine pericardial xenograft, and 40 (42%) a porcine bioprosthesis. The postoperative antithrombotic therapy was prescribed according to the surgeon's preference. RESULTS: Fifty-one (51%) patients received acetylsalicylic acid (ASA group, 100 mg/day), 12 (13%) did not receive any specific antithrombotic therapy (NT group), and 36 (36%) received a vitamin K antagonist (VKA group, INR 2-3). The primary endpoints were the rate of cerebral ischemic events, bleeding events, and survival. The mean follow up was 23 months (range: 3-68 months). There were five early deaths (5%), and eight late deaths (8%). There were five episodes of cerebral ischemic events; these included three patients (8.3%) in the VKA group, one patient (2.0%) in ASA group, and one patient (8.3%) in the NT group (p = 0.351). Of these episodes, two occurred between 24 h and three months after surgery. Only one (2.8%) episode of major bleeding occurred (in the VKA group), due to poor anticoagulation management. CONCLUSION: Each of the antithrombotic therapies evaluated appeared to be safe. There was no evidence to suggest that any specific antithrombotic therapy would be superior in preventing valve thrombosis in patients undergoing bioprosthetic MVR. PMID- 20845886 TI - Tricuspid regurgitation in patients with severe mitral regurgitation and normal left ventricular ejection fraction: risk factors and prognostic implications in a cohort of 895 patients. AB - BACKGROUND AND AIM OF THE STUDY: Although tricuspid regurgitation (TR) is common in patients with mitral regurgitation (MR), its frequency, determinants and prognostic implications in those with severe MR and a normal left ventricular ejection fraction (LVEF) are not fully known. The study aim was to evaluate the risk factors for, and prognostic implications of, TR in patients with severe MR and a normal LVEF. METHODS: In this retrospective cohort study, the authors' echocardiographic database for the period between 1993 and 2003 was screened for patients with severe MR and LVEF > or = 55%. Chart reviews were performed for clinical, pharmacological and surgical details, while survival was analyzed as a function of TR severity. RESULTS: Among 895 patients with severe MR and normal LVEF, 510 (57%) had grade > or = 2+ TR, while 219 (24%) had grade 3 or 4+ TR. Those patients with grade > or = 2+ TR were older (p < 0.0001), more likely to be female (p < 0.0001), and had a higher right ventricular systolic pressure (RVSP) (p < 0.0001). After adjusting for group differences (except for atrial fibrillation), grade > or = 2+ TR was associated with a higher mortality (relative risk 1.4, 95% confidence interval 1.1-1.8, p = 0.02). Mitral valve surgery was associated with a better survival in those with grade > or = 2+TR (p = 0.0003). CONCLUSION: Significant TR is a frequent occurrence in patients with severe MR and a normal LVEF, and is associated with older age, female gender, and a higher RVSP. TR is independently associated with a higher mortality, while mitral valve surgery seems to offer a survival benefit. PMID- 20845887 TI - Determinants of evolution and progression of acute ovine ischemic mitral regurgitation. AB - BACKGROUND AND AIM OF THE STUDY: The optimal treatment of moderate ischemic mitral regurgitation (IMR) remains contested. Thus, radiopaque markers were implanted on valvular structures to investigate the geometric and hemodynamic variables associated with the evolution and progression of acute ovine IMR. METHODS: Eight adult sheep underwent implantation of five radiopaque markers on the edge of the posterior mitral leaflet (PML), and five on the edge of the anterior mitral leaflet (AML). Eight additional markers were sewn around the mitral annulus (MA). The animals were studied immediately after surgery, using biplane videofluoroscopy and transesophageal echocardiography. Data were acquired at Baseline and at two time points (IMR1 and IMR2) during acute snare occlusion of the proximal left circumflex coronary artery and progressive IMR. The orthogonal distance of each leaflet edge marker to the least-squares annular plane, mitral annular area (MAA), and septal-lateral diameter (SL) were calculated at end-systole. The leaflet tenting area (TA) was calculated at valve center (CENT) and near the anterior (ACOM) and posterior (PCOM) commissures. RESULTS: The degree of MR was 0.6 +/- 0.4, 1.8 +/- 0.7, and 2.8 +/- 0.7 for Baseline, IMR1, and IMR2, respectively (p < 0.005). IMR1 was associated with annular dilatation and leaflet restriction near the valve center, and prolapse near the PCOM versus Baseline. Although both left ventricular pressure (LVP) and left ventricular dP/dt decreased significantly from IMR1 to IMR 2, there were no differences in leaflet or annular geometry. CONCLUSION: The initiation of moderate IMR was associated with significant alterations in annular and leaflet geometry, but only a small decrease in LV systolic function, was needed for IMR progression. These data suggest that the surgical repair and optimization of LV function may be important in combination to treat moderate IMR, as only small hemodynamic deterioration and perturbations in valvular geometry are necessary for significant IMR progression. PMID- 20845888 TI - Echocardiographic assessment of the effects of mitral valve repair on mitral valve geometry in rheumatic mitral stenosis. AB - BACKGROUND AND AIM OF THE STUDY: While mitral valve replacement is generally considered as the standard surgical treatment for rheumatic mitral stenosis (MS), mitral valve repair may be an alternative therapeutic option. Several techniques have been used to overcome the anatomic difficulties involved in the repair of a rheumatic mitral valve. In the present study, quantitative echocardiography was used to investigate the effects of mitral valve repair and the influence of surgical procedures on mitral valve geometry in patients with rheumatic MS. METHODS: Mitral valve repair was successfully performed in seven patients with MS, by the same surgeon. Ring annuloplasty and slicing of the anterior mitral leaflet (AML) were performed in all patients. Concomitant surgical techniques included commissurotomy, decalcification, chordal resection, and division of the papillary muscles. The preoperative and postoperative echocardiographic findings in these patients were compared. RESULTS: The thickness of both the AML and posterior mitral leaflet (PML) (p = 0.01 for both), the opening angles of the AML (p = 0.02) and PML (p = 0.01), and the closing angle of the PML, the extent of calcification in the AML, and the pressure half-time (PHT) (p = 0.03 for all three parameters) were all significantly improved after mitral valve repair. CONCLUSION: In the present study, the transmitral peak velocity and mean pressure gradient were not significantly changed after mitral valve repair, whereas the PHT showed a marked improvement. Hence, the PHT may represent a suitable marker for evaluating the efficacy of mitral valve repair for MS. PMID- 20845889 TI - Acute mitral valve endocarditis complicated by right atrial fistula in beta thalassemia major. AB - Infection is considered to be among the major complications encountered in beta thalassemia major, with an incidence that may reach 13%. The majority of cases are caused by repeated blood transfusion potentiated by the associated immune defects among these patients. The present case represents a severe form of infection affecting the mitral valve, causing acute heart failure and a fistulous communication between the left ventricle and right atrium. PMID- 20845890 TI - How can we logically describe the components of the arterial valves? PMID- 20845892 TI - Paraoxonase activity might be predictive of the severity of aortic valve stenosis. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve stenosis (AS) is the most common valvular heart disease in the western world, and in adults is invariably caused by the calcification of a normal tricuspid or congenital bicuspid valve. Calcific AS, as an active disease process, is characterized by lipid accumulation, inflammation and calcification that mimic atherosclerosis. Paraoxonase-1 (PON-1) is a high-density lipoprotein (HDL)-bound enzyme that exerts antiatherogenic properties by protecting low-density lipoprotein (LDL)-cholesterol from oxidative modification. The study aim was to examine the association between PON-1 activity and AS. METHODS: A total of 93 patients with angiographically normal coronary arteries was enrolled into the study. Transthoracic echocardiography was used to diagnose and grade the AS before the patients underwent selective coronary angiography. The patients were allocated to three groups of mild AS (n = 34), moderate AS (n = 31) and severe AS (n = 28). Paraoxonase activity was measured using a spectrophotometric technique. RESULTS: The mean PON-1 activity in patients with severe AS (64.4 +/- 29.8 U/l) was significantly lower than that in patients with mild and moderate AS (97.1 +/- 72.6 and 146.8 +/- 133.9 U/l; p = 0.03 and p = 0.002, respectively). Typically, PON-1 activity tended to be lower in moderate AS than in mild AS (p = 0.07). The serum PON-1 activity correlated positively with the aortic valve area, but negatively with the aortic mean and maximum gradients. CONCLUSION: The study results showed that PON-1 activity is lower in patients with calcific AS. In addition, PON-1 activity was inversely correlated with the severity of AS. PMID- 20845891 TI - Insights into the use of biomarkers in calcific aortic valve disease. AB - Calcific aortic valve disease (CAVD) is the most common acquired valvular disorder in developed countries. CAVD ranges from mild thickening of the valve, known as aortic valve sclerosis (AVSc), to severe impairment of the valve motion, which is termed aortic valve stenosis (AVS). The prevalence of CAVD is nearing epidemic status: its preceding stage, in which there is aortic sclerosis without obstruction of the left ventricular outflow, is present in almost 30% of adults aged over 65 years. As there is no existing medical therapy to treat or slow the progression of CAVD, surgery for advanced disease represents the only available treatment. Aortic valve replacement is the second most frequently performed cardiac surgical procedure after coronary artery bypass grafting, and consequently CAVD represents a major societal and economic burden. The pathophysiological development of CAVD is incompletely defined. At the present time, the major methods for its diagnosis are clinical examination, echocardiography, and cardiac catheterization. Yet, due to the multiple biological pathways leading to CAVD, there are many potential biomarkers that might be suitable for deriving clinically useful information regarding the presence, severity, progression, and prognosis of CAVD. Although at the present time the available data do not permit recommendations for clinicians, they do support a paradigm of screening patients based on multiple biomarkers to provide the information necessary to optimize future therapeutic interventions. This review summarizes the results of several studies investigating the value of potential biomarkers that have been used to predict the severity, progression, and prognosis of CAVD. PMID- 20845893 TI - Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. AB - BACKGROUND AND AIM OF THE STUDY: Bicuspid aortic valve (BAV), the most common form of congenital heart disease, is a leading cause of aortic stenosis (AS) and aortic insufficiency (AI). AS is typically caused by calcific valve disease. Recently, microRNAs (miRNAs) have been shown to modulate gene expression. The study aim was to examine the miRNAs that were altered in the aortic valve leaflets of patients with AS compared to those in patients with AI. In-vitro experiments were also carried out to determine if these miRNAs could modulate calcification-related genes. METHODS: Aortic valve samples (fused and unfused leaflets) were collected from nine male patients (mean age 44.9 +/- 13.8 years) undergoing aortic valve replacement (AVR). PIQOR miRXplore Microarrays containing 1,421 miRNAs were used and hybridized to fused leaflet samples labeled with Cy5; unfused samples were used as controls and labeled with Cy3. A quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to validate the miRNA array results. Cultured human aortic valve interstitial cells (AVICs) were treated with miRNA mimics, and qRT-PCR was carried out to determine any changes in mRNAs. RESULTS: By microarray analysis, seven miRNAs were shown to be statistically different between the AS and AI patients. In the stenotic samples, the MiR-26a and miR-195 levels were shown (by qRT-PCR) to be reduced by 65% and 59%, respectively (p < 0.05), and MiR-30b to be reduced by 62% (p < 0.06). Human AVICs treated with miR-26a or miR-30b mimics showed decreased mRNA levels of calcification-related genes. MiR-26a repressed BMP2 by 36%, alkaline phosphatase (ALPL) by 38%, and SMAD1 by 26%, while MiR-30b reduced the expression of SMAD1 by 18% and of SMAD3 by 12%. In contrast, miR-195-treated AVICs had increased mRNA levels of calcification-related genes, such as BMP2 by 68% and RUNX2 by 11%. CONCLUSION: MiR-26a, miR-30b, and miR-195 were each decreased in the aortic valves of patients requiring AVR due to AS, compared to those requiring replacement due to AI. These miRNAs appear to modulate calcification related genes in vitro. PMID- 20845894 TI - Relationship between aortic valve calcification and the severity of coronary atherosclerotic disease. AB - BACKGROUND AND AIM OF THE STUDY: Aortic valve calcification (AVC), which has been confirmed to be associated with various risk factors of cardiac disease, is common in the elderly and associated with increased cardiovascular mortality. It has been hypothesized that AVC is associated with coronary atherosclerotic disease, and its severity. METHODS: Between July 2007 and November 2007, a total of 235 patients with chest pain or chest distress were admitted to the authors' institution for coronary angiography. The severity of coronary atherosclerotic disease (CAD) was evaluated by the Gensini score, the number of stenosed vessels, and the prevalence of total occlusion. All patients underwent transthoracic echocardiography to detect AVC. RESULTS: Patients with CAD had a higher prevalence of AVC than those without CAD (44% versus 26%, p = 0.005). Likewise, the prevalence of AVC was significantly higher in patients with a higher Gensini score than in those with a lower score. Patients with AVC had a higher prevalence of CAD, and higher Gensini scores and numbers of stenosed coronary arteries, even after stratification by age (65 years). On multivariable logistic regression analysis for CAD, the odds ratio (OR) of AVC was 2.315 (95% confidence interval (CI): 1.158-4.629, p = 0.018); this value was higher than that for total cholesterol (OR = 1.637, p = 0.008), lipoprotein-a (OR = 1.003, p = 0.015) and fibrinogen (OR = 1.009, p = 0.006), and marginally less than that for male gender (OR = 2.665, p = 0.005). CONCLUSION: Patients with AVC had a higher prevalence and greater severity of CAD. PMID- 20845895 TI - Long-term follow up of patients undergoing reoperative surgery with aortic or mitral valve replacement, using a St. Jude Medical prosthesis. PMID- 20845896 TI - Long-term follow up of patients undergoing reoperative surgery with aortic or mitral valve replacement using a St. Jude Medical prosthesis. AB - BACKGROUND AND AIM OF THE STUDY: Between June 1978 and September 2002, a total of 440 reoperative open-heart patients (mean age 62 +/- 14 years; range: 18-91 years), following various primary cardiac operations, underwent single-valve replacement with the St. Jude Medical (SJM) heart valve. Of 241 patients having aortic replacement (AVR) and 199 mitral valve replacement (MVR), 86 (35%) and 42 (21%), respectively, underwent concomitant coronary artery bypass grafting. The study aim was to document patient survival and valve-related events in an experience extending up to 24 years after reoperative open-heart surgery with a single model cardiac valve prosthesis. METHODS: The Cardiac Surgical Associates Research Foundation (CSARF) has maintained an independent database of those patients with the SJM prosthesis since the world's first implant in October 1977. Patients were contacted by questionnaire and/or telephone between November 2002 and June 2003. The hospital course and valve-related events were verified by patient chart review and/or physician contact. RESULTS: Follow up was 94% complete, for a total of 3,114 patient-years (1,671 pt-yr after AVR; 1,443 pt-yr after MVR). The average follow up was 7 +/- 6 years (range: 0.1-24.3 years). The operative mortality was 9% (10% AVR, 8% MVR). Five deaths (13%) were valve related. Freedom from all late mortality at 10 and 20 years, respectively, was 57% and 35% for AVR and 52% and 22% for MVR, and for valve-related mortality was 89% and 77% for AVR and 84% and 22% for MVR. Freedom from thromboembolic events at 10 and 20 years, respectively, was 93% and 93% after AVR and 92% and 81% after MVR; from anticoagulant-related hemorrhage it was 78% and 76% after AVR and 81% and 67% after MVR; and from reoperation it was 94% and 94% after AVR and 95% and 89% after MVR. CONCLUSION: Reoperative valve replacement carries a significant operative morbidity and mortality. Long-term results with the SJM valve demonstrated a durable prosthetic valve, excellent long-term patient survival, and freedom from valve-related events followed reoperative open-heart valve replacement surgery. However, the early postoperative period carried an increased risk for valve-related events. PMID- 20845897 TI - The changing hydrodynamic performance of the decellularized intact porcine aortic root: considerations on in-vitro testing. AB - BACKGROUND AND AIM OF THE STUDY: The most effective method for decellularization of the intact porcine aortic root remains controversial. Additionally, the hydrodynamic effect that such treatment may have on aortic roots has never been previously investigated. The study aim was to compare the in-vitro hydrodynamic performances of intact porcine aortic roots, both before and after decellularization treatment. METHODS: Fifteen fresh porcine aortic roots were tested in the aortic chamber of the Sheffield pulse duplicator (SPD). For study purposes, the roots were first sutured to a silicone aortic root and then hydrodynamically tested. After in-vitro testing, the fresh porcine aortic roots, while still fixed within the silicone root, were decellularized according to various protocols (TRI-COL, TRI-DOC, sodium dodecyl sulfate (SDS) 0.03%, and SDS 0.1%). After decellularization, the valve roots were re-tested, adopting identical testing conditions. Forward flow pressure drop, closing leakage volumes, effective orifice area (EOA), and stroke work loss were each monitored. Three roots, used as a control group, were tested in identical fashion before and after storage (without decellularization) for comparative purposes. RESULTS: The TRI-COL- and TRI-DOC-treated porcine aortic roots showed significantly lower transvalvular gradients, lower stroke work loss, lower valve resistance, and higher EOA than fresh intact porcine roots. In contrast, SDS 0.1%-treated porcine aortic roots showed opposing results, with the transvalvular gradients, stroke work loss and valve resistance each higher, and the EOA lower, than pre-treatment values. SDS 0.03% treatment had no significant effect on the hydrodynamic performance. After decellularization in all treatment groups, the diastolic parameters, total regurgitant volume and valve closing volume were each non significantly increased. The aortic roots used as a control group showed similar results before and after storage. CONCLUSION: Based on these results using the SPD, all treatments except for SDS 0.03% modified the systolic and diastolic functions of intact porcine aortic roots. PMID- 20845898 TI - Leaflet opening and closing dynamics of stentless bioprostheses. AB - BACKGROUND AND AIM OF THE STUDY: Stiffening of the aortic root may entail asynchronous aortic leaflet movement, and result in enhanced flexion-stress in specific areas of the cusps. As stentless prostheses are more flexible than their stented counterparts, they are more likely to exhibit physiologic leaflet movements. The study aim was to compare leaflet movement dynamics in stented versus non-stented aortic valves implanted in pigs. METHODS: Aortic bioprostheses were implanted surgically into adult pigs as follows: stented Mitroflow (n = 6), stentless Solo (n = 5), and stentless Toronto SPV (n = 4). In five control animals, the native aortic valve leaflets were untouched. Postoperatively, the aortic valve was displayed by epicardial echocardiography. M-mode display of the non-coronary leaflet was applied to assess rapid valve-opening velocity (V(open)) and rapid valve-closing velocity (V(close)). RESULTS: The mean V(open) values were 29.2, 25.5, 37.8, and 31.9 cm/s, respectively, for the native, Toronto SPV, Solo, and Mitroflow valves. The mean V(close) values were 23.2, 21.9, 34.1, and 34.3 cm/s, respectively. A comparison of V(open) values showed no statistically significant difference between the valves. The Mitroflow and Solo valves yielded significantly higher V(close) values than the native and Toronto SPV valves. The Toronto SPV exhibited marked systolic leaflet folding. CONCLUSION: The stent of a bioprosthetic valve does not appear to affect leaflet velocities when compared to the stentless bioprosthetic valve. The Solo and Mitroflow valves closed more abruptly than the porcine native aortic valve; however, the Toronto SPV valve displayed diverging systolic leaflet movement patterns. PMID- 20845899 TI - In-vivo assessment of a novel polymer (SIBS) trileaflet heart valve. AB - BACKGROUND AND AIM OF THE STUDY: A novel trileaflet polymer valve, which is a composite design of a biostable and biocompatible polymer poly(styrene-block isobutylene-block-styrene) (SIBS) with an embedded reinforcement polyethylene terephthalate (PET) fabric, is being developed with the intention of providing a valve that has low thrombogenicity, high durability and favorable hemodynamic performance. The study aim was to investigate the biocompatibility and performance of this SIBS valve prototype under physiological loading conditions similar to humans, using a large-animal model. METHODS: Four SIBS valves (two with surface modification using dimyristoyl phosphatidylcholine, DMPC), and two commercial Magna tissue valves, were implanted into sheep. Hemodynamic and blood chemistry measurements were performed periodically during the postoperative period. The explanted SIBS valves were extensively evaluated using macroscopic, histological, radiographical and scanning electron microscopy/energy-dispersive spectroscopy analysis. RESULTS: Three animals, one with the DMPC-coated SIBS valve, and two with the Magna valves, reached the end of the study in satisfactory clinical condition, and were euthanized after 20 weeks. The other three animals (two with SIBS valves, one with a DMPC-coated SIBS valve) died at 6, 6.5, and 10 weeks due either to material failure or myocardial infarction. The explanted valves exhibited stent deformation and cracks on the leaflets, which exposed the underlying PET fabric and resulted in severe blood and tissue reactions. Extrinsic calcification was identified on the leaflets, and was associated with the regions of surface cracks. CONCLUSION: The SIBS valve failed in animal testing because of material failure and calcification. The physical properties of SIBS must be improved in order to provide the structural integrity required for long-term in-vivo use in the form of a heart valve. PMID- 20845900 TI - In-vitro seeding of human umbilical cord vein endothelial cells on hydroxyapatite for mechanical heart valve applications. AB - BACKGROUND AND AIM OF THE STUDY: Although heart valve replacement with either a mechanical or biological prosthesis is an effective method to treat valvular heart disease, both approaches have limitations, including thrombus formation, thromboembolism and degeneration problems. The study aim was to demonstrate the in-vitro endothelialization of hydroxyapatite (HAp) to be used as a biomaterial in heart valve prostheses. METHODS: The HAp samples were characterized using X ray diffractometry to identify the crystalline phase, while the surface morphology of HAp discs was examined using scanning electron microscopy (SEM). Human umbilical vein endothelial cells (HUVECs) were cultured on HAp discs for 1, 3, 5, and 7 days, and on pyrolytic carbon discs for 7 days; cytotoxicity was assessed using the methyl thiazolyl tetrazolium (MTT) assay. The cells were incubated in three groups: (i) an experimental group (cultured with HAp extract); (ii) a negative control (cultured with high-density polyethylene chaff); and (iii) a positive control (culture medium containing 0.1% phenol solution). RESULTS: A morphological examination of the HAp discs revealed the presence of micropores on the disc surface, together with cultured HUVECs. After seven days of culture, the HUVECs began to form a confluent endothelial cell layer covering the HAp discs. There were no visible cells attached to the pyrolytic carbon surface. The MTT assay indicated that HAp did not exert any cytotoxic effect on HUVECs, and low optical density values were obtained in the positive controls. CONCLUSION: The study results showed that HUVECs were able to grow well on HAp discs, and that HAP possessed a good in-vitro bioactivity and biocompatibility towards these cells. Consequently, HAp might be used as a film on mechanical heart valve prostheses, and serve as a promising biomaterial for heart valve replacement. PMID- 20845901 TI - Determinants of short- and long-term outcomes following triple valve surgery. AB - BACKGROUND AND AIM OF THE STUDY: Triple valve surgery (3VS) is required in some cardiac disorders that simultaneously involve the aortic valve (AV), mitral valve (MV), and tricuspid valve (TCV). Herein are reported details of the authors' experience with 3VS, and their attempts to identify those factors associated with a poor clinical outcome. METHODS: The medical records of patients who underwent 3VS between 1985 and 2005 were reviewed. A competing-risks methodology was used to determine the time-related prevalence and associated factors for three mutually exclusive end states after 3VS, namely death, valve reoperation, and survival without subsequent valve reoperation. RESULTS: A total of 206 consecutive patients (124 females, 82 males; median age 34 years; range: 12-82 years) underwent 3VS. The most common underlying pathology for all valves was rheumatic, followed by repair failure and prosthesis dysfunction for AV and MV, and functional regurgitation for TCV. In total, 72 patients (35.0%) had undergone prior valve surgery. At 3VS, the MV and AV were usually replaced (> 70%), whereas the TCV was usually repaired (91%). The operative mortality (prior to hospital discharge) was 11%, and 15-year survival 68%. At 15 years after 3VS, 21% of the patients had died, without subsequent valve reoperation, 50% had undergone valve reoperation, and 30% remained alive without valve reoperation. Baseline factors associated with early mortality after 3VS were older age at operation, TCV replacement, and the use of a mechanical MV during 3VS. A late risk of mortality was associated with poor left ventricular function and renal impairment at the time of the initial 3VS, and MV prosthesis prior to the initial 3VS. Younger age at 3VS and MV repair during the index 3VS were associated with a higher constant risk of valve reoperation, while female gender, MV prosthesis prior to index 3VS, MV replacement with a bioprosthesis during 3VS, and rheumatic TCV disease were associated with an increased late risk of valve reoperation. CONCLUSION: Both, primary and reoperative 3VS can be performed with acceptable operative mortality and long-term survival. However, patients continue to be at risk of valve reoperation, which steadily increases over time. PMID- 20845902 TI - Quality of life following heart valve replacement in the elderly. AB - BACKGROUND AND AIM OF THE STUDY: The purpose of this investigation was to evaluate both long-term functional status and quality of life (QoL) following valvular replacement surgery in octogenarians. The influence of gender and discharge location was also examined. METHODS: A total of 133 patients (age range: 80-89 years) who underwent surgical valve replacement between January 2003 and December 2006 was identified. Two questionnaires evaluating QoL (SF-12v2 and MLHFQ), as well as a demographic questionnaire, were sent to these patients. RESULTS: The response rate was 64.4%. Among the participants, the mean NYHA functional class improved from 2.7 to 1.4 after surgery. Men showed results similar to those of the age-matched general Canadian population on the mental and physical component scales of the SF-12v2. The data on women were similar to those of the general population on the physical component scale, but their scores were significantly lower on the mental component scale of the SF-12v2. Further analysis of the results comparing discharge location for each gender revealed that women discharged to a convalescence resource had significantly better QoL scores than those discharged to home with regards to the physical component scale of the SF-12v2, the total score of the MLHFQ, and the physical dimension score of the MLHFQ. CONCLUSION: Patients aged > or = 80 years benefit from heart valve replacement surgery in terms of both QoL and functional status. Women may be at increased risk of a decline in their emotional well-being and, postoperatively, may benefit more from convalescence than from discharge to home. PMID- 20845903 TI - Left ventricular myxoma resection with minimally invasive mitral valve reconstruction. AB - Ventricular myxomas are rare, accounting for less than 5% of all benign cardiac tumors. Although histologically benign, myxomas can be a source of significant morbidity and mortality. The case is presented of a left ventricular myxoma involving the posterior papillary muscle that was resected using a minimally invasive transmitral approach. A radical mitral valve reconstruction was performed, including the replacement of two chordae tendineae, annuloplasty and valvuloplasty, resulting in excellent postoperative mitral valve function. Precise preoperative imaging and surgical planning are necessary to achieve adequate tumor margins and to minimize the likelihood of recurrence. PMID- 20845904 TI - A novel technique of coronary reconstruction during complex aortic root replacement. AB - Many modifications of the Bentall technique have been described since its introduction in 1968. The crucial phases of the operation include the re establishment of coronary flow and control of intraoperative hemorrhage. Based on their experience with Blalock-Taussig shunts, the proximal take-off of which is at the innominate/right subclavian artery junction, the present authors have developed a novel technique of coronary reconstruction. The details of a new technique of coronary reconstruction to minimize the duration of cardiopulmonary bypass, myocardial ischemia and bleeding, are reported. PMID- 20845905 TI - Recidivant endocarditis: report of two cases. PMID- 20845906 TI - Does isolated annular dilatation cause hemodynamically significant mitral regurgitation? PMID- 20845907 TI - Development of molecular probes for the human 5-HT(6) receptor. AB - In this work we report the synthesis of a set of labeled ligands targeting the human 5-HT(6) receptor (h5-HT(6)R). Among the synthesized compounds, fluorescent probe 10 (K(i) = 175 nM and Phi(f) = 0.21) and biotinylated derivative 15 (K(i) = 90 nM) deserve special attention because they enable direct observation of the h5 HT(6)R in cells. Thus, they represent the first molecular probes for 5-HT(6)R visualization. These results are the starting point for introducing a variety of tags in these or other 5-HT(6)R ligand scaffolds aimed at the development of optimized probes with tailored profiles in terms of fluorescence, affinity, or selectivity. PMID- 20845908 TI - Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus. AB - Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. beta-d 2'-Deoxy-2'-alpha-fluoro-2'-beta-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the beta-d-2'-deoxy-2' alpha-fluoro-2'-beta-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 MUM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate. PMID- 20845909 TI - DNA Core@Inorganic Shell. AB - A chemically well-defined Bio Core@Inorganic Shell nanohybrid, which consists of rationally designed DNA molecule core with a size of ~100 nm and spherical inorganic nanoshell with an overall thickness of ~10 nm reassembled with exfoliated layered metal hydroxide (MH nanosheets), is prepared. The DNA encapsulation and its release, due to the pH-dependent solubility of the MH nanoshell, plays a crucial role in maximizing the stability of base sequence manipulated and probe-functionalized DNA molecules with designed information. The present DNA Core@MH Shell nanohybrid can provide wide bioinspired applications converged with nanotechnology, such as an advanced gene delivery system and a biomedical diagnostics, tracing/collection/sensing system for DNA-based information. PMID- 20845910 TI - Tricyclic 2'-C-modified nucleosides as potential anti-HCV therapeutics. AB - Promising biological activity in a number of therapeutic areas has been reported for both tricyclic nucleosides and 2'-modified nucleosides. In particular, disubstitution at the C-2' position of nucleosides has resulted in significant activity against the hepatitis C virus (HCV). Combining this with the observation that tricyclic nucleosides developed in our laboratory have been shown to inhibit the RNA-dependent RNA polymerase NS5B led to the design of a series of 2' modified tricyclic nucleosides. Details of the synthesis, structural characterization, and preliminary biological results are reported. PMID- 20845911 TI - Versatile set of orthogonal protecting groups for the preparation of highly branched oligosaccharides. AB - A new set of orthogonal protecting groups has been developed based on the use of a diethylisopropylsilyl (DEIPS), methylnaphthyl (Nap), allyl ether, and levulinoyl (Lev) ester. The protecting groups are ideally suited for the preparation of highly branched oligosaccharides and their usefulness has been demonstrated by the chemical synthesis of a beta-D-Man-(1->4)-D-Man disaccharide, which is appropriately protected for making a range of part-structures of the unusual core region of the lipopolysaccharide of Francisella tularensis. PMID- 20845912 TI - Palmyrolide A, an unusually stabilized neuroactive macrolide from Palmyra Atoll cyanobacteria. AB - Palmyrolide A (1) is a new neuroactive macrolide isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf. and Oscillatoria spp. collected from Palmyra Atoll. It features a rare N-methyl enamide and an intriguing t-butyl branch; the latter renders the adjacent lactone ester bond resistant to hydrolysis. Consistent with its significant suppression of calcium influx in cerebrocortical neurons (IC(50) = 3.70 MUM), palmyrolide A (1) showed a relatively potent sodium channel blocking activity in neuro-2a cells (IC(50) = 5.2 MUM), without appreciable cytotoxicity. PMID- 20845913 TI - Highly chemoselective Baylis-Hillman and aldol reactions of 2H-thiopyran-4(3H) one using tertiary amine catalysts in aqueous media. AB - For the first time, the Baylis-Hillman (BH) reaction of 2H-thiopyran-4(3H)-one is investigated, and surprisingly, the reaction of 2H-thiopyran-4(3H)-one with aldehydes in the presence of different tertiary amines shows excellent chemo- and regioselectivity in water. At room temperature, DBU affords BH adducts, but with DABCO, aldol products were obtained. In the case of DABCO, Et(3)N, or DMAP, domino aldol-rearrangement reactions occurred at 45-50 degrees C. PMID- 20845914 TI - Biotemplated aqueous-phase palladium crystallization in the absence of external reducing agents. AB - A new synthetic strategy enabling highly controlled aqueous-phase palladium crystallization on the tobacco mosaic virus (TMV) is demonstrated without the addition of external reducing agents. This low cost, solution processing method yields continuous and uniform coatings of polycrystalline palladium on TMV, creating highly uniform palladium nanowires of tens of nanometers in thickness and hundreds of nanometers in length. Our approach utilizes a palladium chloride precursor to produce metallic Pd coatings on TMV without the need for an external reducing agent. X-ray photoelectron spectroscopy and in situ transmission electron microscopy were used to confirm the reduction of the surface palladium oxide layer on the palladium metal wires during room temperature hydrogenation. This leads to metallic palladium nanowires with surfaces free of residual organics, making these structures suitable for applications in nanoscale electronics. PMID- 20845915 TI - Synthesis of the indolizino[7,6-c]quinoline alkaloid isaindigotidione. AB - The first synthesis of isaindigotidione has been developed utilizing a reaction sequence including an asymmetric rhodium-catalyzed 1,4-conjugate addition, an intramolecular aldol reaction, and a lactamization. PMID- 20845916 TI - Parallel array InAs nanowire transistors for mechanically bendable, ultrahigh frequency electronics. AB - The radio frequency response of InAs nanowire array transistors on mechanically flexible substrates is characterized. For the first time, GHz device operation of nanowire arrays is demonstrated, despite the relatively long channel lengths of ~1.5 MUm used in this work. Specifically, the transistors exhibit an impressive maximum frequency of oscillation, f(max) ~ 1.8 GHz, and a cutoff frequency, f(t) ~ 1 GHz. The high-frequency response of the devices is due to the high saturation velocity of electrons in high-mobility InAs nanowires. The work presents a new platform for flexible, ultrahigh frequency devices with potential applications in high-performance digital and analog circuitry. PMID- 20845917 TI - Nanostructural transformation and formation of heterojunctions from Si nanowires. AB - Si nanowires coated with Ni showed interesting structural transformation behaviors as observed by in situ transmission electron microscopy. Owing to the presence of the native oxide on Si nanowire surfaces, the Ni thin shells initially segregated into nanosized droplets on the oxide surfaces. The native oxide shells protected the Si cores from reacting with Ni at temperatures below 1350 degrees C. Ni started the reaction with Si nanowires preferentially at the defects or bending regions of the nanowires. Because the reaction temperature was sufficiently high, the structural transformation was extremely fast and completed within 0.1 s. The resulting nanowires were single crystalline NiSi(2), the most desirable Ni silicide structure for potential applications. Nanowire junctions of NiSi(2)/Si and nanowire-nanotube junctions of NiSi(2)/SiC have been obtained upon further annealing. PMID- 20845918 TI - Toward high throughput interconvertible graphane-to-graphene growth and patterning. AB - We report a new route to prepare high quality, monolayer graphene by the dehydrogenation of graphane-like film grown by plasma-enhanced chemical vapor deposition. Large-area monolayer graphane-like film is first produced by remote discharged radio frequency plasma beam deposition at 650 degrees C on Cu/Ti coated SiO(2)-Si. The advantages of the plasma deposition include very short deposition time (<5 min) and a lower growth temperature of 650 degrees C compared to the current thermal chemical vapor deposition approach (1000 degrees C). Near edge X-ray adsorption, Raman spectroscopy, and transmission electron microscopy as well as scanning tunneling microscopy have been applied to characterize the graphane-to-graphene transition for the as-deposited films. The fingerprint quantum hall effect of monolayer graphene can be obtained on the fully dehydrogenated graphane-like film; four fully quantized half-integer plateaus are observed. The interconvertibility between graphane-like and graphene here opens up a possible route for the fabrication of regions with varying conductivity in a single deposition system using maskless, laser writing. PMID- 20845919 TI - Transcutaneous glucose sensing by surface-enhanced spatially offset Raman spectroscopy in a rat model. AB - This letter presents the first quantitative, in vivo, transcutaneous glucose measurements using surface enhanced Raman spectroscopy (SERS). Silver film over nanosphere (AgFON) surfaces were functionalized with a mixed self-assembled monolayer (SAM) and implanted subcutaneously in a Sprague-Dawley rat. The glucose concentration was monitored in the interstitial fluid. SER spectra were collected from the sensor chip through the skin using spatially offset Raman spectroscopy (SORS). The combination of SERS and SORS is a powerful new approach to the challenging problem of in vivo metabolite and drug sensing. PMID- 20845920 TI - Noncooled capillary inlet: a source of systematic errors in capillary electrophoresis-based affinity analyses. AB - Capillary electrophoresis (CE) serves as a platform for a large family of temperature-sensitive affinity methods. To control the electrolyte temperature, the heat generated during electrophoresis is removed by actively cooling the capillary. Short parts of the capillary, particularly at its inlet, are not actively cooled, however, and the electrolyte in this part is likely to be at an elevated temperature. Owing to their relatively short lengths, the noncooled parts have never been considered as a potential source of artifacts. Here we report for the first time that electrophoresis of the sample through the short noncooled capillary inlet can lead to large systematic errors in quantitative CE based affinity analyses. Our findings suggest that the noncooled capillary inlet region, in spite of being short, is a source of significant artifacts that must be taken into consideration by developers and users of CE-based affinity methods. We propose a simple solution for this problem: moving the sample through the noncooled inlet into the cooled region by pressure or by a low-strength electric field to save it from exposure to the elevated temperature. PMID- 20845921 TI - Brillouin spectroscopy, calculated elastic and bond properties of GaAsO4. AB - Experimental and theoretical studies have been performed to demonstrate the high performance of the novel piezoelectric material GaAsO(4). Hydrothermally grown single crystals of alpha-quartz phase GaAsO(4) were studied by Brillouin spectroscopy to determine elastic constants. Experimentally obtained values of C(11), C(66), C(33), C(44), C(14) and C(12) are 59.32, 19.12, 103.54, 30.70, 1.7, and 21.1 GPa, respectively. Elastic and piezoelectric tensors were also calculated by a first principles method in this work, leading to a very good agreement with experimental results and confirming the values of elastic components obtained indirectly such as C(14) and the negligible piezoelectric correction for C(11). The thermal behavior of the elastic constant corresponding to the [100] longitudinal L mode (C(11)) was studied up to 1137 K to estimate potential piezoelectric performance. It was found that the thermal behavior is linear up to 1273 K which is just below the thermal decomposition temperature of 1303 K. High thermal stability can be linked to the higher polarizability of large cations Ga and As because of neighboring oxygen atoms. On the basis of thermal behavior, GaAsO(4) is a promising material for high temperature piezoelectric applications. PMID- 20845923 TI - Glowing locked nucleic acids: brightly fluorescent probes for detection of nucleic acids in cells. AB - Fluorophore-modified oligonucleotides have found widespread use in genomics and enable detection of single-nucleotide polymorphisms, real-time monitoring of PCR, and imaging of mRNA in living cells. Hybridization probes modified with polarity sensitive fluorophores and molecular beacons (MBs) are among the most popular approaches to produce hybridization-induced increases in fluorescence intensity for nucleic acid detection. In the present study, we demonstrate that the 2'-N (pyren-1-yl)carbonyl-2'-amino locked nucleic acid (LNA) monomer X is a highly versatile building block for generation of efficient hybridization probes and quencher-free MBs. The hybridization and fluorescence properties of these Glowing LNA probes are efficiently modulated and optimized by changes in probe backbone chemistry and architecture. Correctly designed probes are shown to exhibit (a) high affinity toward RNA targets, (b) excellent mismatch discrimination, (c) high biostability, and (d) pronounced hybridization-induced increases in fluorescence intensity leading to formation of brightly fluorescent duplexes with unprecedented emission quantum yields (Phi(F) = 0.45-0.89) among pyrene-labeled oligonucleotides. Finally, specific binding between messenger RNA and multilabeled quencher-free MBs based on Glowing LNA monomers is demonstrated (a) using in vitro transcription assays and (b) by quantitative fluorometric assays and direct microscopic observation of probes bound to mRNA in its native form. These features render Glowing LNA as promising diagnostic probes for biomedical applications. PMID- 20845922 TI - Determination of the photolysis products of [FeFe]hydrogenase enzyme model systems using ultrafast multidimensional infrared spectroscopy. AB - Ultrafast transient 2D-IR (T-2D-IR) spectroscopy has been used to study the photolysis products of the [FeFe]hydrogenase enzyme model compound (MU propanedithiolate)Fe(2)(CO)(6) in heptane solution following irradiation at ultraviolet wavelengths. Observation of coupling patterns between the vibrational modes of the photoproduct species formed alongside examination of the appearance time scales of these signals has uniquely enabled assignment of the photoproduct spectrum to a single pentacarbonyl species. Comparison of the vibrational relaxation rate of the photoproduct with that of the parent is consistent with the formation of a solvent adduct at the vacant coordination site, while anisotropy data in conjunction with density functional theory simulations indicates substitution in an axial rather than equatorial position. No firm evidence of additional short-lived intermediates is seen, indicating that the subsequent chemistry of these species is likely to be strongly defined by the nature of the first solvation shell. PMID- 20845924 TI - Interaction between grape-derived proanthocyanidins and cell wall material. 2. Implications for vinification. AB - Proanthocyanidins (PAs) were isolated from the skins, seeds and flesh of commercially ripe grapes, and from wine and marc produced from the same source. In the grape berry, skin PAs accounted for 54% of the total extractable PA, while seed and flesh-derived PA accounted for 30% and 15% of the total, respectively. Following fermentation, 25% of the fruit PA was found in the wine, while 27% was found in the pericarp isolated from marc, and 48% was unaccounted for (either remaining in the seed or adsorbed to lees). To investigate the role that cell wall material (CWM) has on PA extraction during fermentation, CWM isolated from skin and flesh were combined with PA in model suspensions. In general, the affinity of flesh CWM for PA increased with increasing PA molecular mass (MM); however, this relationship was not observed for the interaction of skin CWM with skin PA. Subsequent experiments suggest that the differences in the interaction of flesh and skin CWM with PA of higher MM (>15000 g/mol) may be limited by the structure of the CWM. Observed variations in the composition between skin and flesh CWM may explain the differences in PA interaction at high MM. Among wine derived PA, no higher MM material was detected, suggesting that, during vinification, higher MM PA are nonextractable and/or are removed from the wine by interaction with CWM. PMID- 20845925 TI - Optimized synthesis of tetrafluoroterephthalic acid: a versatile linking ligand for the construction of new coordination polymers and metal-organic frameworks. AB - Pure 2,3,5,6-tetrafluoroterephthalic acid (H(2)tfBDC) is obtained in high yields (95%) by reacting 1,2,4,5-tetrafluorobenzene with a surplus (>2 equiv) of n butyllithium in tetrahydrofuran (THF) and subsequent carbonation with CO(2) without any extensive purification procedure. A single crystal X-ray structure analysis of H(2)tfBDC (1) confirms former data obtained for a deuterated sample (P1, Z = 1). Recrystallization from water/acetone leads to single crystals of H(2)tfBDC.2H(2)O (2, P2(1)/c, Z = 2), where an extensive hydrogen bonding network is found. By reacting H(2)tfBDC with an aqueous ammonia solution, single crystals of (NH(4))(2)tfBDC (3, C2/m, Z = 2) are obtained. 3 is thermally stable up to 250 degrees C and shows an enhanced solubility in water compared to H(2)tfBDC. Monosubstituted 2,3,5,6-tetrafluorobenzoic acid (H(2)tfBC, 4) is obtained by reacting 1,2,4,5-tetrafluorobenzene with stoichiometric amounts (1 equiv) of n butyllithium in THF. Its crystal structure (Fdd2, Z = 16) shows dimeric units as characteristic structural feature. PMID- 20845926 TI - Synthesis, crystal structure, atomic Hirshfeld surfaces, and physical properties of hexagonal CeMnNi4. AB - The hexagonal polymorph of CeMnNi(4) has been synthesized using cold crucible, high-frequency induction melting with subsequent Czochralski crystal pulling. Single-crystal X-ray diffraction, multitemperature synchrotron powder X-ray diffraction (90 to 600 K), and neutron powder diffraction data have been measured to establish the detailed crystal structure and in particular the location of the Mn atoms. The neutron diffraction data provide sufficient scattering contrast between Mn and Ni to establish that the 2c site has an occupancy of 13% Mn atoms, while the 3g site has an occupancy of 25% Mn atoms. Thus, the crystal structure is complex with considerable disorder. Rietveld refinement of the multitemperature synchrotron data establishes a near linear thermal expansion coefficient of 13.9(3) * 10(-6) K(-1) and 14.9(3) * 10(-6) K(-1) for the a and c axes, respectively. Atomic Hirshfeld surfaces are introduced as a new tool to investigate the atomic coordination and interactions in intermetallic compounds. The atomic displacement parameters (ADPs) are observed to be much larger for the heavy Ce atom than for the lighter Mn and Ni atoms, and this correlates with the large atomic Hirshfeld volume of Ce relative to Mn and Ni. The fit of a Debye model to the ADPs gives theta(D) = 312(3) K. Magnetic susceptibility data measured between 2 and 350 K indicate ferromagnetic ordering at 122(2) K (Weiss constant) based on a linear fit of the inverse magnetic susceptibility in the paramagnetic region. Transport properties were measured on a polycrystalline sample containing CeO(2) (2.8%) and Ni (7.7%) impurities. The electrical conductivity is observed to be metallic with a distinct kink in the data around 120 K coinciding with the observed Curie temperature. The lattice thermal conductivity (kappa(L)) increases from 0.5 W/Km at 2 K to 8 W/Km at 50 K, and the relatively moderate value of kappa(L) probably reflects the significant structural disorder. PMID- 20845927 TI - Impedimetric biosensor for the assessment of the clotting activity of rennet. AB - Cheese production is relied upon the action of rennet (a mixture of chymosin and pepsin) onto casein micelles of milk. For the first time, the monitoring of this interaction with electrochemical impedance spectroscopy (EIS) was used to develop a faradic impedimetric biosensor for the assessment of the clotting activity of rennet, using hexacyanoferrate(II)/(III) couple as a redox probe. Gold electrodes were modified with self-assembled monolayers of different thiols (thioctic acid, dithiobis-N-succinimidyl propionate, and cysteamine), and (artificial) casein micelles were immobilized on the modified gold surfaces. The proposed method is based on the measurement of charge-transfer resistance (R(ct)) changes attributed to the degradation of the negatively charged immobilized casein micelles by rennet to neutral biostructures. This action results in the increase of the flux of the redox probe, which exists in the bulk solution, to the surface of the electrode and, consequently, in the decrease of R(ct). Experimental parameters such as the micelle loading, the reaction time, the concentration of rennet, and the working pH, were optimized. Besides EIS measurements, cyclic voltammetry, FT IR, and atomic force microscopy (AFM) experiments were also performed before and after the interaction of the immobilized micelles with rennet. Finally, the proposed biosensors were successfully tried for various commercial samples. PMID- 20845929 TI - Rapid reaction of hydrogen sulfide with the neutrophil oxidant hypochlorous acid to generate polysulfides. AB - H2S has been recognized as a signaling molecule and mediator of inflammation. Here, we report the kinetics and mechanism of its reaction with the neutrophil oxidant hypochlorous acid. Stopped flow studies, carried out at high pH, showed this reaction to be extremely fast, with a second-order rate constant extrapolated to be 2 * 109 M-1 s-1 at pH 7.4. The reaction produces polysulfides rather than polythionates and may represent a novel pathway for protein Cys sulfhydration, a recently proposed mechanism for H2S signaling. PMID- 20845931 TI - Dimensional standard for micro X-ray computed tomography. AB - The decrease in the cost of high end computing and the availability of high quality X-ray sources in the laboratory environment has led to an increased use of three-dimensional (3D) X-ray micro computed tomography (MUCT). In the medical community, the primary concern for CT is calibrating for X-ray absorption and ascertaining the difference between healthy tissue and cancerous tissue or examining fractures. Absorption calibration is also important in the materials community, however confirming dimensional accuracy of voids, defects, machined parts, cracks, or the distribution of dispersed particles is typically more important. One key aspect of MUCT that is often overlooked in the literature is the number of radiographs required for dimensional accuracy of the 3D reconstruction and minimization of image noise. In MUCT, a number of radiographs are collected in theta increments as the sample is rotated at least 180 degrees . They are typically collected in 1 degrees increments (or 181 radiographs), 0.25 degrees increments (721 radiographs), or some other multiple. The question that arises, especially in a laboratory based instrument, where the required exposure times are longer to get high-quality signal-to-noise compared to synchrotron sources, is what is the optimal number of images required to reach the volumetric statistics of the sample, and minimize the noise while not overly scanning the sample at a cost in time? A dimensional standard based upon NIST certified glass microspheres dispersed in a low density poly(styrene) matrix to answer this question is proposed. Experiments are shown that describe the microsphere size statistics as a function of number of radiographs calculated using a commercial software package, AvizoFire. These results are important in understanding the distribution of voids in a foam and confirming the accuracy of the 3D measurements obtained. PMID- 20845928 TI - Formation, reactivity, and detection of protein sulfenic acids. AB - It has become clear in recent decades that the post-translational modification of protein cysteine residues is a crucial regulatory event in biology. Evidence supports the reversible oxidation of cysteine thiol groups as a mechanism of redox-based signal transduction, while the accumulation of proteins with irreversible thiol oxidations is a hallmark of stress-induced cellular damage. The initial formation of cysteine-sulfenic acid (SOH) derivatives, along with the reactive properties of this functional group, serves as a crossroads whereby the local redox environment may dictate the progression of either regulatory or pathological outcomes. Protein-SOH are established as transient intermediates in the formation of more stable cysteine oxidation products both under basal conditions and in response to several redox-active extrinsic compounds. This review details both direct and multistep chemical routes proposed to generate protein-SOH, the spectrum of secondary reactions that may follow their initial formation and the arsenal of experimental tools available for their detection. Pioneering studies that have provided a framework for our current understanding of protein-SOH as well as state-of-the-art proteomic strategies designed for global assessments of this post-translational modification are highlighted. PMID- 20845930 TI - Superparamagnetic iron oxide nanotheranostics for targeted cancer cell imaging and pH-dependent intracellular drug release. AB - Studies were conducted to develop antibody- and fluorescence-labeled superparamagnetic iron oxide nanoparticle (SPIO) nanotheranostics for magnetic resonance imaging (MRI) and fluorescence imaging of cancer cells and pH-dependent intracellular drug release. SPIO nanoparticles (10 nm) were coated with amphiphilic polymers and PEGylated. The antibody HuCC49DeltaCH2 and fluorescent dye 5-FAM were conjugated to the PEG of iron oxide nanoparticles (IONPs). Anticancer drugs doxorubicin (Dox), azido-doxorubicin (Adox), MI-219, and 17-DMAG containing primary amine, azide, secondary amine, and tertiary amine, respectively, were encapsulated into IONPs. The encapsulation efficiency and drug release at various pHs were determined using LC-MS/MS. The cancer targeting and imaging were monitored using MRI and fluorescent microscopy in a colon cancer cell line (LS174T). The pH-dependent drug release, intracellular distribution, and cytotoxicity were evaluated using microscopy and MTS assay. The PEGylation of SPIO and conjugation with antibody and 5-FAM increased SPIO size from 18 to 44 nm. Fluorescent imaging, magnetic resonance imaging (MRI) and Prussian blue staining demonstrated that HuCC49DeltaCH2-SPIO increased cancer cell targeting. HuCC49DeltaCH2-SPIO nanotheranostics decreased the T(2) values in MRI of LS174T cells from 117.3 +/- 1.8 ms to 55.5 +/- 2.6 ms. The loading capacities of Dox, Adox, MI-219, and 17-DMAG were 3.16 +/- 0.77%, 6.04 +/- 0.61%, 2.22 +/- 0.42%, and 0.09 +/- 0.07%, respectively. Dox, MI-219 and 17-DMAG showed pH-dependent release while Adox did not. Fluorescent imaging demonstrated the accumulation of HuCC49DeltaCH2-SPIO nanotheranostics in endosomes/lysosomes. The encapsulated Dox was released in acidic lysosomes and diffused into cytosol and nuclei. In contrast, the encapsulated Adox only showed limited release in endosomes/lysosomes. HuCC49DeltaCH2-SPIO nanotheranostics target-delivered more Dox to LS174T cells than nonspecific IgG-SPIO and resulted in a lower IC(50) (1.44 MUM vs 0.44 MUM). The developed HuCC49DeltaCH2-SPIO nanotheranostics provides an integrated platform for cancer cell imaging, targeted anticancer drug delivery and pH-dependently drug release. PMID- 20845932 TI - Catalysis of phosphorus(V)-mediated transformations: dichlorination reactions of epoxides under Appel conditions. AB - A stereospecific triphenylphosphine oxide-catalyzed 1,2-dichlorination reaction of epoxides has been developed. The reaction is effective for a range of terminal and internal epoxides. In contrast to the classical Appel-type dichlorination of epoxides, oxalyl chloride is used as a stoichiometric reagent to generate the chlorophosphonium salt responsible for dichlorination from catalytic triphenylphosphine oxide. PMID- 20845934 TI - Synthesis of inherently chiral calix[4]arenes: stereocontrol through ligand choice. AB - Employing a chiral oxazoline as an ortholithiation directing group allows the synthesis of inherently chiral calix[4]arenes suitable for elaboration into planar chiral molecules. An important finding has been that the diastereoselectivity of the reaction can be tuned by the choice of additive. These results have bearing on the elucidation of the general mechanism of oxazoline-directed ortholithiation. PMID- 20845933 TI - Conjugated polyelectrolyte based fluorescence turn-on assay for real-time monitoring of protease activity. AB - A fluorescence "turn-on" assay for monitoring protease activity is developed on the basis of a water-soluble carboxylated polyfluorene derivative, PFP-CO2Na, and its different fluorescence response toward cytochrome c (cyt c) and its fragments. PFP-CO2Na is synthesized via Suzuki coupling polymerization between 2,7-dibromo-9,9-bis(3'-tert-butyl propanoate)fluorene and 1,4-bis(4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl)-benzene, followed by treatment with trifluoroacetic acid and Na2CO3. The fluorescence of PFP-CO2Na can be significantly quenched by cyt c due to complexation-mediated electron transfer between the polymer and protein. Using the complex of PFP-CO2Na/cyt c as a substrate, a real-time fluorescence turn-on assay for trypsin activity study has been developed. Addition of trypsin to the substrate solution induces gradual recovery of the fluorescence intensity for PFP-CO2Na due to trypsin-catalyzed hydrolysis of cyt c, which dissociates the heme moiety from the polymer vicinity. The time-dependent fluorescence intensity increase of PFP-CO2Na in the presence of trypsin allows us to derive the initial reaction rates and k(cat)/K(m) (5350 M 1 s-1) for trypsin-catalyzed hydrolysis. Addition of trypsin inhibitor efficiently inhibits trypsin-catalyzed hydrolysis reaction of cyt c, which leads to a decreased fluorescence turn-on response of PFP-CO2Na. PMID- 20845936 TI - Synthesis of pi-extended thiadiazole (oxides) and their electronic properties. AB - The syntheses of extended thiadiazole, thiadiazole oxide, and thiadiazole dioxide heterocycles are described. The electron-accepting heterocycles were investigated by X-ray crystallography and optical as well as electrochemical measurements and supported by DFT calculations. The thiadiazole dioxide heterocycles have reduction potentials of -0.7 V vs ferrocene/ferrocenium, suggesting a viable building block for n-type organic materials. PMID- 20845935 TI - Direct comparison of stable isotope labeling by amino acids in cell culture and spectral counting for quantitative proteomics. AB - Numerous experimental strategies exist for relative protein quantification, one of the primary objectives of mass spectrometry based proteomics analysis. These strategies mostly involve the incorporation of a stable isotope label via either metabolic incorporation in cell or tissue culture (15N/14N metabolic labeling, stable isotope labeling by amino acids in cell culture (SILAC)), chemical derivatization (ICAT, iTRAQ, TMT), or enzymatically catalyzed incorporation (18O labeling). Also, these techniques can be cost or time prohibitive or not amenable to the biological system of interest (i.e., metabolic labeling of clinical samples, most animals, or fungi). This is the case with the quantification of fungal proteomes, which often require auxotroph mutants to fully metabolically label. Alternatively, label-free strategies for protein quantification such as using integrated ion abundance and spectral counting have been demonstrated for quantification affording over 2 orders of magnitude of dynamic range which is comparable to metabolic labeling strategies. Direct comparisons of these quantitative techniques are largely lacking in the literature but are highly warranted in order to evaluate the capabilities, limitations, and analytical variability of available quantitative strategies. Here, we present the direct comparison of SILAC to label-free quantification by spectral counting of an identical set of data from the bottom-up proteomic analysis of human embryonic stem cells, which are readily able to be quantified using both strategies, finding that both strategies result in a similar number of protein identifications. We also discuss necessary constraints for accurate quantification using spectral counting and assess the potential of this label free strategy as a viable alternative for quantitative proteomics. PMID- 20845937 TI - The pharmacokinetics of cell-penetrating peptides. AB - Cell-penetrating peptides (CPPs) are able to penetrate the cell membrane carrying cargoes such as peptides, proteins, oligonucleotides, siRNAs, radioisotopes, liposomes, and nanoparticles. Consequently, many delivery approaches have been developed to use CPPs as tools for drug delivery. However, until now a systematic analysis of their in vivo properties including potential tumor binding specificity for drug targeting purposes has not been conducted. Ten of the most commonly applied CPPs were obtained by solid phase peptide synthesis and labeled with (111)In or (68)Ga. Uptake studies were conducted using a panel of six tumor cell lines of different origin. The stability of the peptides was examined in human serum. Biodistribution experiments were conducted in nude mice bearing human prostate carcinoma. Finally, positron emission tomography (PET) measurements were performed in male Wistar rats. The in vitro uptake studies revealed high cellular uptake values, but no specificity toward any of the cell lines. The biodistribution in PC-3 tumor-bearing nude mice showed a high transient accumulation in well-perfused organs and a rapid clearance from the blood. All of the CPPs revealed a relatively low accumulation rate in the brain. The highest uptake values were observed in the liver (with a maximal uptake of 51 %ID/g observed for oligoarginine (R(9))) and the kidneys (with a maximal uptake of 94 %ID/g observed for NLS). The uptake values in the PC-3 tumor were low at all time points, indicating a lack of tumor specific accumulation for all peptides studied. A micro-PET imaging study with (68)Ga-labeled penetratin, Tat and transportan(10) (TP(10)) confirmed the organ distribution data. These data reveal that CPPs do not show evidence for application in tumor targeting purposes in vivo. However, CPPs readily penetrate into most organs and show rapid clearance from the circulation. The high uptake rates observed in vitro and the relatively low specificity in vivo imply that CPPs would be better suited for topical application in combination with cargoes which show passive targeting and dominate the pharmacokinetic behavior. In conclusion, CPPs are suitable as drug carriers for in vivo application provided that their pharmacokinetic properties are also considered in design of CPP drug delivery systems. PMID- 20845938 TI - Antifungal nanoparticles and surfaces. AB - Nosocomial fungal infections, an increasing healthcare concern worldwide, are often associated with medical devices. We have developed antifungal nanoparticle conjugates that can act in suspension or attach to a surface, efficiently killing fungi. For that purpose, we immobilized covalently amphotericin B (AmB), a potent antifungal agent approved by the FDA, widely used in clinical practice and effective against a large spectrum of fungi, into silica nanoparticles. These antifungal nanoparticle conjugates are fungicidal against several strains of Candida sp., mainly by contact. In addition, they can be reused up to 5 cycles without losing their activity. Our results show that the antifungal nanoparticle conjugates are more fungistatic and fungicidal than 10 nm colloidal silver. The antifungal activity of the antifungal nanoparticle conjugates is maintained when they are immobilized on a surface using a chemical adhesive formed by polydopamine. The antifungal nanocoatings have no hemolytic or cytotoxic effect against red blood cells and blood mononuclear cells, respectively. Surfaces coated with these antifungal nanoparticle conjugates can be very useful to render medical devices with antifungal properties. PMID- 20845939 TI - Structure-properties relationship of biosourced stereocontrolled polytriazoles from click chemistry step growth polymerization of diazide and dialkyne dianhydrohexitols. AB - The design of dialkyne and diazide functionalized dianhydrohexitol stereoisomers (1-6) afforded a new family of starch-based polytriazoles (7-15) with defined stereochemistry through A(2) + B(2) CuAAC step growth polymerization. The present strategy gave rise to polytriazoles having a high biosourced weight fraction (superior to 60% wt) and exhibiting relatively high molar masses (M(n) = 8-17 kg/mol) that could be easily dissolved in DMF or DMSO. The obtained materials were amorphous and displayed high transition temperatures (T(g) = 125-166 degrees C) as well as good resistance to thermal degradation (T(d10) = 325-347 degrees C). Monomer stereochemistry proved to be a crucial parameter aiming at generating polymers with high T(g). Thus, optimal thermal properties were obtained with monomers having RR absolute configuration of the C-2 and C-5 carbon atoms (isomannide configuration). PMID- 20845940 TI - Practical approach to structurally diverse monoimine salts and nonsymmetrical metallosalphen complexes. AB - A practical approach toward the synthesis of monoimine NBu(4) salts derived from Zn(salphen) complexes is described. The method involves nucleophilic addition of the hydroxide anion to the imine bond followed by hydrolysis. These monoimines provide accessible and useful reagents for the synthesis of (chiral) metallosalens with fine-tunable properties. PMID- 20845941 TI - Use of genotoxicity information in the development of integrated testing strategies (ITS) for skin sensitization. AB - Skin sensitization is an end point of concern for various legislation in the EU, including the seventh Amendment to the Cosmetics Directive and Registration Evaluation, Authorisation and Restriction of Chemicals (REACH). Since animal testing is a last resort for REACH or banned (from 2013 onward) for the Cosmetics Directive, the use of intelligent/integrated testing strategies (ITS) as an efficient means of gathering necessary information from alternative sources (e.g., in vitro, (Q)SARs, etc.) is gaining widespread interest. Previous studies have explored correlations between mutagenicity data and skin sensitization data as a means of exploiting information from surrogate end points. The work here compares the underlying chemical mechanisms for mutagenicity and skin sensitization in an effort to evaluate the role mutagenicity information can play as a predictor of skin sensitization potential. The Tissue Metabolism Simulator (TIMES) hybrid expert system was used to compare chemical mechanisms of both end points since it houses a comprehensive set of established structure-activity relationships for both skin sensitization and mutagenicity. The evaluation demonstrated that there is a great deal of overlap between skin sensitization and mutagenicity structural alerts and their underlying chemical mechanisms. The similarities and differences in chemical mechanisms are discussed in light of available experimental data. A number of new alerts for mutagenicity were also postulated for inclusion into TIMES. The results presented show that mutagenicity information can provide useful insights on skin sensitization potential as part of an ITS and should be considered prior to any in vivo skin sensitization testing being initiated. PMID- 20845942 TI - Revelation of multiple underlying RuO2 redox processes associated with pseudocapacitance and electrocatalysis. AB - Advances in basic knowledge relevant to the pseudocapacitive and electrocatalytic properties of RuO(2) materials require a detailed understanding of the redox chemistry that occurs at the electrode interface. Although several redox processes have been identified via dc cyclic voltammograms derived from surface confined RuO(2) materials, mechanistic details remain limited because the faradaic signals of interest are heavily masked by the background current. Here, it is shown that the underlying electron transfer reactions associated with the VI to II oxidation states of surface-confined RuO(2) materials in acidic medium are far more accessible in the background current free fourth and higher harmonic components available via large-amplitude Fourier transformed ac voltammetry. Enhanced resolution and sensitivity to both electron transfer and protonation processes and discrimination against solvent and background capacitance are achieved so that the Ru(V) to Ru(VI) process can be studied for the first time. Thus, kinetic and thermodynamic information relevant to each ruthenium redox level is readily deduced. The relative rate of electron transfer and the impact of protonation associated with Ru(VI) to Ru(II) redox processes are found to depend on the nature of the RuO(2) materials (extent of crystallinity and hydration) and concentration of sulfuric acid electrolyte. In the electrocatalytic oxidation of glucose in alkaline medium, access to the underlying electron transfer processes allows ready detection of the redox couple associated with the catalysis. Thus, application of an advanced ac electroanalytical technique is shown to provide the methodology for enhancing our understanding of the charge transfer processes of RuO(2), relevant to pseudocapacitance and electrocatalysis. PMID- 20845943 TI - Controlling surface functionality through generation of thiol groups in a self assembled monolayer. AB - A lithographic method to generate reactive thiol groups on functionalized synthetic diamond for biosensor and molecular electronic applications is developed. We demonstrate that ultrananocrystalline diamond (UNCD) thin films covalently functionalized with surface-generated thiol groups allow controlled thiol-disulfide exchange surface hybridization processes. The generation of the thiol functional head groups was obtained by irradiating phenylsulfonic acid (PSA) monolayers on UNCD surfaces. The conversion of the functional headgroup of the self-assembled monolayer was verified by using X-ray photoelectron spectroscopy (XPS), near-edge X-ray absorption fine structure (NEXAFS), and fluorescence microscopy. Our findings indicate the selective generation of reactive thiol surface groups. Furthermore, we demonstrate the grafting of yeast cytochrome c to the thiol-modified diamond surface and the electron transfer between protein and electrode. PMID- 20845944 TI - Controlling the morphology of Photosystem I assembly on thiol-activated Au substrates. AB - Morphological variations of Photosystem I (PS I) assembly on hydroxyl-terminated alkanethiolate self-assembled monolayer (SAM)/Au substrates with various deposition techniques is presented. Our studies indicate that deposition conditions such as PS I concentration and driving force play a central role in determining organization of immobilized PS I on thiol-activated Au surfaces. Specifically, atomic force microscopy (AFM) and ellipsometry analyses indicate that gravity-driven deposition from concentrated PS I solutions results in a large number of columnar PS I aggregates, which assemble perpendicular to the Au surface. PS I deposition yields much more uniform layers when deposited at lower concentrations, suggesting preassembly of the aggregate formation in the solution phase. Moreover, in electric field assisted deposition at high field strengths, columnar self-assembly is largely prevented, thereby allowing a uniform, monolayer-like deposition even at very high PS I concentrations. In situ dynamic light scattering (DLS) studies of solution-phase aggregation dynamics of PS I suspensions in both the presence and absence of an applied electric field support these observations and clearly demonstrate that the externally imposed electric field effectively fragments large PS I aggregates in the solution phase, thereby permitting a uniform deposition of PS I trimers on SAM/Au substrates. PMID- 20845945 TI - Retinol and retinol-binding protein stabilize transthyretin via formation of retinol transport complex. AB - Transthyretin (TTR) is a plasma hormone carrier protein associated with hereditary and senile forms of systemic amyloid disease, wherein slow tetramer disassembly is thought to be an obligatory step. Plasma transport of retinol is carried out exclusively by the retinol-binding protein (RBP), through complexation with transthyretin. Using mass spectrometry to examine the subunit exchange dynamics, we find that retinol stabilizes the quaternary structure of transthyretin, through its interactions with RBP, reducing the rate of transthyretin disassembly ~17-fold compared to apoTTR. In the absence of retinol but in the presence of RBP, transthyretin is only marginally stabilized with the rate of disassembly reduced ~two-fold with respect to apoTTR. Surprisingly, we found two retinoids that stabilize transthyretin directly, in the absence of RBP, whereas retinol itself requires RBP in order to stabilize transthyretin. Our results demonstrate new roles for RBP and retinoids as stabilizers of transthyretin. PMID- 20845946 TI - Growth patterns of dendrimers and electric potential oscillations during electropolymerization of pyrrole using mono- and mixed surfactants. AB - Fractal and dendrimer growth patterns of polypyrrole were obtained during electrochemical polymerization of pyrrole in systems (A) pyrrole-sodium dodecyl sulfate (NaDS)-water and (B) pyrrole-NaDS-cetyl trimethyl ammonium bromide (CTAB) water. Different morphological transitions including compact -> flower-like and fractal -> dendrimer -> fractal were observed depending on experimental conditions. Growth kinetics during electropolymerization of pyrrole was studied. Growth rate was found to be higher in system A than in B. Effect of [NaDS], [pyrrole], and field intensity on morphology and weight of polymer aggregates was also studied in both the systems. Different empirical equations were obeyed under different conditions. Electropolymerized aggregates were characterized by transmission electron microscopy (TEM), powder X-ray diffraction (XRD), electrical conductivity measurement, and reflectance spectroscopy. TEM studies revealed that the particle size decreased to ~140-200 nm in the presence of CTAB. The decrease in particle size on addition of CTAB was also observed in XRD studies. Reflectance spectra of the polymer aggregates support the large pi conjugation in the dendrimer. During electropolymerization, oscillations in potential were monitored as a function of time. Results indicated that growth pattern and electric potential oscillations were interrelated. In the case of fractal growth, the amplitude of chaotic oscillation was higher than the amplitude of oscillation during the growth of dendrimer. Growth morphologies and electric potential oscillations have been explained on the basis of modified Diaz's mechanism. PMID- 20845947 TI - Molecular relaxation processes in a MOF-5 structure revealed by broadband dielectric spectroscopy: signature of phenylene ring fluctuations. AB - The molecular mobility of a MOF-5 metal-organic framework was investigated by broadband dielectric spectroscopy. Three relaxation processes were revealed. The temperature dependence of their relaxation rates follows an Arrhenius law. The process observed at lower temperatures is attributed to bending fluctuations of the edges of the cages involving the Zn-O clusters. The processes ("region II") at higher temperatures were assigned to fluctuations of phenyl rings in agreement with the NMR data found by Gould et al. (J. Am. Chem. Soc. 2008, 130, 3246). The carboxylate groups might also be involved. The rotational fluctuations of the phenyl rings leading to the low frequency part of relaxation region II might be hindered either by some solvent molecules entrapped in the cages or by an interpenetrated structure and have a broad distribution of activation energies. The high frequency part of region II corresponds nearly to a Debye-like process: This is explained by a well-defined structure of empty pores. PMID- 20845948 TI - Solvent tunable optical properties of a polymerized vinyl- and thienyl substituted ionic liquid. AB - Thermal free radical polymerization of a self-assembled, bifunctional imidazolium based ionic liquid (IL) monomer bearing both vinyl and thienyl groups is reported. FT-IR spectroscopy proves that the polymerization occurs through both the vinyl and thienyl groups. The polymer is resistant to swelling in water and common organic solvents. The as-synthesized polymer can be readily chemically doped and de-doped. Small-angle X-ray scattering studies indicate that the dried polymer adopts a weakly ordered lamellar structure. The p-doped, ethanol-solvated polymer undergoes a structural conversion to a nonlamellar phase. The absorption and photoluminescence spectra can be modulated in both the neutral (thiophene) and p-doped states depending on whether the polymer is dry or ethanol-solvated. The results demonstrate the possibility of incorporating solvent responsive optical characteristics in a pi-conjugated polymer. PMID- 20845950 TI - Zero-field splitting of the lowest excited triplet states of C(60) and C(70) and benzene. AB - The electronic structure of the lowest excited triplet states of C(60) and C(70) are characterized by a magnetic interaction between the unpaired electrons for which the zero-field-splitting parameter D is negative for the former and positive for the latter molecule. The sign of D has so far been qualitatively understood, and its magnitude has been found to critically depend on the degree of delocalization of the singly occupied molecular orbitals. In this contribution, the effect of spin polarization to the zero-field-splitting parameters of the fullerenes is evaluated, the inclusion of which results in quantitative agreement between the experimental and calculated D values. The direct spin-spin contribution is found to be dominant for both molecules. For C(60), a significant contribution of 20% of the total zero-field splitting has been found to derive from spin polarization. The physical reason for the sign difference of D for C(60) and C(70) is traced back to the relative phases of the local p(z) orbitals of adjacent carbon atoms near the equatorial plane in both singly occupied molecular orbitals. These relative phases differ for C(60) and C(70), because C(70) has an additional set of ten carbon atoms in its equatorial plane as compared to C(60). Additionally, the triplet wave function of C(70) is found to contain significant multireference character. In order to evaluate the effect of spin polarization in multireference systems, the zero-field-splitting parameters of the lowest triplet state of benzene have been evaluated in an illustrative and insightful calculation as well. Though this prototypical molecule is much smaller than C(60) and C(70), the electronic structure of its lowest excited triplet state is also of multireference character. For benzene, 18% of the total zero-field splitting arises from spin polarization. PMID- 20845949 TI - Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators. AB - Understanding the biological self-assembly process of virus capsids is key to understanding the viral life cycle, as well as serving as a platform for the design of assembly-based antiviral drugs. Here we identify and characterize the phenylpropenamide family of small molecules, known to have antiviral activity in vivo, as assembly effectors of the hepatitis B virus (HBV) capsid. We have found two representative phenylpropenamides to be assembly accelerators, increasing the rate of assembly with only modest increases in the stability of the HBV capsids; these data provide a physical-chemical basis for their antiviral activity. Unlike previously described HBV assembly effectors, the phenylpropenamides do not misdirect assembly; rather, the accelerated reactions proceed on-path to produce morphologically normal capsids. However, capsid assembly in the presence of phenylpropenamides is characterized by kinetic trapping of assembly intermediates. These traps resolve under conditions close to physiological, but we found that trapped intermediates persist under conditions that favor phenylpropenamide binding and strong core protein-protein interactions. The phenylpropenamides serve as chemical probes of the HBV capsid assembly pathway by trapping on-path assembly intermediates, illustrating the governing influence of reaction kinetics on capsid assembly. PMID- 20845951 TI - Binding modes of flavones to human serum albumin: insights from experimental and computational studies. AB - Pharmaceutical interactions with human serum albumin (HSA) are of great interest, because HSA is a pharmacokinetic determinant and a good model for exploring the protein-ligand interactions. Due to their hydrophobic nature, naturally occurring flavones, which possess various pharmacological activities, bind to HSA in human plasma. Here, we have identified the binding modes of two representative flavones -baicalin (BLI) and its aglycon, baicalein (BLE)--to HSA using a combination of experimental and computational approaches. The association properties were measured by applying spectroscopic methods, and a higher affinity was found for BLE. As evidenced by displacement and chemical unfolding assays, both ligands bind at Sudlow site I. Furthermore, molecular docking was utilized to characterize the models of HSA-flavone complexes, and molecular dynamics (MD) simulations as well as free energy calculations were undertaken to examine the energy contributions and the roles of various amino acid residues of HSA in flavones binding; the mechanism whereby glycosylation affects the association was also discussed. The present work provides reasonable binding models for both flavones to HSA. PMID- 20845952 TI - Reduction and oxidation doping kinetics of an electropolymerized donor-acceptor low-bandgap conjugated copolymer. AB - The electrochemical synthesis of a new dithienylcyclopentadienone-derivative/3 methylthiopene copolymer was performed by cyclic voltammetry. The obtained material shows redox processes very close to those from the pristine DTCPD. A new redox process at -1.24 V, with a large anodic shift (0.51 V) related to the poly(3-methylthiophene) reduction, indicates the existence of a copolymer with a strong influence of the neighboring (n-doped) DTCPD comonomer. The new copolymer is electrochemically n-doped at more cathodic potentials than -750 mV and p-doped at more anodic potentials than 250 mV, with a bandgap of 1.0 eV. The cation's entrance in the film from the solution during n-doping and anion's entrance during p-doping for charge balance was checked by QCM. The reduction of the DTCPD part suffers a partial trapping of the negative charges that can be reoxidized only at high overpotentials (>1 V related to the reduction potentials). After polarization of the material at any potential inside the band gap, subsequent p- or n-doping reactions performed by potential steps start by nucleation-relaxation kinetic control, followed by anodic or cathodic, respectively, chronoamperometric maxima. At the maxima, both reactions were checked to occur under chemical kinetic control, allowing the determination of the reaction orders for p- and n doping processes. PMID- 20845953 TI - A p38alpha-selective chemosensor for use in unfractionated cell lysates. AB - Recent efforts have identified the p38alpha Ser/Thr kinase as a potential target for the treatment of inflammatory diseases as well as non-small cell lung carcinoma. Despite the significance of p38alpha, no direct activity probe compatible with cell lysate analysis exists. Instead, proxies for kinase activation, such as phosphospecific antibodies, which do not distinguish between p38 isoforms, are often used. Our laboratory has recently developed a sulfonamido oxine (Sox) fluorophore that undergoes a significant increase in fluorescence in response to phosphorylation at a proximal residue, allowing for real-time activity measurements. Herein we report the rational design of a p38alpha selective chemosensor using this approach. We have validated the selectivity of this sensor using specific inhibitors and immunodepletions and show that p38alpha activity can be monitored in crude lysates from a variety of cell lines, allowing for the potential use of this sensor in both clinical and basic science research applications. PMID- 20845954 TI - NNScore: a neural-network-based scoring function for the characterization of protein-ligand complexes. AB - As high-throughput biochemical screens are both expensive and labor intensive, researchers in academia and industry are turning increasingly to virtual screening methodologies. Virtual screening relies on scoring functions to quickly assess ligand potency. Although useful for in silico ligand identification, these scoring functions generally give many false positives and negatives; indeed, a properly trained human being can often assess ligand potency by visual inspection with greater accuracy. Given the success of the human mind at protein-ligand complex characterization, we present here a scoring function based on a neural network, a computational model that attempts to simulate, albeit inadequately, the microscopic organization of the brain. Computer-aided drug design depends on fast and accurate scoring functions to aid in the identification of small molecule ligands. The scoring function presented here, used either on its own or in conjunction with other more traditional functions, could prove useful in future drug-discovery efforts. PMID- 20845955 TI - Universal method to calculate the stability, electronegativity, and hardness of dianions. AB - The electronic stability of gas-phase dianions of arbitrary size, X(2-), is determined by the first universal method to calculate second electron affinities, A(2). The model expresses A(2,calc) = A(1) - (7/6)eta(0) by the first electron affinity, A(1), and chemical hardness, eta(0), of the neutral "grandparent" species. A comparison with 37 reference data of atoms, molecules, superatoms, and clusters yields A(2,ref) = 1.004A(2,calc) - 0.023 eV, with a mean unsigned deviation of MUD = 0.095 eV and a correlation coefficient of R = 0.9987. Predictions of second electron affinities are given for a further 24 species. The universality of the model is apparent from the broad variety of compounds formed by 30 diverse elements. The electronegativity and hardness of dianions are determined for the first time as chi(X(2-)) = A(2) and eta(X(2-)) = (7/12)eta(0), respectively. Pearson and Parr's operational assumption regarding the hardness of anionic bases for the hard-soft acid-base (HSAB) principle is rationalized, and predictions for hard and soft dianionic bases are presented. For trianions, first criteria and predictions for electronic stability are given and require A(1) > (7/4)eta(0). PMID- 20845956 TI - CHARMM additive all-atom force field for glycosidic linkages in carbohydrates involving furanoses. AB - Presented is an extension of the CHARMM additive carbohydrate all-atom force field to enable modeling of polysaccharides containing furanose sugars. The new force field parameters encompass 1 <-> 2, 1 -> 3, 1 -> 4, and 1 -> 6 pyranose furanose linkages and 2 -> 1 and 2 -> 6 furanose-furanose linkages, building on existing hexopyranose and furanose monosaccharide parameters. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF) as to contain the key atoms in full carbohydrates. Target data for optimization included two-dimensional quantum mechanical (QM) potential energy scans of the Phi/Psi glycosidic dihedral angles, with geometry optimization at the MP2/6-31G(d) level followed by MP2/cc-pVTZ single-point energies. All possible chiralities of the model compounds at the linkage carbons were considered, and for each geometry, the THF ring was constrained to the favorable south or north conformations. Target data also included QM vibrational frequencies and pair interaction energies and distances with water molecules. Force field validation included comparison of computed crystal properties, aqueous solution densities, and NMR J-coupling constants to experimental reference values. Simulations of infinite crystals showed good agreement with experimental values for intramolecular geometries as well as for crystal unit cell parameters. Additionally, aqueous solution densities and available NMR data were reproduced to a high degree of accuracy, thus validating the hierarchically optimized parameters in both crystalline and aqueous condensed phases. The newly developed parameters allow for the modeling of linear, branched, and cyclic pyranose/furanose polysaccharides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing additive CHARMM biomolecular force fields. PMID- 20845957 TI - Linear and two-dimensional infrared spectroscopic study of the amide I and II modes in fully extended peptide chains. AB - We have carried out structural determination of capped C(alpha,alpha) diethylglycine (Deg) homopeptides with different chain lengths, Ac-(Deg)(n)-OtBu (n = 2-5), solvated in CDCl(3), and investigated vibrational properties of the amide I and II modes by linear and 2D IR spectroscopy, ONIOM calculations, and molecular dynamics simulations. 2D IR experiments were performed in the amide I region using the rephasing pulse sequence under the double-crossed polarization and the nonrephasing sequence under a new polarization configuration to measure cross-peak patterns in the off-diagonal regions. The 2D IR spectra measured in the amide I and II regions reveal complex couplings between these modes. Model spectral calculations finely reproduced the measured spectral profiles by using vibrational parameters that were very close to the values predicted by the ONIOM method. The agreement led to a conclusion that peptide backbones are fully extended with the dihedral angles (phi,psi) ~ (+/-180 degrees ,+/-180 degrees ) and that a sequence of intramolecular C(5) hydrogen bonds forms along the entire chain regardless of the chain length. This conclusion was endorsed by analysis of the molecular dynamics trajectories for n = 3 and 5 that showed an exclusive population of the C(5) conformation. The conformationally well-restrained Deg homopeptides serve as an ideal linear exciton chain, which is scarcely obtainable by protein amino acids. We investigated excitonic properties of the linear chain through analytic modeling and compared the measurement and calculation results of the amide I and II modes. The integrated intensity of the amide II band is larger than that of the amide I for the C(5) structure, untypical behavior in contrast with other secondary structures. This comprehensive study characterized the amide I and II spectral signatures of the fully extended conformation, which will facilitate the conformational analysis of artificial oligopeptides that contain such structural motifs. PMID- 20845958 TI - Enantioselective hydroformylation of N-vinyl carboxamides, allyl carbamates, and allyl ethers using chiral diazaphospholane ligands. AB - Rhodium complexes of diazaphospholane ligands catalyze the asymmetric hydroformylation of N-vinyl carboxamides, allyl ethers, and allyl carbamates; products include 1,2- and 1,3-aminoaldehydes and 1,3-alkoxyaldehydes. Using glass pressure bottles, short reaction times (generally less than 6 h), and low catalyst loading (commonly 0.5 mol %), 20 substrates are successfully converted to chiral aldehydes with useful regioselectivity and high enantioselectivity (up to 99% ee). Chiral Roche aldehyde is obtained with 97% ee from the hydroformylation of allyl silyl ethers. Commonly difficult substrates such as 1,1 and 1,2-disubstituted alkenes undergo effective hydroformylation with 89-97% ee and complete conversion for six examples. Palladium-catalyzed aerobic oxidative amination of allyl benzyl ether followed by enantioselective hydroformylation yields the beta(3)-aminoaldehyde with 74% ee. PMID- 20845960 TI - Unraveling the hydroxypropionaldehyde (HPA) system: an active antimicrobial agent against human pathogens. AB - The hydroxypropionaldehyde (HPA) system is a natural defense system synthesized by the probiotic bacterium Lactobacillus reuteri. To elucidate which of the molecules composing the HPA system (3-hydroxypropionaldehyde (3-HPA), reuterin (HPA dimer), and HPA hydrate) is responsible for the potent antimicrobial activity in biological systems, a combination of biochemical, genetic, and proteomic assays was used. The HPA system reacts with sulfhydryl-containing compounds such as cysteine and reduced glutathione (GSH) in solution. In situ, GSH knock-out Escherichia coli is significantly more susceptible to HPA-mediated cell death than E. coli wild type; GSH supplementation protects either bacteria from HPA attack. Proteomic analysis of HPA-treated bacteria ( Haemophilus influenzae ) revealed induction of redox- and heat shock-related proteins. A new antimicrobial mechanism of HPA is proposed, whereby the activity of HPA leads to depletion of free SH- groups in GSH and proteins through the action of 3 hydroxypropionaldehyde, causing an imbalance of the cellular redox status, ultimately resulting in cell death. PMID- 20845959 TI - Synthesis and biological evaluation of bivalent ligands for the cannabinoid 1 receptor. AB - Dimerization or oligomerization of many G-protein-coupled receptors (GPCRs), including the cannabinoid 1 (CB1) receptor, is now widely accepted and may have significant implications for medications development targeting these receptor complexes. A library of bivalent ligands composed of two identical CB1 antagonist pharmacophores derived from SR141716 linked by spacers of various lengths were developed. The affinities of these bivalent ligands at CB1 and CB2 receptors were determined using radiolabeled binding assays. Their functional activities were measured using GTP-gamma-S accumulation and intracellular calcium mobilization assays. The results suggest that the nature of the linker and its length are crucial factors for optimum interactions of these ligands at CB1 receptor binding sites. Finally, selected bivalent ligands (5d and 7b) were able to attenuate the antinociceptive effects of the cannabinoid agonist CP55,940 (21) in a rodent tail flick assay. These novel compounds may serve as probes that will enable further characterization of CB1 receptor dimerization and oligomerization and its functional significance and may prove useful in the development of new therapeutic approaches to G-protein-coupled receptor mediated disorders. PMID- 20845961 TI - Synthesis and antitumor effect in vitro and in vivo of substituted 1,3 dihydroindole-2-ones. AB - Optimization of the anticancer activity for a class of compounds built on a 1,3 dihydroindole-2-one scaffold was performed. In comparison with recently published derivatives of oxyphenisatin the new analogues exhibited an equally potent antiproliferative activity in vitro and improved tolerability and activity in vivo. The best compounds from this series showed low nanomolar antiproliferative activity toward a series of cancer cell lines (compound (S)-38: IC(50) of 0.48 and 2 nM in MCF-7 (breast) and PC3 (prostate), respectively) and potent antitumor effects in well tolerated doses in xenograft models. The racemic compound (RS)-38 showed complete tumor regression at a dose of 20 mg/kg administered iv on days 1 and 7 in a PC3 rat xenograft. PMID- 20845962 TI - Azole drugs trap cytochrome P450 EryK in alternative conformational states. AB - EryK is a bacterial cytochrome P450 that catalyzes the last hydroxylation occurring during the biosynthetic pathway of erythromycin A in Streptomyces erythraeus. We report the crystal structures of EryK in complex with two widely used azole inhibitors: ketoconazole and clotrimazole. Both of these ligands use their imidazole moiety to coordinate the heme iron of P450s. Nevertheless, because of the different chemical and structural properties of their N1 substituent group, ketoconazole and clotrimazole trap EryK, respectively, in a closed and in an open conformation that resemble the two structures previously described for the ligand-free EryK. Indeed, ligands induce a distortion of the internal helix I that affects the accessibility of the binding pocket by regulating the kink of the external helix G via a network of interactions that involves helix F. The data presented thus constitute an example of how a cytochrome P450 may be selectively trapped in different conformational states by inhibitors. PMID- 20845964 TI - Molecular origin of fast water transport in carbon nanotube membranes: superlubricity versus curvature dependent friction. AB - In this paper, we study the interfacial friction of water at graphitic interfaces with various topologies, water between planar graphene sheets, inside and outside carbon nanotubes, with the goal to disentangle confinement and curvature effects on friction. We show that the friction coefficient exhibits a strong curvature dependence; while friction is independent of confinement for the graphene slab, it decreases with carbon nanotube radius for water inside, but increases for water outside. As a paradigm the friction coefficient is found to vanish below a threshold diameter for armchair nanotubes. Using a statistical description of the interfacial friction, we highlight here a structural origin of this curvature dependence, mainly associated with a curvature-induced incommensurability between the water and carbon structures. These results support the recent experiments reporting fast transport of water in nanometric carbon nanotube membranes. PMID- 20845963 TI - Total synthesis of the Aspidosperma alkaloid (+/-)-subincanadine F via a titanium mediated intramolecular nucleophilic acyl substitution strategy. AB - The total synthesis of the bridge-fused Aspidosperma indole alkaloid (+/-) subincanadine F has been accomplished in seven steps. The synthetic utility of a titanium-mediated intramolecular nucleophilic acyl substitution (INAS) reaction for the construction of the bridge-fused ring system was demonstrated. PMID- 20845965 TI - Spectroscopic characterization of neutral and cation radicals of alpha-tocopherol and related molecules: a satisfactory denouement. AB - Notwithstanding the facile occurrence of one-electron oxidation in alpha tocopherol and its acetate (TOH and TOAc, respectively), and despite the remarkable stability, under appropriate conditions, of the oxidation products (TOH(*+), TO(*), and TOAc(*+)), their spectroscopic characterization is in an unsatisfactory state, calling for a fresh attempt to acquire reliable data. A new, model-free method is developed for analyzing time-resolved spectra showing the progress of the reaction TOH + R(*) -> TO(*) + RH, where R(*) is a stable free radical. The resulting absorption coefficients of TO(*) in dichloromethane and hexane are in severe disagreement with some recent values derived from stopped-flow spectrophotometry. The discrepancy is traced to the imposition of boundary conditions that do not take proper account of the dead time of the apparatus; when multiplied by a factor of two, the stopped-flow data fall mostly in the range epsilon = (7.5 +/- 0.5) * 10(3) M(-1) cm(-1), conforming with the results of this study and the values found by Boguth and Niemann in 1969. Absorption spectra of the radical cations produced (electro)chemically are found to be reliable only in the visible region. Incomplete conversion of the parent compound to the radical cation, an obstacle to the determination of absorption coefficients from electrochemical studies, is circumvented by combining EPR and optical spectroscopy. The absorption coefficients of TOH(*+) and TOAc(*+), determined in this manner, are found to be, respectively, 1.6 * 10(4) and 1.3 * 10(4) M(-1) cm(-1), in accord with the values found first through similar means. PMID- 20845966 TI - Zinc-mediated asymmetric additions of dialkylphosphine oxides to alpha,beta unsaturated ketones and N-sulfinylimines. AB - A catalyst was synthesized on the basis of Trost's dinuclear catalyst characterized by working well without pyridine in the present phospha-Michael reaction. Nevertheless, the presence of pyridine is still advantageous in the present system. The substrate scope was successfully extended to enones employing diallyl phosphine oxide as a nucleophile. Excellent yields and enantioselectivities (up to >99% ee) were achieved for a wide scope of enones employing the catalyst under mild conditions. The detailed reaction mechanism is also discussed herein. Finally, the unprecedented asymmetric additions of dialkylphosphine oxides to N-sulfinylimines were achieved by using Et(2)Zn as a base. PMID- 20845967 TI - Mn(0)-mediated chemoselective reduction of aldehydes. Application to the synthesis of alpha-deuterioalcohols. AB - A mild, simple, safe, chemoselective reduction of different kinds of aldehydes to the corresponding alcohols mediated by the Mn dust/water system is described. In addition to this, the use of D(2)O leads to the synthesis of alpha-deuterated alcohols and constitutes an efficient, inexpensive alternative for the preparation of these compounds. PMID- 20845968 TI - Enhanced pair hydrophobicity in the water-dimethylsulfoxide (DMSO) binary mixture at low DMSO concentrations. AB - We observe a surprisingly sharp increase in the pair hydrophobicity in the water dimethylsulfoxide (DMSO) binary mixture at small DMSO concentrations, with the mole fraction of DMSO (x(D)) in the range 0.12-0.16. The increase in pair hydrophobicity is measured by an increase in the depth of the first minimum in the potential of mean force (PMF) between two methane molecules. However, this enhanced hydrophobicity again weakens at higher DMSO concentrations. We find markedly unusual behavior of the pure binary mixture (in the same composition range) in the diffusion coefficient of DMSO and in the local composition fluctuation of water. We find that, in the said composition range, the average coordination number of the methyl groups (of distinct DMSO) varies between 2.4 and 2.6, indicating the onset of the formation of a chain-like extended connectivity in an otherwise stable tetrahedral network comprising of water and DMSO molecules. We propose that the enhanced pair hydrophobicity of the binary mixture at low DMSO concentrations is due to the participation of the two methane molecules in the local structural order and the emerging molecular associations in the water-DMSO mixture. PMID- 20845969 TI - Investigation of H2 and H2S adsorption on niobium- and copper-doped palladium surfaces. AB - Alloying or doping Pd may be an option for overcoming sulfur poisoning. The current investigation probes the mechanism associated with sulfur binding to determine if Nb and Cu are appropriate doping metals. In this study, the effect of doping Pd with Cu or Nb on the binding strength of H(2) and H(2)S was investigated using plane-wave density functional theory-based electronic structure calculations to determine mechanisms of adsorption. Results of this work indicate that for pure Pd and Pd-doped surfaces, H(2) dissociates with the H atoms most stable on the fcc-fcc site. The overall d-band centers calculated for H(2) adsorption at the fcc-fcc site for the pure and doped-Pd surfaces indicate that the H(2) adsorption strength trend is Pd > Cu > Nb. Regarding H(2)S adsorption on Pd and Pd-doped surfaces, it was found that Cu has a lower affinity for H(2)S compared to Pd and Nb. The calculation of the local density of states of the s-, p-, and d-orbitals of the adsorbate-surface complex reveals an increase in the occupation of s-and p-states of the adsorbate and d-states of the dopant metals upon adsorption. In addition, the H(2)S binding trend is found to be Cu < Pd < Nb, with the doped-Cu surfaces exhibiting the weakest binding and doped-Nb surfaces the strongest binding. Geometry comparisons of each H(2)S adsorbed complex shows that the hydrogen atoms are located closest to the surface in the case of Nb, indicating that the strong H-surface interaction leads to the enhanced adsorption behavior, rather than the S-surface interaction; in fact, the sulfur atom is located furthest from the surface doped with Nb. PMID- 20845970 TI - Profiles of liquid drops at the tips of cylindrical fibers. AB - In 1976, B. J. Carroll derived the equation to show that a symmetric liquid droplet sitting on a thin cylindrical fiber would acquire a bell shape at equilibrium. We have extended his derivation to describe a drop located at the top end of a vertical, cylindrical fiber. By minimizing the Gibbs free energy of the drop at the fiber tip, it was found that the drop consists of two portions, a spherical cap on the fiber tip and a full, symmetrical bell located on the fiber body adjacent to the fiber tip. The experimental verification of the predicted shapes was performed using water, ethylene glycol, and Kaydol drops on nylon cylindrical fibers. Only four parameters are required to obtain agreement between the theoretical shape and the observed shape: the drop volume, the fiber radius, the surface tension of the liquid, and the Young contact angle of the liquid on a flat surface of the same composition as the fiber. PMID- 20845971 TI - Activity landscape representations for structure-activity relationship analysis. PMID- 20845972 TI - Reversible O-O bond cleavage and formation between Mn(IV)-peroxo and Mn(V)-oxo corroles. AB - Mn(IV)-peroxo and Mn(V)-oxo corroles were synthesized and characterized with various spectroscopic techniques. The intermediates were directly used in O-O bond cleavage and formation reactions. Upon addition of proton to the Mn(IV) peroxo corrole, the formation of the Mn(V)-oxo corrole was observed. Interestingly, addition of base to the Mn(V)-oxo corrole afforded the formation of the Mn(IV)-peroxo corrole. Thus, we were able to report the first example of reversible O-O bond cleavage and formation reactions using in situ generated Mn(IV)-peroxo and Mn(V)-oxo corroles. PMID- 20845973 TI - Supramolecular cross-linked networks via host-guest complexation with cucurbit[8]uril. AB - The ability to finely tune the solution viscosity of an aqueous system is critical in many applications ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative medicine, controlled drug delivery, and 'green' self-healing materials. Herein we demonstrate the use of the macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers with high binding constants (K(a) > 10(11)-10(12) M(-2)) leading to a supramolecular hydrogel. Multivalent copolymers were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous, colored supramolecular hydrogel with the cross link density being easily controlled through CB[8] addition. Moreover, the cross links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli. Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second guest dissociation rate constant (k(d)) of 1200 s(-1) for the ternary complex. These materials exhibited intermediate mechanical properties at 5 wt % in water (plateau modulus = 350-600 Pa and zero shear viscosity = 5-55 Pa.s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution viscosity. PMID- 20845974 TI - Role of isoleucine-554 in lithium binding by the Na+/dicarboxylate cotransporter NaDC1. AB - Sodium-coupled transport of citric acid cycle intermediates, such as succinate and citrate, is mediated by the NaDC1 transporter located on the apical membrane of kidney proximal tubule and small intestine cells. Our previous study showed that transmembrane helix (TM) 11 of NaDC1 is important for sodium and lithium binding, as well as for determining citrate affinity [Kahn and Pajor (1999) Biochemistry 38, 6151]. In the present study, 21 amino acids in TM11 and the extracellular loop of NaDC1 were mutated one at a time to cysteine. All of the mutants were well expressed on the plasma membrane, but many of them had decreased transport activity. The G550C, W561C, and L568C mutants were inactive, suggesting that these residues may be critical for function. None of the cysteine mutants was sensitive to inhibition by the membrane-impermeant cysteine reagents, MTSET or MTSES, suggesting that the helix is inaccessible to the extracellular solvent. Although NaDC1 is inhibited by low concentrations of lithium in the presence of sodium, the I554C mutant was stimulated by lithium with a K(0.5) of 4.8 mM. The I554C mutant also had decreased affinity for sodium. We conclude that TM11 is likely to be an outer helix in NaDC1 that contains several residues critical for transport. Ile-554 in the middle of the helix may be an important determinant of cation affinity and selectivity, in particular the high affinity cation binding site that recognizes lithium. PMID- 20845975 TI - Morphological transformations and fusion of PbSe nanocrystals studied using atomistic simulations. AB - Molecular dynamics simulations are performed on capped and uncapped PbSe nanocrystals, employing newly developed classical interaction potentials. Here, we show that two uncapped nanocrystals fuse efficiently via direct surface attachment, even if they are initially misaligned. In sharp contrast to the general belief, interparticle dipole interactions do not play a significant role in this "oriented attachment" process. Furthermore, it is shown that presumably polar, capped PbSe{111} facets are never fully Pb- or Se-terminated. PMID- 20845976 TI - Simple fluidic system for purifying and concentrating diagnostic biomarkers using stimuli-responsive antibody conjugates and membranes. AB - We report a simple fluidic system that can purify and concentrate diagnostic biomarkers through the capture and triggered release of stimuli-responsive polymer-antibody conjugates at porous membranes that are grafted with the same stimuli-responsive polymer. This technique is applied here to the capture and detection of a model streptavidin antigen and subsequently to clinical ranges of the malaria antigen Plasmodium falciparum histidine-rich protein 2 (PfHRP2) from spiked human plasma. The carboxyl end-groups of semi-telechelic poly(N isopropylacrylamide) (pNIPAAm) synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization were modified with tetrafluorophenol to yield amine-reactive ester groups for conjugation to amine groups of anti streptavidin and anti-PfHRP2 antibodies. Stimuli-responsive membranes were constructed from 1.2 MUm pore-size, hydroxylated, nylon-6,6 filters (Loprodyne, from Pall Corporation). The surface hydroxyl groups on the filters were conjugated to a 2-ethylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid (EMP) RAFT chain transfer agent, and the surface-grafted pNIPAAm was obtained by subsequent polymerization. The number average molecular weight (Mn) and polydispersity indices (PDI) of the surface grafts were characterized, and membranes with either 4100 and 8400 dalton pNIPAAm grafts showed greater than 80% anti-streptavidin capture efficiency. The 8400 dalton-graft membrane showed the highest release efficiency, and it was demonstrated that at 0.2 nM starting concentration the streptavidin could be concentrated approximately 40-fold by releasing into a small 50 MUL volume. This concentrator system was applied to the capture and concentration of the PfHRP2 antigen, and results showed that the PfHRP2 antigen could be processed and detected at clinically relevant concentrations of this malaria biomarker. PMID- 20845977 TI - Conjugation of synthetic N-acetyl-lactosamine to azide-containing proteins using the Staudinger ligation. AB - Generation of defined glycoconjugates is necessary for the study of glycoprotein function, as well as the development of therapeutics. The biosynthesis of glycoproteins produces multiple glycoforms, proteins which differ only in the structure of the attached glycan. This inherent heterogeneity complicates the study of isolated glycans and, in particular, could obscure the role of individual glycan epitopes in biological function. We present a general strategy based on the Staudinger ligation to introduce specific glycan epitopes onto azide containing proteins. The use of a phosphane-based Staudinger reagent allows for extremely mild reaction conditions which can be applied to aqueous proteins or cells. We demonstrate that multiple carbohydrate epitopes can be incorporated onto a protein backbone, and that the resulting glycans are competent for recognition by lectins. We propose that this general strategy will allow for testing the role of specific glycan epitopes in cellular and biochemical assays and increasing the stability of protein conjugates. PMID- 20845978 TI - Re(bipy-tBu)(CO)3Cl-improved catalytic activity for reduction of carbon dioxide: IR-spectroelectrochemical and mechanistic studies. AB - Five Re(bipy)(CO)(3)Cl complexes were prepared and studied where bipy was 4,4' dicarboxyl-2,2'-bipyridine (1), 2,2'-bipyridine (2), 4,4'-dimethyl-2,2' bipyridine (3), 4,4'-di-tert-butyl-2,2'-bipyridine (4), and 4,4'-dimethoxy-2,2' bipyridine (5). From this group, a significantly improved catalyst, Re(bipy tBu)(CO)(3)Cl (4), for the reduction of carbon dioxide to carbon monoxide was found. The complex shows two one-electron reductions under argon, one reversible at -1445 mV (vs SCE), and one irreversible at -1830 mV. Under CO(2) the second irreversible wave displays a large catalytic enhancement in current. Diffusion coefficients were determined using the Levich-Koutecky method (1.1 * 10(-5) cm(2)/s for the neutral complex and 8.1 * 10(-6) cm(2)/s for the singly reduced species), and a second order rate constant for the electrochemical reduction with CO(2) of 1000 M(-1) s(-1) was measured. Bulk electrolysis studies were performed to measure Faradaic efficiencies for the primary gaseous products, eta(CO) = 99 +/- 2% in acetonitrile. PMID- 20845979 TI - One-pot etherification of purine nucleosides and pyrimidines. AB - A one-pot synthesis of ethers derived from inosine, guanosine, 2'-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle to 1H-benzotriazol-1 yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs(2)CO(3) produces a reactive intermediate, which is converted to the desired ether by subsequent addition of an appropriate alcohol or phenol and Cs(2)CO(3). Although rapid formation of HMPA from BOP can occur in the presence of an alcohol and base, as demonstrated by the reaction with methanol, under appropriate conditions these heteroaryl ethers can be efficiently synthesized. PMID- 20845980 TI - Verticilactam, a new macrolactam isolated from a microbial metabolite fraction library. AB - Systematic isolation of microbial metabolites has been performed to construct microbial metabolite libraries or fraction libraries. A novel macrolactam, verticilactam (1), was isolated from a library of Streptomyces spiroverticillatus JC-8444. The structure was determined on the basis of NMR and mass spectrometric measurements. 1 had a unique 16-membered macrolactam skeleton including a beta keto-amide moiety. PMID- 20845981 TI - Synthesis of a polymerizable fluorosurfactant for the construction of stable nanostructured proton-conducting membranes. AB - The synthesis of the polymerizable fluorinated surfactant sodium 1,1,2,2 tetrafluoro-2-(1,1,2,2-tetrafluoro-2-(4-vinylphenyl)ethoxy)ethanesulfonate (1) and a number of related fluorocarbon compounds is described. Compound 1 is synthesized using a copper-mediated cross-coupling reaction of 4 bromobenzaldehyde and sodium 5-iodooctafluoro-3-oxapentanesulfonate. The resulting benzaldehyde is converted to a styrene unit using a Wittig reaction with methyltriphenylphosphonium bromide in acetonitrile, using DBU as a base. This strategy for converting an iodo-functionalized fluorosurfactant to a styrene containing fluorosurfactant is highly efficient because both reactions are performed in polar solvents and are compatible with the sulfonate moiety. In addition, the copper-mediated cross-coupling reaction is most efficient with electron-poor aryl bromides like 4-bromobenzaldehyde. We wish to employ 1 for the construction of nanostructured membranes by polymerization of 1 in a microemulsion or in lyotropic liquid crystalline phases. PMID- 20845983 TI - Adsorption mechanism and uptake of methane in covalent organic frameworks: theory and experiment. AB - We determined the methane (CH(4)) uptake (at 298 K and 1 to 100 bar pressure) for a variety of covalent organic frameworks (COFs), including both two-dimensional (COF-1, COF-5, COF-6, COF-8, and COF-10) and three-dimensional (COF-102, COF-103, COF-105, and COF-108) systems. For all COFs, the CH(4) uptake was predicted from grand canonical Monte Carlo (GCMC) simulations based on force fields (FF) developed to fit accurate quantum mechanics (QM) [second order Moller-Plesset (MP2) perturbation theory using doubly polarized quadruple-zeta (QZVPP) basis sets]. This FF was validated by comparison with the equation of state for CH(4) and by comparison with the experimental uptake isotherms at 298 K (reported here for COF-5 and COF-8), which agrees well (within 2% for 1-100 bar) with the GCMC simulations. From our simulations we have been able to observe, for the first time, multilayer formation coexisting with a pore filling mechanism. The best COF in terms of total volume of CH(4) per unit volume COF absorbent is COF-1, which can store 195 v/v at 298 K and 30 bar, exceeding the U.S. Department of Energy target for CH(4) storage of 180 v/v at 298 K and 35 bar. The best COFs on a delivery amount basis (volume adsorbed from 5 to 100 bar) are COF-102 and COF-103 with values of 230 and 234 v(STP: 298 K, 1.01 bar)/v, respectively, making these promising materials for practical methane storage. PMID- 20845982 TI - MbtH-like proteins as integral components of bacterial nonribosomal peptide synthetases. AB - The biosynthesis of many natural products of clinical interest involves large, multidomain enzymes called nonribosomal peptide synthetases (NRPSs). In bacteria, many of the gene clusters coding for NRPSs also code for a member of the MbtH like protein superfamily, which are small proteins of unknown function. Using MbtH-like proteins from three separate NRPS systems, we show that these proteins copurify with the NRPSs and influence amino acid activation. As a consequence, MbtH-like proteins are integral components of NRPSs. PMID- 20845984 TI - Multifunctional homochiral lanthanide camphorates with mixed achiral terephthalate ligands. AB - Seven homochiral lanthanide camphorates with mixed achiral terephthalate ligands, namely, {Ln(2)(cam)(2)(bdc)(H(2)O)(2)}.DMF [Ln = Sm (1), Eu (2), Gd (3), Tb (4), Dy (5), Ho (6), Er (7); d-H(2)cam = d-(+)-camphoric acid; H(2)bdc = 1,4 benzenedicarboxylic acid; DMF = N,N'-dimethylformamide], have been solvothermally synthesized. Single-crystal X-ray diffraction analyses reveal that compounds 1-7 are isostructural and crystallize in orthorhombic, chiral space group P2(1)2(1)2(1). These structures feature three-dimensional open frameworks based on rodlike [Ln(2)(OCO)(6)(H(2)O)(2)](n) secondary building units, with the guest DMF molecules occupying the void space of the host {Ln(2)(cam)(3)(bdc)(H(2)O)(2)} framework. The photophysical and magnetic properties of some of these complexes have been investigated. Notably, the terbium compound 4 is highly emissive with a quantum yield of 63.68%. Additionally, thermogravimetric analyses, variable temperature IR spectroscopy, and powder X-ray diffraction of 2 as a representative were performed to determine its thermal stability, which indicates that the framework still remains intact until 300 degrees C. PMID- 20845985 TI - Identification of a new source of contamination of Quercus sp. oak wood by 2,4,6 trichloroanisole and its impact on the contamination of barrel-aged wines. AB - Thanks to practical experience in various wineries in recent years, it is now clear that, similarly to the well-known phenomenon in corks, there are several sources of unpredictable contamination of oak wood by 2,4,6-trichloroanisole (TCA). TCA affects staves in the same barrel very sporadically, with extremely limited contaminated areas on the surface that may reach several millimeters in depth. The precise origin of the TCP and TCA in oak wood is not known at this stage. Available data indicate that the phase where stavewood is naturally dried and seasoned is the source of these undesirable organochlorine contaminants. The strictly chemical formation of 2,4,6-trichlorophenol (TCP), derived from organochlorine biocides, was demonstrated to be impossible under traditional cooperage conditions, and its accumulation remained highly improbable. Similarly to previous discoveries in corks, all the analyses of oak wood suggested that the TCP was of biochemical origin. The capacity to biomethylate chlorophenols is well known and relatively widespread among the usual microflora in stavewood, but the precise origin of the intermediary leading to TCP formation is still unknown. One probable hypothesis is that this reaction involves chloroperoxidase (CPO). Several ideas have been proposed, but the microorganisms responsible for the formation of the TCA precursor in oak wood have not yet been identified. The extent of this problem is still severely underestimated by coopers and barrel users, due to the extremely unpredictable, localized contamination of the staves. PMID- 20845986 TI - To the nucleolar bodies (nucleoli) in cells of the lymphocytic lineage in patients suffering from B - chronic lymphocytic leukemia. AB - The present study was undertaken to provide more information on nucleoli in lymphocytes of B - chronic lymphocytic leukemia. The computer assisted nucleolar and cytoplasmic RNA image densitometry, reflecting the nucleolar and cytoplasmic RNA concentration at the single cell level, demonstrated a remarkable stability during the differentiation and maturation of B- lymphocytes. In contrast, as it was expected, the nucleolar diameter during the lymphocytic development markedly decreased. Thus the nucleolar RNA content of leukemic B-lymphocytes was apparently related to the nucleolar size. In both immature and mature lymphocytes, the cytostatic treatment increased the incidence of micronucleoli, which represent the "inactive" type of nucleoli. However, the decreased values of the nucleolar diameter were statistically significant only in mature lymphocytes of treated patients. On the other hand, despite such observation, it must be mentioned that "large active" and "ring shaped resting" nucleoli were still present in immature and mature lymphocytes after the cytostatic therapy and such cells might represent a potential pool of proliferating cells. As it is generally accepted "large active nucleoli" with multiple fibrillar centers are known to be characteristic for proliferating cells. "Ring shaped resting nucleoli" are present in sleeping cells, which may be stimulated to return to the cell cycle and to proliferate again. In addition, the nucleolar RNA distribution also indicated that Gumprecht ghosts mostly originated from mature lymphocytes. Increased ratio of the nucleolar to cytoplasmic RNA density in Gumprecht ghosts or apoptotic cells and apoptotic bodies of the lymphocytic origin was related to the decreased cytoplasmic RNA concentration. The increased nucleolar size together with the markedly decreased cytoplasmic RNA concentration characteristic for Gumprecht ghosts just reflected the spreading of lymphocytes during smear preparations. In apoptotic cells or bodies of the lymphocytic origin, the "frozen" nucleolar RNA concentration accompanied by a reduced RNA concentration in the cytoplasm exhibited a remarkable similarity to the apoptotic process induced in vitro by the cytostatic treatment. KEYWORDS: B-chronic lymphocytic leukemia; lymphocytes; nucleolar classes; size; nucleolar RNA image density concentration. PMID- 20845987 TI - +Antisense oligonucleotide targeting survivin inhibits growth by inducing apoptosis in human osteosarcoma cells MG-63. AB - Survivin may play an important role in the development of osteosarcoma. In this study, we chose osteosarcoma cell line MG-63, which highly expressed survivin, to observe the effects of antisense oligonucleotide targeting survivin on the apoptosis induction and proliferation inhibition. It was shown in our results that the apoptosis rate and the proliferation inhibition rate increased significantly in survivin-positive cells MG-63 by using MTT and flow cytometry methods. We found that the growth inhibition rate and apoptosis rate were changed in a dose-dependent way. When the concentration of antisurvivin oligonucleotide was 600 nM, the effects reached the peak. RT-PCR and western-blot methods were used to detect the mRNA and protein expression of survivin in MG-63. We observed that the mRNA and protein expression of survivin reduced after transfected with antisurvivin oligonucleotides at the concentration of 200 nM, 400 nM and 600 nM. At the same time, we found that the mRNA and protein expression of Fas were up regulated with the concentration of antisurvivin oligonucleotides from 200 nM to 600 nM. It was negative associated with the expression change of survivin. These data suggested that survivin should play an important role in the development of osteosarcoma and the survivin blockaded by using antisurvivin oligonucleotide could inhibit the proliferation and induce apoptosis of osteosarcoma by decreasing the expression of survivin and activate the Fas-mediated apoptosis. Down-regulation of survivin by antisense oligonucleotide might be an effective strategy to the treatment of osteosarcoma and might improve the therapeutic effect. KEYWORDS: osteosarcoma, Survivin, apoptosis, Fas. PMID- 20845988 TI - Better detection of Ig heavy chain and TCRgamma gene rearrangement in plasma cell free DNA from patients with non-Hodgkin Lymphoma. AB - Plasma cell-free DNA is the soluble DNA and tumor-derived DNA in plasma which has the same mutation as the tumor cellular DNA. This study aimed at comparing the properties of plasma cell-free DNA with the biopsy's DNA in order to evaluate the clinical significance of IgH and TCRgamma gene rearrangement in plasma cell-free DNA from patients with non-Hodgkin's Lymphoma. A total of 360 samples were studied. IgH (FR3A/VLJH) and TCRgamma (TVG/TJX) were amplified by PCR. Results of plasma cell-free DNA were compared with biopsy's DNA and mononuclear cellular DNA respectively. Plasma cell-free DNA were successfully extracted from 288 cases of newly diagnosed, refractory and relapsed NHL in total 360 patients (80%).But nothing was found in the other 72 remittent patients. The positive percentage of IgH rearrangement in patients with B-NHL was 81% in plasma cell-free DNA and 77% in biopsy's DNA (P>0.05). As to the ratio of TCRgamma rearrangement in patients with T-NHL, the former was 44%, and the latter was 39% (P>0.05). These results show tumor-derived DNA could be detected in tumor loaded plasma, even of underlying cancer patients. For NHL patients, detecting IgH and TCRgamma gene rearrangement of plasma cell-free DNA has the same clinical significance as biopsy's DNA. Moreover, it's more simple, convenient and non-invasive. KEYWORDS: Lymphoma non-Hodgkin, plasma, cell-free DNA, gene rearrangement, immunoglobulin, heavy-chain gene, T-cell receptor.gamma PMID- 20845989 TI - CYP and GST polymorphisms and survival in advanced non-small cell lung cancer patients. AB - Several polymorphisms in cytochrome P-450s (CYP)s and Glutathione S-transferases (GST)s have been reported to be associated with survival rates of patients with non-small cell lung cancer (NSCLC) but the studies in this regard are scarce and the results are contradictory. In this study, CYP1A1 (Ile462Val), CYP1B1(Asn453Ser), GST M1, GSTP1 exon 5 (Ile105Val) and exon 6(Ala114Val) and GSTT1 polymorphisms were determined in 138 patients with advanced NSCLC to evaluate their role in survival. Of the studied CYP and GST polymorphisms only GSTP1 exon 6 variant significantly altered (improved) the survival compared to wild type (p=0.036) with median survival of 22.2 months and 16.1 months, respectively. Multivariate analysis also revealed a significant reduction of adjusted hazard ratio of death associated only with the GSTP1 exon 6 variant genotype of 0.45 (95% confidence interval (95% CI), 0.23-0.89, p=0.022). These results show that the GSTP1 exon 6 variant genotype is associated with improved survival in the patients with advanced NSCLC. KEYWORDS: Cytochrome P-450, glutathione S-transferase, non small cell lung cancer, polymorphism, survival. PMID- 20845990 TI - Overexpression of AEG-1 in renal cell carcinoma and its correlation with tumor nuclear grade and progression. AB - The study was aimed at detecting the expression of a newly found oncogene, astrocyte elevated gene-1 (AEG-1), in renal cell carcinoma (RCC) and its correlation with histopathologic features and the survival of patients. Real-time reverse transcription-PCR and Western blot showed markedly higher expression of AEG-1 in 8 cases of RCC tissue compared with the paired normal tissue from the same patient. The expression level of AEG-1 was also increased in four RCC cell lines in contrast with normal tubular epithelial human kidney cells 2 (HK-2) at both mRNA and protein levels. Furthermore, immunohistochemistry analysis showed highly expressed AEG-1 in 96 of 102 (94.1%) cases of paraffin-embedded archival RCC tissue. Statistical analysis showed a significant correlation of AEG-1 expression with tumor grade (P <0.001), clinical staging (P = 0.003), T classification (P = 0.003) as well as metastasis classification (P=0.032). The means for survival time of low AEG-1 expression group was 76.98m
while high AEG-1expression group was 60.94m. Our results suggest that AEG-1 protein is overexpressed in RCC and plays an important role in tumor differentiation and progression.
High AEG-1 expression is closely associated with poor prognosis. KEYWORDS: Astrocyte elevated gene-1, AEG-1, renal cell carcinoma, prognosis. PMID- 20845991 TI - The impact of several phenotypic features at diagnosis on survival of patients with myelodysplastic syndromes. AB - Multiparametric flow cytometry is a useful co-criterion for diagnostic confirmation of MDS in patients with peripheral cytopenias and a normal karyotype. We examined the impact on patients' survival of several phenotypic aberrancies detected by a small 4-color panel of monoclonal antibodies (MoAbs). Diagnosis of the patients (54) was made by WHO criteria using peripheral blood counts, bone marrow (BM) morphology and karyotype. Flow cytometry was performed at diagnosis, and features obtained were compared to normal BM (24). We could detect 16 alterations: 4 in granulocytic precursors, 4 in monocytes, 6 in CD34+ cells, beside changes in plasmacytoid dendritic cells and basophil precursors. The total number of changes in RAEB was higher (median 8) than in cases with of abnormalities) were independent risk factors for a shorter survival. Our panel was sufficient to confirm the diagnosis of MDS and permitted to detect independent prognostic features. PMID- 20845992 TI - Optimizing of MALDI-ToF-based low-molecular-weight serum proteome pattern analysis in detection of breast cancer patients; the effect of albumin removal on classification performance. AB - Mass spectrometry-based analysis of the serum proteome allows identifying multi peptide patterns/signatures specific for blood of cancer patients, thus having high potential value for cancer diagnostics. However, because of problems with optimization and standardization of experimental and computational design, none of identified proteome patterns/signatures was approved for diagnostics in clinical practice as yet. Here we compared two methods of serum sample preparation for mass spectrometry-based proteome pattern analysis aimed to identify biomarkers that could be used in early detection of breast cancer patients. Blood samples were collected in a group of 92 patients diagnosed at early (I and II) stages of the disease before the start of therapy, and in a group of age-matched healthy controls (104 women). Serum specimens were purified and analyzed using MALDI-ToF spectrometry, either directly or after membrane filtration (50 kDa cut-off) to remove albumin and other large serum proteins. Mass spectra of the low-molecular-weight fraction (2-10 kDa) of the serum proteome were resolved using the Gaussian mixture decomposition, and identified spectral components were used to build classifiers that differentiated samples from breast cancer patients and healthy persons. Mass spectra of complete serum and membrane-filtered albumin-depleted samples have apparently different structure and peaks specific for both types of samples could be identified. The optimal classifier built for the complete serum specimens consisted of 8 spectral components, and had 81% specificity and 72% sensitivity, while that built for the membrane-filtered samples consisted of 4 components, and had 80% specificity and 81% sensitivity. We concluded that pre-processing of samples to remove albumin might be recommended before MALDI-ToF mass spectrometric analysis of the low molecular-weight components of human serum Keywords: albumin removal; breast cancer; clinical proteomics; mass spectrometry; pattern analysis; serum proteome. PMID- 20845993 TI - Prognostic role of Wnt7a expression in ovarian carcinoma patients. AB - Wnt7a is a secreted glycoprotein that regulates normal cellular proliferation and differentiation as well as tumorigenesis and progression. The aim of this study was to investigate the expression and prognostic significance of Wnt7a in ovarian carcinoma. Wnt7a expression was immunohistochemically examined in normal ovaries (n=15), benign tumors (n=50) and ovarian carcinomas (n=78). The correlation of Wnt7a expression with clinicopathological parameters and survival was evaluated. Wnt7a expression was higher in ovarian carcinomas compared to normal ovaries and benign tumors (p<0.001 and p=0.001, respectively). Wnt7a positive expression was significantly correlated with serous subtype (p<0.001), elder age (p=0.017), advanced stage (p<0.001), high grade (p=0.001), a high degree of ascitic fluid volume (p=0.015) and high CA125 expression (p=0.025). Wnt7a was found to be a significant prognostic factor in univariate and multivariate analysis. High Wnt7a expression in ovarian cancer may be associated with poor prognosis. PMID- 20845994 TI - Minimal residual disease detection using real-time quantitative PCR analysis of immunoglobulin and T-cell receptor gene rearrangements in the non-MRD-based ALL IC-BFM 2002 protocol for childhood ALL: Slovak experience. AB - Acute lymphoblastic leukemia is the most common form of cancer in children. The 10-year event-free survival ranged from 77 to 85% after having achieved complete remission rates of 93% or higher. The main cause of treatment failure is relapse arising from outgrowth of residual leukemic cells that are refractory to therapy. An intense effort has been made to develop methods to determine the degree of minimal residual leukemia cells present in patients considered to be in morphological remission. Because of the strong correlation between minimal residual disease (MRD) levels and risk of relapse, monitoring of MRD provides unique information regarding treatment response. The MRD monitoring based on real time quantitative PCR detection of patient-specific immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements is currently considered to be the most reliable tool for MRD-based diagnosis in ALL. Because the significance of MRD monitoring has been strongly supported by several studies and because it has been implemented in the latest protocols, there has been a significant effort to develop MRD monitoring in the Slovak Republic since 2005. Between October 2006 and December 2009, 50 children with ALL who were treated at three Slovak centers were included in the RQ PCR MRD pilot project. A total of 40 patients with BCP ALL ( B cell precursor ALL) and 4 patients with T ALL were analyzed for Ig/TCR rearrangement. We identified 106 different rearrangements in the 44 ALL patients analyzed. Based on MRD stratification, we identified 26 patients who were stratified into the HRG ( high risk group) (n = 3; 11.5%), IRG ( intermediate risk group) (n = 14; 54%) and SRG ) standard risk group) (n = 9; 34.5%). Morphology-based risk stratification allows the identification of most HRG patients identified also by MRD-based stratification, but fails to discriminate the IRG assigned to therapy reduction. Patients in the SRG and the IRG could profit from MRD-based risk assignment PMID- 20845995 TI - Heparanase participates in the growth and invasion of human U-2OS osteosarcoma cells and its close relationship with hypoxia-inducible factor-1alpha in osteosarcoma. AB - Although the expression of heparanase is associated with invasion and metastasis of various human cancers, the effects of heparanase on human osteosarcoma have not been evaluated. We showed that down-regulating the expression of heparanase significantly reduced proliferation and invasion of human U-2OS osteosarcoma cells. Furthermore, heparanase silencing by short-hairpin RNA (shRNA) was associated with decreased hypoxia-inducible factor-1alpha (HIF-1alpha) level, implying that heparanase was associated with the expression of HIF-1alpha. This result was confirmed by immunohistochemistry analysis. In osteosarcoma tissues, immunohistochemical results revealed that heparanase expression had a close correlation with that of HIF-1alpha and they had a strong relation with presence of pulmonary metastasis (P<0.05).Heparanase-positive samples had higher microvessel density (MVD) than heparanase-negative samples. Similarly, compared with HIF-1alpha-negative samples, HIF-1alpha-positive samples had higher MVD. Therefore, heparanase and HIF-1alpha facilitated tumor angiogenesis and promoted pulmonary metastasis of osteosarcoma. PMID- 20845996 TI - Survivin: a promising biomarker in breast carcinoma. AB - The antiapoptotic protein survivin can be detected in most types of malignant tumors, but it is rarely expressed in corresponding normal adult tissues. Therefore, survivin appears to represent a promising diagnostic biomarker. We examined survivin expression in 13 cases of normal breast tissue, 38 cases of fibroadenomas and 80 cases of breast carcinomas by immunohistochemical staining using anti-survivin antibody (DAKO, Clone 12C4). In each section, the intensity of staining, percentage of labeled cells, and the subcellular location of survivin antigen were assessed. Survivin was detected in 4/13 cases of normal breast tissue (30.7%), in 28/38 cases of fibroadenomas (73.7%), and in 67/80 cases of carcinomas (83.8%). Normal breast tissue showed cytoplasmic positivity only. In fibroadenomas, 19 cases (50.0%) revealed cytoplasmic reaction, and in 9 cases (23.7%), small foci of cells with combined nuclear and cytoplasmic location were identified. In carcinomas, cytoplasmic staining was found in 12/80 cases (15.0%), nuclear staining in 10/80 cases (12.5%), and combined cytoplasmic and nuclear staining in 45/80 cases (56.3%). Subcellular location of survivin between benign and malignant lesions revealed significant differences (p<0,001). Our findings point at practical use of survivin detection. We confirm the importance of nuclear staining of survivin antigen in breast carcinoma, which seems to be a notable diagnostic marker for estimation of the degree of neoplasia. PMID- 20845997 TI - Prognostic factors and treatment outcome in 1,516 adult patients with de novo and secondary acute myeloid leukemia in 1999-2009 in 5 hematology intensive care centers in the Czech Republic. AB - Acute myeloid leukemia (AML) is a severe condition with a high mortality. When making decisions about the optimal tailor-made therapy, numerous prognostic factors are considered. The study represents a detailed analysis of the role of these factors and treatment outcomes based on a long-term follow-up of patients treated in 5 hematology intensive care centers in the Czech Republic.The studied group comprised 1,188 patients with de novo AML and 328 patients with secondary AML. The latter were significantly older, had more unfavorable cytogenetic changes and less frequently received curative therapy. Curatively treated patients achieved fewer complete remissions and relapsed more often than those with de novo AML. Patients with secondary AML had lower rates of allogeneic transplantation as part of consolidation therapy and a significantly shorter median overall survival. A lower proportion of the patients were alive at the time of analysis. However, the treatment outcome of de novo AML patients is not satisfactory, the only exception being those with acute promyelocytic leukemia. The analysis, which did not evaluate the intention-to-treat criteria and was without randomization, found allogeneic stem cell transplantation to be the most effective modality of consolidation therapy in both groups of patients. . PMID- 20845998 TI - Endoglin and CD-34 immunoreactivity in the assessment of microvessel density in normal pituitary and adenoma subtypes. AB - Vascularization is a prerequisite of tumor growth, invasion and metastasis. In the present work, microvessel density was assessed by quantitating using two different endothelial cell biomarkers, endoglin (CD-105) and CD-34. Fifty endocrinologically active and 36 clinically nonfunctioning pituitary adenomas, all surgically resected, as well as 10 autopsy-derived normal adenohypophyses were investigated by immunohistochemistry. The results showed that in every pituitary adenoma type endoglin, an assumed biomarker of proliferating endothelial cells, immunostained fewer vessels than CD-34 which revealed immunopositivity in all capillaries. Differences in endoglin versus CD-34 immunoexpression indicate varying degrees of vascularity in pituitary adenoma subtypes. The low levels of endoglin immunoexpression in pituitary tumors exposed to long-acting somatostatin analogs and dopamine agonists are consistent with the view that these agents inhibit angiogenesis. KEYWORDS: immunohistochemistry, endoglin, CD34, microvascular density, angiogenesis, pituitary. PMID- 20845999 TI - Prevalence of high-risk human papillomavirus types (HPV-16, HPV-18) and their physical status in primary laryngeal squamous cell carcinoma. AB - Recently oncogenetic human papilloma virus(HPV) infection has been suggested to promote laryngeal squamous cell carcinoma(LSCC). To determine the prevalence and genotypes of HPV infection in laryngeal cancer specimens, 84 specimens from pathologically confirmed LSCC patients were studied for the presence of viral DNA and possible virus integration into the cellular genome. HPV genotyping was assayed prior to the integration analysis by using two PCR-based assays, including HPV-16 and-18 E7 type-specific and L1 general primers (GP5+/GP6+). Additionally, a quantitative real-time PCR (qRT-PCR) was used to examine the physical status of HPV-16 or-18 in HPV positive LSCC. Using HPV L1 general primer amplification, HPV DNA was detected in 23 (27.4%) of the 84 LSCC samples. When PCR products were cloned and sequenced, HPV16 were found in all 23 L1 positive samples. However, when specific primers for HPV- 16 or -18 were used to amplify E6 and E7 in all samples, 29 cases (34.5%) were positive for HPV-16, while 6 cases (7.1%) were positive for HPV 18. Coinfection of HPV-16 and -18 were found in 4 cases (4.8%). In addition, qRT-PCR assay found that HPV-16 was characterized as episomal in 51.7% of cases, mixed (i.e., episomal and integrated) in 34.5%, and integrated in 13.8%, while HPV-18 was similarly characterized as episomal in 83.3% of cases and mixed in 16.7%. In the present study, about 36.9% of patients with LSCC were found to be infected with HPV-16 and -18 and integration of HPV-16 and -18 DNA into the host genome was found. PMID- 20846001 TI - Correlation between PXR and ABCG2 patterns of mRNA expression in a MCF7 breast carcinoma cell derivative upon induction by proinflammatory cytokines. AB - In this study, we aimed to evaluate the relationship between PXR and ABCG2 gene expression patterns induced by proinflammatory cytokines in MCF7 and MCF7/MX breast carcinoma cell lines. The effects of proinflammatory cytokines on ABCG2 and PXR mRNA expression were studied using the real-time polymerase chain reaction method. Significant inductions in the ABCG2 and PXR mRNA levels were observed in MCF7 cells, upon treatment with interleukin-1beta and tumor necrosis factor-alpha, whereas MCF7/MX cells did not significantly respond to the treatment. The results also show that in comparison to MCF7 cell line the basal mRNA expression level of PXR was higher in the MCF7/MX cell line. In conclusion, interleukin-1beta and tumor necrosis factor-alpha induced ABCG2 and PXR mRNAs in the MCF7 breast cancer cell line; no significant changes on expression of the same genes in MCF7/MX cells were observed. This differential effect of the cytokines on two different cell lines seems to be influenced by basal levels of the mRNAs, which are very high in MCF7/MX cells. Similar patterns of induction in PXR and ABCG2 genes suggest a probable relationship between these two factors. PMID- 20846000 TI - Akt inhibitors in clinical development for the treatment of cancer. AB - IMPORTANCE OF THE FIELD: The evolution of targeted therapies is dependent upon identification of cellular moieties that can be pharmacologically modulated. As one such example, the serine-threonine kinase Akt was identified nearly two decades ago. Since then, its role in mediating multiple signaling cascades (ultimately leading to cell growth and proliferation) has since been identified. More recently, several agents have been developed that antagonize Akt--these agents are in various stages of clinical testing. AREAS COVERED IN THIS REVIEW: Herein, we outline development of several promising Akt inhibitors, including perifosine, MK-2206, RX-0201, PBI-05204, GSK2141795 and others. WHAT THE READER WILL GAIN: The reader will gain insight into the current pipeline of Akt inhibitors, and the degree to which these agents have been examined both clinically and preclinically. TAKE HOME MESSAGE: With an emerging pipeline of agents targeting Akt, it will be critical to decipher which amongst them holds the greatest promise. Herein, we explore this drug pipeline and provide strategies for determining the future clinical application of these agents. PMID- 20846002 TI - Study on DNA-binding and DNA-cleavage properties of Cr(III) complexes with polypyridyl ligands. AB - Two new water-soluble Cr(III) complexes [Cr(IP)(2)Cl(2)](+) and [Cr(PIP)(2)Cl(2)](+) (IP = imidazo[4,5-f][1,10]phenanthroline, PIP = 2 phenylimidazo[4,5-f][1,10]phenanthroline) were synthesized and characterized by elemental analysis, mass spectra, and ultraviolet-visible spectra. The DNA binding properties of the two complexes were investigated by spectroscopic methods and viscosity measurements. The results indicate that both complexes bind to DNA via an intercalative mode with moderate strength. The fluorescence intensity of both complexes decreases with increasing DNA concentration, similar to those of [Cr(phen)(3)](3+) and [Cr(bpy)(3)](3+). Also, both complexes can cleave pBR-322 DNA in the presence of H(2)O(2), and [Cr(PIP)(2)Cl(2)](+) exhibits more effective activity than [Cr(IP)(2)Cl(2)](+) under the same condition. PMID- 20846003 TI - Laparoendoscopic single-site nephrectomy: initial clinical experience in children. AB - OBJECTIVE: To present the initial clinical experience in children undergoing unilateral and bilateral laparoendoscopic single-site nephrectomy. PATIENTS AND METHODS: We reviewed our experience with pediatric patients who had undergone single-port nephrectomy (SPN) at our institution since August of 2009. Access was obtained by using the Hassan technique to place a 2-cm SILSTM Port (Covidien Surgical Devices, Norwalk, CT), which contains a gas insufflation channel and three individual cannulas that can readily accommodate laparoscopic instruments up to 12 mm in diameter. Nephrectomy was performed using a standard set of laparoscopic instruments and a rigid 5 mm 30 degree laparoscope (Karl Storz, Tuttlingen, Germany) with an end-on light source. Patient demographics, operative details, and postoperative treatment parameters were collected and recorded. RESULTS: SPN was successfully performed in three consecutive pediatric patients (one female and two male patients: aged 11, 10, and 13 years, respectively) without placement of additional trocars or conversion to open surgery. The operative time for the unilateral SPN was 188 minutes, whereas bilateral SPNs required 214 and 300 minutes, respectively. Estimated blood loss for the unilateral and bilateral SPNs was 25, 20, and 30 mL; whereas patients were discharged on postoperative days 1, 3, and 12, respectively. The prolonged hospital stay was secondary to fever and pseudomembranous colitis in a patient with dialysis who also required a blood transfusion. CONCLUSIONS: Laparoendoscopic single-site simple nephrectomy is a technically demanding yet feasible procedure in children. Further studies are necessary to define the indications, advantages, and limitations of this technique as compared with standard laparoscopy. PMID- 20846004 TI - Compassionate honesty. PMID- 20846005 TI - Intraoperative evaluation of renal blood flow during laparoscopic partial nephrectomy with a novel Doppler system. AB - INTRODUCTION: Hemostasis remains a major challenge associated with laparoscopic renal surgery. We evaluated a cost-effective novel Doppler probe (DP) for assessment of vascular control during laparoscopic partial nephrectomy (LPN). METHODS: We prospectively collected data during LPN procedures. We documented tumor location and size as well as subjective quality of the hilar dissection. The DP was compared with our standard intraoperative ultrasound system (SUS) for the ability to detect blood flow during hilar dissection and to determine parenchymal ischemia around the tumor after clamping of the renal vessels. RESULTS: Twenty patients underwent LPN by a single surgeon. The mean tumor size was 3.0 cm (range: 1.2-6.3 cm). The times to assess the kidney using the SUS and DP were 68.6 seconds (range: 20-155) and 44.5 seconds (range: 15-180), respectively. Evaluation prior to renal hilar clamping demonstrated the presence of blood flow in all 20 patients (100%) using the SUS and in 17 of 20 (85%) using the DP. Similarly, cessation of blood flow with clamping was documented in 100% of cases with SUS and 85% with DP. Persistent flow was detected by both SUS and DP in two patients requiring further dissection and reclamping. Then, both systems detected the absence of flow before tumor resection. With blood flow interruption confirmation, no patient had significant bleeding at the time of renal parenchymal transection. CONCLUSIONS: Intraoperative Doppler ultrasound technologies minimize the risk of significant bleeding during LPN. The DP is a small, simple, effective probe that can be used to assess blood flow interruption to the kidney during laparoscopic renal surgery. PMID- 20846006 TI - Adrenomedullin as a therapeutic target in angiogenesis. AB - IMPORTANCE OF THE FIELD: Hypoxia, a frequent characteristic in the microenvironment of solid tumors, leads to adrenomedullin (AM) upregulation through the hypoxia inducible factor-1 pathway, explaining its high expression in a variety of malignant tissues. AM is believed to play an important role in tumor progression and angiogenesis in many cancers. Therefore, it could become a new therapeutic target. AREAS COVERED IN THIS REVIEW: We performed a review of the literature based on published data to highlight AM's critical roles in tumor cell growth and cancer invasiveness, and its involvement in tumor angiogenesis through promotion of recruitment of hematopoietic progenitors, vascular morphogenesis, and blood vessel stabilization and maturation. Inhibition of AM has antitumoral effects linked to antiangiogenic effects but in some cases also to direct antiproliferative activity on cancer cells. Several studies demonstrated that systemic inhibition of AM receptors was well tolerated in murine models. WHAT THE READER WILL GAIN: The goal of this review is to inform readers about the role of AM in tumor angiogenesis and cancer progression and, therefore, about its possible place as a new therapeutic target. TAKE HOME MESSAGE: Taken together, these data support targeting the AM pathway as a new potential therapy in cancer, complementary to other existing treatments. PMID- 20846008 TI - "It's a quick way to get what you want": a formative exploration of HIV risk among urban Massachusetts men who have sex with men who attend sex parties. AB - Community-based studies with men who have sex with men (MSM) suggest that between 8% and 25% of MSM have met recent male sexual partners at private sex parties. Little is known about HIV sexual risk behaviors of MSM who attend sex parties and whether risk reduction interventions can be delivered in this setting. In 2008, 40 MSM who reported attending and/or hosting sex parties in Massachusetts in the past 12 months completed a qualitative interview and quantitative assessment. Participants reported attending a mean number of 10 sex parties in Massachusetts in the past 12 months. A significant percentage (43%) reported also hosting sex parties. Participants had made sexual partner connections across multiple venues, including public cruising areas, bars/clubs, and the Internet. At the most recent sex party attended, the majority had used alcohol (58%) and/or drugs (50%), and one quarter (25%) put themselves at risk of acquiring or transmitting HIV or other sexually transmitted infections (STIs) by having unprotected anal sex with a mean number of three serodiscordant male sex partners. Although many participants perceived that communicating about sexual health in the sex party context would "ruin the mood," the majority (80%) considered some form of HIV prevention at sex parties to be appropriate and necessary, as well as acceptable. Nonintrusive prevention and education activities were especially endorsed (i.e., condoms, lubricants, and coupons for free HIV/STI testing). The majority of participants (75%) expressed some interest in "safer sex" parties. MSM attending sex parties appear to be a subpopulation at high risk for HIV and STI acquisition and transmission. Risk reduction interventions responsive to the needs of MSM who attend sex parties are warranted. PMID- 20846009 TI - A cross-site, comparative effectiveness study of an integrated HIV and substance use treatment program. AB - Co-occurrence of HIV and substance abuse is associated with poor outcomes for HIV related health and substance use. Integration of substance use and medical care holds promise for HIV patients, yet few integrated treatment models have been reported. Most of the reported models lack data on treatment outcomes in diverse settings. This study examined the substance use outcomes of an integrated treatment model for patients with both HIV and substance use at three different clinics. Sites differed by type and degree of integration, with one integrated academic medical center, one co-located academic medical center, and one co located community health center. Participants (n=286) received integrated substance use and HIV treatment for 12 months and were interviewed at 6-month intervals. We used linear generalized estimating equation regression analysis to examine changes in Addiction Severity Index (ASI) alcohol and drug severity scores. To test whether our treatment was differentially effective across sites, we compared a full model including site by time point interaction terms to a reduced model including only site fixed effects. Alcohol severity scores decreased significantly at 6 and 12 months. Drug severity scores decreased significantly at 12 months. Once baseline severity variation was incorporated into the model, there was no evidence of variation in alcohol or drug score changes by site. Substance use outcomes did not differ by age, gender, income, or race. This integrated treatment model offers an option for treating diverse patients with HIV and substance use in a variety of clinic settings. Studies with control groups are needed to confirm these findings. PMID- 20846010 TI - Isolation of Mycobacterium tuberculosis from captive Ateles paniscus. AB - An adult female red-faced black spider monkey (Ateles paniscus), housed for 2 years in the Parque Estoril Zoo in Sao Paulo, Brazil, showed apathy. Clinical examination revealed discrete emaciation, swelling and induration of lymph nodes, and presence of a mass in the abdominal cavity. Therapies with enrofloxacin, azithromycin, and ceftiofur were ineffective. The animal died after 6 months. Necropsy and histopathology confirmed granulommas in lymph nodes, parietal and visceral pleura, lungs, liver, spleen, and kidneys. Acid-fast bacilli were isolated and identified as Mycobacterium tuberculosis by polymerase chain reaction restriction analysis and Spoligotyping techniques. The zoo personnel and other animals that had had contact with the infected primate were negative to tuberculosis diagnostic procedures, such as sputum exam (baciloscopy) and thorax radiography. It was impossible to determine whether the infection occurred before or after the arrival of the animal to the Parque Estoril Zoo. This is the first report of M. tuberculosis infection in Ateles paniscus, a neotropical primate. PMID- 20846011 TI - A case of human conjunctival dirofilariosis by Dirofilaria immitis in Italy. AB - This short communication describes a case of human conjunctival dirofilariosis by Dirofilaria immitis. A 51-year-old man from the Emilia-Romagna region of northeastern Italy referred for ocular foreign body sensation in his right eye. A slight swelling of the bulbar conjunctiva was observed. A live, whitish, 10-cm long nematode was extracted from the subconjunctival space. Histology revealed typical features of a filarioid nematode belonging to the genus Dirofilaria sp. Molecular analysis with polymerase chain reaction confirmed that the extracted nematode was a male of D. immitis. The removal of the parasite leads to complete resolution of symptoms. Ocular human dirofilariosis caused by infection with the filarioid nematode D. immitis is extremely rare, but should be considered in humans living in Italian endemic areas. PMID- 20846012 TI - Cattle and the natural history of Rickettsia parkeri in Mississippi. AB - Cattle have been recognized as hosts for Amblyomma maculatum, the Gulf Coast tick, for over 100 years. For nearly as long, A. maculatum have been known to harbor the spotted fever group Rickettsia (SFGR), now known as Rickettsia parkeri. However, human infection with R. parkeri was not documented until 2004. Results presented herein describe a laboratory and a field study evaluating cattle and the natural history of A. maculatum and R. parkeri in Mississippi. In the laboratory study, seroconversion to R. parkeri antigen occurred in calves exposed to R. parkeri by injection or by feeding R. parkeri-infected A. maculatum, and two out of six animals were transiently rickettsemic. All calves remained clinically normal during the study, except for gotch ear-like lesions in all tick-infested calves, regardless of infection status of ticks, suggesting that R. parkeri is not involved in the condition. In the field study, A. maculatum (n=34) removed from Mississippi sale barn cattle (n=183) and the cattle hosts were tested for R. parkeri. Cattle were not rickettsemic by polymerase chain reaction, but 49.7% demonstrated low titers to R. parkeri antigen when tested by indirect fluorescent antibody for SFGR. Of ticks removed from cattle, 11.8% were hemolymph positive and 8.7% were indirect fluorescent antibody positive. Approximately 22% (5/23) and 4% (1/23) of harvested tick extracts were positive for R. parkeri by polymerase chain reaction of the 17 kDa antigen gene and ompA gene, respectively. An amplicon for the ompA gene from one tick was successfully sequenced and showed 100% similarity with the homologous sequence of R. parkeri. Thus, cattle may harbor R. parkeri-infected A. maculatum and produce antibodies to SFGR. Cattle may play a role in the natural history of R. parkeri infection by expanding populations of A. maculatum and transporting R. parkeri infected ticks to various locations, rather than as a reservoir for R. parkeri. PMID- 20846013 TI - Co-circulation of emerging tick-borne pathogens in Middle Germany. AB - From May until October 2007, a total of 658 Ixodes ricinus ticks were collected off birds (189), rodents (273), and vegetation (196) in a certain area of Middle Germany and investigated for infection with Babesia spp., Anaplasma phagocytophilum, and Rickettsia spp. Overall, 13.1% (86/658) of the ticks were infected with at least one pathogen; co-infections occurred in 0.6% (4/658). Babesia spp. specific DNA was detected in 9.7% (64/658) of the ticks, 1.4% (9/658) were infected with A. phagocytophilum, and 2.6% (17/658) harbored rickettsiae. At least two different Rickettsia species were identified: Rickettsia monacensis and Rickettsia helvetica. Our study provides first interesting insights into the circulation and co-circulation of several emerging pathogens not only in ticks parasitizing birds and small mammals as potential reservoirs but also in questing ticks in a single natural habitat. PMID- 20846014 TI - Physiological stress as a fundamental mechanism linking predation to ecosystem functioning. AB - We present a framework to explain how prey stress responses to predation can resolve context dependency in ecosystem properties and functions such as food chain length, secondary production, elemental stoichiometry, and cycling. We first describe the major nonspecific physiological stress mechanisms and their ecologically relevant consequences. We next synthesize the evidence for prey physiological responses to predation risk and demonstrate that they are similar across taxa and fit well within the general stress paradigm. We then illustrate the utility of our idea by applying our understanding of the ecological consequences of stress to explain how herbivore-prey physiological antipredator responses affect ecosystem dynamics. We hypothesize that stressed herbivores should forage on plant species with higher digestible carbohydrates than should unstressed herbivores to meet heightened energy demands. Increased consumption of carbohydrate-rich plants should reduce their relative abundance in the community, hence altering the quantity and quality of plant litter entering the detrital pool. We further hypothesize that stress should change the elemental composition and energy content of prey excreta, egesta, and carcasses that enter the detrital pool. Finally, prey stress should lower energy and nutrient conversion efficiency and hence the transfer of materials and energy up the food chain, which should, in turn, weaken the association between ecosystem productivity and food chain length. PMID- 20846015 TI - Comparative strain analysis of Anaplasma phagocytophilum infection and clinical outcomes in a canine model of granulocytic anaplasmosis. AB - A pilot study was conducted to determine whether existing human or canine strains of Anaplasma phagocytophilum would reproduce clinical disease in experimentally inoculated dogs similar to dogs with naturally acquired granulocytic anaplasmosis. Six hounds were inoculated intravenously with one human and two canine strains of A. phagocytophilum that were propagated in vitro in HL-60 cells or in infected autologous neutrophils. Infected dogs were monitored for lethargy, anorexia, petechiae, lymphadenopathy, and fever. Dogs were assessed for complete blood count (CBC), serum chemistry, and serology (IFA and SNAP(r) 4Dx(r)); for A. phagocytophilum blood load by quantitative polymerase chain reaction; and for cytokine production. Prominent clinical signs were generalized lymphadenopathy and scleral injection; only one dog developed fever lasting 4 days. Notable laboratory alterations included sustained leukopenia and thrombocytopenia in all dogs. A. phagocytophilum morulae were noted in blood between days 10 and 11, although all dogs retained A. phagocytophilum DNA in blood through day 60. All dogs seroconverted by days 10-15 by IFA, and by days 17-30 by SNAP 4Dx; cytokine analyses revealed 10-fold increases in interleukin-2 and interleukin-18 in the neutrophil-propagated 98E4 strain-infected dog. All A. phagocytophilum strains produced infection, although canine 98E4 strain reproduced clinical signs, hematologic changes, and inflammatory cytokine elevations most consistent with granulocytic anaplasmosis when recognized clinically. Therefore, this strain should be considered for use in future studies of A. phagocytophilum canine infection models. PMID- 20846016 TI - Tick-borne disease agents in various wildlife from Mississippi. AB - Because tick-borne diseases are becoming increasingly important throughout the world, monitoring their causative agents in wildlife may serve as a useful indicator of potential human exposure. We assessed the presence of known and putative zoonotic, tick-borne agents in four wildlife species in Mississippi. Animals were tested for exposure to or infection with Ehrlichia chaffeensis, Ehrlichia ewingii, Borrelia lonestari, Rickettsia spp., Anaplasma phagocytophilum, and Francisella tularensis. Whole blood and serum were tested from white-tailed deer (WTD; Odocoileus virginianus) and feral swine (Sus scrofa); serum was tested from raccoons (Procyon lotor) and opossums (Didelphis virginiana). We used polymerase chain reaction to detect all agents in blood, whereas an indirect fluorescent antibody assay was used to detect antibodies to E. chaffeensis, B. lonestari, and Rickettsia parkeri (spotted fever group rickettsiae) antigens in serum. Molecular evidence of infection with E. chaffeensis, B. lonestari, and An. phagocytophilum was detected only in WTD. Antibodies to E. chaffeensis antigen were detected in 43.9% of WTD, 32.8% of swine, 42.1% of raccoons, and 15.8% of opossums. Serologic evidence of exposure to B. lonestari antigen was found in 19.3% of WTD, 6.9% of swine, and 5.3% of raccoons, but not in opossums. Interestingly, the percent of animals with antibodies reactive to spotted fever group rickettsiae (R. parkeri antigen) was highest in raccoons (73.7%) and opossums (57.9%). These results support the role of WTD as reservoirs for E. chaffeensis, B. lonestari, and An. phagocytophilum, as well as provide additional evidence for exposure of raccoons and opossums to E. chaffeensis. Finally, we provide new data that feral swine may have antibodies to these agents. Thus, in general, these four wildlife species are exposed to tick-borne disease agents in Mississippi, suggesting that ticks carry and have the potential to transmit the agents to humans in the state. PMID- 20846017 TI - A gender perspective is fundamental to improve women's health. PMID- 20846019 TI - The association between cervical abnormalities and attitudes toward cervical cancer prevention. AB - BACKGROUND: We investigated whether a history of cervical abnormalities predicts responses to cervical cancer prevention for women and their daughters. METHODS: In 2007, we interviewed 832 mothers of adolescent daughters from North Carolina counties with elevated rates of cervical cancer. We measured the association of experiences with cervical abnormalities and emotions, beliefs, attitudes, and behaviors related to cervical cancer and its prevention. RESULTS: Anxiety about cervical cancer was higher among women who had cervical cancer, hysterectomies, and abnormal Pap test results (including false positives) than in women who had experienced none of these (each p < 0.05). Pap tests were perceived as being more effective at reducing the chance of developing cervical cancer by women with a history of cancer and women who reported hysterectomies relative to women with normal Pap results (each p < 0.05). Intentions to vaccinate their daughters against human papillomavirus (HPV) were highest among women who had cervical cancer, women who had hysterectomies, and women who were treated for precancerous lesions (each p < 0.05). CONCLUSIONS: Women with histories of cervical health abnormalities reported more favorable views of Pap testing and HPV vaccination than women who had received only normal Pap testing results. They also reported higher levels of anxiety about cervical cancer. PMID- 20846018 TI - The effects of a cardiac rehabilitation program tailored for women on global quality of life: a randomized clinical trial. AB - BACKGROUND: Women with heart disease have adverse psychosocial profiles and poor attendance in cardiac rehabilitation (CR) programs. Few studies examine CR programs tailored for women for improving their quality of life (QOL). METHODS: This randomized clinical trial (RCT) compared QOL among women in a traditional CR program with that of women completing a tailored program that included motivational interviewing guided by the Transtheoretical Model (TTM) of behavior change. Two measures of QOL, the Multiple Discrepancies Theory questionnaire (MDT) and the Self-Anchoring Striving Scale (SASS), were administered to 225 women at baseline, postintervention, and 6-month follow-up. Analysis of Variance (ANOVA) was used to compare changes in QOL scores over time. RESULTS: Baseline MDT and SASS scores were 35.1 and 35.5 and 7.1 and 7.0 for the tailored and traditional CR groups, respectively. Postintervention, MDT and SASS scores increased to 37.9 and 7.9, respectively, for the tailored group compared with 35.9 and 7.1 for the traditional group. Follow-up scores were 37.7 and 7.6 for the tailored group and 35.7 and 7.1 for the traditional group. Significant group by time interactions were found. Subsequent tests revealed that MDT and SASS scores for the traditional group did not differ over time. The tailored group showed significantly increased MDT and SASS scores from baseline to posttest, and despite slight attenuation from posttest to 6-month follow-up, MDT and SASS scores remained higher than baseline. CONCLUSIONS: The CR program tailored for women significantly improved global QOL compared with traditional CR. Future studies should explore the mechanisms by which such programs affect QOL. PMID- 20846020 TI - Cellular uptake and intracellular fate of engineered nanoparticles: a review on the application of imaging techniques. AB - The use of imaging tools to probe nanoparticle-cell interactions will be crucial to elucidating the mechanisms of nanoparticle-induced toxicity. Of particular interest are mechanisms associated with cell penetration, translocation and subsequent accumulation inside the cell, or in cellular compartments. The objective of the present paper is to review imaging techniques that have been previously used in order to assess such interactions, and new techniques with the potential to be useful in this area. In order to identify the most suitable techniques, they were evaluated and matched against a list of evaluation criteria. We conclude that limitations exist with all of the techniques and the ultimate choice will thus depend on the needs of end users, and their particular application. The state-of-the-art techniques appear to have the least limitations, despite the fact that they are not so well established and still far from being routine. For example, super-resolution microscopy techniques appear to have many advantages for understanding the details of the interactions between nanoparticles and cells. Future research should concentrate on further developing or improving such novel techniques, to include the development of standardized methods and appropriate reference materials. PMID- 20846021 TI - Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells. AB - Nanomaterials are increasingly used in various food applications. In particular, nanoparticulate amorphous SiO2 is already contained, e.g., in spices. Since intestinal dendritic cells (DC) could be critical targets for ingested particles, we compared the in vitro effects of amorphous silica nanoparticles with fine crystalline silica, and micron-sized with nano-sized TiO2 particles on DC. TiO2- and SiO2-nanoparticles, as well as crystalline silica led to an upregulation of MHC-II, CD80, and CD86 on DC. Furthermore, these particles activated the inflammasome, leading to significant IL-1beta-secretion in wild-type (WT) but not Caspase-1- or NLRP3-deficient mice. Silica nanoparticles and crystalline silica induced apoptosis, while TiO2 nanoparticles led to enhanced production of reactive oxygen species (ROS). Since amorphous silica and TiO2 nanoparticles had strong effects on the activation-status of DC, we suggest that nanoparticles, used as food additives, should be intensively studied in vitro and in vivo, to ensure their safety for the consumer. PMID- 20846022 TI - Potential of the hepatic transcriptome expression profile of the striped seabream (Lithognathus mormyrus) as an environmental biomarker. AB - The potential of the hepatic transcriptome expression profile evaluated in a sentinel feral fish to serve as an environmental biomarker was examined. Expression profiles of Lithognathus mormyrus individuals were exhibited using cDNA microarray and were related to the set of exposure conditions at their sites and dates of collection. Expression profiles of individual fish were reasonably clustered according to the fish samples. In addition, several sample-specific gene clusters were determined, designated sample gene signatures. The selection procedure for future optimal reference RNA is discussed. The relationship between transcriptome expression and fish samples indicated a potential for using the former as an environmental biomarker. PMID- 20846023 TI - Protective effects of Punica granatum in experimentally-induced gastric ulcers. AB - In the present investigation standardized aqueous methanolic extract of Punica (AMP) was used for its possible ulcer protective activity in wistar rats against different experimental models. Preliminary phytochemical screening of AMP reveals the presence of saponin, tannins, and flavonoids, which may be responsible for its activity. HPTLC finger prints of AMP showed the presence of 12 spots at different (retention factor) rf values. Oral administration of AMP (490 and 980 mg/kg bw) significantly reduced the ulcer lesion index produced by alcohol, indomethacin, and aspirin, at both doses in rats. Further, in pylorus-ligated rats AMP significantly reduces the ulcer lesions, gastric volume, and total acidity. It prevents the ulceration by increasing the pH and mucus secretion in pylorus ligated rats. The present study shows the anti-ulcer activity of AMP in experimentally-induced gastric ulcers. PMID- 20846024 TI - 5/35 fiber-modified conditionally replicative adenovirus armed with p53 shows increased tumor-suppressing capacity to breast cancer cells. AB - Conditionally replicative adenoviruses (CRAds) are widely used for cancer biotherapy and show a significant growth-suppressing effect on many types of cancer. However, it was reported that breast cancer was highly resistant to the infection of traditionally used adenovirus of serotype 5 (Ad5)-based CRAds. Although partial substitution of the fiber protein of replication-deficient Ad5 with that of adenovirus of serotype 35 (Ad35) facilitated infection of breast cancer cells by adenoviral vectors, it is still unknown whether this modification can improve CRAds in their tumor-eliminating capacity. We generated a 5/35 fiber modified CRAd with a p53 cDNA construct and investigated whether this alteration in fiber region can make CRAds suppress the growth of breast cancer more effectively. Our data reinforced the proposal that 5/35-modified fiber conferred higher adenovirus infectivity for breast cancer cells than natural Ad5 fiber. Interestingly, 5/35 fiber-modified CRAd replicated more efficiently in breast cancer cells than Ad5-based CRAd. We also found 5/35 fiber-modified CRAd mediated higher expression of p53 in breast cancer cells. In vitro, 5/35 fiber-modified CRAd eliminated breast cancer cells more efficiently. Growth of xenograft tumors in nude mice was also significantly retarded by 5/35 fiber-modified CRAd. The 5/35 fiber-modified CRAd suppressed the growth of breast cancer cells more effectively than Ad5-based CRAd, both in vitro and in vivo. Thus CRAd with 5/35 hybrid fiber may be a promising vector for breast cancer treatment. PMID- 20846025 TI - Effect of Piper betle on cardiac function, marker enzymes, and oxidative stress in isoproterenol-induced cardiotoxicity in rats. AB - The present study was designed to investigate the cardioprotective potential of Piper betle (P. betle) against isoproterenol (ISP)-induced myocardial infarction in rats. Rats were randomly divided into eight groups viz. control, ISP, P. betle (75, 150, and 300 mg/kg) and P. betle (75, 150, and 300 mg/kg) + ISP treated group. P. betle leaf extract (75, 150, or 300 mg/kg) or saline was orally administered for 30 days. ISP (85 mg/kg, s.c.) was administered at an interval of 24 h on the 28(th) and 29(th) day and on day 30 the functional and biochemical parameters were measured. ISP administration showed a significant decrease in systolic, diastolic, mean arterial pressure (SAP, DAP, MAP), heart rate (HR), contractility (+LVdP/dt), and relaxation (-LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). ISP also caused significant decrease in myocardial antioxidants; superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), and myocyte injury marker enzymes; creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH) along with enhanced lipid peroxidation; thiobarbituric acid reacting species (TBARS) in heart. Pre-treatment with P. betle favorably modulated hemodynamic (SAP, DAP, and MAP) and ventricular function parameters ( LVdP/dt and LVEDP). P. betle pre-treatment also restored SOD, CAT, GSH, and GPx, reduced the leakage of CK-MB isoenzyme and LDH along with decreased lipid peroxidation in the heart. Taken together, the biochemical and functional parameters indicate that P. betle 150 and 300 mg/kg has a significant cardioprotective effect against ISP-induced myocardial infarction. Results of the present study suggest the cardioprotective potential of P. betle. PMID- 20846026 TI - Role of oxygenases in guiding diverse metabolic pathways in the bacterial degradation of low-molecular-weight polycyclic aromatic hydrocarbons: a review. AB - Widespread environmental pollution by polycyclic aromatic hydrocarbons (PAHs) poses an immense risk to the environment. Bacteria-mediated attenuation has a great potential for the restoration of PAH-contaminated environment in an ecologically accepted manner. Bacterial degradation of PAHs has been extensively studied and mining of biodiversity is ever expanding the biodegradative potentials with intelligent manipulation of catabolic genes and adaptive evolution to generate multiple catabolic pathways. The present review of bacterial degradation of low-molecular-weight (LMW) PAHs describes the current knowledge about the diverse metabolic pathways depicting novel metabolites, enzyme-substrate/metabolite relationships, the role of oxygenases and their distribution in phylogenetically diverse bacterial species. PMID- 20846027 TI - Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentiation into cartilage. AB - Induced pluripotent stem (iPS) cells can be derived from a wide range of somatic cells via overexpression of a set of specific genes. With respect to their properties, iPS cells closely resemble embryonic stem cells. Because of their main property, pluripotency, iPS cells have excellent prospects for use in substitutive cell therapy; however, the methods of directed differentiation of iPS cells have not been yet sufficiently elaborated. In this work, we derived human iPS cells from fetal neural stem (FNS) cells by transfection with a polycistronic plasmid vector carrying the mouse Oct4, Sox2, Klf4, and c-Myc genes or a plasmid expressing the human OCT4 gene. We have shown that human FNS cells can be effectively reprogrammed despite a low transfection level (10%-15%) and that the use of 2-propylvaleric (valproic) acid and BIX-01294 increases the yield of iPS cell clones to ~7-fold. Further, transient expression of OCT4 alone is sufficient for reprogramming. The iPS cells obtained express all the major markers of embryonic stem cells and are able to differentiate in vitro into ectodermal, mesodermal, and endodermal derivatives. In addition, we have found that the human iPS cells derived from FNS cells can be successfully subjected to in vitro directed chondrogenic differentiation to form functional cartilaginous tissue. PMID- 20846028 TI - Low doses of bone morphogenetic protein 4 increase the survival of human adipose derived stem cells maintaining their stemness and multipotency. AB - Mesenchymal stem cells (MSCs) have emerged as important tools for cell therapy; therefore, identification of factors capable of governing their ex vivo expansion become essential. In this study we demonstrate that human adipose-derived stem cells (ASCs) express all components of the bone morphogenetic protein (BMP)/BMP receptor signaling pathway and respond to BMP4 inducing upregulated expression of its specific target genes Id1-Id4. Moreover, ASCs grown in a medium reduced in serum produce endogenous BMP4 that could affect autocrinely ASC growth. On the contrary, dorsomorphin, an inhibitor of BMP signaling pathway, decreases cell numbers yielded from ASC cultures in correlation with increased apoptosis and decreased cycling cells. Therefore, BMP4 emerges as a possible factor for ex vivo expanding human ASCs. Our results demonstrate that, as other morphogens, BMP4 effects on human MSCs are dose dependent. High doses significantly increased apoptosis and drastically reduced cell proliferation, whereas low doses of BMP4 (0.01-0.1 ng/mL) significantly increase culture cell content, reduce the number of apoptotic cells, and increase that of cycling cells. Further, treatment of human ASCs with low doses of BMP4 does not modify expression of Nanog and Oct4, two transcription factors involved in self-renewal and pluripotency of stem cells or avoid their osteogenic or osteoblastic differentiation capacities when cultured in adequate inducing media, as shown by the induction of specific gene expression (CEBP, PPARgamma, and RUNX2). Our results therefore support BMP4 as a promising factor for expanding human adipose tissue-derived MSCs maintaining their properties of stemness and multipotency. PMID- 20846029 TI - Antimalarial activity of traditionally used Western Ghats plants from India and their interactions with chloroquine against chloroquine-tolerant Plasmodium berghei. AB - An ethnopharmacological investigation was undertaken on Western Ghats plants traditionally used to treat malaria; 50 plants were very carefully selected from total of 372 plants, and 216 extracts were prepared and tested for in vivo antiplasmodial activity alone and in combination with chloroquine (CQ) against CQ tolerant Plasmodium berghei (strain NK65). In in vivo antiplasmodial activity when plant extract alone is used, 81 extracts (or 37.5%) gave 52.90% significant parasitemia inhibition on day 4 postinfection and 39 extracts (or 18%) gave 41 89% mouse survival on day 9 postinfection. In combination with CQ on day 11 postinfection, 103 extracts (or 47.68%) gave mouse survival rate of 92% and on day 14 gave maximum mouse survival up to 70-79%. The fact that these activities were up to fourfold higher with CQ mostly resulted in longer mouse survival because of significant parasitemia inhibition. Our investigation have confirmed that above 70% of the plant extracts showed moderate to high in vivo antimalarial activity when used alone and in combination with CQ, and most of the extracts showed border line to good synergistic activity. PMID- 20846030 TI - Leishmaniasis in an era of conflict in the Middle East. AB - Leishmaniasis is endemic in the Middle East, and both cutaneous and visceral forms are reported from the region ranging from the Levant to Afghanistan. The potential and proven phlebotomine sand fly vectors and reservoir hosts of the Leishmaniases species in Afghanistan, Iran, Iraq, Israel, Jordan, Lebanon, Saudi Arabia, Syria, Turkey, and Yemen are described. This region has seen a movement of populations across the area, due to both military and civilian strife. Refugees, armed forces, and multi-national contractors are particularly at risk to acquire this disease. There has been an upsurge in Leishmaniasis research, especially as new foci are exposed and the need to protect the naive populations moving into endemic areas becomes a public health priority. New sand fly vectors and animal reservoirs have been discovered while novel control methods are being evaluated. Modern molecular techniques are now being used more routinely and revealing some unusual findings. The aim of this review is to collate the most recent data on the burden of the disease, diagnostic applications, eco epidemiology of vectors, and reservoir hosts, and how the control projects have been developing in the Middle East. PMID- 20846031 TI - Quorum sensing in Acinetobacter: an emerging pathogen. AB - Acinetobacter is emerging as one of the major nosocomial infectious pathogens, facilitated by tolerance to desiccation and multidrug resistance. Quorum sensing (autoinducer-receptor mechanism) plays role in biofilm formation in Acinetobacter, though its role in regulation of other virulence factors is yet to be established. Phylogenetic studies indicate that Acinetobacter baumannii is closely related to Burkholderia ambifaria but its quorum sensing genes (abaI and abaR) were acquired horizontally from Halothiobacillus neapolitanus. The prospects of quorum quenching to control the infections caused by Acinetobacter have also been discussed. PMID- 20846032 TI - Acute HIV-1 infection: what's new? Where are we going? AB - This supplemental issue of the Journal of Infectious Diseases is devoted to the important topic of primary human immunodeficiency virus type 1 (HIV-1) infection. It was prompted by the planning of the Acute HIV-1 Infection Meeting in Boston in September 2009, at which leading scientists and practitioners gathered to discuss new insights into the early, critical events of HIV-1 infection. The reviews that follow underline the current state of the field with regard to transmission biology of HIV-1; the clinical presentation, diagnosis, and management of primary HIV-1 infection; the pathogenesis of primary HIV-1 infection; and innate and adaptive immune responses to the virus. We trust that these findings have the potential to influence the development of effective vaccine strategies. PMID- 20846033 TI - The detection of acute HIV infection. AB - Acute human immunodeficiency virus (HIV) infection (AHI) can be defined as the time from HIV acquisition until seroconversion. Incident HIV infection is less well defined but comprises the time from the acquisition of HIV (acute infection) through seroconversion (early or primary HIV infection) and the following months until infection has been well established, as characterized by a stable HIV viral load (viral load set point) and evolution of antibodies with increased concentration and affinity for HIV antigens. During AHI, a viral latent pool reservoir develops, the immune system suffers irreparable damage, and the infected (often unsuspecting) host may be most contagious. It has proved very difficult to find individuals with AHI either in longitudinal cohorts of subjects at high risk for acquiring the virus or through cross-sectional screening, and the opportunity for diagnosis is generally missed during this phase. We review the technical strategies for identifying individuals with acute or incident HIV infection. We conclude that further technical advances are essential to allow more widespread detection of patients with AHI and to affect HIV treatment outcomes and transmission prevention. PMID- 20846034 TI - Clinical management of acute HIV infection: best practice remains unknown. AB - Best practice for the clinical management of acute human immunodeficiency virus (HIV) infection remains unknown. Although some data suggest possible immunologic, virologic, or clinical benefit of early treatment, other studies show no difference in these outcomes over time, after early treatment is discontinued. The literature on acute HIV infection is predominantly small nonrandomized studies, which further limits interpretation. As a result, the physician is left to grapple with these uncertainties while making clinical decisions for patients with acute HIV infection. Here we review the literature, focusing on the potential advantages and disadvantages of treating acute HIV infection outlined in treatment guidelines, and summarize the presentations on clinical management of acute HIV infection from the 2009 Acute HIV Infection Meeting in Boston, Massachusetts. PMID- 20846035 TI - HIV-1 transmission biology: selection and characteristics of infecting viruses. AB - Individuals with recent human immunodeficiency virus type 1 (HIV-1) acquisition are likely to be a major source for other new infections because they have a high level of plasma virus, and the circulating virions possess unique properties that are highly suited for transmission. The acute infection period, however, presents a unique "window of opportunity," because there are a limited number of genetic variants. Studies aim to elucidate the nature of the transmitted viruses and understand the mechanisms that inhibit the majority of variants present in the chronically infected partner from establishing a productive infection in the naive host. Greater understanding of these issues may open promising new ways to effectively block HIV-1 transmission. PMID- 20846036 TI - Innate immune activation in primary HIV-1 infection. AB - There is growing evidence that highlights the role of the immune response during acute human immunodeficiency virus type 1 (HIV-1) infection in the control or development of disease. The adaptive immune responses do not appear until after HIV-1 infection is already well established, so the role of earlier and faster responding innate immunity needs to be more closely scrutinized. In particular, 2 aspects of innate immunity for which there are growing research developments will be examined in this review: the actions of type I interferons and natural killer cells. These two components of the innate immune response contribute to viral control both by killing infected cells and by modulating other immune cells that develop. However, the role of interferon alpha in immune activation is a double edged sword, causing recruitment of adaptive immune cells that can assist in viral control but concurrently contributing to immune activation-dependent disease progression. Understanding the complexity of how innate responses affect the outcome of HIV-1 infection will help in the development of vaccines that can use innate immunity to enhance viral control with minimal pathogenesis. PMID- 20846037 TI - T cell immunity in acute HIV-1 infection. AB - Exceedingly high viral loads and rapid loss of CD4(+) T cells in all tissue compartments are a hallmark of acute human immunodeficiency virus type 1 (HIV-1) infection, which is often accompanied by clinical symptoms such as fever, maculopapular rash, and/or lymphadenopathy. The resolution of the clinical symptoms and the subsequent decrease in plasma viremia are associated with the emergence of HIV-1-specific CD4(+) and CD8(+) T cell responses. The remarkable early inhibition of viremia by CD8(+) T cells appears to be precipitated by only a limited number of specific CD8(+) T cell responses, and the plasma viremia is reduced to a "set point" level. Over time, the breadth and magnitude of CD8(+) T cell responses increase, but without a change in the control of viral replication or further reduction in the viral set point. Moreover, the early viral set point, consequent on the first CD8(+) T cell responses, is highly predictive of the later course of disease progression. Thus, HIV-1-specific CD8(+) T cell responses in acute HIV-1 infection appear uniquely able to efficiently suppress viral replication, whereas CD8(+) T cell responses generated in the chronic phase of infection appear often impaired. PMID- 20846038 TI - Viral evolution and escape during acute HIV-1 infection. AB - The extensive genetic diversity of human immunodeficiency virus type 1 (HIV-1) presents a significant barrier to the development of an effective and durable HIV vaccine. This variability not only makes it difficult to identify the targets against which immune responses should be directed, but it also confers on the virus the capacity for rapid escape from effective immune responses. Here, we describe recent investigations of the genetic diversity of HIV-1 at transmission and of the evolution of the virus as it adapts to the host immune environment during the acute phase of HIV-1 infection. These studies increase our understanding of the virology of the earliest stages of HIV-1 infection and provide critical insights into the mechanisms underlying viral replication and immune control of diverse HIV-1 strains. Such knowledge will inform the design of smarter, more effective vaccines capable of inducing immune control of HIV-1. PMID- 20846039 TI - The humoral response to HIV-1: new insights, renewed focus. AB - During the past 2 decades, significant advances in our understanding of the humoral immune response to human immunodeficiency virus type 1 (HIV-1) infection have been made, yet a tremendous amount of work lies ahead. Despite these advances, strategies to reliably induce antibodies that can control HIV-1 infection are still critically needed. However, recent advances in our understanding of the kinetics, specificity, and function of early humoral responses offer alternative new approaches to attain this goal. These results, along with the new broadly neutralizing antibody specificities, the role for other antibody functions, the increased understanding of HIV-1-induced changes to B cell biology, and results from the RV144 "Thai" trial showing potential modest sterilizing protection by nonneutralizing antibody responses, have renewed focus on the humoral system. In this review, recent advances in our understanding of the earliest humoral responses are discussed, highlighting presentations from the meeting on the Biology of Acute HIV Infection. PMID- 20846040 TI - Immune responses to HIV vaccines and potential impact on control of acute HIV-1 infection. AB - Unanticipated results from 2 recent candidate human immunodeficiency virus type 1 (HIV-1) vaccine regimens in large-scale international trials highlight the importance of understanding the optimal earliest immune defense against HIV-1 infection. Presented here are key findings in these vaccine studies with relevance to the development of future vaccines to control acute HIV-1 infection. PMID- 20846043 TI - Adaptive suppression of subordinate reproduction in cooperative mammals. AB - Attempts to account for observed variation in the degree of reproductive skew among cooperative breeders have usually assumed that subordinate breeding has fitness costs to dominant females. They argue that dominant females concede reproductive opportunities to subordinates to retain them in the group or to dissuade them from challenging for the dominant position or that subordinate females breed where dominants are incapable of controlling them. However, an alternative possibility is that suppressing subordinate reproduction has substantive costs to the fitness of dominant females and that variation in these costs generates differences in the net benefits of suppression to dominants which are responsible for variation in the frequency of subordinate breeding that is not a consequence of either reproductive concessions or limitations in dominant control. Here, we show that, in wild Kalahari meerkats (Suricata suricatta), the frequency with which dominants evict subordinates or kill their pups varies with the costs and benefits to dominants of suppressing subordinate breeding, including the dominants' reproductive status, the size of their group, and the relatedness of subordinates. We review evidence from other studies that the suppression of reproduction by subordinates varies with the likely costs of subordinate breeding to dominants. PMID- 20846045 TI - Relationships of power: implications for interprofessional education. AB - Interprofessional education (IPE) is considered a key mechanism in enhancing communication and practice among health care providers, optimizing participation in clinical decision making and improving the delivery of care. An important, though under-explored, factor connected to this form of education is the unequal power relations that exist between the health and the social care professions. Drawing on data from the evaluation of a large multi-site IPE initiative, we use Witz's model of professional closure (1992) to explore the perspectives and the experiences of participants and the power relations between them. A subset of interviews with a range of different professionals (n = 25) were inductively analyzed to generate emerging themes related to perceptions of professional closure and power. Findings from this work highlight how professionals' views of interprofessional interactions, behaviours and attitudes tend to either reinforce or attempt to restructure traditional power relationships within the context of an IPE initiative. PMID- 20846046 TI - Interprofessional care teams: the role of the healthcare administrator. AB - As the delivery of healthcare services increasingly emphasizes interprofessional activity, one major occupation, healthcare administration, is conspicuously absent from the discussion. This situation reflects the structure of healthcare delivery organizations as professional bureaucracies, with clinical professionals practicing with relative autonomy and with administrators viewed as quasi- or semi-professionals. Not only is this a missed opportunity for administrators, but it seriously weakens the potential for change and improvement promised by interprofessional practice. In this article, we argue that healthcare administrators are important to the success of interprofessional care because they often are in a strong position to champion and implement the system-wide cultural and structural conditions for successful interprofessional care. We also note that changes are needed in the role expectations and education of healthcare administrators to increase the familiarity and comfort of administrators with clinical care and to help them more effectively influence the organizational conditions for collaborative interprofessional exchange. Changes in the expectations and education of clinical professionals also will help accomplish the goal of greater "complementarity" between administrators and clinical healthcare professionals. Such changes are consistent with larger societal forces that are increasing professionalism among administrators and creating more accountability from both administrators and clinical professionals for the quality, cost, and collaboration of services. PMID- 20846047 TI - Hypertension induced by episodic reductions in uteroplacental blood flow in gravid rat. AB - BACKGROUND: The etiology of preeclampsia remains unclear. Animal modeling of preeclampsia has been useful; however, no model to date represents episodic changes in uteroplacental blood flow that may occur in preeclampsia. OBJECTIVE: To develop a gravid rat model characterized by episodic reductions in uteroplacental blood flow. METHOD: Pregnant Sprague Dawley rats were used and subjected to SHAM, reduced uterine perfusion pressure (RUPP), or aortic occlusion on gestational Day 14. Aortic occlusion surgery consisted of implantation of a silastic vascular occluder around the abdominal aorta and silver clips around the uterine-ovarian arteries. Aortic occlusion animals were subjected to five consecutive days of occlusion (40% reduction) each session lasting 1 h. On Day 21, maternal mean arterial pressure (MAP) and fetal morphology were assessed. For isolated blood vessels, resistance-sized mesenteric arteries were harvested and mounted on a pressure arteriograph. RESULT: Occluder animals experienced a 10 mmHg rise in MAP as compared to SHAM (p < 0.05), and RUPP MAP was significantly increased as compared to control subjects (p < 0.05). Pups from Occluder animals exhibited a decrease in fetal weight as compared to SHAM (p < 0.05), but an increase in fetal weight as compared to RUPP (p < 0.05). Myogenic reactivity of second-order mesenteric arteries increased in Occluder animals as compared to SHAM (p < 0.05), but were similar to that of RUPP. CONCLUSION: Episodic reductions in uteroplacental blood flow play a crucial role in the altered vascular reactivity seen in Occluder animals and may represent a new model to investigate the mechanisms associated with episodic reductions in uteroplacental blood flow in pathological pregnancies. PMID- 20846048 TI - The risk of intellectual disability in children born to mothers with preeclampsia or eclampsia with partial mediation by low birth weight. AB - OBJECTIVE: Preeclampsia and eclampsia (PE) are potentially modifiable risk factors for maternofetal complications. Owing to a paucity of research connecting PE to the risk of intellectual disability (ID) in the offspring, this study examined this relationship. Furthermore, we explored how low birth weight (LBW) mediates the effect of PE on ID. METHODS: Data related to South Carolina Medicaid births from 1996 to 2002 were comprised of linked data from maternal Medicaid records, delivery records, birth certificates, Department of Education (DOE), and the Department of Disabilities and Special Needs (DDSNs). After exclusions such as nonidiopathic etiologies of ID, multiple gestations, subsequent siblings in the cohort, pregnancy losses, births under 20 weeks' gestation, and children neither in DOE nor DDSN records, 80,866 maternal-child dyads remained. After adjusting for five covariates of maternal age, race, and education as well as the child's birth year and sex, the effect of PE on ID was examined. RESULTS: The rates of PE and ID were 6.4 and 2.0%, respectively. The rates of ID among children exposed and not exposed to PE were 3.0 and 2.0%, respectively. The crude odds ratio (OR) was 1.549 (95% CI 1.310, 1.832) and the adjusted OR was 1.58 (95% CI 1.334, 1.870). LBW was a significant mediator of the relationship accounting for approximately half of the association. CONCLUSION: Because of the association of PE, ID, and LBW, additional research is needed to explain mechanisms and to investigate possible impacts of different PE treatment. PMID- 20846049 TI - Can we use the Omron T9P automated blood pressure monitor in pregnancy? AB - BACKGROUND: Recent events in our hospital, combined with international recommendations, catalyzed the need to move from mercury sphygmomanometry to automated blood pressure (BP) recording in pregnancy. AIM: To test the accuracy of the Omron T9P automated BP recorder in pregnant women, using mercury sphygmomanometry as the gold standard. SETTING: Antenatal clinics and obstetric day assessment unit, St George Hospital, Sydney. PARTICIPANTS: Eighty-five pregnant women, 11% of whom were receiving antihypertensives. METHODS: Differences in both systolic and diastolic BP between the T9P Omron device and mercury sphygmomanometer were obtained for each woman, using sequential automated and mercury BP recordings, as required by a modified British Hypertension Society (BHS) protocol. The accuracy of the device was graded according to the BHS and the Association for the Advancement of Medical Instrumentation (AAMI) standards. RESULTS: The Omron T9P device received an A/A grade according to this modified BHS and AAMI testing process, though the range of the 255 differences was 1-13 for systolic BP and 1-10 for diastolic BP. CONCLUSIONS: The Omron T9P device is an accurate device for use predominantly in an outpatient antenatal clinical setting. Further studies are required solely within hypertensive pregnant women before its use can be recommended with certainty in this group. PMID- 20846050 TI - Low neonatal birth weight as a possible predictive factor for the onset of postpartum eclampsia. AB - OBJECTIVE: To report about a case of complicated late postpartum eclampsia where neonatal low birth weight could be considered a predictive factor of placental sufferance. METHODS: A 25-year-old woman, without medical or familiar history for hypertension or cerebrovascular diseases, underwent a normal spontaneous delivery with neonatal birth weight of 2340 g (9th percentile). Eight days later the patient presented sudden headache and generalized tonic-clonic seizures. RESULTS: Blood hypertension and alterations in laboratory studies were detected; a diagnosis of late postpartum eclampsia was made. A CT scan showed subarachnoid hemorrhage (Hunt and hess grade I, Fisher grade III). Serial cerebral angiograms did not show any intracranial vascular malformations; epilepsy and hypertension were successfully medically treated; and a repeat CT examination showed the gradual resolution of subarachnoid hemorrhage. Headache progressively disappeared. CONCLUSIONS: Low neonatal birth weight could be linked to placental dysfunction and considered as a predictive factor for the onset of postpartum preeclampsia/eclampsia. We recommend a careful clinical and laboratory management of puerperium up to the first month postpartum, in particular in cases of "sine causa" neonatal low birth weight. PMID- 20846051 TI - In vivo tracking of stem cell by nanotechnologies: future prospects for mouse to human translation. AB - Advances in stem cell research have provided important understanding of the cell biology and offered great promise for developing new strategies for tissue regeneration. Dynamic determination of stem cell migration and distribution in real time is essential for optimizing treatments in preclinical models and designing clinical protocols. Recent developments in the use of nanotechnologies have contributed to advance of the high-resolution in vivo imaging methods, including the positron emission tomography, the single-photon emission computed tomography, the magnetic resonance imaging, and microcomputed tomography. This review examines the use of nanotechnologies for stem cell tracking, the many contrast agents, and detectors that have been proposed and suggest future directions for mouse to human translation of these techniques, for both therapeutic and diagnostic purposes. PMID- 20846052 TI - The beta-interferon scaffold attachment region confers high-level transgene expression and avoids extinction by epigenetic modifications of integrated provirus in adipose tissue-derived human mesenchymal stem cells. AB - Because of their abundance and ease of isolation, multilineage differentiation, and paracrine and immunoregulatory capabilities, genetically engineered adipose tissue-derived mesenchymal stem cells (ASCs) might combine cell- and gene therapy based strategies for efficacious tissue repair/regeneration. In this report, we aimed to analyze and influence the long-term dynamics of transgene expression in ASCs transduced with different gammaretroviral vector configurations incorporating the human beta-interferon scaffold attachment region (IFN-SAR) and/or chicken 5'HS4 beta-globin insulator sequences. In our undifferentiated ASC culture model, naked retroviral vectors experienced EGFP transgene extinction correlating with increases in both H3 histone deacetylation and CpG dinucleotide methylation within the 5' long terminal repeat-primer-binding site proviral region. Retroviral configurations incorporating the referred boundary elements alone or combined were able to prevent the development of the above epigenetic events and to reduce transgene extinction to different degrees. Particularly, the IFN-SAR sustained the highest levels of H3 histone acetylation and transgene expression throughout the study. Analogously, ASCs differentiating to adipocytes or osteocytes experienced a gradual decline of EGFP expression using naked retroviral vectors. In contrast, only retroviral configurations including the IFN SAR alone were able to overcome the epigenetic pressure, yielding high-level, uniform transgene expression throughout both lineage differentiation processes. Thus, embedding the IFN-SAR in retroviral vectors should have positive implications in gene repair strategies using ASCs. PMID- 20846053 TI - Isolation, characterization, and expansion methods for defined primary renal cell populations from rodent, canine, and human normal and diseased kidneys. AB - Chronic kidney disease (CKD) is a global health problem; the growing gap between the number of patients awaiting transplant and organs actually transplanted highlights the need for new treatments to restore renal function. Regenerative medicine is a promising approach from which treatments for organ-level disorders (e.g., neurogenic bladder) have emerged and translated to clinics. Regenerative templates, composed of biodegradable material and autologous cells, isolated and expanded ex vivo, stimulate native-like organ tissue regeneration after implantation. A critical step for extending this strategy from bladder to kidney is the ability to isolate, characterize, and expand functional renal cells with therapeutic potential from diseased tissue. In this study, we developed methods that yield distinct subpopulations of primary kidney cells that are compatible with process development and scale-up. These methods were translated to rodent, large mammal, and human kidneys, and then to rodent and human tissues with advanced CKD. Comparative in vitro studies demonstrated that phenotype and key functional attributes were retained consistently in ex vivo cultures regardless of species or disease state, suggesting that autologous sourcing of cells that contribute to in situ kidney regeneration after injury is feasible, even with biopsies from patients with advanced CKD. PMID- 20846054 TI - Fungal scleritis with exudative retinal detachment. AB - PURPOSE: To report a case of fungal scleritis associated with exudative retinal detachment. DESIGN: A rare case report. METHODS: Nonresolving fungal scleritis mimicking noninfective scleritis was treated with systemic and topical antifungals and low topical steroids after diagnosis was established on scleral scraping. Even after complete resolution of scleritis, exudative retinal detachment persisted. RESULTS: The patient was advised of a possible need to undergo vitreo retinal surgery if exudative retinal detachment persisted for more than a month after complete resolution of the scleritis component. CONCLUSION: Infective scleritis must be ruled out in cases of longstanding scleritis not responding to immunosuppressives. PMID- 20846055 TI - Mobility and access to transport issues as experienced by people with vision impairment living in urban and rural Ireland. AB - PURPOSE: The loss of vision is associated with the impairment of functional ability, including a reduced ability to move around and to utilise all forms of transport. Walking in unfamiliar environments is challenging and driving becomes a legal prohibition. This article explores mobility and access to transport issues of urban and rural dwelling people with vision impairment in Ireland. METHODS: Fourteen focus groups took place consisting of 121 people with vision impairment resident in both urban and rural Ireland. Participant selection was representative of the vision impaired community. Data were recorded, transcribed and analysed using thematic analysis. RESULTS: Poor access to public transport and a perceived absence of public awareness about vision impairment are evident from this study. Customised disability awareness training is deemed essential for both the public and transport staff. Difficulties with access issues within the physical environment are highlighted. CONCLUSION: The lack of availability of accessible transport creates an increased dependency on friends and family, and restricts access to medical, social and rehabilitative services. This study highlights issues concerning inequality of access to appropriate transport for rural vision impaired persons. These issues need to be brought to the attention of social planners and local government. PMID- 20846056 TI - Per Bergsjo, in memoriam. PMID- 20846057 TI - A time to remember. PMID- 20846058 TI - The overlap technique versus end-to-end approximation technique for primary repair of obstetric anal sphincter rupture: a randomized controlled study. AB - OBJECTIVE: To compare the outcome of end-to-end approximation versus the overlap technique for primary repair of obstetric anal sphincter rupture (OASR) at 12 month follow-up. DESIGN: Prospective, randomized controlled study. SETTING: University hospital. Sample. One hundred and twenty-eight patients with grade 3b, 3c or 4 OASR were randomized; 119 (end-to-end 60, overlap 59) received the allocated treatment. We obtained information concerning fecal incontinence from 101 (85%) patients. METHODS: The obstetric team on call performed the repairs. Wexner score, endoanal ultrasound (EAUS), and manometry were used to evaluate anal sphincter function at 12 months post-surgery. MAIN OUTCOME MEASURES: Primary outcome was incidence of solid stool leakage at least once a week. Secondary outcomes were flatus incontinence, Wexner score, external anal muscle defect examined by EAUS, and anal manometry results. RESULTS: One patient in the end-to end group and none in the overlap group reported leakage of solid stool once a week or more. Fourteen patients in the end-to-end group and 10 in the overlap group reported flatus incontinence (p = 0.48). Mean Wexner score was similar in both groups, 2.4 versus 2.2. One patient in the end-to-end group and none in the overlap group had a Wexner score >10 (severe anal incontinence) (NS). External sphincter defect was found in 2/46 in the end-to-end group compared to 0/41 in the overlap group (NS). Anal manometry findings were similar in both groups. CONCLUSION: The overlap repair was not superior to the approximation technique with regard to fecal incontinence at 12 months. PMID- 20846059 TI - Relation between umbilical cord blood pH, base deficit, lactate, 5-minute Apgar score and development of hypoxic ischemic encephalopathy. AB - OBJECTIVE: Umbilical cord acid-base analysis is fundamental for assessing intrapartum hypoxia. The accuracy of arterial umbilical cord blood lactate, pH and base deficit to reflect a low 5-minute Apgar score and hypoxic ischemic encephalopathy (HIE) stage 2-3 was assessed, and new gestational age-adjusted reference standards were compared with traditional stationary reference values. DESIGN AND SAMPLE: A total of 13,735 pH-validated routine cord acid-base values from singleton deliveries were tested with stationary and gestational age adjusted reference values using receiver operating characteristic curves and calculation of area under curve. SETTING: University hospital. MAIN OUTCOME MEASURES: Accuracy of low pH, high base deficit and high lactate, alone or in combination, to imply 5-minute Apgar score < 7 or < 4 or HIE. RESULTS: Gestational age-adjusted values were for all parameters significantly better than crude values to indicate Apgar score < 7. For Apgar score < 4, the differences were not significant. The frequency of HIE was 0.046%, making statistical analyses pointless. Gestational age-adjusted lactate had the overall best accuracy and among combinations; a low age-adjusted pH plus high age-adjusted lactate was slightly better than a low age-adjusted pH plus high age-adjusted base deficit. The sensitivity and positive predictive value were low for all parameters. CONCLUSIONS: Lactate in cord arterial blood at birth is at least as good as base deficit to reflect an impaired condition at birth, and best when gestational age-adjusted values are used. Due to methodological confounding involved in calculation of base deficit, lactate may replace base deficit as an acid-base outcome parameter at birth. PMID- 20846060 TI - Prenatal course and outcome in 103 cases of fetal spina bifida: a single center experience. AB - OBJECTIVE: To investigate the prenatal course and functional outcome for fetuses with spina bifida according to the level of the spinal lesion at prenatal ultrasound examination. DESIGN: Retrospective, descriptive study. SETTING: Tertiary referral center, Germany. POPULATION: A total of 103 fetuses with spina bifida identified between 1993 and 2008. METHODS: The antenatal course and postnatal outcome for affected fetuses were reviewed. The relation of relevant outcome domains to the anatomical level was assessed using Fisher's exact test and the chi(2)-test. MAIN OUTCOME MEASURES: Level and type of spinal lesion, pregnancy outcome, psychomotor development, bladder and bowel function. RESULTS: Our cohort included a total of 31 live born infants, 68 terminated pregnancies, four intrauterine fetal deaths and five postnatal deaths. Four cases were excluded from follow-up. Twenty of the remaining 22 infants had normal or only slightly impaired mental development (91%). Thirteen children (59%) were able to walk, but nine (41%) needed wheelchairs or were paraplegic. The rate of poor motor outcome varied strongly in dependence on the level of the lesion (22.2% at lower lumbosacral levels to 80% at thoracic level). The majority of the affected children (16/22, 72.7%) suffered from impairment of bladder function. In 36% of cases (8/22) anal incontinence was documented. CONCLUSION: Spina bifida can result in a spectrum of disabilities that frequently lead to an impairment of bladder, bowel and motor function. The motor function depended on level of the lesion. PMID- 20846061 TI - Potentiation of the uterus-relaxing effects of beta-adrenergic agonists with nifedipine: studies on rats and the human myometrium. AB - OBJECTIVE: We investigated how progesterone and salmeterol modify the effect of nifedipine in an in vivo preterm birth model in rats, and how terbutaline and nifedipine modify the contractions of the isolated human myometrium. DESIGN: Experimental animal and human myometrial studies. SAMPLE: Twenty-four female Sprague-Dawley rats and 13 human uterine tissues sampled from cesarean section. METHODS: Preterm birth was induced in Sprague-Dawley rats with a combination of mifepristone and prostaglandin-E(2). The animals were treated with nifedipine or its combination with salmeterol and progesterone. Additionally, isolated human myometrial strips from cesarean sections were stimulated with oxytocin, and the inhibitory effects of nifedipine and terbutaline were studied. RESULTS: Nifedipine delayed the preterm delivery in the rats, but its effect was tripled by the addition of beta(2)-mimetics, or abolished after progesterone pretreatment. Synergism was observed in the relaxing effects of nifedipine and terbutaline on the isolated human myometrium. CONCLUSION: The action of nifedipine in delaying labor is impeded by progesterone. A combination of nifedipine and beta(2)-agonists should be considered for the treatment or prevention of preterm birth. PMID- 20846062 TI - Unresolved grief in women and men in Sweden three years after undergoing unsuccessful in vitro fertilization treatment. AB - OBJECTIVE: To explore the experience of undergoing unsuccessful in vitro fertilization (IVF) treatment and of remaining childless 3 years after IVF in both women and men. DESIGN: Qualitative-approach study. SAMPLE: Ten women and nine men who had attended a public fertility clinic in Sweden. METHODS: Individual qualitative semi-structured interviews were conducted with qualitative content analysis guiding the analysis. RESULTS: Three years after the end of IVF treatment, most men and women were still processing and had not adapted to childlessness, indicating that the grieving process was unresolved. Unsuccessful IVF was experienced by women in terms of grief, whereas men took upon themselves a supportive role and did not express grief. A need for professional support and counseling in how to handle grief was described. An unstructured end after IVF treatment left unanswered questions. CONCLUSIONS: The grieving process after unsuccessful IVF treatment was hampered among both men and women. The provision of additional individual support during IVF is recommended as men and women experienced childlessness differently. Support and counseling concerning grief reactions following IVF failure, and a structured final consultation after IVF may facilitate the grieving process after undergoing unsuccessful IVF treatment. PMID- 20846063 TI - Teaching pelvic examination technique using professional patients: a controlled study evaluating students' skills. AB - OBJECTIVE: To compare the skills in pelvic examination technique between students who have had training with professional patients and a control group of students trained using clinical patients. DESIGN: Prospective controlled study. SETTING: University hospital. POPULATION: Students attending three consecutive courses in obstetrics and gynecology at Karolinska University Hospital. METHODS: A study group of 53 students received training in pelvic examination with professional patients and was compared with a control group of 34 students who were trained using clinical patients. MAIN OUTCOME MEASURES: The students' skills in pelvic examination technique were examined by teachers in a practical test. Students' skills were also evaluated by the students themselves and by the patients who participated in the examination. RESULTS: Students who had training with professional patients were more skilled in performing a pelvic examination and better prepared to examine their own patients than students trained using clinical patients. CONCLUSIONS: Training with professional patients is more effective in teaching pelvic examination technique than training with clinical patients. We recommend that the use of professional patients is considered in the training of medical students. PMID- 20846064 TI - Economic analysis of human papillomavirus triage, repeat cytology, and immediate colposcopy in management of women with minor cytological abnormalities in Sweden. AB - OBJECTIVE: To assess the cost-effectiveness of using human papillomavirus testing (HPV triage) in the management of women with minor cytological abnormalities in Sweden. DESIGN: An economic analysis based on a clinical trial, complemented with data from published meta-analyses on accuracy of HPV triage. The study takes perspective of the Swedish healthcare system. SETTING: The Swedish population based cervical cancer screening program. METHODS: A decision analytic model was constructed to evaluate cost-effectiveness of HPV triage compared to repeat cytology and immediate colposcopy with biopsy, stratifying by index cytology (ASCUS = atypical squamous cells of undetermined significance, and LSIL = low grade squamous intraepithelial lesion) and age (23-60 years, <30 years and >=30 years). MAIN OUTCOME MEASURES: Costs, incremental cost, incremental effectiveness and incremental cost per additional high-grade lesion (CIN2+) detected. RESULTS: For women with ASCUS >=30 years, HPV triage is the least costly alternative, whereas immediate colposcopy with biopsy provides the most effective option at an incremental cost-effectiveness ratio (ICER) of SEK 2,056 per additional case of CIN2+ detected. For LSIL (all age groups) and ASCUS (23-60 years and <30 years), HPV triage is dominated by immediate colposcopy and biopsy. Model results were sensitive to HPV test cost changes. CONCLUSION: With improved HPV testing techniques at lower costs, HPV triage can become a cost-effective alternative for follow-up of minor cytological abnormalities. Today, immediate colposcopy with biopsy is a cost-effective alternative compared to HPV triage and repeat cytology. PMID- 20846065 TI - Risk factors in women 40 years of age and younger with endometrial carcinoma. AB - OBJECTIVE: To identify and compare risk factors among endometrial cancer patients <=40 years of age, postmenopausal women with the same malignancy and women <=40 years without malignancy. DESIGN: Retrospective case-control study. SETTING: Athens University, department of obstetrics and gynecology of a tertiary hospital serving a mainly urban population. POPULATION: Endometrial cancer patients <=40 years (study group, n = 40), postmenopausal women with the same malignancy (positive controls, n = 40) and women <=40 (negative controls, n = 40) without endometrial cancer. METHODS: Clinical history, treatment and follow-up of patients were evaluated. Factors studied included age, histology, stage, grade, lymphovascular space involvement, body mass index (BMI), cytology, lymph node status, parity, smoking, family history, hypertension recurrence and survival. MAIN OUTCOME MEASURES: Differences in risk factors and characteristics. RESULTS: Nulliparity, smoking and hypertension were significantly related with endometrial cancer in the study group compared to positive controls (p = 0.001, p < 0.01 and p < 0.001, respectively). BMI >30 significantly characterized patients in the study group compared to negative controls (p = 0.006). Finally, irregular menstruation and family history of cancer were observed more often in the study group compared to both control groups. Stage, grade, myometrial invasion, lymphovascular space involvement and lymph node status were comparable between the study and positive control groups. CONCLUSION: Nulliparity, obesity, unstable menstruation, smoking and cancer in the family are strongly correlated with endometrial cancer risk in women <=40 years. PMID- 20846066 TI - Hormonal and metabolic characteristics of premenopausal women with a history of preeclamptic pregnancy. AB - OBJECTIVE: To investigate whether women with a history of preeclampsia have more signs of hyperandrogenism and insulin resistance in the premenopausal period than women with history of normotensive pregnancies. DESIGN: Case-control study. SETTING: University Hospital. SAMPLE: Eighteen women with a history of preeclamptic first pregnancy and 19 women with prior normotensive first pregnancy studied 23-24 years after delivery. METHODS: Diagnosis of metabolic syndrome was based on the International Diabetes Federation (IDF) criteria. Matsuda's whole body insulin sensitivity index, serum concentrations of follicle-stimulating hormone (FSH), sex hormone-binding globulin, and total and free calculated testosterone were assessed. Polycystic ovary syndrome (PCOS) phenotype was defined using Rotterdam criteria. MAIN OUTCOME MEASURES: Insulin sensitivity, metabolic syndrome and signs of hyperandrogenism. RESULTS: Insulin sensitivity and total and free testosterone were similar in the two groups. However, in women with prior preeclampsia and FSH below the median, calculated free testosterone levels were higher than in women with prior preeclampsia and FSH above the median (median 13.4 range (8.0-22.5) vs. 7.1 (5.1-20.5), p = 0.03). Of the women with previous preeclampsia, 17% (3/18) had metabolic syndrome and 11% (2/18) PCOS, versus 11% (2/19) and 0% of the controls, respectively. CONCLUSIONS: In women with prior preeclampsia, premenopause was not associated with insulin resistance, but signs of hyperandrogenism were present if FSH was within a premenopausal level. PMID- 20846067 TI - Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. AB - OBJECTIVE: To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. DESIGN: A preclinical and a clinical case-control trial. SETTING: Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. POPULATION: Pregnant and nonpregnant women and baboons receiving chemotherapy. METHODS: Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. MAIN OUTCOME MEASURES: Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state. RESULTS: Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. CONCLUSIONS: Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long term follow-up of women treated with chemotherapy during pregnancy is underscored. PMID- 20846068 TI - Potential barriers to the laparoscopic management of ectopic pregnancies: a regional UK study. AB - In this regional UK study across seven hospitals, we examined the potential barriers to undertaking a laparoscopic approach to the surgical management of ectopic pregnancies. Across the region 84% of surgically managed ectopic pregnancies were undertaken laparoscopically, although out of hours operating resulted in a higher rate of laparotomies. Trainees perceived themselves to be competent in carrying out laparoscopy for ectopic pregnancies and reported their training as adequate. Perceived barriers to training were a lack of operating time, service commitments, reduced working hours arising from the European working directive, and a lack of laboratory training facilities. In order to maintain and improve the laparoscopic rate for the management of ectopic pregnancies, it is necessary to ensure that trainees have more supervised operating time and better access to laboratory training facilities. PMID- 20846069 TI - Massive subchorionic thrombohematoma: a series of 10 cases. AB - A retrospective audit identified 10 cases of massive idiopathic subchorionic thrombohematoma. The incidence was 1:3,133. Only six of these pregnancies resulted in a livebirth and only two reached term. In eight cases there were ultrasound abnormalities, including two cases of placentomegaly both of which resulted in a pregnancy loss. There was one placental abruption. Seven of the women were nulliparous. Massive subchorionic thrombohematoma is associated with poor pregnancy outcome. Ultrasound findings of placentomegaly might be a bad prognostic sign. PMID- 20846070 TI - Four repetitive partial hydatidiform moles followed by malignant transformation to an invasive mole. PMID- 20846071 TI - Safety and efficacy of therapeutic plasma exchange in a pregnant patient with familial hypercholesterolemia. PMID- 20846072 TI - MR imaging of a maternal strangulated ileus during early pregnancy. PMID- 20846073 TI - Spontaneous rupture of broad ligament and uterine vessels during pregnancy. PMID- 20846074 TI - Towards comparability of data: using the ICF to map the contrasting definitions of disability in Irish surveys and census, 2000-2006. AB - PURPOSE: To examine how disability was measured and understood within Irish data sources 2000-2006, using the International Classification of Functioning, Disability and Health (ICF) as a guiding framework for a more comprehensive and transformative definition of disability. METHOD: During the EU-funded Measuring Health and Disability in Europe (MHADIE) project (2003-2006), an audit of data sources which included a disability identifier question was conducted. Thirty Irish data sources were examined in total. An overview of these data sources was provided in 'Disability Data Sources in Ireland' (National Disability Authority, unpublished, 2007). Using guidelines developed by Cieza et al. (J Rehabil Med 2002;34:205-210, J Rehabil Med 2002;27:212-218) five data sources were selected for detailed examination and were mapped to the ICF. These were the census (2006), National Disability Survey (2006), National Physical and Sensory Disability Database (2006), Survey of Lifestyles, Attitudes and Nutrition (2002), Euro Student Survey (2003). Subsequent work conducted after the completion of the MHADIE project added to the findings. RESULTS AND CONCLUSIONS: The environmental dimension of disability dominated the data collection exercises which used the ICF as their framework-for the National Disability Survey (NDS) and the National Physical and Sensory Disability Database (NPSDD). Both also had strong focus on activity and participation. When mapped on to the ICF, the data sources which preceded the ICF or did not use it, are shown to focus more on activity and participation data than any other ICF component. Across the five selected data sources, limited information was collected on body function and body structure. PMID- 20846075 TI - The experiences of using an anti-collision power wheelchair for three long-term care home residents with mild cognitive impairment. AB - PURPOSE: Presented are three case analyses of long-term care home residents with cognitive impairment who tested an anti-collision power wheelchair. We discuss technology design and research implications for this population. METHOD: Case studies involved 371 h of participant observation and 7 h of open-ended interview with residents (n = 3), family members (n = 3) and clinical staff (n = 11). Thematic analysis generated themes related to technological, psychological and social aspects of residents' inclination and disinclination towards power mobility use. RESULTS: Themes examined the discordance between others' and residents' reports of anti-collision power wheelchair use; a facet of response bias; unanticipated implications for independence and dependence; and implications of device design for self-presentation. CONCLUSIONS: Technology alone is insufficient to help residents to fully benefit from the autonomy that a wheelchair intervention can provide: close attention is required to the social and organisational factors of institutional life. For technology to be acceptable, the design must meet the functional and aesthetic needs of users. Considerations in the design of future power wheelchairs for residents with cognitive impairment include capabilities to drive on uneven surfaces, effort reducing driving modes, improved user interface usability, and acceptable driving speed, size and appearance. PMID- 20846080 TI - Impact of body mass index and weight loss on cancer-specific and overall survival in patients with surgically resected renal cell carcinoma. AB - OBJECTIVE: This study evaluated the impact of body mass index (BMI) and the influence of preoperative weight loss (WL) in each BMI category on survival in patients with surgically treated renal cell carcinoma (RCC). MATERIAL AND METHODS: In total, 834 patients undergoing nephrectomy for RCC were retrospectively reviewed. Overall survival (OS) and cancer-specific survival (CSS) were estimated by Kaplan-Meier analysis. Univariate and multivariate analyses were accomplished to assess the influence of preoperatively assessed clinical parameters, including BMI and WL, on survival. The mean postsurgical follow-up was 85 months (median 79 months, range 12-191 months). RESULTS: Of the patients studied, 251 (30%) presented with a BMI < 25 kg/m2, while 362 patients (44%) were overweight (BMI >= 25 to < 30 kg/m2) and 221 patients (26%) were obese (BMI >= 30 kg/m2). Fifty-two patients (6.2%) experienced WL. While BMI did not significantly influence OS and CSS, WL had a significant impact on survival in patients with a BMI < 30 kg/m2, in contrast to obese patients presenting with a BMI of >= 30 kg/m2. Further analysis showed overweight to influence significantly disorders in wound healing, but neither other complications nor postoperative mortality. CONCLUSIONS: This is the first study providing information regarding the influence of BMI in relation to WL in patients with surgically treated RCC. While BMI did not significantly influence the survival of patients in the present series, WL had a significant impact on survival of patients presenting with a BMI < 30 kg/m2. Hence, preoperative assessment of WL should be considered for the assessment of individual prognosis. PMID- 20846081 TI - Bladder pain syndrome: do the different morphological and cystoscopic features correlate? AB - OBJECTIVE: For the diagnosis of bladder pain syndrome (BPS), the International Society for the Study of Bladder Pain Syndrome (ESSIC) recommends a specific diagnostic work-up using cystoscopy with hydrodistension and bladder biopsies. This study evaluates the correlation between the histological findings in bladder biopsies handled following ESSIC recommendations, as well as the importance of the histological features in BPS compared with the cystoscopic findings. MATERIAL AND METHODS: The study included 15 men and 93 women. All patients underwent cystoscopy with hydrodistension, and at least three deep biopsies including detrusor muscle were taken. For the cell count the Leder stain was used most frequently. A cut-off point of 28 mast cells/mm(2) was used for detrusor mastocytosis. RESULTS: Significant correlations were found between urothelial damage and inflammatory infiltrate (p < 0.001). Detrusor mastocytosis was significantly more elevated in biopsies with normal urinary epithelium (Tukey corrected p < 0.0001) than in biopsies where the urothelium was damaged. No other correlations were found between histological findings or between histological and cystoscopic findings. CONCLUSION: Both cystoscopy with hydrodistension and histology can be used to illustrate different pathophysiological mechanisms in patients with BPS. These results favour the use of both in the classification of BPS patients. PMID- 20846082 TI - Using information technology to reduce asthma disparities in underserved populations: a pilot study. AB - BACKGROUND: Low health literacy has been identified as an independent predictor of poor asthma control. The Institute of Medicine considers the role of information technology (IT) as critical in providing "safe, effective, patient centered, timely, efficient, and equitable" care with the potential to reduce health disparities in underserved populations. The aim of this study was to design and evaluate an interactive computer-based questionnaire to assess asthma symptoms in children of parents with limited health literacy and/or limited English proficiency. METHODS: Volunteer caregivers attending a mobile asthma clinic were randomly assigned to complete the electronic or the paper-and-pencil version of an asthma screening questionnaire (ASQ) in their language of choice (English or Spanish). In the electronic version, a tablet computer was used to present the ASQ questions as video clips and to collect information through the touchscreen. Participants also completed a demographic questionnaire, a brief health literacy questionnaire, and a system usability and satisfaction questionnaire. Reliability of the paper and electronic self-assessments was evaluated by comparing each participant's answers to information they provided during a nurse-guided structured interview (gold standard). RESULTS: A total of 48 parents participated in the study, 26 completed the electronic ASQ and 21 the paper-and-pencil form. Thirty-five percent of the children had well-controlled asthma (n = 17). Most participants were Spanish speaking (67%) Hispanic (n = 44) mothers (n = 43) with a median age of 32 years. More than half had <=8 years of education (n = 25) and earned <$20,000 per year (n = 27). The median health literacy score was 32 (range 0-36). The correlation between health literacy scores and years of education was significant (rho = .47, p < .01). Concordance between the electronic ASQ and the nurse interview was significantly higher than concordance between the paper ASQ and the nurse interview (68% versus 54%; p < .01). All parents who completed the electronic questionnaire reported being satisfied; 96% felt comfortable using it, and found it simple to use. CONCLUSIONS: By facilitating the assessment of asthma symptoms at manageable cost, interactive information technology tools may help reduce barriers to access due to inadequate levels of English proficiency and health literacy. PMID- 20846083 TI - Symptoms and diagnosis of asthma in a general population – longitudinal results from the SHIP database. AB - BACKGROUND: Against the background of an increasing prevalence of allergies, the epidemiology of asthma in relation to age is still a matter of debate. To further clarify the prevalence of asthma, asthmatic symptoms, and their change over time within a population sample, we analyzed longitudinal data from the Study of Health in Pomerania (SHIP). METHODS: Standardized questionnaires for asthma and asthmatic symptoms were available in 4310 individuals aged 20-79 years [corrected]. The population sample underwent a 5-year follow-up with 3300 subjects reexamined. The questionnaire evaluated estimates to describe the prevalence in wheeze, chest tightness, shortness of breath, coughing, nocturnal symptoms, and asthma attacks in the past 12 months, current medications, current asthma, and nasal allergies at baseline and its longitudinal net change. RESULTS: The prevalence of current asthma at the baseline study was 1.8% [95% confidence interval (CI 1.4-2.2)], those of nasal allergies 16.7% (95% CI 15.6-17.9). Sixteen percent of asthmatic individuals were not medically treated. The net changes in asthmatic symptoms per 60 months of follow-up ranged between a decrease by 2.0% (chest tightness at night) and an increase by 1.2% (nocturnal attack of coughing). The proportions of subjects with current asthma remained unchanged. The prevalence of current asthma and symptoms was higher in young individuals, whereas the net change over time was slightly increasing at the age of 36 and above. CONCLUSION: Despite the fact of a high prevalence of subjects complaining of nasal allergies, the overall prevalence of current asthma remained low over time. The prevalence in asthma and asthmatic symptoms as well as its net changes over 5 years were age dependent. PMID- 20846084 TI - Cut-off points for defining asthma control in three versions of the Asthma Control Questionnaire. AB - INTRODUCTION: The Asthma Control QuestionnaireTM (ACQ) was developed to assess asthma control. The objective of this study is to determine the cut-off points that best differentiate between several types of asthma control in three versions of the ACQ used in clinical practice. MATERIALS AND METHODS: It appears 607 adult asthmatic patients (61% female) were recruited from 43 outpatient clinics in Spain. Once the patients were stratified by severity of asthma, they were then evaluated in an epidemiological study. To determine the optimum cut-off points, the area under the receiver operating characteristics (ROC) curve, as well as sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively), was calculated for each version of the ACQ (ACQ-FEV1 (forced expiratory volume in the first second), ACQ-PEF (peak expiratory flow), and ACQ wLF (without lung function)). RESULTS: The optimal cut-off for ACQ-FEV1 was 1.14 (the sum of 8 points/7 items), for ACQ-PEF 1.28 (the sum of 9 points/7 items), and for ACQ-wLF 0.83 (the sum of 5 points/6 items), and the percentage of correctly classified patients was 76.5%, 77.3%, and 77.2%, respectively. A comparison of ROCs obtained from the three versions of the ACQ shows that ACQ-wLF had a significantly greater area under the curves (AUC) (p = .004) than ACQ-FEV1. Patients were considered as having some control if their ACQ-FEV1 score fell between 1.14 and 1.57, if ACQ-PEF values were between 1.28 and 1.57, or if ACQ wLF scores ranged between 0.83 and 1.5. CONCLUSIONS: Our study, which was carried out in a manner which more closely reflects clinical practice, reveals differences in cut-offs used to define well-controlled asthma among three versions of the ACQ. PMID- 20846085 TI - Clearing clinical barriers: enhancing social support using a patient navigator for asthma care. AB - BACKGROUND: Patients with moderate or severe asthma, particularly those who are minority or poor, often encounter significant personal, clinical practice, and health system barriers to accessing care. OBJECTIVE: To explore the ideas of patients and providers for potentially feasible, individualized, cost-effective ways to reduce obstacles to care by providing social support using a patient advocate or navigator. METHODS: The authors conducted four focus groups of adults with moderate or severe asthma. Participants were recruited from clinics serving low-income and minority urban neighborhoods. Data from these patient focus groups were shared with two additional focus groups, one of nurses and one of physicians. Researchers independently coded and agreed upon themes from all focus groups, which were categorized by types of social support: instrumental (physical aid), informational (educational), emotional (empathizing), validation (comparisons to others). RESULTS: Patients and providers agreed that a patient navigator could help patients manage asthma by giving social support. Both groups found instrumental and informational support most important. However, patients desired more instrumental help whereas providers focused on informational support. Physicians stressed review of medical information whereas patients wanted information to complete administrative tasks. Providers and patients agreed that the patient navigator's role in asthma would need to address both short-term care of exacerbations and enhance long-term chronic self-management by working with practice personnel. CONCLUSIONS: Along with medical information, there is a need for providers to connect patients to instrumental support relevant to acute and long-term asthma-self-management. PMID- 20846086 TI - Characterization of the asthmatic population of St. Vincent and the Grenadines: asthma severity levels and atopic sensitization. AB - BACKGROUND: The developing country of St. Vincent and the Grenadines (SVG) reported a 4.5-fold increase in wheezing incidence between 1986 and 2002. It is unknown whether aeroallergens play a significant role in asthma in SVG. OBJECTIVE: The objective of the study is to investigate the importance of aeroallergens and the association between age and persistence of asthma into adulthood. Methods. Subjects were recruited from the National Asthma Clinic. Asthma was diagnosed in 525 participants and severity levels assigned according to the National Heart, Lung, and Blood Institute guidelines. Participants were separated into three age groups [<=6 years (n=176), 7-18 years (n=164), and >=19 years (n=185)]. Skin testing was performed on 171 participants to dust mite, cat, dog, cockroach, pollens, and mold. Age of asthma onset was obtained. RESULTS: Persistent asthma was diagnosed in 235 participants (44.8%) and increased with increasing age group (p<.0001). Atopy was identified in 121/171 (70.8%) participants and was significantly higher in persistent asthma (p<.004). A significant positive association was seen between atopy and age group (p<.0004) in participants with intermittent asthma but not in participants with persistent asthma. The most common allergen among the atopic participants was house dust mite (93.4%), followed by cockroach (47.9%). Adult participants reporting asthma onset in adulthood were less atopic than those whose asthma developed <=18 years of age (p<.05). CONCLUSIONS: The predominance of asthma with atopy in SVG implicates a role for atopy in the sudden rise in asthma cases. This asthma characteristic and the increase in persistent asthma with age in SVG are similar to those reported in the developed countries. PMID- 20846087 TI - Sensitization to Dermatophagoides, Blomia tropicalis, and other mites in atopic patients. AB - BACKGROUND: House dust mites (HDMs) are important causes of persistent allergic diseases, such as asthma and rhinitis. Various types of mites are found in the house dust of many countries, including Israel. OBJECTIVE: To evaluate the prevalence of sensitization to various HDMs in patients with perennial allergic rhinitis and asthma. METHODS: Sensitization of 117 patients with persistent rhinitis who attended the Allergy and Asthma Center in Tel Aviv (Israel) was evaluated by a skin prick test (SPT) using standardized allergenic extracts. The tested mites were Dermatophagoides farinae (DF), Dermatophagoides pteronyssinus (DP), Lepidoglyphus destructor (LD), Blomia tropicalis (BT), Tyrophagus putrescentiae (TP), Acarus siro (AS), Glycyphagus domesticus (GD), Blomia kulagini (BK), and Tetranychus urticae (TU). RESULTS: Most patients (n = 95, 81%) had a positive SPT to at least one mite extract. The three most frequent positive reactions were to DF (78%), DP (75%), and, unexpectedly, BT (77%). The correlation between DF and DP sensitization was higher than the correlation between DF or DP to BT (r = .78 versus r = .60, p < .05). Six patients had positive skin reactions to at least one mite species other than DF, DP or BT, mainly LD (n = 2, 2.1%) and BK (n = 4, 3.8%). CONCLUSIONS: The findings of this study identified the most ubiquitous mites to which Israeli patients with allergic rhinitis were sensitized and indicated the importance of BT as an allergen. Extracts of these mites may provide a more accurate diagnosis and effective treatment of respiratory diseases due to mite allergy in Israel and probably in other countries with similar climes. PMID- 20846089 TI - Use of Quantitative Structure-Activity Relationship (QSAR) and ADMET prediction studies as screening methods for design of benzyl urea derivatives for anti cancer activity. AB - 2D and 3D quantitative structure-activity relationship studies have been carried out for establishing a correlation between the structural properties of benzyl urea derivatives and their anti-tumour activities. From this correlation, the new chemical entities were designed, and their activity and absorption, distribution, metabolism, excretion, and toxicity properties were also predicted. Finally, the most promising compounds from these screening were synthesized and biologically evaluated for their anti-cancer properties. Compound 1-(2, 4-dimethylphenyl)-3, 3 dimethyl-1-(2-nitrobenzyl) urea (7d) showed significant anti-proliferative activity (at 100 ug/mL) in human cancer cell lines-T-cell leukemia (Jurkat J6), myelogenous leukemia (K562), and breast cancer (MCF-7) compared to reference standard 5-flurouracil. PMID- 20846090 TI - Molecular modelling studies on d-annulated benzazepinones as VEGF-R2 kinase inhibitors using docking and 3D-QSAR. AB - Chemotypes comprising the d-annulated 1,3-dihydro-2H-1-benzazepin-2-one scaffold derived from the paullone structure were found to be potent vascular endothelial growth factor receptor 2 (VEGF-R2) kinase inhibitors. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and docking studies were performed on a series of d-annulated benzazepinones with VEGF-R2 kinase inhibition activities. The comparative molecular field analysis and comparative molecular similarity indices analysis models using 32 molecules in the training set gave r(2)(cv) values of 0.811 and 0.769, r(2) values of 0.962 and 0.953, respectively. 3D contour maps generated from the two models revealed that the electron-withdrawing groups at R(1) and the bulky, electron-withdrawing as well as hydrogen bond donor groups at R(2) position are favourable; the bulky, hydrogen bond acceptor substituent at R(3) and the minor groups at R(4) position may benefit the potency. We have designed a series of novel VEGF-R2 inhibitors by utilizing the SAR results revealed in the present study, which were predicted with excellent potencies in the developed models. The results may aid in designing of potential VEGF-R2 inhibitors with better activities. PMID- 20846091 TI - A FLT3-inhibitory constituent from the rhizomes of Anemarrhena asphodeloides. AB - Bioactivity-guided investigation for the rhizomes of Anemarrhena asphodeloides using the Fms-like tyrosine kinase 3 (FLT3) inhibition assay led to the identification of an active xanthone, mangiferin. Mangiferin was found to inhibit activity of the FLT3 wild type and a mutated form of FLT3 with IC(50) values of 0.7 and 1.2 MUM, respectively. Furthermore, this compound was assessed with a small panel of select kinases anaplastic lymphoma kinase (ALK), insulin receptor, and epidermal growth factor receptor) and was also found to be active in ALK assay. PMID- 20846092 TI - "Cannibalistic" phagocytosis in acute megakaryoblastic leukemia (AML M7) with t(10;17)(p15;q22). PMID- 20846093 TI - Adoptive immunotherapy, chemotherapy, and second allogeneic transplant in the treatment of post-transplant relapse of acute leukemia in children: a single center experience. PMID- 20846094 TI - Evaluation of lymphangiogenic markers in Sezary syndrome. AB - Sezary syndrome (SS) is regarded as a leukemic, aggressive subtype of cutaneous T cell lymphoma (CTCL) characterized by the accumulation of malignant T-cells in the skin, as well as by blood and lymph node involvement. To date there have been no data on the extent of lymphangiogenesis in SS or erythrodermic mycosis fungoides (eMF). Lymphangiogenesis represents the de novo formation of lymphatic vasculature and has been associated with the occurrence of metastatic disease and poor prognosis. In this study we investigated lymphangiogenesis in skin biopsies from patients with SS and eMF. The expression of VEGFR-3 was significantly higher in patients with SS (p = 0.0285) as compared to patients with eMF. LYVE-1, podoplanin (PDPN), and VEGF-C stainings showed a similar tendency. The number of PDPN-expressing lymphatic vessels (p = 0.025) as well as CD31-positive blood vessels (p = 0.0065) correlated with disease progression in patients with SS. We show for the first time a non-vascular pattern of VEGF-C and VEGFR-3, i.e. their epidermal expression in erythrodermic CTCLs, suggesting their role in lymphocyte trafficking to the skin. PMID- 20846095 TI - Therapy-related myelodysplastic syndrome/acute myeloid leukemia following fludarabine therapy for non-Hodgkin lymphoma and chronic lymphocytic leukemia in Thai patients. PMID- 20846096 TI - The quinolone derivative CHM-1 inhibits murine WEHI-3 leukemia in BALB/c mice in vivo. AB - CHM-1 [2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one] is a quinolone derivative that has been reported to induce apoptosis and inhibit invasion of cancer cells. However, there is no available information to address the effects of CHM-1 on leukemia cells in vivo. Therefore, the present study examined the effects of CHM-1 using a mouse model of leukemia. We established leukemia in mice by injecting WEHI-3 cells into BALB/c mice. Mice were then treated with or without CHM-1 (5 and 10 mg/kg). CHM-1 promoted the total survival rate of leukemic mice and these effects were dose-dependent. CHM-1 increased body weight and decreased spleen weight, but did not affect liver weight. The levels of cell markers Mac-3 and CD11b were reduced by CHM-1, indicating that the differentiation of macrophage precursor cells was inhibited. Levels of CD3 and CD19 were induced by CHM-1, suggesting that the differentiation of precursors of T and B cells was promoted in PBMC. Results of the present study indicate that CHM-1 has an inhibitory effect on leukemia induced in mice in vivo and warrants further study as to the mechanisms and effects in other types of cancer. PMID- 20846097 TI - Prognostic significance of CD8 and CD4 T cells in chronic lymphocytic leukemia. AB - The prognostic value of the number of T cells and NK cells at diagnosis in CLL was analyzed in a cohort of 256 patients with CLL diagnosed between 1997 and 2007. Patients with leukemia showed elevated NK cells and T cell populations and CD4/CD8 ratio was inverted in 39.7% cases. Prognostic significance of lymphocytes was analyzed as a ratio of relative number of T cells to the size of the malignant monoclonal B-cell pool (T/NK cells:Malignant monoclonal B-cells ratio). Patients showed higher relative number of CD4 (p = 0.03), CD8 (p = 0.02), and NK cells (p = 0.01) in early Rai stage of disease. The multivariate Cox analysis identified the relative number of CD8 (hazard ratio (HR) = 1.464; p = 0.006) and CD4 T cells (HR = 0.091; p < 0.01) as independent predictors for survival. Additionally, patients with relative CD8 count > 0.074 or CD4 count > 0.1 had higher 10-year overall survival than patients with CD8 count <=0.074 or CD4 count <=0.1 (p = 0.002). Higher CD8 count was associated with significantly higher median time of survival of patients (149.33 vs. 82.06 months). Finally, association of the good prognostic factor of leukemia cells (CD38- with high relative CD8 count identified a group of patients with an indolent clinical course with an overall survival probability at 10 years of 95%. PMID- 20846098 TI - Multidrug resistance: overcoming the good, the bad, and the ugly. PMID- 20846099 TI - An infrequent relapse of multiple myeloma predominantly manifesting as light chain escape: clinical experience from two Chinese centers. AB - Patients with intact immunoglobulin (Ig) multiple myeloma (MM) usually show parallel fluctuations of their intact Ig and light chain (LC) concentrations. Herein we report 11 patients with relapsed, intact Ig MM with a marked increase in urinary LCs in the absence of a parallel rise in serum intact Ig, known as light chain escape (LCE). A major feature accompanying the presentation of LCE was conversion of plasma cell morphology. An important feature preceding the onset of LCE was the use of biological therapies. These patients were not associated with a highly aggressive course. Median overall survival times after the diagnosis of MM and after LCE were 48 months and 24 months, respectively. These cases represent a documented series of a rare but clinically important mode. More attention should be directed toward patients with intact Ig MM when the clinical course deteriorates despite a reduction of intact monoclonal immunoglobins. PMID- 20846100 TI - Response to lenalidomide in a patient with myelodysplastic syndrome with isolated del(5q) and JAK2 V617F mutation. PMID- 20846101 TI - What's new in Waldenström macroglobulinemia. PMID- 20846102 TI - ALK-negative anaplastic large cell lymphoma in leukemic phase with near pentaploidy. PMID- 20846103 TI - Identification and molecular characterization of a novel 3′ mutation in RUNX1 in a family with familial platelet disorder. PMID- 20846104 TI - The relationship between aminoterminal propeptide of type III procollagen and heart rate variability parameters in heart failure patients: a potential serum marker to evaluate cardiac autonomic control and sudden cardiac death. AB - BACKGROUND: Cardiac extra-cellular matrix (ECM) fibrosis plays an important role in the pathophysiology of heart failure (HF). It may provide electrical heterogeneity and a substrate for arrhythmogenicity, which may cause sudden cardiac death (SCD). METHODS: Twenty-one patients with manifestations of HF and a left ventricular ejection fraction (LVEF) <=50% were enrolled. The median age was 62 years and median LVEF was 33%. Time- and frequency-domain analysis of heart rate variability (HRV) on 24 h ambulatory electrocardiography recording was assessed. Serum markers of ECM turnover including type I and III aminoterminal propeptide of procollagen (PINP and PIIINP), matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were analyzed. RESULTS: The serum PIIINP concentration was correlated significantly with standard deviation of all normal to normal R-R intervals (SDNN) (r=-0.722, p=<0.001), percentage of adjacent NN interval differences >50 ms (pNN50) (r= 0.528, p=0.014), percentage of adjacent NN interval differences >20 ms (pNN20) (r=-0.545, p=0.002), very low frequency (VLF) (r=-0.490, p=0.024), low frequency (LF) (r=-0.491, p=0.024), and high frequency (HF) (r=-0.513, p=0.018). PINP, MMP 2, -9, TIMP-1 were not correlated with time- and frequency-domain analysis of HRV. CONCLUSIONS: PIIINP was significantly correlated with time- and frequency domain analysis of HRV in HF patients. PIIINP is a potential serological marker to evaluate cardiac autonomic control and risk of SCD in HF patients. PMID- 20846105 TI - Glycated hemoglobin vs. the oral glucose tolerance test for the exclusion of impaired glucose tolerance in high-risk individuals. AB - BACKGROUND: The aim of this study was to compare the use of glycated hemoglobin (HbA(1c)) and the oral glucose tolerance test (OGTT) in the diagnosis of impaired glucose tolerance in high-risk individuals. METHODS: A total of 713 patients with at least two risk factors for the development of type 2 diabetes were enrolled in the study. Fasting glucose and HbA(1c) were measured in all individuals. Patients whose fasting glucose concentrations were below 7.0 mmol/L underwent an OGTT. RESULTS: From the 713 patients, 234 were euglycemic, 200 had impaired fasting glucose, 118 presented with impaired glucose tolerance and 161 met the diagnostic criteria for type 2 diabetes. OGTT was performed in a total of 596 patients (83.6%). Statistically significant differences were observed for HbA(1c) concentrations in all groups. Receiver operating characteristic curve analysis was performed to assess the capability of HbA(1c) to discriminate between normal glucose tolerance and impaired glucose tolerance. An HbA(1c) value of 36 mmol/mol (5.4%) gave an optimal sensitivity of 85% and a specificity of 73%, and a negative predictive value of 97% for identifying patients with impaired glucose tolerance. CONCLUSIONS: HbA(1c) can be used to rule out patients at high-risk of developing type 2 diabetes. PMID- 20846106 TI - Ovarian hemangioma occurring synchronously with contralateral mature cystic teratoma in an 81-year-old patient. AB - PURPOSE: Ovarian hemangiomas are seen rarely. We present a case of an ovarian hemangioma occurring synchronously with contralateral mature cystic teratoma. CASE HISTORY: An 81-year-old woman presented with hypertension and hyponatremia. In ultrasonographic evaluation a pelvic mass was found located at the left ovary. Histologically, a mature cystic teratoma measuring 9.5 * 9 * 8 cm was seen in left ovary. In the right ovary an incidental vascular lesion measuring 3.5 * 1.5 * 1 cm was observed. Final histopathological examination of this lesion demonstrated a hemangioma of cavernous type. CONCLUSION: To the best of our knowledge, this is the first ovarian hemangioma case occurring synchronously with contralateral mature cystic teratoma. PMID- 20846107 TI - Matrix metalloproteinases. AB - Matrix metalloproteinases (MMPs), also known as matrixins, belong to a group of zinc-dependent proteins, which are thought to play a central role in the breakdown of extracellular matrix. Collagen, elastin, gelatin and casein are major components cleaved by MMPs. The breakdown of these components is essential for many physiological processes such as embryonic development, morphogenesis, reproduction, and tissue resorption and remodelling. MMPs also participate in pathological processes such as arthritis, cancer, cardiovascular and neurological diseases. This review summarizes current knowledge regarding these proteins, their participation in physiological and pathophysiological roles, their involvement in activation and inhibition, and their interactions with other metal binding proteins including metallothioneins. PMID- 20846108 TI - Recent insights on the medicinal chemistry of metal-based compounds: hints for the successful drug design. AB - Although more complex than usually described, the anticancer action mechanism of cisplatin is based on binding to DNA. Following this line of reasoning, most the metal-based compounds discovered soon after cisplatin were designed to acting as DNA-binding agents and their pharmacological properties were thought to be correlated with this mechanism. Apart from the DNA structure, a significant number of proteins and biochemical pathways have been described as drug targets for metal-based compounds. This paper is therefore aimed at discussing the most recent findings on the medicinal chemistry of metal-based drugs. It starts illustrating the design concept behind the bioinorganic chemistry of anticancer complexes. Anticancer metallic compounds that inhibit the protein kinases are concisely discussed as a case study. The accuracy and limitations of molecular docking programs currently available to predict the binding mode of metallic complexes in molecular targets are further discussed. Finally, the advantages and disadvantages of different in vitro screenings are briefly commented. PMID- 20846110 TI - Advances in metal-based probes for MR molecular imaging applications. AB - The role of MRI in the armory of diagnostic modalities for the medicine of the forthcoming years largely depends on how chemistry will provide advanced tools to meet the medical needs. This review aims at outlining the most innovative approaches that have been undertaken in the recent history of MRI contrast agents for tackling the challenges of sensitivity and specificity required by the new generation of contrast agents that should allow the visualization of pathological processes occurring on cellular and molecular scale (the so-called Molecular Imaging). Most of the classes of MRI agents clinically approved or currently under investigation in a preclinical phase exploit peculiar magnetic properties of metals. The conventional agents acting as T(1) or T(2)/T(2)* relaxation enhancers are primarily based on the paramagnetic or the superparamagnetic properties of Gd(III)-, Mn(II)- and iron oxides systems. Recently, there has been a renewed interest towards paramagnetic lanthanide complexes with an anisotropic electronic configuration thanks to their ability to induce strong effect on the resonance frequency of the spins dipolarly coupled with them. Such systems, formerly mainly used as shift reagents, have now attracted much attention in the emerging field of Chemical Exchange Saturation Transfer (CEST) MRI agents. PMID- 20846109 TI - Transport of therapeutic vanadium and ruthenium complexes by blood plasma components. AB - Low molecular weight and high molecular weight metal ion binders present in blood plasma are shortly described. The binding of vanadium and ruthenium complexes by these components has received much attention, namely their interactions with human serum albumin and transferrin, and these studies are critically reviewed. The influence of the protein binding on the bioavailability of the prospective drugs, namely on the transport by blood plasma and uptake by cells is also discussed. It is concluded that vanadium compounds are mainly transported in blood by transferrin, but that no study has properly addressed the influence of albumin and transferrin in the vanadium uptake by cells. Ruthenium complexes bind strongly to HSA, most likely at the level of His residues, leading to the formation of stable adducts. If the kinetics of binding to this protein is fast enough, probably they are mainly transported by this serum protein. Nevertheless, at least for a few Ru(III)-complexes, hTf seems to play an active role in the uptake of ruthenium, while HSA may provide selectivity and higher activity for the compounds due to an enhanced permeability effect. PMID- 20846111 TI - Radiometal complexes in molecular imaging and therapy. AB - Radiometals have become increasingly important because of their use both for diagnostic molecular imaging and therapy in Nuclear Medicine. The focus is on the study of biochemical processes at cellular and sub-cellular level in order to detect metabolic abnormalities associated with various diseases. For that purpose, molecules that selectively accumulate in the organ or tissue of interest by a specific mechanism such as receptor binding or interaction with biomolecules are labeled with (99m)Tc, (68)Ga, (153)Sm, (186/188)Re, (177)Lu, among others and used as radiopharmaceuticals. However, considerable effort is necessary to combine these radionuclides with biomolecules relevant to different pathological conditions. Intensive research on the coordination chemistry of these metals has led to novel labeling methods that yield stable compounds which retained the original biological activity of the ligand. Chemical aspects and clinical applications will be reviewed in this paper. PMID- 20846112 TI - Chelation therapies: a chemical and biochemical perspective. AB - Chelation therapy occupies a central place in modern medicine and pharmacology, because continuous studies with laboratory animals and extensive clinical experience demonstrate that acute or chronic intoxications with a variety of metals can be considerable improved by administration of a suitable chelating agent. In this review the chemical characteristics, properties and uses of the most common chelating agents as well as those of some new and very promising agents of this type, are discussed. In the second part of the review the biological and biochemical impact of these agents, as well as their use for the treatment of some selected diseases and disorders, are also analyzed and discussed in detail. PMID- 20846113 TI - Tailoring NO donors metallopharmaceuticals: ruthenium nitrosyl ammines and aliphatic tetraazamacrocycles. AB - The discovery of the involvement of nitric oxide (NO) in several physiological and pathophysiological processes launched a spectacular increase in studies in areas such as chemistry, biochemistry, and pharmacology. As a consequence, the development of NO donors or scavengers for regulation of its concentration and bioavailability in vivo is required. In this sense, ruthenium nitrosyl ammines and aliphatic tetraazamacrocyles have attracted a lot of attention due to their unique chemical properties. These complexes are water soluble and stable in solution, not to mention that they can deliver NO when photochemically or chemically activated by the reduction of the coordinated nitrosonium (NO+). The tuning of the energies of the charge transfer bands, the redox potential, and the specific rate constants of NO liberation, in both solution and matrices, is desirable for the achievement of selective NO delivery to biological targets, hence making the ruthenium ammines and aliphatic tetraazamacrocyles a quite versatile platform for biological application purposes. These ruthenium nitrosyls have shown to be active in firing neurons in mouse hippocampus, performing redox reactions in mitochondria, acting in blood pressure control, exhibiting cytotoxic activities against trypanosomatids (T.cruzi and L.major) and tumor cells. This tailoring approach is explored here, being heavily supported by the accumulated knowledge on the chemistry and photochemistry of ruthenium complexes, which allows NO donors/scavengers systems to be custom made designed. PMID- 20846114 TI - Potential use of vanadium compounds in therapeutics. AB - Vanadium is a trace element present in practically all cells in plants and animals. While the essentiality of vanadium for human beings remains to be well established, vanadium has become an increasingly important environmental metal. Vanadium compounds exert a variety of biological activities and responses. At pharmacological doses, vanadium compounds display relevant biological actions such as insulin and growth factor mimetic or enhancing effects, as well as osteogenic and cardioprotective activity. On the other hand, depending on the nature of compounds and their concentrations, toxicological actions and adverse side effects may also be shown. Nevertheless, the toxic effects may be useful to develop new antitumoral drugs. In this review, the authors summarize current knowledge and new advances on in vitro and in vivo effects of inorganic and organically-chelated vanadium compounds. The effects of vanadium derivatives on some cellular signaling pathways related to different diseases are compiled. In particular, the pathways relevant to the insulin mimetic, osteogenic, cadioprotective and antitumoral actions of vanadium compounds have been comprehensively reviewed. The knowledge of these intracellular signaling pathways may facilitate the rational design of new vanadium compounds with promising therapeutic applications as well as the understanding of secondary side effects derived from the use of vanadium as a therapeutic agent. PMID- 20846115 TI - Potential therapeutic applications of metal compounds directed towards hypoxic tissues. AB - Medicinal Inorganic Chemistry offers the high diversity of metal coordination chemistry for the development of bioactive compounds for therapeutic or diagnostic medicinal purposes. The design of novel metal-based antitumor agents occupies a privileged position in this discovery process. On the other hand, the research on metal-based radiopharmaceuticals for therapy and imaging is a subarea of high priority and development. This review describes therapeutic applications of metal compounds directed towards hypoxic tissues. Strategies in the search for new bioreductive metal-based prodrugs will be discussed. In addition, approaches for the imaging of hypoxic tissues by using metal radionuclides will be exemplified. PMID- 20846116 TI - Copper compounds in cancer chemotherapy. AB - Transitional metals have a large variety of coordination numbers and geometries, accessible redox states in physiological conditions and a wide range of thermodynamic and reactivity properties which can be successfully tuned by selection of suitable ligands. These characteristics can be used to develop new drugs with numerous advantages over the organic based drugs. Historically, research in this field has focus on platinum and DNA targeting; however, anticancer drug research may be expanded to include alternative metal compounds with different mode of action resulting in markedly different cytotoxic response profiles. Cooper complexes with selected ligands are being extensively studied as agents for the treatment of cancer. Current research on copper compounds as antitumoral compounds is being reviewed in this chapter particularly focused on the family of copper Casiopeinas. PMID- 20846117 TI - Advances and current perspectives in medicinal inorganic chemistry. PMID- 20846118 TI - Chelation of lysosomal iron protects against ionizing radiation. AB - Ionizing radiation causes DNA damage and consequent apoptosis, mainly due to the production of hydroxyl radicals (HO*) that follows radiolytic splitting of water. However, superoxide (O2*-) and H2O2 also form and induce oxidative stress with resulting LMP (lysosomal membrane permeabilization) arising from iron-catalysed oxidative events. The latter will contribute significantly to radiation-induced cell death and its degree largely depends on the quantities of lysosomal redox active iron present as a consequence of autophagy and endocytosis of iron-rich compounds. Therefore radiation sensitivity might be depressed by lysosome targeted iron chelators. In the present study, we have shown that cells in culture are significantly protected from ionizing radiation damage if initially exposed to the lipophilic iron chelator SIH (salicylaldehyde isonicotinoyl hydrazone), and that this effect is based on SIH-dependent lysosomal stabilization against oxidative stress. According to its dose-response-modifying effect, SIH is a most powerful radioprotector and a promising candidate for clinical application, mainly to reduce the radiation sensitivity of normal tissue. We propose, as an example, that inhalation of SIH before each irradiation session by patients undergoing treatment for lung malignancies would protect normally aerated lung tissue against life-threatening pulmonary fibrosis, whereas the sensitivity of malignant lung tumours, which usually are non-aerated, will not be affected by inhaled SIH. PMID- 20846119 TI - Psoriasis: from pathogenesis to novel therapeutic approaches. AB - Psoriasis is one of the commonest chronic inflammatory disorders. Its cause is unknown, but a wealth of studies indicate that the disease results from a complex and dynamic interplay between genetic and environmental factors that trigger an excessive inflammatory response in the skin. Dendritic cells and effector T-cells are central in the development of the psoriastic lesion, and cytokines produced by these cells stimulate keratinocytes to proliferate and increase the migration of inflammatory cells into the skin, promoting epidermal hyperplasia and inflammation. Understanding the immunology of the psoriatic plaque has led to new therapeutic options and novel candidates for immunomodulation, and has changed the ways psoriatic patients are managed. PMID- 20846120 TI - Recombinant mammalian DNA methyltransferase activity on model transcriptional gene silencing short RNA-DNA heteroduplex substrates. AB - The biochemical mechanism of short RNA-induced TGS (transcriptional gene silencing) in mammals is unknown. Two competing models exist; one suggesting that the short RNA interacts with a nascent transcribed RNA strand (RNA-RNA model) and the other implying that short RNA forms a heteroduplex with DNA from the unwound double helix, an R-loop structure (RNA-DNA model). Likewise, the requirement for DNA methylation to enact TGS is still controversial. In vitro assays using purified recombinant murine Dnmt (DNA methyltransferase) 1-dN (where dN indicates an N-terminal truncation), 3a and 3b enzymes and annealed oligonucleotides were designed to question whether Dnmts methylate DNA in a RNA-DNA heteroduplex context and whether a RNA-DNA heteroduplex R-loop is a good substrate for Dnmts. Specifically, model synthetic oligonucleotides were used to examine methylation of single-stranded oligonucleotides, annealed oligonucleotide duplexes, RNA-DNA heteroduplexes, DNA bubbles and R-loops. Dnmt methylation activity on the model substrates was quantified with initial velocity assays, novel ARORA (annealed RNA and DNA oligonucleotide-based methylation-sensitive restriction enzyme analysis), tBS (tagged-bisulfite sequencing) and the quantitative PCR-based method MethylQuant. We found that RNA-DNA heteroduplexes and R-loops are poor substrates for methylation by both the maintenance (Dnmt1) and de novo (Dnmt3a and Dnmt3b) Dnmts. These results suggest the proposed RNA/DNA model of TGS in mammals is unlikely. Analysis of tagged-bisulfite genomic sequencing led to the unexpected observation that Dnmt1-dN can methylate cytosines in a non-CpG context in DNA bubbles. This may have relevance in DNA replication and silencing of transcriptionally active loci in vivo. PMID- 20846121 TI - Plasmin on adherent cells: from microvesiculation to apoptosis. AB - Cell activation by stressors is characterized by a sequence of detectable phenotypic cell changes. A given stimulus, depending on its strength, induces modifications in the activity of membrane phospholipid transporters and calpains, which lead to phosphatidylserine exposure, membrane blebbing and the release of microparticles (nanoscale membrane vesicles). This vesiculation could be considered as a warning signal that may be followed, if the stimulus is maintained, by cell detachment-induced apoptosis. In the present study, plasminogen incubated with adherent cells is converted into plasmin by constitutively expressed tPA (tissue-type plasminogen activator) or uPA (urokinase-type plasminogen activator). Plasmin formed on the cell membrane then induces a unique response characterized by membrane blebbing and vesiculation. Hitherto unknown for plasmin, these membrane changes are similar to those induced by thrombin on platelets. If plasmin formation persists, matrix proteins are then degraded, cells lose their attachments and enter the apoptotic process, characterized by DNA fragmentation and specific ultrastructural features. Since other proteolytic or inflammatory stimuli may evoke similar responses in different types of adherent cells, the proposed experimental procedure can be used to distinguish activated adherent cells from cells entering the apoptotic process. Such a distinction is crucial for evaluating the effects of mediators, inhibitors and potential therapeutic agents. PMID- 20846122 TI - Monitoring of heart failure: comparison of left atrial pressure with intrathoracic impedance and natriuretic peptide measurements in an experimental model of ovine heart failure. AB - Monitoring of HF (heart failure) with intracardiac pressure, intrathoracic impedance and/or natriuretic peptide levels has been advocated. We aimed to investigate possible differences in the response patterns of each of these monitoring modalities during HF decompensation that may have an impact on the potential for early therapeutic intervention. Six sheep were implanted with a LAP (left atrial pressure) sensor and a CRT-D (cardiac resynchronization therapy defibrillator) capable of monitoring impedance along six lead configuration vectors. An estimate of ALAP (LAP from admittance) was determined by linear regression. HF was induced by rapid ventricular pacing at 180 and 220 bpm (beats/min) for a week each, followed by a third week with daily pacing suspensions for increasing durations (1-5 h). Incremental pacing induced progressively severe HF reflected in increases in LAP (5.9 +/- 0.4 to 24.5 +/- 1.6 mmHg) and plasma atrial (20 +/- 3 to 197 +/- 36 pmol/l) and B-type natriuretic peptide (3.7 +/- 0.7 to 32.7 +/- 5.4 pmol/l) (all P<0.001) levels. All impedance vectors decreased in proportion to HF severity (all P<0.001), with the LVring (left ventricular)-case vector correlating best with LAP (r2=0.63, P<0.001). Natriuretic peptides closely paralleled rapid acute changes in LAP during alterations in pacing (P<0.001), whereas impedance changes were delayed relative to LAP. ALAP exhibited good agreement with LAP. In summary, impedance measured with an LV lead correlates significantly with changes in LAP, but exhibits a delayed response to acute alterations. Natriuretic peptides respond rapidly to acute LAP changes. Direct LAP, impedance and natriuretic peptide measurements all show promise as early indicators of worsening HF. ALAP provides an estimate of LAP that may be clinically useful. PMID- 20846124 TI - Cyclooxygenase-2, p53 and glucose transporter-1 as predictors of malignancy in the development of gallbladder carcinomas. AB - Gallbladder carcinoma is the fifth most common malignancy of the gastrointestinal tract. The absolute characteristics of the disease are the high mortality rate due to the late discovery of a tumor and the low therapeutic possibilities except by surgical intervention. In oncology we can predict the outcome of the disease with a combination of classical standard clinico/pathological parameters (stage of the tumors, differentiation) and the intrinsic genetic and biochemical properties of the tumor. Such intrinzic properties of the tumors that are connected with the outcome of the disease are the denominators (markers). The author searched extensively for the expression and influence of 3 markers included in chronic inflammation and early carcinogenesis, cell cycle regulation and tissue hypoxia: cyclooxygenase-2 (COX-2), p53 gene and glucose transporter-1 protein (GLUT-1). The author discusses their possible role in the development as well as fighting this disease, if specific medications targeting them were available. PMID- 20846123 TI - The mechanism of protracted wound healing on oral mucosa in diabetes. Review. AB - Diabetic patients increase their body's susceptibility to infection and diabetes is a risk factor for periodontal diseases and oral infection. Although many studies showed the mechanism of impaired wound healing in diabetes, there are still arguments to shed light on what kind of factors, including local and systemic factors are involved in the protracted wound healing. This review article summarizes reports on the wound healing in diabetes and discusses the mechanism of the protracted wound healing of the oral mucosa in diabetes. Delayed vascularization, reduction in blood flow, decline in innate immunity, decreases in growth factor production, and psychological stresses may be involved in the protracted wound healing of the oral mucosa in diabetics. PMID- 20846125 TI - Dissolution studies of physical mixtures of indomethacin with alpha- and gamma cyclodextrins. AB - Oral administration of indomethacin has been limited by its poor water solubility. Cyclodextrins have been recognized as potential candidates to overcome the poor solubility of indomethacin through the formation of inclusion complexes. The aim of our study was to compare the dissolution profiles of pure indomethacin and its mixtures with alpha- and gamma-cyclodextrins The inclusion complexes of indomethacin with alpha- and gamma-cyclodextrins were prepared by direct mixing in dissolution vessel. Fixed volumes of the dissolution medium were withdrawn at 0,5; 1 and 4 hours. Dissolution tests were performed on the USP Apparatus 2, rotating speed 100 rpm at 37+/-0.5 degrees C, 500 ml, distilled water and 0,1 M HCl solution). Quantification of dissolved indomethacin was performed by UV/VIS spectrophotometric method at the absorption maximum around 320 nm. The results were expressed as relative dissolution rate (ratio between indomethacin dissolved from its physical mixtures with alpha- and gamma cyclodextrins and that dissolved the pure drug). Relative dissolution rates of indomethacin in combination with alpha- and gamma-cyclodextrins at the end of testing were in the range of 91,66 to 337,14 % (for alpha- cyclodextrin) and in the range of 128,57 to 301,92 % (for gamma-cyclodextrin). The complexation of indomethacin with alpha- and gamma-cyclodextrins resulted in the enhancement of dissolution rate. PMID- 20846126 TI - An immunohistochemical analysis of a rat model of proliferative vitreoretinopathy and a comparison of the expression of TGF-beta and PDGF among the induction methods. AB - Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment surgery or ocular trauma. Our previous study indicated that intravitreal co-injection of retinal pigmented epithelial (RPE)-J cells and platelet-rich plasma (PRP) (not RPE-J cells or PRP alone) in Wistar rat eyes can successfully induce a model of PVR. But which cells are involved in this process and why different induction methods, intravitreal injection of RPE-J cells or/and PRP, induced a different situation remain to be unknown. In this study, immunohistochemistry was performed to identify the main cell types involved in this process. The expression levels of transforming growth factor (TGF)-beta2, platelet-derived growth factor (PDGF)-AA and PDGF-BB were tested using enzyme linked immunosorbent assay (ELISA). The results showed that RPE cells, glial cells, fibroblasts and macrophages took part in the pathogenesis of this model. The expression levels and durations of TGF-beta2 and PDGF-BB partially explained the different results induced by the different induction methods. This provides an experimental proof for attenuation of the experimental PVR by targeting at a specific cells or growth factor. PMID- 20846127 TI - Gender and age-related differences in patients with the metabolic syndrome in a highly endogamous population. AB - The objective of the study was to examine the differences in gender and age prevalences of metabolic syndrome (MetS) among adult Qatari population according to the revised criteria of NCEP ATP III and IDF, assess which component contributed to the higher prevalence of the MetS and identify the characteristics of the subjects with MetS. The study was designed as a cross-sectional study. The survey was carried out in urban and semi-urban primary health care centers. The survey was conducted in the period from January 2007 to July 2008 among Qatari nationals above 20 years of age. Of the 1536 subjects who were approached to participate in the study, 1222 (79.6%) gave their consent. Face to face interviews were conducted using a structured questionnaire followed by laboratory tests. MetS was defined using the National Cholesterol Education Program - Third Adult Treatment Panel (ATP III) as well as the International Diabetes Federation (IDF). The overall prevalence of MetS in studied subjects was 26.7% and 33.9% according to ATPIII and IDF (p<0.001) criteria respectively. The prevalence of MetS by both definitions peaked in the 30-39 years age group among males, and the 40-49 years age group among females. The greatest number of males with MetS were university educated; while the greatest number of females with MetS were either illiterate or had a primary school education. The prevalence of MetS was higher among females. Among the components of MetS, the prevalence of central obesity was significantly higher in studied subjects. The overall prevalence of MetS and its components according to IDF criteria was higher in studied subjects than the estimates given by the ATPIII criteria. Overall, the prevalence of the metabolic syndrome in the State of Qatar is about 10-15% higher than in most developed countries, with generally higher prevalence rates for women. Preventive strategies will require identifying socio-demographic factors and addressing modifiable risk behaviours, including lack of physical activity, and dietary intake. PMID- 20846128 TI - Successful percutaneous septal alcohol ablation after surgical myectomy. AB - Hypertrophic obstructive cardiomyopathy (HOCM) is a primary, usually familial and genetically fixed myocardial hypertrophy, with dynamic left ventricular outflow tract obstruction. An alternative to surgical myectomy in the treatment of severe, drug refractory, HOCM is percutaneous transluminal septal myocardial ablation (PTSMA). We report a case of 24 year old female patient who had the first septal myectomy but because of progression of her disease, the percutaneous treatment of hypertrophic obstructive cardiomyopathy was performed. A year after the PTSMA the patient was without of symptoms. PMID- 20846129 TI - Endothelin-1 induced vascular smooth muscle cell proliferation is mediated by cytochrome p-450 arachidonic acid metabolites. AB - Endothelins (ETs) are a family of three peptides (ET-1, ET-2, ET-3) that are implicated in the physiological control of vascular smooth muscle cell (VSMC) and myocardial contractility and growth. ET-1 is vasoactive peptide that acts via ET A receptors coupling inducing vascular smooth muscle cell contraction. ET-1 is involved in the development and maintenance of hypertension. Aim of this study was to investigate whether ET-1 can induce vascular smooth muscle cell proliferation through arachidonic acid (AA) metabolites formed via cytochrome P!450 (CYP-450). VSMC proliferation was measured by [3H]thymidine incorporation in cultured cells treated by ET-1 (10 to l00 nmol/L) in presence of different inhibitors of CYP-450 (17-ODYA 5 MUmol/L), lipoxygenase (LO) (baicalein 20 MUmol/L) and cyclooxygenase (COX) (indomethacin 5 MUmol/L). ET-1 (10 to 100 nmol/L) induced VSMC proliferation and this effect was attenuated by CYP-450 inhibitor (17-ODYA) and lipoxygenase (LO) inhibitor (baicalein) but not by cyclooxygenase (COX) inhibitor (indomethacin). CYP-450 and LO metabolites of AA, 20-hydroxyeicosatetraenoic acid (HETE) and 12-HETE increased [3H]thymidine incorporation in VSMC. Inhibitors of MAP kinase (PD-98059 50 MUmol/L) and cPLA2 (MAFP 50 MUmol/L) attenuated ET-1 as well as 20-HETE induced VSMC proliferation. These results suggest AA metabolites via CYP-450 mediates ET-1 induce VSMC proliferation. PMID- 20846130 TI - Cardiovascular screening in young athletes in Sarajevo Canton. AB - Potential risk of sudden death during sports participation makes screening of competitive athletes of vital importance. Congenital cardiac anomalies and non atherosclerotic, acquired myocardial conditions are primary causes underlying exercise-induced cardiac death in young patients. Since cardiovascular conditions are the leading causes of non-traumatic, exercise-induced cardiac events, cardiovascular screening preceding sports participation in mandatory. The objectives of this study were to determine prevalence of cardiac conditions through cardiovascular screening of young athletes and to establish preventive strategy. The study was conducted at the Sports Medicine Center of Sarajevo Canton and at the Pediatric Clinic of University of Sarajevo Clinics Centre in the period 2007-2009. The study was supported by Canton Sarajevo Ministry of Health and Ministry of sports, science and culture. The study targeted a group of 214 athletes, 8-18 years of age with average age being 15.26. The group was subdivided into five groups according to the age. After taking the anamnesis (family, personal and cardiological) patients were subjected to the measuring of body mass and height, blood pressure and heart rate and oxygen saturation, recording of 12-lead ECG, specialist examination (pediatrician, sports medicine specialist and cardiologist) and complete heart echocardiography. No examined athletes expressed subjective discomfort. Congenital cardiac anomalies were not diagnosed in any athlete. Also, cardiovascular abnormalities requiring additional evaluation, positive cardiac anamnesis, abnormal auscultatory findings, hypertension or abnormal ECG findings were not recognized in any patient. Moderate correlation was found among the left ventricle mass and heart rate (p<0.05). In order to minimalize or even possibly prevent the risk of sudden cardiac death it is necessary to establish an adequate strategy of cardiovascular screening of young athletes. PMID- 20846131 TI - Impairment of the in vitro release of carbamazepine from tablets. AB - Carbamazepine belongs to the class II biopharmaceutical classification system (BCS) which is characterized by a high per-oral dose, a low aqueous solubility and a high membrane permeability. The bioavailability of such a drug is limited by the dissolution rate. The present study deals with the formulations of immediate release tablets of poorly soluble carbamazepine. As model tablets for this investigation, two formulations (named "A" and "B" formulations) of carbamazepine tablets labeled to contain 200 mg were evaluated. The aim of this study was to establish possible differences in dissolution profile of these two formulations purchased from the local market. The increased crystallinity together with enlarged particle size, enhanced aggregation and decreased wettability of the drug, resulted in insufficient dissolution rate for formulation "B". From the dissolution point of view, this formulation was inferior to the formulation "A", due to the solubilization effect. PMID- 20846132 TI - Noise induced hypertension and prehypertension in Pakistan. AB - The present study investigates the relationship of different sound levels with hypertension and prehypertension in Pakistani population. A cross sectional study was conducted to determine the prevalence of hypertension and prehypertension due to exposure of sound level <=80 dBA (A weighted sound pressure level), 81-94 dBA and >=95 dBA in November 11, 2005 to January 30, 2007. Sites were selected with stable sound ranges according to the above mentioned criteria. After selecting sampling sites, workers living in that area for at least 8 hours per day were categorized on the basis of blood pressure in groups called as normotensive, prehypertensive and hypertensive. Persons with diabetes, chronic bacterial or viral infections, alcohol addiction, kidney problems were excluded from the study. For getting homogenous groups, age range of 30-50 years was selected. Out of 566 samples, 90 excluded samples were consisted of 8% diabetic patients, 5% hepatitis C patients, 3% hepatitis B patients and 0% AIDS patients. Out of 476 participants, 389 samples were found with age 40+/-10 years. High noise increased the risks of hypertension (Odds ratio: 4.41; Confidence interval: 2,123-9,196) and prehypertension (Odds ratio: 3,809; Confidence Interval: 1,804-8,042) as compared to the normal sound level. However increased chances of hypertension (Odds ratio: 2,271; Confidence interval: 1,043-4,946) and prehypertension (Odds ratio: 3,028; Confidence Interval: 1,440-6,367) were observed on median noise exposure also. These findings suggest that sound level more than 81 dBA increases the chances for development of hypertension and prehypertension in Pakistani population. PMID- 20846133 TI - Evaluation of carcinogenic effects of electromagnetic fields (EMF). AB - The purpose of this study was to investigate the carcinogenic effects of electromagnetic fields on human. There are many effects of electromagnetic fields on human such as cancer, epidemiology, acute and chronic effects. These effects vary according to the field strength and environmental conditions. There have been many instances of harmful effects of electromagnetic fields from such seemingly innocuous devices as mobile phones, computers, power lines and domestic wiring. The balance of epidemiologic evidence indicates that mobile phone use of less than 10 years does not pose any increased risk of brain tumour or acoustic neuroma. For long-term use, data are sparse, and the following conclusions are therefore uncertain and tentative. PMID- 20846134 TI - In vitro research of the alteration of neurons in vagal core in medulla oblongata at asphyxic deaths. AB - The aim of this study was to research the morphological changes of neurons in the vagus nerve nuclei in medulla oblongata in asphyxia related death cases. Morphological changes that were investigated were mainly in the dorsal motor respiratory center (DMRC), nucleus tractus solitarius (nTS) and nucleus ambigus (nA) in the medulla oblongata. In our research, the autopsy material from asphyxia related death cases was used from various etiologies: monoxide carbon (CO), liquid drowning, strangulation, electricity, clinical-pathological death, firing weapon, explosive weapon, sharp and blunt objects and death cases due to accident. The material selected for research was taken from medulla oblongata and lungs from all lobes. The material from the medulla oblongata and lungs was fixed in a 10% solution of buffered formalin. Special histochemical methods for central nervous system (CNS) were employed like: Cresyl echt violet, toluidin blue, Sevier-Munger modification and Grimelius. For stereometrical analysis of the quantitative density of the neurons the universal testing system Weibel M42 was used. The acquired results show that in sudden asphyxia related death cases, there are alterations in the nuclei of vagal nerve in form of: central chromatolysis, axonal retraction, axonal fragmentation, intranuclear vacuolization, cytoplasmic vacuolization, edema, condensation and dispersion of substance of Nissl, proliferation of oligodendrocytes, astrocytes and microglia. The altered population of vagus nerve neurons does not show an important statistical significance compared to the overall quantity of the neurons in the nuclei of the vagus nerve (p<0.05). PMID- 20846135 TI - Outcomes of 3% green tea emulsion on skin sebum production in male volunteers. AB - This study was aimed to depict potential effects of stable formulation (water in oil emulsion), containing 3% green tea (Camellia sinensis L) extract on skin sebum production in healthy human volunteers. For this purpose formulation was designed using 3% ethanolic green tea extract and Abil(r)EM90 was used as an emulsifier. Formulation was applied to the cheeks of healthy human volunteers (n=10) for a period of 8 weeks. Measurements for skin sebum production were considered using Sebumeter MPA 5. Results were compiled and any effect produced by the formulation was justified statistically. It was observable that statistically significant (p < 0.5%) results were found for skin sebum production after long term application of the formulation. 3% formulation of green tea extract was ideal in all aspects and can be experienced in skin disorders like acne to further investigate its effects in unhealthy volunteers. PMID- 20846136 TI - Oxidative stress in cataractogenesis. AB - The aim of our study was to compare levels of antioxidative agent -total SH groups and the final product of lipid peroxidation- malondialdehyde (MDA) in serum, and glutathione (GSH) and MDA in nucleocortical parts of lens after extracapsular extraction of cataract. Patient were (38 with cataract and 38 controls) matched by sex and years of life. Diagnosis of cataract was established by complete ocular examination. All results are expressed as mean +/- S.D. A Student's t-test was used to estimate differences between the groups. The level of significance was p<0.05. Total sulfhydryl groups were determined in serum by the method of Ellman as well as GSH content in nucleocortical parts of lenses using the method of Sedlak and Lindsay. Lipid peroxidation, evidenced by formation of thiobarbituric acid reactive substances (TBARS), was determined in nucleocortical parts of the lens and in serum. Our results show a statistical significance in concentration of total SH groups (225.37+/-82.19umol/L, controls 311.03+/-60.37umol/L p<0.05) and MDA (20.24+/-8.12, and controls 8.73+/ 2.53umol/L, p<0,001) in serum among patients with age related cataract and controls. There was no statistical significance in concentration of total SH groups and MDA in serum among patients with different type of age related cataract and in nucleocortical parts of lens. The present study concludes that there is a statistical significance in concentration of total SH groups and MDA in serum among patients with age related cataract and controls, but there were no statistical significance in concentration of GSH and MDA in serum and nucleocortical parts of lens in patient with different type of cataract. PMID- 20846137 TI - Inhibition of cyclooxygenase-2 prevents adverse effects induced by phosphodiesterase type 4 inhibitors in rats. AB - BACKGROUND AND PURPOSE: Phosphodiesterase type 4 (PDE4) inhibitors such as roflumilast are currently being developed as anti-inflammatory treatments for chronic airway disorders. However, high doses of PDE4 inhibitors have also been linked to several side effects in different animal species, including pro inflammatory effects in the rat. Here, we analysed PDE4-related toxicological findings in a rat model and how these side effects might be therapeutically prevented. EXPERIMENTAL APPROACH: Wistar rats were treated orally once daily with 10 mg.kg-1 roflumilast for 4 days. Macroscopic changes were monitored throughout the study and further parameters were analysed at the end of the experiment on day 5. In addition, the effects of concomitant treatment with cyclooxygenase (COX) inhibitors were assessed. KEY RESULTS: Supratherapeutical treatment with roflumilast induced marked body and spleen weight loss, diarrhea, increased secretory activity of the harderian glands, leukocytosis, increased serum cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels, and histopathological changes in thymus, spleen, mesentery and mesenteric lymph nodes. All these toxicological findings could be prevented by the non-steroidal anti-inflammatory drug (NSAID) and non-selective COX inhibitor, diclofenac, given orally. Similar protective effects could be achieved by the COX-2 selective inhibitor lumiracoxib, whereas the COX-1 selective inhibitor SC-560 was generally not effective. CONCLUSIONS AND IMPLICATIONS: Treatment with an NSAID inhibiting COX-2 prevents the major effects found after subchronic overdosing with the PDE4 specific inhibitor roflumilast. If this effect translates into humans, such combined treatment may increase the therapeutic window of PDE4 inhibitors, currently under clinical development. PMID- 20846138 TI - Maternal dietary n-6/n-3 fatty acid ratio affects type 1 diabetes development in the offspring of non-obese diabetic mice. AB - Environment factors, including maternal or infant dietary nutrition have been reported to have an influence on the pathogenesis of type 1 diabetes. In the present study, to investigate the effect of maternal or post-weaning offspring's nutrition, in particular the essential fatty acid ratio (n-6/n-3) on the development of type 1 diabetes, we prepared two kinds of chows with n-6/n-3 ratios of 3.0 (L) and 14.5 (H), and provided them to mothers of non-obese diabetic (NOD) mice during gestation and lactation and to the offspring after weaning. The n-6/n-3 ratios in breast milk and erythrocyte membrane of NOD offspring became nearly the same with that of the maternal diet at 2 weeks after birth. In the L chow-fed offspring from L chow-fed mother (LLL), levels of insulitis were higher than those in the H chow-fed offspring from H chow-fed mother (HHH) at 4 weeks of age, while the levels in the LLL offspring became lower than those in the HHH after 6 weeks. Early insulin autoantibody expressions were found from 2 to 6 weeks in the HHH offspring, but not in the LLL. The LLL offspring exhibited strong suppression of overt diabetes development in regard to the onset and accumulated incidence of diabetes compared to the HHH. The study with combined L and H chows during gestation, lactation in mother and in post weaning offspring revealed that only the LLH chow significantly suppressed the development of diabetes with similar kinetics to LLL chow, although the other combinations may delay the onset of diabetes. The present findings suggest that n 6/n-3 ratio of the maternal diet during gestation and lactation rather than that of offspring after weaning strongly affects the development of overt diabetes in NOD mice. PMID- 20846140 TI - Tolerance of Pseudomonas pseudoalcaligenes KF707 to metals, polychlorobiphenyls and chlorobenzoates: effects on chemotaxis-, biofilm- and planktonic-grown cells. AB - Pseudomonas pseudoalcaligenes KF707 is a polychlorinated biphenyls (PCBs) degrader, also tolerant to several toxic metals and metalloids. The work presented here examines for the first time the chemotactic response of P. pseudoalcaligenes KF707 to biphenyl and intermediates of the PCB biodegradation pathway in the presence and absence of metals. Chemotaxis analyses showed that biphenyl, benzoic acid and chlorobenzoic acids acted as chemoattractants for KF707 cells and that metal cations such as Ni(2+) and Cu(2+) strongly affected the chemotactic response. Toxicity profiles of various metals on KF707 cells grown on succinate or biphenyl as planktonic and biofilm were determined both in the presence and in the absence of PCBs. Notably, KF707 cells from both biofilms and planktonic cultures were tolerant to high amounts (up to 0.5 g L(-1)) of Aroclor 1242, a commercial mixture of PCBs. Together, the data show that KF707 cells are chemotactic and can form a biofilm in the presence of Aroclor 1242 and specific metals. These findings provide new perspectives on the effectiveness of using PCB-degrading bacterial strains in bioremediation strategies of metal-co contaminated sites. PMID- 20846141 TI - A molecular probe for Basidiomycota: the spermidine synthase-saccharopine dehydrogenase chimeric gene. AB - By means of an in silico analysis, we demonstrated that a previously described chimeric gene (Spe-Sdh) encoding spermidine synthase, a key enzyme involved in the synthesis of polyamines, and saccharopine dehydrogenase, an enzyme involved in lysine synthesis in fungi, were present exclusively in members of all Basidiomycota subphyla, but not in any other group of living organisms. We used this feature to design degenerated primers to amplify a specific fragment of the Spe-Sdh gene by PCR, as a tool to unequivocally identify Basidiomycota isolates. The specificity of this procedure was tested using different fungal species. As expected, positive results were obtained only with Basidiomycota species, whereas no amplification was achieved with species belonging to other fungal phyla. PMID- 20846142 TI - Soluble and particulate methane monooxygenase gene clusters of the type I methanotroph Methylovulum miyakonense HT12. AB - The gene clusters encoding soluble methane monooxygenase (sMMO) and particulate methane monooxygenase (pMMO) were cloned and sequenced from a new type I methanotroph, Methylovulum miyakonense HT12. The sMMO gene cluster consisted of the structural genes mmoXYBZDC, the regulatory genes mmoG and mmoR and another ORF orf1. Transcriptional analysis revealed that these sMMO genes were transcribed as a single unit from a sigma(54) -dependent promoter located upstream of mmoX. In the pMMO gene cluster, the pmoCAB operon was under the control of a sigma(70) -dependent promoter. The organization of each MMO operon was largely conserved with that of the previously described methanotrophs. However, unlike other methanotrophs, M. miyakonense HT12 harbored only a single copy of the pmoCAB gene. These data provide new insights into the structure of MMO genes. PMID- 20846139 TI - What have positron emission tomography and 'Zippy' told us about the neuropharmacology of drug addiction? AB - Translational molecular imaging with positron emission tomography (PET) and allied technologies offer unrivalled applications in the discovery of biomarkers and aetiological mechanisms relevant to human disease. Foremost among clinical PET findings during the past two decades of addiction research is the seminal discovery of reduced dopamine D(2/3) receptor expression in the striatum of drug addicts, which could indicate a predisposing factor and/or compensatory reaction to the chronic abuse of stimulant drugs. In parallel, recent years have witnessed significant improvements in the performance of small animal tomographs (microPET) and a refinement of animal models of addiction based on clinically relevant diagnostic criteria. This review surveys the utility of PET in the elucidation of neuropharmacological mechanisms underlying drug addiction. It considers the consequences of chronic drug exposure on regional brain metabolism and neurotransmitter function and identifies those areas where further research is needed, especially concerning the implementation of PET tracers targeting neurotransmitter systems other than dopamine, which increasingly have been implicated in the pathophysiology of drug addiction. In addition, this review considers the causal effects of behavioural traits such as impulsivity and novelty/sensation-seeking on the emergence of compulsive drug-taking. Previous research indicates that spontaneously high-impulsive rats--as exemplified by 'Zippy'--are pre-disposed to escalate intravenous cocaine self-administration, and subsequently to develop compulsive drug taking tendencies that endure despite concurrent adverse consequences of such behaviour, just as in human addiction. The discovery using microPET of pre-existing differences in dopamine D(2/3) receptor expression in the striatum of high-impulsive rats suggests a neural endophenotype that may likewise pre-dispose to stimulant addiction in humans. PMID- 20846143 TI - TOL plasmid carriage enhances biofilm formation and increases extracellular DNA content in Pseudomonas putida KT2440. AB - Adherent growth of Pseudomonas putida KT2440 with and without the TOL plasmid (pWWO) at the solid-liquid and air-liquid interface was examined. We compared biofilm formation on glass in flow cells, and assayed pellicle (air-liquid interface biofilm) formation in stagnant liquid cultures by confocal laser scanning microscopy. The TOL-carrying strains formed pellicles and thick biofilms, whereas the same strains without the plasmid displayed little adherent growth. Microscopy using fluorescent nucleic acid-specific stains revealed differences in the production of extracellular polymeric substances: TOL carriage leads to more extracellular DNA (eDNA) in pellicles and biofilms. Pellicles were dissolved by DNase I treatment. Enhanced cell lysis due to plasmid carriage was ruled out as the mechanism for eDNA release. We report, for the first time, that carriage of a conjugative plasmid leads to increased biofilm formation by production of eDNA. PMID- 20846144 TI - Vmr 1p is a novel vacuolar multidrug resistance ABC transporter in Saccharomyces cerevisiae. AB - The Saccharomyces cerevisiae Yhl035p/Vmr1p is an ABC transporter of the MRP subfamily that is conserved in all post Whole Genome Duplication species. The deletion of the YHL035 gene caused growth sensitivity to several amphiphilic drugs such as cycloheximide, 2,4-dichlorophenoxyacetic acid, 2,4-dinitrophenol as well as to cadmium and other toxic metals. Vmr1p-GFP was located in the vacuolar membrane. The ATP-dependent transport of a DNP-S-glutathione conjugate was reduced in a vesicular fraction from the VMR1 deletant. The energy-dependent efflux of rhodamine 6G was increased by VMR1 deletion. Growth sensitivity to cadmium of the VMR1-deleted strain was more pronounced in glycerol/ethanol than in glucose-grown cells. The VMR1 promoter had higher activity when grown in glycerol/ethanol compared with glucose. In glucose, the VMR1 promoter was activated by the deletion of the glucose-dependent repressor ADR1. PMID- 20846145 TI - Barcode technology in yeast: application to pharmacogenomics. AB - The common baker's yeast, Saccharomyces cerevisiae, is one of the oldest domesticated organisms known, and has been exploited by our ancestors in several different applications, particularly in food and fermentations industries and in bioconversion and biodegradation processes. Over the years, yeast has become an excellent experimental model for biological and medical studies, thanks to its genetic tractability, well-known physiology and fast-doubling cycle. In the last decade, the advances in genome sequencing opened the doors to high-throughput studies and yeast quickly has become a model system for drug discovery and mode of action. This review provides a focused overview of the achievements in the field of human medicine and pharmacology by exploiting the molecular tools available for yeast. PMID- 20846146 TI - The biological activity of the wine anthocyanins delphinidin and petunidin is mediated through Msn2 and Msn4 in Saccharomyces cerevisiae. AB - Polyphenols are considered to be responsible for some of the health benefits derived from the consumption of red wine. These protective effects might probably be explained in the context of the xenohormesis theory that considers plant metabolites as interspecific chemical signals. However, the complexity of the polyphenolic constituents of different wines makes it difficult to clarify the specific contribution of polyphenols to such effects. In the present work, we fractionated the polyphenols of a red wine and evaluated the effect of each polyphenolic fraction on the growth pattern of the yeast Saccharomyces cerevisiae. We observed a different contribution of the phenolic fractions to the xenohormetic response of S. cerevisiae, the fractions that were enriched with red pigments being the most protective against oxidative insults. Moreover, we found that red wine phenolic fractions exert their biological activity through the activation of the Yap1 and Msn2 stress-responsive regulators. Above all, the anthocyanins delphinidin 3-glucoside and petunidin 3-glucoside were found to improve significantly the growth rate of S. cerevisiae in an Msn2-, Msn4 dependent manner, indicating that the stress regulators Msn2 and Msn4 participate in the xenohormetic activity of the wine polyphenols delphinidin and petunidin. PMID- 20846147 TI - Chronic pruritus--pathogenesis, clinical aspects and treatment. AB - Chronic pruritus is a major symptom in numerous dermatological and systemic diseases. Similar to chronic pain, chronic pruritus can have a dramatic impact on the quality of life and can worsen the general condition of the patient considerably. The pathogenesis of itch is diverse and involves a complex network of cutaneous and neuronal cells. In recent years, more and more itch-specific mediators and receptors, such as interleukin-31, gastrin-releasing peptide receptor or histamine H4 receptor have been identified and the concept of itch specific neurons has been further characterized. Understanding of the basic principles is important for development of target-specific treatment of patients with chronic pruritus. In this review, we summarize the current knowledge about the pathophysiological principles of itch and provide an overview about current and future treatment options. PMID- 20846148 TI - Considerations in establishing an oral disease clinical research center. AB - Oral Diseases (2010) 16, 586-591 High quality clinical research is necessary to improve oral health and translate research findings to the practice of dentistry. This has led many academic institutions to consider establishing a formal clinical research center. This is not a trivial undertaking and requires that the center have an appropriate physical infrastructure, trained investigators with recognized expertise in the planning and conduct of high quality clinical research, and very importantly, a financial plan to assure its long-term sustainability. The purpose of this paper is to provide some guidance and practical advice with respect to factors that should be considered in developing and maintaining a successful oral disease clinical research center. PMID- 20846149 TI - Using Cochrane reviews for oral diseases. AB - OBJECTIVES: To provide readers with information about the Cochrane Oral Health Group and how the reviews on oral diseases have contributed to guideline developments and the commissioning of trials. MATERIALS AND METHODS: Examples have been selected from the reviews published on The Cochrane Library. Descriptions are given of how these reviews have been used in guideline development and commissioning of trials. Readers are updated on reviews focused on the management of oral cancer and the new venture of diagnostic test reviews. RESULTS: Reviews on the management of oral diseases due to cancer treatments have been included in guidelines and changed practice in the UK. Cochrane reviews on Bell's Palsy have led to a randomised controlled trial which has changed the evidence base. The Cochrane review on recall intervals between routine appointments has input into the NICE guideline and resulted in a randomised controlled trial to look at different intervals including a risk-based interval. CONCLUSION: We hope this article will give readers information on the work of the Cochrane Oral Health Group and insight into the diversity of reviews in oral diseases. The reviews are successfully being used to change practice and as background for the funding of large-scale clinical trials. PMID- 20846150 TI - New thoughts on the initiation of mucositis. AB - It has been slightly more than a decade since the classic mechanistic paradigm that defined the pathogenesis of mucositis was revised. A five-stage sequence of linked biological events forms the basis for our current understanding of how regimen-related mucosal injury occurs. The first stage is the initiation phase, although the gateway to toxicity has been the least studied. This essay proposes new thoughts on the phase's components, how they might interact, and how they present new opportunities for treatment interventions and mucositis risk prediction. PMID- 20846151 TI - A critical review: an overview of genetic influence on dental caries. AB - Dental decay is a complex, chronic disease and one of the most common illnesses in dentistry today. Several dental decay risk factors have been identified during the last years; however, these variables alone may not entirely explain the disease development. Genetic research applied to dental decay began in the 1930s with experimental reports in animals and human observational research. Only recently, have some studies begun to search for genetic polymorphisms in humans and apply linkage analysis. However, due to the complex characteristics of the disease, the strong influence from several biological and environmental factors, and the small number of genetic studies related to dental caries, the genetic basis still requires further study. Therefore, the aim of this review is to provide a brief description of the current methodology for genetic analysis of complex traits, followed by a comprehensive evaluation of the literature related to genetic susceptibility/resistance to dental decay and a discussion of different aspects of the applied methodology. Advances towards the elucidation of the dental decay genetic basis may contribute to the understanding of the disease etiopathogenesis and to the identification of high risk groups, thus providing potential targets for effective screening, prevention and treatment. PMID- 20846152 TI - Anti-inflammatory action of cholecystokinin and melatonin in the rat parotid gland. AB - OBJECTIVE: To define the influence of cholecystokinin and melatonin on the inflammatory response of the lipopolysaccharide-exposed rat parotid gland. MATERIALS AND METHODS: Bacterial lipopolysaccharide was infused retrogradely into the parotid duct. The degree of inflammation three hours postadministration was estimated from the activity of myeloperoxidase, reflecting glandular neutrophil infiltration. RESULTS: The myeloperoxidase activity of the lipopolysaccharide exposed gland was 10-fold greater than that of the contralateral gland. Combined with sulphated cholecystokinin-8 (10 or 25 MUg kg(-1) , given twice intraperitoneally) or melatonin (10 or 25 mg kg(-1) x 2) the lipopolysaccharide induced response was elevated 4.6- and 3.5-folds at the most. The cholecystokinin A receptor antagonist lorglumide reduced the inhibitory effect of cholecystokinin 8, while the melatonin 2-preferring receptor antagonist luzindole had no effect on the melatonin-induced inhibition. Unselective nitric oxide-synthase inhibition abolished the increase in myeloperoxidase activity, whereas inhibition of inducible or neuronal nitric oxide-synthase (of non-nervous origin) halved the inflammatory response. CONCLUSION: Some hormones may contribute to anti inflammatory action in salivary glands in physiological conditions. They are potential pharmacological tools for treating gland inflammation. The inflammation, as judged from the myeloperoxidase activity, was entirely dependent on nitric oxide-synthase activity, indicating that the hormones directly or indirectly reduced the generation of nitric oxide. PMID- 20846153 TI - Hypermethylation of carcinogen metabolism genes, CYP1A1, CYP2A13 and GSTM1 genes in head and neck cancer. AB - OBJECTIVES: To investigate the role of aberrant hypermethylation of carcinogen metabolism pathway genes, CYP1A1, CYP2A13 and GSTM1 in head and neck cancer independently as well as its relation to tobacco and alcohol consumption and CYP1A1 and CYP2A13 polymorphisms in Indian population. METHODS: Seventy-three histologically confirmed head and neck cancer patients undergoing treatment in Postgraduate Institute of Medical Education and Research, Chandigarh, India were recruited. Non-cancerous tissues were obtained from 19 trauma subjects undergoing maxillofacial surgery. Methylation-specific PCR was performed to determine the methylation status of selected genes. RESULTS: The aberrant hypermethylation of CYP1A1, CYP2A13 and GSTM1 genes was found in cancer tissues with frequency of about 39.7%, 27.4%, and 58.1%, respectively, and in normal healthy tissues with a frequency of about 10.5%, 15.8%, and 20.0%, respectively. Hypermethylation of CYP1A1 (P 0.027) and GSTM1 (P 0.010) showed significant association with head and neck cancer. We also observed significant interaction between smoking and methylation status of CYP1A1 (P 0.029) and CYP2A13 (P -0.034) in head and neck cancer. No association was observed between methylation status and alcohol consumption, clinical features and genetic polymorphisms of CYP1A1 and CYP2A13. CONCLUSIONS: Hypermethylation of carcinogen metabolism pathway genes independently and in interaction with smoking is associated with increased risk of head and neck cancer. PMID- 20846154 TI - Effects of alendronate on bone healing after tooth extraction in rats. AB - OBJECTIVES: Tooth extraction has been identified as an important risk factor for bisphosphonate-induced osteonecrosis of the jaw. Therefore, the main goal of this study was to determine the effects of alendronate on healing of the extraction socket and on interdental alveolar bone after tooth extraction in rats. MATERIALS AND METHODS: Animals were injected subcutaneously with vehicle or alendronate for 3-4 weeks before the first mandibular molar was extracted and these treatments were continued during post-extraction periods of 10, 21, 35 and 70 days. Mandibles were processed to evaluate healing of the extraction socket and adjacent alveolar bone by assessing bone formation, bone resorption and vascularity by histomorphometric techniques. RESULTS: Alendronate decreased new woven bone formation, blood vessel area, perimeter and number in the extraction socket at 10 days postextraction, but not at later time points. Furthermore, alendronate-treated rats had increased interdental alveolar bone volume and height only at 10 days postextraction. In addition, a 2.5-fold increase in the percentage of empty osteocyte lacunae was found in alveolar bone of alendronate treated rats only at 10 days postextraction. CONCLUSIONS: Alendronate transiently decreases bone formation and vascularity in the extraction socket and delays the removal of interdental alveolar bone after tooth extraction in rats. PMID- 20846155 TI - Virulence of major periodontal pathogens and lack of humoral immune protection in a rat model of periodontal disease. AB - OBJECTIVE: This study was designed to test the hypothesis that periodontal pathogens Tannerella forsythia and Porphyromonas gingivalis are synergistic in terms of virulence potential using a model of mixed-microbial infection in rats. MATERIALS AND METHODS: Three groups of rats were infected orally with either T. forsythia or P. gingivalis in mono-bacterial infections or as mixed-microbial infections for 12 weeks and a sham-infected group were used as a control. This study examined bacterial infection, inflammation, immunity, and alveolar bone loss changes with disease progression. RESULTS: Tannerella forsythia and P. gingivalis genomic DNA was detected in microbial samples from infected rats by PCR indicating their colonization in the rat oral cavity. Primary infection induced significantly high IgG, IgG2b, IgG1, and IgG2a antibody levels indicating activation of mixed Th1 and Th2 immune responses. Rats infected with the mixed microbial consortium exhibited significantly increased palatal horizontal and interproximal alveolar bone loss. Histological examinations indicated significant hyperplasia of the gingival epithelium with moderate inflammatory infiltration and apical migration of junctional epithelium. The results observed differ compared to uninfected controls. CONCLUSION: Our results indicated that T. forsythia and P. gingivalis exhibit virulence, but not virulence synergy, resulting in the immuno-inflammatory responses and lack of humoral immune protection during periodontitis in rats. PMID- 20846156 TI - Hypoxia inducible factor-1alpha expression in areca quid chewing-associated oral squamous cell carcinomas. AB - OBJECTIVES: Hypoxia inducible factor (HIF)-1alpha gene expression is mainly induced by tissue hypoxia. Overexpression of HIF-1alpha has been demonstrated in a variety of cancers. The aim of this study was to compare HIF-1alpha expression in normal human oral epithelium and areca quid chewing-associated oral squamous cell carcinoma (OSCC) and further to explore the potential mechanisms that may lead to induce HIF-1alpha expression. METHODS: Twenty-five OSCC from areca quid chewing-associated OSCC and 10 normal oral tissue biopsy samples without areca quid chewing were analyzed by immunohistochemistry. The oral epithelial cell line GNM cells were challenged with arecoline, a major areca nut alkaloid, by using Western blot analysis. Furthermore, glutathione precursor N-acetyl-l-cysteine (NAC), AP-1 inhibitor curcumin, extracellular signal-regulated protein kinase inhibitor PD98059, and protein kinase C inhibitor staurosporine were added to find the possible regulatory mechanisms. RESULTS: Hypoxia inducible factor-1alpha expression was significantly higher in OSCC specimens than normal specimen (P<0.05). Arecoline was found to elevate HIF-1alpha expression in a dose- and time-dependent manner (P<0.05). The addition of NAC, curcumin, PD98059, and staurosporine markedly inhibited the arecoline-induced HIF-1alpha expression (P<0.05). CONCLUSIONS: Hypoxia inducible factor-1alpha expression is significantly upregulated in areca quid chewing-associated OSCC and HIF-1alpha expression induced by arecoline is downregulated by NAC, curcumin, PD98059, and staurosporine. PMID- 20846157 TI - Marathon of eponyms: 13 Melkersson-Rosenthal syndrome. AB - The use of eponyms has long been contentious, but many remain in common use, as discussed elsewhere (Editorial: Oral Diseases. 2009: 15; 185). The use of eponyms in diseases of the head and neck is found mainly in specialties dealing with medically compromised individuals (paediatric dentistry, special care dentistry, oral and maxillofacial medicine, oral and maxillofacial pathology, oral and maxillofacial radiology and oral and maxillofacial surgery) and particularly by hospital-centred practitioners. This series has selected some of the more recognised relevant eponymous conditions and presents them alphabetically. The information is based largely on data available from MEDLINE and a number of internet websites as noted below: the authors would welcome any corrections. This document summarises data about Melkersson-Rosenthal syndrome. PMID- 20846158 TI - The terms diplegia, quadriplegia, and hemiplegia should be phased out. PMID- 20846159 TI - Early effects of muscle atrophy on shoulder joint development in infants with unilateral birth brachial plexus injury. AB - AIM: Shoulder deformities in children with a birth brachial plexus injury (BBPI) are caused by muscle imbalances; however, the underlying mechanisms are unclear. The aim of this study was to assess the early interactions between shoulder muscles and shoulder joint development. METHOD: In a retrospective magnetic resonance imaging (MRI) study of 36 infants (21 males, 15 females) younger than 12 months (mean 4.8 mo) with unilateral BBPI, volumes and thicknesses of standardized segments of the infraspinatus, subscapularis, and deltoid muscles were measured in both shoulders and expressed as ratios of pathological/unaffected side. The relation between muscle ratios and humeral head subluxation, passive external rotation, glenoid version, and deformity was analysed. RESULTS: Compared with the unaffected side, the muscles of the affected side were of significantly smaller volume and thickness. The subscapularis was the most severely affected muscle, its volume being only 64% (SD 21%) and its thickness only 79% (SD 23%) of the corresponding values on the unaffected side (p < 0.001). Severe subluxation was predicted by the combination of low infraspinatus and subscapularis volume ratios (r(2) = 0.223; p = 0.014), but not by muscle thickness ratios. Subluxation was related to passive external rotation (p < 0.05), glenoid version (p < 0.01), and deformity (p < 0.01). INTERPRETATION: In infants with BBPI, muscle size is decreased during in the first months of life by both atrophy and, possibly, by a reduction in the number of sarcomeres in series. These effects are strongly related to shoulder joint subluxation. PMID- 20846160 TI - Current approaches to measuring human islet-antigen specific T cell function in type 1 diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by the T cell-mediated destruction of the pancreatic insulin-producing beta cells. Currently there are no widely accepted and standardized assays available to analyse the function of autoreactive T cells involved in T1D. The development of such an assay would greatly aid efforts to understand the pathogenesis of T1D and is also urgently required to guide the development of antigen-based therapies intended to prevent, or cure, T1D. Here we describe some of the assays used currently to detect autoreactive T cells in human blood and review critically their strengths and weaknesses. The challenges and future prospects for the T cell assays are discussed. PMID- 20846161 TI - Moderate exercise improves leucocyte function and decreases inflammation in diabetes. AB - The genesis and progression of diabetes occur due in part to an uncontrolled inflammation profile with insulin resistance, increased serum levels of free fatty acids (FFA), proinflammatory cytokines and leucocyte dysfunction. In this study, an investigation was made of the effect of a 3-week moderate exercise regimen on a treadmill (60% of VO2(max) , 30 min/day, 6 days a week) on inflammatory markers and leucocyte functions in diabetic rats. The exercise decreased serum levels of tumour necrosis factor (TNF)-alpha (6%), cytokine induced neutrophil chemotactic factor 2 alpha/beta (CINC-2alpha/beta) (9%), interleukin (IL)-1beta (34%), IL-6 (86%), C-reactive protein (CRP) (41%) and FFA (40%) in diabetic rats when compared with sedentary diabetic animals. Exercise also attenuated the increased responsiveness of leucocytes from diabetics when compared to controls, diminishing the reactive oxygen species (ROS) release by neutrophils (21%) and macrophages (28%). Exercise did not change neutrophil migration and the proportion of neutrophils and macrophages in necrosis (loss of plasma membrane integrity) and apoptosis (DNA fragmentation). Serum activities of creatine kinase (CK) and lactate dehydrogenase (LDH) were not modified in the conditions studied. Therefore, physical training did not alter the integrity of muscle cells. We conclude that moderate physical exercise has marked anti inflammatory effects on diabetic rats. This may be an efficient strategy to protect diabetics against microorganism infection, insulin resistance and vascular complications. PMID- 20846162 TI - Inflammatory conditions affect gene expression and function of human adipose tissue-derived mesenchymal stem cells. AB - There is emerging interest in the application of mesenchymal stem cells (MSC) for the prevention and treatment of autoimmune diseases, graft-versus-host disease and allograft rejection. It is, however, unknown how inflammatory conditions affect phenotype and function of MSC. Adipose tissue-derived mesenchymal stem cells (ASC) were cultured with alloactivated peripheral blood mononuclear cells (PBMC) (mixed lymphocyte reaction: MLR), with proinflammatory cytokines [interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL) 6] or under control conditions, and their full genome expression and function examined. Proinflammatory cytokines mainly increased indoleamine-2,3-dioxygenase expression, whereas ASC cultured with MLR showed increased expression of COX-2, involved in prostaglandin E(2) production. Both conditions had a stimulatory, but differential, effect on the expression of proinflammatory cytokines and chemokines, while the expression of fibrotic factors was decreased only in response to proinflammatory cytokines. Functional analysis demonstrated that inflammatory conditions affected morphology and proliferation of ASC, while their differentiation capacity and production of trophic factors was unaffected. The immunosuppressive capacity of ASC was enhanced strongly under inflammatory conditions. In conclusion, ASC showed enhanced immunosuppressive capacity under inflammatory conditions, while their differentiation capacity was preserved. Therefore, in vitro preconditioning provides ASC with improved properties for immediate clinical immune therapy. PMID- 20846164 TI - A shift towards a T cell cytokine deficiency along with an anti inflammatory/regulatory microenvironment may enable the synthesis of anti-FVIII inhibitors in haemophilia A patients. AB - Despite the clinical relevance of anti-factor VIII (FVIII) antibodies (anti-FVIII inhibitors) impairing haemostatic activity of haemophilia A (HA) patients, the immunological mechanisms underlying their production are unknown. Aiming to understand more clearly the immune response in patients with [HAalpha-FVIII(+)] and without [HAalpha-FVIII(-)] anti-FVIII inhibitors, we have characterized the cytokine pattern of peripheral blood leucocytes, using an in vitro stimulation of whole blood samples with plasma-derived (pFVIII) or recombinant FVIII (rFVIII). The results highlighted decreased levels of tumour necrosis factor (TNF)-alpha(+) neutrophils with higher interleukin (IL)-5/TNF-alpha ratio in HAalpha-FVIII(+). All HA samples displayed decreased levels of IL-10(+) monocytes when compared to the blood donor (BD) samples. HAalpha-FVIII(+) showed lower levels of TNF alpha(+) monocytes and increased IL-10/TNF-alpha ratio. Analysis of adaptive immunity revealed increased levels of interferon (IFN)-gamma(+) , TNF-alpha(+) and IL-4(+) T-cells, from both CD4(+) and CD8(+) T cells, in HAalpha-FVIII(-) when compared to BD. Moreover, increased frequency of IL-10(+) B cells and higher levels of alpha-FVIII IgG1 were observed in HAalpha-FVIII(-). Basal levels of cytokine(+) B-cells, similar to BD, and higher levels of alpha-FVIII IgG4 are major features in HAalpha-FVIII(+). The global cytokine profile demonstrated a major anti-inflammatory/regulatory pattern in HAalpha-FVIII(+), confirmed by the in vitro stimuli with pFVIII or rFVIII. The polarized anti inflammatory/regulatory immune response in HAalpha-FVIII(+) and the mixed pattern with a bias towards an inflammatory cytokine profile, modulated by IL-4 in HAalpha-FVIII(-), may be the key element to drive the development of distinct subclasses of anti-FVIII antibodies. These finding have implications for the design of safe and effective therapeutic protocols to control inhibitors synthesis in HA patients. PMID- 20846163 TI - The calpain inhibitor calpeptin prevents bleomycin-induced pulmonary fibrosis in mice. AB - Pulmonary fibrosis is characterized by progressive worsening of pulmonary function leading to a high incidence of death. Currently, however, there has been little progress in therapeutic strategies for pulmonary fibrosis. There have been several reports on cytokines being associated with lung fibrosis, including interleukin (IL)-6 and transforming growth factor (TGF)-beta1. We reported recently that two substances (ATRA and thalidomide) have preventive effects on pulmonary fibrosis by inhibiting IL-6-dependent proliferation and TGF-beta1 dependent transdifferentiation of lung fibroblasts. Rheumatoid arthritis is a chronic autoimmune disorder, and its pathogenesis is also characterized by an association with several cytokines. It has been reported that calpain, a calcium dependent intracellular cysteine protease, plays an important role in the progression of rheumatoid arthritis. In this study, we examined the preventive effect of Calpeptin, a calpain inhibitor, on bleomycin-induced pulmonary fibrosis. We performed histological examinations and quantitative measurements of IL-6, TGF-beta1, collagen type Ialpha1 and angiopoietin-1 in bleomycin-treated mouse lung tissues with or without the administration of Calpeptin. Calpeptin histologically ameliorated bleomycin-induced pulmonary fibrosis in mice. Calpeptin decreased the expression of IL-6, TGF-beta1, angiopoietin-1 and collagen type Ialpha1 mRNA in mouse lung tissues. In vitro studies disclosed that Calpeptin reduced (i) production of IL-6, TGF-beta1, angiopoietin-1 and collagen synthesis from lung fibroblasts; and (ii) both IL-6-dependent proliferation and angiopoietin-1-dependent migration of the cells, which could be the mechanism underlying the preventive effect of Calpeptin on pulmonary fibrosis. These data suggest the clinical use of Calpeptin for the prevention of pulmonary fibrosis. PMID- 20846165 TI - Investigation of nuclear factor-kappaB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes. AB - The poor prognosis of obesity is now known to involve a proinflammatory state associated with elevated circulating levels of cytokines and with macrophage infiltration of adipose tissue. In particular, Toll-like receptor (TLR)-4-driven adipose inflammation has been implicated recently in obesity and the development of diabetes. Adipocytes are now recognized as an important source of cytokine and chemokine production, including interleukin (IL)-6 and monocyte chemotractant protein (MCP)-1, and this appears to be a key step in the development of the obesity-associated inflammatory state. Interventions targeted at adipocyte inflammation may therefore form novel therapies to treat or prevent medical complications of obesity. We set out to explore whether anti-inflammatory interventions which are effective in conventional immune cells would operate on primary human cultures of in-vitro differentiated adipocytes. IL-10 was ineffective against TLR-4-induced cytokine secretion due to lack of IL-10 receptor on human adipocytes, in contrast to the widely used murine 3T3-L1 adipocyte model, which is known to respond to IL-10. Adenoviral delivery of an IL 10 receptor construct to the cells restored IL-10 responsiveness as assessed by signal transducer and activator of transcription-3 (STAT-3) phosphorylation. However, the small molecule nuclear factor (NF)-kappaB inhibitors 2 [(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA)-1 and carbobenzoxyl-Ile-Glu(O-t-butyl)-Ala-leucinal (PSI) as well as adenovirally delivered dominant negative inhibitor of IkappaB kinase 2 (IKK2) and wild-type IkappaBalpha were effective inhibitors of TLR-4-driven IL-6 and MCP-1 induction. These data identify a central role for canonical NF-kappaB signalling in adipocyte cytokine induction and indicate that small molecule inhibitors of NF kappaB may form the basis of future treatments for obesity-related conditions where adipocyte inflammatory signalling is implicated. PMID- 20846166 TI - Expert study to select indicators of the occurrence of emerging mycotoxin hazards. AB - This article describes a Delphi-based expert judgment study aimed at the selection of indicators to identify the occurrence of emerging mycotoxin hazards related to Fusarium spp. in wheat supply chains. A panel of 29 experts from 12 European countries followed a holistic approach to evaluate the most important indicators for different chain stages (growth, transport and storage, and processing) and their relative importance. After three e-mailing rounds, the experts reached consensus on the most important indicators for each of the three stages: wheat growth, transport and storage, and processing. For wheat growth, these indicators include: relative humidity/rainfall, crop rotation, temperature, tillage practice, water activity of the kernels, and crop variety/cultivar. For the transport and storage stage, they include water activity in the kernels, relative humidity, ventilation, temperature, storage capacity, and logistics. For wheat processing, indicators include quality data, fraction of the cereal used, water activity in the kernels, quality management and traceability systems, and carryover of contamination. The indicators selected in this study can be used in an identification system for the occurrence of emerging mycotoxin hazards in wheat supply chains. Such a system can be used by risk managers within governmental (related) organizations and/or the food and feed industry in order to react proactively to the occurrence of these emerging mycotoxins. PMID- 20846167 TI - Illustrating risk: anaphylaxis through the eyes of the food-allergic child. AB - The risk perception research is widely focused on children as targets of risk. To date, very few studies have consulted with the impacted group to assess the perceptions of risk associated with the exposures of interest. Much less research has investigated the experiences of children at risk for anaphylaxis, their concerns, and the psychosocial stresses associated with risk. The present study explores the perceptions and experiences of Ontario students with anaphylaxis, and their parents regarding school as a safe place in order to inform school policy around risk management and coping. A "child-centered" analytical framework incorporating illustrative techniques within interpretative analysis is outlined. Five prominent themes: (a) social and environmental barriers to safety, (b) coping strategies, (c) emotional burden of responsibility, (d) balance of responsibility (transitions), and (e) redefining "normal" are discussed. Results found that "child-centered" techniques empowered children in a process that is meaningful and relevant to their lives. A preliminary framework for understanding what risk means to children highlighted the differences in how they cope in the public sphere of school. PMID- 20846168 TI - Workers' perception of chemical risks: a focus group study. AB - Workers' perceptions with respect to health and safety at work are rarely taken into account when considering the development of prevention programs. The aim of this study was to explore workers' perceptions of chemical risks at the workplace, in order to investigate the prerequisites for a workplace health program. A qualitative study was conducted involving seven focus groups of 5-10 participants (blue-collar workers) each. All groups were homogeneous in terms of sex, work status, language, and company membership. Results showed that several factors have an important influence on workers' perception of chemical risks. Workers assess risks by means of both sensory and empirical diagnosis and are concerned about the long-term health consequences. They perceive the threat of chemical risks as high. Despite this, they are resigned to accepting the risks. Existing formal sources of information are rarely consulted because they are judged to be difficult to understand and not user friendly. Instead, workers tend to obtain information from informal sources. Communication problems with and lack of trust in prevention advisers and hierarchy are frequently mentioned. Workers feel that their specific knowledge of their working conditions and their proposals for practical, cost-effective solutions to improve health and safety at the workplace are insufficiently taken into account. The use of focus groups yielded a useful insight into workers' perceptions of chemical risks. Our findings suggest that training programs for prevention advisers should include topics such as understanding of workers' perceptions, usefulness of a participatory approach, and communication and education skills. PMID- 20846169 TI - How probabilistic risk assessment can mislead terrorism risk analysts. AB - Traditional probabilistic risk assessment (PRA), of the type originally developed for engineered systems, is still proposed for terrorism risk analysis. We show that such PRA applications are unjustified in general. The capacity of terrorists to seek and use information and to actively research different attack options before deciding what to do raises unique features of terrorism risk assessment that are not adequately addressed by conventional PRA for natural and engineered systems-in part because decisions based on such PRA estimates do not adequately hedge against the different probabilities that attackers may eventually act upon. These probabilities may differ from the defender's (even if the defender's experts are thoroughly trained, well calibrated, unbiased probability assessors) because they may be conditioned on different information. We illustrate the fundamental differences between PRA and terrorism risk analysis, and suggest use of robust decision analysis for risk management when attackers may know more about some attack options than we do. PMID- 20846170 TI - Nonparametric predictive inference for exposure assessment. AB - Exposure assessment for food and drink consumption requires the combining of information about people's consumption of products with concentration data sets to provide predictions for chemical intake by humans. In this article, we present a method called nonparametric predictive inference (NPI) for exposure assessment. NPI is a distribution-free method relying only on Hill's assumption A(n). Effectively, A(n) is a postdata exchangeability assumption, which is a natural starting point for nonparametric statistics. For further discussion we refer to works by Hill and Coolen. We illustrate how NPI can be implemented to produce predictions for an individual's exposure based on consumption, body weight, and concentration data. NPI has the advantage that we do not have to assume a distribution to implement it. There may, however, be information available to suggest a distribution for a random quantity. Therefore, we present an NPI-Bayes hybrid method where this information can be taken into account by using Bayesian methods while using NPI for the other random quantities in the model. PMID- 20846171 TI - A causal model of chronic obstructive pulmonary disease (COPD) risk. AB - Research on the etiology of chronic pulmonary disease (COPD), an irreversible degenerative lung disease affecting 15% to 20% of smokers, has blossomed over the past half-century. Profound new insights have emerged from a combination of in vitro and -omics studies on affected lung cell populations (including cytotoxic CD8(+) T lymphocytes, regulatory CD4(+) helper T cells, dendritic cells, alveolar macrophages and neutrophils, alveolar and bronchiolar epithelial cells, goblet cells, and fibroblasts) and extracellular matrix components (especially, elastin and collagen fibers); in vivo studies on wild-type and genetically engineered mice and other rodents; clinical investigation of cell- and molecular-level changes in asymptomatic smokers and COPD patients; genetic studies of susceptible and rapidly-progressing phenotypes (both human and animal); biomarker studies of enzyme and protein degradation products in induced sputum, bronchiolar lavage, urine, and blood; and epidemiological and clinical investigations of the time course of disease progression. To this rich mix of data, we add a relatively simple in silico computational model that incorporates recent insights into COPD disease causation and progression. Our model explains irreversible degeneration of lung tissue as resulting from a cascade of positive feedback loops: a macrophage inflammation loop, a neutrophil inflammation loop, and an alveolar epithelial cell apoptosis loop. Unrepaired damage results in clinical symptoms. The resulting model illustrates how to simplify and make more understandable the main aspects of the very complex dynamics of COPD initiation and progression, as well as how to predict the effects on risk of interventions that affect specific biological responses. PMID- 20846172 TI - Nano risk analysis: advancing the science for nanomaterials risk management. AB - Scientists, activists, industry, and governments have raised concerns about health and environmental risks of nanoscale materials. The Society for Risk Analysis convened experts in September 2008 in Washington, DC to deliberate on issues relating to the unique attributes of nanoscale materials that raise novel concerns about health risks. This article reports on the overall themes and findings of the workshop, uncovering the underlying issues for each of these topics that become recurring themes. The attributes of nanoscale particles and other nanomaterials that present novel issues for risk analysis are evaluated in a risk analysis framework, identifying challenges and opportunities for risk analysts and others seeking to assess and manage the risks from emerging nanoscale materials and nanotechnologies. Workshop deliberations and recommendations for advancing the risk analysis and management of nanotechnologies are presented. PMID- 20846173 TI - Melanin coloration has temperature-dependent effects on breeding performance that may maintain phenotypic variation in a passerine bird. AB - Fluctuating selection pressure may maintain phenotypic variation because of different types of individuals being adapted to different environmental conditions. We show that the extensive variation in the coloration of male pied flycatchers (Ficedula hypoleuca) can be maintained through differences in the reproductive success of male phenotypes under different conditions. The effects of weather conditions on the relative success of different male phenotypes varied between different phases of breeding. The reproductive output of black males was the highest when it was cold during egg-laying but warm during the nestling period, whereas the fledgling production of brown males was highest when it was continuously warm. In addition, male forehead and wing patch sizes had context dependent effects on timing of breeding and nestling mortality, respectively. These results indicate that environmental heterogeneity plays a role in maintaining phenotypic variation. As melanin-based coloration is heritable, climate change may alter phenotype frequencies depending on the patterns of warming. PMID- 20846174 TI - Reading between the spikes of the hypothalamic neural code. AB - Reading the spike coding of hypothalamic neurones presents a considerable challenge because they exhibit highly irregular firing patterns. Electrophysiologists working in the motor and sensory systems, in which neurones fire more regularly, have devised satisfactory methods to describe the firing of cells, although the statistical assumptions that underlie the methods do not apply to hypothalamic neurones. Measurement of neural activity is nevertheless vital to characterise the activity of neuroendocrine cells. It has thus become necessary to develop methods suitable for the analysis of the highly irregular spike discharge patterns of both spontaneous and stimulus-evoked firing of hypothalamic neurones. We review techniques used to meet this challenge and demonstrate their considerable capacity to address important physiological questions. We also introduce a novel approach for valid statistical estimation of the information conveyed by the response of a single neurone to a periodic stimulus. The approach demonstrated significant diurnal rhythms of synaptic connectivity between hypothalamic nuclei. PMID- 20846176 TI - Is DHICA the key to dopachrome tautomerase and melanocyte functions? PMID- 20846178 TI - Altered synaptic plasticity and behavioral abnormalities in CNGA3-deficient mice. AB - The role of the cyclic nucleotide-gated (CNG) channel CNGA3 is well established in cone photoreceptors and guanylyl cyclase-D-expressing olfactory neurons. To assess a potential function of CNGA3 in the mouse amygdala and hippocampus, we examined synaptic plasticity and performed a comparative analysis of spatial learning, fear conditioning and step-down avoidance in wild-type mice and CNGA3 null mutants (CNGA3(-/-) ). CNGA3(-/-) mice showed normal basal synaptic transmission in the amygdala and the hippocampus. However, cornu Ammonis (CA1) hippocampal long-term potentiation (LTP) induced by a strong tetanus was significantly enhanced in CNGA3(-/-) mice as compared with their wild-type littermates. Unlike in the hippocampus, LTP was not significantly altered in the amygdala of CNGA3(-/-) mice. Enhanced hippocampal LTP did not coincide with changes in hippocampus-dependent learning, as both wild-type and mutant mice showed a similar performance in water maze tasks and contextual fear conditioning, except for a trend toward higher step-down latencies in a passive avoidance task. In contrast, CNGA3(-/-) mice showed markedly reduced freezing to the conditioned tone in the amygdala-dependent cued fear conditioning task. In conclusion, our study adds a new entry on the list of physiological functions of the CNGA3 channel. Despite the dissociation between physiological and behavioral parameters, our data describe a so far unrecognized role of CNGA3 in modulation of hippocampal plasticity and amygdala-dependent fear memory. PMID- 20846179 TI - Re: "COMLEX-1 and USMLE-1 are not interchangeable examinations". PMID- 20846177 TI - The new paradigm: retinal pigment epithelium cells generated from embryonic or induced pluripotent stem cells. AB - Compared with neural crest-derived melanocytes, retinal pigment epithelium (RPE) cells in the back of the eye are pigment cells of a different kind. They are a part of the brain, form an epithelial monolayer, respond to distinct extracellular signals, and provide functions that far exceed those of a light absorbing screen. For instance, they control nutrient and metabolite flow to and from the retina, replenish 11-cis-retinal by re-isomerizing all-trans-retinal generated during photoconversion, phagocytose daily a portion of the photoreceptors' outer segments, and secrete cytokines that locally control the innate and adaptive immune systems. Not surprisingly, RPE cell damage is a major cause of human blindness worldwide, with age-related macular degeneration a prevalent example. RPE replacement therapies using RPE cells generated from embryonic or induced pluripotent stem cells provide a novel approach to a rational treatment of such forms of blindness. In fact, RPE-like cells can be obtained relatively easily when stem cells are subjected to a two-step induction protocol, a first step that leads to a neuroectodermal fate and a second to RPE differentiation. Here, we discuss the characteristics of such cells, propose criteria they should fulfill in order to be considered authentic RPE cells, and point out the challenges one faces when using such cells in attempts to restore vision. PMID- 20846181 TI - Redescription of Favella ehrenbergii (Claparede and Lachmann, 1858) Jorgensen, 1924 (Ciliophora: Choreotrichia), with phylogenetic analyses based on small subunit rRNA gene sequences. AB - The identification of Favella ehrenbergii, a marine planktonic ciliate, has largely been based on its lorica features. This approach is potentially problematic given the polymorphic lorica during this organism's life cycle. We isolated a population of F. ehrenbergii from the coastal waters of Incheon, Korea, and revealed its infraciliature using the protargol staining method. Phylogenetic analysis based on small subunit rRNA gene sequences was also performed. Results showed that this population possessed 16 collar membranelles (CM) and about 100 somatic kineties. These features are highly conserved, even in later dividers. As such, the number of CM and somatic kineties can be used as key characteristics for identification of Favella species. PMID- 20846182 TI - Rumination in the laboratory: what happens when you go back to everyday life? AB - Rumination has been suggested to mediate the physiological consequences of stress on health. We studied the effects of rumination evoked in the laboratory and subsequent changes over 24 h. Heart rate (HR) and systolic and diastolic blood pressure (SBP, DBP) were monitored in 27 male and 33 female participants during baseline, reading, an anger recall interview, and recovery. Half of the sample was assigned to a distraction condition. The lab session was followed by a 24 hour ambulatory (A)HR and BP recording and self-reports of moods and rumination. Rumination was associated with higher SBP, DBP, and HR and increased negative mood compared to distraction. Rumination during the day was a strong predictor of AHR, ABP, and mood. BP reactivity in the laboratory and increases in ABP during rumination were related. The effects of negative cognition on health go far beyond the recovery periods usually measured in the laboratory, thus playing a pathogenic role. PMID- 20846183 TI - Klebsiella pneumoniae subverts the activation of inflammatory responses in a NOD1 dependent manner. AB - Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Subversion of inflammation is essential for pathogen survival during infection. Evidence indicates that K. pneumoniae infections are characterized by lacking an early inflammatory response although the molecular bases are currently unknown. Here we unveil a novel strategy employed by a pathogen to counteract the activation of inflammatory responses. K. pneumoniae attenuates pro-inflammatory mediators-induced IL-8 secretion. Klebsiella antagonizes the activation of NF kappaB via the deubiquitinase CYLD and blocks the phosphorylation of mitogen activated protein kinases (MAPKs) via the MAPK phosphatase MKP-1. Our studies demonstrate that K. pneumoniae has evolved the capacity to manipulate host systems dedicated to control the immune balance. To exert this anti-inflammatory effect, Klebsiella engages NOD1. In NOD1 knock-down cells, Klebsiella neither induces the expression of CYLD and MKP-1 nor blocks the activation of NF-kappaB and MAPKs. Klebsiella inhibits Rac1 activation; and inhibition of Rac1 activity triggers a NOD1-mediated CYLD and MKP-1 expression which in turn attenuates IL 1beta-induced IL-8 secretion. A capsule (CPS) mutant does not attenuate the inflammatory response. However, purified CPS neither reduces IL-1beta-induced IL 8 secretion nor induces the expression of CYLD and MKP-1 thereby indicating that CPS is necessary but not sufficient to attenuate inflammation. PMID- 20846184 TI - Endocytosis and toxicity of clostridial binary toxins depend on a clathrin independent pathway regulated by Rho-GDI. AB - Clostridial binary toxins, such as Clostridium perfringens Iota and Clostridium botulinum C2, are composed of a binding protein (Ib and C2II respectively) that recognizes distinct membrane receptors and mediates internalization of a catalytic protein (Ia and C2-I respectively) with ADP-ribosyltransferase activity that disrupts the actin cytoskeleton. We show here that the endocytic pathway followed by these toxins is independent of clathrin but requires the activity of dynamin and is regulated by Rho-GDI. This endocytic pathway is similar to a recently characterized clathrin-independent pathway followed by the interleukin-2 (IL2) receptor. We found indeed that Ib and C2II colocalized intracellularly with the IL2 receptor but not the transferrin receptor after different times of endocytosis. Accordingly, the intracellular effects of Iota and C2 on the cytoskeleton were inhibited by inactivation of dynamin or by Rho-GDI whereas inhibitors of clathrin-dependent endocytosis had no protective effect. PMID- 20846185 TI - Secondary anaplastic astrocytoma developing in a young adult with autoimmune lymphoproliferative syndrome (ALPS). PMID- 20846186 TI - Brain and spinal cord affected by amyotrophic lateral sclerosis induce differential growth factors expression in rat mesenchymal and neural stem cells. AB - Stem cell research raises hopes for incurable neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), affecting the motoneurones of the central nervous system (CNS), stem cell-based therapy aims to replace dying host motoneurones by transplantation of cells in disease-affected regions. Moreover, transplanted stem cells can serve as a source of trophic factors providing neuroprotection, slowing down neuronal degeneration and disease progression. AIM: To determine the profile of seven trophic factors expressed by mesenchymal stem cells (MSC) and neural stem cells (NSC) upon stimulation with CNS protein extracts from SOD1-linked ALS rat model. METHODS: Culture of rat MSC, NSC and fibroblasts were incubated with brain and spinal cord extracts from SOD1(G93A) transgenic rats and mRNA expression of seven growth factors was measured by quantitative PCR. RESULTS: MSC, NSC and fibroblasts exhibited different expression patterns. Nerve growth factor and brain-derived neurotropic factor were significantly upregulated in both NSC and MSC cultures upon stimulation with SOD1(G93A) CNS extracts. Fibroblast growth factor 2, insulin-like growth factor and glial-derived neurotropic factor were upregulated in NSC, while the same factors were downregulated in MSC. Vascular endothelial growth factor A upregulation was restricted to MSC and fibroblasts. Surprisingly, SOD1(G93A) spinal cord, but not the brain extract, upregulated brain-derived neurotropic factor in MSC and glial-derived neurotropic factor in NSC. CONCLUSIONS: These results suggest that inherent characteristics of different stem cell populations define their healing potential and raise the concept of ALS environment in stem cell transplantation. PMID- 20846187 TI - Subchronic treatment of rats with oxytocin results in improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis. AB - BACKGROUND AND PURPOSE: Treatment with thiazolidinediones, insulin-sensitizing drugs, enhances adipogenesis, which may result in unwanted increase in adiposity. Based on the suggested metabolic effects of oxytocin, the aims of the present study were to: (i) determine whether chronic treatment with oxytocin exerts positive effects on white adipose tissue growth without increasing adiposity; (ii) investigate possible mechanisms of action of oxytocin by measuring the level of gene expression of adipogenic factors; and (iii) test the hypothesis that oxytocin's effect on adipose tissue involves specific activation of eukaryotic elongation factor 2 (eEF2). EXPERIMENTAL APPROACH: Adult rats were subcutaneously treated with oxytocin (3.6 ug.100 g-1 body weight day-1) via osmotic minipumps for 2 weeks. Adipocytes from epididymal adipose tissue were isolated and their size evaluated by light microscopy. Gene expression of adipogenic and angiogenic factors was determined by real-time PCR and dephosphorylation of eEF2 by immunoblotting. KEY RESULTS: Oxytocin treatment decreased the diameter of adipocytes and increased the epididymal adipose tissue protein content without changing the adipose tissue mass. Increases in fatty acid binding protein, peroxisome proliferator-activated receptor gamma, insulin-sensitive glucose transporter 4, leptin and CD31 mRNA levels were noted in the epididymal and/or retroperitoneal fat tissue of oxytocin-treated rats. Oxytocin enhanced the dephosphorylation of eEF2 in the epididymal adipose tissue. CONCLUSIONS AND IMPLICATIONS: The present results demonstrate that subchronic treatment with oxytocin induces adipogenic and angiogenic effects and that the eEF2 signalling pathway is involved in these effects of oxytocin on adipose tissue in vivo. These findings are likely to motivate further research and indicate new approaches for modulating adipose tissue morphology and metabolism. PMID- 20846188 TI - Effective animal health disease surveillance using a network-enabled approach. AB - There are many benefits that derive from real-time knowledge of the health status of the national livestock population. Effective animal disease surveillance is a requirement for countries that trade in live animals and their products in order to comply with the World Organization for Animal Health (OIE) guidelines. Rapid identification of introduced and emerging disease allows rapid response and mitigation of the economic consequences. Connections between animal and human disease caused by a common pathogen can be recognized and control measures implemented, thereby protecting public health and maintaining public confidence in the food supply. Production-limiting diseases can be monitored, and control programmes be evaluated with benefits accruing from decreased economic losses associated with disease as well as reducing the welfare concerns associated with diseased animals. Establishing a surveillance programme across a wide area with diverse ecosystems and political administrations as Canada is a complex challenge. When funding became available from a government programme to enable early detection of a bio-terrorist attack on livestock, the Canadian Animal Health Surveillance Network (CAHSN) became officially established. An existing web-based information platform that supports intelligence exchange, surveillance and response for public health issues in Canada was adapted to link the network animal health laboratories. A minimum data set was developed that facilitated sharing of results between participating laboratories and jurisdictions as the first step in creating the capacity for national disease trend analysis. In each of the network laboratories, similar quality assurance and bio-containment systems have been funded and supported, and diagnostic staff have been trained and certified on a suite of diagnostic tests for foreign animal diseases. This ensures that national standards are maintained throughout all of the diagnostic laboratories. This paper describes the genesis of CAHSN, its current capability and governance, and potential for future development. PMID- 20846189 TI - Never mind the content, measure the impact: spin bowling for journal impact factors vs. the importance of patient impact. PMID- 20846190 TI - Miracle pills for weight loss: what is the number needed to treat, number needed to harm and likelihood to be helped or harmed for naltrexone-bupropion combination? PMID- 20846191 TI - Health status instrument vs. prognostic instrument for assessing chronic obstructive pulmonary disease in clinical practice. PMID- 20846192 TI - Antimuscarinic agents in elderly people. PMID- 20846193 TI - The public's enthusiasm for complementary and alternative medicine amounts to a critique of mainstream medicine. PMID- 20846194 TI - Multicomponent staging indices for chronic obstructive pulmonary disease in daily patient care: what's the yield? PMID- 20846195 TI - Oxidative stress in critical care medicine. PMID- 20846196 TI - Incorporating the social environment in genotype environment interaction studies of mental disorders. PMID- 20846197 TI - A different way of looking at depression. PMID- 20846198 TI - A 24-week randomised controlled trial comparing usual care and metabolic-based diet plans in obese adults. AB - BACKGROUND: Usual care (UC) practice for weight management often includes providing standardised, ad libitum, low-calorie nutrition plans. However, weight loss using such plans appears comparable with metabolic-based diet (MD) plans that are closer to resting energy expenditure (REE) level. In addition, MD plans are approximately 250-750 kcal/day higher in caloric values compared with UC plans. Therefore, the purpose of this study was to compare weight loss and eating behaviour differences between UC and MD plans. METHODS: Seventy-four obese (30.0 51.7 kg/m(2) ) adults (21-67 years) voluntarily participated in a 24-week randomised study. UC men and women received a fixed, ad libitum, 1600 and 1200 kcal/day nutrient plan, respectively. MD participants received an individualised treatment plan based from measured REE. Bodyweight and eating behaviours (i.e. intake, restraint and uncontrolled eating) were assessed over time. RESULTS: Intent-to-treat analysis indicated no significant difference in weight loss (UC: 5.7 +/- 6.3% vs. MD: -5.3 +/- 7.1% p = 0.67) between groups over time. There was no difference in daily energy intake (UC: 2490 +/- 576 kcal/day vs. MD: 2525 +/- 475 kcal/day) at 24 weeks between groups. Both groups experienced a significant improvement (p < 0.05) in eating dietary restraint and uncontrolled eating yet there was no difference between groups. CONCLUSION: From this study, UC calorie plans do not generate more weight loss or improve eating behaviours in comparison with MD calorie plans. As treatment effects are comparable, clinicians can select UC or MD plan options based on clinician and patient preference. PMID- 20846199 TI - An exploratory analysis of factors associated with weight change in a 16-week trial of oral vs. orally disintegrating olanzapine: the PLATYPUS study. AB - BACKGROUND: We conducted exploratory analyses of the data from a multinational, randomised study to identify factors associated with weight change after 16 weeks of treatment with standard olanzapine tablets (SOT) or sublingual orally disintegrating olanzapine (ODO). METHODS: One hundred and forty nine outpatients who gained weight during prior SOT therapy were enrolled into the study and treated with ODO (N = 84) or SOT (N = 65). Exploratory analyses were conducted with the subset of compliant patients (ODO: n = 60; SOT: n = 47). RESULTS: The decrease in the rate of weight gain at the end of study therapy (change from baseline) was greater in the ODO group than the SOT group (-0.59 kg/week vs. 0.38 kg/week, p = 0.0246). Age was negatively associated with weight change (p = 0.0203) in both treatment groups combined: patients gained 0.7 kg less for every 10 years of age. The least squares mean weight gain was lower with ODO than SOT in male patients (0.35 kg vs. 3.04 kg, p = 0.061), but not female patients and in American patients (0.55 kg vs. 6.21 kg, p < 0.0001), but not Canadian or Mexican patients. CONCLUSIONS: Although not conclusive, these data suggest that ODO may be a reasonable treatment option for some patients who gain weight with SOT. Further research is required to confirm these findings. PMID- 20846200 TI - Comparison of the once-daily levofloxacin-containing triple therapy with the twice-daily standard triple therapy for first-line Helicobacter pylori eradication: a prospective randomised study. AB - BACKGROUND/AIMS: Simple compound of Helicobacter pylori eradication therapy may improve drug compliance of patients. The aims of this study were to compare the efficacy and tolerability of a simple combination containing levofloxacin 7-day once-daily with standard twice-daily triple therapy. PATIENTS AND METHODS: This was a prospective, randomised, open-label trial. A total of 189 consecutive patients diagnosed with peptic ulcer and H. pylori infection were enrolled. Patients were randomly divided into two groups: LEC group--levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily for 7 days; AEC group- amoxicillin 1 g, esomeprazole 40 mg and clarithromycin 500 mg twice daily for 7 days. RESULTS: There were 90 patients in the LEC group and 99 patients in the AEC group. By intention-to-treat and per-protocol analysis, the H. pylori eradication rate was 78.9% [71/90; 95% confidence interval (CI), 70.3-87.5%] and 83.5% (71/85; 95% CI, 75.5-91.6%) respectively, in the LEC group; and 74.8% (74/99; 95% CI, 66.0-83.5%) and 86.0% (74/86; 95% CI, 78.6-93.5%) respectively, in the AEC group. The incidence and tolerability of side effects were similar between these two groups. CONCLUSION: The efficacy and tolerability of once-daily levofloxacin containing triple therapy are equal to those of the standard twice-daily triple therapy in this study. However, none of the treatment regimens evaluated achieved enough eradication efficacies to be considered as a recommendable first-line treatment. PMID- 20846201 TI - New once-daily formulation for trospium in overactive bladder. AB - AIMS We examined the relative efficacy and safety of trospium 20 mg bid and 60 mg extended release formulations and position this drug against other antimuscarinic agents. METHODS: Data were identified on the pharmacology and pharmacokinetics of trospium chloride. Key publications on trospium 20-mg and 60-mg clinical studies in patients with overactive bladder (OAB) were identified and efficacy and safety compared between these formulations as well as other antimuscarinic agents. RESULTS: Trospium offers the principal advantage over other antimuscarinic agents that, as it is a quaternary amine, it does not cross the blood-brain barrier and is therefore less likely to cause central nervous system effects observed with several other agents. Moreover, with its minimal liver metabolisation, independent of the main cytochrome pathways, trospium has a low risk of drug-drug interaction in patients taking multiple pharmacological agents. Trospium 60 mg ER is as effective as trospium 20 mg bid in improving the key outcome parameters associated with OAB, but with a lower rate of dry mouth, the most common side effect of these agents. Trospium has comparable efficacy and safety to the other antimuscarinic agents currently marketed. DISCUSSION: Good patient persistence with treatment has been reported with trospium. There are currently a large number of antimuscarinic drugs on the market without clear evidence to distinguish one agent from another in terms of efficacy, provided that an adequate dose is used in the clinical setting. CONCLUSION: The new formulation of trospium is certainly worth considering as a pharmacological treatment of patients with OAB, particularly in the elderly, in whom one wants to avoid the potential for cognitive dysfunction. PMID- 20846202 TI - Current concepts in the management of hip pain in the young adult. AB - Until recently, surgical management of hip disorders in adults has focused mainly on conventional total hip replacements for advanced arthritis. These have been performed mainly in the elderly, and there have been few surgical options in the younger patient. Over the past decade, the treatment of hip disorders in patients less than 55 years of age has changed rapidly; improved diagnostic techniques as well as newer diagnoses have lead to increased surgical options. This article reviews the recent literature on these advances. PMID- 20846203 TI - The importance of appropriate prophylaxis for the prevention of venous thromboembolism in at-risk medical patients. AB - BACKGROUND: Venous thromboembolism (VTE), which encompasses both deep-vein thrombosis and pulmonary embolism, is a significant healthcare problem, leading to considerable morbidity, mortality and resource utilisation. AIMS: This review discusses the adherence to VTE guideline recommendations and the available clinical evidence on the appropriate type, dose and duration of VTE prophylaxis. METHODS: A literature survey was conducted using Pub Med and EMBASE to identify publications related to appropriate thromboprophylaxis in medically ill patients at risk of VTE. RESULTS: Despite evidence from clinical trials and national guidelines, VTE prophylaxis in medically ill patients remains underutilised. The use of unfractionated heparin three-times-daily, low-molecular-weight heparin once-daily and fondaparinux once-daily has demonstrated effectiveness in clinical trials of medically ill patients. However, controversy exists about the use of unfractionated heparin twice-daily, and fondaparinux has not yet received US Food and Drug Administration approval for VTE prophylaxis in medically ill patients. CONCLUSION: It is important for clinicians to have an understanding of the evidence-based literature when selecting an appropriate drug, at the appropriate dose, for the appropriate duration for VTE prophylaxis in medically ill patients. VTE prophylaxis in medically ill patients is cost-effective, and drugs that are expensive may still be cost-effective when considering improved efficacy and/or safety. Recently, the underutilisation of VTE prophylaxis has led to the involvement of government and other regulatory agencies in an attempt to increase appropriate VTE prophylaxis in US hospitals and improve the clinical and economic outcomes in medical patients at risk of VTE. PMID- 20846204 TI - The effect of sporting events on emergency department attendance rates in a district general hospital in Northern Ireland. AB - BACKGROUND: Previous studies have reported a conflicting relationship between the effect of live and televised sporting events on attendance rates to emergency departments (ED). The objectives of this study were to investigate the relationship of major sporting events on emergency department attendance rates and to determine the potential effects of such events on service provision. METHODS: A retrospective analysis of ED attendances to a district general hospital (DGH) and subsequent admissions over a 24-h period following live and televised sporting activities was performed over a 5-year period. Data were compiled from the hospital's emergency record books including the number of attendances, patient demographics, clinical complaint and outcome. Review patients were excluded. Analysis of sporting events was compiled for live local, regional and national events as well as world-wide televised sporting broadcasts. RESULTS: A total of 137,668 (80,445 men) patients attended from April 2002 to July 2007. Mean attendance rate per day was 80 patients (men = 47). Mean admission rate was 13.6 patients per day. Major sporting events during the study period included; Soccer: 4 FA Cup and 1 World Cup (WC) finals; Rugby: 47 Six Nations, 25 Six nations games involving Ireland, 1 WC final, 2 WC semi-finals, 2 WC quarter-finals and 4 WC games involving Ireland; and Gaelic Football [Gaelic Athletic Association (GAA)]: 5 All-Ireland finals, 11 semi-finals, 11 quarter finals and 5 provincial finals. There was a significantly higher patient admission rate during the soccer FA Cup final, Rugby Six Nations and games involving Ireland and for GAA semi- and quarter-final games (p = 0.001-0.01). There was no difference identified in total attendance or non-admission rates for sporting events throughout the study period. Although there was no correlation identified between any of these sporting events and total emergency department attendances (r < 0.15, p > 0.07), multinomial logistic regression demonstrated that FA Cup final (p = 0.001), Rugby Six Nations (p = 0.019), Rugby WC games involving Ireland (p = 0.003), GAA All-Ireland semi- and quarter-finals (p = 0.016; p = 0.016) were predictors of patient admission rates. CONCLUSION: This study suggests that live or televised sporting events do not significantly affect ED attendances to a DGH. However, some events appeared to be predictors of patient admission rates. Although it may be beneficial to consider the effect of sporting events on service stratification during these periods, the overall effect is probably minimal and should not create a major concern for future service provision despite the implementation of the European Working Time Directive. PMID- 20846205 TI - Nonagenarian surgical admissions for the acute abdomen: who benefits? AB - INTRODUCTION: Patients 90 years and older form an increasing proportion of the general population. Outcomes of their acute surgical admissions are not well documented. METHODS AND MATERIALS: Surgical management of 49 consecutive nonagenarian admissions (median age: 92 years) with an acute abdomen was compared with the management and outcome of 50 younger patients (median age: 53.5) admitted with a suspected acute abdomen over the same period. RESULTS: Nonagenarian group consisted of mainly women (71% vs. 50%; p = 0.003). The use of laboratory investigations and imaging was similar for the patients aged over 90 and the younger patients, although proportionately fewer nonagenarians were investigated by abdominal CT scan (8% vs. 24%). Of the 49 nonagenarian patients admitted, only 4% (n = 2) were operated on. In contrast, 38% (n = 19) of patients aged 50-59 (p = 0.0001) underwent a surgical intervention. A much greater proportion of nonagenarians died in hospital than patients in the 50-59 comparator group (16% nonagenarians vs. 4% comparator patients; p = 0.04). The very large majority of survivors in both age groups were discharged back to their preadmission domicile [39 (95%) nonagenarians vs. 46 (96%) comparator 50-59 year group]. CONCLUSIONS: In this study, when compared with younger patients, very few nonagenarian patients (2%) with a suspected acute abdomen benefited from surgical admission. Instead, the large majority of nonagenarians either died or were discharged back to their home address without surgery. PMID- 20846206 TI - Adherance to protocol during the acute management of diabetic ketoacidosis: would specialist involvement lead to better outcomes? AB - BACKGROUND: Diabetic ketoacidosis (DKA) is a hyperglycaemic emergency associated with major morbidity and mortality. It has been shown that treating patients admitted with DKA using an integrated care pathway, or protocol, reduces time taken to initiate management thus optimising care. Early input from diabetes specialist services should also be sought. A new protocol for managing DKA was introduced in Sherwood Forest Trust in July 2008. AIMS: To assess whether the trust DKA protocol is being followed at Kingsmill and Newark District General Hospitals during acute management (first 4 h) of patients. METHODS: Retrospective case note review of all adult patients coded as DKA from July 2008 to February 2009. RESULTS: Seventy-eight percent of patients were correctly diagnosed according to protocol. Hundred percent of patients had i.v. access and correct blood tests within 1 h of admission. Eighty percent were given appropriate fluid resuscitation within the first hour. Seventy-two percent had correct insulin prescribed and 73% were on the correct sliding scale. Seventy-eight to ninety percent of patients had correct initial investigations ordered. However only 46% of patients requiring High Dependency Unit care were referred appropriately. Between hours 2 and 4 only 38% had repeat electrolytes checked and only 35-60% of patients had the correct fluid prescribed. CONCLUSIONS: The findings indicated that there was awareness of the new DKA protocol. It was referred to and placed in clinical notes but not always followed. Management of patients with DKA within the first hour was compliant. However, subsequent fluid management and electrolyte monitoring was poor. It was found that using a protocol does help to standardise initial management of patients but further education is needed and referral criteria need clarifying. Access to 24-hour specialist services may also help to optimise management. PMID- 20846208 TI - Non-alcoholic fatty liver disease and pharmacological options. PMID- 20846209 TI - Indoor air pollution and childhood asthma: variations between urban and rural areas. AB - Health effects of indoor pollution have been investigated overall in urban areas. To compare the potential effect of home air pollutants on asthma in urban and rural houses, two case-control populations, composed of children living in the city (32 asthmatics and 31 controls) and in the countryside (24 asthmatics and 27 controls) were included. During 1 week, nitrogen dioxide, fine particles, and volatile organic compounds (formaldehyde, acetaldehyde, benzene, toluene, ethylbenzene, and xylenes) were assessed at home. Urban dwellings were found to be more polluted than rural ones, with concentrations up to two times higher. In the whole population, exposure to acetaldehyde and toluene was significantly associated with a higher risk of asthma. In the urban population, the association with toluene was significant in children studied during winter, and with toluene, xylenes, and ethylbenzene when cases were restricted to current asthmatics. In rural settings, a relationship between asthma and formaldehyde exposure was observed (OR = 10.7; 95% CI 1.69-67.61). Our findings suggest that daily continuous exposures to pollutants may be implicated in asthma, even in the case of low exposure, as those found in rural areas. Our results could also indicate a specific effect of indoor pollution in the rural environment. PRACTICAL IMPLICATIONS: Everyday exposure to indoor pollution was associated with a higher risk of childhood asthma. These findings suggest that even at low concentrations, pollutants could be implicated in asthma and reinforce the importance of establishing guideline values to improve indoor air quality by limiting sources or by optimizing ventilation. Specific effects could occur in rural environments where pollution differs from urban area. PMID- 20846210 TI - Single-particle characterization of indoor aerosol particles collected at an underground shopping area in Seoul, Korea. AB - In this study, single-particle characterization of aerosol particles collected at an underground shopping area was performed for the first time. A quantitative single-particle analytical technique, low-Z particle electron probe X-ray microanalysis, was used to characterize a total of 7900 individual particles for eight sets of aerosol samples collected at an underground shopping area in Seoul, Korea. Based on secondary electron images and X-ray spectral data of individual particles, fourteen particle types were identified, in which primary soil-derived particles were the most abundant, followed by carbonaceous, Fe-containing, secondary soil-derived, and secondary sea-salt particles. Carbonaceous particles exist in three types: organic carbon, carbon-rich, and CNO-rich. A significant number of textile particles with chemical composition C, N, and O were encountered in some of the aerosol samples, which were from the textile shops and/or from clothes of passersby. Primary soil-derived particles showed seasonal variation, with peak values in spring samples, reflecting higher air exchange between indoor and outdoor environments in the spring. Secondary soil-derived, secondary sea-salt, and ammonium sulfate particles were frequently encountered in winter samples. Fe-containing particles, contributed from a nearby subway station, were in the range of about 19% relative abundances for all samples. PRACTICAL IMPLICATIONS: In underground shopping areas, particulate matters can be a considerable health hazard to the workers, shoppers, passersby, and shop keepers as they spend their considerable time in this closed microenvironment. However, no study on the characteristics of indoor aerosols in an underground shopping area has been reported to our knowledge. This work provides detailed information on characteristics of underground shopping area aerosols on a single particle level. PMID- 20846211 TI - Association between indoor air pollution measurements and respiratory health in women and children in Lao PDR. AB - This article presents the results of a study on the association between measured air pollutants and the respiratory health of resident women and children in Lao PDR, one of the least developed countries in Southeast Asia. The study, commissioned by the World Health Organisation, included PM(10), CO and NO(2) measurements made inside 181 dwellings in nine districts within two provinces in Lao PDR over a 5-month period (12/05-04/06), and respiratory health information (via questionnaires and peak expiratory flow rate (PEFR) measurements) for all residents in the same dwellings. Adjusted odds ratios were calculated separately for each health outcome using binary logistic regression. There was a strong and consistent positive association between NO(2) and CO for almost all questionnaire based health outcomes for both women and children. Women in dwellings with higher measured NO(2) had more than triple of the odds of almost all of the health outcomes, and higher concentrations of NO(2) and CO were significantly associated with lower PEFR. This study supports a growing literature confirming the role of indoor air pollution in the burden of respiratory disease in developing countries. The results will directly support changes in health and housing policy in Lao PDR. PRACTICAL IMPLICATIONS: This is the first study that investigated indoor air quality and its impact within residential dwellings in Lao PDR, which is one of the poorest and least developed countries in south-east Asia, with a life-expectancy of 56 years in 2008. While there have been other studies published on indoor air quality in other developing countries, the situation in Laos is different because the majority of houses in Laos used wood stoves, and therefore, emissions from wood burning are the dominant sources of indoor air pollution. In other countries, and studies, while emission from wood burning was investigated, wood was rarely the main or the only fuel used, as the houses used in addition (or solely) dung, kerosene or coal. The study quantified, for the first time, concentrations in houses two provinces in Laos PDR and shed light on the impact of human activities and urban design on pollutant concentrations and respiratory health. This study contributes to the accumulation of evidence to provide more reliable estimates of risk and a more informed basis for decision making by concerned governments and communities. PMID- 20846212 TI - Secondhand smoke transfer and reductions by air sealing and ventilation in multiunit buildings: PFT and nicotine verification. AB - Surveys suggest that transfer of secondhand smoke (SHS) between units in multiunit residential buildings is common, but measured data are rare. This study was undertaken to quantify bulk air transfer between units and document transfer of SHS species before and after treatments that sealed boundaries between units and provided a minimum amount of continuous exhaust ventilation of each unit. Six buildings in Minnesota were studied. Treatments were performed in clusters of up to eight units in each building, including zero to two units occupied by smokers. Bulk air transfer was quantified through passive perfluorocarbon tracer (PFT) gas tests. SHS transfer was evaluated using passive nicotine sampling. The median fraction of air entering a unit that came from other units tagged with PFTs ranged from 0.021 in a new condominium building to 0.353 in a 1930s duplex, with an overall median of 0.041. Treatments provided a median decrease of 29% in the fraction of transferred air and reduced PFT concentrations by about 40%, because of increased ventilation of both source and target apartments. Nicotine was transferred at only one-sixth the rate of PFTs. Involuntary exposure to SHS can be reduced but not eliminated by modifying existing, occupied multiunit buildings. PRACTICAL IMPLICATIONS: Recent studies of secondhand smoke exposure in multiunit housing indicate transmission of SHS constituents from smokers' units to those occupied by nonsmokers. A straightforward solution for this problem is to eliminate air leakage transfer between these units. This study describes a 2 year investigation of air sealing and ventilation improvements in six multiunit buildings located in a heating-dominated climate region of the US. The results quantify the reduction in interunit transfer of air between smokers' and nonsmokers' units. While it is possible to reduce the transfer when done with care, it is extremely difficult to eliminate these flows unless the buildings are vacated and extensively rebuilt. Eliminating air leakage between smokers' and nonsmokers' units is not a practical means of solving SHS transmission in an existing building. PMID- 20846213 TI - Measurements of volatile organic compounds in car showrooms in the province of Varese (Northern Italy). AB - Car dealer showrooms furnished with desk areas are a work place whose occupants may be exposed to evaporative emissions from the exhibited cars. The aim of the study was to identify and quantify the main organic compounds present in car dealer showrooms as a result of evaporative emissions from the exhibited cars and to evaluate the personal exposure concentrations of car vendors working in these areas. A total of 19 volatile organic compounds (aromatic compounds, aldehydes and terpenes) were investigated and quantified. Additionally, levels of the same chemicals were measured in the private houses of the car vendors for comparison purposes. All measurements were taken using passive samplers over a consecutive time period of 5 days. Concentrations in the showrooms were on average 12 times higher than the ambient concentration around the showrooms and 10 times higher than the concentrations measured in the private houses of the vendors. Benzene concentrations inside the showrooms ranged from 11 to 93.2 MUg/m(3). The personal exposure concentrations of the vendors reached time-weighted levels up to 57.3 MUg/m(3) with minimum values around 10 MUg/m(3). The results of the study show the significant contributing factor of work place emissions on the vendors' overall exposure load. PRACTICAL IMPLICATIONS: The high concentrations of some volatile organic compounds (VOCs), including benzene, that were measured in the showrooms highlight the need to safeguard the vendors' health. Measures for reducing personal exposure concentrations could include removing the vendors' desks from the showroom where the cars are exhibited, optimizing the ventilation inside the showrooms and minimizing evaporative emissions from the cars. PMID- 20846214 TI - A systematic review of the literature: workplace violence in the emergency department. AB - AIMS AND OBJECTIVES: To synthesise the body of literature on workplace violence in the emergency department and to identify characteristics of intervention studies that are the basis for guiding best practice modelling in the clinical setting. The research question addressed was what are the characteristics and findings of studies since 2004 on workplace violence in the emergency department? BACKGROUND: Emergency departments are prone to increased incidents of workplace violence. Workplace violence in the health care setting has become a hot topic of policy, political debate and research in recent years. Despite the research that has been carried out in this area, little consensus exists as to what are the best practices for mitigating violence in this setting. Design. Systematic literature review. METHODS: Search using four online databases, including MEDLINE, CINAHL, PsycINFO and the Dissertations and Theses Full Text Database. RESULTS: Most research focused on the incidence rates of workplace violence in the emergency department and effects on staff. There was a significant lack of intervention studies to provide a framework for guiding evidence-based practice. Themes of under-reporting violence, barriers and attitudes towards reporting, description and characterisation of incidents of violence, predisposing factors and the concept of safety or lack of fear were all major content areas addressed in the literature. CONCLUSIONS: Incidence of workplace violence in the emergency department has been well documented in numerous published studies. Emergency department workers are exposed to significant rates of physical and verbal abuse. Under-reporting of workplace violence in the emergency department is common and contributes to the difficulty in accurately tracking violence. RELEVANCE TO CLINICAL PRACTICE: Future research must move beyond descriptive studies to include more advanced research methods. Few practice-guiding implications can be gained from this body of research because of the lack of intervention studies. PMID- 20846216 TI - Evaluation of the retentive characteristics of semi-precision extracoronal attachments. AB - The aims of this in vitro study were: to evaluate the repeatability of producing the semi-precision attachment; to establish their estimated longevity by a simulated, repeated denture placement/removal procedure of denture; and to investigate the wear of their components. Four types of semi-precision attachments were evaluated. The attachments represented polymer-to-metal type of friction: Vario-Kugel-Snap, Vario-Soft, Strategy OT and ASC-52, which exhibited metal-to-metal type of friction. Tensile dislodging force was applied to sample to register peak load-to-dislodgment and also to determine the displacement curve. Then the cyclic axial loading tests were performed with insertion/separation machine. To detect worn areas, the surface of each sample was examined under a scanning electron microscope. The large variability of initial retentive force and shape of displacement curves was noted within Vario Soft and Vario-Kugel-Snap group. After the first period of loading (up to 300 cycles), the mechanical properties of all samples were stabilised. The mean retention force of attachments with polymer matrix after 3000 cycles was approximately half the recommended value, while samples of ASC-52 (with metal-to metal friction) withstood 8000 cycles. Results suggest that the inaccuracies of casting and laboratory procedure have only limited influence on the fit of the semi-precision attachments. The attachment with metal-to-metal type of friction exhibits the highest wear resistance (simulated up to 8 years of usage) compared to attachments with polymeric matrix (up to 3 years). All attachments exhibited wear of metal patrix, what can minimise the chance of re-activation in a long run. PMID- 20846215 TI - Bayesian analysis of genetic interactions in case-control studies, with application to adiponectin genes and colorectal cancer risk. AB - Complex diseases such as cancers are influenced by interacting networks of genetic and environmental factors. However, a joint analysis of multiple genes and environmental factors is challenging, owing to potentially large numbers of correlated and complex variables. We describe Bayesian generalized linear models for simultaneously analyzing covariates, main effects of numerous loci, gene-gene and gene-environment interactions in population case-control studies. Our Bayesian models use Student-t prior distributions with different shrinkage parameters for different types of effects, allowing reliable estimates of main effects and interactions and hence increasing the power for detection of real signals. We implement a fast and stable algorithm for fitting models by extending available tools for classical generalized linear models to the Bayesian case. We propose a novel method to interpret and visualize models with multiple interactions by computing the average predictive probability. Simulations show that the method has the potential to dissect interacting networks of complex diseases. Application of the method to a large case-control study of adiponectin genes and colorectal cancer risk highlights the previous results and detects new epistatic interactions and sex-specific effects that warrant follow-up in independent studies. PMID- 20846217 TI - Association of linear growth impairment in pediatric Crohn's disease and a known height locus: a pilot study. AB - The etiology of growth impairment in Crohn's disease (CD) has been inadequately explained by nutritional, hormonal, and/or disease-related factors, suggesting that genetics may be an additional contributor. The aim of this cross-sectional study was to investigate genetic variants associated with linear growth in pediatric-onset CD. We genotyped 951 subjects (317 CD patient-parent trios) for 64 polymorphisms within 14 CD-susceptibility and 23 stature-associated loci. Patient height-for-age Z-score < -1.64 was used to dichotomize probands into growth-impaired and nongrowth-impaired groups. The transmission disequilibrium test (TDT) was used to study association to growth impairment. There was a significant association between growth impairment in CD (height-for-age Z-score < -1.64) and a stature-related polymorphism in the dymeclin gene DYM (rs8099594) (OR = 3.2, CI [1.57-6.51], p = 0.0007). In addition, there was nominal over transmission of two CD-susceptibility alleles, 10q21.1 intergenic region (rs10761659) and ATG16L1 (rs10210302), in growth-impaired CD children (OR = 2.36, CI [1.26-4.41] p = 0.0056 and OR = 2.45, CI [1.22-4.95] p = 0.0094, respectively). Our data indicate that genetic influences due to stature associated and possibly CD risk alleles may predispose CD patients to alterations in linear growth. This is the first report of a link between a stature-associated locus and growth impairment in CD. PMID- 20846218 TI - Editorial: How many roads? Building and sustaining collaborative relationships in an increasingly global environment. PMID- 20846219 TI - A systematic review of health-related quality of life instruments used for people with venous ulcers: an assessment of their suitability and psychometric properties. AB - AIMS AND OBJECTIVES: To review the quality of life questionnaires used to measure the impact of venous ulceration and to evaluate their psychometric properties. BACKGROUND: Venous leg ulcers have a negative impact on quality of life. Health related quality of life can be measured using structured questionnaires. Nurses are the primary care providers for patients with venous ulceration and are ideally placed to assess and develop these types of questionnaires. There may also be an opportunity to use such quality of life instruments to measure the impact of nursing interventions in other areas where nurses are the key care providers. DESIGN: Systematic review. METHOD: Studies were sought that used quality of life instruments to evaluate the impact of venous ulceration. Fourteen electronic bibliographical databases and 11 Internet-based health services research related resources were searched. In addition, grey literature was sought and the reference lists of relevant articles checked. Data were extracted regarding the type of instrument used, sample, number of items and domains and psychometric performance of the instrument. RESULTS: The initial search identified a total of 338 potential citations. After review, a total of 31 studies were included: 17 used generic and 14 used disease-specific instruments. Five different types of generic and seven disease-specific instruments were identified. There was significant heterogeneity between the studies in terms of study design, aetiology of ulceration and times of assessment. The disease specific instruments showed limitations in relation to their applicability to venous ulcer patients because of flaws in design or validation. CONCLUSIONS: The literature on quality of life related to venous ulceration failed to sufficiently distinguish between those with different causes of leg ulceration. There appeared to be problems with the ability of current quality of life instruments to detect changes in quality of life related to ulcer healing. Relevance to clinical practice. There appears to be an opportunity for nurses to develop a health related quality of life health-related quality of life instruments to evaluate their impact on patient outcomes. Such instruments could potentially allow nursing interventions to be assessed more effectively than the recently proposed nursing metrics. PMID- 20846220 TI - Comparison of puberty and psychosocial adjustment between Taiwanese adolescent females with and without diabetes. AB - AIMS AND OBJECTIVES: The aims of this study were to (1) determine the differences in puberty and psychosocial adjustment among Taiwanese adolescent females with and without type 1 diabetes mellitus, and (2) examine the interaction between pubertal timing and diabetes in relation to its effect on adolescent's psychosocial adjustment. BACKGROUND: Rapid physical and sexual changes during puberty elicit a wide array of psychosocial adjustments. The effects of pubertal changes among adolescent females with type 1 diabetes mellitus on psychosocial adjustment are unknown. Design. This study used a comparative, case-controlled design. A total of 82 adolescent females, aged 10-17, were recruited for the study. Forty-one adolescents with type 1 diabetes mellitus were age-matched to 41 adolescents without type 1 diabetes mellitus. METHODS: Adolescents' psychosocial adjustment, including internalising and externalising behaviours, was assessed using the Child Behaviour Checklist (parental report) and the Youth Self-Report (individual self-report). The self-reported Pubertal Development Scale was used to measure adolescents' puberty, including onset of menses, age at menarche and pubertal timing. RESULTS: When compared to their counterparts, adolescent females with type 1 diabetes mellitus reported a delayed menarche and a delayed puberty. Females with type 1 diabetes mellitus had significantly greater internalising and externalising behaviours than their counterparts according to parental reports. Onset of menses and adolescent self-reported psychosocial adjustment were not different between the two groups. Interaction analyses showed that the association between pubertal timing and internalising behaviours was related to the presence of diabetes. According to parental reports, early pubertal timing had positive effects on internalising behaviours for adolescent females with type 1 diabetes mellitus not for adolescent females without type 1 diabetes mellitus. RELEVANCE TO CLINICAL PRACTICE: A multi-informant approach is suggested when health care professionals assess adolescent psychosocial adjustment. Health care professionals must provide female teenagers with information and opportunities to discuss the impact of type 1 diabetes mellitus on their puberty and psychosocial adjustment. PMID- 20846221 TI - The predictors of adopting a health-promoting lifestyle among work site adults with prediabetes. AB - AIM AND OBJECTIVE: To examine how prediabetes knowledge, health beliefs and self efficacy of health behaviour contribute to work site adults adopting a health promoting lifestyle and to analyse these three factors as independent variables to identify key predictors of adopting health-promoting lifestyles. BACKGROUND: Health providers use health-promoting lifestyle interventions as the primary approach in preventing diabetes. However, many influential factors make it difficult for individuals to adopt a health-promoting lifestyle. Furthermore, no previous study has examined prediabetes knowledge, health beliefs, self-efficacy of health behaviour and health-promoting lifestyle in work site adults with prediabetes, especially among Asians. DESIGN: This was a cross-sectional study of 260 adults at four work sites in southern Taiwan. METHOD: Patients with prediabetes were given a cross-sectional questionnaire about prediabetes knowledge, health beliefs, self-efficacy of health behaviour and health-promoting lifestyle. Multiple stepwise regression analysis was used to determine predictors of implementing health-promoting lifestyles. RESULTS: In general, this study found that over age 45 and a BMI above 25 kg/m(2) are risk factors for prediabetes. A 47.5% variance in implementing health-promoting lifestyle was explained by a model that included self-efficacy of health behaviour (beta = 0.519, p < 0.001), perceived action barrier (beta = -0.207, p = 0.001) and perceived action benefits (beta = 0.129, p = 0.023). CONCLUSIONS: Work site health care units should identify prediabetes cases and teach diet control strategies for reducing body weight. By designing behaviour self-regulation protocol to promote self-management for prediabetic individuals, organisations could enhance self-efficacy and delay further development of diabetes. RELEVANCE TO CLINICAL PRACTICE: Findings guide the clinical assessment (e.g. self-efficacy) of prediabetic adults regarding their health-promoting lifestyles and provide effective guidelines for designing lifestyle interventions to prevent prediabetes in high-risk groups. PMID- 20846222 TI - Gender differences on chest pain perception associated with acute myocardial infarction in Chinese patients: a questionnaire survey. AB - AIMS: To investigate gender differences in chest pain perception among Chinese patients with acute myocardial infarction. BACKGROUND: Thrombolytic therapy is beneficial to outcomes of acute myocardial infarction if administered within 12 hours from the onset of chest pain. However, cardiac symptom interpretation may impact time of presentation to hospital. Differences in cardiac symptom reports by gender partly explain misdiagnoses and delays in treatment, particularly among women. Whether, such trends apply to Chinese patients with myocardial infarction is unknown. DESIGN: A descriptive prospective study. METHODS: Using questionnaires, data on demographic variables, the number of patients reporting chest pain and other chest sensations at the onset of acute myocardial infarction and chest pain intensity, description, location and radiation across the chest were collected. RESULTS: A total of 128 participants equally divided by gender were recruited. Chest pain was more prevalent among men than women (84.37% vs. 67.19%, p < 0.05). Although no statistical significance was found, Chinese men had higher mean chest pain intensity scores (7.54 SD 2.35 vs. 7.51 SD 2.25) and reported less atypical chest pain (0.00% vs. 9.3%) compared with women. Men had more upper right sided chest pain (40.74% vs. 20.93%, p = 0.038) whereas women experienced increased neck pain and pain to the upper central chest, middle central chest, upper central back, middle central back and middle right back regions. CONCLUSIONS: Discreet gender differences in chest pain perceptions exist between Chinese men and women, with the latter group, who may be considered as a high-risk group for missed and delayed diagnosis from myocardial infarction, reporting more atypical presentations. RELEVANCE TO CLINICAL PRACTICE: Irrespective of culture, women with myocardial infarction tend to present with atypical chest pain symptoms and therefore they should be aggressively investigated. PMID- 20846223 TI - Routines and rituals: a grounded theory of the pain management of drug users in acute care settings. AB - AIM: This study reviewed the perceptions and strategies of drug users and nurses with regard to pain management in acute care settings. BACKGROUND: Drug users present unique challenges in acute care settings with pain management noted to be at best suboptimal, at worst non-existent. Little is known about why and specifically how therapeutic effectiveness is compromised. DESIGN: Qualitative: constructivist grounded theory. METHOD: A constructivist grounded theory approach incorporating a constant comparative method of data collection and analysis was applied. The data corpus comprised interviews with drug users (n = 11) and five focus groups (n = 22) of nurses and recovering drug users. RESULTS: Moral relativism as the core category both represents the phenomenon and explains the basic social process. Nurses and drug users struggle with moral relativism when addressing the issue of pain management in the acute care setting. Drug users lay claim to expectations of compassionate care and moralise via narration. Paradoxically, nurses report that the caring ideal and mutuality of caring are diminished. Drug users' individual sensitivities, anxieties and felt stigma in conjunction with opioid-induced hyperalgesia complicate the processes. Nurses' and hospitals' organisational routines challenge drug user rituals and vice versa leading both protagonists to become disaffected. Consequently, key clinical issues such as preventing withdrawal and managing pain are left unaddressed and therapeutic effectiveness is compromised. CONCLUSION: This study provides a robust account of nurses' and drug users' struggle with pain management in the acute care setting. Quick technological fixes such as urine screens, checklists or the transient effects of (cognitive-based) education (or training) are not the answer. This study highlights the need for nurses to engage meaningfully with this perceptibly 'difficult' group of patients. RELEVANCE TO CLINICAL PRACTICE: The key aspects likely to contribute to problematic interactions with this patient cohort are outlined so that they can be prevented and, or addressed. PMID- 20846224 TI - Non-nutritive sucking relieves pain for preterm infants during heel stick procedures in Taiwan. AB - AIMS: This study examined the effectiveness of non-nutritive sucking on preterm infant pain, changes in infant behaviour and frequency of abnormal physiological signals during heel stick procedures in Taiwan. BACKGROUND: Preterm infants' repetitive exposure to painful procedures may result in changes to brain organisation. Pain management should be a priority in neonatal care. DESIGN: Randomised control trial. METHODS: Preterm infants (gestational age 28.9-37 weeks) were randomised to two groups: those receiving (experimental, n = 52) or not receiving non-nutritive sucking (control, n = 52) during heel stick procedures. Pain was measured before (for three minutes), during and after (during 10-minute recovery) heel stick procedures by the Premature Infant Pain Profile, changes in infant behaviour and abnormal physiological parameters. Results. Infants in both groups had similar odds ratios for pain and moderate-to severe pain (0.57 and 0.58, respectively), after adjusting for time effects, postconceptional age, heel stick duration, painful experiences and baseline Premature Infant Pain Profile score. The pain scores of infants with non nutritive sucking were significantly lower than those of non-nutritive sucking infants at all eight phases of the heel stick procedures. Infants undergoing heel stick procedures in the experimental group had lower rates ratios for 'grimace' and 'hand to mouth or face' behaviours than control infants (0.73 and 0.78, respectively). CONCLUSION: Non-nutritive sucking effectively reduced pain, particularly mild to moderate pain and behavioural responses to pain in infants receiving heel stick procedures, suggesting that nurses can offer this intervention to relieve pain in preterm infants undergoing invasive procedures. RELEVANCE TO CLINICAL PRACTICE: Infants should be given an appropriate-sized pacifier for comfort during painful procedures. Nurses need to be informed about the effectiveness of non-nutritive sucking, its analgesic mechanisms and how to use and incorporate it into practice. PMID- 20846225 TI - Mediating roles of social support on poststroke depression and quality of life in patients with ischemic stroke. AB - AIMS: The purposes of this study were to examine the associations among social support, poststroke depression and quality of life among patients with first-time ischemic stroke and to further test the impact of the dimensions of social support on poststroke depression and quality of life. The proposed models included mediation hypotheses to examine the mediating roles of social support. BACKGROUND: Although considerable attention has recently been devoted to explaining why poststroke depression and poor quality of life are frequent concomitants of stroke, little empirical work has been conducted to test predictions based on these models, especially in Taiwan. DESIGN: A cross sectional, descriptive correlation design was used. METHODS: The 102 patients with first-time ischemic stroke aged 32-90 (mean = 64.5, SD 11.8) were recruited from a large general hospital in Taiwan and through face-to-face survey interviews. The participants were assessed using the Social Support Inventory, Centre for Epidemiologic Studies Depression Scale, Barthel Index, the Instrumental Activities of Daily Living and Quality of Life Index-Stroke Version. The models were tested and confirmed through the application of structural equations with proposed variables. RESULTS: Nearly half of the Taiwanese patients with stroke felt depressed. Social support fully mediated the prediction of quality of life by age and partially mediated the prediction of quality of life by functional ability. Social support partially mediated the prediction of poststroke depression by functional ability. CONCLUSION: This study provides researchers and nurses with increased understanding of the mediating role of social support between functional ability and poststroke depression/quality of life. Social support may be a promising intervening variable in stroke outcome. RELEVANCE TO CLINICAL PRACTICE: The results suggest several clinical implications. The inclusion of social support in poststroke depression and quality of life after stroke may help nurses in planning stroke programme development, patient education, effective and efficient use of health care resources and effective rehabilitation, especially in those individuals who lack support or who are involved in stressful situations. PMID- 20846226 TI - Haemorrhoidectomy: prevalence and risk factors of urine retention among post recipients. AB - AIMS AND OBJECTIVES: The purpose of this study was to explore the prevalence and risk factors of urine retention among posthaemorrhoidectomy recipients. BACKGROUND. Haemorrhoids are one of the most common functional disorders of the anus. The Haemorrhoidectomy surgical procedure is one of the primary treatments for more severe haemorrhoidal occurrences, such as for third- and/or fourth degree haemorrhoid conditions. Urine retention is a common acute complication after operation, but rare study conducted by nurses in Taiwan to explore the prevalence and risk factors. DESIGN: A retrospective chart review was conducted. METHODS: Data from a prospectively maintained database on patients who had undergone haemorrhoidectomy between April 2004 - August 2008 were retrospectively analysed. A total of 469 charts were used in this analysis. The following outcomes were studied: patient profiles, haemorrhoid type and severity, anaesthesia methods, length of operating room stay, urine retention and management, intravenous fluid given during operation and length of stay. Results. The overall urinary retention rate was 32.8% (n = 153). Significant risk factors associated with postoperative urinary retention included severity of haemorrhoid and anaesthesia methods. Logistic regression analysis revealed that epidural anaesthesia (p = 0.008), spinal anaesthesia (p = 0.016) and haemorrhoids with a severity of three degrees or higher (p = 0.017) were predictors of urinary retention post haemorrhoidectomy. CONCLUSIONS: Acute urinary retention can have an adverse effect on a patient's quality of care. Careful follow-up of patients with these risk factors can help nurses spot posthaemorrhoidectomy urinary retention early. RELEVANCE TO CLINICAL PRACTICE: The prevalence of acute urinary retention post haemorrhoidectomy is common. Surgical ward nurses should therefore take the responsibility regarding the impact of urinary retention and seeking appropriate nursing interventions of induced urination. PMID- 20846227 TI - The role of antenatal pelvic floor muscle exercises in prevention of postpartum stress incontinence: a randomised controlled trial. AB - AIM: This article reports a randomised controlled trial to determine the efficacy of antenatal pelvic floor muscle exercises in the primary prevention of postpartum stress incontinence in primiparous women. BACKGROUND: Pelvic floor muscle exercises are effective in treating stress incontinence, yet prevention studies demonstrate equivocal findings. DESIGN: Randomised controlled trial. METHOD: Pregnant women recruited from two hospitals in North-west England were randomised to an intervention (n = 141) or control group (n = 145). Data were collected from 2005-2006. The intervention comprised four sessions of taught pelvic floor muscle exercise training during pregnancy and 8-12 maximal contractions repeated twice daily at home. A modified Bristol Female Lower Urinary Tract Symptom questionnaire, Leicester Impact Scale and Three Day Diary were administered at 20 and 36 weeks of pregnancy and three months postpartum. RESULTS: The intervention group was more likely to exercise their pelvic floor muscles compared to controls at 36 weeks (p = 0.019) and three months (0.022), reporting fewer episodes of incontinence and a lower score on the Leicester Impact Scale. However, these differences were not statistically significant. CONCLUSION: Significant differences were not demonstrated between the groups in relation to incontinence episodes and degree of bother of symptoms postpartum, although trends indicate a positive effect. Further research is necessary to address issues of adherence and the effect of pelvic floor muscle exercise undertaken during pregnancy on postpartum stress urinary incontinence. RELEVANCE TO CLINICAL PRACTICE: A proportion of women did not meet the required attendance at antenatal class, furthermore, few exercised their pelvic floor muscles during pregnancy according to instructions. Health professionals need to find ways to instruct and motivate women to perform pelvic floor muscles exercises regularly during pregnancy and the postpartum. PMID- 20846228 TI - Psychometric properties of the Chinese version of the Bipolar Spectrum Diagnostic Scale. AB - AIM AND OBJECTIVES: The aim of this study was to test the psychometric properties of the Chinese version of the Bipolar Spectrum Diagnostic Scale (C-BSDS) in a Chinese population to serve as an aid to clinical diagnosis of bipolar disorders. BACKGROUND: Bipolar spectrum disorders are often misdiagnosed because of the wide range of symptoms seen in patients. The consequences of delayed diagnoses or misdiagnoses can be devastating. DESIGN: A cross-sectional research design. METHOD: Two hundred patients with affective disorders from a psychiatric outpatient clinic in Taiwan were enrolled. Internal consistency reliability and two-week test-retest reliability were performed to evaluate the reliability of the C-BSDS. Expert content validity and factor analysis were used for testing construct validity. To evaluate sensitivity and specificity, the Chinese version of the Mini International Neuropsychiatric Interview (MINI) was used as the gold standard for diagnosis. RESULTS: The internal consistency coefficient measured by intra-class correlation (ICC) was 0.81, the test-retest reliability coefficient was 0.85 and the expert validity was 0.85. For construct validity, 'irritable and hyper-energetic factors' and 'depressed and lack of energy factors' were extracted by factor analysis. These two factors reflected the structure of the original scale and accounted for 33.27% of the variance. The optimal cut-off was 12, which yielded a sensitivity of 74 and a specificity of 0.97 for detecting bipolar disorder and for bipolar II disorder these were 0.79 and 0.68, respectively. CONCLUSIONS: The C-BSDS showed good reliability and validity, and the results were consistent with the English version of the BSDS. Therefore, the C-BSDS is an effective tool for evaluation of a Chinese population. RELEVANCE TO CLINICAL PRACTICE: The BSDS can further increase the detection rate of bipolar disorders, especially bipolar II disorder, with satisfactory sensitivity and specificity. It can effectively assist with clinical screening of patients for bipolar spectrum disorders. PMID- 20846229 TI - Partnership-based nursing practice for people with chronic obstructive pulmonary disease and their families: influences on health-related quality of life and hospital admissions. AB - AIMS AND OBJECTIVES: To evaluate the outcome of a coherent nursing practice in the form of partnership that addresses the complexity of living with chronic obstructive pulmonary disease. BACKGROUND: Chronic obstructive pulmonary disease is a wide-ranging and progressive chronic disease that not only requires relentless attentiveness of the persons having the disease but also the families involved. Particular consideration is called for in health care for those with an advanced and complicated stage of the disease. The nursing practice, grounded in the theoretical framework of 'partnership as practice', is participatory comprehensive, long-term and dynamic to individual patient-family needs. DESIGN: Retrospective and prospective pretest-post-test intervention study. Methods. Eleven men and 39 women participated (n = 50). Mean age was 66 years. The majority (n = 36) had severe chronic obstructive pulmonary disease (GOLD stage III and IV). Actual study period was six months (T2). Hospital admission data were collected six months prior to (T1) and six months after that period (T3), a total of 18 months. RESULTS: Hospital admission rate and days spent in hospital because of chronic obstructive pulmonary disease were significantly reduced. Disease-specific health-related quality of life measured by St. George's Respiratory Questionnaire improved significantly. For those with clinical anxiety and depression, both decreased significantly. Of those who were underweight, body mass index improved significantly. Abstinence from smoking changed non significantly. Capability in the use of inhaler medications improved. CONCLUSIONS: These results are in contrast to previous studies on outpatient nursing care for people with chronic obstructive pulmonary disease. The participatory nature of partnership with dialogue as central and which was uniquely implemented in this study might be of particular relevance for individuals and families living with chronic obstructive pulmonary disease. RELEVANCE TO CLINICAL PRACTICE: Complex and comprehensive health needs of people with chronic obstructive pulmonary disease and their families may be effectively addressed in partnership centred on dialogue together with efficient intra-and interdisciplinary collaboration. PMID- 20846230 TI - Perceived levels of satisfaction with the preoperative assessment service experienced by patients undergoing general anaesthesia in a day surgery setting. AB - AIM AND OBJECTIVE: Primary aim--to explore patient satisfaction with preoperative assessment for day surgery and compare patient satisfaction between two specialties, General Surgery and Urology. Secondary aim--to compare numbers of patients being preoperatively assessed in General Surgery and Urology. BACKGROUND: Patient-centred care is increasingly gaining significance, and patient satisfaction is an outcome measure assuming greater importance [Department of Health (2005) Creating a Patient Led NHS. Crown Copyright, London]. There is a paucity of literature on patient satisfaction with preoperative assessment. This article reports the findings of a study investigating satisfaction levels in patients undergoing preoperative assessment for general anaesthesia in a day surgery setting. DESIGN: Cross-sectional survey using a questionnaire. METHOD: A questionnaire was distributed to General Surgery and Urology patients on their day of admission in one general hospital. The questionnaire was designed to capture data on the type of preoperative assessment received and satisfaction levels of patients' experiences of the preoperative assessment service. The questionnaire was completed by 275 patients. RESULTS: There were no significant differences in expressed satisfaction between specialties with the preoperative assessment service or the type of preoperative assessment experienced. However, more General Surgery respondents felt preoperative assessment prepared them for hospital admission than Urology respondents, a chi-square test revealed a significant difference between the specialties (p = 0.046). Although patients expressed overall satisfaction with preoperative assessment, their responses reveal there are key issues. Several themes emerged indicating that exchange of preoperative information, a supportive attitude, anxiety and fearfulness, proceedings and aftercare are significant aspects of preoperative assessment for patients. CONCLUSIONS: Although there is some satisfaction, this study reveals that various aspects of this preoperative assessment service could be improved. This information will help inform future development of the preoperative assessment service. RELEVANCE TO PRACTICE: If preoperative assessment is to be patient centred, enjoying high levels of patient satisfaction, attention to patients' individual needs must be a priority. PMID- 20846231 TI - Patients' perceptions of information and support received from the nurse specialist during HCV treatment. AB - AIM: To identify patients' perceptions of support received from the nurse specialist during Hepatitis C virus (HCV) treatment. BACKGROUND: HCV is a worldwide health problem. However, it is a treatable disease and treatment success rates are high. Unfortunately, treatment comes with a multitude of adverse side effects and patients require informational and psychological support from specialist nurses while on treatment. To date, there is little nursing research on support received from this specialist nursing care. DESIGN: This study used a quantitative descriptive design. METHOD: A 59-item questionnaire collected data from 106 patients with a diagnosis of HCV attending a HCV outpatient clinic. RESULTS: Overall, patients were very satisfied with support received. Advice on contraception was well received. However, many patients did not feel supported with regard to advice on sleep management. There were no statistically significant differences between overall satisfaction and gender, age, genotype and risk factor. However, there were significant correlations found between support received and reported genotype. Those patients presenting with genotype 1, who are mostly infected through blood or blood products, indicated that they require more support in relation to information on side effects of treatment, quality of life and support groups. Specific approaches to support and advice for this cohort may need to be incorporated into current services. CONCLUSION: Results of this study reinforce the need for the ongoing use of specialist nurse services and development of this service where no such facilities exist. In addition, the service may need to further recognise and support the information and psychological needs of patients with differing modes of HCV infection. RELEVANCE TO CLINICAL PRACTICE: Findings provide information to practising nurse specialists about patient's views of information and support received from nurse specialists in HCV treatment centres and identify where deficits exist. PMID- 20846232 TI - Preoperative information needs of children undergoing tonsillectomy. AB - AIMS AND OBJECTIVES: To identify the information needs of children undergoing tonsillectomy with reference to content of information, method of delivery, information providers and timing of information provision. BACKGROUND: Tonsillectomy can be anxiety provoking for children and preoperative preparation programmes are long recognised to reduce anxiety. However, few have been designed from the perspectives of children and to date little is known about how best to prepare children in terms of what to tell them, how to convey information to them, who can best provide information and what is the best timing for information provision. DESIGN: A qualitative descriptive study. METHOD: Data were collected from nine children (aged 6-9) using interviews supported by a write and draw technique. Data were coded and categorised into themes reflecting content, method, providers and timing of information. RESULTS: Children openly communicated their information needs especially on what to tell them to expect when facing a tonsillectomy. Their principal concerns were about operation procedures, experiencing 'soreness' and discomfort postoperatively and parental presence. Mothers were viewed as best situated to provide them with information. Children were uncertain about what method of information and timing would be most helpful to them. CONCLUSION: Preoperative educational interventions need to take account of children's information needs so that they are prepared for surgery in ways that are meaningful and relevant to them. Future research is needed in this area. RELEVANCE TO CLINICAL PRACTICE: Practical steps towards informing children about having a tonsillectomy include asking them what they need to know and addressing their queries accordingly. Child-centred information leaflets using a question and answer format could also be helpful to children. PMID- 20846233 TI - Relatives' information needs and the characteristics of their search for information--in the words of relatives of stroke survivors. AB - AIM AND OBJECTIVES: To explore relatives' information needs and the characteristics of their information-seeking process shortly after the stroke event and six months later. BACKGROUND: Providing relatives of stroke survivors with information is important, as lack of information increases their uncertainty and risk becoming the 'second patient in the family' and early death. Therefore, it is essential to be aware of relatives' information needs and information seeking process the first six months after stroke. DESIGN: This qualitative study has a descriptive design. METHOD: Open-ended interviews were conducted with sixteen relatives after stroke survivor's admission to stroke unit and six months later with nine of these relatives. Data were analysed by means of content analysis. RESULTS: The identified information needs covered the spectrum from stroke survivor's medical condition because nurses' actions to relatives' changed health and life situation. Furthermore, relatives' information-seeking process was found to be related to their level of personal involvement, situational circumstances, different forms of knowledge and sources of information. CONCLUSIONS: Relatives' search for information emerges when health and lifestyle changes occur in survivors or themselves. It is important that this information affect them personally. Also, they need to develop different forms of knowledge when they cannot trust their own competences. As a result, instead of following established curricula based on their beliefs of relatives' information needs, nurses need to practice on identifying relatives' information needs. RELEVANCE TO PRACTICE: Different information needs and characteristics described in the study can serve as guidance in the development and implementation of pedagogical interventions to support relatives of stroke survivors. One pedagogical implication is to explore what a specific relative wants to know by how he/she talks or thinks about it. Thus, it must be taken into consideration that level of personal involvement, situational circumstances, sources of information and factual knowledge, understanding and skills are intertwined. PMID- 20846234 TI - Turkish validity and reliability of the summary of diabetes self-care activities measure for patients with type 2 diabetes mellitus. PMID- 20846235 TI - Modification of a student feedback tool that provides feedback to staff in clinical contexts. PMID- 20846236 TI - Validation and reliability test of Persian version of The Spirituality and Spiritual Care Rating Scale (SSCRS). PMID- 20846237 TI - Pain assessments in day surgery patients. PMID- 20846238 TI - Preemptive liver transplantation in a child with familial hypercholesterolemia. AB - Familial hypercholesterolemia is an autosomal codominant disorder associated with markedly elevated plasma concentration of LDL-cholesterol and increased cardiovascular risk. Homozygous patients have rapid development of atherosclerosis with death from cardiovascular disease even in childhood. Life long recurrent apheresis to reduce plasma LDL-cholesterol is considered the gold standard for treatment. Liver transplantation can be curative for this condition, but is usually only considered after the development of cardiovascular disease. We report a 5.5-yr-old child initially misdiagnosed with heterozygous familial hypercholesterolemia and treated by low-fat diet only. In view of persistent hypercholesterolemia and development of xanthomatosis, new molecular studies indicated the presence of two different mutations in the LDL receptor gene, with one being a deletion of two exons not identifiable with standard sequencing analysis. Recurrent plasma apheresis in combination with statins lowered, but did not normalize plasma LDL-cholesterol levels. It caused progressive reduction of the size of xanthomas and prevented the development of vascular complications. After two yr, liver transplantation normalized LDL-cholesterol levels and completely resolved the skin lesions. Preemptive liver transplantation is a definitive cure of familial homozygous hypercholesterolemia and might be more effective if performed before development of vascular complications. PMID- 20846239 TI - Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome induced by cidofovir. PMID- 20846240 TI - Prospective comparison of parent and adolescent report of health-related quality of life in adolescent solid organ transplant recipients. AB - This 18-month prospective investigation sought to examine changes in HRQOL over time for adolescent solid organ transplant recipients. Additionally, this study examined the relationship between adolescent and parent report of HRQOL and compared parent report of HRQOL to published normative data. Forty-eight adolescent-parent dyads completed the CHQ, a measure of HRQOL, at two time periods. Parent and adolescent reports of HRQOL were stable over time. ICCs between parent and adolescent reports were significant and moderate across most domains of HRQOL, with the exception of family cohesion, physical functioning, and bodily pain. However, mean differences indicated that parents perceived significantly worse self-esteem and general health perceptions compared to their adolescents. Compared to normative data, parents reported significantly lower HRQOL across several domains, including adolescents' physical functioning and the emotional impact of their adolescent's condition on themselves. However, parents also reported higher levels of family cohesion. Results indicate that assessment of HRQOL for transplant recipients should include multiple reporters and that HRQOL as reported by adolescents and parents is generally stable over time without intervention. Further research is needed to understand factors related to differential HRQOL outcomes. PMID- 20846242 TI - Solid organ transplants following hematopoietic stem cell transplant in children. AB - SOT may be indicated for a select group of pediatric patients who experience permanent organ failure following HSCT. However, there is limited information available about outcomes. We identified eight children at our center who received an SOT following an HSCT. Patients were six months to 18 yr at HSCT. Diseases for which children underwent HSCT included thalassemia, Wiskott-Aldrich syndrome, Shwachman-Diamond/bone marrow failure, sickle cell disease (SCD), erythropoietic porphyria (EP), ALL, chronic granulomatous disease, and neuroblastoma. Time from HSCT to SOT was 13 days to seven yr (median, 27 months. Lung SOT was performed for two patients with BO, kidney transplants for three patients, and liver transplants for three patients (VOD, chronic GVHD). Seven patients are alive with functioning allografts 6-180 months from SOT. Advances in organ procurement, operative technique, immunosuppressant therapy, and infection control may allow SOT for a select group of patients post-HSCT. However, scarcity of donor organs available in a timely fashion continues to be a limiting factor. Children who have undergone HSCT and develop single organ failure should be considered for an SOT if there is a high likelihood of cure of the primary disease. PMID- 20846241 TI - Protocol biopsy-driven interventions after pediatric renal transplantation. AB - The therapeutic value of protocol biopsies (PBs) in renal transplant recipients remains unclear. We performed protocol biopsies in 57 children six months after transplantation. We increased the CNI dose in patients with borderline findings. In cases of Banff grade Ia, six prednisolone IV-pulses were given and the CNI dose was increased. CNI toxicity and polyomavirus nephropathy led to a reduction in the CNI dose. GFR was compared with a control group of 51 children with no PBs transplanted in the same period. Forty-two percent of PBs had no pathological changes, 24% IF/TA. Borderline findings were detected in 11%, Banff grade Ia in 15% (CNI), toxicity in 8%, and one case showed polyomavirus nephropathy. GFR after 1.5 and 2.5 yr was similar in both groups. GFR 3.5 yr after transplantation was significantly higher in the intervention group (57 +/- 17 vs. 46 +/- 20). Patients treated with low-dose CNI and everolimus had a significantly lower number of pathological findings in PBs. The performance of protocol biopsies followed by a standardized treatment algorithm led to better graft function 3.5 yr after transplantation. Prospective randomized studies to confirm our findings are needed. PMID- 20846243 TI - Chronic activation of the D2 autoreceptor inhibits both glutamate and dopamine synapse formation and alters the intrinsic properties of mesencephalic dopamine neurons in vitro. AB - Dysfunctional dopamine (DA)-mediated signaling is implicated in several diseases including Parkinson's disease, schizophrenia and attention deficit and hyperactivity disorder. Chronic treatment with DA receptor agonists or antagonists is often used in pharmacotherapy, but the consequences of these treatments on DA neuron function are unclear. It was recently demonstrated that chronic D2 autoreceptor (D2R) activation in DA neurons decreases DA release and inhibits synapse formation. Given that DA neurons can establish synapses that release glutamate in addition to DA, we evaluated the synapse specificity of the functional and structural plasticity induced by chronic D2R activation. We show that chronic activation of the D2R with quinpirole in vitro caused a parallel decrease in the number of dopaminergic and glutamatergic axon terminals. The capacity of DA neurons to synthesize DA was not altered, as indicated by the lack of change in protein kinase A-mediated Ser(40) phosphorylation of tyrosine hydroxylase. However, the spontaneous firing rate of DA neurons was decreased and was associated with altered intrinsic properties as revealed by a prolonged latency to first spike after release from hyperpolarization. Moreover, D2R function was decreased after its chronic activation. Our results demonstrate that chronic activation of the D2R induces a complex neuronal reorganization involving the inhibition of both DA and glutamate synapse formation and an alteration in electrical activity, but not in DA synthesis. A better understanding of D2R induced morphological and functional long-term plasticity may lead to improved pharmacotherapy of DA-related neurological and psychiatric disorders. PMID- 20846244 TI - Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin. AB - Histaminergic neurons of the hypothalamic tuberomammillary nucleus constitute a major wake-promoting system. In animals, cerebrospinal fluid (CSF) histamine levels are increased during wakefulness and after sleep deprivation and decreased during sleep. An involvement of the histamine system in human disorders has not, to our knowledge, been reported. We measured hypocretin-1 and histamine levels in the lumbar CSF of 28 patients with and without excessive daytime sleepiness (EDS) as assessed by the Epworth Sleepiness Scale (ESS). There were 10 patients with EDS (ESS > 10, mean ESS = 14). Diagnoses included narcolepsy (n = 4), idiopathic hypersomnia (n = 2), sleep apnoea (n = 2) and multiple sclerosis (n = 2). Three patients were treated with stimulants. Their mean CSF histamine was 258 +/- 159 PM. There were 18 patients without EDS (ESS < 9, mean ESS = 5). No patients were treated with stimulants. Their mean CSF histamine was significantly higher (624 +/- 481 PM, P = 0.007). There was a significant inverse correlation (r = -0.48, P = 0.02) between ESS and both CSF histamine and hypocretin-1 levels. These observations suggest that narcolepsy and EDS of other origin are associated in humans with lower CSF histamine levels and therefore with a reduced activity of the wake-promoting histaminergic neuronal system. PMID- 20846245 TI - An outcomes evaluation of an Australian Hospital in the Nursing Home admission avoidance programme. AB - AIMS AND OBJECTIVES: To undertake an outcomes evaluation of a Hospital in the Nursing Home (HINH) admission avoidance programme. BACKGROUND: Admission avoidance type services such as Hospital in the Home have a place in improving service delivery for certain population groups. Research related to HINH has been limited, derived from various different health care systems internationally and results are varied. DESIGN: A quasi-experimental study was conducted at one regional hospital. Routinely collected health information system data from two separate data sources were linked to undertake analysis. METHODS: Those in the intervention group were matched to a comparison group of patients on the basis of three characteristics (age, gender and diagnostic category). Other factors that could affect a patient's hospital outcomes and length of stay (LOS) were statistically controlled for. Participants were aged care facility residents enrolled in a HINH programme (n = 62) and a matched group receiving usual in hospital care (n = 115). Emergency department (ED) outcome measures included LOS and re-presentation. Hospital admission-related outcome measures included episode of care LOS, in-hospital LOS and hospital readmission. RESULTS: A significant independent relationship between HINH programme enrolment and shorter in-hospital LOS was identified even after adjusting for other characteristics OR 0.16 (95% CI 0.28, 0.99 p < 0.001). CONCLUSION: The HINH model evaluated, with its focus on delivering acute care for aged care facility residents, can impact on health service delivery. RELEVANCE TO CLINICAL PRACTICE: With a demonstrated reduction in in-hospital LOS, the available bed space created can be used for other patients perhaps waiting in the ED or waiting for surgery. PMID- 20846246 TI - Frequency and barriers of underreported needlestick injuries amongst Iranian nurses, a questionnaire survey. AB - AIMS AND OBJECTIVES: To determine the frequency of needlestick injuries and barriers of reporting such injuries amongst Iranian nurses. BACKGROUND: Exposure to blood-borne pathogens because of needlestick injuries in particular is a potential risk for healthcare workers, including clinical nurses. The burden of sharp injuries sustained by healthcare workers is still unclear, primarily because of underreporting. DESIGN: A cross-sectional study was undertaken amongst 111 clinical nurses working in five major teaching hospitals in Tehran/Iran during 2007-2008 who were randomly selected. METHODS: A validated self-reported questionnaire containing demographic characteristics and history of experiences with contaminated needlesticks as well as probably reason/s for underreporting such injuries was used. RESULTS: More than half of the enrolled nurses (54.1%, n = 60) had no experience of contaminated injuries, while the rest of 45.9% (n = 51) had experienced at least one contaminated needlestick injuries during their clinical performance. More than one-third (34.0%, n = 38) had experienced a mean of 58 contaminated needlestick injuries during the past 12 months (crude incidence: 0.52 NSI/nurse/year). Only 14 nurses (36.8%) with needlestick injuries experiences had officially reported their experiences. The major reasons for not reporting needlestick injuries were dissatisfaction with follow-up investigations by officials after reporting the events (33.3%) and safe/low risk considering of source patients (29.2%). CONCLUSIONS: Increased frequency and underreporting of needlestick injuries amongst Iranian nurses is going to be a major concern. As a preventive strategy, further interventions such as constant staff training, life long learning and standardising postexposure procedures are recommended. RELEVANCE TO CLINICAL PRACTICE: Determining the prevalence, burden and reasons for underreporting needlestick injuries by clinical nurses are required for establishing a preventive strategy to decrease hospital infections. PMID- 20846247 TI - Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population. AB - Several genes have been suggested as dyslexia candidates. Some of these candidate genes have been recently shown to be associated with literacy measures in sample cohorts derived from the general population. Here, we have conducted an association study in a novel sample derived from the Australian population (the Raine cohort) to further investigate the role of dyslexia candidate genes. We analysed markers, previously reported to be associated with dyslexia, located within the MRPL19/C2ORF3, KIAA0319, DCDC2 and DYX1C1 genes in a sample of 520 individuals and tested them for association with reading and spelling measures. Association signals were detected for several single nucleotide polymorphisms (SNPs) within DYX1C1 with both the reading and spelling tests. The high linkage disequilibrium (LD) we observed across the DYX1C1 gene suggests that the association signal might not be refined by further genetic mapping. PMID- 20846248 TI - Surgical treatment of female stress urinary incontinence with a transobturator tape (Monarc): short-term results of a prospective multicenter study. AB - AIM: Transobturator tape (TOT) kits approved as medical instruments are still not available in Japan. This study aimed to: (1) assess the outcomes of TOT using Monarc (American Medical Systems; AMS Inc, Minnetonka, MN, USA) in women with stress urinary incontinence (SUI); (2) evaluate possible different surgical outcomes in women with urethral hypermobility (UH) and/or intrinsic urethral deficiency (ISD); and (3) evaluate the possibility of improvement of preoperative urgency and urge urinary incontinence after TOT in mixed urinary incontinence (MUI). METHODS: Data from 140 women with SUI in a prospective multicenter study were examined at 3-6 months follow-up. RESULTS: 82.1% of the patients were cured and 10.7% showed improvement. The surgical outcome was significantly better in UH than in UH combined with ISD or ISD. In 44 MUI patients, 79.6% were cured and 15.9% showed improvement. Urgency improved in about 75% of patients after TOT. CONCLUSION: TOT is effective for both SUI and MUI, with urgency improving. PMID- 20846249 TI - Rubella outbreak on Tokunoshima Island in 2004: a population-based study of pregnant women. AB - AIM: The purpose of this study was to clarify the risk of rubella infection for pregnant women in the outbreak area. MATERIAL & METHODS: We performed a retrospective, population-based study on all 232 pregnant women during the rubella outbreak period in Tokunoshima Island. All women had a rubella hemagglutination inhibition (HI) titer drawn during their current pregnancy. In 61 women, HI titers were compared between the current and past pregnancies. Rubella IgG antibody titers were measured and IgG avidity index (AI) was calculated for 92 non-infected pregnant women. RESULTS: Of the 232 candidates, 22 pregnant women contracted rubella infection (congenitally infected infants: 2). Seventeen of 61 pregnant women showed a four-fold or greater elevation in HI titer when compared with previous titers. Their previous HI titers were all <=64. Low IgG AIs (<30%) were only observed in women with a HI titer of <=64 (92 non infected women). CONCLUSIONS: The risk of maternal rubella infection in the outbreak was as follows: non-immunized pregnant woman and pregnant woman with a rubella HI antibody titer <=64 and low IgG AI. PMID- 20846250 TI - Statin therapy for hypertrophic cardiomyopathy: too good to be true? PMID- 20846251 TI - A 2-year naturalistic study on cognitive functioning in bipolar disorder. AB - OBJECTIVE: Cognitive alterations in bipolar disorder may reflect genetic influence. However, to what degree mood, medication, thyroid function and other factors impact on longitudinal cognitive functioning remains unclear. METHOD: A group of patients with bipolar (spectrum) disorder (n = 76) underwent two monthly cognitive assessments over a 2-year period in a prospective, repeated measures design. Regression models were used to investigate associations with predictors, corrected for multiple testing. RESULTS: Patients with bipolar disorder performed worse than healthy controls (n = 61) on all cognitive domains tested. Effect sizes were small, with a maximum of -0.36 for sustained attention. However, cognitive performance varied substantially over the 2-year follow-up, co-varying with subjective cognitive complaints and impacting on functioning. Alterations in sustained attention and motor speed were the only impairments that were invariant over time. Predictors had very limited explanatory power on temporal variation in cognition. Use of second-generation antipsychotics was associated with the largest negative effects on cognition, which were evident in the areas of motor speed and basic information processing (-0.35 < beta < -0.5). CONCLUSION: Cognitive function in bipolar disorder varies significantly over time, largely independent of clinical factors. The temporal stability of sustained attention is the exception, suggesting it may represent a possible candidate intermediary phenotype. PMID- 20846252 TI - Are there any cross-ethnic differences in menstrual profiles? A pilot comparative study on Australian and Chinese women with primary dysmenorrhea. AB - AIM: To explore and compare the features of menstruation, perception and management of menstrual pain between two cohorts of Australian and Chinese women. METHODS: A pilot comparison study was carried out using modified valid menstrual questionnaires. The study included 120 Australian women and 122 Chinese women aged from 18 to 45 years with primary dysmenorrhea. RESULTS: Australian women rated menstrual pain as more intense than Chinese women (8.5 +/- 1.5 on a 10 point pain scale vs 7.3 +/- 1.8, P < 0.001), duration of pain was 36% longer (3.0 +/- 2.5 vs 2.2 +/- 0.9 days, P = 0.002) and menarche commenced earlier (12.7 +/- 1.5 vs 14.2 +/- 1.4 years, P < 0.001). The mean reported menstrual interval was also shorter (29.2 +/- 5.3 vs 30.52 +/- 3.7, P = 0.020) with heavier overall menstrual flow (P = 0.002) and fewer clots in menstrual blood (83% vs 95.8%, P = 0.001). There was no significant difference in duration of menstruation (5.2 +/- 1.3 vs 5.4 +/- 1.1 days; P = 0.180). Correlations were found between earlier menarche and increased intensity of menstrual pain (r = -0.16, P = 0.011), and between heavier menstrual flow and increased intensity of menstrual pain (r = 0.19, P = 0.003). CONCLUSION: Evidence from this pilot study suggested that the clinical menstrual presentations in the cohorts of Australian and Chinese women were different. Although the findings are preliminary, evaluating ethnic differences in menstruation and experimental menstrual pain models may not only provide some information about underlying mechanisms but may also predict or explain group differences. PMID- 20846253 TI - Hysteroscopic rollerball endometrial ablation as an alternative treatment for adenomyosis with menorrhagia and/or dysmenorrhea. AB - AIM: The aim of this study was to assess the long-term effectiveness and safety of hysteroscopic rollerball endometrial ablation as a surgical management of adenomyosis with menorrhagia and/or dysmenorrhea. We compared the results of patients who underwent pretreatment with gonadotropin-releasing hormone (GnRH) agonist with the results of those who did not. METHODS: A retrospective study included 190 adenomyotic patients who suffered from menorrhagia and/or dysmenorrhea and underwent hysteroscopic rollerball endometrial ablation. Main outcome measures were rates of successful operation, complications, improvement of abnormal uterine bleeding and pelvic pain after the surgery. RESULTS: The majority of the patients (142, 74.7%) underwent hysteroscopic rollerball endometrial ablation during the early proliferative phase of the menstrual cycle. The rest were operated on after GnRH agonist pretreatment for 6-8 weeks. Ablations were successfully performed on all patients in a day surgery setting. The average operation time was 36.3 +/- 7.1 min. The mean glycine deficit was 583.4 +/- 247.3 mL. The ablation in the no-pretreatment group took a significantly longer time and had more glycine absorption compared to the GnRH agonist pretreatment group (P < 0.0001). Mean postoperative follow-up duration was five years (range 1-10 years). A total of 187 patients (98.4%) who had undergone hysteroscopic endometrial ablation reported decreased bleeding: amenorrhea in 58 (30.5%), hypomenorrhea in 78 (41.1%), and eumenorrhea in 51 (26.8%) patients. Three patients (1.6%) underwent hysterectomy due to symptoms recurrence. A total of 165 (86.8%) patients with dysmenorrhea reported either reduced or no dysmenorrhea. There was no significant difference in the efficacy of hysteroscopic rollerball endometrial ablation between patients who underwent pretreatment with GnRH agonists and those who did not. No major complications related to the procedure were reported. CONCLUSIONS: Hysteroscopic rollerball endometrial ablation as a surgical management of menorrhagia and dysmenorrhea that develops in patients with adenomyosis is an effective and safe procedure. It can reduce the need for the unnecessary major surgery of hysterectomy. PMID- 20846254 TI - Effects of postoperative analgesia on postpartum urinary retention in women undergoing cesarean delivery. AB - AIM: Various analgesics and administration methods are used to provide women undergoing cesarean delivery pain relief after surgery. We compared three methods of postoperative analgesia regarding the incidence of postpartum urinary retention (PUR) in primiparous women undergoing elective cesarean delivery. METHODS: We estimated post-void residual bladder volume after the first postpartum micturition among 150 parturient women. Risk factors stratified for PUR defined by 150-mL post-void residual bladder volume were analyzed. Obstetric parameters and prevalence of lower urinary tract symptoms after surgery were compared among three groups of parturient women given different postoperative analgesia: epidural bolus morphine (EBM), patient-controlled epidural analgesia (PCEA) with ropivacaine-fentanyl, and intramuscular pethidine. RESULTS: The incidence of PUR was higher in the group given EBM (33.3%) than the groups receiving ropivacaine-fentanyl by PCEA (15%) or intramuscular pethidine (16.7%) (P = 0.038). Eighteen (12%) parturient women needed bladder catheterization to resolve their urinary retention at 1 day postpartum but all achieved spontaneous micturition prior to hospital discharge. The need for catheterization was also increased in the group with EBM (21.7%) in comparison with the other two groups (6.7% and 3.3%, respectively, P = 0.011). At the 3-month follow up, six women (4%) had obstructive voiding problems and seven women (4.7%) had irritating voiding problems. At the 1-year follow up, only one woman in the EBM group had incomplete emptying and another in the PCEA group had urinary incontinence. CONCLUSION: Epidural analgesia with morphine was significantly associated with post-cesarean urinary retention. Nonetheless, it was not detrimental to later urinary function. PMID- 20846255 TI - Long-term follow up of cervical cancer patients with unexplained squamous cell carcinoma antigen elevation after post-therapy surveillance using positron emission tomography. AB - AIM: We aimed to define the long-term follow-up results in cervical cancer patients with unexplained squamous cell carcinoma antigen (SCC-Ag) elevation (negative conventional imaging studies, computed tomography or magnetic resonance imaging) after definitive treatment using positron emission tomography (PET). METHODS: Of the 27 women with unexplained SCC-Ag elevation, 13 died or were alive with disease (12 PET true-positive, one PET false-negative) in our previous report. In this study, we reported long-term follow-up results for all the 14 patients remaining cancer-free at cut-off of our previous analysis (seven with true-negative PET and two with false-positive PET, and five with true-positive PET having received successful curative salvage therapy). RESULTS: The seven patients with true-negative PET studies remained recurrence-free (median follow up, 70 months; range, 11-84). Two patients had pelvic inflammatory disease; their SCC-Ag levels returned to the normal range after eradication of infection. Two other patients had recurrent cystitis, and their SCC-Ag levels normalized at 5 and 36 months, respectively. The two patients with false-positive PET/computed tomography were disease-free 73.5 and 70 months from original PET studies, respectively. In contrast, of the five patients with successful salvage, two are alive without disease (at 80 and 86.7 months), one died of radiation cystitis at 54 months, and two died of their cancer subsequent to previous analysis. CONCLUSION: Cystitis or pelvic inflammatory disease may cause unexplained elevation of SCC-Ag after definitive treatment. A negative PET study usually indicates absence of disease. PET is a useful tool to identify curable recurrences, especially when SCC-Ag < 4 ng/mL. PMID- 20846256 TI - Aortic dissection accompanied by preeclampsia and preterm labor. AB - Aortic dissection is a potentially fatal disease rarely encountered in obstetric clinics. A multiparous woman with a prior cesarean delivery was admitted with the complaint of epigastric pain at 33 weeks of gestation. The patient was diagnosed with preeclampsia and preterm labor. An emergent cesarean delivery was performed. Hypertension and epigastric pain could not be controlled after the operation. Computed tomography scan 2 days after the operation revealed aortic dissection, multiple infarct areas in the spleen and liver, and dilations of the intestine and the colon. Ascending aorta replacement followed by massive intestinal resection starting from the ligament of Trietz to the sigmoid colon was performed. Nine hours after the operation the patient had cardiopulmonary arrest. Aortic dissection should be suspected in cases of atypical epigastric pain even if the patient shows signs of preeclampsia and preterm labor. PMID- 20846257 TI - Comparative study between oral and sublingual 600 ug misoprostol for the treatment of incomplete abortion. AB - AIM: To evaluate and compare effectiveness, side effects and patient acceptability between oral and sublingual 600 ug misoprostol for the treatment of incomplete abortion. METHODS: A randomized controlled trial was conducted. Pregnant women of less than 14 weeks gestation, diagnosed with incomplete abortion, were randomly assigned to receive 600 ug misoprostol orally or sublingually. The patients were evaluated at 48 h after drug administration for complete abortion. RESULTS: A total of 64 women were recruited to the study (32 in the oral group and 32 in the sublingual group). The complete abortion rate was not statistically different between oral and sublingual groups (87.5% versus 84.4%, P > 0.05). There was no statistical difference in side effects and satisfaction rate. Fever/chills were the most common side effects. CONCLUSION: Both sublingual and oral 600 ug misoprostol are useful for the management of incomplete abortion. Side effects and satisfaction rates are not different. Thus, these methods may be used as alternative treatments of incomplete abortion. PMID- 20846258 TI - Influence of previous abortions and new paternity on the risk of hypertension in nulliparous parturients in Ibadan: a cohort study. AB - AIM: This study aims to determine the influence of previous abortions and new paternity on the risk of hypertension in a cohort of nulliparous women. METHODS: A prospective cohort study was conducted with development of hypertension in pregnancy as outcome variable. Explanatory variables were previous abortions and paternity. Univariate analysis was by t-test, chi(2) test and Fisher's exact test where applicable. Logistic regression was utilized for multivariate analysis. Stata was utilized for all the analyses. The level of statistical significance was set as P < 0.05. RESULTS: Same paternity abortions reduced the risk of hypertension (OR 0.48, 95% CI 0.31-0.73). Previous abortions did not reduce the odds of hypertension in pregnancy (OR 1.25, 95% CI 0.83-1.88). Rural dwelling reduced the odds of developing hypertension in pregnancy (OR 0.54, 95% CI 0.42 0.70). CONCLUSION: The result of this study supports the immunological theory of the etiology of hypertension in pregnancy. PMID- 20846259 TI - Significant effects of lymph and blood vascular invasion on the prognosis of early-stage cervical squamous cell carcinoma. AB - AIM: In the past 10 years, therapeutic advances have led to improved short-term efficacy for cervical carcinoma; however, the 5-year survival rate was not significantly enhanced. To investigate the effects of blood vessel invasion (BVI) and lymph vessel invasion (LVI) on the prognosis of early-stage cervical squamous carcinoma, we carried out immunohistochemical staining to distinguish blood and lymph vessels. METHODS: Specimens from 111 IB-stage or IIA-stage cervical squamous carcinoma cases were examined for BVI and LVI by streptavidin-peroxidase immunohistochemistry using CD-34 and D2-40 monoclonal antibodies. Data were analyzed with SPSS version 13.0 (SPSS, Chicago, IL, USA) statistical software. The survival rate and survival curve were derived by using the life table method and the Kaplan-Meier method, respectively. Multivariate prognosis analysis was conducted with Cox regression model, and prognosis was evaluated by measuring overall survival (OS) and progression-free survival (PFS). RESULTS: BVI/LVI double positivity was an independent prognostic factor for both OS and PFS, whereas lymph node metastasis and surgical margin positivity affected only PFS. Patients inflicted with either BVI or LVI displayed no significant difference in survival time. Lymph-vascular space invasion (LVSI), referring to blood and/or lymph vessel invasion correlated with lymph node metastasis, surgical margin positivity, depth of cervical interstitial invasion, squamous cell carcinoma antigen (SccAg) and age. LVSI was a risk factor for both recurrence (P = 0.013, relative risk 3.060) and death (P = 0.005, relative risk 4.512). Post-operation auxiliary external radiation did not improve survival for LVSI-positive cases. CONCLUSION: BVI/LVI double positivity constitutes an independent prognostic factor for early-stage cervical squamous carcinoma. PMID- 20846260 TI - Development of the genital ducts and external genitalia in the early human embryo. AB - The course of development of the human genital tract is undifferentiated to the 9th week of development. At this time two symmetrical paired ducts known as the mesonephric (MD) and paramesonephric ducts (PMD) are present, which together with the urogenital sinus provide the tissue sources for internal and external genital development. Normal differentiation of the bipotential external genitalia and reproductive ducts are dependent upon the presence or absence of certain hormones. Masculinization of the internal and external genitalia during fetal development depends on the existence of two discrete testicular hormones. Testosterone secreted from Leydig cells induces the differentiation of the mesonephric ducts into the epididymis, vasa deferentia and seminal vesicles, whereas anti-Mullerian hormone (AMH) produced by Sertoli cells induces the regression of the paramesonephric ducts. The absence of AMH action in early fetal life results in the formation of the fallopian tubes, uterus and upper third of the vagina. In some target tissues, testosterone is converted to dihydrotestosterone, which is responsible for the masculinization of the urogenital sinus and external genitalia. PMID- 20846261 TI - Truncated isoforms of Kap60 facilitate trafficking of Heh2 to the nuclear envelope. AB - Isoforms of importin-alpha have been identified in insect and human cells, and cross-linking experiments suggest that at least one isoform in each species participates in the targeting of integral membrane proteins to the inner nuclear membrane (INM). To directly test this hypothesis, an assay was developed using Saccharomyces cerevisiae. The data show that internal promoters are present within KAP60, and the nested transcripts are translated into three isoforms: Kap60-44, Kap60-30 and Kap60-10. In the absence of the isoforms, the INM protein Heh2-green fluorescent protein (GFP) localized to cytoplasmic membranes, whereas its wild-type localization at the nuclear periphery was restored when the Kap60 44 isoform was reintroduced. An INM-sorting sequence has been identified that cross-links with the isoform of importin-alpha that directs trafficking toward the nuclear envelope (NE). When this sequence in HEH2 was mutated, Heh2 was again localized to cytoplasmic membranes. Thus, this report provides the first evidence that isoforms of Kap60 exist in yeast, and these isoforms participate in the molecular sorting and enrichment of INM proteins to the NE. Herein, we provide additional support for the hypothesis that trafficking of INM proteins to the NE is a regulated process. PMID- 20846262 TI - KRAS gene mutations in lung cancer: particulars established and issues unresolved. AB - Lung cancer, like other cancers, is considered to develop through the accumulation of genetic alterations. Mutation of the KRAS gene is one of the most important events in carcinogenesis of the lung. The KRAS gene, belonging to the RAS gene family, encodes a membrane-bound 21-kd guanosine triphosphate (GTP) binding protein. Single point mutations in this protein result in continuous activation to transmit excessive signals, promoting a variety of biological events. In lung cancers, the mutations concentrate at codon 12 and mostly affect adenocarcinomas (ADCs). They also affect atypical adenomatous hyperplasia, the precursor of ADCs. Therefore, mutation of the KRAS gene is suggested to confer a growth advantage to airway epithelial cells enabling them to expand clonally early in the development of ADCs. The mutation is also a reliable marker of an unfavorable response to certain molecular-targeting therapies. Furthermore, patients with ADCs affected by mutations have been reported to exhibit a significantly higher risk of postoperative disease recurrence. Thus, the significance of KRAS gene mutations has been investigated extensively. However, not all the details emerged. In this review, particulars that have been established are introduced, and important issues remaining to be resolved are discussed, with special reference to carcinogenesis of the lung. PMID- 20846263 TI - Epigenetic inactivation of HOXA5 and MSH2 gene in clear cell renal cell carcinoma. AB - The high-throughput method using microarray is an easy and fast way to analyze the methylation status of hundreds of preselected genes and to screen them for signatures in methylation. The aim of our study is to detect hypermethylated genes and to analyze the association between methylation status and clinicopathological parameters of clear cell renal cell carcinoma. The genetic substrate included 62 cancer tissues and 62 matched adjacent normal kidney tissues. We adapted the GoldenGate genotyping assay to determine the methylation state of 1505 specific CpG sites in 807 genes. We identified two genes (HOXA5 and MSH2) with beta-value differences of more than 0.3 between cancer and normal tissues. The high methylation group in HOXA5 had high Fuhrman's nuclear grade (P= 0.041). Other data in HOXA5 and MSH2 were not significant with methylation status (P > 0.05). Survival curve of the high methylation group in HOXA5 was slightly lower than that of the low methylation group. However, the statistical significances of overall survival in HOXA5 and MSH2 were low (P > 0.05). We report the hypermethylation of two genes in clear cell renal cell carcinoma. The data we obtained could provide the basis for a diagnostic test pathological assessment, or prognosis in clear cell renal cell carcinoma. PMID- 20846264 TI - Assessment of circulating tumor cells (CTCs) in prostate cancer patients with low volume tumors. AB - The objective of this study was to assess the incidence of circulating tumor cells (CTCs) in prostate cancer patients with low-volume tumors (less than 0.5 cc) after radical prostatectomy (RP). Blood samples were collected from 64 RP patients to assess the incidence of CTCs following RP. The specimens were processed by whole-mount section. Clinicopathological data (e.g. patient age, race, specimen weight, tumor volume, grade, stage and surgical margin status) and follow-up PSA data were compared to CTC status. Of the 64 RP patients, nine had 'low-volume prostate cancer'. Seven of these patients had detectable levels of CTCs. In two of the seven patients with detectable CTCs, PSA elevation was also observed. Isolation and detection of circulating epithelial cells is possible in low-volume prostate cancer patients. In the setting of low-volume prostate cancer, CTCs may be associated with the presence of detectable PSA levels. However, the detection of CTCs did not predict PSA failure. PMID- 20846265 TI - Immunohistochemical analysis of colorectal cancer with gastric phenotype: claudin 18 is associated with poor prognosis. AB - Claudin-18 plays a key role in constructing tight junctions, and altered claudin 18 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin-18 in colorectal cancer (CRC). The aim of this study is to investigate the significance of claudin-18 expression in CRC and its association with clinicopathological factors. We performed clinicopathological analysis of claudin-18 expression in a total of 569 CRCs by immunohistochemistry. Moreover, we investigated the association between claudin-18 and various markers including gastric/intestinal phenotype (MUC5AC, MUC6, MUC2 and CD10), CDX2, claudin-3, claudin-4, p53 and Ki-67. Claudin-18 expression was detected in 21 of the 569 CRCs (4%) and was seen exclusively on the cell membrane. Positive expression of claudin-18 showed a significant correlation with positive expression of MUC5AC (P < 0.0001) and negative expression of CDX2 (P= 0.0013). The prognosis of patients with positive claudin 18 expression was significantly poorer than in negative cases (P= 0.0106). Multivariate analysis revealed that T grade, M grade and claudin-18 expression were independent predictors of survival in patients with CRC. We revealed that claudin-18 expression correlates with poor survival in patients with CRC and is associated with the gastric phenotype. PMID- 20846266 TI - Serous cystic neoplasm in an intrapancreatic accessory spleen. AB - Serous cystic neoplasm (SCN) of the pancreas is a benign epithelial neoplasm, except in extremely rare malignant cases. Development of SCN in tissues other than the pancreas has been never reported. Here we present the first reported case of SCN in an intrapancreatic accessory spleen (IPAS). A 54-year-old female patient with von Hippel-Lindau (VHL) syndrome was found to have pancreatic tail mass. Pathologically the 25-mm solid mass was an IPAS showing proliferation of clear cuboidal tumor cells without atypia, forming numerous small cysts. The tumor cells were rich in cytoplasmic glycogen and distributed in the splenic tissue almost diffusely. Immunohistochemically, tumor cells were positive for cytokeratins, MUC6, and neuron-specific enolase, and negative for neuroendocrine markers. From these findings, we diagnosed the lesion as SCN in IPAS. This tumor is suggested to develop as a VHL-associated SCN from coexisting pancreatic tissue in IPAS rather than as a metastatic tumor. PMID- 20846267 TI - Young-aged woman with invasive ductal carcinoma arising in atypical microglandular adenosis: a case report. AB - Microglandular adenosis (MGA) and atypical microglandular adenosis (AMGA) are extremely rare and unique forms of adenosis of the breast. Both forms of adenosis are strongly associated with carcinoma arising in microglandular adenosis (MGACA) and are recognised as precursor lesions of invasive breast carcinoma. Here we provide a clinical report of a young Taiwanese woman who was diagnosed with MGACA and AMGA by means of echo-guided core biopsy. The subsequent lumpectomy revealed a spectrum of lesions ranging from MGA and AMGA to ductal carcinoma in situ (DCIS) and invasive carcinoma. All of the above lesions have similar immunohistochemical results (expression of S-100 protein, the absence of oestrogen receptors, progesterone receptors and Her2/neu, and the lack of p63 and the smooth muscle myosin-heavy chain) with a rather different Ki-67 labelling proliferation index. This report is of practical interest because the diagnosis of AMGA and MGACA had already been made via needle biopsy. PMID- 20846268 TI - Primary appendiceal precursor B lymphoblastic lymphoma with peculiar morphology mimicking diffuse large B cell lymphoma. AB - Precursor B lymphoblastic neoplasm usually presented as childhood leukemia. Most precursor lymphoblastic lymphoma are T-cell lineage and precursor B lymphoblastic lymphoma constitutes only about 10% of cases according to the WHO Classification of Tumours of Haematologic and Lymphoid Tissues. The most frequent sites of involvement in precursor B lymphoblastic lymphoma are the skin, soft tissue, bone and lymph nodes. Primary appendiceal involvement is an uncommon condition. We present an unusual case of primary appendiceal precursor B lymphoblastic lymphoma in an 11-year-old boy with peculiar histological morphology mimicking diffuse large B cell lymphoma. Histologically, the tumor was composed of diffusely infiltrated large cells from mucosa and extended to the subserosal area. The tumor cells were positive to CD79a, CD20, PAX5, BCL2, CD10, TdT, p53 but not to CD3, BCL6 and CD34 by immunohistochemical studies. The response to conventional treatment regimen for lymphoblastic lymphoma was not good, with early relapse within three months. Partial remission was achieved by adding rituximab. Unfortunately, the patient died in ten months due to uncontrolled relapsed disease with generalized lymphadenopathy and massive pleural effusion. The special morphologic changes and poor response to chemotherapy may be related to the overexpression of p53. PMID- 20846269 TI - Sclerosing odontogenic carcinoma with benign fibro-osseous lesion of the mandible: an extremely rare case report. AB - A case of sclerosing odontogenic carcinoma (SOC) admixed with a benign fibro osseous lesion (BFOL) is reported herein. A 67-year-old male had paresthesia in the mental region. Computed tomography detected an intragnathic mass that was focally expansile with disappearance of cortical bone, and contained admixed radiolucency and radio-opacity. Under the pathological diagnosis as benign fibro osseous lesion, it was surgically removed by curettage. Microscopic analysis showed that a few parts of the resected materials contained dispersed thin cords and small nests of epithelial cells accompanied by fibrous stroma. Cellular atypia and mitotic figures were not evident. The diagnosis of BFOL with hyperplastic and metaplastic odontogenic epithelia was ultimately made. Eight months after the operation, the lesion recurred and segmental mandibulectomy was carried out. Histologically, the lesion was predominantly occupied by the fibro osseous component with irregular-shaped foci of epithelial component. The epithelial component exhibited mostly thin cord or small nest patterns and showed definite perineural infiltration. Immunohistochemically, the epithelial cells were positive for p63, cytokeratin (CK) 6 and CK19, and focally positive for CK7 but negative for vimentin. MIB-1 positive nuclei were inconspicuous. To the best of our knowledge, this report is the first case of SOC with BFOL. PMID- 20846270 TI - Adenocarcinoma of small intestinal type in retroperitoneal mature teratoma. AB - We report a case of small intestinal type adenocarcinoma arising in retroperitoneal mature cystic teratoma in a young male. The patient initially experienced intermittent abdominal pain, and radiographic workup revealed an encapsulated retroperitoneal mass. A laparotomy was performed and the resected specimen represented a cystic lesion, the inner surface of which was mostly covered by sebaceous debris with hairs. Microscopically, mature derivatives of all three germ layers as well as completely developed gastrointestinal tract were identified. Adenocarcinoma without stromal invasion was observed adjacent to the small intestinal mucosa. Immunohistochemistry of the adenocarcinoma tissue revealed p53 overexpression and high Ki-67 labeling index as well as positive staining for CD10, cytokeratin 7, and cytokeratin 20. Therefore, the diagnosis of small intestinal adenocarcinoma was made. To our knowledge, this is the first case of small intestinal adenocarcinoma arising in retroperitoneal mature cystic teratoma. A unique feature of this case is that malignant transformation in retroperitoneal mature teratoma arose even in the fully developed intestine. Favorable prognosis due to detection in the 'early stage' is also discussed. PMID- 20846271 TI - Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia. AB - OBJECTIVE: Facial emotion recognition deficits have been consistently demonstrated in schizophrenia and can impair socio-occupational functioning in these patients. Treatments to improve these deficits in antipsychotic-stabilized patients have not been well studied. Yoga therapy has been described to improve functioning in various domains in schizophrenia; however, its effect on FERD is not known. METHOD: Antipsychotic-stabilized patients randomized to receive Yoga (n=27), Exercise (n=17) or Waitlist group (n=22) were assessed at baseline, 2nd month, and 4th month of follow-up by raters blind to group status. Assessments included Positive and Negative Syndrome Scale (PANSS), Socio-Occupational Functioning Scale (SOFS), and Tool for Recognition of Emotions in Neuropsychiatric DisorderS (TRENDS). RESULTS: There was a significant positive correlation between baseline FERD and socio-occupational functioning (r=0.3, P=0.01). Paired samples t test showed significant improvement in positive and negative symptoms, socio-occupational functioning and performance on TRENDS (P<0.05) in the Yoga group, but not in the other two groups. Maximum improvement occurred at the end of 2 months, and improvement in positive and negative symptoms persisted at the end of 4 months. CONCLUSION: Yoga therapy can be a useful add-on treatment to improve psychopathology, FERD, and socio-occupational functioning in antipsychotic-stabilized patients with schizophrenia. PMID- 20846272 TI - Deficits in fronto-posterior interactions point to inefficient resource allocation in schizophrenia. AB - OBJECTIVE: Fronto-posterior networks have been implicated in various cognitive processes that are impaired in schizophrenia. This is the first study on time and frequency resolved fronto-posterior coherence during cognitive control in schizophrenia. METHOD: We examined 16 schizophrenic/schizoaffective patients and 20 age-matched controls performing a choice-reaction task. Fronto-posterior coherence was analyzed for event-related increases with respect to the inter trial interval. Furthermore, we compared the two groups for event-related coherence during the task-related time intervals which showed a significant coherence increase with respect to the inter-trial interval, as well as for absolute coherence during the inter-trial interval. RESULTS: Event-related coherence was significantly reduced in patients during time intervals (0-250 ms poststimulus) when controls showed significant event-related coherence increases. However, patients showed significantly higher absolute coherence during the inter trial interval. These results pointed to differential deficits in fronto posterior connectivity during the inter-trial interval and task-related conditions in schizophrenia. CONCLUSION: Cognitive deficits in schizophrenia might be driven by abnormal fronto-posterior communication. Task-related hypo connectivity and inter-trial interval hyper-connectivity point to resource allocation deficits. The timing of cortico-cortical interactions during crucial task-related intervals may be impaired, while frontal and posterior areas may exhibit increased interactions between the trials. PMID- 20846274 TI - 'I live for today': a qualitative study investigating older people's attitudes to advance planning. AB - This article reports investigation of prevalent understandings and systems of beliefs that underpin older people's attitudes towards making plans for their future. The Mental Capacity Act 2005 (MCA) enables adults with capacity to make plans and decisions in advance, to arrange proxy decision-making and provides safeguards for those who might lose the capacity to make decisions for themselves in the future. This study explored the attitudes of a diverse sample of 37 self declared well older people living in the community in England about their views on drawing up statements of wishes and documenting their decision-making preferences. The study was conducted in early 2009. Findings revealed that most individuals had a personal tendency or preference towards planning, guided by personality, beliefs, living situation and the relevancy of planning to their situation. Financial plans and funeral arrangements were most commonly drawn up with an absence of health and social care plans, which participants tended to postpone considering. Housing and residential care were important for all. Overall, few participants had heard of the MCA and most were unsure where to turn for support. Participants appreciated support when discussing these issues; some turned to family, while others felt professionals were a more appropriate source of advice. The family doctor was cited as trustworthy and a potential place to begin inquiries. Conceptualising onset of certain debilitating conditions also encouraged participants to think about planning for them. This study has implications for public education campaigns and health-related information that could potentially impact on many older people who are interested in making plans but are unaware that legal safeguards and practical support are available to aid this. PMID- 20846273 TI - R0 but not R1/R2 resection is associated with better survival than palliative photodynamic therapy in biliary tract cancer. AB - BACKGROUND: There is a need for better management strategies to improve the survival and quality of life in patients with biliary tract cancer (BTC). AIM: To assess prognostic factors for survival in a large, non-selective cohort of patients with BTC. METHOD: We compared outcomes in 321 patients with a final diagnosis of BTC (cholangiocarcinoma n = 237, gallbladder cancer n = 84) seen in a tertiary referral cancer centre between 1998 and 2007. Survival according to disease stage and treatment category was compared using log-rank testing. Cox's regression analysis was used to determine independent prognostic factors. RESULTS: Eighty-nine (28%) patients underwent a surgical intervention with curative intent, of whom 38% had R0 resections. Among the 321 patients, 34% were given chemo- and/or radiotherapy, 14% were palliated with photodynamic therapy (PDT) and 37% with biliary drainage procedures alone. The overall median survival was 9 months (3-year survival, 14%). R0-resective surgery conferred the most favourable outcome (3-year survival, 57%). Although patients palliated with PDT had more advanced clinical T-stages, their survival was similar to those treated with attempted curative surgery but who had positive resection margins. On multivariable analysis, treatment modality, serum carbohydrate-associated antigen 19-9, distant metastases and vascular involvement were independent prognostic indicators of survival. CONCLUSION: In this large UK series of BTC, palliative PDT resulted in survival similar to those with curatively intended R1/R2 resections. Surgery conferred a survival advantage only in patients with R0 resection margins, emphasising the need for accurate pre-operative staging. PMID- 20846275 TI - Therapeutic hypothermia for newborn infants with hypoxic-ischaemic encephalopathy. AB - Peripartum asphyxia complicated by moderate or severe hypoxic-ischaemic encephalopathy is a devastating global health issue. A therapeutic 'window of opportunity' exists after resuscitation of the asphyxiated newborn and before the delayed phase of neuronal loss. Animal studies demonstrated that neuronal injury following hypoxia-ischaemia can be prevented or reduced by a mild reduction in brain temperature. Human infant pilot studies confirmed feasibility, without major adverse effects. Randomised trials and systematic reviews comprising term infants with moderate or severe encephalopathy and peripartum asphyxia have established the neuroprotective benefit of therapeutic hypothermia. Hypothermia reduces mortality or major disability to 18 months of age, as well as cerebral palsy, and neuromotor and cognitive delay. Importantly, mortality is reduced without any increase in major neurodevelopmental disability in survivors, and with only minor adverse effects. The evidence supports therapeutic hypothermia when used within strict protocols in tertiary centres to improve the outcome for term and near-term newborns with moderate or severe hypoxic-ischaemic encephalopathy. Equally strict protocols in non-tertiary nurseries will enable earlier initiation of hypothermia under guidance of the regional neonatal intensive care unit and transport team. PMID- 20846276 TI - Understanding coronary atherosclerosis in relation to obesity: is getting the distribution of body fatness using dual-energy X-ray absorptiometry worth the effort? A novel perspective using Bayesian Networks. AB - AIM: A relative excess of fat in the upper body region has been proven to be associated with increased coronary artery disease (CAD) risk. Dual-energy X-ray absorptiometry (DXA) is probably the most accurate and precise method available to study fat regional distribution and to directly measure total body fat and lean soft tissue mass. However, while several studies have investigated the abilities of obesity anthropometric measures in predicting CAD, only few studies have evaluated DXA as CAD predictor; particularly, a comparison between a model including information coming from anthropometric measurements and a model in which fat is precisely measured by DXA, is still lacking. In order to verify if CAD severity, as measured by Gensini score, is better predicted when a prognostic model includes DXA measurements rather than anthropometric measures, we compared performance obtained by two Bayesian Networks (BNs) including standard anthropometric measures and DXA, respectively. METHODS: Data come from 58 consecutive patients, 79% of them having suspected and 21% known CAD. Two BNs were implemented: input variables include anamnestic information, biochemical data and obesity measures. In the first model (BN1) obesity was measured by body mass index and waist-to-hip ratio, while in the second one (BN2) it is quantified by DXA-derived parameters. RESULTS: Network graphs and results coming from sensitivity analysis show that in both models lipoproteins and biomarkers of inflammation act as proximal node, while obesity (independently of the chosen measure) appears to be a distal node acting by the intermediation of other variables. Both models show high predictive abilities, the mean percentage classification errors being, respectively, 14.13 and 18.87. CONCLUSIONS: In our study, the BN predictive ability is slightly superior when obesity is measured using anthropometric data instead of DXA measurements. The reason probably relies on the fact that in the BN the obesity role in predicting CAD is mediated by the action of other factors that appear to be more directly influencing the outcome. Thus, the necessity to dispose of a perfect measure becomes less compulsory and the huge effort to precisely estimate body composition with complex methods as DXA could be avoided when using expert system such as BN as predictive tool. PMID- 20846277 TI - Coding accuracy of abdominal aortic aneurysm repair procedures in administrative databases - a note of caution. AB - BACKGROUND: Administrative databases have been used to compare methods used for abdominal aortic aneurysm (AAA) repair. This requires the use of procedural codes whose accuracy has not been established. In this study we measured the accuracy of procedural codes for open AAA repair and endovascular aneurysm repair (EVAR) in administrative databases. METHODS: Between April 2000 and July 2005, we identified all surgeries of non-ruptured AAA using open or EVAR technique at a tertiary-care teaching hospital. During the same time period, we identified all patients who were coded with either an open AAA repair or EVAR. RESULTS: During the study period, 514 people had an elective AAA repair or were coded with one. Coding quality of open AAA repair was poor (sensitivity 48.1%; specificity 77.4%; accuracy 52.9%) while that for EVAR was slightly better (sensitivity 58.2%; specificity 100%; accuracy 93.6%). We developed an algorithm that included similar procedures and considered anaesthetic type to improve the identification of both open repair (sensitivity 97.7%; specificity 86.9%; accuracy 95.9%) and EVAR (sensitivity 84.8%; specificity 99.5%; accuracy 97.3%). CONCLUSION: Administrative database codes that are routinely used to identify open AAA repairs or EVARs are inaccurate. However, slight modifications to the coding algorithms permit the use of administrative databases to study AAA repair. PMID- 20846278 TI - Improving reliability of clinical care practices for ventilated patients in the context of a patient safety improvement initiative. AB - AIMS: To investigate perceived factors relating to the reliable application of four clinical care practices targeting ventilator-associated pneumonias, in the context of a patient safety improvement initiative called the Safer Patients Initiative (SPI). METHODS: Qualitative case study. Seventeen semi-structured individual interviews with clinical operational leads, programme coordinators and executive managers who were involved in the implementation of the programme's critical care work stream during its pilot phase. The interviews had a focus on perceived aspects pertaining to the reliable implementation of the four clinical practices, promoted by the Institute for Healthcare Improvement as the 'ventilator care bundle'. RESULTS: Thematic analysis of the verbatim transcripts revealed three overarching themes experienced by the participants during the implementation of the clinical practices included in the SPI ventilator care bundle: the power of measurement, feedback to peers and experts and improvement tools specific to SPI. Consistent measurement of compliance with the four elements of the bundle and outcomes made the staff realize that their engagement in previous improvement work for ventilated patients was inadequate and motivated them to apply the introduced clinical practices more reliably. Feedback to experts and peers of staff compliance with the four clinical practices and outcome improvement was perceived as a very influential aspect of SPI. Small tests of change (Plan-Do-Study-Act cycles), teaching sessions and daily goal sheets were quoted as particularly useful tools throughout the implementation of the four clinical care practices. CONCLUSIONS: Future initiatives that aim to improve the adherence of clinical staff with clinical practice guidelines in intensive care units could benefit from integrating in their methodology consistent measurement and feedback practices of both process compliance and outcome data. PMID- 20846279 TI - Interhospital variation in appropriateness of cataract surgery. AB - OBJECTIVE: The aim of this study was to analyse the inter-hospital variation in the appropriateness of cataract phacoemulsification in Spain. METHODS: This observational, multicentre, prospective study involved patients aged 18-90 years. Each phacoemulsification intervention was classified as 'necessary', 'appropriate', 'uncertain' or 'inappropriate' according to explicit appropriateness criteria previously established using the RAND/UCLA methodology. A descriptive statistical analysis was performed, followed by univariate and multivariate logistic regression analysis, in order to examine the differences between hospitals. RESULTS: In total, 5063 patients from 15 hospitals were enrolled. The percentage of patients in each hospital who inappropriately underwent phacoemulsification varied from 1.2% to 24.0% (P < 0.0001). The most common inappropriate scenario was that of patients with a simple, unilateral cataract with no limitation of their visual function, with a pre-surgery visual acuity of >= 0.5 in both eyes, and for whom surgical correction would involve low technical complexity. CONCLUSIONS: The variation in appropriateness of phacoemulsification cannot be attributed solely to the clinical differences between the hospitals' patients. There is room for improvement in the appropriate indication of phacoemulsification. Measures based on the dissemination of appropriateness criteria might improve quality of care. PMID- 20846280 TI - Shared care for hearing complaints: guideline effects on patient flow. AB - RATIONALE, AIMS AND OBJECTIVES: A national guideline was proposed to enable shared care in hearing complaints and therefore to change patient flows. In this study the effect of this guideline is evaluated. METHODS: From a total of 3500 patients with hearing complaints, consulting the Ear Nose and Throat Department of a large non-university hospital in the Netherlands in 2002, a random sample of 1000 patients was selected. Patient flow was simulated according to guideline criteria with as main outcome measures: the effect of the guideline on patient flow. RESULTS: Simulation of the consensus guideline did not really alter patient flow, with 89% to 97% of the patients still being referred to the Ear Nose and Throat specialist or Audiological Centre. Age, ear operations in the past and asymmetric hearing loss are the most important factors determining whether a person is labelled as a patient in need of medical care. CONCLUSION: The present study emphasizes the importance of designing evidence-based guidelines for shared care. PMID- 20846281 TI - Patients Assessment of Chronic Illness Care (PACIC) in two Australian studies: structure and utility. AB - AIMS: To validate the Patients Assessment of Chronic Illness Care (PACIC) among patients with chronic disease in the Australian context and to examine the relationship between patient-assessed quality of care and patient and practice characteristics. METHODS: Cross-sectional analysis of baseline data in two independent health service intervention studies that involved patients with type 2 diabetes, ischaemic heart disease and/or hypertension in general practice. The first study involved 2552 patients from 60 urban and rural general practices. The second involved 989 patients from 26 practices in Sydney. Patients were mailed a questionnaire, which included the PACIC and Short Form Health Survey. Factor analysis was performed and the factor scores and total PACIC were analysed using multi-level regression models against practice and patient characteristics. RESULTS: Factor analysis revealed a two-factor solution with similar loading of PACIC items in both studies: one for shared decision making and self-management and the other for planned care. Practice characteristics were not related to PACIC scores. Scores were related to patient characteristics - education, retirement, type and number and duration of conditions. CONCLUSIONS: The two factor structure of the PACIC found in these Australian studies is different from the five-factor structure found in the US and the European studies. This may be related to differences in the way patients interact with the health system especially the use of Team Care plans. The association of total scores with patient characteristics was consistent with those found in other studies including a lack of association with gender, age and ethnicity. These findings should be taken into consideration when comparing patient-assessed quality of care between countries using this tool. PMID- 20846282 TI - Strain in the ostrich mandible during simulated pecking and validation of specimen-specific finite element models. AB - Finite element (FE) analysis is becoming a frequently used tool for exploring the craniofacial biomechanics of extant and extinct vertebrates. Crucial to the application of the FE analysis is the knowledge of how well FE results replicate reality. Here I present a study investigating how accurately FE models can predict experimentally derived strain in the mandible of the ostrich Struthio camelus, when both the model and the jaw are subject to identical conditions in an in-vitro loading environment. Three isolated ostrich mandibles were loaded hydraulically at the beak tip with forces similar to those measured during force transducer pecking experiments. Strains were recorded at four gauge sites at the dorsal and ventral dentary, and medial and lateral surangular. Specimen-specific FE models were created from computed tomography scans of each ostrich and loaded in an identical fashion as in the in-vitro test. The results show that the strain magnitudes, orientation, patterns and maximum : minimum principal strain ratios are predicted very closely at the dentary gauge sites, even though the FE models have isotropic and homogeneous material properties and solid internal geometry. Although the strain magnitudes are predicted at the postdentary sites, the strain orientations and ratios are inaccurate. This mismatch between the dentary and postdentary predictions may be due to the presence of intramandibular sutures or the greater amount of cancellous bone present in the postdentary region of the mandible and requires further study. This study highlights the predictive potential of even simple FE models for studies in extant and extinct vertebrates, but also emphasizes the importance of geometry and sutures. It raises the question of whether different parameters are of lesser or greater importance to FE validation for different taxonomic groups. PMID- 20846283 TI - Association of CD28 gene polymorphism with cervical cancer risk in a Chinese population. AB - Human papilloma virus plays a causal role in cervical carcinogenesis. However, only a small portion of infected individuals develop cervical cancer. Host genetic factors may confer susceptibility to this disease. CD28 participates in the maintenance of immune homeostasis as an important positive co-stimulatory molecule. Allelic variation of immuno-modulatory genes may be associated with alteration in immune function. This study investigated the associations between CD28 IVS3 +17T>C polymorphism and risk of cervical cancer in the Chinese population. Genotypes of CD28 polymorphism were detected in 619 cases with primary cervical cancer and in 985 normal controls. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. A higher frequency of CD28 +17TC heterozygote was determined in patients in comparison with controls (19.4% versus 12.5%). Subjects carrying at least one CD28 IVS3 +17 C allele (TC or CC genotype) had increased risk of cervical cancer (OR=1.66, 95% CI=1.27-2.17). This study suggests that the CD28 IVS3 +17T>C polymorphism might be genetic susceptibility factor for cervical cancer in Chinese population. PMID- 20846284 TI - Creating a multidisciplinary low back pain guideline: anatomy of a guideline adaptation process. AB - RATIONALE, AIMS AND OBJECTIVES: A collaborative, multidisciplinary guideline adaptation process was developed to construct a single overarching, evidence based clinical practice guideline (CPG) for all primary care practitioners responsible for the management of low back pain (LBP) to curb the use of ineffective treatments and improve patient outcomes. METHODS: The adaptation strategy, which involved multiple committees and partnerships, leveraged existing knowledge transfer connections to recruit guideline development group (GDG) members and ensure that all stakeholders had a voice in the guideline development process. Videoconferencing was used to coordinate the large, geographically dispersed GDG. Information services and health technology assessment experts were used throughout the process to lighten the GDG's workload. RESULTS: The GDG reviewed seven seed guidelines and drafted an Alberta-specific guideline during 10 half-day meetings over a 12-month period. The use of ad hoc subcommittees to resolve uncertainties or disagreements regarding evidence interpretation expedited the process. Challenges were encountered in dealing with subjectivity, guideline appraisal tools, evidence source limitations and inconsistencies, and the lack of sophisticated evidence analysis inherent in guideline adaptation. Strategies for overcoming these difficulties are discussed. CONCLUSION: Guideline adaptation is useful when resources are limited and good-quality seed CPGs exist. The Ambassador Program successfully utilized existing stakeholder interest to create an overarching guideline that aligned guidance for LBP management across multiple primary care disciplines. Unforeseen challenges in guideline adaptation can be overcome with credible seed guidelines, a consistently applied and transparent methodology, and clear documentation of the subjective contextualization process. Multidisciplinary stakeholder input and an open, trusting relationship among all contributors will ensure that the end product is clinically meaningful. PMID- 20846285 TI - Unscheduled care following attendance at Minor Illness and Injury Units (MIU): cross-sectional survey. AB - RATIONALE, AIMS AND OBJECTIVES: Minor Illness and Injury Units (MIUs) are becoming a key element in the Urgent Care strategies of Primary Care Trusts. They are intended to both improve access to primary care and to reduce the workload of hospital emergency departments. Their efficiency in resolving patients' needs for health care has been questioned. We sought to describe subsequent health care utilisation among people attending two MIUs in Sunderland, UK. METHOD: Audit of all patients who attended the MIUs during two separate week-long blocks with General Practitioner (GP) case note review of those who had been either treated and discharged or referred to their GP. RESULTS: A total of 1995 patients from 38 practices attended during the study period. 1262 (63.3%) were treated and discharged and 281 (14.1%) referred to the GP. In the subsequent 7 days 336 (21.8%) attended their GP, 37 (2.4%) attended an emergency department and 18 (1.2%) reattended the MIU. Overall, 855 (42.9%) of all attenders required further care, and in 265 (29.9%) this was unscheduled. CONCLUSION: Although most people attending Minor Illness and Injury Units are treated and discharged, subsequent use of health care services is common and in a third of cases is unscheduled. This calls into question the effectiveness of MIUs as an alternative to general practice but may reflect a need for better signposting of patients to the service best suited to their needs. PMID- 20846287 TI - Making sense of polarities in health organizations for policy and leadership. AB - Making sense of complex adaptive clinical practice and health systems is a pressing challenge as health services continue to struggle to adapt to changing internal and external constraints. In this Forum, we begin with Dervin's Sense Making theories and research in communications. This provides a conceptual and theoretical context for this editions research on comparative complexity of family medicine consultations in the USA, models for adaptive leadership in clinical care and social networking to make sense of health promotion challenges for young people. Finally, a Sense-Making schema is proposed. PMID- 20846288 TI - Trends in the perceived complexity of primary health care: a secondary analysis. AB - RATIONALE: If the complexity of the patient's medical problems increases or the complexity of the interactions between the doctor and the patient, the staff or the health care system increase, then complexity of patient care will increase. This study examined trends in patient complexity, and identified doctor, practice and improvement strategy characteristics associated with perceived complexity. METHODS: This secondary analysis used data from three Community Tracking Surveys with 22,134 primary care doctors completing surveys about themselves, their practice setting, practice improvement strategies and complexity of care in three consecutive 2-year time periods (1996-1997, 1998-1999, 2000-2001). Data were analysed using hierarchical logistic regression. RESULTS: The proportion of primary care doctors who perceived that complexity of care had increased over the past 2 years rose from 31.5% to 35.9%. Perceived complexity of patient care was consistently related to being in solo practice and the belief that they could not frequently obtain high-quality services and referrals for patients. As availability of services increased, complexity decreased whereas as use of practice improvement strategies increased, complexity also increased. CONCLUSIONS: Understanding that we cannot determine whether respondents understood care as 'complicated' or 'complex', potential consequences of this increase in complexity include an increase in medical errors and referral rates along with decreased quality of patient care and career satisfaction. PMID- 20846289 TI - Adaptive leadership and the practice of medicine: a complexity-based approach to reframing the doctor-patient relationship. AB - RATIONALE, AIMS AND OBJECTIVES: This paper applies the concepts of 'adaptive leadership', as developed by Ron Heifetz, MD, to the practice of medicine. METHODS: Literature review and theory development. RESULTS: Patients are complex adaptive systems facing both adaptive and technical health challenges. Technical health challenges are amenable to the simple or complicated expert-mediated technical interventions that are common in modern medicine, but complex adaptive challenges can only be addressed by patients doing the adaptive work to learn new attitudes, beliefs and behaviours. In medicine, we often make the mistake of offering technical interventions in lieu of supporting patients' adaptive work. This error can result in poor clinical outcomes and wasted resources. Expecting simple or complicated technical 'solutions' to resolve complex adaptive health challenges is a failure of adaptive leadership and violates Ashby's law of requisite variety. Adaptive leadership behaviours correspond to and complement doctor practices that have been shown to improve health outcomes and doctor patient communication. CONCLUSIONS: Adopting an adaptive leadership framework in the practice of medicine will require adaptive work on our part, but it promises to improve the doctor-patient relationship, increase our effectiveness as healers and reduce unnecessary health care utilization. PMID- 20846290 TI - Designing health innovation networks using complexity science and systems thinking: the CoNEKTR model. AB - RATIONALE, AIMS AND OBJECTIVES: Complex problems require strategies to engage diverse perspectives in a focused, flexible manner, yet few options exist that fit with the current health care and public health system constraints. The Complex Network Electronic Knowledge Translation Research model (CoNEKTR) brings together complexity science, design thinking, social learning theories, systems thinking and eHealth technologies together to support a sustained engagement strategy for social innovation support and enhancing knowledge integration. METHODS: The CoNEKTR model adapts elements of other face-to-face social organizing methods and combines it with social media and electronic networking tools to create a strategy for idea generation, refinement and social action. Drawing on complexity science, a series of networking and dialogue-enhancing activities are employed to bring diverse groups together, facilitate dialogue and create networks of networks. RESULTS: Ten steps and five core processes informed by complexity science have been developed through this model. Concepts such as emergence, attractors and feedback play an important role in facilitating networking among participants in the model. CONCLUSIONS: Using a constrained, focused approach informed by complexity science and using information technology, the CoNEKTR model holds promise as a means to enhance system capacity for knowledge generation, learning and action while working within the limitations faced by busy health professionals. PMID- 20846286 TI - Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. AB - AIM: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS AND PATIENTS: A total of 858 patients [age >= 18 years; glycated haemoglobin (HbA(1c) ) > 6.5 - 10.0%; on stable metformin doses >= 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was non-inferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs. -0.80%, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < 0.0001) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < 0.0001). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs. 0.004%; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatment-related AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar (~4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia. PMID- 20846291 TI - A homozygous inactivating calcium-sensing receptor mutation, Pro339Thr, is associated with isolated primary hyperparathyroidism: correlation between location of mutations and severity of hypercalcaemia. AB - BACKGROUND: Inactivating mutations of the calcium-sensing receptor (CaSR), a G protein-coupled receptor with extracellular (ECD), transmembrane (TMD) and intracellular (ICD) domains, cause familial hypocalciuric hypercalcaemia, neonatal severe primary hyperparathyroidism and occasionally primary hyperparathyroidism in adults. OBJECTIVE: To investigate a patient with typical symptomatic primary hyperparathyroidism for CaSR abnormalities. PATIENT AND DESIGN: A 51-year-old woman with primary hyperparathyroidism was investigated for CaSR abnormalities as her severe hypercalcaemia (3.75 mm) persisted after the removal of two large parathyroid adenomas and she was the daughter of normocalcaemic consanguineous parents. Following informed consent, CASR mutational analysis was undertaken using leucocyte DNA. Wild-type and mutant CaSR constructs were expressed in human embryonic kidney (HEK) 293 cells and assessed by measuring their intracellular calcium responses to changes in extracellular calcium. Clinical data were pooled with previous studies to search for genotype phenotype correlations. RESULTS: The proband was homozygous for a Pro339Thr CaSR missense mutation, located in the ECD, and her normocalcaemic relatives were heterozygous. The mutant Thr339 CaSR had a rightward shift in its dose-response curve with a significantly higher EC(50) = 3.18 mm +/- 0.19 compared to the wild type EC(50) = 2.16 mm +/- 0.1 (P < 0.01), consistent with a loss-of-function mutation. An analysis of CaSR mutations in patients with primary hyperparathyroidism revealed that those of the ECD were associated with a significantly greater hypercalcaemia that was less likely to be corrected after removal of the parathyroid tumours. CONCLUSIONS: A CaSR missense mutation causing a loss-of-receptor-function can cause symptomatic primary hyperparathyroidism in adulthood. PMID- 20846292 TI - Superior discriminating value of ACTH-stimulated serum 21-deoxycortisol in identifying heterozygote carriers for 21-hydroxylase deficiency. AB - BACKGROUND: Congenital adrenal hyperplasia caused by classic 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder with a high prevalence of asymptomatic heterozygote carriers (HTZ) in the general population, making case detection desirable by routine methodology. HTZ for classic and nonclassic (NC) forms have basal and ACTH-stimulated values of 17-hydroxyprogesterone (17OHP) that fail to discriminate them from the general population. 21-Deoxycortisol (21DF), an 11-hydroxylated derivative of 17OHP, is an alternative approach to identify 21OHD HTZ. OBJECTIVE: To determine the discriminating value of basal and ACTH-stimulated serum levels of 21DF in comparison with 17OHP in a population of HTZ for 21OHD (n = 60), as well as in NC patients (n = 16) and in genotypically normal control subjects (CS, n = 30), using fourth generation tandem mass spectrometry after HPLC separation (LC-MS/MS). RESULTS: Basal 21DF levels were not different between HTZ and CS, but stimulated values were increased in the former and virtually nonresponsive in CS. Only 17.7% of the ACTH-stimulated 21DF levels overlapped with CS, when compared to 46.8% for 17OHP. For 100% specificity, the sensitivities achieved for ACTH-stimulated 21DF, 17OHP and the quotient [(21DF + 17OHP)/F] were 82.3%, 53.2% and 87%, using cut-offs of 40, 300 ng/dl and 46 (unitless), respectively. Similar to 17OHP, ACTH-stimulated 21DF levels did not overlap between HTZ and NC patients. A positive and highly significant correlation (r = 0.846; P < 0.001) was observed between 21DF and 17OHP pairs of values from NC and HTZ. CONCLUSION: This study confirms the superiority of ACTH-stimulated 21DF, when compared to 17OHP, both measured by LC MS/MS, in identifying carriers for 21OHD. Serum 21DF is a useful tool in genetic counselling to screen carriers among relatives in families with affected subjects, giving support to molecular results. PMID- 20846293 TI - Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas. AB - OBJECTIVE: Constitutively activating mutations (CAMs) of the TSHR are the major cause for nonautoimmune hyperthyroidism. Re-examination of constitutive activity previously determined in CHO cell lines recently demonstrated the caveats for the in vitro determination of constitutive TSHR activity, which leads to false positive conclusions regarding the molecular origin of hyperthyroidism or hot thyroid carcinomas. DESIGN: Mutations L677V and T620I identified in hot thyroid carcinomas were previously characterized in CHO and in 3T3-Vill cell lines, respectively, stably expressing the mutant without determination of TSHR expression. F666L identified in a patient with hot thyroid nodules, I691F in a family with nonautoimmune hyperthyroidism and F631I identified in a hot thyroid carcinoma were not characterized for their in vitro function. Therefore, we decided to (re)evaluate the in vitro function of these five TSHR variants by determination of cell surface expression, and intracellular cAMP and inositol phosphate levels and performed additionally linear regression analyses to determine basal activity independently from the mutant's cell surface expression in COS-7 and HEK(GT) cells. RESULTS AND CONCLUSIONS: Only one (F631I) of the five investigated TSHR variants displayed constitutive activity for G(alpha) s signalling and showed correlation with the clinical phenotype. The previous false classification of T620I and L677V as CAMs is most likely related to the fact that both mutations were characterized in cell lines stably expressing the mutated receptor construct without assessing the respective receptor number per cell. Other molecular aetiologies for the nonautoimmune hyperthyroidism and/or hot thyroid carcinomas in these three patients and one family should be elucidated. PMID- 20846294 TI - Ethnic differences in Rotterdam criteria and metabolic risk factors in a multiethnic group of women with PCOS studied in Denmark. AB - OBJECTIVE: Clinical manifestations and metabolic risk factors may differ in ethnic subgroups of patients with polycystic ovary syndrome (PCOS). DESIGN: Retrospective trans-sectional study. PATIENTS: One thousand and two premenopausal women with the diagnoses hirsutism or PCOS were divided according to ethnicity: Caucasian (CA, n = 784), Middle East (ME, n = 190), Asian (n = 14) and others (n = 14). MEASUREMENTS: Clinical evaluation (hirsutism, BMI, waist, blood pressure), hormone analyses (testosterone, sex hormone-binding globulin, prolactin, lipids, insulin, glucose) and transvaginal ultrasound were performed. Oral glucose tolerance tests (OGTT) (n = 499) and ACTH tests (n = 434) were performed in a subgroup of patients. RESULTS: (CA vs ME women) CA women were older [32(25-37) vs 25(18-32) years, median (quartiles)] and had increased BMI compared to ME women. After correcting for age and BMI, CA women were less hirsute, but had increased testosterone levels compared to ME women. The Rotterdam criteria were fulfilled in 56% of both populations, but PCO was diagnosed in 47% CA vs 29% ME women, P < 0.01. CA women had increased blood pressure and smoked at a higher frequency (40 vs 23%), whereas area under the curve for insulin during OGTT was decreased, all P < 0.001. Prolactin levels were significantly lower in CA women compared to ME women [7(5-10) vs 9(6-12) MUg/l] and were inversely associated with smoking status. CONCLUSION: CA women had a more adverse cardiovascular profile than ME women, whereas insulin sensitivity was higher. The prevalence of the individual Rotterdam criteria differed significantly in the two study populations. PMID- 20846295 TI - The influence of secular trend for height on ascertainment and eligibility for growth hormone treatment. AB - OBJECTIVE: Assessment of short stature in many instances is based on a comparison with the Centers for Disease Control's (CDC) growth curves. The secular trend for height may limit the utility of CDC data for contemporary populations. We investigate the effect of the secular trend on Australian and US populations. DESIGN: Describe CDC-defined height SDS distributions of contemporary populations for different ages and genders. Compare observed means and standard deviations (SDs) to expected values of 0 and 1. Compare frequency of individuals shorter than the CDC-1st centile to those shorter than 1st centile defined empirically from the contemporary population. SUBJECTS: Healthy Kids Queensland Survey 2006: 1686 boys, 1822 girls. Australian National Children's Nutrition and Physical Activity Survey 2007: 2415 boys, 2379 girls. US National Health and Nutrition Examination Survey 2005-2006: 2160 boys, 2118 girls. MEASUREMENTS: Means, SDs and normality of CDC-defined height SDS distributions. Frequency of individuals shorter than the CDC-1st centile and shorter than an empirically defined 1st centile. RESULTS: In Australia, means of CDC-defined height SDS distributions are always greater than 0 and the CDC-1st centile identifies only the shortest 0.5% of children. Means may vary with age and occasionally between genders in contemporary populations. Normality and SDs of 1 are retained. CONCLUSIONS: The secular trend has resulted in an underestimate of the number of Australian children eligible for GH treatment using the CDC-1st centile cut-off. Contemporary, local data should be used to construct standards. Using the 2nd CDC centile would approximate the 1st local centile until new standards are constructed. The secular trend does not account for the gender bias in GH therapy. PMID- 20846296 TI - Outcomes of surgical treatment for nonfunctioning pituitary adenomas: a systematic review and meta-analysis. AB - BACKGROUND: Surgery is commonly used in the management of pituitary nonfunctioning adenomas (NFPA). The goal of this systematic review and meta analysis is to evaluate the effect of surgery on mortality, surgical complications, pituitary function and vision. METHODS: We searched MEDLINE, EMBASE and Cochrane CENTRAL, queried experts and reviewed the reference list of included publications. Eligible studies were comparative and noncomparative longitudinal studies that enroled patients with NFPA who underwent surgery (alone or in combination with other therapies). Reviewers, working independently and in duplicate, determined study eligibility with adequate reproducibility and extracted descriptive, quality and outcome data. Risks, relative risks (RR) and 95% confidence intervals (CIs) were estimated from each study and pooled using random-effects meta-analysis. RESULTS: Most included studies were uncontrolled case series in which patients received a combination of surgery and radiotherapy. The overall quality of the evidence was very low. Median follow-up was 4.29 years. When surgery was not combined with radiotherapy, there was an increased risk of tumour recurrence (RR 1.97; 95% CI, 1.15-3.35). Complications were more likely with the transcranial than with the transsphenoidal approach (mortality RR 4.89; 95% CI, 3.15-6.47; new anterior pituitary deficits RR 4.90; 95% CI, 2.94 7.82; and persistent diabetes insipidus RR 2.50; 95% CI, 1.05-5.35). Overall, transsphenoidal surgery had fairly low perioperative mortality (<= 1%) and low complication rate (<= 5% for all patient-important outcomes), but only less than a third of the patients had improvement in pituitary function. CONCLUSIONS: Observational evidence supports the association between a combined approach of transsphenoidal surgery with radiotherapy and improvements in visual field defects and reduction in tumour recurrence. PMID- 20846297 TI - "Grading" subclinical thyroid disease may be misleading. PMID- 20846298 TI - Soluble forms of the cell adhesion molecule L1 produced by insect and baculovirus transduced mammalian cells enhance Schwann cell motility. AB - For biotechnological applications, insect cell lines are primarily known as hosts for the baculovirus expression system that is capable to direct synthesis of high levels of recombinant proteins through use of powerful viral promoters. Here, we demonstrate the implementation of two alternative approaches based on the baculovirus system for production of a mammalian recombinant glycoprotein, comprising the extracellular part of the cell adhesion molecule L1, with potential important therapeutic applications in nervous system repair. In the first approach, the extracellular part of L1 bearing a myc tag is produced in permanently transformed insect cell lines and purified by affinity chromatography. In the second approach, recombinant baculoviruses that express L1 Fc chimeric protein, derived from fusion of the extracellular part of L1 with the Fc part of human IgG1, under the control of a mammalian promoter are used to infect mammalian HEK293 and primary Schwann cells. Both the extracellular part of L1 bearing a myc tag accumulating in the supernatants of insect cultures as well as L1-Fc secreted by transduced HEK293 or Schwann cells are capable of increasing the motility of Schwann cells with similar efficiency in a gap bridging bioassay. In addition, baculovirus-transduced Schwann cells show enhanced motility when grafted on organotypic cultures of neonatal brain slices while they retain their ability to myelinate CNS axons. This proof-of-concept that the migratory properties of myelin-forming cells can be modulated by recombinant protein produced in insect culture as well as by means of baculovirus-mediated adhesion molecule expression in mammalian cells may have beneficial applications in the field of CNS therapies. PMID- 20846299 TI - Attenuated stress response to acute restraint and forced swimming stress in arginine vasopressin 1b receptor subtype (Avpr1b) receptor knockout mice and wild type mice treated with a novel Avpr1b receptor antagonist. AB - Arginine vasopressin (AVP) synthesised in the parvocellular region of the hypothalamic paraventricular nucleus and released into the pituitary portal vessels acts on the 1b receptor subtype (Avpr1b) present in anterior pituitary corticotrophs to modulate the release of adrenocorticotrophic hormone (ACTH). Corticotrophin-releasing hormone is considered the major drive behind ACTH release; however, its action is augmented synergistically by AVP. To determine the extent of vasopressinergic influence in the hypothalamic-pituitary-adrenal axis response to restraint and forced swimming stress, we compared the stress hormone levels [plasma ACTH in both stressors and corticosterone (CORT) in restraint stress only] following acute stress in mutant Avpr1b knockout (KO) mice compared to their wild-type controls following the administration of a novel Avpr1b antagonist. Restraint and forced swimming stress-induced increases in plasma ACTH were significantly diminished in mice lacking a functional Avpr1b and in wild-type mice that had been pre-treated with Avpr1b antagonist. A corresponding decrease in plasma CORT levels was also observed in acute restraint stressed knockout male mice, and in Avpr1b-antagonist-treated male wild-type mice. By contrast, plasma CORT levels were not reduced in acutely restraint stressed female knockout animals, or in female wild-type animals pre-treated with Avpr1b antagonist. These results demonstrate that pharmacological antagonism or inactivation of Avpr1b causes a reduction in the hypothalamic-pituitary-adrenal (HPA) axis response, particularly ACTH, to acute restraint and forced swimming stress, and show that Avpr1b knockout mice constitute a model by which to study the contribution of Avpr1b to the HPA axis response to acute stressors. PMID- 20846300 TI - Nonoperative management for large rectal foreign body removal. PMID- 20846301 TI - The cost-effectiveness of bortezomib in relapsed/refractory multiple myeloma: Swedish perspective. AB - OBJECTIVES: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS: We used partitioned survival analysis to assess survival data decomposed into three states: (i) alive before disease progression; (ii) alive after progression; and (iii) dead. The effects of treatment on time to progression and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS: BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per quality-adjusted life-year of BTZ compared to DEX was 2010 SEK 902,874 (?95,073) (95% CI: 514,791, 962,416) and was dominant with respect to LEN/DEX. CONCLUSION: BTZ and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX. PMID- 20846302 TI - Chronic lymphocytic leukemia-associated immune thrombocytopenia treated with rituximab: a retrospective study of 21 patients. AB - INTRODUCTION: There are no standard therapies for chronic lymphocytic leukemia (CLL)-associated immune thrombocytopenia (IT) so far. PATIENTS AND METHODS: We report the results of therapy with single agent rituximab in 21 patients with CLL associated IT. The mean age at CLL and IT diagnosis was 64 and 68 yr, respectively. IT developed at a mean time of 44 months from the diagnosis of CLL. In four cases, IT was diagnosed at the same time as CLL. For three patients, IT was considered fludarabine-related and two patients showed autoimmune hemolysis also. All patients but one received steroids as first-line treatment for IT. Some patients received intravenous high-dose Ig, vincristine, and Cytoxan also, without beneficial effect. After a mean time of 43 d from the diagnosis of IT, all patients were scheduled to receive rituximab at a dosage of 375 mg/mq/weekly. RESULTS: Eighteen (86%) patients completed the scheduled four cycles of rituximab. Irrelevant first infusion side effects were seen only in one patient. Twelve (57%) patients showed a complete response (CR), six (29%) patients a partial response (PR), and three (14%) patients did not respond. In responding patients, the mean duration of response was 21 months (4-49 months). At a mean follow-up of 28 months, 14 (66%) patients were still alive, 10 (48%) of them in CR and three (14%) in PR. CONCLUSIONS: This retrospective analysis prove that rituximab is an effective and well-tolerated alternative treatment for CLL associated IT. PMID- 20846303 TI - The role of stem cell factor and c-KIT in keloid pathogenesis: do tyrosine kinase inhibitors have a potential therapeutic role? AB - BACKGROUND: Keloids are fibroproliferative disorders characterized by increased deposition of extracellular matrix components. Stem cell factor (SCF) and its receptor c-KIT are expressed in a wide variety of cells and have also been demonstrated to be important modulators of the wound healing process. OBJECTIVES: To examine the role of the SCF/c-KIT system in keloid pathogenesis. METHODS: Immunohistochemical staining and Western blot analyses were used to examine localization and expression of SCF and c-KIT in keloid and normal skin tissue. This was followed by the detection of SCF and c-KIT expression in fibroblasts cultured in vitro and fibroblasts exposed to serum. To investigate the effect of epithelial-mesenchymal interactions, a two-chamber system was employed in which keratinocytes on membrane inserts were cocultured with the fibroblasts. SCF and c KIT expression levels in all cell extracts and conditioned media were assayed by Western blotting. In another set of experiments, the effect of imatinib (Glivec((r)), Gleevec((r)); Novartis Pharma AG, Basel, Switzerland) on keloid fibroblasts was examined. RESULTS: SCF and c-KIT were upregulated in keloid scar tissue and in cultured fibroblasts stimulated with serum, highlighting their importance in the initial phase of wound healing. We further demonstrated that epithelial-mesenchymal interactions, mimicked by coculture of keratinocytes and fibroblasts in vitro, not only stimulated secretion of the soluble form of SCF in keloid cocultures but also brought about shedding of the extracellular domain of c-KIT perhaps by upregulation of tumour necrosis factor-alpha converting enzyme which was also upregulated in keloid scars in vivo and keloid cocultures in vitro. In addition keloid cocultures expressed increased levels of phosphorylated c-KIT highlighting an activation of the SCF/c-KIT system. Finally, we demonstrated that imatinib, a tyrosine kinase inhibitor, may be a possible therapeutic agent for keloids. CONCLUSION: These data indicate that the SCF/c-KIT system plays an important role in scar pathogenesis, and underscore the role of imatinib as a key therapeutic agent in keloid scars. PMID- 20846304 TI - Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFalpha therapy. AB - BACKGROUND: Anti-TNFalpha therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis. OBJECTIVES: To elucidate the early effects of adalimumab, a human monoclonal anti-TNFalpha antibody, on the expression of interleukins in psoriatic skin. PATIENTS AND METHODS: Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry. RESULTS: The increased mRNA level of IL-1beta, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-gamma and IL-2 were reduced late in disease resolution. IL-1beta, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation. CONCLUSIONS: This study indicates that an important mechanism of action of anti-TNFalpha therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes. PMID- 20846305 TI - Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK activation pathway. AB - BACKGROUND: Gefitinib (ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with a significant antitumour effect on various cancers. Skin toxicity induced by gefitinib is common, and has been shown to be related to the inhibition of EGFR signalling pathways. However, other mechanisms may be involved in gefitinib-induced skin toxicity. OBJECTIVES: To study the possible EGFR-independent mechanisms of gefitinib-induced skin toxicity. METHODS: The human immortalized keratinocyte cell line HaCaT and human lung adenocarcinoma cell lines (A549 and PC9) were treated with different concentrations of gefitinib for 24, 48 and 72 h. Cell viability was measured by MTT assay [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] after EGFR gene silencing. The signalling pathways were investigated by immunoblot analysis. Keratinocyte apoptosis was evaluated by nuclear condensation and flow cytometric analysis. RESULTS: Gefitinib maintained its cytotoxicity to HaCaT cells after EGFR gene silencing, indicating that an EGFR-independent mechanism exists. Increased phosphorylation of p38 mitogen-activated protein kinase and JNK by gefitinib was observed in a dose-dependent manner in HaCaT cells. The JNK inhibitor, SP600125, attenuated the gefitinib-induced cytotoxicity and apoptosis of HaCaT cells. Immunohistochemical examination of patient specimens showed an increased expression of phosphorylated JNK in lesional epidermis compared with nonlesional epidermis. CONCLUSIONS: Gefitinib can induce keratinocyte apoptosis through an EGFR-independent JNK activation pathway. PMID- 20846306 TI - Dermoscopy of pyogenic granuloma: a morphological study. AB - BACKGROUND: Pyogenic granuloma is a common, benign, vascular lesion of the skin and mucous membranes which is a simulator of amelanotic/hypomelanotic melanoma and other tumours. OBJECTIVES: To determine the diagnostic significance of dermoscopic structures and patterns associated with pyogenic granulomas in a large series of cases. METHODS: Digital dermoscopic images of histopathologically proven cases of 122 pyogenic granulomas and 140 other tumours (28 amelanotic melanomas, seven melanoma metastases, 22 basal cell carcinomas and 83 other tumours) were collected from university hospitals in Spain, Italy, Austria and Turkey. The frequency, sensitivity, specificity, positive predictive value, negative predictive value, intraobserver agreement and interobserver agreement of the dermoscopic structures and patterns associated with pyogenic granulomas were calculated. RESULTS: Vascular structures were observed in 45% of pyogenic granulomas (sensitivity of 45.1% and specificity of 17.9%; both P < 0.001). Seven exclusive patterns were made up from the combination of the structures 'reddish homogeneous area' (RHA), 'white collarette' (WC), 'white rail lines' (WRL) and 'vascular structures' (VS). The pattern composed of RHA, WC and WRL showed the highest sensitivity (22.1%; P < 0.001) and a specificity of 100% (P < 0.001) for pyogenic granulomas. Two other patterns (RHA + WC and RHA + WC + WRL + VS) showed 100% specificity when compared with melanoma (P < 0.001 and P < 0.05, respectively). CONCLUSIONS: Even though some dermoscopic patterns are useful in the recognition of pyogenic granulomas, dermoscopy is not a substitute for histology, mostly when vessels are present, as melanoma cannot be ruled out. PMID- 20846307 TI - Negative herpesvirus-8 immunoreactivity does not exclude a diagnosis of Kaposi sarcoma. PMID- 20846308 TI - Circumscribed palmar hypokeratosis on both hands: distinct keratin expression in multiple depressed lesions. PMID- 20846309 TI - Features of pigmented vulval lesions on dermoscopy. AB - BACKGROUND: The dermoscopic criteria for benign and malignant lesions on the vulva are not well established due to the lack of large series of such lesions. Melanoma should always be included in the differential diagnosis of pigmented lesions on the vulva especially when they are wide, or of recent onset. Elsewhere on the skin dermoscopy plays an important role in the selection of suspicious pigmented lesions, as well as in the selection of the best site to perform the biopsy. OBJECTIVES: To analyse the dermoscopic patterns observed in pigmented lesions of the vulva. METHODS: We analysed a nonselected consecutive series of 68 histopathologically proven cases comprising five melanomas, 16 naevi, 20 lentigos, 12 benign vulval melanoses, 11 cases of postinflammatory pigmentation, three pigmented cases of usual vulval intraepithelial neoplasia (VIN) and one seborrhoeic keratosis seen at our institution. The dermoscope was covered by translucent disposable food wrap and/or antibacterial gel to prevent possible transmission of infections. Descriptive statistics were performed using multiple correspondence analysis. RESULTS: The parallel (37%), ring-like (9%), homogeneous (22%), globular-like (13%) and reticular-like (6%) patterns were observed on benign lesions (naevi, lentigo, vulval melanosis and postinflammatory pigmentation). The cerebriform pattern (6%) was observed only on VIN and seborrhoeic keratosis. The multicomponent pattern (6%) was associated with melanoma (60%). In cases of melanoma we also occasionally observed an irregular pattern, a whitish or blue-whitish veil, irregularly distributed dots and globules and atypical vascular pattern. Using multiple correspondence analysis, we designed a new algorithm for the early detection of vulval melanomas. CONCLUSIONS: Dermoscopy can play a role in the noninvasive classification of vulval melanosis. However, further studies of larger collaborative series are needed to validate our vulval melanoma diagnostic algorithm. VIN and seborrhoeic keratosis share the same dermoscopic features and biopsy should be considered for seborrhoeic-like keratosis. In case of doubt pathological examination of a biopsy remains mandatory. PMID- 20846310 TI - Vitamin D inhibits captopril-induced cell detachment and apoptosis in keratinocytes. AB - BACKGROUND: Captopril, an angiotensin I-converting enzyme inhibitor, is a commonly prescribed antihypertensive drug. Its cutaneous side-effects include pemphigus vulgaris acantholysis and bullous pemphigoid-like cell-matrix detachment. This medication also triggers apoptosis in human keratinocytes. Calcitriol, the hormonally active vitamin D metabolite, protects keratinocytes from programmed cell death induced by various noxious stimuli. OBJECTIVES: To examine if calcitriol protects proliferating keratinocytes from the damage inflicted by captopril. METHODS: Autonomously proliferating HaCaT keratinocytes, used as a model for basal layer keratinocytes, were exposed to captopril. Cell detachment was examined visually by light microscopy. Cytotoxicity was assessed by Hoechst 33342 staining and lactate dehydrogenase release. Apoptotic death was assessed by monitoring caspase 3-like activity. RESULTS: Cells exposed to captopril detached and became round. This process was accompanied by programmed cell death. From time-dependent monitoring of cell detachment and apoptosis, and examination of pan-caspase inhibitor effects on cell detachment we concluded that cell death is the consequence of cell detachment from the culture plate and not vice versa. Pretreatment with calcitriol significantly attenuated these events. The effects of calcitriol were already evident at 1 nmol L(-1) concentration of the hormone. CONCLUSIONS: The results of this study show that calcitriol protects keratinocytes from captopril-induced cell detachment and apoptosis. PMID- 20846311 TI - PHLDA1 (TDAG51) is a follicular stem cell marker and differentiates between morphoeic basal cell carcinoma and desmoplastic trichoepithelioma. AB - BACKGROUND: Morphoeic basal cell carcinoma (BCC) and desmoplastic trichoepithelioma can often be difficult to differentiate on routine sections and few reliable immunohistochemical markers are currently available. Recent cDNA microarray studies revealed the pleckstrin homology-like domain, family A, member 1 protein (PHLDA1) as a highly reliable marker of the hair follicle stem cells. Given the differentiation of trichoepithelioma along the follicular lineage and the proposed role of PHLDA1 as a follicular stem cell marker, we examined the staining pattern of PHLDA1 in the desmoplastic variant of trichoepithelioma and in its differential diagnostic conundrum, morphoeic BCC. OBJECTIVES: To describe the expression pattern of PHLDA1 in morphoeic BCC and desmoplastic trichoepithelioma. METHODS: Evaluation of the staining pattern for PHLDA1 was performed using standard immunohistochemical techniques. For comparison reasons, we analysed staining for PHLDA1 in normal skin structures with particular reference to the hair follicle. RESULTS: With the exception of one case, all 16 desmoplastic trichoepitheliomas were immunoreactive with more than 80% of the cells stained, whereas all 14 morphoeic BCCs were PHLDA1-negative with the exception of ulcerated tumours. In the latter, the tumour islands close to the ulcer were PHLDA1-positive whereas the deeper located tumour portions remained immunonegative. PHLDA 1 was prominently expressed in the hair follicle bulge of terminal and vellus hair follicles. CONCLUSIONS: The hair follicle bulge marker PHLDA1 differentiates between desmoplastic trichoepitheliomas and nonulcerated examples of morphoeic BCCs. We suggest incorporating PHLDA1 in the diagnostic work-up of difficult to differentiate basaloid tumours. PMID- 20846313 TI - Legal claims in English dermatological practice. PMID- 20846312 TI - Endoplasmic reticulum Ca2+ depletion activates XBP1 and controls terminal differentiation in keratinocytes and epidermis. AB - BACKGROUND: Endoplasmic reticulum (ER) Ca(2+) depletion, previously shown to signal pathological stress responses, has more recently been found also to trigger homeostatic physiological processes such as differentiation. In keratinocytes and epidermis, terminal differentiation and barrier repair require physiological apoptosis and differentiation, as evidenced by protein synthesis, caspase 14 expression, lipid secretion and stratum corneum (SC) formation. OBJECTIVES: To investigate the role of Ca(2+) depletion-induced ER stress in keratinocyte differentiation and barrier repair in vivo and in cell culture. METHODS: The SERCA2 Ca(2+) pump inhibitor thapsigargin (TG) was used to deplete ER calcium both in cultured keratinocytes and in mice. Levels of the ER stress factor XBP1, loricrin, caspase 14, lipid synthesis and intracellular Ca(2+) were compared after both TG treatment and barrier abrogation. RESULTS: We showed that these components of terminal differentiation and barrier repair were signalled by physiological ER stress, via release of stratum granulosum (SG) ER Ca(2+) stores. We first found that keratinocyte and epidermal ER Ca(2+) depletion activated the ER-stress-induced transcription factor XBP1. Next, we demonstrated that external barrier perturbation resulted in both intracellular Ca(2+) emptying and XBP1 activation. Finally, we showed that TG treatment of intact skin did not perturb the permeability barrier, yet stimulated and mimicked the physiological processes of barrier recovery. CONCLUSIONS: This report is the first to quantify and localize ER Ca(2+) loss after barrier perturbation and show that homeostatic processes that restore barrier function in vivo can be reproduced solely by releasing ER Ca(2+), via induction of physiological ER stress. PMID- 20846314 TI - Excessively high bilirubin and exchange transfusion in very low birth weight infants. AB - AIM: To evaluate the performance of exchange transfusion in very low birth weight (VLBW) infants with excessively high serum bilirubin levels. METHODS: A population-based observational study using data collected by the Israel National VLBW Infant Database. The study sample comprised 13,499 infants. Two definitions of excessively high-peak bilirubin levels that might be considered as threshold levels for performance of exchange transfusion were used. First, a bilirubin level of >=15 mg/dL for all infants (PSB-15), and second, incremental bilirubin levels ranging from 12 to 17 mg/dL according to gestational age (PSB-GA). RESULTS: Four hundreds sixty-eight (3.5%) and 1035 infants (7.7%) infants in the PSB-15 and in the PSB-GA groups respectively had peak serum bilirubin levels above thresholds for exchange transfusion. Exchange transfusions were performed in 66 (14.1%) of these infants in the PSB-15 group and 91 (8.8%) in the PSB-GA group. Using logistic regression analysis, peak serum bilirubin was found as an independent factor for performing exchange transfusion. CONCLUSION: Exchange transfusion was performed in only 9-14% of VLBW infants with excessively high bilirubin levels. We speculate that this may be a result of an absence of definitive guidelines or the possible belief that the risks of exchange transfusion outweigh the potential risk of bilirubin-induced neurological injuries. PMID- 20846315 TI - Decisions on pharmacogenomic tests in the USA and Germany. AB - BACKGROUND: With the increase in molecular genetic understanding of disease, diagnostic test development and availability are growing rapidly. This study investigated oncologists' decision making on using pharmacogenomic tests for cancer treatment and examined cross-cultural differences between the USA and Germany. METHODS: Pilot studies revealed that the following cues play a role in decisions on pharmacogemonic tests: stage of cancer, availability of treatment options, cost of the treatment options, severity of side effects of the treatments, therapeutic consequence of the test, cost of the test and guideline recommendation specifying use of the test. All cues were used for designing the main study comprising nine scenarios, for each of which oncologists were asked to decide whether they would order a pharmacogenomic test. RESULTS: On average, US oncologists opted for the test in 6.5 out of the nine scenarios (SE = 0.2), and German oncologists in 5.4 scenarios (SE = 0.2). The majority of oncologists' decisions in both the USA (76.1%) and Germany (64%) were best explained by a simple sequential model (heuristical strategy). In the USA, the information about cost of the test was most influential on the decisions; in Germany it was the guideline recommendation of the test. When the side effects of therapy B were described as being more severe within the scenarios, choices in favour of a non recommended test increased by about 20% within both samples. CONCLUSION: Both US and German oncologists were highly inclined to use pharmacogenomic tests, but differed in what information influenced their decisions - a difference possibly explained by the differences in the health insurance systems. Although many oncologists' heuristical decisions were based on the valid cue of a test's guideline recommendation, an alarming number abandoned it when a therapy had potentially severe side effects. PMID- 20846316 TI - The Postoperative Recovery Profile (PRP) - a multidimensional questionnaire for evaluation of recovery profiles. AB - AIMS AND OBJECTIVES: The previously developed Postoperative Recovery Profile (PRP) questionnaire is intended for self-assessment of general recovery after surgery. The aim of this study was to further evaluate the questionnaire regarding the construct validity and ability to discriminate recovery profiles between groups. Furthermore, the item variables of greatest importance during the progress of recovery were investigated. METHODS: Post-operative recovery was assessed during the period from discharge to 12 months after lower abdominal and orthopaedic surgery. Construct validity was evaluated by comparing the assessments from the PRP questionnaire and a global recovery scale. Recovery profiles of the diagnose groups were displayed by the cumulative proportion recovered participants over time. The importance of item variables was investigated by ranking ordering. RESULTS: A total of 158 patients were included. Support was given for good construct validity. The result showed that 7.6% of all possible pairs were disordered when comparing the assessments from the PRP questionnaire and the global recovery scale. Twelve months after discharge the PRP assessments discriminated significantly the recovery profiles of the abdominal and orthopaedic groups. The variable pain was one of the top five most important issues at each follow-up occasion in both study groups. The importance of the item variables was thereby emphasized. CONCLUSIONS: The PRP questionnaire allows for evaluation of the progress of post-operative recovery, and can be useful to assess patient-reported recovery after surgical treatment both on individual and group levels. Knowledge about recovery profiles can assist clinicians in determining the critical time points for measuring change. PMID- 20846317 TI - Insufficient evidence of benefit: a systematic review of home telemonitoring for COPD. AB - RATIONALE, AIMS AND OBJECTIVES: The evidence to support the effectiveness of home telemonitoring interventions for patients with chronic obstructive pulmonary disease (COPD) is limited, yet there are many efforts made to implement these technologies across health care services. METHODS: A comprehensive search strategy was designed and implemented across 9 electronic databases and 11 European, Australasian and North American telemedicine websites. Included studies had to examine the effectiveness of telemonitoring interventions, clearly defined for the study purposes, for adult patients with COPD. Two researchers independently screened each study prior to inclusion. RESULTS: Two randomized trials and four other evaluations of telemonitoring were included. The studies are typically underpowered, had heterogeneous patient populations and had a lack of detailed intervention descriptions and of the care processes that accompanied telemonitoring. In addition, there were diverse outcome measures and no economic evaluations. The telemonitoring interventions in each study differed widely. Some had an educational element that could itself account for the differences between groups. CONCLUSIONS: Despite these caveats, the study reports are themselves positive about their results. However, given the risk of bias in the design and scale of the evaluations we conclude that the benefit of telemonitoring for COPD is not yet proven and that further work is required before wide-scale implementation be supported. PMID- 20846318 TI - Cost-utility analysis of bevacizumab versus ranibizumab in neovascular age related macular degeneration using a Markov model. AB - OBJECTIVE: To evaluate the cost-effectiveness of intravitreal bevacizumab to ranibizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A cost-utility analysis using a Markov model was performed to evaluate incremental cost-effectiveness ratio [ICER, $US per quality-adjusted life year (QALY) gained] between bevacizumab and ranibizumab from a US payer perspective. Transition probabilities for ranibizumab and bevacizumab were extrapolated from published studies and local institutional data. Utility values, likewise, were obtained from another published study. Mortality rates were determined from the Centers for Disease Control 2003 Life Tables. Resource utilization and total direct costs were estimated using the Centers for Medicare and Medicaid Services and the Veterans Affairs Decision Support System. A hypothetical cohort of 1000 patients was simulated through the model for 20 years. Sensitivity analyses were performed using univariate and probabilistic sensitivity analysis (PSA) on all costs, transition probabilities and utility values. An acceptability curve was generated to illustrate the cost-effectiveness probability of bevacizumab to ranibizumab with increasing willingness-to-pay (WTP). RESULTS: The cost effectiveness ratios (CER) for bevacizumab and ranibizumab were $1405 per QALY and $12,177 per QALY, respectively. The ICER for bevacizumab was dominant compared to ranibizumab. The base-case CER was sensitive to drug costs of the study medications with a breakeven point of $44 for ranibizumab and $2666 for bevacizumab. PSA revealed a 95% probability of bevacizumab being more cost effective than ranibizumab at a WTP of $50,000 per QALY gained. CONCLUSION: Based on a WTP defined at $50,000 per QALY gained, bevacizumab was cost-effective versus ranibizumab 95% of the time because of lower acquisition costs and increased efficacy. PMID- 20846319 TI - Routine outcome monitoring and feedback on physical or mental health status: evidence and theory. AB - OBJECTIVES: Routine Outcome Monitoring (ROM) is an important quality tool for measuring outcome of treatment in health care. The objective of this article is to summarize the evidence base that supports the provision of feedback on ROM results to (mental) health care professionals and patients. Also, some relevant theoretical aspects are considered. METHODS: Literature study (Pubmed, Medline, PsychINFO, Embase Psychiatry, 1975-2009) concerning randomized controlled trials (RTC's) of ROM and feedback on physical or mental health status of patients of all ages. Main search terms were routine outcome monitoring/measurement, feedback, health status measurement, patient reported outcome measures. RESULTS: Included were 52 RCT's concerning ROM and feedback with adult or older patients: of these seven RCT's were exclusively focused on physical health and 45 RCT's (also) on the mental health of the patient, although not always in a mental health care setting or as primary outcome measure. There appears to be a positive impact of ROM on diagnosis and monitoring of treatment, and on communication between patient and therapist. Other results were less clear. There were no published RCT's on this topic with children or adolescents. CONCLUSIONS: ROM appears especially effective for the monitoring of patients who are not doing well in therapy. Further research into this topic and the clinical-and cost effectiveness of ROM is recommended, especially in mental health care for both adults and children. Also, more theory-driven research is needed with relevant conceptualizations such as Feedback Intervention Theory, Therapeutic Assessment. PMID- 20846320 TI - Effect of short-term intensive insulin therapy on quality of life in type 2 diabetes. AB - RATIONALE, AIMS AND OBJECTIVES: Short-term intensive insulin therapy (IIT) early in the course of type 2 diabetes can improve pancreatic beta-cell function and even induce normoglycemia that persists post-therapy. In spite of this benefit, insulin is often delayed until late in the course of disease partly because of its perceived negative impact on quality of life (QOL). Therefore, we sought to examine the effect of early implementation of short-term IIT on patient-reported QOL and treatment satisfaction. METHODS: A total of 34 patients with type 2 diabetes (5.9 +/- 6.6 years duration, on zero to two oral antihyperglycaemic agents) underwent 4-8 weeks of IIT consisting of basal detemir and pre-meal insulin aspart. Patient-reported QOL, treatment satisfaction and symptom distress were assessed at baseline and post-IIT using the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), Diabetes Quality of Life Measure (DQOL), and Diabetes Symptoms Checklist-Revised (DSC-R). RESULTS: There was a significant improvement in glycated haemoglobin post-IIT (mean 6.5% vs. 7%; P < 0.001). All 34 patients tolerated IIT well with no severe hypoglycaemia. Following IIT, the SF-36 showed a significant improvement compared to baseline in reported physical functioning (mean 88.2 vs. 83.3, P = 0.009), general health (69.4 vs. 65.6, P = 0.03), and general mental health (85.2 vs. 82.2, P = 0.04). The DQOL demonstrated a significant improvement in global health perception (P = 0.02), diabetes worry (P = 0.006) and treatment satisfaction (P = 0.007). The DSC-R revealed a significant improvement in the diabetes-related total symptom score (P = 0.01). CONCLUSIONS: Contrary to popular perception, a short course of IIT resulted in significant improvements in QOL and treatment satisfaction, demonstrating the patient acceptability of early insulin therapy. PMID- 20846321 TI - Comparison of the efficacy of three PubMed search filters in finding randomized controlled trials to answer clinical questions. AB - OBJECTIVE: The aim of this study was to compare the performance of three search methods in the retrieval of relevant clinical trials from PubMed to answer specific clinical questions. METHODS: Included studies of a sample of 100 Cochrane reviews which recorded in PubMed were considered as the reference standard. The search queries were formulated based on the systematic review titles. Precision, recall and number of retrieved records for limiting the results to clinical trial publication type, and using sensitive and specific clinical queries filters were compared. The number of keywords, presence of specific names of intervention and syndrome in the search keywords were used in a model to predict the recalls and precisions. RESULTS: The Clinical queries sensitive search strategy retrieved the largest number of records (33) and had the highest recall (41.6%) and lowest precision (4.8%). The presence of specific intervention name was the only significant predictor of all recalls and precisions (P = 0.016). CONCLUSION: The recall and precision of combination of simple clinical search queries and methodological search filters to find clinical trials in various subjects were considerably low. The limit field strategy yielded in higher precision and fewer retrieved records and approximately similar recall, compared with the clinical queries-sensitive strategy. Presence of specific intervention name in the search keywords increased both recall and precision. PMID- 20846322 TI - Tonic GABAergic control of mouse dentate granule cells during postnatal development. AB - The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this 'hippocampal gate' is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABA(A) receptors containing alpha(5)- and delta-subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus. PMID- 20846323 TI - Evidence for oligomerization between GABAB receptors and GIRK channels containing the GIRK1 and GIRK3 subunits. AB - The stimulation of inhibitory neurotransmitter receptors, such as gamma aminobutyric acid type B (GABA(B) ) receptors, activates G protein-gated inwardly rectifying K(+) (GIRK) channels, which influence membrane excitability. There is now evidence suggesting that G protein-coupled receptors and G protein-gated inwardly-rectifying K(+) [GIRK/family 3 of inwardly-rectifying K(+) (Kir3)] channels do not diffuse freely within the plasma membrane, but instead there are direct protein-protein interactions between them. Here, we used bioluminescence resonance energy transfer, co-immunoprecipitation, confocal and electron microscopy techniques to investigate the oligomerization of GABA(B) receptors with GIRK channels containing the GIRK3 subunit, whose contribution to functional channels is still unresolved. Co-expression of GABA(B) receptors and GIRK channels in human embryonic kidney-293 cells in combination with co immunoprecipitation experiments established that the metabotropic receptor forms stable complexes with GIRK channels. Using bioluminescence resonance energy transfer, we have shown that, in living cells under physiological conditions, GABA(B) receptors interact directly with GIRK1/GIRK3 heterotetramers. In addition, we have provided evidence that the receptor-effector complexes are also found in vivo and identified that the cerebellar granule cells are one neuron population where the interaction probably takes place. Altogether, our data show that signalling complexes containing GABA(B) receptors and GIRK channels are formed shortly after biosynthesis, probably in the endoplasmic reticulum and/or endoplasmic reticulum/Golgi apparatus complex, suggesting that this might be a general feature of receptor-effector ion channel signal transduction and supporting a channel-forming role for the GIRK3 subunit. PMID- 20846326 TI - Self-organization of repetitive spike patterns in developing neuronal networks in vitro. AB - The appearance of spontaneous correlated activity is a fundamental feature of developing neuronal networks in vivo and in vitro. To elucidate whether the ontogeny of correlated activity is paralleled by the appearance of specific spike patterns we used a template-matching algorithm to detect repetitive spike patterns in multi-electrode array recordings from cultures of dissociated mouse neocortical neurons between 6 and 15 days in vitro (div). These experiments demonstrated that the number of spiking neurons increased significantly between 6 and 15 div, while a significantly synchronized network activity appeared at 9 div and became the main discharge pattern in the subsequent div. Repetitive spike patterns with a low complexity were first observed at 8 div. The number of repetitive spike patterns in each dataset as well as their complexity and recurrence increased during development in vitro. The number of links between neurons implicated in repetitive spike patterns, as well as their strength, showed a gradual increase during development. About 8% of the spike sequences contributed to more than one repetitive spike patterns and were classified as core patterns. These results demonstrate for the first time that defined neuronal assemblies, as represented by repetitive spike patterns, appear quite early during development in vitro, around the time synchronized network burst become the dominant network pattern. In summary, these findings suggest that dissociated neurons can self-organize into complex neuronal networks that allow reliable flow and processing of neuronal information already during early phases of development. PMID- 20846325 TI - Cytochemical and cytological properties of perineuronal oligodendrocytes in the mouse cortex. AB - Neuronal cell bodies are associated with glial cells collectively referred to as perineuronal satellite cells. One such satellite cell is the perineuronal oligodendrocyte, which is unmyelinating oligodendrocytes attaching to large neurons in various neural regions. However, little is known about their cellular characteristics and function. In this study, we identified perineuronal oligodendrocytes as 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive cells attaching to neuronal perikarya immunostained for microtubule-associated protein 2, and examined their cytochemical and cytological properties in the mouse cerebral cortex. 2',3'-Cyclic nucleotide 3'-phosphodiesterase-positive perineuronal oligodendrocytes were immunonegative to representative glial markers for astrocytes (brain-type lipid binding protein and glial fibrillary acidic protein), microglia (Iba-1) and NG2(+) glia. However, almost all perineuronal oligodendrocytes expressed glia-specific or glia-enriched metabolic enzymes, i.e. the creatine synthetic enzyme S-adenosylmethionine:guanidinoacetate N methyltransferase and L-serine biosynthetic enzyme 3-phosphoglycerate dehydrogenase. As to molecules participating in the glutamate-glutamine cycle, none of the perineuronal oligodendrocytes expressed the plasmalemmal glutamate transporters GLAST and GLT-1, although nearly half of the perineuronal oligodendrocytes were immunopositive for glutamine synthetase. Cytologically, perineuronal oligodendrocytes were mainly distributed in deep cortical layers (layers IV-VI), and attached directly and tightly to neuronal cell bodies, making a long concave impression to the contacting neurons. Interestingly, they attached more to glutamatergic principal neurons than to GABAergic interneurons, and this became evident at postnatal day 14, when the cerebral cortex develops and maturates. These cytochemical and cytological properties suggest that perineuronal oligodendrocytes are so differentiated as to fulfill metabolic support to the associating principal cortical neurons, rather than to regulate their synaptic transmission. PMID- 20846324 TI - Robust tonic GABA currents can inhibit cell firing in mouse newborn neocortical pyramidal cells. AB - Within the hippocampus and neocortex, GABA is considered to be excitatory in early development due to a relatively depolarized Cl(-) reversal potential (E(Cl)). Although the depolarizing nature of synaptic GABAergic events has been well established, it is unknown whether cortical tonic currents mediated by extrasynaptically located GABA(A) receptors (GABA(A) Rs) are also excitatory. Here we examined the development of tonic currents in the neocortex and their effect on neuronal excitability. Mean tonic current, recorded from layer 5 (L5) pyramidal cells of the mouse somatosensory cortex, is robust in newborns [postnatal day (P)2-4] then decreases dramatically by the second postnatal week (P7-10 and P30-40). Pharmacological studies, in combination with Western blot analysis, show that neonatal tonic currents are partially mediated by the GABA(A) R alpha5 subunit, and probably the delta subunit. In newborns, the charge due to tonic current accounts for nearly 100% of the total GABA charge, a contribution that decreases to < 50% in mature tissue. Current clamp recordings show that tonic current contributes to large fluctuations in the membrane potential that may disrupt its stability. Bath application of 5 MUM GABA, to induce tonic currents, markedly decreased cell firing frequency in most recorded cells while increasing it in others. Gramicidin perforated patch recordings show heterogeneity in E(Cl) recorded from P2-5 L5 pyramidal cells. Together, these findings demonstrate that tonic currents activated by low GABA concentrations can dominate GABAergic transmission in newborn neocortical pyramidal cells and that tonic currents can exert heterogeneous effects on neuronal excitability. PMID- 20846327 TI - Individual differences in error monitoring in healthy adults: psychological symptoms and antisocial personality characteristics. AB - Recent studies have investigated the relationship between psychological symptoms and personality traits and error monitoring measured by error-related negativity (ERN) and error positivity (Pe) event-related potential (ERP) components, yet there remains a paucity of studies examining the collective simultaneous effects of psychological symptoms and personality traits on error monitoring. This present study, therefore, examined whether measures of hyperactivity-impulsivity, depression, anxiety and antisocial personality characteristics could collectively account for significant interindividual variability of both ERN and Pe amplitudes, in 29 healthy adults with no known disorders, ages 18-30 years. The bivariate zero-order correlation analyses found that only the anxiety measure was significantly related to both ERN and Pe amplitudes. However, multiple regression analyses that included all four characteristic measures while controlling for number of segments in the ERP average revealed that both depression and antisocial personality characteristics were significant predictors for the ERN amplitudes whereas antisocial personality was the only significant predictor for the Pe amplitude. These findings suggest that psychological symptoms and personality traits are associated with individual variations in error monitoring in healthy adults, and future studies should consider these variables when comparing group difference in error monitoring between adults with and without disabilities. PMID- 20846328 TI - Thalamic projections to the macaque caudal ventrolateral prefrontal areas 45A and 45B. AB - We studied the sources of thalamic projections to the caudal ventrolateral prefrontal areas 45A and 45B, which display markedly distinct cortical connections [M. Gerbella et al. (2010) Cereb. Cortex, 20, 141-168], and compared them with those to area 8/FEF (frontal eye field). Both areas 45A and 45B were the targets of highly predominant projections from the mediodorsal nucleus (MD) and of additional projections, mostly from the magnocellular ventral anterior and the medial pulvinar nucleus. The projection profiles from different MD subdivisions clearly distinguished these two areas from one another and from area 8/FEF. Area 45A was the target of predominant projections from parvicellular MD and of minor, albeit robust, projections from magnocellular MD. The opposite was true for area 45B: magnocellular MD was the major source of projections and parvicellular MD contributed minor, albeit robust, projections. Furthermore, area 45B, but not area 45A, was targeted by robust projections from multiform MD, the principal thalamic nucleus for area 8/FEF. These results provide further evidence for the distinctiveness of areas 45A and 45B, and support the idea that area 45B is affiliated with the frontal oculomotor system, challenging the proposed homology of this area with part of the human language-related area 45 (rostral part of Broca's region). Furthermore, the present data provide evidence for potentially robust trans-thalamic (via magnocellular MD) afferent, as well as direct and reciprocal, amygdaloid connections of areas 45A and 45B, suggesting the contribution of emotional information to the differential role of these two areas in non-spatial information processing. PMID- 20846329 TI - Neuronal mechanism of mirror movements caused by dysfunction of the motor cortex. AB - Mirror movements (MMs) are often observed in hemiplegic patients after stroke, and are supposed to reflect some aspects of their recovery process. Therefore, understanding the neuronal mechanism of MMs is important, but from the currently available evidence in human case studies, the mechanism of MMs has not been clearly understood. Here we found that in monkeys, after reversible inactivation of the right primary motor cortex (M1) by microinjection of muscimol, MMs were induced in the right hand during voluntary grasping with the left hand, which were partially affected by the injection. Using this animal model, we investigated the origin of MMs after dysfunction of the M1. We found the MMs thus induced were completely abolished by additional blockade of the left M1. Electromyogram (EMG) activities in some homonymous muscle pairs in bilateral hands were co-activated. Detailed analysis of EMG activities suggested that the enhanced activation of the left M1, which led to MMs in the right hand, was not directly driven by the activity of the right M1, whose activity was likely to be affected by the injection. Rather, the present finding has suggested that common drive of bilateral M1 from higher-order structures and reduction in commissural inhibition from the affected side concomitantly enhanced the activity of the cortico-motoneuronal pathway of the intact side, and led to the MMs. PMID- 20846330 TI - Genetic variability of the stolbur phytoplasma vmp1 gene in grapevines, bindweeds and vegetables. AB - AIM: Evaluation of the genetic variability of stolbur phytoplasma infecting grapevines, bindweeds and vegetables, collected in different central and southern Italian regions. MATERIALS AND RESULTS: Phytoplasma isolates belonging to stolbur subgroup 16SrXII-A were subjected to molecular characterization by polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP), to investigate two different nonribosomal genes: tuf and vmp1. In grapevines, 32% of samples were infected by tuf-a type and 68% by tuf-b type, with different relative incidences in the regions surveyed. All herbaceous samples (bindweeds, tomato, tobacco, pepper, celery) were infected by tuf-b. The gene vmp1 showed higher polymorphism in grapevines (nine profiles) than herbaceous plants (six) by RFLP analysis, in agreement with nucleotide sequences' analysis and virtual digestions. CONCLUSIONS: The phylogenetic analysis of vmp1 gene sequences supports the RFLP data and demonstrates the accuracy of RFLP for preliminary assessments of genetic diversity of stolbur phytoplasmas and for screening different vmp types. SIGNIFICANCE AND IMPACT OF THE STUDY: Stolbur represents a serious phytosanitary problem in the areas under investigation, owing to heavy economic losses in infected grapevines and vegetables. Molecular information about the complex genotyping of the vmp1 gene provides useful data towards a better understanding of stolbur epidemiology. Moreover, this study clarifies some different vmp1 genotype classifications of stolbur, providing molecular data in comparison with previous investigations. PMID- 20846331 TI - Exopolysaccharides produced by Lactobacillus and Bifidobacterium strains abrogate in vitro the cytotoxic effect of bacterial toxins on eukaryotic cells. AB - AIMS: To evaluate the capability of the exopolysaccharides (EPS) produced by lactobacilli and bifidobacteria from human and dairy origin to antagonize the cytotoxic effect of bacterial toxins. METHODS AND RESULTS: The cytotoxicity of Bacillus cereus extracellular factors on Caco-2 colonocytes in the presence/absence of the EPS was determined by measuring the integrity of the tissue monolayer and the damage to the cell membrane (extracellular lactate dehydrogenase activity). Additionally, the protective effect of EPS against the haemolytic activity of the streptolysin-O was evaluated on rabbit erythrocytes. The EPS produced by Bifidobacterium animalis ssp. lactis A1 and IPLA-R1, Bifidobacterium longum NB667 and Lactobacillus rhamnosus GG were able to counteract the toxic effect of bacterial toxins on the eukaryotic cells at 1mg ml(-1) EPS concentration. The EPS A1 was the most effective in counteracting the effect of B. cereus toxins on colonocytes, even at lower doses (0.5mg ml(-1) ), whereas EPS NB667 elicited the highest haemolysis reduction on erythrocytes. CONCLUSIONS: The production of EPS by lactobacilli and bifidobacteria could antagonize the toxicity of bacterial pathogens, this effect being EPS and biological marker dependent. SIGNIFICANCE AND IMPACT OF THE STUDY: This work allows gaining insight about the mechanisms that probiotics could exert to improve the host health. PMID- 20846332 TI - The growth potential of Escherichia coli O157:H7, Salmonella spp. and Listeria monocytogenes in dairy manure-based compost in a greenhouse setting under different seasons. AB - AIM: The pathogen growth in dairy compost was studied in a greenhouse setting under different seasons. METHODS AND RESULTS: The five-strain mixtures of each Escherichia coli O157:H7, Salmonella spp. and Listeria monocytogenes were inoculated separately into dry compost to yield c.1 log CFU g(-1) . After acclimation at room temperature, the inoculated compost was initially adjusted to moisture levels of 10-50% and then kept in a greenhouse under different seasons. The populations of all three pathogens increased by 2.1-3.9log CFU g(-1) within 3 days in autoclaved compost with initial moisture content of at least 40%. Listeria monocytogenes multiplied up to 2.4 log CFU g(-1) in compost with initial moisture content of 30% and was detected up to 28 days for all seasons, whereas populations of both E. coli O157:H7 and Salmonella increased by c. 1 log in compost with initial moisture content of 30% during winter months only. No pathogen growth in nonautoclaved compost was detected. CONCLUSION: Bacterial species, temperature, light intensity and moisture content affected the growth potential and survival of pathogens in compost when the population of background microflora was low. SIGNIFICANCE AND IMPACT OF THE STUDY: Keeping compost as dry as possible and maintaining certain levels of background microflora may be critical to prevent the growth of pathogens. PMID- 20846333 TI - Characterization of a modified rotating disk reactor for the cultivation of Staphylococcus epidermidis biofilm. AB - AIMS: The purpose of this study was to develop a system that would allow biofilms to be cultivated under strictly defined conditions in terms of dissolved oxygen, fluid shear and to assess whether the method was suitable for the detection of respiratory activity stratification in biofilm samples. METHODS: The system is a modified version a commercially available laboratory biofilm reactor and incorporates a number of features such as the provision of defined levels of dissolved oxygen, constant average shear, enhanced gas-liquid mass transfer, aseptic operation and the ability to remove biofilm for ex situ analysis during or after continuous cultivation. CONCLUSIONS: The system was shown to be effective for the characterization of the effects of dissolved oxygen on a pure culture of Staphylococcus epidermidis. The versatility of the system offers the potential for cultivating pure culture biofilm in defined, controlled conditions and facilitates a range of analyses that can be performed ex situ. SIGNIFICANCE AND IMPACT OF THE STUDY: The ability to provide strict regulation of environmental conditions and enhanced transfer of oxygen to the biofilm during cultivation are important, first because oxygen is known to regulate biofilm development in several micro-organisms and second because many conventional biofilm cultivation systems may not provide adequate oxygen supply to the biofilm. PMID- 20846334 TI - Targeted microarray analysis of stationary phase Escherichia coli O157:H7 subjected to disparate nutrient conditions. AB - AIMS: To determine how stress response and virulence gene expression of stationary phase (SP) Escherichia coli O157:H7 are affected by nutrient levels. METHODS AND RESULTS: A targeted microarray (n=125 genes) was used to determine the impact of nutrient deprivation [15 min in 3-(N-Morpholino)propanesulfonic acid buffer] on SP E. coli O157:H7. In total, 24 genes were significantly affected (>1.5-fold; P <0.05) with 17 induced and seven attenuated. Additionally, 11 genes belonging to significantly affected stress response regulons were significantly induced (P<0.05), though <1.5-fold. Induced genes included global and specific stress response regulators, the mar operon, iron acquisition and virulence genes. In contrast, transcript for major porins and replicative genes were repressed. Comparison of the nutrient deprived transcriptome to that derived from nutrient replenished cells revealed a disparate transcriptome, with 44 genes expressed at significantly elevated levels in nutrient replenished cells, including all queried global and specific stress response regulators and key virulence genes. Genes expressed at elevated levels in nutrient deprived cells were related to sigma(S) . The microarray data were validated by qRT-PCR. CONCLUSIONS: SP E. coli O157:H7 were affected by nutrient deprivation, with both starvation-related and unrelated networks induced, thereby demonstrating how the E. coli O157:H7 stress response transcriptome is fine-tuned to environmental conditions. Further, by comparison of starved cells to cells provided with fresh nutrients, it is clear starved E. coli O157:H7 undergo massive physiological reprogramming dominated initially by stress response induction to adapt to a nutrient rich environment. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrated how sigma(S) -induced SP E. coli O157:H7 remain highly sensitive and adaptable to environmental conditions. Further, by examining how starved cells respond to nutrient-rich conditions, we show preliminary adaptation to a nutrient rich environment is dominated by the induction of diverse stress response networks. Combined, this provides E. coli O157:H7 stress physiology-based knowledge that can be used to design more effective food safety interventions. PMID- 20846335 TI - A comparative study of Taxol production in liquid and solid-state fermentation with Nigrospora sp. a fungus isolated from Taxus globosa. AB - AIMS: To determine in liquid (LF) and solid-state fermentation (SSF) the effect of medium concentration on growth and Taxol produced by Nigrospora sp., a fungus isolated from the Mexican yew. METHODS AND RESULTS: Nigrospora sp. was grown at different concentrations of the base culture medium M1D, i.e. two (2*), four (4*), six (6*) and eight times (8*) the base concentration. The titres of Taxol determined by competitive inhibition enzyme immunoassay increased with increasing medium concentration in LF and SSF but were higher in SSF in every medium concentration. The Taxol produced in SSF and LF with 8* medium was 221 and 142 ng l(-1) . The SSF gave also higher biomass, growth and sugar utilization than LF in every medium. The growth and sugar consumption were modelled by the logistic and the Pirt models, respectively. However, the Luedeking-Piret model was unsuitable for Taxol. CONCLUSIONS: The SSF surpassed LF in terms of Taxol, growth and sugar utilization; thus, it has significant advantages over LF. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on Taxol production by SSF and the first contribution to evaluate the influence of the medium on Taxol production in LF and SSF. PMID- 20846336 TI - Novel compound from Trachyspermum ammi (Ajowan caraway) seeds with antibiofilm and antiadherence activities against Streptococcus mutans: a potential chemotherapeutic agent against dental caries. AB - AIM: The objective of this study was to isolate and characterize the active compound from Trachyspermum ammi seeds, exhibiting antibiofilm activity against Streptococcus mutans, a major causal organism of dental caries. METHODS AND RESULTS: Purification of the active compound from the seeds was performed by silica gel chromatography, and spectroscopic methods (FTIR, NMR and MS) were employed for its identification and structure determination. Antibiofilm and antiadherence activities of the active compound against S. mutans were analysed. Confocal microscopy was performed to visualize the effect of the compound on biofilm structure of S. mutans. Around 50% reduction was observed in adherence at 39.06 MUg ml(-1) and in biofilm at 78.13 MUg ml(-1) . It was found effective against adherent cells of S. mutans, reduced water-insoluble glucan synthesis and inhibited the reduction in pH. Confocal microscopy revealed scattered cells at sub-MIC concentration of the compound, resulting in distorted biofilm architecture in contrast to clustered cells seen in control. CONCLUSION: This study revealed a novel compound, a naphthalene derivative, isolated first time from T. ammi seeds with antibiofilm activity against S. mutans. SIGNIFICANCE AND IMPACT OF THE STUDY: Trachyspermum ammi represents an interesting source of a novel compound, (4aS, 5R, 8aS) 5, 8a-di-1-propyl-octahydronaphthalen-1-(2H)-one, with a great potential to be used as a therapeutic agent against dental caries. PMID- 20846338 TI - A combined luciferase imaging and reverse transcription polymerase chain reaction assay for the study of Leishmania amastigote burden and correlated mouse tissue transcript fluctuations. AB - Laboratory mice display features of bona fide hosts for parasites such as Leishmania major and Leishmania donovani. Characterizing the amastigote population size fluctuations and the mouse transcript abundance accounting for these fluctuations demands the capacity to record in real time and integrate quantitative multiparametric datasets from the host tissues where these processes occur. To this end, two technologies, luciferase-expressing Leishmania imaging and a very sensitive quantitative analysis of both Leishmania and mouse transcripts, were combined. After the inoculation of either L. major or L. donovani, the amastigote population size fluctuations - increase, plateau and reduction - were monitored by bioluminescence. It allowed a limited number of mice to be selected for further analysis of both mouse and amastigote transcripts using the real-time quantitative polymerase chain reaction assay we set up. The illustrative examples displayed in the present analysis highlight a correlation between the transcriptional signatures displayed by mouse tissues with the amastigote burden fluctuations. We argue that these two combined technologies will have the potential to provide further insights on complex phenotypes driven by Leishmania developmental programs in the tissues of the mammal hosts. PMID- 20846337 TI - Passive vs. active touch-induced activity in the developing whisker pathway. AB - The mouse trigeminal (V) system undergoes significant postnatal structural and functional developmental changes. Histological modules (barrelettes, barreloids and barrels) in the brainstem, thalamus and cortex related to actively moved (whisking) tactile hairs (vibrissae) on the face allow detailed studies of development. High-resolution [(3) H]2-deoxyglucose (2DG) emulsion autoradiography with cytochrome oxidase histochemistry was used to analyze neuronal activity changes related to specific whisker modules in the developing and mature mouse V system provoked by passive (experimenter-induced) and active (animal-induced) displacements of a single whisker (D4). We tested the hypothesis that neuronal activity patterns change in relation to the onset of active touch (whisking) on postnatal day (P)14. Quantitative image analyses revealed: (i) on P7, when whisker-like patterns of modules are clear, heightened 2DG activity in all appropriate modules in the brainstem, thalamus and cortex; (ii) on P14, a transitory activity pattern coincident with the emergence of whisking behavior that presages (iii) strong labeling of the spinal V subnucleus interpolaris and barrel cortex produced by single-whisker-mediated active touch in adults and (iv) at all above-listed ages and structures, significant suppression of baseline activity in some modules surrounding those representing the stimulated whisker. Differences in activity patterns before and after the onset of whisking behavior may be caused by neuronal activity induced by whisking, and by strengthening of modulatory projections that alter the activity of subcortical inputs produced by whisking behavior during active touch. PMID- 20846339 TI - Morphology, molecular phenotypes and distribution of neurons in developing human corpus callosum. AB - The aim of this study was to investigate the morphology, molecular phenotypes, distribution and developmental history of interstitial neurons in the human corpus callosum, here defined as intracallosal neurons. We analysed 26 fetuses, three newborns, five infants and children, and eight adults [age range - 15 weeks postconception (PCW) to 59 years] by means of acetylcholinesterase (AChE) histochemistry and immunohistochemistry for neuron markers (MAP2, NeuN, NPY, calretinin and calbindin). We found a heterogeneous neuron population, positioned within the callosal trunk itself (aside from neurons present in the transient midline structures such as callosal sling, septa or subcallosal zone), which was most numerous during the second half of gestation and early postnatal years. We named these cells intracallosal neurons. At 15 PCW, the intracallosal neuron population consisted of poorly differentiated, small fusiform or bipolar, migratory-like MAP2- or calretinin-positive neurons which could be observed until mid-gestation. Later the population comprised morphologically diverse, predominantly well-differentiated MAP2-, NPY-, calbindin- and AChE-positive neurons. The morphological differentiation of intracallosal neurons culminated in the newborns and remained pronounced in infants and children. In the adult brain, the intracallosal neurons were found only sporadically, with small somata and poorly stained dendrites. Thus, intracallosal neurons form part of a transitory neuron population with a developmental peak contemporaneous to the critical period of callosal formation. Therefore, they may be involved in processes such as axon guiding or elongation, withdrawal of exuberant axons, fasciculation, or functional tuning, which occur at that time. PMID- 20846340 TI - Oxidative stress status, clinical outcome, and beta-globin gene cluster haplotypes in pediatric patients with sickle cell disease. AB - OBJECTIVE: To correlate the clinical and hematological features of beta-globin gene haplotypes with the oxidative stress status in pediatric patients with sickle cell disease (SCD). METHODS: A total of 95 patients with SCD and 40 healthy children were studied. The beta-globin cluster, plasma lipid peroxidation (LPO) and plasma nitrite plus nitrate (NOx), and erythrocyte content of glutathione (GSH) and glutathione disulfide (GSSG), and glutathione peroxidase (GPx), reductase (GRd), and superoxide dismutase (SOD) activities were measured. RESULTS: Plasma LPO (P < 0.001) and NOx (P < 0.05) were significantly higher in patients than in controls. In erythrocytes of patients with SCD, the activities of GRd (P < 0.001) and SOD (P < 0.05) were lower, and the GSSG/GSH ratio (P < 0.001) and GPx activity (P < 0.001) were higher than in controls. High LPO levels and low SOD plus GRd activities were associated with increased severity of clinical manifestations, which correspond mainly to patients with Bantu and Benin haplotypes. LPO levels were reduced in patients with high fetal hemoglobin (HbF) levels, whereas the NOx levels and GRd activity tended to increase in this group. CONCLUSION: Our results detected an important oxidative stress in patients with SCD and suggest that at least three redox markers, i.e., LPO, GRd, and SOD, were related with their clinical outcomes. Moreover, a relationship between high HbF and low LPO, and high HbF and high GRd activity and NOx levels were found. PMID- 20846342 TI - Atmospheric nitrogen deposition is associated with elevated phosphorus limitation of lake zooplankton. AB - Here, we present data that for the first time suggests that the effects of atmospheric nitrogen (N) deposition on nutrient limitation extend into the food web. We used a novel and sensitive assay for an enzyme that is over-expressed in animals growing under dietary phosphorus (P) deficiency (alkaline phosphatase activity, APA) to assess the nutritional status of major crustacean zooplankton taxa in lakes across a gradient of atmospheric N deposition in Norway. Lakes receiving high N deposition had suspended organic matter (seston) with significantly elevated carbon:P and N:P ratios, indicative of amplified phytoplankton P limitation. This P limitation appeared to be transferred up the food chain, as the cosmopolitan seston-feeding zooplankton taxa Daphnia and Holopedium had significantly increased APA. These results indicate that N deposition can impair the efficiency of trophic interactions by accentuating stoichiometric food quality constraints in lake food webs. PMID- 20846343 TI - Key innovations within a geographical context in flowering plants: towards resolving Darwin's abominable mystery. AB - Elucidating factors associated with diversification have been attempted in lineages as diverse as birds, mammals and angiosperms, yet has met with limited success. In flowering plants, the ambiguity of associations between traits and diversification has sparked debate since Darwin's description of angiosperm diversification as an 'abominable mystery'. Recent work has found that diversification is often diversity-dependent, suggesting that species richness depends on geographical area available more than on traits or the time available to accumulate species. Here, we undertake phylogenetic generalized least squares analyses that jointly examine the effects of age, ecoregion area and four ecological traits on diversification in 409 angiosperm families. Area explained the most variation, dwarfing the effect of traits and age, suggesting that diversity-dependent diversification is controlled by ecological limits. Within the context of area, however, traits associated with biotic pollination (zygomorphy) exhibited the greatest effect, possibly through the evolution of specialization. PMID- 20846344 TI - Substitution treatment or active intravenous drug use should not be contraindications for antiviral treatment in drug users with chronic hepatitis C. AB - INTRODUCTION AND AIMS: International guidelines and routine clinical practice express concerns about antiviral treatment in intravenous drug users (IDUs). We analysed the effect of IDU and/or substitution therapy on chronic hepatitis C (CHC) treatment adherence and response. PATIENTS AND METHODS: Intravenous drug users with CHC were divided into three groups: (A) patients on a substitution programme; (B) active users; and (C) past IDUs. Patients were treated according to the standard of care and followed by a specialist team. RESULTS: A total of 175 patients (mean age 39.4+/-8.8) were included. One hundred and forty-four (65%) were adherent to therapy (completing treatment and 6 months of follow-up). Twenty-two patients (36%) discontinued because of side effects, 28 (46%) discontinued on their own and 11 (18%) completed treatment but did not present at follow-up. Of 142 patients with available treatment outcome, 99 (69.7%) achieved a sustained virological response (SVR), with no differences among the study groups. Patients with genotypes 2-3 and those who completed the treatment schedule had 2.78-fold (95% CI: 1.3-5.8) and 6.4-fold (95% CI: 2.6-15.6) higher probability of achieving SVR. CONCLUSION: Active use of illicit drugs and/or drug substitution do not affect the treatment outcome in patients with CHC as long as they are closely followed and remain adherent to the treatment. PMID- 20846345 TI - Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. AB - BACKGROUND: The debate concerning the potential remodelling and/or reversibility of cirrhotic lesions and biliary fibrosis is still open. AIMS/METHODS: In this work, we have used the precision-cut liver slice (PCLS) model, which maintains cell-cell and cell-matrix interactions to study, by immunohistochemistry, the behaviour of the different fibrogenic cells, i.e. hepatic stellate cells (HSC) and portal fibroblasts, in cultured (for 1 week) PCLS derived from normal and fibrotic human livers. RESULTS: In normal liver, before and after culture, alpha smooth muscle (SM) actin was present only in the vessel walls. Platelet-derived growth factor (PDGF) receptor-beta was expressed before and after culture by portal fibroblasts, and appeared after culture in HSC. Before culture, CD 34 was not expressed in parenchyma, but appeared after culture in sinusoidal endothelial cells. In cirrhotic lesions, before culture, alpha-SM actin, PDGF receptor-beta and Thy-1 were expressed in septa; after culture, alpha-SM actin expression disappeared but the expression of the PDGF receptor-beta and Thy-1 was maintained. In cholestatic liver specimens, alpha-SM actin, PDGF receptor-beta and Thy-1 expression, which was present before culture in enlarged portal areas, disappeared after culture, and apoptosis was detected. In the parenchyma of both cirrhotic and cholestatic livers, the expression of the PDGF receptor-beta and of CD 34, which was not observed before culture, was present in HSC and sinusoidal endothelial cells, respectively, after culture. CONCLUSIONS: These results indicate that during remodelling of pathological tissues in cultured liver slices, the myofibroblastic cells derived from HSC or from portal fibroblasts show different behaviours, suggesting different mechanisms of activation/deactivation. PMID- 20846346 TI - States of fragility: stabilisation and its implications for humanitarian action. AB - This paper explores the evolution of international stabilisation agendas and their significance for humanitarian action. Stabilisation includes a combination of military, humanitarian, political and economic activities to control, contain and manage areas affected by armed conflict and complex emergencies. Encompassing narrow security objectives and broader peace-building efforts, stabilisation is both a conservative and potentially transformative, comprehensive and long-term agenda. The open-ended approach allows for widely varying interpretations and applications in different circumstances and by different actors with an assortment of implications for humanitarian action. The relationship between the two is highly uncertain and contentious, due not only to the controversies surrounding stabilisation policies, but also to deep-seated ambiguities at the heart of humanitarianism. While humanitarian actors are preoccupied with the growing involvement of the military in the humanitarian sphere, the paper argues that it is trends in the humanitarian-political interface that represent the more fundamental dilemma. PMID- 20846347 TI - 'A tradition of forgetting': stabilisation and humanitarian action in historical perspective. AB - While subject to increasing articulation and institutionalisation, stabilisation is a long-standing concept and practice that has consistently engaged with and, at times, conflicted with varied understandings of humanitarianism and humanitarian action. Reviewing selected historical experiences, including the Philippines (1898-1902), Algeria (1956-62), Vietnam (1967-75) and El Salvador (1980-92), this paper argues that contemporary models of stabilisation build on and repeat mistakes of the past, particularly the overt securitisation of aid and the perception that humanitarian and development actors are able to purchase security effectively. Where current stabilisation differs from its earlier incarnations, as in the introduction of the private sector and incorporation of humanitarian action into war-fighting strategies, the implications are shown to be troubling if not outright disastrous. T his examination of historical experience, which includes many failures and few, if any, successes, raises the likelihood that it is not solely the design or implementation of individual stability operations that require modification but perhaps the entire concept of stabilisation itself. PMID- 20846348 TI - Stabilisation and humanitarian access in a collapsed state: the Somali case. AB - Somalia today is the site of three major threats: the world's worst humanitarian crisis; the longest-running instance of complete state collapse; and a robust jihadist movement with links to Al-Qa'ida. External state-building, counter terrorism and humanitarian policies responding to these threats have worked at cross-purposes. State-building efforts that insist humanitarian relief be channelled through the nascent state in order to build its legitimacy and capacity undermine humanitarian neutrality when the state is a party to a civil war. Counter-terrorism policies that seek to ensure that no aid benefits terrorist groups have the net effect of criminalising relief operations in countries where poor security precludes effective accountability. This paper argues that tensions between stabilisation and humanitarian goals in contemporary Somalia reflect a long history of politicisation of humanitarian operations in the country. PMID- 20846349 TI - Stabilising a victor's peace? Humanitarian action and reconstruction in eastern Sri Lanka. AB - This paper focuses on the 'Sri Lankan model' of counter-insurgency and stabilisation and its implications for humanitarian and development actors. The Sri Lanka case shows that discourses, policies and practices associated with 'stabilisation' are not confined to 'fragile state' contexts in which there is heavy (and often militarised) international engagement--even though exemplars such as Afghanistan and Iraq have tended to dominate debates on this issue. Rather than being a single template, the 'stabilisation agenda' takes on very different guises in different contexts, presenting quite specific challenges to humanitarian and development actors. This is particularly true in settings like Sri Lanka, where there is a strong state, which seeks to make aid 'coherent' with its own vision of a militarily imposed political settlement. Working in such environments involves navigating a highly-charged domestic political arena, shaped by concerns about sovereignty, nationalism and struggles for legitimacy. PMID- 20846350 TI - The United Kingdom's stabilisation model and Afghanistan: the impact on humanitarian actors. AB - 'Stabilisation' has emerged as a powerful policy framework since 2004. The United Kingdom has been at the forefront of states adopting and developing a 'stabilisation' model and has adapted government policy, processes and structures in its efforts to deliver 'stability' in Afghanistan's Helmand Province and Iraq- as well as elsewhere, such as in Nepal and Sudan. The experience acquired in Helmand in particular is likely to shape both future UK approaches and those of other donor states. The paper argues that the UK's model has evolved significantly since 2006, from a reconstruction strategy towards one that is based on supporting host-nation governance arrangements. Consequently, this paper addresses three principal themes: the origins and conceptualisation of the stabilisation discourse (and its relationship with state-building and early recovery concepts); the role of the UK's experience in Helmand in shaping the British approach; and the impact of the stabilisation model on the humanitarian community. PMID- 20846351 TI - Security for whom? Stabilisation and civilian protection in Colombia. AB - This paper focuses on three periods of stabilisation in Colombia: the Alliance for Progress (1961-73) that sought to stem the threat of communist revolution in Latin America; Plan Colombia and President Alvaro Uribe's 'democratic security' policy (2000-07) aimed at defeating the guerrillas and negotiating a settlement with the paramilitaries; and the current 'integrated approach', adopted from 2007, to consolidate more effectively the state's control of its territory.(1) The paper assesses the extent to which these stabilisation efforts have enhanced the protection of civilians and ultimately finds that in all three periods there has been a disconnect between the discourse and the practice of stabilisation. While they have all sought to enhance security, in actual fact, they have privileged the security of the state and its allies at the expense of the effective protection of the civilian population. This has not only led to widespread human rights abuses but also has undermined the long-term stability being pursued. PMID- 20846352 TI - Aid and stability in Pakistan: lessons from the 2005 earthquake response. AB - United States foreign assistance to Pakistan has always been driven by security considerations. By 2010, US counter-terrorism and stabilisation objectives resulted in Pakistan becoming the second largest recipient of US foreign aid globally. Given the policy impact of the assumption that aid promotes US security objectives in Pakistan, there is surprisingly little analysis or evidence of its effectiveness in this regard. This paper helps to address this gap by first reviewing the history and assumptions underpinning current US aid and stabilisation policies. It then uses field research on the 2005 earthquake relief efforts in northern Pakistan to assess the impact of the 'War on Terror' on the humanitarian response. In particular, it examines the assumption of influential US policymakers that humanitarian aid following the earthquake was an effective way to promote US security objectives by 'winning hearts and minds'-an assumption that has been used to justify all subsequent major US foreign aid commitments to Pakistan. PMID- 20846353 TI - Addressing symptoms but not causes: stabilisation and humanitarian action in Timor-Leste. AB - Asia's newest nation--Timor-Leste--has an unenviable track record of two Australian-led military stabilisation missions, five United Nations (UN) missions, and a vast humanitarian and international response over the course of the past decade. Two distinct approaches to stabilisation can be observed on this small half-island. The first is a 'security-first' approach, where development activities are complementary and serve to support security sector assistance, while the second emphasises traditional development activities and institution building as the foundation for a stable country. Whereas these different approaches highlight various interpretations of the underlying problems and the task at hand, efforts aimed at stabilisation have crystallised the challenges of coordinating and integrating activities that are clearly interlinked and interdependent, whether within a UN integrated mission or implemented by bilateral actors. Consequently, the question of whether, or how, to measure progress towards this shared objective has gone largely unaddressed. PMID- 20846354 TI - The effects of stabilisation on humanitarian action in Haiti. AB - Haiti is routinely characterised as an archetypical fragile state. In spite of considerable donor investment in security promotion, real and perceived safety have proven frustratingly elusive. In the years before the devastating earthquake of 12 January 2010, the country's capital, Port-au-Prince, was also the site of considerable experimentation to promote security and stability. T his paper reviews the discourse, practice and outcomes associated with three parallel stabilisation initiatives undertaken in Haiti between 2007 and 2009. Although they shared many similar objectives, the paper describes how these separate interventions mobilised very different approaches. The specific focus is on United States, United Nations and combined Brazilian, Canadian and Norwegian stabilisation efforts and their implications for humanitarian actors, including the International Committee of the Red Cross and Medecins Sans Frontieres. The paper concludes with some reflections on the implications of stabilisation before and after the country's most recent natural disaster. PMID- 20846355 TI - Cutaneous and pulmonary sarcoidosis in a patient with human immunodeficiency virus: a late feature of immune restoration syndrome. PMID- 20846356 TI - Spiny acral hyperkeratosis in coincidence with malignant melanoma. PMID- 20846357 TI - A novel mutation in the connexin 26 gene (GJB2) in a child with clinical and histological features of keratitis-ichthyosis-deafness (KID) syndrome. AB - BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare congenital ectodermal disorder, caused by heterozygous missense mutation in GJB2, encoding the gap junction protein connexin 26. The commonest mutation is the p.Asp50Asn mutation, and only a few other mutations have been described to date. AIM: To report the fatal clinical course and characterize the genetic background of a premature male neonate with the clinical and histological features of KID syndrome. METHODS: Genomic DNA was extracted from peripheral blood and used for PCR amplification of the GJB2 gene. Direct sequencing was used for mutation analysis. RESULTS: The clinical features included hearing impairment, ichthyosiform erythroderma with hyperkeratotic plaques, palmoplantar keratoderma, alopecia of the scalp and eyelashes, and a thick vernix caseosa-like covering of the scalp. On histological analysis, features characteristic of KID syndrome, such as acanthosis and papillomatosis of the epidermis with basket-weave hyperkeratosis, were seen. The skin symptoms were treated successfully with acitretin 0.5 mg/kg. The boy developed intraventricular and intracerebral haemorrhage, leading to hydrocephalus. His condition was further complicated by septicaemia and meningitis caused by infection with extended-spectrum beta lactamase-producing Klebsiella pneumoniae. Severe respiratory failure followed, and the child died at 46 weeks of gestational age (13 weeks postnatally). Sequencing of the GJB2 gene showed that the child was heterozygous for a novel nucleotide change, c.263C>T, in exon 2, leading to a substitution of alanine for valine at position 88 (p.Ala88Val). CONCLUSIONS: This study has identified a new heterozygous de novo mutation in the Cx26 gene (c.263C>T; p.Ala88Val) leading to KID syndrome. PMID- 20846358 TI - The effects of probiotics supplementation timing on an ovalbumin-sensitized rat model. AB - The aim of the present study was to investigate the effect of oral probiotic bacteria administration at different times on ovalbumin-sensitized rats. Brown Norway (BN) rats were orally sensitized with ovalbumin for 6 weeks. Probiotics were administered before the initial sensitization (prevention group) or at the end of sensitization period (treatment group). In whole-course intervention group, probiotics were administered 2 weeks before the initial sensitization until 1 week after the end of sensitization period. Ovalbumin-immunoglobulin E (IgE) level, intestinal barrier function and immune responses were analyzed. The positive control group had a significantly increased ovalbumin-IgE level (P<0.05), impaired intestinal barrier function and skewed T-helper 1 (Th1)/Th2 cytokine balance compared with the negative control group. In probiotics prevention and whole-course intervention groups, the infiltration of inflammatory cells (eosinophil and mast cells) in small intestinal mucosa was significantly lower (P<0.05), and the ratio of cytokine interferon-gamma/interleukin-4 produced by spleen and mesenteric lymph nodes significantly higher (P<0.05) than in the positive control group, which suggested a cytokine profile inclined to Th1. Both probiotics prevention and prebiotics treatment could attenuate food allergic response. Probiotics prevention tends to modulate the immune response, whereas probiotics treatment has a more obvious effect in enhancing intestinal integrity. PMID- 20846359 TI - Metaanalysis of P2X7 gene polymorphisms and tuberculosis susceptibility. AB - Although many case-control studies have investigated the association between P2X7 gene polymorphisms and tuberculosis susceptibility, the interpretation of these data has been difficult due to limited power. As a means of better understanding the link between P2X7 and tuberculosis, a systematic review of the literature was conducted using metaanalysis. This approach provided a quantitative summary estimate on the association between P2X7 and tuberculosis. We searched databases (MEDLINE, PUBMED, and OVID) between January 1998 and July 2010 using the search words 'gene' or 'P2X7' in combination with 'tuberculosis,' performed manual citation searches from relevant original studies and review articles and corresponded with researchers in the field of study. The pooled odds ratios (ORs) for studies examining variations in the P2X7 gene 1513 C and -762 C loci were 1.44 [95% confidence interval (CI) 1.23-1.68; P<0.00001] and 1.01 (95% CI 0.70 1.44; P=0.97), respectively, compared with the 1513 A and -762 T alleles. Polymorphisms at the 1513 locus had a statistically significant association with P2X7 variants and tuberculosis susceptibility, while the -762 locus allele variants were not significantly associated with P2X7 variants and tuberculosis susceptibility. PMID- 20846360 TI - Helicobacter heilmannii can induce gastric lymphoid follicles in mice via a Peyer's patch-independent pathway. AB - Helicobacter heilmannii induces gastric lymphoid follicles in mice. However, the pathogenic mechanisms behind the induction of gastric lymphoid follicles by H. heilmannii infection have not been elucidated. The aim of this study was to investigate the roles of Peyer's patches (PP) in H. heilmannii-induced immune responses and the development of gastric lymphoid follicles. C57BL/6J and PP deficient mice were infected with H. heilmannii, and in addition to histological and immunohistological examinations, the expression levels of cytokines and chemokines in gastric mucosa were investigated. Gastric lymphoid follicle formation and the infiltration of dendritic cells, B cells, and helper T cells were milder in the PP-deficient mice 1 month after infection, but they were similar in both types of mice after 3 months. The mRNA expression levels of tumor necrosis factor alpha and CC chemokine ligand 2 were significantly high in the H. heilmannii-infected groups, and CXC chemokine ligand 13 expression was significantly increased in the infected C57BL/6J wild-type mice 1 month after infection. These results suggest that PP are not essential for the formation and development of gastric lymphoid follicles induced by H. heilmannii infection, although they are involved in the speed of gastric lymphoid follicle formation. PMID- 20846361 TI - Isolation and characterization of a Nocardiopsis sp. from honeybee guts. AB - Although actinomycetes are the plant-associated environmental bacteria best known for producing thousands of antibiotics, their presence in the guts of flower feeding honeybees has rarely been reported. Here, we report on the selective isolation of actinomycetes from the gut microbiota of healthy honeybees, and their inhibitory activity against honeybee indigenous bacteria. More than 70% of the sampled honeybees (N>40) in a season carried at least one CFU of actinomycete. The isolates from bees of one location produced inhibitory bioactivities that were almost exclusively against several bee indigenous Bacillus strains and Gram-positive human pathogens but not Escherichia coli. An antibiotic-producing actinomycete closely related to Nocardiopsis alba was isolated from the guts in every season of the year. A DNA fragment encoding a homologous gene (phzD) involved in phenazine biosynthesis was identified in the isolate. Expression of the phzD detected by reverse transcription-PCR can explain the survival of this organism in anaerobic environments as some redox-active extracellular phenazines are commonly regarded as respiratory electron acceptors. The results raise important questions concerning the roles of the antibiotic producing actinomycetes and the phenazine-like molecules in honeybee guts and honey. PMID- 20846362 TI - From Saccharomyces cerevisiae to Candida glabratain a few easy steps: important adaptations for an opportunistic pathogen. AB - The opportunistic human fungal pathogen Candida glabrata is closely related to Saccharomyces cerevisiae, yet it has evolved to survive within mammalian hosts. Which traits help C. glabrata to adapt to this different environment? Which specific responses are crucial for its survival in the host? The main differences seem to include an extended repertoire of adhesin genes, high drug resistance, an enhanced ability to sustain prolonged starvation and adaptations of the transcriptional wiring of key stress response genes. Here, we discuss the properties of C. glabrata with a focus on the differences to related fungi. PMID- 20846363 TI - Recombinant human follicle-stimulating hormone produces more oocytes with a lower total dose per cycle in assisted reproductive technologies compared with highly purified human menopausal gonadotrophin: a meta-analysis. AB - BACKGROUND: Human menopausal gonadotrophins and recombinant human follicle stimulating hormone are the two main gonadotrophin products utilized for controlled ovarian stimulation in assisted reproductive technologies. In this meta-analysis, the number of oocytes was designated as the most relevant endpoint directly resulting from ovarian stimulation, and therefore where the drug effect may be estimated with the best sensitivity. METHODS: All published randomized controlled trials on ovarian stimulation comparing the two gonadotrophin products were evaluated. Internal validity was determined using Chalmers' validated scale. If trials did not meet the established quality criteria, a sensitivity analysis assessed the stability of the results. The comparison of continuous variables was conducted following the weighted mean difference and the standardized mean difference (Cohen's effect size) with the random model. Given the known relationship of baseline conditions on treatment endpoints, results were adjusted for age, body mass index and type of infertility. RESULTS: Sixteen studies involving 4040 patients were included. Treatment with human menopausal gonadotrophins resulted in fewer oocytes (-1.54; 95% CI: -2.53 to -0.56; P < 0.0001) compared to recombinant human follicle-stimulating hormone. When adjusting for baseline conditions, the mean difference estimate was -2.10 (95% CI: -2.83 to -1.36; P < 0.001). A higher total dose of human menopausal gonadotrophin was necessary (mean difference, 235.46 IU [95% CI: 16.62 to 454.30; P = 0.03]; standardized mean difference, 0.33 [95% CI: 0.08 to 0.58; P = 0.01]). The pregnancy absolute risk difference (RD [hMG-r-hFSH]) for fresh transfers was 3% (P = 0.051), and the relative risk 1.10 (P = 0.06). When adjusted for baseline conditions, the relative risk was 1.04 (P = 0.49) and absolute difference was 0.01 (P = 0.34), respectively. CONCLUSIONS: Because baseline conditions are predictive of outcome, meta-analytic results are more sensitive when these variables are considered. Using an endpoint closely associated with the stimulation period, sufficient sensitivity is achieved to compare gonadotrophin treatments. As the largest meta-analysis published to date on this subject, treatment with human menopausal gonadotrophins is characterized by fewer oocytes and a higher total dose. When considering only fresh transfers, pregnancy rates were similar. PMID- 20846364 TI - Hif1alpha down-regulation is associated with transposition of great arteries in mice treated with a retinoic acid antagonist. AB - BACKGROUND: Congenital heart defect (CHD) account for 25% of all human congenital abnormalities. However, very few CHD-causing genes have been identified so far. A promising approach for the identification of essential cardiac regulators whose mutations may be linked to human CHD, is the molecular and genetic analysis of heart development. With the use of a triple retinoic acid competitive antagonist (BMS189453) we previously developed a mouse model of congenital heart defects (81%), thymic abnormalities (98%) and neural tube defects (20%). D-TGA (D transposition of great arteries) was the most prevalent cardiac defect observed (61%). Recently we were able to partially rescue this abnormal phenotype (CHD were reduced to 64.8%, p = 0.05), by oral administration of folic acid (FA). Now we have performed a microarray analysis in our mouse models to discover genes/transcripts potentially implicated in the pathogenesis of this CHD. RESULTS: We analysed mouse embryos (8.5 dpc) treated with BMS189453 alone and with BMS189453 plus folic acid (FA) by microarray and qRT-PCR. By selecting a fold change (FC) >= +/- 1.5, we detected 447 genes that were differentially expressed in BMS-treated embryos vs. untreated control embryos, while 239 genes were differentially expressed in BMS-treated embryos whose mothers had also received FA supplementation vs. BMS-treated embryos. On the basis of microarray and qRT-PCR results, we further analysed the Hif1alpha gene. In fact Hif1alpha is down-regulated in BMS-treated embryos vs. untreated controls (FCmicro = -1.79; FCqRT-PCR = -1.76; p = 0.005) and its expression level is increased in BMS+FA treated embryos compared to BMS-treated embryos (FCmicro = +1.17; FCqRT-PCR = +1.28: p = 0.005). Immunofluorescence experiments confirmed the under-expression of Hif1alpha protein in BMS-treated embryos compared to untreated and BMS+FA treated embryos and, moreover, we demonstrated that at 8.5 dpc, Hif1alpha is mainly expressed in the embryo heart region. CONCLUSIONS: We propose that Hif1alpha down-regulation in response to blocking retinoic acid binding may contribute to the development of cardiac defects in mouse newborns. In line with our hypothesis, when Hif1alpha expression level is restored (by supplementation of folic acid), a decrement of CHD is found. To the best of our knowledge, this is the first report that links retinoic acid metabolism to Hif1alpha regulation and the development of D-TGA. PMID- 20846365 TI - Repetitive part of the banana (Musa acuminata) genome investigated by low-depth 454 sequencing. AB - BACKGROUND: Bananas and plantains (Musa spp.) are grown in more than a hundred tropical and subtropical countries and provide staple food for hundreds of millions of people. They are seed-sterile crops propagated clonally and this makes them vulnerable to a rapid spread of devastating diseases and at the same time hampers breeding improved cultivars. Although the socio-economic importance of bananas and plantains cannot be overestimated, they remain outside the focus of major research programs. This slows down the study of nuclear genome and the development of molecular tools to facilitate banana improvement. RESULTS: In this work, we report on the first thorough characterization of the repeat component of the banana (M. acuminata cv. 'Calcutta 4') genome. Analysis of almost 100 Mb of sequence data (0.15* genome coverage) permitted partial sequence reconstruction and characterization of repetitive DNA, making up about 30% of the genome. The results showed that the banana repeats are predominantly made of various types of Ty1/copia and Ty3/gypsy retroelements representing 16 and 7% of the genome respectively. On the other hand, DNA transposons were found to be rare. In addition to new families of transposable elements, two new satellite repeats were discovered and found useful as cytogenetic markers. To help in banana sequence annotation, a specific Musa repeat database was created, and its utility was demonstrated by analyzing the repeat composition of 62 genomic BAC clones. CONCLUSION: A low-depth 454 sequencing of banana nuclear genome provided the largest amount of DNA sequence data available until now for Musa and permitted reconstruction of most of the major types of DNA repeats. The information obtained in this study improves the knowledge of the long-range organization of banana chromosomes, and provides sequence resources needed for repeat masking and annotation during the Musa genome sequencing project. It also provides sequence data for isolation of DNA markers to be used in genetic diversity studies and in marker-assisted selection. PMID- 20846366 TI - Acute small bowel obstruction secondary to intestinal endometriosis, an elusive condition: a case report. AB - BACKGROUND: Endometriosis is a benign condition affecting females of reproductive age. Although intestinal endometriosis is common it is rare for the condition to manifest as an acute bowel obstruction secondary to ileocaecal and appendicular endometriosis. This case is important to report as it highlights the diagnostic difficulty this particular condition presents to an emergency surgeon. CASE PRESENTATION: We present the case of a 33 year old female of Asian origin who presented with symptoms and signs of an acute small bowel obstruction. A right hemicolectomy for suspected malignancy was performed with an ileocolic anastomosis. Histological examination demonstrated extensive endometriosis of the appendix and ileocaecal junction. CONCLUSION: Enteric endometriosis should be considered as a differential diagnosis when assessing females of reproductive age with acute small bowel obstruction. A high index of suspicion is required to arrive at a diagnosis of this elusive condition. PMID- 20846367 TI - Radiographic correlates of hallux valgus severity in older people. AB - BACKGROUND: The severity of hallux valgus is easily appreciated by its clinical appearance, however x-ray measurements are also frequently used to evaluate the condition, particularly if surgery is being considered. There have been few large studies that have assessed the validity of these x-ray observations across a wide spectrum of the deformity. In addition, no studies have specifically focused on older people where the progression of the disorder has largely ceased. Therefore, this study aimed to explore relationships between relevant x-ray observations with respect to hallux valgus severity in older people. METHODS: This study utilised 402 x-rays of 201 participants (74 men and 127 women) aged 65 to 94 years. All participants were graded using the Manchester Scale - a simple, validated system to grade the severity of hallux valgus - prior to radiographic assessment. A total of 19 hallux valgus-related x-ray observations were performed on each set of x-rays. These measurements were then correlated with the Manchester Scale scores. RESULTS: Strong, positive correlations were identified between the severity of hallux valgus and the hallux abductus angle, the proximal articular set angle, the sesamoid position and congruency of the first metatarsophalangeal joint. As hallux valgus severity increased, so did the frequency of radiographic osteoarthritis of the first metatarsophalangeal joint and a round first metatarsal head. A strong linear relationship between increased relative length of the first metatarsal and increased severity of hallux valgus was also observed. CONCLUSIONS: Strong associations are evident between the clinical appearance of hallux valgus and a number of hallux valgus-related x-ray observations indicative of structural deformity and joint degeneration. As it is unlikely that metatarsal length increases as a result of hallux valgus deformity, increased length of the first metatarsal relative to the second metatarsal may be a contributing factor to the development and/or progression of hallux valgus. PMID- 20846368 TI - Thrombospondin-4 is a putative tumour-suppressor gene in colorectal cancer that exhibits age-related methylation. AB - BACKGROUND: Thrombospondin-4 (THBS4) is a member of the extracellular calcium binding protein family and is involved in cell adhesion and migration. The aim of this study was to evaluate the potential role of deregulation of THBS4 expression in colorectal carcinogenesis. Of particular interest was the possible silencing of expression by methylation of the CpG island in the gene promoter. METHODS: Fifty-five sporadic colorectal tumours stratified for the CpG Island Methylator Phenotype (CIMP) were studied. Immunohistochemical staining of THBS4 protein was assessed in normal and tumour specimens. Relative levels of THBS4 transcript expression in matched tumours and normal mucosa were also determined by quantitative RT-PCR. Colony forming ability was examined in 8 cell lines made to overexpress THBS4. Aberrant promoter hypermethylation was investigated as a possible mechanism of gene disruption using MethyLight. Methylation was also assessed in the normal colonic tissue of 99 patients, with samples biopsied from four regions along the length of the colon. RESULTS: THBS4 expression was significantly lower in tumour tissue than in matched normal tissue. Immunohistochemical examination demonstrated that THBS4 protein was generally absent from normal epithelial cells and tumours, but was occasionally expressed at low levels in the cytoplasm towards the luminal surface in vesicular structures. Forced THBS4 over-expression caused a 50-60% repression of tumour colony growth in all eight cell lines examined compared to control cell lines. Tumours exhibited significantly higher levels of methylation than matched normal mucosa, and THBS4 methylation correlated with the CpG island methylator phenotype. There was a trend towards decreased gene expression in tumours exhibiting high THBS4 methylation, but the correlation was not significant. THBS4 methylation was detectable in normal mucosal biopsies where it correlated with increasing patient age and negatively with the occurrence of adenomas elsewhere in the colon. CONCLUSIONS: THBS4 shows increased methylation in colorectal cancer, but this is not strongly associated with altered gene expression, either because methylation has not always reached a critical level or because other factors influence THBS4 expression. THBS4 may act as a tumour suppressor gene, demonstrated by its suppression of tumour colony formation in vitro. THBS4 methylation is detectable in normal colonic mucosa and its level may be a biomarker for the occurrence of adenomas and carcinoma. PMID- 20846369 TI - Male partner attendance of skilled antenatal care in peri-urban Gulu district, Northern Uganda. AB - BACKGROUND: Male partner attendance of skilled Antenatal Care (ANC) is beneficial to improving maternal outcomes. This study investigated the level, perceived benefits and factors associated with male partner attendance of skilled ANC in a peri-urban community recovering from two decades of civil conflict. METHODS: This cross-sectional survey used multi-stage sampling in 12 villages of Omoro county to select 331 married male respondents aged 18 years or more, whose female spouses had childbirth within 24 months prior to the survey. A structured questionnaire elicited responses about male partner attendance of ANC during pregnancy at a public health facility as the main outcome variable. Analysis used Generalized Linear Model (GLM) in Stata version 10.0 to obtain Prevalence Risk Ratios (PRR) for association between the binary outcome and independent factors. All factors significant at p < 0.15 and potential confounders were included in the multivariable model. RESULTS: Overall, 65.4% (95%CI; 60.3, 70.5) male partners attended at least one skilled ANC visit. Mean age was 31.9 years [SD 8.2]. Perceived benefits of attending ANC were: HIV screening (74.5%), monitoring foetal growth (34%) and identifying complications during pregnancy (18.9%). Factors independently associated with higher ANC attendance were: knowledge of 3 or more ANC services (adj.PRR 2.77; 95%CI 2.24, 3.42), obtaining health information from facility health workers (adj.PRR 1.14; 95%CI 1.01, 1.29) and if spouse had skilled attendance at last childbirth (adj.PRR 1.31; 95%CI 1.04-1.64). However, factors for low attendance were: male partners intending their spouse to carry another pregnancy (adj.PRR 0.83; 95%CI 0.71, 0.97) and living more than 5 Km from a health facility (adj.PRR 0.83, 95%CI 0.70, 0.98). CONCLUSIONS: Men who were knowledgeable of ANC services, obtained health information from a health worker and whose spouses utilised skilled delivery at last pregnancy were more likely to accompany their spouses at ANC, unlike those who wanted to have more children and lived more than 5 km from the health facility. These findings suggest that empowering male partners with knowledge about ANC services may increase their ANC participation and in turn increase skilled delivery. This strategy may improve maternal health care in post conflict and resource-limited settings. PMID- 20846370 TI - Comparison of human papillomavirus detection between freshly frozen tissue and paraffin embedded tissue of invasive cervical cancer. AB - BACKGROUND: Human Papillomavirus (HPV) detection results comparing paraffin embedded cervical tissue and other cervical specimens have been done with varying degrees of agreement. However, studies comparing freshly frozen specimens and paraffin embedded specimens of invasive cervical carcinomas are lacking. The aim of the study was to compare HPV detection using SPF10 broad-spectrum primers PCR followed by DEIA and genotyping by LiPA25 (version 1) between freshly frozen cervical tissue samples and paraffin embedded blocks of cervical tissue from the same patient. There were 171 pairs of paraffin embedded and freshly frozen samples analyzed from cervical carcinoma cases from Kampala, Uganda. RESULTS: 88.9% (95% CI: 83.2%-93.2%) of paraffin embedded samples were HPV positive compared with 90.1% (95% CI: 84.6%-94.1%) of freshly frozen samples, giving an overall agreement in HPV detection between fresh tissue and paraffin embedded tissue at 86.0% (95% CI: 79.8%-90.8%). Although the proportion of HPV positive cases in freshly frozen tissue was higher than those in paraffin blocks, the difference was not statistically significant (p > 0.05). In both types of tissues, single HPV infections were predominant, with HPV16 accounting for 47% of positive cases. Comparison in the overall agreement, taking into accounts not only positivity in general, but also HPV types, showed a 65% agreement (complete agreement of 59.7%, partial agreement of 5.3%) and complete disagreement of 35.0%. HPV detection in squamous cell carcinomas (SCC) and adenocarcinomas (ADC) was similar in fresh tissue or paraffin blocks (p >= 0.05).p16 immunostaining in samples that had at least one HPV negative results showed that 24 out of 25 cases had an over-expressed pattern. CONCLUSIONS: HPV DNA detection was lower among ADC as compared to SCC. However, such differences were minimized when additional p16 testing was added, suggesting that the technical issues may largely explain the HPV negative cases. PMID- 20846371 TI - Assessing the efficiency and significance of Methylated DNA Immunoprecipitation (MeDIP) assays in using in vitro methylated genomic DNA. AB - BACKGROUND: DNA methylation contributes to the regulation of gene expression during development and cellular differentiation. The recently developed Methylated DNA ImmunoPrecipitation (MeDIP) assay allows a comprehensive analysis of this epigenetic mark at the genomic level in normal and disease-derived cells. However, estimating the efficiency of the MeDIP technique is difficult without previous knowledge of the methylation status of a given cell population. Attempts to circumvent this problem have involved the use of in vitro methylated DNA in parallel to the investigated samples. Taking advantage of this stratagem, we sought to improve the sensitivity of the approach and to assess potential biases resulting from DNA amplification and hybridization procedures using MeDIP samples. FINDINGS: We performed MeDIP assays using in vitro methylated DNA, with or without previous DNA amplification, and hybridization to a human promoter array. We observed that CpG content at gene promoters indeed correlates strongly with the MeDIP signal obtained using in vitro methylated DNA, even when lowering significantly the amount of starting material. In analyzing MeDIP products that were subjected to whole genome amplification (WGA), we also revealed a strong bias against CpG-rich promoters during this amplification procedure, which may potentially affect the significance of the resulting data. CONCLUSION: We illustrate the use of in vitro methylated DNA to assess the efficiency and accuracy of MeDIP procedures. We report that efficient and reproducible genome wide data can be obtained via MeDIP experiments using relatively low amount of starting genomic DNA; and emphasize for the precaution that must be taken in data analysis when an additional DNA amplification step is required. PMID- 20846372 TI - HIV-1 is budded from CD4+ T lymphocytes independently of exosomes. AB - The convergence of HIV-1 budding and exosome biogenesis at late endosomal compartments called multivesicular bodies has fueled the debate on whether HIV-1 is budded from its target cells and transmitted in the form of exosomes. The point of contention appears to primarily derive from the types of target cells in question and lack of a well-defined protocol to separate exosomes from HIV-1. In this study, we adapted and established a simplified protocol to define the relationship between HIV-1 production and exosome biogenesis. Importantly, we took advantage of the newly established protocol to unequivocally show that HIV-1 was produced from CD4+ T lymphocytes Jurkat cells independently of exosomes. Thus, this study not only presents a simplified way to obtain highly purified HIV 1 virions for identification of host proteins packaged into virions, but also provides a technical platform that can be employed to define the relationship between exosome biogenesis and budding of HIV-1 or other viruses and its contributions to viral pathogenesis. PMID- 20846373 TI - Role of protease-activated receptor-2 on cell death and DNA fragmentation in Helicobacter pylori-infected gastric epithelial cells. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection is associated with chronic gastritis, peptic ulceration and gastric carcinoma. Protease-activated receptor-2 (PAR-2), which is activated by trypsin, induced the activation of mitogen activated protein kinases (MAPK), cell proliferation and apoptosis in several cells. Previously, we found that H. pylori induces the expression of PAR-2, which mediates the expression of adhesion molecules integrins in gastric epithelial cells. In the present study, the role of PAR-2 on H. pylori-induced cell death was investigated by determining cell viability, DNA fragmentation, and the activation of MAPK in gastric epithelial AGS cells. METHODS: AGS cells were cultured in the presence of H. pylori transfected with PAR-2 antisense (AS) oligonucleotide (ODN) or treated with a soybean trypsin inhibitor (SBTI). Viable cells and DNA fragmentation were determined by trypan blue exclusion assay and the amount of oligonucleosome-bound DNA, respectively. The activation of MAPK such as extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinases (JNK), was assessed by Western blotting for phospho-specific forms of MAPK. RESULTS: H. pylori-induced cell death and DNA fragmentation augmented in the cells transfected with PAR-2 AS ODN or treated with SBTI. The activation of MAPK, induced by H. pylori, were suppressed by transfection with PAR-2 AS ODN or treatment with SBTI. CONCLUSION: PAR-2, whose expression is induced by H. pylori, may prevent cell death and DNA fragmentation with the activation of MAPK in gastric epithelial cells. PMID- 20846374 TI - Effects of antibacterial mineral leachates on the cellular ultrastructure, morphology, and membrane integrity of Escherichia coli and methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: We have previously identified two mineral mixtures, CB07 and BY07, and their respective aqueous leachates that exhibit in vitro antibacterial activity against a broad spectrum of pathogens. The present study assesses cellular ultrastructure and membrane integrity of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli after exposure to CB07 and BY07 aqueous leachates. METHODS: We used scanning and transmission electron microscopy to evaluate E. coli and MRSA ultrastructure and morphology following exposure to antibacterial leachates. Additionally, we employed Baclight LIVE/DEAD staining and flow cytometry to investigate the cellular membrane as a possible target for antibacterial activity. RESULTS: Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) imaging of E. coli and MRSA revealed intact cells following exposure to antibacterial mineral leachates. TEM images of MRSA showed disruption of the cytoplasmic contents, distorted cell shape, irregular membranes, and distorted septa of dividing cells. TEM images of E. coli exposed to leachates exhibited different patterns of cytoplasmic condensation with respect to the controls and no apparent change in cell envelope structure. Although bactericidal activity of the leachates occurs more rapidly in E. coli than in MRSA, LIVE/DEAD staining demonstrated that the membrane of E. coli remains intact, while the MRSA membrane is permeabilized following exposure to the leachates. CONCLUSIONS: These data suggest that the leachate antibacterial mechanism of action differs for Gram-positive and Gram-negative organisms. Upon antibacterial mineral leachate exposure, structural integrity is retained, however, compromised membrane integrity accounts for bactericidal activity in Gram-positive, but not in Gram-negative cells. PMID- 20846375 TI - The effects of a DTNBP1 gene variant on attention networks: an fMRI study. AB - BACKGROUND: Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers. METHODS: The present event related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention. RESULTS: Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks. CONCLUSIONS: BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network. PMID- 20846377 TI - Morphology of the medial collateral ligament of the knee. AB - BACKGROUND: Quantitative knowledge on the anatomy of the medial collateral ligament (MCL) is important for treatment of MCL injury and for MCL release during total knee arthroplasty (TKA). The objective of this study was to quantitatively determine the morphology of the MCL of human knees. METHODS: 10 cadaveric human knees were dissected to investigate the MCL anatomy. The specimens were fixed in full extension and this position was maintained during the dissection and morphometric measurements. The outlines of the insertion sites of the superficial MCL (sMCL) and deep MCL (dMCL) were digitized using a 3D digitizing system. RESULTS: The insertion areas of the superficial MCL (sMCL) were 348.6 +/- 42.8 mm2 and 79.7 +/- 17.6 mm2 on the tibia and femur, respectively. The insertion areas of the deep MCL (dMCL) were 63.6 +/- 13.4 mm2 and 71.9 +/- 14.8 mm2 on the tibia and femur, respectively. The distances from the centroids of the tibial and femoral insertions of the sMCL to the tibial and femoral joint line were 62.4 +/- 5.5 mm and 31.1 +/- 4.6 mm, respectively. The distances from the centroids of dMCL in the tibial insertion and the femoral insertion to the tibial and femoral joint line were 6.5 +/- 1.3 mm and 20.5 +/- 4.2 mm, respectively. The distal portion of the dMCL (meniscotibial ligament - MTL) was approximately 1.7 times wider than the proximal portion of the dMCL (meniscofemoral ligament - MFL), whereas the MFL was approximately 3 times longer than the MTL. CONCLUSIONS: The morphologic data on the MCL may provide useful information for improving treatments of MCL-related pathology and performing MCL release during TKA. PMID- 20846376 TI - LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. AB - Inflammation and microglial activation are associated with Alzheimer's disease (AD) pathology. Somewhat surprisingly, injection of a prototypical inflammatory agent, lipopolysaccharide (LPS) into brains of amyloid precursor protein (APP) transgenic mice clears some of the pre-existing amyloid deposits. It is less well understood how brain inflammation modulates tau pathology in the absence of Abeta. These studies examined the role of LPS-induced inflammation on tau pathology. We used transgenic rTg4510 mice, which express the P301L mutation (4R0N TauP301L) and initiate tau pathology between 3-5 months of age. First, we found an age-dependent increase in several markers of microglial activation as these rTg4510 mice aged and tau tangles accumulated. LPS injections into the frontal cortex and hippocampus induced significant activation of CD45 and arginase 1 in rTg4510 and non-transgenic mice. In addition, activation of YM1 by LPS was exaggerated in transgenic mice relative to non-transgenic animals. Expression of Ser199/202 and phospho-tau Ser396 was increased in rTg4510 mice that received LPS compared to vehicle injections. However, the numbers of silver positive neurons, implying presence of more pre- and mature tangles, was not significantly affected by LPS administration. These data suggest that inflammatory stimuli can facilitate tau phosphorylation. Coupled with prior results demonstrating clearance of Abeta by similar LPS injections, these results suggest that brain inflammation may have opposing effects on amyloid and tau pathology, possibly explaining the failures (to date) of anti-inflammatory therapies in AD patients. PMID- 20846378 TI - A case-controlled validation study of a blood-based seven-gene biomarker panel for colorectal cancer in Malaysia. AB - BACKGROUND: Colorectal cancer (CRC) screening is key to CRC prevention and mortality reduction, but patient compliance with CRC screening is low. We previously reported a blood-based test for CRC that utilizes a seven-gene panel of biomarkers. The test is currently utilized clinically in North America for CRC risk stratification in the average-risk North American population in order to improve screening compliance and to enhance clinical decision making. METHODS: In this study, conducted in Malaysia, we evaluated the seven-gene biomarker panel validated in a North American population using blood samples collected from local patients. The panel employs quantitative RT-PCR (qRT-PCR) to analyze gene expression of the seven biomarkers (ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1 and IL2RB) that are differentially expressed in CRC patients as compared with controls. Blood samples from 210 patients (99 CRC and 111 controls) were collected, and total blood RNA was isolated and subjected to quantitative RT-PCR and data analysis. RESULTS: The logistic regression analysis of seven-gene panel has an area under the curve (AUC) of 0.76 (95% confidence interval: 0.70 to 0.82), 77% specificity, 61% sensitivity and 70% accuracy, comparable to the data obtained from the North American investigation of the same biomarker panel. CONCLUSIONS: Our results independently confirm the results of the study conducted in North America and demonstrate the ability of the seven biomarker panel to discriminate CRC from controls in blood samples drawn from a Malaysian population. PMID- 20846379 TI - A case report of a septic hip secondary to a psoas abscess. AB - Psoas abscess was first described by Mynter in 1881. Though rare, its prevalence is increasing with advances in radiology and an increasing ability to accurately diagnose the condition. The symptoms of a psoas abscess can be insidious and nonspecific, and patients often present with a limp, fever, weight loss, and flank or abdominal pain.A psoas abscess can be classified as either primary or secondary depending on the presence or absence of an underlying disease. Primary psoas abscess has become more prevalent in the developed world, especially in immuno-compromised patients.We present the case of a 48 year old man who presented with fever, left hip pain and difficulty weight-bearing. He had a past medical history of chronic renal failure secondary to hypertension. Following laboratory, radiological and microbiological analyses the patient was diagnosed as having a Staphylococcus Aureus hip sepsis secondary to a psoas abscess.Psoas abscess should be included as a differential diagnosis in all patients presenting with hip pain and constitutional symptoms. The case is discussed with reference to the literature. PMID- 20846380 TI - Actualities on molecular pathogenesis and repairing processes of cerebral damage in perinatal hypoxic-ischemic encephalopathy. AB - Hypoxic-ischemic encephalopathy (HIE) is the most important cause of cerebral damage and long-term neurological sequelae in the perinatal period both in term and preterm infant. Hypoxic-ischemic (H-I) injuries develop in two phases: the ischemic phase, dominated by necrotic processes, and the reperfusion phase, dominated by apoptotic processes extending beyond ischemic areas. Due to selective ischemic vulnerability, cerebral damage affects gray matter in term newborns and white matter in preterm newborns with the typical neuropathological aspects of laminar cortical necrosis in the former and periventricular leukomalacia in the latter. This article summarises the principal physiopathological and biochemical processes leading to necrosis and/or apoptosis of neuronal and glial cells and reports recent insights into some endogenous and exogenous cellular and molecular mechanisms aimed at repairing H-I cerebral damage. PMID- 20846381 TI - Molecular cloning and tissue expression of the fatty acid-binding protein (Es FABP) gene in female Chinese mitten crab (Eriocheir sinensis). AB - BACKGROUND: Fatty acid-binding proteins (FABPs), small cytosolic proteins that function in the uptake and utilization of fatty acids, have been extensively studied in higher vertebrates while invertebrates have received little attention despite similar nutritional requirements during periods of reproductive activity. RESULTS: Therefore, a cDNA encoding Eriocheir sinensis FABP (Es-FABP) was cloned based upon EST analysis of a hepatopancreas cDNA library. The full length cDNA was 750 bp and encoded a 131 aa polypeptide that was highly homologous to related genes reported in shrimp. The 9108 bp Es-FABP gene contained four exons that were interrupted by three introns, a genomic organization common among FABP multigene family members in vertebrates. Gene expression analysis, as determined by RT-PCR, revealed the presence of Es-FABP transcripts in hepatopancreas, hemocytes, ovary, gills, muscle, thoracic ganglia, heart, and intestine, but not stomach or eyestalk. Real-time quantitative RT-PCR analysis revealed that Es-FABP expression in ovary, hemocytes, and hepatopancreas was dependent on the status of ovarian development, with peak expression observed in January. CONCLUSIONS: Evidence provided in the present report supports a role of Es-FABP in lipid transport during the period of rapid ovarian growth in E. sinensis, and indirectly confirms the participation of the hepatopancreas, ovary, and hemocytes in lipid nutrient absorption and utilization processes. PMID- 20846382 TI - Predictive performances of lipid accumulation product vs. adiposity measures for cardiovascular diseases and all-cause mortality, 8.6-year follow-up: Tehran lipid and glucose study. AB - BACKGROUND: The body mass index (BMI) is the most commonly used marker for evaluating obesity related risks, however, central obesity measures have been proposed to be more informative. Lipid accumulation product (LAP) is an alternative continuous index of lipid accumulation. We sought in this study to assess if LAP can outperform BMI, waist-to-height-ratio (WHtR), or waist-to-hip ratio (WHpR) in predicting incident cardiovascular disease (CVD) or all-cause mortality. RESULTS: Among participants of Tehran Lipid and Glucose Study, 6,751 participants (2,964 men), aged >= 30 years, were followed for a median of 8.6 years. We observed 274 deaths (men: 168) and 447 CVD events (men: 257). Levels of common CVD risk factors significantly increased across LAP quartiles. Mortality rates did not differ by LAP quartiles. Among participants free of CVD at baseline [6331 (2,741 men)], CVD incident rates per 1000 person increased in a stepwise fashion with increasing LAP quartile values in both men (from 6.9 to 17.0) and women (from 1.3 to 13.0), (Ps < 0.001). Among women, a 1-SD increment in log-LAP conferred a 41% increased risk for CVD (HR 1.41, 95% CIs 1.02-1.96). Among men, however, LAP was not observed to be independently associated with increased risk of CVD; except in a sub-group of men assigned to the lifestyle modification interventions, where, LAP predicted CVD risk. After adjustment with CVD risk factors LAP turned to be inversely associated with risk of all-cause mortality (HR, men 0.74, 95% CIs 0.61-0.90; women, 0.94 95% CIs 0.74-1.20). Among women, magnitude of increased risk of CVD due to LAP was not different from those of anthropometric measures. Among men, however, WHpR was observed to be more strongly associated with increased risk of CVD than was LAP. Among neither men nor women were the predictive performances (discrimination, calibration, goodness of-fit) of the LAP better than those of different anthropometric measures were. CONCLUSIONS: If LAP is to be used for predicting CVD, it might not be superior to WHtR or WHpR. PMID- 20846383 TI - Molecular characterization of hepatitis A virus isolates from environmental and clinical samples in Greece. AB - BACKGROUND: Hepatitis A virus (HAV) strains detected in environmental and clinical samples were analysed to characterize the genotypes of HAV circulating in Greece. Fifty (50) sewage samples were collected from Patras (South-Western Greece) and Alexandroupolis (North-Eastern Greece) from 2007 until 2009, accordingly. The clinical samples derived from an HAV outbreak involved populations from three neighbouring prefectures of North-Eastern Greece (Xanthi, Rodopi, and Evros). HAV particles were detected by nested RT-PCR, using a previously validated set of primers to amplify a 290-bp fragment encompassing the 5'-NTR. Positive HAV samples were confirmed by sequencing of the PCR product. To determine the relatedness between the different isolated sequences, a phylogenetic tree was constructed. RESULTS: Results showed a 100% prevalence of genotype I, and particularly subgenotype IA. The analyzed HAV strains were closely related between them with the percentage of nucleotide identity ranging between 96% and 100%. CONCLUSIONS: The study revealed the major prevalence of circulating strains of IA genotype in Greece and underlined the usefulness of molecular methods for the detection and typing of viruses in both environmental and clinical samples. The present study is, to our knowledge, the first in Greece to depict the simultaneous molecular characterization of HAV strains isolated from both clinical and environmental samples. PMID- 20846385 TI - Mapping Quantitative Trait Loci (QTL) in sheep. III. QTL for carcass composition traits derived from CT scans and aligned with a meta-assembly for sheep and cattle carcass QTL. AB - An (Awassi * Merino) * Merino single-sire backcross family with 165 male offspring was used to map quantitative trait loci (QTL) for body composition traits on a framework map of 189 microsatellite loci across all autosomes. Two cohorts were created from the experimental progeny to represent alternative maturity classes for body composition assessment. Animals were raised under paddock conditions prior to entering the feedlot for a 90-day fattening phase. Body composition traits were derived in vivo at the end of the experiment prior to slaughter at 2 (cohort 1) and 3.5 (cohort 2) years of age, using computed tomography. Image analysis was used to gain accurate predictions for 13 traits describing major fat depots, lean muscle, bone, body proportions and body weight which were used for single- and two-QTL mapping analysis. Using a maximum likelihood approach, three highly significant (LOD >= 3), 15 significant (LOD >= 2), and 11 suggestive QTL (1.7 <= LOD < 2) were detected on eleven chromosomes. Regression analysis confirmed 28 of these QTL and an additional 17 suggestive (P < 0.1) and two significant (P < 0.05) QTL were identified using this method. QTL with pleiotropic effects for two or more tissues were identified on chromosomes 1, 6, 10, 14, 16 and 23. No tissue-specific QTL were identified.A meta-assembly of ovine QTL for carcass traits from this study and public domain sources was performed and compared with a corresponding bovine meta-assembly. The assembly demonstrated QTL with effects on carcass composition in homologous regions on OAR1, 2, 6 and 21. PMID- 20846384 TI - Phosphorylation of HOX11/TLX1 on Threonine-247 during mitosis modulates expression of cyclin B1. AB - BACKGROUND: The HOX11/TLX1 (hereafter referred to as HOX11) homeobox gene was originally identified at a t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T cell acute lymphoblastic leukemias (T-ALLs). We previously reported a predisposition to aberrant spindle assembly checkpoint arrest and heightened incidences of chromosome missegregation in HOX11 overexpressing B lymphocytes following exposure to spindle poisons. The purpose of the current study was to evaluate cell cycle specific expression of HOX11. RESULTS: Cell cycle specific expression studies revealed a phosphorylated form of HOX11 detectable only in the mitotic fraction of cells after treatment with inhibitors to arrest cells at different stages of the cell cycle. Mutational analyses revealed phosphorylation on threonine-247 (Thr247), a conserved amino acid that defines the HOX11 gene family and is integral for the association with DNA binding elements. The effect of HOX11 phosphorylation on its ability to modulate expression of the downstream target, cyclin B1, was tested. A HOX11 mutant in which Thr247 was substituted with glutamic acid (HOX11 T247E), thereby mimicking a constitutively phosphorylated HOX11 isoform, was unable to bind the cyclin B1 promoter or enhance levels of the cyclin B1 protein. Expression of the wildtype HOX11 was associated with accelerated progression through the G2/M phase of the cell cycle, impaired synchronization in prometaphase and reduced apoptosis whereas expression of the HOX11 T247E mutant restored cell cycle kinetics, the spindle checkpoint and apoptosis. CONCLUSIONS: Our results demonstrate that the transcriptional activity of HOX11 is regulated by phosphorylation of Thr247 in a cell cycle-specific manner and that this phosphorylation modulates the expression of the target gene, cyclin B1. Since it is likely that Thr247 phosphorylation regulates DNA binding activity to multiple HOX11 target sequences, it is conceivable that phosphorylation functions to regulate the expression of HOX11 target genes involved in the control of the mitotic spindle checkpoint. PMID- 20846386 TI - Echoviruses are a major cause of aseptic meningitis in infants and young children in Kuwait. AB - BACKGROUND: The etiologic agents of aseptic meningitis (AM) often include human enteroviruses. The role of enteroviruses causing AM in young children was investigated during a 3-year period in Kuwait. RESULTS: Enteroviral RNA was detected in cerebrospinal fluid (CSF) by reverse transcription-PCR and specific genotypes of enteroviruses were identified by direct DNA sequencing of VP4-VP2 region. Enteroviral RNA was detected in 92 of 387 (24%) suspected AM cases and the results were confirmed by hybridization of amplicons with an internal, enterovirus-specific probe. The CSF samples from 75 of 281 (27%) children < 2 years old but only from 3 of 38 (8%) 4-12 year-old children were positive for enteroviral RNA (p = 0.011). Majority of infections in children < 2 years old (49 of 75, 65%) were due to three echoviruses; echovirus type 9 (E9), E11 and E30. Only three other enteroviruses, namely coxsackievirus type B4, coxsackievirus type B5 and enterovirus 71 were detected among AM cases in Kuwait. CONCLUSIONS: Our data show that three types of echoviruses (E9, E11 and E30) are associated with the majority of AM cases in Kuwait. To the best of our knowledge, this is the first report to characterize different enterovirus genotypes associated with AM in the Arabian Gulf region. PMID- 20846387 TI - The purple line as a measure of labour progress: a longitudinal study. AB - BACKGROUND: Vaginal examination (VE) and assessment of the cervix is currently considered to be the gold standard for assessment of labour progress. It is however inherently imprecise with studies indicating an overall accuracy for determining the diameter of the cervix at between 48-56%. Furthermore, VEs can be unpleasant, intrusive and embarrassing for women, and are associated with the risk of introducing infection. In light of increasing concern world wide about the use of routine interventions in labour it may be time to consider alternative, less intrusive means of assessing progress in labour. The presence of a purple line during labour, seen to rise from the anal margin and extend between the buttocks as labour progresses has been reported. The study described in this paper aimed to assess in what percentage of women in labour a purple line was present, clear and measurable and to determine if any relationship existed between the length of the purple line and cervical dilatation and/or station of the fetal head. METHODS: This longitudinal study observed 144 women either in spontaneous labour (n = 112) or for induction of labour (n = 32) from admission through to final VE. Women were examined in the lateral position and midwives recorded the presence or absence of the line throughout labour immediately before each VE. Where present, the length of the line was measured using a disposable tape measure. Within subjects correlation, chi-squared test for independence, and independent samples t-test were used to analyse the data. RESULTS: The purple line was seen at some point in labour for 109 women (76%). There was a medium positive correlation between length of the purple line and cervical dilatation (r = +0.36, n = 66, P = 0.0001) and station of the fetal head (r = +0.42, n = 56, P < 0.0001). CONCLUSIONS: The purple line does exist and there is a medium positive correlation between its length and both cervical dilatation and station of the fetal head. Where the line is present, it may provide a useful guide for clinicians of labour progress along side other measures. Further research is required to assess whether measurement of the line is acceptable to women in labour and also clinicians. PMID- 20846388 TI - Non-variant specific antibody responses to the C-terminal region of merozoite surface protein-1 of Plasmodium falciparum (PfMSP-1(19)) in Iranians exposed to unstable malaria transmission. AB - BACKGROUND: The C-terminal region of Plasmodium falciparum merozoite surface protein-1 (PfMSP-1(19)) is a leading malaria vaccine candidate antigen. However, the existence of different variants of this antigen can limit efficacy of the vaccine development based on this protein. Therefore, in this study, the main objective was to define the frequency of PfMSP-1(19) haplotypes in malaria hypoendemic region of Iran and also to analyse cross-reactive and/or variant specific antibody responses to four PfMSP-1(19) variant forms. METHODS: The PfMSP 1(19) was genotyped in 50 infected subjects with P. falciparum collected during 2006-2008. Four GST-PfMSP-1(19) variants (E/TSR/L, E/TSG/L, E/KNG/F and Q/KNG/L) were produced in Escherichia coli and naturally occurring IgG antibody to these proteins was evaluated in malaria patients' sera (n = 50) using ELISA. To determine the cross-reactivity of antibodies against each PfMSP-1(19) variant in P. falciparum-infected human sera, an antibody depletion assay was performed in eleven corresponding patients' sera. RESULTS: Sequence data of the PfMSP-1(19) revealed five variant forms in which the haplotypes Q/KNG/L and Q/KNG/F were predominant types and the second most frequent haplotype was E/KNG/F. In addition, the prevalence of IgG antibodies to all four PfMSP-1(19) variant forms was equal and high (84%) among the studied patients' sera. Immunodepletion results showed that in Iranian malaria patients, Q/KNG/L variant could induce not only cross-reactive antibody responses to other PfMSP-1(19) variants, but also could induce some specific antibodies that are not able to recognize the E/TSG/L or E/TSR/L variant forms. CONCLUSION: The present findings demonstrated the presence of non-variant specific antibodies to PfMSP-1(19) in Iranian falciparum malaria patients. This data suggests that polymorphism in PfMSP-1(19) is less important and one variant of this antigen, particularly Q/KNG/L, may be sufficient to be included in PfMSP-1(19)-based vaccine. PMID- 20846389 TI - Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma. AB - BACKGROUND: The canonical Wnt signaling is concurrently important for osteoblast differentiation and myeloma cell proliferation. Its activation in myeloma cells and its inhibition in osteoblasts and their progenitors have been identified in the previous studies. Osteoblast progenitors and myeloma cells from a myeloma patient share the same bone marrow (BM) microenvironment, but respond differently to DKK-1 secreted by myeloma cells. The mechanisms remain unclear. METHODS: Primary multiple myeloma (MM) cells were isolated from BM mononuclear cells of 12 MM patients. Human bone marrow stromal cells (SCs) were obtained from BM adherent cells of these MM patients and 10 healthy donors. The mRNA expression levels of DKK-1 binding receptor LRP5/6 and Kremen1/2 (Krm1/2) were analyzed by Real-time PCR in human myeloma cell line (HMCL) RPMI-8226, NCI-H929, U266, LP-1, CZ-1, KM 3, Sko-007, primary myeloma cells and SCs from 12 MM patients and SCs from 10 healthy donors. The binding capability of DKK-1 binding receptors to DKK-1 on primary myeloma cells and SCs was detected by flow cytometry assay. RESULTS: The mRNA expression levels of DKK-1 binding receptor LRP5/6 and Krm1/2 in SCs from patients with MM were significantly higher than those in myeloma cells and in SCs from healthy donors. The binding capability to DKK-1of DKK-1 binding receptors on SCs from MM patients was obviously higher than those on myeloma cells and SCs from healthy donors by flow cytometry assay. Similar to the effects of coculture with rhDKK1, coculture of SCs from healthy donors with myeloma cells in the presence or absence of a Transwell insert did up-regulate SCs' mRNA levels of LRP5/6 and Krm1/2, and down-regulate their mRNA levels of beta-catenin. CONCLUSION: Compared with myeloma cells, the SCs from MM patients overexpress DKK 1 binding receptors LRP5/6 and Krm1/2 in response to DKK-1 secreted by myeloma cells, which results in intracellular Wnt signaling inhibition. Our study provides a novel insight into mechanisms of myeloma associated osteolytic lesions. PMID- 20846390 TI - Effect of allergen-specific immunotherapy with purified Alt a1 on AMP responsiveness, exhaled nitric oxide and exhaled breath condensate pH: a randomized double blind study. AB - BACKGROUND: Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air. METHODS: This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18) or purified natural Alt a1 (n = 22) subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP) and methacholine, exhaled nitric oxide (ENO), exhaled breath condensate (EBC) pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered. RESULTS: The mean (95% CI) allergen-specific IgG4 value for the active treatment group increased from 0.07 MUg/mL (0.03-0.11) at baseline to 1.21 MUg/mL (0.69-1.73, P < 0.001) at 6 months and to 1.62 MUg/mL (1.02-2.22, P < 0.001) at 12 months of treatment. In the placebo group, IgG4 value increased nonsignificantly from 0.09 MUg/mL (0.06 0.12) at baseline to 0.13 MUg/mL (0.07-0.18) at 6 months and to 0.11 MUg/mL (0.07 0.15) at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P < 0.001) and at 12 months of treatment (P < 0.0001). However, changes in AMP and methacholine responsiveness, ENO and EBC pH levels were not significantly different between treatment groups. The overall incidence of adverse events was comparable between the treatment groups. CONCLUSION: Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy induced increase in IgG4 levels and its effect on airway responsiveness and inflammation. PMID- 20846391 TI - Overexpression of sphingosine kinase 1 is associated with salivary gland carcinoma progression and might be a novel predictive marker for adjuvant therapy. AB - BACKGROUND: Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC. METHODS: The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations. RESULTS: SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (P = 0.005), T classification (P = 0.017), N classification (P = 0.009), M classification (P = 0.002), and pathological differentiation (P = 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients. CONCLUSIONS: Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients. PMID- 20846392 TI - Fully automated system for the quantification of human osteoarthritic knee joint effusion volume using magnetic resonance imaging. AB - INTRODUCTION: Joint effusion is frequently associated with osteoarthritis (OA) flare-up and is an important marker of therapeutic response. This study aimed at developing and validating a fully automated system based on magnetic resonance imaging (MRI) for the quantification of joint effusion volume in knee OA patients. METHODS: MRI examinations consisted of two axial sequences: a T2 weighted true fast imaging with steady-state precession and a T1-weighted gradient echo. An automated joint effusion volume quantification system using MRI was developed and validated (a) with calibrated phantoms (cylinder and sphere) and effusion from knee OA patients; (b) with assessment by manual quantification; and (c) by direct aspiration. Twenty-five knee OA patients with joint effusion were included in the study. RESULTS: The automated joint effusion volume quantification was developed as a four stage sequencing process: bone segmentation, filtering of unrelated structures, segmentation of joint effusion, and subvoxel volume calculation. Validation experiments revealed excellent coefficients of variation with the calibrated cylinder (1.4%) and sphere (0.8%) phantoms. Comparison of the OA knee joint effusion volume assessed by the developed automated system and by manual quantification was also excellent (r = 0.98; P < 0.0001), as was the comparison with direct aspiration (r = 0.88; P = 0.0008). CONCLUSIONS: The newly developed fully automated MRI-based system provided precise quantification of OA knee joint effusion volume with excellent correlation with data from phantoms, a manual system, and joint aspiration. Such an automated system will be instrumental in improving the reproducibility/reliability of the evaluation of this marker in clinical application. PMID- 20846394 TI - Effects on mitochondrial transcription of manipulating mTERF protein levels in cultured human HEK293 cells. AB - BACKGROUND: Based on its activities in vitro, the mammalian mitochondrial transcription termination factor mTERF has been proposed to regulate mitochondrial transcription by favouring termination at its high-affinity binding immediately downstream of the rDNA segment of mitochondrial DNA, and initiation selectively at the PH1 site of the heavy-strand promoter. This defines an rDNA transcription unit distinct from the 'global' heavy-strand transcription unit initiating at PH2. However, evidence that the relative activities of the two heavy-strand transcription units are modulated by mTERF in vivo is thus far lacking. RESULTS: To test this hypothesis, we engineered human HEK293-derived cells for over-expression or knockdown of mTERF, and measured the steady-state levels of transcripts belonging to different transcription units, namely tRNALeu(UUR) and ND1 mRNA for the PH2 transcription unit, and tRNAPhe plus 12S and 16S rRNA for the PH1 transcription unit. The relative levels of 16S rRNA and ND1 mRNA were the same under all conditions tested, although mTERF knockdown resulted in increased levels of transcripts of 12S rRNA. The amount of tRNAPhe relative to tRNALeu(UUR) was unaffected by mTERF over-expression, altered only slightly by mTERF knockdown, and was unchanged during recovery from ethidium bromide-induced depletion of mitochondrial RNA. mTERF overexpression or knockdown produced a substantial shift (3-5-fold) in the relative abundance of antisense transcripts either side of its high-affinity binding site. CONCLUSIONS: mTERF protein levels materially affect the amount of readthrough transcription on the antisense strand of mtDNA, whilst the effects on sense-strand transcripts are complex, and suggest the influence of compensatory mechanisms. PMID- 20846395 TI - A role for the histone deacetylase HDAC4 in the life-cycle of HIV-1-based vectors. AB - HIV-1 integration is mediated by the HIV-1 integrase protein, which joins 3'-ends of viral DNA to host cell DNA. To complete the integration process, HIV-1 DNA has to be joined to host cell DNA also at the 5'-ends. This process is called post integration repair (PIR). Integration and PIR involve a number of cellular co factors. These proteins exhibit different degrees of involvement in integration and/or PIR. Some are required for efficient integration or PIR. On the other hand, some reduce the efficiency of integration. Finally, some are involved in integration site selection. We have studied the role of the histone deacetylase HDAC4 in these processes. HDAC4 was demonstrated to play a role in both cellular double-strand DNA break repair and transcriptional regulation. We observed that HDAC4 associates with viral DNA in an integrase-dependent manner. Moreover, infection with HIV-1-based vectors induces foci of the HDAC4 protein. The related histone deacetylases, HDAC2 and HDAC6, failed to associate with viral DNA after infection. These data suggest that HDAC4 accumulates at integration sites. Finally, overexpression studies with HDAC4 mutants suggest that HDAC4 may be required for efficient transduction by HIV-1-based vectors in cells that are deficient in other DNA repair proteins. We conclude that HDAC4 is likely involved in PIR. PMID- 20846396 TI - Serum lipoproteins attenuate macrophage activation and Toll-Like Receptor stimulation by bacterial lipoproteins. AB - BACKGROUND: Chlamydia trachomatis was previously shown to express a lipoprotein, the macrophage infectivity potentiator (Mip), exposed at the bacterial surface, and able to stimulate human primary monocytes/macrophages through Toll Like Receptor (TLR)2/TLR1/TLR6, and CD14. In PMA-differentiated THP-1 cells the proinflammatory activity of Mip was significantly higher in the absence than in the presence of serum. The present study aims to investigate the ability of different serum factors to attenuate Mip proinflammatory activity in PMA differentiated THP-1 cells and in primary human differentiated macrophages. The study was also extend to another lipoprotein, the Borrelia burgdorferi outer surface protein (Osp)A. The proinflammatory activity was studied through Tumor Necrosis Factor alpha (TNF-alpha) and Interleukin (IL)-8 release. Finally, TLR1/2 human embryonic kidney-293 (HEK-293) transfected cells were used to test the ability of the serum factors to inhibit Mip and OspA proinflammatory activity. RESULTS: In the absence of any serum and in the presence of 10% delipidated FBS, production of Mip-induced TNF-alpha and IL-8 in PMA-differentiated THP-1 cells were similar whereas they were significantly decreased in the presence of 10% FBS suggesting an inhibiting role of lipids present in FBS. In the presence of 10% human serum, the concentrations of TNF-alpha and IL-8 were 2 to 5 times lower than in the presence of 10% FBS suggesting the presence of more potent inhibitor(s) in human serum than in FBS. Similar results were obtained in primary human differentiated macrophages. Different lipid components of human serum were then tested (total lipoproteins, HDL, LDL, VLDL, triglyceride emulsion, apolipoprotein (apo)A-I, B, E2, and E3). The most efficient inhibitors were LDL, VLDL, and apoB that reduced the mean concentration of TNF-alpha release in Mip induced macrophages to 24, 20, and 2%, respectively (p < 0.0001). These lipid components were also able to prevent TLR1/2 induced activation by Mip, in HEK-293 transfected cells. Similar results were obtained with OspA. CONCLUSIONS: These results demonstrated the ability of serum lipids to attenuate proinflammatory activity of bacterial lipoproteins and suggested that serum lipoproteins interact with acyl chains of the lipid part of bacterial lipoproteins to render it biologically inactive. PMID- 20846397 TI - Overexpressed HDGF as an independent prognostic factor is involved in poor prognosis in Chinese patients with liver cancer. AB - BACKGROUND: Hepatoma-derived growth factor (HDGF) is involved in the hepatocarcinogenesis. In this study, we investigated the HDGF expression in hepatocellular carcinoma (HCC) and its correlation with clinicopathologic features, including the survival of patients with HCC. Furthermore, we examined the biological processes regulated by HDGF during the development of using HepG2 cell line as a model system. METHODS: We used immunohistochemistry to compare HDGF protein expression in HCC and normal liver tissues and further analyze the HDGF protein expression in clinicopathologically characterized 137 HCC cases. We stably knocked down the endogenous expression level of HDGF in HepG2 cells with specific shRNA-expressing lentiviral vector. Following the successful establishment of stable cells, we examined in vitro cell growth by MTT assay, anchorage-independent growth by soft-agar colony formation assay and cell migration/invasion by transwell and boyden chamber assay. And in addition, we also investigated the in vivo tumor growth by xenograft transplantation of HepG2 cells into nude mice. RESULTS: Protein expression level of HDGF was markedly higher in HCC tissues than that in the normal liver tissues(P = 0.011). In addition, high expression of HDGF protein was positively correlated with T classification(p < 0.001), N classification (p < 0.001), and clinical stage (p < 0.001) of HCC patients. Patients with higher HDGF expression showed a significantly shorter overall survival time than did patients with low HDGF expression. Multivariate analysis suggested that HDGF expression might be an independent prognostic indicator(p < 0.001) for the survival of patients with HCC. HDGF-specific shRNA (shHDGF) successfully knocked down its endogenous expression in HepG2 cells. Compared to the parental and control shRNA-transfected (shCtrl) HepG2 cells, the shHDGF cells exhibited significantly reduced in vitro cell growth, anchorage-independent growth, cell migration and invasion (p < 0.05). In vivo, the xenograft transplants from shHDGF cells gave rise to much smaller tumors as compared to those from shCtrl cells. CONCLUSION: High HDGF expression is associated with poor overall survival in patients with HCC. Down regulation of HDGF inhibits the growth, anchorage-independent growth, migration and invasion of HepG2 cells. PMID- 20846398 TI - Protein complex prediction based on k-connected subgraphs in protein interaction network. AB - BACKGROUND: Protein complexes play an important role in cellular mechanisms. Recently, several methods have been presented to predict protein complexes in a protein interaction network. In these methods, a protein complex is predicted as a dense subgraph of protein interactions. However, interactions data are incomplete and a protein complex does not have to be a complete or dense subgraph. RESULTS: We propose a more appropriate protein complex prediction method, CFA, that is based on connectivity number on subgraphs. We evaluate CFA using several protein interaction networks on reference protein complexes in two benchmark data sets (MIPS and Aloy), containing 1142 and 61 known complexes respectively. We compare CFA to some existing protein complex prediction methods (CMC, MCL, PCP and RNSC) in terms of recall and precision. We show that CFA predicts more complexes correctly at a competitive level of precision. CONCLUSIONS: Many real complexes with different connectivity level in protein interaction network can be predicted based on connectivity number. Our CFA program and results are freely available from http://www.bioinf.cs.ipm.ir/softwares/cfa/CFA.rar. PMID- 20846401 TI - Evidence of circadian rhythms in non-photosynthetic bacteria? AB - Examples of circadian rhythms have been described in eukaryotic organisms and in photosynthetic bacteria, but direct proof of their existence in other prokaryotes is limited and has been largely ignored. The aim of this article is to review existing evidence and to present preliminary results that suggest that the heterotrophic bacterium Pseudomonas putida shows regular variations in its growth pattern synchronized with light/darkness cycles. We put forward the hypothesis that circadian regulation of certain processes can take place in non photosynthetic prokaryotes and may represent an adaptative advantage in specific environments. PMID- 20846400 TI - Peroxisome proliferator-activated receptors (PPARs)-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice. AB - BACKGROUND: Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. METHODS: Mice were fed a diet containing 30 en% beef tallow (B diet) for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet). Each group was further divided into two groups which were administered PPARalpha and gamma antagonists or vehicle once a day for three weeks. RESULTS: The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. CONCLUSION: These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils. PMID- 20846399 TI - Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand crosslink repair and low ERCC1-XPF expression. AB - BACKGROUND: Cisplatin based chemotherapy cures over 80% of metastatic testicular germ cell tumours (TGCT). In contrast, almost all other solid cancers in adults are incurable once they have spread beyond the primary site. Cell lines derived from TGCTs are hypersensitive to cisplatin reflecting the clinical response. Earlier findings suggested that a reduced repair capacity might contribute to the cisplatin hypersensitivity of testis tumour cells (TTC), but the critical DNA damage has not been defined. This study was aimed at investigating the formation and repair of intrastrand and interstrand crosslinks (ICLs) induced by cisplatin in TTC and their contribution to TTC hypersensitivity. RESULTS: We observed that repair of intrastrand crosslinks is similar in cisplatin sensitive TTC and resistant bladder cancer cells, whereas repair of ICLs was significantly reduced in TTC. gammaH2AX formation, which serves as a marker of DNA breaks formed in response to ICLs, persisted in cisplatin-treated TTC and correlated with sustained phosphorylation of Chk2 and enhanced PARP-1 cleavage. Expression of the nucleotide excision repair factor ERCC1-XPF, which is implicated in the processing of ICLs, is reduced in TTC. To analyse the causal role of ERCC1-XPF for ICL repair and cisplatin sensitivity, we over-expressed ERCC1-XPF in TTC by transient transfection. Over-expression increased ICL repair and rendered TTC more resistant to cisplatin, which suggests that ERCC1-XPF is rate-limiting for repair of ICLs resulting in the observed cisplatin hypersensitivity of TTC. CONCLUSION: Our data indicate for the first time that the exceptional sensitivity of TTC and, therefore, very likely the curability of TGCT rests on their limited ICL repair due to low level of expression of ERCC1-XPF. PMID- 20846402 TI - Expression and localization of apolipoprotein M in human colorectal tissues. AB - BACKGROUND: It has been well documented that apolipoprotein M (apoM) is principally expressed in the liver and kidney. However we found that there was weak apoM expression in other tissues or organs too, which could not be ignored. In the present study, we therefore examined apoM expression in human colorectal tissues including cancer tissues, cancer adjacent normal tissues, polyp tissues and normal mucosa as well as inflammatory mucosa. METHODS: Tissue samples were collected from patients who underwent surgical resection or endoscopic examination. ApoM mRNA levels were determined by the real-time RT-PCR and apoM protein mass were examined by the immunohistochemistry. RESULTS: ApoM protein can be detected in all colorectal tissues. However, apoM protein mass were significantly lower in the cancer tissues than its matched adjacent normal tissues, polyp tissues, normal mucosa and inflammatory mucosa. In parallel, apoM mRNA levels in the colorectal cancer tissues (0.0536 +/- 0.0131) were also significantly lower than those in their adjacent normal tissues (0.1907 +/- 0.0563) (P = 0.033). Interestingly, apoM mRNA levels in colorectal cancer tissues were statistic significant higher in the patients with lymph node metastasis than the patients without lymph node metastasis (P = 0.008). Patients under Dukes' C and D stages had much higher apoM mRNA levels than patients under Dukes' A and B stages (P = 0.034). CONCLUSION: It is concluded that apoM could also be expressed in human colorectal tissues besides liver and kidney. ApoM mRNA levels in the colorectal cancer tissues were significantly increased in the patients with lymph node metastasis. Whether increased apoM expression in the patients with lymph node metastasis being related to patients' prognosis and the physiopathological importance of apoM expression in colorectal tissues need further investigation. PMID- 20846403 TI - Unravelling the neurophysiological basis of aggression in a fish model. AB - BACKGROUND: Aggression is a near-universal behaviour with substantial influence on and implications for human and animal social systems. The neurophysiological basis of aggression is, however, poorly understood in all species and approaches adopted to study this complex behaviour have often been oversimplified. We applied targeted expression profiling on 40 genes, spanning eight neurological pathways and in four distinct regions of the brain, in combination with behavioural observations and pharmacological manipulations, to screen for regulatory pathways of aggression in the zebrafish (Danio rerio), an animal model in which social rank and aggressiveness tightly correlate. RESULTS: Substantial differences occurred in gene expression profiles between dominant and subordinate males associated with phenotypic differences in aggressiveness and, for the chosen gene set, they occurred mainly in the hypothalamus and telencephalon. The patterns of differentially-expressed genes implied multifactorial control of aggression in zebrafish, including the hypothalamo-neurohypophysial-system, serotonin, somatostatin, dopamine, hypothalamo-pituitary-interrenal, hypothalamo pituitary-gonadal and histamine pathways, and the latter is a novel finding outside mammals. Pharmacological manipulations of various nodes within the hypothalamo-neurohypophysial-system and serotonin pathways supported their functional involvement. We also observed differences in expression profiles in the brains of dominant versus subordinate females that suggested sex-conserved control of aggression. For example, in the HNS pathway, the gene encoding arginine vasotocin (AVT), previously believed specific to male behaviours, was amongst those genes most associated with aggression, and AVT inhibited dominant female aggression, as in males. However, sex-specific differences in the expression profiles also occurred, including differences in aggression-associated tryptophan hydroxylases and estrogen receptors. CONCLUSIONS: Thus, through an integrated approach, combining gene expression profiling, behavioural analyses, and pharmacological manipulations, we identified candidate genes and pathways that appear to play significant roles in regulating aggression in fish. Many of these are novel for non-mammalian systems. We further present a validated system for advancing our understanding of the mechanistic underpinnings of complex behaviours using a fish model. PMID- 20846405 TI - Fitness costs associated with unnecessary virulence factors and life history traits: evolutionary insights from the potato late blight pathogen Phytophthora infestans. AB - BACKGROUND: In gene-for-gene models of plant-pathogen interactions, the existence of fitness costs associated with unnecessary virulence factors still represents an issue, both in evolutionary biology and agricultural sciences. Measuring such costs experimentally has proven difficult, especially in pathogens not readily amenable to genetic transformation, since the creation of isogenic lines differing only by the presence or absence of avirulence genes cannot be achieved in many organisms. Here, we circumvented this difficulty by comparing fitness traits in groups of Phytophthora infestans isolates sharing the same multilocus fingerprint, but differing by their virulence/avirulence spectrum. RESULTS: Fitness was assessed from calculations derived from the basic reproduction number, combining several life history traits (latent period, spore density and lesion growth rate) evaluated on leaflets of the potato cultivar Bintje, which is free of resistance genes. A statistically significant fitness cost was found in isolates virulent to the R10 resistance gene. That cost was due to a lower spore production in virulent isolates; however, the latent period was shorter in virulent isolates. Similar trends, although not statistically significant, were observed for the other genes tested. CONCLUSION: The data likely reflect the adaptive response of the pathogen to the cost associated with virulence. They suggest strong trade-offs between life history traits related to pathogenicity and adaptive biology of pathogens. PMID- 20846404 TI - CPP-ZFN: a potential DNA-targeting anti-malarial drug. AB - BACKGROUND: Multidrug-resistant Plasmodium is of major concern today. Effective vaccines or successful applications of RNAi-based strategies for the treatment of malaria are currently unavailable. An unexplored area in the field of malaria research is the development of DNA-targeting drugs that can specifically interact with parasitic DNA and introduce deleterious changes, leading to loss of vital genome function and parasite death. PRESENTATION OF THE HYPOTHESIS: Advances in the development of zinc finger nuclease (ZFN) with engineered DNA recognition domains allow us to design and develop nuclease of high target sequence specificity with a mega recognition site that typically occurs only once in the genome. Moreover, cell-penetrating peptides (CPP) can cross the cell plasma membrane and deliver conjugated protein, nucleic acid, or any other cargo to the cytoplasm, nucleus, or mitochondria. This article proposes that a drug from the combination of the CPP and ZFN systems can effectively enter the intracellular parasite, introduce deleterious changes in its genome, and eliminate the parasite from the infected cells. TESTING THE HYPOTHESIS: Availability of a DNA-binding motif for more than 45 triplets and its modular nature, with freedom to change number of fingers in a ZFN, makes development of customized ZFN against diverse target DNA sequence of any gene feasible. Since the Plasmodium genome is highly AT rich, there is considerable sequence site diversity even for the structurally and functionally conserved enzymes between Plasmodium and humans. CPP can be used to deliver ZFN to the intracellular nucleus of the parasite. Signal-peptide-based heterologous protein translocation to Plasmodium-infected RBCs (iRBCs) and different Plasmodium organelles have been achieved. With successful fusion of CPP with mitochondrial- and nuclear-targeting peptides, fusion of CPP with 1 more Plasmodium cell membrane translocation peptide seems achievable. IMPLICATIONS OF THE HYPOTHESIS: Targeting of the Plasmodium genome using ZFN has great potential for the development of anti-malarial drugs. It allows the development of a single drug against all malarial infections, including multidrug-resistant strains. Availability of multiple ZFN target sites in a single gene will provide alternative drug target sites to combat the development of resistance in the future. PMID- 20846406 TI - High-risk HPV E5-induced cell fusion: a critical initiating event in the early stage of HPV-associated cervical cancer. AB - BACKGROUND: Cervical cancer is strongly associated with high-risk human papillomavirus (HPV) and viral oncoproteins E5, E6 and E7 can transform cells by various mechanisms. It is proposed that oncogenic virus-induced cell fusion may contribute to oncogenesis if p53 or apoptosis is perturbed simultaneously. Recently, HPV-16 E5 was found to be necessary and sufficient for the formation of tetraploid cells, which are frequently found in precancerous cervical lesions and its formation is strongly associated with HPV state. PRESENTATION OF THE HYPOTHESIS: We propose that high-risk HPV E5-induced cell fusion is a critical initiating event in the early stage of HPV-associated cervical cancer. TESTING THE HYPOTHESIS: Our hypothesis can be tested by comparing the likelihood for colony formation or tumorigenic ability in nude mice between normal HaCaT cells expressing all three oncogenic proteins and E5-induced bi-nucleated HaCaT cells expressing E6 and E7. Moreover, investigating premature chromosome condensation (PCC) in HPV-positive and negative precancerous cervical cells is another way to assess this hypothesis. IMPLICATION OF THE HYPOTHESIS: This viewpoint would change our understanding of the mechanisms by which HPV induces cervical cancer. According to this hypothesis, blocking E5-induced cell fusion is a promising way to prevent the progression of cervical cancer. Additionally, establishment of a role of cell fusion in cervical carcinogenesis is of reference value for understanding the pathogenesis of other virus-associated cancers. PMID- 20846407 TI - "Practical knowledge" and perceptions of antibiotics and antibiotic resistance among drugsellers in Tanzanian private drugstores. AB - BACKGROUND: Studies indicate that antibiotics are sold against regulation and without prescription in private drugstores in rural Tanzania. The objective of the study was to explore and describe antibiotics sale and dispensing practices and link it to drugseller knowledge and perceptions of antibiotics and antibiotic resistance. METHODS: Exit customers of private drugstores in eight districts were interviewed about the drugstore encounter and drugs bought. Drugsellers filled in a questionnaire with closed- and open-ended questions about antibiotics and resistance. Data were analyzed using mixed quantitative and qualitative methods. RESULTS: Of 350 interviewed exit customers, 24% had bought antibiotics. Thirty percent had seen a health worker before coming and almost all of these had a prescription. Antibiotics were dispensed mainly for cough, stomachache, genital complaints and diarrhea but not for malaria or headache. Dispensed drugs were assessed as relevant for the symptoms or disease presented in 83% of all cases and 51% for antibiotics specifically. Non-prescribed drugs were assessed as more relevant than the prescribed. The knowledge level of the drugseller was ranked as high or very high by 75% of the respondents. Seventy-five drugsellers from three districts participated. Seventy-nine percent stated that diseases caused by bacteria can be treated with antibiotics but 24% of these also said that antibiotics can be used for treating viral disease. Most (85%) said that STI can be treated with antibiotics while 1% said the same about headache, 4% general weakness and 3% 'all diseases'. Seventy-two percent had heard of antibiotic resistance. When describing what an antibiotic is, the respondents used six different kinds of keywords. Descriptions of what antibiotic resistance is and how it occurs were quite rational from a biomedical point of view with some exceptions. They gave rise to five categories and one theme: Perceiving antibiotic resistance based on practical experience. CONCLUSIONS: The drugsellers have considerable "practical knowledge" of antibiotics and a perception of antibiotic resistance based on practical experience. In the process of upgrading private drugstores and formalizing the sale of antibiotics from these outlets in resource-constrained settings, their "practical knowledge" as well as their perceptions must be taken into account in order to attain rational dispensing practices. PMID- 20846408 TI - Sigma-2: Multiple sequence alignment of non-coding DNA via an evolutionary model. AB - BACKGROUND: While most multiple sequence alignment programs expect that all or most of their input is known to be homologous, and penalise insertions and deletions, this is not a reasonable assumption for non-coding DNA, which is much less strongly conserved than protein-coding genes. Arguing that the goal of sequence alignment should be the detection of homology and not similarity, we incorporate an evolutionary model into a previously published multiple sequence alignment program for non-coding DNA, Sigma, as a sensitive likelihood-based way to assess the significance of alignments. Version 1 of Sigma was successful in eliminating spurious alignments but exhibited relatively poor sensitivity on synthetic data. Sigma 1 used a p-value (the probability under the "null hypothesis" of non-homology) to assess the significance of alignments, and, optionally, a background model that captured short-range genomic correlations. Sigma version 2, described here, retains these features, but calculates the p value using a sophisticated evolutionary model that we describe here, and also allows for a transition matrix for different substitution rates from and to different nucleotides. Our evolutionary model takes separate account of mutation and fixation, and can be extended to allow for locally differing functional constraints on sequence. RESULTS: We demonstrate that, on real and synthetic data, Sigma-2 significantly outperforms other programs in specificity to genuine homology (that is, it minimises alignment of spuriously similar regions that do not have a common ancestry) while it is now as sensitive as the best current programs. CONCLUSIONS: Comparing these results with an extrapolation of the best results from other available programs, we suggest that conservation rates in intergenic DNA are often significantly over-estimated. It is increasingly important to align non-coding DNA correctly, in regulatory genomics and in the context of whole-genome alignment, and Sigma-2 is an important step in that direction. PMID- 20846409 TI - Effects of small Hsp genes on developmental stability and microenvironmental canalization. AB - BACKGROUND: Progression of development has to be insulated from the damaging impacts of environmental and genetic perturbations to produce highly predictable phenotypes. Molecular chaperones, such as the heat shock proteins (HSPs), are known to buffer various environmental stresses, and are deeply involved in protein homeostasis. These characteristics of HSPs imply that they might affect developmental buffering and canalization. RESULTS: We examined the role of nine Hsp genes using the GAL4/UAS-RNAi system on phenotypic variation of various morphological traits in Drosophila melanogaster. The stability of bristle number, wing size and wing shape was characterized through fluctuating asymmetry (FA) and the coefficient of variation (CV), or among-individual variation. Progeny of the GAL4/Hsp-RNAi crosses tended to have reduced trait means for both wing size and wing shape. Transcriptional knockdown of Hsp67Bc and Hsp22 significantly increased FA of bristle number, while knockdown of Hsp67Ba significantly increased FA and among-individual variation of wing shape but only in males. Suppression of Hsp67Bb expression significantly increased among-individual variation of bristle number. The knockdown of gene expression was confirmed for Hsp67Ba, Hsp67Bc, Hsp22, and Hsp67Bb. Correlation between FA and CV or among individual variation of each trait is weak and not significant except for the case of male wing shape. CONCLUSION: Four small Hsp genes (Hsp22, Hsp67Ba, Hsp67Bb and Hsp67Bc) showed involvement in the processes of morphogenesis and developmental stability. Due to possible different functions in terms of developmental buffering of these small Hsps, phenotypic stability of an organism is probably maintained by multiple mechanisms triggered by different environmental and genetic stresses on different traits. This novel finding may lead to a better understanding of non-Hsp90 molecular mechanisms controlling variability in morphological traits. PMID- 20846410 TI - Painful knee joint after ACL reconstruction using biodegradable interference screws- SPECT/CT a valuable diagnostic tool? A case report. AB - With the presented case we strive to introduce combined single photon emission computerized tomography and conventional computer tomography (SPECT/CT) as new diagnostic imaging modality and illustrate the possible clinical value in patients after ACL reconstruction. We report the case of a painful knee due to a foreign body reaction and delayed degradation of the biodegradable interference screws after ACL reconstruction. The MRI showed an intact ACL graft, a possible tibial cyclops lesion and a patella infera. There was no increased fluid collection within the bone tunnels. The 99mTc-HDP-SPECT/CT clearly identified a highly increased tracer uptake around and within the tibial and femoral tunnels and the patellofemoral joint. On 3D-CT out of the SPECT/CT data the femoral graft attachment was shallow (50% along the Blumensaat's line) and high in the notch. At revision arthroscopy a diffuse hypertrophy of the synovium, scarring of the Hoffa fat pad and a cyclops lesion of the former ACL graft was found. The interference screws were partially degraded and under palpation and pressure a grey fluid-like substance drained into the joint. The interference screws and the ACL graft were removed and an arthrolysis performed.In the case presented it was most likely a combination of improper graft placement, delayed degradation of the interference screws and unknown biological factors. The too shallow and high ACL graft placement might have led to roof impingement, chronic intraarticular inflammation and hence the delayed degradation of the screws.SPECT/CT has facilitated the establishment of diagnosis, process of decision making and further treatment in patients with knee pain after ACL reconstruction. From the combination of structural (tunnel position in 3D-CT) and metabolic information (tracer uptake in SPECT/CT) the patient's cause of the pain was established. PMID- 20846411 TI - Calcium/calmodulin-dependent kinase IV contributes to translation-dependent early synaptic potentiation in the anterior cingulate cortex of adult mice. AB - Calcium/calmodulin-dependent kinase IV (CaMKIV) phosphorylates the major transcription factor, cyclic AMP-responsive element binding protein (CREB), which plays key roles in synaptic plasticity and memory consolidation. Our previous study showed that long-term potentiation (LTP) in the anterior cingulate cortex (ACC) was significantly enhanced in transgenic mice overexpressing CaMKIV. Considering that the CaMKIV-CREB pathway plays a central role in the protein synthesis-dependent LTP, it is possible that upregulation of CaMKIV contributes to enhancement of LTP by promoting protein synthesis. To test this possibility, we examined the effects of transcription and translation inhibitors on synaptic potentiation induced by pairing of synaptic activity with postsynaptic depolarization (paired training) in ACC pyramidal neurons of wild-type and CaMKIV transgenic mice. We found that synaptic potentiation induced by paired training was partially inhibited by transcription or translation inhibitors both in wild type and CaMKIV transgenic mice; the extent of inhibition was markedly larger in the CaMKIV transgenic mice than in the wild-type mice. Biochemical and immunohistochemical studies revealed that CaMKIV was distributed in the membrane, cytosol and nucleus of ACC neurons. Our results reveal in the first time a transcription- and translation-dependent component of early synaptic LTP in adult ACC synapses, and demonstrate that CaMKIV enhances early synaptic potentiation by activating new protein synthesis. PMID- 20846412 TI - Dynamic correlation between CTL response and viral load in primary human immunodeficiency virus-1 infected Koreans. AB - BACKGROUND: HIV-1 specific cytotoxic T lymphocytes (CTLs) have an important role as antiviral effector cells for controlling HIV-1 infection. METHODS: To investigate CTL response during the early stage of HIV infection, we measured immunity-related factors including CD4+ T cell counts, CD8+ T cell counts, HIV-1 RNA viral loads and IFN-gamma secretion according to CTL response in 78 selected primary HIV-1-infected Koreans. RESULTS: The CTL response was strongly induced by HIV-1 specific Gag and Nef peptides (p = 0.016) compared with induction by Tat or Env peptides. These results suggest that the major antiviral factors inducing strong HIV-specific CTL responses are associated with the Gag and Nef viral regions in primary HIV-1 infected Koreans. The relationship between viral load and CTL response showed varying correlations with time following HIV infection. CTL response was inversely correlated with viral loads at preseroconversion stage I (r = -0.224 to -0.33) and changed to a positive correlation at the preseroconversion stage II (r = 0.132 to 0.854). Finally, it changed to an inverse correlation again after seroconversion until a viral set point was established on serological profiling (r = -0.195 to -0.407). CONCLUSIONS: These findings demonstrate a dynamic correlation between viral load and subsequent CTL responses during early HIV infection. PMID- 20846413 TI - A regret theory approach to decision curve analysis: a novel method for eliciting decision makers' preferences and decision-making. AB - BACKGROUND: Decision curve analysis (DCA) has been proposed as an alternative method for evaluation of diagnostic tests, prediction models, and molecular markers. However, DCA is based on expected utility theory, which has been routinely violated by decision makers. Decision-making is governed by intuition (system 1), and analytical, deliberative process (system 2), thus, rational decision-making should reflect both formal principles of rationality and intuition about good decisions. We use the cognitive emotion of regret to serve as a link between systems 1 and 2 and to reformulate DCA. METHODS: First, we analysed a classic decision tree describing three decision alternatives: treat, do not treat, and treat or no treat based on a predictive model. We then computed the expected regret for each of these alternatives as the difference between the utility of the action taken and the utility of the action that, in retrospect, should have been taken. For any pair of strategies, we measure the difference in net expected regret. Finally, we employ the concept of acceptable regret to identify the circumstances under which a potentially wrong strategy is tolerable to a decision-maker. RESULTS: We developed a novel dual visual analog scale to describe the relationship between regret associated with "omissions" (e.g. failure to treat) vs. "commissions" (e.g. treating unnecessary) and decision maker's preferences as expressed in terms of threshold probability. We then proved that the Net Expected Regret Difference, first presented in this paper, is equivalent to net benefits as described in the original DCA. Based on the concept of acceptable regret we identified the circumstances under which a decision maker tolerates a potentially wrong decision and expressed it in terms of probability of disease. CONCLUSIONS: We present a novel method for eliciting decision maker's preferences and an alternative derivation of DCA based on regret theory. Our approach may be intuitively more appealing to a decision-maker, particularly in those clinical situations when the best management option is the one associated with the least amount of regret (e.g. diagnosis and treatment of advanced cancer, etc). PMID- 20846414 TI - Potential negative impacts and low effectiveness in the use of African annual killifish in the biocontrol of aquatic mosquito larvae in temporary water bodies. AB - Commentary and discussion on a recent paper promoting the use of Nothobranchius guentheri, a small African annual fish from the Island of Zanzibar as a tool to control mosquito larvae in temporary bodies of freshwater throughout Africa is presented.Arguments on major points; (1) expected low success of annual fish introductions, (2) low success of mosquito control in the field, (3) ecological threats, and (4) ethical issues are detailed.Despite serious problems with mosquito-borne diseases in tropical Africa and elsewhere, we encourage responsible means of biological control of parasite vectors. We show that effectiveness of Nothobranchius translocations is low (the previous attempts failed), likelihood of effective mosquito larvae control under field condition is negligible and ecological threats from Nothobranchius translocations from within and outside the naturally occurring range are serious. We advocate against the proposed next step of the project, i.e. field trials in Tanzania. PMID- 20846415 TI - Two initial vaccinations with the Bm86-based Gavacplus vaccine against Rhipicephalus (Boophilus) microplus induce similar reproductive suppression to three initial vaccinations under production conditions. AB - BACKGROUND: The cattle tick, Rhipicephalus (Boophilus) microplus, affects livestock production in many regions of the world. Up to now, the widespread use of chemical acaricides has led to the selection of acaricide-resistant ticks and to environmental contamination. Gavacplus is a subunit vaccine based on the recombinant Bm86 tick antigen expressed in yeast, capable to control infestations of R. microplus under controlled and production conditions. The vaccine constitutes the core element of broad control programs against this ectoparasite, in which acquired immunity in cattle to Bm86 is combined with a rational use of acaricides. At present, the conventional vaccine scheme consists of three doses that should be administered at weeks 0, 4 and 7, followed by a booster every six months. RESULTS: In this study we assayed a reduction in the number of the initial doses of Gavacplus, evaluated the time course and the level of bovine anti-Bm86 antibodies elicited, and analyzed the vaccine effect on ticks engorging on immunized cattle under production conditions. Following three different immunization schemes, the bovines developed a strong and specific immune response characterized by elevated anti-Bm86 IgG titers. A reduction in the weight of engorging female ticks, in the weight of the eggs laid and also in R. microplus viable eggs percentage was obtained by using only two doses of Gavacplus administered at weeks 0 and 4, followed by a booster six months later. This reduction did not differ from the results obtained on ticks engorging on cattle immunized at weeks 0, 4 and 7. It was also demonstrated that anti-Bm86 antibody titers over 1:640, measured in bovines immunized at weeks 0 and 4, were sufficient to affect weight and reproductive potential of female ticks as compared with ticks engorging on unvaccinated animals. In addition, no statistically significant differences were detected in the average weight of eggs laid by ticks engorged on immunized cattle that showed anti-Bm86 specific titers in the range of 1:640 to 1:81920. CONCLUSION: The administration of two initial doses of Gavacplus containing 100 MUg of Bm86 antigen to non-immunized cattle under production conditions is sufficient to affect the weight and the reproductive capacity of R. microplus engorging females. According to these results, cattle herds' manipulation and vaccine costs could be potentially reduced with a positive impact on the implementation of integrated control programs against R. microplus. PMID- 20846416 TI - Co-expression of nuclear and cytoplasmic HMGB1 is inversely associated with infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer. AB - BACKGROUND: The intratumoral infiltration of T cells, especially memory T cells, is associated with a favorable prognosis in early colorectal cancers. However, the mechanism underlying this process remains elusive. This study examined whether high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) molecule, is involved in the infiltration of T cells and disease progression in locally advanced colon cancer. METHODS: Seventy-two cases of pathologically-confirmed specimens were obtained from patients with stage IIIB (T3N1M0) colon cancer who underwent radical resection between January 1999 and May 2002 at the Cancer Center of Sun Yat-Sen University. The density of tumor infiltrating lymphocytes (TILs) within the tumor tissue and the expression of HMGB1 in the cancer cells were examined via immunohistochemical analysis. The phenotype of CD45RO+ cells was confirmed using a flow cytometric assay. The association between HMGB1 expression, the density of TILs, and the 5-year survival rate were analyzed. RESULTS: The density of CD45RO+ T cells within the tumor was independently prognostic, although a higher density of CD3+ T cells was also associated with a favorable prognosis. More importantly, the expression of HMGB1 was observed in both the nucleus and the cytoplasm (co-expression pattern) in a subset of colon cancer tissues, whereas nuclear-only expression of HMGB1 (nuclear expression pattern) existed in most of the cancer tissues and normal mucosa. The co-expression pattern of HMGB1 in colon cancer cells was inversely associated with the infiltration of both CD3+ and CD45RO+ T cells and 5-year survival rates. CONCLUSIONS: This study revealed that the co-expression of HMGB1 is inversely associated with the infiltration of CD45RO+ T cells and prognosis in patients with stage IIIB colon cancer, indicating that the distribution patterns of HMGB1 might contribute to the progression of colon cancer via modulation of the local immune response. PMID- 20846417 TI - Assessing changes in vascular permeability in a hamster model of viral hemorrhagic fever. AB - BACKGROUND: A number of RNA viruses cause viral hemorrhagic fever (VHF), in which proinflammatory mediators released from infected cells induce increased permeability of the endothelial lining of blood vessels, leading to loss of plasma volume, hypotension, multi-organ failure, shock and death. The optimal treatment of VHF should therefore include both the use of antiviral drugs to inhibit viral replication and measures to prevent or correct changes in vascular function. Although rodent models have been used to evaluate treatments for increased vascular permeability (VP) in bacterial sepsis, such studies have not been performed for VHF. RESULTS: Here, we use an established model of Pichinde virus infection of hamsters to demonstrate how changes in VP can be detected by intravenous infusion of Evans blue dye (EBD), and compare those measurements to changes in hematocrit, serum albumin concentration and serum levels of proinflammatory mediators. We show that EBD injected into sick animals in the late stage of infection is rapidly sequestered in the viscera, while in healthy animals it remains within the plasma, causing the skin to turn a marked blue color. This test could be used in live animals to detect increased VP and to assess the ability of antiviral drugs and vasoactive compounds to prevent its onset. Finally, we describe a multiplexed assay to measure levels of serum factors during the course of Pichinde arenavirus infection and demonstrate that viremia and subsequent increase in white blood cell counts precede the elaboration of inflammatory mediators, which is followed by increased VP and death. CONCLUSIONS: This level of model characterization is essential to the evaluation of novel interventions designed to control the effects of virus induced hypercytokinemia on host vascular function in VHF, which could lead to improved survival. PMID- 20846418 TI - Change in brain activity through virtual reality-based brain-machine communication in a chronic tetraplegic subject with muscular dystrophy. AB - BACKGROUND: For severely paralyzed people, a brain-computer interface (BCI) provides a way of re-establishing communication. Although subjects with muscular dystrophy (MD) appear to be potential BCI users, the actual long-term effects of BCI use on brain activities in MD subjects have yet to be clarified. To investigate these effects, we followed BCI use by a chronic tetraplegic subject with MD over 5 months. The topographic changes in an electroencephalogram (EEG) after long-term use of the virtual reality (VR)-based BCI were also assessed. Our originally developed BCI system was used to classify an EEG recorded over the sensorimotor cortex in real time and estimate the user's motor intention (MI) in 3 different limb movements: feet, left hand, and right hand. An avatar in the internet-based VR was controlled in accordance with the results of the EEG classification by the BCI. The subject was trained to control his avatar via the BCI by strolling in the VR for 1 hour a day and then continued the same training twice a month at his home. RESULTS: After the training, the error rate of the EEG classification decreased from 40% to 28%. The subject successfully walked around in the VR using only his MI and chatted with other users through a voice-chat function embedded in the internet-based VR. With this improvement in BCI control, event-related desynchronization (ERD) following MI was significantly enhanced (p < 0.01) for feet MI (from -29% to -55%), left-hand MI (from -23% to -42%), and right-hand MI (from -22% to -51%). CONCLUSIONS: These results show that our subject with severe MD was able to learn to control his EEG signal and communicate with other users through use of VR navigation and suggest that an internet-based VR has the potential to provide paralyzed people with the opportunity for easy communication. PMID- 20846419 TI - Knowledge in process? Exploring barriers between epidemiological research and local health policy development. AB - BACKGROUND: In the Netherlands municipalities are legally required to draw up a Local Health Policy Memorandum every four years. This policy memorandum should be based on (local) epidemiological research as performed by the Regional Health Services. However, it is largely unknown if and in what way epidemiological research is used during local policy development. As part of a larger study on knowledge utilization at the local level in The Netherlands, an analytical framework on the use of epidemiological research in local health policy development in the Netherlands is presented here. METHOD: Based on a literature search and a short inventory on experiences from Regional Health Services, we made a description of existing research utilization models and concepts about research utilization. Subsequently we mapped different barriers in research transmission. RESULTS: The interaction model is regarded as the main explanatory model. It acknowledges the interactive and incremental nature of policy development, which takes place in a context and includes diversity within the groups of researchers and policymakers. This fits well in the dynamic and complex setting of local Dutch health policy.For the conceptual framework we propose a network approach, in which we "extend" the interaction model. We not only focus on the one-to-one relation between an individual researcher and policymaker but include interactions between several actors participating in the research and policy process.In this model interaction between actors in the research and the policy network is expected to improve research utilization. Interaction can obstruct or promote four clusters of barriers between research and policy: expectations, transfer issues, acceptance, and interpretation. These elements of interactions and barriers provide an actual explanation of research utilization. Research utilization itself can be measured on the individual level of actors and on a policy process level. CONCLUSION: The developed framework has added value on existing models on research utilization because it emphasizes on the 'logic' of the context of the research and policy networks. The framework will contribute to a better understanding of the impact of epidemiological research in local health policy development, however further operationalisation of the concepts mentioned in the framework remains necessary. PMID- 20846420 TI - Prevalent HBV point mutations and mutation combinations at BCP/preC region and their association with liver disease progression. AB - BACKGROUND: Mutations in the basic core promoter (BCP) and its adjacent precore (preC) region in HBV genome are common in chronic hepatitis B patients. However, the patterns of mutation combinations in these two regions during chronic infection are less understood. This study focused on single base mutations in BCP and preC region and the multi-mutation patterns observed in chronic HBV infection patients. METHODS: Total 192 blood samples of chronic HBV infection patients were included. Direct PCR sequencing on the target region of HBV genome was successfully conducted in 157 samples. The rest 35 samples were analyzed by clone sequencing. Only the nucleotide substitutions with their frequencies no less than 10% were included in multi-mutation analysis with the exception for the polymorphic sites between genotypes B and C. RESULTS: Five high frequency mutations (>=10%) were found in BCP and preC region. Thirteen types of multi mutations in one fragment were observed, among which 3 types were common combinations (>=5%). The top three multi-mutations were A1762T/G1764A (36%), A1762T/G1764A/G1896A (11%) and T1753(A/C)/A1762T/G1764A/G1896A (8%). Patients with multi-mutations in viral genomes (>=3) were more likely to have liver cirrhosis or hepatocellular carcinoma (OR = 3.1, 95% CI: 1.6-6.0, P = 0.001). G1896A mutation seemed to be involved in liver disease progression independent of the patient age (OR = 3.6, 95% CI: 1.5-8.6; P = 0.004). In addition, patients with more viral mutations detected (>=3) were more likely to be HBeAg negative (OR = 2.7, 95% CI: 1.1-6.4; P = 0.027). Moreover, G1776A mutation was shown to contribute to HBeAg negativity in our study (OR = 8.6, 95% CI: 1.2-44.9; P = 0.01). CONCLUSIONS: Patients with advanced liver diseases and with HBeAg negativity more likely have multi-mutations in HBV genomes but with different mutation combination patterns. G1896A mutation appears to be independent of infection history. PMID- 20846422 TI - Normalization of prostate specific antigen in patients treated with intensity modulated radiotherapy for clinically localized prostate cancer. AB - BACKGROUND: The purpose of this study was to determine the expected time to prostate specific antigen (PSA) normalization with or without neoadjuvant androgen deprivation (NAAD) therapy after treatment with intensity modulated radiotherapy (IMRT) for patients with clinically localized prostate cancer. METHODS: A retrospective cohort research design was used. A total of 133 patients with clinical stage T1c to T3b prostate cancer (2002 AJCC staging) treated in a community setting between January 2002 and July 2005 were reviewed for time to PSA normalization using 1 ng/mL and 2 ng/mL as criteria. All patients received IMRT as part of their management. Times to PSA normalization were calculated using the Kaplan-Meier method. Significance was assessed at p < 0.05. RESULTS: Fifty-six of the 133 patients received NAAD (42.1%). Thirty-one patients (23.8%) received radiation to a limited pelvic field followed by an IMRT boost, while 99 patients received IMRT alone (76.2%). The times to serum PSA normalization < 2 ng/mL when treated with or without NAAD were 298 +/- 24 and 302 +/- 33 days (mean +/- SEM), respectively (p > 0.05), and 303 +/- 24 and 405 +/- 46 days, respectively, for PSA < 1 ng/mL (p < 0.05). Stage T1 and T2 tumors had significantly increased time to PSA normalization < 1 ng/mL in comparison to Stage T3 tumors. Also, higher Gleason scores were significantly correlated with a faster time to PSA normalization < 1 ng/mL. CONCLUSIONS: Use of NAAD in conjunction with IMRT leads to a significantly shortened time to normalization of serum PSA < 1 ng/mL in patients with clinically localized prostate cancer. PMID- 20846421 TI - Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites. AB - BACKGROUND: Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum. RESULTS: A lineage of isogenic in vivo drug selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (Illumina Solexa) defined the point mutations, insertions, deletions and copy number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme. CONCLUSIONS: This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. PMID- 20846423 TI - Feasibility of a liver transcriptomics approach to assess bovine treatment with the prohormone dehydroepiandrosterone (DHEA). AB - BACKGROUND: Within the European Union the use of growth promoting agents in animal production is prohibited. Illegal use of natural prohormones like dehydroepiandrosterone (DHEA) is hard to prove since prohormones are strongly metabolized in vivo. In the present study, we investigated the feasibility of a novel effect-based approach for monitoring abuse of DHEA. Changes in gene expression profiles were studied in livers of bull calves treated orally (PO) or intramuscularly (IM) with 1000 mg DHEA versus two control groups, using bovine 44K DNA microarrays. In contrast to controlled genomics studies, this work involved bovines purchased at the local market on three different occasions with ages ranging from 6 to 14 months, thereby reflecting the real life inter-animal variability due to differences in age, individual physiology, season and diet. RESULTS: As determined by principal component analysis (PCA), large differences in liver gene expression profiles were observed between treated and control animals as well as between the two control groups. When comparing the gene expression profiles of PO and IM treated animals to that of all control animals, the number of significantly regulated genes (p-value <0.05 and a fold change >1.5) was 23 and 37 respectively. For IM and PO treated calves, gene sets were generated of genes that were significantly regulated compared to one control group and validated versus the other control group using Gene Set Enrichment Analysis (GSEA). This cross validation, showed that 6 out of the 8 gene sets were significantly enriched in DHEA treated animals when compared to an 'independent' control group. CONCLUSIONS: This study showed that identification and application of genomic biomarkers for screening of (pro)hormone abuse in livestock production is substantially hampered by biological variation. On the other hand, it is demonstrated that comparison of pre-defined gene sets versus the whole genome expression profile of an animal allows to distinguish DHEA treatment effects from variations in gene expression due to inherent biological variation. Therefore, DNA-microarray expression profiling together with statistical tools like GSEA represent a promising approach to screen for (pro)hormone abuse in livestock production. However, a better insight in the genomic variability of the control population is a prerequisite in order to define growth promoter specific gene sets that can be used as robust biomarkers in daily practice. PMID- 20846424 TI - Blood cell gene expression associated with cellular stress defense is modulated by antioxidant-rich food in a randomised controlled clinical trial of male smokers. AB - BACKGROUND: Plant-based diets rich in fruit and vegetables can prevent development of several chronic age-related diseases. However, the mechanisms behind this protective effect are not elucidated. We have tested the hypothesis that intake of antioxidant-rich foods can affect groups of genes associated with cellular stress defence in human blood cells. TRIAL REGISTRATION NUMBER: NCT00520819 http://clinicaltrials.gov. METHODS: In an 8-week dietary intervention study, 102 healthy male smokers were randomised to either a diet rich in various antioxidant-rich foods, a kiwifruit diet (three kiwifruits/d added to the regular diet) or a control group. Blood cell gene expression profiles were obtained from 10 randomly selected individuals of each group. Diet-induced changes on gene expression were compared to controls using a novel application of the gene set enrichment analysis (GSEA) on transcription profiles obtained using Affymetrix HG U133-Plus 2.0 whole genome arrays. RESULTS: Changes were observed in the blood cell gene expression profiles in both intervention groups when compared to the control group. Groups of genes involved in regulation of cellular stress defence, such as DNA repair, apoptosis and hypoxia, were significantly upregulated (GSEA, FDR q-values < 5%) by both diets compared to the control group. Genes with common regulatory motifs for aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (AhR/ARNT) were upregulated by both interventions (FDR q-values < 5%). Plasma antioxidant biomarkers (polyphenols/carotenoids) increased in both groups. CONCLUSIONS: The observed changes in the blood cell gene expression profiles suggest that the beneficial effects of a plant-based diet on human health may be mediated through optimization of defence processes. PMID- 20846425 TI - Ostrinia revisited: Evidence for sex linkage in European Corn Borer Ostrinia nubilalis (Hubner) pheromone reception. AB - BACKGROUND: The European Corn Borer, Ostrinia nubilalis (Hubner), is a keystone model for studies on the evolution of sex pheromone diversity and its role in establishing reproductive isolation. This species consists of two sympatric races, each utilizing opposite isomers of the same compound as their major pheromone component. Female production and male response are congruent in each race, and males from each strain exhibit phenotypic differences in peripheral physiology. Both strains possess co-localized pheromone-sensitive olfactory sensory neurons characterized by a larger amplitude action potential (spike) responding to the major pheromone component, and a smaller spike amplitude cell responding to the minor component, i.e. the opposite isomer. These differences in amplitude correspond to differences in dendritic diameter between the two neurons. Previous studies showed that behavioral response to the pheromone blend was sex-linked, but spike amplitude response to pheromone components matched autosomal, not sex-linked inheritance. RESULTS: As part of a larger study to finely map the loci responsible for pheromone communication in this species, we have reanalyzed peripheral physiology among parental, and first and second generation hybrids between the two pheromone strains using tungsten electrode electrophysiology. Our results reveal that differences in spike amplitude ratio between male pheromone-sensitive sensory neurons in O. nubilalis races are controlled, at least partially, by sex-linked genes that exhibit E-strain dominance. CONCLUSIONS: We propose that peripheral olfactory response in O. nubilalis may be affected both by autosomal and sex-linked genes exhibiting a cross-locus dominance effect, and suggest that the genetic basis for pheromone reception and response in the species is more closely linked than previously thought. PMID- 20846426 TI - Inheritance of central neuroanatomy and physiology related to pheromone preference in the male European corn borer. AB - BACKGROUND: The European corn borer (ECB), Ostrinia nubilalis, is a textbook example of pheromone polymorphism. Males of the two strains (Z and E) prefer opposite ratios of the two pheromone components, Z11- and E11-tetradecenyl acetate, with a sex-linked factor underlying this difference in preference. The male antennal lobes of the two strains contain a pheromone sensitive macroglomerular complex (MGC) that is identical in morphology, but reversed in functional topology. However, hybrids prefer intermediate ratios. How a topological arrangement of two glomeruli can accommodate for an intermediate preference was unclear. Therefore we studied the neurophysiology of hybrids and paternal backcrosses to see which factors correlated with male behavior. RESULTS: Projection neuron (PN) recordings and stainings in hybrids and backcrosses show a dominance of the E-type MGC topology, notwithstanding their intermediate preference. Apparently, the topological arrangement of glomeruli does not directly dictate preference. However, two other factors did correlated very well with preference. First, volumetric measurements of MGC glomeruli demonstrate that, whereas in the parental strains the medial MGC glomerulus is more than 2 times larger than the lateral, in hybrids they are intermediate between the parents, i.e. equally sized. Paternal backcrosses showed that the volume ratio is sex-linked and co-dominant. Second, we measured the summed potential difference of the antennae in response to pheromone stimulation using electroantennogram recordings (EAG). Z-strain antennae responded 2.5 times stronger to Z11 than to E11-14:OAc, whereas in E-strain antennae the ratio was approximately equal. Hybrid responses were intermediate to the parents, and also here the antennal response of the paternal backcrosses followed a pattern similar to the behavioral phenotype. We found no differences in frequency and types of projection and local interneurons encountered between the two strains and their hybrids. CONCLUSIONS: Male pheromone preference in the ECB strains serves as a strong prezygotic reproductive isolation mechanism, and has contributed to population divergence in the field. Our results demonstrate that male pheromone preference is not directly affected by the topological arrangement of olfactory glomeruli itself, but that male preference may instead be mediated by an antennal factor, which causes the MGC glomeruli to be differentially sized. We postulate that this factor affects readout of blend information from the MGC. The results are an illustration of how pheromone preference may be 'spelled out' in the ALs, and how evolution may modulate this. PMID- 20846427 TI - Extramedullary hematopoiesis in a case of benign mixed mammary tumor in a female dog: cytological and histopathological assessment. AB - BACKGROUND: Extramedullary hematopoiesis (EMH) is defined as the presence of hematopoietic stem cells such as erythroid and myeloid lineage plus megakaryocytes in extramedullary sites like liver, spleen and lymph nodes and is usually associated with either bone marrow or hematological disorders. Mammary EMH is a rare condition either in human and veterinary medicine and can be associated with benign mixed mammary tumors, similarly to that described in this case. CASE PRESENTATION: Hematopoietic stem cells were found in a benign mixed mammary tumor of a 7-year-old female mongrel dog that presents a nodule in the left inguinal mammary gland. The patient did not have any hematological abnormalities. Cytological evaluation demonstrated two distinct cell populations, composed of either epithelial or mesenchymal cells, sometimes associated with a fibrillar acidophilic matrix, apart from megakaryocytes, osteoclasts, metarubricytes, prorubricytes, rubricytes, rubriblasts, promyelocytes, myeloblasts. Histological examination confirmed the presence of an active hematopoietic bone marrow within the bone tissue of a benign mammary mixed tumor. CONCLUSIONS: EMH is a rare condition described in veterinary medicine that can be associated with mammary mixed tumors. It's detection can be associated with several neoplastic and non-neoplastic mammary lesions, i.e. osteosarcomas, mixed tumors and bone metaplasia. PMID- 20846428 TI - Detecting exacerbations using the Clinical COPD Questionnaire. AB - BACKGROUND: Early treatment of COPD exacerbations has shown to be important. Despite a non-negligible negative impact on health related quality of life, a large proportion of these episodes is not reported (no change in treatment). Little is known whether (low burden) strategies are able to capture these unreported exacerbations. METHODS: The Clinical COPD Questionnaire (CCQ) is a short questionnaire with great evaluative properties in measuring health status. The current explorative study evaluates the discriminative properties of weekly CCQ assessment in detecting exacerbations. RESULTS: In a multicentre prospective cohort study, 121 patients, age 67.4 +/- 10.5 years, FEV1 47.7 +/- 18.5% pred were followed for 6 weeks by daily diary card recording and weekly CCQ assessment. Weeks were retrospectively labeled as stable or exacerbation (onset) weeks using the Anthonisen symptom diary-card algorithm. Change in CCQ total scores are significantly higher in exacerbation-onset weeks, 0.35 +/- 0.69 compared to -0.04 +/- 0.37 in stable weeks (p < 0.001). Performance of the Delta CCQ total score discriminating between stable and exacerbation onset weeks was sufficient (area under the ROC curve 0.75). At a cut off point of 0.2, sensitivity was 62.5 (50.3-73.4), specificity 82.0 (79.3-84.4), and a positive and negative predictive value of 43.5 (35.0-51.0) and 90.8 (87.8-93.5), respectively. Using this cut off point, 22 (out of 38) unreported exacerbations were detected while 39 stable patients would have been false positively 'contacted'. CONCLUSIONS: Weekly CCQ assessment is a promising, low burden method to detect unreported exacerbations. Further research is needed to validate discriminative performance and practical implications of the CCQ in detecting exacerbations in daily care. PMID- 20846429 TI - Assessment of the general public's knowledge about rheumatic diseases: evidence from a Portuguese population-based survey. AB - BACKGROUND: To identify incorrect beliefs and common knowledge about rheumatic diseases in the general population. METHODS: Participants were selected during the follow-up of a representative cohort of adult population of Porto, Portugal; 1626 participants completed a questionnaire that included general knowledge items about rheumatic diseases.Discrete and continuous latent variable models were used to identify knowledge flaws and the target groups. Odds ratios (OR) estimated by multinomial logistic regression, and 95% confidence intervals (95%CI) were computed to evaluate magnitude of associations. RESULTS: A continuous latent variable model identified two dimensions: one related to general beliefs (latent 1) and another concerning characteristics, treatment and impact of rheumatic diseases (latent 2). A 3-class latent variable model refined these results: the first class presented the lowest probabilities of correct answer for items associated with the first latent (mean of 39%), and the second class presented the lowest probabilities of correct answer for items with the second latent (mean of 62%). The third class showed the highest probability of a correct answer for almost all the items (mean of 79%). The age and sex standardized prevalence of the classes was 25.7%, 30.8% and 43.5%.Taking class 2 as reference, class 1 was positively associated with the presence of rheumatic diseases (OR = 2.79; CI95% = (2.10-3.70)), with females (OR = 1.28 CI95% = (0.99-1.67)) and older individuals (OR = 1.04; CI95% = (1.03-1.05)), and was negatively associated with education (OR = 0.84; CI95% = (0.81-0.86)); class 3 was positively associated with education (OR = 1.03; CI95% = (1.00-1.05)) and the presence of rheumatic diseases (OR = 1.29; CI95% = (0.97-1.70)). CONCLUSIONS: There are several knowledge flaws about rheumatic diseases in the general public. One out of four participants considered false general beliefs as true and approximately 30% did not have detailed knowledge on rheumatic disease. Higher education and the presence of disease contributed positively to the overall knowledge. These results suggest some degree of effectiveness of patient education, either conducted by health professionals or self-driven. PMID- 20846430 TI - The GPIIIA PlA2 polymorphism is associated with an increased risk of cardiovascular adverse events. AB - BACKGROUND: The clinical impact of PlA2 polymorphism has been investigated in several diseases, but the definition of its specific role on thrombotic cardiovascular complications has been challenging. We aimed to explore the effect of PlA2 polymorphism on outcome in patients with atherosclerosis. METHODS: We studied 400 consecutive patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention. A replication study was conducted in 74 hypertensive patients with cerebrovascular events while a group of 100 healthy subjects was included as control population. PlA genotype was determined by PCR RFLP on genomic DNA from peripheral blood cells. Major adverse cardiac events (MACE), were considered as end points, and recorded at a mean follow up of 24 +/- 4.3 months. RESULTS: The frequencies of PlA2 polymorphism was similar between groups and genotype distribution was in Hardy-Weinberg equilibrium. In patients with CAD, the presence of PlA2 allele was associated with higher incidence of cardiac death (13.1% vs. 1.5%, p = 0.0001), myocardial infarction (10.7% vs. 2.6%, p = 0.004) and needs of new revascularization (34.8% vs. 17.7%, p = 0.010). Accordingly, the Kaplan-Meier analysis for event free survival in patients harboring the PlA2 allele showed worse long-term outcome for these patients (p = 0.015). Cox regression analysis identified the presence of PlA2 as an independent predictor of cardiac death (OR: 9.594, 95% CI: 2.6 to 35.3, p = 0.002) and overall MACE (OR: 1.829, 95% CI: 1.054 to 3.176, p = 0.032). In the replication study, the PlA2 polymorphism increased the risk of stroke (OR: 4.1, 95% CI: 1.63 12.4, p = 0.02) over TIA and was identified as an independent risk factor for stroke (B:-1.39; Wald: 7.15; p = 0.001). CONCLUSIONS: Our study demonstrates that in patients with severe atherosclerosis the presence of PlA2 allele is associated with thrombotic cardiovascular complications. PMID- 20846432 TI - Cancer incidence and adverse pregnancy outcome in registered nurses potentially exposed to antineoplastic drugs. AB - BACKGROUND: To determine the relationships of potential occupational exposure to antineoplastic drugs with cancer incidence and adverse pregnancy outcomes in a historical prospective cohort study of female registered nurses (RNs) from British Columbia, Canada (BC). METHODS: Female RNs registered with a professional regulatory body for at least one year between 1974 and 2000 formed the cohort (n = 56,213). The identifier file was linked to Canadian cancer registries. An RN offspring cohort from 1986 was created by linkages with the BC Birth and Health Status Registries. Exposure was assessed by work history in oncology or cancer agencies (method 1) and by estimating weighted duration of exposure developed from a survey of pharmacists and nursing unit administrators of all provincial hospitals and treatment centers and the work history of the nurses (method 2). Relative risks (RR) were calculated using Poisson regression for cancer incidence and odds ratios (OR) were calculated for congenital anomaly, stillbirth, low birth weight, and prematurity incidence, with 95% confidence intervals. RESULTS: In comparison with other female RNs, method 1 revealed that RNs who ever worked in a cancer center or in an oncology nursing unit had an increased risk of breast cancer (RR = 1.83; 95% CI = 1.03 - 3.23, 12 cases) and their offspring were at risk for congenital anomalies of the eye (OR = 3.46, 95% CI = 1.08 - 11.14, 3 cases). Method 2 revealed that RNs classified as having the highest weighted durations of exposure to antineoplastic drugs had an excess risk of cancer of the rectum (RR = 1.87, 95% CI = 1.07 - 3.29, 14 cases). No statistically significant increased risks of leukemia, other cancers, stillbirth, low birth weight, prematurity, or other congenital anomalies in the RNs' offspring were noted. CONCLUSIONS: Female RNs having had potential exposure to antineoplastic drugs were not found to have an excess risk of leukemia, stillbirth, or congenital anomalies in their offspring, with the exception of congenital anomalies of the eye, based on only three cases; however, elevated risks of breast and rectal cancer were observed. PMID- 20846431 TI - Probing the pan-genome of Listeria monocytogenes: new insights into intraspecific niche expansion and genomic diversification. AB - BACKGROUND: Bacterial pathogens often show significant intraspecific variations in ecological fitness, host preference and pathogenic potential to cause infectious disease. The species of Listeria monocytogenes, a facultative intracellular pathogen and the causative agent of human listeriosis, consists of at least three distinct genetic lineages. Two of these lineages predominantly cause human sporadic and epidemic infections, whereas the third lineage has never been implicated in human disease outbreaks despite its overall conservation of many known virulence factors. RESULTS: Here we compare the genomes of 26 L. monocytogenes strains representing the three lineages based on both in silico comparative genomic analysis and high-density, pan-genomic DNA array hybridizations. We uncover 86 genes and 8 small regulatory RNAs that likely make L. monocytogenes lineages differ in carbohydrate utilization and stress resistance during their residence in natural habitats and passage through the host gastrointestinal tract. We also identify 2,330 to 2,456 core genes that define this species along with an open pan-genome pool that contains more than 4,052 genes. Phylogenomic reconstructions based on 3,560 homologous groups allowed robust estimation of phylogenetic relatedness among L. monocytogenes strains. CONCLUSIONS: Our pan-genome approach enables accurate co-analysis of DNA sequence and hybridization array data for both core gene estimation and phylogenomics. Application of our method to the pan-genome of L. monocytogenes sheds new insights into the intraspecific niche expansion and evolution of this important foodborne pathogen. PMID- 20846433 TI - Radiosensitization of mammary carcinoma cells by telomere homolog oligonucleotide pretreatment. AB - INTRODUCTION: Ionizing radiation (IR) is a widely used approach to cancer therapy, ranking second only to surgery in rate of utilization. Responses of cancer patients to radiotherapy depend in part on the intrinsic radiosensitivity of the tumor cells. Thus, promoting tumor cell sensitivity to IR could significantly enhance the treatment outcome and quality of life for patients. METHODS: Mammary tumor cells were treated by a 16-base phosphodiester-linked oligonucleotide homologous to the telomere G-rich sequence TTAGGG (T-oligo: GGTTAGGTGTAGGTTT) or a control-oligo (the partial complement, TAACCCTAACCCTAAC) followed by IR. The inhibition of tumor cell growth in vitro was assessed by cell counting and clonogenic cell survival assay. The tumorigenesis of tumor cells after various treatments was measured by tumor growth in mice. The mechanism underlying the radiosensitization by T-oligo was explored by immunouorescent determination of phosphorylated histone H2AX (gammaH2AX) foci, beta-galactosidase staining, comet and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) assays. The efficacy of the combined treatment was assessed in a spontaneous murine mammary tumor model. RESULTS: Pretreatment of tumor cells with T-oligo for 24 hours in vitro enhanced both senescence and apoptosis of irradiated tumor cells and reduced clonogenic potential. Radiosensitization by T oligo was associated with increased formation and/or delayed resolution of gammaH2AX DNA damage foci and fragmented DNA. T-oligo also caused radiosensitization in two in vivo mammary tumor models. Indeed, combined T-oligo and IR-treatment in vivo led to a substantial reduction in tumor growth. Of further significance, treatment with T-oligo and IR led to synergistic inhibition of the growth of spontaneous mammary carcinomas. Despite these profound antitumor properties, T-oligo and IR caused no detectable side effects under our experimental conditions. CONCLUSIONS: Pretreatment with T-oligo sensitizes mammary tumor cells to radiation in both in vitro and in vivo settings with minimal or no normal tissue side effects. PMID- 20846434 TI - Production of functionalized polyhydroxyalkanoates by genetically modified Methylobacterium extorquens strains. AB - BACKGROUND: Methylotrophic (methanol-utilizing) bacteria offer great potential as cell factories in the production of numerous products from biomass-derived methanol. Bio-methanol is essentially a non-food substrate, an advantage over sugar-utilizing cell factories. Low-value products as well as fine chemicals and advanced materials are envisageable from methanol. For example, several methylotrophic bacteria, including Methylobacterium extorquens, can produce large quantities of the biodegradable polyester polyhydroxybutyric acid (PHB), the best known polyhydroxyalkanoate (PHA). With the purpose of producing second-generation PHAs with increased value, we have explored the feasibility of using M. extorquens for producing functionalized PHAs containing C-C double bonds, thus, making them amenable to future chemical/biochemical modifications for high value applications. RESULTS: Our proprietary M. extorquens ATCC 55366 was found unable to yield functionalized PHAs when fed methanol and selected unsaturated carboxylic acids as secondary substrates. However, cloning of either the phaC1 or the phaC2 gene from P. fluorescens GK13, using an inducible and regulated expression system based on cumate as inducer (the cumate switch), yielded recombinant M. extorquens strains capable of incorporating modest quantities of C C double bonds into PHA, starting from either C6= and/or C8=. The two recombinant strains gave poor results with C11=. The strain containing the phaC2 gene was better at using C8= and at incorporating C-C double bonds into PHA. Solvent fractioning indicated that the produced polymers were PHA blends that consequently originated from independent actions of the native and the recombinant PHA synthases. CONCLUSIONS: This work constitutes an example of metabolic engineering applied to the construction of a methanol-utilizing bacterium capable of producing functionalized PHAs containing C-C double bonds. In this regard, the PhaC2 synthase appeared superior to the PhaC1 synthase at utilizing C8= as source of C-C double bonds and at incorporating C-C double bonds into PHA from either C6= or C8=. The M. ex-phaC2 strain is, therefore, a promising biocatalyst for generating advanced (functionalized) PHAs for future high value applications in various fields. PMID- 20846435 TI - Health-related quality of life before planned admission to intensive care: memory over three and six months. AB - BACKGROUND: The validity of Health-Related Quality of Life (HRQOL) recalled by ICU admitted patients have not been published. The aim of this study was to compare the baseline HRQOL measured before surgery and ICU admission with that recalled at 3 and 6 months in a population of patients with planned ICU admission after surgery. METHODS: This prospective study was performed in three Italian centres on patients who had undergone General, Orthopaedic or Urologic surgery. All adult patients with planned ICU admission between October 2007 and July 2008 were considered for enrolment. At hospital admission, the Mini Mental Status Examination and EuroQoL (EQ) questionnaire (referring to the last two weeks) were administered to the patients who consented. Three and six months after ICU admission, the researchers administered by phone the EQ questionnaire and Post Traumatic Stress Syndrome 14 questions Inventory, asking the patients to rate their HRQOL before surgery and ICU admission. Past medical history demographic and clinical ICU-related variables were collected. STATISTICAL ANALYSIS: Chi square test and non parametric statistics were used to compare groups of patients. The EQ-5D was transformed in the time trade-off (TTO) to obtain a continuous variable, subsequently analysed using the Intraclass Correlation Coefficient (ICC). RESULTS: Of the 104 patients assessed at baseline and discharged from the hospital, 93 had the EQ administered at 3 months, and 89 at 6 months. The ICC for TTO recalled at 3 months vs pre-ICU TTO was 0.851, and that for TTO recalled at 6 months vs pre-ICU TTO was 0.833. The ICC for the EQ-VAS recalled at 3 months vs pre-ICU EQ-VAS was 0.648, and that for the EQ-VAS recalled at 6 months vs pre-ICU EQ-VAS was 0.580. Forty-two (45%) patients assessed at 3 months gave the same score in all EQ-5D items as at baseline. They underwent mainly orthopaedic surgery (p 0.011), and perceived the severity of their illness as lower (p 0.009) than patients scoring differently at 3 months in comparison with baseline. CONCLUSIONS: The patients with planned ICU admission have a good memory of their health status as measured by EQ-5D in the period preceding surgery and ICU admission, especially at three months. PMID- 20846437 TI - Parallel multiplicity and error discovery rate (EDR) in microarray experiments. AB - BACKGROUND: In microarray gene expression profiling experiments, differentially expressed genes (DEGs) are detected from among tens of thousands of genes on an array using statistical tests. It is important to control the number of false positives or errors that are present in the resultant DEG list. To date, more than 20 different multiple test methods have been reported that compute overall Type I error rates in microarray experiments. However, these methods share the following dilemma: they have low power in cases where only a small number of DEGs exist among a large number of total genes on the array. RESULTS: This study contrasts parallel multiplicity of objectively related tests against the traditional simultaneousness of subjectively related tests and proposes a new assessment called the Error Discovery Rate (EDR) for evaluating multiple test comparisons in microarray experiments. Parallel multiple tests use only the negative genes that parallel the positive genes to control the error rate; while simultaneous multiple tests use the total unchanged gene number for error estimates. Here, we demonstrate that the EDR method exhibits improved performance over other methods in specificity and sensitivity in testing expression data sets with sequence digital expression confirmation, in examining simulation data, as well as for three experimental data sets that vary in the proportion of DEGs. The EDR method overcomes a common problem of previous multiple test procedures, namely that the Type I error rate detection power is low when the total gene number used is large but the DEG number is small. CONCLUSIONS: Microarrays are extensively used to address many research questions. However, there is potential to improve the sensitivity and specificity of microarray data analysis by developing improved multiple test comparisons. This study proposes a new view of multiplicity in microarray experiments and the EDR provides an alternative multiple test method for Type I error control in microarray experiments. PMID- 20846436 TI - Evaluation of phenoxybenzamine in the CFA model of pain following gene expression studies and connectivity mapping. AB - BACKGROUND: We have previously used the rat 4 day Complete Freund's Adjuvant (CFA) model to screen compounds with potential to reduce osteoarthritic pain. The aim of this study was to identify genes altered in this model of osteoarthritic pain and use this information to infer analgesic potential of compounds based on their own gene expression profiles using the Connectivity Map approach. RESULTS: Using microarrays, we identified differentially expressed genes in L4 and L5 dorsal root ganglia (DRG) from rats that had received intraplantar CFA for 4 days compared to matched, untreated control animals. Analysis of these data indicated that the two groups were distinguishable by differences in genes important in immune responses, nerve growth and regeneration. This list of differentially expressed genes defined a "CFA signature". We used the Connectivity Map approach to identify pharmacologic agents in the Broad Institute Build02 database that had gene expression signatures that were inversely related ('negatively connected') with our CFA signature. To test the predictive nature of the Connectivity Map methodology, we tested phenoxybenzamine (an alpha adrenergic receptor antagonist) - one of the most negatively connected compounds identified in this database - for analgesic activity in the CFA model. Our results indicate that at 10 mg/kg, phenoxybenzamine demonstrated analgesia comparable to that of Naproxen in this model. CONCLUSION: Evaluation of phenoxybenzamine-induced analgesia in the current study lends support to the utility of the Connectivity Map approach for identifying compounds with analgesic properties in the CFA model. PMID- 20846438 TI - Using Landsat satellite data to support pesticide exposure assessment in California. AB - BACKGROUND: The recent U.S. Geological Survey policy offering Landsat satellite data at no cost provides researchers new opportunities to explore relationships between environment and health. The purpose of this study was to examine the potential for using Landsat satellite data to support pesticide exposure assessment in California. METHODS AND RESULTS: We collected a dense time series of 24 Landsat 5 and 7 images spanning the year 2000 for an agricultural region in Fresno County. We intersected the Landsat time series with the California Department of Water Resources (CDWR) land use map and selected field samples to define the phenological characteristics of 17 major crop types or crop groups. We found the frequent overpass of Landsat enabled detection of crop field conditions (e.g., bare soil, vegetated) over most of the year. However, images were limited during the winter months due to cloud cover. Many samples designated as single cropped in the CDWR map had phenological patterns that represented multi-cropped or non-cropped fields, indicating they may have been misclassified. CONCLUSIONS: We found the combination of Landsat 5 and 7 image data would clearly benefit pesticide exposure assessment in this region by 1) providing information on crop field conditions at or near the time when pesticides are applied, and 2) providing information for validating the CDWR map. The Landsat image time-series was useful for identifying idle, single-, and multi-cropped fields. Landsat data will be limited during the winter months due to cloud cover, and for years prior to the Landsat 7 launch (1999) when only one satellite was operational at any given time. We suggest additional research to determine the feasibility of integrating CDWR land use maps and Landsat data to derive crop maps in locations and time periods where maps are not available, which will allow for substantial improvements to chemical exposure estimation. PMID- 20846439 TI - DNA barcoding of the Lemnaceae, a family of aquatic monocots. AB - BACKGROUND: Members of the aquatic monocot family Lemnaceae (commonly called duckweeds) represent the smallest and fastest growing flowering plants. Their highly reduced morphology and infrequent flowering result in a dearth of characters for distinguishing between the nearly 38 species that exhibit these tiny, closely-related and often morphologically similar features within the same family of plants. RESULTS: We developed a simple and rapid DNA-based molecular identification system for the Lemnaceae based on sequence polymorphisms. We compared the barcoding potential of the seven plastid-markers proposed by the CBOL (Consortium for the Barcode of Life) plant-working group to discriminate species within the land plants in 97 accessions representing 31 species from the family of Lemnaceae. A Lemnaceae-specific set of PCR and sequencing primers were designed for four plastid coding genes (rpoB, rpoC1, rbcL and matK) and three noncoding spacers (atpF-atpH, psbK-psbI and trnH-psbA) based on the Lemna minor chloroplast genome sequence. We assessed the ease of amplification and sequencing for these markers, examined the extent of the barcoding gap between intra- and inter-specific variation by pairwise distances, evaluated successful identifications based on direct sequence comparison of the "best close match" and the construction of a phylogenetic tree. CONCLUSIONS: Based on its reliable amplification, straightforward sequence alignment, and rates of DNA variation between species and within species, we propose that the atpF-atpH noncoding spacer could serve as a universal DNA barcoding marker for species-level identification of duckweeds. PMID- 20846440 TI - Improved content aware scene retargeting for retinitis pigmentosa patients. AB - BACKGROUND: In this paper we present a novel scene retargeting technique to reduce the visual scene while maintaining the size of the key features. The algorithm is scalable to implementation onto portable devices, and thus, has potential for augmented reality systems to provide visual support for those with tunnel vision. We therefore test the efficacy of our algorithm on shrinking the visual scene into the remaining field of view for those patients. METHODS: Simple spatial compression of visual scenes makes objects appear further away. We have therefore developed an algorithm which removes low importance information, maintaining the size of the significant features. Previous approaches in this field have included seam carving, which removes low importance seams from the scene, and shrinkability which dynamically shrinks the scene according to a generated importance map. The former method causes significant artifacts and the latter is inefficient. In this work we have developed a new algorithm, combining the best aspects of both these two previous methods. In particular, our approach is to generate a shrinkability importance map using as seam based approach. We then use it to dynamically shrink the scene in similar fashion to the shrinkability method. Importantly, we have implemented it so that it can be used in real time without prior knowledge of future frames. RESULTS: We have evaluated and compared our algorithm to the seam carving and image shrinkability approaches from a content preservation perspective and a compression quality perspective. Also our technique has been evaluated and tested on a trial included 20 participants with simulated tunnel vision. Results show the robustness of our method at reducing scenes up to 50% with minimal distortion. We also demonstrate efficacy in its use for those with simulated tunnel vision of 22 degrees of field of view or less. CONCLUSIONS: Our approach allows us to perform content aware video resizing in real time using only information from previous frames to avoid jitter. Also our method has a great benefit over the ordinary resizing method and even over other image retargeting methods. We show that the benefit derived from this algorithm is significant to patients with fields of view 20 degrees or less. PMID- 20846441 TI - The effect of chair massage on muscular discomfort in cardiac sonographers: a pilot study. AB - BACKGROUND: Cardiac sonographers frequently have work-related muscular discomfort. We aimed to assess the feasibility of having sonographers receive massages during working hours in an area adjacent to an echocardiography laboratory and to assess relief of discomfort with use of the massages with or without stretching exercises. METHODS: A group of 45 full-time sonographers was randomly assigned to receive weekly 30-minute massage sessions, massages plus stretching exercises to be performed twice a day, or no intervention. Outcome measures were scores of the QuickDASH instrument and its associated work module at baseline and at 10 weeks of intervention. Data were analyzed with standard descriptive statistics and the separation test for early-phase comparative trials. RESULTS: Forty-four participants completed the study: 15 in the control group, 14 in the massage group, and 15 in the massage plus stretches group. Some improvement was seen in work-related discomfort by the QuickDASH scores and work module scores in the 2 intervention groups. The separation test showed separation in favor of the 2 interventions. CONCLUSION: On the basis of the results of this pilot study, larger trials are warranted to evaluate the effect of massages with or without stretching on work-related discomfort in cardiac sonographers. TRIAL REGISTRATION: NCT00975026 ClinicalTrials.gov. PMID- 20846442 TI - Does the mind map learning strategy facilitate information retrieval and critical thinking in medical students? AB - BACKGROUND: A learning strategy underutilized in medical education is mind mapping. Mind maps are multi-sensory tools that may help medical students organize, integrate, and retain information. Recent work suggests that using mind mapping as a note-taking strategy facilitates critical thinking. The purpose of this study was to investigate whether a relationship existed between mind mapping and critical thinking, as measured by the Health Sciences Reasoning Test (HSRT), and whether a relationship existed between mind mapping and recall of domain based information. METHODS: In this quasi-experimental study, 131 first-year medical students were randomly assigned to a standard note-taking (SNT) group or mind map (MM) group during orientation. Subjects were given a demographic survey and pre-HSRT. They were then given an unfamiliar text passage, a pre-quiz based upon the passage, and a 30-minute break, during which time subjects in the MM group were given a presentation on mind mapping. After the break, subjects were given the same passage and wrote notes based on their group (SNT or MM) assignment. A post-quiz based upon the passage was administered, followed by a post-HSRT. Differences in mean pre- and post-quiz scores between groups were analyzed using independent samples t-tests, whereas differences in mean pre- and post-HSRT total scores and subscores between groups were analyzed using ANOVA. Mind map depth was assessed using the Mind Map Assessment Rubric (MMAR). RESULTS: There were no significant differences in mean scores on both the pre- and post quizzes between note-taking groups. And, no significant differences were found between pre- and post-HSRT mean total scores and subscores. CONCLUSIONS: Although mind mapping was not found to increase short-term recall of domain-based information or critical thinking compared to SNT, a brief introduction to mind mapping allowed novice MM subjects to perform similarly to SNT subjects. This demonstrates that medical students using mind maps can successfully retrieve information in the short term, and does not put them at a disadvantage compared to SNT students. Future studies should explore longitudinal effects of mind-map proficiency training on both short- and long-term information retrieval and critical thinking. PMID- 20846444 TI - Practice effects in healthy adults: a longitudinal study on frequent repetitive cognitive testing. AB - BACKGROUND: Cognitive deterioration is a core symptom of many neuropsychiatric disorders and target of increasing significance for novel treatment strategies. Hence, its reliable capture in long-term follow-up studies is prerequisite for recording the natural course of diseases and for estimating potential benefits of therapeutic interventions. Since repeated neuropsychological testing is required for respective longitudinal study designs, occurrence, time pattern and magnitude of practice effects on cognition have to be understood first under healthy good performance conditions to enable design optimization and result interpretation in disease trials. METHODS: Healthy adults (N = 36; 47.3 +/- 12.0 years; mean IQ 127.0 +/- 14.1; 58% males) completed 7 testing sessions, distributed asymmetrically from high to low frequency, over 1 year (baseline, weeks 2-3, 6, 9, months 3, 6, 12). The neuropsychological test battery covered 6 major cognitive domains by several well-established tests each. RESULTS: Most tests exhibited a similar pattern upon repetition: (1) Clinically relevant practice effects during high-frequency testing until month 3 (Cohen's d 0.36-1.19), most pronounced early on, and (2) a performance plateau thereafter upon low-frequency testing. Few tests were non-susceptible to practice or limited by ceiling effects. Influence of confounding variables (age, IQ, personality) was minor. CONCLUSIONS: Practice effects are prominent particularly in the early phase of high-frequency repetitive cognitive testing of healthy well-performing subjects. An optimal combination and timing of tests, as extractable from this study, will aid in controlling their impact. Moreover, normative data for serial testing may now be collected to assess normal learning curves as important comparative readout of pathological cognitive processes. PMID- 20846443 TI - Investigating the validity of current network analysis on static conglomerate networks by protein network stratification. AB - BACKGROUND: A molecular network perspective forms the foundation of systems biology. A common practice in analyzing protein-protein interaction (PPI) networks is to perform network analysis on a conglomerate network that is an assembly of all available binary interactions in a given organism from diverse data sources. Recent studies on network dynamics suggested that this approach might have ignored the dynamic nature of context-dependent molecular systems. RESULTS: In this study, we employed a network stratification strategy to investigate the validity of the current network analysis on conglomerate PPI networks. Using the genome-scale tissue- and condition-specific proteomics data in Arabidopsis thaliana, we present here the first systematic investigation into this question. We stratified a conglomerate A. thaliana PPI network into three levels of context-dependent subnetworks. We then focused on three types of most commonly conducted network analyses, i.e., topological, functional and modular analyses, and compared the results from these network analyses on the conglomerate network and five stratified context-dependent subnetworks corresponding to specific tissues. CONCLUSIONS: We found that the results based on the conglomerate PPI network are often significantly different from those of context-dependent subnetworks corresponding to specific tissues or conditions. This conclusion depends neither on relatively arbitrary cutoffs (such as those defining network hubs or bottlenecks), nor on specific network clustering algorithms for module extraction, nor on the possible high false positive rates of binary interactions in PPI networks. We also found that our conclusions are likely to be valid in human PPI networks. Furthermore, network stratification may help resolve many controversies in current research of systems biology. PMID- 20846445 TI - The effect of mesenchymal stem cell transplantation on the recovery of bladder and hindlimb function after spinal cord contusion in rats. AB - BACKGROUND: Mesenchymal stem cells are widely used for transplantation into the injured spinal cord in vivo model and for safety, many human clinical trials are continuing to promote improvements of motor and sensory functions after spinal cord injury. Yet the exact mechanism for these improvements remains undefined. Neurogenic bladder following spinal cord injury is the main problem decreasing the quality of life for patients with spinal cord injury, but there are no clear data using stem cell transplantation for the improvement of neurogenic bladder for in vivo studies and the clinical setting.The purpose of this study was to delineate the effect of human mesenchymal stem cell (hMSCs) transplantation on the restoration of neurogenic bladder and impaired hindlimb function after spinal cord contusion of rats and the relationship between neurotrophic factors such as brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and bladder and hindlimb functions. RESULTS: Modified moderate contusion injury were performed on the thoracic spinal cord of Sprague-Dawley rats using MASCIS impactor and hMSCs, human fibroblasts or phosphate-buffered saline were transplanted into injured spinal cord 9 days after injury for hMSC and two control groups respectively. Ladder test showed more rapid restoration of hindlimb function in hMSC group than in control group, but Basso, Beattie, and Bresnahan score and coupling score were not different significantly among hMSC and two control groups. Neurogenic bladder was not improved in either group. ED1 positive macrophages were significantly reduced in hMSC group than in two control groups, but ELISA and RT-PCR studies revealed BDNF and NT-3 levels in spinal cord and bladder were not different among hMSC and two control groups regardless the experimental duration. CONCLUSION: hMSC transplantation was effective in reducing inflammatory reaction after spinal cord contusion of rats but not sufficient to recover locomotor and bladder dysfunction. BDNF and NT-3 levels in the spinal cord and bladder were not increased 28 and 56 days after hMSC transplantation. PMID- 20846446 TI - How protective is cervical cancer screening against cervical cancer mortality in developing countries? The Colombian case. AB - BACKGROUND: Cervical cancer is one of the top causes of cancer morbidity and mortality in Colombia despite the existence of a national preventive program. Screening coverage with cervical cytology does not explain the lack of success of the program in reducing incidence and mortality rates by cervical cancer. To address this problem an ecological analysis, at department level, was carried out in Colombia to assess the relationship between cervical screening characteristics and cervical cancer mortality rates. METHODS: Mortality rates by cervical cancer were estimated at the department level for the period 2000-2005. Levels of mortality rates were compared to cervical screening coverage and other characteristics of the program. A Poisson regression was used to estimate the effect of different dimensions of program performance on mortality by cervical cancer. RESULTS: Screening coverage ranged from 28.7% to 65.6% by department but increases on this variable were not related to decreases in mortality rates. A significant reduction in mortality was found in departments where a higher proportion of women looked for medical advice when abnormal findings were reported in Pap smears. Geographic areas where a higher proportion of women lack health insurance had higher rates of mortality by cervical cancer. CONCLUSIONS: These results suggest that coverage is not adequate to prevent mortality due to cervical cancer if women with abnormal results are not provided with adequate follow up and treatment. The role of different dimensions of health care such as insurance coverage, quality of care, and barriers for accessing health care needs to be evaluated and addressed in future studies. PMID- 20846447 TI - Vectors and malaria transmission in deforested, rural communities in north central Vietnam. AB - BACKGROUND: Malaria is still prevalent in rural communities of central Vietnam even though, due to deforestation, the primary vector Anopheles dirus is uncommon. In these situations little is known about the secondary vectors which are responsible for maintaining transmission. Basic information on the identification of the species in these rural communities is required so that transmission parameters, such as ecology, behaviour and vectorial status can be assigned to the appropriate species. METHODS: In two rural villages--Khe Ngang and Hang Chuon--in Truong Xuan Commune, Quang Binh Province, north central Vietnam, a series of longitudinal entomological surveys were conducted during the wet and dry seasons from 2003-2007. In these surveys anopheline mosquitoes were collected in human landing catches, paired human and animal bait collections, and from larval surveys. Specimens belonging to species complexes were identified by PCR and sequence analysis, incrimination of vectors was by detection of circumsporozoite protein using an enzyme-linked immunosorbent assay. RESULTS: Over 80% of the anopheline fauna was made up of Anopheles sinensis, Anopheles aconitus, Anopheles harrisoni, Anopheles maculatus, Anopheles sawadwongporni, and Anopheles philippinensis. PCR and sequence analysis resolved identification issues in the Funestus Group, Maculatus Group, Hyrcanus Group and Dirus Complex. Most species were zoophilic and while all species could be collected biting humans significantly higher densities were attracted to cattle and buffalo. Anopheles dirus was the most anthropophilic species but was uncommon making up only 1.24% of all anophelines collected. Anopheles sinensis, An. aconitus, An. harrisoni, An. maculatus, An. sawadwongporni, Anopheles peditaeniatus and An. philippinensis were all found positive for circumsporozoite protein. Heterogeneity in oviposition site preference between species enabled vector densities to be high in both the wet and dry seasons allowing for year round transmission. CONCLUSIONS: In rural communities in north central Vietnam, malaria transmission was maintained by a number of anopheline species which though collected feeding on humans were predominantly zoophilic, this behaviour allows for low level but persistent malaria transmission. The important animal baits- cattle and buffalo--were kept in the village and barrier spraying around these animals may be more effective at reducing vector densities and longevity than the currently used indoor residual spraying. PMID- 20846449 TI - Theoretical generalization of normal and sick coronary arteries with fractal dimensions and the arterial intrinsic mathematical harmony. AB - BACKGROUND: Fractal geometry is employ to characterize the irregular objects and had been used in experimental and clinic applications. Starting from a previous work, here we made a theoretical research based on a geometric generalization of the experimental results, to develop a theoretical generalization of the stenotic and restenotic process, based on fractal geometry and Intrinsic Mathematical Harmony. METHODS: Starting from all the possibilities of space occupation in box counting space, all arterial prototypes differentiating normality and disease were obtained with a computational simulation. Measures from 2 normal and 3 re stenosed arteries were used as spatial limits of the generalization. RESULTS: A new methodology in animal experimentation was developed, based on fractal geometric generalization. With this methodology, it was founded that the occupation space possibilities in the stenotic process are finite and that 69,249 arterial prototypes are obtained as a total. CONCLUSIONS: The Intrinsic Mathematical Harmony reveals a supra-molecular geometric self-organization, where the finite and discrete fractal dimensions of arterial layers evaluate objectively the arterial stenosis and restenosis process. PMID- 20846448 TI - In vivo induction of phase II detoxifying enzymes, glutathione transferase and quinone reductase by citrus triterpenoids. AB - BACKGROUND: Several cell culture and animal studies demonstrated that citrus bioactive compounds have protective effects against certain types of cancer. Among several classes of citrus bioactive compounds, limonoids were reported to prevent different types of cancer. Furthermore, the structures of citrus limonoids were reported to influence the activity of phase II detoxifying enzymes. The purpose of the study was to evaluate how variations in the structures of citrus limonoids (namely nomilin, deacetyl nomilin, and isoobacunoic acid) and a mixture of limonoids would influence phase II enzyme activity in excised tissues from a mouse model. METHODS: In the current study, defatted sour orange seed powder was extracted with ethyl acetate and subjected to silica gel chromatography. The HPLC, NMR and mass spectra were used to elucidate the purity and structure of compounds. Female A/J mice were treated with three limonoids and a mixture in order to evaluate their effect on phase II enzymes in four different tissues. Assays for glutathione S-transferase and NAD(P)H: quinone reductase (QR) were used to evaluate induction of phase II enzymatic activity. RESULTS: The highest induction of GST against 1-chloro-2,4 dinitrobenzene (CDNB) was observed in stomach (whole), 58% by nomilin, followed by 25% isoobacunoic acid and 19% deacetyl nomilin. Deacetyl nomilin in intestine (small) as well as liver significantly reduced GST activity against CDNB. Additionally isoobacunoic acid and the limonoid mixture in liver demonstrated a significant reduction of GST activity against CDNB. Nomilin significantly induced GST activity against 4-nitroquinoline 1-oxide (4NQO), intestine (280%) and stomach (75%) while deacetyl nomilin showed significant induction only in intestine (73%). Induction of GST activity was also observed in intestine (93%) and stomach (45%) treated with the limonoid mixture. Finally, a significant induction of NAD(P)H: quinone reductase (QR) activity was observed by the limonoid mixture in stomach (200%). In addition, the deacetyl nomilin treatment group displayed an increase in QR activity in liver (183%) and intestine (22%). CONCLUSION: The results of the present study suggests that, dietary intake of citrus limonoids may provide a protective effect against the onset of various cancers by inducing the activity of certain phase II detoxifying enzymes in specific organs. PMID- 20846450 TI - Risk of venous thromboembolism after total hip and knee replacement in older adults with comorbidity and co-occurring comorbidities in the Nationwide Inpatient Sample (2003-2006). AB - BACKGROUND: Venous thromboembolism is a common, fatal, and costly injury which complicates major surgery in older adults. The American College of Chest Physicians recommends high potency prophylaxis regimens for individuals undergoing total hip or knee replacement (THR or TKR), but surgeons are reluctant to prescribe them due to fear of excess bleeding. Identifying a high risk cohort such as older adults with comorbidities and co-occurring comorbidities who might benefit most from high potency prophylaxis would improve how we currently perform preoperative assessment. METHODS: Using the Nationwide Inpatient Sample, we identified older adults who underwent THR or TKR in the U.S. between 2003 and 2006. Our outcome was VTE, including any pulmonary embolus or deep venous thrombosis. We performed multivariate logistic regression analyses to assess the effects of comorbidities on VTE occurrence. Comorbidities under consideration included coronary artery disease, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), diabetes, and cerebrovascular disease. We also examined the impact of co-occurring comorbidities on VTE rates. RESULTS: CHF increased odds of VTE in both the THR cohort (OR = 3.08 95% CI 2.05-4.65) and TKR cohort (OR = 2.47 95% CI 1.95-3.14). COPD led to a 50% increase in odds in the TKR cohort (OR = 1.49 95% CI 1.31-1.70). The data did not support synergistic effect of co-occurring comorbidities with respect to VTE occurrence. CONCLUSIONS: Older adults with CHF undergoing THR or TKR and with COPD undergoing TKR are at increased risk of VTE. If confirmed in other datasets, these older adults may benefit from higher potency prophylaxis. PMID- 20846451 TI - Expression of leukotriene receptors in the rat dorsal root ganglion and the effects on pain behaviors. AB - BACKGROUND: Leukotrienes (LTs) belong to the large family of lipid mediators implicated in various inflammatory conditions such as asthma and rheumatoid arthritis. Four distinct types (BLT1, BLT2, CysLT1 and CysLT2) of G-protein coupled receptors for LTs have been identified. Several studies have reported that LTs are involved in inflammatory pain, but the mechanism and the expression of LT receptors in the nociceptive pathway are unknown. RESULTS: We investigated the precise expression of these four types of LT receptors in the adult rat dorsal root ganglion (DRG) using reverse transcription-polymerase reaction (RT PCR) and radioisotope-labeled in situ hybridization histochemistry (ISHH). We detected mRNAs for BLT1 and CysLT2 in the DRG, but not for BLT2 and CysLT1. CysLT2 mRNA was preferentially expressed by small sized DRG neurons (about 36% of total neurons), whereas BLT1 mRNA was expressed by non-neuronal cells. Double labeling analysis of CysLT2 with NF-200, calcitonin gene-related peptide (CGRP), isolectin B4 (IB4), transient receptor potential vanilloid subfamily 1 (TRPV1) and P2X3 receptor revealed that many CysLT2-labeled neurons were localized with unmyelinated and non-peptidergic neurons, and interestingly, CysLT2 mRNA heavily co-localized with TRPV1 and P2X3-positive neurons. Intraplantar injection of LTC4, a CysLT2 receptor agonist, itself did not induce the thermal hyperalgesia, spontaneous pain behaviors or swelling of hind paw. However, pretreatment of LTC4 remarkably enhanced the painful behaviors produced by alpha, beta-methylene adenosine 5'-triphosphate (alphabeta-me-ATP), a P2X3 receptor agonist. CONCLUSIONS: These data suggests that CysLT2 expressed in DRG neurons may play a role as a modulator of P2X3, and contribute to a potentiation of the neuronal activity following peripheral inflammation. PMID- 20846452 TI - Study on association between genetic polymorphisms of haem oxygenase-1, tumour necrosis factor, cadmium exposure and malaria pathogenicity and severity. AB - BACKGROUND: Malaria is the most important public health problems in tropical and sub-tropical countries. Haem oxygenase (HO) enzyme and the pro-inflammatory cytokine tumour necrosis factor (TNF) have been proposed as one of the factors that may play significant role in pathogenicity/severity of malaria infection. HO is the enzyme of the microsomal haem degradation pathway that yields biliverdin, carbon monoxide, and iron. In this study, the association between malaria disease pathogenicity/severity and (GT)n repeat polymorphism in the promoter region of the inducible HO-1 including the effect of cadmium exposure (potent inducer of HO 1 transcription) as well as polymorphism of TNF were investigated. METHODS: Blood samples were collected from 329 cases non-severe malaria with acute uncomplicated Plasmodium falciparum malaria (UM) and 80 cases with Plasmodium vivax malaria (VM), and 77 cases with severe or cerebral malaria (SM) for analysis of genetic polymorphisms of HO-1 and TNF and cadmium levels. These patients consisted of 123 (25.3%) Thai, 243 (50.0%) Burmese and 120 (24.7%) Karen who were present at Mae Sot General Hospital, Mae Sot, Tak Province, Thailand. RESULTS: The number of (GT)n repeats of the HO-1 gene in all patients varied between 16 and 39 and categorized to short (S), medium (M) and long (L) GTn repeats. The genotype of (GT)n repeat of HO-1 was found to be significantly different among the three ethnic groups of patients. Significantly higher frequency of S/L genotype was found in Burmese compared with Thai patients, while significantly lower frequencies of S/S and M/L but higher frequency of M/M genotype was observed in Burmese compared with Karen patients. No significant association between HO-1 and TNF polymorphisms including the inducing effect of cadmium and malaria pathogenicity/severity was observed. CONCLUSIONS: Difference in the expression of HO-1 genotype in different ethnic groups may contribute to different severity of malaria disease. With this limited sample size, the finding of the lack of association between malaria disease pathogenicity/severity genetic polymorphisms of HO-1 (GT)n repeat as well as TNF observed in this study may not entirely exclude their possible link with malaria disease pathogenicity/severity. Further study in larger sample size is required. PMID- 20846454 TI - Augmentation of neovascularization in murine hindlimb ischemia by combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells transplantation. AB - OBJECTIVES: We postulated that combining high-dose simvastatin with bone marrow derived-mesenchymal stem cells (MSCs) delivery may give better prognosis in a mouse hindlimb ischemia model. METHODS: Mouse hindlimb ischemia model was established by ligating the right femoral artery. Animals were grouped (n = 10) to receive local injection of saline without cells (control and simvastatin groups) or with 5 * 106 MSCs (MSCs group). Animals received either simvastatin (20 mg/kg/d, simvastatin and combination groups) or saline(control and MSCs group) gavages for continual 21 days. The blood flow was assessed by laser Doppler imaging at day 0,10 and 21 after surgery, respectively. Ischemic muscle was harvested for immunohistological assessments and for VEGF protein detection using western blot assay at 21 days post-surgery. In vitro, MSCs viability was measured by MTT and flow cytometry following culture in serum-free medium for 24 h with or without simvastatin. Release of VEGF by MSCs incubated with different doses of simvastatin was assayed using ELISA. RESULTS: Combined treatment with simvastatin and MSCs induced a significant improvement in blood reperfusion, a notable increase in capillary density, a highest level of VEGF protein and a significant decrease in muscle cell apoptosis compared with other groups. In vitro, simvastatin inhibited MSCs apoptosis and increased VEGF release by MSCs. CONCLUSIONS: Combination therapy with high-dose simvastatin and bone marrow derived MSCs would augment functional neovascularization in a mouse model of hindlimb ischemia. PMID- 20846453 TI - MAL2 and tumor protein D52 (TPD52) are frequently overexpressed in ovarian carcinoma, but differentially associated with histological subtype and patient outcome. AB - BACKGROUND: The four-transmembrane MAL2 protein is frequently overexpressed in breast carcinoma, and MAL2 overexpression is associated with gain of the corresponding locus at chromosome 8q24.12. Independent expression microarray studies predict MAL2 overexpression in ovarian carcinoma, but these had remained unconfirmed. MAL2 binds tumor protein D52 (TPD52), which is frequently overexpressed in ovarian carcinoma, but the clinical significance of MAL2 and TPD52 overexpression was unknown. METHODS: Immunohistochemical analyses of MAL2 and TPD52 expression were performed using tissue microarray sections including benign, borderline and malignant epithelial ovarian tumours. Inmmunohistochemical staining intensity and distribution was assessed both visually and digitally. RESULTS: MAL2 and TPD52 were significantly overexpressed in high-grade serous carcinomas compared with serous borderline tumours. MAL2 expression was highest in serous carcinomas relative to other histological subtypes, whereas TPD52 expression was highest in clear cell carcinomas. MAL2 expression was not related to patient survival, however high-level TPD52 staining was significantly associated with improved overall survival in patients with stage III serous ovarian carcinoma (log-rank test, p < 0.001; n = 124) and was an independent predictor of survival in the overall carcinoma cohort (hazard ratio (HR), 0.498; 95% confidence interval (CI), 0.34-0.728; p < 0.001; n = 221), and in serous carcinomas (HR, 0.440; 95% CI, 0.294-0.658; p < 0.001; n = 182). CONCLUSIONS: MAL2 is frequently overexpressed in ovarian carcinoma, and TPD52 overexpression is a favourable independent prognostic marker of potential value in the management of ovarian carcinoma patients. PMID- 20846455 TI - Practice of walking and its association with perceived environment among elderly Brazilians living in a region of low socioeconomic level. AB - BACKGROUND: The aim of this study was analyze associations between the practice of walking and environmental perception among elderly Brazilians in a region of low socioeconomic level. METHODS: A cross-sectional study was conducted among 385 elderly people aged 60 years and over. To evaluate walking, the International Physical Activity Questionnaire (IPAQ), long version (leisure and transport modules) was used. The environment was evaluated by means of the Neighborhood Environmental Walkability Scale (NEWS) (adapted Brazilian version). For the statistical analysis, multiple logistic regression models were created separately for men and women. The practice of at least 150 minutes a week of walking was the dependent variable, and the variables of environmental perception were the independent variables. All the models were controlled for schooling level and age. RESULTS: The proportion of elderly people active in walking was 56.9% for the men and 26.4% for the women. The perception of the presence of soccer fields (OR = 4.12) and their proximity, within ten minutes' walk from home (OR = 3.43), were associated with the practice of walking among the men. The perception of the presence of public squares (OR = 4.70) and the proximity of primary healthcare units, within ten minutes' walk from home (OR = 3.71), were associated with the practice of walking among the women. An association with adequate perception of vehicle traffic remained at the threshold of significance for the women. CONCLUSION: Accessibility of leisure structures such as football fields and public squares and of health services such as primary healthcare units were important environmental variables associated with the practice of walking among elderly people living in a region of low socioeconomic level in Brazil. These variables need to be taken into consideration when aiming to promote the practice of walking among elderly people living in similar regions. PMID- 20846456 TI - Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. AB - BACKGROUND: Colorectal cancer (CRC) has long been associated with bacteremia and/or endocarditis by Streptococcus gallolyticus member bacteria (SGMB) but the direct colonization of SGMB along with its molecular carcinogenic role, if any, has not been investigated. We assessed the colonization of SGMB in CRC patients with history of bacteremia (CRC-w/bac) and without history of bacteremia (CRC wo/bac) by isolating SGMB from feces, mucosal surfaces of colorectum, and colorectal tissues and detecting SGMB DNA, via PCR and in situ hybridization (ISH) assays targeting SodA gene in colorectal tissues. Moreover, mRNA of IL1, IL 8, COX-2, IFN-gamma, c-Myc, and Bcl-2 in colorectal tissues of studied groups was assessed via ISH and RT-PCR. RESULTS: SGMB were found to be remarkably isolated in tumorous (TU) and non-tumorous (NTU) tissues of CRC-w/bac, 20.5% and 17.3%, and CRC-wo/bac, 12.8% and 11.5%, respectively while only 2% of control tissues revealed SGMB (P < 0.05); such contrast was not found in mucosal and fecal isolation of SGMB. The positive detection of SGMB DNA in TU and NTU of CRC-w/bac and CRC-wo/bac via PCR, 48.7%, 35.9%, 32.7%, and 23%, respectively, and ISH, 46.1%, 30.7%, 28.8%, and 17.3%, respectively, was higher than in control tissues, 4 and 2%, respectively (P < 0.05). SGMB count measured via quantitative PCR of SGMB DNA in terms of copy number (CN), in TU and NTU of CRC-w/bac and CRC-wo/bac, 2.96-4.72, 1.29-2.81, 2.16-2.92, and 0.67-2.07 log10 CN/g respectively, showed higher colonization in TU than in NTU and in CRC-w/bac than in CRC-wo/bac (P < 0.05). The PCR-based mRNA ratio and ISH-based percentage of positively stained cells of IL-1, 1.77 and 70.3%, COX-2, 1.63 and 44.8%, and IL-8, 1.73 and 70.3%, respectively, rather than IFN-gamma, c-Myc, and Bcl-2, were higher in SGMB positive patients than in control or SGMB negative patients (P < 0.05). CONCLUSIONS: The current study indicated that colorectal cancer is remarkably associated with SGMB; moreover, molecular detection of SGMB in CRC was superior to link SGMB with CRC tumors highlighting a possible direct and active role of SGMB in CRC development through most probably inflammation-based sequel of tumor development or propagation via, but not limited to, IL-1, COX-2, and IL-8. PMID- 20846457 TI - Production, purification and characterization of polyclonal antibody against the truncated gK of the duck enteritis virus. AB - Duck virus enteritis (DVE) is an acute, contagious herpesvirus infection of ducks, geese, and swans, which has produced significant economic losses in domestic and wild waterfowl. With the purpose of decreasing economic losses in the commercial duck industry, studying the unknown glycoprotein K (gK) of DEV may be a new method for preferably preventing and curing this disease. So this is the first time to product and purify the rabbit anti-tgK polyclonal antibody. Through the western blot and ELISA assay, the truncated glycoprotein K (tgK) has good antigenicity, also the antibody possesses high specificity and affinity. Meanwhile the rabbit anti-tgK polyclonal antibody has the potential to produce subunit vaccines and the functions of neutralizing DEV and anti-DEV infection because of its neutralization titer. Indirect immunofluorescent microscopy using the purified rabbit anti-tgK polyclonal antibody as diagnostic antibody was susceptive to detect a small quantity of antigen in tissues or cells. This approach also provides effective experimental technology for epidemiological investigation and retrospective diagnose of the preservative paraffin blocks. PMID- 20846458 TI - Suberoylanilide hydroxamic acid induces apoptosis and sub-G1 arrest of 320 HSR colon cancer cells. AB - BACKGROUND: Histone deacetylases and histone acetyl transferases covalently modify histone proteins, consequentially altering chromatin architecture and gene expression. METHODS: The effects of suberoylanilide hydroxamic acid, a HDAC inhibitor, on 320 HSR colon cells were assessed in 320 HSR colon cancer cells. RESULTS: Concentration and time-dependent inhibition of 320 HSR cell proliferation was observed. Treatment of 320 HSR cells with 5 MUM SAHA for 72 h significantly inhibited their growth by 50% as compared to that of the control. Fluorescence-activated cell sorting analysis demonstrated significant inhibition of cell cycle progression (sub-G1 arrest) and induction of apoptosis upon various SAHA concentrations after 48 h. In addition, the anti-apoptosis proteins, survivin and Bcl-xL, were significantly inhibited by SAHA after 72 h of treatment. Immunocytochemistry analysis revealed that SAHA-resistant cells were positive for cyclin A (85%), ki-67 (100%), p53 (100%), survivin (100%), and p21 (90%) expression. Furthermore, a significant increase cyclin A-, Ki-67-, p53-, survivin-, and p21-positive cells were noted in SAHA-resistant tumor cells. CONCLUSION: Our results demonstrated for the first time in 320 HSR colon adenocarcinoma cells that SAHA might be considered as an adjuvant therapy for colon adenocarcinoma. PMID- 20846459 TI - A study of association between expression of hOGG1, VDAC1, HK-2 and cervical carcinoma. AB - BACKGROUND: Human 8-oguanine glycosylase 1(hOGG1), voltage-dependent anion channel 1(VDAC1), hexokinase 2(HK-2), represented the process of oxidative DNA damage, cell apoptosis and glycolysis, respectively. This study aims to explore the association between expression of hOGG1, VDAC1, HK-2 and cervical carcinoma. METHODS: A case-control study was conducted. 65 cervical biopsy samples consist of 20 control and 45 cases. The expression of hOGG1, VDAC1 and HK-2 were examined with immunohistochemistry(IHC), immunolabeling was evaluated with stereological cell counts. RESULTS: The data showed that the positive proportion of hOGG1 and HK-2 in the case group was higher than that of the control group (P < 0.05). Further, there was an increasing trend for the positive proportion and expression degree of hOGG1 and HK-2 from Control, Mild cervical carcinoma (MCC), Intermediate cervical carcinoma(ICC) to Severe cervical carcinoma(SCC) in order (P < 0.05). To VDAC1, the significant result was not obtained. CONCLUSIONS: The results suggested that there was a close association between expression of hOGG1, HK-2 and cervical cancer. hOGG1 and HK-2 might play a key role at the early stage of cervical cancer, and the findings of hOGG1 and HK-2 should be considered as a significant biomarker at the early stage of cervical cancer. PMID- 20846460 TI - The search for stable prognostic models in multiple imputed data sets. AB - BACKGROUND: In prognostic studies model instability and missing data can be troubling factors. Proposed methods for handling these situations are bootstrapping (B) and Multiple imputation (MI). The authors examined the influence of these methods on model composition. METHODS: Models were constructed using a cohort of 587 patients consulting between January 2001 and January 2003 with a shoulder problem in general practice in the Netherlands (the Dutch Shoulder Study). Outcome measures were persistent shoulder disability and persistent shoulder pain. Potential predictors included socio-demographic variables, characteristics of the pain problem, physical activity and psychosocial factors. Model composition and performance (calibration and discrimination) were assessed for models using a complete case analysis, MI, bootstrapping or both MI and bootstrapping. RESULTS: Results showed that model composition varied between models as a result of how missing data was handled and that bootstrapping provided additional information on the stability of the selected prognostic model. CONCLUSION: In prognostic modeling missing data needs to be handled by MI and bootstrap model selection is advised in order to provide information on model stability. PMID- 20846461 TI - Brain-derived neurotrophic factor signalling mediates antidepressant effects of lamotrigine. AB - The anticonvulsant drug lamotrigine has been shown to produce antidepressant effects in patients with bipolar disorder. To date, only a few preclinical studies have been conducted using lamotrigine treatment in the forced swim test (FST), an animal model of depression with low face validity. The underlying mechanisms by which lamotrigine works have not been well characterized either. This study extends earlier work on the role of brain-derived neurotrophic factor (BDNF) in regulating the antidepressant actions of lamotrigine. We showed that in rats subjected to chronic unpredictable stress, chronic administration of 30 mg/kg lamotrigine ameliorates behavioural deficits of stressed rats in both sucrose preference test (SPT) and novelty-suppressed feeding test (NSFT). In parallel, chronic lamotrigine treatment up-regulates frontal and hippocampal BDNF protein expression in both naive and stressed animals, and restores the stress induced down-regulation of BDNF levels. In addition, inhibition of BDNF signalling by infusion of K252a, an inhibitor of the BDNF receptor TrkB, blocks the antidepressant effects of lamotrigine in SPT, NSFT and FST. Taken together, this study provides further evidence that BDNF is an essential mediator for the antidepressant effects of lamotrigine. PMID- 20846462 TI - Elevated cortical glutamate in young people at increased familial risk of depression. AB - Using proton magnetic resonance spectroscopy (MRS), we have demonstrated regional abnormalities in cortical gamma-aminobutyric acid (GABA) and glutamate in medication-free recovered depressed patients. It is unclear whether these changes represent an underlying trait vulnerability to depression, or an after-effect of episodes of illness or its treatment. We sought to examine this question by examining a group of high-risk, never-depressed, individuals. We used MRS to measure GABA and glutamate in parieto-occipital cortex in young people (ages 16 21 yr) with a family history of parental depression (n=24) but no personal history of illness and a control group without a history of depression in any first-degree relative (n=28). Participants with a parental history of depression had significantly higher levels of glutamate than controls in parieto-occipital cortex (F1,47=5.5, p=0.02). These findings suggest that abnormalities in glutamate neurotransmission may reflect a trait marker of vulnerability to depression. PMID- 20846463 TI - 5-HT2B receptors are expressed on astrocytes from brain and in culture and are a chronic target for all five conventional 'serotonin-specific reuptake inhibitors'. AB - In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the 'serotonin-specific reuptake inhibitor' (SSRI) fluoxetine leads acutely to 5-HT2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) with an EC50 of ~5 MUM, and chronically to ERK1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A2 (cPLA2) with ten fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK1/2 and mRNA and protein expression of cPLA2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT2 receptor, the 5 HT2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA2a expression during chronic treatment; citalopram had a similar effect at 0.1-0.5 MUM; these are therapeutically relevant concentrations. PMID- 20846464 TI - The effect of consanguinity on congenital disabilities in the Kuwaiti population. AB - Consanguinity has been shown to increase homozygosity and to reduce genetic variation in a group, which may protect against the expression of recessive genes that can lead to genetic disorders. Consanguineous marriages are practised widely in Kuwait. The major aim of this study is to delineate the association of consanguineous marriages with congenital disabilities in different Kuwaiti population subcultures. A total of 9104 married Kuwaiti females aged 15-79 years from different backgrounds were selected at ten primary health care centres from six governorates in Kuwait. Data were collected using a questionnaire and analysed with chi-squared tests. The data indicate significant differences in the occurrence of genetic diseases in consanguineous couples' offspring (4.88%) compared with those of non-consanguineous couples (4.13%) (p<0.002). The results also show significant differences in frequencies of genetic/environmental diseases in consanguineous couples' offspring (8.59%) compared with those of non consanguineous couples (8.23%) (p<0.005). No significant differences between the two groups regarding environmental diseases were observed. A higher frequency of genetic diseases was found in first- (6.97%; p<0.001), second- (6.78%; p<0.001) and third-cousin (6.46%; p<0.022) couples' offspring compared with those of non consanguineous couples. The frequency of congenital disabilities in the offspring of couples from consanguineous marriages (2.9%) is higher than that in the offspring of non-consanguineous marriages (2.3%). But this difference is not significant at the 0.05 level. First-cousin marriages have the highest frequency (3.5%) of congenital disabilities compared with other kinds of marriages (2.1 2.3%). Differences across groups are significant (p<0.036). Significant differences are found for first-cousin couples in both physical (2.37; p<0.042) and mental (0.74; p<0.037) disabilities compared with non-consanguineous couples. No significant differences were observed in deafness and blindness disabilities. The data show no significant differences between second- and third-cousin and non consanguineous couples in physical, mental or deafness and blindness disabilities. There are no significant differences in the percentages of offspring with congenital disabilities in consanguineous and non-consanguineous marriages across sub-population groups for the total of four types of congenital disability. PMID- 20846465 TI - Mens' attitudes about abortion in Uganda. AB - Abortion is illegal in Uganda except to save the life of the woman. Nevertheless, the practice is quite common: about 300,000 induced abortions occur annually among Ugandan women aged 15-49 (Singh et al., 2005) and a large proportion of these women require treatment for post-abortion complications. In the male dominant culture of Uganda, where men control most of the financial resources, men play a critical part in determining whether women receive a safe abortion, or appropriate treatment if they experience abortion complications. This study examines men's roles in determining women's access to a safer abortion and post abortion care. It draws on in-depth interviews carried out in 2003 with 61 women aged 18-60 and 21 men aged 20-50 from Kampala and Mbarara, Uganda. Respondents' descriptions of men's involvement in women's abortion care agreed that men's stated attitudes about abortion often prevented women from involving them in either the abortion or post-abortion care. Most men believe that if a woman is having an abortion, it must be because she is pregnant with another man's child, although this does not correspond with women's reasons for having an abortion--a critical disjuncture revealed by the data between men's perceptions of, and women's realities regarding, reasons for seeking an abortion. If the woman does experience post-abortion complications, the prevailing attitude among men in the sample was that they cannot support a woman in such a situation seeking care because if it had been his child, she would not have had a covert abortion. Since money is critical to accessing appropriate care, without men's support, women seeking an abortion may not be able to access safer abortion options and if they experience complications, they may delay care-seeking or may not obtain care at all. Barriers to involving men in abortion decision-making endanger women's health and possibly their lives. PMID- 20846466 TI - The prevalence of, and factors associated with, overweight and obesity in Botswana. AB - The aim of this study was to estimate the prevalence of, and socio-demographic factors associated with, overweight and obesity in Botswana. A cross-sectional survey was conducted in 2007 using a multistage sampling method to select a representative sample of 4107 men and 4916 women aged 20-49 years. Logistic regression analysis was used to identify the socio-demographic factors associated with overweight and obesity. Mean BMI values for men and women were 21.7 kg/m2 and 24.4 kg/m2, respectively. Both overweight and obesity levels were higher among women than men. Overall, 23% of women were overweight compared with 13% of men. Obese women constituted about 15% compared with only 3% of men. However, 19% of men were underweight compared with 12% of women. The main socio-demographic factors associated with overweight and obesity were being older, living in a city/town, being married and having attained higher levels of education, and these relationships were statistically significant at the 5% level. Although over nutrition is prevalent among adult female Botswana, underweight remains an important public health problem for males. Programmes and other interventions aimed at concurrently addressing both under-nutrition and overweight need to be developed. PMID- 20846467 TI - Does possession of assets increase women's participation in reproductive decision making? Perceptions of Nigerian women. AB - This study is based on a population-based, descriptive questionnaire survey, the objective of which was to elicit the perceptions of women in south-eastern Nigeria on whether possession of economic/household assets by women enhanced their capacity to negotiate reproductive issues with their husbands. The findings show that the respondents believed that possession of economic/household assets by women in their communities might not necessarily increase their negotiation power in their reproductive decision-making. Other factors tend to attenuate the effects of women's possession of economic/household assets on their reproductive bargaining power. Notable among these may be social norms that implicitly arrogate control of the assets owned by the conjugal couple to the man, even when they are bought by the women. Planners of reproductive health intervention projects, policy-makers and researchers need to be aware of such sociocultural specific phenomena, which do not fit with widely held international beliefs. PMID- 20846468 TI - Paranoid explanations of experience: a novel experimental study. AB - BACKGROUND: Paranoia is a common experience in the non-clinical population. We use a novel experimental methodology to investigate paranoid ideas in individuals without a history of mental illness. AIMS: We aimed to determine whether this paradigm could elicit unfounded paranoid thoughts and whether these thoughts could be predicted by factors from a cognitive model. METHOD: Fifty-eight individuals took part and completed measures assessing trait paranoia, mood, self and other schema and attributional style. They were exposed to two experimental events: 1) an interruption to the testing session by a stooge, and 2) a recording of laughter played outside the testing room and subsequently asked about their explanations for these events. RESULTS: 15.5% (n = 9) of the sample gave a paranoid explanation for at least one of the experimental events. The remainder reported generally neutral explanations. Individuals with a paranoid explanation reported significantly higher levels of trait paranoia. Factors predictive of a paranoid interpretation were interpersonal sensitivity and attributional style. CONCLUSIONS: The results show that spontaneous paranoid explanations can be elicited in non-clinical individuals, even for quite neutral events. In line with current theories, the findings suggest that emotional processes contribute to paranoid interpretations of events, although, as a novel study with a modest sample, it requires replication. PMID- 20846469 TI - How does thought-action fusion relate to responsibility attitudes and thought suppression to aggravate the obsessive-compulsive symptoms? AB - BACKGROUND: Comprehensive cognitive theories of obsessive compulsive disorder (OCD) propose that clinical obsessions and compulsions arise from specific sorts of dysfunctional beliefs and appraisals, such as inflated sense of responsibility, thought-action fusion (TAF), and thought suppression. AIMS: The present study aimed to examine the mediator roles of responsibility and thought suppression between TAF and obsessive-compulsive symptoms. Specifically, it aimed to explore the relative effects of TAF factors (i.e. morality and likelihood) on inflated sense of responsibility and on thought suppression to increase the obsessive qualities of intrusions. METHOD: Two hundred and eighty-three Turkish undergraduate students completed a battery of measures on responsibility, thought suppression, TAF, OC symptoms, and depression. RESULTS: A series of hierarchical regression analyses, where depressive symptoms were controlled for, indicated that TAF-morality and TAF-likelihood follow different paths toward OC symptoms. Although TAF-morality associated with inflated sense of responsibility, TAF likelihood associated with thought suppression efforts, and in turn these factors increased OC symptoms. CONCLUSIONS: These findings provide support for the critical role of sense of responsibility and thought suppression between the relationship of TAF and OC symptoms. Findings were discussed in line with the literature. PMID- 20846470 TI - Equity in health care: the Irish perspective. AB - Equity is espoused in many national health policy statements but is a complex concept and is difficult to define. The way in which equity is defined in policy has implications for how the health-care system should be structured. Conflicts between different definitions of equity are identified in theory and policy. This paper discusses these issues, with specific focus on the equity principles underpinning the Irish health-care system. The complex mix of public and private funding in the Irish system brings the challenges in identifying (and achieving) equity objectives more sharply into view, and serves as a warning system for other countries. PMID- 20846471 TI - VEGF, substance P and stress, new aspects: a revisited study. AB - Mast cells play an essential role in diverse physiological and pathological processes, such as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis, directly interact with bacteria, and appear to play a vital role in host defense against pathogens. Mast cells could be recruited in the inflammatory site, by MCP-1, RANTES and SCF, to selectively secrete proinflammatory molecules; these could include growth factors, histamine, which is mitogenic (H1) and an immunosuppressant (H2), neovascularization agents, such as heparin, IL-8, and VEGF, as well as proteases that could permit new blood vessel formation. Neurogenic inflammation involves vasodilation and plasma protein extravasation in response to neural stimulation. Upon stimulation, sensory neurons release Substance P and other neuropeptides and activate neurokinin-1 receptors leading to plasma protein extravasation from post-capillary venules. Substance P is a neuropeptide that is released from nerve endings in many tissues and plays an important role in immunological and inflammatory states, and it is also a mediator of tissue injury, asthma, arthritis, allergy and autoimmune diseases. SP positive nerve fibers and mast cell contacts are increased by acute stress in mice leading to dermal mast cell degranulation. VEGF is produced by flammatory cells. IL-33 is the newest inflammatory member of the IL-1 cytokine family and we show here that SP can induce VEGF secretion from mast cells and IL-33 augments the effect of SP in VEGF transcription and translation protein. PMID- 20846472 TI - Tissue infiltrating lymphocytes: the role of cytokines in their growth and differentiation. AB - The second half of the XX century saw a continuous improvement in the understanding of cellular immunology. The discovery of monoclonal antibodies permitted to identify several functional T-cell subpopulations, characterized by a specific pattern of cytokine secretion. According to their functions, cytokines have been divided into two main groups: pro- and anti- inflammatory. Cytokines are involved in several aspects of immunity and inflammation. Because of its importance in host defence, the cytokine system is redundant and therefore different cytokines may perform similar activities. Although cytokines and inflammatory processes have been studied widely in the peripheral blood, it is our opinion that the most important pathogenetic events occur at the tissue level, therefore the study of Tissue-infiltrating lymphocytes (TIL) is of foremost importance. In this review we therefore focus on the cytokine microenvironment; different local tissue cytokine-cocktails can modulate and regulate T-cell proliferation and differentiation. CD4+ T-cells are not characterized by irreversibly differentiated endpoints, but there is an evident plasticity of these cells with a large possibility of differentiation options. We will discuss the issue and give examples of the diseases where the study of TIL and their microenvironment are most significant, including tumors, primary immunodeficiencies, rheumathoid arthritis, inflammatory skin diseases and coronary disease. We also review the role of apoptosis and the environment of mucosal immunity. PMID- 20846473 TI - Current strategies for the treatment of autoimmune diseases. AB - Autoimmune disease therapy may be considered a puzzle under construction. Current treatments for autoimmune diseases include physical therapy, non-steroidal anti inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-inflammatory drugs (DMARDs), anticytokine therapies, inhibition of intracellular-signaling pathways, costimulation inhibition, biological inhibitors of T cell function, B cell anergy and depletion, regulatory T cells, stem cell transplantion. New biologic drugs that target specific cells or cytokines involved in the early inflammatory response started because of their improved efficacy and limited toxicity. The hematopoietic stem cell transplantation represents a possible therapeutic strategy for autoimmune diseases resistant to available treatments. PMID- 20846474 TI - Meat-specific IgG and IgA antibodies coexist with IgE antibodies in sera from allergic patients: clinical association and modulation by exclusion diet. AB - IgE-mediated responses play a pivotal role in allergic patients with food intolerance. However, the association of food-specific IgG and IgA antibodies with the clinical outcome of allergic patients is still a matter of controversy. In this study we investigate whether beef-specific IgG and IgA antibodies may coexist with beef-specific IgE antibodies in food-allergic patients and examined their clinical relevance in different allergic settings. Beef-specific IgE, IgG and IgA antibodies were determined by solid-phase enzymoimmunoassay (ELISA) in a population of allergic patients (N=125) classified into patients with asthma, skin disease or gastrointestinal disorders, as well as in control subjects (N=80). IgE antibodies specific for citric fruits, tomato, cows milk, chickens egg and wheat were also determined. Beef was the predominant allergenic food in the whole population, not only for IgE (57.6 percent; P less than 0.001), but also for IgG and IgA isotypes (53.6 percent and 34.0 percent, respectively, P less than 0.001). Beef-specific IgE, IgG and IgA antibodies increased significantly in sera from patients with asthma, gastrointestinal disorders and skin allergy compared to sera from control subjects (P less than 0.001). Remarkably, IgG and IgA isotypes were significantly detected, even in the absence of IgE, in the three allergic conditions. All allergic patients, including those showing only IgG and IgA antibodies, significantly ameliorated their symptoms, and their levels of beef-specific antibodies were considerably reduced in response to a cow meat exclusion diet. While patients with gastrointestinal or skin allergic diseases were capable of tolerating beef following an established period of diet exclusion, asthmatic patients experienced a relapse of symptoms and showed a considerable increase in IgE, IgG and IgA-specific antibodies when re-challenged with a beef-enriched diet. Thus, beef-specific IgG and IgA antibodies coexist with IgE antibodies in sera from allergic patients and are significantly associated with the clinical course of allergic disorders, particularly asthma. PMID- 20846475 TI - Specific inhibition of protein kinase Cbeta expression by antisense RNA affects the activation of Jurkat T lymphoma cells. AB - Antisense RNA technology was employed to specifically inhibit the expression of the protein kinase Cbeta (PKCbeta) isoform in Jurkat cells, to explore its influence on the expression of surface antigens (CD69) and the cytokines interleukin-8 (IL-8), tumour necrosis factor (TNF)-alpha and beta, and to characterise its controversial involvement in the expression of IL-2 and its receptor (IL-2R). Transfection of cells with an antisense PKCbeta construct (as PKCbeta-pREP3) significantly increased IL-2R/CD25 expression in phorbol 12 myristate 13-acetate (PMA)-stimulated as-PKCbeta-pREP3 transfectants, in contrast to Jurkat cells transfected with a control as-PKCalpha-pREP3 plasmid. IL-2 production, in contrast, was strongly inhibited in both transfectant populations stimulated by PMA plus the calcium ionophore ionomycin. Three clones (asb1/asb2/asb3), selected from as-PKCbeta-pREP3 transfectants, showed decreased PKCbeta protein levels (40 percent, 50 percent and 60 percent, respectively, as determined by western blotting) and mRNA levels. The specific inhibition was confirmed in immunoblots for other PKC (alpha, delta, epsilon, gamma, theta, and lambda lambda/tau) isoforms and in immunoprecipitates from representative (c2/asb2) clones. Stimulation of PKCbeta-depleted clones significantly increased CD25 expression but decreased IL-2 production (similarly to as-PKCbeta-pREP3 transfectants) and IL-2 message levels. CD69 expression and IL-8 secretion were significantly decreased, but TNFbeta message levels were highly increased in asb2/asb3 clones, without affecting TNFalpha secretion. Analysis of the mitogen activated protein kinase (MAP Kinase) signalling pathway showed unaltered extracellular signal regulated kinase 1/2 (ERK1/2) and p38 phosphorylation but increased activation of c-Jun N-terminal kinase (JNK1) and its substrate, the transcription factor ATF-2 (activated transcription factor-2), which are involved in IL-2 gene expression. Our results revealed new PKCbeta functions, affecting CD69 expression and IL-8 production, and support the requirement for PKCbeta in IL-2 secretion/transcription and IL-2R regulation. PMID- 20846476 TI - Leptin and its receptors in obese patients with colorectal cancer. AB - The purpose of this study is to examine serum concentration of leptin and that of the soluble form, the Ob-Re receptor, in patients with colorectal cancer, as well as to examine the level of leptin mRNA and that of its receptors, Ob-Ra and Ob Rb, in large intestine specimens collected from patients with colorectal cancer, depending on cancer clinical and pathological progression and BMI. A total of 146 patients with colorectal cancer in a I-IV stage scale according to the TNM Classification were enrolled. The patients were divided into two groups according to BMI calculations based on body weight and height: a Study group (BMI greater than or equal to 25 kg/m2) of 75 patients aged 57 plus or minus 4.5 years and a Control group (20 less than BMI less than 25 kg/m2) of 71 patients aged 60 plus or minus 5 years. The experimental part of the work was performed in two stages: Stage I regarding the assay of leptin concentration and that of its soluble receptor, Ob-Re, in the serum of patients with the use of the ELISA method; and Stage II to determine the number of leptin mRNA copies and two isoforms of leptin receptors, Ob-Ra and Ob-Rb, using the QRT-PCR method in tissue specimens collected from 146 patients. In our results the concentration of serum leptin and Ob-Re was not dependent on the stage of clinical and pathological progression of the cancer. There was a statistically significant higher serum leptin level in colon cancer patients who were overweight or obese compared to patients with normal weight. No presence of mRNA of the gene encoding leptin was found in tissues collected from colorectal cancer patients. The number of mRNA copies of Ob-Rb was statistically significantly higher in all the study groups compared to the reference tissues. PMID- 20846478 TI - An experimental study on minimally occlusive laser-assisted vascular anastomosis in bypass surgery: the importance of temperature monitoring during laser welding procedures. AB - Laser welding has been proposed as an alternative technique to conventional stitching in microvascular anastomosis, with the advantages of improving the vascular healing process and reducing the risk of malfunction of a bypass. Our group recently proposed a laser-assisted end-to-side anastomotic technique, providing the advantages of laser welding and reducing the occlusion time of the recipient vessel, that is important in neurosurgical bypass procedures, in order to reduce the risk of cerebral ischemia. This in vivo study focuses on the control of the temperature dynamics developing in the welded tissue. A jugular vein graft was harvested and implanted on the rabbit carotid artery by means of two end-to-side anastomosis. Laser welding procedure was then carried out to implant the bypass. A real-time monitoring of the temperature during welding was performed with an infrared thermocamera, in order to control the laser-induced heating effect on the external surface of the vessel walls. The temperature analysis highlighted the dynamic of the heating effect in space and time and enabled us to define an optimal temperature range in operative conditions. The temperature control provided safe tissue heating confined within the directly irradiated area, with negligible damage to surrounding tissues, as well as effective sealing and welding of the vessel edges at the anastomotic sites. The average occlusion time of the carotid artery was about 11 minutes. After a follow up of 30 days, all the bypasses were patent and no signs of thrombosis or leak point pressure were present, thus confirming the safety of this laser-assisted anastomotic procedure. PMID- 20846477 TI - Guanosine protects human neuroblastoma cells from oxidative stress and toxicity induced by Amyloid-beta peptide oligomers. AB - Amyloid-beta (Abeta) peptide aggregation forms such as soluble oligomers (O) have a causal role in neuronal dysfunction and death associated with Alzheimer?s Disease (AD). The main efforts for the development of neuroprotective drugs are therefore focused on preventing Abeta production, aggregation or downstream neurotoxic events. We therefore investigated the effect of guanosine (GUO), a guanine based purine, that exerts neurotrophic and neuroprotective effects. The GUO showed the ability to reduce neuronal death in terms of apoptosis, but not necrosis, elicited by Abeta1-42O in human neuroblastoma SH-SY5Y cells. The neuroprotective effect was recorded only when the GUO was added simultaneously to treatment of the SH-SY5Y cells with Abeta1-42O. By contrast, the GUO treatment of SH-SY5Y cells before and after the appearance of beta1-42O toxicity had no neuroprotective effects. The employment of specific inhibitors showed the involvement of neuronal survival pathways, such as PI3K?Akt and MAPK-ERK for the GUO anti-apoptotic effects observed. In parallel, the SH-SY5Y cells treated with GUO, in experimental conditions similar to those adopted to evaluate neuronal death, showed a marked decrease of the early reactive oxygen species formation induced by Abeta1-42O and pro-oxidant H2O2. In the same neuronal model, GUO was also shown to inhibit the extra- and intra-cellular Abeta1-42 release as well as the beta-secretase activity evoked by H2O2 pro-oxidant action. Based on these findings, GUO and other guanine based purines appear to be a promising class of compounds with neuroprotective properties that may play an important role in the therapy of AD. PMID- 20846479 TI - Subclinical candiduria in patients with gastrointestinal malignancies: a preliminary study on the protective effect of a natural phytocompound. AB - There is a great concern for the increasing incidence of candidiasis in cancer patients following immune-suppressive, cytostatic or antibiotic treatment. There are cancer patients with repeat asymptomatic recovery of candida in the urine in whom the choice of treatment, if any, is still a matter of debate. The aim of the study is to test the efficacy and tolerability of a natural anti-fungal phytocompound in patients with tumors of the gastrointestinal tract with prior or ongoing candiduria. Thirty-nine patients with operated gastrointestinal malignancies (18 still under current chemotherapy) with a history of repeated candiduria were enrolled. Eleven patients showed candiduria on enrolment and were treated with K-712, a natural antifungal phytocompound. Genomic analysis was carried out on blood samples of all patients on a monthly basis for 6 months. Within 3 weeks all 11 treated patients had negative cultures in the urine (10 patients after 2 weeks), 7 patients remained free of candiduria throughout the study period while 4 required a new treatment course. Three patients had positive genomic tests for systemic candidiasis and were treated with fluconazole. Eighteen (64 percent) out of the 28 patients who were free of candiduria on enrolment, developed a urinary candida infection during the 6-month follow-up and all cases were successfully treated with K-712. Seven (38 percent) of these cases presented a further recurrence at a later stage and all responded to a new course of K-172. No positive genomic tests were observed during the follow-up period. These data suggest that a consistent part of patients, mostly with gastrointestinal malignancies develop urinary candida infection when following chemotherapy treatment. A therapeutic approach with a natural antifungal phytocompound seems a safe and effective measure and a tentative prophylactic approach might also be envisaged. PMID- 20846480 TI - Physical exercise activates the poly(ADP-ribosyl)ation system in rat testes. AB - Given the high sensitivity of the male reproductive system to oxidative stress and to temperature changes, the amount of germ cell apoptosis and the activation of the poly(ADP-ribosyl)ation system (a very sensitive index of genotoxic stress) were evaluated in the testicular tissue of adult rats which underwent a 10-wk treadmill training, according to either a mild or a strong protocol; rats were sacrificed 24 h after the last training session or after a single bout of an additional stressing exercise (30 min of swimming). Controls were untrained rats (one resting group and one group with acute exercise). Both training and acute exercise increased marginally germ cell apoptotic indexes (caspase-induced poly(ADP-ribose) polymerase fragmentation and TUNEL-positive cells), while the activity of poly(ADP-ribose) polymerase and poly(ADP-ribose) glycohydrolase enzymes was affected in a way that suggests that acute exercise is associated with reversible genotoxic stress, and that training induces adaptive responses, as demonstrated by the activation of poly(ADP-ribose) polymerase system without subsequent increase in apoptosis. PMID- 20846481 TI - Allergen-specific Ig classes in non-allergic individuals. AB - Allergic rhinitis (AR) is characterized by Th2 polarized immune response, such as increased IL-4 and reduced IFN-gamma production, and by a functional defect of T regulatory cells. This impaired immune response profile influences the pattern of immunoglobulin production in allergic patients. However, there is no study that has explored the pattern of allergen-specific Immunoglobulin (Ig) classes in normal subjects. Therefore, the aim of this study is to investigate the allergen specific IgE, IgG, IgG4, and IgA serum level pattern in a group of non-allergic individuals. Forty healthy non-allergic subjects were enrolled. Serum allergen specific IgE, IgG, IgG4, and IgA for mites, cat, Parietaria, grasses, and birch were quantitatively determined by ELISA method. Allergen-specific IgE, IgG, IgG4, and IgA serum levels were significantly different for each tested allergen (p=0.0001 for each class). In conclusion, the present study provides the first evidence that immunoglobulin production pattern depends on the specificity of the allergenic response in non-allergic subjects as well as in allergic patients. In addition, this study is the first that quantitatively evaluates the Ig classes. PMID- 20846482 TI - Circadian rhythmicity of lymphocyte subpopulations and relationship with neuro endocrine system. AB - Lymphocyte subpopulations present circadian variation of some of their subsets, this variation may influence magnitude and expression of the immune responses and may be related to the variation of neuro-endocrine humoral factors. In our study cortisol, melatonin, TRH, TSH, FT4, GH, IGF1 and IL2 serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every four hours for 24 hours from 11 healthy male subjects aged 38-55 years. A clear circadian rhythm was validated for cortisol serum levels, CD8, CD16, TcRdelta1 with acrophase in the morning and at noon, and for melatonin, TRH, TSH, GH, CD3, CD4, CD4/CD8 ratio, HLA-DR, CD20 and CD25 with acrophase at night. Changes of serum levels of FT4, IGF1 and IL2 did not show circadian rhythmicity. In the photoperiod (06.00-18.00h) and in the scotoperiod (18.00-06.00h) there were significant correlations among the lymphocyte subpopulations and humoral factors studied. The results show that specific lymphocyte subsets present different profiles of nyctohemeral changes and different timed relationships with neuro-endocrine hormones. PMID- 20846483 TI - Relationship between asymmetric dimethylarginine and asymptomatic carotid atherosclerosis. AB - Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) associated with an increased risk of cardiovascular disease (CVD). In this study we assessed the relationship between ADMA and asymptomatic carotid intima media thickness (CIMT). Eighty subjects underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and carotid ultrasound investigation (CUI). None of the subjects had symptoms of carotid atherosclerosis and nor were they taking any medication. Statistical analyses showed that high plasma levels of ADMA were positively correlated to CIMT (p less than 0.001). Total cholesterol, low density lipoprotein cholesterol, triglycerides and C-reactive protein plasma concentrations were significantly associated with asymptomatic carotid atherosclerosis (p less than 0.001). High serum concentrations of ADMA were associated with early carotid atherosclerotic lesions as measured by CIMT and represent a new marker of asymptomatic carotid atherosclerosis. PMID- 20846484 TI - Effects of cigarette smoke on salivary superoxide dismutase and glutathione peroxidase activity. AB - Cigarette smoke contains oxidants such as oxygen-free radicals and volatile aldehydes, which are probably the major causes of damage to biomolecules exposed to cigarette smoke. However, saliva has an antioxidant defense system able to counter toxic activities of radical species that is formed by antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH Px). The purpose of this study is to verify the possible effects of cigarette smoke on SOD and GSH-Px. Forty-four patients (25 males and 19 females) were enrolled in this study. The participants were 20 smokers (12 males and 8 females) and 24 non-smokers (13 males and 11 females). Furthermore, 10 subjects of the control group were ex-smokers (9 males and 1 female). Their mean age plus or minus standard deviation (SD) was 58.8 plus or minus 15.9 years for the case group and 73.8 plus or minus 10.6 years for the control group. All patients were underwent a careful anamnestic investigation and examination of the oral cavity. After rinsing the mouth with water, each subject put 3 cc of non-stimulated saliva inside a test tube. The saliva was centrifuged and oral peroxidase and superoxide dismutase activity was measured according to a specific assay. Statistical analysis was performed to evaluate differences between the groups and significant differences were observed for p less than 0.05. A significant decrease of GSH-Px activity was detected in the smoking group (p less than 0.05), while the SOD activity was similar in the control and case groups. According to the sex, a significant decrease of GSH-Px activity was noted in males of the smoker group (p less than 0.05), while in the sample of females no significant difference of the enzymatic activity was found. Moreover, among ex-smokers, there was a significant difference in the values of GSH-Px between those who had not smoked for less than ten years and those who had not smoked for more than ten years. Cigarette smoke may alter the detoxification of hydrogen peroxide through a decrease of GSH-Px activity. The overproduction of H2O2 may lead to an oxidative stress that is involved in a large number of diseases, including precancerous and neoplastic lesions of the oral cavity. The effects of cigarette smoke on salivary antioxidant enzymes decrease after withdrawal from smoking and the benefits become more evident with the passage of time. PMID- 20846485 TI - Chlamydia pneumoniae infection as a risk factor for accelerated atherosclerosis in hemodialysis patients. AB - Atherosclerotic cardiovascular disease is the main cause of morbidity and mortality for end-stage renal disease patients undergoing chronic haemodialysis (HD). Several studies in recent years have identified Chlamydia pneumoniae, a respiratory pathogen, as risk factor for cardiovascular diseases in the general population. The aim of our study is to evaluate chlamydial load, in peripheral blood mononuclear cells (PBMC) of HD patients. Furthermore, the correlation between DNA chlamydial load and markers of inflammation was also examined. PBMC specimens isolated from 49 HD patients and 46 blood donors were analyzed for the presence of C. pneumoniae DNA by real-time PCR and ompA nested touchdown PCR. In HD patients, plasma levels of several inflammatory markers were also determined. A significantly higher rate of C. pneumoniae DNA was found in HD patients (44.9 percent) than in blood donors (19.6 percent) (p=0.016); HD patients were also more likely to have a significantly high chlamydial load (p=0.0004). HD patients with atherosclerotic cardiovascular diseases have a significantly greater chlamydial load than HD patients without cardiovascular diseases (p= 0.006). A significantly higher value of C-reactive protein, IL-6 and advanced oxidative protein products was found in HD patients with a greater chlamydial load (p less than 0.05). Likewise, a significantly lower monocyte HLA-DR percentage (p=0.011) as well as a lower monocyte HLA-DR expression were found in such patients (p= 0.007). In conclusion, our results show that HD patients are at high risk of C. pneumoniae infection correlated with chronic inflammatory response which in turn can lead to accelerated atherosclerosis and other long-term clinical complications such as myocardial infarction and stroke. PMID- 20846486 TI - Influence of magnesium on fatty acids and their esters in isolated rat hepatocytes. AB - The aim of the study is to analyse the changes in the profile of fatty acids and their esters in rat hepatocytes that were incubated for 5 hours with different concentrations of MgCl2 (2 and 4mM) in hepatocyte culture medium. The methyl esters of fatty acids were identified with a GC-MS system included in the Hewlett?Packard quadrupolar mass spectrometer, coupled with a Hewlett-Pacard 5890 gas chromatograph with an ionisation potential of 70 eV and recorded on a Vectra 386 computer. We observed differences in the amount of saturated, monounsaturated and polyunsaturated fatty acids among the examined samples. In the control sample, the largest component consisted of the pool of saturated and monounsaturated fatty acids. Analysing the changes in the profile of ester-bound fatty acids, we found statistically significant differences when 4 mM MgCl2 was presented. The amount of C18:2, C18:1b and C20:4a decreased in comparison with the control sample. PMID- 20846487 TI - Sodium iodide associated to salicylic acid in the topical management of chronic oral candidiasis: a randomized trial. AB - Candidiasis is a relevant problem in oral medicine practice. We compared the antimycotic activity of nystatin with a solution of sodium iodide associated to salicylic acid (SISA) in the topical management of chronic candidiasis. Consecutive patients affected by chronic candidiasis were randomly allocated to SISA (group A) or nystatin (group B). VAS and swab scores were recorded at the beginning and at the end of the study while the healing index was evaluated at the end of the study only. Data were analyzed by STATA 10 MP. Forty patients (20 male, 20 female) were randomized. SIAS was as effective as nystatin in affecting VAS (p greater than 0.05) and swab score (p greater than 0.05). A statistically significant reduction (p less than 0.05) of healing index was observed in both groups. No side effects were reported. SISA topical application, shows a comparable efficacy to the nystatin in the management of chronic oral candidiasis. Its use could represent an adequate alternative to the nystatin above all in the cases of drug-resistance. Further large scale randomized trials are warranted to confirm these preliminary findings. PMID- 20846488 TI - An evolving integrative physiology: skeleton and energy metabolism. AB - The adipocyte-derived hormone leptin regulates appetite and bone mass. Recent research demonstrates that reciprocally, osteoblasts have a role in controlling energy metabolism. Several genes expressed in osteoblasts are involved in this process, and one of them is the Esp gene. The remaining genes regulate Esp gene expression. OST-PTP, the protein name of Esp, regulates the carboxylation of osteocalcin secreted from osteoblasts, thus affecting insulin sensitivity and insulin secretion. This review provides evidence for a novel interpretation of the connection between bone and energy metabolism and expands our understanding of the novel physiology of bone beyond its classical functions. PMID- 20846489 TI - Maintenance of cellular tetrahydrobiopterin homeostasis. AB - Tetrahydrobiopterin (BH4) is a multifunctional cofactor of aromatic amino acid hydroxylases and nitric oxide synthase (NOS) as well as an intracellular antioxidant in animals. Through regulation of NOS activity BH4 plays a pivotal role not only in a variety of normal cellular functions but also in the pathogenesis of cardiovascular and neurodegenerative diseases, which develop under oxidative stress conditions. It appears that a balanced interplay between BH4 and NOS is crucial for cellular fate. If cellular BH4 homeostasis maintained by BH4 synthesis and regeneration fails to cope with increased oxidative stress, NOS is uncoupled to generate superoxide rather than NO and, in turn, exacerbates impaired BH4 homeostasis, thereby leading to cell death. The fundamental biochemical events involved in the BH4-NOS interplay are essentially the same, as revealed in mammalian endothelial, cardiac, and neuronal cells. This review summarizes information on the cellular BH4 homeostasis in mammals, focusing on its regulation under normal and oxidative stress conditions. PMID- 20846490 TI - Alterations in dopamine and glutamate neurotransmission in tetrahydrobiopterin deficient spr-/- mice: relevance to schizophrenia. AB - Tetrahydrobiopterin (BH4) is a pivotal cofactor for enzymes responsible for the synthesis and release of monoamine neurotransmitters including dopamine (DA) and serotonin (5-HT) as well as the release of glutamate (Glu). Deficiencies in BH4 levels and reduced activities of BH(4)-associated enzymes have been recently reported in patients with schizophrenia. Accordingly, it is possible that abnormalities in the biochemical cascades regulated by BH(4) may alter DA, 5-HT and Glu neurotransmission, and consequently contribute to the pathophysiology of different neuropsychiatric diseases including schizophrenia. The development of a novel strain of mutant mice that is deficient in BH(4) by knocking out the expression of a functional sepiapterin reductase gene (spr -/-) has added new insights into the potential role of BH(4) in the pathophysiology and improved treatment of schizophrenia. PMID- 20846491 TI - Identification of troglitazone responsive genes: induction of RTP801 during troglitazone-induced apoptosis in Hep 3B cells. AB - Troglitazone is an anti-diabetic agent that improves hyperglycemia by reducing peripheral insulin resistance in type II diabetic patients. Troglitazone has been shown to cause growth inhibition of various normal and cancerous cells. However, the molecular mechanism by which troglitazone affects the growth of these cancer cells remains unclear. Here, we report that troglitazone treatment of Hep 3B human hepatocellular carcinoma cells resulted in dose-dependent growth inhibition. Analysis of cell cycle distribution by flow cytometry showed that the number of apoptotic cells was increased in a dose-dependent manner in response to troglitazone treatment. cDNA microarray analysis showed a number of differentially expressed genes in response to troglitazone. Among the upregulated genes, hypoxia-inducible factor 1 (HIF-1)-responsive RTP801 was induced in a dose dependent manner. We also observed HIF-1 accumulation by immnocytochemistry after troglitazone treatment. These results strongly suggest that RTP801 might be involved in troglitazone-induced apoptosis in Hep 3B cells. PMID- 20846492 TI - Inhibitory effects of antithrombin on the expression of secretory group IIA phospholipase A(2) in endothelial cells. AB - Tumor necrosis factor-alpha (TNF-alpha) mediates proinflammatory responses in primary human umbilical vein endothelial cells (HUVECs), and it upregulates the expression of secretory group IIA phospholipase A(2) (sPLA(2)-IIA). sPLA(2)-IIA plays a pivotal role in inflammation, and antithrombin (AT) possesses properties that are beneficial to endothelial cells. Therefore, we investigated the effects of AT on the expression of sPLA(2)-IIA in TNF-alpha-stimulated HUVECs. TNF-alpha potently upregulated the expression of sPLA(2)-IIA, and prior treatment of cells with AT inhibited the expression of sPLA(2)-IIA in HUVECs. Also, antibodies or siRNA for syndecan-4 blocked the protective effect of AT. Furthermore, PI3-kinase and the AKT pathway are significantly involved in the AT-mediated inhibition of the expression of sPLA(2)-IIA. These results show that AT effectively suppresses the upregulated sPLA(2)-IIA expression, which might contribute to the cytoprotective effects of AT in the treatment of severe inflammatory diseases. PMID- 20846493 TI - Coexpression and protein-protein complexing of DIX domains of human Dvl1 and Axin1 protein. AB - The Dvl and Axin proteins, which are involved in the Wnt signaling pathway, each contain a conserved DIX domain in their sequences. The DIX domain mediates interaction between Dvl and Axin, which together play an important role in signal transduction. However, the extremely low production of DIX domain fragments in E. coli has prevented more widespread functional and structural studies. In this study, we demonstrate that the DIX domains of Dvl and Axin are expressed noticeably in a multi-cistronic system but not in a mono-cistronic system. Formation of the DIX(Dvl1)-DIX(Axin1) complex was investigated by affinity chromatography, SEC and crystallization studies. Unstable DIX domains were stabilized by complexing with counterpart DIX domains. The results of the preliminary crystallization and diffraction of the DIX(Dvl1)-DIX(Axin1) complex may prove useful for further crystallographic studies. PMID- 20846494 TI - Propamidine decreas mitochondrial complex III activity of Botrytis cinerea. AB - Propamidine, an aromatic diamidine compound, is widely used as an antimicrobial agent. To uncover its mechanism on pathogenetic fungi, Botrytis cinerea as an object was used to investigate effects of propamidine in this paper. The transmission electron microscope results showed that the mitochondrial membranes were collapsed after propamidine treatment, followed that mitochondria were disrupted. Inhibition of whole-cell and mitochondrial respiration by propamidine suggested that Propamidine is most likely an inhibitor of electron transport within Botrytis cinerea mitochondria. Furthermore, the mitochondrial complex III activity were inhibited by propamidine. PMID- 20846495 TI - Dimethyl sulfoxide elevates hydrogen peroxide-mediated cell death in Saccharomyces cerevisiae by inhibiting the antioxidant function of methionine sulfoxide reductase A. AB - Dimethyl sulfoxide (DMSO) can be reduced to dimethyl sulfide by MsrA, which stereospecifically catalyzes the reduction of methionine-S-sulfoxide to methionine. Our previous study showed that DMSO can competitively inhibit methionine sulfoxide reduction ability of yeast and mammalian MsrA in both in vitro and in vivo, and also act as a non-competitive inhibitor for mammalian MsrB2, specific for the reduction of methionine-R-sulfoxide, with lower inhibition effects. The present study investigated the effects of DMSO on the physiological antioxidant functions of methionine sulfoxide reductases. DMSO elevated hydrogen peroxide-mediated Saccharomyces cerevisiae cell death, whereas it protected human SK-Hep1 cells against oxidative stress. DMSO reduced the protein-carbonyl content in yeast cells in normal conditions, but markedly increased protein-carbonyl accumulation under oxidative stress. Using Msr deletion mutant yeast cells, we demonstrated the DMSO's selective inhibition of the antioxidant function of MsrA in S. cerevisiae, resulting in an increase in oxidative stress-induced cytotoxicity. PMID- 20846496 TI - Endotoxin-induced renal tolerance against ischemia and reperfusion injury is removed by iNOS, but not eNOS, gene-deletion. AB - Endotoxin including lipopolysaccharide (LPS) confers organ tolerance against subsequent challenge by ischemia and reperfusion (I/R) insult. The mechanisms underlying this powerful adaptive defense remain to be defined. Therefore, in this study we attempted to determine whether nitric oxide (NO) and its associated enzymes, inducible NOS (iNOS) and endothelial NOS (eNOS, a constitutive NOS), are associated with LPS-induced renal tolerance against I/R injury, using iNOS (iNOS knock-out) or eNOS (eNOS knock-out) gene-deleted mice. A systemic low dose of LPS pretreatment protected kidney against I/R injury. LPS treatment increased the activity and expression of iNOS, but not eNOS, in kidney tissue. LPS pretreatment in iNOS, but not eNOS, knock-out mice did not protect kidney against I/R injury. In conclusion, the kidney tolerance to I/R injury conferred by pretreatment with LPS is mediated by increased expression and activation of iNOS. PMID- 20846497 TI - Identification of piRNAs in Hela cells by massive parallel sequencing. AB - Piwi proteins and Piwi-interacting RNAs (piRNAs) have been implicated in transposon control in germline from Drosophila to mammals. To examine the profile of small RNA expression in human cancer cells and explore difference in small RNA transcriptome, small RNA libraries prepared from wildtype, HILI overexpressed and HILI knockdowned Hela cells were sequenced using Solexa technology. piRNAs and other repeat- associated small RNAs were observed in Hela cells. By using in situ hybridization, piR-49322 was localized in the nucleolus and around the periphery of nuclear membrane in Hela cells. Following the overexpression of HILI, the retrotransposon elements LINE1 was significantly repressed, while LINE1 associated small RNAs decreased in abundance. The present study demonstrated that HILI along with piRNAs plays a role in LINE1 suppression in Hela cancer cell line. PMID- 20846498 TI - Mucin gene expression and mouse middle ear epithelium. AB - OBJECTIVES: To investigate the expression of recently identified human mucin genes in an in vitro model of cultured mouse middle ear epithelial cells (MMEEC). METHODS: MMEEC were established, RNA was extracted and primers were designed for RT-PCR to assess for expression of mucin genes Muc1, Muc2, Muc3, Muc4, Muc5AC, Muc5B, Muc6, Muc7, Muc8, Muc9, Muc10, Muc11/12, Muc13, Muc15, Muc16, Muc17, Muc18, Muc19 and Muc20 expression. RESULTS: Mucin genes Muc1, Muc2, Muc3, Muc4, Muc5AC, Muc5B, Muc9, Muc10, Muc13, Muc15, Muc16, Muc18, Muc19 and Muc20 were identified and expressed in MMEEC. The genes Muc6, Muc7, Muc8, Muc11/12 and Muc17 were not identified. CONCLUSION: Many of the mucin genes that have been recently identified in human MEE and chinchilla MEE are also expressed in MMEEC. There are differences in expression, however, which may have implications in utilizing various animal models for study of middle ear physiology and pathogenesis; specifically as it relates to mucin gene expression. PMID- 20846499 TI - Lexical effects on spoken word recognition performance among Mandarin-speaking children with normal hearing and cochlear implants. AB - OBJECTIVE: This investigation aimed to examine the effects of word frequency and lexical neighborhood density on spoken word recognition of monosyllables and disyllables in Mandarin by normal hearing children and children with cochlear implants. The lexical characteristics were incorporated from the Neighborhood Activation Model (NAM), which suggests that words in the mental lexicon are organized into similarity neighborhoods. The difficulty of a listener's task is affected by the frequency of the target word and the density of the lexical neighbors from which that word must be identified. The Monosyllabic Lexical Neighborhood Test and the Disyllabic Lexical Neighborhood Test in Mandarin Chinese (Mandarin LNT and MLNT) were developed to take into account the effects of these linguistic and cognitive demands on speech perception performance. METHODS: Three stages were conducted in this investigation. In the first stage, Mandarin words of monosyllables and disyllables were selected and their lexical properties were calculated from the CHILDES database. Four lexically "easy" and four lexically "hard" word lists in Mandarin LNT as well as two word lists across lexical properties among disyllables were determined based on their relative word frequencies and neighborhood densities. In the second stage, word stimuli were verified by 30 children of the NH group and 36 children from the CI group. In the third stage, the inter-list equivalency and test-retest reliability of word lists across lexical properties were determined, and the correlations of Mandarin LNT and MLNT with other measures and inter-rater reliability were also investigated. RESULTS: Word recognition scores were higher among disyllables than among monosyllables. Lexically "easy" disyllabic words were better recognized than their "hard" counterparts and the monosyllables among two groups of children. However, no lexical effects on word recognition of Mandarin monosyllables were observed for either group. No significant differences were found among word lists in each combination of syllable structure and lexical property. Inter-rater reliability, inter-list equivalency, and test-retest reliability were revealed. The Mandarin LNT and MLNT were found to be highly reliable measures of spoken word recognition (r = 0.84; p < 0.01) with acceptable equivalency between lists (r = 0.638-0.876). CONCLUSION: Lexical effects on Mandarin word recognition were only demonstrated among disyllabic words by NH and the CI children, while Mandarin homophones appearing in monosyllabic words were suggested. Lexical effects on spoken word recognition in Mandarin are not substantially demonstrated as in English, but the Mandarin LNT and MLNT provided reliable information on the spoken word recognition of pediatric CI users in the initial stage after implantation as well as in the rehabilitation progress. PMID- 20846500 TI - Tragal cartilage augmentation in repair of cleft palate, a new technique and its clinical implications. AB - BACKGROUND: Cleft palate is one of the most common congenital anomalies of the head and neck worldwide. In addition to the evident feeding and growth problems, patients are involved with and suffer from speech, hearing and dental problems. Many surgical techniques and modifications have been advocated to improve functional outcome and aesthetic results, aiming at normal speech, minimizing growth disturbances, and establishing a competent velopharyngeal sphincter. Despite the variety of techniques described for repair of the clefts, there is still a relatively high incidence of postoperative fistula reaching up to 35%. This is mainly related to type and degree of the defect, and type of surgical repair. OBJECTIVES: To evaluate the efficacy of placement of tragal cartilage free graft between the oral and nasal mucosal layers of the neo-palate in improving success rates, and anatomical and functional outcomes in repair of cleft palate with reduction of the extent of dissection. PATIENTS AND METHODS: Fourteen patients were managed by our technique, only in large cases minimal von Langenbeck lateral release incisions were made. In all cases a tragal cartilage graft was interpositioned and fixed to the muscle layer of the neo-palate, 2-3 extramucosal trans-muscle sutures were placed for 3-4 weeks if needed, and the patients were followed up for a minimum of 12 months during which functional and anatomical assessments were done. RESULTS: Results, including both anatomical and functional outcomes, were favorable with no gross failures, permanent significant fistula formations (one case with minor non-significant fistula), nor donor site co morbidities. CONCLUSION: The use of tragal cartilage free graft to augment the area at the junction between the hard and soft palate appears to be a safe and effective method in repair of cleft palate that reduces the incidence of postoperative palatal fistulae, without donor site comorbidities. PMID- 20846501 TI - Clonal spread of beta-lactamase-producing amoxicillin-clavulanate-resistant (BLPACR) strains of non-typeable Haemophilus influenzae among young children attending a day care in Japan. AB - OBJECTIVE: Resistant strains of non-typeable Haemophilus influenzae (NTHi) are one of the principal causes of recurrent acute otitis media (otitis prone), rhinosinusitis, and pneumonia in young children. Beta-lactamase-nonproducing ampicillin-resistant (BLNAR) strains are particularly common in Japan, and beta lactamase-producing amoxicillin-clavulanate resistant (BLPACR) strains are now emerging. We investigated the nasopharyngeal carriage status of these resistant strains among children attending a same day care center during a 10-year period. METHODS: From 1999 to 2008, we obtained nasopharyngeal swab specimens from young children attending a same day care center and examined the incidence of resistant strains of NTHi. Antimicrobial resistance of NTHi was identified based on PCR analysis of mutation of the penicillin binding protein (PBP) genes. Pulsed-field gel electrophoresis (PFGE) was performed to examine the clonal relationship of each resistant strain. RESULTS: The prevalence of resistant strains of NTHi among the children attending this day care has significantly increased during the past 10 years and most of this day care children recently have resistant strains with PBP gene mutations in their nasopharynx. Genetically BLPACR (gBLPACR) strains have rapidly increased since 2007 and PFGE analysis demonstrated that all gBLPACR were clonally identical. This is the first report of apparent clonal dissemination of gBLPACR strains of NTHi occurring in a certain environment such as day care. CONCLUSIONS: The rapidly increasing prevalence of resistant strains, in particular gBLPACR, in this day care center may predict a high incidence of these resistant bacteria from clinical isolates in the near future and potential serious medical problems worldwide. PMID- 20846502 TI - Vocal tract dimensional development of adolescents: an acoustic reflection study. AB - OBJECTIVE: The purpose of the study was to investigate the effects of age and gender on adolescents' vocal tract dimensional development with acoustic reflection technology (ART). METHODS: A total of ninety-five male and female adolescents aged between 10 and 18 divided into three age groups were tested with acoustic reflection technology (ART) and acoustic program to secure their vocal tract dimensional parameters and the vowel formant frequencies. RESULTS: Significant age and gender effects were found not only in vocal tract length, but also segmental volumetric measurements, as well as the vowel formant frequencies. CONCLUSIONS: The findings of this study have provided insights on the developmental trend of adolescents' vocal tracts. The study has also offered a preliminary anatomical database of adolescents' vocal tract dimensional growth for otolaryngologists, clinical anatomists, speech therapists and other health professionals of swallowing, respiration and communicative disorders. PMID- 20846503 TI - Cisplatinum ototoxicity in children, long-term follow up. AB - OBJECTIVE: To assess the long-term ototoxicity effect of platinum chemotherapy in a series of pediatric patients. DESIGN: A prospective cohort study. METHODS: Patients who received platinum chemotherapy were identified through review of the pharmacy records from 2000 to 2005. Audiograms pre- and post-treatment with cisplatin were noted. The patients were brought back long after treatment for a repeat audiogram and a questionnaire to assess the impact of ototoxicity on their quality of life. RESULTS: Forty-nine patients received platinum chemotherapy. Patients' exclusion: two had no pre-chemo audiograms, one had retinoblastoma with congenital hearing loss, three were lost to follow up, five deceased, and seven refused participation. The total number of patients included was 31 with long term follow up total of 21 patients. The follow up period ranged from 1.5 to 6.6 years (median of 3.4 years). Fourty-two percent (13/31) of the patients suffered from otoxicity (3 mild, 3 moderate, 7 severe-profound). Thirty-three (7/21) of audiograms worsened on long-term follow up. Questionnaire revealed 70% subjective hearing loss with 40% requiring hearing aids. CONCLUSION: Ototoxicity after platinum chemotherapy can present or worsen years after completion of therapy. Therefore, we recommend long-term follow up. PMID- 20846504 TI - Laryngeal juvenile xanthogranuloma: Imaging finding. AB - Laryngeal juvenile xanthogranuloma is rare and there were only four cases have been reported previously in English literature. We report a case of isolated JXG of larynx in the superglottic region. The mass was well-defined and homogeneous hypoechoic in ultrasonography while presented indistinct boundary and soft tissue density in Computed Tomography images. Radiological findings are nonspecific but could help to understand the extent of the lesion. We suggest that JXG should be considered as differential diagnosis for laryngeal stridor. Laryngeal ultrasound is safe and reliable, which could be considered a useful diagnostic tool for supplementing laryngoscopy. PMID- 20846505 TI - Case report: Treatment failure using propanolol for treatment of focal subglottic hemangioma. AB - Subglottic hemangioma is a rare, potentially life threatening tumor of infancy which poses serious treatment challenges. A number of medical and surgical therapies over the years have met with variable success, and are associated with numerous potential morbidities. A potential windfall in the management of infantile hemangiomas has arisen with the recent identification of propanolol as a highly efficacious and relatively safe new treatment modality. At least five reports in the literature have described the rapid, successful treatment of airway hemangiomas with oral propanolol. We describe the first reported treatment failure with propanolol for subglottic hemangioma in an infant who initially responded dramatically to the medication. PMID- 20846506 TI - Development of a bioassay to screen for chemicals mimicking the anti-aging effects of calorie restriction. AB - Suppression of the growth hormone/insulin-like growth factor-I pathway in Ames dwarf (DF) mice, and caloric restriction (CR) in normal mice extends lifespan and delays the onset of age-related disorders. In combination, these interventions have an additive effect on lifespan in Ames DF mice. Therefore, common signaling pathways regulated by DF and CR could have additive effects on longevity. In this study, we tried to identity the signaling mechanism and develop a system to assess pro-longevity status in cells and mice. We previously identified genes up regulated in the liver of DF and CR mice by DNA microarray analysis. Motif analysis of the upstream sequences of those genes revealed four major consensus sequence motifs, which have been named dwarfism and calorie restriction responsive elements (DFCR-REs). One of the synthesized sequences bound to hepatocyte nuclear factor-4alpha (HNF-4alpha), an important transcription factor involved in liver metabolism. Furthermore, using this sequence information, we developed a highly sensitive bioassay to identify chemicals mimicking the anti aging effects of CR. When the reporter construct, containing an element upstream of a secreted alkaline phosphatase (SEAP) gene, was co-transfected with HNF 4alpha and its regulator peroxisome proliferator-activated receptor (PPAR) gamma coactivator-1alpha (PGC-1alpha), SEAP activity was increased compared with untransfected controls. Moreover, transient transgenic mice established using this construct showed increased SEAP activity in CR mice compared with ad libitum fed mice. These data suggest that because of its rapidity, ease of use, and specificity, our bioassay will be more useful than the systems currently employed to screen for CR mimetics, which mimic the beneficial effects of CR. Our system will be particularly useful for high-throughput screening of natural and synthetic candidate molecules. PMID- 20846507 TI - Prophylaxis with human serum butyrylcholinesterase protects guinea pigs exposed to multiple lethal doses of soman or VX. AB - Human serum butyrylcholinesterase (Hu BChE) is currently under advanced development as a bioscavenger for the prophylaxis of organophosphorus (OP) nerve agent toxicity in humans. It is estimated that a dose of 200mg will be required to protect a human against 2*LD(50) of soman. To provide data for initiating an investigational new drug application for the use of this enzyme as a bioscavenger in humans, we purified enzyme from Cohn fraction IV-4 paste and initiated safety and efficacy evaluations in mice, guinea pigs, and non-human primates. In mice, we demonstrated that a single dose of enzyme that is 30 times the therapeutic dose circulated in blood for at least four days and did not cause any clinical pathology in these animals. In this study, we report the results of safety and efficacy evaluations conducted in guinea pigs. Various doses of Hu BChE delivered by i.m. injections peaked at ~24h and had a mean residence time of 78-103h. Hu BChE did not exhibit any toxicity in guinea pigs as measured by general observation, serum chemistry, hematology, and gross and histological tissue changes. Efficacy evaluations showed that Hu BChE protected guinea pigs from an exposure of 5.5*LD(50) of soman or 8*LD(50) of VX. These results provide convincing data for the development of Hu BChE as a bioscavenger that can protect humans against all OP nerve agents. PMID- 20846508 TI - Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase. AB - Many fraudulent nucleosides including the antivirals acyclovir (ACV) and ganciclovir (GCV) must be metabolized to triphosphates to be active. Cyclopropavir (CPV) is a newer, related guanosine nucleoside analog that is active against human cytomegalovirus (HCMV) in vitro and in vivo. We have previously demonstrated that CPV is phosphorylated to its monophosphate (CPV-MP) by the HCMV pUL97 kinase. Consequently, like other nucleoside analogs phosphorylated by viral kinases, CPV most likely must be converted to a triphosphate (CPV-TP) in order to elicit antiviral activity. Once formed by pUL97, we hypothesized that guanosine monophosphate kinase (GMPK) is the enzyme responsible for the conversion of CPV-MP to CPV-DP. Incubation of CPV-MP with GMPK resulted in the formation of CPV-DP and, surprisingly, CPV-TP. When CPV-DP was incubated with GMPK, a time-dependent increase in CPV-TP occurred corresponding to a decrease in CPV-DP thereby demonstrating that CPV-DP is a substrate for GMPK. Substrate specificity experiments revealed that GMP, dGMP, GDP, and dGDP are substrates for GMPK. In contrast, GMPK recognized only acyclovir and ganciclovir monophosphates as substrates, not their diphosphates. Kinetic studies demonstrated that CPV-DP has a K(M) value of 45+/-15MUM. We were, however, unable to determine the K(M) value for CPV-MP directly, but a mathematical model of experimental data gave a theoretical K(M) value for CPV-MP of 332+/-60MUM. We conclude that unlike many other antivirals, cyclopropavir can be converted to its active triphosphate by a single cellular enzyme once the monophosphate is formed by a virally encoded kinase. PMID- 20846509 TI - Effects of postnatal dietary choline manipulation against MK-801 neurotoxicity in pre- and postadolescent rats. AB - Prenatal supplementation of rat dams with dietary choline has been shown to provide their offspring with neuroprotection against N-methyl-d-aspartate (NMDA) antagonist-mediated neurotoxicity. This study investigated whether postnatal dietary choline supplementation exposure for 30 and 60 days of rats starting in a pre-puberty age would also induce neuroprotection (without prenatal exposure). Male and female Sprague-Dawley rats (postnatal day 30 of age) were reared for 30 or 60 concurrent days on one of the four dietary levels of choline: 1) fully deficient choline, 2) 1/3 the normal level, 3) the normal level, or 4) seven times the normal level. After diet treatment, the rats received one injection of MK-801 (dizocilpine 3mg/kg) or saline control. Seventy-two hours later, the rats were anesthetized and transcardially perfused. Their brains were then postfixed for histology with Fluorojade-C (FJ-C) staining. Serial coronal sections were prepared from a rostrocaudal direction from 1.80 to 4.2mm posterior to the bregma to examine cell degeneration in the retrosplenial and piriform regions. MK-801, but not control saline, produced significant numbers of FJ-C positive neurons, indicating considerable neuronal degeneration. Dietary choline supplementation or deprivation in young animals reared for 30-60days did not alter NMDA antagonist induced neurodegeneration in the retrosplenial region. An interesting finding is the absence of the piriform cortex involvement in young male rats and the complete absence of neurotoxicity in both hippocampus regions and DG. However, neurotoxicity in the piriform cortex of immature females treated for 60days appeared to be suppressed by low levels of dietary choline. PMID- 20846510 TI - Neuroprotective effect of astaxanthin on H(2)O(2)-induced neurotoxicity in vitro and on focal cerebral ischemia in vivo. AB - Astaxanthin (AST) is a powerful antioxidant that occurs naturally in a wide variety of living organisms. Much experimental evidence has proved that AST has the function of eliminating oxygen free radicals and can protect organisms from oxidative damage. The present study was carried out to further investigate the neuroprotective effect of AST on oxidative stress induced toxicity in primary culture of cortical neurons and on focal cerebral ischemia-reperfusion induced brain damage in rats. AST, over a concentration range of 250-1000nM, attenuated 50MUM H(2)O(2)-induced cell viability loss. 500nM AST pretreatment significantly inhibited H(2)O(2)-induced apoptosis measured by Hoechst 33342 staining and restored the mitochondrial membrane potential (MMP) measured by a fluorescent dye, Rhodamine 123. In vivo, AST prevented cerebral ischemic injury induced by 2h middle cerebral artery occlusion (MCAO) and 24h reperfusion in rats. Pretreatment of AST intragastrically twice at 5h and 1h prior to ischemia dramatically diminished infarct volume and improved neurological deficit in a dose-dependent manner. Nissl staining showed that the neuronal injury was significantly improved by pretreatment of AST at 80mg/kg. Taken together, these results suggest that pretreatment with AST exhibits noticeable neuroprotection against brain damage induced by ischemia-reperfusion and the antioxidant activity of AST maybe partly responsible for it. PMID- 20846511 TI - Thrombin-induced neuronal protection: role of the mitogen activated protein kinase/ribosomal protein S6 kinase pathway. AB - Our previous studies have found that intracerebral pretreatment with a low dose of thrombin (thrombin preconditioning, TPC) reduces infarct volume and attenuates brain edema after focal cerebral ischemia. In this study, we examined whether TPC protects against the neuronal death induced by oxygen glucose deprivation (OGD), and whether the protection is through thrombin receptors and the p44/42 mitogen activated protein kinases (MAPK)/ribosomal protein S6 kinases (p70 S6K) pathway. Expression of protease-activated receptors (PARs) mRNA was detected in cultured primary rat neurons and thrombin upregulated PAR-1 and PAR-4 mRNA expression. TPC reduced OGD-induced neuronal death (e.g. dead cells: 52.5 +/- 5.4% vs. 72.3 +/- 7.2% in the control group, n=6, p<0.01). Agonists of PAR-1 and PAR-4 mimicked the effects of thrombin and reduced OGD-induced neuronal death. Pretreatment with thrombin or PAR agonists induced the upregulation of activated p44/42 MAPK and p70S6K (Thr 421/Ser 424). PD98059, an inhibitor of p44/42 MAPK kinase, blocked thrombin-induced upregulation of activated p44/42 MAPK and p70S6K. It also reduced TPC-induced neuronal protection (e.g. dead cells: 68.2 +/- 5.2% vs. 56.9 +/- 4.6% in vehicle+TPC group, n=6, p<0.05). These results suggest that TPC induced ischemic tolerance is through activation of thrombin receptors and the p44/42 MAPK/p70S6K pathway. PMID- 20846512 TI - Characterization of sensory neurons in the dorsal root ganglia of Bax-deficient mice. AB - During development, the rescue of spinal motoneurons as well as sensory neurons in the dorsal root ganglion (DRG) from programmed cell death (PCD) depends on the integrity of peripheral target innervation. Following deletion of the pro apoptotic gene Bax, both motoneurons and DRG neurons are rescued from PCD. In the present paper, we asked whether different cell types in the DRG exhibit distinct responses to Bax deletion. In 1-month-old Bax-deficient (Bax-/-) mice, distinct subsets of DRG neurons that were immunopositive for TrkA, CGRP, TRPV1 or TrkC, were all increased in number and exhibited cell atrophy compared to wild type DRG neurons. In addition there was hyperinnervation of the epidermis by CGRP immunopositive processes and a correlated functional hypersensitivity of mechanical nociception in Bax-/- mice. By contrast, the functional properties of populations of rescued thermoreceptor and mechanoreceptor DRG neurons were unchanged. These data indicate that although Bax deletion rescues all of the DRG cell types examined here from PCD, the functional consequences of having excess cells differ between sensory phenotypes. PMID- 20846513 TI - Molecular characterization of the song control nucleus HVC in Bengalese finch brain. AB - Songbirds have a specialized neural substrate for learned vocalization, called the song circuit, which consists of several song nuclei in the brain. The song control nucleus HVC (a letter-based name) is the intersection point of the song learning and vocal motor pathways. Knowledge of the types of genes expressed in the HVC is essential in understanding the molecular aspects of the HVC. Gene expression in the HVC under silent conditions shows the competence necessary for singing. To investigate this, we compared the HVC with its adjacent tissues in searching for the molecular specificities of the song nucleus HVC using an in house cDNA microarray of the Bengalese finch (Lonchura striata var. domestica). Our microarray analysis revealed that 70 genes were differentially expressed in the HVC compared with the adjacent tissue. We investigated 27 of the microarray selected genes that were enriched or repressed in the HVC by in situ hybridization. We found that multiple calcium-binding proteins (e.g., CAPS2, parvalbumin and ATH) were enriched in the HVC. Meanwhile, the adult HVC showed low expression levels of plasticity-related genes (e.g., CAMK2A and MAP2K1) compared with the juvenile HVC. The HVC plays an important role during song learning, but our results suggest that the plasticity of this nucleus may be suppressed during adulthood. Our findings provide new information about the molecular features that characterize the HVC. PMID- 20846514 TI - Effects of loud noise on hippocampal and cerebellar-related behaviors. Role of oxidative state. AB - Living organisms are exposed to potentially hazardous noise levels coming from the environment. Besides the direct effect on hearing, extra-auditory noise associated effects should be considered. Since loud noise has been suggested to induce central nervous system symptoms, the aim of the present work was to investigate the effect of acute (ANE) and chronic noise exposures (CNE) on different behavioral tasks. To understand the mechanisms involved, levels of oxidative status markers were determined in two areas related to memory processes, the hippocampus (Hip) and the cerebellum (CE). 15-day-old male Wistar rats were exposed to loud noise (95-97 dB, 2h/day), at ANE or CNE. At 30 days, rats were subjected to different CE and Hip-related behavioral tasks. Reactive oxygen species (ROS) levels and antioxidant enzyme activities (CAT and SOD) were also assessed. Results show impairments in spatial and associative memory in noise-exposed animals. Moreover, a decrease in anxiety levels and an increase in habituation memory were observed in CNE animals. While an increase in cerebellar ROS levels was found early after the first noise exposure, a decrease was found in the CE and the Hip at 30 days. The activity of hippocampal CAT was increased early and remained high in ANE rats, while it was unchanged in the CE. Finally, although SOD activity was decreased immediately after the first noise exposure, its levels were increased at 30 days in ANE rats. In summary, the present study shows that an imbalance in oxidative status induced by noise exposure could underlie behavioral changes, some of which would be long-lasting. PMID- 20846515 TI - Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro. AB - Endostatin (ES), the C-terminal fragment of collagen XVIII known for its anti angiogenic properties, is associated with neurological diseases in mammals. In this study, we investigated the effect of ES on nerve growth factor (NGF)-induced neuronal differentiation, migration, neuritogenesis, and neurite extension. ES partially inhibited PC12 cell differentiation and cerebellar granule cell migration. In addition, neurite outgrowth was inhibited in a concentration dependent manner. This effect was also matrix-dependent, as we observed better inhibition on PC12 cells grown on collagen compared to laminin matrices. Furthermore, we observed partial NGF depletion by collagen and ES, but not by laminin suggesting that NGF-matrix interactions may be important for promoting neuritogenesis, competitive inhibition by ES or low affinity matrix impairs PC12 differentiation and neurite outgrowth. Finally, using a biosensor technique, we demonstrated a direct interaction between NGF and ES suggesting the mechanism of action of ES may involve NGF sequestration. In conclusion, our study demonstrates the inhibitory effect of ES on different steps of neurogenesis including cell differentiation and migration and neuritogenesis by NGF sequestration. Such sequestration may compromise brain repair following injury, but also may play important role in axon finding as well as a potent therapeutical target in diseases involving abnormal elevated neurotrophic growth factor levels. Taken together, this study raises the consideration of ES as a double-edge sword that carries both deleterious and putative therapeutical effects. PMID- 20846516 TI - Kallikrein-related peptidase 6 in Alzheimer's disease and vascular dementia. AB - Human kallikrein-related peptidase 6 (KLK6) is highly expressed in the central nervous system. Although the physiological roles of this serine protease are unknown, in vitro substrates include amyloid precursor protein and components of the extracellular matrix, which are altered in neurological disease, particularly Alzheimer's disease (AD). We have compared KLK6 expression in post-mortem brain tissue in AD, vascular dementia (VaD) and controls. We studied the distribution of KLK6 in the temporal cortex and white matter by immunohistochemistry, and measured KLK6 mRNA and protein levels in the frontal and temporal cortex from 15 AD, 15 VaD and 15 control brains. Immunohistochemistry showed KLK6 to be restricted to endothelial cells. After adjustment for variations in vessel density by measurement of factor VIII-related antigen, we found KLK6 protein and mRNA levels to be significantly decreased in the frontal but not the temporal cortex in AD. In VaD, KLK6 protein level was significantly increased in the frontal cortex. Our findings suggest that an altered KLK6 expression may contribute to vascular abnormalities in AD and VaD. PMID- 20846517 TI - Induction of the Keap1/Nrf2/ARE pathway by oxidizable diphenols. AB - Inducible Keap1/Nrf2/ARE pathway determines the ability of multicellular organisms to adapt to conditions of stress caused by oxidants and electrophiles through upregulating proteins with versatile cytoprotective functions. Para- and ortho-hydroquinones were among the first identified small-molecule inducers of this pathway. Their oxidative lability strongly suggested that the electrophilic quinone metabolites, and not the hydroquinones themselves, were the ultimate inducers. Molecular orbital calculations re-enforced this notion by showing linear correlations between inducer potency and: (i) the ability of diphenols to release electrons, and (ii) the electron affinity of their corresponding quinones. Consequently, a two-step mechanism was proposed which involves oxidation of the diphenols to their corresponding quinone derivatives, followed by modification of specific cysteine residues of the sensor protein Keap1. Our finding that Cu(2+), as well as other transition metals, enhanced induction by oxidizable diphenols provided a rationale to test this hypothesis. We found that hypoxia inhibits the potentiation of diphenolic inducer activity afforded by copper as oxygen is required to oxidize Cu(+) and regenerate Cu(2+). In the stably transfected AREc32 reporter cell line, exposure to 2-tert-butyl-1,4 hydroquinone (tBHQ) for 30min induced ARE-luciferase (measured 24h later) only in the presence of copper (Cu(2+) or Cu(+)), whereas induction by tert-butyl-1,4 quinone (tBQ) was copper-independent. tBQ, but not tBHQ, reacts with cysteine residues of Keap1. Other para- and ortho-hydroquinones, such as catechol estrogens, dopamine, and l-DOPA, also induce ARE-driven transcription in a Cu(2+) dependent manner. Thus, based on theoretical and experimental evidence, the oxidation of para- and ortho-hydroquinones to their corresponding electrophilic quinones is a requisite step for the activation of the Keap1/Nrf2/ARE pathway. PMID- 20846518 TI - 1-Methoxy-3-indolylmethyl glucosinolate; a potent genotoxicant in bacterial and mammalian cells: Mechanisms of bioactivation. AB - 1-Methoxy-3-indolylmethyl (1-MIM) glucosinolate, contained in many Brassica vegetables, is strongly mutagenic in Salmonella typhimurium TA100 when activated by myrosinase. Here, we describe the synthesis and evaluation of two breakdown products, 1-MIM nitrile and 1-MIM alcohol. 1-MIM nitrile was not mutagenic and 1 MIM alcohol showed low direct mutagenicity in TA100, indicating that other breakdown products mediated the mutagenicity of 1-MIM glucosinoate/myrosinase in this strain. However, 1-MIM alcohol was strongly mutagenic to a TA100-derived strain expressing human sulphotransferase SULT1A1. Likewise, 1-MIM glucosinolate (with myrosinase) showed 10 times higher mutagenic activity in TA100-SULT1A1 than in strain TA100. Identical adducts, N(2)-(1-MIM)-dG and N(6)-(1-MIM)-dA, were detected in both strains, but the levels were higher in TA100-hSULT1A1. A similar influence of SULT1A1 was observed in recombinant V79-hSULT1A1 cells compared to parental SULT-deficient Chinese hamster V79 cells. 1-MIM glucosinolate (with myrosinase) as well as 1-MIM alcohol induced sister chromatid exchange in both cell lines, but with clearly higher efficiency in V79-hSULT1A1 cells. Gene mutation assays were conducted at the HPRT locus with 1-MIM alcohol in V79 hSULT1A1 cells, and with 1-MIM glucosinolate/myrosinase in V79 parental cells. In both cases, the result was clearly positive. Thus, 1-MIM glucosinolate is mutagenic in bacterial and mammalian cells via at least two different metabolites. PMID- 20846519 TI - In vitro cytotoxicity assay to evaluate the toxicity of an electrophilic reactive metabolite using glutathione-depleted rat primary cultured hepatocytes. AB - Glutathione plays an important role as not only a scavenger of reactive oxygen species but also in the conjugation or detoxification of electrophilic reactive metabolites, which has been thought to be one of the causes for idiosyncratic drug toxicity (IDT). Therefore, toxic responses to the reactive metabolites have been expected to be expressed more strongly in a glutathione-depleted condition. In the present study, we attempted to establish an in vitro cytotoxicity assay method to evaluate the toxicity of the reactive metabolite using rat primary cultured hepatocytes with cellular glutathione depletion by l-buthionine-S,R sulfoximine. Also, we investigated whether the IDT risk is predictable by comparing the cytotoxic sensitivity between glutathione-depleted hepatocytes and untreated hepatocytes. Consequently, 10 drugs of 42 approved drugs, which were classified into 4 IDT categories (Withdrawn, Black box warning, Warning, and Safe), demonstrated higher cytotoxic sensitivity in the glutathione-depleted hepatocytes. Furthermore, a correlation was observed between the incidence of drugs with higher cytotoxic sensitivity in the glutathione-depleted hepatocytes and the IDT risk. The incidence was 50% in the Withdrawn category, 38% in the Black box warning category, 22% in the Warning category, and 8% in the Safe category. These results suggest that the IDT risk of some drugs may be predicted by comparing the cytotoxic sensitivity between them. Additionally, this method may be useful as a screening in the early stage of drug development where leads/candidates are optimized. PMID- 20846520 TI - Drug bioactivation and protein adduct formation in the pathogenesis of drug induced toxicity. AB - Adverse drug reactions (ADRs) remain a major complication of drug therapy and can be classified as 'on-target' or 'off-target' (idiosyncratic) reactions. On-target reactions can be predicted from the known primary or secondary pharmacology of the drug and often represent an exaggeration of the pharmacological effect of the drug. In contrast, off-target adverse reactions cannot be predicted from knowledge of the basic pharmacology of the drug. The exact mechanisms of idiosyncratic drug reactions are still unclear; however it is believed that they can be initiated by chemically reactive drug metabolites. It is well known that xenobiotics can undergo metabolic bioactivation reactions which have the potential to cause cellular stress and damage. Bioactivation of drugs is thought to have the potential of initiating covalent linkages between cellular protein and drugs which can be recognised by the adaptive immune system in the absence of detectable cellular stress. This process cannot yet be predicted in pre-clinical models or discovered in clinical trials. Because of this hazard perception, the formation of chemically reactive metabolites in early drug discovery remains a serious impediment to the development of new medicines and can lead to withdrawal of an otherwise effective therapeutic agent. The fear of such reactions occurring at the post-licensing stage - when such problems first become evident - is a major contribution to drug attrition. The first step towards such methodology has been the development of chemically reactive metabolite screens. The chemical basis of drug bioactivation can usually be rationalised and synthetic strategies put in place to prevent such bioactivation. However, there is no simple correlation between drug bioactivation in vitro and adverse drug reactions in the clinic. Such a chemical approach is clearly limited by the facts that (a) not all drugs that can undergo bioactivation by human drug-metabolising enzymes are associated with hypersensitivity in the clinic and (b) drug bioactivation may not always be a mandatory step in drug hypersensitivity. To predict such reactions in early drug development, it will require an integrated understanding of the chemical, immunological and genetic basis of adverse drug reactions in patients, which in turn will depend on the development of novel in vitro experimental systems. PMID- 20846521 TI - Impact of residual renal function and HCV seropositivity on plasma CD40/CD40L system and oxidative status in haemodialysis patients. AB - OBJECTIVES: We evaluated the impact of residual renal function (RRF) on oxidative stress (SOX) and CD40/CD40L system in haemodialysis (HD) patients. DESIGN AND METHODS: We determined sCD40, sCD40L and SOX marker-Cu/Zn superoxide dismutase (Cu/Zn SOD) levels in HD patients with RRF, with anuria (A) and in healthy controls. RESULTS: sCD40 and Cu/Zn SOD plasma levels were higher in both groups of dialyzed patients compared to controls (all p<0.001), and they were higher in A than in RRF patients (all p<0.01). In RRF group, sCD40/sCD40L and Cu/Zn SOD were significantly higher in anti-HCV-seropositive (anti-HCV[+]) patients than in their anti-HCV[-] counterparts. This phenomenon was not observed in A group. Multiple regression analysis showed that Cu/Zn SOD, kt/V and low fibrinogen were the independent factors affecting sCD40 levels in the whole HD group. CONCLUSIONS: The loss of RRF and HCV seropositivity increased plasma levels of sCD40/sCD40L and oxidative status in HD patients. PMID- 20846522 TI - The severity of non-alcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population. AB - OBJECTIVES: We aimed to investigate the correlation between non-alcoholic fatty liver disease (NAFLD) and risk of cardiovascular disease (CVD). DESIGN AND METHODS: We analyzed 724 subjects without CVD according to presence or absence of NAFLD. Logistic regression model was used to determine if NAFLD was an independent risk factor of CVD. RESULTS: Subjects with NAFLD had increased percentage of 10-year cardiovascular risk ?10% compared to those without NAFLD (p<0.001). The severity of NAFLD significantly correlated with increasing Framingham risk score and C-relative protein (CRP) value. After adjusting for conventional CVD risk factors, the presence of NAFLD was an independent predictor for future CVD risk ?10% [odds ratio: 1.89, p=0.004]. Subgroup analysis showed the predictive value of NAFLD was significant among aged subjects and those with increased baseline hsCRP level. CONCLUSIONS: NAFLD is independently associated with increased CVD risk, especially among elderly subjects and those with increased CRP level. PMID- 20846523 TI - Differential effect of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats. AB - The present study was designed to investigate the ameliorative potential of spironolactone in chronic constriction injury and vincristine-induced neuropathic pain in rats. The chronic constriction injury was induced by placing four loose ligatures around the sciatic nerve, while vincristine (50 MUg/kg) was administered for 10 days to induce chemotherapy-induced neuropathic pain. Acetone drop, pin-prick, hot plate and paint brush tests were performed to assess cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia, respectively. The spontaneous pain and postural index in terms of foot deformity was also assessed. The levels of TNF-alpha were measured in the sciatic nerve as an index of inflammation. Chronic constriction injury led to significant development of cold allodynia; mechanical and heat hyperalgesia; dynamic mechanical allodynia; spontaneous pain and foot deformity along with rise in the levels of TNF-alpha. Administration of vincristine was associated with the development of allodynia and hyperalgesia without spontaneous pain, foot deformity and elevation in the levels of TNF-alpha. Administration of spironolactone (10 and 20 mg/kg) significantly attenuated chronic constriction injury-induced pain related behaviour and foot deformity along with attenuation of TNF-alpha levels, without modulating vincristine-induced neuropathic pain. The attenuating effect of spironolactone in chronic constriction injury may be due to its anti-inflammatory properties and ability to decrease pro-inflammatory cytokines, while involvement of non-inflammatory mechanisms in the pathogenesis of vincristine-induced pain may probably explain its lack of beneficial effect in chemotherapy associated pain. PMID- 20846524 TI - The Rsp5 ubiquitin ligase and the AAA-ATPase Cdc48 control the ubiquitin-mediated degradation of the COPII component Sec23. AB - Ubp3/Bre5 complex is a substrate-specific deubiquitylating enzyme which mediates deubiquitylation of Sec23, a component of the COPII complex involved in the transport between endoplasmic reticulum and Golgi apparatus. Here we show that ubiquitylation of Sec23 is controlled by the Rsp5 ubiquitin ligase both in vivo and in vitro. We have recently identified Cdc48, a chaperone-like that plays a key role in the proteasomal escort pathway, as a partner of the Ubp3/Bre5 complex. We now found that cdc48 thermosensitive mutant cells not only accumulate ubiquitylated form of Sec23 but also display a stabilization of this protein at the restrictive temperature. This indicates that Cdc48 controls the proteasome mediated degradation of Sec23. Our data favor the idea that Cdc48 plays a key role in deciphering fates of ubiquitylated Sec23 to degradation or deubiquitylation/stabilization via its cofactors. PMID- 20846525 TI - Immunomodulatory effect of picroliv on the efficacy of paromomycin and miltefosine in combination in experimental visceral leishmaniasis. AB - Combination therapy for the treatment of visceral leishmaniasis has increasingly been advocated as a way to increase treatment efficacy and tolerance, to reduce treatment duration and cost, and to limit the emergence of drug resistance. In the present work, we have adopted a rational approach, which can modulate the immune response to overcome the negative control systems and to boost the positive killing responses. This study was designed to investigate the immunomodulatory effect of picroliv (standardized fraction from the alcoholic extract of root and rhizome of Picrorhiza kurroa) on a combination of paromomycin and miltefosine using Leishmania donovani/hamster model. Picroliv has significantly enhanced antileishmanial efficacy and lymphocyte proliferation when given in combination with paromomycin and miltefosine. Increased toxic oxygen metabolite generation and phagocytosis were also witnessed. Present study thus establishes the possible use of picroliv as adjunct to antileishmanial chemotherapy. PMID- 20846526 TI - SHP2 is a downstream target of ZAP70 to regulate JAK1/STAT3 and ERK signaling pathways in mouse embryonic stem cells. AB - Previous research indicated that ZAP70, a Syk family tyrosine kinase, is expressed in mouse embryonic stem cells (mESCs) and regulates the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 3 (STAT3) signaling through consolidating SHP1 enzymatic activity. In this study, we report that SHP2 is another downstream target of ZAP70 in mESCs. We found that SHP2 phosphorylation and enzymatic activity are affected by Zap70 expression. In addition, we present evidence that ERK pathways activated by ZAP70 and SHP2 reduce the protein level of leukemia inhibitory factor (LIF) receptor. Based on these results, we propose that SHP2 is an essential mediator of the ZAP70 signal to regulate JAK1/STAT3 and ERK pathways in undifferentiated mESCs. PMID- 20846527 TI - Truncation of subunit ND2 disrupts the threefold symmetry of the antiporter-like subunits in complex I from higher metazoans. AB - Three of the conserved, membrane-bound subunits in NADH:ubiquinone oxidoreductase (complex I) are related to one another, and to Mrp sodium-proton antiporters. Recent structural analysis of two prokaryotic complexes I revealed that the three subunits each contain fourteen transmembrane helices that overlay in structural alignments: the translocation of three protons may be coordinated by a lateral helix connecting them together (Efremov, R.G., Baradaran, R. and Sazanov, L.A. (2010). The architecture of respiratory complex I. Nature 465, 441-447). Here, we show that in higher metazoans the threefold symmetry is broken by the loss of three helices from subunit ND2; possible implications for the mechanism of proton translocation are discussed. PMID- 20846529 TI - An update to "The cost-effectiveness of rotavirus vaccination: comparative analyses for five European countries and transferability in Europe". AB - A cost-effectiveness analysis of rotavirus vaccination in Belgium, England and Wales, Finland, France and the Netherlands published in 2009 was updated based on recent studies on rotavirus burden of disease and vaccine efficacy. All the qualitative conclusions in the previous study were found to remain valid. Vaccination remains cost-effective in Finland only when using plausible tender prices. PMID- 20846528 TI - Poly(I:C) is an effective adjuvant for antibody and multi-functional CD4+ T cell responses to Plasmodium falciparum circumsporozoite protein (CSP) and alphaDEC CSP in non human primates. AB - Development of a fully effective vaccine against the pre-erythrocytic stage of malaria infection will likely require induction of both humoral and cellular immune responses. Protein based vaccines can elicit such broad-based immunity depending on the adjuvant and how the protein is formulated. Here to assess these variables, non human primates (NHP) were immunized three times with Plasmodium falciparum (Pf) circumsporozoite protein (CSP) or CSP cloned into MG38, a monoclonal antibody that targets DEC-205 (alphaDEC-CSP), an endocytic receptor on dendritic cells (DCs). Both vaccines were administered with or without poly(I:C) as adjuvant. Following three immunizations, the magnitude and quality of cytokine secreting CD4+ T cells were comparable between CSP+poly(I:C) and alphaDEC CSP+poly(I:C) groups with both regimens eliciting multi-functional cytokine responses. However, NHP immunized with CSP+poly(I:C) had significantly higher serum titers of CSP-specific IgG antibodies and indirect immunofluorescent antibody (IFA) titers against Pf sporozoites. Furthermore, sera from both CSP or alphaDEC-CSP+poly(I:C) immunized animals limited sporozoite invasion of a hepatocyte cell line (HC04) in vitro. To determine whether CSP-specific responses could be enhanced, all NHP primed with CSP or alphaDEC-CSP+poly(I:C) were boosted with a single dose of 150,000 irradiated Pf sporozoites (PfSPZ) intravenously. Remarkably, boosting had no effect on the CSP-specific immunity. Finally, immunization with CSP+poly-ICLC reduced malaria parasite burden in the liver in an experimental mouse model. Taken together, these data showing that poly(I:C) is an effective adjuvant for inducing potent antibody and Th1 immunity with CSP based vaccines offers a potential alternative to the existing protein based pre erythrocytic vaccines. PMID- 20846530 TI - An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home. AB - The study evaluated the immunogenicity and efficacy of a trivalent subunit MF59 adjuvanted influenza vaccine (A/Wisconsin/67/05 (H3N2), A/Solomon Islands/3/06 (H1N1) and B/Malaysia/2506/04) in preventing serologically diagnosed infections in a group of 67 institutionalized elderly volunteers during 2007/2008 winter, characterized by co-circulation of drifted A/H3N2, A/H1N1 and B influenza viruses. Influenza vaccination induced a significant increase in the amounts of hemagglutination inhibiting antibodies, both against the vaccine and the epidemic drifted strains. However, vaccination did not prevent the circulation of the new drifted influenza B virus (B/Florida/4/06-like), belonging to the B/Yamagata/16/88-lineage, antigenically and genetically distinct from B/Victoria/2/87-lineage viruses from which the vaccine B strain was derived. PMID- 20846531 TI - Effects of different doses and schedules of diazepam treatment on lymphocyte parameters in rats. AB - Benzodiazepines (BZD) are widely used for the treatment of anxiety. They enhance GABA-ergic neurotransmission through the binding on specific BDZ recognition sites, within the GABA(A) receptor-ion channel complex. However, recent studies showed that BZD also act on peripheral benzodiazepine receptor sites (PBR) or translocator protein 18 kDa (TSPO). Evidence for a direct immunomodulatory action for BZD emerged from studies that demonstrated the presence of TSPO on immune/inflammatory cells. The present study was designed to analyze the effects of diazepam on rat lymphocyte parameters, specifically on phenotype, cell proliferation and cell death. The effects of both acute and long-term (21 days) diazepam (1 and 10 mg/kg/day) administrations were evaluated. Results showed that diazepam (1 mg/kg) treatment did not change the immune parameters analyzed. However, both diazepam (10 mg/kg) acute and long-term treatments decreased the number of apoptotic cells; they also increased the percentage of T cytotoxic cells; decreased the percentage of B cells and increased the corticosterone serum levels. The induction of functional tolerance was suggested for the highest dose of diazepam (10 mg/kg), but not for the smaller dose (1 mg/kg) used, at least for diazepam effects on corticosterone serum levels. Diazepam effects were discussed as being related to the number of TSPO sites present on immune cells and/or to the increased levels of serum corticosterone observed after the treatments used. PMID- 20846532 TI - [27th Congress of the French Society for Endocrinology, Deauville, France, September 29 - October 2, 2010. Abstracts]. PMID- 20846534 TI - Severe asthma and adherence to peak flow monitoring: longitudinal assessment of psychological aspects. AB - BACKGROUND: Adherence in severe asthma is a difficult health problem. Although psychosocial factors may be responsible for non-adherence, few longitudinal studies have investigated their link with adherence, with most studies having focused on pharmacology. METHODS: Sixty patients with severe asthma were recruited. Adherence was electronically monitored using peak flow measurements at entry and after 1 year of follow-up. Eysenck's Personality Inventory, Rotter's Locus of Control (LOC), and health control beliefs were all studied. Multiple logistic regression (MLR) was used for risk calculations. RESULTS: Initially, subjects with poor adherence had an external LOC (P=.001) and a high extraversion score (P=.003) compared to those with good adherence. The lie score was high in all patients. Nocturnal awakenings were highly significantly correlated with poor adherence (P=.006). After 1 year, patient adherence, extraversion, and neuroticism remained unchanged. The LOC changed in subjects with poor adherence, showing a less "external" orientation (P=.007). The health parameters were better at the end of the study. By MLR analysis, externality, extraversion, and low social desirability were associated with poor adherence. Patients with poor adherence had a greater probability of nocturnal symptoms. CONCLUSION: No specific personality type was associated with lack of adherence in the present study, but a high extraversion score, a low social desirability score, and a high level of externality were all predictors of poor adherence. PMID- 20846535 TI - Daily mood, shortness of breath, and lung function in asthma: concurrent and prospective associations. AB - OBJECTIVE: Previous asthma diary studies have yielded equivocal findings on concurrent associations between lung function and mood, and prospective associations have rarely been explored. We therefore examined concurrent and prospective associations between daily mood, shortness of breath, and lung function, and studied between-individual variability and stability of concurrent associations across different times of the day. METHOD: Twenty asthma patients and 20 healthy controls recorded their positive and negative mood, shortness of breath, physical activity, peak expiratory flow (PEF) and forced expiratory volume in the first second (FEV(1)) using an electronic pocket spirometer with diary functions three times per day for about 21 days. RESULTS: For both groups, PEF showed positive concurrent associations with ratings of various mood states, whereas FEV(1) was only associated with positive mood. Both indices correlated negatively with shortness of breath. Within-individual concurrent associations varied significantly in both groups and their stability varied across time of the day, with overall higher stability for associations with shortness of breath in asthma and PEF for both groups. Prospectively, higher shortness of breath consistently predicted lower lung function later during the day and on the subsequent day. CONCLUSION: The relationship between normal mood variations and lung function is highly variable across individuals and times of the day, limiting the predictive value of average group associations. Shortness of breath is predictive of future lung function decline in asthma. Future longitudinal research should focus on extreme emotional states, effort-independent measures of lung function, and additional indicators of asthma control. PMID- 20846536 TI - Cognitive and behavioural correlates of different domains of psychological adjustment in early-stage multiple sclerosis. AB - OBJECTIVE: This study investigated a cognitive-behavioural model of adjustment to multiple sclerosis (MS). It aimed to determine the contribution of cognitions and behaviours to the explanation of two distinct adjustment outcomes above and beyond measures of MS severity. Illness-related functional impairment was anticipated to be most strongly related to unhelpful thoughts and behaviours that were specific for MS and the experience of symptoms. Psychological distress was hypothesised to be most strongly related to more general unhelpful cognitions about the self and emotions. METHODS: Ninety-four people with MS completed questionnaires. Correlations and hierarchical multiple regressions determined the relative contribution of illness severity, cognitions, and behaviours to the prediction of psychological distress and functional impairment. RESULTS: Illness related functional impairment was related to disease severity, progressive versus relapsing-remitting disease, and unhelpful illness perceptions and cognitive and behavioural responses to symptoms. Illness severity factors accounted for a significant 23.7% of the variance in functional impairment (P<.001). Cognitive and behavioural variables explained a further 22.6% of the variance (P<.001), with behavioural responses to symptoms emerging as the strongest predictor. The correlates of distress were unhelpful beliefs about the self, unhelpful beliefs about emotions, acceptance, and unhelpful cognitive responses to symptoms and illness perceptions. Illness severity factors explained only 2.2% of the variance in distress (P>.05), while cognitive and behavioural variables accounted for 37.1% (P<.001). Unhelpful beliefs about the self were the strongest predictor. CONCLUSION: Longitudinal and experimental research is required to investigate potential causal relationships. However, the cognitions and behaviours identified as important for adjustment are potentially modifiable and thus may be useful to address within interventions for adjustment to MS. PMID- 20846537 TI - An evaluation of illness, treatment perceptions, and depression in hospital- vs. home-based dialysis modalities. AB - OBJECTIVES: Depressive symptoms are common among patients with end-stage renal disease (ESRD). In order to better understand what factors influence these symptoms, we examined the impact of illness and treatment cognitions on emotional adjustment and the influence of dialysis modality (hospital- vs. home-based dialysis) on this relationship. METHODS: A cross-sectional sample of 145 ESRD patients on four different dialysis modalities [hospital hemodialysis (HD), n=52; home HD, n=25; continuous ambulatory peritoneal dialysis (CAPD), n=45; automated PD (APD), n=23] completed the Illness Perceptions Questionnaire, the Illness Effects Questionnaire, the Treatment Effects Questionnaire, and the Beck Depression Inventory. Measures of ESRD severity/comorbidity and biochemistry were also collected. RESULTS: Perceptions of treatment disruptiveness and attributions to poor medical care were significantly greater in CAPD. Home-based treatments were not found to confer an emotional adjustment advantage compared to hospital HD. There were marked differences across home-based modalities, with n=22 (44.4%) CAPD meeting the clinical cutoff of depression (?16) vs. n=6 (26.1%) in APD and n=2 (8%) in home HD. After adjusting for case-mix differences, the mean levels of depressed mood remained significantly higher in CAPD patients compared to APD and home HD (P<.01). On multiple regression analysis, 42.5% of the variance in depression was explained by the End-Stage Renal Severity Index, dialysis modality, perceived treatment disruptiveness, and beliefs about illness consequences and the extent to which the illness could be controlled. CONCLUSION: The findings suggest that the benefits of self-care are not uniformly manifested across dialysis modalities and that patients' cognitions are important determinants of depressed mood with implications for future research and clinical practice. PMID- 20846538 TI - The Hospital Anxiety and Depression Scale: a diagnostic meta-analysis of case finding ability. AB - OBJECTIVE: To quantify the accuracy of the Hospital Anxiety and Depression Scale (HADS) as a case-finding instrument for anxiety and depressive disorders. METHOD: MEDLINE, PSYCHINFO, EMBASE, CINAHL, BNI, and AMED were searched from January 1983 to June 2006. Studies were included that administered the HADS, used a standardized psychiatric interview to establish a diagnosis of anxiety or depression, and provided sufficient data on sensitivity and specificity (N=41). Summary sensitivity, specificity, likelihood ratios, and diagnostic odds ratios were calculated for each study. Random effects meta-analytic pooling across studies at the recommended clinical (7/8) and research (10/11) cutoff points was undertaken and summary receiver operating characteristic curves constructed. RESULTS: For major depressive disorders, a cut point of >=8 gave a sensitivity of 0.82 (95% CI, 0.73-0.89) and a specificity of 0.74 (95% CI, 0.60-0.84) and a cut point >=11 gave a sensitivity of 0.56 (95% CI, 0.40-0.71) and a specificity of 0.92 (95% CI, 0.79-0.97). CONCLUSIONS: Many studies have shown that the HADS is a useful screening tool to identify emotional distress in nonpsychiatric patients. However, it does not appear to be superior to other screening instruments in terms of identifying specific mental disorders in physical health settings. PMID- 20846539 TI - Subgroup differences in psychosocial factors relating to coronary heart disease in the UK South Asian population. AB - OBJECTIVES: To explore the differences in psychosocial risk factors related to coronary heart disease (CHD) between South Asian subgroups in the UK. South Asian people suffer significantly higher rates of CHD than other ethnic groups, but vulnerability varies between South Asian subgroups, in terms of both CHD rates and risk profiles. Psychosocial factors may contribute to the excess CHD propensity that is observed; however, subgroup heterogeneity in psychosocial disadvantage has not previously been systematically explored. METHODS: With a cross-sectional design, 1065 healthy South Asian and 818 white men and women from West London, UK, completed psychosocial questionnaires. Psychosocial profiles were compared between South Asian religious groups and the white sample, using analyses of covariance and post hoc tests. RESULTS: Of the South Asian sample, 50.5% was Sikh, 28.0% was Hindu, and 15.8% was Muslim. Muslim participants were more socioeconomically deprived and experienced higher levels of chronic stress, including financial strain, low social cohesion, and racial discrimination, compared with other South Asian religious groups. In terms of health behaviors, Muslim men smoked more than Sikhs and Hindus, and Muslims also reported lower alcohol consumption and were less physically active than other groups. CONCLUSION: This study found that Muslims were exposed to more psychosocial and behavioral adversity than Sikhs and Hindus, and highlights the importance of investigating subgroup heterogeneity in South Asian CHD risk. PMID- 20846540 TI - Factors associated with suicidal ideation: role of emotional and instrumental support. AB - OBJECTIVES: Suicidal ideation is an important phase in the suicidal process, preceding suicide attempts and completed suicide. Weak social ties and low support from friends or relatives have been significantly associated with suicidal ideation. This study investigated the relationship between social support and suicidal ideation among young and middle-aged adults in Korea. METHODS: The Seoul Citizens Health and Social Indicators Survey conducted face-to face interviews with 10,922 self-reporting adults. Questions were asked to assess suicidal ideation, and several questions focused on social support, social networks, health behaviors, and health status. RESULTS: The strongest association in middle-aged adults was that between suicidal ideation and lack of social support. Poor emotional support significantly influenced suicidal ideation in middle-aged men, whereas lack of instrumental support significantly affected suicidal thoughts in middle-aged women, after controlling for sociodemographic factors, health behaviors, and health status. High alcohol use, functional limitations, and stress were related to suicidal thoughts in young adults, whereas depressive feelings had the strongest association with suicidal ideation in middle-aged women. CONCLUSIONS: Social support is a crucial independent correlate of suicidal ideation, especially in middle-aged adults in an urban community setting. This study shows that it is essential to provide gender specific social support to prevent suicide. PMID- 20846541 TI - Detecting depression in medically ill patients: Comparative accuracy of four screening questionnaires and physicians' diagnoses in Spanish population. AB - OBJECTIVE: The purpose of this study is to compare the diagnostic accuracy of four depression screening tools commonly used in patients with medical disorders, relative to a reference diagnostic standard-a structured psychiatric interview. METHODS: The Depression in the Medically Ill-18 (DMI-18) questionnaire was administered to 167 patients with medical disorders; of those, 53 completed the Beck Depression Inventory for Primary Care (BDI-PC), 67 the Hospital Anxiety and Depression Scale (HADS), and 46 the Patient Health Questionnaire-9 (PHQ-9). The entire sample was also interviewed with a structured psychiatric interview conducted by a mental health professional. Sensitivity, specificity, likelihood ratios (LRs), and area under the curve (AUC) were calculated and compared for the different measures. RESULTS: At their respective recommended cutoff points, sensitivities [95% confidence interval (CI)] were 86% (70-95), 82% (63-94), 93% (86-97), and 68% (47-85) for the HADS-D, BDI-PC, DMI-18, and PHQ-9, respectively, while specificities ranged from 72% (47-90) for BDI-PC to 89% (72-98) for PHQ-9. The sensitivities of DMI-18 were significantly higher compared to those of HADS-D (P=.045) and PHQ-9 (P=.01). The PHQ-9 questionnaire obtained the most favorable positive LR (6.35; 95% CI, 2.48-18.36). In contrast, the DMI-18 showed the best negative LR (0.09; 95% CI, 0.04-0.18). Areas under the curves (95% CI) ranged from 0.92 (0.83-1.02) to 0.84 (0.74-0.94). Statistically significant differences were found between the AUCs of the DMI-10 and the BDI-PC. CONCLUSION: Our results suggest that all evaluated scales have acceptable abilities and can be used as screening instruments for depression in patients with medical disorders. The DMI stands out for its sensitivity. PMID- 20846542 TI - Conscious and unconscious perseverative cognition: is a large part of prolonged physiological activity due to unconscious stress? AB - Prolonged physiological activity is believed to be a key factor mediating between stress and later disease outcomes. Few studies, however, have investigated the crucial psychological factors that cause prolonged activity. This article proposes that conscious as well as unconscious perseverative cognition are the critical factors. Perseverative cognition indicates repetitive or sustained activation of cognitive representations of past stressful events or feared events in the future. In daily life, most prolonged physiological activity is not due to stressful events but to perseverative cognition about them. We and others have already found evidence that conscious perseverative cognition, i.e., worry, has physiological effects, in both laboratory and real life settings, and that perseverative cognition mediates prolonged responses to stressful events. Yet, there are convincing reasons to expect that unconscious perseverative cognition has an even larger role in stress-related prolonged activity. Firstly, since the greater part of cognitive processing operates without awareness, a considerable part of perseverative cognition is likely to be unconscious too. People may not be aware of most of their stress-related cognitive processes. Secondly, our recent studies have shown that increased activity of the autonomic nervous system continues after conscious perseverative cognition has stopped: It goes on for several hours and even during sleep. This and several other findings suggest that a considerable part of increased physiological activity may be due to unconscious perseverative cognition. The article closes with suggesting methods to test unconscious perseverative cognition and ways to change it, and concludes with stating that the notion of unconscious perseverative cognition potentially opens an entirely new area within stress research. PMID- 20846543 TI - Man of unconscious sorrow. PMID- 20846544 TI - Adult attachment measures: a 25-year review. AB - OBJECTIVE: Over the past 25 years, attachment research has extended beyond infant parent bonds to examine dyadic relationships in children, adolescents, and adults. Attachment has been shown to influence a wide array of biopsychosocial phenomena, including social functioning, coping, stress response, psychological well-being, health behavior, and morbidity, and has thus emerged as an important focus of psychosomatic research. This article reviews the measurement of adult attachment, highlighting instruments of relevance to-or with potential use in psychosomatic research. METHODS: Following a literature search of articles that were related to the scales and measurement methods of attachment in adult populations, 29 instruments were examined with respect to their utility for psychosomatic researchers. RESULTS: Validity, reliability, and feasibility were tabulated on 29 instruments. Eleven of the instruments with strong psychometric properties, wide use, or use in psychosomatic research are described. These include the following: Adult Attachment Interview (George, Kaplan, and Main); Adult Attachment Projective (George and West); Adult Attachment Questionnaire (Simpson, Rholes, and Phillips); Adult Attachment Scale (and Revised Adult Attachment Scale) (Collins and Read); Attachment Style Questionnaire (Feeney); Current Relationship Interview (Crowell and Owens); Experiences in Close Relationships (Brennan, Clark, and Shaver) and Revised Experiences in Close Relationships (Fraley, Waller, and Brennan); Parental Bonding Instrument (Parker, Tupling, and Brown); Reciprocal Attachment Questionnaire (West and Sheldon Keller); Relationship Questionnaire (Bartholomew and Horowitz); and Relationship Scales Questionnaire (Grifiin and Bartholomew). CONCLUSION: In addition to reliability and validity, investigators need to consider relationship focus, attachment constructs, dimensions or categories of interest, and the time required for training, administration, and scoring. Further considerations regarding attachment measurement in the context of psychosomatic research are discussed. PMID- 20846545 TI - Record attendance at Austrian EACLPP-ECPR meeting in Innsbruck. PMID- 20846546 TI - Behavior and lifestyle characteristics of male Kuwaiti drivers. AB - INTRODUCTION: The high traffic accident risk among young drivers is a well-known and well-documented fact in most countries. Lifestyle has proven to affect driving behavior as well as accident risk. This study covers the lifestyle component of the problems related to young male Kuwaiti drivers' accident risk. METHODS: The purpose of the study is to measure the relationship between lifestyle and accident risk. Lifestyle is measured through a questionnaire, where 302 male Kuwaiti drivers (mean age=28 years; range 25-35 years) answer 39 questions related to behavioral and social factors, road conditions, police enforcement, and life satisfaction. They also report their involvement in accidents and traffic violations. RESULTS: The questionnaire's validity and reliability (Cronbach's alpha=0.7) were achieved. Principal component analysis reduced the 39 items on the questionnaire to 5 factors. Inadequate police enforcement is strongly correlated (r=0.862) to accident risk and traffic violations and is thus considered the best predictor of traffic accidents in Kuwait. IMPACT ON INDUSTRY: As driving-related incidents (on-the-job and off-the job) are a significant source of fatalities and lost-work-days, the study points to the importance of considering cultural factors in the design of comprehensive safety programs for industry. PMID- 20846547 TI - The development and validation of a psychological contract of safety scale. AB - INTRODUCTION: This paper builds on previous research by the author and describes the development and validation of a new measure of the psychological contract of safety. The psychological contract of safety is defined as the beliefs of individuals about reciprocal safety obligations inferred from implicit and explicit promises. METHOD: A psychological contract is established when an individual believes that perceived employer and employee safety obligations are contingent on each other. A pilot test of the measure is first undertaken with participants from three different occupations: nurses, construction workers, and meat processing workers (N=99). Item analysis is used to refine the measure and provide initial validation of the scale. A larger validation study is then conducted with a participant sample of health care workers (N=424) to further refine the measure and to determine the psychometric properties of the scale. RESULTS: Item and correlational analyses produced the final employer and employee obligations scales, consisting of 21 and 17 items, respectively. Factor analyses identified two underlying dimensions in each scale comparable to that previously established in the organizational literature. These transactional and relational type obligations provided construct validity of the scale. Internal consistency ratings using Cronbach's alpha found the components of the psychological contract of safety measure to be reliable. IMPACT ON INDUSTRY: The refined and validated psychological contract of safety measure will allow investigation of the positive and negative outcomes associated with fulfilment and breach of the psychological contract of safety in future research. PMID- 20846548 TI - A traffic safety evaluation of California's traffic violator school citation dismissal policy. AB - INTRODUCTION: This study evaluated California's traffic violator school (TVS) citation dismissal policy. METHOD: This study identified and compared two large samples of drivers either completing a TVS (N=210,015) or convicted of a traffic citation (N=168,563). RESULTS: Prior to adjudication, the TVS group had characteristics (e.g., lower prior conviction rate and smaller proportion of males) that were predictive of a lower subsequent crash risk. However, the TVS group exhibited significantly more crashes than did the convicted group in the subsequent one-year period. The difference (4.83%) increased to 10% after adjusting for the more favorable characteristics of the TVS group. The TVS group also had a higher adjusted subsequent crash rate at each prior driver record entry level, reflecting a loss in the general and specific deterrence of the non conviction masked status of TVS dismissed citations. It was reported that the TVS dismissal policy results in approximately 12,300 additional crashes annually with economic costs of approximately $398,000,000. CONCLUSIONS: The avoidance of licensing actions resulting from the dismissal policy assists in explaining why the driving public is exposed to an increased crash risk. A number of recommendations are offered to reduce the negative traffic safety impact of the TVS citation dismissal policy. PMID- 20846549 TI - Re-education of young driving offenders: effects on self-reports of driver behavior. AB - INTRODUCTION: Offending drivers are often re-educated, but these courses have seldom been shown to have any safety effects. METHOD: An on-line improvement course for offending drivers below the age of 25 was evaluated with several driver inventories. RESULTS: The drivers reported higher levels of aggression, stress, sensation seeking, drunk driving, and driving violations, six months after the course than before. However, these levels were lower than those of controls, indicating that the initially low levels for the education group were due to socially desirable responding, as measured by a lie scale, an effect that waned after the course. DISCUSSION: The results can be interpreted as a positive effect of the education, although this conclusion is tentative and not in agreement with all effects in the data. IMPACT ON INDUSTRY: The results are in disagreement with previous evaluation studies using the same or similar instruments, and show the need to include controls for social desirability in self-report studies. PMID- 20846550 TI - What kinds of injuries do OSHA inspections prevent? AB - OBJECTIVE: OSHA's enforcement program is one of the major public efforts to protect American workers. We examine both the scope of injury prevention that inspections can contribute and the types of standards that contribute the most. METHODS: We linked Pennsylvania Department of Labor and Industry files for lost time injuries and employment to calculate injury rates for 1998-2005 for all single-establishment manufacturing firms. We linked these to OSHA inspection records. RESULTS: Inspections with penalties did affect injury types unrelated to standards as well as those related. We also found again that citations for violations of the standard requiring personal protective equipment had the largest impact on preventing injuries. IMPACT ON INDUSTRY: Programs requiring protective equipment use deserve added attention from consultants and inspectors. In addition, some inspections spur managers to undertake safety measures that go beyond compliance with standards. PMID- 20846551 TI - Examining traffic crash injury severity at unsignalized intersections. AB - INTRODUCTION: This study presents multiple approaches to the analysis of crash injury severity at three- and four-legged unsignalized intersections in the state of Florida from 2003 until 2006. An extensive data collection process was conducted for this study. METHOD: The dataset used in the analysis included 2,043 unsignalized intersections in six counties in the state of Florida. For the scope of this study, there were three approaches explored. The first approach dealt with the five injury levels, and an ordered probit model was fitted. The second approach was an aggregated one, and dealt with only the severe versus non-severe crash levels, and a binary probit model was used. The third approach dealt with fitting a nested logit model. Results from the three fitted approaches were shown and discussed, and a comparison between the three approaches was shown. RESULTS: Several important factors affecting crash severity at unsignalized intersections were identified. These include the traffic volume on the major approach, and the number of through lanes on the minor approach (surrogate measure for traffic volume), and among the geometric factors, the upstream and downstream distance to the nearest signalized intersection, left and right shoulder width, number of left turn movements on the minor approach, and number of right and left turn lanes on the major approach. As for driver factors, young and very young at-fault drivers were associated with the least fatal probability compared to other age groups. IMPACT ON INDUSTRY: The analysis identified some countermeasures to reduce injury severity at unsignalized intersections. The spatial covariates showed the importance of including safety awareness campaigns for speeding enforcement. Also, having a 90-degree intersection design is the most appropriate safety design for reducing severity. Moreover, the assurance of marking stop lines at unsignalized intersections is very essential. PMID- 20846552 TI - Crash involvement during the different phases of the New Zealand Graduated Driver Licensing System (GDLS). AB - INTRODUCTION: The New Zealand Graduated Driver Licensing System (GDLS) is designed to allow novice drivers to gain driving experience under conditions of reduced risk. METHOD: To examine the effectiveness of the GDLS, an analysis of how the crash involvement of novice drivers changes as drivers move through the GDLS was undertaken. Crash profiles were created by data matching the New Zealand license and crash databases, covering a time period from 1999-2006. RESULTS: The crash profiles show that the initial learner period of the GDLS is relatively safe and the time at which novice drivers have the highest rate of crash involvement is during the first few months of solo driving. Analysis using logistic regression also showed an effect of age and gender, with higher crash involvement associated with younger drivers and males. In addition, individuals who gained a full license within 12-18 months of holding a restricted license, due to completion of a time-discount associated educational program, had a higher level of involvement in crashes than individuals who gained a full license after 18 months. CONCLUSIONS: The crash profiles provide an insight into the crash risk associated with different phases of the New Zealand GDLS. IMPACT ON INDUSTRY: Increasing the age at which drivers first begin to solo drive and the removal of the time-discount associated with completion of an educational program should be considered. PMID- 20846553 TI - Increasing self-awareness among older drivers: the role of self-screening. AB - INTRODUCTION: Self-screening by older drivers has shown considerable promise for increasing self-awareness about functional abilities associated with safe driving. The purpose of this study was to improve upon existing self-screening instruments by focusing entirely on "health concerns" that affect driving - that is, the symptoms that people experience due to medical conditions and the medications used to treat them - rather than the medical conditions or medications themselves. METHOD: A computer-based, easy-to-use self-screening instrument for older drivers was developed to provide individualized feedback intended to increase self-awareness about declines in driving-related abilities, as well as suggestions for behavioral changes or safety tips to maintain safe driving, further evaluation from a physician/health professional, and vehicle modifications to help compensate for driving-related declines. RESULTS: This paper describes the development of the self-screening instrument and summarizes findings relative to increasing self-awareness among older drivers. This research represents an important first step in improving self-awareness among older drivers through self-screening. PMID- 20846554 TI - Bicycle helmet use among children in the United States: the effects of legislation, personal and household factors. AB - INTRODUCTION: Children ages 5-14 years have the highest rate of bicycle-related injuries in the country. Bicycle helmets can prevent head and brain injuries, which represent the most serious type of bicycle-related injury. OBJECTIVES: This paper compares children's bicycle helmet use to that estimated from an earlier study, and explores regional differences in helmet use by existing helmet legislation. METHODS: This study was a cross-sectional, list-assisted random digit-dial telephone survey. Interviews were completed by 9,684 respondents during 2001-2003. The subset with at least one child in the household age 5-14 years (2,409 respondents) answered questions about bicycle helmet use for a randomly selected child in their household. RESULTS: Almost half (48%) of the children always wore their helmet, 23% sometimes wore their helmet, and 29% never wore their helmet. Helmet wearing was significantly associated with race, ethnicity, and child age but was not associated with the sex of the child. Other significant predictors of use included household income, household education, census region, and bicycle helmet law status. Statewide laws were more effective than laws covering smaller areas. The proportion of children who always wore a helmet increased from 25% in 1994 to 48% in 2001-2002. Significant increases in helmet use from 20% to 26% were seen among both sexes, younger (5-9 years) and older (10-14 years) children, and in all four regions of the country. CONCLUSIONS: While there has been substantial progress in the number of children who always wear their helmets, more than half do not. Further progress will require using a combination of methods that have been shown to successfully promote consistent helmet use. IMPACT ON INDUSTRY: minimal. PMID- 20846555 TI - A reporting guide for studies on individual differences in traffic safety. AB - PROBLEM: Studies on individual differences in traffic safety report differently on their methodologies, and use different statistics, and these are therefore difficult to compare and meta-analyze. METHOD: Based upon a previous, extensive review and meta-analysis of the traffic safety literature, several recommendations are made about what features of the methodology of studies on individual differences (including evaluations) in safety need to be reported to facilitate interpretation and meta-analysis. Similarly, some basic types of statistical values are recommended. IMPACT ON INDUSTRY: The accumulation of knowledge about individual differences in traffic safety would be facilitated if scientific authors and journals adhered to these guidelines. PMID- 20846556 TI - [The 2010 Editor's award]. PMID- 20846557 TI - Total pancreatectomy and islet cell autotransplantation as a means of treating patients with genetically linked pancreatitis. AB - BACKGROUND: For patients with severe chronic pancreatitis, total or completion pancreatectomy with islet cell autotransplantation (IAT) can alleviate pain and avoid the complications of diabetes. Several genetic mutations, specifically, PRSS1, CFTR, and SPINK1, are associated with chronic pancreatitis. Few reports have focused on the benefit of this operation for this subset of patients. METHODS: Between February 2000 and July 2009, 118 patients were treated with total pancreatectomy and IAT for chronic pancreatitis. Patients with known genetic mutations were then selected for further analysis. RESULTS: Of the 188 patients, 16 (13.6%) patients were identified as having genetic mutations, including CFTR (n = 10), PRSS1 (n = 4), and SPINK1 (n = 2) mutations. Mean patient age was 31.4 years (range, 15-59) with an equal male-to-female ratio (50:50). Preoperatively, patients required an average of 185 +/- 60 morphine equivalents (MEQ) (median, 123 MEQ) for preoperative pain control. No patients were taking insulin before operation. After resection with IAT, patients were discharged from the hospital with a daily average of 22 +/- 4 units of insulin with 6 (38%) patients requiring fewer than 15 units of insulin at the time of discharge. At a mean follow-up of 22 months, mean insulin requirements decreased to 15 U/d (P = .0172). A total of 7 (44%) patients required 15 or fewer units daily, and 4 (25%) patients were completely insulin-independent. Average daily narcotic usage at most recent follow-up decreased to 70 MEQ (median, 0) with 10 (63%) patients currently narcotic-independent. Analyses of the 36-item short-form health survey and the McGill Pain Questionnaire demonstrated a significant improvement in quality-of-life parameters and pain assessment. CONCLUSION: In patients who suffer from genetically linked chronic pancreatitis, pancreatic resection with IAT should be considered as an early therapeutic option to decrease chronic abdominal pain while preserving endogenous endocrine function. PMID- 20846560 TI - Dramatic improvement of inoperable angiosarcoma with combination paclitaxel and bevacizumab chemotherapy. PMID- 20846561 TI - Development of monoclonal gammopathy in 12 patients receiving efalizumab treatment for chronic plaque psoriasis. PMID- 20846562 TI - Basal cell carcinoma with metastasis to the lung in an African American man. PMID- 20846563 TI - Cutaneous toxicities of antiretroviral therapy for HIV: part I. Lipodystrophy syndrome, nucleoside reverse transcriptase inhibitors, and protease inhibitors. AB - Antiretroviral medications for the treatment of HIV are common drugs with diverse and frequent skin manifestations. Multiple new cutaneous effects have been recognized in the past decade. Dermatologists play an important role in accurately diagnosing and managing the cutaneous toxicities of these medications, thereby ensuring that a patient has as many therapeutic options as possible for life-long viral suppression. Part I of this two-part series on the cutaneous adverse effects of antiretroviral medications will discuss HIV-associated lipodystrophy syndrome, which can be seen as a result of many antiretroviral medications for HIV, and the specific cutaneous effects of the nucleoside reverse transcriptase inhibitors and protease inhibitors. PMID- 20846564 TI - Cutaneous toxicities of antiretroviral therapy for HIV: part II. Nonnucleoside reverse transcriptase inhibitors, entry and fusion inhibitors, integrase inhibitors, and immune reconstitution syndrome. AB - Cutaneous manifestations of antiretroviral medications for HIV are common and potentially dangerous conditions encountered by dermatologists. Part II of this two-part series on the cutaneous effects of antiretroviral medications for HIV will discuss the four most recent classes of medications that have been developed and immune reconstitution syndrome--an important diagnostic consideration when evaluating a dermatologic patient who is taking antiretroviral medications. PMID- 20846565 TI - Treatment of actinic cheilitis with the Er:YAG laser. AB - BACKGROUND: Actinic cheilitis is a common condition with the potential to develop into squamous cell carcinoma. Current treatments have varying cure rates and complications. The role of the erbium:yttrium-aluminum-garnet (Er:YAG) laser in the treatment of actinic cheilitis has not been widely published, despite offering theoretical advantages over current treatment modalities. OBJECTIVE: To evaluate the outcome of a series of patients treated with the Er:YAG laser for actinic cheilitis. METHODS: This was a retrospective, interventional, nonrandomized, sequential case series set in a tertiary referral, dermatologic surgery unit. Ninety-nine consecutive patients with actinic cheilitis treated with the Er:YAG laser between January 2001 and June 2008 underwent a case note review, of which 77 went on to a structured telephone interview. The main outcome measures were a subjective improvement in lip symptoms related to actinic cheilitis and objective improvement in the lips at routine follow-up. RESULTS: Mean time to interview follow-up was 65.7 months. Of those interviewed, 92.2% believed there had been an improvement in the cosmetic appearance of their lips; one hundred percent believed the function of their lips had improved or remained unchanged; and 84.8% remained completely disease free at the time of follow-up. The majority of patients (93.5%) were satisfied with the laser treatment. Scarring as a direct result of the laser occurred in 5.1% of patients. LIMITATIONS: Retrospective nature of data collection; inability to interview all patients who underwent treatment. CONCLUSION: The Er:YAG laser is a successful modality for the treatment of actinic cheilitis with good functional and cosmetic results and only a small risk of long-term scarring. It should be considered as a first-line treatment for the disease. PMID- 20846566 TI - Influence of evaluation of clinical pictures on the histopathologic diagnosis of inflammatory skin disorders. AB - BACKGROUND: Clinical information on histologic referral sheets is usually very limited, and particularly for inflammatory skin disorders, dermatopathologists often ask referring physicians for clinical correlation. OBJECTIVE: In this study we tested the value of clinicopathologic correlation in the histopathologic diagnosis of inflammatory skin disorders. METHODS: One-hundred biopsy specimens were digitalized and stored on 3 DVDs along with the clinical images. All cases were evaluated by 9 independent full-time dermatopathologists, initially without looking at the clinical pictures and subsequently after checking them. All diagnoses were finally compared with the "reference" diagnosis established in Graz, Austria, and the results were statistically analyzed. RESULTS: After evaluation of the clinical images, the number of dermatopathologists making a correct diagnosis was increased in 70 cases, unchanged in 25 cases, and decreased in 5 cases. The total number of correct diagnoses increased from 332 (diagnoses before evaluation of clinical pictures) to 481 (diagnoses after evaluation of clinical pictures), with a 16.6% increase in the total. LIMITATIONS: The computerized setting is different from real-life dermatopathology and physical examination of patients. CONCLUSION: Our study clearly shows that clinical pictures should be added to biopsy request slips of inflammatory skin disorders whenever possible, as they allow a better interpretation of histopathologic findings. PMID- 20846567 TI - Expanding the spectrum of frontal fibrosing alopecia: a unifying concept. AB - BACKGROUND: In frontal fibrosing alopecia (FFA), scalp alopecia dominates the clinical picture. However, eyebrow loss and hair loss in other body sites may also occur; this has been documented clinically, but rarely histopathologically. We describe the clinicopathological findings of 13 cases of FFA, with histopathologic data from the scalp, eyebrow, and body hair. METHODS: Thirteen patients with a diagnosis of FFA, seen between 2006 and 2008, were included. Scalp biopsies were performed in all patients for histology and direct immunofluorescence (DIF). Biopsy specimens for histology were taken from the eyebrow in 6 patients and from the upper limb in 5 patients. RESULTS: All 13 patients were female, 11 of whom were postmenopausal. The median age at onset of alopecia was 57 years. Clinical examination revealed a band of frontal hairline recession in all patients. Eyebrow loss was present clinically in all patients, with loss of body hair in 10 of 13. Histopathologic examination of the scalp, eyebrow, and upper limb skin biopsy specimens showed similar features, including a marked reduction in the number of hair follicles and a perifollicular lymphoid cell infiltrate with perifollicular fibrosis. Direct immunofluorescence was negative in all cases. LIMITATIONS: Not all patients consented to biopsies of the eyebrows or upper limbs. CONCLUSION: Eyebrow and peripheral body hair loss is not uncommon in FFA-a finding that is likely underreported. We have demonstrated that alopecia of the upper limbs in FFA is indeed common and, histopathologically, shows features of lichen planopilaris and scarring, similar to findings in the scalp and eyebrows. Consequently, the process of lichen planopilaris with scarring alopecia is generalized rather than localized only to the frontal scalp and eyebrows. PMID- 20846568 TI - Histologic processing and reporting of cutaneous pigmented lesions: recommendations based on a survey of 94 dermatopathologists. AB - BACKGROUND: Standard operating procedures for laboratory processing and reporting of margins of cutaneous pigmented lesions do not exist. We conducted a survey of 94 dermatopathologists to evaluate these practices. OBJECTIVES: We sought to: (1) identify dominant practices among dermatopathologists; (2) determine the impact of the procedure, intent to excise, and histologic diagnosis on the process of margin evaluation; and (3) propose guidelines based on these findings. METHODS: The survey consisted of 44 questions focused on the impact of procedure (punch, shave, or ellipse), intent (excision or biopsy), and histologic diagnosis (common nevus, congenital nevus, atypical nevus, melanoma) on processing and margin reporting. RESULTS: For ellipses, or specimens indicated as excisions, the majority practice (76%-98%) was to ink the specimens. Although more than 90% of observers report the margins on all melanomas and atypical nevi, fewer than 50% of respondents report margins on all nonatypical nevi. LIMITATIONS: The study consists of a survey sample of dermatopathologists and does not represent the practices of those who did not respond to the survey. CONCLUSIONS: Based on the results of this survey we have arrived at the following recommendations: (1) ink all specimens that are ellipses or designated as excisions; (2) tips should be evaluated separately if the specimen is an ellipse; (3) obtain levels in cases with tumor in the tip but not at ink if the specimen is an ellipse or excision and the diagnosis is atypical nevus or melanoma; and (4) report margins on all atypical nevi and melanomas. PMID- 20846569 TI - Filler complications. PMID- 20846570 TI - A case of comparing effectiveness sine comparative effectiveness. PMID- 20846572 TI - Poor metrics and lost opportunity. PMID- 20846573 TI - Psoralen plus ultraviolet A light phototherapy effectiveness. PMID- 20846574 TI - Dermatology department endowments. PMID- 20846575 TI - Pinpoint white dots in the scalp: dermoscopic and histopathologic correlation. PMID- 20846576 TI - Clinical and dermatoscopic findings in Bazex-Dupre-Christol and Gorlin-Goltz syndromes. PMID- 20846577 TI - Cervical trophic syndrome. PMID- 20846578 TI - A new superficial fungal infection caused by Coniosporium epidermidis. PMID- 20846579 TI - Baldness reversed by chemotherapy. PMID- 20846580 TI - Changes in Haemophilus influenzae capsule locus: possible emergence of novel variants in Brazil. AB - A total of 28 strains of Haemophilus influenzae (Hi) a and b isolated from clinical samples before and after the introduction of the Hib conjugate vaccine in Brazil were analyzed to determine variants of the capsular gene. Our results suggest the occurrence of new variants closely related to types I and II previously described elsewhere. Eleven Hib strains belonged to type I, 8 were type II, and 3 Hia strains were type II. Six strains showed negative results after polymerase chain reaction targeting capsule locus; the variable regions were sequenced and compared with types I and II. Phylogenetic analysis showed that 5 Hib strains were actually subtypes of type I (type I-A), whereas 1 Hia strain was a subtype of type II (type II-A). Types I and II strains were present in both periods of vaccination. This study suggests that a gradual change in the capsule genes of H. influenzae is probably occurring, and novel variants might be emerging among Brazilian isolates. PMID- 20846581 TI - Prevalence of Mycoplasma pneumoniae-associated respiratory tract infections in hospitalized children: results of a 4-year prospective study in Tunis. AB - Specific microbiologic, molecular, and serologic assays are hardly available in Tunis to confirm a suspected infection of Mycoplasma pneumoniae (MP). These diagnosis methods were used for the first time in a Tunisian prospective study to estimate the prevalence of MP infection in children and to evaluate their usefulness for diagnosis. A total of 540 children hospitalized in Tunis for lower respiratory tract infections (LRTIs) between 2005 and 2009 and 580 clinical specimens were investigated for the presence of MP by culture and by end-point polymerase chain reaction (PCR) targeting the P1 and the 16S rRNA genes. Real time PCR was also used for MP detection on 158 respiratory samples. A total of 525 serum samples were tested for detection of MP-specific IgM and IgG. The P1 adhesin type and the antibiotic susceptibility testing were determined for the 9 clinical strains isolated during the study period. MP was detected in 33 (5.7%) clinical samples. Specific MP seropositivity was confirmed in 54 serum samples (10.3%), among which 19 (3.6%) were indicative of acute MP infection. MP infection was confirmed in 39 (7.2%) patients: 24 positive by PCR and/or culture, 10 serologically positive only, and 5 confirmed positive by both methods. MP infections occurred throughout the year with a slight decrease in autumn. The 9 MP isolates were susceptible to erythromycin, tetracycline, and ciprofloxacin, and all belonged to type I. The prevalence of MP infection in children with LRTI was 7.2% between 2005 and 2009, in Tunisia. Combination of direct detection and serology was required to enhance the clinical sensitivity of MP detection in clinical specimens. PMID- 20846582 TI - Diagnosis of acute Q fever with emphasis on enzyme-linked immunosorbent assay and nested polymerase chain reaction regarding the time of serum collection. AB - A commercially available enzyme-linked immunosorbent assay (ELISA) (Virion/Serion [Wuerzburg, Germany]), an indirect fluorescent antibody test (IFAT) (BIOS/Focus [Cypress, CA]), and a nested polymerase chain reaction (PCR) were explored for diagnosis of acute Q fever in reference to time of serum collection. Serum samples of 22 patients with acute Q fever collected around the fifth day of illness were included. A sensitivity of 30% by ELISA and 80% by IFAT (P = 0.1) was found for the first 5 days of illness and 92% by ELISA and 83% by IFAT during the sixth and eleventh day. PCR revealed a positive result in 8 cases (36%) with 6 cases deriving from the first 5 days of illness. We conclude that ELISA aids especially in the diagnosis of Q fever after 5 days of illness. The benefit of PCR as an additional tool to ELISA was especially evident in the early days of serum sampling. PMID- 20846583 TI - Pathotypes of diarrheagenic Escherichia coli in children attending a tertiary care hospital in South India. AB - The prevalence of diarrheagenic Escherichia coli (DEC) in children under 5 years was studied in children with diarrhea and controls in South India. Four polymerase chain reaction (PCR) "schemes" were used to detect genes of the 6 pathotypes of DEC. In 394 children with diarrhea, 203 (52%) DEC infections were found. Among the 198 controls, 126 (63%) DEC infections were found. Enteroaggregative E. coli was the most common pathotype by multiplex PCR both in cases (58, 14.7%) and controls (47, 23.7%), followed by enteropathogenic E. coli seen in 10% cases and 8% of controls. Enterotoxigenic E. coli (ETEC), enterohemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC), and diffusely adherent E. coli (DAEC) were found in 4.1%, 2.0%, 1.0%, and 0.5% of cases, respectively. ETEC was found in 2.5% of controls, but EHEC, EIEC, and DAEC were not detected. Overall, no single assay worked well, but by discounting genes with a pathogenicity index of less than 1, it was possible to use the PCR assays to identify DEC in 75/394 (19%) cases and 12/198 (6.1%) controls, while mixed infection could be identified in 8/394 (2%) cases and 2/198 (1%) controls. PMID- 20846584 TI - Evaluation of the Speed-oligo(r) Mycobacteria assay for identification of Mycobacterium spp. from fresh liquid and solid cultures of human clinical samples. AB - We evaluated the ability of a novel DNA strip assay (Speed-oligo(r) Mycobacteria) to differentiate mycobacterial species. It is based on polymerase chain reaction targeting 16S rRNA and 16S-23S rRNA regions and double-reverse hybridization on a dipstick using probes bound to colloidal gold and to the membrane. We blindly tested its capacity to identify 182 acid-fast bacilli grown on fresh liquid (BacT/Alert, MGIT) and solid (Lowenstein-Jensen) cultures (from Spanish mycobacteriology laboratories), previously identified by means of Genotype((r)) Mycob.CM/AS or Gen-Probe((r)) AccuprobeMTC, and 11 collection strains of mycobacteria-related organisms. Discrepancies were resolved by 16S rRNA sequencing. Results were interpreted by identification of 7 specific bands for the following: Mycobacterium sp., M. fortuitum, Mycobacterium avium intracellulare complex, Mycobacterium tuberculosis complex, Mycobacterium kansasii, M. gordonae, and M. abscessus-chelonae complex. No cross-reactivity was observed with any mycobacteria-related organism. Concordant results were obtained for 177/182 bacilli (97.2%). There was only 1 major discrepancy, misidentification of Mycobacterium marinum as M. kansasii, verified by sequencing. PMID- 20846585 TI - Clinical utility and prognostic value of bronchoalveolar lavage galactomannan in patients with hematologic malignancies. AB - We conducted a single-center retrospective cohort study to determine the performance characteristics of the galactomannan (GM) assay in bronchoalveolar lavage (BAL) in patients with hematologic malignancies. Patients were classified as proven, probable, possible, or no invasive pulmonary aspergillosis (IPA), according to international guidelines. A total of 173 BAL samples from 145 patients were included. There were 5 proven, 7 probable, and 35 possible cases of IPA. Using a GM index cutoff of >= 0.5, the sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) of the BAL GM assay were 100%, 78%, 26%, and 100%, respectively. Using a GM index cutoff of >= 2.0, the sensitivity and NPV remained 100%, but specificity and PPV increased to 93% and 50%, respectively. The BAL GM assay is a highly sensitive screening test for IPA in patients with hematologic malignancies. Increasing the cutoff value to 2.0 would improve the performance of this assay. PMID- 20846586 TI - Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital acquired pneumonia. AB - To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients. PMID- 20846587 TI - Development of a polymerase chain reaction-restriction fragment length polymorphism assay for Leishmania major/Leishmania killicki/Leishmania infantum discrimination from clinical samples, application in a Tunisian focus. AB - Topoisomerase II gene of Leishmania genus was used to develop a molecular tool for detection and species differentiation of Leishmania from clinical samples. Identification was achieved by a polymerase chain reaction followed by digestion with 2 restriction endonucleases BstU1 and Taq1. Despite the relatively low sensitivity, it is able to differentiate between 3 complexes responsible for cutaneous leishmaniasis. PMID- 20846588 TI - Modified Field's staining--a rapid stain for Trichomonas vaginalis. AB - Trichomonas vaginalis, a flagellate protozoan parasite commonly found in the human genitourinary tract, is transmitted primarily by sexual intercourse. Diagnosis is usually by in vitro culture method and staining with Giemsa stain. There are laboratories that use Gram stain as well. We compared the use of modified Field's (MF), Giemsa, and Gram stains on 2 axenic and xenic isolates of T. vaginalis, respectively. Three smears from every sediment of spun cultures of all 4 isolates were stained, respectively, with each of the stains. We showed that MF staining, apart from being a rapid stain (20 s), confers sharper staining contrast, which differentiates the nucleus and the cytoplasm of the organism when compared to Giemsa and Gram staining especially on parasites from spiked urine samples. The alternative staining procedure offers in a diagnostic setting a rapid stain that can easily visualize the parasite with sharp contrasting characteristics between organelles especially the nucleus and cytoplasm. Vacuoles are more clearly visible in parasites stained with MF than when stained with Giemsa. PMID- 20846589 TI - Rapid antigen detection in the diagnosis of highly pathogenic avian influenza (H5N1) virus in Nigeria. AB - Highly pathogenic avian influenza (AI) is an infectious disease of agroeconomic and public health importance. The outbreak that occurred in Nigeria (2006-2008) was devastating to the poultry industry and raised public health concerns. In the course of its control, rapid laboratory confirmation of suspected cases in poultry was essential for prompt mobilization of control logistics for depopulation and decontamination of affected premises. Commercial rapid test kit was evaluated in the diagnosis of highly pathogenic AI (HPAI) as a preliminary to virus isolation. Between 2006 and 2007, 382 cases were tested out of which 149 were positive by rapid antigen detection. Virus isolation yielded 171 positive cases. The relative diagnostic sensitivity of Anigen Rapid AIV Ag test was 84.3% (95% confidence interval [CI], 78.1-88.9%), whereas the relative diagnostic specificity was 97.7% (95% CI, 94.2-99.1%). Rapid antigen detection is a useful technique for prompt diagnosis of HPAI for early detection and containment. PMID- 20846590 TI - Detection of human enterovirus and human parechovirus (HPeV) genotypes from clinical stool samples: polymerase chain reaction and direct molecular typing, culture characteristics, and serotyping. AB - Molecular (polymerase chain reaction [PCR]) methods are increasingly used to detect and type human enteroviruses (HEVs) and parechoviruses (HPeV). Here, we assessed their value in comparison to virus culture and serotyping for detection and typing of HEV and HPeV in stool samples from hospitalized patients. By use of real-time PCR, 221/1174 patients (18.8%) were found positive for HEV/HPeV. By cell culture, a virus could be isolated from 107 of the HEV/HPeV PCR-positive samples. Culture efficiency was correlated to the Ct value, (geno)type, and cell lines used. Of the HEV/HPeV PCR-positive samples, 47% could be genotyped by VP1 genotyping and 25% by serotyping. In conclusion, PCR detection of HEV/HPeV from stool is more sensitive than virus culture, particularly for coxsackieviruses A and HPeVs. However, the genotyping method used here could identify only 47% of the HEV/HPeV strains. Further optimization and validation of direct genotyping are needed, and clinical relevance of HEV/HPeV detection in stool needs to be determined. PMID- 20846591 TI - A first Japanese case of Bartonella henselae-induced endocarditis diagnosed by prolonged culture of a specimen from the excised valve. AB - Bartonella henselae, the causative agent of cat scratch disease, is increasingly recognized as a cause of culture-negative endocarditis. This report describes the first Japanese case, which was diagnosed after a prolonged culture of the excised aortic valve. High IgG and IgM titers to B. henselae pointed to a subacute course of the disease. PMID- 20846592 TI - Cutaneous phaeohyphomycosis in renal allograft recipients: report of 2 cases and review of the literature. AB - Dematiaceous molds are increasingly recognized as important human pathogens. We report 2 cases of cutaneous phaeohyphomycosis in renal allograft recipients, caused by Alternaria alternata and Curvularia spp., respectively, which demonstrate the diversity in clinical presentation, the different therapeutic strategies, and the clinical importance of azole antifungal-induced drug-drug interactions with immunosuppressive therapy. PMID- 20846593 TI - In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies. AB - During phase 3 clinical studies of telavancin for treatment of complicated skin and skin structure infections, a total of 1530 aerobic Gram-positive isolates were identified at baseline. The majority of these strains were Staphylococcus aureus (n = 1214; 62% methicillin-resistant). All isolates were inhibited by <= 1 MUg/mL of telavancin. PMID- 20846594 TI - CTX-M-producing Klebsiella spp. in a Brazilian hospital: what has changed in 6 years? AB - CTX-M-encoding genes from Klebsiella spp. strains isolated in 2000 and 2006 were characterized as well as their genetic environment. CTX-M-2 variants were predominant in Klebsiella pneumoniae strains, which showed a greater variability in bla(CTX-M) genes, integrons, and plasmids in 2006 when compared to strains collected in 2000. CTX-M-9-producing Klebsiella oxytoca was identified in 2000 as clonal dissemination. PMID- 20846595 TI - Respiratory tract colonization by Pasteurella pneumotropica in a patient with an alpha1-antitrypsin deficiency unexpectedly well identified by automated system Vitek 2. PMID- 20846596 TI - Images in cardiology. Microvascular obstruction after radiofrequency ablation of ventricular tachycardia: comprehensive evaluation by magnetic resonance imaging and computed tomography. PMID- 20846598 TI - Revisiting the role of oxygen therapy in cardiac patients. AB - Over the past century, multiple studies lacking the precision of today's advanced technology provided conflicting data on the effects of oxygen therapy in normoxic cardiac patients. More importantly, no randomized, blinded, controlled studies have shown a benefit of such treatment. Yet the use of supplemental oxygen is widespread in cardiac patients. In these conditions, inadvertent hyperoxia commonly occurs because of concerns to ensure sufficient oxygenation and because hyperoxia is not perceived to be detrimental. In recent years, there has been mounting evidence demonstrating the potential adverse effects of hyperoxia on the cardiovascular system. In this report, we review data examining the effects of supplemental oxygen in normoxic patients with acute presentations of coronary artery disease. It is also the aim of this report to emphasize the point that oxygen therapy might have major adverse physiologic effects that must be considered when it is employed. PMID- 20846599 TI - Increased platelet inhibition after switching from maintenance clopidogrel to prasugrel in patients with acute coronary syndromes: results of the SWAP (SWitching Anti Platelet) study. AB - OBJECTIVES: The objective was to evaluate the pharmacodynamic response of switching patients on maintenance phase clopidogrel therapy after an acute coronary syndrome (ACS) to prasugrel. BACKGROUND: Prasugrel P2Y(12) receptor blockade is associated with greater pharmacodynamic platelet inhibition and reduction of ischemic complications compared with that of clopidogrel in ACS patients undergoing percutaneous coronary intervention. The pharmacodynamic effects of switching patients during maintenance phase clopidogrel therapy after an ACS event to prasugrel are unknown. METHODS: The SWAP (SWitching Anti Platelet) study was a phase 2, multicenter, randomized, double-blind, double dummy, active-control trial. After a run-in of daily open-label clopidogrel 75 mg with aspirin therapy for 10 to 14 days, patients were randomly assigned to 1 of the following 3 treatments: placebo loading dose (LD)/clopidogrel 75 mg maintenance dose (MD), placebo LD/prasugrel 10 mg MD, or prasugrel 60 mg LD/10 mg MD. Platelet function was evaluated at 2 h, 24 h, 7 days, and 14 days using light transmittance aggregometry, VerifyNow P2Y(12) assay, and vasodilator-stimulated phosphoprotein phosphorylation. RESULTS: A total of 139 patients were randomized, of whom 100 were eligible for analysis. Maximum adenosine diphosphate-induced platelet aggregation (20 MUM) by light transmittance aggregometry at 1 week (primary end point) was lower after prasugrel MD compared with clopidogrel MD (41.1% vs. 55.0%, p < 0.0001), and was also lower in the prasugrel LD+MD group compared with clopidogrel MD (41.0% vs. 55.0%, p < 0.0001). At 2 h, a prasugrel LD resulted in higher platelet inhibition compared with the other regimens. Similar results were found using light transmittance aggregometry with 5 MUM adenosine diphosphate, VerifyNow P2Y(12), and vasodilator-stimulated phosphoprotein phosphorylation assays. CONCLUSIONS: For patients receiving maintenance clopidogrel therapy after an ACS event, switching from clopidogrel to prasugrel is associated with a further reduction in platelet function by 1 week using prasugrel MD or within 2 h with the administration of a prasugrel LD. (A Pharmacodynamic Comparison of Prasugrel [LY640315] Versus Clopidogrel in Subjects With Acute Coronary Syndrome Who Are Receiving Clopidogrel [SWAP]; NCT00356135). PMID- 20846597 TI - Iron overload cardiomyopathy: better understanding of an increasing disorder. AB - The prevalence of iron overload cardiomyopathy (IOC) is increasing. The spectrum of symptoms of IOC is varied. Early in the disease process, patients may be asymptomatic, whereas severely overloaded patients can have terminal heart failure complaints that are refractory to treatment. It has been shown that early recognition and intervention may alter outcomes. Biochemical markers and tissue biopsy, which have traditionally been used to diagnose and guide therapy, are not sensitive enough to detect early cardiac iron deposition. Newer diagnostic modalities such as magnetic resonance imaging are noninvasive and can assess quantitative cardiac iron load. Phlebotomy and chelating drugs are suboptimal means of treating IOC; hence, the roles of gene therapy, hepcidin, and calcium channel blockers are being actively investigated. There is a need for the development of clinical guidelines in order to improve the management of this emerging complex disease. PMID- 20846600 TI - Level of adenosine diphosphate receptor P2Y12 blockade during percutaneous coronary intervention predicts the extent of endothelial injury, assessed by circulating endothelial cell measurement. AB - OBJECTIVES: We aimed to investigate whether clopidogrel-induced inhibition of platelet reactivity could reduce the level of circulating endothelial cells (CEC), reflecting the endothelial injury induced by percutaneous coronary intervention (PCI). BACKGROUND: Clopidogrel loading dose before percutaneous coronary angioplasty (PCI) reduces platelet activation through a selective and irreversible blockade of the adenosine diphosphate (ADP) receptor P2Y(12). The impact of clopidogrel on endothelial cells has been scarcely studied. METHODS: A total of 149 patients undergoing PCI for stable angina were enrolled. Levels of CEC were measured at baseline (H0) and 6 (H6) and 24 (H24) h after the procedure using a CD146-based immunomagnetic separation assay. The CEC delta-change (CEC at H6 - CEC at H0) was analyzed according to ADP receptor P2Y(12) blockade, assessed by a vasodilator-stimulated phosphoprotein (VASP) assay after a 600-mg loading dose of clopidogrel. RESULTS: The PCI induced a significant rise in CEC levels 6 h after the procedure. The CEC peak value was significantly higher in patients with high on-treatment platelet reactivity (VASP index >=50%: 59.6 +/- 27.5 cells/ml) as compared with good responders (VASP index <50%: 27 +/- 22 cells/ml; p = 0.04). The endothelial injury, assessed by CEC delta-change between H6 and H0, was significantly higher in the high on-treatment platelet reactivity group compared with the good responders group (52.6 +/- 25.6 vs. 18.6 +/- 23.5, respectively; p < 0.001) and correlated with the VASP index (r = 0.59; p < 0.001). In multivariate analysis, VASP group, the number of diseased vessels, and the number of implanted stents independently predicted the endothelial injury (p < 0.001). CONCLUSIONS: Optimal ADP receptor P2Y(12) blockade reduces the endothelial injury during PCI. This protective effect of clopidogrel on endothelial cells could add to the clinical benefit associated with this drug. PMID- 20846601 TI - Clopidogrel and endothelial injury after percutaneous coronary interventions: beyond the antiplatelet effects. PMID- 20846602 TI - Association of combinations of lipid parameters with carotid intima-media thickness and coronary artery calcium in the MESA (Multi-Ethnic Study of Atherosclerosis). AB - OBJECTIVES: The purpose of this study was to determine the association of combinations of lipid parameters with subclinical atherosclerosis. BACKGROUND: Carotid intima-media thickness (CIMT) and coronary artery calcium (CAC) are significantly associated with incident cardiovascular disease (CVD). The association between common dyslipidemias (combined hyperlipidemia, [simple] hypercholesterolemia, dyslipidemia of metabolic syndrome, isolated low high density lipoprotein cholesterol, and isolated hypertriglyceridemia) compared with normolipemia, and CIMT and CAC has not been previously examined. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) participants were White, Chinese, African-American, or Hispanic adults without clinical CVD. Subjects with diabetes mellitus or who were receiving lipid-lowering therapy were excluded. Every participant was classified into only 1 of 6 groups defined by specific low density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglyceride cut points. Multivariate linear and relative risk regressions evaluated the cross-sectional associations with CIMT and CAC after adjusting for CVD risk factors. Interactions with race, sex, and high-sensitivity C-reactive protein were evaluated for CIMT and CAC outcomes. RESULTS: Among 4,792 participants, only those with combined hyperlipidemia and hypercholesterolemia demonstrated both increased common CIMT (combined hyperlipidemia 0.048 mm thicker, 95% confidence interval [CI]: 0.016 to 0.080 mm; hypercholesterolemia 0.048 mm thicker, 95% CI: 0.029 to 0.067 mm) and internal CIMT (combined hyperlipidemia 0.120 mm thicker, 95% CI: 0.032 to 0.208 mm; and hypercholesterolemia 0.161 mm thicker, 95% CI: 0.098 to 0.223 mm) as well as increased risk for prevalent CAC (combined hyperlipidemia relative risk: 1.22, 95% CI: 1.08 to 1.38; hypercholesterolemia relative risk: 1.22, 95% CI: 1.11 to 1.34) compared with normolipemia. The interactions between lipid parameters and race, sex, or high-sensitivity C-reactive protein were not significant for any outcomes. CONCLUSIONS: Combined hyperlipidemia and simple hypercholesterolemia were associated with increased CIMT and prevalent CAC in a relatively healthy multiethnic population. PMID- 20846603 TI - Carotid ultrasound, coronary calcium, and dyslipidemia patterns in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort. PMID- 20846605 TI - Biomarkers in stroke: when will they impact care? PMID- 20846604 TI - Midregional pro-atrial natriuretic peptide and outcome in patients with acute ischemic stroke. AB - OBJECTIVES: The purpose of this study was to examine the prognostic value of midregional pro-atrial natriuretic peptide (MR-proANP) in patients with acute ischemic stroke. BACKGROUND: The rapid and reliable estimation of prognosis in acute ischemic stroke is pivotal to optimize clinical care. MR-proANP, a recently described, stable fragment of the ANP precursor hormone, may be useful in this setting. METHODS: In a prospective observational study, we measured MR-proANP on admission in plasma of 362 consecutive patients presenting with acute ischemic stroke. The prognostic value of MR-proANP to predict mortality within 90 days and functional outcome (defined as a modified Rankin Scale of <=2 or >=3) was evaluated and compared with the National Institutes of Health Stroke Scale (NIHSS) score. RESULTS: The discriminatory accuracy, calculated with the area under the curve (AUC) of the receiver operating characteristics curve, of MR proANP to predict death was comparable to the NIHSS (AUC: 0.86 [95% confidence interval (CI): 0.82 to 0.90] and 0.85 [95% CI: 0.81 to 0.89; p = 0.7]). Combined, the accuracy significantly improved (0.92 [95% CI: 0.88 to 0.96; p < 0.01]). The AUC of MR-proANP to predict functional outcome was 0.70 (95% CI: 0.65 to 0.75), similar to the NIHSS (0.75 [95% CI: 0.70 to 0.80]; p = 0.16). The prognostic value of MR-proANP for both outcomes was independent of the NIHSS. Higher MR proANP concentrations were found in stroke of cardioembolic etiology. CONCLUSIONS: MR-proANP is a prognostic marker in the acute phase of stroke, improving the discriminatory value of the NIHSS, independently predicting post stroke mortality and functional outcome. (The "COSMOS"-Study [Copeptin in Osmoregulation and Stress Assessment]; NCT00390962). PMID- 20846606 TI - Impact of systolic and diastolic deformation indexes assessed by strain-encoded imaging to predict persistent severe myocardial dysfunction in patients after acute myocardial infarction at follow-up. AB - OBJECTIVES: This study evaluated the value of systolic and diastolic deformation indexes determined by strain-encoded imaging to predict persistent severe dysfunction at follow-up in patients after reperfused acute myocardial infarction (AMI) in comparison with late gadolinium enhancement (LGE). BACKGROUND: Animal studies suggest that regional diastolic function provides information about myocardial viability after AMI. However, data in humans are sparse. METHODS: Twenty-six patients underwent magnetic resonance imaging 3 +/- 1 days after successfully reperfused ST-segment elevation myocardial infarction and at a follow-up of 6 months. Cine, strain-encoded, and LGE images were acquired. Peak systolic circumferential strain (E(cc)) and early diastolic strain rate (E(cc)/s) were calculated for each segment at baseline and at follow-up. A cutoff E(cc) value of -9% was used to define severe dysfunction at follow-up. RESULTS: A total of 312 segments were analyzed; 119 segments showed abnormal baseline function. Thirty-five segments showed severe dysfunction at follow-up, which was defined as E(cc) at follow-up <9%. The area under the curve for E(cc)/s was 0.82 (95% confidence interval [CI]: 0.72 to 0.89), for E(cc) 0.74 (95% CI: 0.64 to 0.83), and for LGE 0.85 (95% CI: 0.77 to 0.92). A comparison of receiver-operating characteristic curves demonstrates that LGE is not significantly different than E(cc)/s but is significantly different than E(cc) (p = 0.32 vs. p < 0.05) for prediction of severe dysfunction at follow-up. CONCLUSIONS: Regional diastolic function provides similar accuracy to predict persistent severe dysfunction at follow-up to LGE and is superior to regional systolic function in patients after AMI. Diastolic deformation indexes may serve as a new parameter for assessment of viability in patients after AMI. (SENC in AMI Study; NCT00752713). PMID- 20846607 TI - To whom to refer. PMID- 20846608 TI - Stent overlap in patients undergoing drug-eluting stent implantation. PMID- 20846610 TI - N-acetylcysteine somewhere between Scylla and Charybdis. PMID- 20846612 TI - Assessing clinical utility of carotid intima-media thickness on the basis of reclassification. PMID- 20846614 TI - Carotid plaque assessment: a bumpy road to improved risk prediction. PMID- 20846615 TI - Plasma glucose, lactate, sodium, and potassium levels in children hospitalized with acute alcohol intoxication. AB - The aim of our research was to study prevalence of changes in plasma levels of lactate, potassium, glucose, and sodium in relation to alcohol concentration in children hospitalized with acute alcohol intoxication (AAI). Data from 194 under 18-year-old children hospitalized to the two only children's hospital in Estonia over a 2-year period were analyzed. The pediatrician on call filled in a special form on the clinical symptoms of AAI; a blood sample was drawn for biochemical tests, and a urine sample taken to exclude narcotic intoxication. The most common finding was hyperlactinemia occurring in 66% of the patients (n=128) followed by hypokalemia (<3.5 mmol/L) in 50% (n=97), and glucose above of reference value (>6.1 mmol/L) in 40.2% of the children (n=78). Hypernatremia was present in five children. In conclusion, hyperlactinemia, hypokalemia, and glucose levels above of reference value are common biochemical findings in children hospitalized with acute AAI. PMID- 20846616 TI - Total elbow arthroplasty failure due to a broken snap pin: a case report. PMID- 20846617 TI - An unusual cause of subacromial impingement: a collagenous fibroma in the bursa. PMID- 20846618 TI - Atrophic humeral shaft nonunion treated with teriparatide (rh PTH 1-34): a case report. PMID- 20846619 TI - Mid- to long-term results after bipolar radial head arthroplasty. AB - BACKGROUND: Radial head arthroplasty is considered the treatment of choice for unreconstructable radial head fractures in the acute fracture situation. Although short-term results in the current literature are promising, replacement of the radial head remains controversial as long-term results are still missing. We report our 8.8-year results after treatment with a bipolar radial head prosthesis by Judet. MATERIALS AND METHODS: In our department, 19 patients were treated with bipolar radial head arthroplasty between 1997 and 2001. Seventeen of these patients-14 men and 3 women-were examined retrospectively after 106 months (range, 78-139). Of these, 9 patients were treated primarily, 7 patients secondarily, and 1 because of a tumor. RESULTS: On the Mayo Elbow Performance Score, 6 patients achieved excellent results, 10 good, and one fair. The mean DASH score was 9.8 (range, 0-34). No differences were seen between primary and secondary implantation. Flexion averaged 124 degrees (range, 110-150 degrees ), the extension deficit was 21 degrees (range, 0-40 degrees ), pronation 64 degrees (range, 30-90 degrees ), and supination 64 degrees (range, 30-90 degrees ). The following complications were seen: 2 dislocations and 8 cases of degenerative changes of the capitellum, 1 with severe erosion. Signs of ulnohumeral arthrosis were found in 12 patients. No evidence of loosening, radiolucencies, or proximal bone resorption was detected. CONCLUSION: Despite major primary complications and high incidence of radiographic signs of degenerative changes after 8.8 years, mainly good clinical results were achieved with Judet's bipolar prosthesis. PMID- 20846620 TI - Observations on retrieved humeral polyethylene components from reverse total shoulder arthroplasty. AB - HYPOTHESIS: Analyses of polyethylene components retrieved at revision of total knee, hip, and shoulder replacements have been used to study the effect of design, patient, and surgical factors on initial implant performance, but no studies have reported similar types of findings in retrieved humeral polyethylene components in reverse total shoulder arthroplasty. Our hypothesis is that while the conforming surface of the humeral polyethylene may predispose it to surface wear modalities, as seen in total hip arthroplasty, the presence of clinical instability may also increase the occurrence of focal contact stresses leading to subsurface fatigue failure. MATERIALS AND METHODS: Fourteen humeral polyethylene components were retrieved from revision surgery at a single institution. Each polyethylene was analyzed for 9 modes of damage in each of 4 quadrants into which the bearing surface was divided. For each implant, the most recent radiographs before removal were scored using an adapted radiolucency score, and glenosphere positioning was measured. RESULTS: Despite the short mean length of implantation (0.46 +/- 0.5 years), scratching and abrasion were seen in 14 and 13 components, respectively, followed by third-body debris and pitting. The modes of damage observed were most severe in the inferior quadrant of the humeral polyethylene. Scapular notching, glenoid, and humeral radiolucencies were prevalent on preoperative radiographs, but their long-term significance has not yet been elucidated. Increased glenosphere inclination was associated with decreased superior and total glenoid radiolucency, along with total polyethylene wear scores. DISCUSSION: Promising early, functional results with the use of reverse total shoulder arthroplasty has led to the increased expansion of its use, but high complication and revision rates continue to raise concerns regarding implant longevity. The presence of a clinical, adduction deficit may predispose patients to inferior quadrant polyethylene wear. CONCLUSIONS: Impingement of the humeral polyethylene at the lateral edge of the scapula leads to inferior quadrant wear and associated polyethylene failure, and implant instability may predispose the components to fatigue wear mechanisms. Analysis of retrieved humeral polyethylene components, along with patient, design, and surgical factors, provide important information on the causes of component failure. PMID- 20846621 TI - Blind subacromial injection from the anterolateral approach: the ballooning sign. AB - PURPOSE: Our aim was to verify the association of fullness over the skin distal to anterior acromion termed "ballooning" in relation to accuracy of subacromial injection and determine its accuracy in terms of sensitivity, specificity, and predictive value. We hypothesized that a positive ballooning was a sign of an accurately placed injection into the subacromial bursa. METHODS: Data of 136 shoulders with impingement, which received subacromial steroid injections, were evaluated for presence of ballooning signs, pain, motion, and muscle strength. Injections were performed via anterolateral approach, followed by radiographs to locate the contrast. Data were compared between pre- and post-injections as well as between accurate and inaccurate groups to evaluate the correlations between targeting accuracy and immediate outcomes. RESULTS: Ballooning signs were positive in 104 shoulders (76.5%), of which majority were inaccurate (58.7%). The accuracy rate was 49.3% with sensitivity of 64.2%, specificity 11.6% and positive as well as negative predictive values of 41.3% and 25% consecutively. Dispersal rate to the surrounding structures was 86.6% with majority infiltrated the deltoid (29.4%). Significant improvement was noted between pre- and post injections in all parameters except muscle strength, indicating equal pain relief regardless of locations. CONCLUSION: The ballooning sign is not a reliable indicator for or against subacromial injection. Blind subacromial injections are frequently inaccurate using the anterolateral approach. Nevertheless, immediate improvement of pain, motion, and muscle strength can be expected regardless of location. PMID- 20846622 TI - Proximal humerus fractures with valgus deformity of the humeral head: the spectrum of injury, clinical assessment and treatment. PMID- 20846623 TI - Prognostic value of E/E' ratio in patients with unoperated severe aortic stenosis. AB - OBJECTIVES: The aim of this study was to evaluate the value of clinical and echo Doppler parameters for the prognosis of unoperated severe aortic stenosis (AS). BACKGROUND: Approximately one-third of severe, symptomatic AS patients are denied surgery. Risk stratification of unoperated AS is important to determine eligibility for percutaneous aortic valve replacement, an evolving treatment option for AS patients deemed suboptimal for surgical aortic valve replacement. METHODS: We retrospectively compared clinical and echo-Doppler parameters between survivors and nonsurvivors of 125 patients with unoperated severe AS. RESULTS: The 1-year survival rate was 62.4%. In univariate analysis, survivors compared with nonsurvivors were younger (80.0 +/- 10.9 years vs. 84.9 +/- 11.1 years, p = 0.02), had a greater left ventricular ejection fraction (LVEF) (55 +/- 15% vs. 50 +/- 16%, p = 0.042), a higher left ventricular stroke volume (63 +/- 19 ml vs. 56 +/- 13 ml, p = 0.015), a lower E/E' ratio (12.19 +/- 5.7 vs. 16.87 +/- 7.43, p < 0.001), and a lower prevalence of E/E' > 15 (20% vs. 55%, p < 0.001). Symptomatic status was nonsignificantly different between survivors and nonsurvivors. In patients with an LVEF >= 50%, the subgroup with E/E' <= 15 and with E/E' > 15 had a 73.8% and 47.8% 1-year survival rate, respectively (p = 0.027). In the patients with an LVEF < 50%, the patients with E/E' <= 15 and those with E/E' > 15 demonstrated a 70.6% and 22.3% 1-year survival rate, respectively (p = 0.003). In multivariate analysis, significant predictors of mortality were E/E' > 15 and a combination of E/E' > 15 and B-type natriuretic peptide > 300 ng/ml: adjusted mortality risk 2.34 (95% confidence interval (CI) 1.27 to 4.33, p = 0.0072) and 2.59 (95% CI 1.21 to 5.55, p = 0.014), respectively. CONCLUSIONS: The E/E' ratio is the single most predictive clinical and echo-Doppler parameter in the assessment of overall prognosis in patients with unoperated severe AS. LVEF was a significant predictor of survival only in the univariate analysis. B-type natriuretic peptide alone was not a predictor of prognosis in the study population. However, the combination of E/E' and B-type natriuretic peptide is even more predictive of the 1-year prognosis. PMID- 20846624 TI - Association between visceral adipose tissue area and coronary plaque morphology assessed by CT angiography. AB - OBJECTIVES: We sought to investigate the association between visceral adipose tissue (VAT) with the presence, extent, and characteristics of noncalcified coronary plaques (NCPs) using 64-slice computed tomography angiography (CTA). BACKGROUND: Although visceral adiposity is associated with cardiovascular events, its association with NCP burden and vulnerability is not well known. METHODS: The study population consisted of 427 patients (age 67 +/- 11 years; 63% men) with proven or suspected coronary artery disease who underwent 64-slice CTA. We assessed the presence and number of NCPs for each patient. The extent of NCP was tested for the difference between high (>= 2) and low (<= 1) counts. We further evaluated the vulnerable characteristics of NCPs with positive remodeling (remodeling index >1.05), low CT density (<= 38 HU), and the presence of adjacent spotty calcium. Plain abdominal scans were also performed to measure the VAT and subcutaneous adipose tissue area. RESULTS: A total of 260 (61%) patients had identifiable NCPs. Multivariate analyses revealed that increased VAT area (per 1 standard deviation, 58 cm(2)) was significantly associated with both the presence (odds ratio [OR]: 1.68; 95% confidence interval [CI]: 1.28 to 2.22) and extent (OR: 1.31; 95% CI: 1.03 to 1.68) of NCP. Other body composition measures, including subcutaneous adipose tissue area, body mass index, and waist circumference were not significantly associated with either presence or extent of NCP. Increased VAT area was also independently associated with the presence of NCP with positive remodeling (OR: 1.71; 95% CI: 1.18 to 2.53), low CT density (OR: 1.69; 95% CI: 1.17 to 2.47), and adjacent spotty calcium (OR: 1.52; 95% CI: 1.03 to 2.27). CONCLUSIONS: Increased VAT area was significantly associated with NCP burden and vulnerable characteristics identified by CTA. Our findings may explain the excessive cardiovascular risk in patients with visceral adiposity, and support the potential role of CTA to improve risk stratification in such patients. PMID- 20846625 TI - Not all body fat weighs equally in the acceleration of coronary artery disease. PMID- 20846626 TI - Fused whole-heart coronary and myocardial scar imaging using 3-T CMR. Implications for planning of cardiac resynchronization therapy and coronary revascularization. AB - OBJECTIVES: The aim of this study was to demonstrate the feasibility of providing spatially matched, 3-dimensional (3D) myocardial scar and coronary imaging for the purpose of fused volumetric image display in patients undergoing cardiac resynchronization therapy (CRT) or coronary artery revascularization (CAR). BACKGROUND: Clinical success in coronary vascular-based interventions is mitigated by the presence of scar in related myocardium. Pre-procedural fused volumetric imaging of both myocardial scar and coronary vasculature may benefit pre-procedural planning and patient selection in populations referred for CRT or CAR. METHODS: A total of 55 studies were performed in patients referred for either CRT (n = 42) or CAR (n = 13). Coronary-enhanced and scar-enhanced imaging was performed on a 3-T cardiac magnetic resonance scanner using the same cardiac gated, 3D, free-breathing cardiac magnetic resonance technique during and 20 minutes following slow gadolinium infusion. Matched image datasets were fused and volume-rendered to simultaneously display coronary anatomy and myocardial scar. Visual scoring of coronary artery, coronary vein, and myocardial scar image quality (score 0 to 4) was performed. The clinical impact of imaging was also scored using a physician survey. RESULTS: Mean age was 57 +/- 14 years. Combined 3D coronary and scar imaging was successful in 49 studies (89%). A quality score >= 2 was obtained for 97% of proximal- and mid-coronary artery and vein segments. The mean quality score of 3D scar imaging was 2.8 +/- 1.0 and was scored as >= 2 in 86% of patients with myocardial scar. All patients with a scar quality score >= 2 achieved successful image fusion. Transmural scar was present below >= 1 planned target vessel in 9 patients (39%) planned for CRT and 8 patients (62%) planned for CAR. Physician surveys demonstrated incremental clinical impact in 67% of patients. CONCLUSIONS: Three-dimensional myocardial scar and coronary imaging with fused volumetric display is clinically feasible and may be valuable for the planning of vascular-based interventions when regional myocardial scar is pertinent to therapeutic success. PMID- 20846627 TI - Image fusion: is it merely the blending of pretty pictures? PMID- 20846628 TI - Adenosine stress myocardial contrast echocardiography for the detection of coronary artery disease: a comparison with coronary angiography and cardiac magnetic resonance. AB - OBJECTIVES: To evaluate the accuracy of adenosine myocardial contrast echocardiography (MCE) in diagnosing coronary artery disease (CAD). BACKGROUND: Adenosine stress echocardiography is not routinely used in the assessment of CAD. Since ultrasound microbubble contrast agents enable improved wall motion analysis and simultaneous assessment of myocardial perfusion, we sought to evaluate the diagnostic performance of combined wall motion/perfusion imaging with adenosine MCE in patients with suspected CAD. We evaluated the accuracy of adenosine MCE in identifying 1) the presence of anatomic disease, as defined by X-ray angiography, and 2) the functional significance of CAD, as determined by high field-strength (3-T), multiparametric cardiac magnetic resonance (CMR) imaging. METHODS: Sixty five patients with suspected CAD were studied before angiography with MCE and CMR, at stress (140 MUg/kg/min intravenous adenosine) and at rest. For MCE, 2-, 3 and 4-chamber long-axis images were acquired during intravenous sulfur hexafluoride infusion. For CMR, short-axis first-pass perfusion and delayed enhancement images were acquired following intravenous gadolinium diethylenetriaminepentaacetic acid bolus injections (0.05 mmol/kg). Quantitative coronary angiography served as a reference standard for anatomic disease (significant CAD defined as >= 50% reference diameter in vessels with diameter >= 2 mm). RESULTS: Compared with X-ray angiography, MCE provided diagnostic accuracy of 82%, sensitivity of 85%, and specificity of 76% for detecting significant coronary stenosis. Disease location was also identified with reasonable accuracy (diagnostic accuracy 81% for left anterior descending disease, 77% for left circumflex artery disease, and 84% for right coronary artery disease). With CMR as the reference standard for functional assessment, MCE provided diagnostic accuracy of 79%, sensitivity of 85%, and specificity of 74%. Interobserver agreement for MCE was 79% (95% confidence interval: 67% to 88%). CONCLUSIONS: Adenosine MCE achieved favorable diagnostic performance in identifying the presence and functional significance of coronary stenosis. Adenosine MCE may be useful in the clinical setting for evaluating patients with suspected CAD. PMID- 20846629 TI - Myocardial perfusion imaging using ultrasound contrast agents: now or never? PMID- 20846631 TI - Visualizing the vascular glue "shearing" the barriers to atherosclerotic plaque imaging. PMID- 20846630 TI - Molecular imaging of activated von Willebrand factor to detect high-risk atherosclerotic phenotype. AB - OBJECTIVES: We hypothesized that noninvasive molecular imaging of activated von Willebrand factor (vWF) on the vascular endothelium could be used to detect a high-risk atherosclerotic phenotype. BACKGROUND: Platelet-endothelial interactions have been linked to increased inflammatory activation and prothrombotic state in atherosclerosis. These interactions are mediated, in part, by platelet glycoprotein (GP) Ibalpha, suggesting that dysregulated endothelial vWF is a marker for high-risk atherosclerotic disease. METHODS: Microbubbles targeted to activated vWF were prepared by surface conjugation of recombinant GPIbalpha. Flow-chamber studies were used to evaluate attachment of targeted microbubbles to immobile platelet aggregates bearing activated vWF. Contrast enhanced ultrasound (CEU) molecular imaging of the aorta from mice was performed: 1) ex vivo after focal crush injury and blood perfusion; and 2) in vivo in mice with advanced atherosclerosis produced by deletion of the low-density lipoprotein receptor and ApoBec-1 editing peptide (LDLR(-/-)/ApoBec-1(-/-)). RESULTS: In flow chamber studies, tracer attachment to vWF was >10-fold greater for microbubbles bearing GPIbalpha compared with control microbubbles (p < 0.01). In the ex vivo aortic injury model, CEU signal enhancement for vWF-targeted microbubbles occurred primarily at the injury site and was 4-fold greater than at noninjured sites (p < 0.05). In LDLR(-/-)/ApoBec-1(-/-) mice, inflammatory cell infiltrates and dense vWF expression on the intact endothelium were seen in regions of severe plaque formation. Scanning electron microscopy demonstrated widespread platelet endothelial interaction and only few sites of endothelial erosion. On CEU, signal enhancement for vWF-targeted microbubbles was approximately 4-fold greater (p < 0.05) in LDLR(-/-)/ApoBec-1(-/-) compared with wild-type mice. En face aortic microscopy demonstrated regions where platelet adhesion and microbubble attachment colocalized. CONCLUSIONS: Molecular imaging using GPIbalpha as a targeting moiety can detect the presence of activated vWF on the vascular endothelium. This strategy may provide a means to noninvasively detect an advanced prothrombotic and inflammatory phenotype in atherosclerotic disease. PMID- 20846632 TI - Meta-iodobenzylguanidine iodine-123 and cardiac adrenergic activity in familial dilated cardiomyopathy. PMID- 20846633 TI - New opportunities and challenges for clinical application of mIBG imaging. PMID- 20846634 TI - Anatomy of right atrial structures by real-time 3D transesophageal echocardiography. AB - The rapid development of catheter ablation techniques for atrial arrhythmias has triggered a renewed interest in the anatomy of the right atrium. In particular, some atrial arrhythmias such as focal atrial arrhythmias or atrial flutter have been linked to the anatomic architecture of specific structures such as the crista terminalis or cavotricuspid isthmus. Real-time 3-dimensional transesophageal echocardiography (RT 3D TEE) is a recently developed technique that provides 3D images of unprecedented quality. Because the right atrium is very close to the transducer, this technique may provide high-quality images of those atrial structures involved in ablation procedures. This review describes a step-by-step approach for acquisition and processing of RT 3D TEE images of right atrial structures of relevance to electrophysiologists. For anatomical correlations of RT 3D TEE images, selected images of right atrial structures were matched to anatomical specimens. PMID- 20846635 TI - Relationship between previous training and experience and results of the certification examination in cardiovascular computed tomography. AB - Examinees of the first Certifying Examination in Cardiovascular Computed Tomography were surveyed regarding their training and experience in cardiac computed tomography. The results support the current training pathways within the American College of Cardiology/American Heart Association competency criteria that include either experience-based or formal training program in cardiovascular computed tomography. Increased duration in clinical practice, the number of scans clinically interpreted in practice, and level 3 competency were associated with higher passing rates. PMID- 20846636 TI - 3D echocardiography of the atrial septum: anatomical features and landmarks for the echocardiographer. PMID- 20846637 TI - Fusion images: more informative than the sum of individual images? PMID- 20846638 TI - [Guided home-based vestibular rehabilitation assisted by audiovisual media]. AB - INTRODUCTION: To describe the creation and validation process of a new audiovisual support model for the design of guided home-based vestibular rehabilitation programs (GHVR), we introduce a prospective experimental study. PATIENTS AND METHODS: 89 patients who underwent vestibular rehabilitation (VR) were evaluated throughout 2009. For the model design, we built a video library with VR exercises that can be combined using DVD creation software to tailor VR protocols. Treatment incidents, adherence, need to convert to a posturography based program and variations in the Dizziness Handicap Inventory (DHI) score and dynamic visual acuity (DVA) were assessed. RESULTS: A good response was found, not only with respect to adherence (5.6% abandonment), but also in the clinical parameters, with a mean DHI score variation of 33.14 points, and a decrease in lines lost in the DVA test from 4.24 to 1.52 lines at the end of the treatment. DISCUSSION AND CONCLUSIONS: Our study results show the possibility of building an audiovisual aid for creating GHVR programs. PMID- 20846639 TI - Early and late cardiac ventricular reverse remodeling after catheter ablation for lone paroxysmal atrial fibrillation. AB - AIM: We sought to explore ventricular function in patients with lone paroxysmal atrial fibrillation (AF) and determine the mid- and long-term impact of pulmonary vein isolation on cardiac remodeling. BACKGROUND: The relationship between tachyarrhythmia and ventricular dysfunction is still a matter of debate. Tachycardia-induced cardiomyopathy is defined as reversible myocardial dysfunction following treatment for tachyarrhythmia. METHOD: We prospectively studied 31 patients (56.4 +/- 10 years) presenting with paroxysmal-AF who were treated successfully by catheter ablation and 15 age-matched controls. Left and right ventricular functions were assessed by echocardiography at baseline and at 3-month and 1-year follow-up. RESULTS: In AF-patients, LV-function was slightly lower at baseline than controls (LV-ejection fraction was 60% versus 64%; P = 0.06). More impressive, systolic peak velocity on Doppler tissue imaging was 9 cm/s in AF patients (versus 12 cm/s; P = 0.0004). LV global longitudinal strain was also significantly different between the two groups (patients: -16% versus controls: -19%; P = 0.005). At 1-year follow-up, most functional parameters significantly improved in the AF-patients and no longer differed from the controls. Right ventricular (RV) function was also depressed in AF patients at baseline. At 1-year follow-up, tissue Doppler showed improvement in RV-S' (+27%, P = 0.007) and RV peak systolic strain (+36%, P<0.0001) and became comparable to controls. CONCLUSION: We demonstrate that some degree of arrhythmic cardiomyopathy exists in patients presenting with lone paroxysmal-AF. Catheter ablation improved RV and LV functions. Longitudinal function is the most sensitive component of ventricular systole to monitor when looking for this cardiac reverse remodeling. PMID- 20846640 TI - Minimally invasive radio-guided surgery for primary hyperparathyroidism: From preoperative to intraoperative localization imaging. AB - The introduction and successful implementation of minimally invasive radio-guided parathyroidectomy (MIRP) has revolutionized the surgical approach to remove parathyroid adenomas. A prerequisite for such success is an accurate localization of the offending adenoma. To achieve this goal, a multimodality approach is commonly employed using a combination of anatomical and functional imaging. Of the anatomical cross-sectional techniques, ultrasonography is the most widely available but is operator-dependent and has reduced sensitivity, specially in the presence of thyroid nodules. Similarly, computed tomography and magnetic resonance imaging have low sensitivities but provide value in detecting retrotracheal, retro-oesophageal and mediastinal adenomas. Functional imaging with 99(m)Tc-Sestamibi is currently the most vital imaging procedure in this respect with variable protocols including dual-phase and dual isotope imaging. The sensitivity and specificity can improve by acquiring in single photon emission tomography (SPECT) mode and using co-registration with low dose CT to provide anatomical data (SPECT/CT). The current recommended approach is the combination of functional imaging with 99(m)Tc-Sestamibi and high-resolution ultrasound (US), supplemented with intraoperative gamma probe in certain cases and quick persurgical measurement of parathyroid hormone. This review aims to explore the utility of various imaging modalities, alone and in combination, in detecting parathyroid adenoma and facilitating the current approach of MIRP. PMID- 20846641 TI - Synthesis of ABO histo-blood group type I and II antigens. AB - The ABO histo-blood group system is one of the most clinically important antigen families. As part of our overall goal to prepare the entire set of the A, B and H type I-VI antigens for a range of biochemical investigations, we report herein the synthesis of the type I and II antigens with a 7-octen-1-yl aglycone. This linker was chosen to facilitate not only the future conjugation of the antigens to a protein or solid support but also the synthesis of the H type I and II octyl glycosides for enzyme kinetic studies. PMID- 20846642 TI - Conformational fluctuation in palladium(II)-methyl aldopentopyranoside complexes. AB - Four methyl d-pentopyranosides (beta-Ara, alpha-Lyx, beta-Rib, beta-Xyl), as well as Me-beta-l-Ara, some of them residing in a well-defined conformation in the solution state (Ara, Xyl) and some showing pronounced chair inversion in solution (Lyx, Rib), form bidentate chelates of the general formula [Pd(chxn)(LH-2) kappaO,O'] and [Pd(tmen)(LH-2)-kappaO,O'], chxn=(R,R)-cyclohexane-1,2-diamine, tmen=N,N,N',N'-ethane-1,2-diamine and L=glycoside, with Pd(II)N2-type metal probes. The dynamic behaviour of the free glycosides is maintained in their chelates, the only case where the metal is bonded by a cis-vicinal diol function. Thus, one fluctuating chelate was detected with the lyxopyranoside in the kappaO(2,3) binding mode, and two fluctuating chelates were found for the ribopyranoside (kappaO(2,3) and kappaO(3,4)). No fluctuating chelate was found for the arabinopyranoside (the free arabinopyranoside being non-fluctuating as well), or for the xylopyranoside (no cis-vicinal diol function). In addition, syn diaxial chelation (kappaO(2,4)) was observed for the ribopyranoside and the xylopyranoside. The spectroscopic results were supplemented by X-ray analyses. PMID- 20846643 TI - [Enterobius vermicularis. Lung signs]. PMID- 20846644 TI - [Transparietal-hepatic biliary dilation in a patient with Kasai intervention]. PMID- 20846646 TI - A closer look at nursing documentation on paper forms: preparation for computerizing a nursing documentation system. AB - A small scale documentation analysis was conducted to explore the medical and surgical nursing content of the patient record at a large teaching hospital affiliated with Partners Healthcare System (PHS), in preparation for a computerized documentation system. Through this study, we identified a number of problems associated with the paper record that require resolution in the new computerized system, including elimination of documentation redundancy, areas where more structure is needed to properly capture data on nursing practice, and various design considerations to support a more complete and accurate documentation of nursing care. PMID- 20846645 TI - Do monkeys think in metaphors? Representations of space and time in monkeys and humans. AB - Research on the relationship between the representation of space and time has produced two contrasting proposals. ATOM posits that space and time are represented via a common magnitude system, suggesting a symmetrical relationship between space and time. According to metaphor theory, however, representations of time depend on representations of space asymmetrically. Previous findings in humans have supported metaphor theory. Here, we investigate the relationship between time and space in a nonverbal species, by testing whether non-human primates show space-time interactions consistent with metaphor theory or with ATOM. We tested two rhesus monkeys and 16 adult humans in a nonverbal task that assessed the influence of an irrelevant dimension (time or space) on a relevant dimension (space or time). In humans, spatial extent had a large effect on time judgments whereas time had a small effect on spatial judgments. In monkeys, both spatial and temporal manipulations showed large bi-directional effects on judgments. In contrast to humans, spatial manipulations in monkeys did not produce a larger effect on temporal judgments than the reverse. Thus, consistent with previous findings, human adults showed asymmetrical space-time interactions that were predicted by metaphor theory. In contrast, monkeys showed patterns that were more consistent with ATOM. PMID- 20846647 TI - [Endoscopic techniques in bronchogenic carcinoma. Changes in recent decades]. AB - A 57-year old woman with arterial hypertension under treatment. She has smoked since she was 18 years old with an accumulated index of 70 years/pack. She was studied in our Respiratory Department due to constitutional syndrome, the X-ray showing an image of focal pulmonary lesion in the right upper lobe of more than 3cm of peripheral location. The computed tomography (CT) scan confirmed the existence of a 3.3cm mass in the upper right lobe and detected paratracheal and subcarinal mediastinal abnormal lymph nodes. A subsequent Positron Emission Tomography (PET) confirmed pathological uptake of the mass and both lymph node locations. Which additional studies do you consider to be indicated for a correct diagnosis and mediastinal staging? Do bronchoscopy techniques alone establish the final diagnosis and staging of this patient? PMID- 20846648 TI - [Mushroom poisoning: Clinical characteristics and treatment of eight cases in the Southeast of Spain]. PMID- 20846649 TI - Developmental perspectives on neurocranial proportions in Japan. AB - This study employs juvenile cranial data derived from collections dating to between about 5000 years ago and the present in order to investigate how differences in cranial growth trajectories contributed to inter-group variation in cranial shape among temporally defined Japanese populations. As gene influx from the Asian mainland was insignificant after the Yayoi period (c. CE 300), differences in adult cranial shape among later assemblages from Japan are probably related to developmental adaptations to environmental change. Comparing cranial growth trajectories among groups from different time periods allows indirect testing of several hypotheses about secular changes in cranial growth, including thermoregulatory adaptation, change in levels of masticatory stress, and change in levels of physiological stress. Differences in neurocranial proportions among groups with contrasting adult cranial shapes were found to be already pronounced for the infant cohort (0-3 years of age) and actually tended to decline slightly within later age ranges; differences in mandibular shape were unremarkable early in life, but became more pronounced after infancy. Consequently, changes in chewing stress are unlikely to have been the principal factor driving inter-group differences in cranial proportions. The cranial growth pattern reconstructed from a Medieval Japanese skeletal series showed the greatest magnitude of difference from those reconstructed for other time periods. Unlike in the other groups, there was no marked decline of cephalic index with age for the Medieval series. The unusual trajectory of cranial growth evident in the Medieval sample may result from a high degree of physiological stress due to overall poor nutrition. PMID- 20846650 TI - Hospice care delivered at home, in nursing homes and in dedicated hospice facilities: A systematic review of quantitative and qualitative evidence. AB - BACKGROUND: Hospice care supports patients and their families physically and emotionally through the dying phase. In many countries a substantial portion of specialised end-of-life care is provided through hospices. Such care has developed outside of general healthcare and is commonly provided in a patient's home or in dedicated facilities. Hospice provision may need to increase in the future due to an ageing population with a greater need for access to end-of-life care. OBJECTIVES: In this systematic review we sought to identify the current evidence on (1) the effectiveness, including cost-effectiveness, of hospices, and hospice care in a patient's home and in nursing homes and (2) the experiences of those who use and of those who provide such services. METHODS: We included quantitative and qualitative studies on hospice care that was provided in a patient's home, nursing home or hospice. We did not include studies on end-of life care that was provided as part of general healthcare provision, such as by general practitioners in primary care, community nurses or within general hospitals. For quantitative evaluations we included only those that compared hospice care with usual generalist healthcare. The databases CINAHL, MEDLINE, EMBASE, and The Cochrane Library were searched from 2003 to 2009. Evidence was assessed for quality and data extractions double-checked. For quantitative studies we present the outcome data comparing hospice versus usual care. For qualitative evaluations we organise findings thematically. FINDINGS: Eighteen comparative evaluations and four thematic papers were identified. Quantitative evidence, mostly of limited quality in design, showed that hospice care at home reduced general health care use and increased family and patient satisfaction with care. Main themes in the qualitative literature revealed that home hospice services support families to sustain patient care at home and hospice day care services generate for the patient a renewed sense of meaning and purpose. CONCLUSIONS: Although studies had methodological limitations, in this review we found much evidence to support the benefits of hospice care. There were limited evaluations found on the impact of hospice care on psychological well-being, such as symptoms of depression, and on inpatient hospice care and non-hospital related costs. PMID- 20846651 TI - Iatrogenic hyperhomocysteinemia in patients with metabolic syndrome: a systematic review and metaanalysis. AB - Metabolic syndrome (MetS) is associated with increased cardiovascular mortality and its management incorporates hypolipidemic, antidiabetic and antihypertensive drugs. However, several classes of these drugs, such as biguanides, fibrates and hydrochlorothiazide have been reported to raise circulating total homocysteine (tHcy) levels. During the last decades, numerous large-scale epidemiological studies have identified Hcy as a moderate independent cardiovascular risk factor. Therefore, drug-induced hyperhomocysteinemia in MetS patients may add one cardiovascular risk factor in these high-risk patients. The present systematic review summarizes data from studies which investigated the effects of the above mentioned drugs on tHcy, and calculates the treatment effect of each drug class on tHcy levels. We also discuss the underlying pathophysiology and the issues that should be addressed in the future. PMID- 20846652 TI - Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice. AB - OBJECTIVE: To determine if cannabinoid receptor 2 (CB2) plays a role in atherosclerosis, we investigated the effects of systemic CB2 gene deletion on hyperlipidemia-induced atherogenesis in low density lipoprotein receptor deficient (Ldlr(-/-)) mice. METHODS AND RESULTS: Ldlr(-/-) and CB2/Ldlr double knockout (CB2(-/-)Ldlr(-/-)) mice were fed an atherogenic diet for 8 and 12 weeks. Morphometric analysis revealed no significant difference between the atherosclerotic lesion area in the proximal aortas of Ldlr(-/-) and CB2(-/-)Ldlr( /-) mice after 8 or 12 weeks on the atherogenic diet. The macrophage and smooth muscle cell (SMC) content, as revealed by immunohistochemical staining, did not differ significantly between Ldlr(-/-) and CB2(-/-)Ldlr(-/-) lesions after 8 weeks. However, after 12 weeks, CB2(-/-)Ldlr(-/-) lesions displayed greater macrophage content (86.6 +/- 4.1 versus 75.2 +/- 7.5%, P<0.05) and SMC content (11.1 +/- 5.1 versus 4.2 +/- 2.4%, P<0.05) compared to controls. Lesional apoptosis, as determined by in situ TUNEL analysis, was reduced ~50% in CB2(-/ )Ldlr(-/-) lesions after 12 weeks. CB2(-/-)Ldlr(-/-) lesions displayed significantly reduced collagen content and increased elastin fiber fragmentation after 12 weeks, which was associated with an ~57% increase in matrix metalloproteinase 9 (MMP) levels. In vitro, CB2(-/-) macrophages secreted ~1.8 fold more MMP9 activity than CB2(+/+) macrophages. CONCLUSIONS: CB2 receptor deficiency affects atherogenesis in Ldlr-null mice by increasing lesional macrophage and SMC content, reducing lesional apoptosis and altering extracellular matrix components, in part, by upregulating MMP9. These results suggest that pharmacological manipulation of CB2 receptors might exert multiple and complex effects on atherogenesis and plaque stability. PMID- 20846653 TI - Micro-computed tomography with iodine staining resolves the arrangement of muscle fibres. AB - We illustrate here microCT images in which contrast between muscle and connective tissue has been achieved by means of staining with iodine. Enhancement is shown to be dependent on the concentration of iodine solution (I(2)KI), time in solution and specimen size. Histological examination confirms that the arrangement of individual muscle fibres can be visualised on the enhanced microCT images, and that the iodine accumulates in the muscle fibres in preference to the surrounding connective tissues. We explore the application of this technique to describe the fibrous structure of skeletal muscle, and conclude that it has the potential to become a non-destructive and cost-effective method for investigating muscle fascicle architecture, particularly in comparative morphological studies. PMID- 20846654 TI - A micromechanical model of skeletal muscle to explore the effects of fiber and fascicle geometry. AB - Computational models of muscle generally lump the material properties of connective tissue, muscle fibers, and muscle fascicles together into one constitutive relationship that assumes a transversely isotropic microstructure. These models do not take into account how variations in the microstructure of muscle affect its macroscopic material properties. The goal of this work was to develop micromechanical models of muscle to determine the effects of variations in muscle microstructure on the macroscopic constitutive behavior. We created micromechanical models at the fiber and fascicle levels based on histological cross-sections of two rabbit muscles, the rectus femoris (RF) and the soleus, to determine the effects of microstructure geometry (fiber and fascicle shapes) on the along-fiber shear modulus of muscle. The two fiber-level models predicted similar macroscopic shear moduli (within 13.5% difference); however, the two fascicle-level models predicted very different macroscopic shear moduli (up to 161% difference). We also used the micromechanical models to test the assumption that the macroscopic properties of muscle are transversely isotropic about the fiber (or fascicle) direction. The fiber-level models exhibited behavior consistent with the transverse isotropy assumption; however, the fascicle-level models exhibited transversely anisotropic behavior. Micromechanical models, combined with fiber and fiber bundle mechanical experiments, are needed to understand how normal or pathological variations in microstructure give rise to the observed macroscopic behavior of muscle. PMID- 20846655 TI - Comment on "A biomechanical model of artery buckling" (volume 40, issue 16, 2007) and subsequent comments (volume 43, issue 4, 2010). PMID- 20846656 TI - Tissue vibration in prolonged running. AB - The impact force in heel-toe running initiates vibrations of soft-tissue compartments of the leg that are heavily dampened by muscle activity. This study investigated if the damping and frequency of these soft-tissue vibrations are affected by fatigue, which was categorized by the time into an exhaustive exercise. The hypotheses were tested that (H1) the vibration intensity of the triceps surae increases with increasing fatigue and (H2) the vibration frequency of the triceps surae decreases with increasing fatigue. Tissue vibrations of the triceps surae were measured with tri-axial accelerometers in 10 subjects during a run towards exhaustion. The frequency content was quantified with power spectra and wavelet analysis. Maxima of local vibration intensities were compared between the non-fatigued and fatigued states of all subjects. In axial (i.e. parallel to the tibia) and medio-lateral direction, most local maxima increased with fatigue (supporting the first hypothesis). In anterior-posterior direction no systematic changes were found. Vibration frequency was minimally affected by fatigue and frequency changes did not occur systematically, which requires the rejection of the second hypothesis. Relative to heel-strike, the maximum vibration intensity occurred significantly later in the fatigued condition in all three directions. With fatigue, the soft tissue of the triceps surae oscillated for an extended duration at increased vibration magnitudes, possibly due to the effects of fatigue on type II muscle fibers. Thus, the protective mechanism of muscle tuning seems to be reduced in a fatigued muscle and the risk of potential harm to the tissue may increase. PMID- 20846657 TI - Characterization of warfarin unusual peak profiles on oligoproline chiral high performance liquid chromatography columns. AB - Unusual peak profiles of warfarin were characterized on two oligoproline chiral stationary phases (CSPs). The pattern of 1st peak (S(-)) broadening and the 2nd peak (R(+)) compression was observed under mobile phase of hexane (0.1% TFA)/2 propanol (IPA) on a triproline CSP 1, and with other alcohol modifier such as ethanol, 1-propanol, 1-butanol, 2-butanol, and tert-butanol as well. Through analyzing system peak of additives, the unusual peak profile was interpreted by perturbation of TFA additive system peak. The unusual peak profile was also found in enantioseparation of coumachlor and on a covalently bonded doubly tethered diproline CSP 2. The pattern of 1st peak (S(-)) broadening and the 2nd peak (R(+)) compression can change to pattern of 1st peak compression and the 2nd peak broadening from 15 to 50 degrees C. Chiral separation of warfarin created nonlinear van't Hoff plots on CSP. No peak broadening/compression were observed with methyl tertiary butyl ether or ethyl acetate as the modifier. The peak shapes of the two warfarin enantiomers can thus be tuned by varying alcohol concentration and column temperature. High separation factor and resolution may be carried out to tune the peak profiles into Langmuir/anti-Langmuir band-shape composition. Using none hydrogen donor modifier may avoid interference of the TFA system peak. PMID- 20846658 TI - Novel sensitive determination of steryl glycosides in biodiesel by gas chromatography-mass spectroscopy. AB - A new method was developed for the quantitative analysis of steryl glycosides in biodiesel (fatty acid methyl esters). This method is much more sensitive than existing methods and has minimum limits of quantification of 50 MUg/kg, compared to previously published minimum limits of quantification of about 15 mg/kg. The analysis is based on gas chromatography-mass spectroscopy determination of simple pre-treated and silylated samples via single ion monitoring at 204, 217, 247 m/z, which are specific ions for the silylated sugar moiety. Quantification was carried out using cholesteryl beta-D-glucopyranoside as internal standard. The modified synthesis and purification of the internal standard is also presented as well as the characterization by NMR and mass spectroscopy. The advantage of the method compared with other approaches is the simplified sample preparation avoiding extra pre-treatment steps coupled with complete derivatization of the sugar hydroxyl groups by using N,O-bis(trimethylsilyl)acetamide with 5% trimethylchlorosilane as derivatization reagent. On the given conditions high recovery rates >= 89% can be obtained. Evaluation of lab specific variance and intermediate precision underline the robustness of the method which will be further assessed by Round robin tests. PMID- 20846659 TI - Preparation of styrene-co-4-vinylpyridine magnetic polymer beads by microwave irradiation for analysis of trace 24-epibrassinolide in plant samples using high performance liquid chromatography. AB - In the study, a kind of novel styrene-co-4-vinylpyridine (St-co-4-VP) porous magnetic polymer beads was prepared by microwave irradiation using suspension polymerization. Microwave heating preparation greatly reduced the polymerization time to 1h. Physical characteristic tests suggested that these beads were cross linking and possessed spherical shape, good magnetic response and porous morphologies with a narrow diameter distribution of 70-180 MUm. Therefore, these beads displayed the long-term stability after undergoing 100-time extractions. Then, an analytical method for the determination of trace 24-epiBR in plant samples was developed by magnetic polymer bead extraction coupled with high performance liquid chromatography-fluorescence detection. St-co-4-VP magnetic polymer beads demonstrated the higher extraction selectivity for 24-epiBR than other reference compounds. Linear range was 10.00-100.0 MUg/L with a relative standard deviation (RSD) of 6.7%, and the detection limit was 6.5 MUg/kg. This analytical method was successfully applied to analyze the trace 24-epiBR in cole and breaking-wall rape pollen samples with recoveries of 77.2-90.0% and 72.3 83.4%, respectively, and RSDs were less than 4.1%. The amount of 24-epiBR in real breaking-wall rape pollen samples was found to be 26.2 MUg/kg finally. This work proposed a sensitive, rapid, reliable and convenient analytical method for the determination of trace brassinosteroids in complicated plant samples by the use of St-co-4-VP magnetic polymer bead extraction coupled with chromatographic method. PMID- 20846660 TI - Chemometric quality control of chromatographic purity. AB - It is common practice in chromatographic purity analysis of pharmaceutical manufacturing processes to assess the quality of peak integration combined by visual investigation of the chromatogram. This traditional method of visual chromatographic comparison is simple, but is very subjective, laborious and seldom very quantitative. For high-purity drugs it would be particularly difficult to detect the occurrence of an unknown impurity co-eluting with the target compound, which is present in excess compared to any impurity. We hypothesize that this can be achieved through Multivariate Statistical Process Control (MSPC) based on principal component analysis (PCA) modeling. In order to obtain the lowest detection limit, different chromatographic data preprocessing methods such as time alignment, baseline correction and scaling are applied. Historical high performance liquid chromatography (HPLC) chromatograms from a biopharmaceutical in-process analysis are used to build a normal operation condition (NOC) PCA model. Chromatograms added simulated 0.1% impurities with varied resolutions are exposed to the NOC model and monitored with MSPC charts. This study demonstrates that MSPC based on PCA applied on chromatographic purity analysis is a powerful tool for monitoring subtle changes in the chromatographic pattern, providing clear diagnostics of subtly deviating chromatograms. The procedure described in this study can be implemented and operated as the HPLC analysis runs according to the process analytical technology (PAT) concept aiming for real-time release. PMID- 20846661 TI - Degradation of benzoic acid and its derivatives in subcritical water. AB - In this research, the stability of benzoic acid and three of its derivatives (anthranilic acid, salicylic acid, and syringic acid) under subcritical water conditions was investigated. The stability studies were carried out at temperatures ranging from 50 to 350 degrees C with heating times of 10-630 min. The degradation of the benzoic acid derivatives increased with rising temperature and the acids became less stable with longer heating time. The three benzoic acid derivatives showed very mild degradation at 150 degrees C. Severe degradation of benzoic acid derivatives was observed at 200 degrees C while their complete degradation occurred at 250 degrees C. However, benzoic acid remained stable at temperatures up to 300 degrees C. The degradation products of benzoic acid and the three derivatives were identified and quantified by HPLC and confirmed by GC/MS. Anthranilic acid, salicylic acid, syringic acid, and benzoic acid in high temperature water underwent decarboxylation to form aniline, phenol, syringol, and benzene, respectively. PMID- 20846662 TI - Superhydrophobic surfaces: from natural to biomimetic to functional. AB - Nature is the creation of aesthetic functional systems, in which many natural materials have vagarious structures. Inspired from nature, such as lotus leaf, butterfly' wings, showing excellent superhydrophobicity, scientists have recently fabricated a lot of biomimetic superhydrophobic surfaces by virtue of various smart and easy routes. Whilst, many examples, such as lotus effect, clearly tell us that biomimicry is dissimilar to a simple copying or duplicating of biological structures. In this feature article, we review the recent studies in both natural superhydrophobic surfaces and biomimetic superhydrophobic surfaces, and highlight some of the recent advances in the last four years, including the various smart routes to construct rough surfaces, and a lot of chemical modifications which lead to superhydrophobicity. We also review their functions and applications to date. Finally, the promising routes from biomimetic superhydrophobic surfaces in the next are proposed. PMID- 20846663 TI - Sparsely-distributed silica/PMMA composite particles prepared by static polymerization in aqueous silica dispersion. AB - Silica/poly(methyl methacrylate) (PMMA) composite particles, in which silica particles are sparsely distributed in the surface of PMMA particles, were formed by static dispersion polymerization of methyl methacrylate (MMA) in aqueous dispersions of submicron silica particles. The silica-modified PMMA particles were constructed via Pickering emulsion-like silica/PMMA aggregation based on weak interaction between PMMA and silica. The morphology of the composite particles is governed by the adsorption/partition equilibrium of PMMA with the silica surface. PMID- 20846664 TI - Fast precipitation of uniform CaCO3 nanospheres and their transformation to hollow hydroxyapatite nanospheres. AB - Shape-controlled synthesis of calcium carbonate with specific polymorphs can be achieved by the assistance of organic additives. In this study, highly uniform nanosized calcium carbonate spheres were synthesized by a fast precipitation method in the presence of a simple polymer, poly(styrene sulfonate) (PSS). The polymorph of the synthesized calcium carbonate products changes from pure calcite in PSS-free reactions to vaterite in PSS-containing (1-50 g/L) reactions. The effect of PSS on the formation of vaterite can be attributed to the two aspects: decrease of driving force by reducing the interfacial energy, and phase stabilization effect caused by the adsorbed PSS. A higher PSS concentration (50 g/L) results in highly uniform vaterite nanospheres of 400-500 nm in diameter. Furthermore, PSS is found more effective to induce the formation of vaterite in the Ca(2+)-rich reaction condition (Ca(2+):CO(3)(2-)=5:1) than in the CO(3)(2-) rich conditions (Ca(2+):CO(3)(2-)=1:5). It has also been found that different mixing mode of the calcium and carbonate precursor solutions has a significant influence on the size distribution of the products. Finally, with a controlled anion-exchange method, the as-prepared vaterite nanospheres can be easily transformed to hollow hydroxyapatite spheres, which exhibit great potential to be used as the drug carriers due to their considerably high surface area and biocompatibility. PMID- 20846665 TI - T-cell receptor gamma chain variable and joining region genes of subgroup 1 are clonally rearranged in feline B- and T-cell lymphoma. AB - Lymphoma is one of the most common tumours of domestic cats. Microscopically, it can be challenging to distinguish lymphoma (monoclonal lymphoid proliferation) from reactive lymphoid hyperplasia (polyclonal lymphoid proliferation). Molecular methods that characterize cellular clonality can overcome this diagnostic challenge; however, it is essential to know which variable and joining region variants are utilized by neoplastic lymphocytes before a sensitive and specific assay can be developed. The present study describes a polymerase chain reaction assay that allows for complete sequencing of clonally recombined T-cell receptor (TCR) gamma chain genes from formalin-fixed and paraffin wax-embedded samples of feline lymphoma. The variable (V) and joining (J) region variants of the TCR gamma chain were characterized in 50 feline lymphomas. Amplification and sequencing with primers directed against conserved framework regions 1, 2 and 4 of the TCR gamma chain identified clonal rearrangement in 68% of T-cell lymphomas and 22% of B-cell lymphomas. The distribution of TCR variants present in B- and T cell lymphomas was similar and included V region variants 1 and 3, and J region variants 1.2, 1.3 and 1.5. V region variants 2 and 4 were not identified in either tumour type. Some feline B-cell lymphomas had a clonally rearranged TCR, a finding reported in human, but not canine, B-cell lymphoma. PMID- 20846666 TI - Comparative pathology of pulmonary hydatid cysts in macropods and sheep. AB - The development and appearance of hydatid cysts of Echinococcus granulosus in experimentally infected tammar wallabies (Macropus eugenii) and sheep during the period 9-17 months post-infection (mpi) were studied. Cysts of unknown age were also examined from mature, naturally infected sheep. The cysts grew more rapidly and became fertile within a shorter period in wallabies compared with sheep. Cysts from the wallabies were larger in absolute size and were larger relative to the size of the lungs. Microscopical examination revealed that wallaby hydatid cysts developed in small bronchioles. Hydatid cysts in the wallabies had a thicker germinal membrane, with more nuclei and a thicker laminated layer (LL), than hydatid cysts of similar age found in sheep. In contrast, the adventitial layer was thicker in the ovine cysts, comprising a hyalinized layer of degenerate collagen and necrotic cellular debris surrounded by a layer of granulation tissue that was largely absent from lesions in the wallabies. Multilocular cysts were present in sheep, but not in wallabies. The greater thickness of the germinal membrane in wallaby cysts suggests greater parasite activity, which may explain the more rapid growth rate in this host, whereas the thicker adventitial layer in sheep cysts may be restrictive to growth while simultaneously protecting the hydatid from the host immune response. These differences in the parasite-host relationship between macropods and sheep may reflect the relatively recent introduction of the parasite into Australia. PMID- 20846667 TI - Individual differences in false belief understanding are stable from 3 to 6 years of age and predict children's mental state talk with school friends. AB - Despite a wealth of studies in the field, longitudinal assessments of both the stability and predictive utility of individual differences in preschoolers' understanding of the mind remain scarce. To address these gaps, we applied latent variable analyses to (a) experimental data gathered from a socially diverse sample (N=101, 60 boys and 41 girls) at 3 and 6 years of age and (b) transcript based coding of children's dyadic interactions with a best friend at age 6. Our results showed significant stability between latent factors of false belief understanding at ages 3 and 6 even with effects of verbal ability and inhibitory control controlled at both time points. In addition, false belief understanding at ages 3 and 6 showed both distal and proximal links with the frequency of children's talk about mental states at age 6 even when their overall talk and their friends' mental state talk were also controlled. We conclude that preschoolers' false belief understanding both directly and indirectly supports children's growing ability to discuss thoughts and feelings in their conversations with friends. PMID- 20846668 TI - Situational changes in self-awareness influence 3- and 4-year-olds' self regulation. AB - In adults, heightened self-awareness leads to adherence to socially valued norms, whereas lowered self-awareness is associated with antinormative behavior. Levels of self-awareness are influenced by environmental cues such as mirrors. Do situational changes in self-awareness also have an impact on preschoolers' self regulation? Adherence to a socially valued standard was observed under different conditions of self-focus. In Experiment 1 the standard was prescribed ("don't look in the box"), and in Experiment 2 children had the opportunity to be altruistic. Heightened self-focus was induced using a large mirror. In a neutral condition, the nonreflective side of the mirror was shown. To lower self-focus, children wore a disguise. Preschoolers peeked less and showed more altruism when the mirror image was present. As found for adults, it appears that self-awareness leads 3- and 4-year-olds to adhere to salient social standards. These results suggest that self-focus has a socially adaptive regulatory function from an early age. PMID- 20846669 TI - TNF-alpha gene polymorphisms and excessive daytime sleepiness in pediatric obstructive sleep apnea. AB - OBJECTIVE: To assess sleepiness, TNF-alpha plasma levels, and genomic variance in the TNF-alpha gene in children with obstructive sleep apnea (OSA). STUDY DESIGN: Children being evaluated for OSA (n = 60) and matched control children (n = 80) were assessed with a modified Epworth Sleepiness Scale questionnaire and underwent a blood draw the morning after nocturnal polysomnography. TNF-alpha plasma concentrations were assayed using ELISA, and genomic DNA was extracted. Genotyping and allelic frequencies were determined for 4 TNF-alpha single nucleotide polymorphisms using real-time polymerase chain reaction genotyping assays. RESULTS: Morning TNF-alpha levels and Epworth Sleepiness Scale scores were increased in the presence of OSA, but substantial variability was present. Although TNF-alpha plasma concentrations were globally increased in OSA, most of the variance was attributable to the presence or absence of TNF-alpha -308G gene polymorphism. CONCLUSIONS: TNF-alpha levels are increased in a subset of children with OSA, particularly among those harboring the TNF-alpha -308G single nucleotide polymorphism. Among the latter, significant increases in excessive daytime sleepiness symptoms are also present. The relatively high variability of excessive daytime sleepiness in pediatric OSA may be related to underlying TNF alpha gene polymorphisms, particularly -308G. PMID- 20846670 TI - A comparative study of hearing loss in two microdeletion syndromes: velocardiofacial (22q11.2 deletion) and Williams (7q11.23 deletion) syndromes. AB - OBJECTIVE: To comprehensively assess auditory impairments in velocardiofacial syndrome (VCFS) and Williams syndrome (WS). STUDY DESIGN: Audiologic measurements were conducted with 62 subjects with VCFS and 44 subjects with WS, as well as two control groups consisting of 22 subjects with idiopathic developmental disability and 23 typically developing controls. An association between severity of hearing loss in VCFS and the (158)Val/Met polymorphism of the catechol-O methyltransferase gene (COMT) was explored. RESULTS: Hearing was significantly more impaired in the VCFS and WS groups compared with the developmental disability and typically developing groups. Audiologic abnormalities identified in both the VCFS and WS groups included high-tone hearing loss (predominantly sensorineural or mixed type), loss of acoustic reflex, and middle ear pathologies. In both the VCFS and WS groups, hearing loss severity was positively correlated with age. In the VCFS group, hearing loss was more severe in the subgroup carrying the COMT Val allele compared with the subgroup carrying the COMT Met allele. CONCLUSIONS: Hearing impairments, including sensorineural hearing loss and acoustic reflex dysfunction, are very common in both VCFS and WS. Hearing loss is less severe in subjects with the COMT Met allele, possibly due to the protective effect of dopamine on the hearing system. PMID- 20846671 TI - Pulmonary complications of Down syndrome during childhood. PMID- 20846672 TI - Isolated congenital asplenia: a French nationwide retrospective survey of 20 cases. AB - OBJECTIVE: To better describe the natural history, mode of inheritance, and the epidemiological and clinical features of isolated congenital asplenia, a rare and poorly understood primary immunodeficiency. STUDY DESIGN: A French national retrospective survey was conducted in hospital pediatric departments. A definitive diagnosis of ICA was based on the presence of Howell-Jolly bodies, a lack of detectable spleen, and no detectable cardiovascular malformation. RESULTS: The study included 20 patients (12 males and 8 females) from 10 kindreds neither related to each other nor consanguineous. The diagnosis of ICA was certain in 13 cases (65%) and probable in 7 cases (35%). Ten index cases led to diagnosis of 10 additional cases in relatives. Five cases were sporadic and 15 were familial, suggesting autosomal dominant inheritance. Median age was 12 months at first infection (range, 2-516 months), 11 months at diagnosis of asplenia (range, 0-510 months), and 9.9 years at last follow-up (range, 0.7-52 years). Fifteen patients sustained 18 episodes of invasive bacterial infection, caused mainly by Streptococcus pneumoniae (61%). Outcomes were poor, with 9 patients (45%) dying from fulminant infection. CONCLUSIONS: ICA is more common than was previously thought, with an autosomal dominant inheritance in at least some kindreds. Relatives of cases of ICA should be evaluated for ICA, as should children and young adults with invasive infection. PMID- 20846673 TI - Perspectives of Kennedy's disease. AB - Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare, adult-onset, X-linked, recessive trinucleotide, polyglutamine (poly-G) disorder, caused by expansion of an unstable CAG-tandem-repeat in exon 1 of the androgen receptor (AR) gene on chromosome Xq11-12. Poly-Q-expanded AR accumulates in nuclei, undergoes fragmentation and initiates degeneration and loss of motor neurons and dorsal root ganglia. Phenotypically, patients present with weakness and wasting of the facial, bulbar and extremity muscles, sensory disturbances, and endocrinological disturbances, such as gynecomastia and reduced fertility. In the limb muscles weakness and wasting may be symmetric or asymmetric, proximal or distal, or may predominate at the lower or upper limb muscles. There may be mild to severe hyper-CK-emia, elevated testosterone or other sexual hormones, abnormal motor and sensory nerve conduction studies, and neuropathic or rarely myopathic alterations on muscle biopsy. BSMA is diagnosed if the number of CAG-repeats exceeds 40. No causal therapy is available but symptomatic therapy may be beneficial for weakness, tremor, endocrinological abnormalities, muscle cramps, respiratory failure, or dysphagia. The course is slowly progressive and the ability to walk lost only late in life. Only few patients require ventilatory support and life expectancy is only slightly compromised. PMID- 20846674 TI - Cognitive impairment of vascular origin: neuropathology of cognitive impairment of vascular origin. AB - The term cognitive impairment of vascular origin is used to designate global cognitive deficits as well as focal neurological deficits such as aphasia, apraxia and agnosia of vascular/circulatory origin. It has been useful for identifying early clinical and neuroradiological alterations that might permit therapeutic strategies geared to curbing the progression of cerebrovascular disease. Multi-infarct encephalopathy, infarcts in strategic areas, lacunae and lacunar status, Binswanger's encephalopathy, hippocampal sclerosis, cortical granular atrophy and watershed infarcts are common lesions. Hypertension and vascular diseases such as arteriosclerosis, small blood vessel disease, inflammatory diseases of the blood vessels, Sneddon syndrome, cerebral amyloid angiopathies, cerebral autosomic dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Maeda's syndrome are causative of cognitive impairment of vascular origin. Other less common causes are hereditary endotheliopathy with retinopathy, neuropathy and strokes (HERNS), cerebro retinian vasculopathy (CRV), hereditary vascular retinopathy (HVR) (all three linked to 3p21.1-p21.3), hereditary infantile hemiparesis with arteriolar retinopathy and leukoencephalopathy (HIHRATL) (not linked to 3p21), fibromuscular dysplasia, and moya-moya disease. Lack of uniformity of clinical manifestations, the variety of vascular diseases and circulatory factors, the diverse, but often convergent, neuropathological substrates, and the common association with unrelated neurodegenerative diseases in the elderly, make it hard to assume a single clinical approach in the diagnosis and treatment of cognitive impairment of vascular origin. Rather, environmental and genetic risk factors, underlying vascular diseases, associated systemic, metabolic and neurodegenerative diseases and identification of extent and distribution of lesions with morphological and functional neuroimaging methods should be applied in every individual patient. PMID- 20846675 TI - Cardiac glycosides may affect prostate specific antigen levels. PMID- 20846676 TI - Pediatric urolithiasis: children as little adults. PMID- 20846677 TI - Chronic Kidney Disease Epidemiology Collaboration versus Modification of Diet in Renal Disease equations for renal function evaluation in patients undergoing partial nephrectomy. AB - PURPOSE: A novel equation, the Chronic Kidney Disease Epidemiology Collaboration, has been proposed to replace the Modification of Diet in Renal Disease for estimated glomerular filtration rate due to higher accuracy, particularly in the setting of normal renal function. We compared these equations in patients with 2 functioning kidneys undergoing partial nephrectomy. MATERIALS AND METHODS: We assembled a cohort of 1,158 patients from 5 institutions who underwent partial nephrectomy between 1991 and 2009. Only subjects with 2 functioning kidneys were included in the study. The end points were baseline estimated glomerular filtration rate, last followup estimated glomerular filtration rate (3 to 18 months), absolute and percent change estimated glomerular filtration rate ([absolute change/baseline] * 100%), and proportion of newly developed chronic kidney disease stage III. The agreement between the equations was evaluated using Bland-Altman plots and the McNemar test for paired observations. RESULTS: Mean baseline estimated glomerular filtration rate derived from the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations were 73 and 77 ml/minute/1.73 m(2), respectively, and following surgery were 63 and 67 ml/minute/1.73 m(2), respectively. Mean percent change estimated glomerular filtration rate was -12% for both equations (p = 0.2). The proportion of patients with newly developed chronic kidney disease stage III following surgery was 32% and 25%, according to the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration equations, respectively (p = 0.001). CONCLUSIONS: For patients with 2 functioning kidneys undergoing partial nephrectomy the Chronic Kidney Disease Epidemiology Collaboration equation provides slightly higher glomerular filtration rate estimates compared to the Modification of Diet in Renal Disease equation, with 7% fewer patients categorized as having chronic kidney disease stage III or worse. PMID- 20846678 TI - Safety and efficacy of intravesical bacillus Calmette-Guerin plus interferon alpha-2b therapy for nonmuscle invasive bladder cancer in patients with prosthetic devices. AB - PURPOSE: Patients with bladder cancer who have prosthetic devices, such as a cardiac pacemaker, artificial heart valve or orthopedic hardware, and who undergo intravesical bacillus Calmette-Guerin therapy are theoretically at higher risk for complications, including bacterial seeding of pacemaker wires or orthopedic hardware, and at further risk for infective endocarditis. We assessed the safety and efficacy of bacillus Calmette-Guerin plus interferon alpha-2b therapy in patients with nonmuscle invasive bladder cancer and a pacemaker, artificial heart valve or orthopedic hardware. MATERIALS AND METHODS: We evaluated 1,045 patients with nonmuscle invasive bladder cancer enrolled in a multicenter American phase II trial of bacillus Calmette-Guerin plus interferon alpha-2b therapy, including 143 with a prosthetic device (pacemaker in 87, artificial heart valve in 13 and orthopedic hardware in 43). Weekly physician toxicity assessments and standard adverse effect reporting were done. RESULTS: No patient had infective endocarditis or hardware infection. One patient with a pacemaker, 2 with orthopedic hardware and none with an artificial heart valve required treatment cessation for fever greater than 102.5F. All defervesced within 24 hours and had no long-term sequelae. Due to intolerable, nonlife threatening side effects 12 patients with a pacemaker, 2 with orthopedic hardware and 1 with an artificial heart valve stopped treatment. Of the remaining patients with a prosthesis 99 and 24 stopped treatment due to intolerable, nonlife threatening and serious side effects, respectively. CONCLUSIONS: Patients with a pacemaker, artificial heart valve or orthopedic hardware were no more likely than the general population to have infection or fever, or discontinue treatment due to side effects. These patients should not be excluded from intravesical bacillus Calmette-Guerin plus interferon alpha-2b therapy for nonmuscle invasive bladder cancer. PMID- 20846679 TI - Smoking cessation assistance for patients with bladder cancer: a national survey of American urologists. AB - PURPOSE: Cigarette smoking is a known risk factor for bladder cancer. How urologists address smoking cessation among patients with bladder cancer is not well-known. We assessed the practice patterns of American urologists regarding smoking cessation assistance for patients with bladder cancer. MATERIALS AND METHODS: A questionnaire regarding smoking cessation practice patterns was sent to 1,821 American urologists in the 2008 American Urological Association membership directory. Responses were summarized with frequency and percent. Statistical comparison was made using chi-square tests. Multiple logistic regression was used to detect significant predictors of providing smoking cessation assistance. RESULTS: Responses were received from 601 urologists who collectively treated an estimated 14,713 patients with bladder cancer in the last year. More than half (55.6%) of urologists never discuss smoking cessation while only 19.8% always discuss smoking cessation with patients with bladder cancer. Of urologists who never discuss smoking cessation 40.7% believe that smoking cessation may not alter the course or outcome of the disease and 37.7% do not feel qualified giving smoking cessation counseling. Most urologists (93.7%) have never had formal smoking cessation training. Urologists with smoking cessation training were more likely to always provide smoking cessation assistance compared to those without training (20.6% vs 6.0%, p = 0.0011). Number of patients with bladder cancer treated (OR 3.96) and formal smoking cessation training (OR 13.49) were significant predictors of providing smoking cessation assistance. CONCLUSIONS: American urologists demonstrate a low rate of providing smoking cessation assistance to patients with bladder cancer. Urologists who are trained in smoking cessation most commonly provide smoking cessation assistance. We recommend integrating formal smoking cessation instruction into courses that address bladder cancer and strongly encourage the American Urological Association to adopt practice pattern guidelines. PMID- 20846680 TI - Association of tumor necrosis with pathological features and clinical outcome in 754 patients undergoing radical nephroureterectomy for upper tract urothelial carcinoma: an international validation study. AB - PURPOSE: Tumor necrosis is associated with a poor oncological outcome in patients with upper tract urothelial carcinoma and other malignancies. We validated the association of tumor necrosis with pathological features and clinical outcomes in a large international cohort of patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. MATERIAL AND METHODS: This retrospective study included 754 patients treated with radical nephroureterectomy at a total of 9 centers. Tumor necrosis was scored as greater than 10% of tumor area based on microscopic evaluation. RESULTS: Tumor necrosis was present in 165 specimens (21.9%). The prevalence of tumor necrosis increased with advancing pathological stage, including 7%, 10.6% and 50% for T1, T2 and T3-4, respectively (p <0.001). Tumor necrosis was associated with features of aggressive upper tract urothelial carcinoma, such as high grade, lymph node metastasis, lymphovascular invasion, sessile tumor architecture and concomitant carcinoma in situ (p <0.002). Median followup in censored patients was 40 months (IQR 18 to 75). On univariate Cox regression analysis tumor necrosis was significantly associated with disease recurrence and cancer specific mortality (HR 2.4 and 2.7, p <0.001). However, on multivariate Cox regression analysis including patient age, stage, grade, lymph node status, lymphovascular invasion and adjuvant chemotherapy tumor necrosis was not associated with disease recurrence (HR 1.1, p = 0.49) or cancer specific mortality (HR 1.1, p = 0.51). Excluding 63 patients who received adjuvant chemotherapy and/or 49 with positive lymph nodes did not substantially change these results. CONCLUSIONS: In this large, multicenter international study tumor necrosis was associated with pathological features of biologically aggressive upper tract urothelial carcinoma. However, tumor necrosis was not an independent predictor of clinical outcomes. PMID- 20846681 TI - Comparing prostate specific antigen triggers for intervention in men with stable prostate cancer on active surveillance. AB - PURPOSE: We determined the proportion of men with nonprogressive prostate cancer on active surveillance who had a trigger for treatment using various measures of prostate specific antigen kinetics. MATERIALS AND METHODS: A prospective phase II study of patients with favorable clinical parameters (stage T1b-T2b N0M0, Gleason sum 7 or less, prostate specific antigen 15 ng/ml or less) on active surveillance was initiated in 1995. Those patients considered at high risk for progression were offered radical intervention. The remaining patients were closely monitored and formed the cohort for this study. We calculated the proportion and frequency of patients who had a trigger for treatment based on the various prostate specific antigen triggers (prostate specific antigen doubling time, prostate specific antigen velocity, prostate specific antigen threshold). RESULTS: Of 450 patients followed on surveillance 305 remained on active surveillance without definitive intervention. None of these 305 patients have died of prostate cancer or have had symptomatic metastatic disease develop. Median followup was 6.8 years. The proportion of patients who would have had a trigger for treatment ranged from 14% to 42% for the threshold triggers, 37% to 50% for the prostate specific antigen doubling time triggers and 42% to 84% for the velocity triggers. CONCLUSIONS: Almost all of the prostate specific antigen triggers examined in this study would have led to high rates of trigger for treatment. More work is needed to identify a trigger that better strikes the balance between recommending treatment for patients at high risk for progression and minimizing treatment for those at low risk for progression. PMID- 20846682 TI - Functional and oncologic outcomes of partial adrenalectomy for pheochromocytoma in patients with von Hippel-Lindau syndrome after at least 5 years of followup. AB - PURPOSE: Although the safety and feasibility of partial adrenalectomy in patients with von Hippel-Lindau syndrome have been established, long-term outcomes have not been examined. In this study we evaluate the recurrence and functional outcomes in a von Hippel-Lindau syndrome cohort treated for pheochromocytoma with partial adrenalectomy with a followup of at least 5 years. MATERIALS AND METHODS: We reviewed the records of patients with von Hippel-Lindau syndrome treated with partial adrenalectomy for pheochromocytoma at the National Cancer Institute. Demographic, germline mutation status, surgical indication, oncologic and functional outcome data were collected. Local recurrence was defined as radiographic evidence of recurrent tumor on the ipsilateral side of partial adrenalectomy. Patients were considered steroid dependent if they required steroids at most recent followup. RESULTS: A total of 36 partial adrenalectomies for pheochromocytoma were performed in 26 patients with von Hippel-Lindau syndrome between September 1995 and December 2003. Of these cases 23 were performed open and 13 were performed laparoscopically. Prior surgical history was obtained for all patients. At a median followup of 9.25 years (range 5 to 46) metastatic pheochromocytoma had not developed in any patients. In 3 patients (11%) there were 5 local recurrences treated with surgical extirpation or active surveillance. All recurrences were asymptomatic and detected by radiographic imaging on followup. In addition, 3 of 26 patients (11%) subsequently required partial adrenalectomy for pheochromocytoma on the contralateral adrenal gland. In the entire cohort only 3 patients became steroid dependent (11%). CONCLUSIONS: Outcomes of partial adrenalectomy in patients with von Hippel-Lindau syndrome with pheochromocytoma are encouraging at long-term followup and should be recommended as a primary surgical approach whenever possible. Adrenal sparing surgery can obviate the need for steroid replacement in the majority of patients. Local recurrence rates appear to be infrequent and can be managed successfully with subsequent observation or intervention. PMID- 20846683 TI - Ultrasound estimated bladder weight and measurement of bladder wall thickness- useful noninvasive methods for assessing the lower urinary tract? AB - PURPOSE: In the last decade interest has arisen in the use of ultrasound derived measurements of bladder wall thickness, detrusor wall thickness and ultrasound estimated bladder weight as potential diagnostic tools for conditions known to induce detrusor hypertrophy. However, to date such measurements have not been adopted into clinical practice. We performed a comprehensive review of the literature to assess the potential clinical usefulness of these measurements. MATERIALS AND METHODS: A MEDLINE(r) search was conducted to identify all published literature up to June 2009, investigating measurements of bladder wall thickness, detrusor wall thickness and ultrasound estimated bladder weight. RESULTS: Measurements of bladder and detrusor wall thickness, and ultrasound estimated bladder weight have been studied in men, women and children. A convincing trend has been shown in the ability of these measurements to differentiate men with from those without bladder outlet obstruction. In addition, measurements of bladder wall thickness have revealed a considerable difference between detrusor overactivity and urodynamic stress incontinence. A number of confounding variables and a lack of standardized methodology has resulted in discrepancies among studies. Therefore, reproducible diagnostic ranges or cutoff values have not been established. CONCLUSIONS: Ultrasound derived measurements of bladder and detrusor wall thickness, and ultrasound estimated bladder weight are potential noninvasive clinical tools for assessing the lower urinary tract. PMID- 20846684 TI - Initial atypical diagnosis with carcinoma on subsequent prostate needle biopsy: findings at radical prostatectomy. AB - PURPOSE: Limited data exist on radical prostatectomy findings performed for cancer on repeat biopsy following an initial atypical biopsy (atypical glands suspicious but not diagnostic for carcinoma). MATERIALS AND METHODS: We compared 169 such men to 15,810 without an initial diagnosis of atypical glands suspicious for carcinoma who underwent radical prostatectomy from 1993 to 2008. RESULTS: Median time between atypical biopsy and repeat biopsy showing cancer was 6.1 months (range 0.7 to 94.8). An initial diagnosis of atypical glands suspicious but not diagnostic for carcinoma correlated significantly with nonpalpable disease, biopsy Gleason score 6 and lower tumor volume on needle cores. Compared to radical prostatectomy without prior atypical findings, radical prostatectomy cases with an initial atypical biopsy had a significantly lower Gleason score (p <0.0001) and pathological stage (p = 0.001), with 126 (74.5%) Gleason score 6 and 140 (83.0%) organ confined. Only 2 (1.2%) cases showed seminal vesicle involvement and none had lymph node metastases. In addition to known preoperative parameters (clinical stage and biopsy Gleason score), the presence of initial atypical biopsy was an independent predictor of organ confined disease at radical prostatectomy. However, when tumor volume on needle biopsy was included in the multivariate analysis a diagnosis of atypical glands suspicious but not diagnostic for carcinoma lost its independent predictive value. CONCLUSIONS: Prostate cancer diagnosed on needle biopsy following a diagnosis of atypical glands suspicious but not diagnostic of carcinoma demonstrates a significantly lower tumor grade and pathological stage at radical prostatectomy than cancer without such a diagnosis. Correlating with lower tumor volume on biopsy, the presence of initial atypical biopsy predicts organ confined disease at radical prostatectomy. However, a few cases with high Gleason score and advanced pathological stage in this group emphasize the importance of re-biopsy within 3 to 6 months following such a diagnosis. PMID- 20846685 TI - Risk grouping versus risk continuum in patients with clinically localized prostate cancer: a taxometric test. AB - PURPOSE: Two commonly used risk estimation approaches for clinically localized prostate cancer are nomograms and risk grouping. The basic distinction between these 2 approaches is that risk grouping assigns patients to distinct categories while nomograms align patients along a continuum or dimension. We used the taxometric methods developed by Meehl to compare the competing models of risk grouping vs risk continuum in patients with clinically localized prostate cancer. MATERIALS AND METHODS: The study sample consisted of 80,304 patients from the Surveillance, Epidemiology and End Results database from 2004 to 2006. The 3 clinical variables analyzed were serum prostate specific antigen, Gleason score and American Joint Committee on Cancer T stage. Three taxometric procedures were used in analysis, including maximum covariance, mean above minus mean below a cut and latent mode. The comparison curve fit index was calculated for each procedure and the 3 results were averaged. A priori thresholds for the mean comparison curve fit index were that values greater than 0.55 were considered evidence of categorical structure and values less than 0.45 were considered evidence of dimensional structure. Values between 0.45 and 0.55 were deemed ambiguous. RESULTS: Maximum covariance, mean above minus mean below a cut and latent mode analyses yielded a comparison curve fit index of 0.168, 0.401 and 0.465, respectively (mean 0.345). CONCLUSIONS: Results favor a dimensional rather than a categorical model of risk estimation and provide further support for using nomograms over risk grouping in patients with clinically localized prostate cancer. PMID- 20846686 TI - Detrusor underactivity/underactive bladder: new research initiatives needed. PMID- 20846687 TI - Will posterior tibial nerve stimulation replace sacral nerve root stimulation as the salvage management of drug resistant urinary urge incontinence? PMID- 20846689 TI - Radio frequency ablation of renal tumors in patients with metastatic renal cell carcinoma. AB - PURPOSE: We retrospectively evaluated the feasibility, safety and outcomes of radio frequency ablation of primary renal tumors to control local disease while preserving renal parenchyma in a series of patients with metastatic renal cell carcinoma in a single institutional, multidisciplinary setting. MATERIALS AND METHODS: We evaluated the records of patients with metastatic renal cell carcinoma who underwent percutaneous radio frequency ablation of a primary renal tumor. Patient demographic and disease characteristics, adjunctive medical and surgical therapies, recurrence and clinical outcomes were studied. RESULTS: A total of 15 patients treated between 2002 and 2008 met study inclusion criteria. There was no incomplete ablation or local recurrence. Ten patients had biopsy proven renal cell carcinoma in the ablated renal mass. Eight patients had a solitary metastasis, 3 had metastasis at 2 sites and 4 had 3 or more metastatic sites. Four patients experienced major complications. Median radiographic and clinical followup in patients at risk for an event was 25.5 and 33.0 months, respectively. The overall survival rate 1, 3 and 5 years after radio frequency ablation was 73.3%, 57.1% and 38.1%, respectively. At last evaluation 4 patients were in complete remission, 4 had no evidence of local recurrence but had evidence of distant disease and 7 had died of the disease. CONCLUSIONS: Radio frequency ablation is feasible and safe in highly selected patients with metastatic renal cell carcinoma, resulting in durable local control as part of multimodality management and achieving renal preservation. Further investigation is required to define the role of radio frequency ablation in this patient population. PMID- 20846688 TI - Bacillus Calmette-Guerin with or without interferon alpha-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. AB - PURPOSE: In a multicenter, prospectively randomized study we evaluated bacillus Calmette-Guerin alone vs bacillus Calmette-Guerin plus interferon alpha-2b and megadose vitamins vs recommended daily allowance vitamins during induction and maintenance intravesical therapy in the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Patients who were bacillus Calmette-Guerin naive with carcinoma in situ, Ta or T1 urothelial cancer were randomized to receive intravesical bacillus Calmette-Guerin or bacillus Calmette-Guerin plus interferon alpha-2b. Patients were further randomized to receive a recommended daily allowance or megadose vitamin preparation. Induction bacillus Calmette-Guerin treatment was given weekly for 6 weeks, and patients who were recurrence-free received maintenance treatment at 4, 7, 13, 19, 25 and 37 months. Patients were followed with quarterly cystoscopy for 2 years, then semiannually through year 4 and then annually. The primary end point was biopsy confirmed tumor recurrence or positive cytology. RESULTS: A total of 670 patients were accrued and randomized. At 24-month median followup recurrence-free survival was similar in all groups with 63% in the bacillus Calmette-Guerin with recommended daily allowance vitamins group, 59% in bacillus Calmette-Guerin with megadose vitamins, 55% in bacillus Calmette-Guerin/interferon alpha-2b with recommended daily allowance vitamins and 61% in bacillus Calmette-Guerin/interferon alpha-2b with megadose vitamins (p >0.05). The addition of interferon alpha-2b was associated with a more frequent incidence of fever (11% vs 5%) and constitutional symptoms (18% vs 11%) vs bacillus Calmette-Guerin alone (p <0.05). CONCLUSIONS: Interferon alpha 2b added to bacillus Calmette-Guerin induction and maintenance intravesical therapy did not decrease tumor recurrence in bacillus Calmette-Guerin naive cases, but was associated with increased fever and constitutional symptoms. No difference in time to recurrence was present in patients receiving recommended daily allowance vs high dose vitamins. PMID- 20846690 TI - A simple, effective method to create laparoscopic renal protective hypothermia with cold saline surface irrigation: clinical application and assessment. AB - PURPOSE: We previously described the use of cold saline surface irrigation to achieve protective renal hypothermia in a laparoscopic partial nephrectomy porcine model. We now present our clinical application of this technique and characterization of the hypothermic effect during laparoscopic partial nephrectomy. MATERIALS AND METHODS: Seven patients underwent elective laparoscopic partial nephrectomy augmented with our hypothermia technique. Parenchymal temperature sensors were placed to confirm cooling efficacy and efficiency. After transperitoneal exposure of the kidney we performed temporary hilar vascular occlusion. Surface cooling with almost freezing normal saline was delivered with a laparoscopic suction/irrigation device. Tumor laparoscopic resection and renal reconstruction were completed. Outcome measures included intraoperative changes with hypothermia and postoperative estimated glomerular filtration rate changes. RESULTS: All patients successfully underwent laparoscopic partial nephrectomy without complications or evidence of residual disease. A protective renal parenchymal temperature of less than 20C was achieved at a mean application time of 8.3 minutes. The hypothermic window of 15C to 25C was maintained an average of 30.4 minutes. In 2 cases cooling was repeated and 4 minutes were required to lower the temperature below 20C. The overall mean core body temperature decrease was 1.28C. At a mean followup of 22.4 months the median preoperative, immediate postoperative and final estimated glomerular filtration rate was 75, 65 and 71 ml/minute/1.73 m(2), respectively. There was no evidence of disease recurrence on followup imaging. CONCLUSIONS: Our technique involving cold saline surface irrigation to achieve protective renal hypothermia is reproducible, and uses readily available laparoscopic instruments and equipment. This technique can be done simply and effectively, and may expand the use of laparoscopic partial nephrectomy. PMID- 20846691 TI - Tumor infiltrated hilar and mediastinal lymph nodes are an independent prognostic factor for decreased survival after pulmonary metastasectomy in patients with renal cell carcinoma. AB - PURPOSE: Surgical resection remains the most effective treatment in patients with pulmonary metastasis of renal cell carcinoma. To our knowledge the prognostic significance of mediastinal and hilar lymph node metastasis during pulmonary metastasectomy in patients with renal cell carcinoma is unknown. We analyzed the value of computerized tomography to predict mediastinal/hilar lymph node involvement as well as the impact of systematic lymphadenectomy on survival in patients with pulmonary renal cell carcinoma metastasis. MATERIALS AND METHODS: We analyzed survival in 110 patients who underwent resection of pulmonary metastasis of renal cell carcinoma using the Kaplan-Meier method. Multivariate analysis was done by Cox regression analysis. RESULTS: Lymph node metastasis was histologically proved in 35% of patients. Metastasis was not associated with initial tumor grade, lymph node status, the number of pulmonary metastases or recurrent pulmonary metastasis. Computerized tomography had 84% sensitivity and 97% specificity to predict lymph node metastasis. Sensitivity was markedly better for detecting mediastinal than hilar lymph node metastasis (90% vs 69%). Patients with lymph node metastasis had significantly shorter median survival than patients without lymph node metastasis (19 vs 102 months, p <0.001). Multivariate analysis revealed that tumor infiltrated mediastinal lymph nodes were an independent prognostic factor for patient survival. Match paired analysis showed that after lymph node dissection patients showed a trend toward improved survival. CONCLUSIONS: Mediastinal and hilar lymph node metastases significantly correlate with decreased survival. Systematic lymphadenectomy provides valuable information on staging and prognosis in patients with pulmonary metastasis of renal cell carcinoma, and may prolong survival. PMID- 20846692 TI - Multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer. AB - PURPOSE: The risk of under diagnosed or development of subsequent prostate cancer and the treatment of patients diagnosed with high grade prostatic intraepithelial neoplasia remain controversial. We evaluated the relationship between high grade prostatic intraepithelial neoplasia on initial biopsy and the future presence of prostate cancer. MATERIALS AND METHODS: From December 1997 to February 2008 a total of 328 men underwent a second prostate biopsy after being initially diagnosed with high grade prostatic intraepithelial neoplasia. Men with prostate cancer or atypia on initial biopsy were excluded from study. Another 335 men without high grade prostatic intraepithelial neoplasia, prostate cancer or atypia underwent a second prostate biopsy based on clinical suspicion alone. A Cox proportional hazards model was used to estimate the effect of high grade prostatic intraepithelial neoplasia on the subsequent diagnosis of prostate cancer after adjustment for prostate specific antigen, age, presence of inflammation, abnormal digital rectal examination and number of cores obtained at biopsy. High grade prostatic intraepithelial neoplasia was also stratified into multifocal disease and laterality. Adjusted Kaplan-Meier plots were generated to estimate the rates of prostate cancer. RESULTS: High grade prostatic intraepithelial neoplasia alone on initial prostate biopsy had a significant effect on the subsequent diagnosis of prostate cancer (HR 1.89; 95% CI 1.39, 2.55; p <0.0001). Stratifying high grade prostatic intraepithelial neoplasia into multifocal and bilateral disease significantly increased the hazard ratios to 2.56 (95% CI 1.83, 3.60) and 2.20 (95% CI 1.51, 3.21), respectively, resulting in estimated 3-year cancer rates of 29.0% and 37.0% compared to 12.5% and 18.9%, respectively, following benign biopsy. CONCLUSIONS: Multifocal and bilateral disease are adverse features of high grade prostatic intraepithelial neoplasia that significantly increase the risk of prostate cancer despite adjusting for other clinical indicators such as prostate specific antigen and abnormal digital rectal examination. PMID- 20846693 TI - Disproportionate presentation of high risk prostate cancer in a safety net health system. AB - PURPOSE: Most prostate cancer research is based on relatively homogenous cohorts of men, often with comparatively high socioeconomic status. We describe prostate cancer characteristics in men treated in a public health system and hypothesize a disproportionate burden of high risk disease in this population. MATERIALS AND METHODS: We created a clinical registry from a review of the medical records of 377 men diagnosed with prostate cancer in the San Francisco General Hospital system, which provides care to underserved, uninsured populations. We compared sociodemographic data and cancer characteristics with those in 2 large prostate cancer databases from a community (CaPSURETM) and an academic (University of California-San Francisco tumor registry) setting to assess differences in risk distribution using the D'Amico and Cancer of the Prostate Risk Assessment scoring systems. RESULTS: Compared to men in CaPSURE or the University of California-San Francisco tumor registry those in the San Francisco General Hospital cohort were nonwhite (76%), insured under Medicaid (31%) or uninsured (8%) and had adverse clinical characteristics, including median prostate specific antigen greater than 10 ng/ml at diagnosis and higher Gleason grade. In addition, the majority of patients (67%) had intermediate or high risk disease based on the D'Amico classification and a higher mean Cancer of the Prostate Risk Assessment score. Using ANOVA for continuous variables and the chi-square test for categorical variables, all comparisons were statistically significant (p <0.001). CONCLUSIONS: Men in the San Francisco General Hospital public health system bear a substantially higher burden of high risk disease that those in an academic or a community setting. Populations such as this would benefit most from targeted efforts for early detection and treatment to decrease prostate cancer morbidity and mortality. PMID- 20846694 TI - Health care reform 2010: a fresh view on tort reform. AB - PURPOSE: We reviewed the state of medical malpractice tort reform in the context of a new political climate and the current debate over comprehensive health care reform. Specifically we asked whether medical malpractice tort reform is necessary, and evaluated the strengths and weaknesses of contemporary reform proposals. MATERIALS AND METHODS: The medical, legal and public policy literature related to medical malpractice tort reform was reviewed and synthesized. We include a primer for understanding the current structure of medical malpractice law, identify the goals of the current system and analyze whether these goals are presently being met. Finally, we describe and evaluate the strengths and weaknesses of the current reform proposals including caps on damages, safe harbors and health care courts. RESULTS: Medical malpractice tort law is designed to improve health care quality and appropriately compensate patients for medical malpractice injuries, but is failing on both fronts. Of the 3 proposed remedies, caps on damages do little to advance the quality and compensatory goals, while safe harbors and health care courts represent important advancements in tort reform. CONCLUSIONS: Tort reform should be included in the current health policy debate because the current medical malpractice system is not adequately achieving the basic goals of tort law. While safe harbors and health care courts both represent reasonable remedies, health care courts may be preferred because they do not rely on jury determination in the absence of strong medical evidence. PMID- 20846695 TI - [First Spanish consensus on peptic ulcer bleeding management. Consenso sobre Hemorragia Digestiva por Ulcera Peptica]. PMID- 20846696 TI - [An 80-year-old male with pleural effusion and mediastinal lymph nodes]. PMID- 20846697 TI - [Peripheral arterial disease: a new challenge for HIV-infected patients]. PMID- 20846698 TI - Regulation of synthesis and oxidation of fatty acids by adiponectin receptors (AdipoR1/R2) and insulin receptor substrate isoforms (IRS-1/-2) of the liver in a nonalcoholic steatohepatitis animal model. AB - Nonalcoholic steatohepatitis (NASH) is one of the most frequent causes of abnormal liver dysfunction associated with synthesis and oxidation of fatty acids. Adiponectin receptors (AdipoR1/R2) and insulin receptor substrates (IRS-1/ 2) are known as modulators of these fatty acid metabolisms in the liver; however, the regulatory roles of these receptors in the synthesis and oxidation of fatty acids are unclear in the liver of NASH. In this study, we examined the roles of hepatic AdipoR1/R2 and IRS-1/-2 in NASH using an animal model. After feeding a high-fat and high-cholesterol diet to obese fa/fa Zucker rats for 8 weeks, rats showed fatty liver spontaneously with inflammation and fibrosis that are characteristic of NASH. The expression levels of AdipoR1/R2 and IRS-2 were significantly decreased, whereas IRS-1 was significantly increased, in NASH. As a result of the decrease of AdipoR1/R2 expression, the messenger RNA expression levels of genes located downstream of AdipoR1/R2, adenosine monophosphate activated protein kinase alpha1/alpha2, which inhibits fatty acid synthesis, and peroxisome proliferator-activated receptor alpha, which activates fatty acid oxidation, also decreased. Expression level of sterol regulatory element binding protein-1c was found to be elevated, suggesting the up-regulation of IRS-1, and resulted in increased fatty acid synthesis. Furthermore, increase of forkhead box protein A2 expression was observed, which might be associated with the down regulation of IRS-2, facilitating fatty acid oxidation. Taken together, increased synthesis and oxidation of fatty acids by up- or down-regulation of AdipoR or IRS may contribute to the progression of NASH. Thus, AdipoR and IRS might be crucially important regulators for the synthesis and oxidation of fatty acids in the liver of NASH. PMID- 20846699 TI - Effect of phlebotomy on lipid metabolism in subjects with hereditary hemochromatosis. AB - Genetic predisposition to hereditary hemochromatosis (HH) is associated with primary hypertriglyceridemia (HTG). If iron overload influences the development of HTG, the management of these patients could be different. However, the metabolic syndrome in primary HTG is frequent; and it could partially confuse the association. The objective was to determine whether periodic bloodletting could decrease triglyceride concentrations in subjects with HH and iron overload. We retrospectively studied 155 genetically defined HH patients (C282Y homozygotes and compound heterozygotes C282Y/H63D) with iron overload and under periodic therapeutic phlebotomy. Hypertriglyceridemia (triglycerides >=150 mg/dL) was present in 49 subjects at baseline (31.6%). Phlebotomies significantly decreased triglycerides, especially in subjects with basal HTG (from 287 mg/dL at baseline to 133 mg/dL after phlebotomies, P < .001). Blood glucose and total cholesterol did not change with phlebotomies. The triglyceride-lowering effect was obtained until ferritin concentration decreased to less than 200 MUg/L and transferrin saturation to less than 40%. The triglyceride-lowering effect was obtained for glucose levels both less than and greater than 100 mg/dL. In summary, HH subjects frequently have HTG that improves after therapeutic phlebotomy, independently of basal blood glucose. Our results suggest that therapeutic phlebotomy could be a useful therapeutic approach in patients with HTG and iron overload. PMID- 20846700 TI - Cardiovascular correlates of insulin resistance in normotensive and hypertensive African Americans. AB - Insulin resistance (IR) is associated with obesity and predisposes to diabetes mellitus (DM) and cardiovascular disease. The purpose of this study is to determine if IR is related to cardiovascular function independent of DM or hypertension among African Americans (AA). Four hundred sixty-two nondiabetic AA (50% hypertensive and 51% women) were studied on an inpatient General Clinical Research Center. Measurements included anthropometrics and 24-hour blood pressure (BP), heart rate (HR), fasting blood glucose, plasma aldosterone, and insulin. Stroke volume (SV) and cardiac output (CO) were measured by impedance plethysmography; peripheral vascular resistance (PVRI) and vascular compliance indices (VCI) were computed. These measurements were also obtained in response to mental (computerized math testing) and pharmacologic (graded norepinephrine infusion) stress. Insulin resistance was calculated using the homeostasis model assessment (HOMA-IR). SV, CO, and VCI decreased with increasing HOMA-IR, whereas HR and PVRI increased. Overall, BP, HR, and PVRI were positively correlated with HOMA-IR (P < .01); and SV index, cardiac index, and VCI were negatively correlated with HOMA-IR (P < .0001). The correlations persisted after adjustment for BP, age, sex, plasma aldosterone, total cholesterol, or low-density lipoprotein and high-density lipoprotein cholesterol. In addition, multiple linear regression analyses showed that HOMA-IR contributes to the maximum variability of all the hemodynamic variables. Blood pressure responses to math stress and norepinephrine infusion did not correlate with HOMA-IR. Unrelated to DM and BP, IR is associated with increased PVRI and decreased CO in AA. These observations suggest that an exclusive focus on effects of IR on DM or BP may ignore independent pathophysiologic contributions of IR to cardiovascular disease. PMID- 20846701 TI - Sleep duration is a potential risk factor for newly diagnosed type 2 diabetes mellitus. AB - U-shaped patterns have been observed for the relationship between sleep duration and diabetes. In addition, prediabetes is associated with the risk of cardiovascular diseases and diabetes. However, there are few studies investigating the relationship between sleep duration and prediabetes/newly diagnosed diabetes. The aim of this study is to examine the relationship between sleep duration and prediabetes/newly diagnosed diabetes in a Taiwanese population. After excluding the subjects with a high risk of obstructive sleep apnea, those with a positive history of diabetes, or those taking hypnotic drugs, a total of 3470 adults were recruited from a health checkup center. Each subject completed a self-administrated structured questionnaire on sleep duration and lifestyle factors. Prediabetes/diabetes was defined following the definition of the American Diabetes Association. Subjects with different sleep durations were classified into short (<6.0 hours), normal (6.0~8.49 hours), and long sleepers (>=8.5 hours). The proportion of subjects with normal glucose tolerance, prediabetes, and newly diagnosed diabetes was 71.9%, 22.9%, and 5.2%, respectively. There were significant differences in age, sex, weight, education level, body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, alcohol and coffee drinking habits, family history of diabetes, and sleep duration among the 3 glycemic groups. In multinomial regression, both short and long sleepers had a higher risk of newly diagnosed diabetes; and the odds ratio were 1.55 (95% confidence interval, 1.07-2.24) and 2.83 (1.19-6.73), respectively. However, sleep duration was not found to relate to prediabetes. In conclusion, both short and long sleep durations were independently associated with newly diagnosed diabetes, but not with prediabetes. PMID- 20846702 TI - Type 2 diabetes and impaired glucose tolerance in North-China-based rural community adults. AB - OBJECTIVES: To estimate the prevalence of type 2 diabetes and impaired glucose tolerance (IGT), and to identify potential risk factors among adults in rural areas in North China. STUDY DESIGN: Multistage random cluster sampling in a cross sectional study. METHODS: Data were collected in 2005 from 1058 adults aged >20 years. Body mass index (BMI), waist and hip circumferences, 2-hour postprandial glucose (2-hPG) and other data were collected. RESULTS: The prevalence of diabetes and IGT was higher for both men and women in the study group compared with the national averages (diabetes: 7.17% and 7.01%, respectively; IGT: 7.55% and 7.95%, respectively). Men aged >=60 years and women aged 50-59 years had the highest prevalence of diabetes compared with other age groups (9.62% and 9.21% respectively). Both men and women aged >=60 years had the highest prevalence of IGT. A sudden increase in 2-hPG level was seen in women aged >=40 years. Those with BMI >=28 kg/m(2) were at two-fold higher risk than normal. The risk for glucose tolerance abnormalities was almost 1.55-fold higher in subjects with waist/height ratio (WHtR) >=0.50. The odds ratio for diabetes was 0.32 (95% confidence interval 0.10-0.98) in subjects with an annual family income >=30,000 yuan compared with those with lower incomes. CONCLUSIONS: These results indicate that rural populations in North China have a higher prevalence of type 2 diabetes and IGT compared with national averages. Women aged >=40 years warrant more attention to avoid glucose tolerance abnormalities. BMI and WHtR are predictive of the prevalence of glucose tolerance abnormalities. High annual family income appears to be a protective factor for type 2 diabetes. PMID- 20846703 TI - [Evaluation of the left ventricle with three-dimensional echocardiography: comparison with cardiac magnetic resonance]. AB - OBJECTIVE: Three-dimensional echocardiography (3DE) is becoming increasingly common in clinical environments. However, the quality of the images depends on the acoustic window, and it can be difficult to identify the endocardial borders. The objective of this study was to evaluate the performance of 3DE in determining the volumes and left ventricular ejection fraction in unselected patients against the gold standard, cardiac magnetic resonance (CMR). MATERIAL AND METHODS: In 47 unselected patients who underwent CMR, we performed 3DE using a real-time acquisition technique and semiautomatic border detection. RESULTS: We excluded 4 patients (8.5%) because they had an extremely deficient acoustic window. In the remaining 43 patients, including those with a suboptimal acoustic window, we obtained the following correlations between 3DE and CMR: end-diastolic volume, 0.71; end-systolic volume, 0.77; ejection fraction, 0.74. Although the end diastolic volume was systematically underestimated, no significant differences were observed in the ejection fraction. When the 11 patients with suboptimal acoustic windows were excluded, we observed a systematic underestimation of the end-diastolic and end-systolic volumes, which paradoxically gave rise to improved correlation coefficients (0.79, 0.92, and 0.84, respectively) and a more accurate ejection fraction. CONCLUSIONS: Compared to CMR, 3DE systematically underestimates the ventricular volumes but enables adequate determination of the left ventricular ejection fraction regardless of the quality of the acoustic window. PMID- 20846704 TI - Malignant pleural mesothelioma in a female lion (Panthera leo). AB - An 18-year-old female lion (Panthera leo) was referred to the Department of Animal Pathology of the University of Turin (Italy). At necropsy, multiple nodular, 4-20-mm, confluent white firm nodules were scattered throughout the pleural surfaces of the thoracic wall and of the lungs. Histological lesions were represented by proliferations of papillary structures lined by cuboidal basophilic mesothelial cells with large, oval nuclei and abundant granular eosinophilic cytoplasm. Immunohistochemistry revealed immunoreactivity for pancytokeratin and vimentin. None of the cells expressed calretinin antigen. Asbestos fibers and asbestos bodies were not detected respectively by light microscopy and by Scanning Electron Microscope-Energy Dispersive Spectrometer investigations. On the contrary, chrysotile asbestos were identified in samples from shelter material. Histological and immunohistochemical findings were consistent with the diagnosis of an epithelial malignant mesothelioma. To our best knowledge, this is the first report of a pleural mesothelioma in a lion. PMID- 20846705 TI - PKC-delta mediates TCDD-induced apoptosis of chondrocyte in ROS-dependent manner. AB - Exposure to dioxin-like compounds is associated with arthritis in humans. A recent study reported that 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) induces apoptosis in chondrocytes, which is a critical event in the pathogenesis of cartilage disease. In this study, protein kinase C (PKC) signaling pathway was investigated to determine the mechanism of TCDD-induced rabbit articular chondrocyte apoptosis. TCDD exposure induced glutathione-mediated ROS generation and the translocation of PKC isozymes. Among the PKC isozymes tested, PKC-delta showed the most sensitive translocation. The translocation was then blocked by ROS inhibitors (trolox and N-acetyl cysteine), a PKC-delta inhibitor (rottlerin), a caspase-3 inhibitor (z-DEVD-fmk) or an AhR blocker (alpha-naphthoflavone). TCDD increased caspase-3 activity, the activating enzyme for PKC-delta, and prior treatment with trolox blocked such an increase. These results suggest that the translocation of PKC-delta was mediated by ROS-dependent caspase-3 activity. Pretreatment with rottlerin or trolox dampened TCDD-induced apoptosis of chondrocyte, as determined by TUNEL staining and ELISA. Taken together, this study suggests that ROS generation is an upstream event for TCDD-induced chondrocyte apoptosis and PKC-delta mediates the apoptotic processes through ROS dependent caspase-3 activation. This is a first finding demonstrating the role of PKC-delta in chondrocyte apoptosis stimulated by an environmental pollutant. The results may contribute to understanding the mechanism of joint disease associated with the exposure of dioxin-like compounds and identifying a target for the therapeutic interventions. PMID- 20846706 TI - Characteristic accumulation and soil penetration of polychlorinated biphenyls and polybrominated diphenyl ethers in wastewater irrigated farmlands. AB - The impact of wastewater irrigation on the distribution of two groups of persistent organic pollutants (POPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), in farm soil was investigated in this study. The concentrations of total analyzed PCBs were in the range 256-2140pgg( 1) on dry weight basis in surface soils. There was a higher accumulation of PCBs in farms irrigated by wastewater, with decachlorobiphenyl (CB-209) as the predominant congener. The spatial distributions of PBDEs were similar although not as obvious as that of PCBs, and BDE-209 was the predominant congener at 2040 496000pgg(-1)dw, accounting for >96% of the total analyzed PBDEs. However, no significant correlations could be found between PCB and PBDE concentrations in the topsoil samples, and also with soil organic content between the different sites. On the other hand, soil vertical profiles showed significant relationship with soil organic content in cores taken from farms irrigated with wastewater. The vertical distribution was quite uniform at the topsoil, corresponding to the plowed layer, and decreased thereafter exponentially. Furthermore, the soil vertical distribution was found to be congener specific for PCBs, where less chlorinated congeners were able to penetrate deeper into the soil while heavier congeners were more restricted in their movement. This fractionation process was however not found for PBDEs. Also, the prevalence and high relative concentrations of CB-11 and CB-209 suggests that these PCB congeners should more often be included in routine environmental analysis in order to identifying unusual contamination sources. PMID- 20846707 TI - Just how strapping was KNM-WT 15000? AB - For over twenty years, the young, male Homo erectus specimen KNM-WT 15000 has been the focus of studies on growth and development, locomotion, size, sexual dimorphism, skeletal morphology, and encephalization, often serving as the standard for his species. Prior research on KNM-WT 15000 operates under the assumption that H. erectus experienced a modern human life history, including an adolescent growth spurt. However, recent fossil discoveries, improvements in research methods, and new insights into modern human ontogeny suggest that this may not have been the case. In this study, we examine alternative life history trajectories in H. erectus to re-evaluate adult stature estimates for KNM-WT 15000. We constructed a series of hypothetical growth curves by modifying known human and chimpanzee curves, calculating intermediate growth velocities, and shifting the age of onset and completion of growth in stature. We recalculated adult stature for KNM-WT 15000 by increasing stature at death by the percentage of growth remaining in each curve. The curve that most closely matches the life history events experienced by KNM-WT 15000 prior to death indicates that growth in this specimen would have been completed by 12.3 years of age. These results suggest that KNM-WT 15000 would have experienced a growth spurt that had a lower peak velocity and shorter duration than the adolescent growth spurt in modern humans. As a result, it is likely that KNM-WT 15000 would have only attained an adult stature of 163 cm (~ 5'4 "), not 185 cm (~ 6'1 ") as previously reported. KNM-WT 15000's smaller stature has important implications for evolutionary scenarios involving early genus Homo. PMID- 20846708 TI - Modelling air pollution for epidemiologic research--Part I: A novel approach combining land use regression and air dispersion. AB - A common limitation of epidemiological studies on health effects of air pollution is the quality of exposure data available for study participants. Exposure data derived from urban monitoring networks is usually not adequately representative of the spatial variation of pollutants, while personal monitoring campaigns are often not feasible, due to time and cost restrictions. Therefore, many studies now rely on empirical modelling techniques, such as land use regression (LUR), to estimate pollution exposure. However, LUR still requires a quantity of specifically measured data to develop a model, which is usually derived from a dedicated monitoring campaign. A dedicated air dispersion modelling exercise is also possible but is similarly resource and data intensive. This study adopted a novel approach to LUR, which utilised existing data from an air dispersion model rather than monitored data. There are several advantages to such an approach such as a larger number of sites to develop the LUR model compared to monitored data. Furthermore, through this approach the LUR model can be adapted to predict temporal variation as well as spatial variation. The aim of this study was to develop two LUR models for an epidemiologic study based in Greater Manchester by using modelled NO(2) and PM(10) concentrations as dependent variables, and traffic intensity, emissions, land use and physical geography as potential predictor variables. The LUR models were validated through a set aside "validation" dataset and data from monitoring stations. The final models for PM(10) and NO(2) comprised nine and eight predictor variables respectively and had determination coefficients (R2) of 0.71 (PM(10): Adj. R2=0.70, F=54.89, p<0.001, NO(2): Adj. R2=0.70, F=62.04, p<0.001). Validation of the models using the validation data and measured data showed that the R2 decreases compared to the final models, except for NO(2) validation in the measured data (validation data: PM(10): R2=0.33, NO(2): R2=0.62; measured data: PM(10): R2=0.56, NO(2): R2=0.86). The validation further showed low mean prediction errors and root mean squared errors for both models. PMID- 20846709 TI - Analytical and clinical validation of a new point-of-care testing system for determination of D-Dimer in human blood. AB - D-Dimer testing is used for exclusion of deep venous thrombosis (DVT). AQT90 FLEX D-Dimer (AQT D-Dimer) is a novel time-resolved fluorescence based point-of-care test for quantification of D-Dimer in whole blood or plasma. Presently we have determined the analytical and clinical performance of AQT D-Dimer and compared it with four routine D-Dimer assays. The within-run CV of AQT D-Dimer was 3.8-7.2% and the between-run CV was 5.7- 9.7%. Excellent agreement was found between the D Dimer concentrations recorded in citrate-, heparin- and EDTA stabilised blood. The plasma concentration of D-Dimer was determined with AQT D-Dimer, AxSYM, Biopool Auto-Dimer, STA-Liatest and Vidas New in 170 consecutive patients suspected for DVT. Phlebograms were positive in 64 patients (22 distal, 42 proximal). ROC-curves (ROC), the negative and positive predictive values (NPV, PPV), the sensitivity and specificity of the tests were compared. The area under ROC was comparable for all tests. NPV for all DVT was 87-88%, the sensitivity was 88-92% and the PPV was 45-55%. For proximal DVT the NPV and sensitivity were 100% for all tests, whereas the PPV was 37-48%. For distal DVT we obtained a NPV of 87 88%. The sensitivity was 64-77%, the PPV was 19-24% whereas a specificity of 32 58% was observed. The AQT D-Dimer demonstrates excellent analytical and diagnostic performance. The test is rapidly performed and the measuring range of the assay is wide. The NPV, PPV, specificity, sensitivity and AUC of AQT D-Dimer for both proximal and distal DVT are comparable to routine D-Dimer assays. PMID- 20846710 TI - Comparative immunohistochemistry of synaptic markers in the rodent hippocampus in pilocarpine epilepsy. AB - Pilocarpine-induced epileptic state (Status epilepticus) generates an aberrant sprouting of hippocampal mossy fibers, which alter the intrahippocampal circuits. The mechanisms of the synaptic plasticity remain to be determined. In our studies in mice and rats, pilocarpine-induced seizures were done in order to gain information on the process of synaptogenesis. After a 2-month survival period, changes in the levels of synaptic markers (GAP-43 and Syn-I) were examined in the hippocampus by means of semi-quantitative immunohistochemistry. Mossy fiber sprouting (MFS) was examined in each brain using Timm's sulphide-silver method. Despite the marked behavioral manifestations caused by pilocarpine treatment, only 40% of the rats and 56% of the mice showed MFS. Pilocarpine treatment significantly reduced the GAP-43 immunoreactivity in the inner molecular layer in both species, with some minor differences in the staining pattern. Syn-I immunohistochemistry revealed species differences in the sprouting process. The strong immunoreactive band of the inner molecular layer in rats corresponded to the Timm-positive ectopic mossy fibers. The staining intensity in this layer, representing the ectopic mossy fibers, was weak in the mouse. The Syn-I immunoreactivity decreased significantly in the hilum, where Timm's method also demonstrated enhanced sprouting. This proved that, while sprouted axons displayed strong Syn-I staining in rats, ectopic mossy fibers in mice did not express this synaptic marker. The species variability in the expression of synaptic markers in sprouted axons following pilocarpine treatment indicated different synaptic mechanisms of epileptogenesis. PMID- 20846711 TI - Correlation between serum prostate-specific antigen and cancer volume in prostate glands of different sizes. AB - OBJECTIVES: To further evaluate the relationship of prostate-specific antigen (PSA) with prostate size and tumor volume in a contemporary surgical series. Although early studies showed a strong correlation between PSA and tumor volume, it has been suggested that PSA is no longer a valid marker for prostate cancer and only correlates with prostate size. METHODS: From 2003 to 2009, 1234 men with data on prostate weight and total tumor volume underwent radical prostatectomy by a single surgeon. Prostate size was classified into tertiles: small (<= 41.2 g), medium (41.3-54.5 g), and large (>= 54.6 g). Pearson correlation coefficients were used to examine the relationship of PSA with prostate size and tumor volume across different prostate sizes. RESULTS: Median preoperative PSA was 4.9 ng/mL (standard deviation +/- 4.6), mean prostate size was 51.7 g, and mean tumor volume was 5.6 cm(3). PSA had a significant correlation with prostate size only at a prostate weight >= 54.6 g (P = .02). Regardless of prostate size, PSA had a more robust significant correlation with tumor volume than with prostate size (all P < .0001). CONCLUSIONS: PSA was significantly correlated with prostate size only in the largest prostate glands, but was significantly associated with tumor volume in small, medium, or large prostates. Thus, PSA continues to be a better marker for tumor volume than for prostate size. PMID- 20846712 TI - Robotic instrument insulation failure: initial report of a potential source of patient injury. AB - OBJECTIVES: To report our experience with failures in the accessory tip covers that insulate the monopolar robotic cautery scissor instruments and the patient injuries that have resulted. Currently, there is no data in the literature regarding the failure rate of robotic instruments or their accessory components. METHODS: All robotic surgeries performed at our institution were recorded from July 2008 to January 2009. Instrument tip cover failures were recorded at the time of failure regardless of whether a patient complication occurred. Failure was identified by the arching of the electrical current from the insulated portion of the monopolar scissors or by an intraoperative injury. RESULTS: Four hundred fifty-four robotic procedures were recorded. A total of 12 accessory tip cover failures were discovered, demonstrating a failure rate of 2.6%, with a patient complication rate of 0.6% (25% of all failures). CONCLUSIONS: Failure in robotic accessory tip covers can lead to patient complications. The cause for failure can be attributed to a variety of electrical and mechanical causes. All centers and surgeons performing robotic surgery should be aware of the potential for this problem to occur, and the possible interventions that may reduce tip cover failure. PMID- 20846713 TI - Transplacental transfer of anthracyclines, vinblastine, and 4-hydroxy cyclophosphamide in a baboon model. AB - OBJECTIVE: The paucity of data on the fetal effects of prenatal exposure to chemotherapy prompted us to study transplacental transport of chemotherapeutic agents. METHODS: Fluorouracil-epirubicin-cyclophosphamide (FEC) and doxorubicin bleomycin-vinblastine-dacarbazine (ABVD) were administered to pregnant baboons. At predefined time points over the first 25 h after drug administration, fetal and maternal blood samples, amniotic fluid (AF), urine, fetal and maternal tissues, and cerebrospinal fluid (CSF) were collected. High-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used for bioanalysis of doxorubicin, epirubicin, vinblastine, and cyclophosphamide. RESULTS: In nine baboons, at a median gestational age of 139 days (range, 93-169), FEC 100% (n = 2), FEC 200% (n=1), ABVD 100% (n = 5), and ABVD 200% (n = 1) were administered. The obtained ratios of fetal/maternal drug concentration in the different simultaneously collected samples were used as a measure for transplacental transfer. Fetal plasma concentrations of doxorubicin and epirubicin averaged 7.5 +/- 3.2% (n = 6) and 4.0 +/- 1.6% (n = 8) of maternal concentrations, respectively. Fetal tissues contained 6.3 +/- 7.9% and 8.7 +/- 8.1% of maternal tissue concentrations for doxorubicin and epirubicin, respectively. Vinblastine concentrations in fetal plasma averaged 18.5 +/- 15.5% (n=9) of maternal concentrations. Anthracyclines and vinblastine were neither detectable in maternal nor in fetal brain/CSF. 4-Hydroxy-cyclophosphamide concentrations in fetal plasma and CSF averaged 25.1 +/- 6.3% (n = 3) and 63.0% (n = 1) of the maternal concentrations, respectively. CONCLUSION: This study shows limited fetal exposure after maternal administration of doxorubicin, epirubicin, vinblastine, and 4-hydroxy-cyclophosphamide. PMID- 20846714 TI - Prospective evaluation of an in vitro radiation resistance assay in locally advanced cancer of the uterine cervix: a Southwest Oncology Group Study. AB - OBJECTIVES: To investigate the feasibility of performing a fresh-tissue, in vitro radiation resistance assay (IVRRA) in a cooperative group setting and to assess the association of IVRRA results with clinical outcomes. METHODS: Women with Stages IIB-IVA carcinoma of the uterine cervix without obvious para-aortic lymphadenopathy on imaging were eligible. Primary tumor biopsies were shipped to a central testing facility where agar-based cell suspensions were exposed to 300 cGy of RT +/- cisplatin and cultured for 5 days. 3H-thymidine incorporation was used to determine percent cell inhibition (PCI) of test specimen compared to that of the untreated control. Tumors were considered to exhibit extreme radiation resistance (ERR), intermediate radiation resistance (IRR) or low radiation resistance (LRR) based on a standard data set from 39 previously studied specimens. Standardized doses of external beam radiation and intracavitary brachytherapy, when feasible, in addition to platinum-based chemotherapy were mandated. Progression-free survival (PFS) was the primary endpoint. Clinical response and overall survival (OS) were secondary endpoints. Clinical investigators were blinded to assay data and vice versa. RESULTS: Thirty-six patients were enrolled, but analysis was limited to 17 patients whose specimens were adequate for IVRRA. The median follow-up time among patients still alive at last contact was 40 months (range: 0-56 months). There was no association between IVRRA and response. In the Cox model, IRR/ERR tumors showed worse PFS [HR = 11.2 (95% CI 1.3-96, p = 0.03)] and worse OS [HR=11.7 (95% CI 1.4-99.6, p = 0.03)] compared to LRR tumors when IVRRA was performed with RT alone, but there were no associations between IVRRA and PFS or OS when cisplatin was added to the IVRRA. CONCLUSIONS: IVRRA (RT alone) results correlated with PFS and OS in this prospective trial, but follow-up trials are indicated to address feasibility and to confirm results in an expanded cohort. If confirmed, IVRRA could potentially direct molecular identification of novel targeted therapeutic approaches which might counteract radiation resistance. PMID- 20846715 TI - Randomized phase III trial of tamoxifen versus thalidomide in women with biochemical-recurrent-only epithelial ovarian, fallopian tube or primary peritoneal carcinoma after a complete response to first-line platinum/taxane chemotherapy with an evaluation of serum vascular endothelial growth factor (VEGF): A Gynecologic Oncology Group Study. AB - PURPOSE: To compare progression-free survival (PFS), overall survival (OS) and toxicities of thalidomide versus tamoxifen and to evaluate serum vascular endothelial growth factor (VEGF) in biochemical-recurrent epithelial ovarian cancer, primary peritoneal cancer or fallopian tube carcinoma (EOC/PPC/FTC). METHODS: Biochemical recurrence was defined as a rising CA-125 exceeding twice the upper limit of normal without evidence of disease as defined by RECIST 1.0 criteria. Women with FIGO stages III and IV, histologically confirmed EOC/PPC/FTC who were free of disease following first-line chemotherapy were randomized to oral thalidomide 200mg daily with escalation to a maximum of 400 mg or tamoxifen 20mg orally twice daily for up to 1 year, progression or adverse effect prohibited further treatment. VEGF was quantified by ELISA in pre and post treatment serum. RESULTS: Of the 139 women randomized, 138 were eligible. Interim analysis showed that thalidomide did not reduce the recurrence rate relative to tamoxifen, and the trial was closed. Thalidomide versus tamoxifen was associated with a similar risk of progression (HR = 1.31, 95% confidence interval [CI] = 0.93-1.85), an increased risk of death (HR = 1.76, 95% CI = 1.16-2.68) and more grades 3 and 4 toxicities (55% versus 3%). The most common grades 3 and 4 toxicities were constitutional (12%), somnolence (12%), pulmonary (9%), venous thromboembolism (VTE) (6%) and peripheral neurologic (6%) for thalidomide, with VTE (1.4%) and gastrointestinal (1.4%) for tamoxifen. Serum VEGF was not associated with clinical characteristics, treatment, PFS or OS. CONCLUSION: Thalidomide was not more effective than tamoxifen in delaying recurrence or death but was more toxic. VEGF was not prognostic in this cohort. PMID- 20846716 TI - Tomorrow I could be in trouble...but the sun will come out next year: the effect of temporal distance on adolescents' judgments of life satisfaction. AB - In a series of three studies, we examined adolescents' judgments of temporal life satisfaction (LS). We based our predictions in the notion of temporal distance influence in the level of construal of near- and distant-future events. In Study 1 we found that adolescents enhance future and present LS while devaluating past LS. Manipulating temporal distance in Study 2 and 3 and examining differences between- and within-subjects, respectively, we found that adolescents expected to be more satisfied with their life in the distant- than in the near-future. Moreover, framing LS in the near-future led adolescents to expect lower LS than they reported one week earlier. In contrast, expectations for own LS in the distant-future were not higher than self-reported LS measured one week before the experiment. The authors discuss implications for theory development and implications in the study of adolescents' LS. PMID- 20846717 TI - Capturing the peer context: the paradox of progress. AB - Adolescents lead enormously complicated social lives. Many youth find it difficult to keep track of their own relationships with friends and romantic interests. For the investigator, the task is exponentially more complex because overlapping and interlocking relationships and networks must be disentangled, dissected, and diagrammed. This special issue contains some important new findings about peers, but it is equally noteworthy because it illustrates several significant methodological changes in the way we do business. New ways of thinking about peers and new ways of analyzing data about peer relationships promise to simplify many aspects of our research enterprise. Pictograms occupying every bit of space on laboratory walls are rapidly becoming a thing of the past. By the same token, however, these advances have revealed the limits of our assumptions and the inadequacies of our practices, particularly when it comes to the depth and frequency of our data collection efforts. This is the paradox of progress. In this essay I will summarize some of the methodological developments highlighted in this special section and I will describe some important implications that these improvements hold for research in the future. PMID- 20846718 TI - Development of Atlantic cod (Gadus morhua) exposed to produced water during early life stages: Effects on embryos, larvae, and juvenile fish. AB - Produced water (PW) contains numerous toxic compounds of natural origin, such as dispersed oil, metals, alkylphenols (APs), and polycyclic aromatic hydrocarbons (PAHs). In addition, PW also contains many different chemicals which have been added during the oil production process. In the study described here, cod were exposed to real PW collected from an oil production platform in the North Sea. This was done in order to best recreate the most realistic field-exposure regime in which fish will be affected by a wide range of chemicals. The biological effects found in this study therefore cannot be assigned to one group of chemicals alone, but are the result of exposure to the complex chemical mixture found in real PW. Since APs are well known to cause endocrine disruption in marine organisms, we focused our chemical analysis on APs in an attempt to better understand the long-term effects of APs from PW on the biology of fish. In this study, cod were exposed to several concentrations of real PW and 17beta oestradiol (E(2)), a natural oestrogen, at different developmental stages. Cod were exposed to PW either during the embryo and early larvae stage (up to 3 months of age) or during the early juvenile stage (from 3 to 6 months of age). Results showed that, in general, APs bioconcentrate in fish tissue in a dose and developmental stage dependent manner during PW exposure. However, juveniles appeared able to effectively metabolise the short chain APs. Importantly, PW exposure had no effect on embryo survival or hatching success. However, 1% PW clearly interfered with the development of normal larval pigmentation. After hatching most of the larvae exposed to 1% PW failed to begin feeding and died of starvation. This inability to feed may be linked to the increased incidence of jaw deformities seen in these larvae. In addition, cod exposed to 1% PW, had significantly higher levels of the biomarkers vitellogenin and CYP1A in plasma and liver, respectively. No similar effects were seen in cod exposed to either 0.1% or 0.01% PW. PMID- 20846719 TI - TRPM1: a vertebrate TRP channel responsible for retinal ON bipolar function. AB - The transient receptor potential (TRP) channels affect essential functions widely in sensory systems of various species, both invertebrates and vertebrates. The channel protein encoded by the trp gene, the first identified TRP superfamily molecule, is known to mediate the Drosophila light response. A vertebrate TRP channel playing a crucial role in the visual system has not yet been discovered, although numerous studies have revealed primal functions of TRP superfamily molecules in various sensory systems other than vision. In the retina, which is the entry tissue in the vertebrate visual pathway, the transduction cation channel in ON bipolar cells has been elusive, despite intensive investigation by many researchers over a long period of time. Recent studies finally revealed that TRPM1, the first member of the melanoma-related transient receptor potential (TRPM) subfamily to be discovered, is a visual transduction channel in retinal ON bipolar cells. This review covers the significant discoveries on the physiological function and regulatory mechanism of the TRPM1 channel in retinal ON bipolar cells and the association of human TRPM1 mutations with congenital stationary night blindness. PMID- 20846720 TI - Novel pathway for an old neurotransmitter: dopamine-induced neuronal calcium signalling via receptor-independent mechanisms. AB - Dopamine is one of the key neurotransmitters in the central nervous system and plays an important role in physiological processes, as well as in the development of many diseases. Here we report a receptor-independent signalling pathway induced by dopamine in CNS neurons. In cultured neurons from midbrain, cortex and hippocampus, dopamine uptake via dopamine or monoamine transporters induces plasmalemmal membrane depolarization, leading to opening of voltage gated calcium channels and a cytosolic calcium signal. This dopamine-induced calcium signal is unaffected by inhibition of the known dopamine receptors. In anaesthetized rats, application of dopamine in the presence of dopamine receptor antagonists to brainstem structures controlling cardiovascular activity results in an increase in heart rate, arterial blood pressure and sympathetic nerve activity. These data identify a novel dopamine-induced signalling pathway in CNS neurons which may have an important functional role in the central mechanisms controlling complex behaviours. PMID- 20846721 TI - Paraneoplastic psoriasiform dermatitis preceding the diagnosis of chronic myelogenous leukemia. PMID- 20846722 TI - Follow-up skeletal surveys for suspected non-accidental trauma: can a more limited survey be performed without compromising diagnostic information? AB - OBJECTIVE: Follow-up skeletal surveys have been shown to improve the rate of fracture detection in suspected cases of non-accidental trauma (NAT). As these studies are performed in a particularly radiosensitive population, it is important to evaluate if all of the (approximately 20) radiographs obtained at repeat skeletal survey are clinically useful. Our goal was to evaluate if certain radiographs can be excluded at follow-up skeletal survey without compromising the clinical efficacy. METHODS: This retrospective study included 22 cases of suspected NAT (average age 3.8 months, range 0.7-15 months) in which patients received both initial and follow-up bone surveys. The follow-up survey was performed an average of 16.7 days (range 11-29 days) after the initial survey. Radiographs were reviewed by 2 pediatric radiologists, with discrepancies resolved by consensus. In addition, we combined our data with data from all known previously published reports of follow-up skeletal surveys for NAT for meta analysis. RESULTS: A total of 36 fractures were found on the initial bone survey in 16/22 patients (73%). Six patients had no fractures detected at initial survey. Follow-up bone surveys demonstrated an additional 3 fractures (2 extremities and 1 rib) in 3/22 cases (14%); 1 was in a patient whose initial survey was negative. No additional fractures in the skull, spine, pelvis, feet, or hands were detected in any case. In combination with patients reported in the literature (194 patients total) no new fracture of the skull, spine, pelvis, or hands was detected at follow-up survey. The skull, spine and pelvis radiographs are the highest dose-exposure studies of the skeletal survey. CONCLUSION AND PRACTICE IMPLICATIONS: If no injury is detected or suspected in the pelvis, spine, hands, or skull at initial bone survey for suspected NAT, a limited follow up skeletal survey which excludes the pelvis, lateral spine, hands, and skull should be considered to limit radiation exposure without limiting diagnostic information. PMID- 20846723 TI - Effects of long-term cadmium exposure on growth and metabolomic profile of tomato plants. AB - The response of tomato plants to long-term cadmium exposure was evaluated after a 90-days long culture in hydroponic conditions (0, 20, and 100 MUM CdCl(2)). Cadmium preferentially accumulated in roots, and to a lower extent in upper parts of plants. Absolute quantification of 28 metabolites was obtained through (1)H NMR, HPLC-PDA, and colorimetric methods. The principal component analysis showed a clear separation between control and Cd treated samples. Proline and total ascorbate amounts were reduced in Cd-treated leaves, whereas alpha-tocopherol, asparagine, and tyrosine accumulation increased, principally in 100 MUM Cd treated leaves. Carotenoid and chlorophyll contents decreased only in 100 MUM Cd mature-leaves, which correlate with a reduced expression of genes essential for isoprenoid and carotenoid accumulations. Our results show that tomato plants acclimatize during long-term exposure to 20 MUM Cd. On the contrary, 100MUM Cd treatment results in drastic physiological and metabolic perturbations leading to plant growth limitation and fruit set abortion. PMID- 20846724 TI - The AcrySof Toric intraocular lens in subjects with cataracts and corneal astigmatism: a randomized, subject-masked, parallel-group, 1-year study. AB - PURPOSE: To compare the AcrySof Toric intraocular lens (IOL) and an AcrySof spherical control IOL and to investigate rotational stability of the AcrySof Toric IOL (Alcon Laboratories, Inc., Fort Worth, TX) in subjects with cataracts and preexisting corneal astigmatism. DESIGN: Randomized, subject-masked, parallel group, multicenter, 1-year study. PARTICIPANTS: We included 517 subjects (Toric IOL, n = 256; control IOL, n = 261). METHODS: Unilateral implantation of an AcrySof Toric or AcrySof spherical control IOL (spherical powers, 12.00-25.00 diopters [D]; cylinder powers 1.50, 2.25, or 3.00 D for corneal astigmatism correction of 0.75 to < 1.50, >= 1.50 to <2.00, and >= 2.00 D with no upper limit, respectively). No limbal relaxing incisions were permitted. MAIN OUTCOME MEASURES: Visual acuity outcomes, IOL position, patient-reported spectacle use, and safety. RESULTS: One year postoperatively, best spectacle-corrected distance visual acuity of >= 20/20 was 77.7% (Toric IOL) versus 69.2% (control IOL). Uncorrected distance visual acuity of 20/20 or better was 40.7% (Toric IOL) versus 19.4% (control IOL; P<0.05). Mean absolute residual refractive cylinder was 0.59 D (Toric IOL) versus 1.22 D (control IOL; P<0.0001). Mean rotation was < 4 degrees (range, 0 degrees -20 degrees ) for the Toric IOL. Six-month spectacle freedom was 61.0% (Toric IOL) and 36.4% (control IOL; P < 0.0001). Complications in both groups were few and were as would be expected with cataract surgery. CONCLUSIONS: Favorable efficacy, rotational stability, distance vision spectacle freedom, and safety results support the use of the AcrySof Toric IOL for patients with cataracts and corneal astigmatism. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 20846725 TI - Refining clinical judgment of treatment outcome in obsessive-compulsive disorder. AB - This research aimed to provide clinicians and investigators with optimal treatment outcome criteria for accurately predicting response and remission in both research studies and clinical practice. Data from 153 adult OCD outpatients (ages 18-79) who had participated in a treatment outcome study were examined. Signal detection analysis was conducted to compare levels of Yale-Brown Obsessive Compulsive Scale (Y-BOCS) symptom percent reductions and post treatment absolute scores with Clinical Global Impression (CGI) ratings of symptom improvement and severity. Optimal cutoff criteria were based on sensitivity, specificity and efficiency and were assessed via the Quality Receiver Operating Characteristic curve. A Y-BOCS reduction of 45% was observed to be the most efficient for predicting response in research trials, whereas a reduction of 35% may be optimal for clinical use. A 55% Y-BOCS reduction was determined to be the optimal cutoff for predicting remission in both clinical and research settings. A Y-BOCS absolute raw score of 12 or less was optimal for predicting remission in a clinical setting and a raw score of 14 or below was most favorable in research trials. This research provides the first empirical contrast of optimal outcome criteria in OCD based on differing ideals of both research and practice. PMID- 20846726 TI - Mindfulness based cognitive therapy for psychiatric disorders: a systematic review and meta-analysis. AB - Mindfulness- based Cognitive Therapy (MBCT) is a meditation program based on an integration of Cognitive behavioural therapy and Mindfulness-based stress reduction. The aim of the present work is to review and conduct a meta-analysis of the current findings about the efficacy of MBCT for psychiatric patients. A literature search was undertaken using five electronic databases and references of retrieved articles. Main findings included the following: 1) MBCT in adjunct to usual care was significantly better than usual care alone for reducing major depression (MD) relapses in patients with three or more prior depressive episodes (4 studies), 2) MBCT plus gradual discontinuation of maintenance ADs was associated to similar relapse rates at 1year as compared with continuation of maintenance antidepressants (1 study), 3) the augmentation of MBCT could be useful for reducing residual depressive symptoms in patients with MD (2 studies) and for reducing anxiety symptoms in patients with bipolar disorder in remission (1 study) and in patients with some anxiety disorders (2 studies). However, several methodological shortcomings including small sample sizes, non-randomized design of some studies and the absence of studies comparing MBCT to control groups designed to distinguish specific from non-specific effects of such practice underscore the necessity for further research. PMID- 20846727 TI - An empirical investigation of the structure of anxiety and depressive symptoms in late adolescence: cross-sectional study using the Greek version of the revised Clinical Interview Schedule. AB - Several studies in the past have examined whether the hierarchical structure of anxiety and depressive symptoms can explain the high comorbidity between them but more studies are needed from other settings and with different methods. The present study aimed to examine the structure of common anxiety and depressive symptoms in adolescents 16-18 years old attending secondary schools using the Greek version of the revised Clinical Interview Schedule (CIS-R), a fully structured psychiatric interview. A total of 2431 adolescents were interviewed with the computerized version of the CIS-R. The hierarchical structure of 12 depressive and anxiety symptoms was examined with confirmatory factor analytical methods. Four alternative models of increasing complexity were tested. The best fitting model included three first-order factors, representing the dimensions of anxiety, depression and non-specific distress respectively. A model with a higher order factor representing the broader internalizing dimension was less supported by the data. The findings of this and other studies should be taken into account in future classifications of psychiatric disorders and may have clinical practical implications. PMID- 20846728 TI - Attitudes toward schizophrenia in the general population, psychiatric staff, physicians, and psychiatrists: a web-based survey in Japan. AB - Little is known about possible differences in the attitudes toward schizophrenia between the general public and various healthcare professionals. After screening for the study enrollment, 197 subjects in the general population, 100 psychiatric staff (other than psychiatrists), 112 physicians (other than psychiatrists) and 36 psychiatrists were enrolled in a web-based survey using an Internet-based questionnaire format. To assess subjects' attitudes toward schizophrenia, we used a 13-item questionnaire created by Ucok et al. (2006), to which five items were added. These 18 items were subjected to exploratory factor analysis, which yielded three factors classified as "stigma," "underestimation of patients' abilities," and "skepticism regarding treatment." These factors were compared between the four groups using analysis of covariance (ANCOVA), controlling for potential confounders. The ANCOVA for the "stigma" factor showed that psychiatrists scored significantly lower than the other three groups. The ANCOVA for the "underestimation of patients' abilities" factor revealed that psychiatric staff scored significantly lower than the general population. The present results indicated that attitudes toward schizophrenia consist of at least three separable factors. Psychiatrists had the least negative attitudes toward schizophrenia, which was followed by the psychiatric staff, and attitudes of the general population and of physicians were equally stigmatizing. PMID- 20846729 TI - Increased expression of C5a receptor (CD88) mRNA in canine mammary tumors. AB - Mammary tumors are among the most common neoplastic conditions in dogs, and there is evidence that inflammation plays a role in the development of some tumor types in dogs. The complement system is a major participant in the inflammatory process and the complement activation component, C5a, is a potent inflammatory peptide. This study investigated the mRNA expression of the major receptor for C5a (C5aR; CD88) in histopathological samples of canine mammary tumors by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using canine-specific primers for CD88. A total of seven canine mammary tumors (four malignant carcinomas, two benign mixed mammary tumors, and one myoepithelioma) and eight normal mammary glands were analysed. All the tumor samples expressed low levels of CD88 mRNA, while none of the normal mammary tissues showed any detectable expression. These preliminary results suggest that C5a-CD88 interaction may play a contributory role in the inflammatory response associated with mammary tumor development in dogs. Further studies investigating the mechanisms behind complement activation and C5a receptor expression in canine mammary tumors are warranted. PMID- 20846731 TI - Effect of topical glucocorticoid treatment in chinchilla model of lipopolysaccharide induced otitis media with effusion. AB - OBJECTIVE: To compare the efficacy of topical treatment with three glucocorticoids in lipopolysaccharide induced otitis media with effusion (OME). METHODS: Chinchillas were divided into seven treatment groups consisting of vehicle and three glucocorticoids: dexamethasone sodium phosphate (DSP), fluticasone propionate (FP), and hydrocortisone, each at concentrations of 0.1% and 1.0%. LPS (300 MUg) was injected into the superior bullae of chinchillas to induce OME. Animals were treated with test substances at -2, 24, and 48 h relative to LPS inoculation. After 96 h, chinchillas were euthanized, samples of middle ear effusion (MEE) were collected, and temporal bones were removed for histopathological examination. Reduction of OME was evaluated by measuring MEE volume and thickness of mucosal lining for each bulla. RESULTS: One percent treatment of FP significantly reduced MEE. One percent treatment of DSP and HC significantly reduced the mucosal thickness (MT), DSP (15.0 MUM) more than HC (30.8 MUM). Treatment with 0.1% glucocorticoids did not lead to any significant reduction. CONCLUSIONS: Clearance of otitis media with effusion seems to be a class effect among glucocorticoids. DSP was the best in reducing MT. It is important to evaluate treatment with various glucocorticoids in order to discover alternative drugs for OME. PMID- 20846730 TI - Brain ingress of regulatory T cells in a murine model of HIV-1 encephalitis. AB - CD4+CD25+ regulatory T cells (Treg) transform the HIV-1 infected macrophage from a neurotoxic to a neuroprotective phenotype. This was demonstrated previously in a murine model of HIV-1 encephalitis induced by intracranial injection of HIV 1/vesicular stomatitis virus-infected bone marrow macrophages. In this report, relationships between Treg ingress of end organ tissues, notably the brain, and neuroprotection were investigated. Treg from EGFP-transgenic donor mice were expanded, labeled with indium-111, and adoptively transferred. Treg distribution was assayed by single photon emission computed tomography and immunohistochemistry. Treg readily migrated across the blood brain barrier and were retained within virus-induced neuroinflammatory sites. In non-inflamed peripheral tissues (liver and spleen) Treg were depleted. These observations demonstrate that Treg migrate to sites of inflammation where they modulate immune responses. PMID- 20846733 TI - Diagnostic value of MPO plasma levels in patients admitted for suspected myocardial infarction. AB - BACKGROUND: Besides its well-established role in atherosclerosis, myeloperoxidase (MPO) has gained attention as a prognostic indicator in cardiovascular disease. Previous studies assessed MPO retrospectively and at a single time point. The current study aimed to evaluate the prognostic information of MPO prospectively and in consecutive measurements in patients presenting with chest pain. METHODS: MPO plasma levels were determined in 274 consecutive chest pain patients admitted to the emergency room. RESULTS: A total of 100 patients (36.5%) were finally diagnosed for acute myocardial infarction (AMI). Patients with AMI had significantly higher MPO levels than patients without AMI. Importantly, MPO levels were elevated in patients finally diagnosed for AMI even when troponin I (TNI) was negative (cutoff: 0.032 ng/ml). Overall, MPO yielded a negative predictive value (NPV) of 85.5% (95% confidence interval (CI): 82.6-88.4) and a sensitivity for diagnosing AMI of 80.0% (95% CI: 75.8-84.2) compared to a NPV of 91.7% (95% CI: 89.5-94.0) and a sensitivity of 85.9% (95% CI: 82.3-89.5) for TNI. For patients with a symptom onset of <= 2 h the sensitivity of MPO increased to 95.8% (95% CI: 93.7-97.9) whereas the sensitivity of TNI dropped to 50.0% (95% CI: 44.8-55.2). The negative predictive value of MPO for this group of patients was 95.6% (95% CI: 94.0-97.3) compared to 73.3% (95% CI: 69.8-76.9) for TNI. DISCUSSION: The current data underscore the role of MPO as diagnostic marker in acute coronary disease; however the additive information derived from MPO is restricted to patients presenting in the early phase of symptom onset. PMID- 20846734 TI - Comparison of DVH parameters and loading patterns of standard loading, manual and inverse optimization for intracavitary brachytherapy on a subset of tandem/ovoid cases. AB - PURPOSE: Comparison of inverse planning with the standard clinical plan and with the manually optimized plan based on dose-volume parameters and loading patterns. MATERIALS AND METHODS: Twenty-eight patients who underwent MRI based HDR brachytherapy for cervix cancer were selected for this study. Three plans were calculated for each patient: (1) standard loading, (2) manual optimized, and (3) inverse optimized. Dosimetric outcomes from these plans were compared based on dose-volume parameters. The ratio of Total Reference Air Kerma of ovoid to tandem (TRAK(O/T)) was used to compare the loading patterns. RESULTS: The volume of HR CTV ranged from 9-68 cc with a mean of 41(+/-16.2) cc. Mean V100 for standard, manual optimized and inverse plans was found to be not significant (p=0.35, 0.38, 0.4). Dose to bladder (7.8+/-1.6 Gy) and sigmoid (5.6+/-1.4 Gy) was high for standard plans; Manual optimization reduced the dose to bladder (7.1+/-1.7 Gy p=0.006) and sigmoid (4.5+/-1.0 Gy p=0.005) without compromising the HR CTV coverage. The inverse plan resulted in a significant reduction to bladder dose (6.5+/-1.4 Gy, p=0.002). TRAK was found to be 0.49(+/-0.02), 0.44(+/-0.04) and 0.40(+/-0.04) cGy m(-2) for the standard loading, manual optimized and inverse plans, respectively. It was observed that TRAK(O/T) was 0.82(+/-0.05), 1.7(+/ 1.04) and 1.41(+/-0.93) for standard loading, manual optimized and inverse plans, respectively, while this ratio was 1 for the traditional loading pattern. CONCLUSIONS: Inverse planning offers good sparing of critical structures without compromising the target coverage. The average loading pattern of the whole patient cohort deviates from the standard Fletcher loading pattern. PMID- 20846735 TI - Magnetic resonance imaging at 3.0T for submandibular gland sparing radiotherapy. AB - PURPOSE: Besides sparing the parotid gland, sparing the submandibular gland is considered to be important in preventing xerostomia in head-and-neck cancer patients. Delineation of the submandibular gland at CT, and even on T(1)- and T(2)-weighted MR images, is difficult, due to low contrast with the surrounding tissues. MR sialography might be used for delineation. METHODS AND MATERIALS: Sixteen oropharyngeal cancer patients received a CT and MRI exam as part of the standard treatment imaging protocol. Patients were scanned in their five-point RT immobilization mask. The MRI exam included T(1)- and T(2)-weighted MRI scans and an MR sialography scan. Thirty submandibular glands were delineated on only CT, on the combined CT and T(1)- and T(2)-weighted MRI scans and on all MR images. A Wilcoxon signed-rank test was performed to test if the delineated volumes were significantly different. RESULTS: The delineated volume of the submandibular gland was 7.3mL in the CT-delineation, 7.1mL in the CT/MRI-delineation and 8.1mL in the MRI-delineation. The MRI-delineation was significantly larger than the other delineations (p<0.001). The differences were mainly located in the cranial direction. CONCLUSION: The delineation of the submandibular gland was improved in the cranial direction by using T(1)- and T(2)-weighted MRI and MR sialography, compared to the other delineations. PMID- 20846732 TI - Targeting DNA methylation for epigenetic therapy. AB - Patterns of DNA methylation are established during embryonic development and faithfully copied through somatic cell divisions. Based on current understanding of DNA methylation and other interrelated epigenetic modifications, a comprehensive view of the 'epigenetic landscape' and cancer epigenome is evolving. The cancer methylome is highly disrupted, making DNA methylation an excellent target for anticancer therapies. During the last few decades, an increasing number of drugs targeting DNA methylation have been developed to increase efficacy and stability and to decrease toxicity. The earliest and the most successful epigenetic drug to date, 5-Azacytidine, is currently recommended as the first-line treatment of high-risk myelodysplastic syndromes (MDS). Encouraging results from clinical trials have prompted further efforts to elucidate epigenetic alterations in cancer, and to subsequently develop new epigenetic therapies. This review delineates the latest cancer epigenetic models, the recent discovery of hypomethylation agents as well as their application in the clinic. PMID- 20846736 TI - Reducing radiation exposure to patients from kV-CBCT imaging. AB - BACKGROUND AND PURPOSE: This study explores methods to reduce dose due to kV-CBCT imaging for patients undergoing radiation therapy. MATERIAL AND METHODS: Doses resulting from kV-CBCT scans were calculated using Monte Carlo techniques and were analyzed using dose-volume histograms. Patients were modeled as were CBCT acquisitions using both 360 degrees and 200 degrees gantry rotations. The effects of using the half fan bow-tie and the full fan bow-tie filters were examined. RESULTS: Doses for OBI 1.3 are 15 times (head), 5 times (thorax) and 2 times (Pelvis) larger than the current OBI 1.4. When using 200 degrees scans, the doses to eyes and cord are 0.2 (or 0.65) cGy and 0.35 (or 0.2) cGy when rotating the X-ray source underneath (or above) the patient, respectively. The 360 degrees Pelvis scan dose is 1-2 cGy. The rectum dose is 1.1 (or 2.8) cGy when rotating the source above (or below) the patient with the 200 degrees Pelvis scan. The dose increases up to two times as the patient size decreases. CONCLUSIONS: The dose can be minimized by reducing the scan length, the exposure settings, by selecting the gantry rotation angles, and by using the full fan bow tie whenever possible. PMID- 20846737 TI - Concurrent and adjuvant docetaxel with three-dimensional conformal radiation therapy plus androgen deprivation for high-risk prostate cancer: preliminary results of a multicentre phase II trial. AB - BACKGROUND AND PURPOSE: We evaluate the feasibility of concomitant and adjuvant docetaxel combined with three-dimensional conformal radiotherapy (3D-CRT) and androgen deprivation in high-risk prostate carcinomas. METHODS: Fifty men with high-risk localized prostate cancer (16), locally advanced (28) or very high-risk prostate cancer (6) were included. Seventy Gy were delivered on prostate and seminal vesicles in 35 fractions, concurrently with weekly docetaxel (20mg/m(2)). Three weeks after the completion of 3D-CRT, docetaxel was given for 3 cycles (60mg/m(2)), every 3 weeks. Patients had to receive LHRH agonist during 3 years. RESULTS: The intent to treat analysis shows that four patients out of 15 stopped prematurely the chemotherapy due to grade 3-4 acute toxicity. In the per protocol analysis, 46 patients completed a full-dose chemoradiation regimen representing 413 cycles: five patients experienced a grade 3 toxicity, and 15 patients experienced a grade 2 toxicity. With a median follow-up of 54 months, the 5-year clinical disease-free survival was 66.72% and the 5-year survival was 92.15%. CONCLUSIONS: 3D-CRT with androgen deprivation and concurrent weekly docetaxel, followed by three cycles of adjuvant docetaxel may be considered as feasible in high-risk prostate cancer and deserved to be evaluated in a phase III randomized trial. PMID- 20846738 TI - Differences between experts and novices in kinematics and accuracy of golf putting. AB - In this study, golf-putting movements were examined under three goal distances (short, 1.7m; middle, 3.25m; long, 6m), two different putter weights (500g, 750g), and two levels of expertise (5 experts, 5 novices). The study's aim was to identify differences in kinematics and accuracy between expert and novice golfers. The results demonstrated that experts achieved higher accuracy with lower impact velocity than novices. In addition, while novices showed symmetrical movements, experts exhibited asymmetrical movements, which were achieved by modulating their movement time and amplitude differently from novices. These results demonstrated differences in relative timing, relative amplitude and velocity, but no difference in time-to-contact between novices and experts. The results reaffirmed the role of prior learning and supported the hypothesis of Manoel and Connolly (1995) that motor learning is a hierarchical process organized at both macroscopic and microscopic levels. PMID- 20846739 TI - Medical technology procurement in Europe: a cross-country comparison of current practice and policy. AB - Procurement policy can influence the diffusion of medical devices into national health systems, but limited comparative evidence exists on how countries procure such technologies. This paper discusses the procurement of select medical devices across five countries (England, France, Germany, Italy, and Spain) based on a review of published and grey literature and policy documents, as well as expert interviews. All countries have introduced various regulatory or policy measures that implicitly or explicitly influence device procurement, from lists of devices for purchase to changes in financing mechanisms. There has also been movement toward more centralized procurement with the introduction of purchasing groups or consortiums, notably in England, France, Germany, and Italy. While a number of stakeholder groups are involved in purchasing activities, a greater, more formalized role for physicians and governments is needed to ensure that technologies procured best meet patient needs and align with national health care priorities and other sectoral objectives. A general theme across all national procurement systems was a focus on cost-containment, but like other areas of technology policy (e.g., coverage), basing purchasing decisions on a broader range of criteria, such as quality and health outcomes, might better allow governments to achieve value for money and support patient access to beneficial innovations. More research is needed, however, to substantiate the role and influence of procurement on balancing the adoption and affordability of medical technologies. PMID- 20846740 TI - SOA-based digital library services and composition in biomedical applications. AB - Carefully collected, high-quality data are crucial in biomedical visualization, and it is important that the user community has ready access to both this data and the high-performance computing resources needed by the complex, computational algorithms that will process it. Biological researchers generally require data, tools and algorithms from multiple providers to achieve their goals. This paper illustrates our response to the problems that result from this. The Living Human Digital Library (LHDL) project presented in this paper has taken advantage of Web Services to build a biomedical digital library infrastructure that allows clinicians and researchers not only to preserve, trace and share data resources, but also to collaborate at the data-processing level. PMID- 20846741 TI - Image processing and machine learning for fully automated probabilistic evaluation of medical images. AB - The paper presents results of our long-term study on using image processing and data mining methods in a medical imaging. Since evaluation of modern medical images is becoming increasingly complex, advanced analytical and decision support tools are involved in integration of partial diagnostic results. Such partial results, frequently obtained from tests with substantial imperfections, are integrated into ultimate diagnostic conclusion about the probability of disease for a given patient. We study various topics such as improving the predictive power of clinical tests by utilizing pre-test and post-test probabilities, texture representation, multi-resolution feature extraction, feature construction and data mining algorithms that significantly outperform medical practice. Our long-term study reveals three significant milestones. The first improvement was achieved by significantly increasing post-test diagnostic probabilities with respect to expert physicians. The second, even more significant improvement utilizes multi-resolution image parametrization. Machine learning methods in conjunction with the feature subset selection on these parameters significantly improve diagnostic performance. However, further feature construction with the principle component analysis on these features elevates results to an even higher accuracy level that represents the third milestone. With the proposed approach clinical results are significantly improved throughout the study. The most significant result of our study is improvement in the diagnostic power of the whole diagnostic process. Our compound approach aids, but does not replace, the physician's judgment and may assist in decisions on cost effectiveness of tests. PMID- 20846742 TI - In vivo microscopic imaging of the bronchial mucosa using an endo-cytoscopy system. AB - OBJECTIVES: We investigated the capabilities of an endo-cytoscopy system (ECS) that enables microscopic imaging of the tracheobronchial tree during bronchoscopy, including normal bronchial epithelium, dysplastic mucosa and squamous cell carcinoma. METHODS: The newly developed ECS has a 3.2 mm diameter that can be passed through the 4.2 mm working channel of a mother endoscope for insertion of the ECS. It has a high magnification of 570* on a 17 in. video monitor. Twenty-two patients (7 squamous cell carcinoma, 11 squamous dysplasia and 4 after PDT therapies) were underwent white light, NBI light and AFI bronchoscopy. Both abnormal areas of interest and normal bronchial mucosa were stained with 0.5% methylene blue and examined with ECS at high magnification (570*). Histological examinations using haematoxylin and eosin staining were made of biopsied specimens. Analyzed ECS images were compared with the corresponding histological examinations. RESULTS: In normal bronchial mucosa, ciliated columnar epithelial cells were visible. In bronchial squamous dysplasia, superficial cells with abundant cytoplasm were arranged regularly. In squamous cell carcinoma, large, polymorphic tumor cells showed increased cellular densities with irregular stratified patterns. These ECS images corresponded well with the light microscopic examination of conventional histology. CONCLUSION: ECS was useful for the discrimination between normal bronchial epithelial cells and dysplastic cells or malignant cells during bronchoscopy in real time. This novel technology has an excellent potential to provide in vivo diagnosis during bronchoscopic examinations. PMID- 20846743 TI - Structure and function of native and refolded peridinin-chlorophyll-proteins from dinoflagellates. AB - Peridinin-chlorophyll a-proteins are a class of light-harvesting proteins only found in photosynthetic dinoflagellates. Due to their exceptional stability they are an excellent model system to study carotenoid to chlorophyll energy transfer. We were able to solve structures of these complexes at near atomic resolution, allowing the detailed discussion of pigment-pigment and pigment-protein interactions. Using a refolding system, we also determined structures of complexes with mutated apoproteins and modified pigment compositions. Here we summarize the current understanding of PCP structures, with an emphasis on how the basic dimeric structure may be modified in the oligomeric state of these complexes. PMID- 20846744 TI - [Susac syndrome: variable onset modes and disease courses: two case reports]. AB - INTRODUCTION: Susac syndrome is a rare microangiopathy of unknown etiology, which involves the clinical triad of encephalopathy, visual loss, and hearing loss. Several onset and progression patterns are possible. OBSERVATION: Case 1: a 43 year-old woman developed subacute encephalopathy, which had not been diagnosed and had been evolving for 2 months, as well as left sensorineural hearing loss. The fundus exam found central artery branch occlusion in the left retina. The treatment was based on corticosteroids combined with cyclophosphamide and immunoglobulins. Angiographic monitoring revealed persistent asymptomatic arterial alterations despite positive neurological progression. Case 2: a 27-year old woman presented visual loss in the right eye after recurrent neurological episodes. The triad was completed by deafness in the right ear. Treatment with corticosteroids led to favorable neurological progression and stabilized the ophthalmologic symptoms. DISCUSSION: This syndrome preferentially affects young women. The nearly constant neurological symptoms can differ. Branch occlusions are frequently bilateral and often come with the appearance of vasculitis. Deafness is bilateral, asymmetrical, and of endocochlear origin. Brain MRI shows lesions of the corpus callosum that are distinctive of the syndrome. The disease mainly evolves in a monocyclic way, self-limited in time, and it rarely becomes chronic. Treatment, which has not been codified to date, is based on corticosteroids and, in severe cases, immunosuppressive drugs. Other therapies have not proved to be effective. CONCLUSION: The diagnosis is based on the triad of neurological, ophthalmic, and ENT damage, but sometimes it can be difficult to formulate because of the chronology of symptom onset. Neurological damage, the first manifestation, will help make therapeutic decisions. PMID- 20846745 TI - [Albers-Schonberg's disease with ocular manifestation]. AB - Albers-Schonberg's disease is a rare disease (one case in 100,000 inhabitants), asymptomatic in the majority of cases. It belongs to the four clearly individualized forms of human osteopetrosis and has an autosomal dominant transmission. It induces generalized osteosclerosis, and most symptoms result from complications such as fractures following mild injury, compression of cranial nerves, especially the optic nerve, by stenosis of extracranial ostia, but also osteomyelitis of the lower maxilla. The treatment of Albers-Schonberg's disease is disappointing and only symptomatic, although the responsible genetic anomaly was recently identified. We report here the case of a 54-year-old woman, whose diagnosis of the disease has been known since adolescence, who presented with unilateral loss of vision and perimetric deficit due to papilla edema resulting from stenosis of the optic canal and benign intracranial hypertension. PMID- 20846746 TI - Assessment of horizontal laminar air flow instrument table for additional ultraclean space during surgery. AB - The area in a vertical ultraclean laminar air flow (LAF) theatre is usually too small to accommodate all the equipment needed for major surgery. We investigated the addition of an instrument table supplied with fixed ultraclean LAF and placed alongside the existing main LAF unit, to determine its physical and bacteriological effect on the main unit. In phase 1, with two investigators but without a patient, smoke tests showed no intrusion of air from the table into the main unit and particle counts did not show any adverse effect on the main LAF unit. In phase 2, during patients undergoing two total knee replacements, the LAF table and a table without LAF were placed alongside the main LAF unit. The tables were subjected to the activity of an extra operating room (OR) nurse working from inside the main LAF vigorously simulating handling of instruments. During this activity, the >5MUm particle counts were 275/m(3) at the instrument table with LAF and 8550/m(3) at the table without LAF (P<0.0001). Also, without the OR nurse activity, the particle counts, just inside the main unit and adjacent to the LAF table, were significantly reduced (P<0.03-0.003). Sedimentation plates on the LAF table and in the main unit registered 22 and 25cfu/m(2)/h respectively compared with 45cfu/m(2)/h at the instrument table without LAF. In conclusion, the results from the smoke tests, particle counts and bacteriological evaluation showed that the additional instrument table supplied with LAF is efficient and can be safely used as an extension additional to a main OR LAF unit. PMID- 20846747 TI - Risk factors associated with mupirocin resistance in meticillin-resistant Staphylococcus aureus. AB - Implementation of meticillin-resistant Staphylococcus aureus (MRSA) decolonisation programmes has been increasing and the emergence of mupirocin resistance has been reported. However, the patient-level risk factors associated with mupirocin resistance are not clear. In this study, independent predictors of mupirocin resistance in MRSA among Providence Veterans Affairs Medical Center patients with MRSA-positive culture dates between 1 July 2004 and 30 June 2008 were identified using a frequency-matched case-control study. Forty cases (mupirocin-resistant) were matched on culture date quarter and year to 270 controls (mupirocin-susceptible). The adjusted conditional logistic regression model identified three significant independent predictors associated with mupirocin resistance in MRSA: (1) exposure to mupirocin in the year prior to the culture date [odds ratio (OR): 9.84; 95% confidence interval (CI): 2.93-33.09]; (2) Pseudomonas aeruginosa infection in the year before the culture-related admission (4.85; 1.20-19.61); and (3) cefepime use in the year prior to culture (2.80; 1.03-7.58). In sensitivity analyses, previous mupirocin exposure was associated with low-level [minimum inhibitory concentration (MIC) 8-128mg/L; 23 cases, 202 controls; OR: 6.32; 95% CI: 1.58-25.33] and high-level (MIC >=256mg/L; 17 cases, 151 controls; OR: 11.18; 95% CI: 1.89-66.30) mupirocin resistance. To our knowledge, this is the first case-control study to reveal a strong association between previous mupirocin exposure and subsequent mupirocin resistance in MRSA, with demonstrated robustness in low- and high-level mupirocin resistance. Mupirocin susceptibility monitoring is critical for facilities instituting decolonisation with mupirocin as increased use may reduce effectiveness through resistance. PMID- 20846748 TI - [Urinary incontinence]. PMID- 20846751 TI - [Vitamin D levels in the elderly]. PMID- 20846750 TI - [Usefulness of a geriatric intervention program in the improvement of drug treatment for institutionalised patients]. AB - OBEJECTIVES: To determine the prevalence of polypharmacy, and inadequate or suboptimal prescriptions. To analyse the impact of a geriatric intervention program on the optimisation and rationalisation of the use of drugs in institutionalised patients. MATERIAL AND METHODS: A prospective study on a cohort of 21 sheltered subjects. VARIABLES: Drug prescription, inadequate prescription according to "Screening Tool for Older Person's Prescriptions" (STOPP) criteria and suboptimal prescriptions according to "Screening Tool to Alert doctors to Right Treatment" (START) criteria. The intervention was based on analysing treatments and medication issues, correlate treatments to functional and mental situation, together with life expectancy, determine efficient and safe drugs, prescribe generic drugs, detect and avoid polymedication, inadequate and suboptimal prescriptions. RESULTS: Twenty one subjects were include in the study,(mean age 80.43+/-8.84 years old, with 57.1% women, 76.86+/-27.76 Barthel and 14.52+/-7.73 MMSE). On admittance, the number of drugs was 6.29+/-3.48 (generics on a 20.23% ratio), 14.4% consumed 9 or more, 71.4% complied with any STOPP criteria and 52.4% complied with any START criteria. After the intervention, the number of drugs was 4.9+/-3.03 (generics on a 61.78 % ratio), 14.3% complied with any STOPP criteria and 4.8% complied with any START criteria. CONCLUSIONS: Polymedication, inadequate prescription and suboptimal prescription are frequent issues in residential and nursing environment. For our study population in an intervention program based upon geriatric assessment and the rationalisation on drug use, the drug consumption as well as inadequate and suboptimal prescription has reduced, along with increasing the use of generic drugs. PMID- 20846752 TI - [New tools for psychological intervention with the elderly: the third generation of behavioural therapies]. PMID- 20846753 TI - [Usefulness of procalcitonin and C-reactive protein in community-acquired pneumonia in the emergency department]. PMID- 20846754 TI - Prudent use of antimicrobial agents: revisiting concepts and estimating perspectives in a global world. PMID- 20846755 TI - [Anaerobic bacteraemias and treatment]. PMID- 20846756 TI - [Evaluation of hand hygiene compliance in a Primary Health Care area of Madrid]. AB - INTRODUCTION: Hand hygiene is the most effective measure for preventing infections related to healthcare. This study aims to evaluate the Hand hygiene compliance in Primary Health Care. METHODS: A cross-sectional study was carried out, collecting socio-demographic data and the hand hygiene compliance from 198 Primary Health Care workers. Their hand hygiene compliance was evaluated according to WHO criteria. RESULTS: The level of hand hygiene compliance was 8.1% (95% CI 6.2-10.1). Employment experience of over 20 years was significantly associated with low levels of compliance. CONCLUSION: Primary Health Care workers have a low hand hygiene compliance. Training programs need to be introduced to increase compliance and facilitate access to hydro-alcoholic solutions. PMID- 20846757 TI - [Achromobacter xylosoxidans colonisation in bronchiectasis]. PMID- 20846758 TI - Synthesis and antitumor activity of novel 6-aryl and 6-alkylpyrazolo[3,4 d]pyrimidin-4-one derivatives. AB - A series of new 6-arylpyrazolo[3,4-d]pyrimidin-4-ones and 6-alkylpyrazolo[3,4 d]pyrimidin-4-ones were synthesized. Some of the newly synthesized compounds were tested in vitro on human colon tumor cell line (HCT116). Most of the test compounds exploited potent antitumor activity, especially compound 10a which displayed the highest activity among the test compounds with IC(50) equal to 0.47 MUg/mL. PMID- 20846759 TI - Synthesis and cytotoxic evaluation of 1-carboxamide and 1-amino side chain substituted beta-carbolines. AB - The condensation of alkylenediamine with ethyl beta-carboline-1-carboxylate and 1 bromo-beta-carboline gave beta-carboline-1-carboxamides and 1-amino-beta carbolines, respectively. Some of these beta-carbolines were active against a panel of human tumor cell lines, and 1-amino derivatives were more potent than their 1-carboxamide congeners. In particular, among the 1-amino-beta-carbolines, the N(9)-arylated alkyl substituted beta-carbolines exhibited the most interesting cytotoxic activities with IC(50) value of lower than 20 MUM. The preliminary structure-activity relationships (SARs) analysis suggested that (1) 1 amino substituents were the advisable pharmacophoric group for enhanced cytotoxic activities; (2) the introduction of appropriate arylated alkyl groups into position-9 of beta-carboline facilitated their cytotoxic potencies. PMID- 20846760 TI - Synthesis and biological evaluation of 2-phenylthiazole-4-carboxamide derivatives as anticancer agents. AB - A series of substituted 2-phenylthiazole-4-carboxamide derivatives were synthesized as potential cytotoxic agents and evaluated against three human cancer cell lines including T47D (Breast cancer), Caco-2 (Colorectal cancer) and HT-29 (Colon cancer). The SAR of the arylacetamido pendent connected to the para position of 2-phenylthiazole were explored. It was found that substitution at the 4-position by a methoxy group led to improvement of activity against Caco-2 cells while 2-methoxy substituent could maintain the high activity against HT-29 and T47D cell lines. Also, 3-fluoro analog showed good cytotoxic activity profile against all cell lines with IC(50) values less than 10 MUg/mL. PMID- 20846761 TI - Structural modifications on the phenazine N,N'-dioxide-scaffold looking for new selective hypoxic cytotoxins. AB - We have identified phenazine 5,10-dioxides as prodrugs for antitumour therapy that undergo hypoxic-selective bioreduction to form cytotoxic species. Here, we investigated some structural modifications in order to find new selective hypoxic cytotoxins and to establish the structural requirements for adequate activity. Three different chemical-series were prepared and the clonogenic survival of V79 cells on aerobic and anaerobic conditions was determined. Electrochemical- and DNA-interaction studies were done for the most relevant derivatives. The new fluoro-derivative 7-fluoro-2-aminophenazine 5,10-dioxide displayed selective toxicity towards hypoxic V79 cells having adequate hypoxic cytotoxicity ratio (HCR=6.8) and being the most potent hypoxic cytotoxins (P=2.5 MUM) described for this family of bioreductive agents. The reduction potential of the N-oxide moiety in this new fluoro-derivative was in the range for adequate bioreduction property. According to the fluorescence studies, the DNA-interaction mechanism was especially operative in the phenazine drugs more than in the corresponding prodrugs, phenazine dioxides. PMID- 20846762 TI - [Use of positron emission tomography in sarcoidosis]. AB - FDG-PET, now hybrid positron emission tomography/computed tomography (PET-CT), has become an established diagnostic tool in oncology. Fluorodesoxyglucose ((18)F FDG) is not specific for malignant lesions, as uptake of the tracer depends on its accumulation in cells with an increased glucose metabolism as it is also the case in infectious and inflammatory lesions, like sarcoidosis. Thus, FDG-PET has been proposed for internal medicine indications, one of whom is sarcoidosis. The main characteristics of FDG-PET are its better sensitivity compared to (67)Ga scintigraphy and its ability to be used as an earlier marker of therapeutic response as compared with anatomy-based and conventional scintigraphic imaging. However, FDG-PET should be used in atypical or advanced stage of the disease. Future prospective studies should be awaited before integrating FDG-PET in clinical routine for treatment outcome and disease activity assessment in sarcoidosis. New radiopharmaceutical probes are under development and will improve the performance of PET. PMID- 20846763 TI - [Diffuse alopecia]. PMID- 20846764 TI - [The glycopeptides: stop or else?]. PMID- 20846765 TI - The relationship between lower-extremity stress fractures and the ground reaction force: a systematic review. AB - BACKGROUND: lower-limb stress fracture is one of the most common types of running injuries. There have been several studies focusing on the association between stress fractures and biomechanical factors. In the current study, the ground reaction force and loading rate are examined. There is disagreement in the literature about whether the history of stress fractures is associated with ground reaction forces (either higher or lower than control), or with loading rates. METHODS: a systematic review of the literature was conducted on the relationship between the history of tibial and/or metatarsal stress fracture and the magnitude of the ground reaction force and loading rate. Fixed-effect meta analysis techniques were applied to determine whether or not the ground reaction force and/or loading rate are different between the stress fracture and control groups. FINDINGS: thirteen articles were identified through a systematic search of the literature. About 54% of these articles reported significantly different vertical ground reaction force and/or loading rate between the stress fracture and control groups. Other studies (~46%) did not observe any significant difference between the two groups. Meta-analysis results showed no significant differences between the ground reaction force of the lower-limb stress fracture and control groups (P>0.05). However, significant differences were observed for the average and instantaneous vertical loading rates (P<0.05). INTERPRETATION: the currently available data does not support the hypothesis that there is a significant difference between the ground reaction force of subjects experiencing lower-limb stress fracture and control groups. Instead, the vertical loading rate was found to be significantly different between the two groups. PMID- 20846766 TI - Mechanisms of rotator cuff tendinopathy: intrinsic, extrinsic, or both? AB - The etiology of rotator cuff tendinopathy is multi-factorial, and has been attributed to both extrinsic and intrinsic mechanisms. Extrinsic factors that encroach upon the subacromial space and contribute to bursal side compression of the rotator cuff tendons include anatomical variants of the acromion, alterations in scapular or humeral kinematics, postural abnormalities, rotator cuff and scapular muscle performance deficits, and decreased extensibility of pectoralis minor or posterior shoulder. A unique extrinsic mechanism, internal impingement, is attributed to compression of the posterior articular surface of the tendons between the humeral head and glenoid and is not related to subacromial space narrowing. Intrinsic factors that contribute to rotator cuff tendon degradation with tensile/shear overload include alterations in biology, mechanical properties, morphology, and vascularity. The varied nature of these mechanisms indicates that rotator cuff tendinopathy is not a homogenous entity, and thus may require different treatment interventions. Treatment aimed at addressing mechanistic factors appears to be beneficial for patients with rotator cuff tendinopathy, however, not for all patients. Classification of rotator cuff tendinopathy into subgroups based on underlying mechanism may improve treatment outcomes. PMID- 20846767 TI - Surface electromyography activity of upper limb muscle during wheelchair propulsion: Influence of wheelchair configuration. AB - BACKGROUND: Biomechanical studies have linked handrim wheelchair propulsion with a prevalence of upper limb musculoskeletal disorders. The purpose of this study was to record upper limb muscle recruitment patterns using surface electromyography during wheelchair propulsion. Recordings were made for various wheelchair configurations to understand the effect of wheelchair configuration on muscle recruitment. METHODS: Ten paraplegic and ten able-bodied subjects propelled a test wheelchair on a roller ergometer system at a comfortable speed. Twelve wheelchair configurations were tested. Upper limb surface electromyography and kinematics were recorded for each configuration. Based on the hand position relative to the handrim, the propulsion cycle was divided into three phases to explain the activation patterns. FINDINGS: Compared to the able-bodied subjects, the paraplegic subjects presented higher activation. This is the case for all muscles in the early push phase, for the triceps brachii, pectoralis major and latissimus dorsi in the late push phase and for the trapezius, triceps brachii and latissimus dorsi during recovery. During early push, activation of nearly all muscles was affected by the axle position, where as seat height only affected biceps brachii and pectoralis major activation. During late push, the deltoid anterior was affected by axle position and the biceps brachii by seat height. During recovery, the trapezius was affected by axle position, the deltoid posterior by seat height and the biceps brachii by both. INTERPRETATION: Upper limb muscle recruitment differences highlight that future studies on wheelchair propulsion should only be done with wheelchair experienced paraplegic subjects. Furthermore, this study provides indications on how muscle recruitment is affected by wheelchair configuration. PMID- 20846768 TI - Social venues that protect against and promote HIV risk for young men in Dar es Salaam, Tanzania. AB - Developing effective place-based health interventions requires understanding of the dynamic between place and health. The therapeutic landscape framework explains how place-based social processes and physical geography interact and influence health behavior. This study applied this framework to examine how venues, or social gathering places, influenced HIV risk behavior among young, urban men in Tanzania. Eighty-three public venues where men aged 15-19 met new sexual partners were identified by community informants in one city ward. The majority (86%) of the venues were called 'camps', social gathering places that had formal leaders and members. Observations were conducted at 23 camps and in depth interviews were conducted with 36 camp members and 10 camp leaders in 15 purposively selected camps. Geographic and social features of camps were examined to understand their contributions to men's behaviors. Camps were characterized by a geographic space claimed by members, a unique name and a democratic system of leadership and governance. Members were mostly men and socialized daily at their camp. They reported strong social bonds and engaging in health-promoting activities such as playing sports and generating income. Members also engaged in HIV risk behaviors, such as meeting new sexual partners and having sex in or around the camp at night. Some members promoted concurrent sexual partnerships with their friends and resisted camp leaders' efforts to change their sexual risk behavior. We conclude that camps are strategic venues for HIV prevention programs for young Tanzanian men. They served as both protective and risk landscapes, illustrating three domains of the therapeutic landscape framework: the built environment; identities of landscape occupants; and sites for collective efficacy. The framework and data suggest HIV intervention components might augment the protective features of the camps, while changing environmental features to reduce risk. PMID- 20846769 TI - Young women facing multiple and intersecting stressors of modernity, gender orders and youth. AB - This article aims to explore stressors experienced by Swedish adolescent girls and young women, specifically understood in relation to social context and gender theory. Interviews were conducted with 40 young Swedish women, aged 16-25 years, who had sought help at a youth health centre for stress problems. Using qualitative content analysis we identified three clusters of stressors: "the stressors of modernity", "the stressors of gendered orders", and "the stressors of youth". The results revealed that multiple and intersecting discourse-shaped stressors and demands connected to essential life spheres contribute not only to experiences of distress but also to feelings of constraint. Gendered individualism and healthism proved to be essential in understanding the young women's experienced stress. Failing social support from adults, gendered demands and responsibility taking were also illuminated. This calls for a broad contextualized and gender-sensitive approach to young women's stress and health problems. PMID- 20846770 TI - Contribution of temporal preparation and processing speed to simple reaction time in persons with Alzheimer's disease and mild cognitive impairment. AB - Temporal preparation was assessed in 15 Alzheimer's disease (AD) patients, 20 persons with mild cognitive impairment (MCI) and 28 healthy older adults. Participants completed a simple reaction time task in which the preparatory interval duration varied randomly within two blocks (short versus long temporal window). Results indicated that AD and MCI patients had difficulty preparing for the shortest preparatory interval of the short temporal window. AD and MCI patients also had difficulty maintaining an optimal level of preparation up to 5 s within the short temporal window. These results suggest that AD and MCI patients might show difficulty preparing for rapidly occurring events and maintaining preparation over time. This phenomenon should be considered when using reaction time measures with such patients. PMID- 20846771 TI - Exploring visuomotor priming following biological and non-biological stimuli. AB - Observation of human actions influences the observer's own motor system, termed visuomotor priming, and is believed to be caused by automatic activation of mirror neurons. Evidence suggests that priming effects are larger for biological (human) as opposed to non-biological (object) stimuli and enhanced when viewing stimuli in mirror compared to anatomical orientation. However, there is conflicting evidence concerning the extent of differences between biological and non-biological stimuli, which may be due to stimulus related confounds. Over three experiments, we compared how visuomotor priming for biological and non biological stimuli was affected over views, over time and when attention to the moving stimulus was manipulated. The results indicated that the strength of priming for the two stimulus types was dependent on attentional location and load. This highlights that visuomotor priming is not an automatic process and provides a possible explanation for conflicting evidence regarding the differential effects of biological and non-biological stimuli. PMID- 20846772 TI - Incongruent imagery interferes with action initiation. AB - It has been suggested that representing an action through observation and imagery share neural processes with action execution. In support of this view, motor priming research has shown that observing an action can influence action initiation. However, there is little motor-priming research showing that imagining an action can modulate action initiation. The current study examined whether action imagery could prime subsequent execution of a reach and grasp action. Across two motion analysis tracking experiments, 40 participants grasped an object following congruent or incongruent action imagery. In Experiment 1, movement initiation was faster following congruent compared to incongruent imagery, demonstrating that imagery can prime the initiation of grasping. In Experiment 2, incongruent imagery resulted in slower movement initiation compared to a no-imagery control. These data show that imagining a different action to that which is performed can interfere with action production. We propose that the most likely neural correlates of this interference effect are brain regions that code imagined and executed actions. Further, we outline a plausible mechanistic account of how priming in these brain regions through imagery could play a role in action cognition. PMID- 20846773 TI - Attentional distractor interference may be diminished by concurrent working memory load in normal participants and traumatic brain injury patients. AB - A reduction in congruency effects under working memory (WM) load has been previously described using different attentional paradigms (e.g., Kim, Kim, & Chun, 2005; Smilek, Enns, Eastwood, & Merikle, 2006). One hypothesis is that different types of WM load have different effects on attentional selection, depending on whether a specific memory load demands resources in common with target or distractor processing. In particular, if information in WM is related to the distractors in the selective attention task, there is a reduction in distraction (Kim et al., 2005). However, although previous results seem to point to a decrease in interference under high WM load conditions (Kim et al., 2005), the lack of a neutral baseline for the congruency effects makes it difficult to differentiate between a decrease in interference or in facilitation. In the present work we included neutral trials in the task introduced by Kim et al. (2005) and tested normal participants and traumatic brain injury patients. Results support a reduction in the processing of distractors under WM load, at least for incongruent trials in both groups. Theoretical as well as applied implications are discussed. PMID- 20846774 TI - Human performance on the temporal bisection task. AB - The perception and processing of temporal information are tasks the brain must continuously perform. These include measuring the duration of stimuli, storing duration information in memory, recalling such memories, and comparing two durations. How the brain accomplishes these tasks, however, is still open for debate. The temporal bisection task, which requires subjects to compare temporal stimuli to durations held in memory, is perfectly suited to address these questions. Here we perform a meta-analysis of human performance on the temporal bisection task collected from 148 experiments spread across 18 independent studies. With this expanded data set we are able to show that human performance on this task contains a number of significant peculiarities, which in total no single model yet proposed has been able to explain. Here we present a simple 2 step decision model that is capable of explaining all the idiosyncrasies seen in the data. PMID- 20846775 TI - [Effectiveness of therapeutic education and respiratory rehabilitation programs for the patient with asthma]. AB - Asthma is a chronic complex and heterogeneous disease, with great variability and has a huge impact, not only on patients who suffer the disease but also their families and society in general. The education of the asthmatic patient and their families is essential for therapeutic intervention. Through continuous, dynamic and adaptive education, changes in attitudes and behaviours of the patient and family can be achieved, and will undoubtedly lead to an improvement in their quality of life. Among other non-pharmacological interventions, respiratory rehabilitation is an alternative treatment, and is primarily aimed at patients with moderate to severe asthma. Although the latest clinical practice guidelines published in the scientific literature recommend two strategies for treatment, the results of relevant publications are diverse. The objective of this study was to describe the effectiveness of therapeutic and educational programs in respiratory rehabilitation of the asthmatic patient. PMID- 20846776 TI - [Mediastinitis as a complication after fine needle aspiration using ultrasound guided bronchoscopy]. PMID- 20846777 TI - Emergency airway management by non-anaesthetic trainees. PMID- 20846778 TI - Pregnancy in sickle cell disease: maternal and fetal outcomes in a population receiving prophylactic partial exchange transfusions. AB - OBJECTIVE: To describe pregnancy outcomes for pregnant women with sickle cell disease (SCD) receiving prophylactic transfusions. STUDY DESIGN: This retrospective case-control study compared pregnancy outcomes among women with SCD receiving prophylactic transfusions and women without any hemoglobinopathy, matched for ethnicity, parity, age and hospital. RESULTS: The study included two groups of pregnancies: 128 in women with SCD (95 with SS phenotype and 33 with SC) and 128 in women with AA phenotype. No woman died. Two perinatal deaths (2.1%) and five alloimmunizations (5.3%) occurred, all in the SS group. Compared with the control group, HbSS disease was more often associated with pre-eclampsia (9.4% versus 2.3%, p=.03), preterm delivery (15.8% versus 6.2%, p=.01), birth weight <10th percentile (13.7% versus 3.9%, p=.008) and caesarean delivery (73.6% versus 26.4%, p<.01). CONCLUSION: Despite prophylactic blood transfusions, SCD remains a severe complicating factor in pregnancy. The policy of systematic transfusions should be analyzed in a sufficiently large randomized trial. PMID- 20846779 TI - A biophysical approach to phospholipase A2 activity and inhibition by anti inflammatory drugs. AB - The present study describes the interaction of two nonsteroidal anti-inflammatory drugs (ibuprofen and piroxicam) with PLA(2) from Naja mossambica mossambica and seeks to deepen the knowledge about the influence of the biophysical properties of biomembranes, and the inhibitory effect of the drugs on the enzymatic activity. Fluorescent techniques with and without the use of probes, surface pressure/molecular area isotherms, surface pressure/time and molecular area/time measurements combined with circular dichroism spectroscopy and direct techniques of visualization of lipid membranes (Brewster angle microscopy), revealed that both drugs inhibit PLA(2). Additionally, the structure and characteristics of the lipid bilayer, as well as, the direct interaction of drugs with the enzyme seem to play an important role on the hydrolytic activity of PLA(2) towards membrane model systems. These results open a way of finding new and better strategies that can contribute to the development of suitable agents for relieving inflammatory conditions. PMID- 20846780 TI - Use of strategic environmental assessment in the site selection process for a radioactive waste disposal facility in Slovenia. AB - The benefits of strategic environmental considerations in the process of siting a repository for low- and intermediate-level radioactive waste (LILW) are presented. The benefits have been explored by analyzing differences between the two site selection processes. One is a so-called official site selection process, which is implemented by the Agency for radwaste management (ARAO); the other is an optimization process suggested by experts working in the area of environmental impact assessment (EIA) and land-use (spatial) planning. The criteria on which the comparison of the results of the two site selection processes has been based are spatial organization, environmental impact, safety in terms of potential exposure of the population to radioactivity released from the repository, and feasibility of the repository from the technical, financial/economic and social point of view (the latter relates to consent by the local community for siting the repository). The site selection processes have been compared with the support of the decision expert system named DEX. The results of the comparison indicate that the sites selected by ARAO meet fewer suitability criteria than those identified by applying strategic environmental considerations in the framework of the optimization process. This result stands when taking into account spatial, environmental, safety and technical feasibility points of view. Acceptability of a site by a local community could not have been tested, since the formal site selection process has not yet been concluded; this remains as an uncertain and open point of the comparison. PMID- 20846781 TI - A procedure to design a Permeable Adsorptive Barrier (PAB) for contaminated groundwater remediation. AB - A procedure to optimize the design of a Permeable Adsorptive Barrier (PAB) for the remediation of a contaminated aquifer is presented in this paper. A computer code, including different routines that describe the groundwater contaminant transport and the pollutant capture by adsorption in unsteady conditions over the barrier solid surface, has been developed. The complete characterization of the chemical-physical interactions between adsorbing solids and the contaminated water, required by the computer code, has been obtained by experimental measurements. A case study in which the procedure developed has been applied to a tetrachloroethylene (PCE)-contaminated aquifer near a solid waste landfill, in the district of Napoli (Italy), is also presented and the main dimensions of the barrier (length and width) have been evaluated. Model results show that PAB is effective for the remediation of a PCE-contaminated aquifer, since the concentration of PCE flowing out of the barrier is everywhere always lower than the concentration limit provided for in the Italian regulations on groundwater quality. PMID- 20846782 TI - Peering through the microscope lens into the future. PMID- 20846783 TI - Initial series of robotic radical nephrectomy with vena caval tumor thrombectomy. AB - Laparoscopy has become a standard modality for most renal tumors but not as yet for renal cell carcinoma (RCC) involving the inferior vena cava (IVC). Robotic technology may facilitate such complex procedures. We report the first series of robotic nephrectomy with IVC tumor thrombectomy including the first cases requiring cross-clamping of the IVC in a minimally invasive fashion. Five patients underwent robotic nephrectomy with IVC tumor thrombectomy including one patient having two renal veins, each with an IVC thrombus, for a total of six IVC thrombi. The IVC was opened in all patients, and tumor thrombi were delivered intact, followed by sutured closure. The mean patient age was 64 yr (53-70 yr) with a mean body mass index of 36.6 kg/m(2) (22-43 kg/m(2)). Thrombi protruded 1 cm, 2 cm, 4 cm, and 5 cm into the IVC in five patients and 3 cm and 2 cm in the patient with two thrombi. The mean estimated blood loss was 170 ml (50-400 ml). Mean operative time was 327 min (240-411 min). Mean length of stay was 1.2 d. There were no complications, transfusions, or readmissions. This early series represents a limited experience by a single surgeon with a new procedure and may not be reproducible in larger numbers or by all surgeons. Further experience is necessary to validate this application. PMID- 20846784 TI - Fatal consequences of a simple mistake: how can a patient be saved from inadvertent intrathecal vincristine? PMID- 20846785 TI - Spheres derived from the human SK-RC-42 renal cell carcinoma cell line are enriched in cancer stem cells. AB - Various types of malignant tumor have been found to contain a subpopulation of cancer stem cells (CSCs). In this study, we sought to enrich CSCs from the renal cell carcinoma (RCC) cell line SK-RC-42 using the sphere culture system and characterize their immunophenotype. We demonstrated that a subpopulation of SK-RC 42 cells were capable of growing as tumor spheres in serum-free medium supplemented with EGF and bFGF. The sphere-forming cells (SFCs) had many properties similar to CSCs: ability of self-renewing in vitro and in vivo, higher mRNA expression levels of several 'stemness' genes, stronger tumorigenicity and resistance to chemotherapeutic agents and irradiation compared with the monolayer adherent cells (MACs). The SFCs expressed high levels of MHC class I but low levels of MHC class II, CD80 and CD86. In contrast with MACs, the SFCs had lower expression levels of FasL and Fas, Her2 and hTERT and activating natural killer receptors. Finally, SK-RC-42 SFCs and MACs both expressed significant and comparable levels of the transcription factor forkhead box protein 3 (FoxP3) and membrane complement regulatory proteins (mCRPs). Taken together, these findings indicate that CSCs can be enriched from RCC by culturing the tumor cells as spheres. The immunophenotype of the SFCs demonstrated in this study suggests that CSCs might play an important role in the evasion of tumor growth from immune surveillance. PMID- 20846786 TI - Inhibition of aryl hydrocarbon receptor-dependent transcription by resveratrol or kaempferol is independent of estrogen receptor alpha expression in human breast cancer cells. AB - Resveratrol and kaempferol are natural chemopreventative agents that are also aryl hydrocarbon receptor (AHR) antagonists and estrogen receptor (ER) agonists. In this study we evaluated the role of ERalpha in resveratrol- and kaempferol mediated inhibition of AHR-dependent transcription. Kaempferol or resveratrol inhibited dioxin-induced cytochrome P450 1A1 (CYP1A1) and CYP1B1 expression levels and recruitment of AHR, ERalpha and co-activators to CYP1A1 and CYP1B1. Both phytochemicals induced the expression and recruitment of ERalpha to gene amplified in breast cancer 1 (GREB1). RNAi-mediated knockdown of ERalpha in T-47D cells did not affect the inhibitory action of either phytochemical on AHR activity. Both compounds also inhibited AHR-dependent transcription in ERalpha negative MDA-MB-231 and BT-549 breast cancer cells. These data show that ERalpha does not contribute to the AHR-inhibitory activities of resveratrol and kaempferol. PMID- 20846787 TI - Equilibrium and kinetic analysis of phosphorus adsorption from aqueous solution using waste alum sludge. AB - Excess phosphorus (P) in wastewaters promotes eutrophication in receiving waterways. A cost-effective method such as use of novel low-cost adsorbents for its adsorptive removal would significantly reduce such impacts. Using batch experiments, the intrinsic dynamics of P adsorption by waste alum sludge (an inevitable by-product of drinking water treatment plants) was examined. Different models of adsorption were used to describe equilibrium and kinetic data, calculate rate constants and determine the adsorption capacity. Results indicate that the intraparticle rate constant increased from 0.0075 mg g(-1)min(-1) at 5 mg L(-1) to 0.1795 mg g(-1)min(-1) at 60 mg L(-1) indicating that more phosphate is adsorbed per g min at higher P concentration. Further analyses indicate involvement of film and particle diffusion mechanisms as rate controlling steps at lower and higher concentrations, respectively. Mass transfer coefficient obtained ranged from 1.7 * 10(-6) to 1.8 * 10(-8) indicating a rapid transportation of phosphate molecules onto the alum sludge. These results further demonstrates that alum sludge-hitherto thought of as undesirable waste, can be used as novel adsorbent for P removal from wastewater through various applications, thus offsetting a portion of the disposal costs while at the same time improving water quality in sensitive watersheds. PMID- 20846788 TI - Acid phosphatase production by Rhizopus delemar: a role played in the Ni(II) bioaccumulation process. AB - The microbial growth and activity of acid phosphatase enzyme during the growth of Rhizopus delemar in the presence or absence of Ni(II) ions were investigated. An increase in initial Ni(II) ion concentration inhibited both growth rate of R. delemar and acid phosphatase activity. The maximum-intrinsic specific growth rate (MU(m)) and Monod constant (K(s)) of microorganism in Ni(II)-free medium were found as 0.0649 h(-1) and 1.8928 g/L, respectively. The inhibition of Ni(II) ions on growth rate of R. delemar was found to be a competitive inhibition and the inhibition constant was found to be 67.11 mg Ni(II)/L. The intrinsic Michaelis Menten constant (K(m)) and maximum forward velocity of the reaction (v(m)) were determined as 3.17 mM and 833.3 MUmol/L min, respectively, in Ni(II)-free medium. In the presence of Ni(II) ions, the activity of acid phosphatase was inhibited. Addition of Ni(II) ions decreased the maximum reaction velocity, v(m), showed noncompetitive-type inhibition kinetics and the inhibition constant was determined as 50mg Ni(II)/L. Maximum Ni(II) uptake was obtained by the growing cells of R. delemar, while the uptake capacity of resting cells was lowest. This study proved that acid phosphatase enzyme participated in the Ni(II) bioaccumulation mechanism of growing R. delemar. PMID- 20846789 TI - Preparation of iron-impregnated granular activated carbon for arsenic removal from drinking water. AB - Granular activated carbon (GAC) was impregnated with iron through a new multi step procedure using ferrous chloride as the precursor for removing arsenic from drinking water. Scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis demonstrated that the impregnated iron was distributed evenly on the internal surface of the GAC. Impregnated iron formed nano-size particles, and existed in both crystalline (akaganeite) and amorphous iron forms. Iron-impregnated GACs (Fe-GACs) were treated with sodium hydroxide to stabilize iron in GAC and impregnated iron was found very stable at the common pH range in water treatments. Synthetic arsenate-contaminated drinking water was used in isotherm tests to evaluate arsenic adsorption capacities and iron use efficiencies of Fe-GACs with iron contents ranging from 1.64% to 12.13% (by weight). Nonlinear regression was used to obtain unbiased estimates of Langmuir model parameters. The arsenic adsorption capacity of Fe-GAC increased significantly with impregnated iron up to 4.22% and then decreased with more impregnated iron. Fe-GACs synthesized in this study exhibited higher affinity for arsenate as compared with references in literature and shows great potential for real implementations. PMID- 20846790 TI - Fabrication of FOX-7 quasi-three-dimensional grids of one-dimensional nanostructures via a spray freeze-drying technique and size-dependence of thermal properties. AB - 1,1-Diamino-2,2-dinitroethylene (C(2)H(4)N(4)O(4), FOX-7) quasi-three-dimensional (3D) grids, a promising high-energy-density material with superior sensitivity properties, were synthesized by a spray freeze-drying technique. The FOX-7 3D grids were constructed from one-dimensional nanostructures. The sizes and structures of the FOX-7 3D grids strongly depend on the concentration of the aqueous solution of FOX-7. A possible formation mechanism of this structure was proposed in detail. Thermal analysis reveals that decrease in average particle sizes of FOX-7 grids results in a lower decomposition temperature and a much higher decomposition rate, which is in agreement with those reported about inorganic nanomaterials. PMID- 20846791 TI - Non-functional adrenocortical adenoma: a unique case of combination with myelolipoma and endothelial cysts. AB - A case of non-functioning adrenocortical adenoma combined with myelolipoma and endothelial cysts is reported. A 72-year-old Japanese female was noticed to have right renal and left adrenal tumors by an abdominal CT scan. At surgery, the mildly enlarged left adrenal gland contained a well-demarcated tumor. Macroscopically, it was yellowish to dark red or grayish in color, and was characterized by geographic appearance on the cut surface. Histopathological examination revealed a solid proliferation of clear or compact cells and a normal rim of adrenal gland, coexisting with vascular multiple cysts and myelolipomas. The cysts were filled with clotted blood, fibrinous material, or thrombi, and were partially lined with flattened endothelial cells with focal papillary hyperplasia, which were immunohistochemically positive for CD31 and CD34. These cystic walls were often thickened with hyalinized fibrosis and calcification, and were connected to myelolipomatous elements. To our knowledge, this is the first case report of adrenocortical adenoma associated with myelolipoma and endothelial cysts. It is probable that the extensive degeneration in adenoma might induce myelolipomatous metaplasia and cystic vascular formation. PMID- 20846792 TI - Knockdown of PIK3R1 by shRNA inhibits the activity of the splenic macrophages associated with hypersplenism due to portal hypertension. AB - Phosphatidylinositol 3-kinase (PI3K) plays a central role in the metabolic actions of insulin. One 85 kDa regulatory subunit of PIK3 is encoded by phosphoinositide-3-kinase, the regulatory subunit 1 (PIK3R1). Our previous study has demonstrated that PIK3R1 was up-regulated significantly in the splenic macrophage (MPhi) of portal hypertensive spleen. In the present study, RNA interference specific to PIK3R1 was employed to investigate its inhibitive effects on the activity of MPhi associated with hypersplenism due to portal hypertension (HS-PHT). The expression of PIK3R1 in the spleen was detected by immunohistochemical staining. Plasmid vector pGenesil-1 expressing specific small hairpin RNA (shRNA) against PIK3R1 and the scrambled shRNA control was constructed. MPhi were isolated and purified by anchored cultivation from patients with HS-PHT (HS-PHT-MPhi) and traumatic rupture of the spleen (Con MPhi). After transfection into MPhi, PIK3R1 expression at both the mRNA and the protein level was examined by real-time polymerase chain reaction and Western blot. The activities of MPhi were determined, and the expression and activity of NF-kappaB were also detected. Immunohistochemistry revealed expression and cellular distribution of PIK3R1 in the spleen. The PIK3R1-shRNA was successfully synthesized and cloned into the plasmid vector pGenesil-1, and specifically suppressed PIK3R1 expression at both the mRNA and the protein level. After transfection into HS-PHT-MPhi and Con-MPhi, PIK3R1 knockdown inhibited the viability of MPhi, reduced the phagocytic rate, the rate of antigen-presenting positive cells, the metabolic rate, and the secretion of IL-1beta and TNF-alpha (all p<0.05), and decreased the expression and activity of NF-kappaB. Our data showed that the knocking down of PIK3R1 with shRNA produced by pGenesil-1 led to inhibition of viability and to decreased activity of MPhi associated with HS-PHT in vitro. Therefore, it is tempting to speculate that PIK3R1 might play a considerable role in the pathogenesis of HS-PHT, and inhibition of PIK3R1 expression might be a novel therapeutic strategy for HS-PHT. PMID- 20846793 TI - Concomitant adenocarcinoma and colonic non-Hodgkin's lymphoma in a patient with ulcerative colitis: a case report and molecular analysis. AB - Ulcerative colitis (UC) complicated by colonic lymphoma is rare, although UC is often accompanied by adenocarcinoma of the colon. A concurrent existence of adenocarcinoma and lymphoma in a patient with UC is extremely rare, and has not yet been analyzed at the molecular level. We report a 64-year-old female patient with concomitant adenocarcinoma and diffuse large B-cell lymphoma (DLBCL) in the colon of UC. The genetic changes in these two neoplasms were analyzed. The colon adenocarcinomas had a mutation in MSH6 gene, DNA methylation in CDKN2A gene, and increased microsatellite instability (MSI), although these genetic changes were not recognized in either DLBCL or non-neoplastic UC mucosa. The DLBCL was diagnosed as primary colonic lymphoma, and confirmed Epstein-Barr virus (EBV) infection. The adenocarcinomas and the non-neoplastic UC mucosa were EBV negative. Our case presented here clearly shows that the development of adenocarcinoma and lymphoma in the colon with UC was caused by individual mechanisms. PMID- 20846794 TI - Alcohol and STI risk: evidence from a New Zealand longitudinal birth cohort. AB - BACKGROUND: The present study examined the associations between involvement with alcohol and risks of sexually transmitted infection (STI) during adolescence and early adulthood. METHODS: A 30-year prospective longitudinal study of the health, development, and adjustment of a birth cohort of 1265 New Zealand-born individuals. Measures included repeated assessments of frequency of alcohol use and number of symptoms of alcohol disorder from ages 15 to 30 and rates of STI from ages 14 to 30. Conditional fixed effects regression models augmented by observed time-dynamic covariate factors were used to control for non-observed confounding in the associations between alcohol and STI risk. RESULTS: There were clear and consistent trends for increasing involvement with alcohol to be linked with increased risk of STI diagnoses. Adjustment of the associations for sources of non-observed confounding and time-dynamic covariate factors reduced the magnitude of these associations, but they remained statistically significant (p < .05). CONCLUSIONS: The results of the current study support the notion of the existence of a causal pathway in which increasing levels of alcohol use and symptoms of alcohol abuse/dependence led to increased risks of STI exposure. There was little evidence to suggest that the links between alcohol involvement and STI risk could be fully explained by an underlying predisposing factor that increased the risks of both alcohol involvement and STI. PMID- 20846795 TI - Maternal obesity and infant outcomes. AB - Obesity (Body mass index (BMI) above 30) is one of the major health issues of the 21st century. Over 1.1 billion of the world's population are now classified as obese. In the UK, women are more likely to be obese than men; over 50% of women of reproductive age are overweight or obese. Maternal obesity and the plethora of associated conditions, have a serious impact on the health and development of their offspring. In this review we describe the direct and indirect impact of maternal obesity on the health of the baby. Maternal obesity affects conception, duration and outcome of pregnancy. Offspring are at increased risk of both immediate and long term implications for health. We also briefly review potential mechanisms drawing on data from human and animal studies, and on the outcomes of clinical interventional studies. PMID- 20846796 TI - Does preterm birth increase a child's risk for language impairment? AB - BACKGROUND: Although premature birth is associated with lags in language acquisition, it is unclear whether preterms exhibit an elevated risk for language impairment (LI). This study determined whether preterms, without frank cerebral damage, at 2;6 and 3;6 exhibited a higher rate of risk for LI as compared to full terms, and also sought to identify predictors of risk. METHOD: Sixty-four Italian very immature preterms were assessed longitudinally at 2;6 and 3;6; age-matched full-terms served as controls at 2;6 (n=22) and 3;6 (n=40). Each completed individualized assessments of cognition and language ability. At each time point, using cut-offs specific to each of the language measures, children were differentiated into two groups (at risk for LI, not at risk). RESULTS: The percentage of full-terms at risk for LI at 2;6 (9.1% to 13.6%) and 3;6 (7.5%) was consistent with prior estimates of LI at these ages. The percentage of preterms at risk for LI at 2;6 (16.1% to 24.1%) and 3;6 (34.4%) was higher at both ages and statistically significant at 3;6 (difference=26.8%, 95% CI=12.3% to 41.4%). The best model predicting risk status at 3;6 was preterms' mean length of utterance (MLU) at 2;6, (sensitivity 72.73%, specificity 85%) when adjusting for maternal education. CONCLUSION: Preterms exhibit a heightened risk for LI in the preschool years, since about one in four preterms at 2;6 and one in three preterms at 3;6 experiences significant lags in language acquisition. Findings argue the importance of early identification of language difficulties among preterms coupled with implementation of systematic language-focused interventions for these youngsters. PMID- 20846797 TI - "Breast is best": The evidence. AB - Although the benefits of breastfeeding in reducing morbidity and mortality from gastrointestinal and respiratory infections, sudden infant death syndrome, and (in preterm infants) necrotizing enterocolitis are well-established, long-term health effects are more controversial. The evidence is conflicting concerning the "programming" effect of breastfeeding in protecting against child obesity, hyperlipidemia, hypertension, type 2 diabetes, and atopic disease. Accelerated neurocognitive development has been associated with breastfeeding in many studies, although doubts remain about the potential for residual confounding due to cognitive and behavioural differences between mothers who breastfeed (or those who breastfeed for a longer duration or more exclusively) and those who do not. Most of this paper will summarize the methods and results of a large, cluster randomized trial of a breastfeeding promotion intervention in the Republic of Belarus. Its experimental design and intention-to-treat analysis have yielded important findings bearing on several of these longer-term health and developmental outcomes. PMID- 20846799 TI - Good parenting: Making a difference. AB - The relevance of the quality of parenting to outcomes for children is reviewed, as well as research findings on the important dimensions of parenting in the early years. Some of the limitations of current parenting research are outlined. The contributory parent and child factors that mediate outcomes are identified, and the ways in which they interact in a bi-directional and dynamic process to determine the quality of parenting and the parent-child relationship. This information is applied to the task of parenting neonates and infants, and interventions are identified that indicate the scope and type of improvements or enhancements to parenting capacity that can be achieved. Particular issues and problems relating to the parenting of neonates or infants with special needs are briefly discussed, as well as promising initiatives to enable the care of ill babies to be more relationship-based and family centred. PMID- 20846798 TI - Characterising and treating osteogenesis imperfecta. AB - Osteogenesis imperfecta is characterised by bone fragility leading to fracture and bone deformity, chronic bone pain and reduced mobility. Presentation in infancy may be anticipated through shortened or bowed femurs on antenatal ultrasound scanning, or because of family history. Other conditions can present in the neonatal period with osteoporosis and fractures, but clinical features should allow differentiation. Management is multidisciplinary, with the mainstay of medical intervention being the use of bisphosphonates. Intervention with these medications, in association with specialised nursing, physio- and occupational therapy input, has reduced fracture frequency by up to 50% in published series, and has shown significant effects on vertebral morphometry when started early (around 6 weeks age). Outcomes in older children are encouraging with a reduction in fracture frequency of up to 50%; however, the longer term effects of early intervention remain to be determined. In particular the effects on life-limiting structural outcomes such as scoliosis and basilar invagination remain unclear. PMID- 20846800 TI - Molecular cloning of pig ZPBP2 and mRNA expression of ZPBP1 and ZPBP2 in reproductive tracts of boars. AB - Zona pellucida binding proteins (ZPBPs) are important receptors of zona pellucida on sperm and play an essential role in sperm-egg interaction. In the present study, the full-length coding regions of transcript variant 1 and 2 of ZPBP2 were cloned in the pig. ZPBP1 gene expression was specifically present in testes of boar reproductive tracts; while ZPBP2 mRNA was detected with highly in testes, moderate in seminal vesicles and low in caudal epididymes. We also examined the expression profile of porcine ZPBP1 and ZPBP2 in testes and seminal vesicles at different developmental stages. The results revealed that ZPBP1 mRNA was not detectable until day 70 and kept relative stable from days 70 to 105, then increased sharply from days 105 to 160 during sexual maturity (P<0.01). ZPBP2 mRNA was detected with relative low level until day 70 and but increased significantly from days 70 to 105 (P<0.01), and increased further from days 105 to 160 during sexual maturity (P<0.01). The data indicated that testes are the main origin of ZPBPs and the expression of ZPBPs are parallel with reproduction development. PMID- 20846801 TI - The synthesis, mass spectrometric properties and identification of some N,N-di (beta-arylisopropyl)formamides related to the synthesis of ring-modified amphetamines. AB - This study examines the electron impact (EI) induced mass spectrometric behavior of several N,N-di-(beta-arylisopropyl)formamides, which are connected to the Leuckart synthesis of some amphetamine analogues. Emphasis is laid on the fragmentation paths, which are common for all compounds under investigation and may be used in construction of the prediction scheme useful for identification of similar impurities, especially in absence of desirable authentic material. On the basis of this scheme several new N,N-di-(beta-arylisopropyl)formamides have been identified in selected amphetamine analogues synthesized by the Leuckart method, including 4-methylthioamphetamine (4-MTA), 4-fluoroamphetamine (4-FA), 4 methylamphetamine, 3-trifluoromethylamphetamine, 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxyamphetamine (2,5-DMA), 2,4,5- and 3,4,5 trimethoxyamphetamines (2-TMA and 3-TMA). PMID- 20846802 TI - Validity of the mandibular canine index (MCI) in sex prediction: Reassessment in an Indian sample. AB - The dentition's use in sex assessment has been explored and advocated owing to its strength and resistance to peri- and postmortem insults. Among the teeth, canines have shown the greatest sexual dimorphism; they are also known for greater resistance to pathological alterations and trauma. These factors have prompted some researchers to explore its use alone in sex prediction. Specifically the mandibular canine index (MCI), which is the ratio of the mesiodistal (MD) dimension of the lower right canine and the inter-canine arch width, was developed by Rao et al. [Forensic Sci. Int. 42 (1989) 249-254] who predicted sex correctly in ~86% of cases in a South Indian sample. These results were verified subsequently by other Indian researchers, both on southern and on northern Indians, although such success rates were not apparent in another South Asian population as well as a European group. The present study re-examined the method in 203 Indians (103 males, 100 females) of age 19-32 years who originated from diverse states of the country, constituting all major religious and caste affiliations, and found relatively low sex estimation accuracy using the MCI (~51%). This is in spite of the MD dimension of canines as well as inter-canine arch width - the absolute measurements used for deriving the MCI - showing statistically significant sex differences (p<0.05); also, the application of multivariate statistics, viz. logistic regression analysis, revealed higher accuracy levels of sex estimation for the absolute measurements (~62-66%) vis-a vis the MCI (~50%). The results herein reinforce recent observations that ratios obtained from teeth, such as the MCI, do not reflect sexual dimorphism that may be present in absolute measurements. Furthermore, we believe that the basis for using MCI as a sex assessment tool is questionable, since it depends on the levels of sexual dimorphism between the absolute dimensions-low sexual dimorphism in one (e.g. MD measurement of canines) and proportionately high sexual differences in the other (e.g. inter-canine arch width), or vice versa, would lead to higher sex estimation accuracy of the MCI; on the other hand, relatively equal levels of sexual dimorphism in both would negate the ability of the MCI to accurately estimate sex. These suggest that the MCI has little utility in sex estimation and that its application should be restricted, if not discontinued altogether, in forensic and anthropological sex prediction. PMID- 20846803 TI - Relationship between cognitive functions and prevalence of fatigue in elementary and junior high school students. AB - BACKGROUND: Fatigue is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance, we attempted to determine whether cognitive functions were associated with the prevalence of fatigue. METHODS: Participants were 148 elementary school students from 4th- to 6th-grades and 152 junior high school students from 7th- to 9th grades. Participants completed a questionnaire about fatigue (Japanese version of the Chalder Fatigue Scale) and paper-and-pencil and computerized cognitive tests which could evaluate the abilities of motor processing, immediate, delayed and working memory, selective, divided and alternative attention, retrieve learned material, and spatial construction. RESULTS: We found that in multivariate logistic regression analyses adjusted for grade and gender, slow motor processing was positively correlated with the prevalence of fatigue in the elementary school students and decreases in working memory and divided and alternative attention processing were positively correlated with the prevalence of fatigue in the junior high school students. CONCLUSION: The grade-dependent development of cognitive function influences the severity of fatigue in elementary and junior high school students. PMID- 20846804 TI - Radiological clerkships as a critical curriculum component in radiology education. AB - OBJECTIVE: The aim of this research was to explore the perceived value of clinical clerkships in the radiology curriculum as well as the impact of radiology clerkship on students' beliefs about the profession of radiology as a whole and as a career. METHODS: This study is a sequel to a previous survey in which student perceptions about radiology curriculum components were investigated. The present study focuses on a further analysis of a subsection in this study, based on 14 statements about radiology clerkship and two statements about radiology as a career. RESULTS: Perceived usefulness of the aspects of radiology clerkship as "radiology examination", "skills development" and "diagnosis focus" were awarded the highest scores. The predict value of the subscale "radiology examination" on the level of performance was very high (adjusted R(2)=0.19, p<.001). CONCLUSION: Students expressed highly favorable evaluation of clerkship as a learning environment to learn to order and to interpret imaging studies as well as an unique possibility to attend various radiological examinations and to access to specific radiology software systems, as well as to get a better view on radiology and to improve image interpretation skills. This positive attitude towards clerkship is closely tied to students' beliefs about the profession of radiology as a whole. These aspects of dedicated radiology clerkship are crucial for effective and high-quality education as well as for the choice of radiology as a career. PMID- 20846805 TI - Analysis of radiology education in undergraduate medical doctors training in Europe. AB - OBJECTIVES: The purpose of the present study is to describe how undergraduate radiology teaching is organized in Europe and to identify important characteristics of undergraduate radiology curriculum. METHODS: An electronic survey on undergraduate teaching was distributed by the European Society of Radiology (ESR) to 38 national delegates of the ESR Education Committee. RESULTS: The "classic type" of radiology teaching method is more frequent than the "modular type". In 38% of medical training centres the first experience with radiology is in pre-clinical years. The students enrolled in the fourth medical year experience the largest involvement in radiology education. The total number of teaching hours (mean 89 h, median 76 h) varies across the countries and differs depending on the radiological topic (mean across all topics 14.8h, median 13). Written tests and oral exams were the most frequently used examination modes. Clerkships are reported as a key part of training. CONCLUSION: This first international comparative study of undergraduate radiological curriculum in Europe identifies a large number of differences in curriculum content and teaching methods throughout Europe. More research is needed to establish the radiological educational competences resulting from these differing curricula's to improve and to standardize the teaching according to (inter)national and institutional needs. PMID- 20846806 TI - Molecular epidemiology of Saccharomyces cerevisiae in an immunocompromised host unit. AB - Saccharomyces cerevisiae is increasingly recognized clinically, and repeated isolations from patients on a hematology unit in Turku, Finland, led to an epidemiologic investigation. Isolates were recovered from multiple body sites of 23 patients (n = 180) from 1994 to 1995 and from 29 patients (n = 45) from 1997 to 2002; these plus 2 from the hospital kitchen were identified as S. cerevisiae. Isolates were genotyped by restriction fragment length polymorphism (RFLP) of genomic DNA after EcoR1 digestion. Of 108 isolates, 97 (95 patient isolates and 2 from the hospital kitchen) were DNA group B and identical in RFLP pattern. The remaining 11 isolates were DNA group A; 2 patients that shared a room had identical group A isolates, both converted to DNA group B type colonization within 2 months. In almost all patients, S. cerevisiae was first recovered after admission. These data suggest an endemic source of colonizing organisms, possibly from the hospital food preparation area. PMID- 20846807 TI - Detection of metallo-beta-lactamase-encoding genes among clinical isolates of Pseudomonas aeruginosa in northwest of Iran. AB - The prevalence of metallo-beta-lactamase (MBL) production among 104 clinical isolates of Pseudomonas aeruginosa from northwest of Iran was investigated by phenotypic and polymerase chain reaction (PCR) methods. Thirty-nine (37.50%) of isolates were MBL positive by double-disk synergy test. Results of PCR revealed that 18 (17.31%) and 6 (5.77%) imipenem nonsusceptible isolates of P. aeruginosa carried bla(VIM) and bla(IMP) genes respectively, while 92.4% (62/67) of isolates contained class 1 integron gene. This is the first report of MBL-producing P. aeruginosa from northwest of Iran. PMID- 20846808 TI - Variation in Candida spp. distribution and antifungal resistance rates among bloodstream infection isolates by patient age: report from the SENTRY Antimicrobial Surveillance Program (2008-2009). AB - The variation in Candida spp. causing bloodstream infection (BSI) and the frequency of resistance to fluconazole by patient age have been previously described. However, similar data have been shown for neither the echinocandins nor the newer triazoles. We analyzed the 24-h reference MIC data from the SENTRY Antimicrobial Surveillance Program to compare the antifungal resistance profiles and species distribution of Candida BSI isolates according to patient age. MIC results were obtained for anidulafungin, caspofungin, micafungin, fluconazole, posaconazole, and voriconazole, and recently revised Clinical and Laboratory Standards Institute breakpoints were applied. A total of 1239 Candida BSI isolates were obtained from 79 medical centers in 2008 to 2009: 50.0%, 17.4%, 17.4%, 9.8%, and 1.8% were Candida albicans (Ca), Candida glabrata (Cg), Candida parapsilosis (Cp), Candida tropicalis (Ct), and Candida krusei (Ck), respectively. Ca was most common in the 60- to 79-year age group (52.3%) and least common in the 80- to 99-year age group (46.7%), whereas Cg was most common in the 80- to 99-year age group (28.6%) and least common in the 0- to 19-year age group (2.0%). Cp and Ct were most common in the 0- to 19-year age group (28.5% and 12.9%, respectively), and Ck was most common among the patients in the 20- to 39-year age group (3.5%). No resistance to echinocandins was detected among isolates of Ca, Cp, and Ct from all age groups. Likewise, no resistance to posaconazole or voriconazole was observed in isolates of Ca, Cp, or Ck from all age groups. Resistance to both azoles and echinocandins was most prominent among isolates of Cg with the highest resistance rates to echinocandins (16.7%), fluconazole (16.7%), posaconazole (5.0%), and voriconazole (11.1%) among isolates from the 20- to 39-year age group. Both species distribution and antifungal resistance patterns vary markedly with patient age. Cg BSI isolates may show lower susceptibility rates to both azoles and echinocandins with the highest rates of resistance detected in 20- to 59-year-old patients. PMID- 20846810 TI - Development of a colloidal gold-immunochromatography assay to detect immunoglobulin G antibodies to Treponema pallidum with TPN17 and TPN47. AB - Syphilis remains a worldwide public health problem; it is necessary to develop a new diagnostic approach that is easier and faster than conventional tests. Here, we report a new testing method named colloidal gold-immunochromatography assay (GICA) to detect syphilis instead of fluorescent treponemal antibody-absorption (FTA-Abs). Syphilis-specific immunoglobulin G (IgG) antibody was detected with GICA established on syphilis-specific recombinant proteins, TPN17 and TPN47. FTA Abs Treponema pallidum (TP)-IgG was set as the gold standard. A GICA test was performed to detect the serum of 14 967 subjects who took a serologic test for syphilis at the Xiamen Center of Clinical Laboratory, Fujian, China, from March 2009 to February 2010, among which 1326 cases were diagnosed as syphilitic. The results showed that the sensitivity, specificity, and positive predictive value were 99.38% (1279/1287), 99.96% (12,975/12,980), and 99.61% (1279/1284), respectively. The positive rate between the 2 test methods had no significant difference (chi(2) = 0.003, P > 0.05). Detection on 500 interference specimens indicated that the biologic false-positive rate of the GICA test was extremely low and free from other biologic and chemical factors. The characteristics of GICA TP-IgG correspond to that of FTA-Abs TP-IgG (EUROIMMUN Medizinische Labordiagnostika, Germany). The GICA test is convenient, fast, and inexpensive, and it can be used both as a confirmatory test and a screening indicator, instead of FTA-Abs TP-IgG. PMID- 20846809 TI - Jacalin-unbound fraction of Taenia saginata in immunodiagnosis of neurocysticercosis in human cerebrospinal fluid. AB - The aim of this study was to evaluate jacalin-bound fraction (JBF) and jacalin unbound fraction (JUF) of the total saline extract from Taenia saginata metacestodes for human neurocysticercosis (NC) immunodiagnosis in cerebrospinal fluid. Total extract, JBF, and JUF were separated by affinity chromatography using Sepharose((r))-jacalin and were tested in enzyme-linked immunosorbent assay (ELISA) and Western blotting (WB) to detect immunoglobulin G. In ELISA test, JUF showed the higher diagnostic efficiency and specificity indexes, 92% and 100%, respectively. In WB, 5 immunodominant proteins (39-42, 47-52, 64-68, 70, and 75 kDa) were detected when using JUF. In conclusion, the results achieved demonstrate that JUF, obtained from T. saginata metacestodes, are an important source of specific peptides and are efficient in the diagnosis of NC. PMID- 20846811 TI - Genetic organization of plasmid-mediated Qnr determinants in cefotaxime-resistant Enterobacter cloacae isolates in Korea. AB - Because of the strong association between qnr genes and plasmids carrying beta lactamase genes, we screened 176 clinical isolates of Enterobacter cloacae with cefotaxime MICs of >=16 MUg/mL for qnr genes. The qnrA, qnrB, and qnrS genes were detected in 18 (10.2%), 11 (6.2%), and 1 (0.56%) of the isolates, respectively. The genetic environments of the plasmids encoding these qnr genes were analyzed. PMID- 20846812 TI - First report of class 2 integron in clinical Enterococcus faecalis and class 1 integron in Enterococcus faecium in South China. AB - During 2003 to 2004, class 1 integron was detected in 8 out of 10 tested enterococci isolates, with 2 of them positive for class 2 integron. This is the first report of class 2 integron in Enterococcus faecalis and class 1 integron in Enterococcus faecium. PMID- 20846813 TI - Salvage therapy with tigecycline for recurrent infection caused by ertapenem resistant extended-spectrum beta-lactamase-producing Klebsiella pneumoniae. AB - Optimal antimicrobial therapy for infections due to ertapenem-resistant Enterobacteriaceae remains undetermined. In this study, a diabetic patient with recurrent pyomyositis and osteomyelitis caused by extended-spectrum beta lactamase (ESBL)-producing Klebsiella pneumoniae developed ertapenem resistance after imipenem/cilastatin treatment, which was a currently recommended therapy. He was finally treated successfully using tigecycline. Ertapenem resistance was in part explained by the production of SHV-type ESBL and the absence of an outer membrane protein, OmpK36. Our observation suggests that tigecycline may be an alternative for invasive infections caused by ESBL-producing Enterobacteriaceae with decreased susceptibility to carbapenem. PMID- 20846814 TI - Clinicopathologic characteristics of nontuberculous mycobacterial lung disease in Taiwan. AB - Taiwan is an endemic area for tuberculosis (TB), and the incidence of pulmonary infection caused by nontuberculous mycobacteria (NTMs) is also increasing. This study aims to investigate the clinicopathologic characteristics of patients with NTM lung disease during 1998 to 2007 at a medical center in Taiwan. The medical records of patients with confirmed NTM pulmonary infections who underwent open lung surgery in a medical center were reviewed. Twenty-four patients with confirmed NTM pulmonary infections were identified. These patients were histologically classified into 4 types: fibrocavitary/tuberculoid (n = 10), nodular bronchiectatic (n = 4), sarcoidal (n = 6), and other (n = 4). The fibrocavitary/tuberculoid type usually (90%) develops in the upper lobes of old patients with preexisting lung disease. Pulmonary TB (n = 7, 70%) was the major underlying disease before 2003. Nodular bronchiectatic type occurred mainly in the middle lobe of middle-aged women without preexisting lung disease. Sarcoidal type was usually associated with Mycobacterium avium complex infection and develops in middle-aged women. Immunoreactive bacilli were detected in 21 patients (87 %) by immunohistochemical staining using a polyclonal antibody against Mycobacterium tuberculosis and other mycobacterial species (M. avium intracellulare, Mycobacterium phlei, and Mycobacterium parafortuitum), whereas conventional acid-fast staining was positive in only 21% of patients. In conclusion, TB was the major underlying disease in patients with NTM lung disease in Taiwan. The different histologic types of pulmonary NTM infection suggest each had a distinct pathogenesis. PMID- 20846815 TI - Correlation between gastrointestinal fungi and varying degrees of chronic hepatitis B virus infection. AB - This study aims to compare the diversity of intestinal fungal microbiota in patients with different degrees of chronic hepatitis B virus (HBV) infection. Culture-independent and culture-dependent methods were performed on 38 patients with hepatitis B cirrhosis, 35 patients with chronic hepatitis B, 33 HBV carriers, and 55 healthy volunteers. An overall fungal biodiversity of 37 different operational taxonomic units was found in the clone libraries; only Candida spp. and Saccharomyces cerevisiae were obtained by the culture-dependent analysis. There was a higher richness of fungal species in patients with hepatitis B cirrhosis than in patients with chronic hepatitis B, and the latter was higher than that in HBV carriers and healthy volunteers. There was little difference in enteric fungal diversity between HBV carriers and healthy volunteers. The results indicate that the diversity of enteric fungi was positively correlated with the disease progression of patients with different degrees of chronic HBV infection. PMID- 20846816 TI - HIV reverse transcriptase activity assay: a feasible surrogate for HIV viral load measurement in China. AB - The quantitation of HIV viral load using an assay that measures the activity of reverse transcriptase (RT) may provide an alternative strategy for the monitoring of HIV viral load within resource-limited areas in China. Plasma viral load analyses of 215 samples from 87 patients infected with HIV were detected using the RT activity assay (ExaVir Load versions 2 and 3; Cavidi, Uppsala, Sweden) and RT polymerase chain reaction (PCR) (COBAS TaqMan 48, Amplink version 3.2; Roche Molecular Systems, Branchburg, NJ). The RT activity assay versions 3 (RT3) and 2 (RT2) could detect 95.3% and 86.9% of samples with measurable RNA by RT-PCR, respectively. A stronger correlation was observed between viral loads detected by RT3 and RT-PCR than between RT2 and RT-PCR (r = 0.95, P < 0.001, and r = 0.92, P < 0.001, respectively). The correlation between serial samples collected from 6 patients at 1, 3, 6, 12, 18, and 24 months after beginning triple combination antiretroviral therapy, using the 2 different methodologies, was also strong (r = 0.99, P < 0.001, for RT3 and RT-PCR, r = 0.98, P < 0.001, for RT2 and RT-PCR). The viral loads detected by RT activity assay were inversely correlated with CD4(+) T-cell counts. Reproducibility of the RT activity assay was assessed by testing 3 samples in triplicate by 3 different operators. Viral load testing using assays that measure HIV RT activity is an affordable, feasible, simple, and reliable alternative for HIV RNA viral load determination in laboratories in China and other developing countries. PMID- 20846817 TI - Radiation exposure in endovascular procedures. AB - BACKGROUND: The introduction of percutaneous techniques to treat patients with peripheral vascular disease has placed the vascular surgeon in the unique role as the fluoroscopy supervisor overseeing the radiation protection for patient, self, staff, and trainee. Since radiation is an invisible threat in endovascular interventions, attention to protection may be challenging for the surgeon to understand and enforce. METHODS: General endovascular radiation considerations for endovascular aneurysm repair (EVAR) and peripheral interventions are reviewed. RESULTS: Peripheral atherectomy has the highest estimated skin doses of all endovascular procedures. Renal interventions, visceral balloon angioplasty and stenting, and embolization procedures are some of the procedures that have the highest peak skin doses. Patients with high body mass index (BMI) have been found to have up to three times higher peak skin doses than patients with normal BMI. CONCLUSION: The degree of radiation exposure is dependent on the type of endovascular procedure, the patient's body habitus, and also the safety habits of the surgeon. Radiation exposure needs addressed in an informed consent process as is required for other procedures. Radiation exposure risks also need monitoring just as a surgeon monitors individual morbidity and mortality. PMID- 20846818 TI - Quality-of-care indicators for oesophageal cancer surgery: A review. AB - BACKGROUND: Quality-of-care indicators are measurable elements of practice performance that can assess the (change in) quality of the care provided. To date, the literature on quality-of-care indicators for oesophageal cancer surgery has not been reviewed. METHODS: We performed a review of the literature on quality-of-care indicators for oesophageal cancer surgery. The indicators were classified by their nature of care provision (structural, process, or outcome). RESULTS: One hundred thirty articles were included. For structural measures, most evidence was found for the inverse relationship between hospital or surgeon volume and post-operative mortality. Few articles described the required infrastructural and organisational elements for oesophageal cancer surgery. Regarding process measures, the most common indicators were determinants of patient selection for surgery. Other process indicators with considerable evidence were found (e.g., multidisciplinary team management), though the number of studies was small. For outcome indicators, the level of evidence for pathological outcome measures was strong. Data on post-operative complications as outcome indicators varied widely. CONCLUSION: Since there is considerable variation in the evaluation of quality of care, the uniform use of well-defined quality-of-care indicators to measure and document practice performance holds the promise of improving outcome in patients who undergo oesophageal cancer surgery. PMID- 20846819 TI - Radiofrequency ablation as first-line treatment for small solitary hepatocellular carcinoma: long-term results. AB - AIMS: To evaluate long-term results of patients with small solitary hepatocellular carcinoma (HCC) and well-preserved liver function who received radiofrequency ablation (RFA) as first-line treatment. MATERIALS AND METHODS: Between November 1999 and June 2007, 247 patients with solitary HCC <=5 cm and liver status scored as Child-Pugh class A were enrolled. RFA was performed in 224 patients as first-line treatment; 23 patients excluded from RFA because of unfavorable tumor location or their unwillingness, and all of these patients converted to surgical resection. RESULTS: In the 224 patients treated with RFA, the overall 5-, 7-, 10-year survival rates were 59.8%, 55.2%, 33.9%, respectively, and the median of overall survival was 76.1 months. Complete ablation was achieved in 216 patients (96.4%). Major complications occurred in two patients (0.9%), with no treatment-related death or needle track seeding. Indocyanine green retention rate in 15 min (ICGR15) (P = 0.014) and prothrombin activity (P = 0.004) were associated with overall survival. A subgroup of patients with ICGR15 <= 10% and prothrombin activity >75% had 5-, 7-, 10-year survival rates of 67.1%, 64.2%, 57.1%, respectively, with a median survival of 87.7 months. The 10-year recurrence-free, tumor-free survival rates were 17.5%, 28.2%, respectively. Serum albumin was the only factor that significantly impacted recurrence-free and tumor-free survival (P = 0.008, 0.002, respectively). CONCLUSION: RFA is considered to be the treatment of first choice for patients with solitary HCC <=5 cm and well-preserved liver function. Surgery can be used as second-line therapy for few patients if RFA is unfeasible. PMID- 20846820 TI - [Thyrotoxicosis: adjunctive cholestyramine therapy]. PMID- 20846821 TI - The relationship between phonological processing skills and word and nonword identification performance in children with mild intellectual disabilities. AB - Word and nonword identification skills were examined in a sample of 80 elementary school age students with mild intellectual disabilities and mixed etiologies who were described as struggling to learn to read by their teachers. Performance on measures of receptive and expressive vocabulary, measures of phonological awareness, and measures of word and nonword identification were included for analyses. Hierarchical regression analyses indicated that, after controlling for chronological age and vocabulary knowledge, phonological processing accounted for a large and significant amount of unique variance of both word and nonword identification. In addition, the pattern of results found in this study is similar to that obtained with typically developing learners. As with typically developing children, measures of phonological awareness were significantly correlated with measures of both reading achievement and vocabulary knowledge. PMID- 20846822 TI - Looking inside self-organizing map ensembles with resampling and negative correlation learning. AB - In this work, we focus on the problem of training ensembles or, more generally, a set of self-organizing maps (SOMs). In the light of new theory behind ensemble learning, in particular negative correlation learning (NCL), the question arises if SOM ensemble learning can benefit from non-independent learning when the individual learning stages are interlinked by a term penalizing correlation in errors. We can show that SOMs are well suited as weak ensemble components with a small number of neurons. Using our approach, we obtain efficiently trained SOM ensembles outperforming other reference learners. Due to the transparency of SOMs, we can give insights into the interrelation between diversity and sublocal accuracy inside SOMs. We are able to shed light on the diversity arising over a combination of several factors: explicit versus implicit as well as inter diversities versus intra-diversities. NCL fully exploits the potential of SOM ensemble learning when the single neural networks co-operate at the highest level and stability is satisfied. The reported quantified diversities exhibit high correlations to the prediction performance. PMID- 20846823 TI - Use of a custom designed external fixator system to treat ballistic injuries to the mandible. AB - The authors describe a custom designed mandibular external fixator II system that can be used to treat complex, comminuted fractures. The system is adjustable and lightweight, quick, robust, simple to apply, and allows mouth opening during healing, It is well suited to use in the modern war surgery environment. The authors present a case of successful treatment of a ballistic fracture of the mandible using this device. PMID- 20846824 TI - Mild to moderate aortic stenosis and coronary bypass surgery. AB - BACKGROUND: Aortic stenosis (AS) is the most common valvular disease in adult cardiac surgery and its incidence continues to rise. Increasingly older patients are being referred for coronary artery bypass grafting (CABG) with mild to moderate AS. Concomitant aortic valve replacement (AVR) for patients with moderate or severe AS undergoing CABG is warranted regardless of symptoms. Concomitant AVR remains contentious in patients with less than moderate severity AS undergoing CABG. MATERIALS AND METHODS: We review the contemporary literature aiming to resolve this dilemma in clinical practice. The assessment of these patients is reviewed. Considerations include identifying the rapid progressors, and balancing the risks of concomitant valve surgery against the potential prognostic gains. RESULTS: Pathophysiological links between degenerative calcific AS and coronary artery disease suggest that the disease is an active, progressive process with mutually shared risk factors. Statins, however, offer limited protection against AS, despite its established role in coronary artery disease. Age, atherosclerosis risk, valve morphology, motion, and hemodynamics identify the rapid progressors, whilst the patients' general comorbidities and life expectancy influence the risk-benefit profile of concomitant operations. CONCLUSION: A precise echocardiographic quantification of the stenotic grade is mandatory before adopting any therapeutic strategy. Concomitant AVR for moderate AS is recommended if surgical risk is not prohibitive. Concomitant AVR for mild AS in 'rapid progressors' (i.e. moderate-severe valve calcification) may be considered, but patients should have reasonable life expectancy exceeding 5 years. Moderately restricted leaflet motions, gradient increase of > 10 mm Hg per year, and aortic jet velocity increase > 0.4 m/s per year further supports intervention. Comorbidities increasing atherosclerotic burden and renal dialysis accelerate AS progression and increase surgical risk. Procedural advances in interventional cardiology and minimally invasive cardiac surgery may further expand the options available for these patients. PMID- 20846825 TI - Promoter-specific lentivectors for long-term, cardiac-directed therapy of Fabry disease. AB - In Fabry disease a deficiency of alpha-galactosidase A (alpha-gal A) activity leads to accumulation of globotriaosylceramide (Gb3) in various tissues including the heart. A specific cardiac variant of Fabry disease has also been described. Previously we have demonstrated the feasibility of gene therapy for Fabry disease. Here, to provide efficient transfer and increased specificity of transgene expression, we synthesized lentiviral vectors (LVs) with myocardial specific promoters including: alpha-myosin heavy chain (alpha-MHC), myosin light chain (MLC2v), and cardiac troponin T (cTnT). Initially, neonatal Balb/c mice were injected with such LV constructs engineering expression of luciferase. One month post-injection, we found specific expression of luciferase in hearts of recipient animals when compared with transgene expression driven by the standard EF1-alpha promoter. To examine the feasibility of long-term therapy specifically targeting the heart, recombinant LV/alpha-gal A therapeutic vectors with analogous cardiac promoters were generated and injected into numerous neonatal Fabry mice. No immune response against the corrective alpha-gal A hydrolase was observed in the treated mice. Serum alpha-gal A activity of 10-week-old Fabry mice was increased in LV/alpha-gal A-injected animals compared to controls. In 28 week-old Fabry mice we observed significantly decreased Gb3 accumulation. Neonatal injections with LVs harboring cardiac-specific promoters may thus be an effective long-term treatment strategy for heart manifestations and cardiac variant Fabry disease. These results can be also extended to other progressive pathologies of the heart. PMID- 20846826 TI - CNS infection in childhood does not confer risk for later schizophrenia: a case control study. AB - OBJECTIVE: The hypothesized role of CNS infection during childhood in increasing later risk of brain malfunction manifested as schizophrenia has been supported by some but not other studies. We sought to contribute to this debate by linking data on persons who had been hospitalized for meningitis as children, with a National Psychiatric Hospitalization Registry. METHOD: Data were gathered on 3599 persons who had been hospitalized for a CNS infection before the age of 16, and 6371 controls who had been hospitalized as children for gastroenteritis. Both groups were followed for later hospitalization for schizophrenia between 1970 and 2007 using the Israeli National Psychiatric Hospitalization Case Registry. Data were analyzed using Cox regression analyses. RESULTS: The mean age of the subjects at hospitalization for a CNS infection was 3.4 +/- 3.6 years, mean age of the subjects at follow up was 29.3 +/- 6.0 years. Compared to controls, hospitalization for any CNS infection during childhood was not associated with an increased risk of later hospitalization for schizophrenia, adjusted HR = 0.81, 95% CI: 0.5-1.32. CONCLUSIONS: Overall there was no significant association between childhood CNS infection and schizophrenia. These data do not support the presence of an infectious etiology of schizophrenia. PMID- 20846827 TI - Single report of beta-lactam resistance in an invasive Haemophilus influenzae isolate from South Africa mediated by mutations in penicillin-binding protein 3, 2003-2008. PMID- 20846828 TI - Characterisation of Staphylococcus aureus and Enterococcus faecalis mutants with reduced susceptibility to the investigational oxazolidinone RWJ-416457. AB - RWJ-416457 is a novel investigational oxazolidinone with minimum inhibitory concentrations (MICs) to staphylococci and enterococci that are two- to four-fold lower than those of linezolid. Single-step and serial passage in vitro resistance selection experiments were performed for RWJ-416457 and linezolid with Staphylococcus aureus and Enterococcus faecalis laboratory and clinical isolates. RWJ-416457 selected for resistant mutants in single-step selections at a frequency of <=1*10(-10), similar to that of linezolid. In serial passage selection experiments, a G2576T transversion in the domain V region of the 23S rRNA gene was the predominant mutation observed for both oxazolidinones, suggesting similar 23S rRNA binding sites. The associated development of increasing oxazolidinone resistance in E. faecalis (four 23S rRNA alleles) required fewer passages than with S. aureus isolates (six 23S rRNA alleles), and resistance was generally proportionate to the number of mutated (G2576T) 23S rRNA alleles. Fold changes in MICs were similar for both compounds, and MICs for RWJ 416457 remained two- to four-fold lower than those of linezolid for mutants selected by either compound. Serial passage of linezolid with S. aureus OC 2878 yielded a novel A2572T 23S rRNA mutation, whilst the final passages of S. aureus OC 10517 with RWJ-416457 resulted in the apparent loss of a mutated (G2576T) allele 6. PMID- 20846829 TI - Longitudinal analysis of the in vitro activity profile of oritavancin and comparator glycopeptides against Gram-positive organisms from Europe: 2005-2008. PMID- 20846830 TI - In vitro activity of ceftobiprole against meticillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA), vancomycin-resistant S. aureus (VRSA) and daptomycin-non-susceptible S. aureus (DNSSA). PMID- 20846831 TI - gyrB and parE mutations in urinary Mycoplasma genitalium DNA from men with non gonococcal urethritis. PMID- 20846832 TI - High-dose daptomycin in documented Staphylococcus aureus infections. AB - Daptomycin is approved at a dose of 4-6 mg/kg/day for the treatment of complicated skin and soft-tissue infection and Staphylococcus aureus bloodstream infection. Clinical experience with doses >6 mg/kg/day is limited, but data reported to date suggest that daptomycin can be safe and effective at higher doses. We describe our experience with daptomycin at doses >6 mg/kg/day and <=6 mg/kg/day for S. aureus infections. A retrospective chart review of all patients treated with daptomycin from January 2008 to 28 February 2010 was performed. During the study period, 53 patients received daptomycin, including 22 patients receiving daptomycin at a standard dose (SD) (mean 5 mg/kg/day, range 4-6 mg/kg/day) and 31 patients receiving a higher dose (HD) (mean 8 mg/kg/day, range 7-9 mg/kg). The median treatment duration was 13.5 days and 19 days for the SD and HD groups, respectively. Clinical success was observed in 16/22 patients (73%) in the SD group and 29/31 patients (94%) in the HD group (P=0.05). Microbiological success was observed in 13/19 patients (68%) and 27/29 patients (93%) in the SD and HD groups, respectively (P<0.05). Of the 53 patients, 2/22 treated with SD daptomycin and 3/31 treated with HD daptomycin experienced a grade 1 adverse event while receiving therapy (i.e. anaemia, diarrhoea, nausea, hypokalaemia and arthralgia) but did not require discontinuation of daptomycin treatment. These results suggest that daptomycin may be used at doses higher than 6 mg/kg/day without toxicity and possibly with better outcome than conventional doses. We recommend further randomised controlled prospective studies with higher doses of daptomycin. PMID- 20846833 TI - Empirical first-line treatment with tigecycline for febrile episodes following abdominal surgery in cancer patients. AB - Cancer patients with complicated infections following abdominal surgery represent one of the worst clinical scenarios that is useful for testing the efficacy of empirical antimicrobial therapy. No study so far has evaluated the performance of tigecycline (TIG) when administered as empirical first-line treatment in a homogeneous population of surgical cancer patients with a febrile episode. An observational review of the data records of 24 sequential patients receiving TIG for a febrile episode following a major abdominal procedure in a single cancer institute was performed. Large bowel surgery represented 68% of all procedures, followed by gastric surgery (16%) and urinary-gynaecologic-biliary surgery (16%). Complications following surgery were observed in 68% of febrile episodes, with peritonitis and sepsis accounting for 59% and 24% of complications, respectively. Eight patients needed repeat surgery for source control. The mean duration of TIG treatment was 8 days. Causative pathogens were detected in 16 episodes (64%), and a total of 44 microorganisms were recovered (29% Escherichia coli, 9% Enterococcus faecalis and 9% coagulase-negative staphylococci). TIG was effective in 12 episodes (48%). The success rate was 67% when infectious episodes sustained by intrinsically resistant bacteria and fungi were excluded. Treatment failure was associated with the presence of complications and with microbiologically documented infection. TIG may be useful as a first-line treatment option in cancer patients requiring antibiotic treatment following surgery when complications are not present or suspected on clinical grounds and when local microbial epidemiology shows a low incidence of primary resistant bacteria. PMID- 20846834 TI - Multidrug encapsulation by coaxial tri-capillary electrospray. AB - This study describes how a coaxial tri-capillary electrospray (ES) system can synthesize monodisperse PLGA-coated particles containing multiple drugs in one step. The coaxial arrangement of three separate capillaries in an ES nozzle enables production of composite particles with tri-layered structures without the complicated steps involved in emulsion processes. Various materials can be encapsulated in separate layers of individual composite particles without regard for the hydroscopic property of drugs. At the proper spray setting, nearly 100% drug encapsulation efficiency can be achieved. By varying the feed flowrate of spray solutions, the overall particle sizes, ranging from submicrometer to micrometer, and the thickness of the layers in produced particles can also be controlled. Size and tri-layered structure of the composite particles were characterized by SEM and laser scanning confocal microscopy (LSCM). We further explored the spray technique in the production of tri-layered composite particles having a controlled multidrug-release profile, and compared the release profiles of both core-shell structured particles (produced by coaxial dual-capillary ES) and tri-layered ones (produced by coaxial tri-capillary ES). The comparison showed that composite particles with the tri-layered structure can release multiple drugs in distinct kinetic phases. We further demonstrated that the release profile of tri-layered composite particles can be effectively controlled by varying the thickness and chemical composition of their individual layers. PMID- 20846835 TI - Interactive optimization of biosurfactant production by Paenibacillus alvei ARN63 isolated from an Iranian oil well. AB - The potential of an indigenous bacterial strain isolated from an Iranian oil field for the production of biosurfactant was investigated in this study. After isolation, the bacterium was characterized to be Paenibacillus alvei by biochemical tests and 16S ribotyping. The biosurfactant, which was produced by this bacterium, was able to lower the surface tension of media to 35 mN/m. Accordingly, thin layer chromatography (TLC) and FT-IR has been carried out to determine compositional analysis of the produced biosurfactant. After all the tests related to characterization of the biosurfactant produced by the isolated bacterium, it was characterized as lipopeptide derivative. The combination of central composite rotatable design (CCRD) and response surface methodology (RSM) was exploited to optimize biosurfactant production. Therefore, variations of four impressive parameters, pH, temperature, glucose and salinity concentrations were selected for optimization of growth conditions. The empirical model developed through RSM in terms of effective operational factors mentioned above was found to be adequate to describe the biosurfactant production. A maximum reduction in surface tension was obtained under the optimal conditions of 13.03 g/l glucose concentration, 34.76 degrees C, 51.39 g/l total salt concentration and medium pH 6.89. PMID- 20846836 TI - Interaction of cationic phosphorus dendrimers (CPD) with charged and neutral lipid membranes. AB - Despite the rapid development of modern pharmaceutics, delivery of drugs to sites of action is not always effective. The research on new targeting delivery systems of pharmacologically active molecules is of great importance. Surface properties such as surface charge of drug delivery particles frequently define their pharmacokinetic profile; hence the efficiency of drugs can be increased by application of nanoparticles having appropriate surface properties. The aim of the present work was to study the interactions of cationic phosphorus-containing dendrimers (CPD) with model lipid membranes with no charge or bearing surface charge. The interactions of two generations of phosphorus dendrimers on the thermotropic behavior of model lipid membranes composed of DMPC (uncharged) or DMPC/DPPG (negatively charged) were studied using differential scanning calorimetry (DSC). The results of this study showed that CPDs can alter the thermotropic behaviour of the bilayer by reducing the cooperativity of phospholipids and this effect strongly depends on membrane surface charge. The information resulting from this study may be applied to the rational design of new drug carriers combining liposomal and dendrimeric technology. PMID- 20846837 TI - The adsorption of antifreeze glycoprotein fraction 8 on dry and wet mica. AB - The adsorption of AFGP 8 on mica was studied by atomic force microscopy. The results shown in this paper emphasize the strong adsorption affinity of these proteins to hydrophilic surfaces, in this case mica. The dependence of the surface morphology while drying a droplet of protein solution, and the tendency to form 3-D aggregates at high concentration was observed. The behavior indicates that single-molecule-high aggregates (8.1 A) are formed at low concentration; as the concentration increases, a double layer seems to appear in equilibrium with large aggregates; and as the concentration is increased further, the equilibrium is shifted toward larger aggregates leaving behind residual single-molecule-high aggregates. The hydrophilicity of the protein was demonstrated by the spontaneous adsorption of the protein directly from solution, as monitored by in situ imaging. PMID- 20846838 TI - How can we deal with mental distress in the dissection room?-An evaluation of the need for psychological support. AB - The dissection course (DC) is an essential part of the preclinical medical curriculum that mediates professionalism. The process of dissecting, however, has an inherent additional stress potential. Our study determined student mental stress, their need of psychological support and factors influencing this need. A quantitative longitudinal query before, during and after the DC was performed including the Brief Symptom Inventory (BSI) as well as self-formulated questions used a 5-point Likert scale. Half of the students who anticipated dissection to be a stress factor reported that this declined significantly over time. Instead, student fear of not being able to cope with the work load increased significantly. As many as 64% of the students favored psychological support on the first course day, while 75% rejected this during the period of dissection and 39% appreciated this after the course. Moreover, 42% emphasized the importance of the funeral ceremony. Additionally, 75% documented their need for support in coping with stress and learning strategies. Gender, previous medical training, and BSI levels were identified as psychosocial influence factors. A majority of students named friends, members of their family or workmates as partners with whom they could talk about mental stress. Our results document the need to develop an optimum support during the DC taking into account the ascertained indicators. Exemplarily the Institute of Anatomy and Cell Biology at Ulm University suggests several options like a step by step approach for optimization. These measures reduce mental stress and help students to cope with it by the development of "detached concern" towards their "first patient" as this will decisively influence their future professional behavior. PMID- 20846839 TI - Potentially modifiable predictors of mortality in patients treated with long-term oxygen therapy. AB - INTRODUCTION: Anemia is considered a systemic manifestation of Chronic Obstructive Pulmonary Disease (COPD); however, few studies have described its influence on chronic respiratory failure (CRF) prognosis. We aimed to test the hypotheses that anemia negatively influences survival and also to identify the cut-off points of hematocrit (Htc) and hemoglobin (Hb) associated with higher mortality in CRF patients using long-term oxygen therapy (LTOT). METHODS: One hundred forty two patients with CRF in use of LTOT were evaluated at baseline and followed for three years or until death. Baseline assessment included identification, diagnosis, body composition, dyspnea, health status (HS), spirometry, arterial blood gases, Hb and Htc. Univariate and Cox proportional hazard models were used to evaluate predictors of mortality. We performed ROC curve to identify the best cut-off point of the variables related to survival to construct the Kaplan-Meier curves. RESULTS: Eight-three patients (58%) died after three years. Baseline values of Hb and Htc were significantly lower in the non survivors group and both, Htc (HR, 0.96; 95%CI 0.91-0.99; p = 0.04), Hb (HR, 0.86; 95%CI 0.76-0.98; p = 0.02) were selected as predictors of mortality after three years. The cut-off points determined were: the value of HB is < 11 g/dl (sensitivity 95% specificity 85%), Htc <= 33% (sensitivity 97% specificity 89%). Other prognostic factors were: male gender, low PaCO(2) and SpO(2), higher dyspnea perception and impairment of HS. CONCLUSIONS: Our study shows that anemia is a predictor of mortality in patients with CRF under LTOT treatment. Although anemia is potentially modifiable, the effects of raising hemoglobin on mortality remain undetermined. PMID- 20846840 TI - Who gets cut during cell death? AB - The recent introduction of positional proteomics made it possible to screen for protease processing events on a proteome-wide scale. As a highly regulated and protease-dependent process, cell death has been particularly well-studied with these emerging technologies. This review provides an overview of the results obtained at the exciting interface between proteomics, protease biology and cell death. PMID- 20846843 TI - Surface IR immunosensors for label-free detection of benzo[a]pyrene. AB - Polycyclic aromatic hydrocarbons (PAHs) are a family of contaminants originating from the incomplete combustion of organic compounds, present in the urban air, water, soil and also foodstuff. Due to their recognised carcinogenicity, their concentration in urban air is routinely monitored and governmental instances have set rules as regards their maximum allowable concentration. Benzo[a]pyrene (BaP) is one of the PAHs, highly toxic, whose concentration correlates well with the total PAHs contents in environmental samples; its detection by immunosensors has been rarely described because of its low molecular weight and poor solubility in water. In this paper, we report the design and testing of optical and piezoelectric immunosensors for the determination of BaP by using Polarisation Modulation Infrared Reflection-Absorption Spectroscopy (PM-IRRAS) or Quartz Crystal Microbalance with dissipation measurements (QCM-D) as transduction techniques, and a comparison of their analytical performances. We found relevant to set up immunosensors based on a direct or indirect competitive format. BaP was detected by PM-IRRAS with both immunosensor formats with similar sensitivity, ca. 5 MUM. Flow-injection piezoelectric transduction in the indirect competitive format set up led to a slightly better sensitivity than that reached by PM-IRRAS. No general conclusion about the most efficient set up could be drawn from comparing the sensitivities, but the reported data illustrate the potential of PM IRRAS as well as flow-injection QCM-D as efficient label-free transduction techniques. PMID- 20846844 TI - Ultrathin Pd nanowire as a highly active electrode material for sensitive and selective detection of ascorbic acid. AB - Nanomaterial modified electrode is useful for catalytic, analytical and biotechnological applications. Herein, a simple and sensitive method for the electrocatalytic detection of ascorbic acid (AA) using ultrathin Pd nanowire (NW) modified glassy carbon electrode is presented. Electrochemical data reveal that Pd NWs can effectively enhance the electron transfer between AA and electrode, and thus reduce the overpotential of AA oxidation. Particularly, the current-time curve shows that the catalytic oxidation current is linearly dependent on AA concentration in the range of 25 MUM-0.9 mM with a correlation coefficient 0.9998, and a detection limit of 0.2 MUM (S/N=3) is obtained with an excellent reproducibility. What is more, the present Pd NWs-based electrochemical sensing platform can successfully be used as enhanced element for the detection of AA in the practical samples such as human serum and vitamin C beverage with satisfactory results. PMID- 20846841 TI - Distinct death mechanisms in Drosophila development. AB - Apoptosis and autophagic cell death occur during Drosophila development, and recent advances in their mechanisms have been made. As in other organisms, apoptosis is executed by caspases. In living cells, caspases are kept in check through a combination of IAP-binding and proteolytic inhibition. Once a cell commits to apoptosis, phagocytes recognize them through the immuno-receptor-like proteins Draper and Simu, and initiate corpse engulfment. Drosophila research has significantly contributed to the idea that autophagy is required for certain forms of cell death, and that caspase function in autophagic cell death depends on cell context. Surprisingly, the cell corpse engulfment receptor Draper also functions in autophagic cell death. These advances facilitate our understanding of the cell death mechanisms in development and disease. PMID- 20846845 TI - Development of a novel terbium chelate-based luminescent chemosensor for time resolved luminescence detection of intracellular Zn2+ ions. AB - Time-resolved luminescence detection technique using lanthanide chelates as luminescent probes or sensors is a highly sensitive and widely used tool for the luminescence detections of various biological and bioactive molecules. The essential of this technique is the developments of various functional luminescent probes or sensors that can selectively recognize the biological targets. In this work, a dual-chelating ligand N,N,N(1),N(1)-{2,6-bis(3'-aminomethyl-1'-pyrazolyl) 4-[N,N-bis(2-picolyl)amino-methylenepyridine]} tetrakis(acetic acid) (BBATA) has been designed and synthesized. The luminescence of its Tb(3+) chelate is very weak, but can be selectively and strongly enhanced upon reaction with Zn(2+) ions. Thus a Tb(3+) chelate-based luminescent chemosensor, BBATA-Tb(3+), for highly selective and sensitive time-resolved luminescence detection of Zn(2+) ions was developed. To confirm the utility of new chemosensor for the detection of intracellular Zn(2+) ions, the performance of BBATA-Tb(3+) as a chemosensor for time-resolved luminescent imaging detection of Zn(2+) ions in living cells was investigated. The results demonstrated the efficacy and advantage of the new luminescent chemosensor for time-resolved luminescence detection of intracellular Zn(2+) ions. PMID- 20846846 TI - Functionalized ZnO nanorod-based selective magnesium ion sensor for intracellular measurements. AB - ZnO nanorods were grown on a silver-coated tip of a borosilicate glass capillary (0.7 MUm in tip diameter) and used as selective potentiometric sensor of intracellular free Mg(2+). To functionalize the ZnO nanorods for selectivity of Mg(2+), a polymeric membrane with Mg(2+)-selective ionophores were coated on the surface of the ZnO nanorods. These functionalized ZnO nanorods exhibited a Mg(2+) dependent electrochemical potential difference versus an Ag/AgCl reference microelectrode within the concentration range from 500 nM to 100 mM. Two types of cells, human adipocytes and frog oocytes, were used for the intracellular Mg(2+) measurements. The intracellular concentration of free Mg(2+) in human adipocytes and frog oocytes were 0.4-0.5 and 0.8-0.9 mM, respectively. Such type of nanoelectrode device paves the way to enable analytical measurements in single living cells and to sense other bio-chemical species at the intracellular level. PMID- 20846847 TI - Bacteria adsorption on hydrophilic surfaces for the sensitive detection of pathogenic bacteria using a single tube chamber system. AB - Here, we developed a simple and effective bacterial isolation method that can be directly used for the detection of pathogenic bacteria. This approach only requires a single plastic tube chamber that can performing serial processes such as cell gathering, cell lysis, nucleic acid amplification, and signaling without the need to transfer samples from one chamber to another. A TEOS (tetraethoxysilane) surface was selected for this application because of its superior performance in the amplification process as well as the ability of bacteria to adsorb to its surface, which is necessary for all processes to be performed in single chamber. The optimal aquatic buffer conditions for bacteria adsorption on the hydrophilic surface were determined to be 1% polyethylene glycerol (PEG) and 10 mM MgCl(2) in 100 mM phosphate at pH 4 for the gram negative bacteria, Escherichia coli O157:H7 (E. coli O157:H7) and 10 mM Na(2)SO(4) in 100 mM phosphate in 100 mM phosphate at pH 4 for the gram positive bacteria, Bacillus cereus (B. cereus). When these divalent cation and anion (MgSO(4)) containing acidic solutions were used, 40% of both bacteria adsorbed onto the hydrophilic surface at a loading rate of 2 mL/min after introduction of low concentrations of bacteria. This method was directly employed to detect E. coli O157:H7 in beef using a single plastic tube chamber that was partially filled with nickel micro beads coated with TEOS. In this system, E. coli O157:H7 were lysed by induction heating of the nickel micro beads. The extracted mRNA was readily amplified and detected by adding an isothermal amplification mixture (NASBA, nucleic acid sequence based amplification) containing a hair-loop type reporting probe with FAM and DABCYL. As a result, this highly sensitive sensing tool could detect very low concentrations of E. coli [10(0) CFU/1 g of beef]. PMID- 20846848 TI - Label-free DNA methylation analysis using opto-fluidic ring resonators. AB - The opto-fluidic ring resonator (OFRR) is a sensitive label-free optical biosensor that is uniquely well suited for photonic and fluidic integration. For the first time we have explored the utility of this novel instrument for the analysis of methylation in oligonucleotides using the MBD-2 (methyl binding) protein as the capture molecule. This application has strong relevance to cancer research and future clinical tools through the study of methylation patterns in important gene promoters. In this work we quantitatively characterized the OFRR's response to artificially methylated ssDNA and dsDNA as a function of the number of methylated cytosines and DNA concentration. The effect of hemi- versus fully methylated oligonucleotides was also investigated. Additionally, anti 5 methylcytidine antibody was also used as the capture molecule and compared with MBD-2. It is found that the antibody has stronger affinity for ssDNA, whereas MBD 2 is much better at binding dsDNA. PMID- 20846849 TI - The effect of registration surrogate and patient factors on the interobserver variability of electronic portal image guidance during prostate radiotherapy. AB - Intraprostatic fiducial markers (IPM) and electronic portal imaging (EPI) are commonly used to identify and correct for prostate motion during radiotherapy. However, little data is available on the precision of this image-guidance technique. This study quantified impact of different registration surrogates and patient factors on the interobserver variability of manual EPI alignment during prostate radiotherapy. For 50 prostate radiotherapy patients previously implanted with 3 IPM, five observers manually aligned 150 pairs of orthogonal EPI to the reference digital reconstructed radiograph using Varian Vision EPI analysis software. Images were aligned using: Bony anatomy (BA), single mid-prostate IPM (SM); and 2 strategies using 3 IPM: center of mass (COM) and rotate & translate (R&T). Intraclass correlation coefficients (ICCs) were calculated to quantify interobserver variability. The absolute displacements measured using SM and R&T were compared with those using COM. The impact of patients' pelvic diameter and adjuvant hormone therapy on interobserver variability were also evaluated. Twelve thousand displacement values were collected for analysis. The maximum discrepancy between the 5 observers was >2 mm in 47% of measurements using BA, 5% using SM, 4% using R&T, and 3% using COM. Both of the 3 IPM alignment strategies demonstrated lower interobserver variability than the single IPM strategy (ICC 0.94-0.97 vs. 0.82-0.94). BA had the highest interobserver variability (ICC = 0.43-0.90). Pelvic diameter and hormone therapy had no discernible impact on interobserver variability. Compared with COM, the absolute displacements measured using the other IPM strategies were statistically different (p < 0.001), but 95% of the absolute magnitude of differences between the strategies were <=1 mm. The high reproducibility among the observers demonstrated the precision of prostate localization using multiple IPM and EPI, which was not influenced by the patient factors studied. Bony anatomy displayed the highest interobserver variability of the 4 alignment, likely because of the limited EPI field-of-view. Alignment using more than one IPM is recommended to minimize interobserver variability. PMID- 20846850 TI - Dosimetric comparison of 6 MV and 15 MV single arc rapidarc to helical TomoTherapy for the treatment of pancreatic cancer. AB - We conducted a planning study to compare Varian's RapidArc (RA) and helical TomoTherapy (HT) for the treatment of pancreatic cancer. Three intensity modulated radiotherapy (IMRT) plans were generated for 8 patients with pancreatic cancer: one using HT with 6-MV beam (Plan_(HT6)), one using single-arc RA with 6 MV beam (Plan_(RA6)), and one using single-arc RA with 15-MV beam (Plan_(RA15)). Dosimetric indices including high/low conformality index (CI(100%)/CI(50%)), heterogeneity index (HI), monitor units (MUs), and doses to organs at risk (OARs) were compared. The mean CI(100%) was statistically equivalent with respect to the 2 treatment techniques, as well as beam energy (0.99, 1.01, and 1.02 for Plan_(HT6), Plan_(RA6), and Plan_(RA156,) respectively). The CI(50%) and HI were improved in both RA plans over the HT plan. The RA plans significantly reduced MU (MU(RA6) = 697, MU(RA15) = 548) compared with HT (MU(HT6) = 6177, p = 0.008 in both cases). The mean maximum cord dose was decreased from 29.6 Gy in Plan_(HT6) to 21.6 Gy (p = 0.05) in Plan_(RA6) and 21.7 Gy (p = 0.04) in Plan_(RA15). The mean bowel dose decreased from 17.2 Gy in Plan_(HT6) to 15.2 Gy (p = 0.03) in Plan_(RA6) and 15.0 Gy (p = 0.03) Plan_(RA15). The mean liver dose decreased from 8.4 Gy in Plan_(HT6) to 6.3 Gy (p = 0.04) in Plan_(RA6) and 6.2 Gy in Plan_(RA15). Variations of the mean dose to the duodenum, kidneys, and stomach were statistically insignificant. RA and HT can both deliver conformal dose distributions to target volumes while limiting the dose to surrounding OARs in the treatment of pancreatic cancer. Dosimetric advantages might be gained by using RA over HT by reducing the dose to OARs and total MUs used for treatment. PMID- 20846851 TI - High-throughput, single-cell NF-kappaB dynamics. AB - Single cells in a population often respond differently to perturbations in the environment. Live-cell microscopy has enabled scientists to observe these differences at the single-cell level. Some advantages of live-cell imaging over population-based methods include better time resolution, higher sensitivity, automation, and richer datasets. One specific area where live-cell microscopy has made a significant impact is the field of NF-kappaB signaling dynamics, and recent efforts have focused on making live-cell imaging of these dynamics more high-throughput. We highlight the major aspects of increasing throughput and describe a current system that can monitor, image and analyze the NF-kappaB activation of thousands of single cells in parallel. PMID- 20846853 TI - Logistic distributed activation energy model--Part 1: Derivation and numerical parametric study. AB - A new distributed activation energy model is presented using the logistic distribution to mathematically represent the pyrolysis kinetics of complex solid fuels. A numerical parametric study of the logistic distributed activation energy model is conducted to evaluate the influences of the model parameters on the numerical results of the model. The parameters studied include the heating rate, reaction order, frequency factor, mean of the logistic activation energy distribution, standard deviation of the logistic activation energy distribution. The parametric study addresses the dependence on the forms of the calculated alpha-T and dalpha/dT-T curves (alpha: reaction conversion, T: temperature). The study results would be very helpful to the application of the logistic distributed activation energy model, which is the main subject of the next part of this series. PMID- 20846852 TI - Feasibility of hydrogen production from ripened fruits by a combined two-stage (dark/dark) fermentation system. AB - Anaerobic fermentation for hydrogen (H2) production was studied in a two-stage fermentation system fed with different ripened fruit feedstocks (apple, pear, and grape). Among the feedstocks, ripened apple was the most efficient substrate for cumulative H2 production (4463.7 mL-H2 L(-1)-culture) with a maximum H2 yield (2.2 mol H2 mol(-1) glucose) in the first stage at a hydraulic retention time (HRT) of 18 h. The additional cumulative biohydrogen (3337.4 mL-H2 L(-1)-culture) was produced in the second stage with the reused residual substrate from the first stage. The major byproducts in this study were butyrate, acetate, and ethanol, and butyrate was dominant among them in all test runs. During the two stage system, the energy efficiency (H(2) conversion) obtained from mixed ripened fruits (RF) increased from 4.6% (in the first stage) to 15.5% (in the second stage), which indicated the energy efficiency can be improved by combined hydrogen production process. The RF could be used as substrates for biohydrogen fermentation in a two-stage (dark/dark) fermentation system. PMID- 20846854 TI - Optimization of medium for enhancement of epsilon-poly-L-lysine production by Streptomyces sp. M-Z18 with glycerol as carbon source. AB - The goal of this study was to increase epsilon-Poly-L-Lysine (epsilon-PL) production by Streptomyces sp. M-Z18 through optimization of the culture medium. Glycerol, (NH4)2SO4 and K2HPO4 were the key factors in the fermentation according to the results obtained from the Plackett-Burman experimental design. The optimal concentration of the three factors was further investigated according to the central composite design and determined to be 59.48, 4.43 and -0.49 g/L, respectively. Under optimal conditions, a epsilon-PL concentration of 2.27+/-0.15 g/L was obtained. Compared with glucose, fermentation of glycerol afforded 2.8 fold and 6.3-fold the epsilon-PL titer and yield, respectively. Therefore, glycerol may be an efficient carbon source for epsilon-PL production by Streptomyces sp. M-Z18. PMID- 20846855 TI - A multi-level bioreactor to remove organic matter and metals, together with its associated bacterial diversity. AB - The purpose of this study was to treat complex wastewater consisting of domestic wastewater, tobacco processing and building materials washings. The proposed multi-level bioreactor consists of a biopond-biofilter, anoxic/aerobic (A/O) fluidized beds and a photoautotrophic system. The results show that when the hydraulic load of the bioreactor was 200 m3/d, it successfully and simultaneously removed the organic matter and metals. When the bioreactor was in a relatively steady-state condition, the overall average organic matter and metals removal efficiencies are as follows, COD (89%), UV245 nm-matter (91%), Cu (78%), Zn (79%) and Fe (84%). The growth conditions of the native bacterial habitat were improved, which resulted from the increase of the in bacterial diversity under the rejuvenated conditions induced by the bioreactor. The results demonstrate that the multi-level bioreactor, without a sludge treatment system, can remove heterogeneous organic matter and metals from wastewater. PMID- 20846856 TI - Exploitation of hemicellulose, cellulose and lignin from Hesperaloe funifera. AB - This work seeks the integral use of all major components of Hesperaloe funifera, separating hemicelluose by hydrothermal treatments; cellulose by pulping processes; and exploitation of lignin of pulping liquor by pyrolysis and gasification processes. By using sulfuric acid in the hydrothermal treatment (150 190 degrees C, 0-20 min after reaching operating temperature, 6-10 liquid/solid ratio, 0.1-0.5% sulfuric acid), the glucose and xylose of liquid fraction increase from 1.5% to 5.9%, and 4.0% to 12.4%, respectively; the yields of solid fraction decrease from 91.6% to 79.5%, and the lignin content increase from 23% to 32%. Pulps and paper sheets obtained from solid fractions hydrothermal treatments and from raw material pulped with diethanolamine, are worse than those obtained with soda-anthraquinone (Yield 57.8%; kappa number 24.9; Viscosity 711 mL/g; Brightness 54.8%; Tensile index 73.6 Nm/g; Stretch 2.84%; Burst index 6.13 kN/g and Tear index 1.69 mNm2/g). By acidification (pH 6) of soda pulping liquor it separate lignin-rich solids, which by pyrolysis gave a gas containing 1.13% H2, 31.79% CO and 1.86% CH4 by weight. Gasification of the same sample provided a gas containing 0.18% H2, 24.50% CO and 17.75% CH4. PMID- 20846857 TI - Immobilization of Candida rugosa lipase on glass beads for enantioselective hydrolysis of racemic naproxen methyl ester. AB - Candida rugosa lipase (CRL) was immobilized on glutaraldehyde-activated aminopropyl glass beads by using covalent binding method or sol-gel encapsulation procedure and improved considerably by fluoride-catalyzed hydrolysis of mixtures of RSi(OCH3)3 and Si(OCH3)4. The catalytic properties of the immobilized lipases were evaluated into model reactions, i.e. the hydrolysis of p nitrophenylpalmitate (p-NPP). It has been observed that the percent activity yield of the encapsulated lipase was 166.9, which is 5.5 times higher than that of the covalently immobilized lipase. The enantioselective hydrolysis of racemic Naproxen methyl ester by immobilized lipase was studied in aqueous buffer solution/isooctane reaction system and it was noticed that particularly, the glass beads based encapsulated lipases had higher conversion and enantioselectivity compared to covalently immobilized lipase. In short, the study confirms an excellent enantioselectivity (E>400) for the encapsulated lipase with an ee value of 98% for S-Naproxen. PMID- 20846858 TI - Optimization of the anaerobic treatment of a waste stream from an enhanced oil recovery process. AB - The aim of this work was to optimize the anaerobic treatment of a waste stream from an enhanced oil recovery (EOR) process. The treatment of a simulated waste water containing about 150 mg chemical oxygen demand (COD)/L of total petroleum hydrocarbons (TPH) and the saturation level of CO2 was evaluated. A two-step anaerobic system was undertaken in the mesophilic temperature range (30-40 degrees C). The method of evolutionary operation EVOP factorial design was used to optimize pH, temperature and organic loading rate with the target parameters of CO2 reduction and CH4 production in the first reactor and TPH removal in the second reactor. The results showed 98% methanogenic removal of CO2 and CH4 yield of 0.38 L/gCOD in the first reactor and 83% TPH removal in the second reactor. In addition to enhancing CO2 and TPH removal and CH4 production, application of this method showed the degree of importance of the operational variables and their interactive effects for the two reactors in series. PMID- 20846859 TI - Particle geometry affects differentially substrate composition and enzyme profiles by Pleurotus ostreatus growing on sugar cane bagasse. AB - The growth of Pleurotus ostreatus was analyzed on three particle sizes of sugar cane bagasse: 0.92 mm and 1.68 mm in diameter, in addition to heterogeneous fibers (average 2.9 mm in diameter). Specific growth rate on heterogeneous particles was lower (MU=0.043 h(-1)), although soluble protein production was maximal (809 MUg/g dry wt). Higher MU values were reached on the other two particles sizes (0.049-0.05 h(-1)) with less soluble protein (500 MUg/g dry wt). Xylanases and laccases were favored in heterogeneous particles; while the highest selectivity for xylanases over cellulases was observed in 1.68 mm particles, corresponding with the maximal hemicellulose breakdown. Lignin and cellulose were preferentially degraded in smallest particles. This study shows that the geometrical ratio, shape and size of sugar cane bagasse fibers strongly influence packing density for SSF substrate, with an impact in the production of extracellular enzymes, growth rates and composition changes in substrate. PMID- 20846860 TI - Modulating the development of E. coli biofilms with 2-aminoimidazoles. AB - The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC(50) of 13MUM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400MUM. PMID- 20846861 TI - Discovery of a series of potent, orally active alpha,alpha-disubstituted piperidine NK(1) antagonists. AB - Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists. PMID- 20846862 TI - Novel thienopyridine derivatives as specific anti-hepatocellular carcinoma (HCC) agents: synthesis, preliminary structure-activity relationships, and in vitro biological evaluation. AB - Novel thienopyridine derivatives 1b-1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a-1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity. It can specifically inhibit the proliferation of the human hepatoma HepG2 cells with an IC(50) value of 0.016MUM (compared with doxorubicin as a positive control, whose IC(50) was 0.37MUM). It is inactive toward a panel of five different types of human cancer cell lines. (3) Compound 1g remarkably induces G(0)/G(1) arrest and apoptosis in HepG2 cells in vitro at low micromolar concentrations. These results, especially the HCC-specific anticancer activity of 1g, suggest their potential in targeted chemotherapy for HCC. PMID- 20846863 TI - New non-hydroxamic ADAMTS-5 inhibitors based on the 1,2,4-triazole-3-thiol scaffold. AB - In this Letter we describe the design, synthesis, screening, and optimization of a new family of ADAMTS-5 inhibitors. These inhibitors display an original 1,2,4 triazole-3-thiol scaffold as a putative zinc binding-group. In vitro results are rationalized by in silico docking of the compounds in ADAMTS-5's crystal structure. PMID- 20846864 TI - Clinical importance of micrometastasis in sentinel lymph nodes. AB - INTRODUCTION: We evaluated the incidence of micrometastasis and nonsentinel lymph node metastasis as well as local and axillary recurrence rates after level I-II axillary lymph node dissection. MATERIALS AND METHODS: Patients (n=760) with early-stage breast cancer underwent sentinel lymph node biopsy, and 45 patients (6.0%) with micrometastasis (0.2-2.0mm) were included in this study. Data concerning tumor, patients' characteristics and adjuvant treatments were recorded. RESULTS: The median age was 46 (26-67) years, median breast tumor size was 20 (1-50) mm, and median number of excised sentinel lymph nodes were 2 (1-5). All patients with micrometastasis underwent further level I-II axillary lymph node dissection. Eleven of 45 (24.4%) patients with micrometastasis in their sentinel lymph node biopsy had nonsentinel lymph node metastasis after an axillary lymph node dissection. There was no factor related to nonsentinel lymph node metastasis. Stage migration occurred in 4 of 45 patients (8.8%) due to the detection of micrometastases or macrometastases in nonsentinel lymph nodes. DISCUSSION: The classical treatment after detection of micrometastasis in sentinel lymph nodes is further axillary dissection. However, nonrandomized, nonprospective studies with 4-5 years follow up showed 0.6% axillary recurrence without further axillary lymph node dissection, although we still need the results of randomized controlled studies. PMID- 20846866 TI - Synthesis, cytotoxicity and liposome preparation of 28-acetylenic betulin derivatives. AB - Several novel betulin derivatives were prepared and evaluated for their antitumor activity. 3-O-acetylbetulinic aldehyde served as an ideal starting material for the synthesis of 28-acetylenic derivatives. These compounds were further transformed into pyrazoles and 1,2,3-triazoles. Also, the synthesis of 3-amino substituted butenolides was carried out. The compounds were screened for their antitumor activity in a panel of 15 human cancer cell lines in a sulforhodamine B (SRB) assay. Several compounds showed a noteworthy antitumor activity. In addition, the possibility of encapsulation into liposomes was examined, thereby resulting in an increased cytotoxicity. The results from a trypan-blue test and from DNA laddering provided evidence for an apoptotic cell death. PMID- 20846865 TI - Quantitative structure-activity relationship studies of threo-methylphenidate analogs. AB - Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach partial least squares analysis using a reduced set of Molconn-Z descriptors supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value. PMID- 20846867 TI - Design and preparation of sterol mimetics as potential antiparasitics. AB - We have previously shown that azasterols have activity against Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, which are the causative agents of various neglected tropical diseases. In this paper, we discuss the replacement of the sterol core of the azasterols with sterol mimics. Various mimics were designed, and the structures were minimised to see if they could adopt a similar conformation to that of the azasterols. From this, two series of mimics were synthesised and then evaluated against the parasites. Compounds showed moderate activity. PMID- 20846868 TI - Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2'-monomethyl-4-methyl- and 1'-thia-4-methyl-(3'R,4'R)-3',4'-di-O-(S) camphanoyl-(+)-cis-khellactone (DCK) analogs. AB - In a continuing investigation into the pharmacophores and structure-activity relationship (SAR) of (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2'-monomethyl substituted 1'-oxa, 1'-thia, 1' sulfoxide, and 1'-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2'S-monomethyl-4-methyl DCK (5a)(?) and 2'S-monomethyl-1'-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC(50) values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2'R monomethyl-4-methyl DCK (6) and 2'R-monomethyl-1'-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2'-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class. PMID- 20846869 TI - Radiostrontium and radium analysis in low-level environmental samples following a multi-stage semi-automated chromatographic sequential separation. AB - Strontium isotopes, (89)Sr and (90)Sr, and (226)Ra being radiotoxic when ingested, are routinely monitored in milk and drinking water samples collected from different regions in Canada. In order to monitor environmental levels of activity, a novel semi-automated sensitive method has been developed at the Radiation Protection Bureau of Health Canada (Ottawa, Canada). This method allows the separation and quantification of both (89)Sr and (90)Sr and has also been adapted to quantify (226)Ra during the same sample preparation procedure. The method uses a 2-stage purification process during which matrix constituents, such as magnesium and calcium that are rich in milk, are removed as well as the main beta-interferences (e.g., (40)K, (87)Rb, (134)Cs, (137)Cs, and (140)Ba). The first purification step uses strong cation exchange (SCX) chromatography with commercially available resins. In a second step, fractions containing the radiostrontium analytes are further purified using high-performance ion chromatography (HPIC). While (89)Sr is quantified by Cerenkov counting immediately after the second purification stage, the same vial is counted again after a latent period of 10-14 days to quantify the (90)Sr activity based on (90)Y ingrowth. Similarly, the activity of (226)Ra, which is separated by SCX only, is determined via the emanation of (222)Rn in a 2-phase aqueous/cocktail system using liquid scintillation counting. The minimum detectable concentration (MDC) for (89)Sr and (90)Sr for a 200 min count time at 95% confidence interval is 0.03 and 0.02 Bq/L, respectively. The MDC for (226)Ra for a 100 min count time is 0.002 Bq/L. Semi-annual intercomparison samples from the USA Department of Energy Mixed Analyte Performance Evaluation Program (MAPEP) were used to validate the method for (89)Sr and (90)Sr. Spiked water samples prepared in-house and from International Atomic Energy Agency (IAEA) were used to validate the (226)Ra assay. PMID- 20846870 TI - Influence of ionic interactions on essential oil and phenolic diterpene composition of Dalmatian sage (Salvia officinalis L.). AB - The potential of four essential cations (K(+), Ca(2+), Mg(2+) and Fe(2+)) to alleviate salt toxicity was studied in sage (Salvia officinalis L.) plants grown in pots. Two concentrations of the following chloride salts: KCl, CaCl2, MgCl2 and FeCl3, were used together with 100mM NaCl to study the effects of these nutrients on plant growth, leaf essential oils (EOs) and phenolic diterpenes composition. The sage plants accumulated Na(+) in their leaves (includers); this has affected secondary metabolites' biosynthesis. Treatment with 100mM NaCl slightly decreased borneol and viridiflorol, while increased manool concentrations. Addition of KCl, CaCl2 and MgCl2 increased considerably in a dose dependent manner the oxygen-containing monoterpenes (1.8-cineole, camphor, beta thujone and borneol) in 100mM NaCl-treated sage. Whereas, the contents of viridiflorol decreased further with the addition of KCl in 100mM NaCl-treated sage. Our results suggest that the changes in EOs composition were more related to K(+) and Ca(2+) availability than to Na(+) toxicity. Furthermore, treatment with NaCl decreased by 50% carnosic acid (CA), a potent antioxidant, content in the leaves. K(+) and Ca(2+) promoted the accumulation of CA and its methoxylated form (MCA) in the leaves. The concentration of CA was positively correlated with leaf K(+) (r=0.56, P=0.01) and Ca(2+) (r=0.44, P=0.05) contents. It appears that different salt applications in combination with NaCl treatments had a profound effect on EOs and phenolic diterpene composition in sage. Therefore, ionic interactions may be carefully considered in the cultivation of this species to get the desired concentrations of these secondary metabolites in leaf extracts. PMID- 20846871 TI - Severe intraprosthetic regurgitation by immobile leaflet after trans-catheter aortic valve implantation. AB - Aortic regurgitation mainly in the form of paravalvular leaks is a frequent complication of trans-catheter aortic valve implantation (TAVI). We describe a case of an 86-year-old woman with severe aortic stenosis, who underwent trans apical TAVI with a 23-mm Edwards-SAPIEN valve. Immediately post-implantation, severe intravalvular leak was observed on trans-esophageal echocardiogram (TEE) due to an immobile cusp associated with left-ventricular distension and cardiovascular collapse. Despite successfully treating the leak with the implantation of a second valve of the same diameter within the first one, the hemodynamic status remained unstable. Peripheral extracorporeal membrane oxygenation (ECMO) was established but resulted in a fatal outcome due to intractable heart failure. PMID- 20846872 TI - How to manage the left subclavian artery during endovascular stenting of the thoracic aorta. AB - We performed a systematic review of the literature to establish whether revascularisation of the left subclavian territory is necessary when this artery is covered by a stent. We retrieved data from 99 studies incorporating 4906 patients. Incidences of left-arm ischaemia (0.0% vs 9.2%, p=0.002) and stroke (4.7% vs 7.2%, p<0.001) were significantly less following revascularisation, although mortality (10.5% vs 3.4%, p=0.032) and endoleak incidence (25.8% vs 12.6%, p=0.008) were increased. No significant differences in spinal-cord ischaemia were seen. Revascularisation may reduce downstream ischaemic complications but can cause significant risk. Indications must be carefully considered on an individual patient basis. PMID- 20846873 TI - Risk stratification for adult congenital heart surgery. AB - OBJECTIVE: At this moment, no risk stratification models are available for adult congenital cardiac surgery. This study aims to identify a suitable stratification tool for the adult congenital heart surgery population. Pediatric congenital cardiac surgery score models were therefore tested in an adult congenital population. In addition, an age component was added to these models and performance was compared with the original score systems. METHODS: The Risk Adjustment in Congenital Heart Surgery (RACHS-1), Basic Aristotle Score, Society of Thoracic Surgeons (STS)-European Association for Cardiothoracic Surgery (EACTS) Score and Comprehensive Aristotle Score were calculated for all adult patients who underwent congenital cardiac surgery between January 1990 and January 2007 in a single center (N=963). In addition, an age component was added to these models. Discrimination was then tested for all models with and without the age component. RESULTS: Application of the original pediatric risk scores resulted in c-statistics for 30-day mortality of 0.60, 0.60, 0.60, and 0.66 respectively. Combining these models with the age component resulted in significantly higher c-statistics of 0.69, 0.70, 0.69, and 0.76 respectively. Age as a sole predictor already resulted in a c-statistic of 0.67. Comparable results were found for 1-year mortality. CONCLUSIONS: The discriminatory power of the pediatric risk scores was suboptimal, but increased when adding age as a score component. The best performance was achieved by the combination of age and the Comprehensive Aristotle Score, for both 30-day and 1-year mortality. PMID- 20846874 TI - Comparably improved health-related quality of life after total arterial revascularization versus conventional coronary surgery--Copenhagen arterial revascularization randomized patency and outcome trial. AB - OBJECTIVE: We compared health-related quality of life up to 11 months after coronary artery bypass grafting using total arterial revascularization versus conventional coronary surgery. METHODS: In this randomized single-center trial, 161 patients underwent total arterial revascularization using single or bilateral internal thoracic artery (ITA) and radial artery grafts versus 170 patients conventionally revascularized using left ITA and saphenous vein grafts. Preoperatively, and at 3 and 11 months, postoperatively, patients filled in the generic questionnaire Short Form-36 (SF-36). RESULTS: The mean age was 59+/-8 years and 39 were women (12%). Median EuroSCORE (European System for Cardiac Risk Evaluation) was 2 (interquartile range 1-4). More than 90% of patients filled in the questionnaire at all three time points. Preoperatively, all scores were lower (P<0.001) than for a sample of the general Danish population. On all scales of the SF-36, there was statistically significant improvement at 3 and 11 months in both groups. For 'social functioning', the improvement following total arterial revascularization was significantly higher than following conventional revascularization (P=0.01). For total arterial revascularization, there were also not statistically significant improvements for 'physical component summary' (P=0.09), 'bodily pain' (P=0.07) and 'vitality' (P=0.08). CONCLUSION: Health related quality of life up to 1 year after total arterial revascularization is equal or slightly better than results after conventional coronary surgery. PMID- 20846875 TI - Dosing of zoledronic acid throughout the treatment continuum in breast cancer. AB - Several bisphosphonates including zoledronic acid (ZOL) are approved for treating bone metastases from breast cancer (BC). Recent trials demonstrated that ZOL prevents bone loss and reduces disease recurrence in early BC. This review uses pharmacodynamic, efficacy, and safety data from phase III trials of ZOL in early through metastatic BC to evaluate the dosing regimens used in each setting. The dosing frequencies of ZOL in early stage versus metastatic BC (4 mg 2--4 times per year versus monthly) are based on the respective levels of bone resorption and tumor burden. Data from ongoing clinical trials suggest that monthly dosing facilitates potential synergy between ZOL and chemotherapy in intermediate-risk BC and during neoadjuvant therapy. Overall, available data indicate that treatment with ZOL at appropriate intervals determined by disease characteristics helps attain key therapeutic goals in BC--maintaining skeletal integrity, reducing disease recurrence, and improving clinical outcomes. PMID- 20846876 TI - Obesity and leptin resistance: distinguishing cause from effect. AB - Because leptin reduces food intake and body weight, the coexistence of elevated leptin levels with obesity is widely interpreted as evidence of 'leptin resistance.' Indeed, obesity promotes a number of cellular processes that attenuate leptin signaling (referred to here as 'cellular leptin resistance') and amplify the extent of weight gain induced by genetic and environmental factors. As commonly used, however, the term 'leptin resistance' embraces a range of phenomena that are distinct in underlying mechanisms and pathophysiological implications. Moreover, the induction of cellular leptin resistance by obesity complicates efforts to distinguish the mechanisms that predispose to weight gain from those that result from it. We suggest a framework for approaching these issues and important avenues for future investigation. PMID- 20846878 TI - The BDNF Val66Met polymorphism is not associated with myocardial infarction in Czech patients. PMID- 20846877 TI - Unexploited therapies in breast and prostate cancer: blockade of the prolactin receptor. AB - Breast and prostate cancers are hormone-sensitive malignancies that afflict millions of women and men. Although prolactin (PRL) is known as a survival factor that supports tumor growth and confers chemoresistance in both cancers, its precise role in these tumors has not been studied extensively. Growth hormone and placental lactogen also bind PRL receptor (PRLR) and mimic some of the actions of PRL. Blockade of the PRLR represents a novel treatment for patients with advanced breast or prostate cancer with limited therapeutic options. This review discusses different approaches for generating PRLR antagonists. Emphasis is placed on technological advances which enable high-throughput screening for small molecule inhibitors of PRLR signaling that could serve as oral medications. PMID- 20846881 TI - Current status of the role of stem cells in myocardial biology and repair. AB - The purpose of this article is to present an analysis of current knowledge and understanding of the role of stem cells in myocardial biology and myocardial repair following injury. This rapidly evolving field has assumed relevance for the understanding, diagnosis, and treatment of heart failure. PMID- 20846879 TI - Depressive symptoms are associated with medication use and lower health-related quality of life in overweight women with binge eating disorder. AB - BACKGROUND: Depression is a most burdensome illness, with personal and societal costs surpassing those of any other illness. Furthermore, depression affects women at a much higher rate than men. The most prevalent eating disorder among adult women is binge eating disorder (BED). Depression and obesity are common in women with BED, most of whom seek treatment later in life. Depression, obesity, and age are associated with greater health care use and lower health-related quality of life (HRQOL). Hence, for women with BED estimating the effects of depression can be confounded by both age and body mass index (BMI). The current study examined the relationships between depression, HRQOL, and health care utilization among treatment seeking women with BED. METHODS: Participants (n = 105) completed the Structured Clinical Interview for DSM-IV, a health care utilization and cost survey, the Personality Assessment Inventory depression scale, and the EQ-5D to measure HRQOL. FINDINGS: On average, participants were severely obese with a mean BMI of 38.20 (SD = 6.80); 67.27% had a lifetime history of depression. Participants had higher health care costs and lower HRQOL than published age- and gender-matched norms. After controlling for age and BMI, depressive symptoms were significantly related to greater medication use (excluding antidepressants), and lower HRQOL. CONCLUSION: Results suggest that targeting depressive symptoms may reduce the economic and personal burden of BED for women. PMID- 20846882 TI - The impact of platelet transfusion in massively transfused trauma patients. AB - BACKGROUND: The impact of platelet transfusion in trauma patients undergoing a massive transfusion (MT) was evaluated. STUDY DESIGN: The Institutional Trauma Registry and Blood Bank Database at a Level I trauma center was used to identify all patients requiring an MT (>=10 packed red blood cells [PRBC] within 24 hours of admission). Mortality was evaluated according to 4 apheresis platelet (aPLT):PRBC ratios: Low ratio (<1:18), medium ratio (>=1:18 and <1:12), high ratio (>=1:12 and <1:6), and highest ratio (>=1:6). RESULTS: Of 32,289 trauma patients, a total of 657 (2.0%) required an MT. At 24 hours, 171 patients (26.0%) received a low ratio, 77 (11.7%) a medium ratio, 249 (37.9%) a high ratio, and 160 (24.4%) the highest ratio of aPLT:PRBC. After correcting for differences between groups, the mortality at 24 hours increased in a stepwise fashion with decreasing aPLT:PRBC ratio. Using the highest ratio group as a reference, the adjusted relative risk of death was 1.67 (adjusted p = 0.054) for the high ratio group, 2.28 (adjusted p = 0.013) for the medium ratio group, and 5.51 (adjusted p < 0.001) for the low ratio group. A similar stepwise increase in mortality with decreasing platelet ratio was observed at 12 hours after admission and for overall survival to discharge. After stepwise logistic regression, a high aPLT:PRBC ratio (adjusted p < 0.001) was independently associated with improved survival at 24 hours. CONCLUSIONS: For injured patients requiring a massive transfusion, as the apheresis platelet-to-red cell ratio increased, a stepwise improvement in survival was seen. Prospective evaluation of the role of platelet transfusion in massively transfused patients is warranted. PMID- 20846883 TI - Impact of an outpatient appendectomy protocol on clinical outcomes and cost: a case-control study. AB - BACKGROUND: Although elective outpatient surgery is commonplace, surgeons remain hesitant to discharge patients the same day after emergent surgery. We created a formal protocol to select patients for early discharge after laparoscopic appendectomy for acute appendicitis, and we assessed its safety and potential cost savings. STUDY DESIGN: We matched patients who were discharged early from the recovery room with similar patients from a control group on the basis of age +/- 3 years, presence or absence of a comorbidity, laparoscopic procedure, and nonperforated appendicitis; we compared them to assess the impact of early discharge on morbidity, return visits to the emergency room, and total cost incurred by our institution. RESULTS: During the first year of our protocol, 72 of 161 (45%) patients who presented with acute appendicitis and underwent appendectomy were discharged early, with a median post-operative length of stay of 4.7 hours. When compared with matched controls, patients discharged early had similar complication rates (4.3% early group vs 7.1%, p = 0.72) and number of postoperative visits to the emergency room (11.4% vs 11.4%, p = 0.8), but had a reduced median length of stay (4.7 vs 16.2 hours, p < 0.001) and an average reduction in cost of $323.46 per patient. CONCLUSIONS: Adoption of a protocol to select patients for early discharge after laparoscopic appendectomy resulted in a 45% reduction in the need for in-hospital beds, with no negative impact on return visits to the emergency room or number of complications. This translates to an approximate savings of $323 per patient when compared with standard care. PMID- 20846884 TI - Improving American College of Surgeons National Surgical Quality Improvement Program risk adjustment: incorporation of a novel procedure risk score. AB - BACKGROUND: Risk-adjusted evaluation is a key component of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). The purpose of this study was to improve standard ACS NSQIP risk adjustment using a novel procedure risk score. STUDY DESIGN: Current Procedural Terminology codes (CPTs) represented in ACS NSQIP data were assigned to 136 procedure groups. Log odds predicted risk from preliminary logistic regression modeling generated a continuous risk score for each procedure group, used in subsequent modeling. Appropriate subsets of 271,368 patients in the 2008 ACS NSQIP were evaluated using logistic models for overall 30-day morbidity, 30-day mortality, and surgical site infection (SSI). Models were compared when including either work Relative Value Unit (RVU), RVU and the standard ACS NSQIP CPT range variable (CPT range), or RVU and the newly constructed CPT risk score (CPT risk), plus routine ACS NSQIP predictors. RESULTS: When comparing the CPT risk models with the CPT range models for morbidity in the overall general and vascular surgery dataset, CPT risk models provided better discrimination through higher c statistics at earlier steps (0.81 by step 3 vs 0.81 by step 46), more information through lower Akaike's information criterion (127,139 vs 130,019), and improved calibration through a smaller Hosmer-Lemeshow chi-square statistic (48.76 vs 116.79). Improved model characteristics of CPT risk over CPT range were most apparent for broader patient populations and outcomes. The CPT risk and standard CPT range models were moderately consistent in identification of outliers as well as assignment of hospitals to quality deciles (weighted kappa >= 0.870). CONCLUSIONS: Information from focused, clinically meaningful CPT procedure groups improves the risk estimation of ACS NSQIP models. PMID- 20846885 TI - Current medical intervention alone is now the best solution for asymptomatic carotid stenosis. letter to the editors of Journal of Vascular Surgery and the European Journal of Vascular and Endovascular Surgery regarding trans-atlantic debate no. 1. PMID- 20846886 TI - Tissue factor expression on monocytes from patients with severe dengue fever. PMID- 20846887 TI - A functional screen for regulatory elements that improve retroviral vector gene expression. AB - Recombinant retroviruses constitute the most common class of gene delivery vectors used in hematopoietic cell-based gene therapy. However, the use of these vectors can be limited by inadequate levels of transgene expression, often mediated by expression variegation and vector silencing due to chromosomal position effects. Toward the goal of addressing this problem, we sought to identify cis-regulatory elements from the human genome that can improve the level and stability of retroviral vector gene expression. Libraries of size-selected fragments from the human genome were cloned into the "double-copy" position of the gammaretroviral reporter vector MGPN2, and the resulting vectors underwent several rounds of transduction and selection for high-level vector GFP expression. From this screen we identified both enhancer-like elements and vector mutations associated with increased vector expression. One element, H-11, exhibited enhancer activity in a mouse bone marrow progenitor colony assay, a human promoter trap assay, and a long-term mouse bone marrow transplant assay. This element seems to be an orientation-dependent, tissue-independent enhancer. PMID- 20846888 TI - Coinheritance of Gaucher disease and alpha-thalassemia resulting in confusion between two inherited hematologic diseases. AB - Gaucher type 1 disease has a wide spectrum of phenotypes ranging from asymptomatic individuals to patients with massive hepatosplenomegaly and bone involvement. In most, anemia, thrombocytopenia and splenomegaly are the primary manifestations at diagnosis, findings shared by the hemoglobinopathies. Here we report the co-inheritance of alpha-thalassemia and Gaucher disease in a consanguineous family followed in Iran, which resulted in confusion regarding the diagnosis. This report emphasizes the need to independently establish the diagnosis of every affected member of a family to ensure appropriate management and therapeutic decisions. PMID- 20846889 TI - Treatment of intractable epilepsy in a female with SLC6A8 deficiency. AB - A female heterozygous for a novel, disease causing, missense mutation in the X linked cerebral creatine transporter (SLC6A8) gene (c.1067G>T, p.Gly356Val) presented with intractable epilepsy, mild intellectual disability and moderately reduced cerebral creatine levels. Treatment with creatine monohydrate, to enhance cerebral creatine transport, combined with L-arginine and L-glycine, to enhance cerebral creatine synthesis, resulted in complete resolution of seizures. Heterozygous SLC6A8 deficiency is a potentially treatable condition and should be considered in females with intractable epilepsy and developmental delay/intellectual disability. PMID- 20846890 TI - A common variant near the PRL gene is associated with increased adiposity in males. AB - A common variant (rs4712652) adjacent to the prolactin gene was recently associated with obesity using a genome-wide association study. The aim of this study was to replicate the association between rs4712652 and obesity and further examine if rs4712652 is associated with fat percentage and adiponectin levels in a population based Scandinavian cohort. rs4712652 was genotyped in 4879 participants (mean BMI 26.5+/-4.5 kg/m(2)) from the population-based PPP-Botnia Study and related to BMI, fat percentage and adiponectin levels. We found that the risk A allele of rs4712652 is associated with increased BMI and fat percentage in males (P=0.0047 and P=0.025, respectively), but not in females (P=0.98, P=0.45). Male A allele carriers have a higher risk of being overweight with an OR of 1.16 (P=0.025). While there was a significant negative correlation between adiponectin levels and fat percentage (r=-0.36; P=0.039) in male carriers of the protective GG genotype, this correlation was lost in male carriers of the risk rs4712652 A allele (P=0.33). Thus, the common SNP rs4712652 near the PRL gene seems to affect body fat and adiposity in a sex-specific fashion. It remains to be shown whether this is mediated by different prolactin concentrations or differences in tissue sensitivity to prolactin. PMID- 20846891 TI - Consensus document on controversial issues for the treatment of infections of the central nervous system: bacterial brain abscesses. AB - BACKGROUND: Bacterial brain abscesses remain a serious central nervous system problem despite advances in neurosurgical, neuroimaging, and microbiological techniques and the availability of new antibiotics. The successful treatment of brain abscesses requires surgery, appropriate antibiotic therapy, and eradication of the primary source; nevertheless many controversial issues on the management of this serious infection remain unresolved. CONTROVERSIAL ISSUES: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues were: (1) Which patients with bacterial brain abscesses can be managed safely using medical treatment alone? (1a) What is the efficacy in terms of outcome, tolerability, cost/efficacy, and quality of life of the different antibiotic regimens used to treat bacterial cerebral abscesses? (1b) Which antibiotics have the best pharmacokinetics and/or tissue penetration of brain and/or brain abscess? 2) What is the best surgical approach in terms of outcome in managing bacterial brain abscesses? Results are presented and discussed in detail. METHODS: A systematic literature search using the MEDLINE database for the period 1988 to 2008 of randomized controlled trials and/or non randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence and strength of recommendation was applied. PMID- 20846892 TI - Investigations on the demetalation of metalloporphyrins under ultrasound irradiation. AB - An efficiently facile method for the demetalation from metalloporphyrins has been developed, which uses high-intensity ultrasound to initiate the ligand dissociation in a mixed solvent of (CH(3)CO)(2)O/HCl with FeSO(4). The influences of substituents, bath temperature and reaction time on the reactions were also investigated, on the base of which the mechanism of demetalation and the effect of ultrasound irradiation on metal-ligand cleavage have been discussed in detail. PMID- 20846893 TI - Relationship between (123)I-MIBG scintigrams and REM sleep behavior disorder in Parkinson's disease. AB - BACKGROUND: Uptake of (123)I-labeled meta-iodobenzylguanidine (MIBG) in myocardial scintigrams has been shown to be as low in patients with idiopathic RBD as in Parkinson's disease (PD) patients. AIM FOR STUDY: To clarify whether the existence of RBD accelerates autonomic dysfunction in PD, we investigated the association between MIBG scintigraphic findings and RBD measures among non dementia PD patients. SUBJECTS & METHODS: We conducted clinical interviews to assess REM sleep behavior disorder (RBD) symptoms, and performed polysomnograms (PSG) recordings and MIBG scintigrams on 49 PD patients. The patients were divided into three groups (PD with clinical RBD, PD with subclinical RBD, and PD with normal REM sleep). RESULTS: PD patients with clinical RBD had reduced MIBG uptake as determined by heart-to-mediastinum ratios of the delayed image compared to those with subclinical RBD and those with normal REM sleep. Multiple linear regression analysis revealed that only the existence of RBD symptoms was significantly associated with reduced MIBG uptake among PD patients without dementia after adjusting for demographic and PD symptom-related variables. CONCLUSION: PD patients with clinical RBD might suffer from a wider alpha synuclein pathology, including reduced cardiac sympathetic ganglia function as reflected by a lowered MIBG uptake. PMID- 20846894 TI - Deep brain stimulation does not change neurovascular coupling in non-motor visual cortex: an autonomic and visual evoked blood flow velocity response study. AB - BACKGROUND AND PURPOSE: In Parkinson's disease (PD) subthalamic nucleus deep brain stimulation (STN-DBS) improves motor function. Also an effect on the neurovascular coupling in motor cortex was reported due to a parallel activation of a subthalamic vasodilator area (SVA). To address this issue further we analysed neurovascular coupling in a non-motor area. METHODS: Twenty PD patients selected for bilateral STN-DBS were investigated with functional transcranial Doppler (f-TCD) before and after surgery. Hemodynamic responses to visual stimulation were registered in left posterior cerebral artery (PCA) and analysed with a control-system approach (parameters gain, rate time, attenuation and natural frequency). To exclude autonomic effects of STN-DBS, we also addressed spectrum analysis of heart rate and of systolic arterial blood pressure variability, and baroreceptor gain. Findings in the PD group were compared with healthy age-matched controls. RESULTS: PD patients showed no neurovascular coupling changes in PCA territory, compared to controls, and STN-DBS changed neither blood flow regulatory parameters nor autonomic function. CONCLUSIONS: Improvement of vasoregulation in some motor cortical areas after STN-DBS might be related to an improved neuronal functional rather than indicating an effect on the neurovascular coupling or autonomic function. PMID- 20846895 TI - Reduced volume of the putamen in REM sleep behavior disorder patients. AB - OBJECTIVE: The purpose of this study was to quantify volumes of specific subcortical gray matter nuclei implicated in Parkinson's disease (PD) as a preliminary step for identifying a non-invasive clinical biomarker for PD. We hypothesized that REM sleep behavior disorder (RBD) patients, at risk for developing PD, will demonstrate a pattern of neuronal degeneration reflected in reduced striatal volumes on T1-weighted MRI. METHODS: We compared measures of RBD patients confirmed by polysomnography (PSG) with groups of age/gender-matched Control subjects and early PD (EPD) patients (Hoehn & Yahr < 2). Clinical measurements included the Unified Parkinson's disease Rating Scales (UPDRS), timed gait and finger tapping tasks, the Parkinson's Disease Questionnaire (PDQ 39), and a time-synchronized video recorded single-night PSG. Volumetric measurements were derived from high-resolution T1-weighted 3 T MRI images. RESULTS: The matched Control and EPD groups were statistically similar to the RBD group in age, gender, handedness, and total brain volumes. The RBD group had smaller bilateral putamen volumes (both raw and normalized by brain tissue volume), in addition to some clinical impairment on the UPDRS and PDQ-39. CONCLUSIONS: Reduced putamen volumes may be a structural marker for RBD and reflect a pattern of neurodegeneration that predicts the development of PD. PMID- 20846896 TI - 'Maintaining Talk' among taxi drivers: accomplishing health-protective behaviour in precarious workplaces. AB - This paper contributes to the body of research on the relationship between language, health (behaviour), and place. Drawing on data from a qualitative study of taxi drivers in Ontario, Canada, it illustrates how talk, a dimension of language, might (re)make and maintain an unconventional, precarious workplace through ameliorating its inherent risks and hazards. It shows how a group of taxi drivers, who work in a large, metropolitan city, and whose workplace comprises physical places such as streets, highways, and taxicabs, and social places characterised by disadvantaged social and economic location, enact different kinds of talk in an effort to protect their health. This finding suggest the need for a broader conceptualisation of health behaviour, and for further research into other occupational groups and/or unconventional workplaces in order to further develop or theorise the concept of talk. PMID- 20846897 TI - Structural analysis of cytokines comprising the IL-10 family. AB - Interleukin-10 (IL-10) family of cytokines includes a number of its viral homologs and eight cellular cytokines (IL-19, IL-20, IL-22, IL-24, IL-26, IL-28A, IL-28B, and IL-29). The latter three proteins are also known as IFN-lambda2, IFN lambda3, and IFN-lambda1, and are recognized as type III (or lambda) interferons. Most of the cellular homologs of IL-10 are monomeric in solution, whereas IL-10 and its viral homologs are intercalated dimers consisting of two helical bundle domains topologically similar to the monomeric members of the family. A classical four-helix bundle, a signature element of all helical cytokines, is always found as part of the domain of each member of the IL-10 family. The only crystal structures of these cytokine receptors that have been determined to date are for their extracellular domains (ECDs). Each ECD consists of two beta-sandwich domains connected in the middle by a linkage. Signal transduction occurs when a cytokine binds to its two appropriate receptor chains. IL-10 and its viral homologs use the same IL-10 receptor system, whereas the cellular homologs of IL 10 use their own receptors, which in some cases may overlap and be used in different pairwise combinations. The known structures of binary complexes allowed for marking of the receptor binding site, which always includes helix A, loop AB and helix F (IL-10 notations) on the side of a ligand, loops of the N-terminal and C-terminal domains directed toward the ligand, and the interdomain linkage of the ECD. An analysis of the published structures of both the binary and ternary complexes of all helical cytokines allowed for the generation of a model of the signaling complex of IL-10. The receptor binding site I of the high affinity receptor IL-10R1 is exactly the same as in the crystal structure of the binary IL 10/sIL-10R1 complex, whereas the receptor binding site II is located on the surface of the first and the third helices of the four-helix bundle. The receptor/receptor interface, or site III, is formed between the C-terminal domains of IL-10R1 and IL-10R2. PMID- 20846898 TI - Plant molecular stress responses face climate change. AB - Environmental stress factors such as drought, elevated temperature, salinity and rising CO2 affect plant growth and pose a growing threat to sustainable agriculture. This has become a hot issue due to concerns about the effects of climate change on plant resources, biodiversity and global food security. Plant adaptation to stress involves key changes in the '-omic' architecture. Here, we present an overview of the physiological and molecular programs in stress adaptation focusing on how genes, proteins and metabolites change after individual and multiple environmental stresses. We address the role which ' omics' research, coupled to systems biology approaches, can play in future research on plants seemingly unable to adapt as well as those which can tolerate climatic change. PMID- 20846899 TI - Navigating the future of bacterial molecular epidemiology. AB - Technological advances in high-throughput genome sequencing have led to an enhanced appreciation of the genetic diversity found within populations of pathogenic bacteria. Methods based on single nucleotide polymorphisms (SNPs) and insertions or deletions (indels) build upon the framework established by multi locus sequence typing (MLST) and permit a detailed, targeted analysis of variation within related organisms. Robust phylogenetics, when combined with epidemiologically informative data, can be applied to study ongoing temporal and geographical fluctuations in bacterial pathogens. As genome sequencing, SNP detection and geospatial information become more accessible these methods will continue to transform the way molecular epidemiology is used to study populations of bacterial pathogens. PMID- 20846900 TI - Epidemiology and clinical relevance of microbial resistance determinants versus anti-Gram-positive agents. AB - Gram-positive pathogens are a major cause of community-acquired and hospital acquired infections, and exhibit a remarkable ability to develop antibiotic resistance. Methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide resistant enterococci (GRE) and multidrug-resistant pneumococci are currently the major resistance challenges among Gram-positives, due to their global dissemination and overall clinical impact. The mechanisms of evolution of these resistance phenotypes are based on a diverse array of mutational events and gene transfer phenomena carried out by several types of mobile genetic elements, followed by the dissemination of successful resistant clones. Resistance to glycopeptides in staphylococci remains uncommon, likely due to fitness issues. Resistance to the new anti-Gram-positive agents (linezolid, daptomycin and tigecycline) overall remains very rare. However, a transferable resistance mechanism to linezolid, mediated by ribosomal target modification by the Cfr protein, has recently emerged among S. aureus, being a matter of raising concern. Linezolid resistance among enterococci and coagulase-negative staphylococci is also increasingly reported. Moreover, a role for antibiotic resistance has been advocated in the recent increase of Clostridium difficile infection (CDI) associated with the emergence of hypervirulent strains. PMID- 20846901 TI - A new era in the genomics of bacteria. PMID- 20846902 TI - Spectroscopic investigation on assisted sonocatalytic damage of bovine serum albumin (BSA) by metronidazole (MTZ) under ultrasonic irradiation combined with nano-sized ZnO. AB - The previous work proved that the bovine serum albumin (BSA) could be damaged under the combined action of ultrasonic irradiation and ZnO. In this work, the assisted sonocatalytic damage of BSA using metronidazole (MTZ) as a sensitizer was further investigated by means of UV-vis and fluorescence spectra. The results indicated that the adding of MTZ could obviously promote the sonocatalytic damage of BSA under ultrasonic irradiation in the presence of nano-sized ZnO powder. Furthermore, it was found that the damage degree of BSA was aggravated by some influencing factors except ionic kind and strength. In addition, the damage site of BSA was also studied with synchronous fluorescence technology. It was found that the damage site was mainly at tryptophan (Trp) residue. PMID- 20846903 TI - Development of a novel bead-based multiplex PCR assay for combined subtyping and oseltamivir resistance genotyping (H275Y) of seasonal and pandemic H1N1 influenza A viruses. AB - BACKGROUND: The identification of influenza A virus subtypes in clinical specimens is becoming increasingly important for clinical laboratories since seasonal H1N1, H3N2 and pandemic H1N1 influenza A viruses can have defined antiviral resistance patterns and subtyping can be used as a surrogate for antiviral resistance testing. OBJECTIVES: To develop a novel multiplex PCR (M PCR) assay for the combined identification of influenza A subtype and oseltamivir resistance (H275Y) genotype in a combined assay format using Luminex xMAPTM technology. STUDY DESIGN: The M-PCR assay employed five degenerate primers to amplify the hemagglutinin (HA) and neuraminidase (NA) genes and eight tagged primers in a target specific primer extension reaction (TSPE). Products were analysed using xTAGTM beads containing specific anti-tag oligonucleotides. RESULTS: M-PCR correctly identified the subtype for 54/54 specimens that were influenza A positive, including 13/13 seasonal H3N2, 17/17 seasonal H1N1 and 24/24 pandemic H1N1 for both HA and NA genes. For oseltamivir resistance the M PCR assay correctly identified 41/41 H1N1 viruses as oseltamivir sensitive (H275) or resistant (H275Y). Analysis of sequential specimens from two immunocompromised patients revealed the appearance of the H275Y allele at earlier time points after infection compared with Sanger sequencing. CONCLUSIONS: The combined M-PCR assay correctly subtyped seasonal and pandemic influenza A viruses and accurately detected the H275Y oseltamivir resistance allele. This assay should provide useful information to clinicians for appropriate patient management. PMID- 20846904 TI - Outcomes of passive-active immunoprophylaxis given to infants of mothers infected with hepatitis B virus in Babol, Iran. AB - BACKGROUND: Infants born to chronic hepatitis B virus (HBV) infected mothers may be infected in spite of receiving passive-active immunoprophylaxis. OBJECTIVES: The purpose of this study was to assess the outcome of infants born to women actively infected by HBV. STUDY DESIGN: From April 2004 to September 2009, infants born to women actively infected by HBV received hepatitis B immune globulin (HBIG) and the first dose of hepatitis B vaccine at birth. The second and third doses of HBV vaccine were administered at 1 and 6 months of age. Post vaccination tests to detect HBsAg and anti-HBs were assessed between 12 and 15 months of age. Those who had anti-HBs titers<10mIU/ml received the second series of HBV vaccine. RESULTS: Thirty-four and 201 infants were born to HBeAg seropositive and anti-HBe-seropositive mothers, respectively. HBsAg was detected in 6 (17.6%) infants born to HBeAg-seropositive mothers and in 3 (1.5%) to anti HBe-seropositive mothers (p=0.0001). Anti-HBs >= 10mIU/ml were achieved in 26 (76.5%) and 178 (88.6%) infants of HBeAg-seropositive and anti-HBe-seropositive mothers, respectively (p>0.05). Twenty-two (9.4%) infants were non-responders and 11(50%) of them responded to the second series of HBV vaccine. CONCLUSIONS: The results show that infants of HBeAg-seropositive mothers have higher risk of developing of HBV infection. Some HBsAg-seronegative infants may not respond to passive-active immunoprophylaxis and may remain at risk of HBV infection. PMID- 20846906 TI - Consideration of ethics in primaquine therapy against malaria transmission. AB - Millions of people receive primaquine against sexual plasmodia responsible for malaria transmission. These gametocytes cause no symptoms and do not threaten the host, but they infect mosquitoes and threaten the community. Primaquine causes hemolysis in the small minority of patients with glucose-6-phosphate dehydrogenase deficiency (G6PDd). Clinical studies in the 1950s demonstrated gametocytocidal primaquine to be safe without G6PDd screening. However, the evaluated G6PDd variant, African A-, represents mild sensitivity to primaquine. The view of primaquine as a safe gametocytocide thus rests largely upon observations from a G6PDd variant that is unlikely to challenge safety. The early clinical work does not seem to afford an adequate assessment of safety in G6PDd patients. Potential risk of harm without clinical benefit to the patient raises ethical questions that should be examined. PMID- 20846905 TI - Small-molecule delivery by nanoparticles for anticancer therapy. AB - Using nanoparticles for the delivery of small molecules in anticancer therapy is a rapidly growing area of research. The advantages of using nanoparticles for drug delivery include enhanced water solubility, tumor-specific accumulation and improved antitumor efficacy, while reducing nonspecific toxicity. Current research in this field focuses on understanding precisely how small molecules are released from nanoparticles and delivered to the targeted tumor tissues or cells, and how the unique biodistribution of the drug-carrying nanoparticles limits toxicity in major organs. Here, we discuss existing nanoparticles for the delivery of small-molecule anticancer agents and recent advances in this field. PMID- 20846907 TI - Are synucleinopathies prion-like disorders? AB - A shared neuropathological feature of idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy is the development of intracellular aggregates of alpha-synuclein that gradually engage increasing parts of the nervous system. The pathogenetic mechanisms underlying these neurodegenerative disorders, however, are unknown. Several studies have highlighted similarities between classic prion diseases and these neurological proteinopathies. Specifically, identification of Lewy bodies in fetal mesencephalic neurons transplanted in patients with Parkinson's disease raised the hypothesis that alpha-synuclein, the main component of Lewy bodies, could be transmitted from the host brain to a graft of healthy neurons. These results and others have led to the hypothesis that a prion-like mechanism might underlie progression of synucleinopathy within the nervous system. We review experimental findings showing that misfolded alpha-synuclein can transfer between cells and, once transferred into a new cell, can act as a seed that recruits endogenous alpha synuclein, leading to formation of larger aggregates. This model suggests that strategies aimed at prevention of cell-to-cell transfer of alpha-synuclein could retard progression of symptoms in Parkinson's disease and other synucleinopathies. PMID- 20846908 TI - Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study [corrected]. AB - BACKGROUND: Patients with idiopathic rapid-eye-movement sleep behaviour disorder (IRBD) may develop neurodegenerative conditions associated with substantia nigra dysfunction such as Parkinson's disease. In patients with Parkinson's disease, 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I FP-CIT) SPECT detects striatal dopamine dysfunction resulting from nigral pathology whereas transcranial sonography (TCS) shows increased substantia nigra echogenic size, even before parkinsonism is clinically evident. We postulated that these neuroimaging changes could occur in a proportion of IRBD individuals who might then be at increased risk for development of a neurodegenerative disorder associated with substantia nigra dysfunction. METHODS: In our prospective study, we identified patients with IRBD from individuals referred to our sleep disorders centre in Barcelona, Spain. At baseline, we assessed dopamine transporter [corrected] uptake by use of 123I-FP-CIT SPECT, and estimated echogenicity of the substantia nigra by use of TCS. After a follow-up of 2.5 years, participants were clinically assessed to establish whether they had developed neurodegenerative syndromes. Data were compared with those of matched healthy controls. FINDINGS: 43 individuals with IRBD agreed to participate in the study. We found reduced 123I-FP-CIT binding in the striatum (p=0.045) in 17 (40%) of 43 participants compared with 18 controls, and substantia nigra hyperechogenicity in 14 (36%) of 39 participants with IRBD, compared with 16 (11%) of 149 controls (p=0.0002). Tracer uptake reduction was more pronounced in the putamen than it was in the caudate nucleus. 27 (63%) participants had reduced 123I-FP-CIT binding or substantia nigra hyperechogenicity at baseline. Eight (30%) of these participants developed a neurodegenerative disorder (five Parkinson's disease, two dementia with Lewy bodies, and one multiple system atrophy). Individuals with normal neuroimaging results remained disease-free. Sensitivity of combined 123I-FP-CIT SPECT and TCS to predict conversion to synucleinopathy after 2.5 years was 100% and specificity was 55%. INTERPRETATION: In patients with IRBD, 123I-FP-CIT SPECT and TCS can detect subclinical changes much the same as those typically seen in patients with early Parkinson's disease. Decreased striatal 123I-FP-CIT binding and substantia nigra hyperechogenicity might be useful markers to identify individuals at increased risk for development of synucleinopathies. FUNDING: None. PMID- 20846909 TI - The principles and best practice of question writing for postgraduate examinations. AB - Postgraduate medical education has changed enormously in the last 10 years presenting huge logistical challenges for local, regional and national organisations. Assessment is under change in line with major revisions of postgraduate curricula. Old methods of assessment are changing to newer evidence based methods supported by ongoing research into good practice. This review examines the purpose and practical considerations of written assessment, the pros and cons of different assessment methods and how good practice can be evaluated and quality assured. Good quality assessment comes at a cost in terms of time and money, and organisations need to invest in their assessment strategies to ensure the highest possible standards. PMID- 20846910 TI - Perceptions of barriers and facilitators: self-management decisions by older adolescents and adults with CF. AB - BACKGROUND: Adherence to CF treatments is poor, which can lead to negative health outcomes. The objective of our study was to qualitatively investigate the barriers and facilitators of self-management among older adolescents and adults with CF. METHODS: Individual semi-structured interviews were conducted, audio taped, transcribed verbatim and coded to identify common themes. RESULTS: Twenty five patients were interviewed. Four broad themes were identified: Barriers to Self-Management (e.g., treatment burden (identified by 64% of patients), accidental or purposeful forgetting (60%), no perceived benefit (56%)), Facilitators of Self-Management (e.g., CF clinic visits (76%), social support (68%), perceived benefit (68%)), Substitution of Alternative Approaches to Conventional Management (36%) and Planned Non-adherence (32%). CONCLUSIONS: Older adolescents and adults with CF identified many barriers and facilitators of adherence that may be amenable to self-management counseling strategies, particularly the use of health feedback. PMID- 20846911 TI - Pseudo-affinity chromatographic approach to probe heterogeneity in buffalo pituitary luteinizing hormone: probable pseudolectin-like behavior of immobilized Cibacron Blue 3GA. AB - The alpha (alpha) and beta (beta) subunits of buffalo pituitary luteinizing hormone (LH) were chromatographed on Cibacron Blue 3GA agarose and their immunoreactivity was quantitated using anti-alpha and anti-beta anti sera. Subsequent analyses showed alpha subunits were relatively more hydrophilic than beta subunits. Further, the naturally occurring free alpha and beta subunits were more hydrophobic than their native counterparts which were dissociated and isolated from heterodimeric LH. The lesser sugar content in freely occurring alpha and beta subunits may be attributed for increased hydrophobicity and consequent upon the existence of their uncombined free forms. In order to ascertain putative sugar-dye interaction, crude LH carrying free subunits, pure LH, and non-glycosylated recombinant beta subunit of LH were loaded separately on Cibacron Blue. Methyl mannoside was able to elute 33% of the bound protein in case of crude and pure LH, whereas there was little (3%) elution in case of recombinant LH beta subunit. This study suggests a compositional heterogeneity in free and native subunits of LH from the buffalo pituitary. In addition, our findings reveal the pseudolectin-like behavior of Cibacron Blue. PMID- 20846912 TI - Parallel sample preparation of proteins, from crude samples to crystals ready for MALDI-MS, in an integrated microfluidic system. AB - A microfluidic structure is presented where selective capture of proteins in complex samples, followed by clean-up, enzymatic processing, and MALDI-MS sample preparation of peptides generated, can be performed. The structure uses an affinity column to capture the protein while all other components in the sample are disposed of. The protein of interest is then eluted from the affinity column and captured on a second column on which the enzymatic processing is performed. Salts and hydrophilic contaminants are then removed before the products from the enzymatic reaction are eluted together with a suitable MALDI matrix and the solvent evaporated in a designated MALDI target structure. All steps can be performed automatically in 54 parallel microstructures on a microfluidic compact disc. The process is demonstrated by the selective capture and tryptic digest of recombinant IgG molecules from samples containing other proteins: an excess of bovine serum albumin or spent cell culture media. PMID- 20846913 TI - Determination of aconitine, hypaconitine and mesaconitine in urine using hollow fiber liquid-phase microextraction combined with high-performance liquid chromatography. AB - Hollow fiber liquid-phase microextraction (HF-LPME) coupled with high-performance liquid chromatography was used to simultaneously determine three Aconitum alkaloids, including aconitine (AC), hypaconitine (HA) and mesaconitine (MA) in human urine sample. Analytes were extracted from 5mL urine sample containing 1.0mmol/L NaOH into 1-octanol membrane phase impregnated in the pores of hollow fiber wall, and then back extracted into acidified aqueous solution in the lumen of the hollow fiber. After extraction, 10MUL of the acceptor phase was analyzed directly by HPLC. In this method, some important extraction parameters, such as organic solvent, extraction time, stirring rate, pH of donor phase and acceptor phase, temperature, and the volume of acceptor phase were optimized. This method provided 98- to 288-fold enrichment factors within 60min of extraction and good repeatability with RSDs of 0.99-7.22%. The calibration curves were linear over the ranges of 16.0-128.0MUg/L for AC, 11.0-88.0MUg/L for HA and 8.1-64.8MUg/L for MA in human urine sample, with correlation coefficients of 0.9949, 0.9969 and 0.9904, respectively. Limits of detection were from 0.7 to 1.5MUg/L, and recoveries from spiked urine sample varied from 84.4% to 106.2% for AC, 77.3% to 85.6% for HA and 90.1% to 100.8% for MA. PMID- 20846914 TI - Free fatty acid metabolic profile and biomarkers of isolated post-challenge diabetes and type 2 diabetes mellitus based on GC-MS and multivariate statistical analysis. AB - Isolated post-challenge diabetes (IPD, 2h-PG >=11.1mmol/L and FPG <7.0mmol/L) is often ignored in screening for diabetes by fasting plasma glucose (FPG) levels. The aim of this study was to investigate the metabolic profiles of serum free fatty acids (FFAs) and to identify biomarkers that can be used to distinguish patients with IPD from those with type 2 diabetes mellitus (T2DM) or healthy control individuals. FFA profiles of the subjects were investigated using gas chromatography-mass spectrometry (GC-MS). Principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used for classification and prediction among the three groups. The predictive correct rates were 92.86% for IPD and healthy control individuals and 90.70% for T2DM and healthy control individuals, indicating that PLS-DA could satisfactorily distinguish IPD individuals from healthy controls and those with T2DM. Finally, palmitic acid, stearic acid, oleic acid, linoleic acid and alpha-linolenic acid were identified as potential biomarkers for distinguishing IPD from healthy control and T2DM individuals. These potential biomarkers might be helpful for diagnosis and characterization of diabetes. PMID- 20846915 TI - An automated screening method for drugs and toxic compounds in human serum and urine using liquid chromatography-tandem mass spectrometry. AB - A fully automated screening using liquid chromatography-mass spectrometric method applying data-dependent acquisition was developed to identify toxicologically relevant substances in serum and urine. A library including more than 405 spectra of about 365 compounds (main drugs and important metabolites) was established. An easy to use program was created to automate and accelerate library search. Drugs were identified based on their relative retention times, molecular ions and fragment ions. Limits of detection were tested with 100 of the 365 compounds the majority of these were lower than 100MUg/l (67%). The developed LC-MS-MS system seems to be a valuable alternative to other general unknown screening methods allowing fast and specific identification of drugs in serum and urine samples. PMID- 20846916 TI - Simple, sensitive and rapid HPLC-MS/MS method for the determination of cepharanthine in human plasma. AB - A rapid, sensitive and specific method for the determination of cepharanthine in human plasma using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) was described. Cepharanthine and the internal standard (I.S.), telmisartan, were extracted from human plasma by methanol to precipitate the protein. A centrifuged upper layer was then evaporated and reconstituted with 100MUL methanol. Chromatographic separation was performed on an AGILENT XDB-C(8) column (150mm*2.1mm, 5.0MUm, Agilent, USA) using a gradient mobile phase with 1mmol/L ammonium acetate in water with 0.05% formic acid and methanol. Detection and quantitation was performed by MS/MS using electrospray ionization (ESI) and multiple reaction monitoring (MRM) in the positive ion mode. The most intense [M+H](+) MRM transition of cepharanthine at m/z 607.3->365.3 was used for quantitation and the transition at m/z 515.5->276.4 was used to monitor telmisartan. The calibration curve was linear within the concentration range of 0.5-200.0ng/mL (r=0.9994). The limit of quantification (LOQ) was 0.5ng/mL. The extraction recovery was above 81.1%. The accuracy was higher than 92.3%. The intra- and inter-day precisions were less than 9.66%. The method was accurate, sensitive and simple and was successfully applied to a pharmacokinetic study after single intravenous administration of 50mg cepharanthine in 12 healthy Chinese volunteers. PMID- 20846917 TI - LC-MS/MS method for the determination of several drugs used in combined cardiovascular therapy in human plasma. AB - A simple, fast and validated method is reported for the simultaneous analysis, in human plasma, of several drugs usually combined in cardiovascular therapy (atenolol, bisoprolol, hydrochlorothiazide, chlorthalidone, salicylic acid, enalapril and its active metabolite enalaprilat, valsartan and fluvastatin) using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) with electrospray ionization (ESI), working in multiple reaction monitoring mode (MRM). Separation of analytes and internal standard (pravastatin) was performed on a Luna C18(2) (150mm*4.6mm, 3MUm) column using a gradient elution mode with a run time of 15min. The mobile phase consisted of a mixture of acetonitrile and water containing 0.01% formic acid and 10mM ammonium formate at pH 4.1. Sample treatment consisted of a simple protein precipitation with acetonitrile, enabling a fast analysis. The method showed good linearity, precision (RSD% values between 0.7% and 12.7%) and accuracy (relative error values between 0.9% and 14.0%). Recoveries were within 68-106% range and the ion-suppression was not higher than 22% for any analyte. The method was successfully applied to plasma samples obtained from patients under combined cardiovascular treatment. PMID- 20846918 TI - Facial nerve reconstruction using a muscle flap following resection of parotid gland tumours with thorough recipient bed preparation. AB - BACKGROUND: Recent innovations in facial nerve reconstruction procedures or 'restoration of facial expression', extremely important in patients' social activities, have provided some interesting findings. However, there has been little discussion of immediate facial nerve reconstruction following resection of a parotid carcinoma. In this article, details of our techniques and the concepts are presented. METHODS: Ten patients underwent immediate facial nerve reconstruction following resection of a parotid carcinoma, with thorough 'recipient bed preparation', between October 2003 and October 2009. Postoperative radiotherapy was administered to seven cases, with an average radiation dosage of 55 Gy. Nerve reconstruction was performed using a sural nerve graft and either method 1, using a sternocleidomastoid and platysma muscle flap or method 2, using a pectoralis major muscle flap. RESULTS: Method 1 was used in six cases, and method 2 in four. Postoperative function was House Brackmann (HB) grade II in two cases, grade III in seven, grade IV in one and unassessable in one. Average Sunnybrook facial grading score was 50. No complications, such as contour deformity or Frey syndrome, were detected. CONCLUSIONS: We performed immediate facial nerve reconstruction following resection of parotid tumours with the emphasis on recipient bed preparation using a muscle flap, achieving the following objectives: (1) stable facial nerve reconstruction; (2) avoidance of contour deformity; and (3) prevention of Frey syndrome. We believe this is an extremely useful method, technically easy to perform and provides stable results. PMID- 20846919 TI - Lipolytic effectiveness of phosphatidylcholine in the treatment of 'buffalo hump' of HIV patients. PMID- 20846921 TI - Cemento-ossifying fibroma of the mandible. AB - INTRODUCTION: Cemento-ossifying fibroma is a rare benign tumor most often discovered incidentally. CASE REPORT: A 72-year-old patient was referred for a subclinical lesion of the mandible. The orthopantomogram showed a well circumscribed radiolucent osteolytic image, 1 cm in diameter, on the mandibular angle. On CT, the single lesion had a tissue aspect with a peripheral halo without enhancement after contrast injection. A cortical lacuna on the lingual side was noted. Surgical enucleation of the lesion was performed. The pathological examination confirmed the ossifying fibroma. DISCUSSION/CONCLUSION: Slow and progressive, cemento-ossifying fibroma is a rare benign tumor that reaches the maxilla and more frequently the mandible. The ossifying and cementifying fibromas are differentiated by their clinical, radiological, and histological findings. The authors discuss the pathogenesis and radiological signs guiding the choice of diagnostic and therapeutic methods. The treatment is surgical with an enucleation or wider resection with bone reconstruction for large fibromas. PMID- 20846920 TI - Selected estrogen receptor 1 and androgen receptor gene polymorphisms in relation to risk of breast cancer and fibrocystic breast conditions among Chinese women. AB - BACKGROUND: Polymorphisms in sex hormone receptor-encoding genes may alter the activity of sex hormone receptors and thereby affect susceptibility to breast cancer and related outcomes. METHODS: In a case-control study of women from Shanghai, China, we examined the risk of breast cancer and fibrocystic breast conditions associated with the ESR1 PvuII (rs2234693) and XbaI (rs9340799) and AR CAG repeat ((CAG)(n)) and GGC repeat ((GGC)(n)) polymorphisms among 614 women with breast cancer, 467 women with fibrocystic conditions, and 879 women without breast disease. We also evaluated whether risk differed by the presence/absence of proliferative changes (in the extratumoral epithelium or fibrocystic lesion), menopausal status, or body mass index (BMI). Age-adjusted odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using logistic regression. RESULTS: Only associations with AR (CAG)(n) and (GGC)(n) genotypes were detected. Allocating AR (CAG)(n) genotypes into six categories, with the (CAG)(22 24)/(CAG)(22-24) genotype category designated as the reference group, the (CAG)(>24)/(CAG)(>24) genotype category was associated with an increased risk of fibrocystic breast conditions (OR, 1.8; 95% CI, 1.1-3.0). Relative to the AR (GGC)(17)/(GGC)(17) genotype, the (GGC)(17)/(GGC)(14) genotype was associated with elevated risks of incident breast cancer (OR, 2.6; 95% CI, 1.3-5.4) and fibrocystic conditions (OR, 2.3; 95% CI, 1.1-4.5). Results did not differ according to proliferation status, menopausal status, or BMI. CONCLUSION: Although these data lend support for a link between AR variation and breast disease development, given the low frequency of the putative risk-conferring genotypes and other constraints, further confirmation of our results is needed. PMID- 20846922 TI - Sudden deafness and neurinoma. PMID- 20846923 TI - In-home coal and wood use and lung cancer risk: a pooled analysis of the International Lung Cancer Consortium. AB - BACKGROUND: Domestic fuel combustion from cooking and heating is an important public health issue because roughly 3 billion people are exposed worldwide. Recently, the International Agency for Research on Cancer classified indoor emissions from household coal combustion as a human carcinogen (group 1) and from biomass fuel (primarily wood) as a probable human carcinogen (group 2A). OBJECTIVES: We pooled seven studies from the International Lung Cancer Consortium (5,105 cases and 6,535 controls) to provide further epidemiological evaluation of the association between in-home solid-fuel use, particularly wood, and lung cancer risk. METHODS: Using questionnaire data, we classified subjects as predominant solid-fuel users (e.g., coal, wood) or nonsolid-fuel users (e.g., oil, gas, electricity). Unconditional logistic regression was used to estimate the odds ratios (ORs) and to compute 95% confidence intervals (CIs), adjusting for age, sex, education, smoking status, race/ethnicity, and study center. RESULTS: Compared with nonsolid-fuel users, predominant coal users (OR = 1.64; 95% CI, 1.49-1.81), particularly coal users in Asia (OR = 4.93; 95% CI, 3.73 6.52), and predominant wood users in North American and European countries (OR = 1.21; 95% CI, 1.06-1.38) experienced higher risk of lung cancer. The results were similar in never-smoking women and other subgroups. CONCLUSIONS: Our results are consistent with previous observations pertaining to in-home coal use and lung cancer risk, support the hypothesis of a carcinogenic potential of in-home wood use, and point to the need for more detailed study of factors affecting these associations. PMID- 20846925 TI - General considerations for integrating pharmacogenomics into mainstream medical practice. PMID- 20846924 TI - Altered cardiac repolarization in association with air pollution and air temperature among myocardial infarction survivors. AB - BACKGROUND: Epidemiological studies have shown that ambient particulate matter (PM) and changes in air temperature are associated with increased cardiopulmonary events. OBJECTIVE: We hypothesized that patients with previous myocardial infarction (MI) experience changes in heart rate (HR) and repolarization parameters, such as Bazett-corrected QT interval (QTc), and T-wave amplitude (Tamp), in association with increases in air pollution and temperature changes. METHODS: Between May 2003 and February 2004, 67 MI survivors from the Augsburg KORA-MI registry repeatedly sent 16 sec electrocardiograms (ECGs) with a personal transmitter (Viapac) via telephone to the Philips Monitoring Center, where ECG parameters were immediately analyzed. Meteorological data and air pollutants were acquired from fixed monitoring sites on an hourly basis. Additive mixed models were used for analysis. Effect modification by patient characteristics was investigated. RESULTS: The analysis of the 1,745 ECGs revealed an increased HR associated with interquartile range (IQR) increases in PM levels among participants not using beta-adrenergic receptor blockers and among those with body mass index >= 30 kg/m2. We observed a 24- to 47-hr lagged QTc prolongation [0.5% change (95% confidence interval, 0.0-1.0%)] in association with IQR increases in levels of PM <= 2.5 um in aerodynamic diameter, especially in patients with one [0.6% (0.1-1.0%)] or two [1.2% (0.4-2.1%)] minor alleles of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) single-nucleotide polymorphism rs2364725. Positive immediate (0-23 hr) and inverse delayed (48-71 hr up to 96-119 hr) associations were evident between PM and Tamp. We detected an inverse U-shaped association between temperature and Tamp, with a maximum Tamp at 5 degrees C. CONCLUSIONS: Increased air pollution levels and temperature changes may lead to changes in HR and repolarization parameters that may be precursors of cardiac problems. PMID- 20846926 TI - Endothelial nitric oxide synthase gene polymorphisms -786T > C and 894G > T in coronary artery bypass graft surgery patients. AB - Polymorphisms in the endothelial nitric oxide synthase ( eNOS ) gene (- 786T > C and 894G > T ) enhance endothelial dysfunction and have been studied in relation to coronary artery disease (CAD). In the present study, we examined the association of the above polymorphisms with CAD, as well as with myocardial infarction (MI), hypertension, diabetes and smoking in CAD patients. Study subjects consisted of 154 consecutive coronary artery bypass graft (CABG) patients and 155 non-CAD controls. eNOS - 786T > C and 894G > T polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. The estimated frequencies of the - 786C and 894T alleles did not differ between the two groups ( p = 0.46 and p = 0.84, respectively). The prevalence of eNOS polymorphisms was not associated with MI, hypertension or diabetes in CABG patients; however, we found that the 894TT genotype and 894T allele were significantly more frequent in current/past smoker CABG patients (16.7 per cent and 39.6 per cent, respectively) compared with never smoker CABG patients (6.1 per cent and 24.4 per cent, respectively) ( p = 0.01 and p < 0.01, respectively). We found no association of eNOS - 786C and 894T variant alleles with CAD; however, within CABG patients, a gene-environment interaction was found between the eNOS 894T allele and smoking. PMID- 20846927 TI - An isolated case of lissencephaly caused by the insertion of a mitochondrial genome-derived DNA sequence into the 5' untranslated region of the PAFAH1B1 (LIS1) gene. AB - A 130 base pair (bp) insertion (g.-8delCins130) into the 5' untranslated region of the PAFAH1B1 (LIS1) gene, seven nucleotides upstream of the translational initiation site, was detected in an isolated case of lissencephaly. The inserted DNA sequence exhibited perfect homology to two non-contiguous regions of the mitochondrial genome (8479 to 8545 and 8775 to 8835, containing portions of two genes, ATP8 and ATP6 ), as well as near-perfect homology (1 bp mismatch) to a nuclear mitochondrial pseudogene (NUMT) sequence located on chromosome 1p36. This lesion was not evident on polymerase chain reaction (PCR) sequence analysis of either parent, indicating that the mutation had occurred de novo in the patient. Experiments designed to distinguish between a mitochondrial and a nuclear genomic origin for the inserted DNA sequence were, however, inconclusive. Mitochondrial genome sequences from both the patient and his parents were sequenced and found to be identical to the sequence inserted into the PAFAH1B1 gene. Analysis of parental PCR products from the chromosome 1-specific NUMT were also consistent with the interpretation that the inserted sequence had originated directly from the mitochondrial genome. The chromosome 1-specific NUMT in the patient proved to be refractory to PCR analysis, however, suggesting that this region of chromosome 1 could have been deleted or rearranged. Although it remains by far the most likely scenario, in the absence of DNA sequence information from the patient's own chromosome 1-specific NUMT, we cannot unequivocally confirm that the 130 bp insertion originated from mitochondrial genome rather than from the NUMT. PMID- 20846928 TI - KinSNP software for homozygosity mapping of disease genes using SNP microarrays. AB - Consanguineous families affected with a recessive genetic disease caused by homozygotisation of a mutation offer a unique advantage for positional cloning of rare diseases. Homozygosity mapping of patient genotypes is a powerful technique for the identification of the genomic locus harbouring the causing mutation. This strategy relies on the observation that in these patients a large region spanning the disease locus is also homozygous with high probability. The high marker density in single nucleotide polymorphism (SNP) arrays is extremely advantageous for homozygosity mapping. We present KinSNP, a user-friendly software tool for homozygosity mapping using SNP arrays. The software searches for stretches of SNPs which are homozygous to the same allele in all ascertained sick individuals. User-specified parameters control the number of allowed genotyping 'errors' within homozygous blocks. Candidate disease regions are then reported in a detailed, coloured Excel file, along with genotypes of family members and healthy controls. An interactive genome browser has been included which shows homozygous blocks, individual genotypes, genes and further annotations along the chromosomes, with zooming and scrolling capabilities. The software has been used to identify the location of a mutated gene causing insensitivity to pain in a large Bedouin family. KinSNP is freely available from. PMID- 20846929 TI - Intronic polymorphisms of cytochromes P450. AB - The cytochrome P450 enzymes active in drug metabolism are highly polymorphic. Most allelic variants have been described for enzymes encoded by the cytochrome P450 family 2 (CYP2) gene family, which has 252 different alleles. The intronic polymorphisms in the cytochrome P450 genes account for only a small number of the important variant alleles; however, the most important ones are CYP2D6*4 and CYP2D6*41 , which cause abolished and reduced CYP2D6 activity, respectively, and CYP3A5* 3 and CYP3A5*5 , common in Caucasian populations, which cause almost null activity. Their discoveries have been based on phenotypic alterations within individuals in a population, and their identification has, in several cases, been difficult and taken a long time. In light of the next-generation sequencing projects, it is anticipated that further alleles with intronic mutations will be identified that can explain the hitherto unidentified genetic basis of inter individual differences in cytochrome P450-mediated drug and steroid metabolism. PMID- 20846930 TI - Methylation-mediated deamination of 5-methylcytosine appears to give rise to mutations causing human inherited disease in CpNpG trinucleotides, as well as in CpG dinucleotides. AB - The cytosine-guanine (CpG) dinucleotide has long been known to be a hotspot for pathological mutation in the human genome. This hypermutability is related to its role as the major site of cytosine methylation with the attendant risk of spontaneous deamination of 5-methylcytosine (5mC) to yield thymine. Cytosine methylation, however, also occurs in the context of CpNpG sites in the human genome, an unsurprising finding since the intrinsic symmetry of CpNpG renders it capable of supporting a semi-conservative model of replication of the methylation pattern. Recently, it has become clear that significant DNA methylation occurs in a CpHpG context (where H = A, C or T) in a variety of human somatic tissues. If we assume that CpHpG methylation also occurs in the germline, and that 5mC deamination can occur within a CpHpG context, then we might surmise that methylated CpHpG sites could also constitute mutation hotspots causing human genetic disease. To test this postulate, 54,625 missense and nonsense mutations from 2,113 genes causing inherited disease were retrieved from the Human Gene Mutation Database (http://www.hgmd.org). Some 18.2 per cent of these pathological lesions were found to be C -> T and G -> A transitions located in CpG dinucleotides (compatible with a model of methylation-mediated deamination of 5mC), an approximately ten-fold higher proportion than would have been expected by chance alone. The corresponding proportion for the CpHpG trinucleotide was 9.9 per cent, an approximately two-fold higher proportion than would have been expected by chance. We therefore estimate that ~5 per cent of missense/nonsense mutations causing human inherited disease may be attributable to methylation mediated deamination of 5mC within a CpHpG context. PMID- 20846931 TI - Evolutionary divergence and functions of the human acyl-CoA thioesterase gene ( ACOT ) family. AB - The acyl-CoA thioesterase gene (ACOT ) family encodes enzymes that catalyse the hydrolysis of acyl-CoA thioester compounds, also known as activated fatty acids, to their corresponding non-esterified (free) fatty acid and coenzyme A (CoASH). These enzymes play a very important role in lipid metabolism by maintaining cellular levels and proper ratios of free and activated fatty acids, as well as CoASH. Within the acyl-CoA family there are two distinct subgroups, type I and type II. Despite catalysing the same reaction, the two groups are not structurally similar and do not share sequence homology, strongly suggesting convergent evolution. This suggestion is further supported if one compares the human with the mouse and rat ACOT gene families. To date, four human type I ACOTs have been identified which belong to the alpha/beta-hydrolase fold enzyme superfamily. Type II ACOTs fall into the 'hot dog' fold superfamily. There are currently six human type II genes; however, two homologous proteins, thioesterase superfamily members 4 (THEM4) and 5 (THEM5) share common type II structural features and, in the case of THEM4, acyl-CoA thioesterase activity--suggesting that the family may be larger than previously realised. Although recent studies have greatly expanded the current understanding of these proteins and their physiological importance, there are a number of members whose functions are relatively unexplored and which warrant further investigation. PMID- 20846933 TI - ArrayTrack: a free FDA bioinformatics tool to support emerging biomedical research--an update. AB - ArrayTrack is a Food and Drug Administration (FDA) bioinformatics tool that has been widely adopted by the research community for genomics studies. It provides an integrated environment for microarray data management, analysis and interpretation. Most of its functionality for statistical, pathway and gene ontology analysis can also be applied independently to data generated by other molecular technologies. ArrayTrack has been undergoing active development and enhancement since its inception in 2001. This review summarises its key functionalities, with emphasis on the most recent extensions in support of the evolving needs of FDA's research programmes. ArrayTrack has added capability to manage, analyse and interpret proteomics and metabolomics data after quantification of peptides and metabolites abundance, respectively. Annotation information about single nucleotide polymorphisms and quantitative trait loci has been integrated to support genetics-related studies. Other extensions have been added to manage and analyse genomics data related to bacterial food-borne pathogens. PMID- 20846932 TI - A survey of analysis software for array-comparative genomic hybridisation studies to detect copy number variation. AB - Copy number variants (CNVs) create a major source of variation among individuals and populations. Array-based comparative genomic hybridisation (aCGH) is a powerful method used to detect and compare the copy numbers of DNA sequences at high resolution along the genome. In recent years, several informatics tools for accurate and efficient CNV detection and assessment have been developed. In this paper, most of the well known algorithms, analysis software and the limitations of that software will be briefly reviewed. PMID- 20846935 TI - High frequency of beta-lactam susceptibility in CTX-M-type extended-spectrum-beta lactamase-producing Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis according to the new CLSI recommendations. PMID- 20846936 TI - Telavancin activity against Gram-positive bacteria isolated from respiratory tract specimens of patients with nosocomial pneumonia. AB - OBJECTIVES: The antimicrobial activity of telavancin against 2279 clinical Gram positive cocci obtained from patients with nosocomial pneumonia [NP; including those with ventilator-acquired pneumonia (VAP)] located in numerous medical centres worldwide was evaluated. METHODS: A contemporary collection of 2279 non duplicate consecutive Gram-positive clinical isolates were submitted from 87 hospitals located in North America (913 isolates), Latin America (222 isolates), Europe (690 isolates), and the Asia-Pacific region (454 isolates) as part of the international telavancin surveillance programme for 2007-08. Isolates were tested for susceptibility by the reference broth microdilution method (with 2%-5% lysed horse blood added for testing of streptococci). Interpretive criteria were those from CLSI (M100-S20, 2010) except for telavancin, for which the susceptible breakpoints approved by the US FDA were applied. RESULTS: Telavancin was highly active against Staphylococcus aureus (MIC(90), 0.25 mg/L; 100% susceptible), coagulase-negative staphylococci (MIC(90), 0.25 mg/L), Streptococcus pneumoniae (MIC(90), 0.03 mg/L), viridans group streptococci (MIC(90), 0.06 mg/L; 100% susceptible), beta-haemolytic streptococci (MIC(90), 0.06 mg/L; 100% susceptible) and vancomycin-susceptible enterococci (MIC(90), 0.5 mg/L; 100% susceptible). Telavancin inhibited all staphylococci at <= 0.5 mg/L. Among enterococci non susceptible to vancomycin (all Enterococcus faecium), telavancin was active against isolates exhibiting a VanB phenotype (MIC, 0.06-0.12 mg/L), but less potent against VanA strains (MIC, >= 2 mg/L). CONCLUSIONS: Telavancin demonstrated equal or greater potency than the comparators (vancomycin, teicoplanin, daptomycin, linezolid and quinupristin/dalfopristin) against Gram positive pathogens implicated in NP. Telavancin showed elevated MIC values only against enterococcus isolates showing a VanA phenotype. The continued appearance of multidrug-resistant pathogens among Gram-positive isolates, mainly S. aureus, necessitates the introduction of new agents and longitudinal surveillance to monitor for the potential emergence of resistance. PMID- 20846937 TI - Activity of BAL30376 (monobactam BAL19764 + BAL29880 + clavulanate) versus Gram negative bacteria with characterized resistance mechanisms. AB - BACKGROUND: BAL30376 combines the siderophore monobactam BAL19764 (Syn/PTX 2416) with the bridged monobactam BAL29880 to inhibit AmpC enzymes and with clavulanate to inhibit extended-spectrum beta-lactamases (ESBLs). We tested BAL30376 and its components versus isolates and laboratory strains of Enterobacteriaceae and non fermenters. METHODS: MICs were determined on Mueller-Hinton agar supplemented with 2,2'-bipyridyl to chelate Fe(3+) and induce TonB-mediated uptake. RESULTS: Unprotected BAL19764 had MICs <= 1 mg/L for most cephalosporin-susceptible Enterobacteriaceae, but values for a few isolates ranged up to 8 mg/L; its MICs were substantially raised for isolates with AmpC beta-lactamases and ESBLs. Those of BAL30376 were <= 1 mg/L for 84% of ESBL producers and <= 4 mg/L for 85% of AmpC producers, excluding isolates with exceptional impermeability. Laboratory transformants with metallo- or OXA-48 carbapenemases were susceptible to unprotected BAL19764, but many clinical isolates with these enzymes were resistant, probably having additional mechanisms; BAL30376, by contrast, was active at 4 mg/L versus 31/35 metallo-beta-lactamase producers and 14/19 with OXA 48, although those with KPC carbapenemases were resistant. AmpC-mediated resistance to BAL19764 in Pseudomonas aeruginosa was overcome by BAL30376, as was that due to PER-1 enzyme; but MICs > 16 mg/L were frequent for cystic fibrosis isolates. Many Burkholderia cepacia and carbapenemase-producing Acinetobacter baumannii were susceptible to BAL19764 and BAL30376 at <= 4 mg/L, but others were highly resistant, with MICs >= 128 mg/L. CONCLUSIONS: BAL30376 overcomes most AmpC-, ESBL- and carbapenemase-mediated resistance in Enterobacteriaceae, though strains with KPC carbapenemases are resistant. It was active against many problem non-fermenters, though resistance was common in P. aeruginosa from cystic fibrosis. Raised MICs for some isolates were independent of beta-lactamase. PMID- 20846938 TI - Kidney and liver cysts in autosomal dominant polycystic kidney disease. PMID- 20846939 TI - Trimestral variations of C-reactive protein, interleukin-6 and tumour necrosis factor-alpha are similarly associated with survival in haemodialysis patients. AB - BACKGROUND: The impact of intra-individual changes of inflammatory markers [other than C-reactive protein (CRP)] on mortality in haemodialysis (HD) patients is unknown. We therefore studied survival in relation to trimestral variations of CRP, interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha). METHODS: In 201 prevalent HD patients from the Mapping of Inflammatory Markers in Chronic Kidney Disease cohort, serum CRP, IL-6 and TNF-alpha were measured 3 months apart and survival was assessed during follow-up. Based on fluctuations along tertiles of distribution, four patterns were defined for each inflammatory marker: stable low, decrease, increase and stable high. Hazard ratios were calculated by the Cox proportional hazard model, and Pearson's test was used to correlate changes. CRP analyses were replicated in 472 incident HD patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. RESULTS: Patients with persistently elevated CRP values had the worst mortality in crude [HR 2.98 (95% CI 1.71-5.20)] and adjusted [2.79 (1.58-4.94)] Cox models, together with those who increased in their CRP levels [crude 3.27 (1.91-5.60); adjusted 3.13 (1.79 5.45)]. Similar survival patterns were observed for IL-6 and TNF-alpha variation categories. Correlations among these changes were, however, not strong. In the replication cohort, individuals with persistently elevated CRP values also showed the highest mortality risk [crude 3.38 (2.31-4.94); adjusted 2.33 (1.58-3.45)]. CONCLUSIONS: Trimestral variations of TNF-alpha, IL-6, and CRP are similarly associated with survival in HD patients. The agreement between changes of these biomarkers was low, suggesting that different pathways may trigger each of these markers. PMID- 20846940 TI - Glomerular diseases and transplantation: similarities in pathogenetic mechanisms and treatment options. AB - Glomerular diseases and renal transplantation have always been considered as independent fields of nephrology, due to the supposed prevalent role of antibody production and immune complex formation in glomerulonephritis versus a direct reaction of immune cell towards the grafted kidney. However, both conditions share common pathogenetical pathways, and possible new therapeutic approaches are being envisaged. Innate immunity, particularly Toll-like receptors, dendritic cells and complement pathways, B cells and antibody networks are involved in the development of glomerular damage as well as graft injury. Consequently, new treatments targeting previously not considered immune pathways, like nuclear factor-kappaB or the proteasome and B-cell activation with antibody production, are being tested in glomerular diseases and in transplanted kidneys. PMID- 20846941 TI - Massively parallel sequencing and rare disease. AB - Massively parallel sequencing has enabled the rapid, systematic identification of variants on a large scale. This has, in turn, accelerated the pace of gene discovery and disease diagnosis on a molecular level and has the potential to revolutionize methods particularly for the analysis of Mendelian disease. Using massively parallel sequencing has enabled investigators to interrogate variants both in the context of linkage intervals and also on a genome-wide scale, in the absence of linkage information entirely. The primary challenge now is to distinguish between background polymorphisms and pathogenic mutations. Recently developed strategies for rare monogenic disorders have met with some early success. These strategies include filtering for potential causal variants based on frequency and function, and also ranking variants based on conservation scores and predicted deleteriousness to protein structure. Here, we review the recent literature in the use of high-throughput sequence data and its analysis in the discovery of causal mutations for rare disorders. PMID- 20846942 TI - Functional relevance of the IRF-1 promoter polymorphism rs2549009 on transcriptional activity in a native genomic environment. AB - Interferon regulatory factor-1 (IRF-1), a transcription regulator involved both in inducing and in mediating the effects of interferon, is encoded by a highly polymorphic gene in different ethnic populations. Some of these genetic variations have been described to be associated to disease traits in hepatitis C virus and in human immunodeficiency virus infection, including one single nucleotide polymorphism rs2549009 within the promoter region. This study aimed at investigating the functional relevance of rs2549009 on IRF-1 transcriptional activity in peripheral blood mononuclear cells in its natural genomic environment. Haplotype-specific chromatin immunoprecipitation using antibodies directed against both the transcriptionally inactive and active RNA polymerase II (RNAPII) and allele-specific transcript quantification techniques were applied to ex vivo-derived samples from healthy heterozygous donors. Inactive serine 5 phosphorylated RNAPII was found to be preferentially bound to the rs2549009 A allele in all donors investigated. Active serine 2 phosphorylated (ser2-P) RNAPII, in contrast, was found to be precipitable, depending on the donor, preferentially either with the A or the G promoter variants or without any preference. The ratio of rs2549009 A/G promoter variants engaged by ser2-P RNAPII was closely related to the relative frequency of the respective IRF-1 transcripts, and relative allelic expression was found to be associated to total IRF-1 gene expression. These results provide evidence for a bidirectional IRF-1 gene expression imbalance that appears not to be solely controlled by rs2549009 in cis and may rely on a yet unidentified variant or haplotype or on environmental control in trans. PMID- 20846943 TI - Allele-specific and heritable chromatin signatures in humans. AB - Next-generation sequencing-based assays to detect gene regulatory elements are enabling the analysis of individual-to-individual and allele-specific variation of chromatin status and transcription factor binding in humans. Recently, a number of studies have explored this area, using lymphoblastoid cell lines. Around 10% of chromatin sites show either individual-level differences or allele specific behavior. Future studies are likely to be limited by cell line accessibility, meaning that white-bloodcell-based studies are likely to continue to be the main source of samples. A detailed understanding of the relationship between normal genetic variation and chromatin variation can shed light on how polymorphisms in non-coding regions in the human genome might underlie phenotypic variation and disease. PMID- 20846944 TI - Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. AB - A major obstacle of allogeneic haematopoietic stem cell transplantation is graft versus-host disease, an immune-mediated disorder that affects multiple tissues and organs with varying severity. Neurological complications of acute and chronic graft-versus-host disease are rare but can produce severe clinical problems with significant morbidity and mortality. In this article, we review neurological manifestations of chronic graft-versus-host disease that comprise immune-mediated neuropathies, myasthenia gravis and myositis in the peripheral nervous system and various cerebrovascular complications, demyelination and immune-mediated encephalitis in the central nervous system. The National Institutes of Health consensus on criteria for clinical trials in chronic graft-versus-host disease recommended that the diagnosis of chronic graft-versus-host disease of the nervous system can be made only when other organs are affected by graft-versus host disease and frequent neurological differential diagnoses such as drug induced toxicities or opportunistic infections are excluded. The Consensus Conference on Clinical Practice in chronic graft-versus-host disease, held in autumn 2009 in Regensburg, aimed to summarize the literature and to provide guidelines for the diagnostic approach in children and adults with neurological manifestations of chronic graft-versus-host disease. Moreover, we present therapeutic recommendations and their level of evidence for the management of these complications. Overlapping symptoms and comorbidities after allogeneic haematopoietic stem cell transplantation and the limited knowledge about the underlying biological mechanisms of chronic graft-versus-host disease affecting the nervous system emphasize the need for further experimental and clinical investigations. PMID- 20846945 TI - Post-surgical inflammatory neuropathy. AB - Post-surgical neuropathies are usually attributed to mechanical factors, such as compression, stretch, contusion or transection. The role of inflammatory mechanisms in neuropathies occurring after surgeries is poorly appreciated and not well characterized, and may provide a rationale for immunotherapy. A total of 23 selected patients with post-surgical neuropathies received nerve biopsies, of which 21 demonstrated increased inflammation. Here we report the clinical features in these 21 cases of biopsy-confirmed and 12 cases of clinically suspected post-surgical inflammatory neuropathies, in whom no trauma to the nerves was documented. All neuropathies developed within 30 days of a surgical procedure. Of 33 patients, 20 were male and the median age was 65 years (range 24 83). Surgical procedures were orthopaedic (n=14), abdominal/pelvic (n=12), thoracic (n=5) and dental (n=2). Patients developed focal (n=12), multifocal (n=14) or diffuse (n=7) neuropathies. Focal and multifocal neuropathies typically presented with acute pain and weakness, and focal neuropathies often mimicked mechanical aetiologies. Detailed analyses, including clinical characteristics, electrophysiology, imaging and peripheral nerve pathology, were performed. Electrophysiology showed axonal damage. Magnetic resonance imaging of roots, plexuses and peripheral nerves was performed in 22 patients, and all patients had abnormally increased T(2) nerve signal, with 20 exhibiting mild (n=7), moderate (n=12) or severe (n=1) enlargement. A total of 21 patients had abnormal nerve biopsies that showed increased epineurial perivascular lymphocytic inflammation (nine small, five moderate and seven large), with 15 diagnostic or suggestive of microvasculitis. Evidence of ischaemic nerve injury was seen in 19 biopsies. Seventeen biopsies had increased axonal degeneration suggesting active neuropathy. Seventeen biopsied patients were treated with immunotherapy. In 13 cases with longitudinal follow-up (median 9 months, range 3-71 months), the median neuropathy impairment score improved from 30 to 24 at the time of last evaluation (P=0.001). IN CONCLUSION: (i) not all post-surgical neuropathies are mechanical, and inflammatory mechanisms can be causative, presenting as pain and weakness in a focal, multifocal or diffuse pattern; (ii) these inflammatory neuropathies may be recognized by their spatio-temporal separation from the site and time of surgery and by the characteristic magnetic resonance imaging features; (iii) occasionally post-surgical inflammatory and mechanical neuropathies are difficult to distinguish and nerve biopsy may be required to demonstrate an inflammatory mechanism, which in our cohort often, but not exclusively, exhibited pathological features of microvasculitis and ischaemia; and (iv) recognizing the role of inflammation in these patients' neuropathy led to rational immunotherapy, which may have resulted in the subsequent improvement of neurological symptoms and impairments. PMID- 20846952 TI - Environmental enrichment: a cure for cancer? It's all in the mind. AB - Environmental enrichment is used to enhance mental stimulation and physical activity and has been shown to delay onset and progression of a range of brain disorders. Now, Cao et al. (2010) report in Cell that this paradigm also exerts strong influences beyond the brain and is capable of suppressing tumor growth in mice. PMID- 20846948 TI - Forced expiratory volume predicts all-cause and cancer mortality in Mumbai, India: results from a population-based cohort study. AB - BACKGROUND: Reduction in pulmonary function, as estimated by forced expiratory volume in 1 s (FEV(1)), has been found to predict all-cause mortality in developed-country populations. This study was designed to examine the association between FEV(1) and mortality in an urban developing-country population. METHODS: Data from the large, well-characterized Mumbai Cohort Study (Maharashtra, India) were used to compute hazard ratios (HRs; deaths/100-ml FEV(1)) and 95% confidence intervals (CIs) from Cox proportional hazards regression models in which age, tobacco use, education, height and relative body weight were controlled. RESULTS: A total of 13,261 deaths occurred in this cohort of 148,173 individuals. After controlling for important covariates, there was a 1.7% reduction in risk of overall death in women for each 100-ml increment in FEV(1) (HR = 0.983; 95% CI = 0.980-0.986) and a 1.5% reduction in men (HR = 0.985; 95% CI = 0.984-0.986). There was a 1.6% reduction in cancer deaths in women (HR = 0.984; 95% CI = 0.973 0.996) and a 0.8% reduction in men (HR = 0.992; 95% CI = 0.987-0.997). The largest reductions in women were observed in tuberculosis deaths (3.7%/100-ml increment in FEV(1)), and in men in respiratory system deaths (3.2%). CONCLUSIONS: In a densely populated urban Indian population, FEV(1) predicted overall and cancer mortality. Effects were larger in women and were not attenuated by exclusion of smokers or restricting analyses to subjects dying >2 years from recruitment. Because FEV(1) may be affected by air pollution, which is worsening in urban areas of most developing countries, further research is recommended to deepen understanding of these factors in relation to mortality. PMID- 20846947 TI - Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis. AB - BACKGROUND: Estimates of global DNA methylation from repetitive DNA elements, such as Alu and LINE-1, have been increasingly used in epidemiological investigations because of their relative low-cost, high-throughput and quantitative results. Nevertheless, determinants of these methylation measures in healthy individuals are still largely unknown. The aim of this study was to examine whether age, gender, smoking habits, alcohol drinking and body mass index (BMI) are associated with Alu or LINE-1 methylation levels in blood leucocyte DNA of healthy individuals. METHODS: Individual data from five studies including a total of 1465 healthy subjects were combined. DNA methylation was quantified by PCR-pyrosequencing. RESULTS: Age [beta = -0.011% of 5-methyl-cytosine (%5 mC)/year, 95% confidence interval (CI) -0.020 to -0.001%5 mC/year] and alcohol drinking (beta = -0.214, 95% CI -0.415 to -0.013) were inversely associated with Alu methylation. Compared with females, males had lower Alu methylation (beta = 0.385, 95% CI -0.665 to -0.104) and higher LINE-1 methylation (beta = 0.796, 95% CI 0.261 to 1.330). No associations were found with smoking or BMI. Percent neutrophils and lymphocytes in blood counts exhibited a positive (beta = 0.036, 95% CI 0.010 to 0.061) and negative (beta = -0.038, 95% CI -0.065 to -0.012) association with LINE-1 methylation, respectively. CONCLUSIONS: Global methylation measures in blood DNA vary in relation with certain host and lifestyle characteristics, including age, gender, alcohol drinking and white blood cell counts. These findings need to be considered in designing epidemiological investigations aimed at identifying associations between DNA methylation and health outcomes. PMID- 20846953 TI - From a global view to focused examination: understanding cellular function of lipid kinase VPS34-Beclin 1 complex in autophagy. AB - Phosphoinositide 3 kinase Class III (PIK3C3) or VPS34-Beclin 1 complex plays a key role in the autophagy-lysosome pathway. Previous identification of numerous binding partners for VPS34-Beclin 1 suggested a complex scheme of the autophagy control mechanism. Recent large-scale screening of autophagy network and signaling pathways in mammalian cells not only confirms the previous binding partners, but also reveals additional interactors and intricate connections of VPS34-Beclin 1 complex to other functional groups of autophagy, yielding a wealth of information that will direct future detailed study of the central control mechanism of autophagy mediated by VPS34-Beclin 1 and other regulators. PMID- 20846954 TI - Reverse crosstalk of TGFbeta and PPARbeta/delta signaling identified by transcriptional profiling. AB - Previous work has provided strong evidence for a role of peroxisome proliferator activated receptor beta/delta (PPARbeta/delta) and transforming growth factor beta (TGFbeta) in inflammation and tumor stroma function, raising the possibility that both signaling pathways are interconnected. We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation, which revealed a substantial, mostly reverse crosstalk of both pathways and identified distinct classes of genes. A major class encompasses classical PPAR target genes, including ANGPTL4, CPT1A, ADRP and PDK4. These genes are repressed by TGFbeta, which is counteracted by PPARbeta/delta activation. This is mediated, at least in part, by the TGFbeta induced recruitment of the corepressor SMRT to PPAR response elements, and its release by PPARbeta/delta ligands, indicating that TGFbeta and PPARbeta/delta signals are integrated by chromatin-associated complexes. A second class represents TGFbeta-induced genes that are downregulated by PPARbeta/delta agonists, exemplified by CD274 and IL6, which is consistent with the anti inflammatory properties of PPARbeta/delta ligands. Finally, cooperative regulation by both ligands was observed for a minor group of genes, including several regulators of cell proliferation. These observations indicate that PPARbeta/delta is able to influence the expression of distinct sets of both TGFbeta-repressed and TGFbeta-activated genes in both directions. PMID- 20846955 TI - Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. AB - Small nucleolar RNAs (snoRNAs) and microRNAs are two classes of non-protein coding RNAs with distinct functions in RNA modification or post-transcriptional gene silencing. In this study, we introduce novel insights to RNA-induced gene activity adjustments in human cells by identifying numerous snoRNA-derived molecules with miRNA-like function, including H/ACA box snoRNAs and C/D box snoRNAs. In particular, we demonstrate that several C/D box snoRNAs give rise to gene regulatory RNAs, named sno-miRNAs here. Our data are complementing the increasing number of studies in the field of small RNAs with regulatory functions. In massively deep sequencing of small RNA fractions we identified high copy numbers of sub-sequences from >30 snoRNAs with lengths of >=18 nt. RNA secondary structure prediction indicated for a majority of candidates a location in predicted stem regions. Experimental analysis revealed efficient gene silencing for 11 box C/D sno-miRNAs, indicating cytoplasmic processing and recruitment to the RNA silencing machinery. Assays in four different human cell lines indicated variations in both the snoRNA levels and their processing to active sno-miRNAs. In addition we show that box D elements are predominantly flanking at least one of the sno-miRNA strands, while the box C element locates within the sequence of the sno-miRNA guide strand. PMID- 20846956 TI - Targeted rapid amplification of cDNA ends (T-RACE)--an improved RACE reaction through degradation of non-target sequences. AB - Amplification of the 5' ends of cDNA, although simple in theory, can often be difficult to achieve. We describe a novel method for the specific amplification of cDNA ends. An oligo-dT adapter incorporating a dUTP-containing PCR primer primes first-strand cDNA synthesis incorporating dUTP. Using the Cap finder approach, another distinct dUTP containing adapter is added to the 3' end of the newly synthesized cDNA. Second-strand synthesis incorporating dUTP is achieved by PCR, using dUTP-containing primers complimentary to the adapter sequences incorporated in the cDNA ends. The double-stranded cDNA-containing dUTP serves as a universal template for the specific amplification of the 3' or 5' end of any gene. To amplify the ends of cDNA, asymmetric PCR is performed using a single gene-specific primer and standard dNTPs. The asymmetric PCR product is purified and non-target transcripts containing dUTP degraded by Uracil DNA glycosylase, leaving only those transcripts produced during the asymmetric PCR. Subsequent PCR using a nested gene-specific primer and the 3' or 5' T-RACE primer results in specific amplification of cDNA ends. This method can be used to specifically amplify the 3' and 5' ends of numerous cDNAs from a single cDNA synthesis reaction. PMID- 20846957 TI - Mutational and biochemical analysis of the DNA-entry nuclease EndA from Streptococcus pneumoniae. AB - EndA is a membrane-attached surface-exposed DNA-entry nuclease previously known to be required for genetic transformation of Streptococcus pneumoniae. More recent studies have shown that the enzyme also plays an important role during the establishment of invasive infections by degrading extracellular chromatin in the form of neutrophil extracellular traps (NETs), enabling streptococci to overcome the innate immune system in mammals. As a virulence factor, EndA has become an interesting target for future drug design. Here we present the first mutational and biochemical analysis of recombinant forms of EndA produced either in a cell free expression system or in Escherichia coli. We identify His160 and Asn191 to be essential for catalysis and Asn182 to be required for stability of EndA. The role of His160 as the putative general base in the catalytic mechanism is supported by chemical rescue of the H160A variant of EndA with imidazole added in excess. Our study paves the way for the identification and development of protein or low-molecular-weight inhibitors for EndA in future high-throughput screening assays. PMID- 20846958 TI - By-passing in vitro screening--next generation sequencing technologies applied to antibody display and in silico candidate selection. AB - In recent years, unprecedented DNA sequencing capacity provided by next generation sequencing (NGS) has revolutionized genomic research. Combining the Illumina sequencing platform and a scFv library designed to confine diversity to both CDR3, >1.9 * 10(7) sequences have been generated. This approach allowed for in depth analysis of the library's diversity, provided sequence information on virtually all scFv during selection for binding to two targets and a global view of these enrichment processes. Using the most frequent heavy chain CDR3 sequences, primers were designed to rescue scFv from the third selection round. Identification, based on sequence frequency, retrieved the most potent scFv and valuable candidates that were missed using classical in vitro screening. Thus, by combining NGS with display technologies, laborious and time consuming upfront screening can be by-passed or complemented and valuable insights into the selection process can be obtained to improve library design and understanding of antibody repertoires. PMID- 20846959 TI - Quantitative analysis of the efficiency and mutagenic spectra of abasic lesion bypass catalyzed by human Y-family DNA polymerases. AB - Higher eukaryotes encode various Y-family DNA polymerases to perform global DNA lesion bypass. To provide complete mutation spectra for abasic lesion bypass, we employed short oligonucleotide sequencing assays to determine the sequences of abasic lesion bypass products synthesized by human Y-family DNA polymerases eta (hPoleta), iota (hPoliota) and kappa (hPolkappa). The fourth human Y-family DNA polymerase, Rev1, failed to generate full-length lesion bypass products after 3 h. The results indicate that hPoliota generates mutations with a frequency from 10 to 80% during each nucleotide incorporation event. In contrast, hPoleta is the least error prone, generating the fewest mutations in the vicinity of the abasic lesion and inserting dAMP with a frequency of 67% opposite the abasic site. While the error frequency of hPolkappa is intermediate to those of hPoleta and hPoliota, hPolkappa has the highest potential to create frameshift mutations opposite the abasic site. Moreover, the time (t(50)(bypass)) required to bypass 50% of the abasic lesions encountered by hPoleta, hPoliota and hPolkappa was 4.6, 112 and 1 823 s, respectively. These t(50)(bypass) values indicate that, among the enzymes, hPoleta has the highest abasic lesion bypass efficiency. Together, our data suggest that hPoleta is best suited to perform abasic lesion bypass in vivo. PMID- 20846961 TI - Home-based cardiac rehabilitation is as effective as centre-based cardiac rehabilitation among elderly with coronary heart disease: results from a randomised clinical trial. AB - BACKGROUND: participation in centre-based cardiac rehabilitation (CR) is known to reduce morbidity and mortality but participation rates among the elderly are low. Establishing alternative programmes is important, and home-based CR is the predominant alternative. However, no studies have investigated the effect of home based CR among a group of elderly patients with coronary heart disease with a long-term follow-up. METHODS: randomised clinical trial comparing home-based CR with comprehensive centre-based CR among patients >= 65 years with coronary heart disease. RESULTS: seventy-five patients participated. There were no significant differences in exercise capacity after the intervention between home and centre based CR. Adjusted mean differences of peak VO2 = 0.9 ml/kg/min (95% CI -0.7, 2.4) and of 6 min walk test = -18.7 m (95% CI -56.4, 18.9). In addition, no differences were found in the secondary outcomes of systolic blood pressure (-0.6 mmHg, 95% CI -11.3, 10.0), LDL cholesterol (0.3 mmol/l, 95% CI -0.04, 0.7), HDL cholesterol (0.2 mmol/l, 95% CI -0.01, 0.3), body composition, proportion of smokers and health-related quality of life. A group of patients who did not have an effect of either programmes were characterised by higher age, living alone and having COPD. At 12 months of follow-up, both groups had a significant decline in exercise capacity. CONCLUSIONS: home-based CR is as effective as centre-based CR in improving exercise capacity, risk factor control and health-related quality of life. However, a group of patients did not improve regardless of the type of intervention. Continued follow-up is essential in order to maintain the gained improvements. PMID- 20846960 TI - Molecular basis of engineered meganuclease targeting of the endogenous human RAG1 locus. AB - Homing endonucleases recognize long target DNA sequences generating an accurate double-strand break that promotes gene targeting through homologous recombination. We have modified the homodimeric I-CreI endonuclease through protein engineering to target a specific DNA sequence within the human RAG1 gene. Mutations in RAG1 produce severe combined immunodeficiency (SCID), a monogenic disease leading to defective immune response in the individuals, leaving them vulnerable to infectious diseases. The structures of two engineered heterodimeric variants and one single-chain variant of I-CreI, in complex with a 24-bp oligonucleotide of the human RAG1 gene sequence, show how the DNA binding is achieved through interactions in the major groove. In addition, the introduction of the G19S mutation in the neighborhood of the catalytic site lowers the reaction energy barrier for DNA cleavage without compromising DNA recognition. Gene-targeting experiments in human cell lines show that the designed single chain molecule preserves its in vivo activity with higher specificity, further enhanced by the G19S mutation. This is the first time that an engineered meganuclease variant targets the human RAG1 locus by stimulating homologous recombination in human cell lines up to 265 bp away from the cleavage site. Our analysis illustrates the key features for a la carte procedure in protein-DNA recognition design, opening new possibilities for SCID patients whose illness can be treated ex vivo. PMID- 20846962 TI - The future of orthogeriatrics. PMID- 20846963 TI - N-terminal probrain natriuretic peptide predicts 1-year mortality following acute stroke: possible evidence of occult cardiac dysfunction among patients with acute stroke. PMID- 20846965 TI - Is spinal anaesthesia at L2-L3 interspace safe in disorders of the vertebral column? A magnetic resonance imaging study. AB - BACKGROUND: The varying point at which the spinal cord terminates in the lumbar spinal canal may affect the incidence of spinal cord injuries associated with needle insertion for spinal anaesthesia, especially in patients with vertebral body or intervertebral disc disease. This is a complication which has been frequently reported when spinal needle insertion was performed at higher lumbar spinal levels. METHODS: We retrospectively reviewed magnetic resonance images of the spine in 1047 Chinese patients to determine the conus medullaris terminus (CMT) in patients with and without vertebral disorders. Patients with tumours in and around the spine and those with congenital spinal anomalies were excluded from the study. Patients with mixed vertebral disorders were also excluded. RESULTS: Our data demonstrate that patients with thoracic vertebral compression fractures had lower ending points of the CMT than those without (P<0.05), while patients with lumbar compression fractures did not demonstrate such a correlation. With regard to this difference, females were significantly at higher risk for a lower CMT than males. Conversely, lumbar disc disorders such as intervertebral disc extrusion, herniation, or bulging did not have any significant influence on the level of CMT. Moreover, patients with spondylolisthesis or scoliosis did not demonstrate an abnormal CMT location. CONCLUSIONS: When performing spinal anaesthesia, anaesthesiologists should be aware of potential differences of the CMT location, particularly in female patients with thoracic vertebral compression fractures, who may have a lower CMT than normal, extending to the level of L2. Performing spinal anaesthesia at the L2-L3 interspace would seem to be ill-advised in this patient population. PMID- 20846964 TI - Changes in airway configuration with different head and neck positions using magnetic resonance imaging of normal airways: a new concept with possible clinical applications. AB - BACKGROUND: The sniffing position is often considered optimal for direct laryngoscopy. Another concept of airway configuration involving a laryngeal vestibule axis and two curves has also been suggested. We investigated whether this theory can be supported mathematically and if it supports the sniffing position as being optimal for direct laryngoscopy. METHODS: Magnetic resonance imaging scans were performed in 42 normal adult volunteers. The airway passage was divided into two curves-primary (oro-pharyngeal curve) and secondary (pharyngo-glotto-tracheal curve). Airway configuration was evaluated in the neutral, extension, head lift, and sniffing positions. The airway passage, point of inflection (where the two curves meet), its tangent, and the line of sight were plotted on each scan. RESULTS: The point of inflection lay within the laryngeal vestibule in all positions. The head lift and sniffing positions caused the tangent to the point of inflection to approximate the horizontal plane. The sniffing, extension, and head lift positions caused a reduction in the area between the line of sight and the airway curve compared with the neutral position. CONCLUSIONS: A two-curve theory is proposed as a basis for explaining airway configuration. The changes in these curves with head and neck positioning support the sniffing position as optimal for direct laryngoscopy. Application of this new concept to other forms of laryngoscopy should be investigated. PMID- 20846966 TI - Novel method of measuring the mental workload of anaesthetists during clinical practice. AB - BACKGROUND: Cognitive overload has been recognized as a significant cause of error in industries such as aviation and measuring mental workload has become a key method of improving safety. The aim of this study was to pilot the use of a new method of measuring mental workload in the operating theatre using a previously published methodology. METHODS: The mental workload of the anaesthetists was assessed by measuring their response times to a wireless vibrotactile device and the NASA TLX subjective workload score during routine surgical procedures. Primary task workload was inferred from the phase of anaesthesia. RESULTS: Significantly increased response time was associated with the induction phase of anaesthesia compared with maintenance/emergence, non consultant grade, and during more complex cases. Increased response was also associated with self-reported mental load, physical load, and frustration. These findings are consistent with periods of increased mental workload and with the findings of other studies using similar techniques. CONCLUSIONS: These findings confirm the importance of mental workload to the performance of anaesthetists and suggest that increased mental workload is likely to be a common problem in clinical practice. Although further studies are required, the method described may be useful for the measurement of the mental workload of anaesthetists. PMID- 20846967 TI - Why is 220Rn (thoron) measurement important? AB - New scientific findings based on the latest epidemiological analyses for lung cancer risk due to radon have been demonstrated. The residential radon concentration is mainly measured by passive radon detectors. Although the passive radon detector is usually designed to detect radon efficiently and exclusively, several types of them can detect thoron together with radon. In this case, these detector readings may include both radon and thoron signals. If the readings are overestimated, the lung cancer risk will be given as a biased estimate when epidemiological studies are carried out. In our experience, there seem to be no correlation among radon, thoron and thoron progeny concentrations. Therefore, one parameter cannot be estimated by the other. This study presents the importance of thoron measurement throughout results we have obtained in field and in laboratory so far. PMID- 20846968 TI - Thoron exhalation rates in areas of Japan. AB - Thoron exhalation rates were measured with a newly made portable instrument at 33 areas in 7 prefectures of Japan. Thoron exhalation rates ranged from 49 to 4890 mBq m(-2) s(-1). Radon exhalation rates were also measured in many of the areas at the same time and ranged from 2.1 to 11 mBq m(-2) s(-1). Thoron exhalation rates showed a rough correlation with radon exhalation rates. Both exhalation rates also showed a rough correlation with geological features. PMID- 20846969 TI - Thoron: its metrology, health effects and implications for radon epidemiology: a summary of roundtable discussions. AB - A roundtable discussion was made at the end of the workshop. All the presentations were summarised in this discussion. It involved measurement techniques, quality assurance and dose assessment and health effects of thoron and its progeny. In particular, major epidemiological studies may be affected by thoron interference in radon measurements. Since their data are not sufficient when compared with that of radon, further efforts in thoron studies will be needed. PMID- 20846970 TI - Time-integrated monitoring of thoron progeny concentration around closed uranium mine sites in Japan. AB - Thoron progeny concentrations were determined using the time-integrated method around closed uranium mine sites in Japan. Because the time-integrated radon progeny monitor developed by the authors has the function to detect (212)Po, time integrated monitoring of thoron progeny concentration is also available with the monitor. Assuming that contribution of (216)Po is negligible, equilibrium equivalent concentration of thoron (EECTn) is theoretically calculated from the etch-pit counts by (212)Po. The annual averages of EECTn observed in the investigation area were about 0.2 Bq m(-3), and they had no remarkable differences from one another. PMID- 20846971 TI - Preliminary study of thoron and radon levels in various indoor environments in Slovenia. AB - Using the Raduet discriminative radon-thoron solid-state nuclear track detectors, a limited number of measurements were recently carried out about 1 m away from any wall and 1.5 m above the floor in different environments in Slovenia. The following thoron and radon ranges were obtained, respectively (Bq m(-3)): 33-700 and 25-4900 in 2 dwellings, 11-215 and 22-422 in 5 kindergartens, 21-368 and 40 4609 in 35 elementary schools, 47-1361 and 92-3280 in 4 hospitals, 4-37 and 10 153 in 9 spas and 800-880 and 4060-6870 in 1 karst cave (2 places). In case of thoron and radon concentrations lognormal distribution was confirmed, while the statistical relationship between them was weak. PMID- 20846972 TI - A comparative study of thorium activity in NORM and high background radiation area. AB - Several industrial processes are known to enrich naturally occurring radioactive materials (NORM). To assess such processes with respect to their radiological relevance, characteristic parameters describing this enrichment will lead to interesting information useful to UNSCEAR. In case of mineral treatment plants, the high temperatures used in smelting and refining processes lead to high concentrations of (238)U and (232)Th. Also due to thermal power combustion, concentration of U and Th in the fly ash increases manifold. NORM samples were collected from a Thailand mineral treatment plant and Philippine coal-fired thermal power plants for investigation. Some studies are initiated from a high background radiation area near Gopalpur of Orissa state in India. These NORM samples were analysed by gamma-ray spectrometry as well as inductively coupled plasma mass spectrometry. The radioactivity in case of Orissa soil samples is found to be mainly contributed from thorium. This study attempts to evaluate levels of thorium activity in NORM samples. PMID- 20846973 TI - The ENEA-IRP thoron calibration facility. AB - To check the consistency of a (220)Rn measurement, performed by passive alpha track detector (ATD), the use of an accurate (220)Rn exposure calibration facility is mandatory. The ENEA Radon Service developed a new CR-39 ATD-Tn, coupled to the radon ATD-Rn and, to assess its sensitivity, had to design a small calibration facility, which has been recently modified to improve the spatial homogeneity exposure conditions inside the chamber, to get a continuous monitoring of the (220)Rn concentration and to reduce radon contamination. A better knowledge of the circuit response allowed selecting the best-operating conditions and how to regulate the thoron concentration. The active thoron monitor has been changed to serve as a continuous sampling and measuring device rather than a grab one; particular care has been devoted to assess the (216)Po losses on the device's inner surfaces and to evaluate the chamber transit time correction factor. PMID- 20846974 TI - Influence of soil environmental parameters on thoron exhalation rate. AB - Field measurements of thoron exhalation rates have been carried out using a ZnS(Ag) scintillation detector with an accumulation chamber. The influence of soil surface temperature and moisture saturation on the thoron exhalation rate was observed. When the variation of moisture saturation was small, the soil surface temperature appeared to induce a strong effect on the thoron exhalation rate. On the other hand, when the variation of moisture saturation was large, the influence of moisture saturation appeared to be larger than the soil surface temperature. The number of data ranged over 405, and the median was estimated to be 0.79 Bq m(-2) s(-1). Dependence of geology on the thoron exhalation rate from the soil surface was obviously found, and a nationwide distribution map of the thoron exhalation rate from the soil surface was drawn by using these data. It was generally high in the southwest region than in the northeast region. PMID- 20846975 TI - Bilateral extra-adrenal perirenal myelolipomas: CT features. AB - Myelolipomas are rare benign tumours composed of adipose tissue and haematopoietic cells that are typically found in adrenal glands but have also appeared in extra-adrenal sites. Distinguishing between extra-adrenal myelolipomas and malignant tumours, such as liposarcomas, is crucial to avoid an invasive procedure. To this end, we present a comprehensive report of the CT imaging characteristics of a pathologically proven bilateral extra-adrenal perirenal myelolipoma. PMID- 20846976 TI - Mesenteric desmoid tumour masquerading as a fat-containing cystic mass. AB - Mesenteric desmoid tumour (MDT) is an uncommon neoplasm that typically presents as a solid soft-tissue mass on cross-sectional imaging. MDT manifesting as a fat containing cystic mass on CT has not been described in the literature. We report such an unusual case with clinicopathological correlation. PMID- 20846977 TI - Imaging appearance of bulk fat within an oncocytic adrenocortical neoplasm, a rare and potentially malignant tumour. AB - Oncocytic adrenocortical neoplasm is a rare adrenal tumour that usually follows a benign clinical course. In some cases, however, these tumours have exhibited malignant behaviour. Here, we present the first published case showing bulk fat within an oncocytic adrenocortical neoplasm on CT and MRI, a finding that mimics fat within an adrenal myelolipoma. The distinction between these entities is important, as the current suggested management of an oncocytic adrenocortical neoplasm is resection with subsequent imaging surveillance. PMID- 20846978 TI - Stereotactic core biopsy of an impalpable screen-detected breast lesion using acupuncture-analgesia. AB - Chinese acupuncture-analgesia is used for pain management during various surgical procedures. Over the past 40 years this approach has been introduced in many countries and has been particularly helpful in the investigation and treatment of patients who are unable to tolerate conventional analgesia. We report here the case of a woman with a 17-year history of myalgic encephalitis who underwent a stereotactic core biopsy of the breast under acupuncture-analgesia. A planning session was needed to assess the patient's existing condition and her response to acupuncture. During this session, a range of frequencies for electrical stimulation of the acupuncture needles using electro-acupuncture apparatus was determined. We describe the combined acupuncture and biopsy procedures and the patient's impressions and outcomes are recorded. PMID- 20846979 TI - Bilateral hypertrophic olivary degeneration following surgical resection of a posterior fossa epidermoid cyst. AB - Hypertrophic olivary degeneration is a result of a primary lesion damaging the dento-rubro-olivary pathway. It is a transynaptic form of degeneration and is unique, causing hypertrophy rather than atrophy of the inferior olivary nucleus. We report a case of bilateral hypertrophic olivary degeneration following surgical excision of a posterior fossa epidermoid cyst and review the relevant literature. PMID- 20846980 TI - Dynamic nature of the CT angiographic "spot sign". AB - The "spot sign", first described in 2007, has shown that a focal area of contrast extravasation within an intracerebral haematoma (ICH) can be correlated with haematoma expansion. We describe a case where time-resolved dynamic CT angiography (dCTA) shows the appearance of the "spot sign" only in later images. This finding highlights the importance of timing of the static CT angiogram which, if performed too early, might result in a false-negative diagnosis. PMID- 20846981 TI - A case of a giant mucocoele of the appendiceal stump presented with a palpable mass in the right thigh: pre-operative diagnosis based on characteristic multidetector CT findings. AB - The pre-operative diagnosis of a mucocoele of the appendiceal stump (MAS) may be difficult owing to rarity and non-specific clinical presentation. However, a pre operative diagnosis of a MAS is important to prevent widespread dissemination by inadvertent spillage of mucous contents. We describe a case of a MAS presenting with a palpable mass in the right thigh in which a pre-operative diagnosis was made by characteristic multidetector CT (MDCT) findings. PMID- 20846982 TI - ENLIGHT and other EU-funded projects in hadron therapy. AB - Following impressive results from early phase trials in Japan and Germany, there is a current expansion in European hadron therapy. This article summarises present European Union-funded projects for research and co-ordination of hadron therapy across Europe. Our primary focus will be on the research questions associated with carbon ion treatment of cancer, but these considerations are also applicable to treatments using proton beams and other light ions. The challenges inherent in this new form of radiotherapy require maximum interdisciplinary co ordination. On the basis of its successful track record in particle and accelerator physics, the internationally funded CERN laboratories (otherwise known as the European Organisation for Nuclear Research) have been instrumental in promoting collaborations for research purposes in this area of radiation oncology. There will soon be increased opportunities for referral of patients across Europe for hadron therapy. Oncologists should be aware of these developments, which confer enhanced prospects for better cancer cure rates as well as improved quality of life in many cancer patients. PMID- 20846983 TI - Accuracy of CT parameters for assessment of tumour size and aggressiveness in lung adenocarcinoma with bronchoalveolar elements. AB - Accurate determination of tumour size in lung adenocarcinoma with bronchoalveolar features (BAC) is important for the determination of TNM (tumour, nodes, metastasis) scores used in staging, prognosis and therapy response assessment. However, tumour sizes derived using lung window (LW) CT or soft tissue/mediastinal window (MW) CT often give different results. This study examines which measurement correlates best with actual tumour size and which best identifies advanced disease. This retrospective study included 43 BAC patients who underwent surgical resection with mediastinal lymphadenectomy <4 weeks post CT scan. The largest unidimensional tumour diameter on each CT window was compared with actual histopathological tumour size (HP). LW, MW and HP size measurements and a recently described CT parameter - the modified tumour shadow disappearance rate (mTDR) = (1 - [MW/LW]) - were then used to determine which parameter best discriminated between the presence or absence of advanced disease. There was no difference between HP and LW sizes, but MW significantly underestimated HP size (p<0.0001). Unlike MW (p = 0.01) and mTDR (p = 0.001), neither HP (p = 0.14) nor LW (p = 0.10) distinguished between patients with or without advanced disease. On receiver operating characteristic (ROC) analysis at a cut-off of <=0.13, the sensitivity and specificity of mTDR for detecting advanced disease were 69% and 89%, respectively. In patients with tumours <=3 cm, only mTDR remained a significant predictor of advanced disease (p = 0.017), with best cut-off at <=0.20, giving a sensitivity and specificity of 71% and 94%, respectively. MW better predicts advanced disease than LW and might also need to be recorded for RECIST (response evaluation criteria in solid tumours) assessment for T staging of BAC; however, mTDR appears to be an even better predictor and should also be used. PMID- 20846984 TI - Prognostic significance of MRI-detected bladder muscle and/or serosal invasion in patients with cervical cancer treated with radiotherapy. AB - In cervical cancer, the prognostic significance of bladder wall invasion on MRI without pathological evidence of mucosal invasion is not known. From 454 consecutive patients with cervical cancer who were treated with radiation, we reviewed images and analysed the outcome of 92 patients with the Federation of International Gynecology and Obstetrics (FIGO) stage IIIB-IVA. We analysed the patients in three groups, normal, wall (muscle and/or serosal) invasion and mucosal invasion, according to the findings on the MRI. Kaplan-Meier life table analysis and the log-rank test were used to assess the survival rates and differences according to prognostic factors. MRI detected abnormalities in the bladder wall in 42 patients (45.6%): wall invasion in 24 and mucosal invasion in 18. 5 of 18 patients, suspected on MRI to have mucosal invasion, showed no pathological evidence of mucosal invasion. Median follow-up period was 34 months. 3-year cause-specific survival (CSS) in the normal group compared with the wall invasion group was 76.2% vs 71.4% (p = 0.48). 3-year CSS for the wall invasion group compared with the mucosal invasion group was 71.4% vs 54.3% (p = 0.04). Mucosal invasion on MRI (p = 0.03) and concurrent chemoradiotherapy (p = 0.01) was significant for CSS. The prognosis for patients with cervical cancer with evidence of muscle and/or serosal invasion of the bladder on MRI may not differ from that for patients without abnormality on MRI. In patients with the MRI finding of bladder mucosal invasion, further studies should be conducted regarding the role of cystoscopy to determine the need for pathological confirmation. PMID- 20846985 TI - Time-resolved imaging of contrast kinetics three-dimensional (3D) magnetic resonance venography in patients with pelvic congestion syndrome. AB - The purpose of this study was to assess the role of magnetic resonance venography (MRV) with time-resolved imaging of contrast kinetics (TRICKS) in dynamically evaluating ovarian vein dilation, reflux and direction of flow in patients with suspected pelvic congestion syndrome (PCS). The hypotheses tested were: (i) That conspicuity scores of the ovarian veins across three raters was greater using TRICKS MRV compared with T2W or T(2)* imaging; (ii) That three key MR variables (ovarian vein diameter, timing and grade of reflux) correlated across all raters. We carried out a retrospective study of 13 patients undergoing T2W and TRICKS MRI and pelvic sonography (n = 4) or catheter venography (n = 5). Three observers rated conspicuity, vessel diameter, timing and grade of ovarian vein reflux for T(2)/T2*W and TRICKS MRI. The mean left ovarian diameter for all patients with reflux was 7.9 mm (range 2.2-12 mm). There was high inter-observer agreement for ovarian vein diameter for both sequences. TRICKS showed significantly greater conspicuity than T(2)/T2*W imaging (TRICKS: T(2)/T2* mean (SD) = 7.80 (3.20):5.50 (1.97), F (1,12) = 5.80, p < 0.05). TRICKS MRV demonstrated high inter-observer correlation for timing and grade of reflux (r (36) = 0.77,0.71,0.79, p < 0.01). TRICKS MRA/V was significantly degraded by breathing artefact in two patients. We conclude that TRICKS MRV accurately and dynamically demonstrates ovarian vein reflux in patients with PCS but requires quiet respiration. TRICKS MRV has better image conspicuity than T(2)/T2*W imaging and sufficient temporal resolution to distinguish between Grade I, II and III reflux. PMID- 20846986 TI - The imaging appearances of calyceal diverticula complicated by uroliathasis. AB - The presence of diverticula arising from the calyceal system is a relatively uncommon urological problem, occurring with an incidence of 2.1-4.5 per 1000 intravenous urogram (IVU) examinations. While the incidence of calyceal diverticula is low, the frequency of stone formation within them is high. We describe the aetiology and clinical presentation and describe the role of imaging with ultrasound, intravenous and retrograde pyelography and CT in diagnosis and planning treatment. We also describe the potential of fluid-sensitive magnetic resonance imaging techniques as a radiation-free alternative to the use of more conventional modalities, such as intravenous urography and retrograde pyelography, in delineating the anatomy of calyceal diverticula before surgical and radiological intervention especially in young patients and pregnant women. PMID- 20846987 TI - A young man with a headache. PMID- 20846988 TI - Hepato-pancreatic ascariasis. AB - Intestinal infestation of humans by Ascaris lumbricoides is endemic in India. The usual habitat of the adult worm is the jejunum. Hepatopancreatic ascariasis (HPA) is designated to a rare group of diseases caused by lodgement of adult worms in the bile or pancreatic ducts. This short report illustrates four rare cases of patients with HPA. PMID- 20846989 TI - Epidemiological investigation of scarlet fever in Hefei City, China, from 2004 to 2008. AB - This study aims to explore the epidemiological characteristics of scarlet fever in Hefei City, China, and to provide a scientific basis for the prevention and control of the disease. A total of 731 cases were recruited from 2004 to 2008. The average incidence was 3.159 per 100,000 population. Our results indicated that the major risk factors for scarlet fever were: gender (male); age (3-6 years); time of disease onset (March to June); and area of residence (urban areas). Knowledge of these factors could help clinicians to provide the appropriate interventions for scarlet fever. PMID- 20846990 TI - A case of ectopic fascioliasis in the skin. AB - A four-year-old boy presented to the hospital with a four-month history of recurrent bouts of fever and abdominal pain. Half a month before being admitted to hospital, multiple red cutaneous nodules had emerged at the left epigastric region and a dark red serpentine track appeared under the skin at the same site. The day after the patient was admitted to the hospital, a living worm broke through the skin and appeared at one end of the subcutaneous track. The flatworm was identified as Fasciola hepatica in its juvenile stage. Eosinophilia was distinct in our patient and provides an important clue to diagnosing parasitosis. PMID- 20846991 TI - J-curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) Trial. AB - AIM: In patients with coronary artery disease (CAD), a J-curve relationship has been reported between blood pressure (BP) and future cardiovascular events. However, this is controversial. The purpose of the study was to determine the relationship between on-treatment BP and cardiovascular outcomes in patients with CAD. METHODS AND RESULTS: We evaluated 10 001 patients with CAD and a low-density lipoprotein (LDL) cholesterol level <130 mg/dL, randomized to atorvastatin 80 vs. 10 mg, enrolled in the TNT trial. The post-baseline, time-dependent BPs [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] were categorized into 10 mmHg increments. The primary outcome was a composite of death from coronary disease, non-fatal myocardial infarction (MI), resuscitated cardiac arrest, and fatal or non-fatal stroke. Among the 10 001 patients, 982 (9.82%) experienced a primary outcome at 4.9 years (median) of follow-up. The relationship between SBP or DBP and primary outcome followed a J-curve with increased event rates above and below the reference BP range, both unadjusted and adjusted (for baseline covariates, treatment effect, and LDL levels). A time-dependent, non-linear, multivariate Cox proportional hazard model identified a nadir of 146.3/81.4 mmHg where the event rate was lowest. A similar non-linear relationship with a higher risk of events at lower pressures was found for most of the secondary outcomes of all-cause mortality, cardiovascular mortality, non-fatal MI, or angina. However, for the outcome of stroke, lower was better for SBP. CONCLUSION: In patients with CAD, a low BP (<110-120/<60-70 mmHg) portends an increased risk of future cardiovascular events (except stroke). PMID- 20846992 TI - Cheyne-Stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter defibrillator therapies in patients with congestive heart failure. AB - AIMS: The aim of this first large-scale long-term study was to investigate whether obstructive sleep apnoea (OSA) and/or central sleep apnoea (CSA) are associated with an increased risk of malignant cardiac arrhythmias in patients with congestive heart failure (CHF). METHODS AND RESULTS: Of 472 CHF patients who were screened for sleep disordered breathing (SDB) 6 months after implantation of a cardiac resynchronization device with cardioverter-defibrillator, 283 remained untreated [170 with mild or no sleep disordered breathing (mnSDB) and 113 patients declined ventilation therapy] and were included into this study. During follow-up (48 months), data on appropriately monitored ventricular arrhythmias as well as appropriate cardioverter-defibrillator therapies were obtained from 255 of these patients (90.1%). Time period to first monitored ventricular arrhythmias and to first appropriate cardioverter-defibrillator therapy were significantly shorter in patients with either CSA or OSA. Forward stepwise Cox models revealed an independent correlation for CSA and OSA regarding monitored ventricular arrhythmias [apnoea-hypopnoea index (AHI) >=5 h(-1): CSA HR 2.15, 95% CI 1.40 3.30, P < 0.001; OSA HR 1.69, 95% CI 1.64-1.75, P = 0.001; AHI >=15 h(-1): CSA HR 2.06, 95% CI 1.40-3.05, P < 0.001; OSA HR 1.69, 95% CI 1.14-2.51, P = 0.02] and appropriate cardioverter-defibrillator therapies (AHI >=5 h(-1): CSA HR 3.24, 95% CI 1.86-5.64, P < 0.001; OSA HR 2.07, 95% CI 1.14-3.77, P = 0.02; AHI >=15 h(-1): CSA HR 3.41, 95% CI 2.10-5.54, P < 0.001; OSA HR 2.10, 95% CI 1.17-3.78, P = 0.01). CONCLUSION: In patients with CHF, CSA and OSA are independently associated with an increased risk for ventricular arrhythmias and appropriate cardioverter defibrillator therapies. PMID- 20846993 TI - A propensity score-adjusted retrospective comparison of early and mid-term results of mitral valve repair versus replacement in octogenarians. AB - AIMS: Feasibility and efficacy of mitral repair in the elderly remain controversial. This study aims to compare outcomes of mitral repair and replacement in octogenarians. METHODS AND RESULTS: We compared the outcomes of 322 consecutive octogenarian patients (mean age 82.6 +/- 2.2 years) who underwent mitral repair (n = 227, 70%) or replacement (n = 95, 30%) at Mount Sinai Medical Center and Leipzig Herzzentrum between 1998 and 2008 using propensity score adjustment and univariate and multivariate analyses. Patients undergoing aortic valve replacement were excluded. Coronary bypass was performed in 47.5% (n = 153), and 31.1% (n = 100) required tricuspid repair. Propensity score adjustment yielded comparable groups. Thirty-day mortality in patients undergoing primary elective mitral repair for degenerative disease was 5.1% (2/39). Overall 90-day mortality was 18.9% (43/227) for repair compared with 31.6% (30/95) for replacement (P = 0.014). Pre-discharge echocardiography revealed less than moderate residual regurgitation in 99% of patients (231/232). Adjusted 1-, 3-, and 5-year survival for patients undergoing mitral repair was 71 +/- 3, 61 +/- 4, and 59 +/- 4%, respectively, compared with 56 +/- 5, 50 +/- 6, and 45 +/- 6% for patients undergoing mitral replacement (P = 0.046). Multivariate analysis demonstrated emergency surgery, previous myocardial infarction, concomitant coronary artery bypass surgery, and mitral replacement to be strong independent predictors of early mortality; mitral valve replacement was an independent predictor of reduced survival in degenerative patients. CONCLUSION: Elective mitral repair can be performed with low operative mortality and good long-term outcomes in selected octogenarians with degenerative mitral disease, and is associated with better long-term survival than mitral replacement. The survival benefit associated with surgery for non-degenerative disease is more questionable. PMID- 20846994 TI - Genetic variability in response to clopidogrel therapy: clinical implications. PMID- 20846995 TI - Deliberate self-harm and associated factors in 17-year-old Swedish students. AB - BACKGROUND: Deliberate self-harm (DSH) in young people is an important public health issue. To prevent DSH, more knowledge is needed about its prevalence and associated contextual factors in community samples of adolescents. AIMS: To determine the prevalence of deliberate self-harm in 17-year-old Swedish students and to explore the association of demographic variables, psychological distress, experiences of violence, and school-related factors with DSH. METHODS: Data were derived from a cross-sectional study in which 17-year-old students completed questionnaires during school hours (n = 1,663; 78.3%). The variables used in this analysis are as follows: deliberate self-harm, demographic variables, psychological distress, experiences of violence, and school-related factors. Data were analysed using chi-squared statistics and logistic regression. RESULTS: The lifetime prevalence of DSH was 17%, and it was more common among girls (23.3%) than boys (10.5%). There were considerable socioeconomic differences in reports of DSH. Psychological distress was strongly associated with DSH in both boys and girls, as were experiences of bullying, sexual harassment, physical violence and sexual assault. Social support, safety and academic factors in school were related to reports of DSH in both girls and boys. There were some gender differences with respect to which factors were associated with DSH. CONCLUSIONS: Deliberate self-harm is common and more frequently reported by girls than boys. Psychological distress, experiences of different types of violence, and school related factors (academic, social and safety-related), should be considered risk factors for DSH in young people. Findings can be applied to health-promotion policy and interventions in various contexts, for example schools. PMID- 20846996 TI - Fetal sex determination: obstetricians' attitudes in antenatal screening units in Finland. AB - AIM: To study obstetricians' attitudes in Finnish antenatal screening units concerning fetal sex determination without medical indication. METHODS: A structured questionnaire to all delivery units (n = 37) and the main outpatient screening units (n = 18) in the country. RESULTS: The majority of units made fetal sex determination without medical indication at patient's request during the second-trimester ultrasonographic screening. This examination was seen to have consequences for maternal-fetal attachment, but it was also considered medically useless and sometimes harmful. Only three out of the responding 32 units maintained quality control of the examination. A false diagnosis resulted extremely seldom in any litigation process. CONCLUSIONS: More precise guidelines are needed for fetal sex determination in healthcare organisation. PMID- 20846997 TI - Construction and evaluation of a self-contained index for assessment of diet quality. AB - AIMS: To construct and validate a self-contained index for the evaluation of a health-promoting diet in adults. METHODS: Participants (n = 103) were healthy volunteer adults aged 20 to 64 years. A food consumption questionnaire containing 55 questions was formulated and evaluated against seven-day food records. Key questions best reflecting the health-promoting diet, defined in nutrition recommendations, were identified by correlation and ROC analyses in comparison to calculated food and nutrient intakes from the food records. A shorter questionnaire was scored to compile an Index of Diet Quality (IDQ). RESULTS: Based on ROC analyses 18 questions were sufficient to describe the health promoting diet and comprised the index. IDQ had a sensitivity of 67% and a specificity of 71%. The IDQ score reflected dietary intake, shown as statistically significant correlations between higher IDQ scores and higher intakes of protein (r = 0.35), fibre (r = 0.42), calcium (r = 0.39), iron (r = 0.31), vitamin C (r = 0.31) and a higher ratio of unsaturated to saturated fatty acids (r = 0.23) and a lower intake of saturated fatty acids (r = -0.22) and saccharose (r = -0.25). CONCLUSIONS: IDQ reflects dietary intake of key foods and nutrients associated with health and depicts adherence to dietary recommendations. It is applicable in nutritional studies where diet in its entirety is of interest and also in large-scale studies, being fast in execution with analysis free of complex calculations. PMID- 20846998 TI - Social capital, political trust, and health locus of control: a population-based study. AB - OBJECTIVE: To investigate the association between political trust in the Riksdag and lack of belief in the possibility to influence one's own health (external locus of control), taking horizontal trust into account. DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: The 2008 public health survey in Skane is a cross-sectional postal questionnaire study with a 55% participation rate. A random sample of 28,198 persons aged 18-80 years participated. Logistic regression models were used to investigate the associations between political trust in the Riksdag (an aspect of vertical trust) and lack of belief in the possibility to influence one's own health (external locus of control). The multiple regression analyses included age, country of birth, education, and horizontal trust in other people. RESULTS: A 33.7% of all men and 31.8% of all women lack internal locus of control. Low (external) health locus of control is more common in higher age groups, among people born outside Sweden, with lower education, low horizontal trust, low political trust, and no opinion concerning political trust. Respondents with not particularly strong political trust, no political trust at all and no opinion have significantly higher odds ratios of external locus of control throughout the multiple regression analyses. CONCLUSIONS: Low political trust in the Riksdag seems to be independently associated with external health locus of control. PMID- 20846999 TI - Acute severe memory impairment as a presenting symptom of multiple sclerosis: a clinical case study with 3D double inversion recovery MR imaging. AB - We present the case of a 21-year-old woman with acute memory impairment. It was initially not recognized as organic in nature. Repeated neuropsychological testing confirmed severely disturbed encoding and recall. Three-dimensional double inversion recovery (3D-DIR) MRI confirmed hippocampal and cortical lesions. Further clinical symptoms, visual evoked potential and MRI suggested a diagnosis of multiple sclerosis (MS). The amnestic syndrome has remained for 5 years. This case illustrates that MS can present with acute cortical symptoms which can be difficult to recognize. The hippocampus can be acutely affected and DIR MRI imaging can help to demonstrate cortical lesions that explain the clinical picture. PMID- 20847000 TI - Neither retinal nor brain atrophy can be shown in patients with isolated unilateral optic neuritis at the time of presentation. AB - BACKGROUND: Acute monosymptomatic optic neuritis (ON) may be the earliest manifestation of multiple sclerosis (MS). Atrophy has been shown to be a prominent feature of MS with great impact on disability. OBJECTIVES: The objectives of this study were to evaluate retinal and brain atrophy and possible associations at the earliest possible stages of MS. METHODS: In a prospective observational cohort study we included 60 untreated patients with monosymptomatic ON and 19 healthy volunteers. Unaffected fellow eyes were examined with optical coherence tomography (OCT) and normalized brain volumes were calculated based on MRI. Additionally, visual evoked potentials (VEPs) were recorded. RESULTS: Neither OCT measurements nor brain volume measures revealed signs of localized or generalized atrophy in patients compared with healthy volunteers. Stratification of patients into high risk based on the presence of white matter lesions did not reveal differences. The association between OCT measures and brain volumes previously found could not be confirmed at the time of the first clinical event. VEP latency was significantly prolonged in patients with white matter lesions compared to those without lesions. A trend towards a relationship between VEP amplitude of fellow eyes and brain volumes was noted. CONCLUSIONS: In this cohort we were not able to show atrophic features in the retina or the brain, and the association between structural measures of the retina and the brain as indicated in the later stages of MS could not be reproduced. These findings suggest that atrophy does require time to evolve and indicate the complexity of the relationship between local and general structural measures. PMID- 20847001 TI - Transcriptional characteristics of CD4+ T cells in multiple sclerosis: relative lack of suppressive populations in blood. AB - BACKGROUND: Multiple sclerosis (MS) is hypothetically caused by autoreactive Th1 and Th17 cells, whereas Th2 and regulatory T cells may confer protection. The development of Th subpopulations is dependant on the expression of lineage specific transcription factors. OBJECTIVE: The aim of this study was to assess the balance of CD4(+)T cell populations in relapsing-remitting MS. METHODS: Blood mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 was assessed in 33 patients with relapsing-remitting MS and 20 healthy controls. In addition, flow cytometry was performed to assess T lymphocyte numbers. RESULTS: In relapsing-remitting MS, diminished expression of FOXP3 (Treg) was found (p < 0.05), despite normal numbers of CD4(+)CD25(hi)Treg. Immunoregulatory EBI3 and Th2-associated GATA3 ([a z]+) was also decreased in MS (p < 0.005 and p < 0.05, respectively). Expression of TBX21 (Th1) and RORC (Th17) did not differ between patients and controls. Similar changes were observed when analysing beta-interferon treated (n = 12) or untreated (n = 21) patients. Analysis of transcription factor ratios, comparing TBX21/GATA3 and RORC/FOXP3, revealed an increase in the RORC/FOXP3 ratio in patients with relapsing-remitting MS (p < 0.005). CONCLUSION: Our findings indicate systemic defects at the mRNA level, involving downregulation of beneficial CD4(+)phenotypes. This might play a role in disease development by permitting activation of harmful T cell populations. PMID- 20847002 TI - The integral membrane FtsW protein and peptidoglycan synthase PBP3 form a subcomplex in Escherichia coli. AB - During the cell cycle of rod-shaped bacteria, two morphogenetic processes can be discriminated: length growth of the cylindrical part of the cell and cell division by formation of two new cell poles. The morphogenetic protein complex responsible for the septation during cell division (the divisome) includes class A and class B penicillin-binding proteins (PBPs). In Escherichia coli, the class B PBP3 is specific for septal peptidoglycan synthesis. It requires the putative lipid II flippase FtsW for its localization at the division site and is necessary for the midcell localization of the class A PBP1B. In this work we show direct interactions between FtsW and PBP3 in vivo and in vitro by FRET (Forster resonance energy transfer) and co-immunoprecipitation experiments. These proteins are able to form a discrete complex independently of the other cell-division proteins. The K2-V42 peptide of PBP3 containing the membrane-spanning sequence is a structural determinant sufficient for interaction with FtsW and for PBP3 dimerization. By using a two-hybrid assay, the class A PBP1B was shown to interact with FtsW. However, it could not be detected in the immunoprecipitated FtsW-PBP3 complex. The periplasmic loop 9/10 of FtsW appeared to be involved in the interaction with both PBP1B and PBP3. It might play an important role in the positioning of these proteins within the divisome. PMID- 20847003 TI - Identification of hydrogen peroxide production-related genes in Streptococcus sanguinis and their functional relationship with pyruvate oxidase. AB - Hydrogen peroxide (H(2)O(2)), an important substance produced by many members of the genus Streptococcus, plays important roles in virulence and antagonism within a microbial community such as oral biofilms. The spxB gene, which encodes pyruvate oxidase, is involved in H(2)O(2) production in many streptococcal species. However, knowledge about its regulation and relation with other genes putatively involved in the same pathway is limited. In this study, three genes- ackA, spxR and tpk--were identified as contributing to H(2)O(2) production in Streptococcus sanguinis by screening mutants for opaque colony appearance. Mutations in all three genes resulted in significant decreases in H(2)O(2) production, with 16-31% of that of the wild-type. H(2)O(2) production was restored in the complemented strains. Antagonism against Streptococcus mutans by these three S. sanguinis mutants was reduced, both on plates and in liquid cultures, indicating the critical roles of these three genes for conferring the competitive advantage of S. sanguinis. Analysis by qPCR indicated that the expression of spxB was decreased in the ackA and spxR mutants and significantly increased in the tpk mutant. PMID- 20847004 TI - Acetaldehyde/alcohol dehydrogenase-2 (EhADH2) and clathrin are involved in internalization of human transferrin by Entamoeba histolytica. AB - Transferrin (Tf) is a host glycoprotein capable of binding two ferric-iron ions to become holotransferrin (holoTf), which transports iron in to all cells. Entamoeba histolytica is a parasitic protozoan able to use holoTf as a sole iron source in vitro. The mechanism by which this parasite scavenges iron from holoTf is unknown. An E. histolytica holoTf-binding protein (EhTfbp) was purified by using an anti-human transferrin receptor (TfR) monoclonal antibody. EhTfbp was identified by MS/MS analysis and database searches as E. histolytica acetaldehyde/alcohol dehydrogenase-2 (EhADH2), an iron-dependent enzyme. Both EhTfbp and EhADH2 bound holoTf and were recognized by the anti-human TfR antibody, indicating that they correspond to the same protein. It was found that the amoebae internalized holoTf through clathrin-coated pits, suggesting that holoTf endocytosis could be important for the parasite during colonization and invasion of the intestinal mucosa and liver. PMID- 20847005 TI - Biosynthesis of UDP-xylose and UDP-arabinose in Sinorhizobium meliloti 1021: first characterization of a bacterial UDP-xylose synthase, and UDP-xylose 4 epimerase. AB - Sinorhizobium meliloti is a soil bacterium that fixes nitrogen after being established inside nodules that can form on the roots of several legumes, including Medicago truncatula. A mutation in an S. meliloti gene (lpsB) required for lipopolysaccharide synthesis has been reported to result in defective nodulation and an increase in the synthesis of a xylose-containing glycan. Glycans containing xylose as well as arabinose are also formed by other rhizobial species, but little is known about their structures and the biosynthetic pathways leading to their formation. To gain insight into the biosynthesis of these glycans and their biological roles, we report the identification of an operon in S. meliloti 1021 that contains two genes encoding activities not previously described in bacteria. One gene encodes a UDP-xylose synthase (Uxs) that converts UDP-glucuronic acid to UDP-xylose, and the second encodes a UDP-xylose 4 epimerase (Uxe) that interconverts UDP-xylose and UDP-arabinose. Similar genes were also identified in other rhizobial species, including Rhizobium leguminosarum, suggesting that they have important roles in the life cycle of this agronomically important class of bacteria. Functional studies established that recombinant SmUxs1 is likely to be active as a dimer and is inhibited by NADH and UDP-arabinose. SmUxe is inhibited by UDP-galactose, even though this nucleotide sugar is not a substrate for the 4-epimerase. Unambiguous evidence for the conversions of UDP-glucuronic acid to UDP-alpha-D-xylose and then to UDP-beta L-arabinose (UDP-arabinopyranose) was obtained using real-time (1)H-NMR spectroscopy. Our results provide new information about the ability of rhizobia to form UDP-xylose and UDP-arabinose, which are then used for the synthesis of xylose- and arabinose-containing glycans. PMID- 20847006 TI - Metabolomics as a tool for target identification in strain improvement: the influence of phenotype definition. AB - For the optimization of microbial production processes, the choice of the quantitative phenotype to be optimized is crucial. For instance, for the optimization of product formation, either product concentration or productivity can be pursued, potentially resulting in different targets for strain improvement. The choice of a quantitative phenotype is highly relevant for classical improvement approaches, and even more so for modern systems biology approaches. In this study, the information content of a metabolomics dataset was determined with respect to different quantitative phenotypes related to the formation of specific products. To this end, the production of two industrially relevant products by Aspergillus niger was evaluated: (i) the enzyme glucoamylase, and (ii) the more complex product group of secreted proteases, consisting of multiple enzymes. For both products, six quantitative phenotypes associated with activity and productivity were defined, also taking into account different time points of sampling during the fermentation. Both linear and nonlinear relationships between the metabolome data and the different quantitative phenotypes were considered. The multivariate data analysis tool partial least-squares (PLS) was used to evaluate the information content of the datasets for all the different quantitative phenotypes defined. Depending on the product studied, different quantitative phenotypes were found to have the highest information content in specific metabolomics datasets. A detailed analysis of the metabolites that showed strong correlation with these quantitative phenotypes revealed that various sugar derivatives correlated with glucoamylase activity. For the reduction of protease activity, mainly as-yet-unidentified compounds correlated. PMID- 20847007 TI - The bacterial microbiota in the oral mucosa of rural Amerindians. AB - The oral microbiota plays an important role in buccal health and in diseases such as periodontitis and meningitis. The study of the human oral bacteria has so far focused on subjects from Western societies, while little is known about subjects from isolated communities. This work determined the composition of the oral mucosa microbiota from six Amazon Amerindians, and tested a sample preservation alternative to freezing. Paired oral swabs were taken from six adults of Guahibo ethnicity living in the community of Platanillal, Amazonas State, Venezuela. Replicate swabs were preserved in liquid nitrogen and in Aware Messenger fluid (Calypte). Buccal DNA was extracted, and the V2 region of the 16S rRNA gene was amplified and pyrosequenced. A total of 17 214 oral bacterial sequences were obtained from the six subjects; these were binned into 1034 OTUs from 10 phyla, 30 families and 51 genera. The oral mucosa was highly dominated by four phyla: Firmicutes (mostly the genera Streptococcus and Veillonella), Proteobacteria (mostly Neisseria), Bacterioidetes (Prevotella) and Actinobacteria (Micrococcineae). Although the microbiota were similar at the phylum level, the Amerindians shared only 62 % of the families and 23 % of the genera with non Amerindians from previous studies, and had a lower richness of genera (51 vs 177 reported in non-Amerindians). The Amerindians carried unidentified members of the phyla Bacteroidetes, Firmicutes and Proteobacteria and their microbiota included soil bacteria Gp1 (Acidobacteriaceae) and Xylanibacter (Prevotellaceae), and the rare genus Phocoenobacter (Pasteurellaceae). Preserving buccal swabs in the Aware Messenger oral fluid collection device substantially altered the bacterial composition in comparison to freezing, and therefore this method cannot be used to preserve samples for the study of microbial communities. PMID- 20847008 TI - Multilocus sequence analysis reveals the genetic diversity of European fruit tree phytoplasmas and supports the existence of inter-species recombination. AB - The genetic diversity of three temperate fruit tree phytoplasmas 'Candidatus Phytoplasma prunorum', 'Ca. P. mali' and 'Ca. P. pyri' has been established by multilocus sequence analysis. Among the four genetic loci used, the genes imp and aceF distinguished 30 and 24 genotypes, respectively, and showed the highest variability. Percentage of substitution for imp ranged from 50 to 68 % according to species. Percentage of substitution varied between 9 and 12 % for aceF, whereas it was between 5 and 6 % for pnp and secY. In the case of 'Ca P. prunorum' the three most prevalent aceF genotypes were detected in both plants and insect vectors, confirming that the prevalent isolates are propagated by insects. The four isolates known to be hypo-virulent had the same aceF sequence, indicating a possible monophyletic origin. Haplotype network reconstructed by eBURST revealed that among the 34 haplotypes of 'Ca. P. prunorum', the four hypo virulent isolates also grouped together in the same clade. Genotyping of some Spanish and Azerbaijanese 'Ca. P. pyri' isolates showed that they shared some alleles with 'Ca. P. prunorum', supporting for the first time to our knowledge, the existence of inter-species recombination between these two species. PMID- 20847009 TI - Identification of Vibrio campbellii isolated from diseased farm-shrimps from south India and establishment of its pathogenic potential in an Artemia model. AB - Shrimp diseases are frequently reported to be caused by closely related vibrios, and in many cases they are tentatively but inaccurately identified as Vibrio harveyi and related vibrios. In the present study, 28 biochemically identified V. harveyi-related strains isolated from diseased shrimps were randomly selected for further characterization by molecular tools. Twenty-six strains were identified as Vibrio campbellii and two as V. harveyi by sequence analysis of 16S rRNA and uridylate kinase genes. Haemolysin-gene-based species-specific multiplex PCR also confirmed these results. Experimental challenge studies using Artemia as a model showed that eight isolates were highly pathogenic, three were moderately pathogenic and the remaining 17 were non-pathogenic. Ribotyping with BglI clearly distinguished V. campbellii from V. harveyi, but it failed to separate pathogenic and non-pathogenic clusters. Artemia nauplii challenged with a fluorescently labelled highly pathogenic strain (IPEY54) showed patches in the digestive tract. However, no patches were observed for a non-pathogenic strain (IPEY41). Direct bacterial counts also supported colonization potential for the highly pathogenic strain. To our knowledge, this is the first report on the isolation and accurate identification of large numbers of V. campbellii associated with shrimp disease in aquacultural farms. V. campbellii has long been considered to be non pathogenic and classified with V. harveyi-related bacteria. However, we show that this species may be an emerging aquaculture pathogen. This study will help to formulate suitable strategies to combat this newly identified pathogen. PMID- 20847010 TI - Positive transcriptional control of the pyridoxal phosphate biosynthesis genes pdxST by the MocR-type regulator PdxR of Corynebacterium glutamicum ATCC 13032. AB - The pdxR (cg0897) gene of Corynebacterium glutamicum ATCC 13032 encodes a regulatory protein belonging to the MocR subfamily of GntR-type transcription regulators and consisting of an amino-terminal winged helix-turn-helix DNA binding domain and a carboxy-terminal aminotransferase-like domain. A defined deletion in the pdxR gene resulted in the decreased expression of the divergently orientated pdxST genes coding for the subunits of pyridoxal 5'-phosphate synthase. The pdxST mutant C. glutamicum NJ0898 and the pdxR mutant C. glutamicum AMH17 showed vitamin B(6) auxotrophy that was restored by supplementing the growth medium with either pyridoxal, pyridoxal 5'-phosphate or pyridoxamine. The genetic organization of the 89 bp pdxR-pdxST intergenic region was elucidated by mapping the 5' ends of the respective transcripts, followed by detection of typical promoter sequences. Bioinformatic pattern searches and comparative genomics revealed three DNA motifs with the consensus sequence AAAGTGGW(-/T)CTA, overlapping the deduced promoter sequences and serving as candidate DNA-binding sites for PdxR. DNA band shift assays with the purified PdxR protein demonstrated the specific binding of the transcription regulator to double-stranded 40-mer sequences containing the detected motifs, thereby confirming the direct regulatory role of PdxR in activating the expression of the pdxST genes. PMID- 20847011 TI - Strain-specific diversity of mucus-binding proteins in the adhesion and aggregation properties of Lactobacillus reuteri. AB - Mucus-binding proteins (MUBs) have been revealed as one of the effector molecules involved in mechanisms of the adherence of lactobacilli to the host; mub, or mub like, genes are found in all of the six genomes of Lactobacillus reuteri that are available. We recently reported the crystal structure of a Mub repeat from L. reuteri ATCC 53608 (also designated strain 1063), revealing an unexpected recognition of immunoglobulins. In the current study, we explored the diversity of the ATCC 53608 mub gene, and MUB expression levels in a large collection of L. reuteri strains isolated from a range of vertebrate hosts. This analysis revealed that the MUB was only detectable on the cell surface of two highly related isolates when using antibodies that were raised against the protein. There was considerable variation in quantitative mucus adhesion in vitro among L. reuteri strains, and mucus binding showed excellent correlation with the presence of cell surface ATCC 53608 MUB. ATCC 53608 MUB presence was further highly associated with the autoaggregation of L. reuteri strains in washed cell suspensions, suggesting a novel role of this surface protein in cell aggregation. We also characterized MUB expression in representative L. reuteri strains. This analysis revealed that one derivative of strain 1063 was a spontaneous mutant that expressed a C-terminally truncated version of MUB. This frameshift mutation was caused by the insertion of a duplicated 13 nt sequence at position 4867 nt in the mub gene, producing a truncated MUB also lacking the C terminal LPxTG region, and thus unable to anchor to the cell wall. This mutant, designated 1063N (mub-4867(i)), displayed low mucus-binding and aggregation capacities, further providing evidence for the contribution of cell-wall-anchored MUB to such phenotypes. In conclusion, this study provided novel information on the functional attributes of MUB in L. reuteri, and further demonstrated that MUB and MUB-like proteins, although present in many L. reuteri isolates, show a high genetic heterogeneity among strains. PMID- 20847012 TI - Colonization of healthy children by Moraxella catarrhalis is characterized by genotype heterogeneity, virulence gene diversity and co-colonization with Haemophilus influenzae. AB - The colonization dynamics of Moraxella catarrhalis were studied in a population comprising 1079 healthy children living in Rotterdam, The Netherlands (the Generation R Focus cohort). A total of 2751 nasal swabs were obtained during four clinic visits timed to take place at 1.5, 6, 14 and 24 months of age, yielding a total of 709 M. catarrhalis and 621 Haemophilus influenzae isolates. Between January 2004 and December 2006, approximate but regular 6-monthly cycles of colonization were observed, with peak colonization incidences occurring in the autumn/winter for M. catarrhalis, and winter/spring for H. influenzae. Co colonization was significantly more likely than single-species colonization with either M. catarrhalis or H. influenzae, with genotypic analysis revealing no clonality for co-colonizing or single colonizers of either bacterial species. This finding is especially relevant considering the recent discovery of the importance of H. influenzae-M. catarrhalis quorum sensing in biofilm formation and host clearance. Bacterial genotype heterogeneity was maintained over the 3 year period of the study, even within this relatively localized geographical region, and there was no association of genotypes with either season or year of isolation. Furthermore, chronological and genotypic diversity in three immunologically important M. catarrhalis virulence genes (uspA1, uspA2 and hag/mid) was also observed. This study indicates that genotypic variation is a key factor contributing to the success of M. catarrhalis colonization of healthy children in the first years of life. Furthermore, variation in immunologically relevant virulence genes within colonizing populations, and even within genotypically identical M. catarrhalis isolates, may be a result of immune evasion by this pathogen. Finally, the factors facilitating M. catarrhalis and H. influenzae co-colonization need to be further investigated. PMID- 20847013 TI - Evaluating the microbial diversity of an in vitro model of the human large intestine by phylogenetic microarray analysis. AB - A high-density phylogenetic microarray targeting small subunit rRNA (SSU rRNA) sequences of over 1000 microbial phylotypes of the human gastrointestinal tract, the HITChip, was used to assess the impact of faecal inoculum preparation and operation conditions on an in vitro model of the human large intestine (TIM-2). This revealed that propagation of mixed faecal donations for the production of standardized inocula has only a limited effect on the microbiota composition, with slight changes observed mainly within the Firmicutes. Adversely, significant shifts in several major groups of intestinal microbiota were observed after inoculation of the in vitro model. Hierarchical cluster analysis was able to show that samples taken throughout the inoculum preparation grouped with microbiota profiles observed for faecal samples of healthy adults. In contrast, the TIM-2 microbiota was distinct. While members of the Bacteroidetes and some groups within the Bacilli were increased in TIM-2 microbiota, a strong reduction in the relative abundance of other microbial groups, including Bifidobacterium spp., Streptococcus spp., and Clostridium clusters IV and XIVa, was observed. The changes detected with the HITChip could be confirmed using denaturing gradient gel electrophoresis (DGGE) of SSU rRNA amplicons. PMID- 20847014 TI - Improved quality of life in Norwegian heart failure patients after follow-up in outpatient heart failure clinics: results from the Norwegian Heart Failure Registry. AB - AIMS: To evaluate the quality of life in heart failure (HF) outpatients attending multidisciplinary disease management programmes at HF clinics in Norwegian hospitals. METHODS AND RESULTS: Data from HF patients at 24 hospital outpatient clinics were entered in a common database; The Norwegian Heart Failure Registry. Quality of life assessment was done using Minnesota Living with Heart Failure Questionnaire (MLHF). The quality of life assessment was optional at each hospital and was done both at initial evaluation and after 6 months of stable follow-up. A total of 3632 patients were included in the registry and 1778 patients had at least one assessment of quality of life. The mean MLHF score improved significantly from 2.1 at the initial evaluation to 1.4 six months after leaving the clinic (P < 0.001). There was a significant difference in MLHF score between hospitals and baseline MLHF score was significantly associated with NYHA functional class, hospitalizations 6 months before entering the registry, and brain natriuretic peptide; and inversely related to age and systolic blood pressure. Minnesota Living with Heart Failure score was an independent predictor of mortality in this population. CONCLUSION: Quality of life assessed with MLHF improved after follow-up at outpatient HF clinics. Minnesota Living with Heart Failure score was significantly related to functional status, laboratory and demographic variables, and was an important predictor of prognosis. PMID- 20847015 TI - Limited clinical utility of CT coronary angiography in a district hospital setting. AB - BACKGROUND: Studies have demonstrated considerable accuracy of multi-slice CT coronary angiography (MSCT-CA) in comparison to invasive coronary angiography (I CA) for evaluating coronary artery disease (CAD). The extent to which published MSCT-CA accuracy parameters are transferable to routine practice beyond high volume tertiary centres is unknown. AIM: To determine the accuracy of MSCT-CA for the detection of CAD in a Scottish district general hospital. DESIGN: Prospective study of diagnostic accuracy. METHOD: One hundred patients with suspected CAD recruited from two Glasgow hospitals underwent both MSCT-CA (Philips Brilliance 40 * 0.625 collimation, 50-200 ms temporal resolution) and I-CA. Studies were reported by independent, blinded radiologists and cardiologists and compared using the AHA 15-segment model. RESULTS: Of 100 patients [55 male, 45 female, mean (SD) age 58.0 (10.7) years], 59 and 41% had low-intermediate and high pre test probabilities of significant CAD, respectively. Mean (SD) heart rate during MSCT-CA was 68.8 (9.0) bpm. Fifty-seven per cent of patients had coronary artery calcification and 35% were obese. Patient prevalence of CAD was 38%. Per-patient sensitivity, specificity, positive and negative (NPV) predictive values for MSCT CA were 92.1, 47.5, 52.2 and 90.6%, respectively. NPV was reduced to 75.0% in the high pre-test probability group. Specificity was compromised in patients with sub optimally controlled heart rates, calcified arteries and elevated BMI. CONCLUSION: Forty-Slice MSCT-CA has a high NPV for ruling out significant CAD when performed in a district hospital setting in patients with low-intermediate pre-test probability and minimal arterial calcification. Specificity is compromised by clinically appropriate strategies for dealing with unevaluable studies. Effective heart rate control during MSCT-CA is imperative. National guidelines should be utilized to govern patient selection and direct MSCT-CA reporter training to ensure quality control. PMID- 20847016 TI - Contaminant, or no contaminant, that is the question. PMID- 20847017 TI - Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis. AB - OBJECTIVE: To determine the effect of glucosamine, chondroitin, or the two in combination on joint pain and on radiological progression of disease in osteoarthritis of the hip or knee. Design Network meta-analysis. Direct comparisons within trials were combined with indirect evidence from other trials by using a Bayesian model that allowed the synthesis of multiple time points. MAIN OUTCOME MEASURE: Pain intensity. Secondary outcome was change in minimal width of joint space. The minimal clinically important difference between preparations and placebo was prespecified at -0.9 cm on a 10 cm visual analogue scale. DATA SOURCES: Electronic databases and conference proceedings from inception to June 2009, expert contact, relevant websites. Eligibility criteria for selecting studies Large scale randomised controlled trials in more than 200 patients with osteoarthritis of the knee or hip that compared glucosamine, chondroitin, or their combination with placebo or head to head. Results 10 trials in 3803 patients were included. On a 10 cm visual analogue scale the overall difference in pain intensity compared with placebo was -0.4 cm (95% credible interval -0.7 to -0.1 cm) for glucosamine, -0.3 cm (-0.7 to 0.0 cm) for chondroitin, and -0.5 cm (-0.9 to 0.0 cm) for the combination. For none of the estimates did the 95% credible intervals cross the boundary of the minimal clinically important difference. Industry independent trials showed smaller effects than commercially funded trials (P=0.02 for interaction). The differences in changes in minimal width of joint space were all minute, with 95% credible intervals overlapping zero. Conclusions Compared with placebo, glucosamine, chondroitin, and their combination do not reduce joint pain or have an impact on narrowing of joint space. Health authorities and health insurers should not cover the costs of these preparations, and new prescriptions to patients who have not received treatment should be discouraged. PMID- 20847019 TI - Spiritual dimensions of dying in pluralist societies. PMID- 20847018 TI - Impact of supervision of methadone consumption on deaths related to methadone overdose (1993-2008): analyses using OD4 index in England and Scotland. AB - OBJECTIVE: To evaluate the impact of introduction of supervision of methadone dosing on deaths related to overdose of methadone in Scotland and England between 1993 and 2008 while controlling for increased prescribing of methadone. DESIGN: Analysis of annual trends in deaths related to overdose of methadone in relation to defined daily doses of methadone prescribed. SETTING: Scotland and England. Population Deaths in which methadone was coded as the only drug involved or as one of the drugs implicated. MAIN OUTCOME MEASURE: Annual OD4-methadone index (number of deaths with methadone implicated per million defined daily doses of methadone prescribed in that year). RESULTS: OD4-methadone declined substantially over the four epochs of four years between 1993 and 2008. It decreased significantly (P<0.05) in 10 of 12 epoch changes: in Scotland from 19.3 (95% confidence interval 15 to 24) to 4.1 (2.8 to 5.4) and finally to 3.0 (2.4 to 3.5) for methadone only deaths (and from 58 to 29 to 14 for deaths with any mention of methadone); in England from 27.1 (25 to 29) to 24.8 (23 to 27) and finally to 5.8 (5.3 to 6.3) for methadone only deaths (and from 46 to 42 to 12 for deaths with any mention of methadone). The decreases in OD4-methadone were closely related to the introduction of supervised dosing of methadone in both countries, first in Scotland (1995-2000) and later in England (1999-2005). These declines occurred over periods of substantial increases in prescribing of methadone (18-fold increase in defined daily doses per million population annually in Scotland and sevenfold increase in England). CONCLUSIONS: Introduction of supervised methadone dosing was followed by substantial declines in deaths related to overdose of methadone in both Scotland and England. OD4-methadone index analyses, controlled for substantial increases in methadone prescribing in both countries, identified at least a fourfold reduction in deaths due to methadone related overdose per defined daily dose (OD4-methadone) over this period. PMID- 20847020 TI - Dying matters: let's talk about it. PMID- 20847021 TI - Achieving a good death for all. PMID- 20847022 TI - Having the difficult conversations about the end of life. PMID- 20847023 TI - Recognising and managing key transitions in end of life care. PMID- 20847024 TI - We're all going to die. Deal with it. PMID- 20847025 TI - GPs earnings fall for third year. PMID- 20847026 TI - Why are we copyrighting science? PMID- 20847028 TI - Increasing NHS productivity: working 9 to 5.20. PMID- 20847032 TI - Prospective study on the FDG-PET/CT predictive and prognostic values in patients treated with neoadjuvant chemoradiation therapy and radical surgery for locally advanced rectal cancer. AB - BACKGROUND: 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was carried out before and after neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery for locally advanced rectal cancer (LARC). The aim of this study was to define its predictive and prognostic values. PATIENTS AND METHODS: Patients with cT3-T4 N-/+ carcinoma of medium/low rectum received daily 5-fluorouracil-based chemotherapy infusion and radiation therapy on 6-week period followed by surgery 7-8 weeks later. Tumour metabolic activity, expressed as maximum standardised uptake value (SUV-1 = at baseline and SUV-2 = pre-surgery), was calculated in the most active tumour site. Predictive and prognostic values of SUV-1, SUV-2 and Delta-SUV (percentage change of SUV-1 - SUV-2) were analysed towards pathological response (pR) in the surgical specimen and disease recurrence, respectively. RESULTS: Eighty consecutive patients entered the study. SUV-1, SUV-2 and Delta-SUV appeared singly correlated with pR, but not one of them resulted an independent predictive factor at multivariate analysis. After a median follow-up of 44 months, 13 patients (16.2%) presented local and/or distant recurrence. SUV-2 <=5 was associated with lower incidence of disease recurrence and resulted prognostic factor at multivariate analysis. CONCLUSIONS: Dual-time FDG-PET/CT in patients with LARC treated with NCRT and radical surgery supplies limited predictive information. However, an optimal metabolic response appears associated with a favourable patient outcome. PMID- 20847033 TI - Patients, clients, consumers, survivors et al: what's in a name? PMID- 20847034 TI - Parental authority and pediatric bioethical decision making. AB - In this paper, I offer a view beyond that which would narrowly reduce the role of parents in medical decision making to acting as custodians of the best interests of children and toward an account of family authority and family autonomy. As a fundamental social unit, the good of the family is usually appreciated, at least in part, in terms of its ability successfully to instantiate its core moral and cultural understandings as well as to pass on such commitments to future generations. The putative rights of children to expression, information, freedom of thought, conscience, religion, and to freedom of association with others are, in this essay, assessed from the perspective of those conditions necessary for the family to function as a moral community. In so doing, I respond to the move to liberate children from parental authority and to effect the transformation of the family as implied by the United Nations' "Convention on the Rights of the Child" and the pediatric bioethics it supports. PMID- 20847035 TI - Muscle architecture predicts maximum strength and is related to activity levels in cerebral palsy. AB - BACKGROUND: Muscle architecture is known to be predictive of muscle function. However, it is unknown whether this relationship is similar in children and adolescents with and without cerebral palsy (CP). OBJECTIVE: The objective of this study was to determine whether the architecture of the rectus femoris (RF) and vastus lateralis (VL) muscles was predictive of maximum voluntary knee extensor torque in children and adolescents with and without CP and whether these measures were related to activity and participation levels. DESIGN: A case control design was used. METHODS: Eighteen participants with CP (mean age=12.0 years, SD=3.2) at Gross Motor Function Classification System (GMFCS) levels I through IV and 12 age-matched peers with typical development (mean age=12.3 years, SD=3.9) were evaluated. Muscle thickness, fascicle length, and fascicle angle of the RF and VL muscles were measured with 2-dimensional, B-mode ultrasound imaging. The activity and participation measures used for participants with CP were the Pediatric OUTCOMES: Data Collection Instrument (PODCI) and the Activities Scale for Kids, Performance Version (ASKp). RESULTS: When age and GMFCS level were controlled for, VL muscle thickness was the best predictor of knee extensor isometric torque in the group with CP (R(2)=.85). This prediction was similar to the prediction from VL muscle thickness and age in participants with typical development (R(2)=.91). Rectus femoris muscle fascicle length was significantly correlated with the Sports and Physical Functioning Scale of the PODCI (rho=.49), and VL muscle fascicle angle was correlated with the Transfers and Basic Mobility Scale of the PODCI (r=.47) and with ASKp Locomotion subdomain (r=.50). LIMITATIONS: A limitation of this study was the small sample size. CONCLUSIONS: Ultrasound measures of VL muscle thickness, adjusted for age and GMFCS level, were highly predictive of maximum torque and have the potential to serve as surrogate measures of voluntary strength (force-generating capacity) in children and adolescents with and without CP. PMID- 20847036 TI - Primary care physical therapy in people with fibromyalgia: opportunities and boundaries within a monodisciplinary setting. AB - Despite the fact that people with fibromyalgia syndrome (FMS) frequently are seen by primary care physical therapists, guidelines for the management of FMS are based primarily on outcomes from multidisciplinary and tertiary care treatment studies. Few data addressing the treatment of patients with FMS in primary care currently are available. The evidence-based guidelines on the management of FMS are based, in part, on evidence from studies examining physical therapy treatment components alone (eg, aerobic exercise, education). Thus, the recommendations can be applied to primary care physical therapy. Primary care physical therapy for patients with FMS should include education, aerobic exercise, and strengthening exercise. For other treatment components such as passive treatments, activity management, and relaxation, less evidence currently is available to advocate their use in primary care physical therapy. Superior results are to be expected when various treatment components are combined. PMID- 20847038 TI - Bradykinin-induced lung inflammation and bronchoconstriction: role in parainfluenze-3 virus-induced inflammation and airway hyperreactivity. AB - Inhaled bradykinin causes bronchoconstriction in asthmatic subjects but not nonasthmatics. To date, animal studies with inhaled bradykinin have been performed only in anesthetized guinea pigs and rats, where it causes bronchoconstriction through sensory nerve pathways. In the present study, airway function was recorded in conscious guinea pigs by whole-body plethysmography. Inhaled bradykinin (1 mM, 20 s) caused bronchoconstriction and influx of inflammatory cells to the lungs, but only when the enzymatic breakdown of bradykinin by angiotensin-converting enzyme and neutral endopeptidase was inhibited by captopril (1 mg/kg i.p.) and phosphoramidon (10 mM, 20-min inhalation), respectively. The bronchoconstriction and cell influx were antagonized by the B(2) kinin receptor antagonist 4-(S)-amino-5-(4-{4-[2,4 dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4 pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132) when given by inhalation (1 and 10 MUM, 20 min) and are therefore mediated via B(2) kinin receptors. However, neither intraperitioneal MEN16132 nor the peptide B(2) antagonist icatibant, by inhalation, antagonized these bradykinin responses. Sensitization of guinea pigs with ovalbumin was not sufficient to induce airway hyperreactivity (AHR) to the bronchoconstriction by inhaled bradykinin. However, ovalbumin challenge of sensitized guinea pigs caused AHR to bradykinin and histamine. Infection of guinea pigs by nasal instillation of parainfluenza-3 virus produced AHR to inhaled histamine and lung influx of inflammatory cells. These responses were attenuated by the bradykinin B(2) receptor antagonist MEN16132 and H-(4-chloro)DPhe-2'(1-naphthylalanine)-(3 aminopropyl)guanidine (VA999024), an inhibitor of tissue kallikrein, the enzyme responsible for lung synthesis of bradykinin. These results suggest that bradykinin is involved in virus-induced inflammatory cell influx and AHR. PMID- 20847037 TI - Drug discrimination in methamphetamine-trained rats: effects of cholinergic nicotinic compounds. AB - Accumulating evidence suggests that acetylcholine nicotinic systems may contribute importantly to the abuse-related effects of d-methamphetamine (d-MA). The present study was conducted to compare the effects of indirect dopamine (DA) agonists (d-amphetamine, d-MA, and l-methamphetamine), full [(-)-nicotine, anabaseine, (+)-epibatidine, (-)-epibatidine, isoarecolone] and partial (varenicline) nicotinic agonists, and other cholinergic compounds (mecamylamine, dihydro-beta-erythroidine hydrobromide, methyllycaconitine, atropine, scopolamine, rivastigmine, and donepezil) in rats trained to discriminate 0.3 mg/kg i.p. d-MA from saline. All indirect DA agonists fully substituted for d-MA in a dose-related manner. Among nicotinic agonists, only (-)-nicotine fully substituted for d-MA in a dose-dependent manner, whereas all other nicotinic agonists and, to a limited extent, muscarinic antagonists produced partial d-MA like responding. Other cholinergic compounds failed to produce d-MA-like discriminative stimulus effects. In drug interaction studies, varenicline served to dose-dependently attenuate the d-MA-like effects of (-)-nicotine, whereas mecamylamine, but not varenicline, reduced the discriminative stimulus effects of the training dose of d-MA. Differences between (-)-nicotine and other nicotinic agonists may be related to their ability to activate the DA system. These results provide further evidence that nicotinic mechanisms may be useful neurochemical targets for the development of therapeutics for the management of monoaminergic stimulant abuse and addiction. PMID- 20847039 TI - DNA repair and the accumulation of oxidatively damaged DNA are affected by fruit intake in mice. AB - AGING is associated with elevated oxidative stress and DNA damage. To achieve healthy aging, we must begin to understand how diet affects cellular processes. We postulated that fruit-enriched diets might initiate a program of enhanced DNA repair and thereby improve genome integrity. C57Bl/6 J mice were fed for 14 weeks a control diet or a diet with 8% peach or nectarine extract. The activities of DNA repair enzymes, the level of DNA damage, and gene expression changes were measured. Our study showed that repair of various oxidative DNA lesions was more efficient in liver extracts derived from mice fed fruit-enriched diets. In support of these findings, gas chromatography-mass spectrometry analysis revealed that there was a decrease in the levels of formamidopyrimidines in peach-fed mice compared with the controls. Additionally, microarray analysis revealed that NTH1 was upregulated in peach-fed mice. Taken together, these results suggest that an increased intake of fruits might modulate the efficiency of DNA repair, resulting in altered levels of DNA damage. PMID- 20847040 TI - Age differences in emotion recognition: the task matters. AB - OBJECTIVES: This study examined the impact of context information on emotion recognition from a life-span developmental perspective. The main prediction was that age-related deficits in emotion recognition will only be evident in context poor tasks. METHODS: A sample of 48 younger (M(age) = 23 years) and 35 older women (M(age) = 70 years) watched 48 film clips, each depicting a female target who talked about an emotional biographical episode and expressed one of three target emotions (i.e., happiness, sadness, or anger). Half of the films were presented without sound (context-poor condition) and the other half was presented with sound (context-rich condition). RESULTS: Independent of the condition, younger women were better at recognizing sadness and anger than older women. However, the condition had an effect on age differences in happiness recognition: Age-related deficits were only evident in the context-poor condition. In addition, we found that logical reasoning predicted individual differences and age-related differences in sadness and anger recognition but not in happiness recognition. DISCUSSION: The present findings suggest that age differences in emotion recognition are context and emotion specific. Together, the evidence speaks for substantial plasticity in emotion recognition (i.e., within-person variability) well into old age. PMID- 20847041 TI - Gender differences in perceptions of urge to cough and dyspnea induced by citric acid in healthy never smokers. AB - BACKGROUND: The mechanism of the gender difference in cough reflex threshold has not been clearly elucidated. In the present study, we evaluated gender differences in the cough reflex threshold along with the perceptions of respiratory sensations, urge to cough, and dyspnea. METHODS: Nineteen male and 20 female healthy never smokers were recruited through public postings. The cough reflex threshold and the urge to cough were evaluated by inhalation of citric acid. The perception of dyspnea was evaluated by Borg scores during applications of external inspiratory resistive loads. RESULTS: The cough reflex threshold and suprathreshold to citric acid in women, as expressed by the log transformation of the lowest concentration of citric acid that elicited two or more and five or more coughs, was significantly lower than that in men. The urge-to-cough log-log slope in women (1.47 +/- 0.81 point * L/g) was significantly steeper than in men (0.96 +/- 0.28 point * L/g; P < .03). There were no significant differences in the urge-to-cough threshold estimated between men and women. The slope of the dyspnea Borg score change during the external inspiratory resistive loads is steeper in women (0.17 +/- 0.04 point/cm H2O/L/s) than that in men (0.13 +/- 0.05 point/cm H2O/L/s; P < .01). The urge-to-cough slope significantly correlated with the perception of dyspnea slope (r = 0.537; P < .01). CONCLUSIONS: The gender difference in cough reflex threshold accompanied the gender difference in amplification rate of respiratory sensations in the same direction. The higher central gain for common pathways for respiratory sensations may play a role in lower cough reflex threshold in women. Further studies are needed to elucidate this issue. PMID- 20847042 TI - Carbocisteine protects against emphysema induced by cigarette smoke extract in rats. AB - BACKGROUND: Chronic inflammation, imbalance of proteolytic and antiproteolytic activities, oxidative stress, and apoptosis of lung structural cells contribute to the pathogenesis of COPD. There is increasing evidence that carboxymethylcysteine (also known as carbocisteine) (CMC), which is commonly used for its mucoactive property, has diverse pharmacologic actions, including significant antioxidant activity. We hypothesize that CMC protects against cigarette smoke extract (CSE)-induced emphysema in rats via its antioxidant action. METHODS: Sprague-Dawley rats were divided into four groups (n = 6 in each group): control group, CSE group, CSE + 125 mg/kg/d of CMC group, and CSE + 250 mg/kg/d of CMC group. The CSE was injected intraperitoneally once a week for 3 weeks, and CMC was administered daily via a gastric gavage for the same duration. Antioxidant activity in the pulmonary and serum levels, apoptotic index, caspase 3 activity, and matrix metalloproteinase (MMP)-2 and MMP-9 activities in lung tissues were measured. RESULTS: CMC significantly protected against alveolar enlargement and parenchymal destruction in rats injected with CSE, resulting in prevention of the development of CSE-induced emphysema in the rats. CMC significantly protected the antioxidant activity in both the pulmonary and systemic levels, reduced pathologic apoptosis, and inhibited MMP-2 and MMP-9 activities in the lungs of rats with CSE-induced emphysema. CONCLUSIONS: CMC protected against the development of CSE-induced emphysema in rats. The molecular mechanisms that were involved with stabilizing the biologic antioxidant activity resulted from the administration of CMC, which was connected to the inhibition of apoptosis and the reversal of the imbalance of proteolytic and antiproteolytic enzyme activities, eventually achieving the protection of the alveolar architecture of rats with emphysema. PMID- 20847043 TI - Glucocorticoids modulate microRNA expression and processing during lymphocyte apoptosis. AB - Glucocorticoids modulate immune development and function through the induction of lymphocyte apoptosis via mechanisms requiring alterations in gene expression. Recently, short, noncoding, microRNAs have been identified as key regulators of lymphocyte function; however, it is unknown whether glucocorticoids regulate noncoding microRNAs and whether this regulation contributes to lymphocyte apoptosis. We now show by both microarray and deep sequencing analysis that microRNAs are substantially repressed during glucocorticoid-induced apoptosis of primary rat thymocytes. Mechanistic studies revealed that primary microRNA transcripts were not repressed, whereas the expression of the key microRNA processing enzymes: Dicer, Drosha, and DGCR8/Pasha, were significantly reduced at both the mRNA and protein levels during glucocorticoid-induced apoptosis. To delineate the role of Dicer depletion and microRNA repression in apoptosis, we silenced Dicer expression in two human leukemic cell lines and demonstrated that Dicer depletion significantly enhanced glucocorticoid-induced apoptosis in both model systems. Finally, in vitro and in vivo overexpression of the conserved miR 17-92 polycistron, which was repressed significantly by dexamethasone treatment in both our microarray and deep sequencing studies, blunted glucocorticoid induced apoptosis. These studies provide evidence of altered post-transcriptional microRNA expression and the repression of the microRNA bioprocessing pathway during glucocorticoid-induced apoptosis of lymphocytes, suggesting a role for microRNA processors and specific microRNAs in cell life/death decisions. PMID- 20847044 TI - De novo DNA methyltransferase DNMT3b interacts with NEDD8-modified proteins. AB - DNA methylation and histone modifications play an important role in transcription regulation. In cancer cells, many promoters become aberrantly methylated through the activity of the de novo DNA methyltransferases DNMT3a and DNMT3b and acquire repressive chromatin marks. NEDD8 is a ubiquitin-like protein modifier that is conjugated to target proteins, such as cullins, to regulate their activity, and cullin 4A (CUL4A) in its NEDD8-modified form is essential for repressive chromatin formation. We found that DNMT3b associates with NEDD8-modified proteins. Whereas DNMT3b interacts directly in vitro with NEDD8, conjugation of NEDD8 to target proteins enhances this interaction in vivo. DNMT3b immunoprecipitated two major bands of endogenously NEDDylated proteins at the size of NEDDylated cullins, and indeed DNMT3b interacted with CUL1, CUL2, CUL3, CUL4A, and CUL5. Moreover, DNMT3b preferentially immunoprecipitated the NEDDylated form of endogenous CUL4A. NEDD8 enhanced DNMT3b-dependent DNA methylation. Chromatin immunoprecipitation assays suggest that DNMT3b recruits CUL4A and NEDD8 to chromatin, whereas deletion of Dnmt3b reduces the association of CUL4A and NEDD8 at a repressed promoter in a cancer cell line. PMID- 20847045 TI - Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. AB - To date there is no effective therapy for Alzheimer disease (AD). High levels of circulating high density lipoprotein (HDL) and its main protein, apolipoprotein A I (apoA-I), reduce the risk of cardiovascular disease. Clinical studies show that plasma HDL cholesterol and apoA-I levels are low in patients with AD. To investigate if increasing plasma apoA-I/HDL levels ameliorates AD-like memory deficits and amyloid-beta (Abeta) deposition, we generated a line of triple transgenic (Tg) mice overexpressing mutant forms of amyloid-beta precursor protein (APP) and presenilin 1 (PS1) as well as human apoA-I (AI). Here we show that APP/PS1/AI triple Tg mice have a 2-fold increase of plasma HDL cholesterol levels. When tested in the Morris water maze for spatial orientation abilities, whereas APP/PS1 mice develop age-related learning and memory deficits, APP/PS1/AI mice continue to perform normally during aging. Interestingly, no significant differences were found in the total level and deposition of Abeta in the brains of APP/PS1 and APP/PS1/AI mice, but cerebral amyloid angiopathy was reduced in APP/PS1/AI mice. Also, consistent with the anti-inflammatory properties of apoA I/HDL, glial activation was reduced in the brain of APP/PS1/AI mice. In addition, Abeta-induced production of proinflammatory chemokines/cytokines was decreased in mouse organotypic hippocampal slice cultures expressing human apoA-I. Therefore, we conclude that overexpression of human apoA-I in the circulation prevents learning and memory deficits in APP/PS1 mice, partly by attenuating neuroinflammation and cerebral amyloid angiopathy. These findings suggest that elevating plasma apoA-I/HDL levels may be an effective approach to preserve cognitive function in patients with AD. PMID- 20847046 TI - Polymorphic C-terminal beta-sheet interactions determine the formation of fibril or amyloid beta-derived diffusible ligand-like globulomer for the Alzheimer Abeta42 dodecamer. AB - The relationship between amyloid deposition and cellular toxicity is still controversial. In addition to fibril-forming oligomers, other soluble Abeta forms (amyloid beta-derived diffusible ligands (ADDLs)) were also suggested to form and to present different morphologies and mechanisms of toxicity. One ADDL type, the "globulomer," apparently forms independently of the fibril aggregation pathway. Even though many studies argue that such soluble Abeta oligomers are off fibril formation pathways, they may nonetheless share some structural similarity with protofibrils. NMR data of globulomer intermediates, "preglobulomers," suggested parallel in-register C-terminal beta-sheets, with different N-terminal conformations. Based on experimental data, we computationally investigate four classes of Abeta dodecamers: fibril, fibril oligomer, prefibril/preglobulomer cluster, and globulomer models. Our simulations of the solvent protection of double-layered fibril and globulomer models reproduce experimental observations. Using a single layer Abeta fibril oligomer beta-sheet model, we found that the C terminal beta-sheet in the fibril oligomer is mostly curved, preventing it from quickly forming a fibril and leading to its breaking into shorter pieces. The simulations also indicate that beta-sheets packed orthogonally could be the most stable species for Abeta dodecamers. The major difference between fibril-forming oligomers and ADDL-like oligomers (globulomers) could be the exposure of Met-35 patches. Although the Met-35 patches are necessarily exposed in fibril-forming oligomers to allow their maturation into fibrils, the Met-35 patches in the globulomer are covered by other residues in the orthogonally packed Abeta peptides. Our results call attention to the possible existence of certain "critical intermediates" that can lead to both seeds and other soluble ADDL-like oligomers. PMID- 20847047 TI - Staphylococcal major autolysin (Atl) is involved in excretion of cytoplasmic proteins. AB - Many microorganisms excrete typical cytoplasmic proteins into the culture supernatant. As none of the classical secretion systems appears to be involved, this type of secretion was referred to as "nonclassical protein secretion." Here, we demonstrate that in Staphylococcus aureus the major autolysin plays a crucial role in release of cytoplasmic proteins. Comparative secretome analysis revealed that in the wild type S. aureus strain, 22 typical cytoplasmic proteins were excreted into the culture supernatant, although in the atl mutant they were significantly decreased. The presence or absence of prophages had little influence on the secretome pattern. In the atl mutant, secondary peptidoglycan hydrolases were increased in the secretome; the corresponding genes were transcriptionally up-regulated suggesting a compensatory mechanism for the atl mutation. Using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a cytoplasmic indicator enzyme, we showed that all clinical isolates tested excreted this protein. In the wall teichoic acid-deficient tagO mutant with its increased autolysis activity, GAPDH was excreted in even higher amounts than in the WT, confirming the importance of autolysis in excretion of cytoplasmic proteins. To answer the question of how discriminatory the excretion of cytoplasmic proteins is, we performed a two-dimensional PAGE of cytoplasmic proteins isolated from WT. Surprisingly, the most abundant proteins in the cytoplasm were not found in the secretome of the WT, suggesting that there exists a selection mechanism in the excretion of cytoplasmic proteins. As the major autolysin binds at the septum site, we assume that the proteins are preferentially released at and during septum formation. PMID- 20847048 TI - Stable alpha-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. AB - alpha-Synuclein aggregation and accumulation in Lewy bodies are implicated in progressive loss of dopaminergic neurons in Parkinson disease and related disorders. In neurons, the Hsp70s and their Hsp40-like J-domain co-chaperones are the only known components of chaperone network that can use ATP to convert cytotoxic protein aggregates into harmless natively refolded polypeptides. Here we developed a protocol for preparing a homogeneous population of highly stable beta-sheet enriched toroid-shaped alpha-Syn oligomers with a diameter typical of toxic pore-forming oligomers. These oligomers were partially resistant to in vitro unfolding by the bacterial Hsp70 chaperone system (DnaK, DnaJ, GrpE). Moreover, both bacterial and human Hsp70/Hsp40 unfolding/refolding activities of model chaperone substrates were strongly inhibited by the oligomers but, remarkably, not by unstructured alpha-Syn monomers even in large excess. The oligomers acted as a specific competitive inhibitor of the J-domain co chaperones, indicating that J-domain co-chaperones may preferably bind to exposed bulky misfolded structures in misfolded proteins and, thus, complement Hsp70s that bind to extended segments. Together, our findings suggest that inhibition of the Hsp70/Hsp40 chaperone system by alpha-Syn oligomers may contribute to the disruption of protein homeostasis in dopaminergic neurons, leading to apoptosis and tissue loss in Parkinson disease and related neurodegenerative diseases. PMID- 20847049 TI - A novel p53 phosphorylation site within the MDM2 ubiquitination signal: II. a model in which phosphorylation at SER269 induces a mutant conformation to p53. AB - The p53 DNA-binding domain harbors a conformationally flexible multiprotein binding site that regulates p53 ubiquitination. A novel phosphorylation site exists within this region at Ser(269), whose phosphomimetic mutation inactivates p53. The phosphomimetic p53 (S269D) exhibits characteristics of mutant p53: stable binding to Hsp70 in vivo, elevated ubiquitination in vivo, inactivity in DNA binding and transcription, increased thermoinstability using thermal shift assays, and lambda(max) of intrinsic tryptophan fluorescence at 403 nm rather than 346 nm, characteristic of wild type p53. These data indicate that p53 conformational stability is regulated by a phosphoacceptor site within an exposed flexible surface loop and that this can be destabilized by phosphorylation. To test whether other motifs within p53 have similarly evolved, we analyzed the effect of Ser(215) mutation on p53 function because Ser(215) is another inactivating phosphorylation site in the conformationally flexible PAb240 epitope. The p53(S215D) protein is inactive like p53(S269D), whereas p53(S215A) is as active as p53(S269A). However, the double mutant p53(S215A/S269A) was transcriptionally inactive and more thermally unstable than either individual Ser Ala loop mutant. Molecular dynamics simulations suggest that (i) solvation of phospho-Ser(215) and phospho-Ser(269) by positive charged residues or solvent water leads to local unfolding, which is accompanied by local destabilization of the N-terminal loop and global destabilization of p53, and (ii) the double alanine 215/269 mutation disrupts hydrogen bonding normally stabilized by both Ser(215) and Ser(269). These data indicate that p53 has evolved two serine phosphoacceptor residues within conformationally flexible epitopes that normally stabilize the p53 DNA-binding domain but whose phosphorylation induces a mutant conformation to wild type p53. PMID- 20847050 TI - Nuclear import mechanism for myocardin family members and their correlation with vascular smooth muscle cell phenotype. AB - Myocardin (Mycd), which is essential for the differentiation of the smooth muscle cell lineage, is constitutively located in the nucleus, although its family members, myocardin-related transcription factors A and B (MRTF-A/B), mostly reside in the cytoplasm and translocate to the nucleus in response to Rho signaling. The mechanism for their nuclear import is unclear. Here we investigated the mechanism for the nuclear import of Mycd family members and demonstrated any correlation between such mechanism and the phenotype of vascular smooth muscle cells (VSMCs). In cultured VSMCs, the knockdown of importin beta1 inhibited the nuclear import of Mycd and MRTF-A/B. Their NH(2)-terminal basic domain was identified as a binding site for importin alpha/beta1 by in vitro analyses. However, Mycd had a higher affinity for importin alpha/beta1 than did MRTF-A/B, even in the absence of G-actin, and Mycd affinity for importin alpha1/beta1 was stronger than for any other importin alpha/beta1 heterodimers. The binding of Mycd to importin alpha/beta1 was insensitive to G-actin, whereas that of MRTF-A/B was differently inhibited by G-actin. In dedifferentiated VSMCs, the levels of importins alpha1 and beta1 were reduced concomitant with down regulation of Mycd, serum response factor, and smooth muscle cell markers. By contrast, in differentiated VSMCs, their expressions were up-regulated. Thus, the nuclear import of Mycd family members in VSMCs depends on importin alpha/beta1, and their relative affinities for importin alpha/beta1 heterodimers determine Mycd nuclear import. The expression of Mycd nuclear import machineries is related to the expression levels of VSMC phenotype-dependent smooth muscle cell markers. PMID- 20847051 TI - SIRT6 deficiency results in severe hypoglycemia by enhancing both basal and insulin-stimulated glucose uptake in mice. AB - Glucose homeostasis in mammals is mainly regulated by insulin signaling. It was previously shown that SIRT6 mutant mice die before 4 weeks of age, displaying profound abnormalities, including low insulin, hypoglycemia, and premature aging. To investigate mechanisms underlying the pleiotropic phenotypes associated with SIRT6 deficiency, we generated mice carrying targeted disruption of SIRT6. We found that 60% of SIRT6(-/-) animals had very low levels of blood glucose and died shortly after weaning. The remaining animals, which have relatively higher concentrations of glucose, survived the early post-weaning lethality, but most died within one year of age. Significantly, feeding the mice with glucose containing water increased blood glucose and rescued 83% of mutant mice, suggesting that the hypoglycemia is a major cause for the lethality. We showed that SIRT6 deficiency results in more abundant membrane association of glucose transporters 1 and 4, which enhances glucose uptake. We further demonstrated that SIRT6 negatively regulates AKT phosphorylation at Ser-473 and Thr-308 through inhibition of multiple upstream molecules, including insulin receptor, IRS1, and IRS2. The absence of SIRT6, consequently, enhances insulin signaling and activation of AKT, leading to hypoglycemia. These data uncover an essential role of SIRT6 in modulating glucose metabolism through mediating insulin sensitivity. PMID- 20847052 TI - Fusobacterium nucleatum-associated beta-defensin inducer (FAD-I): identification, isolation, and functional evaluation. AB - Human beta-defensins (hBDs) are small, cationic antimicrobial peptides, secreted by mucosal epithelial cells that regulate adaptive immune functions. We previously reported that Fusobacterium nucleatum, a ubiquitous gram-negative bacterium of the human oral cavity, induces human beta-defensin 2 (hBD2) upon contact with primary oral epithelial cells. We now report the isolation and characterization of an F. nucleatum (ATCC 25586)-associated defensin inducer (FAD I). Biochemical approaches revealed a cell wall fraction containing four proteins that stimulated the production of hBD2 in human oral epithelial cells (HOECs). Cross-referencing of the N-terminal sequences of these proteins with the F. nucleatum genome revealed that the genes encoding the proteins were FadA, FN1527, FN1529, and FN1792. Quantitative PCR of HOEC monolayers challenged with Escherichia coli clones expressing the respective cell wall proteins revealed that FN1527 was most active in the induction of hBD2 and hence was termed FAD-I. We tagged FN1527 with a c-myc epitope on the C-terminal end to identify and purify it from the E. coli clone. Purified FN1527 (FAD-I) induced hBD2 mRNA and protein expression in HOEC monolayers. F. nucleatum cell wall and FAD-I induced hBD2 via TLR2. Porphorymonas gingivalis, an oral pathogen that does not induce hBD2 in HOECs, was able to significantly induce expression of hBD2 in HOECs only when transformed to express FAD-I. FAD-I or its derivates offer a potentially new paradigm in immunoregulatory therapeutics because they may one day be used to bolster the innate defenses of vulnerable mucosae. PMID- 20847053 TI - Oxidative and nitrosative modifications of tropoelastin prevent elastic fiber assembly in vitro. AB - Elastic fibers are extracellular structures that provide stretch and recoil properties of tissues, such as lungs, arteries, and skin. Elastin is the predominant component of elastic fibers. Tropoelastin (TE), the precursor of elastin, is synthesized mainly during late fetal and early postnatal stages. The turnover of elastin in normal adult tissues is minimal. However, in several pathological conditions often associated with inflammation and oxidative stress, elastogenesis is re-initiated, but newly synthesized elastic fibers appear abnormal. We sought to determine the effects of reactive oxygen and nitrogen species (ROS/RNS) on the assembly of TE into elastic fibers. Immunoblot analyses showed that TE is oxidatively and nitrosatively modified by peroxynitrite (ONOO( )) and hypochlorous acid (HOCl) and by activated monocytes and macrophages via release of ONOO(-) and HOCl. In an in vitro elastic fiber assembly model, oxidatively modified TE was unable to form elastic fibers. Oxidation of TE enhanced coacervation, an early step in elastic fiber assembly, but reduced cross linking and interactions with other proteins required for elastic fiber assembly, including fibulin-4, fibulin-5, and fibrillin-2. These findings establish that ROS/RNS can modify TE and that these modifications affect the assembly of elastic fibers. Thus, we speculate that oxidative stress may contribute to the abnormal structure and function of elastic fibers in pathological conditions. PMID- 20847054 TI - Systematic quantification of negative feedback mechanisms in the extracellular signal-regulated kinase (ERK) signaling network. AB - Cell responses are actuated by tightly controlled signal transduction pathways. Although the concept of an integrated signaling network replete with interpathway cross-talk and feedback regulation is broadly appreciated, kinetic data of the type needed to characterize such interactions in conjunction with mathematical models are lacking. In mammalian cells, the Ras/ERK pathway controls cell proliferation and other responses stimulated by growth factors, and several cross talk and feedback mechanisms affecting its activation have been identified. In this work, we take a systematic approach to parse the magnitudes of multiple regulatory mechanisms that attenuate ERK activation through canonical (Ras dependent) and non-canonical (PI3K-dependent) pathways. In addition to regulation of receptor and ligand levels, we consider three layers of ERK-dependent feedback: desensitization of Ras activation, negative regulation of MEK kinase (e.g. Raf) activities, and up-regulation of dual-specificity ERK phosphatases. Our results establish the second of these as the dominant mode of ERK self regulation in mouse fibroblasts. We further demonstrate that kinetic models of signaling networks, trained on a sufficient diversity of quantitative data, can be reasonably comprehensive, accurate, and predictive in the dynamical sense. PMID- 20847055 TI - The forkhead transcription factor Hcm1 promotes mitochondrial biogenesis and stress resistance in yeast. AB - In Saccharomyces cerevisiae, the forkhead transcription factor Hcm1 is involved in chromosome segregation, spindle pole dynamics, and budding. We found that Hcm1 interacts with the histone deacetylase Sir2 and shifts from cytoplasm to the nucleus in the G(1)/S phase or in response to oxidative stress stimuli. The nuclear localization of Hcm1 depends on the activity of Sir2 as revealed by activators and inhibitors of the sirtuins and the Deltasir2 mutant. Hcm1 overexpressing cells display more mitochondria that can be attributed to increased amounts of Abf2, a protein involved in mitochondrial biogenesis. These cells also show higher rates of oxygen consumption and improved resistance to oxidative stress that would be explained by increased catalase and Sod2 activities and molecular chaperones such as Hsp26, Hsp30, and members of Hsp70 family. Microarray analyses also reveal increased expression of genes involved in mitochondrial energy pathways and those allowing the transition from the exponential to the stationary phase. Taken together, these results describe a new and relevant role of Hcm1 for mitochondrial functions, suggesting that this transcription factor would participate in the adaptation of cells from fermentative to respiratory metabolism. PMID- 20847056 TI - Modulation of energy transfer pathways between mitochondria and myofibrils by changes in performance of perfused heart. AB - In the heart, the energy supplied by mitochondria to myofibrils is continuously and finely tuned to the contraction requirement over a wide range of cardiac loads. This process is mediated both by the creatine kinase (CK) shuttle and by direct ATP transfer. The aim of this study was to identify the contribution of energy transfer pathways at different cardiac performance levels. For this, five protocols of (31)P NMR inversion and saturation transfer experiments were performed at different performance levels on Langendorff perfused rat hearts. The cardiac performance was changed either through variation of external calcium in the presence or absence of isoprenaline or through variation of LV balloon inflation. The recordings were analyzed by mathematical models composed on the basis of different energy transfer pathway configurations. According to our results, the total CK unidirectional flux was relatively stable when the cardiac performance was changed by increasing the calcium concentration or variation of LV balloon volume. The stability of total CK unidirectional flux is lost at extreme energy demand levels leading to a rise in inorganic phosphate, a drop of ATP and phosphocreatine, a drop of total CK unidirectional flux, and to a bypass of CK shuttle by direct ATP transfer. Our results provide experimental evidence for the existence of two pathways of energy transfer, direct ATP transfer, and PCr transfer through the CK shuttle, whose contribution may vary depending on the metabolic status of the heart. PMID- 20847057 TI - Identification of the NC1 domain of {alpha}3 chain as critical for {alpha}3{alpha}4{alpha}5 type IV collagen network assembly. AB - The network organization of type IV collagen consisting of alpha3, alpha4, and alpha5 chains in the glomerular basement membrane (GBM) is speculated to involve interactions of the triple helical and NC1 domain of individual alpha-chains, but in vivo evidence is lacking. To specifically address the contribution of the NC1 domain in the GBM collagen network organization, we generated a mouse with specific loss of alpha3NC1 domain while keeping the triple helical alpha3 chain intact by connecting it to the human alpha5NC1 domain. The absence of alpha3NC1 domain leads to the complete loss of the alpha4 chain. The alpha3 collagenous domain is incapable of incorporating the alpha5 chain, resulting in the impaired organization of the alpha3alpha4alpha5 chain-containing network. Although the alpha5 chain can assemble with the alpha1, alpha2, and alpha6 chains, such assembly is incapable of functionally replacing the alpha3alpha4alpha5 protomer. This novel approach to explore the assembly type IV collagen in vivo offers novel insights in the specific role of the NC1 domain in the assembly and function of GBM during health and disease. PMID- 20847059 TI - Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. AB - PURPOSE: We conducted a phase II study to assess the efficacy of continuous dosing of sunitinib in patients with flurodeoxyglucose positron emission tomography (FDG-PET)-avid, iodine-refractory well-differentiated thyroid carcinoma (WDTC) and medullary thyroid cancer (MTC) and to assess for early response per FDG-PET. EXPERIMENTAL DESIGN: Patients had metastatic, iodine refractory WDTC or MTC with FDG-PET-avid disease. Sunitinib was administered at 37.5 mg daily on a continuous basis. The primary end point was response rate per Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included toxicity, overall survival, and time to progression. We conducted an exploratory analysis of FDG-PET response after 7 days of treatment. RESULTS: Thirty-five patients were enrolled (7 MTC, 28 WDTC), and 33 patients were evaluable for disease response. The primary end point, objective response rate per RECIST, was 11 patients (31%; 95% confidence interval, 16-47%). There were 1 complete response (3%), 10 partial responses (28%), and 16 patients (46%) with stable disease. Progressive disease was seen in 6 patients (17%). The median time to progression was 12.8 months (95% confidence interval, 8.9 months-not reached). Repeat FDG-PET was done on 22 patients. The median percent change in average standardized uptake values was -11.7%, -13.9%, and 8.6% for patients with RECIST response, stable disease, and progressive disease, respectively. Differences between response categories were statistically significant (P = 0.03). The most common toxicities seen included fatigue (11%), neutropenia (34%), hand/foot syndrome (17%), diarrhea (17%), and leukopenia (31%). One patient on anticoagulation died of gastrointestinal bleeding. CONCLUSION: Continuous administration of sunitinib was effective in patients with iodine-refractory WDTC and MTC. Further study is warranted. PMID- 20847058 TI - Genetic risk profiles identify different molecular etiologies for glioma. AB - PURPOSE: Genome-wide association studies have recently identified single nucleotide polymorphisms (SNP) in five loci at 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A/CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1) to be associated with glioma risk. Because gliomas are heterogeneous in histology, molecular alterations, and clinical behavior, we have investigated these polymorphisms for potential correlations with tumor histology and patient survival. EXPERIMENTAL DESIGN: We studied the relationship between SNPs and glioma subtype in two large patient cohorts from France and Germany, totaling 1,577 patients, as well as the relationship between SNP genotype and overall survival. RESULTS: In both cohorts, the frequencies of rs2736100 and rs6010620 risk genotypes were highly correlated with high-grade disease (P < 0.001), whereas rs4295627 and rs498872 risk genotypes were inversely related to tumor grade (P < 0.001). These data show that genetic variations at these loci have subtype-specific effects on the risk of developing glioma. In contrast, the rs4977756 genotype was not correlated with tumor grade, consistent with the causal variant having a generic influence on glioma development. None of the five SNPs was associated with prognosis independent of tumor grade. CONCLUSIONS: Our findings provide novel insight into etiologic pathways in the different glioma subtypes. PMID- 20847060 TI - ATP induces synaptic gene expressions in cortical neurons: transduction and transcription control via P2Y1 receptors. AB - Studies in vertebrate neuromuscular synapses have revealed previously that ATP, via P2Y receptors, plays a critical role in regulating postsynaptic gene expressions. An equivalent regulatory role of ATP and its P2Y receptors would not necessarily be expected for the very different situation of the brain synapses, but we provide evidence here for a brain version of that role. In cultured cortical neurons, the expression of P2Y(1) receptors increased sharply during neuronal differentiation. Those receptors were found mainly colocalized with the postsynaptic scaffold postsynaptic density protein 95 (PSD-95). This arises through a direct interaction of a PDZ domain of PSD-95 with the C-terminal PDZ binding motif, D-T-S-L of the P2Y(1) receptor, confirmed by the full suppression of the colocalization upon mutation of two amino acids therein. This interaction is effective in recruiting PSD-95 to the membrane. Specific activation of P2Y(1) (G-protein-coupled) receptors induced the elevation of intracellular Ca(2+) and activation of a mitogen-activated protein kinase/Raf-1 signaling cascade. This led to distinct up-regulation of the genes encoding acetylcholinesterase (AChE(T) variant), choline acetyltransferase, and the N-methyl-d-aspartate receptor subunit NR2A. This was confirmed, in the example of AChE, to arise from P2Y(1) dependent stimulation of a human ACHE gene promoter. That involved activation of the transcription factor Elk-1; mutagenesis of the ACHE promoter revealed that Elk-1 binding at its specific responsive elements in that promoter was induced by P2Y(1) receptor activation. The combined findings reveal that ATP, via its P2Y(1) receptor, can act trophically in brain neurons to regulate the gene expression of direct effectors of synaptic transmission. PMID- 20847061 TI - Imitation of alcohol consumption in same-sex and other-sex dyads. AB - AIM: Being exposed to other people's drinking behavior has been demonstrated to influence individual's drinking levels. Imitation of alcohol consumption has mainly been investigated among same-sex drinking partners. This study examined whether imitation of alcohol consumption differs when people drink with same-sex or other-sex partners. METHOD: To test the imitation effects, a two (drinking condition: alcohol versus no alcohol) by two (sex constellation of dyad: same-sex versus other-sex) mixed between-within subject design was used. In two separate sessions situated in a naturalistic drinking setting (i.e., a bar laboratory), 66 participants were exposed to a same-sex and an other-sex model (i.e., a confederate) who consumed either alcoholic or non-alcoholic beverages. We expected that men would imitate more when drinking with women and men, and that women would imitate less when drinking with men. RESULTS: Imitation of alcohol consumption did not differ when participants were drinking with same-sex partners compared with other-sex partners. No gender differences in imitation were found. CONCLUSION: Imitation of alcohol consumption can be generalized to situations in which people drink with other-sex partners. Men and women seem to imitate regardless of their drinking partner's sex. PMID- 20847062 TI - Mortality for alcohol-related harm by country of birth in Scotland, 2000-2004: potential lessons for prevention. AB - AIMS: Deaths caused by alcohol have increased in the UK, and Scotland in particular, but the change in the rates of alcohol-related deaths for migrants are uncertain, and could yield insights for the general population. METHODS: Alcohol-related mortality in immigrants among Scotland's residents was assessed using 2001 census data and mortality data from 2000 to 2004. RESULTS: Mortality from direct alcohol-related causes accounted for nearly 1500 deaths per year in Scotland. Age-standardized mortality ratios were comparatively low for people born in Pakistan, other parts of the UK (largely England and Wales) and those from elsewhere in the world. CONCLUSIONS: Scotland's propensity to alcohol related deaths is not shared by all its residents. Studying such variations in more depth could yield lessons for prevention. PMID- 20847064 TI - Minimally-invasive coronary surgery in dextrocardia and situs inversus totalis. AB - Dextrocardia associated to situs inversus totalis is a rare congenital conditions (prevalence of 1:10,000) in which the organs are located in a symmetric or mirror position in the opposite side of the body. These individuals usually have a normal life expectancy and the same propensity to develop ischaemic coronary disease as the general population. We report a case of a 59-year-old female patient with a single-vessel obstructive coronary disease successfully resolved via a right anterior small thoracotomy on a beating-heart using the right internal thoracic artery as a conduit for 'left' anterior descending coronary artery. PMID- 20847063 TI - Superior mesenteric artery branch--jejunal artery aneurysm. AB - Visceral artery aneurysm (VAA) is a relatively uncommon disorder and it shows some vague symptoms. Therefore, the clinical diagnosis is difficult and these aneurysms are discovered and diagnosed only after rupture in many cases. This case report describes the history of a woman who had a superior mesenteric artery (SMA) branch aneurysm. A 62-year-old woman presented with fatigue and moderate to severe epigastric and mid-back pain. A computed tomography of the abdomen and pelvis demonstrated a partially thrombosed aneurysm (38*40 mm) rising from the jejunal branch of the SMA. The aneurysm which contains mural thrombus is resected, and a saphenous vein graft interposition is performed between the ends of the same jejuno-jejunal artery. The patient's recovery was unremarkable, and she was discharged on postoperative day 7. Rapid diagnosis, localization, and surgical or endovascular interventions are necessary to avoid devastating consequences in VAAs. Saphenous vein graft interposition is a good choice for surgical intervention for patients not suitable for endovascular treatment. PMID- 20847065 TI - Myocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: a randomised controlled trial. AB - The purpose of this study was to test, whether the late phase of remote ischaemic preconditioning (L-RIPC) improves myocardial protection in coronary artery bypass grafting (CABG) with cold-crystalloid cardioplegia and whether preoperative tramadol modifies myocardial ischaemia-reperfusion injury using the same group of patients in a single-blinded randomized controlled study. One hundred and one adult patients were randomly assigned to either the L-RIPC, control or tramadol group. L-RIPC consisted of three five-minute cycles of upper limb ischaemia and three five-minute pauses using blood pressure cuff inflation 18 hours prior to the operation. Patients in the tramadol group received 200 mg tramadol retard at 19:00 hours, the day before the operation and at 06:00 hours. Serum troponin I levels were measured at eight, 16 and 24 hours after surgery. Myocardial samples for inducible and endothelial nitric oxide synthases (iNOS, eNOS) estimation were drawn twice: before and after cannulation for cardiopulmonary bypass from the auricle of the right atrium. We found that L-RIPC can reduce injury beyond the myocardial protection provided by cold-crystalloid cardioplegia, and tramadol worsened myocardial injury after CABG. Expressions of iNOS were increased in the control (significantly) and L-RIPC groups and dampened in the tramadol group. PMID- 20847066 TI - Combination technique of tumescent anesthesia during endovenous laser therapy of saphenous vein insufficiency. AB - OBJECTIVE: This study aimed at evaluating the efficiency of applying tumescent anesthesia before an ablation procedure and continuously during endovenous laser treatment (EVLT) (combined tumescent technique) of saphenous vein insufficiency to reduce the patients pain and discomfort. METHODS: Twenty-five patients with 31 duplex-confirmed great saphenous vein insufficiency underwent endovenous laser (940 nm) varicose vein treatment between December 2009 and April 2010. The patients were randomized in two groups. In group A (15 patients) tumescent anesthesia was used before the ablation procedure and in group B (10 patients) tumescent anesthesia was used before and continuously during the procedure. Patients were scheduled for a three-day examination after EVLT to assess the level of pain experienced. RESULTS: According to the statistic analysis we observed that the mean level of pain score for the patients given classical tumescent anesthesia showed a higher level (P=0.003) compared with the patients given tumescent anesthesia in the combined procedure. CONCLUSION: Combination technique of administering tumescent anesthesia before ablation and continuously during the EVLT procedure may be an alternative way to reduce the patient's peroperative pain and discomfort. PMID- 20847067 TI - Quality-of-life in octogenarians one year after aortic valve replacement with or without coronary artery bypass surgery. AB - The increasing number of interventions for percutaneous aortic valve replacement (AVR) justify a renewed evaluation of one-year survival rates after open AVR with and without coronary artery bypass in octogenarians. Risk factors influencing mortality are compared, and the patients' quality-of-life (QoL) after one year is assessed. One hundred and fifty-four patients (102 females, 52 males) aged on average 82.9+/-2.5 years, who had undergone open bioprosthetic AVR with (n=80) and without (n=74) coronary artery bypass grafting (CABG) between January 2005 and December 2007 were reviewed retrospectively. Risk factors for mortality were analyzed. The patient's QoL after one year was evaluated by administering the Seattle Angina Questionnaire on the telephone. The mean in-hospital mortality rate was 7.8%. The 12-month survival rate was 81.8%. Preoperative risk factors revealed no difference between survivors and non-survivors: renal insufficiency, chronic obstructive pulmonary disease (COPD), diabetes, cerebrovascular disease (CVD), peripheral vascular disease, logistic EuroSCORE and concomitant CABG. Assessment of QoL revealed a substantial improvement of physical fitness in all 126 patients. Surgery in the aortic valve without CABG is associated with a good outcome. The improvement in QoL after one year supports the decision to operate on patients older than 80 years of age. PMID- 20847068 TI - Combined coronary artery bypass grafting and aortic valve replacement with minimal extracorporeal closed circuit circulation versus standard cardiopulmonary bypass. AB - Isolated aortic valve replacement (AVR) or coronary artery bypass grafting (CABG) using minimized extracorporeal circulation (MECC) has been shown to have less deleterious effects than standard cardiopulmonary bypass (CPB). In this prospective cohort study, we evaluated and compared clinical results of combined AVR with CABG using MECC. We prospectively collected preoperative, intraoperative, postoperative and follow-up data of 65 patients who underwent combined AVR with CABG using MECC and compared these with 135 patients undergoing combined AVR with CABG using standard CPB. No significant differences were seen in patients demographic characteristics or intraoperative data. Patients in the MECC group experienced a smaller preoperative haemoglobin drop (4.5+/-0.8 g/dl vs. 5.0+/-0.5 g/dl, P=0.002) resulting in higher haemoglobin at discharge (11.3+/ 1.3 g/dl vs. 10.8+/-1.1 g/dl, P=0.03). They had decreased blood products requirements (P=0.004) compared to patients in the standard CPB group. No differences were noted in pulmonary complications, neurological events or mortality. We present for the first time data showing that combined AVR with CABG using MECC is feasible and provides better clinical results compared to standard CPB with regard to blood products requirements, without compromising operative morbidity or mortality. PMID- 20847069 TI - Cardiac thrombus associated with Mycoplasma pneumoniae infection. AB - Thrombosis is a very rare complication of Mycoplasma pneumoniae infection. We report the case of a previously healthy nine-year-old boy with cardiac thrombus in the right ventricle associated with M. pneumoniae pneumonia. This cardiac thrombus was detected eight days after the onset of respiratory symptoms. The mechanism underlying thrombosis may be related to autoimmune modulations and was attributable to the production of transient antiphospholipid antibodies. PMID- 20847070 TI - Late isolated metastasis of renal cell carcinoma in the left ventricular myocardium. AB - Metastatic renal cell carcinoma (RCC) involving the heart is a rare phenomenon. We present a case of late metastasis of RCC in the left ventricular myocardium, 23 years after the patient had a nephrectomy for 'organ-confined' primary disease. Open surgical biopsy was required to confirm the diagnosis in this patient. Surgical management or resection of such a metastasis depends on the location and relationship of the tumor to the important local structures. Targeted systemic therapy may be useful for patients in whom complete resection of tumor is not possible. PMID- 20847071 TI - Colchicine as an effective treatment for postpericardiotomy syndrome following a lung lobectomy. AB - Postpericardiotomy syndrome (PPS) is a frequent complication of various cardiac procedures that involve entry into the pericardium, but rarely occurs after pulmonary surgery because the pericardium is usually preserved during this procedure. The standard treatment for PPS is the administration of non-steroidal anti-inflammatory drugs (NSAIDs). Recent studies have indicated however, that colchicine may be useful for the treatment and prevention of this syndrome. Here, we describe the successful use of colchicine to treat PPS in a lung cancer patient who developed this complication following a lung lobectomy. A 64-year-old woman with a stage IA lung tumor underwent a left upper lobectomy with a mediastinal lymph node dissection. Severe precordial pain occurred 10 days after surgery, and accumulations of pericardial and pleural fluid were revealed by chest X-ray, echocardiogram, and chest computed tomography. These symptoms were not alleviated by antibiotics, thoracic cavity drainage, or NSAIDs. However, the administration of colchicine (initial dose of 1.0 mg and maintenance dose of 0.5 mg daily for three months) in combination with NSAIDs resolved these symptoms immediately after the first dosage. In addition, the patient remains free of any recurrent pericarditis at six months after this episode. PMID- 20847072 TI - Temporary epicardial pacing wire removal: is it an innocuous procedure? AB - The safety and efficacy of temporary pericardial pacing wires have been accepted and their use is common after cardiac operations. Complications related to pacing wire removal are unusual but it can be serious and even catastrophic. We report an unusual case of bleeding due the laceration and rent created in the saphenous vein graft wall by the metallic tip of the pacing wire at the time of pacing wire removal. PMID- 20847073 TI - Impact of aerobic exercise capacity and procedure-related factors in lung cancer surgery. AB - Over the past decades, major progress in patient selection, surgical techniques and anaesthetic management have largely contributed to improved outcome in lung cancer surgery. The purpose of this study was to identify predictors of post operative cardiopulmonary morbidity in patients with a forced expiratory volume in 1 s <80% predicted, who underwent cardiopulmonary exercise testing (CPET). In this observational study, 210 consecutive patients with lung cancer underwent CPET with completed data over a 9-yr period (2001-2009). Cardiopulmonary complications occurred in 46 (22%) patients, including four (1.9%) deaths. On logistic regression analysis, peak oxygen uptake (peak V'(O2) and anaesthesia duration were independent risk factors of both cardiovascular and pulmonary complications; age and the extent of lung resection were additional predictors of cardiovascular complications, whereas tidal volume during one-lung ventilation was a predictor of pulmonary complications. Compared with patients with peak V'(O2) >17 mL.kg-1.min-1, those with a peak V'(O2) <10 mL.kg-1.min-1 had a four fold higher incidence of cardiac and pulmonary morbidity. Our data support the use of pre-operative CPET and the application of an intra-operative protective ventilation strategy. Further studies should evaluate whether pre-operative physical training can improve post-operative outcome. PMID- 20847074 TI - Treatment of tuberculosis: update 2010. AB - Currently, the standard short-course chemotherapy for tuberculosis comprises a 6 month regimen, with a four-drug intensive phase and a two-drug continuation phase. Alternative chemotherapy using more costly and toxic drugs, often for prolonged durations generally >18 months, is required for multidrug-resistant and extensively drug-resistant tuberculosis. Directly observed treatment, as part of a holistic care programme, is a cost-effective strategy to ensure high treatment success and curtail development of drug resistance in tuberculosis. New antituberculosis drugs are urgently needed to improve the present standard short course and alternative chemotherapies, by shortening administration durations and increasing cure rates, through the greater potency of these agents. At the same time, the role of adjunctive surgery for drug-resistant tuberculosis has to be better defined. Immunotherapy might improve treatment outcomes of both drug susceptible and -resistant tuberculosis, and warrants further exploration. PMID- 20847076 TI - Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes. AB - The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03 1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes. PMID- 20847075 TI - Determinants of prescription and choice of empirical therapy for hospital acquired and ventilator-associated pneumonia. AB - The objectives of this study were to assess the determinants of empirical antibiotic choice, prescription patterns and outcomes in patients with hospital acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) in Europe. We performed a prospective, observational cohort study in 27 intensive care units (ICUs) from nine European countries. 100 consecutive patients on mechanical ventilation for HAP, on mechanical ventilation>48 h or with VAP were enrolled per ICU. Admission category, sickness severity and Acinetobacter spp. prevalence>10% in pneumonia episodes determined antibiotic empirical choice. Trauma patients were more often prescribed non-anti-Pseudomonas cephalosporins (OR 2.68, 95% CI 1.50-4.78). Surgical patients received less aminoglycosides (OR 0.26, 95% CI 0.14 0.49). A significant correlation (p<0.01) was found between Simplified Acute Physiology Score II score and carbapenem prescription. Basal Acinetobacter spp. prevalence>10% dramatically increased the prescription of carbapenems (OR 3.5, 95% CI 2.0-6.1) and colistin (OR 115.7, 95% CI 6.9-1,930.9). Appropriate empirical antibiotics decreased ICU length of stay by 6 days (26.3+/-19.8 days versus 32.8+/-29.4 days; p=0.04). The antibiotics that were prescribed most were carbapenems, piperacillin/tazobactam and quinolones. Median (interquartile range) duration of antibiotic therapy was 9 (6-12) days. Anti-methicillin-resistant Staphylococcus aureus agents were prescribed in 38.4% of VAP episodes. Admission category, sickness severity and basal Acinetobacter prevalence>10% in pneumonia episodes were the major determinants of antibiotic choice at the bedside. Across Europe, carbapenems were the antibiotic most prescribed for HAP/VAP. PMID- 20847077 TI - Cystic fibrosis and survival to 40 years: a study of cystic fibrosis transmembrane conductance regulator function. AB - Significant survival heterogeneity exists in cystic fibrosis. Our aim was to determine whether residual function of the cystic fibrosis transmembrane conductance regulator (CFTR) is present in long-term survivors with severe mutations. Nasal potential difference (PD) and sweat chloride were measured in 34 long-term survivors (aged >= 40 yrs) and compared with young patients (18-23 yrs) with severe (n = 30) and mild (n = 31) lung disease. Baseline PD was not significantly different across the three groups (long-term survivors, -42.8 (range -71.0- -20.5) mV; young/mild, -40.5 (-58.8- -19.5) mV; young/severe,-46.3 (-74.0- -20.0) mV). Response to amiloride (DeltaAmil) was significantly different across the three groups (p = 0.01); long-term survivors had values (27.8 (range 8.5-46) mV) which were not different to either young group, but the young/severe group had significantly higher values (29.5 (11-47) mV) than those in the young/mild group (22.0 (7-39) mV; p<0.01). Baseline PD and DeltaAmil were associated with forced expiratory volume in 1 s (FEV1) (co-efficient (95% CI) 0.13 (-0.23- -0.03); p = 0.009 and -0.12 (-0.20- -0.04); p = 0.003, respectively). Sweat chloride was lowest (p <0.05) in the young/severe group (93.5 (74-111) mmol.L-1 versus 98.8 (76.5-116.0) mmol.L-1; long-term survivors; and 99.5 (80.0-113.5) mmol.L-1; young/mild). Delta Amil is associated with FEV1 but our findings indicate that long-term survival cannot be explained by residual CFTR function when measurements are taken in later life. PMID- 20847078 TI - Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea. AB - Inflammation may contribute to upper airway pathophysiology in obstructive sleep apnoea (OSA). Our objective was to compare upper airway pro-inflammatory cytokine expression, oxidative stress and connective tissue deposition in severe (n = 25) versus mild (n = 17) OSA patients. Upper airway surgical specimens were separated by predominance of either mucosal or muscle tissue. Expression levels of interleukin (IL)-1alpha, IL-6, interferon-gamma, RANTES (regulated on activation, normal T-cell expressed and secreted), transforming growth factor (TGF)-beta and l-selectin were measured by ribonuclease protection assay. Oxidative stress was assessed via protein carbonyl group detection by immunoblotting. Histochemistry was employed for immunolocalisation of selected cytokines and connective tissue morphometry. In the severe OSA group, expression of IL-1alpha, IL-6 and TGF-beta was significantly higher in mucosa-predominant tissues, whereas in muscle predominant specimens, RANTES expression was greater in severe OSA. Increased protein carbonylation was observed in severe OSA within both mucosal and muscle compartments. Immunohistochemistry localised TGF-beta to submucosal and perimuscular inflammatory cells, while IL-6 was primarily localised to myocytes. Consistent with the pro-fibrotic cytokine profile observed in mucosa-predominant tissue, morphometric analysis revealed greater submucosal and perimuscular connective tissue in severe OSA subjects. There is increased pro-inflammatory and pro-fibrotic cytokine expression, oxidative stress, and connective tissue deposition in upper airway tissues from severe versus mild OSA patients. PMID- 20847079 TI - Pseudomonas aeruginosa accentuates epithelial-to-mesenchymal transition in the airway. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated in the dysregulated epithelial wound repair that contributes to obliterative bronchiolitis (OB) after lung transplantation. Acquisition of Pseudomonas aeruginosa in the transplanted airway has been shown to be a risk factor for the development of OB. We investigated the potential of P. aeruginosa to drive EMT in primary bronchial epithelial cells (PBECs) isolated from lung transplant recipients. Changes in the expression of epithelial and mesenchymal markers was assessed in cells challenged with clinical isolates of P. aeruginosa or co cultured with P. aeruginosa-activated monocytic cells (THP-1) in the presence or absence of transforming growth factor (TGF)-beta1. P. aeruginosa did not drive or accentuate TGF-beta1-driven EMT directly. Co-culturing P. aeruginosa-activated THP-1 cells with PBECs did not drive EMT. However, co-culturing P. aeruginosa activated THP-1 cells with PBECs significantly accentuated TGF-beta1-driven EMT. P. aeruginosa, via the activation of monocytic cells, can accentuate TGF-beta1 driven EMT. These in vitro observations may help explain the in vivo clinical observation of a link between acquisition of P. aeruginosa and an increased risk of developing OB. PMID- 20847080 TI - Interferon-gamma release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. AB - Interferon-gamma release assays (IGRAs) are now established for the immunodiagnosis of latent infection with Mycobacterium tuberculosis in many countries. However, the role of IGRAs for the diagnosis of active tuberculosis (TB) remains unclear. Following preferred reporting items for systematic reviews and meta-analyses (PRISMA) and quality assessment of diagnostic accuracy studies (QUADAS) guidelines, we searched PubMed, EMBASE and Cochrane databases to identify studies published in January 2001-November 2009 that evaluated the evidence of using QuantiFERON-TB(r) Gold in-tube (QFT-G-IT) and T-SPOT.TB(r) directly on blood or extrasanguinous specimens for the diagnosis of active TB. The literature search yielded 844 studies and 27 met the inclusion criteria. In blood and extrasanguinous fluids, the pooled sensitivity for the diagnosis of active TB was 80% (95% CI 75-84%) and 48% (95% CI 39-58%) for QFT-G-IT, and 81% (95% CI 78-84%) and 88% (confirmed and unconfirmed cases) (95% CI 82-92%) for T SPOT.TB(r), respectively. In blood and extrasanguinous fluids, the pooled specificity was 79% (95% CI 75-82%) and 82% (95% CI 70-91%) for QFT-G-IT, and 59% (95% CI 56-62%) and 82% (95% CI 78-86%) for T-SPOT.TB(r), respectively. Although the diagnostic sensitivities of both IGRAs were higher than that of tuberculin skin tests, it was still not high enough to use as a rule out test for TB. Positive evidence for the use of IGRAs in compartments other than blood will require more independent and carefully designed prospective studies. PMID- 20847081 TI - Early treatment of obstructive apnoea and stroke outcome: a randomised controlled trial. AB - The aim of the present study was to assess the impact of nasal continuous positive airway pressure (nCPAP) in ischaemic stroke patients followed for 2 yrs. Stroke patients with an apnoea-hypopnoea index >= 20 events.h-1 were randomised to early nCPAP (n = 71; 3-6 days after stroke onset) or conventional treatment (n = 69). The Barthel Index, Canadian Scale, Rankin Scale and Short Form-36 were measured at baseline, and at 1, 3, 12 and 24 months. The percentage of patients with neurological improvement 1 month after stroke was significantly higher in the nCPAP group (Rankin scale 90.9 versus 56.3% (p < 0.01); Canadian scale 88.2 versus 72.7% (p < 0.05)). The mean time until the appearance of cardiovascular events was longer in the nCPAP group (14.9 versus 7.9 months; p = 0.044), although cardiovascular event-free survival after 24 months was similar in both groups. The cardiovascular mortality rate was 0% in the nCPAP group and 4.3% in the control group (p = 0.161). Early use of nCPAP seems to accelerate neurological recovery and to delay the appearance of cardiovascular events, although an improvement in patients' survival or quality of life was not shown. PMID- 20847083 TI - Occipital nerve stimulation for chronic migraine--interpreting the ONSTIM feasibility trial. PMID- 20847084 TI - Characterization of consistent triggers of migraine with aura. AB - OBJECTIVE: The aim of the present study was to characterize perceived consistent triggers of migraine with aura (MA). METHOD: Questionnaires specifically designed to characterize various trigger factors were sent to 181 participants identified in an earlier study. All participants had formerly identified at least one factor that often or always triggered an MA attack. They only answered questions regarding this or these factor(s). RESULTS: The response rate to the questionnaire was 70% (126/179). A number of subtype triggers were mentioned by a high proportion of patients: too much work (under the stress category 54/64), reflected sunlight (under the light category 35/44), too little sleep (under the sleep category 19/24), red wine (under the alcohol category 20/22), passive smoking (under the smoke category 11/11), menstruation (under the menstruation or break from the pill category 12/14) and perfume (under the fumes/heavy scents category 12/15). Hormones, light and stress were reported to cause at least 50 % of MA attacks in 62%, 47% and 42% of participants, respectively. No participants reported alcohol to be the trigger of 50% or more of their attacks. In the groups of participants with "light", "fumes/heavy scents", "smoke" or "physical effort" as triggers, nearly all patients reported that an exposure time to the trigger of less than 3 hours (90-100% of patients) was necessary to trigger an attack and a latency to onset of attack of less than 3 hours (90-100% of patients). CONCLUSION: Our study has provided new knowledge about factors that in particular patients consistently trigger MA. In daily routine practice this information should be helpful in identifying factors to avoid. Patients with trigger factors that always or usually trigger attacks of MA will be highly useful for imaging and other experimental studies. PMID- 20847082 TI - Neuralized1 causes apoptosis and downregulates Notch target genes in medulloblastoma. AB - Neuralized (Neurl) is a highly conserved E3 ubiquitin ligase, which in Drosophila acts upon Notch ligands to regulate Notch pathway signaling. Human Neuralized1 (NEURL1) was investigated as a potential tumor suppressor in medulloblastoma (MB). The gene is located at 10q25.1, a region demonstrating frequent loss of heterozygosity in tumors. In addition, prior publications have shown that the Notch pathway is functional in a proportion of MB tumors and that Neurl1 is only expressed in differentiated cells in the developing cerebellum. In this study, NEURL1 expression was downregulated in MB compared with normal cerebellar tissue, with the lowest levels of expression in hedgehog-activated tumors. Control of gene expression by histone modification was implicated mechanistically; loss of 10q, sequence mutation, and promoter hypermethylation did not play major roles. NEURL1-transfected MB cell lines demonstrated decreased population growth, colony forming ability, tumor sphere formation, and xenograft growth compared with controls, and a significant increase in apoptosis was seen on cell cycle and cell death analysis. Notch pathway inhibition occurred on the exogenous expression of NEURL1, as shown by decreased expression of the Notch ligand, Jagged1, and the target genes, HES1 and HEY1. From these studies, we conclude that NEURL1 is a candidate tumor suppressor in MB, at least in part through its effects on the Notch pathway. PMID- 20847085 TI - Ciliary ganglioplegic migraine: migraine-related prolonged mydriasis. AB - BACKGROUND: Transient, unilateral mydriasis has been reported in migraine patients, and this has been regarded as a possible co-morbidity between migraine and Adie's tonic pupil. Mydriasis that outlasts the duration of migraine attacks is rare. METHODS: Through an eight-year period we have studied all patients referred to our neurological clinic because of migraine attack with mydriasis. All the patients underwent thorough neurologic and ophthalmologic examinations including MRI of the brain and testing of the pupil response to ocular instillation of dilute pilocarpine (0.125%). RESULTS: Seven women and two men, with a mean age of 33.8 +/- 12.3 years (range: 19-52) were included. The patients presented during one hemicranial migraine attack with an ipsilateral mydriasis that persisted for a mean of three months, while migraine headaches remained with their typical episodic course. In all the patients a cholinergic supersensitivity in the symptomatic pupil was demonstrated, thus pointing to a dysfunction of the ipsilateral ganglionic parasympathetic fibers. CONCLUSIONS: Synchronous co localization of the features suggests a pathogenic link between the pupil dysfunction and migraine, rather than a simultaneous coexistence of two independent disorders. Likely explanations include a latent Adie's pupil that could have been triggered during a particular migraine attack; a ciliar ganglionic lesion/dysfunction produced by the migrainous process; an ophthalmoplegic migraine with selective parasympathycoparesis; or an episodic ciliar ganglionitis with migrainous features. Ciliary ganglioplegic migraine is proposed as a nominal term pointing to the possible anatomic source of the migrainous-related pupil dysfunction; the pathogenesis remains unknown. PMID- 20847086 TI - Treatment of concurrent metastatic renal cell carcinoma and chronic myelogenous leukemia--easier said than done? A case report. AB - Treating two active malignancies concurrently can be exceedingly difficult. Complications can occur from the different treatment regimens, especially if they share common targets, and the progressing diseases can make managing treatment side-effects even more challenging. We report a case of a patient with coexisting CML and mRCC who progressed on multiple lines of mRCC therapy while experiencing significant dose limiting side-effects. PMID- 20847087 TI - Individual breathlessness trajectories do not match summary trajectories in advanced cancer and chronic obstructive pulmonary disease: results from a longitudinal study. AB - Breathlessness is a distressing symptom in advanced disease. Little is known about the trajectories of this symptom over time and towards death. This study aimed to describe and compare the summary and individual trajectories of breathlessness and overall symptom burden over time and towards the end of life following patients with advanced cancer or severe chronic obstructive pulmonary disease (COPD) in inpatient and outpatient health care settings in Germany. The modified Borg Scale, Memorial Symptom Assessment Scale Short Form and Palliative Outcome Scale were used as outcome measures. Data were collected at baseline and then monthly over six months or until death. Forty-nine cancer and 60 COPD patients were included. Both groups had similar demographics. Thirty out of the 49 cancer and 6/60 COPD patients died, 7/49 cancer and 20/60 COPD patients dropped out due to physical deterioration or questionnaire fatigue. In cancer patients, breathlessness increased towards death. In COPD patients, breathlessness increased over time. Twenty-one cancer and 43 COPD patients provided data for individual breathlessness trajectories. These revealed wide individual variations with four different patterns: fluctuation, increasing, stable and decreasing breathlessness. Symptom trajectories on the population level reflecting the whole group mask individual variation, which is reflected in distinct symptom trajectories with different patterns. PMID- 20847088 TI - Can the global uptake of palliative care innovations be improved? Insights from a bibliometric analysis of the Edmonton Symptom Assessment System. AB - Clinical research is undertaken to improve care for palliative patients, but little is known about how to support the broad uptake of resultant innovations. The objectives of this paper are to: (1) explore the uptake of the Edmonton Symptom Assessment System throughout the global palliative care community through the lens of a bibliometric review - a research method that maps out the journey of new knowledge uptake by evaluating where key articles are cited in published literature; (2) construct hypotheses on attributes of the global community of palliative care learners; and (3) make inferences on approaches that could improve knowledge transfer. While preliminary, results of the study suggest several specific approaches that could support widespread uptake of innovations in palliative care: targeting publication in high impact, international journals; explicitly focusing on how the innovation is applied to best practice; encouraging additional research to expand on early studies; consciously targeting key professional groups and organizations to promote discussion in the grey literature; and early translation and promotion within multiple languages. PMID- 20847089 TI - Challenges and achievements in the development of spiritual-care training and implementation in Israel. AB - In recent years, pioneering spiritual-care training programs and services have been developed in Israel. This paper examines the implementation of the training programs and the challenge of integrating program graduates in the healthcare services. The information was collected through in-depth interviews with 12 students and graduates and the directors of the three training programs. All the interviews were transcribed in full and analyzed using qualitative study methods. The interviewees emphasized the importance of practical experience, although many of them encountered some degree of antagonism during their training or placement. Continuation of personal counseling and supervision after the conclusion of the program is also essential. Some were worried that they would not find work or were concerned about negotiations with potential employers. Evidently, the implementation of spiritual-care education must continue apace and careful consideration be given to optimizing its acceptance by the establishment. PMID- 20847090 TI - The molecular basis of recurrent pregnancy loss: impaired natural embryo selection. AB - Recurrent pregnancy loss (RPL) is a common and distressing disorder. Chromosomal errors in the embryo are the single most common cause, whereas uterine factors are invariably invoked to explain non-chromosomal miscarriages. These uterine factors are, however, poorly defined. The ability of a conceptus to implant in the endometrium is normally restricted to a few days in the menstrual cycle. A limited 'window of implantation' ensures coordinated embryonic and endometrial development, thereby minimizing the risk of late implantation of compromised embryos. In this paper, we review emerging evidence, indicating that RPL is associated with impaired differentiation of endometrial stromal cells into specialized decidual cells. From a functional perspective, this differentiation process, termed decidualization, is not only critical for placental development but also signals the end of the implantation window and bestows on the endometrium the ability to recognize, respond to and eliminate implanting compromised embryos. Thus, we propose that spontaneous decidualization of the human endometrium, which inevitably causes menstrual shedding in the absence of a viable conceptus, serves as functional 'window for natural embryo selection'. Conversely, impaired decidualization predisposes to late implantation, negates embryo quality control and causes early placental failure, regardless of the embryonic karyotype. This pathological pathway also explains the common observation that many RPL patients seem exceptionally fertile, often conceiving within one or two cycles. Thus, as the clinical correlate of inappropriate uterine receptivity, 'superfertility' should be considered as a genuine reproductive disorder that requires targeted intervention. PMID- 20847091 TI - DASH-style diet and 24-hour urine composition. AB - BACKGROUND AND OBJECTIVES: We previously observed associations between a Dietary Approaches to Stop Hypertension (DASH)-style diet and large reductions in kidney stone risk. This study examined associations between a DASH-style diet and 24 hour excretions of urinary lithogenic factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied 3426 participants with and without nephrolithiasis in the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Studies (NHS) I and II. A dietary DASH score was based on seven components: high intake of fruits, vegetables, nuts and legumes, dairy products, and whole grains and low intake of sweetened beverages and red and processed meats. We used analysis of covariance to adjust for age, stone history, body size, and other factors. RESULTS: Comparing participants in the highest to lowest quintiles of DASH score, multivariate-adjusted urinary calcium excretion was 3% greater in HPFS (P trend 0.12), 10% greater in NHS I (P trend <0.01), and 12% greater in NHS II (P trend 0.05). Urinary oxalate was 4% to 18% greater (P trend all <=0.03), urinary citrate was 11% to 16% greater (P trend all <0.01), and urinary volume was 16% to 32% greater (P trend all <0.001). Higher DASH score was associated with higher urine potassium, magnesium, phosphate, and pH, and lower relative supersaturations (RSS) of calcium oxalate (women only) and uric acid. CONCLUSIONS: A DASH-style diet may reduce stone risk by increasing urinary citrate and volume. The small associations between higher DASH score and lower RSS suggest unidentified stone inhibitors in dairy products and/or plants. PMID- 20847092 TI - Daily corticosteroids reduce infection-associated relapses in frequently relapsing nephrotic syndrome: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: Relapses of nephrotic syndrome often follow minor infections, commonly of the upper respiratory tract. Daily administration of maintenance prednisolone during intercurrent infections was examined to determine whether the treatment reduces relapse rates in children with frequently relapsing nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a randomized controlled trial (nonblind, parallel group, tertiary-care hospital), 100 patients with idiopathic, frequently relapsing nephrotic syndrome eligible for therapy with prolonged low-dose, alternate-day prednisolone with or without levamisole were randomized to either receive their usual dose of alternate-day prednisolone daily for 7 days during intercurrent infections (intervention group) or continue alternate-day prednisolone (controls). Primary outcome was assessed by comparing the rates of infection-associated relapses at 12-month follow-up. Secondary outcomes were the frequency of infections and the cumulative amount of prednisolone received in both groups. RESULTS: Patients in the intervention group showed significantly lower infection-associated (rate difference, 0.7 episodes/patient per year; 95% confidence intervals [CI] 0.3, 1.1) and lower total relapse rates (0.9 episodes/patient per year, 95% CI 0.4, 1.4) without increase in steroid toxicity. Poisson regression, adjusted for occurrence of infections, showed that daily administration of prednisolone during infections independently resulted in 59% reduction in frequency of relapses (rate ratio, 0.41; 95% CI 0.3, 0.6). For every six patients receiving this intervention, one showed a reduction of relapse frequency to less than three per year. CONCLUSIONS: Daily administration of maintenance doses of prednisolone, during intercurrent infections, significantly reduces relapse rates and the proportion of children with frequently relapsing nephrotic syndrome. PMID- 20847093 TI - Cost-related immunosuppressive medication nonadherence among kidney transplant recipients. AB - BACKGROUND AND OBJECTIVES: Immunosuppressive medications are essential in preventing kidney transplant rejection. Continuous insurance coverage for outpatient immunosuppressive medications remains a major issue. The objective of this study was to establish the prevalence and consequences of cost-related immunosuppressive medication nonadherence. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A descriptive survey of all U.S. kidney transplant programs (n = 254) was conducted. The response rate for the survey exceeded 99%. The main outcome measures included the following: transplant recipient concerns related to medication costs, ability to pay for medications, medication nonadherence and its consequences, and failure of transplant centers to place patients on the transplant waiting list. RESULTS: Continuous insurance coverage for outpatient immunosuppressive drugs is a problem having potentially grave consequences for the majority of kidney transplant recipients. More than 70% of kidney transplant programs report that their patients have an extremely or very serious problem paying for their medications. About 47% of the programs indicate that more than 40% of their patients are having difficulty paying for their immunosuppressive medications. In turn, 68% of the programs report deaths and graft losses attributable to cost-related immunosuppressive medication nonadherence. Some of the problems identified here are more significant for adult than pediatric patients. CONCLUSIONS: The prevalence and consequences of cost-related immunosuppressive medication nonadherence among kidney transplant recipients have now been documented. The results presented here should serve as the necessary impetus for the development of health care policies supporting Medicare coverage of immunosuppressive medications for the life of the transplanted kidney. PMID- 20847094 TI - Effect of circulating soluble receptor for advanced glycation end products (sRAGE) and the proinflammatory RAGE ligand (EN-RAGE, S100A12) on mortality in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: The soluble receptor of advanced glycation end products (sRAGE) may exert anti-inflammatory protective roles on the vasculature. In contrast, the RAGE ligand S100A12 (also known as EN-RAGE) contributes to inflammation and the development of atherosclerosis in animal models. Whether alterations at this level contribute to the increased mortality observed in patients on dialysis is currently unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective study including 184 prevalent hemodialysis patients and 50 healthy controls matched for age and gender. Plasma concentrations of S100A12 and sRAGE were studied in relation to risk profile and mortality after a median follow-up period of 41 months. RESULTS: S100A12 and sRAGE levels were significantly elevated in hemodialysis patients compared with healthy controls. S100A12 had a strong positive correlation with C-reactive protein and IL-6, whereas sRAGE negatively associated with C-reactive protein. S100A12, but not sRAGE, was independently and positively associated with clinical cardiovascular disease (CVD). During follow-up, 85 (33 cardiovascular-related) deaths occurred. Whereas sRAGE did not predict mortality, S100A12 was associated with both all cause (per log(10) ng/ml hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.18 to 3.15) and CVD-related (HR 3.23, 95% CI 1.48 to 7.01) mortality, even after adjustment for age, sex, vintage, and comorbidities. Further adjustment for inflammation made the predictive value of S100A12 disappear for all-cause mortality, but still persisted in CVD-related mortality. CONCLUSIONS: Circulating S100A12 and sRAGE are both elevated in hemodialysis patients. However, only S100A12 associates with mortality, partly explained by its links with inflammation. PMID- 20847096 TI - Profiling live kidney donors in America: cause for optimism and for concern. PMID- 20847095 TI - Determinants and functional significance of renal parenchymal volume in adults. AB - BACKGROUND AND OBJECTIVES: The significance of renal parenchymal volume and the factors that influence it are poorly understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Renal parenchymal volume (RPV) was measured on contrast-enhanced CT scans after exclusion of sinus fat and vessels in 224 healthy subjects evaluated as kidney donors and in a separate cohort of 22 severely obese individuals before and after 6 months of weight loss. GFR was measured by iohexol clearance in 76 of the transplant donors. RPV was correlated with age, GFR, and various anthropometric parameters. RESULTS: In potential transplant donors, RPV correlated with body surface area (BSA; r = 0.68) and was 7% larger in men but did not vary with age or race. Gender and body size were independent determinants of RPV. RPV correlated well with GFR (r = 0.62) and accounted for almost all of the variability in a model of GFR that included age, race, gender, and body surface area. GFR correlated more strongly with RPV than with creatinine-based equations. The same relationship between RPV and BSA was observed in obesity, and RPV decreased with weight loss. CONCLUSIONS: In healthy adults younger than 65 years, renal parenchymal volume is governed by body size and gender but not age or race and is strongly correlated with GFR. This indicates that renal parenchymal volume varies to meet metabolic demand and is closely linked to renal function. PMID- 20847097 TI - FGF23: fashion or physiology? PMID- 20847098 TI - A TSPO-related protein localizes to the early secretory pathway in Arabidopsis, but is targeted to mitochondria when expressed in yeast. AB - AtTSPO is a TspO/MBR domain-protein potentially involved in multiple stress regulation in Arabidopsis. As in most angiosperms, AtTSPO is encoded by a single, intronless gene. Expression of AtTSPO is tightly regulated both at the transcriptional and post-translational levels. It has been shown previously that overexpression of AtTSPO in plant cell can be detrimental, and the protein was detected in the endoplasmic reticulum (ER) and Golgi stacks, contrasting with previous findings and suggesting a mitochondrial subcellular localization for this protein. To ascertain these findings, immunocytochemistry and ABA induction were used to demonstrate that, in plant cells, physiological levels of AtTSPO colocalized with AtArf1, a mainly Golgi-localized protein in plant cells. In addition, fluorescent protein-tagged AtTSPO was targeted to the secretory pathway and did not colocalize with MitoTracker-labelled mitochondria. These results suggest that the polytopic membrane protein AtTSPO is cotranslationally targeted to the ER in plant cells and accumulates in the Trans-Golgi Network. Heterologous expression of AtTSPO in Saccharomyces cerevisiae, yeast devoid of TSPO-related protein, resulted in growth defects. However, subcellular fractionation and immunoprecipitation experiments showed that AtTSPO was targeted to mitochondria where it colocalized and interacted with the outer mitochondrial membrane porin VDAC1p, reminiscent of the subcellular localization and activity of mammalian translocator protein 18 kDa TSPO. The evolutionarily divergent AtTSPO appears therefore to be switching its sorting mode in a species-dependent manner, an uncommon peculiarity for a polytopic membrane protein in eukaryotic cells. These results are discussed in relation to the recognition and organelle targeting mechanisms of polytopic membrane proteins in eukaryotic cells. PMID- 20847099 TI - The identification of aluminium-resistance genes provides opportunities for enhancing crop production on acid soils. AB - Acid soils restrict plant production around the world. One of the major limitations to plant growth on acid soils is the prevalence of soluble aluminium (Al(3+)) ions which can inhibit root growth at micromolar concentrations. Species that show a natural resistance to Al(3+) toxicity perform better on acid soils. Our understanding of the physiology of Al(3+) resistance in important crop plants has increased greatly over the past 20 years, largely due to the application of genetics and molecular biology. Fourteen genes from seven different species are known to contribute to Al(3+) tolerance and resistance and several additional candidates have been identified. Some of these genes account for genotypic variation within species and others do not. One mechanism of resistance which has now been identified in a range of species relies on the efflux of organic anions such as malate and citrate from roots. The genes controlling this trait are members of the ALMT and MATE families which encode membrane proteins that facilitate organic anion efflux across the plasma membrane. Identification of these and other resistance genes provides opportunities for enhancing the Al(3+) resistance of plants by marker-assisted breeding and through biotechnology. Most attempts to enhance Al(3+) resistance in plants with genetic engineering have targeted genes that are induced by Al(3+) stress or that are likely to increase organic anion efflux. In the latter case, studies have either enhanced organic anion synthesis or increased organic anion transport across the plasma membrane. Recent developments in this area are summarized and the structure-function of the TaALMT1 protein from wheat is discussed. PMID- 20847100 TI - Ion transport in seminal and adventitious roots of cereals during O2 deficiency. AB - O(2) deficiency during soil waterlogging inhibits respiration in roots, resulting in severe energy deficits. Decreased root-to-shoot ratio and suboptimal functioning of the roots, result in nutrient deficiencies in the shoots. In N(2) flushed nutrient solutions, wheat seminal roots cease growth, while newly formed adventitious roots develop aerenchyma, and grow, albeit to a restricted length. When reliant on an internal O(2) supply from the shoot, nutrient uptake by adventitious roots was inhibited less than in seminal roots. Epidermal and cortical cells are likely to receive sufficient O(2) for oxidative phosphorylation and ion transport. By contrast, stelar hypoxia-anoxia can develop so that H(+)-ATPases in the xylem parenchyma would be inhibited; the diminished H(+) gradients and depolarized membranes inhibit secondary energy-dependent ion transport and channel conductances. Thus, the presence of two transport steps, one in the epidermis and cortex to accumulate ions from the solution and another in the stele to load ions into the xylem, is important for understanding the inhibitory effects of root zone hypoxia on nutrient acquisition and xylem transport, as well as the regulation of delivery to the shoots of unwanted ions, such as Na(+). Improvement of waterlogging tolerance in wheat will require an increased capacity for root growth, and more efficient root functioning, when in anaerobic media. PMID- 20847101 TI - OptCDR: a general computational method for the design of antibody complementarity determining regions for targeted epitope binding. AB - Antibodies are an important class of proteins with many biomedical and biotechnical applications. Although there are a plethora of experimental techniques geared toward their efficient production, there is a paucity of computational methods for their de novo design. OptCDR is a general computational method to design the binding portions of antibodies to have high specificity and affinity against any targeted epitope of an antigen. First, combinations of canonical structures for the antibody complementarity determining regions (CDRs) that are most likely to be able to favorably bind the antigen are selected. This is followed by the simultaneous refinement of the CDR structures' backbones and optimal amino acid selection for each position. OptCDR is applied to three computational test cases: a peptide from the capsid of hepatitis C, the hapten fluorescein and the protein vascular endothelial growth factor. The results demonstrate that OptCDR can efficiently generate diverse antibody libraries of a pre-specified size with promising antigen affinity potential as exemplified by computationally derived binding metrics. PMID- 20847102 TI - Efficient screening of fungal cellobiohydrolase class I enzymes for thermostabilizing sequence blocks by SCHEMA structure-guided recombination. AB - We describe an efficient SCHEMA recombination-based approach for screening homologous enzymes to identify stabilizing amino acid sequence blocks. This approach has been used to generate active, thermostable cellobiohydrolase class I (CBH I) enzymes from the 390 625 possible chimeras that can be made by swapping eight blocks from five fungal homologs. Constructing and characterizing the parent enzymes and just 32 'monomeras' containing a single block from a homologous enzyme allowed stability contributions to be assigned to 36 of the 40 blocks from which the CBH I chimeras can be assembled. Sixteen of 16 predicted thermostable chimeras, with an average of 37 mutations relative to the closest parent, are more thermostable than the most stable parent CBH I, from the thermophilic fungus Talaromyces emersonii. Whereas none of the parent CBH Is were active >65 degrees C, stable CBH I chimeras hydrolyzed solid cellulose at 70 degrees C. In addition to providing a collection of diverse, thermostable CBH Is that can complement previously described stable CBH II chimeras (Heinzelman et al., Proc. Natl Acad. Sci. USA 2009;106:5610-5615) in formulating application specific cellulase mixtures, the results show the utility of SCHEMA recombination for screening large swaths of natural enzyme sequence space for desirable amino acid blocks. PMID- 20847104 TI - Invited commentary: Gene X lifestyle interactions and complex disease traits- inferring cause and effect from observational data, sine qua non. AB - Observational epidemiology has made outstanding contributions to the discovery and elucidation of relations between lifestyle factors and common complex diseases such as type 2 diabetes. Recent major advances in the understanding of the human genetics of this disease have inspired studies that seek to determine whether the risk conveyed by bona fide risk loci might be modified by lifestyle factors such as diet composition and physical activity levels. A major challenge is to determine which of the reported findings are likely to represent causal interactions and which might be explained by other factors. The authors of this commentary use the Bradford-Hill criteria, a set of tried-and-tested guidelines for causal inference, to evaluate the findings of a recent study on interaction between variation at the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) locus and total energy intake with respect to prevalent metabolic syndrome and hemoglobin A1(c) levels in a cohort of 313 Japanese men. The current authors conclude that the study, while useful for hypothesis generation, does not provide overwhelming evidence of causal interactions. They overview ways in which future studies of gene * lifestyle interactions might overcome the limitations that motivated this conclusion. PMID- 20847105 TI - Effects of folic acid supplementation on serum folate and plasma homocysteine concentrations in older adults: a dose-response trial. AB - The authors' objective in this study was to estimate the changes in serum folate and homocysteine concentration that resulted from 6 weeks of supplementation with folic acid. A randomized, double-blind, placebo-controlled, dose-response trial with a parallel-group design was conducted. A total of 133 participants aged 60 90 years (70% female, 19% nonwhite) were assigned to receive 0, 100, 400, 1,000, or 2,000 MUg/day of folic acid for 6 weeks. Data were collected in the United States between June and September 1996. At baseline, median serum folate and plasma homocysteine concentrations were 5.7 ng/mL (interquartile range (25th-75th percentiles), 4.1-7.8) and 8.3 MUmol/L (interquartile range, 7.1-10.0), respectively. As the folic acid dose increased, serum folate levels increased (P trend < 0.001). There was no dose-response relation with homocysteine level among all participants. In analyses restricted to persons with the lowest serum folate concentration (<4.5 ng/mL) at baseline, there was a trend (P = 0.06) toward decreased homocysteine levels with increasing folic acid dose. In healthy, older adults with adequate folate status, folic acid supplementation is not beneficial for homocysteine reduction. However, for older adults with low serum folate levels, supplementation will improve folate status and may be beneficial for lowering homocysteine concentrations. PMID- 20847106 TI - Association of a cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) polymorphism with elevated hemoglobin A1(c) levels and the prevalence of metabolic syndrome in Japanese men: interaction with dietary energy intake. AB - Genome-wide association studies have identified the cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene as a novel risk factor for type 2 diabetes mellitus. Application of this genetic marker for prevention of type 2 diabetes and metabolic syndrome (MetS) in healthy populations has not yet been evaluated. The authors examined the effects of a CDKAL1 polymorphism (rs9465871) on metabolic phenotype and of gene-lifestyle (CDKAL1-energy intake) interaction on MetS in a cohort of apparently healthy Japanese men examined in 2003. The CC genotype of the CDKAL1 variant was associated with elevated glycosylated hemoglobin A1(c) (HbA1c) levels. The prevalence of MetS was 25.6% for CC and 16.3% for TT + CT (odds ratio = 2.18, 95% confidence interval: 1.06, 4.48; P = 0.035). When dietary energy intake was accounted for, the variant's effect on HbA1c was observed in the highest energy intake group (mean: CC, 5.6% (standard deviation, 1.7); TT + CT, 5.0% (standard deviation, 0.5); P = 0.025). In addition, the positive association between HbA1c and energy intake was stronger in subjects with the CC genotype than in subjects with TT + CT. These results suggest that the interaction between the CDKAL1 polymorphism and dietary energy intake influences the dysglycemic phenotype leading to MetS, possibly through impaired insulin secretion. The CDKAL1 polymorphism may be a marker for MetS in the Japanese population. PMID- 20847107 TI - An informational stair climbing intervention with greater effects in overweight pedestrians. AB - Previous interventions have successfully increased levels of stair climbing in public-access settings (e.g. malls). This study used robust methods to establish the magnitude of intervention effects among a specific target group-the overweight. Ascending stair/escalator users (N = 20 807) were observed in a mall. A 2-week baseline was followed by a 5-week intervention in which message banners, promoting stair climbing, were attached to the stair risers. Standardized silhouettes were used to code individuals as normal/overweight. Logistic regression analyses were conducted with stair/escalator choice as the outcome variable and weight status entered as a moderator alongside condition, gender, ethnicity and 'pedestrian traffic volume'. Overall, the intervention significantly increased the rate of stair climbing [odds ratio (OR) = 1.28, 95% confidence intervals (CI) = 1.08-1.53], with the effects sustained over 5 weeks. There were differential effects between weight categories, with greater increases in overweight (OR = 1.95, CI = 1.34-2.83) versus normal weight individuals (OR = 1.29, CI = 1.09-1.53). In conclusion, message prompts produced larger effects among overweight individuals, who could benefit most from stair climbing. The public health value of these interventions may, therefore, be greater than realized. The heightened effects among the overweight were likely due to the salience of the current message, which linked stair climbing with the target of weight control. PMID- 20847108 TI - Advancing biosocial pedagogy for HIV education. AB - This article develops the concept of biosocial pedagogy in HIV education for this era of expanding biomedical forms of HIV control. With reference to critical pedagogy and teaching and learning materials addressing HIV treatment and prevention, I explain how HIV education can problematize its own role in HIV control. I also discuss how educational practice can be informed by the ethical and political dilemmas that face people affected by HIV. I argue that through biosocially aware HIV pedagogy, individuals and communities can be assisted to act on the opportunities and drawbacks of biomedical HIV control. PMID- 20847109 TI - Coagulation and fibrinolysis in diabetes. AB - Atherothrombotic complications are the main cause of mortality in subjects with diabetes. Premature atherosclerosis, increased platelet reactivity and activation of coagulation factors with associated hypofibrinolysis all contribute to increased cardiovascular risk in this population. Blood clot formation represents the last step in the atherothrombotic process, and the structure of the fibrin network has a role in determining predisposition to cardiovascular disease. In this review, we discuss alterations in coagulation factor plasma levels and/or activity in diabetes and clarify their role in predisposition to cardiovascular events. The effect of diabetes on fibrin network structure/fibrinolysis is reviewed and potential mechanisms that modify clot properties are discussed. Finally, modulation of clotting potential by the various therapeutic agents used in diabetes is examined. Understanding the mechanisms by which diabetes influences the coagulation pathway will help to develop more effective treatment strategies to reduce thrombotic events in subjects with this condition. PMID- 20847110 TI - Awareness and filling-in of the human blind spot: linking psychophysics with retinal topography. AB - PURPOSE: To link psychophysical thresholds for blind spot awareness and filling in with early neural components that underpin these perceptions. METHODS: Blind spot dimensions were quantified, after which an intrinsic stimulus (i.e., a rectangular bar of varying length centered within the blind spot) was used to determine blind spot awareness and filling-in for five subjects. Histologic examination of six human retinas at 20-MUm intervals from the temporal and nasal neural rims of the optic nerve head out to 1040 MUm allowed the quantification of outer nuclear layer thickness, a direct correlate of photoreceptor density. RESULTS: Blind spot awareness was reported for bar extensions beyond 0.4 degrees to 0.8 degrees from the edge of the blind spot. Partial and total blind spot filling-in were reported between 1.1 degrees and 1.3 degrees and beyond 1.5 degrees , respectively. Histologic measures of ONL thickness were correlated with previously published data of photoreceptor spatial density to determine the percentage of photoreceptor density required to trigger a 75% probability response. Blind spot awareness was achieved by stimulating 43% to 70% of the maximum photoreceptor density. Partial and total filling-in of the blind spot required between 78% and 83% and more than 85% photoreceptor spatial densities, respectively. CONCLUSIONS: A novel intrinsic stimulus has been used to concurrently investigate blind spot awareness and blind spot filling-in. Retinal neural correlates of each visual experience have been quantified. Future computational models will have to integrate bottom-up constraints with long-range cortical receptive field activity and higher order cognitive factors. PMID- 20847111 TI - Spontaneous bacterial keratitis in CD36 knockout mice. AB - PURPOSE: CD36 is a Class B scavenger receptor that is constitutively expressed in the corneal epithelium and has been implicated in many homeostatic functions, including the homeostasis of the epidermal barrier. The aim of this study is to determine (1) whether CD36 is required for the maintenance of the corneal epithelial barrier to infection, and (2) whether CD36-deficient mice present with an increased susceptibility to bacterial keratitis. METHODS: The corneas of CD36( /-), TSP1(-/-), TLR2(-/-), and C57BL/6 WT mice were screened via slit lamp microscopy or ex vivo analysis. The epithelial tight junctions and mucin layer were assessed via LC-biotin and Rose Bengal staining, respectively. Bacterial quantification was performed on corneal buttons and GFP-expressing Staphylococcus aureus was used to study bacterial binding. RESULTS: CD36(-/-) mice develop spontaneous corneal defects that increased in frequency and severity with age. The mild corneal defects were characterized by a disruption in epithelial tight junctions and the mucin layer, an infiltrate of macrophages, and increased bacterial binding. Bacterial quantification revealed high levels of Staphylococcus xylosus in the corneas of CD36(-/-) mice with severe defects, but not in wild-type controls. CONCLUSIONS: CD36(-/-) mice develop spontaneous bacterial keratitis independent of TLR2 and TSP1. The authors conclude that CD36 is a critical component of the corneal epithelial barrier, and in the absence of CD36 the barrier breaks down, allowing bacteria to bind to the corneal epithelium and resulting in spontaneous keratitis. This is the first report of spontaneous bacterial keratitis in mice. PMID- 20847112 TI - In vivo evaluation of ocular demodicosis using laser scanning confocal microscopy. AB - PURPOSE: To investigate the applicability of in vivo laser scanning confocal microscopy in the diagnosis and follow-up of ocular demodicosis infestation in a prospective controlled study. METHODS: Fifteen right eyes of 15 patients with blepharitis associated with cylindrical dandruff (10 males, 5 females; mean age: 62.9 +/- 9 years) and eight right eyes of eight age- and sex-matched control subjects underwent HRTII/RCM, evaluation of ocular symptom scores, tear function tests including vital stainings, Schirmer test, and tear clearance test, and evaluation of mite numbers in the eyelids. RESULTS: In vivo confocal microscopy effectively disclosed the mites in the terminal bulbs of the eyelashes, which were not observed after treatment. Eyelids with demodicosis infestation showed marked inflammatory infiltrates around the meibomian glands and conjunctiva, which cleared with tea tree oil treatment. CONCLUSIONS: Laser scanning confocal microscopy seems to be an efficient noninvasive tool in the diagnosis and follow up of ocular demodicosis infestation. PMID- 20847113 TI - Different inner retinal pathways mediate rod-cone input in irradiance detection for the pupillary light reflex and regulation of behavioral state in mice. AB - PURPOSE: Detection of light in the eye contributes both to spatial awareness (form vision) and to responses that acclimate an animal to gross changes in light (irradiance detection). This dual role means that eye disease that disrupts form vision can also adversely affect physiology and behavioral state. The purpose of this study was to investigate how inner retinal circuitry mediating rod-cone photoreceptor input contributes to functionally distinct irradiance responses and whether that might account for phenotypic diversity in retinal disease. METHODS: The sensitivity of the pupillary light reflex and negative masking (activity suppression by light) was measured in wild-type mice with intact inner retinal circuitry, Nob4 mice that lack ON-bipolar cell function, and rd1 mice that lack rods and cones and, therefore, have no input to ON or OFF bipolar cells. RESULTS: An expected increase in sensitivity to negative masking with loss of photoreceptor input in rd1 was duplicated in Nob4 mice. In contrast, sensitivity of the pupillary light reflex was more severely reduced in rd1 than in Nob4 mice. CONCLUSIONS: Absence of ON-bipolar cell-mediated rod-cone input can fully explain the phenotype of outer retina degeneration for negative masking but not for the pupillary light reflex. Therefore, inner retinal pathways mediating rod-cone input are different for negative masking and the pupillary light reflex. PMID- 20847114 TI - Changes in cholinergic amacrine cells after rodent anterior ischemic optic neuropathy (rAION). AB - PURPOSE: Displaced cholinergic amacrine cell neurons comprise a significant fraction of the retinal ganglion cell (RGC) layer. Rodent anterior ischemic optic neuropathy (rAION) is an optic nerve infarct, which results in RGC loss in mice. The goal was to determine whether rAION produces changes in amacrine cell neurons. METHODS: rAION was generated in transgenic mice carrying a cyan fluorescent reporter protein (CFP) gene linked to the Thy-1 promoter, which expresses CFP in RGCs. rAION was induced with standard parameters. Retinas were examined pre-and post-induction by retinal fundus microscopy. rAION induction severity was scored by changes in retinal transparency and RGC loss. Cholinergic amacrine cells were identified via choline acetyltransferase (ChAT) immunohistochemistry. ChAT and CFP expression was evaluated in flat-mounted retinas examined by confocal microscopy and western analysis. RESULTS: Moderate rAION induction levels (defined as early retention of retinal transparency and <70% RGC loss) did not alter amacrine cell numbers in the RGC layer, but changed the relative levels of ChAT expression by immunohistochemistry. No changes in total ChAT protein were seen. Severe rAION induction (defined as loss of retinal transparency and >70% RGC loss) resulted in a trend toward amacrine cell loss and decreased ChAT protein levels. CONCLUSIONS: There is wide disparity in mouse rAION induction levels using standardized parameters. Moderate rAION induction levels without direct retinal compromise produces isolated RGC loss, with displaced amacrine cell changes likely due to changes in RGC-amacrine communication. Severe rAION induction results in both RGC and amacrine cell loss, possibly due to intra-retinal ischemic changes. PMID- 20847115 TI - A comparison of functional and structural measures for identifying progression of glaucoma. AB - PURPOSE: To compare glaucoma progression by functional and structural tests. METHODS: The authors prospectively studied 33 glaucoma patients (55 eyes); 20 eyes (15 patients) had disc hemorrhage, and 35 eyes (18 patients) had exfoliation glaucoma. The following tests were performed at two baseline and three follow-up examinations: frequency doubling perimetry (FDT), 24-2 Humphrey visual fields (HVF), multifocal visual evoked potentials (mfVEP), and optical coherence tomography (OCT). To identify progression, the baseline measurements were averaged and compared to those obtained at the final examination. Stereophotographs of the optic disc were obtained at baseline and compared with those at the final examination. RESULTS: Patients were followed up for 21.1+/-1.8 months. For HVF there were significant changes in mean deviation (MD) in eight (14.5%) eyes but in pattern standard deviation (P/SD) in only two (3.6%) eyes. For FDT, there were significant changes in MD in 13 (23.6%) eyes. Five eyes showed changes in MD for HVF and FDT. For mfVEP, there was an increase in abnormal points in nine (16.4%) eyes. Six of these eyes did not show significant HVF or FDT changes. For OCT, RNFL average thickness values were significantly decreased in nine (16.4%) eyes. Nine (16.4%) eyes showed progression on stereophotography; four of these eyes did not show significant changes on OCT and functional tests. CONCLUSIONS: Each test showed evidence of progression in some eyes. However, agreement among tests and stereophotography regarding which eyes showed progression was poor, illustrating the importance of following up patients with a combination of functional and structural tests. PMID- 20847116 TI - Biosynthetic corneal implants for replacement of pathologic corneal tissue: performance in a controlled rabbit alkali burn model. AB - PURPOSE: To evaluate the performance of structurally reinforced, stabilized recombinant human collagen-phosphorylcholine (RHCIII-MPC) hydrogels as corneal substitutes in a rabbit model of severe corneal damage. METHODS: One eye each of 12 rabbits received a deep corneal alkali wound. Four corneas were implanted with RHCIII-MPC hydrogels. The other eight control corneas were implanted with either allografts or a simple cross-linked RHCIII hydrogel. In all cases, 6.25 mm diameter, 350 MUm thick buttons were implanted by anterior lamellar keratoplasty to replace damaged corneal tissue. Implants were followed for nine months by clinical examination and in vivo confocal microscopy, after which implanted corneas were removed and processed for histopathological and ultrastructural examination. RESULTS: Alkali exposure induced extensive central corneal scarring, ocular surface irregularity, and neovascularization in one case. All implants showed complete epithelial coverage by four weeks postoperative, but with accompanying suture-induced vascularization in 6 out of 12 cases. A stable, stratified epithelium with hemidesmosomal adhesion complexes regenerated over all implants, and subbasal nerve regeneration was observed in allograft and RHCIII MPC implants. Initially acellular biosynthetic implants were populated with host derived keratocytes as stromal haze subsided and stromal collagen was remodeled. Notably, RHCIII-MPC implants exhibited resistance to vascular ingrowth while supporting endogenous cell and nerve repopulation. CONCLUSIONS: Biosynthetic implants based on RHC promoted cell and nerve repopulation in alkali burned rabbit eyes. In RHCIII-MPC implants, evidence of an enhanced resistance to neovascularization was additionally noted. PMID- 20847117 TI - Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model. AB - PURPOSE: To investigate the role of reactive oxygen species (ROS) as the prime initiators of the angiogenic response after alkali injury of the cornea and observe the effects of antioxidants in preventing angiogenesis. METHODS: The corneal epithelia of SOD-1-deficient mice or wild-type (WT) mice were removed after application of 0.15 N NaOH to establish the animal model of alkali burn. ROS production was semiquantitatively measured by dihydroethidium (DHE) fluorescence. Angiogenesis was visualized by CD31 immunohistochemistry. The effects of the specific NF-kappaB inhibitor DHMEQ, the antioxidant N-acetyl-L cysteine (NAC), and hydrogen (H2) solution were observed. RESULTS: ROS production in the cornea was enhanced immediately after alkali injury, as shown by increased DHE fluorescence (P<0.01). NF-kappaB activation and the upregulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were significantly enhanced (P<0.01), leading to a significantly larger area of angiogenesis. Angiogenesis in SOD-1-/- mice corneas were significantly higher in WT mice (P<0.01), confirming the role of ROS. Pretreatment with the specific NF kappaB inhibitor DHMEQ or the antioxidant NAC significantly reduced corneal angiogenesis by downregulating the NF-kappaB pathway (P<0.01) in both WT and SOD 1-/- mice. Furthermore, we showed that irrigation of the cornea with hydrogen (H2) solution significantly reduced angiogenesis after alkali-burn injury (P<0.01). CONCLUSIONS: Immediate antioxidant therapy with H2-enriched irrigation solution is a new potent treatment of angiogenesis in cornea to prevent blindness caused by alkali burn. PMID- 20847118 TI - Age-related differences in the elasticity of the human cornea. AB - PURPOSE: The goal of this study was to determine age-related variation in the elasticity of the human cornea using nondestructive means. METHODS: Organ cultured human corneoscleral buttons were studied. Changes in strain were measured with a radial shearing speckle pattern interferometer after an increase in intraocular pressure from 15.0 to 15.5 mm Hg. Changes in central corneal displacement were calculated by integration, and a bulk corneal Young's modulus was derived by mathematical analysis. RESULTS: Fifty corneas, including 17 pairs, were studied. Donors were aged between 24 and 102 years (mean, 73.1); 29 (58%) specimens were from male donors and 21 from female donors. Young's modulus of the cornea increased with age, with the line of best fit indicating an approximate doubling from 0.27 MPa at age 20 years (95% confidence interval, 0.22-0.31) to 0.52 (0.50-0.54) MPa at age 100 years (R2 = 0.70). CONCLUSIONS: The stiffness of the human cornea increases by a factor of approximately two between the ages of 20 and 100 years. This variation is relevant to the algorithms used to predict the response to incisional and ablative refractive surgery and will also affect the formulas used to calculate intraocular pressure by applanation. PMID- 20847119 TI - Differential effects of PPARgamma ligands on oxidative stress-induced death of retinal pigmented epithelial cells. AB - PURPOSE: To investigate the role of the peroxisome proliferator-activated receptor (PPAR)-gamma in modulating retinal pigmented epithelium (RPE) responses to oxidative stress. METHODS: ARPE-19 cells were treated with the oxidant, t butylhydroperoxide (tBH) to induce apoptosis. Cells pretreated with synthetic PPARgamma agonists of the antidiabetic thiazolidinediones class before tBH challenge were assessed for viability and, by microarray analysis, for effects on gene expression. RESULTS: Treatment of ARPE-19 cells with tBH resulted in a loss of viability and global changes in the pattern of gene expression. PPARgamma ligands were found to have differential modulatory effects on tBH-induced apoptosis of RPE cells. Whereas rosiglitazone and pioglitazone potentiated cell death, troglitazone acted as a potent cytoprotective agent. Downregulation of PPARgamma expression by an siRNA resulted in enhanced cell death in response to tBH treatment and blocked the cytoprotective effect of troglitazone consistent with a role of PPARgamma in mediating this response. Microarray analysis revealed that while rosiglitazone and pioglitazone had little effect on gene changes induced by tBH treatment, troglitazone dramatically reduced the number of changes caused by oxidative stress. A unique subset of genes that were deregulated by tBH and selectively normalized by troglitazone were identified. CONCLUSIONS: These findings demonstrate that PPARgamma agonists can have differential effects on RPE survival in response to oxidative stress. Oxidative stress leads to deregulation of a large set of genes in ARPE-19 cells. A specific subset of these genes can be selectively modulated by troglitazone and represent potential novel targets for cytoprotective therapies. PMID- 20847120 TI - Cell proliferation and interleukin-6-type cytokine signaling are implicated by gene expression responses in early optic nerve head injury in rat glaucoma. AB - PURPOSE: In glaucoma, the optic nerve head (ONH) is the principal site of initial axonal injury, and elevated intraocular pressure (IOP) is the predominant risk factor. However, the initial responses of the ONH to elevated IOP are unknown. Here the authors use a rat glaucoma model to characterize ONH gene expression changes associated with early optic nerve injury. METHODS: Unilateral IOP elevation was produced in rats by episcleral vein injection of hypertonic saline. ONH mRNA was extracted, and retrobulbar optic nerve cross-sections were graded for axonal degeneration. Gene expression was determined by microarray and quantitative PCR (QPCR) analysis. Significantly altered gene expression was determined by multiclass analysis and ANOVA. DAVID gene ontology determined the functional categories of significantly affected genes. RESULTS: The Early Injury group consisted of ONH from eyes with <15% axon degeneration. By array analysis, 877 genes were significantly regulated in this group. The most significant upregulated gene categories were cell cycle, cytoskeleton, and immune system process, whereas the downregulated categories included glucose and lipid metabolism. QPCR confirmed the upregulation of cell cycle-associated genes and leukemia inhibitory factor (Lif) and revealed alterations in expression of other IL-6-type cytokines and Jak-Stat signaling pathway components, including increased expression of IL-6 (1553%). In contrast, astrocytic glial fibrillary acidic protein (Gfap) message levels were unaltered, and other astrocytic markers were significantly downregulated. Microglial activation and vascular-associated gene responses were identified. CONCLUSIONS: Cell proliferation and IL-6-type cytokine gene expression, rather than astrocyte hypertrophy, characterize early pressure-induced ONH injury. PMID- 20847122 TI - Influence of refractive error and axial length on retinal vessel geometric characteristics. AB - PURPOSE: To evaluate the influence of refractive error and axial length (AL) on retinal vascular network geometry measurements in an adult Asian population. METHODS: This was a population-based, cross-sectional study on 2882 persons with diabetes in the Singapore Malay Eye Study. Spherical equivalent refraction was assessed using an autokeratorefractometer and subjective refraction. AL retinal vascular caliber, tortuosity, and branching characteristics were quantified from retinal fundus photographs using a semiautomated computer-assisted program according to a standardized protocol. RESULTS: In multivariate analyses adjusting for age, sex, education, smoking, blood pressure, diabetes status, and antihypertensive medication use, longer AL and more myopic refraction were associated with narrower retinal arterioles and venules (P <= 0.001 for all) and less tortuous (straighter) arterioles (P < 0.001 for both). Longer AL and more myopic refraction were also associated with increased branching coefficients in both arterioles (P < 0.001 for both) and venules (P = 0.02 and P < 0.001, respectively). Longer AL and more myopic refraction were associated with more acute branching angles in arterioles (P < 0.001 for both) but not venules. CONCLUSIONS: Myopic refractive errors and longer AL are associated with narrower retinal arterioles and venules, less tortuous arterioles, and increased branching coefficients in both arterioles and venules. These findings provide insights into ocular blood flow in myopia and also suggest that future studies evaluating these retinal parameters should account for the influence of AL and refractive error. PMID- 20847121 TI - Magnetic resonance imaging of vascular oxygenation changes during hyperoxia and carbogen challenges in the human retina. AB - PURPOSE: To demonstrate blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) of vascular oxygenation changes in normal, unanesthetized human retinas associated with oxygen and carbogen challenge. METHODS: MRI was performed with a 3-T human scanner and a custom-made surface-coil detector on normal volunteers. BOLD MRI with inversion recovery was used to suppress the vitreous signal. During MRI measurements, volunteers underwent three episodes of air and 100% oxygen or carbogen (5% CO(2) and 95% O(2)) breathing. Eye movement was effectively managed with eye fixation, synchronized blinks, and postprocessing image coregistration. BOLD time-series images were analyzed using the cross-correlation method. Percent changes due to oxygen or carbogen inhalation versus air were tabulated for whole-retina and different regions of the retina. RESULTS: Robust BOLD responses were detected. BOLD MRI percent change from a large region of interest at the posterior pole of the retina was 5.2 +/- 1.5% (N = 9 trials from five subjects) for oxygen inhalation and 5.2 +/- 1.3% (N = 11 trials from five subjects) for carbogen inhalation. Group-averaged BOLD percent changes were not significantly different between oxygen and carbogen challenges (P > 0.05). The foveal region had greater BOLD response compared with the optic nerve head region for both challenges. CONCLUSIONS: BOLD retinal responses to oxygen and carbogen breathing in unanesthetized humans can be reliably imaged at high spatiotemporal resolution. BOLD MRI has the potential to provide a valuable tool to study retinal physiology and pathophysiology, such as how vascular oxygenation at the tissue level is regulated in the normal retina, and how retinal diseases may affect oxygen response. PMID- 20847123 TI - Validation of the Chlamydia trachomatis genital challenge pig model for testing recombinant protein vaccines. AB - Chlamydia trachomatis is a Gram-negative obligate intracellular bacterial pathogen that is the leading cause of bacterial sexually transmitted disease in humans in developing countries. A vaccination programme is considered to be the best approach to reduce the prevalence of C. trachomatis infections. However, there are still no commercial C. trachomatis vaccines. In order to develop effective C. trachomatis vaccines, it is important to identify those antigens that elicit a protective immune response, and to develop new and adequate methods and adjuvants for effective vaccine delivery, as conventional methods have failed to induce protective immunity. In order to test different vaccine candidates, animal models are needed. Former studies have used non-primate monkeys, mice or guinea pig infection models. The present study used a pig model for testing recombinant protein vaccines. Two recombinant proteins, polymorphic membrane protein G (PmpG), and secretion and cellular translocation protein C (SctC), were tested for their ability to create protection in a pig C. trachomatis challenge model. The vaccines were administered subcutaneously with GNE adjuvant. Six weeks later, animals were challenged intravaginally with C. trachomatis serovar E. After a further 4 weeks, the pigs were euthanized. PmpG-immunized pigs were better protected than pigs immunized with the less promising SctC candidate vaccine antigen. Interestingly, significant protection was apparently not correlated with a strong humoral immune response upon subcutaneous immunization. In conclusion, the pig model is useful for studying the efficacy of vaccine candidates against genital human C. trachomatis infection. PMID- 20847124 TI - Chromosomal diversity in Lactococcus lactis and the origin of dairy starter cultures. AB - A large collection of Lactococcus lactis strains, including wild-type isolates and dairy starter cultures, were screened on the basis of their phenotype and the macrorestriction patterns produced from pulsed-field gel electrophoresis (PFGE) analysis of SmaI digests of genomic DNA. Three groups of dairy starter cultures, used for different purposes in the dairy industry, and a fourth group made up of strains isolated from the environment were selected for analysis of their chromosomal diversity using the endonuclease I-CeuI. Chromosome architecture was largely conserved with each strain having six copies of the rRNA genes, and the chromosome size of individual strains ranged between 2,240 and 2,688 kb. The origin of L. lactis strains showed the greatest correlation with chromosome size, and dairy strains, particularly those with the cremoris phenotype, had smaller chromosomes than wild-type strains. Overall, this study, coupled with analysis of the sequenced L. lactis genomes, provides evidence that defined strain dairy starter cultures have arisen from plant L. lactis strains. Adaptation of these strains to the dairy environment has involved loss of functions resulting in smaller chromosomes and acquisition of genes (usually plasmid associated) that facilitate growth in milk. We conclude that dairy starter cultures generally and the industrially used cremoris and diacetylactis phenotype strains in particular comprise a specialized group of L. lactis strains that have been selected to become an essential component of industrial processes and have evolved accordingly, so that they are no longer fit to survive outside the dairy environment. PMID- 20847125 TI - Microvascular blood flow in the airway mucosa modulates bronchoconstriction. PMID- 20847126 TI - Vestibular-mediated increase in central serotonin plays an important role in hypergravity-induced hypophagia in rats. AB - Exposure to a hypergravity environment induces acute transient hypophagia, which is partially restored by a vestibular lesion (VL), suggesting that the vestibular system is involved in the afferent pathway of hypergravity-induced hypophagia. When rats were placed in a 3-G environment for 14 days, Fos-containing cells increased in the paraventricular hypothalamic nucleus, the central nucleus of the amygdala, the medial vestibular nucleus, the raphe nucleus, the nucleus of the solitary tract, and the area postrema. The increase in Fos expression was completely abolished or significantly suppressed by VL. Therefore, these regions may be critical for the initiation and integration of hypophagia. Because the vestibular nucleus contains serotonergic neurons and because serotonin (5-HT) is a key neurotransmitter in hypophagia, with possible involvement in motion sickness, we hypothesized that central 5-HT increases during hypergravity and induces hypophagia. To examine this proposition, the 5-HT concentrations in the cerebrospinal fluid were measured when rats were reared in a 3-G environment for 14 days. The 5-HT concentrations increased in the hypergravity environment, and these increases were completely abolished in rats with VL. Furthermore, a 5 HT(2A) antagonist (ketanserin) significantly reduced 3-G (120 min) load-induced Fos expression in the medial vestibular nucleus, and chronically administered ketanserin ameliorated hypergravity-induced hypophagia. These results indicate that hypergravity induces an increase in central 5-HT via the vestibular input and that this increase plays a significant role in hypergravity-induced hypophagia. The 5-HT(2A) receptor is involved in the signal transduction of hypergravity stress in the vestibular nucleus. PMID- 20847127 TI - Endurance training-induced accumulation of muscle triglycerides is coupled to upregulation of stearoyl-CoA desaturase 1. AB - Stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, has recently been shown to be a critical control point in regulation of liver and skeletal muscle metabolism. Herein, we demonstrate that endurance training significantly increases both SCD1 mRNA and protein levels in the soleus muscle, whereas it does not affect SCD1 expression in the EDL muscle and liver. Desaturation index (18:1Delta9/18:0 ratio), an indirect indicator of SCD1 activity, was also significantly higher (3.6-fold) in soleus of trained rats compared with untrained animals. Consistent with greater SCD1 expression/activity, the contents of free fatty acids, diacylglycerol, and triglyceride were elevated in soleus of trained rats. However, training did not affect lipid concentration in EDL and liver. Additionally, endurance training activated the AMP-activated protein kinase pathway as well as increased peroxisome proliferator-activated receptor (PPAR)-delta and PPARalpha gene expression and activity in soleus and liver. Increased lipid accumulation in soleus was coupled with elevated protein levels of fatty acid synthase, mRNA levels of diacylglycerol acyltransferase and glycerol-3-phosphate transferase, as well as increased levels of proteins involved in fatty acid transport (fatty acid translocase/CD36, fatty acid transport protein 1). Interestingly, sterol regulatory element-binding protein (SREBP)-1c expression and SREBP-1 protein levels were not affected by exercise training. Together, the obtained data suggest that SCD1 upregulation plays an important role in adaptation of oxidative muscle to endurance training. PMID- 20847128 TI - Bowman-Birk inhibitor attenuates dystrophic pathology in mdx mice. AB - Bowman-Birk inhibitor concentrate (BBIC), a serine protease inhibitor, has been shown to diminish disuse atrophy of skeletal muscle. Duchenne muscular dystrophy (DMD) results from a loss of dystrophin protein and involves an ongoing inflammatory response, with matrix remodeling and activation of transforming growth factor (TGF)-beta(1) leading to tissue fibrosis. Inflammatory-mediated increases in extracellular protease activity may drive much of this pathological tissue remodeling. Hence, we evaluated the ability of BBIC, an extracellular serine protease inhibitor, to impact pathology in the mouse model of DMD (mdx mouse). Mdx mice fed 1% BBIC in their diet had increased skeletal muscle mass and tetanic force and improved muscle integrity (less Evans blue dye uptake). Importantly, mdx mice treated with BBIC were less susceptible to contraction induced injury. Changes consistent with decreased degeneration/regeneration, as well as reduced TGF-beta(1) and fibrosis, were observed in the BBIC-treated mdx mice. While Akt signaling was unchanged, myostatin activitation and Smad signaling were reduced. Given that BBIC treatment increases mass and strength, while decreasing fibrosis in skeletal muscles of the mdx mouse, it should be evaluated as a possible therapeutic to slow the progression of disease in human DMD patients. PMID- 20847129 TI - In search of complexity. PMID- 20847130 TI - Direct comparison of in vivo Achilles tendon moment arms obtained from ultrasound and MR scans. AB - Accurate and reliable estimation of muscle moment arms is a prerequisite for the development of musculoskeletal models. Numerous techniques are available to estimate the Achilles tendon moment arm in vivo. The purposes of this study were 1) to compare in vivo Achilles tendon moment arms obtained using the center of rotation (COR) and tendon excursion (TE) methods and 2) to assess the reliability of each method. For the COR method, magnetic resonance (MR) images from nine participants were obtained at ankle angles of -15 degrees , 0 degrees , and +15 degrees and analyzed using Reuleaux' method. For the TE method, the movement of the gastrocnemius medialis-Achilles tendon junction was recorded using ultrasonography as the ankle was passively rotated through its range of motion. The Achilles tendon moment arm was obtained by differentiation of tendon displacement with respect to ankle angular excursion using seven different differentiation techniques. Moment arms obtained using the COR method were significantly greater than those obtained using the TE method (P < 0.01), but results from both methods were well correlated. The coefficient of determination between moment arms derived from the COR and TE methods was highest when tendon displacement was linearly differentiated over a +/- 10 degrees interval (R(2) = 0.94). The between-measurement coefficient of variation was 3.9% for the COR method and 4.5-9.7% for the TE method, depending on the differentiation technique. The high reliabilities and strong relationship between methods demonstrate that both methods are robust against their limitations. The large absolute between-method differences (~ 25-30%) in moment arms have significant implications for their use in musculoskeletal models. PMID- 20847132 TI - Controlling matrix formation and cross-linking by hypoxia in cardiovascular tissue engineering. AB - In vivo functionality of cardiovascular tissue engineered constructs requires in vitro control of tissue development to obtain a well developed extracellular matrix (ECM). We hypothesize that ECM formation and maturation is stimulated by culturing at low oxygen concentrations. Gene expression levels of monolayers of human vascular-derived myofibroblasts, exposed to 7, 4, 2, 1, and 0.5% O(2) (n = 9 per group) for 24 h, were measured for vascular endothelial growth factor (VEGF), procollagen alpha1(I) and alpha1(III), elastin, and cross-link enzymes lysyl oxidase (LOX) and lysyl hydroxylase 2 (LH2). After 4 days of exposure to 7, 2, and 0.5% O(2) (n = 3 per group), protein synthesis was evaluated. All analyses were compared with control cultures at 21% O(2). Human myofibroblasts turned to hypoxia-driven gene expression, indicated by VEGF expression, at oxygen concentrations of 4% and lower. Gene expression levels of procollagen alpha1(I) and alpha1(III) increased to 138 +/- 26 and 143 +/- 19%, respectively, for all oxygen concentrations below 4%. At 2% O(2), LH2 and LOX gene expression levels were higher than control cultures (340 +/- 53 and 136 +/- 29%, respectively), and these levels increased even further with decreasing oxygen concentrations (611 +/ 176 and 228 +/- 45%, respectively, at 0.5% O(2)). Elastin gene expression levels remained unaffected. Collagen synthesis and LH2 protein levels increased at oxygen concentrations of 2% and lower. Oxygen concentrations below 4% induce enhanced ECM production by human myofibroblasts. Implementation of these results in cardiovascular tissue engineering approaches enables in vitro control of tissue development. PMID- 20847133 TI - Circadian regulation of locomotor activity and skeletal muscle gene expression in the horse. AB - Circadian rhythms are innate 24-h cycles in behavioral and biochemical processes that permit physiological anticipation of daily environmental changes. Elucidating the relationship between activity rhythms and circadian patterns of gene expression may contribute to improved human and equine athletic performance. Six healthy, untrained mares were studied to determine whether locomotor activity behavior and skeletal muscle gene expression reflect endogenous circadian regulation. Activity was recorded for three consecutive 48-h periods: as a group at pasture (P), and individually stabled under a light-dark (LD) cycle and in constant darkness (DD). Halter-mounted Actiwatch-L data-loggers recorded light exposure and motor activity. Analysis of mean activity (average counts/min, activity bouts/day, average bout length) and cosinor parameters (acrophase, amplitude, mesor, goodness of fit) revealed a predominantly ultradian (8.9 +/- 0.7 bouts/24 h) and weakly circadian pattern of activity in all three conditions (P, LD, DD). A more robust circadian pattern was observed during LD and DD. Muscle biopsies were obtained from the middle gluteal muscles every 4 h for 24 h under DD. One-way qRT-PCR results confirmed the circadian expression (P < 0.05) of six core clock genes (Arntl, Per1, Per2, Nr1d1, Nr1d2, Dbp) and the muscle specific transcript, Myf6. Additional genes, Ucp3, Nrip1, and Vegfa, demonstrated P values approaching significance. These findings demonstrate circadian regulation of muscle function and imply that human management regimes may strengthen, or unmask, equine circadian behavioral outputs. As exercise synchronizes circadian rhythms, our findings provide a basis for future work determining peak times for training and competing horses, to reduce injury and to achieve optimal performance. PMID- 20847131 TI - Muscle energetics changes throughout maturation: a quantitative 31P-MRS analysis. AB - We quantified energy production in 7 prepubescent boys (11.7 +/- 0.6 yr) and 10 men (35.6 +/- 7.8 yr) using (31)P-magnetic resonance spectroscopy to investigate whether development affects muscle energetics, given that resistance to fatigue has been reported to be larger before puberty. Each subject performed a finger flexions exercise at 0.7 Hz against a weight adjusted to 15% of their maximal voluntary strength for 3 min, followed by a 15-min recovery period. The total energy cost was similar in both groups throughout the exercise bout, whereas the interplay of the different metabolic pathways was different. At the onset of exercise, children exhibited a higher oxidative contribution (50 +/- 15% in boys and 25 +/- 8% in men, P < 0.05) to ATP production, whereas the phosphocreatine breakdown contribution was reduced (40 +/- 10% in boys and 53 +/- 12% in men, P < 0.05), likely as a compensatory mechanism. The anaerobic glycolysis activity was unaffected by maturation. The recovery phase also disclosed differences regarding the rates of proton efflux (6.2 +/- 2.5 vs. 3.8 +/- 1.9 mM . pH unit(-1) . min( 1), in boys and men, respectively, P < 0.05), and phosphocreatine recovery, which was significantly faster in boys than in men (rate constant of phosphocreatine recovery: 1.3 +/- 0.5 vs. 0.7 +/- 0.4 min(-1); V(max): 37.5 +/- 14.5 vs. 21.1 +/- 12.2 mM/min, in boys and men, respectively, P < 0.05). Our results obtained in vivo clearly showed that maturation affects muscle energetics. Children relied more on oxidative metabolism and less on creatine kinase reaction to meet energy demand during exercise. This phenomenon can be explained by a greater oxidative capacity, probably linked to a higher relative content in slow-twitch fibers before puberty. PMID- 20847134 TI - Effect of initial gas bubble composition on detection of inducible intrapulmonary arteriovenous shunt during exercise in normoxia, hypoxia, or hyperoxia. AB - Concern has been raised that altering the fraction of inspired O2 (Fi(O2)) could accelerate or decelerate microbubble dissolution time within the pulmonary vasculature and thereby invalidate the ability of saline contrast echocardiography to detect intrapulmonary arteriovenous shunt in subjects breathing either a low or a high Fi(O2). The present study determined whether the gaseous component used for saline contrast echocardiography affects the detection of exercise-induced intrapulmonary arteriovenous shunt under varying Fi(O2). Twelve healthy human subjects (6 men, 6 women) performed three 11-min bouts of cycle ergometer exercise at 60% peak O2 consumption (Vo(2peak)) in normoxia, hypoxia (Fi(O2) = 0.14), and hyperoxia (Fi(O2) = 1.0). Five different gases were used to create saline contrast microbubbles by two separate methods and were injected intravenously in the following order at 2-min intervals: room air, 100% N2, 100% O2, 100% CO2, and 100% He. Breathing hyperoxia prevented exercise induced intrapulmonary arteriovenous shunt, whereas breathing hypoxia and normoxia resulted in a significant level of exercise-induced intrapulmonary arteriovenous shunt. During exercise, for any Fi(O2) there was no significant difference in bubble score when the different microbubble gas compositions made with either method were used. The present results support our previous work using saline contrast echocardiography and validate the use of room air as an acceptable gaseous component for use with saline contrast echocardiography to detect intrapulmonary arteriovenous shunt during exercise or at rest with subjects breathing any Fi(O2). These results suggest that in vivo gas bubbles are less susceptible to changes in the ambient external environment than previously suspected. PMID- 20847135 TI - Not hearing is believing: novel insight into cardiopulmonary function using agitated contrast and ultrasound. PMID- 20847136 TI - Comparative use of isolated hepatocytes and hepatic microsomes for cytochrome P450 inhibition studies: transporter-enzyme interplay. AB - Accurate assignment of the concentration of victim drug/inhibitor available at the enzyme active site, both in vivo and within an in vitro incubation, is an essential requirement in rationalizing and predicting drug-drug interactions. Inhibitor accumulation within the liver, whether as a result of active transport processes or intracellular binding, may best be accounted for using hepatocytes rather than hepatic microsomes to estimate in vitro inhibitory potency. The aims of this study were to compare K(i) values determined in rat liver microsomes and freshly isolated rat hepatocytes of four cytochrome P450 (P450) inhibitors (clarithromycin, enoxacin, nelfinavir, and saquinavir) with known hepatic transporter involvement and a range of uptake (cell/medium concentration ratios 20-3000) and clearance (10-1200 MUl/min/10(6) cells) properties. Inhibition studies were performed using two well established P450 probe substrates (theophylline and midazolam). Comparison of unbound K(i) values showed marked differences between the two in vitro systems for inhibition of metabolism. In two cases (clarithromycin and enoxacin, both low-clearance drugs), inhibitory potency in hepatocytes markedly exceeded that in microsomes (10- to 20-fold), and this result was consistent with their high cell/medium concentration ratios. For nelfinavir and saquinavir (high-clearance, extensively metabolized drugs), the opposite trend was seen in the K(i) values: despite very high cell/medium concentration ratios, stronger inhibition was evident within microsomal preparations. Hence, the consequences of hepatic accumulation resulting from uptake transporters vary according to the clearance of the inhibitor. This study demonstrates that transporter-enzyme interplay can result in differences in inhibitory potency between microsomes and hepatocytes and hence drug-drug interaction predictions that are not always intuitive. PMID- 20847138 TI - A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. AB - Recent regulatory guidance suggests that metabolites identified in human plasma should be present at equal or greater levels in one of the animal species used in safety assessments. In this report, a high-performance liquid chromatography tandem mass spectrometry method is described whereby quantitative comparisons of exposures to metabolites between species can be obtained in the absence of authentic standards of the metabolites, calibration curves, and other attributes of standard bioanalytical methods. This novel method was tested using six drug metabolite combinations. Plasma samples from animals are mixed with control plasma from humans and vice versa to remove possible differential effects of matrices. Through multiple ion monitoring-triggered enhanced product ion (EPI) scans, all metabolites were qualitatively confirmed, and daughter ions were selected for the most sensitive mass transitions to trigger EPI scans. Direct comparisons of metabolites in animal versus human plasma were achieved by calculating the peak area ratios of the metabolites versus an internal standard. Linearity of instrument responses was established by serial dilution. A statistical analysis demonstrated that experimentally measured ratios of the parent and metabolites in rat versus human correlated well with the nominal ratios of concentrations using linear regression with an average slope of 0.99 +/ 0.08 (r = 0.994 +/- 0.005). This analysis showed that if the experimentally determined ratio of mass spectrometer responses is >= 2.0, then the actual exposure ratio is unity or greater (p < 0.01). This method offers time- and resource-sparing advantages to ascertaining metabolite exposure comparisons between humans and laboratory animal species. A strategy for application of this approach within standard drug development processes is described. PMID- 20847137 TI - CYP3A4*16 and CYP3A4*18 alleles found in East Asians exhibit differential catalytic activities for seven CYP3A4 substrate drugs. AB - CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A4*16 (T185S) and CYP3A4*18 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V(max)/K(m)) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K(m) with or without decreased V(max) values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K(m) values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V(max) values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug. PMID- 20847139 TI - Components acting downstream of short day perception regulate differential cessation of cambial activity and associated responses in early and late clones of hybrid poplar. AB - Short days (SDs) in autumn induce growth cessation, bud set, cold acclimation, and dormancy in trees of boreal and temperate forests, and these responses occur earlier in northern than in southern genotypes. Nevertheless, we know little about whether this variation results from differential perception of SDs or differential downstream responses to the SD signal or a combination of the two. We compared global patterns of SD-regulated gene expression in the stems of hybrid poplar (Populus trichocarpa * Populus deltoides) clones that differ in their SD-induced growth cessation in order to address this question. The timing of cessation of cambial cell division caused by SDs differed between the clones and was coincident with the change in the pattern of expression of the auxin regulated genes. The clones also differed in the timing of their SD-regulated changes in the transcript abundance of genes associated with cold tolerance, starch breakdown, and storage protein accumulation. By analyzing the expression of homologs of FLOWERING LOCUS T, we demonstrated that the clones differed little in their perception of SDs under the growth conditions applied but differed substantially in the downstream responses manifested in the timing and magnitude of gene expression after SD treatment. These results demonstrate the existence of factors that act downstream of SD perception and can contribute to variation in SD-regulated adaptive photoperiodic responses in trees. PMID- 20847140 TI - Fibroblast expression of an IkappaB dominant-negative transgene attenuates renal fibrosis. AB - It is not clear whether interstitial fibroblasts or tubular epithelial cells are primarily responsible for the profibrotic effects of NF-kappaB activation during renal fibrogenesis. Here, we crossed mice carrying a conditional IkappaB dominant negative transgene (IkappaBdN) with mice transgenic for cell-specific FSP1.Cre (FSP1(+) fibroblasts) or gammaGT.Cre (proximal tubular epithelia) and challenged all progeny with unilateral ureteral obstruction. We determined NF-kappaB activation by nuclear localization of phosphorylated p65 ((p)p65) in renal tissues after 7 days. We observed inhibition of NF-kappaB activation in interstitial cells and tubular epithelia in obstructed kidneys of FSP1.Cre;IkappaBdN and gammaGT.Cre;IkappaBdN mice, respectively, compared with IkappaBdN controls (P < 0.05). Deposition of extracellular matrix, however, was significantly lower in the obstructed kidneys of FSP1.Cre;IkappaBdN mice but not in gammaGT.Cre;IkappaBdN mice (P < 0.05). In addition, levels of mRNA encoding the profibrotic PAI-1, fibronectin-EIIIA, and type I (alpha1) procollagen were significantly lower in obstructed kidneys of FSP1.Cre;IkappaBdN mice compared with gammaGT.Cre;IkappaBdN mice (P < 0.05). Taken together, these data support a profibrotic role for fibroblasts, but not proximal tubular epithelial cells, in modulating NF-kappaB activation during renal fibrogenesis. PMID- 20847141 TI - Renal actions of RGS2 control blood pressure. AB - G protein-coupled receptors (GPCRs) have key roles in cardiovascular regulation and are important targets for the treatment of hypertension. GTPase-activating proteins, such as RGS2, modulate downstream signaling by GPCRs. RGS2 displays regulatory selectivity for the Galphaq subclass of G proteins, and mice lacking RGS2 develop hypertension through incompletely understood mechanisms. Using total body RGS2-deficient mice, we used a kidney crosstransplantation strategy to examine separately the contributions of RGS2 actions in the kidney from those in extrarenal tissues with regard to BP regulation. Loss of renal RGS2 was sufficient to cause hypertension, whereas the absence of RGS2 from all extrarenal tissues including the peripheral vasculature did not significantly alter BP. Accordingly, these results suggest that RGS2 acts within the kidney to modulate BP and prevent hypertension. These data support a critical role for the renal epithelium and/or vasculature as the final determinants of the intra-arterial pressure in hypertension. PMID- 20847143 TI - HMGB1 contributes to kidney ischemia reperfusion injury. AB - High-mobility group box 1 (HMGB1), a nuclear factor released extracellularly as an inflammatory cytokine, is an endogenous ligand for Toll-like receptor 4 (TLR4). TLR4 activation mediates kidney ischemia-reperfusion injury (IRI), but whether HMGB1 contributes to IRI is unknown. Here, treating wild-type mice with neutralizing anti-HMGB1 antibody protected them against kidney IRI, evidenced by lower serum creatinine and less tubular damage than untreated mice. Mice treated with anti-HMGB1 had significantly less tubulointerstitial infiltration by neutrophils (day 1) and macrophages (day 5) and markedly reduced apoptosis of tubular epithelial cells. Furthermore, anti-HMGB1 antibody-treated IRI kidneys had significantly lower levels of IL-6, TNFalpha, and monocyte chemoattractant protein 1 (MCP1). mRNA, which are downstream of HMGB1. Conversely, administration of rHMGB1 after reperfusion exacerbated kidney IRI in wild-type mice. TLR4 deficient (TLR4(-/-)) mice were protected against kidney IRI; administration of neither anti-HMGB1 antibody nor rHMGB1 affected this renoprotection. In conclusion, endogenous HMGB1 promotes kidney damage after IRI, possibly through the TLR4 pathway. Administration of a neutralizing antibody to HMGB1 either before or soon after ischemia-reperfusion affords significant protection, suggesting therapeutic potential for acute kidney injury. PMID- 20847142 TI - Low socioeconomic status associates with higher serum phosphate irrespective of race. AB - Hyperphosphatemia, which associates with adverse outcomes in CKD, is more common among blacks than whites for unclear reasons. Low socioeconomic status may explain this association because poverty both disproportionately affects racial and ethnic minorities and promotes excess intake of relatively inexpensive processed and fast foods enriched with highly absorbable phosphorus additives. We performed a cross-sectional analysis of race, socioeconomic status, and serum phosphate among 2879 participants in the Chronic Renal Insufficiency Cohort Study. Participants with the lowest incomes or who were unemployed had higher serum phosphate concentrations than participants with the highest incomes or who were employed (P < 0.001). Although we also observed differences in serum phosphate levels by race, income modified this relationship: Blacks had 0.11 to 0.13 mg/dl higher serum phosphate than whites in the highest income groups but there was no difference by race in the lowest income group. In addition, compared with whites with the highest income, both blacks and whites with the lowest incomes had more than twice the likelihood of hyperphosphatemia in multivariable adjusted analysis. In conclusion, low socioeconomic status associates with higher serum phosphate concentrations irrespective of race. Given the association between higher levels of serum phosphate and cardiovascular disease, further studies will need to determine whether excess serum phosphate may explain disparities in kidney disease outcomes among minority populations and the poor. PMID- 20847145 TI - VEGF receptors and glomerular function. PMID- 20847144 TI - Anti-plasminogen antibodies compromise fibrinolysis and associate with renal histology in ANCA-associated vasculitis. AB - Antibodies recognizing plasminogen, a key component of the fibrinolytic system, associate with venous thrombotic events in PR3-ANCA vasculitis. Here, we investigated the prevalence and function of anti-plasminogen antibodies in independent UK and Dutch cohorts of patients with ANCA-associated vasculitis (AAV). We screened Ig isolated from patients (AAV-IgG) and healthy controls by ELISA. Eighteen of 74 (24%) UK and 10/38 (26%) Dutch patients with AAV had anti plasminogen antibodies compared with 0/50 and 1/61 (2%) of controls. We detected anti-plasminogen antibodies in both PR3-ANCA- and MPO-ANCA-positive patients. In addition, we identified anti-tissue plasminogen activator (tPA) antibodies in 13/74 (18%) patients, and these antibodies were more common among patients with anti-plasminogen antibodies (P = 0.011). Eighteen of 74 AAV-IgG (but no control IgG) retarded fibrinolysis in vitro, and this associated with anti-plasminogen and/or anti-tPA antibody positivity. Only 4/18 AAV-IgG retarded fibrinolysis without harboring these antibodies; dual-positive samples retarded fibrinolysis to the greatest extent. Patients with anti-plasminogen antibodies had significantly higher percentages of glomeruli with fibrinoid necrosis (P < 0.05) and cellular crescents (P < 0.001) and had more severely reduced renal function than patients without these antibodies. In conclusion, anti-plasminogen and anti tPA antibodies occur in AAV and associate with functional inhibition of fibrinolysis in vitro. Seropositivity for anti-plasminogen antibodies correlates with hallmark renal histologic lesions and reduced renal function. Conceivably, therapies that enhance fibrinolysis might benefit a subset of AAV patients. PMID- 20847146 TI - Anti-dsDNA antibodies bind to mesangial annexin II in lupus nephritis. AB - Production of anti-dsDNA antibodies is a hallmark of lupus nephritis, but how these antibodies deposit in organs and elicit inflammatory damage remains unknown. In this study, we sought to identify antigens on the surface of human mesangial cells (HMC) that mediate the binding of human anti-dsDNA antibodies and the subsequent pathogenic processes. We isolated anti-dsDNA antibodies from patients with lupus nephritis by affinity chromatography. We used multiple methods to identify and characterize antigens from the plasma membrane fraction of mesangial cells that crossreacted with the anti-dsDNA antibodies. We found that annexin II mediated the binding of anti-dsDNA antibodies to HMC. After binding to the mesangial cell surface, anti-dsDNA antibodies were internalized into the cytoplasm and nucleus. This also led to induction of IL-6 secretion and annexin II synthesis, mediated through activation of p38 MAPK, JNK, and AKT. Binding of anti-dsDNA antibodies to annexin II correlated with disease activity in human lupus nephritis. Glomerular expression of annexin II correlated with the severity of nephritis, and annexin II colocalized with IgG and C3 deposits in both human and murine lupus nephritis. Gene silencing of annexin II in HMC reduced binding of anti-dsDNA antibody and partially decreased IL-6 secretion. In summary, our data demonstrate that annexin II mediates the binding of anti-dsDNA antibodies to mesangial cells, contributing to the pathogenesis of lupus nephritis. This interaction provides a potential target for therapeutic intervention. PMID- 20847147 TI - Prevalence, correlates of, and reasons for using roll-your-own tobacco in a high RYO use country: findings from the ITC New Zealand survey. AB - AIM: To describe the prevalence, correlates of, and reasons for use of roll-your own (RYO) tobacco in a high RYO use and ethnically diverse country: New Zealand (NZ). METHODS: The NZ arm of the International Tobacco Control Policy Evaluation Survey (ITC Project) is sampled from the New Zealand Health Survey, with boosted sampling of Maori, Pacific peoples, and Asian New Zealanders. We surveyed 1,376 current adult smokers using standard ITC project procedures in 2007-2008. RESULTS: Prevalence of regularly smoking RYOs was 53% (with 38% of all smokers being exclusive RYO smokers). RYO use was higher among disadvantaged smokers, heavier smokers, those with a relatively low intention of quitting, and those with more friends who smoke. RYO use increased more in the youngest age groups as disadvantage increased. "Lower price" dominated the reasons smokers' cited for smoking RYOs (at 83%). About one fifth cited "less health concerns" as a reason. CONCLUSIONS: RYO smoking is particularly associated with individual deprivation and high levels of dependence. Its capacity to blunt price signals provided by tobacco taxes is accompanied by misperceptions that it is less hazardous to health and it is particularly prevalent among vulnerable disadvantaged populations (including Maori, young people, and those with mental health problems). Governments should reconsider removing any tax advantages given to RYO tobacco, ensure RYO smokers are properly informed of health risks, and supported to quit as strongly as other smokers. However, governments should also examine a broader range of options including a higher differential tax on RYO tobacco, removing flavors, and controlling all tobacco marketing. PMID- 20847148 TI - Does dual use jeopardize the potential role of smokeless tobacco in harm reduction? AB - INTRODUCTION: The use of smokeless tobacco as part of a strategy to reduce the harm from cigarette smoking is a topic of debate within the tobacco control and public health communities. One concern voiced regarding endorsement of such a tactic is the possibility of actually increasing harm should current smokers adopt dual cigarette/smokeless tobacco use (dual use), which could lead to unintended consequences by perpetuating cigarette smoking, diminishing tobacco cessation, or increasing tobacco-related harm. METHODS: Here, we review the available literature on health effects and trajectories of use among dual users from a variety of U.S. and European epidemiological studies. RESULTS: These data suggest that there are not any unique health risks associated with dual use of smokeless tobacco products and cigarettes, which are not anticipated or observed from cigarette smoking alone. Furthermore, studies show that dual users smoke fewer cigarettes than exclusive smokers, and studies of tobacco use patterns over time (tobacco use trajectory data) indicate that dual users are more likely than exclusive cigarette smokers to cease smoking. CONCLUSIONS: Overall, the concern about dual use appears to be contradicted by the evidence in the literature that dual use of smokeless tobacco and cigarettes may result in reduction in smoking related harm as smoking intensity is decreased and smoking cessation increases. PMID- 20847149 TI - Posttraumatic stress symptoms and cigarette deprivation in the prediction of anxious responding among trauma-exposed smokers: a laboratory test. AB - INTRODUCTION: The present investigation examined the main and interactive effects of posttraumatic stress symptom severity and 12-hr cigarette deprivation (cf. smoking as usual) in the prediction of anxious responding during a 4-min 10% carbon dioxide (CO2)-enriched air laboratory challenge. It was hypothesized that 12-hr cigarette deprivation would exacerbate the effects of posttraumatic stress symptom severity with regard to anxious responding during the challenge. METHODS: Participants were 63 daily smokers (46.0% women; M(age) = 30.79, SD = 13.12, range = 18-60) who reported experiencing one or more traumatic events. The study consisted of two laboratory sessions. At the first session, participants were administered a structured diagnostic interview and completed self-reported measures. Eligible participants were randomly assigned to one of two conditions for the second session: (a) 12-hr cigarette deprivation or (b) noncigarette deprivation (i.e., smoking as usual). At the second session, participants' smoking status was biochemically verified, and all eligible participants then were administered the 10% CO2-enriched air laboratory challenge protocol. RESULTS: The main and interactive effects of posttraumatic stress symptom severity and the smoking-as-usual condition--not the hypothesized 12-hr cigarette deprivation condition--were significantly predictive of peri-challenge anxiety. The interactive effect of posttraumatic stress by smoking as usual was significant at Minutes 3 and 4 of the challenge specifically. CONCLUSIONS: The present investigation provided novel findings related to the roles of cigarette deprivation and smoking with regard to self-reported anxious responding, among trauma-exposed smokers, during a challenge paradigm. PMID- 20847150 TI - Altered speeds and trajectories of neurons migrating in the ventricular and subventricular zones of the reeler neocortex. AB - The Reelin signaling pathway is essential for proper cortical development, but it is unclear to whether Reelin function is primarily important for cortical layering or neuron migration. It has been proposed that Reelin is perhaps required only for somal translocation but not glial-dependent locomotion. This implies that the location of neurons responding to Reelin is restricted to the outer regions of the cortical plate (CP). To determine whether Reelin is required for migration outside of the CP, we used time-lapse imaging to track the behavior of cells undergoing locomotion in the germinal zones. We focused on the migratory activity in the ventricular/subventricular zones where the first transition of bipolar to multipolar migration occurs and where functional Reelin receptors are known to be expressed. Despite Reelin loss, neurons had no difficulty in undergoing radial migration and indeed displayed greater migratory speed. Additionally, compared with the wild-type, reeler neurons displayed altered trajectories with greater deviation from a radial path. These results suggest that Reelin loss has early consequences for migration in the germinal zones that are portrayed as defective radial trajectories and migratory speeds. Together, these abnormalities can give rise to the increased cell dispersion observed in the reeler cortex. PMID- 20847151 TI - Structural and functional reorganization of the corpus callosum between the age of 6 and 8 years. AB - The establishment of an efficient exchange of information between the cerebral hemispheres is of crucial importance in the developing functionally lateralized brain. The corpus callosum, the major connection between the cerebral hemispheres, grows constantly throughout childhood and adolescence. However, behavioral studies suggest the existence of a critical time period for callosal functional development starting around the age of 6 years. In the present longitudinal study, examining a cohort of 20 children at the age of 6 and 8 years, we assessed the relationship between structural and functional callosal development during this time period. The structural development was quantified by calculating the increase in callosal thickness using a shape-based computational analysis of the mid-sagittal corpus callosum as obtained with magnetic resonance imaging. The functional development was assessed with a speech discrimination task based on the dichotic presentation of consonant-vowel syllables. The statistical analysis revealed that children whose callosal isthmus increased in thickness over the course of 2 years showed a decrease in interhemispheric information transfer. However, children exhibiting a decrease in isthmus thickness revealed an increase in information transfer. These results might indicate a refinement process of the callosal connections to optimize the neuronal communication between the developing cerebral hemispheres. PMID- 20847152 TI - Absence of layer-specific cadherin expression profiles in the neocortex of the reeler mutant mouse. AB - Cadherins are a superfamily of Ca(2+)-dependent cell surface glycoproteins that play a morphogenetic role in a wide variety of developmental processes. They provide a code of potentially adhesive cues for layer formation in mammalian cerebral cortex. One of the animal models used for studying corticogenesis is the reeler mouse. Previous investigations showed that radial neuronal migration is impaired in this mutant, possibly resulting in an inversion of cortical layers. However, the extent of this "outside-in" cortical layering remains unclear. In the present study, we investigated the mRNA expression of cadherins (Cdh4, Cdh6, Cdh7, Cdh8, Pcdh8, Pcdh9, Pcdh11, Pcdh17, and Pcdh19) in the cerebral cortex of wild-type (wt) mice and reeler mutants. All cadherins show a layer-specific expression profile in wt mice, but, in reeler cortex, cadherin-expressing cells are distributed widely across the radial dimension. The altered layering in reeler mutants completely disrupts the radial expression of cadherins, which is more patchy, rather than laminar. Regionalized gradient-like expression of cadherins is preserved. Our findings are compatible with a model, in which the ubiquitous dispersion of cadherin-expressing cells results from a dysgenesis of radial glial cells and a misrouting of migrating neuroblasts. PMID- 20847158 TI - Validation of the octamouse for simultaneous 18F-fallypride small-animal PET recordings from 8 mice. AB - Data collection in preclinical small-animal PET studies has been hindered by the small number of recordings typically obtained for a single radiosynthesis. Therefore, we tested procedures for obtaining 8 simultaneous small-animal PET recordings from the brains of 8 mice using an acrylic anesthesia distributor (the Octamouse), with the dopamine D(2/3) ligand (18)F-fallypride serving as a test substance for brain receptor imaging. METHODS: The effect of scatter correction on the small-animal PET recordings was first evaluated in phantom studies in which sources of different radioactivity concentration were placed within the chambers of the Octamouse. Next, potential effects of mass on the (18)F fallypride binding potential (BP(ND)) in the striatum were tested in groups of mice receiving (18)F-fallypride at 2 different specific activities (140 and 50 GBq/MUmol), with and without scatter correction. Finally, the relationship between BP(ND) and injected dose of (18)F-fallypride (3.5-17 MBq/mouse) was tested. RESULTS: Scatter correction improved the contrast between sources and air space within the Octamouse phantom. The magnitude of (18)F-fallypride BP(ND) in mouse striatum was invariant across the tested range of specific activities, and scatter correction increased BP(ND) by a mean of 6%; covariances of the inter- and intraoperator variability of BP(ND) were 10%. There was a positive correlation between radiochemical dose and BP(ND) with (R(2) = 0.53) and without (R(2) = 0.63) scatter correction, which was driven by increasing area under the percentage injected dose curve in the striatum. CONCLUSION: The quantitation of emission sources placed within the Octamouse is linear over a wide range of source activities. In the striatum of living mice, the magnitude of (18)F fallypride BP(ND) was highly reproducible between operators and was constant over a 3-fold range of specific activities, indicating a lack of significant occupancy. Scatter correction improved quantitation but did not entirely correct for the dependence of BP(ND) on injected dose, which was deemed to arise because of effects propagating from detector dead time when the total radiochemical dose in the field of view exceeded 50 MBq. Given this consideration, we were still able to quantify (18)F-fallypride BP(ND) in 16 mice from a single radiosynthesis, an economy that should be generalizable to brain studies of diverse radioligands. PMID- 20847153 TI - The development of audiovisual multisensory integration across childhood and early adolescence: a high-density electrical mapping study. AB - The integration of multisensory information is essential to forming meaningful representations of the environment. Adults benefit from related multisensory stimuli but the extent to which the ability to optimally integrate multisensory inputs for functional purposes is present in children has not been extensively examined. Using a cross-sectional approach, high-density electrical mapping of event-related potentials (ERPs) was combined with behavioral measures to characterize neurodevelopmental changes in basic audiovisual (AV) integration from middle childhood through early adulthood. The data indicated a gradual fine tuning of multisensory facilitation of performance on an AV simple reaction time task (as indexed by race model violation), which reaches mature levels by about 14 years of age. They also revealed a systematic relationship between age and the brain processes underlying multisensory integration (MSI) in the time frame of the auditory N1 ERP component (~ 120 ms). A significant positive correlation between behavioral and neurophysiological measures of MSI suggested that the underlying brain processes contributed to the fine-tuning of multisensory facilitation of behavior that was observed over middle childhood. These findings are consistent with protracted plasticity in a dynamic system and provide a starting point from which future studies can begin to examine the developmental course of multisensory processing in clinical populations. PMID- 20847159 TI - Validation of CT attenuation correction for high-speed myocardial perfusion imaging using a novel cadmium-zinc-telluride detector technique. AB - The aim of this study was to validate attenuation correction (AC) using low-dose standard CT for myocardial perfusion imaging (MPI) on a novel ultra fast gamma camera with cadmium-zinc-telluride (CZT) detector technology. METHODS: Sixty-six patients (body mass index +/- SD, 27.2 +/- 3.5 kg/m(2); range, 19.1-36.0 kg/m(2)) underwent a 1-d (99m)Tc-tetrofosmin adenosine stress-rest imaging protocol with 15-min acquisitions on a standard dual-head SPECT camera. All scans were repeated within minutes on the CZT camera, with 3-min acquisitions for stress (low dose) and 2-min acquisitions for rest (high dose) as recently established. We compared maximum myocardial uptake (20-segment model) from CZT versus standard SPECT MPI by intraclass correlation without and with CT AC. In addition, clinical agreement for each coronary territory for all scans from both devices was assessed, and Bland-Altmann (BA) limits of agreement for percentage uptake were calculated. RESULTS: The clinical agreement between CZT and standard SPECT cameras was 96% for noncorrected low- and high-dose images (r = 0.90 and BA = -18 to 15, and r = 0.91 and BA = -15 to 16, respectively), and agreement after AC was 96% for low- and 99% for high-dose images (r = 0.87 and BA = -16 to 14, and r = 0.88 and BA = 16 to 14, respectively). CONCLUSION: Our results support that AC of MPI on the novel CZT camera, compared with AC MPI on a conventional SPECT camera, is feasible because it provides a high correlation of segmental tracer uptake and an excellent clinical agreement. PMID- 20847160 TI - 18F-FLT PET as a surrogate marker of drug efficacy during mTOR inhibition by everolimus in a preclinical cisplatin-resistant ovarian tumor model. AB - Targeting the mammalian target of rapamycin (mTOR) pathway is a potential means of overcoming cisplatin resistance in ovarian cancer patients. Because mTOR inhibition affects cell proliferation, we aimed to study whether 3'-deoxy-3' (18)F-fluorothymidine ((18)F-FLT) PET could be useful for monitoring early response to treatment with mTOR inhibitors in an animal model of cisplatin resistant ovarian tumor. METHODS: BALB/c nude mice bearing subcutaneous human SKOV3 ovarian cancer xenografts were treated with either the mTOR inhibitor everolimus (5 mg/kg) or vehicle, and (18)F-FLT PET was performed at baseline, day 2, and day 7 of treatment. (18)F-FLT uptake was evaluated by calculation of mean standardized uptake value (SUVmean) corrected for partial-volume effect. Ex vivo immunohistochemistry studies were performed on separate cohorts of mice treated as above and sacrificed at the same time points as for the PET studies. The ex vivo analysis included bromodeoxyuridine incorporation as a marker of cell proliferation, and phosphorylation of ribosomal protein S6 as a downstream marker of mTOR activation. RESULTS: During the treatment period, no significant change in tumor (18)F-FLT uptake was observed in the vehicle group, whereas in everolimus-treated mice, (18)F-FLT SUVmean decreased by 33% (P = 0.003) at day 2 and 66% (P < 0.001) at day 7, compared with baseline. Notably, the reduction of (18)F-FLT uptake observed at day 2 in the everolimus group preceded changes in tumor volume, and a significant difference in (18)F-FLT uptake was observed between vehicle and drug-treated tumors at both day 2 (P = 0.0008) and day 7 (P = 0.01). In ex vivo studies, everolimus treatment resulted in a 98% reduction in phosphorylated ribosomal protein S6 immunostaining at day 2 (P = 0.02) and 91% reduction at day 7 (P = 0.003), compared with the vehicle group. Bromodeoxyuridine incorporation was reduced by 65% at day 2 (not significant) and by 41% at day 7 (P = 0.02) in drug versus vehicle groups. CONCLUSION: Reduction in (18)F-FLT uptake correlates well with the level of mTOR inhibition by everolimus in the SKOV3 ovarian tumor model. These data suggest that early treatment monitoring by (18)F-FLT PET may be of use in future preclinical or clinical trials evaluating treatment of cisplatin-resistant ovarian tumors by mTOR inhibitors. PMID- 20847161 TI - Substructural hippocampal glucose metabolism observed on PET/MRI. AB - The hippocampus is one of the best-known neural structures in the brain and has been of interest in observing the substructures and their metabolic functions. However, it has been difficult to distinguish its substructures and functions in vivo because of its small size. METHODS: (18)F-FDG PET and high-resolution MRI of the hippocampus were performed on 5 healthy subjects using a PET/MRI system. The metabolism of each hippocampal substructure was measured in vivo on the basis of the MR images. RESULTS: The dentate gyrus and cornu ammonis 4 showed the highest glucose uptake in the healthy subjects. CONCLUSION: Measuring glucose metabolism in the substructures of the hippocampus could provide a new tool for the future investigation of related brain diseases or functional studies, such as Alzheimer disease or memory and learning studies. PMID- 20847162 TI - ImmunoSPECT and immunoPET of IGF-1R expression with the radiolabeled antibody R1507 in a triple-negative breast cancer model. AB - The insulinlike growth factor 1 receptor (IGF-1R) is a new target for the treatment of breast cancer. Patients with breast cancer lesions that express IGF 1R may benefit from treatment with anti-IGF-1R antibodies. Therefore, the aim of the present study was to develop a noninvasive, in vivo imaging method, using radiolabeled antibodies, to visualize IGF-1R expression. METHODS: R1507 is a monoclonal antibody directed against the IGF-1R. In vitro, the affinity and internalization kinetics of (111)In-R1507 were determined using the IGF-1R expressing triple-negative breast cancer cell line SUM149. In vivo, the pharmacodynamics of (111)In-R1507 and (125)I-R1507 were determined in mice with subcutaneous SUM149 tumors. (111)In-R1507 SPECT and (89)Zr-R1507 PET images of mice with subcutaneous SUM149 tumors were acquired at 1, 3, and 7 d after injection. RESULTS: (111)In-R1507 (concentration required to inhibit binding by 50%, 0.1 nM) was slowly internalized by SUM149 cells. (111)In-R1507 specifically and efficiently accumulated in the SUM149 xenografts: the tumor uptake was 20 percentage injected dose per gram (%ID/g), 33 %ID/g, and 31 %ID/g at 1, 3, and 7 d after injection, respectively. (125)I-R1507 accumulated in the tumor less efficiently. Small-animal SPECT and small-animal PET of mice clearly visualized the subcutaneous SUM149 xenograft, with increasing contrast at later time points. CONCLUSION: (111)In-R1507 and (89)Zr-R1507 are new tracers to noninvasively determine IGF-1R expression in vivo in breast cancer xenografts using SPECT and PET. In the future, these techniques may enable patient selection for IGF-1R targeted therapy. PMID- 20847163 TI - Multicenter evaluation of a standardized protocol for rest and acetazolamide cerebral blood flow assessment using a quantitative SPECT reconstruction program and split-dose 123I-iodoamphetamine. AB - SPECT can provide valuable diagnostic and treatment response information in large scale multicenter clinical trials. However, SPECT has been limited in providing consistent quantitative functional parametric values across the centers, largely because of a lack of standardized procedures to correct for attenuation and scatter. Recently, a novel software package has been developed to reconstruct quantitative SPECT images and assess cerebral blood flow (CBF) at rest and after acetazolamide challenge from a single SPECT session. This study was aimed at validating this technique at different institutions with a variety of SPECT devices and imaging protocols. METHODS: Twelve participating institutions obtained a series of SPECT scans on physical phantoms and clinical patients. The phantom experiments included the assessment of septal penetration for each collimator used and of the accuracy of the reconstructed images. Clinical studies were divided into 3 protocols, including intrainstitutional reproducibility, a comparison with PET, and rest-rest study consistency. The results from 46 successful studies were analyzed. RESULTS: Activity concentration estimation (Bq/mL) in the reconstructed SPECT images of a uniform cylindric phantom showed an interinstitution variation of +/-5.1%, with a systematic underestimation of concentration by 12.5%. CBF values were reproducible both at rest and after acetazolamide on the basis of repeated studies in the same patient (mean +/- SD difference, -0.4 +/- 5.2 mL/min/100 g, n = 44). CBF values were also consistent with those determined using PET (-6.1 +/- 5.1 mL/min/100 g, n = 6). CONCLUSION: This study demonstrates that SPECT can quantitatively provide physiologic functional images of rest and acetazolamide challenge CBF, using a quantitative reconstruction software package. PMID- 20847164 TI - Injected dose in pediatric PET. PMID- 20847165 TI - Extravasation of hydroxymethylene diphosphonate-induced subcutaneous inflammation, histologically demonstrated in BALB/c mice. AB - We encountered local reactions at injection sites in 7 patients after an intravenous injection of (99m)Tc-hydroxymethylene diphosphonate ((99m)Tc-HDP). Archived bone scans showed radiopharmaceutical extravasation at injection sites in all patients. To identify the mechanism underlying these local reactions, we challenged BALB/c mice with an (99m)Tc-HDP injection and investigated the mechanism involved. METHODS: Seven solutions were prepared: 0.1 M acetic acid, 0.1 M NaOH, 2.1 mM (99m)Tc-HDP, 4.7 mM (99m)Tc-methylene diphosphonate ((99m)Tc MDP), 1.05 mM (99m)Tc-HDP diluted with normal saline, 37 MBq of (99m)Tc pertechnetate, and normal saline. Six female BALB/c mice were subcutaneously injected in their backs with 0.04 mL of each solution. Backs were observed, and skin and subcutaneous tissues were acquired on days 5, 7, and 19 after injection. Two pathologists interpreted the histologic specimens. RESULTS: The pH values of the 0.1 M acetic acid, 0.1 M NaOH, 2.1 mM (99m)Tc-HDP, 4.7 mM (99m)Tc-MDP, 1.05 mM (99m)Tc-HDP diluted with normal saline, 37 MBq (99m)Tc-pertechnetate, and normal saline were 3.28, 14.3, 4.79, 6.45, 6.16, 6.85, and 6.53, respectively. A slight redness was observed at (99m)Tc-HDP injection sites on day 5 after injection, and many inflammatory cells, such as neutrophils, were found to infiltrate subcutaneous tissues by light microscopy, suggesting active inflammation. However, no abnormality was found at (99m)Tc-MDP injection sites. On day 19, (99m)Tc-HDP injection sites appeared to have recovered and showed healed scars and almost-normal microscopic features. CONCLUSION: Our results indicate that the local reaction induced by extravasation of (99m)Tc-HDP is probably caused by high acidity, and (99m)Tc-HDP should be administered carefully to avoid adverse reactions. PMID- 20847166 TI - Correlation of 6-18F-fluoro-L-dopa PET uptake with proliferation and tumor grade in newly diagnosed and recurrent gliomas. AB - 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) measured with PET as a biomarker of amino acid uptake has been investigated in brain tumor imaging. The aims of the current study were to determine whether the degree of (18)F-FDOPA uptake in brain tumors predicted tumor grade and was associated with tumor proliferative activity in newly diagnosed and recurrent gliomas. METHODS: Fifty-nine patients (40 men, 19 women; mean age +/- SD, 44.4 +/- 12.3 y) with newly diagnosed (n = 22) or recurrent (n = 37) gliomas underwent (18)F-FDOPA PET perioperatively. Tumor tissue was obtained by resection or biopsy in all patients. The tumor grade and Ki-67 proliferation index were obtained by standard pathology assays. Tumor (18)F FDOPA uptake was quantified by determining various standardized uptake value (SUV) parameters (mean SUV, maximum SUV [SUVmax], mean values of voxels with top 20% SUVs, and tumor-to-normal-brain tissue ratios) that were then correlated with histopathologic grade and Ki-67 proliferation index. RESULTS: Fifty-nine lesions in 59 patients were analyzed. (18)F-FDOPA uptake was significantly higher in high grade than in low-grade tumors for newly diagnosed tumors (SUVmax, 4.22 +/- 1.30 vs. 2.34 +/- 1.35, P = 0.005) but not for recurrent tumors that had gone through treatment previously (SUVmax, 3.36 +/- 1.26 vs. 2.67 +/- 1.18, P = 0.22). An SUVmax threshold of 2.72 differentiated low-grade from high-grade tumors, with a sensitivity and specificity of 85% and 89%, respectively, using receiver operating-characteristic curve analysis (area under the curve, 0.86). (18)F-FDOPA PET uptake correlated significantly with Ki-67 tumor proliferation index in newly diagnosed tumors (r = 0.66, P = 0.001) but not in recurrent tumors (r = 0.14, P = 0.41). CONCLUSION: (18)F-FDOPA uptake is significantly higher in high-grade than in low-grade tumors in newly diagnosed but not recurrent tumors that had been treated previously. A significant correlation between (18)F-FDOPA uptake and tumor proliferation in newly diagnosed tumors was observed, whereas this correlation was not identified for recurrent tumors. Thus, (18)F-FDOPA PET might serve as a noninvasive marker of tumor grading and might provide a useful surrogate of tumor proliferative activity in newly diagnosed gliomas. PMID- 20847167 TI - Can evaluation of targeted therapy in oncology be improved by means of 18F-FLT? PMID- 20847169 TI - Characterization of a perirectal artifact in 18F-FDG PET/CT. AB - Assessing tumor involvement in the rectal region can sometimes be complicated by what appears to be an artifact on (18)F-FDG PET/CT images. This artifact manifests as a high-intensity region on the PET image, extending posterior to the bladder in the area around the rectum. The aim of this study was to describe this artifact, which-as far as we are aware-has not been previously reported, and to investigate its cause. METHODS: One hundred (18)F-FDG PET/CT studies (ordered subsets expectation maximization reconstruction, CT attenuation correction) of patients with no known malignancy in the pelvis were retrospectively reviewed. Localized regions of apparently high uptake posterior to the bladder were considered an artifact when there was a discrepancy between attenuation-corrected (asymmetric appearance) and non-attenuation-corrected images (symmetric appearance). In addition, an experiment was performed using a body phantom containing 2 cylindric inserts simulating the bladder and a region of low attenuation rectal gas. Attenuation-corrected images were reconstructed with different amounts of spatial misregistration intentionally introduced between the CT and PET images. RESULTS: The artifact was observed in 15 of 100 patient studies and had a mean maximum standardized uptake value of 4.8 +/- 2.7. When fused with sequentially acquired CT images, the artifact always appeared to be in the perirectal region near the bladder and an area of rectal gas. The phantom study indicated this artifact was consistent with an attenuation-correction problem caused by misregistration between CT and PET. Movement of gas within the rectum can cause an air pocket to be present during the PET acquisition at a location where CT indicated soft tissue. The resulting localized overcorrection for attenuation at the margin of the rectum and the extremely high activity concentration in the nearby bladder contributed to the artifact. CONCLUSION: Movement of gas within the rectum between acquisition of CT and PET images can lead to an artifact in attenuation-corrected PET images in the perirectal region. An awareness of this artifact and reference to non-attenuation-corrected images will aid in the interpretation of (18)F-FDG pelvis studies. PMID- 20847168 TI - Human biodistribution and radiation dosimetry of 82Rb. AB - Prior estimates of radiation-absorbed doses from (82)Rb, a frequently used PET perfusion tracer, yielded discrepant results. We reevaluated (82)Rb dosimetry using human in vivo biokinetic measurements. METHODS: Ten healthy volunteers underwent dynamic PET/CT (6 contiguous table positions, each with separate (82)Rb infusion). Source organ volumes of interest were delineated on the CT images and transferred to the PET images to obtain time-integrated activity coefficients. Radiation doses were estimated using OLINDA/EXM 1.0. RESULTS: The highest mean absorbed organ doses (MUGy/MBq) were observed for the kidneys (5.81), heart wall (3.86), and lungs (2.96). Mean effective doses were 1.11 +/- 0.22 and 1.26 +/- 0.20 MUSv/MBq using the tissue-weighting factors of the International Commission on Radiological Protection (ICRP), publications 60 and 103, respectively. CONCLUSION: Our current (82)Rb dosimetry suggests reasonably low radiation exposure. On the basis of this study, a clinical (82)Rb injection of 2 * 1,480 MBq (80 mCi) would result in a mean effective dose of 3.7 mSv using the weighting factors of the ICRP 103-only slightly above the average annual natural background exposure in the United States (3.1 mSv). PMID- 20847170 TI - Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain. AB - Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3',5'-cyclic adenosine-monophosphate and/or cyclic guanosine monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated (18)F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET. METHODS: The biodistribution of (18)F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors. RESULTS: Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 +/- 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A. CONCLUSION: Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET. PMID- 20847171 TI - The alpha-camera: a quantitative digital autoradiography technique using a charge coupled device for ex vivo high-resolution bioimaging of alpha-particles. AB - Bioconjugates used in internal radiotherapy exhibit heterogeneous distributions in organs and tumors, implying a risk of nonuniform dose distribution in therapeutic applications using alpha-particle emitters. Tools are required that provide data on the activity distribution for estimation of absorbed dose on a suborgan level. The alpha-camera is a quantitative imaging technique developed to detect alpha-particles in tissues ex vivo. The aim of this study was to evaluate the characteristics of this imaging system and to exemplify its potential use in the development of alpha-radioimmunotherapy. METHODS: The alpha-camera combines autoradiography with a scintillating technique and optical registration by a charge-coupled device (CCD). The imaging system characteristics were evaluated by measurements of linearity, uniformity, and spatial resolution. The technique was applied for quantitative imaging of (211)At activity distribution in cryosections of tumors, kidney, and whole body. Intratumoral activity distributions of tumor specific (211)At-MX35-F(ab')(2) were studied at various times after injection. The postinjection activity distributions in the renal cortex and whole kidneys were compared for (211)At-F(ab')(2) and (211)At-IgG trastuzumab. RESULTS: Quantitative analysis of alpha-camera images demonstrated that the pixel intensity increased linearly with activity in the imaged specimen. The spatial resolution was 35 +/- 11 MUm (mean +/- SD) and the uniformity better than 2%. Kidney cryosections revealed a higher cortex-to-whole kidney ratio for (211)At F(ab')(2) than for (211)At-IgG (1.38 +/- 0.03 and 0.77 +/- 0.04, respectively) at 2 h after injection. Nonuniform intratumoral activity distributions were found for tumor-specific (211)At-MX35-F(ab')(2) at 10 min and 7 h after injection; after 21 h, the distribution was more uniform. CONCLUSION: The characteristics of the alpha-camera are promising, suggesting that this bioimaging system can assist the development, evaluation, and refinement of future targeted radiotherapy approaches using alpha-emitters. The alpha-camera provides quantitative data on the activity distribution in tissues on a near-cellular scale and can therefore be used for small-scale dosimetry, improving the prediction of biologic outcomes with alpha-particles with short path length and high linear energy transfer. PMID- 20847172 TI - Autocontouring and manual contouring: which is the better method for target delineation using 18F-FDG PET/CT in non-small cell lung cancer? AB - Previously, we showed that a CT window and level setting of 1,600 and -300 Hounsfield units, respectively, and autocontouring using an (18)F-FDG PET 50% intensity level correlated best with pathologic results. The aim of this study was to compare this autocontouring with manual contouring, to determine which method is better. METHODS: Seventeen patients with non-small cell lung cancer underwent (18)F-FDG PET/CT before surgery. The maximum diameter on pathologic examination was determined. Seven sets of gross tumor volumes (GTVs) were defined. The first set (GTV(CT)) was contoured manually using only CT information. The second set (GTV(Auto)) was autocontoured using a 50% intensity level for (18)F-FDG PET images. The third set (GTV(Manual)) was manually contoured using a visual method on PET images. The other 4 sets combined CT and (18)F-FDG PET images fused to one another to become composite volumes: GTV(CT+Auto), GTV(CT+Manual), GTV(CT-Auto), and GTV(CT-Manual). To quantitate the degree to which CT and (18)F-FDG PET defined the same region of interest, a matching index was calculated for each case. The maximum diameter of GTV was compared with the maximum diameter on pathologic examination. RESULTS: The median GTV(CT), GTV(Auto), GTV(Manual), GTV(CT+Auto), GTV(CT+Manual), GTV(CT-Auto), and GTV(CT-Manual) were 6.96, 2.42, 4.37, 7.46, 10.17, 2.21, and 3.38 cm(3), respectively. The median matching indexes of GTV(CT) versus GTV(CT+Auto), GTV(Auto) versus GTV(CT+Auto), GTV(CT) versus GTV(CT+Manual), and GTV(Manual) versus GTV(CT+Manual) were 0.86, 0.65, 0.88, and 0.81, respectively. Compared with the maximum diameter on pathologic examination, the correlations of GTV(CT), GTV(Auto), GTV(Manual), GTV(CT+Auto), and GTV(CT+Manual) were 0.87, 0.83, 0.93, 0.86, and 0.94, respectively. CONCLUSION: The matching index was higher for manual contouring than for autocontouring using a 50% intensity level on (18)F FDG PET images. When using a 50% intensity level to contour the target of non small cell lung cancer, one should also consider using manual contouring of (18)F FDG PET to check for any missed disease. PMID- 20847173 TI - Trafficking macrophage migration using reporter gene imaging with human sodium iodide symporter in animal models of inflammation. AB - The aim of this study was to investigate the feasibility of nuclear molecular imaging using the human sodium iodide symporter (hNIS) as a reporter gene to monitor macrophage migration toward the inflammatory foci. METHODS: A stable macrophage cell line coexpressing hNIS and green fluorescent protein (GFP) genes (RAW264.7/hNIS-GFP and R(NIS) cell) was established from an immortalized macrophage cell line (RAW264.7 cells). (125)I uptake was determined (for hNIS protein functional activity), and flow cytometry analysis (to examine GFP gene expression), a cell proliferation assay, a cytokine assay, and a phagocytic activity assay were performed. (99m)Tc-pertechnetate images were acquired at 1 d after subcutaneous inoculation of R(NIS) cells in nude mice. Chemical inflammation was induced for in vivo imaging in the thigh of nude mice by turpentine oil injection. Small-animal PET with (18)F-FDG and (124)I was performed with an intravenous administration of RAW264.7 or R(NIS) cells in inflammation-induced animals. RESULTS: The expression of hNIS and GFP genes was confirmed in R(NIS) cells by flow cytometry and immunofluorescent staining. (125)I uptake was about 67 times higher in R(NIS) cells than in RAW264.7 cells. No significant difference was observed in cell proliferation, cytokine production, and phagocytic activity between RAW264.7 and R(NIS) cells. (99m)Tc pertechnetate imaging revealed increased tracer uptake at the inoculation site. PET with (124)I demonstrated a donut-shaped uptake, correlating with uptake shown by the (18)F-FDG PET images, at the inflammation site of mice administered R(NIS) cells. (124)I uptake (percentage injected dose per gram) was about 2.12 times higher at the inflammation site in the R(NIS) mice than in RAW264.7 mice. By immunohistochemistry, the migration of macrophages was further confirmed by positive staining for GFP and hNIS at the inflammation site of R(NIS) mice. CONCLUSION: These data support the feasibility of hNIS reporter gene imaging to monitor the macrophage migration toward an inflammatory lesion. Macrophages expressing hNIS may provide a new strategy to investigate the cellular behavior seen with inflammatory response in a preclinical model. PMID- 20847174 TI - Phase I trial of 90Y-DOTATOC therapy in children and young adults with refractory solid tumors that express somatostatin receptors. AB - The purpose of this study was to conduct a phase I trial of (90)Y-DOTATOC to determine the dose-toxicity profile in children and young adults with somatostatin receptor-positive tumors. METHODS: A 3 * 3 design was used to determine the highest tolerable dose of (90)Y-DOTATOC, with administered activities of 1.11, 1.48, and 1.85 GBq/m(2)/cycle given in 3 cycles at 6-wk intervals. An amino acid infusion was coadministered with the radiopharmaceutical for renal protection. Eligibility criteria included an age of 2-25 y, progressive disease, a positive lesion on (111)In-diethylenetriaminepentaacetic acid-D-Phe(1) octreotide scanning, a glomerular filtration rate of 80 mL/min/1.73 m(2) or more, bone marrow cellularity of 40% or more or stored autologous hematopoietic stem cells, 60% or more on the Lansky Play Scale, and informed consent. RESULTS: Seventeen subjects (age, 2-24 y) received at least 1 dose of (90)Y-DOTATOC; diagnoses included neuroblastoma, embryonal and astrocytic brain tumors, paraganglioma, multiple endocrine neoplasia IIB, and neuroendocrine tumors. No dose-limiting toxicities and no individual dose reductions due to renal or hematologic toxicity were noted. No complete responses were observed; 2 subjects experienced partial response, 5 had minor responses, 6 experienced stable disease, 2 had progressive disease, and 2 withdrew. CONCLUSION: Peptide receptor radionuclide therapy with (90)Y-DOTATOC is safe in children and young adults and demonstrated a 12% partial response plus 29% minor response rate in patients with somatostatin receptor-positive tumors. No dose-limiting toxicities were observed. The recommended phase II dosing is 3 cycles of 1.85 GBq/m(2)/dose of (90)Y DOTATOC coadministered with amino acids. PMID- 20847175 TI - Fine-resolution voxel S values for constructing absorbed dose distributions at variable voxel size. AB - This article presents a revised voxel S values (VSVs) approach for dosimetry in targeted radiotherapy, allowing dose calculation for any voxel size and shape of a given SPECT or PET dataset. This approach represents an update to the methodology presented in MIRD pamphlet no. 17. METHODS: VSVs were generated in soft tissue with a fine spatial sampling using the Monte Carlo (MC) code MCNPX for particle emissions of 9 radionuclides: (18)F, (90)Y, (99m)Tc, (111)In, (123)I, (131)I, (177)Lu, (186)Re, and (201)Tl. A specific resampling algorithm was developed to compute VSVs for desired voxel dimensions. The dose calculation was performed by convolution via a fast Hartley transform. The fine VSVs were calculated for cubic voxels of 0.5 mm for electrons and 1.0 mm for photons. Validation studies were done for (90)Y and (131)I VSV sets by comparing the revised VSV approach to direct MC simulations. The first comparison included 20 spheres with different voxel sizes (3.8-7.7 mm) and radii (4-64 voxels) and the second comparison a hepatic tumor with cubic voxels of 3.8 mm. MC simulations were done with MCNPX for both. The third comparison was performed on 2 clinical patients with the 3D-RD (3-Dimensional Radiobiologic Dosimetry) software using the EGSnrc (Electron Gamma Shower National Research Council Canada)-based MC implementation, assuming a homogeneous tissue-density distribution. RESULTS: For the sphere model study, the mean relative difference in the average absorbed dose was 0.20% +/- 0.41% for (90)Y and -0.36% +/- 0.51% for (131)I (n = 20). For the hepatic tumor, the difference in the average absorbed dose to tumor was 0.33% for (90)Y and -0.61% for (131)I and the difference in average absorbed dose to the liver was 0.25% for (90)Y and -1.35% for (131)I. The comparison with the 3D-RD software showed an average voxel-to-voxel dose ratio between 0.991 and 0.996. The calculation time was below 10 s with the VSV approach and 50 and 15 h with 3D-RD for the 2 clinical patients. CONCLUSION: This new VSV approach enables the calculation of absorbed dose based on a SPECT or PET cumulated activity map, with good agreement with direct MC methods, in a faster and more clinically compatible manner. PMID- 20847177 TI - Complementary roles of whole-body diffusion-weighted MRI and 18F-FDG PET: the state of the art and potential applications. AB - (18)F-FDG PET is an established functional imaging modality for the evaluation of human disease. Diffusion-weighted MRI (DWI) is another rapidly evolving functional imaging modality that can be used to evaluate oncologic and nononcologic lesions throughout the body. The information provided by (18)F-FDG PET and DWI can be complementary, because the 2 methods are based on completely different biophysical underpinnings. This article will describe the basic principles, clinical applications, and limitations of DWI. In addition, the available evidence that correlates and compares (18)F-FDG PET and DWI will be reviewed. PMID- 20847178 TI - D-18F-fluoromethyl tyrosine imaging of bone metastases in a mouse model. AB - The presence and localization of metastatic bone lesions is important for the staging of the disease and subsequent treatment decisions. Detecting tumor cells would have additional value over the current indirect bone scintigraphy method for detecting areas of elevated skeletal metabolic activity. d-(18)F-fluoromethyl tyrosine (d-(18)F-FMT) has recently shown good uptake and fast elimination, resulting in good tumor-to-background ratios. The potential of d-(18)F-FMT for imaging bone metastases has been investigated. METHODS: 786-O/luciferase human renal adenocarcinoma cells were injected intracardially, resulting in the formation of bone metastases in mice. Small-animal PET was performed 51 and 65 d after tumor cell inoculation. RESULTS: d-(18)F-FMT showed specific uptake in the bone metastases, giving excellent images with a little background in the pancreas. All imaged metastases were histologically confirmed. A bone scan with (18)F-fluoride showed elevated skeletal metabolic activity in the areas of osteolytic lesions. CONCLUSION: d-(18)F-FMT is a useful PET tracer for the detection of bone metastases and should be evaluated in the clinical setting. PMID- 20847179 TI - Added value of baseline 18F-FDG uptake in serial 18F-FDG PET for evaluation of response of solid extracerebral tumors to systemic cytotoxic neoadjuvant treatment: a meta-analysis. AB - The purpose of this study was to test the hypothesis that the level of baseline (18)F-FDG uptake in the primary tumor adds value to its relative change in (18)F FDG uptake in serial PET scans in predicting the histopathologic response to systemic cytotoxic neoadjuvant treatment of patients with solid extracerebral tumors. METHODS: We performed a literature search from January 1995 through November 2008 using PubMed and Embase. Two reviewers independently selected eligible studies for possible inclusion in the meta-analysis by reviewing titles and abstracts. Inclusion criteria were at least 10 patients, (18)F-FDG PET before and after therapy, (18)F-FDG PET performed with the intention of monitoring the response of solid extracerebral tumors in humans to cytotoxic neoadjuvant systemic therapy, attenuation-corrected (18)F-FDG PET studies, and studies presenting individual patient data (PET results and histopathologic reference test after treatment). Multilevel logistic regression was used to assess the effect of relative change of (18)F-FDG uptake ([baseline - end]/baseline) and baseline (18)F-FDG uptake value with type of tumor and type of treatment as level 1 covariates. RESULTS: Nineteen studies (all observational; a total of 438 patients [median, 23 patients per study; range, 10-40]) were included, aiming at the accuracy of PET versus histopathology. To quantify PET, maximum standardized uptake value (SUV) was used in 6 studies, mean SUV in 7, SUV (subtype unclear) in 1, tumor-to-background ratio in 3, and dose uptake ratio in 1. The average overall histopathologic response rate was 0.47 (median, 0.50), ranging from 0.17 to 0.88. The relative change in (18)F-FDG uptake was the strongest indicator (P < 0.0001) for tumor response. Baseline (18)F-FDG was not significantly associated as a main factor; however, a significant interaction of baseline uptake and relative change after therapy was observed (P < 0.001). CONCLUSION: Relative change in (18)F-FDG uptake was the strongest indicator for tumor response, but the level of baseline (18)F-FDG uptake in the primary tumor provided additional information about prediction of response to therapy. These data corroborate and extend the need for standardization, quality assurance, and control of PET studies quantifying (18)F-FDG in oncologic treatment monitoring. PMID- 20847180 TI - Potential of noninvasive serial assessment of acute renal allograft rejection by 18F-FDG PET to monitor treatment efficiency. AB - We propose (18)F-FDG PET as a method to monitor acute rejection of allogeneic renal transplants in a rat model. METHODS: Allogeneically transplanted (aTX) rats (binephrectomized Lewis-brown Norway to Lewis) served as the renal transplant model. aTX rats treated with cyclosporine A (CSA) served as a therapy monitoring group. Healthy control rats, rats with acute CSA nephrotoxicity, rats with acute tubular necrosis, syngeneically transplanted (sTX) rats, and aTX rats treated with CSA since postoperative day 0 served as controls. After surgery, renal glucose metabolism was assessed in vivo serially up to postoperative day 7 by performing small-animal PET 3 h after intravenous injection of 30 MBq of (18)F FDG. Mean radioactivity (cps/mm(3) of tissue) was measured and the percentage injected dose calculated. Results were confirmed by histologic, functional, and autoradiographic analysis. RESULTS: Renal (18)F-FDG uptake was significantly elevated at postoperative day 4 in aTX rats, when compared with control, sTX, acute tubular necrosis, or CSA-treated rats (P < 0.05). In vivo (18)F-FDG uptake correlated with the results of autoradiography and with inflammatory infiltrates observed on histologic examination. Notably, (18)F-FDG PET assessed the response to therapy 48 h earlier than the time at which serum creatinine decreased and when histologic examination still showed signs of allograft rejection. In aTX rats, the CSA-susceptible graft infiltrate was dominated by activated cytotoxic T cells and monocytes/macrophages. CONCLUSION: (18)F-FDG PET is an option to noninvasively assess early response to therapy in rat renal allograft rejection. PMID- 20847181 TI - Serotonin receptor imaging: clinically useful? AB - Serotonin is a modulatory neurotransmitter in the human brain that regulates mood, anger, reward, aggression, and appetite and plays a central role in brain development. These effects are mediated through the interaction of serotonin with at least 15 different receptor molecules. Through the development and careful characterization of novel radiotracers, we have been able to visualize and quantify in vivo many of the key molecular sites-including serotonin receptors, reuptake transporters, and enzymes-responsible for serotonin metabolism. The clinical goals of serotonin imaging are to aid in determining the pathophysiology of brain disorders, to determine novel therapeutic strategies, to predict treatment, to estimate risk, and to determine individualized dosing strategies. Despite the contradictory results of early studies, the field as a whole has made significant progress on nearly all of these fronts, and advances in methodology suggest paths toward coherence. Through concerted, directed, and cooperative efforts, the routine use of serotonin imaging in the clinic will most likely be achieved in the next decade. PMID- 20847182 TI - Performance evaluation of the FLEX triumph X-PET scanner using the national electrical manufacturers association NU-4 standards. AB - The purpose of this work was to evaluate the performance characteristics of the preclinical X-PET subsystem of the FLEX Triumph PET/CT scanner based on the NU 4 2008 standards of the National Electrical Manufacturers Association (NEMA). METHODS: The performance parameters evaluated include the spatial resolution, scatter fraction, count losses and random coincidences, sensitivity, and image quality characteristics. The PET detector array consisted of 11,520 individual bismuth germanate crystals arranged in 48 rings and 180 blocks, with an axial field of view (FOV) of 11.6 cm and a inner ring diameter of 16.5 cm. The spatial resolution was measured with a small (22)Na point source (diameter, 0.25 mm) at different radial offsets from the center. Sensitivity was calculated using the same source by stepping the source axially through the axial FOV of the scanner. Scatter fraction and counting-rate performances were determined using a mouse- and rat-sized phantom with an (18)F line source insert. The NEMA image-quality phantom and rodent imaging were also performed to access the overall imaging capabilities of the scanner. RESULTS: Tangential spatial resolution in terms of full width at half maximum varied between 2.2 mm at the center of the FOV and 2.3 mm at a radial offset of 2.5 cm. The radial spatial resolution varied between 2.0 at the center and 4.4 mm at a radial offset of 2.3 cm. The peak system absolute sensitivity was 5.9% at the center of the FOV. The absolute system sensitivity was 0.67 counts/s/Bq, and the relative total system sensitivity was 73.9%. The scatter fraction for the mouse-sized phantom was 7.9%, with a peak true counting rate of 168 kilocounts per second (kcps) at 0.3 MBq/mL and a peak noise equivalent counting rate of 106 kcps at 0.17 MBq/mL. The rat-sized phantom had a scatter fraction of 21%, with a peak true counting rate of 93 kcps at 0.034 MBq/mL and a peak noise-equivalent counting rate of 49 kcps at 0.02 MBq/mL. Recovery coefficients for the image-quality phantom ranged from 0.13 to 0.88. CONCLUSION: The performance of the X-PET scanner based on the NEMA NU 4-2008 standards was fully characterized. The overall performance demonstrates that the X-PET system is suitable for preclinical research. PMID- 20847183 TI - Human oocytes express ATP-sensitive K(+) channels. AB - BACKGROUND: ATP-sensitive K(+) (K(ATP)) channels link intracellular metabolism with membrane excitability and play crucial roles in cellular physiology and protection. The K(ATP) channel protein complex is composed of pore forming, Kir6.x (Kir6.1 or Kir6.2) and regulatory, SURx (SUR2A, SUR2B or SUR1), subunits that associate in different combinations. The objective of this study was to determine whether mammalian oocytes (human, bovine, porcine) express K(ATP) channels. METHODS: Supernumerary human oocytes at different stages of maturation were obtained from patients undergoing assisted conception treatments. Bovine and porcine oocytes in the germinal vesicle (GV) stage were obtained by aspirating antral follicles from abattoir-derived ovaries. The presence of mRNA for K(ATP) channel subunits was determined using real-time RT-PCR with primers specific for Kir6.2, Kir6.1, SUR1, SUR2A and SUR2B. To assess whether functional K(ATP) channels are present in human oocytes, traditional and perforated patch whole cell electrophysiology and immunoprecipitation/western blotting were used. RESULTS: Real-time PCR revealed that mRNA for Kir6.1, Kir6.2, SUR2A and SUR2B, but not SUR1, were present in human oocytes of different stages. Only SUR2B and Kir6.2 mRNAs were detected in GV stage bovine and porcine oocytes. Immunoprecipitation with SUR2 antibody and western blotting with Kir6.1 antibody identified bands corresponding to these subunits in human oocytes. In human oocytes, 2,4-dinitrophenol (400 uM), a metabolic inhibitor known to decrease intracellular ATP and activate K(ATP) channels, increased whole cell K(+) current. On the other hand, K(+) current induced by low intracellular ATP was inhibited by extracellular glibenclamide (30 uM), an oral antidiabetic known to block the opening of K(ATP) channels. CONCLUSIONS: In conclusion, mammalian oocytes express K(ATP) channels. This opens a new avenue of research into the complex relationship between metabolism and membrane excitability in oocytes under different conditions, including conception. PMID- 20847184 TI - Serum inhibin B concentrations in pubertal boys conceived by ICSI: first results. AB - BACKGROUND: Currently, no published data exist about the gonadal function of children born after ICSI. To evaluate potential risk of testicular seminal dysfunction in boys born to fathers with compromised spermatogenesis, serum inhibin B (as a marker for spermatogenesis) was assessed. METHODS: We recruited 50 pubertal adolescents from the oldest cohort of infants born following ICSI. Cross-sectional serum inhibin B levels of all 50 ICSI adolescents, and longitudinal serum inhibin B (assessed at 8 and 14 years) in 25 boys, are reported. RESULTS: A statistically significant increase in inhibin B levels was observed between 8 (mean 69 ng/l, SD +/- 35) and 14 years (mean 145 ng/l, SD +/- 41; P < 0.001). In three quarters of the ICSI boys an increase in serum inhibin B levels of at least 30% between 8 and 14 years was observed. In all but 4 of the 14-year-old ICSI boys serum inhibin B was normal. Serum inhibin B levels in boys from fathers with severe oligozoospermia did not differ from concentrations in boys from fathers without severe oligozoospermia (154 +/- 51 and 142 +/- 47 ng/l, respectively; P = 0.4). CONCLUSIONS: The majority of ICSI boys have a significant increase in serum inhibin B, attaining normal values for pubertal status at the age of 14 years. ICSI adolescents from fathers with severely compromised spermatogenesis do not have lower inhibin B levels than those with fathers with normal spermatograms. Further follow-up of the spermatogenic potential of ICSI teenagers up to young adulthood is mandatory to confirm a normal reproductive capacity. PMID- 20847185 TI - Who should be screened for chromosomal abnormalities before ICSI treatment? AB - Guidelines on karyotyping infertile men before ICSI treatment are not consistent. Most guidelines recommend chromosomal screening in azoospermic and severe oligozoospermic men, because they are assumed to have the highest risk of abnormalities. We performed a retrospective cohort study in azoospermic men and men eligible for ICSI. We determined the prevalence of chromosomal abnormalities in relation to sperm concentration and compared our data to studies in the literature. A high prevalence of chromosomal abnormalities in azoospermic men was found, but no difference in the prevalence of abnormalities was seen between different sperm concentration categories in non-azoospermic men. This raises the question of who should be screened for chromosomal abnormalities before ICSI treatment. Considering the costs and benefits, we would propose limiting screening to infertile couples with non-obstructive azoospermia. PMID- 20847186 TI - Identification of copy number variants in miscarriages from couples with idiopathic recurrent pregnancy loss. AB - BACKGROUND: Recurrent pregnancy loss (RPL), defined as two or more miscarriages, affects 3-5% of couples trying to establish a family. Despite extensive evaluation, no factor is identified in ~40% of cases. In this study, we investigated the possibility that submicroscopic chromosomal changes, not detectable by conventional cytogenetic analysis, exist in miscarriages with normal karyotypes (46,XY or 46,XX) from couples with idiopathic RPL. METHODS: Array comparative genomic hybridization (array-CGH) was used to assess for DNA copy number variants (CNVs) in 26 miscarriages with normal karyotypes. Parental array-CGH analysis was performed to determine if miscarriage CNVs were de novo or inherited. RESULTS: There were 11 unique (previously not described) CNVs, all inherited, identified in 13 miscarriages from 8 couples. The maternal origin of two CNVs was of interest as they involved the imprinted genes TIMP2 and CTNNA3, which are only normally expressed from the maternal copy in the placenta. Two additional cohorts, consisting of 282 women with recurrent miscarriage (RM) and 61 fertile women, were screened for these two CNVs using a Quantitative Multiplex Fluorescent PCR of Short Fragments assay. One woman with RM, but none of the fertile women, carried the CTNNA3-associated CNV. CONCLUSIONS: This preliminary study shows that array-CGH is useful for detecting CNVs in cases of RPL. Further investigations of CNVs, particularly those involving genes that are imprinted in placenta, in women with RPL could be worthwhile. PMID- 20847187 TI - Polymorphisms of endocrine gland-derived vascular endothelial growth factor gene and its receptor genes are associated with recurrent pregnancy loss. AB - BACKGROUND: Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor genes [prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2)] have been identified in the last decade and their expression is restricted to the steroidogenic glands (ovary, testis, adrenal gland and placenta). Their expression patterns also suggest a close relationship to early pregnancy. However, little information is available regarding the role of EG-VEGF and its receptors (PKR1 and PKR2) in recurrent pregnancy loss (RPL). This study was conducted to investigate the association between polymorphisms of EG-VEGF and its receptor genes (PKR1 and PKR2) and idiopathic RPL. METHODS: In this case control study, 115 women with a history of idiopathic RPL and 170 controls were included. A total of 11 tag single nucleotide polymorphisms (SNPs) selected from EG-VEGF, PKR1 and PKR2 were genotyped. We further used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. RESULTS: Two tag SNPs of PKR1 (rs4627609, rs6731838) and one tag SNP of PKR2 (rs6053283) were significantly associated with idiopathic RPL (P < 0.05). The frequencies of haplotypes C-G and T-A of PKR1 and haplotype A-G-C-G-G of PKR2 were significantly increased in women with idiopathic RPL (P < 0.05); MDR tests revealed gene-gene interactions between three loci [EG-VEGF (rs7513898), PKR1(rs6731838), PKR2(rs6053283)] based on the association model (P = 0.008). The adjusted odds ratio of high- and low-risk genotype combinations in the three locus model was 3.94 (95% confidence interval: 2.38-6.52). CONCLUSIONS: EG-VEGF receptor (PKR1, PKR2) gene polymorphisms and haplotypes were associated with idiopathic RPL. These three genes (EG-VEGF, PKR1 and PRK2) jointly contribute to RPL in the Taiwanese Han population. PMID- 20847188 TI - Relaxed acceptor site specificity of bacterial oligosaccharyltransferase in vivo. AB - A number of proteobacteria carry the genetic information to perform N-linked glycosylation, but only the protein glycosylation (pgl) pathway of Campylobacter jejuni has been studied to date. Here, we report that the pgl gene cluster of Campylobacter lari encodes for a functional glycosylation machinery that can be reconstituted in Escherichia coli. We determined that the N-glycan produced in this system consisted of a linear hexasaccharide. We found that the oligosaccharyltransferase (OST) of C. lari conserved a predominant specificity for the primary sequence D/E-X(-1)-N-X(+1)-S/T (where X(-1) and X(+1) can be any amino acid but proline). At the same time, we observed that this enzyme exhibited a relaxed specificity toward the acceptor site and modified asparagine residues of a protein at sequences DANSG and NNNST. Moreover, C. lari pgl glycosylated a native E. coli protein. Bacterial N-glycosylation appears as a useful tool to establish a molecular description of how single-subunit OSTs perform selection of glycosyl acceptor sites. PMID- 20847189 TI - In vivo wall shear stress distribution in the carotid artery: effect of bifurcation geometry, internal carotid artery stenosis, and recanalization therapy. AB - BACKGROUND: the purpose of this study was to analyze the in vivo distribution of absolute wall shear stress (WSS(abs)) and oscillatory shear index (OSI) in the carotid bifurcation and to evaluate its dependence on bifurcation geometry, the presence of internal carotid artery (ICA) stenosis, and recanalization therapy. METHODS AND RESULTS: time-resolved 3D blood flow was acquired with flow-sensitive 4D MRI in 64 normal carotid bifurcations and 17 carotid arteries with moderate ICA stenosis (48+/-6%) or after surgical recanalization. Among 64 normal arteries, atherogenic wall parameters were consistently concentrated in proximal bulb regions of the common (CCA) and internal (ICA) carotid arteries. The fraction of the carotid bulb exposed to atherosclerosis-prone wall parameters (low WSS(abs) below and high OSI above group-defined 20% and 10% thresholds) was correlated with the individual bifurcation geometry. Multiple regressions revealed significant (P<0.01) relationships (beta, 0.44 to 0.48) between the areas with atherosclerosis-prone wall parameters and the d(ICA)/d(CCA) diameter ratio. The size of regions exposed to high OSI demonstrated highly significant (P<=0.01) relationships with all analyzed geometry parameters (d(ICA)/d(CCA) beta, 0.48; tortuosity beta, <=-0.56; bifurcation angle beta, >=0.47). Moderate ICA stenosis altered the distribution of wall parameters (45%/61% reduction of individually low WSS(abs)/high OSI in the proximal ICA), which were relocated to segments distal to the arterial stenosis. WSS(abs)/OSI topology after recanalization was similar compared with the normal wall parameter distribution. CONCLUSIONS: flow-sensitive 4D MRI identified alterations in the segmental in vivo WSS distribution associated with atherosclerotic disease, surgical therapy, and individual bifurcation geometry and could be a valuable technique to assess the individual risk of flow-mediated atherosclerosis and carotid plaque progression. PMID- 20847190 TI - Changes in mitral annular geometry and dynamics with beta-blockade in patients with degenerative mitral valve disease. AB - BACKGROUND: remodeling of the mitral annulus contributes to progression of mitral regurgitation (MR). In patients with moderate-to-severe MR, short-term treatment with beta-blockers has been shown to increase left ventricular (LV) end-diastolic and end-systolic volume, and this could deleteriously increase mitral valve annular dimensions. The objective of this study was to quantify the effects of a short duration of beta-blocker treatment on mitral annular dimensions and dynamics in patients with MR due to primary degenerative valve disease. METHODS AND RESULTS: twenty-five patients with moderate-to-severe degenerative MR and normal LV systolic function were studied in a double-blind crossover experiment using a beta1-selective adrenergic blocker and placebo administered for 14+/-3 days. Cardiac MRI images were acquired after each treatment period to quantify mitral annular dimensions. At end diastole, there was no change in annular area (1659+/-331 versus 1632+/-299 mm(2); P<0.19), annular perimeter (154.3+/-16.4 versus 152+/-13.9 mm; P<0.13), septal-lateral (SL) dimension (38.0+/-5 versus 39.0+/-4.5 mm; P<0.15), or annular height (9.8+/-3.8 versus 9.5+/-2.5 mm; P<0.53). beta-blockade resulted in significant end-diastole decreases in commissure-commissure dimension (48.9+/-4.6 versus 47.2+/-4.0 mm; P<0.01) and eccentricity (1.3+/-0.2 versus 1.2+/-0.1; P<0.01). At end systole (ES), beta blockade conferred a small, but significant decrease in annular perimeter (161.0+/-19.3 versus 156.8+/-16.9 mm; P<0.04) and eccentricity (1.2+/-0.1 versus 1.1+/-0.1; P<0.02), and the SL dimension significantly increased (41.5+/-5.7 versus 43.0+/-5.3 mm; P<0.03). Commissure-commissure dimension, annular area, and annular height at ES were not significantly different. CONCLUSIONS: despite significant increases in LV end-diastolic and end-systolic volume, short-term beta-blocker treatment of patients with moderate-to-severe MR reduced or preserved all mitral annular dimensions except SL at ES. PMID- 20847192 TI - Thermally denatured BSA, a surrogate additive to replace BSA in buffers for high throughput screening. AB - The use of thermally denatured bovine serum albumin (tdBSA) as an additive in high-throughput screening (HTS) buffers has been studied with the aim of finding a surrogate to native albumin devoid of its inconveniences, in particular its compound masking effect. The presence of aggregates in the thermally denatured material did not have any negative impact on common readout technologies used in HTS such as fluorescence intensity (FLINT), fluorescence polarization, time resolved fluorescence resonance energy transfer (TR-FRET) and luminescence. tdBSA rendered the same beneficial effects as native albumin in several assays or even improved its performance due to the lack of specific binding properties. Although tdBSA still binds compounds nonspecifically as any other protein does, it mitigates the compound masking effect observed with native albumin and can be postulated as a convenient surrogate to BSA for HTS purposes. PMID- 20847191 TI - Late gadolinium-enhancement cardiac magnetic resonance identifies postinfarction myocardial fibrosis and the border zone at the near cellular level in ex vivo rat heart. AB - BACKGROUND: using a resolution 1000-fold higher than prior studies, we studied (1) the degree to which late gadolinium-enhancement (LGE) cardiac magnetic resonance tracks fibrosis from chronic myocardial infarction and (2) the relationship between intermediate signal intensity and partial volume averaging at distinct "smooth" infarct borders versus disorganized mixtures of fibrosis and viable cardiomyocytes. METHODS AND RESULTS: sprague-Dawley rats underwent myocardial infarction by coronary ligation. Two months later, rats were euthanized 10 minutes after administration of 0.3 mmol/kg intravenous gadolinium. LGE images ex vivo at 7 T with a 3D gradient echo sequence with 50*50*50 MUm voxels were compared with histological sections (Masson trichrome). Planimetered histological and LGE regions of fibrosis correlated well (y=1.01x-0.01; R(2)=0.96; P<0.001). In addition, LGE images routinely detected clefts of viable cardiomyocytes 2 to 4 cells thick that separated bands of fibrous tissue. Although LGE clearly detected disorganized mixtures of fibrosis and viable cardiomyocytes characterized by intermediate signal intensity voxels, the percentage of apparent intermediate signal intensity myocardium increased significantly (P<0.01) when image resolution was degraded to resemble clinical resolution consistent with significant partial volume averaging. CONCLUSIONS: these data provide important validation of LGE at nearly the cellular level for detection of fibrosis after myocardial infarction. Although LGE can detect heterogeneous patches of fibrosis and viable cardiomyocytes as patches of intermediate signal intensity, the percentage of intermediate signal intensity voxels is resolution dependent. Thus, at clinical resolutions, distinguishing the peri-infarct border zone from partial volume averaging with LGE is challenging. PMID- 20847194 TI - Review: clinical pathways improved patient outcomes, documentation and costs. PMID- 20847195 TI - New signs, new diagnosis? PMID- 20847193 TI - "I could move mountains": adults with or at risk for type 2 diabetes reflect on their experiences with yoga practice. AB - PURPOSE: The purpose of this study was to describe firsthand experiences with yoga as shared by adults with or at risk for type 2 diabetes and to examine their beliefs regarding maintenance of yoga practice over time. METHODS: In this qualitative study, 13 adults with or at risk for type 2 diabetes described their experiences with yoga and their beliefs regarding maintenance of yoga practice over time. Semistructured interviews occurred 16 to 20 months after completion of an 8-week yoga-based clinical trial. RESULTS: Themes of readiness for continuing yoga, environmental support for yoga, and integrating yoga emerged through data analysis. CONCLUSIONS: Findings indicate that yoga is appealing to some individuals with diabetes, but maintaining yoga practice over time is a challenge. Diabetes educators may be able to support maintenance by discussing specific strategies with individuals who express interest in yoga practice. PMID- 20847196 TI - Mist and water condensation inside incubators reduce the efficacy of phototherapy. AB - OBJECTIVE: To measure the irradiance in humidified incubator under three different overhead phototherapy devices. DESIGN/METHODS: The effective irradiance of three phototherapy devices was assessed by taking a series of irradiance measurements in the illuminated field. Measurements were made with a fixed bandwidth broadband radiometer (380-530 nm). The distance between the light source and the radiometer was 35 cm for the daylight fluorescent lamp, 40 cm for the light emitting diode (LED) and 50 cm for the halogen phototherapy. A double wall incubator was kept at 36 degrees C and set at three different levels of humidity (60-70%, 80% and equal or above 90%). RESULTS: The irradiance under the overhead daylight fluorescent lamp phototherapy did not change with the increasing humidity. However, above 90% humidity, when water vapour inside the incubator was so saturated to the point of totally condensing in the incubator walls, the measured irradiance decreased 15% of the initial values with the blue LED phototherapy and 45% with the halogen spotlight phototherapy. CONCLUSIONS: Highly humidified incubators are frequently used to treat very low birthweight infants. Health professionals should be aware that mist and water condensation inside an incubator may significantly reduce the efficacy of treatment. PMID- 20847197 TI - The two-thumb is superior to the two-finger method for administering chest compressions in a manikin model of neonatal resuscitation. AB - BACKGROUND: Current neonatal guidelines endorse both the two-thumb and the two finger techniques for performing chest compressions. It remains unclear whether one method is superior to the other in achieving consistent depth. OBJECTIVE: To compare the compression depth, variability, rate and finger placement of the two thumb and two-finger techniques using a compression to ventilation (CV) ratio of 3:1. METHODS: 25 subjects (physicians and neonatal nurses) participated with compressions performed on a manikin. Subjects were video recorded. Evaluations included continuous compression administered for 60 s, followed by 2 min of compressions using a 3:1 CV ratio for each of the two techniques. RESULTS: Depth during 60 s of uninterrupted compressions was greater for the two-thumb than the two-finger technique (27.2+/-5.7 vs 22.1+/-4.6 mm; p=0.0008), variability was less (6.7%+/-3.2% vs 9.0%+/-2.8%; p=0.002) and rate was comparable (118+/-22 vs 116+/-24 compressions/min). With a 3:1 CV ratio, depth was greater for the two thumb compared to the two-finger method (29+/-5.4 vs 23.7+/-5.8 mm; p=0.0009), variability was less (6.1%+/-2.9% vs 9.8%+/-3.1%; p=0.00002) and rate was comparable (192+/-26 vs 197+/-31 compressions/2 min). Correct positioning was accomplished more often with the two-thumb than the two-finger technique (21/25 vs 3/25; p=0.0005). CONCLUSIONS: The two-thumb technique is superior to the two finger technique, achieving greater depth and less variability with each compression. The two-finger technique was incorrectly applied in most cases and deviations in technique may have contributed to the significant differences in depth. PMID- 20847199 TI - Are the UK clinical guidelines for H1N1 influenza infection valid in the hospital setting? AB - The diagnosis of pandemic influenza is clinical. This prospective study questions the validity of the Department of Health guidelines in 77 children admitted to hospital. The positive predictive value for the guidelines was 0.39. Although H1N1 was identified in a sizeable minority of cases using the guidelines, virology testing is still required. PMID- 20847200 TI - A new form of assessment for paediatric trainees: readiness for consultant practice. PMID- 20847201 TI - Using genetic and clinical data to understand response to disease-modifying anti rheumatic drug therapy: data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study. AB - The objective of this review is to report on the progress of the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) Registry data collection and summarize previous research in understanding therapeutic response to DMARDs using clinical and genetic data. The BRASS Registry, established in 2003, is a large, single-centre, prospective and observational cohort of 1100 RA patients. Patients with either new-onset or established RA disease are recruited from the practices of rheumatologists. Annual visits collect information on demographics, 28-joint DAS-CRP3 (DAS-28-CRP3), medication use, comorbidities and functional status (Modified Health Assessment Questionnaire, Short Form Health Survey 12). Two published studies have utilized BRASS to examine genetic predictors of treatment response. In a cross-sectional study, examining the association between candidate single nucleotide polymorphisms (SNPs) and disease activity in a subset of 120 RA patients on MTX monotherapy, the minor allele of ATIC rs4673993 was associated with low disease activity (P=0.01, DAS-28 CRP3<=3.2). In an international collaboration, 55 BRASS patients receiving anti TNF therapy were genotyped for 31 SNPs associated with the risk of RA. With our collaborators, we discovered an SNP at the protein tyrosine phosphatase, receptor type, C (PTPRC) gene locus that was associated with EULAR 'good response'. With accurate data collection and the capacity to run genome-wide association studies and SNP analyses, the BRASS Registry has the ability to determine the contribution of genetic variants to disease onset and to assess their usefulness as biomarkers for treatment response and drug toxicity. PMID- 20847202 TI - Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model. AB - Type I mucopolysaccharidosis (MPS I) is a lysosomal storage disorder caused by the deficiency of alpha-L-iduronidase, which results in glycosaminoglycan accumulation in tissues. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation (the last being present exclusively in the severe Hurler variant). The available treatments, enzyme-replacement therapy and hematopoietic stem cell (HSC) transplantation, can ameliorate most disease manifestations, but their outcome on skeletal and brain disease could be further improved. We demonstrate here that HSC gene therapy, based on lentiviral vectors, completely corrects disease manifestations in the mouse model. Of note, the therapeutic benefit provided by gene therapy on critical MPS I manifestations, such as neurologic and skeletal disease, greatly exceeds that exerted by HSC transplantation, the standard of care treatment for Hurler patients. Interestingly, therapeutic efficacy of HSC gene therapy is strictly dependent on the achievement of supranormal enzyme activity in the hematopoietic system of transplanted mice, which allows enzyme delivery to the brain and skeleton for disease correction. Overall, our data provide evidence of an efficacious treatment for MPS I Hurler patients, warranting future development toward clinical testing. PMID- 20847204 TI - Parasympathetic control of blood flow to the activated human brain. PMID- 20847205 TI - Telomere disrupts, CLL progresses. PMID- 20847203 TI - T-cell receptor signals direct the composition and function of the memory CD8+ T cell pool. AB - SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) nucleates a signaling complex critical for T-cell receptor (TCR) signal propagation. Mutations in the tyrosines of SLP-76 result in graded defects in TCR-induced signals depending on the tyrosine(s) affected. Here we use 2 strains of genomic knock-in mice expressing tyrosine to phenylalanine mutations to examine the role of TCR signals in the differentiation of effector and memory CD8(+) T cells in response to infection in vivo. Our data support a model in which altered TCR signals can determine the rate of memory versus effector cell differentiation independent of initial T-cell expansion. Furthermore, we show that TCR signals sufficient to promote CD8(+) T-cell differentiation are different from those required to elicit inflammatory cytokine production. PMID- 20847206 TI - Transplantation in AML CR1. PMID- 20847207 TI - Immune rage against MAGE unleashed. PMID- 20847208 TI - BRAF, a piece of the LCH puzzle. PMID- 20847209 TI - SR-BI and fatty platelets. PMID- 20847210 TI - Megakaryocytes muscle in. PMID- 20847211 TI - Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. PMID- 20847212 TI - Significantly higher frequencies of alloreactive CD4+ T cells responding to nonpermissive than to permissive HLA-DPB1 T-cell epitope disparities. PMID- 20847213 TI - t(X;14)(p22;q32)/t(Y;14)(p11;q32) CRLF2-IGH translocations from human B-lineage ALLs involve CpG-type breaks at CRLF2, but CRLF2/P2RY8 intrachromosomal deletions do not. PMID- 20847214 TI - Detection of the JAK2V617F mutation with the Ipsogen MutaScreen kit: absence of JAK2V617F does not mean absence of myeloproliferative neoplasm. PMID- 20847215 TI - Beta 2 glycoprotein I is a substrate of thiol oxidoreductases. PMID- 20847216 TI - Characterizing molecular adaptation: a hierarchical approach to assess the selective influence of amino acid properties. AB - MOTIVATION: A number of methods for detecting positive selection in protein coding DNA sequences are based on whether each site/region has a non-synonymous to synonymous substitution rates ratio omega greater than one. However, a site/region may show a relatively large number of non-synonymous mutations that conserve a particular property. Recent methods have proposed to consider as evidence for molecular adaptations how conserving, or radically different, non synonymous mutations are with respect to some key amino acid properties. While such methods have been useful in providing a qualitative assessment of molecular adaptation, they rely on independent statistical analyses for each amino acid property and typically do not properly adjust for multiple comparisons when selection needs to be assessed at several sites. RESULTS: We consider a Bayesian hierarchical model that allows us to jointly determine if a set of amino acid properties are being conserved or radically changed while simultaneously adjusting for multiple comparisons at the codon level. We illustrate how this model can be used to characterize molecular adaptation in two datasets: an alignment from six class I alleles of the human major histocompatibility complex and a sperm lysin alignment from 25 abalone species. We compare the results obtained with the proposed hierarchical models to those obtained with alternative methods. Our analyses indicate that a more complete quantitative and qualitative characterization of molecular adaptation is achieved by taking into account changes in amino acid properties. AVAILABILITY: The R code for implementing the hierarchical models is freely available at http://www.ams.ucsc.edu/~raquel/software/. PMID- 20847217 TI - Spatial quantification and classification of skin response following perturbation using organotypic skin cultures. AB - MOTIVATION: For a mechanistic understanding of skin and its response to an induced perturbation, systems biology is gaining increasing attention. Unfortunately, quantitative and spatial expression data for skin, like for most other tissues, are almost not available. RESULTS: Integrating organotypic skin cultures, whole-slide scanning and subsequent image processing provides bioinformatics with a novel source of spatial expression data. We here used this approach to quantitatively describe the effect of treating organotypic skin cultures with sodium dodecyl sulphate in a non-corrosive concentration. We first measured the differentiation-related spatial expression gradient of Heat-Shock Protein 27 in a time series of up to 24 h. Secondly, a multi-dimensional tissue classifier for predicting skin irritation was developed based on abstract features of these profiles. We obtained a high specificity of 0.94 and a sensitivity of 0.92 compared with manual classification. Our results demonstrate that the integration of tissue cultures, whole-slide scanning and image processing is well suited for both the standardized data acquisition for systems biological tissue models and a highly robust classification of tissue responses. PMID- 20847218 TI - Ruffus: a lightweight Python library for computational pipelines. AB - SUMMARY: Computational pipelines are common place in scientific research. However, most of the resources for constructing pipelines are heavyweight systems with graphical user interfaces. Ruffus is a library for the creation of computational pipelines. Its lightweight and unobtrusive design recommends it for use even for the most trivial of analyses. At the same time, it is powerful enough to have been used for complex workflows involving more than 50 interdependent stages. AVAILABILITY AND IMPLEMENTATION: Ruffus is written in python. Source code, a short tutorial, examples and a comprehensive user manual are freely available at http://www.ruffus.org.uk. The example program is available at http://www.ruffus.org.uk/examples/bioinformatics PMID- 20847219 TI - Combined prediction of Tat and Sec signal peptides with hidden Markov models. AB - MOTIVATION: Computational prediction of signal peptides is of great importance in computational biology. In addition to the general secretory pathway (Sec), Bacteria, Archaea and chloroplasts possess another major pathway that utilizes the Twin-Arginine translocase (Tat), which recognizes longer and less hydrophobic signal peptides carrying a distinctive pattern of two consecutive Arginines (RR) in the n-region. A major functional differentiation between the Sec and Tat export pathways lies in the fact that the former translocates secreted proteins unfolded through a protein-conducting channel, whereas the latter translocates completely folded proteins using an unknown mechanism. The purpose of this work is to develop a novel method for predicting and discriminating Sec from Tat signal peptides at better accuracy. RESULTS: We report the development of a novel method, PRED-TAT, which is capable of discriminating Sec from Tat signal peptides and predicting their cleavage sites. The method is based on Hidden Markov Models and possesses a modular architecture suitable for both Sec and Tat signal peptides. On an independent test set of experimentally verified Tat signal peptides, PRED-TAT clearly outperforms the previously proposed methods TatP and TATFIND, whereas, when evaluated as a Sec signal peptide predictor compares favorably to top-scoring predictors such as SignalP and Phobius. The method is freely available for academic users at http://www.compgen.org/tools/PRED-TAT/. PMID- 20847220 TI - Evidence mining and novelty assessment of protein-protein interactions with the ConsensusPathDB plugin for Cytoscape. AB - SUMMARY: Protein-protein interaction detection methods are applied on a daily basis by molecular biologists worldwide. After generating a set of potential interactions, biologists face the problem of highlighting the ones that are novel and collecting evidence with respect to literature and annotation. This task can be as tedious as searching for every predicted interaction in several interaction data repositories, or manually screening the scientific literature. To facilitate the task of evidence mining and novelty assessment of protein-protein interactions, we have developed a Cytoscape plugin that automatically mines publication references, database references, interaction detection method descriptions and pathway annotation for a user-supplied network of interactions. The basis for the annotation is ConsensusPathDB-a meta-database that integrates numerous protein-protein, signaling, metabolic and gene regulatory interaction repositories for currently three species: Homo sapiens, Saccharomyces cerevisiae and Mus musculus. AVAILABILITY: The ConsensusPathDB plugin for Cytoscape (version 2.7.0 or later) can be installed within Cytoscape on a major operating system (Windows, Mac OS, Unix/Linux) with Sun Java 1.5 or later installed through Cytoscape's Plugin manager (category 'Network and Attribute I/O'). The plugin is freely available for download on the ConsensusPathDB web site (http://cpdb.molgen.mpg.de). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 20847221 TI - Near-infrared spectroscopy for arthroscopic evaluation of cartilage lesions: results of a blinded, prospective, interobserver study. AB - BACKGROUND: Mechanical tests to grade cartilage damage are limited by the instruments used and by the ability to access all areas of cartilage within a joint. Better methods to diagnose cartilage injury or degeneration are needed. Purpose/ HYPOTHESIS: To detect the interobserver variance of arthroscopic cartilage grading by subjective judgment using the International Cartilage Repair Society (ICRS) score and by objective measurement using near-infrared (NIR) spectroscopy. We hypothesized that objective measurement of cartilage lesions by NIR spectroscopy will yield more valid results than routine grading using the ICRS score. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Fifteen patients undergoing arthroscopic knee operations were evaluated by 4 experienced arthroscopists independently. The cartilage lesions within the medial knee compartment were estimated by each observer using the ICRS grade and by measurements with a special arthroscopic NIR spectroscopy probe. RESULTS: The ICRS grading had a poor interobserver agreement, with a mean Fleiss kappa index of kappa = 0.173. Only in 10% (6 of 60) of judged cartilage areas did all 4 surgeons grade the cartilage areas with the same result. In 17 areas (28.3%), the surgeons had a variance of 2 or more grades. In the remaining cases, the surgeons varied within 1 grade. The objective NIR spectroscopy-obtained measurements of cartilage resulted in a significant correlation within the observers of R = 0.885 +/- 0.036 (P < .001). CONCLUSION: Our results of interobserver evaluation in real time arthroscopic cartilage grading suggest that this subjective grading is not satisfactory. This study emphasizes the need for objective measurement techniques for arthroscopic cartilage grading. Near-infrared spectroscopy has a good interobserver correlation. Thus, this method could be developed in the future as a precise method of measuring cartilage lesions. PMID- 20847222 TI - Size variability of the human anterior cruciate ligament insertion sites. AB - BACKGROUND: Current trends in anterior cruciate ligament reconstruction (ACLR) have been toward anatomical reconstruction that restores the normal size and location of the anterior cruciate ligament insertions and its 2 bundles, the posterolateral (PL) and anteromedial (AM) bundles. This has resulted in a more individualized approach to ACLR. Several studies have shown that the size of the anterior cruciate ligament insertion sites is variable; however, these studies are limited by use of relatively small sample sizes and cadaveric specimens. PURPOSE: This study was undertaken to evaluate the in vivo size variability of the anterior cruciate ligament insertion sites and its AM and PL bundles during arthroscopy in a large series of patients and to correlate these findings with individuals' physical characteristics (height, weight, and body mass index). STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: In 137 patients undergoing ACLR during the first 6 months after injury, the femoral and tibial anterior cruciate ligament insertion sites and the 2 bundles were identified, marked with electrocautery, and measured with an arthroscopic ruler. Additionally, physical characteristics of the patients, including self-reported height, weight, and body mass index, were recorded. RESULTS: The tibial anterior cruciate ligament insertion site had a mean length of 17.0 +/- 2.0 mm. The tibial AM bundle length was 9.1 +/- 1.2 mm and the width was 9.2 +/- 1.1 mm. The tibial PL bundle insertion site length averaged 7.4 +/- 1.0 mm and the width averaged 7.0 +/- 1.0 mm. The femoral insertion sites had a mean length of 16.5 +/- 2.0 mm. The length of the femoral AM bundle insertion site averaged 9.2 +/- 1.2 mm and the width averaged 8.9 +/- 0.9 mm. The femoral PL bundle insertion site length averaged 7.1 +/- 1.1 mm and the width averaged 6.9 +/- 1.0 mm. There were significant positive correlations between patient height and weight (P < .05) with femoral and tibial anterior cruciate ligament insertion site length, tibial PL bundle insertion site length, femoral AM bundle insertion site length, and tibial AM bundle and PL bundle insertion site areas. However, the coefficients of determination values were low (1.0% to 19.4%). CONCLUSION: There is a large variation in size of the anterior cruciate ligament insertion sites and the AM and PL bundles. Additionally, there are significant but weak correlations between the size of the insertions and height, weight, and body mass index of the individual patient. PMID- 20847223 TI - In vivo stability and clinical comparison of anterior cruciate ligament reconstruction using low or high femoral tunnel positions. AB - BACKGROUND: Several biomechanical studies have supported placing the femoral tunnel at a low position (10 or 2 o'clock) to achieve anterior and rotational knee stabilities after anterior cruciate ligament (ACL) reconstruction. However, no firm consensus has been reached regarding the merits and demerits of ACL reconstruction using a low femoral tunnel versus a high femoral tunnel (11 or 1 o'clock). HYPOTHESIS: A low femoral tunnel position during ACL reconstruction provides better intraoperative stability (especially, rotational stability) and clinical outcomes than does a high femoral tunnel position. STUDY DESIGN: Cohort study; Level of evidence 2. METHODS: Sixty-two patients who underwent ACL reconstruction were equally allocated to low and high femoral tunnel groups; 58 were followed up for a minimum of 2 years (29 in the each group). After reconstruction and using a navigation system, the authors compared intraoperative anterior, internal rotational, and external rotational stabilities at 0 degrees , 30 degrees , 60 degrees , and 90 degrees of knee flexion and compared clinical outcomes, including Lysholm knee scores, Tegner activity scores, Lachman and pivot-shift test findings, and radiographic stabilities at final follow-up visits. RESULTS: The low group showed significantly better intraoperative internal rotational stability at 0 degrees and 30 degrees of flexion but not at other angles (60 degrees and 90 degrees ). Intraoperatively, no significant intergroup differences were found for anterior and external rotational stabilities at any flexion angle. Furthermore, clinical outcomes, including Lysholm knee and Tegner activity scores, showed no significant differences between the 2 groups at final follow-up visits (P > .05), and Lachman and pivot shift test stability results and radiological stability data obtained at final follow-up were not significantly different between the 2 groups (P > .05). CONCLUSION: The low femoral tunnel group showed better internal rotational stability at time zero during ACL reconstruction but similar anterior and external rotational stabilities. No significant differences were observed between the 2 groups in terms of clinical outcomes and stabilities after a minimum follow up of 2 years. PMID- 20847224 TI - Arthroscopic restoration of terminal elbow extension in high-level athletes. AB - BACKGROUND: Although most people can lead near-normal lives with a limited but functional arc of elbow motion, athletes may find loss of terminal extension severely impairing. HYPOTHESIS: Arthroscopic contracture release is effective in restoring full elbow extension in athletes whose loss of terminal extension impairs their intensities and/or levels of performance in sport. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Between 1997 and 2007, 24 athletes (26 elbows; mean age, 38 years [range, 12-58]) whose chief complaint was limited elbow extension (<=35 degrees ) underwent arthroscopic release of contractures (average follow-up, 33 months [range, 12-88]). All the patients were classified according to a sport-specific scoring system using the subjective patient outcome for return to sports score and the summary outcome determination score. RESULTS: All 26 elbows improved subjectively and objectively with surgery. Of the 26 elbows, 25 were rated by the patients as normal (n = 15) or near-normal (n = 10) at final follow-up. Pain during intense sporting activities was absent in 17, mild and occasional without affecting performance in 6, and severe enough to affect performance in 1. Of the 24 patients (26 elbows), 22 patients (23 elbows) returned to the same sport at the same level of intensity and performance as before injury. Two patients (3 elbows) returned to the same sport but failed to reach their preinjury levels of performance. Extension improved in all patients, with the average flexion contracture decreasing from 27 degrees +/- 7 degrees (range, 10 degrees -35 degrees ) to 6 degrees +/- 9 degrees (range, 10 degrees of hyperextension to 25 degrees ; P < .001). Lack of extension was not a residual impairment factor in any patients. Three patients developed delayed-onset ulnar neuropathy after surgery, 2 of which were treated by subcutaneous transposition. All 3 resolved completely, 2 within the first 6 weeks; the other took longer than a year. CONCLUSION: The arthroscopic release of contractures is a predictable technique to achieve a highly functional elbow in athletes. PMID- 20847225 TI - Overuse injuries in professional road cyclists. AB - BACKGROUND: Little epidemiological information exists on overuse injuries in elite road cyclists. Anecdotal reports indicate anterior knee pain and lower back pain may be common problems. PURPOSE: This study was conducted to register overuse injuries among professional road cyclists with special focus on anterior knee and lower back pain. STUDY DESIGN: Descriptive epidemiology study. METHODS: We attended training camps of 7 professional teams and interviewed 109 of 116 cyclists (94%) on overuse injuries they had experienced in the previous 12 months. Injuries that required attention from medical personnel or involved time loss from cycling were registered. Additional information on anterior knee pain and lower back pain was collected using specific questionnaires. RESULTS: A total of 94 injuries were registered; 45% were in the lower back and 23% in the knee. Twenty-three time-loss injuries were registered-57% in the knee, 22% in the lower back, and 13% in the lower leg. Fifty-eight percent of all cyclists had experienced lower back pain in the previous 12 months, and 41% of all cyclists had sought medical attention for it. Thirty-six percent had experienced anterior knee pain and 19% had sought medical attention for it. Few cyclists had missed competitions because of pain in the lower back (6%) or anterior knee (9%). CONCLUSION: Lower back pain and anterior knee pain were the most prevalent overuse injuries, with knee injuries most likely to cause time loss and lower back pain causing the highest rates of functional impairment and medical attention. CLINICAL RELEVANCE: Future efforts to prevent overuse injuries in competitive cyclists should focus on lower back pain and anterior knee pain. PMID- 20847226 TI - Injury in community-level soccer: development of an injury surveillance system. AB - BACKGROUND: Few descriptive epidemiologic studies of injury in soccer are of community-level players. Although many sports injury surveillance systems have been described in the scientific literature, only 1 has been implemented in community-level soccer and that was restricted to adolescent players in a single club. PURPOSE: The objective of this study was to develop a method for undertaking routine surveillance of injury in community-level soccer. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A cohort of 880 community level players aged 13 years and over was followed over 1 winter competitive season. Each week, each player was contacted by telephone and an interview conducted to collect data on participation in matches and training sessions, injuries, and adherence to injury prevention measures. RESULTS: Seventy-five percent (n = 510) of the cohort was male and the median age was 16 years. Data were collected on 11 268 player-matches totaling 13 483 player-match hours and 11 540 player-training sessions totaling 16 031 player-training hours. A total of 677 match injury events were reported, giving overall incidence rates of 50.2 injury events per 1000 player-match hours and 6.0 injury events per 100 player matches. The incidence rate for match injury events was significantly higher for females than for males (63.9 vs 46.9). A total of 145 training injury events were reported, giving overall incidence rates of 9.0 injury events per 1000 player training hours and 1.3 injury events per 100 player-training sessions. The most common injuries were sprains and strains of the lower limb, and tackling was the most common cause of injury. CONCLUSION: This study has shown that routine injury surveillance, using a cohort design with exposure measurement, can be successfully implemented in community-level soccer. PMID- 20847227 TI - Regulation of pancreatic islet gene expression in mouse islets by pregnancy. AB - Pancreatic beta cells adapt to pregnancy-induced insulin resistance by unclear mechanisms. This study sought to identify genes involved in beta cell adaptation during pregnancy. To examine changes in global RNA expression during pregnancy, murine islets were isolated at a time point of increased beta cell proliferation (E13.5), and RNA levels were determined by two different assays (global gene expression array and G-protein-coupled receptor (GPCR) array). Follow-up studies confirmed the findings for select genes. Differential expression of 110 genes was identified and follow-up studies confirmed the changes in select genes at both the RNA and protein level. Surfactant protein D (SP-D) mRNA and protein levels exhibited large increases, which were confirmed in murine islets. Cytokine induced expression of SP-D in islets was also demonstrated, suggesting a possible role as an anti-inflammatory molecule. Complementing these studies, an expression array was performed to define pregnancy-induced changes in expression of GPCRs that are known to impact islet cell function and proliferation. This assay, the results of which were confirmed using real-time reverse transcription-PCR assays, demonstrated that free fatty acid receptor 2 and cholecystokinin receptor A mRNA levels were increased at E13.5. This study has identified multiple novel targets that may be important for the adaptation of islets to pregnancy. PMID- 20847228 TI - Unphosphorylated STAT and heterochromatin protect genome stability. AB - Heterochromatin is a form of highly compacted chromatin associated with epigenetic gene silencing and chromosome organization. We have previously shown that unphosphorylated nuclear signal transducer and activator of transcription (STAT) physically interacts with heterochromatin protein 1 (HP1) to promote heterochromatin stability. To understand whether STAT and heterochromatin are important for maintenance of genome stability, we genetically manipulated the levels of unphosphorylated STAT and HP1 [encoded by Su(var)205] in Drosophila and examined the effects on chromosomal morphology and resistance to DNA damage under conditions of genotoxic stress. Here we show that, compared with wild-type controls, Drosophila mutants with reduced levels of unphosphorylated STAT or heterochromatin are more sensitive to radiation-induced cell cycle arrest, have higher levels of spontaneous and radiation-induced DNA damage, and exhibit defects in chromosomal compaction and segregation during mitosis. Conversely, animals with increased levels of heterochromatin exhibit less DNA damage and increased survival rate after irradiation. These results suggest that maintaining genome stability by heterochromatin formation and correct chromosomal packaging is essential for normal cellular functions and for survival of animals under genotoxic stress. PMID- 20847230 TI - A charged prominence in the linker domain of the cysteine-string protein Cspalpha mediates its regulated interaction with the calcium sensor synaptotagmin 9 during exocytosis. AB - The cochaperone cysteine-string protein (Csp) is located on vesicles and participates in the control of neurotransmission and hormone exocytosis. Csp contains several domains, and our previous work demonstrated the requirement of the Csp linker domain in regulated exocytosis of insulin in rodent pancreatic beta cells. We now address the molecular details to gain insight into the sequence of events during exocytosis. According to pulldown experiments and in vitro binding assays, Cspalpha interacts indirectly with SNAP-25 and directly with the calcium sensor synaptotagmin 9 (Syt9), which could be an intermediate between the chaperone and the t-SNARE. The C(2)A calcium binding domain of Syt9 and the linker domain of Cspalpha constituted the minimal interacting module. FRET-FLIM experiments confirmed the interaction between Syt9 and Cspalpha. Moreover, the point mutation E93V in the linker domain of Cspalpha significantly reduced the interaction between the two proteins. Molecular modeling revealed that this point mutation abolished a charged prominence on the surface of Cspalpha required for interaction. Strikingly, free calcium in the physiological low micromolar range enhanced the interaction between Syt9 and the linker domain of Cspalpha in vitro. These data indicate that Cspalpha interacts with Syt9, and such a complex may be relevant in the calcium-mediated control of a late stage of exocytosis by triggering the specific recruitment of a folding catalyst at the fusion point. PMID- 20847229 TI - Regulation of Nur77 expression by beta-catenin and its mitogenic effect in colon cancer cells. AB - The orphan nuclear receptor Nur77 is an immediate-early response gene whose expression is rapidly induced by various extracellular stimuli. The aims of this study were to study the role of Nur77 expression in the growth and survival of colon cancer cells and the mechanism by which Nur77 expression was regulated. We showed that levels of Nur77 were elevated in a majority of human colon tumors (9/12) compared to their nontumorous tissues and that Nur77 expression could be strongly induced by different colonic carcinogens including deoxycholic acid (DCA). DCA-induced Nur77 expression resulted in up-regulation of antiapoptotic BRE and angiogenic VEGF, and it enhanced the growth, colony formation, and migration of colon cancer cells. In studying the mechanism by which Nur77 was regulated in colon cancer cells, we found that beta-catenin was involved in induction of Nur77 expression through its activation of the transcriptional activity of AP-1 (c-Fos/c-Jun) that bound to and transactivated the Nur77 promoter. Together, our results demonstrate that Nur77 acts to promote the growth and survival of colon cancer cells and serves as an important mediator of the Wnt/beta-catenin and AP-1 signaling pathways. PMID- 20847231 TI - Keratinocyte proximity and contact can play a significant role in determining mesenchymal stem cell fate in human tissue. AB - Bone marrow-derived human mesenchymal stem cells (hMSCs) possess multipotent differentiation capabilities and are a potent source of paracrine factors. We show how the epidermal keratinocyte can direct hMSC differentiation selectively. Keratinocytes and hMSCs were either cocultured in physical contact (contact cocultures), or separated without physical contact using a transwell insert (noncontact cocultures). We also delivered hMSCs into an ex vivo human excisional wound where subpopulations of the hMSCs were either in contact or were physically separated from the epidermal keratinocytes. In comparison to control hMSCs that were not cocultured, contact cocultured hMSCs adopted an epithelial morphology and expressed keratinocyte markers while noncontact cocultured hMSCs, surprisingly, adopted phenotypes that resembled myofibroblast and early neural lineage, both of which are of dermal origin. Cell fusion was not a requirement in in vitro contact cocultures, as determined by fluorescence-activated cell sorting (FACS) and fluorescence in situ hybridization analysis (FISH). To the best of our knowledge, this work provides the first example of hMSC differentiation into different lineages depending on their proximity to a single cell type. PMID- 20847232 TI - Fast vesicle fusion in living cells requires at least three SNARE complexes. AB - Exocytosis requires formation of SNARE [soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor] complexes between vesicle and target membranes. Recent assessments in reduced model systems have produced divergent estimates of the number of SNARE complexes needed for fusion. Here, we used a titration approach to answer this question in intact, cultured chromaffin cells. Simultaneous expression of wild-type SNAP-25 and a mutant unable to support exocytosis progressively altered fusion kinetics and fusion-pore opening, indicating that both proteins assemble into heteromeric fusion complexes. Expressing different wild-type:mutant ratios revealed a third-power relation for fast (synchronous) fusion and a near-linear relation for overall release. Thus, fast fusion typically observed in synapses and neurosecretory cells requires at least three functional SNARE complexes, whereas slower release might occur with fewer complexes. Heterogeneity in SNARE-complex number may explain heterogeneity in vesicular release probability. PMID- 20847233 TI - Global development. Family planning and the Millennium Development Goals. PMID- 20847235 TI - IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. AB - Heterozygous somatic mutations in the genes encoding isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2) were recently discovered in human neoplastic disorders. These mutations disable the enzymes' normal ability to convert isocitrate to 2 ketoglutarate (2-KG) and confer on the enzymes a new function: the ability to convert 2-KG to d-2-hydroxyglutarate (D-2-HG). We have detected heterozygous germline mutations in IDH2 that alter enzyme residue Arg(140) in 15 unrelated patients with d-2-hydroxyglutaric aciduria (D-2-HGA), a rare neurometabolic disorder characterized by supraphysiological levels of D-2-HG. These findings provide additional impetus for investigating the role of D-2-HG in the pathophysiology of metabolic disease and cancer. PMID- 20847234 TI - Impeding Xist expression from the active X chromosome improves mouse somatic cell nuclear transfer. AB - Cloning mammals by means of somatic cell nuclear transfer (SCNT) is highly inefficient because of erroneous reprogramming of the donor genome. Reprogramming errors appear to arise randomly, but the nature of nonrandom, SCNT-specific errors remains elusive. We found that Xist, a noncoding RNA that inactivates one of the two X chromosomes in females, was ectopically expressed from the active X (Xa) chromosome in cloned mouse embryos of both sexes. Deletion of Xist on Xa showed normal global gene expression and resulted in about an eight- to ninefold increase in cloning efficiency. We also identified an Xist-independent mechanism that specifically down-regulated a subset of X-linked genes through somatic-type repressive histone blocks. Thus, we have identified nonrandom reprogramming errors in mouse cloning that can be altered to improve the efficiency of SCNT methods. PMID- 20847237 TI - Young leaders for biology in India. PMID- 20847236 TI - Propane respiration jump-starts microbial response to a deep oil spill. AB - The Deepwater Horizon event resulted in suspension of oil in the Gulf of Mexico water column because the leakage occurred at great depth. The distribution and fate of other abundant hydrocarbon constituents, such as natural gases, are also important in determining the impact of the leakage but are not yet well understood. From 11 to 21 June 2010, we investigated dissolved hydrocarbon gases at depth using chemical and isotopic surveys and on-site biodegradation studies. Propane and ethane were the primary drivers of microbial respiration, accounting for up to 70% of the observed oxygen depletion in fresh plumes. Propane and ethane trapped in the deep water may therefore promote rapid hydrocarbon respiration by low-diversity bacterial blooms, priming bacterial populations for degradation of other hydrocarbons in the aging plume. PMID- 20847238 TI - Science and the law. With stem cells in court, a history primer. PMID- 20847239 TI - Paleontology. China clamps down on illegal fossil trading. PMID- 20847240 TI - Virology. No meeting of minds on XMRV's role in chronic fatigue, cancer. PMID- 20847242 TI - Newsmaker interview. Genentech scientist to take the helm at Rockefeller University. Interview by Greg Miller. PMID- 20847243 TI - Newsmaker interview. Physicist tapped to turn embattled institute into a fully fledged university. Interview by Dennis Normile. PMID- 20847244 TI - Demography. Has China outgrown the one-child policy? PMID- 20847245 TI - Demography. Of population projections and projectiles. PMID- 20847246 TI - Public health. No vaccines in the time of cholera. PMID- 20847247 TI - 11th International Conference of Archaeozoology. Burying man's best friend, with honor. PMID- 20847248 TI - 11th International Conference of Archaeozoology. Score one for hunting at Olduvai. PMID- 20847249 TI - 11th International Conference of Archaeozoology. In a cold snap, farmers turned to milk. PMID- 20847250 TI - India's courteous creativity. PMID- 20847251 TI - Battling the paper glut. PMID- 20847252 TI - Archaeology augments Tibet's genetic history. PMID- 20847253 TI - Science and society. Achieving scientific eminence within Asia. PMID- 20847254 TI - Cell biology. New roles for codon usage. PMID- 20847255 TI - Atmospheric science. Aerosols in clearer focus. PMID- 20847257 TI - Physics. Quantum walks through a waveguide maze. PMID- 20847256 TI - Biochemistry. A never-ending story. PMID- 20847258 TI - Neuroscience. Should confidence be trusted? PMID- 20847259 TI - Geophysics. Seismic images of the biggest crash on Earth. PMID- 20847260 TI - Tyrannosaur paleobiology: new research on ancient exemplar organisms. AB - Tyrannosaurs, the group of dinosaurian carnivores that includes Tyrannosaurus rex and its closest relatives, are icons of prehistory. They are also the most intensively studied extinct dinosaurs, and thanks to large sample sizes and an influx of new discoveries, have become ancient exemplar organisms used to study many themes in vertebrate paleontology. A phylogeny that includes recently described species shows that tyrannosaurs originated by the Middle Jurassic but remained mostly small and ecologically marginal until the latest Cretaceous. Anatomical, biomechanical, and histological studies of T. rex and other derived tyrannosaurs show that large tyrannosaurs could not run rapidly, were capable of crushing bite forces, had accelerated growth rates and keen senses, and underwent pronounced changes during ontogeny. The biology and evolutionary history of tyrannosaurs provide a foundation for comparison with other dinosaurs and living organisms. PMID- 20847261 TI - Island biogeography reveals the deep history of SIV. AB - Simian immunodeficiency virus (SIV) lineages have been identified that are endemic to Bioko Island. The time the island formed offers a geological time scale calibration point for dating the most recent common ancestor of SIV. The Bioko viruses cover the whole range of SIV genetic diversity, and each Bioko SIV clade is most closely related to viruses circulating in hosts of the same genus on the African mainland rather than to SIVs of other Bioko species. Our phylogeographic approach establishes that SIV is ancient and at least 32,000 years old. Our conservative calibration point and analyses of gene sequence saturation and dating bias suggest it may be much older. PMID- 20847262 TI - Hemispheric aerosol vertical profiles: anthropogenic impacts on optical depth and cloud nuclei. AB - Understanding the effect of anthropogenic combustion upon aerosol optical depth (AOD), clouds, and their radiative forcing requires regionally representative aerosol profiles. In this work, we examine more than 1000 vertical profiles from 11 major airborne campaigns in the Pacific hemisphere and confirm that regional enhancements in aerosol light scattering, mass, and number are associated with carbon monoxide from combustion and can exceed values in unperturbed regions by more than one order of magnitude. Related regional increases in a proxy for cloud condensation nuclei (CCN) and AOD imply that direct and indirect aerosol radiative effects are coupled issues linked globally to aged combustion. These profiles constrain the influence of combustion on regional AOD and CCN suitable for challenging climate model performance and informing satellite retrievals. PMID- 20847264 TI - Quantum walks of correlated photons. AB - Quantum walks of correlated particles offer the possibility of studying large scale quantum interference; simulating biological, chemical, and physical systems; and providing a route to universal quantum computation. We have demonstrated quantum walks of two identical photons in an array of 21 continuously evanescently coupled waveguides in a SiO(x)N(y) chip. We observed quantum correlations, violating a classical limit by 76 standard deviations, and found that the correlations depended critically on the input state of the quantum walk. These results present a powerful approach to achieving quantum walks with correlated particles to encode information in an exponentially larger state space. PMID- 20847263 TI - Evidence for an alternative glycolytic pathway in rapidly proliferating cells. AB - Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression of PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway that decouples adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells. PMID- 20847265 TI - Global distribution of large lunar craters: implications for resurfacing and impactor populations. AB - By using high-resolution altimetric measurements of the Moon, we produced a catalog of all impact craters >=20 kilometers in diameter on the lunar surface and analyzed their distribution and population characteristics. The most-densely cratered portion of the highlands reached a state of saturation equilibrium. Large impact events, such as Orientale Basin, locally modified the prebasin crater population to ~2 basin radii from the basin center. Basins such as Imbrium, Orientale, and Nectaris, which are important stratigraphic markers in lunar history, are temporally distinguishable on the basis of crater statistics. The characteristics of pre- and postmare crater populations support the hypothesis that there were two populations of impactors in early solar system history and that the transition occurred near the time of the Orientale Basin event. PMID- 20847266 TI - Global silicate mineralogy of the Moon from the Diviner lunar radiometer. AB - We obtained direct global measurements of the lunar surface using multispectral thermal emission mapping with the Lunar Reconnaissance Orbiter Diviner Lunar Radiometer Experiment. Most lunar terrains have spectral signatures that are consistent with known lunar anorthosite and basalt compositions. However, the data have also revealed the presence of highly evolved, silica-rich lunar soils in kilometer-scale and larger exposures, expanded the compositional range of the anorthosites that dominate the lunar crust, and shown that pristine lunar mantle is not exposed at the lunar surface at the kilometer scale. Together, these observations provide compelling evidence that the Moon is a complex body that has experienced a diverse set of igneous processes. PMID- 20847267 TI - Highly silicic compositions on the Moon. AB - Using data from the Diviner Lunar Radiometer Experiment, we show that four regions of the Moon previously described as "red spots" exhibit mid-infrared spectra best explained by quartz, silica-rich glass, or alkali feldspar. These lithologies are consistent with evolved rocks similar to lunar granites in the Apollo samples. The spectral character of these spots is distinct from surrounding mare and highlands material and from regions composed of pure plagioclase feldspar. The variety of landforms associated with the silicic spectral character suggests that both extrusive and intrusive silicic magmatism occurred on the Moon. Basaltic underplating is the preferred mechanism for silicic magma generation, leading to the formation of extrusive landforms. This mechanism or silicate liquid immiscibility could lead to the formation of intrusive bodies. PMID- 20847268 TI - Rainforest aerosols as biogenic nuclei of clouds and precipitation in the Amazon. AB - The Amazon is one of the few continental regions where atmospheric aerosol particles and their effects on climate are not dominated by anthropogenic sources. During the wet season, the ambient conditions approach those of the pristine pre-industrial era. We show that the fine submicrometer particles accounting for most cloud condensation nuclei are predominantly composed of secondary organic material formed by oxidation of gaseous biogenic precursors. Supermicrometer particles, which are relevant as ice nuclei, consist mostly of primary biological material directly released from rainforest biota. The Amazon Basin appears to be a biogeochemical reactor, in which the biosphere and atmospheric photochemistry produce nuclei for clouds and precipitation sustaining the hydrological cycle. The prevailing regime of aerosol-cloud interactions in this natural environment is distinctly different from polluted regions. PMID- 20847269 TI - Melting of peridotite to 140 gigapascals. AB - Interrogating physical processes that occur within the lowermost mantle is a key to understanding Earth's evolution and present-day inner composition. Among such processes, partial melting has been proposed to explain mantle regions with ultralow seismic velocities near the core-mantle boundary, but experimental validation at the appropriate temperature and pressure regimes remains challenging. Using laser-heated diamond anvil cells, we constructed the solidus curve of a natural fertile peridotite between 36 and 140 gigapascals. Melting at core-mantle boundary pressures occurs at 4180 +/- 150 kelvin, which is a value that matches estimated mantle geotherms. Molten regions may therefore exist at the base of the present-day mantle. Melting phase relations and element partitioning data also show that these liquids could host many incompatible elements at the base of the mantle. PMID- 20847270 TI - A test of the snowball theory for the rate of evolution of hybrid incompatibilities. AB - Hybrids between species are often sterile or inviable because the long-diverged genomes of their parents cause developmental problems when they come together in a single individual. According to the Dobzhansky-Muller (DM) model, the number of genes involved in these "intrinsic postzygotic incompatibilities" should increase faster than linearly with the divergence time between species. This straightforward prediction of the DM model has remained contentious owing to a lack of explicit tests. Examining two pairs of Drosophila species, we show that the number of genes involved in postzygotic isolation increases at least as fast as the square of the number of substitutions (an index of divergence time) between species. This observation verifies a key prediction of the DM model. PMID- 20847271 TI - Hybrid incompatibility "snowballs" between Solanum species. AB - Among the reproductive barriers that can isolate species, hybrid sterility is frequently due to dysfunctional interactions between loci that accumulate between differentiating lineages. Theory describing the evolution of these incompatibilities has generated the prediction, still empirically untested, that loci underlying hybrid incompatibility should accumulate faster than linearly with time--the "snowball effect." We evaluated the accumulation of quantitative trait loci (QTL) between species in the plant group Solanum and found evidence for a faster-than-linear accumulation of hybrid seed sterility QTL, thus empirically evaluating and confirming this theoretical prediction. In comparison, loci underlying traits unrelated to hybrid sterility show no evidence for an accelerating rate of accumulation between species. PMID- 20847272 TI - The ecological significance of tool use in New Caledonian crows. AB - Tool use is so rare in the animal kingdom that its evolutionary origins cannot be traced with comparative analyses. Valuable insights can be gained from investigating the ecological context and adaptive significance of tool use under contemporary conditions, but obtaining robust observational data is challenging. We assayed individual-level tool-use dependence in wild New Caledonian crows by analyzing stable isotope profiles of the birds' feathers, blood, and putative food sources. Bayesian diet-mixing models revealed that a substantial amount of the crows' protein and lipid intake comes from prey obtained with stick tools- wood-boring beetle larvae. Our calculations provide estimates of larva-intake rates and show that just a few larvae can satisfy a crow's daily energy requirements, highlighting the substantial rewards available to competent tool users. PMID- 20847273 TI - Bifurcation of Toll-like receptor 9 signaling by adaptor protein 3. AB - Endosomal Toll-like receptors (TLRs) 7 and 9 recognize viral pathogens and induce signals leading to the activation of nuclear factor kappaB (NF-kappaB)-dependent proinflammatory cytokines and interferon regulatory factor 7 (IRF7)-dependent type I interferons (IFNs). Recognition of viral nucleic acids by TLR9 requires its cleavage in the endolysosomal compartment. Here, we show that TLR9 signals leading to the activation of type I IFN, but not proinflammatory cytokine genes, require TLR9 trafficking from endosomes to a specialized lysosome-related organelle. Furthermore, we identify adapter protein-3 as the protein complex responsible for the trafficking of TLR9 to this subcellular compartment. Our results reveal an intracellular mechanism for bifurcation of TLR9 signals by selective receptor trafficking within the endosomal system. PMID- 20847274 TI - Differential arginylation of actin isoforms is regulated by coding sequence dependent degradation. AB - The mammalian cytoskeletal proteins beta- and gamma-actin are highly homologous, but only beta-actin is amino-terminally arginylated in vivo, which regulates its function. We examined the metabolic fate of exogenously expressed arginylated and nonarginylated actin isoforms. Arginylated gamma-actin, unlike beta-, was highly unstable and was selectively ubiquitinated and degraded in vivo. This instability was regulated by the differences in the nucleotide coding sequence between the two actin isoforms, which conferred different translation rates. gamma-actin was translated more slowly than beta-actin, and this slower processing resulted in the exposure of a normally hidden lysine residue for ubiquitination, leading to the preferential degradation of gamma-actin upon arginylation. This degradation mechanism, coupled to nucleotide coding sequence, may regulate protein arginylation in vivo. PMID- 20847275 TI - miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. AB - The serotonin transporter (SERT) ensures the recapture of serotonin and is the pharmacological target of selective serotonin reuptake inhibitor (SSRI) antidepressants. We show that SERT is a target of microRNA-16 (miR-16). miR-16 is expressed at higher levels in noradrenergic than in serotonergic cells; its reduction in noradrenergic neurons causes de novo SERT expression. In mice, chronic treatment with the SSRI fluoxetine (Prozac) increases miR-16 levels in serotonergic raphe nuclei, which reduces SERT expression. Further, raphe exposed to fluoxetine release the neurotrophic factor S100beta, which acts on noradrenergic cells of the locus coeruleus. By decreasing miR-16, S100beta turns on the expression of serotonergic functions in noradrenergic neurons. Based on pharmacological and behavioral data, we propose that miR-16 contributes to the therapeutic action of SSRI antidepressants in monoaminergic neurons. PMID- 20847277 TI - Genotyping of DNA samples isolated from formalin-fixed paraffin-embedded tissues using preamplification. AB - DNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue is often fragmented and cross-linked and is therefore difficult to genotype. To enable this source of DNA for genotyping analysis using Taqman probes, we tested whether enrichment of the target genes would increase the amount of available DNA. For enrichment of the target genes, we used preamplification by means of diluted Taqman assays. To establish the appropriateness of preamplification, we used DNA extracted from paraffin-embedded tissue and compared the genotyping results of a series of single nucleotide polymorphisms assessed in DNA samples with and without preamplification. In a subset of patients, DNA was isolated from both blood and FFPE tissue to test the reliability of genotyping results derived after preamplification. We found an increase in call rate after preamplification and a convincing concordance in genotype. Based on our findings, we can safely conclude that preamplification of DNA isolated from paraffin-embedded tissue is a valuable and reliable method to optimize genotyping results. PMID- 20847276 TI - Relating introspective accuracy to individual differences in brain structure. AB - The ability to introspect about self-performance is key to human subjective experience, but the neuroanatomical basis of this ability is unknown. Such accurate introspection requires discriminating correct decisions from incorrect ones, a capacity that varies substantially across individuals. We dissociated variation in introspective ability from objective performance in a simple perceptual-decision task, allowing us to determine whether this interindividual variability was associated with a distinct neural basis. We show that introspective ability is correlated with gray matter volume in the anterior prefrontal cortex, a region that shows marked evolutionary development in humans. Moreover, interindividual variation in introspective ability is also correlated with white-matter microstructure connected with this area of the prefrontal cortex. Our findings point to a focal neuroanatomical substrate for introspective ability, a substrate distinct from that supporting primary perception. PMID- 20847278 TI - Differential DNA methylation as a tool for noninvasive prenatal diagnosis (NIPD) of X chromosome aneuploidies. AB - The demographic tendency in industrial countries to delay childbearing, coupled with the maternal age effect in common chromosomal aneuploidies and the risk to the fetus of invasive prenatal diagnosis, are potent drivers for the development of strategies for noninvasive prenatal diagnosis. One breakthrough has been the discovery of differentially methylated cell-free fetal DNA in the maternal circulation. We describe novel bisulfite conversion- and methylation-sensitive enzyme digestion DNA methylation-related approaches that we used to diagnose Turner syndrome from first trimester samples. We used an X-linked marker, EF3, and an autosomal marker, RASSF1A, to discriminate between placental and maternal blood cell DNA using real-time methylation-specific PCR after bisulfite conversion and real-time PCR after methylation-sensitive restriction digestion. By normalizing EF3 amplifications versus RASSF1A outputs, we were able to calculate sex chromosome/autosome ratios in chorionic villus samples, thus permitting us to correctly diagnose Turner syndrome. The identification of this new marker coupled with the strategy outlined here may be instrumental in the development of an efficient, noninvasive method of diagnosis of sex chromosome aneuploidies in plasma samples. PMID- 20847279 TI - A pyrosequencing-based assay for the rapid detection of IDH1 mutations in clinical samples. AB - Mutations of both the IDH1 and IDH2 (isocitratedehydrogenase enzyme 1 and 2) genes have recently been described in cases of human glioma. Since IDH1 mutations have been associated with better clinical outcome, they are suitable predictive markers for adult glioma patients. We have developed a pyrosequencing assay that allows both the sensitive and rapid detection of mutant IDH1 alleles in DNA extracted from formalin-fixed, paraffin-embedded tissues. PCR products that span exon 4 of IDH1 were used as a template for pyrosequencing. For validation, PCR products were additionally cloned and sequenced conventionally by Sanger sequencing. Sensitivity was measured by titration of wild-type and mutant sequences. PCR kinetic experiments were performed to investigate the influences of PCR cycle number on the accuracy of the assay. We found that a minimum of 5% of mutant IDH1 alleles can easily be detected with the pyrosequencing approach. So far, there are few data regarding IDH1 mutation status in high-grade gliomas of childhood. Therefore, we applied this assay to 47 pediatric high-grade glioma samples (age range 6 weeks to 23 years). Mutations were found in 5/14 astrocytoma III and in 6/33 glioblastomas. In conclusion, we have developed a pyrosequencing based assay for the detection of mutations at the hotspot regions of IDH1 and provide proof for its applicability as a molecular diagnostic assay for clinical samples. PMID- 20847280 TI - Nucleotide extension genotyping by high-resolution melting. AB - One limitation of small amplicon melting is the inability to genotype certain nearest-neighbor symmetric variations without manipulating the sample. We have developed a method for these exceptions: a high-resolution melting single nucleotide extension assay. Single nucleotide extension was performed in a new instrument, the LightScanner 32 (LS32), which uses capillary reaction tubes and is capable of real-time PCR and sequential high-resolution melting of 32 samples. Asymmetric PCR used Platinum Taq and LC Green Plus in the master mix for target amplification. Dideoxynucleotides and extension oligonucleotides were sequestered in the tube cap and added post-PCR, maintaining a closed system. One dideoxynucleotides was used per capillary tube. Samples were cycled five times to incorporate dideoxynucleotides into the extension products using ThermoSequenase, followed by high-resolution melting. Single nucleotide polymorphisms from the RET proto-oncogene (n = 7), hemochromatosis (HFE, n = 30), coagulation factor 2 (F2, n = 29), coagulation factor 5 (F5, n = 30), and methylenetetrahydrofolate reductase (MTHFR, n = 60) genes were genotyped. The DNA melting profiles identified the target single nucleotide polymorphisms by the lowest melting temperature transition. All genotypes had a distinctive melting pattern. The method was 100% concordant with samples previously genotyped at HFE, MTHFR, and F2 and 90% concordant with F5. F5 discordants were genotyped correctly by redesigning the assay. Our results demonstrate that although single nucleotide polymorphisms can be successfully differentiated using this methodology, the method requires careful optimization. PMID- 20847281 TI - HPV genotype detection using hybrid capture sample preparation combined with whole genome amplification and multiplex detection with Luminex XMAP. AB - Infection with a high-risk carcinogenic type of human papillomavirus (HPV) is necessary for the development of cervical cancer. The digene HC2 HPV Test (HC2) is an important screening tool but lacks genotyping capability. To address this issue, we developed an assay for the rapid genotyping of HPV in cervical specimens. The three steps of this assay include Hybrid Capture target enrichment, whole-genome amplification, and Luminex XMAP detection. The assay includes the simultaneous detection of two genomic regions from each of 17 high risk and two low-risk HPV types most associated with disease. The assay performance was tested on HPV plasmids as well as clinical specimens. An analytical limit of detection of 100 copies or less was demonstrated for linear, circular, and integrated HPV DNA. This finding is at least 1 log lower than the HC2 assay limit of detection. There was no cross-reactivity among the HPV types up to 1,000,000 copies. There was also no substantial assay interference from substances in cervical specimens. Although the clinical performance of the assay was not formally tested, the assay had good agreement (Cohen's kappa equal to 0.72) with both a PCR-based HPV genotyping assay (n = 131) and the HC2 assay (n = 502) using representative cervical specimens. This assay may be easy to automate and could be applied for the detection of other targets in future studies. PMID- 20847282 TI - Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: implication in tissue fibrosis. AB - Matrix metalloproteinases (MMPs), which are highly expressed in acute injury, are progressively repressed or silenced in fibrotic liver, favoring extracellular matrix accumulation, while the underlying mechanism is largely unknown. Similarly, normal/quiescent hepatic stellate cells (HSCs) express high levels of MMPs in response to injury signals, such as interleukin-1. After transdifferentiation, the myofibroblastic HSCs are incapable of expressing many MMPs; however, the major signaling pathways required for MMP expression are intact, indicating that repression is at the level of the chromatin. Indeed, both the MMP9 and MMP13 genes are inaccessible to transcription factors and RNA polymerase II, in association with impaired histone acetylation in their promoters. In accordance with impaired histone acetylation at the cellular level, histone deacetylase-4 is accumulated during HSC transdifferentiation. Furthermore, ectopic expression of histone deacetylase-4 in quiescent HSCs results in repression of MMP promoter activities as well as endogenous MMP9 protein expression. Thus, our findings suggest that a histone deacetylase-4 dependent mechanism underlies the epigenetic silencing of MMP genes during tissue fibrogenesis. PMID- 20847283 TI - Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. AB - Glomerular disease can be triggered or exacerbated by microbes that activate the immune system by Toll-like receptor (TLR) ligation. TLR9 activation promotes host defenses through the enhancement of innate and adaptive immune responses that facilitate the recruitment of leukocytes to areas of inflammation. We defined the role of TLR9 in experimental crescentic glomerulonephritis. Wild-type mice administered a TLR9 ligand and sheep anti-mouse glomerular basement membrane antibody developed histological injury with impaired renal function, which was attenuated in TLR9 knockout mice. Consistent with enhanced renal injury, wild type mice exhibited enhanced T helper 1 and T helper 17 cellular immune responses. Kidney mRNA expression of inflammatory cytokines and chemokines as well as leukocyte recruitment were increased in wild-type mice. The use of bone marrow chimeric mice demonstrated that while both bone marrow and tissue cell TLR9 are required for maximal injury, bone marrow TLR9 is more important. Administration of a TLR9 inhibitor before sheep anti-mouse glomerular basement membrane globulin in wild-type mice attenuated cellular nephritogenic immunity that resulted in decreased renal injury. Administration of the inhibitor 7 days after disease initiation decreased glomerular leukocyte recruitment as well as renal injury. These results define the role of TLR9 in experimental crescentic glomerulonephritis and identify therapeutic potential for TLR9 inhibitors in attenuating renal injury, decreasing cellular nephritogenic immunity early in disease, and decreasing kidney effector responses later. PMID- 20847284 TI - Roles of tetrahydrobiopterin in promoting tumor angiogenesis. AB - Nitric oxide (NO), which is derived from endothelial NO synthase (eNOS), provides crucial signals for angiogenesis in the tumor microenvironment. Tetrahydrobiopterin (BH4) is an absolute requirement for eNOS activity. In this study, we investigated whether this activation is both maintained by a wild-type Ras/phosphatidylinositol 3-kinase (PI3K)/Akt-positive feedback loop in endothelial cells and affects tumor angiogenesis. We found that supplementation of BH4 (via the pterin salvage pathway with Sep) increased Akt/eNOS phosphorylation in both human eNOS-transfected COS-7 cells and endothelial cells concomitant with increases in NO production, cell proliferation, migration, and tube formation. This augmentation was abrogated by a PI3K inhibitor. Sepiapterin (Sep) also increased GTP-bound wild-type Ras and PI3K/Akt/eNOS activation, which was prevented by the eNOS inhibitor, Nomega-Nitro-L-arginine methyl ester (L NAME). Furthermore, expression of GTP cyclohydrolase I (the rate-limiting enzyme in de novo BH4 synthesis) under doxycycline control potentiated in vivo tumorigenesis, tumor cell proliferation, as well as angiogenesis. Conversely, both switching off GTP cyclohydrolase I expression as well as inhibiting its enzymatic activity significantly decreased eNOS expression and tumor vascularization. This study demonstrates an important role for BH4 synthesis in angiogenesis by the activation of eNOS for NO production, which is maintained by a PI3K/Akt-positive feedback loop through effects on wild-type Ras in endothelial cells. Our findings suggest that BH4 synthesis may be a rational target for antiangiogenesis therapy for tumors. PMID- 20847285 TI - Lack of fetuin-A (alpha2-HS-glycoprotein) reduces mammary tumor incidence and prolongs tumor latency via the transforming growth factor-beta signaling pathway in a mouse model of breast cancer. AB - The present analyses were done to define the role of fetuin-A (Fet) in mammary tumorigenesis using the polyoma middle T antigen (PyMT) transgenic mouse model. We crossed Fet-null mice in the C57BL/6 background with PyMT mice in the same background and after a controlled breeding protocol obtained PyMT/Fet+/+, PyMT/Fet+/-, and PyMT/Fet-/- mice that were placed in control and experimental groups. Whereas the control group (PyMT/Fet+/+) formed mammary tumors 90 days after birth, tumor latency was prolonged in the PyMT/Fet-/- and PyMT/Fet+/- mice. The majority of the PyMT/Fet-/- mice were tumor-free at the end of the study, at approximately 40 weeks. The pathology of the mammary tumors in the Fet-null mice showed extensive fibrosis, necrosis, and squamous metaplasia. The preneoplastic mammary tissues of the PyMT/Fet-/- mice showed intense phopho-Smad2/3 staining relative to control tissues, indicating that transforming growth factor-beta signaling is enhanced in these tissues in the absence of Fet. Likewise, p19ARF and p53 were highly expressed in tumor tissues of PyMT/Fet-/- mice relative to the controls in the absence of Fet. The phosphatidylinositol 3-kinase/Akt signaling pathway that we previously showed to be activated by Fet, on the other hand, was unaffected by the absence of Fet. The data indicate that Fet is a powerful modulator of breast tumorigenesis in this model system and has the potential to modulate breast cancer progression in humans. PMID- 20847286 TI - Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD) is a progressive, blinding disease characterized by corneal endothelial (CE) cell apoptosis. Corneal transplantation is the only measure currently available to restore vision in these patients. Despite the identification of some genetic factors, the pathophysiology of FECD remains unclear. In this study, we observed a decrease in the antioxidant response element-driven antioxidants in FECD corneal endothelium. We further demonstrated that nuclear factor erythroid 2-related factor 2, a transcription factor known to bind the antioxidant response element and activate antioxidant defense, is down-regulated in FECD endothelium. Importantly, we detected significantly higher levels of oxidative DNA damage and apoptosis in FECD endothelium compared with normal controls and pseudophakic bullous keratopathy (iatrogenic CE cell loss) specimens. A marker of oxidative DNA damage, 8-hydroxy 2'-deoxyguanosine, colocalized to mitochondria, indicating that the mitochondrial genome is the specific target of oxidative stress in FECD. Oxidative DNA damage was not detected in pseudophakic bullous keratopathy corneas, whereas it colocalized with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells in FECD samples. Ex vivo, oxidative stress caused characteristic morphological changes and apoptosis of CE, suggestive of findings that characterize FECD in vivo. Together, these data suggest that suboptimal nuclear factor erythroid 2-related factor 2-regulated defenses may account for oxidant-antioxidant imbalance in FECD, which in turn leads to oxidative DNA damage and apoptosis. This study provides evidence that oxidative stress plays a key role in FECD pathogenesis. PMID- 20847288 TI - Loss of reelin expression in breast cancer is epigenetically controlled and associated with poor prognosis. AB - Reelin is a secreted, signaling protein associated with neuronal cell positioning and migration. Recently, reelin was found to be epigenetically silenced in gastric and pancreatic cancers in which down-regulation was associated with increased migratory ability and reduced survival. Here we analyzed reelin expression by immunohistochemistry in 17 normal breast tissue samples from reduction mammoplasties and in two independent tissue microarrays of 136 and more than 2000 breast cancer biopsy samples, respectively. Results were analyzed with regard to clinical parameters, including BRE (Bloom, Richardson, Elston) grade, nodal status, estrogen receptor and HER2 status, and overall survival. Reelin was expressed in the luminal epithelium and myoepithelium of the normal human breast but not in cancerous breasts. Loss of reelin protein expression correlated significantly with decreased survival (P=0.01) and positive lymph node status (P<0.001). By measuring reelin expression and promoter methylation status in 39 primary breast tumors, as well as in breast cancer-derived cell lines before and after decitabine treatment, we established that reelin expression levels correlated inversely with promoter methylation status, whereas demethylation increased reelin mRNA expression in vitro. Reelin overexpression in MDA-MB231 cells, as well as incubation with recombinant reelin, suppressed cell migration, invadopodia formation, and invasiveness in vitro. We conclude that reelin may play an important role in controlling invasiveness and metastatic potential of breast cancer cells and that its expression is controlled by promoter methylation. PMID- 20847289 TI - Deletions of 16q in Wilms tumors localize to blastemal-anaplastic cells and are associated with reduced expression of the IRXB renal tubulogenesis gene cluster. AB - Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor. PMID- 20847290 TI - A molecular profile of focal segmental glomerulosclerosis from formalin-fixed, paraffin-embedded tissue. AB - Focal segmental glomerulosclerosis (FSGS) is a common form of idiopathic nephrotic syndrome defined by the characteristic lesions of focal glomerular sclerosis and foot process effacement; however, its etiology and pathogenesis are unknown. We used mRNA isolated from laser-captured glomeruli from archived formalin-fixed, paraffin-embedded renal biopsies, until recently considered an unsuitable source of mRNA for microarray analysis, to investigate the glomerular gene expression profiles of patients with primary classic FSGS, collapsing FSGS (COLL), minimal change disease (MCD), and normal controls (Normal). Amplified mRNA was hybridized to an Affymetrix Human X3P array. Unsupervised (unbiased) hierarchical clustering revealed two distinct clusters delineating FSGS and COLL from Normal and MCD. Class comparison analysis of FSGS + COLL combined versus Normal + MCD revealed 316 significantly differentially regulated genes (134 up regulated, 182 down-regulated). Among the differentially regulated genes were those known to be part of the slit diaphragm junctional complex and those previously described in the dysregulated podocyte phenotype. Analysis based on Gene Ontology categories revealed overrepresented biological processes of development, differentiation and morphogenesis, cell motility and migration, cytoskeleton organization, and signal transduction. Transcription factors associated with developmental processes were heavily overrepresented, indicating the importance of reactivation of developmental programs in the pathogenesis of FSGS. Our findings reveal novel insights into the molecular pathogenesis of glomerular injury and structural degeneration in FSGS. PMID- 20847291 TI - Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis. AB - NKT cells are highly enriched within the liver. On activation NKT cells rapidly release large quantities of different cytokines which subsequently activate, recruit, or modulate cells important for the development of hepatic inflammation. Recently, it has been demonstrated that NKT cells can also produce interleukin-17 (IL-17), a proinflammatory cytokine that is also known to have diverse immunoregulatory effects. The role played by IL-17 in hepatic inflammation is unclear. Here we show that during alpha-galactosylceramide (alphaGalCer)-induced hepatitis in mice, a model of hepatitis driven by specific activation of the innate immune system via NKT cells within the liver, NK1.1+ and CD4+ iNKT cells rapidly produce IL-17 and are the main IL-17-producing cells within the liver. Administration of IL-17 neutralizing monoclonal antibodies before alphaGalCer injection significantly exacerbated hepatitis, in association with a significant increase in hepatic neutrophil and proinflammatory monocyte (ie, producing IL-12, tumor necrosis factor-alpha) recruitment, and increased hepatic mRNA and protein expression for the relevant neutrophil and monocyte chemokines CXCL5/LIX and CCL2/MCP-1, respectively. In contrast, administration of exogenous recombinant murine IL-17 before alpha-GalCer injection ameliorated hepatitis and inhibited the recruitment of inflammatory monocytes into the liver. Our results demonstrate that hepatic iNKT cells specifically activated with alpha-GalCer rapidly produce IL-17, and IL-17 produced after alpha-GalCer administration inhibits the development of hepatitis. PMID- 20847292 TI - Highly pathogenic avian influenza virus H7N7 isolated from a fatal human case causes respiratory disease in cats but does not spread systemically. AB - Highly pathogenic avian influenza viruses (HPAIV) of the H5 and H7 subtypes primarily infect poultry but are occasionally transmitted to humans and other mammalian species, often causing severe disease. Previously we have shown that HPAIV H5N1 causes severe systemic disease in cats. In this study, we investigated whether HPAIV H7N7 isolated from a fatal human case is also able to cause disease in cats. Additionally, we compared the cell tropism of both viruses by immunohistochemistry and virus histochemistry. Three domestic cats were inoculated intratracheally with HPAIV H7N7. Virus excretion was restricted to the pharynx. At necropsy, 7 days post inoculation, lesions were restricted to the respiratory tract in all cats. Lesions consisted of diffuse alveolar damage and colocalized with virus antigen expression in type II pneumocytes and nonciliated bronchiolar cells. The attachment patterns of HPAIV H7N7 and H5N1 were similar: both viruses attached to nonciliated bronchiolar epithelial cells, type II pneumocytes, as well as alveolar macrophages. These data show for the first time that a non-H5 HPAIV is able to infect and cause respiratory disease in cats. The failure of HPAIV H7N7 to spread beyond the respiratory tract was not explained by differences in cell tropism compared to HPAIV H5N1. These findings suggest that HPAIV H5N1 possesses other characteristics that allow it to cause systemic disease in both humans and cats. PMID- 20847293 TI - Ancient class of translocated oomycete effectors targets the host nucleus. AB - Pathogens use specialized secretion systems and targeting signals to translocate effector proteins inside host cells, a process that is essential for promoting disease and parasitism. However, the amino acid sequences that determine host delivery of eukaryotic pathogen effectors remain mostly unknown. The Crinkler (CRN) proteins of oomycete plant pathogens, such as the Irish potato famine organism Phytophthora infestans, are modular proteins with predicted secretion signals and conserved N-terminal sequence motifs. Here, we provide direct evidence that CRN N termini mediate protein transport into plant cells. CRN host translocation requires a conserved motif that is present in all examined plant pathogenic oomycetes, including the phylogenetically divergent species Aphanomyces euteiches that does not form haustoria, specialized infection structures that have been implicated previously in delivery of effectors. Several distinct CRN C termini localized to plant nuclei and, in the case of CRN8, required nuclear accumulation to induce plant cell death. These results reveal a large family of ubiquitous oomycete effector proteins that target the host nucleus. Oomycetes appear to have acquired the ability to translocate effector proteins inside plant cells relatively early in their evolution and before the emergence of haustoria. Finally, this work further implicates the host nucleus as an important cellular compartment where the fate of plant-microbe interactions is determined. PMID- 20847294 TI - Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. AB - The indigenous human microbiota is essential to the health of the host. Although the microbiota can be affected by many features of modern life, we know little about its responses to disturbance, especially repeated disturbances, and how these changes compare with baseline temporal variation. We examined the distal gut microbiota of three individuals over 10 mo that spanned two courses of the antibiotic ciprofloxacin, analyzing more than 1.7 million bacterial 16S rRNA hypervariable region sequences from 52 to 56 samples per subject. Interindividual variation was the major source of variability between samples. Day-to-day temporal variability was evident but constrained around an average community composition that was stable over several months in the absence of deliberate perturbation. The effect of ciprofloxacin on the gut microbiota was profound and rapid, with a loss of diversity and a shift in community composition occurring within 3-4 d of drug initiation. By 1 wk after the end of each course, communities began to return to their initial state, but the return was often incomplete. Although broadly similar, community changes after ciprofloxacin varied among subjects and between the two courses within subjects. In all subjects, the composition of the gut microbiota stabilized by the end of the experiment but was altered from its initial state. As with other ecosystems, the human distal gut microbiome at baseline is a dynamic regimen with a stable average state. Antibiotic perturbation may cause a shift to an alternative stable state, the full consequences of which remain unknown. PMID- 20847295 TI - Bioenergetic cost of making an adenosine triphosphate molecule in animal mitochondria. AB - The catalytic domain of the F-ATPase in mitochondria protrudes into the matrix of the organelle, and is attached to the membrane domain by central and peripheral stalks. Energy for the synthesis of ATP from ADP and phosphate is provided by the transmembrane proton-motive-force across the inner membrane, generated by respiration. The proton-motive force is coupled mechanically to ATP synthesis by the rotation at about 100 times per second of the central stalk and an attached ring of c-subunits in the membrane domain. Each c-subunit carries a glutamate exposed around the midpoint of the membrane on the external surface of the ring. The rotation is generated by protonation and deprotonation successively of each glutamate. Each 360 degrees rotation produces three ATP molecules, and requires the translocation of one proton per glutamate by each c-subunit in the ring. In fungi, eubacteria, and plant chloroplasts, ring sizes of c(10)-c(15) subunits have been observed, implying that these enzymes need 3.3-5 protons to make each ATP, but until now no higher eukaryote has been examined. As shown here in the structure of the bovine F(1)-c-ring complex, the c-ring has eight c-subunits. As the sequences of c-subunits are identical throughout almost all vertebrates and are highly conserved in invertebrates, their F-ATPases probably contain c(8) rings also. Therefore, in about 50,000 vertebrate species, and probably in many or all of the two million invertebrate species, 2.7 protons are required by the F ATPase to make each ATP molecule. PMID- 20847296 TI - Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice. AB - Fructose intake is being discussed as a key dietary factor in the development of nonalcoholic fatty liver disease (NAFLD). Bile acids have been shown to modulate energy metabolism. We tested the effects of bile acids on fructose-induced hepatic steatosis. In C57BL/6J mice treated with a combination of chenodeoxycholic acid and cholic acid (100 mg/kg body weight each) while drinking water or a 30% fructose solution for eight weeks and appropriate controls, markers of hepatic steatosis, portal endotoxin levels, and markers of hepatic lipogenesis were determined. In mice concomitantly treated with bile acids, the onset of fructose-induced hepatic steatosis was markedly attenuated compared to mice only fed fructose. The protective effects of the bile acid treatment were associated with a downregulation of tumor necrosis factor (TNF)alpha, sterol regulatory element-binding protein (SREBP)1, FAS mRNA expression, and lipid peroxidation in the liver, whereas hepatic farnesoid X receptor (FXR) or short heterodimer partner (SHP) protein concentration did not differ between groups fed fructose. Rather, bile acid treatment normalized occludin protein concentration in the duodenum, portal endotoxin levels, and markers of Kupffer cell activation to the level of water controls. Taken together, these data suggest that bile acids prevent fructose-induced hepatic steatosis in mice through mechanisms involving protection against the fructose-induced translocation of intestinal bacterial endotoxin. PMID- 20847297 TI - Inhibitory effect of LXR activation on cell proliferation and cell cycle progression through lipogenic activity. AB - Liver X receptor (LXR), a sterol-activated nuclear hormone receptor, has been implicated in cholesterol and fatty acid homeostasis via regulation of reverse cholesterol transport and de novo fatty acid synthesis. LXR is also involved in immune responses, including anti-inflammatory action and T cell proliferation. In this study, we demonstrated that activated LXR suppresses cell cycle progression and proliferation in certain cell types. Stimulation of LXR with synthetic ligand T0901317 or GW3965 inhibited cell growth rate and arrested the cell cycle at the G1/S boundary in several cells, such as RWPE1, THP1, SNU16, LNCaP, and HepG2. However, LXR ligands did not exhibit antiproliferative activity in PC3, HEK293, or HeLa cells. Interestingly, activated LXR-mediated cell cycle arrest is closely correlated with the lipogenic gene expression and triacylglyceride accumulation. In accordance with these findings, suppression of FAS via small-interference RNA (siRNA) partially alleviated the antiproliferative effect of LXR activation in RWPE1 cells. Together, these data suggest that LXR activation with its ligands inhibits cell proliferation and induces G1/S arrest through elevated lipogenic activity, thus proposing a novel effect of activated LXR on cell cycle regulation. PMID- 20847298 TI - Lipopolysaccharide binding protein inhibitory peptide protects against acetaminophen-induced hepatotoxicity. AB - Acetaminophen (APAP)-induced liver injury remains the main cause of acute liver failure in the United States. Our previous work demonstrated that LPS binding protein (LBP) knockout mice are protected from APAP-induced hepatotoxicity. LBP is known to bind avidly to LPS, facilitating cellular activation. In this study, we sought to specifically inhibit the interaction between LBP and LPS to define the role of this interaction in APAP-induced liver injury. The peptide LBPK95A was able to inhibit LBP-mediated LPS activation of RAW 267.4 cells in a dose dependent manner in vitro. In vivo, C57Bl/6 mice were treated with either LBPK95A or vehicle control concurrently with the administration of APAP (350 mg/kg). Mice treated with LBPK95A had significantly lower serum aspartate aminotransferase and alanine aminotransferase levels. Morphometric analysis of the liver tissue showed significantly less liver injury in mice treated with LBPK95A. To assess whether the LBPK95A altered glutathione depletion and APAP metabolism, we measured total glutathione levels in the liver after APAP. We found no difference in the glutathione levels and APAP-adduct formation between LBPK95A vs. vehicle control both at baseline and after APAP. In conclusion, our results support the hypothesis that LBP-induced liver injury after APAP is due to its ability to mediate activation by endogenous LPS. Our results suggest that blocking LBP-LPS interactions is a potential therapeutic avenue for the treatment of APAP-induced liver injury. PMID- 20847299 TI - Combination of starvation interval and food volume determines the phase of liver circadian rhythm in Per2::Luc knock-in mice under two meals per day feeding. AB - Although the circadian liver clock is entrained by the feeding cycle, factors such as food volume and starvation interval are poorly understood. Per2::Luc knock-in mice were given two meals per day with different food volume sizes and/or with different intervals of starvation between two mealtimes with the total food volume per day fixed at 3.6 g (80 food pellets, ~75% of free feeding) per mouse. The bioluminescence rhythm in the liver produced a unimodal peak but not bimodal peak under the regimen of two meals per day over 14-15 days. Peak Per2 expression occurred concurrently with the mealtime of the larger food volume, when the first and second meal were given as different food volume ratios under a 12 h feeding interval. When an equal volume of food was given under different starvation interval (8 h:16 h), the peak of the Per2 rhythm was close to peak by mealtime after long starvation (16 h). When food volumes for each mealtime were changed under 8 h:16 h, the peak rhythm was influenced by combined factors of food volume and starvation interval. Food intake after the 16-h starvation caused a significant increase in liver Per2, Dec1, and Bmal1 gene expression compared with food intake after the 8-h starvation with 8 h:16 h feeding intervals. In conclusion, the present results clearly demonstrate that food-induced entrainment of the liver clock is dependent on both food volume and the starvation interval between two meals. Therefore, normal feeding habits may help to maintain normal clock function in the liver organ. PMID- 20847300 TI - Hedgehog signaling regulates E-cadherin expression for the maintenance of the actin cytoskeleton and tight junctions. AB - In the stomach, strictly regulated cell adherens junctions are crucial in determining epithelial cell differentiation. Sonic Hedgehog (Shh) regulates epithelial cell differentiation in the adult stomach. We sought to identify whether Shh plays a role in regulating adherens junction protein E-cadherin as a mechanism for epithelial cell differentiation. Mouse nontumorigenic gastric epithelial (IMGE-5) cells treated with Hedgehog signaling inhibitor cyclopamine and anti-Shh 5E1 antibody or transduced with short hairpin RNA against Skinny Hedgehog (IMGE-5(Ski)) were cultured. A mouse model expressing a parietal cell specific deletion of Shh (HKCre/Shh(KO)) was used to identify further changes in adherens and tight junctions. Inhibition of Hedgehog signaling in IMGE-5 cells caused loss of E-cadherin expression accompanied by disruption of F-actin cortical expression and relocalization of zonula occludens-1 (ZO-1). Loss of E cadherin was also associated with increased proliferation in IMGE-5(Ski) cells and increased expression of the mucous neck cell lineage marker MUC6. Compared with membrane-expressed E-cadherin and ZO-1 protein in controls, dissociation of E-cadherin/beta-catenin and ZO-1/occludin protein complexes was observed in HKCre/Shh(KO) mice. In conclusion, we demonstrate that Hedgehog signaling regulates E-cadherin expression that is required for the maintenance of F-actin cortical expression and stability of tight junction protein ZO-1. PMID- 20847301 TI - Accurate localization of a fall in pH within the ileocecal region: validation using a dual-scintigraphic technique. AB - Stereotypical changes in pH occur along the gastrointestinal (GI) tract. Classically, there is an abrupt increase in pH on exit from the stomach, followed later by a sharp fall in pH, attributed to passage through the ileocecal region. However, the precise location of this latter pH change has never been conclusively substantiated. We aimed to determine the site of fall in pH using a dual-scintigraphic technique. On day 1, 13 healthy subjects underwent nasal intubation with a 3-m-long catheter, which was allowed to progress to the distal ileum. On day 2, subjects ingested a pH-sensitive wireless motility capsule labeled with 4 MBq (51)Chromium [EDTA]. The course of this, as it travelled through the GI tract, was assessed with a single-headed gamma-camera using static and dynamic scans. Capsule progression was plotted relative to a background of 4 MBq 111Indium [diethylenetriamine penta-acetic acid] administered through the catheter. Intraluminal pH, as recorded by the capsule, was monitored continuously, and position of the capsule relative to pH was established. A sharp fall in pH was recorded in all subjects; position of the capsule relative to this was accurately determined anatomically in 9/13 subjects. In these nine subjects, a pH drop of 1.5 +/- 0.2 U, from 7.6 +/- 0.05 to 6.1 +/- 0.1 occurred a median of 7.5 min (1-16) after passage through the ileocecal valve; location was either in the cecum (n = 5), ascending colon (n = 2), or coincident with a move from the cecum to ascending colon (n = 2). This study provides conclusive evidence that the fall in pH seen within the ileocolonic region actually occurs in the proximal colon. This phenomenon can be used as a biomarker of transition between the small and large bowel and validates assessment of regional GI motility using capsule technology that incorporates pH measurement. PMID- 20847302 TI - Coronary artery disease-related genetic variant on chromosome 10q11 is associated with carotid intima-media thickness and atherosclerosis. AB - OBJECTIVE: To investigate whether chromosome 10q11.21 influences common carotid intima-media thickness (IMT) and atherosclerosis and whether it is associated with stromal cell-derived factor-1alpha (SDF-1alpha) plasma levels. METHODS AND RESULTS: Variation on chromosome 10q11.21 has been consistently associated with coronary artery disease. The genetic variant lies upstream of the gene encoding SDF-1alpha. We genotyped 3 population cohorts (Bruneck [age range, 45 to 94 years; 50.0% men; n=738], Health2000 [age range, 46 to 76 years; 55.4% men; n=1237], and essential hypertension in families collected in the region of Oxford [HTO] [age range, 19 to 88 years; 47.9% men; n=770]) for single-nucleotide polymorphism rs501120 at the 10q11.21 locus and conducted a meta-analysis in these cohorts to ascertain a relationship between the polymorphism and carotid IMT. The analysis showed that individuals with the T/T genotype had a significantly higher carotid IMT than individuals with the C/T or C/C genotype (pooled weighted mean difference, 23 MUm [95% CI, 9 to 37 MUm], P=0.0014 under a fixed-effects model; and 23 MUm [95% CI, 6 to 41 MUm], P=0.009 under a random effects model). In the Bruneck cohort, in which data for carotid atherosclerosis and plasma SDF-1alpha levels were available, we observed an association of the T/T genotype with a higher burden of atherosclerosis and increased susceptibility to the development of atherosclerosis during a 5-year follow-up (multivariable odds ratio, 1.73 [95% CI, 1.18 to 2.52]; P=0.005 for the recessive model) and an association between the T/T genotype and lower SDF-1alpha levels (2.62 ng/mL for T/T versus 2.74 ng/mL for C/C or C/T; P=0.023). CONCLUSIONS: The coronary heart disease-related variant at the 10q11.21 locus is associated with carotid IMT and atherosclerosis. PMID- 20847303 TI - The Wnt antagonist Dickkopf-1 increases endothelial progenitor cell angiogenic potential. AB - OBJECTIVE: To determine the role of Wnt antagonist Dickkopf (DKK) 1 in human endothelial colony-forming cells (ECFCs) in view of the emerging importance of Wnt pathways in vascular biology. METHODS AND RESULTS: Endothelial progenitor cells have been proposed to be crucial in tumor neovascularization. Recombinant DKK1 has been tested in ECFC angiogenic properties in vitro. DKK1 enhanced ECFC proliferation and the capacity of ECFCs to form pseudotubes in Matrigel. These effects have been attributed to enhancement of vascular endothelial growth factor receptor 2, SDF-1, and CXCR4. DKK1 gene silencing has been realized on ECFCs and mesenchymal stem cells, and we found that DKK1 silencing in the 2 cell types decreased their angiogenic potential. We then examined the possible role of DKK1 in tumor neovasculogenesis and found that blood vessels of breast cancer tissues expressed DKK1 far more strongly in human breast tumors than in normal breast tissues. By studying 62 human breast tumors, we found a significant positive correlation between DKK1 expression and von Willebrand factor. In vivo, DKK1 strongly enhanced the vascularization of Matrigel plugs and increased tumor size in a xenograft model of human breast carcinoma in nude mice. CONCLUSIONS: DKK1 enhances angiogenic properties of ECFCs in vitro and is required for ECFC and mesenchymal stem cell angiogenic phenotypes in vivo. DKK1 also increases tumoral angiogenesis. Thus, we demonstrated a major role of DKK1 in angiogenic processes. PMID- 20847304 TI - Endothelial estrogen receptor {alpha} plays an essential role in the coronary and myocardial protective effects of estradiol in ischemia/reperfusion. AB - OBJECTIVE: To assess the coronary endothelial protective effects of 17beta estradiol (E2) and the role of estrogen receptor (ER) alpha in ischemia/reperfusion (I/R). METHODS AND RESULTS: E2 exerts protective effects in cardiac I/R. However, the implication in vivo of the endothelium and the cellular targets of the anti-ischemic effects of E2 are unknown. Mice were subjected to I/R (30 minutes of I and 1 hour of R) in vivo, after which acetylcholine-induced relaxation of isolated coronary segments was assessed ex vivo. I/R induced a coronary endothelial dysfunction in untreated ovariectomized mice that was prevented by long-term treatment with E2 in wild-type, but not in ERalpha(-/-), mice. Chimeric mice inactivated for ERalpha in the hematopoietic compartment remained protected by E2. Further inactivation of endothelial ERalpha abolished the protective action of E2 on coronary endothelial function in Tie2-Cre(+) ERalpha(f/f) mice. More importantly, E2 significantly limited infarct size in wild-type mice but not in mice deficient in endothelial ERalpha, even in the presence of hematopoietic ERalpha. CONCLUSIONS: Endothelial ERalpha plays a crucial role in the E2-induced prevention of endothelial dysfunction after I/R. To our knowledge, we demonstrate for the first time, by using unique genetically modified mice, that targeting endothelial protection per se can confer cardiomyocyte protection in I/R. PMID- 20847305 TI - Low clusterin levels in high-density lipoprotein associate with insulin resistance, obesity, and dyslipoproteinemia. AB - OBJECTIVE: To determine whether obesity and insulin resistance associate with changes in the protein content of high-density lipoprotein (HDL) in 2 different groups of men by using targeted proteomics. METHODS AND RESULTS: Insulin resistance and obesity are hallmarks of type 2 diabetes mellitus and the metabolic syndrome, which confer an increased risk of cardiovascular disease. Recent studies suggest that the protein cargo of HDL makes important contributions to the lipoprotein's cardioprotective effects. In a discovery study, we used isotope dilution mass spectrometry to quantify the relative concentrations of 5 proteins previously implicated in HDL's cardioprotective effects in 3 groups of healthy subjects: lean insulin-sensitive, lean insulin resistant, and obese insulin-resistant individuals. We validated our findings in a different group of subjects. The clusterin concentration in HDL strongly and negatively associated with insulin resistance and body mass index in both populations. HDL clusterin levels were lower in subjects with low HDL and high triglycerides, key components of the metabolic syndrome. There was an inverse correlation between clusterin levels in HDL and very-low-density lipoprotein/low density lipoprotein. CONCLUSIONS: Clusterin levels in HDL are lower in men with reduced insulin sensitivity, higher body mass index, and an unfavorable lipid profile. Our observations raise the possibility that clusterin depletion contributes to the loss of HDL's cardioprotective properties. PMID- 20847306 TI - Indirubin-3'-monoxime blocks vascular smooth muscle cell proliferation by inhibition of signal transducer and activator of transcription 3 signaling and reduces neointima formation in vivo. AB - OBJECTIVE: Our goal was to examine the influence of indirubin-3'-monoxime (I3MO), a natural product-derived cyclin-dependent kinase inhibitor, on vascular smooth muscle cell (VSMC) proliferation in vitro, experimentally induced neointima formation in vivo, and related cell signaling pathways. METHODS AND RESULTS: I3MO dose-dependently inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation by arresting cells in the G(0)/G(1) phase of the cell cycle as assessed by 5-bromo-2'-deoxyuridine incorporation and flow cytometry. PDGF induced activation of the kinases Akt, Erk1/2, and p38(MAPK) was not affected. In contrast, I3MO specifically blocked PDGF-, interferon-gamma-, and thrombin induced phosphorylation of signal transducer and activator of transcription 3 (STAT3). Human endothelial cells (EA.hy926) responded to I3MO with increased endothelial nitric oxide synthase activity as assessed via [(14)C]l arginine/[(14)C]l-citrulline conversion. The specific STAT3 inhibitor Stattic led to decreased VSMC proliferation, and transient expression of a constitutively active form of STAT3 overcame the I3MO-induced cell cycle arrest in mouse embryonic fibroblasts. In a murine femoral artery cuff model, I3MO prevented neointima formation while reducing STAT3 phosphorylation and the amount of proliferating Ki67-positive cells. CONCLUSIONS: I3MO represses PDGF- and thrombin induced VSMC proliferation and, in vivo, neointima formation, likely because it specifically blocks STAT3 signaling. This profile and its positive effect on endothelial NO production turns I3MO into a promising lead compound to prevent restenosis. PMID- 20847307 TI - Body composition as determinant of thrombin generation in plasma: the Hoorn study. AB - OBJECTIVE: The association between obesity and cardiovascular disease and venous thromboembolism might, at least partially, be explained by a hypercoagulable state. The extent to which body fat mass and its distribution contribute to a hypercoagulable state is unknown. In this study, we investigated the association between body composition and thrombin generation and evaluated the potential mediating role of low-grade inflammation. METHODS AND RESULTS: We studied 586 individuals from the Hoorn Study (mean age, 69.7 +/- 6.5 years, 298 women) in whom body composition was assessed by whole body dual-energy absorptiometry. Thrombin generation was measured using the calibrated automated thrombogram. Multiple regression analyses showed a positive association between total body fat and thrombin generation in women but not in men. In addition, detailed analyses of regional body composition showed that central but not peripheral fat mass was associated with greater thrombin generation and that there was a trend toward an inverse association with peripheral lean mass. The reported positive associations were partially attenuated by low-grade inflammation, however. CONCLUSIONS: Body fat mass, in particular a central pattern of fat distribution, is associated with higher levels of thrombin generation in elderly women but not in men. This association may partially be explained by adiposity-related low-grade inflammation, but this hypothesis needs to be further investigated in mechanistic/prospective studies. PMID- 20847308 TI - Association of the vitamin D metabolism gene CYP24A1 with coronary artery calcification. AB - OBJECTIVE: The vitamin D endocrine system is essential for calcium homeostasis, and low levels of vitamin D metabolites have been associated with cardiovascular disease risk. We hypothesized that DNA sequence variation in genes regulating vitamin D metabolism and signaling pathways might influence variation in coronary artery calcification (CAC). METHODS AND RESULTS: We genotyped single-nucleotide polymorphisms (SNPs) in GC, CYP27B1, CYP24A1, and VDR and tested their association with CAC quantity, as measured by electron beam computed tomography. Initial association studies were carried out in a discovery sample comprising 697 Amish subjects, and SNPs nominally associated with CAC quantity (4 SNPs in CYP24A1, P=0.008 to 0.00003) were then tested for association with CAC quantity in 2 independent cohorts of subjects of white European ancestry (Genetic Epidemiology Network of Arteriopathy study [n=916] and the Penn Coronary Artery Calcification sample [n=2061]). One of the 4 SNPs, rs2762939, was associated with CAC quantity in both the Genetic Epidemiology Network of Arteriopathy (P=0.007) and Penn Coronary Artery Calcification (P=0.01) studies. In all 3 populations, the rs2762939 C allele was associated with lower CAC quantity. Metaanalysis for the association of this SNP with CAC quantity across all 3 studies yielded a P value of 2.9*10(-6). CONCLUSIONS: A common SNP in the CYP24A1 gene was associated with CAC quantity in 3 independent populations. This result suggests a role for vitamin D metabolism in the development of CAC quantity. PMID- 20847309 TI - Loss of PI3Kgamma enhances cAMP-dependent MMP remodeling of the myocardial N cadherin adhesion complexes and extracellular matrix in response to early biomechanical stress. AB - RATIONALE: Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)gamma, the isoform linked to G protein-coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial. OBJECTIVE: To characterize molecular and cellular responses of the PI3Kgamma knockout (KO) mice to biomechanical stress. METHODS AND RESULTS: In response to pressure overload, PI3KgammaKO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3alpha. In contrast, isolated single cardiomyocytes from banded PI3KgammaKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KgammaKO mice. beta-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3Kgamma resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3KgammaKO mice resulted in reduced cell adhesion. The beta-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3KgammaKO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels. CONCLUSIONS: The enhanced propensity to develop heart failure in the PI3KgammaKO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/beta-catenin cell adhesion complex. beta-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs. PMID- 20847310 TI - Feedback control through cGMP-dependent protein kinase contributes to differential regulation and compartmentation of cGMP in rat cardiac myocytes. AB - RATIONALE: We have shown recently that particulate (pGC) and soluble guanylyl (sGC) cyclases synthesize cGMP in different compartments in adult rat ventricular myocytes (ARVMs). OBJECTIVE: We hypothesized that cGMP-dependent protein kinase (PKG) exerts a feedback control on cGMP concentration contributing to its intracellular compartmentation. METHODS AND RESULTS: Global cGMP levels, cGMP phosphodiesterase (PDE) and pGC enzymatic activities were determined in purified ARVMs. Subsarcolemmal cGMP signals were monitored in single cells by recording the cGMP-gated current (I(CNG)) in myocytes expressing the wild-type rat olfactory cyclic nucleotide-gated (CNG) channel. Whereas the NO donor S-nitroso-N acetyl-penicillamine (SNAP) (100 MUmol/L) produced little effect on I(CNG), the response increased 2-fold in the presence of the PKG inhibitors KT5823 (50 nmol/L) or DT-2 (2 MUmol/L). The effect of KT5823 was abolished in the presence of the nonselective cyclic nucleotide PDE inhibitor 3-isobutyl-1-methylxantine (IBMX) (100 MUmol/L) or the selective cGMP-PDE5 inhibitor sildenafil (100 nmol/L). PKG inhibition also potentiated the effect of SNAP on global cGMP levels and fully blocked the increase in cGMP-PDE5 activity. In contrast, PKG inhibition decreased by ~50% the I(CNG) response to ANP (10 and 100 nmol/L), even in the presence of IBMX. Conversely, PKG activation increased the I(CNG) response to ANP and amplified the stimulatory effect of ANP on pGC activity. CONCLUSIONS: PKG activation in adult cardiomyocytes limits the accumulation of cGMP induced by NO donors via PDE5 stimulation but increases that induced by natriuretic peptides. These findings support the paradigm that cGMP is not uniformly distributed in the cytosol and identifies PKG as a key component in this process. PMID- 20847311 TI - The FGF-BMP signaling axis regulates outflow tract valve primordium formation by promoting cushion neural crest cell differentiation. AB - RATIONALE: Heart valves develop from precursor structures called cardiac cushions, an endothelial-lined cardiac jelly that resides in the inner side of the heart tube. The cushions are then invaded by cells from different sources, undergo a series of complicated and poorly understood remodeling processes, and give rise to valves. Disruption of the fibroblast growth factor (FGF) signaling axis impairs morphogenesis of the outflow tract (OFT). Yet, whether FGF signaling regulates OFT valve formation is unknown. OBJECTIVE: To study how OFT valve formation is regulated and how aberrant cell signaling causes valve defects. METHODS AND RESULTS: By using mouse genetic manipulation, cell lineage tracing, ex vivo heart culture, and molecular biology approaches, we demonstrated that FGF signaling in the OFT myocardium upregulated Bmp4 expression, which then enhanced smooth muscle differentiation of neural crest cells (NCCs) in the cushion. FGF signaling also promoted OFT myocardial cell invasion to the cushion. Disrupting FGF signaling interrupted cushion remodeling with reduced NCCs differentiation into smooth muscle and less cardiomyocyte invasion and resulted in malformed OFT valves. CONCLUSIONS: The results demonstrate a novel mechanism by which the FGF BMP signaling axis regulates formation of OFT valve primordia by controlling smooth muscle differentiation of cushion NCCs. PMID- 20847312 TI - Myomasp/LRRC39, a heart- and muscle-specific protein, is a novel component of the sarcomeric M-band and is involved in stretch sensing. AB - RATIONALE AND OBJECTIVE: The M-band represents a transverse structure in the center of the sarcomeric A-band and provides an anchor for the myosin-containing thick filaments. In contrast to other sarcomeric structures, eg, the Z-disc, only few M-band-specific proteins have been identified to date, and its exact molecular composition remains unclear. METHODS AND RESULTS: Using a bioinformatic approach to identify novel heart- and muscle-specific genes, we found a leucine rich protein, myomasp (Myosin-interacting, M-band-associated stress-responsive protein)/LRRC39. RT-PCR and Northern and Western blot analyses confirmed a cardiac-enriched expression pattern, and immunolocalization of myomasp revealed a strong and specific signal at the sarcomeric M-band. Yeast 2-hybrid screens, as well as coimmunoprecipitation experiments, identified the C terminus of myosin heavy chain (MYH)7 as an interaction partner for myomasp. Knockdown of myomasp in neonatal rat ventricular myocytes (NRVCMs) led to a significant upregulation of the stretch-sensitive genes GDF-15 and BNP. Conversely, the expression of MYH7 and the M-band proteins myomesin-1 and -2 was found to be markedly reduced. Mechanistically, knockdown of myomasp in NRVCM led to a dose-dependent suppression of serum response factor-dependent gene expression, consistent with earlier observations linking the M-band to serum response factor-mediated signaling. Finally, downregulation of myomasp/LRRC39 in spontaneously beating engineered heart tissue constructs resulted in significantly lower force generation and reduced fractional shortening. Likewise, knockdown of the myomasp/LRRC39 ortholog in zebrafish resulted in severely impaired heart function and cardiomyopathy in vivo. CONCLUSIONS: These findings reveal myomasp as a previously unrecognized component of an M-band-associated signaling pathway that regulates cardiomyocyte gene expression in response to biomechanical stress. PMID- 20847313 TI - Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy. AB - RATIONALE: The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels. OBJECTIVE: We aimed to characterize the ECM, cardiovascular function and responses to elevated cardiovascular load in mice lacking Col XV (Col15a1(-/-)) to define its functional role in the vasculature and in age- and hypertension-associated myocardial remodeling. METHODS AND RESULTS: Cardiac structure and vasculature were analyzed by light and electron microscopy. Cardiac function, intraarterial blood pressure, microhemodynamics, and gene expression profiles were studied using echocardiography, telemetry, intravital microscopy, and PCR, respectively. Experimental hypertension was induced with angiotensin II or with a nitric oxide synthesis inhibitor. Under basal conditions, lack of Col XV resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes. In response to experimental hypertension, Col15a1 gene expression was increased in the left ventricle of wild-type mice, and mRNA expression of natriuretic peptides (ANP and BNP) and ECM modeling were abnormal in Col15a1(-/-) mice. CONCLUSIONS: Col XV is necessary for ECM organization in the heart, and for the structure and functions of microvessels. Col XV deficiency leads to a complex cardiac phenotype and predisposes the subject to pathological responses under cardiac stress. PMID- 20847315 TI - Which patients having asymptomatic carotid artery stenosis might benefit from screening? PMID- 20847314 TI - CXCR4-mediated bone marrow progenitor cell maintenance and mobilization are modulated by c-kit activity. AB - RATIONALE: The mobilization of bone marrow (BM) progenitor cells (PCs) is largely governed by interactions between stromal cell-derived factor (SDF)-1 and CXC chemokine receptor (CXCR)4. Ischemic injury disrupts the SDF-1-CXCR4 interaction and releases BM PCs into the peripheral circulation, where the mobilized cells are recruited to the injured tissue and contribute to vessel growth. BM PCs can also be mobilized by the pharmacological CXCR4 antagonist AMD3100, but the other components of the SDF-1-CXCR4 signaling pathway are largely unknown. c-kit, a membrane-bound tyrosine kinase and the receptor for stem cell factor, has also been shown to play a critical role in BM PC mobilization and ischemic tissue repair. OBJECTIVE: To investigate the functional interaction between SDF-1-CXCR4 signaling and c-kit activity in BM PC mobilization. METHODS AND RESULTS: AMD3100 administration failed to mobilize BM PCs in mice defective in c-kit kinase activity or in mice transplanted with BM cells that expressed a constitutively active c-kit mutant. Furthermore, BM levels of phosphorylated (phospho)-c-kit declined after AMD3100 administration and after CXCR4 deletion. In cells adhering to culture plates coated with vascular cell adhesion molecule 1, SDF-1 and stem cell factor increased phospho-c-kit levels, and AMD3100 treatment suppressed SDF 1-induced, but not SCF-induced, c-kit phosphorylation. SDF-1-induced c-kit phosphorylation also required the activation of Src nonreceptor tyrosine kinase: pretreatment of cells with a selective Src inhibitor blocked both c-kit phosphorylation and the interaction between c-kit and phospho-Src. CONCLUSIONS: These findings indicate that the regulation of BM PC trafficking by SDF-1 and CXCR4 is dependent on Src-mediated c-kit phosphorylation. PMID- 20847316 TI - Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction. AB - BACKGROUND AND PURPOSE: Perfusion CT has been used to assess the extent of blood brain barrier breakdown. The purpose of this study was to determine the predictive value of blood-brain barrier permeability measured using perfusion CT for development of malignant middle cerebral artery infarction requiring hemicraniectomy (HC). METHODS: We retrospectively identified patients from our stroke registry who had middle cerebral artery infarction and were evaluated with admission perfusion CT. Blood-brain barrier permeability and cerebral blood volume maps were generated and infarct volumes calculated. Clinical and radiographic characteristics were compared between those who underwent HC versus those who did not undergo HC. RESULTS: One hundred twenty-two patients (12 HC, 110 no HC) were identified. Twelve patients who underwent HC had developed edema, midline shift, or infarct expansion. Infarct permeability area, infarct cerebral blood volume area, and infarct volumes were significantly different (P < 0.018, P < 0.0211, P < 0.0001, P < 0.0014) between HC and no HC groups. Age (P = 0.03) and admission National Institutes of Health Stroke Scale (P = 0.0029) were found to be independent predictors for HC. Using logistic regression modeling, there was an association between increased infarct permeability area and HC. The OR for HC based on a 5-, 10-, 15-, or 20-cm2 increase in infarct permeability area were 1.179, 1.390, 1.638, or 1.932, respectively (95% CI, 1.035 to 1.343, 1.071 to 1.804, 1.108 to 2.423, 1.146 to 3.255, respectively). CONCLUSIONS: Increased infarct permeability area is associated with an increased likelihood for undergoing HC. Because early HC for malignant middle cerebral artery infarction has been associated with better outcomes, the infarct permeability area on admission perfusion CT might be a useful tool to predict malignant middle cerebral artery infarction and need for HC. PMID- 20847317 TI - Effects of metformin in experimental stroke. AB - BACKGROUND AND PURPOSE: Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an important sensor of energy balance. Stroke-induced AMPK activation is deleterious because both pharmacological inhibition and genetic deletion of AMPK are neuroprotective. Metformin is a known AMPK activator but reduces stroke incidence in clinical populations. We investigated the effect of acute and chronic metformin treatment on infarct volume and AMPK activation in experimental stroke. METHODS: Male mice were subjected to middle cerebral artery occlusion after acute (3 days) or chronic (3 weeks) administration of metformin. Infarct volumes, AMPK activation, lactate accumulation, and behavioral outcomes were assessed. The roles of neuronal nitric oxide synthase and AMPK were examined using mice with targeted deletion of AMPK or neuronal nitric oxide synthase. RESULTS: Acute metformin exacerbated stroke damage, enhanced AMPK activation, and led to metabolic dysfunction. This effect was lost in AMPK and neuronal nitric oxide synthase knockout mice. In contrast, chronic metformin given prestroke was neuroprotective, improved stroke-induced lactate generation, and ameliorated stroke-induced activation of AMPK. Similarly, the neuroprotective effect of chronic prestroke metformin was lost in neuronal nitric oxide synthase knockout mice. CONCLUSIONS: AMPK is an important potential target for stroke treatment and prevention. These studies show that the timing, duration, and amount of AMPK activation are key factors in determining the ultimate downstream effects of AMPK on the ischemic brain. PMID- 20847318 TI - Genetic epidemiology of spontaneous subarachnoid hemorrhage: Nordic Twin Study. AB - BACKGROUND AND PURPOSE: It would be essential to clinicians, familial aneurysm study groups, and aneurysm families to understand the genetic basis of subarachnoid hemorrhage (SAH), but there are no large population-based heritability estimates assessing the relative contribution of genetic and environmental factors to SAH. METHODS: We constructed the largest twin cohort to date, the population-based Nordic Twin Cohort, which comprised 79 644 complete twin pairs of Danish, Finnish, and Swedish origin. The Nordic Twin Cohort was followed up for 6.01 million person-years using nationwide cause-of-death and hospitalization registries. RESULTS: One hundred eighty-eight fatal and 321 nonfatal SAH cases were recorded in the Nordic Twin Cohort. Thus, SAH incidence was 8.47 cases per 100,000 follow-up years. Data for pairwise analyses were available for a total of 504 SAH cases, of which 6 were concordant (5 monozygotic and 1 opposite sex) and 492 discordant twin pairs for SAH. The concordance for SAH in monozygotic twins was 3.1% compared with 0.27% in dizygotic twins, suggesting at most a modest role for genetic factors in the etiology of SAH. The population-based probability estimate for SAH in dizygotic siblings of a patient with SAH is 0.54%, and only 1 of 185 full siblings experience familial SAH. The corresponding risk of SAH in monozygotic twins is 5.9%. Model-fitting, which was based on the comparison of the few monozygotic and dizygotic pairs, suggested that the estimated heritability of SAH is 41%. CONCLUSIONS: SAH appears to be mainly of nongenetic origin, and familial SAHs can mostly be attributed to environmental risk factors. PMID- 20847319 TI - C-kit/CD117 cells from amniotic fluid and membranes and their cardiomyogenic potential. PMID- 20847323 TI - Diabetes mellitus reveals its micro-signature. PMID- 20847325 TI - The cardiac desmosome and arrhythmogenic cardiomyopathies: from gene to disease. AB - Intercellular communication is essential for proper cardiac function. Mechanical and electrical activity need to be synchronized so that the work of individual myocytes transforms into the pumping function of the organ. Mechanical continuity is provided by desmosomes and adherens junctions, while gap junctions provide a pathway for passage of ions and small molecules between cells. These complexes preferentially reside at the site of end-end contact between myocytes, within the intercalated disc. Recognition that some forms of arrhythmogenic cardiomyopathy are caused by mutations in desmosomal protein genes has galvanized interest in the biology of the desmosome and its interactions with other junctional molecules. This review presents the cellular and molecular biology of the desmosome, current knowledge on the relation of desmosomal mutations and disease phenotypes, and an overview of the molecular pathophysiology of arrhythmogenic right ventricular cardiomyopathy. Clinical experience and results from cellular and animal models provide insights into the intercalated disc as a functional unit and into the basic substrates that underlie pathogenesis and arrhythmogenesis of arrhythmogenic right ventricular cardiomyopathy. PMID- 20847324 TI - Two close, too close: sarcoplasmic reticulum-mitochondrial crosstalk and cardiomyocyte fate. AB - Mitochondria are key organelles in cell life whose dysfunction is associated with a variety of diseases. Their crucial role in intermediary metabolism and energy conversion makes them a preferred target in tissues, such as the heart, where the energetic demands are very high. In the cardiomyocyte, the spatial organization of mitochondria favors their interaction with the sarcoplasmic reticulum, thereby offering a mechanism for Ca(2+)-mediated crosstalk between these 2 organelles. Recently, the molecular basis for this interaction has begun to be unraveled, and we are learning how endoplasmic reticulum-mitochondrial interactions are often exploited by death signals, such as proapoptotic Bcl-2 family members, to amplify the cell death cascade. Here, we review our present understanding of the structural basis and the functional consequences of the close interaction between sarcoplasmic reticulum and mitochondria on cardiomyocyte function and death. PMID- 20847326 TI - A dual-monoclonal sandwich ELISA specific for hepcidin-25. AB - BACKGROUND: Hepcidin, a key regulator of iron metabolism, binds to the iron transporter ferroportin to cause its degradation. In humans, hepcidin deficiency has been linked to hemochromatosis and iron overload, whereas increased concentrations have been reported in anemia of cancer and chronic disease. There is currently an unmet clinical need for a specific immunoassay with a low limit of quantification to measure serum concentrations of hepcidin-25, the active form of the protein. METHODS: We generated 2 antihepcidin-25 monoclonal antibodies and used them to build a sandwich ELISA. We correlated ELISA results to hepcidin-25 measurements by LC-MS and used ELISA to measure serum hepcidin-25 concentrations in normal individuals, cancer patients, and patients with rheumatoid arthritis. RESULTS: The sandwich ELISA was highly specific for hepcidin-25, having a limit of quantification of 0.01 MUg/L (10 pg/mL). Serum concentrations of hepcidin-25 measured by ELISA correlated with hepcidin-25 concentrations measured by using an independent LC-MS assay (r = 0.98, P < 0.001). Hepcidin-25 concentrations were increased in patients with cancer (median 54.8 MUg/L, 25%-75% range 23.2-93.5 MUg/L, n = 34) and rheumatoid arthritis (median 10.6 MUg/L, 25%-75% range 5.9 18.4 MUg/L, n = 76) compared with healthy individuals (median 1.20 MUg/L, 25%-75% range 0.42-3.07 MUg/L, n = 100). CONCLUSIONS: The use of 2 monoclonal antibodies in a sandwich ELISA format provides a robust and convenient method for measuring concentrations of the active form of hepcidin. This ELISA should help to improve our understanding of the role of hepcidin in regulating iron metabolism. PMID- 20847328 TI - Assessing veterinary academic leadership. PMID- 20847327 TI - The microRNA spectrum in 12 body fluids. AB - BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in regulating various biological processes through their interaction with cellular messenger RNAs. Extracellular miRNAs in serum, plasma, saliva, and urine have recently been shown to be associated with various pathological conditions including cancer. METHODS: With the goal of assessing the distribution of miRNAs and demonstrating the potential use of miRNAs as biomarkers, we examined the presence of miRNAs in 12 human body fluids and urine samples from women in different stages of pregnancy or patients with different urothelial cancers. Using quantitative PCR, we conducted a global survey of the miRNA distribution in these fluids. RESULTS: miRNAs were present in all fluids tested and showed distinct compositions in different fluid types. Several of the highly abundant miRNAs in these fluids were common among multiple fluid types, and some of the miRNAs were enriched in specific fluids. We also observed distinct miRNA patterns in the urine samples obtained from individuals with different physiopathological conditions. CONCLUSIONS: MicroRNAs are ubiquitous in all the body fluid types tested. Fluid type-specific miRNAs may have functional roles associated with the surrounding tissues. In addition, the changes in miRNA spectra observed in the urine samples from patients with different urothelial conditions demonstrates the potential for using concentrations of specific miRNAs in body fluids as biomarkers for detecting and monitoring various physiopathological conditions. PMID- 20847329 TI - Knowledge, skills, and attitudes of veterinary college deans: AAVMC survey of deans in 2010. AB - The purposes of this Association of American Veterinary Medical Colleges (AAVMC) study was to develop a profile of deans to understand the knowledge, skills, and attitudes that current deans of schools and colleges of veterinary medicine consider important to job success and to inform the association's leadership development initiatives. Forty-two deans responded to an online leadership program needs survey, which found that knowledge, skills, and abilities related to communication, finance and budget management, negotiation, conflict management, public relations, and fundraising were recommended as the most important areas for fulfilling a deanship. Most respondents speculated that the greatest challenges for their institutions will be in the areas of faculty recruitment and retention and financing veterinary education. Reflecting on their experiences, respondents offered an abundance of advice to future deans, often citing the importance of preparation, communication, and leadership qualities as necessary for a successful and satisfying deanship. More than three-quarters of the respondents indicated moderate to high interest in an AAVMC multi-phase leadership training program to develop administrative leaders. A nearly equal number also indicated support for formal leadership training for current veterinary medical college and school deans. The study suggests leadership development topics that AAVMC could provide at existing meetings or through new programming. The study also suggests directions for individual institutions as they seek to implement leadership development activities at the local level. PMID- 20847330 TI - Preparing faculty for the future: AAVMC members' perceptions of professional development needs. AB - Our purpose in this study was to determine professional development needs of faculty in the Association of American Veterinary Medical Colleges' (AAVMC's) member institutions, including those needs associated with current and emerging issues and leadership development. The survey asked respondents to report their level of job satisfaction and their perceptions of professional development as they related to support and resources, teaching, research, career planning, and administration. Five hundred and sixty-five individuals from 49 member institutions responded to an online professional development needs survey. We found that job satisfaction was associated with a variety of workplace variables correlated with academic rank, with those of higher academic rank expressing greater levels of satisfaction. Respondents with tenure also expressed generally higher levels of satisfaction. Most of the respondents expressed interest in learning more about topics related to teaching (e.g., effective questioning, giving feedback, principles of learning and motivation), research (e.g., research design, writing grants), career planning (e.g., mentoring, time management), and administration (e.g., fostering innovation, enhancing productivity, improving the work environment). Just more than half of the respondents indicated moderate to high interest in an AAVMC multi-phase leadership training program. The study suggests topics for which AAVMC should provide professional development opportunities either at existing meetings or through new programming. The study also suggests directions for individual institutions as they seek to implement professional development activities at the local level. PMID- 20847331 TI - Professional development training through the veterinary curriculum at the University of Minnesota. AB - Veterinary education has traditionally focused on clinical skills. Success as a practicing veterinarian, however, also depends on good communication skills, emotional intelligence, and other "soft" skills that can lead to greater employee and employer satisfaction and increased practice revenue. The University of Minnesota has approached this curricular need by convening a task force and creating a series of courses aimed at improving leadership skills, teamwork, and verbal and written communication; managing conflict; and understanding ethics and personal finance. This article describes the evolution and structure of these soft-skill classes and the challenges in securing faculty and student buy-in essential for success. PMID- 20847332 TI - Perceptions of veterinary faculty members regarding their responsibility and preparation to teach non-technical competencies. AB - The development of non-technical competencies has become an important component of veterinary education. In this study, we determined faculty perspectives regarding their perceived involvement and ability in the cultivation of these competencies. A survey was administered to faculty members at five institutions. Respondents were asked whether the competency should be taught in their own courses and how prepared they felt to teach and evaluate the competency. Responses were analyzed by participant institution, gender, terminal degree and year, discipline, rank, and teaching experience. More than 90% of faculty respondents reported a personal responsibility to teach or cultivate critical thinking skills, communication skills, self-development skills, and ethical skills, with more than 85% also agreeing to a role in skills such as interpersonal skills, creativity, and self-management. The lowest percentages were seen for crisis and incident management (64%) and business skills (56%). Perceived preparedness to teach and evaluate these competencies paralleled the preceding findings, especially for the four consensus competencies and self management. Faculty preparedness was lowest for business skills. Junior faculty were somewhat less likely than others to perceive a responsibility to teach non technical competencies; however, instructors were more prepared to teach and evaluate business skills than were other faculty. Institutional trends were evident in faculty preparation. Although male faculty and non-DVM faculty tended to report a higher degree of preparedness, few differences reached statistical significance. Faculty perceptions of their responsibility to teach non-technical competencies vary by competency and parallel their perceived preparedness to teach and evaluate them. PMID- 20847333 TI - Fostering integrated learning and clinical professionalism using contextualized simulation in a small-group role-play. AB - Teaching and learning in a clinical setting is important in veterinary and medical training but presents many challenges, including providing enough hands on experience while not putting patients (animal or human) at risk. Some of the issues have been addressed with the introduction of clinical skills laboratories and communication skills training using role play. However, in both instances skills are learned in isolation, whereas the real task requires the integration of many skills including technical competencies, effective communication, decision making, and professionalism. In our study, we trialed "contextualized simulation" by combining role play with a simulator, the haptic cow, in a small group tutorial, the Simulated Fertility Visit. Students took turns as the veterinarian; they had to establish the cow's history from the farmer (a role player), palpate the simulation, make a diagnosis, and decide on treatment, if appropriate. We included scenarios varying from common cases to challenging situations. The tutorial was introduced in the farm-animal clinical rotation, and feedback was gathered from students by means of a questionnaire. The tutorial was attended by 178 students (98% of that year's students), and 151 questionnaires were returned (85% response rate). Students reported that the tutorial was a positive learning experience and recognized that it presented an opportunity to integrate the skills needed for clinical work. Student feedback suggests that contextualized simulation provides a valuable complement to clinical cases, and we recommend extending this teaching method to other clinical scenarios and species, particularly because it provides a safe environment in which to experience, and learn from, mistakes. PMID- 20847334 TI - Using standardized essays in the veterinary medicine admissions process: are the ratings reliable and valid? AB - The reliability and validity of using essays for veterinary medical school admissions requires investigation. We explored the reliability and construct validity of a structured essay station in the 2009 admission process at the University of Calgary Faculty of Veterinary Medicine. One hundred three applicants (female=80.6%, male=19.4%; mean age=23.05 years, SD=3.96) participated. Each applicant wrote a one-hour supervised essay (750 words). Essays were rated independently by two randomly assigned raters (n=16). Raters scored essays on four items, each on a five-point anchored scale. Nine essays were scored by all raters to perform a decision study. Generalizability analysis resulted in a reliability coefficient of 0.55. The decision study indicated that three raters and four items produces a G of 0.68. Essay score correlated with interview score (r=0.30, p<0.01) but not with GPA (r=0.05, p=ns). Overall reliability was adequate and higher than what has been reported for unsupervised written submissions. Results from the decision study suggest that three raters with four items provide adequate reliability. Correlations with interviews and grade point average provide evidence of construct validity. A time-limited essay with a clear scoring protocol results in adequate reliability and some validity. PMID- 20847335 TI - Assessment of technical skills: best practices. AB - Assessment is an important aspect of veterinary education from the point of view of setting standards, driving learning, providing feedback, and reassuring society that veterinarians are competent to assume the responsibilities entrusted to them. However, no single format exists that can, by itself, assess the complex mixture of knowledge and skills essential to the veterinarian's role. The areas that are most challenging to assess are those involving behaviors and attitudes. These include the various technical skills required for diagnosis and treatment. One approach, aimed at retaining validity but improving reliability compared with traditional, more subjective methods, first described in medicine 35 years ago, is the Objective Structured Clinical Examination (OSCE), which has been introduced into veterinary education as the Objective Structured Practical Veterinary Examination (OSPVE) and run at the Royal Veterinary College since 2004. This approach is good for the assessment of competence in relation to isolated techniques and whole procedures but has been criticized for the way in which these are tested out of context. However, further development of structured clinical assessments, such as the mini-Clinical Examination and the Direct Observation of Procedural Skills, may help address some of these limitations, and the use of multi-source feedback, particularly client feedback, may allow the further domains of professional behaviors, attitudes, and communication to be judged and developed. PMID- 20847336 TI - Assessing the influence of gender, learning style, and pre-entry experience on student response to delivery of a novel veterinary curriculum. AB - We investigated whether a novel veterinary curriculum was biased toward a particular gender, learning style, or pre-university experience (entry following undergraduate degree or direct entry from secondary school). We found no significant difference (p>0.05) in overall performance of first-year male, female, graduate-entry, or school-entry students. Students rated live-animal practical classes and facilitated problem-based learning as the most favored method of teaching, and this response was not biased by gender or pre-vet school experience. Men rated multiple-choice question (MCQ) assessment more highly than women, but there was no significant difference (p>0.05) in male or female performance on MCQ examinations. Men and women also performed comparably well in essays (both knowledge based and critical), suggesting that the retention of knowledge and depth of understanding was not gender biased. However, men performed significantly (p<0.05) better on critical essays compared with knowledge-based essays, and this trend was shown for both graduate-entry and school-entry students alike. We found no significant difference (p>0.05) in performance between groups of students with multimodal, kinesthetic, or reading writing learning styles. Students with an auditory preference consistently performed less well in all types of assessment (p<0.05), but the number of students in this group was very small. Students whose learning style could not be specifically determined by Visual, Auditory, Read/write, Kinesthetic (VARK) tests consistently performed better than other groups, but this finding was not significant. Our results indicate that the Nottingham veterinary course does not bias for or against any of the variables we investigated. PMID- 20847337 TI - Experiences with an in-training community service model in the control of zoonotic sleeping sickness in Uganda. AB - By 2006, the acute and zoonotic Tripanosoma brucei rhodesiense sleeping sickness in Uganda was spreading northward, leading to fear of a merger with the chronic Tripanosoma brucei gambiese type that affects people in the northwest of the country. Eliminating infection in cattle was urgent because they had been confirmed to be spreading the zoonotic type, and eliminating infection would reduce the animal reservoir and subsequently reduce transmission of sleeping sickness. In this article, we describe how the staff and students of the Faculty of Veterinary Medicine, Makerere University, adjusted their approach to training veterinary students who could provide the urgently needed manpower to enable the community to halt the disease's spread. Because it was not usual for university staff and students to implement disease control activities, the government of Uganda had to delegate this responsibility to Makerere University. In turn, the university had to explore available opportunities in its training and outreach mandates. A model was developed that proved to be an effective hands-on training strategy while helping to control a disease that was threatening the health of people in a community that was just recovering from an armed rebellion. In total, 66 students and supervisors participated in the 10-week-long mass treatment activities in the target area and treated more than 190,000 out of 220,000 targeted (>86%) cattle with diminazene aceturate and deltamethrin. Also, the graduates' performance improved, as indicated by 43.5% of graduates securing employment within less than a month after completing the course. PMID- 20847338 TI - Relationships between students' approaches to learning, perceptions of the teaching-learning environment, and study success: a case study of third-year veterinary students. AB - The relationships among veterinary students' approaches to learning, perceptions of the teaching-learning environment, and study success were evaluated in a demanding, discipline-based curriculum. The aim was to elicit elements for improving student counseling. As part of a large multidisciplinary survey, 36 third-year students (74% response rate) answered a modified version of the Experiences of Teaching and Learning Questionnaire in 2006. In this study, the authors used students' responses to questions regarding examinations and the progress of studies. In addition, students were classified in the large survey into four clusters according to their approaches to studying. Study success was evaluated by exploring the number of study credits students had earned and their grade point averages. The differences in study success between the clusters were not statistically significant, but, in general, students applying a deep approach were most successful, whereas unorganized students applying a deep approach showed the largest variation in study progress. The most commonly mentioned factors for enhancing or impeding study progress were related to the curriculum and to the students' actions or experiences. Unorganized students applying a deep approach seemed to suffer the most from the workload and pressure of progressing in their studies according to a predetermined timetable. These students were also most unaware of the examinations' demands. The findings suggested that, in addition to curriculum development, there is a need to explicitly make students aware of their approaches to learning and to support the development of their study practices. PMID- 20847339 TI - Dairy reproductive management: assessing a comprehensive continuing education program for veterinary practitioners. AB - Comprehensive continuing veterinary medical education (CVME) programs are critical for veterinary practitioners to update their knowledge and improve their skills and services. CVME must offer an educational environment in which veterinarians can effectively rejuvenate their knowledge and skills and learn about new practices. The Ohio Dairy Health and Management Certificate Program is a comprehensive CVME program for practicing dairy veterinarians that was developed to provide advanced training on previously identified needs of the dairy industry. Our objectives in this article were (1) to provide a description of a comprehensive CVME program designed to enhance the flow of applied, research based knowledge from educators and researchers to dairy veterinary practitioners and (2) to provide an assessment of outcomes achieved and experiences gained after the delivery of the first two modules on advanced dairy reproductive management. Findings from the two reproductive modules suggested that (1) the designed dairy reproductive management program was able to meet the participants' educational needs, (2) the implemented delivery methods significantly increased participants' knowledge level, and (3) additional educational needs should be addressed with future programming. In conclusion, results from the participants' self-reports suggested that both reproductive modules were relevant and effective, offering new information with immediate field application. These types of educational programs are important for dairy veterinary practitioners because they are a vital source of information and service providers for dairy producers. For the program to be considered completely successful, a detailed follow-up assessment of participants' behavior change, adoption of new practices and skills, and their on-farm impact is needed. PMID- 20847340 TI - Teaching veterinary obstetrics using three-dimensional animation technology. AB - In this three-year study, test scores for students taught veterinary obstetrics in a classroom setting with either traditional media (photographs, text, and two dimensional graphical presentations) were compared with those for students taught by incorporating three-dimensional (3D) media (linear animations and interactive QuickTime Virtual Reality models) into the classroom lectures. Incorporation of the 3D animations and interactive models significantly increased students' scores on essay questions designed to assess their comprehension of the subject matter. This approach to education may help to better prepare students for dealing with obstetrical cases during their final clinical year and after graduation. PMID- 20847341 TI - A laparoscopic surgical skills assessment tool for veterinarians. AB - Our aim in this study was to validate a test of laparoscopic surgical performance by determining the relation of scores from an objective structured assessment of technical skills performed in a canine abdominal model to experience and basic laparoscopic skills. The number of years the participants had performed rigid video-endoscopic procedures (VEP), using triangulation skills, correlated positively with both evaluators' total surgical performance scores for all three evaluation methods: global rating scale, visual analog scale (VAS) rating of overall performance, and operative component rating scale (OCRS). Experience of VEP without triangulation skills (i.e., flexible endoscopy, otoscopy) or video game experience did not correlate with surgical performance. A highly validated basic laparoscopic skills assessment (McGill University inanimate system for training and evaluation of laparoscopic skills, or MISTELS) score was strongly correlated with the VAS score for surgical performance and OCRS scores. Inter rater reliability was high for the VAS and OCRS evaluation methods, and scores from the detailed OCRS method did not differ between evaluators. In conclusion, the surgical performance test correlated with VEP triangulation experience and basic laparoscopic skills. This type of test needs to be evaluated in a larger sample population including higher numbers of veterinary laparoscopic surgeons for further validation. PMID- 20847342 TI - Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988 2006). AB - Vitamin D has been hypothesized to protect against cancer. We followed 16,819 participants in NHANES III (Third National Health and Nutritional Examination Survey) from 1988 to 2006, expanding on an earlier NHANES III study (1988-2000). Using Cox proportional hazards regression models, we examined risk related to baseline serum 25-hydroxyvitamin D [25(OH)D] for total cancer mortality, in both sexes, and by racial/ethnic groups, as well as for site-specific cancers. Because serum was collected in the south in cooler months and in the north in warmer months, we examined associations by collection season ("summer/higher latitude" and "winter/lower latitude"). We identified 884 cancer deaths during 225,212 person-years. Overall cancer mortality risks were unrelated to baseline 25(OH)D status in both season/latitude groups, and in non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans. In men, risks were elevated at higher levels {e.g., for >=100 nmol/L, relative risk (RR) = 1.85 [95% confidence interval (CI), 1.02-3.35] compared with <37.5 nmol/L}. Although risks were unrelated to 25(OH)D in all women combined, risks significantly decreased with increasing 25(OH)D in the summer/higher latitude group [for >=100 nmol/L, RR = 0.52 (95% CI, 0.25-1.15) compared with <37.5 nmol/L; P(trend) = 0.03, based on continuous values]. We also observed a suggestion of an inverse association with colorectal cancer mortality (P(trend) = 0.09) and a positive association with lung cancer mortality among males (P(trend) = 0.03). Our results do not support the hypothesis that 25(OH)D is associated with reduced cancer mortality. Although cancer mortality in females was inversely associated with 25(OH)D in the summer/higher latitude group, cancer mortality at some sites was increased among men with higher 25(OH)D. These findings argue for caution before increasing 25(OH)D levels to prevent cancer. PMID- 20847344 TI - Rescuing sisyphus: the team approach to amputation prevention. PMID- 20847343 TI - High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance. AB - p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. PMID- 20847345 TI - History of the team approach to amputation prevention: pioneers and milestones. AB - This historical perspective highlights some of the pioneers, milestones, teams, and system changes that have had a major impact on management of the diabetic foot during the past 100 years. In 1934, American diabetologist Elliott P. Joslin noted that mortality from diabetic coma had fallen from 60% to 5% after the introduction of insulin, yet deaths from diabetic gangrene of the lower extremity had risen significantly. He believed that diabetic gangrene was preventable. His remedy was a team approach that included foot care, diet, exercise, prompt treatment of foot infections, and specialized surgical care. The history of the team approach to management of the diabetic foot chronicles the rise of a new health profession-podiatric medicine and surgery-and emergence of the specialty of vascular surgery. The partnership among the diabetologist, vascular surgeon, and podiatric surgeon is a natural one. The complementary skills and knowledge of each can improve limb salvage and functional outcomes. Comprehensive multidisciplinary foot-care programs have been shown to increase quality of care and reduce amputation rates by 36% to 86%. Development of distal revascularization techniques to restore pulsatile blood flow to the foot has also been a major advancement. Patients with diabetic foot complications are among the most complex and vulnerable of all patient populations. Specialized diabetic foot clinics of the 21st century should be multidisciplinary and equipped to coordinate diagnosis, off-loading, and preventive care; to perform revascularization procedures; to aggressively treat infections; and to manage medical comorbidities. PMID- 20847346 TI - The costs of diabetic foot: the economic case for the limb salvage team. AB - In 2007, the treatment of diabetes and its complications in the United States generated at least $116 billion in direct costs; at least 33% of these costs were linked to the treatment of foot ulcers. Although the team approach to diabetic foot problems is effective in preventing lower-extremity amputations, the costs associated with implementing a diabetic-foot-care team are not well understood. An analysis of these costs provides the basis for this report. Diabetic foot problems impose a major economic burden, and costs increase disproportionately to the severity of the condition. Compared with diabetic patients without foot ulcers, the cost of care for those with foot ulcers is 5.4 times higher in the year after the first ulcer episode and 2.8 times higher in the second year. Costs for treating the highest-grade ulcers are 8 times higher than are those for treating low-grade ulcers. Patients with diabetic foot ulcers require more frequent emergency department visits and are more commonly admitted to the hospital, requiring longer lengths of stay. Implementation of the team approach to manage diabetic foot ulcers in a given region or health-care system has been reported to reduce long-term amputation rates 62% to 82%. Limb salvage efforts may include aggressive therapy such as revascularization procedures and advanced wound-healing modalities. Although these procedures are costly, the team approach gradually leads to improved screening and prevention programs and earlier interventions and, thus, seems to reduce long-term costs. To date, aggressive limb preservation management for patients with diabetic foot ulcers has not usually been paired with adequate reimbursement. It is essential to direct efforts in patient-caregiver education to allow early recognition and management of all diabetic foot problems and to build integrated pathways of care that facilitate timely access to limb salvage procedures. Increasing evidence suggests that the costs of implementing diabetic foot teams can be offset in the long term by improved access to care and reductions in foot complications and amputation rates. PMID- 20847347 TI - Toe and flow: essential components and structure of the amputation prevention team. AB - At the end of an anatomical peninsula, the foot in diabetes is prone to short- and long-term complications involving neuropathy, vasculopathy, and infection. Effective management requires an interdisciplinary effort focusing on this triad. Herein, we describe the key factors leading to foot complications and the critical skill sets required to assemble a team to care for them. Although specific attention is given to a conjoined model involving podiatric medicine and vascular surgery, the so-called toe and flow model, we further outline three separate programmatic models of care--basic, intermediate, and center of excellence--that can be implemented in the developed and developing world. PMID- 20847348 TI - What you can't feel can hurt you. AB - Throughout our medical training, we are taught how to manage patients who present with symptoms: perform a clinical examination, make a diagnosis, and develop a management plan. However, virtually no time is spent on teaching us how to manage patients who have no symptoms because they have lost the ability to feel pain, that is, patients with peripheral neuropathy. The lifetime incidence of foot ulceration in people with diabetes has been estimated to be as high as 25%, and a variety of contributory factors result in a foot being at risk for ulceration. Most important among these factors is peripheral neuropathy, or the loss of the ability to feel pain, temperature, or pressure sensation in the feet and lower legs. Up to 50% of older type 2 diabetic patients have evidence of sensory loss, putting them at risk for foot ulceration. If we are to succeed in reducing the high incidence of foot ulcers, regular screening for peripheral neuropathy is vital in all patients with diabetes. Those found to have any risk factors for foot ulceration require special education and more frequent review, particularly by podiatric physicians. The key message is, therefore, that neuropathic symptoms correlate poorly with sensory loss and that their absence must never be equated with lack of risk of foot ulceration. If we are to succeed in reducing the high incidence of foot ulceration and particularly recurrent ulceration, we must realize that with loss of pain there is also diminished motivation in the healing and prevention of injury. PMID- 20847349 TI - Debridement of the noninfected wound. AB - The utility of wound debridement has expanded to include the management of all chronic wounds, even in the absence of infection and gross necrosis. Biofilms, metalloproteases on the wound base, and senescent cells at the wound edge irreversibly change the physiologic features of wound healing and contribute to a pathologic, chronic inflammatory environment. The objective of this review is to provide surgeons with a basic understanding of the processes of debridement in the noninfected wound. PMID- 20847350 TI - Off-loading the diabetic foot for ulcer prevention and healing. AB - Retrospective and prospective studies have shown that elevated plantar pressure is a causative factor in the development of many plantar ulcers in diabetic patients and that ulceration is often a precursor of lower-extremity amputation. Herein, we review the evidence that relieving areas of elevated plantar pressure (off-loading) can prevent and heal plantar ulceration. There is no consensus in the literature concerning the role of off-loading through footwear in the primary or secondary prevention of ulcers. This is likely due to the diversity of intervention and control conditions tested, the lack of information about off loading efficacy of the footwear used, and the absence of a target pressure threshold for off-loading. Uncomplicated plantar ulcers should heal in 6 to 8 weeks with adequate off-loading. Total-contact casts and other nonremovable devices are most effective because they eliminate the problem of nonadherence to recommendations for using a removable device. Conventional or standard therapeutic footwear is not effective in ulcer healing. Recent US and European surveys show that there is a large discrepancy between guidelines and clinical practice in off-loading diabetic foot ulcers. Many clinics continue to use methods that are known to be ineffective or that have not been proved to be effective while ignoring methods that have demonstrated efficacy. A variety of strategies are proposed to address this situation, notably the adoption and implementation of recently established international guidelines, which are evidence based and specific, by professional societies in the United States and Europe. Such an approach would improve the often poor current expectations for healing diabetic plantar ulcers. PMID- 20847351 TI - Surgical off-loading of the diabetic foot. AB - Surgical intervention for chronic deformities and ulcerations has become an important component in the management of patients with diabetes mellitus. Such patients are no longer relegated to wearing cumbersome braces or footwear for deformities that might otherwise be easily corrected. Although surgical intervention in these often high-risk individuals is not without risk, the outcomes are fairly predictable when patients are properly selected and evaluated. In this brief review, we discuss the rationale and indications for diabetic foot surgery, focusing on the surgical decompression of deformities that frequently lead to foot ulcers. PMID- 20847352 TI - Wound care: the role of advanced wound-healing technologies. AB - Wound repair and regeneration is a highly complex combination of matrix destruction and reorganization. Although major hurdles remain, advances during the past generation have improved the clinician's armamentarium in the medical and surgical management of this problem. The purpose of this article is to review the current literature regarding the pragmatic use of three of the most commonly used advanced therapies: bioengineered tissue, negative-pressure wound therapy, and hyperbaric oxygen therapy, with a focus on the near-term future of wound healing, including stem cell therapy. PMID- 20847353 TI - Medical therapy of diabetic foot infections. AB - Diabetic foot infections are a common and often serious problem, accounting for more hospital bed days than any other complication of diabetes. Despite advances in antibiotic drug therapy and surgical management, these infections continue to be a major risk factor for amputations of the lower extremity. Although a variety of wound size and depth classification systems have been adapted for use in codifying diabetic foot ulcerations, none are specific to infection. In 2003, the International Working Group on the Diabetic Foot developed guidelines for managing diabetic foot infections, including the first severity scale specific to these infections. The following year, the Infectious Diseases Society of America published their diabetic foot infection guidelines. Herein, we review some of the critical points from the Executive Summary of the Infectious Diseases Society of America document and provide a commentary following each issue to update the reader on any pertinent changes that have occurred since publication of the original document in 2004. The importance of a multidisciplinary limb salvage team, apropos of this special issue jointly published by the American Podiatric Medical Association and the Society for Vascular Surgery, cannot be overstated. PMID- 20847354 TI - A stepwise approach for surgical management of diabetic foot infections. AB - Diabetic foot disease frequently leads to substantial long-term complications, imposing a huge socioeconomic burden on available resources and health-care systems. Peripheral neuropathy, repetitive trauma, and peripheral vascular disease are common underlying pathways that lead to skin breakdown, often setting the stage for limb-threatening infection. Individuals with diabetes presenting with foot infection warrant optimal surgical management to affect limb salvage and prevent amputation; aggressive short-term and meticulous long-term care plans are required. In addition, the initial surgical intervention or series of interventions must be coupled with appropriate systemic metabolic management as part of an integrated, multidisciplinary team. Such teams typically include multiple medical, surgical, and nursing specialties across a variety of public and private health-care systems. This article presents a stepwise approach to the diagnosis and treatment of diabetic foot infections with emphasis on the appropriate use of surgical interventions and includes the following key elements: incision, wound investigation, debridement, wound irrigation and lavage, and definitive wound closure. PMID- 20847355 TI - Noninvasive assessment of lower-extremity hemodynamics in individuals with diabetes mellitus. AB - The timely and accurate noninvasive assessment of peripheral arterial disease is a critical component of a limb preservation initiative in patients with diabetes mellitus. Noninvasive vascular studies can be useful in screening patients with diabetes for peripheral arterial disease. In patients with clinical signs or symptoms, noninvasive vascular studies provide crucial information on the presence, location, and severity of peripheral arterial disease and an objective assessment of the potential for primary healing of an index wound or a surgical incision. Appropriately selected noninvasive vascular studies are important in the decision-making process to determine whether and what type of intervention might be most appropriate given the clinical circumstances. Hemodynamic monitoring is likewise important after either an endovascular procedure or a surgical bypass. Surveillance studies, usually with a combination of physiologic testing and imaging with duplex ultrasound, accurately identify recurrent disease before the occurrence of thrombosis, allowing targeted reintervention. Noninvasive vascular studies can be broadly grouped into three general categories: physiologic or hemodynamic measurements, anatomical imaging, and measurements of tissue perfusion. These types of tests and suggestions for their appropriate application in patients with diabetes are reviewed. PMID- 20847356 TI - Arterial imaging in patients with lower-extremity ischemia and diabetes mellitus. AB - Precise comprehensive imaging of arterial circulation is the cornerstone of successful revascularization of the ischemic extremity in patients with diabetes mellitus. Arterial imaging is challenging in these patients because the disease is often multisegmental, with a predilection for the distal tibial and peroneal arteries. Occlusive lesions and the arterial wall itself are often calcified, and patients with ischemic complications frequently have underlying renal insufficiency. Intra-arterial digital subtraction angiography, contrast-enhanced magnetic resonance angiography, and, more recently, computed tomographic angiography have been used as imaging modalities in lower-extremity ischemia. Each modality has specific advantages and shortcomings in this patient population, which are summarized and contrasted in this review. PMID- 20847357 TI - Current assessment of endovascular therapy for infrainguinal arterial occlusive disease in patients with diabetes. AB - Endovascular therapy has increasingly become the initial clinical option for the treatment of lower-extremity peripheral arterial occlusive disease not only for patients with claudication but also for those with critical limb ischemia. Despite this major clinical practice paradigm shift, the outcomes of endovascular therapy for peripheral arterial disease are difficult to evaluate and compare with established surgical benchmarks because of the lack of prospective randomized trials, incomplete characterization of indications for intervention, mixing of arterial segments and extent of disease treated, the multiplicity of endovascular therapy techniques used, the exclusion of early treatment failures, crossover to open bypass during follow-up, and the frequent lack of intermediate and long-term patency and limb salvage rates in life-table format. These data limitations are especially problematic when one tries to assess the outcomes of endovascular therapy in patients with diabetes. The purpose of the present article is to succinctly review and objectively analyze available data regarding the results of endovascular therapy in patients with diabetes. PMID- 20847358 TI - Challenges of distal bypass surgery in patients with diabetes: patient selection, techniques, and outcomes. AB - Surgical revascularization of the lower extremity using bypass grafts to distal target arteries is an established, effective therapy for advanced ischemia. Recent multicenter data confirm the primacy of autogenous vein bypass grafting, yet there remains significant heterogeneity in the utilization, techniques, and outcomes associated with these procedures in current practice. Experienced clinical judgment, creativity, technical precision, and fastidious postoperative care are required to optimize long-term results. The diabetic patient with a critically ischemic limb offers some specific challenges; however, numerous studies demonstrate that the outcomes of vein bypass surgery in this population are excellent and define the standard of care. Technical factors, such as conduit and inflow/outflow artery selection, play a dominant role in determining clinical success. An adequate-caliber, good-quality great saphenous vein is the optimal graft for distal bypass in the leg. Alternative veins perform acceptably in the absence of the great saphenous vein, whereas prosthetic and other nonautogenous conduits have markedly inferior outcomes. Graft configuration (reversed, nonreversed, or in situ) seems to have little effect on outcome. Shorter grafts have improved patency. Inflow can be improved by surgical or endovascular means if necessary, and distal-origin grafts (eg, those arising from the superficial femoral or popliteal arteries) can perform as well as those originating from the common femoral artery. The selected outflow vessel should supply unimpeded runoff to the foot, conserve conduit length, and allow for adequate soft-tissue coverage of the graft and simplified surgical exposure. This review summarizes the available data linking patient selection and technical factors to outcomes and highlights the importance of surgical judgment and operative planning in the current practice of infrainguinal bypass surgery. PMID- 20847360 TI - Psychometric properties of the HRQOLISP-40: a novel, shortened multiculturally valid holistic stroke measure. AB - BACKGROUND: A recent review showed that no existing instrument measured the entire spectrum of health-related quality of life (HRQOL) in stroke patients. However, the HRQOL in stroke patients (HRQOLISP) questionnaire is valid and exceptionally comprehensive. Founded on a holistic model of human life, it comprises both physical and spiritual spheres. However, its 102-item length may discourage routine use. Therefore, the aim was to determine the psychometric attributes of a shortened version based on a multicultural transnational study. METHODS: HRQOLISP was administered to 100 stroke patients in Ibadan, 103 in Berlin, and control groups of 100 apparently healthy adults in Ibadan and 50 in Berlin. Analyzing data from both cities, items were reduced to 40. Construct validity of the resulting HRQOLISP-40 was assessed by comparison with the National Institutes of Health Stroke Scale (NIHSS), Stroke Levity Scale (SLS), modified Rankin Scale (mRS), and Short Form 36 (SF-36) Health Survey. RESULTS: In multicultural settings, the HRQOLISP-40 showed good internal consistency (alpha = .76, .86) and test-retest reliability. It retained its discriminant validity between stroke and healthy participants and demonstrated good "known-groups" validity in its relationship to the SLS, NIHSS, and mRS in the physical sphere. The physical sphere showed good convergent validity with corresponding facets of the SF-36. CONCLUSIONS: Despite item reduction, the HRQOLISP-40 demonstrated excellent psychometric properties and is valid for routine use and clinical trials in stroke. The relative preservation of the spiritual sphere demonstrated the concept of disability disparity. Its ability to simultaneously assess the physical and spiritual spheres may be beneficial in studies aimed at potentiating internal adaptation in stroke patients. PMID- 20847361 TI - The use of Morycz's desire-to-institutionalize scale across three racial/ethnic groups. AB - OBJECTIVE: The objectives of this study were to assess the dimensionality and reliability of a frequently used scale for predicting the desire to institutionalize among White, African American, and Hispanic caregivers of persons with dementia. METHOD: Exploratory factor analysis (EFA) and reliability analyses were performed on a slightly modified version of Morycz's (1985) Desire to Institutionalize (DTI) scale separately for each racial group using data from the Resources for Enhancing Alzheimer's Caregiver Health (REACH) II study (Belle et al., 2006). RESULTS: The EFA revealed a one-factor structure that was equivalent across all racial groups. The scale demonstrated moderate reliability with KR-20 alpha of .694 for Whites, .742 for African Americans, and .767 for Hispanics. DISCUSSION: Findings suggest that Morycz's DTI scale is a consistently reliable measure for assessing the desire to institutionalize across White, African American, and Hispanic dementia caregivers. PMID- 20847362 TI - Age differences in long-term patterns of change in alcohol consumption among aging adults. AB - OBJECTIVE: To estimate patterns of long-term, within-person, changes in alcohol consumption among adults of different ages and assess key predictors of alcohol use patterns over time. METHOD: Data came from 3,617 adults, interviewed up to four times between 1986 and 2002. Multilevel multinomial logit models estimated the odds of abstinence and heavy drinking relative to moderate drinking. RESULTS: The odds of abstinence increased and the odds of heavy drinking decreased during the study period. Older adults experienced faster increases in abstinence than younger adults. However, data extrapolations suggest that current younger adults are more likely to be abstinent and less likely to be heavy drinkers during late life than current older adults. Time-varying health, social, and lifestyle factors account for some of these patterns. DISCUSSION: Drinking behavior in our aging population appears to be on a relatively promising course, perhaps reflecting the effectiveness of public health efforts. PMID- 20847365 TI - Dengue virus-induced apoptosis in hepatic cells is partly mediated by Apo2 ligand/tumour necrosis factor-related apoptosis-inducing ligand. PMID- 20847363 TI - The effects of a support group on dementia caregivers' burden and depression. AB - OBJECTIVE: The aim of the study is to investigate the effects of a support group on depression levels and burden among dementia caregivers in Taiwan. METHOD: An experimental, pre-intervention postintervention control group design was used in this study. The experimental group received intervention consisting of a 12-week support group for dementia caregivers. A total of 85 subjects were evaluated before intervention, after intervention, and at 1-month follow-up. RESULTS: (a) The depression level of participants in the experimental group was significantly decreased after the intervention and at 1-month follow-up. (b) There was no significant difference in caregiver's burden after the support group intervention and 1-month follow-up. DISCUSSION: The improvement in dementia caregivers' depression levels shows that the support group was effective for reducing caregivers' depression although not effective for relieving their burden of care. PMID- 20847366 TI - Wellness at workplace. PMID- 20847367 TI - Transitioning from HIV sentinel surveillance to programme based surveillance. PMID- 20847368 TI - Use of insecticides for malaria control & the need for reversion of resistance. PMID- 20847369 TI - Gestational prediabetes: a new term for early prevention? AB - Women with gestational diabetes mellitus (GDM) have higher rates of foetal macrosomia, shoulder dystocia and pregnancy-induced hypertension, and are at higher risk of developing type 2 diabetes. Herein, we introduce a new conceptual term, "gestational prediabetes", which requires the absence of diabetes before pregnancy, and the presence of blood glucose levels (or a related marker) in early pregnancy that are higher than normal, but not yet high enough to meet the diagnostic criteria for GDM. Identifying women with gestational prediabetes might be done in early pregnancy (e.g., 12 weeks' gestation) using conventional glycaemic testing, assessment of visceral abdominal adiposity or hepatic fat by ultrasonography, or measuring serum sex hormone-binding globulin or adiponectin. However, none of these approaches has been systematically compared to conventional predictors, such as maternal body mass index or waist circumference. Any early-pregnancy predictor of gestational prediabetes risk needs to have low cost, ease of administration, and a short turnaround time. The theoretical advantage of identifying women with gestational prediabetes would be to "prevent" the onset of GDM (and its inherent risks to the pregnancy) in a timelier manner. One sensible starting point would be an intervention to prevent early excessive weight gain in pregnancy, which is currently being evaluated by two randomized clinical trials. In addition, early intervention could offset the need for resource-intense GDM management or insulin therapy. PMID- 20847370 TI - Utility of Prevention of Parent-to-Child Transmission (PPTCT). Programme data for HIV surveillance in general population. AB - BACKGROUND & OBJECTIVES: HIV sentinel surveillance (HSS) among antenatal clinic (ANC) attendees is used to monitor HIV trends in general population. Recently, information on HIV infection has also become available from prevention of parent to-child transmission (PPTCT) programmes. Systematic appraisal of routinely collected programme data is needed for choosing a scientific, cost-effective, and ethical surveillance strategy. In this study HIV prevalence estimates obtained from PPTCT programme and HSS were compared to find out the utility of PPTCT programme data for HIV surveillance. METHODS: The data of HSS and PPTCT programme were obtained from National AIDS Control Organization, New Delhi. A list of PPTCT programme sites where ANC HSS was also conducted during 2005 to 2007 was prepared. HIV prevalence and 95 per cent confidence interval (CI) were estimated from antenatal attendees in PPTCT and HSS. Correlation coefficient of HIV prevalence in PPTCT and HSS was also examined according to the level of HIV test acceptance in PPTCT programme. Pregnant women presenting directly for labour in PPTCT centers were not included in the analyses. RESULTS: In 2007, HIV test acceptance ranged from 8 to 100 per cent (average 76%) in 372 sites where both PPTCT and HSS were carried out. HIV prevalence was similar in the PPTCT (0.68%, 95% CI 0.66%, 0.70%) as compared to the HSS (0.61%, 95% CI 0.58%, 0.66%). Overall the correlation of HIV prevalence between PPTCT and HSS was quite high at state level (r = 0.9) but low at district or site level (r = 0.6). INTERPRETATION & CONCLUSIONS: HIV prevalence estimates among pregnant women in PPTCT program were similar to that of ANC HSS. Routinely collected PPTCT program data therefore has potential for providing reliable HIV time trends in various states of India. PMID- 20847371 TI - Persistence of DDT, malathion & deltamethrin resistance in Anopheles culicifacies after their sequential withdrawal from indoor residual spraying in Surat district, India. AB - BACKGROUND & OBJECTIVES: Under the national antimalaria programme DDT was introduced in early 1950s for vector control and later hexachloro cyclohexane (HCH) followed by malathion and recently synthetic pyrethroids in 1990s to manage the insecticide resistance in Anopheles culicifacies. Subsequent replacement led to development of multiple resistances in An. culicifacies in Surat district in Gujarat State. Indoor residual spray (IRS) was completely withdrawn in southern villages in Surat in 2002. This study was undertaken in these areas to study the persistence of resistance to DDT, malathion and deltamethrin after sequential withdrawal of IRS with these insecticides at different times. METHODS: Susceptibility tests on An. culicifacies were conducted using standard WHO methods and kits. Mortality, knockdown time and lethal times were calculated for An. culicifacies exposed to WHO prescribed diagnostic concentrations of different insecticide impregnated papers. RESULTS: Persistence of DDT-resistance was observed even after 30 yr of its withdrawal from IRS. Similarly, persistence of malathion resistance was also observed after 9 yr of its withdrawal from IRS, while reversal of deltamethrin-resistance was observed very fast within 2-3 yr after its withdrawal from IRS in 2002. INTERPRETATION & CONCLUSION: Present data indicate that the quantum of reversion of insecticide resistance in a population is relative and depends on the genetic stability of the respective resistance genes in the mosquitoes. In the present study withdrawal of pyrethroid-IRS resulted in increased susceptibility against pyrethroids alone and was independent of existence of resistance to insecticides of other groups. This study emphasizes that appropriate rotation of different insecticides; including carbamates may prevent or delay the onset of resistance. PMID- 20847372 TI - High prevalence of AZFb microdeletion in Iranian patients with idiopathic non obstructive azoospermia. AB - BACKGROUND & OBJECTIVES: Genetic factors contribute about 10 per cent of male infertility. Among these, genes in azoospermia factor (AZF) region including AZFa, AZFb, AZFc and AZFd on the long arm of Y chromosome are considered most important for spermatogenesis. Deletions in these regions are thought to be involved in some cases of male infertility associated with azoospermia or oligozoospermia. We studied the incidence of AZF deletions among Iranian infertile men with idiopathic non-obstructive azoospermia. METHODS: A total of 100 Iranian azoospermic infertile men were selected for the molecular study of Y chromosome microdeletions. The presence of 13 sequence tagged site (STS) markers from AZF region was investigated using multiplex polymerase chain reaction (M PCR). One hundred fertile men were also studied as control group. RESULTS: Twelve (12%) patients showed Y chromosome microdeletions and among these, deletion in AZFb region was the most frequent (66.67%) followed by AZFc (41.67%), AZFd (33.33%) and AZFa (8.33%), respectively. INTERPRETATION & CONCLUSIONS: Because of relatively high incidence of Y chromosome microdeletions among Iranian azoospermic patients, molecular screening may be advised to infertile men before using assisted reproductive treatments. PMID- 20847373 TI - Association of hypoadiponectinemia with non-alcoholic fatty liver disease in urban south Indians--(CURES - 81). AB - BACKGROUND & OBJECTIVES: Association between adiponectin and non-alcoholic fatty liver disease (NAFLD) has been reported in west. Studies in Indian population are lacking. This study was undertaken to assess the association of hypoadiponectinemia with NAFLD in Asian Indians. METHOD: In this cross-sectional study, subjects were randomly selected from Phase 5 of the Chennai Urban Rural Epidemiology Study (CURES), an epidemiological study based on a representative population of Chennai in south India. One hundred twenty one subjects without NAFLD and 72 subjects with NAFLD were selected. NAFLD was diagnosed by ultrasonography. Serum adiponectin levels were measured using radioimmunoassay. Insulin resistance was calculated using Homeostasis Assessment model (HOMA-IR). RESULTS: Serum adiponectin values were significantly lower in subjects with NAFLD compared to those without [5.6 MUg/ml (95% Confidence Interval (CI) 5.0 - 6.3 MUg/ml] vs 7.4 MUg/ml (95% CI: 6.7 - 8.1 MUg/ml, P<0.01). Adiponectin levels decreased with increasing severity of NAFLD. Subjects with moderate to severe steatosis had significantly lower adiponectin levels (5.1MUg/ml, 95% CI: 4.1- 6.4 MUg/ml) compared to subjects with mild steatosis (5.9 MUg/ml, 95% CI: 5.0 - 6.9 MUg/ml; P<0.001) and subjects without NAFLD (7.3 MUg/ml, 95% CI: 6.6 - 8.0 MUg/ml; P<0.01). Multiple logistic regression analysis revealed adiponectin to be negatively associated with NAFLD [Odds Ratio (OR): 0.865, 95% Confidence Interval (CI): 0.792- 0.944, P=0.001]. This remained statistically significant even after adjusting for confounding factors age, gender, body mass index, insulin resistance, waist circumference, total cholesterol, triglycerides and glucose intolerance (OR: 0.873, 95% CI: 0.793 - 0.961; P=0.005). INTERPRETATION & CONCLUSION: NAFLD is associated with lower serum adiponectin levels independent of conventional cardiovascular risk factors in Asian Indians known to have high prevalence of diabetes and coronary artery disease. PMID- 20847374 TI - Proton magnetic resonance spectroscopy of brain in obstructive sleep apnoea in north Indian Asian subjects. AB - BACKGROUND & OBJECTIVES: Repeated apnoeic/hypoapnoeic episodes during sleep may produce cerebral damage in patients with obstructive sleep apnoea (OSA). The aim of this study was to determine the absolute concentration of cerebral metabolites in apnoeic and non-apnoeic subjects from different regions of the brain to monitor the regional variation of cerebral metabolites. METHODS: Absolute concentration of cerebral metabolites was determined by using early morning proton magnetic resonance spectroscopy ((1)H MRS) in 18 apnoeic patients with OSA (apnoeics) having apnoea/hypopnoea index (AHI) >5/h, while 32 were non-apnoeic subjects with AHI< 5/h. RESULTS: The absolute concentration of tNAA [(N acetylaspartate (NAA)+N-acetylaspartylglutamate (NAAG)] was observed to be statistically significantly lower (P<0.05) in apnoeics in the left temporal and left frontal gray regions compared to non-apnoeics. The Glx (glutamine, Gln + glutamate, Glu) resonance showed higher concentration (but not statistically significant) in the left temporal and left frontal regions of the brain in apnoeics compared to non-apnoeics. The absolute concentration of myo-inositol (mI) was significantly high (P<0.03) in apnoeics in the occipital region compared to non-apnoeics. INTERPRETATION & CONCLUSIONS: Reduction in the absolute concentration of tNAA in apnoeics is suggestive of neuronal damage, probably caused by repeated apnoeic episodes in these patients. NAA showed negative correlation with AHI in the left frontal region, while Cho and mI were positively correlated in the occipital region and Glx showed positive correlation in the left temporal region of the brain. Overall, our results demonstrate that the variation in metabolites concentrations is not uniform across various regions of the brain studied in patients with OSA. Further studies with a large cohort of patients to substantiate these observations are required. PMID- 20847375 TI - Assessment of HER-2/neu status in breast cancer using fluorescence in situ hybridization & immunohistochemistry: Experience of a tertiary cancer referral centre in India. AB - BACKGROUND & OBJECTIVES: Determination of HER2 status in breast cancer has become important to identify potential candidates for anti-HER2 therapy. In this study we compared fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for the determination of HER2 status in breast cancer patients referred to a tertiary care referral centre. METHODS: A total of 200 cases of invasive breast cancer were evaluated for HER2 status using IHC and FISH and results were compared. RESULTS: The IHC 3+ (93.9%) and IHC negative (85.9%) cases showed good concordance with the corresponding FISH results; while 66.6 per cent of IHC 2+ cases showed gene amplification by FISH. In addition, hormone receptor expression and HER2 gene status showed a statistically significant inverse association (P<0.05). INTERPRETATION & CONCLUSION: These findings reaffirm IHC as a prudent first-step to screen tissue samples for HER2 status and to determine suitability for technically demanding FISH test and the dual coloured FISH as a gold standard for determination of HER2/neu status in IHC equivocal cases of breast carcinoma. PMID- 20847376 TI - Comparison in pathological behaviours & prognosis of gastric cancers from general hospitals between China & Japan. AB - BACKGROUND & OBJECTIVES: Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related deaths after lung carcinoma. The aim of this study was to understand the difference in clinicopathological behaviours and prognosis of gastric cancer in patients from China and Japan. METHODS: Paraffin fixed tissue samples of gastric cancer were collected retrospectively from two hospitals between 1993 to 2006 in Japan (n=2063) and during 1980-2003 in China (n=2496) respectively, and staging was done by TNM system and typing by Japanese Endoscopy Society criteria or Borrmann's classification. The histological architecture of the tumours was expressed according to Lauren's classification. RESULTS: Compared to Japan, the occurrence of gastric cancer was more common in younger Chinese population and prone to invasion and metastasis in muscularis propia, lymphatic, lymph node, liver, peritoneal parts, and exhibited large tumour size and high TNM staging in both the sexes and in different age groups (P<0.05). Intestinal and mixed types of carcinomas were more frequently observed in Japanese patients compared to Chinese and the difference was significant (P<0.05). It was observed that the commonly reported types in early gastric cancers (EGC) in Japanese patients were IIc, IIa+IIc or IIa while those of Chinese patients were IIc, III or IIb. In the case of advanced gastric cancers (AGC), type II and III were most common in both the countries. The cumulative survival rate of Chinese patients was significantly (P<0.05) higher compared to Japanese in different stratified groups via depth of invasion, TNM staging or Lauren's classification. INTERPRETATION & CONCLUSION: Gastric cancers in Chinese patients had more aggressive pathological characteristics and poorer prognosis than those from Japan. To reduce incidence and to improve treatment facilities, it is necessary to have a systematic screening system. PMID- 20847377 TI - Use of multiplex ligation-dependent probe amplification (MLPA) for Duchenne muscular dystrophy (DMD) gene mutation analysis. AB - BACKGROUND & OBJECTIVES: Duchenne (DMD) and Becker muscular dystrophy (BMD) are X linked recessive disorders, caused by mutations in the dystrophin gene. Genetic diagnosis of the proband becomes crucial, and forms the base for carrier analysis, genetic counselling, prediction of natural history and prognosis, and eligibility for therapeutic strategies. Traditional multiplex PCR assay is the common method used in India to detect DMD gene deletions, mainly in the hot-spot region. Deletions of exons outside the usual 18 or 21 exons in the hot-spot, duplications and carrier analysis are often left without precise genetic diagnosis and require efficient dosage/quantitative analysis. In this study we evaluated the efficacy of using multiplex PCR (mPCR) of 30 exons followed by multiplex ligation-dependent probe amplification (MLPA), to study deletions and duplications in the DMD gene in patients clinically diagnosed as BMD/DMD. METHODS: Using an algorithm of mPCR and MLPA which was less invasive and cost effective, we performed retrospective and prospective analysis on 150 male patients. RESULTS: Multiplex PCR could pick up deletions in 103 of the 150 cases. MLPA was able to detect deletions and duplications including nine additional mutations. Further, the borders of the deletions and duplications were more accurately defined by this recent methodology, which enables one to determine the effect of the mutation on the reading frame. In all, including the single exon deletions, MLPA was efficient in accurately confirming mutations in 35 per cent of all cases. Ten novel mutations were identified in this study. Overall, this approach confirmed mutations in 75 per cent of the patients in our study. INTERPRETATION & CONCLUSIONS: The systematic approach/algorithm used in this study offers the best possible economical mutation analysis in the Indian scenario. PMID- 20847378 TI - Significance of anti-HBc screening of blood donors and its association with occult hepatitis B virus infection: Implications for blood transfusion. AB - BACKGROUND & OBJECTIVES: Expansions of blood donor screening and improved laboratory detection of viral markers have remarkably reduced the risk for infection with transfusion-transmitted viruses. This study was aimed to evaluate the presence of anti-HBc and to determine the presence or absence of HBV DNA in the serum samples from HBsAg negative, anti-HBc positive blood donors in a tertiary care hospital blood bank from Delhi. METHODS: A total of 2175 HBsAg negative, first time volunteer blood donors were included in the study from blood bank, Lok Nayak Hospital, New Delhi. The blood specimens from all these subjects were evaluated for anti-HBV-core antigen (anti-HBc) serology, anti-HBV-surface antigen (anti-HBs) titres and HBeAg. The presence of HBV DNA was evaluated by testing, through polymerase chain reaction (PCR) techniques. RESULTS: Of the 2175 HBsAg negative voluntary blood donors, 413 (19.8%) were tested to be positive for anti-HBc alone. Of these, 153 (group-I) were anti-HBs negative whereas group-II comprises a total of 260 anti-HBs positive cases i.e. 89 out of 413 had anti-HBs titres of 10-99 IU/l and the remaining 171 had anti-HBs titres of 100-500 IU/l. HBV DNA was detected in 7.5 per cent anti-HBc positive samples irrespective of anti-HBs status. INTERPRETATION & CONCLUSION: Our results showed that 18.9 per cent of our donor population was anti-HBc reactive, and hence inclusion of anti HBc testing will lead to a high discard rate. The presence of HBV DNA in fairly high percentage of anti-HBc positive samples highlighted the need for a stringent and better screening system to prevent occult HBV infection. PMID- 20847379 TI - Defects in blood dendritic cell subsets in HIV-1 subtype c infected Indians. AB - BACKGROUND & OBJECTIVES: DCs trigger both innate and adaptive immune responses to control HIV infection and represent a viral reservoir acting as target and HIV carriers for infection of permissive CD4(+) T-cells. DCs thus form a very attractive study subject to further our existing knowledge of HIV induced immunopathogenesis due to its diverse and crucial role in HIV infection establishment, viral dissemination, immune evasion, viral persistence, etc. We aimed to characterize the effect of HIV infection on myeloid and plasmacytoid dendritic cell subsets in a group of HIV-1 subtype C infected treated or untreated Indian individuals. METHODS: Blood DC subset numbers and immunophenotype were studied for 79 HIV infected subjects at various stages of disease and compared with 13 HIV-uninfected controls. Comparisons were also made between groups of subjects based on their CD4(+) T cell counts and also experience of antiretrovirals. RESULTS: Significant decreases were observed in blood DC counts and the two DC subsets in HIV infected individuals. Subjects with lowest CD4(+) T cell counts also had a drastically reduced DC subset pool which correlated positively with plasma viraemia and negatively with CD4(+) T cell counts. DC subsets from HIV infected subjects showed higher expression of co stimulatory molecules CD40 and CD86, and HIV-1 co-receptors CXCR4 and CCR5 which correlated positively with HIV-1 plasma viraemia. The alterations in blood DCs were partly resolved in ART receiving study subjects. INTERPRETATION & CONCLUSIONS: Correlation between DC subset activation state and viraemia supports the role of DC activation on viral replication and CD4(+) T cell depletion. PMID- 20847380 TI - Identification & characterization of Shiga toxin-producing Escherichia coli isolates from patients with diarrhoea in Iran. AB - BACKGROUND & OBJECTIVES: Verotoxigenic Escherichia coli are important serotypes of enterohaemorrhagic E. coli (EHEC) subgroup that cause attaching and effacing lesions in enterocytes by producing verotoxins or shiga-like toxins resulting in haemorrhagic colitis (HC) and haemolytic uremic syndrome (HUS). The aim of this study was to detect these serotypes specially E. coli O157:H7 in stool samples of patients with diarrhoea and identification of virulence genes (STX1, STX2, Hly and EAE) in Shahrekord-Iran area using PCR technique. METHODS: Two hundred diarrhoeal stool samples of patients were collected through 2007-2008. Microbiological and biochemical examinations were done to detect the E. coli. Serological tests carried out to identify the O157 or O157:H7 serotypes. RESULTS: Of the 58 E. coli isolates, 16 (27.6%) were detected as STX1 carrying E. coli, four (6.9%) carrying STX2, eight (13.8%) carrying both STX1 and STX2, and 12 (20.7%) were Hly carrying E. coli, but none of the isolates contained EAE gene. None of the isolates were E. coli O157 or O157:H7 serotypes. INTERPRETATION & CONCLUSIONS: Our results revealed that verotoxigenic E. coli isolates other than O157 serotype were involved in causing diarrhoea in Shahrekord-Iran. PMID- 20847381 TI - Detection of TEM & SHV genes in Escherichia coli & Klebsiella pneumoniae isolates in a tertiary care hospital from India. AB - BACKGROUND & OBJECTIVES: Extended spectrum beta lactamases (ESBLs) have been observed in virtually all the species of family Enterobacteriaceae. The enzymes are predominantly plasmid mediated and are derived from broad-spectrum beta lactamase TEM-1, TEM-2 or SHV-1 by a limited number of mutations. This study was undertaken to characterize ESBL producers among Escherichia coli and Klebsiella pneumoniae by PCR-RFLP, which were initially screened by phenotypic method. METHODS: A total of 100 isolates of each species (E. coli and K. pneumoniae) were screened for ESBL production. PCR analysis for beta-lactamase genes of the family TEM and SHV was also carried out. PCR products of TEM and SHV genes were subjected to digest with three different restriction enzymes. The digested products were run on 1.5 per cent agarose gel, stained and examined for DNA bands. RESULTS: PCR carried out on plasmid DNA alone detected 30 per cent ESBL positive isolates using TEM primer and 38 per cent using SHV primer, whereas PCR for both plasmid and chromosomal DNA showed 56 per cent positivity for TEM and 60 per cent positivity for SHV. INTERPRETATION & CONCLUSION: RFLP yielded homogeneous band pattern, suggesting that there may be a point source or a common evolutionary origin for all the ESBL isolates. PMID- 20847382 TI - Occurrence & significance of kala-azar in Bhutan. PMID- 20847383 TI - Dengue fever caused by dengue virus serotype-3 (subtype-III) in a rural area of Madurai district, Tamil Nadu. PMID- 20847384 TI - Depression in schizophrenia. PMID- 20847385 TI - Evaluating stability and comparing output of feature selectors that optimize feature subset cardinality. AB - Stability (robustness) of feature selection methods is a topic of recent interest, yet often neglected importance, with direct impact on the reliability of machine learning systems. We investigate the problem of evaluating the stability of feature selection processes yielding subsets of varying size. We introduce several novel feature selection stability measures and adjust some existing measures in a unifying framework that offers broad insight into the stability problem. We study in detail the properties of considered measures and demonstrate on various examples what information about the feature selection process can be gained. We also introduce an alternative approach to feature selection evaluation in the form of measures that enable comparing the similarity of two feature selection processes. These measures enable comparing, e.g., the output of two feature selection methods or two runs of one method with different parameters. The information obtained using the considered stability and similarity measures is shown to be usable for assessing feature selection methods (or criteria) as such. PMID- 20847386 TI - A dynamic texture-based approach to recognition of facial actions and their temporal models. AB - In this work, we propose a dynamic texture-based approach to the recognition of facial Action Units (AUs, atomic facial gestures) and their temporal models (i.e., sequences of temporal segments: neutral, onset, apex, and offset) in near frontal-view face videos. Two approaches to modeling the dynamics and the appearance in the face region of an input video are compared: an extended version of Motion History Images and a novel method based on Nonrigid Registration using Free-Form Deformations (FFDs). The extracted motion representation is used to derive motion orientation histogram descriptors in both the spatial and temporal domain. Per AU, a combination of discriminative, frame-based GentleBoost ensemble learners and dynamic, generative Hidden Markov Models detects the presence of the AU in question and its temporal segments in an input image sequence. When tested for recognition of all 27 lower and upper face AUs, occurring alone or in combination in 264 sequences from the MMI facial expression database, the proposed method achieved an average event recognition accuracy of 89.2 percent for the MHI method and 94.3 percent for the FFD method. The generalization performance of the FFD method has been tested using the Cohn-Kanade database. Finally, we also explored the performance on spontaneous expressions in the Sensitive Artificial Listener data set. PMID- 20847387 TI - Age synthesis and estimation via faces: a survey. AB - Human age, as an important personal trait, can be directly inferred by distinct patterns emerging from the facial appearance. Derived from rapid advances in computer graphics and machine vision, computer-based age synthesis and estimation via faces have become particularly prevalent topics recently because of their explosively emerging real-world applications, such as forensic art, electronic customer relationship management, security control and surveillance monitoring, biometrics, entertainment, and cosmetology. Age synthesis is defined to rerender a face image aesthetically with natural aging and rejuvenating effects on the individual face. Age estimation is defined to label a face image automatically with the exact age (year) or the age group (year range) of the individual face. Because of their particularity and complexity, both problems are attractive yet challenging to computer-based application system designers. Large efforts from both academia and industry have been devoted in the last a few decades. In this paper, we survey the complete state-of-the-art techniques in the face image-based age synthesis and estimation topics. Existing models, popular algorithms, system performances, technical difficulties, popular face aging databases, evaluation protocols, and promising future directions are also provided with systematic discussions. PMID- 20847388 TI - An a-contrario approach for subpixel change detection in satellite imagery. AB - This paper presents a new method for unsupervised subpixel change detection using image series. The method is based on the definition of a probabilistic criterion capable of assessing the level of coherence of an image series relative to a reference classification with a finer resolution. In opposition to approaches based on an a priori model of the data, the model developed here is based on the rejection of a nonstructured model-called a-contrario model-by the observation of structured data. This coherence measure is the core of a stochastic algorithm which automatically selects the image subdomain representing the most likely changes. A theoretical analysis of this model is led to predict its performances, in particular regarding the contrast level of the image as well as the number of change pixels in the image. Numerical simulations are also presented that confirm the high robustness of the method and its capacity to detect changes impacting more than 25 percent of a considered pixel under average conditions. An application to land-cover change detection is then provided using time series of satellite images. PMID- 20847389 TI - Computing accurate correspondences across groups of images. AB - Groupwise image registration algorithms seek to establish dense correspondences between sets of images. Typically, they involve iteratively improving the registration between each image and an evolving mean. A variety of methods have been proposed, which differ in their choice of objective function, representation of deformation field, and optimization methods. Given the complexity of the task, the final accuracy is significantly affected by the choices made for each component. Here, we present a groupwise registration algorithm which can take advantage of the statistics of both the image intensities and the range of shapes across the group to achieve accurate matching. By testing on large sets of images (in both 2D and 3D), we explore the effects of using different image representations and different statistical shape constraints. We demonstrate that careful choice of such representations can lead to significant improvements in overall performance. PMID- 20847390 TI - Detecting the number of clusters in n-way probabilistic clustering. AB - Recently, there has been a growing interest in multiway probabilistic clustering. Some efficient algorithms have been developed for this problem. However, not much attention has been paid on how to detect the number of clusters for the general n way clustering (n >= 2). To fill this gap, this problem is investigated based on n-way algebraic theory in this paper. A simple, yet efficient, detection method is proposed by eigenvalue decomposition (EVD), which is easy to implement. We justify this method. In addition, its effectiveness is demonstrated by the experiments on both simulated and real-world data sets. PMID- 20847391 TI - Features versus context: An approach for precise and detailed detection and delineation of faces and facial features. AB - The appearance-based approach to face detection has seen great advances in the last several years. In this approach, we learn the image statistics describing the texture pattern (appearance) of the object class we want to detect, e.g., the face. However, this approach has had limited success in providing an accurate and detailed description of the internal facial features, i.e., eyes, brows, nose, and mouth. In general, this is due to the limited information carried by the learned statistical model. While the face template is relatively rich in texture, facial features (e.g., eyes, nose, and mouth) do not carry enough discriminative information to tell them apart from all possible background images. We resolve this problem by adding the context information of each facial feature in the design of the statistical model. In the proposed approach, the context information defines the image statistics most correlated with the surroundings of each facial component. This means that when we search for a face or facial feature, we look for those locations which most resemble the feature yet are most dissimilar to its context. This dissimilarity with the context features forces the detector to gravitate toward an accurate estimate of the position of the facial feature. Learning to discriminate between feature and context templates is difficult, however, because the context and the texture of the facial features vary widely under changing expression, pose, and illumination, and may even resemble one another. We address this problem with the use of subclass divisions. We derive two algorithms to automatically divide the training samples of each facial feature into a set of subclasses, each representing a distinct construction of the same facial component (e.g., closed versus open eyes) or its context (e.g., different hairstyles). The first algorithm is based on a discriminant analysis formulation. The second algorithm is an extension of the AdaBoost approach. We provide extensive experimental results using still images and video sequences for a total of 3,930 images. We show that the results are almost as good as those obtained with manual detection. PMID- 20847392 TI - Semi-supervised classification via local spline regression. AB - This paper presents local spline regression for semi-supervised classification. The core idea in our approach is to introduce splines developed in Sobolev space to map the data points directly to be class labels. The spline is composed of polynomials and Green's functions. It is smooth, nonlinear, and able to interpolate the scattered data points with high accuracy. Specifically, in each neighborhood, an optimal spline is estimated via regularized least squares regression. With this spline, each of the neighboring data points is mapped to be a class label. Then, the regularized loss is evaluated and further formulated in terms of class label vector. Finally, all of the losses evaluated in local neighborhoods are accumulated together to measure the global consistency on the labeled and unlabeled data. To achieve the goal of semi-supervised classification, an objective function is constructed by combining together the global loss of the local spline regressions and the squared errors of the class labels of the labeled data. In this way, a transductive classification algorithm is developed in which a globally optimal classification can be finally obtained. In the semi-supervised learning setting, the proposed algorithm is analyzed and addressed into the Laplacian regularization framework. Comparative classification experiments on many public data sets and applications to interactive image segmentation and image matting illustrate the validity of our method. PMID- 20847393 TI - Shape from specular flow. AB - An image of a specular (mirror-like) object is nothing but a distorted reflection of its environment. When the environment is unknown, reconstructing shape from such an image can be very difficult. This reconstruction task can be made tractable when, instead of a single image, one observes relative motion between the specular object and its environment, and therefore, a motion field-or specular flow-in the image plane. In this paper, we study the shape from specular flow problem and show that observable specular flow is directly related to surface shape through a nonlinear partial differential equation. This equation has the key property of depending only on the relative motion of the environment while being independent of its content. We take first steps toward understanding and exploiting this PDE, and we examine its qualitative properties in relation to shape geometry. We analyze several cases in which the surface shape can be recovered in closed form, and we show that, under certain conditions, specular shape can be reconstructed when both the relative motion and the content of the environment are unknown. We discuss numerical issues related to the proposed reconstruction algorithms, and we validate our findings using both real and synthetic data. PMID- 20847394 TI - Stereo matching with Mumford-Shah regularization and occlusion handling. AB - This paper addresses the problem of correspondence establishment in binocular stereo vision. We suggest a novel spatially continuous approach for stereo matching based on the variational framework. The proposed method suggests a unique regularization term based on Mumford-Shah functional for discontinuity preserving, combined with a new energy functional for occlusion handling. The evaluation process is based on concurrent minimization of two coupled energy functionals, one for domain segmentation (occluded versus visible) and the other for disparity evaluation. In addition to a dense disparity map, our method also provides an estimation for the half-occlusion domain and a discontinuity function allocating the disparity/depth boundaries. Two new constraints are introduced improving the revealed discontinuity map. The experimental tests include a wide range of real data sets from the Middlebury stereo database. The results demonstrate the capability of our method in calculating an accurate disparity function with sharp discontinuities and occlusion map recovery. Significant improvements are shown compared to a recently published variational stereo approach. A comparison on the Middlebury stereo benchmark with subpixel accuracies shows that our method is currently among the top-ranked stereo matching algorithms. PMID- 20847395 TI - Surface-from-gradients without discrete integrability enforcement: A Gaussian kernel approach. AB - Representative surface reconstruction algorithms taking a gradient field as input enforce the integrability constraint in a discrete manner. While enforcing integrability allows the subsequent integration to produce surface heights, existing algorithms have one or more of the following disadvantages: They can only handle dense per-pixel gradient fields, smooth out sharp features in a partially integrable field, or produce severe surface distortion in the results. In this paper, we present a method which does not enforce discrete integrability and reconstructs a 3D continuous surface from a gradient or a height field, or a combination of both, which can be dense or sparse. The key to our approach is the use of kernel basis functions, which transfer the continuous surface reconstruction problem into high-dimensional space, where a closed-form solution exists. By using the Gaussian kernel, we can derive a straightforward implementation which is able to produce results better than traditional techniques. In general, an important advantage of our kernel-based method is that the method does not suffer discretization and finite approximation, both of which lead to surface distortion, which is typical of Fourier or wavelet bases widely adopted by previous representative approaches. We perform comparisons with classical and recent methods on benchmark as well as challenging data sets to demonstrate that our method produces accurate surface reconstruction that preserves salient and sharp features. The source code and executable of the system are available for downloading. PMID- 20847396 TI - Amyloid-beta induces caspase-dependent loss of PSD-95 and synaptophysin through NMDA receptors. AB - Soluble oligomeric amyloid-beta (Abeta) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Abeta downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 MUM) and high (10 MUM) doses of NMDA, respectively, prevented and potentiated the actions of Abeta. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 MUM NMDA, while the effects of 10 MUM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was found to mediate the synaptotoxic actions of Abeta in an ifenprodil-reversible fashion. Thus, Abeta leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Abeta initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD. PMID- 20847398 TI - Modulation of amyloid-beta peptide-induced toxicity through inhibition of JNK nuclear localization and caspase-2 activation. AB - Amyloid-beta (Abeta) peptide- induced neurotoxicity is typically associated with apoptosis. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous anti-apoptotic bile acid, modulates Abeta-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Abeta and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Abeta-induced nuclear fragmentation was prevented by TUDCA. In addition, Abeta exposure resulted in activation of the early stress c-Jun N terminal kinase (JNK) pathway, JNK nuclear translocation, and caspase-2 activation. Knock-down experiments of JNK established caspase-2 as a specific downstream target of JNK in Abeta-induced apoptosis. Furthermore, active caspase 2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Abeta-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Abeta-induced toxicity, which translocates to the nucleus, activates caspase-2, and is strongly modulated by TUDCA in PC12 neuronal cells. Active caspase-2 cleaves golgin-160, suggesting caspase-2-dependent transduction of Abeta apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Abeta peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway and exact targets of modulation are likely to provide new perspectives for modulation of amyloid-induced apoptosis by TUDCA. PMID- 20847397 TI - The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. AB - The only established genetic determinant of non-Mendelian forms of Alzheimer's disease (AD) is the epsilon4 allele of the apolipoprotein E gene (APOE). Recently, it has been reported that the P86L polymorphism of the calcium homeostasis modulator 1 gene (CALHM1) is associated with the risk of developing AD. In order to independently assess this association, we performed a meta analysis of 7,873 AD cases and 13,274 controls of Caucasian origin (from a total of 24 centers in Belgium, Finland, France, Italy, Spain, Sweden, the UK, and the USA). Our results indicate that the CALHM1 P86L polymorphism is likely not a genetic determinant of AD but may modulate age of onset by interacting with the effect of the epsilon4 allele of the APOE gene. PMID- 20847399 TI - Mediterranean diet, inflammatory and metabolic biomarkers, and risk of Alzheimer's disease. AB - We aimed to investigate the association between adherence to the Mediterranean diet (MeDi) and Alzheimer's disease (AD) risk in a prospective study. Specifically, we analyzed reduced inflammation and improved metabolic profile as a potential medium through which the MeDi reduced the risk of AD. During a 4-year follow-up, 118 incident AD cases were identified among the 1219 non-demented elderly (age >= 65) subjects who provided dietary information and blood samples at baseline. We used high-sensitivity C-reactive protein (hsCRP) as an index of systemic inflammation, and fasting insulin and adiponectin as indexes of metabolic profile. We investigated whether there was a change in the association between MeDi and incident AD risk when the biomarkers were introduced into multivariable adjusted COX models. Better adherence to MeDi was associated with lower level of hsCRP (p =0.003), but not fasting insulin or adiponectin. Better adherence to MeDi was significantly associated with lower risk for AD: compared to those in the lowest tertile of MeDi, subjects in the highest tertile had a 34% less risk of developing AD (p-for-trend =0.04). Introduction of the hsCRP, fasting insulin, adiponectin, or combinations of them into the COX model did not change the magnitude of the association between MeDi and incident AD. Ultimately, the favorable association between better adherence to MeDi and lower risk of AD did not seem to be mediated by hsCRP, fasting insulin, or adiponectin. Other aspects of inflammatory and metabolic pathways not captured by these biomarkers, or non-inflammatory or non-metabolic pathways, may be relevant to the MeDi-AD association. PMID- 20847400 TI - Cortical activation during clock reading as a quadratic function of dementia state. AB - In patients with Alzheimer's disease (AD), neuroimaging studies have demonstrated decreased brain activation, while increased activation was detected in patients with mild cognitive impairment (MCI). It can be hypothesized that increased cerebral activity seen in patients with MCI reflects neural compensation at the beginning of neurodegenerative processes. Later, as patients develop AD, neural integrity is increasingly impaired. This is accompanied by decreased neural activation. In this study we examined cognitive performance and functional magnetic resonance imaging activation on a Clock Reading task (CRT) and a Spatial Control task (SCT) in healthy controls, patients with MCI, and patients with early AD. Correlations between neural-functional activation and cognitive state, measured by the Mini Mental Status Examination, were determined using rank, linear and quadratic correlation models. It could be shown that CRT, in comparison to SCT, specifically activates brain regions in the ventral visual stream and precuneus known to be involved in conceptual processing and spatial imagery. The correlation between brain activity and cognitive state followed a quadratic rather than a linear pattern in several brain regions, including the lingual gyrus, cuneus, and precuneus. The strongest brain activity was found in patients with MCI and less severely impaired early AD subjects. These findings support the hypothesis that patients in early stages of dementia compensate for neuronal loss by the recruitment of additional neural resources reflected by increased neural activation, as measured by the blood oxygen level-dependent signal. PMID- 20847402 TI - Functional representation of olfactory impairment in early Alzheimer's disease. AB - We used [18F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n=24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the "Sniffin' Sticks" test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the "Sniffin' Sticks" test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis. PMID- 20847401 TI - CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model. AB - The inflammatory status of the brain in patients as well as animal models of Alzheimer's disease (AD) has been extensively studied. Accumulation of activated microglia producing tumor necrosis factor-alpha and monocyte chemotactic protein 1 contribute to the pathology of the disease. However, little is known about the changes in the spleen and associated peripheral immunity that might contribute to AD pathology. The goal of this study was to characterize phenotypic and functional changes in spleen, blood and brain cell populations that contribute to development of an AD-like disease in a triple transgenic (3xTg-AD) mouse model. The 3xTg-AD mice had increased percentages of brain Gr-1+ granulocytes, dendritic cells and macrophages, spleen and blood derived CD8+Ly6C+ memory T cells and CCR6+ B cells, as well as increased levels of secreted interleukin-6. Brain tissue from older 12 month old symptomatic 3xTg-AD female mice exhibited highly elevated mRNA expression of CCR6 compared to wild-type mice. Importantly, this pronounced increase in expression of CCR6 was also detected in brain and spleen tissue from pre-symptomatic 5--6 month old 3xTg-AD females and males. Our data demonstrate increased expression of CCR6 in the brain and peripheral immune organs of both pre-symptomatic and symptomatic 3xTg-AD mice, strongly suggesting an ongoing inflammatory process that precedes onset of clinical AD-like disease. PMID- 20847403 TI - Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease. AB - Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57-83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin like growth factor-1, amyloid-beta (Abeta40 and Abeta42). Six months of aerobic exercise improved executive function (MANCOVA, p=0.04), cardiorespiratory fitness (MANOVA, p=0.03), and insulin sensitivity (p=0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p=0.01). For Abeta42, plasma levels tended to decrease for the aerobic group relative to controls (p=0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline. PMID- 20847404 TI - Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease. AB - Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-beta 1-42 (Abeta1-42) levels and cognitive score. Furthermore, total-tau/(Abeta1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Abeta1-42 ratio for early AD diagnosis in women. PMID- 20847405 TI - ERK2 is increased in cerebrospinal fluid of Creutzfeldt-Jakob disease patients. AB - The clinical diagnosis of Creutzfeldt-Jakob disease (CJD) can be supported by several biochemical markers in cerebrospinal fluid (CSF) such as 14-3-3 proteins and tau protein. Unfortunately, none of the currently known markers are suited for screening or seems to be directly related to the pathophysiological process. A marker fulfilling these criteria might facilitate the early detection and might also serve in monitoring drug efficacy. Recently, the extracellular signal regulated kinase ERK1/2 was detected in CSF of patients with neuropsychiatric disorders. Furthermore, ERK1/2 was reported to be activated in brains of animals infected with pathological prion protein. Therefore, we investigated CSF of 19 patients with CJD, 23 patients with other dementias including patients with Alzheimer's disease, and 12 patients with other neurological disorders. The measurement of ERK1/2 in the CSF samples was performed with an electrochemiluminescence assay and Western immunoblot. ERK1/2 and doubly phosphorylated ERK1/2 (pERK1/2) were detected in all patient groups. Significantly elevated mean levels of total ERK1/2 and pERK1/2 were found in the CJD patients. This increase was also observed in a CJD case that was negative for 14-3-3 protein or in CJD cases that had low levels of tau protein. Western immunoblot analysis suggested that ERK2 was the predominant form of ERKs present in our CSF samples. This pilot study suggests that ERK1/2 is a potential CSF biomarker for CJD, directly associated with the pathophysiological processes. Analysis of larger sample cohorts including other diseases with rapid neurodegeneration are required to confirm our findings. PMID- 20847406 TI - The amnestic syndrome of hippocampal type in Alzheimer's disease: an MRI study. AB - The Free and Cued Selective Reminding Test (FCSRT) is a verbal episodic memory test used to identify patients with mild Alzheimer's disease (AD). The present study investigates the relationships between performance on FCSRT and grey matter atrophy assessed with structural MRI in patients with AD. Three complementary MRI based analyses (VBM analysis, ROI-based analysis, and three-dimensional hippocampal surface-based shape analysis) were performed in 35 patients with AD to analyze correlations between regional atrophy and their scores for episodic memory using the FCSRT. With VBM analysis, the total score on the FCSRT was correlated with left medial temporal lobe atrophy including the left hippocampus but also the thalami. In addition, using ROI-based analysis, the total recall score on the FCSRT was correlated with the left hippocampal volume. With three dimensional hippocampal surface-based shape analysis, both free recall and total recall scores were correlated with regions corresponding approximately to the CA1 field. No correlation was found with short term memory scores using any of these methods of analysis. In AD, the FCSRT may be considered as a useful clinical marker of memory disorders due to medial temporal damage, specially the CA1 field of the hippocampus. PMID- 20847407 TI - Functional assessment staging (FAST) in Korean patients with Alzheimer's disease. AB - Functional Assessment Staging (FAST) was devised to meet the need for a more brief patient-derived rating scale for evaluating changes in functional performance and activities of daily living skills in all the stages of Alzheimer's disease (AD). FAST was administered to 464 patients with probable AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. The patients were also evaluated using the Korean version of the Mini Mental Status Examination (K-MMSE), the Clinical Dementia Rating (CDR), the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Global Deterioration Scale (GDS), the Barthel Activities of Daily Living (B-ADL), and the Seoul-Instrumental Activities of Daily Living (S-IADL). For patients with moderate to severe dementia, the Korean versions of the Severe Impairment Battery (SIB-Ko) and Baylor profound mental status examination (BPMSE-Ko) were also administered. There were significant correlations between the FAST and the K-MMSE scores (r= - 0.71, p< 0.001), between the FAST and the SIB-Ko scores (r= - 0.54, p< 0.001) and between the FAST and the BPMSE-Ko scores (r=- 0.46, p< 0.001). The FAST was also correlated with the CDR, the CDR-SB, the B-ADL, and the S-IADL (p< 0.001). Ultimately, FAST is a reliable and valid assessment technique for evaluating functional deterioration in AD patients throughout the disease course. Moreover, the findings of the present study suggest that the FAST elucidates a characteristic pattern of progressive, ordinal, and functional decline in AD in Korean AD patients with dementia. PMID- 20847408 TI - Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE epsilon4 allele, the major late-onset Alzheimer's susceptibility gene. AB - In vivo PET imaging studies of young-adult carriers of the apolipoprotein E epsilon4 allele (APOEepsilon4), the major Alzheimer's disease (AD) susceptibility gene, have demonstrated declines in glucose metabolism in brain areas later vulnerable to AD, such as posterior cingulate cortex, decades before the possible onset of symptoms. We have previously shown in postmortem studies that such metabolic declines in AD are associated with brain regional mitochondrial dysfunction. To determine whether young adult at-risk individuals demonstrate similar mitochondrial functional decline, we histochemically assessed postmortem tissues from the posterior cingulate cortex of young-adult carriers and noncarriers of APOEepsilon4. At-risk epsilon4 carriers had lower mitochondrial cytochrome oxidase activity than noncarriers in posterior cingulate cortex, particularly within the superficial cortical lamina, a pattern similar to that seen in AD patients. Except for one 34 year-old epsilon4 homozygote, the epsilon4 carriers did not have increased soluble amyloid-beta, histologic amyloid-beta, or tau pathology in this same region. This functional biomarker may prove useful in early detection and tracking of AD and indicates that mitochondrial mechanisms may contribute to the predisposition to AD before any evidence of amyloid or tau pathology. PMID- 20847409 TI - Lipid oxidation and modification of amyloid-beta (Abeta) in vitro and in vivo. AB - Oxidative damage and amyloid-beta (Abeta) protein misfolding are prominent features of Alzheimer's disease (AD). In vitro studies indicated a direct linkage between these two features, where lipid oxidation products augmented Abeta misfolding. We tested this linkage further, mimicking specific conditions present in amyloid plaques. In vitro lipid oxidation and lipid modification of Abeta were thus performed with elevated levels of copper or physiological levels of calcium. These in vitro experiments were then confirmed by in vivo immunohistochemical and chemical tagging of oxidative damage in brains from the PSAPP mouse model of AD. Our in vitro findings indicate that: 1) high levels of copper prevent lipid oxidation; 2) physiological concentrations of calcium reduce 4 hydroxy-2-nonenal (HNE) modification of Abeta; and 3) anti-Abeta and HNE antibody epitopes are differentially masked. In vivo we demonstrated increased lipid oxidation around plaques but 4) a lack of immunological colocalization of HNE-adducts with Abeta. Thus, the lack of colocalization of Abeta and HNE-adduct immunostaining is most likely due to a combination of metals inhibiting HNE modification of Abeta, quenching lipid oxidation and a masking of HNE-Abeta histopathology. However, other forms of oxidative damage colocalize with Abeta in plaques, as demonstrated using a chemical method for identifying oxidative damage. Additionally, these findings suggest that HNE modification of Abeta may affect therapeutic antibodies targeting the amino terminal of Abeta and that metals effect on lipid oxidation and lipid modification of Abeta could raise concerns on emerging anti-AD treatments with metal chelators. PMID- 20847410 TI - A population-based study of cognitive function in older people with subjective memory complaints. AB - Given the uncertain relationship between objective and subjective memory complaints (SMC), we conducted a study of cognitive function in older people with memory complaints in a large population-based elderly Spanish cohort (NEDICES). A total of 1,073 subjects with SMC and 1,073 matched controls free from dementia underwent a neuropsychological assessment, including tests of global cognitive performance, frontal executive function, verbal fluency, and memory. SMC were associated with a number of specific objective cognitive deficits including poor verbal fluency, and poor immediate and delayed recall. However, there was a limited association with global cognitive impairment despite a strong influence upon Pfeffer Functional Activities Questionnaire based daily function. In the full sample the strongest predictors of SMC were poor psychological well-being, depressive symptoms (including those taking antidepressants) and hearing impairment. Moderate predictors were age and gender. If individuals with mild cognitive impairment (MCI) were removed, then the strongest predictors were poor psychological well-being, depressive symptoms, hearing impairment, illiteracy, age, and gender. For those with MCI alone, the only significant predictor of memory complaints was poor psychological well-being. Predictors of SMC in those with depressive symptoms included poor psychological well-being and hearing impairment. With depressive symptoms excluded the strongest predictors were poor psychological well-being, hearing impairment, illiteracy, and gender. In this population-based sample, individuals with SMC had evidence of impairments on specific neuropsychological testing which might not be apparent on global measures. Predictors of SMC may differ in those with versus without MCI and those with versus without depressive symptoms. PMID- 20847411 TI - Protection of the blood-brain barrier by pentosan against amyloid-beta-induced toxicity. AB - Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid beta (Abeta) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Abeta showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Abeta1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Abeta fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Abeta1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Abeta peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease. PMID- 20847412 TI - B-vitamins and fatty acids in the prevention and treatment of Alzheimer's disease and dementia: a systematic review. AB - The increasing worldwide prevalence of dementia is a major public health concern. Findings from some epidemiological studies suggest that diet and nutrition may be important modifiable risk factors for development of dementia. In order to evaluate the strength of the available evidence of an association of dietary factors with dementia including Alzheimer's disease (AD), we systematically searched relevant publication databases and hand-searched bibliographies up to end July 2007. We included prospective cohort studies which evaluated the association of nutrient levels with the risk of developing dementia and randomized intervention studies examining the treatment effect of nutrient supplementation on cognitive function. One hundred and sixty studies, comprising ninety one prospective cohort studies and sixty nine intervention studies, met the pre-specified inclusion criteria. Of these, thirty-three studies (19 cohort and 14 randomized controlled trials) investigated the effects of folate, B vitamins, and levels of homocysteine (a biomarker modifiable through B-vitamin supplementation) or fish/fatty acids and are the focus of the present report. Some observational cohort studies indicated that higher dietary intake or elevated serum levels of folate and fish/fatty acids and low serum levels of homocysteine were associated with a reduced risk of incident AD and dementia, while other studies reported no association. The results of intervention studies examining the effects of folic acid or fatty acid supplementation on cognitive function are inconsistent. In summary, the available evidence is insufficient to draw definitive conclusions on the association of B vitamins and fatty acids with cognitive decline or dementia, and further long-term trials are required. PMID- 20847413 TI - Immunomodulation of AbetaPP processing alleviates amyloid-beta-related pathology in Alzheimer's disease transgenic mice. AB - Among the different paradigms aimed at interfering with amyloid-beta (Abeta) related pathology, the attenuation of amyloid-beta protein precursor (AbetaPP) processing to limit Abeta levels seems to be a promising one. Along with the development of BACE1 inhibitors, and the generation of its knock-out mice, accumulating data raise concerns regarding a total inhibition of the enzyme as it shares the processing of other substrates. We described a novel approach to interfere with the specific interaction between AbetaPP and BACE1 using monoclonal antibodies directed to the beta-secretase cleavage site upon the substrate, AbetaPP. Such antibodies limit AbetaPP cleavage in a cellular model of Alzheimer's disease (AD) and avoid the total inhibition of BACE1. Here, we demonstrate the ability of AbetaPP beta-site antibodies to interfere with Abeta production in vivo. Systemic antibody treatment diminished Abeta plaques, membrane-associated oligomers, and intracellular Abeta accumulation, all of which have been implicated in cellular death and synaptic loss, suggesting that this approach may be an applicable strategy for AD treatment. PMID- 20847414 TI - Endothelial dysfunction and repair in Alzheimer-type neurodegeneration: neuronal and glial control. AB - Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific functions in the central nervous system, and how endothelial neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets. PMID- 20847415 TI - Amyloid-beta production via cleavage of amyloid-beta protein precursor is modulated by cell density. AB - Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-beta (Abeta), a proteolytic cleavage product of amyloid-beta protein precursor (AbetaPP). Abeta is generated through a serial cleavage of AbetaPP by beta- and gamma-secretase. Abeta40 and Abeta42 are the two main components of amyloid plaques in AD brains, with Abeta42 being more prone to aggregation. AbetaPP can also be processed by alpha-secretase, which cleaves AbetaPP within the Abeta sequence, thereby preventing the generation of Abeta. Little is currently known regarding the effects of cell density on AbetaPP processing and Abeta generation. Here we assessed the effects of cell density on AbetaPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Abeta40, Abeta42, total Abeta, and the ratio of Abeta42: Abeta40. These results also indicate that cell density is a significant modulator of AbetaPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AbetaPP processing and Abeta generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AbetaPP processing and Abeta levels in the AD brain. PMID- 20847416 TI - Decline of human tactile angle discrimination in patients with mild cognitive impairment and Alzheimer's disease. AB - There is a need to differentiate between patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) from normal-aged controls (NC) in the field of clinical drug discovery. In this study, we developed a tactile angle discrimination system and examined whether the ability to discriminate tactile angle differed between patients with MCI and AD and the NC group. Thirty-seven subjects were divided into three groups: NC individuals (n=14); MCI patients (n=10); and probable AD patients (n=13). All subjects were asked to differentiate the relative sizes of the reference angle (60 degrees ) and one of eight comparison angles by passive touch. The accuracy of angle discrimination was measured and the discrimination threshold was calculated. We discovered that there were significant differences in the angle discrimination thresholds of AD patients compared to the NC group. Interestingly, we also found that ability to discriminate tactile angle of MCI patients were significantly lower than that of the NC group. This is the first study to report that patients with MCI and AD have substantial performance deficits in tactile angle discrimination compared to the NC individuals. This finding may provide a monitor and therapeutic approach in AD diagnosis and treatment. PMID- 20847417 TI - Oren-gedoku-to and its constituents with therapeutic potential in Alzheimer's disease inhibit indoleamine 2, 3-dioxygenase activity in vitro. AB - A well-known traditional Chinese medicinal prescription, Oren-gedoku-to (OGT), has been used in clinical therapies for many types of dementia in China and Japan. Additionally, it ameliorates the age-related deterioration of learning and memory in an Alzheimer's disease (AD) rat model. Indoleamine 2, 3-dioxygenase (IDO-1) is the first and rate-limiting enzyme in the kynurenine pathway of tryptophan catabolism, which ultimately leads to the production of the excitotoxin quinolinic acid (QUIN). IDO-1 has recently been established as one of the key players involved in the pathogenesis of AD. OGT is indicated to prevent cholinergic dysfunction and reduce oxidative stress; however, the exact mechanism underlying its ability to improve cognitive ability remains elusive. Here we present a novel mechanism of OGT's therapeutic potential in AD. We demonstrated that OGT significantly inhibited recombinant human IDO-1 (rhIDO-1) activity in vitro, and its four main constituents (i.e., berberine, palmatine, jatrorrhizine, and baicalein) were potent IDO-1 inhibitors. IC50 values, obtained from a cell based assay, of HEK 293 cells and an enzymatic assay were much lower than the most commonly used IDO-1 inhibitor, 1-methyl tryptophan (1-MT). Berberine was the best inhibitor and had IC50 values of 7 MUM (cell-based assay) and 9.3 MUM (enzymatic assay). Jatrorrhizine and palmatine exhibited irreversible inhibition of rhIDO-1, whereas berberine and baicalein behaved as uncompetitive, reversible inhibitors with Ki values of 8 MUM and 215 MUM, respectively. In conclusion, constituents of OGT show strong IDO-1 inhibitory activity and may have significant therapeutic potential for AD. PMID- 20847418 TI - Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and gamma-secretase independent redistribution. AB - Presenilin mutations are linked to the early onset familial Alzheimer's disease (FAD) and lead to a range of neuronal changes, indicating that presenilins interact with multiple cellular pathways to regulate neuronal functions. In this report, we demonstrate the effects of FAD-linked presenilin 1 mutation (PS1M146L) on the expression and distribution of filamin, an actin cross-linking protein that interacts with PS1 both physically and genetically. By using immunohistochemical methods, we evaluated hippocampal dentate gyrus for alterations of proteins involved in synaptic plasticity. Among many proteins expressed in the hippocampus, calretinin, glutamic acid decarboxylase (GAD67), parvalbumin, and filamin displayed distinct changes in their expression and/or distribution patterns. Striking anti-filamin immunoreactivity was associated with the polymorphic cells of hilar region only in transgenic mice expressing PS1M146L. In over 20% of the PS1M146L mice, the hippocampus of the left hemisphere displayed more pronounced upregulation of filamin than that of the right hemisphere. Anti-filamin labeled the hilar neurons only after the PS1M146L mice reached after four months of age. Double labeling immunohistochemical analyses showed that anti-filamin labeled neurons partially overlapped with cholecystokinin (CCK), somatostatin, GAD67, parvalbumin, and calretinin immunoreactive neurons. In cultured HEK293 cells, PS1 overexpression resulted in filamin redistribution from near cell peripheries to cytoplasm. Treatment of CHO cells stably expressing PS1 with WPE-III-31C or DAPT, selective gamma-secretase inhibitors, did not suppress the effects of PS1 overexpression on filamin. These studies support a gamma-secretase-independent role of PS1 in modulation of filamin-mediated actin cytoskeleton. PMID- 20847419 TI - Executive function predicts survival in Alzheimer disease: a study in Shanghai. AB - We aimed to investigate the natural history of Alzheimer's disease (AD) and the risk factors associated with survival. We performed a 5-year retrospective cohort study on 467 consecutive outpatients clinically diagnosed with AD and treated between January 1, 2003, and December 31, 2006, at Huashan Hospital, Shanghai, China. The primary endpoint in this study was survival. At baseline, we evaluated the patients' demographic characteristics and neuropsychological characteristics, comorbid conditions, neuroimaging findings, complications, and neurological signs. Among the 467 patients, 398 survived. Male gender, age, and disease severity were associated with mortality. Survival analysis using the proportional hazard model with adjustments for gender, age, and disease stage revealed that the cognition factors that predicted longer survival included high total score [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.76-0.96] and sub-scores in the verbal fluency test (animals, vegetables, and fruits). The presence of at least 1 complication was an independent factor predictive of a decreased lifespan (HR, 5.55; 95% CI, 1.91-16.13). In AD patients, presence of complications was an indicator of poor survival, while good performance in assessments of executive function, such as the verbal fluency test and Stroop test, at baseline was associated with longer survival. PMID- 20847421 TI - A combination of CSF tau ratio and midsaggital midbrain-to-pons atrophy for the early diagnosis of progressive supranuclear palsy. AB - Cerebrospinal fluid (CSF) tau ratio decrease (33kDa/55kDa forms) and mid-saggital midbrain-to-pons (MP) atrophy have been suggested as diagnostic markers for progressive supranuclear palsy (PSP). The usefulness of their combined evaluation has never been tested. We evaluated the CSF tau ratio and the MP atrophy as a combined marker for early identification of PSP. A total of 87 subjects, namely 18 PSP, 25 controls (CON), 16 corticobasal syndrome (CBS), and 28 frontotemporal dementia (FTD), were included. Each subject underwent a lumbar puncture and a conventional MRI scan to assess CSF tau 33 kDa/55 kDa ratio and mid-saggital MP measure, respectively. CSF tau ratio and MP ratio were significantly reduced in PSP patients when compared to CON, CBS, and FTD (p< 0.001). Data-based "optimal" combination of CSF tau ratio and MP measure was defined, and the combined marker TrMp= sqrt[3]{CSF Tau ratio}} * {MP ratio} was considered. Considering the combined marker, the difference between the area under the curve (dAUC) of the receiver operating characteristic analysis in PSP versus the various subgroups was higher by about 10% than that obtained by each marker individually. In PSP versus others, a proposed "best" cut-off of TrMP = 0.182 resulted in 94.2% sensitivity and 84.0% specificity. When patients with onset of symptoms <= 2 years were included, TrMP resulted significantly decreased in PSP compared to CBS (p< 0.001) and FTD (p< 0.001). The combined marker increases the discriminative power in identifying PSP and suggests that the interplay of different markers should be considered in future trials to enhance diagnostic accuracy from the early stages. PMID- 20847422 TI - Importance of the caspase cleavage site in amyloid-beta protein precursor. AB - Reports from multiple laboratories have now been published analyzing the critical nature of the caspase cleavage site of amyloid-beta protein precursor (AbetaPP) for cell death induction, synaptic loss, hippocampal atrophy, long-term potentiation, memory loss, neophobia, and other aspects of the Alzheimer's phenotype. Here we review the results and implications of these studies for the understanding of Alzheimer's disease pathophysiology and the potential development of therapeutics that target this site in AbetaPP. PMID- 20847423 TI - Evidence for participation of aluminum in neurofibrillary tangle formation and growth in Alzheimer's disease. AB - This study examines hippocampal CA1 cells from brains of aged humans, with and without Alzheimer's disease, for hyperphosphorylated tau and aluminum during early neurofibrillary tangle (NFT) formation and growth. A very small proportion of hippocampal pyramidal cells contain cytoplasmic pools within their soma that either appear homogeneous or contain short filaments (i.e., early NFTs). The cytoplasmic pools are aggregates of an aluminum/hyperphosphorylated tau complex similar to that found in mature NFTs. The photographic evidence presented combines with existing evidence to support a role for aluminum in the formation and growth of NFTs in neurons of humans with Alzheimer's disease. PMID- 20847425 TI - Greater default-mode network abnormalities compared to high order visual processing systems in amnestic mild cognitive impairment: an integrated multi modal MRI study. AB - We conducted an integrated multi-modal magnetic resonance imaging (MRI) study based on functional MRI (fMRI) data during a complex but cognitively preserved visual task in 15 amnestic mild cognitive impairment (a-MCI) patients and 15 Healthy Elders (HE). Independent Component Analysis of fMRI data identified a functional network containing an Activation Task Related Pattern (ATRP), including regions of the dorsal and ventral visual stream, and a Deactivation Task Related Pattern network (DTRP), with high spatial correspondence with the default-mode network (DMN). Gray matter (GM) volumes of the underlying ATRP and DTRP cortical areas were measured, and probabilistic tractography (based on diffusion MRI) identified fiber pathways within each functional network. For the ATRP network, a-MCI patients exhibited increased fMRI responses in inferior ventral visual areas, possibly reflecting compensatory activations for more compromised dorsal regions. However, no significant GM or white matter group differences were observed within the ATRP network. For the DTRP/DMN, a-MCI showed deactivation deficits and reduced GM volumes in the posterior cingulate/precuneus, excessive deactivations in the inferior parietal lobe, and less fiber tract integrity in the cingulate bundles. Task performance correlated with DTRP-functionality in the HE group. Besides allowing the identification of functional reorganizations in the cortical network directly processing the task stimuli, these findings highlight the importance of conducting integrated multi modal MRI studies in MCI based on spared cognitive domains in order to identify functional abnormalities in critical areas of the DMN and their precise anatomical substrates. These latter findings may reflect early neuroimaging biomarkers in dementia. PMID- 20847426 TI - Astrocytes in Alzheimer's disease: emerging roles in calcium dysregulation and synaptic plasticity. AB - Alzheimer's disease (AD) is caused by the accumulation of amyloid-beta (Abeta), which induces progressive decline in learning, memory, and other cognitive functions. Abeta is a neurotoxic protein that disrupts calcium signaling in neurons and alters synaptic plasticity. These effects lead to loss of synapses, neural network dysfunction, and inactivation of neuronal signaling. However, the precise mechanism by which Abeta causes neurodegeneration is still not clear, despite decades of intensive research. The role of astrocytes in early cognitive decline is a major component of disease pathology that has been poorly understood. Recent research suggests that astrocytes are not simply passive support cells for neurons, but are active participants in neural information processing in the brain. Abeta can disrupt astrocytic calcium signaling and gliotransmitter release, processes that are vital for astrocyte-neuron communication. Therefore, astrocyte dysfunction may contribute to the earliest neuronal deficits in AD. Here we discuss emerging concepts in glial biology and the implications of astrocyte dysfunction on neurodegeneration in AD. PMID- 20847424 TI - Amyloid-beta as a modulator of synaptic plasticity. AB - Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-beta (Abeta) in plaques. However, an exclusively pathological role for Abeta is being challenged by new evidence for an essential function of Abeta at the synapse. Abeta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. Abeta is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of Abeta at the synapse. At physiological levels, Abeta is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric Abeta40 and Abeta42 are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of Abeta are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial Abeta alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and Abeta independently decrease neuronal plasticity. Our laboratory has reported that Abeta, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of Abeta on synaptic plasticity. PMID- 20847427 TI - Regional selectivity of rab5 and rab7 protein upregulation in mild cognitive impairment and Alzheimer's disease. AB - Endocytic alterations are one of the earliest changes to occur in Alzheimer's disease (AD), and are hypothesized to be involved in the selective vulnerability of specific neuronal populations during the progression of AD. Previous microarray and real-time quantitative PCR experiments revealed an upregulation of the early endosomal effector rab5 and the late endosome constituent rab7 in the hippocampus of people with mild cognitive impairment (MCI) and AD. To assess whether these select rab GTPase gene expression changes are reflected in protein levels within selectively vulnerable brain regions (basal forebrain, frontal cortex, and hippocampus) and relatively spared areas (cerebellum and striatum), we performed immunoblot analysis using antibodies directed against rab5 and rab7 on postmortem human brain tissue harvested from cases with a premortem clinical diagnosis of no cognitive impairment (NCI), MCI, and AD. Results indicate selective upregulation of both rab5 and rab7 levels within basal forebrain, frontal cortex, and hippocampus in MCI and AD, which also correlated with Braak staging. In contrast, no differences in protein levels were found in the less vulnerable cerebellum and striatum. These regional immunoblot assays are consistent with single cell gene expression data, and provide protein-based evidence for endosomal markers contributing to the vulnerability of cell types within selective brain regions during the progression of AD. PMID- 20847428 TI - Relationship between proteolytically cleaved gelsolin and levels of amyloid-beta protein in the brains of Down syndrome subjects. AB - Gelsolin plays an important role in the fibrillogenesis of amyloid-beta (Abeta). It binds to Abeta and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43-63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young DS (age 0.5-23 years) and age-matched control subjects. In addition, the levels of both soluble and total Abeta40 and Abeta42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Abeta40 (r2= 0.7820, p < 0.01) and Abeta42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Abeta. The post translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Abeta. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Abeta in the brain. Since soluble non fibrillar forms of Abeta are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin. PMID- 20847429 TI - Neurovascular coupling in Parkinson's disease patients: effects of dementia and acetylcholinesterase inhibitor treatment. AB - Alzheimer's disease (AD) and Parkinson's disease (PD) lead to a cholinergic deficit in the brain which is not only related to dementia, but may also lead to a disturbed neurovascular coupling. We investigated the effect of cholinergic decline on neurovascular coupling in PD patients. Patients with idiopathic PD were divided in groups without (n=59; 65 +/- 9 y) or with moderate dementia as specified by Mini-Mental State Examination. The demented patients were assigned to groups with (n=55; 73 +/- 6 y) or without (n=61; 72 +/- 8 y) acetylcholinesterase inhibitor treatment. Neurovascular coupling was assessed by a simultaneous electroencephalography-Doppler technique applying a contrast-based visual stimulation task. Visually evoked potential amplitudes (N75-P100) and parameters of the hemodynamic response in the posterior cerebral artery were obtained using a control system approach (resting flow velocity, gain, attenuation, rate time, and natural frequency). Data were compared to a healthy control group of a similar age range (n=20; 63 +/- 8 yr). Compared to controls, patient groups presented no differences in evoked potential amplitudes or neurovascular coupling parameters. The reported 30% decline in acetylcholinesterase activity in PD patients did not lead to measurable changes in neurovascular coupling. In AD patients additional factors might explain the uncoupling and higher cerebrovascular risk detected in clinical studies. PMID- 20847431 TI - Is brain amyloid production a cause or a result of dementia of the Alzheimer's type? AB - The amyloid cascade hypothesis has guided much of the research into Alzheimer's disease (AD) over the last 25 years. We argue that the hypothesis of amyloid-beta (Abeta) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline in AD and the deposition of Abeta. Abeta may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population. PMID- 20847432 TI - Pleiotropy in the presence of allelic heterogeneity: alternative genetic models for the influence of APOE on serum LDL, CSF amyloid-beta42, and dementia. AB - The two genetic polymorphisms, rs7412 and rs429358, that collectively form the e2, e3, and e4 alleles of apolipoprotein E (APOE) are among the most widely studied sequence variants in the genome. The predominant model for testing APOE involves the haplotype combinations of e2, e3, and e4 and has been basis of associations with dementia, atherosclerosis, and serum lipid levels. Here, we demonstrate the functional independence of these two component sites, with rs7412 contributing to the majority of variance in serum LDL (p=10-20), whereas rs429358 alone influences variance in CSF amyloid-beta42 (Abeta42) (p=10(-17)). This latter relationship is also reflected in the association of APOE with dementia, where rs429358 strongly influences disease (p=10(-67)), but rs7412 does not. Models based upon e2, e3, and e4 explained less variance for both dementia risk and CSF Abeta42 than did rs429358 alone. When adjusted for CSF Abeta42, the association of rs429358 with dementia is greatly reduced but remains significant indicating that APOE polymorphism influences disease by additional mechanisms distinct from Abeta42 metabolism. We reach four principal conclusion from this study: 1) rs429358 alone is responsible for the association of APOE with dementia; 2) The association of APOE with dementia is substantially mediated by its effect on CNS Abeta42 levels; 3) The association of APOE with dementia is not mediated by its impact on peripheral lipid metabolism; and 4) The dichotomy of effects of rs429358 and rs7412 represents one of the best examples of genetic pleiotropy for complex traits known and illustrates the importance of allelic heterogeneity in APOE. PMID- 20847430 TI - The KATP channel activator diazoxide ameliorates amyloid-beta and tau pathologies and improves memory in the 3xTgAD mouse model of Alzheimer's disease. AB - Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. Plasma and mitochondrial membrane potentials, cell excitability, intracellular Ca2+ levels and bioenergetics were measured in cultured cerebral cortical neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of Abeta oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD. PMID- 20847433 TI - Dying with dementia: what we know after more than a decade of research. AB - Death with dementia is increasingly common. Although prognostication is difficult, it is an incurable life-limiting illness for which palliative care for the patient is often appropriate. Dementia patients are otherwise at risk of overtreatment with burdensome and possibly non-beneficial interventions and undertreatment of symptoms. Although recent studies indicate encouraging trends of improved palliative care, little evidence supports effectiveness of specific treatments. As of January 2010, at least 45 studies, almost all performed after 2000, have reported on treatment, comfort, symptom burden, and families' satisfaction with care. Over half (25; 56%) of these studies were in US settings, and most were small or retrospective. Few randomized trials and prospective observational studies have been performed so far, but several promising studies have been completed recently or are underway in various countries. Guidelines for care and treatment, still mostly consensus-based, support the benefits of advance care planning, continuity of care, and family and practitioner education. Assessment tools for pain, prognosis, and family evaluations of care have been developed and some have been shown to be effective in clinical practice. With increasing numbers of well-designed, large-scale studies, research in the next decade may result in better evidence-based guidelines and practice. PMID- 20847434 TI - Ocular biomarkers for early detection of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia and is clinically characterized by a progressive decline in memory, learning, and executive functions, and neuropathologically characterized by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive premortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred; hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments. While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular-based screening test for AD. PMID- 20847435 TI - Individual prediction of cognitive decline in mild cognitive impairment using support vector machine-based analysis of diffusion tensor imaging data. AB - Although cross-sectional diffusion tensor imaging (DTI) studies revealed significant white matter changes in mild cognitive impairment (MCI), the utility of this technique in predicting further cognitive decline is debated. Thirty-five healthy controls (HC) and 67 MCI subjects with DTI baseline data were neuropsychologically assessed at one year. Among them, there were 40 stable (sMCI; 9 single domain amnestic, 7 single domain frontal, 24 multiple domain) and 27 were progressive (pMCI; 7 single domain amnestic, 4 single domain frontal, 16 multiple domain). Fractional anisotropy (FA) and longitudinal, radial, and mean diffusivity were measured using Tract-Based Spatial Statistics. Statistics included group comparisons and individual classification of MCI cases using support vector machines (SVM). FA was significantly higher in HC compared to MCI in a distributed network including the ventral part of the corpus callosum, right temporal and frontal pathways. There were no significant group-level differences between sMCI versus pMCI or between MCI subtypes after correction for multiple comparisons. However, SVM analysis allowed for an individual classification with accuracies up to 91.4% (HC versus MCI) and 98.4% (sMCI versus pMCI). When considering the MCI subgroups separately, the minimum SVM classification accuracy for stable versus progressive cognitive decline was 97.5% in the multiple domain MCI group. SVM analysis of DTI data provided highly accurate individual classification of stable versus progressive MCI regardless of MCI subtype, indicating that this method may become an easily applicable tool for early individual detection of MCI subjects evolving to dementia. PMID- 20847436 TI - Upregulation of presenilin 1 in brains of sporadic, late-onset Alzheimer's disease. AB - The activity of the beta-secretase involved in the cleavage of amyloid-beta (Abeta) is increased in sporadic late-onset Alzheimer's disease (AD). Whether the corresponding gamma-secretase activity is altered is still uncertain. We evaluated mRNA expression and protein levels of presenilin 1 (PS1) and gamma secretase activity in the frontal cortex of 32 cases with late-onset sporadic AD and those of 29 control subjects. We found a significant increase in PS1 mRNA, protein levels and gamma-secretase activity in AD cases. These findings suggest that upregulation of PS1 leads to Abeta overproduction and accumulation in sporadic AD. PMID- 20847437 TI - Diverse ecdysterones show different effects on amyloid-beta42 aggregation but all uniformly inhibit amyloid-beta42-induced cytotoxicity. AB - Amyloid-beta (Abeta) plays a pivotal role in Alzheimer's disease (AD) pathogenesis and in toxic mechanisms such as oxidative stress, mitochondrial dysfunction, calcium turbulence, and apoptosis induction. Therefore, interfering with Abeta aggregation has long been one of the most promising strategies for AD treatment. Ecdysterones (ECRs) are steroidal hormones in insects and terrestrial plants that have high structural diversity and multiple beneficial pharmacological activities. Here, we studied the effects of six ECRs on Abeta aggregation and cytotoxicity. Two ECRs with an acetoxyl group at the 2 or 3 position and saturated chains as side groups showed apparent promotion of Abeta42 fibrilization, resulting in less Abeta42 oligomers in the samples. Another three with unsaturated side chains clearly inhibited Abeta aggregation and disaggregated preformed fibrils, but increased the Abeta42 oligomer levels. Nevertheless, our MTT results showed that all ECRs tested inhibited Abeta42 induced cytotoxicity. This protective activity may be partly attributable to ECR mediated amelioration of A&beta42-induced release of reactive oxygen species. Taken together, our findings suggest that ECRs, a series of natural compounds in many plants and insects, have therapeutic potential in AD and that the deduced structure-activity relationships may be beneficial in drug design for the treatment of AD and other amyloidoses. PMID- 20847438 TI - Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism. AB - Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible. PMID- 20847439 TI - Changes in cognition and amyloid-beta processing with long term cholesterol reduction using atorvastatin in aged dogs. AB - Human studies suggest either a protective role or no benefit of statins against the development of Alzheimer's disease (AD). We tested the hypothesis that statin mediated cholesterol reduction in aged dogs, which have cognitive impairments and amyloid-beta (Abeta) pathology, would improve cognition and reduce neuropathology. In a study of 12 animals, we treated dogs with 80 mg/day of atorvastatin for 14.5 months. We did not observe improvements in discrimination learning; however, there were transient impairments in reversal learning, suggesting frontal dysfunction. Spatial memory function did not change with treatment. Peripheral levels of cholesterol, LDLs, triglycerides, and HDL were significantly reduced in treated dogs. Abeta in cerebrospinal fluid and brain remained unaffected. However, beta-secretase-1 (BACE1) protein levels and activity decreased and correlated with reduced brain cholesterol. Finally, lipidomic analysis revealed a significant decrease in the ratio of omega-6 to omega-3 essential fatty in temporal cortex of treated aged dogs. Aged beagles are a unique model that may provide novel insights and translational data that can predict outcomes of statin use in human clinical trials. Treatment with atorvastatin may be beneficial for brain aging by reducing BACE1 protein and omega6:omega3 ratio, however, the potential adverse cognitive outcomes reported here should be more carefully explored given their relevance to human clinical outcomes. PMID- 20847440 TI - Anti-inflammatory action of donepezil ameliorates tau pathology, synaptic loss, and neurodegeneration in a tauopathy mouse model. AB - Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1beta and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action. PMID- 20847441 TI - Do amyloid beta-associated factors co-deposit with Abeta in mouse models for Alzheimer's disease? AB - Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-beta protein (Abeta), but also contain many different Abeta-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all influence Abeta deposition, aggregation, and clearance and therefore seem important in the development of human Abeta deposits. To study AD pathology and test new therapeutic agents, many different mouse models have been created. By transgenic expression of the amyloid-beta protein precursor, frequently in combination with other transgenes, these animals develop Abeta deposits that morphologically resemble their human counterparts. Whether this resemblance also applies to the presence of Abeta-associated factors is largely unclear. In this review, the co deposition of factors known to associate with human Abeta deposits is summarized for several different AD mouse models. PMID- 20847442 TI - Caveolin-1 regulates gamma-secretase-mediated AbetaPP processing by modulating spatial distribution of gamma-secretase in membrane. AB - Amyloidogenic processing of amyloid-beta precursor protein (AbetaPP) is associated with cholesterol- and sphingolipid-rich lipid rafts. Caveolin-1, a raft-residing protein, has been implicated in the pathogenesis of Alzheimer's disease. To determine the role of caveolin-1 in governing gamma-secretase mediated AbetaPP proteolysis, cellular gamma-secretase activity was assessed in response to alteration in caveolin-1 expression. We demonstrated that suppression of caveolin-1 expression by RNA interference resulted in a significant increase in gamma-secretase-mediated proteolysis of AbetaPP, generation of amyloid-beta, and cleavage of Notch. Overexpression of caveolin-1 attenuated gamma-secretase mediated proteolysis of AbetaPP and Notch, substantiating the negative regulation of gamma-secretase by caveolin-1. Furthermore, we found that cells deficient in caveolin-1 exhibited significantly increased co-localization of gamma-secretase with clathrin-coated non-caveolar endocytic vesicles, demonstrating that the partitioning of gamma-secretase between caveolar and non-caveolar membranes can be modulated by caveolin-1. Our data also showed that JNK activation is essential for caveolin-1-mediated regulation of gamma-secretase. Together, our results strongly suggest that caveolin-1 is an important regulator of gamma-secretase activity. PMID- 20847443 TI - Amyloid-beta induces cyclooxygenase-2 and PGE2 release in human astrocytes in NF kappa B dependent manner. AB - Both amyloid-beta peptide 1-42 (Abeta1-42) formation and cyclooxygenase-2 (COX-2) have been involved in the pathogenesis of Alzheimer's disease (AD), a devastating neurological disorder. However, the relationship between Abeta1-42 and COX-2 is unclear. We found that the addition of Abeta1-42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE2 synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Abeta1-42 induced COX-2 promoter transcription. Deletion of nuclear factor-kappaB (NF-kappaB) sites of the promoter diminished Abeta1-42-COX-2 dependent transcription. In agreement with this, Abeta1-42 induced transcription of NF-kappaB reporter gene. In contrast, Abeta1-42 neither did not induce NFAT not AP-1 factors activation suggesting that both NFAT and AP-1 was not necessary to control COX-2 transcription induced by Abeta1-42. Over expression of NF-kappaB inhibitory subunit, IkappaB, completely abrogated Abeta1-42-induced COX-2 activity in U-87 cells, whereas the opposite effect was shown when p65/rel A NF-kappaB was over expressed. In addition, Abeta1 42 induced p65/rel A subunit translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NF-kappaB in COX-2 induction and PGE2 synthesis by Abeta1-42 was corroborated by using the pharmacological inhibitor of the NF-kappaB pathway, PDTC. In addition, Abeta1-42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Abeta1-42 was able to induce COX-2 and PGE2 synthesis in astrocytic cells through a NF-kappaB dependent mechanism. This may have implicated in our understanding of AD pathology. PMID- 20847444 TI - High degree of dilated Virchow-Robin spaces on MRI is associated with increased risk of dementia. AB - The clinical significance of dilated Virchow-Robin spaces (dVRS) remains unclear and their impact on cognitive performances has only been reported in small sample studies. Our aim was to assess the association between severity of dVRS and risk of incident dementia and cognitive decline in an elderly cohort. The degree of dVRS in both white matter and basal ganglia were ranked using high-resolution 3D MRI in a population-based sample of 1,778 non-demented participants from 65 to 80 years of age, who had a cerebral MRI at baseline. Cognitive function was assessed and dementia was diagnosed during a 4-year follow-up period. Cox proportional hazard models were used to examine the association between dVRS degree on a four level severity score and incident dementia. The relationship between dVRS degree and change in cognition was examined using linear mixed effect models. During 6,135 person-years of follow-up, 27 individuals developed dementia. The highest degree of dVRS was associated with a strong increase in the risk of incident dementia independently of other standard risk factors of dementia, both for dVRS in white matter (HR=9.8, 95% CI 1.7-55.3) and in basal ganglia (HR =5.8, 95% CI 1.2-28.4). After further adjustment on white matter hyperintensity volume and brain infarcts, this association remained significant for dVRS in white matter. Higher rate of cognitive decline was found to be related to high degree of dVRS in basal ganglia but not in white matter. These results need confirmation but they suggest that assessment of the severity of dVRS may help identify groups of individuals that are at increased risk of dementia. PMID- 20847445 TI - Protein-DNA interaction at the origin of neurological diseases: a hypothesis. AB - A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-beta, tau protein, alpha-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, alpha 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation. PMID- 20847446 TI - Longitudinal changes in fiber tract integrity in healthy aging and mild cognitive impairment: a DTI follow-up study. AB - Cross-sectional studies using diffusion tensor imaging (DTI) suggest decline of the integrity of intracortically projecting fiber tracts with aging and in neurodegenerative diseases, such as Alzheimer's disease (AD). Longitudinal studies on the change of fiber tract integrity in normal and pathological aging are still rare. Here, we prospectively studied 11 healthy elderly subjects and 14 subjects with amnestic mild cognitive impairment (MCI), a clinical risk group for AD, using high-resolution DTI and MRI at baseline and after 13 to 16 months follow-up. Fractional anisotropy (FA), a DTI measure of fiber tract integrity, was compared across time points and groups using a repeated measures linear model and tract based spatial statistics. Additionally, we determined rates of grey matter and white matter atrophy using automated deformation based morphometry. Healthy elderly subjects showed decline of FA in intracortical projecting fiber tracts, such as corpus callosum, superior longitudinal fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulate bundle (p < 0.05, corrected for multiple comparisons). MCI subjects showed significant FA decline predominantly in the anterior corpus callosum (p < 0.05, corrected for multiple comparisons). Grey and white matter atrophy involved prefrontal, parietal, and temporal lobe areas in controls and prefrontal, cingulate, and parietal lobe areas in MCI subjects and agreed with the pattern of fiber tract changes. Our findings indicate that DTI allows detection of microstructural changes in subcortical fiber tracts over time that are related to aging as well as to early stages of AD type neurodegeneration. The underlying mechanisms for these changes are unknown. PMID- 20847447 TI - Regulation of in vitro Abeta1-40 aggregation mediated by small molecules. AB - It is well known that the transient and prolonged misfolding nature of amyloid beta (Abeta) makes it difficult to perform proper in vitro studies and obtain consistent results. From monomers to fibrils, the aggregated forms of Abeta are significant hallmarks in the Alzheimer's disease (AD) cascade and become the valuable targets for early diagnosis and therapy for AD. Thus, development of optimized in vitro fibrillogenic conditions to induce the desired Abeta states is essential to AD research. In this study, fifteen organic amino acid compounds (glycine, taurine, tramiprosate, and their derivatives) were employed to induce different fibrillogenic conditions for Abeta. The fibrillogenic patterns of Abeta peptides in these compounds were analyzed by thioflavin T assay and SDS-PAGE with photoinduced cross-linking of unmodified proteins protocols, then were analyzed and compared to those obtained via transmission electron microscopy and neuronal cell viability assays. Our study suggests various compounds capable of inducing different levels of in vitro Abeta1-40 fibrillogenesis, potentially useful tools in the study of Abeta for AD. PMID- 20847448 TI - Changed clathrin regulatory proteins in the brains of Alzheimer's disease patients and animal models. AB - In the study, the expression of clathrin regulatory proteins dynamin I, AP180, and synaptic vesicle protein synaptophysin in multiple brain regions of the patients with Alzheimer's disease (AD), the transgenic mice carrying the Swedish mutation of amyloid-beta protein precursor (AbetaPP) 670/671 (AbetaPPSWE), and the rats injected by bilateral hippocampus with amyloid-beta peptide (Abeta)1-42 were examined by immunohistochemistry and Nissl staining, Western blotting, and Real-time PCR, respectively. Spatial learning and memory of the rats were evaluated by Morris Water Maze test, and the ability of endocytosis in the cultured rat hippocampal neurons was detected by FM1-43 fluorescence imaging. Significant decreases in protein levels of dynamin I, AP180, and synaptophysin were observed in both AD patients and mice with AbetaPPSWE as compared to controls. Obvious declines of dynamin I and synaptophysin at protein and mRNA levels and impaired learning and spatial memory ability were found in the rats injected with Abeta1-42 as compared to controls. In addition, deposits of Abeta localized in the hippocampus around the sites of Abeta1-42 injection and the decreased numbers of Nissl bodies in neurons were found. Moreover, the disrupted synaptic vesicle endocytosis and decreased dynamin I protein were detected in stimulated hippocampal neurons treated with Abeta1-42. These findings imply a malfunctioning clathrin-mediated endocytosis during AD pathological processes, which might be relevant to the mechanism underlying the cognitive deficit associated with AD. PMID- 20847449 TI - Combining MRI and MRS to distinguish between Alzheimer's disease and healthy controls. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly, and early detection is of great importance if new therapies are to be effectively administered. We have used multivariate data analysis (orthogonal partial least squares to latent structures (OPLS) analysis) to investigate whether the discrimination between AD and elderly healthy control subjects can be improved by adding magnetic resonance spectroscopy (MRS) measures to magnetic resonance imaging (MRI). In this study, 30 AD patients and 36 control subjects were included (mean (SD) age=77(5) and 77(5) years, MMSE=23(4) and 29(1) respectively). High resolution T1-weighted axial magnetic resonance images were obtained from each subject. Automated regional volume segmentation and cortical thickness measures were determined for the images. 1H MRS was acquired from the hippocampus and LCModel was used for metabolite quantification. Altogether, this yielded 54 different volumetric, cortical thickness and metabolite ratio variables which were used for multivariate analysis. All analyses were performed using seven-fold-cross-validation. Combining MRI and MRS measures resulted in a sensitivity of 97% and a specificity of 94% compared to using MRI or MRS measures alone (sensitivity: 93%, 76%, specificity: 86%, 83% respectively). Adding the MRS measures to the MRI measures more than doubled the positive likelihood ratio from 7 to 17. Adding MRS measures to a multivariate analysis of MRI measures resulted in significantly better classification than using MRI measures alone. The OPLS method shows strong potential for discriminating between Alzheimer's disease and controls. PMID- 20847450 TI - Functional connectivity in mild cognitive impairment during a memory task: implications for the disconnection hypothesis. AB - Mild cognitive impairment (MCI) has been considered an intermediate state between healthy aging and dementia. The early damage in anatomical connectivity and progressive loss of synapses that characterize early Alzheimer's disease suggest that MCI could also be a disconnection syndrome. Here, we compare the degree of synchronization of brain signals recorded with magnetoencephalography from patients (22) with MCI with that of healthy controls (19) during a memory task. Synchronization Likelihood, an index based on the theory of nonlinear dynamical systems, was used to measure functional connectivity. During the memory task patients showed higher interhemispheric synchronization than healthy controls between left and right -anterior temporo-frontal regions (in all studied frequency bands) and in posterior regions in the gamma band. On the other hand, the connectivity pattern from healthy controls indicated two clusters of higher synchronization, one among left temporal sensors and another one among central channels. Both of them were found in all frequency bands. In the gamma band, controls showed higher Synchronization Likelihood values than MCI patients between central-posterior and frontal-posterior channels and a high synchronization in posterior regions. The inter-hemispheric increased synchronization values could reflect a compensatory mechanism for the lack of efficiency of the memory networks in MCI patients. Therefore, these connectivity profiles support only partially the idea of MCI as a disconnection syndrome, as patients showed increased long distance inter-hemispheric connections but a decrease in antero-posterior functional connectivity. PMID- 20847451 TI - FK506 reduces amyloid plaque burden and induces MMP-9 in AbetaPP/PS1 double transgenic mice. AB - Deposition of amyloid-beta peptide (Abeta) and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. Recently, calcineurin (CaN) has been reported as a potential modulator of memory function, synaptic plasticity, and neural degeneration in brains of AD animal models. In the present study, we examined the relationship between Abeta accumulations and CaN activity in brains of the AbetaPP/PS1 double transgenic mice. Treatment with FK506, a CaN inhibitor, significantly reduces Abeta burden and restores synaptic proteins (synaptophysin and postsynaptic density protein-95; PSD-95) while inducing matrix metallopeptidase-9 (MMP-9) expression in GFAP-positive astrocytes in the brain. These results suggest a role of FK506 and control of CaN activity in neuroprotection associated with Abeta deposition in AD. PMID- 20847452 TI - CSF alpha-synuclein does not discriminate dementia with Lewy bodies from Alzheimer's disease. AB - In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker alpha-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of alpha-synuclein, amyloid-beta 1-42 (Abeta1-42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF alpha-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Abeta1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower alpha-synuclein was related to lower MMSE scores (beta (SE) = 6(2) and p< 0.05) and fluency (beta (SE) = 4(2), p< 0.05). Ultimately, CSF alpha-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (alpha-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF alpha-synuclein levels are related to worse cognitive performance. PMID- 20847454 TI - From past to better public health programme planning for possible future global threats: case studies applied to infection control. AB - The impact of weather change and global pollution on the development and/or the transformation of microorganisms is no longer to be demonstrated. In this respect, heavy trends can be taken into account. This general context needs the development of anticipation procedures and the knowledge of the perception of prevention by the public for short, medium and long term actions. After a short discussion on the concept of emerging issues, the authors present some past examples of public health programs. These examples (malaria, dengue, chikungunya and cholera) are used to propose optimized ways of decision/action that may help to avoid possible crisis in a rapidly changing world. Then, the different lessons learnt are, under certain limits, associated with a forecasting analysis. PMID- 20847455 TI - A case study of sanitary survey on community drinking water supplies after a severe (post-Tsunami) flooding event. AB - This report presents a case study of a comprehensive sanitary survey on ca. 160 community drinking water supplies after a severe (post-Tsunami) flooding event in Sri Lanka. Sanitary inspection and microbiological and chemical water quality analyses were performed according to specifically-designed procedures established on the World Health Organization (WHO) guidelines. Significant hazards and critical points were identified in almost all the investigated water supplies. The overall results showed a significant level of microbiological and chemical risk associated with drinking water consumption within the investigated areas. The criteria and methods practised in this study are proposed as a model to assure an effective and reliable monitoring in post-emergencies involving possible deterioration of water quality and to identify health priorities related to water consumption. PMID- 20847456 TI - Evaluation of the temporal variation of air quality in Rome, Italy, from 1999 to 2008. AB - The main objective of this study was to asses the temporal variation (1999 trough 2008) of air quality in Rome, focusing on airborne concentration of selected pollutants (PM10 and PM2.5 mass concentration and particle number concentration, PNC, carbon monoxide, CO, nitrogen oxides, NO and NO2) used for health effects assessment in epidemiological analyses. Time series analysis using Seasonal Kendall test has been applied. A statistically significant decreasing trend was found for primary gaseous pollutants and total particle number concentrations. Moreover a decreasing trend was assessed for PM10, PM2.5 and NO2 measured at traffic oriented sites even if the estimated reduction was lower compared with NO, CO and PNC. The urban background PM10 and NO2 concentrations seem to be practically unchanged since 1999 as no statistically significant trends were found. All the pollutants show higher slope of the estimated trend line at traffic oriented sites compared with those observed at the urban background. Thus a reduction of the intra-city concentration variability throughout the years occurred. PMID- 20847457 TI - Non-tuberculous mycobacteria and microbial populations in drinking water distribution systems. AB - Data on the occurrence of non-tuberculous mycobacteria (NTM), in parallel with those obtained for bacterial indicators and amoebae, are presented with the aim to collect information on the spread of NTM in drinking water distribution systems in Italy. Samples were collected from taps of hospitals and households in Central and Southern Italy. The concentration values obtained for the more traditional microbial parameters complied with the mandatory requirements for drinking water. Conversely, moderate-to-high microbial loads (till 300 CFU/L) were observed for the NTM. Positive samples were obtained from 62% of the investigated water samples. Analogous results were observed for amoebae showing a higher percentage of positive samples (76%). In terms of public health, the presence of mycobacteria in water distribution systems may represent a potential risk especially for vulnerable people such as children, the elderly or immunocompromised individuals. PMID- 20847458 TI - Italian network for human biomonitoring of metals: preliminary results from two Regions. AB - The Italian program for human biomonitoring (HBM) of chemical elements, PROgram for Biomonitoring of the Exposure (PROBE), started in 2008 with the aim to provide the knowledge about risk assessment of the Italian population following the environmental exposure to metals. The project is implemented through a HBM campaign for the production of data on 19 metals in the blood and serum of subjects living in different Italian Regions. The metals studied are: antimony, beryllium, cadmium, chromium, cobalt, iridium, lead, manganese, mercury, molybdenum, nickel, palladium, platinum, rhodium, thallium, tin, tungsten, uranium and vanadium. The first phase of the project has included the development and validation of laboratory protocols for the collection of fluids and quantification of metals. The second phase provides the HBM data expressed as the reference values (RVs) for the Italian population, i.e., as the level of metals in the general population not occupationally exposed. In this paper, the experimental protocols used for the maintenance of high standards of analysis and the RVs for metals in serum of inhabitants of two Italian Regions (Calabria and Umbria) are described. PMID- 20847459 TI - Quantitative real-time PCR of enteric viruses in influent and effluent samples from wastewater treatment plants in Italy. AB - The prevalence of enteric viruses in wastewater, the efficacy of wastewater treatments in eliminating such viruses, and potential health risks from their release into the environment or by recycling of treated wastewaters, are very important issues in environmental microbiology. In this study we performed a quantitative TaqMan real-time PCR (polymerase chain reaction) analysis of enteric viruses on samples of influents and effluents from 5 wastewater treatment plants in and around Rome. Three epidemiologically important, waterborne enteric viruses were analyzed: adenoviruses, enteroviruses and noroviruses (GI and GII) and compared to classical bacterial indicators of fecal contamination. The concentration of adenoviruses was the highest, in both raw and treated waters. Mean values in influents were ranked as follows: adenovirus > norovirus GI > norovirus GII > enterovirus. In effluents, the ranking was: adenovirus > norovirus GI > enterovirus > norovirus GII. Removal efficiencies ranged from 35% (enterovirus) to 78% (norovirus GI), while removal efficiency for bacterial indicators was up to 99%. Since molecular quantification does not necessarily indicate an actual threat to human health, we proceeded to evaluate the infectivity of enterovirus particles in treated effluents through integrated cell culture and real-time PCR. Infectivity assays detected live virions in treated water, pointing to potential public health risks through the release of these viruses into the environment. A better understanding of viral presence and resistance to sewage purification processes have the potential of contributing to the effective management of risks linked to the recycling of treated wastewater, and its discharge into the environment. PMID- 20847460 TI - Environmental surveillance of Legionella pneumophila in two Italian hospitals. AB - The aim of this study was to identify the most effective disinfection protocol to reduce the presence of Legionella pneumophila in the water system of two Italian hospitals. From 2004 to 2009, 271 samplings of hot water were carried out in 11 hospital units to detect the presence of L. pneumophila. Additionally, water samples collected from one boiler outlet and the hot water recirculation were tested. From 2004 to 2009, L. pneumophila was present in 37% of the samples. Of these, 68.3% and 18.8% were positive for serogroups 2-14 and 1, respectively. Furthermore, 12.9% of the samples were positive for both serogroups. Finally, a maximal count of 10(4) CFU/L was measured in the most distal sites. To reduce L. pneumophila colonization, a two-year long hyperchlorination (2004-2006) was carried out. Moreover, from June 2005 until now, continuous maintenance of boilers and tanks, substitution of the shower heads and increase of the boiler outlet temperature to 60 degrees C were performed. All these treatments led to a marked reduction of L. pneumophila colonization in the short but not in the medium-long term. Only the use of chlorine dioxide led, after four years, to a reduction of the loads of L. pneumophila to values below 100 CFU/L. However, in the distal sites a persistent degree of colonization (maximum value 700 CFU/L, average 600 CFU/L) was observed probably due to the presence of L. pneumophila in the stagnant water in dead legs. In conclusion, data show that long-term chlorination of hot water sources together with carefully aimed maintenance of water pipes can lead to an effective reduction of L. pneumophila concentration in hospital water systems. PMID- 20847461 TI - Possible involvement of overexposure to environmental selenium in the etiology of amyotrophic lateral sclerosis: a short review. AB - Excess exposure to the metalloid selenium (Se), a trace element with both toxicological and nutritional properties, has been implicated in the etiology of a human motor neuron disease of unknown origin and extremely severe prognosis, sporadic amyotrophic lateral sclerosis (ALS). This relation has been suggested on the basis of two epidemiologic investigations which found an increased risk of ALS associated with residence in a seleniferous area or with consumption of drinking water with unusually high levels of inorganic hexavalent Se, in South Dakota and in northern Italy respectively. Biological plausibility to a Se-ALS relation is provided by veterinary medicine observations and toxicological studies, showing that Se, particularly the inorganic forms, has a selective toxicity to motor neurons in swine and in cattle. Neurotoxic effects of Se species have also been demonstrated in laboratory studies and, for the inorganic forms, even at very low concentrations. Selenium has also been shown to affect muscle function in experimental animal models. Overall, these findings from the epidemiologic and the toxicological literature indicate that environmental Se, particularly in its inorganic forms and at unexpectedly low levels of exposure, might be a risk factor for ALS, suggesting the opportunity to further investigate this issue. PMID- 20847462 TI - Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population based case-control study. AB - A few epidemiologic studies have suggested an association of agricultural work and pesticides exposure with a severe degenerative disease of the motor neurons, amyotrophic lateral sclerosis (ALS), though conflicting results have also been provided. We investigated through a population-based case-control study the possible relation between overall occupational exposure to pesticides and ALS risk in the northern Italy municipality of Reggio Emilia. By administering a questionnaire, we investigated occupational history and leisure-time habits of the 41 ALS patients diagnosed in the 1995-2006 period, and of 82 age- and sex matched randomly sampled population controls. More cases than controls were found to have been exposed to pesticides for at least six months (31.7% vs 13.4%, respectively), in all cases within the occupational environment. In a conditional logistic regression model, we found an excess ALS risk associated with exposure to pesticides, with a relative risk of 3.6 (95% confidence interval 1.2-10.5). Such association persisted after inclusion in the statistical analysis of potential confounders. Despite the limited statistical stability of the risk estimates, these results appear to indicate that occupational exposure to pesticides is a risk factor for ALS, suggesting the need to further investigate this issue. PMID- 20847463 TI - Airborne microorganisms associated with waste management and recovery: biomonitoring methodologies. AB - This paper presents preliminary results from a year-long indoor bioaerosol monitoring performed in three working environments of a municipal composting facility treating green and organic waste. Composting, whereby organic matter is stabilized through aerobic decomposition, requires aeration, causing the dispersion of microbial particles (microorganisms and associated toxins). Waste can, therefore, become a potential source of biological hazard. Bioaerosol samples were collected on a monthly basis. Through a comparison of results obtained using two samplers - the Surface Air System DUO SAS 360 and the BioSampler - the study aimed at assessing the presence of biological pollutants, and at contributing to the definition of standard sampling methods for bioaerosols leading, eventually, to the establishment of exposure limits for these occupational pollutants. PMID- 20847464 TI - The impact measure of solid waste management on health: the hazard index. AB - The risk associated with waste exposure depends on the level of emissions arising from waste disposal and from the effects of these emissions on human health (dose response). In 2007 an epidemiological study was conducted in two Italian provinces of the Campania Region, namely Naples and Caserta, with the aim of assessing the health effects deriving from exposure to waste. In these studies, the important aspect is the population exposure assessment, in relation to the different types of waste disposal. The Regional Agency for Environmental Protection (ARPA Campania) has identified and characterized the various authorized/unauthorized dumping sites in the provinces of Naples and Caserta. Most of the waste disposal used are illegal and invisible (sunken or buried); thus, the toxic substances therein contained are unknown and difficult to identify. In order to locate the possible areas exposed to a higher waste-related health risk, a synthetical "hazard index" (at the municipality level) was designed. By means of GIS, the number of waste impact areas was identified for each of the 196 municipalities in the two provinces; then, Census data (ISTAT 2001) was used to estimate the proportion of the population living in the impact areas. The synthetical hazard index at municipality level accounts for three elements: a) the intrinsic characterization of the waste disposal, determining the way in which the pollutant is released; b) the impact area of the dumping site (within 1 km radius), same areas are influenced by more than one site; c) the density of the population living in the "impact area" surrounding the waste disposal site. PMID- 20847465 TI - Management of health-care waste in Izmir, Turkey. AB - The aim of this study was to evaluate health-care waste in the 18 districts of metropolitan municipality of the third biggest city in Turkey. This cross sectional study was carried out with 825 health institutions established in the 18 districts of Izmir metropolitan municipality, in 2007. The total amount of health-care waste collected was 4841 tons and 621 kilograms per patient's bed in 2007. Most of the medical wastes were collected from Konak, Karsiyaka and Bornova districts and were 2308, 272 and 1020 tons, respectively. Regarding to overpopulation, the number of health institutions in these districts are more than the number of health institutions in the other administrative districts. There was a statistically significant, positive correlation between the amount of health-care waste collected and population of the 18 districts (r = 0.79, p < 0.001), and number of beds/patients (r = 0.83, p < 0.001). To provide a safe health-care waste management metropolitan municipality must provide hazardous waste separation in health institutions, establish sterilization units for infectious waste, and provide the last storage of medical waste in completely different, safe and special areas apart from the municipal waste storage areas. PMID- 20847466 TI - Agricultural soils potentially contaminated: risk assessment procedure case studies. AB - At the moment, the health-environmental risk analysis is used to decision-making targets in the contaminated sites management; this procedure allows to assess the quantitative health risk related to the pollutants presence in environmental compartments, as soil and waters. As regards potentially contaminated agricultural soils, the ingestion of food from vegetable and/or animal source, produced inside the contaminated area, is the most suitable way to assess the health risk. As an official procedure to this assessment is not available, the National Institute for Health (Istituto Superiore di Sanita, ISS) has worked out an operating procedure, organized into several phases, depending on the available specific-site know-how. In this document, agricultural soils potentially contaminated in two sites have been studied; the sites are the following: Brescia Caffaro and Torviscosa. PMID- 20847467 TI - Pesticides and their metabolites in selected Italian groundwater and surface water used for drinking. AB - The control of groundwater and surface water quality in relation to the presence of pesticides and their metabolites is a rather complicated task. National and local authorities with the responsibility to guarantee an adequate quality of water cannot rely on international guidelines for monitoring activities. In a national project, forty-three pesticides and pesticide metabolites were selected on the basis of sale, monitoring and physical-chemical data, and investigated from some of the main Italian agricultural areas, susceptible to pesticide contamination. Twelve compounds were found in the tested water samples at levels exceeding the 0.1 ug/L European Union (EU) limit for drinking water (European Directive 98/83/EC). Maximum levels up to 0.62 were determined. Several water samples were characterized by the simultaneous occurrence of pesticides and their metabolites (up to ten). In some samples, the total concentration of pesticides and their metabolites was higher than the EU limit of 0.5 ug/L. Total triazine concentrations up to 1.02 ug/L were found. In all the cases the highest concentrations were well below the respective guideline values defined by the World Health Organization (WHO) for drinking water quality. PMID- 20847468 TI - Multi-criteria approach for the environmental impact assessment of inland aquaculture. AB - Trout farming, that represents the most important sector for aquaculture inland production in Italy, can cause negative effects on aquatic ecosystems. Recently, in the framework of Water Frame Directive 2000/60/EC and national law DL 152/2006, concerning the sustainable uses of water resources, multi-criteria approaches have been suggested to evaluate the impact of fish farming on aquatic ecosystems. In this study trout farms of central Italy were selected to investigate the effects of their effluents, on receiving water bodies using a multi-criteria approach based on physico-chemical parameters, microbiological and macrobenthonic indicators, detected in sampling stations located upstream/downstream the trout farm. Moreover, antibiotic susceptibility against antibiotics allowed and/or forbidden by current law (D.lgs 193/56/06) was tested on E. coli strains. The results indicate variations of chemical parameters and biological indicators from upstream to downstream sites in some of the investigated farms. Antibiotic resistance of E. coli strains suggested a large use of tetracycline and a possible past use of chloramphenicol. This study represents a first contribute to the knowledge of fish farm impacts on aquatic systems in Central Italy. PMID- 20847469 TI - Survey among agricultural workers about interpretation of plant protection product labels and safety data sheets. AB - The objective of this work was to examine the effectiveness of risk communication in agriculture through examination and interpretation of safety data sheets and product labels for agriculture products classified as hazardous. Labels and safety data sheets were shown to the users inviting them to report their own interpretation of hazard, risk and the need of preventive measures. One area sample was identified in a cluster of wine companies, chosen in a range of medium to large sizes throughout the country, where 100 subjects were interviewed by telephone or direct interview. Participants were surveyed through questions relating to demographic information, education and perception of risk. PMID- 20847470 TI - Foreword: emergence of efficiency in health outcome measurement. AB - Psychosocial measurement in the 21st Century is a dynamic field that is addressing challenges unthinkable even a generation ago. Sophisticated methods and modern technology has brought psychometrics to the cusp of scientific objectivity. This Foreword provides historical context and intellectual foundations for appreciating contemporary psychometric advancements, as well as a perspective on issues that are determining future advances. Efficiency in outcome measurement is one of these forces driving future advances. Efficiency, however, can easily become conflated with expediency, and neither can substitute for effectiveness. Blind efficiency runs risk of degrading measurement properties. Likewise, measurement advancement without accommodation to ordinary needs leads to practical rejection. Bouchard presents a biographical link between scientific physics and Rasch models that opened the door for fundamental psychosocial measurement. Symposium papers presented in this issue present a broad range of ideas about contemporary psychosocial measurement. Granger summarizes key ideas underlying achievement of objective, fundamental measurement. Massof, then, Stenner and Stone present alternative perspectives on scientific knowledge systems, which are prominent landmarks on the psychometric horizon. Fisher and Burton describe fundamental measurement methodology in diagnosis and implementation of technology, which will consolidate isolated and redundant constructs in PROMIS. Hart presents an overview on computer adaptive testing, which is the vanguard in health outcome measurement. Kisala and Tulsky present a qualitative strategy that is improving sensitivity and validity of new outcome measures. Their diversity reflects an intense competition of ideas about solving measurement problems. Their collection together in this special issue is a milestone and tribute to scientific ingenuity. PMID- 20847471 TI - Measuring one variable at a time: the Wright way. AB - This article, based on research for Ben Wright's biography, explores some influences leading to his profound commitment to useful and accurate measures. We briefly touch on his decision to leave a promising career in physics for education and psychometrics, stemming from his belief that understanding how children learn is even more important than understanding molecular structure. Along the way, we focus on a debate over measurement models that Wright began with Fred Lord at an ETS Invitational Conference in 1967. PMID- 20847472 TI - Rasch-derived latent trait measurement of outcomes: insightful use leads to precision case management and evidence-based practices in functional healthcare. AB - The use of Rasch-derived latent trait measurement of outcomes for persons with chronic disease and disablement evolved from other fields, particularly education. Person-metrics is the measurement of how much chronic disease and disablement affects an individual's daily activities physically, cognitively, and through vocational and social role participation. The ability of the Rasch model to assume that the probability of a given person/item interaction is governed by the difficulty of the item and the ability of the person is invaluable to disability measurement. The difference between raw scores and true measures is illustrated by an example of a patient whose physical difficulty is rated on rising from a wheelchair and walking 100m (known to be more difficult), and then walking an additional 200m. Though number ratings of 0-1-2 are assigned to these tasks, they are not equidistant, and only a true measure shows the actual levels of physical difficulty. PMID- 20847473 TI - Generally objective measurement of human temperature and reading ability: some corollaries. AB - We argue that a goal of measurement is general objectivity: point estimates of a person's measure (height, temperature, and reader ability) should be independent of the instrument and independent of the sample in which the person happens to find herself. In contrast, Rasch's concept of specific objectivity requires only differences (i.e., comparisons) between person measures to be independent of the instrument. We present a canonical case in which there is no overlap between instruments and persons: each person is measured by a unique instrument. We then show what is required to estimate measures in this degenerate case. The canonical case encourages a simplification and reconceptualization of validity and reliability. Not surprisingly, this reconceptualization looks a lot like the way physicists and chemometricians think about validity and measurement error. We animate this presentation with a technology that blurs the distinction between instruction, assessment, and generally objective measurement of reader ability. We encourage adaptation of this model to health outcomes measurement. PMID- 20847474 TI - A clinically meaningful theory of outcome measures in rehabilitation medicine. AB - Comparative effectiveness research in rehabilitation medicine requires the development and validation of clinically meaningful and scientifically rigorous measurements of patient states and theories that explain and predict outcomes of intervention. Patient traits are latent (unobservable) variables that can be measured only by inference from observations of surrogate manifest (observable) variables. In the behavioral sciences, latent variables are analogous to intensive physical variables such as temperature and manifest variables are analogous to extensive physical variables such as distance. Although only one variable at a time can be measured, the variable can have a multidimensional structure that must be understood in order to explain disagreements among different measures of the same variable. The use of Rasch theory to measure latent trait variables can be illustrated with a balance scale metaphor that has randomly added variability in the weights of the objects being measured. Knowledge of the distribution of the randomly added variability provides the theoretical structure for estimating measures from ordinal observation scores (e.g., performance measures or rating scales) using statistical inference. In rehabilitation medicine, the latent variable of primary interest is the patient's functional ability. Functional ability can be estimated from observations of surrogate performance measures (e.g., speed and accuracy) or self-report of the difficulty the patient experiences performing specific activities. A theoretical framework borrowed from project management, called the Activity Breakdown Structure (ABS), guides the choice of activities for assessment, based on the patient's value judgments, to make the observations clinically meaningful. In the case of low vision, the functional ability measure estimated from Rasch analysis of activity difficulty ratings was discovered to be a two-dimensional variable. The two visual function dimensions are independent of physical limitations and psychological state. To explain outcome measures (latent variable estimated from difficulty ratings), a theory must be developed that explicitly defines how latent variables are related to the observed manifest variables and to each other. The latent variables are categorized as primary variables, which in the case of low vision are the two visual function dimensions, and as effect modifiers, which in the case of low vision are other physical and psychological latent traits of the patients that can influence the outcome measures. Interventions give rise to latent intervention effect variables that can alter the latent primary variables or independently affect the outcome measures. The latent effect modifier variables, in turn, can alter the latent intervention effect variables. Once developed and validated, a theory of this form will predict the rehabilitation potential of individual patients, i.e., the probability of obtaining criterion outcome measures given the observed state of the patient and the choice of interventions. PMID- 20847475 TI - Embedding measurement within existing computerized data systems: scaling clinical laboratory and medical records heart failure data to predict ICU admission. AB - This study employs existing data sources to develop a new measure of intensive care unit (ICU) admission risk for heart failure patients. Outcome measures were constructed from laboratory, accounting, and medical record data for 973 adult inpatients with primary or secondary heart failure. Several scoring interpretations of the laboratory indicators were evaluated relative to their measurement and predictive properties. Cases were restricted to tests within first lab draw that included at least 15 indicators. After optimizing the original clinical observations, a satisfactory heart failure severity scale was calibrated on a 0-1000 continuum. Patients with unadjusted CHF severity measures of 550 or less were 2.7 times more likely to be admitted to the ICU than those with higher measures. Patients with low HF severity measures (550 or less) adjusted for demographic and diagnostic risk factors are about six times more likely to be admitted to the ICU than those with higher adjusted measures. A nomogram facilitates routine clinical application. Existing computerized data systems could be programmed to automatically structure clinical laboratory reports using the results of studies like this one to reduce data volume with no loss of information, make laboratory results more meaningful to clinical end users, improve the quality of care, reduce errors and unneeded tests, prevent unnecessary ICU admissions, lower costs, and improve patient satisfaction. Existing data typically examined piecemeal form a coherent scale measuring heart failure severity sensitive to increased likelihood of ICU admission. Marked improvements in ROC curves were found for the aggregate measures relative to individual clinical indicators. PMID- 20847476 TI - Implementing computerized adaptive tests in routine clinical practice: experience implementing CATs. AB - This paper traces the development, testing and use of CATs in outpatient rehabilitation from the perspective of one proprietary international medical rehabilitation database management company, Focus On Therapeutic Outcomes, Inc. (FOTO). Between the FOTO data in the United States and Maccabi Healthcare Services data in Israel, over 1.5 million CATs have been administered. Using findings from published studies and results of internal public relations surveys, we discuss (1) reasons for CAT development, (2) how the CATs were received by clinicians and patients in the United States and Israel, (3) results of psychometric property assessments of CAT estimated measures of functional status in routine clinical practice, (4) clinical interpretation of CAT functional status measures, and (5) future development directions. Results of scientific studies and business history provide confidence that CATs are pertinent and valuable to clinicians, patients and payers, and suggest CATs will be prominent in the development of future integrated computerized electronic medical record systems with electronic outcomes data collection. PMID- 20847477 TI - The use of PROMIS and assessment center to deliver patient-reported outcome measures in clinical research. AB - The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed as one of the first projects funded by the NIH Roadmap for Medical Research Initiative to re-engineer the clinical research enterprise. The primary goal of PROMIS is to build item banks and short forms that measure key health outcome domains that are manifested in a variety of chronic diseases which could be used as a "common currency" across research projects. To date, item banks, short forms and computerized adaptive tests (CAT) have been developed for 13 domains with relevance to pediatric and adult subjects. To enable easy delivery of these new instruments, PROMIS built a web-based resource (Assessment Center) for administering CATs and other self-report data, tracking item and instrument development, monitoring accrual, managing data, and storing statistical analysis results. Assessment Center can also be used to deliver custom researcher developed content, and has numerous features that support both simple and complicated accrual designs (branching, multiple arms, multiple time points, etc.). This paper provides an overview of the development of the PROMIS item banks and details Assessment Center functionality. PMID- 20847478 TI - Opportunities for CAT applications in medical rehabilitation: development of targeted item banks. AB - Researchers in the field of rehabilitation medicine have increasingly turned to qualitative data collection methods to better understand the experience of living with a disability. In rehabilitation psychology, these techniques are embodied by participatory action research (PAR; Hall 1981; White, Suchowierska, and Campbell 2004), whereby researchers garner qualitative feedback from key stakeholders such as patients and physicians. Glaser and Strauss (1967) and, later, Strauss and Corbin (1998) have outlined a systematic method of gathering and analyzing qualitative data to ensure that results are conceptually grounded to the population of interest. This type of analysis yields a set of interrelated concepts ("codes") to describe the phenomenon of interest. Using this data, however, becomes somewhat of a methodological problem. While this data is often used to describe phenomena of interest, it is challenging to transform the knowledge gained into practical data to inform research and clinical practice. In the case of developing patient-reported outcomes (PRO) measures for use in a rehabilitation population, it is difficult to make sense of the qualitative analysis results. Qualitative feedback tends to be open-ended and free-flowing, not conforming to any traditional data analysis methodology. Researchers involved in measure development need a practical way to quantify the qualitative feedback. This manuscript will focus on a detailed methodology of empiricizing qualitative data for practical application, in the context of developing targeted, rehabilitation-specific PRO measures within a larger, more generic PRO measurement system. PMID- 20847479 TI - Postscript: emergence of efficiency in health outcomes measurement. AB - The purpose of this postscript is to comment on psychometric issues raised by the collective articles of this special issue of the Journal of Applied Measurement. Topics discussed include the need to engage relevant literature in the psychometric and larger academic communities, the role of measurement models in psychometrics, and challenges to efficient measurement of patient reported outcomes. Finally, I argue that psychometrics should play "second fiddle" to larger scientific questions. PMID- 20847480 TI - Beta cell dysfunction and its clinical significance in gestational diabetes. AB - The aim of this study is to explore beta cell dysfunction and its clinical significance in gestational diabetes mellitus (GDM). We assessed insulin sensitivity and insulin secretion in a total of 277 Japanese women between 24 and 27 weeks of pregnancy who underwent a 2 h, 75 g oral glucose tolerance test (OGTT) because of an abnormal result on a 1 h 50 g oral glucose challenge conducted as part of a standard screening for GDM. Insulin sensitivity was evaluated by an insulin sensitivity index derived from OGTT (IS(OGTT)), whereas insulin secretion was calculated as a ratio of the total area under the insulin curve to the total area under the glucose curve (AUC(ins/glu)). Beta cell function in relation to insulin sensitivity (i.e. disposition index) was derived from the product of insulin sensitivity and insulin secretion (i.e. AUC(ins/glu) * IS(OGTT)). In women diagnosed with GDM (n=57), the disposition index was significantly lower than that in those without GDM, irrespective of obesity. The disposition index in women with GDM was significantly correlated with levels of fasting and mean preprandial capillary glucose and HbA1c before initiating insulin therapy (r = -0.45, -0.38, -0.49, respectively). Furthermore, there was a significant correlation between the disposition index and total insulin dosage to achieve glycemic goal (r = -0.41). In conclusion, we demonstrated beta cell dysfunction in Japanese women with GDM irrespective of obesity. The level of beta cell dysfunction in GDM was associated with the severity of glucose intolerance and total insulin dosage required. These findings underpin clinical significance of beta cell dysfunction in GDM. PMID- 20847482 TI - [Model core curriculum and geriatrics education in medical school]. PMID- 20847481 TI - [Should the elderly patients undergo additional surgery after non-curative endoscopic resection?]. AB - BACKGROUND & AIMS: Endoscopic resection, including endoscopic mucosal dissection (ESD), has gained acceptance widely for early gastric cancer (EGC). However, after therapy, some elderly patients with non-curative resection do not undergo radical surgery, because elderly patients may have limited life expectancy or comorbid disease. The aim of this study is to verify if radical surgery after non curative resection should be performed in the elderly patients as in young patients. METHODS: This is a retrospective review of 432 elderly patients (over 75 years) who had undergone enodscopic resection for EGC at the National Cancer Center Hospital between January 1999 and December 2005. We compared the overall and disease-free survival rate between the curative resection group, non-curative resection with surgery group, and non-curative resection without surgery group. RESULTS: A significant difference in overall and disease-free survival was evident between the patients with curative resection and non-curative resection without surgery. CONCLUSIONS: In the patients with non-curative resection for ECG endoscopically, additional surgery is still necessary even in elderly patients. PMID- 20847483 TI - [Board-certified medical specialties in Japan]. PMID- 20847484 TI - [Medical practice of dementia needed for caring on the job: from the aspect of practice in group home]. PMID- 20847485 TI - [Treatment of BPSD]. PMID- 20847486 TI - [Current situation of medical resources and services required for dementia]. PMID- 20847487 TI - [National study on acceptance by Japanese nursing homes of patients with feeding tubes]. AB - AIM: This study describes the acceptance of patients with feeding tubes in nursing homes for the elderly. METHODS: We sent questionnaires to 1,438 nursing homes in 2006-7 asking how many patients with feeding tubes the nursing homes had and how many new patients with feeding tubes they would accept in the future. RESULTS: The response rate was 63.6%. We analyzed the data of 735 nursing homes. The median range (25-75%) of the number of patients, patients accepted, and total number of patients currently resident was determined. The percentage of tube feedings to total beds in those categories was 8.0% (range 4.0-13.3), 5.0% (0 10.0), and 13.3% (8.0-23.8), respectively. Whereas 6% of the nursing homes had no limits on acceptance of patients with feeding tubes, 27.2% of the nursing homes replied that they would no longer accept such patients. Factors associated with restricted acceptance included nurse responses (odds ratio (OR) 0.54, 95% confidence interval (CI) 0.30-0.95), a facility with over 100 beds (OR 2.14, 95% CI 1.10-4.17), and no current patients with feeding tubes (OR 4.19, 95% CI 2.36 7.43). CONCLUSION: One quarter of nursing homes for the elderly in Japan replied that they would no longer accept patients with feeding tubes. More nurses than other professionals replied that they would accept patients with feeding tubes. Larger nursing homes were less likely to accept tube-feeing patients. Furthermore, nursing homes with no tube-feeding patients were unwilling to accept such patients. PMID- 20847488 TI - [Relationship between quality of life and chronic illnesses in community-dwelling elderly people]. AB - AIM: Chronic illnesses are common among elderly people, and may considerably affect to their quality of life (QOL). We investigated the impact of chronic conditions on QOL among community-dwelling elderly people, and the stability of QOL over time. METHODS: A total of 2,762 community-dwelling elderly persons (men: 47.0%, age 76.7+/-5.8 [mean+/-SD]) completed postal QOL questionnaires twice over 4 years. Chronic illnesses were selected from the following 9 conditions: cerebrovascular disease, hypertension, heart disease, cancer, diabetes mellitus, bone fracture, chronic digestive disease, chronic respiratory disease, and the diseases of joints or muscles. The QOL questionnaire was developed based on the QOL components proposed by Lawton, and consisted of 6 subscales: daily activity, health satisfaction, human support satisfaction, economic state satisfaction, symptoms of depression, and positive mental attitude. The subjects were divided into 3 groups regardless of the presence of chronic illnesses. QOL subscale scores were compared among the 3 groups, and fluctuations over 4 years were also evaluated. RESULTS: The baseline QOL scores showed significant differences among the 3 groups, especially regarding health satisfaction, but not in satisfaction with human support. There were significant differences among the 3 groups in fluctuations over 4 years in health satisfaction, daily activity, and positive mental attitude. CONCLUSIONS: Chronic illnesses have a negative impact on the QOL of elderly people, and also influence fluctuations in QOL over time. Degrees of impacts differed according to each QOL subscale. Therefore, evaluation of QOL in community-dwelling elderly needs multi-dimensional assessment. PMID- 20847489 TI - [Attitudes towards family caregiving of people with dementia among the general public in Japan: scale development and validation]. AB - AIM: To develop a scale for attitudes towards family caregiving of people with dementia among the general public in Japan. METHODS: We conducted a postal self administered questionnaire survey in a sample of the general population aged 20 and over: there were 2,161 (86%) valid responses. Question items in the survey included sociodemographic characteristics, attitude towards family caregiving for people with dementia, and the following three variables associated with dementia and caregiving: respondents' personal anxiety about developing dementia, their knowledge about the Long-Term Care insurance service, and their experiences of caregiving. RESULTS: Factor analysis revealed the following four subscales within this scale: feelings of obligation towards family caregiving (F1), expected feelings of caregiving burden (F2), expectation of personal growth through family caregiving (F3), and negative attitudes towards family caregiving (F4). The Cronbach alpha coefficients for these four subscales ranged from 0.73 to 0.82. In addition, analysis of covariance (ANCOVA), with sociodemographic characteristics as covariates, showed significant relationships (1) between personal anxiety about developing dementia and both F1 and F2, (2) between personal experience of caregiving and F3, and (3) between each of the three variables associated with dementia and caregiving and F4. CONCLUSIONS: The present study confirmed the reliability and validity for the scale of attitudes towards family caregiving of people with dementia among the general public in Japan. PMID- 20847490 TI - [Factors affecting falls self-efficacy of home-bound elderly people]. AB - AIM: Falling is one of the most common health hazards for the elderly. Tinetti et al. (1990) proposed the concept of falls self-efficacy, which explored fear of falling from the perspective of self-efficacy. Falls self-efficacy and its associated factors have not been extensively studied in Japan. This study examined the impact of various factors associated with daily life on falls self efficacy. METHODS: We conducted individual interviews with 180 elderly participants (men=93; women=87) on topics such as falls self-efficacy, perceived health status, and time spent on physical activities. RESULTS: Multiple linear regression analysis revealed that the main factors influencing falls self efficacy were perceived health status, past experience of falling, age, chronic pain, average time spent sitting during a weekday, and moderate or vigorous physical activity time per week. Falls self-efficacy was not significantly associated with gender, human environment, recent falling of acquaintances, or walking time per week. CONCLUSIONS: The results indicated that moderate or vigorous physical activity could enhance falls self-efficacy. Moreover, past falling experiences were negatively associated with falls self-efficacy, whereas perceived health status and chronic pain had a significant impact. Future fall prevention programs should adopt a multifactorial approach that focuses on enhancing falls self-efficacy. PMID- 20847491 TI - [Two cases of acquired hemophilia A in elderly patients]. AB - Acquired hemophilia A is a rare bleeding diathesis caused by autoantibodies against clotting factor VIII. The incidence of acquired hemophilia A increases with age. We report two cases of acquired hemophilia A in elderly patients and their clinical characteristics. Case 1: A 66-year-old man was referred to our hospital with massive subcutaneous and intramuscular hemorrhage. Prolonged APTT, low factor VIII activity and factor VIII inhibitor with high titer (42 BU/ml ) were observed, confirming the diagnosis of acquired hemophilia A. His hemorrhages disappeared soon after 50 mg/day oral prednisolone was administered. Although early steroid withdrawal lead to repeated prolongation of APTT, the addition of 20 mg/day oral prednisolone successfully decreased the inhibitor titer. The underlying disease was not identified. Case 2: An 85-year-old man with advanced gastric cancer was referred to our division because of severe bleeding. His factor VIII inhibitor titer was 64 BU/ml . Activated prothrombin complex concentrates were used to control the bleeding. Initially, he did not seem to respond to 20 mg/day oral prednisolone, but a further 12 weeks of 20 mg/day prednisolone finally achieved normalization of his hemostatic parameters. Subsequently, he successfully underwent surgery for cancer. The responses to immunosuppressive therapy were very different in the two cases, probably because of the difference in the underlying diseases. The immunosuppressive therapy of acquired hemophilia A should be strictly tailored to the patient's characteristics to minimize treatment-related adverse effects. PMID- 20847492 TI - [Proposal concerning personalized nutritional guidance]. PMID- 20847494 TI - Recent development of molecular-targeted drugs in lung cancer. AB - Numerous molecular target drugs have been introduced for the treatment of advanced malignancies. In the treatment of lung cancer, epidermoid growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) demonstrate striking antitumor activity in selected EGFR mutation positive patients. Patient selection by biomarker is extremely important to obtain successful results. The anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, shows a markedly increased response rate, progression free survival of advanced non-squamous cell lung cancer when combined with cytotoxic drugs. The classification of lung cancer is rapidly changing based on the advances in molecular biology. Here, the recent development of new molecular target drugs against lung cancer is thoroughly reviewed in addition to EGFR-TKIs and bevacizumab with special emphasis on the clinical application. PMID- 20847495 TI - Efficacy and safety of therapeutic ERCP for the elderly with choledocholithiasis: comparison with younger patients. AB - OBJECTIVE: To clarify the efficacy and safety of therapeutic endoscopic retrograde cholangiopancreatography for the elderly with choledocholithiasis compared with younger patients. METHODS: Consecutive therapeutic ERCPs performed between 2005 and 2007 at our institution for 118 patients aged 80 years or older (group A) and 205 patients younger than 80 years old (group B) were retrospectively reviewed. Successful cannulation rate, complete stone clearance rate, complications and prognosis were compared between the two groups. RESULTS: Successful cannulation was achieved in 99.2% in group A versus 99.5% in group B. The complete stone clearance rate was significantly lower in group A than in group B (92.4% versus 99.0%, p<0.01). Plastic stent placement was performed for patients with incomplete duct clearance. There was no significant difference in the early complication rate between group A (5.5%) and group B (6.6%). Procedure related mortality did not occur. Cholangitis-free survival was similar between the two groups. The short-term prognosis was comparable between those with complete duct clearance and those with biliary stent placement. CONCLUSION: With a duct clearance rate of more than 90% and plastic stent placement for patients with poor general condition, therapeutic ERCP for choledocholithiasis in patients 80 years of age or older is comparable in safety and effectiveness to that in younger patients. PMID- 20847496 TI - Fibrinogen/fibrin degradation products in acute aortic dissection. AB - BACKGROUND: The elevated D-dimer value is one of the clues used to diagnose acute aortic dissection (AAD), but the rapid D-dimer assay is not used at all emergency hospitals. The fibrinogen/fibrin degradation products (FDP) value is also an indicator of enhanced fibrinolysis and may therefore be a useful marker in patients with AAD. In addition, the association between FDP values and partial thrombosis of the false lumen is not elucidated. PATIENTS: The present study enrolled 50 patients (66.5+/-11.2 years of age; median, 66.5 years of age, male subjects comprised 60.0% of the series) with AAD who were admitted to the hospital between July 2005 and December 2007 and 57 patients with acute myocardial infarction (AMI; 70.8+/-10.4 years of age; median, 71.0 years of age, male subjects comprised 71.9% of the current series) served as a control group. RESULTS: The FDP values (ug/mL) in patients with AAD were significantly higher than those of AMI patients (40.2+/-78.6; median, 14.7 vs. 5.2+/-9.8; median, 1.7, p<0.001). A receiver operating characteristic curves analysis showed that an elevated FDP level (2.05 ug/mL) was predictive of a diagnosis of AAD with a sensitivity and specificity of 98% and 54%, respectively. The FDP levels of patients (n=14) who had partial thrombosis of the false lumen were significantly higher than in discharged patients without a surgical repair (n=21) who had a patent or complete thrombosis of the false lumen (35.8+/-43.2; median, 18.8 vs. 14.0+/-21.3; median, 5.5, p=0.01). CONCLUSION: The measurement of FDP may therefore be useful for the initial assessment of patients with suspected AAD and in the prediction of thrombotic status of the false lumen. PMID- 20847497 TI - Progression of pneumoconiosis in coal miners after cessation of dust exposure: a longitudinal study based on periodic chest X-ray examinations in Hokkaido, Japan. AB - BACKGROUND: The progression rate of pneumoconiosis in retired coal miners over ten years has not been studied in Japan. METHODS: A retrospective longitudinal study was undertaken using chest X-rays of 1091 pneumoconiosis subjects in Hokkaido, Japan between 1985 and 2005. RESULTS: The final numbers of subjects were 207 (19% of the entry) after 1 decade and 85 (8%) after 2 decades. Sixty-two percent of 207 subjects after 1 decade and 29% of 85 showed progression in 2 decades. Thirty-one percent of ILO category 1 and 55% of category 2 subjects showed progression to complicated pneumoconiosis after 1 decade, and 6% (4 of 64) of category 1 and 6% (5 of 77) of category 2 subjects progressed to complicated pneumoconiosis during 2 decades. CONCLUSION: The progression of pneumoconiosis was observed after the cessation of dust exposure, especially during the first 10 years. PMID- 20847498 TI - Isolation of Candida species is an important clue for suspecting gastrointestinal tract perforation as a cause of empyema. AB - BACKGROUND: Empyema due to Candida species is a rare entity, and the significance of isolation of Candida species from the pleural effusion is not fully understood. OBJECTIVE: To elucidate the clinical features of Candida empyema. METHODS: We retrospectively reviewed the cases of 128 patients with culture positive empyema. RESULTS: These 128 patients included 7 whose cause of empyema was esophago- or gastropleural fistula. Empyema was due to Candida species in 5 of the 7 patients. Primary diseases of these 5 patients were spontaneous esophageal rupture in 3 patients, esophageal rupture due to lung cancer invasion in 1 patient, and gastric ulcer perforation in 1 patient. None of these 5 patients had esophageal candidiasis. Among the 121 other patients with empyema not due to esophago- or gastropleural fistula, no patient had empyema due to Candida. CONCLUSION: We believe that the empyema in these 5 patients was caused by normal commensal Candida species entering the pleural cavity when the fistula between the gastrointestinal tract and pleural cavity was formed. Isolation of Candida species can be an important clue for suspecting gastrointestinal tract perforation as a cause of empyema. PMID- 20847499 TI - Measles-related hospitalizations and complications in Japan, 2007-2008. AB - OBJECTIVE: In the present study we aim to describe the clinical features and related complications of severe measles requiring hospitalization in Japan in 2007 and 2008. METHODS: We extracted the records of patients diagnosed with measles between July and December in 2007 and 2008 from the Diagnosis Procedure Combination (DPC) inpatient database and the verified age distribution of patients with measles requiring hospitalization and the rate of measles-related complications. We also examined the rate of measles patients who were pregnant or had malignancies. RESULTS: We identified 1,037 inpatients in 377 hospitals; 879 in 2007 and 158 in 2008. Overall, 554 (53.4%) were male. Patient age distribution showed two peaks; <=4 years (21%) and 15-29 years (45%). Ninety (8.7%) patients had pneumonia, 22 (2.1%) had encephalitis, 7 (0.7%) had intestinal complications, 7 (0.7%) had conjunctivitis, 6 (0.6%) had meningitis, and 4 (0.4%) had otitis media. Patients aged <=14 years were significantly more likely to have pneumonia (16.4%; p<0.001). The rate of encephalitis was relatively low in patients aged <=14 years (0.9%) compared with those aged 15-29 years (3.0%) and those aged >=30 years (2.0%); the difference was not statistically significant (p=0.141). Of 31 pregnant women, 10 had spontaneous abortion or stillbirth. Twenty-eight patients had malignancies. CONCLUSION: The present study adds important information to our knowledge of the clinical features of severe measles. Follow-up monitoring of the trends of this distressing disease using the DPC database will be essential. PMID- 20847500 TI - Community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction. Role of antibiotic combination of linezolid plus levofloxacin. AB - The therapeutic options available for central nervous system (CNS) infections due to resistant Gram-positive cocci remain limited. We report an unusual case of community-acquired methicillin-resistant Staphylococcus aureus meningitis complicated by cerebral infarction in the middle cerebral artery territory in a previously healthy young male. After an initial vancomycin-based regimen, treatment was completed with a seven-week course of linezolid and levofloxacin. The potential role of such a combination and, particularly, linezolid as a first line therapy in serious CNS infections is also discussed. PMID- 20847501 TI - Increase in internal defibrillation threshold during acute myocardial infarction. AB - A 67-year-old man suffered an acute anteroseptal myocardial infarction complicated by multiple episodes of ventricular fibrillation, which were not systematically defibrillated by maximum, internal 35-J shocks delivered by an implanted cardioverter defibrillator (ICD). He had suffered from acute inferior myocardial infarction 6 years earlier, complicated with sustained polymorphic ventricular tachycardia (VT). Due to inducibility of sustained VT on an electrophysiologic study, an ICD was implanted. Defibrillation testing performed after healing of anteroseptal infarction was successful with a 10-J safety margin, suggesting that acute myocardial ischemia transiently elevated the internal defibrillation threshold. PMID- 20847502 TI - Ischemia-induced prominent J waves in a patient with Brugada syndrome. AB - A 75-year-old man was admitted to our hospital in January 2010 for evaluation of syncope and abnormal ECG. ECG showed type 1 ST elevation in lead V(1) and he was diagnosed as Brugada syndrome. During cardiac catheterization, baseline coronary angiography was normal, but intracoronary ergonovine maleate induced spasms of the right and left coronary arteries concomitant with chest pain and ST elevation on ECG. J waves were accentuated or newly developed. Soon after an intracoronary injection of nitroglycerin, chest pain was relieved and ischemia-induced J wave disappeared and the ST segment returned to the same morphology as baseline. Extrastimuli induced ventricular fibrillation. He received an implantable cardioverter-defibrillator. He was also treated with Ca antagonist and isosorbide dinitrate and has had an uneventful course for 5 months. PMID- 20847503 TI - The usefulness of super-selective computed tomography angiography (CTA) for diagnosing and localizing a small insulinoma. AB - Localization of insulinomas by preoperative imaging is critical for successful surgical resection. However, the visualization and localization of small insulinomas by recent imaging modalities still remains a challenge. Here, we report a 77-year-old woman with a small insulinoma successfully localized by performing arterial stimulation and venous sampling (ASVS), and subsequent super selective CTA (SSCTA). It was not visualized by routine non-invasive imaging tests such as digital subtraction angiography (DSA). The small size (1.0 cm) of the surgically removed tumor supports the usefulness of SSCTA for localizing very small insulinomas. PMID- 20847504 TI - A case of type 1 diabetes onset and recurrence of Graves' disease during pegylated interferon-alpha plus ribavirin treatment for chronic hepatitis C. AB - We report a case of type 1 diabetes onset and recurrence of Graves' disease during pegylated interferon (PEG-IFN)-alpha plus ribavirin treatment for chronic hepatitis C. The patient was a 55-year-old woman diagnosed with chronic hepatitis at age 46 years. She was treated for Graves' disease at 50 years of age. Because Graves' disease remitted, PEG-IFN-alpha plus ribavirin treatment was started for chronic hepatitis C. She was examined because of complaints of general fatigue, weight loss, and palpitations after 24 weeks of the treatment. She was diagnosed with a recurrence of Graves' disease, and methimazole treatment was started. However, she complained of malaise, thirst, polyuria, and loss of body weight. Her fasting blood glucose level was 292 mg/dL and HbA1c was 9.3%. Serum anti-GAD (glutamic acid decarboxylase) antibodies were 2.2 U/mL. She was diagnosed with type 1 diabetes with ketosis, and insulin treatment was started. Serum anti-GAD antibodies gradually increased to 15.1 U/mL. Graves' disease and type 1 diabetes are often complicated, and the coincidental occurrence of these 2 diseases is known as autoimmune polyglandular syndrome type III. However, only a few cases have shown that these diseases occur after IFN treatment. PMID- 20847505 TI - Respiratory failure with myxedema ascites in a patient with idiopathic myxedema. AB - Here we report the case of a 50-year-old woman presenting with weight gain, whole body edema, and massive ascites. Blood examination revealed primary hypothyroidism with TSH-blocking antibody, and the echocardiogram showed diffuse hypokinesis of the left ventricle with pericardial effusion. Although she received thyroid hormone replacement therapy immediately, her ascites increased and she developed type II respiratory failure requiring transient noninvasive positive pressure ventilation (NIPPV). She recovered following the temporary drainage of the ascites, administration of diuretics, and continuous thyroid hormone replacement. The amount of ascites decreased during therapy, along with an increase in thyroid hormone levels. Finally, the ascites disappeared completely, followed by the normalization of the cardiac wall motion. Herein we report this rare case in detail, and also discuss the mechanism by which primary hypothyroidism induced such severe conditions in our patient. PMID- 20847506 TI - Small cell lung cancer complicated by pulmonary sarcoidosis. AB - In July 2009, a 69-year-old man was admitted to our hospital because an abnormal chest shadow had been noted on medical examination. Chest radiography and computed tomography showed mediastinal and bilateral hilar lymphadenopathy. Bronchoalveolar lavage fluid (BALF) from the right B(5) revealed an increased CD4/CD8 ratio. Histological examination of the biopsy specimens obtained from the tumor in the left upper bronchus revealed small cell lung cancer, whereas examination of the specimens obtained from the left B(3) revealed noncaseating epithelioid cell granulomas containing giant cells, confirming the diagnosis of sarcoidosis. The patient underwent chemotherapy with carboplatin and etoposide without any steroids. After 4 courses of chemotherapy, bronchoscopic examination revealed that the tumor had shrunk, and the BALF CD4/CD8 ratio had decreased; further, no histological evidence of sarcoidosis was seen in specimens obtained from the left B(3). Concomitant small cell lung cancer and sarcoidosis is rare. Interestingly, cancer chemotherapy might improve pulmonary sarcoidosis. PMID- 20847507 TI - Paradoxical brain embolism induced by Mycoplasma pneumoniae infection with deep venous thrombus. AB - A 21-year-old man had sudden-onset right hemiplegia and aphasia with respiratory infection. A chest X-ray disclosed consolidation in both lungs and magnetic resonance imaging showed an embolism in the left middle cerebral artery. A pelvic computed tomography scan revealed deep venous thrombus in both femoral veins. Patent foramen ovale was detected by transesophageal echocardiogram. Antibodies to M. pneumoniae were highly elevated, and hypercoagulability was subsequently detected. This case suggests that the possible pathogenic mechanism for M. pneumoniae infection-related stroke might be paradoxical brain embolism with deep venous thrombus as a consequence of the hypercoagulability related to this infection. PMID- 20847508 TI - A case of lymphomatoid granulomatosis-like lung lesions with abundant infiltrating IgG4-positive plasma cells whose serum IgG4 levels became high following the start of corticosteroid therapy. AB - A 59-year-old man with a history of prostate hyperplasia was admitted to our hospital for further examination of a lung mass and renal dysfunction. Lung biopsy specimens revealed that inflammatory cells had infiltrated into the blood vessel walls. We initially suspected lymphomatoid granulomatosis, but Epstein Barr virus-encoded small RNA was negative. However, 50% of the infiltrating plasma cells were positive for IgG4. Furthermore, the kidneys and prostate contained abundant IgG4-positive plasma cells. He was diagnosed with IgG4-related sclerosing disease even though serum IgG4 levels were not elevated (45.7 mg/dL). Prednisolone reduced the lung masses and ameliorated renal function, but the serum IgG4 level increased (377 mg/dL). Seronegative IgG4-related sclerosing disease should be considered when patients present with such symptoms and treatment responses, and the secretion of IgG4 might be blocked by its active synthesis. PMID- 20847509 TI - Idiopathic portal hypertension in a patient with mixed connective tissue disease and protein C deficiency. AB - We report a 29-year-old woman with a 2.5 year history of mixed connective tissue disease (MCTD) who developed idiopathic portal hypertension (IPH) and thrombocytopenia as a result of hypersplenism. She had recurrent esophagogastric variceal rupture. Hematological examination also revealed low levels of protein C activity. The liver biopsy specimen showed non-specific mild inflammation and no thrombi. However, portal vein thrombosis developed after splenectomy. This was a rare case of severe complications of IPH accompanying MCTD and protein C deficiency. PMID- 20847510 TI - Liver abscess of Actinomyces israelii in a hemodialysis patient: case report and review of the literature. AB - We had encountered a 74-year-old woman on hemodialysis therapy suffering from liver abscess of Actinomyces israelii. Percutaneous drainage of the abscess before starting antimicrobial therapy followed by correct microbiological identification and susceptibility test led us to determine long treatment with ampicillin and to a successful outcome. Periodontitis was thought to be a possible entry of actinomyces. Hepatic actinomycosis should be recognized as one of the important infectious diseases among patients of end-stage renal disease. PMID- 20847511 TI - Asymptomatic migration of a sirolimus-eluting stent into the aorta. PMID- 20847512 TI - Crowned dens syndrome mimicking meningitis. PMID- 20847513 TI - An isolated horizontal-gaze paresis in a patient with pontine infarction. PMID- 20847514 TI - Reversible cognitive impairment in hypertensive encephalopathy. PMID- 20847515 TI - Multiple cerebral aneurysms caused by HIV-associated vasculopathy. PMID- 20847516 TI - Diarrhea induced by infection of Vibrio parahaemolyticus. AB - Vibrio parahaemolyticus is a human pathogen that naturally inhabits marine and estuarine environments. Infection with V. parahaemolyticus is often associated with the consumption of raw or undercooked seafood, causing gastroenteritis with watery diarrhea. The presence of two type III secretion system (T3SS) proteins, thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH), has been closely associated with the severity of diarrheal illness. TDH and TRH have various biological activities including hemolytic activity, cardiotoxicity, and enterotoxicity. T3SS1 is involved in cytotoxicity to host cells and orchestrates a multifaceted host cell infection by induction of autophagy, cell rounding, and cell lysis. T3SS2 is thought to be related to the enterotoxicity of V. parahaemolyticus. The activities of inducing diarrhea of each of the virulence factors were summarized in this review. PMID- 20847517 TI - Are lectin positive spherical deposits detected in the molecular layer of the hippocampal formation related with neuronal apoptosis? AB - Previously, multi-lectin positive spherical shaped deposits were detected in the hippocampal formation of degenerative demented and schizophrenic brains and reported they possessed some possibility as a predominant tool of postmortem diagnosis, more detected in schizophrenia cases than age-matched control cases. Multi-fluorescent immunohistochemical and lectin histochemical method and immuno electron microscope method were performed on 51 forensic autopsied brains containing 16 cases of schizophrenia. In multi-fluorescent staining, partial disrupted nucleus with decreased staining properties by mean of SYBR green were detected, and lectin and single strand DNA were co-stained in the portion of partial disrupted nucleus. In immuno electron microscope method, lectin positive structures were also detected in the portion of partial disrupted nucleus. These neurons were suspected in the process of apoptosis by their distinguishable features. Some experimental studies were reported that a kind of therapeutic products of major tranquillizers induced neuron apoptosis in dentate gyrus. As the lectin positive spherical shaped deposits were detected in not only 5 schizophrenia cases without drug treatment but also in 11 schizophrenia cases with drug treatment in this study, they might be detected as the intrinsic pathological change of schizophrenia. The lectin positive spherical shaped deposits detected in the hippocampal formation were suspected as the histopathological marker of the postmortem diagnosis for schizophrenia. Further examination for specifying group of neurons detected them in and initiated apoptosis are necessitated. PMID- 20847518 TI - Intensive insulin therapy during cardiovascular surgery. AB - Recent evidence in the fields of surgery, emergency and critical care medicine indicates that strict glycemic control results in lower mortality. Hyperglycemia occurs frequently in patients with and without diabetes during cardiovascular surgery, especially during cardiopulmonary bypass. However, strict glucose control is difficult to achieve during cardiovascular procedures. To establish effective intensive insulin therapy during cardiovascular surgery, we conduct continuous blood glucose monitoring and employ automatic control by using an artificial endocrine pancreas (the STG-22, Nikkiso, Tokyo, Japan). In this review, we will outline the present status and problems of conventional glycemic control for perioperative cardiovascular surgery and introduce the new perioperative blood glucose management method that we are testing now. We will also discuss the importance of perioperative glycemic control for cardiovascular surgery as well as future prospects. PMID- 20847519 TI - Basic study of a diagnostic modality employing a new electrical impedance tomography (EIT) method for noninvasive measurement in localized tissues. AB - The objective of this study is to develop a device for noninvasive local tissue electrical impedance tomography (EIT) using divided electrodes with guard electrodes and to validate its effectiveness using bioequivalent phantoms. For this purpose, we prepared a measurement device and bioequivalent phantoms, measured the electrical characteristics of the phantoms, and validated the method using the phantoms. Monolayer phantoms mimicking the brain and muscle and bilayer phantoms consisting of muscle and brain layers were prepared. The relative differences between the measured electrical conductivities of the monolayer brain and muscle phantoms and the true values determined by the 4-electrode method were both less than 10%. The relative differences between the measured and true values in the bilayer phantoms were less than 20% in both layers. The biological impedance measurement device that we developed was confirmed to be effective for impedance measurement in bilayer phantoms with different electrical impedances. To develop a device for the early diagnosis of breast diseases, the development of a multi-layer phantom and demonstration of the effectiveness of the device for its examination are necessary. If the device that we developed makes impedance measurement in breast tumors possible, it may be used as a new diagnostic modality for breast diseases. PMID- 20847520 TI - Identification of important regulatory region of Th-POK. AB - CD4(+) and CD8(+) T cells develop from CD4(+)CD8(+) thymocytes. Although it has been reported that expression of the transcription factor Th-POK is important for CD4(+) T cell development, the detailed mechanism regulating Th-POK expression is still obscure. By comparing the promoter regions of the Th-POK gene between human and mouse, I found that the region 3600 base pairs (bps) upstream from the transcription initiation site of the Th-POK gene was highly conserved. To identify the important element(s) regulating Th-POK expression in CD4(+) T cells, I investigated the promoter activity of this region using a luciferase assay in the human T cell line Jurkat. I identified a positive regulatory element in this region 22 bps in length located 600 bp upstream from the transcription initiation site. This 22 bp element had a consensus binding sequence for SAP-1, which is encoded by the Elk4 gene and is activated by the Erk pathway. These data suggest that the 22 bp element might positively regulate Th-POK expression through Erk SAP-1 signaling. PMID- 20847521 TI - Long-term treatment with hyperbaric air improves hyperlipidemia of db/db mice. AB - Hyperbaric air (HBA) is used to improve healing of wounds including diabetic ulcer. The aim of this study was to clarify the effects of HBA exposure on lipid and glucose metabolism in db/db mice. HBA did not influence the weight of db/db mice. Serum levels of free fatty acid and triglyceride, but not glucose and insulin, were significantly decreased after 6 weeks of treatment with HBA. The mRNA expressions of CPT-1, PPARalpha and PGC-1alpha genes, which are related to lipid metabolism, were significantly up-regulated in the muscle and liver. Increases in TNFalpha and MCP1 mRNA, which impaired lipid metabolism, were also attenuated by HBA treatment. These results suggest that exposure of HBA could have beneficial effects on lipid metabolism in patients with type 2 diabetes mellitus. PMID- 20847522 TI - Vascular endothelial growth factors and their receptors in the novel human cell line, HN-Eso-1, established from esophageal spindle cell carcinoma. AB - Human carcinosarcomas of esophagus are uncommon malignant neoplasms that are composed both carcinomatous and sarcomatous components. We established a novel cell line, HN-Eso-1, from the metastatic esophageal spindle cell carcinoma (so called carcinosarcoma). In this study, we estimated the vascular endothelial growth factors (VEGFs) and VEGF receptors (VEGFRs). Reverse transcription polymerase chain reaction (RT-PCR) studies revealed that VEGF-A, -C, -D and VEGFR 1, -2 were upregulated. Cisplatin reduced the cell viability of HN-Eso-1 cells and VEGF attenuated its effect. These results suggest that expression of VEGF-A, VEGF-C, VEGF-D, VEGFR-1, and VEGFR-2 are involved in the cell's autocrine system and that VEGF protected these cells from the anti-tumor agent. PMID- 20847523 TI - Effects of ketamine on nicorandil induced ATP-sensitive potassium channel activity in cell line derived from rat aortic smooth muscle. AB - PURPOSE: Nicorandil opens adenosine triphosphate-sensitive potassium (K(ATP)) channels in the cardiovascular system and is being increasingly used for the treatment of angina pectoris. In the present study, we tested whether intravenous anesthetic agent ketamine affected nicorandil-induced native vascular K(ATP) channel activation. METHODS: We used excised inside-out patch clamp configurations to investigate the direct effects of ketamine racemate and S-(+) ketamine on the activities of K(ATP) channels in cultured rat aortic smooth muscle cells. Furthermore, we also investigated whether intracellular MgADP could modulate ketamine inhibition. RESULTS: Nicorandil significantly activated K(ATP) channel activity, whereas this channel activity was completely blocked by glibenclamide, a specific K(ATP) channel blocker. Ketamine racemate inhibited the nicorandil induced K(ATP) channel activity (IC(50)=34+/-1 uM, n=14), but S-(+) ketamine was less potent than ketamine racemate in blocking nicorandil induced K(ATP) channel activities (IC(50)=226+/-7 uM, n=10). Application of MgADP to the intracellular side of the channel was able to decrease the inhibitory potency of ketamine racemate on nicorandil induced K(ATP) channel activities. CONCLUSIONS: Our results indicate that ketamine inhibits nicorandil induced K(ATP) channel activities in a dose dependent and stereoselective manner. Furthermore, increase of intracellular MgADP attenuates the inhibitory potency of ketamine racemate. J. Med. Invest. 57: 237-244, August, 2010. PMID- 20847524 TI - Development and application of a simple LC-MS method for the determination of plasma maraviroc concentrations. AB - Maraviroc is an orally available antagonist of the CCR5 chemokine receptor, which acts as a human immunodeficiency virus type 1 (HIV-1) coreceptor. Binding of maraviroc to this receptor blocks HIV-1 attachment to the coreceptor and prevents HIV-1 from entering host cells. Maraviroc does not require intracellular processing to exert this activity. Drug interaction studies have shown changes in maraviroc exposure when given with other anti-HIV medications, and thus quantification of maraviroc in human plasma is important to manage drug interactions and to evaluate the relationship between plasma concentrations and treatment response. We developed a conventional LC-MS method for determining plasma maraviroc concentrations, validated by estimating precision and accuracy for inter- and intraday analysis in the concentration range of 0.011-2.188 ug/ml. The calibration curve was linear within this range. The average accuracy ranged from 92.7% to 99.7%, while the relative standard deviations of both inter- and intraday assays were less than 7.1%. Recovery of maraviroc exceeded 86.7%. Our LC MS method provides a conventional, accurate and precise way to determine the maraviroc concentration in human plasma. This method enables dose adjustment based on monitoring plasma maraviroc concentrations and permits management of drug interactions and toxicity. PMID- 20847525 TI - The relation between the cancer screening rate and the cancer mortality rate in Japan. AB - The aim of this research was to clarify the relation between the screening rates for five cancers (lung cancer, stomach cancer, colorectal cancer, uterus cancer, and breast cancer) and their mortality rate by using publicly accessible databases. The used information materials were those prepared by the Ministry of Health, Labour and Welfare, the Center for Cancer Control and Information Services, and the National Cancer Center. Our results were as follows: 1) regarding stomach and colorectal cancers, a positive correlation was found between the screening rate and the mortality rate (p<0.001); 2) in the relation between the screening rate and the mortality rate according to administrative divisions, the mortality rate decreased significantly when the lung cancer screening rate improved (p<0.005); 3) the mortality rate for breast cancer increased in those aged 50 or over; 4) the mortality rate for uterus cancer had been slightly increasing since 1990; and 5) regarding the screening rate, a positive correlation was found between breast cancer and uterus cancer (p<0.001). In future, improvement in lifestyle and in the knowledge of cancer should be promoted to enhance the screening rates. PMID- 20847526 TI - A nocturnal decline of salivary pH associated with airway hyperresponsiveness in asthma. AB - Salivary pH is associated with esophageal acid reflux and neutralization of esophageal acid. In this study, we assessed the association between nocturnal decline of salivary pH and airway hyperresponsiveness. Salivary pH was serially assessed in 9 patients with mild asthma (7 men and 2 women; mean age 33.3 years; mean %predicted FEV(1.0) 89.4%) and 10 healthy volunteers (6 men and 4 women; mean age 31.2 years) using a pH indicator tape. The buffering capacity of saliva was defined as the median effective dose (ED(50)) for acidification of saliva with 0.01 N HCl, and airway responsiveness was defined as the dose of methacholine producing a 35% fall in Grs (PD(35)-Grs). There was a significant correlation between the values obtained from the pH indicator tape and those obtained from the electrometric pH meter. Using the indicator tape for sequential monitoring, we observed a nocturnal fall (DeltapH) in salivary pH in all subjects. A significant correlation was found between airway hyperresponsiveness (PD(35)-Grs) and either DeltapH or ED(50) in mildly asthmatic patients. Vagal reflux dysfunction might contribute to nocturnal salivary pH as well as to airway hyperresponsiveness in mild asthmatics. PMID- 20847527 TI - Relationship between FDG uptake and the pathological risk category in gastrointestinal stromal tumors. AB - PURPOSE: To evaluate (18)F-fluorodeoxyglucose (FDG) uptake and the pathological risk category of gastrointestinal stromal tumors (GISTs), and to investigate the possibility of determining the pathological risk category by positron emission tomography/computed tomography (PET/CT). PATIENTS AND METHODS: We undertook 29 PET/CT studies in 20 patients with GISTs. Eleven of the 20 patients underwent PET/CT prior to therapy, with three of these also undergoing follow-up PET/CT after operation or imatinib therapy. RESULTS: All eleven lesions imaged before treatment were FDG-positive on PET/CT. Seven of these eleven primary lesions were categorized as high risk and the other four primary lesions were categorized as low or intermediate risk. There was a significant difference between the maximum standardized uptake value (SUVmax) of the primary lesions categorized as high risk (11.8+/-3.15) and that of the primary lesions categorized as low and intermediate risk (2.88+/-0.47) (p<0.001). Recurrent tumors were also shown as FDG-positive. CONCLUSION: Primary GISTs and recurrent tumors can be detected by PET/CT. Our study suggests that the degree of FDG uptake is a useful indicator of risk category. In addition, PET/CT is probably useful for follow-up examinations of GIST after operation or imatinib therapy. J. Med. Invest. 57: 270-274, August, 2010. PMID- 20847528 TI - Utilization of titanium oxide-like compound as an inorganic phosphate adsorbent for the control of serum phosphate level in chronic renal failure. AB - Hyperphosphatemia adversely affects the prognosis of patients with chronic renal failure (CRF). We synthesized a titanium oxide-like compound (TAP) as a phosphate adsorbent for treatment of hyperphosphatemia in CFR patients. We evaluated the ability of TAP to adsorb inorganic phosphate in vitro and in vivo. TAP was shown to contain sulfate and hydroxyl groups by thermal analysis, which probably involved in phosphate adsorption through an ionic exchange mechanism. TAP constantly adsorbed phosphate (66.20-72.84 mg/g TAP) over a wide pH range (1.22 7.27) in vitro. To evaluate the phosphate binding potential of TAP in vivo, adenine-induced CRF rats were fed AIN-76 diet containing 3% TAP, 10% TAP, 3% sevelamer hydrochloride (clinical phosphate adsorbent), or 3% calcium carbonate, and serum levels of phosphate and calcium and urinary phosphate were compared with those in untreated CRF rats. Orally administered TAP showed the inhibitory effect on serum phosphate level in adenine-induced CRF rats, which was equivalent to that of sevelamer hydrochloride. These results indicate that TAP is a useful alternative phosphate-binder with fewer side effects than sevelamer hydrochloride and calcium carbonate. PMID- 20847529 TI - Growth ability in various macaque cell lines of HIV-1 with simian cell-tropism. AB - We have recently constructed a series of novel human immunodeficiency viruses (HIV-1s) that are tropic for a macaque cell line (mt; macaque cell-tropic) to generate and establish a primate experimental system for HIV-1/AIDS study. In order to determine biological properties of these viruses effectively, several other macaque cell lines with distinct characteristics that can be routinely and easily used, instead of primary cells, for infection experiments are required. In this study, we have examined four macaque cell lines for their surface expression of virus receptor molecules and for their genotype of a major anti-viral capsid gene. Furthermore, we monitored the susceptibility of the cell lines to a standard simian immunodeficiency virus (SIV) clone and three representative basic mt HIV-1 clones. Results obtained here have clearly indicated that these cell lines are exquisitely useful to characterize various SIVs and more importantly, mt HIV-1s. PMID- 20847530 TI - Illness experiences of patients with ischemic heart disease during their transitional phase from hospitalization to discharge in Japan. AB - The purpose of this study was to explore the experience of patients with ischemic heart disease (IHD) during the transitional phase from hospitalization to discharge. Twenty-four patients who experienced IHD for the first time comprised the sample of the study. Semi-structured interviews were conducted during the transitional phase. The results of the qualitative inductive analysis showed two categories of illness experience: (i) the connection of heart attack experience with the self, and (ii) the instability of the self as a patient with heart disease. The participants were found to vacillate between the self as patient with a heart disease and the typical self before the disease onset. The transitional phase is the time when patients experience changes in their symptoms and physical conditions rather than a condition of stability signifying recovery. Patients are expected to manage the symptoms of their heart disease by themselves; however the participants showed signs and symptoms of confusion and anxiety about facilitating their own care. These findings suggest the importance of outpatient nursing practice focusing on the support and emphasis on nursing interventions for patient anxiety and alleviation of confusion through the management of symptoms of heart disease after discharge. PMID- 20847531 TI - Diagnosis of the presence of lymph node metastasis and decision of operative indication using fluorodeoxyglucose-positron emission tomography and computed tomography in patients with primary lung cancer. AB - OBJECTIVES: We evaluate whether integrated fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT) scan can diagnose the presence of lymph node metastasis more accurately than computed tomography (CT) scan alone. METHODS: Forty-two patients with lung cancer preoperatively underwent integrated PET/CT scan using FDG and CT scan and underwent pulmonary resection and lymph node dissection. We judged cases as lymph node metastasis if the lymph node visually accumulated FDG at PET/CT scan and measured 1 cm or greater in the short axis at CT scan. We retrospectively analyzed whether our judgments in each modality were consistent with the pathological diagnosis. RESULTS: Two-hundred and seventeen stations of lymph node were dissected and 21 stations (9.7%) were histologically diagnosed as positive metastasis. Thirty-two stations of lymph node visually accumulated FDG at PET/CT scan and 17 stations measured 1 cm or greater in the short axis at CT scan. Concerning the diagnosis of lymph node metastasis, PET/CT scan showed significantly higher sensitivity than CT scan (81% vs. 48%, p=0.024). The false-positive rate was significantly high in PET-positive lymph nodes measuring less than 1 cm in diameter. There were 4 false-negative lymph nodes with both scans. All of these were less than 7 mm in diameter and had a low percentage of metastatic foci in the lymph node. Concerning the diagnosis of N staging, there was no significant difference between PET/CT scan and CT scan (83% vs. 69%, p=0.124). However, the identification of N2 disease at PET/CT scan was significantly more accurate than that at CT scan (100% vs. 38%, p=0.031). CONCLUSIONS: PET/CT is superior to CT scan in lymph node staging. However, because the false-positive rate is high in PET-positive lymph nodes measuring less than 1 cm in diameter, we think that clinical background should be considered and other modalities or histological examinations should be undertaken if necessary. J. Med. Invest. 57: 305-313, August, 2010. PMID- 20847533 TI - Resin splint as a new conservative treatment for ingrown toenails. AB - Several conservative as well as surgical methods are used for the treatment of ingrown toenails until date. The conservative methods are either based on nail splinting or on orthonyxia, but no methods employing both principles have been reported thus far. Moreover, surgical methods usually involve postoperative pain, prolonged wound healing and restricted activities of daily living. Therefore, considering the need of a simplified, non-invasive method, in this study, we applied a novel splint to treat patients with ingrown toenails and estimated the clinical efficacy as well as rate of recurrence following treatment. The splint is a plate made of resin that is attached to the lateral edge of the nail using a bandage. We studied 61 patients (19 men and 42 women; mean age 36 years), with an average application duration of 9.3 months and an average follow-up period of 10 months in all patients. All patients experienced pain relief within a week of splint application and a decrease in the degree of nail deformity. Moreover, follow-up revealed a recurrence rate of 8.2%. Therefore, we believe that this new device is an excellent conservative treatment method for patients with ingrown toenails. PMID- 20847532 TI - Protective effects of glycoglycerolipids extracted from spinach on 5-fluorouracil induced intestinal mucosal injury. AB - Glycoglycerolipids are mostly found in plants, however the beneficial effects of the glycoglycerolipids on mammalian body have not been understood. In this study, we investigated the effects of glycolipid extracts from spinach, which highly contained glycoglycerolipids, on mucosal injury induced by 5-fluorouracil (5-FU) in rats. Preadministration of glycolipid extracts from spinach (20 mg/kg body weight) prevented villous atrophy, misaligned crypts, and increased inflammatory cytokines in rat jejunum treated with 5-FU (300 mg/kg body weight) compared with the extracts from soybean. The glycolipid extracts from spinach highly contained monogalactosyl-diacylglycerol (MGDG) and diglactosyl-diacylglycerol (DGDG). In Caco-2 cells, MGDG and DGDG inhibited the production of reactive oxygen species induced by phorbol ester. We concluded that glycolipid extracts from spinach has anti-oxidative and anti-inflammatory effects, and the extract may be useful for prevention of drug-induced mucosal injury and other inflammatory diseases. Tokushima PMID- 20847534 TI - Epidemiological and clinical features of lung cancer patients from 1999 to 2009 in Tokushima Prefecture of Japan. AB - Lung cancer is the leading cause of malignancy-related death worldwide. In the present study, we reviewed the epidemiologic and clinical features of lung cancer in Tokushima Prefecture, Japan. Between January 1999 and December 2009, 2,183 patients with lung cancer were enrolled in this study. One thousand five hundred ninety-one (73%) patients were male and 592 (27%) patients were female. Median age was 70 years, with a range of 15-93 years. Seventy-six percent of patients had smoking history. One thousand nine hundred five (87%) patients were non-small cell lung cancer and the predominant histological type was adenocarcinoma (51%). Among all 2,183 patients, 702 (32%) belonged to elderly population. Four hundred seventy-one (22%), 213 (10%), 24 (1%), 116 (5%), 238 (11%), 370 (17%) and 678 (31%) patients had stage IA, IB, IIA, IIB, IIIA, IIIB and IV lung cancer, respectively. In Tokushima University Hospital, 516 (29%), 191 (11%), 58 (3%), 755 (43%) and 216 (12%) patients were initially treated with chemotherapy, chemo radiotherapy, thoracic radiotherapy, operation and best supportive care, respectively. The median time to progression (TTP) and the median survival time (MST) of patients treated with chemotherapy and chemo-radiotherapy were 3.5 months, 13.0 months and 7.0 months, 18.0 months, respectively. The median TTP and the MST of 33 elderly patients treated with chemotherapy were 3.3 months and 18.0 months, respectively, which were comparable with those of total population. These results indicated the benefit of chemotherapy in elderly patients with advanced lung cancer by proper selection. PMID- 20847535 TI - Embolic infarction followed by serial bone SPECT and MR fusion images--the door to SPECT/MR-. AB - We recently experienced a case of cerebral infarction incidentally found by whole body bone scintigraphy for the detection of bone metastasis from renal cell carcinoma. Additional bone SPECT and brain MR fusion images clearly demonstrated the wedge-shaped uptake of tracer corresponded to the abnormal intensity reflecting subacute cerebral infarction. Follow-up bone scan and fused images with MRI showed complete resolution of the abnormal uptake in chronic phase. A breakdown in the normal blood-brain barrier results in abnormal ionic calcium flux into the cells following altered cell membrane integrity leading to precipitation of calcium salts which eventually binds to bone imaging tracer such as (99m)Tc-methylene diphosphonate. That is, increased accumulation of bone seeking agents represents lethal cell death. The recent development of software and hardware has enabled the fusion of functional and anatomic images. Image fusion between SPECT with various tracers and MRI is expected to provide clues as to the underlying cause of diseases and to decide our treatment planning in the near future. PMID- 20847536 TI - Coexistent poorly-differentiated neuroendocrine cell carcinoma and non-invasive well-differentiated adenocarcinoma in tubulovillous adenoma of the rectum: report of a case. AB - A 74-years old man was referred to our hospital for treatment of a rectal mass. Colonoscopy revealed villous tumor covering all the lower rectal lumen. Biopsy yielded a diagnosis of adenoma. CT examination showed tumor shadows of the rectum and the liver. Pelvic MRI examination showed a 10.5*8*7 cm tumor with high signal intensity on the T2 weighted images in the rectum. Rectosigmoidectomy with lymph node dissection was performed with the diagnosis of rectal cancer that metastasized to the liver. Histological and immuno- histochemical features showed coexistent poorly-differentiated small cell neuroendocrine cell (NEC) carcinoma and non-invasive well-differentiated adenocarcinoma in tubulovillous adenoma. However the chemotherapy with FOLFOX and Bevacizumab was performed postoperatively, the patient died in cancer 3 months after surgery. Rectal poorly differentiated NEC carcinomas are thought to be a tumor with a high malignant potential. Recently, the UICC TNM classifications of malignant tumors, 7th edition and the Guidelines for colorectal NEC tumors of European Neuroendocrine Tumor Society have been published. They would be evaluated, and effective multimodal therapy for NEC carcinomas should be established. PMID- 20847537 TI - Immunohistochemical findings in the pancreatic islets of a patient with transfusional iron overload and diabetes: case report. AB - Excessive iron storage sometimes causes diabetes in patients with hemochromatosis, a disease caused by iron overloading. We performed an immunohistochemical analysis to study an autopsy case of aplastic anemia and diabetic hemochromatosis caused by frequent blood transfusions, and extensive hemosiderin deposition was observed in the liver and pancreas. The pancreatic islets of the patient and a control subject were stained to detect glucagon, insulin, and proinsulin. Significantly lower levels of immunoreactivity with both insulin antibodies and proinsulin antibodies, but not with glucagon antibodies, was observed in the islet cells in the patient's tissue than in the islet cells of the control. Hemosiderin deposition in the islets is known to be exclusively distributed in the beta-cells, thus, selective iron-induced damage to the beta cells may have affected insulin synthesis and secretion and led to glucose intolerance in the patient. PMID- 20847538 TI - Treatment of spontaneous chytridiomycosis in captive amphibians using itraconazole. AB - We performed this study in order to establish an effective, simple and safe treatment for chytridiomycosis. The subjects were 12 amphibians (11 anurans of 4 different species and 1 urodela) diagnosed with chytridiomycosis by clinical signs and a PCR test. A 0.01% aqueous solution of the antifungal agent itraconazole was used to treat the subjects, and we evaluated the efficacy of treatment by 3 methods: clinical signs, direct microscopy and a nested PCR test. A 10-min immersion in a 0.01% aqueous solution of itraconazole every other day for a total of 7 treatments resulted in an improvement of clinical signs in 11 of the 12 cases. Specifically, we observed an abatement of increased sloughing and disappearance of zoosporangia by direct microscopy. DNA fragments of Batrachochytrium dendrobatidis were not detected by a PCR test at the end of treatment, nor were they detected after treatment (20-57 days following treatment; average, 34.4 days). No recurrence was observed 12 months after the end of treatment, nor did we observe any obvious side effects from itraconazole. Therefore, we recommend this as a treatment method for chytridiomycosis and as an elimination technique for use in captive amphibians. PMID- 20847539 TI - Starfish, Asterias amurensis and Asterina pectinifera, as potential sources of Th1 immunity-stimulating adjuvants. AB - Saponin is the generic name of steroid or triterpene glycosides, and the capacities of some saponins to stimulate both Th1 immune response and production of cytotoxic T cells are useful as vaccine components against intracellular pathogens. Because saponins have been found commonly in starfish, we assessed the potential of starfish, Asterias amurensis and Asterina pectinifera, as adjuvant sources. Crude starfish saponins had hemolytic activities (EC(50)=10 to 100 ug/ml) and thin layer chromatography indicated heterogeneity of their constituents. When starfish saponis were subcutaneously injected into mice with ovalbumin (OVA), OVA-specific IgG, especially IgG2a instead of IgG1 was produced in mouse blood, suggesting starfish saponins stimulated Th1 type immunity and they were potential sources of new adjuvants. PMID- 20847540 TI - Morphological changes in the endocrine and exocrine pancreas of rats after experimental obstructive jaundice. AB - Obstructive jaundice causes multiple malfunctions in various organs including the pancreas. To establish how such malfunctions occur, we experimentally induced obstructive jaundice through bile duct ligation (BDL) using rats, measured serum bilirubin, amylase and insulin levels, and examined histological, immunohistochemical and cytological changes in the pancreas at 3 days, 1 week, and 4 weeks after the BDL. Morphometrical analysis was also conducted. Serum amylase levels steeply increased at 3 days, and then decreased at 1 and 4 weeks after the BDL to lower than the control level. In contrast, the number of zymogen granules decreased at 3 days after the BDL, then increased and eventually surpassed the control group at 4 weeks after the BDL. On the other hand, serum insulin levels dramatically decreased at 3 days after the BDL but recovered to a level close to that of the control group at 1 week after the BDL. At 4 weeks after the BDL, however, the serum insulin levels again showed a marked decline. Slight decrease in insulin immunoreactivity and number of insulin granules were observed at 4 weeks after the BDL. Cholecystokinin receptors (CCK-R) were expressed in both acinar and islet cells; their immunoreactivity significantly decreased in the acinar cells at 4 weeks after the BDL. Our results suggest that CCK may play a role in regulating changes in the pancreas after obstructive jaundice. PMID- 20847541 TI - Trajectory analysis of serum biomarker concentrations facilitates outcome prediction after pediatric traumatic and hypoxemic brain injury. AB - Traumatic brain injury (TBI) and hypoxic ischemic encephalopathy (HIE) are leading causes of morbidity and mortality in children. Several studies over the past several years have evaluated the use of serum biomarkers to predict outcome after pediatric brain injury. These studies have all used simple point estimates such as initial and peak biomarker concentrations to predict outcome. However, this approach does not recognize patterns of change over time. Trajectory analysis is a type of analysis which can capture variance in biomarker concentrations over time and has been used with success in the social sciences. We used trajectory analysis to evaluate the ability of the serum concentrations of 3 brain-specific biomarkers - S100B, neuron-specific enolase (NSE) and myelin basic protein (MBP) - to predict poor outcome (Glasgow Outcome Scale scores 3-5) after pediatric TBI and HIE. Clinical and biomarker data from 100 children with TBI or HIE were evaluated. For each biomarker, we validated 2-, 3- and 4-group models for outcome prediction, using sensitivity and specificity. For S100B, the 3-group model predicted poor outcome with a sensitivity of 59% and specificity of 100%. For NSE, the 3-group model predicted poor outcome with a sensitivity of 48% and specificity of 98%. For MBP, the 3-group model predicted poor outcome with a sensitivity of 73% and specificity of 61%. Thus, when the models predicted a poor outcome, there was a very high probability of a poor outcome. In contrast, 17% of subjects with a poor outcome were predicted to have a good outcome by all 3 biomarker trajectories. These data suggest that trajectory analysis of biomarker data may provide a useful approach for predicting outcome after pediatric brain injury. PMID- 20847542 TI - Relationship of intracranial pressure and cerebral perfusion pressure with outcome in young children after severe traumatic brain injury. AB - Traumatic brain injury (TBI) is the most common cause of death for children less than 18 years of age. Current standards of care for children with severe TBI include monitoring of intracranial pressure (ICP), and goal-directed therapies to minimize ICP and optimize cerebral perfusion pressure (CPP; the mathematical difference between the mean arterial pressure and ICP). Current guidelines for ICP and CPP thresholds suggest that age-based thresholds should be adopted, but few studies have included the youngest children affected by TBI (those <2 years of age). We performed a retrospective analysis of our pediatric neurotrauma database to determine if ICP and CPP thresholds associated with favorable neurological outcome could be determined, or if the number of episodic alterations in the parameters (ICP >15 or >20 mm Hg; CPP <40 mm Hg, <45 mm Hg or <50 mm Hg) was different between children with favorable and unfavorable outcomes (based on dichotomous Glasgow Outcome Scale score at 6 months after TBI). Data from 22 children (of whom 81% had suffered from inflicted childhood neurotrauma) were analyzed in the first 7 days. Children with unfavorable outcome had more hourly readings of CPP of <45 mm Hg compared to children with favorable outcome [median (25-75%): 2 (1-31) vs. 0 (0-2); p <0.05]. There was no difference between the number of hourly readings of ICP of >20 mm Hg between the outcome groups [median (25-75%): favorable 0 (0-1) vs. unfavorable 1 (0-4); p = 0.17]. To our knowledge, this is the first exploratory report to test if CPP and ICP thresholds can be established for this young population of children after TBI, and it suggests a CPP target threshold of 45 mm Hg. Despite good ICP control in this population, there was still a 50% incidence of unfavorable outcome, suggesting that there may be unique physiologic parameters that need to be targeted in infants with severe TBI. A prospective study is needed to fully determine what goals should be targeted for this vulnerable population. PMID- 20847543 TI - Age is a determinant of leukocyte infiltration and loss of cortical volume after traumatic brain injury. AB - There is increasing evidence that the inflammatory response differs in the injured developing brain as compared to the adult brain. Here we compared cerebral blood flow and profiled the inflammatory response in mice that had been subjected to traumatic brain injury (TBI) at postnatal day (P)21 or at adulthood. Relative blood flow, determined by laser Doppler, revealed a 30% decrease in flow immediately after injury followed by prominent hyperemia between 7 and 35 days after injury in both age groups. The animals were euthanized at 1-35 days after injury and the brains prepared for the immunolocalization and quantification of CD45-, GR-1-, CD4- and CD8-positive (+) cells. On average, the number of CD45+ leukocytes in the cortex was significantly higher in the P21 as compared to the adult group. A similar trend was seen for GR-1+ granulocytes, whereas no age related differences were noted for CD4+ and CD8+ cells. While CD45+ and GR-1+ cells in the P21 group remained elevated, relative to shams, over the first 2 weeks after injury, the adult group showed a time course limited to the first 3 days after injury. The loss of ipsilateral cortical volumes at 2 weeks after injury was significantly greater in the adult relative to the P21 group. While the adult group showed no further change in cortical volumes, there was a significant loss of cortical volumes between 2 and 5 weeks after injury in the P21 group, reaching values similar to that of the adult group by 5 weeks after injury. Together, these findings demonstrate age-dependent temporal patterns of leukocyte infiltration and loss of cortical volume after TBI. PMID- 20847544 TI - Normal ranges of embryonic length, embryonic heart rate, gestational sac diameter and yolk sac diameter at 6-10 weeks. AB - OBJECTIVES: To construct normal ranges for embryonic crown-rump length (CRL), heart rate (HR), gestational sac diameter (GSD) and yolk sac diameter (YSD) at 6 10 weeks of gestation. METHODS: We examined 4,698 singleton pregnancies with ultrasound measurements of CRL, HR, GSD and YSD at 6-10 weeks and CRL at 11-13 weeks resulting in the live birth after 36 weeks of phenotypically normal neonates with birth weight above the 5th centile. Gestational age was derived from CRL at the 11- to 13-week scan using the formula of Robinson and Fleming. Regression analysis was used to establish normal ranges of CRL, fetal HR, GSD and YSD with gestation, and fetal HR, GSD and YSD with CRL. RESULTS: At 6-10 weeks there were significant quadratic associations between CRL, GSD, YSD and gestation and between HR, GSD, YSD and CRL, and a cubic association between HR and gestation. The estimated gestation from CRL was the same as that of Robinson and Fleming for a CRL of 10.2-36.5 mm, but the formula of Robinson and Fleming underestimated the gestation by 1 day for a CRL 7.4-10.2 mm and this increased to 9 days for a CRL of 1 mm. CONCLUSION: This study established normal ranges for early pregnancy biometry. PMID- 20847545 TI - Effects of prenatal ethanol exposure on postnatal growth and the insulin-like growth factor axis. AB - AIMS: To study the effect of in-utero alcohol exposure on the insulin-like growth factor axis (IGF) and leptin during infancy and childhood, considering that exposed children may exhibit pre- and postnatal growth retardation. METHODS: We prospectively identified heavily drinking pregnant women who consumed on average 4 or more drinks of ethanol per day (>= 48 g/day) and assessed growth in 69 of their offspring and an unexposed control group of 83 children, measuring serum IGF-I (radioimmunoassay), IGF-II (immunoradiometric assay, IRMA), insulin-like growth factor-binding protein 3 (IGFBP-3) (IRMA) and leptin (IRMA) at 1 month and 1, 2, 3, 4, and 5 years of age. RESULTS: IGF-II levels increased with age in both groups, but the rate of increase was significantly higher in exposed children, and levels were significantly higher in ethanol-exposed children at 3, 4, and 5 years of age. In exposed children, IGF-I levels were higher at 3 and 4 years and leptin levels were significantly lower at 1 and 2 years. Exposed subjects showed a much lower correlation between IGF-I and growth parameters than unexposed subjects. CONCLUSION: Exposure to ethanol during pregnancy increases IGF-I and IGF-II and decreases leptin during early childhood. The increase in serum IGF-II concentrations in ethanol-exposed children suggests that this hormone should be explored as a potential marker for prenatal alcohol exposure. PMID- 20847546 TI - Normal-weight 14-year-old girl with acanthosis nigricans and markedly increased hepatic steatosis: evidence for the important role of ectopic fat deposition in the pathogenesis of insulin resistance in childhood and adolescence. AB - BACKGROUND: A major factor in the development of insulin resistance is obesity. While the contribution of intrahepatic lipids to insulin resistance is well established in adults, there are only few reports in childhood and adolescence. AIM: To investigate the correlation between ectopic fat deposition and insulin sensitivity in a normal-weight girl with acanthosis nigricans before and after lifestyle intervention. METHODS: Variations in body fat composition and intrahepatic lipids were monitored by means of anthropometric measures and by means of methods based on magnetic resonance imaging and magnetic resonance spectroscopy. RESULTS: We present the case of a normal-weight 14-year-old Caucasian girl with pronounced hepatic steatosis together with acanthosis nigricans, increased waist-circumference and increased visceral fat. During a 7 month period of lifestyle intervention, the girl lost 7.1 kg in weight. Acanthosis nigricans, whole-body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) improved significantly (before intervention: WBISI 0.42, HOMA 22.2; after intervention: WBISI 1.35, HOMA 6.9). Even though all lipid compartments were decreased in size, the intrahepatic lipids showed an extraordinarily great reduction. CONCLUSION: This case presentation of a normal weight girl with acanthosis nigricans and markedly increased hepatic steatosis provides support for the association between intrahepatic fat deposition and insulin resistance in adolescence. PMID- 20847547 TI - Effects on growth and metabolism of growth hormone treatment for 3 years in 36 children with Prader-Willi syndrome. AB - BACKGROUND/AIMS: Prader-Willi syndrome (PWS) is a complex genetic disorder whose many manifestations include obesity and short stature. Diabetes, osteoporosis, and scoliosis are common. We evaluated the effects of human growth hormone (hGH). METHODS: A prospective cohort study of 36 children (1-15 years of age) with genetically confirmed PWS who were given hGH (mean dose 0.033 +/- 0.006 mg/kg/day) for 36 months. At baseline and once yearly, we evaluated growth, insulin-like growth factor-1 (IGF-1), body composition, bone mineral density (BMD), glucose tolerance, serum lipids, and spinal radiographs. RESULTS: Height gain over the 3-year period was 1.2 SD score. Lean body mass increased significantly during each treatment year. Total body fat decreased by 5.42 and 1.17% in the 1st and 2nd years, respectively. BMD remained unchanged during therapy. IGF-1 and homeostasis model assessment index of insulin resistance increased, and glucose intolerance was found in 22.7% of patients at baseline and 0% at 3 years. None of the patients had diabetes. Their lipid profile improved. Scoliosis was present in 27.8% of the patients at baseline and 47.2% at 3 years. CONCLUSION: GH treatment in children with PWS has multiple beneficial effects on growth and body composition. Tolerance is good, with an improvement in glucose metabolism, although IGF-1 levels and insulin resistance parameters should be monitored closely. The high rate of scoliosis warrants monitoring by a pediatric orthopedic surgeon. PMID- 20847548 TI - Differences in neonatal outcome in fetuses with absent versus reverse end diastolic flow in umbilical artery Doppler. AB - OBJECTIVES: It was the aim of this study to evaluate differences in the prognosis of fetuses with absent (AED) and reverse end-diastolic (RED) flow in the umbilical artery based on neonatal outcomes. METHODS: We performed a cross sectional study based on the records of 143 patients attending at Assis Chateaubriand Teaching Maternity between 1 January 1999 and 31 December 2005. Patients were classified according to diagnosis as having either fetal centralization (FC), AED or RED. Obstetrical findings and perinatal outcomes were compared for the 3 groups and between AED and RED by Fisher's exact test. Perinatal outcomes were analyzed quantitatively with logistic or multinomial regression. Odds ratios were calculated for significant risk factors. RESULTS: There was a statistically significant difference in gestational age at diagnosis, Apgar scores at 1 and 5 min, Capurro score, use of surfactant and mechanical ventilation, admission to the neonatal intensive care unit, perinatal and neonatal death. When comparing RED with AED, the odds of neonatal intensive care unit admission, mechanical ventilation, use of surfactant, neonatal mortality and perinatal mortality were 3.2, 1.4, 1.0, 5.1 and 5.3 times higher for RED. Only perinatal mortality kept statistically significant with odds of 5.2 (p = 0.043) when adjusted by gestational age (multivariate analysis). CONCLUSION: The incidence of perinatal mortality was observed to increase with the severity of Doppler findings, with significant differences between the AED and RED groups. PMID- 20847550 TI - Surgical challenge in patients who underwent failed hypospadias repair: is it time to change? AB - INTRODUCTION: Our purpose was to evaluate patients who underwent failed hypospadias repair. PATIENTS AND METHODS: We evaluated 4 different groups of patients who underwent failed hypospadias repair. Group 1: patients who underwent only urethral surgery; group 2: patients who underwent only corpora cavernosa surgery; group 3: patients who underwent urethral and corpora cavernosa surgery; group 4: patients who underwent complex reconstructive surgery. Success was defined as a functional urethra without fistula, with glandular meatus and acceptable esthetic appearance of the genitalia. RESULTS: Out of 1,176 patients, group 1 included 301 patients (25.5%), group two 60 patients (5.2%), group three 166 patients (14.1%) and group four 649 patients (55.2%). The mean follow-up was 60.4 months. Out of 1,176 cases, 1,036 (88.1%) were considered successful and 140 (11.9%) failures. CONCLUSION: In the majority of patients (55.2%) with failed hypospadias repair, urethral reconstruction is associated with complex surgical procedures to fully resurface glands, penile shaft and genitalia. PMID- 20847549 TI - Heparin-binding epidermal growth factor-like growth factor is a potent neurotrophic factor for PC12 cells. AB - Heparin-binding epidermal growth factor EGF-like growth factor (HB-EGF) is a member of the epidermal growth factor family that is expressed in many cell types. We have previously reported the effects of HB-EGF on intestinal epithelial cells and endothelial cells after exposure to ischemia/reperfusion in vivo or anoxia/reoxygenation injury in vitro. However, the effect of HB-EGF on neuronal cells is largely unexplored. In this study, we examined the effect of HB-EGF on neurite outgrowth in pheochromocytoma (PC12) cells as well as the neuroprotective effect of HB-EGF on injured PC12 cells exposed to oxygen and glucose deprivation (OGD), which mimics ischemic conditions. We found that HB-EGF significantly promotes PC12 cell neurite outgrowth and that this effect was blocked by EGF receptor (EGFR) inhibition or mitogen-activated protein kinase (MAPK) inhibition, but not by tyrosine kinase inhibition. In the face of OGD injury, HB-EGF preserves cell viability and decreases apoptosis and LDH release in PC12 cells. HB-EGF-mediated cytoprotection was abolished by EGFR inhibition and MAPK inhibition. We conclude that HB-EGF, through its interaction with the EGF receptor, activates the MAPK signaling pathway in PC12 cells under basal or injury conditions, leading to enhanced neurite outgrowth and neuroprotection against ischemic injury. PMID- 20847551 TI - An intact dorsomedial hypothalamic nucleus, but not the subzona incerta or reuniens nucleus, is necessary for short-day melatonin signal-induced responses in Siberian hamsters. AB - Siberian hamsters provide a useful model to define mechanisms underlying obesity reversal as they naturally transition from their extreme seasonal obesity in long 'summer-like' days (LDs) to a leaner state in short 'winter-like' days (SDs). These day length changes are coded into durational melatonin (MEL) signals by the pineal gland resulting in stimulation of MEL receptors (MEL(1a)-Rs). MEL(1a)-R mRNA is colocalized centrally in sympathetic nervous system (SNS) outflow neurons comprising a chain of neurons that ultimately innervates white adipose tissue (WAT). Neural components in this circuit include the subzona incerta (subZI), dorsomedial hypothalamic nucleus (DMH) and thalamic reuniens nucleus (ReN). SD, long-duration MEL signals induce gonadal regression and increase WAT SNS drive triggering lipolysis and thereby reversing LD obesity. We attempted to block the reversal of SD MEL signal-induced obesity by making electrolytic or sham lesions of the subZI, ReN or DMH in LD-housed hamsters. To create SD-like, long-duration MEL signals, we injected MEL 3 h before lights out, thereby lengthening the naturally occurring nocturnal duration of circulating MEL. ReN and subZI lesions did not block SD-like MEL signal-induced decreases in body, WAT, testicular masses or food intake; by contrast, DMH lesions blocked decreases in WAT and testicular mass. This nonresponsiveness was not due to lesion-induced inappropriate nocturnal LD MEL secretion that would have altered our creation of SD-like signals. Therefore, the DMH appears to participate in the control of both SD energy and reproductive responses, and joins the suprachiasmatic nucleus as sites necessary for SD responses in this species. PMID- 20847552 TI - Peritoneal dialysis in patients with primary cardiac failure complicated by renal failure. AB - BACKGROUND/AIMS: Clinical outcome in cardiorenal syndrome type II and treated with peritoneal dialysis (PD). METHODS: Retrospective analysis over a period of 10 years. RESULTS: Twenty-four patients with mean age at start of dialysis of 67 +/- 10 years had mean survival on dialysis of 1.03 +/- 0.84 years (median survival 1.0 year). The number of hospitalizations for cardiovascular causes were reduced (13.7 +/- 26.5 predialysis vs. 3.5 +/- 8.8 days/patient/month postdialysis, p = 0.001). Patients who survived longer than the median survival time (n = 12) also had a reduced number of hospitalizations for all causes (3.7 +/- 3.8 predialysis vs. 1.4 +/- 2.1 days/patient/month postdialysis, p = 0.041), a lower age (62 +/- 10 vs. 71 +/- 8 years, p = 0.013) and fewer had diabetes (2 vs. 7 patients, p = 0.039), but left ventricular ejection fraction was not different. CONCLUSION: After starting PD for cardiorenal syndrome, hospitalizations for cardiovascular causes were reduced for all patients. Survival after starting PD is highly variable. Age and diabetes seem to be significant prognostic factors, but not left ventricular ejection fraction. PMID- 20847553 TI - APOE epsilon2 allele is associated with larger regional cortical thicknesses and volumes. AB - BACKGROUND: The protective effect of the apolipoprotein E (APOE) epsilon2 allele against Alzheimer's disease (AD) is controversial. OBJECTIVE: Our purpose was to clarify if the epsilon2 allele affects regional cortical thicknesses and volumes. METHODS: Regional cortical thicknesses and volumes were measured with an automated pipeline in 109 subjects with mild cognitive impairment, 114 AD patients and 105 age-matched healthy controls. RESULTS: In the mild cognitive impairment group, the epsilon2 carriers had thicker regional cortices at the transverse temporal cortex and parahippocampal gyrus than the subjects with epsilon3/epsilon3, and a larger cerebral gray matter and smaller lateral ventricles than the epsilon3/epsilon3 and epsilon4 carriers. In the AD group, the epsilon2 carriers had significantly thicker entorhinal and transverse temporal cortices, a larger whole cerebral gray matter, and smaller lateral ventricles than the subjects with the epsilon3/epsilon3 genotype, and a significantly thicker entorhinal cortex and larger cerebral gray matter than epsilon4 carriers. No APOE2 effect was found in the control group. CONCLUSION: The APOE epsilon2 allele is associated with larger regional cortical thicknesses and volumes in mild cognitive impairment and AD. PMID- 20847555 TI - Cerebrospinal fluid tau protein levels and 18F-fluorodeoxyglucose positron emission tomography in the differential diagnosis of Alzheimer's disease. AB - AIMS: In this study, we aimed to compare cerebrospinal fluid (CSF) levels of total tau (t-tau), phosphorylated tau (p-tau(181)) and positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) in the differential diagnosis of Alzheimer's disease (AD) under clinical conditions. METHOD: In a cross sectional, blinded, single-center study, we examined a sample of 75 unselected memory clinic patients with clinical diagnoses of dementia of Alzheimer type (DAT; n = 24), amnestic mild cognitive impairment (MCI; n = 16), other dementias (n = 13) and nondemented controls (n = 22). Discriminative accuracy, sensitivity and specificity were calculated and compared using ROC analyses. RESULTS: p tau(181) and FDG-PET were comparable in separating DAT from controls (sensitivity: 67 vs. 79%; specificity: 91% for both) and patients with other dementias (sensitivity: 71 vs. 79%; specificity: 100% for both). The sensitivity of p-tau(181) in differentiating MCI patients from controls was significantly (p < 0.05) superior to that of FDG-PET (75 vs. 44%) at a comparably high specificity (82 vs. 91%); t-tau measures were less accurate in all analyses. CONCLUSIONS: FDG PET and CSF p-tau(181) levels are able to discriminate DAT in heterogeneous and unselected samples with a high accuracy. CSF p-tau(181) might be somewhat superior for a sensitive detection of patients with MCI. PMID- 20847554 TI - Predictive utility of type and duration of symptoms at initial presentation in patients with mild cognitive impairment. AB - BACKGROUND/AIMS: To assess (1) the duration and symptoms present in participants with mild cognitive impairment (MCI) and (2) the impact of these variables on predicting conversion to Alzheimer's disease (AD). METHODS: Participants with MCI (n = 148) were assessed and followed systematically. RESULTS: Decline in memory was reported as the first symptom in 118 of the cases. Converters had more symptoms (e.g. language decline, depression), and the combination of decline in memory and in performance of high-order social/cognitive activities as well as disorientation more often than nonconverters (p = 0.036). In an age-stratified Cox model, predictors of conversion to AD were shorter time since onset of memory decline and lower baseline MMSE score. CONCLUSIONS: Recent onset of memory decline with older age, decreased MMSE score, change in performance and disorientation indicate a greater likelihood of short-term conversion to AD. PMID- 20847556 TI - Executive dysfunction and left frontal white matter hyperintensities are correlated with neuropsychiatric symptoms in stroke patients with confluent white matter hyperintensities. AB - BACKGROUND/AIMS: This study aimed to determine the clinical and neuroimaging correlates of the presence of neuropsychiatric symptoms in stroke patients with age-related confluent white matter hyperintensities (WMH). METHODS: The Neuropsychiatric Inventory was utilized to detect the presence of 12 symptoms. Multivariate logistic regression models were used to identify clinical and neuroimaging correlates of the presence of symptoms. RESULTS: Seventy-seven stroke patients (mean WMH volume: 39.5 cm(3)) were recruited. Thirty patients (39%) had >= 1 neuropsychiatric symptom. Poor executive function was associated with the presence of any symptoms and symptoms other than depression. More severe left frontal WMH was associated with depression. CONCLUSION: Executive dysfunction and left frontal WMH are correlated with neuropsychiatric symptoms in these patients. PMID- 20847557 TI - Prevalence of dementia in elderly living in two cities of Central Africa: the EDAC survey. AB - BACKGROUND: Data on dementia from low- and middle-income countries are still necessary to quantify the burden of this condition. This multicenter cross sectional study aimed at estimating the prevalence of dementia in 2 large cities of Central Africa. METHODS: General population door-to-door surveys were conducted in the districts of Bangui (Republic of Central Africa) and Brazzaville (Congo) in elderly aged >= 65 years. The subjects were screened with the Community Screening Interview for Dementia and the Five-Words Test. Diagnosis of dementia was made according to the DSM-IV criteria and to the clinical criteria proposed by the NINCDS-ADRDA for Alzheimer's disease. RESULTS: We enrolled 496 subjects in Bangui and 520 in Brazzaville. The prevalence of dementia was estimated at 8.1% (95% CI = 5.8-10.8) in Bangui and 6.7% (95% CI = 4.7-9.2) in Brazzaville. CONCLUSION: The prevalence of dementia in urban areas of Central Africa is close to those observed in high-income countries. PMID- 20847558 TI - Longitudinal associations between blood pressure and dementia in the very old. AB - BACKGROUND/AIMS: Midlife hypertension is associated with an increased risk for dementia, but the association between blood pressure and dementia in very old age is unclear. METHODS: In a population-based cohort study, a total of 102 individuals aged 85, 90 or >= 95 years participated in 2 examinations with a 5 year interval. The investigations consisted of a structured interview, blood pressure measurement, rating scales such as the Mini-Mental State Examination (MMSE) and an investigation of medical charts. RESULTS: The majority of participants exhibited a decline in blood pressure. Baseline systolic blood pressure (SBP), diastolic blood pressure or pulse pressure (PP) were not associated with incident dementia or with decline in MMSE scores in multiple regression analyses adjusted for age and sex. However, incident dementia cases exhibited a greater decline in SBP (p = 0.02) and PP (p = 0.04), and decline in SBP was associated with a decline in MMSE score (p = 0.008). CONCLUSION: In this small longitudinal study on the very old, no association between baseline blood pressure and incident dementia was found, but individuals who developed dementia exhibited a greater blood pressure decline. Low blood pressure could be an effect of dementia in the very old. PMID- 20847559 TI - Midlife smoking, apolipoprotein E and risk of dementia and Alzheimer's disease: a population-based cardiovascular risk factors, aging and dementia study. AB - AIM: To elucidate the effect of midlife smoking on the risk of dementia and Alzheimer's disease (AD), and the possible modification of this relation by the apolipoprotein E (APOE) epsilon4. METHODS: Participants of the Cardiovascular Risk Factors, Aging and Dementia study were randomly selected from population based samples originally studied in midlife (1972, 1977, 1982 or 1988). After an average follow-up of 21 years, 1,449 persons (73%) aged 65-79 years took part in a reexamination in 1998. RESULTS: Smoking in midlife increased the risk of dementia (odds ratio, OR: 4.93; 95% CI: 1.51-16.11) and AD (OR: 6.56; 95% CI: 1.80-23.94) among the APOE epsilon4 carriers, but not among the APOE epsilon4 noncarriers. CONCLUSION: Midlife smoking was associated with an increased risk of dementia and AD later in life only among those individuals carrying the APOE epsilon4 allele. These results suggest that the association between smoking and AD may be complex and vary according to genotype. PMID- 20847560 TI - Critical flicker frequency as a marker of hepatic encephalopathy in patients before and after transjugular intrahepatic portosystemic shunt. AB - BACKGROUND: Overt hepatic encephalopathy (HE) following insertion of a transjugular intrahepatic portosystemic shunt (TIPS) is a problem in some patients. In contrast to overt HE, minimal HE (MHE) following TIPS is studied to a limited degree only. We therefore evaluated the incidence of MHE in patients following TIPS insertion by determination of the critical flicker frequency (CFF). METHODS: 45 cirrhotic patients (Child A/B/C: 7/24/14; Child-Pugh score 8.5 +/- 2.0) underwent TIPS because of recurrent esophageal bleeding (n = 15), refractory ascites (n = 25) or a combination of bleeding and refractory ascites (n = 5). Hemodynamic parameters were recorded during TIPS insertion. CFF was determined using a portable analyzer 2 days before and 3, 28 and 84 days after TIPS. At these time points the number connection test and biochemical markers were recorded as well. RESULTS: TIPS led to a reduction of the portal pressure gradient from 19.1 +/- 5.9 to 9.3 +/- 6.1 mm Hg together with a slight but significant increase in bilirubin from 1.5 +/- 0.9 to 2.2 +/- 1.9 mg/dl and in the international normalized ratio from 1.2 +/- 0.3 to 1.4 +/- 0.5. Creatinine decreased from 1.3 +/- 0.6 to 1.1 +/- 0.5 mg/dl. Pre-TIPS, 27 patients had normal CFF (>38 Hz, CFF 41.1 +/- 2.4 Hz) and 18 patients had altered CFF (<=38 Hz, CFF 34.4 +/- 3.0 Hz): 3 had grade I and 15 MHE. Three days post-TIPS, 3 of the 27 patients (11.1%) with normal CFF deteriorated to MHE, 1 of the patients with grade I HE deteriorated to grade II HE, 1 maintained grade I HE and the other improved. No patient with MHE deteriorated to overt HE. CONCLUSIONS: Using the determination of the CFF, we were able to show that elective TIPS insertion in patients with preserved liver function causes a MHE in only the minority of patients. In addition, patients with preexisting MHE did not deteriorate to overt HE. PMID- 20847561 TI - Association of serum adipocytokines with hepatic steatosis and fibrosis in patients with chronic hepatitis C. AB - BACKGROUND: The pathogenic mechanisms of hepatic steatosis in hepatitis C (HCV) remain unclear. AIM: To assess the potential role of cytokines and adipokines in HCV-related steatosis and fibrosis. METHODS: We profiled several adipokines, cytokines, and related soluble molecules in 99 HCV patients and analyzed their potential associations with hepatic steatosis and fibrosis. RESULTS: Serum leptin and IL-1RA were significantly higher in HCV genotype 1 as compared to genotype 3. On the other hand, serum resistin, IL-8, IL-1B and sIL-6R, were significantly higher in HCV genotype 3. No differences were observed for adiponectin, visfatin, IL-6 and TNF-alpha. Regardless of HCV genotype, steatosis could be predicted by a combination of IL-8, IL-6, and sIL-6R/IL-6. When analysis was repeated for each of the genotypes, the reliability of models improved. Regardless of HCV genotype, moderate to severe fibrosis (Metavir score >F2), was predicted by IL-8 and resistin levels. CONCLUSIONS: Analysis of adipocytokines associated with steatosis supports the hypothesis that steatogenic pathways differ in HCV genotype 3 from those infected with non-genotype 3 infections. PMID- 20847562 TI - Microalbuminuria is not a valuable marker for relapse in Crohn's disease. AB - BACKGROUND: Previous reports correlated microalbuminuria with disease activity in patients with Crohn's disease (CD). The aim of the present study is to determine the value of microalbuminuria as a marker for relapses in quiescent CD. METHODS: In a 1-year prospective maintenance trial with oral budesonide in patients with CD in remission, microalbuminuria was measured at randomization, after 2, 6 and 12 months, plus at the time of a relapse. The association of microalbuminuria with the course of disease was analyzed with logistic regression analysis. Time dependent Cox regression was undertaken to study the association between microalbuminuria and relapse. RESULTS: We included a total of 139 patients. At randomization, microalbuminuria was present in 8 patients. During a 1-year follow up, 29 patients relapsed and in 11% (3/29), microalbuminuria was present during the relapse. We found no statistically significant association between microalbuminuria and relapse (odds ratio 0.92, 95% confidence interval (CI) 0.76 1.13). Time-dependent Cox regression analysis also revealed no statistical predictive value for microalbuminuria (hazard ratio 1.29, 95% CI 0.37-4.39, p = 0.68). CONCLUSION: Microalbuminuria was moderately prevalent in quiescent CD patients, but it could not be associated with disease characteristics or the type of medication before randomization, nor as a predictor for relapses. PMID- 20847563 TI - Determinants of fecal continence in healthy, continent subjects: a comprehensive analysis by anal manometry, rectal barostat and a stool substitute retention test. AB - BACKGROUND/AIMS: This study aimed to identify anal sphincter and rectal factors that determine anorectal filling sensations and continence during rectal filling in health. METHODS: Measurements of anorectal physiology were collected from 42 continent healthy subjects participating in a prospective trial. Rectal function and capacity were assessed by barostat. Anal sphincter functions were assessed by manometry. A validated stool substitute retention test was performed in which a viscous suspension was infused into the rectum at 60 ml/min to 1,500 ml. Multivariate regression was applied to identify physiologic factors that determine anorectal sensation and continence during rectal filling. RESULTS: The volume at which first awareness of rectal filling occurred associated with age (p < 0.03), rectal capacity (p < 0.06) and anal resting pressure (p < 0.003); urgency associated with rectal capacity (p < 0.0007), anal resting (p < 0.04) and squeeze pressure (p < 0.02); volume at first incontinence with rectal capacity (p < 0.0001) and squeeze pressure (p < 0.04) and the maximum volume retained were closely correlated with rectal capacity only (p < 0.0001). CONCLUSION: Anorectal filling sensations and continence in health require a rectal reservoir of adequate capacity and effective voluntary anal sphincter function. Complementary associations between continence, motor and sensory function indicate the presence of an adaptive mechanism that enables timely, appropriate responses to events that threaten fecal continence. PMID- 20847564 TI - Abdominal adhesion prevention: still a sticky subject? AB - BACKGROUND: Adhesion formation remains an almost inevitable consequence of abdominal procedures, potentially resulting in significant morbidity and mortality. There is an ongoing need to evaluate current understanding of adhesion formation and products aimed at prevention. Failure to keep up to date with adhesion treatment may subject clinicians to a greater medico-legal risk. DESIGN: Review of published studies exploring the problem of peritoneal adhesion formation. This encompasses the underlying processes of adhesion formation combined with general approaches to reduce formation. An overview of products trialled to prevent formation in both the animal model and clinical setting describes products of scientific interest and commercial success. RESULTS: Advances in surgical technique, such as laparoscopic surgery, can help minimize the probability of adhesion formation. Currently barrier products, whilst reducing adhesion formation, have not been shown to reduce the risk of readmission with complications related to adhesions. Hybrid products may improve upon this situation. CONCLUSIONS: No single approach has been wholly satisfactory in reducing adhesions. Research into the processes driving adhesion formation is providing exciting new targets for therapeutic agents. It would seem plausible that with many promising avenues of research a revolutionary agent to reduce the incidence of adhesional small bowel obstruction may result. PMID- 20847565 TI - Triangulating stapling technique for anastomosis in laparoscopy-assisted pylorus preserving gastrectomy. AB - BACKGROUND/AIMS: The anastomosis performed during laparoscopy-assisted pylorus preserving gastrectomy (PPG) is usually handsewn; however, the technique is sometimes difficult because it is done through a small incision and the level of skill of each operator may vary. The present study describes a triangulating stapling technique used during an anastomosis in laparoscopy-assisted pylorus preserving gastrectomy. METHOD: The 80-mm stapler was used 3 times for the triangulating stapling technique. The posterior walls, including the stay sutures, were joined by firing the stapler, and the anterior stomach ends were stapled in an everting fashion using two firings of the stapler. Both the anterior staple lines should overlap in the middle. Patient demographics and the operative data were examined. RESULTS: The triangulating stapling technique was performed during laparoscopy-assisted PPG in 9 patients. The median time for the anastomosis during laparoscopy-assisted PPG using the triangulating stapling technique was 19.0 min (16.0-31.0). Postoperative complications, including gastric stasis and anastomotic failure, were not found in any of the present patients. CONCLUSION: The triangulating stapling technique using a linear stapler is a safe and reliable technique to perform and can be easily conducted in a short time. We therefore consider it a useful anastomosis method for laparoscopy assisted pylorus-preserving gastrectomy, even by unskilled surgeons. PMID- 20847566 TI - A model of ischemic isolated acute liver failure in pigs: standardizing monitoring and treatment. AB - BACKGROUND: Acute liver failure (ALF) models in pigs have been widely used for evaluating newly developed liver support systems. But hardly any guidelines are available for the surgical methods and the clinical management. METHODS: The study validated several standard operating procedures describing in detail the surgical method and intensive care monitoring and treatment (control of potassium, glucose and bicarbonate levels, cardiovascular and intracranial pressure monitoring, etc.). ALF was induced in animals with a mean of 56 kg. Two surgical methods were compared: ligation of hepatic arteries with either end-to side portacaval shunt (ESPS) and bile duct ligation or side-to-side portacaval shunt (SSPS) without bile duct ligation. RESULTS: During total portal vein clamping, the animals in the ESPS group developed severe hypotension, splanchnic congestion and metabolic acidosis. One animal died after approximately 1.5 h. This model therefore represents a multiorgan failure model rather than an isolated ALF model. In the SSPS group, none of these side effects were observed, while clinical, laboratory and histopathological signs of ALF were evident. CONCLUSIONS: A reproducible model in pigs representing ALF can be established with the help of the standardized monitoring and treatment procedures presented. PMID- 20847567 TI - Left atrial enlargement induced by pure mitral regurgitation: time frame in a new swine model. AB - BACKGROUND: Atrial enlargement occurs in patients with significant mitral regurgitation. However, the time frame of the development of atrial enlargement induced by mitral regurgitation remains unknown. METHODS: Fourteen Lanyu miniature pigs (age = 6.6 +/- 0.9 months) were studied. Mitral regurgitation was created by placing a predefined hole on the middle scallop of the posterior mitral leaflet under cardiopulmonary bypass. The parasternal long-axis atrial dimension was measured by transthoracic echocardiographic examinations. RESULTS: All animals exhibited grade 3 mitral regurgitation immediately after surgery. Seven pigs expired within 2 weeks after the operation [technical complications (n = 1), acute cardiac tamponade (n = 1), and acute and subacute heart failure (n = 5)]. Seven pigs remained alive at a mean follow-up of 7.7 +/- 2.1 months. The left atrial diameter indices of the 7 pigs increased significantly at 1 month (33.1 +/- 8.6 mm, p = 0.018) and 3 months (41.3 +/- 12.6 mm, p = 0.018) after surgery compared with baseline values (22.8 +/- 5.2 mm), and the left atrial diameter index increased significantly at 3 months compared to 1 month (p = 0.018). CONCLUSIONS: Left atrial enlargement develops rapidly and progresses after the creation of significant pure mitral regurgitation. PMID- 20847568 TI - Accelerated decline of GFR in diabetic nephropathy predicted by interferon release assay to tuberculosis antigens. AB - BACKGROUND: The QuantiFERON(r) test (QFT) is a diagnostic tool for active and latent tuberculosis (TB) infections. High rates of positivity to QuantiFERON(r) have been demonstrated in patients with chronic kidney disease (CKD) and diabetic patients. We performed a pilot study to investigate if QFT positivity in diabetic CKD patients predicted the rate of renal function decline. METHODS: QFT was performed in 38 diabetic patients with CKD 4-5 not on dialysis. The rate of decline in estimated glomerular filtration rate (eGFR) was calculated. RESULTS: 18/38 patients had a positive QFT. Patients with a positive QFT had a steeper decline in eGFR, compared with patients with a negative QFT. Ethnicity (a marker of risk of previous TB exposure), urine protein/creatinine ratio, use of ACE inhibitors/angiotensin II receptor blockers and statins, serum C-reactive protein, vitamin D levels, HbA1c concentration and presenting GFR did not differ significantly. CONCLUSIONS: The finding in this small cohort needs to be replicated in a larger study because our study is susceptible to both type I and type II statistical error. We found that QFT positivity was associated with a more rapid rate of decline in GFR, but this association may be coincidental (with the difference in decline attributed to differences in the blood pressure or proteinuria of the two groups). Moreover, an association does not necessarily mean causality, although it would be interesting to speculate if we are identifying patients with latent TB who have an active interstitial nephritis. Another intriguing possibility is that this assay identifies patients with an immunological phenotype that predisposes to eGFR loss. PMID- 20847569 TI - Demographic and clinical characteristics of patients with autosomal dominant polycystic kidney disease: a multicenter experience. AB - AIM: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. It accounts for 5-10% of patients with end-stage renal disease (ESRD). The aim of this multicenter study was to investigate the demographic and clinical characteristics of patients with ADPKD. METHODS: 1,139 patients with ADPKD who were followed up at 12 different centers were recruited for this study. The investigated demographic and clinical characteristics were gender, age, smoking history, educational status, the existence of hypertension, hematuria, urinary tract infection, urinary tract stones and renal replacement therapy. Patients were considered as hypertensive if they were taking antihypertensive medications or if they had blood pressure (BP) of 140/90 mm Hg or greater. If the patients were currently on antihypertensive drugs, the classes of these agents were noted. RESULTS: 548 male and 591 female patients were included and the mean age at initial diagnosis was 37.1 +/- 16.3 years. 20.3% were current smokers whereas 15% were ex-smokers. The mean systolic and diastolic BPs were 136.1 +/- 29.8 and 84.9 +/- 17.8 mm Hg, respectively. 63.7% used antihypertensive drugs and 73.1% of those used renin-angiotensin system blockers. 11.8% had ESRD, of which 75.8% were treated with hemodialysis. CONCLUSION: This study showed that hypertension is the most common (72.6%) clinical finding in ADPKD patients in Turkey and renin-angiotensin system blockers are widely used. PMID- 20847570 TI - Clinical significance of early-onset hyperuricemia in renal transplant recipients. AB - BACKGROUND/AIMS: It is undetermined whether the effect of uric acid (UA) on graft outcome is independent of graft dysfunction. This study was designed to explore whether early-onset hyperuricemia has clinical significance regardless of graft function. METHODS: This study was conducted based on a retrospective chart review. We calculated time-averaged UA and estimated glomerular filtration rate from the values at 3, 6, and 9 months after transplantation. Cardiovascular complications during follow-up and long-term graft survival were assessed according to UA levels and graft function. RESULTS: 351 patients were enrolled into this study. Hyperuricemia increased the risk of cardiovascular complications (HR = 2.8, 95% CI 1.1-7.1; p = 0.02), but reduced graft function did not. In the hyperuricemia group, 5- and 10-year graft survival was significantly lower than in the normouricemia group (89 and 81% vs. 96 and 92%, respectively; p = 0.02). In the reduced graft function group, these values were also lower than in the normal graft function group (89 and 81% vs. 96 and 93%, respectively; p = 0.02). In the multivariate analysis, both hyperuricemia and reduced graft function were independent risk factors for graft failure and the presence of both factors presented the highest risk. CONCLUSION: Early-onset hyperuricemia is a significant predictor of cardiovascular complications and graft survival independently of graft function. PMID- 20847571 TI - Early acute kidney injury is a risk factor that predicts mortality in patients treated with colistin. AB - The nephrotoxicity of colistin has been reported in the literature. A previous report has shown that acute kidney injury (AKI) occurred after an average of 13.5 days, but we have experienced that AKI developed with colistin administration earlier. We investigated clinical features of patients who developed AKI according to the time of AKI development after colistin use. We retrospectively collected the data of the patients who were admitted to 4 hospitals between January 2007 and May 2009. This study included 119 patients who had received intravenous colistin for over 72 h. We compared the early AKI group (AKI developed within 7 days) with the late AKI group. The patients' age was 64.1 +/- 14.0 years. AKI occurred in 65 of the 119 patients (54.6%). The duration of colistin use was 7.7 +/- 6.4 days. AKI occurred in 46 patients within 7 days after colistin treatment and in 19 patients after 7 days. The patients with early AKI had a higher mortality rate than those with late AKI (OR: 4.37, 95% CI: 1.34, 14.18). In conclusion, clinicians might be cautioned that the mortality rate is higher for the patients with early occurrence of AKI than that for the patients with late occurrence of AKI. PMID- 20847572 TI - Validation of biochemical markers for the prediction of liver fibrosis and necroinflammatory activity in hemodialysis patients with chronic hepatitis C. AB - BACKGROUND: Liver biopsy is an imperfect gold standard for assessing the disease severity in hemodialysis patients with chronic hepatitis C. Our purpose was to compare the accuracy of the FibroTest (FT) and ActiTest (AT) with liver biopsy and the AST-to-platelet ratio index (APRI) in determining hepatic fibrosis and necroinflammatory activity in hemodialysis patients with hepatitis C virus (HCV). METHODS: The FT-AT index combining 6 biochemical markers was assessed in 33 hemodialysis patients with HCV. Liver fibrosis and necroinflammatory activity was staged and graded according to the METAVIR scoring system. RESULTS: The accuracy of FT-AT versus biopsy was 0.46 for significant fibrosis and 0.36 for severe necroinflammatory activity. The FT index had a positive predictive value of 20% for scores greater than 0.6 and a negative predictive value of 45% for scores less than 0.2. Eleven of the 33 patients had scores <=0.2, 6 had significant fibrosis on biopsy. Four out of 5 patients with FT scores >0.6 had mild fibrosis. APRI correlated well with the biopsy. CONCLUSION: The FT-AT test does not seem to be a reliable noninvasive marker for the prediction of necroinflammatory activity and fibrosis in hemodialysis patients with HCV and cannot be used as an alternative to either liver biopsy or APRI. PMID- 20847573 TI - Threshold suprachoroidal-transretinal stimulation current required by different size electrodes in rabbit eyes. AB - AIMS: To evaluate the threshold currents required by different-size electrodes under various stimulus parameters by suprachoroidal-transretinal stimulation (STS) in rabbit eyes. METHODS: An electrode array with 4 differently sized electrode contacts (50, 150, 350 and 500 MUm in diameter) was implanted into the suprachoroidal space of the rabbit eyes. The electrically evoked potential was recorded extradurally on the visual cortex, and the threshold was measured for each size electrode by a biphasic current pulse at the pulse durations of 0.25, 0.5, 0.75 and 1.0 ms. Stimuli were applied at 1, 2 and 4 Hz. RESULTS: The current thresholds with the 50-MUm electrode were 80 +/- 21.2 and 41.4 +/- 6.5 MUA for 0.25- and 1.0-ms pulses, respectively. That obviously exceeded the limits for safe stimulation with platinum. Compared to 350- and 500-MUm electrodes, a lower threshold can be obtained by the 150-MUm electrode just at 1 Hz. And the most significant change in the threshold as the stimulus frequency increased to 4 Hz was obtained by the 150-MUm electrode with short-duration pulse (0.25 ms). CONCLUSION: The large surface electrode with long-duration pulses may be preferable for the STS prosthesis. And stimuli with low frequency are suggested to be the safer choice. PMID- 20847574 TI - Closure of sclerotomies after 25- and 23-gauge transconjunctival sutureless pars plana vitrectomy evaluated by optical coherence tomography. AB - AIMS: To evaluate sclerotomy closure after 25- and 23-gauge transconjunctival sutureless pars plana vitrectomy using optical coherence tomography (OCT). METHODS: Forty-eight eyes (20 with a macular hole and 28 with an epiretinal membrane) of 47 patients (mean age, 66.5 years) who underwent one of the two procedures were included. Three sclerotomy sites in each eye were measured by cross-sectional OCT images vertical and parallel to the limbus on weeks 1 and 2 and months 1, 2 and 3 postoperatively. RESULTS: After 25-gauge vitrectomy, the scleral wounds evaluated by OCT closed in 40.6% of the eyes at 1 week, 53.3% at 2 weeks, 60.5% at 1 month, 63.6% at 2 months and 63.9% at 3 months. There were significant differences in the closure rates between 1 week and 1 month (p = 0.015), 2 months (p = 0.007) and 3 months (p = 0.006) postoperatively. After 23 gauge vitrectomy, the scleral wounds closed in 31.6% of the eyes at 1 week, 50.0% at 2 weeks, 57.4% at 1 month, 63.0% at 2 months, and 61.1% at 3 months postoperatively. There were significant differences in the closure rates between 1 week and 1 month (p = 0.011), 2 months (p = 0.001) and 3 months (p = 0.002) postoperatively. The wound closure rates did not differ significantly between the two procedures. CONCLUSIONS: Scleral wounds after 25- and 23-gauge transconjunctival sutureless pars plana vitrectomy can be evaluated with OCT. Wound healing seems to be complete 2 weeks postoperatively. PMID- 20847575 TI - Intravitreal ranibizumab and bevacizumab in combination with full-fluence verteporfin therapy and dexamethasone for exudative age-related macular degeneration. AB - PURPOSE: To evaluate the efficacy and safety of triple therapy with intravitreal anti-vascular-endothelial-growth-factor (VEGF) antibody, dexamethasone and verteporfin photodynamic therapy (PDT) for exudative age-related macular degeneration (AMD). METHODS: Retrospective, comparative, interventional study. Records of treatment-naive patients who received intravitreal bevacizumab or ranibizumab in monotherapy or in combination with dexamethasone and full-fluence verteporfin PDT in triple therapy were reviewed. logMAR visual acuity, foveal thickness (FT) on optical coherence tomography, intraocular pressure and endophthalmitis occurrence were recorded. RESULTS: Sixty-one eyes were included in the triple-therapy group, 40 eyes were included in the monotherapy group. The mean follow-up was 14.1 +/- 3.4 months in the triple-therapy group and 16.3 +/- 4.1 months in the monotherapy group. The triple-therapy group enjoyed a lower total number of treatments (1.92 +/- 0.44 vs. 3.12 +/- 0.37, p < 0.001) and a longer time before first retreatment (5.4 +/- 3.3 vs. 3.6 +/- 2.5 months, p = 0.001). A significant improvement of visual acuity and FT was present in both groups during the 12 months following first treatment. No adverse effects were observed. CONCLUSION: The combination of intravitreal bevacizumab or ranibizumabwith dexamethasone and full-fluence PDT for exudative AMD provided visual and anatomic improvement and a good safety profile. Triple therapy may reduce the number of retreatments when compared to anti-VEGF alone. PMID- 20847576 TI - New corneal neovascularization model in rabbits for angiogenesis research. AB - PURPOSE: To evaluate a new experimental model of suture-induced corneal neovascularization (NV) for angiogenesis research. METHODS: The new model was created in the right eye of 20 New Zealand rabbits using 5 interrupted silk sutures following an inverted triangle pattern. At different time points after suture placement, calibrated photographs were taken to quantify the corneal surface covered by the sutures (SCS) and the corneal NV response. At the end of the experiment, the corneas were processed for histological study. RESULTS: Vascular sprouts were already observed on the 3rd day. On the 7th day, the mean corneal NV surface was 19.02 +/- 4.65 mm(2). On the 14th day, the mean corneal NV surface increased up to 28.96 +/- 6.33 mm(2), representing 112.18% of the SCS and 21.04% of the total corneal surface. Histological sections showed that the new vessels were located at the two anterior thirds of the corneal stroma with an intense inflammatory infiltration. CONCLUSION: Our results indicate that this experimental model is effective, reliable and reproducible to induce corneal NV for angiogenesis research. PMID- 20847577 TI - Vascular endothelial growth factor gene polymorphisms and risk of neovascular age related macular degeneration in a Chinese cohort. AB - AIMS: To evaluate the association between vascular endothelial growth factor (VEGF) gene polymorphism and the risk of neovascular age-related macular degeneration (AMD) in a case-control study in a Chinese cohort. METHODS: We genotyped 4 common single-nucleotide polymorphisms (SNPs), namely -460T/C (rs833061), +405C/G (rs2010963), +674C/T (rs1413711) and +936C/T (rs3025039), simultaneously detected 7 tag SNPs (tSNPs) in the VEGF gene, in 159 neovascular AMD patients and 140 age- and sex-matched control subjects. Genetic analyses for an additive, dominant and recessive model were performed on all available genotype data. All the possible haplotypes of these 11 SNPs were detected. RESULTS: No evident association was found in the allele frequencies of any individual SNP between patients and controls; the combined p values in each genotype group were greater than 0.05. Haplotype analyses of these SNPs did not provide any evidence for an association with the risk of neovascular AMD in this Chinese cohort (p > 0.05). CONCLUSIONS: Detection of 4 common SNPs and 7 tSNPs in the VEGF gene did not find any statistically significant association with neovascular AMD in the Chinese cohort. Further studies of comprehensive VEGF gene variations are required to characterize the susceptibility of the VEGF gene in the pathogenesis of AMD. PMID- 20847578 TI - Sharp-object-induced open-globe injuries in Iranian children admitted to a major tertiary center: a prospective review of 125 cases. AB - Ocular trauma in children can result in catastrophic visual and psychological outcomes both for the child and his/her family. According to the WHO, childhood blindness is one of the major causes of avoidable blindness and so target of the Vision 2020 program. To achieve this program's goals, it is necessary to explore the epidemiological patterns of ocular trauma in different countries which in its turn could be a valuable means to guide us in developing preventive measures. Our study is a hospital-based prospective study which was conducted to reveal detailed information about children who were admitted to a large tertiary care hospital with the diagnosis of lacerating globe injury due to a sharp object. PATIENTS AND METHODS: During a 6-month period (December 2006 to June 2007), 125 eyes of 125 children (age <=16 years) with the diagnosis of open-globe injury were enrolled. Clinical data were documented. Demographic data and details of the event were explored and documented based on the study questionnaire (adopting the Birmingham Eye Trauma Terminology and the United States Eye Injury Registry model as basis) by interviewing the parents and the child. RESULTS: The mean age was 8.5 years (SD = 4.36 years, range: 1-16). The boys:girls ratio was 2.5:1; this ratio was age dependent, showing a significant increase with age. The home was the most frequent place (61.7%) for the trauma to occur in. Most traumas (50%) occurred in the afternoon (12 midday to 6 p.m.). Almost half of the traumas were unintentional self-injuries and occurred when the child was alone. A knife and fireworks were the two most frequent causes of injury. CONCLUSION: As the home is the most common place of ocular trauma in this age group and as lack of proper supervision and accessibility of sharp objects such as knives are the background of the event in most cases, it is strongly recommended to educate parents about providing a safe environment at home for their children. Work-related eye injuries in this age group should also be reduced by regulations for prohibiting children's work or at least providing the necessary education and safety goggles. PMID- 20847579 TI - Better speech recognition in noise with the fine structure processing coding strategy. AB - BACKGROUND: Recently, a new speech coding strategy named 'fine structure processing' (FSP) has been launched. METHODS: 32 subjects, all users of the MED EL PULSARCI(100) system, have been switched over from a TEMPO+ to an OPUS 2 speech processor. In 22 subjects, the FSP strategy could be implemented (FSP group), in 10 patients not (high-definition continuous interleaved sampling, HDCIS, group). Subjects were tested with the Tempo+ (CIS+) just before switch over and after 12 months of OPUS 2 (FSP/HDCIS) use. Performance with FSP/HDCIS was tested at switch-over, and after 1, 3, 6 and 12 months. A sentence-in-noise test and a Speech Spatial and Qualities of Hearing Scale (SSQ) questionnaire were assessed at each test interval. RESULTS: In the FSP group, the speech reception threshold shows a deterioration of 3.3 dB (n.s.) at the acute switch-over interval, but a significant improvement over time (p < 0.001) with a final benefit of 6.5 dB after 12 months of FSP use. A significant improvement over time can also be seen on the spatial subscore of the SSQ questionnaire (p = 0.009). No significant differences could be seen in the HDCIS group. CONCLUSION: The results show that by enhancing fine structure coding in the lower frequencies, as implemented in the FSP coding strategy, speech perception in noise can be enhanced. PMID- 20847580 TI - Speech perception with cochlear implants as measured using a roving-level adaptive test method. AB - AIMS: This paper uses a new method of speech testing where the hearing aid or cochlear implant (CI) users are tested in a more realistic listening situation. METHODS: Groups of 11 subjects matched for performance with 5 different CI systems, for a total of 55 subjects, were tested with an adaptive test regime where the presentation level of the speech signal roved by +/-10 or +/-15 dB. RESULTS: Speech reception thresholds varied widely between -4.8 and 17.3 dB with the +/-15 dB roving condition being more difficult than the +/-10 dB roving condition. We also found significant differences in speech reception threshold between groups using different devices. CONCLUSION: The test method used in our study, which attempts to test CI users in a more realistic listening situation, is sensitive to the effects of various subject-specific and technical parameters on everyday speech perception with CIs. PMID- 20847581 TI - Expression profile of p63 in 127 patients with laryngeal squamous cell carcinoma. AB - OBJECTIVES: To evaluate p63 expression in laryngeal squamous cell carcinoma and its prognostic significance. METHODS: p63 expression was examined by immunohistochemistry and scored in 127 patients with laryngeal squamous cell carcinomas. RESULTS: Sixty-two cases had scored 3, sixty had scored 2, four had scored 1 and one case did not show any expression (48.8, 47.2, 3.1 and 0.8%, respectively). Overall survival was 73.9% at 24 months and 59.5% at 60 months. The disease-free survival was 77.2 and 75.1%, and the disease-specific survival was 79 and 67% at 24 and 60 months, respectively. Uni- and multivariate analysis identified that decreased immunoexpression of protein p63 was a statistically significant factor for the risk of recurrence and death by cancer. CONCLUSIONS: p63 expression was highly prevalent in laryngeal squamous cell carcinomas, and its underexpression was correlated with a worse prognosis. PMID- 20847582 TI - Expression of IL-17 and its role in bone destruction in human middle ear cholesteatoma. AB - PURPOSE: The present study was designed to elucidate the immunoreactivity and protein level of IL-17 in human cholesteatomas. PROCEDURES: The expression and localization of IL-17 and receptor activator of nuclear factor kappaB ligand (RANKL) were examined by immunohistochemistry in tissue specimens collected from 24 patients with cholesteatomas. The cellular sources of IL-17 were assessed by double staining with CD4. The level of IL-17 protein was determined using an enzyme-linked immunosorbent assay. The degree of bone destruction was compared with the IL-17 immunoreactivity. RESULTS: IL-17 immunoreactivity was detected in the inflammatory cells in the granulation tissues and there were increased levels of IL-17 protein. The localization of IL-17 expression coincided with CD4 positive lymphocytes. IL-17 was correlated with the cells positive for RANKL. The degree of bone destruction was dependent on the number of infiltrated IL-17 positive cells. IL-17-driven pathology was observed in the congenital type as compared with the acquired type. CONCLUSIONS: The present study suggests that IL 17 is related to the pathogenesis of the disease. PMID- 20847583 TI - Pancreatic stellate cell models for transcriptional studies of desmoplasia associated genes. AB - BACKGROUND: Pancreatic stellate cells are emerging as key players in pathophysiopathological processes underlying the development of pancreatic disease, including pancreatitis and cancer. The cells are scarce in the pancreas making their isolation time and resource use consuming. METHODS: Therefore, with the ultimate goal of facilitating mechanistic studies, here we report the isolation, characterization, and immortalization of stellate cell lines from rat and mouse origin. RESULTS: These cell lines display morphological and molecular markers as well as non-tumorigenic characteristics similar to the frequently used hepatic counterparts. In addition, we have tested their robustness as a model for transcriptional regulatory studies. We find that these cells respond well to TGFbeta signaling by triggering a distinct cascade of gene expression, some genes overlap with the TGFbeta response of LX2 cells. These cells express several key chromatin proteins and epigenetic regulators involved in the regulation of gene expression, including co-repressors such as Sin3A (short-term repression), HP1 (long-term repression), as well as CBP/p300 (activation). Furthermore, these cells are well suited for Gal4-based transcriptional activation and repression assays. CONCLUSIONS: The cell model reported here may therefore help fuel investigations in the field of signaling, transcription, and perhaps other studies on similarly exciting cellular processes. and IAP. PMID- 20847584 TI - Psychometric evaluation of the characteristics of delusions rating scale as an expert rating scale. AB - BACKGROUND: Research suggests delusions may be better viewed as multidimensional rather than dichotomous phenomena. The aim of this study was to assess the reliability and validity of a German version of the Characteristics of Delusions Rating Scale (CDRS) as an expert rating scale. METHOD: 200 inpatients with schizophrenic spectrum and affective disorders with delusions were assessed with the CDRS and other delusion rating scales. Factorial validity was analysed, and differences between diagnostic groups on the CDRS subscales as well as on the total score were examined. RESULTS: The CDRS was found to have good inter-rater reliability and internal consistency as an expert rating. Factor analysis yielded an interpretable structure with 3 factors - cognition, emotion and bizarreness - accounting for 70% of the variance. The convergent and differential validity of the scales was supported. Compared to other scales, the CDRS measures all dimensions of delusional experience that have been suggested to date with the exception of behavioural aspects. CONCLUSIONS: The results support the view of delusions as multidimensional phenomena. The CDRS as an expert rating is a reliable and valid assessment tool for dimensions of delusional experience and an economical instrument for research and clinical practice. Further research is needed to examine the dimensional structure underlying delusional phenomena and the relationship of the dimensions to neurobiological and psychotherapeutic processes. PMID- 20847585 TI - Validation of the combined emotional and affective temperament scale in a large sample with high prevalence of psychiatric disorders. AB - BACKGROUND: Based on a model where temperament works as a system with activation, inhibition and control, which produce the affective tone, we developed and validated the Combined Emotional and Affective Temperament Scale (CEATS). This paper aims to validate the CEATS in a large population with high prevalence of psychiatric disorders. METHODS: 4,381 subjects (25.5% males) completed an internet version of the scale on a psychoeducational website on bipolar disorders. The CEATS has both emotional and affective sections and an evaluation of problems and benefits related to temperament. Data were analyzed with standard psychometric batteries. RESULTS: In the emotional section, four factors with an eigenvalue >1 explained 47.3% of the variation. They were interpreted as anger, control, fear and drive. They had a normal distribution and satisfactory Chronbach's alphas. Anger was particularly associated with problems, and drive with benefits. In the Affective section, all 10 categorical affective temperaments were selected, cyclothymic being the most prevalent (32%), and 97.6% of the sample was able to ascribe to at least one affective temperament. Only the euthymic and hyperthymic temperaments were associated with a favorable problem/benefit profile. Each affective temperament had a particular emotional configuration. CONCLUSION: The CEATS is adequate to assess emotional and affective temperament in subjects with high prevalence of psychiatric disorders. PMID- 20847586 TI - Obsessive-compulsive spectrum disorders in obsessive-compulsive disorder and other anxiety disorders. AB - BACKGROUND: There has been debate about whether obsessive-compulsive disorder (OCD) should be classified as one of the anxiety disorders, or should rather be categorized with obsessive-compulsive spectrum conditions. SAMPLING AND METHODS: The question of where OCD should be located in the diagnostic system was addressed by investigating the relationship of OCD, obsessive-compulsive spectrum disorders (OCSDs), and anxiety disorders. We administered a structured diagnostic interview (the SCID-OCSD) for assessing putative OCSDs in patients who presented with a primary diagnosis of OCD, panic disorder with/out agoraphobia (PD) or social anxiety disorder (SAD) in an attempt to address the proposed differentiation of OCD from the other DSM-IV anxiety disorders. RESULTS: Patients with OCD were significantly more likely to have multiple comorbid putative OCSDs than patients with PD or SAD. Some OCSDs, i.e. any tic disorder/Tourette's disorder as well as body-focused repetitive behaviors (self-injury, trichotillomania), and certain impulsive/reward-focused disorders (kleptomania, hypersexual disorder) were more common in OCD. Some of the putative OCSDs (e.g. hypochondriasis and body dysmorphic disorder) were more common in PD and SAD, respectively. Depression had equally high comorbidity with OCD, PD, and SAD, while generalized anxiety disorder and alcohol dependence were particularly associated with SAD. CONCLUSIONS: These findings suggest that some putative OCSDs may be related to OCD, while some may have a closer relationship to other anxiety disorders. From a nosological perspective, it may be useful to include OCD and certain OCSDs under the rubric of an enlarged category of anxiety and OCSDs. PMID- 20847588 TI - Are marketed topical metronidazole creams bioequivalent? Evaluation by in vivo microdialysis sampling and tape stripping methodology. AB - AIM: To evaluate the bioequivalence of 3 marketed topical metronidazole formulations by simultaneous dermal microdialysis and stratum corneum sampling by the tape stripping methodology, and to compare the techniques as tools for the determination of bioequivalence. METHODS: Nine microdialysis probes were inserted in the volar aspect of the left forearm of 14 healthy volunteers and, following application of the 3 metronidazole creams, microdialysis samples were collected for 5 h. On the right forearm, tape strip sampling was performed 30 and 120 min after product application. At the end of the experiment, ultrasound scanning measurements confirmed that all probes were placed inside the dermis. RESULTS: There was no statistical difference in penetration of the 3 topicals as determined by microdialysis. However, their bioequivalence could not be determined due to intersubject variability exceeding the criteria for bioequivalence evaluation. Tape strip sampling established a bioequivalence between 2 of the creams, but rejected any bioequivalence between these 2 formulations and the third. The third formulation was a generic formulation approved despite containing a lower concentration of metronidazole (0.75%) than the innovator formulation (1.0%). The result of the bioequivalence evaluation depends on the methodology employed. CONCLUSION: Whenever the dermis is the target tissue, microdialysis provides the most relevant information on drug bioavailability. PMID- 20847589 TI - Isolation of a fission yeast mutant cell affected in MAP kinase signaling and sterol biosynthesis. AB - We have previously demonstrated that calcineurin and the Pmk1 MAP kinase pathway play an antagonistic role in Cl-homeostasis. Using this relationship, we screened for mutations that show vic (viable in the presence of immunosuppressant and chloride ion) phenotype and isolated a vic6 mutant cell. The vic6 mutant cells also showed sensitivity to high temperature. Using this phenotype, we isolated hmg1+ gene, encoding a HMG-CoA reductase. Consistently, the vic6 mutant cells exhibited hypersensitivity to miconazole, an inhibitor of ergosterol biosynthesis and showed aberrant intracellular localization of filipin, suggesting that the mutant cells are affected in the sterol biosynthesis. In addition, overexpression of the hmg1+ gene complemented the phenotype of vic1-1/cpp1-v1 mutant cells, an allele of the gene encoding a farnesyltransferase, whereas overexpression of the cpp1+ gene exacerbated the temperature-sensitive phenotype of the vic6 mutant cells. PMID- 20847590 TI - Elevation of vascular endothelial growth factor in Indonesian advanced stage nasopharyngeal carcinoma. AB - Studies on the role of vascular endothelial growth factor (VEGF) as the most potent angiogenic factor in disease progression of nasopharyngeal carcinoma (NPC) remain limited, partly be due to the geographical distribution of the disease. However, it has never been reported from Indonesian population despite its common incidence. Therefore, we aimed to study the possible prognostic value of VEGF in Indonesian advanced stage NPC. A clinical examination, CT scan, and the tumor tissue and plasma collection were performed before a combined therapy, and a local control rate was reassessed every 3 months to determine progression-free survival (PFS). Plasma VEGF-A was measured in 40 patients by ELISA, and VEGF and vWF expressions were examined in 30 patients by immunohistochemistry. Survival curves were plotted based on plasma VEGF-A level, VEGF, and microvessel density (MVD) count indicated by vWF expressions vs PFS. The median follow up was 16 months. Patients with high VEGF-A level (>= 834pg/ml) presented shorter survival rate, as compared to those of low level (< 834pg/ml) (41.2% vs 82.6%; p=0.009, log rank 6.81). Patients with overexpressed VEGF (>= 25%) showed shorter survival than those with low expression (<25%) (45.5% vs 79.6%; p=0.05, log rank 3.84). Patients with higher MVD count (>= 25%) also had shorter survival than those with lower MVD count (53.4% vs 80%; p=0.101, log rank=2.70). In conclusion, an elevated plasma VEGF level predicts shorter survival for Indonesian advanced stage NPC in this study. However, more samples may be required to draw a better conclusion on a possible role of VEGF as a prognostic factor in the disease progression of NPC. This data is also substantial for the development of anti VEGF as a possible targeted therapy for NPC. PMID- 20847591 TI - Regulation of SREBP1c expression by mTOR signaling in hepatocytes. AB - The transcription factor sterol regulatory element-binding protein 1c (SREBP1c) plays an important role in the regulation of fatty acid metabolism in the liver. Although the importance of phosphoinositide 3-kinase in the regulation of SREBP1c expression is widely accepted, the role of mammalian target of rapamycin (mTOR) in such regulation has remained unclear. We have now shown that the insulin induced increase in the abundance of SREBP1c mRNA in cultured AML12 mouse hepatocytes was largely abolished by LY294002, an inhibitor of phosphoinositide 3 kinase, but was reduced only slightly by rapamycin, an inhibitor of mTOR. Forced expression of a constitutively active form of Akt containing a myristoylation signal sequence (MyrAkt) in these cells with the use of an adenoviral vector resulted in the phosphorylation of p70 S6 kinase, a downstream target of mTOR signaling, and this effect was inhibited by rapamycin. MyrAkt also increased the abundance of SREBP1c mRNA and protein as well as the expression of the SREBP1c target genes for fatty acid synthase and stearoyl-CoA desaturase 1. These effects of MyrAkt were also markedly inhibited by LY294002 and by rapamycin. These results thus suggest that mTOR signaling plays a major role in Akt-mediated up regulation of SREBP1c expression but that it plays only a minor role in insulin induced expression of this transcription factor. PMID- 20847592 TI - Ontology driven modeling for the knowledge of genetic susceptibility to disease. AB - For the machine helped exploring the relationships between genetic factors and complex diseases, a well-structured conceptual framework of the background knowledge is needed. However, because of the complexity of determining a genetic susceptibility factor, there is no formalization for the knowledge of genetic susceptibility to disease, which makes the interoperability between systems impossible. Thus, the ontology modeling language OWL was used for formalization in this paper. After introducing the Semantic Web and OWL language propagated by W3C, we applied text mining technology combined with competency questions to specify the classes of the ontology. Then, an N-ary pattern was adopted to describe the relationships among these defined classes. Based on the former work of OGSF-DM (Ontology of Genetic Susceptibility Factors to Diabetes Mellitus), we formalized the definition of "Genetic Susceptibility", "Genetic Susceptibility Factor" and other classes by using OWL-DL modeling language; and a reasoner automatically performed the classification of the class "Genetic Susceptibility Factor". CONCLUSION: The ontology driven modeling is used for formalization the knowledge of genetic susceptibility to complex diseases. More importantly, when a class has been completely formalized in an ontology, the OWL reasoning can automatically compute the classification of the class, in our case, the class of "Genetic Susceptibility Factors". With more types of genetic susceptibility factors obtained from the laboratory research, our ontologies always needs to be refined, and many new classes must be taken into account to harmonize with the ontologies. Using the ontologies to develop the semantic web needs to be applied in the future. PMID- 20847593 TI - Metastasis to the lingual lymph node in patients with squamous cell carcinoma of the floor of the mouth: a report of two cases. AB - Cancer of the tongue or the floor of the mouth sometimes metastasizes to the lingual lymph node. We present two patients with squamous cell carcinoma of the floor of the mouth who developed metastases to the lateral lingual lymph nodes. Case 1, a 62-year old male, had squamous cell carcinoma of the floor of the mouth (T3N2cM0). He underwent tumor resection and bilateral neck dissection, and histological examination revealed five metastatic nodes including the lateral lingual node near the hyoid bone. No recurrent tumors were evident, but he died of pneumonia 10 months after the surgery. Case 2, a 62-year old male, had squamous cell carcinoma of the floor of the mouth (T2N2cM0). He underwent tumor resection and bilateral neck dissection, and histological examination revealed three metastatic nodes including the lateral lingual node near the sublingual gland. No recurrence was found in the oral and neck regions, but he died of liver metastasis 18 months after the surgery. Metastasis to the lingual lymph node may cause a recurrence of oral cancer in the neck, since conventional neck dissection cannot remove this node even in the case of en bloc resection of the primary tumor and the neck. When CT, MRI, or intra-operative palpation findings lead to a suspicion of metastasis to the lingual lymph node, the area of neck dissection should be extended to include this node. PMID- 20847594 TI - Analysis of 472 Branemark system TiUnite implants:a retrospective study. AB - PURPOSE: The purpose of this retrospective study was to determine the success of Branemark System TiUnite implants (Nobel Biocare/Sweden) placed in partially or completely edentulous jaws restored with fixed or removable prostheses. PATIENTS AND METHODS: A total of 131 jaws from 110 patients (64 maxillae and 67 mandibles) received 472 implants from July 2003 until March 2008. The patients included 57 men and 53 women, with a median age of 49.6 years and an age range of 16 to 90 years at the time of implant surgery. Twelve maxillae and 10 mandibles were completely edentulous, and 52 maxillae and 57 mandibles were partially edentulous. A single implant was placed in 21 jaws (10 maxillae and 11 mandibles), while multiple implants were placed in the other patients. Among the 131 jaws, removable prostheses were mounted in 10 maxillae and 8 mandibles, and the other jaws were restored with fixed prostheses. RESULTS: Among the 472 implants, 6 maxillary implants and 5 mandibular implants were unsuccessful. The success rate for the implants was 96.56% (96.07% in the maxillae and 97.18% in the mandibles). PMID- 20847595 TI - A transgenic mouse line with a 58-kb fragment deletion in chromosome 11E1 that encompasses part of the Fam20a gene and its upstream region shows growth disorder. AB - Growth disorder is an umbrella term for a range of abnormal growth patterns, such as unusually fast or slow growth in infants or children. The causes of growth disorder include hormonal irregularities, chronic disease, complications during pregnancy or genetic conditions. A complex trait such as body size is influenced by multiple genes as well as environmental factors, giving rise to a continuous spectrum of phenotypes. This causal complexity makes discovery of the genetic determinants of growth disorder rather difficult. We here report our discovery of a transgenic mouse line exhibiting growth disorder, which we happened to discover in the course of generating transgenic mice expressing a viral gene. Although these mice did not express any corresponding viral mRNA or protein due to a deletion in the transgene, they showed slow growth in the 5 weeks after birth and ceased growing thereafter, while maintaining a weight equivalent to that of 3 week-old normal mice. Histopathological analysis of the organs of these mice revealed that malnutrition and metabolic disorder occurred at 5 weeks after birth in the liver. Genetic analysis has revealed that the growth disorder is associated with a 58-kb fragment deletion in chromosome 11E1 that encompasses part of the Fam20a gene and part of its upstream region. The present study thus points out for the first time the possible link between Fam20a mutation and growth disorder. PMID- 20847596 TI - Stress fracture of the fifth metatarsal bone as a late complication of total knee arthroplasty. AB - A 64-year-old man had undergone a right total knee arthroplasty (TKA) as treatment for osteoarthritis of the knee. Six months after the TKA, the patient sustained a stress fracture of the left fifth metatarsal bone, which was a contralateral side of the TKA, without any apparent trauma or cause. The fracture was treated with internal fixation using a screw and low-intensity pulsed ultrasound treatment was added. During two-year followup after internal fixation of the fifth metatarsal fracture, he had no complaints in the knee or foot. The patient felt anxiety of breakage or loosening of the implant of TKA and the patient had been walking bearing mainly on his left leg and foot which was a contralateral side of the TKA. The cause of the stress fracture of the fifth metatarsal bone was speculated to be excessive stress of weight bearing to the left foot during walking. The physicians should be aware of the risk of stress fracture of the fifth metatarsal bone as one of a rare late complication associated with TKA. It is very important to educate the patients, explaining the risk of breakage or loosening of the implant of TKA and instructing the adequate physical and mental benefits of walking. PMID- 20847597 TI - Effects of calcium phosphate cement on the peripheral nerve fibers. AB - Calcium phosphate cement (CPC) is a bioactive ceramic substance. To clarify the effects of CPC on the peripheral nerve, we applied CPC on the peripheral nerve fibers of experimental animals and investigated the nerve fibers by electron microscopy and by immunoblotting analysis using an anti-myelin-associated glycoprotein (anti-MAG) antibody. The results showed that there was neither axonal sprouting at the nodes of Ranvier nor down-regulation of MAG beyond the normal level in the nerve fibers. These findings suggest that there is no harm in using CPC near the peripheral nerve fibers. PMID- 20847598 TI - A new in vitro model of cancer invasion using AlloDerm, a human cadaveric dermal equivalent: a preliminary report. AB - OBJECTIVES: The first stage in the metastasis of squamous cell carcinoma (SCC) of the oral cavity involves the destruction of the basement membrane and invasion into the submucosal tissue. The purpose of this study is to develop a new in vitro model of cancer invasion using a human dermal equivalent, AlloDerm. STUDY DESIGN: Normal epithelial cells from a gingiva and a SCC line originating from human tongue cancer (HSC-3 and 4 cells) were cultured on AlloDerm, and composites of these cells and AlloDerm were evaluated histologically by HE staining and immunostaining with anti-laminin and type IV collagen antibodies. Furthermore, HSC-3 and 4 cells were transplanted into the tongues of nude mice, and regional lymph node metastases were examined histologically. RESULTS: HSC-3 cells had invaded through the basement membrane into the AlloDerm dermis at 25 days after seeding. Decreases in the levels of laminin and type IV collagen were observed in the locations where HSC-3 had invaded. Metastasis to regional lymph nodes was observed at 3 weeks after transplantation in 4 of 10 (40%) mice. On the other hand, normal epithelial cells and HSC-4 cells did not show invasion into AlloDerm. Lymph node metastasis was not observed in the mice bearing HSC-4 cells. CONCLUSION: This experimental model using AlloDerm is a potential new in vitro model of cancer invasion. PMID- 20847599 TI - Association study of RGS2 gene polymorphisms with panic disorder in Japanese. AB - Genetic factors for panic disorder have been consistently observed in family and twin studies. Regulators of G-protein signaling (RGS) is a family of proteins that negatively regulate the intracellular signaling of G protein-coupled receptors such as dopamine and serotonin receptors. RGS2, one of the RGS families, has been suggested to plays a role in anxiety and/or aggressive behavior. Polymorphisms in the RGS2 gene were recently associated with panic disorder, trait anxiety, suicidal behavior, and generalized anxiety disorder. From these findings, we tried to replicate an association between panic disorder and genetic variations of the RGS2 using a case-control study of 186 patients with panic disorder and 380 controls in Japanese. We genotyped five common single nucleotide polymorphisms (SNPs) by the PCR-RFLP method and the TaqMan Assays. Neither genotype distribution nor allele frequency for five SNPs was significant different between the panic disorder and control groups. We found a relative tight LD block in the 5'- flanking region of RGS2 gene. One of the common haplotypes, AC of rs2746071 and rs2746072, has shown a nominally significant association with panic disorder (p=0.027). This significance, however, did not remain after correction for multiple testing. These findings suggest that RGS2 may not be genetically involved in the biological susceptibility to panic disorder in Japanese. PMID- 20847601 TI - Re-evaluation of clinical features and risk factors of acute ischemic stroke in Japanese longevity society. AB - Age is an important factor correlated with stroke prevalence and independently influences stroke outcome especially in Japanese longevity society. To re evaluate the characteristics of acute ischemic stroke in the old-old, analyses of clinical data on 426 patients registered at a Japanese tertiary emergency hospital were performed under appropriate statistical methods. Clinical features, stroke subtypes, current-known risk factors for stroke, time from onset to arrival, the National Institute of Health Stroke scale (NIHSS) score on admission, length of hospital stay, modified Rankin Scale (mRS) at discharge were compared between two stratified groups by age-at-onset (?75 and < 75 years old). Significant differences were demonstrated in categories of sex, NIHSS score, length of hospital stay and m-RS. Current-known risk factors for stroke except atrial fibrillation were not prominent in the elderly group. Our study revealed that clinical phenotype and outcome in stroke patients would have been modified and re-evaluation of risk factors is necessary for prevention of ischemic stroke in Japanese longevity society. PMID- 20847600 TI - Signet-ring cell carcinoma of the stomach metastasizing to renal cell carcinoma: a case report and review of the literature. AB - Metastasis of one neoplasm to another is also known as metastasis of "tumor to tumor", "cancer to cancer", "tumor in tumor", and "one to another". We describe the case of a 75-year-old woman with the metastasis of signet-ring cell carcinoma of the stomach to clear cell renal cell carcinoma. Six years earlier, the patient had undergone gastrectomy for early gastric cancer. She complained of lumbago, and a mass was found in her left kidney. Examination of a partial nephrectomy revealed clear cell renal cell carcinoma containing signet-ring cells. Morphological and immunohistochemical findings of the signet-ring cells found in kidney cancer and gastric cancer were identical. Subsequent examinations revealed the patient had multiple bone metastases. The diagnosis of carcinoma metastasizing to renal cell carcinoma can be challenging; therefore, additional clinical information and immunohistochemical panel studies are requisite. PMID- 20847602 TI - [Type 2 hepatorenal syndrome in a cirrhotic patient who underwent gastric cancer surgery]. PMID- 20847603 TI - [Pathophysiology of portal hypertension, what's new?]. AB - Portal hypertension (PHT) is associated with changes in the intrahepatic, systemic and portosystemic collateral circulations. Alteration in vasoreactivity (vasodilation and vasoconstriction) plays a central role in the pathogenesis of PHT by contributing to increased intrahepatic resistance, hyperdynamic circulation and the expansion of the collateral circulation. PHT is also importantly characterized by changes in vascular structure; termed vascular remodeling, which is an adaptive response of the vessel wall that occurs in response to chronic changes in the environment such as shear stress. Angiogenesis, the sprouting of new blood vessels, also occurs in PHT, especially in the expansion of the portosystemic collateral circulation. These complementary processes of vasoreactivity, vascular remodeling and angiogenesis represent important targets in the research for the treatment of portal hypertension. PMID- 20847604 TI - [Recent advances in diagnosis of portal hypertension]. AB - Complications of portal hypertension are major concerns in liver cirrhosis and significant morbidity and mortality mainly because of variceal bleeding, ascites, bacterial infections, hepatic encephalopathy, and hepatorenal syndrome. Various modalities in the diagnosis of portal hypertension are reviewed. The measurement of hepatic venous pressure gradient (HVPG) is a simple, invasive, reproducible method and regarded as the gold standard for the diagnosis and staging of portal hypertension. Other tests such as transient elastography, per-endoscopic variceal pressure measurement, endoscopic ultrasonography, and Doppler ultrasonography may be complementary and promising. PMID- 20847605 TI - [Treatment update on portal hypertension and complications]. AB - Current understanding of the pathophysiology of portal hypertension has resulted in therapeutic approaches aimed at correcting the increased splanchnic blood flow and some of which have been already used in clinical practice. Recently new perspectives opened and erstwhile paradigm has been changed to focus on increased resistance to portal blood flow and the formation of portosystemic collateralization. Several studies revealed the clear-cut mechanisms of hepatic endothelial dysfunction and abnormal angiogenesis contributing to the development of portal hypertension. Thus the modulations of hyperdynamic circulation or angiogenesis seem to be valuable therapeutic targets. In the current review update, we discuss the multidisciplinary management of modulating hepatic vascular resistance and abnormal angiogenesis associated with portal hypertension. However, these new pharmacological approaches are still under investigation and widescale clinical application are needed to develop effective strategies. PMID- 20847606 TI - [Prevention of esophageal variceal bleeding]. AB - Esophageal varices(EV) are present in 40% and 60% of Child-Pugh A and C patients, respectively when cirrhosis is diagnosed. EV bleeding is a life-threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first EV bleeding or rebleeding is mandatory. In small EV with high risk of bleeding, nonselective beta-blockers should be used for the prevention of first variceal bleeding. For medium to large EV, nonselective beta-blockers or endoscopic variceal ligation (EVL) may be recommended to high risk varices. But, nonselective beta-blockers are the first treatment option to non-high risk varices and EVL is an alternative when nonselective beta-blockers are contraindicated or not tolerated. For the prevention of rebleeding, a combination of nonselective beta-blockers and EVL may be the best option. A great improvement in the prevention of variceal bleeding has emerged over the last years. However, further therapeutic options that combine higher efficacy, better tolerance and fewer side effects are needed. PMID- 20847607 TI - [Ascites, hepatorenal syndrome and spontaneous bacterial peritonitis in patients with portal hypertension]. AB - Ascites, hepatic encephalopathy and variceal hemorrhage are three major complications of portal hypertension. The diagnostic evaluation of ascites involves an assessment of its etiology by determining the serum-ascites albumin gradient and the exclusion of spontaneous bacterial peritonitis. Ascites is primarily related to an inability to excrete an adequate amount of sodium into urine, leading to a positive sodium balance. Sodium restriction and diuretic therapy are keys of ascites control. But, with the case of refractory ascites, large volume paracentesis and transjugular portosystemic shunts are required. In hepatorenal syndrome, splanchnic vasodilatation with reduction in effective arterial volume causes intense renal vasoconstriction. Splanchnic and/or peripheral vasoconstrictors with albumin infusion, and renal replacement therapy are only bridging therapy. Liver transplantation is the only definitive modality of improving the long term prognosis. PMID- 20847608 TI - [Portal hypertensive gastropathy and gastric antral vascular ectasia]. AB - Portal hypertensive gastropathy (PHG) is a term used to define the endoscopic findings of gastric mucosa with a characteristic mosaic-like pattern with or without red spots, and a common finding in patients with portal hypertension. These endoscopic findings correspond to dilated mucosal capillaries without inflammation. The pathogenesis of PHG in not well known, but portal hypertension and some humoral factors seem to be crucial factors for its development. Pharmacological (e.g. propranolol), or interventional radiological (such as transjugular intrahepatic portosystemic shunt) procedures may be useful in preventing re-bleeding from PHG. The classic features of gastric antral vascular ectasia (GAVE) syndrome include red, often haemorrhagic lesions predominantly located in the gastric antrum which can result in significant blood loss. Although the pathogenesis of GAVE is not clearly defined, it seems to be a separate disease entity from PHG, because GAVE generally does not respond to a reduction of portal pressures. Endoscopic ablation (such as argon plasma coagulation) is the first-line treatment of choice. This review will focus on the incidence, clinical importance, etiology, pathophysiology, and treatment of PHG and GAVE syndrome in the setting of portal hypertension. PMID- 20847609 TI - [Small bowel obstruction caused by acute invasive enteric anisakiasis]. AB - Anisakiasis usually occurs in the stomach and can easily be diagnosed by digestive tract endoscopy as opposed to enteric anisakiasis which is very rare and difficult to be diagnosed definitively. The most important and useful tool in diagnosing enteric anisakiasis is obtaining an accurate patient history of having eaten raw fish before the onset of symptoms. We report a case of small bowel obstruction caused by acute invasive enteric anisakiasis. A 60-year-old woman visited the emergency room suffering from sudden abdominal pain. She had eaten raw fish 1 day before the onset of symptom. Radiologic studies showed small bowel obstruction. However, no definitive cause could be found. An emergency laparotomy revealed edematous and dilated proximal jejunum and a focal stenosis of the distal jejunum. Segmental resection of the jejunum was performed, and histopathological examination revealed enteric anisakiasis. The patient was discharged on the 7th day after surgery following an uneventful course of recovery. PMID- 20847610 TI - [A case of synchronous colonic laterally spreading tumors treated by sequential endoscopic submucosal dissection performed on two consecutive days]. AB - Endoscopic submucosal dissection (ESD) is an useful therapeutic technique for large gastrointestinal epithelial tumors that it provides an en bloc resection. Although there is some controversy about the role of ESD for colorectal lesions, for large lesions in the distal rectum, ESD has the advantage of preserving anal function. However, the large amount of insufflating gas used during the procedure can cause severe abdominal pain and discomfort. Moreover, high intra-luminal pressure caused by a by large amount of gas can cause a micro-perforation. There is no consensus as to whether ESD is the optimal treatment for synchronous large colorectal laterally spreading tumors (LSTs) that cannot be removed en-bloc by conventional endoscopic mucosal resection. Here, a case with two neighboring synchronous large LSTs, one located in the rectum and the other in the distal sigmoid colon, were sequentially removed by separate ESD procedures performed on two consecutive days in a patient who could not tolerate a long procedure. PMID- 20847611 TI - [Remission of ulcerative colitis after appendectomy: a case report]. AB - The inverse correlation of appendectomy and ulcerative colitis is well known, but the effect of appendectomy on the clinical course of ulcerative colitis remains unclear. Although the majority of opinions were negative for the therapeutic advantage of appendectomy in patients with ulcerative colitis, advocates for positive effect of appendectomy have been proposed in a few case reports and a prospective study from Western countries. We herein report a case of ulcerative colitis who experienced clinical remission after appendectomy for acute appendicitis. The patient was 35 year old male and had been managed with immunosuppressant before appendectomy. The very acute change in clinical course and a long period of remission after appendectomy highly suggest the therapeutic effect of appendectomy for ulcerative colitis. PMID- 20847612 TI - [Hemobilia as the initial manifestation of cholangiocarcinoma in a patient with choledochoduodenostomy]. AB - Hemobilia occurs when injury or disease causes communication between intrahepatic blood vessels and the intrahepatic or extrahepatic biliary system. The causes of hemobilia include trauma, gallstone disease, vascular malformation, inflammation, and biliary or hepatic tumors. Hemobilia could be diagnosed by endoscopy, hepatic angiography, computed tomography, and ultrasonogram. Patients with hemobilia may present with biliary colic, obstructive jaundice and gastrointestinal bleeding. Extrahepatic cholangiocarcinoma usually presents with obstructive jaundice and is one of the unusual cause of hemobilia. We, herein, report a case of hemobilia caused by cholangiocarcinoma in a 69-year-old woman. She had the past history of lung cancer and choledochoduodenostomy due to gallstone. Esophagogastroduodenoscopy revealed a blood clot protruding from the choledochoduodenostomy site and the ulcerative mass in the common bile duct. Pathologic examination of the ulcerative mass was compatible with those of cholangiocarcinoma. PMID- 20847613 TI - Sorafenib in combination with gemcitabine in recurrent epithelial ovarian cancer: a study of the Princess Margaret Hospital Phase II Consortium. AB - OBJECTIVES: Antiangiogenic strategies have demonstrated efficacy in epithelial ovarian cancer (EOC). Sorafenib is a novel multitargeted kinase inhibitor with antiangiogenic activity. Gemcitabine has known activity against EOC. A phase 1 clinical trial of this combination suggested activity in ovarian cancer with no dose-limiting toxicity. This phase 2 study was designed to examine the safety and efficacy of gemcitabine and sorafenib in patients with recurrent EOC. METHODS: Patients with recurrent EOC after platinum-based chemotherapy and who had subsequently received up to 3 prior chemotherapy regimens were eligible. Gemcitabine (1000 mg/m intravenous [IV]) was administered weekly for 7 of 8 weeks in the first cycle, then weekly for 3 weeks of each subsequent 4-week cycle. Sorafenib (400 mg p.o. bid) was given continuously. The primary end point for this trial was objective response rate by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included Gynecologic Cancer Intergroup (GCIG) CA-125 response, time to progression, overall survival, and toxicity. RESULTS: Forty-three patients were enrolled, and 33 completed at least 1 cycle. Two patients had a partial response (Response Evaluation Criteria in Solid Tumors objective response rate = 4.7%). Ten patients (23.3%) maintained response or stable disease for at least 6 months. GCIG CA-125 response was 27.9%. The median time to progression was 5.4 months, and the median overall survival was 13.0 months. Hematologic toxicity was common but manageable. The most common nonhematologic adverse events were hand-foot syndrome, fatigue, hypokalemia, and diarrhea. CONCLUSION: This trial of gemcitabine and sorafenib in recurrent EOC did not meet its primary efficacy end point, but the combination was associated with encouraging rates of prolonged stable disease and CA-125 response. PMID- 20847614 TI - Assessment of surgical distal margin after rectal resection for cancer. PMID- 20847615 TI - How much do we need to worry about venous thromboembolism after hospital discharge? A study of colorectal surgery patients using the National Surgical Quality Improvement Program database. AB - PURPOSE: It is well recognized that the increased risk of a postoperative venous thrombotic event extends beyond the inpatient treatment period. The purpose of this study was to determine the 30-day incidence and risk factors associated with the occurrence of early postdischarge symptomatic venous thromboembolic events in patients who have undergone major colorectal surgery. METHODS: The National Surgical Quality Improvement Program database was queried for patients who had undergone a colon or rectal resection during the study period (2005-2008). Patient demographics, preoperative risk factors, and operative variables were recorded. The primary outcomes were occurrence of deep venous thrombosis requiring therapy or pulmonary embolism within 30 days after initial surgery. The occurrence of postdischarge venous thromboembolic events was calculated from the days to primary outcome and days from operation to discharge. Univariate and multivariate linear regression models incorporating pre- and intraoperative variables as well as the occurrence of a major or minor complication were used to evaluate the effect of these clinical factors on the early postdischarge venous thromboembolic event rate. RESULTS: A total of 52,555 patients were included in the initial analysis. A total of 240 deep venous thromboses were diagnosed in the postdischarge setting giving a postdischarge incidence of 0.47%. One hundred thirty cases of a pulmonary embolus were diagnosed (0.26% incidence) with 30 patients having a concurrent deep venous thrombosis and pulmonary embolus. The overall cumulative postdischarge symptomatic venous thromboembolic incidence was 0.67% (n = 340). Obesity, preoperative steroid use, "bleeding disorder," ASA class III, and postoperative (major and minor) complications were all independently associated with an increased risk of an early postdischarge venous thromboembolic event. CONCLUSION: This study has identified risk factors that may help stratify patients into different risk profiles and offer prolonged prophylaxis to patients at increased risk on the basis of preoperative risk factors and postoperative complications. PMID- 20847616 TI - Outcomes with the use of bioprosthetic grafts to reinforce the ligation of the intersphincteric fistula tract (BioLIFT procedure) for the management of complex anal fistulas. AB - PURPOSE: This study was undertaken to determine the outcomes of patients whose complex anal fistulas were managed by ligation of the intersphincteric fistula tract reinforced with a bioprosthetic graft (BioLIFT procedure). METHODS: A retrospective analysis was performed of all patients whose anal fistula was managed by use of the BioLIFT technique between May 2005 and May 2008, who had a minimum of 1 year of follow-up after their last treatment. RESULTS: The BioLIFT technique using a bioprosthetic graft was used to treat a complex anal fistula in 31 patients (22 men, 9 women; mean age, 48 y (range, 30-68 y). Clinical healing of the fistula, defined as the absence of drainage with no evidence of residual fistula tract, occurred in 29 (94%) patients. No complications occurred that required intervention. CONCLUSIONS: The BioLIFT procedure is effective for the management of complex fistulas-in-ano. Randomized clinical trials comparing this technique with other sphincter-preserving methods for fistula management need to be performed to further determine the role of this technique in the management of anal fistulas. PMID- 20847617 TI - Close distal margin and rectal cancer recurrence after sphincter-preserving rectal resection. AB - PURPOSE: Negative surgical margins are important for local control of rectal cancer treated with sphincter-preserving surgery. However, the association of rectal cancer recurrence with close distal margin is not well established. METHODS: Data were extracted from a prospective database of patients collected between 1991 and 2003. Included were 627 patients who underwent curative low anterior resection with total mesorectal excision for rectal cancer 2 to 12 cm from the anal verge. Three hundred ninety-nine patients received neoadjuvant therapy, 65 received postoperative adjuvant therapy alone, and 163 were treated with surgery alone. Median follow-up was 5.8 years. RESULTS: On multivariable analysis, overall recurrence was associated with pathologic stage, lymphovascular invasion, and distal margin. Mucosal recurrence was uncommon; only 16 events were recorded, and of those only 8 were at the initial site of isolated tumor recurrence; 7 of the 8 were surgically salvaged. On univariable analysis, mucosal recurrence was associated with close distal margin (5 vs 2% at 5 y) and lymphovascular invasion (7 vs 2%). Pelvic recurrence, other than isolated mucosal recurrence, was associated with distal location (6 vs 4% at 5 y) and lymphovascular invasion (11 vs 4%). Distal margin as a continuous variable was associated with overall recurrence (excluding isolated mucosal recurrence). CONCLUSIONS: Close distal resection margin identifies patients with increased risk of mucosal and overall cancer recurrence. Although neither causality nor a minimally acceptable margin length can be defined, the data support the importance of achieving a clear distal resection margin in the surgical management of rectal cancer. PMID- 20847618 TI - Barrier wound protection decreases surgical site infection in open elective colorectal surgery: a randomized clinical trial. AB - PURPOSE: Surgical site infection following colorectal surgery is a frequent and costly problem. Barrier protection at the time of this form of surgery has been used with varying results. The aim of this randomized study was to examine the efficacy of barrier retractional wound protection in the prevention of surgical site infections in open, elective colorectal surgery. METHODS: One hundred thirty consecutive patients undergoing open elective colorectal resectional surgery were randomly assigned to have either barrier retractional wound protection or standard wound retraction. Patients were then followed up for a minimum of 30 days postoperatively. The primary end point was surgical site infection as defined by the Centers for Disease Control and Prevention. The secondary end point was performance of the wound protector as assessed by operating surgeons. RESULTS: There was a significant reduction in the incidence of incisional surgical site infections when the wound protector was used: 3 of 64 (4.7%) vs 15 of 66 (22.7%); P = .004. Most surgical site infections were diagnosed after discharge from the hospital (78%), and there was no difference in the rates of reoperation, readmission, or formal wound drainage between the 2 groups. Surgeons found the wound protector to be helpful with retraction during surgery, with 88% (7/8) adopting it as part of their standard setup. CONCLUSIONS: In this study the use of barrier wound protection in elective open colorectal resectional surgery resulted in a clinically significant reduction in incisional surgical site infections. Barrier wound protection of this nature should be considered routine in this type of surgery. PMID- 20847619 TI - Quality of life ten and more years after restorative proctocolectomy for patients with familial adenomatous polyposis coli. AB - PURPOSE: Few studies on long-term quality of life after restorative proctocolectomy and ileal pouch-anal anastomosis have been published. Most of them survey a mixed patient population of familial adenomatous polyposis and ulcerative colitis. The present study analyzes long-term results more than 10 years after ileal pouch-anal anastomosis for patients with familial adenomatous polyposis, exclusively. METHODS: One hundred thirty-five patients who underwent ileal pouch-anal anastomosis more than 10 years ago were identified from the prospective familial adenomatous polyposis registry at Heidelberg University hospital. They received the German version of the health-specific Short Form 36 Health Survey and the disease-specific Gastrointestinal Quality of Life Index by mail. To assess the impact of disease-specific factors, 10 questions asking for ability to work, current medication, pouchitis, and extracolonic manifestations of familial adenomatous polyposis were added to the Gastrointestinal Quality of Life Index questionnaire. RESULTS: Among 84 patients who answered the questionnaires the median follow-up was 13.4 years (range, 10.3-23.8 y).The results of the Short Form 36 Health Survey were comparable to a German normative population in all dimensions, whereas the overall score for the Gastrointestinal Quality of Life Index was significantly reduced compared with healthy individuals (111.8 vs 120.8, P = .0014). Carcinoma at the time of ileal pouch-anal anastomosis, desmoid tumors, or duodenal adenomas had no significant influence on quality of life. More than 7 bowel movements during the daytime were found to reduce quality of life significantly (103.5 vs 115, P = .0127). More than 2 defecations per night diminished the score further (101 vs 125, P < .0001). Patients younger than 40 years at the time of ileal pouch-anal anastomosis had significantly better results than older patients (120 vs 109.5, P = .0076). CONCLUSION: Ileal pouch-anal anastomosis is a safe surgical procedure with a high quality of life comparable to that of a normative population after long-term follow-up of patients with familial adenomatous polyposis. PMID- 20847620 TI - Prospective study of health-related quality of life and restorative proctocolectomy in children. AB - PURPOSE: Although restorative proctocolectomy has become the standard surgical treatment for ulcerative colitis and familial adenomatous polyposis, there are no prospective studies in children of the impact of this intervention on health related quality of life. METHODS: A prospective study of health-related quality of life in children with ulcerative colitis or familial adenomatous polyposis undergoing restorative proctocolectomy was performed. Patients and their parents who agreed to participate completed standardized health-related quality-of-life surveys (Medical Outcomes Study Short Form-36 and Child Health Questionnaire Parent Form) within one month before colectomy and approximately one year after completion of their surgery. RESULTS: Of the 60 patients who agreed to participate, 44 completed surveys at the appropriate time periods allowing comparison. The parents of 28 of these subjects also completed paired surveys. Before colectomy, patients with ulcerative colitis had substantially lower health related quality-of-life scores, which were also mirrored in parental surveys. Following surgery patients with ulcerative colitis had significant improvement in 7 of 8 Medical Outcomes Study Short Form-36 patient subscales and all 6 corresponding Child Health Questionnaire Parent Form parental subscales of health related quality of life. Patients with familial adenomatous polyposis showed improvement in the bodily pain subscale alone, whereas their corresponding parental surveys only showed improvement in the mental health subscale. CONCLUSION: There are clearly significant adverse affects on health-related quality of life in children with ulcerative colitis that dramatically improved following restorative proctocolectomy. PMID- 20847621 TI - Risk factors of nodal involvement in T2 colorectal cancer. AB - PURPOSE: Because of the adverse consequences of radical resection of T2 colorectal cancer, criteria are needed for selection of patients who can safely undergo local excision without requiring additional radical surgery. We therefore conducted a retrospective study of patients with T2 colorectal cancer to identify risk factors for nodal involvement that might be used in selecting patients for local excision. METHODS: We reviewed records from consecutive patients who had undergone curative resection of T2 colorectal cancer at the Department of Surgery, National Defense Medical College, Saitama, Japan, between 1985 and 2005. Data on conventional clinicopathologic variables were retrieved from pathology reports at the time of surgery, and archived slides were evaluated regarding potential risk factors such as extent of poorly differentiated component (grade I III), myxoid cancer stroma, tumor budding, and growth pattern and invasion depth in the muscularis propria. RESULTS: A total of 244 patients (139 men and 105 women) treated for T2 colorectal cancer were included. Nodal involvement was found in 7 (8.4%) of 83 patients classified as grade I on the poorly differentiated component vs. 47 (29.2%) of 161 patients classified as grade II or III (P < .001). Of 148 patients negative for myxoid cancer stroma, 30 (16.9%) had nodal involvement vs. 24 (36.4%) of 42 patients who were positive for myxoid cancer stroma (P = .0011). According to multiple variable logistic analysis, significant independent risk factors for nodal involvement included poorly differentiated component (P = .002), myxoid cancer stroma (P = .032), and lymphovascular invasion (P = .022). CONCLUSIONS: Poorly differentiated component, myxoid cancer stroma, and lymphovascular invasion are significant independent risk factors for nodal involvement in T2 colorectal cancer. We need further study to validate these results on another data set, especially in patients with rectal cancer, and to confirm whether local resection of T2 rectal cancer is able to predict the nodal involvement before laparotomy. PMID- 20847622 TI - Intraoperative technical difficulty during laparoscopy-assisted surgery as a prognostic factor for colorectal cancer. AB - BACKGROUND: Laparoscopy-assisted surgery has technical drawbacks compared with open surgery, although laparoscopic surgery has become widely adopted with evidence of oncological safety for colon cancer treatment. The oncological risk of technical difficulties during laparoscopic surgery for colorectal cancer has not been previously reported. We aimed to investigate whether a technical difficulty encountered during laparoscopic surgery can be considered a recurrence related factor for colorectal cancer. METHODS: Data from 427 patients who underwent laparoscopic surgery for colorectal cancer between May 2003 and December 2007 were analyzed. An intraoperative technical difficulty was defined as a significant deviation from the ordinary surgical procedure. All conversions to open surgery and iatrogenic bowel perforation during laparoscopic surgery were included as technical difficulties. The Cox proportional-hazards regression model was used to evaluate the recurrence-related factor in the various risk factors including technical difficulty. RESULTS: Technical difficulties were found in 44 (10.3%) patients, which included 17 (3.9%) conversions to open surgery and 10 (2.4%) with iatrogenic bowel injury. Technical difficulties were encountered more frequently in men compared with women (13.5% vs 6.0%, P = .013), and for cancers located in the mid and low rectum, splenic flexure, and descending colon. The recurrence rates were higher in patients with technical difficulties (local recurrence, 2.6% vs 6.7%, P < .05; systemic recurrence, 6.3% vs 13.6%, P < .05) with a mean follow-up duration of 45.9 months. Multivariate analysis by the Cox proportional-hazards regression model showed that a technical difficulty was an independent factor related to recurrence after laparoscopic surgery (odds ratio, 2.374; 95% CI, 1.006-5.600; P = .048). CONCLUSIONS: This study has demonstrated that a technical difficulty during laparoscopy-assisted surgery jeopardizes oncological safety. It is suggested that surgeons should be prepared to minimize technical difficulties during laparoscopy-assisted surgery. PMID- 20847623 TI - Impaired rectal sensation at anal manometry is associated with anal incontinence one year after primary sphincter repair in primiparous women. AB - PURPOSE: This study investigates the association between endoanal ultrasonography and anorectal manometry in relation to anal incontinence after primary repair of obstetric sphincter injury in primiparous, premenopausal women. METHODS: The study population of this nested case-control study comprised 108 women who had previously been part of a randomized controlled trial comparing immediate with delayed primary repair of obstetric sphincter injuries, and who had been evaluated by anorectal manometry and endoanal ultrasound 1 year after their repair. Twenty cases and 88 controls were defined. Cases were defined as having a score greater than 2 on the Pescatori incontinence scale. Controls had a score of 2 or less. Ten obstetric, 9 ultrasonographic, and 7 manometric variables were studied. RESULTS: Of the manometric variables, volume of first sensation and volume of first urge proved to be associated with anal incontinence at univariate statistical analysis. Volume of first sensation remained independently associated with anal incontinence after multivariate analysis. In addition, age, degree of tear, duration of second stage of labor, and a distal scar at ultrasound proved to be independently associated with anal incontinence. CONCLUSIONS: Impaired rectal sensation at anorectal manometry and a distal scar at endoanal ultrasonography are associated with anal incontinence 1 year after primary sphincter repair in primiparous women. Additional studies need to evaluate whether these findings are associated with increased risk of anal incontinence in women that are continent 1 year after primary repair. PMID- 20847624 TI - Functional external anal sphincter reconstruction for treatment of anal incontinence using muscle progenitor cell auto grafting. AB - PURPOSE: This study aimed to investigate the feasibility of autologous muscle progenitor cell transplantation for anal sphincter regeneration in a rabbit model of anal incontinence. We examined the serial changes in structure, with particular emphasis on histology and functional properties of the anal sphincter. METHODS: External anal sphincterotomy was performed in 21 rabbits; these rabbits were randomly assigned to 2 groups. In group I (n = 9), autologous muscle progenitor cells were isolated from quadriceps myofiber explants, labeled with PKH-26, and injected into sphincter 3 weeks after sphincterotomy. In group II (n = 12), saline buffer was injected at the site of damage. Sphincter electromyography and manometry were performed immediately before sphincterotomy and 14, 28, and 60 days after injection in 3 animals in each group at every interval and the findings were correlated with histomorphological studies. In addition, electromyography and manometry were performed in the remaining 3 rabbits in group II after 6 months. RESULTS: In group II, a flaccid sphincter persisted during the 6 months of follow-up. In group I, muscle progenitor autografting accelerated sphincter myofiber repair and improvement in functional capacity of the damaged sphincter. Fluorescently labeled cells were detected in all of the grafted sphincters; regenerated myotubes were detectable at the injection site as evidenced by the presence of desmin. We also observed a significant decrease in interstitial fibrosis in the 4th week and strikingly higher amounts of Ki-67-positive cells in group I. Manometry and electromyography showed a significant improvement in the mean resting anal canal pressure and sphincteric electrical activity 4 weeks after cell injection, respectively. CONCLUSION: Transplanting muscle progenitor cells showed the potential for recapitulation of a myogenic program when injected into deficient rabbit anal sphincter. Objective anal measures of resting and stimulated pressures and electromyographic profile improved. Stem cell-mediated anal myoplasty warrants additional investigation as a new method to treat anal incontinence before attempting this modality in the clinical setting. PMID- 20847625 TI - Safety and efficacy of a novel continence device in colostomy patients. AB - PURPOSE: This study aimed to assess the safety and efficacy of a novel colostomy continence device. METHODS: This phase II, 142-day, open-label, nonrandomized, multicenter study enrolled patients who had end colostomies for >=3 months. Study stages were usual pouching (21 days), wafer transition (14 days), and the device (107 days). During device wear, up to 8 hours per day, patients recorded the following outcomes in daily diaries: skin condition (if the wafer was changed); stoma color, moisture, and physical condition; and gastrointestinal symptoms. RESULTS: Of the 26 patients enrolled, 25 wore at least one device. The device was worn on 96% of study days and a mean of 6.8 hours per day. Adverse events were reported by 1 patient during the usual pouching 21-day period, by 5 patients during the wafer transition 14-day period, and by 15 patients during the device wear 107-day period. Stoma color and moisture were within normal range on all daily assessments. The device did not affect microbiology or vascularity. During device wear, patients had no unusual gastrointestinal symptoms or odor on >99% and 80% of days, respectively. The mean number of leaks per patient-month was 1.2 with usual pouching, 4.2 with the device overall, and 2.1 during the last 3 weeks with the device, suggesting a learning curve. Approximately 65% of patients preferred the device to usual pouching at the end of study. CONCLUSIONS: The novel continence device was safe and effective for up to 8 hours per day in colostomy patients. PMID- 20847626 TI - Early discontinuation but not the timing of adjuvant therapy affects survival of patients with high-risk colorectal cancer: a population-based study. AB - BACKGROUND: Adjuvant therapy results in significant improvement in survival of patients with high-risk colorectal cancer. Little is known about the significance of timing and early discontinuation of adjuvant treatment in such patients. Our study aims to determine the prognostic impact of timing and completion of adjuvant therapy in patients with high-risk colorectal cancer. METHODS: Medical records of patients with stage III colon and stage II/III rectal cancer diagnosed between 1993 and 2000 in the province of Saskatchewan were reviewed. Cox proportional hazards models were used to analyze the impact of timing and completion of adjuvant therapy on survival. RESULTS: Six hundred sixty-three eligible patients with a median age of 66 years were identified. Sixty-five percent patients received adjuvant <56 days after surgery and 79% patients completed planned treatment. Median follow-up was 54.6 months. Five-year disease free survival and overall survival of patients who received adjuvant therapy <56 days after surgery was 54.6% and 59.5%, respectively, compared with 51.9% and 57.1%, respectively, of patients who received therapy >=56 days after surgery (P = NS). The five-year disease disease-free survival and overall survival of patients who completed planned treatment was 56.7% and 62.3%, respectively, compared with 42.1% and 45%, respectively, of patients who required early treatment discontinuation (P < .0001). On multivariate analysis, age >=65 years, T4 tumor, grade 3 cancer, node-positive disease, rectal tumor, and early treatment discontinuation were identified as poor prognostic factors. CONCLUSIONS: Although time to adjuvant therapy following surgical resection did not impact the outcomes, failure to complete planned therapy was associated with adverse prognosis. PMID- 20847627 TI - Rectal perforation after procedure for prolapse and hemorrhoids: possible causes. AB - PURPOSE: Our aim was to explore possible causes of rectal perforation occurring in patients who undergo the procedure for prolapse and hemorrhoids. METHODS: We evaluated data from cases of rectal perforation that occurred after the procedure for prolapse and hemorrhoids in China in conjunction with case reports from the international medical literature. RESULTS: We identified 7 patients from 5 hospitals in 2 provinces of China who had rectal perforation after the procedure despite having received prophylactic antibiotic treatment. Two patients had a disrupted staple line and 5 had perforations on the rectum wall above the intact staple line. Six patients presented with symptoms in the first 3 days after the procedure. Three patients had concomitant disease: 1 had concomitant constipation and internal rectal prolapse, 1 had concomitant constipation, and 1 had concomitant liver cirrhosis ascites that was not diagnosed preoperatively. Of the 15 cases of rectal perforation found in the literature, 3 patients had an intact staple line and 5 patients had a ruptured staple line. CONCLUSION: The cone shaped tip of the anvil, concomitant rectal prolapse and pelvic floor descent, and concomitant ascites are possible causes of rectal perforation after the procedure for prolapse and hemorrhoids. PMID- 20847628 TI - Clinical implication of false-positive celiac serology in patients with ileal pouch. AB - BACKGROUND: In patients with symptoms of pouchitis retractable to antibiotic therapy, serology is often ordered to exclude concurrent celiac disease. The clinical utility of celiac serology in patients with ileal pouches is unknown. The aim of this study was to investigate the clinical implications of false positive celiac serology in patients with ileal pouches. METHODS: All patients with pouches who had underlying ulcerative colitis and available celiac serology were included from the subspecialty Pouchitis Clinic at the Cleveland Clinic between 2002 and 2007. Chronic antibiotic-refractory pouchitis was diagnosed based on persistent symptomatic pouchitis after a 4-week single- or dual antibiotic therapy. RESULTS: A total of 126 patients were studied, and a false positive celiac serology was observed in 19 patients. Chronic antibiotic refractory pouchitis was diagnosed in 47% (9/19) of patients with false-positive celiac serology compared with 14% (15/107) of patients with a negative celiac serology (P = .003). In multivariate analysis, the association between false positive celiac serology and chronic antibiotic-refractory pouchitis remained significant (odds ratio, 5.4; 95% confidence interval, 1.7-16.7; P = .004) after adjusting for sex (P = .03), pouch duration (P = .83), the presence of autoimmune disorders (P = .46), and extraintestinal manifestations (P = .63). CONCLUSION: False-positive celiac serology appeared to be common in patients with ileal pouch anal anastomosis and it may be associated with chronic antibiotic-refractory pouchitis. PMID- 20847630 TI - United States Preventive Services Task Force recommendations: age to end screening misunderstood. PMID- 20847632 TI - Urinary biomarkers as predictors of long-term allograft function after renal transplantation. PMID- 20847633 TI - Long-term outcomes using deceased donor kidneys from cobra bite brain dead victims. PMID- 20847634 TI - Improvement in renal function after late conversion to sirolimus-based immunosuppression in composite tissue allotransplantation. PMID- 20847635 TI - Management of takotsubo cardiomyopathy in a lung transplant recipient. PMID- 20847636 TI - Long-term outcome and prediction models of activities of daily living in Alzheimer disease with cholinesterase inhibitor treatment. AB - In untreated patients with Alzheimer disease (AD) the functional ability is gradually lost. What happens to the patients after continuous long-term cholinesterase inhibitor (ChEI) treatment is less investigated. The objective of this study was to describe the longitudinal functional outcome and analyze factors affecting the outcome in ChEI-treated patients. In an open, 3-year, nonrandomized, prospective, multicenter study in a routine clinical setting, 790 patients were treated with either donepezil, rivastigmine, or galantamine. At baseline and every 6 months, they were assessed with several rating scales including Instrumental Activities of Daily Living (IADL), Physical Self Maintenance Scale (PSMS), and Mini-Mental State Examination (MMSE). A faster functional decline was associated with lower cognitive ability at baseline, older age, and the interaction of higher education and longer time in the study. The patients residing with a spouse or relative showed slower deterioration in IADL score. A higher mean dose of ChEI, regardless of drug agent, was also related to slower instrumental ADL decline. Prediction models for longitudinal functional outcome were provided. AD severity at baseline is a key factor in obtaining reliable clinical prognoses of the long-term ADL ability. The dosage of ChEI treatment could possibly lead to a different functional outcome. PMID- 20847637 TI - Derivation of a new ADAS-cog composite using tree-based multivariate analysis: prediction of conversion from mild cognitive impairment to Alzheimer disease. AB - Model-based statistical approaches were used to compare the ability of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), cerebrospinal fluid (CSF), fluorodeoxyglucose positron emission tomography and volumetric magnetic resonance imaging (MRI) markers to predict 12-month progression from mild cognitive impairment (MCI) to Alzheimer disease (AD). Using the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set, properties of the 11-item ADAS cog (ADAS.11), the 13-item ADAS-cog (ADAS.All) and novel composite scores were compared, using weighting schemes derived from the Random Forests (RF) tree-based multivariate model. Weighting subscores using the RF model of ADAS.All enhanced discrimination between elderly controls, MCI and AD patients. The ability of the RF-weighted ADAS-cog composite and individual scores, along with neuroimaging or biochemical biomarkers to predict MCI to AD conversion over 12 months was also assessed. Although originally optimized to discriminate across diagnostic categories, the ADAS. All, weighted according to the RF model, did nearly as well or better than individual or composite baseline neuroimaging or CSF biomarkers in prediction of 12-month conversion from MCI to AD. These suggest that a modified subscore weighting scheme applied to the 13-item ADAS-cog is comparable to imaging or CSF markers in prediction of conversion from MCI to AD at 12 months. PMID- 20847638 TI - Minichromosome maintenance protein expression according to the grade of atypism in actinic keratosis. AB - The minichromosome maintenance (MCM) family is a group of proteins that are key initiation factors for DNA replication and are expressed only in cycling cells. Recent studies on various cancerous conditions have shown that MCM proteins are better markers for malignant cells compared to other proliferative markers. It has been also proven that MCM proteins are independent prognostic factors. The aim of this study was to characterize the pattern and frequency of MCM 2 protein expression in actinic keratosis (AK) and determine whether the expression is correlated with the degree of histological atypism. Biopsy samples of 34 patients who had been diagnosed as AK were used in this study. Samples were divided into three groups (grade I, grade II, and grade III) according to the degree of atypism. Immunohistochemical staining for MCM 2 protein, Ki-67, and proliferating cell nuclear antigen was performed, and the number of positively staining cells per unit area (10-4 MUm2) was calculated for evaluation of immunoreactivity. MCM 2 protein was expressed in atypical keratinocytes in AK. Mean numbers of immunoreactive cells positive for MCM 2 were 165.1 in grade I, 304.5 in grade II, and 513.3 in grade III. Moreover, the correlation between the immunoreactivity for MCM 2 protein and AK grade was significantly more positive than that for other markers. Thus, we suggest that MCM 2 protein is a reliable marker for diagnosing and grading AK and further could be hypothesized as an important prognostic factor. PMID- 20847639 TI - Ripple/Carcinoid pattern sebaceoma with apocrine differentiation. AB - Sebaceoma is a benign sebaceous neoplasm, which has been reported to show characteristic growth patterns, such as, ripple, labyrinthine/sinusoidal, and carcinoid-like patterns. Another recent finding regarding in sebaceoma is the observation of apocrine differentiation within the sebaceoma lesion. This report describes a case of carcinoid (a partial ripple and labyrinthine) pattern sebaceoma with apocrine differentiation with a literature review and immunohistochemical studies. The various characteristic growth patterns in sebaceoma were suggested to simply be variations of the same growth pattern arranged in cords, namely, a unified term "ripple/carcinoid pattern." The primitive sebaceous germinative cells in sebaceoma may still have the ability to undergo apocrine differentiation. Most of the reports so far on sebaceoma with apocrine differentiation, including the present case, describe a ripple/carcinoid pattern, thus suggesting that ripple/carcinoid pattern sebaceoma is composed of more primitive sebaceous germinative cells than conventional sebaceoma. PMID- 20847640 TI - Cutaneous squamous cell carcinoma with mucinous metaplasia on the sole associated with high-risk human papillomavirus type 18. AB - A case of superficially invasive cutaneous squamous cell carcinoma (SCC) of the sole containing numerous mucin-producing vacuolated cells resembling "signet ring" cells is reported. The 2 cellular components of the tumor, both squamous and mucinous, were atypical with pleomorphic nuclei, and expressed the same immunophenotype, consistent in weak and focal positivity for cytokeratin 5/6 and epithelial membrane antigen (EMA) and weak cytoplasmic and nuclear positivity for p16. Real-time PCR genotyping demonstrated the presence of high-risk human papillomavirus (HPV) type 18. We diagnose our case as "cutaneous SCC with mucinous metaplasia" and discuss the differential diagnoses with other skin tumors exhibiting mucin-containing cells, in particular with adenosquamous carcinoma and mucoepidermoid carcinoma. Although HPV 18 is not uncommon in cervico-vaginal pathology, where is often associated with mucinous adenocarcinoma or adenosquamous carcinoma of the cervix, its detection has been rarely reported in cutaneous SCC. In our case, the association of mucinous metaplasia and oncogenic high-risk HPV 18 in a cutaneous SCC may be of interest to the dermatopathologist. Further observations need to confirm whether the histopathologic finding of mucinous metaplasia in an atypical squamous cell proliferation could be a clue for investigating the presence of oncogenic high risk HPV infection, with particular regard to HPV 18 subtype. PMID- 20847642 TI - Uncertainty in diagnosis. PMID- 20847643 TI - Generation of a humanized anti-glypican 3 antibody by CDR grafting and stability optimization. AB - Glypican 3 (GPC3), a glycosylphosphatidylinositol-anchored heparan sulfate proteoglycan, is expressed in a majority of hepatocellular carcinoma tissues. The murine monoclonal antibody GC33 that specifically binds to the COOH-terminal part of GPC3 causes strong antibody-dependent cellular cytotoxicity against hepatocellular carcinoma cells and exhibits strong antitumor activity in the xenograft models. To apply GC33 for clinical use, we generated a humanized GC33 from complementarity-determining region grafting with the aid of both the hybrid variable region and two-step design methods. The humanized antibody bound to GPC3 specifically and induced antibody-dependent cellular cytotoxicity as effectively as a chimeric GC33 antibody. To improve stability of the humanized GC33, we further optimized humanized GC33 by replacing the amino acid residues that may affect the structure of the variable region of a heavy chain. Substitution of Glu6 with Gln in the heavy chain significantly improved the stability under high temperatures. GC33 also has the risk of deamidation of the -Asn-Gly- sequence in the complementarity-determining region 1 of the light chain. As substitution of Asn diminished the antigen binding, we changed the neighboring Gly to Arg to avoid deamidation. The resulting humanized anti-GPC3 antibody was as efficacious as chimeric GC33 against the HepG2 xenograft and is now being evaluated in clinical trials. PMID- 20847644 TI - Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs. AB - Oxidative therapy is a relatively new anticancer strategy based on the induction of high levels of oxidative stress, achieved by increasing intracellular reactive oxygen species (ROS) and/or by depleting the protective antioxidant machinery of tumor cells. We focused our investigations on the antitumoral potential of amitriptyline in three human tumor cell lines: H460 (lung cancer), HeLa (cervical cancer), and HepG2 (hepatoma); comparing the cytotoxic effect of amitriptyline with three commonly used chemotherapeutic drugs: camptothecin, doxorubicin, and methotrexate. We evaluated apoptosis, ROS production, mitochondrial mass and activity, and antioxidant defenses of tumor cells. Our results show that amitriptyline produces the highest cellular damage, inducing high levels of ROS followed by irreversible serious mitochondrial damage. Interestingly, an unexpected decrease in antioxidant machinery was observed only for amitriptyline. In conclusion, based on the capacity of generating ROS and inhibiting antioxidants in tumor cells, amitriptyline emerges as a promising new drug to be tested for anticancer therapy. PMID- 20847645 TI - Monitoring drinking behaviour and motivation to drink over successive doses of alcohol. AB - The objective of this study was to compare alcohol urge, drinking behaviour and mood across two beverage conditions (alcohol/soft drink), over multiple drinks. Forty-five (22 men) participants completed two conditions (alcohol/soft-drink). Baseline alcohol urge and mood was measured before an initial drink consumed (0.2 g/kg alcohol or lemonade). Four drinking phases, which provided alcohol and lemonade, followed. Alcohol urge, mood and liking/enjoyment of beverages were measured. Participants' typical drinking habits were recorded, allowing comparisons across drinking factors. Alcohol urge was greater in the alcohol condition (P<0.03), which positively correlated with liking and drinking enjoyment of the alcohol beverage (P<0.04). Binge drinking and weekly alcohol consumption positively related to alcohol urge during the first half of the alcohol condition (P<0.02). Feeling stimulated was positively related to alcohol urge (P<0.01). Sip latency was quickest for alcohol in the alcohol condition (P<0.001) and did not increase over time as in the soft-drink condition (P<0.001). This study presents a paradigm in which alcohol motivation can be assessed within more typical drinking occasion parameters. Urge related to alcohol's positive reinforcing effects. As more alcohol was consumed, a disassociation of liking and wanting alcohol occurred, indicating that different processes may underlie behaviour during different periods of a drinking occasion. PMID- 20847646 TI - Current pharmacological models of social withdrawal in rats: relevance to schizophrenia. AB - Social dysfunction in schizophrenia is one of the core negative symptoms, which to date is not adequately addressed by treatment with both typical and atypical antipsychotics. A number of different pharmacological models of social withdrawal are used to mimic social dysfunction in rats, such as amphetamine, N-methyl-D aspartic acid antagonists, cannabinergic and serotonergic receptor ligands. The purpose of this review is to discuss and compare these models of social withdrawal with a focus on their face, construct and predictive validities. Various techniques and strategies used to observe and analyze rodent social behaviour and other factors that are of relevance to this paradigm have also been examined. After comparing the reports, we are of the opinion that to improve replicability of any given model and its antipsychotic screening potential and the reliability of comparisons made, efforts need to be directed towards cross laboratory standardization of variables that may confound experimental outcomes and cause discrepancies in results reported. In keeping with an earlier suggestion this may be facilitated through the creation of an online consortium for behavioural neuroscientists to share and compare methodologies, laboratory layouts and perhaps even raw data. PMID- 20847647 TI - Three-millimeter incision descemet stripping endothelial keratoplasty using sodium hyaluronate (healon): a survey of 105 eyes. AB - PURPOSE: To report a Descemet stripping automated endothelial keratoplasty (DSAEK) insertion technique using sodium hyaluronate (Healon) and describe complication rates, visual acuity, and endothelial cell counts. METHODS: A retrospective analysis of 105 eyes in 91 patients undergoing DSAEK. Ninety-three eyes had Fuchs endothelial dystrophy, 11 had bullous keratopathy, and 1 had iridocorneal endothelial (ICE) syndrome. We noted pre- and postoperative visual acuity at 3 and 6 months, endothelial cell counts, and complications, including graft detachment rates. Thirty-six of 141 eyes met exclusion criteria of prior incisional corneal, glaucoma, or retinal surgery. RESULTS: Because of graft detachment, 29 of 105 eyes (28%) required a re-bubble procedure at day 1 or week 1. Five of 105 grafts (4.8%) failed. Of note, in the last 35 cases, there were no graft failures and 5 detachments (14%). Twenty-eight percent of patients were 20/40 or better preoperatively compared with 49% at 3 months and 52% at 6 months. Excluding eyes with other ocular comorbidities (34), 62% were 20/40 or better at 3 months and 72% were 20/40 or better at 6 months. Postoperative endothelial cell counts were available for 52 eyes with an average cell loss of 44% at an average of 9.4 months. CONCLUSIONS: DSAEK is an effective treatment for endothelial dysfunction, but the learning curve is steep. Anterior chamber stability, graft positioning, and small incision insertion are advantages to our technique. Disadvantages include a relatively high endothelial loss and dislocation rate. Minimizing endothelial cell loss and graft dislocation continue to be important goals for successful DSAEK. PMID- 20847649 TI - Salzmann nodular regeneration. PMID- 20847650 TI - Treatment of recurrent corneal erosion by extended-wear bandage contact lens. AB - PURPOSE: To assess the efficacy of using a bandage contact lens (BCL) for 3 months for recurrent corneal erosions (RCE) to facilitate epithelial adhesion. METHODS: Retrospective study of patients presented to the Casey Eye Institute (Portland, OR) with RCE after failing at least 6 weeks of medical lubrication therapy. Subjects were treated with an extended-wear BCL for 3 months and then followed for approximately 1 year. The main outcome measure was recurrence of RCE. Best-corrected visual acuity was measured before and after BCL therapy. RESULTS: From the 12 patients studied, 9 (75%) had no recurrence of RCE after approximately 1 year of follow-up. Three subjects had subjective complaints of recurrent erosion during the follow-up period with 1 of these 3 subjects having objective findings of a recurrent erosion. CONCLUSIONS: Three-month BCL treatment is a safe and effective medical therapy with a relatively low recurrence rate of RCE. PMID- 20847651 TI - Management of focal limbal stem cell deficiency associated with soft contact lens wear. AB - PURPOSE: To present the varying manifestations of and the treatment methods for corneal epitheliopathies because of focal limbal stem cell deficiency (LSCD) associated with soft contact lens (SCL) wear. METHODS: The medical records of patients seen at 3 institutions who developed focal LSCD, based on clinical examination, that was attributed to SCL wear were reviewed. Information regarding the patients' demographics, contact lens wearing schedules, medical and surgical treatment modalities, and clinical and visual outcomes were recorded. RESULTS: Eighteen eyes of 10 SCL wearers were found to have varying degrees of corneal epitheliopathy secondary to focal LSCD. Nine of the 10 patients (90%) were women, and the mean age of all patients was 35.1 years (range, 20-58 years). The mean duration of SCL wear was 15.2 years (range, 4-30 years). Two patients wore the lenses for 20 hours per day. Mean follow-up time was 7.0 months (range, 0.25-24 months). Visual acuity at first examination was affected in 10 of the 18 eyes (55.6%) and ranged from 20/30 to hand motions. The focal LSCD was found superiorly in all involved eyes and inferiorly in only 5 of 18 eyes (27.8%). The epitheliopathy resolved or stabilized in 11 eyes (61.1%) with cessation of SCL wear and use of artificial tears. Five eyes required topical corticosteroid eyedrops, and 2 eyes required surgical intervention. One eye had a best spectacle corrected visual acuity of less than 20/30 at last follow-up. CONCLUSIONS: Focal LSCD can be a result of SCL wear, presenting with varying manifestations. SCL wearers should be monitored routinely and counseled on this possible complication. Early identification of focal LSCD in SCL wearers with subsequent cessation of wear may prevent the need for surgical intervention. PMID- 20847652 TI - Role of human herpes virus 6 in corneal inflammation alone or with human herpesviruses. AB - PURPOSE: : The purpose of this study was to determine the association of human herpes virus 6 (HHV-6) and/or other human herpesviruses in corneal inflammation using polymerase chain reaction (PCR). METHODS: : We collected tear films, conjunctival smears, and a corneal button of inflamed cornea, and the presence of HHV-6 and other herpesviruses in these samples were assessed by a nested PCR. RESULTS: : In tear films collected from 3 of 9 patients with dendritic keratitis, HHV-6 DNA was positive twice, together with herpes simplex virus (HSV) or varicella zoster virus DNA most often, during the acute phase of the disease. Two other patients in this group were either positive for HSV-1 and varicella zoster virus or for HSV-1 and Epstein-Barr virus DNA but negative for HHV-6. When another 12 patients' smear samples from corneal ulcer or keratouveitis were examined, 9 were positive for HHV-6 DNA. Of these, 4 were positive for HSV-1 simultaneously, whereas the remaining 5 patients were negative for HSV-1. One patient's smear was positive for HSV-1 but not for HHV-6. In the corneal button, both HSV and HHV-6 DNAs were positive by nested PCR. HHV-6 was also positive by nested PCR in the conjunctival swab obtained from the contralateral inflamed eye of the patient. CONCLUSIONS: : In 22 patients with corneal inflammation, HHV-6 was positive in 14 of 22 patients and HSV-1 was found in 9 of those patients. These data indicated that the association of HHV-6 with disease was more frequent than with other herpesviruses and that HHV-6 may be another sole causative agent for corneal inflammation. PMID- 20847653 TI - Ocular involvement in chronic graft-versus-host disease: therapeutic approaches to complicated courses. AB - Chronic graft-versus-host disease (cGvHD) is a major concomitant phenomenon in recipients of allogeneic hematopoietic stem cell transplantations, affecting multiple organ systems including the eye. Ocular structures, such as lacrimal gland, conjunctiva, and eyelids with meibomian glands, are frequently involved with clinical features ranging from dry eyes and common inflammatory conjunctival disease to severe complications like corneal ulcerations or even perforations. We present 2 patients with complicated courses of ocular cGvHD. In both cases, keratoconjunctivitis sicca refractory to systemic immunosuppressive therapy and to conventional topical treatment resulted in progressive binocular corneal melting and finally repeated perforations. According to our 2 cases and to the current pathophysiological understanding, we discuss possible strategies for the treatment and prevention of ocular cGvHD complications. PMID- 20847654 TI - Surgical technique of deep anterior lamellar keratoplasty in descemetoceles. AB - PURPOSE: To describe a surgical technique of deep anterior lamellar keratoplasty (DALK) to treat patients with descemetocele. METHODS: Twelve eyes of 12 patients with central or paracentral descemetocele after resolved microbial keratitis underwent viscoelastic-assisted DALK. The mean follow-up of the cases was 19.91 +/- 15.80 months (range: 6-48 months). RESULT: In all the eyes, a successful DALK could be performed without any intraoperative complications. At the last follow up visit, all but 1 eye showed significant improvement in visual acuity compared with preoperative visual acuity. The postoperative best-corrected visual acuity did not improve in 1 patient because of glaucomatous optic atrophy, which was present preoperatively. Eight eyes had best-corrected visual acuity of >= 20/80, and all but 2 patients had clear grafts at the final follow-up. None of the patients had any evidence of graft infection. CONCLUSIONS: Viscoelastic-assisted DALK is a useful therapeutic option in selected cases of descemetocele after resolved microbial keratitis. PMID- 20847655 TI - Recurrent primary acquired melanosis with atypia involving a clear corneal phacoemulsification wound. AB - PURPOSE: To report a case of corneal primary acquired melanosis (PAM) with atypia after cataract surgery. METHODS: Retrospective case report with literature review. RESULTS: Excision of an elevated pigmented conjunctival lesion was performed at the time of cataract extraction by clear corneal phacoemulsification by an outside surgeon. Histopathologic examination revealed PAM with atypia. Three months after the initial surgery, recurrent melanosis involving the peripheral corneal epithelium was noted, with extension of pigment into the corneal stroma through the paracentesis site. Excision of the involved corneal epithelium and the adjacent conjunctiva was performed, and microscopically recurrent PAM with atypia was confirmed. Adjuvant cryotherapy was applied at the time of surgery, and topical mitomycin C was given postoperatively. Repeat biopsies revealed no remaining malignancy, and the intrastromal pigment has disappeared during 18 months of follow-up. CONCLUSION: We present this case to illustrate the importance of complete evaluation and treatment of potentially atypical melanocytic conjunctival lesions before proceeding with elective intraocular surgery. PMID- 20847656 TI - Comparison of besifloxacin, gatifloxacin, and moxifloxacin against strains of pseudomonas aeruginosa with different quinolone susceptibility patterns in a rabbit model of keratitis. AB - PURPOSE: Determine the effectiveness of topical besifloxacin, gatifloxacin, and moxifloxacin in treating keratitis caused by 2 strains of Pseudomonas aeruginosa with different quinolone susceptibility profiles. METHODS: Minimal inhibitory concentrations (MICs) were determined for each fluoroquinolone. Sequence analysis was performed on the quinolone resistance determining regions of the ciprofloxacin/levofloxacin-resistant strain. Rabbit corneas were injected with 10 colony-forming units (CFU). After 16 hours, phosphate-buffered saline, besifloxacin (6 mg/mL), gatifloxacin (3 mg/mL), or moxifloxacin (5 mg/mL) was applied topically every 15 minutes for 5 doses, then every 30 minutes for 14 doses. Eyes were examined pre- and posttreatment. Corneas were harvested for bacterial quantitation. RESULTS: MICs against the fully susceptible strain were 0.5, 0.25, and 0.5 MUg/mL for besifloxacin, gatifloxacin, and moxifloxacin, respectively. The MICs against the ciprofloxacin/levofloxacin-resistant strain were 2, 16, and 32 MUg/mL for besifloxacin, gatifloxacin, and moxifloxacin, respectively. Sequence analysis revealed amino acid mutations in all 4 fluoroquinolone target genes. None of the treatments had an effect on clinical severity of eyes infected with the fully susceptible strain (P > 0.05); however, all were effective at significantly reducing the bacterial CFU in the corneas (P < 0.05). For the ciprofloxacin/levofloxacin-resistant strain, clinical scores of besifloxacin-treated eyes were significantly lower than moxifloxacin-treated eyes (P < 0.037). The quantities of ciprofloxacin/levofloxacin-resistant bacteria recovered from corneas of all treatment groups were significantly lower than those recovered from phosphate-buffered saline-treated corneas (P < 0.05). Besifloxacin-treated eyes had significantly lower CFU recovered as compared with that of gatifloxacin- and moxifloxacin-treated eyes (P < 0.05). CONCLUSIONS: These results support clinical investigation of the effectiveness of besifloxacin in treating Pseudomonas keratitis. PMID- 20847657 TI - Efficacy of hydroxypropyl cellulose ophthalmic inserts (LACRISERT) in subsets of patients with dry eye syndrome: findings from a patient registry. AB - PURPOSE: To determine acceptability and efficacy of hydroxypropyl cellulose ophthalmic inserts in patients with dry eye syndrome (DES) and additional comorbidities. DESIGN: A multicenter, 2-visit, open-label, 4-week registry study. PARTICIPANTS: Five hundred twenty patients were recruited to the intent-to-treat group. Four hundred eighteen patients completed the study including 86 contact lens wearers, 79 with cataract diagnosis, 52 with prior cataract surgery, 22 with prior laser-assisted in situ keratomileusis, and 15 with glaucoma. METHODS: Patient questionnaires were completed at baseline and after 4 weeks of treatment to assess mean change in severity of DES symptoms, ocular surface disease index (OSDI) scores, frequency of occurrence of DES symptoms, occurrence of difficulty when performing activities of daily living (ADLs), and frequency of discomfort in various environmental conditions. Mean change was measured from visit 1 to visit 2. MAIN OUTCOME MEASURES: Symptoms, OSDI scores, and measure of degree of difficulty when performing ADLs. RESULTS: Four hundred eighteen patients completed the study. Compared with baseline, this population of patients demonstrated statistically significant improvements in mean OSDI scores (P = 0.0215) and symptoms of discomfort, burning, dryness, grittiness, stinging, and light sensitivity (P < 0.05). Mean improvement in OSDI scores of patients in the 5 identified subsets of patients with comorbid conditions were significant for patients using contact lenses (P < 0.025), who had undergone prior cataract surgery (P < 0.04), and with prior laser-assisted in situ keratomileusis surgery (P < 0.05). Patients diagnosed with cataracts or glaucoma did not show significant changes in any measures in this study. Patients with DES and comorbid conditions experienced relief of symptoms and benefit to ADLs and quality of life similar to patients without comorbid conditions. CONCLUSIONS: In subsets of patients with moderate to severe DES and comorbid conditions, hydroxypropyl cellulose ophthalmic inserts improve the symptoms of DES, ability to perform ADLs, and quality of life. The reported benefits may be additive to those seen with patients' existing therapies. PMID- 20847658 TI - Treatment of ocular graft-versus-host disease with topical cyclosporine 0.05%. AB - PURPOSE: To evaluate the efficacy of topical cyclosporine-A 0.05% (CsA) in the treatment of dry eye syndrome in ocular graft-versus-host disease after bone marrow transplantation (BMT) of hematopoietic stem cells. METHODS: One-hundred five patients were enrolled in a retrospective, comparative, interventional case series. Eighty-one patients received topical CsA starting 1 month before BMT (treatment group), and 24 patients did not receive CsA until at least 6 months after the transplantation (control group). Mean follow-up time was 17.5 +/- 11.0 months (range: 6.0-49.0 months). Clinical history, ocular surface disease index questionnaire, slit-lamp examination, lissamine green and fluorescein staining of the ocular surface, tear breakup time, and Schirmer test with topical anesthesia were obtained to create a composite dry eye-grading score. RESULTS: Dry eye symptoms were significantly more severe in the control group at 3 months, 1 year, and 2 years (P < 0.05). There was no correlation with type of stem cell transplant (related vs. unrelated donor), presenting indication for BMT, or concurrent systemic immunosuppressive medications. CONCLUSIONS: Pre-BMT initiation of topical CsA may reduce the inflammatory response in the lacrimal glands that may be responsible for the development of post-BMT keratitis sicca. PMID- 20847659 TI - Subconjunctival masses associated with central nervous system rosai-dorfman disease. AB - PURPOSE: To describe a case of subconjunctival masses with multiple intracranial masses diagnosed as Rosai-Dorfman disease by biopsy. METHODS: Case report. RESULTS: A 25-year-old white man presented with bilateral subconjunctival masses, left optic nerve pallor, and posterior segment changes suggestive of regressed choroidal disease. Systemic evaluation was instituted including blood testing, neuroimaging, brain biopsy, and biopsy of the left subconjunctival mass. Pathologic analysis of the brain and subconjunctival mass biopsies revealed Rosai Dorfman disease. CONCLUSIONS: The authors present a case of extensive extranodal involvement of Rosai-Dorfman of the eye and the central nervous system. PMID- 20847660 TI - Survival after transplantation of corneas from a rabies-infected donor. AB - PURPOSE: To examine the tissue samples of 2 corneal recipients from a rabies infected donor for the presence of rabies to explain their survival. METHODS: Interventional case series with a review of the literature. The explanted corneal donor buttons were examined via nested reverse transcriptase polymerase chain reaction. The patients were followed up ophthalmologically and neurologically. Antirabies antibodies were measured in blood samples, and skin biopsies were examined by direct fluorescent antibody staining. RESULTS: Two patients received corneas from the same multiorgan donor. Six weeks after transplantation, 3 of the donor's organ recipients became symptomatic and rabies virus was confirmed in tissue from the donor's central nervous system. Immediately, both the corneal recipients underwent active and passive postexposure treatment. The corneal buttons were replaced. Examination of the explanted donor corneas, skin biopsies, and serum and saliva samples showed no signs of rabies infection. The 2 corneal recipients were followed up at our hospital and, to date, are without symptoms of infection. CONCLUSIONS: Transmission of the potentially deadly rabies virus by corneal transplantation has been described previously. To our knowledge, this is the first report in which no rabies virus transmission occurred without immediate postexposure treatment. PMID- 20847661 TI - Intrastromal corneal ring segment implantation for the treatment of keratoconus. AB - PURPOSE: To evaluate the safety and efficacy of intrastromal corneal ring segment implantation using both mechanical and femtosecond-assisted tunnel creation for the treatment of patients with keratoconus. METHODS: A retrospective noncomparative interventional study including 96 eyes of 75 patients with keratoconus. All patients had contact lens intolerance and clear central corneas. Corneal tunnels were made using a femtosecond laser in 26 eyes (femtosecond group) and mechanically in 70 eyes (mechanical group). The Keraring (Mediphacos, Belo Horizonte, Brazil) was implanted in each eye, and a complete ophthalmic examination was performed, including visual acuity, refraction, and keratometric readings. RESULTS: The mean preoperative uncorrected visual acuity for all eyes was 1.40 +/- 0.39 logarithm of the minimal angle of resolution (logMAR) (mean +/- SD) and improved to 0.60 +/- 0.34 logMAR at the sixth month (n = 96, P < 0.001) and 0.50 +/- 0.32 (n = 54, P < 0.001) at the 18th month. The mean preoperative best spectacle-corrected visual acuity (BSCVA) for all eyes (n = 96) was 0.68 +/- 0.36 logMAR. The mean BSCVA was 0.29 +/- 0.21 (n = 96, P < 0.001) at the sixth month and improved to 0.26 +/- 0.20 (n = 54, P < 0.001) at the 18th month. There was a significant reduction in spherical equivalent refractive error from -5.88 +/- 3.65 diopters (D) (n = 96) to -2.26 +/- 1.98 D (n = 54, P < 0.001) at the 18th month. The mean preoperative maximum keratometry (Kmax) was 53.58 +/- 5.90 D and decreased to 49.02 +/- 4.70 (n = 96, P < 0.001) at 6 months and 48.57 +/- 4.36 D (n = 54, P < 0.001) at the 18th month. Sixth month results of the mechanical versus femtosecond groups were as follows: improvement in uncorrected visual acuity (2.08 vs. 1.50 lines), improvement in BSCVA (2.93 vs. 2.19), reduction in spherical equivalent (3.78 vs. 3.75 D), and reduction in maximum keratometry (4.66 vs. 4.62 D). There was no statistically significant difference between both groups for any parameter. CONCLUSIONS: Keraring implantation is effective for the treatment of keratoconus, providing safety and good visual outcomes after both mechanical and femtosecond-assisted tunnel creation. PMID- 20847662 TI - In vivo confocal microscopy of combined pre-descemet membrane corneal dystrophy and fuchs endothelial dystrophy. AB - PURPOSE: To report the in vivo confocal microscopy (CM) findings of a patient with combined pre-Descemet membrane corneal dystrophy and Fuchs endothelial dystrophy. METHODS: A 38-year-old woman with pre-Descemet membrane corneal dystrophy and Fuchs endothelial dystrophy was studied. Routine ophthalmic examination, standard slit-lamp biomicroscopy, pachymetry, and in vivo CM analysis of the morphology of the corneal epithelium, subbasal nerves, stroma, and endothelium were performed. RESULTS: Biomicroscopy revealed bilateral corneal guttae with central corneal edema, beaten metal appearance, and pigment dusting of the endothelium. Numerous tiny pleomorphic opacities located in the deep stroma immediately anterior to Descemet membrane were evidenced in both eyes. In vivo CM showed numerous pleomorphic and highly reflective small particles in the cytoplasm of keratocytes in the deep stroma adjacent to the corneal endothelial layer. No abnormalities could be detected in the epithelial layer and in the midstromal layer. In the endothelial layer, there were multifocal hyporeflective areas with occasional central highlight among hyperreflective endothelial cells. The ultrasonic pachymetry showed corneal thicknesses of 652 and 628 MUm in the right eye and in the left eye, respectively. CONCLUSIONS: In vivo CM is a powerful tool in the study of rare corneal dystrophies and degenerations and nonprogressive or slowly progressive corneal disorders where there is a limited availability of corneal tissue for examination and when the final diagnosis is difficult to obtain with conventional methods. PMID- 20847663 TI - Clear cell carcinoma of the conjunctiva. AB - PURPOSE: To describe a rare case of primary conjunctival clear cell carcinoma. METHODS: The clinical history and pathologic findings were reviewed. RESULTS: An 82-year-old white man presented with a lesion on his right conjunctiva for 8 months. An excisional biopsy was performed with wide margins and mitomycin C. Pathologic examination showed a papillary clear cell carcinoma of the conjunctiva. The patient has been followed for 6 months without recurrence. CONCLUSIONS: Primary clear cell carcinoma, a variant of squamous cell carcinoma, can occur in the conjunctiva. PMID- 20847664 TI - High-resolution spectral domain optical coherence tomography technology for the visualization of contact lens to cornea relationships. AB - PURPOSE: To study the utility of high-resolution spectral domain optical coherence tomography (HR SOCT) in imaging the contact lens (CL) to cornea relationships with advanced CL designs for ecstatic corneas and corneal refractive therapy. METHODS: Copernicus HR SOCT (Optopol Technology SA, Zawiercie, Poland) was used to evaluate different lens materials and designs in situ and for the preliminary assessment of the materials and corneal response to hypoxic situations. RESULTS: SOCT is capable of highlighting very subtle and interesting features of the CL-cornea relationships in a wide range of applications such as in rigid gas-permeable corneal and semiscleral lenses, in corneal refractive therapy and application of CLs in ocular pathology, and in the evaluation of the physiological response of the cornea. CONCLUSIONS: HR SOCT is a powerful tool capable of providing sharp images of the anterior ocular surface highlighting the relationship between lens and cornea with great detail. This methodology has several applications to enhance fitting modeling with modern designs for advanced CL treatments. PMID- 20847665 TI - The quantitative detection of herpes simplex virus, varicella zoster virus, and cytomegalovirus DNAs in recipient corneal buttons. AB - PURPOSE: We detected herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV), and cytomegalovirus (CMV) DNAs in recipient corneal buttons taken at the time of penetrating keratoplasty. METHODS: Twenty-seven corneal buttons were obtained from 27 patients (10 men and 17 women), 7 of whom had a history of HSV keratitis. Excised corneal buttons were immediately frozen in liquid nitrogen in the operating theater and then stored at -80 degrees C until DNA extraction. The detection of HSV-1, HSV-2, VZV, and CMV DNAs was carried out by a nested polymerase chain reaction (PCR) method. The genome copy numbers for the nested PCR-positive samples were subsequently quantified by real time PCR. RESULTS: HSV-1, HSV-2, VZV, and CMV DNAs were detected in 10, 1, 9, and 2 of the 27 recipient corneal buttons, respectively. HSV-1 or HSV-2 DNAs were also detected in 5 of 7 patients with a history of HSV keratitis. Both CMV positive patients (patients 2 and 3) had ocular pemphigoid. Among the nested PCR positive samples, 2 HSV-1, 1 HSV-2, 1 VZV, and 1 CMV sample could be quantified by real-time PCR. Copy numbers ranged from 19 to 928 copies. CONCLUSIONS: All 4 herpesviruses, including CMV, were detected in the corneal buttons. The relationship between CMV in the cornea and ocular diseases of the anterior segment should be further evaluated. PMID- 20847666 TI - Pediatric corneal dystrophies. A plea for pictures. PMID- 20847667 TI - Effectiveness of in vivo confocal microscopy in detecting filamentous fungi during clinical course of fungal keratitis. AB - PURPOSE: To determine the effectiveness of laser confocal microscopy in detecting filamentous fungi in the cornea of patients with fungal keratitis (FK) and in evaluating the effectiveness of the treatment. METHODS: The corneas of 6 patients clinically diagnosed with FK were examined with the Heidelberg Retina Tomograph II-Rostock Cornea Module (HRT II-RCM). Three of these patients were also monitored periodically with the HRT II-RCM after antifungal treatment. RESULTS: The HRT II-RCM examination showed interlocking and branching, white, septated, hyphae-like lines in the cornea of all patients. All 6 patients had positive corneal smears and/or laboratory cultures. Three patients were monitored with HRT II-RCM after antifungal treatment. One patient, whose initial smear was negative, was diagnosed by HRT II-RCM before the positive culture results. In another case, the epithelial regeneration was impaired even 3 weeks after the initial treatment and HRT II-RCM revealed a mass of hyphae in the corneal ulcerated lesion. These findings indicated the necessity of surgical debridement. After the surgical debridement, the corneal epithelial defect was healed. HRT II-RCM was able to detect the morphological changes of hyphae after antifungal treatment and helped in the treatment modifications during the clinical course in all 3 patients. CONCLUSIONS: These results indicate that HRT II-RCM can be used to diagnose FK and to monitor the effect of therapy on FK. PMID- 20847668 TI - Tissue complications during endothelial keratoplasty. AB - PURPOSE: To report 6 cases of apparently inseparable corneal lamellae during intraoperative preparation of tissue for Descemet stripping automated endothelial keratoplasty (DSAEK). METHOD: Collection of clinical case reports from an e-mail survey of The Cornea Society and endothelial keratoplasty discussion group participants and Eye Bank Association of America member eye banks. RESULTS: Five cases involved eye bank precut tissue. Surgery was aborted in 4 of these cases. In the fifth case, a free anterior cap was identified and the posterior lamella was successfully transplanted. In 1 case, in which an incomplete lamellar cut was made in the operating room, the surgery was continued after manual completion of the lamellar dissection. CONCLUSIONS: The most likely causes of inability to separate the lamellae after punching a DSAEK donor cornea are a decentered or incomplete lamellar cut and unsuspected premature separation of the lamellae. Premature separation can occur with an anterior cap that detaches before the central trephination or a posterior lamella that is inadvertently removed from the field after the central trephination. Careful inspection of the donor cornea under the operating microscope can reduce the risk of a decentered cut and can identify the presence of both lamellae. DSAEK may be completed successfully with an intact posterior lamella. PMID- 20847669 TI - Nonobvious obstructive meibomian gland dysfunction. AB - This review presents the rationale and supporting data for a recent paradigm shift in our understanding of meibomian gland dysfunction (MGD). The historical understanding of MGD has been that of an infectious hypersecretory disorder with obvious signs of inflammation, hypersecretion, and purulent excreta. The current understanding of MGD now includes the polar concept of a less obvious or nonobvious type of hyposecretory obstructive MGD, where inflammation and other signs of pathology may be absent unless special examination techniques are employed. A new term, nonobvious obstructive MGD (NOMGD), is used to describe what may be the most common form of obstructive MGD. Obstructive MGD is an area of growing importance because obstructive MGD is now recognized to be the most common cause of evaporative dry eye, and because NOMGD seems to be the precursor to obvious obstructive MGD, it is also an important area to understand. The prevalence of NOMGD seems to be very high but currently significantly underdiagnosed. This review presents the relevant anatomy and physiology, concepts of obstructive MGD, the usual absence of inflammation in obstructive MGD, nomenclature and classification of obstructive and NOMGD, clinical diagnosis of NOMGD emphasizing the necessity for diagnostic expression, the use of a new instrument for diagnostic expression providing a standardized method of assessing meibomian gland functionality, the complementary roles of the aqueous and lipid layers, and the specific treatment of NOMGD, emphasizing that the success of treatment of all forms of obstructive MGD is dependent on the relief of the obstruction. PMID- 20847670 TI - A novel approach to processing descemet stripping automated endothelial keratoplasty specimens for histopathologic analysis. AB - PURPOSE: To describe a new technique for handling Descemet stripping automated endothelial keratoplasty (DSAEK) specimens intraoperatively and during processing. METHODS: The processing method begins by adding a drop of eosin to the specimen intraoperatively, followed by submersion in 10% formalin solution. The specimen appears reddish, allowing for easy identification and is floated onto an immersed slide to maintain an unfolded flattened specimen. After bisection, one half is stained with hematoxylin and eosin and covered with a cover slip, whereas the other half is transferred to filter paper and a cassette and is submitted for paraffin embedding on the cut edge. RESULTS: The technique reduces the chances of a specimen not surviving processing. The new method also allows for 2 views of DSAEK specimens, both topographical and cross-sectional, thus permitting analysis of endothelial cell density, spatial distribution of cells and guttae, endothelial cell count, and thickness measurements. CONCLUSIONS: A novel technique for handling DSAEK specimens to prevent loss and folding, while also allowing for cross-sectional and topographical viewing is reported. PMID- 20847671 TI - Implantation of hydroxyapatite-titanium corneal implants in rat cornea. AB - PURPOSE: To evaluate the biocompatibility of hydroxyapatite-coated titanium (HA/Ti) corneal implants at the molecular levels with histopathology. METHODS: Eighty Sprague-Dawley rats were divided into 2 equal groups. In the study group, HA/Ti prosthetics were implanted into the right corneal stroma. The control group received a sham incision. Corneas were collected and studied with histopathological examination (HE), immunohistochemical, and other stains, including scanned electron microscopy and reverse transcription-polymerase chain reaction, to evaluate inflammatory reactions, tissue repair, and expression of various biological factors during healing. RESULTS: In the control group, corneal neovascularization occurred 7 days after surgery, and the corneas recovered 28 days after surgery. In the study group, corneal vascularization increased substantially on day 7 and stabilized on day 28. For both groups, reverse transcription-polymerase chain reaction detected expressions of 6 primers at all time points. The amplified sequences were consistent with the designed sequences. The expression of matrix metalloproteinase-2, matrix metalloproteinase-9, bFGF, vascular endothelial growth factor, and type III collagen were delayed in the study group compared with the control group. Histological analyses showed a tight attachment of the corneal tissue to the HA/Ti implant on day 28. CONCLUSIONS: The HA/Ti corneal implants can remain stable in corneal tissue for a long time, induce corneal neovascularization, and stimulate inflammatory cells and keratocytes to synthesize or activate matrix metalloproteinases. Artificial cornea made from this material show enhanced stability and biocompatibility in vivo. PMID- 20847672 TI - The association of meibomian gland dysfunction and other common ocular diseases with dry eye: a population-based study in Spain. AB - PURPOSE: To investigate the relationship of meibomian gland dysfunction (MGD) and other prevalent ocular diseases with dry eye (DE) in a general adult population. METHODS: An age-stratified random sample of 1155 subjects aged >=40 years was selected in O Salnes, Spain. From 937 eligible subjects, 654 (69.8%) participated (mean age (SD): 63.6 (14.4) years; range: 40-96; and 37.2% males). A standardized DE questionnaire was administered. Objective evaluation included the Schirmer test, tear film breakup time (TBUT), fluorescein staining, and rose bengal staining. DE was defined as the simultaneous presence of symptoms and at least one sign. The relationship of MGD and other ocular diseases with DE was investigated. A design-based analysis was performed, and all calculations were weighted to give unbiased estimates. RESULTS: DE and MGD prevalence were 11.0% [95% confidence interval (CI), 8.6-13.3] and 30.5% (95% CI, 26.9-34.1), respectively. MGD was present in 45.8% (95% CI, 34.8-57.2) of subjects with DE and was associated, after controlling for age and sex, with DE [adjusted odds ratios (ORa), 1.81]; with symptoms (ORa, 2.26); and with TBUT (ORa, 1.97), fluorescein staining (ORa, 2.09) and rose bengal staining (ORa, 3.25). The remaining ocular diseases were not associated with symptoms. However, pterygium was significantly associated with fluorescein staining (ORa, 1.89); cataract surgery with TBUT (ORa, 2.79); trauma and pseudoexfoliation with rose bengal staining (ORa, 2.75 and ORa, 4.04); and glaucoma with TBUT (ORa, 3.26), fluorescein staining (ORa, 3.40), and rose bengal staining (ORa, 3.46). CONCLUSIONS: DE and MGD are common diseases in this population. MGD is strongly associated with symptoms and signs of DE. Nearly half of the subjects with DE have MGD. Pterygium, trauma, cataract surgery, pseudoexfoliation, and glaucoma are associated with signs of DE. PMID- 20847673 TI - The effect of topical cyclosporine A on clinical findings and cytological grade of the disease in patients with dry eye. AB - PURPOSE: To compare the clinical findings and the cytological grade of the disease before and after 6 months of topical cyclosporine A treatment in patients with dry eye. SETTING: : This single-center prospective study was performed at the Department of Ophthalmology, Ankara University School of Medicine, between January 2007 and June 2008. METHOD: Forty-five patients with dry eye (with 5 mm/5 minutes or less Schirmer test) were included in the study. Patients were treated with cyclosporine A 0.005% ophthalmic emulsion (RESTASIS) twice daily in addition to lubricant eyedrops 5 times a day. Schirmer test values, tear breakup time (BUT), and impression cytology (goblet cell density, nucleus to cytoplasmic ratio, and epithelial cell morphology) were evaluated at baseline and after 6 months. RESULTS: Before and after 6 months of the treatment with topical cyclosporine A, the median Schirmer test scores were found as 3.00 and 4.00 mm, respectively. The median BUT score at baseline was 4.00 seconds, and after treatment, the median score was 5.00 seconds. There were statistically significant differences in the median Schirmer and BUT values between, before, and after 6 months of treatment (P < 0.05). The mean cytological grade according to Nelson grading system was 1.84 at baseline and 1.51 after treatment with topical cyclosporine A for 6 months. Statistically significant improvement in cytological grades after treatment was observed (P < 0.05). CONCLUSION: Treatment of patients with dry eye for 6 months with topical cyclosporine A resulted in an increase in Schirmer test results, an increase in BUT scores, and an improvement in cytological grade of the disease. PMID- 20847674 TI - Scleral necrosis in a patient with congenital erythropoietic porphyria. AB - PURPOSE: To report on a patient with congenital erythropoietic porphyria who presented with scleral necrosis. METHOD: Case report. RESULTS: A 34-year-old man with a long history of congenital erythropoietic porphyria was referred to us for evaluation of necrotizing scleritis of the right eye. The patient presented with a 3-month duration of eye pain and redness, which initially responded to oral and topical corticosteroids. However, upon corticosteroid taper, the symptoms quickly recurred. The patient was initially tried on oral azathioprine therapy, which failed to induce resolution of the symptoms. Full serological investigation did not suggest that the necrotic process was secondary to an immunologically driven process, and we proceeded with scleral biopsy and patch graft. The biopsy disclosed atrophic changes of the sclera with calcium-like plaques, without evidence of inflammation. Aggressive strategy of sun avoidance was implemented and immunosuppressive therapy discontinued. One year after the surgery, the patient remains asymptomatic without recurrence of ocular disease. CONCLUSIONS: This case highlights the usefulness of tissue biopsy in porphyria when one is uncertain as to whether a necrotizing process is driven by inflammation or phototoxic damage. When the underlying mechanism is clearly identified, the appropriate therapy can then be instituted to prevent further damage. PMID- 20847675 TI - Neurotrophic keratitis and congenital insensitivity to pain with anhidrosis--a case report with 10-year follow-up. AB - PURPOSE: To report a rare case of congenital insensitivity to pain with anhidrosis. METHODS: A 3-year-old girl presented with watering in the right eye for 3 days. Slit-lamp examination showed an epithelial defect and hypopyon in the right eye and a corneal scar with thinning and vascularization in the left eye. There was bilateral reduced corneal sensation and evidence of self-mutilated lips and fingers. RESULTS: Neurological manifestations along with ocular features confirmed the diagnosis of congenital insensitivity to pain with anhidrosis. CONCLUSIONS: Patients with congenital insensitivity to pain with anhidrosis are asymptomatic even when they develop corneal ulcer. Parents should be advised regular follow-up and prompt treatment because this is a vision-threatening corneal abnormality. PMID- 20847676 TI - Subconjunctival injection of bevacizumab in the treatment of corneal neovascularization associated with lipid deposition. AB - PURPOSE: To determine the effects on corneal neovascularization (NV) and lipid deposition after subconjunctival injection of bevacizumab in patients who had NV associated with lipid keratopathy. METHODS: A case interventional study enrolled 18 patients (18 eyes) with lipid keratopathy. We gave monthly subconjunctival injections of bevacizumab from 3 to 10 times during the follow-up period according to the clinical response. We evaluated the centricity, extent, and percentage of involved corneal surface (PICS) of the corneal NV; the density and PICS of the corneal lipid deposition; and best-corrected visual acuity before and after treatment. We analyzed the treatment effects using Wilcoxon and Student t tests. RESULTS: After the treatment, the change in best-corrected visual acuity was less than 2 lines. The extent, centricity, and PICS of the corneal NV and the density and PICS of the corneal lipid deposition decreased significantly after treatment (P = 0.014/0.002/0.001 and 0.001/<0.001, respectively). No eyes had side effects. CONCLUSIONS: The effects of subconjunctival injection of bevacizumab in treating corneal NV associated with lipid deposition were significant in some patients. PMID- 20847677 TI - Topical anesthetic abuse keratitis secondary to floppy eyelid syndrome. AB - PURPOSE: To report the diagnosis and management of a patient with chronic ophthalmic topical anesthetic abuse and floppy eyelid syndrome. METHODS: We describe the case of a 47-year-old man suffering from persistent bilateral ocular irritation and chronic corneal erosions. RESULTS: The patient was hospitalized in our ophthalmology department and underwent thorough ophthalmic, systemic, and psychiatric evaluation. Chronic topical anesthetic abuse was discovered. Removal of abused drops and copious lubricating treatment lead to partial improvement further permitting diagnosis of floppy eyelid syndrome. Definitive surgical treatment by horizontal eyelid tightening combined with continuous lubrication resulted in remission of symptoms. CONCLUSIONS: Uncommon conditions may coexist in 1 patient. In this case, floppy eyelid syndrome resulted in topical anesthetic abuse. Ophthalmologists should keep both these conditions in mind when treating patients with otherwise unexplained chronic persistent corneal erosions. PMID- 20847678 TI - Spontaneous perforation of the cornea in mild keratoconus. AB - PURPOSE: Spontaneous corneal perforation during acute hydrops in keratoconus is a very rare complication and has only been described in patients with advanced keratoconus. We describe a case of spontaneous corneal perforation in mild keratoconus in a patient with no identifiable risk factors. METHODS: We report retrospectively on a 34-year-old woman with mild keratoconus (Krumeich stage II) who presented with the spontaneous perforation of the cornea. A literature review was undertaken. RESULTS: The handful of previously reported cases included patients with advanced keratoconus. Our patient had none of the risk factors identified in previously reported cases (eye rubbing, topical steroid use, and raised intraocular pressures). Corneal gluing was performed to restore globe integrity. She retained a visual acuity of 6/9 even through the acute episode. With the resolution of the acute episode, her corneal astigmatism improved and she achieved a final best-corrected visual acuity of 6/6 with spectacles. CONCLUSIONS: To our knowledge, this is the first reported case of spontaneous perforation of the cornea in mild keratoconus. We demonstrate that in this event, a good visual prognosis is possible from gluing alone. PMID- 20847679 TI - Ocular demodicosis as a potential cause of pediatric blepharoconjunctivitis. AB - PURPOSE: To report Demodex infestation in pediatric blepharoconjunctivitis. METHODS: A retrospective review of 12 patients, with ages from 2.5-11 years, with chronic blepharoconjunctivitis who failed to respond to conventional treatments. Demodex was detected by lash sampling and microscopic examination. Patients were treated with 50% tea tree oil (TTO) eyelid scrubs or 5% TTO ointment eyelid massages for 4-6 weeks. RESULTS: Demodex mites were found in all, but 1 case had cylindrical dandruff in the lashes. After 1 week of TTO treatment, all patients showed dramatic resolution of ocular irritation and inflammation while Demodex counts dropped. All corneal signs resolved within 2 weeks except for a residual anterior stromal scar in 1 eye. During a follow-up period of 8.3 +/- 4.6 months, 1 patient showed recurrent inflammation, which was successfully managed by a second round of TTO treatment. CONCLUSIONS: Demodicosis should be considered as a potential cause of pediatric refractory blepharoconjunctivitis. Eyelid scrubs or massage with TTO could be an effective treatment regimen in these cases. PMID- 20847680 TI - Permanent keratoprosthesis combined with pars plana vitrectomy and silicone oil injection for visual rehabilitation of chronic hypotony and corneal opacity. AB - PURPOSE: To present outcomes of combined pars plana vitrectomy, silicone oil (SO) injection, and permanent keratoprosthesis (Kpro) procedure in prephthisical eyes. METHODS: All 3 patients were monocular with chronic severe hypotony, aphakia, and total corneal opacity in their vital eye. Preoperative visual acuity ranged from light perception to counting fingers at 1 foot. Two patients had a history of failed corneal grafts because of SO, and one had funnel retinal detachment. Pars plana vitrectomy and long-term SO tamponade were performed, and a permanent Boston type 1 Kpro was used in lieu of a donor corneal transplantation. RESULTS: No unexpected intraoperative complications were encountered. Patients were followed for a period of 11-13 months. All patients had anatomic success with an attached retina and a clear visual axis. The procedures resulted in increased visual function in all patients ranging from hand motions to 20/800. No case has progressed to phthisis bulbi during the follow-up period. At the last visit, biomicroscopic examination revealed clear Kpro with an attached retina. CONCLUSIONS: Boston type 1 Kpro implantation, as the primary corneal procedure with pars plana vitrectomy and intraocular SO, may be a viable option in selected patients with prephthisical eyes. PMID- 20847681 TI - Binocular visual function in patients with Boston type I keratoprostheses. AB - PURPOSE: To report the postoperative binocular function of patients with Boston type I keratoprostheses implantation for unilateral visual impairment. METHODS: Seventeen patients who underwent implantation of a Boston type I keratoprosthesis and had a best-corrected visual acuity better than 20/50 in the contralateral eye before surgery were evaluated. All subjects prospectively underwent sensory testing of binocular function including Bagolini lenses, Worth-4-dot test, stereoacuity at distance and near, and double Maddox rods. In addition, an assessment of ocular rotations and alignment was performed on each subject. RESULTS: Twenty patients with best-corrected visual acuity better than 20/50 in the contralateral eye at the time of keratoprothesis surgery were identified. Seventeen of the 20 patients underwent binocular visual testing, with 16 of 17 (94%) demonstrating binocular function. Second-degree fusion at near was demonstrated via the Worth-4-dot test in 13 of 17 (76%) patients. Third-degree fusion at near was demonstrated in 7 of 17 (41%) patients. Patients with better postoperative sensory binocular function tended to be of younger age (P = 0.05) and have better postoperative visual acuity (P = 0.006). Five patients were found to have some degree of ocular misalignment. Overall, patients with strabismus had worse binocularity (P = 0.04). CONCLUSIONS: Implantation of the Boston type I keratoprosthesis in patients with good preoperative visual acuity in the fellow eye is associated with useful binocular function in greater than 90% of patients. PMID- 20847682 TI - The successful use of Boston ocular surface prosthesis in the treatment of persistent corneal epithelial defect after herpes zoster ophthalmicus. AB - PURPOSE: To describe the use of the Boston ocular surface prosthesis (BOSP) to successfully treat a persistent corneal epithelial defect (PCED) after herpes zoster ophthalmicus that was minimally responsive to conventional therapies. METHODS: A case report. RESULTS: A 44-year-old man who developed a PCED in the right eye after herpes zoster ophthalmicus was treated with conventional therapies, including topical difluprednate opthalmic emulsion, 0.05% cyclosporine ophthalmic emulsion, topical autologous plasma, and oral doxycycline. Silicone plugs were inserted in the right upper and lower puncta. An 18-mm therapeutic hydrogel contact lens was placed in the right eye. After 4 weeks of this treatment, double layer amniotic membrane transplantation and temporary lateral tarsoraphy were performed. Ten days after the procedure, the amniotic membrane had dissolved and the tarsorrhaphy was opened. Because only partial healing of the corneal epithelial defect was observed, the patient was fit with the BOSP that he wore all waking hours. A soft contact lens was worn overnight after the BOSP was removed. Rapid reepithelization was observed within the week after starting the BOSP. The epithelial defect completely healed after 3 weeks, and the uncorrected visual acuity in the right eye improved to 20/50. CONCLUSIONS: The BOSP should be considered as an important treatment option for management of PCEDs in eyes with altered corneal sensitivity. PMID- 20847683 TI - Use of adjuvant hyperbaric oxygen therapy to support limbal conjunctival graft in the management of recurrent pterygium. AB - PURPOSE: To assess the role of hyperbaric oxygen therapy (HBOT) in the management of recurrent pterygium. METHODS: Thirty-nine eyes with recurrent pterygium were treated with surgical excision and limbal conjunctival autograft, followed by a course of HBOT. Patients were followed for development of recurrence. RESULTS: Of the 39 eyes, 18 had a known history of exposure to beta radiation or mitomycin C. The mean duration of follow-up in this group was 23.1 months. A single recurrence was noted in this group. For the remaining 21 eyes, the mean duration of follow up was 19.4 months. No recurrences were recorded in this group. No significant complications from HBOT were recorded. CONCLUSIONS: The use of HBOT together with excision and limbal conjunctival autograft for recurrent pterygium is associated with a low recurrence rate. Adjuvant HBOT should be considered in the surgical management of recurrent pterygium. PMID- 20847684 TI - A rare unilateral case of ocular mucous membrane pemphigoid. AB - PURPOSE: Ocular mucous membrane pemphigoid (MMP) is known to be rapidly progressive in younger patients and affects both eyes. We are aware of only one other reported case of unilateral ocular MMP. The case presented in this study is unique in that it demonstrates genuinely unilateral ocular MMP in a younger patient. METHODS: We report a case of a 50-year-old man who presented with a 3 month history of left eye redness, irritation, and mild discharge. He also suffered from mouth ulcers, skin lesions, and recurrent nose bleeds secondary to nasal mucosal lesions. RESULTS: Examination revealed unilateral lid granulomas and cicatricial conjunctivitis in his left eye. There were no abnormal findings in his right eye. Biopsy of the lesions showed nonspecific inflammation with positive immunofluorescence for immunoglobulin G and C3 on epithelial basement membranes of conjunctiva, buccal mucosa, and skin, which were consistent with MMP. He was treated with immunosuppression and had no disease progression at 12 month follow-up. CONCLUSIONS: This represents a rare case of unilateral nonprogressive ocular MMP in a younger patient. Histological analysis and immunofluorescence testing excluded a neoplastic process and confirmed the diagnosis. This case demonstrates that the presentation of unilateral eyelid pyogenic granulomas should include ocular MMP in the differential diagnosis once a neoplastic process has been excluded. PMID- 20847685 TI - Update on fungal keratitis from 1999 to 2008. AB - PURPOSE: To report trends in fungal keratitis from a single institution between 1999 and 2008. METHODS: Retrospective chart review of the patients presenting to the cornea service with fungal keratitis from April 1999 to December 2008. RESULTS: Seventy-eight eyes of 76 patients were identified. The most common predisposing factors included contact lens use (35.9%), trauma (21.8%), and history of penetrating keratoplasty (15.4%). There was a significant increase in the rate of contact lens-related Fusarium infections over time, which peaked in 2005 and 2006 (P = 0.021). Almost 40% of fungal keratitis cases [11 of 28 eyes (39.3%)] were soft contact lens-related Fusarium infections in 2005 and 2006, and this decreased to less than 10% [2 of 25 eyes (8%)] in 2007 and 2008. The odds of having a contact lens-related Fusarium infection in 2005-2006 compared with 2007 2008 was 4.40 (95% confidence interval of 0.60-32.50) (P = 0.178). Despite the decrease in contact lens-related Fusarium infections, the number of fungal infections remained elevated in 2007 (10 eyes) and 2008 (14 eyes), including contact lens-related infections (3 in 2007 and 6 in 2008). CONCLUSIONS: A definite increase in the number of fungal keratitis cases began in 2004 and continued through 2006 during the Fusarium outbreak associated with ReNu with MoistureLoc. Despite the decrease in contact lens-related Fusarium infections, the overall number of fungal keratitis cases remained high through 2008. Fungal keratitis was more often associated with contact lens use than with trauma in this time. PMID- 20847686 TI - Etiologic diagnosis of corneal ulceration at a tertiary eye center in Kathmandu, Nepal. AB - PURPOSE: To determine the etiologic diagnosis of infectious corneal ulcers at Tilganga Institute of Ophthalmology, a tertiary teaching hospital in Kathmandu Nepal, from 2006-2009. METHODS: This study involved a review of all microbiology records at Tilganga Institute of Ophthalmology from August 2006 through July 2009. Microbiologic records from the corneal scrapings of all patients suspected of having infectious corneal ulcers were included. RESULTS: Corneal scrapings were obtained from 468 patients. The average patient age was 52 years, and 55% of the affected cases were males. Microorganisms were grown from 185 of the corneal scrapings (40%). Pure bacterial cultures were obtained from 72 patients (39%), and pure fungal cultures were obtained from 113 patients (61%). Gram stain was 75% sensitive (95% confidence interval, 0.632-0.841) in identifying bacterial infection, whereas KOH prep was 80.5% sensitive (95% confidence interval, 0.718 0.871) in identifying fungal organisms. Of 72 bacterial isolates, 50 isolates (69%) were Streptococcus pneumoniae, the most common organism isolated in this study. Of 113 fungal isolates, 40 of isolates (35%) were identified as Aspergillus sp. CONCLUSIONS: Fungal organisms (61%) are the most common cause of infectious keratitis in this patient population. Of all organisms, S. pneumoniae was the most common organism identified. Smear microscopy is reliable in rapidly determining the etiology of the corneal infection and can be used to help guide initial therapy in this setting. PMID- 20847687 TI - A novel technique to center the donor punch for descemet stripping endothelial keratoplasty. AB - PURPOSE: This report describes a method to improve the accuracy of centration of the donor trephination for Descemet stripping endothelial keratoplasty. METHODS: Using trypan blue, the donor corneal cap is outlined. The donor punch is centered on the actual cap rim rather than on a centration mark made either by the surgeon or by the eye bank preparing the precut tissue. RESULTS: Using the described technique, eccentric donor trephination was reduced from 7.7% to 2.4%. CONCLUSIONS: We have described a method to improve the centration of donor trephination and reduce the incidence of eccentric donor punching. PMID- 20847688 TI - Large congenital corneal dermoid with spontaneous partial regression: the first report. AB - PURPOSE: To report a spontaneous partial regression of a large congenital corneal dermoid in a newborn. MATERIALS AND METHODS: Review and follow-up of the medical records of a female newborn presenting with a tumor mass of her right eye and no other congenital abnormalities. The child presented on the first day of life with a mushroom-shaped mass of 15 * 15 mm in diameter that involved the most of the cornea leaving a small clear portion superiorly. The mass protruded through the palpebral aperture. A diagnosis of corneal dermoid was made based on clinical presentation of the mass and radiographic and ultrasound findings. Enucleation of the right eye was discussed, but declined by parents. RESULTS: During the first month of life, a spontaneous partial regression of the mass occurred, so that the patient was able to close the lids completely above the mass. This dermoid is the third type according to Mann's classification. Characterized by involvement of the entire anterior segment and lack of lens. CONCLUSIONS: To the best of our knowledge, the case reported is the first documented spontaneous partial regression of a large corneal dermoid. Surgical excision at an early age may be recommended to avoid development of amblyopia and dramatic growth of the tumor. In our case the tumor regressed and surgical excision would have no impact on visual outcome. Future management of type III corneal dermoid needs to consider whether to perform surgery at an early stage or to recommend conservative management. PMID- 20847689 TI - Preoperative single-dose intravenous dexamethasone during ambulatory surgery: update around the benefit versus risk. AB - PURPOSE OF REVIEW: Pain, emesis, and fatigue are not uncommon symptoms after ambulatory surgery having impact on patients' satisfaction with quality of care. Multimodal management of postoperative pain and nausea and vomiting has become standard of care. RECENT FINDINGS: There is a growing body of evidence for the beneficial effects from preoperative single-dose intravenous (i.v.) glucocorticoids for reducing pain, emesis, and fatigue, thereby improving the recovery process and patient satisfaction. Side-effects are infrequently reported. SUMMARY: The benefits versus risk associated to single preoperative i.v. dose of dexamethasone seem positive based on current evidence facilitating the recovery reducing pain and postoperative nausea and vomiting. PMID- 20847690 TI - The role of multimodal analgesia in pain management after ambulatory surgery. AB - PURPOSE OF REVIEW: As outpatient (day-case) surgery had continued to grow throughout the world, many more complex and potentially painful procedures are being routinely performed in the ambulatory setting. Opioid analgesics, once considered the standard approach to preventing acute postoperative pain, are being replaced by a combination of nonopioid analgesic drugs with diverse modes of action as part of a multimodal approach to preventing pain after ambulatory surgery. This review will provide an update on the topic of multimodal pain management for ambulatory (day-case) surgery. RECENT FINDINGS: Efficacy of multimodal analgesic regimens continues to improve; opioid analgesics are increasingly taking on the role of 'rescue analgesics' for acute pain after day case surgery. The use of multimodal analgesia is rapidly becoming the 'standard of care' for preventing pain after ambulatory procedures at most surgery centers throughout the world. SUMMARY: This article discusses recent evidence from the peer-reviewed literature regarding the role of local anesthetics, NSAIDs, gabapentinoids, and acetaminophen, as well as alpha-2 agonists, ketamine, esmolol, and nonpharmacologic approaches (e.g., transcutaneous electrical stimulation) as parts of multimodal pain management strategies in day-case surgery. PMID- 20847691 TI - The new oral anticoagulants, do they change the benefit vs. risk for thromboprophylaxis in association to ambulatory surgery? AB - PURPOSE OF REVIEW: Several randomized controlled trials have shown that pharmacological thromboprophylaxis with low-dose unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux reduces venous thromboembolism (VTE) after general surgery. No high-quality evidence supports the use of pharmacological thromboprohylaxis with traditional antithrombotic drugs in patients undergoing ambulatory surgery without additional VTE risk factors, stratified at low risk of VTE by the American College of Chest Physicians guidelines. Two new drug classes, the direct thrombin and factor Xa (FXa) inhibitors, have been developed with a potentially better risk-benefit profile. RECENT FINDINGS: Oral administration, predictable anticoagulant responses, low potential for drug-drug interactions render direct thrombin and factor Xa inhibitors good candidates to replace UFH, LMWH and fondaparinux for VTE prophylaxis. Most of all, the positive results of the first published clinical trials in orthopedic thromboprophylaxis allowed dabigatran etexilate and rivaroxaban to be licensed in Canada and in European Union for the prevention of VTE in patients undergoing hip-replacement and knee-replacement surgery. SUMMARY: No randomized trials with the new anticoagulants are ongoing in ambulatory surgery. However, currently available drugs--that is UFH, LMWH or fondaparinux- are administered subcutaneously and the new anticoagulants would offer the clear advantage of an oral administration, without request for blood testing to monitor potential adverse effects such as heparin-induced thrombocytopenia, thus potentially simplifying the treatment out of the hospital. PMID- 20847692 TI - The risk of HIV drug resistance following implementation of pre-exposure prophylaxis. AB - PURPOSE OF REVIEW: Results of trials determining if pre-exposure prophylaxis (PrEP) with antiretroviral drugs prevents transmission of HIV are expected soon. Tenofovir and emtricitabine--currently evaluated as PrEP--are popular in treatment of HIV. Drug resistance could, therefore, be critical in the use of PrEP. We review the literature regarding risks associated with drug resistance owing to PrEP. RECENT FINDINGS: Few studies addressed the issue of drug resistance to tenofovir and/or emtricitabine. Studies in HIV-1-infected individuals followed small numbers of patients for a short time. Studies in macaques were well designed, but used SHIV, which has an attenuated course of infection. The available information suggests that the probability of emergence of drug resistance is small. Infections that occurred despite use of PrEP had reduced peak viremia, which could reduce HIV transmissibility. Mathematical modeling suggests that, although transmitted drug resistance may under some circumstances increase, the benefits of PrEP outweigh the risks associated with resistance. SUMMARY: Tenofovir and emtricitabine are recommended in first-line treatment. The potentially limited impact of drug resistance should, therefore, be confirmed in daily practice. Surveillance of drug resistance is recommended in areas where PrEP is used. Patients that became infected despite use of PrEP should be closely monitored for virological failure. PMID- 20847693 TI - Can HIV infection be eradicated through use of potent antiviral agents? AB - PURPOSE OF REVIEW: This review focuses on recent advances in HIV research and therapy that seek to eradicate persistent HIV in patients on suppressive therapy. RECENT FINDINGS: The source of persistent HIV in patients on suppressive therapy is debated. Recent studies of treatment intensification have produced varied results: no reduction in low-level plasma viremia indicating the source of persistent viremia is long-lived HIV-infected cells that release HIV when activated and increase in episomal HIV DNA indicating active replication persists in some infected individuals on suppressive therapy. In addition, clonal HIV sequences found in plasma from patients on long-term suppressive therapy are rarely found in CD4+ memory T cells. These results indicate that persistent viremia may arise from several different sources. Recent studies emphasize the complexity of HIV latency. Current strategies for HIV eradication focus on compounds that activate viral transcription in memory CD4+ T cells by many routes, including inhibiting histone deacetylation and activating nuclear factor kappa B. Several compounds and combinations of these compounds appear to induce the expression of integrated HIV in different latency models. SUMMARY: The eradication of HIV requires the elimination of persistent HIV during suppressive therapy. Recent studies have focused on the source of persistent viremia, mechanisms of intracellular HIV latency, and reactivation of latent HIV. It remains to be seen whether alternative treatment strategies may be required to eradicate HIV. PMID- 20847694 TI - Elimination of lymphatic filariasis: do we have the drugs to complete the job? AB - PURPOSE OF REVIEW: Lymphatic filariasis is targeted for elimination globally through mass drug administration (MDA) with diethylcarbamazine or ivermectin monotherapy, or either drug in combination with albendazole. However, many countries that have implemented MDA annually for over 5 years are yet to interrupt transmission. This review describes the current drugs used in MDA and highlights the challenges facing the WHO Global Programme to Eliminate Lymphatic Filariasis (GPELF). RECENT FINDINGS: Current drugs used for MDA implementation by national elimination programmes only temporarily clear microfilariae without killing all adult worms. Generally, reports of serious adverse events associated with MDA for lymphatic filariasis using current drugs are uncommon. However, in areas in Africa where lymphatic filariasis co-exists with Loa loa, progressive neurologic decline and encephalopathy within a few days of taking ivermectin have caused great concern. Doxycycline, which is effective at eliminating the Wolbachia symbiont from the lymphatic filariasis parasite, is showing promise as an alternative treatment option for areas where lymphatic filariasis is co endemic with Loa loa. SUMMARY: Alternative and effective MDA regimens and strategies will be needed if the GPELF is to achieve the goals of global elimination of lymphatic filariasis by 2020. Further research to test new drug regimens (including single high doses of albendazole) or alternative treatment regimens (including biannual treatment schedules) may also be necessary. A new drug, moxidectin, which is currently under development for use against onchocerciasis, may be effective against lymphatic filariasis. PMID- 20847695 TI - Melioidosis: advances in diagnosis and treatment. AB - PURPOSE OF REVIEW: Melioidosis is an infectious disease caused by the soil associated Gram-negative bacterium Burkholderia pseudomallei. This review summarizes the evidence underlying current antibiotic regimens and discusses future strategies to reduce mortality. RECENT FINDINGS: Although simple rapid diagnostics exist, they rely on the availability of direct specimen and are not commercially available. Serological tests and nucleic acid detection are not sufficiently specific or sensitive for routine clinical use. Since the original trials defining setting the standard of care as ceftazidime, no antibiotic regimens have been shown to be superior in comparative trials, but ongoing trials are evaluating the efficacy of meropenem (in intensive treatment) and (TMP-SMX) (for eradication treatment). SUMMARY: In endemic areas, empiric antibiotics should include agents active against melioidosis as well as the other common causes of severe sepsis. It is likely that future improvements in mortality will be the result of efforts to improve on the early recognition and management of severe sepsis generally. PMID- 20847696 TI - Assessment of infection risks prior to lung transplantation. AB - PURPOSE OF THIS REVIEW: Infections are major causes of morbidity and mortality after lung transplantation. Pretransplant evaluation can identify patients at risk of infectious complications and guide prophylactic strategies post transplantation. This review focuses on studies published from 2006 to the present that relate to the assessment of risk of infection prior to lung transplantation. RECENT FINDINGS: Pretransplant airways colonization with Pseudomonas, Burkholderia, nontuberculosis mycobacteria, Aspergillus and Scedosporium tend to recur after transplantation and cause disease in the lung allograft. Recently, colonization with Pseudomonas and Aspergillus species has been implicated in the subsequent development of allograft dysfunction. B. cenocepacia and Mycobacterium abscessus are particularly associated with poor outcomes after lung transplantation and are considered to be relative contra indications to lung transplantation in many centers. Tuberculin skin test (TST) has limited value in predicting tuberculosis (TB) reactivation; however, in the absence of a better test, it remains the gold standard for screening patients with latent TB. Serologic screening for histoplasmosis and toxoplasmosis has limited value as these infections rarely occur after lung transplantation. SUMMARY: Recurrence of pretransplant airway infection and reactivation of latent infection are potential sources of infection after lung transplantation. Prospective studies are needed to determine the efficacy of prophylactic antimicrobial strategies. PMID- 20847697 TI - Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. AB - Classic Ehlers-Danlos syndrome is a heritable connective tissue disorder characterized by skin hyperextensibility, fragile and soft skin, delayed wound healing with formation of atrophic scars, easy bruising, and generalized joint hypermobility. It comprises Ehlers-Danlos syndrome type I and Ehlers-Danlos syndrome type II, but it is now apparent that these form a continuum of clinical findings and differ only in phenotypic severity. It is currently estimated that approximately 50% of patients with a clinical diagnosis of classic Ehlers-Danlos syndrome harbor mutations in the COL5A1 and the COL5A2 gene, encoding the alpha1 and the alpha2-chain of type V collagen, respectively. However, because no prospective molecular studies of COL5A1 and COL5A2 have been performed in a clinically well-defined patient group, this number may underestimate the real proportion of patients with classic Ehlers-Danlos syndrome harboring a mutation in one of these genes. In the majority of patients with molecularly characterized classic Ehlers-Danlos syndrome, the disease is caused by a mutation leading to a nonfunctional COL5A1 allele and resulting in haploinsufficiency of type V collagen. A smaller proportion of patients harbor a structural mutation in COL5A1 or COL5A2, causing the production of a functionally defective type V collagen protein. Most mutations identified so far result in a reduced amount of type V collagen in the connective tissues available for collagen fibrillogenesis. Inter- and intrafamilial phenotypic variability is observed, but no genotype-phenotype correlations have been observed. No treatment for the underlying defect is presently available for Ehlers-Danlos syndrome. However, a series of preventive guidelines are applicable. PMID- 20847698 TI - SHOX duplications found in some cases with type I Mayer-Rokitansky-Kuster-Hauser syndrome. AB - PURPOSE: The Mayer-Rokitansky-Kuster-Hauser syndrome is defined as congenital aplasia of mullerian ducts derived structures in females with a normal female chromosomal and gonadal sex. Most cases with Mayer-Rokitansky-Kuster-Hauser syndrome are sporadic, although familial cases have been reported. The genetic basis of Mayer-Rokitansky-Kuster-Hauser syndrome is largely unknown and seems heterogeneous, and a small number of cases were found to have mutations in the WNT4 gene. The aim of this study was to identify possible recurrent submicroscopic imbalances in a cohort of familial and sporadic cases with Mayer Rokitansky-Kuster-Hauser syndrome. METHODS: Multiplex ligation-dependent probe amplification was used to screen the subtelomeric sequences of all chromosomes in 30 patients with Mayer-Rokitansky-Kuster-Hauser syndrome (sporadic, n = 27 and familial, n = 3). Segregation analysis and pyrosequencing were applied to validate the MLPA results in the informative family. RESULTS: Partial duplication of the Xpter pseudoautosomal region 1 containing the short stature homeobox (SHOX) gene was detected in five patients with Mayer-Rokitansky-Kuster-Hauser syndrome (familial, n = 3 and sporadic, n = 2) and not in 53 healthy controls. The duplications were not overlapping, and SHOX was never entirely duplicated. Haplotyping in the informative family revealed that SHOX gene duplication was inherited from the unaffected father and was absent in two healthy sisters. CONCLUSIONS: Partial duplication of SHOX gene is found in some cases with both familial and sporadic Mayer-Rokitansky-Kuster-Hauser type I syndrome. PMID- 20847700 TI - Horner syndrome following a selective cervical nerve root block. AB - A 31-year-old man with cervical degenerative disc disease was seen at an outside institution for a right selective nerve root block at C7. Following the procedure, he had right ptosis and miosis. Pharmacologic testing confirmed a right Horner syndrome. MRI and MRA showed no arterial dissection. This report documents the unusual occurrence of permanent Horner syndrome following a selective cervical nerve root block. PMID- 20847699 TI - Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on suppressive antiretroviral therapy. AB - BACKGROUND: Antiretroviral treatment (ART) significantly reduces cerebrospinal fluid (CSF) HIV-1 RNA levels and residual viremia is less frequently found in CSF than in blood. However, persistent intrathecal immunoactivation is common, even after several years of ART. To investigate whether low-level CSF viremia and residual immunoactivation within the central nervous system (CNS) derive from ongoing local viral replication, we conducted a study of treatment intensification in patients on effective ART. METHODS: Ten patients on ART with plasma HIV RNA <50 copies per milliliter for >18 months were included. Intensification was given for in total 8 weeks: 4 weeks with maraviroc or lopinavir/ritonavir (good CNS penetration), and 4 weeks with enfuvirtide (poor CNS penetration). Lumbar punctures were performed 4 weeks before, at intensification commencement, at switchover after 4 weeks, at the conclusion of, and 4 weeks after the intensification period. RESULTS: No significant changes in HIV RNA, neopterin, beta2-microglobulin, immunoglobulin G index, albumin ratio, and CD4(+) T-cell count were observed, either in CSF or blood, neither before, during, nor after the intensification periods. CONCLUSIONS: ART intensification did not reduce residual CSF HIV RNA levels or intrathecal immunoactivation in patients on ART. These findings do not support an ongoing viral replication in CNS. PMID- 20847701 TI - Endoscopic orbital roof fenestration as an alternative treatment option for idiopathic intracranial hypertension: a cadaveric anatomical study. AB - BACKGROUND: We investigated a new minimally invasive surgical technique for the treatment of idiopathic intracranial hypertension in a cadaveric model. This technique aims at establishing a communication between the intraorbital and intracranial compartments by creating a bone, dural, and periorbital window in the anterior cranial fossa. This procedure is predicated on intraorbital absorptive capability that has been demonstrated in animals and discussed in humans. METHODS: Three fresh cadaver heads were fixed in a head holder so as to mimic the hyperextended supine position. The procedure was conducted bilaterally in each specimen. Our technique is as follows: 1) An incision is made in the eyebrow medial to the supraorbital notch; 2) using an endoscope and a periosteal elevator, the intraorbital surface of the orbital roof is separated from the periorbita in an anteroposterior direction for a length of 1.5-2.5 cm; 3) a 1 cm of the exposed orbital roof is removed, and the dura and arachnoid are opened; and 4) slits are made in the exposed periorbita. RESULTS: We were able to create a communication between the intracranial and the intraorbital compartments in all specimens. CONCLUSION: Our technique is new and does not require any foreign body implantation. Its applicability in humans needs to be evaluated in a clinical context. PMID- 20847702 TI - Treatment of SCFE in a healthy 5-year-old child: case report and review. AB - Slipped capital femoral epiphysis is a common adolescent hip disorder and when patients present at an age younger than 10 years, it is atypical and there is often some identifiable associated metabolic or endocrinologic abnormality. We present the case of a 5-year-old boy with idiopathic bilateral slipped capital femoral epiphysis. This patient underwent staged bilateral pinning in situ using a uniquely modified screw where the distal threads were machined-off for smooth fixation across the physis. The patient had an unremarkable postoperative course and showed evidence of remodeling and patent physes at 1-year follow-up. PMID- 20847703 TI - The development and application of an injury prediction model for noncontact, soft-tissue injuries in elite collision sport athletes. AB - Limited information exists on the training dose-response relationship in elite collision sport athletes. In addition, no study has developed an injury prediction model for collision sport athletes. The purpose of this study was to develop an injury prediction model for noncontact, soft-tissue injuries in elite collision sport athletes. Ninety-one professional rugby league players participated in this 4-year prospective study. This study was conducted in 2 phases. Firstly, training load and injury data were prospectively recorded over 2 competitive seasons in elite collision sport athletes. Training load and injury data were modeled using a logistic regression model with a binomial distribution (injury vs. no injury) and logit link function. Secondly, training load and injury data were prospectively recorded over a further 2 competitive seasons in the same cohort of elite collision sport athletes. An injury prediction model based on planned and actual training loads was developed and implemented to determine if noncontact, soft-tissue injuries could be predicted and therefore prevented in elite collision sport athletes. Players were 50-80% likely to sustain a preseason injury within the training load range of 3,000-5,000 units. These training load 'thresholds' were considerably reduced (1,700-3,000 units) in the late-competition phase of the season. A total of 159 noncontact, soft-tissue injuries were sustained over the latter 2 seasons. The percentage of true positive predictions was 62.3% (n = 121), whereas the total number of false positive and false negative predictions was 20 and 18, respectively. Players that exceeded the training load threshold were 70 times more likely to test positive for noncontact, soft-tissue injury, whereas players that did not exceed the training load threshold were injured 1/10 as often. These findings provide information on the training dose-response relationship and a scientific method of monitoring and regulating training load in elite collision sport athletes. PMID- 20847704 TI - The mechanisms of muscle hypertrophy and their application to resistance training. AB - The quest to increase lean body mass is widely pursued by those who lift weights. Research is lacking, however, as to the best approach for maximizing exercise induced muscle growth. Bodybuilders generally train with moderate loads and fairly short rest intervals that induce high amounts of metabolic stress. Powerlifters, on the other hand, routinely train with high-intensity loads and lengthy rest periods between sets. Although both groups are known to display impressive muscularity, it is not clear which method is superior for hypertrophic gains. It has been shown that many factors mediate the hypertrophic process and that mechanical tension, muscle damage, and metabolic stress all can play a role in exercise-induced muscle growth. Therefore, the purpose of this paper is twofold: (a) to extensively review the literature as to the mechanisms of muscle hypertrophy and their application to exercise training and (b) to draw conclusions from the research as to the optimal protocol for maximizing muscle growth. PMID- 20847705 TI - The effect of an upper-body agonist-antagonist resistance training protocol on volume load and efficiency. AB - The objective of this study was to investigate the acute effects on volume load (VL) (load * repetitions) of performing paired set (PS) vs. traditional set (TS) training over 3 consecutive sets. After a familiarization session 16 trained men performed 2 testing protocols using 4 repetition maximum loads: TS (3 sets of bench pull followed by 3 sets of bench press performed in approximately 10 minutes) or PS (3 sets of bench pull and 3 sets of bench press performed in an alternating manner in approximately 10 minutes). Bench pull and bench press VL decreased significantly from set 1 to set 2 and from set 2 to set 3 under both the PS and TS conditions (p < 0.05). Bench pull and bench press VL per set were significantly less under TS as compared to PS over all sets, with the exception of the first set (bench pull set 1) (p < 0.05). Session totals for bench pull and bench press VL were significantly less under TS as compared to PS (p < 0.05). Paired set was determined to be more efficient (VL/time) as compared to TS. The data suggest that a 2-minute rest interval between sets (TS), or a 4-minute rest interval between similar sets (PS), may not be adequate to maintain VL. The data further suggest that PS training may be more effective than TS training in terms of VL maintenance and more efficient. Paired set training would appear to be an efficient method of exercise. Practitioners wishing to maximize work completed per unit of time may be well advised to consider PS training. PMID- 20847706 TI - Intermittent endurance and repeated sprint ability in soccer players. AB - The ability to perform high-intensity intermittent exercise (i.e., Yo-Yo Intermittent Recovery Test [Yo-Yo IR1]) and to repeat sprints with relatively short recovery times (i.e., 20- to 30-seconds, relatively short time interval [repeated sprint ability (RSA)]) has been shown to be relevant fitness variables in soccer. However, though they potentially share common features, it is not known whether these 2 abilities are associated. The aim of this study was to examine the relationships between Yo-Yo IR1 and RSA performances in elite soccer players. Twenty-three soccer players (age 19 +/- 1 years, height 181 +/- 5.7 cm, body mass 73.2 +/- 4.1 kg, %body fat 11 +/- 2.4) performed the Yo-Yo IR1 and a test for RSA (7 * 30 m with 25-second recovery). Results were 2,289 +/- 409 m, 31.21 +/- 1.13 seconds, and 4 +/- 2.1% for Yo-Yo IR1, total sprint time, and sprint decrement, respectively. Yo-Yo IR1 showed a significant and moderate relationship with sprint decrement (r2 = -0.44, p = 0.04). Splitting the sample into Best and Worst Yo-Yo IR1 performers according to median score (2,320 m), the Best group showed lower RSA total time (30.69 +/- 0.99 vs. 31.79 +/- 1.06, p < 0.05) and speed decrement (2.90 +/- 0.86 vs. 5.09 +/- 2.42, p < 0.01) compared to the Worst group. Sprint-time deterioration over 30 m occurred earlier (from the second sprint on) in the Yo-YoWorst compared with in the Yo-YoBest group (from the fourth sprint on, p < 0.001). Intermittent high-intensity endurance is poorly associated with RSA performance (r2 = 0.19). Consequently, coaches and strength and conditioning professionals should consider both Yo-Yo IR1 and RSA in their testing batteries. A Yo-Yo IR1 performance >=2,320 m could be considered as a reasonable indicator of physical fitness in elite soccer. Relatively short time interval test protocols similar to the present study should consist of at least 5 sprint bouts. PMID- 20847707 TI - Cut down on SSIs. PMID- 20847708 TI - Rethinking service lines. PMID- 20847710 TI - A twelve-item symptom intensity rating scale for cervical spine dysfunction. PMID- 20847709 TI - A randomized pilot study of systemic immunosuppression in the treatment of age related macular degeneration with choroidal neovascularization. AB - BACKGROUND: Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. METHODS: This was a pilot, Phase I/II, prospective, randomized, unmasked, single center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. RESULTS: The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. CONCLUSION: These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated. PMID- 20847711 TI - Metastatic testicular cancer presents as spinal injection complication. PMID- 20847712 TI - Biomechanical comparison of anterior, posterior, and circumferential fixation after one-level anterior cervical corpectomy in the human cadaveric spine. AB - STUDY DESIGN: In vitro biomechanical study of cadaveric cervical spine. OBJECTIVE: To compare the rigidity of the cervical spine after anterior, posterior, and circumferential fixation after 1-level corpectomy, and evaluate the effects of the integrity of the facet capsules and posterior ligaments (PL). SUMMARY OF BACKGROUND DATA: Anterior cervical corpectomy is commonly used for decompression of the spinal canal in the treatment of different pathologic conditions. The effect of the integrity of the facet capsules and PLs on the biomechanical stability provided by anterior, posterior, or circumferential fixation following 1-level corpectomy has not been investigated. METHODS: Nine cadaveric cervical spines were potted rostrally at C2, and caudally at T1-T2, and were tested in 6 directions with pure moment application, in 5 conditions: In the intact spine, after a C5 corpectomy and anterior fixation, after anterior fixation and disruption of the C4-C5 and C5-C6 facet capsules and PL, after circumferential fixation, and after posterior fixation alone without anterior cage. Angular motion of C4 relative to C6 was measured. RESULTS: Despite C5 corpectomy, anterior grafting and plate fixation was more rigid than the intact spine with all loads in flexion, at loads of 0.5 Nm and 1.0 Nm in right axial rotation and right lateral bending, and at all loads in left lateral bending. Posterior ligamentous disruption increased motion in the coronal and axial planes, but not in the sagittal plane. Circumferential instrumentation resulted in a significant reduction in motion of the spine compared with anterior instrumentation in both the coronal and axial planes but not in the sagittal plane. Posterior fixation without anterior cage failed to limit cervical spine motion in the sagittal plane, but was restrictive in axial rotation and lateral bending when compared with circumferential fixation. CONCLUSION: After C5 corpectomy, with intact PLs and facet capsules, anterior instrumentation is sufficient for spinal stabilization as the resultant construct is more rigid than the intact state. In the presence of C5 corpectomy with PL and bilateral facet capsule disruption, anterior plus posterior instrumentation is more rigid than anterior instrumentation alone in the axial and coronal planes and more rigid than posterior instrumentation without anterior cage in the sagittal plane. PMID- 20847713 TI - Predicting SF-6D utility scores from the neck disability index and numeric rating scales for neck and arm pain. AB - STUDY DESIGN: Cross-sectional cohort. OBJECTIVE: This study aims to provide an algorithm to estimate Short Form-6D (SF-6D) utilities using data from the Neck Disability Index (NDI), neck pain, and arm pain scores. SUMMARY OF BACKGROUND DATA: Although cost-utility analysis is increasingly used to provide information about the relative value of alternative interventions, health state values or utilities are rarely available from clinical trial data. The Neck Disability Index (NDI) and numerical rating scales for neck and arm pain are widely used disease-specific measures in patients with cervical degenerative disorders. The purpose of this study is to provide an algorithm to allow estimation of SF-6D utilities using data from the NDI, and numerical rating scales for neck and arm pain. METHODS: SF-36, NDI, neck and arm pain rating scale scores were prospectively collected before surgery, at 12 and 24 months after surgery in 2080 patients undergoing cervical fusion for degenerative disorders. SF-6D utilities were computed, and Spearman correlation coefficients were calculated for paired observations from multiple time points between NDI, neck and arm pain scores, and SF-6D utility scores. SF-6D scores were estimated from the NDI, neck and arm pain scores were estimated using a linear regression model. Using a separate, independent dataset of 396 patients in which NDI scores were available, SF-6D was estimated for each subject and compared to their actual SF-6D. RESULTS: The mean age for those in the development sample was 50.4 +/- 11.0 years and 33% were male. In the validation sample, the mean age was 53.1 +/- 9.9 years and 35% were male. Correlations between the SF-6D and the NDI, neck and arm pain scores were statistically significant (P < 0.0001) with correlation coefficients of 0.82, 0.62, and 0.50, respectively. The regression equation using NDI aloneto predict SF-6D had an R of 0.66 and a root mean square error of 0.056. In the validation analysis, there was no statistically significant difference (P 5 0.961) between actual mean SF-6D (0.49 6 0.08) and the estimated mean SF-6D score (0.49 6 0.08), using the NDI regression model. CONCLUSION: This regression-based algorithm may be a useful tool to predict SF-6D scores in studies of cervical degenerative disease that have collected NDI but not utility scores. PMID- 20847714 TI - Clinical outcome of microsurgical bilateral decompression via unilateral approach for lumbar canal stenosis: minimum five-year follow-up. PMID- 20847715 TI - The complexity of human leukocyte antigen (HLA)-DQ antibodies and its effect on virtual crossmatching. AB - BACKGROUND: We previously reported that in patients possessing human leukocyte antigen (HLA)-DQ-directed antibodies, the target molecule may include the patient's own DQbeta chain if it is paired with non-self-DQalpha chain, thus forming a different DQ target. Herein, we sought to assess the breadth of this phenomenon. METHODS: Serum samples from 104 patients awaiting kidney transplantation, known to have DQ antibodies, were studied. Antibody identification was performed using luminex-based HLA class II single-antigen bead assays from two vendors; DQA1/DQB1 typing was performed using luminex polymerase chain reaction - sequence specific oligo prob hybridization (PCR-SSO) technology. RESULTS: A total of 71% of the 104 serum samples studied contained antibodies reactive against test beads coated with the patient's own DQalpha- or beta-chain components. Of those, 35 patients (34%) exhibited antibodies to their own DQbeta chain when in combination with non-self-DQalpha chains; and 64 patients (62%) had antibodies to their own DQalpha chain when in combination with non-self-DQbeta chains. This is a striking observation. CONCLUSIONS: To the best of our knowledge, this is the first systematic, high-resolution evaluation of DQ antibody repertoire. With the expansion of virtual crossmatching, particularly in the context of a national registry, the need for more detailed DQ antibody or antigen evaluation is critical to improve operational efficiency and patient outcomes. PMID- 20847716 TI - Dalfampridine (Ampyra) for MS. PMID- 20847717 TI - Naproxen/esomeprazole (Vimovo). PMID- 20847718 TI - Nonstandard uses of chelation therapy. PMID- 20847719 TI - Balamuthia mandrillaris transmitted through organ transplantation --- Mississippi, 2009. AB - On December 14, 2009, a physician in Mississippi contacted CDC to report possible transplant-transmitted encephalitis in two kidney transplant recipients who shared the same organ donor. Histopathologic testing of donor autopsy brain tissue at CDC showed amebae, and subsequent testing of specimens from the donor and the two kidney recipients confirmed transmission by transplantation of Balamuthia granulomatous amebic encephalitis (GAE), a rare disease caused by Balamuthia mandrillaris, a free-living ameba found in soil. One kidney recipient, a woman aged 31 years, died; the other recipient, a man aged 27 years, survived with neurologic sequelae. Recipients of the heart and liver from the same donor received preemptive therapy and have shown no signs of infection. The donor, a previously healthy boy aged 4 years, was presumed to have died from acute disseminated encephalomyelitis (ADEM), an autoimmune neurologic disease, after infection with influenza A. An investigation was conducted by the state health departments in Mississippi, Kentucky, Florida, and Alabama and CDC to characterize the cases, elucidate possible exposures in the donor, and develop recommendations for early detection and prevention. This is the first reported transmission of Balamuthia by organ transplantation. Clinicians should be aware of Balamuthia infection as a potentially fatal cause of encephalitis. Organ procurement organizations (OPOs) and transplant centers should be aware of the potential for Balamuthia infection in donors with encephalitis of uncertain etiology, and OPOs should communicate this elevated risk for infection to transplant centers so they can make an informed risk assessment in the decision to accept an organ. PMID- 20847720 TI - National, state, and local area vaccination coverage among children aged 19-35 months --- United States, 2009. AB - Since 1994, the National Immunization Survey (NIS) has been collecting data to monitor childhood immunization coverage. This report describes the 2009 NIS coverage estimates for children born during January 2006--July 2008 and focuses on the more recently recommended vaccines (i.e., hepatitis B [HepB] vaccine birth dose, hepatitis A vaccine [HepA], pneumococcal conjugate vaccine [PCV], and rotavirus vaccine) for children aged 19--35 months. The most recent NIS data indicate that vaccination coverage increased in 2009 compared with 2008 for HepB birth dose (from 55.3% to 60.8%) and HepA (from 40.4% to 46.6%), but coverage for PCV (>=4 doses) remained stable (80.4%). Full coverage for rotavirus vaccine was 43.9% among children born within 2 years of licensure. Coverage for poliovirus (92.8%), measles, mumps, and rubella (MMR) (90.0%), hepatitis B (HepB) (92.4%), and varicella (VAR) (89.6%) vaccines continued to be at or near the national health objective of 90%, although coverage for MMR and HepB vaccines decreased slightly in 2009. The percentage of children who have not received any vaccines remained low (<1%). Parents and primary-care providers continued to ensure that children were vaccinated, in spite of interim recommendations to suspend the booster dose of Haemophilus influenzae type b vaccine (Hib) because of a national shortage, and heightened public awareness of controversies in vaccine safety. PMID- 20847721 TI - CDC Grand Rounds: radiological and nuclear preparedness. AB - Radiological and nuclear disasters are infrequent, but when they occur, they result in large and demonstrable health burdens. Several scenarios can result in the public's exposure to radiation. For example, radiation sources used in health care or other industries can be lost or misused. Incidents in the nuclear power industry, such as those at Chernobyl and Three Mile Island, require significant public health response. In addition, radiological terrorism can involve the use of a radiological dispersal device (RDD) or an improvised nuclear device (IND). State and local health agencies are expected to perform essential public health functions in response to any of these emergencies. PMID- 20847722 TI - Notes from the field: transplant-transmitted Balamuthia mandrillaris --- Arizona, 2010. AB - On August 23, 2010, CDC was notified regarding two organ transplant recipients in Arizona who had encephalitis with multiple ring-enhancing lesions revealed by cerebral magnetic resonance imaging. The common organ donor, a Hispanic male landscaper aged 27 years, had died in Arizona from a presumed stroke on July 21. He had a large skin lesion for approximately 6 months on his back that he had attributed to an insect bite. The ill recipients, a male liver recipient aged 56 years, and a male recipient of a kidney and pancreas aged 24 years, received organ transplants on July 22. In addition, two other recipients received organs from this donor: an adult male heart recipient received his transplant in California on July 22, and an adult male kidney recipient received his transplant in Utah on July 23. PMID- 20847723 TI - Nifedipine, a calcium-channel blocker, attenuated glucose intolerance and white adipose tissue dysfunction in type 2 diabetic KK-A(y) mice. AB - BACKGROUND: To explore the metabolic actions of nifedipine on diabetes, we examined glucose intolerance and white adipose tissue changes in type 2 diabetic KK-A(y) mice. METHODS: Male KK-A(y) mice were treated with nifedipine (1.5 mg/kg/day in lab chow) for 5 weeks, which did not affect blood pressure or feeding of KK-A(y) mice. RESULTS: After treatment with nifedipine, body weight tended to decrease and the weight of white adipose tissue was reduced. Without food restriction, nifedipine decreased plasma insulin level, while plasma glucose level tended to decrease. In oral glucose tolerance test, nifedipine suppressed the increase in glucose level after a glucose load without affecting plasma insulin concentration. Nifedipine also improved the result of insulin tolerance test. In white adipose tissue, nifedipine increased adipocyte number and the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) and adipocyte fatty acid-binding protein related to adipocyte differentiation. In addition, expression of adiponectin, insulin receptor, insulin receptor substrate 1, and glucose transporter type-4 was also increased by nifedipine. Nifedipine also increased the expression of NO synthase in white adipose tissue. Nifedipine did not affect expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in white adipose tissue. Such changes in white adipose tissue were apparent in retroperitoneal adipose tissue. Nifedipine did not change the expression of angiotensin receptors, renin receptor, and angiotensinogen in white adipose tissue. Moreover, nifedipine attenuated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased superoxide dismutase (SOD) activity in white adipose tissue. CONCLUSION: These results suggest that nifedipine can enhance insulin sensitivity and reduce white adipose tissue, possibly related to stimulation of adipocyte differentiation. PMID- 20847724 TI - Prognostic value of white-coat and masked hypertension diagnosed by ambulatory monitoring in initially untreated subjects: an updated meta analysis. AB - BACKGROUND: The prognostic relevance of white-coat hypertension (WCH) and masked hypertension (MH) is controversial. The aim of this study was to perform an updated meta-analysis on the prognostic value of WCH and MH diagnosed by ambulatory monitoring in initially untreated subjects. METHODS: We searched for articles evaluating cardiovascular outcome in WCH or MH or sustained hypertension (SH) in comparison with normotension, investigating untreated subjects at baseline or performing separate analysis for untreated or treated subjects, and reporting adjusted hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Eight studies were identified. Five whole studies and untreated groups of three others were included in the meta-analysis. The pooled population consisted of 7,961 subjects who experienced 696 events. When compared with normotension, the overall adjusted HR was 0.96 (95% CI 0.65-1.42) for WCH (P = 0.85), 2.09 (1.55 2.81) for MH (P = 0.0001), and 2.59 (2.0-3.35) for SH (P = 0.0001). There was no significant difference between WCH and normotension according to normotensive subjects source (same or different study population) and follow-up length. Where reported, prevalence of drug therapy was higher in subjects with WCH than in those with normotension at follow-up. CONCLUSIONS: Cardiovascular risk is not significantly different between WCH and normotension, regardless of normotensive population type and follow-up length. However, at follow-up drug therapy was more frequent in WCH than in normotension and its possible impact on outcome should be evaluated in future studies. MH shows significantly higher risk than normotension, although the best way for its detection and treatment remains to be established. PMID- 20847725 TI - Habitual physical activity and peripheral arterial compliance in young adults: the Amsterdam growth and health longitudinal study. AB - BACKGROUND: It remains unclear whether the impact of habitual physical activity (HPA) differs for central vs. peripheral arterial stiffness, both of which are detrimental to cardiovascular health. We investigated the associations of lifetime HPA of different intensities on brachial and femoral stiffness in young adults, and compared these with those previously obtained for the carotid artery in the same study population. METHODS: Prospectively measured data (eight repeated measures between ages 13 and 36 years) on HPAs, and other lifestyle and biological variables, were retrieved for 373 subjects in whom stiffness of the brachial and femoral, as well as the carotid, arteries was assessed at age 36 years. Generalized estimating equations were used to examine the differences in time spent in HPAs (min/week) across sex-specific tertiles of the brachial and femoral distensibility (DC) and compliance (CC) coefficients. RESULTS: After adjustment for potential confounders, subjects in the highest (more compliant) vs. those in the lowest tertiles of the brachial and femoral CCs (less compliant) at age 36 years had spent on average more time in vigorous (+21.2 (95%CI:2.0; 40.4) and +24.4 (5.0; 43.8), respectively) but not in light-to-moderate HPAs throughout the longitudinal period. These differences were explained by 28 and 62%, respectively, by vigorous-HPA-related favorable impacts on other cardiovascular risk factors. No such associations were observed for the brachial and femoral DCs, however. CONCLUSIONS: Lifetime vigorous, but not light-to moderate, HPA is favorably associated with brachial and femoral compliance, but not DC. Altogether, these and our previous findings thus suggest generalized vigorous-HPA-related adaptations, although of different nature, throughout the arterial tree. PMID- 20847726 TI - Afternoon blood pressure increase: a blood pressure pattern associated with microvascular complications in type 2 diabetes mellitus. AB - BACKGROUND: Minor blood pressure (BP) alterations detected by ambulatory BP monitoring (ABPM) was associated with microvascular disease in type 2 diabetes mellitus (DM). We examined whether a previously described afternoon BP peak is linked to hypertension status and associated with microvascular complications. METHODS: A cross-sectional study was conducted with 207 type 2 DM patients (56 years, 52.7% men). ABPM was determined by oscillometry. RESULTS: An increase in both systolic and diastolic BP occurred in the afternoon; the same pattern was observed across hypertension categories (normotensive, prehypertensive, or hypertensive). We calculated BP increase for the period between 2 and 8 PM as the difference between mean BP at 8 PM and mean BP at 2 PM (calculated by the average of four measurements in each hour). The cohort was then divided into two groups (afternoon BP increase below or above the group's median). The prevalence of diabetic retinopathy (DR) was higher in those with afternoon increment above the group median for both systolic (50 vs. 30%, P = 0.004) and diastolic (47 vs. 33%, P = 0.04) BP. For systolic BP, this result was maintained after adjustments for age, gender, A1c test, DM duration, total cholesterol, and 24-h systolic BP. Afternoon BP increments for both systolic and diastolic BP correlated significantly with urinary albumin excretion rate (UAER) after adjusting for 24-h BP (systolic: r = 0.17, P = 0.01; diastolic: r = 0.16, P = 0.02). However, when adjusted for all covariates, these correlations were no longer significant. CONCLUSIONS: An increment in afternoon BP was observed in type 2 diabetic patients regardless of hypertension status; that increment was associated with higher prevalence of DR but not diabetic nephropathy independently of measured confounders. PMID- 20847727 TI - Vitamin D and the prevention of hypertension and cardiovascular diseases: a review of the current evidence. AB - Vitamin D plays an essential role in bone mineralization and calcium homeostasis. More recently, there has been growing evidence for a role of vitamin D in extraskeletal health, including beneficial effects in the cardiovascular system. Daylight exposure and vitamin D intake in many western populations are insufficient for maintaining an adequate vitamin D status. It is at present unclear whether vitamin D supplementation could improve cardiovascular health. This paper summarizes the evidence from observational studies and randomized controlled trials on the relation of vitamin D with blood pressure (BP) and risk of cardiovascular diseases (CVDs). Epidemiological data suggest that optimal vitamin D status is important for CVD prevention, but results from different studies are conflicting and confounding cannot be ruled out. Randomized controlled trials of vitamin D supplementation and BP have yielded inconsistent results, and trials that addressed the effect of vitamin D on CVDs are lacking. It is therefore premature to recommend supplemental vitamin D intake specifically for the prevention of hypertension or CVDs. Data from large, well-controlled clinical trials in this field with vitamin D supplements of sufficiently high doses are awaited to settle this issue. PMID- 20847728 TI - Neighborhood stressors and race/ethnic differences in hypertension prevalence (the Multi-Ethnic Study of Atherosclerosis). AB - BACKGROUND: The reasons for racial/ethnic disparities in hypertension (HTN) prevalence in the United States are poorly understood. METHODS: Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), we investigated whether individual- and neighborhood-level chronic stressors contribute to these disparities in cross-sectional analyses. The sample consisted of 2,679 MESA participants (45-84 years) residing in Baltimore, New York, and North Carolina. HTN was defined as systolic or diastolic blood pressure >=140 or 90 mm Hg, or taking antihypertensive medications. Individual-level chronic stress was measured by self-reported chronic burden and perceived major and everyday discrimination. A measure of neighborhood (census tract) chronic stressors (i.e., physical disorder, violence) was developed using data from a telephone survey conducted with other residents of MESA neighborhoods. Binomial regression was used to estimate associations between HTN and race/ethnicity before and after adjustment for individual and neighborhood stressors. RESULTS: The prevalence of HTN was 59.5% in African Americans (AAs), 43.9% in Hispanics, and 42.0% in whites. Age- and sex-adjusted relative prevalences of HTN (compared to whites) were 1.30 (95% confidence interval (CI): 1.22-1.38) for AA and 1.16 (95% CI: 1.04-1.31) for Hispanics. Adjustment for neighborhood stressors reduced these to 1.17 (95% CI: 1.11-1.22) and 1.09 (95% CI: 1.00-1.18), respectively. Additional adjustment for individual-level stressors, acculturation, income, education, and other neighborhood features only slightly reduced these associations. CONCLUSION: Neighborhood chronic stressors may contribute to race/ethnic differences in HTN prevalence in the United States. PMID- 20847729 TI - The effects of consuming frequent, higher protein meals on appetite and satiety during weight loss in overweight/obese men. AB - The purpose of this study was to determine the effects of dietary protein and eating frequency on perceived appetite and satiety during weight loss. A total of 27 overweight/obese men (age 47 +/- 3 years; BMI 31.5 +/- 0.7 kg/m(2)) were randomized to groups that consumed an energy-restriction diet (i.e., 750 kcal/day below daily energy need) as either higher protein (HP, 25% of energy as protein, n = 14) or normal protein (NP, 14% of energy as protein, n = 13) for 12 weeks. Beginning on week 7, the participants consumed their respective diets as either 3 eating occasions/day (3-EO; every 5 h) or 6 eating occasions/day (6-EO; every 2 h), in randomized order, for 3 consecutive days. Indexes of appetite and satiety were assessed every waking hour on the third day of each pattern. Daily hunger, desire to eat, and preoccupation with thoughts of food were not different between groups. The HP group experienced greater fullness throughout the day vs. NP (511 +/- 56 vs. 243 +/- 54 mm . 15 h; P < 0.005). When compared to NP, the HP group experienced lower late-night desire to eat (13 +/- 4 vs. 27 +/- 4 mm, P < 0.01) and preoccupation with thoughts of food (8 +/- 4 vs. 21 +/- 4 mm; P < 0.01). Within groups, the 3 vs. 6-EO patterns did not influence daily hunger, fullness, desire to eat, or preoccupation with thoughts of food. The 3-EO pattern led to greater evening and late-night fullness vs. 6-EO but only within the HP group (P < 0.005). Collectively, these data support the consumption of HP intake, but not greater eating frequency, for improved appetite control and satiety in overweight/obese men during energy restriction-induced weight loss. PMID- 20847730 TI - DPP4 gene DNA methylation in the omentum is associated with its gene expression and plasma lipid profile in severe obesity. AB - Severely obese subjects with the metabolic syndrome (MS) have higher dipeptidyl peptidase-4 (DPP4) expression in their visceral adipose tissue (VAT) compared to obese individuals without MS. We tested the hypothesis that methylation level of CpG sites in the DPP4 promoter CpG island in VAT was genotype-dependent and associated with DPP4 mRNA abundance and MS-related phenotypes. The VAT DNA was extracted in 92 severely obese premenopausal women undergoing biliopancreatic derivation for the treatment of obesity. Women were nondiabetic and none of them used medication to treat MS features. Cytosine methylation rates (%) of 102 CpG sites in the DPP4 CpG island were assessed by pyrosequencing of sodium bisulfite treated DNA. Methylation rates were >10% for CpG sites 94-102. Their mean methylation rate (%Meth(94-102)) was different between genotypes for DPP4 polymorphisms rs13015258 (P = 0.001), rs17848915 (P = 0.0004), and c.1926 G>A (P = 0.001). The %Meth(94-102) correlated negatively with DPP4 mRNA abundance (r = 0.25, P < 0.05) and positively with plasma high-density lipoprotein (HDL) cholesterol concentrations (r = 0.22, P < 0.05), whereas DPP4 mRNA abundance correlated positively with plasma total-/HDL-cholesterol ratio (r = 0.25; P < 0.05). In the VAT of nondiabetic severely obese women, genotype-dependent methylation levels of specific CpG sites in the DPP4 promoter CpG island were associated with DPP4 gene expression and variability in the plasma lipid profile. Higher DPP4 gene expression in VAT and its relationship with the plasma lipid profile may be explained by actually unknown DPP4 biological effect or, to another extent, may also be a marker of VAT inflammation known to be associated with metabolic disturbances. PMID- 20847731 TI - Feeding frequency and appetite in lean and obese prepubertal children. AB - To determine the effect of feeding frequency on appetite in normal weight (NW) and obese (OB) prepubertal children, we carried out a prospective, randomized interventional study of 18 NW and 17 OB children ages 6-10. Children received three or five feedings in random order on separate days. Total calories, carbohydrate, protein, and fat composition on each day were equal. Two hours following the last feeding, children were offered ice cream ad lib. The major outcome variable was kilocalories ice cream consumed. A visual analog scale to assess fullness was also administered before consumption of ice cream. We observed that OB children consumed 73.0 +/- 37.4 kcal more after five feedings than after three feedings whereas the NW children consumed 47.1 +/- 27.8 kcal less. There was significant interaction between meal pattern and weight group indicating that this change in ice cream consumption differed significantly between groups (P = 0.014 by two-factor analysis). Ice cream intake/kg was less in OB compared to NW subjects (P = 0.012). Fullness ratings before ice cream did not differ by meal pattern or weight group. However, pre-ice cream fullness predicted ice cream intake in NW but not OB children. In summary, OB and NW children differed in appetite response to meal frequency. Our data suggest that: (i) satiety in OB children is related more to proximity of calories (larger supper) than to antecedent distribution of calories and; (ii) NW children may be more prone to restrict intake based on subjective fullness. PMID- 20847732 TI - Waist circumference, BMI, and visceral adipose tissue in white women and women of African descent. AB - Although waist circumference (WC) is a marker of visceral adipose tissue (VAT), WC cut-points are based on BMI category. We compared WC-BMI and WC-VAT relationships in blacks and whites. Combining data from five studies, BMI and WC were measured in 1,409 premenopausal women (148 white South Africans, 607 African Americans, 186 black South Africans, 445 West Africans, 23 black Africans living in United States). In three of five studies, participants had VAT measured by computerized tomography (n = 456). Compared to whites, blacks had higher BMI (29.6 +/- 7.6 (mean +/- s.d.) vs. 27.6 +/- 6.6 kg/m2, P = 0.001), similar WC (92 +/- 16 vs. 90 +/- 15 cm, P = 0.27) and lower VAT (64 +/- 42 vs. 101 +/- 59 cm2, P < 0.001). The WC-BMI relationship did not differ by race (blacks: beta (s.e.) WC = 0.42 (.01), whites: beta (s.e.) WC = 0.40 (0.01), P = 0.73). The WC-VAT relationship was different in blacks and whites (blacks: beta (s.e.) WC = 1.38 (0.11), whites: beta (s.e.) WC = 3.18 (0.21), P < 0.001). Whites had a greater increase in VAT per unit increase in WC. WC-BMI and WC-VAT relationships did not differ among black populations. As WC-BMI relationship did not differ by race, the same BMI-based WC guidelines may be appropriate for black and white women. However, if WC is defined by VAT, race-specific WC thresholds are required. PMID- 20847733 TI - A potential role for 5-androstene-3beta,7beta,17beta-triol in obesity and metabolic syndrome. AB - Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients. Androstene-3beta,7beta,17beta-triol (beta-AET) an anti-inflammatory metabolite of DHEA, also exhibits GC-opposing and immune-modulating activity when administered to rodents. We hypothesized a role for beta-AET in obesity. We now report that plasma levels of beta-AET positively correlate with BMI in healthy men and women. Together with previous studies, the observations reported here may suggest a compensatory role for beta-AET in preventing the development of metabolic syndrome. The beta-AET structural core may provide the basis for novel pharmaceuticals to treat this disease. PMID- 20847734 TI - Energy-restricted high-fat diets only partially improve markers of systemic and adipose tissue inflammation. AB - This study aimed at investigating whether the weight loss due to energy restricted high-fat diets is accompanied with parallel improvements in metabolic markers and adipose tissue inflammation. Eight-week-old C57BL/6J mice were given free access to a low-fat (LF) or a high-fat (45% of energy from fat-HF) diet for 6 months. Restricting intake of the HF diet by 30% (HFR) during the last 2 months of the HF feeding trial decreased fasting plasma insulin, homeostasis model assessment of insulin resistance (HOMA(IR)), and plasma triglyceride levels and improved hepatic steatosis compared to ad libitum HF feeding, indicating an improved metabolic profile. Further, analysis of gonadal white adipose tissue (GWAT) gene expression by microarray and quantitative PCR analyses demonstrated that HFR downregulated expression of genes linked to cell and focal adhesion, cytokine-cytokine receptor interaction, and endoplasmic reticulum (ER)-associated degradation pathway. However, HFR had no effect on circulating plasminogen activator inhibitor-1 (PAI-1) and nonesterified fatty acid levels, which were persistently higher in both HF and HFR groups compared to the LF group. Furthermore, HFR had a negative effect on plasma total adiponectin level. Finally, while HFR decreased GWAT monocyte chemotactic protein-1 (MCP-1), interleukin-2 (IL-2), and PAI-1 levels, it did not affect several other cytokines including granulocyte-macrophage colony-stimulating factor, interferon-gamma, IL 1beta, IL-6, and IL-10. In summary, energy-restricted high-fat diets improve insulin sensitivity, while only partially improving markers of systemic and adipose tissue inflammation. In conclusion, our study supports the recommended low-fat intake for overall cardiovascular health. PMID- 20847735 TI - Correlates of participation in a pediatric primary care-based obesity prevention intervention. AB - The purpose of this study was to examine the correlates of participation in a childhood obesity prevention trial. We sampled parents of children recruited to participate in a randomized controlled trial. Eligible children were 2.0-6.9 years with BMI >= 95th percentile or 85th to <95th percentile if at least one parent was overweight. We attempted contact with parents of children who were potentially eligible. We recruited 475 parents via telephone following an introductory letter. We also interviewed 329 parents who refused participation. Parents who refused participation (n = 329) did not differ from those who participated (n = 475) by number of children at home (OR 0.94 per child; 95% CI: 0.77-1.15) or by child age (OR 1.07 per year; 95% CI: 0.95-1.20) or sex (OR 1.06 for females vs. males; 95% CI: 0.80-1.41). After multivariate adjustment, parents who were college graduates vs. 95th%ile. One reason appears to be that they less frequently consider their children to have a weight problem. PMID- 20847736 TI - The effect of electronic self-monitoring on weight loss and dietary intake: a randomized behavioral weight loss trial. AB - Technology may improve self-monitoring adherence and dietary changes in weight loss treatment. Our study aimed to investigate whether using a personal digital assistant (PDA) with dietary and exercise software, with and without a feedback message, compared to using a paper diary/record (PR), results in greater weight loss and improved self-monitoring adherence. Healthy adults (N = 210) with a mean BMI of 34.01 kg/m(2) were randomized to one of three self-monitoring approaches: PR (n = 72), PDA with self-monitoring software (n = 68), or PDA with self monitoring software and daily feedback messages (PDA+FB, n = 70). All participants received standard behavioral treatment. Self-monitoring adherence and change in body weight, waist circumference, and diet were assessed at 6 months; retention was 91%. All participants had a significant weight loss (P < 0.01) but weight loss did not differ among groups. A higher proportion of PDA+FB participants (63%) achieved >= 5% weight loss in comparison to the PR group (46%) (P < 0.05) and PDA group (49%) (P = 0.09). Median percent self-monitoring adherence over the 6 months was higher in the PDA groups (PDA 80%; PDA+FB 90%) than in the PR group (55%) (P < 0.01). Waist circumference decreased more in the PDA groups than the PR group (P = 0.02). Similarly, the PDA groups reduced energy and saturated fat intake more than the PR group (P < 0.05). Self-monitoring adherence was greater in the PDA groups with the greatest weight change observed in the PDA+FB group. PMID- 20847737 TI - Mutated genes, pathways and processes in tumours. AB - Integration of the many available sources of cancer gene information--such as large-scale tumour-resequencing studies--identifies the 'usual suspect' genes, mutated in many tumour types, as well as different sets of mutated genes according to the specific tumour type. Scaling-up the analysis reveals that this large collection of mutated genes cluster into a smaller number of signalling pathways and processes. From this, we draw a map of the altered processes, and their combinations, in more than 10 tumours types. Literature searches identify pathways and processes that are covered sparsely in the literature, and invite the proposal of new hypotheses to investigate cancer initiation and progression. PMID- 20847739 TI - Celebrating 100 years of Drosophila research. AB - The seventeenth EMBO Conference on the Molecular and Developmental Biology of Drosophila took place in Kolymbari, Crete, between 20 and 26 June 2010. The conference covered a broad range of topics and much progress was made by combining two or more fields of study. Such combinations included quantitative approaches to cell and developmental biology, dissecting interrelations of physiology and development and integrated genomic analysis. PMID- 20847738 TI - Tissue-specific calibration of extracellular matrix material properties by transforming growth factor-beta and Runx2 in bone is required for hearing. AB - Physical cues, such as extracellular matrix stiffness, direct cell differentiation and support tissue-specific function. Perturbation of these cues underlies diverse pathologies, including osteoarthritis, cardiovascular disease and cancer. However, the molecular mechanisms that establish tissue-specific material properties and link them to healthy tissue function are unknown. We show that Runx2, a key lineage-specific transcription factor, regulates the material properties of bone matrix through the same transforming growth factor-beta (TGFbeta)-responsive pathway that controls osteoblast differentiation. Deregulated TGFbeta or Runx2 function compromises the distinctly hard cochlear bone matrix and causes hearing loss, as seen in human cleidocranial dysplasia. In Runx2+/- mice, inhibition of TGFbeta signalling rescues both the material properties of the defective matrix, and hearing. This study elucidates the unknown cause of hearing loss in cleidocranial dysplasia, and demonstrates that a molecular pathway controlling cell differentiation also defines material properties of extracellular matrix. Furthermore, our results suggest that the careful regulation of these properties is essential for healthy tissue function. PMID- 20847740 TI - Sustainable digital infrastructure. Although databases and other online resources have become a central tool for biological research, their long-term support and maintenance is far from secure. PMID- 20847741 TI - MicroRNAs encoded by Kaposi's sarcoma-associated herpesvirus regulate viral life cycle. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with Kaposi's sarcoma and lymphomas. The pathogenesis of KSHV depends on the balance between two phases of the viral cycle: latency and lytic replication. In this study, we report that KSHV-encoded microRNAs (miRNAs) function as regulators by maintaining viral latency and inhibiting viral lytic replication. MiRNAs are short, noncoding, small RNAs that post-transcriptionally regulate the expression of messenger RNAs. Of the 12 viral miRNAs expressed in latent KSHV-infected cells, we observed that expression of miR-K3 can suppress both viral lytic replication and gene expression. Further experiments indicate that miR-K3 can regulate viral latency by targeting nuclear factor I/B. Nuclear factor I/B can activate the promoter of the viral immediate-early transactivator replication and transcription activator (RTA), and depletion of nuclear factor I/B by short hairpin RNAs had similar effects on the viral life cycle to those of miR-K3. Our results suggest a role for KSHV miRNAs in regulating the viral life cycle. PMID- 20847742 TI - A further case of Dop-ing in bacterial pupylation. PMID- 20847743 TI - Developing drug prototypes: pharmacology replaces safety and tolerability? AB - New medicines are designed to bind to receptors or enzymes and are tested in animal cells, tissues and whole organisms in a highly scientific process. Subsequently they are often administered to human subjects with tolerability as the primary objective. The process of development is considered to be linear and consecutive and passes through the famous four phases of development (Phase I Phase IV). This is efficient for those projects for which the uncertainty about the development is low. There is, however, an increasing number of new prototypical compounds resulting from the increased biological knowledge with a high level of uncertainty. For these prototypical drugs development has to proceed in a much more adaptive manner, using tailor-made objectives, the development of special methodology and a cyclical rather than a linear type of project management. PMID- 20847744 TI - Central roles of NLRs and inflammasomes in viral infection. AB - The immune response to viral infections is determined by a complex interplay between the pathogen and the host. Innate immune cells express a set of cytosolic sensors to detect viral infection. Recognition by these sensors induces the production of type I interferons and the assembly of inflammasome complexes that activate caspase-1, leading to production of interleukin-1beta (IL-1beta) and IL 18. Here, I discuss recent progress in our understanding of the central roles of NOD-like receptors (NLRs) and inflammasomes in the immune response during viral infections. This information will improve our understanding of host defence mechanisms against viruses and provide new avenues for interfering in the pathogenesis of infectious diseases. PMID- 20847745 TI - Cellular sources and immune functions of interleukin-9. AB - Interleukin-9 (IL-9) has attracted renewed interest owing to the identification of its expression by multiple T helper (T(H)) cell subsets, including T(H)2 cells, T(H)9 cells, T(H)17 cells and regulatory T (T(Reg)) cells. Here, we provide a broad overview of the conditions that are required for cells to produce IL-9 and describe the cellular targets and nature of the immune responses that are induced by IL-9. PMID- 20847746 TI - Advances in understanding cancer genomes through second-generation sequencing. AB - Cancers are caused by the accumulation of genomic alterations. Therefore, analyses of cancer genome sequences and structures provide insights for understanding cancer biology, diagnosis and therapy. The application of second generation DNA sequencing technologies (also known as next-generation sequencing) - through whole-genome, whole-exome and whole-transcriptome approaches - is allowing substantial advances in cancer genomics. These methods are facilitating an increase in the efficiency and resolution of detection of each of the principal types of somatic cancer genome alterations, including nucleotide substitutions, small insertions and deletions, copy number alterations, chromosomal rearrangements and microbial infections. This Review focuses on the methodological considerations for characterizing somatic genome alterations in cancer and the future prospects for these approaches. PMID- 20847748 TI - A 'living' prosthetic iris. AB - AIM: To design and demonstrate dynamic pupils, which react to light for use with ocular prostheses. METHODS: The realism of ocular prostheses is limited by the immobility of the pupil. Our solution is to use a liquid crystal display (LCD) in the prosthesis to vary the pupil size as a function of the ambient light. Several liquid crystal cells were fabricated and tested for survivability through the ocular prosthesis manufacturing process. The dynamic pupil is controlled by a novel and entirely autonomous, self-powered passive electronic circuit using a solar cell, matching the minimum diameter of the pupil. RESULTS: The first LCD surviving the rugged conditions of the ocular prosthesis manufacturing steps and an entirely passive circuit controlling the pupil have been demonstrated for the first time to our knowledge. A design for a complete prosthesis with a dynamic pupil has been proposed. Finally, a standard device for the mass production of ocular prostheses is presented. CONCLUSION: We have shown that a practical solution for an autonomous self-powered dynamic pupil is possible, given the constraints of size, fabrication process, weight, cost and manufacturability on a mass scale. We envision that the LCD could be mass produced, and only the final steps for the integration of the iris matched to a patient would be necessary before assembly using standard processing steps for the production of the prosthesis. Using a clinical trial, we hope to demonstrate that the dynamic pupil will have a positive impact on the quality of life of patients. PMID- 20847747 TI - Genomics and the future of conservation genetics. AB - We will soon have complete genome sequences from thousands of species, as well as from many individuals within species. This coming explosion of information will transform our understanding of the amount, distribution and functional significance of genetic variation in natural populations. Now is a crucial time to explore the potential implications of this information revolution for conservation genetics and to recognize limitations in applying genomic tools to conservation issues. We identify and discuss those problems for which genomics will be most valuable for curbing the accelerating worldwide loss of biodiversity. We also provide guidance on which genomics tools and approaches will be most appropriate to use for different aspects of conservation. PMID- 20847749 TI - Causes of blind and partial sight certifications in England and Wales: April 2007 March 2008. AB - PURPOSE: The last complete report on causes of blindness in England and Wales was for the data collected during April 1999-March 2000. This study updates these figures, with data collected during April 2007-March 2008. METHODS: In England and Wales, registration for blindness and partial sight is initiated with certification by a consultant ophthalmologist with the consent of the patient. The main cause of visual impairment was ascertained where possible for all certificates completed during April 2007-March 2008 and a proportional comparison with 1999-2000 figures was made. RESULTS: We received 23,185 Certificates of Vision Impairment (CVIs), of which 9823 were for severe sight impairment (blindness) (SSI) and 12,607 were for sight impairment (partial sight) (SI). These totals were considerably lower than the numbers certified in the year ending 31 March 2000. In 16.6% of CVIs, there were multiple causes of visual impairment as compared with 3% of BD8s in 2000. Degeneration of the macula and posterior pole (mostly age-related macular degeneration (AMD)) contributed to vision impairment in 12,746 newly certified blind or partially sighted. CONCLUSIONS: AMD is still by far the leading cause of certified visual loss in England and Wales. Proportional comparisons are hampered by the increasing use of multiple pathology as a main cause of visual impairment, which is believed to have arisen owing to the change in certificate used for data collection. These figures are not estimates of the total numbers newly blind in the UK because not all those entitled to certification are offered and or accept it, but they do nevertheless document the number of people who are deemed to be sufficiently sight impaired to warrant support and have been both offered and accepted it. This is usually the case when no further ophthalmic intervention is thought likely to be of benefit in terms of restoring or improving vision. PMID- 20847750 TI - LASER demarcation photocoagulation for rhegmatogenous retinal detachments. AB - PURPOSE: to evaluate demarcation laser photocoagulation (DLP) for macula-sparing rhegmatogenous retinal detachments (RRD) with and without symptoms of posterior vitreous separation or progressive visual field defect. METHODS: retrospective, interventional, single surgeon case series of consecutive patients with RRD treated with demarcation laser photocoagulation between March 1999 and February 2008 at an academic center. The null hypothesis was that there exists no difference in the rate of progression for retinal detachment irrespective of the presence ('symptomatic') or absence ('asymptomatic') of symptoms of posterior vitreous separation or visual field defect at presentation. RESULTS: a total of 27 eyes of 26 patients were included in the study. In all, 22 of the 27 eyes (81.4%) did not require additional treatment and remained attached during mean follow-up of 38.4 months. None of the 14 asymptomatic patients required surgery (0%) whereas 5 out of the 13 patients (38.5%) who were symptomatic at presentation required further intervention (p=0.016): one patient required additional laser only and four patients required scleral buckling or vitrectomy. Pre- and post- DLP logMAR visual acuity was 0.15 and 0.14, respectively. CONCLUSION: demarcation laser photocoagulation is an effective alternative to scleral buckling or vitrectomy for treating asymptomatic RRDs. It has a high failure rate among eyes with symptomatic RRD. PMID- 20847752 TI - Preclinical evaluation of a gene therapy treatment for transitional cell carcinoma. AB - Three drugs were compared for their efficacy in treating murine transitional cell carcinoma (TCC) of the bladder. Intravesical gene therapy treatments utilizing expression-targeted plasmids, where the murine cyclooxygenase-2 (Cox-2) promoter was used to drive the expression of exogenously inducible forms of caspases 3 and 9, were compared with treatment modalities employing Bacille Calmette-Guerin (BCG) and celecoxib. When administered via lavage, only the gene therapy regimen was found to be effective at restricting tumor progression following a 7-day incubation of tumor tissues. Celecoxib was also administered via the diet to allow for systemic delivery of the drug. The most efficacious celecoxib use tested yielded tumors with masses of (18.3+/-8.4 mg) versus the gene delivery method, which yielded tumors with masses of (3.6+/-7.7 mg). The difference was significant (t-test, n>=4, P<0.025). The results showed that the Cox-2 expression targeted gene therapy system could efficiently bypass the bladder permeability barrier and more effectively inhibit tumor growth and development than either BCG or celecoxib treatments. Long-term data further demonstrated that the gene therapy system could effectively inhibit tumor growth and elongate life expectancy. PMID- 20847753 TI - Comparison of the outcome of implantation of hydrophobic acrylic versus silicone intraocular lenses in pediatric cataract: prospective randomized study. AB - OBJECTIVE: To compare the postoperative performance of hydrophobic acrylic and silicone square-edge intraocular lenses in pediatric cataract. DESIGN: Prospective randomized study. PARTICIPANTS: Forty-one eyes of 41 children (age 1 month to 8 years) with congenital or developmental cataract. METHODS: Children were randomly divided into 2 groups. All participants underwent phacoaspiration, primary posterior capsulotomy, and anterior vitrectomy. Group A (n = 21) eyes were implanted with acrylic hydrophobic AcrySof SA60AT intraocular lenses (IOLs), and those of Group B (n = 20) were implanted with silicone Tecnis Z9000 IOLs. The children were evaluated for anterior chamber reaction, IOL position, posterior capsular opacification PCO), intraocular pressure, best-corrected visual acuity (BCVA), corneal status, and refractive errors. RESULTS: Postoperatively, 2 eyes in each group had significant anterior chamber reaction with fibrin membrane formation. IOLs were in the capsular bag in all but 1 eye in both groups. Seven eyes in the acrylic group and 6 eyes in the silicone group achieved visual acuity of 20/40 or better. None of the eyes showed glaucoma. BCVA at 1 year was similar in both groups. In the acrylic hydrophobic group, 14 eyes needed hypermetropic correction and 7 eyes were myopic, and in the silicone group 10 eyes had myopia and 10 eyes had hypermetropia at 1 year postoperatively. PCO at 1 year follow-up was more common in eyes implanted with acrylic hydrophobic IOLs (5 eyes) than silicone IOLs (2 eyes). CONCLUSIONS: Both square-edge hydrophobic acrylic and silicone IOLs were found to be compatible and safe for use in pediatric cataract surgery with similar visual axis clarity and postoperative outcome. PMID- 20847751 TI - Enhancement of electric field-mediated gene delivery through pretreatment of tumors with a hyperosmotic mannitol solution. AB - Pulsed electric fields can enhance interstitial transport of plasmid DNA (pDNA) in solid tumors. However, the extent of enhancement is still limited. To this end, the effects of cellular resistance to electric field-mediated gene delivery were investigated. The investigation used two tumor cell lines (4T1 (a murine mammary carcinoma) and B16.F10 (a metastatic subline of B16 murine melanoma)) either in suspensions or implanted in two in vivo models (dorsal skin-fold chamber (DSC) and hind leg). The volume fraction of cells was altered by pretreatment with a hyperosmotic mannitol solution (1 M). It was observed that the pretreatment reduced the volumes of 4T1 and B16.F10 cells, suspended in an agarose gel, by 50 and 46%, respectively, over a 20-min period, but did not cause significant changes ex vivo in volumes of hind-leg tumor tissues grown from the same cells in mice. The mannitol pretreatment in vivo improved electric field mediated gene delivery in the hind-leg tumor models, in terms of reporter gene expression, but resulted in minimal enhancement in pDNA electrophoresis over a few microns distance in the DSC tumor models. These data demonstrated that hyperosmotic mannitol solution could effectively improve electric field-mediated gene delivery around individual cells in vivo by increasing the extracellular space. PMID- 20847754 TI - A trial of topical prednisolone acetate before intravitreal triamcinolone acetonide decreases intraocular pressure spikes. AB - OBJECTIVE: To compare adverse intraocular pressure (IOP) spikes in patients receiving intravitreal triamcinolone acetonide (IVTA) in 2 cohorts: (i) patients who underwent a topical prednisolone acetate trial (PAT) without incurring a short-term IOP rise, and (ii) control patients who did not undergo a PAT. DESIGN: Retrospective cohort study. PARTICIPANTS: Charts of all patients who underwent any intravitreal injection during the study period were reviewed (n = 1150). METHODS: Patients in the PAT group received a 6-week course of prednisolone acetate 1% 4 times per day and had an IOP that did not rise above 25 mm Hg or above 8 mm Hg over the IOP in the contralateral eye. Patients undergoing a PAT and having a short-term IOP rise were not studied. Control patients did not receive a PAT. All patients received 12-20 mg of IVTA. Patients were followed for a minimum of 6 weeks and follow-up lasted for 1 year or until intraocular surgery or another IVTA injection was performed. RESULTS: There were 97 patients in the PAT cohort and 75 control patients. Patients in the PAT cohort had a lower proportional rise between maximum IOP and baseline (43%) compared with controls (64%) (p = 0.035). Patients in the PAT group also had a lower risk of incurring a 40% (p = 0.05), 60% (p = 0.018), and 100% (p = 0.045) increase in maximum IOP (vs baseline) compared with controls and were less likely to require glaucoma filtration surgery (p = 0.035). CONCLUSIONS: Patients undergoing a PAT who did not have a subsequent short-term IOP rise had a lower risk of severe IOP spikes after IVTA compared with those patients receiving IVTA but not having undergone a PAT. PMID- 20847755 TI - Comparison of dynamic contour tonometry and Goldmann applanation tonometry following penetrating keratoplasty. AB - OBJECTIVE: To evaluate dynamic contour tonometry (DCT) versus Goldmann applanation tonometry (GAT) intraocular pressure (IOP) measurements in eyes that underwent penetrating keratoplasty PKP). Prospective, cross-sectional, observational study. PARTICIPANTS: Thirty-one eyes of 28 patients were examined after PKP. METHODS: All eyes had undergone PKP with interrupted sutures. The postoperative period was more than 1 year for 25 eyes and less than 1 year for 6. Sutures were removed based on corneal topography and refraction. IOP was measured by both DCT and GAT methods and was correlated to the number of remaining sutures. RESULTS: IOP readings were successfully obtained in 25/31 (80.6%) with DTC and in 21/31 (67.7%) with GAT (p = 0.25). In eyes with fewer than 4 remaining sutures, both methods were successful. In eyes with more than 4 sutures, the success rates of DCT and GAT were 66.7% and 44.4%, respectively (p = 0.18). In PKPs with a postoperative period of more than 1 year, the success rates of DCT and GAT were 96% and 84%, respectively (p = 0.16). In 20 eyes, both methods measured the IOP. The mean IOP obtained by DCT (16.6 [SD 2.8] mm Hg) was higher than the mean IOP obtained from GAT (15.1 [SD 3.6] mm Hg). The IOPs from the 2 instruments correlated significantly (p < 0.05) and the mean difference was 1.5 mm Hg. CONCLUSIONS: The success rate in measuring IOP with DCT and GAT did not show any statistically significant difference. Both methods were less effective measuring the IOP after recent PKPs and regrafts. However, DCT seemed to be superior to GAT in corneas with more than 4 remaining sutures and in PKPs performed more than 1 year earlier. The absolute values of IOP were higher with DCT than with GAT. PMID- 20847756 TI - Role of the interview in admissions at the University of Toronto ophthalmology program. AB - OBJECTIVE: To investigate the role of the residency interview in admission to the University of Toronto ophthalmology program. DESIGN: Retrospective observational study. PARTICIPANTS: One hundred and sixty-nine candidates for admission to the University of Toronto ophthalmology program, 1998-2008. METHODS: Admissions scores were analyzed retrospectively to determine how the interview affected final candidate rank. Interviewers were not blinded to the candidates' applications. Candidate impressions of interview day were investigated through 2 surveys conducted in 2000 and 2005. Twenty-six of the 33 interviewed candidates responded, for a response rate of 79%. RESULTS: Pre-interview rank was found to correlate with final rank (r = 0.826, p < 0.001, n = 169, 2-tailed) and interview rank (r = 0.426, p < 0.001). Interview rank was also independently correlated with final rank (r = 0.774, p < 0.001). Half the candidates had final ranks within 1 of their pre-interview rank, and 80% were within 3 ranks. The range of rank change was from a loss of 10 ranks to a gain of 11. Survey responses demonstrated that candidates found the interview experience very valuable (14/14) and that it affected their opinion of the program positively (20/26). CONCLUSIONS: While the interview frequently does not substantially change candidate rank order, the occasional large changes suggest that it has the power to make corrections to application scores should they be necessary. The nonblinded design allows interviewers to ask candidates questions specific to their application, resulting in more profound discussion. The surveys show that candidates find the interview to be a valuable experience and likely results in them ranking Toronto's program higher in the match. PMID- 20847757 TI - Effect of docosahexaenoic acid supplementation on the macular function of patients with Best vitelliform macular dystrophy: randomized clinical trial. AB - OBJECTIVE: Best disease is a slowly progressive macular dystrophy that typically has an onset in early childhood. Multiple lines of evidence suggest that dietary docosahexaenoic acid (DHA) protects against the development of macular degeneration. Our trial tested the effect of an oral supplement of DHA on visual function in patients with Best disease. DESIGN: Double-masked, randomized, placebo-controlled, crossover clinical trial. PARTICIPANTS: Eight patients with Best disease. METHODS: Patients were given either an oral supplement of DHA (20 mg/kg daily) or placebo. Primary outcome measures were the multifocal electroretinogram (mfERG) and electro-oculogram (EOG). Plasma DHA was tracked along with visual acuity (Early Treatment Diabetic Retinopathy Study chart), VF 14 scores, and Humphrey visual fields. RESULTS: All 8 patients had increased plasma DHA levels (2-3 fold) during periods of DHA supplementation compared with periods without supplementation. Differences in visual acuity, VF-14 scores, and EOG Arden ratios during periods with and without DHA supplementation were all statistically insignificant. A positive correlation was found between the plasma concentration of DHA and mfERG amplitudes, but amplitude changes during the treatment periods were not significant. A carryover effect of DHA supplementation was a confounding error. CONCLUSIONS: Our pilot trial of DHA supplementation in 8 patients with Best disease did not demonstrate an improvement in macular function. An expanded trial would be needed to examine the full effects of DHA supplementation on visual function in Best disease. PMID- 20847758 TI - Near-infrared and orange-red emission from a continuous-wave, second-Stokes self Raman Nd:GdVO4 laser. AB - We report the first cw intracavity crystalline Raman laser operating at the second-Stokes wavelength. Approximately 950 mW emission is obtained at 1308 nm from a Nd:GdVO(4) self-Raman laser, with an overall (diode to 1308 nm) conversion efficiency of 6.8%. By intracavity sum-frequency mixing the first- and second Stokes lines, 1027 mW emission at 620 nm is demonstrated with an overall (diode to-visible) conversion efficiency of 4.9%. PMID- 20847759 TI - Common-path lateral-shearing nulling interferometry with a Savart plate for exoplanet detection. AB - We propose a common-path lateral-shearing nulling interferometer for direct detection of exoplanets. A Savart plate is placed between crossed polarizers to produce a lateral shear and realize fully achromatic and highly stable nulling interference for starlight. We construct a double-shearing interferometer using two Savart plates for implementing orthogonal x and y shears. A laboratory demonstration is carried out using a broadband light source with a bandwidth of Deltalambda/lambda(0)=0.33 (Deltalambda=0.2 MUm and lambda(0)=0.6 MUm). As a result, achieved extinction levels are 4 * 10(-4) at peak and 4 * 10(-7) at 10lambda(0)/D(L) (D(L) is the diameter of a Lyot stop). PMID- 20847760 TI - Spontaneous four-wave mixing in microring resonators. AB - We consider spontaneous four-wave mixing in a microring resonator, presenting photon-pair generation rates and biphoton wave functions. We show how generation rates can be simply predicted from the performance of the device in the classical regime and that a wide variety of biphoton wave functions can be achieved by varying the pump pulse duration. PMID- 20847761 TI - Interferometric beam combination with discrete optics. AB - We explore the capabilities of discrete diffraction in phase retrieval problems and propose an innovative scheme exploiting a two-dimensional array of coupled waveguides to determine the phase and amplitude of the mutual correlation function between any pair of three telescopes of an astrointerferometer. PMID- 20847762 TI - Enhanced air-cavity effect of periodically oriented embedded air protrusions for high-efficiency InGaN/GaN light-emitting diodes. AB - We report on the development of periodically oriented embedded air protrusion (EAP) structures at the GaN-sapphire interface in InGaN/GaN LEDs. A specific SiO(2) mask pattern and a simple wet etching process were utilized for the fabrication of EAP structures. A strong coupling between closely proximate air cavities and the multiple quantum wells promoted spontaneous emission due to the high-index contrast at the GaN-air interface. As a result, the light output power of the EAP LED was 2.2 times higher than that of a conventional LED at an injection current of 20 mA. PMID- 20847763 TI - 80 W, 120 fs Yb-fiber frequency comb. AB - We report on a high-power fiber frequency comb exhibiting linear chirped-pulse amplification up to 80 W and generating 120 fs pulses. By proper matching of the group delay between the fiber stretcher and compressor, a compression ratio of 3100 could be achieved. Carrier envelope offset self-referencing and long-term phase locking to an rf reference is demonstrated, exemplifying the suitability of this system for generating vacuum and extreme-UV frequency combs via enhancement in passive cavities and high harmonic generation. PMID- 20847764 TI - Dual wavelength digital holographic Laplacian reconstruction. AB - Access to the spatial derivatives of an optical wave field can be used to enhance edge detection, focusing, and holographic imaging. It was recently shown that, by using digital holographic techniques, the Laplacian of an object field can be extracted. Here it is demonstrated that equivalent results can be found using two holograms captured at either two distances or with two appropriately related wavelengths. Experimental and numerical results confirming the theoretical analyses are presented. The proposed two-wavelength-based system requires no mechanical repositioning of the object and is shown to provide superior performance. PMID- 20847765 TI - 0.1 Hz 1.0 PW Ti:sapphire laser. AB - We report on the generation of 1.0 PW, 30 fs laser pulses at a 0.1 Hz repetition rate from a chirped-pulse amplification Ti:sapphire laser system. The energy of the laser pulses is amplified up to 47 J in a final three-pass booster amplifier having 96 J pump energy. To the best of our knowledge, this is the first petawatt Ti:sapphire laser system at a 0.1 Hz repetition rate. The shot-to-shot energy fluctuation of the laser pulses is as low as 0.53% in rms value, and the laser pulses have homogeneous flattop spatial beam profiles. PMID- 20847766 TI - In vivo validation of free-space fluorescence tomography using nuclear imaging. AB - The performance of small animal photonic imaging has been considerably improved since the development of fluorescence diffuse optical tomography (fDOT), which can reconstruct fluorescent probe distribution inside tissue. However, the quantification capabilities of this new technology are still a topic of debate, especially in comparison to classical nuclear imaging techniques. Here, we present a method to in vivo calibrate the quantity and localization of a probe provided by free-space fDOT (where no plate is compressing the mouse) with positron emission tomography (PET) and x-ray computed tomography, respectively. This methodology allowed us to demonstrate a strong linear correlation (R(2)=0.95) between fDOT and PET for probe concentrations ranging from 3 nM to 1 MUM in a deep-seated organ. PMID- 20847768 TI - Waveguide dispersion effects in silicon-on-insulator coupled-resonator optical waveguides. AB - The dispersion of the waveguides that constitute microring resonators can considerably affect the dispersion characteristics of coupled-resonator optical waveguides (CROWs). We derive expressions for CROW dispersion and group delay for silicon-on-insulator microring CROWs, showing both theoretically and experimentally the band-to-band dependence of the bandwidth and group delay on the dispersion properties of the constituent single-mode silicon waveguide. PMID- 20847767 TI - Femtosecond (191 fs) NaY(WO4)2 Tm,Ho-codoped laser at 2060 nm. AB - We report, for the first time to our knowledge, femtosecond-pulse operation of a Tm,Ho:NaY(WO(4))(2) laser at around 2060 nm. Transform-limited 191 fs pulses are produced with an average output power of 82 mW at a 144 MHz pulse repetition frequency. Maximum output power of up to 155 mW is generated with a corresponding pulse duration of 258 fs. An ion-implanted InGaAsSb quantum-well-based semiconductor saturable absorber mirror is used for passive mode-locking maintenance. PMID- 20847769 TI - Master mode-locking theory for few-femtosecond pulses. AB - We propose a model that is valid for ultrafast pulse propagation in a mode-locked laser cavity in the few-femtosecond pulse regime, thus deriving the equivalent of the master mode-locking equation for ultrashort pulses that has dominated mode locking theory for two decades. The short-pulse equation with dissipative gain and loss terms allows for the generation of stable ultrashort optical pulses from initial white noise, thus providing the first theoretical framework for quantifying the pulse dynamics and stability as pulses widths approach the attosecond regime. PMID- 20847770 TI - LIFT: a focal-plane wavefront sensor for real-time low-order sensing on faint sources. AB - We propose the linearized focal-plane technique (LIFT) and compare it to classical sensors, such as the quad-cell wavefront sensor (WFS), pyramid WFS, and Shack-Hartmann WFS. The number of modes sensed by LIFT can be tuned without any hardware modification nor degradation of low-order sensing performance. We derive an analytic model of the noise propagation law, which we validate on end-to-end simulations. PMID- 20847771 TI - Microsecond switching of parametric tunable dispersion compensator. AB - A record-fast, 2 MUs switching operation of an optical tunable dispersion compensator is demonstrated with a parametric tunable dispersion compensation scheme. We alternately switch two optical paths having different net dispersions with a microsecond guard interval of the compensator response and achieve successful transmissions of 43 Gbit/s non-return-to-zero on-off-keying optical signals. The error-free guard time for the switching of the two optical paths is 125 MUs, limited mostly by the clock synchronization of the bit-error detector. The power penalty due to the switching of the compensator is less than 0.5 dB. PMID- 20847772 TI - Bit-rate-variable and order-switchable optical multiplexing of high-speed pseudorandom bit sequence using optical delays. AB - We experimentally demonstrate high-speed optical pseudorandom bit sequence (PRBS) multiplexing with coarse and fine bit-rate tuning capability and a switchable order using optical delays. Data multiplexing of 80 Gbit/s and 160 Gbit/s is shown, each with a tunable rate using a conversion/dispersion-based continuously tunable optical delay and tunable PRBS order with large switchable fiber delays. A 7% bit-rate tunability, i.e., 80-85.6 Gbit/s and 160-171.2 Gbit/s, is shown for both 2(7)-1 and 2(15)-1 PRBS. The rf spectra before and after multiplexing are measured in each case and show a suppression ratio of >30 dB, exhibiting the expected PRBS spectral characteristics. PMID- 20847773 TI - Optical fiber microwire current sensor. AB - We demonstrate a compact optical fiber microwire current sensor based on the Faraday effect with gigahertz frequency of current sensing capabilities. PMID- 20847774 TI - Laser ceramic materials for subpicosecond solid-state lasers using Nd3+-doped mixed scandium garnets. AB - We have successfully developed and demonstrated broadband emission Nd-doped mixed scandium garnets based on laser ceramic technology. The inhomogeneous broadening of Nd(3+) fluorescence lines results in a bandwidth above 5 nm that is significantly broader than that for Nd:YAG and enables subpicosecond mode-locked pulse durations. We have also found the emission cross section of 7.8 * 10(-20) cm(2) to be adequate for efficient energy extraction and thermal conductivity of 4.7 W/mK from these new Nd-doped laser ceramics. The new laser ceramics are good candidates for laser host material in a diode-pumped subpicosecond laser system with high efficiency and high repetition rate. PMID- 20847775 TI - Dysprosium-doped PbGa2S4 laser excited by diode-pumped Nd:YAG laser. AB - We realized a compact mid-IR room temperature operating Dy(3+):PbGa(2)S(4) laser, excited by a diode-pumped Nd:YAG laser at a wavelength of 1318 nm. The pumping laser was operating in pulsed mode with a pulse length of 4 ms and repetition rate of 20 Hz. Maximum pumping energy at a wavelength of 1318 nm was 15 mJ. Energy up to 90 MUJ and mean output power of 1.8 mW was obtained at a wavelength of 4290 nm with a slope efficiency with respect to absorbed pumping energy better than 3%. PMID- 20847776 TI - Accurate retrieval algorithm of amplitude from radial-shearing interferogram. AB - We propose a mathematic formula that can be applied to work out the amplitude distribution of a tested laser beam from its radial-shearing interferogram accurately, even if the amplitude distribution is extremely uneven. Provided that the background irradiance distribution of a tested beam is extracted from its cyclic radial-shearing (CRS) interferogram first, then using the radial-shearing ratio of the CRS interferometer, the amount of lateral shear along the orthogonal directions and the irradiance ratio, the amplitude distribution of a tested beam can be reconstructed accurately by the proposed formula. The simulation computation and experimental results show that the formula allows any amount of lateral shear to happen, as long as the contracted beam maintains its location inside its corresponding expanded version. PMID- 20847777 TI - Second-order coherence of supercontinuum light. AB - We analyze the coherence properties of supercontinuum generated in photonic crystal fibers by applying the second-order coherence theory of nonstationary light. Using an ensemble of simulated realizations, we construct two-frequency cross-spectral density and two-time mutual coherence functions. This allows us to introduce measures of temporal and spectral coherence. We show that, in the long pulse regime, supercontinuum light can be decomposed into a sum of coherent and quasi-stationary contributions. Our approach and findings are also applicable in the short-pulse regime. PMID- 20847778 TI - Gain coupling of class A semiconductor lasers. AB - We report on the development of a gain-coupled class A semiconductor laser for dual-wavelength generation via optical switching. A vertical external cavity surface emitting laser (VECSEL) structure is used, because it provides a flexible platform for high-power, high-brightness output in the near-IR and visible ranges. For the first time (to our knowledge), two VECSEL cavities sharing a common gain region are studied. Because the cavities are in competition for common carriers, birefringent filters in the external cavity control the laser cavity thresholds; this configuration demonstrates the possibility of switching between the two cavities, which can operate at different wavelengths. However, in this Letter we also show, numerically and experimentally, that with the consideration of spontaneous emission, it is possible to maintain simultaneous lasing in each cavity at a different wavelength. PMID- 20847779 TI - Spatial threshold in amplifying random media. AB - We study experimentally as well as numerically the transport and generation of light in multiple scattering media with optical gain. By imaging the spatial distribution of light escaping from the side of the sample, the propagation depth is analyzed. Far below and far above random laser threshold, the spatial profile of emission light is independent of pump intensity, while around threshold, the spatial distribution of emission light changes profoundly. The experimental results are explained by interpreting the numerical solutions to a set of coupled time-dependent diffusion equations on a nonuniform spatial grid. Our studies provide a new and easily accessible method for observing the random laser threshold. PMID- 20847780 TI - Cortical adaptation and visual enhancement. AB - Passive ophthalmic optic devices correct refractive defects of the eye but are not designed to employ neural adaptation processes. An extended depth of focus technology is implemented on conventional refractive devices, such as spectacles and contact lenses, and its testing is described. This technology is capable of simultaneously correcting all refractive errors, such as myopia, hyperopia, presbyopia, regular/irregular astigmatism, as well as their combinations. This is achieved by exploiting the capacity of the visual system for adaptation to contrast as well as its capability of creating a coherent continuous visual field out of discrete lines of sight. PMID- 20847781 TI - Raman fiber laser with 81 W output power at 1480 nm. AB - We demonstrate a Raman fiber laser with an operating wavelength of 1480 nm and record output power of 81 W. High-power operation is enabled by a long-period grating used to frustrate backward lasing at the Stokes wavelength in the Yb doped fiber amplifier. A cascaded Raman fiber with a long-wavelength fundamental mode cutoff enables efficient multiple Stokes scattering from 1117 to 1480 nm while preventing further unwanted scattering to 1590 nm. PMID- 20847782 TI - Thermal stability and photoluminescence of S-doped BaMgAl10O17:Eu2+ phosphors for plasma display panels. AB - Sulfur-doped BaMgAl(10)O(17):Eu(2+) phosphors were synthesized by an environmentally benign synthesis reaction. The photoluminescence spectrum, the energy dispersion spectrum, powder x-ray diffraction, and decay curves were used. The photoluminescence and thermal stability were discussed. It was revealed that sulfur doping leads to an increase in luminance intensity and thermal stability. This could be due to the decrease of defects and lower electronegativity of sulfur while sulfur occupied the unstable O (1) sites. The change of trap concentration was evaluated by the decay curves. The result shows sulfur doping is expected to be potentially applicable to the industrial production of BaMgAl(10)O(17):Eu(2+) phosphors. PMID- 20847783 TI - Gain-assisted propagation of surface plasmon polaritons via electrically pumped quantum wells. AB - We studied the loss compensation of surface plasmon polaritons (SPPs) with InGaAsP quantum wells at telecom wavelength. The quantum wells are buried in the vicinity of a thin Au film. The propagation length of short-range SPPs increases drastically with the gain coefficient of quantum wells, generated by a forward bias. The elongation of SPP propagation is experimentally observed via long-range SPPs, which strongly couple with the short-range SPPs. This study paves a way for electrically manipulated amplification of SPPs in plasmonic circuits. PMID- 20847784 TI - Sub-Doppler cooling of fermionic Hg isotopes in a magneto-optical trap. AB - Laser cooling and trapping of neutral mercury is performed in a single-stage (1)S(0)<->(3)P(1) 3D magneto-optical trap. We give a detailed account of the atom cloud size and temperature for both bosonic ((200)Hg and (202)Hg) and fermionic ((199)Hg and (201)Hg) isotopes. The bosonic isotope temperatures are in close agreement with Doppler cooling theory, while temperatures obtained for the fermionic isotopes are lower, suggesting the presence of sub-Doppler cooling. A minimum temperature of 29+/-4 MUK is achieved for (201)Hg. PMID- 20847785 TI - 50 fs pulses from an all-normal dispersion erbium fiber oscillator. AB - We present a mode-locked, all-normal-dispersion erbium-doped fiber oscillator generating output pulses with broadband spectra covering the range from 1475 to 1620 nm. The oscillator operates at a repetition rate of 109 MHz with output pulse energies of 1.6 nJ. Mode-locked operation is achieved by use of nonlinear polarization evolution in combination with a birefringent filter. The output pulses are dechirped with an external prism compressor to a duration of 50 fs. PMID- 20847786 TI - Quasi-parabolic pulse propagation and breakup in fiber amplifiers with third order dispersion. AB - We present an analytical solution for propagating pulses in normal dispersion fiber amplifiers, including the effect of third-order dispersion. The solution of the generalized nonlinear Schrodinger equation is based on asymptotic methods, first-order perturbation theory, and a renormalization procedure and leads to determination of the critical length corresponding to pulse breakup. We have also found and confirmed numerically the condition on the parameters that govern the propagation, as is necessary to ensure a highly accurate analytical description of the pulses and critical lengths in fiber amplifiers with third-order dispersion. PMID- 20847787 TI - Phase change in a diffracted wave: a Cornu spiral perspective. AB - A simple evaluation of the phase change in a diffracted wave, in terms of the Cornu spiral, is presented to complement the well-known intensity change, which is routinely obtained for this elegant graphical construction of the Fresnel integrals. This is, to the best of our knowledge, the first presentation of this evaluation. It is shown that the phase of a wave diffracted by a slit is equal to the slope of the line tangent to the Cornu spiral, shifted by pi/4. PMID- 20847788 TI - Photoacoustic spectroscopy using coherent synchrotron radiation: application to alpha-lactose monohydrate. AB - We produced coherent synchrotron radiation at the Canadian Light Source between about 5 and 30 cm(-1) in bursting and continuous emission modes and used it to acquire photoacoustic spectra of solids. A band was observed in the spectrum of alpha-lactose monohydrate at 18 cm(-1) and attributed to a rotational mode, in agreement with published data obtained using other numerical and experimental techniques. PMID- 20847789 TI - Efficiency and phase of optical parametric amplification in chirped quasi-phase matched gratings. AB - Three-wave nonlinear interactions in chirped quasi-phase-matched (QPM) gratings are shown to exhibit conversion efficiency approaching 100% with increasing input pump and signal intensities, evading backconversion, as long as the idler vanishes at the input and the QPM grating is sufficiently chirped. The signal phase is described in terms of Kerr-like self- and cross-phase modulations, in the cascade chi((3)) approximation. Achieving high gain and efficiency simultaneously can lead to a large nonlinear phase, and the resulting trade-off is discussed. PMID- 20847790 TI - Contrast enhancement in a Ti:sapphire chirped-pulse amplification laser system with a noncollinear femtosecond optical-parametric amplifier. AB - We experimentally demonstrated the contrast enhancement in a Ti:sapphire chirped pulse amplification (CPA) laser with a noncollinear femtosecond optical parametric amplifier. A total gain of 3.4 * 10(4) and pulse energy of 26 MUJ were achieved. With the clean high-energy seeding pulse, the contrast ratio of the main amplified laser pulse to the amplified spontaneous emission in the Ti: sapphire CPA laser system was improved to around 10(10) within the time scale of hundreds of picoseconds. PMID- 20847791 TI - Observation of linear and nonlinear strongly localized modes at phase-slip defects in one-dimensional photonic lattices. AB - We investigate light localization at a single phase-slip defect in one dimensional photonic lattices, both numerically and experimentally. We demonstrate the existence of various robust linear and nonlinear localized modes in lithium niobate waveguide arrays exhibiting saturable defocusing nonlinearity. PMID- 20847792 TI - Ultraviolet and near-infrared femtosecond temporal pulse shaping with a new high aspect-ratio one-dimensional micromirror array. AB - We demonstrate the capabilities of a new optical microelectromechanical systems device that we specifically developed for broadband femtosecond pulse shaping. It consists of a one-dimensional array of 100 independently addressable, high-aspect ratio micromirrors with up to 3 MUm stroke. We apply linear and quadratic phase modulations demonstrating the temporal compression of 800 and 400 nm pulses. Because of the device's surface flatness, stroke, and stroke resolution, phase shaping over an unprecedented bandwidth is attainable. PMID- 20847793 TI - Coherent addition of laser beams in resonant passive optical cavities. AB - An optical resonator, designed for frequency doubling of cw single-frequency radiation, is simultaneously injected by two phase-coherent laser beams with the same frequency. By using standard methods in laser-cavity stabilization, we are able to stabilize the cavity length on resonance with the laser, as well as the relative phase of the fundamental beams, to fulfill the optimum coupling conditions simultaneously on the two input couplers. By using this method, we generate reliably more than 220 mW of single-frequency radiation at 399 nm using two 0.5 W semiconductor tapered amplifiers at 798 nm. This method can be generalized to a larger number of input couplers and holds promise for improving the performances of extreme-UV frequency combs. PMID- 20847794 TI - Polarization-induced coherence changes of an electromagnetic light wave on scattering. AB - We studied the spectral coherence of an electromagnetic light wave on scattering. It is shown that the spectral degree of coherence of the scattered field of an electromagnetic light wave is closely related to the properties of the scattering medium and the polarization of the incident light wave. In the case of a deterministic scattering medium, the change of the spectral degree of coherence of the scattered field is induced only by the polarization of the incident light wave. PMID- 20847795 TI - Infrared wire-grid polarizer with Y2O3 ceramic substrate. AB - Using two-beam interference lithography and dry etching, we fabricated a mid-IR wire-grid polarizer consisting of a 350 nm pitch WSi grating on an Y(2)O(3) ceramic substrate, which has wider transparency than sapphire. The transmittance of TM polarization was greater than 70% in the 3-7 MUm wavelength range without antireflection films, and the extinction ratio was over 20 dB in the 2.5-5 MUm wavelength range. The wire-grid polarizer with the Y(2)O(3) ceramic substrate provides high durability and good IR transparency. PMID- 20847796 TI - Stimulated Brillouin scattering suppression through laser gain competition: scalability to high power. AB - We demonstrate stimulated Brillouin scattering (SBS) suppression in a Yb-doped fiber amplifier by seeding with a combination of broad- and single-frequency laser beams that are separated sufficiently to suppress four-wave mixing and to allow for efficient laser gain competition between the two signals. In the experiment, a monolithic fiber configuration was used. With appropriate selection of seed power ratio, we were able to generate single-frequency 1064 nm light with a slope efficiency of 78% while simultaneously suppressing the backscattered Stokes light. We discuss scalability to high power wherein a large thermal gradient can be induced at the output end of the fiber via quantum defect heating, leading to an SBS suppression factor comparable to counterpumping. PMID- 20847797 TI - Optical spectroscopy and energy transfer in amorphous AlN-doped erbium and ytterbium ions for applications in laser cavities. AB - Sputter-deposited thin-film amorphous AlN:Er (1 at. %) emits at 554 and 561 nm as a result of (2)H(11/2)->(4)I(15/2) and (4)S(3/2)->(4)I(15/2) transitions. AlN:Yb (1 at. %) gives a weak emission peak at 966 nm as a result of (2)F(5/2) >(2)F(7/2). The codoping of Er and Yb in AlN results in energy transfer from Er(+3) to Yb(+3) and enhances the Yb(+3) emissions by an order of magnitude. Transfer of electrons occurs from the (4)S(3/2) state of Er(+3) to the (2)F(5/2) state of Yb(+3). The weak emission from Yb(+3), when excited by a 532 nm laser in the absence of Er(+3), confirms that the luminescence enhancement in ytterbium is due to energy transfer and not to direct green light excitation by the erbium emission. A possibility of population inversion and a four-level laser cavity formation exists in the Er(+3)-Yb(+3) system. PMID- 20847798 TI - Correction of coherence gate curvature in high numerical aperture optical coherence imaging. AB - We present a method for correcting coherence gate curvature caused by scanning induced path length variations in spectral-domain high-NA optical coherence imaging systems. These variations cause curvature artifacts in optical coherence tomography and effectively restrict the field of view in optical coherence microscopy (OCM). Here we show that the coherence gate curvature can be measured and corrected by recovering the phase of the analytic signal from a calibration image. This phase information can be used directly to process OCM images allowing the coherence gate curvature, as well as any order of system dispersion, to be corrected in a computationally efficient manner. We also discuss the use of various image quality metrics that can be used to adjust the calibrated phase in order to keep the coherence and confocal gates aligned in tissue. PMID- 20847799 TI - Asymmetrical sampling structure to improve the single-longitudinal-mode property based on reconstruction-equivalent-chirp technology. AB - We propose a special asymmetric sampling structure based on reconstruction equivalent-chirp technology to effectively suppress the side mode oscillation in the zeroth channel in a sampled Bragg grating semiconductor laser, which improves greatly the single-longitudinal mode (SLM) oscillation capability of the laser. A numerical simulation is performed. The proposed structure guarantees a normalized threshold gain margin between the main mode and the side mode larger than 0.3. A high side-mode suppression ratio is also observed. The proposed method would be of great importance for the fabrication of high-performance and wideband multiwavelength laser arrays with each laser operating in SLM. PMID- 20847800 TI - Direct observation of below-diffraction-limited optical spot induced by nonlinear saturable absorption of Ag-doped Si nanofilms. AB - In this work, using the scanning near-field optical fiber probe method, we carry out a direct observation of below-diffraction-limited optical spot induced by nonlinear saturable absorption characteristic of Ag-doped Si nanofilms. The experimental results indicate that the squeezed spot size decreases with laser power increase, and the smallest spot can be squeezed to 68% of the diffraction limited focusing spot size, which is very useful and can be applied to superresolution optical recording, optical lithography, and optical imaging. PMID- 20847801 TI - Generation and nonlinear self-trapping of optical propelling beams. AB - We generate optical beams with rotating intensity blades by employing the moire technique. We show that the number of the blades and the speed and direction of rotation can be controlled at ease with a spatial light modulator, while no mechanical movement or phase-sensitive interference is involved. By applying a noninstantaneous self-focusing nonlinearity, we demonstrate both theoretically and experimentally self-trapping of such optical propelling beams. PMID- 20847802 TI - Tilt-modulated spatial phase imaging method for wafer-mask leveling in proximity lithography. AB - We demonstrate a tilt-modulated phase imaging method to adjust the gap inconsistency for wafer-mask leveling in proximity lithography. Two gratings with close periods are etched on the mask and used as leveling marks. At the illumination of a monochromatic planar wave, the diffracted image of one grating is projected back onto the other one beside it through reflection at the wafer surface. Any wafer-mask tilts in two orthogonal sections are directly modulated into the phase distribution of the interference field and can be directly remedied according to the frequency and angle deviation of the two sets of fringes. Finally, wafer-mask leveling can be achieved at only one spot with preserved accuracy. Computational and experimental results confirm that tilts at the magnitude of 10(-3) rad can be readily resolved by this method. PMID- 20847803 TI - Depth enhancement of integral imaging by using polymer-dispersed liquid-crystal films and a dual-depth configuration. AB - In spite of their many advantages, limited image depth still remains as an obstacle to three-dimensional displays based on integral imaging. In this Letter, by combining multiple polymer-dispersed liquid-crystal films and a dual-depth configuration, we propose a method to enhance the depth range of the integral imaging display system. PMID- 20847804 TI - Spectral compression and group delay of optical pulses in silicon Raman amplifiers. AB - We present a general study of pulse amplification in silicon Raman amplifiers, with special emphasis on the effects of spectral compression and group delay due to the Raman gain dispersion. We use the undepleted-pump approximation to analytically calculate the dynamics of an arbitrary pulse spectra and find the temporal profile of the pulse at the amplifier's output. We show that cw-pumped silicon waveguides are extremely inefficient in amplification of subpicosecond optical pulses but provide large net gains and controllable group delays for pulses with widths of ~10 ps. PMID- 20847805 TI - UV-driven in-plane rotation of a liquid crystal director in poly(vinyl cinnamate) films having microscale grooves. AB - The micropatterned poly(vinyl cinnamate) (PVCi) alignment layers are fabricated by a solvent-assisted micromolding method. Without UV irradiation, the alignment layer can induce the unidirectional liquid crystal (LC) orientation, which is influenced by topography-based anchoring energies. With photodimerization of PVCi by UV irradiation, we could modulate the anchoring energies caused by chemical interactions of the alignment layer. It is observed that these two different contributions compete against each other in determining LC rotation on the surface of the alignment layer. The rotation angle of LC directors could be controlled from 45 degrees to 70 degrees by simply changing the UV exposure dose. PMID- 20847806 TI - High-Q hybrid 3D-2D slab-3D photonic crystal microcavity. AB - The radiation loss in the escaping light cone with a two-dimensional (2D) photonic crystal slab microcavity can be suppressed by means of cladding the low Q slab microcavity by three-dimensional woodpile photonic crystals with the complete bandgap when the resonance frequency is located inside the complete bandgap. It is confirmed that the hybrid microcavity based on a low-Q, single defect photonic crystal slab microcavity shows improvement of the Q factor without affecting the mode volume and modal frequency. Whereas 2D slab microcavities exhibit Q saturation with an increase in the number of layers, for the analyzed hybrid microcavities with a small gap between the slab and woodpiles, the Q factor does not saturate. PMID- 20847807 TI - Nonreciprocal Bloch oscillations in magneto-optic waveguide arrays. AB - We show that nonreciprocal optical Bloch-like oscillations can emerge in transversely magnetized waveguide arrays in the presence of an effective index step between the waveguides. Normal modes of the system are shown to acquire different wavenumbers in opposite propagation directions. Significant differences in phase coherence and decoherence between these normal modes are presented and discussed. Nonreciprocity is established by imposing unequal vertical refractive index gradients at the substrate/core and core/cover interfaces in the presence of transverse magnetization. PMID- 20847808 TI - Hydrogen sensor based on metallic photonic crystal slabs. AB - We present a hydrogen sensor based on metallic photonic crystal slabs. Tungsten trioxide (WO(3)) is used as a waveguide layer below an array of gold nanowires. Hydrogen exposure influences the optical properties of this photonic crystal arrangement by gasochromic mechanisms, where the photonic crystal geometry leads to sharp spectral resonances. Measurements reveal a change of the transmission depending on the hydrogen concentration. Theoretical limits for the detection range and sensitivity of this approach are discussed. PMID- 20847809 TI - Measurement of weight in clinical trials: is one day enough? AB - Background. Weight is typically measured on a single day in research studies. This practice assumes negligible day-to-day weight variability, although little evidence exists to support this assumption. We compared the precision of measuring weight on one versus two days among control participants in the Weight Loss Maintenance trial. Methods. Trained staff measured weight on two separate days at baseline, 12 months, and 30 months (2004-2007). We calculated the standard deviation (SD) of mean weight change from baseline to the 12- and 30 month visits using (a) the first and (b) both daily weights from each visit and conducted a variance components analysis (2009). Results. Of the 316 participants with follow-up measurements, mean (SD) age was 55.8 (8.5) years, BMI was 30.8 (4.5) kg/m(2), 64% were women, 36% were black, and 50% were obese. At 12 months, the SD of mean weight change was 5.1 versus 5.0 kg using one versus two days of weight measurements (P = .76), while at 30 months the corresponding SDs were 6.3 and 6.3 kg (P = .98). We observed similar findings within subgroups of BMI, sex, and race. Day-to-day variability within individuals accounted for <1% of variability in weight. Conclusions. Measurement of weight on two separate days has no advantage over measurement on a single day in studies with well standardized weight measurement protocols. PMID- 20847810 TI - Effect of moderate-intensity exercise on plasma C-reactive protein and aortic endothelial function in type 2 diabetic mice. AB - The aim of this study was to evaluate the effects of moderate-intensity exercise on plasma levels of C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF alpha) as markers of low-grade inflammation and endothelial function in diabetic (db/db) mice. Control and db/db mice were divided into sedentary and exercised groups. Aortic endothelial function was evaluated after two- and six-week exercises using a wire myograph. Plasma CRP levels were measured at baseline, and after two and six weeks of exercise. Baseline plasma CRP levels were significantly higher in db/db mice compared to control (P < .05). After two weeks of exercise, aortic endothelial function was significantly improved without affecting body weight or plasma CRP levels. Six weeks of exercise not only improved endothelial function, but also significantly reduced body weight and plasma CRP levels in db/db mice. Thus short-term exercise has beneficial effect on endothelial function without reducing low-grade inflammation while more prolonged exercise periods are required to reduce inflammatory markers. PMID- 20847811 TI - Expression of TLR4-MyD88 and NF-kappaB in the iris during endotoxin-induced uveitis. AB - PURPOSE: To observe the expression of Toll-like receptor-4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-kappaB p65) in iris tissue during endotoxin-induced uveitis (EIU) and evaluate the significance of these factors in uveitis. METHODS: Wistar rats were randomly divided into 5 groups (0 h, 12 h, 24 h, 48 h, and 72 h, n = 10/group). Animal model of acute anterior uveitis was established by a hind footpad injection of 200 MUg Cholera vibrio LPS. Expression of TLR4, MyD88, and NF kappaB p65 in iris ciliary body tissue was detected through immunohistochemical staining. RESULTS: Expression of TLR4 was not detected in normal iris-ciliary body complex, TLR4 positive cells with round morphology appeared in the iris stroma 12 hours after injection, significantly increased (P < .001) 48 hours after injection, and decreased gradually 72 hours after injection. Expression of MyD88 and NF-kappaB p65 is consistent with the change of the TLR4. CONCLUSIONS: The increased expression of TLR4 and its downstream signal transduction moleculesMyD88, NF-kappaB p65 indicate the potential role of pathway in the pathogenesis of acute anterior uveitis (AAU). PMID- 20847812 TI - Redox imbalance in T cell-mediated skin diseases. AB - The skin is permanently exposed to physical, chemical, and biological aggression by the environment. In addition, acute and chronic inflammatory events taking place in the skin are accompanied by abnormal release of pro-oxidative mediators. In this paper, we will briefly overview the homeostatic systems active in the skin to maintain the redox balance and also to counteract abnormal oxidative stress. We will concentrate on the evidence that a local and/or systemic redox dysregulation accompanies the chronic inflammatory disorder events associated to psoriasis, contact dermatitis, and atopic dermatitis. We will also discuss the fact that several well-established treatments for the therapy of chronic inflammatory skin disorders are based on the application of strong physical or chemical oxidants onto the skin, indicating that, in selected conditions, a further increase of the oxidative imbalance may lead to a beneficial outcome. PMID- 20847815 TI - Innovative Breast Cancer Biomarkers. PMID- 20847814 TI - Redox responses in patients with sepsis: high correlation of thioredoxin-1 and macrophage migration inhibitory factor plasma levels. AB - Background. Redox active substances (e.g., Thioredoxin-1, Macrophage Migration Inhibitory Factor) seem to be central hubs in the septic inflammatory process. Materials and Methods. Blood samples from patients with severe sepsis or septic shock (n = 15) were collected at the time of sepsis diagnosis (t0), and 24 (t24) and 48 (t48) hours later; samples from healthy volunteers (n = 18) were collected once; samples from postoperative patients (n = 28) were taken one time immediately after surgery. In all patients, we measured plasma levels of IL-6, TRX1 and MIF. Results. The plasma levels of MIF and TRX1 were significantly elevated in patients with severe sepsis or septic shock. Furthermore, TRX1 and MIF plasma levels showed a strong correlation (t0: r(sp) = 0.720, rho = 0.698/t24: r(sp) = 0.771, rho = 0.949). Conclusions. Proinflammatory/~oxidative and anti-inflammatory/~oxidative agents show a high correlation in order to maintain a redox homeostasis and to avoid the harmful effects of an excessive inflammatory/oxidative response. PMID- 20847816 TI - Biomarkers for Early Cancer Detection - Methodological Aspects. AB - The development of a new breast cancer biomarker for early detection is a process that begins with biomarker discovery, followed by a rigorous definition and evaluation of the whole process of biomarker determination (analytical validation). It terminates with the assessment of the impact of the biomarker on clinical practice (clinical validation). A 4-phase scheme for the analytical validation process of the biomarkers for early diagnosis has recently been proposed with the aim of covering the need for standardized operating procedures as well as the need for monitoring and maintaining their quality. As far as clinical validation of biomarkers for early diagnosis is concerned, however, a well established phased approach exists, and guidelines are available for both planning studies and reporting results. Although analytical and clinical validation should be logically linked, often this is not the case in real-word practice, especially in the early phases of biomarker development. This is also the case with breast cancer biomarkers for early detection. PMID- 20847813 TI - Inflammation, a link between obesity and cardiovascular disease. AB - Obesity, the most common nutritional disorder in industrialized countries, is associated with an increased mortality and morbidity of cardiovascular disease (CVD). Obesity is primarily considered to be a disorder of energy balance, and it has recently been suggested that some forms of obesity are associated with chronic low-grade inflammation. The present paper focuses on the current status of our knowledge regarding chronic inflammation, a link between obesity and CVDs, including heart diseases, vascular disease and atherosclerosis. The paper discusses the methods of body fat evaluation in humans, the endocrinology and distribution of adipose tissue in the genders, the pathophysiology of obesity, the relationship among obesity, inflammation, and CVD, and the adipose tissue derived cytokines known to affect inflammation. Due to space limitations, this paper focuses on C-reactive protein, serum amyloid A, leptin, adiponectin, resistin, visfatin, chemerin, omentin, vaspin, apelin, and retinol binding protein 4 as adipokines. PMID- 20847817 TI - Epigenetic Signatures in Breast Cancer: Clinical Perspective. AB - There is now a compelling body of evidences sustaining the importance of epigenetic mechanisms in the development and progression of cancer. DNA methylation, post-translational histone and other protein modifications, microRNA expression, and nucleosome positioning, all act together to exert their cellular effects. The epigenome is responsible for controlling gene expression thus defining cell differentiation and tissue specificity. This review will focus on DNA methylation and histone modification because these epigenetic events are widely implicated in cancer development and progression. We will in particular address the translational aspects of breast cancer epigenomics including the development of biomarkers and the prospects for epigenetic based pharmacologic treatments. The analysis of DNA methylation has the advantage over other molecular methods (e.g. single gene mutation, microsatellite analysis) that it can be detected with a very high degree of specificity even in the presence of excess unmethylated DNA. Furthermore, the presence of specific CpG methylation signatures makes methylation-based markers attractive diagnostic, prognostic, and predictive tools for better management of breast cancer patients. PMID- 20847818 TI - Circulating Tumor Nucleic Acids: Perspective in Breast Cancer. AB - In 1940, it was demonstrated that free DNA could be identified in the bloodstream. It was later shown that circulating nucleic acids (CNA), both DNA and RNA, are present in several neoplastic and non-neoplastic diseases, and that in cancer they originate mostly from the tumor. In this review, we discuss the potential application of CNA as a breast cancer biomarker for early diagnosis and patient evaluation. Most of the initial studies on CNA compared the levels of CNA in cancer patients and healthy individuals. To increase sensitivity and specificity, cancer-specific molecular alterations were then utilized. In this respect, epigenetic alterations and microRNA offer considerable advantages over mutations because of their easiness of detection. Epigenetic signatures, being early events of carcinogenesis, may also be valuable markers for screening purposes. Monitoring the follow-up of the patients is one of the most interesting applications of CNA-based assays, and it is reasonable to hypothesize that CNA may become a surrogate marker for circulating cancer cells in the prediction of patient outcome. Transferring these findings to the clinical practice is the next effort, and this will be possible when a 'common language' is defined to allow proper validation of these new markers. PMID- 20847819 TI - High-Mobility Group A (HMGA) Proteins and Breast Cancer. AB - The high-mobility group A (HMGA) protein family includes HMGA1a, HMGA1b and HMGA1c, which are encoded by the same gene through alternative splicing, and the closely related HMGA2 protein. HMGA proteins have been found to be abundant in several malignant neoplasias, including colorectal, prostate, cervical, lung, thyroid and breast carcinoma. HMGA proteins can be ideal candidates for the identification of new prognosis and diagnosis factors with non-invasive methods. To provide some clarity regarding the abundance of articles on this topic, here we focus on the relationship between HMGA proteins and breast cancer and their clinical perspective in the development of new therapeutic strategies. PMID- 20847820 TI - Implementation and Benefits of Psychooncological Group Interventions in German Breast Centers: A Pilot Study on Supportive-Expressive Group Therapy for Women with Primary Breast Cancer. AB - BACKGROUND: Psychosocial treatment is an integral component in today's comprehensive breast cancer care. The main goal of this study was to test the feasibility (benefits and acceptance) of supportive-expressive group psychotherapy (SEGT), a short-term breast cancer-specific group therapy developed and tested in Anglo-American countries, within breast centers in Germany. PATIENTS AND METHODS: The study was realized as a single-group pre-post design. Data were analyzed by combining quantitative and qualitative research methods. The sample consisted of 49 women with breast cancer stage 1 or 2 according to TNM classification (tumor, node, metastasis). RESULTS: The results indicate positive acceptance of the group intervention. Quality of life, tumor-related fatigue and coping strategies improved after SEGT. 1 year after the intervention, the patients report lasting positive results from the group intervention. CONCLUSIONS: This pilot study illustrates the importance of psychooncological group interventions for breast cancer patients and indicates that this form of outpatient psychooncological care is feasible within the German health care system, and breast centers in particular. Effectiveness has to be investigated in randomized controlled trials. PMID- 20847821 TI - Flap Anchoring Following Primary Breast Cancer Surgery Facilitates Early Hospital Discharge and Reduces Costs. AB - BACKGROUND: Routine drain placement after breast cancer surgery is standard practice. Anchoring the axillary and mastectomy flaps to the underlying chest wall with sutures has been advocated as a means of avoiding drainage following breast surgery. This study compares outcomes following flap fixation or routine drain placement and uniquely considers the economic implications of each technique. PATIENTS AND METHODS: Data on seroma formation and wound infection following mastectomy and axillary clearance were recorded prospectively. Patients underwent either routine drain placement or flap anchoring using subcutaneous tacking sutures without drainage. Equipment and surgical bed costs were provided by our finance department. RESULTS: Data was available for 135 patients. 76 underwent flap anchoring without drainage and 59 had routine drainage. There was no difference in seroma rates between the two groups: 49% vs. 59% (p = 0.22). However, the length of hospital stay was reduced in the flap fixation group: 1.88 vs. 2.67 days (p < 0.0001). Per patient, flap suturing equated to an estimated financial saving of L 240. CONCLUSIONS: Flap anchoring resulted in a significantly shorter hospital stay than routine drainage, with a comparable rate of seroma formation. This technique presents a viable alternative to drain placement and could lead to a considerable economic savings. PMID- 20847822 TI - Implication of an Intramammary Sentinel Lymph Node in Breast Cancer: Is This a True Sentinel Node? A Case Report. AB - BACKGROUND: Intramammary lymph nodes (ILN) are often diagnosed by final histological examination. Recently, sentinel lymph node biopsy (SLNB) has been developed as a new standard in the treatment of breast cancer. However, reports describing intramammary sentinel nodes (ISLNs) are relatively rare, and the clinical significance of metastases in ISLNs is still unclear. CASE REPORT: We herein report a patient with breast cancer with an ISLN that was detected prior to surgery. In the current case, the ISLN contained foci of carcinoma, but the axillary SLNs (aSLN) did not contain such foci. Previous reports related to ISLNs and aSLNs, including our case, are reviewed. Interestingly, there was no case with negative ISLNs and positive aSLNs. CONCLUSIONS: The current and previous cases have shown that axillary lymph node dissection (ALDN) might rely on the aSLN status but not on the ISLN status. The effect on the prognosis or clinical significance in cases with positive ISLNs has not been fully elucidated. Cases of ISLNs found by SLN navigation are discussed in relation to their clinical significance. PMID- 20847823 TI - Primary Actinomycosis of the Breast Presenting as a Breast Mass. AB - BACKGROUND: Primary actinomycosis of the breast is a rare disease which may present as sinus tract or with mass-like features mimicking malignancy. Clinical presentation makes it difficult to distinguish primary actinomycosis from mastitis and inflammatory carcinoma. CASE REPORT: A 48-year-old woman presented with a mass in the left breast of 2 months duration. Physical examination was significant for a non-tender mass in the left breast. Histopathologic examination of the excisional biopsy of the mass showed granulomatous inflammation with grains of Actinomyces israelii. CONCLUSIONS: Actinomycosis of the breast usually presents as a recurrent abscess with fistulas. It may sometimes present as a breast lump, which is difficult to distinguish from inflammatory carcinoma. The diagnosis is made by histopathologic examination of the specimen, in which we can see the characteristic sulfur granules representing the bacterial colonies. Prolonged antibiotic therapy with penicillin is the treatment of choice. PMID- 20847824 TI - Role of Breast Ultrasound for the Detection and Differentiation of Breast Lesions. AB - Diagnosis of breast cancer has been widely improved since the development of high resolution ultrasound equipment. In the past, ultrasound was only considered useful for the diagnosis of cysts. Meanwhile, it improves the differential diagnosis of benign and malignant lesions, local preoperative staging and guided interventional diagnosis. In dense breasts, mammography has limited sensitivity. Furthermore, women with dense parenchyma have a highly increased risk of breast cancer development. Ultrasound is useful to examine dense breast tissue. Recent studies have shown that the detection of small cancers with high-resolution ultrasound is increased by 3-4 cancers per 1,000 women without clinical or mammographic abnormalities. Furthermore, stage distribution is similar between mammographically and sonographically detected carcinomas. Ultrasound is routinely used for curative diagnosis, to overcome the limitations of mammography. However, within the mammographic screening in Germany, breast density is not considered as important. Ultrasound is only used if a suspicious lesion is detected by mammography. Interestingly, 2 years ago, a screening project started in Austria in which ultrasound is always added in cases of dense breasts. Preliminary data show that the detection of additional carcinomas is increased in the same order as shown in previous studies. Therefore, an improved cancer detection and differentiation can be expected with high-resolution ultrasound. PMID- 20847825 TI - Targeted Therapy in Breast Cancer. PMID- 20847826 TI - The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer. AB - To date, blockade of growth factor receptors is the mainstay of targeted therapy in metastatic breast cancer (mBC). Monoclonal antibodies such as trastuzumab and bevacizumab represent the first generation of molecular-based therapies. Both the HER2 inhibitors and the vascular endothelial growth factor (VEGF) antagonists have shown synergism with a broad spectrum of established cytotoxins, thus being approved for first-line treatment of mBC in combination with taxanes. As a next step, tyrosine kinase inhibitors (TKIs) have been integrated into daily routine as an alternative approach for targeting HER2: The dual HER1/2 inhibitor lapatinib demonstrated activity in trastuzumab-pretreated mBC patients in combination with capecitabine. Furthermore, chemotherapy-free regimens (trastuzumab or lapatinib plus aromatase inhibitors) have been identified as additional options for hormone receptor (HR)- and HER2-positive patients. Recently published data indicate that a combination of two biologicals such as lapatinib and trastuzumab can be effective as a treatment beyond trastuzumab related progression. Multitarget TKIs have the potential to inhibit several signaling pathways involved in breast cancer-related angiogenesis. Until now, they have failed to show a clear benefit in mBC. On the other hand, poly(ADP ribose) polymerase (PARP) inhibition, mediated by a new class of small molecules, is an interesting area of investigation. Future directions of research in HER2 positive breast cancer focus on the evaluation of novel antibodies (pertuzumab, T DM1), and irreversible TKIs (neratinib, BIBW 2992) and inhibitors of HER2-related downstream signaling (mTOR, TORC 1/2, PI3K/Akt) and of receptor cross-talk (IGFR). PMID- 20847827 TI - Targeted Therapy for Early and Locally Advanced Breast Cancer. AB - The treatment of patients with breast cancer continues to evolve, with cytotoxic chemotherapy, endocrine therapy, and molecular targeted therapies representing the backbones of modern systemic breast cancer treatment. As we learn better to understand the biology of breast cancer cells, therapies to target specific pathways continue to be developed with the goal of expanding available effective therapy in specific populations. Several targeted drugs with different molecular pathways have achieved approval for metastatic breast cancer, but for early breast cancer trastuzumab is the only one that is currently approved in combination with chemotherapy for adjuvant or neoadjuvant treatment in women with HER2-positive breast cancer. Lapatinib and bevacizumab are both approved for the treatment of metastatic breast cancer and are now investigated in phase III clinical trials testing their effectiveness in the treatment of early breast cancer. In this publication, we review the current status in the treatment of early and locally advanced breast cancer with molecular targeted therapies that are currently approved or in advanced clinical development. PMID- 20847828 TI - Systemic Therapy for Women with ErbB2-Positive Breast Cancer: New Options, New Challenges. PMID- 20847829 TI - Targeted Therapy in Metastatic Breast Cancer: The HER2/neu Oncogene. AB - SUMMARY: Besides surgery, radiation, chemotherapy, and endocrine treatment, immunotherapy has become an established part of systemic therapy in treating metastatic breast cancer. One of the most interesting targets for the design of anticancer therapeutics is the HER2/ErbB2 receptor which is overexpressed in about 20-25% of breast cancers. Given the poor prognosis of women whose tumors express ErbB2 (HER2) at high levels, accurate determination of the ErbB2 status should be routinely performed in women with newly diagnosed invasive breast cancer. Efficacy and safety data of numerous trials led to the approval of the monoclonal antibody trastuzumab as the first ErbB2-targeting therapy in ErbB2 positive breast cancer. However, the majority of patients who achieve an initial response to trastuzumab-based regimens for metastatic disease develop resistance within 1 year. This underlines the need for alternative or additional anti-ErbB2 targeting strategies. PMID- 20847830 TI - Lapatinib - Member of a New Generation of ErbB-Targeting Drugs. AB - SUMMARY: Women with advanced or metastatic ErbB2 (HER2)-positive breast cancer have limited therapeutic options once their disease has progressed on trastuzumab based standard initial chemotherapy regimens. Therefore, there has been a clear need for alternative treatments in this advanced setting. The small molecule lapatinib is a dual receptor tyrosine kinase inhibitor of both ErbBl and ErbB2. In the pivotal phase III trial, lapatinib combined with capecitabine has demonstrated superior efficacy over capecitabine alone in this group of patients, with a median time to tumor progression of 8.4 months in the combination therapy group versus 4.4 months in the monotherapy arm. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. In addition, with the advent of Lapatinib, the empirically adopted practice of continuing trastuzumab beyond progression has to be seen in a different light. This is especially true since an exploratory analysis has suggested that the earlier use of the combination lapatinib plus capecitabine is associated with a benefit in time to progression and overall survival. PMID- 20847831 TI - Lapatinib in the Treatment of Hormone Receptor-Positive/ErbB2-Positive Breast Cancer. AB - SUMMARY: In women with estrogen receptor(ER)- and ErbB2 (HER2)-positive breast cancer, a vicious cycle is established between ER mechanisms of action and the growth factor receptor network, leading to enhanced cell proliferation and endocrine resistance. As such, co-targeting ErbB1 and ErbB2 with lapatinib in combination with hormonal therapy is an attractive approach to enhance the efficacy of either tamoxifen or estrogen deprivation. As demonstrated in the EGF30008 trial, a combined targeted strategy with letrozole and lapatinib significantly increased progression-free survival and clinical benefit rates in patients with metastatic breast cancer that co-expresses ER and ErbB2. Therefore, women who are not in an acutely life-threatening situation should be considered for upfront treatment with hormonal therapy (e.g. aromatase inhibitors) in combination with an anti-ErbB2 therapy. PMID- 20847832 TI - Cerebellar Ataxia and Overactive Bladder after Encephalitis Affecting the Cerebellum. AB - The cerebellum is one of the regions that contribute to urinary dysfunction in humans. A 43-year-old woman at age 35 had an acute onset of encephalitis that led to fever, generalized convulsion and coma. Six months after the disease onset, she regained consciousness and developed generalized myoclonus, cerebellar ataxia and overactive bladder, e.g., urinary urgency, daytime urinary frequency, and urinary incontinence. Eight years after the disease onset, she was revealed to have cerebellar atrophy on MRI, cerebellar hypoperfusion on SPECT, and detrusor overactivity on urodynamic study. Selective inflammation in the cerebellum seemed to produce cerebellar ataxia and overactive bladder in our case. PMID- 20847833 TI - Giant Intradural Mucocele in a Patient with Adult Onset Seizures. AB - A rare case of mucopyocele in a patient who presented with epileptic seizures is reported. The computed tomography scan (CT) and the magnetic resonance (MR) imaging revealed an intradural extension of a giant fronto-ethmoidal mucopyocele, eroding the cribriform plate and compressing both frontal lobes. The lesion was removed by craniotomy with elimination of the mass effect and reconstruction of the anterior skull base. An intracranial-intradural mucopyocele is an extremely rare cause of generalized convulsion as a presenting symptom, with only 6 cases reported in the literature. The total removal of the lesion associated with anterior fossa reconstruction is the treatment of choice. PMID- 20847834 TI - Excessive Daytime Sleepiness Is a Common Symptom in Fabry Disease. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficient activity of the enzyme alpha-galactosidase A, resulting in a vasculopathic involvement of various organ systems, e.g. cerebral structures. Marked cerebral vasculopathy with subsequent white matter lesions (WML) are a frequent finding in FD patients. Recent studies discussed an association between cerebral white matter changes and sleep-related disturbances of breathing, which may lead to excessive daytime sleepiness (EDS). A 56-year-old Caucasian female FD patient with EDS was admitted to our sleep laboratory. Overnight polysomnography showed a Cheyne-Stokes respiration pattern with significant O(2) desaturation. MR imaging revealed confluent WML including the brain stem, but no renal or cardiac involvement. We then evaluated the clinical data of 49 genetically proven FD patients (27 males; mean age 43 years) from our FD centre. With a frequency of 68%, EDS exceeds the prevalence of other common symptoms of FD (angiokeratomas 61%; acroparaesthesia 51%; renal involvement 29%; cardiac involvement 27%), and the prevalence of chronic fatigue (48%). EDS was independently associated with the physical component summary of the SF-36 data (corrected R(2) = -0.323, p < 0.001). EDS and age explained a quarter of variance in mental component summary (corrected R(2) = -0.253, p < 0.001). We conclude that EDS is a common and underdiagnosed symptom in FD patients, accompanied by a significant impact on quality of life. EDS might be caused by central breathing disorders due to an affection of brain regions associated with respiratory control in FD. PMID- 20847835 TI - Isolated Hemiataxia and Cerebellar Diaschisis after a Small Dorsolateral Medullary Infarct. AB - Isolated hemiataxia after a medullary infarct is rare. We describe a case of isolated hemiataxia after a small infarct localized at the ipsilateral dorsolateral medulla. An 83-year-old man developed acute onset of ataxia in the left arm and in both legs. Speech and extraocular movement were normal, and he did not have any other neurological manifestations. Brain MRI showed a small infarct localized at the left dorsolateral medulla, which involved the inferior cerebellar peduncle. (123)ECD-SPECT showed hypoperfusion in the left cerebellar hemisphere without clear vascular territory. Neuroimaging findings for our patient suggested the involvement of the inferior cerebellar peduncle that projects to the cerebellum in our patient. PMID- 20847836 TI - Calciphylaxis as a Catastrophic Complication in a Patient with POEMS Syndrome. AB - Calciphylaxis is a vascular calcification-cutaneous necrosis syndrome, usually seen in patients with end-stage renal disease and secondary hyperparathyroidism. We report a 57-year-old polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome patient complicated with extensive skin ulcers due to calciphylaxis. He first noted a painful cutaneous ulcer on his left thigh, and then skin lesions rapidly worsened, resulting in multiple intractable ulcers with gangrene on his legs and trunk in a few months. Serum vascular endothelial growth factor (VEGF) was markedly elevated. Biopsy samples from his skin ulcers showed the deposition of calcium in the medial layer of cutaneous vessels, this finding being compatible with calciphylaxis. This is the second reported case with POEMS syndrome complicated with calciphylaxis. Both patients had no evidence of renal failure, hyperparathyroidism, or clotting disorders. The pathogenic link between POEMS syndrome and calciphylaxis is still unclear, but VEGF is known to regulate vascular calcification, in cooperation with bone morphogenetic proteins. Further, corticosteroid and several proinflammatory cytokines activate nuclear factor-kappaB pathway, known as the final common pathway leading to vascular calcification. Taken together, we consider that POEMS syndrome can be an independent risk condition for calciphylaxis. PMID- 20847837 TI - The Health and Demographic Surveillance System (HDSS) in Nouna, Burkina Faso, 1993-2007. AB - The Nouna Health and Demographic Surveillance System (HDSS) is located in rural Burkina Faso and has existed since 1992. Currently, it has about 78,000 inhabitants. It is a member of the International Network for the Demographic Evaluation of Populations and Their Health in Developing Countries (INDEPTH), a global network of members who conducts longitudinal health and demographic evaluation of populations in low- and middle-income countries. The health facilities consist of one hospital and 13 basic health centres (locally known as CSPS). The Nouna HDSS has been used as a sampling frame for numerous studies in the fields of clinical research, epidemiology, health economics, and health systems research. In this paper we review some of the main findings, and we describe the effects that almost 20 years of health research activities have shown in the population in general and in terms of the perception, economic implications, and other indicators. Longitudinal data analyses show that childhood, as well as overall mortality, has significantly decreased over the observation period 1993-2007. The under-five mortality rate dropped from about 40 per 1,000 person-years in the mid-1990s to below 30 per 1,000 in 2007. Further efforts are needed to meet goal four of the Millennium Development Goals, which is to reduce the under-five mortality rate by two-thirds between 1990 and 2015. PMID- 20847839 TI - Pneumonia: bugs, drugs, and laboratory duds. PMID- 20847838 TI - Cellulitis from insect bites: a case series. PMID- 20847840 TI - Fatal pulmonary embolism in a 10-year old with nephrotic syndrome. AB - We present a case report of a 10-year-old male with nephrotic syndrome who presented with a complaint of shortness of breath. The patient had been recently hospitalized for an exacerbation of nephrotic syndrome and had received steroid and diuretic therapy. Initial vital signs showed tachycardia and mild tachypnea. After being observed for more than four hours without deterioration he was discharged home for close follow up. The patient returned 4 hours later with worsening symptoms and went into cardiac arrest in the ED. Autopsy revealed bilateral large pulmonary emboli. Pulmonary embolism is a known complication of nephrotic syndrome. Hyperviscosity occurs due to a variety of mechanisms. Nearly all reported incidents are associated with the use of steroids and diuretics. It is essential to maintain a heightened suspicion of pulmonary embolism (PE) when children with nephrotic syndrome present with pulmonary complaints, particularly when they have been treated with steroids and diuretics. PMID- 20847841 TI - Challenges in the management of acutely decompensated congestive heart failure: disposition decisions in the emergency department. PMID- 20847842 TI - Patients' vs. Physicians' Assessments of Emergencies: The Prudent Layperson Standard. AB - OBJECTIVE: To compare perception of the need for emergency care by emergency department (ED) patients vs. emergency physicians (EPs). METHODS: Mailed survey to EPs and a convenience sample of ED patients. Survey rated urgency of acute sore throat, ankle injury, abdominal pain, and hemiparesis, as well as the best definition of "emergency." Responses were compared with chi-square (p < .05). RESULTS: 119/140 (85%) of EPs and 1453 ED patients responded. EPs were more likely to judge acute abdominal pain (79.8% vs. 43.4%, p < 0.001, odds ratio (OR) 5.16, 95% confidence interval (CI) 3.19-8.40) and hemiparesis (100% vs. 82.6%, p < 0.001, OR 24.9, 95% CI 3.75-94.4) as an emergency. Similar proportions of ED patients and EPs considered sore throat (12.2% vs. 7.6%, p = 0.18, OR 0.59, CI 0.27-1.23) and ankle injury (46.9% vs. 38.6%, p = 0.10, OR 0.71, CI 0.48-1.06) an emergency. EPs (35%) and ED patients (40%) agreed to a similar degree with the "prudent layperson" definition, "a condition that may result in death, permanent disability, or severe pain." (p = .36, OR 1.22, CI 0.81-1.84). EPs were more likely to add, "the condition prevented work," (27% vs. 16%, p = 0.003, OR 0.51, CI 0.33-0.81). Patients more often added, "occurred outside business hours" (15% vs. 4%, p = 0.002, OR 4.0, CI = 1.5-11.3). CONCLUSION: For serious complaints, ED patients' thresholds for seeking care are higher than judged appropriate by EPs. Stroke is not uniformly recognized as an emergency. Absent consensus for the "correct" threshold, the prudent layperson standard is appropriate. PMID- 20847843 TI - Evolution of emergency ultrasound. PMID- 20847844 TI - Combining the Modified Allen's Test and Pulse Oximetry for Evaluating Ulnar Collateral Circulation to the Hand for Radial Artery Catheterization of the ED Patient. PMID- 20847845 TI - Diagnosis of hip effusion with bedside ultrasound in the emergency department. PMID- 20847846 TI - Factors influencing analgesic use for skatepark-related musculoskeletal injuries. AB - OBJECTIVE: This study was designed to determine the proportion of patients with skatepark-related musculoskeletal injuries who were administered analgesics in the emergency department (ED) or at discharge, and to determine if differences in use of pain medication varied by injury type, anatomic location, or patient age. METHODS: This is a retrospective review of a cohort of consecutive patients with musculoskeletal injuries presenting to a large urban ED from a local skatepark over a 1-year period (1999-2000). Patients with non-musculoskeletal injuries were excluded. The outcome measure was analgesic use either in the ED or at discharge. Data included demographics, activity during injury, disposition, injury type (fracture or non-fracture), and injury location (upper or lower body). Analgesic data was abstracted from the medical records. Multivariable logistic regression was used to identify independent predictors of receipt of analgesic medications. RESULTS: 85 injured patients were enrolled. No differences in age, sex, activity, or disposition were found comparing those who received analgesics (n=68) to those who did not (n=17). Overall, analgesia was administered to 80% (95% CI = 70 to 88%) of patients; 67% (95% CI = 56 to 77%) in the ED and 64% (95% CI = 52 to 74%) at discharge. Fractures were more likely to receive analgesia (adjusted OR = 18.5; 95% CI = 4.0 to 86.1) than non-fracture injuries. Lower body injuries were more likely to receive analgesics compared to upper body injuries (adjusted OR = 9.2; 95% CI = 1.5 to 55.8). Age was not independently associated with analgesic use. CONCLUSIONS: A high proportion of skatepark-related musculoskeletal injuries were treated with pain medications either in the ED or at discharge. In this study analgesic medication use was influenced by injury type and location of the injury, but not age. PMID- 20847847 TI - Should academic emergency departments collaborate in pharmaceutical industry sponsored research?: the dangers of industry-funded research in emergency medicine. PMID- 20847848 TI - Interacting with the pharmaceutical industry. PMID- 20847849 TI - Improving metered dose inhaler technique in the emergency department: a prospective study. AB - OBJECTIVE: To determine if improvement in patients' metered dose inhaler (MDI) technique could be achieved in the emergency department (ED) with the use of a simple illustrated instruction sheet. METHODS: Prospective evaluation of a convenience sample of patients with asthma or COPD. Patients were first subjectively and objectively evaluated on their usual MDI technique, then were given an illustrated instruction sheet to study for 5 minutes. There was no verbal coaching prior to the post-test. A post-test evaluation was then performed. Results were compared using paired Student t test. RESULTS: A total of 115 patients were enrolled. Mean age was 34.9+/-13.1 years, and mean years using MDI was 5.7+/-3.8. Subjective improvement in technique was reported by 110 patients (96%) with a mean pre-test score of 7.4+/-1.5 and post-test score of 9.2+/-1.1 (p<0.0001, 10 point scale). Objective improvement was achieved in 113 patients (98%) with a mean pre-test score of 3.9+/-1.3 and post-test score of 5.8+/-1.0 (p<0.0001, 7 point scale), corresponding to a 30% improvement in technique (95% CI: 22,39). Forty-four patients (38%) reported never having been shown proper MDI technique by a health care professional, and 112 patients (97%) found the instruction sheet helpful. CONCLUSIONS: Rapid objective and subjective improvement of MDI technique from both patients' and physicians' perspective is possible in the ED with the use of an illustrated instruction sheet, and requires minimal effort from the treating emergency physician. PMID- 20847850 TI - Intimate partner violence among women presenting to a university emergency department. AB - OBJECTIVE: To establish point and one-year prevalence data regarding partner violence (PV) for women presenting to a university teaching hospital, University of California, Irvine Medical Center (UCIMC), one of 15 emergency departments in Orange County, and to determine differences in partner violence rates when comparing descriptive variables such as race, income and education. METHODS: An anonymous, written survey was administered to a convenience sample of 370 women presenting to University of California Irvine Emergency Department over a 12 month period. RESULTS: Partner violence has a point prevalence of 6.7% and a one year prevalence of 37.0%. Women who have experienced previous abuse are more likely to present with complaints related to PV acutely. Lower income levels correlate with a higher incidence of physical, emotional, and sexual abuse. We found no correlation between race and likelihood of PV. CONCLUSION: PV in Orange County, California occurs quite frequently. The one-year prevalence compares to that of the entire state of California, but is at the higher limit when other areas are compared. Detection rates among EPs should be improved, and services to women who have suffered PV will need to be enhanced within Orange County. PMID- 20847851 TI - Intimate partner violence among men presenting to a university emergency department. AB - OBJECTIVE: We sought to investigate the one-year point prevalence for male intimate partner violence (IPV) in men presenting to a university emergency department, to identify types of violence, to examine differences in male IPV rates based on patient demographics, and to identify any differences in prevalence based on types of partnership. METHODS: This survey study was conducted from September 2001 until January 2002 at a tertiary, academic, Level I Trauma Center with an emergency department (ED) that has 40,000 visits per year. The anonymous written survey consisted of 16 questions previously validated in the Colorado Partner Violence Study, Index of Spouse Abuse and the Conflict Tactics Scale. This survey was administered to all consenting adult men who presented to the ED. Odds ratios (OR) with 95% CI were calculated when appropriate and a p-value of 0.05 was set for significance. RESULTS: The one-year point prevalence rate of male IPV was 24% in our study population (82/346). Among the men who experienced some form of abuse specified as either physical, emotional, or sexual, the prevalence was calculated to be 15.6% (54/346), 13.6% (47/346), and 2.6% (9/346), respectively. Education, income, age, and race did not demonstrate an association for any one variable to be associated with intimate partner abuse (p>0.05) with the exception of increased risk of IPV among unemployed men in the relationship (p<0.04, OR 0.592). IPV towards men was found to affect both heterosexual as well as homosexual relationships. Overall, 2% (8/346) of the men surveyed had received medical treatment as a result of IPV by their intimate partner within the past year. Three percent (11/344) of those men reporting abuse were abusers themselves. CONCLUSION: The point prevalence of IPV among our study population was 24%. In our study of 346 men, male IPV crossed all socioeconomic boundaries, racial differences, and educational levels regardless of the sex of the partner. PMID- 20847852 TI - The effect of anthrax bioterrorism on emergency department presentation. AB - STUDY OBJECTIVE: From September through December 2001, 22 Americans were diagnosed with anthrax, prompting widespread national media attention and public concern over bioterrorism. The purpose of this study was to determine the effect of the threat of anthrax bioterrorism on patient presentation to a West Coast emergency department (ED). METHODS: This survey was conducted at an urban county ED in Oakland, CA between December 15, 2001 and February 15, 2002. During random 8-hour blocks, all adult patients presenting for flu or upper respiratory infection (URI) symptoms were surveyed using a structured survey instrument that included standard visual numerical and Likert scales. RESULTS: Eighty-nine patients were interviewed. Eleven patients (12%) reported potential exposure risk factors. Eighty percent of patients watched television, read the newspaper, or listened to the radio daily, and 83% of patients had heard about anthrax bioterrorism. Fifty-five percent received a chest x-ray, 10% received either throat or blood cultures, and 28% received antibiotics. Twenty-one percent of patients surveyed were admitted to the hospital. Most patients were minimally concerned that they may have contracted anthrax (mean=3.3+/-3.3 where 0=no concern and 10=extremely concerned). Patient concern about anthrax had little influence on their decision to visit the ED (mean=2.8+/-3.0 where 0=no influence and 10=greatly influenced). Had they experienced their same flu or URI symptoms one year prior to the anthrax outbreak, 91% of patients stated they would have sought medical attention. CONCLUSIONS: After considerable exposure to media reports about anthrax, most patients in this urban West Coast ED population were not concerned about anthrax infection. Fear of anthrax had little effect on decisions to come to the ED, and most would have sought medical help prior to the anthrax outbreak. PMID- 20847853 TI - Case report: an unusual case of sudden cardiovascular collapse in an elderly adult. AB - In our report we describe a case of foreign body aspiration leading to arrest. The patient's resuscitation was remarkable for the development of a large pneumothorax and atelectasis of the right lung. Aspiration was suspected and early bronchoscopy was performed. A large grape was found to be obstructing the right main stem bronchus and was retrieved using a bronchoscopic snare. In this case early intervention allowed the removal of the intact grape with subsequent re-expansion of the lung. The technique used for retrieval is described. PMID- 20847854 TI - Ultrasound-guided deep brachial and basilic vein cannulation in the emergency department. PMID- 20847855 TI - Documentation and coding education in emergency medicine residency programs: a national survey of residents and program directors. AB - PURPOSES: To assess attitudes and practices of documentation and coding education for emergency medicine residents (EMRs). METHODS: Questions regarding documentation teaching methods were formulated into online surveys for program directors (PDs) and EMRs. RESULTS: Fifty-three of 104 PDs and 446 of 576 EMRs who received the survey completed it. Although 93% of EMRs and 63% of PDs believe proper chart documentation is an important skill, only 18% of EMRs and 25% of PDs believe their program's teaching was adequate. Eleven percent of EMRs reported that they were comfortable with their knowledge of documentation. EMRs who received formal lectures and feedback reported higher comfort levels with their knowledge of documentation (3.3 +/- 1.1 vs. 4.5 +/- 1.4, p < 0.05) than those who did not receive formal lectures and feedback. CONCLUSIONS: Although most physicians who were surveyed agreed that documentation and coding is a vital skill, many EMRs and PDs report inadequate instruction. Resident education may benefit from broader implementation of formal lectures and formal feedback on documentation and coding skills. PMID- 20847856 TI - Novel approaches to sepsis in the emergency department. PMID- 20847857 TI - Advantages of a Three-year Residency. PMID- 20847858 TI - Advantages of a Four-year Residency. PMID- 20847859 TI - Analgesia and addiction in emergency department patients with acute pain exacerbations. AB - INTRODUCTION: There is ongoing controversy regarding the appropriate use of narcotic analgesia for patients presenting frequently to the emergency department (ED) with subjective acute exacerbations of pain. "Are we treating pain or enabling addiction?" OBJECTIVES: To determine whether the presence of specific factors could be used to identify adults complaining of acute exacerbations of pain for suspected drug addiction, to estimate the percentage of drag addicted patients, to assess the physicians' ability to detect drug addiction and to evaluate Interrater reliability. METHODS: A Drug Abuse Screening Test (DAST-20) was administered to 76 ED patients who presented with acute exacerbations of pain and either multiple ED visits for similar pain complaints, specific narcotic requests, or "allergies" to non-narcotics. The DAST-20 was also administered to 74 age-matched controls. Treating ED physicians rated their suspicion for drug addiction using a visual analog scale (VAS). RESULTS: The overall estimation of drug addiction based on the DAST-20 survey was 17.3% (26/150). Twenty-one percent (16/76) of the analgesia subjects and 13.5% (10/74) of the control subjects scored positive for drug addiction as measured by the DAST-20. Of the analgesia subjects with positive DAST-20 scores for drug addiction, 43.8% (7/16) had multiple ED visits, 43.8% (7/16) requested specific narcotics and 6.3% (1/16) reported "allergies" to non-narcotics. There was no correlation between the VAS scores and the DAST-20 scores. There was a significant correlation between resident and attending VAS scores for their suspicion for drug addiction. CONCLUSION: There exists a clinically significant drug addiction problem among ED patients presenting with acute exacerbations of pain and among low-acuity patients who do not present to the ED for pain management. PMID- 20847860 TI - Monetary resident incentives: effect on patient satisfaction in an academic emergency department. AB - Patient satisfaction most be a priority in emergency departments (EDs). The care provided by residents forms much of the patient contact in academic EDs. OBJECTIVE: To determine if monetary incentives for emergency medicine (EM) residents improve patient satisfaction scores on a mailed survey. METHODS: The incentive program ran for nine months, 1999-2000. Press-Ganey surveys responses from ED patients in 456 hospitals; 124 form a peer group of larger, teaching hospitals. Questions relate to: 1) waiting time, 2) taking the problem seriously, 3) treatment information, 4) home care concerns, 5) doctor's courtesy, and 6) concern with comfort. A 5-point Likert scale ranges from "very poor" (0 points) to "very good" (100). Raw score is the weighted mean, converted to a percentile vs. the peer group. Incentives were three-fold: a year-end event for the EM residents if 80th percentile results were achieved; individual incentives for educational materials of $50/resident (50th percentile), $100 (60th), $150 (70th), or $200 (80th); discount cards for the hospital's espresso cart. These were distributed by 11 EM faculty (six cards/month) as rewards for outstanding interactions. Program cost was <$8,000, from patient-care revenue. Faculty had similar direct incentives, but nursing and staff incentives were ill defined and indirect. RESULTS: Raw scores ranged from 66.1 (waiting time) to 84.3 (doctor's courtesy) (n=509 or ~7.2% of ED volume). Corresponding percentiles were 20th-43rd (mean=31st). We found no difference between the overall scores after the incentives, but three of the six questions showed improvement, with one, "doctors' courtesy," reaching 53(rd) percentile. The faculty funded the 50(th) percentile reward. CONCLUSIONS: Incentives are a novel idea to improve patient satisfaction, but did not foster overall Press-Ganey score improvement. We did find a trend toward improvement for doctor-patient interaction scores. Confounding variables, such as increasing patient census, could account for inability to demonstrate a positive effect. PMID- 20847861 TI - In-flight emergencies at 35,000 feet. PMID- 20847862 TI - Retinal detachment diagnosed by bedside ultrasound in the emergency department. AB - This case study describes a patient who presented with vague visual complaints in the right eye, decreased visual acuity in the affected eye, and a difficult initial eye evaluation, including fundoscopic and slit lamp examinations, in the emergency department (ED). The preliminary finding included a darkened-appearing area of the retina on fundoscopic exam. The patient subsequently had bedside sonography of the eyes done by an emergency medicine (EM) intern which revealed a thin and serpentine strip appearing as a hyperechoic representation of the retina floating freely into the vitreous from the superior-lateral section of the posterior globe. PMID- 20847863 TI - An unusual case of abdominal pain in a female child. AB - Non-traumatic abdominal pain is a common presenting complaint in emergency department (ED) patients, quoted in some contemporary literature as being the third most frequent reason for ED visits. We present the ED and hospital course of an unusual case of an 11 year old female with right lower quadrant abdominal pain. The admission assessment of this patient was "possible appendicitis versus gastroenteritis"; however, laparatomy revealed a right adnexal torsion. The need for emergency medicine physicians to always include gynecologic and other less common causes in the differential diagnosis and workup of abdominal pain in children is emphasized. PMID- 20847864 TI - The Frequency of Reevaluation or Peak Flow Meter Documentation in Acute Asthma Exacerbations in the Emergency Department: Are We Treating in Accordance with NIH/NAEPP Guidelines? AB - OBJECTIVES: To evaluate the frequency of peak expiratory flow rate (PEFR) measurement and clinical re-evaluation in the management of ED asthmatic patients. METHODS: This was a retrospective chart review examining consecutive asthma patients who presented to the University of California Irvine ED between September 1, 2003 and December 31, 2003. Patients were excluded if they had a diagnosis of COPD, lung cancer, pneumonia, congestive heart failure, alpha 1 anti trypsin deficiency or were under 5 years of age. Data collected included patient demographics, pulse oximetry reading(s), ED treatments rendered, and frequencies of PEFR measurement (pre and post therapy), of clinical re-evaluations in the ED, and of ED return visits. RESULTS: Of the 122 ED visits from 111 patients, 11 (10%) patients returned during the 4 month study period, with 5 patients (4.5%) returning in less than 72 hours. Seven (6.0%) patients had PEFR done both pre and post treatment and 24 (20%) had one or more PEFR performed either before or after treatment. Only 61 (50%) of the visits had a documented clinical re-evaluation prior to disposition. CONCLUSIONS: Despite their documented role in asthma treatment algorithms, PEFR was performed infrequently and clinical re-evaluation was documented in only half of cases. Recommended algorithms for asthma management were not commonly followed in this academic ED. PMID- 20847866 TI - Poison control center management of benzocaine exposures. PMID- 20847865 TI - A modified approach to supraclavicular subclavian vein catheter placement: the pocket approach. AB - BACKGROUND: Central venous access is often necessary for the administration of fluids, blood products, and medications. Several approaches to supraclavicular subclavian venous access have been described. This study examines the effectiveness of central venous catheter placement utilizing an alternative set of anatomic landmarks for supraclavicular subclavian vein access. METHODS: This was a two phase study. The first portion involved subclavian vein cannulation using a supraclavicular approach in 28 cadavers. The specific set of anatomic landmarks for the supraclavicular approach, termed the "pocket approach," is described. Cadavers were subsequently dissected to verify appropriate line placement. The second portion was a chart review of Emergency Department (ED) patients who underwent attempted subclavian vein catheter placement utilizing the pocket approach. Charts were extracted following education of the ED faculty and resident staff to determine: 1) Success of subclavian line placement, 2) The incidence of pneumothorax, and 3) The use of supraclavicular subclavian access in the trauma setting, during cardiopulmonary resuscitation (CPR), and in patients who had cervical collars. RESULTS: In 28 cadavers, the success rate of the pocket approach was 100% (34/34; 95% CI 90% to 100%). Chart review of the 68 patients revealed a success rate of 90% (61/68; CI 80% to 96%). No pneumothoraces were recorded (0/68; CI 0% to 5%). The pocket approach was used successfully in 11 patients with cervical collars, (100%, CI 72% to 100%) and in 15 of 16 patients undergoing CPR (94%, CI 70% to 100%). In four fresh cadavers, the average distance from the posterior subclavian vein to the subclavian artery was 0.40cm, and the dome of the pleura was 1.75cm posterior to the vein. CONCLUSION: Our data suggest that the supraclavicular pocket approach to subclavian vein cannulation is a useful and safe method of adult central venous catheterization, with complication and success rates comparable to more common approaches. The anatomic advantage of a great vein that is closer to the skin and farther from the pleural dome makes this an approach worthy of further investigation. PMID- 20847867 TI - Why the US Should Adopt a Universal Health Care Coverage Program. PMID- 20847868 TI - Why the US Government Should Not Adopt a Universal Health Coverage Program. PMID- 20847869 TI - Incidence of negative appendectomy: experience from a company hospital in Nigeria. AB - OBJECTIVE: The aim of this study was to determine the rate of negative appendectomy in a company hospital in Nigeria. BACKGROUND: Appendicitis is one of the most common abdominal conditions requiring surgical intervention. Appendectomy, like most surgical procedures, has its complications and therefore should only be undertaken when indicated. Case series have reported the incidence of negative appendectomy in Western nations. The purpose of this retrospective study is to evaluate the incidence of negative appendectomy in a Nigerian hospital, where all the operations were carried out by consultant surgeons. METHODS: All case files of patients who received an appendectomy at Chevron Hospital in Warri, Nigeria between January, 1999 and December, 2003 were reviewed. Demographic data, symptoms and signs on presentation, intra-operative findings and histological reports on the excised vermiform appendixes were extracted from the case files and analyzed. RESULTS: The incidence of negative appendectomy in this study was 16.1%; all nine patients that had negative appendectomy were female. CONCLUSION: The incidence of negative appendectomy observed at Chevron Hospital in Warri, Nigeria is lower than that reported by most studies; one factor may be that all the patients in the present study were evaluated and operated on by consultant surgeons. PMID- 20847870 TI - Topics in international and travel medicine. PMID- 20847871 TI - Typhoid Fever. PMID- 20847872 TI - Reentrant supraventricular tachycardia in a pediatric trauma patient masquerading as a cardiac contusion. AB - Establishing the etiology of tachycardia in a trauma patient is often difficult. Pediatric trauma patients present an even tougher challenge. Cardiac contusion should be suspected when other more common traumatic injuries that produce hypoxia and blood loss are excluded. The diagnosis of cardiac contusion is notoriously difficult to make largely due to the controversy over the definition of the disease, and the lack of a true gold standard confirmatory test. Atrioventricular nodal reentrant tachycardia (AVNRT) is a common form of supraventricular tachycardia (SVT) that can also present a diagnostic challenge to emergency physicians. While electrophysiologic studies are the gold standard for confirming the diagnosis, there are certain aspects of the history, electrocardiogram (ECG), and responses to cardiac maneuvers that strongly suggest the diagnosis. We present the case of a pediatric trauma patient that presented with new onset AVNRT masquerading as cardiac contusion. PMID- 20847873 TI - The Dark Side of the Moon - the Side Effects of Therapy in a Dynamic Era of Breast Cancer Management. PMID- 20847875 TI - Is Higher Efficacy Always at the Price of More Side Effects during Chemotherapy? AB - Breast cancer remains the most prevalent cancer diagnosed in women worldwide. The number of effective treatments for breast cancer is on the rise, however, the benefit from specific treatments to individual patients and the adverse events experienced vary considerably. Efficacy and safety of anticancer therapies may depend on tumor, treatment, and host characteristics. Advances in the adjuvant chemotherapy of operable breast cancer have come from the introduction of effective agents and the application of the principles of combination chemotherapy. Attempts to advance these principles by substantial escalation of drug dosage have proven unsuccessful with a potentially higher rate of side effects. Another concept to increase efficacy is dose density, the administration of drugs with shortened intertreatment interval, and sequential therapy. The dose dense concept improved clinical outcome significantly and was not accompanied by an increase in toxicity. PMID- 20847874 TI - Towards the Implementation of Quality of Life Monitoring in Daily Clinical Routine: Methodological Issues and Clinical Implication. AB - Quality of life (QOL) has become a widely used outcome parameter in the evaluation of treatment modalities in clinical oncology research. By now, many of the practical problems associated with measuring QOL in clinical practice can be overcome by the use of computer-based assessment methods. QOL assessment in oncology is dominated by two measurement systems, the FACT scales and the EORTC QLQ-C30 with its modules. The amount of human resources required to implement routine data collection has been reduced significantly by advanced computer technology allowing data collection in busy clinical practice. Monitoring of QOL can contribute to oncologic care by facilitating detection of physical and psychological problems and tracking the course of disease and treatment over time. Furthermore, the integration of screening for psychosocial problems into QOL monitoring contributes to the identification of patients who are in need of psychooncologic interventions. Computer-based QOL monitoring does not replace the direct physician-patient communication but enables to identify specific impairments and symptoms including psychological problems. Beyond clinical practice, QOL data can be used for research purposes and may help health care planners to determine those patient services that should be maintained or ones that should be developed. PMID- 20847876 TI - The Role of Supportive Therapy in the Era of Modern Adjuvant Treatment - Current and Future Tools. AB - Recent advances in adjuvant treatment of breast cancer have improved progression free and overall survival. Optimal management of treatment-induced side effects has therefore gained further importance. This review cannot provide a comprehensive overview of treatment-related toxicity and its management, but focuses on important new developments in the field of supportive therapy. Erythropoietins, while highly effective in treating chemotherapy-induced anaemia, may have detrimental effects on outcome, and should only be used with the aim to reduce the number of whole blood transfusions. Granulocyte colony-stimulating factors were a prerequisite for development of dose-dense regimens, and are also necessary in many anthracycline/taxane combination regimens. A potential tumour stimulating effect was not proven in solid cancers. For side effects of conventional chemotherapy, such as mucositis, nausea, or diarrhoea, regularly updated guidelines may improve symptom control. Overall, modern supportive treatment tools will further reduce treatment-related mortality and help increase quality of life. PMID- 20847877 TI - Cognitive Effects of Systemic Therapy in Patients with Breast Cancer. AB - Many patients with breast cancer complain about concentration and memory problems in connection with systemic therapy. A number of studies investigating the possible decrease in cognitive abilities were published in the 1980s. Numerous studies showed impaired performance of patients receiving chemotherapy. The results concerning profile, extent, and duration of cognitive impairments are, however, non-uniform. Increasing interest has been focused in the last years on effects of endocrine therapy on cognitive capacity - especially concerning the effects of the almost complete estrogen depletion caused by aromatase inhibitors. Often, the published studies did not evaluate particular effects of endocrine therapy without considering interference of cytotoxic treatment. Furthermore, the different endocrine medications (antiestrogens vs. aromatase inhibitors) were usually not regarded separately despite different mechanisms of action. Hence, the results of past investigations are also controversial. In the future, prospective trials with larger samples are necessary. Differentiation between chemotherapy and endocrine therapy is essential. Likewise, different types of endocrine therapy should be examined separately. PMID- 20847879 TI - Magnetic Resonance Imaging of a Benign Phyllodes Tumor of the Breast. AB - SUMMARY: BACKGROUND: The aim of this study was to evaluate a phyllodes tumor of the breast with magnetic resonance imaging (MRI) and magnetic resonance spectroscopy. METHODS: MRI of the breasts was performed using a phased array double breast coil with spectroscopic capability on a 1.5T MR scanner. Post contrast sequential imaging was done, and the subtracted images were evaluated. Timesignal intensity curves were obtained. MR spectroscopy using BREASE software was also performed. RESULTS: MRI combined with MR spectroscopy was used in the diagnosis and characterization of a phyllodes tumor of the breast. CONCLUSION: MRI and MR spectroscopy may offer an in vivo imaging technique for the characterization of phyllodes tumors of the breast. PMID- 20847878 TI - Possible Relationship between Basal-Like Breast Carcinoma and Age. AB - SUMMARY: INTRODUCTION: Estrogen receptor expression is lower in breast carcinoma of women <=45 years compared to women >=65 years of age, which may imply a higher frequency of basal-like breast carcinomas in younger women. This study evaluated whether there is any difference in the frequency of basal-like phenotype and estrogen receptor (ER)-/HER2- invasive breast carcinomas between women of these 2 different age groups. PATIENTS AND METHODS: A total of 151 women aged <=45 years or >=65 years with invasive breast carcinomas were evaluated using tissue microarray, and classified into the following phenotypes: luminal A (ER+/HER2-), luminal B (ER+/HER2+), HER2 overexpression (ER-/HER2+), and basal-like (ER-/HER2- and expressing at least 1 of the basal markers p63, CK5 and/or P-cadherin). RESULTS: ER-/HER2- carcinomas were twice as frequent in women aged <=45 years (p = 0.0247). However, when the basal-like phenotype was compared with all the other phenotypes grouped together, no statistically significant difference was found (p = 0.0854). CONCLUSIONS: ER-/HER2- carcinomas were more frequent in younger women compared to all the other phenotypes grouped together. An international consensus will be necessary to establish which markers should be used to define basal-like phenotype. PMID- 20847880 TI - Mandibular Metastasis of a Signet Ring Cell Carcinoma of the Breast in a Patient who Underwent Bilateral Mastectomy more than 25 Years Earlier. AB - SUMMARY: BACKGROUND: Metastatic tumors account for less than 1% of all malignant tumors occurring in the oral cavity. CASE REPORT: The clinical case of a 94-year old patient with a mandibular tumor is reported here. The patient had undergone bilateral mastectomy more than 25 years before. An immunohistochemical study found hormone receptors in signet ring cells, suggesting a diagnosis of breast cancer metastasis. CONCLUSION: Immunohistochemical diagnosis and antineoplastic hormone therapy is the cornerstone in the management of this clinical case. PMID- 20847881 TI - Sentinel Node Biopsy in Breast Cancer: Clinical Implication - Standard of Care - Fututre Prospects. PMID- 20847882 TI - The Epidemiology and Aetiology of Female Breast Cancer. PMID- 20847883 TI - Recent Trends in Breast Cancer Incidence and Mortality in Germany. AB - SUMMARY: BACKGROUND: Breast cancer is the most common cancer among women in Germany with high public health impact. In the last decade rapid changes in risk factor patterns, early breast cancer detection, and therapy have taken place. Their effects on breast cancer epidemiology in Germany are described. MATERIALS AND METHODS: A register-based survey using recent incidence data from German cancer registries was performed. Mortality data were provided by the Central Federal Statistical Office. We calculated age-standardized rates and 5- and 10 year trends. RESULTS: Breast cancer incidence increased until the year 2002, thereafter a discreet decline occurred until 2005 (-6.8%). In the age group 50-59 years this reduction was most pronounced (-12%). Mortality declined from 1996/7 to 2004/5 by 19%, with the strongest effect in women younger than 55 years (approximately 30%). Regional patterns of breast cancer incidence and mortality revealed differences within Germany of greater than 30%. CONCLUSION: Declining hormone replacement therapy prescription is the most likely factor to explain the drop in breast cancer incidence. The reduction in mortality might be caused by better therapy and enhanced early detection during the last decade. Differences in breast cancer incidence and mortality between Eastern and Western Germany give reason for further research and discussion. PMID- 20847884 TI - Established and Suspected Risk Factors in Breast Cancer Aetiology. AB - Although a current decline in breast cancer incidence and mortality is being observed, the disease continues to be the most common malignancy among women. Breast cancer is a worldwide public health problem that causes substantial personal and social burdens. While we do not yet know exactly what causes the disease, we know a large number of risk factors that are linked to breast cancer. In particular, hormonal factors seem to play a key role in the causation of the disease. The aim of this paper is to review the current knowledge of established and suspected risk factors of breast cancer from an epidemiologic point of view. PMID- 20847885 TI - Dense Breast Tissue as an Important Risk Factor for Breast Cancer and Implications for Early Detection. AB - More than 30 years ago, John Wolfe was the first to observe and describe the association between breast density on mammography and increased breast cancer risk. Following this pioneer work, there is now compelling evidence that density in the highest quartile represents a 4-6 times higher risk of breast cancer. This magnitude of risk is only topped by age and BRCA1/2 mutation. The density-based risk is independent of age and other risk factors. Apart from epidemiologic risk factors, additional genetic factors seem to influence density. This could be the reason behind the well-known interaction between genes and environment. Reliable and reproducible breast density measurements are a prerequisite for the use of breast density to monitor primary prevention strategies and for the use of mammographic density to define women at higher breast cancer risk who would benefit from intensified early detection and surveillance protocols. PMID- 20847886 TI - Malignant Mesenchymal Tumor of the Breast: Primary Chondrosarcoma. AB - SUMMARY: BACKGROUND: Primary mesenchymal tumors are an extremely rare malignancy of the breast. CASE REPORT: A 52-year-old woman presented with a rapidly growing breast mass. Physical examination established a large and round mass with regular margins in the upper-outer quadrant of the right breast. Ultrasound showed a hypoechoic solid mass (41 * 36 mm) with lobulated contours. Mammography revealed a hyperdense and relatively regular-shaped mass giving the impression of a benign tumor. However, a pathologic report of atypical cells after fine needle aspiration necessitated surgical excision. The mass was removed with a wide local excision. The tumor was diagnosed as a high-grade chondrosarcoma of the breast by histopathological analysis. Following the final diagnosis, we performed a modified radical mastectomy based on the knowledge that this malignancy is generally refractory to radiotherapy. The regional lymph nodes and local adjacent tissues were free of metastasis. The tumor was negative for estrogen and progesterone receptors as well as HER2. CONCLUSION: Chondrosarcoma tends to grow rapidly. Physical examination usually reveals a large, round mass. The tumor is regular-shaped, round, and complex echoic on Mammography and ultrasound. It usually does not invade regional structures. Surgery remains the only effective treatment. PMID- 20847887 TI - Accessory Breast Carcinoma. AB - SUMMARY: BACKGROUND: Ectopic breast tissue usually develops along the mammary ridges, and the incidence has been reported to be 2-6% of the general population. Occurrence of primary carcinoma in ectopic breast tissue is rare. CASE REPORT: We report the case of 59-year-old woman with accessory breast carcinoma in her left axilla. CONCLUSION: Because an accessory areola or nipple is often missing and awareness of physicians and patients about these unsuspicious masses is lacking, clinical diagnosis of accessory breast carcinoma is frequently delayed. Therefore, a mass along the 'milk line' should be examined carefully, and any suspicious lesions should be evaluated. PMID- 20847888 TI - Shoulder Strain Caused by Mammary Prostheses - an Experimental Comparison of Different Forms of Epicutaneous Prostheses. AB - SUMMARY: BACKGROUND: In the case of breast cancer, removal of the breast can not always be avoided. The use of external prostheses, however, can lead to discomfort for the patients through shoulder pain and muscle hardening. It can be assumed that this is caused by strain on the shoulder due to the weight of the prosthesis. This study was to identify the possibilities to objectively assess patients' complaints associated with this type of supportive treatment. SUBJECTS AND METHODS: In this pilot study, varying types and sizes of prostheses were tested on male subjects, quasi as if they were women amputated on both sides. The strain caused by the prostheses and distributed via the straps of the brassiere were measured by electronic pressure sensors and statistically evaluated. RESULTS: Weight-reduced prostheses significantly decreased the resulting average pressure amplitude (p < 0.01) compared to normal weight prostheses. Furthermore, heavy contact prostheses, which are attached to the chest wall, have a significant advantage (p < 0.01) compared to normal prostheses of the same size. Moreover, evidence was found that contact prostheses have advantages with respect to pressure on the shoulder during physical exercise, e.g. running. CONCLUSION: Currently, weight-reduced contact prostheses present optimal treatment after breast amputation. PMID- 20847889 TI - Effectiveness of a home-based postal and telephone physical activity and nutrition pilot program for seniors. AB - Objective. To evaluate the effectiveness of a 12-week home-based postal and telephone physical activity and nutrition pilot program for seniors. Methods. The program was delivered by mailed material and telephone calls. The main intervention consisted of a booklet tailored for seniors containing information on dietary guidelines, recommended physical activity levels, and goal setting. Dietary and walking activity outcomes were collected via a self-administered postal questionnaire pre- and postintervention and analysed using linear mixed regressions. Of the 270 seniors recruited, half were randomly selected for the program while others served as the control group. Results. The program elicited favourable responses. Postintervention walking for exercise/recreation showed an average gain of 27 minutes per week for the participants in contrast to an average drop of 5 minutes for the controls (P < .01). Little change was evident in errand walking for both groups. The intervention group (n = 114) demonstrated a significant increase in fibre intake (P < .01) but no reduction in fat intake (P > .05) compared to controls (n = 134). Conclusions. The participants became more aware of their health and wellbeing after the pilot program, which was successful in increasing time spent walking for recreation and improving fibre intake. PMID- 20847890 TI - Experience (mostly negative) with the use of sympathomimetic agents for weight loss. AB - Sympathomimetic agents have a poor history of long-term success in the treatment of obesity. From earlier experiences with amphetamine and its analogs, to more recent drugs with direct effects on adrenergic receptors or indirect effects from release of catecholamines or inhibition of reuptake, cardiovascular toxicity (strokes and cardiac arrhythmias) has been the major concern. These concerns also extended to food supplements containing ephedra alkaloids and may require consideration for current supplements containing the sympathomimetic drug, synephrine. PMID- 20847891 TI - Effect of Treatment of Sprague Dawley Rats with AVE7688, Enalapril, or Candoxatril on Diet-Induced Obesity. AB - The objective of this study was to determine the effect of AVE7688, a drug that inhibits both angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activity, on neural and vascular defects caused by diet induced obesity (DIO). Rats at 12 weeks of age were fed a standard or high fat diet with or without AVE7688 for 24 weeks. DIO rats had impaired glucose tolerance and developed sensory neuropathy. Vascular relaxation to acetylcholine and calcitonin gene related peptide was decreased in epineurial arterioles of DIO rats. Rats fed a high fat diet containing AVE7688 did not become obese and vascular and sensory nerve dysfunction and impaired glucose tolerance were improved. DIO is associated with increased expression of NEP in epineurial arterioles. NEP degrades vasoactive peptides which may explain the decrease in neurovascular function in DIO. PMID- 20847892 TI - Evidence for resistance training as a treatment therapy in obesity. AB - Over the last decade, investigators have paid increasing attention to the effects of resistance training (RT) on several metabolic syndrome variables. Evidence suggests that skeletal muscle is responsible for up to 40% of individuals' total body weight and may be influential in modifying metabolic risk factors via muscle mass development. Due to the metabolic consequences of reduced muscle mass, it is understood that normal aging and/or decreased physical activity may lead to a higher prevalence of metabolic disorders. The purpose of this review is to (1) evaluate the potential clinical effectiveness and biological mechanisms of RT in the treatment of obesity and (2) provide up-to-date evidence relating to the impact of RT in reducing major cardiovascular disease risk factors (including dyslipidaemia and type 2 diabetes). A further aim of this paper is to provide clinicians with recommendations for facilitating the use of RT as therapy in obesity and obesity-related metabolic disorders. PMID- 20847893 TI - The role of testosterone in the etiology and treatment of obesity, the metabolic syndrome, and diabetes mellitus type 2. AB - Obesity has become a major health problem. Testosterone plays a significant role in obesity, glucose homeostasis, and lipid metabolism. The metabolic syndrome is a clustering of risk factors predisposing to diabetes mellitus type 2, atherosclerosis, and cardiovascular morbidity and mortality. The main components of the syndrome are visceral obesity, insulin resistance, glucose intolerance, raised blood pressure and dyslipidemia (elevated triglycerides, low levels of high-density lipoprotein cholesterol), and a proinflammatory and thrombogenic state. Cross-sectional epidemiological studies have reported a direct correlation between plasma testosterone and insulin sensitivity, and low testosterone levels are associated with an increased risk of type 2 diabetes mellitus, dramatically illustrated by androgen deprivation in men with prostate carcinoma. Lower total testosterone and sex hormone-binding globulin (SHBG) predict a higher incidence of the metabolic syndrome. Administration of testosterone to hypogonadal men reverses part of the unfavorable risk profile for the development of diabetes and atherosclerosis. PMID- 20847895 TI - Acute impact of moderate-intensity and vigorous-intensity exercise bouts on daily physical activity energy expenditure in postmenopausal women. AB - This study determined whether performing a single moderate- or vigorous-intensity exercise bout impacts daily physical activity energy expenditure (PAEE, by accelerometer). Overweight/obese postmenopausal women underwent a 5-month caloric restriction and moderate- (n = 18) or vigorous-intensity (n = 18) center-based aerobic exercise intervention. During the last month of intervention, in women performing moderate-intensity exercise, PAEE on days with exercise (577.7 +/- 219.7 kcal.d(-1)) was higher (P = .011) than on days without exercise (450.7 +/- 140.5 kcal.d(-1)); however, the difference (127.0 +/- 188.1 kcal.d(-1)) was much lower than the energy expended during exercise. In women performing vigorous intensity exercise, PAEE on days with exercise (450.6 +/- 153.6 kcal.d(-1)) was lower (P = .047) than on days without exercise (519.2 +/- 127.4 kcal.d(-1)). Thus, women expended more energy on physical activities outside of prescribed exercise on days they did NOT perform center-based exercise, especially if the prescribed exercise was of a higher intensity. PMID- 20847894 TI - Physical activity plays an important role in body weight regulation. AB - Emerging literature highlights the need to incorporate physical activity into every strategy intended to prevent weight gain as well as to maintain weight loss over time. Furthermore, physical activity should be part of any plan to lose weight. The stimulus of exercise provides valuable metabolic adaptations that improve energy and macronutrient balance regulation. A tight coupling between energy intake and energy expenditure has been documented at high levels of physical exercise, suggesting that exercise may improve appetite control. The regular practice of physical activity has also been reported to reduce the risk of stress-induced weight gain. A more personalized approach is recommended when planning exercise programs in a clinical weight loss setting in order to limit the compensatory changes associated to exercise-induced weight loss. With modern environment promoting overeating and sedentary behavior, there is an urgent need for a concerted action including legislative measures to promote healthy active living in order to curb the current epidemic of chronic diseases. PMID- 20847896 TI - An evidence-based review of fat modifying supplemental weight loss products. AB - Objective. To review the literature on fat modifying dietary supplements commonly used for weight loss. Methods. Recently published randomized, placebo-controlled trials were identified in PubMed, MEDLINE, International Pharmaceutical Abstracts, Cochrane Database, and Google Scholar using the search terms dietary supplement, herbal, weight loss, obesity, and individual supplement names. Discussion. Data for conjugated linoleic acid (CLA), Garcinia cambogia, chitosan, pyruvate, Irvingia gabonensis, and chia seed for weight loss were identified. CLA, chitosan, pyruvate, and Irvingia gabonensis appeared to be effective in weight loss via fat modifying mechanisms. However, the data on the use of these products is limited. Conclusion. Many obese people use dietary supplements for weight loss. To date, there is little clinical evidence to support their use. More data is necessary to determine the efficacy and safety of these supplements. Healthcare providers should assist patients in weighing the risks and benefits of dietary supplement use for weight loss. PMID- 20847897 TI - Assessment of acute and chronic pharmacological effects on energy expenditure and macronutrient oxidation in humans: responses to ephedrine. AB - Evidence of active brown adipose tissue in human adults suggests that this may become a pharmacological target to induce negative energy balance. We have explored whole-body indirect calorimetry to detect the metabolic effects of thermogenic drugs through administration of ephedrine hydrochloride and have assessed ephedrine's merits as a comparator compound in the evaluation of novel thermogenic agents. Volunteers randomly given ephedrine hydrochloride 15 mg QID (n = 8) or placebo (n = 6) were studied at baseline and after 1-2 and 14-15 days of treatment. We demonstrate that overnight or 23-hour, 2% energy expenditure (EE) and 5% fat (FO) or CHO oxidation effects are detectable both acutely and over 14 days. Compared to placebo, ephedrine increased EE and FO rates overnight (EE 63 kJ day 2, EE 105 kJ, FO 190 kJ, day 14), but not over 23 h. We conclude that modest energy expenditure and fat oxidation responses to pharmacological interventions can be confidently detected by calorimetry in small groups. Ephedrine should provide reliable data against which to compare novel thermogenic compounds. PMID- 20847898 TI - Clinical analysis on alteration of thyroid hormones in the serum of patients with acute ischemic stroke. AB - Low T3 has been associated with increased short-term mortality in intensive care unit and long-term mortality in cardiovascular disease. The objective of this retrospective study is to investigate associations of thyroid hormone status with clinical severity and outcome in acute ischemic stroke, and whether there is association between the pituitary axis abnormality and the anterior/posterior circulation involvement. Patients with no history of thyroid abnormality who presented first ever stroke were studied. Total T3, T4, TSH levels, basic and clinical characteristics were collected and categorized. Neurological impairment was assessed using NIHSS and modified Rankin Scale. Twenty-nine patients (61%) had T3 <= 75 ng/dL. Low T3 group had significant higher NIHSS compared to normal T3 group. There was a significant negative correlation between T3 levels and NIHSS scores on admission. A significantly smaller percentage of patients with low T3 showed favorable neurological function improvement by both NIHSS and mRS measures compared to those with normal T3. There was no significant difference for anterior or posterior circulation involvement between low T3 and normal T3 groups. It is suggested that low T3 is associated with worse neurological outcome. The severity of low T3 may be a predictor of functional improvement in acute ischemic stroke. PMID- 20847899 TI - The Role of PCNA Posttranslational Modifications in Translesion Synthesis. AB - Organisms are predisposed to different types in DNA damage. Multiple mechanisms have evolved to deal with the individual DNA lesions. Translesion synthesis is a special pathway that enables the replication fork to bypass blocking lesions. Proliferative Cell Nuclear Antigen (PCNA), which is an essential component of the fork, undergoes posttranslational modifications, particularly ubiquitylation and sumoylation that are critical for lesion bypass and for filling of DNA gaps which result from this bypass. A special ubiquitylation system, represented by the Rad6 group of ubiquitin conjugating and ligating enzymes, mediates PCNA mono- and polyubiquitylation in response to fork stalling. The E2 SUMO conjugating enzyme Ubc9 and the E3 SUMO ligase Siz1 are responsible for PCNA sumoylation during undisturbed S phase and in response to fork stalling as well. PCNA monoubiquitylation mediated by Rad6/Rad18 recruits special polymerases to bypass the lesion and fill in the DNA gaps. PCNA polyubiquitylation achieved by ubc13 mms2/Rad 5 in yeast mediates an error-free pathway of lesion bypass likely through template switch. PCNA sumoylation appears required for this error-free pathway, and it plays an antirecombinational role during normal replication by recruiting the helicase Srs2 to prevent sister chromatid exchange and hyper recombination. PMID- 20847900 TI - H1N1pdm in the Americas. AB - In late April 2009 the emergence of 2009 pandemic influenza A (H1N1pdm) virus was detected in humans. From its detection through July 18th, 2009, confirmed cases of H1N1pdm in the Americas were periodically reported to the Pan American Health Organization (PAHO) by member states. Because the Americas span much of the world's latitudes, this data provides an excellent opportunity to examine variation in H1N1pdm transmission by season. Using reports from PAHO member states from April 26th, 2009 through July 18th, 2009, we characterize the early spread of the H1N1 pandemic in the Americas. For a geographically representative sample of member states we estimate the reproductive number (R) of H1N1pdm over the reporting period. The association between these estimates and latitude, temperature, humidity and population age structure was estimated. Estimates of the peak reproductive number of H1N1pdm ranged from 1.3 (for Panama, Colombia) to 2.1 (for Chile). We found that reproductive number estimates were most associated with latitude in both univariate and multivariate analyses. To the extent that latitude is a proxy for seasonal changes in climate and behavior, this association suggests a strong seasonal component to H1N1pdm transmission. However, the reasons for this seasonality remain unclear. PMID- 20847901 TI - Label Structured Cell Proliferation Models. AB - We present a general class of cell population models that can be used to track the proliferation of cells which have been labeled with a fluorescent dye. The mathematical models employ fluorescence intensity as a structure variable to describe the evolution in time of the population density of proliferating cells. While cell division is a major component of changes in cellular fluorescence intensity, models developed here also address overall label degradation. PMID- 20847902 TI - Direct, Electrocatalytic Oxygen Reduction by Laccase on Anthracene-2-methanethiol Modified Gold. AB - Laccase, a multicopper oxidase, catalyses the four electron reduction of oxygen to water. Upon adsorption to an electrode surface, laccase is known to reduce oxygen at overpotentials lower than the best noble metal electrocatalysts usually employed. While the electrocatalytic activity of laccase is well established on carbon electrodes, laccase does not typically adsorb to better defined noble metal surfaces in an orientation that allows for efficient electrocatalysis. In this work, we utilized anthracene-2-methanethiol (AMT) to modify the surface of Au electrodes and examined the electrocatalytic activity of adsorbed laccase. AMT facilitated the adsorption of laccase, and the onset of electrocatalytic oxygen reduction was observed as high as 1.13 V(RHE). We observed linear Tafel behavior with a 144 mV/dec slope, consistent with an outer sphere single electron transfer from the electrode to a Cu site in the enzyme as the rate determining step of the oxygen reduction mechanism. PMID- 20847904 TI - Women's Empowerment across Generations in Bangladesh. AB - This study uses qualitative data to examine young women's relationships with their mothers and mothers-in-law to understand how these relationships foster empowerment in the younger generation or fail to do so. The data consist of ethnographic interviews with 20 triads of women-young married women, their mothers and their mothers-in-law. Findings show that the influence of empowerment across generations was greater in the sphere of economic empowerment and education than in relation to marriage and childbearing. The study illustrates how patriarchal institutions resistant to change can limit the effects of women's empowerment on the next generation. PMID- 20847903 TI - The cost-effectiveness of a nonpharmacologic intervention for individuals with dementia and family caregivers: the tailored activity program. AB - OBJECTIVES: To evaluate cost-effectiveness of the Tailored Activity Program (TAP) for individuals with dementia and family caregivers. DESIGN: Cost-effectiveness study of a two-group randomized controlled trial involving 60 patients-caregiver dyads randomized to intervention or wait-list control. SETTING: Participants' homes in Philadelphia region. PARTICIPANTS: Caregivers were aged >= 21 years, lived with patients, and provided >= 4 hours of daily care. Patients had moderate dementia and behavioral symptoms INTERVENTION: Eight sessions of occupational therapy over 4 months to identify patients' preserved capabilities, previous roles, habits and interests, develop customized activities, and train families in their use. MEASUREMENTS: Incremental cost-effectiveness ratios (ICER) expressed as the cost to bring about one additional unit of benefit measured by caregiver hours per day "doing things" and hours per day "being on duty." Decision tree and Monte Carlo analyses tested robustness of the economic models. RESULTS: Total average intervention cost was $941.63 per day. Intervention caregivers saved one extra hour per day "doing things" at a cost of $2.37/day and one extra hour per day "being on duty" at a cost of $1.10/day. Monte Carlo showed that TAP was cost effective 79.2% of the time for "doing things" and 79.6% of the time for "being on duty." Varying the cost assumptions did not change cost-effectiveness. CONCLUSIONS: Findings suggest that investment in TAP is cost-effective and afforded families an important, limited and highly valued resource, needed time off from caregiving. This nonpharmacologic approach should be considered part of the clinical management of dementia. PMID- 20847905 TI - Liberty and injustice for all. PMID- 20847906 TI - Recent neuroscience advances of interest to neurosurgeons, neurologists and neuroscientists - June 2010. PMID- 20847907 TI - Transcranial approach to pituitary adenomas invading the cavernous sinus: A modification of the classical technique to be used in a low-technology environment. AB - OBJECTIVE: Pituitary adenomas invading the cavernous sinus represent a therapeutic challenge. Those tumors have been traditionally treated with incomplete surgical removal, observation and/ or adjunctive medical therapy, and radiotherapy. In relatively recent years, some authors have suggested a main direct surgical approach to cavernous sinus (CS) with the aim of complete removal of the adenoma, either by a modified trans-sphenoidal route, using or not an endoscopy-assisted approach, or by a transcranial direct approach. The latter has the advantage of allowing direct exposure of the lesion with a view of the surgical field unhindered by important neurovascular structures. MATERIALS AND METHODS: We report a technical modification of the classical epidural approach for CS adenoma removal. This was used in 14 patients. Surgical technique included a fronto-orbito-zygomatic craniotomy with extradural anterior clinoidectomy, and intradural approach to the Hakuba's triangle for intracavernous dissection. The tumors were removed under direct vision. RESULTS: Total macroscopical removal was achieved in all but one case. This patient required postoperative radiation therapy as well as adjuvant dopaminergic regime for achieving control of preoperatively increased hormonal values. No other case required radiotherapy. Hormonal and/ or clinical control was also achieved in all the remaining cases. Out of the remaining 13 cases, all appeared to be tumor free at an average postoperative observation at 78 months (34 to 90 months). Significant surgical sequels were detected in only 1 case (persistent 3(rd) nerve palsy and moderate hemiparesis). CONCLUSIONS: This experience, though limited, would suggest that the transcranial limited CS exposure through the Hakuba's triangle may allow adequate removal of intracavernous pituitary adenomas with very good long-term results and acceptable complication rate. PMID- 20847908 TI - Perioperative fatal embolic cerebrovascular accident after radical prostatectomy. AB - BACKGROUND: There is little written about the management of perioperative cerebrovascular accident (CVA). To the best of our knowledge, the present case report represents the first case in the literature of a well-documented intraoperative embolic CVA and perioperative mortality in a relatively healthy, young patient with no contributing comorbidity and no noteworthy intraoperative event. CASE DESCRIPTION: A 53-year-old man presented for radical prostatectomy under general anesthesia. The anesthetic course and procedure were uneventful. In the postanesthesia care unit (PACU), the patient was moving all extremities but was still sedated. One hour later, he developed left hemiplegia, facial dropping, slurred speech and his head was turned to the right. The next day his mental status deteriorated, and on an emergency basis he was intubated. A CT scan of the head showed a malignant hemispheric right cerebrovascular accident with leftward midline shift. Even aggressive treatment, including a right decompressive hemicraniectomy, could not lower the high intracranial pressure, and the patient expired on the third postoperative day. CONCLUSION: Guidelines for identifying and treating perioperative hemispheric CVA are urgently needed, with modification of the antiquated and useless criterion of "patient seen neurologically normal at induction time" to more useful objective criteria including "intraoperative neurophysiological recording change, gross extremity movements, facial dropping, follows simple commands" while excluding a drug-induced, sedative-influenced globally-impaired cognitive state that may last for hours. PMID- 20847910 TI - The United States and the world economy in the future: America's global exceptionalism firmly rooted in entrepreneurship. PMID- 20847909 TI - Tension pneumocephalus as complication of burr-hole drainage of chronic subdural hematoma: A case report. AB - BACKGROUND: Pneumocephalus is the presence of air in the cranial cavity. When this intracranial air causes increased intracranial pressure and leads to neurological deterioration, it is known as tension pneumocephalus (TP). TP can be a major life-threatening postoperative complication, especially after evacuation of chronic subdural hematoma. We report a case of TP after evacuation of chronic subdural hematoma and review the literature. CASE DESCRIPTION: A 70-year-old man developed right-sided weakness after being admitted with minor head trauma a few weeks earlier. He was found to have a chronic subdural hematoma and underwent burr-hole evacuation. On day 3, he suddenly deteriorated and needed intubation and ventilation. Computerized tomography (CT) of the brain showed typical Mount Fuji's sign due to TP. Immediately, 20-30 mL of air was aspirated from the intracranial fossa, and a catheter drain was inserted. The patient became fully awake after few hours and was extubated successfully. The drain was removed on day 5, and he was transferred to the ward before being discharged home. CONCLUSION: TP after evacuation of a chronic subdural hematoma is a neurosurgical emergency and needs immediate resuscitation and therapy; hence it is of vital importance that all acute-care physicians, intensivists and neurosurgeons be aware of this clinical emergency. PMID- 20847913 TI - A free forum for neurosurgery and neuroscience. PMID- 20847912 TI - Type 2 diabetes mellitus: A central nervous system etiology. AB - BACKGROUND: Insulin resistance (hyperinsulinemia) is said to be the signal event and causal in the development of type 2 diabetes mellitus. Pulsatile arterial compression of the right anterolateral medulla oblongata is associated with autonomic dysfunction, including "driving" the pancreas, which increases insulin resistance causing type 2 diabetes mellitus. In this prospective study, we hypothesize that decompressing the right cranial nerve X and medulla will result in better glycemic control in patients with type 2 diabetes mellitus. METHODS: Ten patients underwent retromastoid craniectomy with microvascular decompression for type 2 diabetes mellitus. Patients were followed for 12 months postoperatively by blood glucose monitoring and studies of glycemic control, pancreatic function and insulin metabolism. No changes in diet, weight or activity level were permitted during the course of the project. RESULTS: Seven of the 10 patients who received microvascular decompression for type 2 diabetes mellitus showed significant improvement in their glucose control. This was noted by measurement of diabetes markers and decrease of diabetes medication dosages. One patient was completely off diabetes medication, while attaining euglucemia. The other 3 patients did not improve in their glucose control. The body mass index of these 3 patients was higher (mean, 34.4) than those with better outcomes (mean, 27.9). CONCLUSION: Arterial compression of the right anterolateral medulla appears to be a factor in the etiology of type 2 diabetes mellitus. Microvascular decompression may be an effective treatment for non-obese type 2 diabetes mellitus patients. PMID- 20847914 TI - From the bench to the bedside: BOLDly going where no one has gone before. PMID- 20847911 TI - Deformative stress associated with an abnormal clivo-axial angle: A finite element analysis. AB - BACKGROUND: Chiari malformation, functional cranial settling and subtle forms of basilar invagination result in biomechanical neuraxial stress, manifested by bulbar symptoms, myelopathy and headache or neck pain. Finite element analysis is a means of predicting stress due to load, deformity and strain. The authors postulate linkage between finite element analysis (FEA)-predicted biomechanical neuraxial stress and metrics of neurological function. METHODS: A prospective, Internal Review Board (IRB)-approved study examined a cohort of 5 children with Chiari I malformation or basilar invagination. Standardized outcome metrics were used. Patients underwent suboccipital decompression where indicated, open reduction of the abnormal clivo-axial angle or basilar invagination to correct ventral brainstem deformity, and stabilization/ fusion. FEA predictions of neuraxial preoperative and postoperative stress were correlated with clinical metrics. RESULTS: Mean follow-up was 32 months (range, 7-64). There were no operative complications. Paired t tests/ Wilcoxon signed-rank tests comparing preoperative and postoperative status were statistically significant for pain, bulbar symptoms, quality of life, function but not sensorimotor status. Clinical improvement paralleled reduction in predicted biomechanical neuraxial stress within the corticospinal tract, dorsal columns and nucleus solitarius. CONCLUSION: The results are concurrent with others, that normalization of the clivo-axial angle, fusion-stabilization is associated with clinical improvement. FEA computations are consistent with the notion that reduction of deformative stress results in clinical improvement. This pilot study supports further investigation in the relationship between biomechanical stress and central nervous system (CNS) function. PMID- 20847915 TI - Delayed sub-aponeurotic fluid collections in infancy: Three cases and a review of the literature. AB - BACKGROUND: Sub-aponeurotic fluid collections (SFCs) in the neonatal period are poorly described in the literature. We describe the occurrence, possible etiologies and treatment of sub-aponeurotic fluid collections following the neonatal period. CASE DESCRIPTION: We present 3 cases of previously healthy children who developed soft, fluctuant, extracranial masses several weeks after birth. All 3 children were seen by a pediatric neurosurgeon after parents noticed scalp masses between 5 and 9 weeks of age. All 3 children were found to be otherwise healthy. Two of the children were born via C-section and 1 child was born vaginally. The vaginal delivery was described as difficult and utilized vacuum assist. Scalp electrodes were placed in all 3 children for intensive monitoring during labor. These children received plain skull x-rays to assess for abnormalities, and 2 of the children underwent a non-contrast brain CT scan to better characterize the fluid collection. Plain x-rays and CT scans showed no abnormalities of the skull or ventricles. In both patients who underwent a CT scan, a soft tissue prominence was noted with a Hounsfield unit similar to water. All cases resolved between 5 and 9 weeks after initial presentation, with no long term sequelae. CONCLUSION: SFCs presenting after the neonatal period are usually associated with benign soft tissue swellings. Use of fetal scalp electrodes has been shown to cause cerebrospinal fluid (CSF) leakage in the neonatal period and may result in delayed SFC. This condition is benign, and the recommended course of treatment is conservative management. PMID- 20847916 TI - Bifrontal solitary fibrous tumor of the meninges. AB - BACKGROUND: We report the case of a bifrontal solitary fibrous tumor (SFT) arising from the meninges. The points of interest in this case report are the particular imaging appearance, the immunohistochemical findings and the surgical features. CASE DESCRIPTION: A 53-year-old Caucasian male presented with a 1-year history of behavioral changes, attention disorders and anterograde memory disorders. Magnetic resonance imaging revealed a bifrontal heterogeneous lesion attached to the anterior falx cerebri with a prominent multicompartmental cystic part. The patient underwent craniotomy for a sub-total resection of the tumor. At surgery, the multicystic component was highly vascularized and encased the anterior cerebral arteries. Neuropathological findings were consistent with a solitary fibrous tumor. Despite the absence of malignant features, there was a focal expression of p53. CONCLUSION: SFT is a pathological entity with specific immunohistochemical features; it has frequently been misdiagnosed in the past. The multicystic imaging appearance of this SFT and the particular p53 immunohistochemical staining are features that should be added to the growing data on intracranial SFTs. The surgical features described (high vascularization and partial vessel encasement) may help improve surgical planning. PMID- 20847917 TI - Microsurgical treatment of tentorial meningiomas: Report of 30 patients. AB - BACKGROUND: Tentorial meningiomas represent about 5% of intracranial meningiomas. This article reviews our recent institutional series of patients with tentorial meningiomas, proposes a simplified classification and analyzes postoperative evolution, discussing the salient features in the management of these patients. METHODS: From 1998 to 2005, 30 patients (22 female and 8 male) with tentorial meningiomas were operated at our institution. Thirteen patients had tumor restricted to the infratentorial space; 12, to the supratentorial space; and in 5 cases, the tumor involved both compartments. Follow-up ranged from 1 to 8 years. A total of 35 surgical procedures were performed in 30 patients, where 26 procedures were performed through a single approach (2, ITSC; 10, RS; 5, SOIH; 5, ST; and 4, TT); and 9, through combined approaches (7, ITSC/ SOIH; and 2, RS/ST). RESULTS: Simpson I resection was achieved in 17 patients. Tumors involving both compartments, involving the petrous sinus, and attached to the torcula limited complete resection. Twenty-two out of 30 patients were able to return to their regular life with no or minimal neurological sequelae. Most frequent complications in our series were shunt dependence, CSF fistulae, diffuse brain injury and visual field defects. Overall, our series revealed 3% mortality and 23% morbidity. CONCLUSION: Tentorial meningiomas are associated with significant morbidity related to the nervous and vascular structures surrounding the tumor. Partial tumor removal may be necessary in some cases. PMID- 20847918 TI - Intradiscal electrothermal therapy in the treatment of chronic low back pain: experience with 93 patients. AB - BACKGROUND: Low back pain (LBP) has become a main cause of absenteeism and disability in industrialized societies. Chronic LBP is an important health issue in modern countries. Discogenic LBP is one of the causes of chronic low back pain. The management of chronic discogenic LBP has been limited to either conservative treatment or operative treatment. Intradiscal electrothermal therapy (IDET) is now being performed as an alternative treatment. METHODS: Ninety-three consecutive patients undergoing IDET at 134 disc levels from October 2004 to January 2007 were prospectively evaluated. All patients had discogenic disease with chronic LBP, as determined by clinical features, physical examination and image studies, and had failed to improve with conservative treatment for at least 6 months. Follow-up period was from 1 week to 3 or more years postoperatively. RESULTS: There were 50 male and 43 female patients, with a mean age of 46.07 years (range, 21-65 years). The results were classified as symptom free (100% improvement), better (>=50% improvement), slightly better (<50% improvement), unchanged and aggravated. Eighty-nine patients were followed up in the first week; of them, 77 (86.52%) patients had improvement (4, symptom free; 45, better; and 28, slightly better). The improvement rate gradually decreased to 80.90% in 1 year; and 73.91%, in 3 years. CONCLUSIONS: In conclusion, IDET offers a safe, minimally invasive therapy option for carefully selected patients with chronic discogenic LBP who have not responded to conservative treatment. Although IDET appears to provide intermediate-term relief of pain, further studies with long term follow-up are necessary. PMID- 20847919 TI - The tail wagging the dog. PMID- 20847920 TI - Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival. PMID- 20847921 TI - Imaging features of invasion and preoperative and postoperative tumor burden in previously untreated glioblastoma: Correlation with survival. AB - BACKGROUND: A paucity of data exists concerning the prognostic usefulness of preoperative and postoperative imaging after resection of glioblastoma multiforme (GBM). This study aimed to connect outcome with imaging features of GBM. METHODS: Retrospective computer-assisted volumetric calculations quantified central necrotic (T0), gadolinium-enhanced (T1) and increased T2-weighted signal volumes (T2) in 70 patients with untreated GBM. Clinical and treatment data, including extent of resection (EOR), were obtained through chart review. T1 volume was used as a measure of solid tumor burden; and T2 volume, as an indicator of invasive isolated tumor cell (ITC) burden. Indicators of invasiveness included T2:T1 ratios as a propensity for ITC infiltration compared to solid tumor volumes and qualitative analysis of subependymal growth and infiltration of the basal ganglia, corpus callosum or brainstem. Cox multivariate analysis (CMVA) was used to identify significant associations between imaging features and survival. RESULTS: In the 70 patients studied, significant associations with reduced survival existed for gadolinium-enhancing tumor crossing the corpus callosum (odds ratio, 3.14) and with increased survival with gross total resection (GTR) (GTR median survival, 62 weeks versus 37 and 34 weeks for sub-total resection and biopsy, respectively). For a selected "GTR-eligible" subgroup of 52 patients, prolonged survival was associated with smaller preoperative gadolinium-enhancing volume (T1) and actual GTR. CONCLUSION: Some magnetic resonance (MR) imaging indicators of tumor invasiveness (gadolinium-enhancing tumor crossing the corpus callosum) and tumor burden (GTR and preoperative T1 volume in GTR-eligible subgroup) correlate with survival. However, ITC-infiltrative tumor burden (T2 volume) and "propensity" for ITC invasiveness (T2:T1 ratio) did not impact survival. These results indicate that while the ITC component is the ultimate barrier to cure for GBM, the pattern of spread and volumes of gadolinium enhancing solid tumor are more robust indicators of prognosis. PMID- 20847923 TI - From the bench to the bedside: Emerging science in Parkinson's disease, cholesterol metabolism, and neuroprotection. PMID- 20847922 TI - Successful treatment of a symptomatic L5/S1 discal cyst by percutaneous CT-guided aspiration. AB - BACKGROUND: Discal cysts are a rare cause of lumbar radiculopathy. Benefits of percutaneous computed tomography (CT)-guided aspiration of the cyst include decreased rate of infection, avoidance of general anesthesia, and quicker recovery. However, since the publication of a case of cyst recurrence after CT guided aspiration, few have utilized this potentially valuable technique. CASE DESCRIPTION: We present a patient with a discal cyst arising from the L5/S1 disc causing right S1 radiculopathy. He underwent percutaneous CT-guided aspiration with substantial improvement in his radicular pain with 19 months of follow-up. His improvement was measured quantitatively using the Japanese Orthopedic Association scale: 6/15 pre-procedure, 15/15 post-procedure. CONCLUSION: Percutaneous CT-guided aspiration of discal cysts may be a valid initial treatment option for this condition. Patients who do not respond or who have a recurrence can subsequently be treated by surgical excision. PMID- 20847924 TI - Neuroendoscopic evacuation of intraventricular hematoma associated with thalamic hemorrhage to shorten the duration of external ventricular drainage. AB - BACKGROUND: We report neuroendoscopic evacuation of an intraventricular hematoma (IVH) in 13 patients with thalamic hemorrhage. We discuss strategies to improve the outcome and to shorten the management period by using external ventricular drainage (EVD). METHODS: Patients were classified into fair (modified Rankin scale [mRS] grade 4 or less) and poor (mRS grade 5) outcome groups, and depending on the duration of EVD, into short (7 days or shorter) and long EVD (8 days or longer) groups. RESULTS: The postoperative residual IVH, graded using the Graeb score, was better for the fair outcome group than for the poor outcome group (3.9 [1.2] vs. 5.7 [1.0], P < 0.05). The postoperative Graeb score was significantly better for the short EVD group than for the long EVD group (3.6 [0.8] vs. 6.0 [0.6], P < 0.01). The duration of EVD was not correlated with the IVH at the fourth ventricle, but it was correlated with the IVH at the foramen of Monro (P < 0.05) and the third ventricle (P < 0.01). Reduction in the volume of thalamic hemorrhage had no effect on the neurological outcome or duration of EVD. CONCLUSION: Neuroendoscopic evacuation of the IVH at the foramen of Monro and the third ventricle shortened the duration of EVD for hydrocephalus caused by thalamic hemorrhage with IVH involvement. Removal of the thalamic hemorrhage and IVH at the fourth ventricle was not necessary. PMID- 20847925 TI - Transient Automatic Writing Behavior following a Left Inferior Capsular Genu Infarction. AB - A 79-year-old, right-handed woman was admitted to the hospital with decreased spontaneity. Brain magnetic resonance imaging showed a left inferior capsular genu infarction. (99m) TC-ECD single-photon emission computed tomography revealed a left-dominant diffuse hypoperfusionin the basal ganglia and frontal lobe. The patient showed abulia and increased writing activity without motor or sensory deficit. The writing was mainly perseverative, and words written along lines were legible and without spatial distortions. This augmented writing behavior disappeared on day 21. The writing characteristic was more similar to automatic writing behavior than hypergraphia. Dissociation between speech and writing behavior was present in our patient. We suggest that a disconnection within the frontal-subcortical circuit contributed to the development of motor perseveration in writing. PMID- 20847926 TI - Woman with Sickle Cell Disease with Current Sigmoid Sinus Thrombosis and History of Inadequate Warfarin Use during a Past Thrombotic Event. AB - We report a 20-year-old woman with sickle cell disease (SCD) who presented with a severe pulsating headache, nausea, and vomiting. Her history was significant for a past thrombotic event during which she had not used anticoagulation therapy as prescribed. Her mental status was mildly confused. On funduscopic examination, papilledema and retinal hemorrhages were found. Results of a computed tomogram were normal. A lumbar puncture demonstrated increased intracranial pressure (60 cm H(2)O). Magnetic resonance venography demonstrated a right sigmoid sinus thrombosis. Although SCD has been reported as a cause of thrombotic dural venous sinus events, this case increases the knowledge about neurological complications of SCD. The patient was treated with low molecular weight heparin, blood transfusions, acetazolamide, and methylprednisolone, and her symptoms and signs resolved. PMID- 20847927 TI - Unruptured Cerebral Aneurysm Detected after Intravenous Tissue Plasminogen Activator for Stroke. AB - Therapeutic guidelines of intravenous thrombolysis with tissue plasminogen activator (tPA) for hyperacute ischemic stroke are very strict. Because of potential higher risk of bleeding complications, the presence of unruptured cerebral aneurysm is a contraindication for systemic thrombolysis with tPA. According to the standard CT criteria, a 66-year-old woman who suddenly developed aphasia and hemiparesis received intravenous tPA within 3 h after ischemic stroke. Magnetic resonance angiography during tPA infusion was performed and the presence of a small unruptured cerebral aneurysm was suspected at the anterior communicating artery. Delayed cerebral angiography confirmed an aneurysm with a size of 7 mm. The patient did not experience any adverse complications associated with the aneurysm. Clinical experiences of this kind of accidental off-label thrombolysis may contribute to modify the current rigid tPA guidelines for stroke. PMID- 20847928 TI - Safety Profile and Clinical Recommendations for the Use of Lapatinib. AB - SUMMARY: The toxicity profile of agents blocking the epidermal growth factor receptor pathway excludes many of the severe side effects commonly observed with cytotoxic chemotherapy. Like other tyrosine kinase inhibitors, lapatinib is generally well tolerated. Lapatinib exhibits specific toxicities, the most common being diarrhea and rash, which are mostly mild to moderate in severity. Cardiac toxicity is rarely seen with lapatinib. Generally, lapatinib-associated toxicities are manageable. PMID- 20847929 TI - Future Roles of Lapatinib in ErbB2-Positive Breast Cancer: Adjuvant and Neoadjuvant Trials. AB - SUMMARY: Lapatinib is potentially an ideal therapy for the adjuvant and neoadjuvant treatment of women with breast cancer due to its convenience of use (oral, once-daily administration) and because it has shown activity in the first line and refractory metastatic settings. Furthermore, the dual tyrosine kinase inhibitor appears to have a low incidence of cardiotoxicity, and may decrease the rate of later brain metastases. Therefore, several cooperative groups and academic centers have initiated trials investigating lapatinib in the treatment of early-stage ErbB2 (HER2)-overexpressing breast cancer. PMID- 20847931 TI - 'Above All: We Want to Live, and Hope for Cure' PMID- 20847930 TI - Perspectives: Other ErbB2-Targeted Therapies. AB - SUMMARY: Despite the success of individualized targeted therapies in women with breast cancer with current available compounds, new drugs - especially with different mechanisms of resistance - are under development. A range of novel targeted agents for women with tumors that overexpress ErbB2 (HER2) and progress on trastuzumab and lapatinib have entered clinical studies. Most of these agents are monoclonal antibodies or multifunctional tyrosine kinase inhibitors. Recently published data even showed encouraging synergistic effects of several new substances, which in the future could pose as a chemotherapy-free treatment option in the metastatic setting. PMID- 20847932 TI - Feasibility of bariatric surgery as a strategy for secondary prevention in cardiovascular disease: a report from the Swedish obese subjects trial. AB - Aims. Evaluation of bariatric surgery as secondary prevention in obese patients with ischemic heart disease (IHD). Methods. Analysis of data from 4047 subjects in the Swedish Obese Subjects (SOSs) study. Thirty-five patients with IHD are treated with bariatric surgery (n = 21) or conventional treatment (n = 14). Mean follow-up is 10.8 years. Results. Bariatric surgery resulted in sustained weight loss during the study period. After 2 years, the surgery group displayed significant reductions in cardiovascular risk factors, relief from cardiorespiratory symptoms, increments in physical activity, and improved quality of life. After 10 years, recovery from hypertension, diabetes, physical inactivity, and depression was still more common in the surgery group. There were no signs of increased cardiovascular morbidity or mortality in the surgery group. Conclusion. Bariatric surgery appears to be a safe and feasible treatment to achieve long-term weight loss and improvement in cardiovascular risk factors, symptoms, and quality of life in obese subjects with IHD. PMID- 20847934 TI - Impact of HIV/Aids on Child Mortality before the Highly Active Antiretroviral Therapy Era: A Study in Pointe-Noire, Republic of Congo. AB - Few studies have documented the contribution of HIV/AIDS to mortality among children under 15 years. From June 30 to October 19, 2001, all child deaths (n = 588) registered to the morgue and/or hospitals of the city of Pointe-Noire, Congo, were investigated using a combined approach including an interview of relatives and postmortem clinical and biological HIV diagnosis. Twenty-one percent of children were HIV positive, while 10.5% of deaths were attributed to AIDS. The most common causes of death in HIV-infected children were pneumonia (30%), pyrexia (22%), diarrhoea (16%) and wasting syndrome (16%). Infant mortality rate was estimated 6.3 times higher in children born to HIV-infected mothers compared to HIV-uninfected mothers. This study provides a direct measure of HIV/AIDS as impact on child mortality using a rapid and reliable method. A significant number of deaths could be prevented if HIV infection was diagnosed earlier and infants were provided with antiretroviral treatments. PMID- 20847933 TI - Selenocysteine, pyrrolysine, and the unique energy metabolism of methanogenic archaea. AB - Methanogenic archaea are a group of strictly anaerobic microorganisms characterized by their strict dependence on the process of methanogenesis for energy conservation. Among the archaea, they are also the only known group synthesizing proteins containing selenocysteine or pyrrolysine. All but one of the known archaeal pyrrolysine-containing and all but two of the confirmed archaeal selenocysteine-containing protein are involved in methanogenesis. Synthesis of these proteins proceeds through suppression of translational stop codons but otherwise the two systems are fundamentally different. This paper highlights these differences and summarizes the recent developments in selenocysteine- and pyrrolysine-related research on archaea and aims to put this knowledge into the context of their unique energy metabolism. PMID- 20847935 TI - Involvement of Fatty Acid Binding Protein 5 and PPARbeta/delta in Prostate Cancer Cell Growth. AB - Fatty acid binding protein 5 (FABP5) delivers ligands from the cytosol directly to the nuclear receptor PPARbeta/delta and thus facilitates the ligation and enhances the transcriptional activity of the receptor. We show here that expression levels of both FABP5 and PPARbeta/delta are correlated with the tumorigenic potential of prostate cancer cell lines. We show further that FABP5 comprises a direct target gene for PPARbeta/delta and thus the binding protein and its cognate receptor are engaged in a positive feedback loop. The observations demonstrate that, similarly to effects observed in mammary carcinomas, activation of the FABP5/PPARbeta/delta pathway induces PPARbeta/delta target genes involved in cell survival and growth and enhances cell proliferation and anchorage-independent growth in prostate cancer cells. Furthermore, the data show that downregulation of either FABP5 or PPARbeta/delta inhibits the growth of the highly malignant prostate cancer PC3M cells. These studies suggest that the FABP5/PPARbeta/delta pathway may play a general role in facilitating tumor progression and that inhibition of the pathway may comprise a novel strategy in treatment of cancer. PMID- 20847937 TI - Fertilization rate and number of embryos on day 2 after intrauterine and deep intrauterine insemination using frozen-thawed boar semen in multiparous sows. AB - The present study determines fertilization rate and number of embryos on Day 2 after intrauterine insemination (IUI) and deep intrauterine insemination (DIUI) using frozen-thawed (FT) boar semen in multiparous sows. Twelve crossbred Landrace * Yorkshire multiparous sows were included. The sows were inseminated at 24 h after oestrus detection and reinseminated every 12 h until ovulation took place. The inseminations were conducted using IUI with 2 * 10(9) FT sperm per dose (n = 6) and DIUI with 1 * 10(9) FT sperm per dose (n = 6). The sows were slaughtered at 45.1 +/- 7.2 h after ovulation. Embryos and unfertilized oocytes were flushed from the oviducts. IUI yielded a better fertilization rate than DIUI (66.0% versus 31.0%, P < .001). The number of embryos was 13.5 +/- 2.7 and 6.6 +/ 3.2 embryos/sow in IUI and DIUI groups, respectively (P = .08). The proportion of sows having unilateral fertilization was higher in the DIUI (3/5) than the IUI group (1/6). In conclusion, IUI with at least 2 * 10(9) total number of FT boar spermatozoa is recommended. PMID- 20847936 TI - Toll-like receptors: role in dermatological disease. AB - Toll-like receptors (TLRs) are a class of conserved receptors that recognize pathogen-associated molecular patterns (PAMPs) present in microbes. In humans, at least ten TLRs have been identified, and their recognition targets range from bacterial endotoxins to lipopeptides, DNA, dsRNA, ssRNA, fungal products, and several host factors. Of dermatological interest, these receptors are expressed on several skin cells including keratinocytes, melanocytes, and Langerhans cells. TLRs are essential in identifying microbial products and are known to link the innate and adaptive immune systems. Over the years, there have been significant advances in our understanding of TLRs in skin inflammation, cutaneous malignancies, and defence mechanisms. In this paper, we will describe the association between TLRs and various skin pathologies and discuss proposed TLR therapeutics. PMID- 20847938 TI - Differential Dynamics of ATR-Mediated Checkpoint Regulators. AB - The ATR-Chk1 checkpoint pathway is activated by UV-induced DNA lesions and replication stress. Little was known about the spatio and temporal behaviour of the proteins involved, and we, therefore, examined the behaviour of the ATRIP-ATR and Rad9-Rad1-Hus1 putative DNA damage sensor complexes and the downstream effector kinase Chk1. We developed assays for the generation and validation of stable cell lines expressing GFP-fusion proteins. Photobleaching experiments in living cells expressing these fusions indicated that after UV-induced DNA damage, ATRIP associates more transiently with damaged chromatin than members of the Rad9 Rad1-Hus1 complex. Interestingly, ATRIP directly associated with locally induced UV damage, whereas Rad9 bound in a cooperative manner, which can be explained by the Rad17-dependent loading of Rad9 onto damaged chromatin. Although Chk1 dissociates from the chromatin upon UV damage, no change in the mobility of GFP Chk1 was observed, supporting the notion that Chk1 is a highly dynamic protein. PMID- 20847939 TI - The Enigma of Tripeptidyl-Peptidase II: Dual Roles in Housekeeping and Stress. AB - The tripeptidyl-peptidase II complex consists of repeated 138 kDa subunits, assembled into two twisted strands that form a high molecular weight complex (>5 MDa). TPPII, like many other cytosolic peptidases, plays a role in the ubiquitin proteasome pathway downstream of the proteasome as well as in the production and destruction of MHC class I antigens and degradation of neuropeptides. Tripeptidyl peptidase II activity is increased in cells with an increased demand for protein degradation, but whether degradation of cytosolic peptides is the only cell biological role for TPPII has remained unclear. Recent data indicated that TPPII translocates into the nucleus to control DNA damage responses in malignant cells, supporting that cytosolic "housekeeping peptidases" may have additional roles in cell biology, besides their contribution to protein turnover. Overall, TPPII has an emerging importance in several cancer-related fields, such as metabolism, cell death control, and control of genome integrity; roles that are not understood in detail. The present paper reviews the cell biology of TPPII and discusses distinct roles for TPPII in the nucleus and cytosol. PMID- 20847940 TI - Contrast-Enhanced Dynamic MR Imaging of Uterine Fibroids as a Potential Predictor of Patient Eligibility for MR Guided Focused Ultrasound (MRgFUS) Treatment for Symptomatic Uterine Fibroids. AB - Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a non-invasive treatment approach for symptomatic uterine fibroids. One imaging characteristic considered in selecting patients who may benefit from MRgFUS of their uterine fibroids is the signal intensity of the fibroid compared with surrounding myometrium on T2-weighted MR images. Previous reports suggest that hyper-intense fibroids are less amenable to MRgFUS compared with iso- or hypo-intense fibroids. In this case study, we utilized contrast-enhanced dynamic MR imaging to further characterize the vascularity of a hyper-intense fibroid. Based on the results of dynamic T1-weighted contrast-enhanced images, we assumed that the hyper-intense appearance resulted from high fluid content rather than high vascularity and predicted that the fibroid would respond to MRgFUS. The patient underwent the MRgFUS without complication and reported significant decrease in fibroid symptoms at 3 and 12 months post-treatment. This case suggests that pre-treatment dynamic contrast-enhanced imaging used in conjunction with T2-weighted imaging may improve the criteria for selecting uterine fibroids amenable to treatment with MRgFUS, potentially leading to improved patient outcomes. PMID- 20847942 TI - Mouse WRN Helicase Domain Is Not Required for Spontaneous Homologous Recombination-Mediated DNA Deletion. AB - Werner syndrome is a rare disorder that manifests as premature aging and age related diseases. WRN is the gene mutated in WS, and is one of five human RecQ helicase family members. WS cells exhibit genomic instability and altered proliferation, and in vitro studies suggest that WRN has a role in suppressing homologous recombination. However, more recent studies propose that other RecQ helicases (including WRN) promote early events of homologous recombination. To study the role of WRN helicase on spontaneous homologous recombination, we obtained a mouse with a deleted WRN helicase domain and combined it with the in vivo pink-eyed unstable homologous recombination system. In this paper, we demonstrate that WRN helicase is not necessary for suppressing homologous recombination in vivo contrary to previous reports using a similar mouse model. PMID- 20847941 TI - The Role of PPARalpha Activation in Liver and Muscle. AB - PPARalpha is one of three members of the soluble nuclear receptor family called peroxisome proliferator-activated receptor (PPAR). It is a sensor for changes in levels of fatty acids and their derivatives that responds to ligand binding with PPAR target gene transcription, inasmuch as it can influence physiological homeostasis, including lipid and carbohydrate metabolism in various tissues. In this paper we summarize the involvement of PPARalpha in the metabolically active tissues liver and skeletal muscle and provide an overview of the risks and benefits of ligand activation of PPARalpha, with particular consideration to interspecies differences. PMID- 20847943 TI - Controversies in the management of endometrial cancer. PMID- 20847944 TI - Adaptive radiation therapy for head and neck cancer-can an old goal evolve into a new standard? AB - Current head and neck intensity-modulated radiotherapy (IMRT) techniques cause significant toxicity. This may be explained in part by the fact that IMRT cannot compensate for changes in the location of disease and normal anatomy during treatment, leading to exposure of at-risk bystander tissues to higher-than anticipated doses. Adaptive radiotherapy (ART) is a novel approach to correct for daily tumor and normal tissue variations through online or offline modification of original IMRT target volumes and plans. ART has been discussed on a conceptual level for many years, but technical limitations have hampered its integration into routine care. In this paper, we review the key anatomic, dosimetric, and treatment delivery issues at play in current investigational development of head and neck ART. We also describe pilot findings from initial clinical deployment of head and neck ART, as well as emerging pathways of future research. PMID- 20847945 TI - Long-term outcomes for patients with prostate cancer having intermediate and high risk disease, treated with combination external beam irradiation and brachytherapy. AB - Background. Perception remains that brachytherapy-based regimens are inappropriate for patients having increased risk of extracapsular extension (ECE). Methods. 321 consecutive intermediate and high-risk disease patients were treated between 1/92 and 2/97 by one author (M. Dattoli) and stratified by NCCN guidelines. 157 had intermediate-risk; 164 had high-risk disease. All were treated using the combination EBRT/brachytherapy +/- hormones. Biochemical failure was defined using PSA >0.2 and nadir +2 at last followup. Nonfailing patients followup was median 10.5 years. Both biochemical data and original biopsy slides were independently rereviewed at an outside institution. Results. Overall actuarial freedom from biochemical progression at 16 years was 82% (89% intermediate, 74% high-risk) with failure predictors: Gleason score (P = .01) and PSA (P = .03). Hormonal therapy did not affect failure rates (P = .14). Conclusion. This study helps to strengthen the rationale for brachytherapy-based regimens as being both durable and desirable treatment options for such patients. Prospective studies are justified to confirm these positive results. PMID- 20847946 TI - Regulation of PPARgamma Coactivator-1alpha Function and Expression in Muscle: Effect of Exercise. AB - PPARgamma coactivator-1alpha (PGC-1alpha) is considered to be a major regulator of mitochondrial biogenesis. Though first discovered in brown adipose tissue, this coactivator has emerged as a coordinator of mitochondrial biogenesis in skeletal muscle via enhanced transcription of many nuclear genes encoding mitochondrial proteins. Stimuli such as exercise provoke the activation of signalling cascades that lead to the induction of PGC-1alpha. Posttranslational modifications also regulate the function of PGC-1alpha, with a multitude of upstream molecules targeting the protein to modify its activity and/or expression. Previous research has established a positive correlation between resistance to fatigue and skeletal muscle mitochondrial content. Recently, studies have begun to elucidate the specific role of PGC-1alpha in exercise related skeletal muscle adaptations, with several studies identifying it as a dominant regulator of organelle synthesis. This paper will highlight the function, regulation, and expression of PGC-1alpha, as well as the role of the coactivator during exercise adaptations. PMID- 20847947 TI - DNA polymerase: structural homology, conformational dynamics, and the effects of carcinogenic DNA adducts. AB - DNA replication is vital for an organism to proliferate and lying at the heart of this process is the enzyme DNA polymerase. Most DNA polymerases have a similar three dimensional fold, akin to a human right hand, despite differences in sequence homology. This structural homology would predict a relatively unvarying mechanism for DNA synthesis yet various polymerases exhibit markedly different properties on similar substrates, indicative of each type of polymerase being prescribed to a specific role in DNA replication. Several key conformational steps, discrete states, and structural moieties have been identified that contribute to the array of properties the polymerases exhibit. The ability of carcinogenic adducts to interfere with conformational processes by directly interacting with the protein explicates the mutagenic consequences these adducts impose. Recent studies have identified novel states that have been hypothesised to test the fit of the nascent base pair, and have also shown the enzyme to possess a lively quality by continually sampling various conformations. This review focuses on the homologous structural changes that take place in various DNA polymerases, both replicative and those involved in adduct bypass, the role these changes play in selection of a correct substrate, and how the presence of bulky carcinogenic adducts affects these changes. PMID- 20847948 TI - In Vitro Susceptibility of Canine Influenza A (H3N8) Virus to Nitazoxanide and Tizoxanide. AB - Infection of dogs with canine influenza virus (CIV) is considered widespread throughout the United States following the first isolation of CIV in 2004. While vaccination against influenza A infection is a common and important practice for disease control, antiviral therapy can serve as a valuable adjunct in controlling the impact of the disease. In this study, we examined the antiviral activity of nitazoxanide (NTZ) and tizoxanide (TIZ) against three CIV isolates in vitro. NTZ and TIZ inhibited virus replication of all CIVs with 50% and 90% inhibitory concentrations ranging from 0.17 to 0.21 MUM and from 0.60 to 0.76 MUM, respectively. These results suggest that NTZ and TIZ are effective against CIV and may be useful for treatment of canine influenza in dogs but further investigation of the in vivo efficacy against CIV as well as the drug's potential for toxicity in dogs is needed. PMID- 20847949 TI - An unusual cause of vertebral artery dissection: esophagogastroduodenoscopy. AB - Brain-supplying arterial dissection is considered one of the most common vascular causes of stroke in younger patients. Dissections are usually preceded by trauma or mechanical stress; the vascular stressor may be trivial as this condition has been described in association with manipulation and stretching the neck. Here we describe a case of vertebral artery dissection and stroke following esophagogastroduodenoscopy. This case highlights a potentially serious complication that may occur after procedures that require hyperextension of the neck. PMID- 20847950 TI - Renal cell carcinoma mimicking adrenal tumor. AB - There are a variety of causes of adrenal pseudotumors on computerized tomography (CT) scan, including upper-pole renal mass, gastric diverticulum, prominent splenic lobulation, pancreatic mass, hepatic mass, and periadrenal varices. We present a case of a large subhepatic mass that discrimination of its origin from neighborhood organs was difficult preoperatively. Our patient was a 58 years old man, that three months after an unsuccessful operation in another center for a pseudoadrenal mass underwent a very difficult subcapsular tumorectomy in our center. PMID- 20847951 TI - Hyperphosphorylated FAK Delocalizes from Focal Adhesions to Membrane Ruffles. AB - Cell adhesion and migration are key determinants in tumor metastasis. Adherence of tumor cell to the extracellular matrix is mediated via integrin containing focal adhesions (FAs). Binding of integrins to ECM triggers phosphorylation of two major components of FAs, focal adhesion kinase (FAK) and Src, activating downstream signaling pathway which leads to FA disassembly and cell migration. In this paper, we analyze how phosphorylation of FAK regulates its trafficking at FAs in living human astrocytoma cells. Upon pervanadate-induced FAK phosphorylation, phosphorylated FAK appeared highly expressed at newly formed membrane ruffles. This effect was abolished in presence of the specific Src inhibitor PP2. Our findings demonstrate that upon phosphorylation, FAK delocalizes from FAs to membrane ruffles. PMID- 20847952 TI - Role of Topoisomerase IIbeta in DNA Damage Response following IR and Etoposide. AB - The role of topoisomerase IIbeta was investigated in cell lines exposed to two DNA damaging agents, ionising radiation (IR) or etoposide, a drug which acts on topoisomerase II. The appearance and resolution of gammaH2AX foci in murine embryonic fibroblast cell lines, wild type and null for DNA topoisomerase IIbeta, was measured after exposure to ionising radiation (IR) or etoposide. Topoisomerase II-DNA adduct levels were also measured. IR rapidly triggered phosphorylation of histone H2AX, less phosphorylation was seen in TOP2beta(-/-) cells, but the difference was not statistically significant. IR did not produce topoisomerase II-DNA adducts above control levels. Etoposide triggered the formation of topoisomerase II-DNA adducts and the phosphorylation of histone H2AX, the gammaH2AX foci appeared more slowly with etoposide than with IR. Topoisomerase II-DNA complexes in WT cells but not TOP2beta(-/-) cells increased significantly at 24 hours with the proteasome inhibitor MG132, suggesting topoisomerase IIbeta adducts are removed by the proteasome. PMID- 20847953 TI - Two-stage liver transplantation with temporary porto-middle hepatic vein shunt. AB - Two-stage liver transplantation (LT) has been reported for cases of fulminant liver failure that can lead to toxic hepatic syndrome, or massive hemorrhages resulting in uncontrollable bleeding. Technically, the first stage of the procedure consists of a total hepatectomy with preservation of the recipient's inferior vena cava (IVC), followed by the creation of a temporary end-to-side porto-caval shunt (TPCS). The second stage consists of removing the TPCS and implanting a liver graft when one becomes available. We report a case of a two stage total hepatectomy and LT in which a temporary end-to-end anastomosis between the portal vein and the middle hepatic vein (TPMHV) was performed as an alternative to the classic end-to-end TPCS. The creation of a TPMHV proved technically feasible and showed some advantages compared to the standard TPCS. In cases in which a two-stage LT with side-to-side caval reconstruction is utilized, TPMHV can be considered as a safe and effective alternative to standard TPCS. PMID- 20847954 TI - Activation of CD147 with cyclophilin a induces the expression of IFITM1 through ERK and PI3K in THP-1 cells. AB - CD147, as a receptor for Cyclophilins, is a multifunctional transmembrane glycoprotein. In order to identify genes that are induced by activation of CD147, THP-1 cells were stimulated with Cyclophilin A and differentially expressed genes were detected using PCR-based analysis. Interferon-induced transmembrane 1 (IFITM1) was detected to be induced and it was confirmed by RT-PCR and Western blot analysis. CD147-induced expression of IFITM1 was blocked by inhibitors of ERK, PI3K, or NF-kappaB, but not by inhibitors of p38, JNK, or PKC. IFITM1 appears to mediate inflammatory activation of THP-1 cells since cross-linking of IFITM1 with specific monoclonal antibody against it induced the expression of proinflammatory mediators such as IL-8 and MMP-9. These data indicate that IFITM1 is one of the pro-inflammatory mediators that are induced by signaling initiated by the activation of CD147 in macrophages and activation of ERK, PI3K, and NF kappaB is required for the expression of IFITM1. PMID- 20847955 TI - Retinal Nerve Fiber Layer Decrease during Glycemic Control in Type 2 Diabetes. AB - Purpose. To assess an effect of glycemic control on retinal nerve fiber layer (RNFL) in type 2 diabetes mellitus. Methods. Thirty-eight eyes of 38 patients with type 2 diabetes undergoing blood glucose regulation were enrolled. All patients were examined at (1) initial visit, (2) 1 month, (3) 2 months, and (4) 4 month after the initial examination. On each occasion, glycosylated hemoglobin (HbA1c) levels and optical coherence tomography (OCT) scanning for RNFL thickness were evaluated. 360 degree circular OCT scans with a diameter of 3.4 mm centered on the optic disc were performed. Results. Significant RNFL decrease was seen in the superior area between initial and 4 months examination (P = .043). The relationship between the changes in HbA1c and the changes in RNFL thickness was observed in superior, temporal, and inferior area (P < .05) at 4 months. Conclusions. This study suggests that the glycemic control affects RNFL within 4 months. PMID- 20847956 TI - Shrimp farming practices in the puttallam district of sri lanka: implications for disease control, industry sustainability, and rural development. AB - Shrimp farming has great potential to diversify and secure income in rural Sri Lanka, but production has significantly declined in recent years due to civil conflicts, some unsustainable practices and devastating outbreaks of disease. We examined management practices affecting disease prevention and control in the Puttalam district to identify extension services outputs that could support sustainable development of Sri Lankan shrimp farming. A survey on 621 shrimp farms (603 operational and 18 nonoperational) was conducted within the Puttalam district over 42 weeks comprising a series of three-day field visits from August 2008 to October 2009, covering two consecutive shrimp crops. Fundamental deficits in disease control, management, and biosecurity practices were found. Farmers had knowledge of biosecurity but the lack of financial resources was a major impediment to improved disease control. Smallholder farmers were disproportionately constrained in their ability to enact basic biosecurity practices due to their economic status. Basic breaches in biosecurity will keep disease as the rate limiting step in this industry. Plans to support this industry must recognize the socioeconomic reality of rural Sri Lankan aquaculture. PMID- 20847957 TI - Hyperfunctioning solid/trabecular follicular carcinoma of the thyroid gland. AB - A 68-year-old woman with solid/trabecular follicular thyroid carcinoma inside of an autonomously functioning thyroid nodule is described in this paper. The patient was referred to our clinic for swelling of the neck and an increased pulse rate. Ultrasonography showed a slightly hypoechoic nodule in the right lobe of the thyroid. Despite suppressed TSH levels, the (99m)Tc-pertechnetate scan showed a hot area corresponding to the nodule with a suppressed uptake in the remaining thyroid tissue. Histopathological examination of the nodule revealed a solid/trabecular follicular thyroid carcinoma. To the best of our knowledge, this is the first case of hyperfunctioning follicular solid/trabecular carcinoma reported in the literature. Even if a hyperfunctioning thyroid carcinoma is an extremely rare malignancy, careful management is recommended so that a malignancy will not be overlooked in the hot thyroid nodules. PMID- 20847961 TI - Connecting cardiovascular clinical researchers through the CANadian Network and Centre for Trials INternationally (CANNeCTIN): achieving excellence through collaboration. PMID- 20847960 TI - Canadian Network and Centre for Trials Internationally (CANNeCTIN): a national network for Canadian-led trials in cardiovascular diseases and diabetes mellitus. AB - The Canadian Network and Centre for Trials INternationally (CANNeCTIN) was jointly funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation in April 2008 to provide infrastructure for clinical studies of cardiovascular diseases and diabetes mellitus. Its functional components include a national coordinating centre at the Population Health Research Institute (PHRI) in Hamilton (Ontario), a collaborative Canadian network and an affiliated international network of hospitals and clinics. The rationales for CANNeCTIN include the global health burden of cardiovascular diseases and diabetes, the strengths of randomized controlled trials - particularly large, multicentre and international - and the track record of success of the PHRI. CANNeCTIN will provide investigators from across Canada with opportunities to become the principal investigators of national and international trials coordinated by the PHRI. CANNeCTIN will support priority pilot studies, and successful investigators will be encouraged and assisted to apply for peer review and industrial funding for full studies to be conducted within the network and coordinated by the PHRI. An extensive education program offers hands-on experience in organizing and leading large national/international clinical trials led by accomplished researchers, distance learning courses in clinical research methodology, biostatistics and study coordination, and 'cutting-edge' workshops. A knowledge translation program seeks opportunities arising from clinical trials and encourages research into this paradigm for understanding how best to close the gaps between knowledge and effective practice. The five-year goals are to enhance the capacity of Canadian investigators to lead major clinical studies, facilitate knowledge translation and exchange, and augment Canada's capacity to train the next generation of leaders in cardiovascular and diabetes clinical research. PMID- 20847962 TI - Sex differences in coronary catheterization and revascularization following acute myocardial infarction: time trends from 1994 to 2003 in British Columbia. AB - BACKGROUND: Studies before the turn of the century reported sex differences in procedure rates. It is unknown whether these differences persist. OBJECTIVES: To examine time trends and sex differences in coronary catheterization and revascularization following acute myocardial infarction (AMI). METHODS: A retrospective analysis was performed of all patients 20 years of age or older who were admitted to hospital in British Columbia with an AMI between April 1, 1994, and March 31, 2003. Segmented regression analysis was used to examine the inflection point of the time trend in 90-day catheterization rates post-AMI. Multivariable Cox regression modelling was used to evaluate sex differences in receiving catheterization and revascularization following AMI. RESULTS: Ninety day coronary catheterization rates increased significantly over the study period for both men and women (P<0.0001 for trend), with a steeper increase beginning in September 2000. Women were less likely to undergo catheterization than men, even after adjustment for baseline differences; this sex effect was modified by age and care in the intensive care unit or cardiac care unit (ICU/CCU). Specifically, ICU/CCU admission eliminated the sex difference among patients who were younger than 65 years of age. Conditional on receiving cardiac catheterization post-AMI, female sex was not associated with a lower likelihood of receiving revascularization within one year (HR 0.96; 95% CI 0.91 to 1.02). CONCLUSIONS: Despite recent increases in catheterization rates post-AMI, women were less likely to undergo catheterization than men. Interestingly, access to ICU/CCU care removed the sex difference in catheterization access in patients younger than 65 years of age. PMID- 20847963 TI - Increased myocardial expression of angiopoietin-2 in patients undergoing urgent surgical revascularization for acute coronary syndromes. AB - BACKGROUND: Myocardial ischemia triggers the expression of multiple angiogenic factors including vascular endothelial growth factor and its receptors. However, vascular endothelial growth factor does not act in isolation. OBJECTIVE: To identify other genes important in the angiogenic response to clinically relevant myocardial ischemia. METHODS AND RESULTS: Paired intraoperative biopsies of ischemic and nonischemic myocardium were obtained from 12 patients with acute coronary syndromes (ACS) undergoing urgent coronary artery bypass graft surgery. Real-time polymerase chain reaction demonstrated significant upregulation of angiopoietin-2 (Ang-2) in ischemic myocardium, to a greater extent than other classical angiogenic factors. Microarray gene profiling identified Ang-2 to be among the top 10 differentially upregulated genes, in addition to genes involved in inflammation, cell signalling, remodelling and apoptosis. CONCLUSIONS: The present document is the first report of microarray analysis of patients with ACS, and supports an important role for Ang-2 in the angiogenic response to severe ischemia in the human heart. Common gene expression patterns in ACS may provide opportunities for targeted pharmacological and cellular intervention. PMID- 20847964 TI - Cor triatriatum sinistrum in childhood. A single institution's experience. AB - INTRODUCTION: Cor triatriatum sinistrum (CTS) is a rare congenital cardiac defect that can present with a wide range of symptoms and may be associated with other structural cardiac defects. Very limited data are available for pediatric patients. OBJECTIVE: To analyze the experience with CTS at a single pediatric centre, highlighting symptoms on presentation, mode of diagnosis and outcome. METHODS: Hospital databases were searched to identify patients with CTS who were diagnosed between 1954 and 2005. Medical records with demographic data, clinical evaluation, diagnostic approach, interventions and autopsy results were reviewed. RESULTS: Between 1954 and 2005, 82 patients (43 female children, 52%) with CTS were diagnosed at the institution. Patients were born between 1951 and 2004, and the median age at presentation was eight months (range one day to 16.1 years). The majority of patients (77%) presented with associated cardiac lesions. Of 82 patients, 57 (70%) underwent resection of the fibromuscular diaphragm, 14 (17%) did not require surgery and 11 (13%) did not survive the time to intervention. Nineteen patients (23%) died a median of two months (range one day to 5.5 years) after presentation. Nine of these patients (11%) died before surgery was attempted. Most patients were completely asymptomatic at the time of the last follow-up at a median of three years (range one day to 18 years). Echocardiography significantly facilitated the diagnosis and subsequent management of patients with CTS. CONCLUSIONS: Despite the diversity in presentation and complexity of associated lesions, the outcome for patients with CTS is favourable. PMID- 20847966 TI - Coronary artery calcium score by computed tomography: what does it mean? PMID- 20847965 TI - Prevalence of non-calcified coronary plaque on 64-slice computed tomography in asymptomatic patients with zero and low coronary artery calcium. AB - OBJECTIVES: To study the prevalence of noncalcified plaque in asymptomatic low risk patients with no or mild coronary artery calcium (CAC). METHODS: From 502 patients with coronary risk factors who underwent 64-slice computed tomography, 224 asymptomatic patients were identified with no CAC (n=117) or mild CAC (n=107; defined as patients with Agatston scores from 1 to 100). RESULTS: Patients with no CAC were younger and had diabetes less often. Medications and laboratory data were not significantly different between the two groups. The prevalence of noncalcified plaque was 11.1% in patients with no CAC and 23.4% in the mild CAC group (P=0.0142). Multiple plaques were detected in 2.6% of the group with no CAC and 3.7% of the group with mild CAC (P=0.5934). Significant coronary artery stenosis was found in one patient in the group with no CAC (0.9%) and three patients in the group with mild CAC (2.8%, P=0.3506). CONCLUSIONS: Significant percentages of noncalcified plaque were found in asymptomatic low-risk patients with no or mild coronary calcium. PMID- 20847967 TI - Late outcomes following percutaneous coronary interventions: results from a large, observational registry. AB - BACKGROUND: Randomized controlled trials report short- and medium- term outcomes following percutaneous coronary intervention (PCI), but their applicability to the general population is not known. Data regarding the long-term clinical outcomes of patients undergoing PCI are lacking. OBJECTIVE: To determine the long term outcomes of 'all-comers' undergoing PCI at a large-volume tertiary cardiac referral centre. METHODS: A total of 12,662 consecutive patients undergoing an index procedure and entered into the University Health Network's (Toronto, Ontario) prospective registry between April 2000 and September 2007 were identified. In-hospital outcomes were assessed. Follow-up data were obtained through linkage to a provincial registry. Kaplan-Meier analysis was performed to calculate unadjusted survival rates, and Cox multiple regression analysis identified independent predictors of late mortality, major adverse cardiac events and all cardiovascular events. RESULTS: The population included a relatively high risk patient cohort, with 19% older than 75 years of age, 28% with diabetes, 61% with multivessel disease and 1.3% in cardiogenic shock. Urgent procedures comprised 53% of all cases. The all-cause mortality rate at seven years follow-up was 10.6%. Repeat PCI occurred in 14.2% of patients, and coronary artery bypass grafting in 4.2%. Men showed a significant unadjusted survival advantage compared with women. Procedural characteristics such as incomplete revascularization and residual stenosis, in addition to established risk factors, were predictors of poorer long-term outcomes. Cardiogenic shock was the strongest predictor of late mortality. CONCLUSION: In the present large registry of 'all-comers' for PCI, longterm major adverse cardiac event rates were low and consistent with outcomes from randomized controlled trials. These data reflect a large cohort in real world clinical practice, and may help clinicians further characterize and better treat high-risk patients who are undergoing PCI. PMID- 20847968 TI - Validation of physician billing and hospitalization data to identify patients with ischemic heart disease using data from the Electronic Medical Record Administrative data Linked Database (EMRALD). AB - BACKGROUND: Reporting of ischemic heart disease (IHD) prevalence in Canada has been based on self-report or patients presenting to hospital. However, IHD often presents and can be managed in the outpatient setting. OBJECTIVES: To determine whether the combination of hospital data and physician billings could accurately identify patients with IHD. METHODS: A random sample of 969 adult patients from the Electronic Medical Record Administrative data Linked Database (EMRALD) - an electronic medical record database of primary care physicians in Ontario linked to administrative data for the province of Ontario - was used. A number of combinations of physician billing and hospital discharge abstracts were tested to determine the accuracy of using administrative data to identify IHD patients. RESULTS: Two physician billings within a one-year period (with one of the billings by a specialist or a family physician in a hospital or emergency room setting) or a hospital discharge abstract gave a sensitivity of 77.0% (95% CI 68.2% to 85.9%), a specificity of 98.0% (95% CI 97.0% to 98.9%), a positive predictive value of 78.8% (95% CI 70.1% to 87.5%), a negative predictive value of 97.7% (95% CI 96.8% to 98.7%) and a kappa of 0.76 (95% CI 0.68 to 0.83). CONCLUSIONS: A combination of physician billing and hospital discharge abstracts can be used to identify patients with IHD. Population prevalence of IHD can be measured using administrative data. PMID- 20847969 TI - Utilization patterns of extended-release niacin in Canada: analysis of an administrative claims database. AB - BACKGROUND AND OBJECTIVE: To evaluate utilization patterns with extended-release niacin (ERN) compared with those observed with other lipid-modifying drugs (LMDs). METHODS: A random sample of 17% of patients who had at least one LMD dispensation between January 2004 and February 2007 was obtained from the administrative databases of the Regie de l'assurance maladie du Quebec. Primary outcomes included drug adherence, persistence and discontinuation with ERN and other LMDs, and daily maintenance dose attainment (1500 mg and 2000 mg) with ERN at one-year follow-up. Adherence was defined as the sum of days of all dispensations divided by the total number of days of follow-up. Persistence was defined as renewal of prescription before the end of dispensation plus a grace period (50% prescription duration). RESULTS: Among 26,862 patients, the majority received statins (73.4%), whereas 867 (3.2%) received ERN. The mean age of ERN patients was 62 years and 75% were male. After one year, adherence with ERN was below that of statins (62.0% versus 74.9%), as was persistence (36.1% versus 46.7%), while discontinuation rates were higher (64.0% versus 53.3%). The median time until discontinuation for ERN was shorter than for statins (66 days versus 99 days). After one year, 5.8% of patients were taking 1500 mg or more and 3.2% were on 2000 mg. CONCLUSIONS: In the present cohort of patients from regular clinical practice in Quebec, ERN use was associated with low prescription rates, inferior adherence and persistence compared with other LMDs, high discontinuation rates, and very low 2000 mg dose attainment. PMID- 20847970 TI - Invasive cardiac procedure use and mortality among South Asian and Chinese Canadians with coronary artery disease. AB - BACKGROUND: Previous studies evaluated cardiac procedure use and outcome over the short term, with relatively few Asian patients included. OBJECTIVES: To determine the likelihood of undergoing percutaneous coronary intervention and coronary artery bypass grafting, and survival during 10.5 years of follow-up after coronary angiography among South Asian, Chinese and other Canadian patients. METHODS: Using prospective cohort study data from two large Canadian provinces, 3061 South Asian, 1473 Chinese and 77,314 other Canadian patients with angiographically proven coronary artery disease from 1995 to 2004 were assessed, and their revascularization and mortality rates during 10.5 years of follow-up were determined. RESULTS: Compared with other Canadian patients, South Asian and Chinese patients were slightly less likely to undergo revascularization (riskadjusted HR 0.94, 95% CI 0.90 to 0.98 for South Asian patients; and HR 0.94, 95% CI 0.88 to 1.00 for Chinese patients). However, South Asian patients underwent coronary artery bypass grafting (HR 1.00, 95% CI 0.94 to 1.07) and Chinese patients underwent percutaneous coronary intervention (HR 0.96, 95% CI 0.89 to 1.04) as frequently as other Canadian patients. Although the 30-day mortality rate was similar across the three ethnic groups, the mortality rate in the follow-up period was significantly lower for South Asian patients (HR 0.76, 95% CI 0.61 to 0.95) and marginally lower for Chinese patients (HR 0.80, 95% CI 0.60 to 1.07) compared with other Canadian patients. CONCLUSIONS: South Asian and Chinese patients used revascularization slightly less but had better survival outcomes than other Canadian patients. The factors underlying the better outcomes for South Asian and Chinese patients warrant further study. PMID- 20847971 TI - Thirty-day in-hospital revascularization and mortality rates after acute myocardial infarction in seven Canadian provinces. AB - BACKGROUND: Recent clinical trials have demonstrated benefit with early revascularization following acute myocardial infarction (AMI). Trends in and the association between early revascularization after (ie, 30 days or fewer) AMI and early death were determined. METHODS AND RESULTS: The Statistics Canada Health Person-Oriented Information Database, consisting of hospital discharge records for seven provinces from the Canadian Institute for Health Information Hospital Morbidity Database, was used. If there was no AMI in the preceding year, the first AMI visit within a fiscal year for a patient 20 years of age or older was included. Times to death in hospital and to revascularization procedures were counted from the admission date of the first AMI visit. Mixed model regression analyses with random slopes were used to assess the relationship between early revascularization and mortality. The overall rate of revascularization within 30 days of AMI increased significantly from 12.5% in 1995 to 37.4% in 2003, while the 30-day mortality rate decreased significantly from 13.5% to 10.6%. There was a linearly decreasing relationship - higher regional use of revascularization was associated with lower mortality in both men and women. CONCLUSIONS: These population-based utilization and outcome findings are consistent with clinical trial evidence of improved 30-day in-hospital mortality with increased early revascularization after AMI. PMID- 20847972 TI - Estimating the number of coronary artery bypass graft and percutaneous coronary intervention procedures in Canada: a comparison of cardiac registry and Canadian Institute for Health Information data sources. AB - BACKGROUND: Provincial cardiac registries and the Canadian Institute for Health Information (CIHI) pan-Canadian administrative databases are invaluable tools for understanding Canadian cardiovascular health and health care. Both sources are used to enumerate cardiovascular procedures performed in Canada. OBJECTIVE: To examine the level of agreement between provincial cardiac registry data and CIHI data regarding procedural counts for coronary artery bypass grafts (CABGs) and percutaneous coronary interventions (PCIs). METHODS: CIHI staff obtained CABG and PCI counts from seven provinces that, in 2004, performed these procedures and had a cardiac registry (ie, British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Nova Scotia, and Newfoundland and Labrador). Structured mail questionnaires, and e-mail and telephone follow-ups elicited information from a designated registry respondent. The CIHI derived its counts of CABG and PCI procedures by applying the geographical boundaries, procedural definitions and analytical case criteria used by the cardiac registries to CIHI inpatient and day procedure databases. Steps were taken to reduce double-counting procedures when combining results from the two CIHI databases. Two measures were calculated: the absolute difference between registry and CIHI estimates, and the per cent agreement between estimates from the two sources. RESULTS: All seven cardiac registries identified as eligible for the study participated. Agreement was high between the two sources for CABG (98.8%). For PCI, the level of agreement was high (97.9%) when CIHI sources were supplemented with day procedure data from Alberta. CONCLUSIONS: The high level of agreement between cardiac registry and CIHI administrative data should increase confidence in estimates of CABG and PCI counts derived from these sources. PMID- 20847973 TI - Mode of onset of polymorphic ventricular tachycardia in acute myocardial infarction. AB - BACKGROUND: Polymorphic ventricular tachycardia (PVT) can occur during acute myocardial infarction (MI). In the past, studies investigated the initiation pattern of ventricular tachycardias in different patient populations; however, the mode of onset of PVT in acute MI patients has not been investigated previously. OBJECTIVE: To retrospectively investigate the electrophysiological features of PVT with different initiation patterns in acute MI patients to assess whether there is a relationship of the initiation patterns of PVT with clinical and electrophysiological characteristics. METHODS: Sixty-two rhythm strips defined as PVT from 53 patients (mean [+/- SD] age 63+/-8 years) with acute ST elevation MI were analyzed. All patients were monitored while they were hospitalized in the coronary care unit, and the electrocardiogram strips were obtained from continuous monitoring. PVT was defined as sudden-onset tachycardia if it was not preceded by ventricular ectopic beats. PVT that was preceded by single or multiple ectopic beats was defined as nonsudden-onset tachycardia. RESULTS: Nonsudden-onset episodes were more common than suddenonset episodes (40 episodes [64.5%] versus 22 episodes [35.5%]). In the nonsudden-onset group, 25 episodes (62.5%) were initiated after a single ectopic beat, while 15 episodes (37.5%) were initiated after multiple complexes. The mean (+/- SD) left ventricular ejection fraction of patients with nonsudden-onset PVT was decreased (53+/-6% versus 65+/-7%, P<0.01). Nonsudden-onset tachycardias had lower coupling intervals than suddenonset tachycardias. Similarly, the PVT cycle length was shorter in the presence of nonsudden-onset initiation. When nonsudden-onset PVT episodes were further subclassified based on the morphology of the first beat of tachycardia, 26 PVTs (65%) had a first beat of tachycardia similar to the subsequent PVT beats and 14 (35%) did not. CONCLUSIONS: These results demonstrate that PVT is often preceded by ventricular ectopy in acute MI patients. Nonsudden onset PVT is usually characterized by a lower coupling interval, shorter PVT cycle length and an associated lower ejection fraction. PMID- 20847974 TI - Ultrastructural changes in atherosclerotic plaques following the instillation of airborne particulate matter into the lungs of rabbits. AB - BACKGROUND: Epidemiological studies have established that cardiovascular events account for the greatest number of air pollution-related deaths. However, the underlying structural changes are still unknown. OBJECTIVE: To investigate changes in the ultrastructure of atherosclerotic plaques in Watanabe heritable hyperlipidemic (WHHL) rabbits following the instillation of ambient particulate matter air pollution (particles smaller than 10 um in diameter) into the lungs. METHODS: WHHL rabbits (n=8) exposed to 5 mg of ambient particles (Environmental Health Centre - 1993 [EHC-93]; suspended in saline and instilled in the airway) twice per week for four weeks were compared with control WHHL rabbits (n=8) treated with saline alone. RESULTS: All abdominal aortic plaques were examined using light and electron microscopy, which showed the following: increased accumulation of macrophage-derived foam cells immediately below the endothelial plaque surface (P=0.04); increased contact between these foam cells and the dense subendothelial extracellular matrix (P<0.005) with reduction (P<0.0001) and fragmentation (P<0.0001) of this matrix; and emigration of macrophage- derived foam cells from the plaques in exposed rabbits. In addition, immunohistochemistry verified the presence of type IV collagen in the thickened extracellular matrix material subtending the endothelium. CONCLUSIONS: The ultrastructure of atherosclerotic plaques in EHC-93- instilled rabbits differed from the ultrastructure observed in rabbits that did not receive EHC-93. These ultrastructural differences are consistent with greater endothelial instability in the plaques of atherosclerosis-prone rabbits. PMID- 20847975 TI - Morphological changes in porcine bioprosthetic valves of a HeartMate left ventricular assist device. AB - A 27-year-old man who received a HeartMate (Thoratec Corporation, USA) left ventricular assist device for progressive heart failure as a bridge to orthotopic heart transplantation is described in the present report. The device failed (mechanical failure) after almost 19 months. The porcine bioprosthetic valves in the inflow and outflow cannulae showed hemorrhage, cusp tears and inflammatory cells, located largely on the inflow valve cusps. The role of the inflammatory cell reaction in the bioprosthetic valve is discussed. PMID- 20847976 TI - Cardiac sarcoidosis: recurrent disease in a heart transplant patient following pulmonary tuberculosis infection. AB - Cardiac transplantation is indicated for patients with end-stage cardiomyopathy secondary to cardiac sarcoidosis. Although rare, recurrent disease has been reported in two cases. The current report presents a case of recurrent cardiac sarcoidosis in a patient 45 months postorthotopic heart transplantation and 40 months following reactivation of latent Mycobacterium tuberculosis infection. The patient was the first to have recurrent disease following an infection that has been proposed to be involved in its pathogenesis. The patient's interval between transplant and recurrence is the longest reported to date. PMID- 20847977 TI - Left main mycotic aneurysm causing myocardial infarction. AB - Mycotic coronary aneurysms are rare, and simultaneous involvement of the left main, left anterior descending and circumflex arteries has never been described. In the present case, multislice computed tomography was an invaluable tool to adequately delineate the aneurysm from the surrounding structures and to plan cardiac surgery accordingly. PMID- 20847978 TI - Primary cardiac paraganglioma with dual coronary blood supply presenting with angina chest pain. AB - Primary cardiac paraganglioma (pheochromocytoma) is very rare, constituting only 1% of cardiac tumours. A case of a 44-year-old woman presenting with angina chest pain and a tumour with dual blood supply from both the right and left coronary arteries is reported. PMID- 20847979 TI - Right-sided endocarditis secondary to a peritoneovenous shunt. AB - A 51-year-old woman with a peritoneovenous shunt for refractory ascites presented with three months of increasing fatigue, exertional dyspnea, night sweats and positive blood cultures. Imaging revealed multiple pulmonary emboli. Transthoracic chocardiography demonstrated moderate tricuspid regurgitation and a large pedunculated right atrial mass attached to the interatrial septum. The echocardiographic appearance remained unchanged after one month of antibiotic therapy and nticoagulation. Intraoperatively, the mass was easily excised and the grossly abnormal tricuspid valve replaced. Pathology revealed endocarditis with multiple bacterial colonies, and fibromyxoid changes consistent with postinflammatory valve disease. PMID- 20847980 TI - Double-barrel stenting of distal left main stenosis in a patient with acute coronary syndrome: intravascular ultrasound and optical coherence tomography follow-up at six months. AB - A 58-year-old man presented with frequent episodes of angina at rest. A diagnosis of anterior non-ST elevation myocardial infarction was made. Coronary angiography performed on the day of admission revealed a significant stenosis (50% to 60%) of the distal left main stem (LMS) extending to the ostia of the left anterior descending and left circumflex arteries. Coronary artery bypass graft surgery was advised; however, the patient consistently declined this option. Kissing balloon predilation was performed at the LMS bifurcation, and two stents of the same diameter and length (4.0 mm * 18 mm) were simultaneously deployed at the same high pressure (18 atm) spanning the entire length of the LMS, and extending into the left anterior descending and left circumflex arteries beyond the bifurcation lesion. Six months later, intravascular ultrasound and optical coherence tomography revealed neointimal hyperplasia, especially in the artificial septum. PMID- 20847981 TI - Minimized extracorporeal circulation for the robotic totally endoscopic coronary artery bypass grafting hybrid procedure. AB - Robotically assisted totally endoscopic coronary artery bypass grafting (TECAB) can be performed on the beating heart with cardiopulmonary bypass support in high risk patients or patients for whom technical difficulties are expected with a complete off-pump approach. To minimize the inflammatory response and reduce the requirement for transfusion, minimized extracorporeal circulation is an attractive option for robotic TECAB procedures. The present report describes a case for which minimized extracorporeal circulation was used for the first time in TECAB performed using the da Vinci telemanipulation system. PMID- 20847982 TI - Redo aortic valve replacement due to bileaflet tear of a deteriorated bioprosthesis. PMID- 20847983 TI - When a bullet causes myocardial infarction. PMID- 20847984 TI - Prevention of cardiovascular risk factors: moving upstream. PMID- 20847985 TI - The impact of social determinants on cardiovascular disease. AB - Cardiovascular disease is the leading cause of death among high-income countries and is projected to be the leading cause of death worldwide by 2030. Much of the current research efforts have been aimed toward the identification, modification and treatment of individual-level risk factors. Despite significant advancements, gross inequalities continue to persist over space and time. Although increasing at different rates worldwide, the magnitude of increase in the prevalence of various cardiovascular risk factors has shifted research efforts to study the causes of the risk factors (ie, the 'causes of the causes'), which include the social determinants of health. The social determinants of health reflect the impact of the social environment on health among people sharing a particular community. Imbalances in the social determinants of health have been attributed to the inequities in health observed between and within countries. The present article reviews the role of the social determinants of health on a global level, describing the epidemiological transition and the persistent trend known as the 'inverse social gradient'. The impact of social determinants in Canada will also be examined, including data from ethnic and Aboriginal communities. Possible solutions and future directions to reduce the impact of social factors on cardiovascular health are proposed. PMID- 20847986 TI - Canadian efforts to prevent and control hypertension. AB - Suboptimum blood pressure is estimated to be the leading risk factor for death worldwide and is associated with 13.5% of deaths globally. The clinical diagnosis of hypertension affects one in four adults globally and is expected to increase by 60% between 2000 and 2025. Clearly, global efforts to prevent and control hypertension are important health issues. While Canada had a prevalence of hypertension similar to that of the United States in the early 1990 s, the treatment and control rate was only 13% compared with 25% in the United States. A national strategic plan was developed, and a coalition of organizations and health care professional and scientist volunteers actively implemented parts of the strategy. Specific initiatives that have evolved include the development of hypertension knowledge translation programs for health professionals, the public and people with hypertension, an outcomes research program to assess the impact of hypertension and guide national-, regional- and community-based knowledge translation interventions, and a program to reduce the prevalence of hypertension by decreasing sodium additives in food. These initiatives have relied on the active involvement of health care professional volunteers, health care professional and scientific organizations and various government departments. There have been large increases in the diagnosis and treatment of hypertension, with corresponding reductions in cardiovascular disease and total mortality associated with the start of the hypertension initiatives. As a result, Canada is becoming recognized as a world leader in the prevention, treatment and control of hypertension. PMID- 20847987 TI - Prevention of cardiovascular disease: obesity, diabetes and the metabolic syndrome. AB - The current obesity pandemic is expected to result in considerable downstream morbidity, mortality and incremental costs to health care systems around the world. The major metabolic complications of obesity - type 2 diabetes and the metabolic syndrome - are predicted to be particularly burdensome. Recent randomized controlled trials have demonstrated that lifestyle interventions resulting in modest weight losses are efficacious in delaying or preventing the development of type 2 diabetes in high-risk individuals. However, on a practical level, obesity prevention strategies and programs in the 'real world' have demonstrated limited effectiveness for weight reduction. It is likely that the best that can be expected from current preventive strategies, which have largely focused on modifying individual behaviour, is the prevention of further weight gain. Environmental, social, psychological and economic drivers of the obesity epidemic have, until recently, been underappreciated and underemphasized as contributors to the current pandemic. Future efforts will need to focus on these factors and pansocietal solutions will be required if success in reversing the population-wide weight increases that have occurred over the past several decades is to be achieved. PMID- 20847988 TI - Addressing poor nutrition to promote heart health: moving upstream. AB - Current dietary recommendations for cardiovascular disease prevention suggest dietary patterns that promote achieving healthy weight, emphasize vegetables, legumes, fruit, whole grains, fish and nuts, substituting mono-unsaturated fats for saturated fats and restricting dietary sodium to less than 2300 mg/day. However, trends in nutrient intake and food consumption patterns suggest that the need for improvement in the dietary patterns of Canadians is clear. Influencing eating behaviour requires more than addressing nutrition knowledge and perceptions of healthy eating - it requires tackling the context within which individuals make choices. A comprehensive approach to improving nutrition includes traditional downstream strategies such as counselling to improve knowledge and skills; midstream strategies such as using the media to change social norms; and upstream strategies such as creating supportive environments through public policy including regulatory measures. While the evidence base for more upstream strategies continues to grow, key examples of comprehensive approaches to population change provide a call to action. PMID- 20847989 TI - Updated guidelines for authors. PMID- 20847990 TI - Timing of implant placement after tooth extraction: immediate, immediate-delayed or delayed implants? A Cochrane systematic review. AB - This review is based on a Cochrane systematic review entitled 'Interventions for replacing missing teeth: dental implants in fresh extraction sockets (immediate, immediate-delayed and delayed implants)' published in The Cochrane Library (see http://www.cochrane.org/ for information). Cochrane systematic reviews are regularly updated to include new research, and in response to comments and criticisms from readers. If you wish to comment on this review, please send your comments to the Cochrane website or to Marco Esposito. The Cochrane Library should be consulted for the most recent version of the review. The results of a Cochrane review can be interpreted differently, depending on people's perspectives and circumstances. Please consider the conclusions presented carefully. They are the opinions of the review authors, and are not necessarily shared by the Cochrane Collaboration. PURPOSE: To evaluate success, complications, aesthetics and patient satisfaction among immediate, immediate delayed and delayed implants in post-extractive sockets and whether and when augmentation procedures are necessary and which is the most effective augmentation technique. MATERIALS AND METHODS: The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE were searched up to the 2nd of June 2010 for randomised controlled clinical trials (RCTs) with a follow-up of at least 1 year in function comparing immediate, immediate-delayed and delayed implants, or comparing various bone augmentation procedures around the inserted implants. Outcome measures were prosthesis and implant failures, complications, patient satisfaction and preference including aesthetics, aesthetics evaluated by a dentist, peri-implant marginal bone level changes, etc. Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. The statistical unit of the analysis was the patient. Results were expressed as fixed effects models using mean differences for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CIs). RESULTS: Fourteen eligible RCTs were identified but only seven trials could be included. Four RCTs evaluated implant placement timing. Two RCTs compared immediate versus delayed implants in 126 patients and found no statistically significant differences. One RCT compared immediate-delayed versus delayed implants in 46 patients. After 2 years, patients in the immediate-delayed group perceived the time to functional loading significantly shorter, were more satisfied and an independent blinded assessor judged the level of the peri-implant marginal mucosa in relation to that of the adjacent teeth as more appropriate (RR = 1.68; 95% CI 1.04 to 2.72). These differences disappeared 5 years after loading, and significantly more complications occurred in the immediate-delayed group (RR = 4.20; 95% CI 1.01 to 17.43). One RCT compared immediate with immediately delayed implants in 16 patients for 2 years and found no differences. Three RCTs evaluated different techniques of bone grafting for implants immediately placed in extraction sockets. No statistically significant differences were observed when evaluating whether autogenous bone is needed in post-extractive sites (one trial with 26 patients) or which was the most effective augmentation technique (two trials with 56 patients). CONCLUSIONS: There is insufficient evidence to determine the possible advantages or disadvantages of immediate, immediate-delayed or delayed implants, therefore these preliminary conclusions are based on few underpowered trials often judged to be at high risk of bias. There is a suggestion that immediate and immediate-delayed implants may be at a higher risk of implant failure and complications than delayed implants, on the other hand the aesthetic outcome might be better when placing implants just after tooth extraction. There is not enough reliable evidence supporting or refuting the need for augmentation procedures at immediate implants placed in fresh extraction sockets or whether any of the augmentation techniques is superior to the others. PMID- 20847991 TI - A 5-year report from a multicentre randomised clinical trial: immediate non occlusal versus early loading of dental implants in partially edentulous patients. AB - PURPOSE: To compare peri-implant bone and soft-tissue levels of immediately non occlusally loaded versus non-submerged early loaded implants in partially edentulous patients 5 years after implant placement. MATERIALS AND METHODS: Fifty two patients were randomised in five Italian private practices: 25 in the immediately loaded group and 27 in the early loaded group. To be immediately loaded, single implants had to be inserted with a torque of > 30 Ncm, and splinted implants with a torque of > 20 Ncm. Immediately loaded implants were provided with non-occluding temporary restorations within 48 hours. After 2 months, the provisional restorations were put in full occlusion. Implants were early loaded after 2 months. Final restorations were provided 8 months after implant placement. Outcome measures were prosthesis and implant failures as well as biological and prosthetic complications recorded by non-blinded assessors. Blinded assessors evaluated peri-implant bone and soft-tissue levels. RESULTS: Fifty-two implants were immediately loaded and 52 early loaded. One patient of the early loaded group dropped out after the 1-year recall. One single immediately loaded implant failed 2 months after placement. Only one complication (iatrogenic peri-implantitis) occurred in one patient of the early loading group. Both groups gradually lost peri-implant bone in a highly statistically significant way at 2, 8 and 14 months and at 4 and 5 years. After 5 years, patients of both groups had lost an average of 1.2 mm of peri-implant marginal bone. There were no statistically significant differences in peri-implant bone and soft-tissue level changes between the 2 groups. At 5 years, there was a statistically significant recession (0.2 mm) of the vestibular soft tissues from baseline (delivery of the final restorations 8 months after implant placement) only for immediately loaded implants. CONCLUSIONS: In well maintained patients, complications are uncommon and healthy and stable periimplant tissues can be maintained for 5 years around immediately and early loaded implants. PMID- 20847992 TI - Crestal sinus lift for implant rehabilitation: a randomised clinical trial comparing the Cosci and the Summers techniques. A preliminary report on complications and patient preference. AB - PURPOSE: To compare the effectiveness of two different techniques to lift the maxillary sinus via a crestal approach: the Summers versus the Cosci technique. MATERIALS AND METHODS: Fifteen partially edentulous patients missing bilaterally maxillary molars and/ or premolars having 4 to 7 mm of residual crestal height and at least 5 mm thickness below the maxillary sinuses measured on computed tomography scans were randomised to have implants placed in sinuses crestally lifted according to the Cosci or Summers technique with bone substitutes according to a split-mouth design. Implants were left to heal submerged for 6 months. Implants were loaded with acrylic provisional crowns/prostheses. Screw retained definitive metal-ceramic prostheses were delivered 4 months after provisional loading. Outcome measures were prosthesis and implant failures, any complications, operation time, operator preference, and patient preference assessed 1 month after surgery and 1 month after delivery of the final prostheses by a blinded outcome assessor. All patients were followed up to 5 months after loading (1 year after implant placement). RESULTS: Nineteen study implants were placed according to each technique. No patient dropped out and no implant failed. No discomfort/complications occurred at sites treated with the Cosci technique whereas 12 patients reported discomfort during the augmentation procedure at the side treated with the Summers technique, this was statistically significant, and in one of these patients a perforation of the sinus membrane occurred. Postoperatively, headache was reported by nine patients and swelling occurred in three of these patients at the Summers treated sides. Statistically significantly less time was required to place implants according to the Cosci technique (33 versus 24 minutes, on average). The two operators and 14 out of 15 patients preferred the Cosci technique. CONCLUSIONS: Both crestal sinus lift techniques were successful but the Cosci technique required less surgical time, produced less intra- and postoperative morbidity and was preferred by patients. PMID- 20847993 TI - The efficacy of platelet-rich plasma in grafted maxillae. A randomised clinical trial. AB - PURPOSE: The aim of this randomised, controlled, parallel-group clinical trial was to evaluate the clinical effect of platelet-rich plasma (PRP) on bone graft healing and implant integration in iliac crest grafted maxillae. MATERIALS AND METHODS: Twenty-two consenting patients were randomised to PRP (13 patients) and control (9 patients) groups. Both groups received onlays and 16 patients had their maxillary sinus grafted with particulate bone (lateral window approach) with iliac crest bone grafts. Autologous platelet concentrates were prepared from the patients' blood and autologous thrombin was produced. PRP was mixed with the test group bone grafts. Outcome measures were implant integration, implant stability, soft tissue healing, graft resorption, and donor and recipient site complications. Implant stability measurements were recorded at placement and exposure using a resonance frequency analysis device. Patients were followed up to abutment connection. Multiple linear regression analyses using robust standard error were performed, taking the patient as the unit of measurement. The t test was also used where appropriate. RESULTS: One bone graft failed in the PRP group and regrafting was required. No statistically significant differences were observed for soft tissue healing indices (P = 0.4) and mean graft resorption (P = 0.5) between groups. All implants were found clinically integrated at time of exposure. No statistically significant differences in implant stability were observed between groups at implant placement (P = 0.059) and exposure (P = 0.1). Using a post-hoc analysis, posterior implants in the PRP group showed statistically significantly higher stability values (61 +/- 2.6) than anterior implants (60 +/- 2.4) at implant placement (mean difference -0.95, P = 0.04). However, this difference was not clinically significant. CONCLUSION: No appreciable clinical effect could be observed when using PRP with autologous iliac crest bone graft in the maxilla. PMID- 20847994 TI - Implant treatment software planning and guided flapless surgery with immediate provisional prosthesis delivery in the fully edentulous maxilla. A retrospective analysis of 15 consecutively treated patients. AB - AIMS: To evaluate the clinical outcome of fully edentulous patients in the maxilla, who were treated with immediately loaded implant-supported cross-arch bridges using computer-aided implant surgery. MATERIALS AND METHODS: The clinical outcome of 15 consecutive patients (5 males and 10 females) with a mean age of 52 years (range 40 to 70), with edentulous arches and treated with implant-supported cross-arch bridges was evaluated. Two computed tomography scans were performed, the first with the patient wearing the denture/radiographic guide and the radiographic index, and the second of the denture alone. The guided flapless surgical procedure was performed under local anaesthesia. Ninety implants were placed. The implant length ranged from 10 to 13 mm and the implant diameter was either 4.3 or 5 mm. All implants were immediately loaded with screw-retained provisional acrylic prostheses prepared in advance and delivered immediately after surgery. Clinical and radiographic follow-up visits were scheduled at 6, 12 and 18 months from surgery; implant survival rate, marginal bone levels, patient satisfaction and any complications were recorded. RESULTS: After the follow-up period of 18 months, two patients each lost one implant. After 18 months, patients lost, on average, 1.6 mm of peri-implant marginal bone. A patient satisfaction questionnaire at 18 months revealed a very high level of satisfaction with the treatment. CONCLUSION: Although limited by the number of patients, it can be concluded that software- and computed tomography-guided surgical planning for completely edentulous arches provides reliable results with high success rates. PMID- 20847995 TI - Ligation of an unusually large vessel during maxillary sinus floor augmentation. A case report. AB - PURPOSE: The purpose of the present case report was to document a maxillary sinus floor augmentation procedure involving ligation of a blood vessel with a nearly 3 mm diameter in the lateral wall of the maxillary sinus. MATERIALS AND METHODS: A bilateral maxillary sinus floor augmentation procedure was performed in a 51-year old healthy man. The preoperative computed tomography scan revealed a bony canal within the lateral maxillary sinus wall of the right as well as the left side close to the alveolar ridge. RESULTS: A vessel with a diameter of nearly 3 mm was identified during the sinus floor augmentation on the left side. The vessel was exposed and ligated. A vessel with a diameter of approximately 1 mm was identified on the right side and the sinus floor augmentation was performed without ligation. No complications were observed and the postoperative healing was uneventful. CONCLUSIONS: Although accidental laceration of vessels with an unusually large diameter during maxillary sinus floor augmentation is not life threatening, impaired visualisation may compromise the augmentation procedure, including the elevation of the Schneiderian membrane. Moreover, postoperative bleeding and formation of a haematoma may occur. Therefore, ligation of vessels with an unusually large diameter is recommended during maxillary sinus floor augmentation to minimise intra- and postoperative complications. PMID- 20847996 TI - Reasonable adhesion. PMID- 20847997 TI - FDI World Dental Federation - clinical criteria for the evaluation of direct and indirect restorations. Update and clinical examples. AB - In 2007, new clinical criteria were approved by the FDI World Dental Federation and simultaneously published in three dental journals. The criteria were categorized into three groups: esthetic parameters (four criteria), functional parameters (six criteria), and biological parameters (six criteria). Each criterion can be expressed with five scores, three for acceptable and two for non acceptable (one for reparable and one for replacement). The criteria have been used in several clinical studies since 2007, and the resulting experience in their application has led to a requirement to modify some of the criteria and scores. The two major alterations involve staining and approximal contacts. As staining of the margins and the surface have different causes, both phenomena do not appear simultaneously. Thus, staining has been differentiated into marginal staining and surface staining. The approximal contact now appears under the name "approximal anatomic form" as the approximal contour is a specific, often non esthetic issue that cannot be integrated into the criterion "esthetic anatomical form". In 2008, a web-based training and calibration tool called e-calib (www.e calib.info) was made available. Clinical investigators and other research workers can train and calibrate themselves interactively by assessing clinical cases of posterior restorations, which are presented as high quality pictures. Currently, about 300 clinical cases are included in the database which is regularly updated. Training for 8 of the 16 clinical criteria is available in the program: "Surface luster"; "Staining (surface, margins)"; "Color match and translucency"; "Esthetic anatomical form"; "Fracture of material and retention"; "Marginal adaptation"; "Recurrence of caries, erosion, abfraction"; and "Tooth integrity (enamel cracks, tooth fractures)". Typical clinical cases are presented for each of these eight criteria and their corresponding five scores. PMID- 20847998 TI - Oral microbiota, dental caries and periodontal status in smokeless tobacco chewers in Karnataka, India: a case-control study. AB - PURPOSE: The aim of the present study was to compare dental caries and periodontal disease status associated with oral microflora among smokeless tobacco chewers and non-chewers. MATERIALS AND METHODS: Forty-two smokeless tobacco chewers and 42 non-chewers (age 20 to 60 years) were assessed for dental caries and periodontal disease status using the Decayed Missing Filled Surface (DMFS) Index, Community Periodontal Index (CPI) and Loss of Attachment (LA) Index. Stimulated saliva and subgingival plaque samples were collected from each subject for performing a culture-based analysis of 20 types of oral microorganisms. Qualitative and semi-quantitative culture-based analysis using MacConkey agar, and aerobic and anaerobic blood agar was carried out to determine the total cultivable microflora. Mutans-Sanguis agar, Pfizer selective Enterococcus agar and Rogosa SL agar were used for the culture of microorganisms associated with dental caries. Mann-Whitney U test and Student t test were employed to compare colony-forming units (CFUs) and caries experience between smokeless tobacco chewers and nonchewers. Z proportionality test was used to compare the periodontal disease status. RESULTS: Caries experience among chewers (26 of 42), that is those subjects who were affected by caries, was significantly less at 61.9% (mean DMFS = 3.5) compared to non-chewers (38 of 42, 90.5%) (mean DMFS = 5.5) (P < 0.05). Deep pockets measuring > 5.5 mm on a CPI probe were found among 26.2% of chewers and 19.1% of nonchewers, with no statistically significant differences (P > 0.05). Counts of Lactobacillus species were significantly lower among chewers (median CFU = 0.788 x 105) than among non-chewers (median CFU = 1.52 x 105) (P < 0.05). Prevotella and Porphyromonas species had a median CFU of 0.04 x 105 in chewers and 0.15 x 105 in non-chewers, whereas Fusobacterium species had a median CFU of 0.02 x 105 in chewers and 0.1 x 105 in non-chewers (P < 0.05). CONCLUSIONS: A higher percentage of caries among non-chewers can be explained by greater numbers of Lactobacillus species in this population. Chewers experienced a slightly higher incidence of periodontal disease than non-chewers, but the difference was not significant. These clinical observations suggest a lower ability of Gram-negative bacteria to mediate more periodontal disease in this population. PMID- 20847999 TI - The relationship of malocclusion as assessed by the Dental Aesthetic Index (DAI) with perceptions of aesthetics, function, speech and treatment needs among 14- to 15-year-old schoolchildren of Bangalore, India. AB - PURPOSE: The present study was primarily carried out to assess the severity of malocclusion and treatment needs of 14- to 15-year-old schoolchildren of Bangalore, India, using the Dental Aesthetic Index (DAI) and to correlate them with the subjective perception of aesthetics, function, speech and treatment needs. METHODS: A total of 1618 students aged 14 to 15 years, who were randomly selected from 40 government and private schools, were included in the present study. The subjects were asked about their self-perception of malocclusion using a structured questionnaire. A Likert scale was used to assess their perception. They were then subjected to a clinical examination, wherein the malocclusion and the treatment needs were assessed using the DAI. The data were analysed using the SPSS(r) version 10 statistical package. RESULTS: Most of the subjects were satisfied with the arrangement of their teeth. Weak but statistically significant correlations were found between all of the variables (P < 0.01). Correlation was found to be greater between aesthetics and speech (r = 0.489; P < 0.01), aesthetics and the DAI component (r = 0.342; P < 0.01), and subjectively and objectively perceived treatment needs (r = 0.476; P < 0.01). There was no significant difference observed between the children in private and government schools (P > 0.05). Aesthetics was the most common reason for seeking treatment. CONCLUSIONS: Most of the subjects were satisfied with the appearance of their teeth, masticatory function and speech. The perception of dissatisfaction with dental appearance increased with increasing severity of malocclusion. However, the same did not apply for masticatory function and speech. Self-perception of treatment need was low. PMID- 20848000 TI - Validation of the Persian short version of the Oral Health Impact Profile (OHIP 14). AB - PURPOSE: The Oral Health Impact Profile (OHIP) questionnaire measures oral health related quality of life and is widely used for assessing subjective oral health status. The objective of the present study was to describe the translation and validation of the shortened 14-item OHIP for native Persian (Farsi) speakers living in Iran. MATERIALS AND METHODS: The authors translated the OHIP-14 into Persian (OHIP-14-P), followed by back-translation into English, after which the Persian version was revised and modified. They administered the questionnaire to native Persian-speaking clients at a university-based dental clinic in Tehran, Iran (n = 240, 123 females and 117 males, mean age 39, range 18 to 76). They examined the convergent validity and discriminative validity of OHIP by analysing their association with various self-reported health outcomes. They evaluated the test-retest reliability by administering the instrument to 37 patients a second time. They analysed the internal consistency and reliability using a intraclass correlation coefficients (ICC) and Cronbach's reliability coefficient, respectively. RESULTS: The associations between scores of OHIP-14-P and its subscales with self-reported general (r(s) [Spearman's rank correlation coefficient] range 0.38 to 0.52) and oral health (r(s) range 0.25 to 0.45) confirmed convergent validity. Discriminative validity was confirmed through the significant relationship between OHIP-14-P scores with both the experience of pain and satisfaction with oral health (P < 0.001). The instrument's test-retest reliability (ICCs: 0.75 to 0.88) and internal consistency (Cronbach's alpha: 0.45 to 0.73 and Cronbach's alpha if subscale deleted: 0.88 to 0.85) were satisfactory. CONCLUSIONS: The Persian version of OHIP-14 was found to be a valid and reliable measure, and appropriate to be used among native Persian speakers visiting a dental clinic. PMID- 20848001 TI - Malocclusion and treatment needs of cleft lip and/or palate subjects aged between 12 and 18 years visiting KLE's Hospital, Belgaum, India. AB - PURPOSE: The aim of the present study was to investigate the malocclusion status and treatment needs of adolescents with cleft lip and/or palate aged between 12 and 18 years, and to compare them with those of non-cleft subjects. MATERIALS AND METHODS: A cross-sectional survey was conducted at the Outpatient Department, Plastic and Reconstructive Surgery, KLE's Hospital and Medical Research Centre, Belgaum, India, during the period March to September 2004. The sample comprised 56 cleft lip and/or palate subjects aged between 12 and 18 years who were matched with 168 non-cleft subjects (controls) selected from the general population. The clinical examination was conducted using methods recommended by the World Health Organization oral health surveys. The Dental Aesthetic Index (DAI) was used to record the data. RESULTS: About 37.5% of cleft lip and/or palate subjects and 60.71% of controls scored a DAI <= 25 (no abnormality or minor malocclusion). About 51.78% of cleft lip and/or palate subjects and approximately one-third of controls (35.71%) scored a DAI of 26 to 30 (definite malocclusion). Subjects with cleft lip and/or palate disorder (8.92%) and controls (2.97%) scored a DAI of 31 to 35 (severe malocclusion, P = 0.06). Subjects with cleft lip and/or palate disorder (1.78%) and controls (< 1%) scored a DAI >= 36 (handicapping malocclusion). CONCLUSIONS: A majority of the cleft lip and/or palate subjects exhibited severe malocclusion, and treatment was highly desirable when compared to non-cleft subjects. PMID- 20848002 TI - Screening for oral dryness in relation to salivary flow rate addresses the need for functional tests of saliva. AB - PURPOSE: The aim of the present study was to assess the occurrence of reported subjective oral dryness in relation to objective sialometric values in a randomly selected group and a dental care-seeking group. MATERIALS AND METHODS: A questionnaire assessing subjective oral dryness was sent out to a randomly selected sample of 200 individuals. The dental care-seeking group was recruited from among patients attending the Department of Oral Diagnostics, Malmo University. A total of 200 patients were asked to participate in the present study. In total, 312 individuals (78%) completed the survey and 157 individuals agreed to participate in the complementary clinical examination that included measures of salivary flow rate. RESULTS: The reported subjective oral dryness was 20% and 28.6% for the randomly selected group and the dental care-seeking group, respectively. No statistically significant differences were found between the two study populations with regard to percentage of reported subjective oral dryness, and stimulated and unstimulated salivary flow rates (P > 0.05). In the dental care-seeking group, individuals reporting subjective oral dryness presented 'a small degree of abrasion in the dentine in the incisor region' to a greater extent (P < 0.05). No statistically significant association between subjective oral dryness and unstimulated and stimulated salivary flow rates was found in either of the studied populations (P > 0.05). Individuals identified with subjective or objective oral dryness presented to a greater extent a history of oral rehabilitation compared to individuals who showed no indication of oral dryness. CONCLUSIONS: No association between sialometric measures and subjective report of oral dryness was found in the present study. PMID- 20848003 TI - Sensitivity to bitter and sweet taste perception in schoolchildren and their relation to dental caries. AB - PURPOSE: The objective of the present study was to evaluate whether sensitivity to bitter taste and perception of sweet taste have an influence on dental caries in urban and rural areas. MATERIALS AND METHODS: The caries experience in 181 children, aged 12 years, from rural and urban areas of southern Brazil, was assessed according to World Health Organization guidelines. Sensitivity to the bitterness of phenylthiocarbamide was determined using the Harris-Kalmus procedure, and the sweet taste thresholds of sucrose were measured by Nilsson and Holm's method. RESULTS: The caries index (DMFT > 0) was 3.73 (SD = 2.26) in the rural area and 3.51 (SD = 2.14) in the urban area. The sensitivity to bitter taste and sweet taste perception showed significant association with the gender of schoolchildren (P = 0.04). Girls were predominant in the high sweet perception taster group (62.3%) and the bitter taster group (59.4%). No significant difference in sweet perception status could be observed between the groups of low and high caries severity. The genetic ability to taste bitterness significantly influenced the levels of caries only in children from the urban area (P = 0.005). Bitter non-tasters presented higher severity of caries. A positive correlation was observed between sensitivity to bitter taste and sweet taste perception among children in the rural (r = 0.42, P = 0.002) and urban areas (r = 0.36, P = 0.001). CONCLUSIONS: These findings suggest that the bitter non-tasters are more susceptible to dental caries than the tasters in the urban area. PMID- 20848005 TI - Fluorosis, caries and oral hygiene in schoolchildren on the Ombili Foundation in Namibia. AB - PURPOSE: The aim of the present study was to analyse caries prevalence and fluorosis as well as oral hygiene habits in schoolchildren in north Namibia. MATERIALS AND METHODS: In 2004, 120 pupils (1st to 8th grade, mean age: 12.3 +/- 2.8 years) of the Ombili Primary School were examined by one calibrated clinician for caries (DMFT) according to the World Health Organization criteria, oral hygiene (API) and fluorosis (Dean's index), categorised according to the four different farms where they lived. In addition, samples of drinking water were obtained from the wells of the farms and analysed for quality and mineral content. RESULTS: The pupils at the different farms showed very different caries prevalence (range: 17% to 50% caries-free children) and mean DMFT values (0.96 to 2.67). Oral hygiene measures were not common (60.8% none) or inefficient (mean proximal plaque index: 89.5%) and did not differ greatly between the different farms. The fluoride concentration in drinking water varied considerably (0.28 to 1.06 mg/l). The prevalence of dental fluorosis in all schoolchildren was 65.8%, the Community Fluorosis Index (CFI) was 1.41 and it differed clearly for pupils from the four farms (CFI: 0.5 to 1.65). The DMFT index showed a statistically significant correlation with the fluoride concentration of the drinking water (P < 0.05). CONCLUSIONS: Based on these results, fluoride concentration in drinking water should be monitored in the future. In parallel, a caries-preventive programme should be developed, as high concentrations of fluoride in drinking water alone do not result in acceptable caries levels. PMID- 20848004 TI - Caries-preventive efficacy and retention of a resin-modified glass ionomer cement and a resin-based fissure sealant: a 3-year split-mouth randomised clinical trial. AB - PURPOSE: This prospective clinical trial compared the retention rate and caries preventive efficacy of two types of sealant modalities over a 3-year period. MATERIALS AND METHODS: Using a split-mouth randomised design, 1280 sealants were randomly applied on sound permanent second molars of 320 young patients aged between 12 and 16 years. Half of the teeth (n = 640) were sealed with a resin modified glass ionomer cement (RMGIC) (VitremerTM, 3M ESPE) and the other half (n = 640) with a conventional light-cure, resin-based fissure sealant (LCRB) (Fluoroshield(r), Dentsply Caulk). Teeth were evaluated at baseline, 6-, 12-, 18 , 24-, 30- and 36-month intervals with regard to retention and new caries development. RESULTS: On the sealed occlusal surfaces after 3 years, 5.10% of RMGIC and 91.08% of LCRB sealants were totally intact and 6.37% of RMGIC and 7.65% of LCRB sealants were partially intact. New caries lesions were found in 20.06% of RMGIC sealed occlusal surfaces, compared to 8.91% for LCRB sealants. CONCLUSIONS: The findings of the present clinical study suggest that RMGIC should be used only as a transitional sealant that can be applied to newly erupting teeth throughout the eruptive process, whereas LCRB sealants are used to successfully prevent occlusal caries lesions once an effective rubber dam can be achieved. It can be concluded that there are differences between the RMGIC and LCRB sealants over a 3-year period in terms of the retention rate and caries preventive efficacy. RMGIC can serve as a simple and economic sealing solution, however provisional. Due to its poor retention rate, periodic recalls are necessary, even after 6 months, to eventually replace the lost sealant. PMID- 20848006 TI - Pattern of fluoride-containing dentifrice use and associated factors in preschool children from Ijui, South Brazil. AB - PURPOSE: The aim of the present study was to evaluate the pattern of fluoride containing dentifrice use and associated factors in Brazilian preschoolers. MATERIALS AND METHODS: A structured questionnaire was answered by parents of 432 children, who were aged 2 to 6 years, from 12 public preschools in Ijui, South Brazil. Primary outcomes were age of starting fluoride-containing dentifrice use and amount of dentifrice applied to the toothbrush. Poisson regression with robust variance was used to determine the factors associated with the main outcomes. RESULTS: About 75% of the participants were introduced to fluoride containing dentifrice before the age of 2 years. The current predominant amount of dentifrice used was obtained by transversal (57.7%), followed by longitudinal deposition on the toothbrush (33.6%), corresponding to 0.3 and 0.9 g of dentifrice, respectively. Previous dental visits and maternal education greater than 4 years were associated with the introduction of fluoride-containing dentifrice before 2 years of age. The probability of using dentifrice in amounts higher than the recommendations doubled in children aged 5 and 6 years. CONCLUSIONS: Oral health interventions should reinforce the importance of early introduction of fluoride-containing dentifrice, especially in less-educated mothers. Furthermore, the amount of dentifrice should be reduced to maximise the caries-preventive effect while minimising dental fluorosis. PMID- 20848007 TI - Patterns of oral cleaning habits and use of fluoride among dentate adults in Finland. AB - PURPOSE: The aim of the present study was to identify the underlying patterns of oral cleaning habits and the use of fluoride, and to investigate their variations by studying the socioeconomic characteristics among Finnish dentate adults aged 30 to 64 years. MATERIALS AND METHODS: Participants of the nationwide Health 2000 survey who were dentate, aged 30 to 64 years, and underwent a health interview and a clinical oral examination, were included in the present study (n = 4419). RESULTS: In total, 79% of the women and 46% of the men reported to have brushed their teeth twice or more daily; 16% of the women and 14% of the men reported daily use of an electric toothbrush and 14% of the women and 5% of the men reported daily use of dental floss or an interdental brush. Factor analysis revealed five oral cleaning habit patterns, which were named modern, rational, before-breakfast, social and irrational. The modern cleaning pattern was associated with higher levels of education, and the rational cleaning with younger age, female gender and higher levels of education. The before-breakfast cleaning pattern was associated with male gender and lower levels of education, and the social cleaning with older age, female gender and higher levels of education. The irrational cleaning pattern was associated with older age. CONCLUSIONS: Adults have various oral cleaning habit patterns, each of which is associated with the subjects' socioeconomic characteristics. PMID- 20848008 TI - Review of the effects of infiltrants and sealers on non-cavitated enamel lesions. AB - PURPOSE: The aim of the present study was to perform a review of the effects of infiltrants and sealers on the inhibition of enamel demineralisation. MATERIALS AND METHODS: The authors searched the Cochrane Library, Embase, PubMed and Web of Science (ISI) for papers published between January 1970 and September 2008. The main search terms were 'artificial caries' or 'caries treatment' or 'caries-like lesion' or 'white spot lesion' or 'enamel demineralisation' or 'natural caries' and 'enamel' and 'sealant' or 'resin infiltration'. The inclusion criteria were studies that produced artificial non-cavitated enamel lesions before the application of sealant in in vivo or in vitro studies. Studies excluded were those that had not produced artificial non-cavitated enamel lesions before the application of sealant; had evaluated the inhibition of enamel demineralisation around restorations, sealant and orthodontic bracket/bands; had not evaluated the inhibition of enamel demineralisation after the sealant application; and had not applied sealant materials. Selected papers were given scores, from A to C, according to predetermined criteria. RESULTS: Eighteen studies were identified and included in the project critical appraisal. Two papers were classified as Grade A, nine as Grade B and seven as Grade C. CONCLUSIONS: It can be concluded that while fissure sealing acts as a diffusion barrier on the top of the lesion surface, the infiltration technique creates a barrier inside the lesion by replacing the mineral lost with a low-viscosity light-curing resin. PMID- 20848009 TI - A novel guanidinium grafted poly(aryl ether sulfone) for high-performance hydroxide exchange membranes. AB - A novel poly(aryl ether sulfone) ionomer containing hexaalkylguanidinium groups was synthesized, and membranes formed from this polymer displayed large ionic clusters, high hydroxide conductivity, and excellent solubility in low boiling point water-soluble solvents such as ethanol and methanol. PMID- 20848010 TI - Revisiting the Kinnel-Scheuer hypothesis for the biosynthesis of palau'amine. AB - We propose herein an alternative biosynthetic pathway for palau'amine in order to resolve the stereochemical issue from the original Kinnel-Scheuer hypothesis. Furthermore, we use this revised hypothesis as a guide toward the laboratory synthesis of palau'amine. PMID- 20848011 TI - Microchannel deformations due to solvent-induced PDMS swelling. AB - The compatibility of polydimethylsiloxane (PDMS) channels with certain solvents is a well known problem of soft lithography techniques, in particular when it leads to the swelling of the PDMS blocks. However, little is known about the modification of microchannel geometries when they are subjected to swelling solvents. Here, we experimentally measure the deformations of the roof of PDMS microchannels due to such solvents. The dynamics of impregnation of the solvents in PDMS and its relation to volume dilation are first addressed in a model experiment, allowing the precise measurement of the diffusion coefficients of oils in PDMS. When Hexadecane, a swelling solvent, fills a microchannel 1 mm in width and 50 MUm in height, we measure that the channel roof bends inwards and takes a parabolic shape with a maximum deformation of 7 MUm. The amplitude of the subsidence is found to increase with the channel width, reaching 28 MUm for a 2 mm wide test section. On the other hand, perfluorinated oils do not swell the PDMS and the microchannel geometry is not affected by the presence of perfluorodecalin. Finally, we observe that the trajectories of droplets flowing in this microchannel are strongly affected by the deformations: drops carried by swelling oils are pushed towards the edges of the channel while those carried by non-swelling oils remain in the channel center. PMID- 20848012 TI - Simple and efficient copper-catalyzed cascade synthesis of naphthols containing multifunctional groups under mild conditions. AB - A simple and efficient copper-catalyzed method for synthesis of naphthols containing multifunctional groups has been developed under mild conditions (room temperature to 60 degrees C), and it can tolerate various functional groups. PMID- 20848014 TI - 3-Hydroxypyrrolo[2,3-b]pyridine and related compounds - indoxyl analogues with fused electron deficient rings. AB - Flash vacuum pyrolysis (FVP) of 4-acetyltetrazolo[1,5-a]pyridine 5 at 400 degrees C provides 3-methyl isoxazolo[3,4-b]pyridine 6 whose structure was confirmed by X-ray crystallography. At higher pyrolysis temperatures, the unstable heteroindoxyl 8 was obtained, which exists as the keto form (1,2 dihydropyrrolo[2,3-b]pyridin-3-one) 8K in CDCl(3) solution and the enol tautomer (3-hydroxypyrrolo[2,3-b]pyridine) 8E in DMSO. The heteroindoxyl 8 oxidatively dimerises to the heteroindigotin 9, undergoes condensation reactions at the 2 position and reacts with methoxymethylene Meldrum's acid at the 1-position. FVP of the corresponding acetyltetrazolo[1,5-a]quinoline 19 was much more complex, with 2-(cyanophenyl)acetonitrile 30 (rather than a heteroindoxyl) the major product at 750 degrees C. FVP of 3-acetyl-4-azidoquinoline 24 at 400 degrees C gave 3-methylisoxazolo[4,3-c]quinoline 33, but rearrangement to the heteroindoxyl was not observed at higher temperatures. PMID- 20848013 TI - Evaluation of automated streamwater sampling during storm events for total mercury analysis. AB - Understanding the processes by which mercury is mobilized from soil to stream is currently limited by a lack of observations during high-flow events, when the majority of this transport occurs. An automated technique to collect stream water for unfiltered total mercury (HgT) analysis was systematically evaluated in a series of laboratory experiments. Potential sources of error investigated were 1) carry-over effects associated with sequential sampling, 2) deposition of HgT into empty bottles prior to sampling, and 3) deposition to or evasion from samples prior to retrieval. Contamination from carry-over effects was minimal (<2%) and HgT deposition to open bottles was negligible. Potentially greater errors are associated with evasive losses of HgT from uncapped samples, with higher temperatures leading to greater evasion. These evasive losses were found to take place primarily within the first eight hours. HgT associated with particulate material is much less prone to evasion than HgT in dissolved form. A field test conducted during a high-flow event confirmed unfiltered HgT concentrations sampled with an automated system were comparable to those taken manually, as the mean absolute difference between automated and manual samples (10%) was similar to the mean difference between duplicate grab samples (9%). Results from this study have demonstrated that a standard automated sampler, retrofitted with appropriately cleaned fluoropolymer tubing and glass bottles, can effectively be used for collection of streamwater during high-flow events for low-level mercury analysis. PMID- 20848015 TI - Oxide-ion and proton conducting electrolyte materials for clean energy applications: structural and mechanistic features. AB - This critical review presents an overview of the various classes of oxide materials exhibiting fast oxide-ion or proton conductivity for use as solid electrolytes in clean energy applications such as solid oxide fuel cells. Emphasis is placed on the relationship between structural and mechanistic features of the crystalline materials and their ion conduction properties. After describing well-established classes such as fluorite- and perovskite-based oxides, new materials and structure-types are presented. These include a variety of molybdate, gallate, apatite silicate/germanate and niobate systems, many of which contain flexible structural networks, and exhibit different defect properties and transport mechanisms to the conventional materials. It is concluded that the rich chemistry of these important systems provides diverse possibilities for developing superior ionic conductors for use as solid electrolytes in fuel cells and related applications. In most cases, a greater atomic-level understanding of the structures, defects and conduction mechanisms is achieved through a combination of experimental and computational techniques (217 references). PMID- 20848016 TI - Enhanced photocatalytic properties in well-ordered mesoporous WO3. AB - We used polyisoprene-block-ethyleneoxide copolymers as structure-directing agents to synthesise well-ordered and highly-crystalline mesoporous WO(3) architectures that possess improved photocatalytic properties due to enhanced dye-adsorption in absence of diffusion limitation. PMID- 20848017 TI - Solution-based synthetic strategies for one-dimensional metal-containing nanostructures. AB - One-dimensional (1D) nanostructures, such as nanowires, nanotubes, nanorods, and nanoribbons, have attracted significant attention stemming from the plethora of interesting size-dependent and, more importantly, structure-related properties resulting from confinement effects. In particular, the novel properties of 1D nanostructures of metals and metal oxides (binary and ternary) render them as prime candidates for a wide range of applications including the fabrication of nanoscale devices associated with solar cells, energy storage, fuel cells, molecular computing and information storage, medical imaging, diagnosis and detection, drug delivery, sensors and catalysis. Thus, it has been simultaneously necessary and critical to create synthetic protocols for the production of these materials which not only are reliable and reproducible, but also can generate compositionally pure, monodisperse, highly crystalline products of a desired 1D morphology. Solution-based methodologies have demonstrated significant advantages over other approaches, as they are facile, simple, flexible, 'green' by nature, and can be applied to a wide range of nanomaterials with diverse chemical compositions. Moreover, these methods can often be scaled so as to produce large quantities of products which are advantageous from an applications' standpoint. Herein, we present synthetic advances associated with solution-based approaches. Specifically solvothermal/hydrothermal, molten salt, electrospinning, template directed, solution/one-pot, and sol-gel methodologies are discussed with the primary goal of achieving the reproducible synthesis of 1D motifs of metals, binary metal oxides, and ternary metal oxide systems. PMID- 20848019 TI - Enantiomorphic symmetry breaking in crystallization of molten sodium chlorate. AB - Enantiomorphic symmetry breaking of stirred samples of molten sodium chlorate is demonstrated, revealing the unexpected involvement of an achiral solid phase. The results should stimulate future computational models of nucleation, including symmetry breaking, and have implications for mechanisms that invoke enantiomorphism in natural minerals to explain biohomochirality. PMID- 20848018 TI - Electron induced dissociation (EID) tandem mass spectrometry of octaethylporphyrin and its iron(III) complex. AB - EID tandem mass spectrometry of singly-charged electrosprayed ions of octaethylporphyrin (OEP) and its iron(III) complex results in ionisation to give doubly-charged precursor and fragment ions. Singly-charged fragments are also observed. EID fragmentation differs significantly to that observed in electron ionisation mass spectrometry. PMID- 20848020 TI - Direct structure elucidation by powder X-ray diffraction of a metal-organic framework material prepared by solvent-free grinding. AB - Powder X-ray diffraction (XRD) has been exploited to establish the structural properties of a porous interpenetrated mixed-ligand metal-organic framework material prepared by solid-state grinding, recognizing that product phases from mechanochemical synthesis are typically microcrystalline powders. The importance of subjecting the powder XRD data to rigorous scrutiny in such applications is emphasized. PMID- 20848021 TI - Dispersion of graphene in ethanol using a simple solvent exchange method. AB - A dispersion of graphene in ethanol was achieved using solvent exchange from N methyl-2-pyrrolidone (NMP) that enables broader application of dispersed graphene. PMID- 20848022 TI - Titanium dioxide-supported non-precious metal oxygen reduction electrocatalyst. AB - A new non-precious metal oxygen reduction catalyst was developed via heat treatment of in situ polymerized polyaniline onto TiO(2) particles in the presence of Fe species. The TiO(2) provides for improved performance relative to a carbon black-based catalyst and, at a high catalyst loading, allows for reducing the performance gap between non-precious-metal catalyst and Pt/C to ca. 20 mV in RDE testing. PMID- 20848023 TI - Synthesis and coordination behaviors of P-stereogenic polymers. AB - Optically active polymers containing P-stereogenic bisphosphine and 1,2,3 triazole units in the main chain were obtained by copper-catalyzed Huisgen cycloaddition. The repeating unit of the polymer adopted bidentate as well as tetradentate coordination, leading to the change in the conformations of the polymer via complexation with transition metals. PMID- 20848024 TI - Site-specific photochemical RNA editing. AB - Photo-induced artificial RNA editing was demonstrated using photo-reactive oligonucleotides containing 3-cyanovinylcarbazole nucleoside. This non-enzymatic and sequence-specific methodology will make a major contribution to the elucidation of RNA functions including non-coding RNAs and to the development of drugs based on sequence-specific RNA editing. PMID- 20848025 TI - Contributions of surface and bulk heterogeneities to the NO oxidation activities of ceria-zirconia catalysts with composition Ce(0.76)Zr(0.24)O(2) prepared by different methods. AB - The study of the catalytic activity towards NO oxidation to NO(2) was approached by using ceria-zirconia mixed oxides with the same nominal composition (Ce(0.76)Zr(0.24)O(2)) but prepared by different routes of synthesis: coprecipitation, solid combustion synthesis with urea, citrate complexation route, reversed microemulsion and template synthesis. The characterisation of the catalysts was performed by N(2) adsorption at -196 degrees C, XRD, Raman Spectroscopy, H(2)-TPR and XPS in order to ascertain the relationships between their catalytic activities and their bulk and surface properties. The results showed that the preparation method is critical for the physico-chemical properties of the mixed oxides, exhibiting very different BET surface areas, crystalline phase/s contributions and bulk oxygen mobility. The distribution of Ce and Zr on the surface with regard to the bulk is very much influenced by the preparation method as well. The NO(2) production from NO oxidation was shown to be mostly correlated with the Ce/Zr surface atomic ratio and the proportion of Ce(4+) (presumably in a doped cubic phase) in the uppermost layers. PMID- 20848026 TI - Electrical conductivity and crystallization of amorphous bismuth ruthenate thin films deposited by spray pyrolysis. AB - Amorphous oxide thin films with tailored functionality will be crucial for the next generation of micro-electro-mechanical-systems (MEMS). Due to potentially favorable electronic and catalytic properties, amorphous bismuth ruthenate thin films might be applied in this regard. We report on the deposition of amorphous bismuth ruthenate thin films by spray pyrolysis, their crystallization behavior and electrical conductivity. At room temperature the 200 nm thin amorphous films exhibit a high electrical conductivity of 7.7 * 10(4) S m(-1), which was found to be slightly thermally activated (E(a) = 4.1 * 10(-3) eV). It follows that a long range order of the RuO(6) octahedra is no precondition for the electrical conductivity of Bi(3)Ru(3)O(11). Upon heating to the temperature range between 490 degrees C and 580 degrees C the initially amorphous films crystallize rapidly. Simultaneously, a transition from a dense and continuous film to isolated Bi(3)Ru(3)O(11) particles on the substrate takes place. Solid-state agglomeration is proposed as the mechanism responsible for disintegration. The area specific resistance of Bi(3)Ru(3)O(11) particles contacted by Pt paste on gadolinia doped ceria electrolyte pellets was found to be 7 Omega cm(2) at 607 degrees C in air. Amorphous bismuth ruthenate thin films are proposed for application in electrochemical devices operating at low temperatures, where a high electrical conductivity is required. PMID- 20848027 TI - A SAXS study on nanostructure evolution in water free membranes containing ionic liquid: from dry membrane to saturation. AB - Small-angle X-ray scattering (SAXS) technique has been used to study the evolution of ionomer peak in the recast Nafion membranes containing the ionic liquid 1-ethyl-3-methylimidazolium tetrafluoroborate (EMIBF(4)). To the best of our knowledge, this is the first report dealing with the study of membranes containing different concentrations of the ionic liquid (EMIBF(4)), from the dry (no ionic liquid) to the saturation (containing 70 wt% ionic liquid) state to understand the evolution of the ionomer peak and the formation of ionic aggregates in these anhydrous membranes. The small-angle scattering maximum (ionomer peak) has been observed to shift continuously toward lower scattering vector (q) values as the ionic liquid content increases. The ionic conductivity behavior for the membranes containing ionic liquid has been found to be closely related with the change of slope of the double logarithmic plot between the reciprocal of the position of the ionomer peak and the polymer weight fraction. The q region over which Porod's law has been obeyed in different membranes was initially narrow and has been observed to widen with an increase in the content of the ionic liquid. PMID- 20848028 TI - Asymmetric general base catalysis of the phospho-aldol reaction via dimeric aluminium hydroxides. AB - Dimeric aluminium hydroxide complexes containing the (R,R)-N,N'-bis(2'-hydroxy-3' organobenzyl)-trans-1,2-diaminocyclohexane ligand backbone effect catalysis of the phospho-aldol reaction under ambient, aerobic conditions at catalyst loadings of 0.5 mol% to afford enantioselectivities of ca. 65%. PMID- 20848029 TI - The creation of nanojunctions. AB - This review describes recent progress in creation of nanojunctions between individual nanoobjects. The accomplishments of various strategies used for nanojunction creation are highlighted and the corresponding challenges are discussed. The possible ongoing development for the creation of device-oriented nanojunctions is speculated upon. PMID- 20848030 TI - Polymeric PARACEST MRI contrast agents as potential reporters for gene therapy. AB - Gene therapy is a potentially powerful treatment approach that targets molecular remedies for disease. Among other challenges it remains difficult to monitor gene delivery and its downstream metabolic consequences. Approaches to MRI gene reporters have been reported but few have the potential for translation beyond isolated cell systems. Herein, we report a polycationic polymer MRI contrast agent that binds to DNA in a ratio of one monomer unit per phosphate group of DNA. Significantly, this binding event diminishes the MR contrast signal from the agent itself potentially providing a platform for imaging delivery and release of a gene into cells and tissues. Importantly, we demonstrate here the proof of concept that a positively charged polymeric contrast agent can also act as a transfection agent, delivering the gene for encoding green fluorescent protein into cells. These observations provide support for the radical, new idea of creating a combined transfection/imaging agent for monitoring gene delivery in real time by MRI. PMID- 20848031 TI - A computational analysis of intramolecularity in proton transfer reactions. AB - Hydrogen bonds along which most proton transfers take place are analyzed regarding their contribution to the efficiency of intramolecular processes through the assessment of effective molarities by DFT calculations on rigid intra molecular model systems in comparison with their intermolecular counterparts. A few cyclic systems in which there is no possibility of hydrogen bonding between reactants neither in the ground state nor in the product are identified by theoretical calculations as leading to important rate increases in intramolecular general-base catalysis constituting a new exception to the rule of low effective molarities (EMs) for proton transfers. The recovery of high efficiency in these systems is attributed to the absence of special features facilitating the corresponding intermolecular reactions. This work confirms that any explanation of EMs found in intramolecular systems also requires a careful analysis of the corresponding bimolecular systems. PMID- 20848032 TI - Unveiling the phytoalexin biosynthetic puzzle in salt cress: unprecedented incorporation of glucobrassicin into wasalexins A and B. AB - Salt cress (Thellungiella salsuginea also known as T. halophila) is a wild cruciferous extremophile highly resistant to salt, drought, and cold. The recent discovery that salt cress produces the phytoalexins wasalexins A and B, and the phytoanticipins 1-methoxyglucobrassicin and 4-methoxyglucobrassicin in relatively higher amounts than other cruciferous species, prompted investigation of their biosynthetic relationships. Toward this end, perdeuterated 1-methoxybrassinin, l Trp, glucobrassicin, 1-methoxyindolyl-3-acetaldoxime, brassinin, and methionine, as well as the corresponding natural abundance compounds, were administered to salt cress plants previously irradiated with UV-light (lambda(max) 254 nm). Remarkably, administration of hexadeuterated glucobrassicin led to incorporation of several deuterium atoms into wasalexins A and B, 1-methoxyglucobrassicin and 4 methoxyglucobrassicin. This unprecedented discovery suggests that glucobrassicin is a biosynthetic precursor of wasalexins and methoxylated glucosinolates in salt cress. PMID- 20848034 TI - Concise total synthesis and structural revision of (+)-pestalazine B. AB - A convergent synthesis of the proposed structure of (+)-pestalazine B has been achieved in 4 steps using the N-alkylation of an unprotected tryptophan diketopiperazine with a 3a-bromopyrrolidinoindoline as the key step. Although its structure was confirmed by X-ray analysis, the spectroscopic data did not match those of the natural product. The versatility of the methodology allowed the preparation of several diastereomers, and the database generated led to the proposal of an isomeric structure for the natural alkaloid where the d-leucine and d-phenylalanine residues exchanged positions, which was corroborated by total synthesis. PMID- 20848033 TI - Expeditious chemoenzymatic synthesis of CD52 glycopeptide antigens. AB - CD52 is a glycosylphosphatidylinositol (GPI)-anchored glycopeptide antigen found on sperm cells and human lymphocytes. Recent structural studies indicate that sperm-associated CD52 antigen carries both a complex type N-glycan and an O glycan on the polypeptide backbone. To facilitate functional and immunological studies of distinct CD52 glycoforms, we report in this paper the first chemoenzymatic synthesis of homogeneous CD52 glycoforms carrying both N- and O glycans. The synthetic strategy consists of two key steps: monosaccharide primers GlcNAc and GalNAc were first installed at the pre-determined N- and O glycosylation sites by a facile solid-phase peptide synthesis, and then the N- and O-glycans were extended by respective enzymatic glycosylations. It was found that the endoglycosidase-catalyzed transglycosylation allowed efficient attachment of an intact N-glycan in a single step at the N-glycosylation site, while the recombinant human T-synthase could independently extend the O-linked GalNAc to form the core 1 O-glycan. This chemoenzymatic approach is highly convergent and permits easy construction of various homogeneous CD52 glycoforms from a common polypeptide precursor. In addition, the introduction of a latent thiol group in the form of protected cysteamine at the C-terminus of the CD52 glycoforms will enable site-specific conjugation to a carrier protein to provide immunogens for generating CD52 glycoform-specific antibodies for functional studies. PMID- 20848035 TI - Cell-penetrating hollow spheres based on milk protein. AB - Hollow protein nanospheres are prepared in aqueous solution by molecular self assembly, and they show extraordinary capability to penetrate cell barriers in an energy-independent fashion. PMID- 20848036 TI - Mimicking multipass transmembrane proteins: synthesis, assembly and folding of alternating amphiphilic multiblock molecules in liposomal membranes. AB - Alternating amphiphilic multiblock molecules 1-4, involving fluorescent hydrophobic units, were designed as mimics for multipass transmembrane proteins. Fluorescence spectroscopy of 1-4 in liposomal membranes suggested the face-to face stacking of the hydrophobic units to give folded structures as well as intermolecular assemblies. PMID- 20848037 TI - Self-assembled encapsulation systems with pH tunable release property based on reversible covalent bond. AB - Dynamic diblock polymer PS-r-PEG formed via reversible acylhydrazone connection can be used to construct a pH-responsive self-assembled encapsulation system with high stability and sustained-release property, which shows potential in drug delivery. PMID- 20848038 TI - Metal-free deprotonative functionalization of heteroaromatics using organic superbase catalyst. AB - Metal-free deprotonative functionalization of heteroaromatic compounds was achieved using an organic superbase catalyst; an organosilicon additive such as trimethylsilylpropyne was employed for activating the catalytic cycle of 1,2 addition to carbonyl compounds. PMID- 20848039 TI - Organocatalytic strategies for the asymmetric functionalization of indoles. AB - The desire for new synthetic methodologies for the rapid construction of enantiomerically pure substituted indole has been a fruitful driving force for chemical research in the last few years. This research line has produced a stunning array of enantioselective technologies either metal or organocatalyzed. This critical review documents the development of organocatalytic indole alkylation strategies, until the end of 2009 (127 references). PMID- 20848040 TI - Highly efficient and noble metal-free NiS/CdS photocatalysts for H2 evolution from lactic acid sacrificial solution under visible light. AB - We report the synthesis of highly active NiS/CdS photocatalysts via a simple hydrothermal loading method for H(2) evolution from lactic acid sacrificial solution under visible light. In the absence of noble metals, a high quantum efficiency of 51.3% was measured at 420 nm. PMID- 20848041 TI - Addition of [CH(CN)2]- and [TCNE]- to Ru(VI)=N bearing 8-quinolinolato ligands. AB - Reaction of Ru(VI)=N complexes bearing 8-quinolinolato ligands with NCCH(2)CN/piperidine and NaTCNE afford novel ruthenium(ii) dicyanoimine and diimine/imino-oxazolone complexes, respectively. PMID- 20848042 TI - Effective n-octane isomerization under exceptionally mild conditions using a novel class of superacidic ionic liquids. AB - Superacidic chloroaluminate ionic liquids of the general formula [cation]Cl/AlCl(3)[X(AlCl(3)) > 0.5] + H(2)SO(4) effectively isomerize n-octane to form branched liquid hydrocarbon isomers. Due to the highly acidic character of the ionic liquid the reaction proceeds under extremely mild conditions in a liquid-liquid biphasic reaction mode leading to a minimum of undesired cracking side-reactions. PMID- 20848043 TI - Rapid one-pot synthesis of LiMPO4 (M = Fe, Mn) colloidal nanocrystals by supercritical ethanol process. AB - We report a rapid one-pot supercritical fluid approach to prepare the desired size and morphology controlled LiMPO(4) nanocrystals, using oleylamine as both capping and reducing agent. PMID- 20848044 TI - Novel ball-type four dithioerythritol bridged metallophthalocyanines and their water-soluble derivatives: Synthesis and characterization, and electrochemical, electrocatalytic, electrical and gas sensing properties. AB - The phthalodinitrile derivative 3 was prepared by the reaction of 1,4 dithioerythritol 1 and 4-nitrophthalonitrile 2 in dry DMF as the solvent in the presence of K(2)CO(3) as the base by the method of nucleophilic substitution of an activated nitro group in an aromatic ring. The template reaction of compound 3 with the corresponding metal salts gave the novel binuclear MPcs of ball-type (M = Zn 4, Co 5, Cu 6) and their water soluble phthalocyanines 7-9 were obtained from refluxing a suspension of the compounds bearing eight OH side groups, in aqueous NaOH (%30) solution. Newly synthesized compounds were characterized by elemental analysis, UV/VIS, IR, MALDI TOF mass and (1)H-NMR spectroscopy techniques. The electronic spectra exhibit an intense pi->pi* transition of characteristic Q and B bands of the phthalocyanine core. The electrochemical measurements showed the formation of various mixed-valence oxidation and reduction species of 4 and 6 due to weak intramolecular interactions between the two MPc units. Complex 5 displayed a much higher catalytic activity than those of 4 and 6. It was found that oxygen reduction on the 5-based catalyst occurs through a direct 4-electron transfer pathway with a high water selectivity. However, the overpotential for oxygen reduction is high, probably due to a long distance between the two CoPc units in 5. A.c. and d.c. conductivity measurements were performed as a function of temperature (300-543 K) and frequency (40-10(5) Hz). It was found from d.c. measurements that the values of the pre-exponential factor sigma(0) for the investigated samples are in the interval from 1.36 * 10( 3) to 6.20 * 10(2)Omega(-1) cm(-1), inferring that the conduction occurs most probably by hopping between the localized states in band tails. Based on the existing theory of a.c. conduction, it has been concluded that for the low frequency region the dominant conduction mechanism is multihopping at high temperatures (>390 K) whereas for the high frequency region the correlated barrier hopping model is the dominant mechanism. The sensing properties of the films for CO(2) gas were also investigated. PMID- 20848045 TI - Synthesis and comparative anion binding profiles of two di-aqua Eu(III) complexes. AB - Two di-aqua Eu(iii) complexes of heptadentate ligands are reported that show differing reactivity profiles towards various anions; a cationic complex with two azaxanthone moieties exhibits pronounced selectivity towards bicarbonate with an affinity constant, logK = 2.65 (295 K, 0.1 M NaCl). PMID- 20848046 TI - Biological processes for treatment of landfill leachate. AB - This review presents an overview with critical analysis of the technical applicability of biological treatments for landfill leachate. A particular focus is given to activated sludge (AS), sequencing batch reactors (SBR), aerated lagoons (AL), and upflow anaerobic sludge blankets (UASB). Their advantages and limitations in application are evaluated. Selected information is presented such as pH, hydraulic retention time (HRT), organic loading rate (OLR), characteristics of leachate and treatment performance. It is evident from the literature survey of 188 papers (1976-2010) that none of the individual biological treatments presented is universally applicable for removing recalcitrant contaminants from leachate. Among the biological treatments reviewed, AS, SBR and UASB are the most frequently applied. These treatments are effective not only to remove over 90% of COD with a concentration ranging from 3500-26 000 mg L(-1), but also to achieve 80% of NH(3)-N removal with a concentration ranging from 100-1000 mg L(-1). A combination of physico-chemical and biological treatment into an integrated process is effective for leachate treatment. Almost complete removal of COD and NH(3)-N was reported for combined reverse osmosis (RO) and UASB with an initial COD concentration of 35 000 mg L( 1) and NH(3)-N concentration of 1600 mg L(-1). Integrated Fenton's oxidation and AS could achieve about 98% and 99% of COD and NH(3)-N removal, respectively, with initial COD and NH(3)-N concentrations of 7000 mg L(-1) and 1800 mg L(-1). Overall, the selection of the most suitable treatment for leachate depends on its characteristics, technical applicability and potential constraints, effluent limit required, cost-effectiveness, regulatory requirements and long-term environmental impacts. PMID- 20848047 TI - A liposome-based energy conversion system for accelerating the multi-enzyme reactions. AB - We report the first example of a liposome-based energy conversion system that is useful for entrapping enzymes and NAD coenzyme to accelerate multi-step enzymatic reactions. The liposome generates a much higher catalytic current compared with the non-liposome system, which is in good consistency with numerical simulations. PMID- 20848048 TI - Supraparticle physical chemistry. PMID- 20848049 TI - "Super hybrid tridentate ligands": 4-substituted-2-(1-butyl-1H-1,2,3-triazol-4 yl)-6-(1H-pyrazol-1-yl)pyridine ligands coordinated to Fe(ii) ions display above room temperature spin transitions. AB - A series of novel "super hybrid tridentate ligands" based on (2-(1-butyl-1H-1,2,3 triazol-4-yl)-6-(1H-pyrazol-1-yl)pyridine (tpp) derivatives were synthesized. Their Fe(ii) complexes display around (T(1/2) = 287 K) and above room temperature (T(1/2)? 375 K) spin transition temperatures. PMID- 20848050 TI - Femoral condyle lesion similar to osteochondritis dissecans. PMID- 20848051 TI - Outcome of femoral head ostectomy in dogs and cats. Munich publication reprinted. PMID- 20848052 TI - Cryptococcal meningoencephalitis with fulminant intracranial hypertension: an unexpected cause of brain death. AB - The diagnosis of brain death requires the presence of unresponsiveness and a lack of receptivity, the absence of movement, breathing and brain stem reflexes, as well as a state of coma in which the cause has been identified. We report a case of brain death that was diagnosed based on clinical neurological examinations, and supported by the absence of cerebral blood flow on magnetic resonance angiography and electroencephalography demonstrating the characteristic absence of electrical activity. Thorough clinical examination and repeated imaging of the brain revealed no apparent clinical cause or mechanism of brain death. We proceeded with organ donation of the deceased's liver and corneas. However, postmortem revealed Cryptococcus neoformans meningoencephalitis as the cause of irreversible coma. PMID- 20848053 TI - Pulmonary Scopulariopsis in a chronic tobacco smoker. AB - A 70-year-old male smoker, with a three-month status of post-balloon angioplasty for ischaemic heart disease, presented with a one-week history of fever, haemoptysis and chest discomfort on coughing. The patient did not report any loss of weight or appetite. On examination, he was febrile. Pulmonary function tests revealed obstructive airway disease. High resolution computed tomography of the lungs revealed fibrosis with bronchiectasis in both the upper lobes, and a spiculating subpleural mass in the posterior aspect of the right lung apex. Subsequent bronchoalveolar lavage (BAL) culture yielded the Scopulariopsis species. Our patient was treated with a four-week course of amphotericin B, followed by itraconazole. At the 24-month follow-up, the patient was asymptomatic. Subsequent BAL cultures revealed no fungal growths, and radiological studies showed a regression in the lesion. PMID- 20848054 TI - An unusual case of knee locking. AB - Knee locking is an incapacitating condition that requires urgent orthopaedic intervention. The most common cause is meniscal injury, followed by torn anterior cruciate ligament, osteochondral loose bodies and foreign bodies in the joint space. This report describes a patient who had an unusual case of left knee locking. After clinical examination and radiological investigations, the provisional diagnosis was a lateral meniscal tear, which was not visible on magnetic resonance imaging. Diagnostic arthroscopy of the left knee revealed a 1 cm yellowish lump on the medial meniscus, and the histology revealed pigmented villonodular synovitis. The menisci and cruciate ligaments were intact. PMID- 20848055 TI - Elevated serum CA 19-9 in association with Hashimoto thyroiditis. AB - Tumour markers are widely used in clinical practice. Elevated tumour markers can be observed in both malignant and benign conditions. Therefore, it is important for clinicians to be aware of the association of tumour markers with various disorders so that unnecessary investigations can be avoided without missing the malignant disorders. A 58-year-old woman who presented with weight loss and elevated carbohydrate antigen 19-9 (CA19-9) was referred to our hospital for evaluation and was subsequently diagnosed with Hashimoto thyroiditis. Investigations for underlying malignancy were negative. The CA19-9 level normalised subsequently, with restoration of the euthyroid state. PMID- 20848056 TI - Writing an editorial. AB - An editorial may be written by the editor or someone invited by the editor. It serves many other purposes, including critiques of original articles published in the same issue of the journal, concise reviews of topics that do not warrant a full-length invited review, and other topics on very recent developments that are deemed by the editor to be important to readers of the journal and the community. As there is typically a limited space in which to deliver its contents, the message contained in the editorial needs to be well thought out and concisely delivered. It should contain the correct sequence of the elements of critical argument, ideally supported by evidence, and end with a clear conclusion. PMID- 20848057 TI - HbA1c and factors other than diabetes mellitus affecting it. AB - Glycated haemoglobins are haemoglobins with an attached sugar moiety. They constitute the HbA1 fraction of the adult haemoglobin HbA. HbA1c is the predominant fraction of HbA1 and gives an estimate of the blood sugar levels of an individual over the last three months. It has been observed that an HbA1c value of less than seven percent reduces the microvascular complications in diabetic patients. However, HbA1c is not affected by blood sugar levels alone. Apart from blood sugar, there are other factors that affect HbA1c. This article reviews in detail the structure, formation, methods of measurement, factors affecting HbA1c levels and their clinical significance. PMID- 20848058 TI - Influenza and seasonal influenza vaccination among diabetics in Singapore: knowledge, attitudes and practices. AB - INTRODUCTION: Seasonal influenza vaccination is recommended for diabetics; however, the vaccination uptake rate among diabetics remains low. This study explored the knowledge, attitudes and practices among diabetics in Singapore with regard to influenza and influenza vaccination. METHODS: A survey was conducted among type 1 and 2 diabetes mellitus patients who attended three management centres of the Diabetic Society of Singapore in January 2007. The pilot-tested questionnaire covered influenza and influenza vaccination in terms of the patient demographics, medical history and knowledge, attitudes and practices. RESULTS: A total of 307 diabetics participated in the study. Of these, 139 (45.3 percent) claimed to know the difference between influenza and the common cold, while 98 (31.9 percent) and 18 (5.9 percent) participants thought that influenza vaccines protected against all influenza strains and provided lifelong immunity, respectively. 247 (80.4 percent) participants were aware that they were at a moderate or higher risk for influenza-related complications, while 181 (58.9 percent) considered vaccination to be effective in preventing influenza and its complications. Only 94 (30.6 percent) participants were previously vaccinated. Among those unvaccinated, 117 (54.9 percent) did not think vaccination was necessary, while 104 (48.8 percent) had never considered it. As observed from the multivariate analysis, income was a key predictor of influenza vaccination. While 241 (78.5 percent) participants cited healthcare professional advice as the main guiding factor for getting vaccinated, 199 (64.8 percent) had never been advised on influenza vaccination. Of the 108 (35.1 percent) participants who had received previous advice on influenza vaccination, the majority had received it from their healthcare professionals. CONCLUSION: Uptake of influenza vaccination among diabetics in Singapore is low, and the key predictor is income. Perception and knowledge are the main barriers, and hence, healthcare professionals should educate and encourage vaccination among diabetics. PMID- 20848059 TI - Diabetic eye screening in Malaysia: findings from the National Health and Morbidity Survey 2006. AB - INTRODUCTION: Diabetic retinopathy (DR) is the commonest complication of diabetes mellitus (DM), and is the leading cause of blindness among working adults. Modification of the associated risk factors as well as early detection and treatment of sight-threatening DR can prevent blindness. Clinical practice guidelines recommend annual eye screening for patients with DM. The proportion of patients in Malaysia who adhere to this recommendation was initially unknown. METHODS: The Malaysian National Health and Morbidity Survey is a population-based survey conducted once every decade on the various aspects of health, behaviour and diseases. The DM questionnaire on eye screening was administered as face-to face interviews with 2,373 patients with known DM who were aged 18 years and older. RESULTS: In all, 55 percent of patients with known DM had never undergone an eye examination. Among patients who had undergone eye examinations, 32.8 percent had the last examination within the last one year, 49.8 percent within the last one to two years, and 17.4 percent more than two years ago. A significantly lower proportion of younger patients and patients who received treatment for DM from non-government facilities had previously undergone eye examinations. CONCLUSION: The prevalence of DM observed among Malaysians aged 30 and above is 14.9 percent; thus, there is a significant number of people with potential blinding DR. Adherence to eye screening guidelines and the prompt referral of sight-threatening DR are essential in order to reduce the incidence of blindness among patients with DM. PMID- 20848060 TI - Predictive equation for estimating the basal metabolic rate of Malaysian Armed Forces naval trainees. AB - INTRODUCTION: The basal metabolic rate (BMR) is essential in deriving estimates of energy requirements for a population. The aim of this study was to measure the BMR in order to derive a predictive equation for the Malaysian Armed Forces (MAF) naval trainees. METHODS: A total of 79 naval trainees aged 18 to 25 years from a training centre (Group A) and on board a ship (Group B) participated in the study. Anthropometric measurements included height and weight. Body fat and free fat mass were measured using the bioelectrical impedance analysis method. BMR was measured by indirect calorimetry with a canopy system. RESULTS: The mean height, weight and body fat for Group A was 1.67 +/- 0.04 m, 61.0 +/- 3.9 kg and 12.7 percent +/- 2.5 percent, respectively, and 1.67 +/- 0.05 m, 62.3 +/- 6.2 kg and 14.0 percent +/- 3.5 percent, respectively, for Group B. The mean BMR for Group A (6.28 +/- 0.40 MJ/ day) did not differ significantly (p is more than 0.05) from that of Group B (6.16 +/- 0.67 MJ / day). The Food and Agriculture Organization/World Health Organization/United Nations University and the Henry and Rees equations overestimated the measured BMR by 9 percent (p is less than 0.001) and 0.5 percent (p is more than 0.05), respectively, while the Ismail et al equation underestimated the measured BMR by 5.6 percent (p is less than 0.001). A predictive equation, BMR = 3.316 + 0.047 (weight in kg) expressed in MJ /day with weight as the only independent variable, was derived using regression analysis. CONCLUSION: We recommend that this predictive equation be used to estimate the energy requirements of MAF naval trainees. PMID- 20848061 TI - Exchange transfusion in neonatal hyperbilirubinaemia: a comparison between citrated whole blood and reconstituted blood. AB - INTRODUCTION: Exchange transfusion is performed using many different combinations of blood components. No single component is unequivocally the best. The purpose of this study was to determine the efficacy and adverse events of exchange transfusion (ECT) with whole blood and reconstituted blood in neonatal hyperbilirubinaemia. METHODS: The medical charts of all neonates who had undergone ECT over a two-year period were retrospectively reviewed. The demographic features, causes of jaundice, details of the exchange method and ECT related adverse events of the infants were recorded. A total of 107 ECT procedures were performed in 92 neonates during the study period. The neonates were categorised into those who received whole blood (n is 38) and those who received reconstituted blood (n is 54) for ECT. RESULTS: There was no significant difference in the demographic characteristics and causes of jaundice between the two groups. ABO blood group incompatibility was the most common cause of hyperbilirubinaemia in both groups. The mean pre-ECT haematocrit of exchange transfused patients with whole blood and reconstituted blood was compatible. Although the mean post-ECT haematocrit in the reconstituted group was higher (39.74 +/- 5.65 versus 38.21 +/- 3.59), this difference was not significant (p is 0.15). The mean post-ECT platelet count was 59,000 +/- 29,400 and 73,000 +/- 21,300 in patients who underwent ECT with reconstituted and whole blood, respectively. A similar number of patients in both groups experienced hypocalcaemia and thrombocytopaenia after ECT. No case of ECT-related mortality was observed. CONCLUSION: ECT with either reconstituted or fresh whole blood is an efficient and safe method for reducing hyperbilirubinaemia. PMID- 20848062 TI - The use of baby walkers in Iranian infants. AB - INTRODUCTION: A study was conducted to define the pattern of baby walker usage and the rate of walker-related injuries in infants, as well as to determine the effects of baby walkers on the start of independent walking among infants. METHODS: Families of infants aged six months to two years who presented at health facility clinics in 2007 and 2008 were enrolled in the study. The study team interviewed the primary caregiver and documented the relevant data on a pre designed questionnaire. The data of users of baby walkers was compared with that of non-users. RESULTS: Walkers were used by 54.5 percent of 414 infants. Their use was significantly higher in one-child families (p-value is 0.009) and in those with higher parental education levels (p-value is less than 0.001). 78.6 percent of users and 85 percent of non-users were walking by 12 months of age (p value is 0.283); no significant difference was observed between the two groups in terms of the age at which the infants starting walking (p-value is 0.401). 76.8 percent of parents of users versus 8.2 percent of parents of non-users believed that walkers promote early walking (p-value is less than 0.001). 44.7 percent of parents of users knew that walkers can be hazardous, as compared to 22.3 percent of parents of non-users. No serious injury was reported, but 14.1 percent of infants sustained trivial walker-associated injuries. CONCLUSION: Baby walkers do not hasten independent walking and may be associated with injuries. However, it was noted that knowledge of the associated hazards has not deterred parents from using baby walkers for their infants. PMID- 20848063 TI - 418 cases of laparoscopic colorectal resections: a single-institution experience and literature review. AB - INTRODUCTION: Evidence from randomised controlled trials has shown that laparoscopic colon and rectal cancer resection not only confers short-term benefits but also does not differ considerably in terms of its long-term oncological outcomes, as compared with open surgery. METHODS: All laparoscopic colon and rectal resections performed between January 2005 and December 2007 were included. Patient records were reviewed from a prospective database and the relevant clinical data was obtained, with a subgroup analysis of cancer procedures performed. RESULTS: 418 patients (247 male), median age 63 years (range 24 to 88), underwent laparoscopic resection of the colon and rectum. The median Body Mass Index (BMI) was 22.5 (range 13.5 to 39.3). The majority of the procedures were performed for malignant disease (81.3 percent) and the most common procedure was anterior resection (79.4 percent). The median duration of surgery was 135 minutes (range 65 to 330), with conversions to open surgery in 44 patients (10.5 percent). Complications occurred in 78 patients (18.7 percent), including anastomotic leaks in five (1.20 percent). The median length of hospital stay was five days (range 3 to 90) and the median follow-up was 19 months (range 1 to 46). In the 340 patients with malignant disease, the median number of lymph nodes harvested was 13 (range 5 to 48), and at the latest review, 230 patients (67.6 percent) were disease-free, with locoregional recurrence in 2.9 percent and systemic recurrence in 10 percent. CONCLUSION: To date, this is the largest series of laparoscopic colorectal resections reported locally, and our results show that it is safe, feasible and produces favourable results. PMID- 20848064 TI - Tularaemia outbreaks in Sakarya, Turkey: case-control and environmental studies. AB - INTRODUCTION: Tularaemia is an important zoonotic disease that leads to outbreaks. This study aimed to compare the epidemiological characteristics of two tularaemia outbreaks that occurred in the Sakarya region of Turkey, analyse the risk factors for the development of outbreaks and identify Francisella (F.) tularensis in the water samples. METHODS: Two tularaemia outbreaks occurred in the Kocadongel village in 2005 and 2006. A field investigation and a case-control study with 47 cases and 47 healthy households were performed during the second outbreak. Clinical samples from the patients and filtrated water samples were analysed for F. tularensis via real-time polymerase chain reaction. RESULTS: From the two outbreaks, a total of 58 patients were diagnosed with oropharyngeal tularaemia based on their clinical and serological results. Both outbreaks occurred between the months of January and April, and the number of patients peaked in February. Logistic regression analysis revealed that the consumption of natural spring water was the only significant risk factor for tularaemia infection (odds ratio 3.5, confidence interval 1.23-10.07). F. tularensis was detected in eight clinical samples and in the filtrated natural spring water. CONCLUSION: This study is the first report of tularaemia from this region. The results show that both tularaemia outbreaks were related to the consumption of untreated natural spring water. To prevent waterborne tularaemia, community water supplies should be treated and checked periodically. PMID- 20848065 TI - Factors affecting the diagnostic yield of flexible bronchoscopy without guidance in pulmonary nodules or masses. AB - INTRODUCTION: In day-to-day bronchoscopic practice, no guidance is available to pinpoint the precise location of pulmonary nodules or masses, especially in developing countries. This results in a large number of non-diagnostic testings. The present study aimed to determine the predictors of diagnostic yield in bronchoscopy without guidance and develop a model to predict the decision to perform this procedure. METHODS: A retrospective study was conducted on 330 patients with pulmonary nodules or masses without any sign of atelectasis on chest radiographs, who underwent diagnostic bronchoscopy without guidance between June 2004 and May 2008. The patient characteristics, as well as radiological and bronchoscopic findings were included in the analysis of factors affecting the diagnostic yield. RESULTS: The overall diagnostic yield of bronchoscopy was 55.8 percent. The tumour size, endobronchial visibility and the characteristics of endobronchial abnormalities were predictors of higher diagnostic yield. The prediction model was developed from the data that can be recognised before bronchoscopy. Bronchoscopy provided the diagnosis in 66.4 percent of the patients who had a tumour size of 4 cm or larger. CONCLUSION: The diagnostic yield of bronchoscopy without guidance was influenced by the size of the lesion, the endobronchial visibility and the characteristics of endobronchial abnormalities. Computed tomography (CT) of the chest should be performed to evaluate airway involvement. If the lesion is less than 4 cm in diameter and there is a negative CT illustration of airway involvement, flexible bronchoscopy with guidance should be considered. PMID- 20848066 TI - Cystic pancreatic lesions: a pictorial review and management approach. AB - The majority of cystic pancreatic lesions are incidental findings, especially with the increasing use of advanced imaging modalities for non-related conditions. Most of these lesions were previously attributed to pseudocysts, although cystic neoplasms are now an important differential to be considered and excluded. This article aims to describe the types of cystic pancreatic lesions, demonstrate their imaging findings and discuss the management of these conditions. PMID- 20848067 TI - Reactive perforating collagenosis masquerading as rheumatoid arthritis. PMID- 20848068 TI - Relationship of the abdominal and pelvic viscera with the peritoneum. PMID- 20848070 TI - [HIV, HBV and HCV infected healthcare workers]. PMID- 20848071 TI - [Linear localized scleroderma. Successful treatment with prednisolone pulse therapy and methotrexate]. AB - Linear localized scleroderma is a variant of localized scleroderma characterized by linear bands and sclerotic plaques of the skin, which can result in contractures, muscle atrophy and debilitating deformities. The etiology remains unknown and no specific therapy is available. Regimens combining pulsed high-dose corticosteroids with methotrexate therapy seem promising. Our patient responded well to intravenous prednisolone (500 mg/d) for 3 consecutive days monthly combined with an oral dose of methotrexate of (15 mg/wk). PMID- 20848072 TI - [Neurological rehabilitation]. AB - This article describes state of the art concepts of neurological rehabilitation in Germany. In parallel to enormous growth of knowledge in the neurosciences also neurological rehabilitation has made significant progress. The increasing use of concepts of evidence based medicine and an early translation of knowledge from the neurosciences into clinical rehabilitation practice contribute to therapeutic advances. It is now widely accepted, that rehabilitation should start early and should be organized in a multidisciplinary professional team. Therapeutic procedures selected should be evidence based and have to be modified to find custom tailored solutions for individual patients. General rules derived from neuroscientific knowledge have been shown to be useful to design new therapeutic techniques. Neuromodulatory stimulation and special pharmacological treatments provide further options for enhancing results of rehabilitation. PMID- 20848073 TI - [Cardiovascular rehabilitation]. AB - Cardiovascular rehabilitation encompasses the optimization of secondary prevention to reduce morbidity and mortality, the improvement of physical fitness and quality of life as well as the reintegration into social life and employment. This requires a multifactorial intervention on the physical, psychological, educative and social level by a multidisciplinary team. In Germany, cardiac rehabilitation started early after an index event, could demonstrate a significant reduction of total mortality, myocardial infarction and hospitalization during a follow-up of 1-2 years in 4 cohort studies including 10,758 patients with myocardial infarction and bypass surgery. This reduction of clinical events was obtained in addition to rapid revascularization therapy during the acute coronary event and on top of an evidence based secondary preventive medication. By national and international medical societies, cardiac rehabilitation is recommended as well in patients with congestive heart failure, after valve replacement or valve repair, after heart transplantation and cardioverter/defibrillator implantation. In the future, cardiac rehabilitation in Germany should be evaluated by a randomized controlled trial and multifactorial interventions should be tailored individually to specific patient subgroups and medical conditions. PMID- 20848074 TI - Speed of call delivery is related to context and caller identity in Campbell's monkey males. AB - Call rate can be a salient feature in animal communication. Depending on the species, different psychological variables appear to influence call rates but the exact nature of these relationships remains poorly explored. Here, we demonstrate for free-ranging Campbell's monkeys that the call rates of four different alarm series (termed H, K, K(+), and B series) vary systematically as a function of context, associated behaviour, and identity of the caller. K(+) series were given more rapidly to predation than non-predation events, K(+) and K series more rapidly to visual than auditory predator detection, and H series more rapidly while counterattacking an eagle than staying put. Finally, there were individual differences in B series, suggesting that call rate potentially provides listeners with cues about the caller's anti-predator behaviour, event type experienced, and his identity. PMID- 20848075 TI - ["Theory of mind" and its neuronal correlates in forensically relevant disorders]. AB - Theory of mind (ToM), the ability to recognize mental states of others, and empathy are crucial cognitive-emotional processes for appropriate social interactions. Deficits in these processes can lead to maladjusted social behavior or even to aggressive or criminal behavior. ToM and empathy deficits have been found in different forensically relevant disorders, such as schizophrenia, pedophilia but especially in autism and psychopathy according to Hare. Most notably, autistic and psychopathic patients differ in their type of deficits and in their neuronal correlates. While autistic individuals lack the ability to take the perspective of others, psychopaths lack empathy. The aim of this article is to provide a better understanding of the pathophysiology of ToM and empathy deficits in forensically relevant disorders by reviewing and discussing the findings of neuroimaging and lesion studies and to highlight crucial implications for neuropsychotherapy according to Grawe. PMID- 20848076 TI - [Targeted therapy of urological tumours. Experimental field or established therapeutic approach?]. AB - Unlike conventional systemic chemotherapies, the aim of targeted therapeutic approaches is not to address general mechanisms involved in cellular replication. In contrast, they aim at such regulatory pathways that have been identified to be involved in the progression of human malignant disease. Whereas the application of targeted therapeutic modalities is well established for the treatment of metastatic renal cell cancer, only very few data on their clinical efficacy during the treatment of other urological tumours such as prostate and bladder cancer are currently available. The aim of this paper is to reflect on the current status regarding the relevance of targeted therapeutic approaches during the treatment of urological cancers of different origin. PMID- 20848077 TI - Obesity and the risk of disability in a 12-year cohort study: the role of psychological distress. AB - PURPOSE: Recent cross-sectional findings suggest that co-occurring obesity and psychological problems amplify the risk of disability, but longitudinal evidence is lacking. We assessed this effect in a longitudinal cohort of adults. METHODS: Twelve years of data (1994/1995-2006/2007) were obtained from the Canadian National Population Health Survey. This study followed 8,062 adults that were interviewed every 2 years. Disability status was derived from the Health Utility Index Mark 3. Covariates of interest were repeated psychological distress (Kessler K6 scale) and obesity (body mass index >=30). Incidence of disability was estimated from Cox proportional hazards models, adjusting for sociodemographic and health variables. Hazard rate of disability in those with either obesity (n = 955) or distress (n = 1,044), or both (n = 138) were compared to those without (n = 5,925). RESULTS: Participants with both obesity and repeated distress had double the risk of disability compared to those with obesity or distress alone {adjusted hazard ratio of 2.8 [95% confidence interval (CI) 1.8, 4.5] compared to 1.4 (CI 1.1, 1.8) and 1.8 (CI 1.4, 2.3), respectively}. CONCLUSIONS: Recurrent psychological distress combined with obesity amplified the risk for disability normally associated with these conditions. PMID- 20848078 TI - Construction and psychometric testing of the EMPATHIC questionnaire measuring parent satisfaction in the pediatric intensive care unit. AB - PURPOSE: To construct and test the reliability and validity of the EMpowerment of PArents in THe Intensive Care (EMPATHIC) questionnaire measuring parent satisfaction in the pediatric intensive care unit (PICU). METHODS: Structured development and psychometric testing of a parent satisfaction-with-care instrument with the results of two cohorts of parents (n = 2,046) from eight PICUs in the Netherlands. RESULTS: In the first cohort, 667/1,055 (63%) parents participated followed by 551/991 (56%) parents in the second cohort. The empirical structure of the instrument was established by confirmatory factor analysis with the first sample of parents confirming 65 statements within five theoretically conceptualized domains: information, care and cure, organization, parental participation, and professional attitude. The standardized factor loadings were greater than 0.40 in 63 statements. Cronbach's alpha, a measure of reliability, per domain ranged from 0.73 to 0.93 in both cohorts with no significant difference documenting the reliability over time. Beside rigorous content and face validity, the congruent validity of the instrument showed adequate correlation with four gold standard questions measuring overall satisfaction. The non-differential validity was confirmed with no significant differences between the population characteristics and the domains, except that parents with a child for a surgical admission were more satisfied on information issues. CONCLUSIONS: The final EMPATHIC questionnaire incorporates 65 statements. The empirical structure of the satisfaction statements and domains was satisfactory. The reliability and validity proved to be adequate. The EMPATHIC questionnaire is a valid quality performance indicator to measure quality of care as perceived by parents. PMID- 20848079 TI - High rate ultrafiltration in anasarca: 33 l of net negative fluid balance in 52 h! PMID- 20848080 TI - Rescue treatment for noninvasive ventilation failure due to interface intolerance with remifentanil analgosedation: a pilot study. AB - PURPOSE: To assess the feasibility of remifentanil-based sedation in hypoxemic acute respiratory failure (HARF) patients refusing to continue noninvasive ventilation (NPPV) for intolerance to two different interfaces-helmet and total face mask. DESIGN AND SETTING: Prospective uncontrolled clinical investigation in a 14-bed ICU of an university hospital in Italy. PATIENTS: Thirty-six patients with persistent severe HARF who complained of discomfort and asked for interruption of NPPV session. INTERVENTION: Patients started sedation with remifentanil (0.025 MUg kg(-1) min(-1)) and the infusion rate was increased by 0.01 MUg kg(-1) min(-1) every minute to a maximum of 0.12 MUg kg(-1) min(-1) to obtain patient comfort. MEASUREMENTS AND RESULTS: Twenty-two out of 36 patients (61%) with median (IQR) SAPS II score of 32 (30, 38) continued the NPPV treatment after the introduction of remifentanil infusion. In this success group, median (IQR) respiratory rate decreased from 34 (31, 37) to 24 (20, 26) min(-1) (p < 0.0001) and PaO(2)/FiO(2) ratio increased from 156 (144, 176) to 270 (210, 300) mmHg (p < 0.0001) after 1 h of NPPV with remifentanil-analgosedation either with helmet or total face mask. Fourteen patients failed to continue the noninvasive treatment and were intubated after a mean of 2.5 +/- 2.3 h; they showed a respiratory rate decrease from 35 (30, 38) to 27 (25, 35) min(-1) (p = 0.02) and an inability to increase the PaO(2)/FiO(2) ratio above 180 mmHg. The ICU mortality in the failure group patients was 50 versus 14% in the NPPV success group (p < 0.05). The mean remifentanil dose administered was 0.07 +/- 0.03 MUg kg(-1) min(-1). CONCLUSION: This clinical study suggests that a remifentanil based sedation protocol can decrease the rate of failure in patients with intolerance to NPPV. PMID- 20848082 TI - Evaluation of in vitro antagonism and of in vivo immune modulation and protection against pathogenic experimental challenge of two probiotic strains of Bifidobacterium animalis var. lactis. AB - The aim of the present study was to compare the effect of intragastric administration with two strains of Bifidobacterium animalis subsp. lactis (Bifido A and Bifido B), in gnotobiotic and conventional mice, challenged with Salmonella Typhimurium. In vitro antagonism test showed that the two strains were able to produce antagonistic substances against various pathogenic microorganisms. In an ex vivo antagonism test the production of antagonistic substances was observed only against three out ten pathogens tested. Both Bifidobacterium strains were able to colonize and to maintain high population levels in the digestive tract of gnotobiotic mice. In addition, the two strains had low and limited translocation ability and did not cause any histological lesion in any of the organs analyzed. Both strains were able to reduce the fecal number of Salmonella in gnotobiotic mice challenged with the pathogen, but only Bifido B was able to confer a protection as demonstrated by a lower mortality. Higher levels of sIgA and IL-10 were observed only in Bifido B mono-associated mice when compared to germ free group. We could conclude that, among the parameters analyzed, the strain Bifido B exhibited the more desirable characteristics to be used as a probiotic. PMID- 20848081 TI - Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey. AB - It is unclear whether optimal levels of 25-hydroxyvitamin D (25(OH)D) in whites are the same as in minorities. In adult participants of NHANES, the relationships between 25(OH)D, bone mineral density (BMD), and parathyroid hormone (PTH) differed in blacks as compared to whites and Mexican-Americans, suggesting that optimal 25(OH)D levels for bone and mineral metabolism may differ by race. INTRODUCTION: Blacks and Hispanics have lower 25-hydroxyvitamin D concentrations than whites. However, it is unclear whether 25(OH)D levels considered "optimal" for bone and mineral metabolism in whites are the same as those in minority populations. METHODS: We examined the relationships between 25(OH)D and parathyroid hormone in 8,415 adult participants (25% black and 24% Mexican American) in the National Health and Nutrition Examination Surveys 2003-2004 and 2005-2006; and between 25(OH)D and bone mineral density in 4,206 adult participants (24% black and 24% Mexican-American) in the 2003-2004 sample. RESULTS: Blacks and Mexican-Americans had significantly lower 25(OH)D and higher PTH concentrations than whites (P < 0.01 for both). BMD significantly decreased (P < 0.01) as serum 25(OH)D and calcium intake declined among whites and Mexican Americans, but not among blacks (P = 0.2). The impact of vitamin D deficiency (25(OH)D <= 20 ng/ml) on PTH levels was modified by race/ethnicity (P for interaction, 0.001). Whereas inverse relationships between 25(OH)D and PTH were observed above and below a 25(OH)D level of 20 ng/ml in whites and Mexican Americans, an inverse association between 25(OH)D and PTH was only observed below this threshold in blacks, with the slope of the relationship being essentially flat (P = 0.7) above this cut-point, suggesting that PTH may be maximally suppressed at lower 25(OH)D levels in blacks than in whites or Mexican-Americans. CONCLUSIONS: The relationships between 25(OH)D, BMD, and PTH may differ by race among US adults. Whether race-specific ranges of optimal vitamin D are needed to appropriately evaluate the adequacy of vitamin D stores in minorities requires further study. PMID- 20848083 TI - Intranasal benzo[a]pyrene alters circadian blood pressure patterns and causes lung inflammation in rats. AB - Polycyclic aromatic hydrocarbons, including benzo[a]pyrene (BaP), are environmental contaminants formed during organic material combustion (e.g. burning fossil fuels and cigarette smoke). BaP toxicity is mediated, in part, by activation of the aryl hydrocarbon receptor and formation of reactive metabolites, both of which lead to increased oxidative stress. Since air pollution and cigarette smoking are known to increase cardiovascular disease in humans, the objective of this study was to determine the effects of 7-day intranasal BaP exposure on circadian blood pressure patterns, arterial stiffness, and possible sources of oxidative stress in radiotelemetry-implanted rats. Arterial pulse wave dP/dt was used an indicator of arterial stiffness and was compared to both functional (nitric oxide production and bioactivity, endothelin 1 levels) and structural (wall thickness) features of the arterial wall. In addition, histology of lung, heart, and liver were examined as well as pulmonary and hepatic cytochrome P450 1A1 (CYP1A1) activity. BaP exposure altered the circadian pattern of blood pressure, with a reduction in the normal dipping pattern during sleep. This was associated with increased neutrophil recruitment in the lungs of BaP-exposed rats. In contrast, BaP had no effect on cardiovascular tissue histology, arterial stiffness, oxidative stress or lung and liver CYP1A1 activity. Thus, the current study does not support the hypothesis that BaP reactive metabolites increase oxidative stress leading to reduced vascular NO bioactivity and increased blood pressure. Instead, the current study suggests that inflammation, detected only in the lung, is associated with altered circadian rhythm of blood pressure. PMID- 20848084 TI - Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway. AB - Alveolar type II epithelial cells can regulate immune responses to sepsis-induced acute lung injury. Lipopolysaccharide (LPS), an outer membrane component of Gram negative bacteria, can cause septic shock. This study was designed to evaluate the cytotoxic effects of LPS on human alveolar epithelial A549 cells and its possible molecular mechanisms. Exposure of A549 cells to LPS decreased cell viability in concentration- and time-dependent manners. In parallel, LPS concentration- and time-dependently induced apoptosis of A549 cells. Meanwhile, LPS only at a high concentration of 10 MUg/ml caused mildly necrotic insults to A549 cells. In terms of the mechanism, exposure of A549 cells to LPS increased the levels of cellular nitric oxide and reactive oxygen species (ROS). Pretreatment with N-acetylcysteine (NAC), an antioxidant, significantly lowered LPS-caused enhancement of intracellular ROS in A549 cells and simultaneously attenuated the apoptotic insults. Sequentially, treatment of A549 cells with LPS caused significant decreases in the mitochondrial membrane potential and biosynthesis of adenosine triphosphate. In succession, LPS triggered the release of cytochrome c from the mitochondria to the cytoplasm. Activities of caspase-9 and caspase-6 were subsequently augmented following LPS administration. Consequently, exposure of A549 cells induced DNA fragmentation in a time dependent manner. Pretreatment of A549 cells with NAC significantly ameliorated LPS-caused alterations in caspase-9 activation and DNA damage. Therefore, this study shows that LPS specifically induces apoptotic insults to human alveolar epithelial cells through ROS-mediated activation of the intrinsic mitochondrion cytochrome c-caspase protease mechanism. PMID- 20848085 TI - Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway. AB - Oral helminthic mebendazole (MBZ) has been reported to cause liver injury with inflammatory responses. However, the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether MBZ and other helminthic drugs increase the release of pro-inflammatory cytokines and chemokines using human monocytic cells. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) alpha from human monocytic THP-1 cells was significantly increased by treatment with MBZ, albendazole (ABZ), fenbendazole (FBZ), or oxibendazole (OBZ), but not by albendazole sulfoxide or praziquantel, suggesting that MBZ and structurally similar drugs can stimulate monocytes and increase the release of pro-inflammatory cytokines. MBZ also significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 in THP-1 cells. Pretreatment with the MAP kinase/ERK kinase 1/2 inhibitor U0126 significantly suppressed the increase of IL 8 and TNFalpha levels by MBZ, ABZ, FBZ, or OBZ treatment in THP-1 cells, but the p38 mitogen-activated protein kinase inhibitor SB203580 or JNK1/2 inhibitor SP600125 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFalpha in THP-1 cells treated with MBZ and structurally similar drugs. In conclusion, the release of inflammatory mediators by MBZ might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to hepatotoxicity. PMID- 20848086 TI - Effect of the adenosine A2A receptor antagonist MSX-3 on motivational disruptions of maternal behavior induced by dopamine antagonism in the early postpartum rat. AB - RATIONALE: Mesolimbic dopamine (DA), particularly in the nucleus accumbens, importantly regulates activational aspects of maternal responsiveness. DA antagonism and accumbens DA depletions interfere with early postpartum maternal motivation by selectively affecting most forms of active maternal behaviors, while leaving nursing behavior relatively intact. Considerable evidence indicates that there is a functional interaction between DA D2 and adenosine A(2A) receptors in striatal areas, including the nucleus accumbens. OBJECTIVE: This study was conducted to determine if adenosine A(2A) receptor antagonism could reverse the effects of DA receptor antagonism on early postpartum maternal behavior. METHODS: The adenosine A(2A) receptor antagonist MSX-3 (0.25-2.0 mg/kg, IP) was investigated for its ability to reverse the effects of the DA D2 receptor antagonist haloperidol (0.1 mg/kg, IP) on the maternal behavior of early postpartum female rats. RESULTS: Haloperidol severely impaired the expression of active maternal components, including retrieval and grouping the pups at the nest site, pup licking, and nest building. Co-administration of MSX-3 (0.25-2.0 mg/kg, IP) with haloperidol produced a dose-related attenuation of the haloperidol induced behavioral deficits in early postpartum females. Doses of MSX-3 that effectively reversed the effects of haloperidol (0.5, 1.0 mg/kg), when administered in the absence of haloperidol, did not affect maternal responding or locomotor activity. CONCLUSIONS: Adenosine and DA systems interact to regulate early postpartum maternal responsiveness. This research may potentially contribute to the development of strategies for treatments of psychiatric disorders during the postpartum period, with particular emphasis in maintaining or restoring the mother-infant relationship. PMID- 20848088 TI - Bond length contraction in gold nanoparticles. AB - The structure of nanoparticles typically differs from its bulk counterpart. Predominantly, the structures of gold nanoparticles have been under exceedingly intense discussion since the discovery of their high catalytic activity. We found an increasing bond length contraction with decreasing particle size for citrate stabilized gold nanoparticles in aqueous solution as determined by in situ extended X-ray absorption fine structure (EXAFS) spectroscopy. Particle sizes and size distributions were determined by small-angle X-ray scattering. The analysis of the obtained EXAFS spectra employing ab initio calculations reveals that the Au-Au bond length undergoes a contraction of 2 pm for nanoparticles with a radius of 2.9 nm. NIST reference material RM 8011 gold nanoparticles with a radius of 4.4 nm exhibit a smaller contraction of approximately 1 pm. Finally, gold atoms in RM 8013 particles with a radius of 25.7 nm show distances of 288 pm--identical to the distance in gold foil--and exhibits bulk-like properties. The observed bond length contraction of gold nanoparticles in solution is significantly smaller than previously reported for gold nanoparticle deposited on surfaces, which is up to 15 pm. This indicates that the bond length contraction effect of "free" and "surface-immobilized" nanoparticles differ fundamentally. Such difference could be essential for the understanding of nanoparticle-supported catalysis. PMID- 20848089 TI - Correction of discrepancies in dioxin quantification between immunoassay and gas chromatography-high-resolution mass spectrometry. AB - Due to the toxicity of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F), efforts are made to quantify their emission into the environment. Typically, this quantification is done using gas chromatography-high resolution mass spectrometry (GC-HRMS). However, GC-HRMS is extremely expensive and time consuming, and GC-HRMS facilities are overly requested. In order to decrease the workload on GC-HRMS, another alternative is to use an enzyme-linked immunosorbent assay (ELISA) as a semi-quantitative screening tool. One problem of this solution is that ELISA measures the total PCDD/F content of a sample differently than GC-HRMS; a disparity exists between the two techniques. This paper introduces a congener correction factor that adjusts ELISA results for this incompatibility. The importance of the correction factor is explored by examining the congener profiles of 27 different dioxin sources. The congener profiles for many of these sources are such that large incompatibilities in predicted PCDD/F content would likely exist between uncorrected ELISA and GC-HRMS. The effect that the correction factor has on the correlation between ELISA and GC-HRMS for samples from a test site with dioxin-contaminated soils was also examined. The congener profile at this site was such that the inconsistencies between uncorrected ELISA and GC-HRMS results were relatively small. However, application of the congener correction factor still improved the correlation between ELISA and GC-HRMS by 11% when using sample-specific correction factors and by 5% when using an average site-wide correction factor. The findings of this paper suggest that application of the correction factor is necessary to remove incompatibilities between ELISA and GC-HRMS--particularly when the congener profile at a site would lead to incompatibilities that are large. PMID- 20848087 TI - Early methylphenidate exposure enhances cocaine self-administration but not cocaine-induced conditioned place preference in young adult rats. AB - RATIONALE: Previous studies in rodents show that early exposure to methylphenidate alters later responsiveness to drugs of abuse. An interesting feature of these studies is that early methylphenidate treatment decreases the rewarding value of cocaine when measured by conditioned place preference (CPP), but the same treatment increases cocaine self-administration. OBJECTIVE: The goal of the present study was to examine the effects of early methylphenidate exposure on cocaine-induced responding using both reward paradigms. METHODS: Rats were treated with methylphenidate (0, 2, or 5 mg/kg) from postnatal days (PDs) 11 to 20, and then cocaine-induced CPP or cocaine self-administration was measured in separate groups of rats in adulthood. The CPP procedure included 8 days of acquisition training, 8 days of extinction training, and a reinstatement test. Rats were conditioned with 0, 10, or 20 mg/kg cocaine. Reinstatement was assessed after a priming dose of cocaine (10 mg/kg). For the self-administration experiment, a jugular catheter was implanted and rats were trained to press a lever reinforced with cocaine (0.25 or 0.75 mg/kg/infusion) on a fixed ratio (FR) one schedule. Rats were gradually moved from an FR1 to an FR10 schedule and, after criterion was reached, rats were placed on a progressive ratio schedule for 5 days. RESULTS: Cocaine produced robust rewarding effects as determined by both the CPP and self-administration experiments; however, early methylphenidate exposure only enhanced the reinforcing effects of cocaine on the self administration paradigm. Interestingly, this methylphenidate enhancement was only seen in male rats. CONCLUSIONS: These data suggest that in males, methylphenidate enhances the reinforcing value of cocaine, but not cocaine-associated cues. PMID- 20848090 TI - Three-dimensional cortical bone microstructure in a rat model of hypoxia-induced growth retardation. AB - Little is known about hypoxia-induced modification of the canal network in the cortical bone despite its involvement in intracortical vascularity and bone blood supply. In this study, we examined the effect of chronic hypoxia on the canal network in postnatal bone. Tibiae were harvested from 4- and 8-week-old rats (hyp 4 and -8, n = 8 each), whose growth was retarded owing to postnatal exposure to hypoxia (12-14% O2), and from 3- and 4-week-old normoxic rats (cnt-4 and -5, n = 8 each), which were similar in tibial length and cortical cross-sectional area to hyp-4 and -8, respectively. The diaphyseal canals were detected by monochromatic synchrotron radiation CT with a 3.1-MUm voxel resolution. The anatomical properties of the canal network were compared between age- or size-matched hypoxic and normoxic groups. The canals were larger in diameter, were more densely distributed and connected, and opened into the marrow cavity with a higher density in hyp-4 than in cnt-4. The canal density and connectivity were also higher in hyp-4 than in cnt-3. The canal diameter, density, and connectivity were smaller in hyp-8 than in cnt-4; however, the densities of endocortical and periosteal canal openings did not differ between hyp-8 and cnt-4. We concluded that chronic hypoxia enhanced the formation of cortical canal networks at the postnatal developmental stage, probably facilitating intra- and transcortical vascularization and bone perfusion accordingly. PMID- 20848091 TI - Influence of gestational diabetes mellitus on the stereoselective kinetic disposition and metabolism of labetalol in hypertensive patients. AB - PURPOSE: This study investigated the influence of gestational diabetes mellitus on the kinetic disposition and stereoselective metabolism of labetalol administered intravenously or orally. METHODS: Thirty hypertensive women during the last trimester of pregnancy were divided into four groups: non-diabetic and diabetic women treated with intravenous or oral labetalol. RESULTS: The pharmacokinetics of labetalol was not stereoselective in diabetic or non-diabetic pregnant women receiving the drug intravenously. However, oral administration of labetalol resulted in lower values of the area under the plasma concentration versus time curve (AUC) for the beta-blocker (RR) than for the other enantiomers in both diabetic and non-diabetic women. Gestational diabetes mellitus caused changes in the kinetic disposition of the labetalol stereoisomers when administered orally. The AUC values for the less potent adrenoceptor antagonist (SS) and for the alpha-blocking (SR) isomers were higher in diabetic than in non diabetic pregnant women. CONCLUSIONS: The approximately 100% higher AUC values obtained for the (SR) isomer in diabetic pregnant women treated with oral labetalol may be of clinical relevance in terms of the alpha-blocking activity of this isomer. PMID- 20848092 TI - Neurodegeneration in D-bifunctional protein deficiency: diagnostic clues and natural history using serial magnetic resonance imaging. AB - We report serial neurodegenerative changes on neuroimaging in a rare peroxisomal disease called D-bifunctional protein deficiency. The pattern of posterior to anterior demyelination with white matter disease resembles X-linked adrenoleukodystrophy. We feel this case is important to (1) highlight that D bifunctional protein deficiency should be considered in cases where the neuroimaging resembles X-linked adrenoleukodystrophy, (2) to show different stages of progression to help identify this disease using neuroimaging in children, and (3) to show that neuroimaging suggesting a leukodystrophy can warrant peroxisomal beta-oxidation studies in skin fibroblasts even when plasma very long chain fatty acids are normal. PMID- 20848093 TI - Quantification of recurrence volumes after endovascular treatment of cerebral aneurysm as surrogate endpoint for treatment stability. AB - INTRODUCTION: New coils with unproven clinical benefit enlarge the armamentarium for endovascular aneurysm treatment continuously. Large patient numbers needed to detect benefits of such new techniques prevent timely evaluation of efficacy. We propose measuring the volume of aneurysm recurrences as surrogate endpoint for coil stability. We hypothesize that this method allows detecting effects of new materials with reduced sample sizes in comparison to conventional studies with dichotomous endpoints. METHODS: Institutional review board approval and informed consent were obtained. Fifty-nine patients with decreasing aneurysm size and at least two available follow-up time-of-flight magnetic resonance angiographies (ToF-MRAs) were included. Newly developed software for measuring aneurysm volume differences based on ToF-MRA images was used. Based on the observed recurrence volumes and retreatment rates, the sample size for future studies comparing standard versus "new coils" were calculated. RESULTS: Mean recurrence volume was 38.92 MUl (SD110.85 MUl). To show a 50% reduction of retreatment rate to control (p = 0.05; power 80%) in a regular study (dichotomous endpoint), the required sample size would be n = 356 compared with n = 78 if using the continuous surrogate endpoint "recurrence volume". When extrapolating our data to data given in the literature, sample sizes could be reduced from n = 948 to n = 74 without loss of statistical power. CONCLUSION: Further studies on new materials using volumetric analysis based on ToF-MRA as surrogate endpoint could substantially decrease sample size and allow a more timely assessment of possible benefit of new materials with a fraction of the cost. PMID- 20848094 TI - Lenalidomide enhances antibody-dependent cellular cytotoxicity of solid tumor cells in vitro: influence of host immune and tumor markers. AB - We evaluated the effect of combining lenalidomide with therapeutic antibodies on antibody-dependant cell-mediated cytotoxicity (ADCC) of solid tumor cells, and the requirement for expression of natural killer (NK) cell-activating receptors and their solid tumor surface ligands. Twenty-three human tumor cell lines (colon, breast, lung, head and neck, ovary, and bone sarcoma) were analyzed. NK effector cells were isolated from healthy donors, pre-treated with and without lenalidomide, and incubated with antibody-coated tumor cells to determine ADCC. In blocking experiments, NK cells were pre-incubated with anti-DNAM-1 or anti NKG2D antibodies, and target colorectal cells were pre-incubated with anti-CD155 (PVR), anti-MIC-A/B, or anti-ULBP 3 antibodies. Differences between groups were assessed using unpaired and paired Student's t test and one-way ANOVA. Lenalidomide enhanced NK cell-mediated ADCC of trastuzumab- and cetuximab-coated tumor cells. Activity against colorectal cancer cells was dependent on target antigen expression, but independent of KRAS status and FcgammaRIIIa genotype. The extent of ADCC and its enhancement by lenalidomide correlated with NK cell expression of NKG2D and DNAM-1, and tumor cell expression of PVR and MIC-A. Blocking of NKG2D and, to a lesser extent, DNAM-1 inhibited ADCC. Anti-MIC-A/B monoclonal antibody blocked natural cytotoxicity, but not ADCC. Lenalidomide enhances the ability of IgG1-isotype antibodies to mediate ADCC of solid tumor cells, the extent of which is largely dependent on NKG2D-NKG2D ligand interactions, but appears to be independent of MIC-A/B. This provides a rationale for exploratory clinical studies and an assessment of potential biomarkers predictive of clinical benefit. PMID- 20848096 TI - Unilateral pseudogynecomastia: an occupational hazard in manual metal-pressing factories? AB - BACKGROUND: Five cases of unilateral occupation-related pseudogynecomastia are presented. All the patients in these cases worked in the same metal-pressing factory. METHODS: One patient with grade 4 unilateral gynecomastia in the right breast presented to the authors' outpatient department asking persistently for surgery. He also reported that all his male colleagues working in the same business (a total of 5) had different degrees of unilateral gynecomastia. Their line of work involved holding a long round rod under the axilla and then pressing the distal end of it firmly against a spinning metal plate. The patient underwent a superior pedicle breast reduction, with 1,800 ml of tissue removed from his right breast. Unfortunately, the patient experienced partial nipple loss. However, he was satisfied with the final result, and good symmetry was achieved. RESULTS: All five patients who worked in the same metal-pressing factory presented with unilateral gynecomastia and were examined in our department. Their average age was 51.4 years. All the patients had normal hormonal and biochemical status, and the results of screening for toxins and heavy metal exposure were negative. All the patients were heavy smokers. At examination, none of the patients had nipple discharge or retraction, skin changes, galactorrhea, or lymphadenopathy. Examination showed one patient with grade 4, three patients had grade 2, and one patient with grade 1 unilateral gynecomastia. CONCLUSIONS: The authors believe that gynecomastia may be considered an occupational risk in analogous metal-pressing factories because all the workers in this factory presented with some degree of unilateral gynecomastia. However, they emphasize that this may simply be an observational phenomenon without a true cause and effect relationship. PMID- 20848095 TI - Control of the specificity of T cell-mediated anti-idiotype immunity by natural regulatory T cells. AB - The idiotypes of B cell lymphomas represent tumor-specific antigens. T cell responses induced by idiotype vaccination in vivo are directed predominantly against CDR peptides, whereas in vitro T cells also recognize framework-derived epitopes. To investigate the mechanisms regulating the specificity of idiotype specific T cells, BALB/c or B10.D2 mice were immunized with mature dendritic cells loaded with H-2K(d)-restricted peptides from influenza hemagglutinin, or from shared (J region) or unique (CDR3) structures of the A20 lymphoma idiotype. Antigen-specific T cells were induced in vivo by the CDR3 and influenza epitopes, but not by the J peptide. Gene expression profiling of splenic regulatory T cells revealed vaccination-induced Treg activation and proliferation. Treg activity involved J epitope-dependent IL-10 secretion and functional suppression of peptide-specific effector T cells. Vaccination-induced in vivo proliferation of transgenic hemagglutinin-specific T cells was suppressed by co-immunization with the J peptide and was restored in CD25-depleted animals. In conclusion, Treg induced by a shared idiotype epitope can systemically suppress T cell responses against idiotype-derived and immunodominant foreign epitopes in vivo. The results imply that tumor vaccines should avoid epitopes expressed by normal cells in the draining lymph node to achieve optimal anti-tumor efficacy. PMID- 20848097 TI - How to perform breast augmentation safely for a pectus excavatum patient. AB - BACKGROUND: Pectus excavatum is the most common chest wall deformity. Women with pectus excavatum may have associated hypoplastic breasts and often desire breast augmentation. This report describes how to perform breast augmentation safely for a pectus excavatum patient. METHODS: In the past 5 years, the authors have treated 11 women with hypoplastic breasts and pectus excavatum. Their ages have varied from 21 to 39 years. The women generally were healthy without cardiovascular function impairment. Four of the women had breast asymmetry, with a smaller right breast. It was decided to use wide silicone implants to augment the breast and to camouflage the chest wall deformity. The implants were placed under the pectoralis major muscle in all cases. RESULTS: The follow-up period varied from 10 months to 4.5 years. No acute or late complications related to the breast augmentation were encountered. All the patients were satisfied with the result, and none desired further surgical treatment for pectus excavatum. For two patients, a small depression in the upper part of the breast was persistent after surgery due to insufficient implant coverage. CONCLUSION: Most women with pectus excavatum desire to have the deformity corrected with minimal or no scarring. The chest is known to be an area prone to hypertrophic or keloid scars. The reported approach is simple and safe, easily camouflaging the deformity. It is a short procedure that results in high satisfaction. PMID- 20848098 TI - A morphological methodology for three-dimensional human face soft-tissue landmarks extraction: a preliminary study. AB - Assessment of facial soft tissues could be implemented using only anatomical landmarks. These points are so significant in the medical context because are able to provide significant information about the human face morphology and dimensions. At present their detection and location is made by expert physicians using palpation. Even if this procedure normally provides reliable information, the reliability of the results is proportional to the expertise of the physician. Considering that at present many physicians are beginning to use 3D scanners that provide three-dimensional data of the human face, it is possible to implement a robust and repeatable methodology that supports the physician's diagnosis. To reach this goal it is necessary to implement a methodology based on geometrical codification of landmarks and which mathematically formalizes the physician's visual and palpation analyses of the real patient. PMID- 20848099 TI - Internal lateral nasal osteotomy: double-guarded osteotome and mucosa tearing. AB - For the internal lateral nasal osteotomy, a 4-mm double-guarded straight osteotome that separates the external periost and mucoperiosteum while the osteotomy is progressing is presented. Before the osteotomy, the external periost and the internal mucoperiosteum are infiltrated with local anesthesia and elevated by tunneling with an elevator. As the sharp part is behind the guards, it is not possible for the osteotome to slip away laterally or medially from the nasal bone. By tunneling just at the base of the nasal bones, arteries, veins, and lymphatics are preserved while the superior part of the external periosteum and the internal mucoperichondrium maintained the bones in a stable position with firm support to both sides. Forty consecutive rhinoplasties were studied with an endoscope. In 35 primary rhinoplasties the mucosa laceration rate was 1.5%, whereas in secondary rhinoplasties it was 80%. The approach to the piriform aperture was intranasal in the first 16 cases and intraoral in the last 24 cases. The intraoral mucosal elevation and osteotomy were easier to carry out than in the intranasal approach. In general, minor lower-lid edema and ecchymosis were observed, possibly related to the fact that the periosteum was elevated, thus preserving the supraperiosteal arteries, veins, and lymphatics. When the mucosa was elevated, the internal irrigation of the mucosa and the lymphatics was also preserved, thus avoiding intraoperative bleeding, intranasal packing, and postoperative bleeding. PMID- 20848100 TI - Acute thrombocytopenia: an unusual complication occurring after drug-eluting microspheres transcatheter hepatic chemoembolization. AB - Image-guided transcatheter hepatic chemoembolization (TACE) is accepted worldwide as an effective treatment for patients with unresectable hepatocellular carcinoma and liver metastases from neuroendocrine tumors, colorectal carcinomas, and uveal melanomas. Although the technique is relatively safe, it has been associated with several complications. We report the cases of two patients with colorectal liver metastases who developed acute thrombocytopenia a few hours after TACE. To our knowledge, acute thrombocytopenia occurring after TACE with drug-eluting microspheres has not yet been reported. Here we discuss the hypothetical etiopathogenetic mechanisms. PMID- 20848101 TI - Abstracts of CIRSE (Cardiovascular and Interventional Radiological Society of Europe) 2010. October 2-6, 2010. Valencia, Spain. PMID- 20848102 TI - Thoracic pedicle screw insertion in Asian cadaveric specimen: does radiological pedicle profile affect outcome? AB - PURPOSE: Pedicle screw instrumentation has superior biomechanical as well as clinical outcome. Thoracic pedicles show great variation in different population groups, particularly in Asians who have been shown to have smaller pedicle dimensions. Although plain radiographs are widely performed prior to spine surgery, no studies have been done so far to investigate whether the thoracic pedicle profile on plain radiographs affect thoracic pedicle screw insertion. Therefore, this is a cadaveric study aimed to determine the relationship between plain radiographic thoracic pedicle profile in Asians and the outcome of pedicle screw insertion in the thoracic spine. METHODS: A pre-insertion radiograph with an enlargement reference scale was performed and surgeons were blinded to the plain radiographic morphometry of the thoracic pedicles. From the pre-insertion radiograph, the normalized pedicle width and height (which controls for any magnification error) as well as the pedicle width:body width (PWBW) and pedicle width:pedicle height (PWPH) ratio was derived. 240 pedicle screws were inserted in ten Asian cadavers from T1 to T12 using the funnel technique. 5.0 mm screws were used from T1 to T6 while 6.0 mm screws were used from T7 to T12. Perforations were detected by direct visualization via wide laminectomies after pedicle screw insertion. The outcome of thoracic pedicle screw insertion was correlated with the radiological profile using independent t-test. Pearson correlation coefficient was used to investigate the correlation between the ratios and the normalised pedicle width and height. RESULTS: The narrowest pedicle width is from T3 to T6 determined from normalized measurement of the pedicle width. T5 pedicle width is the smallest measuring 4.1 +/- 1.3 mm. The overall perforation rate is 10.4% (25 perforations). There is only one significant perforation. There were twice as many lateral and inferior perforations compared to the medial perforations. 48% of the perforations occurred at T1, T2 and T3. Pedicles <4.0 mm in width and upper thoracic pedicles are risk factors for pedicle perforation. The normalised pedicle width has a high degree of linear correlation with PWBW and a normalised pedicle width of 4.0 mm correlated with a PWBW ratio of 0.3. CONCLUSIONS: Plain radiographic thoracic pedicle morphometry has an influence on the outcome of thoracic pedicle screw insertion in Asian cadavers. Pedicle width <4.0 mm is associated with higher risk of pedicle perforation. This critical value corresponds to a PWBW ratio of 0.3. Identification of such pedicle profile warrants full evaluation of the morphometry of the thoracic pedicles and possibly extra-pedicular techniques should be employed to avert the risk of critical pedicle perforation. PMID- 20848103 TI - Vitamin D deficiency and anemia. PMID- 20848104 TI - Phase II fludarabine and cyclophosphamide for the treatment of indolent B cell non-follicular lymphomas: final results of the LL02 trial of the Gruppo Italiano per lo Studio dei Linfomi (GISL). AB - Indolent non-follicular non-Hodgkin lymphomas (INFL) are a heterogeneous subset whose treatment has been poorly investigated. In this context we have evaluated the efficacy and safety of combined fludarabine and cyclophosphamide (FC) upfront therapy. Sixty-three patients with advanced INFL were enrolled in the study. Therapy consisted in FC combination (25 and 250 mg/m(2), i.v., respectively, for three consecutive days) every 28 days for six courses. After histological review, 61 patients (36 men, median age 64 years, range 40-70 years) were evaluated (22 small lymphocytic, 11 lymphoplasmacytic, 25 marginal zone and 3 CD5-negative non Hodgkin lymphomas not otherwise specified). Further two patients were excluded for lack of essential data; six patients were withdrawn before the third cycle because of WHO grade III and IV toxicity. At the final evaluation, the overall response rate was 83% with 40.7% of complete remission. Intention-to-treat analysis showed that at the median follow-up of 36 months, overall survival, progression-free survival and failure-free survival were respectively 78%, 60% and 46%; remission duration among the 49 patients achieving complete remission/partial remission at the end of treatment was 65% (44-78) without significant differences between the main histotypes. The most frequent grade III and IV toxic events were haematological (neutropaenia 34%, anaemia 18% and thrombocytopaenia 11%) and infectious (10%). FC is effective for advanced untreated INFL. Early deaths and haematological toxicity suggest careful patient selection and monitoring. PMID- 20848105 TI - Biodegradation of benazolin-ethyl by strain Methyloversatilis sp. cd-1 isolated from activated sludge. AB - Benazolin-ethyl has been used on a wide range of weeds present in various crops since 1964. Because benazolin-ethyl is a potential hazard to the environment and human health, it is important to remove this herbicide from the environment. However, to the best of our knowledge, no report is available in the literature regarding the microbial degradation of benazolin-ethyl by bacteria. In this study, one strain named cd-1, which is capable of degrading benazolin-ethyl, was isolated from benazolin-ethyl wastewater treatment pool. The isolate was identified as Methyloversatilis sp. according to its morphological, physiological, biochemical properties, and 16S rRNA gene sequences analysis. This strain utilizes benazolin-ethyl as the sole carbon source. and degrades 100 mg l 1 benazolin-ethyl to non-detectable level within 48 h. Three metabolites were identified as benazolin, 7-chloro-3-methylbenzo[d]thiazol-2(3H)-one, and 2-chloro 6-(methyleneamino)benzenethiol based on the MS/MS and GC/MS analyses. The first step involved in the degradation of benazolin-ethyl was the cleavage of the ester bond to form benazolin. Benazolin was subsequently subjected to demethylation for decomposition into 7-chloro-3-methylbenzo[d]thiazol-2(3H)-one and methanol. The last step was to form 2-chloro-6-(methyleneamino)benzenethiol. PMID- 20848106 TI - [The role of diagnostic neuropathology in familial tumour syndromes]. AB - Inherited cancer syndromes often involve the central and peripheral nervous system. For the surgical neuropathologist the possibility in individual patients of a familial tumour syndrome needs to be considered in the case of special tumours such as malignant peripheral nerve sheath tumour (MPNST), medulloblastoma with extensive nodularity (MBEN) or even atypical teratoid/rhabdoid tumour (AT/RT) of the brain. Furthermore, tumour location and patient age may point to a familial tumour syndrome as in the case of neurofibromatosis type 2 (NF2) with typical bilateral vestibular schwannoma in young age. This short review discusses some of the diagnostic aspects in this field relating to neurofibromatosis type 1 and 2 (NF1, NF2), as well as the two rare tumors MBEN in Gorlin-Goltz syndrome and AT/RT in particular. PMID- 20848107 TI - [Hereditary breast and ovarian cancers]. AB - Hereditary factors are responsible for 5-10% of all breast cancers and 10% of all ovarian cancer cases and are predominantly caused by mutations in the high risk genes BRCA1 and BRCA2 (BRCA: breast cancer). Additional moderate and low penetrance gene variants are currently being analyzed via whole genome association studies. Interdisciplinary counseling, quality managed genetic testing and intensified prevention efforts in specialized medical centres are essential for members of high risk families considering the high prevalence of malignant tumors and the early age of onset. Furthermore, the identification of BRCA-deficient carcinomas is of particular clinical interest, especially regarding new specific therapeutic options, e.g. treatment with poly (ADP-ribose) polymerase (PARP) inhibitors. There are presently no valid surrogate markers verifying the association of BRCA1/BRC2 in tumors. However, breast cancers harboring pathogenic BRCA1 mutations in particular display specific histopathological features. PMID- 20848108 TI - [Hereditary and non-hereditary syndromic gastointestinal stromal tumours]. AB - The majority of gastrointestinal stromal tumours (GISTs) present as solitary gastrointestinal masses in adults aged 50-70 years. A small subset of GISTs (<=5%) occurs in the setting of familial or idiopathic multitumour syndrome. In decreasing order of frequency, neurofibromatosis Recklinghausen (NF-1), Carney triad (gastric GIST, pulmonary chondroma and extra-adrenal paraganglioma), familial GIST syndromes resulting from germline mutations in c-Kit/PDGFRA and the Carney-Stratakis syndrome (hereditary GIST paraganglioma syndrome caused by germline mutations in the mitochondrial tumour suppressor gene pathway involving the succinate dehydrogenase subunits SDHD, SDHC and SDHB) represent the four most important GIST syndromes characterized to date. Since affected patients and their family members require special treatment and/or counseling and follow-up, early diagnosis and precise classification of this likely still underdiagnosed diseases is of the utmost importance. This review summarizes the pertinent clinicopathological and molecular features of the main GIST syndromes to facilitate their diagnosis and distinction from their non-syndromic mimics. PMID- 20848109 TI - Experimental studies investigating the pathophysiology of nephrogenic systemic fibrosis; what did we learn so far? PMID- 20848110 TI - [Cataract surgery. Effect on the posterior segment of the eye]. AB - Cataract surgery is a safe procedure with a high patient satisfaction rate. However, pseudophakia changes the physiology of the eye and immediate changes include release of inflammatory cytokines. Deformation of the globe and intraoperative fluctuations of intraocular pressure may induce microlesions and alterations of ocular perfusion. The barrier function between the anterior and the posterior segment is compromised after surgery and the geometry of the intraocular chambers changes. Especially the vitreous body is subject to increased destruction during the years after surgery. The occurrence of pseudophakic cystoid macular edema after cataract surgery is a well known complication. Several studies have described a progression of diabetic retinopathy, especially of diabetic macular edema after cataract surgery. In contrast cataract surgery does not seem to have a significant impact on the progression of age-related macular degeneration. However the risk for retinal detachment is significantly increased in pseudophakia for at least 10 years after surgery. Awareness of special risk factors can make cataract surgery, one of the most effective procedures in medicine, even safer. PMID- 20848111 TI - Complex echo classification by echo-locating bats: a review. AB - Echo-locating bats constantly emit ultrasonic pulses and analyze the returning echoes to detect, localize, and classify objects in their surroundings. Echo classification is essential for bats' everyday life; for instance, it enables bats to use acoustical landmarks for navigation and to recognize food sources from other objects. Most of the research of echo based object classification in echo-locating bats was done in the context of simple artificial objects. These objects might represent prey, flower, or fruit and are characterized by simple echoes with a single up to several reflectors. Bats, however, must also be able to use echoes that return from complex structures such as plants or other types of background. Such echoes are characterized by superpositions of many reflections that can only be described using a stochastic statistical approach. Scientists have only lately started to address the issue of complex echo classification by echo-locating bats. Some behavioral evidence showing that bats can classify complex echoes has been accumulated and several hypotheses have been suggested as to how they do so. Here, we present a first review of this data. We raise some hypotheses regarding possible interpretations of the data and point out necessary future directions that should be pursued. PMID- 20848113 TI - Comparative study of percutaneous vertebroplasty and kyphoplasty in the treatment of osteoporotic vertebral compression fractures. AB - OBJECTIVE: To compare the therapeutic effect of percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP) in the treatment of osteoporotic vertebral compression fractures (VCFs). METHODS: A total of 244 patients with VCFs were treated by PVP or PKP and 192 had follow-up for at least 1 year. Clinical outcomes were determined by pain Visual Analog Scale (VAS) and Short Form 36 Health Survey (SF-36). Preoperative and postoperative radiographic assessment included measurement of posterior and anterior vertebral body height (AH and PH), as well as the kyphotic angle by the Cobb method. RESULTS: A total of 192 cases had follow-up for at least 1 year and 52 cases lost. The average amount of polymethylmethacrylate (PMMA) cement introduced per vertebra was 3.4 +/- 1.5 ml in PVP and 4.5 +/- 0.8 ml in PKP (P < 0.05). All patients subjectively reported immediate relief of their typical fracture pain, and the mean VAS decreased significantly from presurgery to postsurgery during the 1-year of follow-up. The RP, BP and GH dimensionality values of SF-36 in PKP were higher than PVP (P < 0.05). The improvement on AH was 11.13 +/- 5.68% in PVP and 21.46 +/- 9.87% in PKP (P < 0.01); on PH was 2.25 +/- 1.36% in PVP and 7.57 +/- 2.49% in PKP (P < 0.01). The average improvement in the kyphotic angle after the procedure was 5.21 +/- 2.33 degrees in PVP and 11.69 +/- 5.18 degrees in PKP (P < 0.01). CONCLUSIONS: PVP and PKP have the ability of reducing pain in osteoporotic VCF patients. The correction of kyphotic deformity and restoration of the anterior vertebral body heights associated with osteoporotic VCFs was better in PKP. PMID- 20848112 TI - Tako-Tsubo syndrome: dying of a broken heart? AB - AIM: The aim of the article is to review the etiology, pathology and epidemiology of a disease entity named Tako-Tsubo syndrome, receiving this name according to the picture obtained during ventriculography resembling a Japanese octopus trap. The Tako-Tsubo syndrome is a diagnosis encountered in patients with acute coronary syndrome and, therefore, is important to consider. METHODS: The literature search was performed in the MEDLINE database to identify the relevant topics. The references reported were used to complete the literature search. RESULTS: The Tako-Tsubo syndrome is rising in incidence and makes up a relevant part of patients with acute coronary syndrome. The prevalence is described to be 0.6-2.5%. Especially, older women in the postmenopause with emotional stress are affected. The clinical changes and ECG alterations resemble the same characteristics like in acute coronary syndrome; however, the coronary arteries often show no impaired blood flow or only marginal changes. The reason for this syndrome is allocated to stress reactions with increased levels of stress hormones. As well, some patients develop contraction abnormalities like in Tako Tsubo syndrome during intracranial bleeding, pheochromocytoma, seizures, infectious causes and sepsis, showing that not only emotional stress is responsible for the manifestation of this disease. CONCLUSION: The prevalence of Tako-Tsubo syndrome is about 2%, therefore this syndrome has to be considered in patients with acute coronary syndrome. Despite the life-threatening complications during the acute phase, a complete regression of the contraction abnormality is often reported. PMID- 20848114 TI - Amyloid deposition in osteoarthritis of the hip. AB - PURPOSE: The aim of this study was to examine the frequency of amyloid deposition in patients with end-stage hip osteoarthritis (OA). Further, their impact on the clinical situation and the OA severity were analyzed. METHODS: Fifty patients with OA who consecutively underwent total hip replacement were prospectively evaluated. The X-rays of the patients were analyzed using a radiological score (Kellgren-Lawrence) to quantify the amount of radiological changes. A clinical score [Harris hip score (HHS)] was preoperatively calculated for every patient. Specimens from the femoral head of bone and cartilage, and additionally 1 cm(2) of the capsule, were obtained from every patient intraoperatively for analyzing the amyloid deposition histologically. A histological grading was also performed. On a subset of patients with amyloid deposits, the subtypes were characterized immunohistologically. RESULTS: The only subtype of amyloid was ATTR. There was a high, significant correlation between articular amyloid deposition and the age of the patient at the time of the operation. No correlation was found for any other measured item, such as signs of inflammation in the blood samples, histological grading, radiological score or clinical score. CONCLUSIONS: The frequency of amyloid deposits in the joint increases with age, and it can generally be considered to be of no pathologic significance, since a correlation with the radiological and histological changes was ruled out by our study. Thus, the presence of ATTR amyloid may simply be an incidental finding in aged joints. PMID- 20848115 TI - Perioperative ultrasound-guided wire marking of calcific deposits in calcifying tendinitis of the rotator cuff. AB - The identification of a calcific deposit in the rotator cuff can often cause difficulties. A new technique is described to identify the calcific deposit perioperatively with a ultrasound-guided wire. The technique allows a safe direct marking of calcific deposits making the procedure faster especially in difficult cases. PMID- 20848116 TI - Ring pessary for all pelvic organ prolapse. AB - PURPOSE: To evaluate the risk factors of unsuccessful fitting of ring pessary in pelvic organ prolapse (POP), continuation rate, and adverse events. METHODS: The ring pessary was offered to 100 symptomatic POP patients. POP was staged according to Pelvic Organ Prolapse Quantification (POP-Q) system. A successful fitting was defined as when patients continued pessary use for more than 2 weeks. Adverse events were evaluated in patients who had a successful fitting. RESULTS: Most patients (71%) were in POP-Q stage III-IV and 77 patients were fitted at the initial visit. Successful fitting was reported in 62 patients (62%). However, 52 patients (52%) continued to use the pessary at 13 months median follow-up. The most common reason for discontinuation was frequent pessary expulsion. Short vaginal length <= 6 cm and wide introitus > 4 fingerbreadths were the significant risk factors for unsuccessful fitting. New onset of stress urinary incontinence (SUI) developed in 28.2% of patients. One third and 21% of patients had vaginal discharge and vaginal erosion, respectively. Only half of the patients could manage the pessary either by themselves or with their caregivers. CONCLUSION: The ring pessary fitting can be attempted in all POP cases irrespective of stage. Short vaginal length <6 cm and wide introitus >4 fingerbreadths were the risk factors for unsuccessful fitting. It has an acceptable continuation rate and manageable adverse events. The self-care of pessary is an important strategy to minimize adverse events. PMID- 20848117 TI - Recurrent pancreatitis induced by hyperparathyroidism in pregnancy. AB - INTRODUCTION: As primary hyperparathyroidism affects mainly middle-aged and elderly women, it is an infrequent finding during gestation and breastfeeding. To date, less than 200 pregnant patients with primary hyperparathyroidism diagnosed during pregnancy have been described. Like in other disorders of the parathyroid gland, the recognition of primary hyperparathyroidism during pregnancy and lactation may be difficult, as clinical symptoms are not specific, while laboratory findings may be masked by some typical pregnancy-induced changes in calcium and phosphate homeostasis. If remains untreated, the disease may result in serious clinical implications for the mother and fetus. Most authors consider surgery within the second trimester of pregnancy as the treatment of choice in this group of patients. CASE REPORT: In our paper, we discuss the case of a 35 year-old female with a history of recurrent acute pancreatitis and recurrent abortions. As the patient declined surgery, conservative management with calcitonin was started and continued throughout the rest of pregnancy, and led to giving birth to the infant whose only health problem was transient hypocalcemia. CONCLUSION: The described case shows that conservative management, if started respectively early and conducted on the basis of a patient's condition, may effectively reduce increased perinatal and maternal morbidity and mortality in pregnant women declining surgery. PMID- 20848118 TI - Surgical management of osteomas of the frontal recess and sinus: extending the limits of the endoscopic approach. AB - Osteomas are among the most common benign tumors of the paranasal sinuses. Symptomatic osteomas are most often found in the frontal recess and the frontal sinus. While the extranasal approach is still a part of the treatment concept for removing osteomas at this localization, over the last years the endoscopically controlled endonasal approach has greatly gained in importance due to the improved surgical equipment. We retrospectively analyzed the surgical indication, surgical approach and outcome of the removal of osteomas of the frontal recess and the frontal sinus performed at our hospital between 1996 and 2010. The exact surgical technique, intra- and postoperative complications, the duration of the hospital stay and the follow-up and subjective contentment of the patients were evaluated. With a total of 24 patients being included, the study comprises one of the largest groups of patients with osteomas of the frontal recess and sinus. Over the study period, the frequency of the endoscopic approach clearly increased. Previously suggested guidelines for the endoscopic resection of a frontal sinus osteoma turned out to be superseded. Endoscopically controlled resection even of large, adversely located osteomas of the frontal recess and the frontal sinus is becoming increasingly possible, but is still naturally limited by the individual anatomic conditions and the need for experienced surgeons. PMID- 20848119 TI - The changing surgical management of juvenile nasopharyngeal angiofibroma. AB - The management of juvenile nasopharyngeal angiofibroma (JNA) has changed during the last decades but it still continues to be a challenge for the multidisciplinary head and neck surgical team. The aim of this study was to review the used treatment approach and outcome of JNA in a single institution series of 27 patients diagnosed and treated during the years 1970-2009. All patients were male, with the median age of 17 years (range 11-33 years). Surgery was used as the primary treatment in every case. Surgical approaches varied, transpalatal approach (N = 14) being the most common approach used in this series. During the last decade various other techniques were applied, including endoscopic (N = 3) resection. Two patients were additionally treated with antiangiogenic agents and one patient with stereotactic radiotherapy. The primary recurrence rate was 37% and it seemed to correlate with vascular density of tumour and the surgical approach used. We suggest that the management of JNA should be planned by an experienced head and neck surgeon, as part of a multidisciplinary team, preferably in a tertiary referral setting, and the recent development of the available therapies should be taken into account to minimise the risk of recurrence. PMID- 20848120 TI - Evaluation of tracheal stenosis: comparison between computed tomography virtual tracheobronchoscopy with multiplanar reformatting, flexible tracheofiberoscopy and intra-operative findings. AB - The aim of the study was to evaluate and compare various helical CT display modes [virtual endoscopy (VE)] and multiplanar reformations (MPR), conventional flexible tracheobronchoscopy (FT) and intra-operative (IO) findings in patients with tracheal stenosis and to analyze the advantage of MPR and VE in diagnosis and treatment planning and in postoperative follow-up. Thirty-seven patients with tracheal stenosis underwent standard neck and chest CT followed by MPR and VE. Results were correlated with the results of FT and IO findings. Thirty-three of the 37 stenoses were correctly graded and measured adequately using VE. Complete correlation among CT, fiberoptic tracheoscopy, and surgery of stenosis grading, stenosis length and length of planned resection segment of the trachea was noted between 33 of 37 patients with tracheal stenosis. Correlation between VE and IO was noted in 35 of 37 patients and between FT and VE was noted in 33 of 37 patients with tracheal stenosis. The sensitivity of VE was 94-97%, specificity was 100% with comparison to IO findings. The sensitivity and accuracy of MPR was 86-89% and specificity was 100% with comparison to FT findings. The results of the study indicate that VE is an excellent, consistent, and objective technique. VE with MPR is very useful in diagnostic evaluation and treatment planning in patients with tracheal stenosis. PMID- 20848121 TI - Considerations for analysis of source monitoring data when investigating hallucinations in schizophrenia research. AB - Self/other (i.e., internal/external) source monitoring is one of the leading paradigms for the study of hallucinations in schizophrenia. The cognitive processes that underlie hallucinations are theorized to transform self-generated (internal) cognitive events into other-generated (external) cognitive events. These proposed cognitive operations also appear to play a role in producing analogous types of errors in self/other source monitoring, namely a memory bias whereby recalled material that was self-generated is misremembered as other generated, referred to as an externalization bias. Externalization biases are more frequent in groups of hallucinating schizophrenia patients than in other groups. One source of measurement error that is inherent in the study of the externalization bias is that, even for never-previously viewed items, there is a tendency to guess an external source under conditions of uncertainty. If such guessing takes place in response to self-generated but forgotten items, these guesses will be summed along with true externalization biases in the frequency count of externalizations, producing measurement error. Multinomial modeling is a statistical technique that has been used to estimate the influence of external source guessing in order to separate it from true externalization bias estimates. However, a number of challenges related to model choice and model validation are involved, and these challenges may render multinomial modeling impractical. We instead recommend analysis of covariance (ANCOVA), or difference score methodology, as an appropriate method for partialling external-source guessing rates (external-source false positives) out of externalization bias rates. PMID- 20848122 TI - Immunohistochemical expression of fibronectin and C5b-9 in the myocardium in cases of carbon monoxide poisoning. AB - Even if there is clinical evidence that carbon monoxide poisoning determines cardiac damage, the literature on the cardiac pathomorphology in such cases is scarce. We investigated the immunohistochemical expression of two known markers of fresh cardiac damage, fibronectin and the terminal complement complex C5b-9, in both cardiac ventricles in 26 cases of CO intoxication (study group, 15 ?, 11 ?, mean age 47 years, mean COHb level 65.9%, min. 51%, max. 85%) compared to a group of 23 cases of hanging (n = 23, 4?, 19?, mean age 42 years) as well as to 25 cases of myocardial infarction (n = 25, 13?, 12?, mean age 64 years). Fresh cardiac damage was detected with the antibody fibronectin in cases of CO poisoning and was prevalently localised at the right ventricle. PMID- 20848123 TI - Tuberculous meningitis in patients infected with human immunodeficiency virus. AB - Tuberculosis is the most common opportunistic infection in human immunodeficiency virus (HIV) infected persons. HIV-infected patients have a high incidence of tuberculous meningitis as well. The exact incidence and prevalence of tuberculous meningitis in HIV-infected patients are not known. HIV infection does not significantly alter the clinical manifestations, laboratory, radiographic findings, or the response to therapy. Still, some differences have been noted. For example, the histopathological examination of exudates in HIV-infected patients shows fewer lymphocytes, epithelioid cells, and Langhan's type of giant cells. Larger numbers of acid-fast bacilli may be seen in the cerebral parenchyma and meninges. The chest radiograph is abnormal in up to 46% of patients with tuberculous meningitis. Tuberculous meningitis is likely to present with cerebral infarcts and mass lesions. Cryptococcal meningitis is important in differential diagnosis. The recommended duration of treatment in HIV-infected patients is 9-12 months. The benefit of adjunctive corticosteroids is uncertain. Antiretroviral therapy and antituberculosis treatment should be initiated at the same time, regardless of CD4 cell counts. Tuberculous meningitis may be a manifestation of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. Some studies have demonstrated a significant impact of HIV co-infection on mortality from tuberculous meningitis. HIV-infected patients with multidrug resistant tuberculous meningitis have significantly higher mortality. The best way to prevent HIV-associated tuberculous meningitis is to diagnose and isolate infectious cases of tuberculosis promptly and administer appropriate treatment. PMID- 20848124 TI - Ultrastructural changes in myotendinous nerve endings induced by injection of botulinum toxin into the extraocular muscle. AB - BACKGROUND: The myotendinous nerve endings located in the extraocular muscles are considered as proprioceptors. The proprioception of extraocular muscles can be altered if botuminium toxin, which is widely used for the treatment of strabismus, damages the endings. The purpose of this study is to investigate the ultrastructural changes in myotendinous nerve endings after injection of botulinum toxin into the extraocular muscles. METHODS: Under general anesthesia, 5 IU of botulinum toxin (0.1 ml) were injected into the superior and medial rectus muscles of one eye in each of 12 cats, and 0.1 ml of normal saline was injected into the muscles of the other eye. The myotendinous junction was harvested in four cats each at 1, 4, and 12 weeks after injection and examined using electron microscopy. The myotendinous junctions of four normal uninjected cats were also examined as a control group. RESULTS: There were no morphological differences between the control group and saline injection group. In the botox injection group, separation of the myelin sheath and an increase in neurofilaments in axons of myelinated and unmyelinated nerve fibers were observed 1 week after injection and persisted until 12 weeks. Around the terminal nerve endings, incomplete Schwann cells with axonal exposure were observed, and fibroblast-like changes in Schwann cells were detected. These findings were not observed in the control group. CONCLUSIONS: Injection of botulinum toxin into the extraocular muscle induced ultrastructural changes in the myotendinous nerve endings. The possibility that those changes might diminish the proprioceptive abilities of the extraocular muscle should be considered when botulinum toxin is used for the treatment of strabismus. PMID- 20848125 TI - Outcomes of 25-gauge vitrectomy for proliferative diabetic retinopathy. AB - BACKGROUND: To evaluate the efficacy and safety of 25-gauge transconjunctival sutureless vitrectomy (25-G TSV) in the management of vitreoretinal complications of proliferative diabetic retinopathy (PDR). METHODS: A retrospective review of a noncomparative interventional case series including 200 eyes of 164 consecutive patients who underwent 25-G TSV for the management of PDR was performed. The main outcome measures were preoperative and postoperative visual acuity and intraocular pressure (IOP), the surgical success rate, and intraoperative and postoperative complications. All cases had a follow-up period of at least 6 months. RESULTS: The mean logarithm of the minimum angle of resolution (LogMAR) visual acuity was significantly improved from 1.55 preoperatively to 0.72 at the final visit. No intraoperative complications related to the 25-G TSV procedure were recorded. Transient hypotony was recorded in 18 eyes (9%) on postoperative day 1 and 15 eyes (7.5%) on postoperative day 5. Two of these eyes (1%) had choroidal detachment on postoperative day 5. One case showed bacterial endophthalmitis after the second surgery. The single operation and final surgical success rates were 81.5% and 98% respectively. CONCLUSION: These outcomes of 25-G TSV showed its safety and efficacy in the management of PDR. PMID- 20848126 TI - Empowering employees with chronic diseases: process evaluation of an intervention aimed at job retention. AB - PURPOSE: Employees with a chronic disease may experience work-related problems that contribute to the risk of job loss. We developed a group-based intervention programme aimed at clarifying problems, making these a subject of discussion at work, and realizing solutions. This process evaluation investigates the intervention's feasibility and the satisfaction of 64 participants in eight groups. METHODS: Data were collected through process evaluation forms and self report questionnaires. RESULTS: The recruitment of participants was time consuming. Highly educated women working in the service sector were overrepresented. The programme was administered as planned, although components were sometimes only discussed briefly, due to lack of time. Satisfaction with the overall programme among participants was high; it was perceived as effective and there were only three dropouts. In particular, the focus on feelings and thoughts about having a chronic disease was highly valued, as were the exchange of experiences and role-playing directed at more assertive communication. CONCLUSIONS: A vocational rehabilitation programme aimed at job retention is feasible and is perceived to be effective. Such a programme should address psychosocial aspects of working with a chronic disease beside practical problems. The recruitment of participants is time-consuming. Cooperation with outpatient clinics is necessary in order to reach all groups of employees with a chronic disease that might benefit from job retention programmes. TRIAL REGISTRATION: ISRCTN77240155. PMID- 20848127 TI - Cardiac output but not stroke volume is similar in a Wingate and VO2peak test in young men. AB - Wingate test (WT) training programmes lasting 2-3 weeks lead to improved peak oxygen consumption. If a single 30 s WT was capable of significantly increasing stroke volume and cardiac output, the increase in peak oxygen consumption could possibly be explained by improved oxygen delivery. Thus, we investigated whether a single WT increases stroke volume and cardiac output to similar levels than those obtained at peak exercise during a graded cycling exercise test (GXT) to exhaustion. Fifteen healthy young men (peak oxygen consumption 45.0 +/- 5.3 ml kg(-1) min(-1)) performed one WT and one GXT on separate days in randomised order. During the tests, we estimated cardiac output using inert gas rebreathing (nitrous oxide and sulphur hexafluoride) and subsequently calculated stroke volume. We found that cardiac output was similar (18.2 +/- 3.3 vs. 17.9 +/- 2.6 l min(-1); P = 0.744), stroke volume was higher (127 +/- 37 vs. 94 +/- 15 ml; P < 0.001), and heart rate was lower (149 +/- 26 vs. 190 +/- 12 beats min(-1); P < 0.001) at the end (27 +/- 2 s) of a WT as compared to peak exercise during a GXT. Our results suggest that a single WT produces a haemodynamic response which is characterised by similar cardiac output, higher stroke volume and lower heart rate as compared to peak exercise during a GXT. PMID- 20848128 TI - Use of milrinone in the management of haemodynamic instability following duct ligation. AB - Haemodynamic instability affects 22% to 29% of very low birth weight infants in the acute period following ligation of the ductus arteriosus and contributes to the mortality seen in this group. Since the sudden elevation of systemic vascular resistance has been recognised to be one of the factors contributing to this instability, milrinone, an afterload reducing agent, might potentially be of significant therapeutic benefit. This report presents the clinical course of an infant born at 26 weeks gestation who required surgical ligation of a haemodynamically significant patent ductus arteriosus after two unsuccessful 6 day courses of intravenous indomethacin. The post-operative period was characterized by oxygenation failure, rising blood pressure and echocardiographic signs indicative of diastolic dysfunction. The infant was successfully managed with milrinone, a phosphodiesterase inhibitor, which acts both as an "inodilator" and has lusitropy properties. Post-duct ligation haemodynamic instability in a preterm infant was successfully managed with milrinone. The role of afterload reducing agents such as milrinone in this setting should, therefore, be systematically analyzed. PMID- 20848129 TI - Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations. AB - Denys-Drash syndrome (DDS) is characterized by progressive glomerulopathy caused by diffuse mesangial sclerosis (DMS), genitourinary defects, and a higher risk of developing Wilms' tumor. It is commonly assumed that the DMS is unresponsive to any medications. In this report, we present a patient with Denys-Drash syndrome, in whom the cyclosporine A (CsA) was found to induce total remission. This observation and observations of other authors confirm that in genetic forms of nephrotic syndrome, the proteinuric effect of CsA may be due to a non-immunologic mechanism. We confirm the beneficial effect of CsA treatment in DDS; however, the potential nephrotoxicity of this drug will probably not allow long-term use. PMID- 20848130 TI - Respiratory epithelial cells in innate immunity to influenza virus infection. AB - Infection by influenza virus leads to respiratory failure characterized by acute lung injury associated with alveolar edema, necrotizing bronchiolitis, and excessive bleeding. Severe reactions to infection that lead to hospitalizations and/or death are frequently attributed to an exuberant host response, with excessive inflammation and damage to the epithelial cells that mediate respiratory gas exchange. The respiratory mucosa serves as a physical and chemical barrier to infection, producing mucus and surfactants, anti-viral mediators, and inflammatory cytokines. The airway epithelial cell layer also serves as the first and overwhelmingly primary target for virus infection and growth. This review details immune events during influenza infection from the viewpoint of the epithelial cells, secretory host defense mechanisms, cell death, and recovery. PMID- 20848131 TI - Mobile ER-to-Golgi but not post-Golgi membrane transport carriers disappear during the terminal myogenic differentiation. AB - The organelles of the exocytic pathway undergo a profound reorganization during the myogenic differentiation. Here, we have investigated the dynamics of the membrane trafficking at various stages of the differentiation process by using the green fluorescent protein-tagged, temperature-sensitive vesicular stomatitis virus G protein (tsG-GFP) as a marker. At the restrictive temperature of 39 degrees C, the tsG-GFP located to the endoplasmic reticulum (ER) at each stage of differentiation. Mobile membrane containers moving from the ER to the Golgi elements were seen in myoblasts and myotubes upon shifting the temperature to 20 degrees C. In adult myofibers, in contrast, such containers were not seen although the tsG-GFP rapidly shifted from the ER to the Golgi elements. The mobility of tsG-GFP in the myofiber ER was restricted, suggesting localization in an ER sub-compartment. Contrasting with the ER-to-Golgi trafficking, transport from the Golgi elements to the plasma membrane involved mobile transport containers in all differentiation stages. These findings indicate that ER-to Golgi trafficking in adult skeletal myofibers does not involve long-distance moving membrane carriers as occurs in other mammalian cell types. PMID- 20848132 TI - KDR-LacZ-expressing cells are involved in ovarian and testis-specific vascular development, suggesting a role for VEGFA in the regulation of this vasculature. AB - Our objectives were to evaluate kinase insert domain protein receptor (KDR)-beta galactosidase (LacZ) expression as a marker for vascular development during gonadal morphogenesis and to determine whether any novel non-angiogenic KDR-LacZ expression was present in mouse testes or ovaries. Gonads were collected from mice expressing LacZ driven by the Kdr promoter (KDR-LacZ) from embryonic day 11 (E11) through postnatal day 60 (P60). At E11.5, mesonephric cells expressing KDR LacZ seemed to migrate into the developing testis and surrounded developing seminiferous cords. Cells expressing KDR-LacZ appeared in the ovary with no apparent migration from the adjacent mesonephros, suggesting a different origin of endothelial cells. Testis organ cultures from E11 mice were treated with 8 MUM VEGFR-TKI, a vascular endothelial growth factor A signal transduction inhibitor; subsequently, the amount of KDR-LacZ staining was reduced by 66%-99% (P<0.002), and the ability of KDR-expressing cells to form a densely organized vascular network was inhibited. Novel non-angiogenic KDR-LacZ staining was detected in the testis on specific subsets of germ cells at E16, E17, P4, P20, P30, and P60. In ovaries, staining was present on oocytes within oocyte cysts at E17 and within late secondary follicles of postnatal mice. Thus, KDR is an excellent marker for analyzing vascular development in the gonads. Inhibition of VEGFA signal transduction prevents the development of testis-specific vasculature. Furthermore, non-vascular KDR-LacZ staining suggests that KDR directly affects both spermatogenesis and somatic-oocyte interactions during gametogenesis. PMID- 20848133 TI - Differential susceptibility to epithelial-mesenchymal transition (EMT) of alveolar, bronchial and intestinal epithelial cells in vitro and the effect of angiotensin II receptor inhibition. AB - The generation of myofibroblasts via epithelial-mesenchymal transition (EMT), a process through which epithelial cells lose their polarity and become motile mesenchymal cells, is a proposed contributory factor in fibrosis of a number of organs. Currently, it remains unclear to what extent epithelia of the upper airways and large intestine are susceptible to this process. Herein, we investigated the ability of model cell lines of alveolar (A549), bronchial (Calu 3) and colonic (Caco-2) epithelial cells to undergo EMT when challenged with transforming growth factor-beta1 (TGF-beta1) and other pro-inflammatory cytokines. Western blot and immunofluorescence microscopy demonstrated that A549 cells readily underwent EMT, as evidenced by a spindle-like morphology, increase in the mesenchymal marker, vimentin, and down-regulation of E-cadherin, an epithelial marker. In contrast, neither Calu-3 nor Caco-2 cells exhibited morphological changes nor alterations in marker expression associated with EMT. Moreover, whilst stimulation of A549 cells enhanced migration and reduced their proliferative capacity, no such effect was observed in epithelial cell lines of the bronchus or colon. In addition, concomitant treatment of A549 cells with telmisartan, an angiotensin II receptor antagonist with antifibrotic properties, was found to reduce cytokine-induced collagen I production and cell migration, although expression levels of vimentin and E-cadherin remained unaltered. Mechanistically, telmisartan failed to inhibit phosphorylation of Smad2/3. Together, these results, using representative in vitro models of the alveolus, bronchus and colon, tentatively suggest that epithelial cell plasticity and susceptibility to EMT may differ depending on its tissue origin. Furthermore, our investigations point to the beneficial effect of telmisartan in partial abrogation of alveolar EMT. PMID- 20848134 TI - Earthworms, as ecosystem engineers, influence multiple aspects of a salamander's ecology. AB - Ecosystem engineers create habitat that can be used by other species in multiple ways, such as refugees from predators, places to breed, or areas with increased prey resources. I conducted a series of enclosure experiments to: (1) determine if salamanders use earthworm burrows, and (2) examine the potential influence of earthworm burrow use and indirect effects on salamander intra- and interspecific competition, predator avoidance, and seasonal performance. I found that one species of woodland salamander, Plethodon cinereus, used earthworm burrows 50% of the time when burrows were present. Neither adults nor juveniles of the congeneric P. glutinosus used earthworm burrows. Intraspecific, but not interspecific, competition by P. cinereus affected salamander behavior when earthworms were absent, with P. cinereus found under cover objects >70% of the time when alone or with a P. glutinosus, but only 40% of the time when with another P. cinereus. When earthworms were present, the behavior of P. cinereus was similar across salamander treatments. Earthworms decreased the amount of leaf litter and microinvertebrates, although this did not affect salamander mass. In subsequent experiments using only P. cinereus, the refuge provided by earthworm burrows increased the survival of P. cinereus over the winter and allowed P. cinereus to avoid being consumed by the common garter snake (Thamnophis sirtalis). Because earthworm burrows provide a refuge for P. cinereus during intraspecific encounters, in the presence of a predator and over the winter, they may serve as an important belowground-aboveground linkage in eastern forests where salamanders are common. PMID- 20848135 TI - Geographical trends in the yolk carotenoid composition of the pied flycatcher (Ficedula hypoleuca). AB - Carotenoids in the egg yolks of birds are considered to be important antioxidants and immune stimulants during the rapid growth of embryos. Yolk carotenoid composition is strongly affected by the carotenoid composition of the female's diet at the time of egg formation. Spatial and temporal differences in carotenoid availability may thus be reflected in yolk concentrations. To assess whether yolk carotenoid concentrations or carotenoid profiles show any large-scale geographical trends or differences among habitats, we collected yolk samples from 16 European populations of the pied flycatcher, Ficedula hypoleuca. We found that the concentrations and proportions of lutein and some other xanthophylls in the egg yolks decreased from Central Europe northwards. The most southern population (which is also the one found at the highest altitude) also showed relatively low carotenoid levels. Concentrations of beta-carotene and zeaxanthin did not show any obvious geographical gradients. Egg yolks also contained proportionally more lutein and other xanthophylls in deciduous than in mixed or coniferous habitats. We suggest that latitudinal gradients in lutein and xanthophylls reflect the lower availability of lutein-rich food items in the northern F. hypoleuca populations and in montane southern populations, which start egg-laying earlier relative to tree phenology than the Central European populations. Similarly, among-habitat variation is likely to reflect the better availability of lutein rich food in deciduous forests. Our study is the first to indicate that the concentration and profile of yolk carotenoids may show large-scale spatial variation among populations in different parts of the species' geographical range. Further studies are needed to test the fitness effects of this geographical variation. PMID- 20848136 TI - Population cycles are highly correlated over long time series and large spatial scales in two unrelated species: greater sage-grouse and cottontail rabbits. AB - Animal species across multiple taxa demonstrate multi-annual population cycles, which have long been of interest to ecologists. Correlated population cycles between species that do not share a predator-prey relationship are particularly intriguing and challenging to explain. We investigated annual population trends of greater sage-grouse (Centrocercus urophasianus) and cottontail rabbits (Sylvilagus sp.) across Wyoming to explore the possibility of correlations between unrelated species, over multiple cycles, very large spatial areas, and relatively southern latitudes in terms of cycling species. We analyzed sage grouse lek counts and annual hunter harvest indices from 1982 to 2007. We show that greater sage-grouse, currently listed as warranted but precluded under the US Endangered Species Act, and cottontails have highly correlated cycles (r = 0.77). We explore possible mechanistic hypotheses to explain the synchronous population cycles. Our research highlights the importance of control populations in both adaptive management and impact studies. Furthermore, we demonstrate the functional value of these indices (lek counts and hunter harvest) for tracking broad-scale fluctuations in the species. This level of highly correlated long term cycling has not previously been documented between two non-related species, over a long time-series, very large spatial scale, and within more southern latitudes. PMID- 20848138 TI - Laparoendoscopic single-site (LESS) retroperitoneal adrenalectomy using a homemade single-access platform and standard laparoscopic instruments. AB - BACKGROUND: This study aimed to evaluate laparoendoscopic single-site (LESS) adrenalectomy via the retroperitoneal approach using the Alexis wound retractor with standard laparoscopic instrumentation. METHODS: Since October 2009, seven LESS retroperitoneal adrenalectomies have been completed successfully with a homemade single port created using an Alexis wound retractor as an access platform through a 3-cm incision beneath the tip of the 12th rib. RESULTS: All the LESS procedures for these seven patients with adrenal tumors (size, 1.3-6.0 cm; 4 right, 1 left) were completed successfully without traditional laparoscopic conversion or complication. The average operative time was 159 min, and the estimated blood loss was 100 ml. The average hospital stay was 2 days (range, 1-3 days). CONCLUSIONS: The preliminary results show that LESS retroperitoneal adrenalectomy is a safe and feasible procedure for functional adrenal tumors using standard laparoscopic instruments. PMID- 20848137 TI - Laparoscopic ileocecal resection for bowel endometriosis. AB - BACKGROUND: Ileocecal endometriosis is a very rare entity, and its diagnosis is usually made during surgery for other endometriosis sites or, rarely, because of direct complications of ileal involvement. This study was designed to analyze perioperative and long-term outcomes after bowel resection for ileocecal endometriosis. METHODS: All patients who underwent surgery for ileocecal endometriosis between October 2004 and January 2008 were prospectively collected and analyzed. RESULTS: Thirty-one women (median age, 34 (range, 25-40) years) were identified. Ileocecal endometriosis was diagnosed during surgery in all patients, and it was associated with colorectal endometriosis in 29 patients (94%). All patients underwent laparoscopic ileocecal resection with no laparotomic conversion. Rectosigmoid or rectal resections was associated in 28 patients (90%) and nodulectomy for sigmoid endometriosis in 1 patient. Median duration of surgery was 301 (range, 90-480) min. Other associated surgical procedures included total hysterectomy (n = 3, 14%), ureterolysis (n = 7, 23%), excision of vesical (n = 4, 13%), vaginal (n = 8, 26%), and parametrial (n = 3, 14%) nodules. There was no mortality. Four patients (13%) required blood transfusions and one a reoperation for bleeding. In a patient who performed ureterolysis, a ureteral fistula occurred. The median hospital stay was 7 (range, 5-18) days. Long-term (>12 months) follow-up data were available for 18 patients. After a median follow-up of 27 months, in 12 of 18 patients (67%) defecation after surgery was normal. Only one patient developed recurrence, which is under medical treatment. CONCLUSIONS: Laparoscopic ileocecal resection is safe and feasible and should be considered as part of surgery for endometriosis with radical intent. PMID- 20848139 TI - Disparities in access to basic laparoscopic surgery at U.S. academic medical centers. AB - BACKGROUND: Laparoscopy is the standard approach used for basic gastrointestinal procedures such appendectomy and cholecystectomy. This study determined the disparities in access to laparoscopic surgery for these commonly performed procedures at U.S. academic medical centers. METHODS: Using appropriate International Classification of Diseases, 9th ed, Clinical Modification (ICD-9 CM) procedure and diagnosis codes, 112,540 basic gastrointestinal procedures were identified from the University HealthSystem Consortium database over a 4-year period (2005-2009). During this period, 82,062 laparoscopic (72.9%) and 30,478 open (27.1%) procedures were performed. The odds ratios (ORs) for laparoscopic versus open procedures were calculated and stratified for age, gender, race/ethnicity, admission status, severity of illness, and primary payer status. RESULTS: Univariate analysis showed that young age (OR, 1.33; 95% confidence interval [CI], 1.27-1.39), white race/ethnicity (OR, 1.07; 95% CI, 1.03-1.11), female gender (OR, 1.79; 95% CI, 1.75-1.84), minor severity of illness (OR, 1.49; 95% CI, 1.44-1.53), and commercial/private payer status (OR, 1.25; 95% CI, 1.21 1.29) increased the likelihood that a laparoscopic approach would be used for the procedures studied. CONCLUSION: A disparity in access to basic laparoscopic surgery exists at U.S. academic medical centers based on age, gender, race/ethnicity, severity of illness, and primary payer status. PMID- 20848141 TI - Transumbilical laparoscopic appendectomy for acute appendicitis: a reliable one port procedure. AB - BACKGROUND: Emergency surgical procedures frequently must be performed at times when availability of adequately trained personnel is problematic yet the requirements for maintaining surgical quality and patient safety remain unchanged. This report aims to describe a safe, effective, transumbilical, one port laparoscopic technique for appendectomy that can be performed by one surgeon. METHODS: Between January 2006 and December 2008, transumbilical one-port laparoscopic appendectomy (TOPLA) was used by two pediatric surgeons in the authors' department to treat 152 consecutive patients presenting with simple and complicated appendicitis. With the patient placed in the Trendelenburg position and rotated to the left, a single surgeon was easily able to perform the procedure using a 10-mm 0 degrees operative laparoscope (Karl Storz) with a 5-mm working channel. The appendix was lifted with transabdominal suspensory sutures to facilitate its removal. The results were compared with those for 112 patients receiving open appendectomy (OA) during the same period. RESULTS: The operative time was significantly shortened using TOPLA (mean, 61.5 min) compared with using OA (mean, 118.3 min) (p = 0.000). Despite significantly higher numbers of patients with complicated appendicitis enrolled in the TOPLA arm of the study, the rate of wound infection was significantly lower after TOPLA (0%, 0/152) than after OA (9.8%, 11/112) (p = 0.000). The number of patients requesting intramuscular or intravenous analgesics for pain relief was significantly lower after TOPLA than after OA. The overall results for TOPLA were comparable with those for the more common three-port laparoscopic procedure, but it offers the alternative of having an inconspicuous scar hidden within the umbilicus. CONCLUSION: This report describes a simple and safe laparoscopic procedure that offers an effective way for one surgeon to treat simple and complicated appendicitis through a single port with satisfactory cosmetic outcomes. PMID- 20848140 TI - Laparoscopic versus open appendectomy for acute appendicitis: a metaanalysis. AB - BACKGROUND: Currently, laparoscopic appendectomy (LA) provides a safe and effective alternative to open appendectomy (OA), but its use remains controversial. This study aimed to evaluate the efficiency and safety of LA through a metaanalysis. METHODS: Randomized controlled trials (RCTs) comparing LA and OA published between January 1992 and February 2010 were included in this study. Strict literature appraisal and data extraction were carried out independently by two reviewers. A metaanalysis then was performed to evaluate operative time, hospital cost, postoperative complications, length of analgesia, bowel function recovery, day liquid diet began, hospital stay, and return to work and normal activity. RESULTS: The metaanalysis comprised 25 RCTs involving 4,694 patients (2,220 LA and 2,474 OA cases). No significant differences were found between the LA and OA groups in terms of age, gender, body mass index (BMI), or type of appendiceal inflammation. Compared with OA, LA showed advantages of fewer postoperative complications (odds ratio [OR], 0.74; 95% confidence interval [CI], 0.55-0.98; p = 0.04), less pain (length of analgesia: weighted mean difference [WMD], -0.53; 95% CI, -0.91 to -0.15; p = 0.007), earlier start of liquid diet (WMD, -0.51; 95% CI, -0.75 to -0.28; p < 0.0001), shorter hospital stay (WMD, 0.68; 95% CI, -1.02 to -0.35; p < 0.0001), and earlier return to work (WMD, 3.09; 95% CI, -5.22 to -0.97; p = 0.004) and normal activity (WMD, -4.73; 95% CI, -6.54 to -2.92; p < 0.00001), but a comparable hospital cost (WMD of LA/OA ratio, 0.11; 95% CI, -0.18 to 0.40; p = 0.47) and a longer operative time (WMD, 10.71; 95% CI, 6.76-14.66; p < 0.00001). CONCLUSION: Despite the longer operative time, LA results in less postoperative pain, faster postoperative rehabilitation, a shorter hospital stay, and fewer postoperative complications than OA. Therefore, LA is worth recommending as an effective and safe procedure for acute appendicitis. PMID- 20848142 TI - The challenges with NOTES retroperitoneal access in humans. AB - BACKGROUND: Animal studies have supported natural orifice transluminal endoscopic surgery (NOTES) retroperitoneal access. NOTES also may offer unique retroperitoneal access in humans. OBJECTIVES: This study was designed to assess the feasibility of endoscopic transgastric and transrectal retroperitoneal access in a cadaver model using prone and supine positioning, and to compare NOTES retroperitoneal examination with endoscopic ultrasound. METHODS: Using a multidisciplinary team, this institutional review board-approved study evaluated transgastric and transrectal retroperitoneal examination in six cadavers (3 male, 3 female; body mass index range, 25-37 kg/m(2)). Endoscopic ultrasound retroperitoneal examination preceded NOTES access. Transgastric Access: Using a prototype dual channel endoscope, a needle knife gastrotomy was created on the preantral posterior gastric wall. Retroperitoneal examination specifically targeted the pancreas and surrounding structures with the cadaver supine and prone. Transrectal Access: Using the same endoscope, a posterior needle knife rectotomy distal to the upper valve of Houston provided extraluminal access. Retroperitoneal examination proceeded with the cadaver prone and supine. Open dissection followed procedure completion. RESULTS: Access into the retroperitoneum succeeded at all sites. Significant challenges locating identifiable landmarks were faced-mostly transrectal and improved transgastric prone. All cadavers, despite body mass index or sex, had significant retroperitoneal adipose tissue limiting the endoscopic view. CONCLUSIONS: Although porcine studies have highlighted successful NOTES retroperitoneal procedures, the abundant human retroperitoneal adipose tissue challenged the translation of porcine research to humans. Additionally, although access to the retroperitoneal space and dissection within this space were accomplished easily, the appearance of cadaveric tissue and lack of blood flow made confident landmark identification impossible. Further study should continue in this area and focus on confident landmark identification for directed dissection. In a cadaveric model, this would best be improved by pre-NOTES anatomic marking or active perfusion of vasculature along with consideration of direct entry into the retroperitoneum from a targeted intraperitoneal site in clinical patients. PMID- 20848143 TI - Computed tomography (CT)-guided versus laparoscopic radiofrequency ablation: a single-institution comparison of morbidity rates and hospital costs. AB - BACKGROUND: Computed tomography (CT)-guided radiofrequency ablation (RFA) is presumed to be less morbid and less costly than laparoscopic RFA. This analysis investigates the 30-day morbidity, hospital cost, and reimbursement for CT-guided RFA versus laparoscopic RFA used to manage hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM). METHODS: A retrospective review was performed for all patients with CRLM or HCC who underwent CT-guided RFA or laparoscopic RFA between January 2002 and August 2008. Demographics, risk stratification, and procedural data were analyzed. Hospital financial data were queried for total cost, reimbursement, and itemized departmental charges. The CRLM and HCC patients were evaluated separately. RESULTS: The study analyzed 18 RFA procedures for the treatment of HCC (8 CT-guided RFA; 10 laparoscopic RFA) and 25 RFA procedures for the treatment of CRLM (6 CT-guided RFA; 19 laparoscopic RFA). Immediate local failures were reported for 33.3% and 12.5% of the CT-guided RFA procedures for CRLM and HCC and for 5.2% and 0.0% of the laparoscopic RFA procedures for CRLM and HCC, respectively. The mean hospital cost was higher for the patients who underwent laparoscopic RFA ($11,808.70 +/- $7,238.90 for HCC vs $9,882.40 +/- $1,926.90 for CRLM) than for those who underwent CT-guided RFA ($7,186.10 +/- $3,899.60 for HCC vs $5,767.50 +/- $2,869.00 for CRLM). The mean reimbursement was lower than the mean hospital cost for the patients who underwent CT-guided RFA for CRLM ($4,329.10 vs $5,767.50). CONCLUSION: Although CT-guided RFA is less expensive, it is poorly reimbursed. Also, CT-guided RFA is associated with a higher immediate local failure rate for both CRLM and HCC and a higher complication rate for patients with CRLM. For patients with HCC, CT-guided RFA is associated with a lower complication rate. Our data suggest that laparoscopic RFA should be used for most patients with CRLM and only selectively for patients with HCC. PMID- 20848144 TI - Systematic review of animal models of post-infectious/post-inflammatory irritable bowel syndrome. AB - AIMS: Post-infectious irritable bowel syndrome (PI-IBS) is a subset of IBS which occurs after an episode of acute gastrointestinal infections. The mechanisms of PI-IBS are not fully understood. Currently, numerous animal models have been used in the study of PI-IBS. This article reviews the strengths and weaknesses of these models. METHODS: All relevant articles were identified by searching in Ovid SP from 1962, the year the term PI-IBS was coined, up to December 31, 2009. The types of model were categorized as either post-infectious or post-inflammatory, and the characteristics of each kind of model were listed. RESULTS: Based on our literature search, 268 articles were identified. Of those articles, 50 were included in this review. The existing PI-IBS models include infection with bacteria (e.g., Campylobacter jejuni, Salmonella enterica, and Campylobacter rodentium), and infection with parasites (e.g., Trichinella spiralis, Nippostrongylus brasiliensis, and Cryptosporidium parvum). The post-inflammatory IBS models are commonly induced with chemical agents, such as acetic acid, deoxycholic acid, dextran sulfate sodium, mustard oil, zymosan, and trinitrobenzene sulfonic acid (TNBS). TNBS is the most commonly used agent for post-inflammatory IBS models, but the experimental protocol varies. These models have one or more aspects similar to IBS patients. CONCLUSIONS: Different methods have been used for the development of post-infectious or post-inflammatory IBS models. Each model has its weaknesses and strengths. More studies are needed to establish post-infection IBS models using more common pathogens. A standard protocol in developing TNBS-induced post-inflammatory IBS model is needed. PMID- 20848145 TI - Myogenic lineage differentiated mesenchymal stem cells enhance recovery from dextran sulfate sodium-induced colitis in the rat. AB - BACKGROUND: Although mounting evidence implicates mesenchymal stem cells (MSCs) in intestinal tissue repair, uncertainty remains concerning the distribution, function, and fate of repopulating MSCs in recipient colonic tissues. Therefore, we investigated the role of transplanted MSCs in the repair phase of DSS colitis. METHODS: LacZ-labeled rat MSCs were transplanted into rats with colitis induced by 4% DSS on day 2. Regular water replaced the DSS solution on day 6. Therapeutic effect was evaluated on day 9 by clinicopathologic and growth factor/cytokine expression profiles. We analyzed the Notch signaling pathway by Western blotting and characterized immunofluorescence of lacZ-labeled MSCs with confocal laser microscopy. In vivo differentiation of MSC was confirmed by transmission electron microscopy (TEM). RESULTS: Recovery of colitis was modestly but significantly promoted by MSC transplantation due to proceeding cell cycle and inhibiting apoptosis in the epithelia. Tgfa mRNA expression increased significantly, while Notch signaling was inhibited in the colonic tissues with MSC transplantation. beta-Galactosidase-positive cells, which expressed alpha-SMA, desmin, and vimentin, were infrequently detected in the lamina propria stroma. DSS exposure in vitro proved to be the most potent inducer for alpha-SMA in MSCs where TEM demonstrated myogenic lineage differentiation. CONCLUSIONS: We found that MSCs transplantation modestly promoted the repair of DSS colitis. The donor-derived MSCs were likely reprogrammed to differentiate to myogenic lineage cells by cues from the micro milieu. Further characterization of these cells is warranted as a basis for applying cell-based therapy for inflammatory bowel disease. PMID- 20848146 TI - Association of hepatitis B virus mutations in basal core promoter and precore regions with severity of liver disease: an investigation of 793 Chinese patients with mild and severe chronic hepatitis B and acute-on-chronic liver failure. AB - OBJECTIVE: To investigate the features of hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutations and genotypes in a large number of mild/severe chronic hepatitis B (CHB-M/CHB-S), and acute-on-chronic liver failure (ACLF) patients and analyze the clinical implications of the virologic features. PATIENTS AND METHODS: Sera of 793 (325 CHB-M, 170 CHB-S, and 298 ACLF) patients admitted to or who had visited Beijing 302 Hospital from January 2005 to December 2008 were collected and successfully amplified for the HBV BCP/PC and a 1225-bp long S/Pol (nt 54-1278) gene regions. Biochemical and serological parameters and HBV DNA level were routinely performed. Viral DNA was extracted and subjected to a nested PCR. Genotypes/subgenotypes were determined based on complete genomic sequence or on analysis of the 1225-bp-long S/Pol-gene sequence. HBV genotyping was performed by direct PCR sequencing followed by molecular evolutionary analysis of the viral sequences. A P value of <0.05 (two-sided) was considered to be statistically significant. CONCLUSIONS: Our findings suggest that CHB patients infected with BCP/PC mutant viruses are more susceptible to severe hepatitis and ACLF than those with the BCP/PC wild-type virus and that ACLF patients with PC mutant viruses have an increased risk of death. As such, the HBV PC mutation is a potential predictive indicator of ACLF outcome. PMID- 20848147 TI - Structural and functional insights into polymorphic enzymes of cytochrome P450 2C8. AB - The cytochrome P450 (CYP) superfamily plays a key role in the oxidative metabolism of a wide range of drugs and exogenous chemicals. CYP2C8 is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel in the human liver. Nearly all previous works about polymorphic variants of CYP2C8 were focused on unpurified proteins, either cells or human liver microsomes; therefore their structure-function relationships were unclear. In this study, two polymorphic enzymes of CYP2C8 (CYP2C8.4 (I264M) and CYP2C8 P404A) were expressed in E. coli and purified. Metabolic activities of paclitaxel by the two purified polymorphic enzymes were observed. The activity of CYP2C8.4 was 25% and CYP2C8 P404A was 30% of that of WT CYP2C8, respectively. Their structure-function relationships were systematically investigated for the first time. Paclitaxel binding ability of CYP2C8.4 increased about two times while CYP2C8 P404A decreased about two times than that of WT CYP2C8. The two polymorphic mutant sites of I264 and P404, located far from active site and substrate binding sites, significantly affect heme and/or substrate binding. This study indicated that two important nonsubstrate recognition site (SRS) residues of CYP2C8 are closely related to heme binding and/or substrate binding. This discovery could be valuable for explaining clinically individual differences in the metabolism of drugs and provides instructed information for individualized medication. PMID- 20848148 TI - Sigma- and pi- electron structure of aza-azoles. AB - The reasons behind changes of aromaticity in 10 unsubstituted aza-azoles were analysed by employing the natural bond orbital (NBO) approach at the MP2/6 311+G(d,p) level of theory. Sum of occupations of p(z) orbitals at atoms in the ring correlates well with the magnetism based aromaticity index NICS as well as with the number of nitrogen atoms in the ring. Changes of NICS depend strongly in a linear way on the number of NN bonds. Classification of azoles based on the number of pyridine-type nitrogen atoms vicinal to NH is supported by plotting the relative occupation of pi orbitals (pi(occ)) against the relative occupation of sigma orbitals (sigma(occ)) for all individual atoms in rings. PMID- 20848149 TI - International workshop on "Modeling interaction in biomolecules IV", held in Hruba Skala, 14-19 September 2009. PMID- 20848150 TI - Risk factors and outcomes of Escherichia coli bacteremia caused by strains that produce CTX-M or non-CTX-M extended-spectrum-beta-lactamases. AB - To determine whether there are differences in risk factors and outcomes among patients with E. coli bacteremia caused by strains that produce CTX-M or non-CTX M extended-spectrum beta-lactamases. From 1 July 2005 to 30 June 2007, patients with positive blood culture of extended-spectrum beta-lactamases (ESBL)-producing E. coli were reviewed. Sixty patients with ESBL-producing E. coli bacteremia were identified. These included 41 (68.3%) isolates with CTX-M beta-lactamases. CTX-M 14 accounted for 31 (75.6%) and CTX-M-3 for 9 (22.0%) of the 41 CTX-M isolates. Patients with CTX-M strains were less likely, by univariate analysis, to have significant risk factors for infection including age >= 65 years, chronic renal insufficiency, ICU stay at bacteremia onset, central venous catheter use and mechanical ventilation. Multivariate analysis revealed that chronic renal failure and ICU stay were independent predictors. Antibiograms were similar for CTX-M and non-CTX-M producers except that CTX-M strains were significantly more susceptible to cefmetazole (92.7 vs 36.8%, p < 0.0001). The overall mortality and length of hospitalization were not significantly different between the two groups. E. coli with CTX-M beta-lactamases was more likely than non-CTX-M strains to invade non compromised patients. There were no differences in clinical outcomes between the two groups. PMID- 20848151 TI - Dynamic ultrasonographic sign for posterior shoulder dislocation. AB - Acute posterior shoulder dislocation is rare, and its early diagnosis remains a challenge to the emergency physician. This report describes two cases of acute posterior shoulder dislocation confirmed by bedside ultrasound scan performed by the emergency physician. Bedside ultrasound for diagnosis of posterior shoulder dislocation is accurate, noninvasive, repeatable, convenient, and without ionizing radiation. Dynamic ultrasound sign of posterior shoulder dislocation and using bedside ultrasound for verification of successful reduction of posterior shoulder dislocation are described. PMID- 20848152 TI - Entropy-driven aggregation of adhesion sites of supported membranes. AB - We study, by means of mean-field calculations and Monte Carlo simulations of a lattice gas model, the distribution of adhesion sites of a bilayer membrane and a supporting flat surface. Our model accounts for the many-body character of the attractive interactions between adhesion points induced by the membrane thermal fluctuations. We show that while the fluctuation-mediated interactions alone are not sufficient to allow the formation of aggregation domains, they greatly reduce the strength of the direct interactions required to facilitate cluster formation. Specifically, for adhesion molecules interacting via a short-range attractive potential, the strength of the direct interactions required for aggregation is reduced by about a factor of two to below the thermal energy k(B)T. PMID- 20848153 TI - From crystal to amorphous: A novel route to unjamming in soft disk packings. AB - Numerical studies on the unjamming packing fraction of bi- and polydisperse disk packings, which are generated through compression of a monodisperse crystal, are presented. In bidisperse systems, a fraction f(+) = 0.400 up to 0.800 of the total number of particles has their radii increased by [Formula: see text] R , while the rest has their radii decreased by the same amount. Polydisperse packings are prepared by changing all particle radii according to a uniform distribution in the range [-DeltaR, DeltaR] . The results indicate that the critical packing fraction is never larger than the value for the initial monodisperse crystal, Phi(o) = pi/?12, and that the lowest value achieved is approximately the one for random close packing. These results are seen as a consequence of the interplay between the increase in small-small particle contacts and the local crystalline order provided by the large-large particle contacts. PMID- 20848154 TI - Pattern formation in bubbles emerging periodically from a liquid free surface. AB - Patterns formed by centimeter scale bubbles on the free surface of a viscous liquid are investigated in a cylindrical container. These bubbles emerge periodically at the surface and interact with each other in the central zone. Their radial emission, due to interaction and radial surface flow, leads to the formation of a variety of patterns. Different star-like and spiral patterns appear spontaneously by increasing the bubble emergence frequency. It is found that these patterns are due to a constant angular shift in the bubble emission direction. Measurements of this angular shift show a supercritical bifurcation accompanied by a transition from a pattern of two opposed straight arms to spiral patterns. By applying the tools and concepts from the study of leaf arrangement in botany (phyllotaxis), the recognized patterns and the mechanism of the pattern formation are discussed. Close similarities to the leaf arrangement are found in the behavior of the angular shift and the patterns. These findings suggest that the observed patterns are formed by a packing mechanism of successively appearing elements (bubbles), which is similar to that of the leaves at the earliest stage of phyllotaxis. PMID- 20848155 TI - The emergence of phosphate as a specific signaling molecule in bone and other cell types in mammals. AB - Although considerable advances in our understanding of the mechanisms of phosphate homeostasis and skeleton mineralization have recently been made, little is known about the initial events involving the detection of changes in the phosphate serum concentrations and the subsequent downstream regulation cascade. Recent data has strengthened a long-established hypothesis that a phosphate sensing mechanism may be present in various organs. Such a phosphate sensor would detect changes in serum or local phosphate concentration and would inform the body, the local environment, or the individual cell. This suggests that phosphate in itself could represent a signal regulating multiple factors necessary for diverse biological processes such as bone or vascular calcification. This review summarizes findings supporting the possibility that phosphate represents a signaling molecule, particularly in bone and cartilage, but also in other tissues. The involvement of various signaling pathways (ERK1/2), transcription factors (Fra-1, Runx2) and phosphate transporters (PiT1, PiT2) is discussed. PMID- 20848157 TI - Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans. AB - We have utilized Caenorhabditis elegans as a model to investigate the toxicity and underlying mechanism of untranslated CAG repeats in comparison to CUG repeats. Our results indicate that CAG repeats can be toxic at the RNA level in a length-dependent manner, similar to that of CUG repeats. Both CAG and CUG repeats of toxic length form nuclear foci and co-localize with C. elegans muscleblind (CeMBL), implying that CeMBL may play a role in repeat RNA toxicity. Consistently, the phenotypes of worms expressing toxic CAG and CUG repeats, including shortened life span and reduced motility rate, were partially reversed by CeMbl over-expression. These results provide the first experimental evidence to show that the RNA toxicity induced by expanded CAG and CUG repeats can be mediated, at least in part, through the functional alteration of muscleblind in worms. PMID- 20848156 TI - Function of chloroplast RNA-binding proteins. AB - Chloroplasts are eukaryotic organelles which represent evolutionary chimera with proteins that have been derived from either a prokaryotic endosymbiont or a eukaryotic host. Chloroplast gene expression starts with transcription of RNA and is followed by multiple post-transcriptional processes which are mediated mainly by an as yet unknown number of RNA-binding proteins. Here, we review the literature to date on the structure and function of these chloroplast RNA-binding proteins. For example, the functional protein domains involved in RNA binding, such as the RNA-recognition motifs, the chloroplast RNA-splicing and ribosome maturation domains, and the pentatricopeptide-repeat motifs, are summarized. We also describe biochemical and forward genetic approaches that led to the identification of proteins modifying RNA stability or carrying out RNA splicing or editing. Such data will greatly contribute to a better understanding of the biogenesis of a unique organelle found in all photosynthetic organisms. PMID- 20848159 TI - Lack of association between plasma myeloperoxidase levels and angiographic severity of coronary artery disease in patients with acute coronary syndrome. AB - OBJECTIVE: To evaluate the association between plasma myeloperoxidase (MPO) levels and angiographic severity of coronary atherosclerotic lesions in patients with non-ST elevation acute coronary syndrome (ACS). DESIGN AND METHODS: This cross-sectional study examined high-risk ACS patients who underwent coronary angiography within 72 h of the onset of symptoms by measuring their plasma MPO levels after sheath insertion. Gensini score was used to evaluate angiographic severity of coronary artery disease. RESULTS: A total of 48 patients were included in the study. Median MPO levels and Gensini scores were 6.9 ng/mL (4.4 73.5 ng/mL) and 10 (0-87.5), respectively. Spearman's correlation coefficient did not show a significant association between MPO levels and Gensini scores (r (s) = 0.2; p = 0.177). There was no correlation between MPO and age, hypertension, diabetes, leukocyte count, troponin I, CK-MB >= 2 * ULN (upper limit of normal), TIMI risk score >= 4 and Gensini score in the multivariate analysis. CONCLUSION: Our findings indicate that MPO expression is not associated with anatomical severity of coronary lesions in ACS. PMID- 20848160 TI - "Old drugs" for the treatment of rheumatoid arthritis: will the cholinergic anti inflammatory pathway and anti-nociceptive pathway work? AB - Based on the newly discovered cholinergic anti-inflammatory pathway, on the anti nociceptive pathway and on our preliminary research, we raise a new strategy for the treatment of rheumatoid arthritis (RA) which mainly focuses on the application of old drugs that can activate both of the above mentioned pathways. It has been reported that nicotinic receptor agonists used for the treatment of neurological diseases were expected to be applied to the therapy of inflammatory diseases (RA). Therefore, it is promising that old drugs available in clinics may exert new functions for the treatment of RA, which may greatly reduce the expense of such treatment, once applied. These currently-used old drugs should be considered as another new resource in exploring anti-rheumatic agents under the guidance of the newly discovered cholinergic anti-inflammatory pathway and the anti-nociceptive pathway. PMID- 20848158 TI - Endothelin. AB - Endothelin-1 is the most potent vasoconstrictor agent currently identified, and it was originally isolated and characterized from the culture media of aortic endothelial cells. Two other isoforms, termed endothelin-2 and endothelin-3, were subsequently identified, along with structural homologues isolated from the venom of Actractapis engaddensis known as the sarafotoxins. In this review, we will discuss the basic science of endothelins, endothelin-converting enzymes, and endothelin receptors. Only concise background information pertinent to clinical physician is provided. Next we will describe the pathophysiological roles of endothelin-1 in pulmonary arterial hypertension, heart failure, systemic hypertension, and female malignancies, with emphasis on ovarian cancer. The potential intervention with pharmacological therapeutics will be succinctly summarized to highlight the exciting pre-clinical and clinical studies within the endothelin field. Of note is the rapid development of selective endothelin receptor antagonists, which has led to an explosion of research in the field. PMID- 20848161 TI - Risk factors for haemorrhage during local intra-arterial thrombolysis for lower limb ischaemia. AB - Assessment of clinical risk factors for haemorrhagic complications in patients undergoing intra-arterial thrombolysis for lower limb ischaemia. Retrospective reviews of consecutive patients subjected to intra-arterial thrombolysis due to lower limb ischemia at the Vascular Center, Malmo University Hospital, during a 5 year period from 2001 to 2005. Two hundred and twenty intra-arterial thrombolytic procedures were carried out in 195 patients (46% women), median age 73 years. Haemorrhagic complications were recorded in 72 procedures (33%), of which 13 were discontinued. Haemorrhage at the introducer and distant sites occurred in 53 and 32 procedures, respectively. Thrombolysis for occluded synthetic grafts was associated with higher risk of haemorrhage (P = 0.043). The platelet count was lower (P = 0.017) and the dose of alteplas higher (P = 0.041) in bleeders than in non-bleeders. Age was not associated with haemorrhage (P = 0.30). Two patients died during thrombolysis, one of them due to intracerebral haemorrhage. The grade of thrombolysis was an independent predictor of both in-hospital amputation (P < 0.001; OR 3.5 [95% CI 2.1-5.8]) and mortality (P = 0.021; OR 3.0 [95% CI 1.2 7.9]). The in-hospital amputation-free survival rate was 85% (188/220). Haemorrhage associated with thrombolysis is common, but does seldom require discontinuation of treatment. Insertion of introducers for local thrombolysis through synthetic grafts, lower platelet count and higher alteplas dose were found to be risk factors for haemorrhage. An algorithm for clinical management of haemorrhage has been proposed. PMID- 20848162 TI - The validity of the INR system for patients with liver disease. PMID- 20848163 TI - Distribution and molecular composition of heterochromatin in the holocentric chromosomes of the aphid Rhopalosiphum padi (Hemiptera: Aphididae). AB - In order to study the structure of holocentric chromosomes in aphids, the localization and the composition of Rhopalosiphum padi heterochromatin and rDNA genes have been evaluated at cytogenetic and molecular level. In particular, heterochromatin resulted located on all the chromosomes both in intercalary and telomeric positions. Moreover, enzymatic digestion of R. padi genome put in evidence a DraI satellite DNA which has been isolated, cloned and sequenced. FISH experiments showed that this satellite DNA clusters in an intercalary C-positive band on the two X chromosomes. PMID- 20848165 TI - Fatty acids inhibit insulin-mediated glucose transport associated with actin remodeling in rat L6 muscle cells. AB - In skeletal muscle cells, insulin stimulates cytoskeleton actin remodeling to facilitate the translocation of glucose transporter GLUT4 to plasma membrane. Defect of insulin-induced GLUT4 translocation and actin remodeling may cause insulin resistance. Free fatty acids cause insulin resistance in skeletal muscle. The aim of this study was to investigate the effects of fatty acids on glucose transport and actin remodeling. Differentiated L6 muscle cells expressing c-myc epitope-tagged GLUT4 were treated with palmitic acid, linoleic acid and oleic acid. Surface GLUT4 and 2-deoxyglucose uptake were measured in parallel with the morphological imaging of actin remodeling and GLUT4 immunoreactivity with fluorescence, confocal and transmission electron microscopy. Differentiated L6 cells showed concentration responses of insulin-induced actin remodeling and glucose uptake. The ultrastructure of insulin-induced actin remodeling was cell projections clustered with actin and GLUT4. Acute and chronic treatment with the 3 fatty acids had no effect on insulin-induced actin remodeling and GLUT4 immunoreactivity. However, insulin-mediated glucose uptake significantly decreased by palmitic acid (25, 50, 75, 100 MUmol/L), oleic acid (180, 300 MUmol/L) and linoleic acid (120, 180, 300 MUmol/L). Oleic acid (120, 300 MUmol/L) and linoleic acid (300 MUmol/L), but not palmitic acid, significantly decreased insulin-mediated GLUT4 translocation. These data suggest that fatty acids inhibit insulin-induced glucose transport associated with actin remodeling in L6 muscle cells. PMID- 20848164 TI - Predominant effects of midazolam for conscious sedation: benefits beyond the early postoperative period. AB - PURPOSE: Conscious sedation with intravenous sedative-hypnotic drugs has the advantage of relaxing patients before invasive procedures. Preoperative anxiety has been suggested to correlate with postoperative comfortableness. In this study, we chose midazolam and droperidol as well-established intravenous sedative hypnotic drugs. We evaluated the preoperative anxiolytic effect on postoperative memories and emotions up to the first postoperative morning. METHODS: In a prospective, double blind study, 120 patients requiring epidural anesthesia were randomly assigned to one of three groups to receive saline, midazolam (0.04 mg/kg), or droperidol (0.1 mg/kg). Cardiovascular and respiratory measurements, observer's assessment of alertness/sedation scale, level of anxiety and discomfort of the patients, pain during the infiltration of local anesthetics, and incidence of adverse effects were recorded. Amnesia, anxiety, and discomfort during the epidural procedure were re-assessed between 12 and 20 h postsurgery. RESULTS: Patients who received sedatives were significantly more sedated (P < 0.0001), but the pain score was significantly higher in the droperidol group (P = 0.0007) at epidural catheterization. On the first postoperative morning, patients receiving midazolam had a significantly lower pain score (P < 0.0001) with less anxiety and discomfort. Patients in both the midazolam and droperidol groups showed a significant decrease in blood pressure (P < 0.0167), but no respiratory impairment. No adverse effects were experienced throughout the study period. CONCLUSION: Conscious sedation with intravenous midazolam 0.04 mg/kg significantly decreased the anxiety and discomfort scores of the patients on the day following surgery but had no effect on these immediately following the epidural catheterization procedure. PMID- 20848166 TI - An analysis tool to calculate permeability based on the Patlak method. AB - Strokes are commonly diagnosed by utilizing images obtained from magnetic resonance imaging (MRI) technology. Nowadays, computer software can play a large role in analyzing these images and arriving at diagnoses quickly and accurately. Additionally, this software can reduce workload for medical personnel and lower misdiagnoses. In this paper a flexible permeability calculation tool called PCT based on the Patlak plot method is presented. Using the PCT we can calculate the permeability co-efficient of the Blood-Brain Barrier (BBB) function. The PCT tool offers both manual and automatic options for diagnosing the regions of the brain affected by stroke. Moreover, the PCT tool supports various extensions such as dicom, nifty and analyze. PMID- 20848167 TI - Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis. AB - BACKGROUND: Common single-nucleotide polymorphisms (SNPs) in microRNAs (miRNA) have been shown to be associated with susceptibility to several human diseases. We evaluated the associations of three SNPs (rs11614913, rs2910164, and rs3746444) in pre-miRNAs (miR-196a2, miR-146a, and miR-499) with the risk of ulcerative colitis (UC) in a Japanese population. METHODS: The rs11614913 (T > C), rs2910164 (C > G), and rs3746444 (A > G) SNPs were genotyped in 170 UC and 403 control subjects. RESULTS: The rs3746444 AG genotype was significantly higher among the UC group (odds ratio (OR) = 1.51, 95% CI = 1.03-2.21, p = 0.037). The rs3746444 AG genotype was associated with onset at an older age (OR = 1.70, 95% CI = 1.04-2.78, p = 0.035), left-sided colitis and pancolitis (left-sided colitis, OR = 2.10, 95% CI = 1.12-3.94, p = 0.024; pancolitis, OR = 1.81, 95% CI = 1.09-3.01, p = 0.028, left-sided colitis + pancolitis, OR = 1.91, 95% CI = 1.26 2.92, p = 0.003), higher number of times hospitalized (OR = 2.63, 95% CI = 1.22 5.69, p = 0.017), steroid dependence (OR = 2.63, 95% CI = 1.27-5.44, p = 0.014), and refractory phenotypes (OR = 2.76, 95% CI = 1.46-5.21, p = 0.002) while the rs3746444 AA genotype was inversely associated with the number of times hospitalized (2~, OR = 0.36, 95% CI = 0.17-0.79, p = 0.012), steroid dependence (OR = 0.42, 95% CI = 0.21-0.88, p = 0.021), and refractory phenotypes (OR = 0.38, 95% CI = 0.20-0.72, p = 0.003). The rs1161913 TT genotype also held a significantly higher risk of refractory phenotype (T/T vs. T/C + C/C, OR = 2.21, 95% CI = 1.17-4.18, p = 0.016). CONCLUSIONS: Our results provided the first evidence that rs3746444 SNP may influence the susceptibility to UC, and both rs3746444 and rs11614913 SNPs may influence the pathophysiological features of UC. PMID- 20848169 TI - Fathering: the relationship between fathers' residence, fathers' sociodemographic characteristics, and father involvement. AB - Literature and research examining father involvement has focused primarily on outcomes associated with the well-being and development of children. The contextual factors associated with fathers, and how these factors shape fathers' involvement with their young children, have received limited attention in this literature. Addressing this limitation, this study focuses on the relationship between fathers' residential status, age, race and ethnicity, educational attainment, financial status and father involvement. Results of the regression models indicate that fathers who reside with their children and fathers who are older are more involved with their children. Given these findings, policymakers, practitioners, and researchers have an opportunity to create and enhance policies and programs that may assist and support fathers in their development as parents and their involvement with their children. PMID- 20848168 TI - Clinical ramifications of the MHC family Fc receptor FcRn. AB - INTRODUCTION: Knowledge that antibodies of the IgG isotype have remarkably extended persistence in circulation and are able to pass through cell barriers has substantial implications. While it is well established that so-called neonatal Fc receptor, FcRn, acts throughout life to confer these unusual properties, its ramifications on clinical medicine and therapeutic uses are not broadly appreciated. SCOPE: Here we discuss basic principles and gaps in understanding of FcRn, including its management of IgG antibodies and along with albumin, its impact on use and design of antibody-based therapeutics, and its genetics. PMID- 20848170 TI - Factors associated with improved MCH epidemiology functioning in state health agencies. AB - This paper discusses characteristics that are associated with enhanced maternal and child health (MCH) epidemiology functioning in state health agencies. The concept of the "MCH Epidemiology Effort" is introduced as "the epidemiologic work carried out by multiple units and agencies aimed at informing program planning and policy development on behalf of women, children and families." This concept focuses attention on MCH epidemiology functioning at the organizational level rather than on individual MCH epidemiologists. The analysis used data from all 50 states and the District of Columbia. Each state participated in a telephone interview and submitted material that demonstrated the breadth, depth, and capacity of its MCH Epidemiology Effort. Several organizations, including the Council for State and Territorial Epidemiologists, the Health Resources and Services Administration/Maternal and Child Health Bureau, and the Centers for Disease Control and Prevention provided additional secondary data. The outcome for analysis was a three-category measure of MCH epidemiology functioning. The findings are consistent with, and add specificity to, those from prior assessments. In a multivariable model, agenda-setting by consensus, involvement of external stakeholders, the total of doctorally trained staff, and accessing CDC assignees or other staff were all significantly related to higher level MCH epidemiology functioning (ORs of 6.1, 6.6, 2.5, and 6.4, respectively; P<0.05). Organizational visibility of the MCH Epidemiology Effort and a data environment marked by routine data-sharing and data integration were marginally related. We provide recommendations for action at the state and federal level for advancing evidence-based decision-making in maternal and child health. PMID- 20848171 TI - Breastfeeding and the child cognitive outcomes: a propensity score matching approach. AB - To estimate the effect of breastfeeding initiation and duration on child development outcomes. 3,271 children and their mothers participating in the Child Development Supplement of the Panel Study of Income Dynamics provide data for these analyses. Main outcomes include Woodcock Johnson Psycho-Educational Battery Revised (WJ-R) test score (letter word, passage comprehension, applied problem, and broad reading), and Wechsler Intelligence Scale for Children-Revised (WISC-R) test score at the 2002 survey. Controlled variables include family, maternal, and child characteristics, many of which can be traced back to the year the child was born. The analytic technique is propensity score matching with multiple imputations. After using propensity scores to adjust for confounding factors, breastfeeding initiation showed statistically significant effects but the practical scale remains small. Breastfeeding duration showed a non-linear effect on those outcomes and most of the effects are not significant. The effects of breastfeeding on child's cognitive outcomes are modest in practical terms. The non-linear effects suggest that selection into breastfeeding may account for the increased score of children who are breastfed. PMID- 20848172 TI - Influence of maternal education on child immunization and stunting in Kenya. AB - In 2003, the child mortality rate in Kenya was 115/1000 children compared to 88/1000 average for Sub-Saharan African countries. This study sought to determine the effect of maternal education on immunization (n=2,169) and nutritional status (n=5,949) on child's health. Cross-sectional data, Kenya Demographic Health Survey (KDHS)-2003 were used for data analyses. 80% of children were stunted and 49% were immunized. After controlling for confounding, overall, children born to mothers with only a primary education were 2.17 times more likely to be fully immunized compared to those whose mothers lacked any formal education, P<0.001. For nutrition, unadjusted results, children born to mothers with primary education were at 94% lower odds of having stunted growth compared to mothers with no primary education, P<0.01. Policy implications for child health in Kenya should focus on increasing health knowledge among women for better child health outcomes. PMID- 20848173 TI - American Indian grand families: a qualitative study conducted with grandmothers and grandfathers who provide sole care for their grandchildren. AB - A qualitative study was conducted to determine the rationale for 31 American Indian grandparents' who provide sole care of their grandchildren, the impact of historical trauma on their decision making process in accessing services, the value of American Indian Child Welfare policies in addressing care issues, and custody status of the grand families. Indian Outreach Workers, Community Health Representatives, Elder Program Directors, and tribal community leaders were key in the recruitment of participants. The grandparents were informed of the purpose of the study and participated in face-to-face, paper and pencil, individual interviews. The subjects included 29 grandmothers and two grandfathers; age 43-86 years, with 20 who lived off reservation land and 11 who lived on reservation land in Michigan. A phenomenological approach of the "world of the lived experience" informed the design of the study. The researchers recorded the subjects' responses via field notes, conducted a comparison of responses to assess internal reliability, and entered the responses into the qualitative data analysis Nvivo program. Findings included; (1) reasons for providing sole care of grandchildren (2) stressors and rewards of providing sole care (3) grandparents decisions affected by historical traumas which focused on the boarding school issues and the removal of children from their homes due to cultural differences causing a reluctance to seek and access national and state programs (4) grandparents preference was to seek and access services provided by their Tribal Nations, and/or American Indian urban agencies (5) most lacked legal custodial status which is an indicator the grandparents' may have benefited from knowledge of the Indian Child Welfare Act (ICWA). PMID- 20848174 TI - Antigenic, genetic, and pathogenic characterization of H5N1 highly pathogenic avian influenza viruses isolated from dead whooper swans (Cygnus cygnus) found in northern Japan in 2008. AB - In April and May 2008, whooper swans (Cygnus cygnus) were found dead in Hokkaido in Japan. In this study, an adult whooper swan found dead beside Lake Saroma was pathologically examined and the identified H5N1 influenza virus isolates were genetically and antigenically analyzed. Pathological findings indicate that the swan died of severe congestive edema in the lungs. Phylogenetic analysis of the HA genes of the isolates revealed that they are the progeny viruses of isolates from poultry and wild birds in China, Russia, Korea, and Hong Kong. Antigenic analyses indicated that the viruses are distinguished from the H5N1 viruses isolated from wild birds and poultry before 2007. The chickens vaccinated with A/duck/Hokkaido/Vac-1/2004 (H5N1) survived for 14 days after challenge with A/whooper swan/Hokkaido/1/2008 (H5N1), although a small amount of the challenge virus was recovered from the tissues of the birds. These findings indicate that H5N1 highly pathogenic avian influenza viruses are circulating in wild birds in addition to domestic poultry in Asia and exhibit antigenic variation that may be due to vaccination. PMID- 20848175 TI - Sexual attraction to others: a comparison of two models of alloerotic responding in men. AB - The penile response profiles of homosexual and heterosexual pedophiles, hebephiles, and teleiophiles to laboratory stimuli depicting male and female children and adults may be conceptualized as a series of overlapping stimulus generalization gradients. This study used such profile data to compare two models of alloerotic responding (sexual responding to other people) in men. The first model was based on the notion that men respond to a potential sexual object as a compound stimulus made up of an age component and a gender component. The second model was based on the notion that men respond to a potential sexual object as a gestalt, which they evaluate in terms of global similarity to other potential sexual objects. The analytic strategy was to compare the accuracy of these models in predicting a man's penile response to each of his less arousing (nonpreferred) stimulus categories from his response to his most arousing (preferred) stimulus category. Both models based their predictions on the degree of dissimilarity between the preferred stimulus category and a given nonpreferred stimulus category, but each model used its own measure of dissimilarity. According to the first model ("summation model"), penile response should vary inversely as the sum of stimulus differences on separate dimensions of age and gender. According to the second model ("bipolar model"), penile response should vary inversely as the distance between stimulus categories on a single, bipolar dimension of morphological similarity-a dimension on which children are located near the middle, and adult men and women are located at opposite ends. The subjects were 2,278 male patients referred to a specialty clinic for phallometric assessment of their erotic preferences. Comparisons of goodness of fit to the observed data favored the unidimensional bipolar model. PMID- 20848177 TI - Sequence variation and secondary structure analysis of the first ribosomal internal transcribed spacer (ITS-1) between Cyprinus carpio carpio and C. carpio haematopterus. PMID- 20848179 TI - Power as a structural phenomenon. AB - In an effort to inform empowerment theory and research, this paper provides a structural conception of power. First, we examine the essential features present in three dominant conceptions of power in community psychology: social power, psychopolitical power, and relational power. Next, commonalities in the key features of power identified by these conceptions are explored and pared down to yield a more parsimonious conception of power that is grounded only in the structural pattern of relationships through which resources are exchanged. Drawing on social exchange theory, we offer a method for measuring this streamlined, structural conception of power that allows for its more precise examination. Finally, we discuss the implications of a structural conception and measurement of power for targeting and facilitating empowering processes and evaluating empowered outcomes. PMID- 20848178 TI - Dissecting chromatin interactions in living cells from protein mobility maps. AB - The genome of eukaryotes is organized into a dynamic nucleoprotein complex referred to as chromatin, which can adopt different functional states. Both the DNA and the protein component of chromatin are subject to various post translational modifications that define the cell's gene expression program. Their readout and establishment occurs in a spatio-temporally coordinated manner that is controlled by numerous chromatin-interacting proteins. Binding to chromatin in living cells can be measured by a spatially resolved analysis of protein mobility using fluorescence microscopy based approaches. Recent advancements in the acquisition of protein mobility data using fluorescence bleaching and correlation methods provide data sets on diffusion coefficients, binding kinetics, and cellular concentrations on different time and length scales. The combination of different techniques is needed to dissect the complex interplay of diffusive translocations, binding events, and mobility constraints of the chromatin environment. While bleaching techniques have their strength in the characterization of particles that are immobile on the second/minute time scale, a correlation analysis is advantageous to characterize transient binding events with millisecond residence time. The application and synergy effects of the different approaches to obtain protein mobility and interaction maps in the nucleus are illustrated for the analysis of heterochromatin protein 1. PMID- 20848180 TI - The impact of EPLINalpha (Epithelial protein lost in neoplasm) on endothelial cells, angiogenesis and tumorigenesis. AB - BACKGROUND: EPLIN (epithelial protein lost in neoplasm) is a cytoskeletal associated protein involved in the regulation of actin dynamics and subsequently in cell motility. EPLIN expression is frequently reduced in a variety of cancer cells and tissues and this loss may account for increased invasive traits in cancer cells. The current study aimed to assess the role of EPLIN in endothelial cells and the angiogenic process. METHODS: EPLINalpha expression was enhanced in HECV endothelial cells through transfection with a pEF6 expression plasmid containing the full coding sequence of EPLINalpha. The impact of EPLINalpha on HECV cells was then assessed using a range of in vitro and in vivo models. RESULTS: transfection and over-expression of HECV cells with EPLINalpha expression plasmid resulted in a significant reduction in cell-matrix adhesion (P = 0.003), the rate of migration (P = 0.009) and tubule formation (P = 0.007) and also enhanced paxillin staining compared to transfection controls. Additionally, MDA-MB-231 breast cancer cells co-injected with HECV(EPLIN exp) cells developed at a slower rate than those co-injected with HECV(pEF6) cells (day 26, P = 0.05; day 33, P = 0.065, overall deviation over time P < 0.001). Treatment of HECV(EPLIN exp) cells with ERK inhibitor could rescue HECV cells from the inhibitory effect of EPLINalpha over-expression on tubule formation, returning these cells to control levels. CONCLUSIONS: EPLINalpha over-expression can regulate HECV cell motility, matrix adhesion and tubule formation in vitro and slow in vivo tumour formation, suggesting an anti-angiogenic role for EPLINalpha. Extracellular signal-regulated kinase (ERK) also appears to be linked to the ability of EPLINalpha to inhibit tubule formation in vitro. PMID- 20848182 TI - Let-7a regulation of insulin-like growth factors in breast cancer. AB - Expression of certain microRNA genes is regulated by DNA methylation, which in turn affects the activities of their downstream molecules. Our previous study showed that methylated let-7a-3 was associated with low IGF-II expression and favorable prognosis of ovarian cancer. The roles of let-7a-3 methylation in breast cancer and in regulation of IGF expression in the tumor are still unknown. Let-7a-3 methylation, IGF mRNAs, and peptides were analyzed in 348 breast cancer samples using quantitative methylation-specific PCR, qRT-PCR, and ELISA, respectively. The associations of let-7a-3 methylation with IGFs, disease features, and patient survivals were analyzed. In vitro experiments were performed using HeLa cells transfected with let-7a precursors to assess the effect of let-7a on IGF expression. Let-7a-3 methylation was detected frequently in breast cancer. An inverse correlation between let-7a-3 methylation and IGF expression was observed in breast cancer, which was similar to that seen in ovarian cancer. Our in vitro experiment showed that let-7a could increase IGF expression in cancer cells which had low endogenous let-7a. Let-7a-3 methylation was also found to be associated with high grade tumors and ER- or PR-negative cancer. However, let-7a-3 methylation was not associated with disease-free survival or overall survival of breast cancer patients. The study provides further evidence in support of the notion that epigenetic regulation of let-7a-3 may affect the actions of IGFs in cancer. Let-7a may up-regulate the expression of IGFs in cancer cells, which is different from its inhibitory effects on other oncogenes. PMID- 20848181 TI - Comparative analysis of angiogenic gene expression in normal and impaired wound healing in diabetic mice: effects of extracorporeal shock wave therapy. AB - Impaired wound healing is a persistent clinical problem which has been treated with mixed results. Studies aimed at elucidating the mechanism of impaired wound healing have focused on small cohorts of genes which leave an incomplete picture of the wound healing process. We aimed to investigate impaired wound healing via a comprehensive panel of angiogenic/inflammation-related genes and wound closure kinetics with and without the application of extracorporeal shock wave therapy (ESWT), which has been demonstrated to improve wound healing. Full-thickness skin from the dorsal surface of "normal" (BALB/c) and "impaired" (db (+)/db (+)) mice was excised, and wound margin tissue was harvested 2, 7, and 10 days post injury. A separate, but identical wound model was established over 40 days in order to measure wound closure kinetics. Over time, the normal non-ESWT treated wounds exhibited varying patterns of elevated expression of 25-30 genes, whereas wounds with impaired healing displayed prolonged elevated expression of only a few genes (CXCL2, CXCL5, CSF3, MMP9, TGF-alpha). In response to ESWT, gene expression was augmented in both types of wounds, especially in the expression of PECAM-1; however, ESWT had no effect on wound closure in either model. In addition, multiple doses of ESWT exacerbated the delayed wound healing, and actually caused the wounds to initially increase in size. These data provide a more complete picture of impaired wound healing, and a way to evaluate various promising treatments. PMID- 20848183 TI - Incorporating margin status information in treatment decisions for women with ductal carcinoma in situ: a decision analysis. AB - To integrate margin status information into the decision to undergo radiation therapy (RT) following breast-conserving surgery (BCS) for women with ductal carcinoma in situ (DCIS). We developed a decision-analytic Markov model to project quality-adjusted life years (QALYs) for a hypothetical cohort of 55-year old women with DCIS over a lifetime horizon treated with or without RT following BCS. We estimated the transition probabilities of local DCIS and invasive recurrences based on the margin status (free, close, or positive) from a systematic literature review. Other probability estimates and utilities were collected from the published literature. Using the conditions defined in this model, expected QALYs after BCS alone were better than those after BCS with RT under the free-margin scenario (15.72 vs. 15.58) and worse in the close-margin (15.44 vs. 15.50) and positive-margin scenarios (15.20 vs. 15.33). The probability of receiving a salvage mastectomy varied from 10 to 28%, depending on margin status and treatment. One-way sensitivity analyses showed that the optimal treatment was sensitive to patients' preferences and RT side effects. Probabilistic sensitivity analyses revealed that BCS alone would be the best strategy in 54% of the cases under the free-margin scenario, 48% under the close margin scenario, and 44% under the positive-margin scenario. This study illustrates that margin status is able to provide supplementary information on the decision of DCIS treatment. Our analyses also highlight the importance of patients' preferences in decision making. Our findings suggest that RT is not necessary for all patients with DCIS undergoing BCS. PMID- 20848184 TI - Two novel variants in the 3'UTR of the BRCA1 gene in familial breast and/or ovarian cancer. AB - For the majority of breast and/or ovarian cancer patients tested for BRCA1/2 genes, mutation screening of the coding regions remains negative. MicroRNAs which negatively regulate mRNA translation by binding to 3' untranslated region (3'UTR) are implicated in cancer. Genetic changes in the 3'UTR of several genes were reported to be associated with higher susceptibility to particular tumor types. The aim of this study was to analyze the BRCA1 3'UTR in patients tested negative for BRCA1/2 deleterious mutations, in order to find variants implicated in the decrease of BRCA1 expression through modification of miRNA binding. Genotyping analyses were performed on genomic DNA of 70 BRCA negatives index cases, selected among patients with breast or ovarian cancer, less than 50 years old, with a strong family history. The co-occurrence of the identified variants with deleterious BRCA1 mutations was then determined in a control population of 210 patients. A luciferase gene reporter assay was used to investigate the impact of the variants on the BRCA1 gene expression. Two novel variants, c.*750A>G and c.*1286C>A, were identified in the 3'UTR of BRCA1 gene, in two patients. The former was found three times in the control population, whereas the latter was absent. The used functional assay did not reveal any effect on the luciferase expression. This study reveals a weak genomic variability in the 3'UTR of the BRCA1 gene. All together, the results led us to classify the variant c.*750A>G as probably neutral, the variant c.*1286C>A remaining unclassified. PMID- 20848185 TI - Oncologic safety of breast conserving surgery after tumour downsizing by neoadjuvant therapy: a retrospective single centre cohort study. AB - The objective of this study is to analyse local recurrence rates in patients receiving neoadjuvant chemotherapy (nCT) comparing mastecomized (MX) patients with those undergoing breast conserving therapy (BCT). Patients undergoing breast cancer surgery after nCT (3xCMF or 3-6xED) between 1995 and 2007 at our department were retrospectively analysed. The median follow up was 60 months for 308 patients. Patients who were downsized from MX to BCT with partial or complete response (n = 104) had a similar local recurrence free survival (LRFS) compared to patients who did not experience successful downsizing (n = 67) and finally undergoing MX (LRFS MX-BCT 81% vs. MX-MX 91%; P = 0.79). Uni- and multivariate analyses demonstrated that BCT itself was not an independent prognostic factor for a worse LRFS (P = 0.07 and 0.14). After no pathologic change or progressive disease the risk of local recurrence was increased in patients undergoing BCT (MX BCT; n = 6 LRFS 66%) compared with MX (n = 44; LRFS 90%; P = 0.04). Overall survival in general was better for the BCT group (n = 197) compared with MX group (n = 111) regardless of clinical response (92% vs. 72%; P < 0.0001). Breast conservation, nodal negativity and low or medium grade histology were prognostic factors for an improved OS (P = 0.02, 0.01, 0.004). In conclusion, our study suggests that BCT is oncologically safe after tumour downsizing by nCT in patients primarily scheduled for mastectomy. These patients, however, should not be treated with breast conservation in the absence of any proven response after nCT. PMID- 20848186 TI - Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence. AB - Concurrent use of tamoxifen and cytochrome P450 2D6 (CYP2D6) inhibitors, such as selective serotonin reuptake inhibitors, has been shown to decrease plasma concentrations of tamoxifen metabolites. However, it is still unclear whether such concurrent use affects tamoxifen's effectiveness. Thus, the objective of this study is to determine whether concurrent use of tamoxifen with CYP2D6 inhibitors increases the risk of recurrence in patients newly diagnosed with breast cancer. We conducted a nested case-control analysis within a population based cohort from the UK General Practice Research Database. The cohort included women with a first-ever diagnosis of breast cancer who were prescribed tamoxifen between January 1, 1998 and June 30, 2008. Cases consisted of all patients with a breast cancer recurrence occurring during follow-up. Up to ten controls were matched to each case on year of birth, date of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RR) of breast cancer recurrence in patients who concurrently used tamoxifen with CYP2D6 inhibitors, compared to patients who only used tamoxifen. The cohort included 9,209 incident users of tamoxifen, of whom 807 were diagnosed with a breast cancer recurrence. Concurrent use was not associated with an increased incidence of breast cancer recurrence (adjusted RR 1.07, 95% 0.88, 1.30). Type and strength of CYP2D6 inhibitors, as well as duration of concurrent use did not affect breast cancer recurrence. These results remained consistent after performing sensitivity analyses. The results of this large population-based study indicate that concurrent use of tamoxifen with CYP2D6 inhibitors does not increase the risk of recurrence. PMID- 20848187 TI - Exploring deliberate practice in medicine: how do physicians learn in the workplace? AB - Medical professionals need to keep on learning as part of their everyday work to deliver high-quality health care. Although the importance of physicians' learning is widely recognized, few studies have investigated how they learn in the workplace. Based on insights from deliberate practice research, this study examined the activities physicians engage in during their work that might further their professional development. As deliberate practice requires a focused effort to improve performance, the study also examined the goals underlying this behaviour. Semi-structured interviews were conducted with 50 internal medicine physicians: 19 residents, 18 internists working at a university hospital, and 13 working at a non-university hospital. The results showed that learning in medical practice was very much embedded in clinical work. Most relevant learning activities were directly related to patient care rather than motivated by competence improvement goals. Advice and feedback were sought when necessary to provide this care. Performance standards were tied to patients' conditions. The patients encountered and the discussions with colleagues about patients were valued most for professional development, while teaching and updating activities were also valued in this respect. In conclusion, physicians' learning is largely guided by practical experience rather than deliberately sought. When professionals interact in diagnosing and treating patients to achieve high quality care, their experiences contribute to expertise development. However, much could be gained from managing learning opportunities more explicitly. We offer suggestions for increasing the focus on learning in medical practice and further research. PMID- 20848188 TI - Does proximity to coal-fired power plants influence fish tissue mercury? AB - Much of the mercury contamination in aquatic biota originates from coal-fired power plants, point sources that release mercury into the atmosphere. Understanding mercury dynamics is primarily important because of the toxic threat mercury poses to wildlife and humans through the consumption of contaminated fish. In this study, we quantified the relative importance of proximity to coal fired power plants on mercury accumulation in two fish species of different trophic positions. Fish, water and sediment were collected and analyzed from 14 lakes, seven near to (<10 km) and seven far from (>30 km) coal-fired power plants. Lower tissue mercury and higher tissue selenium concentrations were measured in fish collected near power plants. Moreover, mercury accumulation in fish was driven by biotic characteristics (e.g., trophic position, total length, age), waterbody characteristics (e.g., pH, dissolved organic carbon and sulfate) and distance from power plants. Proximity to an atmospheric point-source of mercury and selenium, such as a coal-fired power plant, affects the quantities of mercury and selenium accumulated in fish tissue. Differences in accumulation are hypothesized to be driven in part by selenium-mitigated reductions in fish tissue mercury near power plants. Although reduced fish tissue mercury in systems near power plants may decrease mercury-specific risks to human consumers, these benefits are highly localized and the relatively high selenium associated with these tissues may compromise ecological health. PMID- 20848189 TI - Perspectives for genetic engineering of poplars for enhanced phytoremediation abilities. AB - Phytoremediation potential has been widely accepted as highly stable and dynamic approach for reducing eco-toxic pollutants. Earlier reports endorse remediation abilities both in herbaceous plants as well as woody trees. Poplars are dominant trees to the ecosystem structure and functioning in riparian forests of North America Rivers and also to other part of the world. Understanding of the fact that how genetic variation in primary producer structures communities, affects species distribution, and alters ecosystem-level processes, attention was paid to investigate the perspectives of genetic modification in poplar. The present review article furnishes documented evidences for genetic engineering of Populus tree for enhanced phytoremediation abilities. The versatility of poplar as a consequence of its distinct traits, rapid growth rates, extensive root system, high perennial biomass production, and immense industrial value, bring it in the forefront of phytoremediation. Furthermore, remediative capabilities of Populus can be significantly increased by introducing cross-kingdom, non-resident genes encoding desirable traits. Available genome sequence database of Populus contribute to the determination of gene functions together with elucidating phytoremediation linked metabolic pathways. Adequate understanding of functional genomics in merger with physiology and genetics of poplar offers distinct advantage in identifying and upgrading phytoremediation potential of this model forest tree species for human welfare. PMID- 20848190 TI - Sonic hedgehog protects cortical neurons against oxidative stress. AB - Oxidative stress is one of the most important pathological mechanisms in neurodegenerative diseases and ischemia. Recent studies have indicated that the sonic hedgehog (SHH) signaling pathway is involved in these diseases, but the underlying mechanisms remains elusive. Here we report that the SHH pathway was activated in primary cultured cortical neurons after exposure to hydrogen peroxide (H2O2). H2O2 treatment decreased the cell viability of neurons, and inhibition of endogenous SHH signaling exacerbated its neurotoxicity. Activation of SHH signaling protected neurons from H2O2-induced apoptosis and increased the cell viability while those effects were partially reversed by blocking SHH signals. Exogenous SHH increased the activities of Superoxide dismutase (SOD) and Glutathione peroxidase (GSH-PX) in H2O2-treated neurons and decreased production of Malondialdehyde (MDA). It also promoted expression of the anti-apoptotic gene Bcl-2 and inhibited expression of pro-apoptotic gene Bax. Activation of SHH signals upregulated both Neurotrophic factors vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Pretreatment with SHH inhibited the activation of ERK (extracellular signal-regulated kinases) signals induced by H2O2. Our findings demonstrate that activation of SHH signaling protects cortical neurons against oxidative stress and suggest a potential role of SHH for the clinic treatments of brain ischemia and neurodegenerative disorders. PMID- 20848191 TI - Apoptosis inhibition can be threatening in Abeta-induced neuroinflammation, through promoting cell proliferation. AB - Neuronal apoptosis in neurodegenerative diseases is correlated with inflammatory reactions. The beneficial or detrimental role of apoptosis in neuroinflammation is unclear. In this study, we injected beta-amyloid peptide into the rat cortex for induction of neuroinflammation in hippocampus. We observed an increase in TNF alpha as an inflammatory cytokine and caspase3 and TUNEL-positive cells as apoptotic marker. As far as ability of TNF-alpha to induce apoptosis or activate NF-kbeta, the question is what will happen if the balance between two pathways is disturbed by inhibition of apoptosis. Using caspase inhibitors, we inhibited apoptosis and assessed NF-kbeta, Hsp 70 (a hallmark of cancer), cmyc (proto oncogene) and p53 (tumor suppressor protein). There was an unexpected decrease in NF-kbeta while Hsp70 and cmyc upregulated and p53 decreased. These results imply that inhibition of apoptosis due to increased susceptibility to abnormal mitosis may not provide a reliable strategy for treatment of neuroinflammatory diseases. PMID- 20848192 TI - Validation of supra-pubic ultrasonography for preoperative prostate volume measurement in sub-Saharan Africa. AB - BACKGROUND: Advances in urological techniques in sub-Saharan Africa need to be supported with practical ancillary diagnostics. This study aimed at determining the accuracy of suprapubic ultrasonography (SPUS) relative to transrectal ultrasonography (TRUS), the current gold standard, in estimating preoperative prostate volume in a sub-Saharan African hospital. METHODS: Cross-sectional study of prospectively enrolled patients with severe lower urinary tract symptoms and histologically confirmed benign prostatic hyperplasia. The volume of the prostate was estimated using two modalities, SPUS and TRUS. Open prostatectomy was performed on all patients, and the mass of the enucleated prostate adenoma was measured directly. RESULTS: Fifty patients were enrolled, with a mean age of 69 years. The mean prostate volume as determined by TRUS, SPUS, and direct measurement of enucleated prostatic tissue was 96.0, 95.9 and 83.5 mL, respectively. Prostate volume determined by SPUS correlated strongly with the TRUS measurement (rho = 0.98, P < 0.001). The mean difference between the volume estimates by TRUS and SPUS was 0.09 mL [95% CI -2.07 to 1.89, P = 0.93], with upper and lower limits of agreement of -13.8 and +13.6 mL, respectively. Sensitivity, specificity, positive and negative predictive value for SPUS relative to TRUS for classifying patients according to the indication for TURP (prostate volume <=80 mL) versus open prostatectomy (>80 mL) were 95% or higher. The volume of the enucleated adenoma was less than the volume estimated by ultrasonography by approximately 12.5 mL. CONCLUSION: SPUS is accurate relative to TRUS in assessing preoperative volume of the prostate and can be used in the African context to assign patients to open prostatectomy or TURP. PMID- 20848193 TI - Urinary ultrasonography in screening incidental renal cell carcinoma: is it obligatory? AB - PURPOSE: To analyze the rate of incidental renal carcinoma in patients with no upper urinary tract symptoms (UUTS) or hematuria depending on the sonography reports and medical records of the patients and to determine whether there is a need for routine US screening for RCC. MATERIALS AND METHODS: We reviewed the reports of 18.686 consecutive urinary US examinations performed in our department between March 1995 and February 2008. A total of 18.203 urinary US examinations formed the study group. Patients with UUTS, patients with presumed diagnosis of or previously diagnosed renal masses, and patients with hematuria were excluded. RESULTS: There were 11,654 male and 6,549 female patients with a mean age of 55 years. Ultrasonography revealed incidental solid renal masses in 0.44% of the patients. Seven of the 81 patients with incidentally detected renal masses could not be followed up. Thirty-eight of the remaining 74 patients had masses that were proved to be benign with other imaging techniques. Thirty-six of the 74 patients with preoperative diagnosis of renal tumor underwent surgery, and the histopathological diagnosis was renal cell carcinoma in all patients. One patient expired in the postoperative 18th month due to the progression of the metastatic disease. The rest of the patients with malignant renal tumor are disease free and are still under follow-up. CONCLUSION: The rate of incidental renal cancer in patients without UUTS is found to be 0.20%. We believe that scanning for incidental renal masses is not obligatory except for the patients with symptoms suggestive of renal carcinoma. PMID- 20848194 TI - Retroperitoneal laparoscopy rather than an open procedure for resection of pheochromocytomas could minimize intraoperative blood pressure fluctuations and transfusion events. AB - OBJECTIVES: We retrospectively reviewed the outcomes after laparoscopy versus an open procedure for the resection of pheochromocytoma. PATIENTS AND METHODS: Forty nine patients were enrolled into the study between June 2004 and December 2008 having been diagnosed with pheochromocytoma. The selection criteria were patients who were diagnosed with pheochromocytoma on admission based on clinical manifestations, imaging examinations and laboratory tests. Twenty-six patients underwent a retroperitoneal laparoscopic resection of their pheochromocytoma (LRP), and another 23 patients underwent an open resection of the pheochromocytoma (ORP). RESULTS: The ORP was similar to the LRP on the incidence of intraoperative blood pressure fluctuation. While compared to ORP, the process of LRP could effectively control the degree of fluctuations in intraoperative blood pressure(P < 0.05). Patients who received LRP had a significantly reduced volume of fluid in their drain on the first postoperative day than those who received ORP(P < 0.05), and due to the drain being removed sooner, they were consequently able to mobilize earlier(P < 0.05). The LRP cohort consisted of four patients with tumors ranging from 6 to 7 cm and three of them were successfully achieved. Intraoperatively or within 24 h postoperatively, 10 out of 23 patients who had undergone ORP received a transfusion, while none of those in the LRP cohort received a transfusion. CONCLUSIONS: Retroperitoneal LRP allowed patients to mobilize earlier and minimized the occurrence of intraoperative blood pressure fluctuations and transfusion events. Adequate preoperative preparation and skilled laparoscopic manipulation appeared to guarantee the safety of the procedure, and large tumors did not absolutely contraindicate the use of laparoscopy. PMID- 20848195 TI - The impact of type of assistance on characteristics of peritonitis in elderly peritoneal dialysis patients. AB - BACKGROUND: The elderly patients are the fastest-growing end-stage renal disease (ESRD) population in Taiwan. Assisted peritoneal dialysis (PD) has been employed to overcome the barriers to PD. The aim of this retrospective, single-center study was to describe the status of assisted PD and the impact of type of assistance on peritonitis in elderly patients in Taiwan. METHODS: One hundred and two patients initiated PD at the age of 65 or older between 2000 and 2008; 79 episodes of peritonitis occurred during the follow-ups. The patients and episodes of peritonitis were divided into three groups based on the type of assistance: (1) self-care: patients performing dialysis independently, (2) family: patients whose dialysis was performed by family, (3) caregiver: patients whose dialysis was performed by a private caregiver. Patient characteristics and incidence, etiology and outcomes of peritonitis were compared. RESULTS: There were 26 (25.5%), 44 (43.1%), and 32 (31.4%) patients in the self-care, family, and caregiver groups, respectively. The overall peritonitis rate was 1/33 patient months. Patients in the caregiver group were older and had more comorbidities than the self-care group. They had a trend of higher overall peritonitis rate (1/24 patient-months, P = 0.077) and fungal peritonitis rate (P = 0.060) compared to the self-care and family groups, but this was statistically non-significant. CONCLUSIONS: Three-fourths of elderly PD patients in the present study required assistance from family members or private caregivers. Caregiver-assisted patients were significantly older and had more comorbidities. Also, a non-significant trend of higher peritonitis incidence was observed in these patients. PMID- 20848196 TI - Percutaneous nephrolithotomy in renal transplants: a safe approach with a high stone-free rate. AB - OBJECTIVES: The purpose of this report is to assess the safety and efficacy of percutaneous nephrolithotomies (PNL) in transplanted kidneys. METHODS: Patient characteristics, predisposing factors, clinical presentation, surgical details, complications and outcomes were analyzed. RESULTS: Between April 2002 and August 2009, seven patients (average 44 years old, 4 women and 3 men) were treated. Predisposing factors included hyperuricemia, hyperparathyroidism, recurrent urinary tract infection (n = 2 each) and retained double-J ureteral stent (n = 1). Clinical presentation consisted of urinary tract infection alone (n = 3) or in association with impaired renal function (n = 2) but also hematuria (n = 1) or impaired renal function (n = 1). Patients were treated in supine position, and calyx puncture was guided by the combination of ultrasound and fluoroscopy. Combined ultrasound and pneumatic lithotripsy (n = 5) or extraction (n = 2) was performed. Overall average stone size was 32.8 mm (range 20-50). Mean operative time was 102 min (range 75-150). Stone-free status was achieved in 6 patients (85.7%). No intraoperative complications occurred, including major bleeding. Mean initial and postoperative serum creatinine levels were 2.04 and 1.59, respectively. Average admission time was 6.9 days (range 4-9). CONCLUSIONS: PNL of transplanted kidneys is a safe and effective method associated with a high overall stone-free rate. This approach should be considered in centers where expertise is available. PMID- 20848197 TI - Pigment epithelium-derived factor expression is down-regulated in bladder tumors and correlates with vascular endothelial growth factor and matrix metalloproteinase-9. AB - Growth of solid tumor depends on angiogenesis, a process regulated by the balance of pro- and anti-angiogenic factors. We investigated the expression of anti angiogenic factor pigment epithelium-derived factor (PEDF) and proangiogenic factors vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) with immunohistochemistry in 64 bladder tumor samples and 23 normal controls. Compared with normal urothelium, we identified decreased PEDF expression (P = 0.000) whereas increased expression of VEGF (P = 0.000) and MMP-9 (P = 0.000) in tumorous tissue as well as in papillary urothelial neoplasm of low malignant potential (PUNLMP) (P = 0.009 and P = 0.000 accordingly) but MMP-9 (P = 0.704). Decreased PEDF expression was revealed with higher tumor grade (P = 0.014) but stage (P = 0.687). There was no age or gender preference in PEDF, VEGF or MMP-9 expression. Negative correlation of expression in tumorous and cancerous tissue regarding PEDF and VEGF (P = 0.000, r = -0.56, and P = 0.000, r = -0.50, respectively), PEDF and MMP-9 (P = 0.002, r = -0.39, and P = 0.032, r = -0.30, respectively) was identified. There was a negative correlation of expression between PEDF and VEGF (P = 0.016, r = -0.677) and no correlation between PEDF and MMP-9 (P = 0.147, r = -0.45) in PUNLMP. Decreased PEDF and increased VEGF and MMP 9 expression may play considerable roles in differentiation and invasion of bladder tumor. PMID- 20848198 TI - Management of multiple stones in a single session using minimally invasive methods in infants with renal failure: renal salvage. AB - The goal in the treatment of stone disease causing infantile obstructive uropathy is to obtain a quick resolution of the obstruction using the least invasive treatment modality available and rendering the patient stone-free, if possible. Two infants with bilateral kidney stones, the first of whom also had ureteral stone, were referred to our clinic with acute renal failure and were treated successfully in a single session using minimally invasive methods. In this report, we discuss the management of these two cases, aged 9 and 26 months, which resulted in favorable outcomes. PMID- 20848199 TI - Risk factors for hospital-acquired urinary tract infection: a case-control study. AB - The objective is to assess risk factors and microbiological aspects of hospital acquired urinary tract infection (HAUTI) on six wards of a general regional hospital in Serbia. A case-control study was nested within prospective cohort HAUTIs study conducted from January 1 to December 31, 2007. Three controls were identified for each patient with HAUTI, being chronologically the next three patients surveyed who did not develop HAUTI. The patients and controls were matched by sex and age (+/-5 years). Assessment of 8,467 patients during the study period revealed HAUTI in 125 (116 symptomatic and 9 asymptomatic). The overall incidence rate of HAUTI was 14.8 cases/1,000 admissions. The mean age (range) of cases and controls was 64.9 (18-85) and 65.2 (17-86), respectively. Multivariate logistic regression analysis showed that duration of catheterization >5 days (OR = 51.91; 95% CI = 23.46-114.82) and the ASA score (OR = 13.42; 95% CI = 2.14-84.30) were independently associated with increased risk of HAUTIs. The most frequently isolated Gram-negative bacteria were Enterobacter, Klebsiella sp., Proteus mirabilis and Escherichia coli. Enterococcus sp. was the most frequent Gram-positive bacteria. PMID- 20848200 TI - Predictive factors for response to peginterferon-alpha and ribavirin treatment of chronic HCV infection in patients aged 65 years and more. AB - BACKGROUND: Elderly patients with chronic hepatitis C virus (HCV) infection represent an understudied population, and little is known regarding the predictive factors for sustained virological response (SVR) to antiviral therapy in these patients. AIMS: To evaluate the efficacy of pegylated interferon (PEG IFN) and ribavirin therapy in chronic HCV patients aged 65 years, and identify pre- and on-treatment predictors of SVR. METHODS: We studied 57 patients aged >=65 years who underwent PEG-IFN and ribavirin treatment, evaluating the SVR rate and its association with pre-treatment demographic, clinical, biochemical, and virological parameters. Furthermore, we assessed whether 12-week serum HCV-RNA assessment might predict SVR. RESULTS: A SVR was obtained in 25 patients (45%). The only pre-treatment predictor of SVR was HCV genotype 2 and 3 (P = 0.02). A positive serum HCV-RNA or a decline in viral load <=2log(10) at week 12 had 100% negative predictive value for SVR. No major liver-related events or deaths occurred during therapy. Treatment was discontinued due to side effects-mainly cardiovascular-in 10 patients (17%). CONCLUSION: Pre- and on-treatment virological parameters can be used to identify elderly patients who are more likely to obtain a SVR to standard-of-care antiviral therapy for chronic HCV infection. PMID- 20848201 TI - Unusual case of small cell gastric carcinoma: case report and literature review. AB - BACKGROUND: Small cell carcinomas are among the most aggressive, poorly differentiated, and highly malignant of the neuroendocrine tumors (NETs). Of which, small cell gastric carcinoma is a rare small cell neuroendocrine tumor. The purpose of our study was to present this case and perform a comprehensive literature review. METHODS AND RESULTS: We review a case of small cell gastric carcinoma that is particularly unusual in that it occurred in a woman from the US when the majority of cases of small cell gastric carcinoma have been reported in men from East Asia, and more specifically, from Japan. The diagnosis was made after endoscopy revealed a large ulcerated mass in the gastric cardia of Borrmann type 3. Biopsies revealed multiple small basophilic cells underlying the squamous epithelium of the esophagus and cardiac mucosa, indicating the presence of a tumor at the gastroesophageal junction. Immunostaining established the diagnosis with positive stains for chromogranin, synaptophysin, and CD56. Our patient is being treated with chemotherapy, but many different treatment regimens have been tried for small cell gastric carcinoma with variable success. CONCLUSIONS: Overall prognosis for small cell gastric carcinoma is dismal. Neuroendocrine tumors in general have variable clinical behaviors and prognosis is dependent on the neuroendocrine tumor type. The adoption of a standardized classification system for neuroendocrine tumors could improve the recognition of infrequently encountered neuroendocrine tumors like small cell gastric carcinoma and will enhance strategies for treatment and thus improve prognosis for patients with these rare and aggressive tumors. PMID- 20848202 TI - Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma: outcome after liver transplantation. AB - BACKGROUND: Combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma is a rare hepatobiliary malignancy incorporating components derived from both hepatocyte and intrahepatic bile duct epithelium. The natural history, treatment, and prognosis of this distinct cancer differ from hepatocellular carcinoma (HCC) or cholangiocarcinoma (CC) and are not completely understood. There is considerable controversy about the classification, treatment, and survival, which in turn is related to the rarity of the condition. Treatment options include surgical resection and the prognosis is believed to be better than CC but worse than HCC alone. METHODS: We report a single-center liver transplantation experience with the management of three patients with combined HCC-ICC with LT. Two patients were transplanted with presumed HCC within Milan criteria and the other patient was noted to have an incidental nodule in the explanted liver. Histomorphology and immunohistochemical studies revealed the presence of combined HCC-ICC in all three explants. RESULTS: One patient died 144 days after LT due to metastatic tumor. The second patient is alive and is tumor free at 8.5 years post LT, and the third patient died of metastatic tumor at 155 days after LT. CONCLUSION: Good long-term survival can be achieved in at least some patients with this combined tumor type. PMID- 20848203 TI - Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine- and choline deficient diet. AB - BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is associated with fat accumulation in the liver, and develops to cirrhosis with the progression of hepatic fibrosis. Eicosapentaenoic acid (EPA) is used to treat hyperlipidemia, and suppresses hepatic fat accumulation. As the effect of EPA on NASH remains unclear, we assessed the therapeutic effect of EPA and its mechanisms in an animal model of NASH. METHODS: Wistar rats were fed a methionine- and choline deficient (MCD) diet for 20 weeks, and given EPA ethyl ester (EPA-E, 1,000 mg/kg/day) or vehicle by gavage from week 12, at which hepatic fibrosis has already established. The liver was histologically analyzed for fibrosis and alpha smooth muscle actin (alphaSMA) expression, and hepatic levels of transforming growth factor-beta1 (TGF-beta1), fibrogenic gene expression, reactive oxygen species (ROS), and triglyceride (TG) content were determined. Serum oxidative markers were also measured. RESULTS: EPA-E treatment significantly suppressed the MCD-induced increase in fibrotic area of liver sections, with repressed macronodule formation. EPA-E also suppressed increases in hepatic fibrogenic factors, alphaSMA expression, TGF-beta1 level, and messenger RNA (mRNA) levels of procollagens and connective tissue growth factor. EPA-E reduced MCD-induced increases in hepatic ROS level, serum oxidative markers, 8-isoprostane and ferritin, and hepatic TG content. Attenuation of hepatic fibrosis by EPA-E was significantly correlated with hepatic ROS level, but not TG content. CONCLUSIONS: EPA-E attenuates progression of hepatic fibrosis in developed steatohepatitis, and this effect is likely mediated by inhibition of ROS production. These actions may elicit the therapeutic effect of EPA-E against NASH. PMID- 20848204 TI - HCV-related proteins activate Kupffer cells isolated from human liver tissues. AB - PURPOSE: It was reported from this laboratory that Kupffer cells (KCs) were activated in patients infected with HCV. Since dendritic cells, monocytes, and macrophages were activated by stimulation with HCV-related proteins, the specific aim of this study was to investigate the role of HCV-related proteins in activation of KCs, the signal pathway of activation of KCs mediated by Toll-like receptor (TLR) 4, and the influence of HCV infection on function of KCs. METHODS: Kupffer cells isolated from non-cancerous surgical specimen were co-cultured with HCV-related proteins (Core, NS3, NS4, and NS5), and production of cytokines (TNF alpha, IL-1beta, and IL-10) and hydrogen peroxide were assessed. Furthermore, effects of neutralization antibodies against the TLR2, TLR3, or TLR4, and cytochalasin B on the production TNF-alpha by KCs were investigated. RESULTS: Kupffer cells produced markedly a proinflammatory cytokine TNF-alpha by stimulation with all HCV-related proteins studied, and values were as same as production by KCs stimulated with LPS. Importantly, this production in the case of NS3 was significantly blunted by about 60% by neutralization antibodies against the TLR4, but not cytochalasin B. Production of TNF-alpha by isolated KCs stimulated with LPS was significantly greater in the HCV-infected livers than the HCV/HBV-negative livers. CONCLUSIONS: These results indicated that HCV-related proteins may cause prolonged activation of KCs in the HCV-infected liver, leading to accumulation of inflammatory cytokines that contribute to DNA damage and carcinogenesis. Furthermore, function of KCs was difference between patients infected with and without HCV infection. PMID- 20848205 TI - Dieulafoy lesions of the GI tract: localization and therapeutic outcomes. AB - OBJECTIVES: Dieulafoy lesions are a rare cause of gastrointestinal hemorrhage with a striking presentation because of rapid blood loss. Endoscopic therapy is usually successful at achieving primary hemostasis, but the best mode of endoscopic intervention is not clear, and outcomes relating to variables such as gender, medication, alcohol, and smoking are not known. We reviewed the clinical experience with Dieulafoy lesions at our institution, focusing on clinico epidemiological features, management practices, and also survival. METHODS: A retrospective and prospective cohort of patients with Dieulafoy lesions who underwent endoscopy from January 2004 through April 2009 were studied and detailed clinical data were abstracted and collected. RESULTS: We identified 63 patients with a Dieulafoy lesion. The majority were male with an average age 58 years. Hematemesis and melena were the most common presenting symptoms. Almost half the patients were on anticoagulation medication. Most of the Dieulafoy lesions occurred in the upper GI tract, and mostly in the stomach. Single modality endoscopic therapy was used as frequently as combination therapy, and both were effective, as primary hemostasis was achieved in 92% of cases. There were 11 deaths overall; death due to Dieulafoy lesion exsanguination was attributed to three patients. CONCLUSIONS: Dieulafoy lesions occurred in younger patients than previously reported, and were more frequently diagnosed in males. Most DL lesions occurred in the upper GI tract. Primary hemostasis with endoscopic therapy was highly successful. Overall mortality was 17%, and associated with co-morbidities, and not with medical history, gender, age, or medication. PMID- 20848207 TI - Opinion comparison concerning future information technology in Finnish community pharmacies. AB - OBJECTIVE: To compare the opinions of community pharmacy owners, managers and personnel concerning the key features of the future information technology system needed in Finnish community pharmacies. SETTING: The study was targeted to the pharmacists working in community pharmacies as managers (owners and staff pharmacists with M.Sc. degree) or personnel responsible for dispensing and patient counselling (pharmacists with B.Sc. degree). METHOD: A national cross sectional survey to all of Finnish community pharmacy owners (n = 580) and staff pharmacists (B.Sc. and M.Sc. degrees, n = 1709) working in community pharmacies, was conducted in order to determine differences in opinions between these occupation groups with different professional duties. The response rates were 53% for pharmacy owners (n = 308) and 22% for staff pharmacists (n = 373). MAIN OUTCOME MEASURE: The main outcome measure was the perceived importance of 89 potential features for a new IT system ranked by using a five-point Likert scale. RESULTS: The responding community pharmacy managers and staff pharmacists had differences in their ranking of more than half (52%) of the potential features listed in the survey questionnaire. The features related to the pharmacy's internal processes, such as financial management, sales and marketing management and stock holding, were ranked significantly higher by the managers, while the personnel prioritized the features supporting pharmaceutical service provision and personnel management. The managers and personnel shared their opinion on the importance of features supporting drug information and patient counselling, medication safety and interprofessional collaboration. CONCLUSION: The managers and staff pharmacists have different views of the importance of IT features, reflecting their different professional duties in the community pharmacy. A high priority was given for the features familiar to the users and needed in their daily practice. This indicates the need for involving different occupation groups in planning the new IT systems for community pharmacies. PMID- 20848206 TI - Riboflavin depletion impairs cell proliferation in adult human duodenum: identification of potential effectors. AB - BACKGROUND AND AIMS: Riboflavin (vitamin B2) is an essential dietary component with a known function in oxidative metabolism. Our previous data using a rat model of riboflavin deficiency suggested that riboflavin also functions as a luminal signaling molecule regulating crypt development and cell turnover. Riboflavin deficiency is prevalent in both high- and low-income countries across the globe. This study aims to establish whether riboflavin deficiency has consequences for gastrointestinal (GI) morphology in adults and what the effects and effectors of any such alteration may be. METHODS: Duodenal biopsies and blood samples were collected from a cross-section of gastroscopy patients. Crypt morphology and cell division were studied by immunohistochemistry, and biochemical riboflavin status was determined. Additionally a cell culture model of riboflavin deficiency was developed and analyzed using a combination of flow cytometry, and microarray and clonogenic assays. RESULT: Duodenal crypts from subjects in the lowest quartile of riboflavin status were significantly shorter (P=0.023), less cellular (P=0.007), and had fewer cell divisions (P=0.034) than the crypts of subjects in the top quartile of riboflavin status. Following riboflavin depletion of colon cells in culture, cell cycle slowed. Microscopy revealed impaired mitosis and accumulation of aneuploid cells. Alterations in gene expression profiles reflected this alteration, with several mitosis-related genes altered, including AspM, cyclin B1, and Birc5 downregulated and Kif23 upregulated. Riboflavin depletion in vitro caused irreversible loss of proliferative potential of cells. CONCLUSIONS: Riboflavin depletion in adult humans impairs proliferation and proliferative potential of intestinal cells, which may have implications for gastrointestinal function. PMID- 20848208 TI - Assessment of the microbiological safety of dried spices and herbs commercialized in Spain. AB - Spices and herbs are natural products or their blends that must be free of extraneous matter content. Conventional production of these products implicates a number of hygienic problems so spices and herbs may be exposed to a wide range of microbial contamination during pre- and post-harvest and they can present high microbial counts. In this study, we have analyzed the microbial quality of 53 samples of spices and dry herbs collected from Spanish markets detecting a contamination of samples of spices with mesophilic aerobic counts (10%) and Enterobacteriaceae (20%). The analysis from herbs showed that the percentage of contamination was 26% in both microbiological values. Pathogenic microorganisms like Staphylococcus aureus, Yersinia intermedia, Shigella spp., Enterobacter spp., Acinetobacter calcoaceticus and Hafni alvei were also isolated from spices and herbs. These unsatisfactory results showed a poor microbiological quality. Spices and dry herbs are used as ingredients in a variety of products prepared in different ways, this fact suggests the need to provide a control system to improve the quality of herbs and spices. PMID- 20848209 TI - Upregulation of interleukin-1beta production by 1,25-dihydroxyvitamin D(3) in activated human macrophages. AB - 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) plays important roles in the immune system. In contrast to its well known function in the adaptive immune system, much less is known about the immunoregulatory effects of 1,25(OH)(2)D(3) in the innate immune system, especially on activated human macrophages. Here we found that 1,25(OH)(2)D(3) strongly stimulated the production of interleukin-1beta (IL 1beta) in PMA-differentiated U937 cells and human monocyte-derived macrophages treated with lipopolysaccharide (LPS) or PMA. In this study, Erk1/2 appeared to mediate 1,25(OH)(2)D(3)-induced expression of IL-1beta. Parallel to the increased production of IL-1beta, 1,25(OH)(2)D(3) increased the expression and phosphorylation of the CCAAT enhancer-binding protein beta (C/EBPbeta), which is one of the key transcriptional regulatory factors for IL-1beta transcription. These results suggest that 1,25(OH)(2)D(3) may function as a proinflammatory molecule in inflammatory macrophages. PMID- 20848210 TI - Association of genetic variants for FABP3 gene with back fat thickness and intramuscular fat content in pig. AB - The swine fatty acid binding protein gene (FABP3) has been screened with 4 primer sets for 270 purebred Yorkshire pigs from National Institute of Animal Science. The selection of primers was based on the swine cDNA sequence (AJ416019), and primer sets (FABP3-2 and FABP3-3) amplified target segments in real time PCR to analyze expression levels at growth stages, producing 235 and 224 bp of fragments, respectively. Relative expression of the swine FABP3 gene for back and intramuscular fat was continuously increased from day 0 to 150, and decreased at day 210, showing the highest expression levels at day 150 compared with day 0. The results may be caused by requirements of high physiological activities with more gene expressions for growth around day 150. Nucleotide variations were observed at nucleotide positions 80 (A/G), 167 (A/G), 260 (A/G), 295 (A/G), 394 (T/C), and 440 (A/G), showing substitutions of amino acids at positions 80 (S to G), 167 (T to A), and 260 (S to G). FABP3 genotypes at positioned nt167 have been associated with carcass back fat thickness (BFT), and dominance genetic effects were observed for BFT with nt167 and intramuscular fat (IMF) contents with nt80. Our results concluded that the FABP3 polymorphisms can be used as genetic markers in breeding programs for IMF content as well as carcass BFT. PMID- 20848211 TI - Characterization of a late gene, ORF75 from Bombyx mori nucleopolyhedrovirus. AB - Open reading frame 75 (Bm-p33) of Bombyx mori nucleopolyhedrovirus (BmNPV) is a homologue of Autographa californica multiple nucleopolyhedrovirus ORF92. The gene is conserved among all baculoviruses that have been completely sequenced to date and is considered to be a baculovirus core set gene. No amino acid mutation was found in Bm-p33 sequences among six BmNPV strains differing in geography, phenotype, or host. The Bm-p33 transcript can be detected as early as 12 h post infection (h p.i.) and remains detectable until 96 h p.i. The Bm-p33 protein was detected in cell lysates from 18 h p.i. through 96 h p.i., and no positive band could be detected in budded viruses (BVs) and occlusion-derived viruses (ODVs) by western blot using anti-Bm-p33 serum. Immunofluorescence microscopy indicated that Bm-p33 accumulated in the nuclear membrane and the intranuclear region, especially near the nuclear membrane of the virus-infected cells. Bm75 RNAi significantly decreased the mRNA level. However, no obvious effects on ODV formation and BV production in BmNPV-infected cells could be detected. Bm-p33 is a BmNPV late gene encoding a nonstructural protein which may function mainly in the nucleus of the infected cells. PMID- 20848212 TI - Molecular characterization and expression analysis of extracellular copper-zinc superoxide dismutase gene from swimming crab Portunus trituberculatus. AB - An extracellular CuZnSOD cDNA was cloned from the haemocytes of swimming crab Portunus trituberculatus by a reverse-transcription polymerase chain reaction (RT PCR) and rapid amplification of cDNA end (RACE) method. Analysis of the nucleotide sequence revealed that the ecCuZnSOD full-length cDNA consisted of 965 bp with an open reading frame of 579 bp. It encoded a polypeptide of 192 amino acids which had a predicted molecular weight of 20.0 kDa and with an estimated pI of 6.23. The deduced amino acid sequence contained a putative signal peptide of 31 amino acids. It is predicted to possess all the expected features of CuZnSOD members, including amino acids responsible for binding Cu and Zn, two putative CuZnSOD signatures, two cysteines and one N-linked glycosylation site. Sequence comparison showed that the CuZnSOD deduced amino acid sequence of P. trituberculatus has similarity of 80%, 76%, 55% and 50% to that of blue crab Callinectes sapidus, mud crab Scylla serrata, crayfish Pacifastacus leniusculus and freshwater prawn Macrobrachium rosenbergii, respectively. The ecCuZnSOD transcripts expressed in all examined tissues, including haemocytes, hepatopancreas, heart, stomach, intestine, gill, ovary and muscle. RT-PCR analysis indicated that ecCuZnSOD transcripts both in haemocytes and hepatopancreas increased in the first 3 h after Vibrio alginolyticus challenging, as the bacterial infection progressed, the challenged crabs decreased to levels significantly lower than control by 96 h post-infection. These facts indicated that ecCuZnSOD was potentially involved in the acute response against invading bacteria in P. trituberculatus. PMID- 20848213 TI - Identification and genetic effects of a novel polymorphism in the distal promoter region of porcine leptin gene. AB - Leptin is a hormone expressed mainly in white adipose tissue. It acts on satiety centers in the hypothalamus, and by binding to particular receptor OB-Rb, plays a crucial role in controlling appetite, body weight, fat amount and total energy balance. In this study, a novel single nucleotide polymorphism (SNP), i.e., SNP G 2863A, was identified in the distal promoter region of porcine leptin gene. Totally 780 individuals of Duroc, Yorkshire, Laiwu, Lulai Black breeds, and Landrace * Yorkshire crossbred were genotyped by PCR-SSCP approach. The effects of SNP G-2863A on mRNA and serum protein levels of leptin as well as in driving transcription were examined. The results showed that, except for Duroc and Yorkshire pigs, three genotypes of GG, GA and AA were detected. Allele G occurred with a higher frequency in western breeds and Landrace * Yorkshire crossbred pigs, whereas with a lower frequency in Laiwu pigs. Statistical analysis indicated that there were consistent trends toward higher levels in animals with genotype GG than with GA or AA genotypes in backfat thickness of both Landrace * Yorkshire crossbred and Lulai Black pigs, in backfat leptin mRNA and the circulating serum leptin protein level in half-sibling Lulai Black pigs, and the activity of allele G was significantly higher than allele A (P < 0.01) in driving reporter gene expression. These results suggest that SNP G-2863A is a potential DNA marker for backfat thickness and has a regulatory role in leptin transcription. PMID- 20848214 TI - Screening candidate genes related to tenderness trait in Qinchuan cattle by genome array. AB - In order to screen candidate genes related to tenderness trait in Qinchuan cattle, we investigated the gene expression profile of Longuissimus dorsi muscle (LDM) tissue and screened differentially expressed genes in LDM from both male and female Qinchuan cattle at 36 months of age utilising Bovine Genome Array. Significance Analysis of Microarrays (SAM) was used to identify the differentially expressed genes, Go (Gene Ontology) and pathways analysis were conducted on which by a free web-based Molecular Annotation System 2.0 (MAS 2.0). Approximately 11,000 probe sets representing 10,000 genes were detected in LDM of 36 month old Qinchuan cattle. After SAM analysis of the microarray data, 598 genes were shown to be differentially expressed. These genes were predominantly involved in cell adhesion, collagen fibril organization and synthesis, immune responses and cell-matrix adhesion. They included cell adhesion molecules (CAMs) and ECM-receptor interaction molecules. Real-time PCR was performed to validate nine of the differentially expressed genes identified by microarray. The results suggest that at the transcriptional level the residual hardness caused by connective tissues, stroma protein and muscle tissues could mainly result in tenderness differences between male and female Qinchuan cattle. PMID- 20848215 TI - Association of adiponectin gene polymorphisms with the risk of ischemic stroke in a Chinese Han population. AB - Adiponectin is inversely associated with the risk of ischemic stroke through its anti-inflammatory and anti-atherogenic effects. Genetic variations in the adiponectin gene (ADIPOQ) have been shown to be associated with the risk of ischemic stroke in Caucasians and Japanese populations. However, it was unknown whether variations in the ADIPOQ gene were associated with the risk of ischemic stroke in Chinese population. A case-control study was performed among 302 patients with ischemic stroke and 338 unrelated controls in a Chinese Han population. The single-nucleotide polymorphisms (SNPs) rs266729 (-11377C/G), rs2241766 (+45T/G), rs1501299 (+276G/T) in the ADIPOQ gene were genotyped by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of GG genotype and G allele of rs266729 in the patients with ischemic stroke were significantly higher than those in the controls (P = 0.034, P = 0.010, respectively). In univariate logistic analysis, compared with CC genotype, GG genotype of rs266729 increased the risk of ischemic stroke (odds ratio (OR) = 2.062, 95% confidence interval (CI) = 1.145-3.715, P = 0.016). After adjustment for potential risk factors by the multivariate logistic analysis, rs266729 remained positive correlation with ischemic stroke (OR = 2.165; 95% CI = 1.116-4.197, P = 0.022). However, no significant association was observed among rs2241766, rs1501299 and ischemic stroke. In addition, no significant difference was found in haplotype frequencies between the patients with ischemic stroke and control subjects. The present study demonstrated that the promoter polymorphism rs266729 of the ADIPOQ gene was associated with an increased risk of ischemic stroke in the Chinese Han population. PMID- 20848216 TI - Molecular characterization, chromosomal localization, expression profile and association analysis with carcass traits of the porcine dickkopf homolog1 gene. AB - DKK1 (dickkopf homolog 1) is a potent inhibitor of the canonical Wnt/beta cantenin signalling pathway, which plays a pivotal role in myogenesis, adipogenesis, and many other crucial biological processes. In this study, DKK1 was assigned to porcine 14q25-26 by using the radiation hybrid (IMpRH) panel. A G1757A single nucleotide polymorphism site by Csp6I PCR-RFLP was identified. Association analysis showed that different genotypes were associated with loin muscle area (P = 0.0281). Semi-quantitative-RT-PCR analysis revealed that DKK1 was highly expressed in spleen and lymph node at two developmental stages, while in skeletal muscle, further real-time PCR quantified that DKK1 was down-regulated in Large White pigs compared to Tongcheng pigs, accompanied by the down regulation of CTTNB1 and TCF4, the up-regulation of LRP6, suggesting that the phenotypic difference between lean and obese pigs might be correlated with the activity of Wnt/beta-cantenin signalling pathway. PMID- 20848217 TI - Antioxidant activities of recombinant amphioxus (Branchiostoma belcheri) apolipoprotein D. AB - Apolipoprotein D (ApoD), a member of lipocalin, has been recently shown to be involved in regulating protection from oxidative stress. The absence of ApoD in mouse and Drosophila can reduce the resistance to oxidative stress and shorten lifespan. However, little information is available regarding the expression in vitro of ApoD and its biochemical properties. Amphioxus (Branchiostoma belcheri) ApoD, BbApoD, is an archetype of vertebrate ApoD proteins. In this study, the prokaryotic expression plasmid pET32a-BbApoD was constructed and recombinant BbApoD expressed in Escherichia coli BL21 and purified. Antioxidation assays showed that the recombinant BbApoD protein had the capacities to scavenge hydroxyl radicals (>= 240 MUg/ml) and to prevent nicking of the supercoiled DNA (>= 100 MUg/ml) in vitro, providing a biochemical evidence for antioxidant role of ApoD. This supports the notion that ApoD is part of the mechanisms regulating protection from oxidative stresses. PMID- 20848218 TI - Identification of odorant-binding protein genes from antennal expressed sequence tags of the onion fly, Delia antiqua. AB - Insect odorant-binding proteins (OBPs) are thought to play a crucial role in the chemosensation of hydrophobic molecules such as pheromones and host chemicals. The onion fly, Delia antiqua, is a specialist feeder of Allium plants, and utilizes a host odorant n-dipropyl disulfide as a cue for its oviposition. Because n-dipropyl disulfide is a highly hydrophobic compound, some OBPs might be indispensable for perception of it. However, no OBP gene has been identified in D. antiqua. Here, to obtain the DNA sequences of D. antiqua OBPs, we performed an analysis of antennal expressed sequence tags (ESTs). Among 288 EST clones, eight D. antiqua OBP genes were identified for the first time. Phylogenetic analysis revealed that each D. antiqua OBP gene is more closely related to its Drosophila orthologs than to the other D. antiqua OBP genes, suggesting that these OBP genes had emerged before the divergence of Delia and Drosophila species. All of the eight D. antiqua OBPs are expressed not only in the antennae but also in the legs, suggesting additional roles in the taste perception of non-volatile compounds. These findings serve as an important basis for understanding the molecular mechanisms underlying the host adaptations of D. antiqua. PMID- 20848220 TI - Expression and network analysis of genes related to melanocyte development in the Silky Fowl and White Leghorn embryos. AB - Silky Fowl is a natural mutant with hyperpigmentation of various internal tissues. Although the mechanism of hyperpigmentation remains unclear, recent studies have shown that the abnormal migration of melanoblast and the absence of environmental barrier molecules are responsible for the hyperpigmentation in Silky Fowl. In this study, 13 genes related to melanocyte development were selected to detect expression changes between Silky Fowl and White Leghorn [including SRY-box 10 (Sox10), paired box (Pax3), stem cell factor (Scf), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (Kit), endothelin type-B receptor (Ednrb), endothelin 3 (Edn3), microphthalmia-associated transcription factor (Mitf), tyrosinase (Tyr), tyrosinase-related protein-1 (Trp1), tyrosinase related protein-2 (Trp2), melanocortin-1 receptor (Mc1r), Agouti-related proteins (Agrp), and Proopiomelanocortin (Pomc)]. Transcript expression was detected in 11 stages from 2.5 to 15 days of incubation. In these embryonic periods, Mitf, Kit, Scf, and Agrp expressed earlier in Silky Fowl than in White Leghorn. Sox10, Ednrb, Kit, Mc1r, and Agrp, associating with the proliferation and differentiation of melanoblast, expressed higher (P < 0.05) in Silky Fowl than White Leghorn during 5-6 days of incubation. After day 8 of incubation, Mitf, Tyr, Trp1, Trp2, and Mc1r expressed higher (P < 0.05) in Silky Fowl than White Leghorn, while Agrp expressed higher (P < 0.05) in White Leghorn than Silky Fowl. Moreover, a regulatory network for melanocyte development was constructed based on the expression data. The network predicted novel regulatory relationships and confirmed relationships that have been reported. These results provide biological insight into the molecular mechanism of hyperpigmentation in the Silky Fowl. However, further investigation is needed to confirm these regulatory relationships. PMID- 20848219 TI - Targeting interleukin-21 in rheumatoid arthritis. AB - Interleukin-21 (IL-21) is a new member of the type I cytokine superfamily, which binds to a composite receptor that consists of a private receptor (IL-21R) and the common cytokine receptor gamma chain. Recently, increasing evidence has shown that IL-21 contributes to the pathogenesis of chronic inflammatory and autoimmune diseases because of its pro-inflammatory and immune-mediated properties. IL-21 induced T-cell activation and pro-inflammatory cytokine secretion in rheumatoid arthritis (RA). IL-21R RNA transcripts were found in synovial tissue samples of patients with RA. In addition, blockade of the IL-21/IL-21R pathway ameliorated disease in animal models of RA and significantly inhibited inflammatory cytokine production in vitro. Moreover, IL-21R deficiency in the K/BxN mouse model of inflammatory arthritis was sufficient to block arthritis initiation completely. All theses findings suggest that IL-21 has important biological effects in autoimmunity that might be a promising therapeutic target for RA. In this review, we discuss the biological features of IL-21 and summarize recent advances in the role of IL-21 in the pathogenesis and treatment of RA. PMID- 20848221 TI - The value of autopsy and other histological examinations for the safety of tissue transplantation. AB - Directive 2006/17/EC requires that all available medical information, including autopsy reports, is evaluated before releasing tissues for transplantation. The aim of this study was to investigate whether evaluation of results of autopsy and other histological examinations contributes to the safety of tissue transplantation. From the files of all deceased Dutch donors, from whom tissues were retrieved in a 6-month period, results of autopsy and other histological examinations (remnant heart after valve donation and biopsies obtained during retrieval) were evaluated for contraindications for transplantation. Of 758 donors at least one tissue was considered suitable for transplantation at initial assessment. 637 Donors donated corneas, 256 skin, 177 heart valves and 61 musculoskeletal tissues. On 220 donors (29.0%) autopsy was done. Of seven donors no autopsy results were requested, since a contraindication was detected earlier in the medical screening. In 19 donors with autopsy (8.9%) general or tissue specific contraindications were detected. There were no differences in distribution of detected contraindications among donors who donated different tissues. For 136 donors (17.9%) results of histological examinations other than autopsy were available; results of examination of remnant hearts for all, brain autopsy for two (0.3%) and retrieval biopsy for four donors (0.5%). Contraindications were detected in nine of these donors with histology results other than autopsy (6.6%). For 402 donors (53%) no histological examinations were done. Evaluation of results of autopsy and other histological examinations improves the safety of tissue transplantation for all types of tissues. In donors without autopsy alternative histological examinations can contribute to enhance the safety of tissue transplantation. PMID- 20848222 TI - Surgical management and emerging therapies to prolong survival in metastatic neuroendocrine cancer. PMID- 20848224 TI - Effectiveness of image-guided radiotherapy for locally advanced rectal cancer. AB - BACKGROUND: Image-guided radiotherapy (IGRT) combines precise target visualization with optimal delivery of radiation dose to spare normal tissue from radiation and may potentially reduce side-effects and long-term treatment complications. We have assessed the effectiveness of IGRT for locally advanced rectal cancer. METHODS: A retrospective review of 22 patients with locally advanced rectal cancer who underwent preoperative chemoradiation was conducted. RESULTS: Nineteen patients (median age, 69 years) underwent surgical resection after chemoradiation. All 19 patients achieved complete resection with negative margins. Seven patients (32%) had no residual tumor in the surgical specimen. One patient had grade 4 gastrointestinal toxicity and hematological toxicity probably related to inadvertent overdosing of capecitabine. The median survival for the whole group-patients who had pCR and those who did not have pCR-was 14, 17, and 15 months, respectively. CONCLUSIONS: Image-guided radiotherapy provided effective treatment for locally advanced rectal cancer with minimal toxicity and should be investigated in future prospective trials. PMID- 20848223 TI - Laparoscopic pancreatectomy for solid pseudo-papillary tumors of the pancreas is a suitable technique; our experience with long-term follow-up and review of the literature. AB - BACKGROUND: Solid pseudopapillary tumors (SPTs) are rare pancreatic neoplasms of low malignant potential that occur mainly in young women. Only 17 cases of SPT treated laparoscopically have been published in the literature and long-term follow-up data are still lacking. METHODS: Retrospective analysis of ten patients (8 women, 2 men; mean age, 25.4 years) (DS: 12.1; minimum 11, maximum 51) who underwent laparoscopic distal pancreatectomy with a definitive histological diagnosis of SPT. Long-term follow-up data were collected. RESULTS: The average tumor size was 43.8 mm (minimum 20, maximum 65 mm). The mean operative time was 177.5 minutes (DS: 53.7; minimum 120, maximum 255). In all, five patients underwent distal splenopancreatectomy; five patients underwent spleen-preserving distal pancreatectomy of whom three with splenic vessel preservation and two with the Warshaw technique. The conversion rate was nil and no case of perioperative mortality was recorded. The mean hospital stay was 7 days (DS: 2.7; minimum 4, maximum 12). Six patients had an uneventful postoperative course and four had postoperative complications. Two of them underwent reoperation, and the other two had nonsurgical complications. After a median follow-up of 47 (range, 5-98) months, all patients were alive and disease-free. CONCLUSIONS: Laparoscopic pancreatic resection is a safe and feasible procedure that could become the treatment of choice for patients affected by pancreatic SPT. Distal pancreatectomy should be performed, if possible, with spleen-preserving technique, especially in young patients. To avoid metastatic spread, laparoscopic or laparotomic biopsy should not be performed in patients affected by SPT. PMID- 20848225 TI - Expression and clinical significance of hepatoma-derived growth factor as a prognostic factor in human hilar cholangiocarcinoma. AB - BACKGROUND: Overexpressions of hepatoma-derived growth factor (HDGF) and vascular endothelial growth factor (VEGF) play important roles in the development and progression of cancers. This study investigates the expression of HDGF combined with VEGF, their correlation with clinicopathologic features, and their prognosis in human hilar cholangiocarcinoma. MATERIALS AND METHODS: The expressions of HDGF and VEGF were analyzed by immunohistochemistry using the streptavidin peroxidase complex method for 58 patients with hilar cholangiocarcinoma receiving surgery. Their correlation with clinicopathologic features was then investigated. The relationships between them and the survival time of patients were retrospectively analyzed. RESULTS: HDGF and VEGF were positively expressed in 27 (46.6%) and 42 (72.4%) patients, respectively. HDGF and VEGF had a positive correlation (r = 0.370, P = 0.004) in the Spearman rank correlation analysis. HDGF expression was associated with gender and histological type. Patients with positive HDGF expression had a significantly poorer overall survival rate than those with negative HDGF expression (35.7 vs. 73.3%, P = 0.003). Multivariate analysis showed that HDGF expression is an independent prognostic factor. CONCLUSIONS: HDGF expression significantly correlates with VEGF expression and is a valuable prognostic factor for human hilar cholangiocarcinoma. PMID- 20848227 TI - Preclinical imaging of therapy response using metabolic and apoptosis molecular imaging. AB - PURPOSE: Early after therapy, 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) imaging is not always reliable due to the influx of inflammatory cells while apoptosis imaging offers a direct and early measurement of therapy effects. This study uses an improved apoptosis probe ((99m)Tc-hAnxA5) in combination with [(18)F]FDG imaging to evaluate therapy response. PROCEDURES: Daudi tumor tissue was implanted in the spleen of SCID mice. Treatment was performed with adriamycin and cyclophosphamide. Sequential [(18)F]FDG-positron emission tomography (PET) was acquired over 6 days and (99m)Tc-hAnxA5-SPECT was performed before and 1 day after therapy. RESULTS: On day 1, therapy induced apoptosis was visualized with (99m)Tc-hAnxA5 without a measurable change in [(18)F]FDG uptake. [(18)F]FDG uptake decreased significantly on day 3 and was even more pronounced on day 6. CONCLUSION: In this preclinical model, (99m)Tc-hAnxA5 imaging was able to detect apoptosis before metabolic changes were measured. These results confirm the value of apoptosis imaging for therapy response and give more insight in [(18)F]FDG imaging and its parameters to evaluate response. PMID- 20848228 TI - NMDA receptor, PKC and ERK prevent fos expression induced by the activation of group I metabotropic glutamate receptors in the spinal trigeminal subnucleus oralis. AB - Fos, a protein product of immediate early gene c-fos, has been used as a marker for activation of nociceptive neurons in central nervous system including spinal trigeminal nucleus (Vsp). By noxious stimulation applied to orofacial area, the expression of Fos occurred in the Vsp pars oralis (Vo), the subnucleus receiving inputs from trigeminal primary afferents that predominantly innervate intraoral receptive fields. The present study demonstrates that the in vitro activation of group I metabotropic glutamate receptors (mGluRs; mGluR1 and 5) by bath application of their well-known agonist (S)-3,5-dihydroxyphenylglycine (DHPG) increased the number of Fos-expressing neurons in the Vo area. In addition, bath application of DHPG caused inward currents, a parameter of neuronal excitation, in the Vo neurons held at -70 mV in voltage-clamp mode of whole-cell recordings. In further experiments characterizing two phenomena, the increased Fos expression in the Vo was mediated by an additive activation of both mGluR1 and mGluR5, which required the activation of N-methyl-D-aspartate (NMDA) receptors, protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). In contrast, the inward currents were mediated only by mGluR1, but not by others. The data resulting from this in vitro study indicate that the DHPG-induced membrane depolarisation or neuronal excitation may be upstream to, or skip, the NMDA receptor, PKC and ERK pathways for the DHPG-induced Fos expression. PMID- 20848229 TI - Wnt/beta-catenin signaling enhances osteoblastogenic differentiation from human periodontal ligament fibroblasts. AB - Wnt/beta-catenin signaling has been known to influence bone formation and homeostasis. In this study, we investigated the canonical Wnt signaling regulation of osteogenic differentiation from periodontal ligament (PDL) fibroblasts. Stimulating PDL fibroblasts with lithium chloride (LiCl), a canonical Wnt activator, significantly increased mineralized nodule and alkaline phosphatase (ALP) activity in a time- and dose-dependent manner. LiCl up regulated protein expression of osteogenic transcription factors, including the runt-related gene 2, Msx2, and Osterix 2, in the PDL fibroblasts. Treatment of these cells with LiCl also increased the mRNA levels of ALP, FosB, and Fra1 in a dose-dependent manner. Blockage of canonical Wnt signaling by treating the cells with DKK1 inhibited Wnt1-stimulated mRNA expression of these osteogenic factors. Furthermore, pretreatment with DKK1 reduced the ALP activity and matrix mineralization stimulated by Wnt1. Collectively, these results suggest that canonical Wnt signaling leads to the differentiation of PDL fibroblasts into osteogenic lineage with the attendant stimulation of osteogenic transcription factors. PMID- 20848230 TI - Solution structure of antimicrobial peptide esculentin-1c from skin secretion of Rana esculenta. AB - Granular glands in the skins of frogs synthesize and secrete a remarkably diverse range of peptides capable of antimicrobial activity. These anuran skin antimicrobial peptides are commonly hydrophobic, cationic and form an amphipathic alpha-helix in a membrane mimetic solution. Recently, they have been considered as useful target molecules for developing new antibiotics drugs. Esculentin-1c is a 46-amino acid residue peptide isolated from skin secretions of the European frog, Rana esculenta. It displays the most potent antimicrobial activity among bioactive molecules. Esculentin-1c has the longest amino acids among all antimicrobial peptides. The present study solved the solution structure of esculentin-1c in TFE/water by NMR, for the first time. We conclude that this peptide is comprised of three alpha-helices with each helix showing amphipathic characteristics, which seems to be a key part for permeating into bacterial membranes, thus presenting antimicrobial activity. PMID- 20848231 TI - c-Myc stimulates cell invasion by inhibiting FBX8 function. AB - c-Myc is a cellular onco-protein and a transcriptional activator important for cell growth, cell division, and tumorigenesis. Despite all that is known of its function, the mechanism of how c-Myc contributes to tumorigenesis is unclear. To gain insight into the mechanism through which c-Myc protein exerts its oncogenic activity, we performed large-scale, tandem repeat affinity purification and identified the F box only protein 8 (FBX8), an F-box- and Sec7 domain-containing protein, as a novel Myc-binding protein. The c-Myc/FBX8 interaction was mediated by the c-Myc box II (MBII) region. We also confirmed that Myc protein overexpression in 293T cells affected FBX8 cellular translocation and led to recovery from FBX8-mediated inhibition of ADP-ribosylation factor 6 (ARF6) function during cell invasion. Together, these results suggest that FBX8 is a novel c-Myc binding protein and that c-Myc induces cell invasive activity through the inhibition of FBX8 effects on ARF6 function during cell invasion. PMID- 20848232 TI - Visfatin stimulates proliferation of MCF-7 human breast cancer cells. AB - Obesity, a condition characterized by increased fat content and altered secretion of adipokines, is a risk factor for postmenopausal breast cancer. Visfatin has recently been established as a novel adipokine that is highly enriched in visceral fat. Here we report that visfatin regulated proliferation of MCF-7 human breast cancer cells. Exogenous administration of recombinant visfatin increased cell proliferation and DNA synthesis rate in MCF-7 cells. Furthermore, visfatin activated G1-S phase cell cycle progression by upregulation of cyclin D1 and cdk2 expression. Visfatin also increased the expression of matrix metalloproteinases 2, matrix metalloproteinases 9, and vascular endothelial growth factor genes, suggesting that it may function in metastasis and angiogenesis of breast cancer. Taken together, these findings suggest that visfatin plays an important role in breast cancer progression. PMID- 20848233 TI - Applications of polychlorinated biphenyls. AB - BACKGROUND, AIM, AND SCOPE: In the 50 years or so that polychlorinated biphenyls (PCBs) were manufactured in the USA and elsewhere, they were widely used in numerous applications because of their desirable properties. The purpose of this paper is to review and summarize in one place the factual information about the uses of PCBs, as well as to correct some misconceptions that have arisen over the years. The focus is on applications in the USA for which there is ample documentation. However, use patterns were probably similar worldwide. MATERIALS AND METHODS: Review. RESULTS: PCBs were used primarily as electrical insulating fluids in capacitors and transformers and also as hydraulic, heat transfer, and lubricating fluids. PCBs were blended with other chemicals as plasticizers and fire retardants and used in a range of products including caulks, adhesives, plastics, and carbonless copy paper. In the USA, PCBs were manufactured from 1929 through mid-1977, although many products remained in service for decades after the manufacture of PCBs was terminated. This article reviews the historic uses of PCBs in the USA and discusses, where possible, the relative sales volumes. Especially with smaller volume, military, and third-party uses, documenting a use and/or differentiating between a commercial use and an experimental test batch is not possible. DISCUSSION: A major contribution of this paper is to differentiate reported commercial applications of PCBs that can be documented from those which cannot. Undocumented uses may include actual minor uses as well as reported applications that are unlikely ever to have been commercialized. PMID- 20848234 TI - Elucidation of phosphatidylcholine composition in krill oil extracted from Euphausia superba. AB - High performance liquid chromatography-electrospray tandem mass spectrometry was used to elucidate the phospholipids in krill oil extracted from Euphausia superba, an emerging source for human nutritional supplements. The study was carried out in order to map the species of the choline-containing phospholipid classes: phosphatidylcholine and lyso-phosphatidylcholine. In addition, the prevalent phosphatidylcholine class was quantified and the results compared with prior analysis. The qualification was performed with separation on a reverse phase chromatography column, while the quantification was obtained with class separation on a normal phase chromatography column. An Orbitrap system was used for the detection, and pulsed-Q dissociation fragmentation was utilized for the identification of the species. An asymmetrical exclusion list was applied for detection of phospholipid species of lower concentration, significantly improving the number of species observed. A total of 69 choline-containing phospholipids were detected, whereof 60 phosphatidylcholine substances, among others seven with probable omega-3 fatty acids in both sn-1 and sn-2. The phosphatidylcholine concentration was estimated to be 34 +/- 5 g/100 g oil (n = 5). These results confirm the complexity of the phospholipid composition of krill oil, and the presence of long chained, heavily unsaturated fatty acids. PMID- 20848236 TI - Patients admitted with acute abdominal conditions are at high risk for venous thromboembolism but often fail to receive adequate prophylaxis. AB - INTRODUCTION: The aim was to determine the frequency with which thromboprophylaxis is prescribed, factors predicting its prescription, and the frequency of symptomatic venous thromboembolism in patients admitted with acute abdominal conditions. METHODS: Charts of patients admitted with acute abdominal conditions that did not have surgery for at least 24 h following admission were audited to identify if thromboprophylaxis was prescribed, if it was prescribed appropriately, factors affecting its prescription, and the rate of symptomatic venous thromboembolism. RESULTS: Of 350 patients (176 females, mean age 64.9 +/- 18.6), 194 (55.4%) were admitted for bowel obstruction, 113 (32.3%) for biliary conditions, 14 (4.0%) for diverticulitis, 8 (2.3%) for pancreatitis, and 21 (6.0%) for other conditions. One hundred forty-two (40.6%) underwent surgery. Two hundred fifty-two (72.0%, 95% CI 67.3-76.7%) received thromboprophylaxis although only 199 (56.9%, 95% CI 51.7-62.1%) received adequate thromboprophylaxis. Hospital site and having surgery were associated with prescription of thromboprophylaxis. Twelve patients (3.4%, 95% CI 1.5-4.3%) developed symptomatic venous thromboembolism (nine deep venous thrombosis, three pulmonary embolism). CONCLUSIONS: Despite patients admitted with acute abdominal conditions being at high risk for development of symptomatic venous thromboembolism, many do not receive adequate thromboprophylaxis. Further work is required to decrease this gap in care. PMID- 20848235 TI - Follow-up actions on electronic referral communication in a multispecialty outpatient setting. AB - OBJECTIVES: Electronic health records (EHR) enable transmission and tracking of referrals between primary-care practitioners (PCPs) and subspecialists. We used an EHR to examine follow-up actions on electronic referral communication in a large multispecialty VA facility. METHODS: We retrieved outpatient referrals to five subspecialties between October 2006 and December 2007, and queried the EHR to determine their status: completed, discontinued (returned to PCP), or unresolved (no action taken by subspecialist). All unresolved referrals, and random samples of discontinued and completed referrals were reviewed to determine whether subspecialists took follow-up actions (i.e., schedule appointments anytime in the future) within 30 days of referral-receipt. For referrals without timely follow-up, we determined whether inaction was supported by any predetermined justifiable reasons or associated with certain referral characteristics. We also reviewed if PCPs took the required action on returned information. RESULTS: Of 61,931 referrals, 22,535 were discontinued (36.4%), and 474 were unresolved (0.8%). We selected 412 discontinued referrals randomly for review. Of these, 52% lacked follow-up actions within 30 days. Appropriate justifications for inaction were documented in 69.8% (150/215) of those without action and included lack of prerequisite testing by the PCP and subspecialist opinion that no intervention was required despite referral. We estimated that at 30 days, 6.3% of all referrals were associated with an unexplained lack of follow up actions by subspecialists. Conversely, 7.4% of discontinued referrals returned to PCPs were associated with an unexplained lack of follow-up. CONCLUSIONS: Although the EHR facilitates transmission of valuable information at the PCP subspecialist interface, unexplained communication breakdowns in the referral process persist in a subset of cases. PMID- 20848237 TI - Study on Zn relative concentration and state in sheep duodenum by XAFS. AB - Synchrotron-based X-ray absorption fine structure (XAFS) spectroscopy is not widely used in animal science. The objective of this study was to employ the XAFS technique to determine changes in zinc absorption and concentrations in the sheep interstinal sac using different zinc sources. Forty-eight sheep were slaughtered and their duodena were dissected. The duodena were randomly assigned to six zinc sources (ZnO, ZnSO(4), ZnMet, ZnLys, ZnSO(4) + methionine, ZnSO(4) + lysine). Ten centimeters of duodenal sac midpiece was incubated for 40 min in vitro using the everted intestinal sac technique in culture medium containing zinc from different sources. The amount of zinc present was normalized to 4 mg. XAFS was used to analyze the relative concentration and oxidation state of zinc, and atomic absorption spectrometry (AAS) was used to verify zinc concentration. The results showed that, for increasing zinc concentrations, organic zinc was a better source than inorganic zinc. In addition, the zinc concentration achieved using ZnMet was higher than that for ZnO and ZnSO(4) (P < 0.05) as measured by atomic absorption spectroscopy. The results using XAFS were consistent with that of AAS. The states of organic zinc and inorganic zinc were identical after being incubated for 40 min. As observed in these experiments, organic zinc was more easily absorbed than inorganic zinc. Our data demonstrate that organic zinc was dissociated into ions and then absorbed as inorganic zinc. In our experiments, we are the first investigators to use XAFS spectroscopy to determine zinc absorption in the sheep duodenal wall. We observed reduced absorption of inorganic zinc in the presence of methionine or lysine. Taken together, we postulate that the optimal molar ratio of inorganic zinc and ligand requires further study. PMID- 20848238 TI - Langerhans cell histiocytosis of the thyroid is a rare entity, but an association with a papillary thyroid carcinoma is often described. PMID- 20848239 TI - Tension-type headache and migraine in multiple sclerosis. AB - We review the evidence for a link between multiple sclerosis (MS) and two of the most common primary headache disorders: tension-type headache and migraine. We argue that the association between migraine and MS is biologically plausible and is confirmed by most studies. We discuss possible explanations for the association. First, we consider the possibility that the association is spurious. Next, we consider unidirectional causal models in which one of the conditions increases the risk of the other. A bidirectional model would suggest that each disease predisposes to the other. Alternatively, genetic or environmental risk factors shared by each condition may account for the association between them. We also address the question of whether coexisting migraine or tension-type headache in a patient with MS affects the symptom profile, clinical course, and radiographic characteristics of MS. PMID- 20848241 TI - Child abuse and the legal system: the orthopaedic surgeon's role in diagnosis. AB - BACKGROUND: Orthopaedic surgeons have unique training and experience in diagnosis of fractures, both accidental and nonaccidental. That experience is valuable in identifying physical child abuse and in avoiding false accusations or convictions. Both aspects are important to the welfare of children and their families. The events that follow a report of child abuse are outside the training and experience of most orthopaedic surgeons. QUESTIONS/PURPOSES: What process follows a report of suspected child abuse? What unexpected outcomes or results occur in this process? Are medical conclusions used in this process consistent with the state of our knowledge? METHODS: The child abuse legal process is described as experienced by one orthopaedic surgeon. Examples of unexpected problems that occurred in cases that went to trial are described. CONCLUSIONS: Inappropriate outcomes can result from incomplete or incorrectly applied information. The input of the orthopaedic surgeon is often needed to provide the best information available to ensure that the best interests of the child and the family are protected. Working within a hospital team is the preferred method, but direct courtroom testimony is sometimes necessary. PMID- 20848240 TI - Overview of the genetics of major depressive disorder. AB - Major depressive disorder (MDD) is a common psychiatric illness with high levels of morbidity and mortality. Despite intensive research during the past several decades, the neurobiological basis and pathophysiology of depressive disorders remain unknown. Genetic factors play important roles in the development of MDD, as indicated by family, twin, and adoption studies, and may reveal important information about disease mechanisms. This article describes recent developments in the field of psychiatric genetics, with a focus on MDD. Early twin studies, linkage studies, and association studies are discussed. Recent findings from genome-wide association studies are reviewed and future directions discussed. Despite all efforts, thus far, no single genetic variation has been identified to increase the risk of depression substantially. Genetic variants are expected to have only small effects on overall disease risk, and multiple genetic factors in conjunction with environmental factors are likely necessary for the development of MDD. Future large-scale studies are needed to dissect this complex phenotype and to identify pathways involved in the etiology of MDD. PMID- 20848242 TI - Sex differences in factors influencing recovery from arthroscopic knee surgery. AB - BACKGROUND: Many factors affect recovery from arthroscopic partial meniscectomy, including patient sex. However, sex differences in time to maximal recovery of knee function and factors influencing differential rates of recovery are unknown. QUESTIONS/PURPOSES: We determined (1) preoperative sex differences, (2) sex differences in rate and extent of recovery through 1 year postoperatively, and (3) clinical and fitness variables that could explain potential sex differences in recovery from partial meniscectomy. PATIENTS AND METHODS: The study sample consisted of 180 patients undergoing arthroscopic partial meniscectomy. Sex, age, body mass index, history of prior injury, length of time between knee injury/impairment and surgical evaluation, weekly exercise frequency, and self reported fitness were assessed preoperatively, and extent of osteoarthritis was recorded postoperatively. We used the Tegner-Lysholm scale to assess knee function preoperatively and postoperatively at weeks 1, 3, 8, 16, 24, and 48 followups. RESULTS: Females had worse knee function and delayed maximal recovery, requiring 1 year, compared with males, who required only 4 months. History of prior knee injury and lower self-reported fitness were associated with slower recovery in females but not in males. Osteoarthritis was associated with slower recovery but not related to sex. Body mass index, length of time between injury/impairment and surgical evaluation, and weekly exercise frequency did not influence rate of recovery. CONCLUSIONS: Females have delayed recovery after arthroscopic partial meniscectomy. Prior knee injury and self-reported low fitness are associated with delayed recovery for females but not for males. PMID- 20848243 TI - Incidence and reasons for nonrevision reoperation after total knee arthroplasty. AB - BACKGROUND: A dramatic increase in the demand for TKA is expected. The current burden of revision TKA is well known but the incidence and etiology of nonrevision reoperations after primary TKA is not. QUESTIONS/PURPOSES: We determined the rate, reason, timing, and predictors of nonrevision reoperation after TKA. METHODS: Using our institutional joint arthroplasty database, we identified 10,188 TKA performed on 7,613 patients between April 2000 and March 2008. A nonrevision reoperation was defined as any procedure requiring anesthetic in which components with bony interfaces were not removed or exchanged. Procedures after revision TKA were excluded. Potential risk factors investigated included age, gender, laterality, and simultaneous bilateral versus staged bilateral versus unilateral TKA. The minimum followup was 1 year (median, 4.1 years; range, 1.1 to 9.1 years). RESULTS: Three hundred fifty-three patients of 7,613 (4.6%) underwent 434 nonrevision reoperations on 384 of 10,188 (3.8%) knees. The most common indication for nonrevision reoperation was stiffness (58%; 252 of 434), followed by patellar clunk (12%; 53), infection (12%; 52), wound revision (6%; 26), hematoma (4.4%; 19), among others. The median time to reoperation was 74.5 days (range, 1-3058 days) but varied widely. Younger patients and those with unilateral TKA were more likely to have a nonrevision reoperation. CONCLUSIONS: The majority of nonrevision reoperations are performed for stiffness. Patellar clunk and infection also result in a large number of nonrevision reoperations. In weighing the future economic and workforce burden of TKA, nonrevision reoperations need to be acknowledged, and preventive measures need to be implemented. LEVEL OF EVIDENCE: Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 20848244 TI - Wear versus thickness and other features of 5-Mrad crosslinked UHMWPE acetabular liners. AB - BACKGROUND: The low wear rates of crosslinked polyethylenes provide the potential to use larger diameters to resist dislocation. However, this requires the use of thinner liners in the acetabular component, with concern that higher contact stresses will increase wear, offsetting the benefits of the crosslinking. QUESTIONS/PURPOSES: We asked the following questions: Is the wear of conventional and crosslinked polyethylene liners affected by ball diameter, rigidity of backing, and liner thickness? Are the stresses in the liner affected by thickness? METHODS: Wear rates were measured in a hip simulator and stresses were calculated using finite element modeling. RESULTS: Without crosslinking, the wear rate was 4% to 10% greater with a 36-mm diameter than a 28-mm diameter. With crosslinking, wear was 9% lower with a 36-mm diameter without metal backing and 4% greater with metal backing. Reducing the thickness from 6 mm to 3 mm increased the contact stress by 46%, but the wear rate decreased by 19%. CONCLUSIONS: The reduction in wear with 5 Mrad of crosslinking was not offset by increasing the diameter from 28 mm to 36 mm or by using a liner as thin as 3 mm. CLINICAL RELEVANCE: The results indicate, for a properly positioned 5-Mrad crosslinked acetabular component and within the range of dimensions evaluated, neither wear nor stresses in the polyethylene are limiting factors in the use of larger diameter, thinner cups to resist dislocation. PMID- 20848245 TI - Percutaneous vertebroplasty relieves pain in metastatic cervical fractures. AB - BACKGROUND: Percutaneous vertebroplasty is currently an alternative for treating vertebral fractures of the thoracic and lumbar spine, providing both pain control and vertebral stabilization. In the cervical spine, however, percutaneous vertebroplasty is technically challenging because of the complex anatomy of this region. QUESTIONS/PURPOSES: We evaluated the technical feasibility, complication rate, and ability of percutaneous vertebroplasty to provide pain relief in patients with painful metastatic cervical fractures. METHODS: We retrospectively reviewed 62 patients (24 men) who, between May 2005 and May 2009, underwent vertebroplasty to treat painful metastatic cervical fractures. Each patient was evaluated by a visual analog scale for pain, number of pain analgesics, and CT and MRI before, the day after, and at 3 months after the procedure. RESULTS: Two of the 62 patients had asymptomatic cement leakage in the soft tissues. We observed no delayed complications. Mean pretreatment and 24-hour posttreatment visual analog scale pain scores were 7.9+/-1.7 and 1.5+/-2, respectively. Immediately after surgery, the pain completely disappeared in 25 (40%) patients. Administration of analgesics was suspended in 34 (55%) patients whereas in 27 (39%) patients the median analgesics use decreased from two pills per day (range, 0-3) to 0 (range, 0-3). In two (3%) patients, analgesics administration was continued due to the persistence of pain. At 3 months, the patients reported a mean visual analog scale pain score of 1.7+/-2. CONCLUSIONS: Our data suggest, in selected patients, percutaneous vertebroplasty may be performed with a high technical success rate combined with a low complication rate, providing immediate pain relief lasting at least 3 months and a reduction in the use of analgesic drugs. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20848246 TI - Bernese periacetabular osteotomy in males: is there an increased risk of femoroacetabular impingement (FAI) after Bernese periacetabular osteotomy? AB - BACKGROUND: The Bernese periacetabular osteotomy (PAO) is a popular option for treating symptomatic acetabular dysplasia. We noted symptomatic impingement after PAO in several male patients. QUESTIONS/PURPOSES: We therefore determined (1) the incidence of clinical signs of FAI after PAO in the male population; and (2) whether any factors were associated with the positive impingement signs after PAO in males. PATIENTS AND METHODS: We retrospectively reviewed 38 males who underwent 46 periacetabular osteotomies (PAO) between 2000 and 2007. Clinical and radiographic data were analyzed with the focus on pre- and postoperative incidence of femoroacetabular impingement. Minimum followup was 12 months (average, 43 months; range, 12-90 months). RESULTS: We found a positive impingement sign in 19 of the 46 hips during the preoperative examination compared to 22 (47.8%) hips postoperatively. The ROM (flexion and internal rotation) decreased postoperatively compared to preoperatively. Radiographic parameters of coverage LCE-, ACE- and Tonnis angle improved into the normal range. Twenty hips had postoperative heterotopic ossification to varying degrees, mostly minor. WOMAC scores improved in the function and pain domains postoperatively. CONCLUSIONS: Despite normalization of coverage we found a high postoperative rate of clinical signs of FAI after PAO in males. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20848247 TI - Fishing for the hidden peptidome in health and disease (drug abuse). AB - The proteome and peptidome are defined as the set of proteins and peptides present in a tissue or other biological sample. In most proteomic studies, only abundant proteins are detected and, although these are important molecules, they are often well-studied structural proteins. A number of approaches have been used to examine less abundant molecules that play roles in signaling or otherwise have regulatory functions, including peptides as well as proteins such as enzymes and receptors. The overarching goals of this special issue involve defining the peptidome, identifying the current state of the field, and discussing methods to characterize the peptides, their receptors, and future needs for such measurements. PMID- 20848248 TI - Expression of thyroid transcription factor-1 in malignant pleural effusions. AB - Separating adenocarcinoma of the lung from non-pulmonary adenocarcinoma or malignant mesothelioma is difficult, especially in cytology specimens. Consequently, it is important to identify markers that may facilitate this distinction. Thyroid transcription factor-1 (TTF-1) is a homeodomain containing transcription factor expressed selectively in the thyroid, lung, and diencephalon. TTF-1 is also expressed in adenocarcinomas of the lung and is widely used as a pulmonary adenocarcinoma marker in surgical specimens. However, the utility of TTF-1 has rarely been investigated in cytology. In this study, we evaluated the expression of TTF-1 in malignant pleural effusions. The primary tumors included 26 pulmonary adenocarcinomas, 26 non-pulmonary adenocarcinomas (13 breast, 5 ovarian, 2 gastric, 2 prostatic, 1 esophageal, 1 colonic, 1 pancreatic and 1 renal) and 4 malignant mesotheliomas. Immunocytochemistry was performed on sections of cell blocks, using a mouse monoclonal TTF-1 antibody (clone 8G7G3/1) and a biotin-streptavidin detection system. Nuclear immunoreactivity for TTF-1 was detected in 19 pulmonary adenocarcinomas. All non pulmonary adenocarcinomas and malignant mesotheliomas were negative. These data indicate that TTF-1 maintains its sensitivity (73%) and specificity (100%) in cell block preparations and is useful in separating adenocarcinoma of the lung from non-pulmonary adenocarcinoma and malignant mesothelioma in cytology specimens. PMID- 20848249 TI - Activation of the PI3K/Akt pathway mediates bone morphogenetic protein 2-induced invasion of pancreatic cancer cells Panc-1. AB - Bone morphogenetic proteins (BMPs) signaling has an emerging role in pancreatic cancer. However, because of the multiple effects of different BMPs, no final conclusions have been made as to the role of BMPs in pancreatic cancer. In our studies, we have focused on bone morphogenetic protein 2(BMP-2) because it induces an epithelial to mesenchymal transition (EMT) and accelerates invasion in the human pancreatic cancer cell line Panc-1. It has been reported that the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediates invasion of gastric and colon cancer cells, which is unrevealed in pancreatic cancer cells. The objective of our study was to investigate whether BMP-2 mediated invasion might pass through the PI3K/Akt pathway. Our results show that expression of phosphorylation of Akt was increased by treatment with BMP-2, but not Noggin, a BMP-2 antagonist. Then pretreatment of Panc-1 cells with LY294002, an inhibitor of the PI3K/AKT pathway, significantly inhibited BMP-2-induced EMT and invasiveness. The data suggest that BMP-2 accelerates invasion of panc-1 cells via the PI3K/AKT pathway in panc-1 cells, which gives clues to searching new therapy targets in advanced pancreatic cancer. PMID- 20848250 TI - Breast cancer under 40 years of age: increasing number and worse prognosis. AB - Breast cancer at a relatively young age with a poor prognosis is currently exhibiting an increasing incidence. In a retrospective cohort analysis of early breast cancer cases after surgery from our institutional patient registry, 141 patients aged <= 40 years constituted the younger group, with 300 randomly selected patients aged >40 years as controls. A significant and steady increase was found in the relative number of younger cases during the years 2004-2009. The histological type and grade and the lymph node status of the cancers differed significantly between the two groups, with more aggressive biological behaviour, a more advanced stage and a worse prognosis in the younger group. Half of the cancers in the younger cohort were ER-negative, while two-thirds in the control group were ER-positive. Comparatively more tumours were PR-positive and HER2 negative in the control group than in the younger group. The rates of triple negative cases were 25% and 13% in the younger age and the control group, respectively (p = 0.026). Significantly higher mastectomy and axillary block dissection rates were observed in the younger age group, and more chemotherapy was administered than in the control group. Our findings demonstrate the significance of breast cancer in cases aged <40 years, and draw attention to the need for appropriate care in these cases. PMID- 20848252 TI - PET-CT imaging and reality. AB - The spectrum of human diseases caused by members of the Aspergillus genus is extensive. It ranges from allergic reactions to colonization of preexisting pulmonary cavities to invasion and destruction of lung parenchyma with pyemic spread to brain, skin, and other organs, causing rapid death. The immune status of the host is a crucial factor in determining the phenotype and severity of the disease. In this case report Chronic Necrotizing Pulmonary Aspergillosis (CNPA), a rare, locally- or semi-invasive variant of pulmonary Aspergillosis, mimicking lung metastasis is presented. The 60-year-old male patient had earlier received multiple cycles of systemic chemotherapy due to colorectal carcinoma. Our case report focuses on the benefits and the possible disadvantages of PET-CT imaging in CNPA. PMID- 20848251 TI - Combined antitumor effect of Ad-bFGF-siRNA and Ad-Vpr on the growth of xenograft glioma in nude mouse model. AB - Basic fibroblast growth factor (bFGF) has been demonstrated to correlate with glioma grade and clinical outcome and has established its possible usefulness as a target for glioma therapy. Vpr has been described as an antitumor agent and displays a potent antitumor nature. Here, we try to investigate whether a combined treatment with bFGF-siRNA and Vpr gene would have a enhanced effectiveness on glioma in vitro and in vivo.After treatments with only Ad-bFGF siRNA, only Ad-Vpr, and a combination of both, we assessed the changes in cell proliferation, cell cycle, and apoptosis in vitro by the methods of MTT, PI and FITC-AnnexinV double staining, respectively. In addition, we also evaluated the combined effect of bFGF-siRNA and Vpr gene therapy on glioma in vivo using xenograft glioma models in nude mice. Combined Ad-bFGF-siRNA and Ad-Vpr treatment was more better successful in inhibiting cell proliferation in comparison with treatments of either Ad-bFGF-siRNA or Ad-Vpr alone. Treatment of Ad-Vpr alone or a treatment of a combination of Ad-bFGF-siRNA and Ad-Vpr induced the G2/M cell cycle arrest and apoptosis; however, combined treatment was more effective than the Ad-Vpr treatment alone. Although each single treatment can slow the growth of xenograft glioma, the combined treatment with Ad-bFGF-siRNA and Ad-Vpr was better than either the Ad-bFGF-siRNA or Ad-Vpr treatment alone. Our results suggest that the combination therapy with bFGF-siRNA and Vpr gene can achieve a enhanced activity of anti-glioma, supporting the idea that the combination of these two antitumor agents could open new perspectives in glioma therapy. PMID- 20848253 TI - Integrating functional MRI information into radiotherapy planning of CNS tumors early experiences. AB - The purpose of our study was to examine the integration of functional MRI (fMRI) information into 3D based planning process of the central nervous system (CNS) malignancies. Between 01.01.2008 and 01.12.2008 four patients with astrocytoma were enrolled to this study. Before the planning process conventional planning CT, postoperative MR and individual functional MRI examinations were delivered. For the functional MRI examination the following four types of stimulus were applied: acoustic, visual, somatosensory and numeral. Three different theoretical planning situations were applied and compared: 3D conformal plan without fMRI information, 3D conformal plan with fMRI information and IMRT plan with fMRI information. For plan comparison DVH analysis, and NTCP model were used. fMRI based OR definition resulted in 4 additional OR's in the contouring process. As these cases demonstrate, an average of 50% dose reduction was achieved in OR, OR2 and OR3 with IMRT and fMRI based 3D planning, especially in case of midline localization and big tumor extent. IMRT provides additional sparing effect in the optic tract and brainstem, especially for localizations close to the midline. Our results demonstrated that using fMRI information in conventional 3D based treatment planning potentially benefits significant dose reduction in critical organs, with no compromise in PTV coverage. fMRI can be widely used even in low grade cases (long life expectancies, lower acute and late toxicity in radiotherapy) and in cases with high grade astrocytomas or metastases (higher dose to PTV with better risk organ sparing in radiotherapy). PMID- 20848254 TI - The truncation artifact. PMID- 20848255 TI - Unusual intrathoracic activity of Tc-99m sestamibi in a patient with chest pains. PMID- 20848257 TI - Knowledge and attitudes regarding colorectal cancer screening among medical students: a tale of two schools. AB - Colorectal cancer (CRC) screening has been shown to decrease the incidence of CRC cancers and decrease mortality. Studies show that the most important predictor of patient compliance with CRC screening is physician recommendation. We assessed the knowledge and attitudes of medical students regarding cancer screening. A study-specific questionnaire was distributed to medical students (MS) at two medical schools. There was a significant difference in the percentage of correctly answered questions regarding screening recommendations between first year MS and all other years for both schools. However, MS attitudes towards CRC screening were consistent between classes and schools. Although most MS had positive attitudes regarding cancer screening our survey identified several important deficits in knowledge. PMID- 20848256 TI - Safety of regadenoson in patients with end-stage liver disease. AB - BACKGROUND: Regadenoson is a selective A(2A) receptor agonist that is used for vasodilator stress myocardial perfusion imaging (MPI). Since the drug is partially metabolized by the liver, its safety in patients with end-stage liver disease (ESLD) needs to be determined. METHODS AND RESULTS: We studied 168 consecutive patients with ESLD who had regadenoson stress gated single photon emission computed tomography MPI between January 2008 and March 2010 before planned orthotopic liver transplantation and compared the hemodynamic responses and safety profile to 168 control patients. There were 72 women (43%) in ESLD versus 87 (52%) in the control group (P = .1). The patients with ESLD were younger (58 +/- 7 vs 62 +/- 12 years, P = .0002), but more likely to be Caucasians (P = .002). The MPI images were normal in 161 patients (96%) in each group. The left ventricular ejection fraction was 72 +/- 10% in ESLD and 66 +/- 11% in the control patients (P = .0001). The heart rate increase in response to regadenoson was lower in patients with ESLD than in the control group (16 +/- 11 vs 23 +/- 16 bpm, P = .0001), but the changes in systolic and diastolic blood pressures were similar (-9 +/- 12 vs -11 +/- 14 mmHg and -6 +/- 8 vs -7 +/- 10 mmHg, respectively, P = NS). There were no deaths or medication-related adverse events that required hospitalization in either group within 30 days of the study. CONCLUSION: This is the first study to document the tolerability and safety profile of regadenoson in patients with ESLD. PMID- 20848258 TI - The wisdom of experience: becoming an effective principal investigator. AB - As an American Cancer Society mentored research scholar recipient, I interviewed 11 experienced principal investigators actively engaged in cancer research with Indigenous peoples throughout the USA to learn helpful skills and advice for someone beginning a research career. Emergent themes provide helpful advice for beginning researchers as well as reminders for experienced investigators. Themes could serve as a catalyst for continued conversations among researchers and include: being a visionary, keeping up with the science, building relationships, protecting research participants and the community, publishing and disseminating, being organized, recognizing opportunity, understanding funders, being budget wise, staying focused, learning from failures, being holistic, being open to learning, having fun, and practicing self-care. PMID- 20848259 TI - [Patient satisfaction in acute coronary syndrome. Improvement through the establishment of a chest pain unit]. AB - BACKGROUND AND PURPOSE: Chest pain units (CPUs) were established primarily in the United States with the aim of reducing hospital admissions and costs, whilst improving quality of life and patient care. Clinical trials have shown that these units are safe and practical; however, there was a need to investigate to what extent patients are satisfied with the care in CPUs. The aim of this study is to evaluate the experiences of patients receiving CPU care and routine emergency department (ED) treatment for acute chest pain. PATIENTS AND METHODS: Patients presenting with acute chest pain at the ED between May 2004 and June 2005 and at the CPU between July 2005 and May 2006 were evaluated in this retrospective analysis. Standardized data collection using all available clinical data as well as telephone follow-up was carried out. Evaluation was carried out on a school mark basis and a quality assessment was performed. RESULTS: Of the total population, 479 patients (323 male, 156 female) were treated in the ED, whereas 1176 (743 male, 433 female) in the CPU. In the ED, 26 patients (5.4%) were diagnosed as ST segment elevation myocardial infarction (STEMI), 39 (8.1%) as non ST segment elevation myocardial infarction (NSTEMI) and 16 (3.3%) as unstable angina pectoris (UAP). In 398 patients (83.1%) acute coronary syndrome (ACS) could be ruled out. In the CPU, the incidence of STEMI was 74 (6.3%), of NSTEMI 141 (12%) and of UAP 153 (13%). ACS was excluded in 808 patients (68.7%). Data on satisfaction with in-hospital treatment was available in 78.5% of cases. In the CPU, 92.2% of the patients judged their treatment as excellent/good, 5.9% as appropriate and 1.9% as poor. The distribution of satisfaction in the ED was significantly lower with 78.6% excellent/good, 18.5% appropriate and 2.9% poor. CONCLUSION: The establishment of a CPU at the University Medical Center of Mainz demonstrated a higher level of patient satisfaction compared to the treatment of patients with acute chest pain in the general ED. PMID- 20848261 TI - [From the virtual world into gerontologic reality]. PMID- 20848262 TI - [Special care units for the treatment of acutely ill, cognitively impaired geriatric patients in Germany]. AB - During recent years, specialized wards have been established in geriatric hospital departments as a consequence of the growing need of special care for acutely ill older patients, who are also cognitively impaired. However, there are neither established standards nor any commonly agreed concept of care. A written survey among 12 specialized wards in Germany revealed some characteristics of these wards: extended geriatric assessment, special education of staff including validation and gerontopsychiatric issues, and particular equipment/architecture, such as hidden doors and group rooms, and in some cases loop tracks for walking, therapeutic facilities, and 'living rooms' on the wards. There is a wide variability with respect to the designation of these wards, the number of beds, length of stay, and admission criteria. It appears from this survey that there should be an exchange of empirical experience made on these wards, and there is a need of collaborative research on its usefulness. PMID- 20848268 TI - [A drug addict presenting with complicated tricuspid valve endocarditis]. AB - The right-sided heart valves are affected in about 10% of patients with infective endocarditis. However, the tricuspid valve is the most frequently involved valve in intravenous drug users with infective endocarditis. When treated with antibiotics, the prognosis is considered favorable. Reported here is the case of a drug-addicted patient with polymicrobial (Staphylococcus aureus and Streptococcus pneumoniae) infective endocarditis of the tricuspid valve and a lethal outcome due to multiple organ failure. The indications and options to perform cardiac surgery in patients with infective endocarditis of the tricuspid valve are discussed. PMID- 20848269 TI - High-mobility group box 1 exacerbates concanavalin A-induced hepatic injury in mice. AB - High-mobility group box 1 (HMGB1) is a nuclear factor released extracellularly as an early endogenous alarmin of inflammation following injury and as a late mediator of lethality in sepsis. Although HMGB1 has been implicated in acute lung injury, rheumatoid arthritis, and allograft rejection, its role in T-cell mediated hepatitis remains obscure. Here, we investigated the role and the underlying mechanisms of HMGB1 in concanavalin A (Con A) induced hepatic injury. We demonstrate that high levels of HMGB1 were detected in the necrotic area and in the cytoplasm of hepatocytes after Con A treatment. Administration of exogenous recombinant HMGB1 enhanced Con A-induced hepatitis, while blockade of HMGB1 protected animals from T cell-mediated hepatitis as evidenced by decreased serum transaminase, associated with reduced hepatic necrosis and mortality. Blockade of HMGB1 by a neutralizing antibody inhibited proinflammatory cytokine production, NFkappaB activity, and the late stage of T/NKT cell activation. These finding thus suggest a pivotal factor of HMGB1 in Con A-induced hepatitis. Blockage of extracellular HMGB1 may represent a novel therapeutic strategy to prevent hepatic injury in T cell-mediated hepatitis. PMID- 20848270 TI - New slow-rusting leaf rust and stripe rust resistance genes Lr67 and Yr46 in wheat are pleiotropic or closely linked. AB - The common wheat genotype 'RL6077' was believed to carry the gene Lr34/Yr18 that confers slow-rusting adult plant resistance (APR) to leaf rust and stripe rust but located to a different chromosome through inter-chromosomal reciprocal translocation. However, haplotyping using the cloned Lr34/Yr18 diagnostic marker and the complete sequencing of the gene indicated Lr34/Yr18 is absent in RL6077. We crossed RL6077 with the susceptible parent 'Avocet' and developed F(3), F(4) and F(6) populations from photoperiod-insensitive F(3) lines that were segregating for resistance to leaf rust and stripe rust. The populations were characterized for leaf rust resistance at two Mexican sites, Cd. Obregon during the 2008-2009 and 2009-2010 crop seasons, and El Batan during 2009, and for stripe rust resistance at Toluca, a third Mexican site, during 2009. The F(3) population was also evaluated for stripe rust resistance at Cobbitty, Australia, during 2009. Most lines had correlated responses to leaf rust and stripe rust, indicating that either the same gene, or closely linked genes, confers resistance to both diseases. Molecular mapping using microsatellites led to the identification of five markers (Xgwm165, Xgwm192, Xcfd71, Xbarc98 and Xcfd23) on chromosome 4DL that are associated with this gene(s), with the closest markers being located at 0.4 cM. In a parallel study in Canada using a Thatcher * RL6077 F(3) population, the same leaf rust resistance gene was designated as Lr67 and mapped to the same chromosomal region. The pleiotropic, or closely linked, gene derived from RL6077 that conferred stripe rust resistance in this study was designated as Yr46. The slow-rusting gene(s) Lr67/Yr46 can be utilized in combination with other slow-rusting genes to develop high levels of durable APR to leaf rust and stripe rust in wheat. PMID- 20848271 TI - Minimum 6-year outcomes for interstitial cystitis treated with sacral neuromodulation. AB - INTRODUCTION AND HYPOTHESIS: Interstitial cystitis is a multifaceted medical condition consisting of pelvic pain, urgency, and frequency. Can sacral neuromodulation be successfully utilized for the medium term of >= 6 years in interstitial cystitis patients for whom standard drug therapies have failed? METHODS: In our observational, retrospective, case-controlled review (January 2002-March 2004), we sought to discern whether neuromodulation could be successfully implemented with acceptable morbidity rates in interstitial cystitis patients. Thirty-four female patients underwent stage 1 and 2 InterStim placements under a general anesthetic. Simple means and medians were analyzed. RESULTS: Mean pre-op/post-op pelvic pain and urgency/frequency scores were 21.61 +/- 8.6/9.22 +/- 6.6 (p < 0.01), and mean pre-op/post-op visual analog pain scale (VAPS) were 6.5 +/- 2.9/2.4 +/- 1.1 (p < 0.01). Median age was 41 +/- 14.8 years with a mean follow-up of 86 +/- 9.8 months. CONCLUSIONS: With a minimum 6-year follow-up we determined that sacral neuromodulation provides adequate improvement for the symptoms of recalcitrant interstitial cystitis. PMID- 20848272 TI - Differences between zofenopril and ramipril, two ACE inhibitors, on cough induced by citric acid in guinea pigs: role of bradykinin and PGE2. AB - Dry and persistent cough is one of the commonest side effects experienced by patients treated with angiotensin-converting enzyme (ACE) inhibitors for the therapy of hypertension and congestive heart failure. The present study investigated the effect of zofenopril and ramipril on cough induced by citric acid in guinea pig and the involvement of bradykinin (BK) and prostaglandin E2 (PGE2) in mediating the responses of these drugs. Zofenopril (10 mg/kg) or ramipril (3-10 mg/kg), which is threefold more potent than zofenopril, on a mg basis, in lowering blood pressure, was orally administered daily in drinking water for 2 weeks. At the end of this period, aerosol of citric acid solution (0.1 M) was performed and the number of cough counted for 10 min. The role of the kinin B(2) receptor was also investigated. BK and PGE2 levels in the bronchoalveolar lavage (BAL) fluid were measured after repeated oral treatment with zofenopril or ramipril (10 mg/kg). Ramipril (3-10 mg/kg) increased citric acid-induced cough by 40% and 60%, respectively, as compared to the vehicle control group (15.0 +/- 1.8), while zofenopril (10 mg/kg) was without effect. The enhancement of citric acid-induced cough caused by ramipril (10 mg/kg) was reduced by the kinin B(2) receptor antagonist MEN16132 (0.25 mg/kg ip). BK and PGE2 levels in the BAL fluid were increased, in comparison to the control group, after ramipril treatment, while they were unchanged after zofenopril administration. Zofenopril, contrary to ramipril, did not affect either citric acid-induced cough in the guinea pigs or BK and PGE2 production in the airways. PMID- 20848273 TI - Thaliporphine ameliorates cardiac depression in endotoxemic rats through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF kappaB signaling. AB - Thaliporphine was found to ameliorate endotoxin-induced circulatory failure and mortality in rodents. The aims of the present study were to assess whether thaliporphine could improve cardiac function in endotoxemic rats and to investigate the underlying mechanisms. Cardiac function was evaluated by pressure volume loop analysis in pentobarbital-anesthetized rats 24 h after intravenous injection of lipopolysaccharide (LPS) (4 mg/kg) with or without thaliporphine (1 mg/kg, iv). The intracellular Ca(2+) transients, nitric oxide (NO), and reactive oxygen species (ROS) in enzymatically isolated ventricular cells were measured by fluorescent indicators. Western blotting was used to analyze the change of protein expression in response to LPS with or without thaliporphine in rat ventricle, H9C2 and Raw264.7 cells. Cardiac depression was found to coincide with the decreased intracellular Ca(2+) transients and the increased expression of nitrotyrosine on SERCA2 in rat ventricles after 24-h endotoxemia. Thaliporphine decreased intracellular NO and ROS level in ventricular cells and the nitrosylation of SERCA2, which resulted in recovering the functional properties of intracellular Ca(2+) handling and cardiac contraction. In H9C2 cells, LPS induced nuclear translocation of nuclear factor kappa B (NF-kappaB) could be attenuated by thaliporphine. In Raw264.7 cells, thaliporphine attenuated LPS induced TAK-1 phosphorylation and IkappaBalpha degradation in association with the inhibition of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNF-alpha) expression and the production of NO and ROS. In conclusion, thaliporphine ameliorates LPS-induced cardiac depression through attenuating TLR4 signaling in the downstream of TAK-1 phosphorylation and NF kappaB signaling in both cardiomyocytes and macrophage to prevent cardiac SERCA2 from nitrosylation by peroxynitrite via decreasing iNOS and TNF-alpha expression. PMID- 20848274 TI - The persecution of pharmacologists in Nazi Germany and Austria. AB - The present article is based on the brochure Verfolgte Deutschsprachige Pharmakologen 1933 by Loffelholz and Trendelenburg (2008). This book that describes the fate of the Persecuted German-speaking Pharmacologists commemorates these victims of an inhumane ideology. Half of the persecuted pharmacologists emigrated in 1933, while the majority of the German 'non-Aryans' refrained from emigrating until 1938. The reasons for the early emigration of most of the persecuted pharmacologists were the instantaneous dismissals in 1933 of almost all 'non-Aryan' scientists employed in research institutions and the fair chance to continue scientific careers in exile. The German pharmacologists emigrated to 12 different countries; at first to neighbouring countries, later on to USA (about 40%) and Great Britain (29%). Turkey, Brazil and the Jewish research institutions in Palestine hoped that immigration of these scientists would raise their academic level towards that of the Western industrial nations. The individual life stories of the persecuted pharmacologists exposed the whole range of persecution: the humiliating dismissals, the desperate odyssey of emigration, the dramatic escape from the concentration camps, and the Holocaust. On the other hand, there were cases of brilliant scientific careers in exile (especially in Great Britain). The behaviour of the 'Aryan' colleagues in Germany also exhibited a wide range, from fanatic following of the Nazi policy, opportunism and Prussian obedience to the Nazi government on the one hand, to opposition and resistance on the other. The present study describes the fate of persecuted pharmacologists against the background of the persecution policy of the Nazis. PMID- 20848275 TI - Can imagery become reality? AB - Previous studies showed that highly hypnotizable persons imagining a specific sensory context behave according to the corresponding real stimulation and perceive their behaviour as involuntary. The aim of the study was to confirm the hypothesis of a translation of sensory imagery into real perception and, thus, of a true involuntary response. We studied the imagery-induced modulation of the vestibulospinal (VS) reflex earlier component in highly (Highs) and low hypnotizable subjects (Lows), as it is not affected by voluntary control, its amplitude depends on the stimulus intensity, and the plane of body sway depends on the position of the head with respect to the trunk. Results showed that the effects of the "obstructive" imagery of anaesthesia are different from those elicited by the "constructive" imagery of head rotation. Indeed, both Highs and Lows having their face forward and reporting high vividness of imagery experienced anaesthesia and reduced their VS reflex amplitude in the frontal plane, while only Highs changed the plane of body sway according to the imagined head rotation that is from the frontal to the sagittal one. These effects cannot be voluntary and should be attributed to translation of sensory imagery into the corresponding real perception. PMID- 20848276 TI - Movement timing and reach to reach variability during a repetitive reaching task in persons with chronic neck/shoulder pain and healthy subjects. AB - Neck/shoulder pain is linked to movement repetition, awkward postures, and muscular fatigue. Studies have examined the influence of pain and fatigue on movement characteristics, but few report spatial and temporal characteristics within- and between-dynamic movements. The combined influences of fatigue and pain on these parameters are examined here. A shoulder-injured group (PAIN) (intensity >3/10, duration >3 consecutive months) and an age-sex-matched control group (CTRL) (n = 16 in each) performed a repetitive reaching task to voluntary termination. Kinematics, heart rate, and muscle activity were recorded. Group comparisons were made at the beginning and end of task. Both pain and fatigue changed movement parameters with CTRL subjects adapting to fatigue with increased arm movement, while the PAIN group increased center of mass (CoM) and minimized shoulder movement. Fatigue was associated with decreased arm relative variability, while pain caused increased arm and decreased CoM relative variability. Time to peak velocity tended to indicate increased joint coupling in the CTRL group only. Together, this suggests that despite initial differences in movement strategies, both groups tend to move toward more fixed movement strategies at the end of the task. Those of CTRL are more fixed temporally and spatially (in the arm), whereas the PAIN group adaptations are primarily spatial in nature and appear to focus on controlling CoM. PMID- 20848277 TI - Unobstructive total anomalous pulmonary venous return: impact of early elective repair on the need for prolonged mechanical ventilatory support. AB - Optimal timing for elective repair of total anomalous pulmonary venous return (TAPVR) in the case of an unobstructed anomalous pathway is unclear. All infants with a diagnosis of TAPVR as an isolated lesion who underwent surgical repair at Children's Hospital of Wisconsin from 1991 to 2007 were reviewed to assess location of drainage, presence of obstruction, age at presentation, age at surgery, death, need for extracorporeal membrane oxygenation (ECMO), length of hospital stay, length of mechanical ventilation (MV), and late pulmonary venous obstruction. A total of 65 patients were identified: 38 (59%) with supracardiac drainage, 10 (15%) with cardiac drainage, 11 (17%) with infracardiac drainage, and 6 (9%) with mixed drainage. For 39 (60%) of the 65 patients, obstruction was identified preoperatively. Three early and five late deaths occurred after surgery (12%), all involving patients with preoperative obstruction. Most of the late deaths (80%) involved patients who experienced recurrent obstruction. Of the 65 patients, 26 (40%) had no obstruction preoperatively, and none died, required ECMO support, or experienced late obstruction. For the 26 patients without obstruction, the timing of surgery was elective at the discretion of the supervising cardiologist. Among these 26 patients, 15 had surgery less than 10 days after presentation (median age, 18 days), and 53% of these 15 patients (8/15) had MV less than 5 days. In contrast, all 11 patients who had elective surgery more than 10 days after presentation (median age, 56 days) required MV for more than 5 days (p = 0.007). Isolated TAPVR appears to be at the highest risk for death and late postoperative obstruction when obstruction is present preoperatively. Patients with unobstructive TAPVR do very well, but potential morbidity related to prolonged MV appears to be significantly reduced by early elective surgery. PMID- 20848278 TI - 4D phase-contrast flow cardiovascular magnetic resonance: comprehensive quantification and visualization of flow dynamics in atrial septal defect and partial anomalous pulmonary venous return. AB - The case of an 8-year-old girl with atrial septal defect and associated anomalous pulmonary venous return is presented to illustrate the advantages of four dimensional flow (4D flow) over the current two dimensional flow (2D flow) in terms of time efficiency, easy planning, accurate and individual quantification of the blood sources contributing to the left-to-right shunting from one single acquisition, internal validation of flow measurement accuracy, possibility of reanalysis without rescanning in case of unexpected findings during the postprocessing, and comprehensive understanding of flow insight by use of particle tracing visualization. PMID- 20848279 TI - Investigating 22q11.2 deletion and other chromosomal aberrations in fetuses with heart defects detected by prenatal echocardiography. AB - Congenital heart disease (CHD) is the most common birth defect and the leading cause of mortality in the first year of life. In fetuses with a heart defect, chromosomal abnormalities are very frequent. Besides aneuploidy, 22q11.2 deletion is one of the most recognizable chromosomal abnormalities causing CHD. The frequency of this abnormality varies in nonselected populations. This study aimed to investigate the incidence of the 22q11.2 deletion and other chromosomal alterations in a Brazilian sample of fetuses with structural cardiac anomalies detected by fetal echocardiography. In a prospective study, 68 fetuses with a heart defect were evaluated. Prenatal detection of cardiac abnormalities led to identification of aneuploidy or structural chromosomal anomaly in 35.3% of these cases. None of the fetuses with apparently normal karyotypes had a 22q11.2 deletion. The heart defects most frequently associated with chromosomal abnormalities were atrioventricular septal defect (AVSD), ventricular septal defect (VSD), and tetralogy of Fallot. Autosomal trisomies 18 and 21 were the most common chromosomal abnormalities. The study results support the strong association of chromosome alterations and cardiac malformation, especially in AVSD and VSD, for which a chromosome investigation is indicated. In fetuses with an isolated conotruncal cardiopathy, fluorescence in situ hybridization (FISH) to investigate a 22q11.2 deletion is not indicated. PMID- 20848280 TI - 18F-FDG PET/CT in paediatric lymphoma: comparison with conventional imaging. AB - PURPOSE: In children with Hodgkin's disease and non-Hodgkin's lymphoma, the ability of (18)F-fluoro-2-deoxy-D-glucose PET/CT and conventional imaging (CI) to detect malignant lesions and predict poor lesion response to therapy was assessed and compared. METHODS: A retrospective review of findings reported on PET/CT and CI was performed using a lesion-based analysis of 16 lymph node and 8 extra-nodal regions. Lesions were defined by histopathological findings or follow-up > 6 months. RESULTS: The study included 209 PET/CT scans with a valid CI comparator. A total of 5,014 regions (3,342 lymph node, 1,672 extra-nodal) were analysed. PET/CT performed significantly better than CI in the detection of malignant lesions with sensitivity and specificity of 95.9 and 99.7% compared to 70.1 and 99.0%, respectively. For predicting poor lesion response to therapy, PET/CT had fewer false-positive lesions than CI. The specificity for predicting poor lesion response to treatment for PET/CT was 99.2% compared to 96.9% for CI. PET/CT was the correct modality in 86% of lesions with discordant findings. CONCLUSION: PET/CT is more accurate than CI in detecting malignant lesions in childhood lymphoma and in predicting poor lesion response to treatment. In lesions with discordant findings, PET/CT results are more likely to be correct. PMID- 20848282 TI - A dissenting opinion and perspective on "gift authorship". PMID- 20848281 TI - Is there a role for 11C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml? AB - PURPOSE: The aim of this study was to evaluate the potential usefulness of whole body (11)C-choline PET/CT in the re-staging of prostate cancer (PC) patients previously treated with radical prostatectomy (RP), who presented a mild increase of prostate-specific antigen (PSA) <1.5 ng/ml (early biochemical relapse) during follow-up (FU). METHODS: We evaluated 102 consecutive patients (mean age = 68 years, range = 54-82 years) previously treated with RP and who presented during FU a mild increase of trigger PSA serum levels <1.5 ng/ml: mean 0.86 +/- 0.40 ng/ml (range 0.2-1.5) and median 0.93 ng/ml (range 0.67-1.10). In this patient series (11)C-choline PET/CT was used as the first imaging examination at the time of the detection of a mild serum PSA increase <1.5 ng/ml. (11)C-Choline PET/CT was performed following standard procedures in our centre. At the time of PET/CT, 86 patients were not receiving any pharmacologic treatment, while 16 were under anti-androgenic therapy. Positive PET findings were validated by: (a) transrectal ultrasound (TRUS)-guided biopsy in cases of local recurrence, (b) surgical lymphadenectomy, (c) other imaging procedures or (d) FU lasting for at least 12 months. Univariate and multivariate analyses were used to evaluate the following variables: age, TNM staging, Gleason score, time from RP to the biochemical relapse, anti-androgen therapy at the time of (11)C-choline PET/CT scan, trigger PSA value and PSA kinetics, i.e. PSA doubling time (PSAdt) and PSA velocity (PSAvel), in order to assess the significant predictive factors related to the findings of a positive (11)C-choline PET/CT scan. RESULTS: Overall, (11)C-choline PET/CT showed positive findings in 29 of 102 patients (28% of cases). In detail, (11)C-choline PET/CT detected: local relapse in 7 patients, bone metastases in 13 patients (4 single and 9 multiple) and lymph node metastases in 9 patients (6 single and 3 multiple). Positive PET findings were validated by: (a) TRUS-guided biopsy in 7 patients with local recurrence, (b) surgery and lymphadenectomy in 3 patients, (c) other targeted imaging procedures (MR or bone scan) in 5 patients and (d) clinical FU lasting a minimum of 12 months and including also a contrast enhanced CT (CECT), an MR, a bone scan and a repeated (11)C-choline PET/CT in 14 patients. Age, time to biochemical relapse (TTR), initial T staging, Gleason score and trigger PSA were not statistically significant in predicting a positive (11)C-choline PET/CT scan both at univariate and multivariate analysis. Instead, PSA kinetics (PSAdt and PSAvel), N status and anti-androgenic therapy at the time of PET scan were statistically significant predictive factors at univariate analysis. Of note, only PSAdt and initial N status were found to be significant and independent predictive factors at multivariate analysis. The mean PSAdt in PET-positive patients was 4.34 months (SD 2.82) while in PET-negative patients it was 13.30 months (SD 9.75) (p = 0.0001). The optimal threshold for PSAdt established by receiver-operating characteristic (ROC) analysis was 7.25 months (AUC 0.85; 95% confidence interval 0.77-0.91) providing 93% sensitivity, 74% specificity, 60% positive predictive value and 96% negative predictive value. CONCLUSION: In our study, (11)C-choline PET/CT was able to detect recurrent disease in 28% of the patients with mild biochemical relapse characterized by very low trigger PSA levels (PSA <1.5 ng/ml). Very interestingly (11)C-choline PET/CT detected distant unexpected metastases in 21% of the patients. At multivariate statistical analysis only PSAdt and node status were shown to be significant and independent predictive factors for positive (11)C-choline PET/CT. Therefore, (11)C-choline could be suggested to be performed early during initial biochemical relapse in patients presenting with fast PSA kinetics. The early detection of the site of recurrence could lead to a prompt instauration of the most appropriate treatment, i.e. local surgery or radiation treatment vs systemic treatment. In this view, one of the main advantages should be the avoidance of unnecessary local radiotherapy in those patients showing distant metastasis at (11)C-choline PET/CT. PMID- 20848283 TI - The role of K-ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines. AB - PURPOSE: Pancreatic ductal and lung adenocarcinomas are the most common and prevalent types of human neoplasms with a greater than 80% mortality rate. The poor prognosis of both these cancers are likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. Most notably, the early development of pancreatic intraepithelial neoplasia and lung lesions is suggested to be the result of a mutation in the K ras (G12D) oncogene. Tumor necrosis factor-related-apoptosis-inducing-ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells, while leaving normal cells unharmed. However, some cancers show resistance to TRAIL treatment, leaving a gap in the understanding of its exact etiology. METHODS: TRAIL-induced resistance to cell death was investigated in pancreatic and lung cancer cell lines. Cell survival was determined by SRB and apoptosis by ELISA-based cell death assay. Activation of bid and caspases were evaluated by Western blotting. RESULTS: Our study demonstrated that TRAIL significantly suppressed cell survival, by inducing apoptosis in a dose-dependent manner, in the pancreatic cancer BxPC-3 (wild type G12) and lung cancer A549 (G12S) cell lines. In contrast, Panc-1 pancreatic and SK-LU-1 lung cancer cell lines, which have a mutated (G12D) K-ras genotype, were resistant to the actions of TRAIL. CONCLUSIONS: This study demonstrates an association between TRAIL resistance to apoptosis in human pancreatic and lung cancer cell lines and G12D K ras(12) mutation. PMID- 20848284 TI - Hyaluronic acid-paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. AB - PURPOSE: Hyaluronan (HA)-receptors (mainly CD44 and RHAMM) are overexpressed in a wide variety of cancers including ovarian tumors, and HA-bioconjugates have been developed to enhance selective entry of cytotoxic drugs into HA receptor expressing cancerous cells. Here, we evaluated the potential application of a new HA-paclitaxel bioconjugate, ONCOFID-P, for intraperitoneal (IP) treatment of ovarian cancer. METHODS: In vitro cytotoxic effect of ONCOFID-P was first assessed on CD44(+) OVCAR-3 and SKOV-3 human ovarian cancer cell lines. Studies were performed in female Balb/c athymic mice IP implanted with OVCAR-3 or SKOV-3 and treated with IP ONCOFID-P, and IP and intravenous (IV) free paclitaxel, at their maximum tolerated dose (MTD 168, 80 and 80 mg/kg, total dose, respectively). The potential detrimental effect of the IP ONCOFID-P and IP free paclitaxel on hematopoiesis was also assessed on peripheral blood, bone marrow and spleen. RESULTS: Results show that ONCOFID-P cytotoxicity against both OVCAR 3 and SKOV-3 cell lines was somewhat less effective than free paclitaxel. Conversely, in in vivo experiments, IP treatment with ONCOFID-P was overall more effective than IV and IP free paclitaxel in inhibiting intra-abdominal tumor dissemination, abrogating ascites, prolonging survival and curing mice. ONCOFID-P and IP free paclitaxel were equivalent in terms of myelotoxicity, although the former was administered at a two-fold higher dose. CONCLUSIONS: Present data strongly support the development of ONCOFID-P for locoregional treatment of ovarian cancer. PMID- 20848285 TI - Synergistic interactions between peloruside A and other microtubule-stabilizing and destabilizing agents in cultured human ovarian carcinoma cells and murine T cells. AB - PURPOSE: Microtubule-stabilizing agents are an important class of anticancer compounds. Peloruside A and laulimalide bind to a different site on the microtubule to taxoid site drugs such as paclitaxel (Taxol((r))), docetaxel (Taxotere((r))), ixabepilone (Ixempra((r))), the epothilones, and discodermolide. The purpose of this study was to examine the synergistic interactions of these drugs when given in combination in relation to the differences in their binding sites on the microtubule. METHODS: Human ovarian carcinoma cells (1A9 cells) and murine T cells were treated with different combinations of microtubule stabilizing or destabilizing agents. The compounds were given individually and in combination, and the antiproliferative activity was assessed to calculate a combination index (CI) from the equation: CI = D(1)/Dx(1) + D(2)/Dx(2) in which D(1) and D(2) are the concentrations of drug 1 and drug 2 that when given together give the same response as drug 1 and 2 alone (Dx(1) and Dx(2)). Thus, a CI value of less than 1.0 indicates a synergistic effect between the two drugs in which the response to the two drugs given together is greater than the additive response of the two drugs if given on their own. RESULTS: As anticipated from previous in vitro studies, peloruside A and laulimalide did not synergize with each other. They also failed to synergize with the microtubule-destabilizing agents vinblastine and 2-methoxyestradiol. Peloruside A and laulimalide did, however, synergize with the epothilones, as had been previously shown, but not with docetaxel or discodermolide. CONCLUSIONS: Combining two microtubule targeting agents with different binding sites does not guarantee a synergistic interaction in cells, and additional factors are likely to be involved. This study highlights the importance of preclinical testing of actual combinations of drugs before proceeding into clinical trials. PMID- 20848286 TI - A two-component histidine kinase, MoSLN1, is required for cell wall integrity and pathogenicity of the rice blast fungus, Magnaporthe oryzae. AB - A two-component signal transduction system is a common mechanism for environmental sensing in bacteria. The functions of the two-component molecules have been also well characterized in the lower eukaryotic fungi in recent years. In Saccharomyces cerevisiae, the histidine kinase Sln1p is a major component of the two-component signaling pathways and a key regulator of the osmolarity response. To determine the function of MoSLN1, a Sln1 homolog of Magnaporthe oryzae, we cloned the MoSLN1 gene and generated specific mutants using gene knock out strategy. Disruption of MoSLN1 resulted in hypersensitivity to various stresses, reduced sensitivity to cell wall perturbing agent Calcofluor white, and loss of pathogenicity, mainly due to a penetration defect. Additionally, we showed that MoSLN1 is involved in oxidative signaling through modulation of intra and extracellular peroxidase activities. These results indicate that MoSLN1 functions as a pathogenicity factor that plays a role in responses to osmotic stress, the cell wall integrity, and the activity of peroxidases. PMID- 20848288 TI - Bowel perforation after pediatric living donor liver transplantation. AB - PURPOSE: Bowel perforation after liver transplantation (LT) is a rare, but highly lethal complication with a poor prognosis. Here, we report the outcome of cases of bowel perforation after pediatric LT in our department. PATIENTS AND METHODS: The study subjects were 148 patients who underwent pediatric living donor liver transplantation. The 114 with biliary atresia (BA) were divided into two groups: those with associated bowel perforation (Group A) and those without (Group B). RESULTS: Four patients in all (2.5%) suffered bowel perforation. Their original disease was BA and emergency surgery was performed in all cases, with a mortality rate of 50.0%. Comparison of Groups A and B revealed significant differences in the patient age, body weight, duration of surgery, cold ischemic time, and blood loss volume. The survival rates in Groups A and B were 50.0 and 99.1%, respectively (p < 0.01). Duration of surgery was an independent risk factor (p = 0.05). CONCLUSION: Bowel perforation after LT is a potentially fatal complication. LT is a procedure that requires care and precision, and the possibility of bowel perforation should always be borne in mind during post operative management, when the duration of surgery has been long. PMID- 20848287 TI - Nerve growth factor receptor immunohistochemistry has a limited additional value to diagnose Hirschsprung's disease. AB - PURPOSE: The diagnosis of Hirschsprung's disease (HSCR) is based on the histopathological evaluation of rectal suction biopsies (RSB), using haematoxylin and eosin (H&E) stains and acetylcholinesterase (AChE) histochemistry. The use of different immunohistochemical markers, such as nerve growth factor receptor (NGFR), has been suggested to facilitate the diagnosis of HSCR. The aim of this study was to evaluate the addition of NGFR immunohistochemistry to diagnose HSCR. METHODS: RSB from 23 HSCR patients and 16 patients investigated for, but not diagnosed with, HSCR were retrospectively reviewed. The histopathology report supported or did not support the diagnosis of HSCR. RESULTS: In patients with HSCR, the primary biopsies confirmed the diagnosis in 21 of 23 cases with H&E staining, in 16 of 23 cases with AChE histochemistry, and in 8 of 23 cases with NGFR immunohistochemistry. Due to inadequate biopsies or equivocal interpretation, the biopsies were repeated in seven of the patients with HSCR and two patients underwent biopsies a third time. In the 16 patients investigated for but not diagnosed with HSCR, the three tests were normal in all cases. CONCLUSION: We conclude that NGFR immunohistochemistry has limited additional value to diagnose HSCR. PMID- 20848289 TI - Endoscopic balloon dilatation for congenital membranous stenosis in the jejunum in an infant. AB - INTRODUCTION: As endoscopic equipment and instruments have improved, the indications for endoscopic treatment have also been extended. This report presents an applicable procedure of endoscopic balloon dilatation for an infant patient with congenital membranous stenosis in the jejunum. METHODS: We used a 9 mm flexible endoscope and a through-the-scope multidiameter balloon catheter in the endoscopic treatment. RESULTS: Dilatation was performed for dilatation diameters 10, 12, and 15 mm each for 2 min. After carrying out balloon dilatation, the endoscope could be smoothly inserted through the opening. CONCLUSION: In upper jejunal stenosis, endoscopic balloon dilatation was minimally invasive and effective as a treatment modality. PMID- 20848290 TI - Inhibitory effect of N-adamantyl-3,4-dihydroxybenzamide on melanogenesis in melan a cells and brown guinea pigs. AB - To find novel depigmenting agents, a new synthetic compound, N-adamantyl-3,4 dihydroxybenzamide (NADB) was produced and the effects on melanogenesis were investigated. Our results showed that NADB reduced melanin synthesis in a dose dependent manner in melan-a cells. Tyrosinase activity was also reduced by NADB treatment in melan-a cells. However, NADB did not inhibit tyrosinase activity directly in a cell-free system. Treatment of melan-a cells with NADB caused a marked decrease in protein and mRNA levels of tyrosinase along with tyrosinase related protein 1 and dopachrome tautomerase. To determine whether NADB reduces skin pigmentation, the dorsal skin of brown guinea pigs was shaved and irradiated with UV for 3 weeks using a solar simulator. Then NADB (2 or 1% in propylene glycol:ethanol:water = 5:3:2) was applied topically twice daily for 4 weeks. Visual inspection and Fontana-Masson staining both demonstrated that NADB resulted in lower skin pigmentation and total epidermal melanin in comparison to vehicle-treated areas. These findings suggest that NADB is useful in the treatment of hyperpigmentation. PMID- 20848293 TI - Action-effect learning in early childhood: does language matter? AB - Previous work showed that language has an important function for the development of action control. This study examined the role of verbal processes for action effect learning in 4-year-old children. Participants performed an acquisition phase including a two-choice key-pressing task in which each key press (action) was followed by a particular sound (effect). Children were instructed to either (1) label their actions along with the corresponding effects, (2) verbalize task irrelevant words, (3) or perform without verbalization. In a subsequent test phase, they responded to the same sound effects either under consistent or under inconsistent sound-key mappings. Evidence for action-effect learning was obtained only if action and effects were labeled or if no verbalization was performed, but not if children verbalized task-irrelevant labels. Importantly, action-effect learning was most pronounced when children verbalized the actions and the corresponding effects, suggesting that task-relevant verbal labeling supports the integration of event representations. PMID- 20848291 TI - Administration of rat acute-phase protein alpha(2)-macroglobulin before total body irradiation initiates cytoprotective mechanisms in the liver. AB - Previously, we showed that administration of the acute-phase protein alpha(2) macroglobulin (alpha(2)M) to rats before total-body irradiation with 6.7 Gy (LD(50/30)) of X-rays provides the same level of radioprotection as amifostine. Here, we compare the cytoprotective effects of alpha(2)M and amifostine on rat liver. The potential of the liver to replenish cells destroyed by ionizing radiation was assessed by immunoblot analysis with antibody to proliferating cell nuclear antigen (PCNA). After irradiation, in unprotected rats PCNA decreased 6 fold from the basal level. In rats pretreated with either alpha(2)M or amifostine, PCNA was increased throughout a 4 week follow-up period, indicating that hepatocyte proliferation was unaffected. Since PCNA is an important component of the repair machinery, its increased expression was accompanied by significantly lower DNA damage in alpha(2)M- and amifostine-treated rats. At 2 weeks after irradiation, the Comet assay revealed a 15-fold increase in DNA damage in unprotected rats, while in alpha(2)M- and amifostine-treated rats we observed 3- and 4-fold rise in damage, respectively. The improved protection to DNA damage was supported by elevated activity of the antioxidant systems. Compared to untreated rats, pretreatments with alpha(2)M and amifostine led to similar increases in levels of the inflammatory cytokine IL-6 and the redox sensitive transcription factor NFkappaB, promoting upregulation of MnSOD, the major component of the cell's antioxidant axis, and subsequent increases in Mn/CuZnSOD and catalase enzymatic activities. The results show that alpha(2)M induces protein factors whose interplay underlies radioprotection and support the idea that alpha(2)M is the central effector of natural radioprotection in the rat. PMID- 20848294 TI - Unraveling the metabolism of HEK-293 cells using lactate isotopomer analysis. AB - HEK-293 is the most extensively used human cell line for the production of viral vectors and is gaining increasing attention for the production of recombinant proteins by transient transfection. To further improve the metabolic characterization of this cell line, we have performed cultures using 13C-labeled substrates and measured the resulting mass isotopomer distributions in lactate by LC/MS. Simultaneous metabolite and isotopomer balancing allowed improvement and validation of the metabolic model and quantification of key intracellular pathways. We have determined the amounts of glucose carbon channeled through the PPP, incorporated into the TCA cycle for energy production and lipids biosynthesis, as well as the cytosolic and mitochondrial malic enzyme fluxes. Our analysis also revealed that glutamine did not significantly contribute to lactate formation. An improved and quantitative understanding of the central carbon metabolism is greatly needed to pursue the rational development of engineering approaches at both the cellular and process levels. PMID- 20848295 TI - PCR diagnostics and monitoring of adenoviral infections in hematopoietic stem cell transplantation recipients. AB - After stem cell transplantation, human patients are prone to life-threatening opportunistic infections with a plethora of microorganisms. We report a retrospective study on 116 patients (98 children, 18 adults) who were transplanted in a pediatric bone marrow transplantation unit. Blood, urine and stool samples were collected and monitored for adenovirus (AdV) DNA using polymerase chain reaction (PCR) and real-time PCR (RT-PCR) on a regular basis. AdV DNA was detected in 52 (44.8%) patients, with mortality reaching 19% in this subgroup. Variables associated with adenovirus infection were transplantations from matched unrelated donors and older age of the recipient. An increased seasonal occurrence of adenoviral infections was observed in autumn and winter. Analysis of immune reconstitution showed a higher incidence of AdV infections during periods of low T-lymphocyte count. This study also showed a strong interaction between co-infections of AdV and BK polyomavirus in patients undergoing hematopoietic stem cell transplantations. PMID- 20848296 TI - Complete genome sequence of PhiMH1, a Leuconostoc temperate phage. AB - Bacteriophage PhiMH1, a newly isolated temperate phage from a UV-induced lysate of Leuconostoc pseudomesenteroides, has an isometric head, a noncontractile tail, and a double-stranded DNA genome with a length of 38709 bp. Bioinformatic analysis of the phage genome revealed 65 putative open reading frames (ORFs). Predicted protein products of the ORFs were determined and described. PhiMH1 can be classified as a member of the family Siphoviridae by morphology and genome structure. The phage did not show any significant similarity to other previously reported bacteriophages of Leuconostoc species. To our knowledge, this is the first report of genomic sequencing and characterization of a L. pseudomesenteroides temperate phage. PMID- 20848298 TI - The impact of presumed consent laws and institutions on deceased organ donation. AB - This article purports to advance the literature on the impact of presumed consent laws on deceased donation rates by examining the interactions between a presumed consent legal regime and other customs and institutions, using data on health expenditure, death rates caused by cerebro vascular diseases, motor vehicle accidents and homicides, legislation, legal systems, family consent, civil rights and liberties and donor registry systems, for 24 countries over a 14-year period. Countries in which presumed consent is enacted exhibit significantly higher donation rates only if family consent is routinely sought and a combined registry is maintained or neither practice is administered. Otherwise, presumed consent legislation does not have a sizeable impact on deceased donation rates. PMID- 20848297 TI - A large abdominal intercostal hernia in a patient with vascular type Ehlers Danlos syndrome: a surgical challenge. AB - A patient with vascular type Ehlers-Danlos syndrome developed a large abdominal intercostal hernia secondary to coughing. The tissue friability and associated risks for arterial ruptures and visceral perforations in these patients make hernia repair challenging. The hernia was successfully treated using a novel approach. PMID- 20848299 TI - Early or delayed radiosurgery for WHO grade II astrocytomas. AB - To evaluate the role of gamma knife stereotactic radiosurgery (SRS) in the management of newly diagnosed (early) or progressive (delayed) WHO grade II astrocytomas, the authors reviewed 25 patients who underwent SRS for pathologically proven WHO grade II astrocytomas between 1987 and 2009 at the University of Pittsburgh. The median patient age was 30 years (range 8-68 years). Sixteen patients had early SRS after stereotactic biopsy (n = 14), resection (n = 1) or radiation therapy (n = 1), and 9 underwent delayed SRS for progression after surgical resection (n = 3), radiation therapy (n = 4) or both (n = 2). The median tumor volume was 3.7 cm(3) (range 0.6-17.0 cm(3)) and the median margin dose was 14 Gy (range 11-20 Gy). At a median of 65 months of follow-up (range 6 208 months), tumor control was observed in 13 patients (52%). The progression free survival rates after SRS at 1, 5 and 10 years were 91.3, 54.1 and 37.1%, respectively. On both univariate and multivariate analysis smaller tumor volume (<6 cm(3)), higher marginal dose (>=15 Gy) and absence of contrast enhancement on imaging studies were associated with better progression free-survival. Gamma knife SRS is an additional option for patients with small volume, deep seated, non-enhancing and well-demarcated WHO grade II astrocytomas and does not preclude later conventional fractionated radiation therapy, cyst aspiration, or cautious debulking if feasible. It may also benefit patients with residual or recurrent tumors that have progressed after surgery, radiation therapy or both. PMID- 20848300 TI - Correlation of MRI sequences to assess progressive glioblastoma multiforme treated with bevacizumab. AB - In the context of bevacizumab therapy for the treatment of progressive malignant gliomas, it is currently unclear how different magnetic resonance imaging (MRI) sequences correlate with each other over time. The objective of this study was to determine if a reliable and predictable relationship over time exists between post-gadolinium based contrast agent T1-weighted (T1 + GBCA), T2-weighted, and FLAIR MRI in patients with progressive glioblastoma multiforme (GBM) receiving bevacizumab and chemotherapy. The MRI lesion volumes of 10 patients with progressive GBM that received bevacizumab plus chemotherapy were manually calculated by two independent reviewers. T2 and FLAIR volumes were analyzed by analysis of covariance (ANCOVA) as a function of T1 + GBCA lesion enhancement volume, reviewer, and time interval between MRI acquisitions. Pearson product moment correlation (r) was used to compare pre and post treatment volumes for the group of 10 patients and for each individual patient over their treatment course. ANCOVA demonstrated a significant association between T1 + GBCA and T2-weighted volumes (P = 0.0006) and between T1 + GBCA and FLAIR volumes (P < 0.0001). These associations remained constant over time. The correlation between T1 + GBCA and both T2-weighted and FLAIR volumes improved after bevacizumab treatment. Individual correlations between T1 + GBCA and FLAIR were strong (r >= 0.63) with one exception, while correlations between T1 + GBCA and T2 were more variable (r = 0.18-0.99). These findings suggest that FLAIR MRI should be evaluated in addition to T1 + GBCA MRI when evaluating GBM responses. PMID- 20848301 TI - Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors. AB - Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non-radioactive 10B is irradiated with low energy thermal neutrons to produce alpha-particles (10B[n,alpha] Li). Carboranylporphyrins are a class of substituted porphyrins containing multiple carborane clusters. Three of these compounds, designated H2TBP, H2TCP, and H2DCP, have been evaluated in the present study. The goals were two-fold. First, to determine their biodistribution following intracerebral (i.c.) administration by short term (30 min) convection enhanced delivery (CED) or sustained delivery over 24 h by AlzetTM osmotic pumps to F98 glioma bearing rats. Second, to determine the efficacy of H2TCP and H2TBP as boron delivery agents for BNCT in F98 glioma bearing rats. Tumor boron concentrations immediately after i.c. pump delivery were high and they remained so at 24 h. The corresponding normal brain concentrations were low and the blood and liver concentrations were undetectable. Based on these data, therapy studies were initiated at the Massachusetts Institute of Technology (MIT) Research Reactor (MITR) with H2TCP and H2TBP 24 h after CED or pump delivery. Mean survival times (MST) +/- standard deviations of animals that had received H2TCP or H2TBP, followed by BNCT, were of 35 +/- 4 and 44 +/- 10 days, compared to 23 +/- 3 and 27 +/- 3 days, respectively, for untreated and irradiated controls. However, since the tumor boron concentrations of the carboranylporphyrins were 3-5* higher than intravenous (i.v.) boronophenylalanine (BPA), we had expected that the MSTs would have been greater. Histopathologic examination of brains of BNCT treated rats revealed that there were large numbers of porphyrin-laden macrophages, as well as extracellular accumulations of porphyrins, indicating that the seemingly high tumor boron concentrations did not represent the true tumor cellular uptake. Nevertheless, our data are the first to show that carboranyl porphyrins can be used as delivery agents for BNCT of an experimental brain tumor. Based on these results, we now are in the process of synthesizing and evaluating carboranylporphyrins that could have enhanced cellular uptake and improved therapeutic efficacy. PMID- 20848302 TI - Amine-modified poly(vinyl alcohol)s as non-viral vectors for siRNA delivery: effects of the degree of amine substitution on physicochemical properties and knockdown efficiency. AB - PURPOSE: The objective of this study was to investigate how the degree of amine substitution of amine-modified poly(vinyl alcohol) (PVA) affects complexation of siRNA, protection of siRNA against degrading enzymes, intracellular uptake and gene silencing. METHODS: A series of DEAPA-PVA polymers with increasing amine density was synthesized by modifying the hydroxyl groups in the PVA backbone with diethylamino propylamine groups using CDI chemistry. These polymers were characterized with regard to their ability to complex and protect siRNA against RNase. Finally, their potential to mediate intracellular uptake and gene silencing in SKOV-luc cells was investigated. RESULTS: A good correlation between amine density and siRNA complexation as well as protection of siRNA against RNase was found. Consisting solely of tertiary amines, this class of polymer was able to mediate efficient gene silencing when approximately 30% of the hydroxyl groups in the PVA backbone were modified with diethylamino propylamine groups. Polymers with a lower amine density (up to 23%) were inefficient in gene silencing, while increasing the amine density to 48% led to non-specific knockdown effects. CONCLUSION: DEAPA-PVA polymers were shown to mediate efficient gene silencing and offer a promising platform for further structural modifications. PMID- 20848303 TI - Poly(epsilon-caprolactone)-block-poly(ethyl ethylene phosphate) micelles for brain-targeting drug delivery: in vitro and in vivo valuation. AB - PURPOSE: The purpose of this work was to investigate the potential of poly(epsilon-caprolactone)-block-poly(ethyl ethylene phosphate) (PCL-PEEP) micelles for brain-targeting drug delivery. METHOD: The coumarin-6-loaded PCL PEEP micelles (CMs) were prepared and characterized. The cellular uptake of CMs was evaluated on in vitro model of brain-blood barrier (BBB), and the brain biodistribution of CMs in ICR mice was investigated. RESULTS: PCL-PEEP could self assemble into 20 nm micelles in water with the critical micelle concentration (CMC) 0.51 MUg/ml and high coumarin-6 encapsulation efficiency (92.5 +/- 0.7%), and the micelles were stable in 10% FBS with less than 25% leakage of incorporated coumarin-6 during 24 h incubation at 37 degrees C. The cellular uptake of CMs by BBB model was significantly higher and more efficient than coumarin-6 solution (CS) at 50 ng/ml. Compared with CS, 2.6-fold of coumarin-6 was found in the brains of CM-treated mice, and C(max) of CMs was 4.74% of injected dose/g brain. The qualitative investigation on the brain distribution of CMs indicated that CMs were prone to accumulate in hippocampus and striatum. CONCLUSION: These results suggest that PCL-PEEP micelles could be a promising brain-targeting drug delivery system with low toxicity. PMID- 20848304 TI - Bio-inorganic synthesis of ZnO powders using recombinant His-tagged ZnO binding peptide as a promoter. AB - Inorganic-binding peptides termed as genetically engineered polypeptides for inorganics (GEPIs), are small peptide sequences selected via combinatorial biology-based protocols of phage or cell surface display technologies. Recent advances in nanotechnology and molecular biology allow the engineering of these peptides with specific affinity to inorganics, often used as molecular linkers or assemblers, to facilitate materials synthesis, which provides a new insight into the material science and engineering field. As a case study on this biomimetic application, here we report a novel biosynthetic ZnO binding protein and its application in promoting bio-inorganic materials synthesis. In brief, the gene encoding a ZnO binding peptide(ZBP) was genetically fused with His(6)-tag and GST tag using E.coli expression vector pET-28a (+) and pGEX-4T-3. The recombinant protein GST-His-ZBP was expressed, purified with Ni-NTA system, identified by SDS PAGE electrophoresis and Western blot analysis and confirmed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) analysis. Affinity adsorption test demonstrated that the fusion protein had a specific avidity for ZnO nanoparticles (NPs). Results from the bio-inorganic synthesis experiment indicated that the new protein played a promoting part in grain refinement and accelerated precipitation during the formation of the ultra-fine precursor powders in the Zn(OH)(2) sol. X-ray diffraction (XRD) analysis on the final products after calcining the precursor powders showed that hexagonal wurtzite ZnO crystals were obtained. Our work suggested a novel approach to the application about the organic-inorganic interactions. PMID- 20848305 TI - Online social networking technologies, HIV knowledge, and sexual risk and testing behaviors among homeless youth. AB - This study evaluates associations between online social networking and sexual health behaviors among homeless youth in Los Angeles. We analyzed survey data from 201 homeless youth accessing services at a Los Angeles agency. Multivariate (regression and logistic) models assessed whether use of (and topics discussed on) online social networking technologies affect HIV knowledge, sexual risk behaviors, and testing for sexually transmitted infections (STIs). One set of results suggests that using online social networks for partner seeking (compared to not using the networks for seeking partners) is associated with increased sexual risk behaviors. Supporting data suggest that (1) using online social networks to talk about safe sex is associated with an increased likelihood of having met a recent sex partner online, and (2) having online sex partners and talking to friends on online social networks about drugs and partying is associated with increased exchange sex. However, results also suggest that online social network usage is associated with increased knowledge and HIV/STI prevention among homeless youth: (1) using online social networks to talk about love and safe sex is associated with increased knowledge about HIV, (2) using the networks to talk about love is associated with decreased exchange sex, and (3) merely being a member of an online social network is associated with increased likelihood of having previously tested for STIs. Taken together, this study suggests that online social networking and the topics discussed on these networks can potentially increase and decrease sexual risk behaviors depending on how the networks are used. Developing sexual health services and interventions on online social networks could reduce sexual risk behaviors. PMID- 20848306 TI - Modeling structural, dyadic, and individual factors: the inclusion and exclusion model of HIV related behavior. AB - Changing HIV-related behaviors requires addressing the individual, dyadic, and structural influences that shape them. This supplement of AIDS & Behavior presents frameworks that integrate these three influences on behavior. Concepts from these frameworks were selected to model the processes by which structural factors affect individual HIV-related behavior. In the Inclusion/Exclusion Model, material and symbolic inclusions and exclusions (sharing versus denying resources) regulate individuals' ability and motivation to detect, prevent, and treat HIV. Structural interventions create inclusions that increase one's ability or motivation to perform these behaviors or exclusions that hinder one's ability or motivation to execute counterproductive behaviors. The need to expand research regarding multilevel influences on HIV-related behavior is also discussed, particularly concerning further understanding of sustained behavior change and effective dissemination of evidence-based intervention strategies. PMID- 20848308 TI - Freshwater shrimp (Palaemonetes australis) as a potential bioindicator of crustacean health. AB - Palaemonetes australis is a euryhaline shrimp found in southwestern Australian estuaries. To determine if P. australis is a suitable bioindicator species for monitoring the health of estuarine biota, they were exposed to measured concentrations of the polycyclic aromatic hydrocarbon, benzo[a]pyrene (B[a]P) at 0.01, 0.1, or 1 ppm for 14 days under laboratory conditions. At the end of exposure the shrimp were sacrificed for biomarker [ethoxycoumarin O-deethylase (ECOD), 8-oxo-dG concentration, and sorbitol dehydrogenase (SDH) activity] analyses. Gender did not appear to influence biomarker responses of the shrimp in this study. ECOD activity was induced in the treatment groups in a linear fashion from three (0.01 ppm) times to 12 (1 ppm) times the negative controls. 8-oxo-dG concentration was reduced three times in treatment groups below the controls suggesting impaired DNA repair pathways. There was no increase in SDH, signifying hepatopancreatic cell damage had not occurred in any treatment group. The response of P. australis to B[a]P exposure indicates that this crustacean is suitable bioindicator species for both laboratory studies and field monitoring. A combination of ECOD and SDH activities and 8-oxo-dG concentration represent a suitable suite of biomarkers for environmental monitoring of the sublethal effects of organic pollution to crustaceans from an estuarine environment. PMID- 20848309 TI - Distribution and abundance of macrobenthic polychaetes along the South Indian coast. AB - Macrobenthic polychaetes play a significant role in marine benthic food chain. A study was carried out to observe the abundance and diversity of soft bottom macrobenthic polychaetes along the South Indian coast, along with observations on sediment characteristics. The present study indicated an increase in the polychaete diversity as compared to earlier reports. Sixty-three different forms of polychaetes were identified along the coast, which constitute the bulk of the macrobenthic fauna. Thirty-eight species of polychaetes showed higher abundance along the west coast, whereas 25 species showed higher abundance along the east coast. Seabed composition showed a spatial variation in its composition along the coast. Occurrence of Prionospio pinnata and Capitella capitata the deposit feeders and indicators of organic pollution suggesting the sampled area is organically rich. Polychaete abundance was found to be higher along the west coast and was attributed to loose texture of sediment due to high sand and sandy silt resulting in higher interstitial space for organisms to harbor. Canonical correspondence analysis indicated that majority of polychaete species preferred low organic carbon, sandy silt, or sandy-clay substratum. The lower polychaete abundance at high organic carbon and high silt and clay areas can be attributed to avoidance of organisms to rich organic matter and suboxic levels, being a possible indication that these characteristics adversely affects the polychaete abundance and distribution. PMID- 20848307 TI - A trifluoromethyl analog of verbenachalcone promotes neurite outgrowth and cell proliferation of NeuroScreen-1 cells. AB - Past research has shown that natural products of plant and marine origins and their congeners enhance the actions of neuritogenic factors of the central nervous system (CNS) such as nerve growth factor (NGF). However, the role of fluorine substitutions in their structure-activity relationship (SAR) has not been explored. We have synthesized a trifluoromethyl analog of verbenachalcone (VC), a pharmacologically active natural compound previously shown to potentiate NGF activity. This analog, designated C278, enhances neurite outgrowth and proliferation of NeuroScreen-1TM (NS-1) cells, a subclone of PC12 pheochromocytoma cells. C278 increases the percentage of neurite bearing cells in the presence of suboptimal doses of NGF in comparison with controls treated with NGF alone. In addition, C278 stimulates cell growth in reduced serum and serum free cell culture conditions based on our observation of increases in cell number and metabolic assessment with MTT reduction and resazurin assays. The addition of C278 partially restored inhibition of NGF-induced neurite outgrowth by the mitogen-activated protein kinase kinase (MEK) inhibitors PD98059 and U0126. Short term sequential exposure of cells to U0126, C278, and NGF enhanced phosphorylation of extracellular signal-regulated kinase (ERK) in comparison with cells treated with only the MEK inhibitor and NGF. C278 also attenuated cell growth arrest caused by exposure to PD98059, U0126 and the phosphatidylinositol-3 kinase (PI3K) inhibitor, LY294002 but did not alter phosphorylation of Akt, a classic downstream target of PI3K during cell survival. These data suggest that C278 promotes NGF-dependent neurite outgrowth in NS-1 cells through a MEK signaling pathway by a mechanism that alters short-term activation of ERK. In contrast, C278 promotes PI3K-mediated survival independently of Akt phosphorylation. PMID- 20848310 TI - Eco-physiological performance of two invasive weed congeners (Ageratum conyzoides L. and Ageratum houstonianum Mill.) in the Indo-Gangetic plains of India. AB - Morphological (easily measureable) and physiological (hard to measure) traits of two closely related invasive alien congeners-Ageratum conyzoides L. and Ageratum houstonianum Mill. were studied with a perspective that which species will be potentially be more successful as an invader in the Indo-Gangetic plains of India. Leaf construction cost (LCC) is considered as a quantifiable measure of energy demand for biomass production and is related to energy use efficiency as it include component of both morphological and physiological traits. We hypothesised that a low LCC would give the invaders growth advantage by utilizing energy efficiently. Low LCC of A. houstonianum on mass basis (0.54 g glucose g( 1)) and area basis (20.48 g m( -2)) gives insight into the success of this invasive weed over A. conyzoides. The present study gives evidence that how the morphological traits are linked to physiological traits that could directly affect invasive attributes of the invader, which in turn would be crucial to prioritize species for ecosystem management. PMID- 20848311 TI - Carbon footprint: current methods of estimation. AB - Increasing greenhouse gaseous concentration in the atmosphere is perturbing the environment to cause grievous global warming and associated consequences. Following the rule that only measurable is manageable, mensuration of greenhouse gas intensiveness of different products, bodies, and processes is going on worldwide, expressed as their carbon footprints. The methodologies for carbon footprint calculations are still evolving and it is emerging as an important tool for greenhouse gas management. The concept of carbon footprinting has permeated and is being commercialized in all the areas of life and economy, but there is little coherence in definitions and calculations of carbon footprints among the studies. There are disagreements in the selection of gases, and the order of emissions to be covered in footprint calculations. Standards of greenhouse gas accounting are the common resources used in footprint calculations, although there is no mandatory provision of footprint verification. Carbon footprinting is intended to be a tool to guide the relevant emission cuts and verifications, its standardization at international level are therefore necessary. Present review describes the prevailing carbon footprinting methods and raises the related issues. PMID- 20848312 TI - Convenient synthesis of polyfunctional dihydrothiophenes with tandem reaction of 1,3-thiazolidinedione, aldehyde, arylamine and ethyl cyanoacetate. AB - New, highly-functionalized dihydrothiophenes are conveniently synthesized from the novel tandem, four-component reactions of 1,3-thiazolidinedione, aldehyde, arylamine, and ethyl cyanoacetate, catalyzed by triethylamine. The reaction mechanism involves the use of Knoevenagel condensation, Michael addition, and ring-opening of 1,3-thiazolidinedione, followed by intramolecular ring closure process. The reaction is diastereoselective and only trans-2,3-dihydrothiophenes were produced in moderate yields. The functionalized dihydrothiophenes can be converted efficiently to the corresponding thiophenes by DCC dehydrogenation reaction. PMID- 20848314 TI - Simulation of the interaction between muscle fiber conduction velocity and instantaneous firing rate. AB - In this study, the relationships between the early and late afterpotentials and velocity and amplitude recovery functions (VRF and ARF) in skeletal muscle were examined using model simulation. A mathematical model of the muscle fiber action potential, that incorporated a tubular slow potassium conductance, was developed and used to simulate muscle fiber action potentials at a range of interpulse intervals. The slow potassium conductance produced an afterhyperpolarization which resulted in supernormal action potential conduction velocity and amplitude for interpulse intervals>7 ms. Increasing the number of conditioning stimuli caused a further increase in conduction velocity and amplitude, and an additional phase of supernormality, with a peak at approximately 100 ms. Positive correlations between instantaneous firing rate and both conduction velocity and amplitude were also observed during simulation of repetitive stimulation of the muscle fiber. The relationships were eliminated when the slow potassium conductance channel was removed from the model. The results suggest that an afterhyperpolarization, possibly due to a slow tubular potassium conductance, could cause the VRF and ARF observed in muscle. They additionally suggest that the positive correlations between instantaneous firing rate, conduction velocity, and amplitude are directly related to the VRF and ARF. PMID- 20848315 TI - Biotransport phenomena in freezing mammalian oocytes. AB - Water transport across the cell plasma membrane and intracellular ice formation (IIF)-the two biophysical events that may cause cell injury during cryopreservation-were studied by cryomicroscopy and modeling using mammalian (Peromyscus) oocytes. Unusually high activation energy for water transport across the cell plasma membrane was identified indicating that the water transport process is unusually sensitive to temperature (and cooling rate). Although literally all studies on IIF were conducted using protocols with ice-seeding (seeding extracellular ice usually at >=-7 degrees C), it is not used for cell cryopreservation by vitrification that is becoming increasingly popular today. In this article, we show that ice-seeding has a significant impact on IIF. With ice seeding and cooling at 60 degrees C/min, IIF was observed to occur over a wide range from approximately -8 to -48 degrees C with a clear change of the ice nucleation mechanism (from surface- to volume-catalyzed nucleation) at approximately -43 degrees C. On the contrary, without ice-seeding, IIF occurred over a much narrower range from approximately -19 to -27 degrees C without a noticeable change of the nucleation mechanism. Moreover, the kinetics of IIF without ice-seeding was found to be strongly temperature (and cooling rate) dependent. These findings indicate the importance of quantifying the IIF kinetics in the absence of ice-seeding during cooling for development of optimal vitrification protocols of cell cryopreservation. PMID- 20848316 TI - Autonomy, free will and embodiment. PMID- 20848317 TI - Adeno-tonsillectomy and rapid maxillary distraction in pre-pubertal children, a pilot study. AB - INTRODUCTION: When both narrow maxilla and moderately enlarged tonsils are present in children with obstructive sleep apnea, the decision of which treatment to do first is unclear. A preliminary randomized study was done to perform a power analysis and determine the number of subjects necessary to have an appropriate response. Thirty-one children, 14 boys, diagnosed with OSA based on clinical symptoms and polysomnography (PSG) findings had presence of both narrow maxillary complex and enlarged tonsils. They were scheduled to have both adeno tonsillectomy and RME for which the order of treatment was randomized: group 1 received surgery followed by orthodontics, while group 2 received orthodontics followed by surgery. Each child was seen by an ENT, an orthodontist, and a sleep medicine specialist. The validated pediatric sleep questionnaire and PSG were done at entry and after each treatment phase at time of PSG. Statistical analyses were ANOVA repeated measures and t tests. RESULTS: The mean age of the children at entry was 6.5 +/- 0.2 years (mean +/- SEM). Overall, even if children presented improvement of both clinical symptoms and PSG findings, none of the children presented normal results after treatment 1, at the exception of one case. There was no significant difference in the amount of improvement noted independently of the first treatment approach. Thirty children underwent treatment 2, with an overall significant improvement shown for PSG findings compared to baseline and compared to treatment 1, without any group differences. CONCLUSION: This preliminary study emphasizes the need to have more than subjective clinical scales for determination of sequence of treatments. PMID- 20848319 TI - Prevalence of sleep apnea in HRH Princess Maha Chakri Srinthorn Medical Center, Thailand. AB - PURPOSE: Many studies have been conducted to find the prevalence of obstructive sleep apnea (OSA) in Western countries. Limited data have been demonstrated in Asian countries; however, no such data have been reported in Thailand. The purpose of this study was to examine the prevalence of OSA and their related factors in Thai adults. METHODS: This study was performed in a university hospital in a rural area of central Thailand and data were collected. The population included office-based workers and people who came to contact with the hospital. RESULTS: Among the total of 2,685 participants at the baseline examination, a random sample of 199 men and women was studied with employment of overnight full polysomnography to determine the prevalence of OSA and OSA syndrome (OSAS). The percentage of habitual snorers in the study population was 26.4%. The prevalence of OSA (apnea-hypopnea index 5) was 11.4%. When OSAS was defined by an apnea-hypopnea index 5 plus excessive daytime sleepiness, its prevalence was 4.4%. The prevalence of OSA and OSAS in men was 15.4% and 4.8% and in women was 6.3% and 1.9%, respectively. Logistic regression analyses showed that gender, body mass index, age, hypertension, alcohol consumption, and smoking were associated with the risk of OSA. CONCLUSION: This study demonstrates that OSA is a common problem in the Thai adult population as in Western and other Asian countries. Understanding and treatment may be essential to reduce the risk of related medical problems. PMID- 20848321 TI - A practical guide to using the World Federation for Medical Education standards. WFME 2: educational program. AB - BACKGROUND: Preparing a medical school for institutional review of all aspects of the school's programs requires an understanding of the international standards being used and adequate preparation and planning (MacCarrick et al. in Med Teach 32(5):e227, 2010; MacCarrick in Ir J Med Sci, 2010). This series examines each of the nine standards developed by the World Federation for Medical Education (WFME) (World Federation for Medical Education in Basic medical education WFME global standards for quality improvement, WFME Office, University of Copenhagen, Denmark, 2003) with practical advice on their use in both self-review and independent accreditation processes. CONCLUSION: The WFME standard 2 (Educational Program) examines in detail the program offered by the medical school, the instructional methods used to deliver the program, how the program is managed and how the program is linked with subsequent stages of the medical education continuum. Evidence of a strong nexus between the research activities of the medical school and the school's teaching mission is vital. Accrediting teams will examine carefully the school's resource allocation model and seek evidence of effective consultation by the school's central curriculum committee. PMID- 20848320 TI - Automatic cardiac ventricle segmentation in MR images: a validation study. AB - PURPOSE: Segmenting the cardiac ventricles in magnetic resonance (MR) images is required for cardiac function assessment. Numerous segmentation methods have been developed and applied to MR ventriculography. Quantitative validation of these segmentation methods with ground truth is needed prior to clinical use, but requires manual delineation of hundreds of images. We applied a well-established method to this problem and rigorously validated the results. METHODS: An automatic method based on active contours without edges was used for left and the right ventricle cavity segmentation. A large database of 1,920 MR images obtained from 59 patients who gave informed consent was evaluated. Two standard metrics were used for quantitative error measurement. RESULTS: Segmentation results are comparable to previously reported values in the literature. Since different points in the cardiac cycle and different slice levels were used in this study, a detailed error analysis is possible. Better performance was obtained at end diastole than at end systole, and on mid-ventricular slices than apical slices. Localization of segmentation errors were highlighted through a study of their spatial distribution. CONCLUSIONS: Ventricular segmentation based on region driven active contours provided satisfactory results in MRI, without the use of a priori knowledge. The study of error distribution allows identification of potential improvements in algorithm performance. PMID- 20848322 TI - Surgery for oesophageal cancer at Galway University Hospital 1993-2008. AB - BACKGROUND: Surgical volume and outcome remain controversial in the management of oesophageal cancer. AIMS: To assess the outcome of oesophagectomy for cancer at Galway University Hospital (GUH). METHODS: Between 1994 and 2008, patients who underwent oesophagectomy were analysed. RESULTS: During the study period, 126 oesophagectomies were performed for cancer. The average surgeon volume was 9 cases per year. The 30-day and overall in-hospital mortality rates were 6.3 and 7.9%, respectively. Restructuring of our critical care services has led to a reduction in 30-day mortality from 8.2 to 5.1%. The use of neoadjuvant chemoradiotherapy has increased from 17 to 35% during the study period. In patients who underwent resection, the 3 and 5-year overall survival rates were 45 and 29%, respectively. CONCLUSIONS: Operative morbidity and mortality at GUH are comparable with worldwide outcomes. Improved resources and national restructuring of cancer services have significantly improved the quality of care and outcomes of patients. PMID- 20848324 TI - Management of patent foramen ovale and stroke. AB - OPINION STATEMENT: Paradoxical embolization is a rare but well-recognized cause of stroke. Some studies have suggested a link between patent foramen ovale (PFO) and a higher risk of ischemic stroke through this mechanism. PFO is more commonly seen in patients with cryptogenic stroke, but a clear causative relationship between the two is not well established. Other anatomic features associated with a PFO could increase the risk of a recurrent stroke, including an atrial septal aneurysm (ASA), a large PFO, and spontaneous right-to-left shunt at rest. An underlying hypercoagulable state should be ruled out if a PFO is found in a patient with a stroke or transient ischemic attack who has no other identifiable source. Options for secondary prevention in these patients include antiplatelet therapy, anticoagulation, and surgical or endovascular closure. Studies have not shown any advantage of warfarin over aspirin. Surgical closure is a less favorable option because of its high perioperative risks. To date, retrospective studies show variable results of endovascular closure for prevention of stroke. Several randomized prospective studies currently under way are expected to conclusively answer this question. Until these data is available, antiplatelet therapy remains the first-line treatment and endovascular closure should be considered in selected cases. PMID- 20848323 TI - Establishing targets for hypertension control in patients with comorbidities. AB - Most current guidelines recommend tighter blood pressure (BP) control in hypertensive patients with comorbidities. These recommendations are based on epidemiologic data indicating that cardiovascular risk increases at lower BP levels in hypertensive patients with comorbidities than in those without comorbidities. Hypertension guidelines usually reflect outcomes from previous studies, but current recommendations for patients with comorbidities have preceded the evidence. We review recent studies investigating whether these new targets can be achieved, whether they are well tolerated, and whether they positively affect the outcomes. The results of the few current studies about outcomes in lower BP target groups are either negative or somewhat--but not decidedly--positive. There is a need for new trials designed to evaluate the validity of current recommendations for tighter BP control in hypertensive patients with comorbidities. Additionally, existing data from published trials could be reanalyzed to provide further clarification. PMID- 20848325 TI - Acute treatment of hypertensive intracerebral hemorrhage. AB - OPINION STATEMENT: Hypertensive intracerebral hemorrhage remains an entity in search of definitive treatment. It requires management in a specialized unit, where hypertension, hyperglycemia, seizures, and elevated intracranial pressure can be expertly managed. However, the exact target range of hypertensive therapy is uncertain. Extraventricular drainage and surgery for cerebellar hemorrhage can both be life-saving. The role of craniotomy for hematoma resection remains unclear. Surgery for deep or pontine hemorrhages has questionable value. The reduction of clot expansion acutely may lead to improved outcomes. One option to this end, the tight control of hypertension acutely, may be difficult to prove effective. Another, the use of factor VIIa, eluded validation in one trial. Efforts are under way to reduce intraventricular hemorrhage, and with it, hydrocephalus. The role of clot evacuation in the subset of individuals with lobar hemorrhage is also being studied. In all likelihood, the key to acute treatment of this condition will be early intervention, with implementation of blood pressure control, administration of clotting factors in the emergency department, or both. This treatment will be followed by transfer to a specialized unit, with appropriate interventions in selected patients. However, morbidity and mortality will remain high, pointing out the importance of prevention through management of hypertension. PMID- 20848326 TI - Treatment of tics and tourette syndrome. AB - OPINION STATEMENT: Tics come in a variety of types and frequencies; have a waxing and waning course; are exacerbated by stress, anxiety, and fatigue; and often resolve or improve in the teenage or early adult years. Tourette syndrome requires the presence of chronic, fluctuating motor and phonic tics. In addition to tics, individuals with Tourette syndrome often have a variety of comorbid conditions such as attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder, depression and anxiety, episodic outbursts, and academic difficulties. These conditions often are a greater source of difficulty than the tics themselves. All patients with tics should be evaluated to assure proper diagnosis and to identify any associated psychopathology or academic difficulty. The treatment of tics begins with education of the patient and family, including discussions about the fundamentals of tics: their characteristics, etiology, outcomes, and available treatments. Therapy should be individualized based on the extent of impairment, available support, ability to cope, and the presence of other problems. Indications for the treatment of tics include psychosocial problems (loss of self-esteem, comments from peers, excessive worries about tics, diminished participation in activities), functional difficulties, classroom disruption, and physical discomfort. A variety of behavioral approaches can be used. Recent studies have emphasized the value of comprehensive behavioral intervention for tics (CBIT). Because habit reversal is the major component of CBIT, a cooperative patient, the presence of a premonitory urge, and a committed family are essential ingredients for success. If tic-suppressing medication is required, a two-tier approach and monotherapy are recommended. First-tier medications, notably the alpha-adrenergic agonists, are recommended for individuals with milder tics, especially persons with both tics and ADHD. Second tier medications include various typical and atypical neuroleptics. Their sequence of prescription is often based on physician experience; I favor pimozide and fluphenazine. Atypical antipsychotics, such as risperidone and aripiprazole, have some advantages based on their side-effect profile and are particularly beneficial in individuals with significant co-existing behavioral issues. As will become readily apparent, however, few medications have been adequately assessed. Deep brain stimulation is an emerging therapy, but further data are required to optimize the location of electrode placement and stimulation and to determine precise indications for its implementation. Stimulant medication is effective in treating ADHD in children with tics; studies reducing concerns about its use are discussed. PMID- 20848327 TI - Newer anticonvulsant medications in pediatric neurology. AB - OPINION STATEMENT: Antiepileptic drugs (AEDs) are the mainstay of treatment for recurrent seizures. Uncontrolled seizures may cause medical, developmental, and psychological disturbances. The medical practitioner should thus strive to eliminate or minimize seizures. Treatment advances in epilepsy include 1) identification of the basic mechanisms of epilepsy and action of AEDs, 2) the introduction of new AEDs, and 3) the use of neurostimulation, including vagus nerve stimulation. Treatment with AEDs involves balancing each AED's efficacy against its side effects. In some patients, effective AEDs must be discontinued because of intolerable side effects. Although all AEDs have a proven efficacy, the choice of AEDs should be based on better efficacy for individual seizure types or epilepsy syndromes. Side effects also differ from drug to drug and must be taken into account. This article focuses on studies and expert opinion consensus to guide the choice of AEDs. PMID- 20848328 TI - Diabetes mellitus, acute hyperglycemia, and ischemic stroke. AB - OPINION STATEMENT: Acute brain ischemia is a dynamic process susceptible to multiple modulating factors, such as blood glucose level. During acute ischemic brain injury, hyperglycemia exacerbates multiple deleterious derangements. Timely and sufficient correction of hyperglycemia during acute brain ischemia may limit the brain injury and improve clinical outcomes. The clinical efficacy of such intervention remains to be proven. Although results from animal and clinical observational studies suggest that hyperglycemia during acute brain ischemia may exacerbate the brain injury, there is no evidence from randomized treatment trials that rapid correction of the hyperglycemia improves outcomes. Given the excess effort, cost, and risk involved in rapid and safe correction of hyperglycemia during acute stroke, less aggressive treatments with subcutaneous insulin seem appropriate at this time. Subcutaneous insulin protocols can maintain blood glucose levels below 200 mg/dL a majority of the time in most patients, especially if basal insulin is added. When available, an endocrinology consultant can optimize the acute treatment and help the transition to long-term care. Given the multiple reports linking admission hyperglycemia with symptomatic hemorrhagic conversion of ischemic stroke treated with thrombolytic drugs, it may be best to rapidly lower severe hyperglycemia in such patients. For example, if the admission blood glucose is approximately 300 mg/dL and the patient is a candidate for thrombolytic therapy, consider giving an intravenous bolus of regular insulin 8 units. Somewhat lower or higher insulin doses may be best for lesser or greater hyperglycemia. Such a bolus will start lowering the blood glucose in about 5 min. A temporary continuous intravenous insulin infusion may then be used in most patients to maintain the glucose closer to normal levels (eg, below 180 or 140 mg/dL). PMID- 20848329 TI - Management of stenosis of the extracranial internal carotid artery: endarterectomy versus angioplasty and stenting. AB - OPINION STATEMENT: Recent randomized clinical trial data support the safety and efficacy of carotid artery stenting and carotid endarterectomy for treatment of symptomatic and asymptomatic carotid occlusive disease. Endarterectomy is more effective in preventing stroke, but this may be countered by a higher risk of perioperative myocardial infarction. Age is an important determinant in selecting patients for either carotid endarterectomy or stenting. Patients older than 70 years achieve better outcomes with endarterectomy, and younger patients achieve better outcomes with stenting. Comparative clinical and anatomic durability of endarterectomy and stenting will require additional follow-up from recently completed trials. The efficacy of carotid revascularization compared with modern medical therapy in asymptomatic patients remains an important and unanswered clinical question. PMID- 20848330 TI - Pharmacologic treatment of behavioral symptoms associated with autism and other pervasive developmental disorders. AB - OPINION STATEMENT: Pervasive developmental disorders (PDDs), including autistic disorder (autism), Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD NOS), are neurodevelopmental disorders of childhood onset. These disorders persist throughout the lifespan of affected individuals and are characterized by impaired social behavior and communication, along with repetitive, stereotypic behaviors. Early diagnosis and subsequent behavioral therapy have been shown to improve outcomes for these individuals. Risperidone and aripiprazole have been approved by the United States Food and Drug Administration (FDA) for treatment of irritability associated with autism in children and adolescents. Despite their efficacy, use of these medications is limited by their side effects. In individuals with severe irritability, the first line treatment is often risperidone. Because of its relatively lower risk of weight gain and metabolic side effects, aripiprazole may be used initially if there is a personal or family history of obesity or diabetes. Monitoring of body mass index and metabolic profiles is indicated with both medications. Stereotypic behaviors associated with autism, though clearly driven by neurobiologic processes, can also be understood as coping mechanisms used to decrease anxiety. From this perspective, therapies targeting reduction of these symptoms may be contraindicated. However, when these symptoms are severe and interfering, pharmacotherapy may be necessary. Serotonin reuptake inhibitors are of limited efficacy in children and adolescents, but risperidone and aripiprazole have been shown to reduce these symptoms. There remains a need for further safety and efficacy research in this area. Hyperactivity and inattention are currently treated with a variety of medications, including guanfacine, which has a relatively benign side effect profile. Stimulant medications are generally avoided as first-line treatment for hyperactivity because of concerns about increased irritability. Currently, social impairment is best addressed through behavioral therapy and social skills training. Novel pharmacotherapies to improve social impairment are in the early stages of research. PMID- 20848331 TI - Antiplatelet therapy for prevention of recurrent stroke. AB - OPINION STATEMENT: Stroke is a common public health problem. About 25% of strokes are recurrent ones. Stroke subtype should be defined to determine the best evidence-based antithrombotic treatment option for preventing recurrent stroke. When choosing an antiplatelet agent for this purpose, clinicians should take into account cost, side effect profile, medical comorbidity, and patient preference.To prevent recurrent stroke, aspirin alone (50-325 mg/d), a combination of aspirin (25 mg) plus extended-release dipyridamole (200 mg), given twice daily, or clopidogrel (75 mg/d) may be used as initial treatment. Aspirin is an efficacious, relatively safe, widely available, inexpensive, and easy-to-use antiplatelet agent. Current evidence suggests that administration of low-dose aspirin (< 325 mg/d or < 100 mg/d in various studies) is at least as efficacious as higher-dose aspirin (eg, > 325 mg/d) but is safer. The combination of aspirin plus extended-release dipyridamole is more efficacious than low-dose aspirin alone (eg, 50 or 75 mg/d) in preventing recurrent stroke.Clopidogrel (75 mg/d) may be more efficacious than aspirin alone (325 mg/d) for prevention of recurrent stroke. Clopidogrel is a prodrug that must be converted in the liver to its active metabolite by cytochrome P450 enzymes. Certain polymorphisms (eg, CYP2C19) may prevent this conversion and lead to failure of clopidogrel to prevent major cardiovascular events.In patients with well-controlled or treated cardiovascular risk factors, aspirin plus extended-release dipyridamole and clopidogrel may provide similar results in preventing recurrent stroke, but aspirin plus extended release dipyridamole may be associated with a slightly higher risk of major hemorrhage. Careful control of vascular risk factors is an important strategy for prevention of recurrent stroke, and blood pressure control reduces the risk of both brain hemorrhage and infarction.Prasugrel, a new thienopyridine derivative, more quickly and consistently inhibits platelets than clopidogrel. In stroke patients, prasugrel may be associated with a higher risk of brain hemorrhage, so it may not be indicated when there is a history of cerebrovascular disease. PMID- 20848332 TI - Treatment news bulletin. PMID- 20848334 TI - Treatment news bulletin. PMID- 20848333 TI - Treatment news bulletin. PMID- 20848336 TI - Treatment news bulletin. PMID- 20848335 TI - Treatment news bulletin. PMID- 20848337 TI - Treatment news bulletin. PMID- 20848338 TI - Treatment news bulletin. PMID- 20848339 TI - Treatment news bulletin. PMID- 20848340 TI - Treatment news bulletin. PMID- 20848341 TI - Treatment news bulletin. PMID- 20848342 TI - Treatment news bulletin. PMID- 20848343 TI - Hereditary sideroblastic anemia: pathophysiology and gene mutations. AB - Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron accumulation in perinuclear mitochondria due to impaired iron utilization. There are two forms of sideroblastic anemia, i.e., inherited and acquired sideroblastic anemia. Inherited sideroblastic anemia is a rare and heterogeneous disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or Fe-S cluster transport, and mitochondrial metabolism. The most common inherited sideroblastic anemia is X linked sideroblastic anemia (XLSA) caused by mutations of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2), which is the first enzyme of heme biosynthesis in erythroid cells. Sideroblastic anemia due to SLC25A38 gene mutations, which is a mitochondrial transporter, is the next most common inherited sideroblastic anemia. Other forms of inherited sideroblastic anemia are very rare, and accompanied by impaired function of organs other than hematopoietic tissue, such as the nervous system, muscle, or exocrine glands due to impaired mitochondrial metabolism. Moreover, there are still significant numbers of cases with genetically undefined inherited sideroblastic anemia. Molecular analysis of these cases will contribute not only to the development of effective treatment, but also to the understanding of mitochondrial iron metabolism. PMID- 20848344 TI - Extracorporeal membrane oxygenation induced cardiac dysfunction in newborn lambs. AB - Extracorporeal membrane oxygenation (ECMO) is routinely used to support cardiopulmonary failure in infants and children. Suboptimal outcomes for primary cardiac support suggest a need for investigation of the impact of ECMO on the heart. Twenty-four newborn lambs received a brief period of ECMO support to investigate the hypothesis that ECMO produces cardiac dysfunction in newborn lamb. Dorset newborn lambs, 4-7 days of age, were exposed to ECMO for 5 min at a 100 ml/kg flow rate and quickly weaned off. Measurements included echocardiographic mean left ventricular (LV) velocity of circumferential fiber shortening corrected for heart rate (mVCFc), LV shortening fraction, and peak systolic wall stress plus hemodynamic measurement of LV maximum rate of pressure change with time (LV dp/dt max), maximum rate of pressure change divided by developed pressure (LV dp/dtP), right atrial pressure, pulmonary capillary wedge pressure, mean pulmonary artery pressure, LV peak and end-diastolic pressure, and aortic pressure. These measures were also obtained after an exposure to 5 min of ECMO and immediate disconnect for 5 min, followed by ECMO administration for 1 h again, followed by discontinuation of ECMO. LV mVCFc is decreased after exposure to 5 min of ECMO support despite a decrease in LV peak systolic wall stress that provides afterload reduction. LV mVCFc is inversely related to peak systolic wall stress at a significance level of p < 0.0001. The time period after initiation of ECMO is a significant factor in the model (p = 0.0097). Time [baseline] was different from the other time points with p = 0.0010. Average mVCFc at baseline is 1.27 +/- 0.35 and decreases to 1.01 +/- 0.42 after 5 min of ECMO that is then withdrawn. Peak systolic wall stress decreases from 36.0 +/- 13.1 at baseline to 29.8 +/- 12.1 after 5 min of ECMO. LV dp/dt max decreases from 1,769 +/- 453 mmHg/s at baseline to 1,311 +/- 513 mmHg/s after exposure to 5 min of ECMO (p = 0.0005). Baseline LV dp/dt max is different from each point after start of ECMO. Diastolic LVdp/dt min increased from -1,340 +/- 477 mmHg/s to -908 +/- 393 mmHg/s at 5 min. Echocardiographic mVCFc, when considered in isolation or as a function of LV peak systolic wall stress, shows diminished LV function after ECMO. Hemodynamic measurement of LV dp/dt max and LV dp/dt min confirms the observation. Separation of the humoral from mechanical effect of ECMO with the short exposure to the extracorporeal circuit shows that an immediate decrement of LV function occurs at initiation of ECMO, a finding that has not been stressed with previous studies of extracorporeal support. This implies a potentially outcome-limiting deleterious effect for the patient who requires ECMO support for the heart rather than the lungs. We should continue to strive to understand and ameliorate this deleterious effect of the extracorporeal circulation circuit. PMID- 20848345 TI - Hypothalamic SOCS-3 expression and the effect of intracerebroventricular angiotensin II injection on water intake and renal sodium handling in SHR. AB - In rats, the acute central dipsogenic and natriuretic action of angiotensin II (AngII) seems to be independent of the hemodynamic effects of the peptide; however, in genetically hypertensive models, this relationship has not yet been investigated. It has been demonstrated that AngII induces the suppressor of cytokine signaling (SOCS-3) expression in the brain that, in turn, modulates further activation of the pathway, leading to desensitization to AngII stimuli with regard to its dipsogenic effect. This study investigates age-related Janus kinase (JAK-2) and SOCS-3 hypothalamic expression, by immunoblotting, and the involvement of SOCS-3 expression in urinary sodium handling and dipsogenic response in spontaneously hypertensive rats (SHR), compared with age-matched Wistar-Kyoto (WKy) rats. The intracerebroventricular (i.c.v.) application of AngII significantly enhanced the dipsogenic response, reduced C(Cr), and reciprocally promoted increased absolute and fractional rates of excretion of sodium in WKy rats. The central AngII-induced dipsogenic effect in WKy and SHR was significantly attenuated by prior i.c.v. administration of DUP753. In addition, the magnitude of the dipsogenic and renal response to AngII was significantly attenuated in age-matched SHR. Blocking of hypothalamic SOCS-3 expression by an antisense oligonucleotide resulted in partial reversal of the refractory nature of AngII in thirst responses in SHR. The altered centrally applied AngII response in SHR associated with increased hypothalamic JAK-2/SOCS-3 expression may suggest that abnormal regulation of the central angiotensin pathways may contribute to dysfunction of water-electrolyte homeostasis in SHR. PMID- 20848347 TI - Current status of percutaneous valvular procedures. AB - OPINION STATEMENT: During the past few decades, percutaneous valvular procedures have been used in mitral and aortic stenosis. Percutaneous mitral commissurotomy, which has virtually replaced surgical commissurotomy in the treatment of mitral stenosis, has been performed since the mid-1980s and has provided good results in thousands of patients worldwide. Percutaneous balloon aortic valvuloplasty has largely been abandoned due to its limited efficacy and the risks involved. New percutaneous procedures are currently being developed in mitral regurgitation and aortic stenosis, which represent the two most frequent valve diseases in industrialized countries. They are in the early stages of development but have opened a very exciting field of investigation. Two percutaneous mitral valve treatment techniques have been used: the edge-to-edge technique and the prosthetic ring annuloplasty. Preliminary series show that they are feasible; however, they need to be further evaluated in comparison with contemporary treatment to accurately assess their effectiveness and the risks involved. Since 2003, percutaneous aortic valve replacement has been performed in approximately 100 compassionate cases with end-stage aortic stenosis, formally declined for surgery. It results in hemodynamic and clinical improvement, with an acceptable risk in this highly selected population. The evaluation of these new percutaneous procedures requires a close collaboration between interventionalists, echocardiographers, engineers, and surgeons. It is probable that they will play an important role in the treatment of valve disease in the future. PMID- 20848346 TI - Identification of sources of environmental lead in South Africa from surface soil geochemical maps. AB - The bioavailability of lead in soil is of considerable importance to human and animal health. Although selective extraction has been explored as a more appropriate technique than total heavy metal analysis in environmental pollution assessments, such studies remain scarce globally and are almost non-existent in developing countries. Results for a large-scale study of extractable lead levels in undisturbed soil samples in South Africa identify several geographic areas of concern. Lead levels are considerably elevated relative to background levels in the Johannesburg urban and industrial area. Areas of active lead mining also exhibit higher surface soil values. Interestingly, areas of active and intensive coal mining activity display relatively low soil Pb values, possibly attributable to the relatively low heavy metal content of South African coal. In all instances, distribution of cadmium, a carcinogenic element, correlates with that of lead. The results demonstrate the usefulness of the quick and easy Mehlich-3 single extractant technique, an established technique in micronutrient studies, to simultaneously provide valuable environmental data for toxic metals such as Pb and Cd. PMID- 20848348 TI - Treatment news bulletin. PMID- 20848349 TI - Treatment news bulletin. PMID- 20848350 TI - Treatment news bulletin. PMID- 20848351 TI - Cardiomyopathy in children. AB - OPINION STATEMENT: | Cardiomyopathy in children is a rare but serious disease leading to heart failure with a high mortality rate. Dilated cardiomyopathy (DCM) and hypertrophic cardio-myopathy (HCM) are more common than restrictive cardiomyopathy (RCM). Arrhythmogenic right ventricular dysplasia (ARVD) is extremely rare in pediatric age groups. Treatment should be targeted at the cause of the cardiomyopathy, if identified. Nutritional deficiencies, metabolic disorders, and inborn errors of metabolism should be corrected if possible. Immunosuppressive therapy may be considered in patients with lymphocytic myocarditis. Maximal medical therapy with inotropic drugs or cardiac glycosides, diuretic drugs, and angiotensin-converting enzyme inhibitors improve heart failure symptoms in patients with DCM. Beta-blocker therapy in adults with DCM is well established and is being evaluated in children with DCM. High-dosage beta blocker or calcium channel blocker therapy improves the survival rate in children with HCM. The cautious use of diuretics and angiotensin-converting enzyme inhibitors in patients with RCM improves symptoms. Anticoagulation to prevent thromboembolism in patients with DCM and RCM is indicated. Antiarrhythmia therapy is needed in patients with DCM- or HCM-associated dysrhythmia. Cardiac transplant is indicated in patients with progressive deterioration. PMID- 20848352 TI - Treatment news bulletin. PMID- 20848354 TI - Treatment news bulletin. PMID- 20848353 TI - Treatment news bulletin. PMID- 20848355 TI - Treatment news bulletin. PMID- 20848357 TI - Treatment news bulletin. PMID- 20848356 TI - Vitamin E: cautionary issues. AB - CONCLUSION: Compared with many medications used in the patient with cardiovascular disease, vitamin E is a relatively safe supplement. There are a few populations in which caution needs to be employed, however. Patients receiving warfarin therapy should be discouraged from using vitamin E supplements and should be closely monitored if they do. Smokers should avoid vitamin E due to potential negative effects on vitamin C, and vitamin E should never be administered in conjunction with beta-carotene in this population. The rare patient requiring vitamin A therapy or having retinitis pigmentosa should also avoid vitamin E supplementation. Because of the increased risk of bleeding, vitamin E should be discontinued in the perioperative period in any patient requiring surgery. PMID- 20848358 TI - Treatment news bulletin. PMID- 20848359 TI - Treatment news bulletin. PMID- 20848360 TI - Treatment news bulletin. PMID- 20848361 TI - Treatment news bulletin. PMID- 20848362 TI - NF-kappaB and innate immunity. AB - Members of the NF-kappaB transcription factor family play a critical role in the development of innate immunity. Upon recognition of pathogen infections or tissue damage, the NF-kappaB pathway is strongly activated by cellular pattern recognition receptors, including Toll-like receptors and multiple cytosolic receptors such as RIG-I-like helicases and NOD family proteins. NF-kappaB is required not only for the expression, but also for subsequent signal transduction of numerous downstream cytokines. NF-kappaB-responsive genes affect a diverse array of cellular processes including apoptosis and cell survival, and often directly control the course of a pathogen infection. In this review, we will examine signaling pathways leading to NF-kappaB activation during the innate immune response and mechanisms of pathogen-modulation of these pathways; the specifics of NF-kappaB-dependent gene programs, and the physiological consequences for the immune system caused by the absence of individual NF-kappaB subunits. PMID- 20848363 TI - Amputee Virtual Environment Support Space--a vision for virtual military amputee support. PMID- 20848364 TI - Prevalence and degree of hearing loss among males in Beaver Dam cohort: comparison of veterans and nonveterans. AB - The Epidemiology of Hearing Loss Study (EHLS) conducted in Beaver Dam, Wisconsin, was a population-based study that focused on the prevalence of hearing loss among 3,753 participants between 1993 and 1995. This article reports the results of several auditory measures from 999 veteran and 590 nonveteran males 48 to 92 years of age included in the EHLS. The auditory measures included pure tone thresholds, tympanometry and acoustic reflexes, word recognition in quiet and in competing message, and the Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) version. Hearing loss in the auditory domains of pure tone thresholds, word recognition in quiet, and word recognition in competing message increased with age but were not significantly different for the veterans and nonveterans. No significant differences were found between participant groups on the HHIE-S; however, regarding hearing aid usage, mixed differences were found. PMID- 20848365 TI - Self-reported cognitive symptoms following mild traumatic brain injury are poorly associated with neuropsychological performance in OIF/OEF veterans. AB - Mild traumatic brain injury (mTBI) is not uncommon among Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) veterans, and many individuals within this group report lingering cognitive difficulties following their injury. For Department of Veterans Affairs clinicians, an accurate assessment of cognitive symptoms is important in providing appropriate clinical care. Although self-assessment is commonly employed to screen for difficulties in cognitive functioning, little is known about the accuracy of self-report in this population. This study collected cognitive, psychiatric, and self-report data from 105 OIF/OEF veterans with mTBI to examine the relationship between self reported cognitive functioning and objective neuropsychological test performance. Additionally, clinicians who frequently work with OIF/OEF veterans were asked to predict the magnitude of these associations. Self-reported cognitive functioning was not significantly correlated with objective cognitive abilities, suggesting that objective neuropsychological testing should be used when cognitive weakness is suspected. Perceived cognitive deficits were associated with depression, anxiety, and posttraumatic stress disorder, illustrating the additional importance of adequate assessment and treatment of psychiatric symptoms. Clinicians tended to overestimate the association between self-report and test performance. PMID- 20848366 TI - Effect of bracing on dynamic patellofemoral contact mechanics. AB - Decreases in patellofemoral pain have been demonstrated with bracing; however, the mechanisms of pain reduction remain unclear. Our purpose was to evaluate the hypothesis that patellofemoral bracing decreases peak pressure on the retropatellar surface through an increase in patellofemoral contact area. Nine cadaveric knees were tested during simulated free-speed walking with no brace, a knee sleeve, two different patellar stabilization sleeves, and a wrap-style patellar stabilization brace. Contact area and pressure were measured using a dynamic pressure sensor located in the patellofemoral joint. For the unbraced knee, contact area and peak pressure varied with knee flexion angle, ranging from 0.30 +/- 0.3 cm(2) and 1.80 +/- 1.7 MPa at full extension to 2.28 +/- 0.5 cm(2) and 4.19 +/- 1.7 MPa at peak knee flexion. All braces increased contact area, while the wrap-style brace decreased peak pressure (p < 0.001). Sleeve braces compress the quadriceps tendon causing the patella to engage the trochlear groove earlier during knee flexion. The wrap-style brace reduced peak pressure by shifting the location of highest pressure to a region with increased articular cartilage thickness. Sleeve braces may be useful for treatment of patellar subluxation disorders, while wrap-style braces may be effective for treatment of disorders associated with degenerative cartilage changes. PMID- 20848367 TI - Effects of prosthetic foot forefoot flexibility on oxygen cost and subjective preference rankings of unilateral transtibial prosthesis users. AB - The investigators conducted a double-blind randomized crossover study to determine the effects of prosthetic foot forefoot flexibility on oxygen cost and subjective preference rankings of 13 unilateral transtibial prosthesis users. Five experimental feet were fabricated for use in the study: F1, F2, F3, F4, and F5. F1 was most flexible, F5 was least flexible, and F3 was designed to conform to a biomimetic ankle-foot roll-over shape. The experimental feet were modeled after the Shape&Roll prosthetic foot (originally produced by Northwestern University, Chicago, Illinois; now in public domain) but had different numbers of saw cuts within the forefoot members, allowing more or less flexibility during walking. Participants walked at the same comfortable, freely selected speed on the treadmill for 7 min with each foot while energy expenditure was measured. No significant difference was found in oxygen cost (mL O(2)/kg/m) between the different feet (p = 0.17), and the order of use was also not significant (p = 0.94). However, the preference ranking was significantly affected by the flexibility of the feet (p = 0.002), with the most flexible foot (F1) ranking significantly poorer than feet F3 (p = 0.003) and F4 (p = 0.004). Users may prefer prosthetic feet that match the flexibility of an intact ankle-foot system, even though we did not detect an energetic benefit at freely selected speeds. PMID- 20848368 TI - Prevalence, predictors, and outcomes of poststroke falls in acute hospital setting. AB - Falls are a serious medical complication following stroke. The objectives of this study were to (1) confirm the prevalence of falls among patients with stroke during acute hospitalization, (2) identify factors associated with falls during the acute stay, and (3) examine whether in-hospital falls were associated with loss of function after stroke (new dependence at discharge). We completed a secondary analysis of data from a retrospective cohort study of patients with ischemic stroke who were hospitalized at one of four hospitals. We used logistic regression to identify factors associated with inpatient falls and examine the association between falls and loss of function. Among 1,269 patients with stroke, 65 (5%) fell during the acute hospitalization period. We found two characteristics independently associated with falls: greater stroke severity (National Institutes of Health Stroke Scale [NIHSS] >=8, adjusted odds ratio [OR] = 3.63, 95% confidence interval [CI]: 1.46-9.00) and history of anxiety (adjusted OR = 4.90, 95% CI: 1.70-13.90). Falls were independently associated with a loss of function (adjusted OR = 9.85, 95% CI: 1.22-79.75) even after adjusting for age, stroke severity, gait abnormalities, and past stroke. Stroke severity (NIHSS >8) may be clinically useful during the acute inpatient setting in identifying those at greatest risk of falling. Given the association between falls and poor patient outcomes, rehabilitation interventions should be implemented to prevent falls poststroke. PMID- 20848369 TI - Responsiveness and validity of three dexterous function measures in stroke rehabilitation. AB - In this study, we compared the responsiveness and validity of the Box and Block Test (BBT), the Nine-Hole Peg Test (NHPT), and the Action Research Arm Test (ARAT). We randomized 59 patients with stroke into one of three rehabilitation treatments for 3 weeks. We administered six outcome measures (BBT, NHPT, ARAT, Fugl-Meyer Assessment [FMA], Motor Activity Log [MAL], and Stroke Impact Scale [SIS] hand function domain) pretreatment and posttreatment. We used the standardized response mean (SRM) to examine responsiveness and the Spearman rank correlation coefficient (rho) to examine concurrent validity. The BBT, NHPT, and ARAT were moderately responsive to change and not significantly different (SRM = 0.64-0.79). The correlations within the BBT, NHPT, and ARAT were moderate to good at pretreatment (rho = -0.55 to -0.80) and posttreatment (rho = -0.57 to -0.71). The BBT and ARAT showed fair to moderate correlations with the FMA, MAL, and SIS hand function domain at pretreatment and posttreatment (rho = 0.31-0.59), whereas the NHPT demonstrated low to fair correlations with the FMA and MAL (rho = -0.16 to -0.33) and moderate correlations with the SIS hand function domain (rho = 0.58 to -0.66). Our results indicate that the BBT, NHPT, and ARAT are suitable to detect changes over time. While simultaneously considering the responsiveness and validity attributes, the BBT and ARAT can be considered more appropriate for evaluating dexterous function than the NHPT. Further studies with larger samples are needed to validate these findings. PMID- 20848370 TI - At-home training with closed-loop augmented-reality cueing device for improving gait in patients with Parkinson disease. AB - Shuffling and freezing while walking can impair function in patients with Parkinson disease (PD). Open-loop devices that provide fixed-velocity visual or auditory cues can improve gait but may be unreliable or exacerbate freezing of gait in some patients. We examined the efficacy of a closed-loop, accelerometer driven, wearable, visual-auditory cueing device in 13 patients with PD with off state gait impairment at baseline and after 2 weeks of twice daily (30 minute duration) at-home use. We measured gait velocity, stride length, and cadence using a validated electronic gait-analysis system. Subjects underwent standard motor assessment and completed a self-administered Freezing of Gait Questionnaire (FOGQ) (range 0-24; lower is better). After training, device use enhanced walking velocity (61.6 +/- 20.1 cm/s to 72.6 +/- 26.5 cm/s, p = 0.006) and stride length (74.3 +/- 16.4 cm to 84.0 +/- 18.5 cm, p = 0.004). Upon device removal, walking velocity (64.5 +/- 21.4 cm/s to 75.4 +/- 21.5 cm/s, p < 0.001) and stride length (79.0 +/- 20.3 cm to 88.8 +/- 17.7 cm, p = 0.003) exhibited a greater magnitude of change, suggesting immediate residual benefits. Also upon device removal, nearly 70 percent of subjects improved by at least 20 percent in either walking velocity, stride length, or both. An overall improvement in gait was measured by the FOGQ (14.2 +/-1.9 to 12.4 +/- 2.5, p = 0.02). Although issues related to compliance and response variability render a definitive interpretation of study outcome difficult, devices using closed-loop sensory feedback appear to be effective and desirable nonpharmacologic interventions to improve walking in selected individuals with PD. PMID- 20848371 TI - Using geographic information system tools to improve access to MS specialty care in Veterans Health Administration. AB - Access to appropriate and timely healthcare is critical to the overall health and well-being of patients with chronic diseases. In this study, we used geographic information system (GIS) tools to map Veterans Health Administration (VHA) patients with multiple sclerosis (MS) and their access to MS specialty care. We created six travel-time bands around VHA facilities with MS specialty care and calculated the number of VHA patients with MS who resided in each time band and the number of patients who lived more than 2 hours from the nearest specialty clinic in fiscal year 2007. We demonstrate the utility of using GIS tools in decision-making by providing three examples of how patients' access to care is affected when additional specialty clinics are added. The mapping technique used in this study provides a powerful and valuable tool for policy and planning personnel who are evaluating how to address underserved populations and areas within the VHA healthcare system. PMID- 20848372 TI - Transient hepatic nodular lesions associated with patent ductus venosus in preterm infants. AB - We report on two cases of low-birth-weight preterm infants with patent ductus venosus associated with hepatic hypoechoic lesions of the fourth segment in an otherwise normal liver. Although tumorlike hepatic lesions have been previously reported in association with portosystemic shunts in children and adults, they were never described in preterm infants during physiological patency of ductus venosus. In our patients, hepatic lesions disappeared shortly after the spontaneous ductus closure. Physiopathologic interactions are discussed regarding altered portal blood supply caused by ductus venosus shunt. PMID- 20848373 TI - [Tensometry - development of a measurement technique of the tube function in a temporal bone model]. AB - OBJECTIVE: Middle ear pressure depends widely on the function of the eustachian tube. Tube dysfunction is often a trigger for middle ear diseases like chronic otitis media but also for barotrauma. Patients with impaired tubal function should not be exposed to situations with extreme pressure changes. Until today, there is no valid examining method for long-time measuring of the development of middle ear pressure. MATERIAL AND METHODS: The basic idea was to develop a thin flexible film with integrated strain gauges made of platinum and gold, which can be applied directly on the surface of the tympanic membrane. Using these, shifts or distensions of the tympanic membrane in a temporal bone model can be measured and documented. RESULTS: We were able to show that the measuring system was sensitive enough to register pressure variations in the middle ear volume of a temporal bone model. While using a full bridge design of the strain gauge resistors it could be shown that the measuring voltage of the strain gauges were in phase of the pressure measurement curve or according to the positioning in opposite phase. In single resistor mode the measurement were not so positioning depended. Measuring tympanic membrane movement in case of perforation was feasible. CONCLUSIONS: To improve the longtime stability of the strain gauge film the next development step will be to make a new design with Konstantan resistors (CU-Ni-Mn). After a testing period, longtime measurements in clinical studies will follow. PMID- 20848374 TI - [RCT on discharge planning for high utilisers of mental health care: conduct and quality of the intervention]. AB - OBJECTIVE: To evaluate feasibility of a structured discharge planning intervention for high utilisers of mental health care developed in a multicentre RCT. METHODS: Data of N = 241 participants (discharge and 3-month follow-up) allocated to the intervention group are analysed with regard to the intervention's quality of implementation, acceptance, and changes in needs. RESULTS: The intervention was well accepted among patients and staff. However, a subgroup of participants showed manual violations. Total and unmet needs could be reduced between baseline and follow-up. Amount and change of needs substantially varied by centre and there was a trend towards variation by dose. CONCLUSIONS: The intervention was feasible. Further analyses are needed to explore differential efficacy. PMID- 20848375 TI - [Psychiatric expert opinions on asylum seekers in Germany]. AB - OBJECTIVE: To investigate the frequency of traumatisation, suicidality and given diagnoses in expert opinions on asylum seekers and to describe the sociodemographic characteristics of this population. METHODS: The psychiatric expert opinions on asylum seekers, furnished in an 8-year-period at Hannover Medical School, were analysed retrospectively for qualitative and quantitative characteristics. RESULTS: 62 psychiatric expert opinions on asylum seekers were included in this study. The asylum seekers originated from 18 different countries, mainly from Turkey and former Yugoslavia. Most expert opinions were given in secondary asylum procedures, i. e. after the initial asylum request had been rejected. The asylum seekers reported on traumatisation in 82.3 %. The most frequently reported forms of traumatisation were rape in female, and torture in male persons. According to ICD-10 or DSM-IV-R criteria posttraumatic stress disorder (PTSD) was the most frequent diagnosis (74.1 %) in this study. The second most common diagnoses were depressive disorders (ICD-10: F32.x in 33.9 % and ICD-10: F33.x in 25.9 %). Suicidal tendency was found in 56.5 % of the asylum seekers. CONCLUSIONS: Cultural differences, language barriers, a heavy burden by psychological symptoms, and clinical severity are difficulties in the process of psychiatric assessment of refugees in legal asylum procedures. PMID- 20848376 TI - [Comparison of "home treatment" with traditional inpatient treatment in a mental hospital in rural southern Germany]. AB - OBJECTIVE: To investigate the clinical effectiveness of "Home Treatment" (HT) in comparison to the usual inpatient treatment in patients with acute psychiatric illness. METHODS: In a prospective observational study we compared 60 of our HT patients to 18 patients receiving inpatient treatment as usual (TAU) with regard to psychopathological symptoms (PANSS, HAM-D 21), global functioning (GAF), symptom severity (HoNOS-D) and sociodemographic parameters at admission and discharge. RESULTS: HT was a feasible alternative in patients with several different psychiatric diagnoses and appeared to be similar to TAU in view of clinical effectiveness. CONCLUSIONS: In potentially suitable patients fulfilling criteria of hospital admission, the alternative of HT can be actively considered. PMID- 20848377 TI - [Preventive medical checkups and consultations in people with schizophrenia and a comparison group of similar social status]. AB - OBJECTIVE: To examine whether the utilisation of preventive medical checkups and contacts to doctors differs between people with schizophrenia and a comparison group of comparable social status in Germany. METHOD: 120 patients, each 40 from a hospital, an out-patient clinic and a residential home, were interviewed as well as 118 attendants of a social welfare office as a comparison group. RESULTS: Cancer screenings were realised less frequently than in the general population both among the patients and the controls. Contacts with doctors of somatic disciplines were more frequent among patients than among controls and the general population. CONCLUSION: The health behaviour of patients with schizophrenia was not significantly different from a comparison group with similar social status. PMID- 20848378 TI - [QTc prolongation during treatment with agomelatine]. AB - A 58 years old woman with a depression showed a QTc prolongation during treatment with agomelatine which was fully reversible after stopping administration. QTc prolongation during antidepressant treatment is not unknown especially when tricyclic antidepressants are administered. This case is the first occurrence of a QTc prolongation during treatment with agomelatine. PMID- 20848379 TI - [Lung cancer in Germany - the current state of management]. AB - BACKGROUND: The care of lung cancer patients in Germany has not been systematically evaluated yet. The aim of this article is to give an overview on the current state of lung cancer care on the basis of existing data. METHODS: In April and May 2010, a literature search was performed in order to collect relevant information concerning epidemiology as well as diagnostic, therapeutic (systemic therapy, radiotherapy, surgery, palliative therapy), and interdisciplinary structures in lung cancer treatment. RESULTS: The published database on lung cancer care in Germany is overall deficient. Treatment of lung cancer patients is mainly located in hospitals, particularly in chest clinics or specialised departments. The access of hospitals for an outpatient treatment as provided per S 116 b SGB V has not yet been realised in all German states. CONCLUSIONS: A systematic and prospective evaluation of lung cancer care is necessary in order to better allocate resources in the future. PMID- 20848380 TI - [Authorization and reimbursement of orphan drugs in an international comparison]. AB - BACKGROUND: This paper analyses schemes to promote the authorisation of and reimbursement for orphan drugs. METHODS: 8 countries - Australia, Canada, Germany, Great Britain, France, Netherlands, Switzerland, USA - were studied to compare specific regulations for orphan drugs regarding drug admission, health technology assessment (HTA), decision-making for reimbursement, and off-label and compassionate use. Information was obtained by reviewing published and grey literature. Expert interviews were also conducted. RESULTS: The comparison of orphan drug legislation reveals that the EU and the USA offer the greatest incentives for the development of orphan drugs, whereas there is a tendency for Australia and Switzerland to profit from incentives in other countries. Although not explicitly stated, economic evaluation of orphan drugs takes the special circumstances for orphan drugs into account. In addition to common reimbursement practices, special schemes or programmes for the reimbursement of high-priced orphan drugs exist in all countries that were analysed. Therefore access to orphan drugs seems to be warranted. However, due to co-payments of 5%, the USA may form an exception. CONCLUSION: On the one hand, the use of special criteria for drug admission, HTA, and reimbursement promotes R&D for orphan drugs. On the other hand, high opportunity costs arise, because huge efforts are made for a minority of patients. A solution for this moral dilemma may be the application of "rule of rescue" or of "no cure, no pay" programmes. PMID- 20848381 TI - [Excise taxes on tobacco and the problem of smuggling - concerning the credibility of the tobacco industry's "Discarded-Cigarette-Packages-Study"]. AB - The consumption of tobacco products is one of the main causes of illnesses. An often neglected but highly effective instrument for fiscal and preventive purposes is higher taxes on tobacco products. The tobacco industry however claims that higher taxes have tremendous effects on smuggling activity with additional costs with regard to law enforcement. The claim appears to be substantiated by a study which collects and documents the amounts of discarded empty cigarette packs, and which is used to estimate the fraction of illegally imported cigarettes. We show that this study makes use of systematic misspecifications and impreciseness and thus seems to pursue the aim of showing an exaggerated high amount of illegally imported cigarettes. The industry's claim that two thirds of non-taxed cigarettes in Germany are imported illegally, thus lacks any sound, well-grounded empirical corroboration. PMID- 20848382 TI - [The arduous path to better continuing education for specialists]. PMID- 20848383 TI - Diagnosis of appendicitis by a pediatric emergency medicine attending using Point of-Care Ultrasound/ a case report. AB - Over the past decade Point/of/Care Ultrasound (POC US) is increasingly performed in adult emergency medicine for a variety of indications. Pediatric emergency medicine has been much slower to embrace POC US. The authors report a case of a 15/year/old boy that presented to the pediatric emergency department with abdominal pain. A diagnosis of appendicitis was made using real/time POC US by a pediatric emergency medicine attending. Knowledge of the sonographic characteristics of appendicitis can help the physician in the prompt diagnosis of this condition, thereby reducing morbidity and mortality that may result from a delay in diagnosis. PMID- 20848384 TI - Illustrations as a patient education tool to improve recall of postoperative cataract medication regimens in the developing world. AB - PURPOSE: To assess the impact of medication frequency illustrations in patient education for use in the developing world. METHODS: This was a randomized controlled trial of a study population of patients undergoing cataract surgery in St/Louis du Nord, Haiti. Patients and accompanying family members were randomized prior to surgery to receive either standard oral post/operative instructions or oral instructions with detailed illustrations regarding the morning, noon, evening, and bedtime use of topical antibiotic and steroid drops. On postoperative day 1, patients and enrolled family members were questioned regarding when and how often the patient was to use his or her eye drops by a blinded examiner, and results were compiled. RESULTS: Of the 65 patients enrolled in the study 32 patients were randomized to the oral group, 33 were randomized to the illustration group. The morning recall was 76% in the illustration group and 50% in the oral group without illustrations (p = 0.0259). Bedtime recall was 67% in the illustration group and 38% in the oral group (p = 0.0139). There was a statistically significant improvement in recall for the illustration group with the morning and bedtime doses. There was a trend in favor of the illustration group on the afternoon and evening doses; however this was not statistically significant. CONCLUSION: Illustrations appear to be a useful adjunct in explaining complex medication regimens to patients in the developing world where cultural and language barriers can be difficult to bridge. This better understanding could translate into improved medication compliance and outcomes. PMID- 20848385 TI - Perspective on racial/ethnic birth weight. AB - OBJECTIVE: Comprehensive birth weight analyses of single primiparous infants of Samoan, Caucasian, Chinese, Filipino, Hawaiian/Part Hawaiian, Japanese racial ethnic groups. Sampling of intrauterine growth designed to reflect antecedent intra- and extra-environmental factors and insure uniform racial-ethnic data for any later genetic and phenotypic birth weight modeling. STUDY DESIGN: Based upon predetermined relevant gestational age criteria, 121, 197 single primiparous infants birth weight records analyzed. The racial-ethnic basic research paradigms also specified parental diallelic crosses representing intra-and inter-ethnic racial ancestry. Hypotheses tested: 1) the mean birth weight of single primiparous infants of Samoan parentage will be significantly larger than the mean birth weight of similar single primiparous infants of Caucasian, Chinese, Filipino, Hawaiian/Part Hawaiian, and Japanese parentage; 2) mean birth weight of single primiparous infants of only Samoan intra-parentage will be significantly larger t han the mean birth weights of single primiparous infants of only Caucasian, Chinese, Filipino, Hawaiian/Part Hawaiian, and Japanese parentage and 3) mean birth weight of single primiparous infants Samoan mothers and non-Samoan fathers will be significantly larger than single primiparous infants of Caucasian, Chinese, Filipino, Hawaiian/Part Hawaiian, and Japanese mothers and non-Caucasian, non-Chinese, non-Filipino, non-Hawaii/Part Hawaiian and non Japanese father. CONCLUSION: Two of three proposed associated hypotheses adopted: namely, that the mean birth weight of single primiparous infants of one, primary Samoan maternal parentage, and two, of only Samoan maternal and paternal parentage, will be significantly larger than their comparative counterparts. Hypotheses 3 based on Samoan mothers and non-Samoan fathers is tenable, but questionable relative to Caucasian parental background. Research highlights importance of control for potentially confounding variables and assets inherent in independent racial-ethnic cohort investigations. PMID- 20848386 TI - Preview of Hawaii Cancer Facts and Figures 2010. AB - Each year, nearly 6,700 Hawaii residents are diagnosed with cancer and more than 2,000 die from the disease. Detailed data on the burden of cancer in Hawaii, including cancer incidence and mortality rates, are available in Hawaii Cancer Facts & Figures 2010 (CF&F). A collaborative effort of the Cancer Research Center of Hawaii, the American Cancer Society and the Hawaii Department of Health, this update of the original version published in 2003 is intended as a tool for public health education, research, and planning. The following are highlights of years 2000-2006 (a 6-year period) data as featured in Hawaii Cancer Facts & Figures 2010. PMID- 20848387 TI - Collecting high-quality pancreatic tissue for experimental study from organ donors with signs of beta-cell autoimmunity. AB - BACKGROUND: The aim of this study was to create a new research strategy to obtain high-quality pancreatic tissues from subjects with preclinical or clinical type 1 diabetes, which would open up new avenues for studying the mechanisms of the beta cell damaging process in humans. RESEARCH DESIGN AND METHODS: A nationwide collaboration network (the PanFin network) was established in Finland to start an on-call screening of diabetes-associated autoantibodies from deceased organ donors and subsequent processing of pancreases from autoantibody-positive donors. This protocol was integrated into the national organ transplantation procedure. RESULTS: Only a few modifications were needed to the normal transplantation practices. One additional blood sample was obtained from donors for autoantibody analyses, the transplantation team was informed about the autoantibody result and the pancreas of autoantibody-positive donors was transported to the core laboratory. Altogether, 307 donors were screened and 22 (7.2%) were positive for at least one autoantibody and 3 tested positive for two or more autoantibodies out of the five tested (islet cell antibodies, insulin autoantibodies and autoantibodies to glutamic acid decarboxylase, islet antigen 2 and zinc transporter 8). The quality of collected pancreatic tissue was superior to that from autopsies and allowed the detection of both RNA and proteins. CONCLUSIONS: The study protocol was proven feasible to be carried out on a nationwide scale. It did not interfere with the normal transplantation activities and provided valuable tissue material for research. PMID- 20848388 TI - Formulation and evaluation of chitosan microspheres of aceclofenac for colon targeted drug delivery. AB - The objective of this investigation was to develop novel colon specific drug delivery. Aceclofenac, a NSAID, was successfully encapsulated into chitosan microspheres. Various formulations were prepared by varying the ratio of chitosan, span-85 and stirring speed and the amount of glutaraldehyde. The SEM study showed that microspheres have smooth surfaces. Microspheres were characterised by Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) to confirm the absence of chemical interactions between drug and polymer and to know the formation of microspheres structure. The microspheres were evaluated for particle size, encapsulation efficiency, drug loading capacity, mucoadhesion studies, stability studies, in vitro and in vivo drug release studies. Particle sizes, as measured by the laser light scattering technique, were of an average size in the range 41-80 um. The swelling index was in the range 0.37-0.82 and the entrapment efficiency range was 51-75% for all the formulations. The optimised batch ACM(13) released 83.6% at 8 h and 104% at 24 h in SCF containing rat caecal content. Eudragit coated chitosan microspheres prevented the release of the aceclofenac in the physiological environment of the stomach and small intestine and released 95.9+/-0.34% in the colon. With regard to release kinetics, the data were best fitted with the Higuchi model and showed zero order release with non-Fickian diffusion mechanism. The in vivo findings suggest that aceclofenac microspheres exhibit a prolonged effect of aceclofenac in rats and produce a significant anti-inflammatory effect. The findings of the present study conclusively state that chitosan microspheres are promising for colon targeting of aceclofenac to synchronise with chronobiological symptoms of rheumatoid arthritis. PMID- 20848390 TI - Analysis of nordihydroguaiaretic acid in Larrea divaricata Cav. extracts by micellar electrokinetic chromatography. AB - INTRODUCTION: Larrea divaricata Cav. is a common shrub used in folk medicine to treat a variety of diseases. The main product extracted from this bush is nordihydroguaiaretic acid (NDG), which is a potent antioxidant. OBJECTIVE: In this paper we propose a novel method for the quantification of NDG in different extracts of Larrea divaricata. The concentration of NDG in two different aqueous extracts (I and D) and an ethanolic extract (Eet) was analysed, in order to evaluate the safe use of the extracts for pharmacological purposes. METHODOLOGY: Micellar electrokinetic chromatography (MEKC) was performed under the following conditions: the background electrolyte used consisted of 20 mm phosphate buffer (pH 7.5), 10 mm sodium dodecyl sulphate and 10% acetonitrile. RESULTS: The limits of detection and quantitation of NDG were 4.54 * 10(-4) and 10.6 * 10(-4) mg/mL, respectively. The concentration of this acid in both aqueous extracts was within the safe levels. However, the decoction must be used carefully because the concentration of the acid was almost over the recommended limit. In the case of ethanolic extracts, the amount of NDG was above the safe concentration, which is in agreement with the solubility of the active compound in ethanol. CONCLUSIONS: The conclusions of this study demonstrate that most of these plant extracts should be used with care, especially those which are used with medicinal purposes. This is the first research on the quantification of NDG using MEKC in jarilla extracts. PMID- 20848389 TI - Altered electrolyte handling of the choroid plexus in rats with glycerol-induced acute renal failure. AB - The altered electrolyte handling of the choroid plexus was investigated in rats with acute renal failure (ARF) using lithium and rubidium as surrogate markers for sodium and potassium, respectively. Firstly, the transport of these two markers from the plasma to cerebrospinal fluid (CSF) was evaluated after they were concurrently injected into the femoral vein. As a result, their disposition from the plasma to CSF was shown to decrease in ARF rats, but the relationship profile between those two markers was not different from that observed in normal rats, indicating that the decreased disposition of lithium and rubidium occurs without affecting the stoichiometric balance. To clarify the mechanisms accounting for the decreased disposition, an inhibition study was then performed. When bumetanide, an inhibitor of the Na(+) /K(+) /2Cl(-) co-transporter, was directly introduced into the cerebroventricle prior to lithium and rubidium being intravenously administered, a marked increase in the markers' disposition was observed. However, such an increased disposition did not occur when bumetanide was injected into the femoral vein. Other inhibitors, such as amiloride for the Na(+) /H(+) exchanger and ouabain for Na(+) /K(+) -ATPase, did not show any effects on marker disposition regardless of the inhibitor being administered into either the cerebroventricle or femoral vein. These findings suggest that the decreased marker disposition in ARF rats is due to an increased efflux process of the choroid plexus mediated by the Na(+) /K(+) /2Cl(-) co-transporter. That is, electrolyte efflux from the CSF to plasma increases, and thereby the electrolyte influx from the plasma to CSF is counteracted. PMID- 20848391 TI - Development of capillary electrophoresis fingerprint for quality control of rhizoma Smilacis Glabrae. AB - INTRODUCTION: Rhizoma Smilacis Glabrae (RSG) is a Chinese herbal medicine used for detoxication and as a diuretic. However, in some regions of China, RSG is used confusedly with some other herbs. OBJECTIVE: To develop a capillary electrophoresis (CE)-DAD fingerprint method for quality evaluation, species differentiation and product identification of RSG. METHODOLOGY: The CE separation conditions and extraction procedure were optimised. Eighteen batches of RSG samples were analysed and the standard fingerprint used for authentication was simulated by the average of all tested samples. RESULTS: The optimal CE separation conditions were developed with running buffer of 20 mm borax containing 3 mm beta-cyclodextrin at pH 9.4, voltage of 25 kV and temperature of 25 degrees C. The separation could be completed within 8 min. Nine peaks were found in the electropherogram of RSG and five peaks were identified as astilbin, taxifolin, 5-O-caffeoylshikimic acid, shikimic acid and trans-resveratrol, respectively. Methanol and sonication were recommended for the sample preparation. All RSG samples showed similar chromatographic profile and six 'held in common' peaks were found. By the standard fingerprint, RSG could be well distinguished from its two confusable species, rhizoma Smilacis Chinae and rhizoma Heterosmilacis. CONCLUSION: A CE-DAD fingerprint analysis method was developed for the quality control of RSG. The standard fingerprint could represent the chemical profile of RSG and be used for its authentication. PMID- 20848392 TI - Comparing the composition and bioactivity of Crataegus Monogyna flowers and fruits used in folk medicine. AB - INTRODUCTION: Studying local plant foods is of particular interest as they often contain high amounts of bioactive compounds. Furthermore, their nutritional and medicinal impact must be documented and supported with scientific studies. Crataegus monogyna is an example of 'functional food' traditionally used all over South European countries. OBJECTIVE: A complete chemical and bioactive characterization of flower buds, flowers, unripe, ripened and over ripened fruits was performed. METHODOLOGY: Chemical characterization included determination of proteins, fats, ash, and carbohydrates, particularly sugars by HPLC-RI, fatty acids by GC-FID, tocopherols by HPLC-fluorescence, phenolics, flavonoids, beta carotene and ascorbic acid, by spectrophotometric techniques. Bioactivity was evaluated through screening of antioxidant properties: radical scavenging effects, reducing power, and inhibition of lipid peroxidation. RESULTS: Flowers revealed the highest tocopherols and ascorbic acid contents, as also the best n 6/n-3 fatty acids ratio. Over ripened fruits showed the highest levels of carbohydrates, sugars and SFA. Unripe fruits presented the highest PUFA contents with the best PUFA/SFA ratio, as also the highest levels of phenolics and the most promising antioxidant properties (EC50 < 20.83 ug/ml; even better than trolox). CONCLUSION: This study shows the potential of different parts of Crataegus monogyna as sources of several compounds, including nutrients and nutraceuticals. Moreover, it supports the documented nutritional and medicinal impact of this species. PMID- 20848393 TI - Contrasting perceptions of health professionals and older people in Australia: what constitutes elder abuse? AB - OBJECTIVES: To explore the perceptions of family carers, older people and health professionals in Australia about what constitutes elder abuse. METHODS: The Caregiving Scenario Questionnaire (CSQ) was disseminated to health professionals from two metropolitan hospitals, older volunteers and carers of older people with dementia recruited for other studies. RESULTS: One hundred and twenty health professionals, 361 older people and 89 carers returned the surveys. chi(2) analyses indicated that significantly more health professionals than older people identified locking someone in the house alone all day (chi(2) (2) = 10.20, p = 0.006, Cramer's V = 0.14), restraining someone in a chair (chi(2) (2) = 19.984, p = 0.0005, Cramer's V = 0.19) and hiding medication in food (chi(2) (2) = 8.72, p = 0.013, Cramer's V = 0.13) as abusive. There were no significant differences between healthy volunteer older people and carers in their perceptions of elder abuse. A significant minority (40.8%) of health professionals and over 50% of carers did not identify locking the care recipient alone in the house all day as abusive. CONCLUSION: In Australia, there is limited consensus between older people, carers and health professionals regarding what constitutes elder abuse. Health professionals were more likely to identify abusive and potentially abusive strategies correctly than carers or healthy older people, but nonetheless between one quarter and two-fifths [correction made here after initial online publication] of health professionals did not identify the abusive strategies. PMID- 20848395 TI - Analysis of fatty acids in A. szechenyianum Gay. by microwave-assisted extraction and gas chromatography-mass spectrometry. AB - INTRODUCTION: Aconitum szechenyianum Gay. is a traditional Chinese medicinal herb with the detumescent and styptic effects and antitumor activity. There have been only a few researches on its chemical components, but no detailed report has appeared on its fatty acids. OBJECTIVE: To develop a simple and effective method for the extraction of fatty acids from A. zechenyianum Gay. and then to investigate the fatty acid components. METHODOLOGY: Microwave-assisted extraction (MAE) was optimized with response surface methodology, and the fatty acid compositions of extract were determined by GC-MS with previous derivatisation to fatty acid methyl esters (FAMEs). The results were compared with that obtained by classical Soxhlet extraction (SE). RESULTS: Compared with SE, MAE showed significantly higher fatty acid yields, shorter extraction time, and lower energy and solvent consumption. The major fatty acids in A. szechenyianum Gay. are linoleic acid, palmitic acid, linolenic acid, oleic acid and stearic acid, and the unsaturated fatty acids occupy 66.4% of the total fatty acids. PMID- 20848394 TI - Metabolic profiling of Rhodiola rosea rhizomes by 1H NMR spectroscopy. AB - INTRODUCTION: Rhodiola rosea is a broadly used medicinal plant with largely unexplored natural variability in secondary metabolite levels. OBJECTIVE: The aim of this work was to develop a non-target procedure for 1H NMR spectroscopic fingerprinting of rhizome extracts for pattern recognition analysis and identification of secondary metabolites responsible for differences in sample composition. To achieve this, plants from three different geographic areas (Swiss Alps, Finland, and Altai region in Siberia) were investigated. RESULTS: A sample preparation procedure was developed in order to remove polymeric polyphenols as the 1H NMR analysis of low-molecular-weight metabolites was hampered by the presence of tannins. Principal component analysis disclosed tight clustering of samples according to population. PCA models based on the aromatic region of the spectra showed that the first two components reflected changes in the content of salidroside and rosavin, respectively, the rosavin content being negatively correlated to that of rhodiocyanoside A and minor aromatics. Score plots and non parametric variance tests demonstrated population-dependent changes according to harvest time. Data consistency was assessed using score plots and box-and-whisker graphs. In addition, a procedure for presenting loadings of PCA models based on bucketed data as high-resolution plots, which are reminiscent of real 1H NMR spectra and help to identify latent biomarkers, is presented. CONCLUSION: This study demonstrated the usefulness of the established procedure for multivariate non-target 1H NMR metabolic profiling of Rhodiola rosea. PMID- 20848396 TI - Phenolic composition and antioxidant properties of some traditionally used medicinal plants affected by the extraction time and hydrolysis. AB - INTRODUCTION: Polyphenolic phytochemicals in traditionally used medicinal plants act as powerful antioxidants, which aroused an increasing interest in their application in functional food development. OBJECTIVE: The effect of extraction time (5 and 15 min) and hydrolysis on the qualitative and quantitative content of phenolic compounds and antioxidant capacity of six traditionally used medicinal plants (Melissa officinalis L., Thymus serpyllum L., Lavandula officinalis Miller, Rubus fruticosus L., Urtica dioica L., and Olea europea L.) were investigated. METHODOLOGY: The content of total phenols, flavonoids, flavan-3-ols and tannins was determined using UV/Vis spectrophotometric methods, while individual phenolic acids, flavones and flavonols were separated and detected using HPLC analysis. Also, to obtain relevant data on the antioxidant capacity, two different assays, (2,2-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging and ferric reducing/antioxidant power (FRAP) assays were used. RESULTS: The extraction efficiency of phenolics, as well as the antioxidant capacity of plant extracts, was affected by both prolonged extraction and hydrolysis. The overall highest content of phenolic compounds was determined in hydrolyzed extract of blackberry leaves (2160 mg GAE/L), followed by the non hydrolyzed extract of lemon balm obtained after 15 min of extraction (929.33 mg GAE/L). The above extracts also exhibited the highest antioxidant capacity, while extracts of olive leaves were characterized with the lowest content of phenolic compounds, as well as the lowest antioxidant capacity. The highest content of rosmarinic acid, as the most abundant phenolic compound, was determined in non hydrolyzed extract of lemon balm, obtained after 15 min of extraction. Although the hydrolysis provided the highest content of polyphenolic compounds, longer extraction time (15 min) was more efficient to extract these bioactives than shorter extraction duration (5 min). CONCLUSION: The distribution of detected phenolic compounds showed a wide variability with regard to their botanical origin. Examined medicinal plants showed to be a valuable supplement to a daily intake of bioactive compounds. PMID- 20848397 TI - An open-safety study of dual antiviral therapy in real-world patients with chronic hepatitis C. AB - PURPOSE: Treatment of patients with chronic hepatitis C with alpha-interferon and ribavirin usually produces adverse events within the first 3 months. We aimed to assess safety and predictors of discontinuation or dose modification of these drugs. METHODS: Observational study of 312 patients with predominantly genotype 1 chronic hepatitis C treated openly along 5 years in a clinical practice setting. RESULTS: Eighty-four percent of patients experienced at least one adverse event (853 events in total, 3.3 per patient on average). Incidence rate was higher during the first 90 days and decreased thereafter (<5%). Discontinuation rates at 30 and 90 days and at end of treatment were 2, 4 and 8%, respectively. Seventy percent of discontinuation cases were due to adverse events rather than to laboratory abnormalities. Serious adverse events were rare (<1%). Dose modifications were made in 158 patients (51%) on 237 occasions. After adjusting for covariates, older age was a predictor of early discontinuation, whereas HCV genotypes 1-4 and daily ribavirin dose of 1000 mg or more were predictors of dose modification. CONCLUSIONS: The majority of real-world patients with chronic hepatitis C tolerate acceptably dual therapy and very few discontinue it. Subjective decisions on dose reduction of either compound appears to have a major impact on adherence of patients. There is a need to better define, collect and analyse clinical features which may predict adverse events and safety-related decisions during therapy of chronic hepatitis C. PMID- 20848398 TI - Inhibitors of hyaluronan export from hops prevent osteoarthritic reactions. AB - SCOPE: An early reaction in osteoarthritic chondrocytes is hyaluronan overproduction followed by proteoglycan loss and collagen degradation. We recently found that hyaluronan is exported by the ATP-binding cassette transporter multidrug resistance associated protein 5 (MRP5) in competition with cGMP and that some phosphodiesterase 5 inhibitors also inhibited hyaluronan export. These inhibitors also prevented osteoarthritic reactions in cartilage. In an effort to identify the improved inhibitors directed primarily toward MRP5, we analyzed the flavonoids. METHODS AND RESULTS: Prenylflavonoids from hop xanthohumol, isoxanthohumol and 8-prenylnaringenin inhibited MRP5 export at lower concentrations than phosphodiesterase 5 activity. They were analyzed for their effect on IL-induced osteoarthritic reactions in bovine chondrocytes. Xanthohumol was the superior compound to inhibit hyaluronan export, as well as proteoglycan and collagen loss. It also prevented the shedding of metalloproteases into the culture medium. It directly inhibited MRP5, because it reduced the export of the MRP5 substrate fluorescein immediately and did not influence the hyaluronan synthase activity. CONCLUSIONS: Xanthohumol may be a natural compound to prevent hyaluronan overproduction and subsequent reactions in osteoarthritis. PMID- 20848400 TI - Necrotizing fasciitis of the head and neck. AB - BACKGROUND: Necrotizing fasciitis of the head and neck is a rapidly progressing and life-threatening condition. The purpose of this study was to describe the patients with a focus on clinical presentation, microbiology, treatment, and prognosis. PATIENTS AND RESULTS: Seventeen patients (10 men; median age, 54 years) were included. Nine patients underwent minor head and neck surgery immediately prior to necrotizing fasciitis. The typical course was a quickly spreading erythema, pronounced tenderness, and severe pain. Imaging demonstrated diffuse swelling of the soft tissue, poorly differentiated dilated fat layers, and subcutaneous gas. All patients underwent surgical debridement within 2 days, and received broad-spectrum antibiotics and hemodynamic support, hyperbaric oxygen, and immunoglobulin. All patients survived, although 12 of 17 suffered sequelae. CONCLUSIONS: Early diagnosis is of utmost importance. Quickly spreading erythema and extreme pain in the affected area serve as red flags. With the current intensive multimodality regimen, the mortality was zero, although 70% suffered sequelae. PMID- 20848401 TI - Temoporfin-mediated photodynamic therapy in patients with advanced, incurable head and neck cancer: A multicenter study. AB - BACKGROUND: The aim of this study was to confirm the efficacy of temoporfin (Foscan)-mediated photodynamic therapy (PDT) in patients with end-stage head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-nine patients with recurring HNSCC lesions <=10 mm in depth were injected with temoporfin, followed by illumination of the tumor surface. RESULTS: Of 39 treated patients, 19 achieved complete response, 2 partial response, 5 stable disease, 5 had progressive disease, and 8 patients were nonevaluable. Thus, in the per-protocol analysis, the response rate was 68%. Of the treated patients 54% had a response. Median survival was significantly longer for responders (37 months) than for nonresponders (7.4 months). Nine patients were alive at 3.7 to 6.5 years (median, 4.8 years) post-treatment, 7 free of disease. No major toxicities were observed. CONCLUSIONS: Patients with advanced HNSCC with lesions <=10 mm in depth, who have exhausted other treatment options, can achieve significant local control and survival benefit from temoporfin-mediated PDT. PMID- 20848399 TI - Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. AB - BACKGROUND: Cumulative evidence implicates the epidermal growth factor receptor (EGFR) as an important therapeutic target in head and neck squamous cell carcinoma (HNSCC). The basis for the lack of correlation between EGFR expression in the HNSCC tumor and clinical responses to EGFR inhibitors is incompletely understood. Although a variety of mechanisms likely contribute to the effectiveness of EGFR blockade, this review focuses on the biologic implications of known EGFR variations and the role of the immune system in mediating clinical responses to EGFR inhibitors. METHODS: A Medline review of articles published in the last 10 years (1999-present) on EGFR in HNSCC was performed in combination with preliminary data from our laboratories. RESULTS: Studies published to date suggest no association between the expression of EGFR on HNSCC tumors and clinical responses to EGFR inhibitors. Several mechanisms have been proposed to mediate clinical response to EGFR inhibitors in HNSCC. Cumulative results from our laboratories support the role of several mechanisms, including cellular immune activation and mutated EGFR variants, in contributing to the discrepancy between level of EGFR expression and clinical response to EGFR inhibitors. CONCLUSION: The efficacy of EGFR targeted therapies may be mediated, at least in part, by the immune system and the presence of the truncated EGFR variant, EGFRvIII, among other factors. Criteria to identify the subset of patients likely to be responsive to EGFR targeted therapies are needed. PMID- 20848402 TI - Diminishing diagnosis of follicular thyroid carcinoma. AB - BACKGROUND: Follicular carcinomas have been reported as 10% to 15% of thyroid malignancies. Refinements in the histologic criteria applied in the classification of follicular lesions have occurred. We aim to document the true incidence of follicular cancers in a cohort from a high-volume endocrine practice. METHODS: Patient charts were reviewed and cancers were classified into major subtypes; papillary cancers were further classified by common variants. Proportions were compared to historic Surveillance, Epidemiology, and End Results (SEER) database proportions. RESULTS: Only 2.7% of patients had follicular carcinoma. The proportion of patients with follicular cancer was less than the reported rates of 10% to 15%, and less than the 6.7% extrapolated from SEER. CONCLUSION: The proportion of follicular cancers is less than traditionally reported. This change is due to an increased incidence of papillary cancers, and modifications of the histologic criteria used for classification of encapsulated follicular lesions. There are potential prognostic consequences, as follicular cancers have been perceived as more aggressive. PMID- 20848404 TI - Ultrasound-guided mechanical fragmentation of sialoliths (sonoguide forceps). AB - BACKGROUND: Little data about the efficacy and limitations of ultrasound-guided mechanical intraductal stone fragmentation and removal of sialoliths (Sonoguide Forceps) exist. METHODS: This was a chart review of patients treated within the last 4 years at 2 tertiary care centers. RESULTS: Sonoguide Forceps were used as a second-line treatment in 22 patients with sialolithiasis. Ten patients were free of stones and symptoms afterwards (7 of 17 submandibular, 2 of 4 parotid, 1 of 1 sublingual). Six patients were primarily treated for parotid sialolithiasis, 4 with successful stone retrieval. The reasons for failure were a lack of accessibility to the stone by the forceps (n = 9), the impossibility of grasping the stone (n = 5), and/or the concomitant grabbing of soft tissue together with the stone (n = 3). CONCLUSION: The efficacy of Sonoguide Forceps as both a secondary and primary treatment modality makes it an interesting, simple, and inexpensive therapeutic alternative. Relevant parameters for treatment success include the size and position of the stones. PMID- 20848403 TI - Utility of TL-201 SPECT in clarifying false-positive FDG-PET findings due to osteoradionecrosis in head and neck cancer. AB - BACKGROUND: This study aimed to determine whether Tl-201 single photon emission CT (SPECT) is potentially useful in differentiating false-positive fluorodeoxyglucose positron emission tomography (FDG-PET) findings caused by osteoradionecrosis (ORN) from recurrent head and neck cancer after radiotherapy. METHODS: Five patients were recruited. Dual-phase FDG-PET and dual-phase Tl-201 SPECT were performed for each patient. RESULTS: All 5 patients proved to have ORN without recurrent cancer. By visual interpretation, the results were 4 positive versus 1 negative for PET, and 4 negative versus 1 positive for Tl-201 SPECT. The Tl-201 SPECT clarified 3 of the 4 false-positive PETs to be ORN. Dual-phase semiquantitative studies showed decreased standardized uptake value (SUV) over time in 3 of the 4 false-positive PETs and decreased lesion/background ratio over time in the false-positive Tl-201 SPECT. CONCLUSION: The Tl-201 SPECT may help clarify suspected false-positive FDG uptake caused by ORN. Dual-phase FDG-PET and dual-phase Tl-201 SPECT may also have some value. PMID- 20848405 TI - Tracheostomaplasty: A surgical method for improving retention of an intraluminal stoma button for hands-free tracheoesophageal speech. AB - BACKGROUND: We describe a minimally invasive surgical technique, tracheostomaplasty, to overcome anatomical deformities of the stoma that preclude successful retention of a stoma button for hands free tracheoesophageal (TE) speech. METHODS: We conducted a retrospective analysis of 21 patients who underwent tracheostomaplasty after laryngectomy to accommodate an intraluminal valve attachment for hands-free TE speech. RESULTS: Sixteen men and 5 women (median age, 65 years; median follow-up, 27.7 months) underwent tracheostomaplasty; 6 patients developed a mild cellulitis that required therapy and 5 patients required a minor revision surgery. At last follow-up, 15 (71%) patients successfully achieved hands-free TE speech using an intraluminal stoma button. Three patients only retained the intraluminal device to facilitate digital occlusion. Tracheostomaplasty failed in 3 patients because of granulation tissue formation or stomal stenosis. CONCLUSIONS: Tracheostomaplasty is a successful technique to improve intraluminal retention of a stoma button for hands-free TE speech in laryngectomy patients. PMID- 20848406 TI - Expression of Cyr61 (CCN1) in human oral squamous cell carcinoma: An independent marker for poor prognosis. AB - BACKGROUND: Cysteine-rich 61 (Cyr61 [CCN1]) has disparate functions in tumorigenesis that are dependent on the cell types. The aim of the study was to investigate its role in the growth of oral squamous cell carcinoma (SCC). METHODS: The study used immunohistochemistry to examine Cyr61 expression in 93 oral SCC specimens and assessed the effect of Cyr61 overexpression on proliferation and migration of oral SCC cells in vitro and xenograft growth in severe combined immunodeficient (SCID) mice. RESULTS: High expression of Cyr61 significantly correlated with large tumor size (p = .009) and advanced tumor stage (p = .036). Multivariate analysis revealed that high Cyr61 (relative risk [RR] 2.44, 95% confidence interval [CI] 1.209-4.95, p = .010) significantly correlated with mortality. Forced expression of Cyr61 stimulated the motility and growth of Ca9-22 cells in vitro and enhanced xenograft growth in SCID mice. CONCLUSIONS: Cyr61 is a positive growth modulator of oral SCC and Cyr61 overexpression is an independent prognostic indicator for patients with oral SCC. PMID- 20848407 TI - Diagnostic accuracy of fine-needle aspiration cytology in Warthin tumors. AB - BACKGROUND: Our aim was to evaluate the diagnostic accuracy of fine-needle aspiration cytology (FNAC) for Warthin tumors of the parotid gland. METHODS: All cytologic diagnoses of Warthin tumor between 1990 and 2007 were correlated with available histology. In addition, our results were compared to current literature. RESULTS: In 310 cases, Warthin tumor was diagnosed by FNAC. In 133 cases, (43%) both cytology and histology were available. In 127 of these 133 cases (95.5%), the diagnosis Warthin tumor was confirmed by histology. In 4 cases (3%), a benign lesion was diagnosed and 2 (1.5%) revealed a malignant lesion. On review, those cytologic diagnoses were not certain. In the literature, 11 missed malignancies (5.4%) in 202 cases were reported. CONCLUSION: The diagnostic accuracy of FNAC for the diagnosis of Warthin tumor is high and the percentage of missed malignant tumors is very low. Our results imply that a cytologic diagnosis of Warthin tumor may justify conservative treatment. PMID- 20848408 TI - c-Met expression as an indicator of survival outcome in patients with oral tongue carcinoma. AB - BACKGROUND: Hepatocyte growth factor (HGF) can promote proliferation, invasion, and angiogenesis in various tumor cells. However, the prognosis according to expression of HGF/c-Met has not been reported in patients with squamous cell carcinoma of the oral tongue (SCCOT). METHODS: Tumors from 61 patients with SCCOT were evaluated for the expression of HGF and c-Met by immunohistochemistry. For Western blot, we used fresh normal and cancer tissues from 3 patients with SCCOT. RESULTS: The positive rates of HGF and c-Met immunostaining in SCCOT were 57.3% and 54.1%, respectively. The c-Met staining was significantly correlated with lymph node metastasis (p = .005), tumor classification (p = .004), and recurrence (p = .018). Survival was significantly affected in patients with positive c-Met expression (p = .003). HGF and c-Met were strongly expressed in cancer tissues on Western blot. CONCLUSION: The c-Met expression may play an important role in the progression and the survival outcome of patients with SCCOT. PMID- 20848409 TI - Feasibility of reirradiation of recurrent sinonasal carcinoma in the periorbital region using hypofractionated image-guided intensity-modulated radiation therapy. AB - BACKGROUND: Recurrent periorbital tumors pose management challenges because they are often unresectable and chemorefractory. Proximity to critical structures renders reirradiation difficult. With image-guided intensity-modulated radiation therapy (IG-IMRT), real-time corrections to patient setup are possible, enabling significant shrinkage of planning target volume margins and safe dose escalation with hypofractionation. Here, we present our experience with hypofractionated IG IMRT in a patient with multiply recurrent sinonasal carcinomas in the periorbital region. METHODS: The patient is a 67-year-old woman with sinonasal carcinoma, treated with surgery and 2 prior courses of high-dose radiotherapy. She developed a second tumor recurrence in the right lateral orbit, which was reirradiated using hypofractionated IG-IMRT (24 Gy in 3 fractions). RESULTS: Near-complete resolution of her ocular symptoms was observed at 4 months. Progress scans demonstrated a decrease in size of the orbital lesion. CONCLUSION: Preliminary results of reirradiation using hypofractionated IG-IMRT suggest that it is safe and effective. PMID- 20848410 TI - Evaluation of lymphangiogenesis in premalignant conditions of the head and neck mucosa. AB - BACKGROUND: Our aim was to determine whether lymphangiogenesis occurs in the early steps of cancerogenesis of the upper aerodigestive tract. METHODS: We assessed the number of lymphatics per unit area (lymphatic vascular density [LVD]) and the percent area occupied by the lymphatic vessels (lymphatic vascular area [LVA]) by computer-assisted morphometric analysis in 56 samples immunohistochemically stained with the lymphatic marker D2-40. The results were compared to those obtained in 63 invasive squamous cell carcinomas. RESULTS: No significant difference was observed between normal mucosa, hyperplasia/mild dysplasia, and moderate/severe dysplasia for LVD (p = .8) and LVA (p = .7). Conversely, invasive carcinomas presented a higher LVD than normal mucosa and precancerous lesions (p < .001), whereas there was no difference for LVA (p = .1). CONCLUSION: Lymphangiogenesis does not occur in premalignant lesions of the upper aerodigestive tract and it is rather a late event associated with the development of an invasive phenotype. PMID- 20848411 TI - Perceptual characteristics of tracheoesophageal speech production using the new indwelling Provox Vega voice prosthesis: a randomized controlled crossover trial. AB - BACKGROUND: The objective of this study was to determine if the design enhancements incorporated into the new Provox Vega Indwelling Voice prostheses result in any positive benefits in vivo. METHODS: Using a randomized, crossover study design, 31 participants using tracheoesophageal speech postlaryngectomy completed a 3-week trial of the Provox Vega and a comparator device. Main outcome measures included patient perceptions of vocal effort and quality using each device, and perceptual judgments of voice quality produced. RESULTS: The majority of patients (72%) indicated the Provox Vega gave them overall better voice quality and 52% felt they required less effort to phonate. Voice samples produced with the Provox Vega were also perceived by listeners to be significantly (p < .05) less strained, easier to understand, produced with less effort, and the better speech sample overall. CONCLUSION: Results support that the aerodynamic improvements incorporated in the design of the new Provox Vega facilitate enhanced voice and speech qualities. PMID- 20848412 TI - Prognostic implication of sentinel lymph node biopsy in cutaneous head and neck melanoma. AB - BACKGROUND: Current therapy for intermediate thickness melanoma involves wide local excision with sentinel lymph node biopsy (SLNB). SLNB provides important prognostic information and immediate regional lymphadenectomy for a positive sentinel lymph node (SLN) may improve survival and identifies patients who are candidates for adjuvant therapy and/or clinical trials. The head and neck site is unique because of its complex lymphatic drainage pattern to multiple nodal basins and because of the risk of site-specific morbidity associated with regional lymphadenectomy when compared to other body sites. The goal of this study is to report the results of SLNB for head and neck cutaneous melanoma in locating the sentinel node and to report on the prognostic implications of SLNB for this cohort of patients. METHODS: A prospectively entered melanoma database was used to review consecutive patients with head and neck cutaneous melanoma undergoing SLNB at Memorial Sloan-Kettering Cancer Center between 1996 and 2007. The database, along with a retrospective chart review, was used to evaluate the success of SLNB at locating an SLN and the success rate of frozen section and permanent section analysis at diagnosing metastatic disease. Recurrence at all sites including the nodal basin and status at last follow-up was recorded. Characteristics of the patients' primary melanoma were included. Descriptive statistics along with univariate and multivariate survival analysis were performed. RESULTS: Between 1996 and 2007, 234 patients with a diagnosis of head and neck cutaneous melanoma underwent SLNB and had at least 1 month of follow-up. At least 1 SLN was identified in 218 of these patients (93%) by lymphoscintigraphy. In 16 patients, no SLN was found. These patients had a much shorter time to recurrence (4.75 months) than either the SLN-positive group (10.7 months) or the SLN-negative group (26.0 months). They had a disease-specific survival (DSS) in between the SLN-positive and SLN-negative group. Of the patients in whom an SLN was identified, 28 patients (12%) had at least 1 positive SLN. Of these, the SLNs of 14 patients (50%) were identified on frozen section; 14 (50%) could only be identified after further sectioning or immunohistochemical analysis postoperatively. Among 190 patients with a negative SLNB, 12 patients had recurrences in the nodal basin. This resulted in a sensitivity of 70%, a negative predictive value of 94%, and a false-negative rate of 30%. The 3-year disease-free survival for SLN-negative and SLN-positive patients was 84% (p < .031) and 58% (p < .102), respectively. The 3-year melanoma-specific survival was 98% (p < .012) and 75% (p < .201), respectively. CONCLUSION: The SLN status is an important predictor of survival. The technique, performed in the head and neck is complex and associated with a high false-negative rate. PMID- 20848413 TI - Mastoid recurrence after radiotherapy for nasopharyngeal carcinoma: two case studies. AB - BACKGROUND: The mastoid is a rare site of nasopharyngeal carcinoma recurrence after radiotherapy, and no relevant reports are currently in the literature. METHODS: Two case reports are presented describing patients with a history of nasopharyngeal carcinoma who received primary radical radiotherapy. The first was treated by conventional radiotherapy, using 2-dimensional techniques, while the second was delivered by intensity-modulated radiation therapy (IMRT). RESULTS: The patients presented with progressive mastoid recurrence after radiotherapy at 12 and 16 months, respectively. Clinical presentation of mastoid recurrence was similar to mastoiditis. Meanwhile, distant metastasis occurred in both cases. To date, 1 has died of distant metastasis, and the other is alive with disease stabilization following chemotherapy treatment. CONCLUSION: This is the first report of mastoid recurrence after radiotherapy for nasopharyngeal carcinoma, which should alert clinicians to probe into the pathogenesis and pay attention to the relationship between mastoid recurrence and distant metastasis. PMID- 20848414 TI - SPECT/CT for sentinel lymph node mapping in head and neck melanoma. AB - BACKGROUND: The additional value of single photon emission computed tomography with CT (SPECT/CT) for detection and localization of sentinel nodes in patients with a melanoma of the head and neck was determined. METHODS: Thirty-eight patients received conventional lymphoscintigraphy followed by hybrid SPECT/CT. The number of sentinel nodes visualized and anatomic information provided were analyzed. Changes in surgical approach due to additional information from the SPECT/CT were evaluated in 20 patients. RESULTS: SPECT/CT visualized a mean of 2.6 sentinel nodes per patient (range, 1-6). SPECT/CT depicted an additional sentinel node in 16% of the patients and clearly showed the anatomic location of the hot nodes in all patients. The surgical approach was adjusted on the basis of SPECT/CT images in 11 patients (55%). CONCLUSION: SPECT/CT visualizes more sentinel nodes than conventional images and shows their anatomic location. SPECT/CT is recommended in patients with a melanoma in the head or neck. PMID- 20848415 TI - Factors affecting access to head and neck cancer care after a natural disaster: a post-Hurricane Katrina survey. AB - BACKGROUND: Our aim was to survey the factors affecting access to cancer care in patients with head and neck cancer after Hurricane Katrina. METHODS: In this cross-sectional survey, 207 patients with head and neck cancer were identified post-Hurricane Katrina, but only 83 patients completed the questionnaires and were analyzed. Clinical, demographic, and socioeconomic data were recorded. Chi square test and t test were used for comparisons. RESULTS: Patients who felt that there was a lack of access to cancer care would have sought treatment earlier had they had better access to cancer care (chi-square[1] = 32; p < .0001). Patients who felt that there was a lack of access to cancer care also had difficulty receiving treatment (chi-square[1] = 48; p < .0001). Availability of transportation affected access to cancer care in patients with early-stage cancers (chi-square[1] = 4; p < .035). CONCLUSION: In the postdisaster environment, patients who felt the lack of access to cancer care post-Hurricane Katrina would have sought treatment earlier with better access to cancer care. These patients also reported difficulty obtaining cancer treatment. Availability of transportation affected access to cancer care in patients with early-stage cancers. Clinical, demographic, and socioeconomic factors did not influence access to cancer care. PMID- 20848416 TI - Lymphatic drainage of the external ear. AB - BACKGROUND: Lymphoscintigraphy reveals inconsistencies in our knowledge of the lymphatic anatomy of the external ear. METHODS: Fifteen external ears from 9 unembalmed human cadavers were studied. Six percent hydrogen peroxide was used to find the lymphatic vessels using a surgical microscope. They were injected with a radio-opaque mixture, dissected, photographed, and radiographed to demonstrate lymphatic vessels in the tissue. Final results were transferred to the computer for analysis. RESULTS: Four groups of lymph collecting vessels were found. The anterior branch, in all specimens, drained directly or indirectly (having merged with a vessel descending from the scalp) into the preauricular lymph nodes. The superior, middle, and inferior (lobule) branches drained to their multiple first tier lymph nodes. CONCLUSION: An accurate lymphatic map of the external ear is described to upgrade our anatomic knowledge. It will be of benefit for the clinical management of malignancies in this region. PMID- 20848417 TI - Frequent epigenetic inactivation of Myocardin in human nasopharyngeal carcinoma. AB - BACKGROUND: Epigenetic silencing of tumor suppressor genes plays an important role in nasopharyngeal carcinoma (NPC) tumorigenesis. In the present study, we explore a novel target gene of epigenetic silencing in NPC, Myocardin, which is inactivated by promoter hypermethylation. METHODS: Transcriptional expression levels of Myocardin were evaluated by reverse transcription-polymerase chain reaction (RT-PCR). Methylation status was addressed by methylation-specific PCR and bisulfite genomic sequencing. RESULTS: Myocardin mRNA expression was inactivated in 4 of 5 NPC cell lines. Myocardin was aberrantly methylated in 4 of 5 NPC cell lines (80%) and in 48 of 65 NPC primary tumors (73.8%, but not in any of the 12 normal nasopharyngeal tissues tested. Myocardin expression could be reactivated in NPC cells after treatment with the demethylating agent 5-aza-2' deoxycytidine (5-aza-dC). CONCLUSIONS: Epigenetic inactivation of Myocardin is a frequent and tumor-specific event in NPC. Our findings suggest that Myocardin is a candidate tumor suppressor gene in NPC. PMID- 20848418 TI - Risk factors for developing synchronous esophageal neoplasia in patients with head and neck cancer. AB - BACKGROUND: This study investigated the risk factors for synchronous esophageal neoplasia in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: All 315 consecutive patients with newly diagnosed HNSCC received endoscopic esophageal screening with image-enhanced endoscopy. RESULTS: Sixty nine patients (21.9%) had synchronous esophageal neoplasia, 37 (53.6%) with superficial neoplasia and 21 (30.4%) with multiple esophageal lesions. Univariate analysis revealed age <50 years, drinking alcohol, and location of index HNSCC were significant risk factors for developing synchronous esophageal neoplasia. In multivariate analysis, drinking alcohol (odds ratio [OR], 3.792; p = .0035), index oropharynxgeal cancers (OR, 3.618; p = .0045) and hypopharyngeal cancers (OR, 2.627; p = .0029) were independent risk factors. Drinking alcohol was clearly dose-response related (p = .001). CONCLUSION: Alcohol consumption and index tumor location are associated with the development of synchronous esophageal neoplasia in patients with HNSCC. Because of the high prevalence, routine endoscopic examination of the esophagus should be recommended, especially in patients with the risk factors identified. PMID- 20848419 TI - Case-matching analysis of head and neck squamous cell carcinoma in racial and ethnic minorities in the United States--possible role for human papillomavirus in survival disparities. AB - BACKGROUND: Several studies have documented disparities in head and neck cancer outcomes for black patients in the United States. Recent studies have found that differences in oropharyngeal tumor human papillomavirus (HPV) status may be a cause of this disparity. METHODS: In all, 76,817 cases of head and neck squamous cell carcinoma (HNSCC) recorded in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program were analyzed. Racial/ethnic groups were studied, for disease-specific survival in both case-matched and nonmatched cohorts. Calculation of expected disparity magnitudes based on HPV status was performed using data reported in the literature. RESULTS: A disease-specific survival disparity was demonstrated for Hispanic patients. However, case matching eliminated this disparity. Conversely, the disparity for black patients persisted in matched cohorts. The oropharyngeal subsite was found to be the dominant contributor to this disparity. CONCLUSIONS: The survival disparity for Hispanic patients in SEER with HNSCC is explained by differences in presentation and treatment. Also, HPV tumor status is likely a key determinant of the disparity for black patients. PMID- 20848420 TI - Enlarged tracheoesophageal puncture after total laryngectomy: a systematic review and meta-analysis. AB - BACKGROUND: Enlargement of the tracheoesophageal puncture (TEP) is a challenging complication after laryngectomy with TEP. We sought to estimate the rate of enlarged puncture, associated pneumonia rates, potential risk factors, and conservative treatments excluding complete surgical TEP closure. METHODS: A systematic review was conducted (1978-2008). A summary risk estimate was calculated using a random-effects meta-analysis model. RESULTS: Twenty-seven peer reviewed manuscripts were included. The rate of enlarged puncture and/or leakage around the prosthesis was reported in 23 articles (range, 1% to 29%; summary risk estimate, 7.2%; 95% confidence interval [CI], 4.8% to 9.6%). Temporary removal of the prosthesis and TEP-site injections were the most commonly reported conservative treatments. Prosthetic diameter (p = .076) and timing of TEP (p = .297) were analyzed as risk factors; however, radiotherapy variables were inconsistently reported. CONCLUSION: The overall risk of enlarged puncture seems relatively low, but it remains a rehabilitative challenge. Future research should clearly establish risk factors for enlarged puncture and optimal conservative management. PMID- 20848421 TI - Accuracy of whole-body PET and PET-CT in initial M staging of head and neck cancer: a meta-analysis. AB - BACKGROUND: A meta-analysis was conducted to evaluate the accuracy of whole-body positron emission tomography (PET) and PET-CT in initial M staging of head and neck cancer. METHODS: After a systematic review of English language studies, sensitivity, specificity, and other measures of whole-body PET and PET-CT were pooled. Summary receiver operating characteristic (SROC) curves were also used to summarize overall test performance. RESULTS: Eight PET and 7 PET-CT studies were identified. The pooled sensitivity estimates for PET and PET-CT were 0.848 (95% confidence interval [CI], 0.776-0.905) and 0.875 (95% CI, 0.787-0.936). The pooled specificity estimates were 0.952 (95% CI, 0.933-0.967) and 0.950 (95% CI, 0.931-0.964). The Q* index estimates for PET-CT (0.9409) were not significantly higher than for PET (0.9154; p > .05). CONCLUSION: Whole-body PET and PET-CT have good diagnostic performance in initial M staging of head and neck cancer; although PET-CT tends to have higher accuracy than PET. PMID- 20848422 TI - Impact and management of airway obstruction in patients with squamous cell carcinoma of the larynx. AB - BACKGROUND: We compared postoperative complications and oncologic results after laryngectomy of patients with laryngeal squamous cell carcinoma (SCC), with and without airway obstruction. METHODS: We retrospectively reviewed the medical records of 544 patients with laryngeal SCC between 1990 and 2000. Of 175 advanced cases receiving total laryngectomy, 32 initially presented with upper airway obstruction. RESULTS: Postoperative complications after laryngectomy did not differ significantly between patients with and without airway obstruction (36% vs 28%; p = .353). Although patients with airway obstruction had more T4 (81% vs 42%; p < .001) and stage IV disease (82% vs 48%; p = .0004), tumor recurrence rates did not increase (21% vs 29%; p = .374). Five-year overall (52% vs 60%; p = .251), disease-specific (73% vs 70%; p = .982), and relapse-free (72% vs 68%; p = .982) survival did not differ significantly between groups. CONCLUSION: After appropriate management of airway obstruction, the postoperative complications and oncologic results were similar to those without airway obstruction. PMID- 20848423 TI - Long-term results of 28 esthesioneuroblastomas managed over 35 years. AB - BACKGROUND: The purpose of our study was to assess the long-term results in the management of patients with esthesioneuroblastoma. METHODS: A total of 28 patients were retrospectively reviewed to analyze their clinical features, treatment outcomes, pattern of failures, and course of the disease. RESULTS: The patients were classified as 2 patients with T1, 10 patients with T2, 10 patients with T3, and 6 patients with T4; the results of all were included in this study. Twenty-six patients underwent surgery and 23 had postoperative radiotherapy over the tumor bed, only 9 had radiotherapy over the nodes. The average follow-up was 99.11 months. Fifteen-year and 20-year disease-specific and disease-free survival rates were 88.6% to 66.4% and 59.6% to 29.8%, respectively. Six patients had recurrences and 60% of them occurred more than 10 years after treatment. In the first decade, nodal recurrences appeared earlier than local ones when patients with N0 did not undergo neck irradiation. CONCLUSION: Surgery on patients with T presentations and adjuvant radiotherapy on T and N0 neck presentations seem to be essential to treat esthesioneuroblastoma. A follow-up for a minimum of 20 years is necessary to ensure complete cure. PMID- 20848424 TI - Evolving treatment strategies in thin cutaneous head and neck melanoma: 1 institution's experience. AB - BACKGROUND: Although existing melanoma literature provides recommendations for thinner lesions (<=1 mm) within a heterogeneous population, a focus on the head and neck group is less pervasive. METHODS: The records of 49 node-negative individuals with thin head and neck melanoma that underwent surgical intervention +/- sentinel lymph node (SLN) biopsy were reviewed. RESULTS: A significant increased Breslow thickness and mitotic rate, and a trend toward significance in Clark level >= IV were shown in patients that underwent an SLN biopsy versus those that did not. The total number of positive biopsies was 2 (5%). In our subset analysis using the modified American Joint Committee on Cancer recommendations by Wong and colleagues, the incidence of positive SLN biopsy would have increased to 11%. CONCLUSION: We advocate performing an SLN biopsy in thin head and neck melanomas for primary tumors > 0.75 mm, regardless of "high risk" features as described by Wong and colleagues. PMID- 20848425 TI - Calpain 10 gene and laryngeal cancer: a survival analysis. AB - BACKGROUND: Laryngeal carcinoma is a common upper respiratory tract cancer with different environmental and genetic factors involved in its development. Calpains are Ca2+-dependent cysteine proteases that modulate cellular function. A novel association between calpain 10 (CAPN10) haplotypes and laryngeal cancer has been found recently. Therefore, the goal of this study was to analyze the contribution of CAPN10 alleles to laryngeal cancer survival. METHODS: Patients were recruited from southern Spain. Genotypes were determined using pyrosequencing technology. We analyzed CAPN10 UCSNP-44, UCSNP-43, UCSNP-19, and UCSNP-63 allelic distributions in 199 patients with unrelated laryngeal cancer. Survival curves were calculated from the date of the intervention to the date of death. Multivariate analyses were done using the Cox proportional risk model. RESULTS: UCSNP-19, UCSNP-43, and UCSNP-44 were unrelated to survival in both univariate and multivariate analyses. However, for UCSNP-63 genotype 12 a significant relationship was observed in multivariate analysis (hazard ratio [HR] = 2.73; 95% confidence interval [CI], 1.21-6.20). CONCLUSION: CAPN10 UCSNP-63 genotype 12 seems to be related with a worse prognosis in laryngeal cancer. PMID- 20848426 TI - Spurious hypercalcitoninemia and heterophilic antibodies in patients with thyroid nodules. AB - BACKGROUND: The purpose of our study was to examine the prevalence of significant heterophilic antibody (HAb) interferences in serum calcitonin measurement in a large cohort of patients with thyroid nodules. METHODS: Enrolled in the study were 378 patients with thyroid nodules shown not to have medullary thyroid carcinoma (MTC) after extensive diagnostic workup. Serum calcitonin measurement was performed before and after incubating each serum sample in heterophilic blocking tubes (HBTs) and the differences were calculated. Samples showing an absolute percentage difference greater than 3 SD from the mean percentage difference were considered as affected by heterophilic antibody interference. RESULTS: Five of 378 patients (1.3%) with HAb interferences were identified, 4 with clinically relevant false-positive calcitonin results. CONCLUSION: A false positive calcitonin result due to HAb interference occurs more frequently than MTC (1.3% vs 0%) in our patient series. A serum pretreatment in HBTs should be considered when increased serum calcitonin levels are found in a patient with a thyroid nodule to prevent unwarranted investigations or therapies. PMID- 20848427 TI - Intensity-modulated radiotherapy for locally advanced cancers of the larynx and hypopharynx. AB - BACKGROUND: Limited data evaluate intensity-modulated radiotherapy (IMRT) for cancers of the hypopharynx and larynx. We report clinical outcomes and failure patterns for these patients. METHODS: Between September 2001 and December 2007, 42 patients with squamous cell carcinoma (SCC) of the hypopharynx (n = 23) and larynx (n = 19) underwent IMRT, 11 postoperatively and 31 definitively. Thirty six received systemic therapy. Median follow-up was 30 months among surviving patients. RESULTS: Three local failures occurred within the high-dose region and 3 occurred in regional nodes. Seven patients developed distant metastasis as the initial failure. Three-year actuarial estimates of locoregional control, freedom from distant metastasis, and overall survival rates were, respectively, 80%, 72%, and 46%. CONCLUSIONS: IMRT provides good locoregional control for SCC of the hypopharynx and larynx compared with historical controls. Locoregional relapses occurred in the high-dose volumes, suggesting adequate target volume delineation. Hypopharyngeal tumors, which fare worse than laryngeal tumors, warrant investigation of more aggressive treatment. PMID- 20848428 TI - Associations between quality of life, coping styles, optimism, and anxiety and depression in pretreatment patients with head and neck cancer. AB - BACKGROUND: Head and neck cancer is often diagnosed at a late stage and consequently radical treatment is necessary. The pretreatment phase is a time of high anxiety and depression for patients. This study aimed to investigate whether anxiety and depression are related to quality of life, coping styles, and dispositional optimism. METHODS: One hundred and three patients were recruited after diagnosis to a questionnaire study. Measures included the Hospital Anxiety and Depression Scale; SF12v2 Health Survey; Brief COPE, and the Revised Life Orientation Test. RESULTS: Quality of life, in particular emotional role explained a large proportion of the variance in pretreatment anxiety and depression. In addition, the use of negative coping styles was related to high anxiety levels and low levels of optimism were related to higher levels of depression. CONCLUSION: There are a small but significant proportion of pretreatment patients that may benefit from individualized support. PMID- 20848429 TI - Heat and moisture exchange capacity of the upper respiratory tract and the effect of tracheotomy breathing on endotracheal climate. AB - BACKGROUND: The aim of this study was to assess the heat and moisture exchange (HME) capacity of the upper respiratory tract and the effect of tracheotomy breathing on endotracheal climate in patients with head and neck cancer. METHODS: We plotted the subglottic temperature and humidity measurements in 10 patients with head and neck cancer with a temporary precautionary tracheotomy during successive 10-minute periods of nose, mouth, and tracheotomy breathing in a randomized sequence. RESULTS: End-inspiratory temperatures of nose, mouth, and tracheotomy breathing were 31.1, 31.3, and 28.3 degrees C, respectively. End inspiratory humidity measurements of nose, mouth, and tracheotomy breathing were 29.3, 28.6, and 21.1 mgH2O/L, respectively. There was a trend toward lower end inspiratory humidity in patients with radiotherapy or with large surgery-induced oropharyngeal mucosal defects, whereas temperatures were similar. CONCLUSION: This study gives objective information about the HME capacity of the upper respiratory tract in patients with head and neck cancer with precautionary tracheotomy, and thus provides target values for HMEs for laryngectomized and tracheotomized patients. PMID- 20848430 TI - Voice-related quality of life (V-RQOL) outcomes in laryngectomees. AB - BACKGROUND: Laryngeal cancer has a significant impact on patients. This study compared the Voice-Related Quality of Life (V-RQOL) outcomes specific to 3 different postlaryngectomy voice rehabilitation methods. METHODS: We conducted a retrospective review of 75 patients with laryngectomy from our V-RQOL questionnaire database. RESULTS: The database included 18 electrolaryngeal speech (ELS), 15 esophageal speech (ES), and 42 tracheoesophageal speech (TES) patients. Pairwise comparisons of V-RQOL outcomes showed that TES was perceived to be better than ELS (p < .001). ES was perceived as better than ELS, but this was driven by a difference in the total and social-emotional V-RQOL scores (p < .05). There was no difference between TES and ES groups. Only ELS showed a positive correlation with time after surgery and older age. CONCLUSIONS: Patients using TES had similar V-RQOL outcomes compared to ES and both performed significantly better than ELS. For ELS, the total V-RQOL score was better with longer time after surgery and older age. PMID- 20848431 TI - Percutaneous treatment of facial venous malformations: a matched comparison of alcohol and bleomycin sclerotherapy. AB - BACKGROUND: Venous malformations (VMs) are common vascular anomalies; 40% are found in the head and neck. Percutaneous sclerotherapy is 1 treatment of choice. METHODS: In all, 17 patients with facial VMs were treated by percutaneous sclerotherapy using alcohol and individually matched to lesions treated with bleomycin. Treatment details and outcomes were compared. The average numbers of sessions were 1.7 for alcohol and 3.4 for bleomycin. Average dose administered was 8.1 cm3 alcohol and 9.1 units bleomycin. RESULTS: Of those treated with alcohol, 2 developed adverse effects and 7 developed complications. None treated with bleomycin developed adverse effects or complications. All patients treated with alcohol improved clinically. In all, 15 patients treated with bleomycin improved after treatment and 2 were unchanged. CONCLUSIONS: Alcohol has a slightly higher success rate and requires fewer treatment sessions. Bleomycin has a lower complication rate and less postprocedural swelling. Bleomycin treatment may be better tolerated and is thus preferred over alcohol sclerotherapy. PMID- 20848432 TI - First bite syndrome as a presenting symptom of a parapharyngeal space malignancy. AB - BACKGROUND: First bite syndrome is a known complication after parapharyngeal space surgery. This syndrome is usually encountered when the surgery is extensive but the parotid gland is preserved. A disruption in the balance between sympathetic and parasympathetic innervation to the parotid gland has been posited to play a role. METHODS: We report a 74-year-old woman with a parapharyngeal space malignancy who presented with first bite syndrome prior to any surgical intervention. The tumor and left parotid gland were resected via a transcervical approach. During the operation, the sympathetic chain was found to be directly involved with the tumor. RESULTS: The patient reported complete resolution of first bite syndrome immediately after the operation, and remained free of this symptom at 6 months' follow-up. CONCLUSION: To our knowledge, this is the first report of first bite syndrome presenting prior to any surgical intervention. Parotidectomy, if included in the surgical plan, may lead to the resolution of first bite syndrome. PMID- 20848433 TI - Endoscopic carbon dioxide laser diverticulostomy versus endoscopic staple assisted diverticulostomy to treat Zenker's diverticulum. AB - BACKGROUND: The 2 most frequently used endoscopic methods to treat Zenker's diverticulum are staple-assisted and CO(2) laser esophagodiverticulostomy. METHODS: The study centered around a retrospective evaluation of 107 patients with Zenker's diverticulum who were treated endoscopically by CO(2) laser (n = 72) or staple-assisted diverticulostomy (n = 35). RESULTS: Patients in the staple assisted group had a shorter duration of postoperative hospitalization, attributed to earlier oral intake, than patients in the CO(2) laser group. There were no serious postoperative complications in either group. Postoperative fever and emphysema in the neck or mediastinum occurred more frequently in the CO(2) laser group, but this did not lead to any complications. Most patients reported partial or complete relief of their symptoms and there was no significant difference in the number of reoperations between the 2 treatment groups. CONCLUSIONS: Zenker's diverticulum was treated safely and effectively by the 2 endoscopic techniques, but the staple-assisted method seemed to be the most favorable. PMID- 20848434 TI - Role of core needle biopsy and ultrasonographic finding in management of indeterminate thyroid nodules. AB - BACKGROUND: Thyroid fine-needle aspiration (FNA) is used as a screening test of choice for evaluation of thyroid nodules. However, approximately 15% to 25% of the cases are classified as indeterminate, posing dilemmas in decision-making. This study was designed to compare the diagnostic performances of second FNA and core needle biopsy of indeterminate nodules by initial FNA. METHODS: From February 2005 through June 2009, 258 patients who completed scheduled follow-ups were enrolled and the follow-up results were analyzed. RESULTS: Nondiagnostic results were obtained in 41.8% of the second FNA group and in 1.7% of the core needle biopsy group (p < .001; chi-square). The nodules that show borderline features in preoperative ultrasonography had a malignancy rate of 18.3% and could be identified successfully with core needle biopsy. CONCLUSION: Core needle biopsy is a better method for evaluating indeterminate nodules by initial FNA than second FNA, especially in patients with ultrasonographic findings of a borderline nodule. PMID- 20848435 TI - Technical refinement of ultrasound-guided transoral resection of parapharyngeal/retropharyngeal thyroid carcinoma metastases. AB - BACKGROUND: The transoral approach to the parapharyngeal and retropharyngeal space (PPS/RPS) for the management of well-differentiated thyroid carcinoma (WDTC) has been previously described in other articles. However, limited exposure with this approach can be a challenge. METHODS: This is a retrospective review of 6 patients who underwent ultrasound-guided transoral excision of PPS/RPS WDTC metastases from October 2003 to March 2009 in a cancer center setting. Ultrasound guided methylene blue dye injection of the node was used in 3 patients to facilitate intraoperative identification. The technique, safety, and feasibility of the procedure are described in this study. RESULTS: Successful resection of the metastases was accomplished in all cases without intraoperative complication. The 1 definite recurrence was further treated with transmandibular excision. CONCLUSION: Transoral excision of PPS/RPS WDTC metastases with ultrasound-guided methylene blue dye injection into the metastatic node is safe, feasible, and may further improve intraoperative identification of metastases in poorly accessible locations in the head and neck. PMID- 20848436 TI - Localization and identification of parapharyngeal metastases from differentiated thyroid carcinoma by 131I-SPECT/CT. AB - BACKGROUND: Parapharyngeal metastasis is a rare event in differentiated thyroid carcinoma (DTC). The (131) I-single photon emission CT (SPECT)/CT allows better localization and definition for metastases in DTC. The aim of this study was to assess the value of (131) I-SPECT/CT for the diagnosis of parapharyngeal metastasis in patients with DTC. METHODS: Consecutive patients with DTC (n = 561) treated with (131) I for the ablation of remnant or treatment of metastases were enrolled. A (131) I-SPECT/CT was performed when there were abnormal findings indicative of parapharyngeal metastasis on (131) I-whole-body scan (WBS). RESULTS: A total of 15 lesions were found to be parapharyngeal metastasis in 14 of 561 patients with DTC after the use of (131) I-SPECT/CT. The incidence rate of parapharyngeal metastasis was about 2.5% in DTC. Of the 15 lesions, only 5 lesions were CT-positive. The remaining 10 lesions were either ignored or indeterminate by the CT alone. CONCLUSION: The (131) I-SPECT/CT can identify parapharyngeal metastasis at an early stage. Parapharyngeal metastasis in DTC is relatively frequent after the use of (131) I-SPECT/CT. PMID- 20848437 TI - Genomic profiling of sinonasal squamous cell carcinoma. AB - BACKGROUND: Sinonasal squamous cell carcinomas (SCCs) are rare tumors with no etiologic link to tobacco and alcohol, as opposed to other SCCs of the head and neck (HNSCC). Little is known about the genetic changes in sinonasal SCC. METHODS: DNA copy number changes of sinonasal SCC were analyzed by multiplex ligation-dependent probe amplification (MLPA) and microarray comparative genomic hybridization (maCGH), and results were related to clinicopathologic features. RESULTS: Copy number losses most frequently included genes at 9p21, 13q14, 17p13, 17q21, and 18q11. Frequent gains were observed on 8q24, 11q13, 17q12, 19p13, and 20q11-q13. CONCLUSION: The genomic profile of sinonasal SCC showed a number of chromosomal regions with copy number changes similar to those known in HNSCC, in spite of the differences in etiology. PMID- 20848438 TI - Increased radiation sensitivity of head and neck squamous cell carcinoma with sphingosine kinase 1 inhibition. AB - BACKGROUND: Sphingosine kinase 1 (SphK1) is an important regulator of apoptosis, survival, and proliferation in cancer cells. SphK1 expression in head and neck squamous cell cancer (HNSCC) cell lines and tumor tissue was assessed, and the efficacy of SphK1 knockdown in increasing tumor radiosensitivity was evaluated in vitro and in vivo. METHODS: Expression of SphK1 was determined by immunohistochemistry, Western blot, and real-time polymerase chain reaction (RT PCR) in 34 prospectively collected HNSCC tumor samples. HNSCC cell lines squamous cell carcinoma (SCC)-15 and SCC-25 were treated with SphK1 inhibitor SKI-II and siRNA targeting SphK1 with and without radiation, and the cell viability was assessed. SCC-15 cells with and without transfection of SphK1 siRNA were then injected into athymic nude mice to develop tumor xenografts, and these 2 groups were further divided into 1 group that received radiation and 1 group that did not. Tumor size was measured over 18 days, when the animals were killed and the tumors were evaluated by immunohistochemistry. RESULTS: SphK1 is found in both HNSCC cell lines and human tumor samples, with higher expression correlated with advanced tumor stage, nodal involvement, and recurrence. In vitro, both SCC-15 and SCC-25 were found to be radioresistant; however, they were sensitized by administration of SKI-II and transfection with siRNA targeting SphK1. In vivo, SphK1-siRNA transfected xenografts were decreased in size compared with both nonradiated control and radiated control mice, whereas mice with both SphK1-siRNA and radiation treatment showed a synergistic reduction in tumor volume. Histopathologic analysis demonstrated a decreased proliferative state in SphK1 siRNA transfected tumors. CONCLUSION: SphK1 is upregulated in HNSCC, and inhibition of SphK1 sensitizes HNSCC to radiation-induced cytotoxicity. PMID- 20848439 TI - Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma. AB - BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. Most of the approximately 250,000 cases occurring annually in the United States are small, nonaggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures, and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and can have an increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve the outcomes for patients with aggressive CSCC. METHODS: We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-insulin-like growth factor-I receptor (IGF-IR) antibody, A12, alone or in combination with an anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC. RESULTS: Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of squamous cell carcinoma (SCC) cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA), microvessel density, and increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92%, respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = .044 and p < .001, respectively). CONCLUSION: These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC. PMID- 20848440 TI - Immunoregulatory properties of CD44+ cancer stem-like cells in squamous cell carcinoma of the head and neck. AB - BACKGROUND: CD44 was found as a surface marker in cancer stem cell (CSC) of squamous cell carcinoma of the head and neck (SCCHN); however, the immunologic properties of such CSCs have not yet been elucidated. METHODS: The immunologic properties of CD44+ cancer stem-like cells were compared with those of CD44- cells using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: CD44+ cells exhibited weak HLA-A2 and class II expression. Interestingly, downregulation of transporter antigen processing (TAP)2 was found in CD44+ cells. The CD44+ cell population produced significantly higher levels of interleukin (IL)-8, granulocyte colony-stimulating factor (G-CSF), and transforming growth factor (TGF)-beta than the CD44- cell population. Moreover, CD44+ cells have been shown to not only more strongly inhibit T-cell proliferation, but also to more efficiently inhibit regulatory T cells (Treg cells) and myeloid-derived suppressor cells (MDSC) as compared with CD44- cells. Additionally, CD44+ cells suppressed Th1 responses and enhanced regulatory T cell responses. CONCLUSION: CSCs might have higher malignant potential with numerous escape strategies from immune attack. PMID- 20848441 TI - Human papillomavirus infections in laryngeal cancer. AB - Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we review the currently known associations of HPV infections in diseases of the larynx and their potential for oncogenicity. Using several methods of detection, HPV DNA has been detected in benign (papillomatosis), indolent (verrucous carcinoma), and malignant (squamous cell carcinoma) lesions of the larynx. Consistent with the known oncogenic risk of HPV infections, common HPV types associated with laryngeal papillomatosis include low-risk HPV types 6 and 11, with high-risk HPV types 16 and 18 more commonly present in neoplastic lesions (verrucous carcinoma and squamous cell carcinoma). Although a broad range of prevalence has been noted in individual studies, approximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta-analysis, with common involvement of high-risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high-risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein. Despite this knowledge, the clinical significance of these infections and the implications on disease prevention and treatment are unclear and require further investigation. PMID- 20848442 TI - Association between bisphosphonates and jaw osteonecrosis: a study in Wistar rats. AB - BACKGROUND: This work aimed at determining whether bisphosphonate therapy produces a sufficient condition for jaw osteonecrosis after tooth extraction. METHODS: Rats were allocated into 3 groups: (1) 11 rats treated with alendronate, (2) 10 rats treated with zoledronic acid, and (3) 10 control rats. The animals were subjected to tooth extractions, and at the end of bisphosphonate therapy, they were humanely killed. Histologic sections of the surgical site were processed and analyzed. RESULTS: The zoledronic acid group showed higher incidences of osteonecrosis, inflammatory infiltrate, and microorganisms. There was no significant difference for epithelial or connective tissue, root fragments, vital bone, and positive staining for vascular endothelial growth factor (VEGF) among the groups. CONCLUSION: Zoledronic acid is associated with jaw osteonecrosis, whereas alendronate did not produce a condition sufficient for osteonecrosis after tooth extraction. Neither zoledronic acid nor alendronate was associated with a reduced immunohistochemical expression of VEGF in vital bone at the tooth extraction site. PMID- 20848443 TI - Preoperative CT diagnosis of right nonrecurrent inferior laryngeal nerve. AB - BACKGROUND: The nonrecurrent inferior laryngeal nerve is an anomaly associated with the absence of the brachiocephalic artery (BCA) and the presence of arteria lusoria. METHODS: The preoperative CT scans from 290 patients (9 nonrecurrent, 281 recurrent) were retrospectively reviewed. We identified the BCA or the arteria lusoria, and classified the relationship between the right subclavian artery (SCA) and the tracheoesophagus into 2 subtypes. RESULTS: The arteria lusoria was identified in 6 nonrecurrent cases. The BCA was identified in 143 recurrent cases. The right SCA was detected on the ventral side of the membranous wall of the trachea in 273 recurrent cases, whereas it was detected on the dorsal side in 8 recurrent cases with enlarged thyroid, and it was detected on the dorsal side in 9 nonrecurrent cases without pressure sign. CONCLUSIONS: It is possible to predict a nonrecurrent inferior laryngeal nerve by identifying the arteria lusoria or other features on the preoperative CT. PMID- 20848444 TI - Signet ring carcinoma parotid gland: a case report. AB - BACKGROUND: Signet ring adenocarcinoma is a recently characterized entity occurring in the minor salivary glands. All reported cases have occurred in minor salivary gland. Pure signet ring adenocarcinoma of a major salivary gland has not been reported in the literature. METHODS: A 38-year-old woman presented with a mass in the parotid region. Microscopy showed signet ring cells positive for mucicarmine. Immunohistochemistry showed cytokeratin and focal smooth muscle actin (SMA) positivity; an exhaustive search for primary elsewhere did not reveal any suspicious focus. RESULTS: A diagnosis of low-grade signet ring adenocarcinoma of the parotid gland was made. On 6-month follow-up the patient was alive and well. CONCLUSIONS: The present case highlights a rare occurrence of this tumor in the parotid gland, which until now was labeled as a tumor exclusive to minor salivary glands. Thus this entity should be kept as a differential while investigating mucinous tumors of parotid. PMID- 20848445 TI - Frequency of bilateral cervical metastases in oropharyngeal squamous cell carcinoma: a retrospective analysis of 352 cases after bilateral neck dissection. AB - BACKGROUND: The decision whether to perform an elective neck dissection in patients with head and neck squamous cell carcinoma (HNSCC) and clinically negative lymph nodes (cN0) is made based on the probability of micrometastases in the neck for the given subsite and size of the primary. To date there is limited information about contralateral and bilateral cervical lymph node metastases of oropharyngeal carcinoma. METHODS: A retrospective chart review was performed of 352 patients with oropharyngeal SCC who received a bilateral neck dissection. The frequency of histologically unveiled bilateral neck metastases was determined. RESULTS: Carcinomas of the tonsillar fossa starting with a T2 classification and carcinomas of the soft palate, base of tongue, and pharyngeal wall at any stage showed a high frequency of bilateral metastases. CONCLUSIONS: Bilateral neck dissection should be recommended for all but T1 and selected cases of T2 carcinomas of the tonsillar fossa. PMID- 20848446 TI - Expression of the Sonic hedgehog pathway in squamous cell carcinoma of the skin and the mucosa of the head and neck. AB - BACKGROUND: Activation of the hedgehog pathway may contribute to carcinogenesis. This study characterizes the expression pattern in squamous cell carcinoma of the skin and the head and neck. METHODS: Tissue microarrays were constructed with samples of squamous cell carcinoma of the skin and the head and neck. All tissue samples were immunohistochemically stained for 7 Hedgehog pathway molecules. RESULTS: Significant (p < .0001) overexpression of all evaluated molecules could be observed in the tumor samples compared with healthy control tissues. Expression of Gli-2 showed significant upregulation and that of Smoothened and Patched significant downregulation in head and neck compared with skin carcinoma. High expression of Sonic hedgehog correlates significantly (p = .001) with poor overall survival in patients with head and neck cancer. CONCLUSIONS: Hedgehog signaling is differentially regulated in squamous cell carcinomas of the skin and the head and neck. Sonic hedgehog expression may serve as a prognostic factor in patients with head and neck cancer. PMID- 20848447 TI - Peripheral glutamate signaling in head and neck areas. AB - The major excitatory neurotransmitter glutamate is also found in the periphery in an increasing number of nonexcitable cells. In line with this it became apparent that glutamate can regulate a broad array of peripheral biological responses, as well. Of particular interest is the discovery that glutamate receptor reactive reagents can influence tumor biology. However, the knowledge of glutamate signaling in peripheral tissues is still incomplete and, in the case of head and neck areas, is almost lacking. The roles of glutamate signaling pathways in these regions are manifold and include orofacial pain, periodontal bone production, skin and airway inflammation, as well as salivation. Furthermore, the interrelations between glutamate and cancers in the oral cavity, thyroid gland, and other regions are discussed. In summary, this review shall strengthen the view that glutamate receptor reagents may also be promising targets for novel therapeutic concepts suitable for a number of diseases in peripheral tissues. The contents of this review cover the following sections: Introduction; The "Glutamate System"; The Taste of Glutamate; Glutamate Signaling in Dental Regions; Glutamate Signaling in Head and Neck Areas; Glutamate Signaling in Head and Neck Cancer; A Brief Overview of Glutamate Signaling in Other Cancers; and Conclusion. PMID- 20848448 TI - Prognostic significance of p16 in locally advanced squamous cell carcinoma of the head and neck treated with concurrent cisplatin and radiotherapy. AB - BACKGROUND: Human papillomavirus (HPV)-related squamous cell cancer of the head and neck (SCCHN) has emerged as a distinct clinical entity. The expression of p16 protein can be used as a surrogate for HPV status. METHODS: p16 immunohistochemistry (IHC) was assessed in archival paraffin-embedded material for 55 patients with locally advanced SCCHN treated with a uniform regimen of cisplatin and radiation. HPV status was assessed by colorimetric in situ hybridization (CISH) and polymerase chain reaction (PCR). RESULTS: Compared with p16- and HPV-negative patients, the p16- and HPV-positive patients had improved overall survival, disease-free survival, and locoregional recurrence rates. CONCLUSIONS: p16 IHC may serve as a useful surrogate and prognostic marker for patients with HPV-related SCCHN treated with cisplatin and radiation. PMID- 20848449 TI - Co-overexpression of p21 and Ki-67 in head and neck squamous cell carcinoma relative to a significantly poor prognosis. AB - BACKGROUND: Head and neck squamous cell carcinomas (HNSCC) are treated by surgery or radiotherapy. Tumor cell death-related markers, such as p21 and Ki-67, may predict response to therapy and improve treatment choice. We evaluated and compared the effect of their coexpression between patients treated by surgery or radiotherapy. METHODS: Immunohistochemistry for p21 and Ki-67 expression in 144 pharyngeal and laryngeal HNSCC samples was analyzed and correlated with follow-up parameters. RESULTS: p21 expression correlated significantly with positive cN classification (p < .001), locoregional relapse (p = .031), and poor overall survival (p = .016), and Ki-67 positivity with poor survival only (p = .025). Coexpressing tumor phenotypes showed the worst survival (p = .009), observed primarily in patients treated by radiotherapy (p = .077). CONCLUSIONS: Coexpression of p21/Ki-67 is a strong negative prognostic factor in HNSCC and could be of particular relevance in tumors treated by primary radiotherapy. PMID- 20848450 TI - Intraoperative parathyroid hormone monitoring to determine long-term success of total parathyroidectomy for secondary hyperparathyroidism. AB - BACKGROUND: Use of intraoperative parathyroid hormone (ioPTH) monitoring during total parathyroidectomy for secondary hyperparathyroidism is common, although its ability to predict long-term normoparathyroid state is not known. METHODS: Prospective evaluation of 57 consecutive patients undergoing total parathyroidectomy for renal hyperparathyroidism with ioPTH monitoring and follow up PTH assays were used to categorize the patients into 3 groups: success, adequate biochemical control, and failure. RESULTS: There was no statistically significant difference in percentage reduction of ioPTH between the 3 groups (p = .07), although there was a moderate negative correlation between percentage reduction of ioPTH and percentage reduction of PTH at follow-up (R = 0.57). CONCLUSIONS: When used under current guidelines, ioPTH monitoring is of no use in predicting long-term cure for these patients because it does not predict success. Patients that undergo total parathyroidectomy are required to have long-term calcium and PTH assay follow-up because normoparathyroidism cannot be assumed. Using the regression equation calculated, success may be predicted for future patients. PMID- 20848451 TI - Downregulation of Ches1 and other novel genes in oral cancer cells chronically exposed to areca nut extract. AB - BACKGROUND: This study was undertaken to identify the genes in response to areca nut extract, a potential carcinogen of oral cancer. METHODS: Two oral cancer sublines chronically treated with areca nut extract were established. Methods such as microarray and immunohistochemistry were used to screen and validate the genes' altered expressions in areca nut extract-sublines or in cancer tissues. RESULTS: A total of 35 genes were differentially expressed in both sublines. Several functional pathways were significantly altered. Six genes were confirmed over 2-fold of changes, including Ches1. Functional analyses showed that overexpression of Ches1 suppressed cell growth and arrested cells in the G2/M phase. Consistently, this gene has reduced expression in 52% of oral cancer tissues, which was significantly correlated with the areca nut chewing habit of patients (p = .04). CONCLUSION: We identified 35 candidates and validated 6 genes that may be associated with areca nut-induced oral cancer. Loss of Ches1 may be attributed to areca nut extract-induced oral carcinogenesis. PMID- 20848452 TI - Antitumor activity of satraplatin in cisplatin-resistant oral squamous cell carcinoma cells. AB - BACKGROUND: The aim of the current study was to identify the antitumor activity of satraplatin in paired cisplatin (CDDP)-resistant oral squamous cell carcinoma (OSCC) cell line and its parental cell line. METHODS: CDDP-resistant (KB-R) cells and parental cells (KB) pair were used. Viability was assessed using the MTT and clonogenic assay. Real-time polymerase chain reaction (PCR), glutathione (GSH) assay, and flow cytometric analysis were used for further assessment. RESULTS: KB R cells did not show cross-resistance to satraplatin. The expression status of almost all transporters was upregulated in the KB-R cells. There was no difference in the GSH levels between the KB and KB-R cells. Flow cytometric analysis indicated that with satraplatin the G2/M phase was arrested in the KB-R cells. KB-R cells contain enriched side population cells. CONCLUSION: These data suggested that satraplatin has antitumor activity against the CDDP-resistant OSCC cells. The mechanism of cross-resistance to platinum agents seems to be multifactorial. PMID- 20848453 TI - Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of NI-0401 (a fully human anti-CD3 monoclonal antibody) in patients with moderate to severe active Crohn's disease. AB - BACKGROUND: NI-0401 is a fully human monoclonal antibody, which binds to the CD3 subunit of the T-cell receptor, causing modulation of T-cell activity. We investigated the safety and the ability to modulate the TCR-CD3 complex of NI 0401 in patients with active Crohn's disease (CD). METHODS: A double-blind, placebo-controlled, randomized, multicenter, dose-escalating trial was conducted in CD patients age 18-70 years, a Crohn's Disease Activity Index (CDAI) of 220 450, and detectable levels of C-reactive protein. The primary outcome was safety and the ability of NI-0401 to modulate the TCR-CD3 complex on T cells. Efficacy parameters included the proportion of patients achieving remission (CDAI <150), clinical response (CDAI fall >=100), and change from baseline in the CD Endoscopy Index of Severity (CDEIS). RESULTS: Forty patients received placebo (n = 7) or NI 0401 (n = 33) 0.05-10 mg daily for 5 days. NI-0401 doses <=1 mg were well tolerated. Infusion reactions occurred at doses >=2 mg. The extent and duration of TCR-CD3 modulation increased with dose. No differences between groups were observed in the proportions of patients achieving clinical remission or response. The mean CDEIS at week 6 differed significantly between the 1-mg and placebo group. CONCLUSIONS: NI-0401 was tolerated at doses <=1 mg with manageable side effects. NI-0401 induced a dose-dependent modulation of the TCR-CD3 complex. No significant improvement of CDAI was observed but 1 mg NI-0401 demonstrated an improvement in CDEIS. PMID- 20848454 TI - Efficacy and safety of mesalamine suppositories for treatment of ulcerative proctitis in children and adolescents. AB - BACKGROUND: Treatment of ulcerative proctitis has not been well studied in pediatric populations. We conducted an open-label trial to evaluate the clinical efficacy of a mesalamine suppository (500 mg) to treat pediatric patients with mild to moderate ulcerative proctitis. METHODS: Pediatric patients (5-17 years of age) with ulcerative proctitis were enrolled for baseline evaluations, including a flexible sigmoidoscopic (or colonoscopic) assessment with biopsies performed at study entry. Eligible patients were started on mesalamine suppositories (500 mg) at bedtime. Two follow-up visits were scheduled after 3 and 6 weeks of treatment. The dose could be increased to 500 mg twice daily at the week 3 follow-up visit if deemed appropriate by the investigator based on the Disease Activity Index (DAI) assessment. The primary outcome measure was a DAI derived from a composite score of stool frequency, urgency of defecation, rectal bleeding, and general well-being. RESULTS: Forty-nine patients were included in the intent-to-treat analysis. The mean DAI value decreased from 5.5 at baseline to 1.6 and 1.5 at weeks 3 and 6, respectively (P < 0.0001). Only 4 patients had their dose increased to 500 mg twice daily at week 3. Forty-one patients experienced at least one adverse event, most of which were deemed mild and unrelated to study therapy. The most common treatment-emergent adverse events were gastrointestinal (n = 30, 61.2%). CONCLUSIONS: This study showed that a daily bedtime dose of a 500 mg mesalamine suppository is safe and efficacious in children with ulcerative proctitis. PMID- 20848456 TI - Ask the doctor about inflammatory bowel disease on the Internet: experience after more than 1000 questions. PMID- 20848455 TI - Characterization of intestinal gene expression profiles in Crohn's disease by genome-wide microarray analysis. AB - BACKGROUND: Genome-wide microarray expression analysis creates a comprehensive picture of gene expression at the cellular level. The aim of this study was to investigate differential intestinal gene expression in patients with Crohn's disease (CD) and controls with subanalysis of confirmed CD susceptibility genes, associated pathways, and cell lineage. METHODS: In all, 172 biopsies from 53 CD and 31 control subjects were studied. Paired endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum (TI) for RNA extraction and histology. The 41,058 expression sequence tags were analyzed using the Agilent platform. RESULTS: Analysis of all CD biopsies versus controls showed 259 sequences were upregulated and 87 sequences were downregulated. Upregulated genes in CD included SAA1 (fold change [FC] +7.5, P = 1.47 * 10(-41)) and REGL (FC +7.3, P = 2.3 * 10(-16)), whereas cellular detoxification genes including-SLC14A2 (FC-2.49, P = 0.00002) were downregulated. In the CD TI biopsies diubiquitin (FC+11.3, P < 1 * 10(-45)), MMP3 (FC+7.4, P = 1.3 * 10(-11)), and IRTA1 (FC-11.4, P = 4.7 * 10(-12)) were differentially expressed compared to controls. In the colon SAA1 (FC+6.3, P = 5.3 * 10(-8)) was upregulated and thymic stromal lymphopoietin (TSLP) (FC-2.3, P = 2.7 * 10(-6)) was downregulated comparing noninflamed CD and control biopsies, and the colonic inflammatory CD signature was characterized by downregulation of the organic solute carriers-SLC38A4, SLC26A2, and OST alpha. Of CD susceptibility genes identified by genome-wide association scan IL-23A, JAK2, and STAT3 were upregulated in the CD group, confirming the dysregulation of Th17 signaling. CONCLUSIONS: These data characterize the dysregulation of a series of specific inflammatory pathways highlighting potential pathogenic mechanisms as well as areas for translation to therapeutic targets. PMID- 20848457 TI - Capsule endoscopy in inflammatory bowel disease type unclassified and indeterminate colitis serologically negative. AB - BACKGROUND: The value of capsule endoscopy in the setting of inflammatory bowel disease type unclassified (IBDU) and indeterminate colitis (IC) remains obscure. The aim was to evaluate the clinical impact of capsule endoscopy on IBDU/IC patients with negative serology. METHODS: Eighteen patients with long-standing IBDU (n = 14) and IC (n = 4) were enrolled to undergo a capsule endoscopy and then followed prospectively. Lesions considered diagnostic of Crohn's disease (CD) were 4 or more erosions/ulcers and/or a stricture. The median follow-up time after capsule endoscopy was 32 +/- 11 months (23-54 months). RESULTS: Total enteroscopy was possible in all patients. In 2 patients the examination was normal (Group 1). In 9 patients subtle findings were observed (Group 2): focal villi denudation (n = 1) and fewer than 4 erosions/ulcers (n = 8). In 7 patients, 4 or more erosions/ulcers were detected (Group 3), leading to a diagnosis of CD. However, their treatment was not reassessed on the basis of the capsule findings. Until now, a definitive diagnosis has been achieved in 2 additional patients: 1 from Group 1 (ulcerative colitis) and another patient from Group 2 (CD), who began infliximab infusions. Nine patients remained indeterminate at follow-up. CONCLUSIONS: Although capsule endoscopy enabled the diagnosis of CD in 7 patients, in none of them was the clinical management changed. Moreover, a change in therapy due to a diagnosis of CD was made for only 1 patient, who presented nonspecific findings. Our results suggest that capsule findings are not helpful in the work-up of these patients. PMID- 20848458 TI - Local injection of adalimumab for perianal Crohn's disease: better than infliximab? PMID- 20848459 TI - Risk factors for metabolic bone disease in Crohn's disease patients. AB - BACKGROUND: The aim was to evaluate the presence of metabolic bone disease (MBD) in patients with Crohn's disease (CD) and to identify potential etiologic factors. METHODS: The case-control study included 99 patients with CD and 56 controls with a similar age and gender distribution. Both groups had dual-energy x-ray absorptionmetry and a nutritional evaluation. Single nucleotide polymorphisms at the IL1, TNF-alpha, LTalpha, and IL-6 genes were analyzed in patients only. Statistical analysis was performed using SPSS software. RESULTS: The prevalence of MBD was significantly higher in patients (P = 0.006). CD patients with osteoporosis were older (P < 0.005), small bowel involvement and surgical resections were more frequent (P < 0.005), they more often exhibited a penetrating or stricturing phenotype (P < 0.05), duration of disease over 15 years (P < 0.005), and body mass index (BMI) under 18.5 kg/m(2) (P < 0.01) were more often found. No association was found with steroid use. Patients with a Z score < -2.0 more frequently had chronic active disease (P < 0.05). With regard to diet, low vitamin K intake was more frequent (P = 0.03) and intake of total, monounsaturated, and polyunsaturated fat was higher in patients with Z-score < 2.0 (P < 0.05). With respect to genetics, carriage of the polymorphic allele for LTalpha252 A/G was associated with a higher risk of osteoporosis (P = 0.02). Regression analysis showed that age over 40 years, chronic active disease, and previous colonic resections were independently associated with the risk of developing MBD. CONCLUSIONS: The prevalence of MBD was significantly higher in CD patients. Besides the usual risk factors, we observed that factors related to chronic active and long-lasting disease increased the risk of MBD. PMID- 20848460 TI - Inflammatory bowel disease and completed suicide in Danish adults. AB - BACKGROUND: The risk of suicide is increased among people with inflammatory bowel disease (IBD); however, most of the evidence regarding this association comes from studies of all-cause mortality, with small numbers of people who have committed suicide, or from clinical case reports. The current study examined the association between the two forms of IBD: Crohn's disease (CD) and ulcerative colitis (UC), and completed suicide in a population-based sample. METHODS: Data for this nested case-control study were obtained from the Danish national healthcare and social registries. We included 27,053 cases who completed suicide between January 1, 1981, and December 31, 2006. Controls were selected from the general population and matched to cases on gender, date of birth, and calendar time (n = 551,060). RESULTS: There was an increased rate of suicide among participants with both CD (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.1, 2.3) and UC (OR = 1.9, 95% CI: 1.4, 2.4), when adjusting for the matched factors and identified confounders. CONCLUSIONS: The current study suggests that physicians treating IBD patients should be vigilant about expressions of suicidal ideation or signs and symptoms of self-harm. PMID- 20848461 TI - Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. AB - BACKGROUND: In a murine model of inflammatory bowel disease (IBD), treatment of colitis in IL-10 gene-deficient mice with the parasitic helminth Heligmosomoides polygyrus ameliorates colonic inflammation. The cellular and molecular mechanisms driving this therapeutic host response are being studied vigorously. One proposed mechanism is that H. polygyrus infection favors the outgrowth or suppression of certain bacteria, which in turn help modulate host immunity. METHODS: To quantify the effect of H. polygyrus infection on the composition of the gastrointestinal (GI) tract microbiota, we conducted two independent microbial ecology analyses of C57BL/6 mice. We obtained and analyzed 3,353 bacterial 16S rRNA encoding gene sequences from the ileum and cecum of infected and uninfected mice as well as incective H. polygyrus larvae at the outset of the second experiment and adult worms taken directly from the mouse duodenum at the end of the second experiment. RESULTS: We found that a significant shift in the abundance and relative distribution of bacterial species in the ileum of mice is associated with H. polygyrus infection. Members of the bacterial family Lactobacillaceae significantly increased in abundance in the ileum of infected mice reproducibly in two independent experiments despite having different microbiotas present at the outset of each experiment. CONCLUSIONS: These data support the concept that helminth infection shifts the composition of intestinal bacteria. The clinical consequences of these shifts in intestinal flora are yet to be explored. PMID- 20848462 TI - Endoscopic evaluation of Crohn's disease activity: comparison of the CDEIS and the SES-CD. AB - BACKGROUND: Few data exist of prospective parallel scoring of the validated endoscopic scores in Crohn's disease (CD), Crohn's Disease Index of Severity (CDEIS), and Simple Endoscopic Score for Crohn's Disease (SES-CD). METHODS: Both the CDEIS and the SES-D were scored immediately after each endoscopy of 86 CD patients referred for ileocolonoscopy in a cross-sectional study. Furthermore, after CD therapy, 32 CD patients underwent a follow-up endoscopy with scoring of the CDEIS and SES-CD. Endoscopic scorings were graded as inactive, mild, moderate, or severe. Clinical activity was assessed with the Crohn's Disease Activity Index (CDAI) and serum C-reactive protein (CRP) was measured. RESULTS: The SES-CD correlated with the CDEIS significantly (Spearman's r = 0.938, P < 0.0001). Weaker correlations were detected between the SES-CD and the CDAI (r = 0.473) or CRP (r = 0.525, both P < 0.0001). Grading of SES-CD from inactive to severe correlated significantly with grading of the CDEIS (r = 0.859, P < 0.0001). Changes between baseline and follow-up endoscopy scores correlated significantly (r = 0.828 between delta-CDEIS and delta-SES-CD, P < 0.001), but failed to correlate with delta-CDAI or delta-CRP (all P > 0.05). CONCLUSIONS: Both validated endoscopic scores, the CDEIS and SES-CD, and their changes during CD therapy demonstrated a close correlation. For scoring of endoscopic activity in clinical routine, the SES-CD could replace the CDEIS. PMID- 20848464 TI - EBV hepatitis in a young Crohn's disease patient on prolonged remission with azathioprine. PMID- 20848463 TI - Inflammatory bowel disease and asthma: a population-based, case-control study. AB - BACKGROUND: A few cross-sectional studies reported an increased risk of inflammatory bowel disease (IBD) among asthmatics. We conducted a population based, case-control study that applied predetermined criteria for asthma and IBD to determine whether asthma, as a T-helper 2 (Th2) condition, reduces the risk of IBD, a Th1 condition. METHODS: This was a population-based, case-control study using criteria-based ascertainment for IBD and asthma. Subjects were all Rochester, Minnesota, residents who had developed IBD between 1964 and 1983 and their age- and gender-matched controls, using 1:1 matching. Controls were randomly selected from the community using the Rochester Epidemiology Project database and confirmed not to have IBD. All cases and controls were merged with the database comprising all Rochester residents with or without asthma between 1964 and 1983. RESULTS: Of the 231 IBD cases, 55% had ulcerative colitis and the remainder had Crohn's disease. Of these, 50.4% were male and 98.1% were Caucasians. The mean age at the time of IBD diagnosis was 33.8 years. Four cases (1.7%) had asthma prior to the index date of IBD, whereas two controls (0.9%) had asthma (unadjusted odds ratio [OR]: 3.0, 95% confidence interval [CI]: 0.31 28.84, P = 0.34). Similarly, 16 IBD cases (6.9%) had asthma ever while 12 controls (5.2%) had asthma ever (unadjusted OR: 1.4, 95% CI: 0.62-3.38, P = 0.40). CONCLUSIONS: Asthma as a Th2 condition does not reduce the risk of IBD as a Th1 condition. Because of the limitations of our study and others, the association between asthma and IBD needs to be further studied. PMID- 20848465 TI - Are accelerated infliximab infusions safe in patients with inflammatory bowel disease? AB - BACKGROUND: Infliximab is a monoclonal antibody used in the treatment of inflammatory bowel disease (IBD). The manufacturer-recommended administration is over 2 hours followed by 2 hours of patient observation. The data relating to adverse outcomes in patients receiving accelerated infusions for IBD are limited. METHODS: Our unit utilizes an accelerated protocol for infliximab infusion in selected patients with IBD (those with no adverse reaction in their first four standard infusions). Our aim was to assess if the accelerated infusion protocol (infusion over 1 hour or 30 minutes with 1 hour or no monitoring according to protocol) was associated with any increase in adverse outcomes. Data were collected retrospectively on protocol used and adverse outcomes for all infliximab infusions between October 2005 and June 2008. RESULTS: Out of 69 patients, 27 received the accelerated protocol (130 infusions). All patients received a total of 306 infusions on the standard protocol. No adverse reactions were reported in the accelerated protocol patients. In patients on the standard protocol, 16 adverse reactions were observed: seven were acute (occurring during infusion); nine were delayed (occurring within 1-7 days following infusion). No patient required intramuscular adrenaline or hospitalization. CONCLUSIONS: Our findings suggest that an accelerated protocol for infliximab infusion is well tolerated in selected patients. The monitoring period following infusion may not be necessary, as all acute reactions occurred within an hour of initiating infusion and did not warrant hospitalization. The accelerated infusion may allow more efficient utilization of hospital resources and reduce patient inconvenience. PMID- 20848466 TI - Inflammatory bowel diseases in patients with adaptive and complement immunodeficiency disorders. AB - Crohn's disease and ulcerative colitis are idiopathic chronic inflammatory diseases that primarily affect the gastrointestinal tract. The underlying causes remain poorly understood, but there is a growing body of evidence advocating a likely primary pathogenic role for immunodeficiency in the development of Crohn's lesions. Concordantly, a number of congenital immunodeficiencies disrupting the cellular innate immune system strongly predispose to noninfectious, Crohn's-like inflammatory bowel disease. There are case reports and series suggesting that the same may be true for some of the congenital adaptive and complement immunodeficiencies. This review considers and critiques these potential associations. PMID- 20848467 TI - Role of transforming growth factor-beta in inflammatory bowel disease and colitis associated colon cancer. AB - Transforming growth factor-beta (TGF-beta) plays a central role in a wide array of cellular functions including control of cell growth and differentiation, embryonic development, wound healing, angiogenesis, and immune regulation. In the gastrointestinal tract, TGF-beta can either promote or suppress inflammation and cancer formation. This report reviews recent data on the role of TGF-beta in the pathogenesis of inflammatory bowel disease and how TGF-beta might contribute to the cancer risk associated with chronic inflammation of the gut. PMID- 20848468 TI - Fatigue and health-related quality of life in inflammatory bowel disease: results from a population-based study in the Netherlands: the IBD-South Limburg cohort. AB - BACKGROUND: The importance of fatigue in chronic disease has been increasingly recognized; however, little is known about fatigue in inflammatory bowel disease (IBD). The aim of the present study was to investigate the prevalence and severity of fatigue and the impact on health-related quality of life (HRQoL) in patients included in a population-based IBD cohort in the Netherlands. METHODS: IBD patients, diagnosed between January 1st, 1991, and January 1st, 2003, were followed up for a median of 7.1 years. They completed a questionnaire, which included a disease activity score, the Multidimensional Fatigue Inventory (MFI 20), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the Short Form health survey (SF-36). Hemoglobin levels were recorded. RESULTS: Data were available in 304 Crohn's disease (CD), 368 ulcerative colitis (UC), and 35 indeterminate colitis (IC) patients. During quiescent disease, the prevalence of fatigue was nearly 40%. MFI-20 and HRQoL scores were significantly worse in IBD patients having active disease. In a multivariate analysis, disease activity was positively related with the level of fatigue in both CD and UC. In UC, anemia influenced the general fatigue score independently of disease activity. Disease activity as well as fatigue were independently associated with an impaired IBDQ. CONCLUSIONS: In IBD, even in remission, fatigue is an important feature. Both in CD and in UC, fatigue determined HRQoL independently of disease activity or anemia. This implies that in IBD patients physicians need to be aware of fatigue in order to better understand its impact and to improve the HRQoL. PMID- 20848469 TI - Probiotic and prebiotic use in patients with inflammatory bowel disease: a case control study. AB - BACKGROUND: The use of complementary and alternative medicine in inflammatory bowel disease (IBD) has been extensively studied. However, the use of probiotics and prebiotics is poorly documented, despite evidence of efficacy of particular probiotic strains in specific forms of IBD. METHODS: A case-control study comprising interviewer-administered questionnaires was conducted in IBD patients and healthy controls. Data regarding use and knowledge of probiotics and prebiotics, demographic, and clinical information were collected. RESULTS: In total, 334 participants (234 IBD, 100 controls) were interviewed. Significantly more IBD patients than controls had ever used probiotics to manage their health (Crohn's disease [CD] 43%, ulcerative colitis [UC] 51%, controls 21%, P < 0.001). Prebiotic use was negligible. On logistic regression analysis, having UC (odds ratio [OR] 4.30, 95% confidence interval [CI] 2.27-8.12) or CD (OR 3.05, 95% CI 1.66-5.60) were the strongest predictors of probiotic use. Within IBD patients the strongest predictor of probiotic use was current steroid use (OR 2.4, 95% CI 1.11-5.18). IBD patients had greater probiotic knowledge scores than controls (P = 0.003), although 20% of IBD probiotic users could not provide a definition of a probiotic. Less than half of IBD probiotic users discussed probiotic use with healthcare professionals, with commercial advertising being the primary source of information. CONCLUSIONS: Patients with IBD use probiotics to manage their health but frequently choose strains without evidence of efficacy in IBD. Patients rely on nonclinical sources of information and often do not disclose probiotic use to healthcare professionals. Conventional healthcare providers should inquire about probiotic use among their patients and offer evidence-based advice. PMID- 20848470 TI - IL-1 receptor-associated kinase M downregulates DSS-induced colitis. AB - BACKGROUND: Ulcerative colitis is associated with increased colon permeability resulting in bacterial translocation into the lamina propria. We investigate the importance of the Toll-like receptor (TLR) regulating protein IL-1 receptor associated kinase M (IRAK-M) using the erosive dextran sulfate sodium (DSS) induced model of colitis. METHODS: IRAK-M-competent and -incompetent mice were treated with 3% DSS for 5 days followed by 2 days of regular drinking water. Clinical signs of disease were followed for 7 days. At day 7 the mice were sacrificed and plasma and tissue were collected for histopathological examination and analyses of the production of cytokines and chemokines as well as expression of T-cell transcription factors. RESULTS: At day 7 IRAK-M-deficient mice display a reduced total body weight (77.1 +/- 2.1 versus 88.5 +/- 2.0, *P = 0.002) and an increased macroscopical (2.7 +/- 0.2 versus 1.6 +/- 0.1, *P = 0.002) and histopathological (6.0 +/- 0 versus 3.3 +/- 0.5, *P = < 0.001) colon score compared to wildtype mice. Furthermore, IRAK-M-deficient mice have increased colon mRNA expression of proinflammatory cytokines and increased tumor necrosis factor concentrations (41.1 +/- 13.5 versus 12.8 +/- 2.0 pg/mL, *P = 0.010) in plasma. CONCLUSIONS: This is the first report examining the role of IRAK-M in colitis. We find that IRAK-M is of critical importance in downregulating induction and progression of DSS colitis, and thereby suggesting that IRAK-M might be a target for future interventional therapies. PMID- 20848472 TI - Combined approach with biologics and surgery for enterocutaneous fistulas in Crohn's disease. PMID- 20848471 TI - Dextran sulfate sodium leads to chronic colitis and pathological angiogenesis in Endoglin heterozygous mice. AB - BACKGROUND: Pathological angiogenesis is an intrinsic component of chronic intestinal inflammation, which results in remodeling and expansion of the gut microvascular bed. Endoglin is essential for endothelial cell function and physiological angiogenesis. In this study we investigated its potential role in the regulation of inflammation by testing the response of Endoglin heterozygous (Eng(+/-)) mice to experimental colitis. METHODS: C57BL/6 Eng(+/-) and littermate control mice drank water supplemented with 3% dextran sulfate sodium (DSS) for 5 days and were monitored for up to 26 days for clinical signs of colitis. Inflammation, crypt damage, and angiogenic index were scored on histological sections of distal colon. Levels of the vascular endothelial growth factor (VEGF) and angiopoietins were measured by real-time polymerase chain reaction, enzyme linked immunosorbent assay, and/or Western blots. Vascular permeability was assessed using Evans Blue. RESULTS: Eng(+/-) and control mice developed acute colitis, which peaked at day 9. While control mice recovered by days 19-26, Eng(+/-) mice progressed to chronic colitis and showed numerous vascular protrusions penetrating into the serosa of the inflamed distal colon. Prior to DSS induction, VEGF levels and vascular permeability were higher in the distal colon of Eng(+/-) mice, while angiopoietin 1 and 2 levels were unchanged. In the chronic phase of colitis, VEGF levels were increased in both groups of mice and remained significantly higher in the Eng(+/-) mice. CONCLUSIONS: Higher VEGF levels and increased vascular permeability in the distal colon may predispose Eng(+/-) mice to progress to chronic and persistent bowel inflammation, associated with pathological angiogenesis. PMID- 20848473 TI - Safety of infliximab in Crohn's disease: a large single-center experience. AB - BACKGROUND: The aim of this study was to evaluate the short- and long-term safety experience of infliximab treatment in patients with Crohn's disease (CD) in clinical practice. METHODS: The medical records of 297 consecutive patients with CD treated with infliximab at the Beth Israel Deaconess Medical Center were reviewed for demographic features and adverse events. RESULTS: The 297 patients received a total of 1794 infusions. Patients received a median of four infusions and had a median follow-up of 14.3 months. Forty-four patients (15%) experienced a serious adverse event, requiring the infusion to be stopped in 33 patients (11%). Acute infusion reactions occurred in 18 patients (6%) including respiratory problems in 10 patients (3%) and an anaphylactoid reaction in 1 patient (0.3%). Serum sickness-like disease occurred in one patient (0.3%) and three patients (1%) developed drug-induced lupus. One patient developed a probable new demyelination disorder. Eight patients (2.7%), all of whom were on concurrent immunosuppressants, developed a serious infection, one resulting in fatal sepsis. Six patients (2%) developed malignancies including two lymphomas and two skin cancers. A total of four (1.3%) deaths were observed (median age 72.5 years); two due to gastrointestinal bleeding, one due to sepsis, and one due to malignancy. CONCLUSIONS: While short- and long-term infliximab therapy was generally well tolerated, serious adverse events occurred in 15% of patients including drug-induced lupus, fatal sepsis, and malignancy. Concomitant immunosuppressants were significantly associated with infections and deaths, particularly among elderly patients. PMID- 20848474 TI - Myeloproliferative disorders in patients with inflammatory bowel disease on anti TNF-alpha therapy: report of two cases and review of the literature. PMID- 20848475 TI - Onset of severe perianal disease in Crohn's disease under treatment with infliximab: successful treatment with adalimumab and setons drainage. PMID- 20848477 TI - Glycogen synthase kinase 3-beta: a master regulator of toll-like receptor mediated chronic intestinal inflammation. AB - BACKGROUND: A disturbed regulation of Toll-like receptor (TLR) signal transduction resulting in the exclusive activation of proinflammatory signaling pathways may be critical for the perpetuation of established chronic colitis. Glycogen synthase kinase 3-beta (GSK3-beta) was recently identified as an important regulator of TLR signaling mediating excessive inflammatory responses. The aim of this study was to assess the role of GSK3-beta activity in chronic intestinal inflammation. METHODS: Chronic colitis was induced by dextran sodium sulfate (DSS) treatment. Mice were treated intraperitoneally with phosphate buffered saline (PBS), CpG-ODN, or GSK3-beta inhibitors (SB216763, LiCl). Intestinal inflammation was evaluated by histologic analysis and cytokine secretion of mesenteric lymph node cells (MLC). Nuclear extracts of MLC and lamina propria mononuclear cells (LPMC) were analyzed for nuclear factor kappaB (NF-kappaB) and CREB activity. Murine and human intestinal immune cells were stimulated in vitro with CpG-ODN, lipopolysaccharide (LPS), or anti-CD3 with or without LiCl. RESULTS: GSK3-beta blockade significantly reduced chronic intestinal inflammation and even abolished the colitis-intensifying effects of CpG-ODN treatment. In vitro inhibition of GSK3-beta reduced the proinflammatory phenotype of both murine and human intestinal immune cells from chronic inflamed tissue. In vivo blockade of GSK3-beta resulted in a shift from NF-kappaB activity toward CREB activity in murine MLC and LPMC. CONCLUSIONS: Blockade of GSK3-beta attenuates excessive proinflammatory TLR-mediated immune responses. GSK3-beta inhibition therefore constitutes a promising therapeutic option for selectively reducing exaggerated intestinal immune reactions toward the luminal flora in inflammatory bowel disease. PMID- 20848476 TI - Genetic predictors of medically refractory ulcerative colitis. AB - BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC. METHODS: A GWAS comparing 324 MR-UC patients with 537 non MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls. RESULTS: MR-UC was associated with more extensive disease (P = 2.7 * 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 * 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 * 10(-6)). CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC. PMID- 20848478 TI - Genetics in twins with Crohn's disease: less pronounced than previously believed? AB - BACKGROUND: The influence of genetics in inflammatory bowel disease is emphasized by twin concordance. Previous studies have methodological limitations. The aims were to establish reliable concordance rates and compare phenotypic characteristics in concordant and discordant monozygotic pairs, anticipating the former reflects a genetically determined subgroup. METHODS: By re-running the Swedish twin registry with the Swedish hospital discharge register, observation time was extended. Diagnoses and phenotype were based on medical notes. Pairs with unknown zygosity and where both twins were not alive or not responding to the questionnaire were excluded. In all, 149 new twin pairs of the same sex, born 1909-1980 were identified. RESULTS: Of new pairs, 4/29 monozygotic, 0/38 dizygotic, and 0/1 twin pairs with unknown zygosity were concordant for Crohn's disease (CD). In ulcerative colitis (UC), 4/31 monozygotic, 4/48 dizygotic, and 0/1 twin pairs with unknown zygosity were concordant. New pairs were added to the original cohort. Restricting analyses to pairs born 1886-1958, the time period used in the original cohort, 9/33 monozygotic and 1/50 dizygotic pairs were concordant for CD (P = 0.008), 6/41 and 3/49, correspondingly, for UC (P = 0.29). There was a trend for concordant twins to have less colonic CD than discordant twins, 15% versus 35% (P = 0.09) in twins born 1886-1980. CONCLUSIONS: Previous twin studies have overestimated the influence of genetics in CD. A trend for phenotypic difference between concordant and discordant pairs was observed, suggesting that the clinical entity represents diseases with different pathophysiological backgrounds. PMID- 20848479 TI - Development of communicating hydrocephalus after infliximab infusion. PMID- 20848480 TI - Minimally invasive colectomy for Crohn's colitis: a single institution experience. AB - BACKGROUND: Minimally invasive surgery for Crohn's ileocolitis is well established but few data exist regarding laparoscopic techniques for Crohn's colitis. We aimed to describe outcomes associated with minimally invasive surgery for Crohn's colitis, including predictors of conversion to laparotomy and postoperative complications. METHODS: We identified all Crohn's patients who underwent minimal invasive colectomy at our institution from 1997-2008. Data represent frequency (proportion) or median (interquartile range). Multivariate regression identified factors associated with conversion and 30-day complications (odds ratio [95% confidence interval]). RESULTS: Over 11 years we identified 92 patients, median age 40 (26-51) years, body mass index (BMI) 22.9 (19.3-26.4) kg/m(2); 61% were women. Median Crohn's duration was 6.5 (4-15) years, 11% had prior intestinal resection; medications included immunomodulators (62%), corticosteroids (54%), infliximab (35%). Forty-three cases (47%) were total colectomy, 17 (18%) subtotal colectomy, 32 (35%) were segmental. Straight laparoscopy was used in 57%; 43% were hand-assisted. Median operative time was 248 (190-292) minutes. There were 15 (16%) conversions; only small bowel disease predicted conversion (OR 7 [1.6-35]). Conversion was not associated with increased length of stay or with postoperative complications. Overall postoperative length of stay was 5 (4-7) days. Short-term complications occurred in 34% with reoperation in 5: obstruction n = 3, anastomotic leak n = 2. Only perianal disease predicted complications (2.6 [1.0-6.6]). There was no 30-day mortality. CONCLUSIONS: Minimally invasive colectomy in patients with Crohn's colitis can be safely accomplished with reasonable operative times, conversion rates, and excellent postoperative outcomes. PMID- 20848481 TI - Effect of alpha4beta7 blockade on intestinal lymphocyte subsets and lymphoid tissue development. AB - BACKGROUND: Blockade of the integrin alpha4beta7 has promise as a therapy for inflammatory bowel disease. alpha4beta7 plays diverse roles in the intestinal immune system, including lymphocyte homing and lymphoid tissue formation; however, the effects of alpha4beta7 blockade on these processes during inflammation and their relationship to the efficacy of alpha4beta7 blockade and its potential untoward effects are largely unknown. METHODS: alpha4beta7 function was inhibited by genetic manipulation or antibody blockade. The effects of these manipulations on lymphoid tissues and the presence of lymphocyte subpopulations in the murine small intestine and colon were evaluated in the unchallenged state, during the acute injury dextran sodium sulfate model, and during the splenocyte transfer chronic inflammation model. RESULTS: alpha4beta7 inhibition resulted in a decrease in the B-lymphocyte population in the diffuse lamina propria and a decrease in the number of lymphoid aggregates in the uninflamed intestine and in the acute injury model. alpha4beta7 blockade did not reduce the Foxp3- T lymphocyte population but did decrease the Foxp3+ T-lymphocyte population located selectively within the lymphoid aggregates in the uninflamed intestine and in the acute injury model. In contrast, alpha4beta7 blockade reduced the intestinal T lymphocyte population and decreased the production of inflammatory cytokines in the T-lymphocyte mediated chronic inflammation model. CONCLUSIONS: These findings demonstrate differential use of alpha4beta7 by B-lymphocytes, Foxp3- T lymphocytes, and Foxp3+ T-lymphocytes to home to the gut, and suggest that alpha4beta7 blockade may serve as a targeted therapy that selectively inhibits the accumulation of pathogenic T-lymphocyte populations in the chronically inflamed intestine. PMID- 20848483 TI - Novel highly effective medical treatment of severe treatment refractory Crohn's disease using sympathomimetic amines: case report. PMID- 20848482 TI - Identification of microRNAs associated with ileal and colonic Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) and ulcerative colitis (UC) are associated with expression differences in genes involved in immune function, wound healing, and tissue remodeling. MicroRNAs (miRNAs) are small, noncoding RNAs that act as potent negative regulators of gene expression and are differentially expressed in chronic inflammatory diseases, including UC. We examined the expression of miRNAs in tissues from different intestinal regions and in patients with active ileal and colonic CD. METHODS: Colonoscopic pinch biopsies were obtained from the terminal ileum, cecum, transverse colon, sigmoid colon, and rectum of normal, healthy adults and from the ileum and sigmoid colon of patients with active ileal and colonic CD. miRNA expression was assessed using miRNA microarray and validated by mature miRNA quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: Ten intestine region-specific miRNAs were identified. Three miRNAs were increased and one miRNA was decreased in the terminal ileum as compared to the colon. Six other miRNAs expressed varying levels of expression among the colon regions. Five miRNAs were found to be differentially expressed in tissues of patients with active colonic CD, with three increased and two decreased as compared to normal, healthy controls. Similarly, four miRNAs were found to be significantly increased in tissues of patients with active ileal CD. CONCLUSIONS: The expression differences between ileal CD, colonic CD, and previously identified UC-associated miRNAs support the likelihood that miRNAs influence differing inflammation-related gene expression in each inflammatory bowel disease (IBD) subtype and may form the basis for future diagnostic tests and therapeutic targets for IBD. PMID- 20848484 TI - Opportunistic streptococcal gastritis in a patient with ulcerative colitis mimicking gastric involvement by inflammatory bowel disease. PMID- 20848485 TI - Peripheral regulatory T cells and serum transforming growth factor-beta: relationship with clinical response to infliximab in Crohn's disease. AB - BACKGROUND: CD4(+)Foxp3(+) regulatory T cells (Treg) inhibit T-cell proliferation in vitro and are effective in suppressing colitis in mouse models. Tumor necrosis factor (TNF)-alpha, which is centrally involved in Crohn's disease (CD) pathogenesis, also impairs Treg function. Here we investigated the influence of anti-TNF therapy on Treg frequency and function in CD. METHODS: Twenty CD patients were treated with infliximab administered at weeks 0, 2, and 6. Blood was collected immediately before the first infusion and after 10 weeks. Treg frequency was quantified by flow cytometry. Treg function was measured using a standard coculture assay. Serum levels of transforming growth factor (TGF)-beta1 and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Pretreatment Treg frequency and serum TGF-beta1 levels were significantly higher in nonresponder than responder patients. Clinical improvement in 12 CD patients was associated with a significant increase of Treg frequency after 10 weeks. Treg were functionally active before and after treatment with infliximab, both in responder and nonresponder CD patients. In responder patients the restoration of Treg pool was accompanied by a parallel significant increase of serum TGF-beta1 and IL-10. No significant change in the elevated Treg or serum TGF-beta1 was seen in nonresponder patients. CONCLUSIONS: This study suggests that there may be a relationship between numbers of Treg in the blood, serum TGF-beta1, and response to infliximab; however, further prospective studies are needed. PMID- 20848486 TI - Adalimumab for Crohn's disease in clinical practice at Mayo clinic: the first 118 patients. AB - BACKGROUND: We sought to assess the effectiveness and safety of adalimumab for the treatment of Crohn's disease (CD) in clinical practice. METHODS: Demographic, clinical, and treatment data were abstracted from the medical record. The primary outcome was clinical response to induction therapy with adalimumab for CD (complete, partial, or nonresponse). RESULTS: In all, 118 patients were prescribed adalimumab for CD between January 2003 and June 2007. All but five subjects (96%) had received prior infliximab and 50 were on systemic corticosteroids at the time of initial adalimumab dose (44%). A complete response was achieved in 53 patients and 20 patients had no response. The cumulative probability of any response (complete or partial) was 81.3% at 1 year. Dose escalation was required in 59 patients (1-year cumulative probability, 54.0%). Among patients with complete response, 18 lost response during follow-up (1-year cumulative probability, 21.4%). Among 50 patients on corticosteroids at baseline the median daily dose was 20 mg, which decreased to a median of 0 mg during treatment. Sixty-four patients (54%) experienced a total of 117 adverse events. Thirteen patients (11%) experienced 15 serious adverse events. Sixteen patients (14%) discontinued adalimumab due to an adverse event. CONCLUSIONS: Adalimumab was both effective and well tolerated for the treatment of CD in this tertiary practice with a high prevalence of past infliximab exposure. This experience largely predates FDA approval of adalimumab for CD. PMID- 20848487 TI - Cux1 transcription factor is induced in inflammatory bowel disease and protects against experimental colitis. AB - BACKGROUND: Cux1 is a ubiquitous transcriptional factor that has been associated with cell proliferation, migration, invasion, and differentiation. Cux1 is an effector of the transforming growth factor beta (TGFbeta) pathway, PAR(2) receptor signaling, and cellular migration, mechanisms intimately related to inflammatory bowel diseases (IBD). METHODS: CD1 mice treated with dextran sulfate sodium (DSS) in drinking water and cultured intestinal epithelial cells were used to determine Cux1 expression under inflammatory conditions. A commercial cDNA library was used to monitor CUX1 expression in IBD patients. The Cux1(DeltaHD/DeltaHD) hypomorphic mouse model (Cux1DeltaHD) treated with DSS in drinking water was used and the disease severity assessed. RESULTS: Cux1 expression increased in cultured intestinal epithelial cells stimulated with tumor necrosis factor alpha (TNFalpha), in the mouse intestinal epithelium during experimental colitis and in human IBD patient samples. DSS-induced colitis in Cux1DeltaHD mice was more severe according to clinical observations such as weight loss, colon length, and rectal bleeding. Histological observations confirmed an increase of IBD-related morphological changes including ulceration and mucosal infiltration of leukocytes in Cux1DeltaHD mice. An increased number of pSer(276)-RelA-positive cells and higher expression levels of proinflammatory cytokines were also measured in the colon of Cux1DeltaHD diseased animals. Elevated levels of Cxcl1 were measured before and after DSS-treatment and a greater neutrophilic infiltration was quantified in DSS-treated Cux1DeltaHD mice. Finally, mucosal healing was significantly impaired in Cux1DeltaHD mice during recovery from DSS treatment. CONCLUSIONS: CUX1 is increased in response to inflammatory stress and its nuclear expression is crucial to protect against DSS induced colitis and subsequent mucosal healing. PMID- 20848488 TI - Hepatitis B reactivation in patients with inflammatory bowel disease: A prospective survey on screening and prevention practices at general hospitals in France. PMID- 20848489 TI - Intestinal growth factors: potential use in the treatment of inflammatory bowel disease and their role in mucosal healing. AB - BACKGROUND: A key feature of inflammatory bowel disease (IBD) is impaired epithelial repair. Human growth factors comprise an array of signaling molecules that lead to ligand-specific signal transduction. Their downstream effects are associated with several cellular functions including epithelial healing in response to injury. Several studies have described specific growth factor deficiencies in patients with IBD, implicating their role in disease pathophysiology. The aim of this review was to describe currently known enterocyte-targeted growth factors, their mechanisms of action, and their potential therapeutic utility. METHODS: The National Library of Medicine (http://www.pubmed.gov) and meeting abstracts were searched using the following terms: growth factor, intestine, colon, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis, animal model, transforming growth factor, bone morphogenetic protein, activins, growth hormone, fibroblast growth factor, epidermal growth factor (EGF), keratinocyte growth factor (KGF), glucagon-like peptide II, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF) inhibitors, and trefoil factors. RESULTS: Several growth factors are therapeutic candidates in IBD. Growth hormone, KGF, EGF, teduglutide, GM-CSF/G CSF have entered early clinical trials, whereas others are currently in preclinical evaluation. CONCLUSIONS: There are several growth factors responsible for epithelial repair. Preliminary studies using recombinant growth factors seem promising in IBD preclinical and clinical trials. PMID- 20848490 TI - Atherogenic diets exacerbate colitis in mice deficient in glutathione peroxidase. AB - BACKGROUND: The proinflammatory effect of high-fat diet has been observed beyond the cardiovascular system, but there is little evidence to support its role in triggering inflammatory bowel disease. GPx1/2-double-knockout (DKO) mice deficient in 2 intracellular glutathione peroxidases, GPx1 and GPx2, on a C57BL/6 (B6) background, have mild ileocolitis on a conventional chow. METHODS: We fed B6 DKO mice 2 atherogenic diets to test the dietary effect on atherosclerosis and ileocolitis. Both atherogenic diets have high cholesterol-the Chol+/CA diet has cholic acid (CA), and the Chol+ diet has no CA. RESULTS: The Chol+/CA diet induced severe colitis, but not ileitis, in the DKO mice compared with the Chol+ and the Chol- control diet. On the Chol+/CA diet, the wild-type (WT) mice had levels of aortic lesions and hypercholesterolemia similar to those of DKO mice but had no intestinal pathology. The diet-associated inflammatory responses in the DKO mice included increased colonic proinflammatory serum amyloid A3 expression, plasma lipopolysaccharide, and TNF-alpha levels. The Chol+/CA diet lowered the expression of the unfolded protein response genes ATF6, CHOP, unspliced Xbp(U) , and Grp78/Bip, in WT and DKO mice compared with mice on the Chol- diet. CONCLUSIONS: We concluded that a cholesterol diet weakens the colon unfolded protein response, which can aggravate spontaneous colitis, leading to gut barrier breakdown. GPx has no impact on atherosclerosis without ultrahypercholesterolemia. PMID- 20848492 TI - Dysbiosis of fecal microbiota in Crohn's disease patients as revealed by a custom phylogenetic microarray. AB - BACKGROUND: A custom phylogenetic microarray composed of small subunit ribosomal RNA probes, representing ~500 bacterial species from the human and animal gut, was developed and evaluated for analysis of gut microbial diversity using fecal samples from healthy subjects and Crohn's disease (CD) patients. METHODS: Oligonucleotide probes (~40 mer) used on the microarray were selected from published articles or designed with the "GoArray" microarray probe design program using selected bacterial 16S rRNA sequences. Fecal 16S rDNA from individual samples of six healthy subjects and six CD patients were used as template to generate fluorescently labeled cRNA that was hybridized to the microarray. Differences revealed by the microarray in relative abundance of microbial populations between healthy and diseased patients were verified using quantitative real-time polymerase chain reaction (PCR) with species-specific primer sets. RESULTS: The microarray analyses showed that Eubacterium rectale, Bacteroides fragilis group, B. vulgatus, Ruminococcus albus, R. callidus, R. bromii, and Faecalibacterium prausnitzii were 5-10-fold more abundant in the healthy subjects than in the CD patients, while Enterococcus sp., Clostridium difficile, Escherichia coli, Shigella flexneri, and Listeria sp. were more abundant in the CD group. CONCLUSIONS: The microarray detected differences in abundance of bacterial populations within the phylum Firmicutes that had been reported previously for the same samples based on phylogenetic analysis of metagenomic clone libraries. In addition, the microarray showed that Enterococcus sp. was in higher abundance in the CD patients. This microarray should be another useful tool to examine the diversity and abundance of human intestinal microbiota. PMID- 20848491 TI - Immunosuppressive effects of tacrolimus on macrophages ameliorate experimental colitis. AB - BACKGROUND: Tacrolimus is a novel immunomodulator for inflammatory bowel diseases. Immunosuppressive effects of tacrolimus on T cells are well known; however, the effects of tacrolimus on macrophages remain unclear. The aim of this study was to investigate the effects of tacrolimus on activated macrophages and to examine its efficacy in murine colitis models. METHODS: Proinflammatory cytokine production from lipopolysaccharide (LPS)-stimulated peritoneal macrophages of IL-10-knockout (KO) mice with and without tacrolimus was measured. We investigated the effects of tacrolimus on nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinase (MAPK), and caspase activation in macrophages and the induction of apoptosis in macrophages in vitro and examined the in vivo apoptotic effect of tacrolimus on colonic macrophages in IL-10-KO mice. We evaluated the effect of the rectal administration of tacrolimus on colonic inflammation in IL-10-KO mice and dextran sulfate sodium (DSS)-induced colitis in CB.17/SCID mice. RESULTS: Proinflammatory cytokine production from tacrolimus treated macrophages was significantly lower than that from untreated cells. Tacrolimus suppressed LPS-induced activation of both NF-kappaB and MAPK in macrophages and induced apoptosis of macrophages via activation of caspases 3 and 9. Rectal administration of tacrolimus evoked apoptosis of colonic macrophages in IL-10-KO mice. Moreover, the rectal administration of tacrolimus ameliorated colitis in IL-10-KO mice and DSS-induced colitis in CB.17/SCID mice. Gene expression of inflammatory cytokines in colonic mucosa was significantly lower in tacrolimus-treated mice than in untreated mice. CONCLUSIONS: Tacrolimus suppresses the function of activated macrophages and promotes their apoptosis, which may lead to the amelioration of colonic inflammation. PMID- 20848493 TI - Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis. AB - BACKGROUND: Bromelain, a mixture of proteolytic enzymes typically derived from pineapple stem, decreases production of proinflammatory cytokines and leukocyte homing to sites of inflammation. We previously showed that short-term oral treatment with bromelain purified from pineapple stem decreased the severity of colonic inflammation in C57BL/6 Il10(-/-) mice with chronic colitis. Since fresh pineapple fruit contains similar bromelain enzymes but at different proportions, this study aimed to determine whether long-term dietary supplementation with pineapple (supplied as juice) could decrease colon inflammation and neoplasia in Il10(-/-) mice with chronic colitis as compared with bromelain derived from stem. METHODS: Colitis was triggered in Il10(-/-) mice by exposure to the non-steroidal anti-inflammatory drug piroxicam. Mice with colitis were supplemented with fresh vs. boiled pineapple juice or bromelain purified from stem for up to 6 months. RESULTS: Experimental mice readily consumed fresh pineapple juice at a level that generated mean stool proteolytic activities equivalent to 14 mg bromelain purified from stem, while control mice received boiled juice with inactive enzymes. Survival was increased in the group supplemented with fresh rather than boiled juice (P = 0.01). Mice that received fresh juice also had decreased histologic colon inflammation scores and a lower incidence of inflammation associated colonic neoplasia (35% versus 66%; P < 0.02), with fewer neoplastic lesions/colon (P = 0.05). Flow cytometric analysis of murine splenocytes exposed to fresh pineapple juice in vitro demonstrated proteolytic removal of cell surface molecules that can affect leukocyte trafficking and activation. CONCLUSIONS: These results demonstrate that long-term dietary supplementation with fresh or unpasteurized frozen pineapple juice with proteolytically active bromelain enzymes is safe and decreases inflammation severity and the incidence and multiplicity of inflammation-associated colonic neoplasia in this commonly used murine model of inflammatory bowel disease. PMID- 20848494 TI - Acute hepatic cytolysis following H1N1 vaccination in a patient with Crohn's disease on infliximab. PMID- 20848495 TI - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression is downregulated in patients with active ulcerative colitis. PMID- 20848496 TI - New desensitization regimen with mesalamine granules in a patient with ulcerative colitis and mesalamine intolerance. PMID- 20848497 TI - Case report of aseptic meningitis in a patient with Crohn's disease under infliximab therapy. PMID- 20848498 TI - Protein tyrosine phosphatase non-receptor Type 2 regulates IFN-gamma-induced cytokine signaling in THP-1 monocytes. AB - BACKGROUND: We have previously shown that the Crohn's disease (CD)-associated gene protein tyrosine phosphatase non-receptor Type 2 (PTPN2) regulates interferon gamma (IFN-gamma)-induced signaling and barrier function in intestinal epithelial cells. Overactivation of immature immune cells has been demonstrated in CD and elevated levels of proinflammatory cytokines, such as IFN-gamma, play an important pathophysiological role in this disease. Here we studied the role of PTPN2 in the regulation of IFN-gamma-induced signaling in THP-1 monocytic cells. METHODS: Protein analysis was performed by Western blotting, PTPN2 knockdown was induced by siRNA, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: We demonstrated that IFN-gamma (1000 U/mL) treatment of THP-1 cells elevates PTPN2 protein, reaching a peak by 24 hours. Increased PTPN2 expression, in turn, correlated with decreased activity of the signaling molecules, signal transducer and activator of transcription (STAT) 1 and STAT3. Loss of PTPN2 potentiated IFN-gamma-induced phosphorylation of both of the STATs and of the mitogen-activated protein kinase (MAPK) family member, p38. However, PTPN2 loss did not affect the phosphorylation of extracellular signal regulated kinase (ERK) 1/2 or c-Jun N-terminal kinase. As a functional consequence, PTPN2 knockdown elevated the IFN-gamma-induced secretion of the proinflammatory cytokines interleukin-6 (IL-6) and macrophage chemoattractant protein 1 (MCP-1). CONCLUSIONS: Our data demonstrate that IFN-gamma enhances PTPN2 protein in THP-1 cells and loss of PTPN2 promotes IFN-gamma-induced STAT signaling and secretion of IL-6 and MCP-1. Therefore, we show that PTPN2 regulates inflammation-related events and PTPN2 dysregulation may contribute to the onset as well as to the perpetuation of inflammatory events associated with CD. PMID- 20848499 TI - Anti-TNF treatment of ulcerative colitis associated with idiopathic thrombocytopenic purpura. PMID- 20848500 TI - Dosage adjustment during long-term adalimumab treatment for Crohn's disease: clinical efficacy and pharmacoeconomics. AB - BACKGROUND: Data from CHARM, a 56-week, randomized controlled trial of adalimumab for patients with moderately to severely active Crohn's disease (CD), were used to evaluate outcomes of adalimumab dosage adjustment. METHODS: Patients randomized to blinded adalimumab 40 mg every other week (EOW) in CHARM were the focus of the analysis. At >=12 weeks, patients with flares or lack of response versus baseline (including patients who responded and then lost response) could move sequentially to open-label (OL) adalimumab EOW and then to OL adalimumab weekly. RESULTS: Of 260 patients randomized to adalimumab EOW, 140 (54%) continued blinded EOW therapy and 120 (46%) moved to OL therapy. Of patients on OL therapy, 49 (19%) continued EOW therapy and 71 (27%) moved to weekly therapy; 36 (14%) completed the trial on weekly therapy. Of 71 patients on weekly therapy, 37% achieved clinical remission (Crohn's Disease Activity Index [CDAI] <150), 58% achieved CR-100 (CDAI decreased >=100 points), and 63% achieved CR-70 (CDAI decreased >=70 points). Of the 49 patients who remained on OL EOW therapy, 39% achieved clinical remission, 59% achieved CR-100, and 63% achieved CR-70. In a logistic regression, greater baseline CDAI predicted changing to weekly therapy. A model of dosage-adjustment cost indicated a modest per-patient drug-acquisition cost increase ($574 over yearly EOW dosing cost [$22,518]). CONCLUSIONS: Of patients randomized to blinded EOW therapy, 19% moved to OL EOW therapy and 27% moved to OL weekly therapy for flares or lack of response versus baseline. Weekly therapy was associated with clear clinical benefits and a small cost increase. PMID- 20848501 TI - QuantiFERON TB gold testing for tuberculosis screening in an inflammatory bowel disease cohort in the United States. AB - BACKGROUND: Reactivation of latent Mycobacterium tuberculosis (TB) is a rare, yet devastating infectious complication associated with anti-tumor necrosis factor alpha (TNF-alpha) therapy. We evaluated the performance of the QuantiFERON TB Gold test (QFT-G) for TB screening in a cohort of inflammatory bowel disease (IBD) patients in the United States. METHODS: We performed a retrospective, observational study of patients initiated and/or maintained on an anti-TNF-alpha agent in a single IBD referral center and recorded the frequency and the test results of QFT-G testing and the rate of TB reactivation. RESULTS: 512 QFT-G tests were done in 340 patients. Five patients (1.5%) had a positive, nine (2.7%) indeterminate, and 326 patients (95.8%) had a negative QFT-G. After a mean follow up of 17 months there was one case of TB reactivation (0.3%). The use of immunosuppressive therapy or anti-TNF therapy at the time of testing did not affect the results of the QFT-G testing. Test-retest had substantial concordance (kappa = 0.72). 25% of patients (n = 85) had TST testing. Concordance between the TST and QFT-G was found to be moderate (kappa = 0.4152, P = 0.0041). CONCLUSIONS: Most patients with negative QFT-G tolerated anti-TNF therapy with no evidence of TB reactivation. Concomitant use of immunosuppressive therapy or anti-TNF did not seem to affect QFT-G results. One patient had an indeterminate QFT-G while on infliximab and later developed miliary TB. Concordance with TST is moderate. PMID- 20848502 TI - Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine. AB - BACKGROUND: Nodular regenerative hyperplasia (NRH) is a rare hepatic disorder that may lead to severe portal hypertension. Cases of NRH have been reported in patients receiving thiopurines for inflammatory bowel disease (IBD). Since azathioprine (AZA) is used more and more frequently as a maintenance treatment in IBD, the risk of NRH must be known. The objective of this study was to evaluate the prevalence of NRH and its predictive factors in IBD patients treated with AZA. MATERIALS AND METHODS: From the same tertiary referral center, 1888 consecutive IBD patients treated with AZA were studied. Clinical diagnosis of NRH was proven by liver biopsy in all cases except one. The cumulative risk of NRH was estimated with the Kaplan-Meier method. Factors associated with NRH were tested independently with the log-rank method and multivariate proportional hazards model with time-dependent covariates. RESULTS: Fifteen patients developed NRH in a median treatment duration of 52.4 months (SE 1.6). The cumulative incidence of NRH was 1.28+/-0.45% at 10 years. Only two variables were independently associated with NRH occurrence: male gender (P=0.0001, hazard ratio [HR] 8.5, 95% confidence interval [CI] 1.9-37.9) and small bowel resection>=50 cm (P<0.0001, HR 6.6, 95% CI 2.2-20.0), either prior to or after AZA initiation. CONCLUSIONS: The risk of developing NRH during AZA treatment is low. This study suggests that male patients with small bowel resection>=50 cm constitute the group with the higher risk of developing NRH while treated with AZA. PMID- 20848503 TI - Effect of corticosteroid dose and duration of administration on colonic anastomosis. AB - BACKGROUND: Surgical intervention under concomitant steroid therapy can be complicated by impaired anastomotic healing. The aim of this experimental study was to investigate the effects of a corticosteroid (methylprednisolone) on healing colonic anastomoses in relation to the dose and duration of administration. METHODS: Fifty male Spraque-Dawley rats weighing 200-220 g were divided into five groups each containing 10 rats. No treatment was given in the control group. Group HDST: high-dose methylprednisolone (1 mg/kg/day, intramuscular) treatment for a short term of 2 days; group HDLT: high-dose methylprednisolone treatment for a long term of 60 days; group LDST: low-dose methylprednisolone (0.28 mg/kg/day) treatment for a short term of 2 days; and group LDLT: low-dose methylprednisolone treatment for a long term of 60 days. Standard left colonic anastomosis was performed in all rats. Anastomotic bursting pressure, hydroxyproline measurement, and histopathological data were evaluated in all groups on postoperative day 4. RESULTS: The mean anastomotic bursting pressure value was significantly lower in the HDLT group (P < 0.05). The mean hydroxyproline levels were significantly lower in all groups (P < 0.05). Histopathological results demonstrated significant changes according to neutrophil infiltration, granulation tissue formation, presence of vascularization, and peritonitis in the HDLT, LDST, and LDLT groups (P < 0.05). CONCLUSIONS: High and low doses of the corticosteroid produced adverse effects on the healing of colon anastomosis in rats regardless of whether it was administered over a long or short preoperative period. However, the most prominent negative effect was associated with high-dose, long-term corticosteroid administration. PMID- 20848504 TI - Predictive value of epithelial gene expression profiles for response to infliximab in Crohn's disease. AB - BACKGROUND: Infliximab (IFX) has become the mainstay of therapy of refractory Crohn's disease (CD). However, a subset of patients shows incomplete or no response to this agent. In this study we investigated whether we could identify a mucosal gene panel to predict (non)response to IFX in CD. METHODS: Mucosal biopsies were obtained during endoscopy from 37 patients with active CD (19 Crohn's colitis [CDc] and 18 Crohn's ileitis [CDi]) before and after first IFX treatment. Response was defined based on endoscopic and histologic findings. Total RNA was analyzed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) was used to confirm microarray data. RESULTS: At baseline, significant gene expression differences were found between CDc and CDi. For predicting response in CDc, comparative analysis of CDc pretreatment expression profiles identified 697 significant probe sets between CDc responders (n = 12) and CDc nonresponders (n = 7). Class prediction analysis of CDc top 20 and top 5 significant genes allowed complete separation between CDc responders and CDc nonresponders. The CDc top 5 genes were TNFAIP6, S100A8, IL11, G0S2, and S100A9. Only one patient with CDi completely healed the ileal mucosa. Even using less stringent response criteria, we could not identify a predictive gene panel for IFX responsiveness in CDi. CONCLUSIONS: This study identified a 100% accurate predictive gene signature for (non)response to IFX in CDc, whereas no such a predictive gene set could be identified for CDi. PMID- 20848505 TI - Coping skills for reducing pain and somatic symptoms in adolescents with IBD. AB - BACKGROUND: The current study involved the development and evaluation of a skills based, psychological intervention for adolescent females with inflammatory bowel disease (IBD) and their parents. Psychological interventions were used to improve coping with pain and other somatic physical symptoms, as well as improve parental responses to children and adolescents who experience such symptomatology. METHODS: Thirteen and 11 adolescent females and one of their parents made up the treatment and wait-list control groups, respectively, for a total of 24 parent child dyads. Adolescents and parents attended a 1-day intervention that taught disease-related coping skills, pain management, relaxation techniques, communication, and limit setting (parents only). The treatment day was followed by 6 weeks of Web-based skill review including homework assignments and weekly group chat sessions. RESULTS: Following treatment, significant improvements were found in adolescents' somatic symptoms and adaptive coping strategies. Further, parents reported reductions in irrational thoughts and improved behavioral reactions related to their daughter's physical symptoms. Implications of these findings, as well as limitations and future directions, are discussed. CONCLUSION: Overall, preliminary support suggests that programmatic psychosocial interventions for reducing physical symptoms and improving coping may be beneficial for adolescents with IBD and their families. PMID- 20848506 TI - Perforating Crohn's ileitis: delay of surgery is associated with inferior postoperative outcome. AB - BACKGROUND: A perforating phenotype is associated with an increased postoperative morbidity in patients with Crohn's disease undergoing ileocolic resection. Sequential conservative treatment attempts applied to patients with unrecognized perforating complications may lead to a delay of surgery and a further increase in morbidity. METHODS: In all, 197 patients underwent 231 bowel resections for perforating ileitis between 1992 and 2009. The duration or clinical deterioration was calculated from the onset of clinical exacerbation unresponsive to any medical treatment to the date of surgery. RESULTS: The median duration of clinical deterioration leading to surgery was 5 months. Patients with preoperative exacerbation lasting for >5 months had a higher number of structures involved in the inflammatory mass (3.3 versus 2.8 structures, P = 0.013), and had a higher probability to take immunosuppressive drugs (26% versus 14%, P = 0.042), budesonide (29% versus 14%, P = 0.009), and a multiple-drug combination (31% versus 16%, P = 0.015) at the time of surgery. Patients with symptoms lasting >5 months prior to surgery had a higher incidence of postoperative septic complications (31% versus 13%, P = 0.002), both by univariate and multivariate analysis. There was a significant increase in duration of preoperative clinical deterioration, size of the inflammatory mass, incidence of preoperative weight loss, intake of immunosuppressants and multiple-drug combination, and postoperative morbidity during the last 5 years of the study. CONCLUSIONS: Delay of surgery in patients presenting with symptoms attributable to perforating ileitis is associated with an increased postoperative risk. PMID- 20848507 TI - Homing of immune cells: role in homeostasis and intestinal inflammation. AB - Rather like a satellite navigation system directing a vehicle to a particular destination defined by post-code, immune cells have homing molecules or "immune post-codes" enabling them to be recruited to specific organs, such as the intestine or skin. An efficient system would be designed such that the site of entry of an antigen influences the homing of effector T cells back to the appropriate organ. For example, to mount an immune response against an intestinal pathogen, T cells with a propensity to home to the gut to clear the infection would be induced. In health, there is such a sophisticated and finely tuned system in operation, enabling an appropriate balance of immune activity in different anatomical compartments. In disease states such as inflammatory bowel disease (IBD), which is characterized by intestinal inflammation and often an inflammatory process involving other organs such as skin, joints, liver, and eye, there is accumulating evidence that there is malfunction of this immune cell trafficking system. The clinical importance of dysregulated immune cell trafficking in IBD is reflected in recently proven efficacious therapies that target trafficking pathways such as natalizumab, an alpha4 integrin antibody, and Traficet-EN, a chemokine receptor-9 (CCR9) antagonist. Here we review the mechanisms involved in the homing of immune cells to different tissues, in particular the intestine, and focus on alterations in immune cell homing pathways in IBD. Unraveling the mechanisms underlying the immune post-code system would assist in achieving the goal of tissue-specific immunotherapy. PMID- 20848508 TI - Lost in translation: helping patients understand the risks of inflammatory bowel disease therapy. AB - Patients with inflammatory bowel disease are commonly treated with immunomodulators and biologic therapy. These treatments can be very effective, but are associated with risks of adverse events that need to be discussed with patients. Effectively communicating risks of therapy can be challenging based on time constraints, misinformation available on the Internet and from others, and the lack of tools to efficiently share accurate data with patients and their families. Providers need to acknowledge the emotional aspect involved in the perception of risk, and be aware of mistakes that can easily be made in communicating with patients. Tools are available to make medical data easier to understand, and these techniques have been adapted for patients with inflammatory bowel disease. By more clearly communicating with patients, we can ensure that they are making informed medical decisions that fit with their personal preferences for treatment. PMID- 20848509 TI - Expression and regulation of the chemokine CXCL16 in Crohn's disease and models of intestinal inflammation. AB - BACKGROUND: CXCL16 mediates adhesion and phagocytosis of both Gram-negative and Gram-positive bacteria and is a strong chemoattractant for CXCR6+ T cells. In this study, we determined the so far unknown expression and signal transduction of the novel CXCL16-CXCR6 chemokine-ligand receptor system in intestinal inflammation in vivo and in vitro. METHODS: CXCL16 mRNA was measured by quantitative PCR in human colonic biopsies of patients with Crohn's disease (CD) as well as in the TNFDeltaARE mouse model of ileitis and in murine cytomegalovirus (MCMV)-induced colitis. CXCL16 serum levels were analyzed by ELISA. CXCL16-induced signal transduction was analyzed in intestinal epithelial cells with phospho-specific antibodies for mitogen-activated protein (MAP) kinases and Akt. RESULTS: We found an inverse expression pattern of CXCL16 and CXCR6, with highest CXCL16 mRNA expression in the proximal murine small intestine and the highest CXCR6 mRNA expression in the distal colon. CXCL16 and CXCR6 mRNA were expressed in colorectal cancer (CRC)-derived intestinal epithelial cell (IEC) lines. CRC-expressed CXCR6 was functional, as demonstrated by CXCL16 induced MAP kinase and Akt activation. Intestinal CXCL16 expression was elevated in the TNFDeltaARE mouse model of ileitis and in MCMV-induced colitis (P < 0.05) and in the sera and colons of patients with CD (P < 0.05), where its expression correlated highly with CXCR6 and IL-8 levels (r = 0.85 and 0.89, respectively). CONCLUSIONS: CRC-derived IECs express the functional CXCL16 receptor CXCR6. CXCL16 mRNA and protein expression is up-regulated in intestinal inflammation in vitro and in CD patients, suggesting an important role for this chemokine in intestinal inflammation. PMID- 20848510 TI - Therapy with anti-TNFalpha antibody enhances number and function of Foxp3(+) regulatory T cells in inflammatory bowel diseases. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are associated with up-regulation of TNFalpha, hyperactivation of proinflammatory effector T cells (Teffs) and inefficient control by regulatory CD4(+) CD25(+) Foxp3(+) T cells (Tregs). The aim of this prospective study was to investigate the short-term impact of treatment of IBD patients with anti-TNFalpha antibodies (infliximab or adalimumab) on the frequency, phenotype, and suppressive function of Tregs. METHODS: Active IBD patients including 16 with Crohn's disease and 9 with ulcerative colitis were treated with anti-TNFalpha mAb. PBMCs were harvested immediately before and 2 weeks after the first injection. The frequency and phenotype of circulating CD4(+) CD25(+) Foxp3(+) Tregs were analyzed by flow cytometry, and their suppressive function was assessed by the ability of purified CD4(+) CD25(+) CD127(-) Tregs to inhibit the proliferation of allogenic CD4(+) CD25(-) Teffs. RESULTS: CD4(+) CD25(+) Foxp3(+) Treg frequency was significantly lower in active IBD patients than in controls (2.8% +/- 0.4% vs. 4.6% +/- 0.6%, respectively; P = 0.01). On day 14 following the first anti-TNFalpha infusion, the frequency of circulating Tregs was significantly enhanced in IBD patients (4.0% +/- 0.5% vs. 2.8% +/- 0.4%, before treatment; P = 0.001), with a 2- to 3 fold increase in the intensity of Foxp3 expression. In addition, infliximab treatment enhanced the suppressive function of circulating Tregs, as shown by inhibition of Teff proliferation at a 1:8 Treg/Teff ratio (28% +/- 5% vs. 66% +/- 10%, after treatment; P = 0.04). CONCLUSIONS: These data demonstrate that anti TNFalpha treatment of active IBD rapidly enhances the frequency of functional Foxp3(+) Tregs in blood and potentiates their suppressive function. This indicates that Treg potentiation may represent an unanticipated outcome of anti TNFalpha biotherapy in IBD. PMID- 20848511 TI - Leukocytoclastic vasculitis: A rare adverse effect secondary to infliximab. PMID- 20848512 TI - Are your patients taking their medicine? Validation of a new adherence scale in patients with inflammatory bowel disease and comparison with physician perception of adherence. AB - BACKGROUND: To date no adherence survey has been validated in IBD. The aim was to administer an improved medication adherence survey to IBD patients, to validate the scale in IBD, and to compare the results to perceived adherence by the gastroenterologists. METHODS: IBD patients were given the Morisky Medication Adherence Scale (MMAS-8). To validate the scale, prescription claim information, calculated as continuous single-interval medication availability (CSA) and mean possession ratio (MPR), was correlated to the MMAS-8 scale. Nonpersistence or low adherence was defined as a CSA or MPR<0.8. Treating gastroenterologists, blinded to the instrument, then assessed adherence in these patients. RESULTS: Of 110 IBD patients in the study, MMAS-8 identified 54 patients as low adherers (LAs) to their IBD medication and 56 patients as medium or high adherers (MHAs). Eighty five percent of LAs had nonpersistent fill rates, as per CSA, compared with 11% of MHAs. Physicians correctly classified 95% of patients who were MHAs but only 33% of LAs. Underestimation of adherence only occurred in 5% of patients, whereas overestimation occurred in 67% (P<0.0001). In a linear regression analysis, CSA was significantly correlated with disease activity score (P<0.001). CONCLUSIONS: LAs are a challenge to identify. This study demonstrates that the MMAS-8 scale is a valid instrument for assessing medication adherence in IBD. This is the first adherence scale to be validated in IBD. PMID- 20848513 TI - Gracilis muscle transposition for complex fistula and persistent nonhealing sinus in perianal Crohn's disease. AB - BACKGROUND: Complex fistulas and persistent perineal sinuses as a result of perianal Crohn's disease remain a major therapeutic challenge. A muscle transposition may promote wound healing by filling the perineal cavity and increasing tissue oxygenation. We aimed to evaluate the outcomes of the treatment at our institution over 8 years. METHODS: A retrospective review was performed for patients who underwent gracilis muscle transposition for complex perianal Crohn's disease between 1999 and 2007. Data collected included patients' demographic data, previous treatments (medical and surgical), and outcome of the operation. A structured telephone interview was conducted to evaluate medium- to long-term outcomes of the treatment. RESULTS: Eighteen patients (8 men and 10 women, median age 33 years, range 17-59 years) underwent a gracilis muscle transposition between 1999 and 2007. Fourteen patients had a complex fistula, and 4 patients had a persistent nonhealing perineal sinus. Gracilis muscle transposition healed the perineum of 11 patients (61%) at a median follow-up of 10 months (range 1-88 months). The success rate for complex fistulas was 64% and that for persistent nonhealing perineal sinuses was 50%. Eight graft site infections and delayed healing were noted. There were no donor-site problems or major complication. Healing was maintained in 8 of 9 patients who were available for medium- to long-term follow-up (median 64 months, range 23-123 months), with high patient satisfaction. CONCLUSIONS: Gracilis transposition is a viable option as a treatment for complex perianal Crohn's disease. Efficacy was maintained in nearly 90% of patients in the medium to long term. PMID- 20848514 TI - Strong overexpression of CXCR3 axis components in childhood inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a polygenetic disorder. Our group previously showed that a variant within the CXCL9 gene is associated with pediatric Crohn's disease. As CXCL9, CXCL10, and CXCL11 are the 3 ligands to the receptor CXCR3, the aim of this study was to investigate the colonic transcriptional activity of the CXCR3 axis and to perform SNP genotyping of a CXCL11 polymorphism in a large pediatric and adult IBD cohort. METHODS: mRNA expression of CXCR3, CXCL9, CXCL10, CXCL11, and IL8 was analyzed in colonic biopsies using real-time PCR. CXCL11 rs6817952 nucleotide substitution was determined in 501 German individuals with IBD (336 CD, 165 UC) including 258 children and 243 adults as well as in 231 controls by a TaqMan SNP genotyping assay. RESULTS: CXCR3 axis genes were significantly overexpressed in inflamed colonic tissue of pediatric CD and UC patients. The prevalence of hetero- and homozygous variants of the rs6817952 genotype was higher in pediatric but not in adult CD patients compared with that in controls (P = 0.04). Moreover, carriers of the hetero- and homozygous genotype variants of rs6817952 were at increased risk for UC in all age groups (P = 0.009). CONCLUSIONS: Our study provides evidence of the significant overexpression of the CXCR3 axis in active IBD, suggesting it has a role in IBD pathogenesis. The rs6817952 A variant is a risk allele for pediatric CD and UC in all age groups. Therapeutic studies will have to show whether the blockade of chemokine receptors such as CXCR3 can modulate intestinal inflammation in a clinical application. PMID- 20848515 TI - Development, validation, and responsiveness of a novel disease activity index for intestinal Behcet's disease. AB - BACKGROUND: There is no disease activity index (DAI) currently available that can objectively assess the disease status of intestinal Behcet's disease (BD). The aim of this study was to develop a novel specific DAI for intestinal BD through a prospective study. METHODS: Items included in the index were produced and graded by experts in intestinal BD. Two separate cohorts of patients (weighting and validation cohorts) with intestinal BD were prospectively enrolled, and their clinical and laboratory data were collected. Through weighting items by multiple regression modeling, the DAI for intestinal BD (DAIBD) was derived using the weighting cohort and validated using the validation cohort. The index's responsiveness was evaluated using a longitudinal cohort derived from the weighting cohort at a follow-up visit 2-3 months later. RESULTS: A total of 110 patients with intestinal BD were enrolled in the weighting cohort. Eight of the 17 items selected by the experts accounted for 86.8% of the physician's global assessment (PGA) variance. The DAIBD calculated with gradations of weighted items correlated more strongly with PGA (r=0.850) than did the Crohn's disease activity index (CDAI) (r=0.649) in 50 patients of the validation cohort. Furthermore, quiescent, mild, moderate, and severe could be discriminated using the best cutoff scores. The DAIBD showed much higher responsiveness than did the CDAI (r=0.812 vs. 0.645, respectively) in 109 patients in the longitudinal cohort. CONCLUSIONS: This novel DAIBD is an easy, valid, and responsive index to assess disease activity and can be useful to physicians who treat intestinal BD. PMID- 20848517 TI - Single-port laparoscopic access for Crohn's disease complicated by enterocutaneous fistula. PMID- 20848516 TI - The role of self-efficacy in inflammatory bowel disease management: preliminary validation of a disease-specific measure. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) require self-management skills that may be influenced by self-efficacy (SE). Self-efficacy represents an individual's perception of his or her ability to organize and execute the behaviors necessary to manage disease. The goal of this study was to develop a valid and reliable measure of IBD-specific SE that can be used in clinical and research contexts. METHODS: One hundred and twenty-two adults with a verified IBD diagnosis participated in the study. Data were pooled from 2 sources: patients from an outpatient university gastroenterology clinic (n=42) and a sample of online respondents (n=80). All participants (N=122) completed the IBD Self Efficacy Scale (IBD-SES) and the Inflammatory Bowel Disease Questionnaire. Additionally, online participants completed the Brief Symptom Inventory-18 and the Rosenberg Self-Esteem Scale, whereas those in the clinic sample completed the Perceived Health Competence Scale, the Perceived Stress Questionnaire, and the Short Form Version 2 Health Survey. RESULTS: The IBD-SES was initially constructed to identify 4 distinct theoretical domains of self-efficacy: (1) managing stress and emotions, (2) managing medical care, (3) managing symptoms and disease, and (4) maintaining remission. The 29-item IBD-SES has high internal consistency (r=0.96), high test-retest reliability (r=0.90), and demonstrates strong construct and concurrent validity with established measures. CONCLUSIONS: The IBD-SES is a critical first step toward addressing an important psychological construct that could influence treatment outcomes in IBD. PMID- 20848518 TI - Thrombosis and inflammatory bowel disease: a call for improved awareness and prevention. AB - Thrombotic complications in patients with inflammatory bowel disease (IBD) are common and require improved awareness and prevention. In this review the interface between IBD and thrombosis is discussed, with emphasis on risk assessment and data to aid clinical decision making. Thromboembolic complications are 3-fold more likely in IBD patients than controls and the relative risk exceeds 15 during disease flares. Improved assessment of thrombosis risk for an individual patient includes thorough personal and family history and awareness of prothrombotic medications and lifestyle choices. Patients with the highest risk of thrombosis are those with active colonic disease, personal or strong family history of thrombosis, and those with significant acquired risk factors. Combined risk factors or hospitalization should prompt mechanical thromboprophylaxis. Indications for prophylactic anticoagulation are not defined currently by clinical studies, especially in pediatric patients, although some groups now advocate prophylactic anticoagulation for all hospitalized IBD patients and even some outpatients with disease flares. Thrombosis management requires a multidisciplinary therapeutic approach to balance anticoagulation and bleeding risk. While bleeding may occur with anticoagulation in IBD, data and experience indicate that therapeutic heparin is safe and bleeding manifestations can be managed supportively in most patients. Until prospective trials of prophylactic anticoagulation are published, management of thrombotic risk and prophylaxis in IBD will remain a clinical challenge. PMID- 20848519 TI - Predicting the need for surgery in obstructive Crohn's disease: how hot is PET/CT? PMID- 20848520 TI - Liver diseases associated with anti-tumor necrosis factor-alpha (TNF-alpha) use for inflammatory bowel disease. AB - The conventional treatment of inflammatory bowel disease (IBD) has focused on nonspecifically targeting mucosal inflammation. In the last decade, with the advent of novel biological agents that directly inhibit proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), rapid progress has been made in clinical management of complex and challenging patients with IBD. However, there remain many unanswered questions about the short and long-term side effects; this article focuses on hepatic complications. This review aims to provide a concise update to gastroenterologists on the well-known, as well as the potential rare consequences of anti-TNFalpha therapy on the liver and recommendations for clinical management. We performed a focused literature review for reports of the effect of anti-TNF therapy on preexisting liver disease as well as de novo hepatitis and drug-induced hepatotoxicity. Search terms used included anti-TNF therapy, biologics, liver disease, inflammatory bowel disease, hepatitis, hepatotoxicity, opportunistic infections,, and hepatitis virus reactivation. There are multiple potential effects of anti-TNF therapy on the liver during treatment of patients with IBD. Often treatment may be complicated by preexisting chronic liver disease. Clinicians should be aware of potential hepatic side effects and appropriate management options. PMID- 20848521 TI - Intestinal tissue kallikrein-kinin system in inflammatory bowel disease. AB - Tissue kallikrein cleaves kininogens to release kinins. Kinins mediate inflammation by activating constitutive bradykinin receptor-2 (BR2), which are rapidly desensitized, and induced by inflammatory cytokines bradykinin receptor-1 (BR1), resistant to desensitization. Intestinal tissue kallikrein (ITK) may hydrolyze growth factors and peptides, whereas kinins are responsible for capillary permeability, pain, synthesis of cytokines, and adhesion molecule neutrophil cascade. Our and others results have demonstrated ITK in intestinal goblet cells and its release into interstitial space during inflammation. Kallistatin, an inhibitor of ITK, has been shown in epithelial and goblet cells, and was decreased in inflamed intestine as well as in plasma compared with noninflammatory controls. BR1 was upregulated in patients with inflammatory bowel disease (IBD), and it has expressed in an apical part of enterocytes in inflamed intestine, but in the basal part in normal intestine. ITK and BR1 were visualized in macrophages forming granuloma in Crohn's disease. In animal studies BR2 blockade decreased intestinal contraction, but had limited effect on inflammatory lesions. BR1 was found to be upregulated in animal inflamed intestine, in part dependent on tumor necrosis factor alpha (TNF-alpha). A selective BR1 receptor antagonist decreased morphological and biochemical features of experimental intestinal inflammation. Both BR1 and BR2 mediate epithelial ion transport that leads to secretory diarrhea. The upregulation of BR1 in inflamed intestine provides a structural basis for the kinins function, suggesting that a selective BR1 antagonist may have potential in therapeutic trial of IBD patients. PMID- 20848522 TI - Breastfeeding in inflammatory bowel disease: positive results for mother and child. PMID- 20848523 TI - Risk-benefit analysis of adalimumab versus traditional non-biologic therapies for patients with Crohn's disease. AB - BACKGROUND: Adalimumab is indicated for the treatment of moderately to severely active Crohn's disease (CD). A systematic analysis of risks and benefits of adalimumab versus traditional non-biologic therapies for patients refractory to non-biologic therapy is lacking. METHODS: A base-case analysis compared expected benefits of adalimumab therapy with a 12-week stopping rule for non-responders versus non-biologic therapies using data from clinical trials (CHARM, CLASSIC I). Adverse events (AEs) recorded in clinical trials (CHARM, CLASSIC I, CLASSIC II, GAIN, open-label extensions) were compiled. Sensitivity analyses incorporated all observed benefits of adalimumab and placebo (CHARM, CLASSIC I, GAIN) and observed AEs from a systematic literature review of non-biologic therapies (MEDLINE search of randomized trials 1990-2007). Distributional information from maintenance clinical trial observations and benefit model predictions were used in a probabilistic simulation. Incremental net benefits were estimated based on utility estimates from the literature. RESULTS: Average time in remission (i.e., CDAI <150) over 1 year of therapy was 39.9% for adalimumab versus 6.6% for traditional non-biologic therapies. Adalimumab was associated with fewer expected hospitalizations, better fistula closure rates, and lower AE rates. These findings were robust in sensitivity analyses. In the probabilistic simulation, with serious AEs as a composite of risks, adalimumab provided greater benefits with fewer AEs versus non-biologic therapies (P < 0.01). Adalimumab demonstrated greater incremental net quality-adjusted life-years (0.12) versus non-biologic therapies. CONCLUSIONS: Adalimumab demonstrated greater benefits and lower rates of AEs versus traditional non-biologic therapies for patients with moderately to severely active CD who were refractory to non-biologic therapies. PMID- 20848524 TI - Association of FcgR2a, but not FcgR3a, with inflammatory bowel diseases across three Caucasian populations. AB - BACKGROUND: The Fc receptors II and III (FcgR2a, and FcgR3a) play a crucial role in the regulation of the immune response. The FcgR2a*519GG and FcgR3a*559CC genotypes have been associated with several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, nephritis, and possibly to type I diabetes, and celiac disease. In a large multicenter, two-stage study of 6570 people, we tested whether the FcgR2a and FcgR3a genes were also involved in inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We genotyped the FcgR2a*A519G and FcgR3a*A559C functional variants in 4205 IBD patients in six well-phenotyped Caucasian IBD cohorts and 2365 ethnically matched controls recruited from the Netherlands, Spain, and New Zealand. RESULTS: In the initial Dutch study we found a significant association of FcgR2a genotypes with IBD (P-genotype = 0.02); while the FcgR2a*519GG was more common in controls (23%) than in IBD patients (18%; odds ratio [OR] = 0.75; 95% confidence interval [CI] 0.61-0.92; P = 0.004). This association was corroborated by a combined analysis across all the study populations (Mantel-Haenszel [MH] OR = 0.84; 0.74-0.95; P = 0.005) in the next stage. The Fcgr2a*GG genotype was associated with both UC (MH-OR = 0.84; 0.72 0.97; P = 0.01) and CD (MH-OR = 0.84; 0.73-0.97; P = 0.01), suggesting that this genotype confers a protective effect against IBD. There was no association of FcgR3a*A559C genotypes with IBD, CD, or UC in any of the three studied populations. CONCLUSIONS: The FcgR2a*519G functional variant was associated with IBD and reduced susceptibility to UC and to CD in Caucasians. There was no association between FcgR3a*5A559C and IBD, CD or UC. PMID- 20848525 TI - Adalimumab for the treatment of fistulas in patients with Crohn's disease. PMID- 20848526 TI - Specific differences in migratory function of myofibroblasts isolated from Crohn's disease fistulae and strictures. AB - BACKGROUND: Recently we found that migration of colonic lamina propria fibroblasts in Crohn's disease patients (CD-CLPF) from inflamed mucosa is significantly reduced as compared to control-CLPF. The behavior of CD-CLPFs isolated from fistulae and strictures was now investigated in detail. METHODS: Initially migration assays for all CLPF cultures (CD-CLPF, fibrosis-CLPF, and fistula-CLPF) were performed in the modified 48-well Boyden chamber. Subsequently, for a migration assay more resembling the in vivo situation a 3D matrix model was developed. After seeding of cells into the 3D matrix the CLPF layer was wounded by an ERBIUM:YAG laser leading to circular cell rupture without effect on the extracellular matrix. RESULTS: In the modified Boyden chamber migration of fistula-CLPF was significantly reduced compared to CD-CLPF. This was correlated with a decrease in FAK-protein expression, whereas in migrating fibrosis-CLPF an increase in FAK-protein expression, -autophosphorylation and migratory potential was found. This was confirmed in the 3D matrix wounding assay: Fistula-CLPF migrated less than CD-CLPF, whereas fibrosis-CLPF migrated significantly more in the 3D matrix wounding assay. Between 1 to 36 hours incubation time fibrosis-CLPF always displayed increased migration ability as compared to CD-CLPF. In contrast, fistula-CLPF migratory potential was always below that of CD-CLPF. CONCLUSIONS: Myofibroblasts isolated from inflamed, fibrostenotic, or fistulized CD mucosa differ in their migratory potential both in the modified Boyden chamber as well as in a 3D matrix model. These different migratory behaviors could be an explanation for impaired or excess wound healing and subsequently for fistula and fibrosis formation. PMID- 20848527 TI - Randomized, placebo-controlled, double-blind trial of Boswellia serrata in maintaining remission of Crohn's disease: good safety profile but lack of efficacy. AB - BACKGROUND: Complementary therapies are frequently used by patients with inflammatory bowel disease (IBD). The aim of this study was to evaluate the efficacy and safety of long-term therapy with a new Boswellia serrata extract (Boswelan, PS0201Bo) in maintaining remission in patients with Crohn's disease (CD). METHODS: In 22 German centers a double-blind, placebo-controlled, randomized, parallel study was performed. In all, 108 outpatients with CD in clinical remission were included. Patients were randomized to Boswelan (3*2 capsules/day; 400 mg each) or placebo for 52 weeks. The primary endpoint was the proportion of patients in whom remission was maintained throughout the 52 weeks. Secondary endpoints were time to relapse, changes of Crohn's Disease Activity Index (CDAI), and IBD Questionnaire (IBDQ) scores. RESULTS: The trial was prematurely terminated due to insufficient discrimination of drug and placebo with regard to the primary efficacy endpoint. A total of 82 patients were randomized to Boswelan (n=42) or placebo (n=40). Sixty-six patients could be analyzed for efficacy. 59.9% of the actively treated patients and 55.3% of the placebo group stayed in remission (P=0.85). The mean time to diagnosis of relapse was 171 days for the active group and 185 days for the placebo group (P=0.69). With respect to CDAI, IBDQ, and laboratory measurements of inflammation, no advantages in favor of active treatment were detected. Regarding safety concerns, no disadvantages of taking the drug compared to placebo were observed. CONCLUSIONS: The trial confirmed good tolerability of a new Boswellia serrata extract, Boswelan, in long-term treatment of CD. However, superiority versus placebo in maintenance therapy of remission could not be demonstrated. PMID- 20848528 TI - Anxiety and depression in patients with inflammatory bowel disease: comparisons with chronic liver disease patients and the general population. AB - BACKGROUND: Studies on anxiety and depression in inflammatory bowel disease (IBD) yielded inconsistent results. We compared anxiety and depression of patients with Crohn's disease (CD) and ulcerative colitis (UC) controlled for sociodemographic and medical variables with age- and sex-matched controls. METHODS: In all, 422 IBD patients (50% females, 314 CD, 108 UC) of different settings were compared with 140 age- and sex-matched patients with chronic liver diseases (CLD) of a tertiary care center and with 422 age- and sex-matched persons of a representative sample of the general German population (GP). Anxiety and depression and probable mental disorder were assessed by the German version of the Hospital Anxiety and Depression Scale. Comparisons between CD and UC were adjusted for medical (disease activity, number of IBD-associated diseases) and sociodemographic factors (age, gender, marital status). RESULTS: CD and UC patients did not differ in the levels of anxiety and depression or in the frequency of a probable mental disorder. The levels of anxiety and depression of IBD patients with active disease were higher than that of the GP, but not of the IBD patients in remission. The depression score of the CLD sample was higher than that of the IBD sample (P<0.001), but not the anxiety score. Mental disorders were more frequent in IBD patients with slight (27.7%) and moderate/severe disease activity (49.3%) compared to GP (10.4%) (P<0.001), but not in IBD patients in remission (11.3%). CONCLUSIONS: Patients with active IBD should be screened for anxiety and depression. PMID- 20848529 TI - Lymphocytic esophagitis: a possible manifestation of pediatric upper gastrointestinal Crohn's disease. AB - BACKGROUND: Lymphocytic esophagitis (LE) is histologically defined by marked esophageal lymphocytosis with no or only rare intraepithelial granulocytes. This study was performed to investigate the association between LE and pediatric Crohn's disease (CD). METHODS: Blinded retrospective morphologic analysis was performed on gastrointestinal biopsies from pediatric patients with an established diagnosis of CD (n = 60) and ulcerative colitis (UC; n = 30), as well as a spectrum of non-inflammatory bowel disease (IBD) patients (n = 38). The highest density of intraepithelial lymphocytes (IEL), neutrophils (IEN), and eosinophils (IEE) per high power field (hpf; 40*) were counted. LE was defined as >50 IEL/hpf and a ratio of >50:1 IEL to intraepithelial granulocytes (IEG). RESULTS: LE was identified in 17/60 patients with CD, and only 2/30 patients with UC and 1/38 non-IBD control patients; P = 0.0263 (CD versus UC) and P = 0.0002 (CD versus non-CD). In all, 6/60 CD patients had esophagitis with granulomas and three of these met the diagnostic criteria for LE. There was no difference in the incidence of upper gastrointestinal (UGI) symptoms between the CD patients with LE (7/17, 41%) and CD patients with esophagitis with granulomas (3/6; P = 1.0). CONCLUSIONS: The histologic diagnosis of LE is associated with pediatric CD and was found in 28% of CD patients. If LE is identified in pediatric CD, it is likely a manifestation of UGI-CD rather than esophagitis due to other etiologies or a variant of normal. PMID- 20848530 TI - Thiazolidinedione use and ulcerative colitis-related flares: an exploratory analysis of administrative data. AB - BACKGROUND: Recent animal studies and clinical trials suggest that thiazolidinediones, a class of oral antidiabetic agents, are efficacious in reducing inflammation, yet no studies have evaluated their effectiveness in preventing flares. We examined the association between thiazolidinedione use and ulcerative colitis (UC)-related flares. METHODS: We conducted a retrospective cohort study using administrative data from 87 health plans across 33 states. Individuals with both UC and diabetes were identified using administrative definitions. Exposure to thiazolidinediones or other oral antidiabetic agents was ascertained through outpatient pharmacy claims. The primary outcome was occurrence of a UC flare defined by: 1) a new prescription for oral steroids, infliximab, or oral/rectal salicylates, or 2) a claim for colectomy. Secondary analyses analyzed outcomes separately. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression after matching each thiazolidinedione user to a comparable oral antidiabetic user on propensity score. RESULTS: This study included 142 thiazolidinedione and 468 other oral antidiabetic users with a mean follow-up of 7.3 and 6.2 months, respectively. Thiazolidinedione use was not associated with UC-related flares as measured by the composite outcome (HR = 1.05, 95% CI: 0.66, 1.68). However, thiazolidinedione use was associated with a nonsignificant reduction in risk of oral steroid use when analyzed as a separate outcome (HR = 0.53, 95% CI: 0.20, 1.44). CONCLUSIONS: Thiazolidinediones do not provide any benefit over other oral antidiabetics in preventing UC-related flares as measured by our primary composite outcome. However, thiazolidinedione use may reduce the risk of more significant disease flares requiring oral steroid treatment. PMID- 20848531 TI - Risk factors for colectomy in ulcerative colitis patients with severe flare-up: some of the few things comparable between the US and Central Europe. PMID- 20848533 TI - Bacterial induction of proinflammatory cytokines in inflammatory bowel disease. AB - It has become increasingly clear that inflammatory bowel disease (IBD) develops on the background of genetic defects in the host, conveying an increased susceptibility to an environmental antigen or antigens. The environmental factor implicated in the pathophysiology of gut inflammation, which is undergoing increased scrutiny, is the intestinal flora. The intestinal flora as a whole and specific bacteria and their products have been found to trigger cytokine expression in various cell types. Consistently, multiple bacterial strains were found to induce tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) in macrophage and epithelial cell systems, respectively, in particular in Crohn's disease. Interestingly, various cell types from patients with IBD display an increased susceptibility to specific bacterial products, including flagellin, pili, and lipopolysaccharides. It remains to be determined whether additional effector proteins regulate cytokine expression and the aberrant mucosal immune response in IBD. PMID- 20848532 TI - Endogenous IGFBP-3 regulates excess collagen expression in intestinal smooth muscle cells of Crohn's disease strictures. AB - BACKGROUND: Stricture formation occurs in ~30% of patients with Crohn's disease (CD) and is a significant cause of morbidity. Strictures are characterized by intestinal smooth muscle cell hyperplasia, smooth muscle cell hypertrophy, and fibrosis due to excess net extracellular matrix production, including collagen. Transforming growth factor-beta1 (TGF-beta1) has profibrotic effects in many tissues due to its ability to regulate collagen expression and extracellular matrix dynamics. We previously showed that both insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) and TGF-beta1 are expressed by normal human intestinal smooth muscle cells, bind to, and activate TGF-betaRII/I receptors in these cells. METHODS: Smooth muscle cells isolated from the muscularis propria of patients were used to prepare RNA, protein lysates, or placed into primary culture. IGFBP-3, TGF-beta1, and collagen IalphaI expression was measured with quantitative reverse-transcription polymerase chain reaction (RT-PCR) and protein levels by enzyme-linked immunosorbent assay (ELISA) or immunoblot. RESULTS: Expression and production of IGFBP-3, TGF-beta1, and collagen IalphaI were significantly increased specifically in smooth muscle cells isolated from regions of strictured intestine in CD compared to nonstrictured histologically normal resection margin. IGFBP-3 and TGF-beta1 regulated collagen IalphaI expression and production via a TGF-betaRII/I-dependent and Smad2/3-dependent mechanism. Upregulated (excess) collagen IalphaI expression and production in smooth muscle cells of strictures and basal collagen IalphaI in smooth muscle cells of normal margin were inhibited by immunoneutralization of IGFBP-3 or TGF-beta1. CONCLUSIONS: The findings indicate that upregulated endogenous IGFBP-3 and TGF beta1 expression regulates excess collagen IalphaI production and contributes to fibrosis and stricture formation in CD. PMID- 20848534 TI - New insights into the role of IL-17 in inflammatory bowel disease. PMID- 20848535 TI - Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens. AB - BACKGROUND: High antibody reactivity toward microbial antigens in Crohn's disease (CD) patients is predictive of a more aggressive disease course. However, few ulcerative colitis (UC) patients exhibit serologic reactivity toward microbial antigens. Mucosal expression of IFN-gamma plays a pivotal role in inflammatory bowel disease (IBD) pathogenesis. Recent genome-wide association studies (GWAS) surprisingly link UC, but not CD, risk loci to IFNG. We recently demonstrated that mucosal T cells from IBD patients exhibit distinct patterns of IFNG methylation compared to controls. This study evaluated the relationship between IFNG methylation and serologic and clinical profiles in peripheral T cells from IBD patients. METHODS: DNA from peripheral T cells of 163 IBD patients (91 CD and 64 UC) and 42 controls was analyzed for methylation of eight IFNG sites. Serum markers ASCA, OmpC, I2, CBir, and pANCA were measured by enzyme-linked immunosorbent assay (ELISA). IFN-gamma secretion was measured by ELISA. RESULTS: IBD patients requiring surgery exhibited reduced IFNG methylation compared to nonsurgical patients (P < 0.02). Enhancement of IFN-gamma secretion (P < 0.003), along with high antibody responses toward multiple microbial antigens (P < 0.017) in UC, but not CD, patients was correlated with decreased IFNG methylation. pANCA levels were not correlated with IFNG methylation. CONCLUSIONS: Levels of IFNG methylation were correlated with immune response to microbial components and expression of IFN-gamma in UC patients. Serological and epigenetic markers identify a subset of UC patients with an expression profile of a key TH1 pathogenic cytokine. These data may provide a useful tool to classify a more homogeneous subset of UC patients, allowing for improved diagnostics and targeted therapeutics. PMID- 20848536 TI - Expression profiling of Wnt family of genes in normal and inflammatory bowel disease primary human intestinal myofibroblasts and normal human colonic crypt epithelial cells. AB - BACKGROUND: Wnt signaling regulates intestinal epithelial stem cell function. Wnt ligands bind Frizzled (Fz) receptors and low-density lipoprotein-receptor-related protein (LRP) 5 and 6. Secreted Frizzled-related protein (SFRP) and Dickkopf families inhibit Wnt signaling. Our aim was to study expression of Wnt family of genes in isolated intestinal myofibroblasts and crypt epithelial cells. METHODS: Myofibroblasts were isolated from normal colonic and small intestinal mucosal samples and those affected by ulcerative colitis (UC) and Crohn's disease. Expression of the Wnt family of genes was studied by polymerase chain reaction (PCR) array. Epithelial proliferation was studied using IEC-6 cells. RESULTS: Most of the myofibroblast isolates expressed Wnt2, Wnt5A, Wnt5B, Fzd1, Fzd2, Fzd4, Fzd6, Fzd7, Fzd8, LRP6, Dickkopf1, and SFRP1. Compared to myofibroblasts isolated from normal colonic mucosal samples, real-time reverse transcription-PCR studies (using additional isolates) showed significantly reduced expression of SFRP1 in UC myofibroblasts (3.34-fold reduction, P < 0.01). Recombinant SFRP1 inhibited proliferation of IEC-6 epithelial cells. In colonic crypt epithelial cells, expression of Wnt ligands and their inhibitors was generally either absent or very weak. By contrast, all the crypt epithelial preparations expressed Fzd1, Fzd5, Fzd7, Fzd8, and LRP6. CONCLUSIONS: Human intestinal myofibroblasts expressed a number of Wnt ligands, their receptors, and inhibitors. In contrast, colonic crypt epithelial cells predominantly expressed Wnt receptors. Compared to myofibroblasts isolated from normal colonic mucosa, those affected by UC showed significantly reduced expression of SFRP1. Since reduced SFRP1 expression has been associated with malignancy, low myofibroblast expression of this Wnt inhibitor may be implicated in increased risk of cancer in UC. PMID- 20848538 TI - Crohn's disease activity index does not correlate with endoscopic recurrence one year after ileocolonic resection. AB - BACKGROUND: Crohn's disease clinical trials utilize the Crohn's Disease Activity Index (CDAI) to measure primary endpoint assessments of clinical recurrence and remission. We evaluated the extent of agreement between clinical recurrence/remission as defined by the CDAI and endoscopic recurrence 1 year after intestinal resection for Crohn's disease (CD). METHODS: Twenty-four CD patients who had been randomly assigned to a postoperative clinical trial had 1 year clinical, endoscopic, and histological assessment for disease recurrence. The primary endpoint was the extent of agreement between endoscopic recurrence and clinical recurrence 1 year after intestinal resection for CD. Secondary endpoints were extent of agreement between endoscopic recurrence and the surrogate markers of CD activity, i.e., histological activity, sedimentation rate, and C-reactive protein (CRP). RESULTS: Twelve of the 24 patients (50%) were in endoscopic remission (i0, i1) and 12 (50%) had endoscopic recurrence (i2, i3, or i4). There was good agreement between endoscopy and histological activity scores (intraclass correlation coefficient = 0.53, kappa coefficient = 0.58). In contrast, there was little to no relationship between endoscopy and CDAI scores; median CDAI scores for endoscopy scores of i0/i1, i2, i3, and i4 were 118, 76, 156, and 78, respectively (P for trend = 0.88). The kappa coefficient (of agreement) between endoscopy score +/- 2 and CDAI score +/- 150 was 0.12 (exact P = 0.68), indicating poor agreement. Similarly, there was no consistent association observed between endoscopy scores and mean CRP and ESR values at week 54. CONCLUSIONS: The CDAI shows poor agreement with endoscopic recurrence 1 year after intestinal resection. Endoscopic recurrence should be the primary endpoint of future postoperative studies and ileocolonoscopy the gold standard test to detect postoperative recurrence. PMID- 20848539 TI - Frequent occurrence of gastritis and duodenitis in patients with inflammatory bowel disease. AB - BACKGROUND: The purpose was to study the epidemiology of Helicobacter-negative gastritis among a large group of patients with inflammatory bowel disease (IBD) and healthy controls. METHODS: From a computerized database of surgical pathology reports we selected 5493 patients who underwent colonoscopy and upper gastrointestinal endoscopy with biopsy results from both procedures. The presence of gastritis and duodenitis was compared among 550 case subjects with IBD and 4943 healthy control subjects. The results are expressed as prevalence rates, as well as age- and sex-adjusted odds ratios with 95% confidence intervals. RESULTS: Any type gastritis was found in 13% of controls and 25% of IBD patients (Crohn's disease [CD] 33%, ulcerative colitis [UC] 19%). Duodenitis was found in 1% of controls and 13% of IBD patients (CD 26%, UC 3%). In subjects younger than 18 years the prevalence of gastritis and duodenitis were 53% and 40% in CD, respectively, and 38% and 0% in UC, respectively. Similar prevalence rates were found in men and women. The odds ratio for Helicobacter-negative chronic active gastritis associated with CD was 11.7 (7.5-18.0) and with UC 2.8 (1.4-5.0). The corresponding values for focally enhanced gastritis were 40.1 (15.5-114.9) in CD and 0 in UC. CONCLUSIONS: Helicobacter-negative gastritis and duodenitis occur significantly more often in patients with IBD than healthy controls. Such upper gastrointestinal inflammation appears to be particularly common in CD and younger patients. PMID- 20848540 TI - Physician density and hospitalization for inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel diseases (IBDs) are chronic illnesses that require frequent and regular healthcare contact. Regular maintenance care may reduce complications or the need for hospitalization. Availability of physicians may be an important determinant of IBD hospitalizations. METHODS: Using 2008 inpatient data from the Wisconsin Hospital Association, we identified all IBD hospitalizations through ICD-9-CM discharge codes. County-level rates of primary care physicians and gastroenterologists were calculated for each county (using data from the American Medical Association and the US Census Bureau), with counties in the highest tertile by physician density being classified as "high density" counties. Multivariate regression analysis was performed to identify the independent effect of physician density on IBD outcomes. RESULTS: A total of 26 counties were defined as high density (mean physician density 162/100,000 population; 2090 IBD hospitalizations) with the remaining 46 counties being low density counties (mean physician density 78/100,000 population; 3441 hospitalizations). The overall rate of IBD hospitalizations was similar for residents of high and low density counties. However, hospitalizations from low physician density counties were more likely to have hypovolemia (26% versus 22%, P=0.003), malnutrition (5.6% versus 4.3%, P=0.04), Clostridium difficile infection (4.1% versus 1.9%, P<0.001), require total parenteral nutrition (TPN) (4.3% versus 2.5%, P<0.001), or be admitted emergently (41.5% versus 35.1%, P<0.001). Residence in a county with high physician density was associated with 4% shorter length of stay and 10% lower hospitalization charges. CONCLUSIONS: Residence in counties with high physician density is associated with less complicated disease on hospitalization and lower hospitalization charges for IBD. PMID- 20848541 TI - Infliximab for severe peripheral ulcerative keratopathy revealing Crohn's disease. PMID- 20848537 TI - The struggle within: microbial influences on colorectal cancer. AB - Recently, an unprecedented effort has been directed at understanding the interplay between chronic inflammation and development of cancer, with the case of inflammatory bowel disease (IBD)-associated colorectal cancer at the forefront of this research endeavor. The last decade has been particularly fertile, with the discovery of numerous innovative paradigms linking various inflammatory, proliferative, and innate and adaptive immune signaling pathways to the development of colorectal cancer. Because of the preponderant role of the intestinal microbiota in the initiation and progression of IBD, recent efforts have been directed at understanding the relationship between bacteria and colorectal cancer. The microbiota and its collective genome, the microbiome, form a diverse and complex ecological community that profoundly impacts intestinal homeostasis and disease states. This review will discuss the differential influence of the microbiota on the development of IBD-associated colorectal cancer and highlight the role of innate immune sensor-dependent as well as independent mechanisms in this pathology. PMID- 20848543 TI - Use of complementary and alternative medicine by patients with inflammatory bowel disease. AB - In this review article we provide a broad overview of complementary and alternative medicine (CAM) use in inflammatory bowel diseases (IBDs), including prevalence of use, common therapies used, and reasons for and factors associated with CAM use. CAM is commonly used by those suffering from IBD. Multiple forms of CAM are used to treat IBD, and often patients use multiple CAM therapies and continue to use conventional medical therapies. Patients using CAM report benefits that extend beyond simply improved disease control. Using CAM allows patients to exert a greater degree of control over their disease and its management than they are afforded by conventional medicine. There is limited evidence on the efficacy of CAM therapies in IBD. It is important for physicians caring for those with IBD to be familiar with common forms of CAM and to be able to provide general counseling to their patients about CAM use. PMID- 20848542 TI - Dynamic changes in the expression of MicroRNA-31 during inflammatory bowel disease-associated neoplastic transformation. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. Aberrant microRNA (miR) expression has been linked to carcinogenesis; however, no reports document a relationship between IBD related neoplasia (IBDN) and altered miR expression. In the current study we sought to identify specific miR dysregulation along the normal-inflammation cancer axis. METHODS: miR microarrays and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect dysregulated miRs. Receiver operating characteristic curve analysis was employed to test for potential usefulness of miR-31 as a disease marker of IBDNs. In silico prediction analysis, Western blot, and luciferase activity measurement were employed for target identification. RESULTS: Several dysregulated miRs were identified between chronically inflamed mucosae and dysplasia arising in IBD. MiR-31 expression increases in a stepwise fashion during progression from normal to IBD to IBDN and accurately discriminated IBDNs from normal or chronically inflamed tissues in IBD patients. Finally, we identified factor inhibiting hypoxia inducible factor 1 as a direct target of miR-31. CONCLUSIONS: Our study reveals specific miR dysregulation as chronic inflammation progresses to dysplasia. MiR-31 expression levels increase with disease progression and accurately discriminates between distinct pathological entities that coexist in IBD patients. The novel effect of miR-31 on regulating factor inhibiting hypoxia inducible factor 1 expression provides a new insight on the pathogenesis of IBDN. PMID- 20848544 TI - Osteoprotegerin in pediatric Crohn's disease and the effects of exclusive enteral nutrition. AB - BACKGROUND: Osteoprotegerin (OPG) may have proinflammatory roles in addition to its contribution to the maintenance of bone mass. Exclusive enteral nutrition (EEN) is an established therapy for the induction of remission in Crohn's disease (CD). The aims of this study were to ascertain serum, fecal, and mucosal expression of OPG in children with CD and to investigate the effects of EEN on OPG expression. METHODS: OPG was measured by enzyme-linked immunosorbent assay in serum, mucosal, and fecal samples collected from children with CD and controls. Fecal and Serum OPG was measured prior to and following 6-8 weeks of EEN therapy. RESULTS: Children with CD (n=82) and controls (n=45) were included. Mucosal and fecal OPG levels were elevated in CD compared to controls (P=0.018 and P<0.0001, respectively). Serum OPG was elevated in children with severe CD (P=0.005). Serum and fecal OPG levels dropped significantly following EEN therapy (P=0.0001 and P=0.002, respectively). CONCLUSIONS: Increased serum and fecal OPG are seen in active CD and likely originate from the inflamed gut. Fecal and serum OPG decrease following EEN therapy. Further investigation of OPG and related proteins in the setting of IBD is now required. PMID- 20848545 TI - Information needs and preferences of recently diagnosed patients with inflammatory bowel disease. AB - BACKGROUND: The aim of this study was to assess the information needs and experiences of patients who were recently diagnosed with inflammatory bowel disease (IBD). METHODS: Seventy-four patients, diagnosed with Crohn's disease or ulcerative colitis, 3-24 months previously were recruited from gastroenterology practices and completed the information needs survey. RESULTS: The most frequent sources of information in the first 2 months after diagnosis were the gastroenterologist and the Internet. In all, 24% of patients reported feeling dissatisfied with the information they were given at the time of their diagnosis, 31% were moderately satisfied, and 45% were very satisfied. There were many areas of information about the disease, its treatment, and self management that patients considered to be important and received little or no information about. When patients described how they would prefer to receive information if they were considering a new treatment in the future, 68% indicated that they preferred information from a medical specialist. CONCLUSIONS: Given the large number of topics judged by patients to be important and the complexity of the information required, it would be very difficult to communicate this information in oral discussion during typical consultation visits. Supplementing physician-patient consultations with well-designed written information or a Website recommendation may produce more effective communication and education. Patients rated these sources of information as having a high level of acceptability. PMID- 20848546 TI - Validation of a lower radiation computed tomography enterography imaging protocol to detect Crohn's disease in the small bowel. AB - BACKGROUND: The purpose was to validate a lower radiation dose computed tomography enterography (CTE) imaging protocol to detect the presence of Crohn's disease (CD) in the small bowel using two different reference standards and to identify a prediction model based on CTE signs for the presence of active CD. METHODS: This retrospective study included patients with known or suspected CD who underwent CTE between January and October 2006 according to a lower radiation dose protocol. Two gastrointestinal radiologists blindly and independently classified each CTE as being active or inactive. Reference standards included ileocolonoscopy +/- biopsy and a comprehensive clinical reference standard (retrospectively created by a gastroenterologist, also including history, physical, follow-up course, and subsequent endoscopy, imaging, or surgery). Logistic regression was used to identify CTE findings that predicted the presence of active CD based on the combined clinical reference standard. RESULTS: In all, 137 patients underwent CTE and ileocolonoscopy. Using an endoscopic reference standard, the sensitivity of CTE to detect active CD for the two readers was 81% and 89%, respectively. Using the clinical reference standard, the sensitivity of CTE to detect active CD was 89% and 98%, respectively. For both readers the sensitivity of CTE increased by 8%-9% when using the comprehensive reference standard. Multivariate analysis showed that a combination of mural thickness and hyperenhancement best predicted active CD (area under the curve [AUC] = 0.92 0.93, P < 0.0001). CONCLUSIONS: Lower radiation dose CTE exams are sensitive for the detection of active small bowel CD. The combination of mural thickness and hyperenhancement are the best radiologic predictors of active CD. PMID- 20848547 TI - Ulcerative colitis-associated colorectal cancer shows a poorer survival than sporadic colorectal cancer: a nationwide Japanese study. AB - BACKGROUND: The clinicopathological features of ulcerative colitis-associated colorectal cancer (UC-CRC) have not yet been fully clarified, especially in Asian populations. This study aimed to clarify the prognosis and clinicopathological features of UC-CRC in comparison with sporadic CRC in the Japanese population. METHODS: Histologically diagnosed UC-CRC patients between 1978 to 1998 were extracted from the Multi-Institutional Registry of Large-Bowel Cancer in Japan, a large nationwide CRC database, and the clinicopathological features and postoperative survival rates of UC-CRC patients and sporadic CRC patients were compared. RESULTS: Among the 108,536 CRC patients registered between 1978 and 1998, a total of 169 UC-CRC patients were identified, including 121 patients who had been treated surgically. The proportion of UC-CRC patients increased in the period between 1995 and 1998 compared to that between 1978 and 1994. Comparisons with the sporadic CRC patients showed that the UC-CRC patients were younger, had a higher proportion of multiple cancer lesions, had higher proportions of superficial type lesions and invasive type lesions morphologically, and had higher proportions of mucinous or signet ring cell carcinomas. In stage III, UC CRC patients had a poorer survival rate than the sporadic CRC patients (43.3% versus 57.4%, P = 0.0320). CONCLUSIONS: UC-CRC increased over the investigated time periods and showed a poorer survival than sporadic CRC in the advanced stage, while no difference was observed in the early stage. By detecting UC-CRC at an early stage we can expect a similar postoperative outcomes to that of sporadic CRC. These results stress the importance of surveillance for the early detection of UC-CRC. PMID- 20848548 TI - Introduction to Cochrane systematic reviews. PMID- 20848549 TI - How different from random are docking predictions when ranked by scoring functions? AB - Docking algorithms predict the structure of protein-protein interactions. They sample the orientation of two unbound proteins to produce various predictions about their interactions, followed by a scoring step to rank the predictions. We present a statistical assessment of scoring functions used to rank near-native orientations, applying our statistical analysis to a benchmark dataset of decoys of protein-protein complexes and assessing the statistical significance of the outcome in the Critical Assessment of PRedicted Interactions (CAPRI) scoring experiment. A P value was assigned that depended on the number of near-native structures in the sampling. We studied the effect of filtering out redundant structures and tested the use of pair-potentials derived using ZDock and ZRank. Our results show that for many targets, it is not possible to determine when a successful reranking performed by scoring functions results merely from random choice. This analysis reveals that changes should be made in the design of the CAPRI scoring experiment. We propose including the statistical assessment in this experiment either at the preprocessing or the evaluation step. PMID- 20848550 TI - Optimization of culture conditions for osteogenically-induced mesenchymal stem cells in beta-tricalcium phosphate ceramics with large interconnected channels. AB - The aim of this study was to optimize culture conditions for human mesenchymal stem cells (hMSCs) in beta-tricalcium phosphate ceramics with large interconnected channels. Fully interconnected macrochannels comprising pore diameters of 750 um and 1400 um were inserted into microporous beta-tricalcium phosphate (beta-TCP) scaffolds by milling. Human bone marrow-derived MSCs were seeded into the scaffolds and cultivated for up to 3 weeks in both static and perfusion culture in the presence of osteogenic supplements (dexamethasone, beta glycerophosphate, ascorbate). It was confirmed by scanning electron microscopic investigations and histological staining that the perfusion culture resulted in uniform distribution of cells inside the whole channel network, whereas the statically cultivated cells were primarily found at the surface of the ceramic samples. It was also determined that perfusion with standard medium containing 10% fetal calf serum (FCS) led to a strong increase (seven-fold) of cell numbers compared with static cultivation observed after 3 weeks. Perfusion with low-serum medium (2% FCS) resulted in moderate proliferation rates which were comparable to those achieved in static culture, although the specific alkaline phosphatase (ALP) activity increased by a factor of more than 3 compared to static cultivation. Gene expression analysis of the ALP gene also revealed higher levels of ALP mRNA in low-serum perfused samples compared to statically cultivated constructs. In contrast, gene expression of the late osteogenic marker bone sialoprotein II (BSPII) was decreased for perfused samples compared to statically cultivated samples. PMID- 20848551 TI - Large-scale comparison of protein essential dynamics from molecular dynamics simulations and coarse-grained normal mode analyses. AB - A large-scale comparison of essential dynamics (ED) modes from molecular dynamic simulations and normal modes from coarse-grained normal mode methods (CGNM) was performed on a dataset of 335 proteins. As CGNM methods, the elastic network model (ENM) and the rigid cluster normal mode analysis (RCNMA) were used. Low frequency normal modes from ENM correlate very well with ED modes in terms of directions of motions and relative amplitudes of motions. Notably, a similar performance was found if normal modes from RCNMA were used, despite a higher level of coarse graining. On average, the space spanned by the first quarter of ENM modes describes 84% of the space spanned by the five ED modes. Furthermore, no prominent differences for ED and CGNM modes among different protein structure classes (CATH classification) were found. This demonstrates the general potential of CGNM approaches for describing intrinsic motions of proteins with little computational cost. For selected cases, CGNM modes were found to be more robust among proteins that have the same topology or are of the same homologous superfamily than ED modes. In view of recent evidence regarding evolutionary conservation of vibrational dynamics, this suggests that ED modes, in some cases, might not be representative of the underlying dynamics that are characteristic of a whole family, probably due to insufficient sampling of some of the family members by MD. PMID- 20848553 TI - A case series of facial depigmentation associated with low fluence Q-switched 1,064 nm Nd:YAG laser for skin rejuvenation and melasma. AB - BACKGROUND AND OBJECTIVE: In recent years, "laser toning" using low fluence, large spot size, multiple passed Q-switched 1,064 nm Nd:YAG laser has gained much popularity in Asian countries for non-ablative skin rejuvenation and the treatment of melasma. This case series highlights one of the complications associated with laser toning, which is facial depigmentation. MATERIALS AND METHODS: Fourteen patients with laser toning-associated facial depigmentation were assessed with cross-polarized and ultraviolet (UV) photographic images. The laser toning regimens received by these patients, as well as the treatment given for depigmentation, were analyzed retrospectively. RESULTS: All 14 patients were Chinese females, 9 of whom received laser toning for non-ablative skin rejuvenation and the other 5 for melasma. The treatment regimens received by these patients were highly variable. The total number of treatments received ranged from 6 to 50 (mean 22.07). In all cases, UV photographic images demonstrated facial mottled depigmentation. Laser toning failed to significantly improve melasma in all five patients. Five patients received targeted narrowband UVB for depigmentation with good clinical results. CONCLUSIONS: Laser toning with low fluence Q-switched 1,064 nm Nd:YAG laser for skin rejuvenation and melasma can be associated with mottled depigmentation. With laser toning being frequently performed, this complication may become more commonly encountered in clinical practice. The depigmentation can appear after only a few treatment sessions, and can cause much disfigurement, especially in cases with background melasma. Further studies on laser toning are needed with the view to optimizing efficacy and minimizing side-effects. PMID- 20848552 TI - Factors influencing tumor response to photodynamic therapy sensitized by intratumor administration of methylene blue. AB - BACKGROUND AND OBJECTIVES: We examined tumor response to methylene blue (MB) mediated photodynamic therapy (PDT) in a murine tumor model. The goal was to investigate the effects of drug-light interval (DLI), injection vehicle, and fluence on tumor destruction. Fluorescence and reflectance spectroscopy informed our understanding. MATERIALS AND METHODS: EMT6 tumor cells were implanted intradermally on the backs of female BALB/c mice and grown to ~4-mm diameter. Mice were given a 35 ul, single site, intratumor injection of 500 ug/ml MB administered in either a water or a 5% ethanol-5% Cremophor-90% saline vehicle. PDT was begun either immediately or after a 1-hour DLI with a fluence rate of 60 mW/cm(2). Each animal received a fluence of 240 or 480 J/cm(2). Fluorescence and reflectance spectra were captured before and during irradiation. RESULTS: A protocol consisting of the Cremophor-based vehicle, 0 DLI, and a fluence of 480 J/cm(2) was the most effective, with a 55% cure rate as measured by no evidence of tumor 90 days after PDT. Use of the water vehicle with this fluence and DLI reduced the cure rate to 20%. Reducing the fluence to 240 J/cm(2) similarly reduced treatment efficacy with 0 and 1-hour DLIs. Univariate Cox proportional hazards analysis identified increased fluence, 0 versus 1-hour DLI, and the Cremophor versus water vehicle as highly significant independent predictors of long term tumor control (P < 0.01 in each case). Multivariate analysis with model selection revealed fluence and injection vehicle as the best predictors of survival hazards. Fluorescence spectroscopy in vivo showed that MB fluorescence decreased monotonically during a 2-hour dark interval but was restored by irradiation. Reflectance spectroscopy revealed that MB at this injected concentration attenuates the treatment beam significantly. CONCLUSION: Sensitizer delivery vehicle, drug-light interval, and fluence contribute significantly to the tumor response to MB-mediated PDT. PMID- 20848554 TI - Ability of optical coherence tomography to detect caries beneath commonly used dental sealants. AB - BACKGROUND AND OBJECTIVE: The onset and progression of early tooth decay is often preventable with dental sealants. However, occasionally decay progresses underneath the sealant. Current technology does not permit monitoring of potential lesion progression or arrest. Dental sealants themselves mask the visual cues that identify early tooth decay, and radiographs are not sufficiently sensitive. Therefore, clinicians can be reluctant to use dental sealant. The objective of this ex vivo study was to evaluate the ability of dentists to detect decay beneath commonly used dental sealants using optical coherence tomography (OCT) imaging. STUDY DESIGNS/MATERIALS/METHODS: Forty extracted teeth were divided into equal groups of carious and non-carious teeth, as determined by visual inspection. After radiographs and OCT imaging, teeth were randomly assigned for sealant placement with one of four commonly purchased dental sealants: ClinproTM, Fuji TriageTM, Embrace Wet BondTM, and DeltonTM.Following sealant placement, teeth were radiographed, imaged with OCT, sectioned, examined histologically, and scored as healthy/not healthy. OCT and radiographic images were scored separately. The gold standard was histopathological diagnosis from the serial sections.Cohen's kappa, sensitivity, negative predictive value, and positive predictive value were computed for all measures. RESULTS: After 90 minutes training, pre-standardized dentists were able to detect tooth decay more accurately using OCT than with visual or radiographic examination. Detection using OCT was somewhat better prior to sealant placement than afterwards. This effect varied in size depending on the type of sealant used. Radiographic diagnosis was also less accurate after sealant placement. Of the four dental sealants, Delton provided excellent positive predictive value and the best post sealant negative predictive values. CONCLUSION: In this ex vivo study, dentists were able to detect tooth decay beneath four commonly used dental sealants based on OCT images. Clinical investigations are now underway to determine the usefulness of this approach in vivo. PMID- 20848555 TI - Missense mutations in the sodium borate cotransporter SLC4A11 cause late-onset Fuchs corneal dystrophy. AB - Homozygous mutations in the Borate Cotransporter SLC4A11 cause two early-onset corneal dystrophies: congenital hereditary endothelial dystrophy (CHED) and Harboyan syndrome. More recently, four sporadic patients with late-onset Fuchs corneal dystrophy (FCD), a common age-related disorder, were also reported to harbor heterozygous mutations at this locus. We therefore tested the hypothesis that SLC4A11 contributes to FCD and asked whether mutations in SLC4A11 are responsible for familial cases of late-onset FCD. We sequenced SLC4A11 in 192 sporadic and small nuclear late-onset FCD families and found seven heterozygous missense novel variations that were absent from ethnically matched controls. Familial data available for one of these mutations showed segregation under a dominant model in a three-generational family. In silico analyses suggested that most of these substitutions are intolerant, whereas biochemical studies of the mutant protein indicated that these alleles impact the localization and/or posttranslational modification of the protein. These results suggest that heterozygous mutations in SLC4A11 are modest contributors to the pathogenesis of adult FCD, suggesting a causality continuum between FCD and CHED. Taken together with a recent model between FCD and yet another early onset corneal dystrophy, PPCD, our data suggest a shared pathomechanism and genetic overlap across several corneal dystrophies. PMID- 20848556 TI - Metabolic engineering of resveratrol and other longevity boosting compounds. AB - Resveratrol, a compound commonly found in red wine, has attracted many attentions recently. It is a diphenolic natural product accumulated in grapes and a few other species under stress conditions. It possesses a special ability to increase the life span of eukaryotic organisms, ranging from yeast, to fruit fly, to obese mouse. The demand for resveratrol as a food and nutrition supplement has increased significantly in recent years. Extensive work has been carried out to increase the production of resveratrol in plants and microbes. In this review, we will discuss the biosynthetic pathway of resveratrol and engineering methods to heterologously express the pathway in various organisms. We will outline the shortcuts and limitations of common engineering efforts. We will also discuss briefly the features and engineering challenges of other longevity boosting compounds. PMID- 20848557 TI - High-dose vitamin D repletion-related falls and fractures: an uncontrolled mobility gain? PMID- 20848558 TI - Pineapple bromelain induces autophagy, facilitating apoptotic response in mammary carcinoma cells. AB - Bromelain, from pineapple, possesses potent anticancer effects. We investigated autophagic phenomenon in mammary carcinoma cells (estrogen receptor positive and negative) under bromelain treatment and also illustrated the relationship between autophagy and apoptosis in MCF-7 cells. MCF-7 cells exposed to bromelain showed delayed growth inhibitory response and induction of autophagy, identified by monodansylcadaverine localization. It was succeeded by apoptotic cell death, evident by sub-G1 cell fraction and apoptotic features like chromatin condensation and nuclear cleavage. 3-Methyladenine (MA, autophagy inhibitor) pretreatment reduced the bromelain-induced autophagic level, also leading to decline in apoptotic population, indicating that here autophagy facilitates apoptosis. However, addition of caspase-9 inhibitor Z-LEHD-FMK augmented the autophagy levels, inhibited morphological apoptosis but did not prevent cell death. Next, we found that bromelain downregulated the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), whereas that of c-jun N terminal kinase (JNK) and p38 kinase were upregulated. Also, MA had no influence on bromelain-suppressed ERK1/2 activation, yet, it downregulated JNK and p38 activation. Also, addition of mitogen-activated protein kinase (MAPK) inhibitors enhanced the autophagic ratios, which suggested the role of MAP kinases in bromelain-induced autophagy. All three MAPKs were seen to be constantly activated over the time. Bromelain was seen to induce the expressions of autophagy-related proteins, light chain 3 protein B II (LC3BII), and beclin-1. Using ERK1/2 inhibitor, expressions of LC3BII and beclin-1 increased, whereas p38 and JNK inhibitors decreased this protein expression, indicating that bromelain-induced autophagy was positively regulated by p38 and JNK but negatively regulated by ERK1/2. Autophagy-inducing property of bromelain can be further exploited in breast cancer therapy. PMID- 20848559 TI - Prescribing of inappropriate medication in nursing home residents in Germany according to a French consensus list: a cross-sectional cohort study. AB - PURPOSE: The current use of inappropriate medication in elderly nursing home residents (NHRs) in Germany is unclear. We therefore set out to analyse the frequency and patterns of potentially inappropriate drug prescriptions in elderly NHRs in Germany. METHODS: We utilised prescription data for NHRs 65 years or older from a large German health insurance company during a period of 3 months. Inappropriate drugs were identified from a recently reported French consensus list. RESULTS: Data for 7271 (83.7%) females and 1414 (16.3%) males were available for analysis. The average age was 83.6 +/- 7.3 years. Overall 48 inappropriate drugs were prescribed resulting in a total of 3825 inappropriate drug prescriptions which accounted for 4.3% of all documented prescriptions (n = 88,695). One thousand nine hundred and three (21.9%) residents received at least one inappropriate drug prescription. Using logistic regression we detected no significant influence of gender or level of care on frequency of inappropriate prescriptions. However, age had a significant influence; with increasing age the frequency of residents receiving inappropriate medications decreased steadily (r = -0.92, p = 0.003) and ranged from a maximum of 32.8% in the group between 65 and 69 years to a minimum of 15.2% in residents older than 94 years. This observation was paralleled by a significant and continuous decrease of drug prescription rates with increasing age (r = -0.88, p = 0.009). CONCLUSION: The present analysis demonstrates that about one out of five elderly NHRs received at least one inappropriate drug prescription. Additional studies may aim to establish a list of frequently prescribed inappropriate drugs for Germany. PMID- 20848560 TI - Neuroprotective properties of resveratrol in different neurodegenerative disorders. AB - The natural phytocompound resveratrol has been considered for many years a potential anticancer drug, but recently it has come to the attention of neuroscientist too, as it displays neuroprotective actions and activates the sirtuins' family member SIRT1. Sirtuins are enzymes with preferential deacetylase activity. Human sirtuins are coded by seven genes (SIRT1-7). The most investigated sirtuin is SIRT1, which is involved in several physiologic and pathologic processes including apoptosis, autophagy, diabetes, cancer, cardiovascular disorders, and neurodegeneration. Resveratrol has neuroprotective features both in vitro and in vivo in models of Alzheimer's disease (AD), but it has proved to be beneficial also in ischemic stroke, Parkinson's disease, Huntington's disease, and epilepsy. Here, we summarize the in vitro and in vivo experimental results highlighting the possible role of resveratrol as neuroprotective biofactor with a particular focus on AD. PMID- 20848561 TI - A potential competition bias in the detection of safety signals from spontaneous reporting databases. AB - PURPOSE: To study whether reports related to known drug-event associations could hinder the detection of new signals by increasing the detection thresholds when using disporportionality analyses in spontaneous reporting (SR) databases. METHODS: The French SR database (2005-2006 data) was used to test this hypothesis for the following events: bleeding, headache, hepatitis, myalgia, myocardial infarction, stroke, and toxic epidermal necrolysis (TEN). For each of these, using the Proportional Reporting Ratio (PRR) and the Reporting Odds Ratio (ROR), the number of cases needed to trigger a signal out of 50, 100, and 200 reports for a hypothetical newly introduced drug were computed before and after removing from the database reports involving drugs known to be associated with the event. RESULTS: For bleeding and stroke, removing potentially competitive data resulted in a decrease of the number of cases needed to trigger a signal for a newly introduced drug for both PRR and ROR (e.g., from 9 to 4, and 5 to 3 cases out of 50 reports for bleeding and stroke, respectively using the PRR). They were not or only slightly modified for the other studied events. CONCLUSIONS: Removing reports related to known drug-event associations could increase the sensitivity of signal detection in SR databases. This should be considered when using SR databases for signal detection as it could result in earlier identification of new drug-event associations. PMID- 20848562 TI - Clinical Images: Scurvy in the modern era. PMID- 20848564 TI - The transcriptional response of normal and rheumatoid arthritis synovial fibroblasts to hypoxia. AB - OBJECTIVE: Hypoxia is a prominent feature in rheumatoid arthritis (RA) synovium. However, its contribution to the pathogenesis of RA remains unclear. We undertook this study to systematically characterize the changes in gene expression induced by hypoxia in synovial fibroblasts. METHODS: We used microarray expression profiling in paired normoxic and hypoxic cultures of healthy synovial fibroblasts (HSFs) and RA synovial fibroblasts (RASFs). We used Student's paired t-test with Benjamini and Hochberg multiple testing correction to determine statistical significance. Validation of microarray data was performed by quantitative real time reverse transcription-polymerase chain reaction analysis of selected genes. Biologic pathways differentially modulated by hypoxia in RASFs or HSFs were identified using unsupervised Ingenuity Pathways Analysis. RESULTS: Hypoxia induced significant changes in the expression of a large group of genes in both HSFs and RASFs. In RASFs, we observed a lower number of hypoxia-regulated genes and partial differences in their functional categories. The number of differentially expressed genes in RASFs compared with HSFs was significantly increased by hypoxia. Multiple gene sets involved in energy metabolism, intracellular signal transduction, angiogenesis, and immune and inflammatory pathways were significantly modified, the last in both proinflammatory and antiinflammatory directions. CONCLUSION: These data demonstrate that hypoxia induces significant changes in gene expression in HSFs and RASFs and identify differences between RASF and HSF profiles. The hypoxia-induced gene expression program in synovial fibroblasts identifies new factors and pathways relevant to understanding their contribution to the pathogenesis of chronic arthritis. PMID- 20848565 TI - Posterior reversible encephalopathy syndrome in systemic lupus erythematosus: comment on the article by Efthimiou et al. PMID- 20848566 TI - Synovial tissue-infiltrating natural killer cells in osteoarthritis and periprosthetic inflammation. AB - OBJECTIVE: Infiltrating immune cells play a central role in degenerative joint disease associated with osteoarthritis (OA) and particle-mediated periprosthetic osteolysis. The goal of this study was to characterize a newly identified population of synovial tissue-infiltrating natural killer (NK) cells obtained from patients with OA or patients with periprosthetic joint inflammation. METHODS: Synovial and interfacial tissue samples were collected from patients with OA who were undergoing primary or revision total joint replacement (TJR) surgery. The histologic features of OA synovium obtained from patients undergoing primary surgery and interfacial tissue obtained from patients undergoing revision surgery were determined by immunohistochemistry and immunofluorescence. Synovial tissue-infiltrating NK cells were evaluated for the expression of surface receptors, using flow cytometry. Chemoattractant and cytokine protein and RNA levels in synovial and interfacial tissue and fluid were assessed by Luminex assay and real-time quantitative polymerase chain reaction. Cytokine production and degranulation by stimulated synovial tissue versus normal blood NK cells were evaluated by intracellular cytokine staining. RESULTS: NK cells comprised nearly 30% of the CD45+ mononuclear cell infiltrate in synovial tissue obtained from patients undergoing primary TJR and from patients undergoing revision TJR. NK cells from both groups expressed CXCR3, CCR5, L-selectin, alpha4 integrins, and cutaneous lymphocyte antigen. Synovial fluid from patients undergoing revision surgery contained elevated concentrations of the NK cell attractants CCL4, CCL5, CXCL9, and CXCL10; all levels in synovial fluid obtained from patients undergoing revision surgery were higher than those in synovial fluid from patients undergoing primary surgery. Cytokine-stimulated interferon-gamma production was significantly impaired in NK cells derived from primary and revision TJRs compared with blood NK cells. CONCLUSION: NK cells are a principal tissue infiltrating lymphocyte subset in patients with OA and patients with periprosthetic inflammation and display a quiescent phenotype that is consistent with postactivation exhaustion. PMID- 20848567 TI - Clinical images: Recurrent effusion of the knee in a "double-layered" discoid lateral meniscus. PMID- 20848569 TI - Testing pharmacogenetic indices to predict efficacy and toxicity of methotrexate monotherapy in a rheumatoid arthritis patient cohort. PMID- 20848568 TI - Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus. AB - OBJECTIVE: To assess whether genetically determined Amerindian ancestry predicts increased presence of risk alleles of known susceptibility genes for systemic lupus erythematosus (SLE). METHODS: Single-nucleotide polymorphisms (SNPs) within 16 confirmed genetic susceptibility loci for SLE were genotyped in a set of 804 Mestizo lupus patients and 667 Mestizo healthy controls. In addition, 347 admixture informative markers were genotyped. Individual ancestry proportions were determined using STRUCTURE. Association analysis was performed using PLINK, and correlation between ancestry and the presence of risk alleles was analyzed using linear regression. RESULTS: A meta-analysis of the genetic association of the 16 SNPs across populations showed that TNFSF4, STAT4, ITGAM, and IRF5 were associated with lupus in a Hispanic Mestizo cohort enriched for European and Amerindian ancestry. In addition, 2 SNPs within the major histocompatibility complex region, previously shown to be associated in a genome-wide association study in Europeans, were also associated in Mestizos. Using linear regression, we predicted an average increase of 2.34 risk alleles when comparing an SLE patient with 100% Amerindian ancestry versus an SLE patient with 0% Amerindian ancestry (P < 0.0001). SLE patients with 43% more Amerindian ancestry were predicted to carry 1 additional risk allele. CONCLUSION: Our results demonstrate that Amerindian ancestry is associated with an increased number of risk alleles for SLE. PMID- 20848570 TI - Efficacy of hydrogastric sonography and spiral Computed Tomography in staging of gastric carcinoma--a comparative study. AB - OBJECTIVE: Accurate preoperative diagnosis and staging of patients with gastric cancer is essential for optimal treatment. The standard of care for staging gastric carcinoma is helical CT. This study was conducted to compare the efficacy of hydrogastric sonography (HGS) with that of helical CT in the staging of patients with gastric carcinoma. METHODS: A total of 42 consecutive patients (29 men and 13 women) diagnosed with gastric carcinoma after endoscopy and biopsy were staged on the basis of TNM classification, preoperatively with HGS and helical CT and postoperatively with histopathologic examination (HPE). The findings of HGS and helical CT were compared with those on HPE with respect to TNM stage. RESULTS: Regarding T stage, the accuracy of HGS was 78.6% (kappa = 0.68) and that of helical CT was 66.7% (kappa = 0.48). In evaluating the nodal status, the accuracy of HGS was 66.7% (kappa = 0.52) and that of helical CT was 54.6% (kappa = 0.39). Regarding distant metastases, accuracy was the same with HGS and helical CT (accuracy 95.2%, kappa = 0.89). CONCLUSIONS: When compared with HPE, HGS was found to be more accurate than helical CT for assessment of T and N staging. Sonographic and helical CT were equally accurate for the assessment of M stage. PMID- 20848571 TI - Intracardiac echogenic focus and fetal outcome. AB - BACKGROUND: To study the outcome of the fetuses with intracardiac echogenic focus (ICEF). METHODS: All patients who were found to have one or more ICEF on sonographic (US) examination at our center from January 2007 through January 2009 were included in this retrospective study. ICEF was defined as a discrete area of echogenicity noted in the left or right ventricle, which was as bright as bone. Patients were followed up to know pregnancy outcome. RESULTS: Of 762 fetuses evaluated by US, 48 (6.3%) were found to have an ICEF. Thirty-one of these 48 fetuses had an isolated ICEF; 11 had associated major malformations, and the remaining 6 had no major US abnormalities but were found to have other soft markers. Invasive prenatal testing was done in 21 cases for risk factors other than ICEF and was found to be abnormal in two cases. Seven pregnancies were terminated due to associated major malformations. CONCLUSION: The prevalence of ICEF was 6.3%. Of 31 fetuses with an isolated ICEF, outcomes of 28 fetuses are known and all neonates were reported to be normal at birth. Thus we infer that the presence of an isolated ICEF has no adverse effect on outcome of the neonate. PMID- 20848572 TI - Sonographic diagnosis of neurogenic heterotopic ossification in patients with severe acquired brain injury in a neurorehabilitation unit. AB - PURPOSE: To illustrate the ultrasonographic (US) and power Doppler US (PDUS) features of neurogenic heterotopic ossification (NHO) in consecutive patients with severe acquired brain injury and to evaluate the role of bedside US in diagnosis of NHO. METHODS: Ninety-two consecutive patients with severe acquired brain injury underwent clinical and laboratory screening for NHO. In 6 of 92 patients, bedside US confirmed the clinical suspicion of NHO. US diagnosis of NHO was then confirmed by other imaging methods. RESULTS: The incidence of clinical NHO was 7% (9/92) with one patient having multifocal involvement. In NHO of the hip, US demonstrated the classic pattern of zone phenomenon, and PDUS demonstrated vascular signal within mineralized NHO and in outer hypoechoic area. No vascular signal was observed in the central hypoechoic core. In NHO of the knee, a heterogeneously hypoechoic mass was seen and in the elbow a hyperechoic mineralized mass was visualized, with vascular signals seen within the lesions. Spectral wave analysis demonstrated low resistance vessels in NHO. CONCLUSIONS: Bedside US is a useful tool in the diagnosis of NHO. PDUS adds data regarding neoangiogenetic activity of NHO. PMID- 20848573 TI - Sonographic findings in Nicolau syndrome following intramuscular diclofenac injection: a case report. AB - Nicolau syndrome (also known as embolia cutis medicamentosa and livedoid dermatitis) is a rare but severe localized adverse drug reaction of intramuscular injection of various drugs. The typical presentation is pain around the injection site soon after injection, followed by erythema, livedoid patch, hemorrhagic patch, and finally necrosis of skin, subcutaneous fat, and muscle tissue. We report a case that occurred in a 34-year-old woman after intramuscular injection of diclofenac sodium. Sonography showed diffuse thickening with increased echogenicity of the skin and subcutaneous fat layer, while MRI revealed extensive edema involving gluteal and piriformis muscles and deep fascia, and fluid collection. PMID- 20848574 TI - Unsuspected sonographic findings in patients with posttraumatic shoulder complaints. AB - PURPOSE: To prospectively assess the frequency of abnormal sonographic findings in patients with posttraumatic shoulder pain and/or disability in whom ultrasound (US) was not considered and to assess the effect of sonographic findings on working diagnosis and therapeutic strategy, to analyze the possible role of US in the diagnostic workup of these patients. METHODS: A survey was performed under general practitioners and orthopedic surgeons. They were requested to refer patients with persistent posttraumatic complaints for an US examination of the shoulder and to fill out a questionnaire concerning working diagnosis and therapy. In 50 patients examinations were performed separately by two radiologists. Findings were confirmed with additional radiographs and/or MRI and/or surgery. Four weeks after the US examination, the survey was repeated to inquire about changes in diagnosis and/or treatment that resulted from US. RESULTS: US showed relevant pathology in 45 (90%) of 50 patients, a proximal humerus fracture in 25 (50%) patients, and a rotator cuff tear in 43 (86%) patients. Twenty-three (92%) fractures were accompanied by a rotator cuff tear, and 23 (54%) rotator cuff tears were accompanied by a fracture. Ten fractures were initially missed radiographically. US findings changed the working diagnosis and therapeutic strategy in 37 (74%) and 26 (52%) patients, respectively. CONCLUSION: In patients with posttraumatic shoulder complaints, US showed a high rate (90%) of relevant pathology. This changed the initial working diagnosis in 74% of the patients and the therapeutic strategy in more than half of the patients. Active referral for US examination may identify these abnormalities in an earlier phase and improve clinical outcome. PMID- 20848575 TI - Mobile echoes in liver cysts: a form of range-ambiguity artifact. AB - PURPOSE: Faint moving echoes are occasionally encountered in large hepatic cysts, as an example of range-ambiguity artifacts. The aim of this article is to describe the pattern of these intracystic mobile echoes, to analyze the mechanism of their formation, and to discuss options to clear them. METHODS: We analyzed the size and location of the hepatic cysts, the movement of the artifactual echoes, and the relationship between pulse repetition frequency (PRF) and the depth of these intracystic mobile echoes in 10 cases. In three cases examination at a lower PRF was made to ascertain whether the artifactual echoes would disappear. RESULTS: Intracystic range-ambiguity echoes appeared when the heart was located distal to the hepatic cyst and these echoes moved according to cardiac motion. The depth of the intracystic artifacts changed according to the PRF and they disappeared at a low PRF. CONCLUSION: Intracystic range-ambiguity artifacts are caused by an erroneous display of the returning echoes from the heart. Knowledge of the mechanism and appearance of this artifact helps prevent misdiagnosis of internal echoes in large hepatic cysts. Observation at different PRFs is key to recognizing this artifact, and examination at lower PRFs should be done to confirm the artifactual nature of the echoes. PMID- 20848576 TI - Determining the minimum clinically important differences for outcomes in the DOMINO trial. AB - BACKGROUND: Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes, whether or not a treatment has delivered a specified minimum clinically important difference (MCID) is also relevant to patients and their caregivers and doctors. Many dementia treatment randomised controlled trials (RCTs) have not reported MCIDs and, where they have been done, observed differences have not reached these. METHODS: As part of the development of the Statistical Analysis Plan for the DOMINO trial, investigators met to consider expert opinion- and distribution based values for the MCID and triangulated these to provide appropriate values for three outcome measures, the Standardised Mini-mental State Examination (sMMSE), Bristol Activities of Daily Living Scale (BADLS) and Neuropsychiatric Inventory (NPI). Only standard deviations (SD) were presented to investigators who remained blind to treatment allocation. RESULTS: Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE, BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE, 3.5 for BADLS and 8.0 for NPI. CONCLUSIONS: Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs. PMID- 20848577 TI - Structured analyses of interventions to prevent delirium. AB - BACKGROUND: Delirium is one of the most serious complications in hospitalized elderly, with incidences ranging from 3-56%. The objective of this meta-analysis was two-fold, first to investigate if interventions to prevent delirium are effective and second to explore which factors increase the effectiveness of these interventions. METHODS: An electronic search was carried out on articles published between January 1979 and July 2009. Abstracts were reviewed, data were extracted and methodologic quality was assessed by two independent reviewers. Effect sizes of the interventions were expressed as ORs (odds ratios) and 95%CIs (confidence intervals). A random effect model was used to provide pooled ORs. To explore which factors increase the effectiveness of the interventions, ORs were stratified for several factors. RESULTS: Sixteen relevant studies were found. Overall the included studies showed a positive result of any intervention to prevent delirium (pooled OR: 0.64; 95%CI: 0.46-0.88). The largest effect was seen in studies on populations with an incidence of delirium above 30% in the control group (pooled OR: 0.34; 95%CI: 0.16-0.71 versus 0.76; 95%CI: 0.60-0.97). CONCLUSIONS: Interventions to prevent delirium are effective. Interventions seem to be more effective when the incidence of delirium in the population under study is above 30%. To maximize the options for a cost-effective strategy of delirium prevention it might be useful to offer an intervention to a selected population. PMID- 20848578 TI - Laughter yoga versus group exercise program in elderly depressed women: a randomized controlled trial. AB - BACKGROUND: Laughter Yoga founded by M. Kataria is a combination of unconditioned laughter and yogic breathing. Its effect on mental and physical aspects of healthy individuals was shown to be beneficial. OBJECTIVE: The objective of this study was to compare the effectiveness of Kataria's Laughter Yoga and group exercise therapy in decreasing depression and increasing life satisfaction in older adult women of a cultural community of Tehran, Iran. METHODS: Seventy depressed old women who were members of a cultural community of Tehran were chosen by Geriatric depression scale (score>10). After completion of Life Satisfaction Scale pre-test and demographic questionnaire, subjects were randomized into three groups of laughter therapy, exercise therapy, and control. Subsequently, depression post-test and life satisfaction post-test were done for all three groups. The data were analyzed using analysis of covariance and Bonferroni's correction. RESULTS: Sixty subjects completed the study. The analysis revealed a significant difference in decrease in depression scores of both Laughter Yoga and exercise therapy group in comparison to control group (p<0.001 and p<0.01, respectively). There was no significant difference between Laughter Yoga and exercise therapy groups. The increase in life satisfaction of Laughter Yoga group showed a significant difference in comparison with control group (p<0.001). No significant difference was found between exercise therapy and either control or Laughter Yoga group. CONCLUSION: Our findings showed that Laughter Yoga is at least as effective as group exercise program in improvement of depression and life satisfaction of elderly depressed women. PMID- 20848579 TI - On comparing competing structural models of PTSD: comments on Miller et al. AB - In this commentary, the author evaluates the results and conclusions of Miller et al. (2010) with respect to the debate surrounding the posttraumatic stress disorder (PTSD) structural models of King, Leskin, King, and Weathers (1998) and Simms, Watson, and Doebbeling (2002). Although Miller et al. are to be commended for attempting to move this literature forward through a comparative assessment of the models' respective convergent and discriminant validities, the author questions their conclusions based on the data presented. His read of their data, in the context of the broader literature, is that the Simms model has advantages over the King model with respect to discriminant validity. It is premature to declare a winner in the ongoing debate on the merits of these structural models. PMID- 20848580 TI - Longitudinal assessment of health-related quality of life in an observational cohort of patients with cystic fibrosis. AB - BACKGROUND: Patient-reported outcomes (PROs) are increasingly used to evaluate the efficacy of new treatments and the progression of chronic diseases. The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is a disease-specific, PRO measure of health-related quality of life (HRQOL). We evaluated associations between changes in health status over time and HRQOL in a national CF database. METHODS: Using the Epidemiologic Study of Cystic Fibrosis (ESCF) data, we identified participants who had completed age-appropriate CFQ-R assessments on two occasions separated by 9-15 months. Next, we developed multivariate regression models to test whether associations existed between (1) changes in respiratory signs/symptoms and changes in the respiratory health domains of the CFQ-R, (2) changes in nutritional health status and changes in the nutritional health domains of the CFQ-R, and (3) changes in treatment complexity and changes in the Treatment Burden scale of the CFQ-R. RESULTS: We analyzed 1,947 pairs of assessments: 337 child (mean age 8.9, range 6-13 years), 581 parent (mean age of child 8.8, range 6-13 years), 398 adolescent (mean age 15.3, range 14-17 years), and 631 adult (mean age 26.9, range 18-73 years). On average, we found little change in both health status indicators and CFQ-R domain scores over 1 year. Significant associations over time, however, were found between increases in respiratory symptoms and worse CFQ-R Respiratory Symptom scores, declining weight and worsening scores on CFQ-R nutritional health domains, and increases in treatment complexity and worsening CFQ-R Treatment Burden scores for parent respondents. CONCLUSION: Health status and HRQOL changes were small over a 1-year period in this CF population. However, changes in respiratory symptoms and weight were associated with significant changes on relevant CFQ-R scores, indicating that this PRO is sensitive to changes in health status over time. PMID- 20848581 TI - The relationship between infant lung function and the risk of wheeze in the preschool years. AB - RATIONALE: There is evidence that perinatal lung development predicts childhood wheeze. However, very few studies have examined whether preschool wheeze is associated with lower premorbid lung function in early infancy, and as yet there is no information relating atopic and non-atopic preschool wheeze to early lung development. OBJECTIVE: To examine the association between premorbid infant lung function and preschool wheeze, and to explore associations with atopic and non atopic wheeze phenotypes. METHODS: Infant lung function was measured in 147 healthy term infants aged 5-14 weeks. Rapid thoracoabdominal compression was performed during tidal breathing and at raised volume to measure maximal expiratory flow at functional residual capacity (V' max FRC) and forced expiratory volume in 0.4 sec (FEV(0.4)). Atopic status was determined by skin prick testing at 3 years and wheeze ascertained from parental questionnaires (1 and 3 years). MEASUREMENTS AND MAIN RESULTS: Lower early infancy V' max FRC was associated with wheeze in both the first and third years of life (P=0.002 and 0.006, respectively). Lower early infancy FEV(0.4) was associated with wheeze in the first year (P=0.03). Compared to non-atopic children who did not wheeze, non atopic children who wheezed in their third year of life had lower FEV(0.4) (P=0.02), while FEV(0.4) values of atopic children who wheezed were not significantly different (P=0.4). CONCLUSIONS: Lower premorbid infant lung function was present in infants who subsequently wheezed during the first and third years of life. Lower FEV(0.4) in early infancy was associated with non atopic wheeze but not atopic wheeze at 3 years of age. PMID- 20848582 TI - Lung function in preschool children with a history of wheezing measured by forced oscillation and plethysmographic specific airway resistance. AB - RATIONALE: Wheezing is common in preschool children, but objective evidence for airway obstruction and its reversibility are rarely available in clinical practice. We assessed whether abnormalities of lung function and bronchodilator response can be detected in preschool children using the forced oscillation technique and measurements of specific airway resistance. METHODS: Fifty-nine children with a history of wheeze and 24 healthy controls aged 3-6 years were recruited. Resistance and reactance at 6 and 8 Hz (Rrs6, Rrs8, Xrs6 and Xrs8, respectively) were measured using the forced oscillation technique and specific airway resistance was measured in a plethysmograph. z-Scores were calculated from published reference data. Tests were repeated 15 min after 400 mcg salbutamol. Bronchodilator response was expressed as the log-transformed ratio of postbronchodilator/prebronchodilator values. RESULTS: Technically acceptable measurements using the forced oscillation technique were obtained in n = 77 (93%) of children and in n = 56 (68%) using plethysmography. There was no significant difference in baseline lung function or bronchodilator response, assessed by either technique, between those with a history of wheeze and healthy controls. CONCLUSION: Measurement of lung function is feasible in preschool children, but neither of these techniques was able to identify diminished lung function or reversibility to bronchodilator in children with a history of wheeze. PMID- 20848583 TI - Quality of life protocol in the early asthma diagnosis in children. AB - INTRODUCTION: Asthma is considered an important problem in children and influences on their everyday functioning. This study was concerned with the impact of asthma on the health-related quality of life (HRQOL) of newly recognized pediatric asthma patients and their parents. METHODS: Patients were identified by a general respiratory survey. HRQOL was assessed by self-report measures: disease-specific questionnaire for children, the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) and generic for parents-the Quality of Life in Child's Chronic Disease Questionnaire (QLCCDQ). RESULTS: Twenty-nine newly diagnosed asthmatic children aged 7-11 years (mean age = 8.6; SD = 1.4) were identified from a population-based respiratory health survey. The most impaired HRQOL domains differed in parents and children. In children, activity limitation was the most impaired; however in parents, emotional functioning and symptom perception domains were most impaired. There were no statistically significant differences in patient and parental HRQOL observed in either the group where symptoms were present or in the group were symptoms were not present. Baseline spirometry showed correlation for FEV(1)%FVC and PAQLQ symptom domain (r = 0.42). Exercise test showed correlations between FEV(1)%FVC and QLCCDQ emotional domain (r = 0.7); MEF 25-75% and family roles (r = 0.81), as well as social functioning (r = 0.81). Activity limitation on the PAQLQ correlated with the MEF 25-75% (r = 0.44) and PEF (r = 0.55). CONCLUSIONS: HRQOL newly recognized children with asthma and their parents does not correlate closely with clinical status. Patient and parental HRQOL should be considered as independent dimensions. PMID- 20848584 TI - Isolated central sleep apnea in type I Chiari malformation: improvement after surgery. AB - Sleep apnea is a rare but well-known clinical feature of disorders of the craniocervical junction. It may be obstructive or central in nature, and rarely presents without other neurological symptoms. We report the cases of two children, presenting with isolated central sleep apnea leading to a diagnosis of type I Chiari malformation. Surgical treatment resulted in a dramatic improvement in respiratory parameters during sleep, both clinically and on polysomnography. We discuss this uncommon presentation of type I Chiari malformation and suggest that it be considered in the differential diagnosis of central sleep apnea in children, as posterior fossa decompression may lead to significant clinical improvement. PMID- 20848585 TI - Fractional exhaled nitric oxide exchange parameters among 9-year-old inner-city children. AB - OBJECTIVES AND HYPOTHESIS: To determine the feasibility of using a multiple flow offline fractional exhaled nitric oxide (FeNO) collection method in an inner-city cohort and determine this population's alveolar and conducting airway contributions of NO. We hypothesized that the flow independent NO parameters would be associated differentially with wheeze and seroatopy. METHODS: As part of a birth cohort study, 9-year-old children (n=102) of African-American and Dominican mothers living in low-income NYC neighborhoods had FeNO samples collected offline at constant flow rates of 50, 83, and 100 ml/sec. Seroatopy was defined as having measurable (>= 0.35 IU/ml) specific IgE to any of the five inhalant indoor allergens tested. Current wheeze (last 12 months) was assessed by ISAAC questionnaire. Bronchial NO flux (J(NO) ) and alveolar NO concentration (C(alv)) were estimated by the Pietropaoli and Hogman methods. RESULTS: Valid exhalation flow rates were achieved in 96% of the children. Children with seroatopy (53%) had significantly higher median J(NO) (522 pl/sec vs. 161 pl/sec, P<0.001) when compared to non-seroatopic children; however, median C(alv) was not significantly different between these two groups (5.5 vs. 5.8, P=0.644). Children with wheeze in the past year (21.6%) had significantly higher median C(alv) (8.4 ppb vs. 4.9 ppb, P<0.001), but not J(NO) (295 pl/sec vs. 165 pl/sec, P=0.241) when compared with children without wheeze. These associations remained stable after adjustment for known confounders/covariates. CONCLUSIONS: The multiple flow method was easily implemented in this pediatric inner-city cohort. In this study population, alveolar concentration of NO may be a better indicator of current wheeze than single flow FeNO. PMID- 20848586 TI - Variation in immunoreactive trypsinogen concentrations among Michigan newborns and implications for cystic fibrosis newborn screening. AB - OBJECTIVE: To investigate variation in immunoreactive trypsinogen (IRT) concentrations by race, sex, birth weight, and gestational age and their implications for the use of percentile-based cutoffs for cystic fibrosis (CF) newborn screening (NBS) programs. PATIENTS AND METHODS: This cross-sectional population-based study of resident infants screened in Michigan investigates associations between demographic and perinatal variables and IRT concentrations after controlling for covariates. This study also analyzed how 96th and 99.8th IRT concentration percentiles values calculated by Michigan NBS vary by demographic and perinatal factors. Characteristics of infants having high (>=99.8th percentile) IRT concentrations and negative DNA tests are also explored. RESULTS: IRT mean concentrations and percentiles vary significantly by race, birth weight, gestational age, and to a lesser degree by sex. The greatest variation in mean IRT concentrations was observed among racial categories; black infants had an adjusted mean concentration of 36 ng/ml and Asian/Pacific Islander infants had a mean concentration of 25 ng/ml compared to an average concentration of 28 ng/ml in white infants and infants of other races. CONCLUSIONS: Variation in IRT concentrations resulted in the over-representation of certain groups referred for secondary testing, particularly referrals for sweat testing based on very high (>=99.8th percentile) concentrations alone, which is no longer recommended in Michigan. Further research may be warranted to evaluate initial IRT cutoffs used for CF NBS. PMID- 20848587 TI - Life span extension by resveratrol, rapamycin, and metformin: The promise of dietary restriction mimetics for an healthy aging. AB - Life expectancy at the turn of the 20th century was 46 years on average worldwide and it is around 65 years today. The correlative increase in age-associated diseases incidence has a profound public health impact and is an important matter of concern for our societies. Aging is a complex, heterogeneous, and multifactorial phenomenon, which is the consequence of multiple interactions between genes and environment. In this review, we survey animals models that have been of great help for both investigating mechanism of aging and identifying molecules, which slow down the onset of age-related diseases. Resveratrol (RSV) is one of those. We will report evidences supporting RSV as a molecule that acts by mimicking the beneficial effects of dietary restriction, and may share common downstream targets with rapamycin and metformin. Although those molecules do not reveal all the secrets of the fountain of youth, they may help us maintaining the quality of life in the old age. PMID- 20848588 TI - Therapeutic potential of activators and inhibitors of sirtuins. AB - Sirtuins are evolutionary conserved NAD(+)-dependent acetyl-lysine deacetylases and ADP ribosyltransferases dual-function enzymes involved in the regulation of metabolism and lifespan. Sirtuins are also implicated in determining the balance between apoptosis, cell survival, and cell proliferation. In humans, seven sirtuins isoforms (SIRT1-7) have been identified that localize either in the nucleus, cytoplasm, or mitochondria. The genetic demonstration that increasing gene dosage of sirtuin orthologs in eukaryotes, including yeast and multicellular Caenorhabditis elegans and Drosophila melanogaster, leads to prolonged lifespan induced considerable interest toward the discovery of sirtuin-activating molecules, on the ground that the phenomenon of sirtuin-induced lifespan prolongation-which is consequential to improved metabolic control-can be exploited therapeutically to counteract insulin resistance and diabetes. Conversely, ample evidence that either pharmacological inhibition or activation of sirtuin isoforms is potentially beneficial in study models of cancer and neurodegenerative diseases have been obtained. Here, we (i) survey the key roles of sirtuin isoforms and discuss the evidence in favor of activatory versus inhibitory targeting of sirtuins, (ii) discuss some of the inhibitors and activators of the sirtuin family members that have been described in the literature, (iii) review model systems in which these molecules have proved to exert therapeutic effects, and (iv) discuss the outcome of pharmacokinetic studies and phase I and II clinical trials employing sirtuin modulators. PMID- 20848590 TI - Cervical cancer patterns with automation-assisted and conventional cytological screening: a randomized study. AB - The purpose was to evaluate alternative cytological screening methods in population-based screening for cervical cancer up to cancer incidence and mortality outcome. Automation-assisted screening was compared to conventional cytological screening in a randomized design. The study was based on follow-up of 503,391 women invited in the Finnish cervical cancer screening program during 1999-2003. The endpoints were incident cervical cancer, severe intraepithelial neoplasia and deaths from cervical cancer. One third of the women had been randomly allocated to automation-assisted screening and two thirds to conventional cytology. Information on cervical cancer and severe neoplasia were obtained through 1999-2007 from a linkage between screening and cancer registry files. There were altogether 3.2 million woman-years at risk, and the average follow-up time was 6.3 years. There was no difference in the risk of cervical cancer between the automation-assisted and conventional screening methods; the relative risk (RR) of cervical cancer between the study and control arm was 1.00 (95% confidence interval [CI] = 0.76-1.29) among all invited and 1.08 (95% CI = 0.76-1.51) among women who were test negative at entry. Comparing women who were test negative with nonscreened, RR of cervical cancer incidence was 0.26, 95% CI = 0.19-0.36 and of mortality 0.24 (0.13-0.43). Both methods were valid for screening. Because cervical cancer is rare in our country, we cannot rule out small differences between methods. Evidence on alternative methods for cervical cancer screening is increasing and it is thus feasible to evaluate new methods in large-scale population-based screening programs up to cancer outcome. PMID- 20848591 TI - Associations of overall and abdominal adiposity with area and volumetric mammographic measures among postmenopausal women. AB - Whereas mammographic density and adiposity are positively associated with postmenopausal breast cancer risk, they are inversely associated with one another. To examine the association between these two risk factors, a secondary analysis of data from a randomized controlled trial of a year-long aerobic exercise intervention was done. Participants were 302 postmenopausal women aged 50-74 years. Dense fibroglandular and nondense fatty tissue were measured from mammograms using computer-assisted thresholding software for area measurements and a technique relying on the calibration of mammography machines with a tissue equivalent phantom for volumetric measurements. Adiposity was measured by anthropometry (body mass index, waist circumference), whole-body dual x-ray absorptiometry scans (body fat) and computed tomography scans (abdominal adiposity). Correlations were estimated between and within women, the latter representing the association between the 1-year change in adiposity and mammographic measures. Adiposity was correlated with nondense area and volume (0.50 <= r <= 0.66 between women; 0.18 <= r <= 0.46 within women). Between women, adiposity was correlated with dense area and volume (-0.12 <= r <= -0.30) and with percent dense area and volume (-0.28 <= r <= -0.48). Because measurements made with scans explained at most only 3% more of the variation in absolute or percent density beyond that explained by anthropometric measurements, anthropometric measurements are likely sufficient for adjustment of the association between mammographic density and breast cancer risk. Adiposity is associated with breast fatty tissue and possibly weakly inversely associated with fibroglandular tissue. PMID- 20848589 TI - Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice. AB - Searching for efficacious and safe agents for the chemoprevention and therapy of prostate cancer has become the top priority of research. The objective of this study was to determine the effects of a group of tanshinones from a Chinese herb Salvia Miltiorrhiza, cryptotanshinone (CT), tanshinone IIA (T2A) and tanshinone I (T1) on prostate cancer. The in vitro studies showed that these tanshinones inhibited the growth of human prostate cancer cell lines in a dose-dependent manner via cell cycle arrest and apoptosis induction. Among three compounds, T1 had the most potent activity with IC(50) s around 3-6 MUM. On the other hand, tanshinones had much less adverse effects on the growth of normal prostate epithelial cells. The epigenetic pathway focused array assay identified Aurora A kinase as a possible target of tanshinone actions. The expression of Aurora A was overexpressed in prostate cancer cell lines. Moreover, knockdown of Aurora A in prostate cancer cells significantly decreased cell growth. Tanshinones significantly downregulated the Aurora A expression, suggesting Aurora A may be a functional target of tanshinones. Tanshinones, especially T1, also showed potent anti-angiogenesis activity in vitro and in vivo. Furthermore, T1 inhibited the growth of DU145 prostate tumor in mice associated with induction of apoptosis, decrease of proliferation, inhibition of angiogenesis and downregulation of Aurora A, whereas it did not alter food intake or body weight. Our results support that T1 may be an efficacious and safe chemopreventive or therapeutic agent against prostate cancer progression. PMID- 20848592 TI - Generation of mice with a conditional and reporter allele for Tmem100. AB - Activin receptor-like kinase 1 (ACVRL1; ALK1) is predominantly expressed in arterial endothelial cells and plays an important role in angiogenesis. ACVRL1 mutations cause hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder for which the underlying mechanism is poorly understood. We have found that expression of transmembrane protein 100 (Tmem100) is downregulated in the lung of Acvrl1-deficient mice; however, its function is unknown. To elucidate the role of Tmem100 in vivo, we generated a conditional knockout allele for Tmem100 in which exon3, containing the entire coding sequence, was flanked by loxP sequences. The targeted allele also possessed a lacZ reporter cassette in intron2 for visualization of Tmem100 expression. We found that Tmem100 was predominantly expressed in arterial endothelial cells of developing embryos. The conditional and reporter allele will be a useful resource to investigate the in vivo role of Tmem100, especially in angiogenesis. PMID- 20848593 TI - Controlling cell behavior through the design of polymer surfaces. AB - Polymers have gained a remarkable place in the biomedical field as materials for the fabrication of various devices and for tissue engineering applications. The initial acceptance or rejection of an implantable device is dictated by the crosstalk of the material surface with the bioentities present in the physiological environment. Advances in microfabrication and nanotechnology offer new tools to investigate the complex signaling cascade induced by the components of the extracellular matrix and consequently allow cellular responses to be tailored through the mimicking of some elements of the signaling paths. Patterning methods and selective chemical modification schemes at different length scales can provide biocompatible surfaces that control cellular interactions on the micrometer and sub-micrometer scales on which cells are organized. In this review, the potential of chemically and topographically structured micro- and nanopolymer surfaces are discussed in hopes of a better understanding of cell-biomaterial interactions, including the recent use of biomimetic approaches or stimuli-responsive macromolecules. Additionally, the focus will be on how the knowledge obtained using these surfaces can be incorporated to design biocompatible materials for various biomedical applications, such as tissue engineering, implants, cell-based biosensors, diagnostic systems, and basic cell biology. The review focusses on the research carried out during the last decade. PMID- 20848594 TI - Structure-morphology-property relationships of non-perfluorinated proton conducting membranes. AB - A fundamental understanding of structure-morphology-property relationships of proton exchange membranes (PEMs) is crucial in order to improve the cost, performance, and durability of PEM fuel cells (PEMFCs). In this context, there has been an explosion over the past five years in the volume of research carried out in the area of non-perfluorinated, proton-conducting polymer membranes, with a particular emphasis on exploiting phase behavior associated with block and graft copolymers. This progress report highlights a selection of interesting studies in the area that have appeared since 2005, which illustrate the effects of factors such as acid and water contents and morphology upon proton conduction. It concludes with an outlook on future directions. PMID- 20848595 TI - Photoresist latent and developer images as probed by neutron reflectivity methods. AB - Photoresist materials enable the fabrication of advanced integrated circuits with ever-decreasing feature sizes. As next-generation light sources are developed, using extreme ultraviolet light of wavelength 13.5 nm, these highly tuned formulations must meet strict image-fidelity criteria to maintain the expected performance gains from decreases in feature size. However, polymer photoresists appear to be reaching resolution limits and advancements in measurements of the in situ formed solid/solid and solid/liquid interface is necessary. This Review focuses on the chemical and physical structure of chemically amplified photoresists at the lithographic feature edge at length scales between 1 nm and 100 nm. Neutron reflectivity measurements provide insight into the nanometer scale composition profiling of the chemical latent image at an ideal lithographic line-edge that separates optical resolution effects from materials processing effects. Four generations of advanced photoresist formulations were examined over the course of seven years to quantify photoresist/photoacid and photoresist/developer interactions on the fidelity of lithographic features. The outcome of these measurements complement traditional resist design criteria by providing the effects of the impacts of the photoresist and processing on the feature fidelity. These physical relations are also described in the context of novel resist architectures under consideration for next-generation photolithography with extreme-ultraviolet radiation. PMID- 20848596 TI - Nanoparticle stripes, grids, and ribbons produced by flow coating. PMID- 20848597 TI - Improving the knowledge on Piper betle: targeted metabolite analysis and effect on acetylcholinesterase. AB - Piper betle is a species growing in South East Asia, where its leaves are economically and medicinally important. To screen the highest possible number of volatile and semivolatile components, the leaves were subjected to headspace solid-phase microextraction, hydrodistillation and Soxhlet extraction, prior to analysis by GC/MS. Fifty compounds (identified by comparison with standard compounds or tentatively by National Institute of Standards and Technology database) were determined, 23 being described for the first time in this matrix. An aqueous extract was also analysed, in which only seven compounds were characterized. The organic acids' composition of this extract was determined by HPLC/UV and eight compounds are reported for the first time in P. betle. This extract also displayed acetylcholinesterase inhibitory capacity. PMID- 20848599 TI - Isoselenocyanates derived from amino acid esters: an expedient synthesis and application to the assembly of selenoureidopeptidomimetics, unsymmetrical selenoureas and selenohydantoins. AB - An important class of organoselenium compounds-alpha-isoselenocyanato esters 4 has been prepared by a reaction of alpha-isocyano esters with elemental selenium powder. The reaction issimple, rapid and all the isoselenocyanates have been isolated as stable ones after chromatographic purification. These hitherto unreported classes of molecules would be useful building blocks for the preparation of variety of selenium containing peptidomimetics. In this study, the utility of the title molecules in the preparation of selenoureidopeptidomimetics 6, unsymmetrical selenoureas 8 and selenohydantoins 10 is demonstrated. PMID- 20848598 TI - Study of atypical kinetic behaviour of cytochrome P450 2C9 isoform with diclofenac at low substrate concentrations by sweeping-MEKC combination. AB - In view of the fact that several studies have shown that diclofenac hydroxylation by cytochrome P450 2C9 deviated from Michaelis-Menten kinetics at low substrate concentrations, sweeping combined with MEKC was applied for the kinetic study of this pharmacologically important reaction. A 50 MUm fused silica capillary (56 cm effective length) was used to carry out all separations. 70 mM SDS in 20 mM phosphate 20 mM tetraborate buffer, pH 8.6, was used as the BGE. Injection was accomplished by the application of 50 mbar (5 kPa) pressure to the sample vial for 52 s. Separation was performed at 22 kV (positive polarity), with a capillary temperature of 25 degrees C and detection at 200 nm. The higher sensitivity of the sweeping-MEKC combination compared with the simple MEKC method enabled this reaction to be fitted to a Hill kinetic model and confirmed the findings of other authors. A Michaelis constant of 2.91+/-0.10 MUM, maximum reaction velocity of 9.16+/-0.16 nmol/min/nmol and Hill coefficient of 1.66+/ 0.08 were determined. This value of Hill coefficient confirms the presence of a positive cooperativity at low diclofenac concentrations and supports the hypothesis of two substrates binding at or near the active site. PMID- 20848600 TI - Extinction of spatial memory alters CREB phosphorylation in hippocampal CA1. AB - Although the importance of cAMP-response element binding protein (CREB) phosphorylation in long-term memory formation is well documented for hippocampus dependent tasks, little is known about the changes in phosphorylated CREB (pCREB) that occur during the process of extinction. The purpose of this study was to characterize the temporal patterns of pCREB in the CA1 and the amygdala after the extinction of previously acquired spatial information in the water maze. Mice were trained to find a hidden platform located at a fixed position and then were given extinction sessions in which the platform was either absent (NoPF) or relocated every day (RandomPF). We show that water maze spatial training evoked a biphasic response of pCREB in the CA1, with two different peaks occurring 15 min and 8 h postacquisition. The extinction of the original spatial preference significantly reduced the two peaks of CA1 pCREB in both RandomPF and NoPF groups whereas CA1 pCREB at 60 min post-training remained unaffected. Moreover, the early and late phases of extinction training produced regionally dissociable effects on pCREB in the CA1 and the lateral nucleus of the amygdala. These findings provide new insights on the molecular dynamics and anatomical dissociations underlying spatial memory and extinction learning. PMID- 20848601 TI - GluK1 inhibits calcium dependent and independent transmitter release at associational/commissural synapses in area CA3 of the hippocampus. AB - CA3 pyramidal cells receive three main excitatory inputs: the first one is the mossy fiber input, synapsing mainly on the proximal apical dendrites. Second, entorhinal cortex cells form excitatory connections with CA3 pyramidal cells via the perforant path in the stratum lacunosum moleculare. The third input involves the ipsi-and contralateral connections, termed the associational/commissural (A/C) pathway terminating in the stratum radiatum of CA3, thus forming a feedback loop within this region. Since this excitatory recurrent synapse makes the CA3 region extremely prone to seizure development, understanding the regulation of synaptic strength of this connection is of crucial interest. Several studies suggest that kainate receptors (KAR) play a role in the regulation of synaptic strength. Our aim was to characterize the influence of KAR on A/C synaptic transmission: application of ATPA, a selective agonist of the GluK1 KAR, depressed the amplitude fEPSP without affecting the size of the fiber volley. Blockade of GABA receptors had no influence on this effect, arguing against the influence of interneuronal KARs. Pharmacological and genetic deletion studies could show that this effect was selectively due to GluK1 receptor activation. Several lines of evidence, such as PPF changes, coefficient of variance-analysis and glutamate uncaging experiments strongly argue for a presynaptic locus of suppression. This is accompanied by an ATPA-mediated reduction in Ca(2+) influx at excitatory synaptic terminals, which is most likely mediated by a G-Protein dependent mechanism, as suggested by application of pertussis toxin. Finally, analysis of miniature EPSCs in the presence and absence of extracellular Ca(2+) suggest that presynaptic KAR can also reduce transmitter release downstream and therefore independent of Ca(2+) influx. PMID- 20848602 TI - Recognition memory: material, processes, and substrates. AB - The proposal that a system centering on the perirhinal cortex is responsible for familiarity discrimination, particularly for single items, whereas a system centering on the hippocampus is responsible for recollective and more complex associational aspects of recognition memory is reviewed in the light of recent findings. In particular, the proposal is reviewed in relation to recent animal work with rats and results from human clinical studies. Notably, progress has been made in determining potential neural memory substrate mechanisms within the perirhinal cortex in rats. Recent findings have emphasized the importance of specifying the type of material, the type of test, and the strategy used by subjects to solve recognition memory tests if substrates are to be accurately inferred. It is to be expected that the default condition is that both the hippocampal and perirhinal systems will contribute to recognition memory performance. Indeed, rat lesion experiments provide examples of where cooperation between both systems is essential. Nevertheless, there remain examples of the independent operation of the hippocampal and perirhinal systems. Overall, it is concluded that most, though not all, of the recent findings are in support of the proposal. However, there is also evidence that the systems involved in recognition memory need to include structures outside the medial temporal lobe: there are significant but as yet only partially defined roles for the prefrontal cortex and sensory association cortices in recognition memory processes. PMID- 20848604 TI - P2X7 receptor differentially modulates astroglial apoptosis and clasmatodendrosis in the rat brain following status epilepticus. AB - Recently, it has been reported that astroglial loss/dysfunction plays a role in epileptogenesis. In addition, astroglial loss is accompanied by up-regulation of P2X7 receptor expression in microglia. Therefore, we investigated whether P2X7 receptor is involved in astroglial damages induced by status epilepticus (SE). In the present study, astroglial loss showed the regional-specific manner and the differential responses to P2X7 receptor functions. Both OxATP and brilliant blue G (P2X7 receptor antagonists) infusion prevented apoptotic astroglial loss in the molecular layer of the dentate gyrus and the frontoparietal cortex, while it promoted clasmatodendrosis in the CA1 region as compared to saline treatment. In contrast, BzATP (a P2X7 receptor agonist) treatment exacerbated apoptotic astroglial loss in the molecular layer of the dentate gyrus and the frontoparietal cortex, but alleviated SE-induced astroglial swelling in the CA1 region. Astroglial loss in the piriform cortex was not affected by P2X7 receptor agonist- or antagonist-infusion. These findings suggest that P2X7 receptor function differently modulates SE-induced astroglial loss in distinct brain regions. PMID- 20848603 TI - Measuring recollection and familiarity in the medial temporal lobe. AB - Many recent studies have investigated how the structures of the medial temporal lobe (MTL) support recollection and familiarity, which are two processes widely thought to support recognition memory. The behavioral methods that are used to isolate recollection and familiarity in neuroimaging and lesion studies typically assume that recollection is a categorical process and not a continuous process. A categorical process is one that either occurs or does not occur for a particular test item (yielding high confidence and high accuracy when it does occur), whereas a continuous process is one that comes in degrees (yielding varying degrees of confidence and accuracy). Studies suggesting that the hippocampus selectively supports the recollection process (such as those that use the Remember/Know procedure or rely on Receiver Operating Characteristic analysis) generally depend on the categorical view of recollection, but much recent evidence suggests that recollection is a continuous process. If recollection is a continuous process (i.e., if recollection comes in degrees), then evidence that has been taken to mean that the hippocampus selectively supports recollection is also compatible with the idea that the hippocampus supports both recollection and familiarity. We suggest that an alternative method can be used to effectively investigate recollection and familiarity in the MTL, one that is valid whether recollection is a categorical or a continuous process. PMID- 20848605 TI - Amygdala gene expression of NMDA and GABA(A) receptors in patients with mesial temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and affects 40% of the patients. Seizures arising from the mesial temporal lobe structures (i.e., amygdala and hippocampus) are common, whereas neocortical seizures are rare. In recent years, many studies aimed to identify the pattern of gene expression of neurotransmitters involved in molecular mechanisms of epilepsy. We used real-time PCR to quantify the expression of GABA(A) (subunits alpha1, beta1, beta2) and NMDA (subunits NR1, NR2A, and NR2B) receptor genes in amygdalae of 27 patients with TLE and 14 amygdalae from autopsy controls. The NR1 subunit was increased in patients with epilepsy when compared with controls. No differences were found in expression of NMDA subunits NR2A and NR2B or in alpha1, beta1, and beta2 subunits of GABA(A) receptors. Our results suggest that the NR1 subunit of NMDA receptors is involved in the amygdala hyperexcitability in some of the patients with TLE. PMID- 20848608 TI - Early life stress followed by subsequent adult chronic stress potentiates anxiety and blunts hippocampal structural remodeling. AB - Early life stress produces long-term alterations in cognition, emotionality, and stress responsiveness. The stress-sensitive hippocampal formation plays a role in producing many of these alterations. We report that adult male rats exposed to early life stress, in the form of maternal separation (MS), exhibit baseline impairment of hippocampal dependent memory and following three weeks of chronic restraint stress (CRS) exhibit heightened anxiety-like behavior and alterations in the morphology of hippocampal CA3 pyramidal neurons. Specifically, as measured by the object placement task, MS offspring demonstrated impaired spatial memory compared with nonmaternally separated rats (NMS). Moreover, compared with NMS rats, subsequent CRS exposure of MS rats increased novelty-induced corticosterone secretion and potentiated anxiety-like behavior as measured by the elevated plus maze. Further, CRS exposed MS rats did not exhibit shortening of apical dendritic length compared with nonstressed MS rats, whereas CRS exposed NMS rats did show significant dendritic shrinkage compared with nonstressed NMS rats. The blunted CRS-induced remodeling of apical dendritic length in MS rats is likely due to a baseline deficiency in dendritic length; MS rats exhibit a trend towards shorter apical dendrites in comparison to NMS rats. CRS exposure in both MS and NMS rats, however, induced a reduction in apical dendritic branching. Finally, there was a significant correlation between apical dendritic length and novelty-induced corticosterone level, while there was not a significant correlation with anxiety like behavior. Overall, our results suggest preserved but blunted hippocampal structural plasticity in MS rats that is not sufficient to compensate for hippocampal dysfunction and hypersensitivity to CRS. PMID- 20848607 TI - Synaptic loss and retention of different classic cadherins with LTP-associated synaptic structural remodeling in vivo. AB - Cadherins are synaptic cell adhesion molecules that contribute to persistently enhanced synaptic strength characteristic of long-term potentiation (LTP). What is relatively unexplored is how synaptic activity of the kind that induces LTP associated remodeling of synapse structure affects localization of cadherins, particularly in mature animals in vivo, details which could offer insight into how different cadherins contribute to synaptic plasticity. Here, we use a well described in vivo LTP induction protocol that produces robust synaptic morphological remodeling in dentate gyrus of adult rats in combination with confocal and immunogold electron microscopy to localize cadherin-8 and N-cadherin at remodeled synapses. We find that the density and size of cadherin-8 puncta are significantly diminished in the potentiated middle molecular layer (MML) while concurrently, N-cadherin remains tightly clustered at remodeled synapses. These changes are specific to the potentiated MML, and occur without any change in density or size of synaptophysin puncta. Thus, the loss of cadherin-8 probably represents selective removal from synapses rather than overall loss of synaptic junctions. Together, these findings suggest that activity-regulated loss and retention of different synaptic cadherins could contribute to dual demands of both flexibility and stability in synapse structure that may be important for synaptic morphological remodeling that accompanies long-lasting plasticity. PMID- 20848606 TI - Recollection and familiarity: examining controversial assumptions and new directions. AB - It is well accepted that recognition memory reflects the contribution of two separable memory retrieval processes, namely recollection and familiarity. However, fundamental questions remain regarding the functional nature and neural substrates of these processes. In this article, we describe a simple quantitative model of recognition memory (i.e., the dual-process signal detection model) that has been useful in integrating findings from a broad range of cognitive studies, and that is now being applied in a growing number of neuroscientific investigations of memory. The model makes several strong assumptions about the behavioral nature and neural substrates of recollection and familiarity. A review of the literature indicates that these assumptions are generally well supported, but that there are clear boundary conditions in which these assumptions break down. We argue that these findings provide important insights into the operation of the processes underlying recognition. Finally, we consider how the dual process approach relates to recent neuroanatomical and computational models and how it might be integrated with recent findings concerning the role of medial temporal lobe regions in other cognitive functions such as novelty detection, perception, implicit memory and short-term memory. PMID- 20848609 TI - Layer-specific alterations to CA1 dendritic spines in a mouse model of Alzheimer's disease. AB - Why memory is a particular target for the pathological changes in Alzheimer's Disease (AD) has long been a fundamental question when considering the mechanisms underlying this disease. It has been established from numerous biochemical and morphological studies that AD is, at least initially, a consequence of synaptic malfunction provoked by Amyloid beta (Abeta) peptide. APP/PS1 transgenic mice accumulate Abeta throughout the brain, and they have therefore been employed to investigate the effects of Abeta overproduction on brain circuitry and cognition. Previous studies show that Abeta overproduction affects spine morphology in the hippocampus and amygdala, both within and outside plaques (Knafo et al., (2009) Cereb Cortex 19:586-592; Knafo et al., (in press) J Pathol). Hence, we conducted a detailed analysis of dendritic spines located in the stratum oriens and stratum radiatum of the CA1 hippocampal subfield of APP/PS1 mice. Three-dimensional analysis of 18,313 individual dendritic spines revealed a substantial layer specific decrease in spine neck length and an increase in the frequency of spines with a small head volume. Since dendritic spines bear most of the excitatory synapses in the brain, changes in spine morphology may be one of the factors contributing to the cognitive impairments observed in this AD model. PMID- 20848610 TI - In vivo BDNF modulation of hippocampal mossy fiber plasticity induced by high frequency stimulation. AB - Changes in synaptic efficacy and morphology have been proposed as mechanisms underlying learning and memory processes. In our previous studies, high frequency stimulation (HFS) sufficient to induce LTP at the hippocampal mossy fiber (MF) pathway, leads to MF synaptogenesis, in a prominent contralateral form, at the stratum oriens of hippocampal CA3 area. Recently we reported that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy at the MF projection accompanied by a structural reorganization at the CA3 area within the stratum oriens region in a prominent ipsilateral form. It is considered that the capacity of synapses to express plastic changes is itself subject to variation dependent on previous experience. Here we used intrahippocampal microinfusion of BDNF to analyze its effects on functional and structural synaptic plasticity induced by subsequent mossy fiber HFS sufficient to induce LTP in adult rats, in vivo. Our results show that BDNF modifies the ability of the MF pathway to present LTP by HFS. Moreover BDNF modified the structural reorganization pattern produced by HFS, presenting a balanced bilateral appearance. Microinfusion of K252a blocks the functional and morphological effects produced by BDNF, revealing that the BDNF modulation is dependent on its TrkB receptor activation. These findings support the idea that BDNF actions modify subsequent synaptic plasticity; a homeostatic mechanism thought to be essential for synaptic integration among prolonged temporal domains in the adult mammalian brain. PMID- 20848611 TI - Put them out to pasture? What are old granule cells good for, anyway...? AB - In this issue, Alme and colleagues propose a novel hypothesis that young adult born neurons represent the functional population of the dentate gyrus, and that old granule cells "retire" from relevance. Here, we present several implications of this interesting theory for the function of both neurogenesis and the dentate gyrus. PMID- 20848612 TI - Drug-induced autoimmune hepatitis: an easily reversible type of liver fibrosis? PMID- 20848613 TI - VCD studies on cyclic peptides assembled from L-alpha-amino acids and a trans-2 aminocyclopentane- or trans-2-aminocyclohexane carboxylic acid. AB - The increasing interest in peptidomimetics of biological relevance prompted us to synthesize a series of cyclic peptides comprising trans-2-aminocyclohexane carboxylic acid (Achc) or trans-2-aminocyclopentane carboxylic acid (Acpc). NMR experiments in combination with MD calculations were performed to investigate the three-dimensional structure of the cyclic peptides. These data were compared to the conformational information obtained by electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) spectroscopy. Experimental VCD spectra were compared to theoretical VCD spectra computed quantum chemically at B3LYP/6 31G(d) density functional theory (DFT) level. The good agreement between the structural features derived from the VCD spectra and the NMR-based structures underlines the applicability of VCD in studying the conformation of small cyclic peptides. PMID- 20848614 TI - Neurogenesis in subclasses of vomeronasal sensory neurons in adult mice. AB - The vomeronasal sensory epithelium contains two distinct populations of vomeronasal sensory neurons. Apical neurons express G(i) (2) (alpha) -linked V1R vomeronasal receptors and project to the anterior portion of the accessory olfactory bulb, while basal neurons express G(o) (alpha) -linked V2R receptors and project to the posterior portion. Sensory neurons expressing V1R and V2R vomeronasal receptors are sensitive to different stimuli. Neurons in the vomeronasal system undergo continuous cell turnover during adulthood. To analyze over time neurogenesis of the different sensory cell populations, adult mice were injected with bromodeoxyuridine (BrdU) and sacrificed at postinjection days 1, 3, 5, 7, and 11. Newborn vomeronasal neurons were revealed by antibodies against BrdU while subclasses of vomeronasal neurons were identified using antibodies against G(o) (alpha) or G(i) (2) (alpha) proteins. To ascertain whether G proteins are early expressed during neurogenesis, multiple labeling experiments using PSA-NCAM and doublecortin were performed. Distribution of BrdU-labeled cells was analyzed in angular segments from the margin of the sensory epithelium. No sexual differences were found. Within survival groups, BrdU-G(o) (alpha) labeled cells were found more marginally when compared with BrdU-G(i) (2) (alpha) labeled cells. The number of BrdU-positive cells decreased from day 1 to day 3 to remain constant afterwards. The relative proportions of BrdU-G(i) (2) (alpha) and BrdU-G(o) (alpha) labeled cells remained similar and constant from postinjection day 1 onwards. This rate was also comparable with BrdU-positive cells starting day 3. These results indicate an early, constant, and similar rate of neurogenesis in the two major subclasses of vomeronasal neurons, which suggests that both cell populations maturate independently. PMID- 20848616 TI - Multimethod study of distress tolerance and PTSD symptom severity in a trauma exposed community sample. AB - Despite initial evidence linking distress tolerance to posttraumatic stress disorder (PTSD) symptom severity, there is a need for the investigation of interrelations among multiple measures of distress tolerance and PTSD symptom severity. Therefore, the present study investigated concurrent relations among multiple measures of distress tolerance, as well as the relations between these measures and PTSD symptom severity, within a trauma-exposed community sample. The sample consisted of 81 trauma-exposed adults (63.1% women). Results indicated that Distress Tolerance Scale (Simons & Gaher, 2005) scores, but no other measures of distress tolerance were significantly related to PTSD symptom severity above and beyond the variance accounted for by number of traumas, trait level neuroticism, and participant sex. Implications and future directions are discussed. PMID- 20848615 TI - Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. AB - SCOPE: Curcumin is a polyphenol with a variety of pharmacologic effects. We evaluate the effect of dietary curcumin on the severity of repeated colitis associated colorectal cancer. METHODS AND RESULTS: Six-week-old C57BL/6 mice were randomized into two dietary groups: standard diet and curcumin at 0.6% diet. The mice were exposed to 15 cycles of 0.7% dextran sodium sulphate for 1 week followed by distilled water for 10 days. After curcumin diet, the disease activity index presented a statistical reduction in the last cycles, macroscopic tumors were not seen and the microscopic study showed minor neoplasic lesions with respect to standard diet-group. beta-Catenin translocation to the cytoplasm and/or nucleus was observed in the tumor tissue, but this translocation and its intensity were significantly minor in the curcumin diet-DSS animals. Cytokines as tumor necrosis factor-alpha and IFN-gamma were significantly diminished in DSS animals fed with curcumin. Conversely, non-modification of p53 expression was observed and cyclo-oxygenase-2 and inducible nitric oxide synthase were significantly reduced in the curcumin diet-DSS group. CONCLUSION: We demonstrate the protective/preventive effect of curcumin in the progression of colorectal cancer associated to colitis, which was correlated with a lowered immunoreactivity of beta-catenin, a non-modification of p53 expression, a reduction of proinflammatory cytokine levels and a decrease of inflammatory protein overexpression. PMID- 20848617 TI - Intimate relationships among returning soldiers: the mediating and moderating roles of negative emotionality, PTSD symptoms, and alcohol problems. AB - Research examining relationship quality among combat veterans largely focuses on the role of posttraumatic stress disorder (PTSD), with less attention devoted to other correlates of PTSD and relationship quality, such as personality and problematic drinking. In a sample of combat-exposed National Guard soldiers recently returned from Iraq (N = 308), we examined (a) a meditational pathway from negative emotionality, to elevated postdeployment PTSD symptoms, to poorer relationship quality; and (b) the moderating role of problematic drinking. Moderated mediation regression strategies supported the mediating role of postdeployment PTSD symptoms, but not the moderating role of problematic drinking on soldiers' relationship quality. Findings suggest negative emotionality creates a vulnerability to more severe early postdeployment PTSD symptoms and poorer early postdeployment relationship quality. PMID- 20848618 TI - The impact of dissociation, shame, and guilt on interpersonal relationships in chronically traumatized individuals: a pilot study. AB - The aim of this study was to systematically examine the impact of shame, guilt, and dissociation on interpersonal relationships. Study 1 assessed 81 participants attending a trauma-related treatment service with the Structured Interview for Disorders of Extreme Stress and the Community and Interpersonal Connectedness Scale. Study 2 assessed 21 traumatized participants from the same service with the above measures, as well as the Dissociative Experiences Scale. Lifetime shame and current dissociation made significant contributions to relationship disconnectedness, with dissociation having the most significant impact in all analyses. Both dissociation and shame appear to have a severing effect on interpersonal relationships. PMID- 20848620 TI - Pallidal stimulation in siblings with pantothenate kinase-associated neurodegeneration: four-year follow-up. PMID- 20848621 TI - The grasp reflex: a symptom in need of treatment. AB - The grasp reflex is one of the primitive reflexes frequently observed in neurodegenerative diseases. However, quality of life and treatment of the grasp reflex are neglected in the literature. Following two brief case vignettes of patients seen recently who experienced disability from a grasp reflex, we briefly review its phenomenology, anatomy-physiology and epidemiology in neurodegenerative movement disorders, and assess the limited current literature regarding the quality of life and treatment. PMID- 20848622 TI - A selective Ru-catalyzed semireduction of alkynes to Z olefins under transfer hydrogenation conditions. AB - By using a readily available, air- and moisture-stable dihydrido-Ru complex, a variety of Z olefins are accessible under transfer-hydrogenation conditions with formic acid as the hydrogen source in excellent yields and Z/E selectivities. PMID- 20848623 TI - Dicationic tellurium analogues of the classic N-heterocyclic carbene. AB - The synthesis and comprehensive characterization of the first dicationic tellurium analogues of N-heterocyclic carbenes (NHCs) has been reported, in both the +2 and +4 oxidation states. For the +2 oxidation state, a base-stabilized form of TeCl(2) is used as the starting material. The dications are isolated by means of halide metathesis and the solid-state structures confirm the previously calculated diimine bonding arrangement. For Te(IV), a diamine is used in a high yielding dehydrohalogen coupling reaction from TeCl(4). The dicationic NHC analogue is isolated in a base-stabilized form through halide abstraction and subsequent coordination by pyridine. PMID- 20848625 TI - A general and convenient palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides. PMID- 20848624 TI - An adamantyl amino acid containing gramicidin S analogue with broad spectrum antibacterial activity and reduced hemolytic activity. AB - The cyclic cationic antimicrobial peptide gramicidin S (GS) is an effective topical antibacterial agent that is toxic for human red blood cells (hemolysis). Herein, we present a series of amphiphilic derivatives of GS with either two or four positive charges and characteristics ranging between very polar and very hydrophobic. Screening of this series of peptide derivatives identified a compound that combines effective antibacterial activity with virtually no toxicity within the same concentration range. This peptide acts against both Gram negative and Gram-positive bacteria, including several MRSA strains, and represents an interesting lead for the development of a broadly applicable antibiotic. PMID- 20848626 TI - A short formal total synthesis of strychnine with a samarium diiodide induced cascade reaction as the key step. PMID- 20848627 TI - Identification of a nonaketide product for the iterative polyketide synthase in biosynthesis of the nine-membered enediyne C-1027. PMID- 20848628 TI - A geometric approach to the crystallographic solution of nonconventional DNA structures: helical superstructures of d(CGATAT). PMID- 20848629 TI - Intramolecular electron transfer in the photooxidized peptides tyrosine-histidine and histidine-tyrosine: a time-resolved CIDNP study. PMID- 20848630 TI - Reticulated heterojunctions for photovoltaic devices. PMID- 20848632 TI - Visualizing tyrosine kinase activity with bipartite tetracysteine display. PMID- 20848633 TI - Cucurbit[7]uril as a tool in the green synthesis of gold nanoparticles. AB - A simple, green, one-pot synthesis of gold nanoparticles was achieved through the reaction of an aqueous mixture of potassium tetrachloroaurate(III) and the macrocycle cucurbit[7]uril in the presence of sodium hydroxide at room temperature without introducing any kind of traditional reducing agents and/or external energy. The as-prepared gold nanoparticles showed catalytic activity for the reduction reaction of 4-nitrophenol in the presence of NaBH(4), which has been established by visual inspection and UV/Vis spectroscopy. This report is the first for the preparation of gold nanoparticles using cucurbit[7]uril in aqueous media through chemical reduction without employing conventional reducing agents and/or external energy. PMID- 20848634 TI - 3He impurities in nearly frictionless transport of solid 4He at low temperatures. AB - Glassy matter, when subjected to high shear rates exhibit shear thinning, that is, the viscosity diminishes with increasing shear rate. One possible outcome for the almost vanishing viscosity is nearly frictionless transport, which is possible in solid (4)He due to the presence of minute concentrations of (3)He. The glassy state of solid (4)He is also relevant to the possible onset of superfluidity in solid (4)He. By treating the solid (4)He locally as an amorphous matter and using the transition-rate dependent model together with the specific activation energy, we observe a series of sudden changes of the shearing stresses (which directly relates to the resistance) at corresponding onset temperatures of supersolid (4)He (ranging from 175 to 1200 mK) for different activation volumes of (3)He. Even at higher concentrations of (3)He than previous reported (around 1700 ppm), the supersolidity of (4)He still occurs. PMID- 20848635 TI - Reconstruction of MRI data encoded with arbitrarily shaped, curvilinear, nonbijective magnetic fields. AB - A basic framework for image reconstruction from spatial encoding by curvilinear, nonbijective magnetic encoding fields in combination with multiple receivers is presented. The theory was developed in the context of the recently introduced parallel imaging technique using localized gradients (PatLoc) approach. In this new imaging modality, the linear gradient fields are generalized to arbitrarily shaped, nonbijective spatial encoding magnetic fields, which lead to ambiguous encoding. Ambiguities are resolved by adaptation of concepts developed for parallel imaging. Based on theoretical considerations, a practical algorithm for Cartesian trajectories is derived in the case that the conventional gradient coils are replaced by coils for PatLoc. The reconstruction method extends Cartesian sensitivity encoding (SENSE) reconstruction with an additional voxelwise intensity-correction step. Spatially varying resolution, signal-to noise ratio, and truncation artifacts are described and analyzed. Theoretical considerations are validated by two-dimensional simulations based on multipolar encoding fields and they are confirmed by applying the reconstruction algorithm to initial experimental data. PMID- 20848636 TI - Multicentric castleman disease in a child with primary immunodeficiency. AB - Multicentric Castleman disease is a rare lymphoproliferative disorder mostly seen in adults with HIV. It presents with fever and systemic symptoms and is extremely uncommon in children. We describe a novel case of multicentric Castleman disease associated with primary immunodeficiency (common variable immunodeficiency) and discuss pathophysiologic mechanisms and recent advances in understanding this disease. PMID- 20848637 TI - The controversy of varicella vaccination in children with acute lymphoblastic leukemia. AB - BACKGROUND: The available guidelines for varicella vaccination of susceptible children with acute lymphoblastic leukemia (ALL) have become increasingly conservative. However, vaccination of those who have remained in continuous complete remission for 1 year and are receiving chemotherapy is still considered a reasonable option. There is little available data to allow a comparison of the risk versus benefit of vaccinating these patients. PROCEDURE: We retrospectively reviewed mortality due to varicella in the records of 15 pediatric ALL study groups throughout Europe, Asia, and North America during the period 1984-2008. RESULTS: We found that 20 of 35,128 children with ALL (0.057%; 95% confidence interval [CI], 0.037-0.088%) died of VZV infection. The mortality rate was lower in North America (3 of 11,558 children, 0.026%; 95% CI, 0.009-0.076%) than in the Asian countries (2 of 4,882 children, 0.041%; 95% CI, 0.011-0.149%) and in Europe (15 of 18,688 children, 0.080%; 95% CI, 0.049-0.132%) consistent with the generally higher rate of VZV vaccination in North America. Fourteen of the 20 patients (70%) died during the first year of treatment for ALL. One death was attributed to varicella vaccination. CONCLUSIONS: The negligible rate of fatal varicella infection in children with ALL, the risk that accompanies vaccination, and the necessity of withholding chemotherapy for vaccination appear to outweigh the potential benefit of varicella vaccination for children during treatment of ALL. PMID- 20848638 TI - Clinicopathologic comparison of familial versus sporadic atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system. AB - BACKGROUND: Central nervous system (CNS) atypical teratoid/rhabdoid tumors (AT/RT) are aggressive tumors usually diagnosed in young children and characterized by SMARCB1 (INI1, hSNF5) gene abnormalities. Despite initial chemo radiation responsiveness, most children die of progressive disease (PD). Little data regarding familial AT/RT clinical course exist. This study described and compared familial (F) versus sporadic (S) AT/RT and elucidated SMARCB1 mutations and inheritance patterns. METHODS: A retrospective chart review, pedigree, and SMARCB1 analysis were done. RESULTS: Between January 1989 and June 2009, 20 children with CNS AT/RT were diagnosed, 8-S and 12-F. Median age at diagnosis (months) of S and F patient were: 13 and 4.8, respectively. Median survival (months) was S-21, F4.5, and 8-all. Pedigree analyses showed unaffected parent carriers with multiple affected offspring. CONCLUSIONS: Children with F-AT/RT are younger, have more extensive disease, and are more likely to die from PD than children with S-AT/RT. Surgery, radiation, and chemotherapy were important in achieving long-term survival. Pedigree analysis supports autosomal dominant inheritance pattern with incomplete penetrance. Germline SMARCB1 mutation analysis is important in all patients diagnosed with AT/RT to (1) determine actual incidence of F-AT/RT, (2) determine penetrance of predisposing mutations, (3) provide appropriate genetic counseling, and (4) establish surveillance screening guidelines. PMID- 20848639 TI - Long-term fine caliber hair removal with an electro-optic Q-switched Nd:YAG Laser. AB - BACKGROUND: In spite of major advances in hair removal therapy, fine caliber hair remains a significant challenge for laser- and light-based devices. OBJECTIVE: Evaluate a novel Electro-Optic (EO) Q-switched Nd:YAG laser for pigmented fine caliber hair removal in the Standard Single and a double pulse (DP) mode. METHODS: Eleven patients underwent four laser treatments at monthly intervals. Bilateral anatomical regions received to one side the standard single pulse (SSP) while the other side the DP option. Blinded investigators conducted hair counts at 6 months post-treatment and after 24 months. Patients assessed hair loss and discomfort. Six patients rated their satisfaction at 6 months. RESULTS: At 6 months, investigators found a reduction of 50% in hair counts with the DP and 46% with standard pulse. Ninety percent in DP and 50% in SSP reported none to mild discomfort. Transient erythema and edema was observed with a lower severity rating with the DP. There were no other untoward effects. 83.3% of patients who completed the study at 6 months expressed satisfaction with the results. At 24 months hair loss was maintained at the same rate. CONCLUSION: The EO Q-switched Nd:YAG laser is an effective option for the permanent treatment of unwanted fine hair and has a high-patient satisfaction rate. There is less therapeutic discomfort in the DP mode. PMID- 20848640 TI - An aggressive systemic juvenile xanthogranuloma clonally related to a preceding T cell acute lymphoblastic leukemia. AB - Juvenile xanthogranuloma (JXG) is a disorder of disputed origin thought to be related to the dermal/interstitial macrophage. A 5-year-old female presented with an aggressive systemic JXG that developed 5 months after the diagnosis of T-cell acute lymphoblastic leukemia (T-ALL). Examination of the T-cell receptor gamma (TCR-gamma) rearrangement in T-ALL blasts, JXG infiltrated lymph node biopsies and micro-dissected JXG histiocytes revealed an identical bi-allelic TCR-gamma rearrangement in all samples, thus providing evidence for a clonal relationship between T-ALL and JXG in this case. PMID- 20848641 TI - Tumor vaccination for high-grade glioma. PMID- 20848642 TI - Influence of charge distribution on the discrepant MS/MS fragmentation of the native and oxidized FMRF: evidence for the mobile proton model. AB - Using the mobile proton model as a framework, the influence of charge distribution on the discrepant fragmentation of peptides FMRF, FM(O)RF and FM(O(2))RF (with united peptide sequence) was explored by mass spectrometry experiments and quantum chemical calculations. With the added O atoms, more negative charges were prompted to deposit in the main protonation sites of the oxidation products. Consequently, the solvated proton to the oxidized peptides could flow to the amide bonds in an easier manner and made these bonds fragment easily. Oxidation also induced the discrepant fragmentation of these bonds in a predictable manner: the more negative charges deposited in an amide bond, the more daughter ions (a(n), b(n), y(n) ions and their derivatives) were produced. The combined methods proposed here refined the mobile proton model for peptide fragmentation and opened the way to probe the discrepant fragmentation of peptides in peptide/protein identification. PMID- 20848643 TI - The repeat domain of the type III effector protein PthA shows a TPR-like structure and undergoes conformational changes upon DNA interaction. AB - Many plant pathogenic bacteria rely on effector proteins to suppress defense and manipulate host cell mechanisms to cause disease. The effector protein PthA modulates the host transcriptome to promote citrus canker. PthA possesses unusual protein architecture with an internal region encompassing variable numbers of near-identical tandem repeats of 34 amino acids termed the repeat domain. This domain mediates protein-protein and protein-DNA interactions, and two polymorphic residues in each repeat unit determine DNA specificity. To gain insights into how the repeat domain promotes protein-protein and protein-DNA contacts, we have solved the structure of a peptide corresponding to 1.5 units of the PthA repeat domain by nuclear magnetic resonance (NMR) and carried out small-angle X-ray scattering (SAXS) and spectroscopic studies on the entire 15.5-repeat domain of PthA2 (RD2). Consistent with secondary structure predictions and circular dichroism data, the NMR structure of the 1.5-repeat peptide reveals three alpha helices connected by two turns that fold into a tetratricopeptide repeat (TPR) like domain. The NMR structure corroborates the theoretical TPR superhelix predicted for RD2, which is also in agreement with the elongated shape of RD2 determined by SAXS. Furthermore, RD2 undergoes conformational changes in a pH dependent manner and upon DNA interaction, and shows sequence similarities to pentatricopeptide repeat (PPR), a nucleic acid-binding motif structurally related to TPR. The results point to a model in which the RD2 structure changes its compactness as it embraces the DNA with the polymorphic diresidues facing the interior of the superhelix oriented toward the nucleotide bases. PMID- 20848644 TI - Chiral separation of neonicotinoid insecticides by polysaccharide-type stationary phases using high-performance liquid chromatography and supercritical fluid chromatography. AB - The enantiomeric separations of three neonicotinoid insecticides (identified as compounds 1, 2, and 3) were performed on three polysaccharide-type chiral columns, that is, Chiralcel OD-H, Chiralpak AD-H, and Chiralpak IB, by high performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC). Effects of the modifier percentage and column temperature on chiral recognitions of chiral stationary phases were also studied. Both 1 and 2 could be resolved on all three columns selected, with the highest R(s) values obtained on Chiralpak AD-H and Chiralcel OD-H, respectively. However, satisfactory separation of the four stereoisomers of 3 was only achieved on Chiralcel OD-H. Considering the effects of ethanol on the values of k, alpha, and R(s), we concluded that hydrogen bonding, pi-pi, and/or dipole-dipole interactions might be all responsible for the chiral separation. In comparison to HPLC, a shorter run time was achieved for 1 and 2 by SFC. However, 3 could not be stereoselectively resolved using SFC. On the basis of the calculated thermodynamic parameters, we found that the separation processes of enantiomers of 1 and 2 were entropy controlled and enthalpy controlled, respectively. PMID- 20848645 TI - Rotational strength sign and normal modes description: A theoretical and experimental comparative study in bicyclic terpenes. AB - A comparative study of the Vibrational circular dichroism (VCD) patterns in three bicyclic terpenes with related molecular structures, (+)-(R)-alpha-pinene, (-) (S)-beta-pinene, and (-)-(S)-verbenone, is carried out. The study is done in the light of normal mode descriptions from a previous vibrational analysis. Although normal modes corresponding to identical molecular moieties shown the same description, rotational strength does not follow the Cahn-Ingold-Prelog descriptor-related sign in some cases, i.e., they do not present opposite signs depending on stereochemical description of the molecule. PMID- 20848646 TI - Mechanistic modelling and mechanistic monitoring: simulation and shadowgraph imaging of particulate dissolution in the flow-through apparatus. AB - Accurate mechanistic modelling of a complex system requires insight into the process being simulated, in addition to a theoretical 'first-principles' approach. The current work uses a numerical mechanistic model to simulate dissolution of a particulate system in the flow-through dissolution apparatus. A shadowgraph imaging method is also used to monitor the dissolution process, providing real-time estimates of particle motion, number and total dissolution time. Experimental dissolution studies of ibuprofen particles are used to assess the accuracy of the model. The numerical model adequately predicts the ibuprofen particle dissolution rate at 16 mL min(-1) . Parameter sensitivity analysis identified dissolution test circumstances requiring more, or less, accuracy in the particle size and density calculations. The shadowgraph imaging method successfully determined the total dissolution time and decreasing particle numbers over time. The images confirmed the pulsing particle motion of the numerical model but revealed some more complex velocity patterns, assisting numerical model development. Further optimisation of the sampling window is required to capture all relevant particle motion and changing particle size distribution. A mechanistic model can successfully simulate particulate dissolution in the flow-through apparatus, and when used along with shadowgraph imaging, can give valuable insight into the dissolution process mechanisms and environment. PMID- 20848647 TI - Cytochrome P450-dependent disposition of the enantiomers of citalopram and its metabolites: in vivo studies in Sprague-Dawley and Dark Agouti rats. AB - The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and ( )-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n = 9) and DA (n = 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 +/- 0.05 vs. 0.80 +/- 0.03, P < 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R) enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites. PMID- 20848648 TI - Synthesis and in vitro evaluation of gabapentin prodrugs that target the human apical sodium-dependent bile acid transporter (hASBT). AB - Gabapentin is a zwitterionic drug that exhibits low and variable oral absorption at therapeutic doses. The human apical sodium-dependent bile acid transporter (hASBT; SLC10A2) is a potential prodrug target to increase oral drug absorption. The objective was to evaluate several bile acid conjugates of gabapentin as potential prodrugs that target hASBT. Five analogues were synthesized and varied in ionic nature and the presence or absence of glutamic acid linker between the bile acid and drug. Analogues were evaluated for their inhibition and uptake properties using stably transfected hASBT-MDCK cells. The two monoanionic conjugates were potent hASBT substrates, with high affinity (K(m) of 16.3 and 5.99 MUM) and high capacity (V(max) of 0.656 and 0.842 pmol/cm(2) /s). The dianionic conjugate inhibited hASBT with moderate potency but was not a substrate. The two monoanionic conjugates were catalytically degraded in Caco-2 homogenate and rat liver microsomes. Each yielded gabapentin from prodrug. These two conjugates are novel prodrugs of gabapentin and illustrate prodrugs that can be designed to target hASBT. PMID- 20848649 TI - Increased sensitivity of KRAS mutation detection by high-resolution melting analysis of COLD-PCR products. AB - Considerable effort has been invested in the development of sophisticated technologies enabling detection of clinically significant low-level tumor specific KRAS mutations. Coamplification at lower denaturation temperature-PCR (COLD-PCR) is a new form of PCR that selectively amplifies mutation-containing templates based on the lower melting temperature of mutant homoduplexes versus wild-type homoduplexes. We have developed a fast COLD-PCR and high-resolution melting (HRM) protocol to increase the sensitivity of KRAS mutation detection. The clinical applicability of COLD-PCR for KRAS mutation detection was assessed by analyzing 61 colorectal cancer specimens, for which KRAS mutation status has been evaluated by the FDA approved TheraScreen((r)) KRAS mutation kit. The sensitivity was increased by 5- to 100-fold for melting temperature decreasing mutations when using COLD-PCR compared to standard PCR. Mutations, undetectable by the TheraScreen((r)) kit in clinical samples, were detected by COLD-PCR followed by HRM and verified by sequencing. Finally, we have observed a previously undescribed low prevalence synonymous mutation (KRAS c.39C>T, codon 13) in colorectal cancer specimens and in the peripheral blood from an unaffected individual. In conclusion, COLD-PCR combined with HRM, is a simple way of increasing the sensitivity of KRAS mutation detection without adding to the complexity and cost of the experiments. PMID- 20848650 TI - Hereditary fructose intolerance: functional study of two novel ALDOB natural variants and characterization of a partial gene deletion. AB - Hereditary fructose intolerance (HFI) is an autosomal recessive metabolic disease caused by impaired functioning of human liver aldolase (ALDOB). At least 54 subtle/point mutations and only two large intragenic deletions have been found in the ALDOB gene. Here we report two novel ALDOB variants (p.R46W and p.Y343H) and an intragenic deletion that we found in patients with suspected HFI. The residual catalytic activity of the recombinant p.R46W and p.Y343H variants toward F1P was particularly altered. We also characterized a large intragenic deletion that we found in six unrelated patients. This is the first report of six unrelated patients sharing the same ALDOB deletion, thus indicating a founder effect for this allele in our geographic area. Because this deletion involves ALDOB exon 5, it can mimic worldwide common pathogenic genotypes, that is, homozygous p.A150P and p.A175D. Finally, the identification of only one ALDOB mutation in symptomatic patients suggests that HFI symptoms can, albeit rarely, appear also in heterozygotes. Therefore, an excessive and continuous fructose dietary intake may have deleterious effects even in apparently asymptomatic HFI carriers. PMID- 20848652 TI - Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations. AB - Mutations in LMNA cause a variety of diseases affecting striated muscle including autosomal Emery-Dreifuss muscular dystrophy (EDMD), LMNA-associated congenital muscular dystrophy (L-CMD), and limb-girdle muscular dystrophy type 1B (LGMD1B). Here, we describe novel and recurrent LMNA mutations identified in 50 patients from the United States and Canada, which is the first report of the distribution of LMNA mutations from a large cohort outside Europe. This augments the number of LMNA mutations known to cause EDMD by 16.5%, equating to an increase of 5.9% in the total known LMNA mutations. Eight patients presented with either p.R249W/Q or p.E358K mutations and an early onset EDMD phenotype: two mutations recently associated with L-CMD. Importantly, 15 mutations are novel and include eight missense mutations (p.R189P, p.F206L, p.S268P, p.S295P, p.E361K, p.G449D, p.L454P, and p.W467R), three splice site mutations (c.IVS4 + 1G>A, c.IVS6 - 2A>G, and c.IVS8 + 1G>A), one duplication/in frame insertion (p.R190dup), one deletion (p.Q355del), and two silent mutations (p.R119R and p.K270K). Analysis of 4 of our lamin A mutations showed that some caused nuclear deformations and lamin B redistribution in a mutation specific manner. Together, this study significantly augments the number of EDMD patients on the database and describes 15 novel mutations that underlie EDMD, which will contribute to establishing genotype phenotype correlations. PMID- 20848653 TI - Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome. AB - Gitelman syndrome (GS) is characterized by salt-losing hypotension, hypomagnesemia, hypokalemic metabolic alkalosis, and hypocalciuria. To better model human GS caused by a specific mutation in the thiazide-sensitive Na(+) -Cl( ) cotransporter (NCC) gene SLC12A3, we generated a nonsense Ncc Ser707X knockin mouse corresponding to human p.Ser710X (c.2135C>A), a recurrent mutation with severe phenotypes in Chinese GS patients. Compared with wild-type or heterozygous littermates, homozygous (Hom) knockin mice fully recapitulated the phenotype of human GS. The markedly reduced Ncc mRNA and virtually absent Ncc protein expression in kidneys of Hom mice was primarily due to nonsense-mediated mRNA decay (NMD) surveillance mechanisms. Expression of epithelial Na(+) channel (Enac), Ca(2+) channels (Trpv5 and Trpv6), and K(+) channels (Romk1 and maxi-K) were significantly increased. Late distal convoluted tubules (DCT) volume was increased and DCT cell ultrastructure appeared intact. High K(+) intake could not correct hypokalemia but caused a further increase in maxi-K but not Romk1 expression. Renal tissue from a patient with GS also showed the enhanced TRPV5 and ROMK1 expression in distal tubules. We suggest that the upregulation of TRPV5/6 and of ROMK1 and Maxi-K may contribute to hypocalciuria and hypokalemia in Ncc Ser707X knockin mice and human GS, respectively. PMID- 20848651 TI - Detection of clinically relevant exonic copy-number changes by array CGH. AB - Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes. PMID- 20848654 TI - Convergent genesis of an adult neural crest-like dermal stem cell from distinct developmental origins. AB - Skin-derived precursors (SKPs) are multipotent dermal stem cells that reside within a hair follicle niche and that share properties with embryonic neural crest precursors. Here, we have asked whether SKPs and their endogenous dermal precursors originate from the neural crest or whether, like the dermis itself, they originate from multiple developmental origins. To do this, we used two different mouse Cre lines that allow us to perform lineage tracing: Wnt1-cre, which targets cells deriving from the neural crest, and Myf5-cre, which targets cells of a somite origin. By crossing these Cre lines to reporter mice, we show that the endogenous follicle-associated dermal precursors in the face derive from the neural crest, and those in the dorsal trunk derive from the somites, as do the SKPs they generate. Despite these different developmental origins, SKPs from these two locations are functionally similar, even with regard to their ability to differentiate into Schwann cells, a cell type only thought to be generated from the neural crest. Analysis of global gene expression using microarrays confirmed that facial and dorsal SKPs exhibit a very high degree of similarity, and that they are also very similar to SKPs derived from ventral dermis, which has a lateral plate origin. However, these developmentally distinct SKPs also retain differential expression of a small number of genes that reflect their developmental origins. Thus, an adult neural crest-like dermal precursor can be generated from a non-neural crest origin, a finding with broad implications for the many neuroendocrine cells in the body. PMID- 20848655 TI - Transplantation of GABAergic neurons from ESCs attenuates tactile hypersensitivity following spinal cord injury. PMID- 20848656 TI - Synthesis and characterization of a cytotoxic cationic polyvinylpyrrolidone curcumin conjugate. AB - Curcumin has been studied as a potential drug for many diseases including cancer. One of the serious limitations projected on curcumin is its poor water solubility and the substantially low bioavailability. With a view to enhance the aqueous solubility of curcumin, we synthesized polyvinylpyrrolidone-curcumin conjugates. Polyvinylpyrrolidone was used for the conjugation considering its long history of safe usage as a biomaterial for various medical applications. The drug conjugates self-assembled in aqueous solution to form nanosized micellar aggregates. The formation of micellae stabilized curcumin against hydrolytic degradation. Another interesting feature of the conjugate was its cationic nature. The net zeta potential in the pH range from 3 to 7.4 was +25 to +20 mV, reflecting the potential stability of the conjugate micellae at physiological pH. We quantified cytotoxic potential of the conjugate by the MTT assay, using L929 fibroblast cells. The results showed that the conjugate had higher cytotoxicity than that of the free curcumin. It is expected that the relative enhanced cytotoxicities are the result of enhanced aqueous solubility and polymer-mediated drug internalization. The conjugate has the potential to circumvent limitations of curcumin and thereby to extrapolate further its applications as an effective anticancer drug. PMID- 20848657 TI - Development of a polymeric patch impregnated with naproxen as a model of transdermal sustained release system. AB - This paper describes the preparation and characterization of transdermal patches impregnated with naproxen. A mixture of ethylene vinyl acetate and Eudragit E100 (80:20, w/w) is used as a polymeric matrix to obtain a thin membrane to be impregnated. Drug impregnation is carried out under pressurized CO(2) as a processing medium according to a two-step procedure. The patch is first soaked at 1000 psi and 22 degrees C for 2 h, and then foamed as a result of the rapid release of CO(2) pressure in order to increase the porosity of the surface. Subsequently, the naproxen solution is placed in contact with the membrane and then soaked in CO(2) at 450 psi and 37 degrees C for 2.5 h to enhance the mass transfer of drug into the polymer matrix. The characterization of the resulting samples by liquid chromatography, microscopy, and calorimetry provides information on naproxen content and distribution. Patches synthesized in this way are loaded with about 1% naproxen. The drug release and diffusion process through a membrane have been studied chromatographically using a Franz diffusion cell. Results have shown that a sustained delivery for more than 24 h is obtained. PMID- 20848658 TI - Identification of FOXP1 deletions in three unrelated patients with mental retardation and significant speech and language deficits. AB - Mental retardation affects 2-3% of the population and shows a high heritability.Neurodevelopmental disorders that include pronounced impairment in language and speech skills occur less frequently. For most cases, the molecular basis of mental retardation with or without speech and language disorder is unknown due to the heterogeneity of underlying genetic factors.We have used molecular karyotyping on 1523 patients with mental retardation to detect copy number variations (CNVs) including deletions or duplications. These studies revealed three heterozygous overlapping deletions solely affecting the forkhead box P1 (FOXP1) gene. All three patients had moderate mental retardation and significant language and speech deficits. Since our results are consistent with a de novo occurrence of these deletions, we considered them as causal although we detected a single large deletion including FOXP1 and additional genes in 4104 ancestrally matched controls. These findings are of interest with regard to the structural and functional relationship between FOXP1 and FOXP2. Mutations in FOXP2 have been previously related to monogenic cases of developmental verbal dyspraxia. Both FOXP1 and FOXP2 are expressed in songbird and human brain regions that are important for the developmental processes that culminate in speech and language. PMID- 20848660 TI - Quantitative assessments of residual stress fields at the surface of alumina hip joints. AB - In-depth and in-plane response functions of photo- and electro-stimulated probes have been modeled and quantitatively evaluated in order to assess their suitability to detect the highly graded residual stress fields generated at the surface of alumina hip joints. Optical calibrations revealed large differences in probe size, which strongly affected the detected magnitude of residual stress. A comparison between the responses of Raman and fluorescence probes in polycrystalline alumina showed that the depth of those probes spread to an extent in the order of the tens of microns even with using a confocal probe configuration. On the other hand, the electro-stimulated luminescence emitted by oxygen vacancy sites (F(+) center) in the alumina lattice represented the most suitable choice for confining to a shallow volume the stress probe. This latter probe enabled us to reduce the measurement depth to the order of the tens of nanometers. We show maps of surface residual stress as collected on both main wear and nonwear zones of an alumina femoral head. A comparison among stress maps taken at exactly the same location, but employing different probes, revealed averaging effects on the stress magnitude detected with photo-stimulated probes, while proving the superior spatial resolution of the electron probe. PMID- 20848659 TI - Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. AB - Biallelic inactivating germline mutations in the base excision repair MUTYH (MYH) gene have been shown to predispose to MUTYH-associated polyposis (MAP), which is characterized by multiple colorectal adenomas and carcinomas. In this study, we successfully prepared highly homogeneous human MUTYH type 2 recombinant proteins and compared the DNA glycosylase activity of the wild-type protein and fourteen variant-type proteins on adenine mispaired with 8-hydroxyguanine, an oxidized form of guanine. The adenine DNA glycosylase activity of the p.I195V protein, p.G368D protein, p.M255V protein, and p.Y151C protein was 66.9%, 15.2%, 10.7%, and 4.5%, respectively, of that of the wild-type protein, and the glycosylase activity of the p.R154H, p.L360P, p.P377L, p.452delE, p.R69X, and p.Q310X proteins as well as of the p.D208N negative control form was extremely severely impaired. The glycosylase activity of the p.V47E, p.R281C, p.A345V, and p.S487F proteins, on the other hand, was almost the same as that of the wild-type protein. These results should be of great value in accurately diagnosing MAP and in fully understanding the mechanism by which MUTYH repairs DNA in which adenine is mispaired with 8-hydroxyguanine. PMID- 20848661 TI - Viscoelastic and fatigue properties of model methacrylate-based dentin adhesives. AB - The objective of the current study is to characterize the viscoelastic and fatigue properties of model methacrylate-based dentin adhesives under dry and wet conditions. Static, creep, and fatigue tests were performed on cylindrical samples in a 3-point bending clamp. Static results showed that the apparent elastic modulus of the model adhesive varied from 2.56 to 3.53 GPa in the dry condition, and from 1.04 to 1.62 GPa in the wet condition, depending upon the rate of loading. Significant differences were also found for the creep behavior of the model adhesive under dry and wet conditions. A linear viscoelastic model was developed by fitting the adhesive creep behavior. The developed model with 5 Kelvin Voigt elements predicted the apparent elastic moduli measured in the static tests. The model was then utilized to interpret the fatigue test results. It was found that the failure under cyclic loading can be due to creep or fatigue, which has implications for the failure criterion that are applied for these types of tests. Finally, it was found that the adhesive samples tested under dry conditions were more durable than those tested under wet conditions. PMID- 20848662 TI - Taqman genotyping assays can be used on decalcified and paraffin-embedded tissue from patients with osteosarcoma. AB - BACKGROUND: In cancers like osteosarcoma with a 5-year overall survival of 50 60%, archived histological specimens can be a useful source of biological material. However, this material generally has been decalcified and formalin fixed for many years. In our study, we investigated whether DNA obtained from these tissues can be used for reliable single nucleotide polymorphism (SNP) genotyping. PROCEDURE: We studied two SNPs in the drug transporter MDR1 using Taqman(r) SNP genotyping assays. Genotypes of the germ line DNA derived from freshly isolated DNA of 20 surviving patients with osteosarcoma were compared with genotypes obtained from archived material from decalcified formalin-fixed, paraffin-embedded (FFPE) blocks of the same patients. RESULTS: Decalcified FFPE derived DNA yielded smaller PCR fragments compared to DNA extracted from peripheral blood cells, with a reliable size of ~200 bp. However, we were able to evaluate each SNP in 19 of 20 cases included in this study. All successfully genotyped samples showed 100% concordance between genotypes obtained from DNA of FFPE tissue and the genotypes obtained from DNA of blood from the same patients. CONCLUSIONS: In conclusion, we have demonstrated that decalcified FFPE tissue can be used for genetic polymorphism analysis using Taqman(r) allelic discrimination assays. This forms a unique opportunity to combine new insights in genetic research with historical patient cohorts. PMID- 20848663 TI - Finding cancer stem cells: are aldehyde dehydrogenases fit for purpose? AB - Despite many years of intensive effort, there is surprisingly little consensus on the most suitable markers with which to locate and isolate stem cells from adult tissues. By comparison, the study of cancer stem cells is still in its infancy; so, unsurprisingly, there is great uncertainty as to the identity of these cells. Stem cell markers can be broadly categorized into molecular determinants of self renewal, clonogenicity, multipotentiality, adherence to the niche, and longevity. This review assesses the utility of recognizing cancer stem cells by virtue of high expression of aldehyde dehydrogenases (ALDHs), probably significant determinants of cell survival through their ability to detoxify many potentially cytotoxic molecules, and contributing to drug resistance. Antibodies are available against the ALDH enzyme family, but the vast majority of studies have used cell sorting techniques to enrich for cells expressing these enzymes. Live cells expressing high ALDH activity are usually identified by the ALDEFLUOR kit and sorted by fluorescence activated cell sorting (FACS). For many human tumours, but notably breast cancer, cell selection based upon ALDH activity appears to be a useful marker for enriching for cells with tumour-initiating activity (presumed cancer stem cells) in immunodeficient mice, and indeed the frequency of so-called ALDH(bri) cells in many tumours can be an independent prognostic indicator. PMID- 20848664 TI - Flash chemistry: flow microreactor synthesis based on high-resolution reaction time control. AB - This article addresses a fascinating aspect of flash chemistry, high-resolution reaction-time control by virtue of a flow microreactor system, and its applications. The length of time that the solution remains inside the reactor is called the residence time. The residence time between the addition of a reagent and that of a quenching agent or the next reagent in a flow microreactor is the reaction time, and the reaction time can be greatly reduced by adjusting the length of a reaction channel in a flow microreactor. This feature is quite effective for conducting reactions involving short-lived reactive intermediates. A reactive species can be generated and transferred to another location to be used in the next reaction before it decomposes by adjusting the residence time in the millisecond to second timescale. The principle of such high-resolution reaction-time control, which can be achieved only by flow microreactors, and its applications to synthetic reactions including Swern-Moffatt-type oxidation, as well as the generation and reactions of aryllithium compounds bearing electrophilic substituents, such as alkoxycarbonyl groups, are presented. Integration of such reactions using integrated flow microreactor systems is also demonstrated. PMID- 20848665 TI - Catalytic carboborations. AB - Transition-metal-catalyzed carboborations, in which organic and boryl groups are introduced concomitantly to unsaturated organic molecules, have been developed. Direct carboborations, which proceed via activation of B-C bonds of cyanoboranes and alkynylboranes, and transmetalative carboborations, in which activation of B Cl bonds is followed by transmetalation from organotin and organozirconium reagents, are overviewed. In addition, as representative results and mechanistic considerations, the scientific background and a personal view behind the study are also described. PMID- 20848666 TI - Development of selective inhibitors of necrosis. AB - Oxidative stress-induced necrosis plays an important role in ischemia-reperfusion injury, such as stroke and heart attack. Here, we describe the development of selective inhibitors of necrosis, MS-1 and IM-54, as potential cardioprotective agents and biological tools for investigating the molecular mechanisms of cell death. By means of chemical modifications of kinase inhibitor BM I, its affinity for various kinases was successfully removed and a potent and selective inhibitor of necrosis, IM-54, was obtained. IM-54 inhibits necrosis induced by oxidative stress, but not apoptosis induced by anticancer drugs. PMID- 20848667 TI - Reversal of memory deficits by Coriandrum sativum leaves in mice. AB - BACKGROUND: Coriandrum sativum L., commonly known as coriander and belonging to the family Apiaceae (Umbelliferae), is cultivated throughout the world for its nutritional value. The present study was undertaken to investigate the effects of fresh Coriandrum sativum leaves (CSL) on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. In this study, CSL (5, 10 and 15% w/w of diet) was fed orally with a specially prepared diet for 45 days consecutively to experimental animals. Elevated plus-maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam, scopolamine and ageing-induced amnesia served as the interoceptive behavioral models. RESULTS: CSL (5, 10 and 15% w/w of diet) produced a dose-dependent improvement in memory scores of young as well as aged mice. CSL also reversed successfully the memory deficits induced by scopolamine (0.4 mg kg(-1), i.p.) and diazepam (1 mg kg(-1), i.p.). Interestingly, brain cholinesterase activity and serum total cholesterol levels were considerably reduced by CSL administration in daily diets concomitantly for 45 days. CONCLUSION: CSL may be a useful remedy in the management of Alzheimer's disease on account of its multifarious effects such as, memory-improving property, cholesterol-lowering property and anticholinesterase activity. PMID- 20848668 TI - Gene therapy strategies for hemophilia: benefits versus risks. AB - Hemophilia is an inherited bleeding disorder caused by a deficiency of functional clotting factors VIII or IX in the blood plasma. The drawbacks of the classical protein substitution therapy fueled interest in alternative treatments by gene therapy. Hemophilia has been recognized as an ideal target disease for gene therapy because a relatively modest increase in clotting factor levels can result in a significant therapeutic benefit. Consequently, introducing a functional FVIII or FIX gene copy into the appropriate target cells could ultimately provide a cure for hemophilic patients. Several cell types have been explored for hemophilia gene therapy, including hepatocytes, muscle, endothelial and hematopoietic cells. Both nonviral and viral vectors have been considered for the development of hemophilia gene therapy, including transposons, gamma-retroviral, lentiviral, adenoviral and adeno-associated viral vectors. Several of these strategies have resulted in stable correction of the bleeding diathesis in hemophilia A and B murine as well as canine models, paving the way towards clinical trials. Although clotting factor expression has been detected in hemophilic patients treated by gene therapy, the challenge now lies in obtaining prolonged therapeutic FVIII or FIX levels in these patients. This review highlights the benefits and potential risks of the different gene therapy strategies for hemophilia that have been developed. PMID- 20848669 TI - Development of an inflammation-inducible gene expression system using helper dependent adenoviral vectors. AB - BACKGROUND: Clinical studies have shown that gene therapy is a promising approach for treating such genetic diseases as the eye disease, Leber's congenital amaurosis. Development of gene therapy approaches for treating chronic inflammatory diseases is, however, more challenging because it requires the production of anti-inflammatory molecules at the diseased tissues only when they are needed. METHODS: We designed such a system by modifying the human interleukin (IL)-6 gene promoter to direct transgene expression and delivered the system into cultured cells as well as mouse lungs using a helper-dependent adenoviral vector. RESULTS: We have demonstrated both in vitro and in vivo that the reporter LacZ or human IL-10 gene can be induced by inflammatory stimuli. CONCLUSIONS: The results obtained indicate that the inflammation inducible gene expression system based on the modified human IL-6 gene promoter has the potential to be used for developing gene therapy for treating inflammatory diseases. PMID- 20848670 TI - Acidulant and oven type affect total anthocyanin content of blue corn cookies. AB - BACKGROUND: Anthocyanins, pink to purple water-soluble flavonoids, are naturally occurring pigments with claimed health benefits. However, they are sensitive to degradation by high pH, light and temperature. Blue corn (maize) contains high levels of anthocyanins. Cookies are popular snacks and might serve as a vehicle to deliver antioxidants. A cookie formula with a high level of blue corn was developed with added acidulents and baked in ovens with different heat transfer coefficients. RESULTS: The best whole-grain blue corn flour/wheat pastry flour ratio (80:20 w/w), guar gum level (10 g kg(-1), flour weight basis) and water level (215 g kg(-1), flour weight basis) were determined based on response surface methodology analysis. The interactions of citric and lactic acids and glucono-delta-lactone with three oven types having different heat transfer coefficients (impingement oven 179 degrees C/4 min, reel oven 204 degrees C/10 min and convection oven 182 degrees C/4 min) influenced the total anthocyanin content (TAC) remaining in blue corn-containing cookies after baking. CONCLUSION: Cookies baked with citric acid in the convection oven retained the maximum TAC (227 +/- 3 mg kg(-1)). By baking rapidly at lower temperatures and adding acidulents, it may be possible to increase residual natural source antioxidants in baked foods. PMID- 20848671 TI - Pelvic floor muscle training for stress urinary incontinence: a randomized, controlled trial comparing different conservative therapies. AB - BACKGROUND AND PURPOSE: Pelvic floor muscle training (PFMT) is an effective therapy for stress urinary incontinence (SUI). There is little and inconsistent data about different strategies of PFMT. Finding the right, patient-oriented treatment decision seems to be essential in order to achieve good results in conservative management of SUI. It was the aim of this prospective randomized controlled trial (RCT) to compare three different strategies using electromyography (EMG) biofeedback-assisted PFMT with and without electrical stimulation (ES) for treatment of SUI in women capable of voluntarily contracting the pelvic floor when a home-training device with vaginal electrode was used. METHOD: Three-arm RCT comparing 1) EMG biofeedback-assisted PFMT and conventional ES; 2) EMG biofeedback-assisted PFMT and dynamic ES; and 3) EMG biofeedback assisted PFMT. Primary outcome measures were quality of life (King's Health Questionnaire) and degree of suffering (rated on a visual analogue scale from 1 to 10). Secondary outcome measures were number of pads used, pad weight test, contractility of the pelvic floor measured by digital palpation and intra-vaginal EMG. RESULTS: The quality of life significantly increased over the 12-week training. The number of pads used was reduced, the pad weight test and the contractility of the pelvic floor significantly improved. There were no significant differences between the three groups. CONCLUSION: This RCT shows significant improvement in patients' quality of life for conservative therapy of SUI. Differences between the three therapeutic options analyzed could not be found. Additional ES showed no benefit for patients with SUI, capable of voluntary pelvic floor contraction. PMID- 20848672 TI - A combined top-down and bottom-up MS approach for the characterization of hemoglobin variants in Rhesus monkeys. AB - Sickle cell disease is caused by one of the 1200 known hemoglobin variations. A single-point mutation beta6(A3)Glu->Val leads to sickling of red blood cells, which in turn causes a lack of oxygen supply to tissue and organs. Although sickle cell disease is well understood, treatment options are currently underdeveloped. The only Food and Drug Administration-approved drug is hydroxyurea, an inducer of fetal gamma-hemoglobin, which is known to have a higher oxygen affinity than adult hemoglobins and thus alleviates symptoms. In the search for better cures, Rhesus monkeys (Macaca mulatta) serve as models for monitoring success of induction of fetal gamma-hemoglobins and with recent advances in proteomics, MS has become the leading technique to determine globin expression. Similar to humans, Rhesus monkeys possess hemoglobin variants that have not been sufficiently characterized to initiate such a study. Therefore, we developed a combined bottom-up and top-down approach to identify and characterize novel hemoglobin variants of the umbilical cord blood of Rhesus monkeys. A total of four different variants were studied: alpha, beta, gamma1 and gamma2. A new alpha- and beta-hemoglobin variant was identified, and the two previously hypothesized gamma-hemoglobins were identified. In addition, glutathionylation of both gamma-hemoglobin variants at their cysteines has been characterized. The combined approach outperformed either bottom-up or top-down alone and can be used for characterization of unknown hemoglobin variants and their PTMs. PMID- 20848673 TI - Intact mass detection, interpretation, and visualization to automate Top-Down proteomics on a large scale. AB - Applying high-throughput Top-Down MS to an entire proteome requires a yet-to-be established model for data processing. Since Top-Down is becoming possible on a large scale, we report our latest software pipeline dedicated to capturing the full value of intact protein data in automated fashion. For intact mass detection, we combine algorithms for processing MS1 data from both isotopically resolved (FT) and charge-state resolved (ion trap) LC-MS data, which are then linked to their fragment ions for database searching using ProSight. Automated determination of human keratin and tubulin isoforms is one result. Optimized for the intricacies of whole proteins, new software modules visualize proteome-scale data based on the LC retention time and intensity of intact masses and enable selective detection of PTMs to automatically screen for acetylation, phosphorylation, and methylation. Software functionality was demonstrated using comparative LC-MS data from yeast strains in addition to human cells undergoing chemical stress. We further these advances as a key aspect of realizing Top-Down MS on a proteomic scale. PMID- 20848675 TI - Comparison of physicochemical and sensory changes in fresh and frozen herring (Clupea harrengus L.) during marinating. AB - BACKGROUND: The influence of freezing on the changes during ripening is better described for salted fish than marinades. Therefore in the present study the effect of preliminary freezing of raw material on the ripening of carcasses and fillets marinated during 18 days at a temperature of 10 degrees C, in brine with 6% salt and 5% acetic acid was examined. RESULTS: In both cases the marinating of thawed frozen material resulted in larger mass losses and decrease of the value of meat colour parameters. The semi-marinades from raw herring were characterised by higher values of total estimation based on sensory analysis. The statistical analysis showed weak correlation between the discriminants of sensory assessment and the studied physicochemical parameters of semi-marinades. CONCLUSIONS: These results suggest that the semi-marinades from raw fish are characterised by higher sensory quality, better colour parameters and higher yield than those from frozen thawed fish. PMID- 20848676 TI - Robotic surgery in gynecologic oncology fellowship programs in the USA: a survey of fellows and fellowship directors. AB - BACKGROUND: In order to understand how robotic surgery impacts gynecologic oncology fellowship training and surgical practices, a survey of fellows and fellowship directors was conducted. METHODS: Questionnaires designed to determine the prevalence, application, and acceptance of robotics were sent to fellows and fellowship directors in approved U.S. programs. RESULTS: Of the respondents, 95% have a robot at their institution and 95% utilize it. Most responding fellowship directors (70%) reported that fellow education is enhanced by robotic surgery. Most fellows (65%) who responded feel comfortable using the robot, and 94% plan on performing robotic surgery upon completion of fellowship training. CONCLUSIONS: This survey demonstrates that robotic surgery is utilized in the majority of responding gynecologic oncology fellowship programs for a wide array of indications. Fellowship directors and fellows-in-training generally have a favorable view of this evolving technology. Based on these responses, robotic surgery will play an increasingly important role in the future. PMID- 20848674 TI - Top-down protein characterization facilitated by ion/ion reactions on a quadrupole/time of flight platform. AB - In comparison to bottom-up proteomics approaches, whereby peptides derived from proteolytic digestion are analyzed, top-down approaches, involving direct analysis of intact proteins, provide higher specificity for protein identification and are better-suited for the characterization of sequence variants. However, top-down protein characterization usually requires more sophisticated instrumentation and methodologies to deal with the more complex tandem mass spectra derived from dissociation of high mass multiply charged intact proteins. Gas-phase ion/ion reactions are universally applicable and have proved to be useful in mixture analysis and top-down biomolecule characterization. The coupling of the ion/ion proton transfer reaction in the context of MS/MS has been demonstrated to expand informing power in top-down protein characterization, particularly with platforms that employ electrodynamic ion trap and TOF mass analysis. In addition, probing protein primary structure using ion/ion electron transfer dissociation usually provides extensive structurally informative fragmentation and also allows for the localization of labile PTMs. Here, the performance of the widely used quadrupole/TOF platform, equipped with ion/ion reaction functionality, for top-down protein characterization is summarized, and various methodologies employing ion/ion reactions are reviewed. PMID- 20848677 TI - Protective effect of dried safflower petal aqueous extract and its main constituent, carthamus yellow, against lipopolysaccharide-induced inflammation in RAW264.7 macrophages. AB - BACKGROUND: Safflower, whose botanic name is Carthamus tinctorius L., is a member of the family Compositae or Asteraceae. Carthamus yellow (CY) is the main constituent of safflower and is composed of safflomin A and safflomin B. Dried safflower petals are used in folk medicine and have been shown to invigorate blood circulation, break up blood stasis, and promote menstruation. In addition, dried safflower petals contain yellow dyes that are used to color food and cosmetics. In this study, we investigated the effects of dried safflower petals aqueous extracts (SFA) and CY on lipopolysaccharide (LPS)-induced inflammation using RAW264.7 macrophages. RESULTS: Our data showed that treatment with SFA (1 1000 microg mL(-1)) and CY (1-2000 microg mL(-1)) does not cause cytotoxicity in cells. SFA and CY inhibited LPS-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)), and interleukin 1beta (IL-1beta) release, through attenuation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression. Further, SFA and CY suppressed the LPS-induced phosphorylation of nuclear factor-kappaB, which was associated with the inhibition of IkappaB-alpha degradation. CONCLUSION: These results suggest that SFA and CY provide an anti inflammatory response through inhibiting the production of NO and PGE(2) by the downregulation of iNOS and COX-2 gene expression. Thus safflower petals have the potential to provide a therapeutic approach to inflammation-associated disorders. PMID- 20848678 TI - Bisphosphonates and atypical femoral fractures. PMID- 20848679 TI - Bisphosphonates and atypical femoral fractures. PMID- 20848680 TI - Infliximab, azathioprine, or combination therapy for Crohn's disease. PMID- 20848681 TI - Infliximab, azathioprine, or combination therapy for Crohn's disease. PMID- 20848682 TI - Syphilis and social upheaval in China. PMID- 20848683 TI - Defining medical expenses--an early skirmish over insurance reforms. PMID- 20848684 TI - Images in clinical medicine. Ocular loiasis. PMID- 20848685 TI - [Psychotic/schizophrenic patients]. PMID- 20848686 TI - [Circulatory collapse in bodybuilder in connection with anesthesia]. PMID- 20848687 TI - [Diabetes simulation model]. PMID- 20848688 TI - [Reply to a feature article defending Danish Borrelia diagnostics]. PMID- 20848689 TI - [Fighting with the Danish Medical Agency--core activity of the medical profession?]. PMID- 20848690 TI - [Open letter to the National Board of Health about alcohol recommendations]. PMID- 20848691 TI - [Report on vitamin D]. PMID- 20848692 TI - Commentaries on Viewpoint: Standards for quantitative assessment of lung structure. Air space connectivity. PMID- 20848693 TI - Commentaries on Viewpoint: Standards for quantitative assessment of lung structure. Quantifying lung microstructure by MRI with hyperpolarized gases. PMID- 20848694 TI - Adherence to guidelines in bleeding oesophageal varices and effects on outcome: comparison between a specialized unit and a community hospital. AB - OBJECTIVES: Randomized controlled trials have shown beneficial effects of vasoactive drugs, endoscopic treatment and prophylactic antibiotics on the outcome of bleeding oesophageal varices (BOV). However, translating guidelines based on randomized controlled trials into clinical practice is difficult. Our aims were to compare adherence to evidence-based guidelines in BOV between a specialized unit and a community hospital, and to investigate whether differences in adherence affected the outcome. METHODS: Two cohorts hospitalized during 2000 2007 with a first episode of BOV were retrospectively enrolled, one in a community hospital comprising 66 patients and one in a specialized unit comprising 111 patients. Data on treatment, rebleeding and mortality were collected from medical records according to the Baveno III/IV Criteria. RESULTS: Treatments in the specialized unit versus the community hospital were: vasoactive drugs 79 vs. 66% (P = 0.06), prophylactic antibiotics 55 vs. 27% (P < 0.01), endoscopic treatment 86 vs. 74% (P= 0.04) and Sengstaken-Blakemore tube was used in 5 vs. 21% (P < 0.01). Secondary prophylaxis with pharmacological, endoscopic or transjugular intrahepatic portosystemic shunt therapy was initiated in 91 vs. 74% (P < 0.01) (specialized vs. community). Six-week mortality was 17 vs. 24% (P = 0.25) with 5-day mortality of 6 vs. 3% (P = 0.34) and mortality day 6-42, 12 vs. 22% (P = 0.07) (specialized vs. community). Failure to control bleeding and failure to prevent rebleeding were not statistically different. CONCLUSION: Our study shows that patients with BOV are more likely to receive therapy according to guidelines when hospitalized in a specialized unit compared with a community hospital. This however did not affect mortality. PMID- 20848695 TI - Cine-angiography of the mitral valve. PMID- 20848696 TI - Lysergic acid diethylamide. PMID- 20848697 TI - Insanity of King George III. PMID- 20848699 TI - Complications of intrauterine devices. PMID- 20848700 TI - Neonatal goitre. PMID- 20848698 TI - Improved analgesia after the realisation of a pain management programme in ICU patients after cardiac surgery. AB - BACKGROUND AND OBJECTIVE: Although clinical guidelines recommend systematic evaluation of pain in ICU patients, we know little about the effects from such systematic pain evaluation. This study aims to quantify the effect of a pain management programme in the ICU. METHODS: In this prospective two-phase study, pain levels scored by ICU patients after cardiac surgery through sternotomy were compared before and after the implementation of a pain management programme. The pain management programme consisted of a three-fold strategy; all staff was trained in assessing pain and in providing adequate analgesia, a new patient data management system obliged nurses to ask patients for their pain score three times a day and the preferred analgesic treatment was optimised. The numeric rating scale (NRS 0-10) was used by 190 patients. A NRS at least 4 was considered unacceptable. A generalised linear mixed-effects model was used for analysing repeated measurements data. RESULTS: The occurrence of unacceptable pain (NRS > or = 4) was significantly lower in the intervention group [odds ratio 2.54 (95% confidence interval 1.22-5.65; P = 0.01) for the control group]. Patients in the intervention group received significantly more morphine (29.3 vs. 22.6 mg a day, P<0.01), with higher morphine amounts administered to patients with higher NRS scores (P = 0.01). In the control group, no such relationship was observed (P = 0.66). There was no difference in length of stay in the ICU or in ventilation time. CONCLUSION: The intervention programme successfully reduced the occurrence of unacceptable pain. Further improvement of pain management should focus on the prevention of pain. PMID- 20848701 TI - Diet and diverticulitis. PMID- 20848702 TI - Labelling drugs. PMID- 20848703 TI - Osteomalacia in Asian Immigrants during pregnancy. PMID- 20848704 TI - Rickets in British children. PMID- 20848706 TI - Diurnal enuresis. PMID- 20848705 TI - Amoebiasis--a diagnostic problem in Great Britain. PMID- 20848708 TI - Disorder of differential growth. PMID- 20848707 TI - Treatment of Ulcerative Colitis. PMID- 20848709 TI - Syringe-transmitted hepatitis and heroin addicts. PMID- 20848711 TI - Suture removal forceps. PMID- 20848712 TI - Patients and tablets. PMID- 20848710 TI - A prospective study of the case-notes of MRSA-positive patients: a vehicle of MRSA spread. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) has received much publicity and remains a major problem for the health service. The aim of this study was to determine whether case-notes of MRSA-positive patients can act as a vehicle for MRSA transmission. PATIENTS AND METHODS: A prospective study was performed of patients with active MRSA infection identified from a microbiology department database. Two swabs were taken from the cover of the case-notes and the page with the most recent entry for identification of MRSA using MRSA ID (Chromogenic agar medium), Pastorex and DNase tests. Positive case-notes were re swabbed 96 h later. RESULTS: A total of 50 MRSA-positive patients were identified from medical, surgical, high dependency and intensive care wards. Three sets of notes were MRSA positive (3/50; 6%). None of the positive case-notes was positive on re-swabbing at 96 h. CONCLUSIONS: Case-notes of MRSA-positive patients can act as carriers of MRSA with the potential to spread MRSA to both healthcare and non healthcare workers without direct contact with infected patients. We recommend extending the universal precautions to the handling of case-notes belonging to MRSA-infected patients. PMID- 20848714 TI - Institute of neurology. PMID- 20848713 TI - Parameters. PMID- 20848715 TI - Cheadle Royal's bicentenary. PMID- 20848717 TI - Award to junior staff. PMID- 20848716 TI - Salaries and cardiographers. PMID- 20848719 TI - Future of the health service. PMID- 20848720 TI - Medical witnesses' fees. PMID- 20848718 TI - The effects of thermal injury on immature rat ear cartilage. AB - The purpose of this study was to research regeneration and growing properties of an immature rat ear cartilage and its adjacent tissue after a thermal injury. Fifteen 30-day-old male Sprague-Dawley rats were used. Burn wounds were created by applying a heated plaque. All the rats, based on their tissue sampling day, were placed in two groups for histopathologic evaluation. In group I (n = 5), the burned right auricles were amputated on the first day,and the left auricles were amputated as a control at the same time. In group II (n = 10), the burned right auricles were amputated on the 30th day, and the left auricles were amputated as a control at the same time. Epithelization of skin was completed in period ranging between 12 and 15 days in all burned ears. The skin appendages were few throughout the affected area.Chondroid tissue regenerated from perichondrium and increased capillary vessels were observed.On the first day of the burn injury, electron microscopic findings were karyopyknosis, karyorrhexis, and karyolysis of the nucleus, and there were also signs of necrosis. New chondroblasts were formed around the collagen fibrils in the scar tissue on the 30th day. CD-31 immunohistochemical staining showed increased capillary vessels in the burned ear. The peripheral nerve fibers decreased and regenerative signs of nerves were shown with the use of S-100 immunohistochemical staining. Differentiation of chondroblasts to chondrocytes occurs in the burned immature ear, and new cartilage tissue regenerates from perichondrium. In addition, regenerative signs of nerves appear. PMID- 20848722 TI - Merit awards. PMID- 20848721 TI - Dispensing doctors. PMID- 20848724 TI - Single-handed practice. PMID- 20848723 TI - Consultants at the periphery. PMID- 20848725 TI - Bile Bean March. PMID- 20848726 TI - Review body's report. PMID- 20848727 TI - Skin discoloration and phenindione. PMID- 20848728 TI - Words of wisdom. Re: defining success after surgery for pelvic organ prolapse. PMID- 20848729 TI - Ovulation induction in polycystic ovary syndrome: No. 242, May 2010. AB - OBJECTIVE: To review current non-pharmacologic and pharmacologic options for ovulation induction in women with polycystic ovary syndrome (PCOS). OPTIONS: This guideline reviews the evidence for the various options for ovulation induction in PCOS. OUTCOMES: Ovulation, pregnancy and live birth rates, risks, and side effects are the outcomes of interest. EVIDENCE: Published literature was retrieved through searches of Medline using appropriate controlled vocabulary and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and of health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The evidence gathered was reviewed and evaluated by the Reproductive Endocrinology and Infertility Committee of the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was quantified using the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: Benefits include weight reduction and improvements in ovulation, pregnancy, and live birth rates. Potential harms include medication side effects and multiple pregnancies. VALIDATION: These guidelines have been reviewed and approved by the Reproductive Endocrinology and Infertility Committee of the SOGC. PMID- 20848730 TI - The N170 is not modulated by attention in autism spectrum conditions. AB - Face processing deficits are characteristic of autism spectrum conditions. However, event-related potential studies of autism spectrum conditions have found inconsistent results for the face selective N170 component. In this study, 15 adult males with autism spectrum conditions and 15 matched, typically developing controls completed a task in which pictures of faces were either attended to or ignored. In the control group, the N170 was larger when faces were attended to. However, there was no such modulation in the autism spectrum conditions group. This finding helps clarify the results from the earlier event-related potential studies of face processing in autism spectrum conditions and suggests that visual attention does not enhance face processing in autism spectrum conditions as it does in typical development. PMID- 20848731 TI - Multiple metastases from cutaneous malignant melanoma patients may display heterogeneous genomic and epigenomic patterns. AB - Disseminated melanoma is an aggressive disease with fatal outcome. Better understanding of the underlying biology is needed to find effective treatment. We applied microarray-based comparative genomic hybridization, gene expression and CpG island methylation analysis of primary tumors and multiple metastases from five melanoma patients with the aim of analyzing the molecular patterns of melanoma progression. Epigenetic profiling showed that the multiple metastases after a single primary melanoma share similar methylation patterns for many genes, although differences in methylation between the lesions were evident for several genes, example, PTEN, TFAP2C, and RARB. In addition, DNA copy number and global gene expression profiles of tumors from individual patients were highly similar, confirming common origin of metastases. Some of the identified genomic aberrations, for example, gain of chromosome 6p and loss of chromosomes 6q and 10, persisted during progression, indicating early changes highly important for melanoma development. Homozygous deletions at 3p26.1 and 6q23.2-q23.3 appeared in two consecutive metastases originating from the same primary tumor, respectively, in a mutually exclusive manner that provides evidence for two genetically different subclones. However, in another case, the similarity of the copy number aberrations in subsequent metastatic lesions suggests sequential metastatic development through the clonal evolution. These data are further corroborated by a switch in CDH1 and CDH2 expression between metastases from the same patient. In conclusion, our results provide evidence for different models of metastatic progression in melanoma. PMID- 20848733 TI - Metallothionein 1E is methylated in malignant melanoma and increases sensitivity to cisplatin-induced apoptosis. AB - DNA methylation plays a major role in cancer by silencing tumour suppressor genes. In melanoma, only a discrete number of methylated genes have been identified so far. After the treatment of melanoma cells with a DNA methyltransferase inhibitor and subsequent transcriptomic profiling, we had identified earlier a cohort of melanoma progression-associated genes regulated by methylation. Here, we identified which of these genes are directly methylated in melanoma cell lines and tissues. First, we examined 16 genes by bisulphite sequencing in the WM793 isogenic cell line model series. Five of these genes (CYBA, FABP5, MT1E, TSPY1 and TAC1) displayed increased methylation in several invasive cell lines compared with the parental WM793 cells, indicating their involvement in progression. Next, we analyzed several matched primary/metastatic tumours using methylation-specific PCR, which revealed that MT1E (one of the five genes assessed) was methylated in the largest proportion of tumours. Examination of a larger cohort of samples showed that 1 of 17 (6%) of the benign naevi, 16 of 43 (37%) primary tumours and 6 of 13 (46%) of the metastases displayed MT1E methylation. In addition, ectopic over-expression of MT1E mediated sensitization to cisplatin-induced apoptosis. Overall, these studies suggest that MT1E is a potential tumour suppressor gene, whose loss may promote resistance to apoptosis inducing therapies. PMID- 20848732 TI - The pharmacokinetics of commonly used antiepileptic drugs in immature CD1 mice. AB - Rodents eliminate antiepileptic drugs (AEDs) faster than humans, creating challenges for designing clinically relevant protocols. Half-lives of AEDs in immature mice are unknown. The pharmacokinetics of commonly used AEDs were examined in CD1 mice using a single-dose protocol at postnatal day 19. After intraperitoneal therapeutic dosing, blood serum concentrations spanning 1-48 h post-administration and corresponding brain tissue concentrations at 4 h were analyzed. Half-lives of valproate, phenobarbital, diazepam (and metabolites), phenytoin, and levetiracetam were 2.6, 15.8, 22.3, 16.3, and 3.2 h, respectively, compared to 0.8, 7.5, 7.7, 16.0, and 1.5 h reported for adult mice. Brain-to blood ratios were comparable with adult ratios. AEDs tested had longer half-lives and maintained therapeutic plasma concentrations longer than reported in mature mice, making clinically relevant protocols feasible. PMID- 20848734 TI - Na/K ATPase activity is coordinated with the persistent sodium current amplitude. AB - It is known that the Na+/K+ ATPase may control the frequency of slow action potential bursts that can be found in motor patterns generating neurons. Thus, Na+/K+ ATPase can participate in the formation of firing patterns in neurons and it is likely that the ATPase activity is coordinated with the expression of ionic channels. However, so far, there is no such evidence. Here it is shown that, in pyramidal neurons of the rat prefrontal cortex, the density of electrogenic sodium-potassium ATPase current was correlated with the density of the persistent sodium current (R2=0.62, P<0.002). It is speculated that such coordination may improve the control of the firing patterns in prefrontal cortex pyramidal neurons. PMID- 20848735 TI - The frontal and temporal lobe in the identification of laryngeal contrasts. AB - To investigate neuroanatomical correlates of the categorization of laryngeally contrastive phonemes, an event-related functional magnetic resonance imaging was performed during an auditory identification task in which 10 participants were distinguished among the three types of word-initial stop phonemes, either lax, tense, or aspirated. Perception of the aspirated consonant series elicited significantly higher activation in the inferior frontal gyrus as compared with both the lax and tense series, and the tense series showed significantly higher activation in the left superior temporal gyrus in comparison with either the lax or the aspirated series. The results show differential involvement of frontal and temporal lobe language areas for distinct phonemic contrasts, supporting a linguistic feature formulation model that posits variably specified phonological representations for the three-way distinctions. PMID- 20848736 TI - Acquiring a novel coordination skill without practicing the correct motor commands. AB - There is evidence that experience of the sensory consequences, in the absence of practice of the required motor commands, is sufficient to learn new bimanual coordination patterns. This was shown through improvements of an incongruent group who practiced a desired 30 degrees phase offset between the limbs while 1 limb was weighted such that the desired phase relation was achieved when synchronous motor commands were sent to the limbs (P. Atchy-Delama, P. G. Zanone, C. E. Peper, & P. J. Beek, 2005). In addition to testing a similar incongruent and congruent group (i.e., no weight), the authors extended this experiment by removing visual feedback during practice and by including an auditory modeling and passive guidance group. All groups showed improvement, except for the modeling group. The passive guidance group made more errors in posttests than the congruent and incongruent groups. Only the congruent group increased the amount of time around 30 degrees after practice. Active experience of the sensory consequences combined with practice sending appropriate motor commands is the most effective method for learning, even though strategic improvements can be attained without experience of the latter. PMID- 20848737 TI - Working with early Alzheimer's disease. PMID- 20848739 TI - [Working principle and accuracy of electronic thermometers]. PMID- 20848738 TI - Alcohol and pedestrians. PMID- 20848740 TI - [Laboratory screenings for febrile illness]. PMID- 20848741 TI - Abstracts of the Annual Congress of the European Association of Nuclear Medicine. October 9-13, 2010. Vienna, Austria. PMID- 20848742 TI - Commentaries on Viewpoint: Standards for quantitative assessment of lung structure. Air space connectivity. PMID- 20848743 TI - Commentaries on Viewpoint: Standards for quantitative assessment of lung structure. Quantifying lung microstructure by MRI with hyperpolarized gases. PMID- 20848744 TI - Abstracts of the 58th Congress of the German Society of Gynecology and Obstetrics. October 5-8, 2010. Munich, Germany. PMID- 20848745 TI - Words of wisdom. Re: androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. PMID- 20848746 TI - Words of wisdom. Re: androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. PMID- 20848747 TI - Words of wisdom. Re: effect of dutasteride on the risk of prostate cancer. PMID- 20848748 TI - Words of wisdom. Re: overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. PMID- 20848749 TI - Words of wisdom. Re: penile reconstruction: is the radial forearm flap really the standard technique? PMID- 20848750 TI - What to make of ACCORD. Surprising new results from the landmark diabetes study. PMID- 20848751 TI - A simple way to reduce hospital infections. PMID- 20848752 TI - Do you really need that heartburn med? PMID- 20848753 TI - Consultation corner. Prostate cancer vaccine offers new direction. PMID- 20848754 TI - I've read that some people are aspirin resistant and do not benefit from the daily use of aspirin to prevent a heart attack or stroke. Should I be tested for aspirin resistance? PMID- 20848755 TI - Early climate change consensus at the National Academy: the origins and making of "Changing Climate". AB - The 1983 National Academy of Sciences report entitled "Changing Climate," authored by a committee of physical and social scientists chaired by William Nierenberg, was an early comprehensive review of the effects of human-caused increases in the levels of atmospheric CO2. Study of the events surrounding the committee's creation, deliberations, and subsequent report demonstrates that the conclusions of the report were the consensus of the entire committee and in line with the scientific consensus of the time. This result contraverts a 2008 paper in which Naomi Oreskes, Erik M. Conway, and Matthew Shindell asserted that the report contradicted a growing consensus about climate change, and that Nierenberg for political reasons deliberately altered the summary and conclusions of the report in a way that played down the concerns of the other physical scientists on the committee. Examining the production of the report and contextualizing it in contemporaneous scientific and political discussion, we instead show how it was a multi-year effort with work divided among the various members of the committee according to their expertise. The synthesis and conclusions were expressly a joint statement of the committee and were consistent with other assessments of that time expressing deep concern over the potential issues while stopping short of recommending major policy changes due to the uncertainties, and to a lack of good alternatives. PMID- 20848756 TI - Complementary? Alternative? Integrative? PMID- 20848757 TI - New perspectives in medicine are required - from CAM to integrative medicine. PMID- 20848758 TI - We need a conceptual integration of conventional and complementary medicine. PMID- 20848759 TI - Integrative medicine: the roof, the house and the rooms. PMID- 20848760 TI - Let's be more integrative without being exclusive. PMID- 20848761 TI - We need a pluralism of therapies and medicines. PMID- 20848763 TI - Drug recalls: ignorance isn't bliss. PMID- 20848762 TI - How to help a child with ADHD. PMID- 20848764 TI - Brittle bones: what to do. PMID- 20848765 TI - Surviving a heart attack: know the signs and save a life. PMID- 20848766 TI - IMI Scottish Regional Meeting, Glasgow, 24 February 2010. Report. PMID- 20848767 TI - Approval of new drugs 1999-2007: comparison of the US, the EU and Japan situations. AB - BACKGROUND AND OBJECTIVE: 'Drug lag' was a much-debated issue around the world during the 1970s and 1980s. Because public recognition of drug lag is recent in Japan, the issue has not been studied extensively. Therefore, we created a database of new drug approvals in the US, the European Union (EU) and Japan between 1999 and 2007 and examined the drug lag situation in these three major pharmaceutical markets. METHODS: New drugs approved in the US, the EU and Japan between 1999 and 2007 were identified by their International Non-proprietary Names (INN), and information was gathered primarily from the websites of regulatory agencies of said regions and 'IMS R&D Focus'. In assessing absolute drug lag, we used as variables the number and the percentage of approved drugs in each region out of a total of new drugs approved either in the three regions in the study period. In assessing relative drug lag, two variables were used; one variable was the number and percentage of first approvals in the regions, and the other variable was the approval lag against the first approval granted to each drug in the three regions. Sub-group analyses were conducted according to the originator's nationality, the origin of the substance (biopharmaceuticals and non biopharmaceuticals) and the therapeutic group. RESULTS AND DISCUSSION: Of the 398 new drugs, 325 (81.7%) were approved in the US, 314 (78.9%) in the EU and 220 (55.3%) in Japan. The median approval lag for the US, the EU and Japan was 0 months, 2.7 months and 41.0 months, respectively. Although the US was ahead of the other two regions, the difference between the US and the EU was small. On the contrary, a striking drug lag was observed for Japan. The approval rate in Japan was low for both the drugs of US origin (43.6%) and EU origin (56.1%). Meanwhile, the drugs of Japanese origin were approved at a high rate in Japan (94.5%). It was surmised that the delay in filing new drug applications for drugs of non Japanese origin was the main reason for the drug lag in Japan. However, the percentage of approval of new drugs varied according to the therapeutic group, implying that there were different reasons for the drug lag in each group. CONCLUSION: This report provides a comprehensive view of drug lag in the three regions. More detailed analyses are necessary in order for a more in-depth discussion of the background factors, impacts and measures for the drug lag,which is especially noticeable in Japan. PMID- 20848768 TI - [Q & A. A case of multiple lesions in the pancreas]. PMID- 20848769 TI - [Anti-tumor effects induced by the DNA vaccine coding human and mouse soluble VEGFR2]. AB - OBJECTIVE: To develop a novel anti-angiogenesis strategy based on a DNA vaccine coding both human and mouse soluble VEGFR2. METHODS: The gene fragments coding human and mouse sVEGFR2 were amplified with PCR and cloned into pVITRO2 to generate pVITRO2-hm-sVEGFR2 recombinant. The in vitro VEGF blocking effect of the pVITRO2-hm-sVEGFR2 expression products on HUVEC cells were evaluated. The anti tumor effect of pVITRO2-hm-sVEGFR2 was studied in mouse B16 model. The microvessels were stained by using CD31 antibody. RESULTS: The co-expressing vector pVITRO2-hm-sVEGFR2 was constructed successfully, confirmed by the restriction endonuclease digestion and sequencing. The expressing products of pVITRO2-hm-sVEGFR2 could obviously block the function of VEGF on promoting the proliferation of HUVEC in vitro. The tumor growth in mice was also significantly inhibited by pVITRO2-hm-sVEGFR2 expression. CD31 staining demonstrated that the microvessel density obviously decreased in tumor tissues treated with pVITRO2-hm sVEGFR2. Both anti-tumor and anti-angiogenesis effects of pVITRO2-hm-sVEGFR2 were stronger than that of plasmids which coding only human or mouse sVEGFR2. CONCLUSION: pVITRO2-hm-sVEGFR2 could be a novel DNA vaccine for the anti-tumor therapy by inhibiting angiogenesis. PMID- 20848770 TI - [IL-15 enhance the therapeutic effects of whole cell vaccine in mouse CT26 colon carcinoma model]. AB - OBJECTIVE: To determine the enhancement effects of IL-15 to the tumor whole cell vaccine in tumor immunotherapy. METHODS: CT26 colon carcinoma model was established with BALB/c mice. Thirty two mice with CT26 colon carcinoma were divided randomly into four groups, which were subcutaneously injected at several spots with PBS (200 microL), CT26 whole cell vaccine (2 x 10(6) cells in 200 microL PBS), mIL-15 (20 microg, encapsulated with liposome in 200 microL 5% glucose solution) and CT26 whole cell vaccine (2 x 10(6) cells in 100 microL PBS) plus mIL-15 (20 microg, encapsulated with liposome in 100 microL 5% glucose solution) respectively every three days for six doses, the plasmid was injected beside the vaccine injecting spots. The size of tumors was measured every four days. All mice were sacrificed 30 days after tumor implantation. The pathologic observation and apoptotic analysis of tumors were preceded. RESULTS: CT26 whole cell vaccine combined with mIL-15 inhibited tumor growth by 45% compared with that of control group, the differences between CT26 + mIL-15 group and the other three groups were significant (P < 0. 05). The HE staining showed that the necrosis areas in tumors of the CT26 + mIL-15 group were larger than those of other three groups. The apoptotic index of tumors from the CT26 + mIL-15 group was (46.7 +/- 7.2)%, higher than that of the other three groups obviously (P < 0.05). CONCLUSION: IL-15 could enhance the therapeutic effects of CT26 whole cell vaccine in tumor immunotherapy. PMID- 20848771 TI - [Preparation and identification of a monoclonal antibody against recombinant human L-type pyruvate kinase N]. AB - OBJECTIVE: To prepare and identify the monoclonal antibody (mAb) against pyruvate kinase N terminal (PK-N). METHODS: BALB/C mice were immunized with immunogen PK-N GST-tag. Then the spleen cells were isolated and fused with SP2/0 cells. After several rounds of detecting and cloning, the hybridoma cell strains secreting anti-PK-N mAb were obtained. Its specificity was evaluated with ELISA and Western blot, and the titer, immunoglobulin subtype and affinity of the mAb were measured. RESULTS: Two cell strains of hybridoma, 2B2E4G and 2C6F5, were obtained. The hybridoma cell strains secreting anti-PK-N mAb belonged to IgG2b subtype, with a mAb titer in ascetic fluid of 1 : 409600 and 1 : 102400, respectively. Their affinity reached 3.54 x 10(8) L/mol and 2.72 x 10(8) L/mol, respectively, as determined by ELISA. Western blot demonstrated that the mAb could specifically recognize the immunogen and the natural cell lysis protein. The cell immunohistochemistry proved that the antibody could recognize human L type pyruvate kinase expressed in the plasma of HL-7702 cell strain and paraffin slice of hepatoma. CONCLUSION: The success in anti-PK-N mAb preparation provides a foundation for further studies into glycolysis in normal condition and metabolic diseases. PMID- 20848772 TI - [Expressions of Ki67, PCNA and mitotic index in ovarian epithelial tumors]. AB - OBJECTIVE: To analyze the expressions of Ki67, PCNA and mitotic index in ovarian epithelial tumors and their relationship with clinical pathological features. METHODS: The expressions of Ki67, PCNA protein and mitotic index in ovarian tissues from 20 patients with normal ovarian tissues, 28 patients with ovarian benign tumors, 20 patients with borderline tumors and 109 (73 metastatic ovarian cancer) patients with malignant tumors were retrospectively tested using the American GBI immunohistochemistry two-step method. The expressions of Ki67 and PCNA mRNA were also detected by in situ hybridization (ISH) in ovarian tissues from 37 patients with primary ovarian cancer, 14 patients with borderline tumors, 11 patients with benign tumors and 12 patients with normal ovarian tissues. The relationship between clinical pathologic parameters and the expressions of Ki67 and, PCNA and mitotic index in human ovarian tumors was analyzed. RESULTS: (1) The expressions of Ki67 mRNA and protein in ovarian epithelial tumors was higher than in the controls (P = 0.003; P = 0.009; P = 0.001; P = 0.001). But no significant differences appeared in the expression and overexpression of PCNA mRNA and pratein (P = 0.327; P = 0.718; P = 0.123; P = 0.125). Positive correlations between the expressions of mRNA and protein for Ki67 and PCNA were found (r = 0.449, P = 0.025; r = 0.484, P = 0. 014). (2) The expression of Ki67 in ovarian epithelial was higher in low differential carcinoma and at FIGO III-IV stage (P = 0.008; P = 0.007). The expression of Ki67 protein in serous tumor tissues was high, but low or missed in other types of tumor tissues such as malignant mixed mullerian tumor and transitional cell carcinoma (P = 0. 018). No significant differences in other clinicopathological features were found. The high expression of PCNA did not coincide with histological grading, clinical stage and histological types (P = 0.447; P = 0.763; P = 0.657). There were 72 patients with high mitotic index (66.1%). The high expression of mitotic index coincided with histological grading and clinical stage, but not with histological types (P = 0.002; P = 0.040). (3) The combined overexpression of Ki67 and high mitotic index occurred in 57 patients, which coincided with histological grading, clinical stage and histological types (P = 0.018; P = 0.001; P = 0.020). (4) In the 73 patients with metastatic ovarian cancers, the expressions of Ki67 (58.9%), PCNA protein (91.8%) and high MI (61.6%) in primary cancer tissues were greater than in the metastatic cancer tissues (peritoneum and epiploon, Ki67 41.4%, P = 0.031; PCNA 74%, P = 0.004; high MI 38.4%, P = 0.005). The positive intensity of Ki67 protein expression in primary ovarian cancers was significantly higher than in metastatic ovarian cancers (P = 0.040). There was no significant difference in positive intensity of PCNA between primary and metastatic ovarian cancers (P = 0.514). CONCLUSION: Ki67 and mitotic index can serve as biomolecular markers for predicting the proliferation of malignant ovarian epithelial tumors. PCNA can not discriminate between benign and malinant ovarian tumors. PMID- 20848773 TI - [Study on the molecular expression and regulation of toll pathway in HT-29 cells]. AB - OBJECTIVE: To investigate the changes of TLR4, MD2 and HBD2 in transcription and protein expression levels in HT-29 colon cancer cell line after inducing by cytokines TNF-alpha, IL-1beta, IFN-gamma and LPS, and its relationship with NF kappaB activation. METHODS: HT-29 cells were divided into 8 groups, by adding RPMI 1640, TNF-alpha (20 ng/mL), IL-1beta (20 ng/mL), IFN-gamma (20 ng/mL), LPS (50 ng/mL), TNF-alpha (20 ng/mL) + LPS (50 ng/ mL), IL-1beta (20 ng/mL) + LPS (50 ng/mL), IFN-gamma (20 ng/mL) + LPS(50 ng/mL) respectively for intervention. ELISA was applied to detect the IL-8 in the supernatants of each group. The level of TLR4, MD2 and HBD2 mRNA were assayed by RT-PCR. The expressions of TLR4 and NF kappaB protein of each group were determined by western blot. RESULTS: IL-8 expressions in supernatant of cytokines and cytokine plus LPS group were higher than that of control (P < 0.01). Pre-incubation with cytokines, following by LPS stimulation, HT-29 cells further augmented IL-8 secretion (P < 0.01). Increased levels of TLR4 and MD2 mRNA in HT-29 cells with Cytokines and cytokine plus LPS stimulating were observed (P < 0.01). The level of HBD2 mRNA were elevated in IL 1beta and LPS plus (TNF-alpha, IL-1beta, IFN-gamma) groups (P < 0.05). Elevated expressions of TLR4 and NF-kappaB protein in HT-29 cells with cytokine and cytokine plus LPS were also observed (P < 0.01). Pre-incubation with cytokines, following by LPS stimulation, HT-29 cells further up-regulated NF-kappaB protein expression (P < 0.05). CONCLUSIONS: Cytokines (TNF-alpha, IL-1beta, IFN-gamma) can enhance TLR4 and MD-2 expressions and promote the reaction with LPS in intestinal epithelial cells (IEC), which leads to over activity of IEC with commensal bacteria and initiation or aggravation of intestinal inflammation. Inflammatory stimuli (IL-1beta, LPS + TNF-alpha, LPS + IFN-gamma) may induce the transcription and expression of HBD2 gene in IEC, which leads to enhancing intestinal adaptive immune responses and affects the progress of intestinal inflammation. PMID- 20848774 TI - [The expression and clinical significance of AKT2, phosphorylated AKT2 in non small cell lung cancer]. AB - OBJECTIVE: To study the expression and clinical significance of AKT2, phosphorylated AKT2 (p-AKT2) in non-small cell lung cancer (NSCLC). METHODS: The tumor tissues were obtained from 137 cases of NSCLC, the expressions of AKT2 and p-AKT2 in the tissues were measured by immunohistochemistry. The statistic analysis was carried on to study the correlation of AKT2, p-AKT2 expression to the type of lung cancer, TNM stage, pathological grading. Survival analysis was also studied. RESULTS: The positive rates of AKT2 in lung adenocarcinoma and squamous carcinoma were 60.5% and 54.1% respectively (P > 0.05). While the positive rates of p-AKT2 in lung adenocarcinoma and squamous carcinoma were 68.4% and 47.5% (P < 0.05). The expressions of AKT2 and p-AKT2 were not correlated with age, gender, TNM stage and cell differentiation degree. Further more, survival analysis revealed that 5-year survival rate and median survival time for the patients with positive expression of p-AKT2 were significantly poorer than those with negative expression (20% vs 56%, (28.464 +/- 2.235) months vs (39.214 +/- 3.075) months, P < 0.053, while there were no significant differences with regard to AKT2 expression. CONCLUSION: The positive expression of p-AKT2 in lung adenocarcinoma was higher than that in lung squamous carcinomas. p-AKT2 may be a prognostic factor for non-small cell lung cancer. PMID- 20848775 TI - [Different expression of GluR5 and GluR6 in rat astrocyte induced with coriaria lactone and ATPA]. AB - OBJECTIVE: To investigate the different expression of GluR5 and GluR6 in rat astrocyte induced with Coriaria Lactone (CL) and ATPA and to discuss the possible mechanism of the inducing epileptic model. METHODS: Astrocyte of neonate rats was treated with CL and ATPA respectively and the astrocyte treated with normal saline as control. The mRNA and protein levels of GluR5 and GluR6 were detected by RT-PCR and western blotting. RESULTS: Compared with the control, the expression of GluR5 was increased significantly in the astrocyte induced by ATPA (P < 0.05), however, there was no alteration of GluR6 expression. The expression of GluR5 and GluR6 were decreased significantly in CL-treated group (P < 0.05). CONCLUSION: The present study showed ATPA up-regulated mRNA and protein levels of GluR5, but coriaria lactone down-regulated the GluR5 and GluR6 of astrocyte. The results indicate that there are different pathologic mechanisms of GluR5 and GluR6 in different neurotoxicants inducing model of epilepsy. The molecular mechanism need to be studied further in the future. PMID- 20848776 TI - [Effects of EGFR inhibitor AG1478 in combination with celecoxib on the growth of gastric cancer cells]. AB - OBJECTIVE: To investigate whether EGFR inhibitor AG1478 combined with celecoxib could enhance the inhibitive effects on the growth of gastric cancer cells. METHODS: Human gastric cancer cell line SGC-7901 was cultured and treated with different concentration of AG1478 and celecoxib, the proliferation of SGC-7901 cells was determined by MTT. The expression of proliferation cell nuclear antigen (PCNA) of SGC-7901 cells was detected by immunocytochemistry. ERK and p-ERK expression were determined by immunoblot. The TdT-mediated dUTP nick end labeling (TUNEL) assay was used to detect apoptosis. RESULTS: When SGC-7901 cells was treated with AG1478 or celecoxib alone, cell growth was only inhibited by high concentration of the two agents (10, 100 micromol/L) significantly, the IC50 of AG1478 and celecoxib were 69.69 micromol/L and 70.98 micromol/L respectively. Compared with AG1478 or celecoxib alone, combination of AG1478 and celecoxib at different doses significantly enhanced the inhibitive effects on cell growth (P < 0.01). Compared with control (56. 55%), the expression of PCNA was decreased in the cells treated with AG1478, celecoxib and the combination of these two agents, PCNA indeices were 26.24%, 38.16%, and 9.08%, respectively (P < 0.01). AG1478 induced cell apoptosis at 10 micromol/L, the rate was 7.88% vs. 3.54% in control (P < 0.01), and the combination of AG1478 with celecoxib showed an enhanced effect, the apoptosis rate was 14.90%. There were no any effects on ERK expression with the treatments of either AG1478, celecoxib alone or toghether, but the phospholation of ERK was decreased by AG1478 (P < 0.01). CONCLUSION: AG1478 combined with celecoxib results in enhanced inhibitive effect on the growth of SGC-7901, which may partly due to the suppression of ERK phospholation. PMID- 20848777 TI - [Activation of TLR3 pathway in the pathogenesis of nephrotic syndrome induced by respiratory syncytial virus in rat model]. AB - OBJECTIVE: To explore the activation of toll-like receptor 3 (TLR3) pathway on the process of respiratory syncytial virus (RSV) induced nephropathy. METHODS: SD rats were inoculated intranasally and intraperitoneally with 6 X 10(6) plaque forming unit(PFU) RSV and sacrificed on days 4, 14, 30 postinoculation (RSV4, RSV14 and RSV30). The normal rats without intervention were set as control. Renal tissues were obtained, and the morphological changes were studied. The expressions of TLR3, NF-kappaB and IL-13 in the rats' kidney were measured with real-time quantitative RT-PCR, and indirect IF staining. RESULTS: After the inoculation of RSV, the rats had proteinuria and the fusion of foot processes of glomerular epithelial cells, resembling human minimal changed nephrotic syndrome (MCNS). The expressions of TLR3, NF-kappaB and IL-13 in renal tissues increased obviously at Day 4 and Day 14 postinoculation, the differences were significant when compared with normal control rats (P < 0.05). The expressions of these three factors decreased at Day 30, which were not significantly different to those of normal control group (P > 0.05). CONCLUSION: TLR3 signal pathway may play an important role in early stage of RSV nephropathy. PMID- 20848778 TI - [Protective effect of over-expression OGCP on HEK293 cells treated by rotenone and mutant Parkin protein]. AB - OBJECTIVE: To study the effect of alpha-ketoglutarate carrier protein (2 oxoglutarate carrier protein, OGCP) and the Parkin protein on HEK293 cell function. METHODS: The cell apoptosis rate, mitochondrial membrane potential and intracellular reactive oxygen species of HEK293 cells treated with rotenone, OGCP and / or Parkin protein were detected by using flow cytometry methods (FCM). RESULTS: (1) Over-expression wild-type Parkin protein and/or OGCP can increase mitochondrial membrane potential of HEK293 cells induced by rotenone, reduce intracellular reactive oxygen species and cell apoptosis rate of HEK293 cells induced by rotenone, while over-expression mutant Parkin (R42P and T240R) protein can decrease the mitochondrial membrane potential of HEK293 cells, especially the HEK293 cells induced by rotenone, but increase intracellular reactive oxygen species and promote apoptosis. (2) In addition, we also found that OGCP can inhibit the increasing of mitochondrial membrane potential and reactive oxygen species and decreasing of cell apoptosis caused by mutant Parkin protein (R42P and T240R). CONCLUSION: (1) Parkin protein and OGCP may be associated with the maintenance of normal function of mitochondria. (2) Over-expression of mutant parkin (R42P and T240R) protein may inhibit mitochondrial function and promote apoptosis. (3) Over-expression OGCP has protective effect on cell toxicity caused by rotenone and mutant parkin protein. PMID- 20848779 TI - [Effects of metallothionein on rifampicin (RFP)-induced hepatotoxicity in mice]. AB - OBJECTIVE: To investigate the effect of metallothionein (MT) on rifampicin (RFP) induced hepatotoxicity and the possible mechanisms. METHODS: Male MT- I / II null (MT-/-) and wild type (MT+/+) mice were randomly divided into 4 groups, respectively, and were orally administered RFP (50, 100 or 200 mg/kg) or equal volumes of solvent daily for 15 consecutive days. Levels of plasma alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DB) were determined. Liver indexes were calculated and liver histopathologic changes were examined by hematoxylin and eosin (HE) staining. The content of glutathione (GSH) as well as the activities of glutathione peroxydase (GPx) and glutathione reductases (GR) were measured in the liver homogenates. RESULTS: RFP treatment induced significant increases in plasma ALT, AST and DB, as well as liver index. Significant histopathologic changes which were charactered as fatty degeneration in liver were noteced. Moreover, augmentations of GSH content and GR activity and attenuation of GPx activity were observed. More severe hepatic injuries in MT-/- mice were observed as compared to MT+/+ mice, which were evidenced by higher liver/body weight ratio and GR activity, lower GSH content and GPx activity, and more serious fatty degeneration. CONCLUSION: RFP-induced hepatotoxicity was associated with cholestasis and oxidative damage. MT -/- mice were more susceptible than MT +/+ mice to RFP-induced hepatotoxicity and the enhanced hepatotoxicity involves increased oxidative stress. PMID- 20848780 TI - [The effect of SenQi FuZheng injection on lung cell apoptosis following cardiopulmonary bypass in dogs]. AB - OBJECTIVE: To study the effect and possible mechanism of SenQi FuZheng injection on lung cell apoptosis in dogs with ischemia reperfusion (I/R) following cardiopulmonary bypass (CPB). METHODS: CPB dog models were established. The 12 mongrel dogs were randomly divided into two groups: CPB I/R group (control) and SenQi FuZheng injection group (therapy). The lung tissue samples of 1.0 cm3 from the same lobes of lung were obtained at 10 min before CPB (T1) and 60 (T2), 120 min (T3) after reperfusion. These samples were fixed and then embedded in paraffin imbedding, and cut into thin slices (5 microm). Streptavidin/peroxidase (SP) immunohistochemical method was employed to detect Caspase -3, Bcl-2, and Bax protein expressions. RESULTS: The expressions of Caspase-3 and Bax protein in the tissues with SenQi FuZheng therapy were significantly lower at 60 and 120 min after reperfusion than the controls (P < 0.05). The expression of Bcl-2 protein and the Bcl-2/Bax ratio in the tissues with SenQi FuZheng therapy were significantly higher at 60 and 120 min after reperfusion than the controls (P < 0.05). CONCLUSION: Administration of SenQi FuZheng injection in CPB dogs can inhibit apoptosis of alveolar cells by reducing the expressions of Caspase-3 and Bax protein and increasing the expression of Bcl-2 protein. PMID- 20848781 TI - [Effect of visfatin on the expression of basic fibroblast growth factor in rat hepatic stellate cells]. AB - OBJECTIVE: To investigate the effect of visfatin on the expression of basic fibroblast growth factor (FGF-2) in rat hepatic stellate cells (HSCs). METHODS: Culture-activated rat HSCs were incubated with visfatin under different dose (50, 100, 200 ng/mL) for 6, 12, 24 and 36 hours respectively. Total RNA were collected at each time point. FGF-2 mRNA expression was detected by real-time reverse transcriptase polymerase chain reaction. RESULTS: The mRNA expression of FGF-2 was dose-dependently up-regulated in rat HSCs when incubated with 50, 100 and 200 ng/mL visfatin (1.71 +/- 0.34 vs. 1, 2.25 +/- 0.26 vs. 1, 3.25 +/- 0.29 vs. 1, P < 0.05, respectively). FGF-2 mRNA expression also increased after 100 ng/mL visfatin treatment for 12 hours (1.68 +/- 0.31 vs. 1, P < 0.05), and the mRNA levels were time-dependently elevated from 24 hours to 36 hours (2.25 +/- 0.26 vs. 1, 2.95 +/- 0.32 vs. 1, P < 0.05, respectively). CONCLUSION: Visfatin could induce FGF-2 mRNA expression in rat HSCs in a dose- and time-dependent manner. Visfatin might be involved in the pathogenesis of liver fibrosis. PMID- 20848783 TI - [Investigation of effect of bicuculline on expression of alpha-smooth muscle actin and airway remodeling in asthmatic mice]. AB - OBJECTIVE: To observe the effect of bicuculline, which is a selective GABA receptor antagonist on expression of alpha-SMA in the lung tissue of rats with chronic asthma, to explore the role of the bicuculline on the airway remodeling in asthmatic mice. METHODS: Forty BALB/c mice were randomly divided into four groups: the control group (A), the asthma model group (B), the bicuculline group (C) and bicuculline with budesonide group (D). The asthmatic model was established by sensitization and challenge with ovalbumin. The expression of alpha-SMA in the lung tissue and the thickness of the airways of mice was detected by semi-quantitative reverse transcription-polymerase chain reaction (RT PCR) and immunohistochemical staining. RESULTS: There was little expression of alpha-SMA in the lung tissue of normal mice compared with the asthma model group (P < 0.05). The expressions of alpha-SMA in the group C and D decreased compared with that in group B (P < 0.01), but no significant difference (P > 0.05) was observed between group C and D. The WAt/Pbm, WAi/Pbm, and WAm/Pbm were significantly increased in the asthma group compared with that in normal group (P < 0.05), and the WAt/Pbm, WAi/Pbm, and WAm/Pbm were decrased in the group compared with that of group B (P < 0. 01), the wAm/Pbm was decreased in the group C (P < 0. 05). CONCLUSION: Over expression of alpha-SMA in asthmatic lung tissue is closely related to the onset of asthmatic. GABAAR antagonist bicuculline could inhibit the expression of alpha-SMA and alpha-SMA mRNA and alleviate airway remodeling with equivalent potency of inhaled corticosteroid. Our data suggest that GABAAR involve in the pathogenesis of asthmatic airway remodeling by upregulating the expression of alpha-SMA inducing the airway smooth muscle constriction and hyperplasia. PMID- 20848782 TI - [Curcumin inhibits hypoxia-induced proliferation of MRC-5 and collagen I synthesis]. AB - OBJECTIVE: To investigate the effect of curcumin on MRC-5 in human embryo fibroblast (HEF) under hypoxia and possible underlying mechanism. METHODS: The MRC-5 were cultured in vivo under 5 different conditions, including normal control, SB203580 (10 micromol/L), LY-294002 (10 micromol/L) and curcumin (5,10 and 20 micromol/L, respectively). The proliferation of MRC-5 was assessed by MTT assay and the expressions of pro-collal, p-p38 and p-AKT were detected by western blot. RESULTS: Compared with the nomoxia control, hypoxia enhanced the proliferation of MRC-5 and the expressions of pro-collal, p-p38 and p-AKT (P < 0.05). Curcumin inhibited the hypoxia-induced proliferation of MRC and the expression of pro-collal and p-p38 (P < 0.05), but not the expression of p-AKT (P > 0.05). CONCLUSION: Hypoxia might enhance the proliferation of MRC-5 cells and the expression of collagen I through PI3K/AKT and p38MAPK. Curcumin blocks the hypoxia influence through is impact on p38MAPK. PMID- 20848784 TI - [The role of protein kinase C in the process of HL-60 cells induced into dendritic cells by calcium ionophore A23187]. AB - OBJECTIVE: To Investigate the role of protein kinase C (PKC) signal transduction in the process of HL-60 leukemic cells induced into dendritic cells (DCs) by calcium ionophore A23187. METHODS: HL-60 cells were pretreated with protein kinase C (PKC) inhibitor Bis-1 for 24 hours followed by cultured with A23187 for another 36 hours, and the morphology, immunophenotype and function of stimulating proliferation of allogeneic T cells were compared with the cells only treated with A23187. RESULTS: The morphological changes, surface marker expressions and ability to stimulating the proliferation of allogeneic T cells were inhibited in DCs derived from HL-60 cells treated with PKC inhibitor Bis-1. The percentage of CD83, CD80, CD86 expressing on DCs induced by A23187 significantly decreased to (28.97 +/- 4.05)% vs. (13.23 +/- 2.15)%, (19.10 +/- 5.46)% vs. (9.70 +/- 1.69)%, (41.03 +/- 6.43)% vs. (23.37 +/- 7.50)%, respectively (P < 0.05). CONCLUSION: The induction of HL-60 cells induced into DCs by A23187 can be inhibited by PKC inhibitor Bis-1, this suggested that PKC signal transduction pathway might be involved in the process of HL-60 leukemic cells differentiated into DCs by A23187 induction. PMID- 20848785 TI - [Effects of glycyrrhizic acid on the growth and acid-producing of Streptococcus mutans in vitro]. AB - OBJECTIVE: To investigate the antibacterial activity of glycyrrhizic acid against Streptococcus mutans (S. mutans, ATCC 25175) in vitro. METHODS: The minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBC) of glycyrrhizic acid against S. mutans were detected using doubling dilution. The effects of glycyrrhizic acid on the growth and acidogenic profile of S. mutans and the inhibition ratio of glycyrrhizic acid on growth and acid-producing of S. mutans were investigated by detecting the Abs of bacteria suspension and the pH value of medium at definite time intervals (0 h, 3 h, 7 h, 12 h, 23 h, 40 h) during cultivation. RESULTS: The MIC determined for glycyrrhizic acid was 1.57 mg/mL and there was no bactericidal effect when concentration of glycyrrhizic acid up to 12.5 mg/mL. The glycyrrhizic acid inhibited the multiplication and acid-producing of S. mutans significantly and the effects became stronger with concentration increasing. When concentration up to 1.57 mg/mL, the inhibition ratio of glycyrrhizic acid on the growth and acid-producing of S. mutans were exceeded 80 and 70 percent, respectively. CONCLUSION: The glycyrrhizic acid can inhibit the growth and acid-producing of S. mutans in vitro. PMID- 20848786 TI - [Study on the role of Th17 cells in the islet transplantation]. AB - OBJECTIVE: To study the role of Th17 cells in the Immune rejection of islet transplantation, explore the feasibility of immune tolerance of islet transplantation induced by the combination applying of IL-23R antibody and Anti CD154mAb. METHODS: The in vitro experiments were divided into 5 groups: Blank control group, SD rat islet cells were cultured alone; A group, co-culture of rat pancreatic islet cells and lymphocytes, without IL-23R antibodies; B, C, D groups, co-culture of rat pancreatic islet cells and lymphocytes, respectively with IL-23R antibodies 0.1 microg/mL, 0.5 microg/mL, 1.0 microg/mL. Cells were harvested for Acridine orange (AO)/propidium iodide (PD) fluorescence staining, insulin and glucagon staining and glucose-stimulated insulin secretion test. The in vivo experiments (the purified islet to be transplanted under the left kidney capsule of the mice) were divided into four groups: Control group, BABL/c mice were transplanted with islets of SD rats with no treatments, IL-23R antibody (200 microg) treatment alone, anti-CD154mAb (200 microg) treatment alone and a combination of both. The blood glucose of the transplanted mice were monitored. The kidney of islet grafts were sliced for HE staining and insulin and glucagon immunohistochemical detection. RESULTS: Three days after mixed cultivation, the glucose stimulation index was 3.66 +/- 0.10 in blank control group, which was higher than that of other groups. Stimulation index of D group was 1.95 +/- 0.75, which was significantly higher than that of other groups. The functional graft survival of all experimental groups were significantly better than that of control group as demonstrated by immunohistochemical staining of insulin and glucagon, as well as in vitro and in vivo experiments. After three days of islet transplantation, the blood glucose of control group was higher than that of experimental groups, but no significant difference was observed among experimental groups. CONCLUSION: Th17 cells were involved in the islet transplant rejection. The expression of IL-17 could be considerably reduced through the block of the IL-23R, the effect of the block had a positive correlation in a dose dependent manner. The combination of Anti-CD154 mAb and IL-23R antibody could prevent the acute rejection to some extent. However, there's no significant difference compared with the Anti-CD154mAb alone. PMID- 20848787 TI - [Percutaneous transcather closure of atrial septal defect guided by transthoracic echocardiography and transesophageal echocardiography]. AB - OBJECTIVE: To evaluate the reliability of the combined use of TTE and TEE in guiding percutaneous closure of atrial septal defect. METHODS: A total of 120 patients were recruited, all accepting TTE and TEE examinations before surgery. The release of ASD occluders was guided by TTE. The patients were divided into two groups. Patients in Group A received ASD occluders with > or = 24 mm diameter. Group B received ASD occluders with < 24 mm diameter. Each group comprised patients with and without retroaortic rim. The patients were followed up with TTE and ECG examinations 24 h, 1, 3 and 6 months after the procedure. RESULTS: ASD closure was successful for 94% and 100% of the patients in group A and group B, respectively. The difference of the ASD diameter measured by TEE and TTE was (2.7 +/- 2.8) mm in group A and (1.7 +/- 2) mm in group B, P < 0.05. The ASD diameter measured by TEE had a (4.87 +/- 1.10) mm and (4.2 +/- 0.80) mm difference with the diameter of ASD occluders for patients in Group A and Group B, respectively (P < 0.05). The ASD diameter measured by TTE had a (7.51 +/- 2.72) mm and (5.89 +/- 2.26) mm difference with the diameter of ASD occluders for patients in Group A and Group B, respectively (P < 0.05). The ASD diameter measured by TEE had a greater correlation coefficient with the ASD occluder diameter than that measured by TTE. The ASD diameters measured by TEE(x1) and TTE(x2) were both linearly correlated with the ASD occluder diameter(y). There was no difference in the successful rate of ASD closure between the patients with and without deficient retroaortic rim. In group A, the procedure failed in 4 patients; misalignment of the ASD occlude occurred in one patient; one patient suffered from second degree type II atrio-ventricular block; one patient had ischemic cerebral stroke. No such complications occurred in group B. CONCLUSION: The combined use of TTE and TEE before the intervention procedure and the release of ASD occluder guided by TTE enables high successful closure rate with little complication. It is an effective and safe method. It can be performed in patients with deficient retroaortic rim. PMID- 20848788 TI - [MR DTI and DTT study on the development of optic radiation in patients with anisometropia amblyopia]. AB - OBJECTIVE: To evaluate the development of optic radiations (ORs) in patients with anisometropia amblyopia using magnetic resonance diffusion tensor imaging (DTI) and diffusion tensor tractography (DTT), and to explore possible mechanism of pathogenesis of amblyopia. METHODS: Brain scan was performed with 3.0 Tesla scanner on 8 patients with anisometropia amblyopia and 15 control subjects with normal sights. The fractional anisotropy (FA) values, the apparent diffusion coefficient (ADC) values, the numbers of neural fiber bundle of ORs, and the voxel numbers of ORs were compared between the patients with anisometropia amblyopia and those with normal sights and between the ipsilateral ORs and the contralateral ORs in the patients with amblyopia. RESULTS: No differences in the FA values, the ADC values, the numbers of neural fiber bundle of ORs and the voxel numbers of ORs were found between the ipsilateral ORs and the contralateral ORs in the patients with amblyopia (P > 0.05). Significant decreases in the FA values and the voxel numbers of ORs were found in the patients with amblyopia compared with the controls (P < 0.05). No differences in the voxel numbers of both ORs in the anterior parts were found between the patients with amblyopia and the controls (P > 0.05). However, the patients with amblyopia had more voxel numbers of ORs in the posterior parts than the controls (P < 0.05). The differences in the ADC values and the numbers of neural fiber bundle of ORs between the patients with amblyopia and the controls were not significant (P > 0.05). CONCLUSION: The compactability, integrity and directivity of ORs decrease in patients with anisometropia amblyopia. The projection of OR fibers is abnormal. The ORs are underdeveloped, especially in the posterior parts, although no abnormal morphologic changes occur. The DTI and DTT can detect the underdevelopment of optic radiations in patients with anisometropia amblyopia indirectly. PMID- 20848789 TI - [Contrast sensitivities of the fellow eyes in children with anisometropic and strabismic amblyopia]. AB - OBJECTIVE: To investigate the contrast sensitivities of the fellow eyes in children with anisometropic and strabismic amblyopia. METHODS: A retrospective study was undertaken. Medical records containing contrast sensitivity data of the fellow eyes in 107 children with anisometropic amblyopia, 110 children with strabismic amblyopia, and 30 normal children were retrieved. The contrast sensitivities of the fellow eyes in those children were compared using independent t-test and one-way analysis of variance (ANOVA) with post hoc (modified LSD) multiple comparison test. RESULTS: Contrast sensitivity functions of the fellow eyes of children with anisometropic and strabismic amblyopia were weaker than those of the controls. The fellow eyes of children with moderate and severe strabismic amblyopia had better contrast sensitivities than those with anisometropic amblyopes. In strabismic amblyopic children, the contrast sensitivities of the fellow eyes grew with the degree of amblyopia. Occlusion therapy did not change contrast sensitivities of the fellow eyes. CONCLUSION: The abnormal intraocular interactions between amblyopic and nonamblyopic "normal" eyes decrease the contrast sensitivity functions of the fellow eyes. Compared with anisometropic amblyopic children, the fellow eyes of children with moderate and severe strabismic amblyopia show more superiority in the binocular competition. Occlusion therapy may not depress contrast sensitivities of the fellow eyes in children with amblyopia. PMID- 20848790 TI - [Experimental study on selective hepatic lobectomy using nitinol alloy net blocker of biliary intrahepatic duct]. AB - OBJECTIVE: To investigate the feasibility and possible mechanism of non traditional hepatic lobectomy using nitinol alloy net blocker of biliary intrahepatic duct. METHODS: Biliary intrahepatic ducts of the experimental pigs were blocked with and without dissepiment blockers. The histological changes and expressions of TGF-betal and TIMP-1 in the livers were compared. RESULTS: Blockage of biliary intrahepatic duct using nitinol alloy net blocker without dissepiment resulted in obvious atrophy of the focus liver. The mean weight and size of the focus liver was only 1/4 of the controls (P < 0.05), with liver cells almost completely taken by collagen fibers. Higher expressions of TGF-beta1 and TIMP-1 were found in the group without dissepiment than in the group with dissepiments (P < 0.05). CONCLUSION: Using nitinol alloy net blocker for selective hepatic lobectomy is as effective as traditional hepatic lobectomy. It may offer a new way for treating intrahepatic bile duct stones. PMID- 20848791 TI - [Metabonomic study of the urine of rat acute gouty arthritis model]. AB - [ OBJECTIVE: To analysis the metabonome characteristics of the urine of MSU crystal-induced acute gouty arthritis rats by the method of metabolomics. METHODS: Based on the method of metabolomics, which applies LC/MS as data acquisition platform, incorporating with the means of stoechiometry such as principal component analysis, we analyzed the metabonome difference between the urine of acute gouty arthritis rats and that of normal rats. RESULTS: Compare with control group, the metabolism status of acute gouty arthritis model group deviated. After that, with the time lapsed, it retrieved gradually to the incipient metabolism status. The variation of metabolism locus of rats measured by the methods of metabolomics properly reflects the genesis, development, and recuperation course of acute gouty arthritis. CONCLUSION: The whole metabolism status of rat model is able to be presented finely with the method of metabolomics. The metabolomics study could offer a satisfactory research approach to acute gouty arthritis. PMID- 20848792 TI - [Flow cytometric analysis of cerebrospinal fluid in the diagnosis of central nervous system leukemia]. AB - OBJECTIVE: To evaluate the value of flow cytometric immunophenotyping of cerebrospinal fluid (CSF) cells in the diagnosis of central nervous system leukemia. METHODS: Ninety two CSF samples were analyzed with 4-color flow cytometry. Antibody panles CD19/CD34/CD3/CD45, CD117/CD34/CD5/CD45, CD7/CD34/ CD19/CD45, CD7/CD3/HLA-DR/CD45, CD20/CD10/CD3/CD45, and anti-g/anti lambda/CD19/CD45 were used in determining cell composition and detecting abnormal cells. The results of flow cytometry were compared with conventional cell count and morphology. Flow cytometry analysis was repeated for five samples 48 hours after the initial test. RESULTS: Abnormal cells were found in 33 out of the 92 (35.9%) samples. Among the 59 samples taken from patients with lymphocyte neoplasm, CD19 + blast cells were found in the CSF in 13 patients with B-cell lymphoblastic leukemia; CD7+ blast cells were found in 4 T-ALL cases; and monoclonal CD19+ cells were found in 6 other types of lymphoma cases. In the 32 patients with clinically diagnosed myeloid leukemia, CD117+ myeloid cells were found in the CSF of 7 patients and B cell blast cells were found in 2 CML cases. The abnormal cells in the CSF detected by immunophenotyping decreased significantly 48 hours after the initial test. Abnormal cells were detected in 25 samples (27.2%) by morphology, less than those detected by immunophenotyping. The cell concentrations of the eight samples in which abnormal cells were only detected by flow cytometry were lower than 10 X 10(6)/L. The immunophenotyping results of two ALL patients were still positive when morphologic results had become negative after chemotherapy. CONCLUSION: Flow cytometric analysis of CSF may be helpful in the diagnosis of meningeal leukemia. It has higher positive rate and better accuracy than cytomorphology and cell count. PMID- 20848793 TI - [Association between polymorphism in DVWA and IL-1beta and Kashin-Beck disease]. AB - OBJECTIVE: To investigate the association between IL-1beta and DVWA gene and Kashin-Beck disease (KBD). METHODS: Peripheral genomic DNA were extracted from 105 patients with KBD and 98 healthy controls. PCR-RFLP were performed to detect SNP loci of IL-1beta gene and DVWA gene. RESULTS: The patients with KBD had significantly higher frequency of rs16944 (IL-1beta) locus (chi2 = 24.28, P < 0.001) and single allele frequency of rs16944 (chi2 = 5.683, P = 0.0171) than the healthy controls. There were no significant differences in genotype frequencies,single allele frequencies and haplotypes in rs4685241 and rs1143627 between the patients with KBD and the healthy controls. CONCLUSION: rs16944 (IL 1beta) is associated with KBD. PMID- 20848794 TI - [Relationship between polymorphism of hypoxia inducible factor-1alpha and cervical cancer in Han population in Sichuan Province of China]. AB - OBJECTIVE: To investigate the relationship between single nucleotide polymorphism (SNP) of hypoxia inducible factor-1alpha (HIF-1alpha) C1772T and genetic susceptibility to and clinical-pathological features of cervical cancers in Han population in Sichuan province of China. METHODS: A case control study was undertaken in Sichuan province of China, with 97 patients with uterine cervical cancer as case group and 117 negative for intraepithelial lesion or malignancy (NILM) patients as control group. Their gene types in HIF-1alpha C1772T were identified with a combination of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The distribution of the frequencies of T/T, T/C and C/C genotypes in the two groups differed significantly (P < 0.01); T allele frequency in the patients with cervical cancer was much higher than that in the controls (P < 0.01). There were no significant differences in the distributions of T/T, T/C and C/C genotypes among cervical cancer patients at different FIGO stages, pathological grading, stromal invasive depth, lymph node metastasis and vascular invasions (P > 0.05). CONCLUSION: T/C and T/T genotypes of HIF-1alpha C1772T are genetic susceptibility factors for cervical cancer in Han population in Sichuan province of China. HIF-1alpha C1772T SNP probably has no relationship with clinical-pathological features of cervical cancer. PMID- 20848795 TI - [Culture and quality of life assessment in Chinese populations]. AB - OBJECTIVE: To investigate the impact of cultural factors on quality of life (QOL) and to identify appropriate ways of dividing sub-populations for population norm based quality of life assessment. METHODS: The WHOQOL-BREF was used as a QOL instrument. Another questionnaire was developed to assess cultural values. A cross-sectional survey was undertaken in 1090 Guangzhou residents, which included 635 respondents from communities and 455 patients who visited outpatient departments of hospitals. Cronbach's a coefficients and item-domain correlation coefficients were calculated to test the reliability and validity of the WHOQOL BREF, respectively. Student t test, ANOVA and stepwise multiple linear regression analysis were performed to identify the variables that might have an impact on the QOL. Two regression models with and without including cultural variables were constructed, and the extent of impact exerted by the cultural factors was assessed through a comparison of the change of adjusted R square values. RESULTS: A total of 1052 (96%) valid questionnaire were returned. The Cronbach's alpha coefficients of the WHOQOL-BREF ranged from 0.67 to 0.78. Age, education, occupation and family income were correlated with all of the domains of the WHOQOL-BREF. Chronic condition was correlated with physical, psychological, and social relationship domains of the WHOQOL-BREF. Gender was correlated with physical and psychological domains of the WHOQOL-BREF. The multiple regression analysis showed that social and demographic factors contributed to 6.3%, 13.6%, 10.4% and 8.7% of the predicted variances for the physical, psychological, social relationship, and environment domains, respectively. Social support, horizontal collectivism, vertical individualism, escape acceptance, fear of death, health value, supernatural belief had a significant impact on QOL. However, social support was the only one factor that had an impact on all of the four QOL domains. CONCLUSION: It is necessary to divide sub-cultural populations for population norm-based QOL assessment. Further research is needed to develop a practical approach to the sub-cultural population division. PMID- 20848796 TI - [Source of variations of serum urea levels and consideration of reference interval in urban Chengdu]. AB - OBJECTIVE: To determine the serum Urea levels in healthy adults living in urban Chengdu and to identify factors that influence the serum urea levels for the purpose of establishing reference interval. METHODS: Serum urea levels were determined in 17 787 healthy adults in urban Chengdu who underwent physical examinations. The characteristics of distribution of serum urea levels in the population and its relationships with liver function, renal function, serum glucose, and serum lipid were analyzed. RESULTS: Increased Crea, Uric, Glu, and HDL-C levels and decreased Glb level were associated with increased serum urea levels, which was independent of the impact of sex and age. The association between serum urea and Crea, Glu, and HDL-C existed in normal healthy adults. Men had higher urea levels than women. Regardless of gender, serum urea increased with age (with a cut off point at 30, 50, 60 and 70 years). CONCLUSION: Serum urea levels in healthy adults living in urban Chengdu vary in different gender and age groups. Serum urea levels are associated with serum Crea, Glu, the HDL-C levels. It is necessary to establish gender and age-specific reference intervals for serum urea. PMID- 20848797 TI - [Risk factors on the occurrence and prognosis of neonatal hyaline membrane disease]. AB - OBJECTIVE: To identify risk factors with related to the occurrence and prognosis of neonatal hyaline membrane disease (HMD) and to develop effective measures to prevent and treat the disease. METHODS: A case control (1 : 4 paired) study was undertaken, with 62 neonates with HMD as a case group paired with 248 sick neonates without HMD and respiratory disorders as a control group. The controls were matched with the cases by admission time (+/- 7 d), birth weight (+/- 200 g) and gestational age (+/- 3 d). All of the patients came from the neonatal intensive care unit (NICU) in the West China Second University Hospital from June 2008 to January 2009. Conditional logistic regression analysis was performed to identify risk factors associated with the development and prognosis of HMD. RESULTS: Fetal distress, placenta previa, preeclampsia, placental abruption, maternal diabetes, and multiple births were identified as risk factors associated with the development of HMD, with an OR 10.459, 9.382, 8.884, 7.817, 7.727, and 7.217, respectively (P < 0.05). The Cochran Armitage trend test showed that the mortality of HMD decreased with the increase of gestational age and birth weight (P < 0.05). The mortality of HMD increased significantly in the patients with complication such as pulmonary hemorrhage, respiratory failure, neonatal asphyxia, and gastrointestinal hemorrhage (P < 0.05). CONCLUSION: Prevention of premature birth and treatment with high risk pregnancy and complications can reduce the mortality of HMD. PMID- 20848798 TI - [Cremophor EL test for identification of Malassezia species]. AB - OBJECTIVE: To establish a new method using cremophor EL test for the identification of Malassezia. METHODS: The suspension of Malassezia fur fur was incubated in a broth containing different concentrations of cremophor EL at 32 degrees C. Cell growth of the yeast was counted by hematocytometer at the 4th, 6th, 8th, 10th and 12th day, respectively. The optimum concentration of cremophor EL for Malassezia was determined by means of variance analysis. Then the 11 species of Malassezia were inoculate in the agar containing the optimum concentration of cremophor EL, and the growth of colony of each species were observed and compared with those inoculated under traditional conditions. RESULTS: The optimum concentration of cremophor EL for Malassezia fur fur was 4% (P < 0.05). The growth of the 11 species in the agar containing 4% cremophor EL were identical with those inoculated under the traditional conditions. The new method was easy to perform and demanded less culture medium and strains of yeast. CONCLUSION: The cremophor EL test can improve the efficiency and reduce the cost of identification of Malassezia species. PMID- 20848799 TI - [Determination of lidocaine and its metabolites in human plasma by liquid chromatography in combination with tandem mass spectrometry]. AB - OBJECTIVE: To establish a liquid chromatography tandem mass spectrometry (HPLC MS/MS) method for the determination of lidocaine (LDC) and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in human plasma. METHODS; The assay was conducted with an API 3000 HPLC-MS/MS system consisted of a Ultimate C18 column (50 x 4.6 mm, 5 microm). The mobile phase consisted of methanol: 5 mmol/ L ammonium acetate (50:50, pH was adjusted to 5.0 by formic acid) and the flow rate was set at 0.2 mL/min. The alkalinized sample was extracted with ethyl acetate. After evaporation of the organic layer, the residue was dissolved in mobile phase and the drug was determined by HPLC-MS/MS using electrospray ionization. RESULTS: The calibration curve was linear in a range from 15.625 to 2000 ng/mL for LDC. Linear calibration curves were obtained in the range of 1.5625 to 200 ng/mL for both for MEGX and GX. The limit of quantification for LDC, MEGX and GX was set at 15.625, 1.5625 and 1.5625 ng/mL. CONCLUSION: This method for the quantitative determination of lidocaine and its metabolites in human plasma is simple, rapid, sensitive and accurate. Therefore it can be used for the determination of lidocaine and its metabolites in clinical practice. PMID- 20848800 TI - [Design and synthesis of novel PPARgamma agonists]. AB - OBJECTIVE: To design and synthesize novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. METHODS: A series of novel PPARgamma agonists were designed based on the binding character of PPARgamma agonists and the distribution of pharmacophore. The target compounds were synthesized using p hydroxybenzaldehyde, 1, 2-dibromoethane, phenol, hydantoin and 2-thiohydantoin as materials. RESULTS: Twelve compounds were synthesized by etherification and Knoevenagle condensation. CONCLUSION: The target compounds were efficiently synthesized under mild condition and the structures of the target compounds were confirmed by 1HNMR and MS. PMID- 20848801 TI - [Repair and reconstruction of diaphragmatic defect during transcranial pituitary adenoma surgery]. AB - OBJECTIVE: To investigate the application value of titanium-clip and artificial menigeal in the sella diaphragm repair and reconstruction during transcranial pituitary adenoma surgery. METHODS: Thirty eight patients undergoing transcranial pituitary adenoma surgery received sella diaphragmatic defect repair and reconstruction after the removal of tumor, intraoperative diaphragmatic defect was classified as three grades, titanium-clip, artificial menigeal and EC glue were used for the sella diaphragmatic repair and reconstruction. The short-term and long-term complications were compared with those in the control group which contains 74 patients without diaphragmatic reconstruction. RESULTS: As 14 to 46 months' follow-up in the diaphragmatic reconstruction group, there were no leakage of cerebrospinal fluid(CSF), infections, empty sella syndrome (ESS), optic nerve damage, and any other severe complications was found. Only one inter sella hemorrhage without optic nerve damage was found 3 hours after surgery by CT scan. In the group without diaphragmatic reconstruction, more secondary empty sella, cerebrospinal fluid rhinorrhea and intra-cranial infection were found after the following transsphenoidal surgery (P < 0.05), there was one case underwent the 2nd time transcranial surgery 1 hours later due to severe inter sella hemorrhage resulting in vision damage and conscious disturbance. There was no significant difference in pituitary function and vision improvement between the two groups as the occurrence of diabetes insipidus (P > 0.05). CONCLUSION: It is important to repair the sellae diaphragm defect during transcranial pituitary adenoma surgery, which could reduce short-term and long-term complication. PMID- 20848802 TI - [Digital subtract arteriographic (DSA) characteristics of lower extremities and ankle-brachial index in patients with diabetic feet]. AB - OBJECTIVE: To evaluate the Digital Subtract Arteriography (DSA) characteristics of lower limb arterial diseases in patients with diabetic feet and to explore the correlation between DSA and Ankle-brachial index (ABI). METHODS: Fifty-two patients with diabetic feet were recruited in this study. ABI and DSA of bilateral lower extremities were examined to assess the severity of vasculopathy. The relationship between ABI and DSA was analyzed. RESULTS: ABI values for 91 lower extremities were obtained, with a mean of 0.73 +/- 10.43 (0.15-1.97), among which 19.8% ranged from 0.9 to 1.3, 69.2% were less than 0.9, and 11% were more than 1.3. Based on the integrated angiographic images, the arteries with < or = 50% degree of stenosis, 50%-99% degree of stenosis and occlusion comprised 49.5%, 22%, and 28.5% for femoral artery; 79.1%, 14.3%, and 6.6% for popliteal artery; 25.3%, 8.8%, and 65.9% for anterior tibial artery; 29.7%, 14.3%, and 56% for posterior tibial artery; 25.3%, 20.9%, and 53.8% for peroneal artery; and 54.9%, 14.3%, and 30.8% for dorsal pedis artery. Forty (50.5%) limbs had three or more above-mentioned arteries occluded simultaneously. The average vascular score was 8.5 +/- 4.3 with a range between 0 and 18. The spearman correlation analysis showed that ABI inversely correlated with artery stenosis score (r = -0. 588, P < 0.05). CONCLUSION: Arterial diseases of lower extremities in patients with diabetic feet are wide-spread, ranging from femoral artery to the dorsal pedis artery. Multiple segments of arteries are involved. Severe stenosis and occlusion are more common in anterior and posterial tibial arteries, and peroneal artery. PMID- 20848803 TI - The farmer, the hunter, and the census taker: three distinct views of animal behavior. AB - The purpose of this paper is to explore the relationship between evolutionary theory and ethology in the work of Konrad Lorenz, Niko Tinbergen and V.C. Wynne Edwards, the farmer, hunter, and census taker of the title respectively. I am especially interested in the idea of the ethologists Lorenz and Tinbergen that animal behavior and human behavior were equally appropriated subjects of biological analysis. Their approach is contrasted with Wynne-Edwards's group selective account of the evolution of social behavior. Finally, I argue that Wynne-Edwards's dogged commitment to group selection theory helped create the theoretical space within which subsequent researchers could develop more careful analyses. PMID- 20848804 TI - The embryo in ancient Rabbinic literature: between religious law and didactic narratives. An interpretive essay. AB - At a time when bioethical issues are at the top of public and political agendas, there is a renewed interest in representations of the embryo in various religious traditions. One of the major traditions that has contributed to Western representations of the embryo is the Jewish tradition. This tradition poses some difficulties that may deter scholars, but also presents some invaluable advantages. These derive from two components, the search for limits and narrativity, both of which are directly connected with the manner in which Jewish tradition was constructed in Antiquity. The article accomplishes three goals: To introduce some central elements in ancient Rabbinic literature on the subject of the embryo and its representation; To present this body of literature as clearly as possible, noting some of the difficulties encountered by scholars who engage in its study; To explain how the literature's textuality came about, examining the particular sociopolitical circumstances of Judaism at that time, including the reasons for the delay in the production of scientific texts, transmitted as such, as compared to other philosophical or religious traditions. The article claims that these circumstances engendered a tradition peculiarly relevant for the study and teaching of medical ethics today. PMID- 20848805 TI - Systems biology and the mechanistic framework. AB - Philosophical analyses of biology have recently been dominated by a mechanistic perspective. Examples taken from different domains in the life sciences, from molecular biology to physiology, seem to support mechanistic accounts. In this paper, I examine the emerging field of systems biology and argue that some of its approaches do not fit the mechanistic framework. I present an example of what can be called design explanation and show how it differs from classical mechanistic explanations. First, it is a non-causal kind of explanation that does not show how a function is produced by a mechanism but illustrates how a system's function determines its structure. Second, it points to general design principles that do not depend much on evolutionary contingency. Thus, systems biology has theoretical ambitions, but I argue that its modeling strategy can help it to avoid classical problems encountered by theoretical efforts in biology in the past, by giving it a strong empirical grounding. PMID- 20848806 TI - Introduction to "Writing Genomics". PMID- 20848807 TI - Making room for new faces: evolution, genomics and the growth of bioinformatics. AB - Genomics poses challenges that are specific to historians of science. Such challenges are not necessarily met by most recent sociologically-oriented approaches. This paper argues that historians of genomics can draw some lessons from the history of molecular biology, in part because some of the actors, concepts, and tools have made a transition between the two fields. More importantly, historians face the marginalization of scientific fields and actors that played a role in the integration of both ultra-disciplines. While biochemistry and genetics played an underrated role in the rising of molecular biology, research on the molecular evolution of informational molecules (molecular phylogenetics) played a neglected but nevertheless central role in the development of conceptual and analytical bioinformatics tools for genomics. Even today genomic tools incorporate underlying assumptions that show their origins in problems of comparative biology. This is particularly true in the case of the algorithms for sequence alignment, first proposed by Needleman and Wunsch (1970). The present essay also makes reference to areas in the history of science that require further investigation for an understanding of the transformations brought about by genomics to biological research, namely, the role of automation--beyond sequencing--and the intersection of biology and mathematics. PMID- 20848808 TI - Historiographic reflections on model organisms: or how the mureaucracy may be limiting our understanding of contemporary genetics and genomics. AB - Scholarship in the history of biology focused on model organisms has burgeoned along with the growth of the use of these organisms in genetic research in the closing decades of the 20th century. This paper draws on criticisms of model organism-based research, particularly the epistemological dangers of focus on a relatively limited number of species whose very development has become canalized through processes of standardization, to articulate the analogous historical pitfalls of these blinders for developing a fuller history of genetics and genomics. PMID- 20848809 TI - Documenting the emergence of bio-ontologies: or, why researching bioinformatics requires HPSSB. AB - This paper reflects on the analytic challenges emerging from the study of bioinformatic tools recently created to store and disseminate biological data, such as databases, repositories, and bio-ontologies. I focus my discussion on the Gene Ontology, a term that defines three entities at once: a classification system facilitating the distribution and use of genomic data as evidence towards new insights; an expert community specialised in the curation of those data; and a scientific institution promoting the use of this tool among experimental biologists. These three dimensions of the Gene Ontology can be clearly distinguished analytically, but are tightly intertwined in practice. I suggest that this is true of all bioinformatic tools: they need to be understood simultaneously as epistemic, social, and institutional entities, since they shape the knowledge extracted from data and at the same time regulate the organisation, development, and communication of research. This viewpoint has one important implication for the methodologies used to study these tools; that is, the need to integrate historical, philosophical, and sociological approaches. I illustrate this claim through examples of misunderstandings that may result from a narrowly disciplinary study of the Gene Ontology, as I experienced them in my own research. PMID- 20848810 TI - An obituary--on the death of antibiotics! PMID- 20848811 TI - New Delhi Metallo-beta lactamase (NDM-1) in Enterobacteriaceae: treatment options with carbapenems compromised. AB - BACKGROUND: Carbapenems are among the few useful antibiotics against multidrug resistant gram negative bacteria particularly those with extended spectrum beta lactamase. However resistance to carbapenems occurs and is mediated by mechanisms like loss of outer membrane proteins and production of beta lactamase that is capable of hydrolyzing carbapenems. An alert issued in the UK in 2009 warned of an increasing number of carbapenem resistant Enterobacteriaceae strains identified in UK hospital patients. Many of them were recently hospitalized in India and Pakistan and had new type of metallo beta lactamase designated as New Delhi Metallo-1 (NDM-1). OBJECTIVE: To assess the production of NDM-1 type Metallo beta lactamase enzyme in Enterobacteriaceae at a tertiary care centre in Mumbai. MATERIALS AND METHODS: Consecutive carbapenem resistant Enterobacteriaceae isolates were collected from August 2009 to November 2009. Susceptibility testing for carbapenems was performed by the disc diffusion method. Carbapenemase production was confirmed by Modified Hodge test. These strains were then subjected to single target PCR. A 475bp product was amplified by the NDM primers and visualized on 3% agarose gel. RESULTS AND CONCLUSIONS: Modified Hodge test was positive for all carbapenem resistant isolates. Of 24 carbapenem resistant Enterobacteriaceae 22 were NDM producers while 2 were NDM non producers. Amongst the 22 NDM producing organisms 10 were Klebsiella spp, 9 were Escherichia coli, 2 were Enterobacter spp and 1 was Morganella morganii. This high number in a relatively short span is a worrisome trend that compromises the treatment options with the carbapenems. PMID- 20848812 TI - Prevalence of overweight and obesity in Indian adolescent school going children: its relationship with socioeconomic status and associated lifestyle factors. AB - AIMS AND OBJECTIVES: Obesity and overweight have become a worldwide epidemic, and there is an urgent need to examine childhood obesity and overweight across countries using a standardized international standard. In the present study we have investigated the prevalence of obesity and overweight and their association with socioeconomic status (SES) and the risk factors like diet, physical activity like exercise, sports, sleeping habit in afternoon, eating habits like junk food, chocolate, eating outside at weekend, family history of diabetes and obesity. MATERIAL AND METHODS: The study was carried out in 5664 school children of 12-18 years of age and having different SES. The obesity and overweight were considered using an updated body mass index reference. SES and life style factors were determined using pre-tested questionnaire. RESULTS: Age-adjusted prevalence of overweight was found to be 14.3% among boys and 9.2% among girls where as the prevalence of obesity was 2.9% in boys and 1.5% in girls. The prevalence of overweight among children was higher in middle SES as compared to high SES group in both boys and girls whereas the prevalence of obesity was higher in high SES group as compared to middle SES group. The prevalence of obesity as well as overweight in low SES group was the lowest as compared to other group. Eating habit like junk food, chocolate, eating outside at weekend and physical activity like exercise, sports, sleeping habit in afternoon having remarkable effect on prevalence on overweight and obesity among middle to high SES group. Family history of diabetes and obesity were also found to be positively associated. CONCLUSION: Our data suggest that the prevalence of overweight and obesity varies remarkably with different socioeconomic development levels. PMID- 20848813 TI - AIDS-associated cancers: an emerging challenge. AB - OBJECTIVES: To study the incidence and effects of anti-retroviral therapy along with cancer chemotherapy on outcome of AIDS associated Cancers in Indian patients. METHOD: 3832 cancers patients were investigated over a period of 5 years. 46 AIDS-associated cancers were identified. HIV status was evaluated by ELISA, Western Blot, viral load and CD4/CD8 counts. Patients were treated with different modalities of cancer management and anti-retroviral therapy was discussed with the patient and relatives. Patients were followed up 6 monthly. RESULTS: Incidence of AIDS-associated cancers was 1.2 percent. AIDS-Defining Cancers (ADC) were seen in 26 (54.35%) while non-AIDS-Defining Cancers (NADC) were observed in 21 (45.65%). Non Hodgkin Lymphoma was the commonest form of AIDS defining cancers in 21 (84%) patients, cervical cancers in 4 (16%) women while there was not a single case of Kaposi's Sarcoma. AIDS associated cancers were common in males. Mean age was 38.5 years. Only 33.5% patients received treatment for HIV and cancers. Development of immune reconstitution syndrome was observed in 9.09% patients. Hepatitis B infection was seen in only one patient (2.17%). CONCLUSIONS: AIDS-associated cancers are seen in advanced stage of HIV infection. Concurrent chemotherapy and anti-retroviral therapy for ARL is significantly effective. Cervical cancers and non-AIDS-defining cancers do not show predictable response to anti-retroviral therapy. Mortality in non-AIDS related cancers was significantly higher than AIDS related cancers. PMID- 20848814 TI - Molecular mimicry in human diseases--phenomena or epiphenomena? AB - Molecular mimicry is one mechanism by which infectious agents (or other exogenous substances) trigger an immune response against the host antigens. When a susceptible host acquires an infection with an organism that has antigens immunologically similar to the host antigens but differ sufficiently, to induce, an immune response when presented to T cells, results in loss of tolerance to host antigens. Further more there is development of a pathogen-specific immune response that cross-reacts with host structures to cause tissue damage and disease. Till date the advances in the research in molecular biology has documented evidence to suggest that molecular mimicry plays in important role in pathogenesis of a number of diseases. This review is a brief overview of some of these disorders. PMID- 20848815 TI - Neuroimage--hydatid cyst of brain. PMID- 20848816 TI - A young female with left sided focal seizure. PMID- 20848817 TI - Antiphospholipid antibody syndrome. AB - The 2006 International Consensus Statement on an Update of the Classification Criteria for Definite Antiphospholipid Syndrome has increased the time between the two laboratory studies required for diagnosis from 6 to 12 weeks. Antibody to beta2 glycoprotein 1 has been included as a criterion. Various non-criteria diagnostic clues such as livedo reticularis, heart valve disease, thrombocytopenia, renal thrombotic microangiopathy, neurological manifestations, non-criteria antibodies (IgA aCL, IgA anti-beta2 glycoprotein I) and some research laboratory-identified antibodies (antiphosphatidylserine antibodies, antiphosphatidylethanolamine antibodies, antibodies against prothrombin alone and antibodies to the phosphatidylserine-prothrombin complex) have been recognised. New concepts of pathogenesis now implicate complement activation and participation of the innate immune system upstream to thrombosis. Warfarin remains the treatment of choice for patients who have suffered thrombosis, but antiplatelet agents and heparin are other options. Target INR is 2.0-3.0. The other drugs which are used in resistant cases are: rituximab, hydroxychloroquine, thrombin inhibitors and statins. PMID- 20848818 TI - Complicated typhoid fever. AB - Acute typhoid fever, caused by the gram negative bacterium Salmonella typhi may have a wide spectrum of clinical presentation. We report a young boy with typhoid fever, who developed myocarditis and splenic abscess, two of the unusual complications in the course of the disease. Judicious use of corticosteroid and antibiotic helped in achieving a favourable outcome. PMID- 20848820 TI - A young male heart transplant recipient who developed CKD due to cyclosporine therapy after a decade. AB - We report cyclosporine-induced chronic kidney disease (CKD) in a 38year old man who underwent cadaveric orthotopic heart transplant done 13 years ago. He was on triple immuno-suppression including micro-emulsion form of cyclosporine (neoral) with monitoring of his blood cyclosporine levels and serum creatinine. We discuss the pathophysiological mechanisms of cyclosporine toxicity in heart transplant recipients. PMID- 20848821 TI - Mycophenolate induced diarrhoea. AB - Mycophenolate (MMF) has arisen as an important addition in the immunosuppression armamentarium. GI disturbances (diarrhea) and bone marrow suppression are its main side effects requiring dose reduction or even withdrawal. The mechanism of diarrhoea is unknown, although some theories have been postulated. We evaluated three of our patients on MMF who came to us with chronic diarhoea. Their evaluation consisted of CBC, stool routine examination, stool culture, endoscopy and biopsy. Histopathologic examination in all three cases showed villous atrophy. All of them improved with discontinuation of MMF and addition of folic acid suggesting that diarrhoea was related to MMF. Since this complication is seen in only a few cases, we can hypothesize that it may be due to lower levels of the enzyme inosine monophosphate dehydrogenase (IMPDH)--the site of action of MMF. PMID- 20848819 TI - Bilateral vertebral artery dissection caused by atlantoaxial dislocation. AB - Craniovertebral anomalies are rare causes of vertebral artery dissection. Therefore, appropriate evaluation is necessary in vertebrobasilar strokes, specially in the young. This is particularly true for patients with vertebral stroke without risk factors. RESULTS: Here we report a 24-year-old male presenting with posterior circulation infarcts. The patient had no obvious vascular risk factors. However, digital subtraction angiography showed chronic dissection of both vertebral arteries with partial recanalization. Further evaluation with computed tomogram of neck revealed atlantoaxial dislocation. This is a rare case in which atlantoaxial dislocation has resulted in bilateral vertebral artery dissection and stroke in young. PMID- 20848822 TI - Intravenous catheter associated complications. AB - Two cases of intravenous catheter associated complications are reported herewith. PMID- 20848823 TI - Whipple's disease. AB - A 74 year old male patient with weight loss, diarrohea, loss of appetite, anemia, thrombocytopenia and culture negative endocarditis was diagnosed to have Whipple's disease. We are reporting this case, as it is a rare disease with fewer than 1000 validated cases reported in literature. PMID- 20848824 TI - MIBG negative pheochromocytoma. AB - We present a case of a left sided pheochromocytoma, who had normal levels of 24 urinary vanilylmandelic acid and a normal MIBG scan. The diagnosis was confirmed on histopathology of the adrenal gland. PMID- 20848825 TI - Medical philately (medical theme on stamps). Camillo Golgi and Ramon y Cajal who peeped into the mysterious world of nervous system. PMID- 20848826 TI - R2 syndrome: religion and renal failure. PMID- 20848827 TI - Indian Diabetic Risk Score and its utility in steroid induced diabetes. PMID- 20848828 TI - State-sponsored programs help PA hospitals reduce HAIs. AB - Creating culture of safety seen as key to success in new CUSP program. State makes liaison advisors available to help identify opportunities to improve. Even with "packaged" programs, hospitals must address their unique needs. PMID- 20848829 TI - Bar-code/eMAR combo reduces errors. AB - Study covers usage of system in multiple hospital units. Make sure your system meets the specific needs of your facility. Compliance should be viewed as a journey, not an isolated event. PMID- 20848830 TI - Medical home model can be complementary. AB - The medical home model could avoid 25% of current readmissions. The model also could reduce utilization. Some states have moved forward on the medical home model, using it for Medicaid patients or mandating its availability for all insured patients. PMID- 20848831 TI - Medical home model helps DP process with care. PMID- 20848832 TI - Physicians use checklists for quality DP. PMID- 20848833 TI - What does DP do at patient EOL? PMID- 20848834 TI - [The control and prevention of viral diarrheal]. PMID- 20848835 TI - [Study on the epidemiological of rotavirus diarrhea in Lulong in 2008-2009]. AB - OBJECTIVE: To analyze the feature of epidemiological of rotavirus diarrhea in Lulong county, Hebei province. METHODS: 426 stool specimens were collected from inpatant with acute diarrhea from children less than 5 years old. Rotavirus positive specimens were identified by ELISA kit. G/P typing assays were confirmed with multiplex seminested RT-PCR. RESULTS: Rotavirus was detected in 202 of 426 (47.42%) specimens. Genotyping of rotavirus showed that G3 was predominant (57.9%), followed by Gmix (16.3%), G9 (14.9% ), G1 (7.9%), G4 (1%), G2 (0.5%), P genotyping showed that P [8], Pmix, P [4], P [9], type were found in 58.4%, 28.7%, 6.9% and 1% respectively. The most common G/P combination identified was G3P [8]. CONCLUSION: Group A rotaviruses was a major pathogen of diarrhea in Children in Lulong. G3P [8] was the predominant type in 2009, Gmix and Pmix abound, and G9 serotypes has become the second predominant after G3 strain in the region. PMID- 20848836 TI - [The preparation of P particle of the norovirus strain SZ9711 from China and its affinity analysis with human histo-blood group antigens in saliva]. AB - OBJECTIVE: To study the binding profile of NV strain SZ9711 (GII-4) with human histo-blood group antigens (HBGAs). METHODS: The P domain-encoding fragment was amplified by RT-PCR from the stain SZ9711 and cloned into the pGEX-4T-1 vector. The recombinant fusion protein was expressed in E. coli and purified using the column Sepharose 4B. The P protein was released by thrombin cleavage. The binding of P particles of SZ9711 and VA387 with the HBGAs were measured by saliva-based EIA method. RESULTS: The expression of the recombinant fusion protein was shown by the SDS-PAGE, in which a 38 x 10(3)-P protein was obtained. Saliva-based EIA revealed that the P particle of SZ9711 bound to HBGAs in saliva similar to that of the strain VA387 reported previously. It bound strongly to saliva of type A, B and O(secretor) but did not interact with saliva of type O(non-secretor). Noteworthy, binding ability of SZ9711 P particle to type A saliva was lower than that of the VA387 P particle. CONCLUSION: This is the first time that a P particle was prepared from a norovirus strain isolated in China and the binding ability of the P particle with HBGAs was analyzed. The result indicated the binding profile of the SZ9711 P particle was similar to that of VA387 reported previously. These data may be valuable in studying the relationship between noroviruses and their bindings to HGBA receptors. PMID- 20848837 TI - [Analysis on epidemiologic characteristics of viral diarrhea among infants in Taiyuan, Shanxi province, 2007-2008]. AB - OBJECTIVE: To study the epidemiologic characteristics of virus-induced acute diarrhea in children under 5 years old in Taiyuan, Shanxi province. METHODS: Stool specimens and clinical data were collected from 346 inpatients with acute diarrhea from children less than 5 years old. Rotavirus-positive specimens were identified by ELASA kit. Calicivirus and astrovirus were detected by reverse transcription-polymerase chain reaction (RT-PCR). Adenovirus was done by polymerase chain reaction (PCR). RESULTS: Of the 346 specimens, the percentage of samples with Rotavirus, Calicivirus, Astrovirus, and Adenovirus was 40.8%, 7.5%, 6.4% and 3.2%. Among 141 rotavirus positive samples, serotype G1 (42.6%) was the predominant strain. More than 95% of viral diarrhea patients under hospitalization occurred among children younger than 2 years. CONCLUSION: Rotavirus is the major pathogen contributing to the acute diarrhea. The disease generally peaks at autumn/winter. The predominant rotavirus strain circulated was G1P[8]. PMID- 20848838 TI - [Detection of Aichi virus in stool samples from children in Lanzhou]. AB - OBJECTIVE: To identification and analysis Aichi virus from diarrhea and normal children in Lanzhou, and discuss the relationship between Aichi virus and Infant Diarrhea. METHODS: According to the literature published data, Using RT-PCR method to amplified Aichi virus 3CD fragment and the positive products were sequenced and determined, and made the alignment analysis between the nucleotide sequences of the amplified fragment with the known sequence of this virus. RESULTS: There was 1 case detection of Aichi virus in the 46 hospitalized children with diarrhea and 299 children with diarrhea out-patients specifically, Overall detection rate was 0.06%, and there was no Aichi virus was detected in normal control children. 2 viral 3CD gene and the known reference strains of nucleotide sequences were 97%, while phylogenetic analysis showed that genotype of 2 viral belongs to the B. CONCLUSIONS: There existed B Genotype of Aichi virus in China, and more research is needed to clarified the etiology and epidemiology of Aichi virus characteristics. PMID- 20848839 TI - [Sequence the complete sequence of bocavirus I with SISPA-PCR]. AB - OBJECTIVE: To sequence the complete sequence of bocavirus I with sequence independent single primer amplification (SISPA-PCR). METHODS: To exclude the co effection samples, all clinical samples of diarrhea cases were screened with special primers of rotavirus, astrovirus, adenovirus, calicivirus and bocavirus I. The virus were enriched through ultracentrifugation. Other nucleic acids, such as human and bacteria genomes, were degradated by DNase I and RNase. DNA of bocavirus was Amplificated with SISPA-PCR, then purificated, cloned and sequenced. The sequences were alighmented in nr with blastn and assembled with DNAstar. RESULTS: A 4834bp sequence of bocavirus I were assembled. CONCLUSION: SISPA-PCR is an economical and efficient technique for sequence a virus complete genome. PMID- 20848840 TI - [Loss of the balance between Th17 and Th1 populations in HIV/AIDS patients]. AB - OBJECTIVE: To evaluate the Th17/Th1 response in HIV infected patients and the mutual relationship between the response of Th17 and Th1. METHODS: 38 chronic HIV infected patients as well as 24 healthy volunteers were performed in this study. The patients were divided into two groups, one group before treatment, the other after therapy. The whole blood intracellular cytokine staining was used, samples detected by BD FACSCanto, after that, the expression of CD4+ IL-17+ T cell and CD4 IFN-gamma+ T cell were analyzed by FACSDiva software and lastly compared the differences among different groups. RESULTS: The expression of CD4+ IL-17+ T cell in naive-therapy patients were significantly lower than that of the healthy controls (1.14 +/- 0.7)9% vs (3.98 +/- 1.14)%, P = 0.000, but increased remarkably after HARRT(highly antiretroviral treatment) (2.22 +/- 1.00)%, P = 0.001; however there were no significant differences in the expression of CD4+ IFN-gamma+ T cell before and after therapy (34.35 +/- 24.38)% vs (42.10 +/- 15.57%), also with the healthy control (P = 0.383). The frequency of CD4 IL-17+ T cell was positively correlated with CD4+ T counts (R = 0.345, P = 0.034), but no significant correlations was observed between the expression of CD4+ IFN-gamma T cell and CD4+ T counts (R = -0.247, P = 0.136). CONCLUSION: The infection of HIV virus down-regulated Th17 immune response and disturbed the balances between Th17 and Th1 evidently in human. Th17 response may play an important role in the pathogenesis of HIV infection. PMID- 20848848 TI - [Detection of the serum level of interleukin-17 and interleukin-6 in the chronic hepatitis B patients]. AB - OBJECTIVE: To research serum level of interleukin-17 (IL-17) associated with the progression of hepatic injury in the chronic patients with hepatitis B. METHODS: The serum level of IL-17 was measured by ELISA and the serum levels of IL-6, IL-8 were measured by RIA in patient groups and healthy group, the patient groups including 42 mild patients, 37 moderate patients and 38 severe patients. RESULTS: IL-17,IL-6 and IL-8 levels in patient patients were significantly higher than those in healthy people (P < 0.01). There is no significant difference among mild patients and moderate patients. Compared with mild patients and moderate patients,the cytokines lever were significantly higher in severe patients (P < 0.01). CONCLUSION: IL-17 as a new cytokine probably play a multiple role as immune factor and inflammation element in the progression of the chronic hepatitis B disease. Maybe, it can provide a new approach to the therapy of the chronic hepatitis B. PMID- 20848849 TI - [The effect of antiviral therapy for patients with HBeAg-negative cirrhosis]. AB - OBJECTIVE: To investigate the efficacy of nucleot(s)ide analogues therapy in patients with HBeAg-negative cirrhosis in China. METHODS: 111 patiens with HBeAg negative cirrhosis were divided into antiviral group (58 cases, 25 entecavir, 19 adefovir dipivoxil, 13 lamivudine, 1 telbivudine) and control group (53 cases, supportive and symptomatic treatment). These two groups were matched for demography, liver function and Child-Pugh score. RESULTS: At the 96th week, the rate of ALT normalization and HBV DNA drop (1g copies/ml) in antiviral group were higher than those in control group (P < 0.05). The rates of HBV DNA negative (< 500 copies/ml) were 88.7% (47/53) and 32. 5% (13/40), respectively (P < 0.05 ). There were no differences in the rates of developing HCC and undergoing variceal bleeding between antiviral group and control group (P > 0.5). 15.4% patients with lamivudine treatment emerged YMDD mutations. 10.5% patients with adefovir dipivoxil treatment emerged virologic breakthrough and hepatitis flare during the second year. 2 patients (3.5%) in treatment group and 6 patients (11.5%) in control group died of liver failure or variceal bleeding or HCC ( P > 0.05 ). CONCLUSIONS: Neucleot(s)ide analogues are effective in suppressing HBV replication in patients with HBeAg-negative cirrhosis, but the impact of which on the mortality and complications of cirrhosis should be prolongly observed. For continuing treatment, the neucleot(s)ide analogues with strong effective and low resistance are the first choices to prevent viral mutation and drug resistance. PMID- 20848845 TI - [The expression of CD95 and activated antigens in peripheral blood lymphocyte subsets in patients with hand foot and mouth disease (HFMD)]. AB - OBJECTIVE: To investigate the expression of CD95 and special marker for activation of peripheral blood lymphocytes in patients with hand foot and mouth disease (HFMD) and its significance. METHODS: Immunofluorescent two-color flow cytometry was used to study the expression of CD95 and HLA-DR on lymphocytes in 58 patients with HFMD and 34 normal controls. RESULTS: Expression of CD3+ T cells was significantly lower in patients (63.82 +/- 7.74)% than that in controls (P < 0.001), meanwhile the expression of CD4+ T cells was (34.29 +/- 7.33)%, significantly lower than that of the controls (P < 0.005). The percentage of lymphocytes expressing HLA-DR in patients was (23.77 +/- 5.78)%, significantly higher than that of the controls (P < 0.005). Significant difference was observed in the expression of HLA- DR on CD8+ T cells in patients (1.34 +/- 1.12)% as compared with controls (P < 0.005). No significant difference in the expression of CD95 on lymphocytes was observed between patients and the controls (P > 0.05). CONCLUSION: The findings support that cellular immunodeficiency exists in patients and that lymphocytes were abnormally activated in the patients. The activation of peripheral blood T lymphocytes in patients mainly involves CD8 subset and it may play an important role in the immune response to antiviral infection. PMID- 20848847 TI - [Short-term efficacy of adefovir dipivoxil as an add-on therapy in the pegylated IFNalpha-2a treatment for HBeAg positive chronic hepatitis B patients]. AB - OBJECTIVE: To investigate whether the combination therapy of pegylated IFNalpha 2a plus adefovir dipivoxil (ADV) improve the efficacy of the treatment in CHB patients with HBeAg positive or not. METHODS: 57 CHB patients with HBeAg positive received 48-week pegylated IFNalpha-2a therapy were enrolled into this study. If serum HBV DNA levels exceeded 1000 copies/ml at week 24, the patients were assigned to group A (pegylated IFN-alpha2a plus ADV, 21 cases) or group B (pegylated IFNalpha-2a only, 14 cases); otherwise, they received the unceasing monotherapy of pegylated IFNalpha-2a (group C, 22 cases). RESULTS: At week 48, HBeAg seroconversion rates were 23.8%, 28.6% and 63.6% (A vs C,P = 0.014), but rates of aminotransferases normalization and HBV DNA suppression (< 1000 copies/ml) were not statistically significant among three groups. But during week 24 to week 48, rates of HBeAg seroconversion, aminotransferases normalization and HBV DNA suppression were also not statistically significant between group A and B. But amplitude of DNA drop in group A was much more than that in group B (2.60 +/- 1.37 vs 0.86 +/- 2.09, P = 0.005). CONCLUSION: An ADV add-on therapy in pegylated IFNalpha-2a treatment seems able to improve the inhibition of HBV DNA in chronic hepatitis B patients with HBeAg positive. It requires a large, double blind, randomized clinical trial to further provent. PMID- 20848842 TI - [Human papillomavirus type 16 intratypic variant infection and risk for cervical neoplasia]. AB - OBJECTIVE: To study the distribution of human papillomavirus type 16 (HPV16) variants and their clinical significance in Han women with Cervical Intraepithelial Neoplasia (CIN). METHODS: Randomly making a collection of DNA samples of cervical cells from 77 Han out-patients infected with HPV16, PCR amplification of HPV16 DNA fragments containing E6 and E7 genes and sequenced. To study the HPV16 variants types in these out-patients and explore the relationship between the HPV16 variants and CIN by comparing the E6 genes sequenced with the reference strains downloaded from the GenBank. RESULTS Among 77 patients, the minimum age is 21 years old, the maximum age is 56 years old, and the average age is 36.39 +/- 6.86 years old. 61 patients (accounting for 79.2%) were diagnosed as CIN II and higher grade lesions while 16 patients (accounting for 20.8%) as CIN I. In this research, only European variant and Asian variant were found by Parsimony analyses of the sequences. There are 38 Asian variants and 39 European variants. With Chi2 test, Chi2 = 0.0034, P = 0.9535 > 0.05, it suggested that there was no enough evidence to support Asian- and European-variants had the different risk in the cause of cervical intraepithelial neoplasia and cervical cancer. CONCLUSION: It was not found Asian- and European-variants of HPV16 had different effect on the cervical cancer, but found only two major variants-Asian- and European-variants in Han people in this research. So we have reason to speculate that there are two major HPV16 variants (Asian- and European-variants) in China's Han women, while other variants, especially high cancer-causing Asian/American variant are not common. PMID- 20848841 TI - [Studies about the level of CD4+ CD25+ regulatory T cells and relation between expression of Foxp3 and CD127 in peripheral blood of chronic HBV infection]. AB - OBJECTIVE: To investigate the level of CD4+ CD25+ Foxp3+ regulatory T cells and observe relation between expression of Foxp3 and CD127 in peripheral blood of chronic HBV infection. METHODS: CD4+ CD25+ Foxp3+ and CD4+ CD25+ CD127low Treg in peripheral blood from 34 patients of immune tolerance stage, 26 patients of immune clearance stage and 31 patients of non-active status were quantitatively analyzed by flow cytometry. RESULTS: Immune tolerance group presented a higher fraction of CD4+ CD25+ Foxp3+ and CD4+ CD25+ CD127low Treg than non-active group in chronic HBV infection (Z = -2.693, P = 0.007 and t = 3.251, P = 0.002), and HBV positive group also presented a higher fraction than non-active group (t = 2.266, P = 0.026 and t = 3.208, P = 0.002), But ALT normal group is similar to ALT abnormal group (P > 0.05). In this study, the relation between expression of CD127low and Foxp3+ from CD4+ CD25+ regulatory T cells was observed, and CD4+ CD25+ CD127low Treg presented a higher fraction than CD4+ CD25+ Foxp3+ Treg. CONCLUSION: Peripheral Treg in HBV active replication group is higher than HBV negative group of chronic HBV infection. Expression of CD127low is consistent with Foxp3+ in CD4+ CD25+ regulatory T cells, but the former is significantly higher than the latter. PMID- 20848846 TI - [Decreased expression of serum cortisol in patients with severe hepatitis]. AB - OBJECTIVE: To investigate the profile of serum cortisol levels in patients with severe hepatitis. METHODS: Fifty patients with viral hepatitis (including 30 severe hepatitis patients and 20 chronic hepatitis B patients) were enrolled in this present study. Serum cortisol concentration was tested using radioimmunoassay. Furthermore, liver function, coagulation and other related laboratory indices were also determined. RESULTS: Serum cortisol concentration of severe hepatitis group was lower than that of chronic hepatitis B group (P < 0.05) and lower than that of healthy controls (P < 0.05) serum cortisol concentration of severe hepatitis patients was significantly positively correlated with PTA (r = 0.445, P < 0.05); serum cortisol concentration has no relation with ALT in patients with severe hepatitis (P > 0.05), and serum cortisol concentration was significantly negatively correlated with the ratio of AST/ALT in patients with severe hepatitis (r = -0.367, P < 0.05). No significant relationship was found between serum cortisol concentration and total Bilirubin (P > 0.05). Serum cortisol concentration in death group of severe hepatitis was lower than that in survival group of severe hepatitis (P < 0.05). Of severe hepatitis patients with MELD score, the higher MELD score, the lower the cortisol concentration. CONCLUSION: Cortisol concentration decreased in patients with severe hepatitis, which was related to functional liver reserve and disease severity. Cortisol can be related to the prognosis of severe hepatitis patients. PMID- 20848844 TI - [Construction and characterization of hepatitis B surface antigen "a" epitope virus-like particles]. AB - OBJECTIVE: To construct virus-like particles of hepatitis B core antigen, with HBsAg "a" epitope exposed on the surface. METHODS: Hepatitis B surface antigen "a" epitope were inserted into the Hepatitis B core antigen, between the 78th (Asp) and the 79th (Pro) amino acids. The gene was synthesized after the codon optimized, then it was ligated to the express vector after been enzyme digest. The virus-like particles were observed by electron microscope and detected by ELISA after been expressed and purified. Immune the rabbits by the VLPs, then detect the antibody. RESULT: The virus-like particles were confirmed by electron microscope. Its antigenicity and immunogenicity were identified by ELISA. CONCLUSION: The prokaryotic express plasmid with the fusion gene has been constructed successfully. The virus-like particles have been expressed, purified and identified, which lays the foundation for its application in the further. PMID- 20848843 TI - [Expression and purification of avian influenza virus H5N1 NP protein, and screening interaction proteins of host cells in vitro]. AB - OBJECTIVE: To express and purify H5N1 influenza virus (A/Anhui/1/2005) NP in prokaryotic system and to explore the NP-interacting proteins of human bronchial epithelial cells BEAS-2B in vitro. METHODS: The full length H5N1 NP gene fragment was amplified by PCR, inserted into prokaryotic expression vector (pET30a) to generate NP expression plasmid pET30a-NP. After transforming pET30a-NP into E. coli (BL21), the expression of soluble NP protein was induced by IPTG. The expressed NP protein was purified by two steps with metal chelation chromatography and ion exchange chromatography. Then the total proteins of BEAS 2B cells was extracted for screening the components which have protein-protein interaction with purified NP by pull-down and LC-MS/MS methods. RESULTS: The expression of H5N1 NP protein could be induced by IPTG in bacterial system using expression plasmid pET30a-NP. The soluble NP was purified. Twenty proteins were found by pull-down and LC-MS/MS, the further experiments may be needed to prove protein-protein interaction between them. CONCLUSION: The soluble H5N1 NP fusion protein with high purity was obtained and twenty proteins were found which could interact with it by pull-down and LC-MS/MS. PMID- 20848850 TI - [Study on the relations between hepatitis B virus large surface protein (LHBs) and HBV YMDD mutation]. AB - OBJECTIVE: To explore the Relations between hepatitis B virus large surface protein (LHBs) and HBV YMDD mutation, by detecting the hepatitis B virus large protein (LHBs) in Serum of patients with hepatitis B virus YMDD mutation. METHODS: Selected patients after lamivudine treatment, to HBV YMDD mutation detection, then detected LHBs and HBV DNA in Serum of all patients. Serum HBV-DNA was quantitively detected by using real-time polymerase chain reaction (RT-PCR), the LHBS was detected by using enzyme linked immunosorbent assay (ELISA). RESULTS: There was positive correlation between the A value of LHBs and HBV DNA level in 65 cases of mutation patients (r = 0.961). There was positive correlation between the A value of LHBs and HBV DNA level in 75 cases of non mutation patients (r = 0.954). CONCLUSION: There were positive correlation between the A value of LHBs and HBV DNA level in non-mutation patients and mutation patients, showed that LHBs can partially reflect the level of viral replication in patients, but not the impact of hepatitis B virus YMDD mutation. PMID- 20848852 TI - [Construction and evaluation of hepatitis C virus (HCV) DNA vaccine containing E2 gAD fusion gene]. AB - OBJECTIVE: To rational design HCV DNA vaccine candidates and evaluate their specific We design to construct two DNA vaccine candidates, one consists of immunity to HCV in mice. METHODS: We design to construct two DNA vaccine candidates, one consists of E2 (the envelope glycoprotein 2 of HCV) gene only, the second consists of E2-gAD (Globular Domain of Human Adiponectin) fusion gene via overlapping PCR. Confirm the expression of the DNA vaccines by Western blotting, and then vaccinated by injection of DNA vaccines with gene electrotransfer (GET) in BALB/c mice. The immune response was measured by IFN gamma ELISPOT. RESULTS: The DNA vaccine candidate consists of E2-gAD could effectively express in vitro , and it could induced a higher anti-HCV T cell response in mice than the one consists of E2 only. CONCLUSION: The HCV DNA vaccine consists of E2-gAD fusion can increase the immunity of the E, to some extend, and the research paved a way to develop and optimize the novel HCV DNA vaccine. PMID- 20848851 TI - [The detection and clinical significance of hepatic fibrosis index]. AB - OBJECTIVE: To study the relationship between levels of serum HA, LN, IV-C, PC III of chronic hepatitis and indexes of hepatic fibrosis. METHODS: The levels of serum HA, LN, IV-C and PC III of chronic hepatitis of 124 cases and health 18 cases were measured by radio immunoassay, combined with clinical characteristics and 33 cases pathologic slice etc. The diagnostic of the indexes of serum was analyzed with statistics. RESULTS: HA and IV-C are parallel in chronic hepatitis periods. LN and PC III are concert in the same pathologic periods. In G4 period PC III is nearly closed with comparative group. The value of HA, LN, NV-C and PC III in the chronic hepatitis group was significantly higher than that in the normal comparative group. Conclusion The levels of serum HA LN IV-C and PC III are in concert with the degree of hepatic fibrosis, and these indexes are valuable for chronic hepatitis diagnoses combined with the clinic. LN and PC III are coincidence with hepatic fibrosis degree before G4 period. PMID- 20848853 TI - [Development of pseudoviral competitive internal controls for RT-PCR detection of dengue virus]. AB - OBJECTIVE: Development of pseudoviral competitive internal controls for RT-PCR laboratory detection of dengue virus. METHODS: The internal controls target gene were obtained by insertion of a 180 bp non-related DNA fragment into RT-PCR detection target of dengue virus between the forward and reverse PCR primer binding regions. A yellow florescence protein reporter gene was induced at downstream of internal controls target gene via internal ribosome entry site gene. HEK 293T cells were transfected with plasmid containing this whole cassette and lentiviral packaging support plasmid. Pseudoviral particle was recovered from the supernatant and analyzed quantitatively and qualitatively in simulated samples at the same tube under different experimental conditions. RESULTS: The established pseudoviral competitive internal controls can be used in the RT-PCR detection of different serotype dengue virus and the whole detection process can be monitored. The obtained fragment is easy to be differentiated in agarose electrophoresis. CONCLUSION: The pseudoviral competitive internal controls could be used for the quality control of the laboratory diagnosis process, simple to prepare, stable for storage, easy to be transformed into internal controls for other RNA virus. PMID- 20848854 TI - [Construction and identification of a vector inserted with complete genome of poliovirus strain Sabin I]. AB - OBJECTIVE: To develop a vector inserted with complete genome of poliovirus strain Sabin I. METHODS: The 3 fragments of the complete genome of Sabin I was amplified and cloned to pEASY-T3 by molecular biological technology. These cloned pEASY-T3 were then digested by Restriction enzymes and ligated to pWSK29 step by step and identified. RESULTS: The complete genome of poliovirus strain Sabin I was successfully cloned into vector pWSK29 with 9 nucleotide mutations. CONCLUSION: The complete genome plasmid was constructed and it provided a basis for further research of the function of Sabin I. PMID- 20848855 TI - [Transient expression and identification of gene P and NP of NDV LaSota strain in two different cells]. AB - OBJECTIVE: To Construction of P and NP genes eukaryotic expression vectors of Newcastle Disease Virus LaSota strain,study its reverse genetics and functional genome of NDV. METHODS: P, NP genes were amplified and cloned into pGEM-T easy vector and then subcloned into pcDNA3.1 (+) expression vector respectively, the recombinant plasmids were named pcDNA3.1 (+)-P and pcDNA3.1 (+)-NP, Recombinant plasmids were transfected into 293 and BHK-21 cells respectively and were detected using IE and Western blot analysis. RESULTS: Expression of P, NP genes were detected and confirmed by the IE and WB analysis. CONCLUSION: The recombinant eukaryotic plasmids pcDNA3. 1(+)-P, pcDNA3.1 (+)-NP were expressed in 293 and BHK-21 cells successfully. This research may be helpful for further study of reverse genetics and functional genome of NDV. PMID- 20848856 TI - [Development of new methods for the diagnosis of nasopharyngeal carcinoma]. AB - OBJECTIVE: Development of new methods, ELISA and immunostrip test, for the diagnosis of nasopharyngeal carcinoma. METHODS: The engineering purified antigens coat plate or absorb on nitrocellulose filter. The plate and diagnostic strips carrying antigens were used for detection of IgG antibody in the sera from nasopharyngeal carcinoma patients and outpatients patients. RESULTS: 127 cases sera from nasopharyngeal carcinoma patients were parallel detected TK/IgG antibody by ELISA and immunostrips. The TK/IgG antibody are all positive in the 127 cases of nasopharyngeal carcinoma patients. 55 cases show positive by ELISA, 58 cases positive by immunostrips in 247cases sera from outpatient. The antibody positive rate to early antigen p54 lower then to TK. Conclusion ELISA and imuunostrips are sensitive and specific means for detection of the IgG antibody to TK of EBV and the diagnosis of nasopharyngeal carcinoma. PMID- 20848857 TI - [The study of the sensitive and specificity on HBV DNA replication by HBV-lP detecting]. AB - OBJECTIVE: To detect HBV-LP and HBV DNA of the patients with hepatitis B, and to study the sensitive and specificity of HBV-LP detecting and its evaluate on for clinical application. METHODS: The ELISA was used for HBV-LP detecting and RT-PCR for HBV DNA detecting. RESULTS: The sensitive and specificity of HBV-LP and HBV DNA were 64.89%, 99.68%, 60.63% and 100% respectively (P > 0.05); +LR, -LR were 202.78, 60.63, 0.3522 and 0.3937, and there were significance between +LR of the detecting (P < 0.005). CONCLUSION: The sensitive and specificity of HBV-LP and HBV DNA detecting are considerable, +LR of HBV-LP are higher comparing HBV DNA. The HBV-LP is better serology index for detecting replication of HBV DNA. PMID- 20848858 TI - [Study on the knowledge, behavior and attitude of influenza A (H1N1) among residents in Shuangqiao District, Chengde city]. AB - OBJECTIVE: To understand the the residents' knowledge, behavior and attitude of influenza A (H1N1) in Shuangqiao District of Chengde city, and provide the basis for making proper strategies of health education, prevention and control on influenza A (H1N1). METHODS: 211 residents from 1 community and 1 village of Shuangqiao District were selected to participate the questionnaire interview with multi-stage clustering sampling. RESULTS: 97.6% of the interviewed had received some kind of information on influenza A (H1N1); Total awareness rate of influenza A (H1N1) knowledge was 58.5%, which increased with the level of education and varied among diverse occupations; 48.2% of respondents conceded that their lives was affected by the influenza A ( H1N1) in some degree, and 9% of selected residents believed that there would be a severe pandemicity in this winter, while 7% of respondents didn't consider any form of preventive methods in the future; 78% of respondents expressed their wishes to be vaccinated, but 11.0% of respondents refused to received inoculation explicitly; on the issue of assessment on services provided by governments and health facilities, 93% of respondents expressed their satisfaction hierarchically. Conclusion Residents in Shuangqiao District lacked of comprehensive knowledge of influenza A (H1N1), and some specific health education should be carried out. PMID- 20848859 TI - [Virological characteristics of pandemic (H1N1) 2009 influenza virus]. AB - In the spring of 2009, a novel swine-origin H1N1 virus, whose antigenicity is quite different from those of seasonal human H1N1 strains, emerged in Mexico and readily transmitted and spread among humans, resulting in the first influenza pandemic in the 21st century. This novel H1N1 virus was shown to be a triple reassortant comprising genes derived from avian, human, and swine viruses. Here, we review our current knowledge of this pandemic influenza virus and discuss future aspects of the pandemic. PMID- 20848860 TI - [Clinical and sociological prospectives on pandemic (H1N1) 2009]. AB - A new pandemic influenza A (H1N1) virus has emerged and rapidly spread throughout the world. The clinical and pathological findings associated with severe illness in Pandemic (H1N1) 2009 and the risk factors are similar to the high pathogenic avian influenza (H5N1). The effective treatment methods for severe influenza in Pandemic (H1N1) 2009 could strongly refer to the treatment method for human H5N1 infection. In this article, the experiences, the investigation and our collaboration studies for Pandemic (H1N1) 2009 in Mexico and Avian Influenza (H5N1) in Vietnam and the examination for the past pandemic influenza will be described. The effective treatments for critical pneumonia caused by influenza will be discussed from the medical, regional and global point-of-view which can be applied to any type of pandemic influenza. PMID- 20848861 TI - [Looking back upon the confusion of avian, swine, and pandemic influenza]. AB - "Avian influenza", "swine influenza", and "new influenza" are not the names of disease but "influenza" in humans. The preparedness for pandemic influenza should be based on the measures how to control the seasonal influenza that causes thousands of deaths and hundreds of encephalopathy every year in Japan. PMID- 20848862 TI - [Survival strategies of human norovirus]. AB - Human norovirus is a mutatable non-enveloped RNA virus capable of causing acute gastroenteritis in humans. Thus far, no experimental systems can propagate this virus in large amounts. Recent progresses in viral genomics and bioinformatics have led to a better understanding of molecular evolution of this virus in human populations. In addition, progresses in studies of the related noroviruses, those are replicable in laboratory systems, have led to a rapid accumulation of information on structural biology of norovirus. Furthermore, progresses in public health and water environment researches have led to a better understanding of viral ecology. In this review, I will first summarize fundamental characteristics of norovirus and its molecules. Then, I will summarize structure and molecular evolution of norovirus GII/4 subtype, which is now responsible for majorities of norovirus outbreaks in the world. Finally I will discuss survival strategies of human norovirus in nature by integrating the information. PMID- 20848863 TI - [Toward the elimination of rotavirus gastroenteritis by universal vaccination]. AB - Rotavirus is the most important cause of severe gastroenteritis in children worldwide, and is most effectively controlled by vaccines. The Strategic Advisory Group of Experts (SAGE) of the World Health Organization (WHO) recommended, in 2009, the inclusion of rotavirus vaccination of infants into all national immunization programs. Two, live, orally-administrable vaccines are licensed globally. They are Rotarix, a G1P[8] monovalent, human rotavirus-based vaccine (GlaxoSmithKline), and RotaTeq, a pentavalent, bovine-human reassortant vaccine (Merck). Although the two vaccines are very different in antigenic composition and administration schedule, they are almost equally safe with respect to intussusception and 90-100% efficacious against severe rotavirus diarrhea. Countries where either vaccine was introduced into the national childhood immunization program have witnessed not only a drastic decrease in the number of rotavirus hospitalizations but a near 50% reduction in the number of all-cause diarrhea hospitalizations. Rotavirus diarrhea, an emerging infectious disease because of its discovery in 1973, may now be among vaccine preventable diseases. PMID- 20848864 TI - [The lost decade of global polio eradication and moving forward]. AB - The Global Polio Eradication Initiative was aimed to eradicate poliomyelitis by the year 2000, however, polio eradication is still not in sight even in 2010, over 10 years after the initial target date. In 2010, indigenous transmission of wild polioviruses has been interrupted throughout the world except four countries, Afghanistan, Pakistan, India, and Nigeria. Despite the intense use of monovalent oral polio vaccines, type 1 and type 3 wild polioviruses still circulate in the four remaining polio-endemic countries, and multiple importations of wild polioviruses have also occurred extensively from Nigeria and India to a number of previously polio-free countries in Africa, Asia, and Europe. Furthermore, the emergence of type 2 vaccine-derived polioviruses has raised concerns about low level of immunity against type 2 poliovirus in some polio endemic areas like Nigeria and India. On the other hand, operational improvements in 2009 were reported in high-risk states in northern Nigeria and transmission of type 1 and type 3 polioviruses in Nigeria is markedly declining from 2009 to 2010. Moreover, bivalent oral polio vaccine containing Sabin 1 and Sabin 3 strains has been introduced in 2010 as a promising tool to improve and simplify the supplemental immunization activities in high-risk areas. Although there was no apparent decline in the annual number of polio cases in 2000-2009 globally, it would be critical to review our experience during "the lost decade of global polio eradication" to move forward into the final stage of global polio eradication. PMID- 20848865 TI - [Progress towards the 2012 measles elimination goal in Japan]. AB - The WHO Western Pacific Regional Office including Japan sets 2012 as the target year of the measles elimination. Japan notified "National Measles Elimination Plan in December 2007" aiming at being eliminate measles from the country by 2012. In 2009, total 741 cases (5.80 per 1,000,000 population) were reported (as of January 7, 2010). It was a remarkable decrease compared with 11,015 cases in 2008. However, the vaccination rate as of the end of 2008 fiscal year (the end of March) doesn't reach 95%. The first vaccination rate was 94%, and the second vaccinations for age groups of 5-6 years, 12-13 years and 17-18 years were 92%, 85%, and 77%, respectively. To prevent the spread of measles and eliminate in Japan, the whole nation recognizes that measles is a serious illness related to the life, and the department of the public health, the education, the medical units, and the research laboratories make an effort aiming at the goal for measles elimination is necessary. PMID- 20848866 TI - [Evaluation of alum-adjuvanted whole virus influenza vaccine and future aspects of influenza A (H1N1) 2009 vaccine]. AB - For preparedness of H5N1 pandemic, several types of influenza prototype vaccine have been developed in several countries. Alum-adjuvanted whole virus influenza vaccine, which has been developed in Japan, had excellent priming effect after two doses, and the third shot of the heterologous strain to the subjects primed two years previously elicited strong and broad cross immunity. Moreover, solicited local and general reactions were acceptable. However, influenza A (H1N1) 2009 virus, which had much different antigenicity from A Russia lineage, was detected in April 2009 and developed pandemic. According to clinical studies of (H1N1) 2009 monovalent vaccine in adults, split vaccine could induce appropriate secondary immune responses after one dose. These results suggested that adults had immune memory to (H1N1) 2009 virus, and that vaccination strategy to this virus was efficient by using seasonal influenza vaccination strategy. Additionally, since WHO speculates (H1N1) 2009 virus could be endemic in near future, the (H1N1) 2009 virus-derived strain is included in the 2010/11 seasonal influenza vaccine. PMID- 20848867 TI - [Direct cytopathic effects of particular hepatitis B virus genotypes in immunosuppressive condition]. AB - Little is known about the direct cytopathic effect of hepatitis B virus (HBV) and its association with particular viral genotype or genetic mutation. In some immunosuppressed chronic HBV patients who had liver transplantation or HIV coinfection, high viremia and liver fibrosis may occur. These findings suggest that hepatic injuries could arise in the absence of a mature immune system and the difference of genotype and/or specific mutation would affect cytopathic potential of the virus. We investigate HBV genotype-related differences in viral replication, antigens expression and histopathology using in vitro replication model or uPA/SCID mice harboring human hepatocytes, demonstrating that different HBV genotypes and even particular mutation are associated with different virological and histopathological characteristics. Infection with HBV/C2 as well as PC mutant of the HBV/B1 in immunosuppressive conditions can induce direct cytopathic effect in "humanized" part of the murine liver. PMID- 20848868 TI - [Advances in research on HCV replication and virion formation]. AB - Hepatitis C virus (HCV) establishes a persistent infection and is recognized as a major cause of chronic liver diseases worldwide. Although much work remains to be done regarding the viral life cycle, significant progress has been made with respect to the molecular biology of HCV, especially the viral genome replication and virion formation. A variety of host cell factors, which play roles in replication of the viral genome RNA, have been identified. Involvement of lipid droplet, lipid metabolism and the viral nonstructural proteins in the production of the infectious particles has also been revealed. PMID- 20848869 TI - [Cell culture system for hepatitis E virus]. AB - Early studies reported propagation of hepatitis E virus (HEV) in primary hepatocytes or several established cell lines, but replication was inefficient. Recently, using inocula comprised of fecal suspensions with high loads of HEV, originally obtained from Japanese patients who contracted domestic infection of genotype 3 HEV (the JE03-1760F strain, 2.0 x 10(7) copies/ml) or genotype 4 HEV (the HE-JF5/15F strain, 1.3 x 10(7) copies/ml), we developed an efficient cell culture system for HEV in PLC/PRF/5 and A549 cells, which yielded the highest HEV load of 10(8) copies/ml in the culture supernatant, and we successfully propagated six or more generations in serial passages of culture supernatant. In addition, we constructed a full-length infectious cDNA clone (pJE03-1760F/wt) of the JE03-1760F strain, which can replicate efficiently in PLC/PRF/5 and A549 cells. Using a derivative ORF3-deficient (delta ORF3) mutant, we demonstrated that the ORF3 protein of HEV is responsible for virion egress from infected cells and is present on the surface of released HEV particles, which is associated with lipids. Various HEV strains in blood circulation were also propagated efficiently in PLC/PRF/5 and A549 cells. Our in vitro cell culture system can be used for propagation of a wide variety of HEV strains in feces and sera from various infected patients, allowing extended studies on viral replication specific to different HEV strains. PMID- 20848870 TI - [Envelope virus assembly and budding]. AB - For many enveloped viruses, viral matrix and retroviral Gag proteins are able to bud from the cell surface by themselves in the form of lipid-enveloped, virus like particles (VLPs), suggesting that these proteins play important roles in viral assembly and budding. The major three-types of L-domain motifs, PPxY, P(T/S)AT, and YP(x)(n)L have been identified within these proteins. Many viruses have been shown to commonly utilize cellular ESCRT pathway via direct interaction between the L-domains and the components of the pathway for efficient viral budding. However, for many enveloped viruses, L-domain motifs have not yet been identified, and the involvement of the ESCRT pathway in virus budding is still unknown. Among such viruses, we have been focusing on Sendai virus (SeV) and shown that (i) SeV M functionally and physically interact with a component of the ESCRT complex, Alix/AIP1, although budding of M-VLPs does not seem to be dependent on the pathway; (ii) one of the accessory proteins of SeV, C, also interact with Alix/AIP1, and recruit it to the plasma membrane for efficient budding of M-VLPs; (iii) the C protein regulate balance of viral genome and antigenome RNA synthesis for optimized production of infectious virus particles. These results demonstrate a unique mechanism for budding of SeV as well as a novel mechanism of regulated synthesis of viral genome RNAs for efficient production of infectious particles. PMID- 20848871 TI - A 7-year prospective study of sense of humor and mortality in an adult county population: the HUNT-2 study. AB - OBJECTIVE: To prospectively explore the significance of sense of humor for survival over 7 years in an adult county population. METHODS: Residents in the county of Nord-Trondelag, Norway, aged 20 and older, were invited to take part in a public health survey during 1995-97 (HUNT-2), and 66,140 (71.2 %) participated. Sense of humor was estimated by responses to a cognitive (N = 53,546), social (N = 52,198), and affective (N = 53,132) item, respectively, taken from the Sense of Humor Questionnaire (SHQ). Sum scores were tested by Cox survival regression analyses applied to gender, age, and subjective health. RESULTS: Hazard ratios were reduced with sense of humor (continuous scale: HR = 0.73; high versus low by median split: HR = 0.50) as contrasted with increase of HR with a number of classical risk factors (e.g., cardiovascular disease: HR = 6.28; diabetes: HR = 4.86; cancer: HR = 4.18; poor subjective health: HR = 2.89). Gender proved to be of trivial importance to the effect of sense of humor in survival. Subjective health correlated positively with sense of humor and therefore might have presented a spurious relation of survival with humor, but sense of humor proved to reduce HR both in individuals with poor and good subjective health. However, above age 65 the effect of sense of humor on survival became less evident. CONCLUSION: Sense of humor appeared to increase the probability of survival into retirement, and this effect appeared independent of subjective health. Age under 65 mediated this effect, whereas it disappeared beyond this age. PMID- 20848872 TI - Life stress and atherosclerosis: a pathway through unhealthy lifestyle. AB - OBJECTIVE: To examine the relationship between a general measure of chronic life stress and atherosclerosis among middle aged adults without clinical cardiovascular disease via pathways through unhealthy lifestyle characteristics. METHODS: We conducted an analysis of The Multi-Ethnic Study of Atherosclerosis (MESA). The MESA collected in 2000 includes 5,773 participants, aged 45-84. We computed standard regression techniques to examine the relationship between life stress and atherosclerosis as well as path analysis with hypothesized paths from stress to atherosclerosis through unhealthy lifestyle. Our outcome was sub clinical atherosclerosis measured as presence of coronary artery calcification (CAC). RESULTS: A logistic regression adjusted for potential confounding variables along with the unhealthy lifestyle characteristics of smoking, excessive alcohol use, high caloric intake, sedentary lifestyle, and obesity yielded no significant relationship between chronic life stress (OR 0.93, 95% CI 0.80-1.08) and CAC. However, significant indirect pathways between chronic life stress and CAC through smoking (p = .007), and sedentary lifestyle (p = .03) and caloric intake (.002) through obesity were found. CONCLUSIONS: These results suggest that life stress is related to atherosclerosis once paths of unhealthy coping behaviors are considered. PMID- 20848873 TI - It's not over when it's over: long-term symptoms in cancer survivors--a systematic review. AB - BACKGROUND: The number of cancer survivors is steadily increasing. Following completion of primary cancer treatment and many years thereafter, specific symptoms continue to negatively affect cancer survivors. The purpose of this article is to review the evidence of symptom burden following primary treatment for cancer in survivors of the most common types of cancer (breast, gynecological, prostate, and colorectal). METHODS: A systematic review of literature published between the years 2000-2008 that reported late-effects and/or long-term psychosocial symptoms associated with cancer survivorship post completion of primary cancer treatment was conducted. The symptoms include physical limitations, cognitive limitations, depression/anxiety, sleep problems, fatigue, pain, and sexual dysfunctions. RESULTS: Symptom burden associated with cancer survivorship was consistent among the four most common types of cancer (breast, gynecological, prostate, and rectal/colon), despite various types of treatment exposure. Generally, across the cancer groups, depressive symptoms, pain, and fatigue were commonly found in cancer survivors. CONCLUSIONS: Based on longitudinal and cross-sectional evidence, cancer survivors can experience symptoms for more than 10 years following treatment. These symptoms were present in survivors of all four cancer types who underwent a wide variety of treatment. The results indicate that these symptoms should be evaluated and managed to optimize long-term outcomes. PMID- 20848874 TI - The quest to solve the cancer survivorship puzzle: starting at the edges. PMID- 20848875 TI - Screening for major depression in post-myocardial infarction patients: operating characteristics of the Beck Depression Inventory-II. AB - OBJECTIVE: To assess the operating characteristics of the Beck-Depression Inventory-II (BDI-II) and the BDI-II cognitive subscale (BDI-II-cog) in screening for major depression (MDD) in post-myocardial infarction (MI) patients. METHODS: Between October 2003 and July 2005, 131 post-MI patients admitted to an urban academic medical center completed the BDI-II and a semi-structured interview for depression within 72 hours of symptom onset. Sensitivity, specificity, positive and negative predictive values, overall correct classification, and likelihood ratios for various cutoff values on both scales were evaluated by comparing scores to interview diagnosis of MDD. Receiver-operator curves (ROC) were also calculated and area under the curve (AUC) measured. RESULTS: The optimal cutoff value for the BDI-II was > or = 16, with a sensitivity of 88.2% and a specificity of 92.1%. Cutoff values of > or = 3 or > or = 4 were both acceptable for the BDI II-cog (sensitivity = 88.2% and 82.4%, respectively; specificity = 81.6% and 88.6 %, respectively). AUC was 0.96 for the BDI-II and 0.89 for the cognitive subscale. CONCLUSIONS: Effective depression screening is important in post-MI patients because of depression's independent association with morbidity and mortality following MI. Our results suggest that the BDI-II and its cognitive subscale are effective tools for screening for MDD in post-MI patients. PMID- 20848876 TI - Hepatitis C and depressive symptoms: psychological and social factors matter more than liver injury. AB - OBJECTIVE: Given that the hepatitis C virus (HCV) crosses the blood-brain barrier, biological factors are commonly blamed for the high rates of mood disturbance in HCV-infected patients. However, no study assessing the potential contribution of psychosocial factors to depression in HCV has yet been conducted. METHODS: A cross-sectional survey of 65 patients was undertaken to identify biological, psychological, and sociological contributions to depression. Biological, psychological, and sociological variables were tested for their association with depressive symptomatology as measured by the BDI-II. Separate analyses were conducted on health-related quality of life (HRQOL), as measured by the SF-36, in order to confirm findings in previous work. RESULTS: Psychosocial variables assessed in the study, such as less social functioning, less religious faith, less ability to work, less salary, personal suicide attempt, worse reaction to diagnosis, and feeling "stressed out" were all associated with higher depression scores and lower HRQOL. Biological variables, including viral load, liver enzyme levels, INR, and stage of liver fibrosis on biopsy, were not associated with higher depression or lower HRQOL. CONCLUSIONS: The amount of disease as measured by laboratory abnormalities such as viral load, liver function tests, liver biopsy, and INR do not provide much useful information about a patient's depressive symptoms. Instead, these depressive symptoms are more influenced by psychological and social factors. Psychosocial support may therefore be beneficial to HCV patients. PMID- 20848877 TI - Factors predicting adherence with psychiatric follow-up appointments for patients assessed by the liaison psychiatric team in the emergency department. AB - BACKGROUND: Several factors may predict adherence with psychiatric follow-up appointment for patients seen in the emergency department (ED) by liaison psychiatric teams. Awareness of these factors would allow for interventions targeted at vulnerable groups. AIM: To examine the factors which could predict adherence with psychiatric follow-up appointments for patients assessed in the ED by the liaison psychiatric team. METHODS: The records of all patients assessed over a 3-month period by the liaison psychiatric team in the emergency department of Beaumont Hospital who were then referred for follow-up to their community mental health team were examined for relevant demographic and clinical variables. Phone contact was then made with the teams to which patients had been referred, to confirm the appointments made and if the patients had attended for their follow-up appointment. The data was analyzed with SPSS (version 17) using descriptive statistics and logistic regression. RESULTS: Overall, 56% of the patients were found to have attended their follow-up appointments. Being previously known to psychiatric services was the only statistically significant predictor of adherence with out-patient appointments; with an odds ratio of 7 and p-value of 0.034 when controlling for other variables. CONCLUSION: Patients who are not known to psychiatric services prior to assessment in the emergency department may need a more proactive outreach if compliance with psychiatric follow-up appointments is to be improved. PMID- 20848878 TI - Survey cover pages: to take or not to take. AB - In survey research, the elements of informed conset, including contact information for the researchers and the Institutional Review Board, may be located on a cover page, which participants are advised that they may take. To date, we are not aware of any studies examining the percentage of research participants that actually take these cover pages, which was the purpose of this study. Among a consecutive sample of 419 patients in an internal medicine setting, 16% removed the cover page. There were no demographic predictors regarding who took versus did not take the cover page. PMID- 20848879 TI - A new ranavirus isolated from Pseudacris clarkii tadpoles in playa wetlands in the southern High Plains, Texas. AB - Mass die-offs of amphibian populations pose a challenging problem for conservation biologists. Ranaviruses often cause systemic infections in amphibians and, in North America, are especially virulent and lethal to larvae and metamorphs. In this paper we describe a novel ranavirus isolate as well as the first recorded occurrence of ranavirus in the southern High Plains of Texas and in associated populations of the spotted chorus frog Pseudacris clarkii. The breeding sites were playas, that is, wetlands that fill via isolated thunderstorms that can occur infrequently; thus, not every playa has water or breeding amphibians annually. We did not detect ranavirus in sympatric anurans, but other reports document ranaviruses in Pseudacris spp. elsewhere. The occurrence of multiple isolates of ranavirus in a number of Pseudacris species suggests that this genus of frogs is highly susceptible to ranaviruses and may experience exceptionally high mortality rates from infection. Thus, the virus may contribute to substantial seasonal population declines and low seasonal recruitment, with negative impacts on populations of breeding adults in successive years. PMID- 20848880 TI - A comparison of heavy metal concentrations and health assessment in Asian clams Corbicula fluminea from Florida and North Carolina. AB - The Asian clam Corbicula fluminea was introduced into the United States in 1938 and has since become established in much of the country. This invasive species can compete with native bivalves and compromise industrial water supply systems and power plants. Numerous studies have examined bivalves as bioindicators. The purpose of this study was to compare the heavy metal concentrations of the hard and soft tissues of specimens from Florida and North Carolina and to assess the clams' health by microscopic examination of their soft tissues. Although the sample size was small, this study suggests that the Asian clams from the watersheds examined are healthy and that they accumulate lower levels of heavy metals than have been reported for clams from other, more polluted aquatic environments. PMID- 20848881 TI - Cloning, expression, and immunogenicity of Flavobacterium columnare heat shock protein dnaJ. AB - The Flavobacterium columnare heat shock protein (HSP) gene dnaJ* was isolated, cloned, expressed, and used as an antigen in a recombinant vaccine strategy for channel catfish Ictalurus punctatus. The F. columnare dnaJ* sequence was obtained from genomovars I and II and showed intraspecies variability. Recombinant protein was expressed and purified from Escherichia coli cultures and injected intraperitoneally (12 microg of purified DnaJ/fish) into fingerling channel catfish. In addition, induced (expressing the recombinant DnaJ) and uninduced (no recombinant protein being produced) E. coli cultures were also used to immunize fish. At 28 d postimmunization, antibody response was evaluated and the fish were challenged with F. columnare. A specific immune response against DnaJ was observed in fish immunized with DnaJ or E. coli cultures expressing DnaJ. No protection against the disease, however, was observed in F. columnare-challenged fish that had been immunized with DnaJ. Some level of protection was observed in fish immunized with uninduced and induced E. coli lysates. Although HSPs have been shown to be immunodominant and good candidates for subunit vaccines in other animals, DnaJ failed to protect against columnaris disease in channel catfish. PMID- 20848882 TI - The effects of Myxobolus cerebralis on Apache and Gila trout in laboratory exposures. AB - Whirling disease has been implicated in salmonid population declines in several western states. To determine the risk of a species or strain of salmonid to whirling disease it is critical to establish its relative susceptibility to Myxobolus cerebralis infection. Gila trout Oncorhynchus gilae and Apache trout Oncorhynchus gilae apache were exposed to various doses of M. cerebralis triactinomyxons (TAMs) in laboratory experiments. In trials conducted in consecutive years, fish were exposed to TAMs in doses ranging from 25 to 2,000/fish at ages ranging from 66 to 201 d posthatch (dph). All fish were held for 900 degree-days, and then the infection intensity of each fish was determined by histological examination. In 2002, 98% of the Gila trout died during exposure or within 48 h postexposure. Seventy-four percent of the Apache trout died before the end of the 90-d study period. Those that survived the entire study period had an average histological score of more than 4.0. In subsequent trials, the TAM dosage was decreased to 25-1,000/fish. Also, the age of the fish was increased from 66-72 dph to 89-201 dph. The survival rate increased from 16.0% to 49.1%. Average histological grades ranged from 1.6 to 4.8. Based on this data, it can be concluded that both Apache and Gila trout are highly susceptible to M. cerebralis in laboratory trials. PMID- 20848883 TI - Neurofibroma in a striped mullet: histochemical and immunohistochemical study. AB - A case of neurofibroma is reported in a wild striped mullet Mugil cephalus. Macro and microscopic features are described. The tumor arose on the head as a white grayish, firm mass protruding outwards but covered by the epidermis. The neoplastic tissue showed well-defined borders and was encapsulated; it was predominantly composed of elongated cells with ellipsoid, hyperchromatic nuclei and pale cytoplasm. The cells were irregularly arranged; in the context of the neoplastic proliferation, these cells were usually densely packed, sometimes forming parallel arrays, but without distinctive nuclear palisades. The diagnosis of neurofibroma is also supported by the positive immunostaining for S-100 and vimentin as well as by the negative calretinin reaction. PMID- 20848884 TI - Potential for largemouth bass virus to associate with and gain protection from bacterial biofilms. AB - Quantitative PCR (qPCR) was used to investigate whether largemouth bass virus (LMBV) can exist within biofilms. Suspended LMBV was partitioned into either laboratory-grown Pseudomonas fluorescens biofilms or pond-grown, mixed-population biofilms. Biofilm-entrapped LMBV retained infectivity when tested on epithelioma papillosum cyprini tissue culture cells. The LMBV associated with P. fluorescens biofilms were resistant to disinfection by sodium hypochlorite and an iodine based compound (betadine) but were susceptible to ethanol. Largemouth bass virus was not detected in biofilms or water from ponds that had previously contained LMBV-positive fish, suggesting either that the viral concentrations were below the detection limit of qPCR or that the fish represented the main LMBV reservoir. This study illustrates the potential for LMBV to associate with bacterial biofilms and thereby gain protection from some chemical disinfectants. PMID- 20848885 TI - Preliminary amphibian health survey in the Delaware Water Gap National Recreation Area. AB - To detect aquatic animal diseases of national concern, 111 individual amphibians, including wood frogs Rana sylvatica (28), spring peepers Pseudacris crucifer (35), red-spotted newts Notophthalmus viridescens (41), and gray tree frogs Hyla versicolor (7), were sampled at seven different sites in the Delaware Water Gap National Recreation Area (DGNRA), Pennsylvania, from June 14 to July 19, 2007. These samples were screened for Batrachochytrium dendrobatidis and viral pathogens at the U.S. Fish and Wildlife Service's Fish Health Center in Lamar, Pennsylvania. Cell culture revealed cytopathic effect (CPE) in two cell lines (epithelioma papillosum cyprini and fathead minnow) inoculated with liver, kidney, and spleen samples from one sample pool of Notophthalmus viridescens (4 individuals). Polymerase chain reaction was conducted on cell culture supernatant exhibiting CPE. Sequencing revealed the resulting product to be identical to frog virus 3, a ranavirus in the family Iridoviridae. Upon gross examination, two Notophthalmus viridescens were found to exhibit dermal swelling and lethargy. Histological examination of these lesions revealed involvement by an Ichthyophonus sp. In summary, two pathogens of concern were found in amphibians in the DGNRA: a ranavirus with a major capsid protein sequence identical to that of frog virus 3 and a mesomycetozoan, Ichthyophonus sp. Although no epizootic die offs were observed during this health survey, the results warrant further research into the distribution of these pathogens throughout the DGNRA because they have the potential to cause mass mortalities in amphibians. PMID- 20848886 TI - Efficacy of florfenicol for control of mortality caused by Flavobacterium columnare infection in channel catfish. AB - The studied in channel catfish Ictalurus punctatus fingerlings held in 80-L aquaria. Nonabraded fish were challenged by immersion on day 0. Thirty 80-L tanks were randomly assigned in equal numbers to two treatment groups, one in which fish were fed a commercial diet without florfenicol (unmedicated feed) and one in which they were fed a diet containing 10 mg of florfenicol/kg of body weight (medicated feed) for ten consecutive days. Mortality was monitored during the treatment period and a 14-d posttreatment observation period. At the end of the posttreatment period, all fish were euthanized, examined for gross lesions, and cultured for F. columnare. Significantly fewer fish fed the medicated diet died (8.0%) than fish fed the unmedicated diet (54.2%). Flavobacterium columnare was cultured from 15.0% of the medicated fish, compared with 68.9% of the unmedicated fish. The gross lesions in the fish were consistent with columnaris disease, and F. columnare was cultured from 99.5% of the dead fish. No differences were observed in weight gain and appetence between the medicated and unmedicated groups. For the F. columnare strain used in this study, the minimal inhibitory concentration of florfenicol ranged from 0.5 to 1.0 mg/mL in the 30 bacterial cultures obtained from infected fish, and the mean disk diffusion zone of inhibition was 40 mm. There were no adverse effects among the medicated fish. Administration of florfenicol at a dosage of 10 mg/kg body weight for 10 d was efficacious and safe for the control of mortality from F. columnare infection in channel catfish. PMID- 20848887 TI - Hematological and plasma biochemical parameters of aquarium-maintained cownose rays. AB - There is generally a dearth of information involving reference ranges of health variables for numerous elasmobranch species commonly housed in zoos and aquaria; thus, extrapolation from a few existing elasmobranch studies is commonly used to assess health parameters in these species. The primary objective of this study was to establish baseline complete blood cell count and plasma chemistry reference ranges for captive individuals of the cownose ray Rhinoptera bonasus, an elasmobranch that is widely displayed in zoos and aquaria worldwide. This study was conducted using 18 adult cownose rays currently housed at the Mystic Aquarium and Institute for Exploration in Connecticut. Median blood and plasma values were 550 cells/microL for total white blood cell count; 511,250 cells/microL for total red blood cell count; 31% for packed cell volume; 5.8 g/L for total solids; 2.85 g/dL for total protein; 33 units (U)/L for aspartate aminotransferase; 34 U/L for alkaline phosphatase; 0.2 mg/dL for total bilirubin; 1,155 mg/dL for urea nitrogen; 0.1 mg/dL for creatinine; 0.6 g/dL for albumin; 2.15 g/dL for globulins; 144 mg/dL for cholesterol; 157 mg/dL for triglycerides; 45 mg/dL for glucose; 16.9 mg/dL for calcium; 5.8 mg/dL for phosphorus; 294 mmol/L for sodium; 1.55 mmol/L for potassium; and 270 mmol/L for chloride. Gamma glutamyl transpeptidase, amylase, creatine kinase, and lactate dehydrogenase were below the detectable limits for several samples. In nine samples, alanine aminotransferase levels were below the instrument range (< 4 U/L). No significant differences between sexes were detected. The reference ranges reported in this study should provide a useful guide for routine health monitoring of captive cownose rays. PMID- 20848888 TI - Resistance and protective immunity in Redfish Lake sockeye salmon exposed to M type infectious hematopoietic necrosis virus (IHNV). AB - Differential virulence of infectious hematopoietic necrosis virus (IHNV) isolates from the U and M phylogenetic subgroups is clearly evident in the Redfish Lake (RFL) strain of sockeye salmon Oncorhynchus nerka. In these fish, experimental immersion challenges with U isolates cause extremely high mortality and M isolates cause low or no mortality. When survivors of M virus immersion challenges were exposed to a secondary challenge with virulent U type virus they experienced high mortality, indicating that the primary M challenge did not elicit protective immunity. Delivery of a moderate dose (2 x 10(4) plaque-forming units [PFU]/fish) of virus by intraperitoneal injection challenge did not overcome RFL sockeye salmon resistance to M type IHNV. Injection challenge with a high dose (5 X 10(6) PFU/fish) of M type virus caused 10% mortality, and in this case survivors did develop protective immunity against a secondary U type virus challenge. Thus, although it is possible for M type IHNV to elicit cross protective immunity in this disease model, it does not develop after immersion challenge despite entry, transient replication of M virus to low levels, stimulation of innate immune genes, and development of neutralizing antibodies in some fish. PMID- 20848889 TI - [Effects of electroacupuncture on the expression of corticotropin-releasing factor (CRF) family and CRF receptor 1 in traumatic injury rats]. AB - OBJECTIVE: To observe the effects of electroacupunture (EA) on the abnormal hypothalamus-pituitary-adrenal (HPA) axis and the expression of hypothalamic corticotropin-releasing factor (CRF) peptides family and CRF receptor (R)1 mRNA in traumatized rats, so as to study its underlying mechanism in improving traumatic injury. METHODS: Forty male Sprague-Dawley rats were randomly divided into normal control group (n=10), normal+ EA group (n=10), surgical trauma (model) group (n=10), and model+ EA group (n=10). Traumatic injury model was established by performing an exploratory laparotomy in the rats under anesthesia. EA (2 Hz/15 Hz, 1-2 mA) was administered for 30 min via two stainless steel needles inserted in "Zusanli" (ST 36) and "Sanyinjiao" (SP 6). Serum adrenocorticotropic hormone (ACTH) , corticosterone (Cort), luteinizing hormone (LH) and testosterone (T) contents were detected by double-antibody radioimmnoassay. Hypothalamic CRF and ORF R1 mRNA expression was assayed by reversed transcription polymerase chain reaction (RT-PCR) technique. RESULTS: The serum ACTH concentration decreased significantly in model group (P < 0.05) compared with those in normal control and normal+ EA groups, and was significantly higher in model+ EA group than that in model group (P < 0.05). No significant difference was found between normal control and normal+ EA groups in serum ACTH levels (P > 0.05). The serum Cort level increased significantly in model group (P < 0.05) compared with those in normal control and normal + EA groups, and was obviously lower in model+EA group than that in model group (P < 0.05). While serum LH and T contents had no apparent changes in the four groups (P > 0.05). The expression of hypothalamic CRF mRNA decreased significantly in model group (P < 0.05) compared with that in normal control group, but increased significantly in model + EA group (P < 0.05) compared with that in model group. However, no significant difference was found between normal control and normal + EA groups in the CRF mRNA expression level. The expression of hypothalamic Ucn 1 mRNA increased significantly in model group than that in normal control group (P < 0.05), and decreased considerably in model+ EA group than that in model group (P < 0.05). There were no significant changes in the expression of hyp, thalamic Ucn 2 mRNA, Ucn 3 mRNA and CRF R1 mRNA in the four groups (P > 0.05). CONCLUSION: EA of "Zusanli" (ST 36) and "Sanyinjiao"(SP 6) can improve surgical trauma induced HPA disorders, which is probably related to its effects in upregulating CRF mRNA expression and downregulating Ucn 1 mRNA expression in the hypothalamus. PMID- 20848890 TI - [Effect of acupuncture of "Taixi" (KI 3) on protein expression in the renal tissues of healthy rats]. AB - OBJECTIVE: To observe the changes of renal protein expression after electroacupuncture (EA) of "Taixi" (KI 3) of the Kidney Meridian of Foot-Shaoyin in healthy rats so as to explore the relationship between KI 3 and the Kidney. METHODS: Twelve adult male Wistar rats were randomly divided into normal control group (n=6) and EA group (n=6). EA (2 Hz/100 Hz, 2-4 mA) was applied to bilateral KI 3 for 20 min, once a day for 7 days. Under anesthesia, the rats were perfused transcardiacally with ice saline and their kidneys removed for extracting the total proteins and assaying the differentially expressed proteins with two dimensional gel electrophoresis (2-DE), Image Master 2 D Platinum Software and matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) MALDI TOF-MS, respectively. RESULTS: Image Master 2 D Platinum Software analysis showed that after EA, 9 protein points of the kidney tissues expressed differentially above 3-fold in comparison with control group were upregulated, 2 of which were identified to be NAD-dependent isocitrate dehydrogenase and Quinone reductase. No downregulated differentially expressed proteins were found in the kidney tissues. CONCLUSION: EA of "Taixi" (KI 3) can increase the expression of NAD-dependent isocitrate dehydrogenase and Quinone reductase in the kidney tissue, suggesting an increase of energy metabolism after EA and a close correlation between the KI 3 (source-point) and the kidney. PMID- 20848891 TI - [Effect of electroacupuncture on the proliferation of stem cells in the subependymal zone of the lateral ventricle of the brain in rats with hyperlipemia and cerebral ischemia]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) and acupuncture (A) on the proliferation of stem cells in the subependymal zone (SPZ) of the lateral ventricle and the frontal lobe cortex in hyperlipemia(HL) combined with cerebral ischemia (CI) rats. METHODS: A total of 72 male SD rats were randomized into control, HL, HL+EA, CI, CI+A, HL+CI, HL+CI+EA I and HL+CI+EA II groups (n=9 /group). HL model was established by feeding the animals with high fat forage for 6 weeks and CI model was established by FeCl3-induced occlusion of the unilateral middle cerebral artery. EA was applied to "Sanyinjiao" (SP 6) and "Fenglong" (ST 40) once daily for 17 days for HL+ EA group; and acupuncture to "Baihui" (GV 20) and "Shuigou" (GV 26) once daily for 7 days for CI + A group. For HL+CI+EA I group, EA was applied to SP 6 + ST 40 first before CI, once daily for 10 days, followed by EA of SP 6+ST 40 and acupuncture of GV20+GV26 for 7 days after CI. For HL+CI+EA II group, no treatment was given before CI, then, acupuncture of GV 20 + GV 26 and EA of SP 6 + ST 40 were given once daily for 7 days after CI. The immunoactivity of Nestin and proliferation cell nuclear antigen (PONA) of SPZ was detected by immunohistochemistry. RESULTS: In comparison with normal control group, the numbers of both Nestin and PCNA immunoreaction (IR) positive cells in the dorsolateral extension and the wall of the lateral ventricle of the brain increased significantly in CI and HL+CI groups (P < 0.01). Compared with CI group, the numbers of Nestin and PCNA IR positive cells in the dorsolateral extension and the wall of the lateral ventricle in CI + A group increased considerably (P < 0.01). In comparison with HL+CI group, both Nestin and PCNA IR positive cell numbers in the dorsolateral extension and the wall of the lateral ventricle of the brain in HL+CI+EA I and HL+CI+EA II groups increased significantly (P < 0.01), and the effect of HL+CI+EA I group was markedly superior to that of HL+CI+EA II group in upregulating the numbers of Nestin and PCNA IR positive cells in the aforementioned regions of the lateral ventricle (P < 0.01). No significant differences were found between HL and control groups, and between HL+EA and HL groups in the numbers of Nestin and PCNA IR positive cells in the dorsolateral extension and the wall of the lateral ventricle of the brain (P > 0.05). CONCLUSION: EA can upregulate Nestin and PCNA expression of the dorsolateral extension and the wall of the lateral ventricle of the brain on the ischemic side in rats with CI, and with HL+CI, which may contribute to its effects in promoting the proliferation and migration of neural stem cells in the brain. PMID- 20848892 TI - [Protective effect of "neiguan" (PC 6)-electroacupuncture preconditioning on the myocardium in myocardial ischemia/reperfusion rats]. AB - OBJECTIVE: To investigate the effects of "Neiguan" (PC 6)-electroacupunture (EA) preconditioning on the myocardium and its mast cells in myocardial ischemia/reperfusion (MI/R) rats. METHODS: Eighteen male SD rats were randomly assigned to sham group, model (IR) group and EA group (n=6/ group). MI/R model was established by occlusion of the descending anterior branch of the coronary artery. Blood samples were taken from the femoral vein before MI (T0), EA for 30 min (T1), 30 min after MI (T2), 30 min after MI/R (T3) and 120 min after MI/R (T4) for assaying serum tumor necrosis factor (TNF)-alpha and histamine contents by using ELISA. Serum lactate dehydrogenase (LDH) and creatinkinase isoenzyme (CK MB) levels were measured at T0, T3 and T4 by using an automatic biochemistry analyzer. The infarct size was detected by Evan's blue and tetrazolium chloride (TTC) staining. Myocardial TNF-alpha and histamine contents were detected by ELISA. The percentage of mast cell degranulation was determined by toluidine blue staining. RESULTS: Following MI/R, serum LDH and CK-MB levels at phase T3 and T4, serum TNF-alpha and histamine contents at phase T2 and T3, and myocardial mast cell degranulation rate increased significantly, and myocardial TNF-alpha and histamine contents decreased in model group in comparison with pre-MI/R (P < 0.05). Compared with IR model group, serum LDH and CK-MB levels at phase T3 and T4, myocardial TNF-alpha and histamine contents all decreased significantly (P < 0.05), but serum TNF-al infarct size was remarkably smaller in EA group than that in IR model group (P < 0.05). CONCLUSION: "Neiguan" (PC 6)-EA preconditioning has a cardioprotective effect on the ischemia-reperfusion myocardium by promoting mast cell degranulation. PMID- 20848893 TI - [A reinforcement of acupuncture on the cardiac effect of dobatamine: exhibition of acupoint's functional specificity]. AB - OBJECTIVE: To investigate the functional specificity of acupoint by means of acupoint injection of Dobutamine Hydrochloride (DH). METHODS: Male SD rats were randomized into normal control (NC), EA-Neiguan (PC6) + acupoint injection (AI, EA-PC 6 + AI), EA-Zusanli (ST 36) + AI (EA-ST 36 + AI), and EA-intramuscular injection site (IMIS) + intramuscular injection (EA-IMIS+ IMI) groups,with 8 rats being in each group. EA (2 Hz/15 Hz, 3 mA) was applied to bilateral "Neiguan" (PC 6), "Zusanli "(ST 36) and muscular-injection site for 10 min. DH (a beta1 adrenoceptor agonist) solution (100 microg/kg) was injected intramuscularly into the gluteus maximus after termination of EA intervention. The left ventricular systolic pressure (LVSP), heart rate (HR) and + dp/dt max were recorded before and 2, 5, 15 and 30 min after injection of DH. RESULTS: The values of LVSP, HR and + dp/dt max in EA-PC 6 + AI group were significantly higher than those in NC, EA-ST 36 + AI, and EA-IMIS + IMI groups (P < 0.01) 2 and 5 minutes after EA plus acupoint injection of DH. No significant differences were found between EA-ST 36 + AI and EA-IMIS+ IMI groups in LVSP, HR and +dp/dt max (P > 0.05). After injection of DH for 30 minutes, the values of LVSP, HR and + dp/dt max in EA-PC 6 + AI group were still significantly higher than those in NC group (P < 0.01). CONCLUSION: EA-PC 6+ AI DH is significantly superior to EA-ST 36 + AI DH and EA IMIS+ IMI DH in producing a stronger cardiac excitatory effect and a longer post effect, showing a relative specificity of the acupoint in upregulating cardiac functional activities. PMID- 20848894 TI - [Distribution of the activated acupoints after acute gastric mucosal injury in the rat]. AB - OBJECTIVE: To observe the dynamic distribution of the extravasated Evans Blue (EB) dye points (neurogenic inflammatory response) at the skin after acute gastric mucosal injury (AGMI) and its relation to the related regular acupoints in the locations in rats. METHODS: A total of 70 Wistar rats were randomized into normal control (n=10), normal saline (n=10), and AGMI (n=50) groups. The AGMI group was further divided into 5 h, 2 d, 3 d, 4 d and 5 d subgroups with 10 rats in each. AGMI model was duplicated by intragastric perfusion of diluted hydrochloric acid (HCl, 0.5 mol/L). Evans Blue Dye (50 mg/kg, 50 mg/mL in 0.9% saline) was given to the rats before AGMI modeling. The plasma extravasated EB points at the skin of the whole body were observed after removal of the hair. RESULTS: The extravasated EB points presented a nerve-segmental distribution, with the proportion of the points in the location being 47.5% for "Geshu" (BL 17),58. 82% for "Jizhong" (GV 6), 88.23% for "Pishu" (BL 20), 82.35% for "Weishu" (BL21), 17.64% for "Zhongwan" (CV 12), and 5.88% for "Shangwan" (CV 13), respectively. The plasma extravasation of EB seldom appeared in normal rats and only fewer points were found in rats accepted administration of 0.9% saline. Significant differences were found between model and normal control groups, and between model and normal saline groups in the numbers of the extravasated EB points (P < 0.01, P < 0.05). The number of the extravasated EB points was related to the phase of gastric mucosa injury, being most on the 2nd and 3rd day after modeling and disappearing gradually along with the natural repair of AGMI. CONCLUSION: AGMI promotes the plasma extravasation of EB and the extravasated EB points present a nerve-segmental distribution and have a higher corresponding rate with some acupoints including "Pishu" (BL 20), "Weishu" (BL 21), etc., suggesting an activation of the normally silent acupoints under diseased conditions. PMID- 20848895 TI - [Involvement of the hypothalamus-pituitary-adrenal axis in moxibustion-induced changes of NF-kappaB signaling in the synovial tissue in rheumatic arthritic rats]. AB - OBJECTIVE: To observe the effect of moxibustion of "Shenshu" (BL 23) and "Zusanli"(ST 36) on synovial nuclear factor (NF)-kappaB p65 expression, and plasma adrenocorticotropic hormone (ACTH) and serum cortisol (CS) contents in rheumatic arthritis (RA) rats with adrenalectomy (ADX) so as to study the underlying mechanism in ameliorating RA. METHODS: Fifty male SD rats were randomly divided into control (n=10), model (n=10), moxibustion (n=10), ADX (n=10) and false ADX (n=10) groups according to SPSS-aided random digits table. RA model was established by injecting 0.1 mL Freund's complete adjuvant into the right paw. ADX operation was performed on the sixth day after successful establishment of RA model. Moxibustion was given to "Shenshu" (BL 23) and "Zusanli" (ST 36) from the 7th day on, five moxa cones each session, and once daily for 18 days. Then plasma ACTH and serum CS contents, for which the blood was collected during night, were detected by ELISA, and NF-kappaB p 65 immunoactivity in synovial tissue was detected by immunohistochemistry. RESULTS: In comparison with control group, the foot volumes (swelling degree) of model, moxibustion, ADX, and false ADX groups increased significantly (P < 0.01), while compared with model group, the swelling degrees of moxibustion and false ADX groups were decreased remarkably after the treatment (P < 0.01). No significant difference was found between ADX and model groups in the foot volume (P > 0.05). Compared with control group, plasma ACTH content in RA model group decreased obviously (P < 0.05), while serum CS level and NF-kappaB p 65 immunoactivity increased apparently in model group (P < 0.01). Compared with model group, serum CS contents in moxibustion, ADX and false ADX groups and synovial NF-kappaB p 65 immunoactivity in moxibustion and false ADX groups reduced considerably (P < 0.01, P < 0.05). No significant difference was found between ADX and model groups in synovial NF-kappaB p 65 immunoactivity (P > 0.05). CONCLUSION: Moxibustion treatment can reduce inflammation reactions in RA rats, which is closely associated with its effects in upregulating plasma ACTH, downregulaing serum CS level and synovial NF-kappaB p 65 immunoactivity, and the intact hypothalamus pituitary-adrenal axis (HPAA). PMID- 20848896 TI - [Effect of electroacupuncture at "Ciliao"(BL 32) on c-fos expression in the sacral segment of spinal cord in rats with detrusor hyperreflexia]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Ciliao" (BL 32) on detrusor hyperreflexia and c-fos expression in the sacral segment of spinal cord in rats with spinal cord injury (SCI). METHODS: Thirty-seven adult female Sprague-Dawley rats were randomized into normal control (n=5), SCI model (n=16) and EA (n=16) groups. EA (20 Hz, 3 mA) was applied to bilateral BL 32 for 2 hours, once daily for 14 days. Intravesical pressure was detected by using a pressure transducer and a bioelectric amplifier. The expression of c-fos gene was detected by immunohistochemistry. RESULTS: In comparison with normal control group, the maximum intravesical pressure (MIVP) raised significantly in model group (P < 0.05), and the compliance of the bladder decreased remarkably (P < 0.05). While compared with model group, MIVP decreased significantly in SCI rats of EA group after EA intervention (P < 0.05), and the vesical compliance increased obviously (P < 0.05). In comparison with normal control group, the mean optical density (OD) value of c-fos immuno-reaction (IR) positive products increased significantly in the sacral cord after SCI in model group (P < 0.05), while compared with model group, the mean OD value of c-fos IR positive products in EA group declined evidently but still being higher than that of normal control group (P < 0.05), displaying a downregulation of c-fos expression after EA. CONCLUSION: Electroacupuncture at "Ciliao" (BL 32) can inhibit the overactivity of bladder in SCI rats and reduce the c-fos expression in the sacral cord, suggesting that the declined C-fibers' activity after EA may be one of its mechanism underlying improving detrusor hyperreflexia in spinal cord injury. PMID- 20848898 TI - [Observation on changes of oxygen partial pressure in the deep tissues along the large intestine meridian during acupuncture in healthy subjects]. AB - OBJECTIVE: To observe changes of the partial oxygen pressure in the deep tissues along the Large Intestine Meridian (LIM) during acupuncture stimulation, so as to reveal the characteristics of energy metabolism in the tissues along the LIM. METHODS: Thirty-one healthy volunteer subjects were enlisted in the present study. Partial oxygen pressure (POP) in the tissues (at a depth of about 1.5 cm) of acupoints Binao (LI 14), Shouwuli (LI 13), Shousanli (LI 10), 2 non-acupoints [the midpoints between Quchi (LI 11) and LI 14, and between Yangxi (LI 5) and LI 11) of the LIM, and 10 non-meridian points, 1.5-2.0 cm lateral and medial to each of the tested points of the LIM was detected before, during and after electroacupuncture (EA) stimulation of Hegu (LI 4) by using a tissue oxygen tension needle-like sensor. RESULTS: In normal condition, the POP values in the deep tissues along the LIM were significantly higher than those of the non meridian control points on its bilateral sides. During and after EA of Hegu (LI 4), the POP levels decreased significantly in the deep tissues along the LIM in comparison with pre-EA (P < 0.01), and had no apparent changes in the non meridian control points (P > 0.05). CONCLUSION: POP is significantly higher in the deep tissues along the LIM of healthy subjects under normal conditions, which can be downregulated by EA of Hegu (LI 4), suggesting an increase of both the utilization rate of oxygen and energy metabolism after EA. PMID- 20848897 TI - [Effects of electroacupuncture plus oxygenmedicine on the expression of Bcl-2 and Bax proteins in the hippocampal CA 1 area in rats with global cerebral ischemia/reperfusion injury]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) plus oxygenmedicine (OM) on the expression of Bcl-2 and Bax in the hippocampal CA 1 area in cerebral ischemia/reperfusion injury (CI/RI) rats. METHODS: Thirty SD rats were randomized into sham-operation, model, EA, OM, EA+OM groups (n=6 /group). CI/RI model was established by using modified Pulsinelli 4 vessel occlusion and reperfusion. EA (100 Hz, 3.5 mA) was applied to "Baihui" (GV 20) and "Zusanli" (ST 36) 30 min, once daily for 4 days. Rats of OM and EA+ OM groups were put into a box filled with oxygen and atomized herbal medicines containing Bingpian (Borneolum), Shexiang (Moschus), Huangjing (Rhizoma Polygonati), Shouwu (Radix Polygoni Multiflori), etc. for 30 min, once daily for 4 days. Bcl-2 and Bax expression of the hippocampal CA 1 area was detected by immunohistochemistry. RESULTS: Compared with sham group, the numbers of Bcl-2 immunoreaction (IR) and Bax IR positive cells, and the immunoactivity of Bcl-2 IR and Bax IR positive products in the hippocampal CA 1 area were increased significantly in model group (P < 0.05, P < 0.01). In comparison with model group, the number of Bcl-2 IR positive cells and Bcl-2 immunoactivity in EA, OM and EA+OM groups increased considerably (P < 0.01), while Bax IR positive cell numbers and Bax immunoactivity in EA, OM and OM+ EA groups decreased significantly (P < 0.01). The effects of EA+ OM were significantly superior to those of EA and OM groups in upregulating Bcl-2 IR positive cell number and Bcl-2 immunoactivity and downregulating Bax IR positive cell number and Bax immunoactivity (P < 0.01). No significant differences were found between EA and OM groups in the abovemen-EA and OM and EA+OM can effectively regulate the expression of Bcl-2 and Bax in tioned indexes (P > 0.05). CONCLUSION: EA and OM and EA + OM can effectively regulate the expression of Bcl-2 and Bax in the hippocampal CA 1 area in CI/RI rats, and the effects of EA+OM are significantly superior to those of simple EA and simple OM, which may contribute to their effect in improving cerebral ischemia. PMID- 20848899 TI - [Clinical observation on the effect of electroacupuncture of Sanyinjiao (SP 6) on labor]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of Sanyinjiao (SP 6) on labor in parturients. METHODS: A total of 349 parturients were randomly divided into EA (n=117), sham-EA (n=117) and control (n=115) groups. The visual analog scale (VAS) was used to assess the pain intensity of puerperas with labor before and after acupuncture intervention. After excluding those puerperas with cesarean section, the time required for each stage of labor and the total duration of labor were observed in 286 cases of natural delivery women including 92 cases in the control group, 94 cases in the sham-EA group and 100 cases in the EA group. EA (2 Hz/100 Hz, 20 mA) was given to the puerperas for 30 min after the needle in a cannula was tapped into Sanyinjiao(SP 6) and when the dilatation of cervix was about 2-3 cm wide. For puerperas of sham-EA group, the operation was similar, but no real acupuncture needle and no real electric current were given. RESULTS: The VAS score for childbirth pain intensity was significantly lower in EA group than in control group (P < 0.05) and had no significant difference between sham-EA and control group (P > 0.05). The duration of the active phase of the first stage of labor was significantly lower in EA group than in sham-EA group (P < 0.05), but had no significant difference between sham-EA and control groups (P > 0.05). No significant differences were found among the 3 groups in the latency of the first stage of labor, in the duration of the 2nd and the 3rd stages of labor and in the total phase of labor (P > 0.05). CONCLUSION: EA of SP 6 can relieve the pain intensity of the labor and shorten the duration of the active period of first stage of labor in puerperas, suggesting an improvement of the quality of delivery after EA. PMID- 20848900 TI - [Effect of "tranquilization needling" on the sleep quality in patients with insomnia of heart-spleen deficiency type]. AB - OBJECTIVE: To observe the effect of "Tranquilization Needling" (TN) and acupuncture of "Eight Confluence Acupoints" (ECA) on Pittsburgh Sleep Quality Index (PSQI) in patients with insomnia of the deficiency type of both heart and spleen. METHODS: A total of 60 insomnia patients with the deficiency of both heart and spleen were randomly divided into TN group and ECA group. For patients of TN group, Sishencong (EX-HN 1), Shenmen (HT 7) and Sanyinjiao (SP 6) were punctured, and for those of ECA group, Shenmai (BL 62) and Zhaohai (KI 6) were punctured, once daily for 40 sessions. The PSQI score was used to assess the changes of the patients' sleeping quality. RESULTS: After the treatment, of the two 30 cases of TN group and ECA group, 12 (40.0%) and 7 (23.3%) were cured, 11 (36.7%) and 10 (33.3%) experienced marked improvement, 5 (16.6%) and 8 (26.7%) had an improvement, and 2 (6.7%) and 5 (16.7%) failed, with the total effective rates being 93.3% and 83.3% respectively. The effective rate of TN group was significantly higher than that of ECA group (P < 0.05). Self-comparison showed that PSOI scores of the sleeping quality, ramp duration, sleep efficiency and the total PSQI score in these two groups all declined significantly after the treatment (P < 0.05, P < 0.01), and the scores of ramp duration and the total PSQI score of TN group were evidently lower than those of ECA group (P < 0.05). After the treatment, the integrative scores of symptoms of two groups both decreased significantly (P < 0.01), and the integrative score of TN group was remarkably lower than that of ECA group (P < 0.05). CONCLUSION: Both TN and acupuncture of ECA can effectively improve insomnia patients' clinical symptoms, and the therapeutic effect of TN is more effective than that of ECA in shortening ramp duration and the total PSQI score. PMID- 20848901 TI - [Analysis on the key factors affecting the inheritance of the acupuncture learning]. AB - On the basis of systematicly reviewing the developmental history of acupuncture and moxibustion and profoundly understanding its academic connotations, the authors of the present article make a summary and analysis on the key factors influencing the development of acupuncturology. These key factors are (1) the emergence of "microacupuncture needle regulating-Qi" and the establishement of their corresponding theory system, (2) a large number of practitioners who inherited the learnings of acupuncturology generations by generations, and abundant medical classical works which recorded the valuable academic thoughts and clinical experience of the predecesors, (3) the application of acupuncture charts and manikins, and (4) modernizing changes of acupuncture learnings after introduction of western medicine to China. Just under the influence of these key factors, the acupuncture medicine separates itself from the level of the simple experience medicine, and has formed a set of special theory system and developed into a mature subject. PMID- 20848902 TI - [Clinical application and research on ziwu-liuzhu (midnight-noon ebb-flow) acupuncture therapy]. AB - Ziwu-liuzhu (Midnight-noon Ebb-flow) acupuncture therapy is a natural therapy by taking the time as a princi-Ziwu-liuzhu (Midnight-noon Ebb-flow) acupuncture therapy is a natural therapy by taking the time as a principal condition. It has been being widely applied in clinical practice. In the present paper, the authors review the progress of clini-pal condition. It has been being widely applied in clinical practice. In the present paper, the authors review the progress of clinical application and related researches on Midnight-noon Ebb-flow acupuncture method in the past years, and also summarize some scholars' opinions about its extent problems and shortcomings. PMID- 20848903 TI - [Review on the safety of deep acupuncture at Tianshu (ST 25)]. AB - Tianshu (ST 25) is a frequently-used acupoint in acupuncture practice. It is reported that deep acupuncture has a better therapeutic effect than routine depth acupuncture. On the basis of reviewing the available literature, the present paper gives a definition about "deep acupuncture" of Tianshu (ST 25) from the anatomy angle, and makes a summary about its safety. This paper also puts forward a set of operation standards for needling Tianshu (ST 25). Moreover, the authors of the present paper also make a systematic analysis on the factors affecting the safety from the punctured depth, the diameter of the acupuncture needle and the operation technique. These methods and standards have an important significance in guiding clinical practice of acupuncture. PMID- 20848904 TI - [Comments on the thickness of abdominal acupuncture needles]. AB - In the present paper, the authors make a summary about the development of acupuncture needles in Chinese ancient times recorded in the literature, and have a discussion on the effect of the thickness of acupuncture needles on clinical therapeutic efficacy in accordance with modern medical theories, the development of its clinical application and by combining their own experience in acupuncture practice. They conclude that the thickness of the abdominal needle is a negligible factor influencing the therapeutic efficacy of the reinforcing reducing manipulations. In the treatment of deficiency pattern disorders, a thinner acupuncture needle is suitable, while for excess syndrome, a thicker acupuncture needle is recommended. In the light of the patient' s constitution and different state of clinical conditions, a flexible application of the acupuncture needle with different diameters is highly recommended in clinical practice. In this way, the clinical therapeutic effect would be improved much. PMID- 20848905 TI - Creation of a new system to study insulators in Drosophila melanogaster. PMID- 20848906 TI - Study of the mucosal immune response duration in mice after administration of a candidate edible vaccine based on transgenic tomato plants carrying the TBI-HBS gene. PMID- 20848907 TI - Hindering of proteinopathy-induced neurodegeneration as a new mechanism of action for neuroprotectors and cognition enhancing compounds. PMID- 20848908 TI - Nonspecific activation of translation of encapsidated potexviral RNA with involvement of potato virus X movement protein TGB1. PMID- 20848909 TI - Interaction of signal systems (nitric oxide and calcium) in regulation of hydrolytic activity of tonoplast H(+)-pyrophosphatase under normal conditions and stress. PMID- 20848910 TI - Role of thermoinduced dissociation in interaction between alpha-crystallin as an oligomeric chaperone and glyceraldehyde-3-phosphate dehydrogenase as an oligomeric protein substrate. PMID- 20848911 TI - The effect of hypothermia on the ornithine decarboxylase activity in tissues of rats. PMID- 20848913 TI - Mutation in LSU4 gene affects flower development in Arabidopsis thaliana. PMID- 20848912 TI - Specifically activated dendritic cells--cell-based vaccine against lymphosarcoma exhibiting multiple drug resistance phenotype. PMID- 20848914 TI - Effect of Omnipaque on the optical properties and laser-induced changes in the thermostability of nucleus pulposus of the intervertebral disk. PMID- 20848915 TI - Cytokinins evoke rapid activation of phospholipase D in sensitive plant tissues. PMID- 20848916 TI - Genetic variability of bird schistosomes (class Trematoda, family Schistosomatidae) of Naroch Lake: identification of a new species in the Trichobilharzia ocellata group. PMID- 20848917 TI - Adaptation of mycoplasmas to adverse environments: phytopathogenicity and peculiarities of protein expression of vegetative and nonculturable forms of Mycoplasma gallisepticum S6 cells. PMID- 20848918 TI - Interaction of cholinesterase from the visual ganglia of the Commander squid Berryteuthis magister from different areas of the range with reversible inhibitors. PMID- 20848919 TI - Enzymological characteristic of monoamine oxidase from the visual ganglia of the Pacific squid Todarodes pacificus. PMID- 20848920 TI - [It is necessary to do psychological intervention for patients with cleft lip and palate]. AB - Psychological intervention is one of the most important parts in cleft lip/palate team approach. However, the psychological intervention has not been taken into deep consideration until now in China, and thus practical experience has not been obtained in this field. Based on a profound analysis of the reason of psychological abnormality and the psychological characteristics of cleft patients, we suggest that the psychological healthy should be the final destination of cleft lip/palate team approach. We further suggest that, based on the practical condition and experience in China, some therapies like psychological counseling should be feasible at the present time. PMID- 20848921 TI - [A preliminary study on the effects of the exogenous creatine phosphate on rat masseter muscle after unilateral chew]. AB - OBJECTIVE: To study the effect of energy therapy on Ca2+ concentration and Ca2+ ATP enzyme activity in rat master muscle after unilateral chew, and to discuss the protective action of the exogenous creatine phosphate on rat masseter muscle after unilateral chew. METHODS: The 20 rats were randomly divided into 4 groups, A: Creatine phosphate normal control group; B: Creatine phosphate experimental group; C: Saline normal control group; D: Saline experimental group. The Ca2+ concentration were determined by atomic absorption spectrophotometry, the activity of the Ca2+ -ATP enzyme were determined by super-micro volume Ca2+ -ATP enzyme kit. RESULTS: (1) The Ca2+ concentration of the extraction side of group D which received the saline injection had significant difference compared with the non-extraction side (P = 0.007), the group C (P = 0.009) and the extraction side of group B (P = 0.01); (2) Ca2+ -ATP enzyme activity of group D were higher than its non-extraction side (P = 0.001), group C (P = 0.003) and the extraction side of group B (P = 0.001); (3) The ultrastructural changes of the rat masseter muscle under transmission electron microscope were as follows: The extraction side of group D have more severe pathological manifestations than non-extraction side. Both the extraction side and the non-extraction side of group B had a similar manifestation to the normal control group. CONCLUSION: Exogenous energy material, creatine phosphate, may have certain degree of protective effect on rat masseter muscles after unilateral chew. And it may become a possible way to improve the injury of the masseter muscle. PMID- 20848922 TI - [Association between interferon regulatory factor 6 gene polymorphism and non syndromic oral clefting]. AB - OBJECTIVE: To investigate the association between interferon regulatory factor 6 (IRF6) gene polymorphism and non-syndromic oral clefting (NSOC). METHODS: Experimental group consisted of 186 Ningxia NSOC patients, their parents (183 fathers and 174 mothers), 172 core families (patient+parents), and control group consisted of 200 normal children. DNA was extracted and PCR-restriction fragment length polymorphism (PCR-RFLP) was used to identify the genotypes of the samples, case-control analyses and transmission-disequilibrium test (TDT) were carried out. RESULTS: Compared with control group, there were significant differences in both rs642961's and rs4844880's AA genotype and A allele among NSOC patients (P < 0.05), but no difference in cleft palate (P = 0.15, P = 0.967, respectively). In TDT analysis, the A allele of rs642961 had a strong over-transmission in NSOC (P < 0.05), so did the rs4844880'A allele (P < 0.05), but neither of them had significant difference in cleft palate (P = 0.91, P = 0.95, respectively). CONCLUSION: IRF6 gene polymorphism is associated with NSOC. PMID- 20848923 TI - [The preliminary study on transforming growth factor-beta 3, activin receptor like kinase 5 expression in 2, 3, 7, 8-tetrachloro-p-dibenzodioxin and dexamethasone induced palatal cleft in mice]. AB - OBJECTIVE: To establish a good animal model of cleft palate and confirm whether 2, 3, 7, 8-tetrachloro-p-dibenzodioxin (TCDD) and Dexamethasone (DEX) induced palatal cleft in mice is related to the fold change of transforming growth factor beta 3 (TGF-beta3) and activin receptor-like kinase 5 (Alk5). METHODS: Pregnant mice were treated with oral medication of TCDD and intraperitoneal injection with DEX on GD10-12 in experimental group while the control group without any treatment. Then embryos were examined on GD17.5 under stereomicroscope for calculating the incidence of cleft palate and palatal shelves were dissected from the staged embryos respectively for RNA extraction on GD13.5, GD14.5 and GD15.5. At last the real-time PCR and SYBR Green I detection were used for RNA relative quantification. RESULTS: Cleft palate could be induced 100% in C57BL/6J fetal mice with TCDD and DEX, thus established a stable animal model for further molecular studies of cleft palate. There were no significant difference in expression level of TGF-beta3 and Alk5 on GD13.5 among the groups, but the differences were statistically significant on GD14.5 and GD15.5 (P < 0.05). On the contrary, the expression level of Alk5 were significantly higher in experimental group (P < 0.05). CONCLUSION: Combined effects of TCDD and DEX could induce a stable formation of cleft palate and down-regulated mRNA of TGF-beta3 and up-regulated Alk5 may contribute to the occurrence of cleft palate. PMID- 20848924 TI - [Effect of cold-light bleaching technique on human permanent teeth enamel surface]. AB - OBJECTIVE: To study the effects of the cold-light bleaching technique on crystals and microstructure of the dental enamel. METHODS: The human premolars extracted for orthodontic reasons were treated by a standard cold-light bleaching procedure. After the treatment, all samples were detected by high resolution micro-area X-ray diffractometer, Fourier transform infrared spectroscope and scanning electron microscope. RESULTS: After the permanent teeth were treated with cold-light bleaching technique, the enamels' crystal dimension, crystallinity decreased and irregular surfaces and shallow disk pits appeared. CONCLUSION: The cold-light bleaching technique could lead to the changes of crystals and microstructure in the surface layer of dental enamel. PMID- 20848925 TI - [Experimental study on the anti-tumor effect of monocytes/macrophages against Tca8113 cells and the secretion of vascular endothelial growth factor in acid microenvironment]. AB - OBJECTIVE: To investigate the anti-tumor effect of monocytes/macrophages against Tca8113 cells and the secretion of vascular endothelial growth factor (VEGF) in acid microenvironment in vitro. METHODS: Peripheral blood mononuclear cells were extracted from healthy person's blood and cultivated to transform into monocytes/macrophages. The monocytes/macrophages were cultured with Tca8113 in acid microenvironment (pH6.6 and pH6.8) and in normal microenvironment (pH7.2). The anti-tumor effect of monocytes/macrophages against Tca8113 cells were examined by MTT assay. The expression of VEGF was detected by enzyme-link immunoassay (ELISA). RESULTS: The anti-tumor effect of monocytes/macrophages against Tca8113 cells in acid environment was lower than in normal environment (P < 0.05). VEGF excreted by mononuclear/macrophage was significantly higher in acid microenvironment than in normal microenvironment. CONCLUSION: Due to acid microenvironment inside tumor, the anti-tumor effect of monocytes/macrophages against tumor cell was decreased, but the secretion of VEGF was gradually increased. However, the function of monocytes/macrophages on anti-tumor need more research. PMID- 20848926 TI - [Research on the resin bond durability of glass-infiltrated alumina ceramic]. AB - OBJECTIVE: To analyze the effect of different silane coupling agents on the resin bond durability of glass-infiltrated alumina ceramic. Methods A glass-infiltrated alumina ceramic was silanized or not by three silane coupling agents. The treated ceramic surfaces were bonded with two resin cements. Their micro-bond strength were measured after 0, 30,000 thermal cycles. RESULTS: Before thermal cycling, resin cement A had lowest bond strength to ceramic, and ceramic treated by silane coupling agent A with two cements had lower bond strength than those treated by silane coupling agent B and C. After thermal cycling, cement A had no bond strength with no treated ceramic, only ceramic treated by silane coupling agent A with two cements had more than 5 MPa bond strength. CONCLUSION: The glass infiltrated alumina cermaic treated by the silane coupling agent activated by 10 methacryloyloxydecyl-dihydrogen phosphate could obtain better bond durability with different type of resin cements. PMID- 20848927 TI - [The antibacterial efficacy of KaVo KEY laser on Enterococcus faecalis within infected root canals and roots surface in vitro]. AB - OBJECTIVE: To evaluate the antibacterial efficacy of KaVo KEY laser on Enterococcus faecalis (E. faecalis) within infected root canals and roots surface in vitro. METHODS: Fifty single-rooted teeth were selected, and infected root canals and roots surface vitro models were prepared. Then, these specimens were divided into three groups. First group were untreated as blank control. The other two groups were the laser groups: Irradiated 15 s and 30 s respectively with 80 mJ and 140 mJ in root canals and on roots surface. Microbiological samples were collected from root canals and roots surface at two time points (before irrigation and immediately after irrigation). The dentin chips from three different zone of part of root canals in each group were immediately collected and were cultured for 24 h in brain heart infusion (BHI). RESULTS: The number of E. faecalis in root canal and root surface in each of the groups were effectively reduced (P < 0.05), and there was no significant difference between each two groups (P > 0.05). Compared with the blank control, the bacterial number in 100 microm of dental tubules decreased after specimens treated with 80 mJ, and the experimental group irradiated 15 s was a significant decease (P < 0.05). The other groups were no changed in different zone of dental tubules. CONCLUSION: KaVo KEY laser is effective on sterilizing infected root canals and roots surface. It has also significant effect on bacterial in superficial dental tubules with low energy and short time. PMID- 20848928 TI - [Study on the posterior teeth mesiodistal tipping degree of normal occlusion subjects among different facial growth patterns]. AB - OBJECTIVE: To study the relationship between the mesiodistal tipping degree of maxillary and mandible posterior teeth and different vertical facial skeletal types of subjects with normal occlusion. METHODS: 163 subjects with normal occlusion were selected, lateral cephalograms were taken and divided into three different facial skeletal types. The difference of the mesiodistal tipping degrees and intersection angles of upper and lower posterior teeth between the three different facial skeletal types were analyzed. RESULTS: Among 163 subjects, vertical growth pattern, average growth pattern and horizontal growth pattern were 24, 96 and 43 respectively. There were statistic differences of mesiodistal tipping degrees of the first and second maxillary and mandible premolar and the first permanent molar between vertical growth and horizontal growth pattern, horizontal growth and average growth pattern (P < 0.05). But there were no statistically significant differences between vertical growth and average growth pattern (P > 0.05). The differences of the maxillary and mandible posterior teeth's intersection angle among three vertical facial skeletal types had no statistic significance (P > 0.05). CONCLUSION: Different vertical facial skeletal type has its own normal and coordinated posterior teeth mesiodistal tipping degrees. PMID- 20848929 TI - [Detecting caries susceptible population in children with gtfB oligonucleotide probe]. AB - OBJECTIVE: To establish a quick, exact and inexpensive method to detect caries susceptibility in children. METHODS: 125 caries free children, aged 3-4 years, were randomly sampled. A combination of polymerase chain reaction (PCR) and gtfB oligonucleotide probe hybridization method was used to detect Streptococcus mutans in saliva. The participants were followed up for a year and the clinical examination results were compared with the laboratory results. The perspective study was used to evaluate the detecting approach. RESULTS: When the combination of PCR and hybridization method was used to detect caries susceptibility of the sample, the predictive sensitivity, predictive specificity and predictive reliability were all increased to 69.2%, 46.8% and 54.3%, respectively as compared to only PCR, which were 56.4%, 44.2% and 48.3%, respectively. The samples with both the positive and negative results of hybridization detection had caries clinically, but the dmft index and prevalence were higher in the positive (dmft was 2.15 +/- 0.86, and the prevalence was 23.28%) than in the negative(dmft was 1.58 +/- 0.51, and the prevalence was 10.34%) which was statistically significant (P < 0.05). CONCLUSION: The probe was found to be quite potential in detecting caries susceptibility, but the predictive specificity and predictive reliability values were not significant. PMID- 20848930 TI - [Relationship between periodontitis and levels of high-sensitivity C-reactive protein]. AB - OBJECTIVE: To evaluate the relationship between periodontitis and the traditional risk factors of coronary heart disease (CHD), as well as the role in the mechanisms responsible for high-sensitivity C-reactive protein (hsCRP) in the relationship of peridontitis and CHD. METHODS: A periodontal examination was conducted on a total of 356 subjects, and community periodontal index of treatment needs (CPITN) was obtained from each subject. Periodontal status was categorized into TN < or =2, TN=3, TN=4 three groups according to the CPITN indexes. Fasting venous blood samples were collected from all the three group subjects, the serum hsCRP concentration and serological changes used in diagnosing CHD routinely were determined, and software of SPSS 16.0 were used to analyzed the relationship of periodontal, hsCRP concentration and routinely CHD serological indexes. RESULTS: In the groups of TN < or =2, TN=3 and TN=4, the hsCRP level was (1.10 +/- 1.16), (1.86 +/- 2.34), (2.25 +/- 2.75) mg x L(-1), respectively. Compared with Group TN < or =2, the concentration of hsCRP in Group TN=3 and TN=4 were higher (OR = 1.24, OR = 1.31, respectively). Compared with group hsCRP < 3.0 mg x L(-1), more calculus and deep periodontal pockets were found in the Group hsCRP > or = 3.0 mg x L(-1) (P < 0.05). CONCLUSION: The serum hsCRP level is correlated with the severity of periodontal disease. PMID- 20848931 TI - [Selective embolization for surgical treatment of carotid body tumor]. AB - OBJECTIVE: To investigate the value of carotid arteriography and selective embolization in surgical treatment of carotid body tumor. METHODS: Seven patients with carotid body tumor were operated, and four patients were performed with carotid arteriography and selective embolization before operation. All patients were treated by stripping the carotid body tumor from the carotid artery. Treatment effectiveness of the patients with and without selective embolization were compared. RESULTS: Seven cases were classified as Shamblin III type. The CT scan and digital subtraction angiography (DSA) showed the tumor lesion in the carotid bifurcation, and the tumor and its relation with the surrounding arteries were expressed by CT and three dimensional CT images. All cases of carotid body tumor were resected without any carotid artery ligation. No serious complications occurred after operation. There was average 160 mL blood loss in operation of four patients that had angiograms and were preoperatively embolized, and average 2.5 h were expended. There was average 600 mL blood loss in operation of three patients without preoperatively embolized, and average 4 h were expended. Preoperatively high-selected embolization of the tumor-feeding artery could effectively reduce the intraoperative bleeding. With 1.5-3 years follow-up, none of the carotid body tumor recurred in all the seven cases. CONCLUSION: Carotid arteriography and embolization therapy may decrease blood loss and higher risk for operation in the patients with carotid body tumor. PMID- 20848932 TI - [Clinical research on repairing alveolar cleft with osteoinduction active material]. AB - OBJECTIVE: To study the feasibility and authenticity of repairing alveolar defects in alveolar cleft patients with osteoinduction active material (OAM) in clinic. METHODS: Twenty-seven cases of alveolar defect chosen from clinic were divided into two groups (test group and control group). For test group (12 cases), OAM was transplanted to repair the alveolar cleft. For control group (15 cases), autogenous ilium cancellous bone were transplanted into the defect region to repair alveolar cleft. At 6 months after operation, CT and three-dimensional reconstruction were used to observe alveolar appearance, and the effect and clinical success rate of recover alveolar cleft by using different repair material were compared. RESULTS: In the 27 cases, all the maxillary continuity was restored except two of test group and two of control group. There was no significant difference between test group and control group regarding the clinical success rate of the alveolar cleft repair (P = 1.000). CONCLUSION: OAM was used to repair the alveolar cleft that can result in new bone formations and the burgeon of canines from the bone grafted areas. There is no significant difference between OAM and autogenous ilium cancellous bone regarding the effect of the alveolar cleft repair. PMID- 20848933 TI - [Morphological characteristics of mandibular symphysis in adult skeletal class II and class III malocclusions with abnormal vertical skeletal patterns]. AB - OBJECTIVE: To figure out the differences of the morphological characteristics of mandibular symphysis between Class II and Class III adult skeletal malocclusions with different abnormal vertical skeletal patterns. METHODS: 109 Chinese female adults of skeletal Class II and Class III were chosen and divided into four groups according to vertical and sagittal skeletal pattern: Class II--vertical growth-pattern group (n=30), Class III--vertical-growth-pattern group (n=25), Class II--horizontal-growth-pattern group (n=29), Class III--horizontal-growth pattern (n=25). Lateral cephalograms were taken. The symphyseal widths and heights, along with lower incisor positions were evaluated. Observation and statistics analysis were done to clarify the morphological characteristics of the symphyseal region of different skeletal patterns. RESULTS: There were morphological differences of symphyseal region between Class II and Class III skeletal malocclusions, but not significant in width and total height. With a vertical-growth-pattern, Class II malocclusions had higher alveolus than Class III, but smaller chin prominence and lower basal bone (P < 0.01). With a horizontal-growth-pattern, Class II malocclusions had higher alveolus (P < 0.05) and larger alveolar top width (P < 0.001). With a same sagittal skeletal pattern, vertical-growth-pattern group had thinner but higher symphyseal region and bigger chin prominence (P < 0.001 in Class II while P < 0.05 in Class III). Besides, a vertical-growth-pattern malocclusion was prone to have a cucurbit-morph chin, of which Id width was larger than basal width (P < 0.01). CONCLUSION: There are morphological differences in symphyseal region between Class II and Class III skeletal malocclusions with different abnormal vertical skeletal patterns. The influence of abnormal vertical skeletal pattern to symphyseal morphological characteristics is greater than that of abnormal sagittal skeletal pattern. There is a risk of orthodontic movement of low incisors in vertical-growth-pattern skeletal malocclusion. PMID- 20848934 TI - [The soft tissue change of Angle's Class II division 1 malocclusion patients with vertical growth pattern after tooth extraction orthodontic treatment]. AB - OBJECTIVE: This study is to evaluate the soft tissue change of Angle's Class II division 1 malocclusion patients with vertical growth pattern after tooth extraction orthodontic treatment, and to provide experimental results to help to make orthodontic treatment plan and treatments. METHODS: 38 Angle's Class II division 1 malocclusion patients with vertical growth pattern and with tooth extraction orthodontic treatment were included in this study. The pre- and post treatment cephalometric X-rays were made and 26 measurement items were measured. The change value of pre- and post-treatment, youngsters and adults were compared. RESULTS: TUL-EP, TLL-EP, upper and lower lip position, Stoms-Stomi, U1-Ptm were reduced after treatment. Upper lip sulcus and flange thickness, upper and lower lip length, upper and lower lip inclination angle, nasolabial angle, Z angle, mentolabial sulcus inclination angle were enlarged after treatment. The upper lip sulcus thickness, lower lip length and A'-Ptm of adolescent were enlarged, but adult were on the contrary. The change of upper lip length, mentolabial sulcus inclination angle and U1-Ptm between adolescent and adult was statistically different. CONCLUSION: The best treatment period of patients with Angle's Class II division 1 malocculsion with vertical growth pattern was in the rapid growth and development period of adolescent. PMID- 20848935 TI - [Analyzing the production of organic acid of different genotype streptococcus mutans isolated from children with different caries experience]. AB - OBJECTIVE: To compare the production of organic acid of different genotype Streptococcus mutans (S. mutans) isolated from children with different caries experience. METHODS: 66 strains of S.mutans isolated from dental plaques of children aged from 3 to 5 with different caries experience were chosen as test bacteria. The quantities of organic acid include formic acid, acetic acid and lactic acid which produced by different genotype of S. mutans, were measured by gas chromatograph. RESULTS: There were significant difference in production of organic acid among the different genotypes of S. mutans isolated from children with different caries susceptibility, and so were the strains isolated from children within the same caries susceptibility (P < 0.05). The more genotypes the strain had, the more organic acid it produced (P < 0.05). Among all the organic acid, the quantity of lactic acid was much more than that of formic acid and acetic acid. CONCLUSIONS: There were significant difference in the ability of the strains with different genotypes to produce organic acid, and the more genotypes it has, the more organic acid it produced. PMID- 20848936 TI - [The statistical analysis for the use of the 55,787 finished resin teeth]. AB - OBJECTIVE: To analyze the use situation of finished resin teeth for the different location, and to provide reference for manufacturers of finished resin teeth and all the buyers. METHODS: To analyze the use situation of finished resin teeth in the Dental Laboratory of the Affiliated Hospital of Stomatology of Chongqing Medical University from January 2006 to December 2008 by using statistic methods. RESULTS: During the use of 55,787 finished resin teeth, the study found some rules. (1) The top use of finished resin teeth was D6 with the percentage of 5.31%, and the lowest use of finished resin teeth was D3 with the percentage of 1.94%. (2) Except the maxillary canines and the mandibular lateral incisors, there was no significant difference between the usage of other same name finished resin teeth (P > 0.05). (3) Among all finished resin teeth, the usage of section B exceeded section A, and the usage of maxillary finished resin teeth exceeded mandibular finished resin teeth (P < 0.05). (4) The use of the complete denture and single complete denture was about 1/3 of the total usage of finished resin teeth. (5) Except the use situation of complete denture and single complete denture, the frequency of simultaneously using mandibular left and right central incisors was the most with the percentage of 81.46%, for the frequency of simultaneously using maxillary left and right canines was 43.26% of the total, which was the lowest. CONCLUSION: There is significant difference in the use frequency of finished resin teeth for different location. For such reason, the manufacturers should produce finished resin teeth pro rata as well as the buyers for their purchase. PMID- 20848937 TI - [Clinical research of immediate restoration implant with mini-implants in edentulous space]. AB - OBJECTIVE: The purpose of this study was to investigate the clinical effective of immediate restoration with Osstem MS mini-implant in the edentulous space of 5-6 mm. METHODS: The sample consisted of 36 consecutively treated partially edentulous patients who had a total of 36 Osstem MS mini-implants, which were 2.5 mm or 3.0 mm in diameter and placed in 5-6 mm gap. The chair-side-made or laboratory-made provisional crowns for implants were fabricated at the time of fixtures placed. The final restorations were fabricated with gold alloy-fused porcelain crown 3 to 5 months later. During the mean 21.3 months (12-37 months) follow-up time since fixtures placement, all implants were examined clinically and radiologically. RESULTS: No implant failed before restoration. One implant led an adjacent tooth pulp necrosis after the implantation, but the natural tooth and implant were successfully retained by root canal therapy. 36 implants in 36 patients who were followed-up were successful and their aesthetic results were satisfactory. CONCLUSION: Immediate loaded implant with Osstem MS mini-implant has good clinical prosthetic effects in the edentulous space of 5-6 mm. PMID- 20848938 TI - [The expression of interleukin-10 mRNA in gingival lesion of different clinical states in patients with adult periodontitis]. AB - OBJECTIVE: To investigate the expression of interleukin-10 (IL-10) mRNA in gingival tissue of active and stable stage in patients with adult periodontitis. METHODS: 12 patients with acute abscesses of the periodontium, 12 patients after periodontal initial treatment and 6 periodontal healthy patients having extraction of impacted wisdom tooth were randomly divided into group A (active stage group), group B (stable stage group) and the control group. Biopsies of gingival tissues were collected from every subject of three groups. Technique of in situ hybridization was applied to observe the expression of IL-10 mRNA in the biopsies from three groups semi-quantitatively. RESULTS: IL-10 mRNA was positively expressed in lymphocytes, macrophages and fibroblasts. The quantity of IL-10 mRNA of group A was the lowest in the three groups and was significantly lower than that of control group and group B respectively (P < 0.01). The quantity of IL-10 mRNA of group B was the highest in the three groups and was significantly higher compared with the control group and group A (P < 0.01). CONCLUSION: The quantities of IL-10 mRNA expression are closely related with various clinical states of periodontitis. PMID- 20848939 TI - [Tyrosine kinase A and vascular endothelial growth factor receptor 2 in the invasion and metastasis of salivary adenoid cystic carcinoma]. AB - OBJECTIVE: To determine the effect of tyrosine kinase A (TrkA) and vascular endothelial growth factor receptor 2 (VEGFR2) in the invasion and metastasis of salivary adenoid cystic carcinoma (SACC). METHODS: The expression of TrkA and VEGFR2 were detected by immunohistochemical staining in 47 cases of SACC of salivary glands. Clinical data were reviewed by multivariate prognostic analysis. RESULTS: The positive rate of TrkA and VEGFR2 in SACC was 87.23% (41/47) and 85.11% (40/47) respectively. Express of TrkA and VEGFR2 in perineural invasion and recurrence group were higher than non-perineural invasion and non-recurrence group. Significant difference was found in microvessel density (MVD) and VEGFR2 expression within different groups (P < 0.05). MVD in perineural invasion group (25.14 +/- 2.83) was significantly higher than that in none perineural invasion group (18.81 +/- 1.33) (P < 0.05). MVD in recurrence or metastasis group (26.58 +/- 2.38) was significantly higher than that (19.06 +/- 1.39) in none recurrence nor metastasis group (P < 0.05). CONCLUSION: Positive correlation between expression of TrkA, VEGFR2 and nerve invasion and vessel metastasis of SACC indicate that TrkA and VEGFR2 play important roles in the invasion and metastasis of SACC. It is possible that TrkA and VEGFR2 could be an aid for evaluating the prognosis of SACC patients. PMID- 20848940 TI - [Bone morphogenetic protein expression in distraction osteogenesis correction for cleft palate in Rhesus monkeys]. AB - OBJECTIVE: To study the expression and distribution of bone morphogenetic protein (BMP) in newly formed bone by distraction osteogenesis (DO), and to explore the mechanism of the DO bone formation and remodeling. METHODS: The cleft palate (CP) experimental animal models (23 Rhesus monkeys) were established surgically. In experimental group (21 Rhesus monkeys), the palatal defects were corrected by means of DO at the rhythm of 0.4 mm twice per day. The specimens were retrieved under euthanasia at 1, 2, 4, 6, 8, 12, 24 weeks intervals respectively in retention period. BMP immunohistochemical study was then performed. The blank control and experimental group (each of 2 animals) were set for comparison study. RESULTS: The immunohistochemical study showed that BMP existed mainly in cytoplasma of osteoblasts, during the process of new bone formation. In early stage of 1 or 2 weeks, abundant osteoblasts aggregating on surfaces of the new bone trabeculae with positive DAB dye were observed. Through 4 to 6 weeks, the proliferative osteoblasts with very strong positive DAB dye indicating BMP expression were recorded. From 8 to 12 weeks, the expression of BMP and quantity of osteoblasts decreased gradually while more matured new bone structures were observed. CONCLUSION: During the whole retention period, the expression of BMP showed a tendency from weak to strong and then to final cessation, this indicated a process of formation, remodeling and maturation of osteogenesis. PMID- 20848941 TI - [Construction of recombinant gene adenovirus encoding enhanced green fluorecence protein-peroxisome proliferator-activated receptor gamma2 fusion protein and its expression in bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To construct mouse enhanced green fluorecence protein (EGFP) peroxisome proliferator-activated receptor (PPAR)gamma2, and to detect EGFP PPARgamma2 expression in infected mouse bone marrow mesenchymal stem cells (BMSC). METHODS: Cut the fragment of PPARgamma2 from the expression plasmid pcDNA flag PPARgamma2, then cloned the gene fragment into pEGFP-C1 and pEGFP-N1 vector. Subsequently, subclone the fragment EGFP-PPARgamma2 from pEGFP-C1-PPARgamma2 into the shuttle plasmid DC315. HEK293 cells were co-transfected with the constructed recombinant shuttle plasmid DC315-EGFP-PPARgamma2 and large adenovirus helper plasmid pBHGlox deltaE1, 3Cre in mediation of liposome. The obtained replication defective recombinant adenovirus Ad-EGFP-PPARgamma2 was confirmed. Then it was propagated in HEK293 cells. After the BMSC were transfected for 72 h, adipogenic differentiation was demonstrated. RESULTS: HEK293 cells were transfected with the pEGFP-C1-PPARgamma2 or pEGFP-N1-PPARgamma2 in mediation of liposome. The former green fluorescence protein was better than the latter by fluorescence microscope. The recombinant plasmids were digested and identified. Western blot analysis showed the expression of EGFP-PPARgamma2 in vitro. EGFP-PPARgamma2 protein was detectable in the nucleus of BMSC. CONCLUSION: The recombinant adenovirus encoding EGFP-PPARgamma2 fusion protein was successfully constructed, which provided a basis for application of EGFP-PPARgamma2 gene to adenovirus-mediated gene therapy. PMID- 20848942 TI - [The effect of experimental osteoporosis on bone healing of autologous iliac crest graft around implants]. AB - OBJECTIVE: To investigate the influences of experimental osteoporosis (OP) on bone healing of autologous iliac crest graft around dental implants in rabbits. METHODS: Twenty Japanese rabbits were randomly divided into two groups. Bilaterally ovariectomy was performed on experimental group and control group received sham-operation. Twelve weeks later, femoral bones were examined for bone mineral density (BMD) to verify OP status. Then bone defects were made in the proximal metaphysis of the tibiae and autologous iliac crest grafts with simultaneous implant placement were performed. The animals were killed at 8 and 12 weeks after bone graft surgery. Undecalcified sections were prepared and examined histologically and histomorphometrically. RESULTS: Osteoporotic status caused by ovariectomy was verified by significantly decreased BMD in experimental group (P < 0.001). At 8 and 12 weeks after bone graft surgery, osseointegration was observed in both groups. However, thickness of cortical bone (TCB), bone volume in cancellous area (BVC), implant-bone contact rate (IBCR) at bone graft area all significantly decreased in experimental group when compared with control group (P < 0.01). Newly formed bone was also less in experimental group than that in control group. CONCLUSION: Although experimental OP may not delay osseointegration of dental implants in autologous iliac crest graft, it certainly promotes resorption of bone grafts, decreases cancellous bone volume and implant bone contact rate. Therefore it may be an important risk factor for patients receiving autologous bone graft with simultaneous implant placement. PMID- 20848943 TI - [The expression of human major histocompatibility complex-I in oral leukoplakia]. AB - OBJECTIVE: The purpose of this study was to examine the expression of human major histocompatibility complex-I at different degrees of dysplasia leukoplakia, and to investigate local immune status and discuss their associations with oral leukoplakia. METHODS: The monoclonal antibody of MHC class I antigen was employed in this study. There were 55 oral leukoplakias, 31 primary oral squamous cell carcinomas and 28 histologically normal oral epithelia were detected for the presence of the MHC class I molecule by using immunohistochemistry method. RESULTS: The MHC class I antigen expression of the severe dysplasia and oral squamous cell carcinoma was significantly lower than that of the normal epithelia (P < 0.05). But their expression did not show statistically difference between the normal epithelia and other groups of oral leukoplakia (P > 0.05). CONCLUSION: The expression levels of the MHC class I antigen is reduced in oral leukoplakia, particularly in severe dysplasia oral leukoplakia, it is relevant to the degree of dysplasia. PMID- 20848944 TI - [Effects of high mobility group box 1 in activating periodontal ligament fibroblasts to express cytokine]. AB - OBJECTIVE: To investigate the influence of high mobility group box 1 (HMGB1) on the expression of interleukin 6 (IL-6), receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) on periodontal ligament fibroblasts. METHODS: Human periodontal ligament fibroblasts were stimulated with HMGB1 at concentrations of 10, 30, and 100 ng x mL(-1) for 24 h. RT-PCR and Western blot analysis were performed to check mRNA and protein expression of IL 6, RANKL and OPG on the cells. RESULTS: The ratio of RANKL/OPG was increased at both mRNA and protein level after HMGB1 stimulation at 10, 30, 100 ng x mL(-1). Inflammatory cytokine IL-6 was upregulated by HMGB1 at the concentration of 100 ng x mL(-1). CONCLUSION: Increased ratio of RANKL/OPG and IL-6 on periodontal ligament fibroblasts suggests that HMGB1 might play a role in the pathogenesis and progression of periodontal disease. PMID- 20848945 TI - [Use of atomic force microscopy to observe the surface and the dynamic forming process of biofilms of Enterococcus faecalis]. AB - OBJECTIVE: To observe the surface of Enterococcus faecalis and the dynamic forming process of those biofilms using atomic force microscopy (AFM) in air condition. METHODS: The surface of Enterococcus faecalis which were dried in air were observed with AFM. We used the cellulose nitrate film to construct the Enterococcus faecalis biofilms model in vitro, and then placed the biofilms under AFM to observe the surface changes of biofilms' development. RESULTS: The cell surfaces of strain Enterococcus faecalis were not regular because of the presence of the amorphous substance on the colony surface, which congregated globular, fibrous structure. Gradually determined that at 6 h the initial biofilm formed and at 24 h the biofilms maintained the steady-state. AFM height images showed topographical changes due to biofilms' development, which were used to characterize several aspects of the bacterial surface, such as the presence of extracellular polymeric substance, and the biofilms' development stage. CONCLUSION: Application of AFM in physiological conditions could be useful in observing Enterococcus faecalis surface ultrastructure and dynamic process of biofilms formation. PMID- 20848946 TI - [Giant cell tumor of temporal bone and mandibular condyle: a case report]. AB - Giant cell tumor of bone (GCTB) seldom occurs in the head or face. This article reported a case that GCTB occurred simultaneously in the temporal bone and mandibular condyle, and analyzed their clinical and pathological features. PMID- 20848947 TI - [Analysis of misdiagnosis of calcifying epithelioma in oral and maxillofacial head and neck region]. AB - Eight patients misdiagnosed as calcifying epithelioma during 2003-2008 at Department of Oral and Maxillofacial Surgery of Cangzhou Central Hospital were retrospectively analyzed. The pertinent literatures were reviewed and the pathogenesis, clinical manifestations, imaging performance and differential diagnosis of calcifying epithelioma were discussed. PMID- 20848948 TI - [The fabrication and clinical application of semi-fixed mandibular lingual arch expansion appliance]. AB - Semi-fixed mandibular lingual arch expansion appliance is composed of a mandibular molar band, a keyway and arch expansion spring. The arch expansion spring are used to expand maxillary arch symmetrically or asymmetrically when bolts of the two ends are inset into keyways. Dental arch expansion appliance for 25 patients with mandibular arch stenosis showed that semi-fixed mandibular lingual arch expansion had good effect and could be used to expand mandibular arch. PMID- 20848949 TI - [Human genomic project and human genomic haplotype map project: opportunitiy, challenge and strategy in stomatology]. AB - The human genomic project and the international HapMap project were designed to create a genome-wide database of patterns of human genetic variation, with the expectation that these patterns would be useful for genetic association studies of common diseases, thus lead to molecular diagnosis and personnel therapy. The article briefly reviewed the creation, target and achievement of those two projects. Furthermore, the authors have given four suggestions in facing to the opportunities and challenges brought by the two projects, including cultivation improvement of elites, cross binding of multi-subjects, strengthening construction of research base and initiation of natural key scientific project. PMID- 20848950 TI - Computer-aided surgery. A GPS for the OR. AB - Computer-aided surgery lets you visualize the position of instruments and implants during procedures. It improves surgical accuracy and enhances capabilities in areas where direct visibility is limited. How does the technology work, and how might it affect your budget? PMID- 20848951 TI - Fixing bad links. Preventing misconnections in your hospital. AB - Misconnecting lines and cables can have deadly consequences. Equipment designs that reduce the risks are gradually becoming available, but much of the burden for safe connections still falls on the hospital. Read our current recommendations for protecting your patients. PMID- 20848952 TI - Hazard report. Internal wire breakage in reusable electrosurgical active electrode cables may cause sparking and surgical fires. AB - Breaks in the internal wires of reusable electrosurgical active electrode cables can increase the risk of injuries and surgical fires. Careful visual and manual inspection during reprocessing and immediately before use, coupled with periodic replacement, can help limit the risk. PMID- 20848953 TI - Hazard report update. ECRI Institute revises its recommendation for temperature limits on blanket warmers. AB - ECRI Institute now recommends that temperature settings on blanket warming cabinets be limited to 130 degrees F (54 degrees C). We had previously recommended a limit of 110 degrees F (43 degrees C) because solutions were often being warmed in the same cabinets as blankets, and the lower temperature eliminated the serious burn risk presented by excessively heated solutions. With increasing recognition in the healthcare community that solutions should be kept at lower temperatures than--and therefore heated separately from--blankets, we believe that our recommendation for blankets can be made less stringent. We continue to recommend that solution warming cabinets be limited to 110 degrees F. PMID- 20848954 TI - User experience network. Supply gas failure alarm on Cardinal Health Infant Flow SiPAP units may not activate. AB - The supply gas failure alarm on Cardinal Health Infant Flow SiPAP units manufactured before April 2009 may not activate in the event of a gas supply loss if the device's silencer accessory is attached. However, the unit's FiO2 (fraction of inspired oxygen) and low-airway-pressure alarms will activate in such cases. If both of these alarms activate simultaneously, users should suspect a failure of the gas supply pressure. Identifying affected units requires testing that can be conducted during the device's next scheduled maintenance. PMID- 20848955 TI - Premium CT systems. Get the picture on five high-end scanners. PMID- 20848956 TI - Hazard report. Mismatched electrical requirements between heated-wire breathing circuits and heated humidifiers can jeopardize patients. AB - Just because heated-wire breathing circuits and heated humidifiers are physically compatible, it doesn't necessarily mean they're electrically compatible. If electrical requirements are not matched, the heated wire may overheat, potentially resulting in melting or ignition of the circuit and injury to the patient. Facilities should ensure that processes are in place to verify electrical compatibility. PMID- 20848957 TI - Hazard report. Upside-down insertion of Zoll M series multifunction cable connector into M series defibrillator paddles could delay therapy. AB - Under certain conditions, the Zoll M Series defibrillator multifunction cable (MFC) connector can be inserted upside down into the defibrillator's external paddles, preventing shock delivery and potentially delaying defibrillation. Performing the manufacturer-recommended routine shift checks, including checking for damaged cables and connectors, will aid in avoiding this problem during clinical use. Clinicians should be aware that, though it is not a commonly suspected problem, upside-down MFC connector insertion is among the potential reasons for a failure-to-shock condition. PMID- 20848958 TI - Hazard report update. ECRI institute no longer recommends against purchasing curlin CMS and PainSmart infusion pumps. AB - To address the potential for dangerous gravity flow, Curlin Medical recently announced the availability of administration sets with integral antisiphon valves (ASVs) for all of its 2000 Series, 4000 Series, 6000 Series, and PainSmart infusion pumps. The company has indicated that use of these sets nullifies its previous recommendation for hospitals to test the pumps between patients within the hospital setting. Based on these changes, ECRI Institute lifts its earlier recommendation against the purchase of these models. We continue to recommend that facilities purchase and use only integral-ASV sets for all care settings. PMID- 20848960 TI - Measuring up. PMID- 20848959 TI - Real-time locating systems. PMID- 20848961 TI - Hazard report. Incorrect measurement of uterine cavity while using Hologic NovaSure endometrial ablation system can result in patient injury. AB - If the uterine cavity is improperly or inaccurately measured during use of the Hologic NovaSure endometrial ablation system, it could result in thermal or perforation injuries. This article describes some of these injuries and offers guidance on reducing their likelihood. PMID- 20848962 TI - Hazard report. Reducing the risk of burns from surgical light sources. AB - Surgical light sources can heat instruments enough to burn patients and can even start small fires in the operating room. Hospitals can reduce this risk by educating clinicians on the proper use of these devices and by purchasing models that incorporate certain safety features. PMID- 20848963 TI - Hazard report. Still getting stuck--protective devices alone won't always prevent needlestick injuries. AB - Despite widespread use of needlestick-prevention devices (NPDs), staff injuries can occasionally occur, often because of improper technique or device failure. Although no protective device is 100% effective, hospitals can limit injuries by ensuring that their needlestick-prevention programs incorporate ongoing staff education on the use of NPDs as well as on proper handling and disposal of sharps. PMID- 20848964 TI - What goes around. PMID- 20848965 TI - 3-D on your PC. PMID- 20848966 TI - Hazard report. Tipping of portable LOX containers increases risk of injuries and fires. AB - Most portable liquid oxygen (LOX) containers are designed to be used upright; a few models can be used either upright or on their backs. If tipped into other positions, the containers may leak, presenting a risk of injury and increasing the chances of a fire. Healthcare providers who work with patients using these devices--whether in the hospital or home care setting--must know which positions the devices can be safely operated in, as well as how to react if the devices are tipped into unsafe positions. PMID- 20848967 TI - Hazard report. Loose mounting screws on Cardinal Health Avea ventilator cart may cause cart to tip or collapse. AB - If the four mounting screws that connect the support column to the base of certain older Avea ventilator carts loosen, the cart may tip over as a result. The supplier's technical bulletin about this problem was not received by all users. Facilities with affected units should inspect the carts to verify that a thread-locking compound has been applied to the mounting screws, as recommended by the supplier. PMID- 20848968 TI - CE/IT collaboration. Putting the pieces together. AB - The responsibilities of the clinical engineering and information technology departments are intersecting more and more. Here are some real-world examples of the challenges that can emerge, and our recommendations for developing effective collaboration between the two groups. PMID- 20848969 TI - Molecular testing in your lab? What you need to know to make the decision. AB - Not only is molecular testing more sensitive and able to return results faster than traditional testing, it also opens the door to a variety of new tests. What questions do you need to ask when considering a molecular testing program for your lab? We provide a starter set of considerations to put you on the right path. PMID- 20848970 TI - Hazard report. Shift checks and semiannual preventive maintenance are important in detecting critical failures in Zoll M series defibrillators. AB - The manufacturer-recommended shift check for Zoll M Series defibrillators cannot detect some critical failures that could inhibit defibrillation or pacing. To improve detection of these failures and to limit their impact on patient care, hospitals should perform not only the routine perform not only the routine shift check, but also the twice-annual preventive maintenance procedure recommended by Zoll. Additionally, units exhibiting an error code--even one that appears to resolve itself--should be immediately removed from service and evaluated by the clinical engineering department. PMID- 20848971 TI - Hazard report. Physio-Control Lifepak 20 defibrillator/monitor may misrepresent critical failures as incomplete self-test. AB - ECRI Institute is concerned that the Physio-Control Lifepak 20's display of "Self test did not complete" does not adequately alert users that the device may be inoperative. Users need to be aware that the message may indicate a more serious problem and must be trained on how to respond to the message when encountered during routine inspection and during emergency use. In addition, users should configure their Lifepak 20 units to print self-test results to provide a permanent indicator if a problem occurs. PMID- 20848973 TI - Teacher quality matters!! PMID- 20848972 TI - Hazard report. Karl Storz fluid management system may not warn against fluid overload. AB - If not set up properly, the Karl Storz hysteroscopic fluid management system may fail to warn users that potentially life-threatening amounts of fluid are being lost inside the patient. Users should verify proper assembly before each case. To assist in device setup, users of systems shipped before October 2008 should obtain and install "spacers," add-on components currently available free of charge from the manufacturer. PMID- 20848974 TI - Symposium explores animal rights tactics, responses. PMID- 20848975 TI - USDA announces enhanced animal welfare act enforcement. PMID- 20848976 TI - ["Vuvuzela"-induced thyroid gland cyst]. PMID- 20848977 TI - [How can widespread health care be assured?]. PMID- 20848978 TI - [Fit enough for airplane travel?]. PMID- 20848979 TI - [How do I adjust the internal clock?]. PMID- 20848980 TI - [Sick on sea voyage (interview by Dipl.-Biol. Birgit Frohn)]. PMID- 20848981 TI - [Treatment of chronic hepatitis B. High response rate in general practice]. PMID- 20848982 TI - [Naturopathy consultation. Arthrosis]. PMID- 20848983 TI - [Stroke is the number 1 problem worldwide]. PMID- 20848984 TI - [Passive oxygen insufflation in cardiocerebral resuscitation. Can it also be done with my 2 liter flask?]. PMID- 20848985 TI - [The wise man thinks of himself--first?]. PMID- 20848986 TI - [Crohn's disease and ulcerative colitis: in young women often misdiagnosed as anorexia]. PMID- 20848987 TI - [Inflammatory bowel disease: diagnostics and management of acute flares]. PMID- 20848988 TI - [Inflammatory bowel disease: longterm management]. PMID- 20848989 TI - [Emergency checklist: macroscopic hematuria]. PMID- 20848990 TI - [Hypothyroidism]. PMID- 20848991 TI - [Differential diagnosis of dermatocysts]. PMID- 20848992 TI - Radioprotection from radiation-induced lymphedema without tumor protection. AB - Lymphedema or tissue swelling from impaired lymph drainage commonly occurs after regional nodal dissection and/or radiation therapy for cancer control. Treatment options for this disabling and life-altering complication involve long-term labor intensive commitments. Sentinel node biopsy can forestall removal of negative regional nodes, offering some protection against lymphedema, however, most preventive measures are elusive, ineffective, or unproven. Our goal was to determine whether the radioprotectant amifostine could prevent or retard the development of lymphedema in a rodent radiation therapy-dependent model yet not offer tumor protection from the therapeutic effects of radiation therapy. We pre treated rats after unilateral radical groin dissection with the organic thiophosphate radioprotectant amifostine or placebo prior to single dose post operative groin radiation therapy and monitored hindlimb volumes, wound scores, and tissue lymphostasis. In addition, we determined whether amifostine protected human MCF7 breast cancer cells exposed to a range of radiation therapy doses in an in vitro clonogenic assay and an in vivo MCF7 tumor xenograft model. Our findings indicate that amifostine markedly reduced the volume of limb lymphedema and dramatically improved wound healing and tissue lymphostasis in the rodent lymphedema model. The in vivo and in vitro studies further demonstrated that amifostine offered no MCF7 tumor protection from radiation therapy. These pre clinical findings provide proof-of-principle to further delineate specific mechanisms underlying amifostine's beneficial effects, determine optimal amifostine-radiation therapy dosing regimens, and thereby expedite translation into clinical trials to reduce lymphedema incidence and severity in cancer patients at high lymphedema risk in whom radiation therapy is the recommended therapy. PMID- 20848993 TI - The role of Ang/Tie signaling in lymphangiogenesis. AB - The angiopoietin/Tie system plays a key role in remodeling and maturation of blood vessels as well as lymphatic vessels. The angiopoietin family includes four ligands (Ang-1, Ang-2 and Ang-3/4) and two corresponding tyrosine kinase receptors (Tie1 and Tie2). The best characterized angiopoietins are Ang-1 and Ang 2. Ang-1 acts as an obligate agonist of the Tie2 receptor. Binding of Ang-1 to Tie2 induces its autophosphorylation and promotes vascular stability and integrity. Ang-1 induces lymphatic vessel enlargement, sprouting and proliferation in a VEGFR-3-dependent manner. In contrast, whether Ang-2 is agonistic or antagonistic is dependent on dose and context. Ang-2 modulates angiogenesis in a cooperative manner with another important angiogenic factor, vascular endothelial growth factor A. In the presence of VEGF-A, Ang-2 promotes vascular sprouting. When in the absence of VEGF-A, Ang-2 induces vascular regression. However, genetic studies have revealed that Ang-2-deficient mice exhibit more severe defects in the lymphatic vasculature than in blood vessels. Ang-2 seems to be involved in the remodeling and stabilization of lymphatic vessels. Although the Ang/Tie system is essential for blood and lymphatic vessel remodeling and maturation, defining its precise role in blood and lymphatic development has been a major challenge. This review provides an update on our current understanding of the angiopoietin/Tie system in lymphangiogenesis. PMID- 20848994 TI - Different lymphscintigraphic patterns in patients with lymphedema distichiasis. AB - Mutation of the transcription factor FOXC2 gene has been identified as the cause of lymphedema-distichiasis syndrome (LD). Subjects with LD usually present with lower extremity lymphedema and distichiasis--an additional row of eyelashes. Typically, lymphscintigrams of patients with LD show good transport of the radiotracer from the feet to the inguinal lymph nodes accompanied by reflux of tracer to the skin of the lower extremities ("dermal backflow"). We have examined two patients with LD syndrome and were able to demonstrate two different distinct lymphscintigraphic patterns: lymphatic hyperplasia with reflux and obstructive. PMID- 20848995 TI - Effect of lateralization and handedness on the function of the lymphatic system of the upper limbs. AB - In the upper limbs (UL), lateralization or handedness coincides with functional (and/or anatomical) asymmetries. Scintigraphic techniques were used to investigate the function of the UL lymphatic system and to determine whether significant differences exist between right and left limbs. With limbs at rest, 99mTc-labeled HSA nanosized colloids were injected intradermally into the forearms in 19 volunteers. Activities in the axillary nodes were recorded 1 minute later, then every 20 minutes up to100 minutes later and reported as per ten thousands of injected activity. When comparing right injections to left injections, no significant difference was found using an unpaired statistical test. However, with paired t-tests, axillary node activity (mean +/- SD) was significantly higher when the right limb was injected than when the left limb was injected, both overall (n = 19) (at 100 minutes: 454 +/- 88 versus 299 +/- 45: p = 0.014) and when the 13 right-handed cases were analyzed separately (501 +/- 116 versus 285 +/- 65: p = 0.004). No difference was found for the six left-handed volunteers. Our results demonstrate, at least in the right handed subjects, the functional asymmetry of the superficial lymphatic system of the right and left upper limbs. PMID- 20848996 TI - Correlation between bioelectrical spectroscopy and perometry in assessment of upper extremity swelling. AB - Lymphedema is a common side effect of breast cancer treatment and is associated with increased upper extremity volume, functional impairment, and pain. While there is no cure for lymphedema, physical therapy treatment can often alleviate symptoms. To measure the efficacy of treatment, accurate assessment of the limbs is important. Current methods of assessment are complex (water displacement), marginally accurate (circumferential measurements), or expensive (opto-electrical systems). A new method for estimating tissue fluid is bioelectrical spectroscopy (BIS). This method measures impedance to small currents applied to the body and is easily performed. Acceptance of BIS devices for assessment of limb fluid will be dependent on the establishment of sufficient reliability and validity, and the objective of this study was to evaluate reliability and validity of this device compared to perometry. Both upper limbs of ten subjects previously treated for breast cancer were measured using BIS and perometry. We found that inter-rater reliability (r = 0.987) and intrarater reliability (r = 0.993) were acceptably high for the BIS unit and concurrent validity was r = -0.904, when compared to perometry. These results confirm that BIS can produce valid and reliable data related to the assessment of upper limbs affected by lymphedema. PMID- 20848997 TI - Paperless NHS hospital medical records. PMID- 20848998 TI - The future of the NHS. PMID- 20848999 TI - The European Working Time Directive and the impact on training: the current evidence. PMID- 20849000 TI - Role contradiction in physician-assisted suicide. PMID- 20849001 TI - Revalidation: an RCP perspective. PMID- 20849002 TI - Assisted suicide and voluntary euthanasia: role contradictions for physicians. AB - It is widely assumed by the general public that if assisted suicide (AS) or euthanasia (VE) were legalised doctors must be essentially involved in the whole process including prescribing the medication and (in euthanasia) administering it. This paper explores some reasons for this assumption and argues that it flatly contradicts what it means to be a doctor. The paper is thus not mainly concerned with the ethics of AS/VE but rather with the concept of a doctor that has evolved since the time of Hippocrates to current professional guidance reflected in healthcare law. The paper argues that the most common recent argument for AS/VE--that patients have a right to control when and how they die- in fact points to the involvement not of doctors but of legal agencies as decision makers plus technicians as agents. PMID- 20849003 TI - How to reduce morbidity and mortality from chest infections in rheumatoid arthritis. AB - Morbidity and mortality from pneumonia is increased in patients with rheumatoid arthritis. Factors contributing to this have been recently identified and a number of recommendations have been implemented in an attempt to reverse this trend. The present paper shows that these measures have combined to produce a fourfold reduction in both admissions and case fatality rates. In the study population, immunisation rates against influenza and pneumococcus have improved to 86% and 65%, oral steroid consumption has halved and disease modifying drugs were usually appropriately suspended during acute infection. These measures may now merit more widespread adoption. PMID- 20849004 TI - Impact of EWTD on patient:doctor ratios and working practices for junior doctors in England and Wales 2009. AB - The European Working Time Directive (EWTD) has resulted in large changes in the working patterns of junior doctors in the U.K. All consultant physicians in England and Wales were invited to anonymously submit data on their teams for 11 am and 11 pm on 5 November 2009. Data on doctor number, grade, location and patient number were collected. Data were available on 887 hospital teams at 11 am and on 670 teams at 11 pm. At 11 am, the average number of patients per ward doctor was 11 (2-65). At 11 pm the average number of patients per doctor was 61 (1-400). Consultants were present overnight in 6.1% of teams. Doctors in the first two years of training were the most senior medical cover in 63 teams. Sickness rates varied between 1.5% and 3.5% for junior doctors, and were significantly higher in the second foundation year. Vacancy rates at the specialist registrar level were 8.6%. Trainees were available for training 66-80% of the time. These findings have significant implications for patient safety and quality of medical training in the U.K. PMID- 20849005 TI - The NHS: the story so far (1948-2010). AB - The NHS has long held a paradoxical position in the national psyche: a constant, reassuring presence that seems to be in a state of continual flux. This is partly because while the service is based in the public sector (with its reputation for risk aversion and change at a glacial pace), it is also exposed to the ever present currents of political pressure. Equally important is the changing nature of both medical technology and public expectation, each of which exert constant and inexorable pressures on the service. This article will briefly describe the story of the NHS from its inception in 1948 to the present day, with an emphasis on developments over the last 20 years. During this time the notion of organising healthcare has developed and formed the focus of much of the change in systems across the developed world. The narrative will highlight some of the major challenges that the NHS will face over the next few years, and introduce the series about the future of the NHS that will appear in this journal signposting some of the topics that will be followed up in these articles. PMID- 20849006 TI - Do heart failure patients understand their diagnosis or want to know their prognosis? Heart failure from a patient's perspective. AB - The management of heart failure has evolved to become a multidisciplinary affair. Constraints of time and resources limit the amount of counselling that is given to heart failure patients in hospital and, with the advent of community heart failure specialist nurses, there is a trend to move more of these services into the community. Most heart failure patients are elderly and may find the information given to them, at the time of diagnosis and later on at home by heart failure nurses, difficult to grasp. In this study, patients' perspectives of a diagnosis of heart failure, their understanding of the diagnosis as well as what being diagnosed with heart failure means to them were recorded. Patients were questioned on whether the news of the heart failure diagnosis was broken to them in a sympathetic manner and how they felt about the information provided at diagnosis. PMID- 20849007 TI - Development of a web-based training programme for respiratory physicians in Yorkshire. AB - This article describes the establishment of a web-based training programme for postgraduate respiratory trainees. A pilot survey assessed trainees' experiences of online learning. All trainees had used the internet for work-related purposes with commonly used resources being Google, national society websites and specialty journals. A modular training programme based on article review, multiple choice questions (MCQs) and a reflective feedback exercise was subsequently established and trainees' experiences reviewed at three and 15 months. Trainees found that topics covered were appropriate, contained novel information and subjectively impacted on practice. Common problems were technical difficulties accessing the site (37%) and journal articles (74%), ambiguity of MCQs and difficulty finding time during normal working hours to complete modules. Trainees felt that feedback from MCQs and discussion with colleagues and their educational supervisor were useful methods to support their learning, but did not find the self-reflection exercise helpful. PMID- 20849008 TI - Taking training into your own hands. AB - The Young Diabetologists' Forum (YDF) is a group designed and run by specialist trainees in endocrinology and diabetes that aims to provide high quality educational events. The YDF recognised that not all trainees in the specialty had equitable access to training opportunities and resolved to try and remedy the situation. This article describes the history and evolution of the YDF into an organisation representing over 400 trainees in endocrinology and diabetes, providing up to seven training events per year and with a budget of over pounds 200,000. As well as offering education and training another key purpose of the YDF is to give trainees from around the country the opportunity to meet up and exchange thoughts and ideas. The overall aim of the organisation is to improve the lives of people with diabetes by helping to ensure that future specialists are fully equipped for their role. PMID- 20849009 TI - The simple clinical score: a tool for benchmarking of emergency admissions in acute internal medicine. AB - Quality of care in intensive care and surgery has benefited from establishing comparative standards. At present there is no accepted tool to compare outcomes for emergency admissions in internal medicine. The Simple Clinical Score (SCS) was used in 1098 consecutive medical emergency admissions to adjust mortality for severity of illness. Hospital mortality adjusted for severity of illness and length of stay in the cohort was in keeping with mortality in the Irish derivation study with a trend towards lower mortality in the very high-risk group. Three parameters with poor reproducibility were identified. The SCS has several potential applications: identification of patients with low risk of death suitable for early hospital discharge; early identification of patients with a high risk of death, who will require care in critical care areas (or specialist palliative care); and benchmarking of acute medical departments internationally in a similar way to how APACHE II scoring has been used in critical care units worldwide. PMID- 20849010 TI - A review of grading systems for evidence-based guidelines produced by medical specialties. AB - The development of evidence-based guidelines requires scrupulous attention to the method of critical appraisal. Many critical appraisal systems give 'gold standard' status to randomised controlled trials (RCTs) due to their ability to limit bias. While guidelines with a prominent research base consisting of RCTs have been well served by such systems, specialist societies with research bases consisting of a wide range of study designs have been at a disadvantage, potentially leading to inappropriately low grades being given for recommendations. A review of the Scottish Intercollegiate Guidelines Network, the Grading of Recommendations Assessment, Development and Evaluation, the Graphic Appraisal Tool for Epidemiology and the National Service Framework for Long Term Conditions grading systems was therefore undertaken. A matrix was developed suggesting the optimum grading system for the type of guideline being developed or question being addressed by a specialist society. PMID- 20849011 TI - Medical professionalism: what does the public think? AB - In the context of professionalism being viewed increasingly as a social contract, a survey was conducted to investigate the importance placed by the general public on doctors' professional attributes. A quota sample of 953 responded to a 55-item online inventory of professional attributes. The quotas closely represented the national census. The majority of the highly important attributes focused on the relationship with patients. Statistically, the responses emerged as a three-facet model (clinicianship, workmanship and citizenship) of medical professionalism. The general public did not equate professionalism with social standing, wealth production, physique or appearance. They recognised doctors as professionals by their good behaviour, high values and positive attitudes as clinicians, workmen and citizens. Although, their preference of professional attributes varied with the setting, eg patient consultation, working with others and behaving in society, they expected doctors to be confident, reliable, dependable, composed, accountable and dedicated across all settings. PMID- 20849012 TI - Ethnicity in rheumatic disease. PMID- 20849013 TI - The National Quality Agenda and its implications for specialist societies. PMID- 20849014 TI - Invited service reviews. PMID- 20849015 TI - A 66-year-old woman with recurrent pulmonary oedema. PMID- 20849016 TI - Concise guidance: diagnosis and management of giant cell arteritis. AB - Giant cell arteritis (GCA) or temporal arteritis (TA) with polymyalgia rheumatica (PMR) is among the most common reasons for long-term steroid prescription. GCA is a critically ischaemic disease, the most common form of vasculitis and should be treated as a medical emergency. Visual loss occurs in up to a fifth of patients, which may be preventable by prompt recognition and treatment. The British Society for Rheumatology (BSR) and the British Health Professionals in Rheumatology (BHPR) have recently published guidelines on the management of PMR. The purpose of this concise guidance is to draw attention to the full guidelines to encourage the prompt diagnosis and urgent management of GCA, with emphasis on the prevention of visual loss. They provide a framework for disease assessment, immediate treatment and referral to specialist care for management and monitoring of disease activity, complications and relapse. PMID- 20849017 TI - Neurology of endocrine disease. PMID- 20849018 TI - What's new in dementia? PMID- 20849019 TI - New thoughts on first seizure. PMID- 20849020 TI - Guillain-Barre syndrome. PMID- 20849021 TI - The bedside assessment of vertigo. PMID- 20849022 TI - Diarrhoea in a family from Pakistan. PMID- 20849023 TI - Acute aortic dissection with a high D-dimer and pleuritic chest pain in an airline passenger. PMID- 20849024 TI - Dr. Winkel's crucifix--moral ambiguity in The Third Man. PMID- 20849025 TI - Consultation skills training for specialist trainees. PMID- 20849026 TI - Acute heart failure. PMID- 20849027 TI - Managing capacity and demand across the patient journey. PMID- 20849028 TI - 'With a pinch of salt' revisited. PMID- 20849029 TI - Experience of a consultant-led service to improve the safety of insertion of chest drains. PMID- 20849030 TI - The polypill available for general purchase? PMID- 20849031 TI - The effect of causal chain length on counterfactual conditional reasoning. AB - We investigated German and Nichols' finding that 3-year-olds could answer counterfactual conditional questions about short causal chains of events, but not long. In four experiments (N = 192), we compared 3- and 4-year-olds' performance on short and long causal chain questions, manipulating whether the child could draw on general knowledge to answer. We failed to replicate German and Nichols' result, finding instead that in two experiments (Experiments 1 and 3) there was no difference in performance on short and long causal chain questions and in two experiments (Experiments 2 and 4) children showed the opposite pattern: short causal chain questions were more difficult than long. These two unexpected patterns of results were replicated in a fifth study (N = 97). Children with lower language ability found short causal chains more difficult than long. Performance by children with higher language ability was unaffected by the length of the causal chain they had to consider. We found no evidence that children showed precocious counterfactual thinking when asked about recent events in a causal chain and conclude that counterfactual thinking develops after 4 years of age. PMID- 20849032 TI - Concepts of kinship relations and inheritance in childhood and adolescence. AB - This paper examines the development and consistency of children's (4, 7, 10, and 14 years) naive concepts of inheritance using three tasks. A modified adoption task asked participants to distinguish between biological and social parentage in their predictions and explanations of the origins of different feature types (physical characteristics, disabilities, and personality traits). The causal mechanisms task asked participants to rate their preference for various mechanisms of inheritance for physical features. The family relatedness task required participants to provide judgements on the relatedness of family members and explain their understanding of kinship terms. Developmental trends were revealed in all three tasks. There was a trend towards increased consistency in judgements across tasks with age, but low correlations between explanations given in different task contexts. Findings are discussed with reference to the onset and variability of inheritance concepts and the implications for education and future research. PMID- 20849033 TI - Development of metaphor and metonymy comprehension: receptive vocabulary and conceptual knowledge. AB - Figurative language, such as metaphor and metonymy are common in our daily communication. This is one of the first studies to investigate metaphor and metonymy comprehension using a developmental approach. Forty-five typically developing individuals participated in a metaphor-metonymy verbal comprehension task incorporating 20 short picture-stories. Cross-sectional trajectory analyses linking task performance to either chronological age or receptive vocabulary (mental age, MA) were used to compare the development of metaphor and metonymy. Results showed that development of metaphor and metonymy comprehension is strongly linked with chronological and MA, but metaphor comprehension develops at a slower rate compared to metonymy. It was also found that participants, across all ages, consistently showed around 21% better performance on metonymy. The relationship between metaphor and metonymy comprehension is discussed in terms of linguistic and cognitive models of figurative language comprehension arguing that metonymy is cognitively more basic than metaphor. PMID- 20849034 TI - Children's scripts for social emotions: causes and consequences are more central than are facial expressions. AB - Understanding and recognition of emotions relies on emotion concepts, which are narrative structures (scripts) specifying facial expressions, causes, consequences, label, etc. organized in a temporal and causal order. Scripts and their development are revealed by examining which components better tap which concepts at which ages. This study investigated whether a facial expression or a brief story describing an emotion's cause and consequence was the stronger cue to basic-level and social emotions. Children (N = 120, 4-10 years) freely labelled the emotion implied by faces and, separately, stories for six basic-level emotions (happiness, anger, fear, surprise, disgust, and contempt) and three social emotions (embarrassment, compassion, and shame). Cause-and-consequence stories were the stronger cue overall, especially for fear, disgust, and social emotions. Faces were the stronger cue only for surprise. Younger children assimilated social emotions into basic-level emotion categories (sadness and anger); older children differentiated them. Differentiation occurred earlier for stories than for faces. PMID- 20849035 TI - The facilitatory effect of negative feedback on the emergence of analogical reasoning abilities. AB - This paper focuses on the development of analogical reasoning abilities in 5- and 6-year-old children. Our particular interest relates to the way in which analogizing is influenced by the provision of task-based feedback coupled with a self-explanation requirement. Both feedback and self-explanation provide children with opportunities to engage in self-reflective thinking about the process of analogical reasoning. To examine the role of such metacognitive factors in analogical strategy development the reported study combined a proportional analogy paradigm with a small-scale microgenetic approach involving multiple testing sessions over a restricted time period. The key manipulation involved exposing participants either to the correct or incorrect analogy completions of another reasoner that they were then asked to explain. The data revealed that the development of an effective analogizing strategy embodying a 'relational shift' from superficial to relational responding was modulated by the feedback condition that the child was placed in, with a negative feedback intervention providing the greatest developmental benefit. We suggest that the value of negative feedback for the acquisition of analogical reasoning abilities derives from the way in which a self-reflective analysis of the reasons for erroneous responses sensitizes the child to a deeper understanding of how to make effective relational mappings. PMID- 20849036 TI - Children's conceptions of mental illness: a naive theory approach. AB - This paper reports two studies that investigated children's conceptions of mental illness using a naive theory approach, drawing upon a conceptual framework for analysing illness representations which distinguishes between the identity, causes, consequences, curability, and timeline of an illness. The studies utilized semi-structured interviewing and card selection tasks to assess 6- to 11 year-old children's conceptions of the causes and consequences (Study 1) and the curability and timeline (Study 2) of different mental and physical illnesses/ailments. The studies revealed that, at all ages, the children held coherent causal-explanatory ideas about the causes, consequences, curability, and timeline of both mental and physical illnesses/ailments. However, while younger children tended to rely on their knowledge of common physical illnesses when thinking about mental illnesses, providing contagion and contamination explanations of cause, older children demonstrated differences in their thinking about mental and physical illnesses. No substantial gender differences were found in the children's thinking. It is argued that children hold coherent conceptions of mental illness at all ages, but that mental illness only emerges as an ontologically distinct conceptual domain by the end of middle childhood. PMID- 20849037 TI - Children with autism's perception and understanding of ambiguous figures: evidence for pictorial metarepresentation, a research note. AB - A large body of autism research over the last 20 years has shown that people with autism have difficulties understanding mental states. This has been conceived of as a metarepresentational deficit. An open question is whether people with autism's metarepresentational deficit is limited to the mental domain. This research explores individuals with autism's understanding of the representational nature of pictures. With the use of ambiguous figures, where a single stimulus is capable of representing two distinct referents, we compared metarepresentational abilities in the pictorial and mental domains and the perception of pictorial ambiguity. Our findings indicate that individuals with autism are impaired in mental metarepresentation but not in pictorial metarepresentation. These findings suggest that children with autism understand the representational nature of pictures. We conclude that children with autism's understanding of the representational nature of pictures is in advance of their metarepresentational understanding of mind. Their perception of figure ambiguity is comparable to the typical population. PMID- 20849038 TI - Longitudinal associations between adolescent alcohol use and parents' sources of knowledge. AB - The aim of this study was to test the direction of effect in the relationship between parents' sources of knowledge (parental monitoring and child disclosure) and adolescent alcohol use. The participants were 215 adolescents and their mothers, randomly selected from urban and rural areas in Cyprus. A 3-month, two timepoint longitudinal design was used in which adolescents completed the alcohol use disorders identification test while mothers completed a parental knowledge questionnaire. The results of this study showed that parental monitoring did not predict subsequent adolescent alcohol use. However, child disclosure at Time 1 negatively predicted adolescent alcohol use at Time 2. Moreover, adolescents' alcohol dependence symptoms at Time 1 negatively predicted both sources of parental knowledge at Time 2. PMID- 20849039 TI - Behavioural precursors of attachment representations in middle childhood and links with child social adaptation. AB - Concordance between age-6 attachment behaviour and age-8 doll play attachment representations during the school-age period, and associations between these measures and child social adaptation at school were examined. One hundred and twenty-nine 6-year-olds and their mothers participated in a separation/reunion protocol. Two years later, 104 children completed a doll play narrative task. Teachers evaluated child behaviour problems and prosocial behaviour at both ages. Results showed a significant four-way concordance between age-6 attachment behaviour and age-8 doll play classifications. Each of the four attachment classifications was concordant in the absence of major negative life-events, but only the disorganized classifications remained concordant when at least one negative life-event occurred between the two assessment times. Children with a disorganized attachment classification or representation had higher externalizing scores than secure and avoidant children at both timepoints. Finally, the avoidant and disorganized behavioural classifications predicted avoidant and disorganized representations, respectively, even when controlling for age-6 teacher reports of social adaptation. PMID- 20849040 TI - Immigrant children's peer acceptance and victimization in kindergarten: the role of local language competence. AB - The study investigates peer acceptance and victimization of immigrant and Swiss children in kindergarten classes. Our first aim is to compare peer acceptance and victimization of Swiss and immigrant children. Secondly, we explore the role of their local language competences (LLCs). The sample was drawn from kindergartens in communities in the German-speaking part of Switzerland. A representative sample of 568 boys and 522 girls (mean age 5.8 years) took part in the research. Teachers completed questionnaires on children's victimization, bullying, and LLC. The nationality background of parents was indicated by teachers and parents. To assess peer acceptance, a peer nomination method was used. Immigrant children showed less acceptance by peers and were more often victimized than their Swiss peers. There was a significant interaction effect for LLC and national background of mothers, showing that LLC was positively associated with peer acceptance for children of an immigrant background but not for Swiss children. Furthermore, peer acceptance mediated the effect of national background of mothers on victimization. Results are discussed in terms of the need to improve immigrant children's LLC. PMID- 20849041 TI - Media use and school achievement--boys at risk? AB - In work done at the German Criminological Research Institute of Lower Saxony (KFN) various methods have been used to investigate how specific inappropriate media usage patterns affect academic performance in children and adolescents. The findings are paralleled by current international research indicating a negative relationship between these two variables. Based on a cross-sectional survey of 5,529 fourth grade students and a longitudinal panel study with 1,157 primary schoolchildren, a key finding can be demonstrated: the more time students spend on consuming media and the more violent its contents are, the worse are their marks at school, even when controlling for vital factors such as family, educational, or immigrant background. In particular, boys who gender-specifically are better equipped with electronic media devices, who partially have extensive media usage times and who strongly prefer violent media content, are at the risk of showing poor school performance. In fact, a decrease in academic performance of boys can be observed in German school statistics. By presenting first results of a school-based intervention programme, a promising approach to the reduction of detrimental effects of electronic media use on school performance is introduced. PMID- 20849042 TI - Protective effect of the thoracic cage on parenchyma in response to trauma direction in blunt thoracic trauma: an experimental study. AB - BACKGROUND: We aimed to investigate the protective potential of the thoracic cage on the parenchyma in response to blunt trauma from different directions in an animal model. METHODS: Female Wistar albino rats were divided into control, anterolateral, lateral and posterolateral trauma groups, with six rats in each group. A weight of 500 g was dropped from a height of 40 cm on the left hemithorax to produce an energy of 1.96 joules, using a specially designed platform. Respiratory rates and heart rates were noted before and at 0, 1, and 5 minutes after trauma. Twenty-four hours later, the left lungs were excised for wet lung weight measurement, histological examinations and tissue malondialdehyde determination. RESULTS: Severe pulmonary contusion was observed in all trauma groups according to histological parameters. Malondialdehyde was increased in both the lateral and posterolateral groups. Wet lung weight was increased only in the posterolateral trauma group when compared to controls. Histologically, macrophages were increased and mononuclear cell infiltration was significant in the posterolateral trauma group. There were no significant changes in physiological parameters in the groups. CONCLUSION: Lung parenchyma seems to be badly affected after trauma to the posterolateral thoracic wall. Different thoracic regions may respond differently to the same traumatic stress, and this may be related to the biomechanical properties of the thoracic cage. PMID- 20849043 TI - Levosimendan up-regulates transforming growth factor-beta and smad signaling in the aorta in the early stage of sepsis. AB - BACKGROUND: This prospective, controlled experimental study was planned to investigate the effects of levosimendan on transforming growth factor (TGF)-beta3 and Smad1, Smad2 and Smad3 expression in the early stages of sepsis. METHODS: Twenty-four rats were randomized into four groups: (1) sham-operated controls, (2) dobutamine group--subjected to abdominal hypertension and peritonitis-induced sepsis using cecal ligation and puncture (CLP), then treated with 10 microg x kg( 1) min(-1) intravenous (IV) dobutamine infusion, (3) levosimendan group--as in 2, then treated with levosimendan IV bolus 200 microg x kg(-1) followed by 200 microg x kq(-1) min(-1) IV infusion, and (4) a control group as in 2, with no treatment. All rats were killed 8 hours after CLP. Aorta tissue samples were analyzed by immunohistochemical staining. RESULTS: CLP caused mild interleukin (IL)-1 immunostaining in both control and dobutamine groups. Immunoreactivity of tumor necrosis factor (TNF)-alpha was mild in both sham and control groups. TGF beta3 immunostaining was mildly increased in groups sham, control and dobutamine, whereas it was found moderate in group levosimendan. Smad1, Smad2 and Smad3 were found moderately increased only in group levosimendan. CONCLUSION: Beneficial effects of levosimendan on hemodynamics and global oxygen transport were reported in experimental and clinical trials. Besides its potency on C++ ion sensitivity, it should influence inflammatory cytokine production by diminishing TGF-beta3 and Smad1, Smad2 and Smad3 expression. PMID- 20849044 TI - Pilot implementation of a technologically advanced system for the optimization of pre-hospital, trauma patient care. AB - BACKGROUND: Cooperation between medical informatics, wireless communication and pre-hospital emergency services is essential for the optimal pre-hospital patient treatment. The use of technological innovations improves medical care in the pre hospital setting with regard to the organization of an integrated center, which coordinates all parties involved for the patient's best interest. METHODS: A dispatch center was developed in the city of Patras, in southwestern Greece, equipped with a Geographic Information System (GIS), which immediately points out the location of emergency vehicles (EVs) on a digital map depicting the city plan. Additionally, three ambulances of the National Center of Immediate Aid (NCIA) were equipped with a decentralized traffic management system for the vehicle's traffic priority at signaled junctions. The system consisted of a cellular-based (GSM) telemedicine module, a Global Positioning System (GPS) and a web camera system in the vehicle cabin. RESULTS: The aforementioned system provided considerable assistance to the pre-hospital treatment first by selecting the ambulance closest to the accident's location and then by pinpointing the optimum route to the hospital, thus significantly reducing the overall transportation time. CONCLUSION: The project's objective to coordinate emergency hospital departments involved in the treatment of trauma patients with other emergency services by utilizing high technology was achieved within this interdisciplinary effort. PMID- 20849045 TI - Traumatic vascular injuries of the lower extremity: report of the Iranian National Trauma Project. AB - BACKGROUND: This study aimed to determine the pattern of traumatic lower extremity vascular injuries in Iran. METHODS: Patients with vascular injury of the lower extremity were selected from the Iranian National Trauma Project. This project was conducted in eight major cities during 2000-2004 and consisted of more than 17000 patients. RESULTS: Sixty-three subjects (54 men) with a total of 92 vascular injuries of the lower extremity were identified. Mean age of the patients was 25.87 +/- 13.37 years. Blunt trauma was more frequent than penetrating (62% vs. 38%). In 36 cases (57%), road traffic crash (RTC) was the cause of injury. In 21% of the patients (n=24), vascular injury resulted from occupational trauma. Workers (n=23, 20%) were the most frequently affected group. Three patients (5%) died due to severity of the associated injuries. CONCLUSION: Our results revealed that RTC is the most frequent cause of lower extremity vascular injuries in Iran. Our findings also showed that occupational injuries have considerable prevalence. Establishment of preventive strategies to reduce the frequency of these injuries is recommended. PMID- 20849046 TI - A cost analysis of radiologic imaging in pediatric trauma patients. AB - BACKGROUND: The aim of this study was to examine the cost of radiologic imaging in pediatric trauma patients admitted to the pediatric emergency department. METHODS: All patients were retrospectively evaluated according to age, gender, details of injury, radiological investigations ordered and their results, cost of radiologic imaging, length of stay, outcome of the injury, and hospitalization rates. RESULTS: The cost of radiologic imaging was retrospectively analyzed in 1231 trauma patients aged between one month and 15 years (mean 5.91 +/- 3.82 years). For the 996 patients who had radiological imaging, 3382 images were taken in total. Of these, only 300 (8.8%) were abnormal. The mean (and SD) total cost of radiologic imaging was US$ 40.42 ($34.38) (range $4.67 to $139.26). Total cost correlated inversely with Glasgow Coma Scale (GCS) (r = -0.37, p < 0.001), directly with Injury Severity Score (ISS) (r = -0.27, p < 0.001) and was not correlated with the Pediatric Trauma Score (PTS) (r = -0.16, p > 0.05). The mean (and SD) duration of hospital stays was 8.54 (10.91) hours. CONCLUSION: Advanced radiological images may help in early diagnosis of trauma cases. However, periodic education programs to prevent unnecessary radiological imaging in emergency departments are also necessary to decrease the cost of these imaging modalities. PMID- 20849047 TI - The real victims of the islamic feast of sacrifice: injuries related to the sacrifice. AB - BACKGROUND: During the Feast of Sacrifice in Muslim countries, thousands of animals are slaughtered every year. Many injuries occur during the sacrifice. Thus, the aim of this study was to determine the demographic characteristics of patients, their slaughtering experience, types of injury, and related hospital costs. METHODS: This prospective observational study was conducted in Emergency Departments (EDs) of Gazi University and Ankara Training and Research Hospital. One hundred and twenty adult patients were admitted to EDs with injuries related to the slaughter and processing of meat during two consecutive Feasts of Sacrifice. RESULTS: The average age of patients was 41.85 +/- 13.6, and 101 patients (84.2%) were male. One hundred sixteen patients (96.7%) were not professionals. Ninety-seven patients (80.8%) were admitted to EDs on the first day of the feasts. Ninety-nine injuries (82.5%) were related to cutting tools, and 21 patients (17.5%) were admitted with complaints of either falling or being harmed by animals. Fourteen patients (11.7%) with tendon lacerations, finger amputations, extremity fractures, and eye traumas were taken into surgery. Hospital costs were a median 104.76 [67.48-322.12] Turkish Liras (74.30 [47.86 228.45] USD). CONCLUSION: Proper conditions for slaughter should be provided and professionals should perform the slaughter and/or processing of the meat. EDs should be supplied both more equipment and physicians, especially on the first days of the feast. PMID- 20849048 TI - In-sleeve on-table colonic irrigation in telescopic fashion and intraoperative colonoscopy: a novel technique. AB - BACKGROUND: In the management of large bowel obstruction, on-table lavage and intraoperative colonoscopy allow a safe resection and primary anastomosis in selected patients. Previous techniques carry serious disadvantages, in the form of inconvenient drainage route and spillage. A novel technique of in-sleeve on table colonic lavage using a camera sleeve is described. METHODS: Six patients (58-80 years old, median 73) who admitted to emergency service between 2003 and 2009 with colonic obstruction due to tumor underwent colonic resection and primary anastomosis after on-table lavage. The colon was divided proximally to the obstruction, and then was introduced into a nylon sleeve and sutured. A Foley catheter was inserted to the cecum for irrigation. After irrigation, intraoperative colonoscopy was accomplished. RESULTS: The technique was successfully used in all patients. The colonic irrigation took 12-16 minutes and colonoscopy was completed in 7-20 minutes. There was no contamination during the washout of the colon. Four patients underwent left hemicolectomy; extended right hemicolectomy and total colectomy was performed in the remaining two. There were no complications in the postoperative period. CONCLUSION: The described technique of in-sleeve on-table lavage is safe and quick to washout the fecal load in the obstructed colon. It prevents the contamination risk and shortens the operative period for resection and primary anastomosis. This method also enables an effective intraoperative colonoscopy. PMID- 20849049 TI - Small bowel tumors in emergency surgery. AB - BACKGROUND: The aim of the present study was to describe the clinical presentation, diagnostic work-up, surgical therapy, and prognosis of 13 patients with small bowel tumor admitted for surgical procedures in an emergency setting. METHODS: From 1996 to 2008, 13 consecutive surgical cases of small bowel tumors were treated at the Cumhuriyet University Faculty of Medicine, Department of General Surgery, and Kutahya State Hospital, Department of General Surgery. Clinical and radiological charts of these patients were reviewed retrospectively from the department database. RESULTS: Intestinal obstruction (7 cases) and perforation (5 cases) were the most common clinical presentations, followed by intussusception (1 case). Adenocarcinoma was the most frequent histologic type (4 cases), while small bowel sarcoma was seen in three cases and non-Hodgkin lymphoma in two cases. The remaining cases had carcinoid tumor, small bowel angioleiomyoma, Brunner's gland adenoma, and inflammatory pseudotumor of the small intestine. CONCLUSION: Small bowel tumors are rare, the symptoms often non specific, and the accuracy of different diagnostic tests remains to be improved. Timing and type of the intervention to the process and biological behavior of the pathological cells predict the prognosis. PMID- 20849050 TI - Unstable metacarpal and phalangeal fractures: treatment by internal fixation using AO mini-fragment plates and screws. AB - BACKGROUND: Accurate open reduction and internal fixation for metacarpal and phalangeal fractures of the hand is required in less than 5% of the patients; otherwise, closed treatment techniques offer satisfactory results in most of these cases as these fractures are stable either before or after closed reduction. AO mini-fragment screws and plates, when used in properly selected cases, can provide rigid fixation, allowing early mobilization of joints and hence good functional results while avoiding problems associated with protruding K-wires and immobilization. The advantages of such internal fixation urged us to undertake such a study in our state where such hand injuries are commonly seen. METHODS: Forty patients with 42 unstable metacarpal and phalangeal fractures were treated with open reduction and internal fixation using AO mini-fragment screws and plates over a period of three years in a prospective manner. RESULTS: The overall results were good in 78.5% of cases, fair in 19% of cases and poor in 2.5% of cases, as judged according to the criteria of the American Society for Surgery of the Hand. CONCLUSION: This technique is a reasonable option for treating unstable metacarpal and phalangeal fractures as it provides a highly rigid fixation, which is sufficient to allow early mobilization of the adjacent joints, thus helping to achieve good functional results. PMID- 20849051 TI - Diagnostic process and management of diaphragmatic injuries: approach in patients with blunt and penetrating trauma. AB - BACKGROUND: Diaphragmatic rupture is one of the most commonly missed injuries in trauma cases. Traditionally, laparotomy or thoracotomy has been the treatment of choice for this condition. We aimed to evaluate the diagnostic process in patients with diaphragmatic injuries (DIs) who were diagnosed with diaphragm rupture during the preoperative or intraoperative course together with morbidity and mortality rates. METHODS: Sixteen patients with DIs were admitted to our department during the last seven-year period. Surgical procedure, accompanying injuries, duration of hospital stay, transfusion necessity, and morbidity and mortality rates were analyzed retrospectively. RESULTS: In seven years, 16 patients were treated and followed-up for DI. Female/male ratio was 2/14. Fifteen patients were operated and one was treated conservatively. The mortality rate was 2/16. CONCLUSION: DIs are being seen with increasing frequency in recent years. In patients with high Injury Severity Score (ISS), probability of DI should be taken into consideration. PMID- 20849052 TI - Gallstone ileus as an unexpected complication of cholelithiasis: diagnostic difficulties and treatment. AB - BACKGROUND: Gallstone ileus is a rare complication of cholelithiasis, mostly in the elderly. The aim of this study was to evaluate our experience with 12 gallstone ileus cases and discuss current opinion as reported in the literature. METHODS: Data of 12 patients operated between January 1998 and January 2008 with gallstone ileus were retrospectively studied. RESULTS: There were 12 cases (9 F, 75%; 3 M, 25%) with a mean age of 63.6 (50-80) years. Median duration of symptoms before admission to the hospital was 4.1 (1-15) days. Preoperative diagnosis was made in only five cases (41.6%). Enterolithotomy was done in nine cases (75%). Enterolithotomy and resection of the small intestine--required for decubital necrosis from the gallstone--was performed in one case (8.3%). In one case (8.3%), enterolithotomy was completed in one stage with cholecystectomy and closure of the fistula during acute surgery, and in another case (8.3%), enterolithotomy + primary suturing of the jejunal perforation was performed. There were two (16.6%) perioperative mortalities. CONCLUSION: Gallstone ileus remains a diagnostic challenge despite advances in imaging techniques, and pre operative diagnosis is often delayed. Gallstone ileus should be suspected in all cases admitted to the emergency service with acute intestinal obstruction with a history of cholelithiasis, especially in the elderly and females. PMID- 20849053 TI - Acute mechanical intestinal obstructions. AB - BACKGROUND: In this study, we evaluated our treatment modality and timing of surgery in acute mechanical intestinal obstruction (AMIO) patients who were admitted to the emergency room. METHODS: Only patients with the diagnosis of AMIO were included in this study. Surgery was performed in patients with hemodynamic instability despite fluid resuscitation and peritoneal signs upon physical examination. Patients were divided into two groups. Adhesion cases were assigned to Group 1, while non-adhesion cases were assigned to Group 2. The decision to provide surgical or medical therapy was assessed 24 hours (h) after admission. RESULTS: Twenty-two patients in Group 1 and 53 patients in Group 2 underwent surgical procedures. The difference between the groups was statistically different (p < 0.05). The mean monitoring time after admission to the hospital was 128.3 +/- 24.85 h and 43.1 +/- 15.51 h in Groups 1 and 2, respectively (p = 0.0001). In Group 2, 76.6% of the patients who were monitored for over 24 hours required surgery. In contrast, this rate was only 36% in Group 1 (p < 0.05). CONCLUSION: Our clinical experience shows that medical therapy and monitoring over 24 hours is not a good substitute for surgical treatment of AMIO when the obstruction is not due to an adhesion. PMID- 20849054 TI - Our 18-month experience at a new burn center in Gaziantep, Turkey. AB - BACKGROUND: This study is a retrospective analysis of 411 cases admitted to Cengiz Gokcek State Hospital Burn Center from 1 May 2007 to 10 October 2008. METHODS: Through an electronic database of medical records of the burn center, all patients admitted to the center were traced. With respect to the numbers of burns according to sex, 35.7% (147) of the cases were female and 64.3% (264) were male. RESULTS: For total burn surface area (TBSA) of 20-35%, the hospital stays for electric, flame and scald burns were 28, 18 and 12 days, respectively. For TBSA of 35-50%, electric burns resulted in a mean stay of 44 days, followed by chemical burns (33 days), flame (31 days), and scald (22 days). For TBSA over 50%, electric and scald burns resulted in hospital stays of > or =40 days. Case fatality was 5.6% (23 patients). 1.2% of the study group experienced at least one episode of epilepsy during treatment. Six cases had acute renal failure that responded to hemofiltration during treatment. Eight cases, which were flame burns, also had inhalation injury, and four of these cases required mechanical ventilation. CONCLUSION: Members of the burn care team not only carry a heavy workload in the treatment of burn victims, we believe they also have the responsibility of recording and publishing their own data to increase the overall knowledge related with the subject, which will guide future studies. PMID- 20849055 TI - [Analysis of preventable deaths according to postmortem reports in traumatic deaths]. AB - BACKGROUND: In this study, we aimed to investigate preventable deaths due to trauma among cases in whom autopsy and postmortem examinations were performed in Diyarbakir Council of Forensic Medicine. METHODS: In this study, which was planned as retrospectively descriptive, demographic data, type of injury, cause of injury, locations of injuries, cause of death, and scene of death data were withdrawn through the reports of deaths due to trauma in Diyarbakir Council of Forensic Medicine between 1 January 2008 and 31 December 2008. Medical errors in these deaths and preventable deaths were analyzed with this data. The criteria of American College of Surgeons Committee on Trauma was used for definition classification of errors and compose of preventability criteria. RESULTS: It was concluded that of the 747 cases taken into consideration, 4.15% (n=31) were preventable, 16.20% (n=121) were potentially preventable and 79.65% (n=595) were unpreventable. Suboptimal care in 49.34% (n=75), delay in treatment in 41.45% (n=63), missed diagnosis in 10.53% (n=16), clinical judgment error in 10.53% (n=16), missed medical administration in 7.23% (n=11), and other mistakes in 3.95% (n=6) of the cases were determined. CONCLUSION: When the results were compared with the studies performed in the areas in which modern trauma care and trauma centers are located, the preventable death ratio was found high. As a result, it has been determined that development of a modern trauma system and trauma centers have significant roles in decreasing preventable death ratios. PMID- 20849056 TI - [Our childhood cases with intussusception and pneumatic reduction]. AB - BACKGROUND: Intussusception is defined as telescopic insertion of the terminal ileum in to the colon after the cecum and colon. The aim of this study was to present our experience in pneumatic reduction of intussusception. METHODS: In our study, 118 intussusception cases treated between 1996 and 2008 were analyzed. Age, gender, admission time, diagnostic/treatment methods, types of intussusception including leading point, and postoperative complications were evaluated. RESULTS: Of these patients, 76 (64%) were male and 42 (36%) were female. Mean age was 25 +/- 34 months (3-180 months). The most common clinical presentations were vomiting, abdominal pain/irritable crying and bloody stools. Intussusceptions were ileocolic in 109 (92.3%) patients, ileoileal in 7 (6%) patients, and colocolic in 2 (1.7%) patients. No mortality was noted. Fifty-three patients (45%) were treated by nonoperative reduction whereas the remainder were treated surgically. Among 65 patients operated, 13 leading points were detected. Pneumatic reduction success rate was 86%. Age significantly reduced the pneumatic reduction success rate; however, the duration between the beginning of symptoms and hospital admission and bloody stool were not effective. CONCLUSION: Intussusception can be treated by non-operative methods when diagnosed early. Our results suggest that pneumatic reduction of intussusception in the pediatric population should be considered as a first choice. PMID- 20849057 TI - Reconstruction of lower extremity close-range shotgun injuries with gracilis free flap: a report of two cases. AB - Close-range shotgun injury to the lower extremity is a devastating problem and is a challenge to the surgeon. Point-blank shotgun injuries to the extremities create a typical wound that is deep but not wide. These wounds almost always need to be treated with local or distant tissue transfer. We report two cases of shotgun injury to the lower extremity at point-blank range, which were treated using debridement, vacuum-assisted closure and free gracilis muscle flap transfer. PMID- 20849058 TI - [Scar endometriosis in the rectus abdominis muscle]. AB - Endometriosis is defined as the presence of ectopic functional endometrial tissue outside the uterine cavity. The most common locations are within the pelvis. Unusual sites ofendometriosis outside the pelvis have been reported, including the bladder, intestine, appendix, surgical scars, hernia sac, lung, kidney, and extremities. The diagnosis of scar endometriosis is usually not difficult and is based on history and physical examination. We report here two cases who developed endometriosis on the abdominal wall in the rectus abdominis muscle and were treated with local excisions. PMID- 20849059 TI - Wooden foreign body in the forearm--presentation after eight years. AB - We report herein a case in which symptoms appeared eight years after the apparent trauma, which had been forgotten. Surgery yielded a wooden foreign body in the forearm. A 10-year-old boy presented with a six-week history of pain followed by swelling in his left forearm occurring after a trivial blunt trauma, with occasional bouts of fever. There was an oval swelling (7 cm x 3 cm) on the posterolateral aspect of the upper third of the left forearm. Tenderness, increased local temperature and elicitable fluctuation, with no scars or wounds (signs of trauma), were noted. Radiographs of the forearm revealed a soft tissue swelling but no fracture, periosteal reaction or other bony lesion. Aspiration of the swelling yielded purulent material (gram stain negative). The abscess was drained and exploration of the cavity revealed a 14 mm long slender wooden foreign body embedded in granulation tissue. On retrospective enquiry, the family reported that the child had sustained a penetrative injury eight years before after falling on a broomstick. Presence of a foreign body must be kept in mind while investigating a suspicious swelling on the extremities. A thorough history and careful imaging are the keys to diagnosis. PMID- 20849060 TI - Delayed complete gastric outlet obstruction due to a dinner fork: report of a case. AB - Ingestion of foreign bodies can be a common problem especially among children, alcoholics, psychiatric patients, and senile patients, but ingestion of a metallic dinner fork is uncommon. Foreign bodies with smooth edges usually do not pose significant problems, but a sharp foreign object that is not retrieved at the earliest may penetrate the wall and cause complications. Ingested foreign bodies usually pass the intestinal tract without problems, and perforation occurs in less than 1%. In this paper, a case of rare gastric outlet obstruction due to a dinner fork, which was ingested 25 days before, is reported. PMID- 20849061 TI - Air bag-mediated fatal craniocervical trauma: a case report. AB - This case report describes a four-year-old girl (102 cm, 17 kg) who sustained fatal craniocerebral injuries as a result of an inflating automobile air bag. The car struck the lid of the sewer system, which was 15 cm above the ground level, at a low speed, and both the driver and passenger air bags inflated. Despite the fact that air bag usage has lessened both the possibility and severity of occupant injuries in frontal collisions, case reports of serious injuries and even deaths especially in children due to air bag deployment, particularly during low speed impacts, highlight the need for changes in both system design and possibly the threshold speed of air bag deployment. PMID- 20849063 TI - Assessing the fate of nitrosamine precursors in wastewater treatment by physicochemical fractionation. AB - Source control or elimination of precursors of NDMA and other nitrosamines in wastewater requires information on their physicochemical properties, which is still limited. Thus we developed a multistep fractionation method based on a combination of consecutive filtration steps to <1 MUm, <0.2 MUm, and <2.5 kDa followed by solid-phase extraction on a C18 column and validated it using model NDMA precursors covering a wide polarity range. The membrane filtration to <2.5 kDa was suitable to separate a low-molecular weight precursor fraction but partially removed hydrophobic compounds by sorption. Fractionation on a C18 column allowed distinguishing highly polar precursors (such as dimethylamine) from less polar ones (such as ranitidine or other pharmaceuticals). Application of the fractionation procedure together with the formation potential test revealed that in the influent of one studied wastewater treatment plant about 50% of all precursors were associated with colloids or macromolecules, suggesting that these fractions comprise sorbed hydrophobic precursors. During activated sludge treatment small polar and charged NDMA and other nitrosamines' precursors were removed to about 80%. In contrast, less polar precursors were more recalcitrant. In advanced treatment steps, only small fractions of the precursors were removed by the prechlorination/ultrafiltration step, while reverse osmosis removed >98% of all precursors. PMID- 20849062 TI - Optimization of the N-lost drugs melphalan and bendamustine: synthesis and cytotoxicity of a new set of dendrimer-drug conjugates as tumor therapeutic agents. AB - Bendamustine and melphalan are very promising alkylating drugs with applicability in the treatment of various tumoral diseases, e.g., chronic lymphocytic leukemia (CLL) or breast cancer. However, numerous adverse effects limited their use. Therefore, 1,3,5-tris(3-aminopropyl)benzene (G0) and its G1 analogue 3,5-bis(3 aminopropyl)-N-(3-{3,5-bis[3-{3,5-bis(3 aminopropyl)benzoylamino}propyl]phenyl}propyl)benzamide were selected to design cytostatic drug-dendrimer conjugates to achieve tumor cell accumulation by endocytosis as already demonstrated for platinum complexes. The dendrimers act as carriers and an N-(2-hydroxyethyl)maleimide spacer between drug and carrier should guarantee a selective release of the cytostatics in the tumor cells. The resulting cytotoxicity was determined in vitro using the human MCF-7 and MDA-MB 231 breast cancer cell lines. It was demonstrated that melphalan caused cytotoxic effects depending on its free amino group (Boc protection strongly decreased the activity) but independent of a derivation of the carboxylic group (dendrimers and spacer binding). Esterification of bendamustine with the N-(2 hydroxyethyl)maleimide spacer strongly increased the hydrolytic stability of the N-lost moiety, so antiproliferative effects were yet observed in vitro. PMID- 20849064 TI - Researchers in a brave new web 2.0 world. PMID- 20849068 TI - Peptide arrays identify isoform-selective substrates for profiling endogenous lysine deacetylase activity. AB - This paper reports the development of a class of isoform-selective peptide substrates for measuring endogenous lysine deacetylase (KDAC) activities in cell culture. The peptides were first identified by comparing the substrate specificity profiles of the four KDAC isoforms KDAC2, KDAC3, KDAC8, and sirtuin 1 (SIRT1) on a 361-member hexapeptide array wherein the two C-terminal residues to the acetylated lysine were varied. The arrays were prepared by immobilizing the peptides to a self-assembled monolayer of alkanethiolates on gold and could therefore be analyzed by a mass spectrometry technique termed SAMDI (self assembled monolayers for matrix assisted laser desorption/ionization time-of flight mass spectrometry). Arrays presenting the selective substrates were treated with nuclear extracts from HeLa, Jurkat, and smooth muscle cells and analyzed to measure endogenous deacetylase activities. We then use the arrays to profile KDAC activity through the HeLa cell cycle. We find that the activity profile of the KDAC3 selective peptide closely mirrors the changing acetylation state of the H4 histone, suggesting a role for this enzyme in cell cycle regulation. This work is significant because it describes a general route for identifying selective substrates that can be used to understand the differential roles of members of the deacetylase enzyme family in complex biological processes and further because the label-free approach avoids perturbation of enzyme activity that has plagued fluorescence-based assays. PMID- 20849069 TI - Proteomic approach identifies alterations in cytoskeletal remodelling proteins during decidualization of human endometrial stromal cells. AB - Decidualization is a tissue remodelling process within the uterus in preparation for embryo implantation and pregnancy. In this study we isolated primary human endometrial stromal cells and stimulated decidualization with cAMP. We then used 2D- differential in-gel electrophoresis (DIGE) to identify proteins induced by decidualization. Eighty-eight out of 2714 spots were differentially regulated, 18 of which were assigned clear identities by mass spectrometry. Many of these are proteins known to be associated with cell structure and cytoskeletal remodelling. We validated five of these proteins by Western blot and immunohistochemistry on human endometrial tissue. The validated proteins are caldesmon 1, src substrate contactin 8, tropomyosin alpha-4 chain, protein disulfide isomerase 1A, and LIM and SH3 domain protein. With the exception of caldesmon 1, none of the identified proteins have previously been associated with decidualization. This study provides insight into our understanding of decidualization, which is important for successful embryo implantation and establishment of pregnancy. PMID- 20849070 TI - Environmental scientists, biologically active compounds, and sustainability: the vital role for small-scale science. PMID- 20849073 TI - Mechanistic studies of the reaction of Ir(III) porphyrin hydride with 2,2,6,6 tetramethylpiperidine-1-oxyl to an unsupported Ir-Ir porphyrin dimer. AB - Reaction of hydrido[5,10,15,20-tetrakis(p-tolyl)porphyrinato]iridium(III) (Ir(ttp)H) (1) with 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) (2) at room temperature gave a 90% yield of the unsupported iridium(II) porphyrin dimer, Ir(II)(2)(ttp)(2) (3). Kinetic measurements revealed that the oxidation followed overall second-order kinetics: rate = k[Ir(ttp)H][TEMPO], k(25 degrees C) = 6.65 * 10(-4) M(-1). The entropy of activation (DeltaS(?) = -25.3 +/- 2.5 cal mol(-1) K(-1)) and the kinetic isotope effect of 7.2 supported a bimolecular associative mechanism in the rate-determining hydrogen atom transfer from Ir(ttp)H to TEMPO. PMID- 20849074 TI - Cytotoxic 3,4-seco-Atisane Diterpenoids from Croton barorum and Croton goudotii. AB - In a screening program directed to the discovery of new anticancer agents from Madagascan plants, ethyl acetate extracts of Croton barorum and C. goudotii showed strong cytotoxic activity, with 100% inhibition at 10 MUg/mL in a primary screen using the murine lymphocytic leukemia P388 cell line. Bioassay-guided fractionation led to the isolation of two new 3,4-seco-atisane diterpenoids, crotobarin (1) and crotogoudin (2). Their structures were elucidated by spectroscopic data interpretation. Compounds 1 and 2 produced a net progression in the number of cells arrested at the G2/M growth stage in the cell cycle of the K562 human leukemia cell line at 4 MUM. PMID- 20849075 TI - Convergent route to the spirohexenolide macrocycle. AB - Using key functional dissections, the synthesis of spirohexenolides is examined through a three-component strategy that features a 1,2-addition to couple tetronate and aldehyde components forming the C2-C3 bond and a Stille coupling to install the third sulfone-containing component. The macrocycle is completed by an intramolecular Julia-Kocienski reaction to form the C10-C11 trans-disubstituted olefin. Application of this strategy is described in progress toward the synthesis of (+/-)-spirohexenolide B. PMID- 20849076 TI - Reversible dispersion and release of carbon nanotubes using foldable oligomers. AB - Foldamers are synthetic and designable oligomers that adopt a conformationally ordered state in selected solvents. We found that oligo(m-phenylene ethynylene)s, which are single-stranded foldamers, can be made to reversibly disperse and release single-walled carbon nanotubes (SWCNTs) simply by changing the solvent, consistent with a change from an unfolded state to a folded state. Using absorption spectroscopy, atomic force microscopy, Raman spectroscopy, and electrical measurements, we observed that the foldamer-dispersed SWCNTs are individually well-dispersed and have a strong interfacial interaction with the foldamers. In contrast, the released SWCNTs appeared to be free of foldamers. Under illumination, transistors based on the foldamer-dispersed SWCNTs demonstrated significant photoresponse, apparently due to photoinduced charge transfer between the foldamers and SWCNTs. The reported nanocomposites may open an alternative way of developing optoelectronic devices or sensors based on carbon nanotubes. PMID- 20849077 TI - Enantioselective organocatalytic Michael addition of aldehydes to trifluoroethylidene malonates. AB - An efficient, highly enantioselective, organocatalytic Michael addition reaction of aldehydes with trifluoroethylidene malonates is described. The asymmetric reaction provided highly optically pure beta-trifluoromethyl aldehydes which can be conveniently transformed into 4,4,4-trifluoromethyl butyric acid and trifluoromethyl substituted delta-lactones without loss in enantioselectivity. PMID- 20849078 TI - TEMED enhanced photoluminescent imaging detection of proteins in human serum using quantum dots after PAGE. AB - In this paper, the development of a novel enhanced photoluminescent (PL) imaging method for human serum proteins detection after polyacrylamide gel electrophoresis (PAGE) is described. Thioglycolic acid (TGA)-capped CdTe QDs and enhanced reagent tetramethylethylenediamine (TEMED) have been introduced, resulting in direct detection of various proteins in native polyacrylamide gels and expanded application scope to SDS gels. Some relatively low-abundance proteins such as Zinc-alpha(2)-glycoprotein (ZAG) and alpha(2)-HS-glycoprotein (alpha(2)-HSG) are easily detected by TEMED enhanced PL imaging and identified by MS and MS/MS techniques. In the present study, the PL imaging conditions such as QDs concentration, alkali concentration, and enhanced reagents are optimized and the possible mechanisms are analyzed. The sensitivity of TEMED enhanced PL imaging is satisfying, with a linear range of 11.7-375 ng for ferritin, comparing with 46.9-375 ng in CBB-R250 staining and 23.4-375 ng in direct PL imaging. As a novel PL imaging detection method that is simple, fast, and sensitive, it shows great analytical potential in proteome research and in biochemistry. PMID- 20849079 TI - Active metalloproteases of the A Disintegrin and Metalloprotease (ADAM) family: biological function and structure. AB - The "a disintegrin and metalloproteases" (ADAMs) are membrane-anchored metzincins of the adamalysin subfamily. This review gives an overview over the biological function and structure of ADAMs focusing on members of the family that display proteolytic activity. ADAMs are involved in a range of human diseases such as cancer metastasis, inflammatory disorders, neurological disease or asthma. It is, however, often difficult to assign a definitive role to a specific member of the ADAM family in a given disease mechanism due to overlapping activities and redundancy in function, as shown in various knock-out studies. The review discusses the structural domains that are not directly linked to protease activity followed by a more detailed overview over the role of the metalloprotease domain. Different family members are critically reviewed with respect to their role in biological processes with particular emphasis on disease relevant functions. PMID- 20849080 TI - Impact of prenatal disorders on the metabolic profile of second trimester amniotic fluid: a nuclear magnetic resonance metabonomic study. AB - This paper describes a metabonomic study of prenatal disorders using nuclear magnetic resonance (NMR) spectroscopy of amniotic fluid (AF) collected in the second trimester of pregnancy, to search for metabolite markers of fetal malformations, prediagnostic gestational diabetes (GD), preterm delivery (PTD), early rupture of membranes (PROM), and chromossomopathies. Fetal malformations were found to have the highest impact on AF metabolite composition, enabling statistical validation to be achieved by several multivariate analytical tools. Results confirmed previous indications that malformed fetuses seem to suffer altered energy metabolism and kidney underdevelopment. Newly found changes (namely in alpha-oxoisovalerate, ascorbate, creatinine, isoleucine, serine, threonine) suggest possible additional effects on protein and nucleotide sugar biosynthesis. Prediagnostic GD subjects showed an average increase in glucose and small decreases in several amino acids along with acetate, formate, creatinine, and glycerophosphocholine. Small metabolite changes were also observed in the AF of subjects eventually undergoing PTD and PROM, whereas no relevant changes were found for chromossomopathies (for which a low number of samples was considered). The potential value of these results for biochemical insight and prediction of prenatal disorders is discussed, as well as their limitations regarding number of samples and overlap of different disorders. PMID- 20849082 TI - Thermodynamic stability and folding kinetics of the major G-quadruplex and its loop isomers formed in the nuclease hypersensitive element in the human c-Myc promoter: effect of loops and flanking segments on the stability of parallel stranded intramolecular G-quadruplexes. AB - Overexpression of the c-Myc proto-oncogene is associated with a broad spectrum of human cancers. Nuclease hypersensitivity element III(1) (NHE III(1)) of the c-Myc promoter can form transcriptionally active and silenced forms, and the formation of DNA G-quadruplex structures has been shown to be critical for c-Myc transcriptional silencing. The major G-quadruplex formed in c-Myc NHE III(1) is a mixture of four loop isomers, which have all been shown to be biologically relevant to c-Myc transcriptional control. In this study, we performed a thorough thermodynamic and kinetic study of the four c-Myc loop isomers in a K(+) solution. The four loop isomers all form parallel-stranded G-quadruplexes with short loop lengths. While the parallel-stranded G-quadruplex has been known to favor short loop lengths, our results show that the difference in thermodynamic and kinetic properties of the four loop isomers, and hence between the parallel G quadruplexes with similar loop lengths, is more significant than previously recognized. At 20 mM K(+), the average difference in the T(m) values between the most stable loop isomer 14/23 and the least stable loop isomer 11/20 is more than 10 degrees C. In addition, the capping structures formed by the extended flanking segments are shown to contribute to a stabilization of 2-3 degrees C in T(m) for the c-Myc promoter G-quadruplex. Understanding the intrinsic thermodynamic stability and kinetic properties of the c-Myc G-quadruplex loop isomers can aid in our understanding of their biological roles and drug targeting. PMID- 20849083 TI - Nanocavity redox cycling sensors for the detection of dopamine fluctuations in microfluidic gradients. AB - Electrochemical mapping of neurotransmitter concentrations on a chip promises to be an interesting technique for investigating synaptic release in cellular networks. In here, we present a novel chip-based device for the detection of neurotransmitter fluctuations in real-time. The chip features an array of plane parallel nanocavity sensors, which strongly amplify the electrochemical signal. This amplification is based on efficient redox cycling via confined diffusion between two electrodes inside the nanocavity sensors. We demonstrate the capability of resolving concentration fluctuations of redox-active species in a microfluidic mixing gradient on the chip. The results are explained by a simulated concentration profile that was calculated on the basis of the coupled Navier-Stokes and convection-diffusion equations using a finite element approach. PMID- 20849081 TI - The functionally active Mistic-fused histidine kinase receptor, EnvZ. AB - Mistic is a small Bacillus subtilis protein which is of current interest to the field of structural biology and biochemistry because of its unique ability to increase integral membrane protein yields in Escherichia coli expression. Using the osmosensing histidine kinase receptor, EnvZ, an E. coli two-component system, and its cytoplasmic cognate response regulator, OmpR, we provide the first evidence that a Mistic-fused integral membrane protein maintains functionality both in vitro and in vivo. When the purified and detergent-solubilized receptor EnvZ is fused to Mistic, it maintains the ability to autophosphorylate on residue His(243) and phosphotransfers to residue Asp(55) located on OmpR. Functionality was also observed in vivo by means of a beta-galactosidase assay in which RU1012 [Phi(ompC-lacZ)10-15, DeltaenvZ::Km(r)] cells transformed with Mistic-fused EnvZ led to an increase in downstream signal transduction events detected by the activation of ompC gene expression. These findings illustrate that Mistic preserves the functionality of the Mistic-fused cargo protein and thus provides a beneficial alternate approach to study integral membrane proteins not only by improving expression levels but also for direct use in functional characterization. PMID- 20849085 TI - Characterizing short-lived protein folding intermediates by top-down hydrogen exchange mass spectrometry. AB - This work combines pulsed hydrogen/deuterium exchange (HDX) and top-down mass spectrometry for the structural characterization of short-lived protein folding intermediates. A custom-built flow device with three sequential mixing steps is used for (i) triggering protein folding, (ii) pulsed D(2)O labeling, and (iii) acid quenching. The earliest folding time point that can be studied with this system is 10 ms. The mixing device was coupled online to the electrospray source of a Fourier transform mass spectrometer, where intact protein ions are fragmented by electron capture dissociation (ECD). The viability of this experimental strategy is demonstrated by applying it to the refolding of horse apo-myoglobin (aMb), a reaction known to involve a transient intermediate. Cooling of the mixing device to 0 degrees C reduces the reaction rate such that the folding process occurs within the experimentally accessible time window. Top down ECD provides an average spatial resolution of ca. 2 residues, surpassing the resolution typically achieved in traditional proteolytic digestion/HDX studies. Amide back exchange is virtually eliminated by the short (~1 s) duration of the acid quenching step. The aMb folding intermediate exhibits HDX protection in helices G and H, whereas the remainder of the protein is largely unfolded. Marginal protection is seen for helix A. Overall, the top-down ECD approach used here offers insights into the sequence of events leading from the unfolded state to the native conformation, with envisioned future applications in the areas of protein misfolding and aggregation. The time-resolved experiments reported herein represent an extension of our previous work, where HDX/MS with top-down ECD was employed for monitoring "static" protein structures under equilibrium conditions (Pan et al. J. Am. Chem. Soc. 2009, 131, 12801). PMID- 20849084 TI - Near infrared luminescent oxygen nanosensors with nanoparticle matrix tailored sensitivity. AB - The development of sensors for noninvasive determination of oxygen levels in live cells and tissues is critical for the understanding of cellular functions, as well as for monitoring the status of disease, such as cancer, and for predicting the efficacy of therapy. We describe such nontoxic, targeted, and ratiometric 30 nm oxygen nanosensors made of polyacrylamide hydrogel, near-infrared (NIR) luminescent dyes, and surface-conjugated tumor-specific peptides. They enabled noninvasive real-time monitoring of oxygen levels in live cancer cells under normal and hypoxic conditions. The required sensitivity, brightness, selectivity, and stability were achieved by tailoring the interaction between the nanomatrix and indicator dyes. The developed nanosensors may become useful for in vivo oxygen measurements. PMID- 20849086 TI - Optical, electrical and surface plasmon resonance methods for detecting telomerase activity. AB - Three different sensing platforms for the analysis of telomerase activity in human cells are described. One sensing platform involves the label-free analysis of the telomerase activity by a field-effect-transistor (FET) device. The telomerase-induced extension of a primer associated with the gate of the FET device, in the presence of the nucleotide mixture dNTPs, alters the gate potential, and this allows the detection of telomerase extracted from 65 +/- 10 293T (transformed human embryonic kidney) cells/MUL. The second sensing platform involves the optical detection of telomerase using CdSe/ZnS quantum dots (QDs). The telomerase-stimulated telomerization of the primer-functionalized QDs in the presence of the nucleotide mixture dNTPs results in the synthesis of the G-rich telomeres. The stacking of hemin on the self-organized G-quadruplexes found on the telomers results in the electron transfer quenching of the QDs, thus providing an optical readout signal. This method enables the detection of telomerase originating from 270 +/- 20 293T cells/MUL. The third sensing method involves the amplified surface plasmon resonance (SPR) detection of telomerase activity. The telomerization of a primer associated with Au film-coated glass slides, in the presence of telomerase and the nucleotide mixture (dNTPs), results in the formation of telomeres on the surface, and these alter the dielectric properties of the surface resulting in a shift in the SPR spectrum. The hybridization of Au NPs functionalized with nucleic acids complementary to the telomere repeat units with the telomeres amplifies the SPR shifts due to the coupling between the local plasmon of the NPs and the surface plasmon wave. This method enables the detection of telomerase extracted from 18 +/- 3 293T cells/MUL. PMID- 20849087 TI - Sonication-assisted synthesis of CdS quantum-dot-sensitized TiO2 nanotube arrays with enhanced photoelectrochemical and photocatalytic activity. AB - A sonication-assisted sequential chemical bath deposition (S-CBD) approach is presented to uniformly decorate CdS quantum dots (QDs) on self-organized TiO2 nanotube arrays (TNTAs). This approach avoids the clogging of CdS QDs at the TiO2 nanotube mouth and promotes the deposition of CdS QDs into the nanotubes as well as on the tube walls. The photoelectrochemical and photocatalytic properties of the resulting CdS-decorated TNTAs were explored in detail. In comparison with a classical S-CBD approach, the sonication-assisted technique showed much enhancement in the photoelectrochemical and photocatalytic activities of the CdS QDs-sensitized TNTAs. PMID- 20849088 TI - Highly luminescent and triboluminescent coordination polymers assembled from lanthanide beta-diketonates and aromatic bidentate O-donor ligands. AB - The reaction of hydrated lanthanide hexafluoroacetylacetonates, [Ln(hfa)(3)(H(2)O)(2)], with 1,4-disubstituted benzenes afforded a new series of one-dimensional coordination polymers [Ln(hfa)(3)(Q)](infinity), where Ln = Eu, Gd, Tb, and Lu and Q = 1,4-diacetylbenzene (acbz), 1,4-diacetoxybenzene (acetbz), or 1,4-dimethyltherephtalate (dmtph). X-ray single crystal analyses reveal [Ln(hfa)(3)(acbz)](infinity) (Ln = Eu, Gd, Tb) consisting of zigzag polymeric chains with Ln-Ln-Ln angles equal to 128 degrees , while the arrays are more linear in [Eu(hfa)(3)(acetbz)](infinity) and [Eu(hfa)(3)(dmtph)](infinity), with Ln-Ln-Ln angles of 165 degrees and 180 degrees , respectively. In all structures, Ln(III) ions are 8-coordinate and lie in distorted square antiprismatic environments. The coordination polymers are thermally stable up to 180-210 degrees C under a nitrogen atmosphere. Their volatility has been tested in vacuum sublimation experiments at 200-250 degrees C and 10(-2) Torr: the metal-organic frameworks with acetbz and dmtph can be quantitatively sublimed, while [Ln(hfa)(3)(acbz)](infinity) undergoes thermal decomposition. The triplet state energies of the ancillary ligands, 21,600 (acetbz), 22,840 (acbz), and 24,500 (dmtph) cm(-1), lie in an ideal range for sensitizing the luminescence of Eu(III) and/or Tb(III). As a result, all of the [Ln(hfa)(3)(Q)](infinity) polymers display bright red or green luminescence due to the characteristic (5)D(0) -> (7)F(J) (J = 0-4) or (5)D(4) -> (7)F(J) (J = 6-0) transitions, respectively. Absolute quantum yields reach 51(Eu) and 56(Tb) % for the frameworks built from dmtph. Thin films of [Eu(hfa)(3)(Q)](infinity) with 100-170 nm thickness can be obtained by thermal evaporation (P < 3 * 10(-5) Torr, 200-250 degrees C). They are stable over a long period of time, and their photophysical parameters are similar to those of the bulk samples so that their use as active materials in luminescent devices can be envisaged. Mixtures of [Ln(hfa)(3)(dmpth)](infinity) with Ln = Eu and Tb yield color-tunable microcrystalline materials from red to green. Finally, the crystalline samples exhibit strong triboluminescence, which could be useful in the design of pressure and/or damage detection probes. PMID- 20849089 TI - Three-component one-pot approach to synthesize benzopyrano[4,3-d]pyrimidines. AB - A novel benzopyrano[4,3-d]pyrimidine scaffold was generated via a three-component one-pot reaction from iodochromone, alkyne, and an amidine through a Sonogashira coupling, condensation, and cycloaddition. This combinatorial synthetic approach provides an efficient, easy construction of a diversified heterocyclic compounds library. PMID- 20849090 TI - Total synthesis of (+)-demethoxycardinalin 3. AB - The total synthesis of (+)-demethoxycardinalin 3 is described. The synthetic strategy features the synthesis of dimeric Fischer carbene and its use in a bidirectional Dotz benzannulation reaction to set the dimeric structure of the cardinalins. The oxa-Pictet-Spengler reaction was used to construct the pyran rings. The synthesis is completed in seven steps and an overall yield of 7%. PMID- 20849091 TI - Geometries and tautomerism of OHN hydrogen bonds in aprotic solution probed by H/D isotope effects on (13)C NMR chemical shifts. AB - The (1)H and (13)C NMR spectra of 17 OHN hydrogen-bonded complexes formed by CH(3)(13)COOH(D) with 14 substituted pyridines, 2 amines, and N-methylimidazole have been measured in the temperature region between 110 and 150 K using CDF(3)/CDF(2)Cl mixture as solvent. The slow proton and hydrogen bond exchange regime was reached, and the H/D isotope effects on the (13)C chemical shifts of the carboxyl group were measured. In combination with the analysis of the corresponding (1)H chemical shifts, it was possible to distinguish between OHN hydrogen bonds exhibiting a single proton position and those exhibiting a fast proton tautomerism between molecular and zwitterionic forms. Using H-bond correlations, we relate the H/D isotope effects on the (13)C chemical shifts of the carboxyl group with the OHN hydrogen bond geometries. PMID- 20849093 TI - Fluorescence visualization and modeling of a micelle-free zone formed at the interface between an oil and an aqueous micellar phase during interfacial surfactant transport. AB - This study examines the transport of surfactant that occurs when an aqueous micellar phase is placed in contact with a clean oil phase in which the surfactant is soluble. Upon contact with oil, surfactant monomer on the aqueous side of the interface adsorbs onto the oil/water interface and subsequently desorbs into the oil and diffuses away from the surface. The depletion of aqueous monomer underneath the interface disturbs the monomer-micelle equilibrium, and aggregates break down to replenish the monomer concentration and accelerate the interfacial transport. The depletion of monomer and micelles drives the diffusive flux of these species toward the surface, and the combined effects of diffusion and aggregate kinetic disassembly, alongside kinetic adsorption and desorption at the interface and diffusion away from the interface into the oil, determine the interfacial transport rate. This interfacial transport is examined here in the quasi-static limit in which the diffusion of monomer and micelles in the aqueous phase is much slower than the time scale for micelle disassembly. In this limit, when the initial bulk concentration of micelles in the aqueous solution is small, the micelle diffusive flux to the surface cannot keep up with the micelle breakdown under the interface, and a micelle-free zone forms. This zone extends from the surface into the aqueous phase up to a boundary that demarcates the beginning of a zone, containing micelles, that extends further into the aqueous phase. Micelles diffuse from the micelle zone to the boundary, where they break down, causing the boundary to retreat. Released monomer diffuses through the micelle-free zone and partitions into the oil phase. The focus of this study is to verify this transport picture by visualizing the micelle-free zone and comparing the movement of the zone to predictions obtained from a transport model based on this two-zone picture. A small hydrophobic dye molecule (Nile red) is incorporated into the micelles; the dye fluoresces only in the hydrophobic environment of the micelles, providing visual contrast between the two zones. Through spatial mapping of the fluorescence using confocal microscopy, the movement of the micelle-free zone boundary can be measured and is shown to compare favorably with simulations of the transport model. PMID- 20849092 TI - Aryl ketone synthesis via tandem orthoplatinated triarylphosphite-catalyzed addition reactions of arylboronic acids with aldehydes followed by oxidation. AB - Tandem orthoplatinated triaryl phosphite-catalyzed addition reactions of arylboronic acids with aldehydes followed by oxidation to yield aryl ketones is described. 3-Pentanone was identified as a suitable oxidant for the tandem aryl ketone formation reaction. By using microwave energy, aryl ketones were obtained in high yields with the catalyst loading as low as 0.01%. PMID- 20849094 TI - Direct imprinting of porous substrates: a rapid and low-cost approach for patterning porous nanomaterials. AB - This work describes a technique for one-step, direct patterning of porous nanomaterials, including insulators, semiconductors, and metals without the need for intermediate polymer processing or dry etching steps. Our process, which we call "direct imprinting of porous substrates (DIPS)", utilizes reusable stamps with micro- and nanoscale features that are applied directly to a porous material to selectively compress or crush the porous network. The stamp pattern is transferred to the porous material with high fidelity, vertical resolution below 5 nm, and lateral resolution below 100 nm. The process is performed in less than one minute at room temperature and at standard atmospheric pressure. We have demonstrated structures ranging from subwavelength optical components to microparticles and present exciting avenues for applications including surface enhanced Raman spectroscopy (SERS), label-free biosensors, and drug delivery. PMID- 20849095 TI - Effect of particle size on hydrogen release from sodium alanate nanoparticles. AB - Density functional theory and the cluster expansion method are used to model 2-10 nm sodium alanate (NaAlH(4)) nanoparticles and related decomposition products Na(3)AlH(6), NaH, and Al. While bulk sodium alanate releases hydrogen in a two step process, our calculations predict that below a certain size sodium alanate nanoparticles decompose in a single step directly to NaH, Al, and H(2) due to the effect of particle size on decomposition thermodynamics. This may explain why sodium alanate nanoparticles, unlike bulk sodium alanate, have been observed to release hydrogen in the operating temperature range of proton exchange membrane fuel cells. In addition, we identify low-energy surfaces that may be important for the dynamics of hydrogen storage and release from sodium alanate nanoparticles. PMID- 20849096 TI - Enantioselective synthesis of beta-fluoroamines from beta-amino alcohols: application to the synthesis of LY503430. AB - N,N-Dialkyl-beta-amino alcohols were enantiospecifically and regioselectively rearranged by using N,N-diethylaminosulfur trifluoride (DAST) to give optically active beta-fluoroamines in excellent yields and enantiomeric excesses. This rearrangement was applied to the enantioselective synthesis of LY503430, a potential therapeutic agent for Parkinson's disease. PMID- 20849098 TI - Weinreb amides in carbene chemistry: a time-resolved IR investigation into a potential intramolecular stabilization mechanism. AB - A chloromethylhydroxamiccarbene was generated photochemically in an attempt to form an intramolecularly stabilized carbene. A rapidly formed intermediate at 1645 cm(-1) decayed with an observed rate of 1.99 * 10(6) s(-1). Other intermediates were also observed. These also decayed, albeit much more slowly (k(obs) = 3.47 * 10(3) and 1.98 * 10(4) s(-1)). Multiple intermediates are apparently a function of both the proximal N,O-dimethylhydroxamic ester and multiple conformers of both the carbene and precursor. PMID- 20849099 TI - A novel approach to oral delivery of insulin by conjugating with low molecular weight chitosan. AB - A new oral delivery system for insulin was developed aiming to improve bioavailability based on a conjugate between insulin and low molecular weight chitosan (LMWC) of narrow molecular weight distribution. The conjugate was synthesized from the reaction between site-specifically modified insulin at the lysine residue of the B-chain and sulfhydryl-modified LMWC. To investigate the effect of MWs of LMWC on oral bioavailability of insulin, various LMWCs (3, 6, 9, and 13k average MW) with narrow MW distribution were used to synthesize LMWC insulin conjugates. The content of insulin in the LMWC-insulin conjugates was calculated by UV spectrophotometer: 62%, 44%, 38%, and 29% for 3, 6, 9, and 13 kDa LMWC, respectively. The biological activity of insulin in LMWC(6k)-insulin conjugate in vivo was 43 +/- 0.7%. LMWC-insulin conjugates after oral administration to diabetic rat models could control blood glucose levels effectively for several hours. Of those conjugates, LMWC(9k)-insulin exhibited the highest pharmacodynamic bioavailability of 3.7 +/- 0.3% relative to that of subcutaneously (s.c.) injected insulin (100%). PMID- 20849100 TI - Polyhydroxybutyrate and its copolymer with polyhydroxyvalerate as biomaterials: influence on progression of stem cell cycle. AB - Poly(3-hydroxybutyrate) (PHB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) are biopolyesters reported to provide favorable microenvironments for cell culture and possess potential for tissue engineering applications. Both biopolymers have been investigated for applications in a variety of medical scenarios, including nerve and bone repair. This study investigated the influence these biomaterials exerted on cell cycle progression of olfactory ensheathing cells (OECs) and mesenchymal stem cells (MSCs) commonly used in the engineering of nerve and bone tissues. Cell cycle regulation is important for cell survival; analysis revealed that the biomaterials induced significant cell cycle progression in both MSCs and OECs. Significantly higher percentages of cells were cycled at synthesis (S) phase of the cycle on PHBV films compared to PHB, with MSCs more susceptible than OECs. Furthermore, detection of early stages of apoptotic activation showed significant differences in the two cell populations exhibiting necrosis and apoptosis when cultivated on the biomaterials. OECs compromised on PHB (5.6%) and PHBV (2.5%) compared to MSCs with 12.6% on PHB and 17% on PHBV. Significant differences in crystallinity and surface rugosity were determined between films of the two biomaterials, 88% and 1.12 MUm for PHB and 76% and 0.72 MUm for PHBV. While changes in surface properties may have influenced cell adhesion, the work presented here suggests that application of these biomaterials in tissue engineering are specific to cell type and requires a detailed investigation at the cell-material interface. PMID- 20849101 TI - Exploration of new C-O electrophiles in cross-coupling reactions. AB - Since their development in the 1970s, cross-coupling reactions catalyzed by transition metals have become one of the most important tools for constructing both carbon-carbon and carbon-heteroatom bonds. Traditionally, organohalides were widely studied and broadly used as the electrophile, both in the laboratory and in industry. Unfortunately, the high cost, environmental toxicity, and sluggish preparation often associated with aryl halides can make them undesirable for the large-scale syntheses of industrial applications. However, with the further development of catalytic systems, and particularly of the ligands contained therein, a variety of electrophiles have now been successfully applied to cross coupling reactions. Oxygen-based electrophiles have attracted much attention due to their ready availability from phenol and carbonyl compounds. Initially, aryl and alkenyl triflates were used in cross-coupling reactions due to their high reactivity; however, low moisture stability and high cost hampered their application. Later, with the development of highly efficient catalytic systems, the less reactive sulfonates and phosphates were successfully employed in cross coupling reactions. Although they have higher stability and can be easily prepared, low atom economy remains an obstacle to their broader utility. Our group has worked to directly apply the abundant and readily available oxygen containing compounds, such as phenols, alcohols, ethers, and carbonyl compounds, to cross-coupling reactions. In this Account, we describe our recent efforts in transition-metal-catalyzed cross-coupling reactions of new O-based electrophiles via C-O bond activation. We began by developing the methylation of aryl methyl ethers and benzyl methyl ethers via Ni-catalyzed selective C-O bond cleavage. With the refined Ni-based catalytic system, we further applied aryl/alkenyl carboxylates and carbamates to Suzuki-Miyaura, Negishi, and Kumada-Tamao-Corriu reactions to construct various biaryl scaffolds and highly substituted alkenes. To further improve the carbon atom economy, we developed the diaryl sulfates as one-by-one electrophiles (that is, both aryl groups are used in the reaction). Most recently, we have achieved the first successful cross-coupling reaction of magnesium naphtholates with aryl Grignard reagents. These results extend aryl and benzyl ethers, aryl and alkenyl carboxylates/carbamates, and magnesium naphtholates as novel electrophiles in cross-coupling reactions. More importantly, these studies contribute to our better understanding the intrinsic nature of C-O bonds, which were traditionally considered "inert" but clearly show enormous synthetic potential with the proper catalysts. PMID- 20849102 TI - The role of exact exchange in the description of Cu(2+)-(H(2)O)(n) (n = 1-6) complexes by means of DFT methods. AB - This paper analyses the behavior of different density functionals in the description of the most stable structures of Cu(2+)-(H(2)O)(n) complexes (n = 1 6). From n = 3 to n = 6, different coordination numbers of the metal cation were considered. The structures and energies of the complexes were theoretically determined by means of density functional methods that include different amounts of exact exchange: the BLYP functional (0% of exact exchange), the B3LYP functional (20% of exact exchange), the MPWB1K functional (44% of exact exchange), and BHLYP functional (50% of exact exchange). In addition, CCSD(T) calculations with a large basis set were carried out. It has been found that the functionals with lesser amount of exact exchange, especially BLYP, fail to describe the relative energies between the different structures of each cluster because these functionals tend to overestimate the stability of low-coordinated structures. The inclusion of the exact exchange into the functional improves the results, those obtained with MPWB1K and BHLYP being in very good agreement with the CCSD(T) ones. This behavior is related to the poor description of the second ionization energy of Cu by pure functionals, which leads to a too delocalized spin density in the complex with GGA functionals. PMID- 20849103 TI - Importance of speciation in understanding mercury bioaccumulation in tilapia controlled by salinity and dissolved organic matter. AB - We explored the roles of mercury speciation on the bioaccumulation (both aqueous and dietary uptake and elimination) of inorganic mercury (Hg[II]) and methylmercury (MeHg) in tilapia (Oreochromis niloticus) by controlling the mercury binding to inorganic and organic ligands. For the aqueous uptake, we showed that the uptake rates of Hg(II) were significantly higher at 0 psu compared with those at 10 psu and 28 psu. Based on the mercury-Cl complexes distribution, we found a positive relationship between the Hg(II) aqueous uptake rate and the abundance of neutral HgCl(2). Such relationship was further confirmed by the uptake experiments conducted over a lower salinity range (0-6 psu), suggesting that HgCl(2)(0) was the predominant species taken up by tilapia. In the presence of dissolved organic carbon (DOC) from different sources (Suwannee River and natural local waters), mercury uptake rates all decreased dramatically over a wide range of salinity, especially for Hg(II), indicating the overwhelming influence of DOC as opposed to the single effect of salinity. Using the mercury-Cl-DOC model, we demonstrated for the first time that the inhibition of DOC was dependent on the Cl(-), which was less significant at middle salinity level for both mercury forms. In contrast to the complex influence of water conditions on dissolved uptake, we found no significant influence of acclimated salinity on the dietary assimilation and elimination of both mercury species in tilapia. Our results demonstrated the importance of speciation in understanding the mercury bioaccumulation in various natural systems and its broad biogeochemical cycling. PMID- 20849104 TI - Spatially and size selective synthesis of Fe-based nanoparticles on ordered mesoporous supports as highly active and stable catalysts for ammonia decomposition. AB - Uniform and highly dispersed gamma-Fe(2)O(3) nanoparticles with a diameter of ~6 nm supported on CMK-5 carbons and C/SBA-15 composites were prepared via simple impregnation and thermal treatment. The nanostructures of these materials were characterized by XRD, Mossbauer spectroscopy, XPS, SEM, TEM, and nitrogen sorption. Due to the confinement effect of the mesoporous ordered matrices, gamma Fe(2)O(3) nanoparticles were fully immobilized within the channels of the supports. Even at high Fe-loadings (up to about 12 wt %) on CMK-5 carbon no iron species were detected on the external surface of the carbon support by XPS analysis and electron microscopy. Fe(2)O(3)/CMK-5 showed the highest ammonia decomposition activity of all previously described Fe-based catalysts in this reaction. Complete ammonia decomposition was achieved at 700 degrees C and space velocities as high as 60,000 cm(3) g(cat)(-1) h(-1). At a space velocity of 7500 cm(3) g(cat)(-1) h(-1), complete ammonia conversion was maintained at 600 degrees C for 20 h. After the reaction, the immobilized gamma-Fe(2)O(3) nanoparticles were found to be converted to much smaller nanoparticles (gamma Fe(2)O(3) and a small fraction of nitride), which were still embedded within the carbon matrix. The Fe(2)O(3)/CMK-5 catalyst is much more active than the benchmark NiO/Al(2)O(3) catalyst at high space velocity, due to its highly developed mesoporosity. gamma-Fe(2)O(3) nanoparticles supported on carbon-silica composites are structurally much more stable over extended periods of time but less active than those supported on carbon. TEM observation reveals that iron based nanoparticles penetrate through the carbon layer and then are anchored on the silica walls, thus preventing them from moving and sintering. In this way, the stability of the carbon-silica catalyst is improved. Comparison with the silica supported iron oxide catalyst reveals that the presence of a thin layer of carbon is essential for increased catalytic activity. PMID- 20849105 TI - Sensitive detection of polycyclic aromatic hydrocarbons using CdTe quantum dot modified TiO2 nanotube array through fluorescence resonance energy transfer. AB - CdTe quantum dots (QDs) are prepared on TiO(2) nanotubes (TiO(2) NTs), for the first time, with pulse electrodeposition. A novel single-drop optical sensor is prepared with the CdTe QDs-modified TiO(2) NTs, and applied for the detection of polycyclic aromatic hydrocarbons (PAHs) based on fluorescence resonance energy transfer (FRET). Excited at 270 nm, the sensor shows fluorescence emission at around 370 nm. As PAHs are with absorption/fluorescence emission at around 364/410 nm, FRET happens between the CdTe QDs and PAHs with the CdTe QDs as donors and PAHs as receptors. The sensitivity is dependent on the number of rings of the PAHs, with the highest sensitivity observed in the response to benzo(a)pyrene (BaP). Using FRET, the sensitivity to BaP is enhanced by about 2 orders with respect to the direct fluorescent spectrometry. The proposed sensor shows a linear response to the logarithm of BaP concentration in the range of 400 nM to 40 pM, with a detection limit of 15 pM, which is much close to the quality criteria (15.1 pM) in drinking water set by U.S. Environment Protection, suggesting that the proposed sensor can be used for quick scanning of PAHs. The achieved sensitivity is much higher than that of the published sensor-based methods. As PAHs are quantified based on the relative fluorescence intensity at 410-370 nm, the sensor need no calibration with a standard sensor, avoiding the influence from the sensor-to-sensor difference. The practicability of the sensor is tested by analyzing PAHs in Xiangjiang River water, the PAHs contents ranges from 0.045 to 2.847 ng/L based on the sampling spots. PMID- 20849106 TI - Enzymatically triggered actuation of miniaturized tools. AB - We demonstrate a methodology that utilizes the specificity of enzyme-substrate biomolecular interactions to trigger miniaturized tools under biocompatible conditions. Miniaturized grippers were constructed using multilayer hinges that employed intrinsic strain energy and biopolymer triggers, as well as ferromagnetic elements. This composition obviated the need for external energy sources and allowed for remote manipulation of the tools. Selective enzymatic degradation of biopolymer hinge components triggered closing of the grippers; subsequent reopening was achieved with an orthogonal enzyme. We highlight the utility of these enzymatically triggered tools by demonstrating the biopsy of liver tissue from a model organ system and gripping and releasing an alginate bead. This strategy suggests an approach for the development of smart materials and devices that autonomously reconfigure in response to extremely specific biological environments. PMID- 20849107 TI - Cyanocarbanion-based spin-crossover materials: photocrystallographic and photomagnetic studies of a new iron(II) neutral chain. AB - A new iron(II) chain of formula [Fe(abpt)(2)(tcpd)] [1; (tcpd)(2-) = [C(10)N(6)](2-) = (C[C(CN)(2)](3))(2-) = 2-dicyanomethylene-1,1,3,3 tetracyanopropanediide anion, abpt = 4-amino-3,5-bis(pyridin-2-yl)-1,2,4 triazole] has been synthesized and characterized by IR spectroscopy, detailed variable-temperature single-crystal X-ray diffraction, magnetic and photomagnetic measurements. The crystal structure determination of 1 reveals a one-dimensional structural architecture in which the (tcpd)(2-) cyanocarbanion acts as a MU(2) bridging ligand and the two abpt molecules act as chelating ligands. Detailed X ray diffraction studies as a function of the temperature (293-10 K) showed a strong modification of the iron coordination sphere, whose characteristics are in agreement with the presence of a spin-crossover transition from high spin (HS) to low spin (LS) in 1. The average Fe-N distances at room temperature, at 10 K following a flash cooling, and at 10 K after subsequent HS-to-LS relaxation are in the range expected for 100%, 50%, and 25% fractions of HS Fe(II), respectively. These observations are consistent with the presence of ca. 25% residual HS species at low temperatures, as derived from the magnetic data. The signature of a photoinduced metastable HS state in 1 has been detected by performing coupled photomagnetic and photocrystallographic analyses. The limiting T(LIESST) value associated with the light-induced excited-spin-state trapping effect was derived as 35 K, in good agreement with the thermal dependence of the unit cell volume upon irradiation. Kinetic studies governing the photoinduced HS/LS process have been recorded at different temperatures; a reverse-LIESST effect has been evidenced at 10 K as a reduction of the residual HS fraction by irradiating the sample at 830 nm. PMID- 20849109 TI - Metal insertion in a microporous metal-organic framework lined with 2,2' bipyridine. AB - Reaction of AlCl(3).6H(2)O with 2,2'-bipyridine-5,5'-dicarboxylic acid (H(2)bpydc) affords Al(OH)(bpydc) (1, MOF-253), the first metal-organic framework with open 2,2'-bipyridine (bpy) coordination sites. The material displays a BET surface area of 2160 m(2)/g and readily complexes metals to afford, for example, 1.xPdCl(2) (x = 0.08, 0.83) and 1.0.97Cu(BF(4))(2). EXAFS spectroscopy performed on 1.0.83PdCl(2) reveals the expected square planar coordination geometry, matching the structure of the model complex (bpy)PdCl(2). Significantly, the selectivity factor for binding CO(2) over N(2) under typical flue gas conditions is observed to increase from 2.8 in 1 to 12 in 1.0.97Cu(BF(4))(2). PMID- 20849108 TI - Shape-controlled synthesis of single-crystalline nanopillar arrays by template assisted vapor-liquid-solid process. AB - Highly regular, single-crystalline nanopillar arrays with tunable shapes and geometry are synthesized by the template-assisted vapor-liquid-solid growth mechanism. In this approach, the grown nanopillars faithfully reproduce the shape of the pores because during the growth the liquid catalyst seeds fill the space available, thereby conforming to the pore geometry. The process is highly generic for various material systems, and as an example, CdS and Ge nanopillar arrays with square, rectangular, and circular cross sections are demonstrated. In the future, this technique can be used to engineer the intrinsic properties of NPLs as a function of three independently controlled dimensional parameters--length, width and height. PMID- 20849110 TI - Efficient covalent modification of a carbon surface: use of a silyl protecting group to form an active monolayer. AB - A global strategy to prepare a versatile and robust reactive platform for immobilizing molecules on carbon substrates with controlled morphology and high selectivity is presented. The procedure is based on the electroreduction of a selected triisopropylsilyl (TIPS)-protected ethynyl aryldiazonium salt. It avoids the formation of multilayers and efficiently protects the functional group during the electrografting step. After TIPS deprotection, a dense reactive ethynyl aryl monolayer is obtained which presents a very low barrier to charge transfer between molecules in solution and the surface. As a test functionalization, azidomethylferrocene was coupled by "click" chemistry with the modified surface. Analysis of the redox activity highlights a surface concentration close to the maximum possible attachment considering the steric hindrance of a ferrocenyl group. PMID- 20849111 TI - Total synthesis of (+)-korupensamine B via an atropselective intermolecular biaryl coupling. AB - The asymmetric total synthesis of nonracemic korupensamine B is reported. It includes a newly designed and highly trans-diastereoselective (>20:1 dr) route to the tetrahydroisoquinoline ring and an unprecedented atropdiastereoselective Suzuki-Miyaura coupling for construction of the fully fashioned naphthylisoquinoline framework that invokes pi stacking as a possible source of stereocontrol. PMID- 20849112 TI - Acetylation of GAGA factor modulates its interaction with DNA. AB - GAGA is a Drosophila transcription factor that shows a high degree of post translational modification. Here, we show that GAGA factor is acetylated in vivo. Lysine residues K325 and K373 on basic regions BR1 and BR3 of the DNA binding domain, respectively, are shown to be acetylated by PCAF. While BR1 is strictly required to stabilize DNA binding, BR3 is dispensable. However, acetylation of both lysine residues, either alone or in combination, weakens the binding to DNA. Despite the high degree of conservation of K325 and K373 in flies, their mutation to glutamine does not affect DNA binding. Molecular dynamics simulations, using acetylated K325 and a K325Q mutant of GAGA DNA binding domain in complex with DNA, are fully consistent with these results and provide a thermodynamic explanation for this observation. We propose that while K325 and K373 are not essential for DNA binding they have been largely conserved for regulatory purposes, thus highlighting a key regulatory system for GAGA factor in flies. PMID- 20849113 TI - Solid-phase synthesis of highly diverse purine-hydroxyquinolinone bisheterocycles. AB - Solid-phase synthesis of bisheterocyclic compounds that contain purine and the 3 hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure is described. The reaction sequence started from the primary amines immobilized on aminomethylated polystyrene resin equipped with an acid-labile linker (4-(4-formyl-3-methoxyphenoxy)butyric acid). After the arylation of amines with 2,6-dichloropurine via its C(6), purine N(9) was alkylated and subsequently the chlorine at purine C(2) was substituted with aliphatic diamines. The resulting terminal amino group was used as the starting point for the synthesis of 3-hydroxyquinolin-4(1H)-one precursors based on the acylation with 3-amino-4-(methoxycarbonyl)benzoic acid followed by the saponification of the methyl ester and esterification of the resulting carboxylic acid with various haloketones. The intermediates were cleaved from the resin, and their cyclization to the target purine-hydroxyquinolinone bisheterocycles was accomplished by heating in acetic or trifluoroacetic acid. PMID- 20849114 TI - Spreading behavior of water droplets on fractal agar gel surfaces. AB - Agar gels with hierarchical rough surfaces, referred to as "fractal agar gels," were prepared to model biological surfaces coated with mucus. Agar gels with rough surfaces of fractal dimension D = 2.2 were synthesized by transferring a fractal surface structure of alkylketene dimer (AKD). The rough structure accelerated the spreading of water droplets and induced the appearance of a wicking front. The mechanism of acceleration of the spreading on fractal surfaces based on a semiquantitative theoretical model was also clarified. PMID- 20849115 TI - Functionalizable collagen model peptides. AB - The functionalizability and conformational properties of azidoproline (Azp) containing collagen model peptides (CMPs) were studied. The results show that (4R)Azp has a similar stabilizing effect on the collagen triple helix as (4R)hydroxyproline and that functionalized CMPs are readily accessible by "click" chemistry. The resulting triazole-functionalized CMPs form stable triple helices, demonstrating that sterically demanding moieties in three symmetry-related positions in all strands are tolerated. The straightforward synthesis and facile functionalizability of the Azp-containing CMPs are intriguing for the development of functional collagen-based materials. PMID- 20849116 TI - Synthesis of a new zwitterionic surfactant containing an imidazolium ring. Evaluating the chameleon-like behavior of zwitterionic micelles. AB - Synthesis of a new zwitterionic surfactant containing the imidazolium ring 3-(1 tetradecyl-3-imidazolio)propanesulfonate (ImS3-14) is described. The solubility of ImS3-14 is very low but increases on addition of a salt which helps to stabilize the micellized surfactant. Fluorescence quenching and electrophoretic evidence for ImS3-14 shows that the micellar aggregation number is only slightly sensitive to added salts, as is the critical micelle concentration, but NaClO(4) markedly increases zeta potentials of ImS3-14 in a similar way as in N-tetradecyl N,N-dimethylammonio-1-propanesulfonate (SB3-14) micelles. The rate of specific hydrogen ion catalyzed hydrolysis of 2-(p-heptoxyphenyl)-1,3-dioxolane and equilibrium protonation of 1-hydroxy-2-naphthoate ion in zwitterionic micelles of ImS3-14 and SB3-14 are increased markedly by NaClO(4) which induces anionoid character and uptake of H(3)O(+), but NaCl is much less effective in this respect. Comparison of ImS3-14 with SB3-14 is based on experimental evidence, and computational calculations indicate similarities and differences in structures of both compounds. PMID- 20849117 TI - Superadditive effects of ethanol and flunitrazepam: implications of using immunopharmacotherapy as a therapeutic. AB - While benzodiazepine intoxication alone may elicit sedative and antianxiety effects, alcohol coingestion greatly amplifies this central nervous system depression. As a result, this drug combination gained notoriety for its role in cases of facilitated sexual assault and fatal overdose. We previously validated the ability of the novel antiflunitrazepam monoclonal antibody (mAb) RCA3A3 to bind flunitrazepam (FLU) in vivo and block FLU-induced impairment of locomotion and memory. A therapeutically relevant application of this high affinity mAb (K(d,app) = 200 nM), however, is to the more tenuous indication of flunitrazepam (FLU) and alcohol cointoxication. Employing a murine behavioral model, passive immunization with mAb RCA3A3 before injection of ethanol (EtOH: low-dose, 1 g/kg, or high-dose, 1.5 g/kg), FLU (0.06 mg/kg), or a cocktail of both drugs offered partial to full restoration of motor activity levels in co-drug treated and FLU treated mouse groups (n = 12), respectively. Whereas all drug treatments left contextual learning intact, auditory cued learning was severely disrupted. Prophylactic administration of mAb RCA3A3 prevented this deficit in cued learning in FLU-treated mice but not in the FLU- and EtOH-treated mice, in which co-drug exposure exacerbated the impairment in cued fear conditioning. To substantiate this finding, a dose-response study was performed, and the changes in locomotor activity incurred by different FLU (low-dose, 0.06 mg/kg, or high-dose, 0.09 mg/kg), EtOH (1.0 g/kg, 1.5 g/kg), and mAb RCA3A3 (14.5 mg/kg, 21.8 mg/kg) dose combinations illustrated the potentiation in motor effects by concomitant exposure to FLU and EtOH. Thus, motor activity and fear conditioning results demonstrated that both the amount of FLU left unbound by antibody and the pharmacological additivity between FLU and EtOH, a GABA mimetic, were limiting factors in the therapeutic efficacy of mAb RCA3A3. In sum, our study highlights the complex nature of psychomotor impairment upon co-drug versus singular drug exposure, which may pose a unique challenge to therapeutic treatment. PMID- 20849118 TI - High-efficiency green organic light-emitting devices utilizing phosphorescent bis cyclometalated alkynylgold(III) complexes. AB - A new phosphorescent material of cyclometalated alkynylgold(III) complex, [Au(2,5 F(2)C(6)H(3)-C?N?C)(C=C-C(6)H(4)N(C(6)H(5))(2)-p)] (1) (2,5-F(2)C(6)H(3)-HC?N?CH = 2,6-diphenyl-4-(2,5-difluorophenyl)pyridine), has been synthesized, characterized, and its device performance investigated. This luminescent gold(III) complex was found to exhibit rich PL and EL properties and has been utilized as phosphorescent dopants of OLEDs. At an optimized dopant concentration of 4%, a device with a maximum external quantum efficiency (EQE) of 11.5%, corresponding to a current efficiency of 37.4 cd/A and a power efficiency of 26.2 lm/W, has been obtained. Such a high EQE is comparable to that of Ir(ppy)(3) based devices. The present work suggests that the alkynylgold(III) complex is a promising phosphorescent material in terms of both efficiency and thermal stability, with the additional advantages of its relatively inexpensive cost and low toxicity. PMID- 20849119 TI - Direct carbon-carbon bond formation via reductive soft enolization: a kinetically controlled syn-aldol addition of alpha-halo thioesters and enolizable aldehydes. AB - The direct addition of enolizable aldehydes and alpha-halo thioesters to produce beta-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic alpha-hydroxy aldehyde derivative is used. PMID- 20849120 TI - Cell-directed integration into three-dimensional lipid-silica nanostructured matrices. AB - We report a unique approach in which living cells direct their integration into 3D solid-state nanostructures. Yeast cells deposited on a weakly condensed lipid/silica thin film mesophase actively reconstruct the surface to create a fully 3D bio/nano interface, composed of localized lipid bilayers enveloped by a lipid/silica mesophase, through a self-catalyzed silica condensation process. Remarkably, this integration process selects exclusively for living cells over the corresponding apoptotic cells (those undergoing programmed cell death), via the development of a pH gradient, which catalyzes silica deposition and the formation of a coherent interface between the cell and surrounding silica matrix. Added long-chain lipids or auxiliary nanocomponents are localized within the pH gradient, allowing the development of complex active and accessible bio/nano interfaces not achievable by other synthetic methods. Overall, this approach provides the first demonstration of active cell-directed integration into a nominally solid-state three-dimensional architecture. It promises a new means to integrate "bio" with "nano" into platforms useful to study and manipulate cellular behavior at the individual cell level and to interface living organisms with electronics, photonics, and fluidics. PMID- 20849121 TI - Aggregation of fullerol C60(OH)24 nanoparticles as revealed using flow field-flow fractionation and atomic force microscopy. AB - The effects of solution pH and 1:1 electrolyte concentration on the aggregation behavior of fullerol C(60)(OH)(24) nanoparticles were investigated using flow field-flow fractionation (FlFFF). Particle separations were confirmed by examining FFF fractions using atomic force microscopy (AFM). Results showed that fullerol C(60)(OH)(24) nanoparticles remain stable at low salt concentration (0.001 M NaCl) and basic pH (pH 10). Changing the pH did not affect the size significantly, but increasing the salt concentration promoted some aggregation. Fullerol C(60)(OH)(24) nanoparticles did not form large clusters and reached a maximum size of at most several nanometers. Particle interaction analysis using the colloid interaction theory as described by the energetics of electrostatic repulsion and van der Waals attraction explained the differences in the colloidal stability of the fullerol C(60)(OH)(24) nanoparticles under different solution conditions. PMID- 20849122 TI - Monovalent cations trigger inverted bilayer formation of surfactant films. AB - We monitored single-layer Langmuir-Blodgett films of behenic acid deposited on silanized glass or silicon substrates by atomic force microscopy (AFM) in liquid. We observed the in situ transformation of the monolayer to a bilayer when the surrounding solution was NaOH or KOH with pH > 8.3. The final state is that of an inverted bilayer, in which both the hydrophobic OTS (octadecyltrichlorosilane) and the alkane chains are exposed to the surrounding solution, defying common intuition based on hydrophobic-hydrophilic energy considerations. Strong sodium containing carboxylic dimers formed between the headgroups are shown to be responsible for the stabilization of this configuration; calcium ions slow down/inhibit the transformation. PMID- 20849123 TI - Troponin in both smooth and striated muscles of Ascidian Ciona intestinalis functions as a Ca2+-dependent accelerator of actin-myosin interaction. AB - Troponin, a Ca2+-dependent regulator of muscle contraction, acts as an inhibitor of the actin-myosin interaction in the absence of Ca2+ during contraction in vertebrate striated muscle. However, variation has been observed in the mode of troponin-dependent regulation among the animals belonging to Protochordata, the taxon most closely related to Vertebrata. Although troponin in striated muscle of a cephalochordate amphioxus functions as an inhibitor in the absence of Ca2+ as in vertebrates [Dennisson, J. G., et al. (2010) Zool. Sci. 27, 461-469], troponin in the smooth muscle of a urochordate ascidian (Halocynthia roretzi) regulates actin-myosin interaction as an activator in the presence of Ca2+ and not an inhibitor in the absence of Ca2+ as in vertebrates [Endo, T., and Obinata, T. (1981) J. Biochem. 89, 1599-1608]. In this study, to further clarify the functional diversity of troponin, we examined the role of troponin in Ca2+ dependent regulation of the actin-myosin interaction in striated and smooth muscles in another member of Ascidiacea (Ciona inetestinalis) using three recombinant troponin components, TnT, TnI, and TnC, produced using an Escherichia coli expression system. On the basis of actomyosin ATPase assays, we show here that troponins in both smooth and striated muscles of ascidian function as a Ca2+ dependent activator of the actin-myosin interaction and TnT is the component responsible for this activation. These results indicate that troponin of ascidian has evolved in a manner different from that of amphioxus and vertebrates in terms of function. PMID- 20849124 TI - A mixed 3d-4f 14-metallacrown-5 complex that displays slow magnetic relaxation through geometric control of magnetoanisotropy. AB - We describe the synthesis and magnetic properties of a unique mixed 3d-4f 14 metallacrown-5 complex. This is the first metallacrown family to feature MU-O and MU-OH bridges as well as to incorporate a Ln(III) ion into the ring. Alternating current SQUID magnetometry of the Tb, Dy, and Ho derivatives reveals slow magnetic relaxation, a hallmark property of single-molecule magnets. For the Dy structure (4), an effective energy barrier U(eff) of 16.7 K and a relaxation time of 4.9 * 10(-8) s were calculated. Because of the relatively small total spin, this behavior most likely results from a large magnetoanisotropy, which is controlled through geometric constraints. PMID- 20849125 TI - 6-(3,5-Dimethyl-1H-pyrazol-1-yl)-2,2'-bipyridine as ligand for actinide(III)/lanthanide(III) separation. AB - With the aim of better understanding the selectivity of the established system 2,6-ditriazinylpyridine (BTP) for actinide(III)/lanthanide(III) separations, a related model system was synthesized and studied. The N donor complexing ligand 6 (3,5-dimethyl-1H-pyrazol-1-yl)-2,2'-bipyridine (dmpbipy) was synthesized having a fused N heterocycle ring structure modified from the BTP partitioning ligand, and its extraction performance and selectivity for trivalent actinide cations over lanthanides was evaluated. X-ray diffraction (XRD), extended X-ray absorption fine structure (EXAFS), and time-resolved laser fluorescence spectroscopy (TRLFS) results show that 1:1 complexes are formed, unlike the 1:3 complex for BTP systems. The equilibrium constant for curium complex formation with dmpbipy was determined to be log K = 2.80, similar to that for nitrate. The Gibbs free energy, DeltaG(20 degrees C), of 1:1 Cm-dmpbipy formation in n-octan-1-ol was measured to be -15.5 kJ/mol. The dmpbipy ligand in 1-octanol does not extract Am(III) Eu(III) from HNO(3) but was found to extract Am(III) with limited selectivity over Eu(III) (SF(Am(III)/Eu(III)) ~ 8) dissolved in 2-bromohexanoic acid and kerosene at pH > 2.4. PMID- 20849126 TI - Cell-trappable quinoline-derivatized fluoresceins for selective and reversible biological Zn(II) detection. AB - The synthesis and spectroscopic characterization of two new, cell-trappable fluorescent probes for Zn(II) are presented. These probes, 2-(4,5-bis(((6-(2 ethoxy-2-oxoethoxy)quinolin-8-yl)amino)methyl)-6-hydroxy-3-oxo-3H-8 xanthen-9 yl)benzoic acid (QZ2E) and 2,2'-((8,8'-(((9-(2-carboxyphenyl)-6-hydroxy-3-oxo-3H xanthene-4,5-diyl)bis(methylene))bis(azanediyl))bis(quinoline-8,6 diyl))bis(oxy))diacetic acid (QZ2A), are poorly emissive in the off-state but exhibit dramatic increases in fluorescence upon Zn(II) binding (120 +/- 10-fold for QZ2E, 30 +/- 7-fold for QZ2A). This binding is selective for Zn(II) over other biologically relevant metal cations, toxic heavy metals, and most first-row transition metals and is of appropriate affinity (K(d1)(QZ2E) = 150 +/- 100 MUM, K(d2)(QZ2E) = 3.5 +/- 0.1 mM, K(d1)(QZ2A) = 220 +/- 30 MUM, K(d2)(QZ2A) = 160 +/- 80 MUM, K(d3)(QZ2A) = 9 +/- 6 MUM) to reversibly bind Zn(II) at physiological levels. In live cells, QZ2E localizes to the Gogli apparatus where it can detect Zn(II). It is cell-membrane-permeable until cleavage of its ester groups by intracellular esterases produces QZ2A, a negatively charged acid form that cannot cross the cell membrane. PMID- 20849127 TI - Organometallic complexes with terminal imidazolato ligands and their use as metalloligands. AB - Compounds [Re(bipy)(CO)(3)(HIm)]OTf (1) and [Mo(eta(3)-C(3)H(4)-R 2)(CO)(2)(HIm)(phen)]BAr'(4) [R = Me (2a), H (2b); Ar' = 3,5 bis(trifluoromethyl)phenyl; HIm = 1H-imidazole] were prepared from 1H-imidazole and either [Re(OTf)(bipy)(CO)(3)] or [MoCl(eta(3)-C(3)H(4)-R-2)(CO)(2)(phen)]. Compounds 1, 2a, and 2b were deprotonated to afford the terminal kappa-N imidazolate complexes [Re(bipy)(CO)(3)(Im)] (3) and [Mo(eta(3)-C(3)H(4)-R 2)(CO)(2)(Im)(phen)] [R = Me (4a), H (4b)], which were fully characterized, including an X-ray structural determination of 3. The topological analysis of the electron density (obtained from the X-ray diffraction study) and its Laplacian were used to characterize the differences in the electron density at the five membered ring ligand between the imidazole and imidazolate complexes 1 and 3. The reaction of complexes 3, 4a, and 4b with the appropriate organometallic complexes afforded the bimetallic imidazolate-bridged compounds [{Re(bipy)(CO)(3)}(2)(MU Im)]OTf (5), [{Mo(eta(3)-C(4)H(7))(CO)(2)(phen)}(2)(MU-Im)]OTf (6), and [{Mo(eta(3)-C(3)H(5))(CO)(2)(phen)}(MU-Im){Re(phen)(CO)(3)}]OTf (7). The reaction of [Mo(eta(3)-C(4)H(7))(CO)(2)(Im)(phen)] (4a) with SnClPh(3) led to the formation of the trinuclear complex [{Mo(eta(3)-C(4)H(7))(CO)(2)(phen)(MU Im)}(2){SnPh(3)}]BAr'(4) (8). PMID- 20849128 TI - Bis-exo-2-norbornylboron triflate for stereospecific enolization of 3,3,3 trifluoropropionates. AB - The first boron-mediated enolization-aldolization of 3,3,3-trifluoropropionates has been reported. The preparation and application of bis-exo bicyclo[2.2.1]heptan-2-ylboron triflate as a superior reagent for diastereospecific enolization has also been described. PMID- 20849129 TI - Mechanistic insight into the alcohol oxidation mediated by an efficient green [CuBr(2)(2,2'-bipy)]-TEMPO catalyst by density functional method. AB - Density functional theory (DFT) calculations have been performed to investigate the alcohol oxidation to acetaldehyde catalyzed by [CuBr(2)(2,2'-bipy)]-TEMPO (TEMPO stands for 2,2,6,6-tetramethylpiperidinyloxy; bipy stands for bipyridine). The total charge for the studied catalytic system is +1. The catalytic cycle consists of two parts, namely, alcohol oxidation and TEMPO regeneration. In alcohol oxidation, the reaction follows the Sheldon's mechanism for the proposed two mechanisms, i.e., Semmelhack's mechanism and Sheldon's mechanism. The water participation plays minor role in the H atom abstraction step. In TEMPO regeneration, the proposed three paths are competitive in energy. By comparing with experimental observation, it is found that the path, in which alcohol provides the proton to TEMPO(-) to produce TEMPOH followed by the oxidation of TEMPOH directly to TEMPO by O(2), is favored. In TEMPO regeneration, CH(3)CN acts as the ligand to stabilize the Cu(I) species during the catalytic cycle. PMID- 20849130 TI - Carboxylic acid-promoted copper(I)-catalyzed azide-alkyne cycloaddition. AB - In this article, we proved that all three key steps in the catalytic cycle of CuAAC can proceed in the presence of carboxylic acids and the latter two steps can be promoted significantly by carboxylic acids. Benzoic acid showed the best promotion activity, and the acids with strong chelating ability to Cu(I) ion could not serve for this purpose. Thus, the first carboxylic acid-promoted highly efficient CuAAC was established. PMID- 20849131 TI - Copper-catalyzed thiolation annulations of 1,4-dihalides with sulfides leading to 2-trifluoromethyl benzothiophenes and benzothiazoles. AB - Copper-catalyzed double thiolation reaction of 1,4-dihalides with sulfides has been developed for selectively synthesizing 2-trifluoromethyl benzothiophenes and benzothiazoles. In the presence of CuI, a variety of 2-halo-1-(2-haloaryl)-3,3,3 trifluoropropylenes smoothly underwent the thiolation annulation with Na(2)S to afford 2-trifluoromethyl benzothiophenes in moderate to good yields. Moreover, the conditions are compatible with N-(2-haloaryl)trifluoroacetimidoyl chlorides in the presence of NaHS and K(3)PO(4), leading to 2-trifluoromethyl benzothiazoles. PMID- 20849132 TI - Real time observation of chemical reactions of individual metal nanoparticles with high-throughput single molecule spectral microscopy. AB - Real time observation of chemical reactions of individual noble metal nanoparticles (MNPs) is fundamentally important to their controlled synthesis, chemical sensing and catalysis applications. Here, with a simple and high throughput single-molecule darkfield spectral imaging technique, we demonstrate that the reaction-induced plasmonic resonance variations of multiple MNPs could be monitored in parallel. Oxidation kinetics of individual gold nanorods (AuNRs), either immobilized on a glass substrate or moving freely in homogeneous solution, was recorded successfully. Heterogeneous reaction pathways and intermediate states unobservable in ensemble UV-visible measurements were revealed. Interestingly, the oxidation rate of individual immobilized AuNRs was much slower than that of the bulk AuNR solution, which implies the existence of a novel self catalysis mechanism. This high-throughput darkfield spectral imaging technique could be applied to chemical reaction kinetics and heterogeneous catalysis studies of other MNPs at single particle level. PMID- 20849133 TI - Behavior of 1,2-dioleoyl-sn-glycero-3-phosphocholine at the surface of 3 hydroxypropionitrile near the critical micelle concentration. AB - The existence of a local minimum of surface tension near the critical micelle concentration has been reported for various surfactant solutions. In some cases, this is interpreted as an indication for the presence of impurities. Recently, this phenomenon has been interpreted as an inhibition of the aggregation for POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) in HPN (3 hydroxypropionitrile). This notion is supported by the present experiments on the phospholipid DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) at the surface of HPN. Comparison of the results of both systems delivers improved understanding of the aggregation of surfactants in solution. PMID- 20849134 TI - Intermolecular interactions of IgG1 monoclonal antibodies at high concentrations characterized by light scattering. AB - Light scattering intensity measurements of solutions of two purified monoclonal antibodies were performed over a wide range of concentrations (0.5-275 mg/mL) and ionic strengths (0.02 to 0.6 M). Despite extensive sequence homology between these mAbs, alteration of ~20 amino acids in the complementarity determining regions resulted in different net intermolecular interactions and responses to solution ionic strength. The concentration dependence of scattering was analyzed by comparison with the predictions of three models, allowing for intermolecular interaction of various types. In order of increasing complexity, the three models account for: (1) steric repulsions (simple hard-sphere model), (2) steric repulsion with short-ranged attractive interactions of varying magnitude (adhesive hard-sphere model), and (3) steric and nonsteric repulsive interactions between several species whose relative concentrations may change as a function of total protein concentration as dictated by equilibrium self-association (effective hard-sphere mixture model). Simple scattering models of noninteracting and adhesive hard-sphere species permitted qualitative interpretation of contributions from excluded volume, electrostatic, and van der Waals interactions on net mAb interactions at high concentration as a function of ionic strength. mAb2 electrostatic interactions were repulsive, whereas mAb1 interactions were net attractive at low ionic strengths, attributed to an anisotropic distribution of molecular charge. The effective hard-sphere mixture model can account quantitatively for the dependence of scattering for both antibodies over the entire concentration range and at salt concentrations exceeding 40 mM. This analysis showed that at high ionic strength both mAbs self-associate weakly to form dimer with an affinity that varies little with salt concentration at concentrations exceeding 75 mM. In addition, mAb1 appears to self-associate further to form oligomers with stoichiometry of 4-6 and an affinity that declines substantially with increasing ionic strength. All three models lead to the conclusion that at high concentrations repulsive interactions are predominantly due to excluded volume, whereas additional features are salt-dependent and reflect a substantial electrostatic contribution to intermolecular interactions of both mAbs. PMID- 20849135 TI - Molecular dynamics and physical stability of amorphous anti-inflammatory drug: celecoxib. AB - By using dielectric spectroscopy we analyzed the relation between molecular mobility and tendency of the amorphous celecoxib to recrystallize. We found that celecoxib is kinetically a fragile glassformer, contrary to the conclusion reached by others from thermodynamic fragility. The possible correlation of the large tendency of celecoxib to crystallize with various molecular motions have been investigated. Our study shows that the structural relaxation seems to be responsible for devitrification of celecoxib if stored at room temperature ~293 K. Notwithstanding, the crystallization can be considered to ultimately be affected by the beta-process (JG-relaxation) because it is the precursor of the structural alpha-relaxation. PMID- 20849136 TI - Reaction dynamics of H(3)(+) + CO on an interpolated potential energy surface. AB - An accurate potential energy surface for H(3)(+) + CO has been constructed by interpolation of ab initio data. The reaction cross sections and thermal rate coefficients for the production of HCO(+) and HOC(+) have been evaluated using quasiclassical trajectory simulations. PMID- 20849137 TI - Thermodynamic, dynamic, and structural properties of ionic liquids comprised of 1 butyl-3-methylimidazolium cation and nitrate, azide, or dicyanamide anions. AB - Molecular dynamics simulations of ionic liquids (IL) comprised of 1-butyl-3 methylimidazolium [bmim] cation and nitrate [NO(3)], azide [N(3)], or dicyanamide [N(CN)(2)] anions were conducted using the polarizable APPLE&P force field. Comparison of thermodynamic properties such as densities, enthalpies of vaporization, and ion binding energies as well as structural correlations obtained from simulations at atmospheric pressure and temperature range 298-393 K showed that IL with the N(CN)(2) anion shows significantly different characteristics as compared to ILs with the N(3) and NO(3) anions. [bmim][N(CN)(2)] IL was found to have the lowest enthalpy of vaporization and the weakest ion-ion structural correlation as compared to ILs with the other two ions. This trend was further manifested in dynamical properties characterized by self-diffusion coefficients and molecular rotational relaxation times, where IL with the N(CN)(2) anion showed the fastest dynamics as compared to other ILs. We also examine the dynamic correlations between the ions' translational and rotational motions as well as discuss the anisotropy of the latter. PMID- 20849138 TI - Probing the hydration structure of polarizable halides: a multiedge XAFS and molecular dynamics study of the iodide anion. AB - A comprehensive analysis of the H(2)O structure about aqueous iodide (I(-)) is reported from molecular dynamics (MD) simulation and X-ray absorption fine structure (XAFS) measurements. This study establishes the essential ingredients of an interaction potential that reproduces the experimentally determined first solvation shell of aqueous iodide. XAFS spectra from the iodide K, L(1), and L(3) edges were corefined to establish the complete structure of the first hydration shell about aqueous iodide. Further, we have utilized molecular dynamics simulations employing both DFT (+dispersion) and empirical polarizable interaction potentials to generate an ensemble of structures that were directly compared to the XAFS data. Our results indicate that DFT-MD simulations provide a description of the molecular structure that is more consistent with the XAFS experimental data. The experimental data yield approximately 6.3 water molecules located at I-H and I-O distances of 2.65 and 3.50 A, respectively. The differences in the two interaction potentials can be traced to the treatment of the electronic charge density in the vicinity of the iodide. The empirical polarizable interaction potential yields a significantly higher induced dipole for the aqueous iodide than the DFT study. The lower induced dipole moment from the DFT simulation produces a higher coordination number and leads to a more symmetric solvation environment than that produced by the empirical polarizable interaction potential. Furthermore, the hydrogen bonding of second-shell water with the first-shell water establishes a strong ordering of the water about the iodide surface. PMID- 20849139 TI - Alkylsulfides of Ag(I) and Au(I) as metallosurfactants. AB - Several representative, interfacially active silver(I) nitrate alkylsulfide complexes were synthesized and characterized in detail. The complexes form extended structures in the solid state and in solution. Interestingly, a two phase approach, in which aqueous silver nitrate is combined with organically dissolved sulfides, leads to the in situ formation of the complexes at the water organic interface and a strong reduction of the surface tension. Despite their low solubility in water or organic solvent, these complexes are capable of stabilizing eicosane emulsions and dispersions in water. Thus, these silver nitrate alkyl sulfides represent a new class of metallosurfactants in which the metal ion is crucial for the interfacial activity. Gold(I) chloride alkyl sulfides show the same effect to a lesser extent. PMID- 20849140 TI - Optical models for the characterization of silica nanosphere monolayers prepared by the Langmuir-Blodgett method using ellipsometry in the quasistatic regime. AB - We investigated different optical models (one-layer, multilayer, parametric multilayer, and statistical parametric) for the ellipsometric characterization of thin films made of silica spheres in the diameter (D) range of 90-450 nm prepared by the Langmuir-Blodgett (LB) technique. As a continuation of a previous work (Nagy, N., et al. Langmuir 2006, 22, 8416) in terms of threshold wavelength determination and optical models, we investigated the wavelength range of the quasistatic limit (requirement for the effective medium approximation) depending onD.We compared the above models in the aspect of fit quality, stability, uncertainty of parameters, and the amount of information that can be obtained from the evaluation. Besides fundamental properties like diameter, coverage, or packing density, using sophisticated models we can also determine the size distribution of the particles. The ellipsometric results were compared with the results of dynamic light scattering and of scanning electron microscopy. PMID- 20849141 TI - Tunable assembly of nanoparticles on patterned porous film. AB - This paper describes an approach to fully selective assembly of nanoparticles on patterned porous surface. Copolymers of polystyrene-block-poly(N,N dimethylaminoethyl methacrylate) synthesized by atom transfer radical polymerization were used to prepare honeycomb-patterned porous films by the breath figure method. The regularity and pore size of the films can be modulated by changing the polymer composition and casting conditions such as concentration and airflow speed. Positively charged films were fabricated directly from the quaternized copolymers or by surface quaternization. X-ray photoelectron spectroscopy and adsorption of negatively charged fluorescein sodium salt confirmed the quaternization. Then assembly of negatively charged silica nanoparticles from its aqueous dispersion was performed. Results indicate that they assemble on the external surface of patterned porous films that without prewetting. For prewetted films, the nanoparticles assemble both on the external surface and in the pores. Poly(acrylic acid) deposited from its aqueous solution can serve as an effective blocking layer, which directs the selective assembly of nanoparticles into the pores, instead of the external surface of the film. It is concluded that the Cassie-Wenzel transition is the key to the selective assembly on the highly porous films. The well-defined selective assembly forms unique hierarchical structures of nanoparticles and greatly enlarges the diversity of structures of nanoparticle aggregates. This general approach also opens a straightforward route to the selective modification of patterned porous films. PMID- 20849142 TI - Antimicrobial activity of single-walled carbon nanotubes: length effect. AB - This study investigated the effect of SWCNTs' length on their antimicrobial activity to bacterial cells in suspensions. Three different lengths of SWCNTs (<1 MUm, 1-5 MUm, and ~5 MUm) were tested. At same weight concentration, longer SWCNTs exhibited stronger antimicrobial activity. The fluorescence and SEM images revealed that the longer SWCNTs aggregated with bacterial cells more effectively, whereas short length SWCNTs tended to aggregate themselves without involving many bacterial cells. Moreover, longer SWCNTs exhibited more pronounced concentration dependence and treatment time-dependence on their antimicrobial activity. PMID- 20849143 TI - Azido gauche effect on the backbone conformation of beta-azidoalanine peptides. AB - To study the azido gauche effect on the backbone conformation of beta azidoalanine (Aza) dipeptide (AAD, Ac-Aza-NHMe) and tripeptide (AAT, Ac-Aza-Aza NH(2)), we used spectroscopic methods in combination with quantum chemistry calculations and molecular dynamics (MD) simulations. From the (1)H NMR coupling constants and (1)H,(1)H NOESY experimental data, we found that AAD in water mainly adopts a seven-membered cyclic (C(7)) rather than polyproline II (P(II)) backbone conformation and prefers the gauche- (g(-)) side-chain conformer. From the amide I IR absorption and circular dichroism (CD) spectra, the backbone conformation of AAD in water is found to deviate from P(II) but is rather close to C(7). Thus, the backbone conformation of AAD differs from that of alanine dipeptide (AD, Ac-Ala-NHMe), which is mainly P(II) in water. The underlying origin of the backbone conformational difference between AAD and AD in water was elucidated by quantum chemistry calculations with density functional theory (DFT). It was found that the C(7)/g(-) conformer is the lowest energy structure of an isolated AAD. Here, the beta-azido group forms intramolecular electrostatic interactions with two neighboring peptide bonds, which are facilitated by the azido gauche effect. Thus, the beta-azido group appears to be responsible for directing the peptide backbone conformation toward the C(7) structure. The quantum mechanical/molecular mechanical (QM/MM) MD simulations show that AAD in water adopts neither P(II) nor right-handed alpha-helix (alpha(R)) and prefers the g(-) conformer. Thus, the intramolecular electrostatic interactions between the beta-azido group and two nearby peptide bonds are also found even in the aqueous solution structure of AAD. Consequently, the beta-azido group appears to be an effective C(7)-conformation-directing element, which may also be useful for tuning the structures of other amino acids and polypeptides. PMID- 20849144 TI - Formal total synthesis of okadaic acid via regiocontrolled gold(I)-catalyzed spiroketalizations. AB - Both C19 and C34 spiroketal domains of okadaic acid were assembled using gold(I) chloride catalyzed spiroketalizations, and the two resulting fragments were coupled to give the C15-C38 fragment of okadaic acid, a known intermediate for the total synthesis of this important natural product. PMID- 20849145 TI - Synthesis of N-arylindazoles and benzimidazoles from a common intermediate. AB - A variety of N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields. The product selectivity depends upon the base used in the reaction, as triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine promoted the formation of N arylindazoles. This method is valuable to the synthetic community because both indazoles and benzimidazoles are prevalent in pharmaceuticals. PMID- 20849149 TI - Detection of lipid peroxidation-induced DNA adducts caused by 4-oxo-2(E)-nonenal and 4-oxo-2(E)-hexenal in human autopsy tissues. AB - DNA adducts are produced both exogenously and endogenously via exposure to various DNA-damaging agents. Two lipid peroxidation (LPO) products, 4-oxo-2(E) nonenal (4-ONE) and 4-oxo-2(E)-hexenal (4-OHE), induce substituted etheno-DNA adducts in cells and chemically treated animals, but the adduct levels in humans have never been reported. It is important to investigate the occurrence of 4-ONE- and 4-OHE-derived DNA adducts in humans to further understand their potential impact on human health. In this study, we conducted DNA adductome analysis of several human specimens of pulmonary DNA as well as various LPO-induced DNA adducts in 68 human autopsy tissues, including colon, heart, kidney, liver, lung, pancreas, small intestine, and spleen, by liquid chromatography tandem mass spectrometry. In the adductome analysis, DNA adducts derived from 4-ONE and 4 OHE, namely, heptanone-etheno-2'-deoxycytidine (HepsilondC), heptanone-etheno-2' deoxyadenosine (HepsilondA), and butanone-etheno-2'-deoxycytidine (BepsilondC), were identified as major adducts in one human pulmonary DNA. Quantitative analysis revealed 4-ONE-derived HepsilondC, HepsilondA, and heptanone-etheno-2' deoxyguanosine (HepsilondG) to be ubiquitous in various human tissues at median values of 10, 15, and 8.6 adducts per 10(8) bases, respectively. More importantly, an extremely high level (more than 100 per 10(8) bases) of these DNA adducts was observed in several cases. The level of 4-OHE-derived BepsilondC was highly correlated with that of HepsilondC (R(2) = 0.94), although BepsilondC was present at about a 7-fold lower concentration than HepsilondC. These results suggest that 4-ONE- and 4-OHE-derived DNA adducts are likely to be significant DNA adducts in human tissues, with potential for deleterious effects on human health. PMID- 20849146 TI - The physicochemical properties, in vitro metabolism and pharmacokinetics of a novel ester prodrug of EXP3174. AB - EXP3174 is the major active metabolite of losartan, a drug currently widely used for the treatment of cardiovascular diseases. This study was designed to evaluate the physicochemical properties of EXP3174-pivoxil (a novel synthesized prodrug of EXP3174) and characterize its metabolism, regional intestinal absorption and pharmacokinetics by in vitro and in vivo studies. An in vitro metabolism study was conducted in liver and intestinal S9 fractions from different species including rat, dog and human. In vivo absorption was investigated following regional intestinal dosing in rats, and the pharmacokinetics was determined using rats after a single oral administration. EXP3174-pivoxil exhibited predictable stability in the aqueous solution within a pH range of 1.2-9.0 as well as in the solid form of powder. An in vitro metabolism study revealed that EXP3174-pivoxil was rapidly and efficiently converted into EXP3174 by enzymatic hydrolysis. The dose administered into the duodenum and jejunum resulted in higher values for the AUC(0-24h) and C(max) than those following ileum dosing (p < 0.05). Furthermore, the AUC(0-24h) and C(max) values for EXP3174 increased in a dose-dependent manner as dose increased from 0.5 to 5 mg/kg. A comparable AUC(0-24h), shortened T(max) and a significant increase in the plasma C(max) of EXP3174 were observed following oral administration of EXP3174-pivoxil (as EXP3174, 1 mg/kg) compared with those of losartan (as EXP3174, 5 mg/kg) in rats, suggesting faster absorption and a 5-fold enhancement in the bioavailability of EXP3174. These results suggest that EXP3174-pivoxil may serve as a more effective drug even at lower clinical doses by exhibiting increased bioavailability and faster therapeutic response, compared with losartan. PMID- 20849150 TI - Role of human glutathione S-transferases in the inactivation of reactive metabolites of clozapine. AB - The conjugation of reactive drug metabolites to GSH is considered an important detoxification mechanism that can be spontaneous and/or mediated by glutathione S transferases (GSTs). In case GSTs play an important role in GSH conjugation, genetically determined deficiencies in GSTs may be a risk factor for adverse drug reactions (ADRs) resulting from reactive drug metabolites. So far, the role of GSTs in the detoxification of reactive intermediates of clozapine, a drug-causing idiosyncratic drug reactions (IDRs), has not been studied. In the present study, we studied the ability of four recombinant human GSTs (hGST A1-1, hGST M1-1, hGST P1-1, and hGST T1-1) to catalyze the GSH conjugation of reactive metabolites of clozapine, formed in vitro by human and rat liver microsomes and drug metabolizing P450 BM3 mutant, P450 102A1M11H. Consistent with previous studies, in the absence of GSTs, three GSH conjugates were identified derived from the nitrenium ion of clozapine. In the presence of three of the GSTs, hGST P1-1, hGST M1-1, and hGST A1-1, total GSH conjugation was strongly increased in all bioactivation systems tested. The highest activity was observed with hGST P1-1, whereas hGST M1-1 and hGST A1-1 showed slightly lower activity. Polymorphic hGST T1-1 did not show any activity in catalyzing GSH conjugation of reactive clozapine metabolites. Interestingly, the addition of hGSTs resulted in major changes in the regioselectivity of GSH conjugation of the reactive clozapine metabolite, possibly due to the different active site geometries of hGSTs. Two GSH conjugates found were completely dependent on the presence of hGSTs. Chlorine substitution of the clozapine nitrenium ion, which so far was only observed in in vivo studies, appeared to be the major pathway of hGST P1-1-catalyzed GSH conjugation, whereas hGST A1-1 and hGST M1-1 also showed significant activity. The second GSH conjugate, previously also only found in in vivo studies, was also formed by hGST P1-1 and to a small extent by hGST A1-1. These results demonstrate that human GSTs may play a significant role in the inactivation of reactive intermediates of clozapine. Therefore, further studies are required to investigate whether genetic polymorphisms of hGST P1-1 and hGST M1-1 contribute to the interindividual differences in susceptibility to clozapine-induced adverse drug reactions. PMID- 20849151 TI - Stable expression of short interfering RNA for DT-diaphorase induces neurotoxicity. AB - DT-Diaphorase has been proposed to play a neuroprotective role in dopaminergic neurons by preventing aminochrome neurotoxicity. There are several studies supporting this idea, but in all studies, we used dicoumarol, an inhibitor of DT diaphorase. We have designed and developed two siRNA to silence the expression of DT-diaphorase to study its role in aminochrome metabolism. We transduced RCSN-3 cells with retroviral particles containing a pRetroSuper plasmid coding a siRNA for DT-diaphorase. The cells selected in the presence of puromycin generated a stable cell line RCSN-3Nq6 and RCSN-3Nq7 with low expression of DT-diaphorase (27% and 33% of wild type, respectively). A significant cell death was observed in RCSN-3 cells expressing siRNA Nq6 and Nq7 for DT-diaphorase when were incubated with 100 MUM aminochrome during 48 (4- and 3.5-fold, respectively; P < 0.01). These results support the protective role of DT-diaphorase against aminochrome neurotoxicity in dopaminergic neurons containing neuromelanin and show that Nq6 and Nq7 siRNA are very useful tools to study the role of DT diaphorase in aminochrome metabolism. PMID- 20849152 TI - Communication: Are hydrodynamic models suited for describing the reorientational dynamics of ions in ionic liquids? A case study of methylimidazolium tetra(hexafluoroisopropoxy)aluminates. AB - We report on dielectric relaxation spectra of six homologous ionic liquids (ILs) with tetra(hexafluoroisopropoxy)aluminate ([Al(hfip)(4)](-)) as a common anion. The dominating mode on the time scale of several 100 ps mainly results from cation reorientation. Because the viscosities are low and cation modification does not substantially change the viscosity, these ILs are interesting candidates for testing hydrodynamic models of rotational dynamics. The calculated hydrodynamic volumes are extraordinarily low, and roughly agree with values calculated from literature data for ILs with the same cations, but different anions. Comparison with magnetic relaxation data shows that the peculiarities are founded in the rotational dynamics and are not special to dielectric relaxation. Collectively, the observations make a strong case against the applicability of hydrodynamic approaches to the orientational dynamics of ions. PMID- 20849153 TI - Communication: Simple self-correlation corrections to the Ragot-Cortona model of local correlation energy. AB - The Ragot-Cortona or RC model of local correlation energy [J. Chem. Phys. 121, 7671 (2004)] improves the standard local approximation in various respects. This letter aims at illustrating the origin of this improvement. To that aim, simple self-interaction corrected versions of the RC model are implemented, which involve local energy differences only. Several correlation functionals are selected for direct comparison using Hartree-Fock charge densities of atomic ions (H(-) to Ar). One of the self-interaction corrected versions of the RC model shows surprising improvements over the initial RC model. First, it dramatically improves the atomic correlation energies of atomic ions. Second, the impact on the contribution of the correlation energy to ionization potentials or electron affinities is still more convincing. In both cases, the accuracy achieved is close to or better than a selection of gradient-level functionals. PMID- 20849154 TI - Communication: Near edge x-ray absorption fine structure spectroscopy of aqueous adenosine triphosphate at the carbon and nitrogen K-edges. AB - Near edge x-ray absorption fine structure (NEXAFS) spectroscopy at the nitrogen and carbon K-edges was used to study the hydration of adenosine triphosphate in liquid microjets. The total electron yield spectra were recorded as a function of concentration, pH, and the presence of sodium, magnesium, and copper ions (Na(+)/Mg(2+)/Cu(2+)). Significant spectral changes were observed upon protonation of the adenine ring, but not under conditions that promote pi stacking, such as high concentration or presence of Mg(2+), indicating that NEXAFS is insensitive to the phenomenon. Intramolecular inner-sphere association of Cu(2+) did create observable broadening of the nitrogen spectrum, whereas outer-sphere association with Mg(2+) did not. PMID- 20849155 TI - Communication: Explicit construction of functional derivatives in potential driven density-functional theory. AB - We propose a method for imposing an important exact constraint on model Kohn-Sham potentials, namely, the requirement that they be functional derivatives of functionals of the electron density rho. In particular, we show that if a model potential v(r) involves no ingredients other than rho, ?rho, and ?(2)rho, then the necessary and sufficient condition for v(r) to be a functional derivative is ?v/??rho=?(?v/??(2)rho). Integrability conditions of this type can be used to construct functional derivatives without knowing their parent functionals. This opens up possibilities for developing model exchange-correlation potentials that do not lead to unphysical effects common to existing approximations. Application of the technique is illustrated with examples. PMID- 20849156 TI - Communication: Effective spectroscopic Hamiltonian for multiple minima with above barrier motion: Isomerization in HO(2). AB - We present a two-dimensional potential surface for the isomerization in the hydroperoxyl radical HO(2) and calculate the vibrational spectrum. We then show that a simple effective spectroscopic fitting Hamiltonian is capable of reproducing large scale vibrational spectral structure above the isomerization barrier. Polyad breaking with multiple resonances is necessary to adequately describe the spectral features of the system. Insight into the dynamical nature of isomerization related to the effective Hamiltonian is gained through classical trajectories on the model potential. Contrary to physical intuition, the bend mode is not a "reaction mode," but rather isomerization requires excitation in both stretch and bend. The dynamics reveals a Farey tree formed from the 2:1 and 3:1 resonances, corresponding to the resonance coupling terms in the effective Hamiltonian, with the prominent 5:2 (2:1+3:1) feature dividing the tree into parts that we call the 3:1 and 2:1 portions. PMID- 20849157 TI - Communication: Pade spectrum decomposition of Fermi function and Bose function. AB - Pade approximant is exploited for an efficient sum-over-poles decomposition of Fermi and Bose functions. The resulting poles are all pure imaginary and can therefore be used to define Pade frequencies, in analogy with the celebrated Matsubara frequencies. The proposed Pade spectrum decomposition is shown to be equivalent to a truncated continued fraction. It converges significantly faster than other schemes such as the Matsubara expansion at all temperatures. By introducing the characteristic validity length as the measure of approximant, we analyze the convergence properties of different schemes thoroughly. Our results qualify the present scheme the best among all sum-over-poles approaches. Thus, it is of great value in efficient numerical evaluations of integrals involving Fermi/Bose function in various condensed-phase matter problems. PMID- 20849158 TI - Virial coefficients of model alkanes. AB - We report the results from Mayer-sampling Monte Carlo calculations of the virial coefficients of the united-atom TraPPE-UA model of normal alkanes. For alkane chain lengths from n=2 to 20 (where n is the number of carbon atoms), results are given for the virial coefficients B(2), B(3), and B(4); results for B(5) are given for chains up to length n=12; and results for B(6) are given for chains of length n=2, 3, and 4. In all cases, values are given for temperatures ranging from 200 K to 2000 K in 20-50 K increments. The values are used to calculate the equation of state for butane and the pressure-density behavior is compared to experimental data at 350 and 550 K. Critical points are calculated for all systems and compared to simulation data previously taken for the same molecular model, and to experiment. The comparison with temperature is very good (within 1.5% for all chain lengths up to n=12), while the critical density is underestimated by about 5%-15% and the critical pressure is given within about 10%. The convergence behavior of the virial equation of state as applied across the n-alkane series is well characterized by corresponding states, meaning that the accuracy at a given density relative to the critical density does not deteriorate with increasing chain length. PMID- 20849159 TI - Improving upon CCSD(TQ(f)) for potential energy surfaces: LambdaCCSD(TQ(f)) models. AB - We consider classes of noniterative (~n(7)) LambdaCCSD(TQ(f)) (coupled cluster singles and doubles with noniterative triples and quadruples) for bond breaking including approximations based on Lambda(2)CCSD(TQ(f)). All methods are applied to the standard tests for the treatment of potential energy curves for small molecules (HF, F(2), H(2)O, N(2), and C(2)) where unambiguous comparison to full configuration interaction exists. Depending on the nature of the electron correlation substantial improvements are obtained at the same ~n(7) cost over CCSD(T). PMID- 20849160 TI - Rung 3.5 density functionals. AB - This work proposes a new term on the "Jacob's ladder" of approximate exchange correlation functionals in Kohn-Sham density functional theory. In these Rung 3.5 functionals, the exchange-correlation energy density at a point depends linearly (rather than quadratically) on the nonlocal Kohn-Sham one-particle density matrix in a finite neighborhood around the point. These functionals are intermediate in complexity between the semilocal approximations of Rungs 1-3, and fully nonlocal Rung 4 approximations such as global hybrids. Rung 3.5 functionals built on the model for exchange in [B. G. Janesko, J. Chem. Phys. 131, 234111 (2009)] predict molecular thermochemistry and kinetics with accuracy intermediate between their "parent" semilocal functional and the corresponding global hybrid. The best Rung 3.5 functional presented here gives mean absolute errors of 5.7 kcal/mol for G3/99 thermochemistry, 5.2 kcal/mol for HTBH38/04 hydrogen-transfer reaction barriers, and 5.7 kcal/mol for NHTBH38/04 nonhydrogen-transfer reaction barriers, while incorporating only two empirical parameters. PMID- 20849162 TI - Basis set dependence of the doubly hybrid XYG3 functional. AB - In the present study, we investigated the basis set dependence of XYG3, a newly developed doubly hybrid functional [Y. Zhang, X. Xu, and W. A. Goddard III, Proc. Natl. Acad. Sci. U.S.A. 106, 4963 (2009)], in prediction of (1) heats of formation (HOFs), (2) bond dissociation enthalpies (BDEs), (3) reaction barrier heights (RBHs), and (4) nonbonded interactions (NBIs). We used basis sets of triple-zeta quality starting from 6-311+G(d,p) with increasing completeness of the polarization functions to the largest Pople-type basis set 6-311++G(3df,3pd) and found that there was a continued improvement with larger basis sets. We showed that while HOF predictions were prone to basis set deficiencies, the basis set dependences in calculating BDEs, RBHs, and NBIs were mild. All of them converged fast with the increase of basis set size. We extended XYG3 to propose the XYG3o functional which was specifically optimized for a particular basis set in order to enhance its performance when using basis set of moderate size. With the 6-311+G(2df,p) basis set, XYG3o led to MADs of 2.56 kcal/mol for HOFs of the G3/99 set, 1.17 kcal/mol for BDEs of the BDE92/07 set, 1.11 kcal/mol for RBHs of the NHTBH38/04 and HTBH38/04 sets, and 0.40 kcal/mol for NBIs of the NCIE31/05 set, being comparable to those obtained by using XYG3/6-311++G(3df,3pd). PMID- 20849163 TI - Musings on thermostats. AB - In 2005, Bright et al. gave numerical evidence that among the family of time reversible deterministic thermostats known as MU-thermostats, the conventional MU=1 thermostat proposed by Hoover and Evans is the only thermostat that is capable of generating an equilibrium state. Using the recently discovered relaxation theorem, we give a mathematical proof that this is true. PMID- 20849164 TI - Efficient evaluation of triple excitations in symmetry-adapted perturbation theory via second-order Moller-Plesset perturbation theory natural orbitals. AB - An accurate description of dispersion interactions is required for reliable theoretical studies of many noncovalent complexes. This can be obtained with the wave function-based formulation of symmetry-adapted perturbation theory (SAPT) provided that the contribution of triple excitations to dispersion is included. Unfortunately, this triples dispersion correction limits the applicability of SAPT due to its O(N(7)) scaling. The efficiency of the evaluation of this correction can be greatly improved by removing virtual orbitals from the computation. The error incurred from truncating the virtual space is reduced if second-order Moller-Plesset perturbation theory (MP2) natural orbitals are used in place of the canonical Hartree-Fock molecular orbitals that are typically used. This approximation is further improved if the triples correction to dispersion is scaled to account for the smaller virtual space. If virtual MP2 natural orbitals are removed according to their occupation numbers, in practice, roughly half of the virtual orbitals can be removed (with the aug-cc-pVDZ basis set) with negligible errors if the remaining triples dispersion contribution is scaled. This typically leads to speedups of 15-20 times for the cases considered here. By combining the truncated virtual space with the frozen core approximation, the triples correction can be evaluated approximately 50 times faster than the canonical computation. These approximations cause less than 1% error (or at most 0.02 kcal mol(-1)) for the cases considered. Truncation of greater fractions of the virtual space is possible for larger basis sets (leading to speedups of over 40 times before additional speedups from the frozen core approximation). PMID- 20849165 TI - New closed Newton-Cotes type formulae as multilayer symplectic integrators. AB - In this paper, we introduce new integrators of Newton-Cotes type and investigate the connection between these new methods, differential methods, and symplectic integrators. From the literature, we can see that several one step symplectic integrators have been obtained based on symplectic geometry. However, the investigation of multistep symplectic integrators is very poor. In this paper, we introduce a new numerical method of closed Newton-Cotes type and we write it as a symplectic multilayer structure. We apply the symplectic schemes in order to solve Hamilton's equations of motion which are linear in position and momentum. We observe that the Hamiltonian energy of the system remains almost constant as integration proceeds. PMID- 20849161 TI - Energy variational analysis of ions in water and channels: Field theory for primitive models of complex ionic fluids. AB - Ionic solutions are mixtures of interacting anions and cations. They hardly resemble dilute gases of uncharged noninteracting point particles described in elementary textbooks. Biological and electrochemical solutions have many components that interact strongly as they flow in concentrated environments near electrodes, ion channels, or active sites of enzymes. Interactions in concentrated environments help determine the characteristic properties of electrodes, enzymes, and ion channels. Flows are driven by a combination of electrical and chemical potentials that depend on the charges, concentrations, and sizes of all ions, not just the same type of ion. We use a variational method EnVarA (energy variational analysis) that combines Hamilton's least action and Rayleigh's dissipation principles to create a variational field theory that includes flow, friction, and complex structure with physical boundary conditions. EnVarA optimizes both the action integral functional of classical mechanics and the dissipation functional. These functionals can include entropy and dissipation as well as potential energy. The stationary point of the action is determined with respect to the trajectory of particles. The stationary point of the dissipation is determined with respect to rate functions (such as velocity). Both variations are written in one Eulerian (laboratory) framework. In variational analysis, an "extra layer" of mathematics is used to derive partial differential equations. Energies and dissipations of different components are combined in EnVarA and Euler-Lagrange equations are then derived. These partial differential equations are the unique consequence of the contributions of individual components. The form and parameters of the partial differential equations are determined by algebra without additional physical content or assumptions. The partial differential equations of mixtures automatically combine physical properties of individual (unmixed) components. If a new component is added to the energy or dissipation, the Euler-Lagrange equations change form and interaction terms appear without additional adjustable parameters. EnVarA has previously been used to compute properties of liquid crystals, polymer fluids, and electrorheological fluids containing solid balls and charged oil droplets that fission and fuse. Here we apply EnVarA to the primitive model of electrolytes in which ions are spheres in a frictional dielectric. The resulting Euler-Lagrange equations include electrostatics and diffusion and friction. They are a time dependent generalization of the Poisson-Nernst-Planck equations of semiconductors, electrochemistry, and molecular biophysics. They include the finite diameter of ions. The EnVarA treatment is applied to ions next to a charged wall, where layering is observed. Applied to an ion channel, EnVarA calculates a quick transient pile-up of electric charge, transient and steady flow through the channel, stationary "binding" in the channel, and the eventual accumulation of salts in "unstirred layers" near channels. EnVarA treats electrolytes in a unified way as complex rather than simple fluids. Ad hoc descriptions of interactions and flow have been used in many areas of science to deal with the nonideal properties of electrolytes. It seems likely that the variational treatment can simplify, unify, and perhaps derive and improve those descriptions. PMID- 20849166 TI - Magic and hot giant fullerenes formed inside ion irradiated weakly bound C(60) clusters. AB - We find that the most stable fullerene isomers, C(70)-C(94), form efficiently in close-to central collisions between keV atomic ions and weakly bound clusters of more than 15 C(60)-molecules. We observe extraordinarily high yields of C(70) and marked preferences for C(78) and C(84). Larger even-size carbon molecules, C(96) C(180), follow a smooth log-normal (statistical) intensity distribution. Measurements of kinetic energies indicate that C(70)-C(94) mainly are formed by coalescence reactions between small carbon molecules and C(60), while C(n) with n>=96 are due to self-assembly (of small molecules) and shrinking hot giant fullerenes. PMID- 20849167 TI - A new ab initio potential energy surface and microwave and infrared spectra for the Ne-CO(2) complex. AB - We report a new three-dimensional potential energy surface for Ne-CO(2) including the Q(3) normal mode for the upsilon(3) antisymmetric stretching vibration of the CO(2) molecule. The potential energies were calculated using the supermolecular method at the coupled-cluster singles and doubles level with noniterative inclusion of connected triples [CCSD(T)], using a large basis set supplemented with midpoint bond functions. Two vibrationally averaged potentials with CO(2) at both the ground (upsilon=0) and the first (upsilon=1) vibrational upsilon(3) excited states were generated from the integration of the three-dimensional potential over the Q(3) coordinate. Each potential was found to have a T-shaped global minimum and two equivalent linear local minima. The radial DVR/angular FBR method and the Lanczos algorithm are applied to calculate the rovibrational energy levels. Comparison with the available observed values showed an overall excellent agreement for the microwave and infrared spectra. The calculated band origin shifts were found to be 0.1306 and 0.1419 cm(-1) for Ne-CO(2) and Ne C(18)O(2), respectively, which are very close to the experimental values of 0.1303 and 0.1432 cm(-1). PMID- 20849168 TI - Mechanism for the abiotic synthesis of uracil via UV-induced oxidation of pyrimidine in pure H(2)O ices under astrophysical conditions. AB - The UV photoirradiation of pyrimidine in pure H(2)O ices has been explored using second-order Moller-Plesset perturbation theory and density functional theory methods, and compared with experimental results. Mechanisms studied include those starting with neutral pyrimidine or cationic pyrimidine radicals, and reacting with OH radical. The ab initio calculations reveal that the formation of some key species, including the nucleobase uracil, is energetically favored over others. The presence of one or several water molecules is necessary in order to abstract a proton which leads to the final products. Formation of many of the photoproducts in UV-irradiated H(2)O:pyrimidine=20:1 ice mixtures was established in a previous experimental study. Among all the products, uracil is predicted by quantum chemical calculations to be the most favored, and has been identified in experimental samples by two independent chromatography techniques. The results of the present study strongly support the scenario in which prebiotic molecules, such as the nucleobase uracil, can be formed under abiotic processes in astrophysically relevant environments, namely in condensed phase on the surface of icy, cold grains before being delivered to the telluric planets, like Earth. PMID- 20849169 TI - Theoretical predictions of trends in spectroscopic properties of gold containing dimers of the 6p and 7p elements and their adsorption on gold. AB - Fully relativistic, four-component density functional theory electronic structure calculations were performed for the MAu dimers of the 7p elements, 113 through 118, and their 6p homologs, Tl through Rn. It was shown that the M-Au bond strength should decrease from the 6p to 7p homologs in groups 13 and 14, while it should stay about the same in groups 15 through 17 and even increase in group 18. This is in contrast with the decreasing trend in the M-M bond strength in groups 15 through 17. The reason for these trends is increasingly important relativistic effects on the np AOs of these elements, particularly their large spin-orbit splitting. Trends in the adsorption energies of the heaviest elements and their homologs on gold are expected to be related to those in the binding energies of MAu, while sublimation enthalpies are closely connected to the binding energies of the MM dimers. Lack of a correlation between the MAu and MM binding energies means that no correlation can also be expected between adsorption enthalpies on gold and sublimation enthalpies in groups 15 through 17. No linear correlation between these quantities is established in the row of the 6p elements, as well as no one is expected in the row of the 7p elements. PMID- 20849170 TI - An "adiabatic-hindered-rotor" treatment allows para-H(2) to be treated as if it were spherical. AB - In para-H(2)-{molecule} interactions, the common assumption that para-H(2) may be treated as a spherical particle is often substantially in error. For example, quantum mechanical eigenvalues on a full four-dimensional (4D) potential energy surface for para H(2)-{linear molecule} species often differ substantially from those calculated from the corresponding two-dimensional (2D) surface obtained by performing a simple spherical average over the relative orientations of the H(2) moiety. However, use of an "adiabatic-hindered-rotor" approximation can yield an effective 2D surface whose spectroscopic properties are an order of magnitude closer to those yielded by a full 4D treatment. PMID- 20849171 TI - Long-range dispersion coefficients for Li, Li(+), and Be(+) interacting with the rare gases. AB - The long-range dispersion coefficients for the ground and excited states of Li, Li(+), and Be(+) interacting with the He, Ne, Ar, Kr, and Xe atoms in their ground states are determined. The variational Hylleraas method is used to determine the necessary lists of multipole matrix elements for He, Li, Li(+), and Be(+), while pseudo-oscillator strength distributions are used for the heavier rare gases. Some single electron calculations using a semiempirical Hamiltonian are also performed for Li and Be(+) and found to give dispersion coefficients in good agreement with the Hylleraas calculations. Polarizabilities are given for some of the Li and Li(+) states and the recommended (7)Li(+) polarizability including both finite-mass and relativistic effects was 0.192 486 a.u. The impact of finite-mass effects upon the dispersion coefficients has been given for some selected interatomic interactions. PMID- 20849172 TI - Melting and freezing lines for a mixture of charged colloidal spheres with spindle-type phase diagram. AB - We have measured the phase behavior of a binary mixture of like-charged colloidal spheres with a size ratio of Gamma=0.9 and a charge ratio of Lambda=0.96 as a function of particle number density n and composition p. Under exhaustively deionized conditions, the aqueous suspension forms solid solutions of body centered cubic structure for all compositions. The freezing and melting lines as a function of composition show opposite behavior and open a wide, spindle shaped coexistence region. Lacking more sophisticated treatments, we model the interaction in our mixtures as an effective one-component pair energy accounting for number weighted effective charge and screening constant. Using this description, we find that within experimental error the location of the experimental melting points meets the range of melting points predicted for monodisperse, one-component Yukawa systems made in several theoretical approaches. We further discuss that a detailed understanding of the exact phase diagram shape including the composition dependent width of the coexistence region will need an extended theoretical treatment. PMID- 20849173 TI - Pair-correlation properties and momentum distribution of finite number of interacting trapped bosons in three dimensions. AB - We study the ground state pair-correlation properties of a weakly interacting trapped Bose gas in three dimensions by using a correlated many-body method. The use of the van der Waals interaction potential and an external trapping potential shows realistic features. We also test the validity of shape-independent approximation in the calculation of correlation properties. PMID- 20849174 TI - Two hard spheres in a pore: Exact statistical mechanics for different shaped cavities. AB - The partition function of two hard spheres in a hard-wall pore is studied, appealing to a graph representation. The exact evaluation of the canonical partition function and the one-body distribution function in three different shaped pores are achieved. The analyzed simple geometries are the cuboidal, cylindrical, and ellipsoidal cavities. Results have been compared with two previously studied geometries; the spherical pore and the spherical pore with a hard core. The search of common features in the analytic structure of the partition functions in terms of their length parameters and their volumes, surface area, edges length, and curvatures is addressed too. A general framework for the exact thermodynamic analysis of systems with few and many particles in terms of a set of thermodynamic measures is discussed. We found that an exact thermodynamic description is feasible based on the adoption of an adequate set of measures and the search of the free energy dependence on the adopted measure set. A relation similar to the Laplace equation for the fluid-vapor interface is obtained, which expresses the equilibrium between magnitudes that in extended systems are intensive variables. This exact description is applied to study the thermodynamic behavior of the two hard spheres in a hard-wall pore for the analyzed different geometries. We obtain analytically the external reversible work, the pressure on the wall, the pressure in the homogeneous region, the wall fluid surface tension, the line tension, and other similar properties. PMID- 20849175 TI - Role of OH radicals in the formation of oxygen molecules following vacuum ultraviolet photodissociation of amorphous solid water. AB - Photodesorption of O(2)(X (3)Sigma(g) (-)) and O(2)(a (1)Delta(g)) from amorphous solid water at 90 K has been studied following photoexcitation within the first absorption band at 157 nm. Time-of-flight and rotational spectra of O(2) reveal the translational and internal energy distributions, from which production mechanisms are deduced. Exothermic and endothermic reactions of OH+O((3)P) are proposed as plausible formation mechanisms for O(2)(X (3)Sigma(g) (-) and a (1)Delta(g)). To examine the contribution of the O((3)P)+O((3)P) recombination reaction to the O(2) formation following 157 nm photolysis of amorphous solid water, O(2) products following 193 nm photodissociation of SO(2) adsorbed on amorphous solid water were also investigated. PMID- 20849176 TI - Demixing of a binary symmetric mixture studied with transition path sampling. AB - We present transition path sampling simulations of the nucleation of the demixing transition in a binary symmetric Lennard-Jones fluid. In this system the demixing transition takes place between two phases of the same density but different compositions. The appropriateness of the reaction coordinate of classical nucleation theory is examined. Using paths harvested with transition path sampling, we investigate the nucleation mechanism and analyze the properties of critical nuclei obtained by determining the transition state ensemble. Our simulations show that despite the fact that the densities of the coexisting phases are equal, the density of the growing cluster plays a crucial role in the nucleation process: nucleation tends to proceed either via small, compact clusters with densities below that of the metastable fluid or via large clusters with even lower densities. PMID- 20849177 TI - Excess entropy scaling of dynamic quantities for fluids of dumbbell-shaped particles. AB - We use molecular simulation to study the ability of entropy scaling relationships to describe the kinetic properties of two Lennard-Jones dumbbell models. We begin by examining the excess entropy, the key quantity used to correlate dynamic properties within entropy scaling strategies. We compute the thermodynamic excess entropy as well as contributions to the two-body excess entropy stemming from translational and orientational intermolecular correlations. Our results indicate that the total two-body contribution accounts for more than 70% of the thermodynamic excess entropy at all state conditions explored. For the two dumbbell models studied here, the orientational component of the two-body excess entropy dominates at moderate and high fluid densities. We next investigate the relationships between kinetic properties and various contributions to the excess entropy. Four dynamic properties are considered: translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate scattering function. We find that the thermodynamic excess entropy provides the best metric for describing kinetic properties. For each of the dynamic properties considered, reduced data collapse onto a common curve when expressed as a function of the thermodynamic excess entropy. The likelihood of a two-body contribution to the excess entropy serving as a reliable scaling variable is linked to the extent to which it correlates with the thermodynamic excess entropy. The total two-body term contributes significantly to the excess entropy, and therefore this quantity generally serves as a suitable scaling variable. PMID- 20849178 TI - Gas temperature dependent sticking of hydrogen on cold amorphous water ice surfaces of interstellar interest. AB - Using the King and Wells method, we present experimental data on the dependence of the sticking of molecular hydrogen and deuterium on the beam temperature onto nonporous amorphous solid water ice surfaces of interstellar interest. A statistical model that explains the isotopic effect and the beam temperature behavior of our data is proposed. This model gives an understanding of the discrepancy between all known experimental results on the sticking of molecular hydrogen. Moreover, it is able to fit the theoretical results of Buch et al. [Astrophys. J. 379, 647 (1991)] on atomic hydrogen and deuterium. For astrophysical applications, an analytical formula for the sticking coefficients of H, D, H(2), D(2), and HD in the case of a gas phase at thermal equilibrium is also provided at the end of the article. PMID- 20849179 TI - The vibrational behavior of silica clusters at the glass transition: Ab initio calculations and thermodynamic implications. AB - We present the results of a computational investigation with ab initio procedures of the structure-energy and vibrational properties of silica clusters in a dielectric continuum with dielectric constant epsilon=3.8, through density functional theory/B3LYP gas phase calculations coupled with a polarized continuum model approach [integral equation formalism applied to a polarized continuum (IEFPCM)] and those of the periodical structure D(6h) which leads to the alpha cristobalite polymorph of silica when subjected to symmetry operations with the same functional within the linear combination of atomic orbitals (LCAO) approximation and in the framework of Bloch's theorem. Based on the computed energies and vibrational features, an aggregate of the D(6h) network and the monomer locally ordered in the short-medium range and both present in the glass in a mutual arrangement lacking of spatial continuity reproduces satisfactorily the experimentally observed low T heat capacity and the deviation from the Debye T(3) law. Above T(g), the experimental heat capacity of the liquid is perfectly reproduced summing to the internal modes the translational and rotational contributions to the bulk heat capacity and subtracting the (acoustic) terms arising from coherent motion (no longer existent). PMID- 20849180 TI - Counting metastable states within the adsorption/desorption hysteresis loop: A molecular simulation study of confinement in heterogeneous pores. AB - A molecular simulation approach has been used to model simple fluid adsorption in heterogeneous tubular pores mimicking mesoporous materials such as MCM-41 or porous silicon, allowing to determine the amount adsorbed rho as a function of the chemical potential MU. A hysteresis loop is observed in adsorption/desorption cycles, which is closely connected to the appearance of many metastable states. The density of these metastable states is studied in the MU-rho plane. Experimentally, the accessible metastable states are those that can be attained by the MU-path, i.e., a series of increasing or decreasing MU steps. One could also imagine using a quench from high temperature. Although the total density of metastable states is not directly accessible to experiments, it is of primary theoretical importance to understand the structure of metastable states in the hysteresis as determined experimentally. The disorder associated with the porous material realizations is accurately taken into account, and a systematic system size analysis is also performed in order to study the thermodynamic limit. It is shown that the quenched complexity is the relevant quantity to understand the hysteresis structure in the thermodynamic limit. It clearly exhibits a distinctive behavior depending on the distribution of heterogeneities characterizing the disorder in the pore. Some analogies can be found with the situation where an out-of-equilibrium transition appears, but careful examination of the data suggests another interpretation. PMID- 20849182 TI - Preconditioning immobilized imidazole arrays for optimal proton-transfer feasibility. AB - Classical molecular dynamics have been carried out in order to study the proton transfer feasibility in immobilized imidazole arrays, taking into account their applications in new polymer electrolyte membrane fuel cells. The resulting trajectories have been analyzed with respect to the ability of forming hydrogen bonds, considering the angle distribution between the proton donor and acceptor groups. The dependence of the hydrogen-bond network is studied with respect to the variations of temperature, density of imidazole groups, and spacer lengths. According to the results, arrays of alkyl-imidazole molecules with three mobile CH(2) groups are the most favorable to a proton-transfer reaction. Regarding the alkyl-imidazole density, no significant difference for the arrays with a spacing of 6 or 7 A between the alkyl-imidazole molecules could be observed, whereas the 10 A array presents a lower probability of a proton transfer. The optimal arrangement of the investigated systems is a spacing of 6 A and a flexible chain length of three CH(2) groups. These results confirm previous experimental and simulation analyses. PMID- 20849181 TI - Comparison of bond scission sequence of methanol on tungsten monocarbide and Pt modified tungsten monocarbide. AB - The ability to control the bond scission sequence of O-H, C-H, and C-O bonds is of critical importance in the effective utilization of oxygenate molecules, such as in reforming reactions and in alcohol fuel cells. In the current study, we use methanol as a probe molecule to demonstrate the possibility to control the decomposition pathways by supporting monolayer coverage of Pt on a tungsten monocarbide (WC) surface. Density functional theory (DFT) results reveal that on the WC and Pt/WC surfaces CH3OH decomposes via O-H bond scission to form the methoxy (*CH3 O) intermediate. The subsequent decomposition of methoxy on the WC surface occurs through the C-O bond scission to form *CH3, which reacts with surface *H to produce CH4. In contrast, the decomposition of methoxy on the Pt/WC surface favors the C-H bond scission to produce *CH2 O,which prevents the formation of the *CH3 species and leads to the formation of a *CO intermediate through subsequent deprotonation steps. The DFT predictions are validated using temperature programmed desorption to quantify the gas-phase product yields and high resolution electron energy loss spectroscopy to determine the surface intermediates from methanol decomposition on Pt, WC,and Pt/WC surfaces. PMID- 20849183 TI - Electron-electron scattering in a double quantum dot: Effective mass approach. AB - We present a theoretical description of the first-order scattering of interacting electrons and holes in a double quantum dot. Assuming infinitely high walls, strong confinement, and a two-band approximation, we derive general expressions for the two-particle matrix elements of the screened Coulomb potential. We also determine the selection rules for different scattering channels and consider special cases where the corresponding matrix elements can be represented by simple analytical expressions. Numerical calculations of the matrix elements and an analysis of their dependence on the geometrical and material parameters of the double quantum dot have also been performed. PMID- 20849184 TI - Helium atom diffraction measurements of the surface structure and vibrational dynamics of CH(3)-Si(111) and CD(3)-Si(111) surfaces. AB - The surface structure and vibrational dynamics of CH(3)-Si(111) and CD(3)-Si(111) surfaces were measured using helium atom scattering. The elastic diffraction patterns exhibited a lattice constant of 3.82 A, in accordance with the spacing of the silicon underlayer. The excellent quality of the observed diffraction patterns, along with minimal diffuse background, indicated a high degree of long range ordering and a low defect density for this interface. The vibrational dynamics were investigated by measurement of the Debye-Waller attenuation of the elastic diffraction peaks as the surface temperature was increased. The angular dependence of the specular (theta(i)=theta(f)) decay revealed perpendicular mean square displacements of 1.0*10(-5) A(2) K(-1) for the CH(3)-Si(111) surface and 1.2*10(-5) A(2) K(-1) for the CD(3)-Si(111) surface, and a He-surface attractive well depth of ~7 meV. The effective surface Debye temperatures were calculated to be 983 K for the CH(3)-Si(111) surface and 824 K for the CD(3)-Si(111) surface. These relatively large Debye temperatures suggest that collisional energy accommodation at the surface occurs primarily through the Si-C local molecular modes. The parallel mean-square displacements were 7.1*10(-4) and 7.2*10(-4) A(2) K(-1) for the CH(3)-Si(111) and CD(3)-Si(111) surfaces, respectively. The observed increase in thermal motion is consistent with the interaction between the helium atoms and Si-CH(3) bending modes. These experiments have thus yielded detailed information on the dynamical properties of these robust and technologically interesting semiconductor interfaces. PMID- 20849185 TI - Laser-induced scanning tunneling microscopy: Linear excitation of the junction plasmon. AB - We introduce the cross-polarized double-beat method for localized excitation of the junction plasmon of a scanning tunneling microscope with femtosecond laser pulses. We use two pulse trains derived from a Ti:sapphire laser operating at a repetition frequency of f(s)=76 MHz, with a relative shift between their carrier frequencies omega(a)/2pi=f(s)+f(b) controlled with an acousto-optic modulator. The trains are cross-polarized and collinearly focused on the junction, ensuring constant radiation flux. The anisotropic susceptibility of the junction plasmon mixes the fields, which modulate the tunneling current at f(b) (the difference between carrier beat and repetition frequency) at base-band frequencies that can be used for direct detection of the tunneling current. The interferometric cross correlation of the pulses and the polarization dependence of the mixing identify the coupling to the radiation to be through the coherent z-displacement of the tip plasmon. Single Ag atoms are used to demonstrate microscopy under irradiation. In the linear coupling regime, the laser-induced displacement of the plasmon is operationally indistinguishable from the mechanical displacement of the junction gap. PMID- 20849186 TI - Pearl-necklace structures of molecular brushes with rigid backbone under poor solvent conditions: A simulation study. AB - Bottle-brush polymers, where flexible side chains containing N=20 to 50 effective monomers are grafted to a rigid backbone, are studied by molecular dynamics simulations, varying the grafting density sigma and the solvent quality. Whereas for poor solvents and large enough sigma the molecular brush is a cylindrical object, homogeneous in axial direction, for intermediate values of sigma an axially inhomogeneous structure of "pearl-necklace" type is formed. The "pearls," however, have a strongly nonspherical ellipsoidal shape, due to the fact that several side chains cluster together in one pearl, qualitatively consistent with predictions of Sheiko et al. [Eur. Phys. J. E 13, 125 (2004)] We analyze the structure of these pearls and study both the transition to the axially uniform cylinder at high sigma and to the trivial pearl-necklace structure at small sigma, where each pearl contains a single collapsed chain only. PMID- 20849187 TI - Dynamic free energies, cage escape trajectories, and glassy relaxation in dense fluids of uniaxial hard particles. AB - We extend the naive mode coupling theory and nonlinear Langevin equation theory of coupled translational-rotational activated dynamics in dense fluids of uniaxial hard particles to more anisotropic rods, and mechanistically analyze in depth the dynamic free-energy surface, hopping process, kinetic vitrification, and fragility. Universal behavior is predicted for the transient center-of-mass (CM) localization length and angle based on a differential volume fraction that quantifies the distance from the dynamic crossover and proper geometric nondimensionalization of the localization quantities. The thermally activated real space cage escape process is increasingly controlled by the CM translation relative to the rotational motion as the particle aspect ratio grows. The mean first passage or structural relaxation time grows faster than exponentially with volume fraction, and is a nonmonotonic function of aspect ratio. The latter results in a kinetic vitrification volume fraction and dynamic fragility that vary nonmonotonically with shape anisotropy. The barrier hopping time based on the simplified CM theory where particle rotation is dynamically frozen is massively reduced by ~2-3.5 orders of magnitude if the cooperative rotation translation paths are exploited to escape local cage constraints. PMID- 20849188 TI - Probability distribution of the radius of gyration of freely jointed chains. AB - In this paper, we present a new approach to study the probability distribution of the radius of gyration of freely jointed chains. In this approach, we study the joint distribution P(N)(R(g) (2),R(G)), where R(g) is the radius of gyration and R(G) is the vector from the first bead to the center of the chain. We derive an iteration relation between the probability distributions of chains with lengths N and N+1. When the chain length is large, the iteration relation can be approximated by an evolution equation with integral determining condition. The equation is solved to obtain the probability distribution function, which yields the known result obtained by Fixman [J. Chem. Phys. 36, 306 (1962)] using the integral method. We hope the iteration method in this paper could be used to study the probability distribution of the structure factor of polymer molecules. PMID- 20849189 TI - Diffusion anomaly and dynamic transitions in the Bell-Lavis water model. AB - In this paper we investigate the dynamic properties of the minimal Bell-Lavis (BL) water model and their relation to the thermodynamic anomalies. The BL model is defined on a triangular lattice in which water molecules are represented by particles with three symmetric bonding arms interacting through van der Waals and hydrogen bonds. We have studied the model diffusivity in different regions of the phase diagram through Monte Carlo simulations. Our results show that the model displays a region of anomalous diffusion which lies inside the region of anomalous density, englobed by the line of temperatures of maximum density. Further, we have found that the diffusivity undergoes a dynamic transition which may be classified as fragile-to-strong transition at the critical line only at low pressures. At higher densities, no dynamic transition is seen on crossing the critical line. Thus evidence from this study is that relation of dynamic transitions to criticality may be discarded. PMID- 20849191 TI - Probability distributions of molecular observables computed from Markov models. II. Uncertainties in observables and their time-evolution. AB - Discrete-state Markov (or master equation) models provide a useful simplified representation for characterizing the long-time statistical evolution of biomolecules in a manner that allows direct comparison with experiments as well as the elucidation of mechanistic pathways for an inherently stochastic process. A vital part of meaningful comparison with experiment is the characterization of the statistical uncertainty in the predicted experimental measurement, which may take the form of an equilibrium measurement of some spectroscopic signal, the time-evolution of this signal following a perturbation, or the observation of some statistic (such as the correlation function) of the equilibrium dynamics of a single molecule. Without meaningful error bars (which arise from both approximation and statistical error), there is no way to determine whether the deviations between model and experiment are statistically meaningful. Previous work has demonstrated that a Bayesian method that enforces microscopic reversibility can be used to characterize the statistical component of correlated uncertainties in state-to-state transition probabilities (and functions thereof) for a model inferred from molecular simulation data. Here, we extend this approach to include the uncertainty in observables that are functions of molecular conformation (such as surrogate spectroscopic signals) characterizing each state, permitting the full statistical uncertainty in computed spectroscopic experiments to be assessed. We test the approach in a simple model system to demonstrate that the computed uncertainties provide a useful indicator of statistical variation, and then apply it to the computation of the fluorescence autocorrelation function measured for a dye-labeled peptide previously studied by both experiment and simulation. PMID- 20849190 TI - Only signaling modules that discriminate sharply between stimulatory and nonstimulatory inputs require basal signaling for fast cellular responses. AB - In many types of cells, binding of molecules to their receptors enables cascades of intracellular chemical reactions to take place (signaling). However, a low level of signaling also occurs in most unstimulated cells. Such basal signaling in resting cells can have many functions, one of which is that it is thought to be required for fast cellular responses to external stimuli. A mechanistic understanding of why this is true and which features of cellular signaling networks make basal signaling necessary for fast responses is unknown. We address this issue by obtaining the time required for activation of common types of cell signaling modules with and without basal signaling. Our results show that the absence of basal signaling does not have any dramatic effects on the response time for signaling modules that exhibit a graded response to increasing stimulus levels. In sharp contrast, signaling modules that exhibit sharp dose-response curves which discriminate sensitively between stimuli to which the cell needs to respond and low-grade inputs (or stochastic noise) require basal signaling for fast cellular responses. In such cases, we find that an optimal level of basal signaling balances the requirements for fast cellular responses while minimizing spurious activation without appropriate stimulation. PMID- 20849192 TI - Kinetics and mechanism of the unfolding native-to-loop transition of Trp-cage in explicit solvent via optimized forward flux sampling simulations. AB - The native-to-loop (N-L) unfolding transition of Trp-cage protein was studied via optimized forward flux sampling (FFS) methods with trajectories evolved using molecular dynamics. The rate constant calculated from our simulations is in good agreement with the experimental value for the native-to-unfolded transition of this protein; furthermore, the trajectories sampled a phase region consistent with that reported in previous studies for the N-L transition using transition path sampling and transition interface sampling. A new variant of FFS is proposed and implemented that allows a better control of a constant flux of partial paths. A reaction coordinate model was obtained, at no extra cost, from the transition path ensemble generated by FFS, through iterative use of the FFS-least-square estimation method [E. E. Borrero and F. A. Escobedo, J. Chem. Phys. 127, 164101 (2007)] and an adaptive staging optimization algorithm [E. E. Borrero and F. A. Escobedo, J. Chem. Phys. 129, 024115 (2008)]. Finally, we further elucidate the unfolding mechanism by correlating the unfolding progress with changes in the root mean square deviation from the alpha carbons of the native state, the root mean square deviation from an ideal alpha-helix, and other structural properties of the protein. PMID- 20849195 TI - Injections that kill: nosocomial bacteraemia and degedege in Tanzania. AB - CONTEXT: In Tanzania and some other African rural settings, a traditional proscription of injections for the treatment of cerebral malaria (degedege) stems from parents' fear that injections will kill a child with fever and convulsions. The re-use of injection equipment in rural clinics is associated with bacterial contamination even where sterilization is practiced to prevent HIV transmission. A secondary infection with bacterial sepsis is indistinguishable from non responsive malaria on clinical examination, and may be a significantly under reported adverse event in rural Tanzania. In a prospective survey of patients whose venous catheter was culture positive on removal, 61% developed bloodstream infections. ISSUE: Parents report having witnessed a child's death following an injection for the treatment of fever and convulsions in rural Tanzania, and some traditional healers who would refer a child with uncomplicated malaria for Western biomedical treatment are convinced that injections are fatal for a child with convulsions. Injection drug users learn aseptic technique to avoid what is called a 'dirty hit', a systemic infection that is felt immediately after injecting, indicating sudden deterioration is likely in a sick child if an IV injection is unsafe. Community mistrust of injection providers has been too casually attributed to superstition; to address parents' concerns, injection safety should be a priority in rural health services. Intravenous injections carry a 0.2% risk of acute bacteremia when given with unsterile equipment, while unsafe infusions carry a 3.7% risk of infection, much greater than the risk from intramuscular injections of vaccine. Sepsis should be considered an important adverse event in the management of severe malaria, but the diagnosis of nosocomial bloodstream infections is a challenge in hospitals that cannot culture for bacteria. When the auto-disable syringe was introduced, patient safety improved at a Tanzanian district hospital; a reduction in the burden of serious secondary infections large enough to reduce the average inpatient length of stay was observed. Nosocomial bloodstream infections are a common cause of fever in Tanzanian hospitals. In Tanzania, bacteremia is sometimes associated with more deaths in hospitals than malaria. LESSONS LEARNED: Although other obstacles to appropriate treatment for malaria may be more important in rural Tanzania, the belief that injections will kill a child is suggestive of avoidable adverse events. The intensity of malaria treatment in rural areas and frequent recourse to informal sector health care presented a significant challenge for the prevention of adverse events including sepsis and HIV transmission. A household survey in rural Tanzania found that 27% of malaria treatment occurs at drug stores, and 30% of patients seek treatment at a general shop. A majority of rural patients evaluated for malaria in the formal sector have taken chloroquine before coming to the clinic. A new national injection safety policy banning the import of non-auto-disable syringes prevents injection equipment re-use in the informal sector. Improving injection safety in rural Tanzania through the introduction of auto-disable syringes will ensure that parents have nothing to fear from quinine injections and infusions that are usually life saving. PMID- 20849197 TI - Late onset hypogonadism, sexuality and fertility. AB - The numerous and varying effects of androgen deficiency in males cause an array of symptoms and complaints any of which can be the trigger for a medical consultation. It is, therefore, important to consider the possibility of late onset hypogonadism (LOH) in a patient who is presenting with any such symptoms. This review describes LOH and the current guidelines for its treatment and management. Also discussed are the normal changes undergone by men as they age and the effects that are expected due to this change. The relationship between LOH and its effects on both sexuality and fertility are also considered. PMID- 20849198 TI - Effect of metformin taken in the 'fresh' in vitro fertilization/intracytoplasmic sperm injection cycle upon subsequent frozen embryo replacement in women with polycystic ovary syndrome. AB - OBJECTIVE: We aimed to determine whether metformin when taken during a fresh in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle affects live birth rate (LBR) in subsequent frozen embryo replacement cycles (FERC). DESIGN: A retrospective database analysis of women with polycystic ovary syndrome (PCOS) undergoing FERC at a university teaching hospital between 2002 and 2007 (n = 142). The outcome of FERC in women who had taken metformin in the 'fresh' IVF/ICSI cycle (group A, n = 28) and those who had not (group B, n = 114) were compared. RESULTS: In the first FERC there was a significantly higher LBR (A = 28.6%, B = 12.3%, OR 2.86 95% CI 1.06-7.71). Women who had elective cryopreservation due to ovarian hyperstimulation syndrome risk were found to have significantly higher LBRs if metformin was taken in the fresh IVF/ICSI cycle (A = 44.4%, B = 7.9%, OR 9.33 95% CI 1.60-54.58). CONCLUSIONS: Women with PCOS who take metformin during IVF/ICSI may have a higher LBR in subsequent FERC, especially in those who have elective cryopreservation for OHSS risk. The findings of this study are limited by its retrospective design and small sample size and require confirmation in an adequately powered prospective randomized controlled trial. PMID- 20849196 TI - Impact of Chlamydia trachomatis in the reproductive setting: British Fertility Society Guidelines for practice. AB - Chlamydia trachomatis infection of the genital tract is the most common sexually transmitted infection and has a world-wide distribution. The consequences of infection have an adverse effect on the reproductive health of women and are a common cause of infertility. Recent evidence also suggests an adverse effect on male reproduction. There is a need to standardise the approach in managing the impact of C. trachomatis infection on reproductive health. We have surveyed current UK practice towards screening and management of Chlamydia infections in the fertility setting. We found that at least 90% of clinicians surveyed offered screening. The literature on this topic was examined and revealed a paucity of solid evidence for estimating the risks of long-term reproductive sequelae following lower genital tract infection with C. trachomatis. The mechanism for the damage that occurs after Chlamydial infections is uncertain. However, instrumentation of the uterus in women with C. trachomatis infection is associated with a high risk of pelvic inflammatory disease, which can be prevented by appropriate antibiotic treatment and may prevent infected women from being at increased risk of the adverse sequelae, such as ectopic pregnancy and tubal factor infertility. Recommendations for practice have been proposed and the need for further studies is identified. PMID- 20849199 TI - Blastomere multinucleation: Contributing factors and effects on embryo development and clinical outcome. AB - INTRODUCTION: The aim of the study was to discover which intracytoplasmic sperm injection (ICSI) cycle parameters could influence the presence of multinucleated blastomeres (MNBs) and how ICSI outcomes are influenced by this event. MATERIAL AND METHODS: Embryos derived from normally fertilised oocytes were divided into two groups: embryos that had only mononucleated blastomeres (NBs group n = 2818) and embryos that had at least one multinucleated blastomere (MNB group, n = 404). The effects of ICSI cycle factors on multinucleation were investigated and embryo development was compared between the groups. The cycles were also split into those in which only NB embryos were present (NB cycles, n = 298) and cycles in which MNB embryos were present (MNB cycles, n = 203). ICSI outcomes were compared between the groups. RESULTS: A higher incidence of MNB embryos arose in pituitary blockage with gonadotropin-releasing hormone agonists, male factor infertility and in cycles with higher number of retrieved oocytes. Embryos that had only one affected blastomere showed greater development than embryos with more than one affected blastomere. Finally, the implantation rate decreased when MNB embryos were transferred. CONCLUSION: Multinucleation events may be affected by aspects of the ICSI cycle and compromise embryo quality and implantation rate. PMID- 20849200 TI - Experience of fertility preservation among younger people diagnosed with cancer. AB - Of the 293,600 cancers diagnosed annually in the UK, 11% occur in the 15- to 49 year age group. Fertility preservation options exist for those faced with the loss of fertility as a consequence of radiotherapy or chemotherapy. The aim of this study was to explore experiences, attitudes and perceptions of fertility advice and treatment among cancer survivors, and the subsequent impact upon their lives. Eighteen people aged 19-42 years with a diagnosis of cancer made more than 5 years earlier and, registered with general practices in North East England, were interviewed using a grounded approach. Survival was the universal focus of patients at the point of diagnosis and they commonly failed to appreciate the effect of treatment upon future fertility. A positive experience was linked to the quality of information about fertility preservation or action offered, but this needed to be tailored to the patients' age, stage in their life course, relationships and fears. Possible loss of future fertility only becomes important beyond survival but patients wanted their potential future fertility addressed sensitively at the time of diagnosis and backed up by access to written or web based patient information, or a fertility specialist. PMID- 20849201 TI - Sperm donor recruitment within an NHS fertility service since the removal of anonymity. AB - The marked decline in the number of sperm donors recruited in the UK has been largely attributed to changes in regulations and in particular those related to the removal of anonymity. After a 5-year period of inactivity, the sperm donor bank in Nottingham was provided with limited resources to try and recruit donors who were willing to be identified on the HFEA register. Marketing was sporadic and at first low cost and the enquiry rate only increased significantly when the centre's website became operational and higher cost advertising was used. Over a 4-year period, a total of 151 enquiries gave rise to 14 useable donors at a cost of approximately L5,500 each. Donor sperm was generally of high quality having been density gradient prepared prior to cryopreservation and provided an overall ongoing pregnancy rate of 21.6% and 45.6% by IUI and IVF, respectively. The overall exercise demonstrated that identifiable donors were coming forward but in lower numbers compared to those observed before 2005. At current treatment prices, centres should be aware that recouping the costs of donor recruitment and processing may be difficult and that the cost of both donor sperm and donor insemination are likely to rise significantly. PMID- 20849204 TI - Topical treatment options for drug-induced toxic epidermal necrolysis (TEN). AB - IMPORTANCE OF THE FIELD: Drug-induced toxic epidermal necrolysis (TEN) is a dreadful skin condition. The mortality rate of 25 - 30% is mainly due to both metabolic failures and septicemia following loss of epidermal integrity. Topical treatments are important options in these patients. AREAS COVERED IN THIS REVIEW: Topical TEN care includes specific bedding, debridement of epidermal necrosis, applications of bioactive skin substitutes or semi-synthetic and synthetic dressings, as well as antiseptic and antibiotic agents. WHAT THE READER WILL GAIN: In the early exudating phase of TEN, the use of airfluidized bed combined with gentle debridement are recommended. Next, an alternating pressure mattress and silver impregnated absorbent dressings should be used. During the re epithelialization phase, antiseptic or antibiotic creams overlaid with nonadherent dressings favor an optimized moist and bacteria-controlled environment. TAKE HOME MESSAGE: A suitable topical treatment is mandatory in TEN. Skin care procedures must be managed according to the skin condition corresponding to the initial highly exudating/necrotic phase, the secondary moderately exudating stabilized phase and the later re-epidermization phase. Bedding modalities, debridement procedures, applications of bioactive, semi synthetic and synthetic dressings (silver-impregnated or not) and antiseptic/antibiotic creams should be adapted accordingly. PMID- 20849205 TI - Fundal height: a useful screening tool for fetal growth? AB - OBJECTIVE: To determine the utility of fundal height in screening for small-for gestational-age (SGA) and large-for-gestational-age (LGA) neonates at term. STUDY DESIGN: This was a retrospective cohort study of 3627 women at University of California, San Francisco from 2002 to 2006 with term, singleton pregnancies specifically examining the 448 who had third trimester ultrasounds for size unequal to dates by fundal height. chi(2) analyses determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of fundal height as a screening tool for abnormal intrauterine growth. RESULTS: The sensitivity of fundal height was 16.6% for detecting actual birthweight (BWt) > 90th percentile (p < 0.001) and 17.3% for < 10 th percentile (p < 0.001). Specificity ranged from 92.4 to 95.4%. Significant differences existed among subgroups by maternal weight, parity, age, and ethnicity. Sensitivity was lower for SGA among overweight/obese women but higher among multiparous women. Additionally, women >= 35 years showed higher sensitivity for extreme LGA, and several notable differences were found by ethnicity such as higher sensitivity for extreme LGA among Caucasian women. CONCLUSION: The sensitivity of fundal height for detecting abnormal intrauterine growth was less than 35% for all subgroups, although specificity was more ideal at >90%. Other modalities should be considered to screen for growth abnormalities. PMID- 20849206 TI - 5-HT2C receptor modulators: a patent survey. AB - IMPORTANCE OF THE FIELD: The 5-HT(2C) receptor is a GPCR and is one of the 14 subtypes that constitute the serotonin receptor family. The 5-HT2(C) receptor is exclusively expressed in the CNS where it demonstrates a wide distribution and displays high-affinity interactions with a wide variety of psychiatric medications. Modulators of 5-HT2(C) have been implicated as a potential treatment for diseases of significant unmet medical need, including obesity, schizophrenia, depression, anxiety, Parkinson's disease, drug addiction, erectile dysfunction and urinary incontinence. Thus, there is a great interest in developing potent and selective 5-HT2(C) receptor modulators. AREAS COVERED IN THIS REVIEW: This review article highlights the research progress in 5-HT2(C) receptor modulators published in the patent literature between January 2003 and June 2010, giving emphasis to the medicinal chemist's standpoint. WHAT THE READER WILL GAIN: Readers will rapidly gain an overview of the various 5-HT2(C) receptor modulators reported in the patent literature in the past 8 years. Furthermore, the readers will learn which structure type can interact with the 5-HT2(C) receptor. In addition, the readers will be aware of the pharmaceutical companies that have been the main players in the field. TAKE HOME MESSAGE: There is substantial evidence supporting the concept that a selective 5-HT2(C) receptor modulator should provide benefit in the treatment of a variety of CNS disorders. Although research efforts have identified several promising 5-HT2(C) receptor modulators that display high functional selectivity, further clinical efficacy and safety data are needed to prove their actual clinical utility. Therefore, the query for selectively acting 5-HT2(C) receptor modulators is still ongoing. PMID- 20849207 TI - Strategies for proprotein convertase subtilisin kexin 9 modulation: a perspective on recent patents. AB - IMPORTANCE OF THE FIELD: Proprotein convertase subtilisin kexin 9 (PCSK9) is a new actor discovered in 2003 that is implicated in autosomal dominant hypercholesterolemia, cholesterol homeostasis and coronary heart disease. It has been shown to degrade the low-density lipoprotein (LDL) receptor independently of its catalytic activity. Several pharmacological strategies to reduce PCSK9 are being thoroughly investigated. AREAS COVERED IN THIS REVIEW: This article reviews all different strategies that are presently pursued to modulate the functional activity of PCSK9 which is a prime target for controlling LDL-cholesterol. It also provides a briefing of all the patents up to July 2010 from various organizations including pharmaceutical companies and academic institutions that have been submitted and/or approved. WHAT THE READER WILL GAIN: This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation and in the development of cholesterol lowering drugs. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9 including antisense technology and specific antibodies. TAKE HOME MESSAGE: Clinical trials have been launched using RNA interference approaches to reduce PCSK9 expression or specific antibodies targeting and inhibiting PCSK9 interaction with the LDL receptor. They constitute very promising approaches to reducing cholesterol levels and coronary heart disease. PMID- 20849208 TI - Low bone mass in urban Indian women above 40 years of age: prevalence and risk factors. AB - OBJECTIVE: To assess the prevalence and the relative importance of risk factors for low bone mass in Indian pre- and post-menopausal women. METHODS: Data were collected on anthropometry and lifestyle factors in apparently healthy 80 pre- and 92 post-menopausal (40-75 years) women. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry. Fasting blood samples were analysed for Parathyroid hormone, vitamin D, calcium and zinc. RESULTS: BMD at all three sites was significantly lower in post-menopausal than the pre-menopausal women (p < 0.001). Prevalence of osteoporosis was highest at the lumbar spine (25.8%) in post-menopausal women, while prevalence of osteopenia was high in pre-menopausal women (44.3%). Vitamin D deficiency was seen in 54.5% pre and 41.8% post menopausal women and significant correlation of serum 25(OH)D levels (r = 0.16) was obtained only for total hip Z-score (p < 0.05). Correlation between sun index and lumbar spine BMD was marginally significant (r = 0.14, p = 0.07). Generalised linear models revealed that after adjusting for age, weight and height, percent decrease of 2.1-4.5% in BMD may be attributed to menopause. CONCLUSION: Age, weight, height, menopause, low intakes of calcium and low 25(OH)D along with poor sunlight exposure are the major factors contributing to bone loss in Indian women above 40 years of age. PMID- 20849209 TI - A 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice: a large, multicentre, observational study. AB - BACKGROUND: A 2:1 (150 IU:75 IU) follitropin alfa:lutropin alfa formulation has been developed. A 3-year post-marketing surveillance study is ongoing in Germany to explore the use of this formulation in routine clinical practice. MATERIALS AND METHODS: An 11-month interim analysis of data from assisted reproductive technology (ART) cycles only is described. RESULTS: Data were available from 857 patients undergoing 919 cycles of ART at 19 centres. Most patients (58.7%) were aged >= 35 years, and many (41.3%) were undergoing their first ART cycle. Main reasons cited by physicians for prescribing this formulation were poor response in a previous treatment cycle (n = 303) and low basal luteinizing hormone (LH) level (n = 107). Mean (standard deviation) duration of ovarian stimulation was 10.8 (2.6) days. In 90.7% of cycles, the 2:1 formulation was administered throughout the stimulation period. Most frequent LH daily dose was 75 IU. Embryo transfer was conducted in 741 cycles; clinical pregnancy rate per transfer was 27.5%. Three cases of ovarian hyperstimulation syndrome developed in three patients (3/741 [0.4%] cycles); one required hospitalization. No other major safety events were reported. CONCLUSION: This interim analysis shows that use of the 2:1 formulation for ovarian stimulation during routine ART procedures is effective in achieving clinical pregnancies and is associated with a positive safety profile. PMID- 20849210 TI - Human platelets contain and release TWEAK. AB - The multifunctional cytokine, TWEAK (TNF-like weak inducer of apoptosis), is a member of the TNFalpha superfamily. TWEAK is found in a broad range of cell types and has been linked to cell growth and survival, angiogenesis and other inflammatory processes. These functions and their importance in inflammatory diseases have made TWEAK an attractive pharmaceutical target, particularly for immunotherapy with monoclonal antibodies (mAbs). Immunotherapy targeting another TNFalpha family member, CD154, was associated with thrombosis in clinical trials. Subsequent studies identified platelets, which contain CD154, as a possible contributing factor to thrombosis in these trials. Since clinical trials with anti-TWEAK mAbs have already begun, we considered it important to determine whether platelets contain TWEAK. Using a variety of immunologic methods we found that, upon activation, human platelets expose TWEAK antigen and release it in soluble form (sTWEAK). By flow cytometry we determined that human platelets activated by TRAP (Thrombin Receptor Agonist Peptide) and other agonists expose TWEAK antigen (22% median positivity) and release TWEAK positive microparticles. The presence of TWEAK on platelets was confirmed by confocal microscopy. By ELISA, we found that sTWEAK is released by activated platelets. Finally, western blot analysis revealed TWEAK protein (34 kDa) in washed platelet lysates. The finding that human platelets contain TWEAK raises important questions about its possible functions in normal physiology, as well as in inflammatory diseases and their treatment. PMID- 20849211 TI - Long term changes in platelet counts after H. pylori eradication in non-ITP patients. AB - Helicobacter pylori eradication is becoming a first-line therapy against idiopathic thrombocytopenic purpura (ITP) and its long term efficacy has already been reported. In contrast, eradication therapy reduced peripheral platelets in non-ITP patients 8 weeks later. To confirm the long term efficacy of Helicobacter eradication on platelet counts in non-ITP patients, we evaluated changes in peripheral platelet counts in endoscopically diagnosed patients with Helicobacter infection. Endoscopically diagnosed patients with Helicobacter infection received eradication therapy using amoxicillin (1500 mg/day), clarithromycin (400 mg/day) and lansoprazole (60 mg/day). The changes in platelet counts after Helicobacter eradication were serially evaluated for as long as 3 years or more. In total, 294 patients were enrolled: 243 patients successfully received eradication therapy and 51 were unsuccessfully treated. As a whole, peripheral platelet counts significantly decreased after Helicobacter eradication, being reduced by more than 1.0 * 109/l by 5-6 months, 1 year, 2 years and 3 years or more (from 24.2+/ 5.6 to 23.1+/-5.0, 23.0+/-5.0, 22.1+/-4.5, 22.4+/-5.6, and 21.6+/-5.3 * 109/l: p = <0.0001, <0.0001, 0.0001, 0.0052, and <0.0001, respectively). Helicobacter pylori eradication finally reduced peripheral platelet counts around 2.0 * 109/l in non-ITP patients. There was a definite difference in platelet regulation by Helicobacter pylori between ITP and non-ITP patients. These bivalent effects, upregulation and downregulation, on the peripheral platelet induced by Helicibacter pylori infection appeared to originate from quite different mechanisms. PMID- 20849212 TI - Cellular recognition and trafficking of amorphous silica nanoparticles by macrophage scavenger receptor A. AB - The cellular uptake of engineered nanoparticles (ENPs) is known to involve active transport mechanisms, yet the biological molecules involved are poorly understood. We demonstrate that the uptake of amorphous silica ENPs by macrophage cells, and the secretion of proinflammatory cytokines, is strongly inhibited by silencing expression of scavenger receptor A (SR-A). Conversely, ENP uptake is augmented by introducing SR-A expression into human cells that are normally non phagocytic. Confocal microscopy analyses show that the majority of single or small clusters of silica ENPs co-localize with SR-A and are internalized through a pathway characteristic of clathrin-dependent endocytosis. In contrast, larger silica ENP agglomerates (>500 nm) are poorly co-localized with the receptor, suggesting that the physical agglomeration state of an ENP influences its cellular trafficking. As SR-A is expressed in macrophages throughout the reticulo endothelial system, this pathway is likely an important determinant of the biological response to ENPs. PMID- 20849214 TI - Uptake of gold nanoparticles in murine macrophage cells without cytotoxicity or production of pro-inflammatory mediators. AB - More information characterizing the biological responses to nanoparticles is needed to allow the U.S. Food and Drug Administration to evaluate the safety and effectiveness of products with nano-scale components. The potential cytotoxicity and inflammatory responses of Au NPs (60 nm, NIST standard reference materials) were investigated in murine macrophages. Cytotoxicity was evaluated by MTT and LDH assays. Cytokines (IL-6, TNF-alpha), nitric oxide, and ROS were assayed to assess inflammatory responses. Morphological appearance and localization of particles were examined by high resolution illumination microscopy, transmission electron microscopy (TEM), and scanning TEM coupled with EDX spectroscopy. Results showed no cytotoxicity and no elevated production of proinflammatory mediators; however, imaging analyses demonstrated cellular uptake of Au NPs and localization within intracellular vacuoles. These results suggest that 60 nm Au NPs, under the exposure conditions tested, are not cytotoxic, nor elicit pro inflammatory responses. The localization of Au NPs in intracellular vacuoles suggests endosomal containment and an uptake mechanism involving endocytosis. PMID- 20849215 TI - A closer look at unilateral versus bilateral deep brain stimulation: results of the National Institutes of Health COMPARE cohort. AB - OBJECT: In this paper, the authors' aim was to examine reasons underpinning decisions to undergo, or alternatively forgo, a second-sided deep brain stimulation (DBS) implantation in patients with Parkinson disease (PD). METHODS: Fifty-two patients with Parkinson disease (PD) were randomized to receive DBS to the subthalamic nucleus or globus pallidus internus (GPi) as part of the COMPARE trial. Forty-four patients had complete data sets. All patients were offered a choice at 6 months after unilateral implantation whether to receive a contralateral DBS implant. All patients had advanced PD. The mean patient age was 59.8 years (range 43-76 years), and the mean duration of disease was 12.2 years (range 5-21 years). The mean baseline Unified Parkinson's Disease Rating Scale (UPDRS)-III motor score was 42.7. The main outcome measures used in this study were the UPDRS-III Motor Scale and the UPDRS-IV Dyskinesia Scale. RESULTS: Twenty one (48%) of the 44 patients in the cohort did not undergo bilateral implantation and have been successfully treated for an average of 3.5 years; of these, 14 (67%) had a GPi target. The most common reason for adding a second side was inadequacy to address motor symptoms. Patient satisfaction with motor outcomes after unilateral DBS implantation was the most common reason for not undergoing bilateral implantation. Those who chose a second DBS procedure had significantly higher baseline UPDRS-III motor and ipsilateral UPDRS-III scores, and a significantly lower asymmetrical index. The logistic regression analysis revealed that the odds of proceeding to bilateral DBS was 5.2 times higher for STN than for GPi DBS. For every 1% increase in asymmetry, the odds of bilateral DBS decreased [corrected] by 0.96. CONCLUSIONS: Unilateral DBS is an effective treatment for a subset of patients with PD. Baseline asymmetry is an important factor in the effectiveness and decision-making process between unilateral and bilateral DBS. Patients with GPi DBS in this cohort were more likely to choose to remain with unilateral implantation. PMID- 20849217 TI - Pitfalls in the publication of scientific literature: a road map to manage conflict of interest and other ethical challenges. AB - The process of publishing scientific research can be hampered by potential pitfalls for journals and researchers alike; the definition and determination of authorship, legal documentation, data accuracy, and disclosure of financial conflicts of interest are all examples. In the current article, the authors discuss the challenges related to scientific medical writing and provide updated recommendations for both the prevention and management of these issues. PMID- 20849216 TI - Symptomatic posterior fossa and supratentorial subdural hygromas as a rare complication following foramen magnum decompression for Chiari malformation Type I. AB - Symptomatic subdural hygroma due to foramen magnum decompression for Chiari malformation Type I is extremely rare. The authors present their experience with 2 patients harboring such lesions and discuss treatment issues. They conclude that the possibility of subdural hygromas should be considered in all patients presenting with increased intracranial tension following foramen magnum decompression for Chiari malformation Type I. Immediate neuroimaging and appropriate surgical intervention provides a good outcome. PMID- 20849218 TI - Cerebral watershed hypoperfusion in subarachnoid hemorrhage: computed tomography perfusion analysis. AB - OBJECT: A better understanding of the pathophysiology of vasospasm-induced delayed cerebral ischemia and earlier detection of hypoperfusion before ischemic injury are needed to guide therapy in subarachnoid hemorrhage (SAH). The cerebrovascular physiology of the major arterial territories differs from that of the watershed zones (WZs) in a way that would suggest a differential topographic sensitivity of the brain to vasospasm. The primary end point of the study was to investigate the vasospasm-induced hypoperfusion in relation to cerebrovascular topography and timing from the onset of SAH. METHODS: Forty-one patients were prospectively enrolled and scheduled for perfusion-weighted (PW) CT at 3 time points (<= 3 days, Days 4-8, and Days 9-15 after SAH). Perfusion-weighted CT maps were visually assessed for side-to-side perfusion asymmetry. The PW CT topographic pattern was categorized into absence of asymmetry, WZ, and vascular territory hypoperfusion. Perfusion-weighted CT revision was performed by investigators blinded to clinical information. The null hypothesis for the primary end point was that there would be no difference in hypoperfusion space time distribution among the different vascular territories. Multivariate logistic regression and Cox proportional hazards modeling were used for statistical analysis. RESULTS: Delayed cerebral ischemia occurred in 26 patients and its predicting variables were increasing age (p = 0.045), Fisher grade (p = 0.007), and hypoperfusion on the PW CT performed within the 1st 72 hours after SAH (p = 0.004). The timing of the PW CT with respect to the day of SAH affected the topographic pattern of hypoperfusion: watershed-zone hypoperfusion was more common within the first 3 days after SAH (p = 0.018), while the proportion of territorial hypoperfusion increased subsequently. Among the different covariates, a young age was independently associated with a higher risk of developing hypoperfusion in the WZs (p = 0.02). CONCLUSIONS: This study suggests the existence of a cerebral topographic heterogeneity to the hemodynamic effects of SAH and differential pathogenetic mechanisms of hypoperfusion according to timing, age, and brain topography. Hypoperfusion in the WZs may be an early precursor to more profound ischemic events. The PW CT detection of such brain sensitive zones could offer a warning signal of the early hemodynamic effects of SAH and cerebral vasospasm. PMID- 20849219 TI - Conflict of interest. PMID- 20849220 TI - Unilateral or bilateral deep brain stimulation. PMID- 20849221 TI - Establishing new paradigms while reexamining the old ones. Preface. PMID- 20849222 TI - Factors regulating sperm capacitation. AB - Capacitation is broadly defined as the functional modifications rendering sperm competent to fertilize, encompassing the ability of the sperm to bind the zona pellucida and subsequently undergo the acrosome reaction, hyperactivated motility, and the capacity to fuse with the oocyte. Although discovered in 1951, research over the past 15 years has considerably clarified the mechanisms leading to capacitation. The purpose of this review is to discuss the challenges of studying capacitation and to summarize recent notions regarding its regulation. Of particular interest is an atypical soluble adenylyl cyclase that is stimulated by bicarbonate to activate protein kinase A and drive sperm protein tyrosine phosphorylation. The identities of the phosphorylated sperm-protein substrates and the kinase(s) responsible for their tyrosine phosphorylation have fostered major questions regarding this pathway. Recent investigations, however, have made exciting advances toward resolving these queries. Advanced proteomic approaches have revealed the tyrosine phosphorylated substrates to be implicated in a diverse range of cellular activities. SRC tyrosine kinase is a particularly interesting candidate as the mediator of the protein kinase A-driven sperm protein tyrosine phosphorylation. Future studies are merited to fully characterize additional signaling mediators such as phosphatases and other kinases that may be involved, to elucidate the functional importance of the tyrosine phosphorylation on those particular substrates and to appreciate the differences that may exist among species. PMID- 20849223 TI - What to do when ICSI fails. AB - The refinement of gamete micromanipulation techniques has made conception possible for couples with male factor infertility who otherwise would remain childless. Moreover, intracytoplasmic sperm injection (ICSI) has ensured that such refractory cases can now generate offspring as successfully as in couples that merely require in vitro insemination. However, despite the now sterling record of ICSI it does not assure a successful outcome for every patient. This can be due, for instance, to the inability of the spermatozoon to activate the oocyte, and applies obviously in cases where spermatozoa are absent from the ejaculate or testicular biopsy. In the present paper we describe in detail the reasons for such failure and review the options that may help overcome it. In particular, we outline the treatment protocol for the situation in which spermatozoa are unable to induce oocyte activation. Further, we report on the clinical outcome achieved with spermatozoa retrieved from the testis, and in cases of extreme oligozoospermia we also explore the option of replicating a single spermatozoon while gaining information on its genomic content. For the most extreme situation in which men have no identifiable germ cells, we will discuss the current status of efforts to accomplish neo-gametogenesis through embryonic stem cell differentiation. PMID- 20849224 TI - Epigenetic aspects of fertilization and preimplantation development in mammals: lessons from the mouse. AB - During gametogenesis, the parental genomes are separated and are epigenetically marked by modifications that will direct the expression profile of genes necessary for meiosis as well as for the formation of the oocyte and sperm cell. Immediately after sperm-egg fusion, the parental haploid genomes show great epigenetic asymmetry with differences in the levels of DNA methylation and histone tail modifications. The epigenetic program acquired during oogenesis and spermatogenesis must be reset for the zygote to successfully proceed through preimplantation development and this occurs as the two genomes approach each other in preparation for karyogamy. During preimplantation development, the embryo is vested with the responsibility of maintaining the primary imprints. In addition, female embryos must silence one of the X-chromosomes in order to transcribe equal levels of X-linked genes as their male counterparts. This review is intended as a survey of the epigenetic modifications and mechanisms present in zygotes and preimplantation mouse embryos, namely DNA methylation, histone modifications, dosage compensation, genomic imprinting, and regulation by non coding RNAs. PMID- 20849226 TI - Copper metabolism disorders affect testes structure and gamete quality in male mice. AB - In the present study, animals with a genetic defect in copper metabolism were used as a model organism to study the role of copper in reproduction and to determine whether the disturbances in copper and zinc metabolism affect the testicular tissue and gamete quality in males. Mice with an X-linked mosaic mutation (Atp7a(mo-ms)) exhibit pathological features characteristic of affected copper metabolism. This mutation usually leads to lethality of the mutant males which generally expire on about day 16. Only 4% of mutant animals survive the critical period, achieve maturity, and become fertile. To improve the mutants' viability they were treated with subcutaneous injections of cupric chloride. We measured copper and zinc concentration in the gonads of young (14-day-old) and adult (5-month-old) mutant and control males. Results indicate that copper content was increased but zinc was decreased in the mutant testes. Analysis of the morphology of the testis of the young animals indicate that apoptosis (characteristic for the gonads of young males) was increased in the gonads of the 14-day-old mutants. This process was less advanced in the group of 14-day-old copper treated control males. Apoptosis was also increased in the testes of the adult mutants. Moreover in adult mutants we observed pathological changes in testes morphology (atrophic and sclerotic tubules). Copper and zinc disorders also negatively influenced semen quality parameters, including sperm motility, head morphology, tail cytoplasmic membrane integrity, and number of viable spermatozoa. Poor semen quality of the mutant males seems to be responsible for affected in vivo fertilization efficiency. Treatment with cupric chloride did not influence semen quality except in maturation rate, which was even slower in both mutant and control males after treatment. Additionally, in mutants, copulatory plugs and fertile copulation outcome were decreased after copper treatment. PMID- 20849227 TI - Immunogenicity of recombinant maltose-binding protein (MBP)-gonadotropin releasing hormone I (GnRH-I). AB - A recombinant fusion protein, maltose-binding protein (MBP)--gonadotropin releasing hormone I (GnRH-I), was produced by cloning a gene fragment encoding a tandem repeated GnRH-I hexamer peptide (GnRH-I6) into the pMAL-c4x vector which was subsequently expressed in E. coli TB1. MBP-GnRH-I6 was affinity purified. MBP GnRH-I6 was verified by SDS-PAGE and Western blot and immunogenicity tested in boars. Injection of the recombinant fusion protein into boars yielded a high titer antibody specific for GnRH-I. This was followed by serum testosterone and the degeneration of spermatogenesis. These results showed that MBP-GnRH-I6 acted as a strong immunogen and could be a candidate for an immune antifertility vaccine. PMID- 20849228 TI - Chlamydia trachomatis prevalence in unselected infertile couples. AB - Chlamydia (C.) trachomatis, an obligate intracellular bacterium, is responsible for the most common sexual transmitted disease and infertility. The purpose of this study was to evaluate: a) the frequency of chlamydial infection in unselected infertile couples and b) whether chlamydial infection could be identified in the semen sample as effectively as in the urethral swab of infertile patients. To accomplish this, 73 unselected, consecutive infertile couples were enrolled. Both male and female partners underwent a complete work-up to identify the cause of their infertility. A PCR method was used to detect C. trachomatis in urethral swabs and the semen samples of the male partners and in the cervical swabs of the female partners. C. trachomatis infection was found in 6 couples (8.2%). Three couples had both partners infected, 2 couples had only the male partner infected, and 1 only the female partner. C. trachomatis infection was found in the urethral swab of all 5 men infected, whereas the bacterial DNA was found in the semen sample of 2 of them. These findings suggest that C. trachomatis infection is present in about 8% of unselected infertile couples and that the bacterium should be searched in the male partner urethral swab which has a higher sensitivity. PMID- 20849229 TI - The relationship of language and emotion: N400 support for an embodied view of language comprehension. AB - According to embodied theories, the symbols used by language are meaningful because they are grounded in perception, action, and emotion. In contrast, according to abstract symbol theories, meaning arises from the syntactic combination of abstract, amodal symbols. If language is grounded in internal bodily states, then one would predict that emotion affects language. Consistent with this, advocates of embodied theories propose a strong link between emotion and language [Havas, D., Glenberg, A. M., & Rinck, M. Emotion simulation during language comprehension. Psychonomic Bulletin & Review, 14, 436-441, 2007; Niedenthal, P. M. Embodying emotion. Science, 316, 1002-1005, 2007]. The goal of this study was to test abstract symbol vs. embodied views of language by investigating whether mood affects semantic processing. To this aim, we induced different emotional states (happy vs. sad) by presenting film clips that displayed fragments from a happy movie or a sad movie. The clips were presented before and during blocks of sentences in which the cloze probability of mid sentence critical words varied (high vs. low). Participants read sentences while ERPs were recorded. The mood induction procedure was successful: Participants watching the happy film clips scored higher on a mood scale than those watching the sad clips. For N400, mood by cloze probability interactions were obtained. The N400 cloze effect was strongly reduced in the sad mood compared with the happy mood condition. Furthermore, a difference in late positivity was only present for the sad mood condition. The mood by semantic processing interaction observed for N400 supports embodied theories of meaning and challenges abstract symbol theories that assume that processing of word meaning reflects a modular process. PMID- 20849230 TI - Electrophysiological evidence for different inhibitory mechanisms when stopping or changing a planned response. AB - People are able to adapt their behavior to changing environmental contingencies by rapidly inhibiting or modifying their actions. Response inhibition is often studied in the stop-signal paradigm that requires the suppression of an already prepared motor response. Less is known about situations calling for a change of motor plans such that the prepared response has to be withheld but another has to be executed instead. In the present study, we investigated whether electrophysiological data can provide evidence for distinct inhibitory mechanisms when stopping or changing a response. Participants were instructed to perform in a choice RT task with two classes of embedded critical trials: Stop signals called for the inhibition of any response, whereas change signals required participants to inhibit the prepared response and execute another one instead. Under both conditions, we observed differences in go-stimulus processing, suggesting a faster response preparation in failed compared with successful inhibitions. In contrast to stop-signal trials, changing a response did not elicit the inhibition-related frontal N2 and did not modulate the parietal mu power decrease. The results suggest that compared with changing a response, additional frontal and parietal regions are engaged when having to inhibit a response. PMID- 20849231 TI - Causal role of the sensorimotor cortex in action simulation: neuropsychological evidence. AB - Interest in sensorimotor cortex involvement in higher cognitive functions has recently been revived, although whether the cortex actually contributes to the simulation of body part movements has not yet been established. Neurosurgical patients with selective lesions to the hand sensorimotor representation offer a unique opportunity to demonstrate that the sensorimotor cortex plays a causal role in hand action simulations. Patients with damage to hand representation showed a selective deficit in simulating hand movements compared with object movements (Experiment 1). This deficit extended to objects when the patients imagined moving them with their own hands while maintaining the ability to visualize them rotating in space (Experiment 2). The data provide conclusive evidence for a causal role of the sensorimotor cortex in the continuous update of sensorimotor representations while individuals mentally simulate motor acts. PMID- 20849232 TI - The involvement of posterior parietal cortex in feature and conjunction visuomotor search. AB - Successful interaction with the environment often involves the identification and localization of an item. Right posterior parietal cortex (rPPC) is necessary for the completion of conjunction but not feature visual search, regardless of the attentional requirements. One account for this dissociation is that the rPPC is primarily involved in processing spatial information. For target identification, conjunction tasks require that spatial information is used to determine if features occur at the same location, whereas feature search does not require such a process. This account suggests that if the requirement to localize the target is made explicit, then rPPC may also be necessary for feature search. This was examined using TMS and by manipulating the response mode: Participants were either required to press a button indicating the presence/absence of the target or else had to point to the target. TMS over rPPC did not disrupt performance of the feature task when a button press was required but significantly increased response time and movement time for the same task in the pointing condition. Conjunction search in both response conditions was significantly impaired by TMS. Performance on a task that required pointing to a target in the absence of distractors and thus did not involve visual search was unaffected by rPPC stimulation. We conclude that rPPC is involved in coding and representing spatial information and is therefore crucial when the task requires determining whether two features spatially co-occur or when search is combined with explicit target localization via a visuomotor transformation. PMID- 20849233 TI - Rapid modulation of sensory processing induced by stimulus conflict. AB - Humans are constantly confronted with environmental stimuli that conflict with task goals and can interfere with successful behavior. Prevailing theories propose the existence of cognitive control mechanisms that can suppress the processing of conflicting input and enhance that of the relevant input. However, the temporal cascade of brain processes invoked in response to conflicting stimuli remains poorly understood. By examining evoked electrical brain responses in a novel, hemifield-specific, visual-flanker task, we demonstrate that task irrelevant conflicting stimulus input is quickly detected in higher level executive regions while simultaneously inducing rapid, recurrent modulation of sensory processing in the visual cortex. Importantly, however, both of these effects are larger for individuals with greater incongruency-related RT slowing. The combination of neural activation patterns and behavioral interference effects suggest that this initial sensory modulation induced by conflicting stimulus inputs reflects performance-degrading attentional distraction because of their incompatibility rather than any rapid task-enhancing cognitive control mechanisms. The present findings thus provide neural evidence for a model in which attentional distraction is the key initial trigger for the temporal cascade of processes by which the human brain responds to conflicting stimulus input in the environment. PMID- 20849234 TI - Distinct neural systems involved in agency and animacy detection. AB - We designed an fMRI experiment comparing perception of human faces and robotic faces producing emotional expressions. The purpose of our experiment was to investigate engagement of different parts of the social brain by viewing these animate and inanimate agents. Both human and robotic face expressions evoked activity in face-responsive regions in the fusiform gyrus and STS and in the putative human mirror neuron system. These results suggest that these areas mediate perception of agency, independently of whether the agents are living or not. By contrast, the human faces evoked stronger activity than did robotic faces in the medial pFC and the anterior temporal cortex--areas associated with the representation of others' mental states (theory of mind), whereas robotic faces evoked stronger activity in areas associated with perception of objects and mechanical movements. Our data demonstrate that the representation of the distinction between animate and inanimate agents involves areas that participate in attribution of mental stance. PMID- 20849235 TI - Returning to freud. AB - In this article I attempt to renew interest in the importance of Freud's work for both the practice of psychoanalysis and in the training of psychoanalysts. I hope to stimulate readers to return to Freud's writings in detail, which seem to be increasingly neglected these days both in training and in the many conflicting contemporary models of psychoanalysis. I propose that the identity of psychoanalysis can still be based on Freud's work, and his approach can form a fundamental center from which there are various channels of divergence that may be useful when the patient seems to need them. But the centerpiece of our training and our orientation, I suggest, should be the basic principles spelled out in Freud's numerous volumes, in spite of the many changes and contradictions and even outright mistakes and cultural blindness he displays in some instances. I proceed to review some of these basic principles in the hope of persuading the reader to return to Freud again. I present these with some commentary from my own 50 years of clinical experience. I briefly review the clinical cornerstones of Freud's approach as developed in his early books, his controversial papers on technique, and his later emendations, which constitute the actual reality of Freud at work in psychoanalysis (that sometimes--and sometimes wisely--violates his papers on technique), and I discuss his notion of curative factors in psychoanalysis. All of this is to revive an interest in Freud's thought and to emphasize the lasting value of his work, both in its contemporary clinical relevance and as the proposed foundation stone of our identity as psychoanalysts. PMID- 20849236 TI - Why one should (or shouldn't) read freud: commentary on "Returning to Freud" by Richard D. Chessick. PMID- 20849238 TI - Psychoanalysis--on its way down a dead-end street? A concerned commentary. AB - The author discusses the problems when psychoanalysis not only neglects socio critical issues, diversifies its concepts and sets about to define their common ground with the help of brain research findings and/or of infant observation, but also ignores the implications of attempts to legitimate its scientific status by verifying the outcome of its treatments via nomological and/or qualitative study designs. It is argued that if we reduce psychoanalysis to a mere psychotherapeutic measure we displace the factors essential to neurotic disorders into the blind spot of our field of vision, thus rendering psychoanalysis to be a pseudoscience based on appearances alone. Conceptual clarity, it is argued, cannot be gained from the findings of infant observation or those of brain research. Neither can psychoanalytic treatments be investigated in these manners as long as our current understanding of technical concepts remains highly contradictory. In the author's view present-day psychoanalysis gambles Freud's inheritance away and with it, probably, its own future. PMID- 20849239 TI - Psychotherapy of psychoses: some principles for practice in the real world. AB - Treatment of psychoses must include psychological treatments for the mind joined with the commonly employed biological treatments for the brain. There are various schools of psychotherapy, but psychoanalytic treatment is the only Western discipline devoted to comprehensive understanding of the subjective mind. Psychoanalytic authorities have written extensively on the psychodynamics involved in treatment of psychoses, but such approaches are limited by the realities of limited resources and number of therapists who have advanced training. Also, the techniques and understandings developed by prominent authors cannot always be implemented by many therapists who do not enjoy as robust a theoretic background. Presented here are five principles that are useful to keep in mind during the treatment of people with psychotic problems. These principles are: safety in the therapeutic situation, empathy as a means of understanding the patient and avoiding countertransference problems, validation in the therapeutic situation as enhancing safety and promoting ego strength in a fragile ego, being a "real person" with the patient rather than a taciturn traditional psychoanalytic "mirror", and "transmuting internalization" as the way in which the therapeutic process promotes the development of a stronger self able to live in conventional reality. These principles are easy to keep in mind and are compatible with cognitive and behavioral techniques as well as other psychoanalytic theories and approaches. PMID- 20849240 TI - Adolescence and the reorganization of infant development: a neuro-psychoanalytic model. AB - The psychoanalytic view of adolescence as a phase of turbulence and reorganization occupied a central position in child and adolescent psychiatry until about 1980. The view of adolescence as a silent-transition phase then prevailed and diverged from the psychoanalytic perspective. This article reviews infant and adolescent development using an interdisciplinary, neuro psychoanalytic model in which psychoanalytic, neurobiological, and developmental perspectives converge and complement each other. Recent empirical research focuses attention on adolescence as a phase in which a far-reaching neurobiological and psychological reorganization takes place. According to the ontogenetic principle of psychoanalysis, the development and organization of the basic psychic functions occur in the first five years of life, while a reorganization takes place in adolescence. Neurobiological research confirms that the basic growth and maturation of the brain occurs in the first five years of life, and that a substantial reorganization in brain development transpires in adolescence. Research also verifies the clinical psychoanalytic concept that neurobiological and psychological maturation in adolescence remain unfinished till approximately age 23. The long-term and late biopsychosocial maturation in adolescence implies that adequate monitoring by parents and school remains necessary. The view that adolescents need to separate, and discover their individuality and independence alone, is unsupported by recent findings. The adolescent must acquire his independence, personal identity, and self-agency ("scaffolding") step by step. It is important that the adolescent knows that his parents are in the background monitoring and intervening as necessary; that he is not entirely alone, adrift and at risk for potential fragmentation. The long-term plasticity of the brain in adolescence implies greater vulnerability for the development of psychopathology, but offers opportunity for psychotherapeutic interventions to have greater impact. PMID- 20849242 TI - Pulsed laser light forces cancer cells to absorb anticancer drugs--the role of water in nanomedicine. AB - Anticancer drugs executing their function intracellularly enter cancer cells via diffusive processes. Complementary to these slow processes, cells can be forced to incorporate drugs by convection - a more efficient transport process. Transmembrane convection is induced by moderately intense pulsed laser light (or light emitting diodes) changing the structure of nanoscopic water layers in cells. This is a fundamental difference with the method of photodynamic therapy. In a model system we demonstrate that a total irradiation time of one minute is sufficient to completely inhibit proliferation of cancer cells. Transmembrane convection protects healthy cells from extended chemotherapy exposure, could be exploited to overcome multidrug resistance, and is a promising new tool in a variety of therapies as well as in skin rejuvenation. PMID- 20849243 TI - Impact of CYP2D6*4 genotype on progression free survival in tamoxifen breast cancer treatment. AB - OBJECTIVE: The cytochrome P450 2D6 (CYP2D6) polymorphism was reported to have a significant impact on outcome of tamoxifen treatment in estrogen receptor positive breast cancer patients. The objective of this study was to explore the effect of the CYP2D6*4 polymorphism on tamoxifen treatment outcome in a cohort of patients from a single clinical trial which included women with a history of previous chemotherapy. RESEARCH DESIGN AND METHODS: A total of 493 patients of the Austrian TIGER study receiving adjuvant tamoxifen therapy were studied for this pharmacogenetic interaction. All women with estrogen receptor positive tumors and tamoxifen therapy longer than 6 months were genotyped for CYP2D6*4 using TaqMan technology. Time to tumor progression, defined as local, regional, distant recurrence or contralateral breast cancer and progression free survival, was analyzed. RESULTS: No significant difference in time to tumor progression or progression free survival between the CYP2D6*4 genotype groups in the overall study cohort was found. In a subgroup of patients treated with chemotherapy the CYP2D6*4 poor metabolizers had a tendency towards a shorter mean time to progression. In this group the mean time to tumor progression and the progression free survival were 1.0 years in the CYP2D6*4/*4 group, 6.3 years in the *1/*4 group and 4.97 years in the *1/*1 group (Wilcoxon p = 0.104). CONCLUSION: While earlier data on CYP2D6 and tamoxifen excluded women with prior chemotherapy, the present analysis suggests that CYP2D6*4 genotype might be particularly crucial in this group of high-risk patients. Key limitations are restriction to the CYP2D6*4 allele and missing data of comedication. PMID- 20849244 TI - Value of N-terminal brain natriuretic peptide as a prognostic marker in patients with CKD: results from the CREATE study. AB - BACKGROUND AND OBJECTIVES: This study assessed plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) as a prognostic marker of cardiovascular risk in patients with chronic kidney disease stages 3-4 and anaemia treated with epoetin beta to two haemoglobin target ranges. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Of 603 patients enrolled in the Cardiovascular Risk Reduction by Early Anaemia Treatment with Epoetin Beta (CREATE) trial (baseline creatinine clearance 15-35 mL/min; haemoglobin 11.0-12.5 g/dL), 291 were included in this sub-study. Patients received subcutaneous epoetin beta either immediately after randomisation (target 13.0-15.0 g/dL; Group 1), or after their haemoglobin levels had fallen < 10.5 g/dL (target 10.5-11.5 g/dL; Group 2). Chronic heart failure New York Heart Association class III-IV was an exclusion criterion. (ClinicalTrials.gov Identifier: NCT00321919) RESULTS: Cardiovascular event rates were higher in patients with baseline NT-proBNP > 400 vs. <= 400 pg/mL (39 vs. 13 events; p = 0.0002). Dialysis was initiated in 68 vs. 42 patients with NT-proBNP > 400 vs. <= 400 pg/mL (p = 0.0003). Amongst patients with NT-proBNP > 400 pg/mL, there was no significant difference between treatment groups in risk of cardiovascular events (HR = 0.57; p = 0.08) or time to dialysis (HR = 0.65; p = 0.08). The overall interpretation of this substudy is, however, limited by its relatively small sample size which, together with low clinical event rates, result in a lack of statistical power for some analyses and should be viewed as being hypothesis-generating in nature. CONCLUSIONS: In chronic kidney disease patients with mild-to-moderate anaemia, elevated baseline plasma NT-proBNP levels are associated with a higher risk of cardiovascular events and an accelerated progression towards end-stage renal disease. PMID- 20849245 TI - Towards objective evaluation of perceived roughness and breathiness: an approach based on mel-frequency cepstral analysis. AB - Within this paper, the authors report on an experiment on automatic labelling of perceived voice roughness (R) and breathiness (B), according to the GRBAS scale. The main objective of the experiment has not been to correlate objective measures to perceived R and B, but to automatically evaluate R and B. For this purpose, a system has been trained that extracts the first mel-frequency cepstral coefficients (MFCC) of available sustained vowel phonations. Afterwards, a classifier has been trained to estimate the corresponding degrees of roughness and breathiness. The obtained results reveal a significant correlation between subjective and automatic labelling, hence indicating the feasibility of objective evaluation of voice quality by means of perceptually meaningful measures. PMID- 20849246 TI - Manifestation of speech and language disorders in children with hearing impairment compared with children with specific language disorders. AB - Children with hearing impairment (HI) often suffer from speech and language disorders. We wondered if the manifestation of these disorders resembled the ones in children with specific language impairment (SLI). Using matched pairs, we compared the manifestation of a speech and language disorder in 5- and 6-year-old children with HI and SLI. We looked at receptive language skills using the Reynell scales, the lexicon, syntax and morphology, output phonology, and phonological short-term memory. Receptive language skills were more impaired in HI children. No significant differences were recorded for all other domains. We conclude that language deficits that are at least partially caused by the hearing impairment affect receptive language skills to a greater extent than expressive language skills. PMID- 20849247 TI - The Swedish version of the Voice Handicap Index adapted for singers. AB - This study evaluates a Swedish version of the Voice Handicap Index adapted for singers. A total of 96 healthy singers and 30 singer-patients completed the questionnaire. Validity and reliability, internal coherence, and group differences were assessed. The singer-patient group had significantly higher scores than the control group. Reliability was confirmed by high Cronbach's (>0.78) for test-retest scores, and for each of the sub-scales. Test-retest stability in both groups was confirmed by high correlation values alpha (>0.8). Overall scores compared closely to those from previous reports. The Swedish translation of the adapted VHI for singers (RHI-s) is valid and reliable and shows sensitivity to the singer's concerns. It can be considered a useful tool in the clinical assessment of Swedish healthy or pathological singers. PMID- 20849248 TI - A virtual castrato? AB - In this investigation the voice source from trained boy singers was processed with a transfer function that contained the singer's formant cluster of a bass, a baritone, or a tenor. The modified voices were evaluated by a panel of highly specialized experts. The experts were asked 1) to assess how similar the examples sounded to the voice of the last castrato Alessandro Moreschi, and 2) to rate how similar they thought the examples were to their imagination of an 18th-century castrato voice. For both questions, the voices with tenor formants produced significantly higher ratings than the other voice types. However, the mean ratings for the second question were generally lower than those for the first. PMID- 20849249 TI - Growth of school children in different urban environments in Argentina. AB - BACKGROUND: Nutritional transition has been described in various countries, each showing inherent characteristics. Furthermore, different patterns also appear within the same country. AIM: To compare the nutritional status of schoolchildren, of both sexes, living in two Argentine cities with different urban and environment characteristics, from the perspective of nutritional transition. SUBJECTS AND METHODS: The sample comprised 5355 children (6-13 years) living in Puerto Madryn (Chubut) and General Alvear (Mendoza), Argentina. Weight and height were transformed into Z-scores according to NHANES I- II; underweight, stunting and wasting defined by - 2 SD and overweight and obesity calculated according the cut-off proposed by IOTF. Prevalences of nutritional status were estimated. RESULTS: Comparison of the two cities revealed significant chi2 values for the indicators of nutritional status analysed. Puerto Madryn had higher prevalences of overweight and obesity. General Alvear exhibited higher stunting and underweight values. CONCLUSIONS: The cities studied are in different stages of nutritional transition. Puerto Madryn is undergoing growing industrialization and urbanization and thus exhibits characteristics typical of an 'obesogenic' environment. General Alvear, a less complex urban centre, where some cultural patterns related to an agrarian way of life appear to have been retained, is situated at a less advanced stage. PMID- 20849250 TI - Agreement between body mass index, waist circumference and skin-fold thickness in the United Kingdom Army. AB - BACKGROUND: Body Mass Index (BMI) does not distinguish between fat-free mass and fat mass, yet this distinction is important as a clinical tool, especially in the military and occupations for which physical fitness is important. AIM: This study assessed the level of agreement between BMI, sum of skin-folds and waist circumference in UK Army personnel. SUBJECTS AND METHODS: Three hundred and eighty-six males were selected to study the level of agreement between BMI, waist circumference, waist circumference/height and sum of skin-folds at four sites. As the units of measurement differ, this study generated standardized distributions with skewness of zero. RESULTS: The limits of agreement between BMI and waist circumference were fairly wide (between boundaries 1.75 z-score) and wide between BMI and sum of skin-folds (2.57 z-score) and waist circumference and skin-folds (2.37 z-score). The standard deviations of the differences of BMI and waist circumference decreased with increasing means of these two measures. The kappa statistic for BMI and waist circumference was 0.7 and ~0.5 if compared against sum of skin-folds. CONCLUSION: The level of agreement between BMI and waist circumference is acceptable regardless of method to assess obesity, but would be poor for assessing thinness. The level of agreement with sum of skin-folds was mediocre. PMID- 20849251 TI - Acute and chronic Chlamydia pneumoniae infection in pregnancy complicated with preeclampsia. AB - OBJECTIVE: To investigate whether Chlamydia pneumoniae (Cp) infection is more common in women whose current pregnancy is complicated with preeclampsia (PE) as compared to pregnant women without PE. METHODS: Thirty pregnant women with PE and 30 pregnant women without PE were studied between 29 and 30 weeks of gestation. The presence of an acute or chronic Cp infection was determined by the estimations of serum IgG, IgM, and IgA Cp antibodies. RESULTS: None of the women were diagnosed as having acute Cp infection. Prevalence of chronic Cp infection was 53 and 66% in the PE and control groups, respectively (X(2), p = 0.068). CONCLUSION: Chronic Cp infection is not more common in women whose pregnancy is complicated with PE as compared to pregnant women without PE. Therefore, no association between Cp infection and PE can be established. PMID- 20849252 TI - Endothelial nitric oxide genotypes and haplotypes are not associated with end stage renal disease. AB - The identification of genetic markers associated with chronic kidney disease (CKD) may help to predict its development. Because reduced nitric oxide (NO) bioavailability and endothelial dysfunction are involved in CKD, genetic polymorphisms in the gene encoding the enzyme involved in NO synthesis (endothelial NO synthase [eNos]) may affect the susceptibility to CKD and the development of end-stage renal disease (ESRD). We compared genotype and haplotype distributions of three relevant eNOS polymorphisms (T(-786)C in the promoter region, Glu298Asp in exon 7, and 4b/4a in intron 4) in 110 healthy control subjects and 127 ESRD patients. Genotypes for the T(-786)C and Glu298Asp polymorphisms were determined by TaqMan((r)) Allele Discrimination assay and real time polymerase chain reaction. Genotypes for the intron 4 polymorphism were determined by polymerase chain reaction and fragment separation by electrophoresis. The software program PHASE 2.1 was used to estimate the haplotypes frequencies. We considered significant a probability value of p < 0.05/number of haplotypes (p < 0.05/8 = 0.0063). We found no significant differences between groups with respect to age, ethnicity, and gender. CKD patients had higher blood pressure, total cholesterol, and creatinine levels than healthy control subjects (all p < 0.05). Genotype and allele distributions for the three eNOS polymorphisms were similar in both groups (p > 0.05). We found no significant differences in haplotype distribution between groups (p > 0.05). The lack of significant associations between eNOS polymorphisms and ESRD suggests that eNOS polymorphisms may not be relevant to the genetic component of CKD that leads to ESRD. PMID- 20849253 TI - Structural characteristics and phylogenetic analysis of the mitochondrial genome of the sugarcane borer, Diatraea saccharalis (Lepidoptera: Crambidae). AB - The sugarcane borer, Diatraea saccharalis (F.), is an economically important pest of several major crops in North and South America. There is great concern over potential resistance development to the valuable transgenic Bacillus thuringiensis corn. Cost-effective monitoring methods, especially regarding molecular markers that could detect early changes in resistance allele frequency in field populations of D. saccharalis, are needed. This article reports the complete mitochondrial genome sequence of D. saccharalis (GenBank: FJ240227). The mitochondrial genome sequence of D. saccharalis has the typical metazoan mitogenome structure including 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes, with a total size of 15,490 bp. The A+T content of the full mitogenome is 80.1% and the significant A+T bias is at the control region (94.9%), as compared to the extremely low G content (0.6%). In all 13 protein coding genes, 9 start with the common Met initiator codon (ATA or ATG) and 3 use ATT (Ile), whereas CGA (Arg) is used as a start codon in COI. Eleven of the 13 protein coding genes use complete termination codon (TAA), whereas COI and COII use incomplete ones, which terminated with a single T-nucleotide abutting on tRNA. There are seven major noncoding spacers (628 bp), including six intergenic spacers and an A+T-rich region, which are scattered in the mitogenome. Several microsatellite-like elements were observed in these noncoding regions. The complete mitochondrial sequences of D. saccharalis reported in this study can provide useful data in analyzing divergence of lepidopteran insects and in developing DNA-based diagnoses and genetic makers. PMID- 20849254 TI - Significant evidence of association between polymorphisms in ZNF533, environmental factors, and nonsyndromic orofacial clefts in the Western Han Chinese population. AB - The etiology of nonsyndromic orofacial clefts (NSOC) has been considered "complex" or "multifactorial." Etiologic heterogeneity induces disparities in the results among different populations. The zinc finger protein 533 (ZNF533) and several environmental factors have been revealed to be associated with NSOC in several populations. We investigated three single-nucleotide polymorphisms (SNPs) and 10 environmental factors in 211 case-parent trios and 188 control individuals in the Western Han Chinese population to confirm the relationship between ZNF533, environmental factors, and the etiology of NSOC in the Western Han Chinese population. The transmission disequilibrium test, case-control analysis, multiple logistic regression, log-linear model, and conditional logistic regression were tested to confirm the contribution of the ZNF533 gene and environmental factors to the etiology of NSOC. Strong statistically significant evidence of association was found between the rs6757845 and rs1139 markers and NSOC. The haplotype G-G for rs6757845-rs1139 showed significant overtransmission among cleft lip with or without cleft palate (CL/P) trios and among cleft palate only trios. Additional 11 and 5 haplotypes were significantly overtransmitted and undertransmitted among CL/P and among cleft palate only trios, respectively. Maternal disease, use of medication, and passive smoking during the first trimester of pregnancy may increase the risk of NSOC. Maternal folic acid supplementation during the first trimester of pregnancy showed a protective effect on the etiology of NSOC. Genotype-environment interaction test showed a significant evidence of interaction effects between the genotypes at rs6757845 and maternal passive smoking during the first trimester among CL/P trios. These results confirm the effects of the ZNF533 gene and environmental factors on the etiology of NSOC. PMID- 20849255 TI - Breast cancer. Introduction. PMID- 20849256 TI - Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: a review of the randomised data. AB - Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation. PMID- 20849257 TI - Hyperthermia for locally advanced breast cancer. AB - Hyperthermia (HT) has a proven benefit for treating superficial malignancies, particularly chest wall recurrences of breast cancer. There has been less research utilising HT in patients with locally advanced breast cancer (LABC), but available data are promising. HT has been combined with chemotherapy and/or radiotherapy in the neoadjuvant, definitive and adjuvant setting, albeit in series with small numbers of patients. There is only one phase III trial that examines hyperthermia in LABC, also with relatively small numbers of patients. The goal of this review is to highlight important research utilising HT in patients with LABC as well as to suggest future directions for its use. PMID- 20849259 TI - Reirradiation combined with hyperthermia in breast cancer recurrences: overview of experience in Erasmus MC. AB - For superficial hyperthermia a custom-built multi-applicator multi-amplifier superficial hyperthermia system operating at 433 MHz is utilised. Up to 6 Lucite Cone applicators can be used simultaneously to treat an area of 600 cm2. Temperatures are measured continuously with fibre optic multi-sensor probes. For patients with non-standard clinical problems, hyperthermia treatment planning is used to support decision making with regard to treatment strategy. In 74% of our patients with recurrent breast cancer treated with a reirradiation scheme of 8 fractions of 4 Gy in 4 weeks, combined with 4 or 8 hyperthermia treatments, a complete response is achieved, approximately twice as high as the CR rate following the same reirradation alone. The CR rate in tumours smaller than 30 mm is 80-90%, for larger tumours it is 65%. Hyperthermia appears beneficial for patients with microscopic residual tumour as well. To achieve high CR rates it is important to heat the whole radiotherapy field, and to use an adequate heating technique. PMID- 20849258 TI - Magnetic resonance imaging: a potential tool in assessing the addition of hyperthermia to neoadjuvant therapy in patients with locally advanced breast cancer. AB - The poor overall survival for patients with locally advanced breast cancers has led over the past decade to the introduction of numerous neoadjuvant combined therapy regimens to down-stage the disease before surgery. At the same time, more evidence suggests the need for treatment individualisation with a wide variety of new targets for cancer therapeutics and also multi modality therapies. In this context, early determination of whether the patient will fail to respond can enable the use of alternative therapies that can be more beneficial. The purpose of this review is to examine the potential role of magnetic resonance imaging (MRI) in early prediction of treatment response and prognosis of overall survival in locally advanced breast cancer patients enrolled on multi modality therapy trials that include hyperthermia. The material is organised with a review of dynamic contrast (DCE)-MRI and diffusion weighted (DW)-MRI for characterisation of phenomenological parameters of tumour physiology and their potential role in estimating therapy response. Most of the work published in this field has focused on responses to neoadjuvant chemotherapy regimens alone, so the emphasis will be there, however the available data that involves the addition of hyperthermia to the regimen will be discussed The review will also include future directions that include the potential use of MRI imaging techniques in establishing the role of hyperthermia alone in modifying breast tumour microenvironment, together with specific challenges related to performing such studies. PMID- 20849260 TI - Proteomics, morphoproteomics, saliva and breast cancer: an emerging approach to guide the delivery of individualised thermal therapy, thermochemotherapy and monitor therapy response. AB - The field of proteomics is in its infancy; however the discipline, its technology, and our abilities to translate the proteomic data are rapidly evolving. In the near future proteomics should significantly improve our ability to make early cancer diagnoses, direct appropriate personalised therapy, and monitor response to therapy, including thermal therapy. The potential role of proteomics in breast cancer early diagnosis, prediction of aggressiveness is clear. Its potential importance in guiding treatment choice and prediction of treatment response is especially intriguing. This paper reviews the varied methodologies used in the field of proteomics, including gel-free, label-free proteomics, quantitative proteomics, phosphoproteomics, protein extraction from formalin-fixed, paraffin-embedded tissue sections (FFPE) proteomics, laser capture microdissection proteomics, and targeted proteomics. It also discusses two new areas, morphoproteomics and salivary proteomics cancer diagnostics, as well as selected pre-clinical and clinical analyses using the described methodologies. Morphoproteomics defines which signal transduction pathways exist within the tumour cells and the surrounding tissue comprising a patient's cancer biopsy specimen. Morphoproteomics, and the other histology-based proteomic techniques are actually beginning to clinically make possible individualised treatment of breast cancer. Salivary proteomics, in part because it is non invasive, is a new area of breast cancer diagnostics that can be used to non invasively monitor an individual patient's response to treatment with every treatment cycle. The current literature demonstrates that a diagnosis of breast cancer can be readily made using proteomic methodologies, and that proteomics can also define cancers with a poor prognosis at the time of diagnosis. With such early prognostic information we expect proteomics will soon be a science that on the basis of prognosis, guides individualised therapy and as well, have the ability to monitor the results of thermal therapy, radiation, and chemotherapy treatment during therapy. PMID- 20849262 TI - Conformal microwave array (CMA) applicators for hyperthermia of diffuse chest wall recurrence. AB - PURPOSE: This article summarises the evolution of microwave array applicators for heating large area chest wall disease as an adjuvant to external beam radiation, systemic chemotherapy, and potentially simultaneous brachytherapy. METHODS: Current devices used for thermotherapy of chest wall recurrence are reviewed. The largest conformal array applicator to date is evaluated in four studies: (1) ability to conform to the torso is demonstrated with a CT scan of a torso phantom and MR scan of the conformal water bolus component on a mastectomy patient; (2) specific absorption rate (SAR) and temperature distributions are calculated with electromagnetic and thermal simulation software for a mastectomy patient; (3) SAR patterns are measured with a scanning SAR probe in liquid muscle phantom for a buried coplanar waveguide CMA; and (4) heating patterns and patient tolerance of CMA applicators are characterised in a clinical pilot study with 13 patients. RESULTS: CT and MR scans demonstrate excellent conformity of CMA applicators to contoured anatomy. Simulations demonstrate effective control of heating over contoured anatomy. Measurements confirm effective coverage of large treatment areas with no gaps. In 42 hyperthermia treatments, CMA applicators provided well tolerated effective heating of up to 500 cm(2) regions, achieving target temperatures of T(min) = 41.4 +/- 0.7 degrees C, T(90) = 42.1 +/- 0.6 degrees C, T(ave) = 42.8 +/- 0.6 degrees C, and T(max) = 44.3 +/- 0.8 degrees C as measured in an average of 90 points per treatment. CONCLUSION: The CMA applicator is an effective thermal therapy device for heating large-area superficial disease such as diffuse chest wall recurrence. It is able to cover over three times the treatment area of conventional hyperthermia devices while conforming to typical body contours. PMID- 20849261 TI - Feeling too hot or cold after breast cancer: is it just a nuisance or a potentially important prognostic factor? AB - There is widespread recognition among both patients and caregivers that breast cancer patients often experience debilitating deficiencies in their ability to achieve thermal comfort, feeling excessively hot or cold under circumstances when others are comfortable. However, this symptom receives little clinical or scientific attention beyond identification and testing of drugs that minimise menopausal-like symptoms. Could some of these symptoms represent an important prognostic signal? Could thermal discomfort be among other cytokine-driven sickness behaviour symptoms seen in many breast cancer patients? While the literature reveals a strong link between treatment for breast cancer and some menopausal vasomotor symptoms (e.g. hot flashes also known as "hot flushes"), there is little data on quantitative assessment of severity of different types of symptoms and their possible prognostic potential. However, recent, intriguing studies indicating a correlation between the presence of hot flashes and reduced development of breast cancer recurrence strongly suggests that more study on this topic is needed. In comparison to reports on the phenomenon of breast cancer associated hot flashes, there is essentially no scientific study on the large number of women who report feeling excessively cold after breast cancer treatment. Since similar acquired thermal discomfort symptoms can occur in patients with cancers other than breast cancer, there may be as yet unidentified cancer- or treatment-driven factor related to temperature dysregulation. In general, there is surprisingly little information on the physiological relationship between body temperature regulation, vasomotor symptoms, and cancer growth and progression. The goal of this article is twofold: (1) to review the scientific literature regarding acquired deficits in thermoregulation among breast cancer survivors and (2) to propose some speculative ideas regarding the possible basis for thermal discomfort among some of these women. Specifically, we suggest a potential association with excessive pro-inflammatory cytokine activity, similar to other cytokine-driven symptoms experienced after breast cancer, including fatigue and depression. We highlight the similarity of some breast cancer-associated thermal discomfort symptoms to those which occur during fever, suggesting the possibility that there may be common underlying changes in pro-inflammatory cytokine activity in both conditions. We anticipate that this contribution will stimulate additional scientific interest among researchers in identifying potential mechanisms and prognostic significance of this under studied aspect of breast cancer biology and survivorship. PMID- 20849264 TI - Improving conformal tumour heating by adaptively removing control points from waveform diversity beamforming calculations: a simulation study. AB - Waveform diversity is a phased array beamforming strategy that determines an optimal sequence of excitation signals to maximise power at specified tumour control points while simultaneously minimising power delivered to sensitive normal tissues. Waveform diversity is combined with mode scanning, a deterministic excitation signal synthesis algorithm, and an adaptive control point removal algorithm in an effort to achieve higher, more uniform tumour temperatures. Simulations were evaluated for a 1444 element spherical section ultrasound phased array that delivers therapeutic heat to a 3 cm spherical tumour model located 12 cm from the array. By selectively deleting tumour control points, the tumour volume heated above 42 degrees C increased from 2.28 cm3 to 11.22 cm3. At the expense of a slight increase in the normal tissue volume heated above the target temperature of 42 degrees C, the size of the tumour volume heated above 42 degrees C after tumour points were deleted was almost five times larger than the size of the original heated tumour volume. Several other configurations were also simulated, and the largest heated tumour volumes, subject to a 43 degrees C peak temperature constraint, were achieved when the tumour control points were located along the back edge of the tumour and laterally around the tumour periphery. The simulated power depositions obtained from the results of the adaptive control point removal algorithm, when optimised for waveform diversity combined with mode scanning, consistently increased the penetration depth and the size of the heated tumour volume while increasing the heated normal tissue volume by a small amount. PMID- 20849263 TI - Present and future technology for simultaneous superficial thermoradiotherapy of breast cancer. AB - This paper reviews systems and techniques to deliver simultaneous thermoradiotherapy of breast cancer. It first covers the clinical implementation of simultaneous delivery of superficial (microwave or ultrasound) hyperthermia and external photon beam radiotherapy, first using a Cobalt-60 teletherapy unit and later medical linear accelerators. The parallel development and related studies of the Scanning Ultrasound Reflector Linear Arrays System (SURLAS), an advanced system specifically designed and developed for simultaneous thermoradiotherapy, follows. The performance characteristics of the SURLAS are reviewed and power limitation problems at high acoustic frequencies (>3 MHz) are discussed along with potential solutions. Next, the feasibility of simultaneous SURLAS hyperthermia and intensity modulated radiation therapy/image-guided radiotherapy (IMRT/IGRT) is established based on published and newly presented studies. Finally, based on the encouraging clinical results thus far, it is concluded that new trials employing the latest technologies are warranted along with further developments in treatment planning. PMID- 20849269 TI - Ontogenetic diet shifts result in niche partitioning between two consumer species irrespective of competitive abilities. AB - Tilman's theory predicts the outcome of competition between two consumers sharing two resources on the basis of the shape of zero net-growth isoclines (ZNGIs). In his theory, intraspecific differences in resource use are not accounted for. Here we extend this theory to include situations where organisms undergo ontogenetic diet shifts, as these characterize the life histories of many species. In a situation that without diet shifts would lead to neutral coexistence of consumer species, we investigate whether ontogenetic diet shifts lead to niche partitioning. We analyze a model describing competition for two resources between two competitors with distinctive diets over ontogeny, using copepods (showing ontogenetic diet shifts) and daphnids (not showing ontogenetic diet shifts) as appropriate representatives. We show that an ontogenetic diet shift affects the shape of the ZNGI, changing it from reflecting perfectly substitutable resources to reflecting essential resources. Furthermore, we show that resource supply determines population stage structure and stage-dependent resource consumption in copepods and influences the competitive outcome with daphnids. In particular, we show that in itself, an ontogenetic diet shift can provide a competitive advantage if the supply of the adult resource is lower than the supply of the juvenile resource but that it always causes a disadvantage if the supply of the adult resource exceeds that of the juvenile resource. PMID- 20849265 TI - Absolute temperature imaging using intermolecular multiple quantum MRI. AB - PURPOSE: A review of MRI temperature imaging methods based on intermolecular multiple quantum coherences (iMQCs) is presented. Temperature imaging based on iMQCs can provide absolute temperature maps that circumvent the artefacts that other proton frequency shift techniques suffer from such as distortions to the detected temperature due to susceptibility changes and magnetic field inhomogeneities. Thermometry based on iMQCs is promising in high-fat tissues such as the breast, since it relies on the fat signal as an internal reference. This review covers the theoretical background of iMQCs, and the necessary adaptations for temperature imaging using iMQCs. MATERIALS AND METHODS: Data is presented from several papers on iMQC temperature imaging. These studies were done at 7T in both phantoms and in vivo. Results from phantoms of cream (homogeneous mixture of water and fat) are presented as well as in vivo temperature maps in obese mice. RESULTS: Thermometry based on iMQCs offers the potential to provide temperature maps which are free of artefacts due to susceptibility and magnetic field inhomogeneities, and detect temperature on an absolute scale. CONCLUSIONS: The data presented in the papers reviewed highlights the promise of iMQC-based temperature imaging in fatty tissues such as the breast. The change in susceptibility of fat with temperature makes standard proton frequency shift methods (even with fat suppression) challenging and iMQC-based imaging offers an alternative approach. PMID- 20849270 TI - Incorporating clade identity in analyses of phylogenetic community structure: an example with hummingbirds. AB - An important challenge in community ecology is to determine how processes occurring at multiple spatial, temporal, and phylogenetic scales influence the structure of local communities. While indexes of phylogenetic structure, which measure how related species are in a community, provide insight into the processes that shape species coexistence, they fail to pinpoint the phylogenetic scales at which those processes occur. Here, we explore a framework to identify the species and clades responsible for the inferred patterns of phylogenetic structure within a given community. Further, we evaluate how communities that share the nonrandom representation of species from a given clade in the phylogeny are distributed across geography and environmental gradients. Using Ecuadorian hummingbird communities, we found that multiple patterns of phylogenetic structure often occur within a local assemblage. We also identified four geographic regions where species from certain clades exhibit nonrandom representation: the eastern Amazonian lowlands, the western dry lowlands, the Andes at middle elevations, and the Andes at high elevations. The environmental gradients along which changes in the local coexistence of species occurred were mainly elevation, annual precipitation, and seasonality in both temperature and precipitation. Finally, we show how these patterns can be used to generate hypotheses about the processes that allow species coexistence. PMID- 20849272 TI - Accuracy and repeatability of anthropometric facial measurements using cone beam computed tomography. AB - OBJECTIVE: The purpose of this study was to determine the accuracy and repeatability of linear anthropometric measurements on the soft tissue surface model generated from cone beam computed tomography scans. MATERIALS AND METHODS: The study sample consisted of seven cadaver heads. The accuracy and repeatability were assessed by means of a series of 21 standardized, linear facial measurements derived from 11 landmarks taken both directly on the face with a set of digital calipers and indirectly from a three-dimensional soft tissue surface model generated from a cone beam computed tomography scan of the heads using SimPlant(r) Ortho Pro software. The landmarks and measurements were chosen to cover various regions of the face with an emphasis on the oral-nasal region. The cone beam computed tomography measurements were compared with the physical measurements. Statistical analysis for the repeatability was done by means of the intraclass coefficient. Accuracy was determined by means of the absolute error and absolute percentage error. RESULTS: The cone beam computed tomography measurements were very accurate when compared with the physical measurements (0.962 to 0.999). Except for one measurement, between point tragion (t) and nasion (n) (mean, 1.52 mm), all the measurements had a mean absolute error of less than 1.5 mm. CONCLUSIONS: The three-dimensional surface models derived from cone beam computed tomography images are sufficiently precise and accurate for the anthropometric measurements. PMID- 20849271 TI - Hidden consequences of living in a wormy world: nematode-induced immune suppression facilitates tuberculosis invasion in African buffalo. AB - Most hosts are infected with multiple parasites, and responses of the immune system to co-occurring parasites may influence disease spread. Helminth infection can bias the host immune response toward a T-helper type 2 (Th2) over a type 1 (Th1) response, impairing the host's ability to control concurrent intracellular microparasite infections and potentially modifying disease dynamics. In humans, immune-mediated interactions between helminths and microparasites can alter host susceptibility to diseases such as HIV, tuberculosis (TB), and malaria. However, the extent to which similar processes operate in natural animal populations and influence disease spread remains unknown. We used cross-sectional, experimental, and genetic studies to show that gastrointestinal nematode infection alters immunity to intracellular microparasites in free-ranging African buffalo (Syncerus caffer). Buffalo that were more resistant to nematode infection had weaker Th1 responses, there was significant genotypic variation in nematode resistance, and anthelminthic treatment enhanced Th1 immunity. Using a disease dynamic model parameterized with empirical data, we found that nematode-induced immune suppression can facilitate the invasion of bovine TB in buffalo. In the absence of nematodes, TB failed to invade the system, illustrating the critical role nematodes may play in disease establishment. Our results suggest that helminths, by influencing the likelihood of microparasite invasion, may influence patterns of disease emergence in the wild. PMID- 20849273 TI - Healthcare-associated infection: a significant cause of hospital readmission. PMID- 20849274 TI - Seasonal and ascending trends in the incidence of carriage of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species in 2 German hospitals. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing strains of bacteria have become a major public health concern. In the present study, the incidence of carriage of ESBL-producing strains was analyzed for general trends and seasonality. METHODS: Monthly data on ESBL-producing strains were collected retrospectively at 2 large university hospitals in Germany. The mean monthly temperatures for the 2 settings were collected from Germany's national meteorological service. Multivariable time series analyses were performed to explain variations in the monthly incidence densities of carriage of ESBL producing bacteria (number of cases involving ESBL-producing Escherichia coli and/or Klebsiella species per 1,000 patient days). For the final models, we incorporated variables for the ascending linear trends and other variables representing the mean monthly temperature. RESULTS: Our models demonstrated that there was an increasing trend in the incidences of carriage of ESBL-producing bacteria. In addition, the incidences of carriage of all ESBL-producing bacteria responded positively to the mean temperature, meaning that during the summer, more cases involving ESBL-producing bacteria were detected than during the winter. The same methodology was also applied to the incidence of methicillin resistant Staphylococcus aureus carriage, but no association was found with the mean temperature. CONCLUSIONS: In the present study, we demonstrated that the monthly incidence of carriage of ESBL-producing bacteria was highly correlated with the mean monthly temperature, a fact that should be considered in experimental studies as an additional parameter influencing the incidence of ESBL producing bacteria. PMID- 20849275 TI - Detection of Usutu virus within a West Nile virus surveillance program in Northern Italy. AB - Usutu virus (USUV) is a mosquito-borne flavivirus belonging to the Japanese encephalitis serocomplex, recently related to neurological disease in immunosuppressed patients. In the same area of Northern Italy where USUV human cases occurred in 2009, a regional West Nile virus (WNV) surveillance program based on mosquito monitoring and wild birds screening has been implemented since 2008. Mosquito pools and wild birds were tested using three different polymerase chain reactions (Flavivirus, WNV, and USUV). During summer 2009, 56 pools (54 consisting of Culex pipiens and 2 of Aedes albopictus) and 27 pools (Cx. pipiens) out of 1789 mosquito pools were, respectively, USUV and WNV positive. Moreover, out of 1218 wild birds tested, 44 were WNV positive, whereas only 11 birds were USUV positive by polymerase chain reaction. Data collected during 2009 prove a cocirculation of USUV and WNV in Northern Italy, but these two viruses show different incidence values in both mosquitoes and birds, suggesting involvement of different animals (other bird species or mammals) in their natural cycles. The cocirculation of WNV and USUV poses a new potential threat to human health in this area. The extent of WNV surveillance to other Flaviviruses will require new diagnostic procedures able to process a large number of samples in a limited period of time and highlights the importance of developing more specific serological tests that could be used in field. PMID- 20849276 TI - Laboratory testing practices for West Nile virus in the United States. AB - We surveyed state public health and commercial diagnostic reference laboratories regarding current testing practices for West Nile virus (WNV). The majority of WNV testing is now performed in commercial diagnostic reference laboratories using commercially available Food and Drug Administration-cleared kits labeled for the presumptive diagnosis of WNV. However, only 25% of surveyed state public health or commercial diagnostic reference laboratories currently have the capacity to perform the recommended confirmatory testing. These findings indicate the need for both manufacturers and laboratories to monitor the performance of these WNV test kits. Further, clinicians should be aware of the limitations of these kits and the need for additional testing to confirm a diagnosis of WNV disease. PMID- 20849277 TI - Tick surveillance in Great Britain. AB - The ability for public/veterinary health agencies to assess the risks posed by tick-borne pathogens is reliant on an understanding of the main tick vector species. Crucially, the status, distribution, and changing trends in tick distribution and abundance are implicit requirements of any risk assessment; however, this is contingent on the quality of tick distribution data. Since 2005 the Health Protection Agency has promoted an enhanced tick surveillance program. Through engagement with a variety of public and veterinary health agencies and practitioners (e.g., clinicians and veterinarians), wildlife groups (deer society, zoos, animal refuge centers, and academics), and amateur entomologists, >4000 ticks from 900 separate records across Great Britain have been submitted, representing 14 tick species (Ixodes ricinus, Ixodes hexagonus, Ixodes acuminatus, Ixodes arboricola, Ixodes canisuga, Ixodes frontalis, Ixodes lividus, Ixodes trianguliceps, Ixodes ventalloi, Carios vespertilionis, Dermacentor reticulatus, Haemaphysalis punctata, Hyalomma marginatum, and Amblyomma species). The majority of ticks submitted were I. ricinus (81%), followed by I. hexagonus (10%) and I. frontalis (2.5%). Predominant host groups include companion animals (411 records), humans (198 records), wild birds (111 records), and large wild mammals (88 records), with records also from small/medium wild mammals, livestock, the environment and domestic/aviary birds. The scheme has elucidated the detection of two nonnative tick species, the expansion of previously geographically restricted D. reticulatus and produced ground data on the spread of I. ricinus in southwest England. It has also provided a forum for submission of ticks from the concerned public and particularly those infected with Lyme borreliosis, thus raising awareness among public health agencies of the increased peri-urban tick problem in Britain. Our results demonstrate that it is possible to run a cost-effective nationwide surveillance program to successfully monitor endemic tick species, identify subtle changes in their distribution, and detect the arrival and presence of exotic species. PMID- 20849278 TI - Preferences of patients with advanced lung cancer regarding the involvement of family and others in medical decision-making. AB - OBJECTIVE: To explore the preferences of competent patients with advanced lung cancer regarding involvement of family and/or others in their medical decision making, and their future preferences in case of loss of competence. METHODS: Over 1 year, physicians in 13 hospitals in Flanders, Belgium, recruited patients with initial non-small-cell lung cancer, stage IIIb or IV. The patients were interviewed with a structured questionnaire every 2 months until the fourth interview and every 4 months until the sixth interview. RESULTS: At inclusion, 128 patients were interviewed at least once; 13 were interviewed 6 consecutive times. Sixty-nine percent of patients wanted family members to be involved in medical decision-making and this percentage did not change significantly over time. One third of these patients did not achieve this preference. Ninety-four percent of patients wanted family involvement if they lost competence, 23% of these preferring primary physician control over decision-making, 41% shared physician and family control, and 36% primary family control. This degree of preferred family involvement expressed when competent did not change significantly over time at population level, but did at individual level; almost half the patients changed their minds either way at some point during the observation period. CONCLUSIONS: The majority of patients with lung cancer wanted family involvement in decision-making, and almost all did so in case of future loss of competence. However, as half of the patients changed their minds over time about the degree of family involvement they wanted if they lost competence, physicians should regularly rediscuss a patient's preferences. PMID- 20849279 TI - Safety and peri-operative outcomes during learning curve of robot-assisted laparoscopic prostatectomy: a multi-institutional study of fellowship-trained robotic surgeons versus experienced open radical prostatectomy surgeons incorporating robot-assisted laparoscopic prostatectomy. AB - PURPOSE: To analyze and compare the safety and peri-operative outcomes of fellowship-trained robotic surgeons (FEL) and experienced open surgeons (OE) incorporating robot-assisted laparoscopic prostatectomy (RALP) into practice. MATERIALS AND METHODS: Multiinstitutional, prospective data were collected on the first 30 RALP performed by FEL and OE (defined as over 1000 prostatectomies) incorporating RALP into practice. Morbidity from the peri-operative course was evaluated as were operative outcomes. The second 30 cases from the OE group were evaluated to assess for improvement with experience. RESULTS: There were no rectal injuries or death in either group. Blood transfusion rates did not differ between the two groups (2% vs. 3%, p = 0.65). Open conversion occurred three times in the OE group but only within the first 30 cases. In the first 30 cases FEL had statistically lower rates of positive margins (15% vs. 34%, p = 0.008) and decreased likelihood of prolonged urethral catheter leakage (5% vs. 19%, p = 0.009). The FEL group had lower rates of failure of prostate-specific antigen to nadir < 0.15 ng/mL (2% vs. 10%, p = 0.056). There were no reoperations in the FEL group but present in 2% of the OE group initially. The second 30 cases of the OE group noted a statistical improvement for all parameters with margin rates and the requirement of prolonged catheterization becoming statistically comparable to those of the FEL group. CONCLUSIONS: OE can safely incorporate RALP into practice and achieve outcomes comparable to FEL quickly. As anticipated, FEL achieve these endpoints earlier in their practice. PMID- 20849281 TI - Editorial Comment. PMID- 20849280 TI - Endoscopic cystocele surgery: lateral repair with combined suture/mesh technique. AB - The lateral repair is an accepted method for the reconstitution of paravaginal defects. Several open or vaginal approaches have been described, but there is still a deficit of reproducible laparoscopic approaches. Thus, only a few clinics perform the laparoscopic approach although it offers several advantages compared to open or vaginal surgery. This article describes our modified laparoscopic approach with inlay of a polypropylene mesh. Operation time will go on about 50 minutes using the here-presented modified approach. The inlay of a mesh with induction of connective tissue may increase long-term stability. PMID- 20849282 TI - Review of ocular immune privilege in the year 2010: modifying the immune privilege of the eye. AB - The original evidence for the existence of immunologically privileged sites in the body was based on the prolonged survival of genetically disparate transplanted tissue in the anterior chamber of the eye. The failure of the immune system to elicit an immune response in this and other such sites constitutes the hallmark of the immune privilege status. The remarkably successful field of corneal transplantation in clinical practice is undoubtedly associated with corneal immune privilege. Several investigations have addressed the regulatory mechanisms governing this phenomenon, which involves a complex interplay between multiple molecular and cellular pathways. Furthermore, the use of various transgenic mouse models has facilitated the identification of critical pathways, which upon disruption can modify the immune privileged status of the eye. Understanding these pathways not only reveals the mechanisms underlying various ocular inflammatory disease conditions, but also has clinical implications for the transplantation field and for the treatment of autoimmunity. PMID- 20849283 TI - Controversies in ocular inflammation and immunology laser flare photometry. AB - Laser flare photometry (LFP) is a method used to detect flare in the anterior chamber (AC). Until now several laser flare photometers have been developed and are in use. LFP is not yet used in all major uveitis centres and, in order to understand this reluctance and know whether use of LFP is justified and should be recommended, an expert meeting was deemed necessary leading to this publication. Besides others results included the following: There is variation between users with regard to how many readings are necessary varying from 3 to 10. It appears appropriate to use at least 6-10 readings. LFP is most useful in patients with anterior uveitis. In patients with posterior and intermediate uveitis, at least 15 photons in the anterior chamber is considered the necessary threshold to be reliable to monitor evolution of inflammation. Factors influencing the measurement of LFP are cataract, corneal opacity, pupil size, intraocular lens and shallow anterior chamber but this is mostly irrelevant in pathological situation. LFP can be used to adjust the management of patients with uveitis, but not necessarily influence treatment. Exceptions may be patients with JIA and Behcet's Disease. LFP results should always be interpreted in conjunction with the usually clinical observations. There is some evidence that worsening of the flare on two consecutive visits is predictive of a relapse, especially in patients with Behcet's disease. LFP maybe also useful for predicting rejection of corneal transplant when the cornea is not thickened. PMID- 20849284 TI - Role of Spectralis HRA+OCT spectral domain optical coherence tomography in the diagnosis and management of fungal choroidal granuloma. AB - OBJECTIVE: To report the usefulness of inverted scan technique using Spectral domain Optical Coherence Tomography (OCT) in inflammatory fungal chorioretinitis. DESIGN: Case Report-Interventional. METHODS: We present a 53 year old female with sudden painful blurring of vision in left eye. Ocular examination revealed retinochoroiditis.OCT using the inverted scan technique showed a choroidal mass lesion. Polymerase chain reaction was positive for panfungal genome. She was treated with systemic fluconazole. RESULTS: Symptoms improved and the choroidal mass was diminished in size after one week of therapy. CONCLUSIONS: Inverted OCT scan technique is useful in the diagnosis and management of choroidal inflammatory mass lesion. PMID- 20849286 TI - Postnatal depression by HIV status among women in Zimbabwe. AB - BACKGROUND: Postnatal depression (PND) is a serious public health problem in resource-limited countries. Research is limited on PND affecting HIV-infected women in sub-Saharan Africa. Zimbabwe has one of the highest antenatal HIV infection rates in the world. We determined the prevalence and risk factors of PND among women attending urban primary care clinics in Zimbabwe. METHODS: Using trained peer counselors, a simple random sample of postpartum women (n = 210) attending the 6-week postnatal visit at two urban primary care clinics were screened for PND using the Shona version of the Edinburgh Postnatal Depression Scale (EPDS). All women were subsequently subjected to mental status examination using the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for major depression by two psychiatrists who had no knowledge of the EPDS test results. RESULTS: Of the 210 mothers (31 HIV positive, 148 HIV negative, 31 unknown status) enrolled during the postpartum period, 64 (33%) met DSM-IV criteria for depression. The HIV prevalence was 14.8%. Of the 31 HIV-infected mothers, 17(54%) met DSM-IV criteria for depression. Univariate analysis showed that multiparity (prevalent odds ratio [OR] 2.22, 95% confidence intervals [CI] 1.15-4.31), both parents deceased (OR 2.35, 95% CI 1.01-5.45), and having experienced a recent adverse life event (OR 8.34, CI 3.77-19.07) were significantly associated with PND. Multivariate analysis showed that PND was significantly associated with adverse life event (OR 7.04, 95% CI 3.15-15.76), being unemployed (OR 3.12, 95% CI 1.23-7.88), and multiparity (OR 2.50, 95% CI 1.00-6.24). CONCLUSIONS: Our data indicate a high burden of PND among women in Zimbabwe. It is feasible to screen for PND in primary care clinics using peer counselors. Screening for PND and access to mental health interventions should be part of routine antenatal care for all women in Zimbabwe. PMID- 20849287 TI - Weight and visual field deficits in women with idiopathic intracranial hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disorder of elevated intracranial pressure (ICP) with no identifiable cause, associated with papilledema, vision loss, and headache. Previous studies have observed a relationship between weight gain and vision loss in women with IIH. We retrospectively examined a population of women with IIH to determine an association between weight gain in the year before diagnosis and the presence of visual field deficits. METHODS: This cross-sectional study included women who enrolled in the Intracranial Hypertension Registry (IHR) between 2003 and 2005 and met study criteria for IIH. Data were obtained from mailed questionnaires and review of registrant medical charts. Prevalence ratios were used to assess the relationship between weight measures during the year before diagnosis and abnormal visual field findings at diagnosis. RESULTS: The study population consisted of 159 females aged 13-64. The mean weight of the study population 1 year before diagnosis was 92 kg (standard deviation [SD] 27 kg). Mean weight gain was 5 kg (SD 13 kg) over the year before diagnosis. Visual field findings at diagnosis were abnormal in 84% (n = 122) of study subjects. There was no association between visual field deficits and body mass index (BMI), weight gain, or percent change in ideal body weight (IBW). CONCLUSIONS: Weight change over the year before diagnosis was not associated with visual field deficits at diagnosis in this registry population of women with IIH. PMID- 20849289 TI - A novel technique to skin graft abdominal wall wounds surrounding enterocutaneous fistulas. AB - BACKGROUND: Enterocutaneous fistulas often are associated with large abdominal wall wounds. Successful skin grafting of these sites is difficult, as the bed is constantly bathed by enteric contents. A method to graft these sites successfully would provide an important advance in their treatment. METHODS: The medical records of patients undergoing skin grafting of a site around an enterocutaneous fistula were reviewed. The amount of fistula output at the time of grafting was recorded. The method of grafting, as well as the means of protecting the graft from enteric exposure, were noted. Skin grafts were evaluated for the extent of "take." RESULTS: Seven patients met the inclusion criteria. After 1-2 weeks, the graft take was 90% in three patients, 80% in two patients, and 50% in two patients. After 1 month, there was complete epithelialization in 85% of patients, and the remaining patient had most of the site epithelialized. This healing allowed placement of an ostomy appliance in all patients. The fistula output was >400 mL per day in 70% of the patients. Multiple techniques were used to divert enteric flow away from the graft, but the most common was placement of a negative pressure dressing that concomitantly secured the graft and allowed enteric diversion. CONCLUSION: The presence of a high-output enterocutaneous fistula does not preclude successful skin grafting. Such grafting can accelerate wound healing as well as improve skin and site hygiene by allowing the placement of an ostomy device. PMID- 20849288 TI - Educating Hispanic women about breast cancer prevention: evaluation of a home based promotora-led intervention. AB - OBJECTIVES: Trained community health promoters (i.e., promotoras) conducted home based group educational interventions (home health parties) to educate Hispanic women from the Lower Yakima Valley of Washington state about breast cancer and mammography screening. METHODS: Women aged 40-79 participating in the parties completed baseline and follow-up surveys 6 months postintervention (n = 70). Changes in general cancer knowledge, breast cancer screening practices, and intentions to be screened among participants from baseline to follow-up were measured using McNemar's test for marginal homogeneity to evaluate the effectiveness of the parties. RESULTS: The average age of the sample was 50.0 years (standard deviation [SD] 10.0), 84% reported less than an eighth grade education, and 54% were covered by the state's Basic Health Care Plan. Significant changes between baseline and follow-up were observed with respect to (1) believing that risk of cancer could not be reduced (41% vs. 15%, respectively, p = 0.001), (2) ever having a mammogram (83% vs. 91%, p = 0.014), (3) discussing a mammogram with a doctor (37% vs. 67%, p < 0.001), and (4) intending to have a mammogram within the next few months among women who did not report having a mammogram between baseline and follow-up (61% vs. 81%, p = 0.046). CONCLUSIONS: Participation in home-based group educational interventions delivered by promotoras may be associated with improved breast cancer screening practices among Hispanic women. PMID- 20849290 TI - A wound protector shields incision sites from bacterial invasion. AB - BACKGROUND: Superficial surgical site infection (SSI) can be caused by bacterial invasion during surgery. We investigated whether bacteria are found at the wound margin during surgery and whether a wound protector (WP; Alexis(r) Wound Retractor; Applied Medical, Rancho Santa Margarita, CA) contributes to preventing invasion of the incision margin. METHODS: We studied 272 patients who underwent gastrointestinal surgery (115 gastric, 157 colorectal, including emergency operations) between October 2005 and July 2007. The WP was used in all operations. After the intra-abdominal procedures were complete, bacterial swabs were taken from the abdominal cavity side of the WP and from the incision margin and used to prepare smears and cultures. After the swabbing, peritoneal lavage was performed using 3,000-5,000 mL of physiologic saline, and, after suture of the fascia, 500-1,000 mL of physiologic saline was used to irrigate the subcutaneous tissue. RESULTS: Nine gastric surgery patients and 15 colorectal surgery patients had positive cultures from the abdominal cavity. No patients had positive cultures from the incision margin. Of the 24 patients with positive cultures, three suffered SSIs, all of whom had undergone colorectal surgery. Of the patients who had negative cultures, SSI occurred in only one patient, who had undergone colorectal surgery. CONCLUSIONS: These results suggest that the WP protects an incision site from bacterial invasion. PMID- 20849291 TI - Coping with terminal illness: the experience of attending Specialist Palliative Day Care. AB - BACKGROUND: The provision of supportive and palliative care for people with life shortening illness has been emphasized throughout Department of Health and National Institute of Clinical Excellence (NICE) cancer guidance. However, the question of whether services are achieving this aim has been sparsely researched to date particularly in relation to Specialist Palliative Day Care (SPDC) services. The current study aims to explore the experiences of patients attending SPDC with regard to coping with a terminal illness. DESIGN AND METHOD: The views of 11 patients attending SPDC were explored using semistructured interviews. An exploratory methodology (Interpretative Phenomenological Analysis [IPA]) was used to analyze the data to allow for an in-depth investigation. RESULTS: Emerging themes suggest that SPDC provides an environment in which patients are helped to cope with stressors through a sense of self, belonging, acceptance of the reality of death, and a focus on life. CONCLUSIONS: This work provides a piece of the puzzle in the exploration of the processes underpinning attendance at SPDC from a patient's perspective. It suggests that SPDC provides an environment in which patients receive help in coping with terminal illness. In such an under researched area it provides an insight regarding SPDC attendance which can be built upon or challenged by future research. PMID- 20849292 TI - Cross-talk between protein kinase A and the MAPK-activated protein kinases RSK1 and MK5. AB - Typical mammalian mitogen-activated protein kinase (MAPK) pathways consist of a cascade of three consecutive phosphorylation events exerted by a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK), and finally a MAPK. MAPKs not only target non-protein kinase substrates, they can also phosphorylate other protein kinases designated as MAPK-activated protein kinases (MAPKAPK). The MAPKAPK family includes the ribosomal-S6-kinases (RSK1-4), the MAPK-interacting kinases (MNK1 and 2), the mitogen-and stress-activated kinases (MSK1 and 2), and the MAPKAPK (MK2, 3, and 5) subfamilies. Although several reports indicate extensive cross talk between the MAPK and protein kinase A (PKA) pathways, evidence of a direct interaction at the level of the MAPKAPK only appeared recently. The MAPKAPKs RSK1 and MK5 can bind to PKA, but the features of these interactions are distinct. This review discusses the different characteristics of regulating the activity and subcellular localization of MK5 and RSK1 by PKA and the functional implications of these interactions. PMID- 20849293 TI - Biomarkers of oxidative stress in ruminant medicine. AB - The study of oxidative stress is a relatively young field of research in ruminant medicine. Oxidative stress results from increased exposure to or production of oxidants, or from decreased dietary intake, de novo synthesis or increased turnover of antioxidants. The understanding of the role of oxidants and antioxidants in physiological and pathological conditions is rapidly increasing. Oxidative stress is an active field of research in veterinary medicine and has been implicated in numerous disease processes including sepsis, mastitis, acidosis, ketosis, enteritis, pneumonia, respiratory, and joint diseases. Compared to human medicine, only a limited number of conditions have been investigated in regard to the effects of oxidative stress in ruminants. Studies in cattle have been sporadic and mainly with mastitis, pneumonia, and retained placenta. More recently, studies have been focused on metabolic diseases that affect dairy cows during the peripartum period. Numerous and rapidly evolving methodologies for evaluating oxidative stress are available to researchers and clinicians, each with their own distinct advantages and disadvantages. Differences in models and methodologies make it difficult to make meaningful comparisons, even for studies that seem quite similar superficially. With this in mind, it is the goal of this review to discuss the advantages and shortfalls of different methodologies commonly used to measure oxidative stress and damage in ruminants. Clarity of understanding of the pathophysiology of oxidative stress in ruminants will allow the design of specific antioxidant therapies. Future research should focus on the establishment of a reference panel of biomarker of oxidative stress to be used in ruminant medicine. To help accelerate practical applications, we propose the development of an oxidative stress index as an approach in ruminant and veterinary medicine. PMID- 20849297 TI - Navigating the challenges of global reproductive health research. AB - Reproductive health research in low-resource settings poses unique and complex challenges that must be addressed to ensure that global research is conducted with strict adherence to ethical principles, offers direct benefit to the research subjects, and has the potential for adoption of positive findings to the target population. This article addresses challenges to conducting reproductive health research in low-resource settings in the following areas: (1) establishment and maintenance of global collaboration, (2) community partnerships, (3) ethical issues, including informed consent and the role of incentives, (4) staff training and development, (5) data collection and management, and (6) infrastructure and logistics. Particular attention to these challenges is important to ensure that research is culturally appropriate and methodologically sound and enhances the adoption of health-promoting behaviors. Rigorous evaluation of interventions in low-resource settings may be a cost effective and time-efficient way to identify interventions for large-scale program replication to improve women's health. PMID- 20849298 TI - Provider support for CAM: usefulness, ethics, and dilemma. PMID- 20849299 TI - Evaluating the BED capture enzyme immunoassay to estimate HIV incidence among adults in three countries in sub-Saharan Africa. AB - Serological assays for estimating HIV-1 incidence are prone to misclassification, limiting the accuracy of the incidence estimate. Adjustment factors have been developed and recommended for estimating assay-based HIV-1 incidence in cross sectional settings. We evaluated the performance of the recommended adjustment factors for estimating incidence in national HIV surveys in three countries in sub-Saharan Africa. The BED-capture enzyme immunoassay was applied to stored blood specimens from (1) pregnant women aged 15-49 years attending antenatal clinics in Cote d'Ivoire (1998-2004), (2) adults aged 15-49 years participating in a demographic health survey in Kenya (2003), and (3) adults aged 15-49 years participating in a national household serosurvey in South Africa (2005). Assay derived incidence estimates were corrected for misclassification using recommended adjustment factors and, where possible, were compared to mathematically modeled incidence in the same populations. Trends in HIV prevalence were compared to trends in assay-derived incidence to assess plausibility in the assay-derived trends. Unadjusted incidence was 3.8% [95% confidence interval (CI) 3.3-4.5] in Cote d'Ivoire, 3.5% (2.7-4.3) in Kenya, and 4.4% (CI 2.3-6.5]) in South Africa. Adjusted incidence was 2.9% (CI 2.1-3.7) in Cote d'Ivoire, 2.6% (CI 2.0-3.2) in Kenya, and 2.4% (CI 1.7-3.1) in South Africa. After adjustment, peak incidence shifted from older to younger age groups in Cote d'Ivoire and South Africa. Modeled HIV incidence was 1.0% (CI 1.02-1.08) in Kenya and 2.0% (CI 1.7-2.4) in South Africa. After applying the recommended adjustments factors, adjusted assay-derived estimates remained implausibly high in two of three populations evaluated. For more accurate measures of assay-derived population incidence, adjustment factors must be locally derived and validated. Until improved assays are available, caution should be applied in the use and interpretation of data from incidence assays. PMID- 20849300 TI - Characterization of integrase region polymorphisms in HIV type 1 CRF06_cpx viruses in treatment-naive patients in Estonia. AB - Natural polymorphisms of HIV-1, often associated with drug resistance, are widely described in protease and reverse transcriptase regions but data on their presence in the integrase region, especially in non-B subtypes, are still very limited. We aimed to characterize naturally occurring polymorphisms in the integrase region in 104 treatment-naive and 10 treatment-experienced patients infected predominantly with HIV-1 CRF06_cpx and its recombinant with subtype A1 and/or CRF03_AB viruses. No primary drug resistance mutations against integrase inhibitors were found, but resistance-associated polymorphisms such as V72I, L74I, V201I, and T206S were seen in more than 90% of viruses. Substitutions E157Q and E157K, associated with raltegravir resistance, were found in only two CRF06_cpx strains. We conclude that similar to other HIV-1 non-B subtypes, the CRF06_cpx and its recombinants with subtype A1 and CRF03_AB are rich in integrase region natural polymorphisms, which may impact the development of resistance against integrase inhibitors. PMID- 20849301 TI - Analysis of selection pressure and mutational pattern of HIV type 1 reverse transcriptase region among treated and nontreated patients. AB - Variation of the HIV-1 subtype C reverse transcriptase region (RT) resulting in response to the selective pressures of drug therapy remains poorly characterized. Here, we compared the genetic variation resulting in the presence and absence of antiretroviral drug selective pressures on HIV-1 subtype C RT among nontreated and treated patients. The nucleotide variability, nonsynonymous and synonymous ratio, and the positively selected mutations were determined by comparing the RT sequences isolated at two time points among nontreated (baseline and follow-up) and treated patients (baseline and treatment failure). Compared to the nontreated patients, the intrapatient nucleotide variability, the number of nonsynonymous and synonymous substitutions was significantly higher among the treated patients. Among the mutations positively selected, the frequency of D121Y, I135R, and Q207E increased and the frequency of mutation S48T decreased significantly during treatment failure. Further studies are essential to discover the role of these mutations during treatment in HIV-1 subtype C. PMID- 20849302 TI - Antiretroviral drug resistance mutations in antiretroviral-naive patients from Senegal. AB - To evaluate the presence of drug resistance mutations in antiretroviral-naive patients in Dakar (Senegal), cross-sectional studies were conducted since the circulation of ARVs in the country. Protease and RT genes were sequenced in 96 baseline samples from patients included in the Senegalese Initiative for Antitretroviral Access treatment between 1998 and 2001 and for 104 samples from naive, recently diagnosed patients in 2003, 2005, and 2007. Phylogenetic analysis showed a predominance of CRF02_AG [128/200 (64%)] and a high genetic diversity with 10 other variants and 25 URFs. Analysis for the presence of drug resistance mutations according to the WHO SDRM 2009 list showed a prevalence of 4.16% for nucleoside inhibitors and 1.04% for protease inhibitors at the start of the structured Senegalese ART initiative and 1.9% for protease inhibitors at the time of scaling up. The prevalence in untreated patients remains low and stable, below 5% after 10 years of ARV circulation. PMID- 20849303 TI - Genetic subtypes of HIV type 1 circulating in Slovakia. AB - Slovakia belongs to the group of European countries with a low prevalence of HIV infection. The major proportion of HIV-positive cases in Slovakia is still represented by MSM, followed by heterosexuals infected through unprotected sexual intercourse. This study was conducted to update the description of HIV subtypes circulating in Slovakia. HIV-1 partial pol gene sequences from 143 individuals were prospectively collected from 2004 to 2008 and analyzed. Phylogenetic analysis based on HIV-1 partial pol gene sequences revealed the highest prevalence of HIV-1 B subtype (93.0 %), predominantly associated with the MSM group. Ten (7.0%) individuals were infected with HIV-1 non-B subtypes. The pure subtypes were more frequent (7; 4.9%) than CRFs (3; 2.1%) and their occurrence was as follows: subtype C (3; 2, 1%), subtype A (2; 1.4%), subtype F (2; 1.4%), CRF_01AE (1; 0.7%), CRF_02AG (1; 0.7%), and CRF08_BC (1; 0.7%). Data show slightly increasing HIV-1 subtype diversity, with HIV-1 subtype B still having the highest prevalence in the Slovak-infected population. PMID- 20849304 TI - Single-incision retroperitoneoscopic adrenalectomy and single-incision laparoscopic adrenalectomy. AB - OBJECTIVE: Single-incision surgery is by now practicable in many fields of surgery, including surgery of the adrenal gland. We report on first experience with laparoscopic transperitoneal and retroperitoneoscopic single-incision adrenalectomy. PATIENTS AND METHODS: Between September 2009 and February 2010, eight patients underwent single-incision adrenalectomy. Four patients received single-incision retroperitoneoscopic adrenalectomy, and four patients transperitoneal single-incision laparoscopic adrenalectomy. Technical feasibility and perioperative data are presented. RESULTS: All patients had benign adrenal tumors (Conn's adenoma, n = 7; pheochromocytoma, n = 1). Tumor size ranged between 1.2 and 2.4 cm. Mean operation time was 76 minutes for single-incision retroperitoneoscopic adrenalectomy and 82 minutes for single-incision laparoscopic adrenalectomy. Blood loss was irrelevant in both groups. CONCLUSIONS: Single-incision adrenalectomy is safe and feasible in appropriate operation time, both by the retroperitoneoscopic technique and by the laparoscopic technique. It is also associated with good cosmetic outcome. PMID- 20849305 TI - Biliary peritonitis after percutaneous nephrolithotomy: case studies and management concerns. AB - PURPOSE: To evaluate cases of gallbladder injury, a rare and potentially serious complication, in the setting of percutaneous nephrolithotomy. PATIENTS AND METHODS: We report two cases of gallbladder injury after percutaneous nephrolithotomy and review the literature on this rare complication. RESULTS: Both cases of gallbladder injury at our institution along with the four other case reports in the literature all necessitated cholecystectomy. Medial right sided collecting system access during percutaneous nephrolithotomy may increase the risk for biliary injury. CONCLUSIONS: Both recognized and unrecognized gallbladder injury may lead to biliary peritonitis necessitating subsequent cholecystectomy. PMID- 20849306 TI - Retrograde ureteroscopic treatment for upper ureteral stones: a 5-year retrospective study. AB - PURPOSE: To review our 5-year experience with retrograde ureteroscopic treatment for patients with upper ureteral stones and to compare the outcome, safety, and efficiency of pneumatic and holmium laser lithotripsy in managing upper ureteral stones. PATIENTS AND METHODS: We retrospectively analyzed the hospital records of 372 patients who underwent 384 retrograde ureteroscopic procedures for upper ureteral stones at our center from January 2003 to December 2007. Patient and stone characteristics, treatment variables. and clinical outcomes were assessed. Factors such as failure of the procedure, stone clearance, intraoperative and postoperative morbidity, procedure duration, and hospital stay were analyzed and compared between pneumatic (group 1) and laser lithotripsy (group 2). RESULTS: Overall, the stone-free rate was 90.4%, the mean operative duration was 41.2 +/- 10.7 minutes, the mean postoperative hospital stay was 2.7 +/- 0.9 days, and the rates of intraoperative and postoperative complications were 14.6% and 3.9%, respectively, for groups 1 and 2. In comparing group 1 and group 2, the significantly higher number of intraoperative complications coincide with a significantly lower stone-free rate. Nevertheless, the incidence of intraoperative and postoperative complications between the two groups was not statistically significant except in the case of stone upward migration. The mean operative time of group 2 was 43.3 +/- 11.1 minutes, which was significantly longer than that for group 1, which was 38.7 +/- 9.1 minutes (P < 0.05). CONCLUSION: Retrograde ureteroscopy is a safe and effective method for managing upper ureteral stones. A high postoperative stone-free rate is associated with the refined use of a holmium laser lithotriptor to ensure thoroughness while avoiding migration of the stones into the renal pelvis. Although laser lithotripsy has a longer operative time, it remains the more appropriate choice for managing upper ureteral stones. PMID- 20849307 TI - Efficacy of early use of snake retractor in retroperitoneoscopic nephrectomy or nephroureterectomy. AB - BACKGROUND AND PURPOSE: A snake retractor is generally used to create a better surgical field and space, but when to start using it is still controversial. In this study, we used a snake retractor starting in an early stage of the procedure to safely perform surgery and compared the results with a control group in which the procedure depended on operator discretion. PATIENTS AND METHODS: Twelve patients were enrolled in this study and compared with a control group (n = 12) in which no special technique was used. We used four ports in both right- and left sided cases and used a snake retractor when removing the flank pad to create a better surgical space and field. We compared two groups in operative time, intraoperative blood loss, and body mass index (BMI). RESULTS: Three surgeons were enrolled. In the intervention group (early use of snake retractor), operative time was 107 to 300 minutes (median 162 min), and intraoperative blood loss was 0 to 462 g (69.5 g). In the control group, operative time was 185 to 485 minutes (258 min) and intraoperative blood loss was 0 to 302 g (40 g). Operative time was significantly shorter in the intervention group than the control group (P = 0.0034). There was no significant correlation with intraoperative blood loss volume and BMI in these two groups. We did not have any patients with metastasis or recurrence of cancer in either group in post-operative follow-up. Only the control group included a case with a slight duodenum injury. CONCLUSIONS: Early use of the snake retractor in retroperitoneoscopic nephrectomy or nephroureterectomy may produce a significantly safer operative procedure. PMID- 20849308 TI - Renal dosimetry in peptide radionuclide receptor therapy. AB - Abstract This study evaluates the predictive value of absorbed dose, biological effective dose, and time-dose-fractionation factors for use in patients receiving peptide radionuclide receptor therapy treatments by reanalyzing data in two different patient populations that have been reported in the literature. The analysis suggested that the alternative time-dose-fractionation model is as good and, in some cases, may be better in predicting kidney toxicity in these two patient populations than biological effective dose. This study suggests that future investigations proceed with more critical evaluation of different dosimetric quantities that may be more clinically useful in providing optimal patient treatment prescriptions for peptide radionuclide receptor therapy, rather than rely solely on a single methodology derived from experience with external beam therapy. PMID- 20849309 TI - Preparation of 177Lu-labeled oxine in lipiodol as a possible agent for therapy of hepatocellular carcinoma: a preliminary animal study. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent forms of cancer with high morbidity. (131)I-lipiodol is used clinically and has been found to be effective for the treatment of HCC. However, this preparation has its limitations, including compromised yield and stability of exchange labeling and unnecessary dose burden from gamma emissions. In the present study, (177)Lu-oxine in lipiodol was considered as a possible alternative for radioiodinated lipiodol. Oxine or 8-hydroxyquinoline was labeled with (177)Lu obtained by neutron irradiation of natural lutetium. Under optimized conditions, the radiolabeled complex was obtained with yields >98% and adequate in vitro stability. (177)Lu oxine dispersed in lipiodol showed appreciable uptake into rat liver cells (normal and HCC-induced) in vitro. (177)Lu-oxine-lipiodol showed initial localization in the liver, but subsequent leakage of radioactivity with deposition in the skeletal tissue was seen. The studies suggest that (177)Lu oxine dispersed in lipiodol might not be suitable for treatment of HCC. PMID- 20849310 TI - Durable complete response of refractory, progressing metastatic melanoma after treatment with a patient-specific vaccine. AB - A patient with metastatic melanoma who experienced a durable complete response after treatment with a patient-specific vaccine has been described in this article. This 59-year-old woman presented with cervical spine metastases and, within the year, had experienced local disease progression and, despite various therapies, metastases to the axilla, rectum, gall bladder, and multiple soft tissue sites. She had previously received radiation therapy, combination chemotherapy, interleukin-2 plus interferon biotherapy, and gamma knife radiosurgery, and undergone multiple surgical resections. At the time vaccine therapy was initiated, she had multiple, new, measurable, soft-tissue metastases that were increasing in size. She was treated with a vaccine consisting of autologous dendritic cells incubated with irradiated tumor cells from an autologous tumor cell line and suspended in granulocyte-macrophage colony stimulating factor (GM-CSF), with subcutaneous injections once a week for 3 weeks and monthly for 5 months. There was evidence of disease regression by the completion of therapy. A few months later a complete response was documented by radiologic scans, and subsequently reconfirmed at 6-month intervals. She remains in complete remission >2.5 years after starting the vaccine, and >2 years after completing the vaccine, and survives >4 years after her initial presentation with bone, bowel, and lymph node metastases. This is the first time she has been in a complete remission since her initial diagnosis. Patient-specific vaccines can sometimes induce durable complete regression of progressing soft-tissue melanoma metastases. PMID- 20849311 TI - Pretherapy prediction of nephrotoxicity after peptide radionuclide receptor therapy (PRRT). PMID- 20849312 TI - Multidisciplinary care in oncology: Are we united? PMID- 20849313 TI - GP-delivered secondary prevention cardiovascular disease programme; early predictors of likelihood of patient non-adherence. AB - INTRODUCTION: The aim of this study was to determine how routinely recorded data could predict early the likelihood of patient non-adherence to a primary care delivered secondary prevention programme for established coronary heart disease (CHD), with patients with CHD (10,851) invited to attend four times per year. METHOD: Non-adherence was defined as attending no more than three GP visits ever. The study sample was selected to allow a possible two-year recorded follow-up period in which patients could take up invitations. Administrative recordings of visit dates and intervals between visits, baseline results of key parameters and early changes were examined using logistic regression to determine independent predictors of non-adherence. RESULT: Longer interval between early visits, no family history of CHD, smoking and being outside target for exercise at baseline were independently associated with non-adherence. CONCLUSION: Early identification by GPs of those who fail to attend on time or who defer appointments, in addition to persistence of lifestyle factors unchanged by a prior serious cardiac event should serve as a warning sign that targeted interventions to maintain adherence in primary care-delivered secondary prevention programmes are necessary. PMID- 20849314 TI - Spirometry for detection of undiagnosed chronic obstructive pulmonary disease in primary care. AB - OBJECTIVE: The aim of this study was to assess the utility of family physicians' office spirometry, to detect previously undiagnosed chronic obstructive pulmonary disease (COPD) in individuals who smoke. Furthermore, agreement between doctors with more or less experience in performing spirometry was assessed. METHODS: Cross-sectional study. Smokers aged 40-69 years who attended a family practice centre were invited to participate. Variables considered were tobacco pack-years, time of tobacco use, smoking cessation, COPD symptoms, Medical Research Council Dyspnoea Scale values, pre- and post-bronchodilator spirometry data, and acceptability of spirometry curves. RESULTS: 212 subjects underwent spirometry, and 179 yielded acceptable spirometry curves. Of these, 173 subjects underwent reversibility testing, of whom 39 (22.5%, 95% CI: 16.2-29.1%) were diagnosed as COPD. Of these, 48.7% were classified as COPD Stage I and 41.0% as Stage II following GOLD criteria. Age, gender, pack-years and cough were related to airflow obstruction levels. Symptom number was not related to presence of airflow obstruction. More than 80% of spirometry curves were acceptable. Agreement on curve acceptability between junior doctors and a family physician trainer was very good, but moderate between junior doctors and a pulmonologist. CONCLUSIONS: Forced spirometry data from smokers attending general practice doctors can be used to identify a significant number of previously undiagnosed COPD cases. PMID- 20849315 TI - Fracture risk of patients suffering from dizziness: a retrospective cohort study. AB - BACKGROUND: Dizziness is known to be associated with the risk of falls. However, there is not much evidence for the increase of fractures caused by dizziness. OBJECTIVES: The aim of the study was to investigate whether the symptom of dizziness is associated with an increased fracture rate. METHODS: We performed a retrospective cohort study using a population-based administrative database in the Province of Quebec, Canada. A cohort of n = 2442 patients with at least one diagnosis of dizziness was compared to n = 16,125 unexposed patients. The main outcome measure was any kind of first fracture after the index date of dizziness. RESULTS: Analysis revealed a moderate effect of dizziness as an independent contributing factor to fractures (adjusted hazard ratio (HR) 1.26, 95% confidence interval 1.03 to 1.55). A fracture in the year before the index date was highly associated with the incidence of a subsequent fracture (HR 2.69, 2.09 to 3.47), and fractures were less frequent in women (HR 0.70, 0.60-0.82). Analysis further revealed that dizziness (HR 1.31, 1.05-1.64) and prior fractures (HR 2.41, 1.81 3.22) were associated with non-osteoporotic fractures, which were also less frequent in women (HR 0.59, 0.50-0.71). The incidence of fractures in sites typical for osteoporosis correlated with a precedent fracture (HR 3.91, 2.31 6.63), but not with dizziness (HR 1.10, 0.69-1.75). CONCLUSION: Besides the 'typical' elderly female patient being at risk of osteoporotic fractures, male patients suffering from dizziness should be carefully evaluated, and prevention strategies should be considered to minimise their risk of suffering non osteoporotic fractures. PMID- 20849316 TI - Coronary calcification in patients with marker-positive acute coronary syndrome. AB - BACKGROUND: The value of assessing coronary artery calcium (CAC) with regard to characterizing unstable coronary artery disease remains controversial. PURPOSE: To evaluate the amount of CAC in patients with an acute marker-positive coronary syndrome in segments containing the culprit lesion compared with the remote coronary segments. MATERIAL AND METHODS: Thirty-two patients with a marker positive acute coronary syndrome were examined using electron-beam computed tomography (EBCT), selective coronary angiography and, in some, intravascular ultrasound. The coronary anatomy was analyzed according to the segmental classification proposed by the American Heart Association (AHA). RESULTS: The total EBCT coronary artery calcium score (CAC, Agatston method) was 251+/-371 (range 0-1629). In 81% of the patients, a greater CAC score was observed than expected on the basis of age and gender. In 30 patients, significant stenoses were detected. The CAC score of the culprit vessel was 108+/-163 vs 78+/-134 in the non-culprit vessels and did not differ significantly (P=0.4). The mean CAC score of the coronary segment (AHA classification) containing the culprit lesion was 51+/-82 vs 29+/-45 in the other coronary artery segments (P=0.14). Of the two patients with no CAC detected by EBCT, one had no coronary atherosclerosis (confirmed by intravascular ultrasound) and one had one vessel coronary artery disease. CONCLUSION: Coronary calcium related to the culprit lesion in patients with a marker-positive acute coronary syndrome showed a tendency for an increased amount but was not statistically different from the amount of coronary calcium in remote vessel segments. PMID- 20849317 TI - Image quality and attenuation values of multidetector CT coronary angiography using high iodine-concentration contrast material: a comparison of the use of iopromide 370 and iomeprol 400. AB - BACKGROUND: Effects of high iodine-concentration contrast material on the image quality of coronary CT angiography (CCTA) have not been well evaluated. PURPOSE: To compare the image quality and attenuation values of CCTA between patients administered iopromide 370 and iomeprol 400 with the use of 64-slice multidetector CT. MATERIAL AND METHODS: Patients were prospectively enrolled and were randomized into two groups (group A, 151 patients received iopromide 370, iodine flux = 1.48 g I/s; group B, 146 patients received iomeprol 400, iodine flux = 1.60 g I/s). CT attenuation was measured in the coronary arteries and great arteries and measurements were standardized based on an iodine flux of 1.50 g I/s. The image quality of 15 coronary artery segments was graded by two radiologists in consensus with the use of a four-point scale (1 = excellent to 4 = poor enhancement). Non-parametric statistical approaches were used to compare the two groups. RESULTS: The median attenuation values in the coronary arteries were 454 HU and 464 HU for iopromide 370 and iomeprol 400, respectively, and they did not differ (P = 0.26). When standardizing for an iodine flux, significantly higher attenuation values were found for iopromide 370 (median = 460 HU, range = 216-791 HU) compared with iomeprol 400 (median = 435 HU, range = 195-758 HU) (P = 0.006). The median image quality score of coronary arterial segments was 1 (range 1-2) for both groups (P = 0.84). CONCLUSION: The attenuation values in the coronary arteries after injection of the same amount of two high iodine concentration contrast materials at the same flow rate with different iodine fluxes are similar with no difference in image quality. With standardization for an iodine flux, the attenuation is significantly higher when using iopromide 370. PMID- 20849318 TI - Early rebleeding after coiling of ruptured intracranial aneurysms. AB - BACKGROUND: Early rebleeding after coiling of a ruptured intracranial aneurysm (IA) may cause disability or death. The incidence and predictors of early rebleeding have previously been sparsely investigated. PURPOSE: To assess the incidence and risk factors of early rebleeding after coiling of a ruptured IA and to analyze the outcome of the patients suffering early rehemorrhage. MATERIAL AND METHODS: The data of 194 consecutive acutely (within 3 days) coiled patients with saccular ruptured IAs were analyzed. Age, gender, hypertension, aneurysm multiplicity, Hunt et Hess (HH) grade, intracerebral hematoma (ICH), intraventricular hematoma (IVH), external ventricular drainage (EVD), aneurysm location and size, and the grade of the initial aneurysm occlusion were tested to find the risk factors for early rebleeding. The outcome of the patients suffering rehemorrhage was verified. RESULTS: Early rebleeding after coiling occurred in 7 patients out of 194 (3.6%). The presence of an ICH at admission and HH grade 3-5 before coiling were significant risk factors for rebleeding. An early rehemorrhage appeared as an enlargement of the initial ICH in all of these patients. Six of seven patients had good outcome (Glasgow Outcome Scale, GOS, 3 5). Logistic regression analysis did not find any other statistically significant risk factors. CONCLUSION: The incidence of early rebleeding after acutely coiled ruptured IA was 3.6%. Risk factors for post-procedural rehemorrhage were the presence of ICH on the initial CT and HH grade 3-5 before coiling. Early rebleeding appeared exclusively as an enlargement of the initial ICH and not an increased amount of blood in the subarachnoid space. PMID- 20849319 TI - GE-145, a new low-osmolar dimeric radiographic contrast medium. AB - BACKGROUND: Contrast-induced nephrotoxicity is a significant risk when using radiographic contrast media clinically, especially in high risk patients. Consequently, there is a need for a new contrast agent with improved clinical safety with regards to nephrotoxicity. PURPOSE: To evaluate the physicochemical properties as well as the preclinical safety and biodistribution parameters of the newly developed radiographic contrast medium GE-145. MATERIAL AND METHODS: Standard methods for radiographic contrast media were used for evaluation of physicochemical properties. The acute toxicity in rats was studied at 8, 10, and 12.5 gI/kg, the clinical chemistry parameters were determined, and histology of the kidneys was performed. Biodistribution was studied in rats using 123I-labeled GE-145. RESULTS: GE-145 is more hydrophilic than iodixanol and has a considerably lower osmolality. The viscosity is similar to that of iodixanol and the protein binding is low. The acute toxicity is similar to that of iodixanol and the biodistribution is similar to that of other radiographic contrast media, showing mainly renal excretion. Kidney histology showed a moderate reversible vacuolization, similar to that of iodixanol. CONCLUSION: GE-145 exhibits similar preclinical properties to other dimeric radiographic contrast media. In addition, the low osmolality enables an iso-osmolar formulation containing a significantly higher concentration of electrolytes than Visipaque. PMID- 20849320 TI - Clinico-radio-pathologic features of a solitary solid renal mass at MDCT examination. AB - BACKGROUND: incidental detection of solid renal masses has been increasing since the multidetector computed tomography (MDCT) scanner was introduced. PURPOSE: to evaluate the clinico-radio-pathologic features of a solitary solid renal mass at MDCT examination. MATERIAL AND METHODS: a total of 466 non-fatty solid renal masses in 466 patients undergoing nephrectomy were evaluated by MDCT examination. MDCT was performed before and after intravenous injection of contrast material. We obtained the incidences of benign tumors versus malignant tumors, renal cell carcinoma (RCC) versus non-RCC, and asymptomatic RCCs versus symptomatic RCCs. MDCT accuracy for detection of RCC was obtained with a threshold of more than 20 HU tumor attenuation difference between unenhanced and contrast-enhanced CT images. Nuclear grade was also compared between small RCCs (<=4 cm) and large RCCs (>4 cm). RESULTS: of 466 tumors, 443 (95%) were malignant and 23 (5%) were benign. Of 443 malignant tumors, 437 (99%) were RCC and 6 (1%) were non-RCC. Of 437 RCCs, 324 (74%) were asymptomatic and 113 (26%) were symptomatic. Asymptomatic RCCs (n=183, 56%) were more frequently pT1a than symptomatic RCCs (n=28, 25%) (P<0.05). MDCT accuracy for detection of RCC was 94% (437/466). Of 220 RCCs <=4 cm, low grade RCC (53%) was more common than high grade RCC (47%). CONCLUSION: most solitary solid renal masses are early stage RCCs and can be diagnosed preoperatively at MDCT examination. PMID- 20849321 TI - Cerebral diffusion and perfusion deficits in North Sea divers. AB - BACKGROUND: Diving is associated with a risk of cerebral decompression illness, and the prevalence of neurological symptoms is higher in divers compared with control groups. Microvascular dysfunction due to gas microembolism and exposure to hyperoxia are possible mechanisms, which may result in cerebral diffusion and perfusion deficits. PURPOSE: To investigate if possible functional derangements of the microvasculature and microstructure would be more prevalent among symptomatic divers. MATERIAL AND METHODS: Magnetic resonance imaging (MRI) was performed in 91 former divers and 45 controls. Individual parametric images of apparent diffusion coefficient (ADC), cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were generated on the basis of diffusion- and perfusion-weighted imaging. To identify regions with statistically significant differences between groups (P < 0.05, corrected for false discovery rate), voxel-wise ANCOVA analysis was performed for each of the four parametric images. RESULTS: Significant regional group differences were found in all four parametric comparisons. Gross regional ADC differences were seen throughout the brain, including large frontal and temporal white-matter regions, the hippocampus, and parts of the cerebellum. Differences in the perfusion maps were localized in fewer and smaller clusters, including parts of the cerebellum, the putamen, and the anterior watershed regions. CONCLUSION: Regional functional abnormalities as measured by diffusion- and perfusion-weighted imaging were identified in the divers, and there was a partial co-localization of the regions identified in the perfusion and the diffusion images. The findings may explain some of the long-term clinical symptoms reported among professional divers. PMID- 20849322 TI - The internet for self-diagnosis and prognostication in ALS. AB - Persons with ALS, and those close to them, may use the internet to explore symptoms prior to formal diagnosis, and as a source of information about prognosis and treatment thereafter. We used an internet search engine to rank the sensitivity of a variety of symptom search terms a patient might use for the diagnosis of ALS/MND. We also studied search engine responses to questions about life expectancy and possible 'cure'. An internet search engine in relation to ALS currently lacks sensitivity, and results varied greatly with only minor differences in the search terms used. The prognostic information did not reflect the inherent heterogeneity. Results in relation to 'cure' were misleading and may promulgate false hopes. There is a need to guide those with ALS (and particularly their children) to sources of reliable web-based information in addition to open discussion. PMID- 20849323 TI - How common are behavioural changes in amyotrophic lateral sclerosis? AB - Our objectives were to assess the frequency of behavioural changes in patients with amyotrophic lateral sclerosis (ALS) and to compare the clinical profile of ALS patients with those with behavioural variant frontotemporal dementia (bvFTD). Ninety-two patients with ALS and their carers participated in a postal survey. ALS patients completed self-report measures of motor function and mood. Eighty one carers of ALS patients and 25 carers of bvFTD patients completed the revised version of the Cambridge Behavioural Inventory (CBI-R). Results showed that reduced motivation was reported in more than 80% of the ALS cases, with almost 41% of them having moderate-severe apathy. Depression was present in 30% of ALS patients and did not contribute significantly to the presence of behavioural symptoms. Bulbar and limb onset ALS patients did not differ. Abnormal behaviour and stereotypical and motor behaviours were present to a moderate-severe degree in around 20%, and 11% reached the criteria for FTD. The rate of behavioural symptoms was significantly higher in the bvFTD group than ALS in all behavioural domains (p <0.001). In conclusion, apathy was the most prominent feature in ALS patients. A substantial proportion of ALS patients manifested behavioural changes of the type seen in FTD, with 11% fulfilling the criteria for FTD. PMID- 20849324 TI - Chronic administration of the HNO donor Angeli's salt does not lead to tolerance, cross-tolerance, or endothelial dysfunction: comparison with GTN and DEA/NO. AB - Nitroxyl (HNO) displays distinct pharmacology to its redox congener nitric oxide (NO(*)) with therapeutic potential in the treatment of heart failure. It remains unknown if HNO donors are resistant to tolerance development following chronic in vivo administration. Wistar-Kyoto rats received a 3-day subcutaneous infusion of one of the NO(*) donors, glyceryl trinitrate (GTN) or diethylamine/NONOate (DEA/NO), or the HNO donor Angeli's salt (AS). GTN infusion (10 MUg/kg/min) resulted in significantly blunted depressor responses to intravenous bolus doses of GTN, demonstrating tolerance development. By contrast, infusion with AS (20 MUg/kg/min) or DEA/NO (2 MUg/kg/min) did not alter their subsequent depressor responses. Similarly, ex vivo vasorelaxation responses in isolated aortae revealed that GTN infusion elicited a significant 6-fold decrease in the sensitivity to GTN and reduction in the maximum response to acetylcholine (ACh). Chronic infusion of AS or DEA/NO had no effect on subsequent vasorelaxation responses to themselves or to ACh. No functional cross-tolerance between nitrovasodilators was evident, either in vivo or ex vivo, although an impaired ability of a nitrovasodilator to increase tissue cGMP content was not necessarily indicative of a reduced functional response. In conclusion, HNO donors may represent novel therapies for cardiovascular disease with therapeutic potential over clinically used organic nitrates. PMID- 20849325 TI - Sperm donation in the United Kingdom in 2010. AB - The use of intracytoplasmic sperm injection (ICSI) has resolved many issues in male infertility management and abolished the need in many instances for donor insemination (DI). Despite this, clinics in the UK have, for some years, struggled to maintain the necessary infrastructure to recruit adequate numbers of sperm donors to provide for the national need. A significant proportion of treatment is for single women and same sex couples. Many patients now seek treatment abroad either to avoid waiting lists, or access care to which they are excluded in the NHS. In addition, many patients now have treatment using sperm imported from abroad. A number of solutions to the UK shortage might be considered, e.g. re-evaluation of the limitation of family numbers, paying donors, gamete sharing and exchange schemes or changing sperm quality thresholds for the acceptance of donors. The development of a centrally funded national service framework is being piloted at the present time. PMID- 20849327 TI - The clinical toxicology of metamfetamine. AB - INTRODUCTION: Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drug's toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication. AIM: The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management. METHODS: A summary of the literature on metamfetamine was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis. Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic monoamines results in an increased activation of central and peripheral alpha+/-- and beta-adrenergic postsynaptic receptors. This can cause detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from ~5 to 30 h. Clinical features. The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for sympathomimetic effects and their associated complications. CONCLUSION: Metamfetamine may cause severe sympathomimetic effects in the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery. PMID- 20849328 TI - Cocaine, metamfetamine, and MDMA abuse: the role and clinical importance of neuroadaptation. AB - INTRODUCTION: This article reviews the role and clinical importance of specific neuroadaptations that may occur following use of cocaine, metamfetamine, and 3,4,methylenedioxymetamfetamine (MDMA). METHODS: A literature search was performed using OVID MEDLINE and PubMed for all years to the present date, which identified 250 papers of which 154 were considered relevant. MECHANISMS OF ACTION OF COCAINE AND METAMFETAMINE: Cocaine and metamfetamine increase central nervous system synaptic dopamine primarily by increasing the release of dopamine into the synapse and binding to the dopamine reuptake transporter, which prevents the reuptake of dopamine from the synapse back into the nerve cell. Synaptic dopamine then stimulates post synaptic receptors. The continued release of dopamine and prevention of reuptake results in a supraphysiological concentration of dopamine, which causes euphoria or a "high." The greater the concentration of dopamine, the greater the high. Continued supraphysiological concentrations of dopamine and postsynaptic receptor stimulation may cause physiological and anatomical changes (neuroadaptations) in the central nervous system (CNS) synapse that attempt to maintain homeostasis. An example of a dopaminergic neuroadaptation is the decrease in number of post synaptic D2 receptors that occurs when synaptic dopamine concentrations remain supraphysiological. This neuroadaptation attempts to maintain homeostasis, that is, the decreased number of D2 receptors provides fewer receptors to be constantly stimulated by increased synaptic dopamine. Although metamfetamine also increases synaptic dopamine similarly to cocaine, metamfetamine also increases cytoplasmic dopamine, which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. MECHANISMS OF ACTION OF MDMA: MDMA increases concentrations of synaptic serotonin by increasing the release of serotonin and binding to the serotonin reuptake transporter, preventing the reuptake of serotonin from the synapse back into the nerve cell. An example of a serotonergic neuroadaptation is a decrease in the number of serotonin presynaptic autoreceptors (one of the regulators of synaptic serotonin concentration) to maintain homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation, but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Pharmacogenomics may play a role in the varied response of the individual to MDMA. CONCLUSIONS: Neuroadaptations may be transient or permanent. The duration of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age at the initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations that occur will allow clinicians to better understand the interindividual variability in response to drugs of abuse. PMID- 20849329 TI - Predicting acute complicated glyphosate intoxication in the emergency department. AB - BACKGROUND: Glyphosate herbicide intoxication results in a range of mortality and morbidity, depending on patients' factors. Predicting which patient will need intensive medical treatment might help reduce mortality by providing prompt treatment, as well as triage those patients not likely to develop complications. Thus, we sought to identify independent factors that could predict which patient will develop subsequent medical complications. METHODS: Seventy-six patients presenting with acute glyphosate herbicide ingestion at Chonnam National University Hospital were enrolled in this retrospective study. To identify the predictive factors for complications, objective variables easily assessed at presentation including previously reported predictive factors for mortality, such as age, vital signs, X-ray abnormalities, and laboratory findings, were analyzed by univariate and multivariate stepwise logistic regression analyses. RESULTS: Of the 76 patients, 32 (42.1%) had medical complications and 2 (2.6%) died. Metabolic acidosis was the most common medical complication. Whereas metabolic acidosis, respiratory failure, hypotension, acute kidney injury, hyperkalemia, and seizures developed within 24 h, acute pancreatitis occurred a few days after the ingestion. The univariate analysis showed that an advanced age, amount ingested >100 mL, X-ray abnormalities, elevated amylase, alanine aminotransferase (ALT), and blood nitrogen urea were significant factors. However, the multivariate analysis showed that advanced age, elevated ALT, and X-ray abnormalities were independent factors associated with serious complications and the need for intensive medical treatment. CONCLUSIONS: The results of this study showed that age > 50 years, X-ray abnormalities, and ALT > 40 U/L were significant predictive factors for complications in patients with glyphosate surfactant herbicide poisoning; patients with these findings might require admission to the intensive care unit. PMID- 20849330 TI - Dimethylformamide metabolism following self-harm using a veterinary euthanasia product. AB - BACKGROUND: A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (DMF; T-61(r) or Tanax(r)) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent DMF. The protective role of N-acetylcysteine (NAC) administration remains debatable. MATERIAL AND METHODS: Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 h in the second). Urine was collected for the serial determination of DMF, N methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC). RESULTS: Both patients developed only mild signs of liver injury. The metabolite of DMF, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of DMF and DMF metabolites were slightly slower than those reported in exposed workers. CONCLUSIONS: While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion. Further investigations of NMF and AMCC excretion, with and without NAC, would be indicated. PMID- 20849331 TI - Acute illnesses associated with exposure to fipronil--surveillance data from 11 states in the United States, 2001-2007. AB - INTRODUCTION: Fipronil is a broad-spectrum phenylpyrazole insecticide widely used to control residential pests and is also commonly used for flea and tick treatment on pets. It is a relatively new insecticide and few human toxicity data exist on fipronil. OBJECTIVE: This paper describes the magnitude and characteristics of acute illnesses associated with fipronil exposure. METHODS: Illness cases associated with exposure to fipronil-containing products from 2001 to 2007 were identified from the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides Program and the California Department of Pesticide Regulation. RESULTS: A total of 103 cases were identified in 11 states. Annual case counts increased from 5 in 2001 to 30 in 2007. Of the cases, 55% were female, the median age was 37 years, and 11% were <15 years old. The majority (76%) had exposure in a private residence, 37% involved the use of pet-care products, and 26% had work-related exposures. Most cases (89%) had mild, temporary health effects. Neurological symptoms (50%) such as headache, dizziness, and paresthesia were the most common, followed by ocular (44%), gastrointestinal (28%), respiratory (27%), and dermal (21%) symptoms/signs. Exposures usually occurred from inadvertent spray/splash/spill of products or inadequate ventilation of the treated area before re-entry. CONCLUSIONS: Our findings indicate that exposure to fipronil can pose a risk for mild, temporary health effects in various body systems. Precautionary actions should be reinforced to prevent fipronil exposure to product users. PMID- 20849332 TI - Lead poisoning from use of bronze drinking vessels during the late Chinese Shang dynasty: an in vitro experiment. AB - INTRODUCTION: Bronze drinking vessels famous for their intricate carvings and used by the aristocracy in the Chinese Shang dynasty (1555-1145 BCE) are known to have been fabricated with alloys containing soft metallic lead. The contribution of lead leaching from such vessels into the fermented grain wines drunk by the Chinese nobility in ancient times has not been previously estimated. METHODS: Three bronze vessels containing 8% lead by weight were fabricated to resemble the late Shang bronze goblets. Shaoxing drinking rice wine was purchased locally and placed in the vessels, using a white grape wine and water as comparisons. Sampling was performed at baseline, 2 min, and then at days 1, 2, 4, and 7. Lead concentrations in the liquid matrix were measured using atomic absorption spectroscopy. RESULTS: Significant amounts of lead leached into the liquid within one day: 13,900 MUg/L in water, 45,900 MUg/L in rice wine, and 116,000 MUg/L in white wine. Lead continued to leach into both the grape and rice wines with the passage of time. DISCUSSION: Significant lead contamination of Shaoxing rice wine was detected when it was left in bronze goblets fabricated to resemble the Shang dynasty vessels. If a liter of contaminated wine was drunk daily, the daily intake of lead could have been as high as 85 mg. Such a high degree of contamination could cause chronic lead poisoning, affecting the health of the Shang nobility who used bronze beverage containers, before lead was excluded from the manufacture of bronze. PMID- 20849333 TI - Postmortem changes in carbon monoxide poisoning. PMID- 20849334 TI - Cutaneous loxoscelism caused by Loxosceles anomala. AB - A previously healthy 35-year-old female was bitten on the anterior right thigh by a brown spider while dressing her trousers; the spider was stored and later identified as an adult female Loxosceles anomala. Clinical evolution involved a relatively painless bite with mild itching, followed by local, indurated swelling and a transient, generalized erythrodermic rash at 24 h post-bite. The local discomfort was progressive, and involved changes in the lesion pattern, with pain of increasing intensity. The patient was admitted 60 h post-bite, showing an irregular blue plaque surrounded by an erythematous halo lesion, located over an area of indurated swelling. Considering the presumptive diagnosis of cutaneous loxoscelism, she was treated with five vials of anti-arachnidic antivenom i.v. without adverse effects. There was progressive improvement, with no dermonecrosis or hemolysis; complete lesion healing was observed by Day 55. The clinical features and outcome were compatible with cutaneous loxoscelism and similar to those reported for other Loxosceles species. PMID- 20849335 TI - Methemoglobinemia induced by indoxacarb intoxication. AB - Indoxacarb is a recently introduced insecticide whose mode of action is blockage of voltage-gated sodium channels. There are limited data on human ingestion. A case of 68-year-old healthy male who presented with general cyanosis because of methemoglobinemia following the ingestion of indoxacarb is presented. After receiving a methylene blue injection, the patient recovered without sequelae. PMID- 20849336 TI - Response to "A multicenter comparison of the safety of oral versus intravenous acetylcysteine for treatment of acetaminophen overdose". PMID- 20849338 TI - Occupational toxicology of asbestos-related malignancies. AB - INTRODUCTION: Asbestos is banned in most Western countries but related malignancies are still of clinical concern because of their long latencies. This review identifies and addresses some controversial occupational and clinical aspects of asbestos-related malignancies. METHODS: Papers published in English from 1980 to 2009 were retrieved from PubMed. A total of 307 original articles were identified and 159 were included. ASSESSMENT OF EXPOSURE: The retrospective assessment of exposure is usually performed by using questionnaires and job exposure matrices and by careful collection of medical history. In this way crucial information about manufacturing processes and specific jobs can be obtained. In addition, fibers and asbestos bodies are counted in lung tissue, broncho-alveolar lavage, and sputum, but different techniques and interlaboratory variability hamper the interpretation of reported measurements. SCREENING FOR MALIGNANCIES: The effectiveness of low-dose chest CT screening in exposed workers is debatable. Several biomarkers have also been considered to screen individuals at risk for lung cancer and mesothelioma but reliable signatures are still missing. ATTRIBUTION OF LUNG CANCER: Exposures correlating with lung cancer are high and in the same range where asbestosis occurs. However, the unresolved question is whether the presence of fibrosis is a requirement for the attribution of lung cancer to asbestos. The etiology of lung cancer is difficult to define in cases of low-level asbestos exposure and concurrent smoking habits. MESOTHELIOMA: The diagnosis of malignant mesothelioma may also be difficult, because of procedures in sampling, fixation, and processing, and uses of immunohistochemical probes. CONCLUSIONS: Assessment of exposure is crucial and requires accurate medical and occupational histories. Quantitative analysis of asbestos body burden is better performed in digested lung tissues by counting asbestos bodies by light microscopy and/or uncoated fibers by transmission electron microscopy. The benefits of screenings for asbestos-related malignancies are equivocal. The attribution of lung cancer to asbestos exposure is difficult in a clinical setting because of the need to assess asbestos body burden and the fact that virtually all these patients are also tobacco smokers or former smokers. Given the premise that asbestosis is necessary to causally link lung cancer to asbestos, it follows that the assessment of both lung fibrosis and asbestos body burden is necessary. PMID- 20849339 TI - Management of phosgene-induced acute lung injury. AB - CONTEXT: Phosgene is a substance of immense importance in the chemical industry. Because of its widespread industrial use, there is potential for small-scale exposures within the workplace, large-scale accidental release, or even deliberate release into a built-up area. OBJECTIVE: This review aims to examine all published studies concerning potential treatments for phosgene-induced acute lung injury and incorporate them into up-to-date clinical guidance. In addition, it aims to contrast the approaches when dealing with small numbers of patients known to be exposed (possibly with dose information) with the presentation of a large and heterogeneous population of casualties following a significant industrial accident or deliberate release; no published guidelines have specifically addressed this second problem. METHODS: PubMed and Embase were searched for all available years till April 2010 and 584 papers were identified and considered. EXPERIMENTAL STUDIES: Because of the nature of the injury, there have been no human trials of patients exposed to phosgene. Multiple small and large animal studies have been performed to examine potential treatments of phosgene-induced acute lung injury, but many of these used isolated organ models, pretreatment regimens, or clinically improbable doses. Recent studies in large animals using both realistic time frames and dosing regimens have improved our knowledge, but clinical guidance remains based on incomplete data. Management of a small-scale, confirmed exposure. In the circumstance of a small-scale, confirmed industrial release where a few individuals are exposed and present rapidly, an intravenous bolus of high-dose corticosteroid (e.g., methylprednisolone 1 g) should be considered, although there are no experimental data to support this recommendation. The evidence is that there is no benefit from nebulized steroid even when administered 1 h after exposure, or methylprednisolone if administered intravenously >=6 h after exposure. Consideration should also be given to administration of nebulized acetylcysteine 1-2 g, though there is no substantive evidence of benefit outside a small animal, isolated lung model and there is a possibility of adverse effects. If the oxygen saturation falls below 94%, patients should receive the lowest concentration of supplemental oxygen to maintain their SaO(2) in the normal range. Once patients require oxygen, nebulized beta-agonists [e.g., salbutamol (albuterol) 5 mg by nebulizer every 4 h] may reduce lung inflammation if administered within 1 h of exposure. Elective intubation should be considered early using an ARDSnet protective ventilation strategy. Management of a large-scale, non-confirmed exposure. In the circumstances of a large-scale industrial or urban release, not all patients presenting will have been exposed and health services are likely to be highly stretched. In this situation, patients should not be treated immediately as there is no evidence that delaying therapy causes harm, rather they should be rested and observed with regular physical examination and measurement of peripheral oxygen saturations. Once a patient's oxygen saturation falls below 94%, treatment with the lowest concentration of oxygen required to maintain their oxygen saturations in the normal range should be started. Once oxygen has been started, nebulized beta-agonists [e.g., salbutamol (albuterol) 5 mg by nebulizer every 4 h] may reduce lung inflammation if administered within 1 h of exposure, though delayed administration which is likely following a large scale release has not been tested formally. There is no benefit from nebulized steroid even when administered 1 h after exposure, or high-dose corticosteroid if administered intravenously >=6 h after exposure. Although there are no experimental data to support this recommendation, an intravenous bolus of high dose corticosteroid (e.g., methylprednisolone 1 g) may be considered if presentation is <6 h and resources allow. Depending on the numbers of casualties presenting, invasive ventilation should be initiated either electively once symptoms present (especially where there is a short latent period, indicating likelihood of more significant injury), or delayed until required. Ventilation should be with high positive end expiratory pressure, ARDSnet recommended ventilation. CONCLUSIONS: The mechanisms underlying the phosgene-induced acute lung injury are not well understood. Future experimental work should ensure that potential treatments are tested in a large animal model using realistic dosing regimens and clinically relevant timings, such as those that might be found in a mass casualty situation. PMID- 20849340 TI - Management of Datura poisoning. PMID- 20849345 TI - Magnetic N-succinyl chitosan/alginate beads for carbamazepine delivery. AB - CONTEXT: Epilepsy is a chronic condition characterized by recurrent unprovoked seizures. The most optimal use of drugs was limited due to their widespread systemic and central side effects. In contrast, focal drug delivery to epileptogenic focus based on superparamagnetic carrier is considered to be a promising and safe alternative. This delivery system could arrive exactly at the targeted tissue and deliver the loaded drug there with the help of an external magnetic field. OBJECTIVE: A new magnetic delivery system was established to inhibit paradoxical discharge once the onset of seizures. MATERIALS AND METHODS: Carbamazepine was incorporated into N-succinyl chitosan (NSC)/alginate hydrogel beads by ionic interaction. The characteristics of the beads including morphology, release behavior, and magnetic property were also investigated. RESULTS: Acceptable spherical morphology, excellent slow-release property, and superparamagnetic property of the NSC/alginate hydrogel beads were observed. DISCUSSION AND CONCLUSION: The magnetic NSC/alginate beads may be acted as a sustained-release formulation. The drugs exhibit the potential magnetic property owing to Fe3O4 particles. It is promising that the released drugs are induced by the weak magnetic field of epileptogenic zone and have the potential of locating them so as to inhibit paradoxical discharge once the onset of seizures. PMID- 20849346 TI - pH-responsive dual pulse multiparticulate dosage form for treatment of rheumatoid arthritis. AB - BACKGROUND: Dual pulse multiparticulate systems may provide relief from circadian disorder rheumatoid arthritis. AIM: The aim of this study was to develop a pH responsive dual pulse multiparticulate dosage form containing a model drug ketoprofen, a nonsteroidal anti-inflammatory drug used for rheumatoid arthritis. METHOD: The pellets were prepared by using extrusion-spheronization method and the core pellets were coated with a pH-sensitive poly(methyl) acrylate copolymer (Eudragit(r) L100-55, Eudragit(r) S100) to achieve site-specific drug release with a lag time. The formulated pellets were characterized for shape and size uniformity, friability, surface morphology studies, coating uniformity, and drug excipient compatibility studies. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. RESULTS: The particle size of core and polymer-coated pellets was found to be in the range of 0.95-1.3 and 1.42-1.61 mm, respectively. The pellets were spherical in shape with smooth texture and uniformity in size. The dual pulse was aimed at release after a lag time of 2 and 5 hours. In vitro dissolution tests were carried out for the first and second dose pellets in a USP type II dissolution apparatus in media simulating pH conditions of the gastrointestinal tract. The first dose release of the ketoprofen from the formulated pellets was established in pH 1.2 for a period of 2 hours, followed by pH 6.8. The second dose pellets were passed through pH 1.2, pH 6.8 followed by pH 7.5 for the rest of the study. CONCLUSION: The study concluded that the formulated multiparticulate dosage form of ketoprofen was able to relieve circadian symptoms of rheumatoid arthritis during midnight and early morning. PMID- 20849347 TI - Electroporation of polymeric nanoparticles: an alternative technique for transdermal delivery of insulin. AB - PURPOSE: The aim was to study transdermal electroporation of insulin-loaded nanocarriers as a methodology for delivering macromolecules. METHODS: The efficacy of electroporation of insulin as solution and nanoparticles was compared in vitro and in vivo. Histology and confocal laser scanning microscopy were used to assess the effects of electroporation on skin structure, whereas the latter also demonstrated the depth of permeation of the nanoparticles. In vivo studies were performed on streptozotocin-diabetic male Wistar rats and compared with subcutaneous administration. RESULTS: A linear increase in insulin flux was noted on increasing the applied voltage (R(2) = 0.9514), the number of pulses (R(2) = 0.8515), and the pulse length (R(2) = 0.9937). Electroporation of nanoparticles resulted in fourfold enhancement in insulin deposition in rat skin in contrast to solution. In vivo studies showed maximum reduction of 77 +/- 5% (87.2 +/- 6.4 mIU/mL, t = 2 hours) and 85 +/- 8% (37.8 +/- 10.2 mIU/mL, t = 4 hours) in blood glucose levels for solution and nanoparticles, respectively, with therapeutic levels maintained for 24 and 36 hours. CONCLUSION: Overall, electroporation of polymeric nanosystems proved to be an ideal alternative to injectable administration. PMID- 20849348 TI - Selection of the most suitable dissolution method for an extended release formulation based on IVIVC level A obtained on cynomolgus monkey. AB - OBJECTIVE: The purpose of this study is primarily to identify the most suitable in vitro dissolution method(s) for their ability to predict the in vivo performance of extended release prototype tablet formulations designed for a new chemical entity, Biopharmaceutic Classification System class II drug, weak base, based on the data collected in cynomolgus monkey. MATERIALS AND METHODS: Different types of buffer at different pH were selected as dissolution medium resulting in a broad variety of release patterns (slow to fast). The in vivo and in vitro data were put in relation. RESULTS: As a consequence of the discrimination between both tested formulations, the in vitro-in vivo correlation (IVIVC) qualities and shapes changed significantly. The obtained level A showed that the simple HCl medium was superior to biorelevant media and media containing surfactant when investigating IVIVCs in cynomolgus monkey. In addition, the results of dissolution in HCl suggested rather a diffusion mechanism of the extended release matrix formulation as the main factor of the release. CONCLUSION: Adjusting dissolution testing conditions to match the behavior of the formulations in vitro with that in vivo by taking into account the properties of the drug and the formulation is a straightforward and useful approach in identifying a predictive method in the development of the IVIVC. These investigations will definitely help by derisking of new formulations as well as by rating changes in existing formulations with regard to their impact on bioavailability before entry into human. PMID- 20849349 TI - Preparation and evaluation of in situ gelling ophthalmic drug delivery system for methazolamide. AB - PURPOSE: In this study, a thermosensitive in situ gelling vehicle was prepared to increase the precorneal resident time and the bioavailability of methazolamide (MTA). METHOD: Poloxamer analogs were used as the gelling agents, and the in situ gel was obtained by using a cold method. The gelation temperature, rheological properties, in vitro release as well as in vivo evaluation (the elimination of MTA in aqueous humor and intraocular-lowering effect) of the optimized formulations were investigated. RESULTS: The optimum concentrations of poloxamer analogs for the in situ gel-forming delivery system were 21% (w/w) poloxamer 407 and 10% (w/w) poloxamer P188. This formulation was able to flow freely under nonphysiological conditions and underwent sol-gel transition in the cul-de-sac upon placement into the eye. In vitro release studies demonstrated a diffusion controlled release of MTA from the poloxamer solutions over a period of 10 hours. In vivo evaluation indicated that the poloxamer solutions had a better ability to retain drug than MTA eyedrops did. CONCLUSION: These results suggested that in situ gelling ophthalmic drug delivery system may hold some promise in ocular MTA delivery. PMID- 20849350 TI - Enhanced oral bioavailability of Wurenchun (Fructus Schisandrae Chinensis extracts) by self-emulsifying drug delivery systems. AB - BACKGROUND: Wurenchun is the alcohol extract from Fructus Schisandrae Chinensis, which has good efficiency in lowering abnormal serum glutamic pyruvic transaminase (SGPT) level of patients suffering from acute or chronic hepatitis. The main purpose of this work is to prepare self-emulsifying drug delivery systems (SEDDS) for enhancing the solubility, dissolution rate, and oral bioavailability of poorly water-soluble traditional Chinese medicines, Wurenchun. METHODS: Pseudoternary phase diagrams were used to evaluate the efficient self emulsification domains, and particle size distributions of resultant emulsions were determined. The dissolution test was performed according to the second method of Chinese Pharmacopoeia dissolution procedure. The pharmacokinetic study in rats for the optimized formulation was performed and compared to commercial capsules. RESULTS: The optimized formulation for bioavailability assessment consisted of 20% oleic acid, 65% Tween 20, and 15% Transcutol P. The mean droplet size distribution of the optimized SEDDS was approximately 240 nm when diluted with 1000-fold volume of the distilled water. The in vitro dissolution rates of the active components of Wurenchun SEDDS were significantly higher than those of the commercial capsules. SEDDS have significantly increased the C(max) and area under the curve) (AUC) of Wurenchun compared to reference capsules (P < 0.05). And the relative bioavailability of SEDDS for schisandrin and schisandrin B was 292.2% and 205.8% compared to the commercial capsules, respectively. CONCLUSION: The results suggest the potential use of SEDDS to improve oral absorption of the sparingly soluble drugs or traditional Chinese medicine, such as Wurenchun. PMID- 20849351 TI - Design and optimization of a stomach-specific drug delivery system of repaglinide: application of simplex lattice design. AB - The current study involves the development of oral bioadhesive hydrophilic matrices of repaglinide and the optimization of their in vitro drug release and ex vivo bioadhesion. A simplex lattice design was employed to systematically optimize the drug delivery containing two polymers and a filler. The proportions of polyethylene oxide (PEO), microcrystalline cellulose (MCC) and lactose were varied to be fitted in simplex lattice design. Mucoadhesion (M), drug release at 2 h (Q2) and drug release at 8 h (Q8) were taken as responses. Response surface plots were drawn and the optimum formulation was selected by desirability function. The criteria for optimized formulation were set for mucoadhesion as maximum, Q2 as 20% and Q8 as 80%. The formulations were also checked for their swelling index and showed good swelling characteristic. In vitro drug release study was carried out using simulated gastric fluid (SGF) pH 1.2. The experimental values of M, Q2 and Q8 for check point batch were found to be 0.211N, 21.87% and 80.86% respectively. The release profile indicated anomalous (non-Fickian) transport mechanism. The optimized formulation was further checked for its compatibility with other excipients by studying FTIR and DSC studies and they indicated the absence of any significant chemical interaction within drug and excipients. PMID- 20849352 TI - Dysregulation of the immune system caused by silica and asbestos. AB - Silica and asbestos cause pneumoconioses known as silicosis and asbestosis, respectively, that are each characterized by progressive pulmonary fibrosis. While local effects of inhaled silica particles alter the function of alveolar macrophages and sequential cellular and molecular biological events, general systemic immunological effects may also evolve. One well-known health outcome associated with silica exposure/silicosis is an increase in the incidence of autoimmune disorders. In addition, while exposure to silica--in the crystalline form--has also been seen to be associated with the development of lung cancers, it remains unclear as to whether or not silicosis is a necessary condition for the elevation of silica-associated lung cancer risks. Since asbestos is a mineral silicate, it would be expected to also possess generalized immunotoxicological effects similar to those associated with silica particles. However, asbestos exposed patients are far better known than silicotic patients for development of malignant diseases such as lung cancer and mesothelioma, and less so for the development of autoimmune disorders. With both asbestos and crystalline silica, one important dysregulatory outcome that needs to be considered is an alteration in tumor immunity that allows for silica- or asbestos- (or asbestos-associated agent)-induced tumors to survive and thrive in situ. In this review, the immunotoxicological effects of both silica and asbestos are presented and contrasted in terms of their abilities to induce immune system dysregulation that then are manifest by the onset of autoimmunity or by alterations in host-tumor immunity. PMID- 20849353 TI - Chromatographic determination of fatty acids in biological material. AB - Fatty acids participate in different metabolic mechanisms, but their key role is connected with their participation in membrane phospholipid organizations. This review introduces the current knowledge of fatty acid analysis with an emphasis on the analysis of these compounds in biological samples. Therefore this manuscript is focused on various aspects of biological sample preparation methods, such as lipid extraction, lipid and phospholipid fractionation (TLC and SPE), derivatization, and on the methodologies of fatty acid analysis by gas chromatography (GC) and high-performance liquid chromatography (HPLC). The wide spectrum of columns and detectors used in these techniques for selective separation and determination of bioactive fatty acids are discussed. The abilities of using a sensitive tandem LC/MS and GC/MS assay are also shown. PMID- 20849354 TI - Human serum albumin nanoparticles modified with apolipoprotein A-I cross the blood-brain barrier and enter the rodent brain. AB - Nanoparticles made of human serum albumin (HSA) and modified with apolipoproteins have previously been shown to transport drugs, which normally do not enter the brain, across the blood-brain barrier (BBB). However the precise mechanism by which nanoparticles with different apolipoproteins on their surface can target to the brain, as yet, has not been totally elucidated. In the present study, HSA nanoparticles with covalently bound apolipoprotein A-I (Apo A-I) as a targetor for brain capillary endothelial cells were injected intravenously into SV 129 mice and Wistar rats. The rodents were sacrificed after 15 or 30 min, and their brains were examined by transmission electron microscopy. Apo A-I nanoparticles could be found inside the endothelial cells of brain capillaries as well as within parenchymal brain tissue of both, mice and rats, whereas control particles without Apo A-I on their surface did not cross the BBB during our experiments. The maintenance of tight junction integrity and barrier function during treatment with nanoparticles was demonstrated by perfusion with a fixative containing lanthanum nitrate as an electron dense marker for the permeability of tight junctions. PMID- 20849355 TI - Airborne Asian sand dust enhances murine lung eosinophilia. AB - There is no experimental study demonstrating the effects of airborne Asian sand dust (AASD) on allergic lung eosinophilia. The organic substances adsorbed onto AASD collected from the atmosphere of Iki-island in Japan were excluded by heat treatment at 360 degrees C for 30 min. The effects of AASD or heated-AASD (H AASD) towards allergic lung inflammation were compared in murine lungs to investigate the role of organic substances. ICR mice were administrated with the two kinds of AASD and/or ovalbumin (OVA) intratracheally four times at 2-week intervals. AASD and H-AASD enhanced eosinophil recruitment induced by OVA in the alveoli and in the submucosa of the airway, which has a goblet cell proliferation in the bronchial epithelium. AASD and H-AASD synergistically increased Th2 cytokines-interleukin-13 (IL-13), eosinophil-relevant cytokine and chemokine, such as IL-5, and monocyte chemotactic protein-3 (MCP-3) induced by OVA in whole lung lavage fluid. The enhancing effects were much greater in AASD than in H AASD. AASD induced adjuvant effects on OVA-specific immunoglobulin E (IgE) and IgG1 production. In an in vitro study using RAW264.7 cells, AASD increased the expression of Toll-like receptors 2 (TLR2) mRNA, but not TLR4 mRNA. AASD increased mRNA expression of NALP3, ASC, and IL-1beta compared with the control. H-AASD caused no expression of either mRNA. These results suggest that the aggravated lung eosinophilia in AASD is due to activation of a Th2-associated immune response and that the activation of TLR2 and NALP3 inflammasome by microbial materials could be participating in this phenomenon. PMID- 20849356 TI - Factors affecting the difference between morning and evening home blood pressure: the Finn-Home study. AB - OBJECTIVE: The aim of this study was to assess the determinants of home morning and evening blood pressure (BP) differences in general population. METHODS: We studied a representative sample of the general Finnish adult population with 1919 study subjects, aged 41-74 years. Study subjects underwent a clinical interview, clinical examination and home BP measurement (28 measurements performed twice in the morning and in the evening during 7 consecutive days). RESULTS: In untreated hypertensive subjects, systolic home BP was lower in the morning than in the evening while no difference was detected for diastolic home BP (137.7/85.1 vs 141.5/85.2 mmHg, p < 0.001/0.64). In treated hypertensive subjects, the difference between systolic morning and evening BP was smaller (136.2 vs 137.1 mmHg, p = 0.023) and diastolic morning BP was even higher than evening BP (83.3 vs 82.1 mmHg, p < 0.001). In the univariate analysis, higher home BP and higher body mass index were associated with relatively higher morning BP compared with evening BP. In addition, men, excessive alcohol users, subjects with cardiovascular disease, sleep apnea and subjects using antihypertensive medication had relatively higher morning BP compared with evening BP. In the multivariate analysis, male gender, excessive alcohol consumption, cardiovascular disease, sleep apnea and use of antihypertensive medication were independent determinants of elevated morning BP compared with evening BP. CONCLUSION: Knowledge of the underlying causes affecting morning and evening home BP difference in patients facilitates physicians to make rational antihypertensive medication and lifestyle adjustments, such as examining probable sleep disorder, and give alcohol and cardiovascular disease prevention counseling. PMID- 20849357 TI - Erythrocyte sodium-lithium countertransport activity is inversely correlated to adiponectin, retinol binding protein 4 and body height. AB - BACKGROUND: We have previously described that the sodium/lithium countertransport (SLC) in the erythrocyte cell membrane is closely linked to obesity and insulin resistance. Adiponectin and retinol-binding protein 4 (RBP-4) are believed to affect obesity and insulin resistance. In the present study, we aimed to further characterize the relationship between SLC, inflammatory markers, adiponectin and RBP-4. METHODS: We included 93 clinically healthy 58-year-old men selected to display variations in insulin sensitivity. High sensitivity C-reactive protein (hs-CRP), TNF-alpha, soluble TNF-alpha-receptors (sTNFR) 1 and 2, IL-6 and RBP-4 were measured using antibody-based techniques. Adiponectin was determined by a radioimmunoassay kit. The lithium concentration in the special flux medium was measured by atomic absorption spectrophotometry. RESULTS: In univariate analyses, SLC correlated negatively with RBP-4 (r(s) = -0.256, p = -0.017) and to adiponectin (r(s) = -0.316, p = 0.003) and positively with TNF-alpha (r(s) = 0.346, p = 0.001) and hs-CRP (r(s) = 0.288, p = 0.005). There were no statistically significant correlations with sTNFR 1 or 2 or IL-6. SLC was negatively associated to body height (r(s) = -0.256, p = 0.013). CONCLUSIONS: We are the first to report that SLC correlates negatively with adiponectin and RBP 4. This finding is intriguing, as adiponectin is anti-inflammatory and anti diabetic whereas RBP-4 supposedly decreases insulin sensitivity. We also observed a negative association between SLC activity and body height indicating that SLC activity is not primarily influenced by fat mass. The positive association of SLC with markers of inflammatory activity such as TNF-alpha and hs-CRP is in line with the proposed link between inflammation and insulin resistance. PMID- 20849358 TI - Mean platelet volume is increased in patients with severe obstructive sleep apnea. AB - Increased platelet activation and aggregation which are closely related to cardiovascular complications have been reported in patients with obstructive sleep apnea (OSA). The aim of this study was to assess the mean platelet volume (MPV), an indicator of platelet activation in patients with OSA. The 95 subjects referred for evaluation of OSA underwent overnight polysomnography. Blood samples were taken for MPV determination. According to the apnea-hypopnea index (AHI), subjects were divided into three groups; group 1: control subjects without OSA (AHI < 5, n = 24), group 2: patients with mild to moderate OSA (AHI: 5-30, n = 42), and group 3: severe OSA (AHI > 30, n = 29). Body mass index (BMI) of patients with severe OSA was significantly higher than control subjects (31.5 +/- 4.0 vs. 28.2 +/- 5.0; p = 0.02). The MPV was significantly higher in patients with severe OSA than in the control group (8.9 +/- 1.0 vs. 8.2 +/- 0.7 fl; p = 0.01). Correlation analysis within 71 patients with OSA indicated that MPV was correlated with AHI (p < 0.001, r = 0.44) and DI (p = 0.001, r = 0.37). In multivariate regression analysis, when MPV was taken as independent with other study variables which are potential confounders such as age, gender and BMI, MPV was independently correlated with both AHI (beta = 0.44, p < 0.001) and DI (beta = 0.38, p < 0.001). We have shown that MPV was significantly higher in patients with severe OSA when compared with control subjects and MPV was correlated with AHI and DI. PMID- 20849359 TI - Efficiency of voluntary closing hand and hook prostheses. AB - The Delft Institute of Prosthetics and Orthotics has started a research program to develop an improved voluntary closing, body-powered hand prosthesis. Five commercially available voluntary closing terminal devices were mechanically tested: three hands [Hosmer APRL VC hand, Hosmer Soft VC Male hand, Otto Bock 8K24] and two hooks [Hosmer APRL VC hook, TRS Grip 2S]. The test results serve as a design guideline for future prostheses. A test bench was used to measure activation cable forces and displacements, and the produced pinch forces. The measurements show that the hands require higher activation forces than the hooks and 1.5-8 times more mechanical work. The TRS hook requires the smallest activation force (33 N for a 15 N pinch force) and has the lowest energy dissipation (52 Nmm). The Hosmer Soft hand requires the largest activation force (131 N for a 15 N pinch force) and has the highest energy dissipation (1409 Nmm). The main recommendations for future prostheses are the following: (1) Required activation forces should be below the critical muscle force (~18% of maximum), to enable continuous activation without muscle fatigue; and (2) hysteresis of mechanism and glove should be lowered, to increase efficiency and controllability. PMID- 20849360 TI - The significance of CD14+ monocytes in peripheral blood stem cells for the treatment of rat liver cirrhosis. AB - BACKGROUND AIMS: Circulating monocytes have been exploited as an important progenitor cell resource for hepatocytes in vitro and are instrumental in the removal of fibrosis. We investigated the significance of monocytes in peripheral blood stem cells (PBSC) for the treatment of liver cirrhosis. METHODS: Rat CD14+ monocytes in PBSC were mobilized with granulocyte-colony-stimulating factor (G CSF) and harvested by magnetic cell sorting (MACS). Female rats with carbon tetrachloride (CCl4-induced liver cirrhosis were injected CM-DiI-labeled monocytes, CD14- cells (1 x 107 cells/rat) or saline via the portal vein. RESULTS: Rat CD14+ and CD11b+ monocytes in PBSC were partly positive for CD34, CD45, CD44, Oct3/4 and Sox2, suggesting monocytes with progenitor capacity. Compared with CD14- cell-infused and saline-injected rats, rats undergoing monocyte transplantation showed a gradually increased serum albumin level and decreased portal vein pressure, resulting in a significantly improved survival rate. Meanwhile, monocyte transplantation apparently attenuated liver fibrosis by analysis for fibronectin, alpha2-(1)-procollagen, alpha-smooth muscle aorta (SMA) and transforming growth factor (TGF)-beta. Transplanted monocytes mainly clustered in periportal areas of liver, in which 1.8% cells expressed hepatocyte marker albumin and CK18. The expression level of hepatocyte growth factor (HGF), TGF-alpha, extracellular matrix (EGF) and vascular endothelial growth factor (VEGF) increased, while monocyte transplantation enhanced hepatocyte proliferation. On the other hand, the activities and expression of matrix metalloproteinases (MMP) increased while tissue inhibitor of metalloproteinase (TIMP)-1 expression significantly reduced in monocyte-transplanted livers. Some transplanted monocytes expressed MMP-9 and -13. CONCLUSIONS: The data suggest that CD14+ monocytes in PBSC contribute to hepatocyte regeneration and extracellular matrix (ECM) remodeling in rat liver cirrhosis much more than CD14- cells, and might offer a therapeutic alternative for patients with liver cirrhosis. PMID- 20849362 TI - Gene profiling of bone marrow- and adipose tissue-derived stromal cells: a key role of Kruppel-like factor 4 in cell fate regulation. AB - BACKGROUND AIMS: Bone marrow- and adipose tissue-derived mesenchymal stromal cells (MSC) represent promising sources for regenerative medicine. However, the precise molecular mechanisms underlying MSC stemness maintenance versus differentiation are not fully understood. The aim of this study was to compare the genome-wide expression profiles of bone marrow-and adipose tissue-derived MSC, in order to identify a common molecular stemness core. METHODS: Molecular profiling was carried out using Affymetrix microarray and relevant genes were further validated by Q-PCR. RESULTS: We identified an overlapping dataset of 190 transcripts commonly regulated in both cell populations, which included several genes involved in stemness regulation (i.e. self-renewal potential and the ability to generate differentiated cells), various signaling pathways and transcription factors. In particular, we identified a central role of the Kruppel like factor 4 (KLF4) DNA-binding protein in regulating MSC transcriptional activity. CONCLUSIONS: Our results provide new insights toward understanding the molecular basis of MSC stemness maintenance and underline the ability of KLF4 to maintain cells in an undifferentiated state. PMID- 20849361 TI - A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. AB - BACKGROUND: Natural killer (NK) cells derived from patients with cancer exhibit diminished cytotoxicity compared with NK cells from healthy individuals. We evaluated the tumor response and in vivo expansion of allogeneic NK cells in recurrent ovarian and breast cancer. METHODS: Patients underwent a lymphodepleting preparative regimen: fludarabine 25 mg/m(2) * 5 doses, cyclophosphamide 60 mg/kg * 2 doses, and, in seven patients, 200 cGy total body irradiation (TBI) to increase host immune suppression. An NK cell product, from a haplo-identical related donor, was incubated overnight in 1000 U/mL interleukin (IL)-2 prior to infusion. Subcutaneous IL-2 (10 MU) was given three times/week * 6 doses after NK cell infusion to promote expansion, defined as detection of >=100 donor-derived NK cells/MUL blood 14 days after infusion, based on molecular chimerism and flow cytometry. RESULTS: Twenty (14 ovarian, 6 breast) patients were enrolled. The median age was 52 (range 30-65) years. Mean NK cell dose was 2.16 * 10(7)cells/kg. Donor DNA was detected 7 days after NK cell infusion in 9/13 (69%) patients without TBI and 6/7 (85%) with TBI. T-regulatory cells (Treg) were elevated at day +14 compared with pre-chemotherapy (P = 0.03). Serum IL-15 levels increased after the preparative regimen (P = <0.001). Patients receiving TBI had delayed hematologic recovery (P = 0.014). One patient who was not evaluable had successful in vivo NK cell expansion. CONCLUSIONS: Adoptive transfer of haplo-identical NK cells after lymphodepleting chemotherapy is associated with transient donor chimerism and may be limited by reconstituting recipient Treg cells. Strategies to augment in vivo NK cell persistence and expansion are needed. PMID- 20849363 TI - Cross-reaction to rifabutin after rifampicin induced flu-like syndrome and thrombocytopenia. PMID- 20849364 TI - Clinical features and outcomes of disseminated infections caused by non tuberculous mycobacteria in a university hospital in Taiwan, 2004-2008. AB - This retrospective study investigated the clinical characteristics and prognostic factors of patients with disseminated infections caused by non-tuberculous mycobacteria (NTM) in Taiwan. Forty patients who fulfilled the criteria for disseminated NTM infection at a medical centre from January 2004 to December 2008 were analyzed. More than half of the patients (n = 22, 55%) were HIV-infected and fever was the most common initial presentation (n = 21, 52.5%). There were 13 episodes of co-infection with other bacterial pathogens in 11 patients (30%). The most common site of NTM isolation from culture was blood (62.5%), followed by respiratory tract (52.5%). Mycobacterium avium complex was the most common species (70%). The overall mortality rate due to disseminated NTM infection was 30%. Univariate survival analysis showed significantly higher mortality rates in female patients, patients without anti-NTM treatment and patients co-infected with other bacterial pathogens. Multivariate analysis showed that lack of anti NTM treatment was the only prognostic factor for a poor outcome (p = 0.001). In conclusion, maintaining a high level of suspicion and starting appropriate anti NTM treatment promptly after diagnosis are crucial to improve outcome in patients with disseminated NTM infection. PMID- 20849365 TI - Mantoux test reactions among children managed for tuberculosis in Maiduguri, Nigeria. AB - Abstract We conducted a study of Mantoux reactions in children managed for tuberculosis (TB) at the University of Maiduguri Teaching Hospital (UMTH) over a period of 4 y. Of the 97 eligible children managed for various forms of TB on whom a Mantoux test was conducted, 82 (84.5%) had a negative Mantoux reaction and 15 (15.5%) had a positive reaction. No statistically significant difference was found in relation to age groups and sex between the patients with positive and negative Mantoux reactions (p = 0.602 and p = 0.484, respectively). No significant difference in Mantoux reaction was observed among BCG-vaccinated and non-vaccinated children (p = 0.321). Although malnutrition and HIV infection were significantly associated with a negative Mantoux reaction, disseminated TB was not associated. We therefore recommend proper clinical assessment and other investigations for the diagnosis of TB in children in settings with a high prevalence of HIV infection and malnutrition, as Mantoux reaction results may be unreliable. PMID- 20849366 TI - Non-typhoidal Salmonella and Campylobacter infections among HIV-positive patients in Denmark. AB - Non-typhoidal Salmonella (NTS) and Campylobacter are common causes of diarrhoea in human immunodeficiency virus (HIV)-positive patients. To investigate if incidence has changed since the introduction of highly active antiretroviral therapy (HAART), we combined data from The Danish Surveillance Registry for Enteric Pathogens and The Danish National Hospital Registry. We found that the incidences of NTS- and Campylobacter-related illness among HIV-positive patients in Denmark have declined since the introduction of HAART, although the incidences remained higher compared to the background population. Moreover our study suggests that there is an increased incidence of Campylobacter-related illness among homosexual men in the HIV-positive population. PMID- 20849367 TI - Some dogmas related to prosthodontics, temporomandibular disorders and occlusion. AB - It is the aim of this paper to give a few examples of dogmas related to prosthodontics and oral implants and to discuss the controversial role of occlusion in the aetiology of temporomandibular disorders. New knowledge is developing at a rapidly increasing rate in dentistry, as in other areas of society. Our lecturers at university taught us many useful things. But, as time goes by, what is still relevant? Some methods are so well established that they deserve to be called dogmas. It is implied that a dogma is not supported by strong evidence, even though it has existed and been practised for a long time. In the era of evidence-based dentistry it is appropriate to scrutinize such issues. A review of the current literature indicates that conflicting opinions exist concerning a number of common procedures in clinical dentistry, mainly due to a scarcity of good studies with unambiguous results. There is therefore a need for more high-quality clinical research in attempting to reach the goal of evidence-based clinical practice. The dental community should take an active part in this process. PMID- 20849368 TI - Integration of CAD/CAM planning into computer assisted orthopaedic surgery. AB - Modern Computer Aided Design/Modeling (CAD/CAM) software allows complex surgical simulations, but it is often difficult to transfer and execute precisely the planned scenarios during actual operations. We describe a new method of integrating CAD/CAM surgical plans directly into a computer surgical navigation system, and demonstrate its use to guide three complex orthopaedic surgical procedures: a periacetabular osteotomy of a dysplastic hip, a corrective osteotomy of a post-traumatic tibial deformity, and a multi-planar resection of a distal femoral tumor followed by reconstruction with a CAD custom prosthesis. PMID- 20849369 TI - Self-reported health problems, health care utilisation and unmet health care needs of elderly men and women in an urban municipality and a rural area of Bhaktapur District of Nepal. AB - The study aimed to identify the felt common health problems, utilisation of health services and unmet needs of urban and rural elderly people of Bhaktapur district, Nepal. It was a cross sectional population study of people aged 60 years or more where 204 respondents were interviewed in 2009. The common felt problems were pain and swelling of joints (65.7%), indigestion (63.7%), excessive tiredness (38.2%) and hypertension (35.8%). Pain and swelling of joints (72.5%) and back pain (40.4%) were higher in rural elderly population whereas indigestion (67.6%) and hypertension (37.85%) were higher in urban population. Pain and swelling of joints (66.7%) and indigestion (69.6%) were higher in males, and hypertension (50.0%), back pain (38.2%) and chronic bronchitis/asthma (39.2%) were higher in females. The unmet needs varied between different health problems. In general women had more unmet needs than men, where 80 unmet needs were identified for the 102 men compared with 105 for the 102 women, and these unmet needs increased dramatically with age. This approach yields new insights into the health care needs of the elderly and will be helpful to health care planners. PMID- 20849370 TI - Dietary intake and the risk of hyperuricemia, gout and chronic kidney disease in elderly Taiwanese men. AB - INTRODUCTION: This study was conducted to examine the relationship between dietary intake and the risk of chronic kidney disease (CKD), treated hyperuricemia (or gout) without CKD, and untreated hyperuricemia without CKD in elderly men. METHODS: The study population comprised 752 men aged 65 or older who had been included in the Elderly Nutrition and Health Survey (1999-2000) (Elderly NAHSIT). RESULTS: Statistical analysis using a polychotomous logistic regression model revealed that compared with the individuals in the normouricemic group, the individuals in the other groups exhibited a significant association between a higher prevalence of CKD and the following factors: advanced age, drug use for hypertension, egg and shellfish consumption and consumption of poultry with the skin and meat with fat. The significant risk factors for the patients who did not have CKD and were undergoing treatment for hyperuricemia were as follows: BMI >= 25 kg/m(2); drug use for hypertension; intake of poultry with skin; increased daily consumption of shellfish, fried food, sugar and juice. CONCLUSIONS: Men who use anti-hypertensive drugs and who consume fewer soy products and more shellfish may be at a higher risk of developing hyperuricemia or CKD. PMID- 20849371 TI - Short-term digestive tolerance of high-dose of NUTRIOSE(r)FB10 in adult. AB - NUTRIOSE(r)FB10 is a dextrin considered a dietary fiber. The present study aims to assess the digestive tolerance of a high dose of NUTRIOSE(r)FB10 consumed over the day, and its effect on digestive symptoms. In a randomized, double-blind, cross-over trial, 12 healthy men ingested 1 l/day orange juice containing 50 g either NUTRIOSE(r)FB10 or placebo (maltodextrin) in three equal doses at breakfast, lunch and 4:00 pm meal. Bloating, borborygmus, flatulence, nausea feelings, stomach ache, transit and stool consistency were evaluated at different times after the first consumption. Questionnaires on well-being and bowel movement were completed at 24 and 48 h. For all data except stool consistency, the area under the curve, the maximum score and the time of this maximum were calculated. For stool consistency, the mean score over 48 h was determined. There was no statistical difference between NUTRIOSE(r)FB10 and placebo on each criterion. NUTRIOSE(r)FB10 is well tolerated during a single day at 50 g divided into three doses. PMID- 20849372 TI - Neuronal activity controls the antagonistic balance between peroxisome proliferator-activated receptor-gamma coactivator-1alpha and silencing mediator of retinoic acid and thyroid hormone receptors in regulating antioxidant defenses. AB - Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-gamma coactivator (PGC) 1alpha is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1alpha strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1alpha-mediated antioxidant effects. The antagonistic balance between PGC-1alpha and SMRT is upset in favor of PGC-1alpha by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concomitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1alpha in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1alpha transcription. Activity-dependent targeting of PGC-1alpha results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1alpha and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1alpha-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1alpha and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivator-corepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability. PMID- 20849374 TI - How proteins form disulfide bonds. AB - The identification of protein disulfide isomerase, almost 50 years ago, opened the way to the study of oxidative protein folding. Oxidative protein folding refers to the composite process by which a protein recovers both its native structure and its native disulfide bonds. Pathways that form disulfide bonds have now been unraveled in the bacterial periplasm (disulfide bond protein A [DsbA], DsbB, DsbC, DsbG, and DsbD), the endoplasmic reticulum (protein disulfide isomerase and Ero1), and the mitochondrial intermembrane space (Mia40 and Erv1). This review summarizes the current knowledge on disulfide bond formation in both prokaryotes and eukaryotes and highlights the major problems that remain to be solved. PMID- 20849375 TI - p53 pro-oxidant activity in the central nervous system: implication in aging and neurodegenerative diseases. AB - Recent advances in delineating the biological functions of p53 had shed the light on its key role in the multifacets of cellular homeostasis. After its activation, via DNA damage, oxidative stress, or aberrant expression of oncogenes, p53 transduces its classical effect through several mechanisms comprising activation of the DNA repair machinery, cell cycle arrest, and initiation of apoptosis or senescence. In the mammalian brain, p53 plays critical functions in normal development, tumor suppression, neurodegenerative diseases, and aging. Herein, we focus on the constitutive pro-oxidant activity of p53 in neurons and discuss the potential implication of this finding in the context of neurodegenerative diseases and normal brain aging. PMID- 20849373 TI - Impaired adaptive cellular responses to oxidative stress and the pathogenesis of Alzheimer's disease. AB - As is generally true with other age-related diseases, Alzheimer's disease (AD) involves oxidative damage to cellular components in the affected tissue, in this case the brain. The causes and consequences of oxidative stress in neurons in AD are not fully understood, but considerable evidence points to important roles for accumulation of amyloid beta-peptide upstream of oxidative stress and perturbed cellular Ca(2+) homeostasis and energy metabolism downstream of oxidative stress. The identification of mutations in the beta-amyloid precursor protein and presenilin-1 as causes of some cases of early onset inherited AD, and the development of cell culture and animal models based on these mutations has greatly enhanced our understanding of the AD process, and has greatly expanded opportunities for preclinical testing of potential therapeutic interventions. In this regard, and of particular interest to us, is the elucidation of adaptive cellular stress response pathways (ACSRP) that can counteract multiple steps in the AD neurodegenerative cascades, thereby limiting oxidative damage and preserving cognitive function. ACSRP can be activated by factors ranging from exercise and dietary energy restriction, to drugs and phytochemicals. In this article we provide an overview of oxidative stress and AD, with a focus on ACSRP and their potential for preventing and treating AD. PMID- 20849377 TI - Redox regulation of protein kinases as a modulator of vascular function. AB - Reactive oxygen species (ROS) are continuously generated in vascular tissues by various oxidoreductase enzymes. They contribute to normal cell signaling, and modulate vascular smooth muscle tone and endothelial permeability in response to physiological agonists and to various cellular stresses and environmental factors, such as hypoxia. While concentrations of ROS are normally tightly controlled by cellular redox buffer systems, if produced in excess they may contribute to vascular disease. Protein kinases are essential components of most cell signaling pathways, including those involving ROS. The functioning of several members of this highly diverse group of enzymes, which include receptor and nonreceptor tyrosine kinases, protein kinase C, mitogen-activated kinases, and Rho-kinase, are modified by ROS, either through direct oxidative modification or indirectly through modification of associated proteins such as tyrosine phosphatases and monomeric G proteins. In this review, we discuss the molecular mechanisms of redox modification of these proteins, the downstream pathways affected, the often complex interaction between major kinase pathways, and feedback to ROS production itself. We also discuss complicating factors such as differential actions of superoxide anion and hydrogen peroxide, questions concerning concentration dependence, and the significance of signaling microdomains. PMID- 20849378 TI - The folding of disulfide-rich proteins. AB - The articles in this forum issue describe various aspects of the folding of disulfide-rich proteins. They include review articles using proteins such as bovine pancreatic trypsin inhibitor as models to highlight the range of folding pathways seen in disulfide-rich proteins, along with a detailed analysis of the methods used to study them. Following two comprehensive reviews on the methods and applications of protein folding, three original articles in this issue focus on two specific classes of disulfide-rich proteins that have applications in drug design and development, namely cyclotides and conotoxins. Cyclotides are head-to tail cyclic and disulfide-rich proteins from plants and function as a defense against insect attack. Conotoxins are the disulfide-rich components of the venom of marine cone snails that is used to capture prey. These research articles report on factors that modulate protein folding pathways in these molecules and determine the outcomes of protein folding, that is, yield and heterogeneity of products. Finally, the issue concludes with a comprehensive review on a different type of disulfide bond, namely those that have a functional rather than structural role in proteins, with a particular focus on allosteric disulfide bonds that modify protein function. PMID- 20849379 TI - Practice knowledge: the forgotten aspect of evidence-based practice. PMID- 20849376 TI - Redox regulation of intracellular zinc: molecular signaling in the life and death of neurons. AB - Zn(2+) has emerged as a major regulator of neuronal physiology, as well as an important signaling agent in neural injury. The intracellular concentration of this metal is tightly regulated through the actions of Zn(2+) transporters and the thiol-rich metal binding protein metallothionein, closely linking the redox status of the cell to cellular availability of Zn(2+). Accordingly, oxidative and nitrosative stress during ischemic injury leads to an accumulation of neuronal free Zn(2+) and the activation of several downstream cell death processes. While this Zn(2+) rise is an established signaling event in neuronal cell death, recent evidence suggests that a transient, sublethal accumulation of free Zn(2+) can also play a critical role in neuroprotective pathways activated during ischemic preconditioning. Thus, redox-sensitive proteins, like metallothioneins, may play a critical role in determining neuronal cell fate by regulating the localization and concentration of intracellular free Zn(2+). PMID- 20849380 TI - Epidermal stem cells are preserved during commercial-scale manufacture of a bilayered, living cellular construct (Apligraf(r)). AB - It is unknown if epidermal stem cells are maintained during the commercial-scale manufacture of Apligraf, a bilayered living cellular construct (BLCC). To answer this question, we genetically marked replicating keratinocytes, derived from production-scale expansion of working cell banks, in two-dimensional culture with a beta-galactosidase-expressing retrovirus and monitored their fate after incorporation into BLCC and subsequent in vivo transplantation to a nude mouse. Histological analysis of BLCCs showed distinct beta-galactosidase-positive clusters similar to clonal proliferation units visible 8-32 weeks after grafting. Keratinocytes recovered from grafts at week 32 were expanded in vitro in two dimensional culture, and clonal growth of recovered cells was then compared to the original pregraft population of keratinocytes by colony-forming efficiency (CFE) assays. The CFE of the cells regrown from the grafts was similar to pregraft CFEs (45% and 40%, respectively). Cells regrown from the grafts were then used to produce a second BLCC and generated a well-differentiated epithelium that was histologically similar to pregraft BLCC. These findings provide clear evidence that epidermal stem cells were sustained during the process of large scale tissue fabrication and that the process of isolation and expansion of cells in BLCC construction retains viable stem cells. PMID- 20849381 TI - Gelatin-based laser direct-write technique for the precise spatial patterning of cells. AB - Laser direct-writing provides a method to pattern living cells in vitro, to study various cell-cell interactions, and to build cellular constructs. However, the materials typically used may limit its long-term application. By utilizing gelatin coatings on the print ribbon and growth surface, we developed a new approach for laser cell printing that overcomes the limitations of MatrigelTM. Gelatin is free of growth factors and extraneous matrix components that may interfere with cellular processes under investigation. Gelatin-based laser direct write was able to successfully pattern human dermal fibroblasts with high post transfer viability (91% +/- 3%) and no observed double-strand DNA damage. As seen with atomic force microscopy, gelatin offers a unique benefit in that it is present temporarily to allow cell transfer, but melts and is removed with incubation to reveal the desired application-specific growth surface. This provides unobstructed cellular growth after printing. Monitoring cell location after transfer, we show that melting and removal of gelatin does not affect cellular placement; cells maintained registry within 5.6 +/- 2.5 MUm to the initial pattern. This study demonstrates the effectiveness of gelatin in laser direct-writing to create spatially precise cell patterns with the potential for applications in tissue engineering, stem cell, and cancer research. PMID- 20849382 TI - Lymphopenia a simple prognostic factor in lymphoma and other cancers: why not use it more as a guide? PMID- 20849383 TI - Minimal residual disease diagnostics in patients with acute myeloid leukemia in the post-transplant period: comparison of peripheral blood and bone marrow analysis. AB - Considering the high relapse rates of AML after allogeneic hematopoietic stem cell transplant, research aims to improve post-transplant surveillance. To determine the value of peripheral blood (PB) for post-transplant minimal residual disease monitoring, we compared 38 PB and bone marrow (BM) sample pairs in 25 stem cell recipients with NPM1-mutated AML (12 males, 13 females, ages 21-73 years). NPM1A mutation levels and chimerism ratios were determined in non separated BM/PB. We observed congruent results in 28/38 (74%). In 14/38 sample pairs (37%), BM and PB were negative for the NPM1A mutation. Fourteen sample pairs were positive in BM and PB, albeit at higher mutation levels in the BM in 11 cases (4- to 278-fold). Results were discordant in 10 cases (26%), with weakly positive mutation levels in the BM but negative levels in the PB. Cases with >=0.2% NPM1A mutation level in BM were always positive in PB. Chimerism was concordant in BM and PB in 21/34 (62%) of sample pairs. In conclusion, MRD monitoring with qPCR for the NPM1 mutation and chimerism from non-separated PB contributes to surveillance in patients with AML in the post-transplant period, but even with highly sensitive qPCR there is a risk of failure to detect the mutation in PB. PMID- 20849384 TI - Prognostic potential of detection of WT1 mRNA level in peripheral blood in adult acute myeloid leukemia. AB - We retrospectively analyzed the potential of Wilms' tumor gene 1 (WT1) mRNA levels in peripheral blood for predicting the prognosis of 50 patients with AML. After achieving complete remission (CR), 34 patients (69.4%) were determined to be positive and 15 (30.6%) were negative for WT1. The relapse rate of the positive and negative patients was 73.5% and 40.0% (p = 0.02), respectively. After consolidation therapy, only 15 patients (32.6%) were positive and 31 (67.4%) were negative for WT1. Although the relapse rate of the positive and negative patients was 80.0% and 54.8% (p = 0.10), respectively, the rate of relapse within 1 year was 73.3% in positive patients and only 33.3% in negative patients (p = 0.01), respectively. The disease-free survival (DFS) rate at 3 years was 20.0% for positive patients and 50.0% for negative patients (p = 0.01). The overall survival (OS) rate at 3 years was 42.8% in positive patients and 69.8% in negative patients (p = 0.04), respectively. WT1 mRNA levels in the peripheral blood can predict relapse after CR, and its levels after consolidation therapy are closely correlated with DFS, OS, and early relapse. PMID- 20849385 TI - Suppression of STAT5A increases chemotherapeutic sensitivity in imatinib resistant and imatinib-sensitive K562 cells. AB - STAT proteins are cytoplasmic transcription factors that are involved in the regulation of numerous cellular activities such as cell growth, differentiation, and survival. In this study, we aimed to identify the expression pattern of STAT genes in imatinib-sensitive and -resistant K562 cells, and further, to reveal the effects of STAT5A siRNA knockdown on cell growth and apoptosis induction. The XTT cell proliferation assay showed that both sensitive and resistant K562 cells were sensitized to imatinib upon transfection with STAT5A siRNA. Caspase-3 enzyme activity was increased significantly in both cells. These results may open up new opportunities to overcome chemotherapeutic resistance in leukemia. PMID- 20849386 TI - Response assessment of patients with chronic myeloid leukemia receiving imatinib mesylate (Glivec) therapy: experience from a single center in a developing country. AB - Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is a standard of care for chronic myeloid leukemia (CML). There are few publications on responses of patients with CML from the Indian subcontinent. This study analyzed the response rate, progression-free survival (PFS), overall survival (OS), and toxicities in patients with CML given imatinib. Analysis included patients with CML who received imatinib under the GIPAP program at our institution from January 2002 to December 2008. Standard criteria for hematological and cytogenetic responses were used. There were 400 patients, with a median follow-up of 47 months. One hundred and seventy received prior non-imatinib therapy and 230 patients received imatinib upfront. Ninety-five percent of patients achieved complete hematological response. The cumulative best rate of major cytogenetic response was 72%, with 53% complete cytogenetic response and 19% partial cytogenetic response. The estimated PFS and OS at median follow-up for the whole group was 76% and 94%, respectively. Differences in PFS and OS in prior non imatinib and upfront imatinib groups were not statistically significant. However, better PFS and OS were seen in the upfront imatinib group. Imatinib was well tolerated in our study. PMID- 20849387 TI - Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: fundamental aspects and practical considerations. AB - Glucocorticoids (GCs) are integral components in the treatment protocols of acute lymphoblastic leukemia, multiple myeloma, and non-Hodgkin lymphoma owing to their ability to induce apoptosis of these malignant cells. Resistance to GC therapy is associated with poor prognosis. Although they have been used in clinics for decades, the signal transduction pathways involved in GC-induced apoptosis have only partly been resolved. Accumulating evidence shows that this cell death process is mediated by a communication between nuclear GR affecting gene transcription of pro-apoptotic genes such as Bim, mitochondrial GR affecting the physiology of the mitochondria, and the protein kinase glycogen synthase kinase-3 (GSK3), which interacts with Bim following exposure to GCs. Prevention of Bim up regulation, mitochondrial GR translocation, and/or GSK3 activation are common causes leading to GC therapy failure. Various protein kinases positively regulating the pro-survival Src-PI3K-Akt-mTOR and Raf-Ras-MEK-ERK signal cascades have been shown to be activated in malignant leukemic cells and antagonize GC induced apoptosis by inhibiting GSK3 activation and Bim expression. Targeting these protein kinases has proven effective in sensitizing GR-positive malignant lymphoid cells to GC-induced apoptosis. Thus, intervening with the pro-survival kinase network in GC-resistant cells should be a good means of improving GC therapy of hematopoietic malignancies. PMID- 20849388 TI - Lymphopenia as a prognostic factor in patients with peripheral T-cell lymphoma, unspecified. AB - Peripheral T-cell lymphoma, unspecified (PTCLU) is the most common T-cell lymphoma variant. The molecular heterogeneity of PTCLU is reflected by a diverse clinical course. Several prognostic factors have been studied, but further refinement is needed. The aim of our study was to retrospectively evaluate the presence of lymphopenia, defined as a lymphocyte count of<1000 cells/mm3, as a prognostic factor for survival in patients with PTCLU. Sixty-nine cases with a pathological diagnosis of PTCLU were included in our analysis. Lymphopenia was seen in 38% of the patients and was statistically associated with a worse response to chemotherapy. In univariate analysis, lymphopenia, IPI score>2, and Prognostic Index for PTCLU (PIT) score>2 were associated with a worse overall survival. In multivariate analysis, lymphopenia and a PIT score>2 were the only independent poor prognostic factors, implying an important role of the patient's immune system in both response to therapy and survival. PMID- 20849389 TI - Present applications of analytical methods: prospects for high throughput screening of pharmaceutically active compounds (part 3). PMID- 20849390 TI - Bacterial invasion of eukaryotic cells can be mediated by actin-hydrolysing metalloproteases grimelysin and protealysin. AB - Earlier, we have shown that spontaneously isolated non-pathogenic bacteria Serratia grimesii and Serratia proteamaculans invade eukaryotic cells, provided that they synthesize thermolysin-like metalloproteases ECP32/grimelysin or protealysin characterized by high specificity towards actin. To address the question of whether the proteases are active players in entry of these bacteria into host cells, in this work, human larynx carcinoma Hep-2 cells were infected with recombinant Escherichia coli expressing grimelysin or protealysin. Using confocal and electron microscopy, we have found that the recombinant bacteria, whose extracts limitedly cleaved actin, were internalized within the eukaryotic cells residing both in vacuoles and free in cytoplasm. The E. coli-carrying plasmids without inserts of grimelysin or protealysin gene did not enter Hep-2 cells. Moreover, internalization of non-invasive E. coli was not observed in the presence of protealysin introduced into the culture medium. These results are consistent with the direct participation of ECP32/grimelysin and protealysin in entry of bacteria into the host cells. We assume that ECP32/grimelysin and protealysin mediate invasion being injected into the eukaryotic cell and that the high specificity of the enzyme towards actin may be a factor contributed to the bacteria internalization. PMID- 20849392 TI - Effect of polyacetylenic acids from Prunella vulgaris on various plant pathogens. AB - AIMS: This study is aiming at characterizing antifungal substances from the methanol extract of Prunella vulgaris and at investigating those substances' antifungal and antioomycete activities against various plant pathogens. METHODS AND RESULTS: Two polyacetylenic acids were isolated from P. vulgaris as active principles and identified as octadeca-9,11,13-triynoic acid and trans-octadec-13 ene-9,11-diynoic acid. These two compounds inhibited the growth of Magnaporthe oryzae, Rhizoctonia solani, Phytophthora infestans, Sclerotinia sclerotiorum, Fusarium oxysporum f. sp. raphani, and Phytophthora capsici. In addition, these two compounds and the wettable powder-type formulation of an n-hexane fraction of P. vulgaris significantly suppressed the development of rice blast, tomato late blight, wheat leaf rust, and red pepper anthracnose. CONCLUSIONS: These data show that the extract of P. vulgaris and two polyacetylenic acids possess antifungal and antioomycete activities against a broad spectrum of tested plant pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the occurrence of octadeca-9,11,13-triynoic acid and trans-octadec-13-ene-9,11-diynoic acid in P. vulgaris and their efficacy against plant diseases. The crude extract containing the two polyacetylenic acids can be used as a natural fungicide for the control of various plant diseases. PMID- 20849393 TI - Ribosomal operon intergenic sequence region (ISR) heterogeneity in Campylobacter coli and Campylobacter jejuni. AB - AIMS: The intergenic sequence regions (ISR) between the 16S and 23S genes of Campylobacter jejuni and Campylobacter coli are markedly different for each species. However, in the genomic sequence for Camp. coli RM2228, two rRNA operons have an ISR that is characteristic of Camp. coli, and the third operon is characteristic of Camp. jejuni. The aim of this study was to determine the prevalence of ISR heterogeneity in these organisms. METHODS AND RESULTS: PCR primers were designed to yield a 327-base pair (bp) product for Camp. coli and 166-bp product for Camp. jejuni. A strain like Camp. coli RM2228 should yield products of both sizes. DNA from a panel of Camp. coli (n=133) and Camp. jejuni (n=134) isolates were tested. All of the isolates yielded products of the predicted size for the species. To verify the data for Camp. coli RM2228, each ribosomal operon from the isolate was individually amplified by PCR and tested with the ISR primer pair. Products of both sizes were produced as predicted. CONCLUSIONS: The cross-species heterogeneity of the ISR seen in Camp. coli RM2228 is uncommon. SIGNIFICANCE AND IMPACT OF THE STUDY: The heterogeneity must have been caused by horizontal gene transfer at a frequency lower than predicted from housekeeping gene data. Thus, it can be expected that species identification based on the ISR can be confused in rare isolates. PMID- 20849394 TI - Comparative evaluations of cellulosic raw materials for second generation bioethanol production. AB - AIMS: To evaluate sugar recoveries and fermentabilities of eight lignocellulosic raw materials following mild acid pretreatment and enzyme hydrolysis using a recombinant strain of Zymomonas mobilis. METHODS AND RESULTS: Dilute acid pretreatment (2% H(2) SO(4) ) with 10% (w/v) substrate loading was performed at 134 degrees C for 60 min followed by enzyme hydrolysis at 60 degrees C. The results demonstrated that hydrolysis of herbaceous raw materials resulted in higher sugar recoveries (up to 60-75%) than the woody sources (<50%). Fermentation studies with recombinant Z. mobilis ZM4 (pZB5) demonstrated that final ethanol concentrations and yields were also higher for the herbaceous hydrolysates. Significant reduction in growth rates and specific rates of sugar uptake and ethanol production occurred for all hydrolysates, with the greatest reductions evident for woody hydrolysates. Further studies on optimization of enzyme hydrolysis established that higher sugar recoveries were achieved at 50 degrees C compared to 60 degrees C following acid pretreatment. CONCLUSIONS: Of the various raw materials evaluated, the highest ethanol yields and productivities were achieved with wheat straw and sugarcane bagasse hydrolysates. Sorghum straw, sugarcane tops and Arundo donax hydrolysates were similar in their characteristics, while fermentation of woody hydrolysates (oil mallee, pine and eucalyptus) resulted in relatively low ethanol concentrations and productivities. The concentrations of a range of inhibitory compounds likely to have influence the fermentation kinetics were determined in the various hydrolysates. SIGNIFICANCE AND IMPACT OF THE STUDY: The study focuses on lignocellulosic materials available for second generation ethanol fermentations designed to use renewable agricultural/forestry biomass rather than food-based resources. From the results, it is evident that relatively good sugar and ethanol yields can be achieved from some herbaceous raw materials (e.g. sugarcane bagasse and sorghum straw), while much lower yields were obtained from woody biomass. PMID- 20849395 TI - Antimicrobial activity of sodium citrate against Streptococcus pneumoniae and several oral bacteria. AB - AIMS: The aim of this study is to assess the antibacterial activity of sodium citrate against Streptococcus pneumoniae and several oral bacteria. METHODS AND RESULTS: The antibacterial activity was determined by broth microdilution method. The results showed that although Enterocuccus faecium OB7084 and Klebsiella pneumoniae OB7088 had high tolerance to sodium citrate, several oral bacteria including Fusobacterium nucleatum JCM8532(T) , Streptococcus mutans JCM5705(T) and Strep. pneumoniae NBRC102642(T) were susceptible. Furthermore, the bactericidal activity of sodium citrate against Strep. pneumoniae NBRC102642(T) was not influenced by pH in the range of 5.0-8.0, whereas that of sodium lactate was weakened at neutral or weak alkaline pH. When Strep. pneumoniae NBRC102642(T) was treated with sodium citrate for 2 h, many burst cells were observed. However, addition of MgCl(2) or CaCl(2) to an assay medium weakened the antimicrobial activity although ZnCl(2) or MnCl(2) did not influence. CONCLUSIONS: Independent of pH, sodium citrate inhibited the growth of oral bacteria, which suggests that the mechanism is different from that of sodium lactate. SIGNIFICANCE AND IMPACT OF THE STUDY: The results presented in this study would be available for understanding the antimicrobial property of sodium citrate. PMID- 20849396 TI - Screening of genes expressed in vivo after infection by Vibrio anguillarum M3. AB - AIMS: Genes uniquely expressed in vivo may contribute to the overall pathogenicity of an organism and are likely to serve as potential targets for the development of new vaccine. This study aims to screen the genes expressed in vivo after Vibrio anguillarum infection by in vivo-induced antigen technology (IVIAT). METHODS AND RESULTS: The convalescent-phase sera were obtained from turbot (Scophthalmus maximus) survived after infection by the virulent V. anguillarum M3. The pooled sera were thoroughly adsorbed with M3 cells and Escherichia coli BL21 (DE3) cells. A genomic expression library of M3 was constructed and screened for the identification of immunogenic proteins by colony immunoblot analysis with the adsorbed sera. After three rounds of screening, 19 putative in vivo-induced (ivi) genes were obtained. These ivi genes were catalogued into four functional groups: regulator/signalling, metabolism, biological process and hypothetical proteins. Three ivi genes were insertion-mutated, and the growth and 50% lethal dose (LD(50) ) of these mutants were evaluated. CONCLUSIONS: The identification of ivi genes in V. anguillarum M3 sheds light on understanding the bacterial pathogenesis and provides novel targets for the development of new vaccines and diagnostic reagents. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, this is the first report describing in vivo-expressed genes of V. anguillarum using IVIAT. The screened ivi genes in this study could be new virulent factors and targets for the development of vaccine, which may have implications for the development of diagnostic regents. PMID- 20849397 TI - rRNA-based analysis to monitor succession of faecal bacterial communities in Holstein calves. AB - AIMS: To quantitatively analyse the faecal bacterial communities of Holstein calves and track their succession up to 12 weeks of age. METHODS AND RESULTS: Faecal samples obtained from four female Holstein calves were analysed by the RNA based, sequence-specific rRNA cleavage method. Twelve scissor probes covering major rumen bacterial groups were used, detecting c. 60-90% of the total 16S rRNAs. At 1 week of age, 16S rRNAs from members of the Bacteroides-Prevotella group (40.0% of the total 16S rRNAs), Faecalibacterium (21.7%), the Clostridium coccoides-Eubacterium rectale group (16.7%) and the Atopobium cluster (10.9%) were detected at high levels. Throughout the 12-week period, rRNAs of the Bacteroides-Prevotella and the Cl. coccoides-Eu. rectale groups constituted the major fraction of microbiota (c. 50-70% of the total). The relative abundances of the Atopobium cluster, Faecalibacterium, and some probiotic bacteria (such as those of the genera Lactobacillus and Bifidobacterium) decreased as the animal aged. Instead, an uncultivated rumen bacterial group, as well as Ruminococcus flavefaciens and Fibrobacter emerged at the detectable levels (1-2%) in the faeces sampled at a postweaning age. In addition, certain bacterial groups that were not covered by the probe suite increased as the animals aged. CONCLUSIONS: Young calves undergo dynamic changes in their intestinal bacterial community during the first 12 weeks of life. As young ruminants undergo metabolic and physiological development in their digestive tracts in the transition from a monogastric to a ruminant animal at an early age, the intestinal bacterial community may reflect such development. SIGNIFICANCE AND IMPACT OF THE STUDY: The succession of the bacterial communities in the faeces of calves was quantitatively monitored in the present study for the first time. The approach used here was demonstrated to be a useful means for determining the populations of predominant faecal bacterial groups in a variety of calf experiments in response to diet, stress and disease. PMID- 20849398 TI - Glial fibrillary acidic protein mutations in adult-onset Alexander disease: clinical features observed in 12 Japanese patients. AB - OBJECTIVE: To clarify the clinical manifestations of adult-onset Alexander disease (AOAD) in Japanese patients with glial fibrillary acidic protein (GFAP) gene mutations. METHODS AND MATERIALS: Twelve patients of AOAD with GFAP mutations detected in our centre were examined for neurological and magnetic resonance imaging (MRI) findings. RESULTS: Major symptoms were pyramidal and bulbar signs. In addition, three patients presented abnormal behaviour and/or memory disturbance. Two of the three patients also had Parkinsonism and had been diagnosed with fronto-temporal dementia or progressive supranuclear palsy until GFAP mutations were detected. Abnormalities of the medulla oblongata and cervical spinal cord were observed on MRI in all patients. CONCLUSIONS: Patients presenting with pyramidal and/or bulbar signs with abnormalities of the medulla oblongata and cervical spinal cord on MRI should be considered for GFAP analysis as this is the typical presentation of AOAD. Abnormal behaviour and cognitive disorders including deterioration of memory were rare symptoms but could be an obstacle to diagnosing Alexander disease. PMID- 20849399 TI - More CLEC16A gene variants associated with multiple sclerosis. AB - OBJECTIVES: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. METHODS: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. RESULTS: Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. CONCLUSION: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases. PMID- 20849401 TI - Market-implied spread for earthquake CAT bonds: financial implications of engineering decisions. AB - In the event of natural and man-made disasters, owners of large-scale infrastructure facilities (assets) need contingency plans to effectively restore the operations within the acceptable timescales. Traditionally, the insurance sector provides the coverage against potential losses. However, there are many problems associated with this traditional approach to risk transfer including counterparty risk and litigation. Recently, a number of innovative risk mitigation methods, termed alternative risk transfer (ART) methods, have been introduced to address these problems. One of the most important ART methods is catastrophe (CAT) bonds. The objective of this article is to develop an integrative model that links engineering design parameters with financial indicators including spread and bond rating. The developed framework is based on a four-step structural loss model and transformed survival model to determine expected excess returns. We illustrate the framework for a seismically designed bridge using two unique CAT bond contracts. The results show a nonlinear relationship between engineering design parameters and market-implied spread. PMID- 20849400 TI - Impact of duration of symptoms on CSF dynamics in idiopathic normal pressure hydrocephalus. AB - OBJECTIVE: Cerebrospinal fluid (CSF) pressure-volume compensation may change over time as part of normal ageing, where the resistance to CSF outflow increases and the formation of CSF decreases with age. Is CSF compensation dependent on duration of symptoms in idiopathic normal pressure hydrocephalus (iNPH)? METHODS: We investigated 92 patients presenting with iNPH. Mean age was 73 (range 47-86). There were 60 men and 32 women. They all presented with gait disturbance and ventricular dilatation. Memory deficit occurred in 72% and urinary incontinence in 52% of patients. All patients underwent computerized CSF infusion tests. Sixty four shunted patients were available for follow-up, and their improvement was expressed using the NPH score. RESULTS: Mean intracranial pressure (ICP) was 10.1+/-5.1 mmHg, and mean resistance to CSF outflow was 17.3+/-5.2 mmHg/(ml/min). Mean duration of symptoms was 24+/-19 months (range from 2 weeks to 86 months). Baseline ICP, magnitude of ICP pulse waveform, brain compliance and improvement after shunting (72% of patients improved) did not exhibit any dependency on the duration of symptoms. The resistance to CSF outflow showed a strong tendency to decrease in time with the duration of symptoms beyond 2 years (R= -0.702; P<0.005). CONCLUSION: This is a preliminary observation, and it suggests that for patients with duration of symptoms longer than 2-3 years, the threshold for normal resistance to CSF outflow should be duration-adjusted. PMID- 20849402 TI - Probabilistic modeling of the fate of Listeria monocytogenes in diced bacon during the manufacturing process. AB - To assess the impact of the manufacturing process on the fate of Listeria monocytogenes, we built a generic probabilistic model intended to simulate the successive steps in the process. Contamination evolution was modeled in the appropriate units (breasts, dice, and then packaging units through the successive steps in the process). To calibrate the model, parameter values were estimated from industrial data, from the literature, and based on expert opinion. By means of simulations, the model was explored using a baseline calibration and alternative scenarios, in order to assess the impact of changes in the process and of accidental events. The results are reported as contamination distributions and as the probability that the product will be acceptable with regards to the European regulatory safety criterion. Our results are consistent with data provided by industrial partners and highlight that tumbling is a key step for the distribution of the contamination at the end of the process. Process chain models could provide an important added value for risk assessment models that basically consider only the outputs of the process in their risk mitigation strategies. Moreover, a model calibrated to correspond to a specific plant could be used to optimize surveillance. PMID- 20849403 TI - Storing apheresis platelets without agitation with simulated shipping conditions during two separate periods: immediately after collection and subsequently between Day 2 and Day 3. AB - BACKGROUND: Apheresis platelet (PLT) units are not routinely agitated during transit. Our study compared the in vitro properties of apheresis PLT units that were stored with continuous agitation (CA) and without continuous agitation (WCA) during two separate periods, immediately after collection and between Day 2 and Day 3 of storage. STUDY DESIGN AND METHODS: Two identical apheresis PLTs units were prepared from collections with Amicus (n = 11, Fenwal, Inc.) and Trima (n = 10, CaridianBCT) cell separators. One apheresis PLT unit was continuously agitated, starting routinely within 30 minutes of collection, and an identical apheresis PLT unit was held without agitation initially for 7 to 8 hours and subsequently for 24 hours between Day 2 and Day 3 of storage. The apheresis PLT units were maintained WCA at 20 to 24 degrees C in a shipping box. In vitro PLT properties were evaluated on Day 1 (day after collection), after 5 and 7 days of storage. RESULTS: With both Amicus and Trima apheresis PLT units, the mean PLT content and concentration of CA and WCA were comparable and essentially constant throughout storage. Mean pH levels (+/- 1 SD) after 5 days for Amicus apheresis PLT units were 6.97 +/- 0.20 (WCA) and 7.13 +/- 0.16 (p < 0.001, CA) and for Trima apheresis PLT units 6.97 +/- 0.21 (WCA) and 7.22 +/- 0.17 (p < 0.001, CA). In vitro variables, including percentage of disc PLTs, extent of shape change, and hypotonic stress levels, after 5 days of storage, showed mean differences between WCA and CA that were less than 15%. CONCLUSION: The in vitro results show that apheresis PLT units can be stored without agitation for 7 to 8 hours immediately after collection and also subsequently during storage for 24 hours with minimal influence on in vitro PLT properties compared to continuously agitated PLTs. PMID- 20849404 TI - Is there a clinical need for a diagnostic test allowing detection of chain type specific anti-A and anti-B? AB - BACKGROUND: Hemagglutination for detection and semiquantification of ABO antibodies is associated with large center-to-center variations and poor reproducibility. Because acceptance for transplantation and diagnosis of rejection in ABO-incompatible transplantation rely on the levels and specificity of ABO antibodies, reproducible tests that allow their detection and specificity determination are required. STUDY DESIGN AND METHODS: The level of chain type specific anti-A and anti-B were analyzed in the sera of 44 healthy individuals of known ABO blood group using an enzyme-linked immunosorbent assay (ELISA) with polyacrylamide (PAA) conjugates of blood group A and B trisaccharides or Type 2 chain A and B tetrasaccharides. Selected sera were further analyzed by hemagglutination and in an ELISA with Types 1 to 4 chain A or B neoglycolipids (NGL) as antigens. RESULTS: Immunoglobulin (Ig)G anti-A and anti-B levels were higher (p <= 0.05) in blood group O than in B and A individuals. More IgM anti-A and anti-B cross-reactivity was detected in AB serum on PAA-conjugated A and B trisaccharides than on the tetrasaccharides. One of 11 blood group B and two of 12 A individuals had IgG antibodies binding the tetrasaccharide despite lack of, or very low reactivity with, the trisaccharides. IgG antibodies preferring the A and B Type 2 tetrasaccharides were of the IgG2 subclass. The NGL ELISA further supported the presence of chain type-specific anti-A and -B antibodies among nonsensitized, healthy individuals. CONCLUSION: An ELISA with structurally defined ABH antigens will allow the antibody class and fine specificity of ABO antibodies to be determined, which may improve risk assessment in ABO incompatible transplantation. PMID- 20849405 TI - Survival of Plasmodium falciparum in human blood during refrigeration. AB - BACKGROUND: Transfusion-transmitted malaria remains a serious concern for blood safety. Viable Plasmodium parasites must be present in human blood to transmit malaria, but their survival in blood over time stored under refrigeration has never been carefully investigated. STUDY DESIGN AND METHODS: We spiked leukoreduced normal human blood with Plasmodium falciparum (3D7 strain) asexual ring-stage parasites and stored it at 4 degrees C for 28 days, taking samples at different days intervals. We evaluated the samples for parasitemia by blood film microscopy and by culturing red blood cells (RBCs) to allow further development of parasites. RESULTS: We observed a significant reduction in parasitemia (0.5% vs. 0.12%) after only 1 day in storage at 4 degrees C. Thereafter, reduction in parasitemia was relatively gradual. Microscopically detectable parasites were present even after 28 days of storage. However, after storing for more than 14 days at 4 degrees C, parasites no longer replicated when cultured in vitro. CONCLUSION: Although the storage of asexual blood-stage P. falciparum parasites at 4 degrees C is detrimental to their survival (a 7.1-fold reduction in parasitemia after 14 days in storage), parasites remained microscopically detectable for 28 days, the end time point of our study. Further in vitro and in vivo studies will be needed to confirm loss of viability of P. falciparum after 14 days in storage, but our initial efforts repeatedly failed to show maturation and development of the parasites in cultured RBCs after that time. PMID- 20849406 TI - Use of additive solutions and pathogen inactivation treatment of platelet components in a regional blood center: impact on patient outcomes and component utilization during a 3-year period. AB - BACKGROUND: The Etablissement Francais du Sang Alsace (EFS Alsace) successively implemented universal use of platelet additive solutions (PASs) and pathogen inactivation (PI) for platelet components (PCs). To assess the impact of these changes, EFS Alsace evaluated PC use, red blood cell (RBC) component use, and transfusion-related adverse events after implementation of these new technologies. STUDY DESIGN AND METHODS: EFS Alsace prospectively collects data on production, distribution, and response to transfusion of all blood components with greater than 99.5% data acquisition. Adverse events attributed to platelet (PLT) transfusions were collected through a mandatory, active hemovigilance program. A retrospective review of prospectively collected data was conducted covering three periods: 1) apheresis and whole blood-derived PCs in plasma, 2) apheresis and whole blood-derived PCs with PAS, and 3) PCs prepared with PI and PAS. Data on component utilization were analyzed for all patients receiving PCs in each period and for the subset of hematology-oncology patients to evaluate PC use in an intensely transfused population. Values for all continuous variables were summarized as mean and standard deviation, median, and range. RESULTS: Approximately 2000 patients received PCs in each period. PLT and RBC use per patient was not increased after PI (analysis of variance, F = 1.9 and 2.9, respectively) and the incidence of acute transfusion reactions was significantly reduced (p < 0.001). CONCLUSIONS: Universal use of PI was implemented without impacting component use, as indicated by total dose of PLTs per patient, and outcomes to transfusion were improved. PMID- 20849407 TI - Screening plateletpheresis donors for HLA antibodies on two high-throughput platforms and correlation with recipient outcome. AB - BACKGROUND: To determine the prevalence and impact of transfusing plasma containing white blood cell antibodies, we compared two high-throughput HLA antibody screening assays and prospectively examined the medical records of all platelet (PLT) recipients to detect subtle manifestations of transfusion-related acute lung injury and other transfusion reactions. STUDY DESIGN AND METHODS: Serum samples from 136 plateletpheresis donors were tested for HLA Class I and II antibodies using microbead (LABScreen PRA, One Lambda) and microchip (Dynachip, Invitrogen) assays. Electronic medical records of all recipients were reviewed for vital signs and nursing documentation before and after transfusion. RESULTS: In the microchip assay with a cutoff value of 0.25, 2.9% of samples were positive for Class I and 8.9% for Class II antibodies; with a cutoff value of 0.1, the results were 14.9 and 21.6%, respectively. In the microbead assay (normalized background ratio, 1.5), 15% were positive for Class I and 21% for Class II antibodies. The prevalence of HLA antibodies was 17% in donors without pregnancy or transfusion history and 47% in donors with such history. The PLTs were transfused in 265 episodes to 67 patients. There were no reported reactions; however, symptoms or vital sign changes were noted in seven transfusion episodes. The incidence of reactions was 2.7% (2/75) for antibody-positive units and 2.6% (5/190) for antibody-negative units. CONCLUSIONS: Microbead and microchip assays yielded similar results. The prevalence of HLA antibodies was greater in donors with a history of pregnancy or transfusion, but no increase in the incidence of transfusion reactions was noted in recipients of components from donors with HLA antibodies. PMID- 20849408 TI - Analysis of Chinese donors' return behavior. AB - BACKGROUND: It is important to understand donor return behavior. Converting first time donors to become repeat donors is essential for maintaining an adequate blood supply. STUDY DESIGN AND METHODS: Characteristics of 241,552 whole blood (WB) donations from first-time and repeat donors who donated in 2008 at the five blood centers in China were compared. A subset of 54,394 WB donors who donated between January 1 and March 31, 2008, were analyzed for their return behavior in 2008 after the index donation using logistic regression. RESULTS: Of all donations, 64% were from first-time donors. Donors with self-reported previous donations tended to be male, older, and married; donated larger volume (>= 300 mL); and were heavier in weight. Among donors who donated from January to March 2008, 14% returned for subsequent WB donations by the end of 2008. The number of previous donations and blood collection location were the two strongest predictors for making subsequent donations. Donors with one, two to three, and more than three previous donations were 3.7, 5.7, and 11.0 times more likely to return than first-time donors. Those who donated in a blood collection vehicle were four times more likely to return than those who donated at a blood center. Being female, younger, and of a lower education level (middle school or less) were positively associated with subsequent return blood donation during the follow-up period observed in this study. CONCLUSION: Most of the Chinese blood supply is from first-time donors. Strategies aimed at encouraging current donors to become repeat donors are needed. PMID- 20849409 TI - The cost-effectiveness of introducing nucleic acid testing to test for hepatitis B, hepatitis C, and human immunodeficiency virus among blood donors in Sweden. AB - BACKGROUND: The purpose of this study was to estimate the cost-effectiveness of using individual-donor nucleic acid testing (ID-NAT) in addition to serologic tests compared with the sole use of serologic tests for the identification of hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) among blood donors in Sweden. STUDY DESIGN AND METHODS: The two strategies analyzed were serologic tests and ID-NAT plus serologic tests. A health-economic model was used to estimate the lifetime costs and effects. The effects were measured as infections avoided and quality-adjusted life-years (QALYs) gained. A societal perspective was used. RESULTS: The largest number of viral transmissions occurred with serologic testing only. However, the risks for viral transmissions were very low with both strategies. The total cost was mainly influenced by the cost of the test carried out. The cost of using ID-NAT plus serologic tests compared to serologic tests alone was estimated at Swedish Krona (SEK) 101 million (USD 12.7 million) per avoided viral transmission. The cost per QALY gained was SEK 22 million (USD 2.7 million). CONCLUSION: Using ID-NAT for testing against HBV, HCV, and HIV among blood donors leads to cost-effectiveness ratios that are far beyond what is usually considered cost-effective. The main reason for this is that with current methods, the risks for virus transmission are very low in Sweden. PMID- 20849410 TI - The impact of temporary deferral due to low hemoglobin: future return, time to return, and frequency of subsequent donation. AB - BACKGROUND: This study investigated the effects of a 6-month deferral due to low hemoglobin (Hb) on the subsequent donation patterns of Australian whole blood donors. STUDY DESIGN AND METHODS: The study was a retrospective cohort study of the donation patterns of all whole blood donors deferred for low Hb during a 2 month period compared with donors who were not deferred. Donations 3 years after eligibility to give blood were recorded. Analysis of proportion returning, time to return, and frequency of donation was performed using logistic regression, survival analysis, and negative binomial regression. RESULTS: Among first-time donors, 20.9% of low Hb-deferred donors returned during the follow-up period versus 69.9% of those not deferred. Among repeat donors, 64.0% of deferred donors returned versus 91.0% of those not deferred. Temporary deferral delayed time to first return (p < 0.001), reduced frequency of donation (2.4 donations per donor before deferral compared to 1.1 per donor in first year of follow-up), and increased the likelihood of dropping out in later years of follow-up. However, if a donor returned promptly once eligible and gave more donations in the first year, the negative impact on future donation patterns was diminished. High frequency of attendance before deferral was the strongest predictor of time to return and future donation frequency. CONCLUSION: Deferral for low Hb had a strong effect on first-time and repeat donors. This study highlights the influence of strong donation habits on return after deferral and the importance of encouraging donors to return promptly once eligible. PMID- 20849411 TI - Implications of demographics on future blood supply: a population-based cross sectional study. AB - BACKGROUND: Data on blood recipients are sparse and unconnected to data on blood donors. The objective was to analyze the impact of the demographic change on future blood demand and supply in a German federal state. STUDY DESIGN AND METHODS: A population-based cross-sectional study was conducted. For all in hospital transfused red blood cells (RBCs; n = 95,477), in the German federal state Mecklenburg-Pomerania in 2005, characteristics of the patient and the blood donor (118,406 blood donations) were obtained. Population data were used to predict blood demand and supply until 2020. RESULTS: By 2020 the population increase of those aged 65 years or more (+26.4%) in Mecklenburg-Pomerania will be paralleled by a decrease of the potential donor population (18-68 years; -16.1%). Assuming stable rates per age group until 2020, the demand for in-hospital blood transfusions will increase by approximately 25% (24,000 RBC units) while blood donations will decrease by approximately 27% (32,000 RBC units). The resulting, predicted shortfall is 47% of demand for in-hospital patients (56,000 RBC units). Validation using historical data (1997-2007) showed that the model predicted the RBC demand with a deviation of only 1.2%. Demographic changes are particularly pronounced in former East Germany, but by 2030 most European countries will face a similar situation. The decrease of younger age groups requires an increase of blood donation rates and interdisciplinary approaches to reduce the need for transfusion to maintain sufficient blood supply. CONCLUSIONS: Demography is a major determinant of future transfusion demand. All efforts should be made by Western societies to systematically obtain data on blood donors and recipients to develop strategies to meet future blood demand. PMID- 20849412 TI - Behavior and symptom change among women treated with placebo for sexual dysfunction. AB - INTRODUCTION: In clinical trials of drug treatments for women's sexual dysfunction, placebo responses have often been substantial. However, little is known about the clinical significance, specificity, predictors, and potential mechanisms of placebo response in sexual dysfunction. AIM: We aimed to determine the nature and predictors of sexual function outcomes in women treated with placebo for female sexual arousal disorder (FSAD). METHODS: We conducted a secondary analysis of data from the placebo arm of a 12-week, multisite, randomized controlled pharmaceutical trial for FSAD (N=50). We analyzed the magnitude, domain specificity, and clinical significance of sexual function scores at baseline, 4, 8, and 12 weeks (post-treatment). We examined longitudinal change in sexual function outcomes as a function of several baseline variables (e.g., age, symptom-related distress) and in relation to changes in sexual behavior frequency during the trial. MAIN OUTCOME MEASURE: Female Sexual Function Index total score. RESULTS: The magnitude of change at post-treatment was clinically significant in approximately one-third of placebo recipients. Effect sizes were similar across multiple aspects of sexual function. Symptom improvement was strongly related to the frequency of satisfying sexual encounters during treatment. However, the relationship between sexual encounter frequency and outcome varied significantly between participants. CONCLUSIONS: A substantial number of women experienced clinically significant improvement in sexual function during treatment with placebo. Changes in sexual behavior during the trial, more so than participant age or symptom severity at baseline, appeared to be an important determinant of outcome. Contextual and procedural aspects of the clinical trial may have influenced outcomes in the absence of an active drug treatment. PMID- 20849414 TI - An unusual perianal Crohn's mass. PMID- 20849416 TI - Optimization of conditions for the glycosyltransferase activity of penicillin binding protein 1a from Thermotoga maritima. AB - Cell wall biosynthesis is a key target for antibacterial drugs. The major constituent of the bacterial wall, peptidoglycan, is a netlike polymer responsible for the size and shape of the cell and for resisting osmotic pressure. It consists of glycan chains of repeating disaccharide units cross linked through short peptide chains. Peptidoglycan assembly is catalyzed by the periplasmic domain of bifunctional class A penicillin-binding proteins. Cross linking of the peptide chains is catalyzed by their transpeptidase module, which can be inhibited by the most widely used antibiotics, the beta-lactams. In contrast, no drug in clinical use inhibits the polymerization of the glycan chains, catalyzed by their glycosyltransferase module, although it is an obvious target. We report here the purification of the ectodomain of the class A penicillin-binding protein 1a from Thermotoga maritima (Tm-1a*), expressed recombinantly in Escherichia coli. A detergent screen showed that detergents with shorter aliphatic chains were better solubilizers. Cyclohexyl-hexyl-beta-D maltoside-purified Tm-1a* was found to be monomeric and to have improved thermal stability. A miniaturized, multiwell continuous fluorescence assay of the glycosyltransferase activity was used to screen for optimal reaction conditions. Tm-1a* was active as a glycosyltransferase, catalyzing the formation of glycan chains up to 16 disaccharide units long. Our results emphasize the importance of the detergent in preparing a stable monomeric ectodomain of a class A penicillin binding protein. Our assay could be used to screen collections of compounds for inhibitors of peptidoglycan glycosyltransferases that could serve as the basis for the development of novel antibiotics. PMID- 20849415 TI - MBP-1 is efficiently encoded by an alternative transcript of the ENO1 gene but post-translationally regulated by proteasome-dependent protein turnover. AB - The c-myc promoter-binding protein-1 (MBP-1) is a transcriptional suppressor of tumorigenesis and thought to be the product of alternative translation initiation of the alpha-enolase (ENO1) transcript. In the present study, we cloned a 2552-bp novel cDNA with a putative coding sequence of MBP-1 and functionally examined its ability to encode the MBP-1 protein. Similarly to ENO1, the obtained MBP-1 was widely and differentially expressed in a variety of normal tissues and cancer cells. Experiments using MBP-1 promoter-driven luciferase reporter assays, biochemical cell fractionation followed by RT-PCR detection of the cytoplasmic mRNA, and transcription/translation-coupled reactions, consistently demonstrated that this novel transcript was alternatively transcribed from intron III of the ENO1 gene and was feasible for MBP-1 production. Hypoxia treatments significantly increased the transcriptional activation of the MBP-1 gene. Blocking the proteasomal degradation by MG132 stabilized the MBP-1 protein in cells. Compared with the translation efficiency for production of the MBP-1 protein, the MBP-1 transcript was 17.8 times more efficient than the ENO1 transcript. Thus, we suggest that this newly discovered transcript is a genuine template for the protein synthesis of MBP-1 in cells, and optimal expression of this gene in tumors may lead to effective clinical therapies for cancers. PMID- 20849417 TI - A novel G-quadruplex motif modulates promoter activity of human thymidine kinase 1. AB - G-quadruplex motifs constitute unusual DNA secondary structures formed by stacking of planar hydrogen-bonded G-tetrads. Recent genome-wide bioinformatics and experimental analyses have suggested the interesting possibility that G quadruplex motifs could be cis-regulatory elements. Here, we identified a characteristic potential G-quadruplex-forming sequence element within the promoter of human thymidine kinase 1 (TK1). Our NMR, UV and CD spectroscopy and gel electrophoresis data suggested that this sequence forms a novel intramolecular G-quadruplex with two G-tetrads in K(+) solution. The results presented here indicate the role of this G-quadruplex motif in transcription of TK1 in cell-based reporter assays. Specific nucleotide substitutions designed to destabilize the G-quadruplex motif resulted in increased promoter activity, supporting direct involvement of the G-quadruplex motif in transcription of TK1. These studies suggest that the G-quadruplex motif may be an important target for controlling critical biological processes, such as DNA synthesis, mediated by TK1. PMID- 20849418 TI - Autolytic activity of human calpain 7 is enhanced by ESCRT-III-related protein IST1 through MIT-MIM interaction. AB - Calpain 7, a mammalian ortholog of yeast Cpl1/Rim13 and fungal PalB, is an atypical calpain that lacks a penta-EF-hand domain. Previously, we reported that a region containing a tandem repeat of microtubule-interacting and transport (MIT) domains in calpain 7 interacts with a subset of endosomal sorting complex required for transport (ESCRT)-III-related proteins, suggesting involvement of calpain 7 in the ESCRT system. Although yeast and fungal calpains are thought to be involved in alkaline adaptation via limited proteolysis of specific transcription factors, proteolytic activity of calpain 7 has not been demonstrated yet. In this study, we investigated the interaction between calpain 7 and a newly reported ESCRT-III family member, increased sodium tolerance-1 (IST1), which possesses two different types of MIT-interacting motifs (MIM1 and MIM2). We found that glutathione-S-transferase (GST)-fused tandem MIT domains of calpain 7 (calpain 7MIT) pulled down FLAG-tagged IST1 expressed in HEK293T cells. Coimmunoprecipitation assays with various deletion or point mutants of epitope tagged calpain 7 and IST1 revealed that both repetitive MIT domains and MIMs are required for efficient interaction. Direct MIT-MIM binding was confirmed by a pulldown experiment with GST-fused IST1 MIM and purified recombinant calpain 7MIT. Furthermore, we found that the GST-MIM protein enhances the autolysis of purified Strep-tagged monomeric green fluorescent protein (mGFP)-fused calpain 7 (mGFP-calpain 7-Strep). The autolysis was almost completely abolished by 10 mmN ethylmaleimide but only partially inhibited by 1 mm leupeptin or E-64. The putative catalytic Cys290-substituted mutant (mGFP-calpain 7(C290S)-Strep) showed no autolytic activity. These results demonstrate for the first time that human calpain 7 is proteolytically active, and imply that calpain 7 is activated in the ESCRT system. PMID- 20849419 TI - Identification of groundwater parameters using an adaptative multiscale method. AB - The identification of groundwater parameters in heterogeneous systems is a major challenge in groundwater modeling. Flexible parameterization methods are needed to assess the complexity of the spatial distributions of these parameters in real aquifers. In this article, we introduce an adaptative parameterization to identify the distribution of hydraulic conductivity within the large-scale (4400 km(2) ) Upper Rhine aquifer. The method is based on adaptative multiscale triangulation (AMT) coupled with an inverse problem procedure that identifies the parameters' distributions by reducing the error between measured and simulated heads. The AMT method has the advantage of combining both zonation and interpolation approaches. The AMT method uses area-based interpolation rather than an interpolation based on stochastic features. The method is applied to a standard 2D groundwater model that takes into account the interactions between the aquifer and surface water bodies, groundwater recharge, and pumping wells. The simulation period covers 204 months, from January 1986 to December 2002. Recordings at 109 piezometers are used for model calibration. The simulated heads are globally quite accurate and reproduce the main dynamics of the system. The local hydraulic conductivities resulting from the AMT method agree qualitatively with existing local experimental observations across the Rhine aquifer. PMID- 20849421 TI - Disconnected surface water and groundwater: from theory to practice. AB - When describing the hydraulic relationship between rivers and aquifers, the term disconnected is frequently misunderstood or used in an incorrect way. The problem is compounded by the fact that there is no definitive literature on the topic of disconnected surface water and groundwater. We aim at closing this gap and begin the discussion with a short introduction to the historical background of the terminology. Even though a conceptual illustration of a disconnected system was published by Meinzer (1923), it is only within the last few years that the underlying physics of the disconnection process has been described. The importance of disconnected systems, however, is not widely appreciated. Although rarely explicitly stated, many approaches for predicting the impacts of groundwater development on surface water resources assume full connection. Furthermore, management policies often suggest that surface water and groundwater should only be managed jointly if they are connected. However, although lowering the water table beneath a disconnected section of a river will not change the infiltration rate at that point, it can increase the length of stream that is disconnected. Because knowing the state of connection is of fundamental importance for sustainable water management, robust field methods that allow the identification of the state of connection are required. Currently, disconnection is identified by showing that the infiltration rate from a stream to an underlying aquifer is independent of the water table position or by identifying an unsaturated zone under the stream. More field studies are required to develop better methods for the identification of disconnection and to quantify the implications of heterogeneity and clogging processes in the streambed on disconnection. PMID- 20849422 TI - Volunteers needed for making an impact on public groundwater policy. PMID- 20849424 TI - Plume persistence in fractured sedimentary rock after source zone removal. PMID- 20849425 TI - Ovary starch reserves and pistil development in avocado (Persea americana). AB - In avocado, only a very small fraction of the flowers are able to set fruit. Previous work in other woody perennial plant species has shown the importance of carbohydrates accumulated in the flower in the reproductive process. Thus, in order to explore the implications of the nutritive status of the flower in the reproductive process in avocado, the starch content in the pistil has been examined in individual pollinated and non-pollinated flowers at anthesis and during the days following anthesis. Starch content in different pistilar tissues in each flower was quantified with the help of an image analysis system attached to a microscope. Flowers at anthesis were rich in highly compartmentalized starch. Although no external morphological differences could be observed among flowers, the starch content varied widely at flower opening. Starch content in the ovary is largely independent of flower size because these differences were not correlated with ovary size. Differences in the progress of starch accumulation within the ovule integuments between pollinated and non-pollinated flowers occurred concomitantly with the triggering of the progamic phase. The results suggest that starch reserves in the ovary could play a significant role in the reproductive process in avocado. PMID- 20849426 TI - Meningococcal disease in travelers: a rare but devastating disease. PMID- 20849427 TI - Meningococcal disease: the organism, clinical presentation, and worldwide epidemiology. PMID- 20849428 TI - The risk of meningococcal disease in travelers and current recommendations for prevention. PMID- 20849429 TI - Travelers' protection against meningococcal disease: a new vaccine option. PMID- 20849430 TI - The TCF7L2 diabetes risk variant is associated with HbA1(C) levels: a genome-wide association meta-analysis. AB - Genome-wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes-related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta-analysis of glycated haemoglobin (HbA1(C) ) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2-3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Korcula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta analysis. The strongest association was with the TCF7L2 gene (rs7903146, P= 1.48 * 10-7). This is also the strongest common genetic risk factor for T2D but it has not been identified in previous genome-wide studies of glycated haemoglobin. PMID- 20849431 TI - Administration of interferon for two or more years decreases early stage hepatocellular carcinoma recurrence rate after radical ablation: A retrospective study of hepatitis C virus-related liver cancer. AB - BACKGROUND: Since hepatocellular carcinoma often recurs after surgical resection or radiofrequency ablation, we analyzed a retrospective large cohort of patients with small hepatocellular carcinoma caused by hepatitis C virus (HCV). METHODS: Among 379 patients with HCV RNA-positive small hepatocellular carcinoma (multiple up to three nodules, 3 cm or less each), 77 received interferon-alpha injection and 302 received no anti-viral therapy. RESULTS: Four patients (5.2%) attained sustained virological response (SVR). Cumulative recurrence rates in the treated and untreated groups were 41.1% and 57.5% at the end of the third year, and 63.0% and 74.5% at the fifth year, respectively (P = 0.013). Fifth year-recurrence rates in treated group were 25.0% in SVR, 85.7% in biochemical response, 71.1% in no response, and 46.7% in patients with continuous administration. When four patients with SVR were excluded, recurrence rates in short-term interferon therapy (<2 years) and long-term therapy (>=2 years) were 46.2% and 39.3% at the third year, and 66.2% and 57.4% at the fifth year, respectively (P = 0.012). Multivariate analysis showed that long-term interferon therapy significantly decreased recurrence rate (hazard ratio for interferon <2 years 0.80, interferon >=2 years 0.60, P = 0.044), after adjustment with background covariates including indocyanine green retention rate (P = 0.018), alpha-fetoprotein (P = 0.051), and tumor treatment (P = 0.066). CONCLUSION: A long-term administration of low-dose interferon significantly decreased recurrence of hepatocellular carcinoma after surgical resection or radiofrequency ablation. PMID- 20849432 TI - Simultaneous versus two-stage implant placement and guided bone regeneration in the canine: histomorphometry at 8 and 16 months. AB - AIM: To compare the effect of timing of implant placement and guided bone regeneration (GBR) procedure on osseointegration and newly formed bone at 8 and 16 months. MATERIAL AND METHODS: In seven dogs, four different sites were bilaterally established: (1) an implant placed in a 6-month healed (6m-GBR) bovine bone mineral (BBM) grafted site; (2) a simultaneously placed implant with the grafted BBM (Si-GBR) followed by a membrane coverage; (3) an implant placed in a membrane-protected non-grafted defect; and (4) an implant placement in a naturally healed site (Cont). Histomorphometry was obtained at 8 and 16 months post-implant placement. Bone-implant contact (BIC), crestal bone resorption (CBR), vertical intra-bony (VIB) defect, bone (BAF) and particle (PAF) area fractions, and osteoconductivity (CON) levels were measured. RESULTS: In all sites, BIC ranged between 62% and 79% with no significant differences. PAF ranged from 17% to 27%, with no effect of time. At 8 and 16 months, BAF was significantly smaller at the Si-GBR site when compared with all other sites, CON was significantly greater at the 6m-GBR site, and CBR and VIB were significantly smaller at the 6m-GBR when compared with the Si-GBR sites. CONCLUSIONS: The simultaneous and delayed techniques both showed a similar osseointegration level over time. However, the staged approach showed enhanced newly formed bone, higher osteoconduction around the grafted mineral, less CBR, and smaller vertical bone defect over time compared with the combined approach. PMID- 20849433 TI - Clinical and microbiological effects of mechanical instrumentation and local antimicrobials during periodontal supportive therapy in aggressive periodontitis patients: smoker versus non-smoker patients. AB - AIM: To compare the clinical and microbiological effects of ultrasonic mechanical instrumentation (UMI) associated to home-care use of amine fluoride/stannous fluoride (AmF/SnF(2) )-containing mouthrinse and toothpaste in smoker and non smoker patients affected by generalized aggressive periodontitis (G-AgP) during a recall session of supportive periodontal therapy (SPT). MATERIAL AND METHODS: Thirteen smokers and 25 non-smokers G-AgP patients enrolled in an SPT programme received a single session of UMI associated with home-care use of AmF/SnF(2) containing mouthrinse and toothpaste. Clinical and microbiological parameters were assessed pre-treatment, at 6 and 12 weeks post-treatment. RESULTS: In both groups, UMI plus AmF/SnF(2) -implemented oral hygiene use determined a significant decrease of total bacterial counts, with non-smokers exhibiting a lower count compared with smokers at 12 weeks. No significant differences were observed between smokers and non-smokers in the counts of total pathogens and red complex species at each observation interval. Clinically, a significant reduction of supragingival plaque, gingival inflammation and probing pocket depth was similarly observed in both groups. CONCLUSIONS: A combined mechanical/chemical plaque control approach based on UMI and the use of AmF/SnF(2) agents resulted in the reduction of supragingival plaque deposits, gingival inflammation and subgingival periodontal pathogens in G-AgP patients during SPT, with no substantial difference between smokers and non-smokers. PMID- 20849434 TI - Skin infections in Egyptian renal transplant recipients. AB - BACKGROUND: The risk of skin infections in renal transplant recipients (RTRs) has been described previously; however, it differs markedly by ethnic groups, skin type, and geographical location. We investigated the prevalence and nature of skin infections in a large series of RTRs in our locality in Egypt. PATIENTS AND METHODS: A total 302 RTRs (216 males and 86 females) were included in this study. They were screened for the presence of bacterial, fungal, and viral skin infections depending on clinical signs, Woods lamp examinations, culture, and biopsy if indicated. The patients were compared with 300 healthy controls matched for age and sex (200 males and 100 females). RESULTS: We found 191 (63.25%) RTRs had some kind of skin infection. Folliculitis (10.3%), tinea versicolor (30.1%), dermatophytosis (19.5%), and onychomycosis (7.6%) were statistically significantly more common in RTRs compared with control subjects. CONCLUSION: Our RTRs have higher prevalence rates of folliculitis and superficial fungal infections than the healthy population and they should be searched for in every patient with renal transplantation to ensure early treatment and avoid complications. Low-dose ketoconazole should be considered in renal transplant populations with high rates of superficial fungal infections, as it may reduce risk of such infections. PMID- 20849435 TI - Combined modality of mechanical breakdown and intraembolus thrombolysis in failed systemic thrombolysis of subacute pulmonary embolism patients. AB - OBJECTIVES: Acute massive pulmonary embolism with failed systemic thrombolysis has a high morbidity and mortality with few treatment options available. This study assesses the role of combined modality of mechanical fragmentation and intralesional thrombolysis in failed systemic thrombolysis. METHODS: Seven (13.5%) of 52 patients with massive pulmonary embolism with persistent cardiogenic shock that failed systemic thrombolysis underwent imaging to confirm pulmonary embolism, and then mechanical fragmentation and intralesional thrombolysis. Mechanical breakdown of embolus was accomplished with 5-F multipurpose catheter to re-establish flow, followed by intralesional infusion of urokinase (4,400 IU/kg over 10 minutes followed by 4,400 IU/kg per hour over 24 hours). RESULTS: Four (57.1%) of 7 were unsuccessfully thrombolyzed outside the hospital by urokinase, 2 (28.6%) with recombinant tissue-type plasminogen activator (rtPA) and 1 (14.3%) with streptokinase systemically before 24-48 hours of admission. At presentation, average heart rate and shock index were 121.7/min and 1.45, respectively. Average systolic pulmonary arterial pressure was 73 +/- 2.65 mmHg at presentation, and postoperatively was significantly reduced to 39.7 +/- 10.44 mmHg (P < 0.001). Mortality at 24 hours, 30 days, and 2 years follow-up was 0% (0/7). CONCLUSIONS: Mechanical breakdown of thrombus followed by urokinase infusion may be a cost-effective, minimally invasive, and potentially life-saving procedure for the management of acute massive pulmonary embolism. Randomized controlled trials are required to compare this new strategy to contemporary conventional approaches. PMID- 20849436 TI - Estimating the likelihood of sustained virological response in chronic hepatitis C therapy. AB - The likelihood of a sustained virological response (SVR) is the most important factor for physicians and patients in the decision to initiate and continue therapy for chronic hepatitis C (CHC) infection. This study identified predictive factors for SVR with peginterferon plus ribavirin (RBV) in patients with CHC treated under 'real-life' conditions. The study cohort consisted of patients from a large, retrospective German multicentre, observational study who had been treated with peginterferon alfa-2a plus RBV or peginterferon alfa-2b plus RBV between the years 2000 and 2007. To ensure comparability regarding peginterferon therapies, patients were analysed in pairs matched by several baseline variables. Univariate and multivariate logistic regression analyses were used to determine the effect of nonmatched baseline variables and treatment modality on SVR. Among 2378 patients (1189 matched pairs), SVR rates were 57.9% overall, 46.5% in HCV genotype 1/4-infected patients and 77.3% in genotype 2/3-infected patients. In multivariate logistic regression analysis, positive predictors of SVR were HCV genotype 2 infection, HCV genotype 3 infection, low baseline viral load and treatment with peginterferon alfa-2a. Negative predictors of SVR were higher age (>=40 years), elevated baseline gamma-glutamyl transpeptidase (GGT) and low baseline platelet count (<150,000/MUL). Among patients treated with peginterferon plus RBV in routine clinical practice, genotype, baseline viral load, age, GGT level and platelet levels all predict the likelihood of treatment success. In patients matched by baseline characteristics, treatment with peginterferon alfa 2a may be a positive predictor of SVR when compared to peginterferon alfa-2b. PMID- 20849437 TI - Psychological stress is associated with relapse in type 1 autoimmune hepatitis. AB - BACKGROUND/AIM: The pathophysiological basis of relapse and recrudescence in type 1 autoimmune hepatitis (AIH) is poorly understood. This study examined factors associated with biochemical relapse in type 1 AIH, and specifically addressed whether psychological stress was associated with a relapsing-remitting disease course. METHODS: A case-control study design was used to analyse 33 patients with AIH followed at the Yale Liver Clinic during a 4-year period. Twenty-two patients with 46 episodes of relapse or recrudescence (cases) and 11 controls in long-term remission were identified during this period. Clinical variables were collected to establish factors associated with relapse. All patients were administered the Social Readjustment Rating Scale (SRRS), a psychological stress questionnaire consisting of 43 weighted life events. Stress is judged to be low when the score is 0-150; mild, 151-200; moderate, 201-300 and major >300. RESULTS: AST, ALT, prednisone dose and SRRS score were all significantly different between cases and controls. The mean SRRS score for cases with relapse/recrudescence was 239 vs 152 for the control group, P=0.048 and remained significant on ancova analysis which accounted for covariables, P=0.05. Cases also identified additional stressors not represented in the SRRS at a significantly higher rate than controls. Conversely, the controls spontaneously identified coping strategies that may have allowed them to manage stress more effectively. CONCLUSION: Psychological stress is a significant factor that is associated with relapse in type 1 autoimmune hepatitis. Management of AIH may benefit from strategies to reduce stress and promote psychological well being. PMID- 20849438 TI - Clinical interpretation of Fibroscan(r) results: a real challenge. PMID- 20849439 TI - Demyelinating lesions with features of Balo's concentric sclerosis in a patient with active hepatitis C and human herpesvirus 6 infection. PMID- 20849440 TI - Mechanisms contributing to stability in ecosystem function depend on the environmental context. AB - Stability in ecosystem function is an important but poorly understood phenomenon. Anthropogenic perturbations alter communities, but how they change stability and the strength of stabilizing mechanisms is not clear. We examined temporal stability (invariability) in aboveground productivity in replicated 18-year time series of experimentally perturbed grassland plant communities. We found that disturbed annual-dominated communities were more stable than undisturbed perennial communities, coincident with increases in the stabilizing effect of mean-variance scaling. We also found that nitrogen-fertilized communities maintained stability despite losses in species richness, probably because of increased compensatory dynamics and increased dominance by particularly stable dominant species. Among our communities, slight variation in diversity was not the strongest mechanism driving differences in stability. Instead, our study suggests that decreases in individual species variabilities and increases in the relative abundance of stable dominant species may help maintain stability in the functioning of ecosystems confronted with eutrophication, disturbance, and other global changes. PMID- 20849441 TI - Principles of high-frequency ultrasonography for investigation of skin pathology. AB - Ultrasonography is a valuable diagnostic tool widely used in medicine. During the last three decades, this non-invasive skin imaging method has been extended to dermatology. High-frequency ultrasonography with higher than 20MHz scanners is well-established for measuring tumour thickness and skin thickness when treating inflammatory skin diseases such as scleroderma or psoriasis. High-frequency ultrasonography has become extremely helpful for the preoperative assessment of skin melanoma. The correlation between ultrasonic and histological measurements of melanomas thickness is significantly similarly good using transducers of 20, 75 or 100MHz frequency (r range from 0.895 to 0.99) and better compared with transducers of 7.5MHz frequency (r=0.76). The preoperative sonographically estimated thickness of skin melanoma is sometimes overestimated, because of an underlying inflammatory infiltrate and other reasons. Assessment of skin melanoma thickness using transducers of 100MHz frequency has better agreement with histology, compared with ultrasonography with 20MHz transducers. However, the ultrasonic penetration depth is limited to 1.5mm in case of 100MHz. The newer ultrasonic techniques such as high-frequency ultrasonography and colour Doppler sonography could be used for assessment of the tumour vascularization and its metastatic potential. The wide variety of diagnostic information provided by high frequency ultrasonography undoubtedly improves the management of oncological and inflammatory skin conditions and underlines its essential position in dermatological practice. PMID- 20849442 TI - Ecological processes in a hormetic framework. AB - There is increasing evidence that some non-essential substances or environmental stressors can have stimulatory or beneficial effects at low exposure levels while being toxic at higher levels, and that environmental 'priming' of certain physiological processes can result in their improved functioning in later life. These kinds of nonlinear dose-response relationships are referred to as hormetic responses and have been described across a wide range of organisms (from bacteria to vertebrates), in response to exposure to at least 1000 different chemical and environmental stressors. Although most work in this area has been in the fields of toxicology and human health, the concept of hormesis also has general applicability in ecology and evolutionary biology as it provides an important conceptual link between environmental conditions and organism function - both at the time of initial exposure to stressors and later in life. In this review, we discuss and clarify the different ways in which the term hormesis is used and provide a framework that we hope will be useful for ecologists interested in the fitness consequences of exposure to stressors. By using ecologically relevant examples from the existing literature, we show that hormesis is connected with both acclimation and phenotypic plasticity, and may play an important role in allowing animals to adjust to changing environments. PMID- 20849443 TI - Linking stoichiometric homoeostasis with ecosystem structure, functioning and stability. AB - Ecosystem structure, functioning and stability have been a focus of ecological and environmental sciences during the past two decades. The mechanisms underlying their relationship, however, are not well understood. Based on comprehensive studies in Inner Mongolia grassland, here we show that species-level stoichiometric homoeostasis was consistently positively correlated with dominance and stability on both 2-year and 27-year temporal scales and across a 1200-km spatial transect. At the community level, stoichiometric homoeostasis was also positively correlated with ecosystem function and stability in most cases. Thus, homoeostatic species tend to have high and stable biomass; and ecosystems dominated by more homoeostatic species have higher productivity and greater stability. By modulating organism responses to key environmental drivers, stoichiometric homoeostasis appears to be a major mechanism responsible for the structure, functioning and stability of grassland ecosystems. PMID- 20849444 TI - Evaluation of disease activity and damage in different subtypes of cutaneous lupus erythematosus using the CLASI. AB - BACKGROUND: The Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) is a scoring system for patients with cutaneous lupus erythematosus (CLE) to assess disease activity and damage. Objective The aim of this study was to evaluate whether the CLASI is a useful instrument which reflects the different subtypes of CLE comparably well in each parameter. METHODS: A total of 50 patients (42 female, 8 male) with different subtypes of CLE, including acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE) and LE tumidus (LET), from the Departments of Dermatology, University of Dusseldorf, Germany, and Danderyd Hospital, Stockholm, Sweden, were evaluated using the CLASI at one time point. RESULTS: The total CLASI activity score was significantly lower in patients with LET compared with ACLE (P<0.05) and CCLE (P<0.001), and the total CLASI damage score was significantly lower in patients with LET than with ACLE (P<0.05), SCLE (P<0.001) and CCLE (P<0.001). The erythema score and the scale/hypertrophy score were significantly lower in LET than in ACLE (P<0.05, both) and CCLE (P<0.05 and P < 0.001, respectively). The dyspigmentation score was lowest in patients with LET, differing significantly from ACLE (P<0.05), SCLE (P<0.05) and CCLE (P<0.001). The scarring/atrophy/panniculitis score was significantly higher in patients with CCLE in contrast to SCLE and LET (P<0.05 and P<0.001, respectively). CONCLUSION: These data characterize the CLASI as an overall useful instrument to analyse disease activity and damage in CLE. However, the CLASI does not give an accurate assessment of all disease subtypes; therefore, a revision of the CLASI with critical analysis of all parameters is recommended. PMID- 20849445 TI - Nodular basal cell carcinoma is associated with increased hyaluronan homeostasis. AB - BACKGROUND: Basal cell carcinoma (BCC) is one of the most frequent forms of malignancy in humans. Although BCC is a tumour of low degree of malignancy, if left untreated, it can be locally aggressive, eat away at tissues and cause ulceration. Nodular is the most common subtype of BCC (>50%). Although apparently non-invasive, micronodular, a certain subgroup of nodular, is likely to recur. Glycosaminoglycans (GAGs), such as hyaluronic acid (HA), are extracellular matrix molecules of high importance in malignant transformation, metastasis and other complex remodelling processes. OBJECTIVES: To investigate the expression of GAGs and their metabolizing enzymes in nodular BCC, when compared with adjacent healthy human skin tissue specimens. METHODS: Total GAGs were isolated and purified from nodular BCC and normal adjacent human skin tissue specimens. GAGs were subsequently fractionated by electrophoresis on cellulose acetate membranes and characterized using specific GAG-degrading enzymes. The content of HA in total GAGs was measured using ELISA and the expression of HA synthases (HAS), hyaluronidases (HYAL) and HA receptors (CD44 and receptor hyaluronic acid mediated motility (RHAMM) was assessed using RT-PCR. RESULTS: Nodular BCC is associated with increased levels of HA concomitant with upregulation of gene expression of HAS3, HYAL3 and RHAMM, when compared with normal adjacent skin. CONCLUSION: These results indicate that HA homeostasis in nodular BCC shows distinct features which may be helpful in understanding the complex behaviour of nodular subtype of BCC, thus eventually leading to new treatment strategies. PMID- 20849446 TI - Enterohaemorrhagic Escherichia coli gains a competitive advantage by using ethanolamine as a nitrogen source in the bovine intestinal content. AB - The bovine gastrointestinal tract is the main reservoir for enterohaemorrhagic Escherichia coli (EHEC) responsible for food-borne infections. Characterization of nutrients that promote the carriage of these pathogens by the ruminant would help to develop ecological strategies to reduce their survival in the bovine gastrointestinal tract. In this study, we show for the first time that free ethanolamine (EA) constitutes a nitrogen source for the O157:H7 EHEC strain EDL933 in the bovine intestinal content because of induction of the eut (ethanolamine utilization) gene cluster. In contrast, the eut gene cluster is absent in the genome of most species constituting the mammalian gut microbiota. Furthermore, the eutB gene (encoding a subunit of the enzyme that catalyses the release of ammonia from EA) is poorly expressed in non-pathogenic E. coli. Accordingly, EA is consumed by EHEC but is poorly metabolized by endogenous microbiota of the bovine small intestine, including commensal E. coli. Interestingly, the capacity to utilize EA as a nitrogen source confers a growth advantage to E. coli O157:H7 when the bacteria enter the stationary growth phase. These data demonstrate that EHEC strains take advantage of a nitrogen source that is not consumed by the resident microbiota, and suggest that EA represents an ecological niche favouring EHEC persistence in the bovine intestine. PMID- 20849447 TI - Zooplankton and aggregates as refuge for aquatic bacteria: protection from UV, heat and ozone stresses used for water treatment. AB - Aggregates and zooplankton may provide refuge for aquatic bacteria against external hazards. The ability of attached bacteria to survive and recover from stressors commonly used for water treatment was tested in the laboratory. Without zooplankton or aggregates, both UV and ozone significantly reduced abundance of free-living bacteria in both freshwater and marine medium. The presence of zooplankton carcasses and aggregates, however, allowed some of the attached bacteria to survive and recover quickly within 3 days. Heat exposure was the least effective as both free-living and attached bacteria were able to recover quickly. Selective survival of bacterial phylotypes led to large changes in bacterial community composition after stress exposures, and some of the bacteria that recovered belonged to groups with known pathogens. This study demonstrates that zooplankton and aggregates protected various aquatic bacteria from external stressors, and organic remains generated from zooplankton and aggregates after stress exposure even enabled the surviving bacteria to quickly regrow and subsequently be released into the surrounding water. Hence, water disinfection treatments that overlooked the potential persistence of bacteria associated with organisms and aggregates may not be effective in preventing the spread of undesirable bacteria. PMID- 20849448 TI - Streptomyces associated with a marine sponge Haliclona sp.; biosynthetic genes for secondary metabolites and products. AB - Terrestrial actinobacteria have served as a primary source of bioactive compounds; however, a rapid decrease in the discovery of new compounds strongly necessitates new investigational approaches. One approach is the screening of actinobacteria from marine habitats, especially the members of the genus Streptomyces. Presence of this genus in a marine sponge, Haliclona sp., was investigated using culture-dependent and -independent techniques. 16S rRNA gene clone library analysis showed the presence of diverse Streptomyces in the sponge sample. In addition to the dominant genus Streptomyces, members of six different genera were isolated using four different media. Five phylogenetically new strains, each representing a novel species in the genus Streptomyces were also isolated. Polyphasic study suggesting the classification of two of these strains as novel species is presented. Searching the strains for the production of novel compounds and the presence of biosynthetic genes for secondary metabolites revealed seven novel compounds and biosynthetic genes with unique sequences. In these compounds, JBIR-43 exhibited cytotoxic activity against cancer cell lines. JBIR-34 and -35 were particularly interesting because of their unique chemical skeleton. To our knowledge, this is the first comprehensive study detailing the isolation of actinobacteria from a marine sponge and novel secondary metabolites from these strains. PMID- 20849450 TI - Principles of hemostasis in children: models and maturation. AB - Hemostasis is an active process regulating the formation and dissolution of fibrin clot to preserve vascular integrity. The different phases of hemostasis are coordinated so that effective clotting occurs only at the site of vascular injury while maintaining blood flow in other parts of the circulation. Procoagulant processes culminate in thrombin generation and fibrin clot formation to protect the vasculature against uncontrolled bleeding after injury. Conversely, anticoagulant processes limit clot extension to unaffected portions of the vasculature. Lastly, fibrinolysis is responsible for clot dissolution once tissue repair and regeneration permit the return of normal blood flow. A precise and delicate interplay exists among these processes to ensure normal hemostasis. The hemostatic system is incompletely developed at birth and matures throughout infancy. Both full-term and preterm neonates are born with low levels of most procoagulant proteins including all the contact activation factors and vitamin K dependent factors. Similarly, levels of the major anticoagulant proteins are low at birth. Although often characterized as 'immature', the neonatal hemostatic system is nevertheless functionally balanced with no tendency toward coagulopathy or thrombosis. In this article, we will review the current models of hemostasis and the maturation of the hemostatic system. Our goal is to help clinicians gain a better understanding of the actions of procoagulant agents and of the disruptive effects of serious systemic illnesses on the precarious hemostatic balance of infants. PMID- 20849449 TI - A blueprint of ectoine metabolism from the genome of the industrial producer Halomonas elongata DSM 2581 T. AB - The halophilic gamma-proteobacterium Halomonas elongata DSM 2581(T) thrives at high salinity by synthesizing and accumulating the compatible solute ectoine. Ectoine levels are highly regulated according to external salt levels but the overall picture of its metabolism and control is not well understood. Apart from its critical role in cell adaptation to halophilic environments, ectoine can be used as a stabilizer for enzymes and as a cell protectant in skin and health care applications and is thus produced annually on a scale of tons in an industrial process using H. elongata as producer strain. This paper presents the complete genome sequence of H. elongata (4,061,296 bp) and includes experiments and analysis identifying and characterizing the entire ectoine metabolism, including a newly discovered pathway for ectoine degradation and its cyclic connection to ectoine synthesis. The degradation of ectoine (doe) proceeds via hydrolysis of ectoine (DoeA) to Nalpha-acetyl-L-2,4-diaminobutyric acid, followed by deacetylation to diaminobutyric acid (DoeB). In H. elongata, diaminobutyric acid can either flow off to aspartate or re-enter the ectoine synthesis pathway, forming a cycle of ectoine synthesis and degradation. Genome comparison revealed that the ectoine degradation pathway exists predominantly in non-halophilic bacteria unable to synthesize ectoine. Based on the resulting genetic and biochemical data, a metabolic flux model of ectoine metabolism was derived that can be used to understand the way H. elongata survives under varying salt stresses and that provides a basis for a model-driven improvement of industrial ectoine production. PMID- 20849451 TI - Aspects of pharmacokinetics and pharmacodynamics of sufentanil in pediatric practice. AB - Sufentanil is a potent synthetic opioid. Like other opioids, sufentanil creates a stable hemodynamic environment in cardiovascularly compromised pediatric patients. Clearance, expressed as per kilogram, is increased in children compared to adults. The P450 CYP3A4 enzyme is responsible for the major metabolic N dealkylation pathway. Enzyme activity is reduced in neonates but the maturation of sufentanil clearance is not described. The free active fraction is affected by age because of the reduced alpha(1) -acid glycoprotein plasma concentrations in neonates. Intranasal administration of sufentanil is a possible option for premedication, procedural sedation and analgesia in children, as this option has been found to be safe and effective. Studies concerning the pharmacokinetics and dynamics of sufentanil administered as a bolus or continuous infusion in children are few. PMID- 20849452 TI - Epigenetic mechanisms in senescence, immortalisation and cancer. AB - Cancer is controlled not only by genetic events but also by epigenetic events. The active acquisition of epigenetic changes is a poorly understood but very important process in mammalian development, differentiation, and disease. It is well established that epigenetic events are controlled by a specific subgroup of proteins, such as DNA methyltransferases, histone acetylases histone lysine methyltransferases or histone deacetylases, that influence methylation or acetylation patterns to modulate gene expression. We and others have identified S adenosylhomocysteine hydrolase in a high-throughput genetic screen focused on discovering novel genes whose inhibition induces immortalisation of primary cells. Herein, we address the importance of genes involved in epigenetic mechanisms during senescence and how their effects might determine senescence bypass and immortalisation. The ways in which genes that regulate epigenetic mechanisms might modulate senescence/immortalisation and how these pathways could influence cancer development are explored. Overall, epigenetic modifications seem to play a major role in cancer, influencing tumour outcome by interfering with key senescence pathways. PMID- 20849453 TI - Fingerprint CD34 immunopositivity. PMID- 20849455 TI - Fact or fiction? PMID- 20849456 TI - Nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors are overexpressed in extramammary Paget's disease. AB - BACKGROUND: Neurotrophin (NT) systems appear to play important roles in the pathogenesis of several tumors, but their expression in extramammary Paget's disease (EPD) has not been investigated. METHODS: Thirty-four paraffin-embedded EPD specimens (32 primary EPD and 2 metastatic to lymph nodes) were subject to immunohistochemical staining for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT3, NT4, their high-affinity receptors (TrkA, TrkB and TrkC) and the common low-affinity receptor, p75 NT receptor (p75). RESULTS: All 34 EPD specimens, including 2 metastatic to lymph nodes, showed cytoplasmic overexpression of NGF, BDNF, TrkA and TrkB. The expression (% positive cells) of NGF, BDNF, NT3, NT4, TrkA and TrkB (81.6 +/- 14.9, 86.0 +/- 10.4, 89.6 +/- 14.9, 87.8 +/- 17.9, 83 +/- 14.4 and 86.2 +/- 11.7%) in EPD was significantly higher than in normal skin (21.6 +/- 6.5, 27.6 +/- 4.5, 19.7 +/- 10.1, 8.2 +/- 10.0, 25.0 +/- 5.3 and 25.4 +/- 6.4%), and the expression of these factors in invasive EPD was significantly higher than in noninvasive EPD. Interestingly, Paget cells were negative for p75 and TrkC in all the 34 EPD specimens. CONCLUSIONS: These results suggest that overexpression of NGF, BDNF and their high-affinity receptors (TrkA and TrkB) might play a role in the pathogenesis of EPD. PMID- 20849457 TI - A transient epidermolysis bullosa simplex-like phenotype associated with bexarotene treatment in a G138E KRT5 heterozygote. AB - Basal keratinocyte lysis is the hallmark histopathological finding of epidermolysis bullosa simplex (EBS), a group of rare heritable mechanobullous disorders characterized by intraepidermal blister formation and skin fragility. Over 100 mutations, found predominantly in the genes encoding keratins 5 and 14 (KRT5, KRT14), have been described to account for a variety of clinical subtypes. EBS with mottled pigmentation (EBS-MP) is a rare variant featuring childhood onset reticulate hyperpigmentation and focal palmoplantar keratoderma, typically associated with a P25L KRT5 mutation. In this report, we present the case of a 77 year-old woman with a history of palmoplantar keratoderma who developed a transient EBS-MP-like phenotype associated with bexarotene treatment for cutaneous T-cell lymphoma. Genetic sequencing revealed a heterozygous G138E KRT5 variant, present in approximately 10% of the European population and only rarely associated with pathology. Bexarotene, which has been reported to alter keratin synthesis, caused vesiculobullous reactions with similar frequency in clinical trials. We propose that the cumulative effect of drug treatment and underlying G138E polymorphism resulted in transient basal keratinocyte lysis in our patient and provides a plausible explanation for this unusual bexarotene side effect. PMID- 20849458 TI - Generalized eruptive xanthoma with prominent deposition of naked chylomicrons: evidence for chylomicrons as the origin of urate-like crystals. AB - Eruptive xanthoma is defined by the combination of its clinical and histopathological features. While a nodular dermal infiltrate rich in foamy macrophages and associated with extracellular lipid deposition is typical of eruptive xanthoma, some microscopical variability can be seen. Herein, we report an unusual case of eruptive xanthoma exhibiting triglyceride deposition in a peculiar configuration. A biopsy from a papular lesion showed prominent deposition of crystalline material, surrounded by many foamy histiocytes, in the upper and middle dermis. Such material has been previously termed 'urate-like crystals'. An immunohistochemical analysis using antibodies to lipoprotein suggested that the substance is composed of chylomicrons. This observation suggests that naked chylomicrons may be deposited in the dermis of patients with severe hypertriglyceridemia. PMID- 20849459 TI - Recurrent erythema multiforme triggered by progesterone sensitivity. AB - Determining the underlying etiology of recurrent erythema multiforme (EM) can be a difficult endeavor. Although infection with herpes simplex virus (HSV) has been implicated in some cases, the precise trigger of a given patient's recurrent EM often remains elusive. We discuss the case of a woman with a recurrent blistering eruption that was clinically and histopathologically consistent with EM. An investigation into the etiology of the patient's EM suggested that HSV was not the causative factor but instead pointed toward a hormonal influence that we interpret as autoimmune progesterone dermatitis (APD). This case is presented to highlight the importance of considering hormonal triggers in women with recurrent EM that consistently flares during the luteal phase of the menstrual cycle, the point at which serum progesterone levels peak. A brief review of the literature regarding the diagnosis, histopathology, etiology and treatment of APD is further provided. PMID- 20849461 TI - Genotypes, antibiotic resistance profiles and microarray-based characterization of methicillin-resistant Staphylococcus aureus strains isolated from livestock and veterinarians in Switzerland. AB - Using different typing methods (MLST, spa-, SCCmec- and agr-typing), PFGE and DNA microarray-based chip analysis, we characterized 20 MRSA strains isolated from livestock and veterinarians. PFGE analysis after macrorestriction with EagI provided seven different band patterns, which could be grouped into four clusters. One cluster consisted of all MRSA ST398 strains isolated from pigs, calves, mastitis milk and two veterinarians. One strain of ST398 from a veterinarian and the two strains of ST1 and ST8 formed the three other clusters. Antimicrobial susceptibility testing showed that 15 of 20 strains were resistant to ampicillin, cefoxitin, clindamycin, erythromycin, oxacillin, penicillin and tetracycline. All strains were susceptible to rifampin and vancomycin, 19 were susceptible to ciprofloxacin and 18 were susceptible to sulphamethoxazole/trimethoprim. Genes encoding different enterotoxins, leukotoxins and haemolysins were found in certain strains. PMID- 20849463 TI - Exchange transfusions and top-up transfusions in neonates with Kell haemolytic disease compared to Rh D haemolytic disease. AB - OBJECTIVE: To evaluate neonatal outcome in Kell haemolytic disease compared to Rh D haemolytic disease. STUDY DESIGN: Retrospective study of all (near)-term neonates with Kell (n=34) and Rh D haemolytic disease (n=157) admitted to our centre between January 2000 and December 2008. We recorded the need for exchange transfusion and top-up transfusions up to 3 months of age. RESULTS: Neonates in the Kell group required less days of phototherapy than neonates in the Rh D group [2.4 vs. 4.1 days, respectively (P<0.01)]. The percentage of neonates requiring an exchange transfusion was lower in the Kell group than in the Rh D group [6% (2/34) and 62% (98/157), respectively (P<0.01)]. The percentage of neonates in the Kell group and Rh D group requiring a top-up transfusion was 62% (21/34) and 72% (113/157), respectively (P=0.20). The median number of top-up transfusions per neonate in the Kell group and Rh D group was 1 [interquartile range (IQR) 0 2] and 2(IQR 0-2), respectively (P=0.07). CONCLUSION: Neonates with Kell haemolytic disease require less phototherapy and less exchange transfusions compared to neonates with Rh D haemolytic disease, but an equal number of top-up transfusions. PMID- 20849465 TI - Dramatic efficiency of pegylated interferon in sinus histiocytosis with massive lymphadenopathy. PMID- 20849466 TI - Multiple lymphadenopathy as an initial sign of extramammary Paget disease. AB - Extramammary Paget disease (EMPD) often develops in external genitalia. Paget cells can, however, adopt an invasive phenotype and metastasize to regional lymph nodes and beyond, leading to poor patient outcomes. Based on this clinical observation, multiple lymphadenopathy may represent an initial sign of EMPD. To address the potential significance of multiple lymph node swelling in EMPD, we report two patients with cutaneous primary EMPD who showed multiple lymphadenopathy as an initial sign during the clinical course of the disease as well as tumour metastasis. Significantly, marked lymphatic vessel growth was observed in regional lymph nodes that underwent massive tumour cell invasion. Therefore, nodal lymphangiogenesis may promote tumour cell invasion and metastasis to distant organs, including the lymph nodes, emphasizing the clinical relevance of multiple lymphadenopathy. PMID- 20849464 TI - p53 prevents progression of nevi to melanoma predominantly through cell cycle regulation. AB - p53 is the central member of a critical tumor suppressor pathway in virtually all tumor types, where it is silenced mainly by missense mutations. In melanoma, p53 predominantly remains wild type, thus its role has been neglected. To study the effect of p53 on melanocyte function and melanomagenesis, we crossed the 'high p53'Mdm4+/- mouse to the well-established TP-ras0/+ murine melanoma progression model. After treatment with the carcinogen dimethylbenzanthracene (DMBA), TP ras0/+ mice on the Mdm4+/- background developed fewer tumors with a delay in the age of onset of melanomas compared to TP-ras0/+ mice. Furthermore, we observed a dramatic decrease in tumor growth, lack of metastasis with increased survival of TP-ras0/+: Mdm4+/- mice. Thus, p53 effectively prevented the conversion of small benign tumors to malignant and metastatic melanoma. p53 activation in cultured primary melanocyte and melanoma cell lines using Nutlin-3, a specific Mdm2 antagonist, supported these findings. Moreover, global gene expression and network analysis of Nutlin-3-treated primary human melanocytes indicated that cell cycle regulation through the p21WAF1/CIP1 signaling network may be the key anti-melanomagenic activity of p53. PMID- 20849467 TI - Lichen striatus and blaschkitis: reappraisal of the concept of blaschkolinear dermatoses. AB - BACKGROUND: Blaschkitis (BL) and lichen striatus (LS) are rare dermatoses occurring along the Blaschko lines of the skin with preferential occurrence in distinct age categories. Controversy exists regarding the pathogenesis and classification of BL and LS within the spectrum of blaschkolinear dermatoses. OBJECTIVES: To describe the clinicopathological characteristics of six cases of BL/LS with special emphasis on immunophenotyping the inflammatory infiltrate. Additionally, we review and critically discuss current concepts of the blaschkolinear dermatoses. METHODS: Skin biopsies from six patients with BL and LS were analysed retrospectively. The immunophenotypes of the inflammatory cells were determined and related to clinical features. RESULTS: The clinical characteristics of the diseases occurred equally in both genders and all ages. BL and LS had similar histopathological findings with respect to epidermal changes and composition of the inflammatory infiltrates. Characteristically, a lichenoid lymphocytic infiltrate with exocytosis of inflammatory cells and obvious alterations of the interface zone was observed. CONCLUSIONS: We characterize the two main blaschkolinear dermatoses BL and LS sensu stricto morphologically and open new insights into the pathogenesis of these diseases. We propose the concept of a wide spectrum of blaschkolinear dermatoses with BL and LS located somewhere within the spectrum. We do not think that it is helpful for clinicians to enlarge the spectrum of blaschkolinear diseases and to create numerous 'new' entities. Rather, our aim was to unify diseases with similar clinical and histopathological features and common genetic pathomechanisms underlying phenotypic variations. PMID- 20849468 TI - Combined mass spectrometry- and immunohistochemistry-based approach to determine protein expression in archival melanoma--proof of principle. PMID- 20849469 TI - Incorporation of multicellular spheroids into 3-D polymeric scaffolds provides an improved tumor model for screening anticancer drugs. AB - Development of cancer therapeutics requires a thorough evaluation of drug efficacy in vitro before animal testing and subsequent clinical trials. Three dimensional (3-D) in vitro models have therefore been investigated for drug screening. In this study, we have developed a novel in vitro model in which multicellular aggregates, or spheroids, were incorporated into 3-D porous scaffolds. Drug resistance assays showed that spheroid-seeded scaffolds have much higher drug resistance than monolayer cultures, spheroids on flat substrates, or scaffolds seeded with dispersed cells. Furthermore, spheroid-seeded scaffolds demonstrated higher lactate production leading to acidosis, and higher expression of angiogenic factors. These data suggest that the spheroid-seeded 3-D scaffolds might serve as a useful in vitro system for screening cancer therapeutics. PMID- 20849470 TI - Effect of controlled-release levodopa on the microstructure of sleep in Parkinson's disease. AB - BACKGROUND: Dopamine is an important neurotransmitter in the regulation of the sleep-wake cycle, and parkinsonian patients suffer from prominent sleep abnormalities. Hence, the question arises whether the disrupted sleep pattern in Parkinson's disease (PD) is responsive to dopaminergic treatment. METHODS: Thirty two patients (18 women, 45-82 years old; mean 61 +/- 8 years) with dopamine responsive, akinetic-rigid PD, not taking neuroleptic medication or suffering from dementia were randomized into two groups. Both groups had to withhold their usual dopaminergic medication after noon. At bedtime, one group received 200 mg controlled-release (CR) levodopa/carbidopa, whilst the other group spent the night in the 'off'-state. Polysomnographic recordings were obtained in all patients and 16 age-matched, healthy controls. RESULTS: Compared to healthy controls, patients with PD suffered from significantly decreased total sleep time, REM sleep and slow wave sleep (SWS), whilst the time spent awake was increased. The administration of levodopa/carbidopa CR had no impact on any of these variables. CONCLUSION: Levodopa/carbidopa CR has previously been found effective for treating night-time akinesia, but according to this study, it has no impact on the altered sleep structure in PD. PMID- 20849471 TI - Prevalence of single crowns and fixed partial dentures in elderly citizens in the southern and northern parts of Finland. AB - The epidemiology of oral rehabilitation using fixed prosthodontics has received little attention. The aim of this study was to evaluate the prevalence of single crowns, fixed partial dentures (FPDs), resin-bonded FPDs and implants in elderly Finnish patients and to identify factors that might be associated with the findings. The survey was carried out in the southern and northern parts of Finland. The target population consisted of all persons born in 1919, 1922, 1925, 1928, 1931, 1934 and 1937, who lived in Kirkkonummi and in Lakeus (n=1733) in 1996. The age range of the subjects was 60-78years. In addition to a clinical examination, panoramic radiograph was taken. Data on background factors were obtained using questionnaires and/or interviews. The presence of single crowns, FPDs, resin-bonded FPDs and implants were determined from the panoramic radiographs. Overall, 12.4% of men and 12.1% of women had single crowns, while 4.8% of men and 8.0% of women had FPDs. A logistic regression analysis showed that the presence of crowns and FPDs was significantly associated with a southern place of residence, high and middle levels of education and high frequency of dental visits. PMID- 20849472 TI - Case reports. Trepopnea associated with paroxysmal severe tricuspid regurgitation triggered at left lateral decubitus position. AB - A 78-year-old male patient was referred cardiovascular risk evaluation before elective resection of a bronchial carcinoma. A myocardial infarction with a subsequent coronary artery bypass revascularization and a mitral prosthetic valve surgery were known. Left lateral decubitus (LLD) was permanently avoided because of significant trepopnea since several years. No signs of heart failure were found in the physical examination. A mitral valve prosthesis presented normal characteristics at examination. Left ventricular dimensions and function were normal. A severe tricuspid regurgitation could be documented during examination in the LLD, with changing characteristics in dorsal decubitus, when it could be graded as moderate. Trepopnea associated with severe paroxysmal tricuspid regurgitation was never described before in the literature. Sympathetic/parasympathetic modulation of papillary muscles of the tricuspid valve can be proposed as a probable cause of this dynamic valvular dysfunction. PMID- 20849473 TI - Staphylococcus aureus infective endocarditis mimicking a hydatid cyst. AB - We report an atypical echocardiographic presentation of Staphylococcus aureus infective endocarditis (IE) of the mitral valve in an octogenarian female. Echocardiography revealed perforation of the anterior mitral valve leaflet (AMVL), with a large cystic mass seemingly attached to the AMVL and surrounded by a thin membranous structure. These images were strongly reminiscent of a hydatid cyst. The significant comorbidity of the patient did not justify an urgent surgical approach, and the patient subsequently expired of cardiogenic and septic shock. Autopsy revealed a large vegetation attached to the interatrial septum in the immediate proximity of the AMVL, without signs of the membranous structure and without pathological evidence for septic embolism. This atypical presentation of IE prompted us to discuss a brief review of intracardiac cystic masses. PMID- 20849474 TI - An unusual case of a giant pseudoaneurysm formation after myocardial infarction. AB - In the era of early and invasive therapeutic approaches, myocardial rupture has become an uncommon complication of myocardial infarction. We report an uncommon complication following inferior myocardial infarction with both left ventricular and right ventricular rupture and subsequent communication via a shared pseudoaneurysm. PMID- 20849475 TI - An incidental finding of mitral valve network. AB - A 63-year-old male presented with a 6-month history of worsening exertional dyspnea and was found to have three-vessel coronary artery disease. Transesophageal echocardiography revealed a filamentous structure attached to the anterior mitral valve leaflet, which was confirmed during surgery as filamentous network. To our knowledge, this is the first report to describe such a network attached to the mitral valve. PMID- 20849476 TI - Utility of intracardiac echocardiography for atrial baffle leak closure in repaired transposition of the great arteries. AB - A 27-year-old male with dextro-transposition of great arteries had Senning atrial switch repair in childhood and dual-chamber pacemaker placement for sinus node dysfunction in adulthood. Transthoracic echocardiography showed a lead in the systemic (anatomic right) ventricle. Multidetector computed tomography showed the lead perforating the baffle in the region of the body of the systemic venous atrium into the systemic ventricle. The lead was extracted, and a new lead was placed in the pulmonary (anatomic left) ventricle. A bidirectional baffle shunt persisted. The iatrogenic baffle leak was percutaneously closed with an Amplatzer septal occluder device using both intracardiac echocardiography (ICE) and three dimensional transesophageal echocardiography (3D-TEE). We report the first use of ICE for baffle leak closure, which provided a good definition of the complex anatomy and guided the procedure. PMID- 20849477 TI - Original Investigations. Potential faces of patent foramen ovale (PFO PFO). AB - BACKGROUND: Patent foramen ovale (PFO) is diagnosed on echocardiography by saline contrast study with or without color Doppler evidence of shunting. PFO is benign except when it causes embolic events. METHODS AND RESULTS: In this report, we describe unique additional manifestations related to the diagnosis and presentation of PFO. These include demonstration of PFO during the release phase of "sigh" on the ventilator in the operating room, use of a separate venipuncture to allow preparation of blood-saline-air mixture after multiple failed saline bubble injections, resting and stress hypoxemia related to left to right shunting across a PFO in the absence of pulmonary hypertension, presentation of quadriperesis secondary to an embolic event from a PFO and development of a thrombus on the left atrial aspect of PFO in a patient with atrial fibrillation, and on the right atrial aspect of PFO in a patient who had undergone repair of a flail mitral valve. Finally, in one patient with end-stage renal disease, aortic valve endocarditis and periaortic abscess, PFO acted as a vent valve relieving right atrial pressure following development of aortoatrial fistula. CONCLUSION: PFO diagnosis can be elusive if appropriate techniques are not used during saline contrast administration. PFO can present as hypoxemia in the absence of pulmonary hypertension, can be a rare cause of quadriperesis, and can be associated with thrombus formation on either side of interatrial septum. Finally, PFO presence can be lifesaving in those with sudden increase in right atrial pressure such as with aortoatrial fistula. PMID- 20849478 TI - Characteristics of exercise-induced intrapulmonary arteriovenous fistula in patients with unexplained exertional dyspnea. AB - Dynamic appearance of intrapulmonary arteriovenous fistula (AVF) during exercise may be associated with unexplained exertional dyspnea (UED) and can be diagnosed with an agitated saline contrast study during exercise echocardiography. However, the occurrence of AVF during exercise in patients with UED has not been well described. Thus, the frequency of exercise-induced intrapulmonary AVF in the outpatients with UED was retrospectively analyzed. Thirty-nine outpatients (age: 53 +/- 12, 33 female) with UED underwent symptom-limited supine bicycle exercise echocardiography. Ten patients (26%) developed exercise-induced intrapulmonary AVF. Patients with and without AVF showed the similar peak exercise heart rate, systolic blood pressure, and rate-pressure product. The patients with AVF demonstrated a small but significant decrease in arterial oxygen saturation with exercise as compare to baseline (95.6 +/- 2.8% at peak, vs. 97.5 +/- 2.5% at baseline, P < 0.05 with a paired Student t-test). Our study suggests that exercise-induced intrapulmonary AVF is relatively common in the outpatients with UED and associated with mild exercise desaturation; however, the mechanism of desaturation could not be determined by this study. Further investigation to characterize and determine the clinical significance of AVF is warranted. PMID- 20849479 TI - Echocardiographic study of a Mestizo-Mexican population with Marfan syndrome. AB - BACKGROUND: The cardiovascular manifestations of Marfan syndrome (MFS) are the main causes of morbidity and mortality. This study describes the clinical and echocardiographic findings in a Mestizo-Mexican population affected by the disease. METHODS: A total of 166 patients previously diagnosed with MFS were recruited for the study, 114 of them underwent complete clinical history, with emphasis on Ghent nosology criteria, and transthoracic echocardiography, with 68 patients also undergoing transesophageal study. RESULTS: Major cardiovascular criteria from the Ghent nosology predominated in adults (P < 0.0001), minor criteria in children (P = 0.007). Among pediatric patients, 83% had a New York Heart Association (NYHA) functional class of I; however, 64% of the adult patients had an NYHA class >=II, (P < 0.0001). Corrected aortic echocardiographic measurements of both groups demonstrated statistically significant differences. Children had a greater prevalence of mitral valve prolapse, while adults more frequently presented with aortic complications. Seven patients died during follow up from aortic complications, one child and six adults. CONCLUSIONS: Based on the data, we can conclude that MFS in the Mestizo-Mexican population has a distinctly different clinical pattern in children and adults, and a graver prognosis in adults. Adult patients with MFS are significantly more likely, than children, to have aortic dilation, aortic aneurysm, aortic regurgitation, aneurysm rupture, aortic dissection, and fatal outcome. Children with MFS are more likely, than adults, to present with asymptomatic mitral and tricuspid prolapse and mitral valve regurgitation. PMID- 20849480 TI - A simplified echocardiographic measurements of direct effects of restrictive annuloplasty on mitral valve geometry. AB - OBJECTIVE: The purpose of this study was to evaluate the direct effects of restrictive mitral annuloplasty on mitral valve geometry. METHODS: We studied 23 patients (mean age: 63 +/- 5 years) with functional mitral regurgitation (moderate to severe) and advanced cardiomyopathy (ejection fraction: 25 +/- 8%) with ischemic (n = 15) or nonischemic (n = 8) conditions, who underwent restrictive annuloplasty. We determined annular septal-lateral diameter, tenting height, tenting area, vertical length of coaptation of the mitral leaflets (coaptation length), and ratio of coaptation length to septal-lateral diameter (coaptation length index) at end-systole, before and after surgery, using transthoracic echocardiography. RESULTS: Annular septal-lateral diameter, tenting height, and tenting area were significantly decreased (34 +/- 7 to 20 +/- 5 mm, P < 0.05; 9 +/- 4 to 5 +/- 2 mm, P < 0.05; 210 +/- 120 to 80 +/- 50 mm(2) , P < 0.05, respectively), whereas coaptation length and coaptation length index were significantly increased (3.4 +/- 1.3 to 6.5 +/- 2.9 mm, P < 0.05; 0.11 +/- 0.06 to 0.33 +/- 0.15, P < 0.05, respectively). Spearman's rank correlation analysis revealed that these five variables had a statistically significant correlation with the degree of mitral regurgitation. Furthermore, stepwise regression analysis showed that coaptation length index, in contrast to coaptation length, was the most important correlate with the degree of mitral regurgitation. CONCLUSION: Our simplified parameters were useful for quantitative and geometrical descriptions of mitral valve geometry, and may also provide important information for developing a surgical strategy for functional mitral regurgitation. PMID- 20849481 TI - Right ventricular function in adult patients with Eisenmenger physiology: insights from quantitative echocardiography. AB - BACKGROUND: The favorable outcomes of Eisenmenger syndrome (ES) relative to other forms of pulmonary arterial hypertension (PAH) have been partially attributed to a unique adaptation of the right ventricle (RV). However, conventional measures of RV function may not adequately express this adaptation. METHODS: We studied 23 patients with ES (age 43 +/- 17 years, 16 women, pulmonary artery systolic pressure [PASP] 93 +/- 26 mmHg), 25 patients with PAH (age 44 +/- 13 years, 17 women, PASP 92 +/- 19 mmHg), and 25 subjects without known structural disease (age 45 +/- 16 years, 17 women). We evaluated long- and short-axis function of the RV with two-dimensional strain and anatomical M-mode echocardiography, respectively. RESULTS: Long-axis function of the RV was comparable between patients with ES and PAH although depressed relative to controls (global strain, 15.6 +/- 4.7, -14.9 +/- 4.3, and -22.4 +/- 2.8%, respectively, P < 0.001; global RV systolic strain rate, -0.77 +/- 0.26, -0.84 +/- 0.24, and -1.11 +/- 0.21 1/sec, respectively, P < 0.001). However, short-axis RV function was significantly better in patients with ES versus those with PAH and preserved relative to controls (RV fractional shortening by anatomical M-mode, median [interquartile range], 21%[14-33%], 14%[10-16%], and 26%[22-36%], respectively, P = 0.002 for ES vs. PAH, P = 0.09 for ES vs. controls). This differential was not reflected in conventional measures of RV function (fractional area change, 32 +/- 10 vs. 29 +/- 8% in ES and PAH, respectively, P = 0.26). CONCLUSION: In patients with ES, the RV is characterized by preserved short-axis function, despite a depressed long-axis function. Thus, conventional assessment of RV function might not be suitable for patients with ES. PMID- 20849482 TI - New, simple echocardiographic indexes for the estimation of filling pressure in patients with cardiac disease and preserved left ventricular ejection fraction. AB - BACKGROUND: There are few data on echocardiographic indexes incorporating peak mitral inflow velocity (E), left atrial volume index (LAVi), and pulmonary artery pressure (PAP) for estimation of left ventricular (LV) filling pressure in patients with preserved LV ejection fraction (EF >= 50%). METHODS: Patients underwent echocardiography <=20 minutes of cardiac catheterization. Echocardiographic variables were compared to invasively measured LV end-diastolic pressure (LVEDP). RESULTS: Of the 122 patients, 67 (55%) were women, the mean age was 55 +/- 9 years, the mean left ventricular ejection fraction (LVEF) was 61 +/- 6%, 107 (88%) were hypertensive, and 79 (65%) had significant coronary artery disease at catheterization. E/Ea correlated with LVEDP (R = 0.68, P < 0.0001), compared to PAP (R = 0.53, P < 0.001), peak E velocity (R = 0.48, P < 0.001), and LAVi (R = 0.48, P < 0.001). E/Ea > 12 had 75% sensitivity and 78% specificity for LVEDP >= 20 mmHg (area under curve (AUC) = 0.79, P < 0.0001), compared with (PAP + LAVi)/2 > 30 (sensitivity = 72%, specificity = 80%, AUC = 0.84, P < 0.001) and (E + LAVi)/2 > 57 (sensitivity = 73% and specificity = 81%, AUC = 0.82, P < 0.001) (P = NS). E <60 cm/sec had 94% negative, and E>90 cm/sec had 96% positive, predictive value for LVEDP >= 20 mmHg. (E + LAVi)/2 added incrementally to E/Ea when E/Ea was in the gray zone. CONCLUSIONS: New, simple echocardiographic equations, (E + LAVi)/2 and (PAP + LAVi)/2, have comparable accuracy to E/Ea for LVEDP estimation in patients with cardiac disease and preserved LVEF, and (E + LAVi)/2 added incrementally to E/Ea alone when E/Ea was in the gray zone. Peak E velocity alone had high negative and positive predictive value for elevated LVEDP in this population. These simple echocardiographic variables could be used-in isolation or with E/Ea-in patients with cardiac disease and preserved LVEF for the diagnosis of diastolic heart failure. PMID- 20849483 TI - The effect of cardiac fibrosis on left ventricular remodeling, diastolic function, and N-terminal pro-B-type natriuretic peptide levels in patients with nonischemic dilated cardiomyopathy. AB - BACKGROUND: Cardiac fibrosis is common and associated with poor prognosis in patients with heart failure. We investigated the effect of cardiac fibrosis on the left ventricular (LV) diastolic function, functional capacity, LV remodeling, and biochemical parameters in patients with nonischemic dilated cardiomyopathy (NIDC). In addition, we investigated the biochemical and echocardiographic predictors of cardiac fibrosis in this group. METHODS AND RESULTS: Forty patients with NIDC were enrolled. Cardiac fibrosis was evaluated according to the presence of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging. Nineteen patients had cardiac fibrosis (Group I) and 21 patients did not have cardiac fibrosis (Group II). LV systolic and diastolic parameters were assessed with conventional and tissue Doppler echocardiography. N-terminal pro-B-type natriuretic peptide (NT-pro BNP) levels of each patient were recorded. Patients with cardiac fibrosis had impaired diastolic function, higher functional class and NT-pro BNP levels, and significant LV remodeling than the patients without cardiac fibrosis. A correlation analysis revealed that the cardiac fibrosis severity was associated with functional class, cardiac chamber sizes, NT-pro BNP levels, diastolic parameters such as E/Se. A linear regression analysis demonstrated that NT-pro BNP and E/Se were the independent predictors of cardiac fibrosis. CONCLUSION: Cardiac fibrosis correlates with impaired LV diastolic function and functional capacity, elevated NT-proBNP levels, and adverse cardiac remodeling in patients with NIDC. Therefore, the assessment of cardiac fibrosis can be useful in the management of these patients. PMID- 20849484 TI - Left ventricular diastolic function and right atrial size are important rhythm outcome predictors after intraoperative ablation for atrial fibrillation. AB - BACKGROUND: Left ventricular (LV) diastolic function and right atrial (RA) size are not routinely included in preoperative echocardiographic examination in patients undergoing cardiac surgery with concomitant ablation for atrial fibrillation (AF). OBJECTIVE: To investigate the role of echocardiographic variables including LV diastolic function and RA area in long-term rhythm outcome prediction, in patients with documented AF undergoing intraoperative ablation concomitant to coronary artery bypass grafting (CABG). METHODS: Thirty-five consecutive patients, scheduled for CABG, and with a history of paroxysmal or permanent AF for 8.5 +/- 11.3 years (mean +/- SD) (median 5.8 years), were included in this prospective study. Echocardiography was performed prior to and 2.3 +/- 0.4 years after the surgical procedure. RESULTS: Both LA and RA areas, LV diastolic function, paroxysmal AF, and sinus rhythm (SR) preoperatively were associated with SR at long-term follow-up. In the multivariate analysis, RA area (P = 0.004), and decreased LV diastolic function preoperatively, measured as the maximal LV long-axis relaxation velocity (P = 0.02), predicted SR at follow-up. CONCLUSIONS: RA size and LV diastolic function may be important variables in prediction of long-term rhythm outcome after intraoperative ablation for AF. PMID- 20849485 TI - New annular tissue Doppler markers of pulmonary hypertension. AB - BACKGROUND: Tissue Doppler imaging (TDI) of mitral (MA) and tricuspid annulus (TA) events characterizes systolic and diastolic properties of each respective ventricle. However, the effect of chronic pulmonary hypertension (cPH) on these TDI annular events has not been well described. METHODS: Measurements of right ventricular (RV) performance with TDI of the lateral mitral and tricuspid annuli, to measure isovolumic contraction (IVC) and systolic (S) signals were recorded from 50 individuals without PH and from 50 patients with cPH. To avoid confounding variables, all patients had normal left ventricular ejection fraction and were in normal sinus rhythm at the time of the examination. RESULTS: As expected, markers of RV systolic performance were markedly reduced while LV systolic function remained largely unaffected in cPH patients when compared to patients without PH. TDI interrogation of the MA revealed lengthening of the time interval between IVC and systolic signal (70 +/- 17 msec) when compared to individuals without PH (43 +/- 8 msec; P < 0.0001). In contrast, cPH markedly shortened the time interval between IVC and the TA systolic signal (34 +/- 12 msec) when compared to individuals without PH (65 +/- 17 msec; P < 0.0001). CONCLUSIONS: cPH lengthens time interval between the IVC and the MA systolic signal while shortening this same interval when the TA is interrogated with TDI; reflecting the potential influence that cPH exerts in biventricular performance. Whether measuring these intervals be routinely used in the follow-up of cPH patients will require further study. PMID- 20849486 TI - Noninvasive evaluation of coronary flow velocity reserve in homozygous familial hypercholesterolemia by transthoracic Doppler echocardiography. AB - OBJECTIVE: To evaluate the value of transthoracic Doppler echocardiography (TTDE) of the left anterior descending coronary for the detection of early abnormalities of coronary arteries in asymptomatic patients with homozygous familial hypercholesterolemia (HoFH). METHODS: Seventeen asymptomatic patients with HoFH and 10 controls had plasma total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides measured and underwent TTDE of their left coronary descending artery to determine peak and mean flow velocities under basal conditions and under hyperemia induced by adenosine infusion. Coronary flow velocity reserve (CFVR) was calculated from the mean flow velocities. The presence of aortic supravalvular stenosis was also determined from supravalvular flow velocity and aortic valve thickening values. RESULTS: HoFH patients had similar basal but significantly lower hyperemic flow velocities and CFVR than control patients. Eight of the 17 HoFH patients had supravalvular aortic stenosis, and these patients had significantly higher LDL cholesterol and lower CFVR than those without this stenosis. Treatment with lipid-lowering drugs lowered lipid levels and increased CFVR values, but neither of these parameters reached normal values. CONCLUSIONS: TTDE is a suitable noninvasive technique to detect early abnormalities of coronary arteries and to monitor the clinical efficacy of lipid-lowering treatment in asymptomatic HoFH patients. PMID- 20849487 TI - Assessment of coronary flow parameters by transesophageal echocardiography in patients with isolated coronary artery ectasia: effect of intravenous nitroglycerin. AB - BACKGROUND: We sought to assess coronary flow parameters in patients with isolated coronary artery ectasia (CAE) as compared to subjects with normal coronaries. METHODS: Consecutively, we enrolled 30 patients with ectasia of the left anterior descending (LAD) coronary artery (study group), and 10 subjects with normal coronaries (control group). All patients underwent transesophageal echocardiography to visualize the LAD. Spectral recordings of proximal LAD flow velocities were made and velocity time integrals were calculated. The diameter of the proximal LAD was measured and LAD blood flow was calculated. Nitroglycerin (0.3 mg) was administered intravenously and measurements were repeated 5 minutes later. RESULTS: The mean age of the whole series was 48.6 +/- 8 years, 39 (97.5%) being males. A significantly higher baseline systolic, diastolic, and total coronary blood flow was found in the study group as compared to the control group (46.1 +/- 34.3 vs. 23.1 +/- 8.2, 123.9 +/- 73.3 vs. 68.1 +/- 21.6, 170.1 +/- 97.9 vs. 91.1 +/- 26.8 cm(3) /min, respectively, P < 0.05 for all). Within the study group, nitroglycerin administration caused a significant decrease in peak diastolic velocity; systolic, diastolic, and total velocity time integrals; and both diastolic and total coronary blood flow (P < 0.05 for all). Meanwhile, within the control group, nitroglycerin administration caused a significant increase in the total coronary blood flow (P < 0.05). CONCLUSIONS: Patients with CAE have higher resting coronary blood flow in comparison with subjects with normal coronaries. Intravenous nitroglycerin administration causes significant reduction of coronary blood flow in ectatic coronary arteries. PMID- 20849488 TI - Feasibility of using real time "Live 3D" echocardiography to visualize the stenotic aortic valve. AB - BACKGROUND: Aortic stenosis valve area (AS AVA) using the continuity equation (CE AVA) has limitations. Thus anatomic assessment of AS AVA would be useful. METHOD: AS AVA was measured using "live three-dimensional (3D)" echocardiography that is a two-dimensional (2D) display of a three-dimensionally acquired 2-3 cm thick pyramidal image. In 52 aortic stenosis patients with CE AVA measurements, attempts were made at measuring AS AVA using 2D echocardiography (2D AVA) and real time, Live 3D echocardiography (3D AVA). 3D AVA and 2D AVA were compared to each other and to CE AVA. RESULTS: 2D AVA could be obtained in 30 patients (58%) and 3D AVA in 50 patients (96%). Of the 30 patients in whom 3D AVA and 2D AVA were both measured, the correlation was 0.831 (P < 0.001). 3D AVA was smaller in 19 patients. In 17 of these patients, 3D AVA was closer to CE AVA. In two patients, 2D AVA was smaller than 3D AVA and in both patients 3D AVA was closer to CE AVA. The correlations between 2D AVA and CE AVA and 3D AVA and CE AVA were 0.581 and 0.673, respectively (all P < 0.001). CONCLUSION: A simplified 3D technique that is a "thick slice" 2D examination, can obtain AS AVA more often than a "thin slice" 2D echocardiogram. This 3D AVA correlates well with 2D AVA but is smaller and correlates better with CE AVA suggesting that the effective AS orifice is not planar but is more of a "tunnel" than a "flat ring." PMID- 20849489 TI - Relationship between bicuspid aortic valve morphology and aortic wall degeneration: further evidence is emerging. PMID- 20849491 TI - Achieving racial parity in pediatric kidney transplantation: yes we can. PMID- 20849492 TI - The evolution of cooperative breeding in the African cichlid fish, Neolamprologus pulcher. AB - The conundrum of why subordinate individuals assist dominants at the expense of their own direct reproduction has received much theoretical and empirical attention over the last 50 years. During this time, birds and mammals have taken centre stage as model vertebrate systems for exploring why helpers help. However, fish have great potential for enhancing our understanding of the generality and adaptiveness of helping behaviour because of the ease with which they can be experimentally manipulated under controlled laboratory and field conditions. In particular, the freshwater African cichlid, Neolamprologus pulcher, has emerged as a promising model species for investigating the evolution of cooperative breeding, with 64 papers published on this species over the past 27 years. Here we clarify current knowledge pertaining to the costs and benefits of helping in N. pulcher by critically assessing the existing empirical evidence. We then provide a comprehensive examination of the evidence pertaining to four key hypotheses for why helpers might help: (1) kin selection; (2) pay-to-stay; (3) signals of prestige; and (4) group augmentation. For each hypothesis, we outline the underlying theory, address the appropriateness of N. pulcher as a model species and describe the key predictions and associated empirical tests. For N. pulcher, we demonstrate that the kin selection and group augmentation hypotheses have received partial support. One of the key predictions of the pay-to-stay hypothesis has failed to receive any support despite numerous laboratory and field studies; thus as it stands, the evidence for this hypothesis is weak. There have been no empirical investigations addressing the key predictions of the signals of prestige hypothesis. By outlining the key predictions of the various hypotheses, and highlighting how many of these remain to be tested explicitly, our review can be regarded as a roadmap in which potential paths for future empirical research into the evolution of cooperative breeding are proposed. Overall, we clarify what is currently known about cooperative breeding in N. pulcher, address discrepancies among studies, caution against incorrect inferences that have been drawn over the years and suggest promising avenues for future research in fishes and other taxonomic groups. PMID- 20849493 TI - Using learning networks to understand complex systems: a case study of biological, geophysical and social research in the Amazon. AB - Developing high-quality scientific research will be most effective if research communities with diverse skills and interests are able to share information and knowledge, are aware of the major challenges across disciplines, and can exploit economies of scale to provide robust answers and better inform policy. We evaluate opportunities and challenges facing the development of a more interactive research environment by developing an interdisciplinary synthesis of research on a single geographic region. We focus on the Amazon as it is of enormous regional and global environmental importance and faces a highly uncertain future. To take stock of existing knowledge and provide a framework for analysis we present a set of mini-reviews from fourteen different areas of research, encompassing taxonomy, biodiversity, biogeography, vegetation dynamics, landscape ecology, earth-atmosphere interactions, ecosystem processes, fire, deforestation dynamics, hydrology, hunting, conservation planning, livelihoods, and payments for ecosystem services. Each review highlights the current state of knowledge and identifies research priorities, including major challenges and opportunities. We show that while substantial progress is being made across many areas of scientific research, our understanding of specific issues is often dependent on knowledge from other disciplines. Accelerating the acquisition of reliable and contextualized knowledge about the fate of complex pristine and modified ecosystems is partly dependent on our ability to exploit economies of scale in shared resources and technical expertise, recognise and make explicit interconnections and feedbacks among sub-disciplines, increase the temporal and spatial scale of existing studies, and improve the dissemination of scientific findings to policy makers and society at large. Enhancing interaction among research efforts is vital if we are to make the most of limited funds and overcome the challenges posed by addressing large-scale interdisciplinary questions. Bringing together a diverse scientific community with a single geographic focus can help increase awareness of research questions both within and among disciplines, and reveal the opportunities that may exist for advancing acquisition of reliable knowledge. This approach could be useful for a variety of globally important scientific questions. PMID- 20849495 TI - The effects of droperidol and ondansetron on dispersion of myocardial repolarization in children. AB - OBJECTIVES: To compare the effects of droperidol and ondansetron on electrocardiographic indices of myocardial repolarization in children. AIM: To refine understanding of the torsadogenic risk to children exposed to anti-emetic prophylaxis in the perioperative period. BACKGROUND: QT interval prolongation is associated with torsades des pointes (TdP), but is a poor predictor of drug torsadogenicity. Susceptibility to TdP arises from increased transmural dispersion of repolarization (TDR) across the myocardial wall, rather than QT interval prolongation per se. TDR can be measured on the electrocardiogram as the time interval between the peak and end of the T wave (Tp-e). Tp-e may therefore provide a readily available, noninvasive assay of drug torsadogenicity. The perioperative period is one of high risk for TdP in children with or at risk of long QT syndromes. Droperidol and ondansetron are two drugs commonly administered perioperatively, for prophylaxis of nausea and vomiting, which can prolong the QT interval. This study investigated their effects on myocardial repolarization. METHODS: One hundred and eight ASA1-2 children undergoing elective day-case surgery were randomized to receive droperidol, ondansetron, both or neither. Pre- and post-administration 12-lead electrocardiogram (ECGs) were recorded. QT and Tp e intervals were measured and compared within and between groups, for the primary endpoint of a 25 ms change in Tp-e. RESULTS: Eighty children completed the study. There were no demographic or baseline ECG differences between groups. QT intervals lengthened by 10-17 ms after allocated treatments, with no between group differences. Values remained within normal limits for all groups. Tp-e intervals increased by 0-7 ms, with no between-group differences. There were no instances of dysrhythmia. CONCLUSIONS: Droperidol and ondansetron, in therapeutic anti-emetic doses, produce equivalent, clinically insignificant QT prolongation and negligible Tp-e prolongation, suggesting that neither is torsadogenic in healthy children at these doses. PMID- 20849496 TI - Behavior and quality of life measures after anesthesia for tonsillectomy or ear tube insertion in children. AB - BACKGROUND: Past research examining the psychosocial impact of general anesthesia and day case surgery on children has been hampered by a lack of valid and reliable assessment tools. AIM: The purpose of the current study was to assess the feasibility of using a well-validated scale (i.e. the Pediatric Quality of Life Inventory Generic Core Scales Version 4.0, PedsQL) in the perioperative setting and to establish changes seen in a sample of children having day case surgery when using this scale. METHOD: Eighty-nine children (aged 3-12 years) scheduled for general anesthesia for day case tonsillectomy or ear tube insertions were recruited into a prospective study in Melbourne, Australia. Parents completed the PedsQL and the Post Hospitalization Behavioral Questionnaire (PHBQ), and children completed the PedsQL (child self-report) at baseline (preanesthesia), 7 days following anesthesia and 30 days following anesthesia. RESULTS: The response rate at day 7 and day 30 was modest but when returned the PedsQL and PHBQ had minimal missing data. On the PedsQL, parents rated children's physical functioning as worse at day 7 than at baseline but psychosocial functioning did not differ significantly from baseline. At 30 days, both physical and psychosocial functioning was rated by parents to be better than baseline levels. From children's perspective, there was little evidence of a change in their physical or psychosocial functioning on the self-report PedsQL at day 7, but by day 30 both physical and psychosocial functioning was above baseline levels. A similar pattern was observed on the PHBQ, with little difference in ratings of behavioral problems between baseline and day 7, but less behavioral problems reported at day 30 compared with baseline. CONCLUSIONS: The PedsQL is feasible for use in the perioperative setting. Future studies should take into account the possibility that deterioration of psychosocial functioning is uncommon at 1 -month postsurgery compared to the preoperative baseline. PMID- 20849498 TI - Does ultrasound guidance improve the efficacy of dorsal penile nerve block in children? AB - BACKGROUND: Penile nerve block (PNB) is a well-established technique used for circumcision; it requires the injection of local anesthetics close to the dorsal nerve of the penis. The goal of this study was to compare the efficacy of ultrasound-guided PNB versus the classical landmark-based technique (LBT) in children undergoing circumcision. METHODS: Forty boys, aged 1-14 years old that were scheduled for circumcision were randomly assigned to ultrasound-guided and landmark-based groups. All patients were placed under standard anesthesia with sevoflurane. In each group, patients received the penile block with ropivacaine, 0.75 mg.kg(-1) per side, and 0.05 mg.kg(-1) at the penis base. Groups were compared for intraoperative failure rate of the block, anesthesia time, postoperative pain scale, time of first required dose of paracetamol, time to first micturition, and average duration of stay in the postanesthesia care unit. RESULTS: The failure rate of dorsal PNB was not statistically different between groups (P = 0.5). Ultrasound guidance improved the efficacy of the PNB compared to the LBT in terms of postoperative pain scores on arrival in the PACU (P < 0.01) and after 30 min (P < 0.01). The ultrasound-guided technique also delayed the time to the first paracetamol dose administration (P < 0.0001), but the duration of the procedure, defined as the time between anesthesia induction and the end of surgery, was increased by 10 min in the US-guided group (P = 0.001). CONCLUSION: Ultrasound-guided PNB improved the efficacy of the block compared with the LBT in terms of the postoperative pain during the first postoperative hour and the time to the first requirement for postoperative analgesia. PMID- 20849497 TI - A comparison of four sedation techniques for pediatric dental surgery. AB - BACKGROUND: We prospectively assessed the efficacy and side effects of four sedation techniques in our dental clinic: oral midazolam, intranasal (IN) midazolam, IN midazolam combined with oral transmucosal fentanyl citrate (OTFC), and IN midazolam combined with IN sufentanil. MATERIALS & METHODS: With IRB approval, a nonrandomized open label study of moderate sedation in children undergoing dental surgery was administered during a 6 -month period. The sedation regimen was rotated daily at the anesthesiologist's discretion. Each sedation was monitored by a research nurse who assessed the quality of sedation and the frequency of complications. All children were monitored during the procedure and recovery for at least 20 min, before discharge based on the University of Michigan Sedation and Ohio State behavior rating scores. RESULTS: One hundred and two children were sedated in the dental clinic during this period. The sedation was successful in 73% (range 64% to 88%) of the children. The time to onset was greatest with OTFC (37 min) and least with IN midazolam (17 min) compared with the other two groups (20 and 30 min). Recovery after OTFC was prolonged (39 min) significantly compared with the other three groups (26.5-30 min). Efficacy of sedation and frequency of complications (9% incidence of nausea and 6% of mild hemoglobin desaturation) were similar among the groups. CONCLUSIONS: All four sedation regimens were equally effective in this cohort of healthy children. The onset and recovery with OTFC was significantly delayed compared with the other regimens. The frequency of side effects was small; there were no side effects in the PO midazolam group. PMID- 20849499 TI - Parental presence, clowns or sedative premedication to treat preoperative anxiety in children: what could be the most promising option? AB - BACKGROUND AND OBJECTIVES: A significant number of children undergo surgery experience high levels of anxiety in the presurgical period. The aim of this study is to investigate which intervention is more effective in reducing preoperative anxiety. METHODS/MATERIALS: The sample was composed of 75 subjects (aged 5-12 years) who had to undergo minor day surgery. Children were randomly assigned to: the Clowns group (N = 25) accompanied to the preoperative room by the clowns and by a parent; Premedication group (N = 25) premedicated with oral midazolam and accompanied to the preoperative room by one parent; or the Control group (N = 25) only accompanied by one parent. Anxiety in the preoperative period was measured by using the Modified Yale Preoperative Anxiety Scale (m-YPAS). Parental anxiety was measured by using the State-Trait Anxiety Inventory (STAI Y 1/Y-2). RESULTS: The Clown group was significantly less anxious during the induction of anesthesia compared with Premedication group and Control group. There were not any significant differences between Control group and Premedication group. There was an increased level of anxiety in the induction room in comparison with the waiting room: this difference was statistically significant for Control group and Premedication group, whereas it was not significant in Clown group. CONCLUSIONS: PPIA+clown intervention is more effective in reducing anxiety in children during the preoperative period than PPIA alone or PPIA+oral midazolam. PMID- 20849500 TI - Children with spinal dysraphism: transversus abdominis plane (TAP) catheters to the rescue! AB - Transversus abdominis plane (TAP) block catheters may offer an alternative to a central neuraxial blockade for patients undergoing major abdominal surgery (Paediatr Anaesth 19: 2009; 296). This case series consists of two children with spinal dysraphism in whom bilateral TAP block catheters were placed for postoperative pain relief. Administration of low dose, low concentration local anesthetic provided both children with excellent postoperative analgesia. PMID- 20849501 TI - Successful resuscitation of bupivacaine-induced cardiotoxicity in a neonate. AB - We report a case of bupivacaine-induced cardiotoxicity in a neonate following caudal epidural block under general anesthesia for urologic surgery. Prompt recognition of the complication allowed early intervention with both standard resuscitative measures and administration of 20% Intralipid((r)) , resulting in a good outcome. PMID- 20849502 TI - Successful resuscitation after inadvertent intravenous injection of bupivacaine in an adolescent. PMID- 20849503 TI - Harlequin appearance postepidural analgesia in a child following thoracotomy. PMID- 20849504 TI - The biceps femoris muscle as a landmark for performing the popliteal sciatic nerve block using ultrasound guidance in pediatric patients. PMID- 20849506 TI - Airway responses to desflurane with laryngeal mask airways in children. PMID- 20849507 TI - Remifentanil infusion reduces desflurane airway irritation via proseal laryngeal mask in children. PMID- 20849508 TI - Impacted toothbrush in the oropharynx: a challenging airway. PMID- 20849509 TI - Who can pull it out? PMID- 20849510 TI - Congenital diaphragmatic hernia repair in neonates: is thoracoscopy feasible? PMID- 20849511 TI - Late diagnosis of H-Type tracheoesophageal fistula. PMID- 20849512 TI - Airway management of undiagnosed tracheoesophageal fistula detected accidentally intraoperatively. PMID- 20849513 TI - Gabapentin as part of multimodal analgesia in a newborn with epidermolysis bullosa. PMID- 20849514 TI - Propofol overdose in a preterm baby: may propofol infusion syndrome arise in two hours? PMID- 20849515 TI - Nitrous oxide for glycine encephalopathy. PMID- 20849516 TI - Fibroblasts from the growing margin of keloid scars produce higher levels of collagen I and III compared with intralesional and extralesional sites: clinical implications for lesional site-directed therapy. AB - BACKGROUND: Overproduction of collagen and its abnormal assembly are hallmarks of keloid scars. Type I/III collagen ratios are altered in keloids compared with normal skin. Fibroblasts from different sites in keloid tissue, perilesional compared with intralesional and extralesional sites, show differential apoptosis and contraction. Additionally, early vs. later cell culture passages display differential collagen expression. We therefore hypothesize that keloid fibroblasts from the growing margin of the keloid express higher levels of collagen type I and III, and that collagen production is altered by extended cell culture passage. OBJECTIVES: (i) To measure collagen I and III at mRNA and protein levels quantitatively in keloid fibroblasts, growth media and tissue sections; and (ii) to perform tissue staining for collagen I and III expression in different lesional sites. METHODS: Keloid fibroblast cultures from intralesional, perilesional and extralesional sites (n = 8 separate keloid cases, yielding 64 biopsy samples) were established from passage 0 to passage 3. Collagen I and III mRNA was quantified using quantitative reverse transcription polymerase chain reaction. We also measured the protein levels quantitatively by developing a highly specific and sensitive capture sandwich enzyme-linked immunosorbent assay. A novel in-cell Western blotting was carried out in addition to haematoxylin and eosin and Herovici staining on keloid tissue sections for collagen I and III. RESULTS: Collagen types I and III were significantly higher (P < 0.03) in fibroblasts from the growing margin (perilesional site) compared with extralesional and intralesional keloid biopsy sites. As the passage number increased, the amount of collagen I significantly (P < 0.05) decreased and the collagen I/III ratio also decreased. CONCLUSIONS: Our data show that cells from the growing margin of keloid scars have a higher production of collagen I and III compared with other lesional sites. Additionally, temporal extension of cell passage affects collagen production. Clinically these findings may influence selection and interpretation of extended cell passage and provide future direction for lesional site-specific therapy in keloid scars. PMID- 20849517 TI - No mutation of elastin and fibulin-5 genes in a patient with acquired cutis laxa associated with chronic urticaria. PMID- 20849518 TI - Collagen triple helix repeat containing-1 in the differential diagnosis of dermatofibrosarcoma protuberans and dermatofibroma. AB - BACKGROUND: The distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) is a well-known challenge for dermatopathologists. Immunohistochemical stains have been used to augment routine histological examination to aid in differentiating DF from DFSP. Collagen triple helix repeat containing-1 (Cthrc1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury. It is indicated to be a cell type-specific inhibitor of transforming growth factor-beta, which in turn impacts collagen type I and III deposition, neointimal formation, and dedifferentiation of stem cells. Cthrc1 has also been shown to be highly active and potent in degrading extracellular matrix proteins and was found to be overexpressed in several malignant tumours, such as breast cancer and malignant melanoma. To our knowledge, however, expression of Cthrc1 in DFSP and DF has not been studied before. OBJECTIVES: To assess the expression of Cthrc1 in DFSP and DF and to ascertain whether Cthrc1 is superior to antibodies traditionally used in differentiating DF from DFSP. METHODS: Immunohistochemical staining was performed on 23 cases of DFSP and 35 cases of DF, using antibodies to Cthrc1, CD34, factor XIIIa, CD10 and stromelysin-3 (ST3). RESULTS: Twenty-two of 23 (96%) DFSP samples were positive for Cthrc1, whereas 32 of 35 (91%) DF samples were negative. CD34 was expressed in most DFSPs (22 of 23, 96%), whereas it was completely negative in most cases of DF (29 of 35, 83%). Expression of factor XIIIa was found in most cases of DF (33 of 35, 94%), whereas it was completely absent in 21 of 23 (91%) DFSP cases. Expression of CD10 was found in most cases of DF (30 of 35, 86%), whereas it was completely absent in 13 of 23 (57%) DFSP cases. ST3 was expressed strongly in most cases of DF (32 of 35, 91%), whereas it was completely absent in 18 of 23 (78%) DFSP cases. The preferential Cthrc1 staining of DFSP in comparison with DF was statistically significant (P < 0.01). CONCLUSIONS: We confirmed that Cthrc1 is a positive marker for DFSP and that Cthrc1 staining might be more reliable than markers traditionally used. Cthrc1 was not positive in absolutely [corrected] all cases of DFSP, and combination with CD34, factor XIIIa and ST3 immunostaining could make the distinction more reliable. PMID- 20849519 TI - Iranian nursing students' comprehension and experiences regarding evaluation process: a thematic analysis study. AB - In this study, a qualitative design based on a thematic analysis approach was employed to explore the comprehension and experiences of Iranian nursing students regarding evaluation process in both classroom and clinical setting. After utilising purposeful sampling to choose 13 bachelor's degree nursing students, semi-structured interviews were held for data gathering. During the data analysis, three main themes emerged: 'definition of evaluation process', 'unfair evaluation' and 'ideal evaluation'. The second theme consisted of two sub-themes: 'problematic process' and 'unexpected outcome'. Our study findings showed a gap between what Iranian nursing students depicted as a fair and equitable evaluation and what they experienced during their academic career. There is a need to bring a change to process of evaluation to increase the feeling of fairness and justice regarding evaluation among nursing students. The findings can be helpful for international nurse instructors to be exposed to the unheard perspectives of nursing students and reconsider the weaknesses of evaluation process conducted by them. PMID- 20849520 TI - Documentation of diabetes care in home nursing service in a Swedish municipality: a cross-sectional study on nurses' documentation. AB - OBJECTIVES: To assess what was documented by Registered Nurses regarding diabetes care in a Swedish municipality's home nursing service; to what extent diabetes related nursing actions were planned for, performed and evaluated according to the goals of metabolic control, treatment and prevention of complications. DESIGN: Cross-sectional study. SUBJECTS: Registered Nurses' documentation of patients with diabetes mellitus (n=172). MAIN OUTCOME MEASURES: Number of recorded different nursing actions planned, performed and evaluated. RESULT: The overall standard of records was insufficient. Evaluation of blood glucose levels and metabolic control was documented in 61% of the records; weight was documented in 4% of the records. Blood pressure was recorded in 10%. Ongoing foot ulcers were documented in 21%. Patient education or actions to prevent foot ulcers was not recorded. Tablet and insulin administration were well recorded. The nursing process was not followed. STUDY LIMITATION: Updated medicine lists were missing in many files, this might have resulted in an underestimation of the number of included records. CONCLUSION: The Registered Nurses are responsible for a vulnerable patient group suffering from multi-organ disease unable to maintain their own diabetes self-care. Insufficient documentation may lead to impaired quality of care. We suggest that improved documentation routines include a structure of planning, performing and evaluation of metabolic control (blood glucose measurements, Hba1c, weight and nutrition status), complications (regular blood pressure measurements, protective foot care) and education of health care assistants in assisted diabetes self-care. PMID- 20849521 TI - Increased effect of the ApoE gene on survival at advanced age in healthy and long lived Danes: two nationwide cohort studies. AB - Studies of Nordic twins suggest an increased genetic influence on mortality with age. Contrary to this, the heterogeneity hypothesis predicts that the mortality of individuals carrying a 'frail' or 'risky' genotype in a population will approach that of noncarriers with age because of selection pressure. The ApoE epsilon4 allele is associated with an increased mortality risk, and its effect has been suggested to decrease with age. Here, we investigated the effect of ApoE epsilon4 allele on survival in a sample of the healthiest and long-lived Danes. The study population comprised Danes born in 1905 and a replicate sample of the 1895 cohort. For the 1905 cohort, a total of 350 carriers and 1256 noncarriers of the ApoE epsilon4 allele were followed from 1998 until death or end of follow-up. Cox regression models were used for the analysis. Of the 1606 persons with known ApoE epsilon4 status in 1998, 1546 had died at the end of the 10-year follow-up. Carriers of the ApoE epsilon4 allele had an increased mortality compared to noncarriers, and the influence of ApoE status on mortality increased in the age interval 92-103. For the covariates sex and independency status, the difference in relative risk of death between groups decreased with advancing age. Our findings of increasing influence of ApoE epsilon4 allele on mortality with age do not support previous findings of decreased influence ApoE epsilon4 allele on mortality with age, and alternative models such as the multifactorial threshold models should be considered for understanding the genetic effects on mortality at advanced age. PMID- 20849522 TI - Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. AB - Genetic variation in FOXO3A has previously been associated with human longevity. Studies published so far have been case-control studies and hence vulnerable to bias introduced by cohort effects. In this study we extended the previous findings in the cohorts of oldest old Danes (the Danish 1905 cohort, N=1089) and middle-aged Danes (N=736), applying a longitudinal study design as well as the case-control study design. Fifteen SNPs were chosen in order to cover the known common variation in FOXO3A. Comparing SNP frequencies in the oldest old with middle-aged individuals, we found association (after correction for multiple testing) of eight SNPs; 4 (rs13217795, rs2764264, rs479744, and rs9400239) previously reported to be associated with longevity and four novel SNPs (rs12206094, rs13220810, rs7762395, and rs9486902 (corrected P-values 0.001 0.044). Moreover, we found association of the haplotypes TAC and CAC of rs9486902, rs10499051, and rs12206094 (corrected P-values: 0.01-0.03) with longevity. Finally, we here present data applying a longitudinal study design; when using follow-up survival data on the oldest old in a longitudinal analysis, we found no SNPs to remain significant after the correction for multiple testing (Bonferroni correction). Hence, our results support and extent the proposed role of FOXO3A as a candidate longevity gene for survival from younger ages to old age, yet not during old age. PMID- 20849523 TI - Mitochondrial functional impairment with aging is exaggerated in isolated mitochondria compared to permeabilized myofibers. AB - Mitochondria regulate cellular bioenergetics and apoptosis and have been implicated in aging. However, it remains unclear whether age-related loss of muscle mass, known as sarcopenia, is associated with abnormal mitochondrial function. Two technically different approaches have mainly been used to measure mitochondrial function: isolated mitochondria and permeabilized myofiber bundles, but the reliability of these measures in the context of sarcopenia has not been systematically assessed before. A key difference between these approaches is that contrary to isolated mitochondria, permeabilized bundles contain the totality of fiber mitochondria where normal mitochondrial morphology and intracellular interactions are preserved. Using the gastrocnemius muscle from young adult and senescent rats, we show marked effects of aging on three primary indices of mitochondrial function (respiration, H(2) O(2) emission, sensitivity of permeability transition pore to Ca(2+) ) when measured in isolated mitochondria, but to a much lesser degree when measured in permeabilized bundles. Our results clearly demonstrate that mitochondrial isolation procedures typically employed to study aged muscles expose functional impairments not seen in situ. We conclude that aging is associated with more modest changes in mitochondrial function in sarcopenic muscle than suggested previously from isolated organelle studies. PMID- 20849524 TI - Heart rate recovery after constant-load exercise tests is decreased in proportion to the importance (severity and diffusion) of exercise-induced lower-limb ischaemia. AB - BACKGROUND: Conditions that may influence heart rate recovery at 1 min of recovery from exercise (HRR1: end-exercise heart rate minus heart rate 1 min after exercise) are not fully understood. We hypothesized that the 'importance' (both local severity and regional diffusion) of peripheral skeletal muscle ischaemia is associated with low HRR1. DESIGN AND METHODS: In 529 patients with suspected or confirmed peripheral vascular disease not receiving beta-blockers (61.4 +/- 11.3 years old), we retrospectively studied the relationship of HRR1 to exercise-induced changes in transcutaneous oxygen DROP index (limb changes minus chest changes from rest). The sum of DROP indices observed on both calves and both buttocks (DROPtot) provides the unique opportunity to estimate both the severity and the diffusion of exercise-induced ischaemia on the right and left side simultaneously. It was used during a constant-load treadmill test (3.2 km h( 1) ; 10% grade) to classify patients in quartiles, the fourth quartile representing the more 'important' ischaemias. RESULTS: There was an inverse relationship between quartiles of DROPtot and HRR1, even after adjustment for heart rate reserve (Delta HR: end-exercise minus resting heart rate), age (<= or >60 years), gender, body mass index, treadmill maximal walking distance and ankle brachial index: adjusted R = 0.629; P<0.0001. CONCLUSIONS: During constant-load treadmill testing, DROPtot, an index of the 'importance' of exercise-induced lower-limb ischaemia, correlates with HRR1. Whether HRR1 is improved in proportion of DROPtot improvement in patients undergoing surgery or rehabilitation for peripheral artery disease is a fascinating issue for future studies. PMID- 20849525 TI - Bioassay-guided evaluation of antioxidant and antinociceptive activities of carvacrol. AB - We examined the antioxidant properties in vitro and the antinociceptive effect of carvacrol (CARV) in several models of pain in mice. CARV presented a strong antioxidant potential according to the TRAP/TAR evaluation; it also presented scavenger activity against nitric oxide and prevented lipid peroxidation in vitro. In mice, when evaluated against acetic acid-induced abdominal writhing, CARV (25, 50 and 100 mg/kg, i.p.) reduced (p < 0.001) the number of writhing compared to the control group, without opioid participation. In the formalin test, CARV also significantly inhibited both the early (neurogenic pain) and the late (inflammatory pain) phases of formalin-induced licking, with inhibition percentage values of 56.8% (100 mg/kg) for the neurogenic phase and 41.2% (25 mg/kg), 73.8% (50 mg/kg) and 99.7% (100 mg/kg) for the inflammatory phase. CARV also produced a significant inhibition of the pain caused by capsaicin (63.1, 67.1 and 95.8%, p < 0.001) and glutamate (46.4, 61.4 and 97.9%, p < 0.01). When assessed in a thermal model of pain, CARV (100 mg/kg, i.p.) caused a significant increase (p < 0.05) in the latency response on the hot-plate test. Such results were unlikely to be provoked by motor abnormality. Together, these results indicate that the properties of CARV should be more thoroughly examined in order to achieve newer tools for management and/or treatment of painful conditions, including those related to pro-oxidant states. PMID- 20849526 TI - Phenotype prediction of non-synonymous single-nucleotide polymorphisms in human ATP-binding cassette transporter genes. AB - A large number of non-synonymous single-nucleotide polymorphisms (nsSNPs) have been found in human genome, but there is poor knowledge on the relationship between the genotype and phenotype of these nsSNPs. Human ATP-binding cassette (ABC) transporters are able to transport a number of important substrates including endogenous and exogenous compounds. This study aimed to predict the phenotypical impact of nsSNPs of human ABC transporter genes, and the predicted results were further validated by reported phenotypical data from site-directed mutagenesis and clinical genetic studies. One thousand and six hundred thirty-two nsSNPs were found from 49 human ABC transporter genes. Using the PolyPhen and SIFT algorithms, 41.8-53.6% of nsSNPs in ABC transporter genes were predicted to have an impact on protein function. The prediction accuracy was up to 63-85% when compared with known phenotypical data from in vivo and in vitro studies. There was a significant concordance between the prediction results using SIFT and PolyPhen. Of nsSNPs predicted as deleterious, the prediction scores by SIFT and PolyPhen were significantly related to the number of nsSNPs with known phenotypes confirmed by experimental and human studies. The amino acid substitution variants are supposed to be the pathogenetic basis of increased susceptibility to certain diseases with Mendelian or complex inheritance, altered drug resistance and altered drug clearance and response. Predicting the phenotypic consequence of nsSNPs using computational algorithms may provide a better understanding of genetic differences in susceptibility to diseases and drug response. The prediction of nsSNPs in human ABC transporter genes would be useful hints for further genotype-phenotype studies. PMID- 20849528 TI - Cellular and molecular Ca2+ microdomains in olfactory cilia support low signaling amplification of odor transduction. AB - Signal transduction depends critically on the spatial localization of protein constituents. A key question in odor transduction is whether chemotransduction proteins organize into discrete molecular complexes throughout olfactory cilia or distribute homogeneously along the ciliary membrane. Our recordings of Ca(2+) changes in individual cilia with unprecedented spatial and temporal resolution, by the use of two-photon microscopy, provide solid evidence for Ca(2+) microdomains (transducisomes). Dissociated frog olfactory neurons were preloaded with caged-cAMP and fluo-4 acetoxymethyl ester probe Ca(2+) indicator. Ca(2+) influx through cyclic nucleotide-gated (CNG) channels was evoked by uniformly photoreleasing cAMP, while ciliary Ca(2+) was measured. Discrete fluorescence events were clearly resolved. Events were missing in the absence of external Ca(2+) , consistent with the absence of internal Ca(2+) sources. Fluorescence events at individual microdomains resembled single-CNG channel fluctuations in shape, mean duration and kinetics, indicating that transducisomes typically contain one to three CNG channels. Inhibiting the Na(+) /Ca(2+) exchanger or the Ca(2+) -ATPase prolonged the decay of evoked intraciliary Ca(2+) transients, supporting the participation of both transporters in ciliary Ca(2+) clearance, and suggesting that both molecules localize close to the CNG channel. Chemosensory transducisomes provide a physical basis for the low amplification and for the linearity of odor responses at low odor concentrations. PMID- 20849527 TI - gamma-protocadherins are enriched and transported in specialized vesicles associated with the secretory pathway in neurons. AB - Gamma protocadherins (Pcdh-gammas) resemble classical cadherins and have the potential to engage in cell-cell interactions with homophilic properties. Emerging evidence suggests non-conventional roles for some protocadherins in neural development. We sought to determine whether Pcdh-gamma trafficking in neurons is consistent with an intracellular role for these molecules. Here we show that, in contrast to the largely surface localization of classical cadherins, endogenous Pcdh-gammas are primarily intracellular in rat neurons in vivo and are equally distributed within organelles of subsynaptic dendritic and axonal compartments. A strikingly higher proportion of Pcdh-gamma-containing organelles in synaptic compartments was observed at postnatal day 16. To determine the origin of Pcdh-gamma-trafficking organelles, we isolated organelles with Pcdh-gamma antibody-coupled magnetic beads from brain organelle suspensions. Vesicles with high levels of COPII and endoplasmic reticulum-Golgi intermediate compartment (ERGIC) components were isolated with the Pcdh-gamma antibody but not with the classical cadherin antibody. In cultured hippocampal neurons, Pcdh-gamma immunolabeling partially overlapped with calnexin- and COPII-positive puncta in dendrites. Mobile Pcdh-gamma-GFP profiles dynamically codistributed with a DsRed construct coupled to ER retention signals by live imaging. Pcdh-gamma expression correlated with accumulations of tubulovesicular and ER-like organelles in dendrites. Our results are consistent with the possibility that Pcdh-gammas could have a unique function within the secretory pathway in addition to their documented surface roles. PMID- 20849529 TI - Acute genetic perturbation of exocyst function in the rat calyx of Held impedes structural maturation, but spares synaptic transmission. AB - The exocyst is an octameric protein complex mediating polarized secretion by tethering vesicles to target membranes. In non-vertebrate neurons, the exocyst has been associated with constitutive membrane addition at growth cones and nerve terminals, but its function in synaptic vesicle trafficking at mammalian nerve terminals remains unclear. Here, we examined the role of the exocyst complex in immature postnatal day (P)13 and mature P21 rat calyces of Held. Exo70, an exocyst subunit conferring membrane anchoring of the complex, was tagged with green fluorescent protein (GFP) and overexpressed as a full-length subunit or as a dominant-negative C-terminally truncated variant (Exo70DeltaC) disrupting membrane targeting. In vivo expression of the Exo70 subunits in the calyx was achieved by stereotaxic adeno-associated virus-mediated gene transfer into globular bushy cells of the rat ventral cochlear nucleus at P2. Overexpression of dominant-negative Exo70DeltaC, but not full-length Exo70, decreased the structural complexity and volume of calyces, as assayed by confocal microscopy and three-dimensional reconstructions. The distribution of active zones and synaptic vesicles remained unaffected. Neither perturbation changed the characteristics of spontaneous and evoked neurotransmitter release, short-term depression or recovery from depression. Together, these data suggest that in central mammalian synapses, the exocyst complex mediates the addition of membrane during postnatal presynaptic maturation, but does not function as a tethering complex in local recycling of vesicles within the synaptic vesicle cycle. PMID- 20849531 TI - Investigative dermatology: where do we stand and where do we go? PMID- 20849530 TI - Intramuscular AAV delivery of NT-3 alters synaptic transmission to motoneurons in adult rats. AB - We examined whether elevating levels of neurotrophin-3 (NT-3) in the spinal cord and dorsal root ganglion (DRG) would alter connections made by muscle spindle afferent fibers on motoneurons. Adeno-associated virus (AAV) serotypes AAV1, AAV2 and AAV5, selected for their tropism profile, were engineered with the NT-3 gene and administered to the medial gastrocnemius muscle in adult rats. ELISA studies in muscle, DRG and spinal cord revealed that NT-3 concentration in all tissues peaked about 3 months after a single viral injection; after 6 months NT-3 concentration returned to normal values. Intracellular recording in triceps surae motoneurons revealed complex electrophysiological changes. Moderate elevation in cord NT-3 resulted in diminished segmental excitatory postsynaptic potential (EPSP) amplitude, perhaps as a result of the observed decrease in motoneuron input resistance. With further elevation in NT-3 expression, the decline in EPSP amplitude was reversed, indicating that NT-3 at higher concentration could increase EPSP amplitude. No correlation was observed between EPSP amplitude and NT-3 concentration in the DRG. Treatment with control viruses could elevate NT-3 levels minimally resulting in measurable electrophysiological effects, perhaps as a result of inflammation associated with injection. EPSPs elicited by stimulation of the ventrolateral funiculus underwent a consistent decline in amplitude independent of NT-3 level. These novel correlations between modified NT-3 expression and single-cell electrophysiological parameters indicate that intramuscular administration of AAV(NT-3) can exert long-lasting effects on synaptic transmission to motoneurons. This approach to neurotrophin delivery could be useful in modifying spinal function after injury. PMID- 20849532 TI - TLR-2-mediated cytokine and chemokine secretion in human keratinocytes. AB - The human epidermis provides a first line of defense against exogenous pathogens. Resistance to bacterial skin infections, e.g. with Staphylococcus aureus (S. aureus), is based on the function of intact innate immune mechanisms in the epidermis, mainly provided by keratinocytes. They establish the local cytokine and chemokine milieu which is necessary for attracting other cells participating in an immune response. Toll-like receptor (TLR)-2 recognizes components of S. aureus and is known to be expressed on keratinocytes. The aim of this study was to investigate TLR-2-mediated chemokine and cytokine secretion on human primary keratinocytes (HPKs) both on mRNA and on protein level. As there is no selective TLR-2 ligand known so far, we chose Pam3Cys that acts via TLR-2/TLR-1 heterodimers, lipoteichoic acid (LTA) that acts via TLR-2/TLR-6 and peptidoglycan (PGN) which acts via TLR-2 and Nod. Pam3Cys stimulation yielded in an enhanced secretion of CCL20, CCL2, MMP9 and IL-8 in HPK, whereas stimulation with PGN or LTA showed no or solely slight effects. Our findings show evidence for a functional TLR-2/TLR-1 signalling profile in HPKs upon stimulation with Pam3Cys contributing to the defense against bacterial skin infections. PMID- 20849533 TI - Proteomic profiling reveals a catalogue of new candidate proteins for human skin aging. AB - Studies of skin aging are usually performed at the genomic level by investigating differentially regulated genes identified through subtractive hybridization or microarray analyses. In contrast, relatively few studies have investigated changes in protein expression of aged skin using proteomic profiling by two dimensional (2-D) gel electrophoresis and mass spectrometry, although this approach at the protein level is suggested to reflect more accurately the aging phenotype. We undertook such a proteomic analysis of intrinsic human skin aging by quantifying proteins extracted and fluorescently labeled from sun-protected human foreskin samples pooled from 'young' and 'old' men. In addition, we analyzed these candidate gene products by 1-D and 2-D western blotting to obtain corroborative protein expression data, and by both real-time PCR (RT-PCR) and microarray analyses to confirm expression at the mRNA level. We discovered 30 putative proteins for skin aging, including previously unrecognized, post translationally regulated candidates such as phosphatidyl-ethanolamine binding protein (PEBP) and carbonic anhydrase 1 (CA1). PMID- 20849534 TI - Interferon-gamma induces upregulation and activation of the interleukin-31 receptor in human dermal microvascular endothelial cells. AB - Interleukin-31 (IL-31), a recently discovered cytokine derived from T helper cells, is involved in chronic dermatitis and pruritus. This study demonstrates for the first time that the IL-31 receptor complex for IL-31 is substantially upregulated in human dermal microvascular endothelial cells after stimulation with interferon-gamma (IFN-gamma). Activation of the IL-31 receptor complex results in the induction of the intracellular ERK1/2 signaling pathway and downregulation of IFN-gamma-induced monokine induced by IFN-gamma expression. Inhibitor studies revealed that the IFN-gamma-induced IL-31RA upregulation is processed via JNK and PI3 kinase activation. In sum, our study points toward an interaction between the T(H) 1-derived cytokine IFN-gamma and the T(H) 2-derived cytokine IL-31 on endothelial cells. PMID- 20849535 TI - PTCH promoter methylation at low level in sporadic basal cell carcinoma analysed by three different approaches. AB - Basal cell carcinoma (BCC) is the most common form of skin cancer. Mutations of the PTCH hallmark gene are detected in about 50-60% of BCCs, which raises the question whether other mechanisms such as promoter methylation can inactivate PTCH. Therefore, we performed methylation analysis of the PTCH promoter in a total of 56 BCCs. The sensitivity of three different methods, including direct bisulphite sequencing PCR, MethyLight and high-resolution melting (HRM), was applied and compared. We found that HRM analysis of DNA from fresh tissue [rather than formalin-fixed and paraffin-embedded tissue (FFPE)] was the most sensitive method to detect methylation. Low-level methylation of the PTCH promoter was detected in five out of 16 analysed BCCs (31%) on DNA from fresh tissue but only in two (13%) samples on short-time stored FFPE DNA from the very same tumors. In contrast, we were unable to detect methylation by HRM on long-time stored DNA in any of the remaining 40 BCC samples. Our data suggest that (i) HRM on DNA extracted from fresh tissue is the most sensitive method to detect methylation and (ii) methylation of the PTCH promoter may only play a minor role in BCC carcinogenesis. PMID- 20849536 TI - Human umbilical cord blood cells form epidermis in the skin equivalent model. AB - Recently, human embryonic stem cells have been differentiated in vitro into functional epidermal keratinocytes. Here, we demonstrated that these cells can be generated also from non-embryonic, human umbilical cord blood (hUCB) cells that have the potential to differentiate into cells of non-hematopoietic lineage. Human UCB mono-nucleated cells were cultivated in monolayer and in three dimensional skin equivalent cultures and assayed for the presence of phenotype specific markers. Our results determined that after one month of culturing in serum containing medium, the hUCB cells produced morphologically homogeneous colonies of epithelial cells expressing keratinocyte-specific markers. They also formed stratified epidermis in organ cultures that contained sporadic CD1a positive cells within the accurate strata. We concluded that hUCB cells have the capacity to differentiate into functional epidermal keratinocytes and may serve as a source of high-quality keratinocytes for clinical applications. PMID- 20849537 TI - Development of an in vitro coculture of primary sensitive pig neurons and keratinocytes for the study of cutaneous neurogenic inflammation. AB - Cutaneous neurogenic inflammation (CNI) is often associated with skin disorders. Activated sensory neurons secrete neuropeptides, such as substance P (SP), which initiate or aggravate inflammation in the skin. The discovery of new molecules acting on these neurons is hampered by the difficulty of reproducing the interactions between nerve endings and skin in vitro. We developed an in vitro model based on the coculture of porcine primary keratinocytes and sensory neurons, which mimics skin innervation. To test the relevance of this model, we compared the effects of different substances on CNI by measuring SP secretion in vitro using a sensitive enzyme immunoassay. Collectively, our results indicate that the use of porcine cells could be very useful to perform an in vitro model of CNI. By adding capsaicin, which induces the secretion of SP by neurons, to the culture, we show that our model mimics CNI in vitro, allowing us to screen for molecules that inhibit this inflammatory response. Such a model can be used to test the effects of different substances on CNI and may be useful for dermatological or cosmetic applications. Based on our screen, we found that extracts of Laminaria digitata and Vernonia sublutea inhibit CNI. PMID- 20849538 TI - Direct high-frequency stimulation of peri-implant rabbit bone: a pilot study. AB - OBJECTIVE: This study aimed to evaluate the effect of direct high-frequency mechanical stimulation on the peri-implant tissue healing. MATERIALS AND METHODS: A total of 48 custom-made 2-mm diameter titanium implants were inserted in the tibial epiphyses of 12 rabbits. Half of the implants were stimulated by direct vibration (60+/-10 Hz) immediately after insertion for 1 and 4 weeks, respectively. The other half served as controls. The samples were collected after the animals were sacrificed and were histologically processed into paraffin sections and stained with haematoxylin and eosin. The bone fraction was measured in an area of 50 and 400 um around the implant. To rate significant differences a one-way analysis of variance was used with alpha set at 5%. RESULTS: No significant difference in bone fraction was found between test and control groups. When the bone fractions of the 50 and 400 um peri-implant regions were compared, a significantly larger bone fraction was found in the 50 um peri implant region for the 4-week stimulated group. CONCLUSION: Histomorphometric analyses could not reveal a pronounced effect of direct immediate high-frequency implant loading. PMID- 20849539 TI - Primary stability determination by means of insertion torque and RFA in a sample of 4,135 implants. AB - OBJECTIVES: The aims of the present study are to evaluate the primary stability of a sample of 4,135 implants and to investigate the correlations between primary stability and mechanical characteristic of the implant and bone density at insertion time. MATERIAL AND METHODS: The study was conducted from March 2002 to January 2009 at a private practice in Bologna (Italy). Patients were eligible for the study if they needed the insertion of single or multiple implants. Bone density, length, and diameter of each implant were recorded. During surgery for each implant, peak insertion torque (IT) was recorded; the resonance frequency analysis (RFA) values were also collected. Finally, it was recorded whether an implant was lost or removed at an early stage (within 6months from insertion surgery). RESULTS: A total of 1,045 consecutive patients were included in the study. A total of 4,135 of implants were inserted. The sample presented 1,184 implants inserted in a postextractive site. The mean peak IT was 34.82+/-19.36. The mean RFA was 71.57+/-10.63 implant stability quotient. Spearman correlation analysis shows the presence of a weak positive correlation between IT and RFA. The statistical analysis shows a relevant dependency between IT and bone quality and a very weak dependency between RFA and bone quality. Again, the statistical analysis shows a quite weak correlation between length or diameter and IT, but it shows a relevant correlation between length and RFA. Postextractive implants presented a higher mean IT and a lower RFA compared with implants inserted in healed sites. Twenty-eight (0.7%) implants were considered to have failed and removed within 6months. CONCLUSIONS: The results show that the implants studied obtain a good primary stability with a standard protocol. The IT and RFA appear as two independent features of primary stability. Data show that only IT is influenced by bone density as well as only RFA is correlated to the length of implants used. Finally, it is possible to obtain a good primary stability also in postextractive sites. PMID- 20849540 TI - Trilobed flap reconstruction for distal nasal skin defects. AB - BACKGROUND: The bilobed flap is reliable for reconstruction of Mohs defects on the lower third of the nose. It uses skin from the proximal nose to reconstruct defects of the nasal tip and ala. The goal is to avoid alar rim displacement and asymmetry. The trilobed flap's design and execution leverage the strengths of the bilobed flap to allow application to a broader range of surgical nasal defect sizes and locations, particularly distal defects. OBJECTIVE: To present our surgical execution and application of the trilobed flap for reconstruction of distal nasal Mohs surgery defects. METHODS AND MATERIALS: Mohs surgery defects of the distal nose of 31 patients were reconstructed using a trilobed flap over a 3 year period. Pre- and postoperative photographs were independently and blindly evaluated and graded for alar symmetry and overall cosmesis. RESULTS: Median alar symmetry and overall cosmesis scores based on three reviewers were excellent. CONCLUSION: The trilobed flap offers a successful reconstructive option for Mohs defects of the distal nose that may not be optimally amenable to bilobed flap repair. Over 3 years, 31 trilobed flap repairs were performed with overall excellent outcomes. PMID- 20849541 TI - Evolution of basal cell carcinoma. PMID- 20849542 TI - Topical 5-aminolevulinic acid with intense pulsed light versus intense pulsed light for photodamage in Chinese patients. AB - BACKGROUND: It has been suggested that the adjunctive use of 5-aminolevulinic acid (ALA) with intense pulsed light (IPL), known as ALA-IPL photodynamic therapy (PDT), increases the benefits of IPL therapy for photoaging. OBJECTIVE: To evaluate the efficacy and safety of ALA-IPL PDT for photoaging in Chinese subjects with Fitzpatrick skin types III and IV. METHOD: This was a prospective, controlled, split-face study with 26 subjects. Subjects received three split-face treatments 4 weeks apart. A blinded investigator assessed the signs of photodamage. Satisfaction was also assessed. RESULT: Twenty-four subjects completed the trial. Better results were achieved for global score, fine lines, and coarse wrinkles on the PDT/IPL treated side than on the IPL-only side at the final visit (50% vs 12.5%p=.005 for global score, 70.8% vs 33.3%p=.009 for fine lines, 50% vs. 12.5%, p=.005 for coarse wrinkles). Phototoxic reactions such as erythema and edema were the primary side effects, as well as an increase in postinflammatory hyperpigmentation. CONCLUSION: ALA-IPL PDT has superior rejuvenation effects over IPL alone in Chinese subjects. Taking reasonable precaution to prevent the postinflammatory hyperpigmentation is the most important point in making ALA-IPL PDT a successful therapy. PMID- 20849543 TI - Use of a towel clamp as a surgical instrument. PMID- 20849544 TI - Suprascapular nerve injury during Mohs surgery and review of the surgical anatomy of the nervous structures of the supraclavicular triangle. PMID- 20849545 TI - Lentigo malignant melanoma presenting with cutaneous horn. PMID- 20849546 TI - Noninvasive extramammary Paget's disease treated with photodynamic therapy: case series from the Roswell Park Cancer Institute. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is a rare low-grade cutaneous malignancy that affects apocrine gland-bearing areas and most commonly occurs on the perineal skin. Photodynamic therapy (PDT) may represent a useful treatment option for extensive, noninvasive EMPD, alone or as part of multimodal therapy. OBJECTIVE: To analyze the clinical outcomes of PDT for noninvasive EMPD with topical aminolevulinic acid (ALA) or intravenous porfimer sodium as photosensitizing agents and argon laser as the photoactivator. METHODS: Retrospective case series of patients with noninvasive EMPD treated at Roswell Park Cancer Institute with PDT from April 20, 1995, to December 4, 2008. Identified patients included five men and three women aged 50 to 80 (mean age 67) with a total of 24 distinct lesions of noninvasive EMPD without distant metastases. Four patients received topical ALA only as a photosensitizer, three received intravenous porfimer sodium only, and one received both. All patients were treated using a 632.8-nm argon-pumped dye laser, and some were also treated using a red lamp (590-729 nm). RESULTS: Seven of nine lesions (78%) treated with PDT using intravenous porfimer sodium showed a complete response (CR) and were disease free at 12 to 96 months. Eight of 16 lesions (50%) treated with PDT using topical ALA showed a CR, and 38% were disease free at 9 to 88 months. None of the treated patients developed any serious cosmetic or functional impairments, such as loss of sphincter control or dysesthesias. CONCLUSION: PDT with intravenous porfimer sodium or topical ALA and argon laser may represent a useful, surgery sparing therapeutic option for management of noninvasive EMPD in selected patients. Prospective, randomized clinical trials are necessary to compare the effectiveness of PDT with that of surgery for noninvasive EMPD. PMID- 20849547 TI - On estimating the relationship between longitudinal measurements and time-to event data using a simple two-stage procedure. AB - Ye, Lin, and Taylor (2008, Biometrics 64, 1238-1246) proposed a joint model for longitudinal measurements and time-to-event data in which the longitudinal measurements are modeled with a semiparametric mixed model to allow for the complex patterns in longitudinal biomarker data. They proposed a two-stage regression calibration approach that is simpler to implement than a joint modeling approach. In the first stage of their approach, the mixed model is fit without regard to the time-to-event data. In the second stage, the posterior expectation of an individual's random effects from the mixed-model are included as covariates in a Cox model. Although Ye et al. (2008) acknowledged that their regression calibration approach may cause a bias due to the problem of informative dropout and measurement error, they argued that the bias is small relative to alternative methods. In this article, we show that this bias may be substantial. We show how to alleviate much of this bias with an alternative regression calibration approach that can be applied for both discrete and continuous time-to-event data. Through simulations, the proposed approach is shown to have substantially less bias than the regression calibration approach proposed by Ye et al. (2008). In agreement with the methodology proposed by Ye et al. (2008), an advantage of our proposed approach over joint modeling is that it can be implemented with standard statistical software and does not require complex estimation techniques. PMID- 20849549 TI - Letter to the editor "Comment on Proschan and Nason (2009), Biometrics 65, 316 322". PMID- 20849552 TI - An MHC-defined primate model reveals significant rejection of bone marrow after mixed chimerism induction despite full MHC matching. AB - In murine models, mixed hematopoietic chimerism induction leads to robust immune tolerance. However, translation to primates and to patients has been difficult. In this study, we used a novel MHC-defined rhesus macaque model to examine the impact of MHC matching on the stability of costimulation blockade-/sirolimus mediated chimerism, and to probe possible mechanisms of bone marrow rejection after nonmyeloablative transplant. Using busulfan-based pretransplant preparation and maintenance immunosuppression with sirolimus, as well as CD28 and CD154 blockade, all recipients demonstrated donor engraftment after transplant. However, the mixed chimerism that resulted was compartmentalized, with recipients demonstrating significantly higher whole blood chimerism compared to T cell chimerism. Thus, the vast majority of T cells presenting posttransplant were recipient-rather than donor-derived. Surprisingly, even in MHC-matched transplants, rejection of donor hematopoiesis predominated after immunosuppression withdrawal. Weaning of immunosuppression was associated with a surge of antigen-experienced T cells, and transplant rejection was associated with the acquisition of donor-directed T cell alloreactivity. These results suggest that a reservoir of alloreactive cells was present despite prior costimulation blockade and sirolimus, and that the post-immunosuppression lymphocytic rebound may have lead to a phenotypic shift in these recipient T cells towards an activated, antigen-experienced phenotype, and ultimately, to transplant rejection. PMID- 20849553 TI - Chronic care improvement in primary care: evaluation of an integrated pay-for performance and practice-based care coordination program among elderly patients with diabetes. AB - OBJECTIVE: To examine the effects of an intervention comprising (1) a practice based care coordination program, (2) augmented by pay for performance (P4P) for meeting quality targets, and (3) complemented by a third-party disease management on quality of care and resource use for older adults with diabetes. DATA SOURCES/STUDY SETTING: Claims files of a managed care organization (MCO) for 20,943 adults aged 65 and older with diabetes receiving care in Alabama, Tennessee, or Texas, from January 2004 to March 2007. STUDY DESIGN: A quasi experimental, longitudinal study in which pre- and postdata from 1,587 patients in nine intervention primary care practices were evaluated against 19,356 patients in MCO comparison practices (>900). Five incentivized quality measures, two nonincentivized measures, and two resource-use measures were investigated. We examined trends and changes in trends from baseline to follow-up, contrasting intervention and comparison group member results. PRINCIPAL FINDINGS: Quality of care generally improved for both groups during the study period. Only slight differences were seen between the intervention and comparison group trends and changes in trends over time. CONCLUSIONS: This study did not generate evidence supporting a beneficial effect of an on-site care coordination intervention augmented by P4P and complemented by third-party disease management on diabetes quality or resource use. PMID- 20849554 TI - Improving timely childhood immunizations through pay for performance in Medicaid managed care. AB - OBJECTIVE: To evaluate the impact of a "piece-rate" pay-for-performance (P4P) program aimed at rewarding up-to-date immunization delivery to 2-year-olds according to the recommended series. DATA SOURCES/STUDY SETTING: Plan-level data from New York State's Quality Assurance Reporting Requirement and claims data from Hudson Health Plan for 2003-2007. In 2003 Hudson Health Plan, a not-for profit Medicaid-focused managed care plan, introduced a U.S.$200 bonus payment for each fully immunized 2-year-old and provided administrative supports for identifying children who may need immunization. This represented a potential bonus of 15-25 percent above base reimbursement for eligible 2-year-olds. STUDY DESIGN: Case-comparison and interrupted times series. PRINCIPAL FINDINGS: Immunization rates within Hudson Health Plan rose at a significantly, albeit modestly, higher rate than the robust secular trend noted among comparison health plans. Supplementary analyses suggest that there was no significant change in preexisting disparities during the study period, and that children with chronic conditions have significantly greater odds of being fully immunized during the entire study period. CONCLUSIONS: This study suggests that a piece-rate P4P program with appropriate administrative supports can be effective at improving childhood immunization rates. PMID- 20849551 TI - Transplantation outcomes in primary hyperoxaluria. AB - Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life-table methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976-2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1-, 3- and 5-year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death-censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000-09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses. PMID- 20849555 TI - Provider-hospital "fit" and patient outcomes: evidence from Massachusetts cardiac surgeons, 2002-2004. AB - OBJECTIVE: To examine whether the "fit" of a surgeon with hospital resources impacts cardiac surgery outcomes, separately from hospital or surgeon effects. DATA SOURCES: Retrospective secondary data from the Massachusetts Department of Public Health's Data Analysis Center, on all 12,983 adult isolated coronary artery bypass surgical admissions in state-regulated hospitals from 2002 through 2004. Clinically audited chart data was collected using Society of Thoracic Surgeons National Cardiac Surgery Database tools and cross-referenced with administrative discharge data in the Division of Health Care Finance and Policy. Mortality was followed up through 2007 via the state vital statistics registry. STUDY DESIGN: Analysis was at the patient level for those receiving isolated coronary artery bypass surgery (CABG). Sixteen outcomes included 30-day mortality, major morbidity, indicators of perioperative, and predischarge processes of care. Hierarchical crossed mixed models were used to estimate fixed covariate and random effects at hospital, surgeon, and hospital * surgeon level. PRINCIPAL FINDINGS: Hospital volume was associated with significantly reduced intraoperative durations and significantly increased probability of aspirin, beta blocker, and lipid-lowering discharge medication use. The proportion of outcome variability due to unobserved hospital * surgeon interaction effects was small but meaningful for intraoperative practices, discharge destination, and medication use. For readmissions and mortality within 30 days or 1 year, unobserved patient and hospital factors drove almost all variability in outcomes. CONCLUSIONS: Among Massachusetts patients receiving isolated CABG, consistent evidence was found that the hospital * surgeon combination independently impacted patient outcomes, beyond hospital or surgeon effects. Such distinct local interactions between a surgeon and hospital resources may play an important part in moderating quality improvement efforts, although residual patient-level factors generally contributed the most to outcome variability. PMID- 20849556 TI - Predictors of nursing home residents' time to hospitalization. AB - OBJECTIVES: To model the predictors of the time to first acute hospitalization for nursing home residents, and accounting for previous hospitalizations, model the predictors of time between subsequent hospitalizations. DATA SOURCES: Merged file from New York State for the period 1998-2004 consisting of nursing home information from the minimum dataset and hospitalization information from the Statewide Planning and Research Cooperative System. STUDY DESIGN: Accelerated failure time models were used to estimate the model parameters and predict survival times. The models were fit to observations from 50 percent of the nursing homes and validated on the remaining observations. PRINCIPAL FINDINGS: Pressure ulcers and facility-level deficiencies were associated with a decreased time to first hospitalization, while the presence of advance directives and facility staffing was associated with an increased time. These predictors of the time to first hospitalization model had effects of similar magnitude in predicting the time between subsequent hospitalizations. CONCLUSIONS: This study provides novel evidence suggesting modifiable patient and nursing home characteristics are associated with the time to first hospitalization and time to subsequent hospitalizations for nursing home residents. PMID- 20849557 TI - Twenty years of coverage: an enhanced current population survey-1989-2008. AB - OBJECTIVE: To create a consistent time series to understand coverage trends by harmonizing 20 years of insurance coverage estimates from the Current Population Survey (CPS) that are an available public resource. DATA SOURCE: 1990-2009 CPS Annual Social and Economic Supplement data. STUDY DESIGN: CPS data are enhanced to account for methodological and conceptual changes in health insurance measurement and population control totals. PRINCIPAL FINDINGS: The enhancements to the CPS result in an approximately 1 percent reduction in uninsurance rates. Reductions vary over time and by age group. Changes over the last two decades differ slightly using the two data sources. For example, the enhanced data show a greater erosion of private coverage. CONCLUSION: The enhanced data provide the most consistent measure of health insurance coverage over the past two decades. PMID- 20849558 TI - Employee choice of a high-deductible health plan across multiple employers. AB - OBJECTIVE: To determine factors associated with selecting a high-deductible health plan (HDHP) rather than a preferred provider plan (PPO) and to examine switching and market segmentation after initial selection. DATA SOURCES/STUDY SETTING: Claims and benefit information for 2005-2007 from nine employers in western Pennsylvania first offering HDHP in 2006. STUDY DESIGN: We examined plan growth over time, used logistic regression to determine factors associated with choosing an HDHP, and examined the distribution of healthy and sick members across plan types. DATA EXTRACTION: We linked employees with their dependents to determine family-level variables. We extracted risk scores, covered charges, employee age, and employee gender from claims data. We determined census-level race, education, and income information. PRINCIPAL FINDINGS: Health status, gender, race, and education influenced the type of individual and family policies chosen. In the second year the HDHP was offered, few employees changed plans. Risk segmentation between HDHPs and PPOs existed, but it did not increase. CONCLUSIONS: When given a choice, those who are healthier are more likely to select an HDHP leading to risk segmentation. Risk segmentation did not increase in the second year that HDHPs were offered. PMID- 20849559 TI - Impact of chronic condition status and severity on the time to first dental visit for newly Medicaid-enrolled children in Iowa. AB - OBJECTIVE: To assess the extent to which chronic condition (CC) status and severity affected how soon children had a dental visit after enrolling in Medicaid. Data Source. Enrollment and claims data (2003-2008) for newly Medicaid enrolled children ages 3-14 in Iowa. STUDY DESIGN: 3M Clinical Risk Grouping methods were used to identify CC status (no/yes) and CC severity (less severe/more severe). Survival analysis was used to identify the factors associated with earlier first dental visits after initially enrolling in Medicaid. PRINCIPAL FINDINGS: Children with a CC were 17 percent more likely to have earlier first dental visits after enrolling in Medicaid (p < .0001). There was no significant difference by CC severity. Children who lived in a dental health professional shortage area and those who did not utilize primary medical care had significantly later first Medicaid dental visits, whereas these factors failed to reach statistical significance for children with a CC. CONCLUSION: While newly Medicaid-enrolled children with a CC were significantly more likely to have earlier first dental visits, we failed to detect a relationship between CC severity and the time to first Medicaid dental visit. The determinants of first Medicaid dental visits were heterogeneous across subgroups of newly Medicaid-enrolled children. Future studies should identify the sociobehavioral factors associated with CCs that are potential barriers to earlier first Medicaid dental visits for newly Medicaid-enrolled children. PMID- 20849560 TI - Positive relationships between genetic diversity and abundance in fishes. AB - Molecular markers, such as mitochondrial DNA and microsatellite loci, are widely studied to assess population genetics and phylogeography; however, the selective neutrality of these markers is increasingly being questioned. Given the importance of molecular markers in fisheries science and conservation, we evaluated the neutrality of both mtDNA and microsatellite loci through their associations with population size. We surveyed mtDNA and microsatellite data from the primary literature and determined whether genetic diversity increased with abundance across a total of 105 marine and freshwater fishes, with both global fisheries catch data and body size as proxies for abundance (with an additional 57 species for which only body size data were assessed). We found that microsatellite data generally yielded higher associations with abundance than mtDNA data, and within mtDNA analyses, number of haplotypes and haplotype diversity were more strongly associated with abundance than nucleotide diversity, particularly for freshwater fishes. We compared genetic diversity between freshwater and marine fishes and found that marine fishes had higher values of all measures of genetic diversity than freshwater fishes. Results for both mtDNA and microsatellites generally conformed to neutral expectations, although weaker relationships were often found between mtDNA nucleotide diversity and 'abundance' compared to any other genetic statistic. We speculate that this is because of historical events unrelated to natural selection, although a role for selection cannot be ruled out. PMID- 20849561 TI - Of glaciers and refugia: a decade of study sheds new light on the phylogeography of northwestern North America. AB - Glacial cycles have played a dominant role in shaping the genetic structure and distribution of biota in northwestern North America. The two major ice age refugia of Beringia and the Pacific Northwest were connected by major mountain chains and bordered by the Pacific Ocean. As a result, numerous refugial options were available for the regions taxa during glacial advances. We reviewed the importance of glaciations and refugia in shaping northwestern North America's phylogeographic history. We also tested whether ecological variables were associated with refugial history. The recurrent phylogeographic patterns that emerged were the following: (i) additional complexity, i.e. refugia within refugia, in both Beringia and the Pacific Northwest; and (ii) strong evidence for cryptic refugia in the Alexander Archipelago and Haida Gwaii, the Canadian Arctic and within the ice-sheets. Species with contemporary ranges that covered multiple refugia, or those with high dispersal ability, were significantly more likely to have resided in multiple refugia. Most of the shared phylogeographic patterns can be attributed to multiple refugial locales during the last glacial maximum or major physiographic barriers like rivers and glaciers. However, some of the observed patterns are much older and appear connected to the orogeny of the Cascade-Sierra chain or allopatric differentiation during historic glacial advances. The emergent patterns from this review suggest we should refine the classic Beringian-southern refugial paradigm for northwestern North American biota and highlight the ecological and evolutionary consequences of colonization from multiple refugia. PMID- 20849563 TI - All issues of Acta Ophthalmologica since 1923 are now available online. PMID- 20849564 TI - Effectiveness of canalicular laceration repair using monocanalicular intubation with Monoka tubes. AB - PURPOSE: This study aimed to evaluate the clinical efficacy of canalicular laceration repair using monocanalicular intubation with Monoka tubes. METHODS: A total of 36 single lacerated canaliculi were repaired using monocanalicular intubation with Monoka tubes, without mucosal anastomosis of the canaliculi, and were retrospectively reviewed. Demographic information, injury locations, associated ocular injuries, complications and outcomes were analysed. RESULTS: Mean patient age was 34 years (range 1-64 years). Tubes were removed at a mean of 4.2 months (range 3-6 months). There were 26 lower canalicular lacerations (72%) and 10 upper canalicular lacerations (28%). Overall, 34 of 36 cases (92%) showed improvement in symptoms and exhibited positivity on the dye disappearance test at 4-12 months after the procedure (mean 7.8 months). In total, 21 patients (58%) achieved complete success, 13 patients (36%) achieved partial success and two patients (6%) suffered surgical failure. Complications were seen in five cases and included two early tube protrusions, two punctal slits and one punctal granuloma. CONCLUSIONS: Monocanalicular intubation with Monoka tubes leads to successful outcomes without significant complications and offers an alternative to bicanalicular intubation in the treatment of monocanalicular lacerations. PMID- 20849565 TI - Sequencing free-living protists: the case for metagenomics. PMID- 20849566 TI - Osmotic adjustment and requirement for sodium in marine protist thraustochytrid. AB - A non-invasive ion-selective microelectrode technique was used to elucidate the ionic mechanisms of osmotic adjustment in a marine protist thraustochytrid. Hypoosmotic stress caused significant efflux of Na(+), Cl(-) and K(+) from thraustochytrid cells. Model calculations showed that almost complete osmotic adjustment was achieved within the first 30 min after stress onset. Of these, sodium was the major contributor (more than half of the total osmotic adjustment), with chloride being the second major contributor. The role of K(+) in the process of osmotic adjustment was relatively small. Changes in Ca(2+) and H(+) flux were attributed to intracellular signalling. Ion flux data were confirmed by growth experiments. Thraustochytrium cells showed normal growth patterns even when grown in a sodium-free solution provided the medium osmolality was adjusted by mannitol to one of the seawater. That suggests that the requirement of sodium for thraustochytrid growth cycle is due to its role in cell osmotic adjustment rather than because of the direct Na(+) involvement in cell metabolism. Altogether, these data demonstrate the evidence for turgor regulation in thraustochytrids and suggest that these cells may be grown in the absence of sodium providing that cell turgor is adjusted by some other means. PMID- 20849568 TI - Changes in B-lymphocyte stimulator protein levels during treatment with albinterferon alfa-2b in patients with chronic hepatitis C who have failed previous interferon therapy. AB - AIM: The pharmacodynamics of albinterferon alfa-2b (alb-IFN), a novel recombinant protein consisting of interferon-alpha-2b genetically fused to human albumin, was evaluated in patients with chronic hepatitis C with a previous non response to interferon-alpha-based therapy. B-lymphocyte stimulator (BLyS) is an essential in vivo regulator of B-lymphocyte homeostasis. This analysis examined the relationship between serum BLyS level and virologic response across a range of alb-IFN doses. METHODS: In all, 115 patients were randomized initially to three alb-IFN treatment arms (900 and 1200 ug every two weeks [q2wk], and 1200 ug every four weeks) with weight-based ribavirin, followed by sequential enrollment in two higher dose arms (1500 and 1800 ug q2wk). Serum BLyS level was assessed by enzyme-linked immunosorbent assay. RESULTS: Serum BLyS levels at baseline were lower in African-Americans (P < 0.001). Significant BLyS inductions were observed at weeks 12 and 24 versus pretreatment; in general, serum BLyS levels returned to pretreatment levels following treatment completion. Induction of BLyS was greater in the highest dose group; a significant dose-response trend was observed at weeks 12 (P = 0.002) and 24 (P < 0.001), as well as a significant time trend, with further BLyS induction increases at week 24 versus 12 (P < 0.001). Week 24 BLyS level change correlated with hepatitis C virus RNA reduction (r = -0.28; P = 0.006), driven primarily by patients with BLyS increases > 400%, but did not correlate with sustained virologic response. CONCLUSION: Higher alb-IFN doses demonstrated dose-related BLyS increases, although the correlation with virologic response was modest. PMID- 20849569 TI - ABO-blood type incompatible living donor liver transplantation in a patient with Budd-Chiari Syndrome secondary to essential thrombocythemia. AB - Budd-Chiari syndrome (BCS) results from diverse causative factors. Myeloproliferative disorders (MPDs) including essential thrombocythemia (ET) account for a minority of BCS cases in Japan. ABO-blood-type incompatible living donor liver transplantation (LDLT) in adults has become an acceptable procedure owing to the development of new strategies for preventing antibody-mediated rejection. This report presents a rare case of BCS secondary to ET, which was cured by an ABO-incompatible (AB to A) LDLT. In this case, prostaglandin E(1) and gabexate mesilate were administered into portal vein and rituximab prophylaxis was applied. No splenectomy was performed as it is in most ABO-incompatible cases, since a flow cytometry showed no anti-B antibodies in the splenocytes collected by a wedge biopsy during the LDLT. The postoperative course was uneventful. Anti-coagulation therapy was initiated with aspirin and warfarin instead of hydroxyurea. This report describes an ABO-incompatible LDLT without a splenectomy for BCS secondary to ET. PMID- 20849570 TI - The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. AB - BACKGROUND: Neuropathic pain is reported to be common based on studies from specialty centers and survey studies. However, few prevalence estimates have been completed in a community population using clinical evaluation. OBJECTIVE: To develop an estimate of the prevalence of neuropathic pain in community-dwelling adults. METHODS: Data from a mailed survey (N = 3,575 community respondents), telephone interview (N = 907), and a clinical examination (N = 205) were linked to estimate the population prevalence of neuropathic pain. Using the clinical examination as the "gold" standard, estimates from several screening tools were developed and adjusted to the Olmsted County, MN adult population. RESULTS: The estimated community prevalence of neuropathic pain from the clinical examination (gold standard) was 9.8%. Most other estimates were lower, including a 3.0% population prevalence using the Berger criteria and 8.8% using the Leeds Assessment of Neuropathic Symptoms and Signs. Only the prevalence rate based on self-report of nerve pain was higher (12.4%). Overlap among the groups each tool identified as having "neuropathic predominant pain" was only modest and the groups had significantly different rates of depressive symptoms, anxiety, limited functional ability, and use of complementary and alternative medicine. CONCLUSIONS: The estimated rates and personal characteristics of community residents with "neuropathic pain" vary widely depending on the tools used to identify neuropathic pain. None of the screening tools compared well with clinical evaluation. The differences in the groups identified by alternative screening methods become of major importance when reporting neuropathic pain epidemiology, studying therapies for neuropathic pain, or attempting to translate neuropathic pain research into clinical practice. PMID- 20849572 TI - Conserved developmental expression of Fezf in chordates and Drosophila and the origin of the Zona Limitans Intrathalamica (ZLI) brain organizer. AB - BACKGROUND: The zona limitans intrathalamica (ZLI) and the isthmus organizer (IsO) are two major secondary organizers of vertebrate brain development. These organizers are located at the interface of the expression domains of key patterning genes (Fezf-Irx and Otx-Gbx, respectively). To gain insights into the evolutionary origin of the ZLI, we studied Fezf in bilaterians. RESULTS: In this paper, we identified a conserved sequence motif (Fezf box) in all bilaterians. We report the expression pattern of Fezf in amphioxus and Drosophila and compare it with those of Gbx, Otx and Irx. We found that the relative expression patterns of these genes in vertebrates are fully conserved in amphioxus and flies, indicating that the genetic subdivisions defining the location of both secondary organizers in early vertebrate brain development were probably present in the last common ancestor of extant bilaterians. However, in contrast to vertebrates, we found that Irx-defective flies do not show an affected Fezf expression pattern. CONCLUSIONS: The absence of expression of the corresponding morphogens from cells at these conserved genetic boundaries in invertebrates suggests that the organizing properties might have evolved specifically in the vertebrate lineage by the recruitment of key morphogens to these conserved genetic locations. PMID- 20849573 TI - A comprehensive fate map by intracellular injection of identified blastomeres in the marine polychaete Capitella teleta. AB - BACKGROUND: The polychaete annelid Capitella teleta (formerly Capitella sp. I) develops by spiral cleavage and has been the focus of several recent developmental studies aided by a fully sequenced genome. Fate mapping in polychaetes has lagged behind other spiralian taxa, because of technical limitations. RESULTS: To generate a modern fate map for C. teleta, we injected 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (DiI) into individual identified blastomeres through fourth-quartet micromere formation. Confocal laser scanning microscopy at single-cell resolution was used to characterize blastomere fates during larval stages. Our results corroborate previous observations from classic studies, and show a number of similarities with other spiralian fate maps, including unique and stereotypic fates for individual blastomeres, presence of four discrete body domains arising from the A, B, C and D cell quadrants, generation of anterior ectoderm from first quartet micromeres, and contributions to trunk ectoderm and ventral nerve cord by the 2d somatoblast. Of particular interest are several instances in which the C. teleta fate map deviates from other spiralian fate maps. For example, we identified four to seven distinct origins of mesoderm, all ectomesodermal. In addition, the left and right mesodermal bands arise from 3d and 3c, respectively, whereas 4d generates a small number of trunk muscle cells, the primordial germ cells and the anus. We identified a complex set of blastomere contributions to the posterior gut in C. teleta, which establishes the most complete map of posterior gut territories to date. CONCLUSIONS: Our detailed cellular descriptions reveal previously underappreciated complexity in the ontogenetic contributions to several spiralian larval tissues, including the mesoderm, nervous system and gut. The formation of the mesodermal bands by 3c and 3d is in stark contrast to other spiralians, in which 4d generates the mesodermal bands. The results of this study provide a framework for future phylogenetic comparisons and functional analyses of cell-fate specification. PMID- 20849574 TI - ClustalXeed: a GUI-based grid computation version for high performance and terabyte size multiple sequence alignment. AB - BACKGROUND: There is an increasing demand to assemble and align large-scale biological sequence data sets. The commonly used multiple sequence alignment programs are still limited in their ability to handle very large amounts of sequences because the system lacks a scalable high-performance computing (HPC) environment with a greatly extended data storage capacity. RESULTS: We designed ClustalXeed, a software system for multiple sequence alignment with incremental improvements over previous versions of the ClustalX and ClustalW-MPI software. The primary advantage of ClustalXeed over other multiple sequence alignment software is its ability to align a large family of protein or nucleic acid sequences. To solve the conventional memory-dependency problem, ClustalXeed uses both physical random access memory (RAM) and a distributed file-allocation system for distance matrix construction and pair-align computation. The computation efficiency of disk-storage system was markedly improved by implementing an efficient load-balancing algorithm, called "idle node-seeking task algorithm" (INSTA). The new editing option and the graphical user interface (GUI) provide ready access to a parallel-computing environment for users who seek fast and easy alignment of large DNA and protein sequence sets. CONCLUSIONS: ClustalXeed can now compute a large volume of biological sequence data sets, which were not tractable in any other parallel or single MSA program. The main developments include: 1) the ability to tackle larger sequence alignment problems than possible with previous systems through markedly improved storage-handling capabilities. 2) Implementing an efficient task load-balancing algorithm, INSTA, which improves overall processing times for multiple sequence alignment with input sequences of non-uniform length. 3) Support for both single PC and distributed cluster systems. PMID- 20849576 TI - BACE1 gene variants do not influence BACE1 activity, levels of APP or Abeta isoforms in CSF in Alzheimer's disease. AB - The BACE1 gene encodes the beta-site APP-cleaving enzyme 1 and has been associated with Alzheimer's disease (AD). BACE1 is the most important beta secretase responsible for the generation of Alzheimer-associated amyloid beta proteins (Abeta) and may play a role in the amyloidogenic process in AD. We hypothesized that BACE1 gene variants might influence BACE1 activity or other markers for APP metabolism in the cerebrospinal fluid (CSF) and thereby contribute to the development of AD. We genotyped a Swedish sample of 269 AD patients for the rs638405 single nucleotide polymorphism (SNP) in the BACE1 gene and correlated genotype data to a broad range of amyloid-related biomarkers in CSF, including BACE1 activity, levels of Abeta40, Abeta42, alpha- and beta cleaved soluble APP (alpha-sAPP and beta-sAPP), as well as markers for Alzheimer type axonal degeneration, i.e., total-tau and phospho-tau181. Gene variants of BACE1 were neither associated with amyloid-related biomarkers, nor with markers for axonal degeneration in AD. PMID- 20849575 TI - Preformed expression of defense is a hallmark of partial resistance to rice blast fungal pathogen Magnaporthe oryzae. AB - BACKGROUND: Partial resistance to plant pathogens is extensively used in breeding programs since it could contribute to resistance durability. Partial resistance often builds up during plant development and confers quantitative and usually broad-spectrum resistance. However, very little is known on the mechanisms underlying partial resistance. Partial resistance is often explained by poorly effective induction of plant defense systems. By exploring rice natural diversity, we asked whether expression of defense systems before infection could explain partial resistance towards the major fungal pathogen Magnaporthe oryzae. The constitutive expression of 21 defense-related genes belonging to the defense system was monitored in 23 randomly sampled rice cultivars for which partial resistance was measured. RESULTS: We identified a strong correlation between the expression of defense-related genes before infection and partial resistance. Only a weak correlation was found between the induction of defense genes and partial resistance. Increasing constitutive expression of defense-related genes also correlated with the establishment of partial resistance during plant development. Some rice genetic sub-groups displayed a particular pattern of constitutive expression, suggesting a strong natural polymorphism for constitutive expression of defense. Constitutive levels of hormones like salicylic acid and ethylene cannot explain constitutive expression of defense. We could identify an area of the genome that contributes to explain both preformed defense and partial resistance. CONCLUSION: These results indicate that constitutive expression of defense-related genes is likely responsible for a large part of partial resistance in rice. The finding of this preformed defense system should help guide future breeding programs and open the possibility to identify the molecular mechanisms behind partial resistance. PMID- 20849577 TI - A 64-week, multicenter, open-label study of aripiprazole effectiveness in the management of patients with schizophrenia or schizoaffective disorder in a general psychiatric outpatient setting. AB - OBJECTIVE: To evaluate the overall long-term effectiveness of aripiprazole in patients with schizophrenia in a general psychiatric practice setting in Taiwan. METHODS: This was a prospective, open-label, multicenter, post-market surveillance study in Taiwanese patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled. Eligible patients were titrated to aripiprazole (5-30 mg/day) over a 12-week switching phase, during which their previous medication was discontinued. Patients could then enter a 52-week, long-term treatment phase. Aripiprazole was flexibly dosed (5-30 mg/day) at the discretion of the treating physicians. Efficacy was assessed using the Clinical Global Impression scale Improvement (CGI I) score, the Clinical Global Impression scale Severity (CGI-S) score, The Brief Psychiatry Rating Scale (BPRS), and the Quality of Life (QOL) scale, as well as Preference of Medicine (POM) ratings by patients and caregivers. Safety and tolerability were also assessed. RESULTS: A total of 245 patients were enrolled and switched from their prior antipsychotic medications, and 153 patients entered the 52-week extension phase. In all, 79 patients (32.2%) completed the study. At week 64, the mean CGI-I score was 3.10 and 64.6% of patients who showed response. Compared to baseline, scores of CGI-S, QOL, and BPRS after 64 weeks of treatment also showed significant improvements. At week 12, 65.4% of subjects and 58.9% of caregivers rated aripiprazole as better than the prestudy medication on the POM. The most frequently reported adverse events (AEs) were headache, auditory hallucinations and insomnia. A total of 13 patients (5.3%) discontinued treatment due to AEs. No statistically significant changes were noted with respect to fasting plasma glucose, lipid profile, body weight, and body mass index after long-term treatment with aripiprazole. CONCLUSIONS: Although the discontinuation rate was high, aripiprazole was found to be effective, safe and well tolerated in the long-term treatment of Taiwanese patients with schizophrenia who continued to receive treatment for 64 weeks. PMID- 20849578 TI - Incidence of genital warts among the Hong Kong general adult population. AB - BACKGROUND: The objective of this study is to estimate the incidence of genital warts in Hong Kong and explore a way to establish a surveillance system for genital warts among the Hong Kong general population. METHODS: A total of 170 private doctors and all doctors working in the 5 local Social Hygiene Clinics (SHC) participated in this study. During the 14-day data collection period (January 5 through 18, 2009), the participating doctors filled out a log-form on a daily basis to record the number of patients with genital warts. The total number of new cases of genital warts presented to private and public doctors in Hong Kong was projected using the stratification sampling method. RESULTS: A total of 721 (0.94%) adults presented with genital warts to the participating doctors during the two-week study period, amongst them 73 (10.1%) were new cases. The projected number of new cases of genital warts among Hong Kong adults was 442 (297 male and 144 female) during the study period. The incidence of genital warts in Hong Kong was estimated to be 203.7 per 100,000 person-years (respectively 292.2 and 124.9 per 100,000 person-years for males and females). CONCLUSIONS: The incidence of genital warts is high among adults in Hong Kong. The study demonstrates the importance of collecting surveillance data from both private and public sectors. PMID- 20849579 TI - Multivariate meta-analysis of proteomics data from human prostate and colon tumours. AB - BACKGROUND: There is a vast need to find clinically applicable protein biomarkers as support in cancer diagnosis and tumour classification. In proteomics research, a number of methods can be used to obtain systemic information on protein and pathway level on cells and tissues. One fundamental tool in analysing protein expression has been two-dimensional gel electrophoresis (2DE). Several cancer 2DE studies have reported partially redundant lists of differently expressed proteins. To be able to further extract valuable information from existing 2DE data, the power of a multivariate meta-analysis will be evaluated in this work. RESULTS: We here demonstrate a multivariate meta-analysis of 2DE proteomics data from human prostate and colon tumours. We developed a bioinformatic workflow for identifying common patterns over two tumour types. This included dealing with pre processing of data and handling of missing values followed by the development of a multivariate Partial Least Squares (PLS) model for prediction and variable selection. The variable selection was based on the variables performance in the PLS model in combination with stability in the validation. The PLS model development and variable selection was rigorously evaluated using a double cross validation scheme. The most stable variables from a bootstrap validation gave a mean prediction success of 93% when predicting left out test sets on models discriminating between normal and tumour tissue, common for the two tumour types. The analysis conducted in this study identified 14 proteins with a common trend between the tumour types prostate and colon, i.e. the same expression profile between normal and tumour samples. CONCLUSIONS: The workflow for meta-analysis developed in this study enabled the finding of a common protein profile for two malign tumour types, which was not possible to identify when analysing the data sets separately. PMID- 20849580 TI - 'Rumours' and clinical trials: a retrospective examination of a paediatric malnutrition study in Zambia, southern Africa. AB - BACKGROUND: Many public health researchers conducting studies in resource constrained settings have experienced negative 'rumours' about their work; in some cases they have been reported to create serious challenges and derail studies. However, what may appear superficially as 'gossip' or 'rumours' can also be regarded and understood as metaphors which represent local concerns. For researchers unaccustomed to having concerns expressed from participants in this manner, possible reactions can be to be unduly perturbed or conversely dismissive.This paper represents a retrospective examination of a malnutrition study conducted by an international team of researchers in Zambia, Southern Africa. The fears of mothers whose children were involved in the study and some of the concerns which were expressed as rumours are also presented. This paper argues that there is an underlying logic to these anxieties and to dismiss them simply as 'rumours' or 'gossip' would be to overlook the historic and socio economic factors which have contributed to their production. METHODS: Qualitative interviews were conducted with the mothers whose children were involved in the study and with the research nurses. Twenty five face-to-face interviews and 2 focus group discussions (FGDs) were conducted with mothers. In addition, face-to face interviews were conducted with research nurses participating in the trial. RESULTS: A prominent anxiety expressed as rumours by the mothers whose children were involved in the study was that recruitment into the trial was an indicator that the child was HIV-infected. Other anxieties included that the trial was a disguise for witchcraft or Satanism and that the children's body parts would be removed and sold. In addition, the liquid, milk-based food given to the children to improve their nutrition was suspected of being insufficiently nutritious, thus worsening their condition.The form which these anxieties took, such as rumours related to the stealing of body parts and other anxieties about a stigmatised condition, provide an insight into the historical, socio-economic and cultural influences in such settings. CONCLUSIONS: Employing strategies to understand local concerns should accompany research aims to achieve optimal success. The concerns raised by the participants we interviewed are not unique to this study. They are produced in countries where the historic, socio-economic and cultural settings communicate anxieties in this format. By examining this study we have shown that by contextualizing these 'rumours', the concerns they express can be constructively addressed and in turn result in the successful conduct of research aims. PMID- 20849581 TI - Managers' perceptions of the manager role in relation to physicians: a qualitative interview study of the top managers in Swedish healthcare. AB - BACKGROUND: This study focused on the manager role in the manager-physician relationship, considered from the manager perspective. The aim was to understand how top executives in Swedish healthcare regard management of physicians in their organisations, and what this implies for the manager role in relation to the medical profession. Abbott's theory of professional jurisdiction was used to inform thinking about managerial control and legitimacy in relation to physicians. METHODS: Data from semi-structured individual interviews with 18 of the 20 county council chief executive officers (CEOs) in Sweden were subjected to qualitative analysis. RESULTS: The results show that, when asked about their views on management of physicians, the CEOs talked about "how physicians are" rather than describing their own or their subordinate managers' managerial behaviour or strategies. Three types of descriptions of physicians were identified: 1) they have high status and expertise; 2) they lack knowledge of the system; 3) they do what they want in the organisation. The CEOs seldom reported that general management strategies were used to manage physicians. Instead, they described four types of physician-specific management strategies that were used in their organisations: organisational separation of physicians; "nagging and arguing"; compensations; relying on the physician role. These strategies seemed to reflect pragmatic behaviour on behalf of the managers that helped them to maintain control over physicians in daily work. However, in a longer perspective, they seemed to decrease the legitimacy of the manager role and also contribute to weakening of that role in the organisation. CONCLUSIONS: Many CEOs seemed to regard the manager role in their organisations as weak and described difficulties in both taking and defining that role (for themselves or others) in relation to the physician role. Further research is needed to elucidate how managers in healthcare organisations assume the manager role in relation to the medical profession. Studies indicate that lack of clarity concerning manager role authority and responsibility may have negative consequences not only for the working conditions of managers, physicians, and other healthcare professionals, but also for the quality of care. PMID- 20849582 TI - Posterior migration of Ahmed glaucoma valve tube in a patient with Reiger anomaly: a case report. AB - BACKGROUND: To describe, a yet non-documented complication of GDI surgery (glaucoma drainage incision surgery)--anterior to posterior segment migration of Ahmed Glaucoma Valve (AGV) tube. CASE PRESENTATION: We report a young 9 year old boy, diagnosed with refractory glaucoma with Reiger anomaly. History included of poor vision in both eyes, left more than right with glare since childhood. He underwent GDI surgery with AGV implantation following which he developed posterior migration of AGV tube. The detailed ocular history, ophthalmic findings, clinical course, surgical management and development of the posterior tube migration is discussed. CONCLUSION: Posterior Migration of AGV tube has yet not been described. Also there is a role of expectant management of the complication in this case as evidenced by the benign course of events. PMID- 20849583 TI - A BAC/BIBAC-based physical map of chickpea, Cicer arietinum L. AB - BACKGROUND: Chickpea (Cicer arietinum L.) is the third most important pulse crop worldwide. Despite its importance, relatively little is known about its genome. The availability of a genome-wide physical map allows rapid fine mapping of QTL, development of high-density genome maps, and sequencing of the entire genome. However, no such a physical map has been developed in chickpea. RESULTS: We present a genome-wide, BAC/BIBAC-based physical map of chickpea developed by fingerprint analysis. Four chickpea BAC and BIBAC libraries, two of which were constructed in this study, were used. A total of 67,584 clones were fingerprinted, and 64,211 (~11.7 x) of the fingerprints validated and used in the physical map assembly. The physical map consists of 1,945 BAC/BIBAC contigs, with each containing an average of 28.3 clones and having an average physical length of 559 kb. The contigs collectively span approximately 1,088 Mb. By using the physical map, we identified the BAC/BIBAC contigs containing or closely linked to QTL4.1 for resistance to Didymella rabiei (RDR) and QTL8 for days to first flower (DTF), thus further verifying the physical map and confirming its utility in fine mapping and cloning of QTL. CONCLUSION: The physical map represents the first genome-wide, BAC/BIBAC-based physical map of chickpea. This map, along with other genomic resources previously developed in the species and the genome sequences of related species (soybean, Medicago and Lotus), will provide a foundation necessary for many areas of advanced genomics research in chickpea and other legume species. The inclusion of transformation-ready BIBACs in the map greatly facilitates its utility in functional analysis of the legume genomes. PMID- 20849584 TI - Instability of chromosome number and DNA methylation variation induced by hybridization and amphidiploid formation between Raphanus sativus L. and Brassica alboglabra Bailey. AB - BACKGROUND: Distant hybridization can result genome duplication and allopolyploid formation which may play a significant role in the origin and evolution of many plant species. It is unclear how the two or more divergent genomes coordinate in one nucleus with a single parental cytoplasm within allopolyploids. We used cytological and molecular methods to investigate the genetic and epigenetic instabilities associated with the process of distant hybridization and allopolyploid formation, measuring changes in chromosome number and DNA methylation across multiple generations. RESULTS: F1 plants from intergeneric hybridization between Raphanus sativus L. (2n = 18, RR) and Brassica alboglabra Bailey (2n = 18, CC) were obtained by hand crosses and subsequent embryo rescue. Random amplification of polymorphic DNA (RAPD) markers were used to identify the F1 hybrid plants. The RAPD data indicated that the hybrids produced specific bands similar to those of parents and new bands that were not present in either parent. Chromosome number variation of somatic cells from allotetraploids in the F4 to F10 generations showed that intensive genetic changes occurred in the early generations of distant hybridization, leading to the formation of mixopolyploids with different chromosome numbers. DNA methylation variation was revealed using MSAP (methylation-sensitive amplification polymorphism), which showed that cytosine methylation patterns changed markedly in the process of hybridization and amphidiploid formation. Differences in cytosine methylation levels demonstrated an epigenetic instability of the allopolyploid of Raphanobrassica between the genetically stable and unstable generations. CONCLUSIONS: Our results showed that chromosome instability occurred in the early generations of allopolyploidy and then the plants were reverted to largely euploidy in later generations. During this process, DNA methylation changed markedly. These results suggest that, epigenetic mechanisms play an important role in intergeneric distant hybridization, probably by maintaining a genetic balance through the modification of existing genetic materials. PMID- 20849585 TI - MetNetGE: interactive views of biological networks and ontologies. AB - BACKGROUND: Linking high-throughput experimental data with biological networks is a key step for understanding complex biological systems. Currently, visualization tools for large metabolic networks often result in a dense web of connections that is difficult to interpret biologically. The MetNetGE application organizes and visualizes biological networks in a meaningful way to improve performance and biological interpretability. RESULTS: MetNetGE is an interactive visualization tool based on the Google Earth platform. MetNetGE features novel visualization techniques for pathway and ontology information display. Instead of simply showing hundreds of pathways in a complex graph, MetNetGE gives an overview of the network using the hierarchical pathway ontology using a novel layout, called the Enhanced Radial Space-Filling (ERSF) approach that allows the network to be summarized compactly. The non-tree edges in the pathway or gene ontology, which represent pathways or genes that belong to multiple categories, are linked using orbital connections in a third dimension. Biologists can easily identify highly activated pathways or gene ontology categories by mapping of summary experiment statistics such as coefficient of variation and overrepresentation values onto the visualization. After identifying such pathways, biologists can focus on the corresponding region to explore detailed pathway structure and experimental data in an aligned 3D tiered layout. In this paper, the use of MetNetGE is illustrated with pathway diagrams and data from E. coli and Arabidopsis. CONCLUSIONS: MetNetGE is a visualization tool that organizes biological networks according to a hierarchical ontology structure. The ERSF technique assigns attributes in 3D space, such as color, height, and transparency, to any ontological structure. For hierarchical data, the novel ERSF layout enables the user to identify pathways or categories that are differentially regulated in particular experiments. MetNetGE also displays complex biological pathway in an aligned 3D tiered layout for exploration. PMID- 20849586 TI - Mid term results after bone marrow laser revascularization for treating refractory angina. AB - BACKGROUND: To evaluate the midterm results of patients with angina and diffuse coronary artery disease treated with transmyocardial revascularization in combination with autologous stem cell therapy. METHODS: Nineteen patients with diffuse coronary artery disease and medically refractory class III/IV angina were evaluated between June 2007 and December 2009 for sole therapy TMR combined with intramyocardial injection of concentrated stem cells. At the time of surgery, autologous bone marrow (120cc) was aspirated from the iliac crest. A cardiac MRI and an isotopic test were performed before and after the procedure. Follow-up was performed by personal interview. RESULTS: There were no perioperative adverse events including no arrhythmias. Mean number of laser channels was 20 and the mean total number of intramyocardially injected cells per milliliter were: total mononuclear cells(83.6 * 10(6)), CD34+ cells(0.6 * 10(6)), and CD133+ cells(0.34 * 10(6)). At 12 months mean follow-up average angina class was significantly improved (3.4 +/- 0.5 vs 1.4 +/- 0.6; p = 0.004). In addition, monthly cardiovascular medication usage was significantly decreased (348 +/- 118 vs. 201 +/- 92; p = 0.001). At six months follow up there was a reduction in the number of cardiac hospital readmissions (2.9 +/- 2.3 vs. 0.5 +/- 0.8; p < 0.001). MRI showed no alterations regarding LV volumes and a 3% improvement regarding ejection fraction. CONCLUSIONS: The stem cell isolator efficiently concentrated autologous bone marrow derived stem cells while the TMR/stem cell combination delivery device worked uneventfully. An improvement in clinical status was noticed in the midterm follow-up. Images test showed no morphological alterations in the left ventricle after the procedure. PMID- 20849587 TI - Data-driven assessment of eQTL mapping methods. AB - BACKGROUND: The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis. RESULTS: Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods. CONCLUSIONS: Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods. PMID- 20849588 TI - Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. AB - INTRODUCTION: TNFAIP3 interacting protein 1, TNIP1 (ABIN-1) is involved in inhibition of nuclear factor-kappaB (NF-kappaB) activation by interacting with TNF alpha-induced protein 3, A20 (TNFAIP3), an established susceptibility gene to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recent genome wide association studies revealed association of TNIP1 with SLE in the Caucasian and Chinese populations. In this study, we investigated whether the association of TNIP1 with SLE was replicated in a Japanese population. In addition, association of TNIP1 with RA was also examined. METHODS: A case-control association study was conducted on the TNIP1 single nucleotide polymorphism (SNP) rs7708392 in 364 Japanese SLE patients, 553 RA patients and 513 healthy controls. RESULTS: Association of TNIP1 rs7708392C was replicated in Japanese SLE (allele frequency in SLE: 76.5%, control: 69.9%, P = 0.0022, odds ratio [OR] 1.40, 95% confidence interval [CI] 1.13-1.74). Notably, the risk allele frequency in the healthy controls was considerably greater in Japanese (69.9%) than in Caucasians (24.3%). A tendency of stronger association was observed in the SLE patients with renal disorder (P = 0.00065, OR 1.60 [95%CI 1.22-2.10]) than in all SLE patients (P = 0.0022, OR 1.40 [95%CI 1.13-1.74]). Significant association with RA was not observed, regardless of the carriage of human leukocyte antigen DR beta1 (HLA DRB1) shared epitope. Significant gene-gene interaction between TNIP1 and TNFAIP3 was detected neither in SLE nor RA. CONCLUSIONS: Association of TNIP1 with SLE was confirmed in a Japanese population. TNIP1 is a shared SLE susceptibility gene in the Caucasian and Asian populations, but the genetic contribution appeared to be greater in the Japanese and Chinese populations because of the higher risk allele frequency. Taken together with the association of TNFAIP3, these observations underscore the crucial role of NF-kappaB regulation in the pathogenesis of SLE. PMID- 20849589 TI - An isolated perfused pig heart model for the development, validation and translation of novel cardiovascular magnetic resonance techniques. AB - BACKGROUND: Novel cardiovascular magnetic resonance (CMR) techniques and imaging biomarkers are often validated in small animal models or empirically in patients. Direct translation of small animal CMR protocols to humans is rarely possible, while validation in humans is often difficult, slow and occasionally not possible due to ethical considerations. The aim of this study is to overcome these limitations by introducing an MR-compatible, free beating, blood-perfused, isolated pig heart model for the development of novel CMR methodology. METHODS: 6 hearts were perfused outside of the MR environment to establish preparation stability. Coronary perfusion pressure (CPP), coronary blood flow (CBF), left ventricular pressure (LVP), arterial blood gas and electrolyte composition were monitored over 4 hours. Further hearts were perfused within 3T (n = 3) and 1.5T (n = 3) clinical MR scanners, and characterised using functional (CINE), perfusion and late gadolinium enhancement (LGE) imaging. Perfusion imaging was performed globally and selectively for the right (RCA) and left coronary artery (LCA). In one heart the RCA perfusion territory was determined and compared to infarct size after coronary occlusion. RESULTS: All physiological parameters measured remained stable and within normal ranges. The model proved amenable to CMR at both field strengths using typical clinical acquisitions. There was good agreement between the RCA perfusion territory measured by selective first pass perfusion and LGE after coronary occlusion (37% versus 36% of the LV respectively). CONCLUSIONS: This flexible model allows imaging of cardiac function in a controllable, beating, human-sized heart using clinical MR systems. It should aid further development, validation and clinical translation of novel CMR methodologies, and imaging sequences. PMID- 20849590 TI - Availability and utilization of malaria prevention strategies in pregnancy in eastern India. AB - BACKGROUND: Malaria in pregnancy in India, as elsewhere, is responsible for maternal anemia and adverse pregnancy outcomes such as low birth weight and preterm birth.It is not known whether prevention and treatment strategies for malaria in pregnancy (case management, insecticide-treated bednets, intermittent preventive therapy) are widely utilized in India. METHODS: This cross-sectional study was conducted during 2006-2008 in two states of India, Jharkhand and Chhattisgarh, at 7 facilities representing a range of rural and urban populations and areas of more versus less stable malaria transmission. 280 antenatal visits (40/site) were observed by study personnel coupled with exit interviews of pregnant women to assess emphasis upon, availability and utilization of malaria prevention practices by health workers and pregnant women. The facilities were assessed for the availability of antimalarials, lab supplies and bednets. RESULTS: All participating facilities were equipped to perform malaria blood smears; none used rapid diagnostic tests. Chloroquine, endorsed for chemoprophylaxis during pregnancy by the government at the time of the study, was stocked regularly at all facilities although the quantity stocked varied. Availability of alternative antimalarials for use in pregnancy was less consistent. In Jharkhand, no health worker recommended bednet use during the antenatal visit yet over 90% of pregnant women had bednets in their household. In Chhattisgarh, bednets were available at all facilities but only 14.4% of health workers recommended their use. 40% of the pregnant women interviewed had bednets in their household. Only 1.4% of all households owned an insecticide-treated bednet; yet 40% of all women reported their households had been sprayed with insecticide. Antimalarial chemoprophylaxis with chloroquine was prescribed in only 2 (0.7%) and intermittent preventive therapy prescribed in only one (0.4%) of the 280 observed visits. CONCLUSIONS: A disconnect remains between routine antenatal practices in India and known strategies to prevent and treat malaria in pregnancy. Prevention strategies, in particular the use of insecticide-treated bednets, are underutilized. Gaps highlighted by this study combined with recent estimates of the prevalence of malaria during pregnancy in these areas should be used to revise governmental policy and target increased educational efforts among health care workers and pregnant women. PMID- 20849591 TI - Generation and analysis of ESTs from strawberry (Fragaria xananassa) fruits and evaluation of their utility in genetic and molecular studies. AB - BACKGROUND: Cultivated strawberry is a hybrid octoploid species (Fragaria xananassa Duchesne ex. Rozier) whose fruit is highly appreciated due to its organoleptic properties and health benefits. Despite recent studies on the control of its growth and ripening processes, information about the role played by different hormones on these processes remains elusive. Further advancement of this knowledge is hampered by the limited sequence information on genes from this species, despite the abundant information available on genes from the wild diploid relative Fragaria vesca. However, the diploid species, or one ancestor, only partially contributes to the genome of the cultivated octoploid. We have produced a collection of expressed sequence tags (ESTs) from different cDNA libraries prepared from different fruit parts and developmental stages. The collection has been analysed and the sequence information used to explore the involvement of different hormones in fruit developmental processes, and for the comparison of transcripts in the receptacle of ripe fruits of diploid and octoploid species. The study is particularly important since the commercial fruit is indeed an enlarged flower receptacle with the true fruits, the achenes, on the surface and connected through a network of vascular vessels to the central pith. RESULTS: We have sequenced over 4,500 ESTs from Fragaria xananassa, thus doubling the number of ESTs available in the GenBank of this species. We then assembled this information together with that available from F. xananassa resulting a total of 7,096 unigenes. The identification of SSRs and SNPs in many of the ESTs allowed their conversion into functional molecular markers. The availability of libraries prepared from green growing fruits has allowed the cloning of cDNAs encoding for genes of auxin, ethylene and brassinosteroid signalling processes, followed by expression studies in selected fruit parts and developmental stages. In addition, the sequence information generated in the project, jointly with previous information on sequences from both F. xananassa and F. vesca, has allowed designing an oligo-based microarray that has been used to compare the transcriptome of the ripe receptacle of the diploid and octoploid species. Comparison of the transcriptomes, grouping the genes by biological processes, points to differences being quantitative rather than qualitative. CONCLUSIONS: The present study generates essential knowledge and molecular tools that will be useful in improving investigations at the molecular level in cultivated strawberry (F. xananassa). This knowledge is likely to provide useful resources in the ongoing breeding programs. The sequence information has already allowed the development of molecular markers that have been applied to germplasm characterization and could be eventually used in QTL analysis. Massive transcription analysis can be of utility to target specific genes to be further studied, by their involvement in the different plant developmental processes. PMID- 20849592 TI - Bimodal action of the flavonoid quercetin on basophil function: an investigation of the putative biochemical targets. AB - BACKGROUND: Flavonoids, a large group of polyphenolic metabolites derived from plants have received a great deal of attention over the last several decades for their properties in inflammation and allergy. Quercetin, the most abundant of plant flavonoids, exerts a modulatory action at nanomolar concentrations on human basophils. As this mechanism needs to be elucidated, in this study we focused the possible signal transduction pathways which may be affected by this compound. METHODS: K2-EDTA derived leukocyte buffy coats enriched in basophil granulocytes were treated with different concentrations of quercetin and triggered with anti IgE, fMLP, the calcium ionophore A23187 and the phorbol ester PMA in different experimental conditions. Basophils were captured in a flow cytometry analysis as CD123bright/HLADRnon expressing cells and fluorescence values of the activation markers CD63-FITC or CD203c-PE were used to produce dose response curves. The same population was assayed for histamine release. RESULTS: Quercetin inhibited the expression of CD63 and CD203c and the histamine release in basophils activated with anti-IgE or with the ionophore: the IC50 in the anti-IgE model was higher than in the ionophore model and the effects were more pronounced for CD63 than for CD203c. Nanomolar concentrations of quercetin were able to prime both markers expression and histamine release in the fMLP activation model while no effect of quercetin was observed when basophils were activated with PMA. The specific phosphoinositide-3 kinase (PI3K) inhibitor wortmannin exhibited the same behavior of quercetin in anti-IgE and fMLP activation, thus suggesting a role for PI3K involvement in the priming mechanism. CONCLUSIONS: These results rule out a possible role of protein kinase C in the complex response of basophil to quercetin, while indirectly suggest PI3K as the major intracellular target of this compound also in human basophils. PMID- 20849593 TI - Rv1985c, a promising novel antigen for diagnosis of tuberculosis infection from BCG-vaccinated controls. AB - BACKGROUND: Antigens encoded in the region of difference (RD) of Mycobacterium tuberculosis constitute a potential source of specific antigens for immunodiagnosis. In the present study, recombinant protein Rv1985c from RD2 was cloned, expressed, purified, immunologically characterized and investigated for its potentially diagnostic value for tuberculosis (TB) infection among BCG vaccinated individuals. METHODS: T-cell response to Rv1985c was evaluated by IFN gamma ELISPOT in 56 TB patients, 20 latent TB infection (LTBI) and 30 BCG vaccinated controls in comparison with the commercial T-SPOT. TB kit. Humoral response was evaluated by ELISA in 117 TB patients, 45 LTBI and 67 BCG-vaccinated controls, including all those who had T-cell assay, in comparison with a commercial IgG kit. RESULTS: Rv1985c was specifically recognized by cellular and humoral responses from both TB and LTBI groups compared with healthy controls. Rv1985c IgG-ELISA achieved 52% and 62% sensitivity respectively, which outperformed the sensitivity of PATHOZYME-MYCO kit (34%) in detecting active TB (P = 0.011), whereas IFN-gamma Rv1985c-ELISPOT achieved 71% and 55% sensitivity in detecting active and LTBI, respectively. Addition of Rv1985c increased sensitivities of ESAT-6, CFP-10 and ESAT-6/CFP-10 combination in detecting TB from 82.1% to 89.2% (P = 0.125), 67.9% to 87.5% (P < 0.001) and 85.7% to 92.9% (P = 0.125), respectively. CONCLUSIONS: In conclusion, Rv1985c is a novel antigen which can be used to immunologically diagnose TB infection along with other immunodominant antigens among BCG-vaccinated population. PMID- 20849594 TI - When Indian crabs were not yet Asian--biogeographic evidence for Eocene proximity of India and Southeast Asia. AB - BACKGROUND: The faunal and floral relationship of northward-drifting India with its neighboring continents is of general biogeographic interest as an important driver of regional biodiversity. However, direct biogeographic connectivity of India and Southeast Asia during the Cenozoic remains largely unexplored. We investigate timing, direction and mechanisms of faunal exchange between India and Southeast Asia, based on a molecular phylogeny, molecular clock-derived time estimates and biogeographic reconstructions of the Asian freshwater crab family Gecarcinucidae. RESULTS: Although the Gecarcinucidae are not an element of an ancient Gondwana fauna, their subfamily Gecarcinucinae, and probably also the Liotelphusinae, evolved on the Indian Subcontinent and subsequently dispersed to Southeast Asia. Estimated by a model testing approach, this dispersal event took place during the Middle Eocene, and thus before the final collision of India and the Tibet-part of Eurasia. CONCLUSIONS: We postulate that the India and Southeast Asia were close enough for exchange of freshwater organisms during the Middle Eocene, before the final Indian-Eurasian collision. Our data support geological models that assume the Indian plate having tracked along Southeast Asia during its move northwards. PMID- 20849595 TI - Knowledge and adherence to antiretroviral therapy among adult people living with HIV/AIDS treated in the health care centers of the association "Espoir Vie Togo" in Togo, West Africa. AB - BACKGROUND: The efficiency of antiretroviral therapy (ART) depends on a near perfect level of patients' adherence. The level of adherence of adults HIV infected patients treated in the HIV/AIDS health care centres of the association "Espoir Vie Togo" in Togo, West Africa is not properly documented. The aim of the present study was to examine by means of self-reports the knowledge, the adherence level and associated factors to antiretroviral therapy (ART) among these patients. METHODS: We conducted a cross-sectional survey among adult people living with HIV/AIDS (PLWHA) through a structured questionnaire. RESULTS: A total of 99 patients were enrolled. Among them, 55.6% knew the name of antiretroviral agents of regimens prescribed. All patients had a good knowledge of treatment schedule. The treatment regimens based on 2 NRTIs + 1 NNRTI were used in 90% of patients. The average adherence rate was 89.8% of the total doses prescribed while 62.62% of patients showed an adherence rate of 95% or above. The treated groups were similar in term of median % of medication doses taken according to PLWHA epidemiological characteristics. However, patients reported forgetting (34.9%), travel (25.6%), cost of treatment (13.9%) and side effects (11.6%) as the main factors of missing at least once a dose intake. CONCLUSION: These results should encourage the association and all the involved actors in the HIV/AIDS's program to strengthen counseling, education and information interventions for HIV-infected patients in order to overcome the potential barriers of poor adherence. PMID- 20849596 TI - Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients. AB - BACKGROUND: There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI). METHODS: Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni- and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA. RESULTS: Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.03-2.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI. CONCLUSIONS: High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC. PMID- 20849597 TI - Involvement of hyaluronidases in colorectal cancer. AB - BACKGROUND: Hyaluronidases belong to a class of enzymes that degrade, predominantly, hyaluronan. These enzymes are known to be involved in physiological and pathological processes, such as tumor growth, infiltration and angiogenesis, but their exact role in tumor promotion or suppression is not clear yet. Advanced colorectal cancer is associated with elevated amounts of hyaluronan of varying size. The aim of the present study was therefore to illuminate the importance of hyaluronidases in colon carcinoma progression. METHODS: The patients' samples (macroscopically normal and cancerous) were subjected to sequential extraction with PBS, 4 M GdnHCl and 4 M GdnHCl --1% Triton X-100. The presence of the various hyaluronidases in the extracts was examined by zymography and western blotting. Their expression was also examined by RT-PCR. RESULTS: Among hyaluronidases examined, Hyal-1, -2, -3 and PH-20 were detected. Their activity was higher in cancerous samples. Hyal-1 and Hyal-2 were overexpressed in cancerous samples, especially in advanced stages of cancer. Both isoforms were mainly extracted with PBS. Hyal-3 was observed only in the third extract of advanced stages of cancer. PH-20 was abundant in all three extracts of all stages of cancer. The expression of only Hyal-1 and PH-20 was verified by RT-PCR. CONCLUSION: A high association of hyaluronidases in colorectal cancer was observed. Each hyaluronidase presented different tissue distribution, which indicated the implication of certain isoforms in certain cancer stages. The results provided new evidence on the mechanisms involved in the progression of colorectal cancer. PMID- 20849598 TI - Engaging the oldest old in research: lessons from the Newcastle 85+ study. AB - BACKGROUND: Those aged 85 and over, the oldest old, are now the fastest growing sector of the population. Information on their health is essential to inform future planning; however, there is a paucity of up-to-date information on the oldest old, who are often excluded from research. The aim of the Newcastle 85+ Study is to investigate the health of a cohort of 85-year-olds from a biological, medical and psychosocial perspective. This paper describes the methods employed for the successful recruitment, retention and evaluation of this cohort. METHODS: Participants were all individuals born in 1921 and registered with a participating general practice in Newcastle and North Tyneside, UK. Involvement comprised detailed health assessments, by a nurse, in their usual place of residence and/or review of their general practice medical records. RESULTS: Of the 1453 individuals eligible to participate, 72% (n = 1042) were recruited; 59% (n = 851) consented to both health assessment and review of general practice records. Key factors for successful involvement included protected time to engage with family and other key gatekeepers, minimising participant burden, through for example home based assessment, and flexibility of approach. Cognitive impairment is a significant issue; due consideration should be given to the ethical and legal issues of capacity and consent. Interim withdrawal rates at phase 2 (18 month post baseline), show 88 out of 854 participants (10%) had withdrawn with approval for continued use of data and materials and a further 2 participants (0.2%) had withdrawn and requested that all data be destroyed. Attrition due to death of participants within this same time frame was 135 (16%). CONCLUSION: Our recruitment rates were good and compared favourably with other similar UK and international longitudinal studies of the oldest old. The challenges of and successful strategies for involving, recruiting and retaining the oldest old in research, including those in institutions, are described to facilitate adequate representation of this growing population in future research into ageing. PMID- 20849599 TI - Understanding reactions to an internet-delivered health-care intervention: accommodating user preferences for information provision. AB - BACKGROUND: It is recognised as good practice to use qualitative methods to elicit users' views of internet-delivered health-care interventions during their development. This paper seeks to illustrate the advantages of combining usability testing with 'theoretical modelling', i.e. analyses that relate the findings of qualitative studies during intervention development to social science theory, in order to gain deeper insights into the reasons and context for how people respond to the intervention. This paper illustrates how usability testing may be enriched by theoretical modelling by means of two qualitative studies of users' views of the delivery of information in an internet-delivered intervention to help users decide whether they needed to seek medical care for their cold or flu symptoms. METHODS: In Study 1, 21 participants recruited from a city in southern England were asked to 'think aloud' while viewing draft web-pages presented in paper format. In Study 2, views of our prototype website were elicited, again using think aloud methods, in a sample of 26 participants purposively sampled for diversity in education levels. Both data-sets were analysed by thematic analysis. RESULTS: Study 1 revealed that although the information provided by the draft web pages had many of the intended empowering benefits, users often felt overwhelmed by the quantity of information. Relating these findings to theory and research on factors influencing preferences for information-seeking we hypothesised that to meet the needs of different users (especially those with lower literacy levels) our website should be designed to provide only essential personalised advice, but with options to access further information. Study 2 showed that our website design did prove accessible to users with different literacy levels. However, some users seemed to want still greater control over how information was accessed. CONCLUSIONS: Educational level need not be an insuperable barrier to appreciating web-based access to detailed health-related information, provided that users feel they can quickly gain access to the specific information they seek. PMID- 20849600 TI - Human vascular adhesion protein-1 (VAP-1): serum levels for hepatocellular carcinoma in non-alcoholic and alcoholic fatty liver disease. AB - BACKGROUND: The incidence of hepatocellular cancer in complicated alcoholic and non-alcoholic fatty liver diseases is on the rise in western countries as well in our country. Vascular adhesion protein-1 (VAP-1) levels have been presented as new marker. In our study protocol, we assessed the value of this serum protein, as a newly postulant biomarker for hepatocellular cancer in patients with a history of alcoholic and non-alcoholic fatty liver diseases. METHODS: Pre operative serum samples from 55 patients with hepatocellular cancer with a history of alcoholic and non-alcoholic fatty liver diseases and patients with cirrhosis were assessed by a quantitative sandwich ELISA using anti-VAP-1 mAbs. This technique is used to determine the levels of soluble VAP-1 (sVAP-1) in the serum. RESULTS: sVAP-1 levels were evaluated in patients with hepatocellular cancer and liver cirrhosis. There was a significant difference in mean VAP-1 levels between groups. Serum VAP-1 levels were found higher in patients with hepatocellular cancer. CONCLUSION: These findings indicate that the serum level of sVAP-1 might be a beneficial marker of disease activity in chronic liver diseases. PMID- 20849601 TI - An educational approach based on a non-injury model compared with individual symptom-based physical training in chronic LBP. A pragmatic, randomised trial with a one-year follow-up. AB - BACKGROUND: In the treatment of chronic back pain, cognitive methods are attracting increased attention due to evidence of effectiveness similar to that of traditional therapies. The purpose of this study was to compare the effectiveness of performing a cognitive intervention based on a non-injury model with that of a symptom-based physical training method on the outcomes of low back pain (LBP), activity limitation, LBP attitudes (fear-avoidance beliefs and back beliefs), physical activity levels, sick leave, and quality of life, in chronic LBP patients. METHODS: The study was a pragmatic, single-blind, randomised, parallel-group trial. Patients with chronic/recurrent LBP were randomised to one of the following treatments: 1. Educational programme : the emphasis was on creating confidence that the back is strong, that loads normally do not cause any damage despite occasional temporary pain, that reducing the focus on the pain might facilitate more natural and less painful movements, and that it is beneficial to stay physically active. 2. Individual symptom-based physical training programme : directional-preference exercises for those centralising their pain with repetitive movements; 'stabilising exercises' for those deemed 'unstable' based on specific tests; or intensive dynamic exercises for the remaining patients. Follow-up questionnaires (examiner-blinded) were completed at 2, 6 and 12 months. The main statistical test was an ANCOVA adjusted for baseline values. RESULTS: A total of 207 patients participated with the median age of 39 years (IQR 33-47); 52% were female, 105 were randomised to the educational programme and 102 to the physical training programme. The two groups were comparable at baseline. For the primary outcome measures, there was a non significant trend towards activity limitation being reduced mostly in the educational programme group, although of doubtful clinical relevance. Regarding secondary outcomes, improvement in fear-avoidance beliefs was also better in the educational programme group. All other variables were about equally influenced by the two treatments. The median number of treatment sessions was 3 for the educational programme group and 6 for the physical training programme group. CONCLUSIONS: An educational approach to treatment for chronic LBP resulted in at least as good outcomes as a symptom-based physical training method, despite fewer treatment sessions. PMID- 20849602 TI - Characterization of a novel Lactobacillus species closely related to Lactobacillus johnsonii using a combination of molecular and comparative genomics methods. AB - BACKGROUND: Comparative genomic hybridization (CGH) constitutes a powerful tool for identification and characterization of bacterial strains. In this study we have applied this technique for the characterization of a number of Lactobacillus strains isolated from the intestinal content of rats fed with a diet supplemented with sorbitol. RESULTS: Phylogenetic analysis based on 16S rRNA gene, recA, pheS, pyrG and tuf sequences identified five bacterial strains isolated from the intestinal content of rats as belonging to the recently described Lactobacillus taiwanensis species. DNA-DNA hybridization experiments confirmed that these five strains are distinct but closely related to Lactobacillus johnsonii and Lactobacillus gasseri. A whole genome DNA microarray designed for the probiotic L. johnsonii strain NCC533 was used for CGH analysis of L. johnsonii ATCC 33200T, L. johnsonii BL261, L. gasseri ATCC 33323T and L. taiwanensis BL263. In these experiments, the fluorescence ratio distributions obtained with L. taiwanensis and L. gasseri showed characteristic inter-species profiles. The percentage of conserved L. johnsonii NCC533 genes was about 83% in the L. johnsonii strains comparisons and decreased to 51% and 47% for L. taiwanensis and L. gasseri, respectively. These results confirmed the separate status of L. taiwanensis from L. johnsonii at the level of species, and also that L. taiwanensis is closer to L. johnsonii than L. gasseri is to L. johnsonii. CONCLUSION: Conventional taxonomic analyses and microarray-based CGH analysis have been used for the identification and characterization of the newly species L. taiwanensis. The microarray-based CGH technology has been shown as a remarkable tool for the identification and fine discrimination between phylogenetically close species, and additionally provided insight into the adaptation of the strain L. taiwanensis BL263 to its ecological niche. PMID- 20849603 TI - Multiplexed methylation profiles of tumor suppressor genes and clinical outcome in lung cancer. AB - BACKGROUND: Changes in DNA methylation of crucial cancer genes including tumor suppressors can occur early in carcinogenesis, being potentially important early indicators of cancer. The objective of this study was to examine a multiplexed approach to assess the methylation of tumor suppressor genes as tumor stratification and clinical outcome prognostic biomarkers for lung cancer. METHODS: A multicandidate probe panel interrogated DNA for aberrant methylation status in 18 tumor suppressor genes in lung cancer using a methylation-specific multiplex ligation-dependent probe amplification assay (MS-MLPA). Lung cancer cell lines (n = 7), and primary lung tumors (n = 54) were examined using MS-MLPA. RESULTS: Genes frequently methylated in lung cancer cell lines including SCGB3A1, ID4, CCND2 were found among the most commonly methylated in the lung tumors analyzed. HLTF, BNIP3, H2AFX, CACNA1G, TGIF, ID4 and CACNA1A were identified as novel tumor suppressor candidates methylated in lung tumors. The most frequently methylated genes in lung tumors were SCGB3A1 and DLC1 (both 50.0%). Methylation rates for ID4, DCL1, BNIP3, H2AFX, CACNA1G and TIMP3 were significantly different between squamous and adenocarcinomas. Methylation of RUNX3, SCGB3A1, SFRP4, and DLC1 was significantly associated with the extent of the disease when comparing localized versus metastatic tumors. Moreover, methylation of HTLF, SFRP5 and TIMP3 were significantly associated with overall survival. CONCLUSIONS: MS-MLPA can be used for classification of certain types of lung tumors and clinical outcome prediction. This latter is clinically relevant by offering an adjunct strategy for the clinical management of lung cancer patients. PMID- 20849604 TI - Dipolar cortico-muscular electrical stimulation: a novel method that enhances motor function in both - normal and spinal cord injured mice. AB - BACKGROUND: Electrical stimulation of the central and peripheral nervous systems is a common tool that is used to improve functional recovery after neuronal injury. METHODS: Here we described a new configuration of electrical stimulation as it was tested in anesthetized control and spinal cord injury (SCI) mice. Constant voltage output was delivered through two electrodes. While the negative voltage output (ranging from -1.8 to -2.6 V) was delivered to the muscle via transverse wire electrodes (diameter, 500 MUm) located at opposite ends of the muscle, the positive output (ranging from + 2.4 to +3.2 V) was delivered to the primary motor cortex (M1) (electrode tip, 100 MUm). The configuration was named dipolar cortico-muscular stimulation (dCMS) and consisted of 100 pulses (1 ms pulse duration, 1 Hz frequency). RESULTS: In SCI animals, after dCMS, cortically elicited muscle contraction improved markedly at the contralateral (456%) and ipsilateral (457%) gastrocnemius muscles. The improvement persisted for the duration of the experiment (60 min). The enhancement of cortically-elicited muscle contraction was accompanied by the reduction of M1 maximal threshold and the potentiation of spinal motoneuronal evoked responses at the contralateral (313%) and ipsilateral (292%) sides of the spinal cord. Moreover, spontaneous activity recorded from single spinal motoneurons was substantially increased contralaterally (121%) and ipsilaterally (54%). Interestingly, spinal motoneuronal responses and muscle twitches evoked by the test stimulation of non treated M1 (received no dCMS) were significantly enhanced as well. Similar results obtained from normal animals albeit the changes were relatively smaller. CONCLUSION: These findings demonstrated that dCMS could improve functionality of corticomotoneuronal pathway and thus it may have therapeutic potential. PMID- 20849605 TI - Is globalization healthy: a statistical indicator analysis of the impacts of globalization on health. AB - It is clear that globalization is something more than a purely economic phenomenon manifesting itself on a global scale. Among the visible manifestations of globalization are the greater international movement of goods and services, financial capital, information and people. In addition, there are technological developments, more transboundary cultural exchanges, facilitated by the freer trade of more differentiated products as well as by tourism and immigration, changes in the political landscape and ecological consequences. In this paper, we link the Maastricht Globalization Index with health indicators to analyse if more globalized countries are doing better in terms of infant mortality rate, under five mortality rate, and adult mortality rate. The results indicate a positive association between a high level of globalization and low mortality rates. In view of the arguments that globalization provides winners and losers, and might be seen as a disequalizing process, we should perhaps be careful in interpreting the observed positive association as simple evidence that globalization is mostly good for our health. It is our hope that a further analysis of health impacts of globalization may help in adjusting and optimising the process of globalization on every level in the direction of a sustainable and healthy development for all. PMID- 20849606 TI - Local erythropoietin and endothelial progenitor cells improve regional cardiac function in acute myocardial infarction. AB - BACKGROUND: Expanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI. METHODS AND RESULTS: In vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone. CONCLUSION: Intramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling. PMID- 20849607 TI - Smoking during pregnancy and risk of abnormal glucose tolerance: a prospective cohort study. AB - BACKGROUND: Disturbances in glucose metabolism during pregnancy are associated with negative sequalae for both mother and infant. The association between smoking and abnormal glucose tolerance (AGT) remains controversial. Therefore, the aim of this study was to examine the relationship between smoking prior to and during pregnancy and risk of AGT. METHODS: We utilized data from a prospective cohort of 1,006 Hispanic (predominantly Puerto Rican) prenatal care patients in Western Massachusetts. Women reported pre- and early pregnancy smoking at recruitment (mean = 15 weeks) and mid pregnancy smoking at a second interview (mean = 28 weeks). AGT was defined as > 135 mg/dL on the routine 1-hour glucose tolerance test (1-hr OGTT). We used multivariable regression to assess the effect of pre, early, and mid-pregnancy smoking on risk of AGT and screening plasma glucose value from the 1-hr OGTT. RESULTS: In age-adjusted models, women who smoked > 0-9 cigarettes/day in pre-pregnancy had an increased risk of AGT (OR = 1.90; 95% CI 1.02-3.55) compared to non-smokers; this was attenuated in multivariable models. Smoking in early (OR = 0.48; 95% CI 0.21-1.10) and mid pregnancy (OR = 0.38; 95% CI 0.13-1.11) were not associated with AGT in multivariable models. Smoking during early and mid pregnancy were independently associated with lower glucose screening values, while smoking in pre-pregnancy was not. CONCLUSIONS: In this prospective cohort of Hispanic women, we did not observe an association between smoking prior to or during pregnancy and risk of AGT. Findings from this study, although based on small numbers of cases, extend prior research to the Hispanic population. PMID- 20849608 TI - Cytotoxicity screening of Bangladeshi medicinal plant extracts on pancreatic cancer cells. AB - BACKGROUND: There has been a long standing interest in the identification of medicinal plants and derived natural products for developing cancer therapeutics. Our study focuses upon pancreatic cancer, due to its high mortality rate, that is attributed in part to the lack of an effective chemotherapeutic agent. Previous reports on the use of medicinal plant extracts either alone or alongside conventional anticancer agents in the treatment of this cancer have shown promising results. This work aims to investigate the therapeutic properties of a library of medicinal plants from Bangladesh. METHODS: 56 extracts of 44 unique medicinal plants were studied. The extracts were screened for cytotoxicity against the pancreatic adenocarcinoma cell line Panc-1, using a label-free biosensor assay. The top cytotoxic extracts identified in this screen were tested on two additional pancreatic cancer cell lines (Mia-Paca2 and Capan-1) and a fibroblast cell line (Hs68) using an MTT proliferation assay. Finally, one of the most promising extracts was studied using a caspase-3 colorimetric assay to identify induction of apoptosis. RESULTS: Crude extracts of Petunia punctata, Alternanthera sessilis, and Amoora chittagonga showed cytotoxicity to three cancer cell lines with IC50 values ranging between 20.3 - 31.4 MUg/mL, 13.08 - 34.9 MUg/mL, and 42.8 - 49.8 MUg/mL, respectively. Furthermore, treatment of Panc 1 cells with Petunia punctata was shown to increase caspase-3 activity, indicating that the observed cytotoxicity was mediated via apoptosis. Only Amoora chittagonga showed low cytotoxicity to fibroblast cells with an IC50 value > 100 MUg/mL. CONCLUSION: Based upon the initial screening work reported here, further studies aimed at the identification of active components of these three extracts and the elucidation of their mechanisms as cancer therapeutics are warranted. PMID- 20849609 TI - The risk of adverse pregnancy outcomes in women who are overweight or obese. AB - BACKGROUND: The prevalence of obesity amongst women bearing children in Australia is rising and has important implications for obstetric care. The aim of this study was to assess the prevalence and impact of mothers being overweight and obese in early to mid-pregnancy on maternal, peripartum and neonatal outcomes. METHODS: A secondary analysis was performed on data collected from nulliparous women with a singleton pregnancy enrolled in the Australian Collaborative Trial of Supplements with antioxidants Vitamin C and Vitamin E to pregnant women for the prevention of pre-eclampsia (ACTS). Women were categorized into three groups according to their body mass index (BMI): normal (BMI 18.5-24.9 kg/m2); overweight (BMI 25-29.9 kg/m2) and; obese (BMI 30-34.9 kg/m2). Obstetric and perinatal outcomes were compared by univariate and multivariate analyses. RESULTS: Of the 1661 women included, 43% were overweight or obese. Obese women were at increased risk of pre-eclampsia (relative risk (RR) 2.99 [95% confidence intervals (CI) 1.88, 4.73], p < 0.0001) and gestational diabetes (RR 2.10 [95%CI 1.17, 3.79], p = 0.01) compared with women with a normal BMI. Obese and overweight women were more likely to be induced and require a caesarean section compared with women of normal BMI (induction - RR 1.33 [95%CI 1.13, 1.57], p = 0.001 and 1.78 [95%CI 1.51, 2.09], p < 0.0001, caesarean section - RR 1.42 [95%CI 1.18, 1.70], p = 0.0002 and 1.63 [95%CI 1.34, 1.99], p < 0.0001). Babies of women who were obese were more likely to be large for gestational age (LFGA) (RR 2.08 [95%CI 1.47, 2.93], p < 0.0001) and macrosomic (RR 4.54 [95%CI 2.01, 10.24], p = 0.0003) compared with those of women with a normal BMI. CONCLUSION: The rate of overweight and obesity is increasing amongst the Australian obstetric population. Women who are overweight and obese have an increased risk of adverse pregnancy outcomes. In particular, obese women are at increased risk of gestational diabetes, pregnancy induced hypertension and pre-eclampsia. Effective preventative strategies are urgently needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN00416244. PMID- 20849610 TI - Knockdown and overexpression of Unc-45b result in defective myofibril organization in skeletal muscles of zebrafish embryos. AB - BACKGROUND: Unc-45 is a myosin chaperone and a Hsp90 co-chaperone that plays a key role in muscle development. Genetic and biochemical studies in C. elegans have demonstrated that Unc-45 facilitates the process of myosin folding and assembly in body wall muscles. Loss or overexpression of Unc-45 in C. elegans results in defective myofibril organization. In the zebrafish Danio rerio, unc 45b, a homolog of C. elegans unc-45, is expressed in both skeletal and cardiac muscles. Earlier studies indicate that mutation or knockdown of unc-45b expression in zebrafish results in a phenotype characterized by a loss of both thick and thin filament organization in skeletal and cardiac muscle. The effects of unc-45b knockdown on other sarcomeric structures and the phenotype of Unc-45b overexpression, however, are poorly understood in vertebrates. RESULTS: Both knockdown and overexpression provide useful tools to study gene function during animal development. Using such methods, we characterized the role of Unc-45b in myofibril assembly of skeletal muscle in Danio rerio. We showed that, in addition to thick and thin filament defects, knockdown of unc-45b expression disrupted sarcomere organization in M-lines and Z-lines of skeletal muscles in zebrafish embryos. Western blotting analysis showed that myosin protein levels were significantly decreased in unc-45b knockdown embryos. Similarly, embryos overexpressing Unc-45b also exhibited severely disorganized myosin thick filaments. Disruption of thick filament organization by Unc-45b overexpression depends on the C-terminal UCS domain in Unc-45b required for interaction with myosin. Deletion of the C-terminal UCS domain abolished the disruptive activity of Unc-45b in myosin thick filament organization. In contrast, deletion of the N terminal TPR domain required for binding with Hsp90alpha had no effect. CONCLUSION: Collectively, these studies indicate that the expression levels of Unc-45b must be precisely regulated to ensure normal myofibril organization. Loss or overexpression of Unc-45b leads to defective myofibril organization. PMID- 20849611 TI - A method for encoding clinical datasets with SNOMED CT. AB - BACKGROUND: Over the past decade there has been a growing body of literature on how the Systematised Nomenclature of Medicine Clinical Terms (SNOMED CT) can be implemented and used in different clinical settings. Yet, for those charged with incorporating SNOMED CT into their organisation's clinical applications and vocabulary systems, there are few detailed encoding instructions and examples available to show how this can be done and the issues involved. This paper describes a heuristic method that can be used to encode clinical terms in SNOMED CT and an illustration of how it was applied to encode an existing palliative care dataset. METHODS: The encoding process involves: identifying input data items; cleaning the data items; encoding the cleaned data items; and exporting the encoded terms as output term sets. Four outputs are produced: the SNOMED CT reference set; interface terminology set; SNOMED CT extension set and unencodeable term set. RESULTS: The original palliative care database contained 211 data elements, 145 coded values and 37,248 free text values. We were able to encode ~84% of the terms, another ~8% require further encoding and verification while terms that had a frequency of fewer than five were not encoded (~7%). CONCLUSIONS: From the pilot, it would seem our SNOMED CT encoding method has the potential to become a general purpose terminology encoding approach that can be used in different clinical systems. PMID- 20849612 TI - Diffusion tensor imaging correlates with lesion volume in cerebral hemisphere infarctions. AB - BACKGROUND: Both a large lesion volume and abnormalities in diffusion tensor imaging are independently associated with a poor prognosis after cerebral infarctions. Therefore, we assume that they are associated. This study assessed the associations between lesion volumes and diffusion tensor imaging in patients with a right-sided cerebral infarction. METHODS: The lesion volumes of 33 patients (age 65.9 +/- 8.7, 26 males and 7 females) were imaged using computed tomography (CT) in the acute phase (within 3-4 hours) and magnetic resonance imaging (MRI) in the chronic phase (follow-up at 12 months, with a range of 8-27 months). The chronic-phase fractional anisotropy (FA) and mean diffusivity (MD) values were measured at the site of the infarct and selected white matter tracts. Neurological tests in both the acute and chronic phases, and DTI lateralization were assessed with the Wilcoxon signed-rank test. The effects of thrombolytic therapy (n = 10) were assessed with the Mann-Whitney U test. The correlations between the measured parameters were analysed with Spearman's rho correlation. Bonferroni post-hoc correction was used to compensate for the familywise error rate in multiple comparisons. RESULTS: Several MD values in the right hemisphere correlated positively and FA values negatively with the lesion volumes. These correlations included both lesion area and healthy tissue. The results of the mini-mental state examination and the National Institutes of Health Stroke Scale also correlated with the lesion volume. CONCLUSIONS: A larger infarct volume is associated with more pronounced tissue modifications in the chronic stage as observed with the MD and FA alterations. PMID- 20849613 TI - A cluster randomised controlled trial of the community effectiveness of two interventions in rural Malawi to improve health care and to reduce maternal, newborn and infant mortality. AB - BACKGROUND: The UN Millennium Development Goals call for substantial reductions in maternal and child mortality, to be achieved through reductions in morbidity and mortality during pregnancy, delivery, postpartum and early childhood. The MaiMwana Project aims to test community-based interventions that tackle maternal and child health problems through increasing awareness and local action. METHODS/DESIGN: This study uses a two-by-two factorial cluster-randomised controlled trial design to test the impact of two interventions. The impact of a community mobilisation intervention run through women's groups, on home care, health care-seeking behaviours and maternal and infant mortality, will be tested. The impact of a volunteer-led infant feeding and care support intervention, on rates of exclusive breastfeeding, uptake of HIV-prevention services and infant mortality, will also be tested. The women's group intervention will employ local female facilitators to guide women's groups through a four-phase cycle of problem identification and prioritisation, strategy identification, implementation and evaluation. Meetings will be held monthly at village level. The infant feeding intervention will select local volunteers to provide advice and support for breastfeeding, birth preparedness, newborn care and immunisation. They will visit pregnant and new mothers in their homes five times during and after pregnancy.The unit of intervention allocation will be clusters of rural villages of 2500-4000 population. 48 clusters have been defined and randomly allocated to either women's groups only, infant feeding support only, both interventions, or no intervention. Study villages are surrounded by 'buffer areas' of non-study villages to reduce contamination between intervention and control areas. Outcome indicators will be measured through a demographic surveillance system. Primary outcomes will be maternal, infant, neonatal and perinatal mortality for the women's group intervention, and exclusive breastfeeding rates and infant mortality for the infant feeding intervention.Structured interviews will be conducted with mothers one-month and six-months after birth to collect detailed quantitative data on care practices and health-care-seeking. Further qualitative, quantitative and economic data will be collected for process and economic evaluations. TRIAL REGISTRATION: ISRCTN06477126. PMID- 20849614 TI - Akt is required for Stat5 activation and mammary differentiation. AB - INTRODUCTION: The Akt pathway plays a central role in regulating cell survival, proliferation and metabolism, and is one of the most commonly activated pathways in human cancer. A role for Akt in epithelial differentiation, however, has not been established. We previously reported that mice lacking Akt1, but not Akt2, exhibit a pronounced metabolic defect during late pregnancy and lactation that results from a failure to upregulate Glut1 as well as several lipid synthetic enzymes. Despite this metabolic defect, however, both Akt1-deficient and Akt2 deficient mice exhibit normal mammary epithelial differentiation and Stat5 activation. METHODS: In light of the overlapping functions of Akt family members, we considered the possibility that Akt may play an essential role in regulating mammary epithelial development that is not evident in Akt1-deficient mice due to compensation by other Akt isoforms. To address this possibility, we interbred mice bearing targeted deletions in Akt1 and Akt2 and determined the effect on mammary differentiation during pregnancy and lactation. RESULTS: Deletion of one allele of Akt2 in Akt1-deficient mice resulted in a severe defect in Stat5 activation during late pregnancy that was accompanied by a global failure of terminal mammary epithelial cell differentiation, as manifested by the near complete loss in production of the three principal components of milk: lactose, lipid, and milk proteins. This defect was due, in part, to a failure of pregnant Akt1(-/-);Akt2(+/-) mice to upregulate the positive regulator of Prlr-Jak-Stat5 signaling, Id2, or to downregulate the negative regulators of Prlr-Jak-Stat5 signaling, caveolin-1 and Socs2. CONCLUSIONS: Our findings demonstrate an unexpected requirement for Akt in Prlr-Jak-Stat5 signaling and establish Akt as an essential central regulator of mammary epithelial differentiation and lactation. PMID- 20849615 TI - Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease. AB - BACKGROUND: Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved. METHODS: It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured. RESULTS: Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007). CONCLUSIONS: Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD. PMID- 20849616 TI - Ways and means of coping with uncertainties of the relationship of the genetic blue print to protein structure and function in the cell. AB - As one of the disciplines of systems biology, proteomics is central to enabling the elucidation of protein function within the cell; furthermore, the question of how to deduce protein structure and function from the genetic readout has gained new significance. This problem is of particular relevance for proteins engaged in cell signalling. In dealing with this question, I shall critically comment on the reliability and predictability of transmission and translation of the genetic blue print into the phenotype, the protein. Based on this information, I will then evaluate the intentions and goals of today's proteomics and gene-networking and appraise their chances of success. Some of the themes commented on in this publication are explored in greater detail with particular emphasis on the historical roots of concepts and techniques in my forthcoming book, published in German: Von Molekulen zu Zellen. 100 Jahre experimentelle Biologie. Betrachtungen eines Biochemikers. PMID- 20849617 TI - Analysis and characterization of the genes encoding the Dicer and Argonaute proteins of Schistosoma japonicum. AB - BACKGROUND: The Dicer and Argonaute(AGO) proteins within the small RNA regulatory pathways (SRRPs) play an indispensable role in regulation of gene expression. In this study, we analyzed two genes, Dicer and Argonaute, from Schistosoma japonicum, along with their expression through a combination of bioinformatics and experimental approaches. RESULTS: Our results indicate that one Dicer and four Argonaute genes exist in Schistosoma japonicum, termed SjDicer and SjAGO1, 2, 3, and 4, respectively. SjDicer encodes 2590 amino acid residues that contains 5 conserved domains, including one amino-terminal helicase domain, one PAZ (Piwi Argonaut-Zwille) domain, two RNAse III domains, and one dsRNA-binding domain. SjAGO1, 2, and 3 encode 1009, 945, and 904 amino acid residues, respectively, all of which contain PAZ and PIWI domains. In addition, we analyzed the expression profiles of SjDicer and SjAGO1 genes by qRT-PCR in eggs, miracidium, cercariae, schistosomula, and adult worms. Results showed consistent expression of both SjDicer and SjAGO1 in different stages; however, their expression levels were stage-dependent, with the highest being in the miracidium stage. CONCLUSIONS: This study provided the sequence of the Dicer and Ago genes of S. japonicum and their expression profiles which are essential for further investigation of functions of miRNA in Schistosoma japonicum. PMID- 20849618 TI - Multiple functions of CXCL12 in a syngeneic model of breast cancer. AB - BACKGROUND: A growing body of work implicates chemokines, in particular CXCL12 and its receptors, in the progression and site-specific metastasis of various cancers, including breast cancer. Various agents have been used to block the CXCL12-CXCR4 interaction as a means of inhibiting cancer metastasis. However, as a potent chemotactic factor for leukocytes, CXCL12 also has the potential to enhance anti-cancer immunity. To further elucidate its role in breast cancer progression, CXCL12 and its antagonist CXCL12(P2G) were overexpressed in the syngeneic 4T1.2 mouse model of breast carcinoma. RESULTS: While expression of CXCL12(P2G) significantly inhibited metastasis, expression of wild-type CXCL12 potently inhibited both metastasis and primary tumor growth. The effects of wild type CXCL12 were attributed to an immune response characterized by the induction of CD8+ T cell activity, enhanced cell-mediated cytotoxicity, increased numbers of CD11c+ cells in the tumor-draining lymph nodes and reduced accumulation of myeloid-derived suppressor cells in the spleen. CONCLUSIONS: This study highlights the need to consider carefully therapeutic strategies that block CXCL12 signaling. Therapies that boost CXCL12 levels at the primary tumor site may prove more effective in the treatment of metastatic breast cancer. PMID- 20849619 TI - Effectiveness of adjuvant occupational therapy in employees with depression: design of a randomized controlled trial. AB - BACKGROUND: Major depressive disorder is among the medical conditions with the highest negative impact on work outcome. However, little is known regarding evidence-based interventions targeting the improvement of work outcomes in depressed employees. In this paper, the design of a randomized controlled trial is presented in order to evaluate the effectiveness of adjuvant occupational therapy in employees with depression. This occupational intervention is based on an earlier intervention, which was designed and proven effective by our research group, and is the only intervention to date that specifically targets work outcome in depressed employees. METHODS/DESIGN: In a two-arm randomized controlled trial, a total of 117 participants are randomized to either 'care as usual' or ' care as usual' with the addition of occupational therapy. Patients included in the study are employees who are absent from work due to depression for at least 25% of their contract hours, and who have a possibility of returning to their own or a new job. The occupational intervention consists of six individual sessions, eight group sessions and a work-place visit over a 16-week period. By increasing exposure to the working environment, and by stimulating communication between employer and employee, the occupational intervention aims to enhance self-efficacy and the acquisition of more adaptive coping strategies. Assessments take place at baseline, and at 6, 12, and 18-month follow-ups. Primary outcome measure is work participation (hours of absenteeism and time until work resumption). Secondary outcome measures are work functioning, symptomatology, health-related quality of life, and neurocognitive functioning. In addition, cost-effectiveness is evaluated from a societal perspective. Finally, mechanisms of change (intermediate outcomes) and potential patient treatment matching variables are investigated. DISCUSSION: This study hopes to provide valuable knowledge regarding an intervention to treat depression, one of the most common and debilitating diseases of our time. If our intervention is proven (cost-) effective, the personal, economic, and health benefits for both patients and employers are far-reaching. TRIAL REGISTRATION NUMBER: NTR2057. PMID- 20849620 TI - The use of a commercial vegetable juice as a practical means to increase vegetable intake: a randomized controlled trial. AB - BACKGROUND: Recommendations for daily dietary vegetable intake were increased in the 2005 USDA Dietary Guidelines as consumption of a diet rich in vegetables has been associated with lower risk of certain chronic health disorders including cardiovascular disease. However, vegetable consumption in the United States has declined over the past decade; consequently, the gap between dietary recommendations and vegetable intake is widening. The primary aim of this study is to determine if drinking vegetable juice is a practical way to help meet daily dietary recommendations for vegetable intake consistent with the 2005 Dietary Guidelines and the Dietary Approaches to Stop Hypertension (DASH) diet. The secondary aim is to assess the effect of a vegetable juice on measures of cardiovascular health. METHODS: We conducted a 12-week, randomized, controlled, parallel-arm study consisting of 3 groups of free-living, healthy volunteers who participated in study visits at the Ragle Human Nutrition Research Center at the University of California, Davis. All subjects received education on the DASH diet and 0, 8 or 16 fluid ounces of vegetable juice daily. Assessments were completed of daily vegetable servings before and after incorporation of vegetable juice and cardiovascular health parameters including blood pressure. RESULTS: Without the juice, vegetable intake in all groups was lower than the 2005 Dietary Guidelines and DASH diet recommendations. The consumption of the vegetable juice helped participants reach recommended intake. In general, parameters associated with cardiovascular health did not change over time. However, in the vegetable juice intervention groups, subjects who were pre-hypertensive at the start of the study showed a significant decrease in blood pressure during the 12-week intervention period. CONCLUSION: Including 1-2 cups of vegetable juice daily was an effective and acceptable way for healthy adults to close the dietary vegetable gap. Increase in daily vegetable intake was associated with a reduction in blood pressure in subjects who were pre-hypertensive at the start of the trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT01161706. PMID- 20849622 TI - Remission of severe restless legs syndrome and periodic limb movements in sleep after bilateral excision of multiple foot neuromas: a case report. AB - INTRODUCTION: Restless legs syndrome is a sensorimotor neurological disorder characterized by an urge to move the legs in response to uncomfortable leg sensations. While asleep, 70 to 90 percent of patients with restless legs syndrome have periodic limb movements in sleep. Frequent periodic limb movements in sleep and related brain arousals as documented by polysomnography are associated with poorer quality of sleep and daytime fatigue. Restless legs syndrome in middle age is sometimes associated with neuropathic foot dysesthesias. The causes of restless legs syndrome and periodic limb movements in sleep are unknown, but the sensorimotor symptoms are hypothesized to originate in the central nervous system. We have previously determined that bilateral forefoot digital nerve impingement masses (neuromas) may be a cause of both neuropathic foot dysesthesias and the leg restlessness of restless legs syndrome. To the best of our knowledge, this case is the first report of bilateral foot neuromas as a cause of periodic limb movements in sleep. CASE PRESENTATION: A 42-year-old Caucasian woman with severe restless legs syndrome and periodic limb movements in sleep and bilateral neuropathic foot dysesthesias was diagnosed as having neuromas in the second, third, and fourth metatarsal head interspaces of both feet. The third interspace neuromas represented regrowth (or 'stump') neuromas that had developed since bilateral third interspace neuroma excision five years earlier. Because intensive conservative treatments including repeated neuroma injections and various restless legs syndrome medications had failed, radical surgery was recommended. All six neuromas were excised. Leg restlessness, foot dysesthesias and subjective sleep quality improved immediately. Assessment after 18 days showed an 84 to 100 percent reduction of visual analog scale scores for specific dysesthesias and marked reductions of pre-operative scores of the Pittsburgh sleep quality index, fatigue severity scale, and the international restless legs syndrome rating scale (36 to 4). Polysomnography six weeks post operatively showed improved sleep efficiency, a marked increase in rapid eye movement sleep, and marked reductions in hourly rates of both periodic limb movements in sleep with arousal (135.3 to 3.3) and spontaneous arousals (17.3 to 0). CONCLUSION: The immediate and near complete remission of symptoms, the histopathology of the excised tissues, and the marked improvement in polysomnographic parameters documented six weeks after surgery together indicate that this patient's severe restless legs syndrome and periodic limb movements in sleep was of peripheral nerve (foot neuroma) origin. Further study of foot neuromas as a source of periodic limb movements in sleep and as a cause of sleep dysfunction in patients with or without concomitant restless legs syndrome, is warranted. PMID- 20849621 TI - Corpus callosum agenesis and rehabilitative treatment. AB - Corpus callosum agenesis is a relatively common brain malformation. It can be isolated or included in a complex alteration of brain (or sometimes even whole body) morphology. It has been associated with a number of neuropsychiatric disorders, from subtle neuropsychological deficits to Pervasive Developmental Disorders.Etiology and pathogenetic mechanisms have been better understood in recent years, due to the availability of more adequate animal models and the relevant progresses in developmental neurosciences. These recent findings are reviewed (through a MedLine search including papers published in the last 5 years and most relevant previously published papers) in view of the potential impact on children's global functioning and on the possible rehabilitative treatment, with an emphasis on the possibility to exploit brain plasticity and on the use of the ICF-CY framework. PMID- 20849623 TI - Clinical outcomes of stereotactic body radiotherapy for stage I non-small cell lung cancer using different doses depending on tumor size. AB - BACKGROUND: The treatment schedules for stereotactic body radiotherapy (SBRT) for lung cancer vary from institution to institution. Several reports have indicated that stage IB patients had worse outcomes than stage IA patients when the same dose was used. We evaluated the clinical outcomes of SBRT for stage I non-small cell lung cancer (NSCLC) treated with different doses depending on tumor diameter. METHODS: Between February 2004 and November 2008, 124 patients with stage I NSCLC underwent SBRT. Total doses of 44, 48, and 52 Gy were administered for tumors with a longest diameter of less than 1.5 cm, 1.5-3 cm, and larger than 3 cm, respectively. All doses were given in 4 fractions. RESULTS: For all 124 patients, overall survival was 71%, cause-specific survival was 87%, progression free survival was 60%, and local control was 80%, at 3 years. The 3-year overall survival was 79% for 85 stage IA patients treated with 48 Gy and 56% for 37 stage IB patients treated with 52 Gy (p = 0.05). At 3 years, cause-specific survival was 91% for the former group and 79% for the latter (p = 0.18), and progression free survival was 62% versus 54% (p = 0.30). The 3-year local control rate was 81% versus 74% (p = 0.35). The cumulative incidence of grade 2 or 3 radiation pneumonitis was 11% in stage IA patients and 30% in stage IB patients (p = 0.02). CONCLUSIONS: There was no difference in local control between stage IA and IB tumors despite the difference in tumor size. The benefit of increasing the SBRT dose for larger tumors should be investigated further. PMID- 20849624 TI - Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature. AB - INTRODUCTION: Liver injury is a frequent complication associated with anorexia nervosa, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 IU/mL and deep coma are very rare complications and the mechanism of pathogenesis is largely unknown. CASE PRESENTATION: A 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-ammonemia. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels after administration of nutritional support. CONCLUSIONS: Our case report demonstrates that transaminase levels had an inverse relationship with the consciousness of our patient, although the pathogenesis of coma remains largely unknown. This indicates that transaminase levels can be one of the key predictors of impending coma in patients with anorexia nervosa. Therefore, frequent monitoring of transaminase levels combined with rigorous treatment of the underlying nutritional deficiency and psychiatric disorder are necessary to prevent this severe complication. PMID- 20849625 TI - A targeted decision aid for the elderly to decide whether to undergo colorectal cancer screening: development and results of an uncontrolled trial. AB - BACKGROUND: Competing causes of mortality in the elderly decrease the potential net benefit from colorectal cancer screening and increase the likelihood of potential harms. Individualized decision making has been recommended, so that the elderly can decide whether or not to undergo colorectal cancer (CRC) screening. The objective is to develop and test a decision aid designed to promote individualized colorectal cancer screening decision making for adults age 75 and over. METHODS: We used formative research and cognitive testing to develop and refine the decision aid. We then tested the decision aid in an uncontrolled trial. The primary outcome was the proportion of patients who were prepared to make an individualized decision, defined a priori as having adequate knowledge (10/15 questions correct) and clear values (25 or less on values clarity subscale of decisional conflict scale). Secondary outcomes included overall score on the decisional conflict scale, and preferences for undergoing screening. RESULTS: We enrolled 46 adults in the trial. The decision aid increased the proportion of participants with adequate knowledge from 4% to 52% (p < 0.01) and the proportion prepared to make an individualized decision from 4% to 41% (p < 0.01). The proportion that preferred to undergo CRC screening decreased from 67% to 61% (p = 0. 76); 7 participants (15%) changed screening preference (5 against screening, 2 in favor of screening) CONCLUSION: In an uncontrolled trial, the elderly participants appeared better prepared to make an individualized decision about whether or not to undergo CRC screening after using the decision aid. PMID- 20849626 TI - Task sharing in Zambia: HIV service scale-up compounds the human resource crisis. AB - BACKGROUND: Considerable attention has been given by policy makers and researchers to the human resources for health crisis in Africa. However, little attention has been paid to quantifying health facility-level trends in health worker numbers, distribution and workload, despite growing demands on health workers due to the availability of new funds for HIV/AIDS control scale-up. This study analyses and reports trends in HIV and non-HIV ambulatory service workloads on clinical staff in urban and rural district level facilities. METHODS: Structured surveys of health facility managers, and health services covering 2005 07 were conducted in three districts of Zambia in 2008 (two urban and one rural), to fill this evidence gap. Intra-facility analyses were conducted, comparing trends in HIV and non-HIV service utilisation with staff trends. RESULTS: Clinical staff (doctors, nurses and nurse-midwives, and clinical officers) numbers and staff population densities fell slightly, with lower ratios of staff to population in the rural district. The ratios of antenatal care and family planning registrants to nurses/nurse-midwives were highest at baseline and increased further at the rural facilities over the three years, while daily outpatient department (OPD) workload in urban facilities fell below that in rural facilities. HIV workload, as measured by numbers of clients receiving antiretroviral treatment (ART) and prevention of mother to child transmission (PMTCT) per facility staff member, was highest in the capital city, but increased rapidly in all three districts. The analysis suggests evidence of task sharing, in that staff designated by managers as ART and PMTCT workers made up a higher proportion of frontline service providers by 2007. CONCLUSIONS: This analysis of workforce patterns across 30 facilities in three districts of Zambia illustrates that the remarkable achievements in scaling-up HIV/AIDS service delivery has been on the back of sustained non-HIV workload levels, increasing HIV workload and stagnant health worker numbers. The findings are based on an analysis of routine data that are available to district and national managers. Mixed methods research is needed, combining quantitative analyses of routine health information with follow-up qualitative interviews, to explore and explain workload changes, and to identify and measure where problems are most acute, so that decision makers can respond appropriately. This study provides quantitative evidence of a human resource crisis in health facilities in Zambia, which may be more acute in rural areas. PMID- 20849627 TI - Homoeolog-specific transcriptional bias in allopolyploid wheat. AB - BACKGROUND: Interaction between parental genomes is accompanied by global changes in gene expression which, eventually, contributes to growth vigor and the broader phenotypic diversity of allopolyploid species. In order to gain a better understanding of the effects of allopolyploidization on the regulation of diverged gene networks, we performed a genome-wide analysis of homoeolog-specific gene expression in re-synthesized allohexaploid wheat created by the hybridization of a tetraploid derivative of hexaploid wheat with the diploid ancestor of the wheat D genome Ae. tauschii. RESULTS: Affymetrix wheat genome arrays were used for both the discovery of divergent homoeolog-specific mutations and analysis of homoeolog-specific gene expression in re-synthesized allohexaploid wheat. More than 34,000 detectable parent-specific features (PSF) distributed across the wheat genome were used to assess AB genome (could not differentiate A and B genome contributions) and D genome parental expression in the allopolyploid transcriptome. In re-synthesized polyploid 81% of PSFs detected mid-parent levels of gene expression, and only 19% of PSFs showed the evidence of non-additive expression. Non-additive expression in both AB and D genomes was strongly biased toward up-regulation of parental type of gene expression with only 6% and 11% of genes, respectively, being down-regulated. Of all the non additive gene expression, 84% can be explained by differences in the parental genotypes used to make the allopolyploid. Homoeolog-specific co-regulation of several functional gene categories was found, particularly genes involved in photosynthesis and protein biosynthesis in wheat. CONCLUSIONS: Here, we have demonstrated that the establishment of interactions between the diverged regulatory networks in allopolyploids is accompanied by massive homoeolog specific up- and down-regulation of gene expression. This study provides insights into interactions between homoeologous genomes and their role in growth vigor, development, and fertility of allopolyploid species. PMID- 20849629 TI - Isolation of cell-free bacterial inclusion bodies. AB - BACKGROUND: Bacterial inclusion bodies are submicron protein clusters usually found in recombinant bacteria that have been traditionally considered as undesirable products from protein production processes. However, being fully biocompatible, they have been recently characterized as nanoparticulate inert materials useful as scaffolds for tissue engineering, with potentially wider applicability in biomedicine and material sciences. Current protocols for inclusion body isolation from Escherichia coli usually offer between 95 to 99% of protein recovery, what in practical terms, might imply extensive bacterial cell contamination, not compatible with the use of inclusion bodies in biological interfaces. RESULTS: Using an appropriate combination of chemical and mechanical cell disruption methods we have established a convenient procedure for the recovery of bacterial inclusion bodies with undetectable levels of viable cell contamination, below 10-1 cfu/ml, keeping the particulate organization of these aggregates regarding size and protein folding features. CONCLUSIONS: The application of the developed protocol allows obtaining bacterial free inclusion bodies suitable for use in mammalian cell cultures and other biological interfaces. PMID- 20849628 TI - Duodenal carcinoma at the ligament of Treitz. A molecular and clinical perspective. AB - BACKGROUND: There is very small occurrence of adenocarcinoma in the small bowel. We present a case of primary duodenal adenocarcinoma and discuss the findings of the case diagnostic modalities, current knowledge on the molecular biology behind small bowel neoplasms and treatment options. CASE: The patient had a history of iron deficiency anemia and occult bleeding with extensive workup consisting of upper endoscopy, colonoscopy, capsule endoscopy, upper gastrointestinal series with small bowel follow through and push enteroscopy. Due to persistent abdominal pain and iron deficiency anemia the patient underwent push enteroscopy which revealed adenocarcinoma of the duodenum. The patient underwent en-bloc duodenectomy which revealed T3N1M0 adenocarcinoma of the 4th portion of the duodenum. CONCLUSIONS: Primary duodenal carcinoma, although rare should be considered in the differential diagnosis of occult gastrointestinal bleeding when evaluation of the lower and upper GI tract is unremarkable. We discuss the current evaluation and management of this small bowel neoplasm. PMID- 20849630 TI - Effectiveness of an intervention in groups of family caregivers of dependent patients for their application in primary health centers. Study protocol. AB - BACKGROUND: Although Primary Health Care (PHC) Teams are used to deal with prevention and treatment of sanitary problems in adults with chronic diseases, they usually have a lack of experience in development of psychotherapeutic interventions. However, these interventions are the ones that achieve better results to reduce symptomatology and improve emotional state of caregivers.The study aims to evaluate the effectiveness of an intervention of psychotherapy in improving the mental health and Quality of life of caregivers. This intervention is based on theoretical approaches to care adjusted to cognitive theory, in order to be applied in primary health care centres. METHODS/DESIGN: This is multicentre clinical trials study, randomized in two parallel groups, carry out in two PHC, Study population: 150 caregivers will be included by consecutive sampling and they will be randomized the half to experimental group and the other half to control group. They provide mostly all the assistance to care-dependent familiars receiving attention in PHC Centers. MEASUREMENTS: Each caregiver will be evaluated on a personal interview. The caregivers' assessment protocol: 1) Assessment of different socio-demographic related to care, and caregiver's personal situation. 2)Care-dependent individuals will also be assessed by Barthel Index and Pfeiffer Questionnaire (SPMSQ). 3)Change in caregivers will be the principal measure: family function (Family APGAR Questionnaire), burden short questionnaire (Short Zarit Burden Interview), quality of life (Ruiz & Baca: 1993 Questionnaire), the Duke-UNK Functional Social Support Questionnaire, the General Health Questionnaire-12, and changes in Dysfunctional Thoughts about caring. 4) Intervention implementation measures will also be assessed. INTERVENTION: A psychotherapeutic intervention will be 8 sessions of 90 minutes in groups. This intervention has been initially developed for family caregivers of patients with dementia. DISCUSSION: Psychotherapeutic interventions have been proved to obtain better results to reduce symptomatology and improve emotional state of caregivers. Moreover, this intervention has been proved to be effective in a different setting other than PHC, and was developed by professionals of Mental Health. If we found that this intervention is effective in PHC and with our professionals, it would be an important instrument to offer to caregivers of care dependent patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01177696. PMID- 20849631 TI - Low-grade oligodendroglioma of the pineal gland: a case report and review of the literature. AB - BACKGROUND: Gliomas are a very rare subtype of pineal region tumours, whereas oligodendrogliomas of the pineal region are exceedingly rare, since there have been only 3 cases of anaplastic oligodedrogliomas reported this far. METHODS RESULTS: We present a case of a low-grade oligodendroglioma arising in the pineal gland of a 37 year-old woman. The patient presented with diplopia associated with a cystic pineal region mass demonstrated on MRI. Total resection was performed and histological examination showed that the cystic wall consisted of tumour cells with a central nucleus a perinuclear halo and minimal pleomorphism. Immnunohistochemical analysis showed that these cells were diffusely positive for CD57, and negative for GFAP, CD10, CD99, cytokeratins, neurofilaments and synaptophysin. FISH analysis was performed in a small number of neoplastic cells, which were not exhausted after immunohistochemistry and did not reveal deletion of 1p and 19q chromosome arms. However, the diagnosis of a low grade oligodendroglioma of the pineal gland was assigned. CONCLUSION: Although the spectrum of tumours arising in the pineal gland is broad, the reports of oligodendrogliomas confined to this location are exceedingly rare, and to the best of our knowledge there is no report of a low-grade oligodendroglioma. However, they should be added in the long list of tumours arising in the pineal gland. PMID- 20849632 TI - Temporal trends in misclassification patterns of measured and self-report based body mass index categories--findings from three population surveys in Ireland. AB - BACKGROUND: As the use of self-reported data to classify obesity continues, the temporal change in the accuracy of self-report measurement when compared to clinical measurement remains unclear. The objective of this study was to examine temporal trends in misclassification patterns, as well as sensitivity and specificity, of clinically measured versus self-report based body mass index (BMI) from three national lifestyle surveys over a 10-year period. METHODS: The Surveys of Lifestyle Attitudes and Nutrition (SLAN) were interview based cross sectional survey/measurements involving nationally representative samples in 1998, 2002 and 2007. Data from a subsample of both self-reported and measured height and weight were available from 66 men and 142 women in 1998, 147 men and 184 women in 2002 and 909 men and 1128 women in 2007. Respondents were classified into the BMI categories normal (< 25 kg m-2), overweight (25- < 30 kg m-2) and obese (>= 30 kg m-2). RESULTS: Underreporting of BMI increased across the three surveys (14%->21%->24%; p = 0.002). Sensitivity scores for the normal category exceeded 94% in all three surveys but decreased for the overweight (75%->68% >66%) and obese categories (80%->64%->53%). Simultaneously, specificity levels remained high. CONCLUSIONS: BMI values based on self-reported determinations of height and weight in population samples are underestimating the true prevalence of the obesity epidemic and this underestimation is increasing with time. The decreased sensitivity and consistently high specificity scores in the obese category across time, highlights the limitation of self-report based BMI classifications and the need for simple, readily comprehensible indicators of obesity. PMID- 20849633 TI - The site of embolization related to infarct size, oedema and clinical outcome in a rat stroke model - further translational stroke research. AB - BACKGROUND AND PURPOSE: Reliable models are essential for translational stroke research to study the pathophysiology of ischaemic stroke in an effort to find therapies that may ultimately reduce oedema, infarction and mortality in the clinic. The purpose of this study was to investigate the relation between the site of arterial embolization and the subsequent oedema, infarction and clinical outcome in a rat embolic stroke model. METHODS: Thirty-six male Sprague-Dawley rats were thromboembolized into the internal carotid artery. The site of occlusion was demonstrated by arteriography. Following histological preparation and evaluation, the size of the hemispheres and the infarcts were measured by quantitative histology and planimetry. Another parallel stroke model study was subsequently examined to investigate if the conclusions from the first study could be applied to the second study. RESULTS: The median size of the infarct was 40% of the ipsilateral hemisphere in both the 19 animals with occlusion localised to the intracranial part of the internal carotid artery and in the 11 animals where the main trunk of the middle cerebral artery was occluded. In 5 animals, occlusion of the extracranial part of the internal carotid artery resulted in significantly smaller infarcts compared to other groups (p < 0.01). Another independent study re-confirmed these results. Furthermore, significant correlations (R > 0.76, p < 0.0001) were found between 1) cortical, subcortical, and total infarct volumes, 2) oedema in percent of the left hemisphere, 3) clinical score before termination and 4) postoperative weight loss. CONCLUSIONS: Distal occlusions of the intracranial part of the internal carotid or middle cerebral arteries resulted in comparable large sized infarctions and oedema. This indicates that investigators do not need a similar number of such occlusions in each experimental group. Contrary to observations in the clinic, distal internal carotid artery occlusions did not result in worse outcome than middle cerebral stem occlusions, but this finding may be explained by the controlled emboli size in this experimental stroke model. PMID- 20849634 TI - The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds. AB - The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebridae, a largely distributed family with more than 300 described species, indicate they have evolutionary and pharmacological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species from the West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost their venom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationships within the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary results indicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attractive line of research to discover and develop new therapeutics that target ion channels and receptors. Using conotoxins as a guideline, and innovative natural products discovery strategies, such as the Concerted Discovery Strategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource. PMID- 20849635 TI - Identifying risk factors for healthcare-associated infections from electronic medical record home address data. AB - BACKGROUND: Residential address is a common element in patient electronic medical records. Guidelines from the U.S. Centers for Disease Control and Prevention specify that residence in a nursing home, skilled nursing facility, or hospice within a year prior to a positive culture date is among the criteria for differentiating healthcare-acquired from community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections. Residential addresses may be useful for identifying patients residing in healthcare-associated settings, but methods for categorizing residence type based on electronic medical records have not been widely documented. The aim of this study was to develop a process to assist in differentiating healthcare-associated from community-associated MRSA infections by analyzing patient addresses to determine if residence reported at the time of positive culture was associated with a healthcare facility or other institutional location. RESULTS: We identified 1,232 of the patients (8.24% of the sample) with positive cultures as probable cases of healthcare-associated MRSA based on residential addresses contained in electronic medical records. Combining manual review with linking to institutional address databases improved geocoding rates from 11,870 records (79.37%) to 12,549 records (83.91%). Standardization of patient home address through geocoding increased the number of matches to institutional facilities from 545 (3.64%) to 1,379 (9.22%). CONCLUSIONS: Linking patient home address data from electronic medical records to institutional residential databases provides useful information for epidemiologic researchers, infection control practitioners, and clinicians. This information, coupled with other clinical and laboratory data, can be used to inform differentiation of healthcare-acquired from community-acquired infections. The process presented should be extensible with little or no added data costs. PMID- 20849636 TI - Unstated factors in orthopaedic decision-making: a qualitative study. AB - BACKGROUND: Total joint replacement (TJR) of the hip or knee for osteoarthritis is among the most common elective surgical procedures. There is some inequity in provision of TJR. How decisions are made about who will have surgery may contribute to disparities in provision. The model of shared decision-making between patients and clinicians is advocated as an ideal by national bodies and guidelines. However, we do not know what happens within orthopaedic practice and whether this reflects the shared model. Our study examined how decisions are made about TJR in orthopaedic consultations. METHODS: The study used a qualitative research design comprising semi-structured interviews and observations. Participants were recruited from three hospital sites and provided their time free of charge. Seven clinicians involved in decision-making about TJR were approached to take part in the study, and six agreed to do so. Seventy-seven patients due to see these clinicians about TJR were approached to take part and 26 agreed to do so. The patients' outpatient appointments ('consultations') were observed and audio-recorded. Subsequent interviews with patients and clinicians examined decisions that were made at the appointments. Data were analysed using thematic analysis. RESULTS: Clinical and lifestyle factors were central components of the decision-making process. In addition, the roles that patients assigned to clinicians were key, as were communication styles. Patients saw clinicians as occupying expert roles and they deferred to clinicians' expertise. There was evidence that patients modified their behaviour within consultations to complement that of clinicians. Clinicians acknowledged the complexity of decision making and provided descriptions of their own decision-making and communication styles. Patients and clinicians were aware of the use of clinical and lifestyle factors in decision-making and agreed in their description of clinicians' styles. Decisions were usually reached during consultations, but patients and clinicians sometimes said that treatment decisions had been made beforehand. Some patients expressed surprise about the decisions made in their consultations, but this did not necessarily imply dissatisfaction. CONCLUSIONS: The way in which roles and communication are played out in decision-making for TJR may affect the opportunity for shared decisions. This may contribute to variation in the provision of TJR. Making the importance of these factors explicit and highlighting the existence of patients' 'surprise' about consultation outcomes could empower patients within the decision-making process and enhance communication in orthopaedic consultations. PMID- 20849637 TI - Effects of osteopontin inhibition on radiosensitivity of MDA-MB-231 breast cancer cells. AB - BACKGROUND: Osteopontin (OPN) is a secreted glycophosphoprotein that is overexpressed in various tumors, and high levels of OPN have been associated with poor prognosis of cancer patients. In patients with head and neck cancer, high OPN plasma levels have been associated with poor prognosis following radiotherapy. Since little is known about the relationship between OPN expression and radiosensitivity, we investigated the cellular and radiation induced effects of OPN siRNA in human MDA-MB-231 breast cancer cells. METHODS: MDA-MB-231 cells were transfected with OPN-specific siRNAs and irradiated after 24 h. To verify the OPN knockdown, we measured the OPN mRNA and protein levels using qRT-PCR and Western blot analysis. Furthermore, the functional effects of OPN siRNAs were studied by assays to assess clonogenic survival, migration and induction of apoptosis. RESULTS: Treatment of MDA-MB-231 cells with OPN siRNAs resulted in an 80% decrease in the OPN mRNA level and in a decrease in extracellular OPN protein level. Transfection reduced clonogenic survival to 42% (p = 0.008), decreased the migration rate to 60% (p = 0.15) and increased apoptosis from 0.3% to 1.7% (p = 0.04). Combination of OPN siRNA and irradiation at 2 Gy resulted in a further reduction of clonogenic survival to 27% (p < 0.001), decreased the migration rate to 40% (p = 0.03) and increased apoptosis to 4% (p < 0.005). Furthermore, OPN knockdown caused a weak radiosensitization with an enhancement factor of 1.5 at 6 Gy (p = 0.09) and a dose modifying factor (DMF10) of 1.1. CONCLUSION: Our results suggest that an OPN knockdown improves radiobiological effects in MDA-MB-231 cells. Therefore, OPN seems to be an attractive target to improve the effectiveness of radiotherapy. PMID- 20849638 TI - Macular hole formation, progression, and surgical repair: case series of serial optical coherence tomography and time lapse morphing video study. AB - BACKGROUND: To use a new medium to dynamically visualize serial optical coherence tomography (OCT) scans in order to illustrate and elucidate the pathogenesis of idiopathic macular hole formation, progression, and surgical closure. CASE PRESENTATIONS: Two patients at the onset of symptoms with early stage macular holes and one patient following repair were followed with serial OCTs. Images centered at the fovea and at the same orientation were digitally exported and morphed into an Audiovisual Interleaving (avi) movie format. Morphing videos from serial OCTs allowed the OCTs to be viewed dynamically. The videos supported anterior-posterior vitreofoveal traction as the initial event in macular hole formation. Progression of the macular hole occurred with increased cystic thickening of the fovea without evidence of further vitreofoveal traction. During cyst formation, the macular hole enlarged as the edges of the hole became elevated from the retinal pigment epithelium (RPE) with an increase in subretinal fluid. Surgical repair of a macular hole revealed initial closure of the macular hole with subsequent reabsorption of the sub-retinal fluid and restoration of the foveal contour. CONCLUSIONS: Morphing videos from serial OCTs are a useful tool and helped illustrate and support anterior-posterior vitreofoveal traction with subsequent retinal hydration as the pathogenesis of idiopathic macular holes. PMID- 20849639 TI - Is elevated SUA associated with a worse outcome in young Chinese patients with acute cerebral ischemic stroke? AB - BACKGROUND: Elevated serum uric acid (SUA) levels can enhance its antioxidant prosperities and reduce the occurrence of cerebral infarction. Significantly elevated SUA levels have been associated with a better prognosis in patients with cerebral infarction; however, the results from some studies on the relationship between SUA and the prognosis of patients with cerebral infarction remain controversial. METHODS: We analyzed the relationship between SUA and clinical prognosis of 585 young Chinese adults with acute ischemic stroke as determined by the modified Rankin Scale at discharge. Using multivariate logistic regression modeling, we explore the relationship between SUA levels and patient's clinical prognosis. RESULTS: Lower SUA levels at time of admission were observed more frequently in the lowest quintile for patients with severe stroke (P = 0.02). Patients with cerebral infarction patients caused by small-vessel blockage had higher SUA concentrations (P = 0.01) and the lower mRS scores (P < 0.01) were observed in, while the lowest SUA concentrations and the highest mRS scores were seen in patients with cardiogenic cerebral infarction patients. Logistic regression analysis adjusted for confounders confirmed the following independent predictors for young cerebral infarction: uric acid (-0.003: 95%CI 0.994 to 0.999) and platelet (0.004, 95%CI 0.993 to 0.996). CONCLUSION: Elevated SUA is an independent predictor for good clinical outcome of acute cerebral infarction among young adults. PMID- 20849640 TI - Self-reported dental hygiene, obesity, and systemic inflammation in a pediatric rural community cohort. AB - BACKGROUND: A growing body of epidemiologic evidence links oral health, obesity, and cardiovascular health, though few studies have reported on these relationships in children. While underlying mechanisms are unclear, adult studies have suggested sub-acute systemic inflammation, also implicated in the etiology of both obesity and cardiovascular disease. This study investigated associations between self-reported dental hygiene, obesity, and systemic inflammation in children. METHODS: 128 children < 19 years of age from rural counties in West Virginia participated in a community-based health screening that included anthropometric assessments, blood collection, and a questionnaire about dental hygiene and self-assessed oral health. RESULTS: Participants ranged from 3.0-18.7 years. Univariate analysis demonstrated an association between parent-reported dental hygiene, including frequency of preventive dental care and parent-assessed overall dental health, and markers of systemic inflammation but not obesity. In multivariable regression, parent-assessed overall dental health and obesity were independent predictors of systemic inflammation, after adjustment for age, gender, and parent education. CONCLUSIONS: This is the first known study of the association between dental hygiene, obesity, and systemic inflammation in children. These results highlight the importance of preventive dental care in overall, systemic health in children and are consistent with previous reports in adults. PMID- 20849641 TI - Profiling of cellular proteins in porcine reproductive and respiratory syndrome virus virions by proteomics analysis. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is an enveloped virus, bearing severe economic consequences to the swine industry worldwide. Previous studies on enveloped viruses have shown that many incorporated cellular proteins associated with the virion's membranes that might play important roles in viral infectivity. In this study, we sought to proteomically profile the cellular proteins incorporated into or associated with the virions of a highly virulent PRRSV strain GDBY1, and to provide foundation for further investigations on the roles of incorporated/associated cellular proteins on PRRSV's infectivity. RESULTS: In our experiment, sixty one cellular proteins were identified in highly purified PRRSV virions by two-dimensional gel electrophoresis coupled with mass spectrometric approaches. The identified cellular proteins could be grouped into eight functional categories including cytoskeletal proteins, chaperones, macromolecular biosynthesis proteins, metabolism-associated proteins, calcium-dependent membrane-binding proteins and other functional proteins. Among the identified proteins, four have not yet been reported in other studied envelope viruses, namely, guanine nucleotide-binding proteins, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase, peroxiredoxin 1 and galectin-1 protein. The presence of five selected cellular proteins (i.e., beta-actin, Tubulin, Annexin A2, heat shock protein Hsp27, and calcium binding proteins S100) in the highly purified PRRSV virions was validated by Western blot and immunogold labeling assays. CONCLUSIONS: Taken together, the present study has demonstrated the incorporation of cellular proteins in PRRSV virions, which provides valuable information for the further investigations for the effects of individual cellular proteins on the viral replication, assembly, and pathogenesis. PMID- 20849642 TI - Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation. AB - BACKGROUND: Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant) chronic systems. METHODS: To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days) or chronic (12 weeks) cigarette smoke exposure (CSE) using female, C57BL/6 mice (n = 7-10). To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg-1; i.n., q.d.), roflumilast (3 mg kg-1; p.o., q.d.) and fluvastatin (2 mg kg-1; p.o., b.i.d.) were dosed 1 h before (and 5 h after for fluvastatin) CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF) leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies. RESULTS: To start, we confirmed that the inflammatory phenotypes were different after acute (3 days) versus chronic (12 weeks) CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs), macrophage and lymphocyte numbers were all increased (p < 0.05). In the acute model, both roflumilast and fluvastatin reduced BALF PMNs (p < 0.01) after 3 days of CSE, while budesonide had no effect on BALF PMNs. In the chronic model, therapeutically administered fluvastatin reduced the numbers of PMNs and macrophages in the BALF (p <= 0.05), while budesonide had no effect on PMN or macrophage numbers, but did reduce BALF lymphocytes (p < 0.01). Roflumilast's inhibitory effects on inflammatory cell infiltrate were not statistically significant. CONCLUSIONS: These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound's efficacy in chronic smoke exposure models. PMID- 20849644 TI - Welcome to open access publishing at EvoDevo: a macroevolutionary change in sharing data. PMID- 20849643 TI - Quantitative analysis of interferon alpha receptor subunit 1 and suppressor of cytokine signaling 1 gene transcription in blood cells of patients with chronic hepatitis C. AB - BACKGROUND: Interferon (IFN)-alpha receptor 1 (ifnar1) and suppressor of cytokine signaling 1 (socs1) transcription levels were quantified in peripheral blood mononuclear cells (PBMC) of 59 patients infected with hepatitis C virus (HCV) and 17 non-infected individuals. Samples were obtained from patients infected with HCV that were either untreated or treated with IFN-alpha2 plus ribavirin for 1 year and divided into responders and non-responders based on viral load reduction 6 months after treatment. Ifnar1 and socs1 transcription was quantified by real time RT-PCR, and the fold difference (2(-DeltaDeltaCT)) with respect to hprt housekeeping gene was calculated. RESULTS: Ifnar1 transcription increased significantly in HCV-infected patients either untreated (3.26 +/- 0.31), responders (3.1 +/- 0.23) and non-responders (2.18 +/- 0.23) with respect to non infected individuals (1 +/- 0.34; P = 0.005). Ifnar1 transcription increased significantly (P = 0.003) in patients infected with HCV genotypes 1a (4.74 +/- 0.25) and 1b (2.81 +/- 0.25) but not in 1a1b (1.58 +/- 0.21). No association was found of Ifnar1 transcription with disease progress, initial viral load or other clinical factors. With respect to socs1 transcription, values were similar for non-infected individuals (1 +/- 0.28) and untreated patients (0.99 +/- 0.41) but increased in responders (2.81 +/- 0.17) and non-responder patients (1.67 +/- 0.41). Difference between responder and non-responder patients was not statistically significant. Socs1 transcription increased in patients infected with HCV genotypes 1a and 1b (2.87 +/- 0.45 and 2.22 +/- 0.17, respectively) but not in 1a1b (1.28 +/- 0.40). Socs1 transcript was absent in three patients infected with HCV genotype 1b. A weak correlation between ifnar1 and socs1 transcription was found, when Spearman's correlation coefficient was calculated. CONCLUSION: Our results suggest that HCV infection may up-regulate ifnar1 transcription. HCV genotypes differ in their capacity to affect ifnar1 and socs1 transcription, as well as in the ability to evade the antiviral response. PMID- 20849645 TI - Expression of FoxA and GATA transcription factors correlates with regionalized gut development in two lophotrochozoan marine worms: Chaetopterus (Annelida) and Themiste lageniformis (Sipuncula). AB - BACKGROUND: A through gut is present in almost all metazoans, and most likely represents an ancient innovation that enabled bilaterian animals to exploit a wide range of habitats. Molecular developmental studies indicate that Fox and GATA regulatory genes specify tissue regions along the gut tube in a broad diversity of taxa, although little is known about gut regionalization within the Lophotrochozoa. In this study, we isolated FoxA and GATA456 orthologs and used whole mount in situ hybridization during larval gut formation in two marine worms: the segmented, polychaete annelid Chaetopterus, which develops a planktotrophic larva with a tripartite gut, and the non-segmented sipunculan Themiste lageniformis, which develops a lecithotrophic larva with a U-shaped gut. RESULTS: FoxA and GATA456 transcripts are predominantly restricted to gut tissue, and together show regional expression spanning most of the alimentary canal in each of these lophotrochozoans, although neither FoxA nor GATA456 is expressed in the posterior intestine of Chaetopterus. In both species, FoxA is expressed at the blastula stage, transiently in presumptive endoderm before formation of a definitive gut tube, and throughout early larval development in discrete foregut and hindgut domains. GATA456 genes are expressed during endoderm formation, and in endoderm and mesoderm associated with the midgut in each species. Several species-specific differences were detected, including an overlap of FoxA and GATA456 expression in the intestinal system of Themiste, which is instead complimentary in Chaetopterus. Other differences include additional discrete expression domains of FoxA in ectodermal trunk cells in Themiste but not Chaetopterus, and expression of GATA456 in anterior ectoderm and midgut cells unique to Chaetopterus. CONCLUSIONS: This study of gene expression in a sipunculan contributes new comparative developmental insights from lophotrochozoans, and shows that FoxA and GATA456 transcription factors are part of an ancient patterning mechanism that was deployed during early evolution of the metazoan through gut. The common utilization of FoxA and GATA456 throughout gut formation by species with contrasting life history modes indicates that both genes are core components of a gut-specific gene regulatory network in spiralians. Despite a highly conserved pattern of early development, and probably similar ontogenic origins of gut tissue, there are molecular differences in gut regionalization between lophotrochozoan species. PMID- 20849646 TI - A conserved cluster of three PRD-class homeobox genes (homeobrain, rx and orthopedia) in the Cnidaria and Protostomia. AB - BACKGROUND: Homeobox genes are a superclass of transcription factors with diverse developmental regulatory functions, which are found in plants, fungi and animals. In animals, several Antennapedia (ANTP)-class homeobox genes reside in extremely ancient gene clusters (for example, the Hox, ParaHox, and NKL clusters) and the evolution of these clusters has been implicated in the morphological diversification of animal bodyplans. By contrast, similarly ancient gene clusters have not been reported among the other classes of homeobox genes (that is, the LIM, POU, PRD and SIX classes). RESULTS: Using a combination of in silico queries and phylogenetic analyses, we found that a cluster of three PRD-class homeobox genes (Homeobrain (hbn), Rax (rx) and Orthopedia (otp)) is present in cnidarians, insects and mollusks (a partial cluster comprising hbn and rx is present in the placozoan Trichoplax adhaerens). We failed to identify this 'HRO' cluster in deuterostomes; in fact, the Homeobrain gene appears to be missing from the chordate genomes we examined, although it is present in hemichordates and echinoderms. To illuminate the ancestral organization and function of this ancient cluster, we mapped the constituent genes against the assembled genome of a model cnidarian, the sea anemone Nematostella vectensis, and characterized their spatiotemporal expression using in situ hybridization. In N. vectensis, these genes reside in a span of 33 kb with the same gene order as previously reported in insects. Comparisons of genomic sequences and expressed sequence tags revealed the presence of alternative transcripts of Nv-otp and two highly unusual protein-coding polymorphisms in the terminal helix of the Nv-rx homeodomain. A population genetic survey revealed the Rx polymorphisms to be widespread in natural populations. During larval development, all three genes are expressed in the ectoderm, in non-overlapping territories along the oral-aboral axis, with distinct temporal expression. CONCLUSION: We report the first evidence for a PRD class homeobox cluster that appears to have been conserved since the time of the cnidarian-bilaterian ancestor, and possibly even earlier, given the presence of a partial cluster in the placozoan Trichoplax. Very similar clusters comprising these three genes exist in Nematostella and diverse protostomes. Interestingly, in chordates, one member of the ancestral cluster (homeobrain) has apparently been lost, and there is no linkage between rx and orthopedia in any of the vertebrates. In Nematostella, the spatial expression of these three genes along the body column is not colinear with their physical order in the cluster but the temporal expression is, therefore, using the terminology that has been applied to the Hox cluster genes, the HRO cluster would appear to exhibit temporal but not spatial colinearity. It remains to be seen whether the mechanisms responsible for the evolutionary conservation of the HRO cluster are the same mechanisms responsible for cohesion of the Hox cluster and other ANTP-class homeobox clusters that have been widely conserved throughout animal evolution. PMID- 20849647 TI - Gene expression suggests conserved aspects of Hox gene regulation in arthropods and provides additional support for monophyletic Myriapoda. AB - Antisense transcripts of Ultrabithorax (aUbx) in the millipede Glomeris and the centipede Lithobius are expressed in patterns complementary to that of the Ubx sense transcripts. A similar complementary expression pattern has been described for non-coding RNAs (ncRNAs) of the bithoraxoid (bxd) locus in Drosophila, in which the transcription of bxd ncRNAs represses Ubx via transcriptional interference. We discuss our findings in the context of possibly conserved mechanisms of Ubx regulation in myriapods and the fly.Bicistronic transcription of Ubx and Antennapedia (Antp) has been reported previously for a myriapod and a number of crustaceans. In this paper, we show that Ubx/Antp bicistronic transcripts also occur in Glomeris and an onychophoran, suggesting further conserved mechanisms of Hox gene regulation in arthropods.Myriapod monophyly is supported by the expression of aUbx in all investigated myriapods, whereas in other arthropod classes, including the Onychophora, aUbx is not expressed. Of the two splice variants of Ubx/Antp only one could be isolated from myriapods, representing a possible further synapomorphy of the Myriapoda. PMID- 20849648 TI - Early development of Ensatina eschscholtzii: an amphibian with a large, yolky egg. AB - BACKGROUND: Comparative analyses between amphibians, concentrating on the cellular mechanisms of morphogenesis, reveal a large variability in the early developmental processes that were thought to be conserved during evolution. Increased egg size is one factor that could have a strong effect on early developmental processes such as cleavage pattern and gastrulation. Salamanders of the family Plethodontidae are particularly appropriate for such comparative studies because the species have eggs of varying size, including very large yolky eggs. RESULTS: In this paper, we describe for the first time the early development (from fertilization through neurulation) of the plethodontid salamander Ensatina eschscholtzii. This species has one of the largest eggs known for an amphibian, with a mean +/- SD diameter of 6 +/- 0.43 mm (range 5.3-6.9; n = 17 eggs). Cleavage is meroblastic until approximately the 16-cell stage (fourth or fifth cleavage). At the beginning of gastrulation, the blastocoel roof is one cell thick, and the dorsal lip of the blastopore forms below the equator of the embryo. The ventral lip of the blastopore forms closer to the vegetal pole, and relatively little involution occurs during gastrulation. Cell migration is visible through the transparent blastocoel roof of the gastrula. At the end of gastrulation, a small archenteron spreading dorsally from the blastopore represents the relatively small and superficial area of the egg where early embryonic axis formation occurs. The resulting pattern is similar to the embryonic disk described for one species of anuran. CONCLUSIONS: Comparisons with the early development of other species of amphibians suggest that an evolutionary increase in egg size can result in predictable changes in the patterns and rate of early development, but mainly within an evolutionary lineage. PMID- 20849649 TI - Germ cell specification and ovary structure in the rotifer Brachionus plicatilis. AB - BACKGROUND: The segregation of the germline from somatic tissues is an essential process in the development of all animals. Specification of the primordial germ cells (PGCs) takes place via different strategies across animal phyla; either specified early in embryogenesis by the inheritance of maternal determinants in the cytoplasm of the oocyte ('preformation') or selected later in embryonic development from undifferentiated precursors by a localized inductive signal ('epigenesis'). Here we investigate the specification and development of the germ cells in the rotifer Brachionus plicatilis, a member of the poorly-characterized superphyla Lophotrochozoa, by isolating the Brachionus homologues of the conserved germ cell markers vasa and nanos, and examining their expression using in situ hybridization. RESULTS: Bpvasa and Bpnos RNA expression have very similar distributions in the Brachionus ovary, showing ubiquitous expression in the vitellarium, with higher levels in the putative germ cell cluster. Bpvas RNA expression is present in freshly laid eggs, remaining ubiquitous in embryos until at least the 96 cell stage after which expression narrows to a small cluster of cells at the putative posterior of the embryo, consistent with the developing ovary. Bpnos RNA expression is also present in just-laid eggs but expression is much reduced by the four-cell stage and absent by the 16-cell stage. Shortly before hatching of the juvenile rotifer from the egg, Bpnos RNA expression is re activated, located in a subset of posterior cells similar to those expressing Bpvas at the same stage. CONCLUSIONS: The observed expression of vasa and nanos in the developing B. plicatilis embryo implies an epigenetic origin of primordial germ cells in Rotifer. PMID- 20849650 TI - Health worker performance in the management of paediatric fevers following in service training and exposure to job aids in Kenya. AB - BACKGROUND: Improving the way artemether-lumefantrine (AL) is provided to patients attending clinics is critical to maximize the benefit of this new medicine. In 2007, a new initiative was launched in one part of Kenya to improve malaria case-management through enhanced in-service training and provision of job aids. METHODS: An evaluation of the intervention using pre- and post-intervention cross sectional health facility surveys was conducted in Bondo district. The surveys included: audit of government health facilities, health worker structured interviews and exit interviews with caretakers of sick children below five years of age. The outcome indicators were the proportions of febrile children who had AL prescribed, AL dispensed, and four different dispensing and counseling tasks performed. RESULTS: At baseline 33 government health facilities, 48 health workers and 386 febrile child consultations were evaluated. At follow-up the same health facilities were surveyed and 36 health workers and 390 febrile child consultations evaluated. The findings show: 1) no health facility or health worker was exposed to all components of the intervention; 2) the proportion of health workers who received the enhanced in-service training was 67%; 3) the proportion of febrile children with uncomplicated malaria treated with the first line anti-malarial drug, artemether-lumefantrine (AL), at health facilities where AL was in stock increased from 76.9% (95%CI: 69.4, 83.1) to 87.6% (95% CI: 82.5, 91.5); 4) there were modest but non-significant improvements in dispensing and counseling practices; and 5) when the analyses were restricted to health workers who received the enhanced in-service training and/or had received new guidelines and job aids, no significant improvements in reported case-management tasks were observed compared to baseline. CONCLUSION: In-service training and provision of job aids alone may not be adequate to improve the prescribing, dispensing and counseling tasks necessary to change malaria case-management practices and the inclusion of supervision and post-training follow-up should be considered in future clinical practice change initiatives. PMID- 20849652 TI - Older hip fracture patients: three groups with different needs. AB - BACKGROUND: Norway, and particularly Oslo, has the highest reported incidence of hip fractures in the world. It is increasingly common to care for older hip fracture patients in orthogeriatric units where orthopaedic care is combined with interdisciplinary geriatric care. The characteristics and needs of older hip fracture patients are poorly described. The aim of this paper is to describe the characteristics of these patients in order to better understand their need for care and rehabilitation. METHODS: This is an observational study based on a quality register for all patients 65+ years in an orthogeriatric unit who are operated for a hip fracture. The unit covers 250,000 inhabitants in Oslo. Patient data were collected in the aim of quality control. The quality database includes demographic, medical, and functional data collected from routine assessment by the interdisciplinary team. RESULTS: From January 2007 to September 2009, 1010 patients, included 241 (24%) from long-term care institutions, were enrolled in the database. Mean age was 85.1 years (SD 7.1), 76% were female, and 83% had experienced an indoor fall. Chronic diseases were registered in 88%, and 38% of the community-dwelling patients had pre-fracture cognitive impairment defined as IQCODE-SF > 3.6. Complications were observed in 51% of the patients, of which the most common were a need for blood transfusion, delirium, and urinary tract infections. Post-operative orthopaedic infections were rare (3.1%). Patients from long-term care were older, (87 vs. 84 years, p < 0.001), more had American Society of Anaesthesiologists (ASA) score >/= 3 (67% vs. 48%, p < 0.001) and a higher number of chronic medical conditions (mean 2.2 vs. 1.6, p < 0.001). Among community-dwelling patients, those who had fallen indoors were older, more often female, had ASA score >/= 3, chronic medical conditions, impairment in pre fracture ADL and cognitive function, and more complications during hospital stay. CONCLUSIONS: Older hip fracture patients in this orthogeriatric unit may be divided into three groups; patients who are relatively fit and have experienced outdoors falls (17%), frail community-dwelling patients who have fallen indoors (59%), and patients from long-term care institutions (24%). Different caring pathways are needed for these groups. PMID- 20849651 TI - Identification of sequence polymorphism in the D-Loop region of mitochondrial DNA as a risk factor for hepatocellular carcinoma with distinct etiology. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is frequently preceded by hepatitis virus infection or alcohol abuse. Genetic backgrounds may increase susceptibility to HCC from these exposures. METHODS: Mitochondrial DNA (mtDNA) of peripheral blood, tumor, and/or adjacent non-tumor tissue from 49 hepatitis B virus-related and 11 alcohol-related HCC patients, and from 38 controls without HCC were examined for single nucleotide polymorphisms (SNPs) and mutations in the D-Loop region. RESULTS: Single nucleotide polymorphisms (SNPs) in the D-loop region of mt DNA were examined in HCC patients. Individual SNPs, namely the 16266C/T, 16293A/G, 16299A/G, 16303G/A, 242C/T, 368A/G, and 462C/T minor alleles, were associated with increased risk for alcohol- HCC, and the 523A/del was associated with increased risks of both HCC types. The mitochondrial haplotypes under the M haplogroup with a defining 489C polymorphism were detected in 27 (55.1%) of HBV HCC and 8 (72.7%) of alcohol- HCC patients, and in 15 (39.5%) of controls. Frequencies of the 489T/152T, 489T/523A, and 489T/525C haplotypes were significantly reduced in HBV-HCC patients compared with controls. In contrast, the haplotypes of 489C with 152T, 249A, 309C, 523Del, or 525Del associated significantly with increase of alcohol-HCC risk. Mutations in the D-Loop region were detected in 5 adjacent non-tumor tissues and increased in cancer stage (21 of 49 HBV-HCC and 4 of 11 alcohol- HCC, p < 0.002). CONCLUSIONS: In sum, mitochondrial haplotypes may differentially predispose patients to HBV-HCC and alcohol-HCC. Mutations of the mitochondrial D-Loop sequence may relate to HCC development. PMID- 20849653 TI - Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats. AB - BACKGROUND: Berberine is an active compound in Coptidis Rhizoma (Huanglian) with multiple pharmacological activities including antimicrobial, antiviral, anti inflammatory, cholesterol-lowering and anticancer effects. The present study aims to determine the hepatoprotective effects of berberine on serum and tissue superoxide dismutase (SOD) levels, the histology in tetrachloride (CCl4)-induced liver injury. METHODS: Sprague-Dawley rats aged seven weeks were injected intraperitoneally with 50% CCl4 in olive oil. Berberine was orally administered before or after CCl4 treatment in various groups. Twenty-four hours after CCl4 injection, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, serum and liver superoxide dismutase (SOD) activities were measured. Histological changes of liver were examined with microscopy. RESULTS: Serum ALT and AST activities significantly decreased in a dose-dependent manner in both pre-treatment and post-treatment groups with berberine. Berberine increased the SOD activity in liver. Histological examination showed lowered liver damage in berberine-treated groups. CONCLUSION: The present study demonstrates that berberine possesses hepatoprotective effects against CCl4 induced hepatotoxicity and that the effects are both preventive and curative. Berberine should have potential for developing a new drug to treat liver toxicity. PMID- 20849654 TI - Folk medicine used to heal malaria in Calabria (southern Italy). AB - In Italy, malaria was an endemic disease that was eradicated by the mid-20th century. This paper evaluates the prophylactic and therapeutic remedies used by folk medicine to cure malaria in Calabria (southern Italy).The data has been collected by analysing works of physicians, ethnographers, folklorists and specialists of the study of Calabrian history between the end of the 19th century and the 20th century. The data collected have allowed us to describe the most common cures used by the Calabrian people to treat malaria and the most evident symptoms of this disease, such as intermittent fever, hepato-spleenomegaly, asthenia and dropsy. This approach uncovered a heterogeneous corpus of empirical, magical and religious remedies, which the authors have investigated as evidences of past "expert medicine" and to verify their real effectiveness in the treatment of malaria. PMID- 20849655 TI - Obesity and eating habits among college students in Saudi Arabia: a cross sectional study. AB - BACKGROUND: During the last few decades, the Kingdom of Saudi Arabia (KSA) experienced rapid socio-cultural changes caused by the accelerating economy in the Arabian Gulf region. That was associated with major changes in the food choices and eating habits which, progressively, became more and more "Westernized". Such "a nutritional transition" has been claimed for the rising rates of overweight and obesity which were recently observed among Saudi population. Therefore, the objectives of the current work were to 1) determine the prevalence of overweight and obesity in a sample of male college students in KSA and 2) determine the relationship between the students' body weight status and composition and their eating habits. METHODS: A total of 357 male students aged 18-24 years were randomly chosen from College of Health Sciences at Rass, Qassim University, KSA for the present study. A Self-reported questionnaire about the students' eating habits was conducted, and their body mass index (BMI), body fat percent (BF%), and visceral fat level (VFL) were measured. Data were analyzed using SPSS statistical software, and the Chi-square test was conducted for variables. RESULTS: The current data indicated that 21.8% of the students were overweight and 15.7% were obese. The total body fat exceeded its normal limits in 55.2% of the participants and VFL was high in 21.8% of them. The most common eating habits encountered were eating with family, having two meals per day including breakfast, together with frequent snacks and fried food consumption. Vegetables and fruits, except dates, were not frequently consumed by most students. Statistically, significant direct correlations were found among BMI, BF% and VFL (P < 0.001). Both BMI and VFL had significant inverse correlation with the frequency of eating with family (P = 0.005 and 0.007 respectively). Similar correlations were also found between BMI and snacks consumption rate (P = 0.018), as well as, between VFL and the frequency of eating dates (P = 0.013). CONCLUSIONS: Our findings suggest the need for strategies and coordinated efforts at all levels to reduce the tendency of overweight, obesity and elevated body fat, and to promote healthy eating habits in our youth. PMID- 20849656 TI - A SRY-HMG box frame shift mutation inherited from a mosaic father with a mild form of testicular dysgenesis syndrome in Turner syndrome patient. AB - BACKGROUND: Sex determining factor (SRY) located on the short arm of the Y chromosome, plays an important role in initiating male sex determination, resulting in development of testicular tissue. Presence of the SRY gene in females results in XY sex reversal and increased risk of gonadal germ cell tumours if the karyotype also includes the so-called GonadoBlastoma on the Y chromosome (GBY) region. The majority of mutations within the SRY gene are de novo affecting only a single individual in the family. The mutations within the high-mobility group (HMG) region have the potential to affect its DNA binding activity. CASE PRESENTATION: We performed G- and R-banding cytogenetic analysis of the patient and her family members including her father. We also performed molecular genetic analysis of SRY gene. Cytogenetic analysis in the patient (Turner Syndrome) revealed the mosaic karyotype as 45, X/46, XY (79%/21% respectively) while her father (milder features with testicular dysgenesis syndrome) has a normal male karyotype (46, XY). Using molecular approach, we screened the patient and her father for mutations in the SRY gene. Both patient and her father showed the same deletion of cytosine within HMG box resulting in frame shift mutation (L94fsX180), the father in a mosaic pattern. Histological examination of the gonads from the patient revealed the presence of gonadoblastoma formation, while the father presented with oligoasthenozoospermia and a testicular seminoma. The frameshift mutation at this codon is novel, and may result in a mutated SRY protein. CONCLUSION: Our results suggest that lack of a second sex chromosome in majority cells of the patient may have triggered the short stature and primary infertility, and the mutated SRY protein may be associated with the development of gonadoblastoma. It is of importance to note that mosaic patients without a SRY mutation also have a risk for malignant germ cell tumors. PMID- 20849657 TI - Evaluation of combinatorial cis-regulatory elements for stable gene expression in chicken cells. AB - BACKGROUND: Recent successes in biotechnological application of birds are based on their unique physiological traits such as unlimited manipulability onto developing embryos and simple protein constituents of the eggs. However it is not likely that target protein is produced as kinetically expected because various factors affect target gene expression. Although there have been various attempts to minimize the silencing of transgenes, a generalized study that uses multiple cis-acting elements in chicken has not been made. The aim of the present study was to analyze whether various cis-acting elements can help to sustain transgene expression in chicken fibroblasts. RESULTS: We investigated the optimal transcriptional regulatory elements for enhancing stable transgene expression in chicken cells. We generated eight constructs that encode enhanced green fluorescent protein (eGFP) driven by either CMV or CAG promoters (including the control), containing three types of key regulatory elements: a chicken lysozyme matrix attachment region (cMAR), 5'-DNase I-hypersensitive sites 4 (cHS4), and the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE). Then we transformed immortalized chicken embryonic fibroblasts with these constructs by electroporation, and after cells were expanded under G418 selection, analyzed mRNA levels and mean fluorescence intensity (MFI) by quantitative real-time PCR and flow cytometry, respectively. We found that the copy number of each construct significantly decreased as the size of the construct increased (R2 = 0.701). A significant model effect was found in the expression level among various constructs in both mRNA and protein (P < 0.0001). Transcription with the CAG promoter was 1.6-fold higher than the CMV promoter (P = 0.027) and the level of eGFP expression activity in cMAR- or cHS4-flanked constructs increased by two- to three-fold compared to the control CMV or CAG promoter constructs. In addition, flow cytometry analysis showed that constructs having cis-acting elements decreased the level of gene silencing as well as the coefficient of variance of eGFP-expressing cells (P < 0.0001). CONCLUSIONS: Our current data show that an optimal combination of cis-acting elements and promoters/enhancers for sustaining gene expression in chicken cells is suggested. These results provide important information for avian transgenesis and gene function studies in poultry. PMID- 20849658 TI - Empirical studies on informal patient payments for health care services: a systematic and critical review of research methods and instruments. AB - BACKGROUND: Empirical evidence demonstrates that informal patient payments are an important feature of many health care systems. However, the study of these payments is a challenging task because of their potentially illegal and sensitive nature. The aim of this paper is to provide a systematic review and analysis of key methodological difficulties in measuring informal patient payments. METHODS: The systematic review was based on the following eligibility criteria: English language publications that reported on empirical studies measuring informal patient payments. There were no limitations with regard to the year of publication. The content of the publications was analysed qualitatively and the results were organised in the form of tables. Data sources were Econlit, Econpapers, Medline, PubMed, ScienceDirect, SocINDEX. RESULTS: Informal payments for health care services are most often investigated in studies involving patients or the general public, but providers and officials are also sample units in some studies. The majority of the studies apply a single mode of data collection that involves either face-to-face interviews or group discussions.One of the main methodological difficulties reported in the publication concerns the inability of some respondents to distinguish between official and unofficial payments. Another complication is associated with the refusal of some respondents to answer questions on informal patient payments.We do not exclude the possibility that we have missed studies that reported in non-English language journals as well as very recent studies that are not yet published. CONCLUSIONS: Given the recent evidence from research on survey methods, a self-administrated questionnaire during a face-to-face interview could be a suitable mode of collecting sensitive data, such as data on informal patient payments. PMID- 20849659 TI - Effect of a multispecies probiotic supplement on quantity of irritable bowel syndrome-related intestinal microbial phylotypes. AB - BACKGROUND: Probiotics can alleviate the symptoms of irritable bowel syndrome (IBS), possibly by stabilizing the intestinal microbiota. Our aim was to determine whether IBS-associated bacterial alterations were reduced during multispecies probiotic intervention consisting of Lactobacillus rhamnosus GG, L. rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS and Bifidobacterium breve Bb99. The intervention has previously been shown to successfully alleviate gastrointestinal symptoms of IBS. METHODS: The faecal microbiotas of 42 IBS subjects participating in a placebo-controlled double-blind multispecies probiotic intervention were analysed using quantitative real-time polymerase chain reaction (qPCR). Eight bacterial targets within the gastrointestinal microbiota with a putative IBS association were measured. RESULTS: A phylotype with 94% similarity to Ruminococcus torques remained abundant in the placebo group, but was decreased in the probiotic group during the intervention (P = 0.02 at 6 months). In addition, the clostridial phylotype, Clostridium thermosuccinogenes 85%, was stably elevated during the intervention (P = 0.00 and P = 0.02 at 3 and 6 months, respectively). The bacterial alterations detected were in accordance with previously discovered alleviation of symptoms. CONCLUSIONS: The probiotic supplement was thus shown to exert specific alterations in the IBS-associated microbiota towards the bacterial 16S rDNA phylotype quantities described previously for subjects free of IBS. These changes may have value as non-invasive biomarkers in probiotic intervention studies. PMID- 20849660 TI - Risk factors for development of left ventricular thrombus after first acute anterior myocardial infarction-association with anticardiolipin antibodies. AB - BACKGROUND: Left ventricular thrombus(LVT] formation is a frequent complication in patients with acute anterior myocardial infarction(MI). LVT is associated with increased risk of embolism and higher mortality rates after acute MI. Anticardiolipin antibodies (ACA) are immunoglobulins that react with phospholipid binding proteins interfering with the prothrombin activator complex. The effects of phospholipids on pathophysiology of cardiovascular thrombotic events are well known. In this study, we aimed to evaluate the importance of clinical and biochemical parameters including anticardiolipin antibodies on left ventricular thrombus formation after acute anterior MI. METHODS AND RESULTS: Seventy patients with a first anterior AMI were prospectively and consecutively enrolled. Patients with previous MI, autoimmune disease, collagen vascular disease and arterial or venous thrombosis history were excluded from this study. At the time of hospitalization, key demographic and clinical characteristics were collected including age, gender, ethanol intake and presence of traditional risk factors for atherosclerosis (hypertension, diabetes, smoking, hyperlipidemia, positive family history). Patients were evaluated for echocardiographic data, blood chemistry and ACA. Two-dimensional and Doppler echocardiographic examinations were performed in all patients within the first week and at 14 days after MI. LV thrombus was detected in 30 (42.8%) patients. ACA IgM levels were significantly higher in the patient group with LV thrombus than in the group without thrombus (12.44 +/-4.12 vs. 7.69 +/- 4.25 mpl, p = 0,01). ACA IgG levels were also found higher in the group with LV thrombus (24.2 +/- 7.5 vs.17.98 +/- 6.45 gpl, p = 0.02). Multivariate analyses revealed diabetes mellitus, higher WMSI, lower MDT and higher ACA IgM and higher ACA IgG levels as independent predictors of left ventricular thrombus formation. CONCLUSIONS: Our data demonstrate that beside the low ejection fraction, lower MDT and higher wall motion score index, modestly elevated ACA IgM and ACA IgG levels are associated with LV thrombus formation in patients with anterior MI. PMID- 20849662 TI - Partial rupture of the quadriceps muscle in a child. AB - BACKGROUND: The quadriceps femoris muscle ruptures usually occur in the middle aged population. We present a 4-year-old patient with partial rupture of the quadriceps femoris muscle. To our knowledge, this is the youngest patient reported with a quadriceps femoris muscle rupture. CASE PRESENTATION: A 4-year old girl admitted to our clinic with left knee pain and limitation in knee movements. Her father reported that she felt pain while jumping on sofa. There was no direct trauma to thigh or knee. We located a palpable soft tissue swelling at distal anterolateral side of thigh. The history revealed that 10 days ago the patient was treated for upper tract respiratory infection with intramuscular Clindamycin for 7 days. When we consulted the patient with her previous doctor and nurse, we learnt that multiple daily injections might be injected to same side of left thigh. MRI showed a partial tear of vastus lateralis muscle matching with the injection sites. The patient treated with long leg half-casting for three weeks. Clinical examination and knee flexion had good results with conservative treatment. CONCLUSIONS: Multiple intramuscular injections may contribute to damage muscles and make prone to tears with muscle contractions. Doctors and nurses must be cautious to inject from different parts of both thighs. PMID- 20849661 TI - Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma. AB - BACKGROUND: BamHI-A rightward frame-1 (BARF1) is a carcinoma-specific Epstein Barr virus (EBV) encoded oncogene. Here we describe the BARF1 sequence diversity in nasopharyngeal carcinoma (NPC), other EBV-related diseases and Indonesian healthy EBV carriers in relation to EBV genotype, viral load and serology markers. Nasopharyngeal brushings from 56 NPC cases, blood or tissue from 15 other EBV-related disorders, spontaneous B cell lines (LCL) from 5 Indonesian healthy individuals and several prototype EBV isolates were analysed by PCR direct sequencing. RESULTS: Most NPC isolates revealed specific BARF1 nucleotide changes compared to prototype B95-8 virus. At the protein level these mutations resulted in 3 main substitutions (V29A, W72G, H130R), which are not considered to cause gross tertiary structure alterations in the hexameric BARF1 protein. At least one amino acid conversion was detected in 80.3% of NPC samples compared to 33.3% of non-NPC samples (p < 0.001) and 40.0% of healthy LCLs (p = 0.074). NPC isolates also showed more frequent codon mutation than non-NPC samples. EBV strain typing revealed most isolates as EBV type 1. The viral load of either NPC or non-NPC samples was high, but only in non- NPC group it related to a particular BARF1 variant. Serology on NPC sera using IgA/EBNA-1 ELISA, IgA/VCA p18 ELISA and immunoblot score showed no relation with BARF1 sequence diversity (p = 0.802, 0.382 and 0.058, respectively). NPC patients had variable antibody reactivity against purified hexameric NPC-derived BARF1 irrespective of the endogenous BARF1 sequence. CONCLUSION: The sequence variation of BARF1 observed in Indonesian NPC patients and controls may reflect a natural selection of EBV strains unlikely to be predisposing to carcinogenesis. The conserved nature of BARF1 may reflect an important role in EBV (epithelial) persistence. PMID- 20849663 TI - Better than nothing? Patient-delivered partner therapy and partner notification for chlamydia: the views of Australian general practitioners. AB - BACKGROUND: Genital chlamydia is the most commonly notified sexually transmissible infection (STI) in Australia and worldwide and can have serious reproductive health outcomes. Partner notification, testing and treatment are important facets of chlamydia control. Traditional methods of partner notification are not reaching enough partners to effectively control transmission of chlamydia. Patient-delivered partner therapy (PDPT) has been shown to improve the treatment of sexual partners. In Australia, General Practitioners (GPs) are responsible for the bulk of chlamydia testing, diagnosis, treatment and follow up. This study aimed to determine the views and practices of Australian general practitioners (GPs) in relation to partner notification and PDPT for chlamydia and explored GPs' perceptions of their patients' barriers to notifying partners of a chlamydia diagnosis. METHODS: In-depth, semi-structured telephone interviews were conducted with 40 general practitioners (GPs) from rural, regional and urban Australia from November 2006 to March 2007. Topics covered: GPs' current practice and views about partner notification, perceived barriers and useful supports, previous use of and views regarding PDPT.Transcripts were imported into NVivo7 and subjected to thematic analysis. Data saturation was reached after 32 interviews had been completed. RESULTS: Perceived barriers to patients telling partners (patient referral) included: stigma; age and cultural background; casual or long-term relationship, ongoing relationship or not. Barriers to GPs undertaking partner notification (provider referral) included: lack of time and staff; lack of contact details; uncertainty about the legality of contacting partners and whether this constitutes breach of patient confidentiality; and feeling both personally uncomfortable and inadequately trained to contact someone who is not their patient. GPs were divided on the use of PDPT--many felt concerned that it is not best clinical practice but many also felt that it is better than nothing.GPs identified the following factors which they considered would facilitate partner notification: clear clinical guidelines; a legal framework around partner notification; a formal chlamydia screening program; financial incentives; education and practical support for health professionals, and raising awareness of chlamydia in the community, in particular amongst young people. CONCLUSIONS: GPs reported some partners do not seek medical treatment even after they are notified of being a sexual contact of a patient with chlamydia. More routine use of PDPT may help address this issue however GPs in this study had negative attitudes to the use of PDPT. Appropriate guidelines and legislation may make the use of PDPT more acceptable to Australian GPs. PMID- 20849664 TI - The ancient function of RB-E2F pathway: insights from its evolutionary history. AB - BACKGROUND: The RB-E2F pathway is conserved in most eukaryotic lineages, including animals and plants. E2F and RB family proteins perform crucial functions in cycle controlling, differentiation, development and apoptosis. However, there are two kinds of E2Fs (repressive E2Fs and active E2Fs) and three RB family members in human. Till now, the detail evolutionary history of these protein families and how RB-E2F pathway evolved in different organisms remain poorly explored. RESULTS: We performed a comprehensive evolutionary analysis of E2F, RB and DP (dimerization partners of E2Fs) protein family in representative eukaryotic organisms. Several interesting facts were revealed. First, orthologues of RB, E2F, and DP family are present in several representative unicellular organisms and all multicellular organisms we checked. Second, ancestral E2F, RB genes duplicated before placozoans and bilaterians diverged, thus E2F family was divided into E2F4/5 subgroup (including repressive E2Fs: E2F4 and E2F5) and E2F1/2/3 subgroup (including active E2Fs: E2F1, E2F2 and E2F3), RB family was divided into RB1 subgroup (including RB1) and RBL subgroup (including RBL1 and RBL2). Third, E2F4 and E2F5 share more sequence similarity with the predicted E2F ancestral sequence than E2F1, E2F2 and E2F3; E2F4 and E2F5 also possess lower evolutionary rates and higher purification selection pressures than E2F1, E2F2 and E2F3. Fourth, for RB family, the RBL subgroup proteins possess lower evolutionary rates and higher purification selection pressures compared with RB subgroup proteins in vertebrates, CONCLUSIONS: Protein evolutionary rates and purification selection pressures are usually linked with protein functions. We speculated that function conducted by E2F4/5 subgroup and RBL subgroup proteins might mainly represent the ancient function of RB-E2F pathway, and the E2F1/2/3 subgroup proteins and RB1 protein might contribute more to functional diversification in RB-E2F pathway. Our results will enhance the current understanding of RB-E2F pathway and will also be useful to further functional studies in human and other model organisms. PMID- 20849665 TI - Evaluation of a rapid diagnostic test, NanoSign(r) Influenza A/B Antigen, for detection of the 2009 pandemic influenza A/H1N1 viruses. AB - BACKGROUND: This study evaluated the clinical accuracy and analytical sensitivity of the NanoSign(r) Influenza A/B antigen kit in detecting 2009 pandemic influenza A/H1N1 viruses. The kit is one of the most popular rapid diagnostic tests for detecting influenza in Republic of Korea. RESULTS: The NanoSign(r) Influenza A/B kit resulted in 79.4% sensitivity and 97.2% specificity compared to RT-PCR in the detection of the viruses from 1,023 specimens. In addition, the kit was able to detect two strains of novel influenza viruses, Influenza A/California/12/2009(H1N1) and clinically isolated wild-type novel influenza A/H1N1, both of which are spreading epidemically throughout the world. In addition, the correlation between NanoSign(r) Influenza A/B test and conventional RT-PCR was approximately 94%, indicating a high concordance rate. Analytical sensitivity of the kit was approximately 73 +/- 3.65 ng/mL of the purified viral proteins and 1.13 +/- 0.11 hemagglutination units for the cultured virus. CONCLUSIONS: As the NanoSign(r) Influenza A/B kit showed relatively high sensitivity and specificity and the good correlation with RT-PCR, it will be very useful in the early control of influenza infection and in helping physicians in making early treatment decisions. PMID- 20849666 TI - Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis and bronchial asthma: a case report. AB - OBJECTIVE: Strongyloides stercoralis is a soil-transmitted intestinal nematode that has been estimated to infect at least 60 million people, especially in tropical and subtropical regions. Strongyloides infection has been described in immunosupressed patients with lymphoma, rheumatoid arthritis, diabetes mellitus etc. Our case who has rheumatoid arthritis (RA) and bronchial asthma was treated with low dose steroids and methotrexate. METHODS: A 68 year old woman has bronchial asthma for 55 years and also diagnosed RA 7 years ago. She received immunusupressive agents including methotrexate and steroids. On admission at hospital, she was on deflazacort 5 mg/day and methotrexate 15 mg/week. On her physical examination, she was afebrile, had rhonchi and mild epigastric tenderness. She had joint deformities at metacarpophalengeal joints and phalanges but no active arthritis finding. RESULTS: Oesophagogastroduodenoscopy was performed and it showed hemorrhagic focus at bulbus. Gastric biopsy obtained and showed evidence of S.Stercoralis infection. Stool and sputum parasitological examinations were also all positive for S.stercoralis larvae. Chest radiography result had no pathologic finding. Albendazole 400 mg/day was started for 23 days. After the ivermectin was retrieved, patient was treated with oral ivermectin 200 MUg once a day for 3 days. On her outpatient control at 15th day, stool and sputum samples were all negative for parasites. CONCLUSION: S.stercoralis may cause mortal diseases in patients. Immunosupression frequently causes disseminated infections. Many infected patients are completely asymptomatic. Although it is important to detect latent S. stercoralis infections before administering chemotherapy or before the onset of immunosuppression in patients at risk, a specific and sensitive diagnostic test is lacking. In immunosupressed patients, to detect S.stercoralis might help to have the patient survived and constitute the exact therapy. PMID- 20849667 TI - Diversity of sponge mitochondrial introns revealed by cox 1 sequences of Tetillidae. AB - BACKGROUND: Animal mitochondrial introns are rare. In sponges and cnidarians they have been found in the cox 1 gene of some spirophorid and homosclerophorid sponges, as well as in the cox 1 and nad 5 genes of some Hexacorallia. Their sporadic distribution has raised a debate as to whether these mobile elements have been vertically or horizontally transmitted among their hosts. The first sponge found to possess a mitochondrial intron was a spirophorid sponge from the Tetillidae family. To better understand the mode of transmission of mitochondrial introns in sponges, we studied cox 1 intron distribution among representatives of this family. RESULTS: Seventeen tetillid cox 1 sequences were examined. Among these sequences only six were found to possess group I introns. Remarkably, three different forms of introns were found, named introns 714, 723 and 870 based on their different positions in the cox 1 alignment. These introns had distinct secondary structures and encoded LAGLIDADG ORFs belonging to three different lineages. Interestingly, sponges harboring the same intron form did not always form monophyletic groups, suggesting that their introns might have been transferred horizontally. To evaluate whether the introns were vertically or horizontally transmitted in sponges and cnidarians we used a host parasite approach. We tested for co-speciation between introns 723 (the introns with the highest number of sponge representatives) and their nesting cox 1 sequences. Reciprocal AU tests indicated that the intron and cox 1 tree are significantly different, while a likelihood ratio test was not significant. A global test of co phylogeny had significant results; however, when cnidarian sequences were analyzed separately the results were not significant. CONCLUSIONS: The co speciation analyses thus suggest that a vertical transmission of introns in the ancestor of sponges and cnidarians, followed by numerous independent losses, cannot solely explain the current distribution of metazoan group I introns. An alternative scenario that includes horizontal gene transfer events appears to be more suitable to explain the incongruence between the intron 723 and the cox 1 topologies. In addition, our results suggest that three different intron forms independently colonized the cox 1 gene of tetillids. Among sponges, the Tetillidae family seems to be experiencing an unusual number of intron insertions. PMID- 20849668 TI - The capacity of foodstuffs to induce innate immune activation of human monocytes in vitro is dependent on food content of stimulants of Toll-like receptors 2 and 4. AB - The ingestion of fatty meals is associated with a transient, low-grade systemic inflammatory response in human subjects, involving the activation of circulating monocytes and the secretion of pro-inflammatory cytokines. However, it is not yet clear how different foodstuffs may promote inflammatory signalling. In a screen of forty filter-sterilised soluble extracts from common foodstuffs, seven were found to induce the secretion of TNF-alpha and IL-6 from human monocytes in vitro. To investigate what may differentiate inflammatory from non-inflammatory food extracts, stimulants of Toll-like receptor (TLR) 2 and TLR4 were quantified using human embryonic kidney-293 cells transfected with each TLR, and calibrated with defined bacterial lipopeptide (BLP) and lipopolysaccharide (LPS) standards. These assays revealed that while most foods contained undetectable levels of TLR2 or TLR4 stimulants, all TNF-alpha-inducing foods contained stimulants of either TLR2 (up to 1100 ng BLP-equivalent/g) or TLR4 (up to 2700 ng LPS-equivalent/g) in both the soluble and insoluble fractions. TLR stimulants were present mainly in meat products and processed foods, but were minimal or undetectable in fresh fruit and vegetables. The capacity of food extracts to induce TNF-alpha secretion in monocytes correlated with the content of both TLR2 (r 0.837) and TLR4 stimulants (r 0.748), and was completely abolished by specific inhibition of TLR2 and TLR4. LPS and BLP were found to be highly resistant to typical cooking times and temperatures, low pH and protease treatment. In conclusion, apparently unspoiled foodstuffs can contain large quantities of stimulants of TLR2 and TLR4, both of which may regulate their capacity to stimulate inflammatory signalling. PMID- 20849669 TI - The prevalence and abundance of helminth parasites in stray dogs from the city of Queretaro in central Mexico. AB - The prevalence of helminth species in stray dogs, from the capital city of the state of Queretaro, was evaluated. A total of 378 dogs were captured and examined for the presence of helminths from January to December 2008. The results showed that 275 (72.8%) of examined dogs were infected with one or more helminth species. Single infections were observed in 139 (50.5%) of infected dogs and 136 (49.5%) harboured mixed infections. Out of the 378 dogs examined, 208 (55.2%) presented nematodes and 182 (48.1%) cestodes. The prevalences (confidence interval) and mean intensities of infection ( +/- SD) of nematodes and cestodes encountered were: Ancylostoma caninum 42.9% (37.9-47.8) and 22.1 ( +/- 34.3); Toxocara canis 15.1% (11.8-19.0) and 8.3 ( +/- 15.0); Spirocerca lupi 4.5% (2.7 7.1) and 3.9 ( +/- 4.8); Toxascaris leonina 2.3% (1.1-4.5) and 4.8 ( +/- 3.5); Physaloptera praeputialis 1.9% (0.8-3.8) and 9.7 ( +/- 14.9); Dirofilaria immitis 1.3% (0.4-3.1) and 5.6 ( +/- 2.1); Oslerus osleri 0.3% (0.0-1.6) and 5 ( +/- 0.0); Dipylidium caninum 44.9% (40.0-50.0) and 18.1 ( +/- 27.7); Taenia spp. 6.9% (4.7-9.9) and 6.9 ( +/- 7.1). There were no significant differences in prevalences observed either between female (68.5%) and male (76.8%) or between young (70.6%) and adult (74.2%) animals. No differences were observed in the ANOVA test for the mean intensity of infection of any of the parasites (P>0.05). PMID- 20849670 TI - Bone-anchored hearing aids in children and young adults: the Freeman Hospital experience. AB - OBJECTIVE: To investigate the utilisation of bone-anchored hearing aids and Softband, as well as the effects on quality of life, amongst the paediatric and young adult population of Freeman Hospital, Newcastle Upon Tyne, UK. METHOD: Retrospective, anonymised, cross-sectional survey using the Glasgow Benefit Inventory and Listening Situation Questionnaire (parent version), administered at least three months following the start of bone-anchored hearing aid or Softband use. RESULTS: One hundred and nine patients were included, of whom syndromic children made up a significant proportion (22 of 109). Patients using bone anchored hearing aids obtained significant educational and social benefit from their aids. The mean Listening Situation Questionnaire difficulty score was 17 (15 patients), which is below the trigger score of 22+ at which further reassessment and rehabilitation is required. 87% (of 15 patients) did not require further intervention. The overall mean GBI score for the 22 patients (syndromic and non-syndromic) was +29. CONCLUSION: The use of bone-anchored hearing aids and Softband results in significant improvements in quality of life for children and young adults with hearing impairment. There is significant under-utilisation of bone-anchored hearing aids in children with skull and congenital abnormalities, and we would advocate bone-anchored hearing aid implantation for these patients. PMID- 20849671 TI - The structural basis of function in Cys-loop receptors. AB - Cys-loop receptors are membrane-spanning neurotransmitter-gated ion channels that are responsible for fast excitatory and inhibitory transmission in the peripheral and central nervous systems. The best studied members of the Cys-loop family are nACh, 5-HT3, GABAA and glycine receptors. All these receptors share a common structure of five subunits, pseudo-symmetrically arranged to form a rosette with a central ion-conducting pore. Some are cation selective (e.g. nACh and 5-HT3) and some are anion selective (e.g. GABAA and glycine). Each receptor has an extracellular domain (ECD) that contains the ligand-binding sites, a transmembrane domain (TMD) that allows ions to pass across the membrane, and an intracellular domain (ICD) that plays a role in channel conductance and receptor modulation. Cys-loop receptors are the targets for many currently used clinically relevant drugs (e.g. benzodiazepines and anaesthetics). Understanding the molecular mechanisms of these receptors could therefore provide the catalyst for further development in this field, as well as promoting the development of experimental techniques for other areas of neuroscience.In this review, we present our current understanding of Cys-loop receptor structure and function. The ECD has been extensively studied. Research in this area has been stimulated in recent years by the publication of high-resolution structures of nACh receptors and related proteins, which have permitted the creation of many Cys loop receptor homology models of this region. Here, using the 5-HT3 receptor as a typical member of the family, we describe how homology modelling and ligand docking can provide useful but not definitive information about ligand interactions. We briefly consider some of the many Cys-loop receptors modulators. We discuss the current understanding of the structure of the TMD, and how this links to the ECD to allow channel gating, and consider the roles of the ICD, whose structure is poorly understood. We also describe some of the current methods that are beginning to reveal the differences between different receptor states, and may ultimately show structural details of transitions between them. PMID- 20849673 TI - Discontinuing cholinesterase inhibitors: results of a survey of Canadian dementia experts. AB - BACKGROUND: Cholinesterase inhibitors (ChEIs) are being used for increasingly long periods of time, even in patients with severe Alzheimer's disease. Because there is little data to help clinicians to decide on when it is safe and appropriate to discontinue ChEIs after long-term use, practices may vary widely. METHODS: An internet-based survey was undertaken of Canadian dementia experts (geriatric psychiatrists, neurologists, geriatricians) involved in clinical trial research. Recommendations for ChEI discontinuation were determined based on responses to questions dealing with patient/caregiver preference, administrative considerations, effectiveness, and adverse events. RESULTS: There was reasonable consensus that ChEIs should be discontinued based on patient and caregiver preference, and in the presence of severe bothersome adverse events. There was much less consensus on issues related to effectiveness - in particular, what constitutes greater than expected decline. There was a general reluctance to rely on any single measure of cognition, function and/or behavior, and in particular, the MMSE was seen as unhelpful for making decisions about discontinuation. CONCLUSION: Recommendations for discontinuing ChEIs after long-term use from a survey of dementia experts are presented. Ideally, clinical practice guidelines based on controlled discontinuation trials are needed. PMID- 20849674 TI - Post-traumatic stress symptoms linked to hidden Holocaust trauma among adult Finnish evacuees separated from their parents as children in World War II, 1939 1945: a case-control study. AB - BACKGROUND: The aim of this study was to identify long-term effects of diagnostic criteria on the Post Traumatic Stress Disorder Checklist (PCL-C) for a test group of Finnish evacuees from World War II and compare the outcome effect with a control group of children who lived in Finland during the war in 1939-1945. METHODS: 152 participants were recruited by the local leader of the Finnish War Child Association in Sweden and Finland. The selected group answered questions on the Post Traumatic Stress Disorder Checklist (PCL-C) and the EMBU (Swedish acronym for "Own Memories of Parental Rearing"). RESULTS: Evidence suggests a link between childhood parental separation and termination of the internalized attachment hierarchy of origin in a detachment process among Finnish evacuees. Based on the Post Traumatic Stress Disorder Total (PCL-C) diagnosis an extreme traumatization for 36.7% of the test group subjects was identified, including a hidden Holocaust trauma in the population of Finnish evacuees. CONCLUSIONS: The study met the criteria for satisfying global evidence value. Sixty-five years after the end of World War II and in line with other studies on war children, the data show high levels of different trauma exposures from the war with 10.6 higher risk (odds ratio) for the exposed group of Finnish evacuees. Despite some limitations, the data highlight the need for further investigation into different parts of the detachment process among seriously traumatized groups to reveal resilience and other dimensions of importance in professional mental health creation. PMID- 20849675 TI - Motives for caring: relationship to stress and coping dimensions. AB - BACKGROUND: Although research has highlighted the importance of including cultural factors in the analysis of caregiver stress, little is known about the effects of motives for caregiving on the stress and coping process. This study is aimed at analyzing the dimensional structure of the Cultural Justifications for Caregiving Scale - Revised (CJCS-R), and the effects of motives for caregiving on stressors, caregiver resources and outcome variables. METHODS: Dementia caregivers (N = 166) were interviewed and the following variables were assessed: motives for caregiving (CJCS-R), stressors (frequency of behavioral problems), resources (rumination, cognitive reappraisal), and outcomes (depression, anxiety and anger). RESULTS: A bidimensional structure was obtained for the CJCS-R, and the two factors were labeled Intrinsic and Extrinsic motives for caregiving. Participants were divided into four groups corresponding to four motivation profiles: HIHE = High Intrinsic Motives + High Extrinsic motives; LILE = Low Intrinsic Motives + Low Extrinsic Motives; HILE = High Intrinsic Motives + Low Extrinsic Motives; and LIHE = Low Intrinsic Motives + High Extrinsic Motives. No differences between groups were found in frequency of behavioral problems. Caregivers in the LIHE group had significantly worse consequences on caregiver resources and outcome variables compared to the other groups. CONCLUSIONS: The results support the usefulness of considering motives for caregiving as a multidimensional construct. Analyzing caregivers' motivation profiles may constitute a useful strategy for identifying caregivers at risk. Caregivers scoring simultaneously low on intrinsic motives and high on extrinsic motives may be at particular risk for negative caregiving outcomes. PMID- 20849672 TI - Clinical progression of moderate-to-severe Alzheimer's disease and caregiver burden: a 12-month multicenter prospective observational study. AB - BACKGROUND: Prospective studies on the clinical progression of Alzheimer's disease (AD) and its relationship to caregiver burden are needed to improve illness management and use of resources. METHODS: This national, multicenter, observational study evaluated 1235 moderate to severe AD patients under routine care in Spain. Baseline cross-sectional sociodemographic and clinical data, and changes from baseline to month 12 of various neuropsychological tests and clinical ratings, including Blessed Dementia Scale, Mini-mental State Examination (MMSE), Hughes Clinical Dementia Rating sum-of-boxes (CDR-SB), Clinical Global Impression of Change (CGIC) and Zarit Caregiver Burden scales, were recorded and comprehensively analyzed. RESULTS: Baseline data were in accordance with characteristics consistently reported to influence AD risk regarding anthropometrics, sociocultural features and comorbidities. Significant progressive functional impairments (i.e. in routine activities and essential daily tasks) and cognitive (i.e. MMSE and CDR-SB) impairments were found at month 12. However, patients' behavior and caregivers' burden improved slightly, but significantly, corroborating the major influence of behavioral symptoms on caregivers' distress. Caregivers showed significantly lower burden with patients with higher levels of education and, to a lesser extent, when patients received AD-specific medication. Physicians accurately detected AD clinical evolution as their CGIC ratings significantly correlated with all tests. CONCLUSIONS: These findings reinforce previous AD knowledge and add data on the clinical course of advanced stages of AD. Caregiver burden depended more on patients' behavioral alterations than on their functional or cognitive declines; and it was diminished by their patients having higher levels of education and being treated with AD specific medications. Research into unexplored factors that might reduce caregiver burden, ultimately benefiting both patients and caregivers, is encouraged. PMID- 20849676 TI - Memory and communication support in dementia: research-based strategies for caregivers. AB - BACKGROUND: Difficulties with memory and communication are prominent and distressing features of dementia which impact on the person with dementia and contribute to caregiver stress and burden. There is a need to provide caregivers with strategies to support and maximize memory and communication abilities in people with dementia. In this project, a team of clinicians, researchers and educators in neuropsychology, psychogeriatrics, nursing and speech pathology translated research-based knowledge from these fields into a program of practical strategies for everyday use by family and professional caregivers. METHODS: From the available research evidence, the project team identified compensatory or facilitative strategies to assist with common areas of difficulty, and structured these under the mnemonics RECAPS (for memory) and MESSAGE (for communication). This information was adapted for presentation in a DVD-based education program in accordance with known characteristics of effective caregiver education. RESULTS: The resultant DVD comprises (1) information on the nature and importance of memory and communication in everyday life; (2) explanations of common patterns of difficulty and preserved ability in memory and communication across the stages of dementia; (3) acted vignettes demonstrating the strategies, based on authentic samples of speech in dementia; and (4) scenarios to prompt the viewer to consider the benefits of using the strategies. CONCLUSION: Using a knowledge-translation framework, information and strategies can be provided to family and professional caregivers to help them optimize residual memory and communication in people with dementia. Future development of the materials, incorporating consumer feedback, will focus on methods for enabling wider dissemination. PMID- 20849677 TI - Is the proposed DSM-V Suicide Assessment Dimension suitable for seniors? PMID- 20849678 TI - Living at an altitude adversely affects exercise capacity in Fontan patients. AB - BACKGROUND: Data assessing the effect of altitude on Fontan haemodynamics are limited to experimental models and case reports. Both suggest a detrimental impact. This study describes exercise performance in patients with Fontan circulation and matched controls at a low altitude versus at sea level. We sought to assess the impact of increasing altitude on functional capacity in patients with Fontan palliation. METHODS: A retrospective review of 22 patients at low altitude (1602 metres) and 119 patients at sea level with Fontan circulation, as well as age-, gender-, and altitude-matched controls, underwent maximal cardiopulmonary exercise testing. Linear regression models were created to determine the influence of altitude on differences in exercise variables between Fontan patients and their matched controls. RESULTS: Peak oxygen consumption was 28.4 millilitres per kilogram per minute (72% predicted) for the sea-level cohort and 24.2 millilitres per kilogram per minute (63% predicted) for the moderate altitude cohort. The matched case-control differences for patients at moderate altitude were greater for peak oxygen consumption (-29% against -13%, p = 0.04), anaerobic threshold (-36% against -5%, p = 0.001), and oxygen pulse (-35% against -18%, p = 0.007) when compared with patients living at sea level. When compared to institution-matched controls, the same parameters fell by 3%, 8.9%, and 4.2%, respectively, for each increase of 1000 feet in residential altitude (p = 0.03, p = 0.001, and p = 0.05, respectively). CONCLUSIONS: Patients with Fontan circulation at a higher altitude have impairment in aerobic capacity when compared with patients at sea level. Reduction in exercise capacity is associated with a reduction in stroke volume, likely related to increased pulmonary vascular resistance. PMID- 20849680 TI - Clustering and local magnification effects in atom probe tomography: a statistical approach. AB - Local magnification effects and trajectory overlaps related to the presence of a second phase (clusters) are key problems and still open issues in the assessment of quantitative composition data in three-dimensional atom probe tomography (APT) particularly for tiny solute-enriched clusters. A model based on the distribution of distance of first nearest neighbor atoms has been developed to exhibit the variations in the apparent atomic density in reconstructed volumes and to correct compositions that are biased by local magnification effects. This model was applied to both simulated APT reconstructions and real experimental data and shows an excellent agreement with the expected composition of clusters. PMID- 20849679 TI - Dilated cardiomyopathy presenting in childhood: aetiology, diagnostic approach, and clinical course. AB - OBJECTIVE: To determine the outcome of dilated cardiomyopathy presenting in childhood and the features that might be useful for prognostic stratification. METHODS: Retrospective study of 41 consecutive children affected by dilated cardiomyopathy - aged 0-14 years; median 33.4 plus or minus 49.25 - between 1993 and 2008. We reviewed the medical history to determine age at diagnosis, family history, previous viral illness, aetiology, symptoms and signs at presentation, treatment, and outcome. The diagnosis was made on the basis of cardiomegaly and evidence of poor left ventricular function by echocardiography. We also carried out a metabolic evaluation including blood lactate, pyruvate, carnitine, amino acids, urine organic acids, assessment of respiratory chain enzymes, and analysis of histopathological material. Survival curves were constructed by the Kaplan Meier method. RESULTS: Follow-up ranged from 10 days to 162 months - median 45.25 plus or minus 41.15 months. Freedom from death or cardiac transplantation was 68.3% at 5 years. The primary end-point of death/cardiac transplantation was associated with the need for intravenous inotropic support. A trend towards a poorer prognosis was found for age at diagnosis of more than 5 years and for a metabolic aetiology of dilated cardiomyopathy. For the children affected by cardiomyopathy as part of a multi-system involvement, mortality was 50%. CONCLUSIONS: In children, dilated cardiomyopathy is a diverse disorder with outcomes that depend on cause, age, and cardiac failure status at presentation. Overt cardiac failure at presentation is a major prognostic factor for death or cardiac transplantation. Older age at presentation and metabolic aetiology may be associated with a poorer prognosis. PMID- 20849681 TI - Cardiovascular effects of edible oils: a comparison between four popular edible oils. AB - Edible oils form an essential part of the modern diet. These oils play a role as an energy source, and provide the diet with many beneficial micronutrients. Although a popular conception may be that fat should be avoided, certain edible oils as a dietary supplement may play an important role in the improvement of cardiovascular health. CVD has become one of the leading causes of death worldwide. Dietary supplementation with different oils may have beneficial effects on cardiovascular health. While olive oil and sunflower-seed oil are known to reduce serum cholesterol, fish oil has become well known for reducing potentially fatal cardiac arrhythmias. Recently, red palm oil research has shown beneficial effects on cardiac recovery from ischaemia-reperfusion injury. It is clear that dietary supplementation with edible oils may play a vital role in reducing the mortality rate due to heart disease. The specific benefits and disadvantages of these oils should, however, be explored in greater depth. The present review will attempt to identify the benefits and shortcomings of four popular edible oils, namely olive oil, sunflower-seed oil, fish oil and palm oil. Additionally the present review will aim to reveal potential areas of research which could further enhance our understanding of the effects of edible oils on cardiovascular health. PMID- 20849682 TI - Cognitive behaviour therapy for withdrawal from antidepressant medication: a single case series. AB - BACKGROUND: Research has clearly established the efficacy of pharmacotherapy and cognitive behaviour therapy (CBT) for depression. There is less literature addressing cessation of treatment, such as relapse during withdrawal from antidepressant medication. AIMS: The current study examines the role of psychological constructs that may influence relapse or fear of relapse and lead to resumption of medication. This hypothesizes that during withdrawal individuals may misinterpret normal variations in mood and dysphoric or other symptoms as reduced levels of medication in their bodies in keeping with a simplistic rationale for antidepressants. METHOD: The study uses an intensive single case AB style design in three cases during the withdrawal process. All participants had been treated with CBT plus antidepressants and had previously attempted to withdraw from antidepressants. The first part of the study naturalistically tracks belief changes as medication decreases; the second examines changes in these if/when a CBT intervention is introduced due to relapse or potential near relapse. Daily self-monitoring diaries were used to measure target variables, together with standardized questionnaires up to 6 months follow-up. RESULTS: Changes in symptoms, appraisal of symptoms, and beliefs about medication changed throughout the study. All participants remained medication free at 6 months follow-up. Two cases received CBT intervention due to possible relapse; the third underwent an unproblematic withdrawal. CONCLUSIONS: Patterns of change are discussed in terms of current approaches to medication cessation and the role of CBT during withdrawal. PMID- 20849683 TI - Performance of small general practices under the UK's Quality and Outcomes Framework. AB - BACKGROUND: Small general practices are often perceived to provide worse care than larger practices. AIM: To describe the comparative performance of small practices on the UK's pay-for-performance scheme, the Quality and Outcomes Framework. DESIGN OF STUDY: Longitudinal analysis (2004-2005 to 2006-2007) of quality scores for 48 clinical activities. SETTING: Family practices in England (n = 7502). METHOD: Comparison of performance of practices by list size, in terms of points scored in the pay-for-performance scheme, reported achievement rates, and population achievement rates (which allow for patients excluded from the scheme). RESULTS: In the first year of the pay-for-performance scheme, the smallest practices (those with fewer than 2000 patients) had the lowest median reported achievement rates, achieving the clinical targets for 83.8% of eligible patients. Performance generally improved for practices of all sizes over time, but the smallest practices improved at the fastest rate, and by year 3 had the highest median reported achievement rates (91.5%). This improvement was not achieved by additional exception reporting. There was more variation in performance among small practices than larger ones: practices with fewer than 3000 patients (20.1% of all practices in year 3), represented 46.7% of the highest-achieving 5% of practices and 45.1% of the lowest-achieving 5% of practices. CONCLUSION: Small practices were represented among both the best and the worst practices in terms of achievement of clinical quality targets. The effect of the pay-for-performance scheme appears to have been to reduce variation in performance, and to reduce the difference between large and small practices. PMID- 20849684 TI - The UK pay-for-performance programme in primary care: estimation of population mortality reduction. AB - BACKGROUND: General practices in the UK contract with the government to receive additional payments for high-quality primary care. Little is known about the resulting impact on population health. AIM: To estimate the potential reduction in population mortality from implementation of the pay-for-performance contract in England. DESIGN OF STUDY: Cross-sectional and modelling study. SETTING: Primary care in England. METHOD: Twenty-five clinical quality indicators in the contract had controlled trial evidence of mortality benefit. This was combined with condition prevalence, and the differences in performance before and after contract implementation, to estimate the potential mortality reduction per indicator. Improvement was adjusted for pre-existing trends where data were available. RESULTS: The 2004 contract potentially reduced mortality by 11 lives per 100 000 people (lower-upper estimates 7-16) over 1 year, as performance improved from baseline to the target for full incentive payment. If all eligible patients were treated, over and above the target, 56 (29-81) lives per 100 000 might have been saved. For the 2006 contract, mortality reduction was effectively zero, because new baseline performance for a typical practice had already exceeded the target performance for full payment. CONCLUSION: The contract may have delivered substantial health gain, but potential health gain was limited by performance targets for full payment being set lower than typical baseline performance. Information on both baseline performance and population health gain should inform decisions about future selection of indicators for pay-for performance schemes, and the level of performance at which full payment is triggered. PMID- 20849685 TI - Prodromal schizophrenia in primary care: a randomised sensitisation study. AB - BACKGROUND: GPs are often the first point of contact for patients with prodromal schizophrenia. Early intervention, and therefore early detection, of schizophrenia is pivotal for the further disease course. However, recent studies have revealed that, due to its low prevalence in general practice and its insidious features, prodromal schizophrenia often remains unnoticed. AIM: To test whether a repeated sensitisation method using clinical vignettes can improve diagnostic knowledge of GPs. DESIGN OF STUDY: Postal survey using anonymous questionnaires. Repeated sensitisation model using clinical vignettes. SETTING: GPs in three distinct regions in Switzerland covering a general population of 1.43 million. METHOD: The study was conducted between September 2008 and October 2009. Questionnaires were sent to 1138 GPs at baseline, and at 6 and 12 months. After randomisation, 591 GPs were sensitised at 1, 3, and 5 months, while no sensitisation was carried out in the remaining 547 GPs. RESULTS: The overall response rate was 66% (750 GPs). Sensitised GPs demonstrated a highly significant increase in diagnostic knowledge at 6 and at 12 months when compared to their own baseline knowledge scores and also to non-sensitised GPs (P<0.001). In particular, awareness of insidious features, such as functional decline and social withdrawal as signs of prodromal schizophrenia, accounted for this effect. CONCLUSION: Theoretical knowledge of prodromal schizophrenia among GPs can successfully be increased by repeated sensitisation models using clinical vignettes. PMID- 20849686 TI - GPs' attitudes, awareness, and practice regarding early diagnosis of dementia. AB - BACKGROUND: In primary care, the diagnosis of dementia is often delayed and the 2007 National Audit Office Report concluded action was needed to improve patient care and value for money. AIM: To investigate the attitudes, awareness, and practice of GPs in England regarding early diagnosis and management of patients with dementia, and perceptions of local specialist services, to identify training or support needs. DESIGN OF STUDY: Secondary analysis of survey data that capture the above attitudes, awareness, and practice. SETTING: Online survey, targeting GP members of medeConnect. METHOD: Survey data were obtained using an anonymised online self-completion questionnaire, and then analysed using standard data analysis software. RESULTS: A total of 1011 GPs across the eight English regions responded. Older GPs were more confident in diagnosing and giving advice about dementia, but less likely to feel that early diagnosis was beneficial, and more likely to feel that patients with dementia can be a drain on resources with little positive outcome. Younger GPs were more positive and felt that much could be done to improve quality of life. Attitudes had no correlation with sex. GPs in general felt they had not had sufficient basic and post-qualifying training in dementia, and overall knowledge about dementia was low. CONCLUSION: Much could be done to improve GPs' knowledge of dementia, and the confidence of older GPs could be an educational resource. However, greater experience may create scepticism about early diagnosis because of the perceived poor quality of specialist services. PMID- 20849687 TI - Positive predictive values of >=5% in primary care for cancer: systematic review. AB - BACKGROUND: The positive predictive value (PPV) for cancer of symptoms, signs, and non-diagnostic test results of patients routinely consulting a GP (unselected primary care populations) can help to determine when malignancy should be excluded. Comparisons with other illness indicate that a value of 5% or more may be regarded as highly predictive. AIM: To identify symptoms, signs, and non diagnostic test results in unselected primary care populations that are highly predictive of cancer. DESIGN OF STUDY: Systematic review. SETTING: Primary care. METHOD: Fourteen bibliographic databases were searched, using terms for primary care, cancer, and predictive values. Reference lists of relevant papers were hand searched. Data were extracted and the quality of each paper was assessed using predefined criteria, and checked by a second reviewer. RESULTS: Twenty-five studies were identified. PPVs of 5% or more in specific age and sex groups were reported for: rectal bleeding, change in bowel habit, and iron deficiency anaemia and colorectal cancer; haematuria and urological cancer; malignant rectal examination and prostate cancer; haemoptysis and lung cancer; dysphagia and oesophageal cancer; breast lump and breast cancer; and postmenopausal bleeding and gynaecological cancer. CONCLUSION: Robust evidence was found for eight symptoms, signs, and non-diagnostic test results as strongly indicative of cancer for specific age and sex groups in unselected primary care populations. These have the potential to improve the early diagnosis of some cancers in primary care by the use of computer warning flags, improved guidelines, audit, and appraisal. PMID- 20849689 TI - The White Paper: a framework for survival? PMID- 20849690 TI - Quality and Outcomes Framework: time to take stock. PMID- 20849691 TI - The predictive value of cancer symptoms in primary care. PMID- 20849692 TI - Time for a rethink of treatment for patients with depression in primary care. PMID- 20849693 TI - Patient characteristics correlated with quality indicator outcomes in diabetes care. AB - BACKGROUND: Quality indicators were adopted to compare quality of care across health systems. AIM: To evaluate whether patient characteristics influence primary care physicians' diabetes quality indicators. DESIGN OF STUDY: Retrospective cohort study. SETTING: Primary care setting. METHOD: The study was conducted in the Central District of Clalit Health Service in Israel. The five measures of diabetes follow-up were: the percentage of patients with diabetes for whom glycosylated haemoglobin (HbA(1c)), microalbumin, low-density lipoprotein (LDL)-cholesterol, and blood pressure were measured at least once, and the percentage of patients who were seen by an ophthalmologist, during 2005. Three outcome measures were chosen: the percentage of patients with diabetes and HbA(1c) <7 mg%, the percentage of patients with diabetes and blood pressure <130/80 mmHg, and the percentage of patients with diabetes and LDL-cholesterol <100 mg/dl in 2005. Sociodemographic information was retrieved about all the physicians' patients with diabetes. RESULTS: One-hundred and seventy primary care physicians took care of 18 316 patients with diabetes. The average number of patients with diabetes per physician was 107 (range 10-203). A lower quality indicator score for HbA(1c) <7 mg% was correlated with a higher percentage of patients of low socioeconomic status (P<0.001) and new immigrants (P = 0.002), and correlated with borderline significance with higher mean patients' body mass index (P = 0.024); lower quality indicator score for blood pressure <130/80 mmHg was related to higher patients' age (P = 0.006). None of the diabetes follow-up measures were related to patients' characteristics. CONCLUSION: Achieving good glycaemic control is dependent on patient characteristics. New immigrants, patients of low socioeconomic status, and older patients need special attention to avoid disparities. PMID- 20849694 TI - Are patients with dementia treated as well as patients without dementia for hypertension, diabetes, and hyperlipidaemia? AB - BACKGROUND: Patients suffering from dementia are at risk of being treated differently by GPs from patients without it. Explanations for this could be stigmatisation, treatment with a palliative approach, and the result of the disease process. AIM: To ascertain whether patients with dementia are treated differently, the index diseases of hypertension, diabetes, and hyperlipidaemia were used to measure care. DESIGN OF STUDY: Retrospective matched control study. SETTING: German general practice. METHOD: Sixteen GP practices recruited all their patients with dementia and at least one of the index diseases. Patients without dementia but only the index diseases were matched for age, sex, index disease, and practice, resulting in 216 pairs of patients with and without dementia. From the files, blood pressure, blood sugar/glycated haemoglobin, cholesterol, the dates of measurement, the number of doctor-patient contacts, and the prescribed medication to treat the three conditions under scrutiny were documented. For analysis, t-tests and chi(2)-tests were used. RESULTS: No differences were found in treatment outcomes between the two patients groups, except one significant difference: one of the two documented systolic blood pressure values is lower in the dementia group. Furthermore, patients with dementia more often do not receive any medication or are treated with low-priced medications for hypertension (nearly significant). CONCLUSION: GPs do not seem to treat patients with dementia differently. The use of lower-priced antihypertensive medication could be the only indication for some kind of difference in approach. PMID- 20849695 TI - Variability of office, 24-hour ambulatory, and self-monitored blood pressure measurements. AB - BACKGROUND: The diagnosis of hypertension is difficult when faced with several different blood pressure measurements in an individual. Using the average of several office measurements is recommended, although considerable uncertainty remains. Twenty-four-hour ambulatory monitoring is often considered the gold standard, but self-monitoring of blood pressure has been proposed as a superior method. AIM: Determination of within-individual variability of blood pressure measured in the office, by ambulatory monitoring, and by a week of self monitoring. DESIGN OF STUDY: Retrospective analysis of a clinical trial of 163 subjects. METHOD: Within-patient variability of office and ambulatory blood pressure was determined from measurements at 0 and 6 weeks. Subjects had performed self-monitoring of blood pressure twice each morning and evening, for at least 6 weeks; variability was determined from the means of week 1 and week 6. RESULTS: The within-individual coefficients of variation (CVs) for systolic blood pressure were: office, 8.6%; ambulatory, 5.5%; self, 4.2%. Equivalent values for diastolic blood pressure were 8.6%, 4.9%, and 3.9%. CVs tended to be lower with longer self-monitoring duration, and higher with longer intervals between self monitoring. CONCLUSION: Office blood pressure is impractical for precise assessment, as 10-13 measurements are required to give the accuracy required for rational titration of antihypertensive drugs. Twenty-four-hour ambulatory monitoring is better than a single office measurement, but considerable uncertainty remains around the estimate. A week of self-monitoring appears to be the most accurate method of measuring blood pressure, but remains imperfect. Further research may identify superior self-monitoring schedules. Given the inherent accuracy in blood pressure measurement, the importance of considering overall cardiovascular risk is emphasised. PMID- 20849696 TI - Two-week cancer referrals: what do you tell the patient? PMID- 20849699 TI - Patients' perceptions of hypertension management: a concern for healthcare practitioners. PMID- 20849698 TI - Asthma inhalers and colour coding: universal dots. PMID- 20849700 TI - Steroid treatment cards: patient safety remains at risk. PMID- 20849701 TI - New competencies ignored: general practice is in danger in Italy. PMID- 20849703 TI - MMR and egg allergy: to vaccinate or not to vaccinate? PMID- 20849704 TI - Smoking cessation. PMID- 20849706 TI - Physical activity promotion. PMID- 20849708 TI - The unethical use of BMI in contemporary general practice. PMID- 20849709 TI - Can GPs diagnose benign paroxysmal positional vertigo and does the Epley manoeuvre work in primary care? PMID- 20849712 TI - GP commissioning consortia: is there a role for physician assistants in routine care? PMID- 20849713 TI - Non epileptic motor phenomena in the newborn. PMID- 20849714 TI - [Effects of selective head cooling with mild hypothermia on serum levels of caspase-3 and IL-18 in neonates with hypoxic-ischemic encephalopathy]. AB - OBJECTIVE: The study examined the changes of serum caspase-3 and IL-8 levels following selective head cooling with mild hypothermia (SHC) treatment in neonates with hypoxic-ischemic encephalopathy (HIE) in order to explore the mechanism of neuroprotection of SHC against HIE. METHODS: Thirty-three neonates with moderate or severe HIE were randomly assigned to two groups: SHC treatment (n=16) and conventional treatment (n=17). Serum levels of caspase-3 and IL-18 were measured using ELISA before treatment and 24 hrs, 48 hrs, 72 hrs and 5 days after treatment. RESULTS: Serum caspase-3 levels in the SHC group decreased 24 and 48 hrs after treatment (3.8+/-1.9 and 2.6+/-1.2 ng/mL, respectively) compared with 6.1+/-2.3 ng/mL at 24 hrs and 7.2+/-3.1 ng/mL at 48 hrs in the conventional treatment group (P<0.05). Serum IL-18 levels in the SHC group decreased 24 hrs, 48 hrs and 72 hrs after treatment (119+/-30, 76+/-33 and 71+/-40 ng/mL, respectively) compared with those in the conventional treatment group (138+/-28 ng/mL at 24 hrs, 156+/-60 ng/mL at 48 hrs and 182+/-54 ng/mL at 72 hrs; P<0.01). CONCLUSIONS: SHC treatment can inhibit the release of caspase-3 and the expression of IL-18 in neonates with moderate or severe HIE. This may contribute to the neuroprotection of SHC against HIE. PMID- 20849715 TI - [Effects of probiotics on feeding intolerance in low birth weight premature infants]. AB - OBJECTIVE: To study the efficacy and safety of probiotics for the prevention of feeding intolerance in low birth weight (LBW) premature infants. METHODS: Sixty eligible LBW premature infants were randomly divided into probiotics and conventional treatment groups (n=30 each). Both groups received treatment of the primary disease. Additionally, the probiotics treatment group was administered with probiotics (0.25 g, twice daily). The incidence of feeding intolerance, the time to regain birth weight and to reach full enteral nutrition and the length of hospitalization were compared between the two groups. The occurrence of adverse reactions was recorded. RESULTS: The incidence of feeding intolerance in the probiotics treatment group was lower than that in the conventional treatment group (4% vs 14%; P<0.01). The time to regain birth weight (6.8+/-1.2 days vs 7.7+/-1.6 days; P<0.05) and the time to reach full enteral nutrition (8.0+/-1.4 days vs 9.0+/-2.0 days; P<0.05) in the probiotics treatment group were shorter than those in the conventional treatment group. No adverse reactions were observed in the probiotics treatment group. CONCLUSIONS: Probiotics can reduce the incidence of feeding intolerance in LBW premature infants, can promote weight gain and shorten the time to reach full enteral nutrition. The application of probiotics appears to be safe in LBW premature infants. PMID- 20849716 TI - [Bedside treatment of retinopathy of prematurity by laser photocoagulation]. AB - OBJECTIVE: To study the efficacy of bedside treatment by laser photocoagulation for retinopathy of prematurity (ROP) in preterm infants hospitalized in the Neonatal Intensive Care Unit (NICU). METHODS: The clinical data of 30 cases of ROP who underwent peripheral laser ablation on bedside in the NICU from March to August 2009 were studied retrospectively. RESULTS: A total of 59 eyes from 30 patients received the laser therapy, with a total cure rate of 95%. According to the International Classification of ROP, 26 eyes of 13 infants had zone 1 disease, and 33 eyes of 17 infants had zone 2 disease. The birth gestational age and birth weight as well as corrected gestational age and corrected weight at operation in the zone 1 disease group were significantly lower than those in the zone 2 disease group. The number of laser spots in the zone 1 disease group was significantly higher than that in the zone 2 disease group. The cure rate in the zone 2 disease group (100%) was significantly higher than that in the zone 1 disease group (88%). CONCLUSIONS: Laser retinal photocoagulation on bedside in the NICU is effective for both zone 1 and zone 2 ROP. As compared with the infants with zone 2 disease, the infants with zone 1 disease may have a poor outcome. PMID- 20849717 TI - [Clinical characteristics of neonatal Klebsiella pneumoniae sepsis and the antibiotic sensitivity pattern of strains]. AB - OBJECTIVE: To study the clinical characteristics of neonatal sepsis caused by Klebsiella pneumoniae and the antibiotic sensitivity pattern of Klebsiella pneumoniae strains. METHODS: The clinical data of 42 cases of neonatal sepsis caused by Klebsiella pneumoniae from January, 2000 to August, 2009 were retrospectively studied. RESULTS: The clinical presentations were non-specific, including fever or hypothermia, tachypnea, apnea and feeding intolerance. C reactive protein (CRP) level increased in 95% of the cases. The mortality was 21%. In neonates with early onset sepsis, Klebsiella pneumoniae strains were sensitive to amoxicillin/clavulanic-acid, piperacillin/tazobactam, cefoxitin, imipenem, cefoperazone/and sulbactam. In neonates with late onset sepsis, the sensitive antibiotics of Klebsiella pneumoniae strains were less, including cefoxitin, piperacillin/tazobactam and imipenem. Klebsiella pneumoniae strains were not sensitive to penicillins and cephalosporins in either neonates with early onset sepsis or late onset sepsis. The extended spectrum beta-lactamases (ESBLs)-producing strains were found in 92% of the cases. The neonates with late onset sepsis presented a higher prevalence of ESBLs-producing strains than those with early onset sepsis (100% vs 70%; P<0.05). CONCLUSIONS: The clinical manifestations of neonatal sepsis caused by Klebsiella pneumoniae are usually non specific. CRP detection is valuable for early diagnosis of sepsis. There are differences in the antibiotic sensitivity of strains between the neonates with early onset and late onset Klebsiella pneumoniae sepsis. PMID- 20849719 TI - [Surgical outcomes of pediatric symptomatic epilepsy and their influencing factors]. AB - OBJECTIVE: To investigate the surgical outcomes of pediatric symptomatic epilepsy and the influencing factors for postoperative outcomes. METHODS: A cohort of 48 children with symptomatic epilepsy received surgical treatment from October 2004 to September 2008. The surgical outcomes were followed up. RESULTS: A 27.3 months (range 12-51 months) follow-up was performed in 43 cases. Engel classification for evaluating postoperative epileptic outcomes showed that class I in 32 cases (74%), class II in 4 cases (9%), class III in 4 cases (9%) and class IV in 3 cases (7%). Preoperative seizure frequency is an independent predictor of postoperative epileptic outcomes (P<0.05). CONCLUSIONS: Operative treatment can lead to a favorable result in children with symptomatic epilepsy. Preoperative seizure frequency is an independent influencing factor for postoperative outcomes. PMID- 20849718 TI - [Clinical features of various subtypes of attention deficit hyperactivity disorders in children]. AB - OBJECTIVE: To study the features of various subtypes of attention deficit hyperactivity disorders (ADHD) in children. METHODS: Sex composition, risk factors, comorbidities, intelligence quotient and behavioral problems were investigated in 175 children with ADHD who met the Diagnostic Statistical Manual of Mental Disorder Criteria (DSM-IV). The children were classified into three groups: ADHD predominantly inattentive (ADHD-I, n=82), ADHD predominantly hyperactive-impulsive (ADHD-HI, n=24) and ADHD combined type (ADHD-C, n=69). RESULTS: There were no significant differences in the sex composition among the three groups. The rates of birth abnormality in the ADHD-I and the ADHD-C groups were higher than those in the ADHD-HI group. Negative parenting practices were noted more frequently in the ADHD-HI and the ADHD-C groups than the ADHD-I group. There were no significant differences in the performance intelligence quotient (PIQ), verbal intelligence quotient (VIQ) and full intelligence quotient (FIQ) among the three groups. However, the incidence of imbalance between VIQ and PIQ in the ADHD-I group was higher than the other two groups. The rate of comorbidities with oppositional defiant disorder (ODD) and tic disorder (TD) in the ADHD-C and the ADHD-HI groups was higher than that in the ADHD-I group. Both the ADHD-I and the ADHD-C groups had a higher rate of comorbidities with learning disorder (LD) than the ADHD-HI group. The impulsive/hyperactive and conduct problems were more severe and the hyperactivity index was higher in the ADHD-C and the ADHD-HI groups than those in the ADHD-I group, while the learning difficulties in the ADHD-I group were the most severe. CONCLUSIONS: The children with ADHD-C or ADHD-HI have higher incidences of comorbidities with ODD and TD than those with ADHD-I who the learning difficulties and the imbalance between VIQ and PIQ are more severe. PMID- 20849720 TI - [Clinical features of endogenous bronchial foreign bodies and application of bronchoscopy in children]. AB - OBJECTIVE: To study the clinical features of endogenous bronchial foreign bodies and the value of bronchoscopy in children. METHODS: One hundred and six children who presented lobe or lung segment atelectasis by the chest X-ray and bronchial foreign body inhalation was excluded by bronchoscopy were enrolled. The original diseases included Mycoplasma pneumonia (n=62), endobronchial tuberculosis (n=24), bronchial pneumonia (n=16), nephrotic syndrome (n=2), laryngotracheal bronchitis (n=1) and bronchiolitis (n=1). On the basis of conventional treatment of the original diseases, bronchoscopy was performed in the children. Eighty children with bronchial foreign body inhalation severed as the control group. RESULTS: Bronchoscopy showed the properties of endogenous foreign bodies: mucus emboli in 77 cases, cheese substances in 24 cases, dendritic white membrane in 4 cases, thrombosis in 1 case, and flaky pseudomembrane in 1 case. Hyperplasia of granulation tissue was seen in 25 cases. Of the 25 cases, endobronchial tuberculosis as the original disease was found in 22 cases. Mediastinal emphysema and pneumothorax occurred in 4 cases in the control group, but none in the endogenous foreign bodies group. The number of bronchoalveolar lavage by bronchoscopy in the endogenous foreign bodies group was significantly higher than that in the control group. CONCLUSIONS: Bronchoscopy is valuable in the diagnosis and treatment of endogenous bronchial foreign bodies. PMID- 20849721 TI - [Dynamical changes of lung function and immunologic markers in asthmatic children receiving specific immunotherapy with standardized house dust mite extract]. AB - OBJECTIVE: To study the effects of specific immunotherapy with standardized house dust mite extract on the lung function and immunologic markers in children with asthma. METHODS: Thirty-two children with mild to moderate asthma who were allergic to house dust mite were assigned to two groups: an immunotherapy group that received subcutaneous specific immunotherapy with standardized house dust mite extract beside glucocorticoids treatment (n=15) and a control group that received glucocorticoids treatment alone (n=17). Lung function was determined before treatment and 3, 6, 12, 18 and 24 months after treatment. The frequency of asthma attacks was observed before treatment and 12 and 24 months after treatment. Serum immunological markers, including total IgE, specific IgE and specific IgG4 against house dust mite (Dermatophagoides pteronyssinus, Der P), ECP, IL-10, IL-4, and IFN-gamma, were measured before treatment and 12 and 24 months after treatment. RESULTS: The parameters of lung function were kept at the normal level or near normal level after treatment in the immunotherapy group. Compared with before treatment, the percentage of patients without asthma attacks increased significantly after treatment in the immunotherapy group (P<0.05) and increased more significantly with a prolonged treatment time (P<0.05). The level of serum sIgG4 against Der P increased significantly throughout the period of the immunotherapy treatment compared with before treatment (P<0.01). There were no significant differences in the levels of serum total IgE, sIgE against Der P, ECP, IL-10, IL-4 and IFN-gamma before and after treatment in the immunotherapy group. There were no significant differences in all the parameters measured before and after treatment in the control group. CONCLUSIONS: Subcutaneous specific immunotherapy with standardized house dust mite extract for two years decreases the frequency of asthma attacks and the lung functions are kept in a normal level in children with asthma. The role of the specific immunotherapy may attribute to the increased level of serum sIgG4 against Der P. PMID- 20849722 TI - [Investigation of allergens in 3,504 children with allergic diseases]. AB - OBJECTIVE: To investigate the allergens of various allergic diseases in children. METHODS: Serum levels of Fx5E, Phadiatop and specific IgE were measured by the UniCAP100 System in 3 504 children with allergic diseases. RESULTS: The positive rate of aeroallergens was obviously higher than that of food allergens in children with allergic rhinitis, allergic conjunctivitis, asthma and papular urticaria. In contrast, the positive rate of food allergens was obviously higher than that of aeroallergens in children with Henoch-Schonlein purpura and digestive diseases. The serum specific IgE level of aeroallergens was higher than that of food allergens. The dust and mite specific IgE levels reached to grade 6, while the food allergen specific IgE levels were lower than grade 3. CONCLUSIONS: Aaeroallergens or food allergens vary remarkably in different allergic diseases in children. The level of specific IgE of aeroallergens is higher than that of food allergens. PMID- 20849723 TI - [Clinical analysis of vasovagal syncope in children]. AB - OBJECTIVE: To study the changes in clinical features of vasovagal syncope (VVS) in children. METHODS: From January 2000 to September 2009, 841 children with unexplained syncope or prodromata were enrolled. They were assigned to two groups according to the period of visiting hospital: group A (from January 2000 to December 2004, n=129) and group B (from January 2005 to September 2009, n=712). They were assigned to three age groups: 4-6 years old, 7-10 years old and 11-18 years old. A head-up tilt table test (HUTT) was performed on all the subjects. RESULTS: The total positive rate of HUTT was 45.3% (381/841). Compared with that in group A, the positive rate of HUTT in group B increased significantly (47.5% vs 33.3%; P<0.05). The positive rate of HUTT in female children was significantly higher than that in male children (49.3% vs 37.9%; P<0.05). The positive rate of HUTT increased with age and it was the highest in children at age of 11-18 years (49.2%), followed by in children at age of 7-10 years (44.1%) and 4-6 years (37.1%) (P<0.05). The children at age of 7-10 years and 11-18 years from group B showed significantly higher positive rate of HUTT than those from group A (46.2% vs 27.8%; 54.0% vs 32.6%, P<0.05). Vasodepressor type was the most common response type (70.9%) shown by HUTT compared with mixed type (25.5%) and cardioinhibitory type (3.6%) (P<0.05). The proportion of children with vasodepressor response type in group B was significantly higher than that in group A (72.5% vs 58.1%; P<0.05). CONCLUSIONS: There were obvious changes in the prevalence of VVS and response types before and after five years, suggesting that the development of VVS may be attributed to many factors, such as social factors, mental factor and life style. PMID- 20849724 TI - [Value of microbial gene 16SrRNA in the identification of antenatal infection]. AB - OBJECTIVE: To study the relationship between microbial gene 16SrRNA and intrauterine infection. METHODS: Thirty cases of single preterm birth were enrolled, including 16 cases due to premature rupture of membranes (PROM) (rupture time>18 hrs), 6 cases due to spontaneous preterm birth and 8 cases due to iatrogenic preterm birth. Ten cases of single term birth were used as the control group. Fetal membrane and placenta samples were obtained. Amniotic fluid, blood from cord or newborn babies as well as gastric fluid and tracheal secretions from infants with mechanical ventilation were also obtained. The histological features of placenta and fetal membranes were observed. Polymerase chain reaction (PCR) was used to detect the presence of microbial 16SrRNA and ureaplasma urealyticum (UU) in placenta, fetal membranes and other samples. RESULTS: Twenty-one (70%) cases were diagnosed as chorioamnionitis, characterized by neutrophil infiltration in fetal membrane and placenta tissues, especially in fetal membranes. Chorioamnionitis was most frequent in babies whose gestational age less than 32 weeks or birth weight lower than 1 500 g. Positive 16SrRNA gene was found in 12 cases, and positive UU gene in 10 cases in the preterm birth group. Neither 16SrRNA nor UU gene was detected in the control group. The PROM preterm babies developed more frequent infection than the babies premature born due to other causes, but there were no statistically significant differences in the incidence of infection. CONCLUSIONS: Chorioamnionitis may be the major cause of PROM and premature birth. The detection of microbial genes is valuable in identification of intrauterine infection. PMID- 20849725 TI - [Relationship between the polymorphism of growth hormone receptor Ex3 and the efficacy of rhGH treatment in children with idiopathic short stature]. AB - OBJECTIVE: To assess the influence of growth hormone receptor (GHR) Ex3 genotype on the short-term response to recombinant human growth hormone (rhGH) therapy in children with idiopathic short stature (ISS). METHODS: Thirty prepubertal children with ISS receiving rhGH treatment [0.116+/-0.02 IU/(kg/d)] were randomly recruited. The GHR Ex3 locus was genotyped using a PCR multiplex assay. The growth data including growth velocity, height SDS for chronological age (HtSDSCA), height SDS for bone age (HtSDSBA) and predict final height were compared in children with different GHR genotypes 6 months after rhGH treatment. RESULTS: After 6 months of rhGH treatment, the children with ISS carrying d3/d3 alleles showed a significantly higher increment in growth velocity than those carrying fl/fl alleles (6.3+/-1.6 cm/year vs 3.4+/-0.5 cm/year; P<0.05). CONCLUSIONS: The polymorphism in GHR Ex3 is associated with the responsiveness to rhGH treatment, showing that the growth velocity in ISS children with d3/d3 genotype is significantly higher than those with fl/fl genotype. PMID- 20849726 TI - [Meta analysis of lactic acid bacteria as probiotics for the primary prevention of infantile eczema]. AB - OBJECTIVE: To determine whether lactic acid bacteria as probiotics is efficacious in the primary prevention of infantile eczema or atopic eczema. METHODS: For this meta analysis of randomized controlled trials (RCT) describing the efficacy of probiotics in infants with eczema or atopic eczema at ages of <=2 years, a comprehensive search in the databases was performed up to January 2010. Three reviewers independently evaluated the studies for methodological qualities. RevMan 5.0.2 software was used for meta analysis. RESULTS: Twelve RCTs on the preventive effects of lactic acid bacteria as probiotics on infantile eczema were included, and 7 of the 12 RCTs reported the preventive effect of lactic acid bacteria on atopic eczema. The meta analysis showed that there was an overall significant reduction in infantile eczema and atopic eczema favoring lactic acid bacteria compared with placebo. The relative risk (RR) ratios for eczema and atopic eczema were 0.80 (95%CI: 0.70-0.90; P<0.01) and 0.78 (95%CI: 0.64-0.97; P<0.01), respectively. Lactic acid bacteria combined with other probiotics decreased significantly the incidence of eczema, with a RR ratio of 0.79 (95%CI: 0.68-0.93; P<0.01). The use of lactic acid bacteria alone did not result in a reduction in the incidence of eczema, with a RR ratio of 0.85 (95%CI: 0.69-1.05; P>0.05). CONCLUSIONS: The data from this meta analysis suggest that lactic acid probiotics combined with other probiotics play a role in the prevention of infantile eczema. There is insufficient evidence to recommend single use of lactic acid bacteria for prevention of eczema. Further studies are required to determine whether the findings are reproducible. PMID- 20849727 TI - [Effect of early high fat diet on pancreatic beta cellularity and insulin sensibility in young rats]. AB - OBJECTIVE: To study the effects of early high fat diet on sugar metaboliam, insulin sensibility and pancreatic beta cellularity in young rats. METHODS: Sixty male weaned young rats were randomly fed with high fat diet (high fat group) and normal diet (control group). The body weight, viscus fattiness and fasting plasma glucose (FPG) were measured after 3, 6 and 9 weeks. Serum insulin level was measured with radioimmunoassay. The ultrastructure of pancreas was observed under an electricmicroscope. RESULTS: The high fat group had significantly higher body weight and visceral fat weight than the control group after 3 weeks. There were no significant differences in the FPG level between the two groups at all time points. The levels of fasting insulin and HOMA?IR in the high fat group were significantly higher than those in the control group after 3, 6 and 9 weeks (P<0.01). Dilation of rough endoplasmic reticulum and mild swelling of mitochondria of islet beta-cells were observed in the high fat group after 6 weeks. CONCLUSIONS: Early high fat diet may induce a reduction in insulin sensitivity and produce insulin resistance in young rats. Endoplasmic reticulum expansion in beta-cells may be an early sign of beta-cell damage due to obesity. PMID- 20849728 TI - [Expression of cystathionine-gamma-lyase/hydrogen sulfide pathway in CVB3-induced myocarditis in mice]. AB - OBJECTIVE: Previous studies have shown that hydrogen sulfide (H2S) plays key roles in a number of biological processes, including vasorelaxation, inflammation, apoptosis, ischemia/reperfusion and oxidative stress, which are involved in the pathogenesis of myocarditis. This study aimed to examine the expression of cystathionine-gamma-lyase(CSE)/H2S pathway in mice with viral myocarditis. METHODS: Six-week-old inbred male mice were randomly assigned to control (n=25) and myocarditis group (n=30). The myocarditis and the control groups were inoculated intraperitoneally with 0.1 mL 10-5.69TCID50/mL CVB3 or vehicle (PBS) alone respectively. Ten mice were sacrificed 4 and 10 days after injection. Blood and heart specimens were harvested for measuring the content of serum H2S and the H2S production rates in cardiac tissues. Heart sections were stained with hematoxylin and eosin. Immunohistochemisty was used to detect the CSE protein expression in the heart. RESULTS: In the myocarditis group, the serum H2S content and H2S production rates in cardiac tissues were significantly higher than those in the control group 4 and 10 days after injection (P<0.05). The expression of CSE protein in the heart in the myocarditis group was also significantly higher than that in the control group (P<0.05). CONCLUSIONS: CSE and its downstream production H2S increase in mice with acute viral myocarditis. The increased expression of CSE/H2S pathway might be involved in the pathogenesis of viral myocarditis. PMID- 20849729 TI - [Lactulose use in bowel preparation before pediatric colonoscopy]. PMID- 20849730 TI - [Diagnosis and treatment of Henoch-Schonlein purpura complicated by intussusception: experience of 14 cases]. PMID- 20849731 TI - [Nenatal screening of inherited metabolic diseases: analysis of 5,400 cases]. PMID- 20849732 TI - [Bodily symptoms associated with mental disorders in two children]. PMID- 20849733 TI - [Mechanism of airway hyperresponsiveness in bronchial asthma]. PMID- 20849735 TI - Why WORLD NEUROSURGERY? Winds of change. PMID- 20849734 TI - Recombinant human growth hormone for the treatment of growth disorders in children: a systematic review and economic evaluation. AB - BACKGROUND: Recombinant human growth hormone (rhGH) is licensed for short stature associated with growth hormone deficiency (GHD), Turner syndrome (TS), Prader Willi syndrome (PWS), chronic renal insufficiency (CRI), short stature homeobox containing gene deficiency (SHOX-D) and being born small for gestational age (SGA). OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of rhGH compared with treatment strategies without rhGH for children with GHD, TS, PWS, CRI, SHOX-D and those born SGA. DATA SOURCES: The systematic review used a priori methods. Key databases were searched (e.g. MEDLINE, EMBASE, NHS Economic Evaluation Database and eight others) for relevant studies from their inception to June 2009. A decision-analytical model was developed to determine cost effectiveness in the UK. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers, and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. Quality of included studies was assessed using standard criteria, applied by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through a narrative review. RESULTS: Twenty-eight randomised controlled trials (RCTs) in 34 publications were included in the systematic review. GHD: Children in the rhGH group grew 2.7 cm/year faster than untreated children and had a statistically significantly higher height standard deviation score (HtSDS) after 1 year: -2.3 +/- 0.45 versus -2.8 +/- 0.45. TS: In one study, treated girls grew 9.3 cm more than untreated girls. In a study of younger children, the difference was 7.6 cm after 2 years. HtSDS values were statistically significantly higher in treated girls. PWS: Infants receiving rhGH for 1 year grew significantly taller (6.2 cm more) than those untreated. Two studies reported a statistically significant difference in HtSDS in favour of rhGH. CRI: rhGH-treated children in a 1-year study grew an average of 3.6 cm more than untreated children. HtSDS was statistically significantly higher in treated children in two studies. SGA: Criteria were amended to include children of 3+ years with no catch-up growth, with no reference to mid-parental height. Only one of the RCTs used the licensed dose; the others used higher doses. Adult height (AH) was approximately 4 cm higher in rhGH-treated patients in the one study to report this outcome, and AH-gain SDS was also statistically significantly higher in this group. Mean HtSDS was higher in treated than untreated patients in four other studies (significant in two). SHOX-D: After 2 years' treatment, children were approximately 6 cm taller than the control group and HtSDS was statistically significantly higher in treated children. The incremental cost per quality adjusted life-year (QALY) estimates of rhGH compared with no treatment were: 23,196 pounds for GHD, 39,460 pounds for TS, 135,311 pounds for PWS, 39,273 pounds for CRI, 33,079 pounds for SGA and 40,531 pounds for SHOX-D. The probability of treatment of each of the conditions being cost-effective at 30,000 pounds was: 95% for GHD, 19% for TS, 1% for PWS, 16% for CRI, 38% for SGA and 15% for SHOX-D. LIMITATIONS: Generally poorly reported studies, some of short duration. CONCLUSIONS: Statistically significantly larger HtSDS values were reported for rhGH-treated children with GHD, TS, PWS, CRI, SGA and SHOX-D. rhGH treated children with PWS also showed statistically significant improvements in body composition measures. Only treatment of GHD would be considered cost effective at a willingness-to-pay threshold of 20,000 to 30,000 pounds per QALY gained. This analysis suggests future research should include studies of longer than 2 years reporting near-final height or final adult height. PMID- 20849736 TI - Leadership, organizational concepts, and content. PMID- 20849737 TI - World neurosurgery: the emergence of a new global forum. PMID- 20849738 TI - World Neurosurgery and the World Federation of Neurosurgical Societies (WFNS). PMID- 20849759 TI - World neurosurgery: creating the kaleidoscope for needs and opportunities. PMID- 20849760 TI - The development of a calculator to predict the risk of rupture of unruptured intracranial aneurysms--@neuRisk. PMID- 20849761 TI - Concurrent intracranial and thoracic aortic aneurysms. PMID- 20849762 TI - The sunset of the CT scan? PMID- 20849763 TI - From standard treatment to personalized medicine: role of IDH1 mutations in low grade glioma evolution and treatment. PMID- 20849764 TI - Cancer, cerebrovascular diseases, and neurosurgery at the University of Sao Paulo. PMID- 20849765 TI - Does the dream of rewiring neurons become a picture of reality? PMID- 20849766 TI - The XIV World Congress of Neurosurgery: August 30-September 4, 2009, Boston, Massachusetts. PMID- 20849771 TI - Action Africa! AB - In Sub-Saharan Africa because of the prevailing economy, the equipping of neurological and neurosurgical services, as well the training of younger colleagues remains a recurrent problem. Therefore, all currently available resources ought to be mobilized and put together to obtain very rapid, short-term results. This is not a dream. The forces of the improvement of development lie in our hands. PMID- 20849772 TI - African neurosurgery, the 21st-century challenge. AB - Two major challenges facing African neurosurgery include quality and quantity, in both recourses and personnel. Discrepancy is noted between the two poles, namely, the north and south of the continent and the sub-Saharan area. Although reasonably advanced in the north and south, neurosurgery remains poorly distributed and has multiple deficiencies. The sub-Saharan region, where the demand is high and services are scarce, suffers from a similar lack of both qualified personnel and well-equipped neurosurgical facilities. Insufficient state funding and research facilities aggravate the situation and discourage the few well-trained African neurosurgeons to practice in their homeland. For those who do return home, cultural, social, economical, and political issues hinder their performance and hence the quality of neurosurgery delivered in Africa. Strategies for rectification of these handicaps are presented, including the need for high-standard local training and support from international organizations. PMID- 20849773 TI - Neurosurgery and global health: going far and fast, together. PMID- 20849774 TI - History of neurosurgery in Kenya, East Africa. AB - Neurosurgery, in one form or another, has a long tradition in Kenya. Early skull trepanations in Kenya were reported by previous studies, which reveal that these procedures have a long tradition, being passed down from generation to generation. Modern neurosurgical development in Kenya has its origins in the late 1940s when the first elective neurosurgical procedures were performed by Dr. J. F. Jarvis, Chief of Head and Neck Surgery at the now Kenyatta National Hospital, when he operated on anterior encephaloceles, and later also performed anterior third ventriculostomies for hydrocephalus. Formal neurosurgery developed from these initial steps, with the arrival of the first trained specialist, Dr. Renato Ruberti, whose pioneering efforts resulted in the founding of the Neurological Society of Kenya (NSK), the Pan African Association of Neurological Sciences (PAANS), and the African Federation of Neurosurgical Societies (AFNS). The last quarter of the 20th century has seen the progress of neurosurgery reach its present respectable levels, with dedicated and well-trained Kenyan neurosurgical specialists focusing not only on its practice but diligently pursuing its development. PMID- 20849775 TI - The pattern of neurosurgical disorders in rural northern Tanzania: a prospective hospital-based study. AB - BACKGROUND/OBJECTIVES: The prudent allocation of neurosurgical resources and training efforts requires an understanding of prevalence and clinical pattern of neurosurgical disorders in a particular region. The aim of our study was to assess the hospital-based prevalence of neurosurgical disease in the setting of rural sub-Saharan Africa. METHODS: The study was conducted at Haydom Lutheran Hospital in northern Tanzania. Over a period of 8 months, all patients suspected of having neurologic or neurosurgical disorders were seen by a neurologist in consecutive order. Patients were assessed clinically and with plain radiographs, a computed tomography scanner was not available. RESULTS: Of 8676 admissions, 151 patients (1.7%) were given a neurosurgical diagnosis. The most frequent diagnoses were traumatic brain injury (n=90), followed by tuberculosis of the spine (n=22), spina bifida (n=14), space-occupying cerebral lesion (n=13), and hydrocephalus (n=12). The overall mortality was 10.6%; it was especially high in patients with hydrocephalus (25%), space-occupying cerebral lesions (54%), and spina bifida (29%). CONCLUSIONS: Initial neurosurgical training and resource allocation in sub Saharan Africa should focus on neurotrauma, spinal infections, congenital malformations, and hydrocephalus. PMID- 20849776 TI - The consequence of delayed neurosurgical care at Tikur Anbessa Hospital, Addis Ababa, Ethiopia. AB - Tikur Anbessa Hospital (TAH) is the major teaching hospital for Addis Ababa University and the only tertiary referral hospital for neurosurgery in Ethiopia. We explore the consequence of delayed treatment by examining the current system in place for treating patients and the wait times experienced by patients. A retrospective chart review was carried out on patients who received a neurosurgical operation at TAH between January 1 and June 30, 2007. We divided patients into those requiring an elective procedure and those requiring emergency surgical care. Based on data entered in the chart, we determined the length of time from symptom onset to neurosurgical consultation and the time from consultation to receiving an operation. Selective cases were chosen to illustrate the effects of delayed care. A total of 172 neurosurgical operations were performed between January 1 and June 30, 2007, at TAH. Of these, 107 (62.2%) charts were available for retrospective review. Fifty-six elective cases were reviewed. The median time from symptom onset to neurosurgical consultation was 185 days. The median time from neurosurgical consultation to operation was 44 days. Fifty-one trauma/emergency surgical cases were reviewed. The median time from symptom onset or traumatic event to neurosurgical consultation was 3 days. The median time from neurosurgical consultation to operation was 1 day. Delayed neurosurgical care comes with a high personal and social cost. By measuring the time from diagnosis to treatment and taking note of institutional practices, changes can be initiated to improve patient waiting times. PMID- 20849777 TI - The African experience: a proposal to address the lack of access to neurosurgery in rural sub-Saharan Africa. AB - Restricted access to neurosurgical care in rural sub-Saharan Africa remains an unaddressed and formidable challenge. Despite the implementation of a rigorous 5 year curriculum to train and certify indigenous neurosurgeons "in continent" as Fellows of the College of Surgeons in Neurosurgery for East, Central, and Southern Africa (FCS-ecsa-NS), provincial and rural hospitals are likely to see no change in this woeful status quo for the foreseeable future. Modifying that curriculum with a two-tiered training experience that includes fast-track certification of general surgeons to perform basic neurosurgical procedures in their own hospitals is a viable alternative to redress this problem in a timely fashion. Founded on a competence-based as opposed to a time-served assessment of clinical/surgical skills along the lines of a 2002 landmark study in the United Kingdom, such an approach (in tandem with retaining separate FCS certification for prospective faculty in the NSTP-ECSA program) deserves urgent reconsideration. PMID- 20849778 TI - Impact of mobile endoscopy on neurosurgical development in East Africa. AB - Hydrocephalus, a disease frequently associated with poverty, becomes even more challenging to treat in developing regions because of lack of neurosurgical manpower, inadequately equipped public health care facilities, meager resource allocations, high rates of neonatal infection, difficulty of accessibility to hospitals able to treat hydrocephalus, and high complication rates in patients who are able to access and receive shunting procedures. Definitive treatment of hydrocephalus that avoids shunting procedures and long-term shunt dependence is a safer option. In environments such as Sub-Saharan Africa (and, indeed, in other similar resource-challenged regions), neuroendoscopic ventriculostomy (NEV), in appropriately selected patients can overcome the problems associated with shunting, including long-term shunt dependence. A novel approach promoted by volunteer neurosurgical teams from the Neurosurgery Education Development (NED) Foundation is described, and its important role in successfully providing NEV at hospitals in regional sites away from main tertiary referral hospitals is outlined. Using a single portable neuroendoscopy equipment system and a versatile free-hand, single operator neuroendoscope, an easily mobile outreach model has been successfully used to perform 187 procedures in 19 hospital sites around six countries and on two continents. Neuroendoscopy is not just a priority surgical tool for East Africa; it represents a best practices philosophy of what is possible within a highly sophisticated surgical speciality like neurosurgery in developing countries. It offers an opportunity to highlight the importance of tertiary care specialties like neurosurgery in this region, to develop closer relationships between African neurosurgeons and to convince medical students, general residents, and nurses that "world-class neurosurgery" can be possible in a developing region. PMID- 20849779 TI - Myelography as a stand-alone diagnostic procedure for degenerative spine disease in developing nations. AB - The use of "stand-alone" contrast myelography (i.e., without computed tomography) has a proven track record in developing nations where few patients have access to magnetic resonance imaging, whether on the basis of prohibitive cost or the absence of such a modality altogether. To substantiate the author's 12-year experience with more than 300 myelograms performed in 16 different countries (plus some 1500 studies during 30 years of practice in the United States), a prospective pilot study was undertaken over 1 month in a community-based neurosurgical setting in western Kenya. Forty patients underwent cervical or lumbar myelography at Tenwek Hospital under the auspices of the Neurosurgery Training Program for East, Central, and South Africa (NSTP-ECSA) following failure of conservative measures to treat spine-related pathology. Thirty-five of the forty patients (88%) came to definitive surgery on the basis of a positive study that correlated with their clinical history and physical examination. There were no significant complications from the procedures, and no false-positive studies, with virtually all patients returning to normal activity and/or gainful employment within 3 weeks of their surgery. Myelography as a stand-alone diagnostic procedure is a sensitive, specific, and cost-effective means of diagnosing symptomatic degenerative spine disorders. Accordingly, its use should be encouraged at every NSTP-ECSA training site to address such ubiquitous pathology. PMID- 20849780 TI - The Foundation for International Education in Neurological Surgery. AB - The Foundation for International Education in Neurological Surgery (FIENS) was established in 1969 for the purpose of promoting neurosurgical education and patient care in the developing world. Ghana, the first African site, was adopted in 1989. In 2005 a neurosurgical training program was developed for Ethiopia, Kenya, Tanzania, and Uganda in East Africa and the College of Surgeons of Central, East, and Southern Africa (COSECSA) approved the curriculum. PMID- 20849781 TI - Initial audit of a basic and emergency neurosurgical training program in rural Tanzania. AB - OBJECTIVE: As of 2006, only three formally trained neurosurgeons are licensed in Tanzania. Recently, efforts have increased toward training local Tanzanian physicians and assistant medical officers (AMOs) to meet the basic neurosurgical needs of nonurban areas. Between January and July 2006, an initial attempt at such an apprenticeship was undertaken with a locally trained AMO already performing general surgery at Haydom Lutheran Hospital, Tanzania. METHODS: Fifty one neurosurgical patients were identified and their patient charts were requested from the medical records office. Records were not available for 4 of the 51 patients for undeterminable reasons. RESULTS: The neurosurgical infrastructure at HLH is basic but adequate for a number of procedures. Cases performed included ventriculoperitoneal shunts, repair of myelomeningoceles, and burr holes and craniotomies for trauma and biopsies. Of 51 patients initially identified, 14 (27%) were confirmed deceased and 20 (39%) confirmed living. The remaining 17 (33%) were lost to follow-up. There were no significant differences in the mortality rates of patients receiving care from the American-trained neurosurgeon and those receiving care from the Tanzanian AMO trained and mentored by the American neurosurgeon. CONCLUSIONS: This initial audit provides support for the development of limited neurosurgery programs in underserved communities. Combined utilization of available neurosurgeons and continued training for available local clinicians may help to meet this need. PMID- 20849782 TI - Pediatric hydrocephalus in East Africa: prevalence, causes, treatments, and strategies for the future. AB - The burden of infant hydrocephalus in East Africa is significant, with more than 6000 new cases estimated per year. The majority is caused by neonatal infection, and should thus be preventable. With about 1 neurosurgeon per 10,000,000 people in East Africa, initial treatment for hydrocephalus is often unavailable. This also renders shunt dependence more dangerous in East Africa than in the developed world. Endoscopic third ventriculostomy combined with choroid plexus cauterization (ETV/CPC) has proven effective in avoiding shunt dependence in the majority of infants. Unlike shunts, most failures of endoscopic treatment are evident in the early months after surgery, with later failures being rare. Easily accessible clinical parameters can be used to predict the likelihood of success in a given patient. There appears to be no developmental advantage to shunt dependence compared to treatment by ETV/CPC. Cooperative efforts such as the East African Neurosurgical Research Collaboration are needed to broaden the scope of research and training needed to significantly reduce the morbidity and mortality of this disease. PMID- 20849783 TI - Surgical limits in transnasal approach to opticocarotid region and planum sphenoidale: an anatomic cadaveric study. PMID- 20849784 TI - Insufficiencies of osteoporotic compression fractures. PMID- 20849785 TI - Molecular imaging, part 1: apertures into the landscape of genomic medicine. AB - Conventional imaging paradigms rely on the detection of anatomical changes in disease that are preceded by molecular genetic changes that go otherwise undetected. With the advent of molecular imaging, it will be possible to detect these changes prior to the manifestation of disease. Molecular imaging is the amalgamation of molecular biology and imaging technology that was spawned by parallel advances in the two fields. Fundamental to this technique is the ability to directly image biological processes that precede the anatomical changes detected by conventional imaging techniques. The two main strategies for imaging of biologic processes are direct and indirect imaging techniques. Direct techniques use molecules that have specific affinities for targets of interest that can be radiolabeled or otherwise detected on imaging. Indirect imaging uses reporter genes that are coexpressed with therapeutic proteins or other proteins of interest to image vector-transfected cells. Optical imaging and nanotechnology paradigms will also prove to be important additions to the imaging armamentarium. The first installment of this two-part series on molecular imaging seeks to demonstrate basic principles and illustrative examples for the uninitiated neophyte to this field. PMID- 20849786 TI - Intracranial in situ side-to-side microvascular anastomosis: principles, operative technique, and applications. AB - OBJECTIVE: Side-to-Side microvascular anastomosis is a revascularization technique used to create an artificial conduit between two similar adjacent vessels. This technique is used for microsurgical clipping of aneurysms, when indicated. It is important to study the angiographic results, both immediate and long term, along with the clinical outcomes and indications of the procedure. METHODS: Fifteen patients who had this procedure over a fourteen-year period were reviewed for patency of bypass by intra-arterial digital subtraction angiography (DSA) and computed tomographic arteriograms (CTA) and their clinical outcomes were studied. The mean age of the study group was 53.4 years and mean angiographic follow up period was 14 months. RESULTS: All surviving patients (14 patients) had patent anastomosis with good clinical outcomes. None of the patients developed a clinically manifested stroke due to the procedure, while one had a small asymptomatic infarct detected post operatively. CONCLUSION: This technique is a useful and durable solution for correcting critical stenosis or complete occlusion of the vessels, while clipping intracranial aneurysms. PMID- 20849787 TI - Surgical limits in transnasal approach to opticocarotid region and planum sphenoidale: an anatomic cadaveric study. AB - BACKGROUND: The significance of medial and lateral opticocarotid recesses and the planum sphenoidale region in skull base pathologies for the transsphenoidal transplanum approach were evaluated. METHODS: The sphenoid bone block samples were extracted from adult cadavers. Dissections and measurements in the opticocarotid and planum sphenoidale regions were performed in 29 samples using a surgical microscope. For histologic evaluation, oblique sections through the bilateral opticocarotid regions were obtained and examined in eight samples. RESULTS: Optic, carotid prominences, and medial and lateral opticocarotid recesses can be identified as lateral markers intraoperatively to the extent of the exposure. The lateral opticocarotid recess was observed to be prominent in all samples. In all samples, the groove formed by optic and carotid prominences between the medial and lateral opticocarotid recesses was seen. This groove was designated the inter-recess sulcus. In the transsphenoidal-transplanum approach, the area needed for a reliable bone resection was measured as a mean of 237.32 +/ 30.96 mm(2). The mean angle between optic nerves was 115.41 +/- 18.39 degrees. The mean anteroposterior length of the planum sphenoidale was 14.84 +/- 1.52 mm. In histologic sections, collagenous ligaments between the anterior part of cavernous sinus and the adventitia layer of internal carotid artery were more frequent and regular than the inferior part of optic nerve. CONCLUSIONS: The lateral opticocarotid recess is a reliable and persistent indicator for extended transsphenoidal surgery. To approach the opticocarotid region near the internal carotid artery and optic nerve, a careful dissection is needed to minimize surgical injuries to the optic nerve and carotid artery. Other factors determining a reliable bone resection are the anteroposterior length of the planum sphenoidale and the distance and width of the angle between optic nerves. Attention should be given to individual anatomic variations of the region when planning and performing transsphenoidal-transplanum surgery. PMID- 20849788 TI - Intraoperative conversion from endoscopic to microscopic approach for the management of sellar pathology: incidence and rationale in a contemporary series. AB - BACKGROUND: The endoscopic transsphenoidal approach has become widely used for pituitary and extended skull base operations. Intraoperative conversion to a microscopic approach may be an important option in selected cases. We aim to characterize the operative situations in which such conversion occurred and facilitated the procedure. METHODS: From April 2008 through August 2009, 148 planned endoscopic transsphenoidal approaches were performed. All cases were retrospectively reviewed to identify those patients converted to a microscopic approach. Clinical and operative characteristics, reasons for conversion, and patient outcomes were reviewed. RESULTS: Of the 148 endoscopic cases, conversion was undertaken in 27 (18%). Ten patients (37%) had undergone previous transsphenoidal surgery. Reasons for conversion in nonreoperation cases were atypical nasal anatomy (6 patients), acromegaly with distorted anatomy (5 patients), desire for binocular vision (3 patients), complex sphenoid sinus anatomy and difficulty visualizing sella/midline (2 patients), and obstructive mucosal bleeding (1 patient). Of the 10 reoperation procedures, conversions occurred in 3 patients with Cushing's disease and 2 with acromegaly. The primary reasons for conversion in reoperations were scarring with loss of anatomic landmarks (4 patients), mucosal bleeding (2 patients), acromegaly with distorted anatomy (2 patients), technical problem with visualization (1 patient), and desire for binocular surgery (1 patient). CONCLUSIONS: Although endoscopic transsphenoidal surgery provides superior visualization in most patients, conversion to a microscopic or endoscopic-assisted approach may provide essential visualization in selected patients. This may be especially true in patients undergoing reoperation and patients with acromegaly or Cushing's disease. Trainees learning the endoscopic transsphenoidal approach should become familiar with the benefits and limitations of the various transsphenoidal approaches. PMID- 20849789 TI - Surgical, medical, and hardware adverse events in a series of 141 patients undergoing subthalamic deep brain stimulation for Parkinson disease. AB - BACKGROUND: Subthalamic deep brain stimulation has proved significant efficacy in the treatment of Parkinson disease. Adverse events, due to surgical and hardware related complications, must be clearly addressed to properly balance the cost effectiveness of the therapy. In addition, limited data exists about medical adverse events after surgery. METHODS: One hundred forty-one patients undergoing subthalamic deep brain stimulation for Parkinson disease from 1998 to 2007 were considered. Medical records, operative notes, clinical findings at follow-up and final outcome were accurately recorded to identify surgical- and hardware-related complications, infections and delayed adverse medical events. RESULTS: Five hundred twenty-two surgical procedures were performed, including electrodes positioning and impulse programmable generators implantation and substitutions. Mean follow-up of the patients was 4.6 years (9 months-10 years). Surgical complications were observed in 5.6% of patients, including two hemorrhages (1.4%) and three (2.1%) inabilities to complete the surgical procedure. Medical delayed adverse events affected 1.4% of patients, with a patient having a fatal aspiration pneumonia. Infections were seen in 5.6% of patients; removal of the hardware was necessary in 3.6%. Hardware-adverse events were observed in 7% of patients, generally requiring minor surgery. Direct surgical mortality was 0%; overall mortality was 0.7% and permanent surgical morbidity was 0.7%. CONCLUSIONS: Deep brain stimulation can be regarded as a safe procedure. Mortality and permanent morbidity are very low, and surgical complications are relatively rare. Nevertheless, minor complications are not infrequent; hence the importance of continuous monitoring of the patients during the follow-up period. PMID- 20849790 TI - Therapeutic strategies for patients with internal carotid or middle cerebral artery occlusion complicated by severe coronary artery disease. AB - BACKGROUND/OBJECTIVES: Ischemic stroke is one of major complications of cardiac surgery. Although a current American Heart Association (AHA) guideline states that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) for the carotid stenosis, there is no report that analyzed optimal strategies in cardiac surgery for patients with total occlusion of the internal carotid artery (ICA) or the middle cerebral artery (MCA). Therefore, this preliminary study was aimed to clarify whether preoperative blood flow measurements and prophylactic superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis could reduce the incidence of perioperative ischemic stroke during cardiac surgery in patients with total occlusion of the ICA or MCA. METHODS: This prospective study included eight patients who were admitted to undergo cardiac surgery including CABG. All of them had total ICA or MCA occlusion on preoperative magnetic resonance (MR) examinations. Preoperative cerebral blood flow and its reactivity to acetazolamide were quantitatively determined in all eight patients using single photon emission computed tomography or positron emission tomography. RESULTS: Preoperative blood flow measurements revealed that two (25%) of eight patients had normal cerebral hemodynamics because of well-developed collaterals. They safely underwent cardiac surgery. However, a marked impairment of cerebral perfusion reserve was identified in six (75%) of eight patients in the ipsilateral hemispheres. Of these, four patients underwent prophylactic STA-MCA anastomosis prior to CABG. Subsequently, they safely underwent CABG without perioperative ischemic stroke. CONCLUSION: This is the first report suggesting that preoperative identification of hemodynamic compromise and prophylactic STA MCA anastomosis may reduce perioperative ischemic stroke during cardiac surgery in patients with ICA or MCA occlusion, although further studies are needed to assess the validity. PMID- 20849791 TI - Cognitive function and anxiety before and after surgery for asymptomatic unruptured intracranial aneurysms in elderly patients. AB - BACKGROUND: The prevalence of patients with asymptomatic unruptured intracranial aneurysms (UIAs) will likely increase as the general population ages. The goal of the present study was to prospectively assess cognitive function and anxiety before and after surgical repair of asymptomatic UIAs in patients >= 70 years. METHODS: A total of 28 patients >= 70 years with UIAs underwent cognitive testing using the Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale (WMS), and the Rey-Osterrieth Complex Figure test (ROCF) 1 month before and 1 month after surgery. All patients also underwent anxiety testing at these time points using the State-Trait Anxiety Inventory. RESULTS: Group-rate analysis demonstrated that the performance intelligence quotient (IQ) and ROCF recall trial scores were significantly increased postoperatively, whereas there were no postoperative differences in verbal IQ, WMS, and ROCF copy trial scores. State anxiety scores were significantly decreased postoperatively, but there was no change in trait anxiety scores. Furthermore, a significant negative correlation was observed between changes in state anxiety scores and preoperative verbal IQ, performance IQ, and WMS. None of the patients developed postoperative cognitive functional impairments as demonstrated by event-rate analysis. CONCLUSIONS: Surgical treatment of UIAs does not impair cognitive function and results in improvement in state anxiety in elderly patients. PMID- 20849792 TI - Recovery of third nerve palsy following surgical clipping of posterior communicating artery aneurysms. AB - BACKGROUND: The objective of the study was to identify the predictors of improved third cranial nerve (CN III) function in patients who underwent surgical clipping for posterior communicating artery (PComA) aneurysms with varying degrees of CN III palsy at presentation. METHODS: We retrospectively evaluated the outcome of the CN III function in a series of 26 patients with CN III dysfunction due to PComA aneurysms that were treated by surgical clipping. RESULTS: CN III palsy was complete in 18 patients (69%) and partial in 8 patients (31%) at the time of admission. In 15 patients (58%), there was total improvement of CN III function. Partial improvement was noted in 5 patients (19%). Overall improvement (partial and total) of CN III function was observed in 20 (77%) of the 26 patients. The improvement in CN III function following early surgery (0-3 days) was 81.3% when compared to 75% when surgery was performed after 3 days. In univariate analysis, the only variable showing significant association with total improvement of CN III function was type of third nerve palsy at admission (complete vs partial) (P=.004). There was no statistical significant association between early surgery and improvement of CN III function (P=.722). In multivariate analysis, among all the factors, the type of third nerve palsy at presentation (complete and partial) was the significant predictor of the improved CN III function (P=.0038). CONCLUSION: Surgical clipping of the PComA aneurysm in patients with CN III palsy results in improvement of the CN III function in the majority of patients. The type of the CN III palsy at admission (complete/partial) is a significant predictor of complete improvement in CN III function. PMID- 20849793 TI - Effect of acute cocaine use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Although acute cocaine use has been correlated with aneurysmal subarachnoid hemorrhage, its effect on vasospasm and outcome is controversial. We investigated the effect of acute cocaine use on response to vasospasm treatment and neurologic outcome in patients with aneurysmal subarachnoid hemorrhage. METHODS: Data from 600 patients with aneurysmal subarachnoid hemorrhage admitted to the University of Illinois Medical Center in Chicago between June 2002 and July 2007 were retrospectively analyzed. Patients who were positive for cocaine on urine toxicology or admitted to cocaine use within 72 hours of admission were compared with control patients with no history of cocaine use. Patients with unknown or remote history were excluded. RESULTS: Of the 600 patients with aneurysmal subarachnoid hemorrhage, 27 (5%) were excluded. Thirty-one patients (5%) acutely used cocaine before admission. Cocaine users were younger than control (45.1 vs 54.1; P <= .0003), and were more likely to smoke tobacco, drink alcohol, and have renal dysfunction. There was no significant difference in Hunt Hess or Fisher grade. In univariate and multivariate analyses, there was no difference in unfavorable short-term outcome (modified Rankin scale > 3), incidence of symptomatic or radiologic vasospasm, stroke, or death. The number of interventional procedures for the treatment of vasospasm did not differ between the two groups. CONCLUSIONS: There is no significant difference in incidence of symptomatic vasospasm or neurologic outcome between cocaine users and nonusers. The severity of the vasospasm and the response to treatment, as indicated by the number of vasospasm interventions, did not differ between the two groups. PMID- 20849794 TI - Trends in the management of adult moyamoya disease in the United States: results of a nationwide survey. AB - BACKGROUND: Moyamoya disease is a rare, progressive, steno-occlusive disease of the distal branches of the carotid arteries associated with the development of a profuse basal collateral vascular network. In the United States, the disease occurs sporadically and literature on the topic in limited. With data lacking relative to moyamoya epidemiology and management, we report our survey results among a sample of neurovascular surgeons. METHODS: A 16-question survey was sent as a hyperlink by electronic mail to 46 vascular neurosurgery centers and physicians who have published on this topic. Data included patient demographics, referral patterns, treatment, and follow-up. RESULTS: Response rate was 70%. Of 32 respondents, 72% evaluated 10 or fewer adults per year, usually referred by a neurologist within their referral pattern. Fifteen (47%) respondents reported that the disease had a bilateral occurrence between 50% and 75% of the time. Most respondents (88%) reported that fewer than 25% of their patients had a previous surgery for the disease. Symptomatology (91%) was the criterion to recommend surgery. Nineteen (59%) respondents regularly assessed cerebrovascular reserve by the addition of acetazolamide challenge to their imaging method of choice, typically single photon emission computed tomography. Treatment was antiplatelets (55%) in asymptomatic adults and superficial temporal artery-to-middle cerebral artery bypass for >75% of symptomatic patients, as assessed by 48% of respondents. Yearly follow-up included cerebral angiography for both superficial temporal artery-to-middle cerebral artery bypass and indirect revascularization. CONCLUSIONS: Our survey results quantify epidemiologic trends of moyamoya disease in the United States. Finding a lack of consensus in management strategies, we conclude that collaborative efforts may help to create guidelines for the management of this puzzling entity. PMID- 20849795 TI - Multimodality treatment of intracranial dural arteriovenous fistulas in the Onyx era: a single center experience. AB - BACKGROUND: The results of treatment of intracranial dural arteriovenous fistulas (DAVFs) since Onyx became available as an embolic agent at our institution is reported. An algorithm is presented for treatment of DAVFs with Onyx, and the role of endovascular transvenous, surgical, and radiosurgical approaches are presented. METHODS: Thirty-two patients with DAVFs treated between November 2005 and November 2008 by endovascular embolization, surgery, or radiosurgery were identified by a retrospective chart review. Treatment strategies were based on the location or complexity of the fistula and the patient's clinical status. Data collected included DAVF characteristics, obliteration rates, complications, and outcomes. The results were analyzed and correlated with the treatment modality. RESULTS: Presenting symptoms were as follows: hemorrhage (n = 12 patients), headaches (n = 12), tinnitus (n = 5), orbital symptoms (n = 7), and seizures (n = 1). Thirty patients were treated by endovascular embolization (transarterial only with Onyx-21, transvenous only with platinum coils-6, transarterial [Onyx] and transvenous [coils]-3). Five patients (4 after incomplete/failed embolization) had surgical excision of the fistula. Three patients were treated with Gamma Knife radiosurgery (primary-1, 2 after incomplete/failed embolization). The locations of the fistulas were transverse sigmoid (10 patients), petrotentorial (7 patients), indirect carotid cavernous fistula (7 patients), parasagittal/falcine (3 patients), middle fossa dura (3 patients), torcula (1 patient), and anterior fossa dura (1 patient). The distribution of patients according to Borden classification was I-6, II-13, and III-13. Complete obliteration of the fistula was achieved in 26/32 (81%) patients after multimodal treatment. All surgical cases had complete obliteration. In the high-risk group with cortical venous reflux, 23/26 (89%) patients were cured. Endovascular complications included a stuck microcatheter tip with fracture of the tip in two patients and cranial nerves V and VII palsies in one patient. At last follow-up (range 1-36 months), 24 patients had modified Rankin score of 0-2, 5 patients had modified Rankin score of 3-5, and 3 patients were dead. Two patients died during admission due to the insult of the hemorrhage, and one died after an accidental fall with subsequent traumatic subdural hematoma. CONCLUSIONS: Multimodality treatment of DAVFs has high success rates for cure at our center. Transarterial embolization with Onyx has become the primary treatment for intracranial DAVFs at our center and is associated with high safety profile and efficacy. Transvenous coil embolization is still preferred in DAVFs with supply from arterial branches supplying cranial nerves, predominant internal carotid artery feeders and potential extracranial-intracranial collateral anastomosis. In our series, patients with incompletely treated DAVFs were treated with surgery and those with partially treated type I fistulas had radiosurgery for palliation. PMID- 20849796 TI - Preliminary use of the Leo stent in the endovascular treatment of wide-necked cerebral aneurysms. AB - BACKGROUND: Currently available stents for intracranial use usually are Neuroform (Boston Scientific/Target, Fremont, CA) and Leo (Balt, Montmorency, France) stents. We present the results of our initial experience in using the Leo stent to treat patients with wide-necked cerebral aneurysms. METHODS: Fifteen consecutive patients with wide-necked intracranial aneurysm were treated with a combined approach that consisted of delivery of a flexible self-expending neurovascular stent through a microcatheter to cover the neck of the aneurysm and subsequent filling of the aneurym with coils through the stent interstices. We assessed the clinical history, aneurysm dimensions, and technical details of the procedures, including any difficulties with stent deployment, degree of aneurysm occlusion, and complications. RESULTS: During a 1-year period, 15 patients with 17 broad-necked aneurysms (n = 13; average neck length, 5.1 mm; average aneruysm size, 9 mm) were treated with the Leo stent. Fifteen stents were deployed successfully; two failed. Of the coiled aneurysms, complete or subtotal (more than 95%) occlusion was achieved in 11 aneurysms, and partial occlusion was achieved in 2 aneurysms. One patient had multiple stents placed. One patient had a ruptured aneurysm at the time of treatment. Technical problems included difficulty in deploying the stent (n = 2). Two periprocedural thromboembolic complications occurred. One patient had palsy after thrombolysis was attempted. The other patient made an excellent functional recovery after undergoing successful thrombolysis of a thrombosed internal carotid artery stent. CONCLUSIONS: Preliminary data demonstrated that the Leo stent is useful device for the treatment of patients with wide-necked aneurysms. In cases with tortuous cerebral vasculature, delivery and deployment may be technically challenging. Clinically significant complications are uncommon. PMID- 20849797 TI - Clinical outcomes of endovascular treatment for intracranial pial arteriovenous fistulas. AB - BACKGROUND: Pial arteriovenous fistula is a rare disease and surgical treatment for these lesions is difficult. We present our clinical outcomes of endovascular treatment for intracranial pial arteriovenous fistula (AVF). METHODS: We reviewed the clinical and radiologic data of 16 patients with intracranial pial AVFs who were treated endovascularly at the Beijing Tiantan Hospital between 1998 and 2008. RESULTS: Six patients presented with intracranial hemorrhage, six presented with headaches, two with seizures, one with neurologic deficit, and one with transient ischemic attack. Cerebral angiograms showed that these pial AVFs were supplied by the middle cerebral artery (n = 6), the anterior cerebral artery (n = 4), the posterior cerebral artery (n = 3), the basilar artery (n = 2), and the inferoposterior cerebellar artery (n = 1). All AVFs were associated with large venous varices. One of the lesions had two associated feeding artery aneurysms. The venous drainage was deep in 11 lesions. All AVFs were embolized transarterially through the feeding arteries. Coils was used in 14 patients with a combination of liquid embolic agent (n-butyl cyanoacrylate and Onyx [Micro Therapeutics Inc., Irvine, CA]) in five patients; Onyx was used in three patients. Immediate complete angiographic obliteration was achieved in 13 patients. Three patients incompletely treated with coils showed complete obliteration at follow-up. Twelve patients experienced an angiographic and clinical cure without any complications at 3 months. Three patients (18.75%) experienced hydrocephalus after the procedure caused by venous thrombosis. Glasgow outcome scores were good in 15 patients (93.75%) and poor in 1 patient (6.2%) at follow-up. CONCLUSIONS: Transarterial embolization of the arterial feeders using coils and/or liquid embolic agents may be a good treatment for pial AVFs. Hydrocephalus caused by venous thrombosis is the main complication. PMID- 20849798 TI - MicroNester coils as an adjunct to endovascular embolization. AB - OBJECTIVES/BACKGROUND: In June 2003, detachable balloons were removed from the US market and were supplanted with coil embolization for parent artery sacrifice in difficult or nonsurgical aneurysms and other vascular pathologies. The current series examines the use of MicroNester pushable coils (Cook Medical, Bloomington, IN) as a low-cost and effective adjunct to detachable coils in the treatment of selected neurovascular pathologies. METHODS: A retrospective analysis of all patients undergoing neurointerventional procedures from November 2003 through May 2008 was performed to identify patients in whom MicroNester coils were used as part of treatment. Analysis of coil type and number as well as pathology was performed. RESULTS: MicroNesters were used in 26 cases, of which 21 were for arterial sacrifice--19 for the internal carotid artery and 2 for the vertebral artery. Fourteen were performed for intracranial aneurysms, 3 for pseudoaneurysms, 2 for carotid cavernous fistulae, 1 for a carotid blowout, and 1 for an arteriovenous malformation. Five additional procedures were transvenous, for treatment of dural arterial venous fistulae. The mean number of coils for artery sacrifice was 13, with an average of 10 MicroNesters. For transvenous embolizations, the means were 30 and 6, respectively. CONCLUSION: MicroNesters are not the coil of choice for most neurointerventional procedures because they are not retrievable. However, when parent artery sacrifice or transvenous occlusion of dural arteriovenous fistulas is the goal, MicroNesters are a relatively inexpensive and equally effective alternative to more expensive, detachable coils and can reduce the procedural costs by $3600 to $6000 for the current series. PMID- 20849799 TI - Early complications related to approach in thoracic and lumbar spine surgery: a single center prospective study. AB - BACKGROUND: Thoracic and lumbar spine surgical procedures are performed for a variety of pathologies. The literature consists of multiple retrospective reviews examining complication prevalence with the surgical treatment of these disorders. However, there is limited direct examination of perioperative complications through a prospective approach. Of the prospective assessments, the majority focuses on specific surgical procedures or provides a limited assessment of certain spinal implants. Prospective assessments of complication incidence in broad patient populations are limited. This article analyzes a prospectively collected database of patients who underwent a thoracic and/or lumbar spine surgery at a large tertiary care center and the effect of surgical approach (anterior or posterior) on the incidence of early complications. METHODS: Data collection was performed prospectively on 128 patients on the neurosurgical spine service at Thomas Jefferson University hospital from May to December 2008. Data on preoperative diagnosis, medical comorbidities, body mass index, surgical approach and procedure, length of stay, and complication occurrence was recorded and analyzed. Acute complications or adverse events occurring within the initial 30 days after each operative procedure were included. All medical adverse events were included as complications. A previously circumstantiated binary definition of major and minor complications was used to stratify the data. RESULTS: Overall, 76 of 128 patients (59.4%) in this cohort experienced at least one complication. Anterior thoracic and lumbar procedures had an 83.3% (5/6) incidence of complications. Of those patients having solely a posterior thoracic and lumbar procedures, 37 of 75 (49.3%) experienced at least one complication. Combined anterior and posterior surgical procedure had a complication incidence of 34 of 47 (72.3%). The mean number of complications reached significance for the minor and overall complications groups (P = .0076 and .0172, respectively, Poisson regression). Comparing the incidence of complications reveals the overall complications in the posterior alone group compared with the anterior/posterior combined group was significantly lower (P = .0134). Those undergoing instrumented fusions were statistically more likely to encounter complications (P < .001). CONCLUSIONS: There is a considerably higher complication incidence than previously reported for thoracic, thoracolumbar, and lumbar spine operations. A prospective approach and a broad definition of perioperative complications increased the recorded incidence of perioperative adverse events and complications. The case complexity of a tertiary referral center may also have escalated the increased incidence. Complications were more common in patients undergoing anterior and anterior/posterior procedures. PMID- 20849800 TI - Long-term outcome of cervical and thoracolumbar dural arteriovenous fistulas with emphasis on sensory disturbance and neuropathic pain. AB - BACKGROUND: Clinical features and prognosis of sensory disturbance in spinal dural arteriovenous fistula (SDAVF) have not been well documented. Here we report long-term outcomes and detailed sensory evaluations of surgically treated SDAVF, including 14 patients with the craniocervical fistulas. METHODS: Thirty-four consecutive patients with SDAVF treated at our institute during a period of 14 years were reviewed (mean age, 64.6 years; 67.6% men). Fistulas were located at the craniocervical junction in 14 patients (CC group) and in the thoracolumbar spine in 20 patients (TL group). In the CC group, six patients presented with subarachnoid hemorrhage. Fistulas were found incidentally in seven patients. One patient in the CC group and all patients in the TL group presented with progressive myelopathy. Most patients underwent microsurgery either alone (30 patients) or combined with embolization (3 patients). One patient was treated by embolization only. The follow-up ranged from 12 to 145 months (mean, 57 months). RESULTS: All but one patient in the CC group had excellent surgical outcome. Most patients in the TL group stabilized or improved neurologically. Shorter duration before treatment indicated better gait recovery. Important, a few patients in the TL group suffered worsening or development of new pain, as well as lesser degree of improvement in gait and micturition. Spinal cord atrophy was correlated with clinical deterioration. CONCLUSIONS: In craniocervical SDAVF, surgical treatment provides favorable long-term outcomes without risk of recurrence. In the thoracolumbar SDAVF, irreversible structural changes, such as spinal cord atrophy, may lead to poor recovery. Early diagnosis and treatment are thus warranted. PMID- 20849801 TI - Therapeutic efficacy of injectable calcium phosphate cement in osteoporotic vertebral compression fractures: prospective nonrandomized controlled study at 6 month follow-up. AB - BACKGROUND: Alternative biocompatible filler materials replacing polymethylmethacrylate (PMMA) cement have been introduced and clinically tested. Callos calcium phosphate cement (CPC) is one of them. A prospective nonrandomized controlled study was performed to assess the clinical and radiologic results after balloon kyphoplasty with Callos CPC in osteoporotic vertebral compression fractures. METHODS: Twenty-six patients were enrolled in this study. Clinical outcome was assessed using the Visual Analogue Scale (VAS) and the Oswestry Disability Index (ODI). The degree of vertebral height loss and changes in the kyphotic angle were measured using plain-film x-rays. Blood tests were carried in all cases out to observe the variation in postoperative serum calcium levels. RESULTS: The VAS and ODI scores decreased from 7.5 +/- 1.1 to 2.2 +/- 1.4 (P = .000) and from 31.7 +/- 1.6 to 16.9 +/- 1.7 (P = .000), respectively. Although vertebral height loss (M = 25.4% +/- 17.4%) was reduced after the operation (M=22.1% +/- 15.3%, P = .002), recurrent progression of height loss was observed during the follow-up (M = 32.7% +/- 19.6%, P = .001). The kyphotic angle (M = 8.1 degrees +/- 4.8 degrees ) did not significantly change postoperatively (M = 8.7 degrees +/- 5.5 degrees , P = .350), and the serum calcium level was within normal ranges. CPC leakage to the spinal canal was observed in 15 cases (48.4%), and none of them presented any related clinical symptoms except one patient, who had transient intercostal neuralgia. CONCLUSIONS: Subsequent loss of augmentation properties during follow-up is a serious problem of kyphoplasty using injectable CPC in osteoporotic vertebral compression fractures. The clinical use of injectable CPC in kyphoplasty should be reconsidered. PMID- 20849802 TI - Intraventricular hemorrhage as an unusual presenting form of Sneddon syndrome. AB - BACKGROUND: Intraventricular hemorrhage, which has a poor prognosis, is an extremely rare presenting symptom of central nervous system vasculitis. Sneddon syndrome, which is a systemic vasculitic disease, generally presents with ischemic stroke and livedo reticularis. Intraventricular hemorrhage is extremely rare in Sneddon syndrome and has not been reported as the presenting complaint. METHODS: We report a 37-year-old woman who presented with acute intraventricular hemorrhage, and on further evaluation her condition was diagnosed as Sneddon syndrome. RESULTS: Patient underwent ventriculoperitoneal shunting operation for hydrocephalus and her condition markedly improved 6 months later; she was independent in her activities of daily living. CONCLUSIONS: In this report, we emphasize the importance of multisystemic evaluation of patients, especially those with obscure angiography findings. PMID- 20849803 TI - Glossopharyngeal neuralgia treated with gamma knife radiosurgery. AB - BACKGROUND: Although gamma knife radiosurgery is an established treatment option for trigeminal neuralgia, its role in the management of glossopharyngeal neuralgia is unclear. We report a case of glosspharyngeal neuralgia treated effectively with gamma knife radiosurgery, review the literature, and discuss the rationale supporting dose and target selection. CASE DESCRIPTION: A 47-year-old woman presented with persistent lancinating pain to the left throat, which was refractory to medical therapy. She declined a microvascular decompression and instead chose stereotactic radiosurgery. Gamma knife radiosurgery to the glossopharyngeal nerve at the glossopharyngeal meatus was used, and a maximum dose 80 Gy was delivered. She was pain-free off medications 1 month after the procedure and remains pain-free 11 months. There were no adverse neurologic effects attributable to the procedure. CONCLUSIONS: This clinical response provides encouraging evidence for the treatment of glossopharyngeal neuralgia with stereotactic radiosurgery and is consistent with previous reports. Further investigation is needed to define the role of stereotactic radiosurgery in the management of glossopharyngeal neuralgia. PMID- 20849804 TI - Indigenous customized sponge shunt for a recurrent brainstem cyst. AB - BACKGROUND: Various treatment modalities are available for treatment of cystic lesions of the brainstem. However, cyst refilling and recurrences are very common. This article describes a young boy who presented with an intra-axial brainstem cyst following radiation for a pilocytic astrocytoma. METHODS: The cyst was decompressed surgically once but it soon refilled. The use of a novel customized synthetic sponge acting as a shunt for the treatment of a cystic brainstem lesion is discussed. The sponge was fashioned like a dumbbell and inserted across the fenestration in the cyst wall. RESULTS: The dumbbell design made it self-retaining. The characteristics of the sponge permitted continuous capillary drainage, with a low risk of occlusion. There was a dramatic decrease in the cyst size on follow-up scans, with resolution of clinical deficits. CONCLUSIONS: A customized sponge shunt can serve as an easily available and effective internal shunt for intra-axial craniospinal cysts. PMID- 20849806 TI - Identification of plant tissues from the gut of Phlebotomus papatasi by DNA analysis. AB - Sugar and cellulose assays can determine if an insect has fed on sugar and plant tissue but they cannot identify the species of source plant. In this study, we used DNA analysis together with traditional cellulose and sugar assays to examine the plant feeding habits of wild Phlebotomus papatasi during the dry season in the Lower Jordan Valley, Israel. About 37% of the sand flies were positive for sugar, 45% were positive for cellulose in the gut, and 41% contained amplifiable plant DNA. All of the plant DNA fragments sequenced from both males and females were identified as Suaeda asphaltica. PMID- 20849805 TI - Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. AB - BACKGROUND & AIMS: Patients with cirrhosis and minimal hepatic encephalopathy (MHE) have driving difficulties but the effects of therapy on driving performance is unclear. We evaluated whether performance on a driving simulator improves in patients with MHE after treatment with rifaximin. METHODS: Patients with MHE who were current drivers were randomly assigned to placebo or rifaximin groups and followed up for 8 weeks (n = 42). Patients underwent driving simulation (driving and navigation tasks) at the start (baseline) and end of the study. We evaluated patients' cognitive abilities, quality of life (using the Sickness Impact Profile), serum levels of ammonia, levels of inflammatory cytokines, and model for end-stage-liver disease scores. The primary outcome was the percentage of patients who improved in driving performance, calculated as follows: total driving errors = speeding + illegal turns + collisions. RESULTS: Over the 8-week study period, patients given rifaximin made significantly greater improvements than those given placebo in avoiding total driving errors (76% vs 31%; P = .013), speeding (81% vs 33%; P = .005), and illegal turns (62% vs 19%; P = .01). Of patients given rifaximin, 91% improved their cognitive performance, compared with 61% of patients given placebo (P = .01); they also made improvements in the psychosocial dimension of the Sickness Impact Profile compared with the placebo group (P = .04). Adherence to the assigned drug averaged 92%. Neither group had changes in ammonia levels or model for end-stage-liver disease scores, but patients in the rifaximin group had increased levels of the anti-inflammatory cytokine interleukin-10. CONCLUSIONS: Patients with MHE significantly improve driving simulator performance after treatment with rifaximin, compared with placebo. PMID- 20849807 TI - Selection of reference genes for gene expression studies in astrocytomas. AB - This study was aimed to test a panel of six housekeeping genes (GAPDH, HPRT1, POLR2A, RPLP0, ACTB, and H3F) so as to identify and validate the most suitable reference genes for expression studies in astrocytomas. GAPDH was the most stable and HPRT1 was the least stable reference gene. The effect of reference gene selection on quantitative real-time polymerase chain reaction data interpretation was demonstrated, normalizing the expression data of a selected gene of interest. Thus, GAPDH may be recommended for data normalization in gene expression studies in astrocytomas. Nevertheless, a preliminary validation of reference gene stability is required prior to every study. PMID- 20849808 TI - Direct detection of acetylcholinesterase inhibitor binding with an enzyme-based surface plasmon resonance sensor. AB - Acetylcholinesterase (AChE) inhibitors are potentially lethal but also have applications as therapeutic drugs for neurodegenerative diseases such as Alzheimer's. Enzyme inhibitor binding are difficult to be detected directly by surface plasmon resonance (SPR) due to their small molecular weight. In this article, we describe the detection of AChE inhibitor binding by SPR without the use of competitive binding or antibodies. AChE was immobilized on the gold surface of an SPR sensor through covalent attachment to a self-assembled monolayer (SAM) of a COOH-terminated alkanethiol. The activity of the immobilized protein and the surface density were determined by using a standard photometric assay. Binding of two reversible inhibitors, which are used as therapeutic drugs, was detectable by SPR without the need to further modify the surface or the use of other reagents. The binding affinities (K(A)) obtained from the fits were 3.8 * 10(3)M(-1) for neostigmine and 1.7 * 10(3)M(-1) for eserine, showing a higher affinity of the sensor for neostigmine. We believe that the SPR sensor's ability to detect these inhibitors is due to conformational changes of the enzyme structure on inhibitor binding. PMID- 20849809 TI - Multiplexed protease assays using element-tagged substrates. AB - Inductively coupled plasma-mass spectrometry (ICP-MS)-based assays lend themselves to multiplexing due to the high resolution between mass channels, the sensitivity, and the reliability of the technique. Here the potential of ICP-MS based protease assays is demonstrated with a quadruplex assay of cysteine proteases and metalloproteases. Four orthogonal peptide substrates were synthesized for the proteases calpain-1, caspase-3, matrix metalloprotease-9 (MMP 9), and a disintegrin and metalloprotease-10 (ADAM10). Each substrate carries a biotin tag at the C terminus and a diethylenetriaminepentaacetic acid (DTPA) based lanthanide complex at the N terminus. The results demonstrate that this is a simple and reproducible analysis technique with excellent correlation between the single and multiplex assay formats. PMID- 20849810 TI - Oxidative phosphorylation in cancer cells. AB - Evidence suggests that mitochondrial metabolism may play a key role in controlling cancer cells life and proliferation. Recent evidence also indicates how the altered contribution of these organelles to metabolism and the resistance of cancer mitochondria against apoptosis-associated permeabilization are closely related. The hallmarks of cancer growth, increased glycolysis and lactate production in tumours, have raised attention due to recent observations suggesting a wide spectrum of oxidative phosphorylation deficit and decreased availability of ATP associated with malignancies and tumour cell expansion. More specifically, alteration in signal transduction pathways directly affects mitochondrial proteins playing critical roles in controlling the membrane potential as UCP2 and components of both MPTP and oxphos complexes, or in controlling cells life and death as the Bcl-2 proteins family. Moreover, since mitochondrial bioenergetics and dynamics, are also involved in processes of cells life and death, proper regulation of these mitochondrial functions is crucial for tumours to grow. Therefore a better understanding of the key pathophysiological differences between mitochondria in cancer cells and in their non-cancer surrounding tissue is crucial to the finding of tools interfering with these peculiar tumour mitochondrial functions and will disclose novel approaches for the prevention and treatment of malignant diseases. Here, we review the peculiarity of tumour mitochondrial bioenergetics and the mode it is linked to the cell metabolism, providing a short overview of the evidence accumulated so far, but highlighting the more recent advances. PMID- 20849811 TI - Impact of the biofilm mode of growth on the inner membrane phospholipid composition and lipid domains in Pseudomonas aeruginosa. AB - Many studies using genetic and proteomic approaches have revealed phenotypic differences between planktonic and sessile bacteria but the mechanisms of biofilm formation and the switch between the two growth modes are not well understood yet. In this study, we focused on inner membrane lipidome modifications when Pseudomonas aeruginosa cells were grown as biofilm. Lipid analyses were performed by Electrospray Ionization Mass Spectrometry. Results showed a drastic decrease of the uneven-numbered chain phospholipids and a slight increase of long chain PEs in sessile organisms as compared with planktonic counterparts, suggesting a better lipid stability in the bilayer and a decrease in membrane fluidity. The impact of sessile growth on lipid domains was then investigated by Brewster Angle Microscopy (BAM) and Atomic Force Microscopy (AFM). Observations showed that inner membrane lipids of P. aeruginosa formed domains when the pressure was close to physiological conditions and that these domains were larger for lipids extracted from biofilm bacteria. This is coherent with the mass spectrometry analyses. PMID- 20849812 TI - Arabidopsis DREB2C functions as a transcriptional activator of HsfA3 during the heat stress response. AB - The dehydration-responsive element binding protein (DREB) family is important in regulating plant responses to abiotic stresses. DREB2C is one of the Arabidopsis class 2 DREBs and is induced by heat stress (HS). Here, we present data concerning the interaction of DREB2C with heat shock factor A3 (HsfA3) in the HS signal transduction cascade. RT-PCR showed that HsfA3 is the most up-regulated gene among the 21 Arabidopsis Hsfs in transgenic plants over-expressing DREB2C. DREB2C and HsfA3 displayed similar transcription patterns in response to HS and DREB2C specifically transactivated the DRE-dependent transcription of HsfA3 in Arabidopsis mesophyll protoplasts. Yeast one-hybrid assays and invitro electrophoretic mobility shift assays further showed that DREB2C interacts with two DREs located in the HsfA3 promoter with a binding preference for the distal DRE2. Deletion mutants of DREB2C indicated that transactivation activity was located in the C-terminal region. In addition, dual activator-reporter assays showed that the induction of heat shock protein (Hsp) genes in transgenic plants could be attributed to the transcriptional activity of HsfA3. Taken together, these results indicate that DREB2C and HsfA3 are key players in regulating the heat tolerance of Arabidopsis. PMID- 20849813 TI - Prolyl hydroxylase 3 interacts with Bcl-2 to regulate doxorubicin-induced apoptosis in H9c2 cells. AB - Prolyl hydroxylases (PHDs) are dioxygenases that use oxygen as a co-substrate to hydroxylate proline residues. Three PHD isoforms (PHD1, PHD2 and PHD3) have been identified in mammalian cells. PHD3 expression is upregulated in some cardiac diseases such as cardiomyopathy, myocardial ischemia-reperfusion injury and congestive heart failure, all of which are associated with apoptosis. However, the role of PHDs in cardiomyocyte apoptosis remains unknown. Here, we have found that exposure of embryonic rat heart-derived H9c2 cells to doxorubicin (DOX) induced cell apoptosis as evaluated by caspase-3/7 activity, mitochondrial membrane potential (Deltapsim) and cell viability, and that this apoptosis was linked to PHD3 upregulation. PHD inhibition or PHD3 silencing substantially ameliorated DOX-induced apoptosis, but PHD1 or PHD2 knockdown did not significantly influence apoptosis. Furthermore, immunoprecipitation experiments showed that PHD3 upregulation reduced the formation of the Bax-Bcl-2 complex, inhibiting the anti-apoptotic effect of Bcl-2. Thus, PHD3 upregulation may be partially responsible for DOX-induced cardiomyocyte apoptosis via its interaction with Bcl-2. Inhibition of PHD3 is likely to be cardioprotective against apoptosis in some heart disorders. PMID- 20849814 TI - Reduction in hepatic drug metabolizing CYP3A4 activities caused by P450 oxidoreductase mutations identified in patients with disordered steroid metabolism. AB - Cytochrome P450 3A4 (CYP3A4), the major P450 present in human liver metabolizes approximately half the drugs in clinical use and requires electrons supplied from NADPH through NADPH-P450 reductase (POR, CPR). Mutations in human POR cause a rare form of congenital adrenal hyperplasia from diminished activities of steroid metabolizing P450s. In this study we examined the effect of mutations in POR on CYP3A4 activity. We used purified preparations of wild type and mutant human POR and in vitro reconstitution with purified CYP3A4 to perform kinetic studies. We are reporting that mutations in POR identified in patients with disordered steroidogenesis/Antley-Bixler syndrome (ABS) may reduce CYP3A4 activity, potentially affecting drug metabolism in individuals carrying mutant POR alleles. POR mutants Y181D, A457H, Y459H, V492E and R616X had more than 99% loss of CYP3A4 activity, while POR mutations A287P, C569Y and V608F lost 60-85% activity. Loss of CYP3A4 activity may result in increased risk of drug toxicities and adverse drug reactions in patients with POR mutations. PMID- 20849816 TI - The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets. AB - An appropriate regulation of the insulin production and secretion in pancreatic beta-cells is necessary for the control of blood glucose homeostasis. The pancreatic duodenal homeobox factor-1 (Pdx-1) is among the various factors and signals which are implicated in the regulation of the insulin synthesis and secretion in the pancreatic beta-cells. Recently, we identified Pdx-1 as a substrate for protein kinase CK2. Since CK2 is implicated in the regulation of many different cellular signaling pathways we now asked whether it might also be involved in the regulation of the insulin regulation in beta-cells. Here, we show that insulin treatment of beta-cells resulted in an elevated CK2 kinase activity. On the other hand down-regulation of CK2 activity by quinalizarin led to an elevated level of insulin. These results demonstrate that CK2 is implicated in the insulin regulation on pancreatic beta-cells. PMID- 20849815 TI - Crosstalk between insulin receptor and G protein-coupled receptor signaling systems leads to Ca2+ oscillations in pancreatic cancer PANC-1 cells. AB - We examined crosstalk between the insulin receptor and G protein-coupled receptor (GPCR) signaling pathways in individual human pancreatic cancer PANC-1 cells. Treatment of cells with insulin (10 ng/ml) for 5 min markedly enhanced the proportion of cells that display an increase in intracellular [Ca2+] induced by picomolar concentrations of the GPCR agonist neurotensin. Interestingly, insulin increased the proportion of a subpopulation of cells that exhibit intracellular [Ca2+] oscillations in response to neurotensin at concentrations as low as 50-200 pM. Insulin enhanced GPCR-induced Ca2+ signaling in a time- and dose-dependent manner; a marked potentiation was obtained after an exposure to a concentration of 10 ng/ml for 5 min. Treatment with the mTORC1 inhibitor rapamycin abrogated the increase in GPCR-induced [Ca2+](i) oscillations produced by insulin. Our results identify a novel aspect in the crosstalk between insulin receptor and GPCR signaling systems in pancreatic cancer cells, namely that insulin increases the number of [Ca2+](i) oscillating cells induced by physiological concentrations of GPCR agonists through an mTORC1-dependent pathway. PMID- 20849817 TI - Three new powerful oseltamivir derivatives for inhibiting the neuraminidase of influenza virus. AB - Owing to its unique function in assisting the release of newly formed virus particles from the surface of an infected cell, neuraminidase, an antigenic glycoprotein enzyme, is a main target for drug design against influenza viruses. The group-1 neuraminidase of influenza virus possesses a 150-cavity, which is adjacent to the active pocket, and which renders conformational change from the 'open' form to the 'closed' form when the enzyme is binding with a ligand. Using AutoGrow evolutionary algorithm, one very unique fragment is screened out from the fragment databases by exploiting additional interactions with the 150-cavity. Subsequently, three derivatives were constructed by linking the unique fragment to oseltamivir at its three different sites. The three derivatives thus formed show much stronger inhibition power than oseltamivir, and hence may become excellent candidates for developing new and more powerful drugs for treating influenza. Or at the very least, the findings may stimulate new strategy or provide useful insights for working on the target vitally important to the health of human beings. PMID- 20849818 TI - Trafficking of amyloid beta-precursor protein products C83 and C99 on the endocytic pathway. AB - Amyloid beta-precursor protein (APP) proteolytic products C83 and C99 are substrates for gamma-secretase as well as products, respectively, of alpha- or beta-secretase. In contrast to APP, C83 and C99 were derivatized by a water soluble biotinylation reagent to a much greater extent at 18 degrees C than at 0 degrees C in CHO cells expressing the Swedish mutant form of APP750. Intracellular C99 and C83 cycle to the cell surface when maintained in buffered saline at 18 degrees C thus identifying proteins derivatized at 18 degrees C as residing in recycling compartments. More than 80% of C99 and C83 biotinylated at 18 degrees C is associated with detergent resistant membrane (DRM). There thus appears to be no differential distribution of alpha- or beta-secretase products into the DRM fraction that would be expected if localization to DRM determines alternative secretase pathways. gamma-Secretase inhibitors increased the fraction of C99 but not C83 in the 18 degrees C pool by >50% and doubled the half-life of C99 in that compartment, showing that a substantial amount of C99 is proteolyzed by gamma-secretase in a compartment rich in recycling proteins. The temporal appearance of APP on the cell surface preceded that of C99 in the recycling compartment, further supporting the cleavage of APP in recycling endosomes. PMID- 20849819 TI - Comparative study of the chondrogenic potential of human bone marrow stromal cells, neonatal chondrocytes and adult chondrocytes. AB - Cartilage tissue engineering is still a major clinical challenge with optimisation of a suitable source of cells for cartilage repair/regeneration not yet fully addressed. The aims of this study were to compare and contrast the differences in chondrogenic behaviour between human bone marrow stromal cells (HBMSCs), human neonatal and adult chondrocytes to further our understanding of chondroinduction relative to cell maturity and to identify factors that promote chondrogenesis and maintain functional homoeostasis. Cells were cultured in monolayer in either chondrogenic or basal medium, recapitulating procedures used in existing clinical procedures for cell-based therapies. Cell doubling time, morphology and alkaline phosphatase specific activity (ALPSA) were determined at different time points. Expression of chondrogenic markers (SOX9, ACAN and COL2A1) was compared via real time polymerase chain reaction. Amongst the three cell types studied, HBMSCs had the highest ALPSA in basal culture and lowest ALPSA in chondrogenic media. Neonatal chondrocytes were the most proliferative and adult chondrocytes had the lowest ALPSA in basal media. Gene expression analysis revealed a difference in the temporal expression of chondrogenic markers which were up regulated in chondrogenic medium compared to levels in basal medium. Of the three cell types studied, adult chondrocytes offer a more promising cell source for cartilage tissue engineering. This comparative study revealed differences between the microenvironment of all three cell types and provides useful information to inform cell-based therapies for cartilage regeneration. PMID- 20849820 TI - Crystallographic analysis reveals a unique conformation of the ADP-bound novel rice kinesin K16. AB - Biochemical studies revealed that the novel rice plant-specific kinesin K16 has several unique enzymatic characteristics as compared to conventional kinesins. The ADP-free form of K16 is very stable, whereas the ADP-free form of conventional kinesins is labile. In the present study, the crystal structure of the novel rice kinesin motor domain (K16MD) complexed with Mg-ADP was determined at 2.4 A resolutions. The overall structure of K16MD is similar to that of conventional kinesin motor domains, as expected from the high amino acid sequence similarity (43.2%). However, several unique structures in K16 were observed. The position and length of the L5, L11, and L12 loops, which are key functional regions, were different from those observed in conventional kinesins. Moreover, the neck-linker region of the ADP-bound K16MD showed an ordered conformation at a position quite different from that previously observed in conventional kinesins. These structural differences may reflect the unique enzymatic characteristics of rice kinesin K16. PMID- 20849821 TI - ERK1/2 is involved in cyclic compressive force-induced IL-6 secretion in MLO-Y4 cells. AB - We previously reported that cyclic compressive force (CCF) induced interleukin-6 mRNA expression in osteocyte-like MLO-Y4 cells. But little is known about how the stimuli are converted into the biochemical signals in MLO-Y4 cells. The aim of this research was to study the effect of CCF on the IL-6 secretion and the role of extracellular signal-regulated kinases 1/2 (ERK1/2) in this process. The cells were exposed to CCF with different magnitudes (1000, 2000 and 4000 MUstrain), frequencies (0.5, 1.0 and 2.0 Hz) and durations (10 min, 30 min, 1h, 3h and 6h) by a four-point bending system. The IL-6 secretion and ERK1/2 phosphorylation of the cells were determined by ELISA and Western blotting, respectively. The results showed that IL-6 protein secretion was significantly up-regulated in response to CCF in a magnitude-, frequency- and duration-dependent fashion. The phosphorylation of ERK1/2 also increased in all cases but not depended on the magnitude, frequency or duration of CCF. Furthermore, the inhibition of the ERK1/2 pathway by its specific inhibitor PD098059 decreased but not completely abrogated the IL-6 secretion from stressed MLO-Y4 cells. These findings demonstrate that CCF-induced IL-6 secretion occurs via a mechanism that involves ERK1/2 signaling pathway and suggest that modulation of this event contributes to the pathogenesis of osteoporosis and stress-induced pathological bone resorption as well. PMID- 20849822 TI - Teasing apart a three-way symbiosis: transcriptome analyses of Curvularia protuberata in response to viral infection and heat stress. AB - The fungus Curvularia protuberata carries a dsRNA virus, Curvularia thermal tolerance virus, and develops a three-way symbiotic relationship with plants to enable their survival in extreme soil temperatures. To learn about the genome of C. protuberata and possible mechanisms of heat tolerance a collection of expressed sequence tags (ESTs) were developed from two subtracted cDNA libraries from mycelial cultures grown under control and heat stress conditions. We analyzed 4207 ESTs that were assembled into 1926 unique transcripts. Of the unique transcripts, 1347 (70%) had sequence similarity with GenBank entries using BLASTX while the rest represented unknown proteins with no matches in the databases. The majority of ESTs with known similarities were homologues to fungal genes. The EST collection presents a rich source of heat stress and viral induced genes of a fungal endophyte that is involved in a symbiotic relationship with plants. Expression profile analyses of some candidate genes suggest possible involvement of osmoprotectants such as trehalose, glycine betaine, and taurine in the heat stress response. The fungal pigment melanin, and heat shock proteins also may be involved in the thermotolerance of C. protuberata in culture. The results assist in understanding the molecular basis of thermotolerance of the three-way symbiosis. Further studies will confirm or refute the involvement of these pathways in stress tolerance. PMID- 20849823 TI - Transcriptional repression of ceramide kinase in LPS-challenged macrophages. AB - Ceramide kinase (CERK) produces the bioactive lipid ceramide 1-phosphate (C1P). Both CERK and C1P have been identified as mediators of cell growth and survival. Recent evidence showed that CERK is down-regulated during M1-type macrophage activation, which is known to promote cell growth arrest. However, the mechanism has not been investigated yet and, in particular, whether growth arrest might be the signal for down-regulation of CERK is currently unknown. Here, we found that LPS-mediated TLR-4 engagement reduces Cerk mRNA levels in mouse primary macrophages. Reporter gene assays in RAW264.7 macrophages showed that LPS inhibits the transcriptional activity of the Cerk proximal promoter. The G1-cell cycle blocker mimosine did not inhibit Cerk transcription, suggesting that transcriptional repression of Cerk by LPS is not a primary consequence of LPS induced cell cycle blockade. PMID- 20849824 TI - Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. AB - Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity. PMID- 20849826 TI - Ubiquitin-like protein MNSFbeta/endophilin II complex regulates Dectin-1-mediated phagocytosis and inflammatory responses in macrophages. AB - Post-translational modification by monoclonal nonspecific suppressor factor beta (MNSFbeta) has been implicated in the regulation of a variety of cellular events. Previous studies have demonstrated that MNSFbeta covalently binds to the intracellular pro-apoptotic protein Bcl-G in a macrophage cell line, Raw264.7, suggesting involvement of this ubiquitin-like protein in apoptosis. Most recently, we found that MNSFbeta covalently conjugates to endophilin II, a member of the endophilin A family, and inhibits phagocytosis by macrophages. In this study, we further examined the mechanism of action of MNSFbeta/endophilin II complex in the phagocytosis of zymosan. MNSFbeta/endophilin II I mediated inhibition of phagocytosis in Raw264.7 cells was neutralized by anti-Decti-1, beta-glucan receptor, mAb, indicating that MNSFbeta/endophilin II is a mediator of Dectin-1 signaling in regulating phagocytosis. The beta-glucan-dependent TNFalpha response to zymosan was significantly increased by the treatment with endophilin II siRNA and/or MNSFbeta siRNA. Conversely, cotransfection of endophilin II and MNSFbeta cDNAs inhibited the enhancement of zymosan-induced TNFalpha production. Interestingly, endophilin II siRNA did not affect Pam3CSK4 (TLR2 specific ligand)-induced TNFalpha production. Endophilin II and/or MNSFbeta siRNA enhanced zymosan-induced IkappaBalpha degradation. Together, these results demonstrate that MNSFbeta/endophilin II inhibits the signal pathway upstream of IKK activation, but not downstream of TLR2 signaling. PMID- 20849825 TI - Cyclic stretch-induced stress fiber dynamics - dependence on strain rate, Rho kinase and MLCK. AB - Stress fiber realignment is an important adaptive response to cyclic stretch for nonmuscle cells, but the mechanism by which such reorganization occurs is not known. By analyzing stress fiber dynamics using live cell microscopy, we revealed that stress fiber reorientation perpendicular to the direction of cyclic uniaxial stretching at 1 Hz did not involve disassembly of the stress fiber distal ends located at focal adhesion sites. Instead, these distal ends were often used to assemble new stress fibers oriented progressively further away from the direction of stretch. Stress fiber disassembly and reorientation were not induced when the frequency of stretch was decreased to 0.01 Hz, however. Treatment with the Rho kinase inhibitor Y27632 reduced stress fibers to thin fibers located in the cell periphery which bundled together to form thick fibers oriented parallel to the direction of stretching at 1Hz. In contrast, these thin fibers remained diffuse in cells subjected to stretch at 0.01 Hz. Cyclic stretch at 1 Hz also induced actin fiber formation parallel to the direction of stretch in cells treated with the myosin light chain kinase (MLCK) inhibitor ML-7, but these fibers were located centrally rather than peripherally. These results shed new light on the mechanism by which stress fibers reorient in response to cyclic stretch in different regions of the actin cytoskeleton. PMID- 20849827 TI - Effects of cardiac myosin binding protein-C on the regulation of interaction of cardiac myosin with thin filament in an in vitro motility assay. AB - Modulatory role of whole cardiac myosin binding protein-C (sMyBP-C) in regulation of cardiac muscle contractility was studied in the in vitro motility assay with rabbit cardiac myosin as a motor protein. The effects of cMyBP-C on the interaction of cardiac myosin with regulated thin filament were tested in both in vitro motility and ATPase assays. We demonstrate that the addition of cMyBP-C increases calcium regulated Mg-ATPase activity of cardiac myosin at submaximal calcium. The Hill coefficient for 'pCa-velocity' relation in the in vitro motility assay decreased and the calcium sensitivity increased when sMyBP-C was added. Results of our experiments testifies in favor of the hypothesis that sMyBP C slows down cross-bridge kinetics when binding to actin. PMID- 20849829 TI - A three-dimensional organotypic assay to measure target cell killing by cytotoxic T lymphocytes. AB - Cytotoxic T lymphocytes (CTL) mediate antigen- and cell-cell contact dependent killing of target cells, such as cancer cells and virus-infected cells. In vivo, this process requires the active migration of CTL towards and away from target cells. We here describe an organotypic 3D collagen matrix assay to monitor CTL migration together with CTL-mediated killing of target cells. The assay supports both, time-lapse microscopy of killing dynamics as well as population analysis of killing after matrix digestion and flow cytometry. The assay was used to assess the detrimental effect of cyclosporine A (CsA) present during CTL activation, which caused an inhibition of CTL-target cell conjugation and strongly impaired CTL-mediated killing, particularly at low effector-target ratios. Thus, the organotypic assay is useful to monitor spatiotemporal control mechanisms of cytotoxic immune effector functions. PMID- 20849828 TI - A novel N-hydroxy-N'-aminoguanidine derivative inhibits ribonucleotide reductase activity: Effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C). AB - Ribonucleotide reductase (RR; EC 1.17.4.1) is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA replication. RR is upregulated in tumor cells and therefore considered to be an excellent target for cancer chemotherapy. ABNM-13 (N-hydroxy-2-(anthracene-2-yl-methylene)-hydrazinecarboximidamide), a novel N hydroxy-N'-aminoguanidine has been designed to inhibit RR activity using 3D molecular space modeling techniques. In this study, we evaluated its effect on human HL-60 promyelocytic leukemia cells. ABNM-13 proved to be a potent inhibitor of RR which was displayed by significant alterations of deoxyribonucleoside triphosphate (dNTP) pool balance and a highly significant decrease of incorporation of radiolabeled cytidine into DNA of HL-60 cells. Diminished RR activity caused replication stress which was consistent with activation of Chk1 and Chk2, resulting in downregulation/degradation of Cdc25A. In contrast, Cdc25B was upregulated, leading to dephosphorylation and activation of Cdk1. The combined disregulation of Cdc25A and Cdc25B was the most likely cause for ABNM-13 induced S-phase arrest. Finally, we combined ABNM-13 with the first-line antileukemic agent arabinofuranosylcytosine (Ara-C) and found that ABNM-13 synergistically potentiated the antineoplastic effects of Ara-C. Due to these promising results, ABNM-13 deserves further preclinical and in vivo testing. PMID- 20849830 TI - UNBS1450, a steroid cardiac glycoside inducing apoptotic cell death in human leukemia cells. AB - Cardiac steroids are used to treat various diseases including congestive heart failure and cancer. The aim of this study was to investigate the anti-leukemic activity of UNBS1450, a hemi-synthetic cardenolide belonging to the cardiac steroid glycoside family. Here, we report that, at low nanomolar concentrations, UNBS1450 induces apoptotic cell death. Subsequently, we have investigated the molecular mechanisms leading to apoptosis activation. Our results show that UNBS1450 inhibits NF-kappaB transactivation and triggers apoptosis by cleavage of pro-caspases 8, 9 and 3/7, by decreasing expression of anti-apoptotic Mcl-1 and by recruitment of pro-apoptotic Bak and Bax protein eventually resulting in cell death. PMID- 20849831 TI - Ameliorative effects of a non-competitive BACE1 inhibitor TAK-070 on Abeta peptide levels and impaired learning behavior in aged rats. AB - We examined the effects of TAK-070, a novel non-competitive beta-secretase (BACE1) inhibitor, on the levels of Abeta peptides and behavioral deficits in rats. TAK-070 reduced soluble Abeta40 and Abeta42 levels of the cerebral cortex in a time- and dose-dependent manner in young rats. We found that the insoluble Abeta42 content increased significantly with aging from 22 months old without changing Abeta40 content. TAK-070 normalized the Abeta42 levels to those in young rats when they were fed chow containing TAK-070 starting at 19 months old for 6.5 months. Repeated administration of TAK-070 to aged rats for 2 weeks ameliorated the impaired spatial learning in the Morris water maze task and reduced the levels of soluble and insoluble Abeta peptides at doses of 0.3-1mg/kg, (p.o.). Interestingly, TAK-070 significantly recovered the reduced brain synaptophysin levels in aged rats to those in young rats. Our findings support the idea that partial inhibition of BACE1 by TAK-070 exerts symptomatic as well as disease modifying effects for the treatment of Alzheimer's disease. PMID- 20849832 TI - Involuntary switching of attention mediates differences in event-related responses to complex tones between early and late Spanish-English bilinguals. AB - Most research with bilinguals has used speech stimuli to demonstrate differences in auditory processing abilities. Two main factors have been identified as modulators of such differences: proficiency and age of acquisition of the second language (L2). However, whether the bilingual brain differs from the monolingual in the efficient processing of non-verbal auditory events (known to be critical to the acoustic analysis of the speech stream) remains unclear. In this EEG/ERP study, using the mismatch negativity (MMN), P3a, and late negativity (LN), we examined differences in discrimination, involuntary switching of attention and reorienting of attention between monolinguals and bilinguals as they processed complex tones. Further, we examined the role that age of acquisition plays in modulating such responses. A group of English monolinguals and a group of proficient Spanish-English bilinguals were presented with a multiple-deviant oddball paradigm with four deviant conditions (duration, frequency, silent gap, and frequency modulation). Late bilinguals, who learned English after age 10, exhibited larger MMN and P3a responses than early bilinguals, across all deviant conditions. Significant associations were found between amplitude of the responses and both age of L2 acquisition and years of L2 experience. Individuals who acquired English at later ages and had fewer years of L2 experience had larger MMN, P3a, and LN responses than those who learned it earlier. These findings demonstrate that age of L2 acquisition is an important modulator of auditory responses in bilinguals even when processing non-speech signals. Involuntary attention switching is suggested as the main factor driving these differences. PMID- 20849833 TI - Effects of tetramethylpyrazine on nitric oxide/cGMP signaling after cerebral vasospasm in rabbits. AB - Tetramethylpyrazine (TMP), an ingredient of Chinese herbal Szechwan lovage rhizome, shows vasorelaxant effect. Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) is associated with high mortality and morbidity. Here, we evaluated the effect of TMP in a model of CVS and sought to identify the underlying mechanisms of action. A rabbit SAH model was established by injection of the autoblood via cisterna magna. Cerebral blood flow and arterial diameter were measured by Transcranial Doppler (TCD) and Computed Tomography Angiography (CTA). Expression of eNOS and PDE-V in basilar artery (BA) was assessed by western blots. Levels of nitric oxide (NO) in plasma and cerebral spinal fluid, and of intra-endothelium Ca(2+) were measured. Significantly reduced diameter and accelerated blood flow velocity were detected in BAs of SAH animals (P<0.05 vs. sham group). Expression of eNOS and NO was increased, and PDE-V expression was reduced by TMP.TMP ameliorated cerebral vasospasm (P<0.05 vs. SAH group), and L NAME (a NOS inhibitor) partly abrogated the effects of TMP. TMP induced a dose dependent increase of intra-endothelium Ca(2+). The current results demonstrated that the vasorelaxant effect of TMP was at least in part via regulation of NO/cGMP signaling. PMID- 20849834 TI - Genetic labeling of both the axons of transduced, glutamatergic neurons in rat postrhinal cortex and their postsynaptic neurons in other neocortical areas by herpes simplex virus vectors that coexpress an axon-targeted beta-galactosidase and wheat germ agglutinin from a vesicular glutamate transporter-1 promoter. AB - Neuronal circuits comprise the foundation for neuronal physiology and synaptic plasticity, and thus for consequent behaviors and learning, but our knowledge of neocortical circuits is incomplete. Mapping neocortical circuits is a challenging problem because these circuits contain large numbers of neurons, a high density of synapses, and numerous classes and subclasses of neurons that form many different types of synapses. Expression of specific genetic tracers in small numbers of specific subclasses of neocortical neurons has the potential to map neocortical circuits. Suitable genetic tracers have been established in neurons in subcortical areas, but application to neocortical circuits has been limited. Enabling this approach, Herpes Simplex Virus (HSV-1) plasmid (amplicon) vectors can transduce small numbers of neurons in a specific neocortical area. Further, expression of a particular genetic tracer can be restricted to specific subclasses of neurons; in particular, the vesicular glutamate transporter-1 (VGLUT1) promoter supports expression in VGLUT1-containing glutamatergic neurons in rat postrhinal (POR) cortex. Here, we show that expression of an axon-targeted beta-galactosidase (beta-gal) from such vectors supports mapping specific commissural and associative projections of the transduced neurons in POR cortex. Further, coexpression of wheat germ agglutinin (WGA) and an axon-targeted beta gal supports mapping both specific projections of the transduced neurons and identifying specific postsynaptic neurons for the transduced neurons. The neocortical circuit mapping capabilities developed here may support mapping specific neocortical circuits that have critical roles in cognitive learning. PMID- 20849835 TI - Quantification of cystatin C in cerebrospinal fluid from various neurological disorders and correlation with G73A polymorphism in CST3. AB - Cystatin C (CC) is a cysteine protease inhibitor abundantly expressed in the central nervous system. Bunina bodies, small eosinophilic intraneuronal inclusions, are stain positive for CC and are the most specific histological hallmark of amyotrophic lateral sclerosis (ALS). In this study, employing a latex turbidimetric immunoassay, levels of CC in cerebrospinal fluid (CSF) were quantified in 130 age-matched individuals with either a neurological disorder [ALS, Alzheimer's disease (AD), Parkinson's disease (PD), tauopathy (TP), multiple system atrophy (MSA), chronic inflammatory demyelinating polyneuropathy (CIDP)] or no known neurological condition (normal control, NC). The CC level in CSF was found to be correlated with the age during the investigation but not the protein concentration. There was no difference in CC levels between NC and ALS or CIDP cases, whereas CC levels were significantly lower in MSA compared with NC. Of the 130 cases, 96 were genotyped, and G/A or A/A polymorphism at +73 within the CST3 gene was found in 28 individuals. The CC level was significantly lower in the combined group of G/A and A/A genotypes compared with G/G. The present data demonstrate that the level of CC in CSF should not be considered as a biomarker of ALS, but there is a correlation between CC levels and the CST3 genotype. PMID- 20849836 TI - Developmental changes of gene expression after spinal cord injury in neonatal opossums. AB - Changes in gene expression have been measured 24h after injury to mammalian spinal cords that can and cannot regenerate. In opossums there is a critical period of development when regeneration stops being possible: at 9 days postnatal cervical spinal cords regenerate, at 12 days they do not. By the use of marsupial cDNA microarrays, we detected 158 genes that respond differentially to injury at the two ages critical for regeneration. For selected candidates additional measurements were made by real-time PCR and sites of their expression were shown by immunostaining. Candidate genes have been classified so as to select those that promote or prevent regeneration. Up-regulated by injury at 8 days and/or down-regulated by injury at 13 days were genes known to promote growth, such as Mitogen-activated protein kinase kinase 1 or transcription factor TCF7L2. By contrast, at 13 days, up-regulation occurred of inhibitory molecules, including annexins, ephrins, and genes related to apoptosis and neurodegenerative diseases. Certain genes such as calmodulin 1 and NOGO, changed expression similarly in animals that could and could not regenerate without any additional changes in response to injury. These findings confirmed and extended changes of gene expression found in earlier screens on 9 and 12 ay preparations without lesions and provide a comprehensive list of genes that serve as a basis for testing how identified molecules, singly or in combination, promote and prevent central nervous system regeneration. PMID- 20849837 TI - PAH intermediates: Links between the atmosphere and biological systems. AB - China is now the world's largest emitter of polycyclic aromatic hydrocarbons (PAHs). In addition, PAHs, and their reactive intermediates, undergo trans Pacific atmospheric transport to the Western U.S. The objectives of our research are to predict, identify and quantify novel PAH intermediates in the atmosphere and biological systems, using computational methods, as well as laboratory and field experiments. Gaussian is used to predict the thermodynamic properties of parent structure PAHs, as well as the associated nitro-, oxy-, and hydroxy-PAH intermediates. Based on these predictions, state-of-the-art analytical chemistry techniques are used to identify and quantify these potential intermediates on Asian particulate matter before and after reaction in a continuous flow photochemical reactor. These same techniques are used to identify the relative proportion of PAH intermediates in PAH source regions (such as Beijing, China) and during long-range atmospheric transport to the Western U.S. PAH personal exposure studies in China and the Confederated Tribes of the Umatilla Indian Reservation in Oregon will be used to assess the similarities and differences in the PAH intermediates in biological systems relative to the atmosphere. PMID- 20849838 TI - The fusion of synaptic vesicle membranes studied by lipid mixing: the R18 fluorescence assay validity. AB - The various experimental approaches and octadecyl rhodamine B chloride (R18) assay's capability to meet the criteria for examining the Ca2(+)dependent synaptic vesicles (SVs) fusion with target membranes have been investigated. The existence of at least two simultaneous processes one of which attributed to real Ca2(+)-dependent membrane fusion, while another is considered to be non-specific probe transfer has been shown. The differences in response to temperature changes were found for R18 fluorescence dequenching upon stimulation of membrane fusion or nonspecific probe transfer. The temperature dependences of the probe dequenching rate were the same for heterotypic and homotypic membrane systems and increased with the temperature growth. The combination of R18 fluorescence studies with the data obtained by dynamic light scattering (DLS) offers a unique opportunity for the determination of SVs aggregation and the membrane fusion. The cholesterol content of the synaptosomal plasma membrane was modulated by methyl beta-cyclodextrin (MCD). The MCD molecule has proven to bind directly the membrane cholesterol and interact with lipophilic probe R18 that affects its fluorescence. The obvious distinctions in probe dequenching due to the membrane mixing or the MCD effect were observed. The cholesterol depletion from the synaptosomal plasma membranes was found to inhibit the process of Ca2(+)-induced membrane fusion with SVs. Thus, the manipulations with conditions of R18 probe dequenching at the model conditions, specific for the Ca2(+)-triggered fusion steps of regulated exocytosis, allowed us to determine the relative contribution of probe transfer and genuine membrane fusion to the overall fluorescence signal. PMID- 20849839 TI - Expression of brain-derived neurotrophic factor in mature spermatozoa from fertile and infertile men. AB - BACKGROUND: Neurotrophins, a family of growth factor, are not only required for the survival and differentiation of the nervous system but also important for the development of reproductive tissues. We identified the expression of brain derived neurotrophic factor (BDNF) transcript and protein in human spermatozoa. METHODS: The presence of BDNF in human spermatozoa was investigated using RT-PCR, immunofluorescence and Western blotting. Real-time PCR and ELISA were employed to determine expression levels of BDNF. RESULTS: BDNF mRNA and protein were detected in human spermatozoa. Immunofluorescence staining showed that BDNF protein was localized in the head, neck, and tail of human spermatozoa. The amount of BDNF mRNA expressed in spermatozoa of oligoasthenozoospermic group was lower than that of fertile group (P < 0.05). The concentration of BDNF in seminal plasma from oligoasthenozoospermic group (2.8 +/- 0.7 ng/ml) was both lower than that from fertile group (3.6 +/- 0.4 ng/ml) and asthenozoospermic group (3.4 +/- 0.5 ng/ml) (P < 0.05). CONCLUSIONS: The data showed that the decrease in BDNF transcript and protein in oligoasthenozoospermic group may be associated with pathogenesis in some types of male infertility. PMID- 20849840 TI - Quantitative monitoring of single nucleotide mutations by allele-specific quantitative PCR can be used for the assessment of minimal residual disease in patients with hematological malignancies throughout their clinical course. AB - BACKGROUND: Monitoring of minimal residual disease (MRD) in patients with hematological malignancies is important for evaluating the patients' therapeutic response and risk of relapse. Single nucleotide mutations associated with leukemogenesis can be considered as applicable MRD markers. METHODS: We developed an allele-specific quantitative polymerase chain reaction (AS-qPCR) for FLT3 2503G>T, KIT 2446G>T, and KIT 2447A>T and compared the change in the expression levels of the FLT3 or KIT mutations assessed by AS-qPCR to those of the RUNX1 RUNX1T1 fusion gene and WT1 by conventional quantitative PCR. RESULTS: The AS qPCR using primers including template-mismatched nucleotide or template mismatched nucleotide plus locked nucleic acid substituted nucleotide provided higher selectivity for mutant nucleotides. The change in the expression levels of the FLT3 or KIT mutations at the time of relapse and just after hematopoietic stem cell transplantation correlated well with that of the RUNX1-RUNX1T1 fusion gene and WT1. Moreover, during complete remission, only AS-qPCR could detect low level expression of residual mutations. CONCLUSIONS: The AS-qPCR for analyzing single nucleotide mutations contributes to the monitoring of MRD in patients without recurrent fusion gene throughout the clinical course and thus broadens the spectrum of patients in whom MRD can be monitored. PMID- 20849841 TI - A network of Wnt, hedgehog and BMP signaling pathways regulates tooth replacement in snakes. AB - Most dentate vertebrates, from fish to humans, replace their teeth and yet the molecular basis of tooth replacement is poorly understood. Canonical Wnt signaling regulates tooth number in mice and humans, but it is unclear what role it plays in tooth replacement as it naturally occurs. To clarify this, we characterized Wnt signaling activity in the dental tissues of the ball python Python regius. This species replaces teeth throughout life (polyphyodonty) and in the same manner as in humans, i.e., sequential budding of teeth from the tip of the dental lamina. From initiation stage onwards, canonical Wnt read-out genes (Lef1 and Axin2) are persistently expressed by cells in the dental lamina tip and surrounding mesenchyme. This implies that molecular signaling at work during dental initiation carries over to tooth replacement. We show that canonical Wnt signaling promotes cell proliferation in python dental tissues and that by confining Wnt activity in the dental lamina the structure extends instead of thickens. Presumably, lamina extension creates space between successive tooth buds, ensuring that tooth replacement occurs in an ordered manner. We suggest that hedgehog signaling confines Wnt activity in the dental epithelium by direct planar repression and, during tooth replacement stages, by negatively regulating BMP levels in the dental mesenchyme. Finally, we propose that Wnt-active cells at the extending tip of the python dental lamina represent the immediate descendents of putative stem cells housed in the lingual face of the lamina, similar to what we have recently described for another polyphyodont squamate species. PMID- 20849843 TI - Gail Martin selected for 2011 FASEB Excellence in Science Award. PMID- 20849842 TI - Wnt signaling controls the stem cell-like asymmetric division of the epithelial seam cells during C. elegans larval development. AB - Metazoan stem cells repopulate tissues during adult life by dividing asymmetrically to generate another stem cell and a cell that terminally differentiates. Wnt signaling regulates the division pattern of stem cells in flies and vertebrates. While the short-lived nematode C. elegans has no adult somatic stem cells, the lateral epithelial seam cells divide in a stem cell-like manner in each larval stage, usually generating a posterior daughter that retains the seam cell fate and an anterior daughter that terminally differentiates. We show that while wild-type adult animals have 16 seam cells per side, animals with reduced function of the TCF homolog POP-1 have as many as 67 seam cells, and animals with reduced function of the beta-catenins SYS-1 and WRM-1 have as few as three. Analysis of seam cell division patterns showed alterations in their stem cell-like divisions in the L2-L4 stages: reduced Wnt signaling caused both daughters to adopt non-seam fates, while activated Wnt signaling caused both daughters to adopt the seam fate. Therefore, our results indicate that Wnt signaling globally regulates the asymmetric, stem cell-like division of most or all somatic seam cells during C. elegans larval development, and that Wnt pathway regulation of stem cell-like behavior is conserved in nematodes. PMID- 20849844 TI - Aquaporin-4 water channel oligomers are associated with the transverse tubules of skeletal myofibers. AB - Transverse (T) tubules comprise a tortuous network inside the skeletal myofibers enclosing a distinct osmotic environment. Here we have examined whether the T tubules contain aquaporin type 4 (AQP4) water channels to mediate rapid transmembrane water flow. Separation of T tubular and sarcolemmal membranes by sucrose density gradient centrifugation revealed that two main isoforms of AQP4, namely M23 and M1, were present in both membrane fractions. Compatible with this, expression of fluorescent Venus-AQP4.M23 in rat muscle showed the protein both in the T tubules and at the sarcolemma. Blue-Native polyacrylamide gel electrophoresis showed that higher order oligomers typical to the AQP4 water channel were present in both membrane compartments. Interestingly, alpha syntrophin that mediates binding of AQP4 to the sarcolemmal dystrophin glycoprotein complex was also present in the T tubule fraction. Deletion of the syntrophin-binding sequence of AQP4 increased its mobile fraction at the sarcolemma but not in the T tubules. Taken together, our results strongly suggest that both the sarcolemma and the T tubules harbor higher order oligomers of the AQP4 water channel but the interactions with adjacent macromolecules are different. PMID- 20849845 TI - Long-term persistence of acquired resistance to 5-fluorouracil in the colon cancer cell line SW620. AB - Treatment resistance to antineoplastic drugs represents a major clinical problem. Here, we investigated the long-term stability of acquired resistance to 5 fluorouracil (FU) in an in vitro colon cancer model, using four sub-clones characterised by increasing FU-resistance derived from the cell line SW620. The resistance phenotype was preserved after FU withdrawal for 15weeks (~100 cell divisions) independent of the established level of drug resistance and of epigenetic silencing. Remarkably, resistant clones tolerated serum deprivation, adopted a CD133(+) CD44(-) phenotype, and further exhibited loss of membrane bound E-cadherin together with predominant nuclear beta-catenin localisation. Thus, we provide evidence for a long-term memory of acquired drug resistance, driven by multiple cellular strategies (epithelial-mesenchymal transition and selective propagation of CD133(+) cells). These resistance phenomena, in turn, accentuate the malignant phenotype. PMID- 20849848 TI - Technical factors that influence neural transplant safety in Huntington's disease. PMID- 20849847 TI - Endothelin, astrocytes and glaucoma. AB - It has become increasingly clear that astrocytes may play an important role in the genesis of glaucoma. Astrogliosis occurs in response to ocular stress or the presence of noxious stimuli. Agents that appear to stimulate reactive gliosis are becoming increasingly clear. One class of agents that is emerging is the endothelins (ETs; specifically, ET-1). In this review we examine the interactions of ET-1 with astrocytes and provide examples where ET-1 appears to contribute to activation of astrocytes and play a role in the neurodegenerative effects that accompany such reactivation resulting in astrogliosis. These actions are presented in the context of glaucoma although information is also presented with respect to ET-1's role in the central nervous system and brain. While much has been learned with respect to ET-1/astrocyte interactions, there are still a number of questions concerning the potential therapeutic implications of these findings. Hopefully this review will stimulate others to examine this potential. PMID- 20849849 TI - Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. AB - Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics. PMID- 20849846 TI - A biomechanical paradigm for axonal insult within the optic nerve head in aging and glaucoma. AB - This article is dedicated to Rosario Hernandez for her warm support of my own work and her genuine enthusiasm for the work of her colleagues throughout her career. I first met Rosario as a research fellow in Harry Quigley's laboratory between 1991 and 1993. Along with Harry, John Morrison, Elaine Johnson, Abe Clark, Colm O'Brien and many others, Rosario's work has provided lamina cribrosa astrocyte cellular mechanisms that are biomechanically plausible and in so doing provided credibility to early notions of the optic nerve head (ONH) as a biomechanical structure. We owe a large intellectual debt to Rosario for her dogged persistence in the characterization of the ONH astrocyte and lamina cribrosacyte in age and disease. Two questions run through her work and remain of central importance today. First, how do astrocytes respond to and alter the biomechanical environment of the ONH and the physiologic stresses created therein? Second, how do these physiologic demands on the astrocyte influence their ability to deliver the support to retinal ganglion cell axon transport and flow against the translaminar pressure gradient? The purpose of this article is to summarize what is known about the biomechanical determinants of retinal ganglion cell axon physiology within the ONH in the optic neuropathy of aging and Glaucoma. My goal is to provide a biomechanical framework for this discussion. This framework assumes that the ONH astrocytes and glia fundamentally support and influence both the lamina cribrosa extracellular matrix and retinal ganglion cell axon physiology. Rosario Hernandez was one of the first investigators to recognize the implications of this unique circumstance. Many of the ideas contained herein have been initially presented within or derived from her work (Hernandez, M.R., 2000. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 19, 297-321.; Hernandez, M.R., Pena, J.D., 1997. The optic nerve head in glaucomatous optic neuropathy. Arch Ophthalmol. 115, 389-395.). PMID- 20849850 TI - Echinostoma caproni (Trematoda): differential in vivo cytokine responses in high and low compatible hosts. AB - In order to investigate the factors determining the expulsion of intestinal trematodes, we have analyzed the in vivo cytokine responses at several levels and the local responses against Echinostoma caproni (Trematoda) in two host species displaying different compatibility with the parasite. The response of the high compatible host (mice) is characterized by a mixed Th1/Th2 phenotype in the spleen, Peyer's patches and mesenteric lymph nodes. At the intestine, a marked Th1 response with a marked increase of IFN-gamma together with elevated number of mucosal neutrophils and expression of induced nitric oxide synthase were observed. The responses in the host of low compatibility (rats) with the parasite at the spleen, Peyer's patches and mesenteric lymph node did not show clear differences with regard to the mice. However, the response in the intestine was markedly different. In rats, a Th2 response with increase in the levels of IL-5, IL-6 and IL-13 expression was detected. According to these results, the local production of IFN-gamma and the local inflammatory responses with neutrophilic infiltration are associated with the development of chronic infections, whereas the worm expulsion is related with the development of Th2 responses and appears to be based on effects on non-bone narrow-derived cells. PMID- 20849851 TI - Counteracting MDM2-induced HIPK2 downregulation restores HIPK2/p53 apoptotic signaling in cancer cells. AB - Homeodomain-interacting protein kinase-2 (HIPK2) is a crucial regulator of p53 apoptotic function by phosphorylating serine 46 (Ser46) in response to DNA damage. In tumors with wild-type p53, its tumor suppressor function is often impaired by MDM2 overexpression that targets p53 for proteasomal degradation. Likewise, MDM2 targets HIPK2 for protein degradation impairing p53-apoptotic function. Here we report that zinc antagonised MDM2-induced HIPK2 degradation as well as p53 ubiquitination. The zinc inhibitory effect on MDM2 activity leads to HIPK2-induced p53Ser46 phosphorylation and p53 pro-apoptotic transcriptional activity. These results suggest that zinc derivatives are potential molecules to target the MDM2-induced HIPK2/p53 inhibition. PMID- 20849852 TI - Proliferating cell nuclear antigen in the cytoplasm interacts with components of glycolysis and cancer. AB - Proliferating cell nuclear antigen (PCNA) is involved in a wide range of functions in the nucleus. However, a substantial amount of PCNA is also present in the cytoplasm, although their function is unknown. Here we show, through Far Western blotting and mass spectrometry, that PCNA is associated with several cytoplasmic oncoproteins, including elongation factor, malate dehydrogenase, and peptidyl-prolyl isomerase. Surprisingly, PCNA is also associated with six glycolytic enzymes that are involved in the regulation of steps 4-9 in the glycolysis pathway. PMID- 20849853 TI - EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. AB - Estrogen depletion following menopause has been correlated with an increased risk of developing Alzheimer's disease (AD). We previously explored the beneficial effect of (-)-epigallocatechin-3-gallate (EGCG) on AD mice and found increased non-amyloidogenic processing of amyloid precursor protein (APP) through the alpha secretase a disintegrin and metallopeptidase domain 10 (ADAM10). Our results in this study suggest that EGCG-mediated enhancement of non-amyloidogenic processing of APP is mediated by the maturation of ADAM10 via an estrogen receptor-alpha (ERalpha)/phosphoinositide 3-kinase/Ak-transforming dependent mechanism, independent of furin-mediated ADAM10 activation. These data support prior assertions that central selective ER modulation could be a therapeutic target for AD and support the use of EGCG as a well-tolerated alternative to estrogen therapy in the prophylaxis and treatment of this disease. PMID- 20849854 TI - Overexpression of SCYL1-BP1 stabilizes functional p53 by suppressing MDM2 mediated ubiquitination. AB - Previously, we defined SCY1-like 1 binding protein 1 (SCYL1-BP1) to be a substrate of Pirh2 that binds to mouse double minute gene number 2 (MDM2). In the current study, we found that an increase in SCYL1-BP1 protein levels caused a parallel change in the amount of p53 protein due to the inhibition by SCYL-BP1 of MDM2-mediated p53 ubiquitination. SCYL1-BP1 was not able to alter the ubiquitination of p53 by human papillomavirus protein E6, indicating that the effect was specific for MDM2. Increases in the level of SCYL1-BP1 protein in cells led to the greater transcriptional activation of p21 and gadd45, reduced rate of cellular proliferation, increased levels of apoptosis and inhibition of tumorigenicity. Thus, we propose that SCYL1-BP1 is a novel regulator of the MDM2 p53 feedback loop and that it may be a potential tumor suppressor. PMID- 20849855 TI - Pathogenesis of cholestatic liver disease and therapeutic approaches. AB - Cholestatic liver disorders are caused by genetic defects, mechanical aberrations, toxins, or dysregulations in the immune system that damage the bile ducts and cause accumulation of bile and liver tissue damage. They have common clinical manifestations and pathogenic features that include the responses of cholangiocytes and hepatocytes to injury. We review the features of bile acid transport, tissue repair and regulation, apoptosis, vascular supply, immune regulation, and cholangiocytes that are associated with cholestatic liver disorders. We now have a greater understanding of the physiology of cholangiocytes at the cellular and molecular levels, as well as genetic factors, repair pathways, and autoimmunity mechanisms involved in the pathogenesis of disease. These discoveries will hopefully lead to new therapeutic approaches for patients with cholestatic liver disease. PMID- 20849856 TI - Increased memory load-related frontal activation after estradiol treatment in postmenopausal women. AB - Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD)=59.13 (5.5)) were randomly assigned to three months of 1mg oral 17-beta estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions. PMID- 20849858 TI - The NADPH-cytochrome P450 reductase family in Trypanosoma cruzi is involved in the sterol biosynthesis pathway. AB - Trypanosoma cruzi flavoproteins TcCPR-A, TcCPR-B and TcCPR-C are members of the NADPH-dependent cytochrome P-450 reductase family expressed in the parasite. Epimastigotes over-expressing TcCPR-B and TcCPR-C showed enhanced ergosterol biosynthesis and increased NADP(+)/NADPH ratio. Transgenic parasites with augmented ergosterol content presented a higher membrane order with a corresponding diminished bulk-phase endocytosis. These results support a significant role for TcCPR-B and TcCPR-C in the sterol biosynthetic pathway and to our knowledge for the first time reveals the participation of more than one CPR in this metabolic route. Notably, TcCPR-B was found in reservosomes while TcCPR-C localised in the endoplasmic reticulum. In addition, we suggest a different role for TcCPR-A, since its over-expression is lethal, displaying cells with an increased DNA content, aberrant morphology and severe ultrastructural alterations. PMID- 20849857 TI - A component of Premarin((r)) enhances multiple cognitive functions and influences nicotinic receptor expression. AB - In women, ovarian hormone loss at menopause has been related to cognitive decline, and some studies suggest that estrogen-containing hormone therapy (HT) can mitigate these effects. Recently, the Women's Health Initiative study found that conjugated equine estrogens, the most commonly prescribed HT, do not benefit cognition. Isolated components of conjugated equine estrogens (tradename Premarin((r))) have been evaluated in vitro, with delta(8,9)-dehydroestrone (?(8)E1) and equilin showing the strongest neuroprotective profiles. It has not been evaluated whether ?(8)E1 or equilin impact cognition or the cholinergic system, which is affected by other estrogens and known to modulate cognition. Here, in middle-aged, ovariectomized rats, we evaluated the effects of ?(8)E1 and equilin treatments on a cognitive battery and cholinergic nicotinic receptors (nAChR). Specifically, we used (125)I-labeled epibatidine binding to assay brain nicotinic receptor containing 4alpha and 2beta subunits (alpha4beta2-nAChR), since this nicotinic receptor subtype has been shown previously to be sensitive to other estrogens. ?(8)E1 enhanced spatial working, recent and reference memory. ?(8)E1 also decreased hippocampal and entorhinal cortex alpha4beta2-nAChR expression, which was related to spatial reference memory performance. Equilin treatment did not affect spatial memory or rat alpha4beta2-nAChR expression, and neither estrogen impacted (86)Rb(+) efflux, indicating lack of direct action on human alpha4beta2 nAChR function. Both estrogens influenced vaginal smear profiles, uterine weights, and serum luteinizing hormone levels, analogous to classic estrogens. The findings indicate that specific isolated Premarin((r)) components differ in their ability to affect cognition and nAChR expression. Taken with the works of others showing ?(8)E1-induced benefits on several dimensions of health-related concerns associated with menopause, this body of research identifies ?(8)E1 as a new avenue to be investigated as a potential component of HT that may benefit brain health and function during aging. PMID- 20849860 TI - Ensemble approaches for improving HLA class I-peptide binding prediction. AB - Accurately predicting peptides binding to major histocompatibility complex (MHC) I molecules is of great importance to immunologists for elucidating the underlying mechanism of immune recognition and facilitating the design of peptide based vaccine. Various computational methods have been developed for MHC I peptide binding prediction, and several of them are reported to achieve high accuracy in recent evaluation on benchmark datasets. For attending the machine learning in immunology competition (MLIC) in prediction of human leukocyte antigen (HLA)-binding peptides, we (FudanCS) have made use of ensemble approaches to further improve the prediction performance by integrating the outputs of several leading predictors. Two ensemble approaches, PM and AvgTanh, have been implemented for attending MLIC. AvgTanh and PM achieved the fourth and the seventh out of all 20 submissions in MLIC in terms of the average AUC. In addition, AvgTanh was awarded the winner in the category of HLA-A*0101 of 9-mer. Overall, the competition results validate the effectiveness of ensemble approaches. PMID- 20849859 TI - Non-random organization of the Biomphalaria glabrata genome in interphase Bge cells and the spatial repositioning of activated genes in cells co-cultured with Schistosoma mansoni. AB - Biomphalaria glabrata is a major intermediate host for the parasitic trematode Schistosoma mansoni, a causative agent of human schistosomiasis. To decipher the molecular basis of this host-parasite interaction, the Bge embryonic cell line provides a unique in vitro model system to assess whether interactions between the snail and parasite affect the cell and genome biology in either organism. The organization of the B. glabrata genome in Bge cells was studied using image analysis through positioning territories of differently sized chromosomes within cell nuclei. The snail chromosome territories are similar in morphology as well as in non-random radial positioning as those found in other derived protostome and deuterostome organisms. Specific monitoring of four gene loci, piwi, BgPrx, actin and ferritin, revealed non-random radial positioning of the genome. This indicates that specific parts of the snail genome reside in reproducible nuclear addresses. To determine whether exposure to parasite is reflected in genome organization, the interphase spatial positioning of genes was assessed after co culturing Bge cells with either normal or irradiation attenuated miracidia for 30 min to 24 h. The loci of actin and ferritin, genes that are up-regulated in the snail when subjected to infection, were visualized by fluorescence in situ hybridisation (FISH) and their radial nuclear positions i.e. their position in the interphase nucleus with respect to the nuclear edge/envelope, mapped. Interestingly, large scale gene repositioning correlated to temporal kinetics of gene expression levels in Bge cells co-cultured with normal miracidia while irradiated parasites failed to elicit similar gene expression or gene loci repositioning as demonstrated using the ferritin gene. This indicates that normal but not attenuated schistosomes provide stimuli that evoke host responses that are reflected in the host's nuclear architecture. We believe that this is not only the first time that gene-repositioning studies have been attempted in a mollusc but also demonstrates a parasite influencing the interphase genome organization of its host. PMID- 20849861 TI - Unmetabolized fenofibrate, but not fenofibric acid, activates AMPK and inhibits the expression of phosphoenolpyruvate carboxykinase in hepatocytes. AB - AIMS: A lipid-lowering agent, fenofibrate, has been reported to reduce hepatic glucose production and the expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme for gluconeogenesis in the liver. However, the precise mechanisms of these effects have remained unclear. MAIN METHODS: Rat hepatoma-derived H4IIE cells and murine myoblast-derived C2C12 cells were incubated with the ester form of fenofibrate and fenofibric acid, a metabolite of fenofibrate ester, and the phosphorylation of AMPK, acetyl-CoA carboxylase (ACC), PEPCK mRNA expression and glucose production were assessed. KEY FINDINGS: Incubation of H4IIE hepatoma cells with the ester form of fenofibrate increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) and decreased PEPCK mRNA expression and glucose production. Fenofibrate-induced reductions in PEPCK expression and glucose production were abrogated by compound C, a specific AMPK inhibitor. Fenofibric acid, a metabolite of fenofibrate ester, had no effects on AMPK phosphorylation, PEPCK gene expression, or glucose production in H4IIE cells. Fenofibrate-treated mice exhibited increases in AMPK phosphorylation and a decrease in PEPCK expression in the liver but not in skeletal muscles, suggesting that unmetabolized fenofibrate accumulated and affected AMPK only in the liver. SIGNIFICANCE: These results demonstrate that fenofibrate inhibits PEPCK gene expression and hepatic glucose production in the liver via AMPK activation, even though the metabolite loses its effects on AMPK and does not work in vivo in myocytes. This novel feature of fenofibrate may provide additional benefit for the treatment of patients with disorders of both lipid and glucose metabolism. PMID- 20849862 TI - Cdc42-mediated inhibition of GSK-3beta improves angio-architecture and lumen formation during VEGF-driven pathological angiogenesis. AB - Vascular endothelial growth factor-A (VEGF) typically induces abnormal angiogenesis in the adult, thereby aggravating disease pathology and limiting utility of VEGF for therapeutic angiogenesis. To identify strategies for rectifying defects in pathological VEGF neovessels, we investigated consequences of modulating the Rho GTPase Cdc42. In a mouse skin model of VEGF-driven pathological angiogenesis, transduction with active Cdc42 (L28Cdc42) markedly improved VEGF neovessels, as measured by increased lumen formation, enlarged vessel diameter, and enhanced perfusion of macromolecular tracers. Conversely, transduction with dominant negative Cdc42 (N17Cdc42) impaired endothelial cell (EC) assembly into lumenized blood vessels and reduced neovessel diameter and tracer perfusion. In vitro, active Cdc42 improved coordination between actin filaments and microtubules and enhanced formation of vascular cords, suggesting that active Cdc42 rectifies defects in angiogenesis by improving cytoskeletal dynamics and capillary morphogenesis. Analyses of Cdc42 signaling in microvascular ECs indicated that active Cdc42 also inhibits glycogen synthase kinase-3beta (GSK-3beta), a multi-functional serine/threonine protein kinase. Pharmacological inhibition of GSK-3beta improved vascular cord formation in vitro and promoted proper neovessel formation in vivo comparably to active Cdc42, thus linking GSK-3beta inhibition to the mechanism by which active Cdc42 rectifies pathological neovascularization. These studies identify activation of Cdc42 and inhibition of GSK-3beta as novel strategies for correcting abnormalities associated with VEGF-driven angiogenesis, and they suggest new approaches for achieving improved therapeutic neovascularization with VEGF. PMID- 20849863 TI - The long-term impact of footshock stress on addiction-related behaviors in rats. AB - We investigated the impact of electric shocks--frequently used to model post traumatic stress disorder in rodents--on behaviors relevant to drug abuse in rats. Rats exposed to 10 shocks of 3 mA over 5 min showed a robust conditioned fear 28 days later, which confirms the traumatic nature of shock exposure. A different set of rats was studied in the conditioned place preference paradigm beginning with the 27th post-shock day. 10mg/kg morphine induced a marked place preference in both shocked and non-shocked rats. Although the magnitude of place preference was not affected, extinction was markedly delayed in shocked rats. We also investigated tolerance to the hyperthermic effects of morphine. A low dose (5mg/kg) that was administered 4 weeks after shock exposure robustly increased body temperature in both shocked and non-shocked rats. Repeated injections resulted in a mild tolerance in non-shocked controls; yet, morphine readily increased body temperature in these rats on the 5th day of injections. In contrast, the temperature-heightening effect of morphine was abolished in shocked rats after 2 days. Thus, shock exposure considerably delayed the extinction of place preference induced by, and dramatically accelerated the tolerance to the effects of, morphine. Our study shows that electric shocks durably affect behavior in tests relevant to drug abuse in conjunction with the development of post-traumatic stress disorder-like behavioral dysfunctions. PMID- 20849864 TI - Reelin as a putative vulnerability factor for depression: examining the depressogenic effects of repeated corticosterone in heterozygous reeler mice. AB - We examined a potential two-hit murine animal model of depression by assessing whether a genetic deficit in reelin increases vulnerability to the depressogenic effects of the stress hormone corticosterone. Stress is an identified risk factor for the onset of depressive symptoms, but depression also has a significant genetic component, suggesting that environmental factors and genetic background likely interact in the etiology of depression. Previous results have revealed that reelin levels are decreased in post-mortem hippocampal tissue from patients with schizophrenia, bipolar disorder and depression, and also in an animal model of depression. Therefore, we hypothesized that heterozygous reeler mice (HRM), with approximately 50% normal levels of reelin, would be more sensitive to the depressogenic effects of corticosterone than wild-type mice (WTM). Mice received subcutaneous injections of either vehicle or 5 mg/kg, 10 mg/kg, or 20 mg/kg of corticosterone for 21 consecutive days, and then they were assessed for changes in depression-like behavior, hippocampal reelin expression, and hippocampal neurogenesis. Corticosterone produced dose-dependent increases in depression-like behavior and decreases in reelin expression, neurogenesis, and cell maturation regardless of mouse genotype. There were no differences between the vehicle injected HRM and WTM in these measures. However, the effects of CORT on behavior, the number of reelin-positive cells in the subgranular zone or hilus, and hippocampal neurogenesis were more pronounced in the HRM than in the WTM, providing support for the idea that mice with impaired reelin signaling may be more vulnerable to the deleterious effects of glucocorticoids. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 20849867 TI - Effects of olfactory and gustatory stimuli on neural excitability for swallowing. AB - This project evaluated the effects of olfactory and gustatory stimuli on the amplitude and latency of motor-evoked potentials (MEPs) from the submental muscles when evoked by transcranial magnetic stimulation (TMS). Sixteen healthy volunteers (8 males; age range 19-43) participated in the study. Lemon concentrate at 100% and diluted in water to 25% were presented separately as odor and tastant stimuli. Tap water was used as control. 15 trials of TMS-evoked MEPs triggered by volitional contraction of the submental muscles and volitional swallowing were measured at baseline, during control condition, during stimulus presentation, and immediately, 30-, 60-, and 90-min poststimulation for each of the four stimulus presentations. Experiments were repeated using the combined odor and tastant concentrations that most influenced the MEP independently. Differences in MEP amplitude measured during swallowing were seen at 30-, 60-, and 90-min poststimulation for simultaneous olfactory and gustatory stimulation as opposed to no differences seen at any point for stimuli presented separately. This study has shown that combined odor and tastant stimulation (i.e., flavor) can increase MEP amplitude during swallowing and that this enhancement of MEP can persist for at least 90min following stimulation. As increased MEP amplitude has been associated with improved swallowing performance, a follow-up study is underway to determine the biomechanical changes produced by altered MEPs to facilitate translation of these data to clinical dysphagia management. PMID- 20849865 TI - Vasopeptidase inhibitor ilepatril (AVE7688) prevents obesity- and diabetes induced neuropathy in C57Bl/6J mice. AB - Previously we demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuro-active peptides, and angiotensin converting enzyme (ACE) with a vasopeptidase inhibitor improves vascular and neural function in diabetic rat models. The purpose of this study was to determine whether inhibition of NEP and ACE or deletion of NEP provides protection from nerve impairment caused by diabetes or diet induced obesity (DIO). To determine the role of NEP and ACE inhibition in neuropathy related to insulin-deficient diabetes or DIO we used C57Bl/6J mice treated with AVE7688, a vasopeptidase inhibitor, or NEP deficient (-/-) mice. Mice at 12 weeks of age were fed a high fat diet for 12 weeks or were diabetic for duration of 12 weeks following a single injection of high dose streptozotocin. Both a prevention and intervention protocol was used for AVE7688 treatment. Glucose utilization was impaired in DIO C57Bl/6J and NEP -/- mice. However, treating DIO C57Bl/6J or NEP /- mice with AVE7688 improved glucose tolerance. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and DIO C57Bl/6J mice but not in AVE7688 treated C57Bl/6J mice or NEP -/- mice exposed to either streptozotocin-induced diabetes or a high fat diet. Intraepidermal nerve fiber (IENF) profiles were decreased in the hindpaw of C57Bl/6J diabetic or DIO mice and this improved when the mice were treated with AVE7688. IENF profiles were not decreased in diabetic or DIO NEP (-/-) mice. These studies suggest that NEP plays a role in regulating nerve function in insulin-deficient diabetes and DIO. PMID- 20849868 TI - Effects of single macronutrients on serum cortisol concentrations in normal weight men. AB - A previous study reported that a high carbohydrate meal, in contrast to a high protein/fat meal, significantly increased cortisol concentrations in visceral obese subjects. The objective of this study was to identify effects of single macronutrients on plasma cortisol concentrations. Ten male subjects (age 27.3+/ 7.4y, BMI 22.1+/-1.7kg/m(2)) were studied in a randomized crossover design on four days around lunchtime after consuming breakfast matched for daily energy requirements (DER 20%). For lunch they consumed one liter of a shake (DER 18%) containing either fat, protein or carbohydrate, with a raspberry taste and similar hedonic value (59+/-2mm on a 100mm VAS), using water as control. Serum cortisol concentrations were measured before lunch and during three hours following lunch. Baseline cortisol concentrations did not differ among treatments. The protein as well as the fat lunch caused a significant decrease in cortisol concentrations when compared to the carbohydrate lunch, and showed no difference from the control condition (p<0.05). The cortisol response in the protein condition (AUC=37,024+/-3518nmol/L min) and in the fat condition (AUC=35,977+/-3562nmol/L min) were significantly smaller when compared with the cortisol response in the carbohydrate condition (AUC=47,310+/-3667nmol/L min) (p<0.03), but did not differ from the control condition (AUC=32,784+/-1683nmol/L min) (Fig. 1). The cortisol response in the carbohydrate condition was significantly higher when compared with the response in the control condition (p<0.004). We conclude that cortisol concentrations decreased after protein or fat intake, which was not different from control; this decrease was prevented by carbohydrate intake. PMID- 20849866 TI - The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects. AB - Although Delta(9)-tetrahydrocannabinol (THC) and other mixed CB(1)/CB(2) receptor agonists are well established to elicit antinociceptive effects, their psychomimetic actions and potential for abuse have dampened enthusiasm for their therapeutic development. Conversely, CB(2) receptor-selective agonists have been shown to reduce pain and inflammation, without eliciting apparent cannabinoid behavioral effects. In the present study, we developed a novel ethyl sulfonamide THC analog, O-3223, and compared its pharmacological effects to those of the potent, mixed CB(1)/CB(2) receptor agonist, CP55,940, in a battery of preclinical pain models. Competitive cannabinoid receptor binding experiments revealed that O 3223 was approximately 80-fold more selective for CB(2) than CB(1) receptors. Additionally, O-3223 behaved as a full CB(2) receptor agonist in [(35)S]GTPgammaS binding. O-3223 reduced nociceptive behavior in both phases of the formalin test, reduced thermal hyperalgesia in the chronic constriction injury of the sciatic nerve (CCI) model, and reduced edema and thermal hyperalgesia elicited by intraplantar injection of LPS. These effects were blocked by pretreatment with the CB(2) receptor-selective antagonist SR144528, but not by the CB(1) receptor antagonist, rimonabant. Unlike CP55,940, O-3223 did not elicit acute antinociceptive effects in the hot-plate test, hypothermia, or motor disturbances, as assessed in the rotarod test. These data indicate that the CB(2) receptor-selective agonist, O-3223, reduces inflammatory and neuropathic nociception, without affecting basal nociception or eliciting overt behavioral effects. Moreover, this compound can serve as a template to develop new CB(2) receptor agonists with increased receptor selectivity and increased potency in treating inflammatory and neuropathic pain. PMID- 20849869 TI - Synthesis and biological evaluation of some nitrogen containing steroidal heterocycles. AB - epi-Androsterone 1 was converted into its hydrazone derivative through the reaction with hydrazine hydrate 80%. Hydrazonoandrostane derivative 2b reacted with hydrazonoyl halides in the presence of K(2)CO(3) forming the corresponding hydrazopyridazinoandrostane derivatives 6a-d. The 3beta-acetyl-17 hydrazonoandrostane derivative 2b reacted with a halogen reagent, benzoyl chloride, to form the non-cyclic 16-benzoylated hydrazone 9. On the other hand, compound 2b produced the corresponding pyridazinoandrostane derivatives 11 and 12 via its reaction with phenacyl bromide and chloroacetone respectively. Reaction of the hydrazono derivative 2b with benzaldehyde in the presence of acetic acid drops led to the formation of the benzylidenehydrazonoandrostane derivative 13. The product 14, phosphinom-ethylenehydrazonoandrostane was obtained by the reaction of the derivative 13 with trisdimethylaminophosphine in the presence of dry benzene. The reaction of compound 2b with phenyl isothiocyanate followed by boiling in chloroacetic acid or thioglycolic acid produced the pyrazoloandrostane derivatives 17 and 18 respectively. The biological activity of compounds 6a, 6d, 11, 12, and 15 was evaluated as inhibitor of growth in a human liver carcinoma cell line and doxorubicine was used for comparison. Compounds 15 and 12 showed a higher potency than the other tested compounds. PMID- 20849871 TI - Molecular mechanisms for plasmacytoid dendritic cell function and development. AB - Dendritic cells (DCs) are activated by immune adjuvants in a DC subset-specific manner. Plasmacytoid DC (pDC) is a unique subset that senses nucleic acid immune adjuvants only through two Toll-like receptors (TLRs), TLR7 and TLR9 and produces large amounts of type I interferons. Here I review recent trend in pDC function and development. PMID- 20849870 TI - Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set. AB - A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts led to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data. PMID- 20849872 TI - Induction of lamina propria Th17 cells by intestinal commensal bacteria. AB - Th17 cells constitute a subset of activated CD4(+) T cells, characterized by their production of interleukin (IL)-17, IL-17F, and IL-22, that play a critical role in host defence against extracellular pathogens. An intriguing feature of these cells is their selective and constitutive presence in the intestinal lamina propria. The development of intestinal Th17 cells is controlled by intestinal commensal bacteria. Recently, segmented filamentous bacterium (SFB) was identified as a specific bacterial taxon that promotes Th17 differentiation in the small intestine of mice. We discuss the recent advances in our understanding of the mechanism of intestinal Th17 synthesis and its potential implications for the treatment of inflammatory bowel diseases. PMID- 20849873 TI - Innate immunity and vaccine. AB - Immune adjuvant is an artificial pathogen-associated molecular patterns (PAMP) for potentiating various immune responses. Vaccine represents one event that is capable of inducing immune response caused by antigen and PAMP stimuli, which act on antigen-presenting dendritic cells (mDCs). Here, we introduce the pathways by which CTL and NK cells are driven through mDC maturation in response to adjuvants. PMID- 20849874 TI - The role of adjuvants in vaccines for seasonal and pandemic influenza. AB - Current seasonal influenza vaccines aim to induce high-titred virus-neutralizing antibody to the viral hemagglutinin (HA), which is the best form of protection against infection, but these vaccines can be poorly efficacious in the elderly and other target groups that rely on them most. Furthermore, little cross protection is provided against significantly drifted strains and even less against different subtypes of virus with pandemic potential. Adjuvants could theoretically have two different roles in improving control of influenza through vaccination. Firstly, a role in enhancing the antibody response in situations where the split virus preparation is poorly immunogenic or if there is an imperative to provide "dose sparing" in the context mass vaccination with a virus to which the population is immunologically naive. Secondly, adjuvants could be used to allow induction of additional arms of the immune response that are not stimulated by current split virus vaccines. Briefly reviewed here are our efforts to investigate the role of adjuvants in both these contexts. PMID- 20849875 TI - Color constancy. AB - A quarter of a century ago, the first systematic behavioral experiments were performed to clarify the nature of color constancy-the effect whereby the perceived color of a surface remains constant despite changes in the spectrum of the illumination. At about the same time, new models of color constancy appeared, along with physiological data on cortical mechanisms and photographic colorimetric measurements of natural scenes. Since then, as this review shows, there have been many advances. The theoretical requirements for constancy have been better delineated and the range of experimental techniques has been greatly expanded; novel invariant properties of images and a variety of neural mechanisms have been identified; and increasing recognition has been given to the relevance of natural surfaces and scenes as laboratory stimuli. Even so, there remain many theoretical and experimental challenges, not least to develop an account of color constancy that goes beyond deterministic and relatively simple laboratory stimuli and instead deals with the intrinsically variable nature of surfaces and illuminations present in the natural world. PMID- 20849876 TI - Zebrafish mast cells possess an FcERI-like receptor and participate in innate and adaptive immune responses. AB - We previously identified a zebrafish mast cell (MC) lineage and now aim to determine if these cells function analogously in innate and adaptive immunity like their mammalian counterparts. Intraperitoneal (IP) injection of compound 48/80 or live Aeromonas salmonicida resulted in significant MC degranulation evident histologically and by increased plasma tryptase compared with saline injected controls (p=0.0006, 0.005, respectively). Pre-treatment with ketotifen abrogated these responses (p=0.0004, 0.005, respectively). Cross-reactivity was observed in zebrafish to anti-human high-affinity IgE receptor gamma (FcERIgamma) and IgE heavy chain-directed antibodies. Whole mount in situ hybridization on 7 day embryos demonstrated co-localization of cpa5, a MC-specific marker, with myd88, a toll-like receptor adaptor, and zebrafish FcERI subunit homologs. Zebrafish injected IP with matched dinitrophenyl-sensitized mouse (anti-DNP) IgE and DNP-BSA or trinitrophenyl-sensitized mouse (anti-TNP) IgE and TNP-BSA demonstrated increased plasma tryptase compared with mismatched controls (p=0.03, 0.010, respectively). These results confirm functional conservation and validate the zebrafish model as an in vivo screening tool for novel MC modulating agents. PMID- 20849877 TI - Prior colonisation with Candida species fails to guide empirical therapy for candidaemia in critically ill adults. AB - OBJECTIVES: Pre-emptive fluconazole (fcz) anti-fungal therapy is often based upon Candida colonisation of at least 2 non-contiguous non-sterile sites. The aim of this study was to evaluate the relationship between candidaemia and prior colonisation of non-sterile sites. METHODS: A retrospective observational study was performed in the intensive care unit/high dependency unit (ICU/HDU) of a University hospital on alternate years from 1999-2007, where a pre-emptive anti fungal therapy policy was introduced in 2005. RESULTS: A higher proportion of blood isolates were Candida glabrata compared with non-sterile isolates (16/46 vs 106/1062; p < 0.001), similarly a greater proportion of blood isolates were fcz resistant compared with non-sterile isolates (15/46 vs 101/1062; p < 0.001). No trend over time was detected in the proportion of C. glabrata and Candida albicans isolates from blood and non-sterile sites, or in the fcz-sensitivity of isolates from these sites. C. glabrata candidaemia was more likely to occur in the absence of non-sterile site colonisation compared with non-glabrata candidaemia (12/16 vs 8/30; p = 0.005). Of candidaemic patients, 43% had no preceding colonisation by any Candida spp.; in 67% of these patients, candidaemia was due to C. glabrata. CONCLUSIONS: Pre-emptive therapy based upon colonisation of at least two sites may be inadequate as 43% of candidaemic patients had no evidence of prior colonisation, 67% of whom had candidaemia due to C. glabrata. Furthermore if pre-emptive anti-fungal therapy is instituted in non-colonised patients there is a risk of selecting an inappropriate anti-fungal for C. glabrata. Despite the introduction of pre-emptive fcz therapy, no time trend was detected in the proportion of fcz-sensitive isolates from blood and non-sterile sites. PMID- 20849878 TI - Real-time reverse transcription-PCR assay for differentiating the Pandemic H1N1 2009 influenza virus from swine influenza viruses. AB - Since the Pandemic H1N1 2009 (H1N1pdm) influenza virus emerged in human in 2009, H1N1pdm, classical swine H1, Eurasian avian-like H1, human-like H1 and human-like H3 swine influenza viruses have circulated in pig populations, and avian H9N2 viruses have been isolated in pigs as well. In this study, TaqMan single-step real-time reverse transcription-PCR (rtRT-PCR) assays targeting the hemagglutinin gene were developed to differentiate H1N1pdm from other genetic lineages of the H1 subtype and other subtypes of influenza viruses circulating in human and pig populations for veterinary use. H1N1pdm rtRT-PCR detected H1N1pdm RNA and did not cross-react with classical swine H1, Eurasian avian-like H1, human-like H1, human like H3 swine and avian H9 influenza viruses RNA. Classical swine H1, Eurasian avian-like H1, human-like H1 and H3 and avian H9 rtRT-PCR were reacted exclusively with viral RNA of their respective lineages and subtypes. The results demonstrate that these assays are useful for the diagnosis of the H1N1pdm virus in both human- and animal-health-related fields. PMID- 20849879 TI - A cross-reactive neutralizing monoclonal antibody protects mice from H5N1 and pandemic (H1N1) 2009 virus infection. AB - A novel influenza (H1N1) virus caused an influenza pandemic in 2009, while highly pathogenic H5N1 avian influenza viruses have continued to infect humans since 1997. Influenza, therefore, remains a serious health threat. Currently, neuraminidase (NA) inhibitors are the mainstay for influenza therapy; however, drug-resistant mutants of seasonal H1N1 and H5N1 viruses have emerged highlighting the need for alternative therapeutic approaches. One such approach is antibody immunotherapy. Here, we show that the monoclonal antibody C179, which recognizes a neutralizing epitope common among H1, H2, H5, and H6 hemagglutinins (HAs), protected mice from a lethal challenge with various H5N1 and pandemic (H1N1) 2009 viruses when administered either intraperitoneally or intranasally. The protective efficacy of intranasally inoculated C179 was comparable to that of intraperitoneal administration. Our results suggest that direct administration of this anti-influenza antibody to viral replication sites is an effective strategy for prophylaxis and therapy. PMID- 20849880 TI - Cistanches Herba enhances learning and memory by inducing nerve growth factor. AB - Nerve growth factor (NGF) has potent biological activities such as preventing neuronal death, promoting neurite outgrowth, supporting synapse formation, and enhancing memory function. NGF and NGF-like molecules can potentially be used to treat neurodegenerative disorders, such as dementia. This study investigated the effects of Cistanches Herba, a widely used medicinal herb, on NGF regulation and its neuronal actions, including neurite outgrowth, synapse formation, and learning and memory enhancement. Cistanches Herba extract (CHE; 250 MUg/ml) increased NGF induction in C6 cells and led to neurite extension in PC12 cells. It also stimulated NGF secretion in the cortex and hippocampus of the mouse brain at 5 and 20mg/kg/day (3 days, p.o.). Furthermore, CHE increased neuronal cell differentiation, neurite length, and synapse formation in the mouse hippocampus. CHE significantly enhanced learning and memory, as demonstrated by passive avoidance test and novel object recognition test. These results suggest that CHE is useful for improving memory function via its action in upregulating NGF. PMID- 20849881 TI - Adolescent social isolation changes social recognition in adult mice. AB - Rearing in social isolation has profound effects on several aspects of behavior in adult rodents. However, little is known about effects of social stress on social behavior in these animals. In the present study, we examined social recognition in mice of both sexes that were individually housed from 30 days of age until testing at approximately 80 days of age, individually housed from day 30 until day 60, followed by group housing from day 60 until testing at around 80 days of age and in control mice that were group housed throughout experiment. A standard social recognition test was performed with ovariectomized female conspecifics introduced into the home cage of tested mice for 1 min, eight consecutive times with 9 min breaks between tests, and in the ninth test, new, unfamiliar females were introduced. The time spent investigating stimulus mice during each of the nine tests was recorded. Group housed male and female mice showed strong pattern of social learning, whereas mice reared in isolation from day 30 until testing did not show evidence of social recognition. Interestingly, mice reared in isolation from 30 until 60 days of age and then group housed again, also showed reduced ability for social learning in comparison to the controls housed in groups through the entire period. These results therefore show that social isolation has a profound effect on social behavior in mice, and that even isolation for a limited period can produce lasting behavioral deficits. PMID- 20849882 TI - Central carbon metabolism of Plasmodium parasites. AB - The central role of metabolic perturbation to the pathology of malaria, the promise of antimetabolites as antimalarial drugs and a basic scientific interest in understanding this fascinating example of highly divergent microbial metabolism has spurred a major and concerted research effort towards elucidating the metabolic network of the Plasmodium parasites. Central carbon metabolism, broadly comprising the flow of carbon from nutrients into biomass, has been a particular focus due to clear and early indications that it plays an essential role in this network. Decades of painstaking efforts have significantly clarified our understanding of these pathways of carbon flux, and this foundational knowledge, coupled with the advent of advanced analytical technologies, have set the stage for the development of a holistic, network-level model of plasmodial carbon metabolism. In this review we summarize the current state of knowledge regarding central carbon metabolism and suggest future avenues of research. We focus primarily on the blood stages of Plasmodium falciparum, the most lethal of the human malaria parasites, but also integrate results from simian, avian and rodent models of malaria that were a major focus of early investigations into plasmodial metabolism. PMID- 20849883 TI - The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages. AB - The Toll-like receptors (TLRs) play a pivotal role in innate immunity for the detection of highly conserved, pathogen-expressed molecules. Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent. To investigate whether this iNOS/Src/FAK pathway is a general mechanism for macrophages to mobilize in response to engagement of TLRs other than TLR4, peptidoglycan (PGN, TLR2 ligand), polyinosinic polycytidylic acid (polyI:C, TLR3 ligand) and CpG-oligodeoxynucleotides (CpG, TLR9 ligand) were used to treat macrophages in this study. Like LPS stimulation, simultaneous increase of cell motility and Src (but not Fgr, Hck, and Lyn) was detected in RAW264.7, peritoneal macrophages, and bone marrow-derived macrophages exposed to PGN, polyI:C and CpG. Attenuation of Src suppressed PGN-, polyI:C-, and CpG-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by the reintroduction of siRNA-resistant Src. Besides, knockdown of FAK reduced the mobility of macrophages stimulated with anyone of these TLR ligands. Remarkably, PGN-, polyI:C-, and CpG-induced Src expression, FAK Pi-Tyr861, and cell mobility were inhibited in macrophages devoid of iNOS, indicating the importance of iNOS. These findings corroborate that iNOS/Src/FAK axis occupies a central role in macrophage locomotion in response to engagement of TLRs. PMID- 20849884 TI - Quantification methods for Bacillus cereus vegetative cells and spores in the gastrointestinal environment. AB - There is an interest to understand the fate and behaviour of the food-borne pathogen Bacillus cereus in the gut, a challenging environment with a high bacterial background. We evaluated the current detection methods to select an appropriate strategy for B. cereus monitoring during gastrointestinal experiments. Application of quantitative real-time PCR (qPCR) in a gastrointestinal matrix required careful selection of the qPCR reaction and elaborate optimization of the DNA extraction protocol. Primer competition and depletion problems associated with qPCR reactions targeting general 16S rRNA gene can be avoided by the selection of a target sequence that is unique for and widespread among the target bacteria, such as the toxin gene nheB in the case of pathogenic B. cereus. Enumeration of B. cereus during the ileum phase was impossible by plating due to overgrowth by intestinal bacteria, while a carefully optimized qPCR enabled specific detection and quantification of B. cereus. On the other hand, plating allowed the distinction of viable, injured and dead bacteria and the germination of spores, which was not possible with qPCR. In conclusion, both plating and qPCR were necessary to yield the maximal information regarding the viability and physiology of the B. cereus population in various gastrointestinal compartments. PMID- 20849885 TI - Construction of a novel shuttle vector for use in Haemophilus influenzae and H. parainfluenzae. AB - Haemophilus influenzae is an important human pathogen. A number of complete genome sequences of various haemophili are available; however, functional studies have been limited by the lack of an effective shuttle vector which functions in all strains. Here, we have constructed a shuttle vector, pEJ6, which transfers genes between Escherichia coli and H. influenzae and H. parainfluenzae. The vector contains an origin of replication from pLS88 which is functional in E. coli and H. influenzae. In addition it contains an RP4 mobilisation region. The vector can be introduced by electroporation and conjugation into capsulate and non-typeable H. influenzae and is functional for allelic replacement and mutant complementation. The vector will be useful for investigating gene function in Haemophilus spp. PMID- 20849886 TI - Rapid method for screening enoate reductase activity in yeasts. AB - Old Yellow Enzymes (OYEs, EC 1.6.99.1) are flavin-dependent oxidoreductases that catalyze the asymmetric reduction of electron-poor alkenes (enoate reductase activity). Since OYEs are involved in detoxification of acrolein, a high throughput method for selecting yeasts expressing high enoate reductase activity, based on their acrolein resistance, was developed. The screening method was based on the measurement of growth in acrolein-supplemented medium, in 96-well microtiter plate cultures. A quantitative descriptor (Acrolein Resistance Factor=ARF) was firstly designed for quantifying the influence of both acrolein concentration and time of exposure on yeast growth. Besides, the efficiency of bioconversion of ketoisophorone (KIP) was exploited to measure OYE activity. In order to validate the method, ARF was correlated with the bioconversion of KIP on thirty yeast strains, belonging to 7 genera. With only a few exceptions, all strains exhibiting the highest ARF also displayed the maximum OYE activity. The presence of OYE genes in the strains showing OYE activity was confirmed by PCR amplification. Based on the results herein reported, this method should be profitably used as a fast screening procedure aimed at selecting outstanding strains for whole-cell bioconversions and could open many possibilities for the isolation and the biocatalytic exploitation of new OYEs from yeasts. PMID- 20849887 TI - Application of a non-species dependent ELISA for the detection of antibodies in sera of Burkholderia pseudomallei-immunized goats. AB - A modified, non-species dependent ELISA was performed to detect antibodies in sera of Burkholderia pseudomallei-immunized goats using protein G- or protein A peroxidase conjugates. The rise of antibody titers during the immunization period exhibited corresponding results by modified ELISA comparison to conventional ELISA and the IHA. Regarding the increase of antibody levels from the pre immunized baseline to the post-immunized status, the antibody titer detected by modified ELISA was higher than IHA but lower than conventional ELISA. Further efforts are needed to improve the modified ELISA for the diagnosis of melioidosis in animals. PMID- 20849888 TI - Fluorescence in situ hybridization of uncultured zoosporic fungi: Testing with clone-FISH and application to freshwater samples using CARD-FISH. AB - Recently, molecular environmental surveys of the eukaryotic microbial community in lakes have revealed a high diversity of sequences belonging to uncultured zoosporic fungi commonly known as chytrids. These microorganisms have two different stages in their life cycle and are known as algal parasites (i.e. host attached infective sporangia) and as food sources for zooplankton (i.e. free living zooflagellate propagules) in aquatic systems. However, because of their small size and their lack of distinctive morphological features, traditional microscopy does not allow the detection of chytrids, particularly of zoospores which have probably been misidentified as phagotrophic flagellates in previous studies. Hence, quantitative data on chytrids in natural environments is missing. We have adapted a clone-FISH approach known from prokaryotes to optimize the hybridization conditions of a designed oligonucleotidic probe specific to Chytridiales (i.e. the largest group of the true-fungal division of Chytridiomycota), before application to natural samples using the CARD-FISH approach. When these conditions were applied, the CARD-FISH assay demonstrated high specificity and sensitivity, and offers a promising tool for quantitative assessment of natural zoosporic fungi, primarily of zoospores which contributed up to 60% of the total abundance of heterotrophic flagellates. Although the field results from the CARD-FISH approach were considered preliminary and mainly as 'proof of concept', findings were consistent with ecological considerations known from pelagic habitats and host versus parasite populations, with recurrent ecological patterns in two contrasting lake ecosystems. We conclude that this approach will contribute to a better understanding of the ecological significance of zoosporic organisms in microbial food webs of pelagic ecosystems. PMID- 20849889 TI - The DiversiLab system versus pulsed-field gel electrophoresis: characterisation of extended spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae. AB - Fast and reliable epidemiological typing methods for identifying outbreaks and epidemic strains of extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae are urgently needed. The DiversiLab system (DL) has been proposed for these purposes. We compared DL to pulsed-field gel electrophoresis (PFGE) on a national collection of ESBL-producing Escherichia coli (n=258; of which 226 isolates were typeable with PFGE) and Klebsiella pneumoniae (n=48) isolated in 2007. For E. coli the Wallace coefficients showed that the probability of two isolates of the same DL type having the same PFGE type was only 19.8% and the probability of two isolates of the same PFGE type having the same DL type was 90.4%. For K. pneumoniae the Wallace coefficients showed that the probability of two isolates of the same DL type having the same PFGE type was 100% and the probability of two isolates of the same PFGE type having the same DL type was 79%, indicating that for this K. pneumoniae strain collection DL was slightly more discriminatory. Only four of 48 isolates had discordant results with the two methods. In E. coli 42% of the isolates were sequence type 131 and these isolates were related at >95% similarity with DL and at >=60% similarity with PFGE. In summary, for E. coli DL performed well in identifying isolates related by PFGE, but overestimated the genetic relatedness in the studied collection. This indicates that DL could be a primary screening method for excluding unrelated isolates. Isolates shown to be related must be confirmed with a more discriminatory method. For K. pneumoniae, DL discriminated well but overestimated the diversity of the isolates compared to PFGE, assuming a risk of missing possible genetic relatedness. PMID- 20849890 TI - qPCR assays to quantify genes and gene expression associated with microbial perchlorate reduction. AB - Quantitative PCR (qPCR) assays targeting cld (developed in this work) and pcrA (previously described) were used to quantify these perchlorate-related genes in a perchlorate-reducing enrichment culture. Transcript copies were quantified in perchlorate-reducing Rhodocyclaceae strain JDS4. Oxygen and nitrate inhibited expression of cld and pcrA. PMID- 20849891 TI - Semi-automated extraction of microbial DNA from feces for qPCR and phylogenetic microarray analysis. AB - The human gastrointestinal tract (GI-tract) harbors a complex microbial ecosystem, largely composed of so far uncultured species, which can be detected only by using techniques such as PCR and by different hybridization techniques including phylogenetic microarrays. Manual DNA extraction from feces is laborious and is one of the bottlenecks holding up the application of microarray and other DNA-based techniques in large cohort studies. In order to enhance the DNA extraction step we combined mechanical disruption of microbial cells by repeated bead-beating (RBB) with two automated DNA extraction methods, KingFisher with InviMag Stool DNA kit (KF) and NucliSENS easyMAG (NeM). The semi-automated DNA extraction methods, RBB combined with either KF or NeM, were compared to the manual extraction method currently considered the most suited method for fecal DNA extraction by assessing the yield of 16S rRNA gene copies by qPCR and total microbiota composition by the HITChip, a phylogenetic microarray. Parallel DNA extractions from infant fecal samples by using the three methods showed that the KF and manual methods gave comparable yields of 16S rRNA gene copies as assessed by qPCR, whereas NeM showed a significantly lower yield. All three methods showed highly similar microbiota profiles in HITChip. Both KF and NeM were found to be suitable methods for DNA extraction from fecal samples after the mechanical disruption of microbial cells by bead-beating. The semi-automated methods could be performed in half of the time required for the manual protocol, while being comparable to the manual method in terms of reagent costs. PMID- 20849892 TI - Maturational changes of 5 Hz SSVEPs elicited by intermittent photic stimulation. AB - We investigated the development of the magnitude and phase alignment of steady state visual evoked potentials induced by 5 Hz intermittent photic stimulation in 46 children (3 to 16 years) and 8 adults, as a function of age. We found that, over the occipital region, magnitude values were the highest in 8-11-year old children, but decreased with age over all other cerebral regions. Phase alignment values increased with age over the occipital, parietal and frontal cerebral regions. We interpret these findings in terms of the development of functional interactions between different cortical areas involved in the processing of visual stimuli. PMID- 20849893 TI - Introduction of tag epitopes in the inter-AUG region of foot and mouth disease virus: effect on the L protein. AB - Foot-and-mouth disease virus (FMDV) initiates translation from two in-frame AUG codons producing two forms of the leader (L) proteinase, Lab (starting at the first AUG) and Lb (starting at second AUG). In a previous study, we have demonstrated that a cDNA-derived mutant FMDV (A24-L1123) containing a 57 nucleotide transposon (tn) insertion between the two AUG initiation codons (inter AUG region) was completely attenuated in cattle, suggesting that this region is involved in viral pathogenesis. To investigate the potential role of the Lab protein in attenuation, we have introduced two epitope tags (Flag: DYKDDDK and HA: YPYDVPDYA) or a small tetracysteine motif (tc: CCGPCC) into the pA24-L1123 infectious DNA clone. Mutant viruses with a small plaque phenotype similar to the parental A24-L1123 were recovered after transfection of constructs encoding the Flag tag and the tc motif. However, expression of the Flag- or tc-tagged Lab protein was abolished or greatly diminished in these viruses. Interestingly, the A24-L1123/Flag virus acquired an extra base in the inter-AUG region that resulted in new AUG codons in-frame with the second AUG, and produced a larger Lb protein. This N terminal extension of the Lb protein in mutant A24-L1123/Flag did not affect virus viability or L functions in cell culture. PMID- 20849894 TI - A new fluorescent imaging of renal inflammation with RCP. AB - The objective of this study is to design a fluorescent imaging agent with R-Gel, one of the recombinant polymers (RCP), for renal inflammation. The R-Gel based on human type I collagen has multiple Arg-Gly-Asp (RGD) motifs which are ligands for some types of integrin receptors on the cell surface. After intravenous administration of R-Gel labeled by Cy7 of a fluorescent dye to three animal models of nephritis mousse, interstitial nephritis (by using UUO model mice), glomerulonephritis (HIGA mice), and ischemia-reperfusion injured kidney (I/R mice), the extent of fluorescent imaging at the renal inflammation was assessed. The Cy7-labeled R-Gel was accumulated in the inflammation site to a significantly greater extent than in the normal one at 24h after administration. The renal pattern of fluorescent imaging was similar to that of administration anti-Mac1 antibody. Taken together, it is conceivable that the R-Gel was targeted to macrophages infiltrated into the inflammation site of kidney. PMID- 20849895 TI - Associations of parenting styles, parental feeding practices and child characteristics with young children's fruit and vegetable consumption. AB - The purpose of this study was to investigate the role of parent and child characteristics in explaining children's fruit and vegetable intakes. In 2008, parents of preschoolers (mean age 3.5 years) from 56 schools in Belgium-Flanders completed questionnaires including a parent and child fruit and vegetable food frequency questionnaire, general parenting styles (laxness, overreactivity and positive interactions), specific food parenting practices (child-centered and parent-centered feeding practices) and children's characteristics (children's shyness, emotionality, stubbornness, activity, sociability, and negative reactions to food). Multiple linear regression analyses (n = 755) indicated a significant positive association between children's fruit and vegetable intake and parent's intake and a negative association with children's negative reactions to food. No general parenting style dimension or child personality characteristic explained differences in children's fruit and vegetable intakes. Child-centered feeding practices were positively related to children's fruit and vegetable intakes, while parent-centered feeding practices were negatively related to children's vegetable intakes. In order to try to increase children's fruit and vegetable consumption, parents should be guided to improve their own diet and to use child-centered parenting practices and strategies known to decrease negative reactions to food. PMID- 20849896 TI - The study of food addiction using animal models of binge eating. AB - This review summarizes evidence of "food addiction" using animal models of binge eating. In our model of sucrose bingeing, behavioral components of addiction are demonstrated and related to neurochemical changes that also occur with addictive drugs. Evidence supports the hypothesis that rats can become dependent and "addicted" to sucrose. Results obtained when animals binge on other palatable foods, including a fat-rich food, are described and suggest that increased body weight can occur. However, the characterization of an addiction-like behavioral profile in animals with binge access to fat requires further exploration in order to dissociate the effect of increased body weight from the diet or schedule of feeding. PMID- 20849897 TI - Intracerebroventricular administration of apelin-13 inhibits distal colonic transit in mice. AB - Apelin is a novel bioactive peptide as the endogenous ligand for the orphan G protein-coupled receptor (GPCR), APJ, a receptor distributed in various tissues such as the hypothalamus and the gastrointestinal tract. Recent reports showed that apelin regulated many biological functions, including blood pressure, neuroendocrine, drinking behavior and food intake. However, the role of apelin in regulating gastrointestinal motility remains unknown. The present study aimed to investigate the actions of intracerebroventricularly administered apelin-13 on colonic transit as well as the actions of apelin-13 on the contraction of isolated distal colon in vitro. Intracerebroventricular (i.c.v.) injection of apelin-13 (0.3, 0.5, 1 and 3 MUg/mouse) dose-dependently inhibited fecal pellet output and bead expulsion. This effect was significantly antagonized by the APJ receptor antagonist apelin-13(F13A), indicating an APJ receptor-mediated mechanism. Furthermore, naloxone could also reverse the inhibitory effect of apelin-13 on fecal pellet output and bead expulsion, suggesting the involvement of opioid receptors in the suppressive effect of apelin-13 on distal colon transit. However, apelin-13 (10-8-10-6 M) did not affect distal colonic contractions in vitro. PMID- 20849899 TI - Role of TPPP/p25 on alpha-synuclein-mediated oligodendroglial degeneration and the protective effect of SIRT2 inhibition in a cellular model of multiple system atrophy. AB - Multiple system atrophy (MSA) is a progressive neurodegenerative disorder presenting variable combinations of parkinsonism, cerebellar ataxia, corticospinal and autonomic dysfunction. Alpha-synuclein (alpha-SYN) immunopositive glial cytoplasmic inclusions (GCIs) represent the neuropathological hallmark of MSA, and tubulin polymerization promoting protein (TPPP)/p25 in oligodendroglia has been known as a potent stimulator of alpha-SYN aggregation. To gain insight into the molecular pathomechanisms of GCI formation and subsequent oligodendroglial degeneration, we ectopically expressed alpha-SYN and TPPP in HEK293T and oligodendroglial KG1C cell lines. Here we showed that TPPP specifically accelerated alpha-SYN oligomer formation and co immunoprecipitation analysis revealed the specific interaction of TPPP and alpha SYN. Moreover, phosphorylation of alpha-SYN at Ser-129 facilitated the TPPP mediated alpha-SYN oligomerization. TPPP facilitated alpha-SYN-positive cytoplasmic perinuclear inclusions mimicking GCI in both cell lines; however, apoptotic cell death was only observed in KG1C cells. This apoptotic cell death was partly rescued by sirtuin 2 (SIRT2) inhibition. Together, our results provide further insight into the molecular pathogenesis of MSA and potential therapeutic approaches. PMID- 20849900 TI - Genetic evaluation of the TNF-alpha -238G>A and -308G>A promoter polymorphisms in Croatian patients with type I diabetes. AB - A case-control study was performed to establish a potential association of two TNF-alpha gene promoter SNPs (-238G>A and -308G>A) with occurrence of type 1 Diabetes mellitus (T1DM) in Croatian population (174 patients and 193 healthy controls). Genotypes (obtained by polymerase chain reaction-restriction fragment length polymorphism), and the clinical parameters of T1DM patients were statistically evaluated by SPSS 13 and Arlequin software, G*Power 3.0.10 program, and calculator for Hardy-Weinberg equilibrium. The frequency of the risk (A) allele, as well as the distribution of high-expression (GA, AA) genotypes were significantly higher (p < 0.0001) in T1DM patients only at locus -308. The distribution of the -238G/-308A haplotype was also significantly higher in patients compared with controls (27.6% vs 9.6%, p < 0.0001). Gender-dependent analysis revealed that female T1DM -308GA genotype carriers exhibit considerably stronger association with T1DM (odds ratio = 6.37, 95% confidence interval = 3.16 12.85) than male -308GA patients (odds ratio = 2.71, 95% confidence interval = 1.31-5.59). Clinical parameter analysis of T1DM patients revealed significantly decreased level of hemoglobin A(1)c (HbA(1)c) in -238A allele carriers compared with -238G allele carriers (6.55% vs 7.17%, p = 0.022), as well as the tendency of the risk allele carriers at -238 or -308 locus to develop T1DM earlier in life compared with non-risk allele carriers. In conclusion, susceptibility to T1DM in the Croatian population is strongly associated with the TNF-alpha -308G>A polymorphism, especially in women. In addition, significantly lower HbA(1c) levels found in T1DM -238A allele carriers might indicate better glycemic control in these patients. PMID- 20849898 TI - Heat shock protein 70 upregulation by geldanamycin reduces brain injury in a mouse model of intracerebral hemorrhage. AB - This study investigated the effect of geldanamycin post-treatment on the development of secondary brain injury and neurological deficits in a mouse model of intracerebral hemorrhage. CD-1 mice received stereotactic injection of collagenase type VII into the right basal ganglia. Treatment groups were administered 1 mg/kg (low dose) or 10 mg/kg (high dose) of geldanamycin. Mice were euthanized at two time-points: 24 h or 72 h. Blood-brain-barrier permeability, brain edema, and neurobehavioral deficits were assessed. Additionally, the effects of geldanamycin on heat shock protein 27 and 72; tumor necrosis factor-alpha and interleukin 1 beta expressions were evaluated. High dose geldanamycin significantly attenuated blood-brain barrier disruption and brain edema after intracerebral hemorrhage. Neurobehavioral outcomes were significantly improved in some parameters by high dose treatment. Molecular results showed a marked increase in heat shock protein 72 expression in ipsilateral brain of geldanamycin treated groups with a reduction in the pro inflammatory tumor necrosis factor-alpha. CONCLUSION: Geldanamycin post-treatment is neuroprotective in the mouse model of intracerebral hemorrhage. Geldanamycin administration results in reduction of inflammation, preservation of blood-brain barrier and amelioration of neurobehavioral deficits after an insult possibly by upregulation of heat shock protein 72. PMID- 20849901 TI - The state of antibody therapy. AB - Therapeutic antibodies are widely used in the treatment of various diseases and disease conditions, including cardiovascular diseases, autoimmune disorders, malignancies, and infections. With at least 23 therapeutic agents currently in clinical use and a successful business generating large revenues, major technological advances are now in place to improve the specificity and efficacy of those antibodies already in the market and also generate new, safe and effective macromolecules for the treatment of other ailments. This review provides a summary of the current state of antibody therapy, highlights and discusses recent developments in the field of antibody-based therapeutics production, combination therapy and shows the status of some of the agents that are in clinical trial. PMID- 20849902 TI - Neonatal CD8+ T-cell differentiation is dependent on interleukin-12. AB - Neonatal CD8(+) T-cell activation is significantly impaired compared with that in adults. Recent studies have demonstrated that interleukin (IL)-12 is necessary as a third signal, in addition to antigen and co-stimulation, to authorize the differentiation of naive CD8(+) T cells. We examined whether human neonatal CD8(+) T cells, which possess an exclusively naive T-cell phenotype, required a third signal to authorize a productive T-cell response. IL-12 enhanced activated naive CD8(+) T-cell survival, expansion, CD25 expression, and IL-2 production. Activated CD8(+) T cells produced interferon-gamma and intracellular granzyme B and were cytotoxic only in the presence of IL-12. Sustained IL-12 signaling for 72 hours was required for optimal interferon-gamma production. IL-12, in concert with T cell receptor (TCR) stimulation, sustained late-stage (48-72 hours) intracellular phosphorylation and particularly total protein levels of the proximal TCR components, Lck, and CD3xi. The requirement for a third signal for productive human neonatal CD8(+) T-cell differentiation may have implications for neonatal vaccination strategies. PMID- 20849903 TI - Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population. AB - Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL 2RA/CD25 was associated with type 1 diabetes (chi(2) = 26.8, p < 0.001 for alleles and chi(2) = 29.6, p < 0.001 for genotypes). The C allele (odds ratios [OR] = 1.59) and C/C genotype (OR = 1.56) were identified as susceptibility variants, whereas the A allele (OR = 0.63), A/A genotype (OR = 0.14), and A/C genotype (OR = 0.69) as protective variants. IL-2RA/CD25 is associated with both early-onset and late-onset type 1 diabetes, but with a larger effect size in early-onset disease. There was a nonsignificant tendency toward transmission distortion (p = 0.063). Except a tendency toward younger age at onset in carriers of the C/C genotype, no correlations with disease phenotype, immune markers, HLA DQ, INS and PTPN22 were observed. Also, the frequency of the susceptible genotype was higher in early-onset compared with late-onset TID patients (p = 0.015). In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers. PMID- 20849904 TI - Increased serum leucine, leucine-37 levels in psoriasis: positive and negative feedback loops of leucine, leucine-37 and pro- or anti-inflammatory cytokines. AB - Expression of leucine, leucine-37 (LL-37) is enhanced in keratinocytes of skin lesions with psoriasis. We examined serum LL-37 levels in patients with psoriasis vulgaris. Serum LL-37 levels in patients were higher than in normal controls, and were reduced after cyclosporine A treatment. In both groups, LL-37 and interleukin (IL)-17 levels inversely correlated. In patients, LL-37 levels correlated with interferon (IFN)-gamma and IL-10 levels. In controls, LL-37 levels inversely correlated with tumor necrosis factor (TNF)-alpha, IL-6, IL 1beta, and IL-22 levels. IFN-gamma, IL-17, IL-22, TNF-alpha, IL-6, and IL-1beta enhanced, and IL-10, IL-4, IL-13, and cyclosporine A suppressed, LL-37 secretion from keratinocytes and neutrophils. LL-37 enhanced IFN-gamma, IL-4, IL-13, and TNF-alpha secretion from CD3/CD28-stimulated T cells, suppressed TNF-alpha, IL 1beta, IL-6, and IL-10 secretion from lipopolysaccharide-stimulated monocytes, and IL-17, IL-22, IL-1beta, IL-6, and IL-10 secretion from CD3/CD28-stimulated T cells. LL-37 may sustain its production by enhancing IFN-gamma or reducing IL-10 production, while suppressing its production by reducing IL-17, IL-22, TNF-alpha, IL-1beta, or IL-6 and enhancing IL-4 or IL-13 production. In patients, systemic LL-37 production is enhanced, and an IFN-gamma/LL-37-positive feedback loop may exist. In controls, negative feedback by LL-37 on TNF-alpha, IL-1beta, IL-22, and IL-6 may exist. In both groups, negative feedback by LL-37 on IL-17 may exist. LL 37 may act as an effector and regulator. PMID- 20849905 TI - Free-base nicotine in tobacco products. Part II. Determination of free-base nicotine in the aqueous extracts of smokeless tobacco products and the relevance of these findings to product design parameters. AB - Reports in the peer-reviewed literature and popular press have alleged that smokeless tobacco product (STP) manufacturers increase the addictiveness of their products by adjusting formulae to increase the relative percentage of nicotine in STP that is not protonated. Such nicotine is more popularly, but incorrectly, known as free-base nicotine ("FBN") as it is a calculated amount as opposed to a real chemical species in the STP. Some regulators have mandated reporting of FBN as estimated by Henderson-Hasselbalch equation ("HHE") using the pH-value of an aqueous suspension (or extract) of STP. This is technically incorrect because the HHE is only valid in pure dilute aqueous solution of a single base and its conjugate acid. The aqueous suspensions (or extracts) of STP often contain high concentrations of salts and polymeric anions such as pectate and many other compounds, and there is a molar excess of ammonia over nicotine in some products. These are heretofore-unrecognized sources of error in use of the HHE to estimate relative amount of nicotine that is not protonated results in inaccurate FBN values. Thus, it is not surprising that attempts to show the relevance of estimated value of FBN in STP to human physiology have failed. PMID- 20849906 TI - A case of schizophrenia with Meige syndrome induced by long-term aripiprazole successfully treated with perospirone. PMID- 20849907 TI - Potential analgesic, anti-inflammatory and antioxidant activities of hydroalcoholic extract of Areca catechu L. nut. AB - The hydroalcoholic extract of Areca catechu L. (ANE) nut was screened for its analgesic, anti-inflammatory and in vitro antioxidant potential. Three doses of ANE (250, 500 and 1000 mg/kg orally) were tested for analgesic and anti inflammatory activities. Evaluation of analgesic activity of ANE was performed using hot plate and formalin test in mice. ANE showed maximum increase in hot plate reaction time (56.27%, p<0.01), while reduced the duration of licking/biting behaviors in first (39.45%, p<0.05) and second (92.71%, p<0.01) phases of the formalin test indicating significant analgesic activity. ANE reduced the paw edema considerably (86.79% inhibition after 24h, p<0.01) in dose dependent manner compared to carrageenan-induced rat. In addition, in vitro antioxidant activity of ANE was investigated by total phenolic content (TPC) and hydrogen peroxide assay. The IC(50) observed in hydrogen peroxide assay was 83.14 MUg/ml and TPC 120.56+/-21.09 mg QE/g. Altogether, these results suggest that the hydroalcoholic extract of Areca catechu could be considered as a potential analgesic, anti-inflammatory and antioxidant agent. PMID- 20849908 TI - Phenols and antioxidant activity of hydro-alcoholic extracts of propolis from Algarve, South of Portugal. AB - Propolis is a natural honeybee product known to be beneficial for human health, with a complex chemical composition, highly dependent on the collection site. The objective of the present research was to evaluate phenols and antioxidant activity of propolis samples collected in three main areas of Algarve, South of Portugal. Water revealed to be less effective for extracting phenolic compounds from propolis than the methanol and water/ethanol. The last two were good extraction solvents of phenols. Nevertheless water/ethanol was the solvent chosen because it was able to extract phenols in considerable amounts being less toxic than methanol. In spring, higher amounts of phenols (total phenols, flavones, flavonols, flavanones and dihydroflavonols) were detected in hydro-alcoholic extracts of propolis than in winter. Among the three main areas of Algarve where samples were collected, those from Barrocal had the highest levels of polyphenols, independent on the season (winter or spring). Within each area, the levels of phenols changed according to the zone. Concerning antioxidant activity, samples from Barrocal presented better radical scavenging abilities than those from the remaining areas, independent on the antioxidant method and collection season. Such results correlated closely with the levels of total phenols, flavones and flavonols in samples. PMID- 20849909 TI - Clerodendron glandulosum.Coleb extract ameliorates high fat diet/fatty acid induced lipotoxicity in experimental models of non-alcoholic steatohepatitis. AB - This study evaluates the protective role of Clerodendron glandulosum.Coleb (CG) aqueous extract against high fat diet/fatty acid induced lipotoxicity in experimental models of non-alcoholic steatohepatitis (NASH). Supplementation of NASH mice with CG extract (1% and 3% in high fat diet for 16 weeks) prevented high fat diet induced elevation in liver enzymes, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status and histopathological damage to hepatocytes. Furthermore, results from in vitro study indicates, addition of CG extract (20-200 MUg/ml for 24h) to HepG2 cells minimizes oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that CG extract has the potential of preventing high fat/fatty acid induced NASH. PMID- 20849910 TI - Polycyclic aromatic hydrocarbons in binary mixtures modulate the efficiency of benzo[a]pyrene to form DNA adducts in human cells. AB - Exposure to polycyclic aromatic hydrocarbons (PAHs) always involves complex mixtures that may induce synergistic or antagonistic effects on the genotoxic properties and make risk assessment more difficult. In this study, we evaluated how particulate PAHs modulated the formation of DNA damage induced by carcinogenic benzo[a]pyrene (B[a]P). Single strand breaks and alkali labile sites, as well as BPDE-N2-dGuo DNA adducts were measured in the competent HepG2 cells by Comet assay and HPLC-tandem mass spectrometry, respectively. B[a]P, alone or in binary mixture with other PAHs (1 MUM each), led to low amounts of strand breaks. In contrast, formation of BPDE-N2-dGuo adducts was significant and found to be enhanced in HepG2 co-treated for 14 h by B[a]P in the presence of either benzo[b]fluoranthene (B[b]F), dibenz[a,h]anthracene (DB[a,h]A) or indeno[1,2,3-cd]pyrene (IP). Opposite results were obtained with benzo[k]fluoranthene (B[k]F). The same observations were made when cells were pre incubated with PAH before incubation with B[a]P. These results show that the interactions between PAHs are not direct competition reactions. Emphasis was then placed on the modulation of B[a]P-induced DNA damage by B[b]F and B[k]F. No difference in the time-course formation of DNA damage was observed. However, dose response relationship differed between these two PAHs with a concentration dependent inhibition of BPDE-N2-dGuo DNA by B[k]F whereas a constant level of potentiation for B[b]F was observed for concentrations higher than 1 MUM. Altogether, these results show that the genotoxicity of B[a]P in binary mixtures with other carcinogenic PAH may be modulated. In such cases, a potentiation of BPDE-N2-dGuo adduct formation is most often observed with exception of B[k]F. Several biological mechanisms may account for these observations, including binding of PAHs to the Ah receptor (AhR), their affinity toward CYP450 and competition for metabolism. These different interactions have to be considered when addressing the intricate issue of the toxicity of mixtures. PMID- 20849911 TI - Effect of nephrotoxic treatment with gentamicin on rats chronically exposed to uranium. AB - Uranium is a radioactive heavy metal with a predominantly chemical toxicity, affecting especially the kidneys and more particularly the proximal tubular structure. Until now, few experimental studies have examined the effect of chronic low-dose exposure to uranium on kidney integrity: these mainly analyse standard markers such as creatinine and urea, and none has studied the effect of additional co-exposure to a nephrotoxic agent on rats chronically exposed to uranium. The aim of the present study is to examine the potential cumulative effect of treating uranium-exposed rats with a nephrotoxic drug. Neither physiological indicators (diuresis and creatinine clearance) nor standard plasma and urine markers (creatinine, urea and total protein) levels were deteriorated when uranium exposure was combined with gentamicin-induced nephrotoxicity. A histological study confirmed the preferential impact of gentamicin on the tubular structure and showed that uranium did not aggravate the histopathological renal lesions. Finally, the use of novel markers of kidney toxicity, such as KIM-1, osteopontin and kallikrein, provides new knowledge about the nephrotoxicity threshold of gentamicin, and allows us to conclude that under our experimental conditions, low dose uranium exposure did not induce signs of nephrotoxicity or enhance renal sensitivity to another nephrotoxicant. PMID- 20849912 TI - Adaptive changes results in activation of alternate signaling pathways and resistance to aromatase inhibitor resistance. AB - Hormone therapy is an effective approach for the treatment of breast cancer. The antiestrogen tamoxifen has had a major impact on the disease. Recently, aromatase inhibitors which reduce estrogen synthesis have proved to be more effective and these agents are now used as first line therapy for postmenopausal breast cancer. Nevertheless, resistance to treatment eventually may occur. We have investigated mechanisms involved in resistance to AIs and devised strategies to overcome the resistance. Using a xenograft model, we have identified adaptive changes that results in activation of alternate signaling pathways in tumors resistant to aromatase inhibitors. Expression of ERalpha and aromatase was decreased in the tumors after long term treatment with AIs. In contrast increased expression was observed of tyrosine kinase receptors such as HER-2 and IGFR as well as of downstream signaling proteins, including MAPK. We have demonstrated functional activation of the MAPKinase pathway and shown dependency on growth factor receptor signaling in letrozole resistant cells. Furthermore, our studies indicate that HER-2 is a negative regulator of ER. Thus, when HER-2 was blocked with antibody (herceptin, trastuzumab) ER expression was increased rendering the cells and tumors responsive to aromatase inhibitors and resulting in tumor regression. PMID- 20849913 TI - Adaptive increase in force variance during fatigue in tasks with low redundancy. AB - We tested a hypothesis that fatigue of an element (a finger) leads to an adaptive neural strategy that involves an increase in force variability in the other finger(s) and an increase in co-variation of commands to fingers to keep total force variability relatively unchanged. We tested this hypothesis using a system with small redundancy (two fingers) and a marginally redundant system (with an additional constraint related to the total moment of force produced by the fingers, unstable condition). The subjects performed isometric accurate rhythmic force production tasks by the index (I) finger and two fingers (I and middle, M) pressing together before and after a fatiguing exercise by the I finger. Fatigue led to a large increase in force variance in the I-finger task and a smaller increase in the IM-task. We quantified two components of variance in the space of hypothetical commands to fingers, finger modes. Under both stable and unstable conditions, there was a large increase in the variance component that did not affect total force and a much smaller increase in the component that did. This resulted in an increase in an index of the force-stabilizing synergy. These results indicate that marginal redundancy is sufficient to allow the central nervous system to use adaptive increase in variability to shield important variables from effects of fatigue. We offer an interpretation of these results based on a recent development of the equilibrium-point hypothesis known as the referent configuration hypothesis. PMID- 20849914 TI - Perceptual load modifies processing of unattended stimuli both in the presence and absence of attended stimuli. AB - This study explored effects of perceptual load on stimulus processing in the presence and absence of an attended stimulus. Participants were presented with a bilateral or unilateral display and asked to perform a discrimination task at either low or high perceptual load. Electrophysiological responses to stimuli were then compared at the P100 and N100. As in previous studies, perceptual load modified processing of attended and unattended stimuli seen at occipital scalp sites. Moreover, perceptual load modulated attention effects when the attended stimulus was presented at high perceptual load for unilateral displays. However, this was not true when the attended and unattended stimulus appeared simultaneously in bilateral displays. Instead, only a main effect of perceptual load was found. Reductions in processing contralateral to the unattended stimulus at the N100 provide support for Lavie's (1995) theory of selective attention. PMID- 20849915 TI - Proteomics of voltage-gated ion channels. PMID- 20849916 TI - The role of CD4-dependent signaling in interleukin-16 induced c-Fos expression and facilitation of neurite outgrowth in cerebellar granule neurons. AB - Neuronal interleukin 16 (NIL-16) is the larger neural-specific splice variant of the interleukin-16 (IL16) gene and shows restricted expression to post-mitotic neurons of the mammalian hippocampus and cerebellum. Although the N-terminus of NIL-16 is unique to the neuronal variant, the C-terminus is identical to pro-IL 16, the IL-16 precursor expressed primarily in T-cells. IL-16 was originally described as a proinflammatory cytokine and has diverse immunoregulatory effects which involve signaling through CD4. NIL-16-expressing neurons can secrete IL-16 and may express CD4; moreover, treatment of cultured cerebellar granule neurons (CGCs) with IL-16 increases the expression of c-Fos, an immediate-early gene which transcriptionally regulates genes directing survival, proliferation, and growth. Taken together, we hypothesize that IL-16 functions as a neuroregulatory cytokine which signals through neuronal CD4 receptors. In this study, we investigated the role of CD4 in IL-16-induced c-Fos expression in CGCs, as well as the effects of IL-16 on neuronal survival and growth. We detected components involved in IL-16-signaling in lymphocytes, including CD4 and the associated tyrosine kinase p56(lck), in CGCs using qRT-PCR and immunoblotting. We also show that IL-16 induces c-Fos expression in wild-type CGCs, but not CD4-deficient CGCs or following inhibition of p56(lck). Finally, treatment of CGCs with IL-16 enhanced neurite outgrowth, an effect also observed in CD4-deficient CGCs. Taken together, our results indicate that IL-16-signaling affects neuronal gene expression and growth through CD4-dependent and independent pathways. PMID- 20849917 TI - Effects of intra-hippocampal injections of the NK2 receptor antagonist saredutant on the elevated plus maze, and the mouse defense test battery. AB - Intracerebroventricular (i.c.v.) or intraperitoneal (IP) administration of saredutant (SR48968), an NK2 receptor antagonist, produces anxiolytic-like effects in rodents in a number of animal models of anxiety. NK2 binding sites are present in several limbic structures in rats, including the hippocampus, thalamus, septum and prefrontal cortex, suggesting involvement in the modulation of emotional processes. The current study investigated the behavioral effects of saredutant infused into the ventral hippocampus (VH), a structure associated with cognitive and emotional processes, to clarify the neural substrate underlying the anxiolytic-like effect of the compound. Saredutant (10, 100 or 500 pmol/0.2 MUL) was injected bilaterally into the VH of male CD-1 mice tested in the elevated plus-maze and mouse defense test battery (MDTB). Results from the EPM showed that microinjections of 10 pmol/0.2 MUL of saredutant increased entries and time spent in the open arms and enhanced end-arm exploration. In the MDTB, saredutant (500 pmol/0.2 MUL) decreased vocalizations and increased escape attempts in mice confronted with a rat. Taken together, these results suggest that hippocampal tachykinin mechanisms are involved in the modulation of anxiety and defensive behaviors. PMID- 20849918 TI - The influence of negative emotion on brand extension as reflected by the change of N2: a preliminary study. AB - The aim of the present study is to find the neural features of the impact of induced negative emotion on brand extension. Facing three sequential stimuli in triples consisted of negative emotion pictures (stimulus 1), beverage brand names (stimulus 2), and product names (stimulus 3) in other categories, 20 participants were asked to indicate the suitability of extending the brand in stimulus 2 to the product category in stimulus 3. The stimulus triples were divided into six conditions depending on the emotion (neutral and negative) and the extension product category in stimulus 3: beverage, clothing, and the household appliance. A negative component reflecting conflict, N2, was recorded for each condition on the subjects' scalp. The induced negative emotion elicited significantly larger amplitude of N2 than did the induced neutral emotion in the moderate extension type (extending to the clothing product), whereas no significant difference was observed in any of the other two extension types. The findings indicate that the induced negative emotion has a specific negative impact on moderate brand extension, and the amplitude of N2 can be viewed as a reference measure reflecting such effect. PMID- 20849920 TI - IGF-I stimulates Rab7-RILP interaction during neuronal autophagy. AB - Restoration of autophagy represents a potential therapeutic target for neurodegenerative disorders, but factors that regulate autophagic flux are largely unknown. When deprived of trophic factors, cultured Purkinje neurons die by an autophagy associated cell death mechanism. The accumulation of autophagic vesicles and cell death of Purkinje neurons is inhibited by insulin-like growth factor, by a mechanism that enhances autophagic vesicle turnover. In this report, we identify Rab7 as an IGF-I regulated target during neuronal autophagy. Purkinje neurons transfected with EGFP-Rab7-WT and constitutively active EGFP-Rab7-Q67L contained few RFP-LC3 positive autophagosomes and little co-localization with GFP Rab7 under control conditions. Upon induction of autophagy, RFP-LC3 positive autophagosomes increased and co-localized with GFP-Rab7. Conversely, expression of the dominant negative mutant EGFP-Rab7-T22N increased the accumulation of autophagosomes under control conditions, which accumulated even further during trophic factor withdrawal. There was no vesicular co-localization between Rab7 T22N and RFP-LC3 under control or trophic factor withdrawal conditions. During prolonged trophic factor withdrawal, a condition that leads to the accumulation of autophagic vesicles and cell death, Rab7 activity decreased significantly. IGF I, added at the time of trophic factor withdrawal, prevented the deactivation of Rab7 and increased the interaction of Rab7 with its interacting protein (RILP), restoring autophagic flux. These results provide a novel mechanism by which IGF-I regulates autophagic flux during neuronal stress. PMID- 20849919 TI - Neuropathology of dementia with Lewy bodies in advanced age: a comparison with Alzheimer disease. AB - Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by alpha-synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70 79, 80-89 and >= 90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80-89 and >= 90 year cases compared to 70-79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70-79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group. PMID- 20849921 TI - Knockdown of tissue nonspecific alkaline phosphatase impairs neural stem cell proliferation and differentiation. AB - In the adult mammalian brain the subependymal layer of the lateral ventricles houses neural stem cells giving rise to young neurons migrating towards the olfactory bulb. The molecular cues controlling essential functions within the neurogenesis pathway such as proliferation, short and long distance migration, differentiation and functional integration are poorly understood. Neural progenitors in situ express the tissue nonspecific form of alkaline phosphatase (TNAP), a cell surface-located nonspecific phosphomonoesterase capable of hydrolyzing extracellular nucleotides. To gain insight into the functional role of TNAP in cultured multipotent neural stem cells we applied a knockdown protocol using RNA interference with shRNA and retroviral infection. We show that TNAP knockdown reduces cell proliferation and differentiation into neurons or oligodendrocytes. This effect is abrogated by addition of alkaline phosphatase to the culture medium. Our results suggest that TNAP is essential for NSC proliferation and differentiation in vitro and possibly also in vivo. PMID- 20849922 TI - Dopamine D3 receptor knock-out mice display deficits in locomotor sensitization after chronic morphine administration. AB - Locomotor sensitization is the progressive and enduring enhancement of locomotion induced by stimulants such as drugs, which alter rodent locomotion in a long standing manner. The dopamine D3 receptor has been reported to play a role in morphine addiction. The aim of the present study was to investigate the role of dopamine D3 receptor in the morphine induced locomotor sensitization using dopamine D3 receptor knock-out mice. The dopamine D3 receptor knock-out mice did not display an enhanced behavioral response to acute morphine administration or develop an increased rate of locomotor sensitization to intermittent morphine administration. When 2mg/kg naloxone was co-administered with 10mg/kg morphine, morphine-induced locomotion sensitization in wild-type mice was significantly blocked while the locomotion in the D3 receptor knock-out mice was decreased. Then the wild-type mice were administered with dopamine D3 antagonist nafadotride. It was found that co-administration of morphine with nafadotride could effectively suppress the level of morphine induced behavioral sensitization. It was concluded that a loss of the dopamine D3 receptor gene may inhibit acute morphine induced hyperlocomotor activity and chronic morphine induced behavioral sensitization. PMID- 20849923 TI - HIV-Tat elicits microglial glutamate release: role of NAPDH oxidase and the cystine-glutamate antiporter. AB - Excitotoxicity and/or microglial reactivity might underlie neurologic dysfunction in HIV patients. The HIV regulatory protein Tat is both neurotoxic and pro inflammatory, suggesting that Tat might participate in the pathogenesis of HIV associated neurocognitive disorders (HAND). The present study was undertaken to evaluate if Tat can increase extracellular glutamate, and was specifically designed to determine the degree to which, and the mechanisms by which Tat could drive microglial glutamate release. Data show that application of Tat to cultured primary microglia caused dose-dependent increases in extracellular glutamate that were exacerbated by morphine, which is known to worsen Tat cytotoxicity. Tat induced glutamate release was decreased by inhibitors of p38 and p42/44 MAPK, and by inhibitors of NADPH oxidase and the x(c)(-) cystine-glutamate antiporter. Furthermore, Tat increased expression of the catalytic subunit of x(c)(-) (xCT), but Tat-induced increases in xCT mRNA were not affected by inhibition of NADPH oxidase or x(c)(-) activity. Together, these data describe a specific and biologically significant signaling component of the microglial response to Tat, and suggest that excitotoxic neuropathology associated with HIV infection might originate in part with Tat-induced activation of microglial glutamate release. PMID- 20849924 TI - Association study between a functional polymorphism of FK506-binding protein 51 (FKBP5) gene and personality traits in healthy subjects. AB - Previous studies have shown that the function of hypothalamic-pituitary-adrenal (HPA) axis is involved in the characterization of personality traits. FK506 binding protein 51 (FKBP51 or FKBP5) is a co-chaperone of heat-shock protein 90, and plays an important role in the negative feedback regulation of HPA axis function. It has been reported that a C/T single nucleotide polymorphism in the intron 2 of FKBP5 gene (rs1360780) affects FKBP5 protein levels and cortisol response to dexamethasone and psychological stress tests. Therefore, it is hypothesized that the FKBP5 polymorphism affects personality traits. In the present study, we studied the association between this polymorphism and personality traits in 826 Japanese healthy subjects. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the FKBP5 genotype was detected by a real-time PCR and cycling probe technology for SNP typing. In total subjects, the group with the T allele predictive of impaired negative feedback regulation of the HPA axis had higher scores of harm avoidance (HA) (p=0.043) and lower scores of cooperativeness (CO) (p=0.019) compared to that without the T allele. The T allele was associated with higher scores of HA in females (p=0.020) and lower scores of CO in males (p=0.015). The present study thus suggests that the FKBP5 polymorphism affects HA and CO in healthy subjects, with gender specificity. PMID- 20849925 TI - Localizing sensory and cognitive systems for pre-attentive visual deviance detection: an sLORETA analysis of the data of Kimura et al. (2009). AB - Pre-attentive deviance detection in the visual environment has been known to be reflected by an event-related brain potential (ERP) component, deviant-related negativity. Recently, however, we demonstrated that deviant-related negativity comprises two, temporally and spatially overlapping ERP components, by using an experimental protocol consisting of oddball and equiprobable sequences [M. Kimura, J. Katayama, H. Ohira, E. Schroger, Visual mismatch negativity: new evidence from the equiprobable paradigm, Psychophysiology 46 (2009) 402-409]: (1) visual N1 that reflects a sensory, refractoriness-based deviance detection system and (2) visual mismatch negativity (MMN) that reflects a cognitive, memory comparison-based deviance detection system. In the present paper, we further elucidated the neural generators of the visual N1 and visual MMN with standardized low-resolution brain electromagnetic tomography (sLORETA). Results showed that the visual N1 was involved in neural activations of the primary and nonprimary visual areas, while the visual MMN was involved in neural activations of the nonprimary visual areas and the prefrontal areas. These results suggest that the sensory and cognitive deviance detection systems subserved by distinct neural structures underlie our efficient pre-attentive visual deviance detection. PMID- 20849926 TI - A subpopulation of serotonin 1B receptors colocalize with the AMPA receptor subunit GluR2 in the hippocampal dentate gyrus. AB - The serotonin(1B) receptor (5-HT(1B)R) plays a role in cognitive processes that also involve glutamatergic neurotransmission via amino-3-hydroxy-5-methyl-4 isoxazoleproprionic acid (AMPA) receptors. Accumulating experimental evidence also highlights the involvement of 5-HT(1B)Rs in several neurological disorders. Consequently, the 5-HT(1B)R is increasingly implicated as a potential therapeutic target for intervention in cognitive dysfunction. Within the hippocampus, a brain region critical to cognitive processing, populations of pre- and post-synaptic 5 HT(1B)Rs have been identified. Thus, 5-HT(1B)Rs could have a role in the modulation of hippocampal pre- and post-synaptic conductance. Previously, we demonstrated colocalization of 5-HT(1B)Rs with the N-methyl-D-aspartate (NMDA) receptor subunit NR1 in a subpopulation of granule cell dendrites (Peddie et al. [53]). In this study, we have examined the cellular and subcellular distribution of 5-HT(1B)Rs with the AMPA receptor subunit GluR2. Of 5-HT(1B)R positive profiles, 28% displayed colocalization with GluR2. Of these, 87% were dendrites, corresponding to 41% and 10% of all 5-HT(1B)R labeled or GluR2 labeled dendrites, respectively. Dendritic labeling was both cytoplasmic and membranous but was not usually associated with synaptic sites. Colocalization within dendritic spines and axons was comparatively rare. These findings indicate that within the dentate gyrus molecular layer, dendritic 5-HT(1B)Rs are expressed predominantly on GluR2 negative granule cell processes. However, a subpopulation of 5-HT(1B)Rs is expressed on GluR2 positive dendrites. Here, it is suggested that activation of the 5-HT(1B)R may play a role in the modulation of AMPA receptor mediated conductance, further supporting the notion that the 5-HT(1B)R represents an interesting therapeutic target for modulation of cognitive function. PMID- 20849927 TI - Organization of postural equilibrium in several planes in ballet dancers. AB - This study analyzed the balance strategies of ballet dancers during postural equilibrium in three single leg balance conditions with and without vision and regard to age. Dancers participating formed two groups of 20 dancers each, one aged between 8 and 16 years (young group) and the other aged between 17 and 30 years (adult group). Ground reaction forces (GRFs) (mediolateral (ML), anteroposterior (AP) components, vertical (V)) were recorded. Results analysis enabled us to extract some spatiotemporal data for each component of the GRF (number of GRF oscillations, variability and impulses). Young dancers are characterized, compared to adult dancers, by an instability combined with an increase of oscillations number and a decrease variability mainly visible on the ML component. In the two groups, the absence of vision implies an increase of AP, ML and V impulsions and GRF variability. Balance with the gesturing limb to the rear increases the age and vision effect compared to balances with the limb forward or to the side. Young dancers are less efficient at controlling their balance than adult dancers. This observation may be related to the number of hours practicing dance, which differs between groups. The dancers have a visual dependence to control the postural balance. PMID- 20849928 TI - Perturbation-evoked electrodermal responses are sensitive to stimulus and context dependent manipulations of task challenge. AB - Recent work has demonstrated that postural instability evokes an electrodermal response (EDR) that is temporally coupled to perturbation onset. The purpose of this study was to determine whether arousal linked to balance recovery is associated with the size of the perturbation (stimulus-dependent variations); and/or the challenge of executing a motor response to recover stability (context dependent task variations). Twelve healthy subjects received whole-body perturbations while seated in a tilting chair that required a compensatory upper limb reaction to regain balance following instability. The influence of perturbation amplitude (stimulus-dependent challenge- slow vs. fast perturbations) and task condition (context-dependent challenge- unrestricted vs. restricted movement) on EDR timing and magnitude parameters were examined. While EDR latency was consistent across conditions with onset occurring approximately 2s after the perturbation, peak-to-peak EDR amplitude was influenced by both stimulus-dependent and context-dependent challenges and also mirrored postural response amplitude. Compared to the Slow condition, EDR amplitude was 27 +/- 6% larger in the Fast condition (p=0.0004). Similarly, EDR amplitude was 244 +/- 86% larger in the Restricted task condition relative to the Unrestricted task condition (p=0.006). Context-dependent EDR modulation suggests that autonomic reactivity is associated with some higher level of processing independent of the degree of challenge related to stimulus characteristics. This work has potential implications for understanding determinants of central nervous system reactivity among individuals with impaired limb control where the recovery challenge is uniquely linked to the context. PMID- 20849930 TI - Organization and neurochemical properties of intersegmental interneurons in the lumbar enlargement of the adult rat. AB - Intersegmental interneurons with relatively short axons perform an important role in the coordination of limb movement but surprisingly little is known about their organization and how they contribute to neuronal networks in the adult rat. We undertook a series of anatomical tract-tracing studies to label cell bodies and axons of intersegmental neurons in the lumbar cord and characterized their neurochemical properties by using immunocytochemistry. The b-subunit of cholera toxin was injected into L1 or L3 segments of seven rats in the vicinity of lateral or medial motor nuclei. In L5 lumbar segments, cells were found to be concentrated in contralateral lamina VIII, and in ipsilateral lamina VII and laminae V-VI following injections into the lateral and medial motor nuclei respectively. About 25% of labelled cells contained calbindin or calretinin or a combination of both. Calbindin positive cells were mainly distributed within the ipsilateral side of the L5 segment, especially within the ipsilateral dorsal horn whereas there was a concentration of calretinin cells in contralateral lamina VIII. A small population of cells around the central canal were cholinergic. We also examined axon terminals that projected from L1/3 to the L5 contralateral lateral motor nucleus. The majority of these axons were excitatory (75%) and made direct contacts with motoneurons. However, most inhibitory axons in L5 contained a mixture of GABA and glycine (20%) and about 22% of the total population of axons contained calbindin. In contrast, 19% of all intra-segmental axons in the L3 contralateral lateral motor nucleus were found to be purely glycinergic and 17% contained a mixture of GABA and glycine. This study shows that short range interneurons form extensive ipsi- and contralateral projections within the lumbar enlargement and that many of them contain calcium binding proteins. Those projecting contralaterally to motor nuclei are predominantly excitatory. PMID- 20849929 TI - Expression and distribution of Kv4 potassium channel subunits and potassium channel interacting proteins in subpopulations of interneurons in the basolateral amygdala. AB - The Kv4 potassium channel alpha subunits, Kv4.1, Kv4.2, and Kv4.3, determine some of the fundamental physiological properties of neurons in the CNS. Kv4 subunits are associated with auxiliary beta-subunits, such as the potassium channel interacting proteins (KChIP1 - 4), which are thought to regulate the trafficking and gating of native Kv4 potassium channels. Intriguingly, KChIP1 is thought to show cell type-selective expression in GABA-ergic inhibitory interneurons, while other beta-subunits (KChIP2-4) are associated with principal glutamatergic neurons. However, nothing is known about the expression of Kv4 family alpha- and beta-subunits in specific interneurons populations in the BLA. Here, we have used immunofluorescence, co-immunoprecipitation, and Western Blotting to determine the relative expression of KChIP1 in the different interneuron subtypes within the BLA, and its co-localization with one or more of the Kv4 alpha subunits. We show that all three alpha-subunits of Kv4 potassium channel are found in rat BLA neurons, and that the immunoreactivity of KChIP1 closely resembles that of Kv4.3. Indeed, Kv4.3 showed almost complete co-localization with KChIP1 in the soma and dendrites of a distinct subpopulation of BLA neurons. Dual-immunofluorescence studies revealed this to be in BLA interneurons immunoreactive for parvalbumin, cholecystokin-8, and somatostatin. Finally, co-immunoprecipitation studies showed that KChIP1 was associated with all three Kv4 alpha subunits. Together our results suggest that KChIP1 is selectively expressed in BLA interneurons where it may function to regulate the activity of A-type potassium channels. Hence, KChIP1 might be considered as a cell type-specific regulator of GABAergic inhibitory circuits in the BLA. PMID- 20849931 TI - Alterations in synaptic curvature in the dentate gyrus following induction of long-term potentiation, long-term depression, and treatment with the N-methyl-D aspartate receptor antagonist CPP. AB - Alterations in curvature of the post synaptic density (PSD) and apposition zone (AZ), are believed to play an important role in determining synaptic efficacy. In the present study we have examined curvature of PSDs and AZs 24 h following homosynaptic long-term potentiation (LTP), and heterosynaptic long-term depression (LTD) in vivo, in awake adult rats. High frequency stimulation (HFS) applied to the medial perforant path to the dentate gyrus induced LTP while HFS stimulation of the lateral perforant path induced LTD in the middle molecular layer of the dentate gyrus (DG). Curvature changes were analysed in this area using three dimensional (3-D) reconstructions of electron microscope images of ultrathin serial sections. Very large and significant changes in 3-D measurements of AZ and PSD curvature occurred 24 h following both LTP and LTD, with a flattening of the normal concavity of mushroom spine heads and a change to convexity for thin spines. An N-methyl-D-aspartate (NMDA) receptor antagonist CPP (3-[(R)-2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid) blocked the changes in curvature of mushroom and thin spine PSDs and apposition zones, actually increasing the concavity of mushroom spines as the spine engulfed the presynaptic bouton. In order to establish whether these changes resulted from the effect of the NMDA antagonist or from its coincidence with synaptic activation during testing we examined the effects of CPP alone on PSD and apposition zone curvature. It was found that CPP alone also caused a small decrease in curvature of both PSD and apposition zone of mushroom and thin spines. PMID- 20849933 TI - Impairment of recognition memory and hippocampal long-term potentiation after acute exposure to clioquinol. AB - Clioquinol (CQ) was associated with cases of transient global amnesia and with the neurodegenerative syndrome subacute myelo-optico-neuropathy (SMON) in humans. However, CQ forms lipophilic chelates with cations and has the potential as a scientific and clinical tool used for selective modulation of histochemically reactive zinc pools. The relationship among transient lack of synaptic zinc release, hippocampal long-term potentiation (LTP) induction and cognitive memory is poorly understood. To evaluate the role of synaptic zinc release, in the present study, hippocampal LTP induction and cognitive behavior were examined in young rats after i.p. injection of CQ (30 mg/kg). Intracellular zinc detected by Timm's stain and extracellular (synaptic cleft) zinc detected by ZnAF-2 were significantly decreased in the hippocampus 6 h after CQ injection. The molecular layer of the dentate gyrus, in which perforant path-granule cell synapses exist, was most responsive to CQ injection. Dentate gyrus LTP was induced similarly to the control 2 h after CQ injection, while significantly attenuated 6-24 h after CQ injection. In the training trial of the object recognition memory 2 h after CQ injection, there was no significant difference in learning behavior between the control and CQ-treated rats. In the test trial, CQ-treated rats showed normal recognition memory 1 h after the training, whereas recognition memory deficit 24 h after the training unlike the control rats. These results indicate that acute exposure to CQ impairs long-term (24 h) memory in the hippocampus of young rats. The CQ-mediated attenuation of dentate gyrus LTP, which may be associated with the transient lack of zinc release from zincergic neurons, seems to be involved in the impairment of the long-term memory. PMID- 20849932 TI - Fos expression in the brains of rats performing an attentional set-shifting task. AB - Impairments in executive function and cognitive control are a common feature of neuropsychiatric and neurodegenerative disorders. A promising behavioral paradigm for elucidating the neural mechanisms of executive function is extradimensional/intradimensional (ED/ID) shifting, which places demands on executive function by requiring the adjustment of behavioral responses based on affective or attentional information. To augment the understanding of the brain systems required for these aspects of executive function, we examined the induction of Fos protein in rats tested in the ED/ID paradigm. We found increased Fos-like immunoreactivity (Fos-LI) in several cortical areas, including medial and orbital frontal cortex (OFC), in rats performing affective or attentional shifts relative to rats performing control discriminations. However, increased Fos-LI was also present in rats that performed a yoked number of additional control discrimination trials, without affective or attentional shifting. These observations suggest that cortical networks required for affective and attentional shifting are also activated during comparable discrimination tasks that do not require shifting, consistent with a role for these networks in monitoring ongoing behavior even in situations in which adaptation to changing behavioral demands is not required. PMID- 20849934 TI - The role of the GABAergic and dopaminergic systems in the brain response to an intragastric load of alcohol in conscious rats. AB - The brain's response to ethanol intake has been extensively investigated using electrophysiological recordings, brain lesion techniques, and c-Fos immunoreactivity. However, few studies have investigated this phenomenon using functional magnetic resonance imaging (fMRI). In the present study, we used fMRI to investigate the blood oxygenation level-dependent (BOLD) signal response to an intragastric (IG) load of ethanol in conscious, ethanol-naive rats. An intragastrically infused 10% ethanol solution induced a significant decrease in the intensity of the BOLD signal in several regions of the brain, including the bilateral amygdala (AMG), nucleus accumbens (NAc), hippocampus, ventral pallidum, insular cortex, and cingulate cortex, and an increase in the BOLD signal in the ventral tegmental area (VTA) and hypothalamic regions. Treatment with bicuculline, which is an antagonist of the gamma-aminobutyric acid A (GABA(A)) receptor, increased the BOLD signal intensity in the regions that had shown decreases in the BOLD signal after the IG infusion of 10% ethanol solution, but it did not affect the BOLD signal increase in the hypothalamus. Treatment with SCH39166, which is an antagonist of D1-like receptors, eliminated the increase in the BOLD signal intensity in the hypothalamic areas but did not affect the BOLD signal decrease following the 10% ethanol infusion. These results indicate that an IG load of ethanol caused both a GABA(A) receptor-mediated BOLD decrease in the limbic system and the cortex and a D1-like receptor-mediated BOLD increase in the hypothalamic regions in ethanol-naive rats. PMID- 20849935 TI - Expression of connexin57 in mouse development and in harmaline-tremor model. AB - Connexin57 (Cx57) was previously reported in retinal cells but not in brain nerve cells. This occurrence was tested in this study, by searching for the expression of Cx57 RNA and protein transcripts during the postnatal development of the mouse CNS. Both the Cx57 RNA (investigated by reverse transcriptase-polymerase chain reaction (RT-PCR)) and the protein (Western-Blot and immunohistochemistry using a polyclonal antibody generated in chicken) transcripts were firstly expressed in the late postnatal development (P12). The expression of Cx57 in adult life (studied at P28, by in situ hybridization and immunohistochemical analysis) concerned few regions of the brain stem (inferior olive, lateral reticular nucleus and motor trigeminal nucleus), the cerebellum (Purkinje cells and cerebellar nuclei) and the spinal cord (alpha-motoneurons). Double immunohistochemical studies using the Cx57 antibody and antibodies, which specifically labelled neuronal nuclei (NeuN) and astrocyte cells glial fibrillary acidic protein (GFAP), showed the expression of Cx57 segregated in neuronal cells. The study also confirmed the expression of Cx57 in the horizontal cells of the retinal outer plexiform layer, reported in previous investigations. Given the expression of Cx57 in the cerebellum and pre-cerebellar nuclei, such as olivary and lateral reticular nuclei, a possible role of Cx57 was hypothesized in the electrical coupling of the cerebellum. This hypothesis was tested by searching for the expression of the Cx57 transcripts in the mouse cerebellum of the harmaline-tremor model. The up-regulation of the Cx57 transcripts reported in this model suggested a possible involvement of Cx57 in the electrotonic coupling of the cerebellar system. PMID- 20849936 TI - Pineal melatonin synthesis is altered in Period1 deficient mice. AB - Melatonin is an important endocrine signal for darkness in mammals. Transcriptional activation of the arylalkylamine-N-acetyltransferase gene encoding for the penultimate enzyme in melatonin synthesis drives the daily rhythm of the hormone in the pineal gland of rodents. Rhythmic arylalkylamine-N acetyltransferase expression is controlled by the cAMP-signal transduction pathway and involves the activation of beta-adrenergic receptors and the inducible cAMP early repressor. In addition, the rat arylalkylamine-N acetyltransferase promoter contains an E-box element which can interact with clock proteins. Moreover, the pineal gland of mice shows a circadian rhythm in clock proteins such as the transcriptional repressor Period1, which has been shown to control rhythmic gene expression in a variety of tissues. However, the role of Period1 in the regulation of pineal melatonin synthesis is still unknown. Therefore, circadian rhythms in arylalkylamine-N-acetyltransferase, beta adrenergic receptor, and inducible cAMP early repressor mRNA levels (real time PCR), arylalkylamine-N-acetyltransferase enzyme activity (radiometric assay) and melatonin concentration radio immuno assay (RIA) were analyzed in the pineal gland of mice with a targeted deletion of the Period1 gene (Per1-/-) and the corresponding wildtype. In Per1-/- the amplitude in arylalkylamine-N acetyltransferase expression was significantly elevated as compared to wildtype. In contrast, beta-adrenergic receptor and inducible cAMP early repressor mRNA levels were not affected by the Period1-deficiency. This indicates that the molecular clockwork alters the amplitude of arylalkylamine-N-acetyltransferase expression. In vitro, pineal glands of Per1-/- mice showed a day night difference in arylalkylamine-N-acetyltransferase expression with high levels at night. This suggests that a deficient in Period1 elicits similar effects as the activation of the cAMP-signal transduction pathway in wildtype mice. PMID- 20849937 TI - Successful treatment of auditory perceptual disorder in individuals with Friedreich ataxia. AB - Friedreich ataxia (FRDA) is a neurodegenerative disease affecting motor and sensory systems. This study aimed to investigate the presence and perceptual consequences of auditory neuropathy (AN) in affected individuals and examine the use of personal-FM systems to ameliorate the resulting communication difficulties. Ten individuals with FRDA underwent a battery of auditory function tests and their results were compared with a cohort of matched controls. Friedreich ataxia subjects were then fit with personal FM-listening devices and evaluated over a 6 week period. Basic auditory processing was affected with each FRDA individual showing poorer temporal processing and figure/ground discrimination than their matched control. Speech perception in the presence of background noise was also impaired, with FRDA listeners typically able to access only around 50% of the information available to their normal peers. The use of personal FM-listening devices did however, dramatically improve their ability to hear and communicate in everyday listening situations. PMID- 20849938 TI - Beneficial effect of the insulin sensitizer (HSP inducer) BGP-15 on olanzapine induced metabolic disorders. AB - Olanzapine is a widely used atypical antipsychotic, with well known metabolic side effects such as weight gain, insulin resistance and blood glucose abnormalities. It has been previously shown in a phase II clinical trial that BGP 15, an amidoxim derivative has insulin-sensitizing effects. The aim of this study was to investigate the efficacy of BGP-15 for the treatment of olanzapine-induced metabolic side effects, in healthy volunteers. Thirty-seven (37) subjects (ages 18-55 years) with normal glucose metabolism were randomly assigned to 17 days of once-daily treatment with 400mg of BGP-15 or placebo and 5mg of olanzapine for 3 days followed by 10mg for 14 days. Total body and muscle tissue glucose utilization was determined by hyperinsulinemic-euglycemic clamp technique. As expected the 17-day olanzapine treatment provoked insulin resistance and body weight gain (p<0.05) in both groups. Administration of BGP-15 significantly reduced olanzapine-induced insulin resistance. The protective effect of BGP-15 on insulin stimulated glucose utilization had the highest magnitude in the values calculated for the muscle tissue (p=0.002). In healthy individuals BGP-15 was safe and well tolerated during the whole study period. It is suggested that BGP 15 can be a successful insulin sensitizer agent to prevent side effects of olanzapine treatment. PMID- 20849939 TI - Alteration in airway microvascular leakage induced by sensorineural stimulation in rats exposed to inhaled formaldehyde. AB - Inhaled formaldehyde can rapidly produce microvascular leakage in the airway through stimulation of tachykinin NK1 receptors by tachykinins released from sensory nerves. Tachykinin NK1 receptors are known to be internalized in the cytoplasm after being stimulated, thus leading to transient attenuation of their action. We investigated time changes in airway microvascular leakage during formaldehyde inhalation for 45 min, and whether pre-inhalation of formaldehyde (5 ppm, 30 min) decreases the responses induced by subsequent inhaled formaldehyde (5 ppm, 15 min), intravenous capsaicin (75 MUg/kg) and intravenous substance P (10 MUg/kg) in rat airway. Evans blue dye content extravasated into the tissues was measured as an index of plasma leakage. Formaldehyde rapidly produced dye leakage in the airway, a response that ended within 15 min after the start of formaldehyde inhalation. Pre-inhalation of formaldehyde markedly decreased the responses induced by formaldehyde and capsaicin, but not substance P. However, dye leakage induced by formaldehyde was significantly enhanced by formaldehyde inhalation 20 h earlier. Our results suggest that tachyphylaxis in neurogenic airway microvascular leakage seen after formaldehyde inhalation may be due to impairment of tachykinin release from sensory nerves or decreases in tachykinins within sensory nerves. However, desensitization of tachykinin NK1 receptors was unlikely to be important in the tachyphylactic response. PMID- 20849940 TI - Tablet splitting: Product quality assessment of metoprolol succinate extended release tablets. AB - Metoprolol succinate extended release tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. Despite the flexibility that controlled release pellets may offer, segregation is one of the challenges that commonly occur during tableting for such drug delivery system. Since all commercial metoprolol succinate extended release tablets are scored, they are deemed suitable for splitting. The present study was aimed at utilizing an innovative technology to determine the dose uniformity for split tablets. Four marketed drug products consisting of innovator and generics were evaluated for effect of splitting on weight, assay and content uniformity. Novel analytical tool such as near infrared (NIR) chemical imaging was used to visualize the distribution of metoprolol succinate and functional excipients on the surfaces of the marketed tablets. The non-homogeneous distribution of directly compressed metoprolol succinate beads on the surface of the tablets as well as the split intersection explained the large variation in the split tablets' weight and content uniformity results. The obtained results indicated the usefulness of NIR chemical imaging to determine the need for content uniformity studies for certain split tablets. PMID- 20849941 TI - Selective induction of apoptosis through activation of caspase-8 in human leukemia cells (Jurkat) by dandelion root extract. AB - AIM OF STUDY: Dandelion extracts have been used in traditional Native American Medicine and Traditional Chinese Medicine (TCM) for treatment of leukemia and breast cancer; however, the mechanism of action remains unknown. Today, DRE is mainly marketed for management of gastrointestinal and liver disorders. The current study aims to determine the anti-cancer activity of dandelion root extract (DRE) against human leukemia, and to evaluate the specificity and mechanism of DRE-induced apoptosis. MATERIALS AND METHODS: The effect of DRE on cell viability was evaluated using the colorimetric-based WST-1 assay. Apoptotic cell death was monitored by nuclear condensation and confirmed by exposure of phosphatidylserine to outer leaflet of plasma membrane. Activation of caspases was detected using a fluorogenic substrate specific to either caspase-8 or -3. Loss of mitochondrial membrane potential was observed by microscopy using JC-1 dye. The apoptotic effect of DRE was also evaluated on a dominant-negative FADD (Fas-associated death domain) cell line and non-cancerous peripheral blood mononuclear cells (PBMCs). RESULTS: Aqueous DRE effectively induces apoptosis in human leukemia cell lines in a dose and time dependent manner. Very early activation of caspase-8 and the subsequent activation of caspase-3 indicate that DRE may be inducing extrinsic or receptor-mediated apoptosis. Caspase inhibition rendered this extract ineffective, thus DRE-induced apoptosis is caspase dependent. Moreover, the dominant-negative FADD cells that are unable to form a complete DISC (death-inducing signaling complex) were resistant to DRE treatment, which further confirms our hypothesis that DRE induces receptor-mediated apoptosis. Interestingly, non-cancerous peripheral blood mononuclear cells (PBMCs) exposed to aqueous DRE under the same treatment conditions as leukemia cells were not significantly affected. CONCLUSION: Our results suggest that aqueous DRE contains components that act to induce apoptosis selectively in cultured leukemia cells, emphasizing the importance of this traditional medicine and thus presents a potential novel non-toxic alternative to conventional leukemia therapy. PMID- 20849942 TI - Anti-inflammatory principles of Suregada multiflora against nitric oxide and prostaglandin E2 releases. AB - AIM OF THE STUDY: The stem bark of Suregada multiflora and the isolated compounds were carried out to investigate for anti-inflammatory activity. MATERIALS AND METHODS: The stem bark of Suregada multiflora and its isolated compounds were tested for their anti-inflammatory effects against lipopolysaccharide (LPS) induced nitric oxide (NO) and prostraglandin E(2) (PGE(2)) releases in RAW264.7 cells as well as the anti-inflammatory mechanism on mRNA expression of the active compound (5, helioscopinolide A). RESULTS: The extract of Suregada multiflora possessed potent NO inhibitory effect with an IC(50) value of 8.6 MUg/ml. Among the isolated compounds, helioscopinolide A (5) exhibited the highest activity against NO release with an IC(50) value of 9.1 MUM, followed by helioscopinolide C (6) and suremulol D (2) with IC(50) values of 24.5 and 29.3 MUM, respectively. The IC(50) value of 5 against PGE(2) production was found to be 46.3 MUM. The mechanism in transcriptional level of compound 5 was found to inhibit iNOS and COX-2 mRNA expressions in dose-dependent manners. CONCLUSIONS: The present study may support the traditional use of Suregada multiflora stem bark for treatment of inflammatory-related diseases. PMID- 20849943 TI - Enhancement of stress resistances and downregulation of Imd pathway by lower developmental temperature in Drosophila melanogaster. AB - Ambient temperature affects the lifespan of cold-blooded organisms such as Drosophila melanogaster. To better understand what influences the lifespan of an adult fruit fly, we tested whether developmental temperature could affect stress responses used as surrogate markers for the aging process. When 2-day-old adult flies developed at two representative temperatures (18 degrees C and 25 degrees C) were challenged with three stresses (starvation, oxidation, and heat), both male and female flies developed at 18 degrees C exhibited stronger resistance to all three stresses compared to those developed at 25 degrees C. Nutrient composition analyses showed that fat, protein, and glycogen levels increased when male flies were developed at 18 degrees C. These differences in stress resistance by developmental temperature were sustained even between 30-day-old male flies of two groups aged at the same temperature. We also showed that development at a lower temperature represented by 18 degrees C significantly downregulates anti microbial peptide genes, AttA and DptB, of Imd pathway. PMID- 20849944 TI - Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. AB - The brain is a major target of circulating insulin. Enhancing central nervous insulin action has been shown to improve memory functions in animals as well as in humans, benefitting in particular hippocampus-dependent (declarative) memory. As Alzheimer's disease (AD) is associated with reduced central nervous insulin signaling and attenuated permeation of blood-borne insulin across the blood-brain barrier, the cognitive decline in AD patients may at least in part be derived from impaired brain insulin signaling. Thus, therapeutic strategies to overcome central nervous system insulin deficiency and resistance might be an attractive option in the treatment of cognitive impairments like AD. Insulin can be effectively delivered directly to the brain via the intranasal route that enables the hormone to bypass the blood-brain barrier and modulate central nervous functions. This review summarizes a series of studies demonstrating beneficial effects of intranasal insulin on memory functions both in healthy humans and in patients with cognitive impairments such as AD. These experiments in humans consistently indicate that enhancing brain insulin signaling by intranasal administration of the hormone improves hippocampus-dependent memory in the absence of adverse side effects. Considering that insulin also acts as a neuroprotective signal, up-regulating brain insulin levels by intranasal insulin administration appears to be a promising approach in the treatment and prevention of central nervous system insulin deficiency and resistance as found in AD. PMID- 20849945 TI - Emerging mitochondrial signaling mechanisms in physiology, aging processes, and as drug targets. AB - Advances in research on mitochondria have elucidated their importance in cell survival and cell death regulation in addition to their function in energy production. Mitochondria are further implicated in various metabolic and aging related diseases, which are now assumed to be caused by misregulation of physiological systems rather than pure accumulation of oxidative damage. Thus, the signaling mechanisms within mitochondria and between the organelle and its environment have gained interest as potential drug targets. Emerging mitochondrial signaling systems with potential for exploiting them for therapeutic intervention include, among others, the NAD(+)-dependent protein deacetylases of the Sirtuin family, the redox enzyme p66(Shc), and enzymes of the cyclic adenosine monophosphate (cAMP) signaling pathways. Here, we discuss functions of these signaling systems in mitochondria, their roles in aging processes and disease, and their potential to serve as therapeutic targets. PMID- 20849946 TI - TOR on the brain. AB - Signaling by target of rapamycin (mTOR in mammals) has been shown to modulate lifespan in several model organisms ranging from yeast to mice. In mice, reduced mTOR signaling by chronic rapamycin treatment leads to life span extension, raising the possibility that rapamycin and its analogs may benefit the aging brain and serve as effective treatments of age-related neurodegenerative diseases. Here, we review mTOR signaling and how neurons utilize mTOR to regulate brain function, including regulation of feeding, synaptic plasticity and memory formation. Additionally, we discuss recent findings that evaluate the mechanisms by which reduced mTOR activity might benefit the aging brain in normal and pathological states. We will focus on recent studies investigating mTOR and Alzheimer's disease, Parkinson's disease, and polyglutamine expansion syndromes such as Huntington's disease. PMID- 20849947 TI - Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. AB - A remarkable discovery of recent years is that, despite the complexity of ageing, simple genetic interventions can increase lifespan and improve health during ageing in laboratory animals. The pathways involved have often proved to sense nutrients and to match costly activities of organisms, such as growth, metabolism and reproduction, to nutrient status. For instance, the insulin/insulin-like growth factor and Target of Rapamycin signalling network has proved to play a function in ageing, from yeast to mammals, seemingly including humans. In the fruit fly Drosophila, altered activity of several components of this network can increase lifespan and improve locomotor and cardiac function during ageing. The fly brain, fat body (equivalent of mammalian liver and white adipose tissue) and the germ line are important in determination of lifespan, with considerable communication between different tissues. Cellular detoxification pathways, increased autophagy and altered protein synthesis have all been implicated in increased lifespan from reduced IIS/TOR activity, with the role of defence against oxidative stress unresolved. Reduced IIS/TOR signalling can alter or block the response of lifespan to dietary restriction. Reduced IIS can act acutely to lower death rate, implying that it may ameliorate the effects of ageing-related damage, rather than preventing it. PMID- 20849948 TI - Countering neurodegeneration by reducing the activity of the insulin/IGF signaling pathway: current knowledge and future prospects. AB - Human neurodegenerative maladies share two common key features: a mechanistic link to the accumulation and deposition of aberrantly aggregated proteins and late onset. These similarities among otherwise unrelated disorders suggest that the aging process plays an active role in enabling the emergence of these diseases late in life. Invertebrate-based studies have shown that the manipulation of aging by the reduction of the Insulin/IGF signaling (IIS), a prominent aging regulatory pathway, protects model organisms from neurodegeneration-linked toxic protein aggregation. Recent studies have also indicated that the counter proteotoxic effect of IIS reduction is conserved from worms to mice as reduced IGF-1 signaling protected Alzheimer's-model mice from the disease-like behavioral impairments, pathological phenotypes and premature death typical to these model animals. In this article I review the current knowledge on the protective mechanisms that are suppressed by the IIS and discuss the future therapeutic potential of IIS reduction as a treatment for neurodegenerative disorders. PMID- 20849949 TI - Genomic Croesus: experimental evolutionary genetics of Drosophila aging. AB - For more than 40 years, multiple laboratories have studied Drosophila stocks that have been forced to evolve slowed rates of aging and increased average longevities. These stocks have been used to test both physiological and genetic theories of aging, yielding a number of interesting findings. A little-noticed problem is that these tests have too frequently produced positive results with respect to physiological and genetic mechanisms underlying slowed aging. A genomic interpretation of this copious success is that hundreds of genetic loci have undergone changes in allele frequency or gene expression as a result of selection for slowed aging. This implicates many genetic mechanisms in the control of aging, in general, across the diversity of aging species. As the technology for surveying genomes and transcriptomes continues to improve rapidly, the loci of aging are becoming ever easier to identify. But interpreting the detailed functional consequences of all of these loci presents a radically larger challenge. Like Croesus, experimental gerontology is faced with the problem of genomic foundations for aging which are extremely rich. PMID- 20849950 TI - The Pyk2 FERM regulates Pyk2 complex formation and phosphorylation. AB - The focal adhesion kinase Pyk2 integrates signals from cell adhesion receptors, growth factor receptors, and G-protein-coupled receptors leading to the activation of intracellular signaling pathways that regulate cellular phenotypes. The intrinsic mechanism for the activation of Pyk2 activity remains to be fully defined. Previously, we reported that mutations in the N-terminal FERM domain result in loss of Pyk2 activity and expression of the FERM domain as an autonomous fragment inhibits Pyk2 activity. In the present study, we sought to determine the mechanism that underlies these effects. Utilizing differentially epitope-tagged Pyk2 constructs, we observed that Pyk2 forms oligomeric complexes in cells and that complex formation correlates positively with tyrosine phosphorylation. Similarly, when expressed as an autonomous fragment, the Pyk2 FERM domain formed a complex with other Pyk2 FERM domains but not the FAK FERM domain. When co-expressed with full-length Pyk2, the autonomously expressed Pyk2 FERM domain formed a complex with full-length Pyk2 preventing the formation of Pyk2 oligomers and resulting in reduced Pyk2 phosphorylation. Deletion of the FERM domain from Pyk2 enhanced Pyk2 complex formation and phosphorylation. Together, these data indicate that the Pyk2 FERM domain is involved in the regulation of Pyk2 activity by acting to regulate the formation of Pyk2 oligomers that are critical for Pyk2 activity. PMID- 20849951 TI - Emerging roles for beta-arrestin-1 in the control of the pancreatic beta-cell function and mass: new therapeutic strategies and consequences for drug screening. AB - Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in beta-cell mass, decreased beta-cell survival and impaired glucose-dependent insulin release. Pancreatic beta-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. beta-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that beta-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for beta arrestin-1 in the regulation of insulin secretion and beta-cell survival by GPCRs. PMID- 20849953 TI - In vitro evaluation of liposomes containing bio-enhancers for the oral delivery of macromolecules. AB - The aim of this work was to develop a new type of liposomes containing bio enhancers for oral delivery of hydrophilic macromolecules. The study focused on EPC/cholesterol-based formulations combined with TPGS 1000 and 400, cholylsarcosine (CS), cetylpyridinium chloride (CpCl) and stearylamine (SA) covering a broad range of different types of enhancers. Most of the tested liposomal formulations and enhancers showed neither influence on cell viability in the Alamar Blue(r) assay nor an increase in lactate dehydrogenase LDH release. But, at a concentration of 1 mM, CpCl exhibited a strong toxicity after 2 h, TPGS 1000 reduced the cell viability at the same concentration after 8h significantly. Only one liposomal formulation with 25% CpCl led to a decrease in viability to 60.0% after 8h at a total lipid concentration of 5 mM. In the Caco-2 Transwell(r) model, one formulation with 5% TPGS 400 improved the permeation of FITC-dextran 70 kDa 3.34 +/- 0.62-fold, one with 10% CpCl 3.69 +/- 0.67 and one with 10% CS and 2.5% SA 3.41 +/- 0.51-fold without influencing the TER. Liposomes with 10% SA or 25% CpCl increased the permeation of FITC-dextran 29.02 +/- 5.84, respectively 39.28 +/- 2.10-fold, but led also to a strong reduction in the TER. Especially, the three formulations which enhanced the permeation of FITC-dextran around 3.5 fold without showing any cell toxicity or decrease in TER should be safe and effective candidates for the development of an oral delivery system for hydrophilic macromolecules. PMID- 20849952 TI - Zebrafish models of Tauopathy. AB - Tauopathies are a group of incurable neurodegenerative diseases, in which loss of neurons is accompanied by intracellular deposition of fibrillar material composed of hyperphosphorylated forms of the microtubule-associated protein Tau. A zebrafish model of Tauopathy could complement existing murine models by providing a platform for genetic and chemical screens, in order to identify novel therapeutic targets and compounds with disease-modifying potential. In addition, Tauopathy zebrafish would be useful for hypothesis-driven experiments, especially those exploiting the potential to deploy in vivo imaging modalities. Several considerations, including conservation of specialized neuronal and other cellular populations, and biochemical pathways implicated in disease pathogenesis, suggest that the zebrafish brain is an appropriate setting in which to model these complex disorders. Novel transgenic zebrafish lines expressing wild-type and mutant forms of human Tau in CNS neurons have recently been reported. These studies show evidence that human Tau undergoes disease-relevant changes in zebrafish neurons, including somato-dendritic relocalization, hyperphosphorylation and aggregation. In addition, preliminary evidence suggests that Tau transgene expression can precipitate neuronal dysfunction and death. These initial studies are encouraging that the zebrafish holds considerable promise as a model in which to study Tauopathies. Further studies are necessary to clarify the phenotypes of transgenic lines and to develop assays and models suitable for unbiased high-throughput screening approaches. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases. PMID- 20849954 TI - Altered juvenile hormone metabolism, reproduction and stress response in Drosophila adults with genetic ablation of the corpus allatum cells. AB - Juvenile hormone (JH), which controls many developmental and physiological processes in Drosophila melanogaster, is synthesized de novo in the specialized endocrine glands, corpus allatum (CA). The present study concerns JH metabolism, reproduction and stress resistance in Drosophila with genetic ablation of a part of CA cells. The correlated regulation of JH biosynthesis and degradation in Drosophila adults has been found: ablation of CA cells led to (1) a dramatic decrease in activity of the key regulatory enzyme of JH biosynthesis, juvenile hormone acid methyl transferase and (2) a considerable increase in JH-hydrolyzing activity. It has been also shown that ablation of CA cells caused three significant physiological changes: (1) an increase in the intensity of response of JH degradation system to heat stress; (2) a disturbance of reproduction; (3) a decrease in stress resistance. Pharmacological rise of JH level rescued JH hydrolyzing activity, fecundity and stress resistance in CA-ablated females. Pronouncedly, all the physiological effects caused by CA ablation were significant in females but not in males indicating a sexual dimorphism of JH physiological roles in Drosophila adults. PMID- 20849955 TI - Pharmacokinetics of a F(ab')2 scorpion antivenom administered intramuscularly in healthy human volunteers. AB - This paper presents the first study of F(ab')(2) scorpion antivenom pharmacokinetics in humans after intramuscular (im) administration. The specific anti-Centruroides scorpion antivenom was used in 6 human healthy volunteers. The fabotherapeutic was administered as a 47.5mg im bolus. Blood samples were drawn at 0, 5, 15, 30, 45, 60 , 90, 120, and 180 min, 6h and at 1, 2, 3, 4, 10 and 21 days after antivenom administration. We measured antivenom concentrations in serum using a specific high sensitivity ELISA method for F(ab')(2). Antivenom concentration in serum was fit to a 3 compartment model (inoculation site, plasma and extra vascular extracellular space), it was assumed that the venom may also be irreversibly removed from plasma. Calculated time course of antivenom content shows that at any time no more that 16.6 (5.3, 31.9)% (median and 95% confidence interval) of the antivenom bolus is present in plasma. The time to peak plasma [F(ab')(2)] was 45 (33, 74) h. The most significant antivenom pharmacokinetic parameters determined were: AUC(im,infinity)=803 (605, 1463) mg.h.L(-1); V(c)=8.8 (2.8, 23.6) L; V(ss,im)=55 (47, 64) L; MRT(im)=776(326, 1335) h; CL(t)=3.7 (0.6, 1.9) mL.min(-1); f(im,)V(ss)=0.300 (0.153, 0.466). Comparing these parameters with the ones obtained intravenously by Vazquez et al., the parameters were more disperse between subjects, determined with more uncertainty in each individual subject, and the peak F(ab')(2) in plasma occurred with considerable delay; all indicating that the IM route should not be used to administer the antivenom, with the possible exception of cases occurring very far from hospitals, as an extreme means to provide some protection before the IV route becomes available. PMID- 20849956 TI - TNF-alpha potentiates glutamate-induced spinal cord motoneuron death via NF kappaB. AB - Besides glutamate excitotoxicity, the neuroinflammatory response is emerging as a relevant contributor to motoneuron loss in amyotrophic lateral sclerosis (ALS). In this regard, high levels of circulating proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) have been shown both in human patients and in animal models of ALS. The aim of this work was to study the effects of TNF alpha on glutamate-induced excitotoxicity in spinal cord motoneurons. In rat spinal cord organotypic cultures chronic glutamate excitotoxicity, induced by the glutamate-uptake inhibitor threohydroxyaspartate (THA), resulted in motoneuron loss that was associated with a neuroinflammatory response. In the presence of TNF-alpha, THA-induced excitotoxic motoneuron death was potentiated. Co-exposure to TNF-alpha and THA also resulted in down-regulation of the astroglial glutamate transporter 1 (GLT-1) and in increased extracellular glutamate levels, which were prevented by nuclear factor-kappaB (NF-kappaB) inhibition. Furthermore, TNF-alpha and THA also cooperated in the induction of oxidative stress in a mechanism involving the NF-kappaB signalling pathway as well. The inhibition of this pathway abrogated the exacerbation of glutamate-mediated motoneuron death induced by TNF-alpha. These data link two important pathogenic mechanisms, excitotoxicity and neuroinflammation, suggested to play a role in ALS and, to our knowledge, this is the first time that TNF-alpha-induced NF-kappaB activation has been reported to potentiate glutamate excitotoxicity on motononeurons. PMID- 20849957 TI - Foxa2 regulates the expression of Nato3 in the floor plate by a novel evolutionarily conserved promoter. AB - The development of the neural tube into a complex central nervous system involves morphological, cellular and molecular changes, all of which are tightly regulated. The floor plate (FP) is a critical organizing center located at the ventral-most midline of the neural tube. FP cells regulate dorsoventral patterning, differentiation and axon guidance by secreting morphogens. Here we show that the bHLH transcription factor Nato3 (Ferd3l) is specifically expressed in the spinal FP of chick and mouse embryos. Using in ovo electroporation to understand the regulation of the FP-specific expression of Nato3, we have identified an evolutionarily conserved 204 bp genomic region, which is necessary and sufficient to drive expression to the chick FP. This promoter contains two Foxa2-binding sites, which are highly conserved among distant phyla. The two sites can bind Foxa2 in vitro, and are necessary for the expression in the FP in vivo. Gain and loss of Foxa2 function in vivo further emphasize its role in Nato3 promoter activity. Thus, our data suggest that Nato3 is a direct target of Foxa2, a transcription activator and effector of Sonic hedgehog, the hallmark regulator of FP induction and spinal cord development. The identification of the FP specific promoter is an important step towards a better understanding of the molecular mechanisms through which Nato3 transcription is regulated and for uncovering its function during nervous system development. Moreover, the promoter provides us with a powerful tool for conditional genetic manipulations in the FP. PMID- 20849958 TI - Improved isolation of proteins tagged with glutathione S-transferase. AB - A common affinity tag used to express and purify fusion proteins is glutathione S transferase. However, many researchers have reported difficulty eluting GST tagged proteins from the affinity matrix. This report demonstrates that the problem likely is due to the propensity of glutathione S-transferase to dimerize combined with a propensity of the tagged protein to oligomerize, which results in formation of large oligomers of fusion protein that are chelated by the affinity matrix. The solution to the problem is to use S-butylglutathione instead of glutathione to elute, as S-butylglutathione binds more tightly to glutathione S transferase and overcomes the chelate effect. Moreover, in contrast to glutathione, S-butylglutathione has no reducing capability that might inactivate a tagged protein. PMID- 20849959 TI - False positives in neuroimaging genetics using voxel-based morphometry data. AB - Voxel-wise statistical inference is commonly used to identify significant experimental effects or group differences in both functional and structural studies of the living brain. Tests based on the size of spatially extended clusters of contiguous suprathreshold voxels are also widely used due to their typically increased statistical power. In "imaging genetics", such tests are used to identify regions of the brain that are associated with genetic variation. However, concerns have been raised about the adequate control of rejection rates in studies of this type. A previous study tested the effect of a set of 'null' SNPs on brain structure and function, and found that false positive rates were well-controlled. However, no similar analysis of false positive rates in an imaging genetic study using cluster size inference has yet been undertaken. We measured false positive rates in an investigation of the effect of 700 pre selected null SNPs on grey matter volume using voxel-based morphometry (VBM). As VBM data exhibit spatially-varying smoothness, we used both non-stationary and stationary cluster size tests in our analysis. Image and genotype data on 181 subjects with mild cognitive impairment were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At a nominal significance level of 5%, false positive rates were found to be well-controlled (3.9-5.6%), using a relatively high cluster-forming threshold, alpha(c)=0.001, on images smoothed with a 12 mm Gaussian kernel. Tests were however anticonservative at lower cluster-forming thresholds (alpha(c)=0.01, 0.05), and for images smoothed using a 6mm Gaussian kernel. Here false positive rates ranged from 9.8 to 67.6%. In a further analysis, false positive rates using simulated data were observed to be well-controlled across a wide range of conditions. While motivated by imaging genetics, our findings apply to any VBM study, and suggest that parametric cluster size inference should only be used with high cluster-forming thresholds and smoothness. We would advocate the use of nonparametric methods in other cases. PMID- 20849960 TI - A pilot study of human brain tissue post-magnetic resonance imaging: information from the National Deep Brain Stimulation Brain Tissue Network (DBS-BTN). AB - INTRODUCTION: The safety of magnetic resonance imaging (MRI) for deep brain stimulation (DBS) patients is of great importance to both movement disorders clinicians and to radiologists. The present study utilized the Deep Brain Stimulation Brain Tissue Network's (DBS-BTN's) clinical and neuropathological database to search for evidence of adverse effects of MRI performed on implanted DBS patients. HYPOTHESIS: Performing a 1.5 T MRI with a head receive coil on patients with implanted DBS devices should not result in evidence of adverse clinical or pathological effects in the DBS-BTN cohort. Further, exposing post mortem DBS-BTN brains with DBS leads to extended 3T MRI imaging should not result in pathological adverse effects. METHODS: An electronic literature search was performed to establish clinical and neuropathological criteria for evidence of MRI-related adverse reactions in DBS patients. A retrospective chart review of the DBS-BTN patients was then performed to uncover potential adverse events resulting from MRI scanning. DBS patient characteristics and MRI parameters were recorded for each patient. In addition, 3T MRI scans were performed on 4 post mortem brains with DBS leads but without batteries attached. Detailed neuropathological studies were undertaken to search for evidence of MRI-induced adverse tissue changes. RESULTS: No clinical signs or symptoms or MRI-induced adverse effects were discovered in the DBS-BTN database, and on detailed review of neuroimaging studies. Neuropathological examination did not reveal changes consistent with MRI-induced heating damage. The novel study of four brains with prolonged 3T post-mortem magnetic field exposure (DBS leads left in place) also did not reveal pathological changes consistent with heat related damage. DISCUSSION: The current study adds important information to the data on the safety of MRI in DBS patients. Novel post-mortem MRI studies provide additional information regarding the safety of 3T MRI in DBS patients, and could justify additional studies especially post-mortem scans with battery sources in place. CONCLUSION: The lack of pathological findings in the DBS-BTN database and the lack of tissue related changes following prolonged exposure to 3T MRI in the post mortem brains suggest that MRI scanning in DBS patients may be relatively safe, especially under current guidelines requiring a head receive coil. Subsequent studies exploring the safety of 1.5 T versus 3T MRI in DBS patients should utilize more in depth post-mortem imaging to better simulate the human condition. PMID- 20849961 TI - Lesion Explorer: a comprehensive segmentation and parcellation package to obtain regional volumetrics for subcortical hyperintensities and intracranial tissue. AB - Subcortical hyperintensities (SH) are a commonly observed phenomenon on MRI of the aging brain (Kertesz et al., 1988). Conflicting behavioral, cognitive and pathological associations reported in the literature underline the need to develop an intracranial volumetric analysis technique to elucidate pathophysiological origins of SH in Alzheimer's disease (AD), vascular cognitive impairment (VCI) and normal aging (De Leeuw et al., 2001; Mayer and Kier, 1991; Pantoni and Garcia, 1997; Sachdev et al., 2008). The challenge is to develop processing tools that effectively and reliably quantify subcortical small vessel disease in the context of brain tissue compartments. Segmentation and brain region parcellation should account for SH subtypes which are often classified as: periventricular (pvSH) and deep white (dwSH), incidental white matter disease or lacunar infarcts and Virchow-Robin spaces. Lesion Explorer (LE) was developed as the final component of a comprehensive volumetric segmentation and parcellation image processing stream built upon previously published methods (Dade et al., 2004; Kovacevic et al., 2002). Inter-rater and inter-method reliability was accomplished both globally and regionally. Volumetric analysis showed high inter rater reliability both globally (ICC=.99) and regionally (ICC=.98). Pixel-wise spatial congruence was also high (SI=.97). Whole brain pvSH volumes yielded high inter-rater reliability (ICC=.99). Volumetric analysis against an alternative kNN segmentation revealed high inter-method reliability (ICC=.97). Comparison with visual rating scales showed high significant correlations (ARWMC: r=.86; CHIPS: r=.87). The pipeline yields a comprehensive and reliable individualized volumetric profile for subcortical vasculopathy that includes regionalized (26 brain regions) measures for: GM, WM, sCSF, vCSF, lacunar and non-lacunar pvSH and dwSH. PMID- 20849962 TI - Molecular systematics of the enigmatic Middle American genus Vieja (Teleostei: Cichlidae). AB - The genus Vieja represents a group of heroine cichlids (Teleostei: Cichlidae) distributed on the Atlantic and Pacific slopes of North and Central America from southern Mexico to Panama. Sixteen species of Vieja are presently recognized; however, based on long-standing taxonomic problems, the genus itself appears to be weakly defined. A number of different generic designations have been proposed for members of Vieja, and recent systematic studies of heroine cichlids have not specifically addressed the validity of the grouping and have not included all species in the genus. Therefore, the purpose of this study was to assess the monophyly of the genus Vieja by including all nominal species in the genus using the mitochondrial encoded cytochrome b gene and nuclear S7-1 intron. Results of Maximum Parsimony, Bayesian inference, and topology tests (constraint tree searches and post-burn-in Bayesian filtering) indicate that the genus is not monophyletic as it is currently recognized. The genus Herichthys was recovered as sister to a clade consisting of a number of Vieja species (V. fenestrata, V. guttulata, V. zonata, V. hartwegi, V. bifasciata, V. breidohri, V. argentea, V. regani, V. melanura, V. synspila, and V. maculicauda, as well as Paraneetroplusbulleri). A clade consisting of V. intermedia, V. godmanni, and V. microphthalma was recovered sister to Theraps. Additionally, V. heterospila and V. tuyrensis were recovered outside of Vieja and Herichthys clades. Based on the results of this comprehensive study, we suggest a revised classification of Vieja species. PMID- 20849963 TI - Alignment of, and phylogenetic inference from, random sequences: the susceptibility of alternative alignment methods to creating artifactual resolution and support. AB - We used random sequences to determine which alignment methods are most susceptible to aligning sequences so as to create artifactual resolution and branch support in phylogenetic trees derived from those alignments. We compared four alignment methods (progressive pairwise alignment, simultaneous multiple alignment of sequence fragments, local pairwise alignment, and direct optimization) to determine which methods are most susceptible to creating false positives in phylogenetic trees. Implied alignments created using direct optimization provided more artifactual support than progressive pairwise alignment methods, which in turn generally provided more artifactual support than simultaneous and local alignment methods. Artifactual support derived from base pairs was generally reinforced by the incorporation of gap characters for progressive pairwise alignment, local pairwise alignment, and implied alignments. The amount of artifactual resolution and support was generally greater for simulated nucleotide sequences than for simulated amino acid sequences. In the context of direct optimization, the differences between static and dynamic approaches to calculating support were extreme, ranging from maximal to nearly minimal support. When applied to highly divergent sequences, it is important that dynamic, rather than static, characters be used whenever calculating branch support using direct optimization. In contrast to the tree-based approaches to alignment, simultaneous alignment of sequences using the similarity criterion generally does not create alignments that are biased in favor of any particular tree topology. PMID- 20849964 TI - Sampling port for real-time analysis of bioaerosol in whole body exposure system for animal aerosol model development. AB - INTRODUCTION: Multiple factors influence the viability of aerosolized bacteria. The delivery of aerosols is affected by chamber conditions (humidity, temperature, and pressure) and bioaerosol characteristics (particle number, particle size distribution, and viable aerosol concentration). Measurement of viable aerosol concentration and particle size is essential to optimize viability and lung delivery. The Madison chamber is widely used to expose small animals to infectious aerosols. METHODS: A multiplex sampling port was added to the Madison chamber to measure the chamber conditions and bioaerosol characteristics. Aerosols of three pathogens (Bacillus anthracis, Yersinia pestis, and Mycobacterium tuberculosis) were generated under constant conditions and their bioaerosol characteristics were analyzed. Airborne microbes were captured using an impinger or BioSampler. The particle size distribution of airborne microbes was determined using an aerodynamic particle sizer (APS). Viable aerosol concentration, spray factor (viable aerosol concentration/inoculum concentration), and dose presented to the mouse were calculated. Dose retention efficiency and viable aerosol retention rate were calculated from the sampler titers to determine the efficiency of microbe retention in lungs of mice. RESULTS: B. anthracis, Y. pestis, and M. tuberculosis aerosols were sampled through the port. The count mean aerodynamic sizes were 0.98, 0.77, and 0.78 MUm with geometric standard deviations of 1.60, 1.90, and 2.37, and viable aerosol concentrations in the chamber were 211, 57, and 1 colony-forming unit (CFU)/mL, respectively. Based on the aerosol concentrations, the doses presented to mice for the three pathogens were 2.5e5, 2.2e4 and 464 CFU. DISCUSSION: Using the multiplex sampling port we determined whether the animals were challenged with an optimum bioaerosol based on dose presented and respirable particle size. PMID- 20849965 TI - Validation of a cell-based assay to differentiate between the cytotoxic effects of elapid snake venoms. AB - INTRODUCTION: Acanthophis genus (i.e. death adders) and the Naja genus (i.e. cobras) belong to the family elapidae. The current study compared the in vitro cytotoxicity of venoms from four Acanthophis spp. and three Naja spp. on rat aortic smooth muscle cells, A7r5, and rat skeletal muscle cells, L6. The ability of CSL death adder antivenom and SAIMR antivenom, for Acanthophis spp. and Naja spp. venom respectively, to negate the cytotoxicity was also examined. METHODS: A cell proliferation assay was used to determine cell viability following treatment with venom in the presence or absence of antivenom. Sigmoidal growth curves were obtained, and IC(50) values were determined. RESULTS: Acanthophis spp. and Naja spp. venoms produced concentration-dependent inhibition of cell proliferation in both cell lines. Naja spp. venoms were significantly more cytotoxic than the most potent Acanthophis venom (i.e. A. antarcticus) in both cell lines. Naja spp. venoms also displayed higher sensitivity in L6 cells. SAIMR antivenom significantly inhibited the cytotoxic actions of all Naja spp. venoms in both A7r5 and L6 cells. However, death adder antivenom (CSL Ltd) was unable to negate the cytotoxic effects of Acanthophis spp. venoms. DISCUSSION: Concentrations of the predominantly cytotoxic Naja spp. venoms used were approximately three times less than the predominantly neurotoxic Acanthophis spp. venoms. SAIMR antivenom was partially effective in neutralising the effects of Naja spp. venoms. Death adder antivenom (CSL Ltd) was not effective in negating the cytotoxic effects of venom from Acanthophis spp. These results indicate that the cell-based assay is suited to the examination of cytotoxic snake venoms and may be used in conjunction with organ bath experiments to pharmacologically characterise snake venoms. Furthermore, the results suggest that the use of a skeletal muscle cell line is likely to be more clinically relevant for the examination of cytotoxic snake venoms. PMID- 20849966 TI - Reversibility of object recognition but not spatial memory impairment following binge-like alcohol exposure in rats. AB - Excessive alcohol use leads to neurodegeneration in several brain structures including the hippocampal dentate gyrus and the entorhinal cortex. Cognitive deficits that result are among the most insidious and debilitating consequences of alcoholism. The object exploration task (OET) provides a sensitive measurement of spatial memory impairment induced by hippocampal and cortical damage. In this study, we examine whether the observed neurotoxicity produced by a 4-day binge ethanol treatment results in long-term memory impairment by observing the time course of reactions to spatial change (object configuration) and non-spatial change (object recognition). Wistar rats were assessed for their abilities to detect spatial configuration in the OET at 1 week and 10 weeks following the ethanol treatment, in which ethanol groups received 9-15 g/kg/day and achieved blood alcohol levels over 300 mg/dl. At 1 week, results indicated that the binge alcohol treatment produced impairment in both spatial memory and non-spatial object recognition performance. Unlike the controls, ethanol treated rats did not increase the duration or number of contacts with the displaced object in the spatial memory task, nor did they increase the duration of contacts with the novel object in the object recognition task. After 10 weeks, spatial memory remained impaired in the ethanol treated rats but object recognition ability was recovered. Our data suggest that episodes of binge-like alcohol exposure result in long-term and possibly permanent impairments in memory for the configuration of objects during exploration, whereas the ability to detect non-spatial changes is only temporarily affected. PMID- 20849967 TI - Both mineralocorticoid and glucocorticoid receptors regulate emotional memory in mice. AB - Corticosteroid hormones are thought to promote optimal behavioral adaptation under fearful conditions, primarily via glucocorticoid receptors (GRs). Here, we examined - using pharmacological and genetic approaches in mice - if mineralocorticoid receptors (MRs) also play a role in fearful memory formation. As expected, administration of the GR-antagonist RU38486 prior to training in a fear conditioning paradigm impaired contextual memory when tested 24 (but not when tested 3) h after training. Tone-cue memory was enhanced by RU38486 when tested at 4 (but not 25) h after training. Interestingly, pre (but not post) training administration of MR antagonist spironolactone impaired contextual memory, both at 3 and 24h after training. Similar effects were also found in forebrain-specific MR knockout mice. Spironolactone also impaired tone-cue memory, but only at 4h after training. These results reveal that - in addition to GRs - MRs also play a critical role in establishing fear memories, particularly in the early phase of memory formation. PMID- 20849968 TI - Antimicrobial susceptibility and heteroresistance in Chinese Clostridium difficile strains. AB - One hundred and ten toxigenic Clostridium difficile isolates collected between December 2008 and May 2009 at Fudan University Hospital Huashan were analyzed for their antibiotic susceptibility patterns and resistance molecular basis. The heteroresistance to metronidazole in fresh isolates were detected as well. Sixteen different PCR ribotypes were identified with a dominant clone 017 accounting for 37.3% of the isolates, followed by 001 and H. Ribotype 027 was not found but one isolate belonged to ribotype 078. All the isolates were susceptible to vancomycin and piperacillin/tazobactam. Seventy-eight fresh isolates were tested for heteroresistance to metronidazole, 18 (23.1%) of them were found to be positive. Resistance to moxifloxacin, ciprofloxacin, levofloxacin, erythromycin, clindamycin, tetracycline, rifampin, rifaximin and fusidic acid was found in 61.8%, 100%, 66.4%, 85.3%, 88.1%, 62.7%, 29.1%, 29.1% and 8.2% of the isolates, respectively. The isolates of common PCR ribotypes were more frequently resistant than the uncommon ribotypes. The prevalence of resistance genes and mutations among the resistant isolates was as follows: ermB, 69.1%; tetM, 97.1%; gyrA mutation, 63.2%; gyrB mutation, 4.4%; gyrA and gyrB mutation, 32.4%; rpoB mutation, 100%, respectively. The resistance related fusA mutation was only found in one isolate with minimum inhibitory concentration of 4 mg/L. PMID- 20849970 TI - Age and total-body irradiation in addition to corticosteroid dose are important risk factors for avascular necrosis of the bone. PMID- 20849969 TI - Feasibility of reduced-intensity cord blood transplantation as salvage therapy for graft failure: results of a nationwide survey of adult patients. AB - To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 * 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC >=2.5 * 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced intensity conditioning regimen for GF. PMID- 20849972 TI - Identification and characterization of genes responsible for biosynthesis of kojic acid, an industrially important compound from Aspergillus oryzae. AB - Kojic acid is produced in large amounts by Aspergillus oryzae as a secondary metabolite and is widely used in the cosmetic industry. Glucose can be converted to kojic acid, perhaps by only a few steps, but no genes for the conversion have thus far been revealed. Using a DNA microarray, gene expression profiles under three pairs of conditions significantly affecting kojic acid production were compared. All genes were ranked using an index parameter reflecting both high amounts of transcription and a high induction ratio under producing conditions. After disruption of nine candidate genes selected from the top of the list, two genes of unknown function were found to be responsible for kojic acid biosynthesis, one having an oxidoreductase motif and the other a transporter motif. These two genes are closely associated in the genome, showing typical characteristics of genes involved in secondary metabolism. PMID- 20849973 TI - Secondary metabolism: then, now and tomorrow. PMID- 20849971 TI - Heterogeneity in the muscle satellite cell population. AB - Satellite cells, the adult stem cells responsible for skeletal muscle regeneration, are defined by their location between the basal lamina and the fiber sarcolemma. Increasing evidence suggests that satellite cells represent a heterogeneous population of cells with distinct embryological origin and multiple levels of biochemical and functional diversity. This review focuses on the rich diversity of the satellite cell population based on studies across species. Ultimately, a more complete characterization of the heterogeneity of satellite cells will be essential to understand the functional significance in terms of muscle growth, homeostasis, tissue repair, and aging. PMID- 20849974 TI - Identification of a cDNA encoding for Ghrelin in the testis of the frog Pelophylax esculentus and its involvement in spermatogenesis. AB - GHRELIN (GHRL) is an acylated peptide that contains 28-amino acids prevalently expressed in the stomach of several species. Specifically, it contributes to energy balance, but some new evidence highlights its role in the regulation of reproductive functions. In fact, this protein has been detected at testicular level in the tubular and interstitial compartments of several vertebrate species, and previous research has demonstrated that GHRL affects various aspects of spermatogenesis and steroidogenesis. GHRL clearly plays an inhibitory role in mammalian reproduction, in contrast GHRL stimulates reproductive functions in non mammalian vertebrate. We have focused our attention on the comparative aspect of GHRL, thus studying its expression in an amphibian seasonal breeder, Pelophylax esculentus, to verify the presence and localization, of Ghrl transcript variations during the frog reproductive cycle, in order to demonstrate that Pelophylax esculentus may represent a useful animal model to assess the role of GHRL in male fertility. PMID- 20849975 TI - [Cell surface hydrophobicity as an indicator of other virulence factors in Candida albicans]. AB - OBJECTIVE: To evaluate virulence factors involved in the adhesion process, such as cell surface hydrophobicity (CSH), adherence to plastic capacity, adherence capacity to buccal epithelial cells (BEC), and biofilm formation, in 17 strains of C. albicans isolated from bronchial aspirates of critically ill patients. METHOD: The CSH of the strains of C. albicans was determined using the MATH method, a microbial adhesion to hydrocarbons test. The study of adherence to plastic was performed in microtitre plates in accordance with Christensen's technique. Biofilm formation was studied in polystyrene microtitre plates, according to the method of Ramage. Adherence to BEC was evaluated by quantifying the percentage of adhered yeasts to cells. RESULTS: All the strains studied showed factors directly involved in adhesion, with variability in the degree of expression among them. Medium-high levels of CSH were found in 52.9% of the strains. The percentage of strains with high values in adherence to plastic was 35.3%. The most hydrophobic strains were the most adherent to plastic, with a correlation coefficient of 0.76. Of the 12 biofilm-producing strains, 6 were high producers. These strains had also high levels of CSH and adherence to plastic, with significant results. All the strains studied adhered to BEC, with results ranging widely from 45 to 157 yeasts/100 BEC, with no significant correlation with the rest of the parameters studied, although CSH was seen to be an indispensable prior requisite for adherence to cells. CONCLUSION: CSH is a variable characteristic in C. albicans and is directly related to adherence to plastic and biofilm formation. Ease in evaluating CSH permits its quantification, and could be used as an indicator of the presence of other determinants of pathogenicity. PMID- 20849976 TI - Impact of aging on viral infections. AB - Older people are more susceptible to a variety of viral infections, including those that induce respiratory disease, resulting in higher morbidity and mortality than younger people. Aging impacts both innate and adaptive arms of the immune system to impair control of viral infections. This review will summarize key findings on how aging impacts immunity to viral infection. PMID- 20849977 TI - Fine structure of corpora allata of castes with different rates of juvenile hormone production in the termite Reticulitermes flavipes. AB - The aim of this work is to describe corpora allata (CA) of several castes of the termite Reticulitermes flavipes that have different rates of juvenile hormone (JH) synthesis, with respect to differences in fine structure, volume, and intensity of allatostatin immunoreactivity in their innervation. The castes chosen are workers and their potential derivatives, apterous secondary reproductives and pre-soldiers (the precursors of soldiers). These castes, at the stages chosen, produce JH at low, high and intermediate rates respectively. Hormone production is positively correlated with volume and negatively correlated with intensity of allatostatin immunoreactivity in axons within the glands. Characteristics of fine structure that correlate with increased activity are increase in abundance and width of mitochondria, decrease in ability to fix and visualize smooth endoplasmic reticulum. These features have previously been described for CA of cockroaches and other insects. Glycogen in the CA of all of the castes studied, especially the large amounts in highly active glands of physogastric apterous reproductive females, is the most striking difference between the CA cells of R. flavipes and previously described CA of cockroaches, in which glycogen is absent throughout the reproductive cycles. This suggests that glycogen is an important source of energy for hormone production by termite CA. PMID- 20849978 TI - Unresolved direction of host transfer of Plasmodium vivax v. P. simium and P. malariae v. P. brasilianum. AB - The evolutionary history of two human malaria parasites, Plasmodium vivax and Plasmodium malariae, remains unresolved. The near genetic identity between human P. vivax and P. malariae, and primate P. simium and P. brasilianum, respectively, suggests that recent host transfers occurred, but questions remain, such as whether the transfer was from humans to New World monkeys or vice versa, and when the transfers occurred. Here, we investigate the phylogenies, haplotype networks, positive selection and genetic diversity among these parasite species by means of four genes. Human P. vivax and primate P. simium recently derived one from the other; at least two host transfers have occurred. Human P. malariae and primate P. brasilianum also have recently derived one from the other by lateral host transfer. The direction of the host transfer cannot be decided in either one of the two pairs of species, owing to the scarcity of available strains from the primate parasites. PMID- 20849979 TI - Genetic diversity of human isolates of Mycobacterium bovis assessed by spoligotyping and Variable Number Tandem Repeat genotyping. AB - A collection of clinical isolates including 9 Mycobacterium bovis bacille Calmette-Guerin (BCG), 37 M. bovis and 1 isolate identified as M. bovis/caprae intermediate, recovered from humans in Tuscany, Italy, from 1990 to 2009, was genotyped by spoligotyping and Variable Number Tandem Repeat (VNTR) typing. Spoligotyping detected 15 unique profiles; the "BCG-like" SIT482/SB0120 spoligotype was largely prevalent accounting for 63.8% of isolates. VNTR typing, based on the 15 VNTR loci commonly tested for Mycobacterium tuberculosis, detected 29 unique profiles; only 8 VNTR loci (VNTR 43, MIRU 04, QUB-11b, ETR-A, VNTR 47, MIRU 31, QUB-26 and VNTR 53) provided a satisfactory allelic diversity in the VNTR analysis. Combined together, spoligotyping and VNTR typing yielded 33 unique patterns and 5 clusters including a total of 19 isolates. Clustered isolates, further typed for additional 9 VNTR loci, finally yielded 3 distinct clusters including 3 M. bovis BCG isolates each, and 1 cluster of 6 M. bovis isolates. Minimum spanning tree analysis showed that, in spite of the many distinct VNTR profiles, most M. bovis isolates displayed a high phylogenetic proximity, due to the variation of a single VNTR allele, thus indicating that the population of human M. bovis isolates in our setting is relatively homogeneous and conserved. PMID- 20849980 TI - Altered redox status of coenzyme Q9 reflects mitochondrial electron transport chain deficiencies in Caenorhabditis elegans. AB - Mitochondrial disorders are often associated with primary or secondary CoQ10 decrease. In clinical practice, Coenzyme Q10 (CoQ10) levels are measured to diagnose deficiencies and to direct and monitor supplemental therapy. CoQ10 is reduced by complex I or II and oxidized by complex III in the mitochondrial respiratory chain. Therefore, the ratio between the reduced (ubiquinol) and oxidized (ubiquinone) CoQ10 may provide clinically significant information in patients with mitochondrial electron transport chain (ETC) defects. Here, we exploit mutants of Caenorhabditis elegans (C. elegans) with defined defects of the ETC to demonstrate an altered redox ratio in Coenzyme Q9 (CoQ9), the native quinone in these organisms. The percentage of reduced CoQ9 is decreased in complex I (gas-1) and complex II (mev-1) deficient animals, consistent with the diminished activity of these complexes that normally reduce CoQ9. As anticipated, reduced CoQ9 is increased in the complex III deficient mutant (isp-1), since the oxidase activity of the complex is severely defective. These data provide proof of principle of our hypothesis that an altered redox status of CoQ may be present in respiratory complex deficiencies. The assessment of CoQ10 redox status in patients with mitochondrial disorders may be a simple and useful tool to uncover and monitor specific respiratory complex defects. PMID- 20849981 TI - Care of elderly patients with diabetes mellitus: a focus on frailty. AB - The prevalence and incidence of type 2 diabetes mellitus (DM) increase with age, and its diagnosis and treatment in older people present a challenge. Applying evidence to elderly patients can be problematic, because older persons with frailty, multiple comorbidities, and functional disabilities are generally excluded from diabetes clinical trials. Frailty is characterized by multisystem decline and vulnerability to adverse health outcomes. Insulin resistance predicts frailty, and DM accelerates muscle strength loss. Geriatric diabetes care guidelines have refocused from risk factor control to geriatric syndromes. The European Diabetes Working Party guidelines for elderly type 2 DM patients consider frailty, recommending a conservative target (hemoglobin A1c <8%). Diabetic care-home residents with physical disabilities, cognitive impairment, tube feeding, and the inability to communicate pose particular challenges. Tight glycemic control for such patients increases the risk of hypoglycemia and significant functional decline; a mean hemoglobin A1c <7% did not protect them from care-home-acquired pneumonia. In conclusion, caring for elderly diabetic patients poses unique challenges. Little is known about diabetes care of elderly people with frailty, disabilities, or multiple comorbidities. The interrelationship between frailty and DM deserves further investigation. Practice guidelines for care-home residents with DM are needed to ensure quality of care. PMID- 20849982 TI - Redox properties of a thioredoxin-like Arabidopsis protein, AtTDX. AB - AtTDX is an enzyme present in Arabidopsis thaliana which is composed of two domains, a thioredoxin (Trx)-motif containing domain and a tetratricopeptide (TPR)-repeat domain. This enzyme has been shown to function as both a thioredoxin and a chaperone. The midpoint potential (E(m)) of AtTDX was determined by redox titrations using the thiol-specific modifiers, monobromobimane (mBBr) and mal PEG. A NADPH/Trx reductase (NTR) system was used both to validate these E(m) determination methods and to demonstrate that AtTDX is an electron-accepting substrate for NTR. Titrations of full-length AtTDX revealed the presence of a single two-electron couple with an E(m) value of approximately -260 mV at pH 7.0. The two cysteines present in a typical, conserved Trx active site (WCGPC), which are likely to play a role in the electron transfer processes catalyzed by AtTDX, have been replaced by serines by site-directed mutagenesis. These replacements (i.e., C304S, C307S, and C304S/C307S) resulted in a complete loss of the redox process detected using either the mBBr or mal-PEG method to monitor disulfide/dithiol redox couples. This result supports the conclusion that the couple with an E(m) value of -260 mV is a disulfide/dithiol couple involving Cys304 and Cys307. Redox titrations for the separately-expressed Trx-motif containing C-domain also revealed the presence of a single two-electron couple with an E(m) value of approximately -260 mV at 20 degrees C. The fact that these two E(m) values are identical, provides additional support for assignment of the redox couple to a disulfide/dithiol involving C304 and C307. It was found that, while the disulfide/dithiol redox chemistry of AtTDX was not affected by increasing the temperature to 40 degrees C, no redox transitions were observed at 50 degrees C and higher temperatures. In contrast, Escherichia coli thioredoxin was shown to remain redox-active at temperatures as high as 60 degrees C. The temperature-dependence of the AtTDX redox titration is similar to that observed for the redox activity of the protein in enzymatic assays. PMID- 20849983 TI - Stability of Ni in nitinol oxide surfaces. AB - The stability of Ni in titanium oxide surface layers on nitinol wires known to release certain amounts of Ni was investigated by first principles density functional theory and transmission electron microscopy. The oxides were identified as a combination of TiO and TiO(2) depending on the thickness of the layer. The calculations indicate that free Ni atoms can exist in TiO at ambient temperature while Ni particles form in TiO(2), which was confirmed by the transmission electron microscopy observations. The results are discussed with respect to surface stability and Ni release due to free Ni atoms and Ni particles. PMID- 20849984 TI - Aligned natural-synthetic polyblend nanofibers for peripheral nerve regeneration. AB - Peripheral nerve regeneration remains a significant clinical challenge to researchers. Progress in the design of tissue engineering scaffolds provides an alternative approach for neural regeneration. In this study aligned silk fibroin (SF) blended poly(L-lactic acid-co-epsilon-caprolactone) (P(LLA-CL)) nanofibrous scaffolds were fabricated by electrospinning methods and then reeled into aligned nerve guidance conduits (NGC) to promote nerve regeneration. The aligned SF/P(LLA CL) NGC was used as a bridge implanted across a 10mm defect in the sciatic nerve of rats and the outcome in terms of of regenerated nerve at 4 and 8 weeks was evaluated by a combination of electrophysiological assessment and histological and immunohistological analysis, as well as electron microscopy. The electrophysiological examination showed that functional recovery of the regenerated nerve in the SF/P(LLA-CL) NGC group was superior to that in the P(LLA CL) NGC group. The morphological analysis also indicated that the regenerated nerve in the SF/P(LLA-CL) NGC was more mature. All the results demonstrated that the aligned SF/P(LLA-CL) NGC promoted peripheral nerve regeneration significantly better in comparison with the aligned P(LLA-CL) NGC, thus suggesting a potential application in nerve regeneration. PMID- 20849985 TI - Biomimetic composite coating on rapid prototyped scaffolds for bone tissue engineering. AB - The objective of this present study was to improve the functional performance of rapid prototyped scaffolds for bone tissue engineering through biomimetic composite coating. Rapid prototyped poly(epsilon-caprolactone)/tri-calcium phosphate (PCL/TCP) scaffolds were fabricated using the screw extrusion system (SES). The fabricated PCL/TCP scaffolds were coated with a carbonated hydroxyapatite (CHA)-gelatin composite via biomimetic co-precipitation. The structure of the prepared CHA-gelatin composite coating was studied by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy and Fourier transform infrared spectroscopy. Compressive mechanical testing revealed that the coating process did not have any detrimental effect on the mechanical properties of the scaffolds. The cell-scaffold interaction was studied by culturing porcine bone marrow stromal cells (BMSCs) on the scaffolds and assessing the proliferation and bone-related gene and protein expression capabilities of the cells. Confocal laser microscopy and SEM images of the cell-scaffold constructs showed a uniformly distributed cell sheet and accumulation of extracellular matrix in the interior of CHA-gelatin composite-coated PCL/TCP scaffolds. The proliferation rate of BMSCs on CHA-gelatin composite-coated PCL/TCP scaffolds was about 2.3 and 1.7 times higher than that on PCL/TCP scaffolds and CHA-coated PCL/TCP scaffolds, respectively, by day 10. Furthermore, reverse transcription polymerase chain reaction and Western blot analysis revealed that CHA-gelatin composite-coated PCL/TCP scaffolds stimulate osteogenic differentiation of BMSCs the most, compared with PCL/TCP scaffolds and CHA-coated PCL/TCP scaffolds. These results demonstrate that CHA-gelatin composite-coated rapid prototyped PCL/TCP scaffolds are promising for bone tissue engineering. PMID- 20849986 TI - Through-thickness control of polymer bioresorption via electron beam irradiation. AB - Predicable and controlled degradation is not only central to the accurate delivery of bioactive agents and drugs, it also plays a vital role in key aspects of bone tissue engineering. The work addressed in this paper investigates the utilisation of e-beam irradiation in order to achieve a controlled (surface) degradation profile. This study focuses on the modification of commercially and clinically relevant materials, namely poly(L-lactic acid) (PLLA), poly(L-lactide hydroxyapatite) (PLLA-HA), poly(L-lactide-glycolide) co-polymer (PLG) and poly(L lactide-DL-lactide) co-polymer (PLDL). Samples were subjected to irradiation treatments using a 0.5MeV electron beam with delivered surface doses of 150 and 500 kGy. In addition, an acrylic attenuation shield was used for selected samples to control the penetration of the e-beam. E-beam irradiation induced chain scission in all polymers, as characterized by reduced molecular weights and glass transition temperatures (T(g)). Irradiation not only produced changes in the physical properties of the polymers but also had associated effects on surface erosion of the materials during hydrolytic degradation. Moreover, the extent to which both mechanical and hydrolytic degradation was observed is synonymous with the estimated penetration of the beam (as controlled by the employment of an attenuation shield). PMID- 20849987 TI - Long-term in vitro degradation of PDLLA/bioglass bone scaffolds in acellular simulated body fluid. AB - The long-term (600days) in vitro degradation of highly porous poly(D,L-lactide) (PDLLA)/Bioglass-filled composite foams developed for bone tissue engineering scaffolds has been investigated in simulated body fluid (SBF). Foams of ~93% porosity were produced by thermally induced phase separation (TIPS). The degradation profile for foams of neat PDLLA and the influence of Bioglass addition were comprehensively assessed in terms of changes in dimensional stability, pore morphology, weight loss, molecular weight and mechanical properties (dry and wet states). It is shown that the degradation process proceeded in several stages: (a) a quasi-stable stage, where water absorption and plasticization occurred together with weight loss due to Bioglass particle loss and dissolution, resulting in decreased wet mechanical properties; (b) a stage showing a slight increase in the wet mechanical properties and a moderate decrease in dimensions, with the properties remaining moderately constant until the onset of significant weight loss, whilst molecular weight continued to decrease; (c) an end stage of massive weight loss, disruption of the pore structure and the formation of blisters and embrittlement of the scaffold (evident on handling). The findings from this long-term in vitro degradation investigation underpin studies that have been and continue to be performed on highly porous poly(alpha-hydroxyesters) scaffolds filled with bioactive glasses for bone tissue engineering applications. PMID- 20849988 TI - Resveratrol-conjugated poly-epsilon-caprolactone facilitates in vitro mineralization and in vivo bone regeneration. AB - Incorporation of osteoinductive factors in a suitable scaffold is considered a promising strategy for generating osteogenic biomaterials. Resveratrol is a polyphenol found in parts of certain plants, including nuts, berries and grapes. It is known to increase DNA synthesis and alkaline phosphatase (ALP) activity in osteoblasts and to prevent femoral bone loss in ovariectomized (OVX) rats. In the present study resveratrol was coupled through a hydrolysable covalent bond with the carboxylic acid groups in porous poly-epsilon-caprolactone (PCL) surface grafted with acrylic acid (AA). The osteogenic effect of this new scaffold was evaluated in mesenchymal cell culture and in the rat calvarial defect model. We found that the incorporation of resveratrol caused increased ALP activity of rat bone marrow stromal cells and enhanced mineralization of the cell-scaffold composites in vitro. After 8 weeks the calvarial defects implanted with resveratrol-conjugated PCL displayed a higher X-ray density than the defects implanted with control PCL. Bone-like structures, positively immunostained for bone sialoprotein, were shown to be more extensively formed in the resveratrol conjugated PCL. These results show that incorporation of resveratrol into the AA functionalized porous PCL scaffold led to a significant increase in osteogenesis. PMID- 20849989 TI - Use of pneumatic lithotripsy for managing difficult CBD calculi. AB - INTRODUCTION: About 7-12% of patients who harbor gallbladder calculi concomitant common bile duct (CBD) calculi are present. The treatment of gallbladder calculi has standardized in the form of laparoscopic cholecystectomy but management of CBD calculi is still evolving. Endoscopic removal of CBD calculi <2 cm in diameter is successful in 90-100% of cases but patients harboring stones >2 cm in diameter high failure rates can be seen. Traditionally, laparoscopically one can achieve success rate comparable to endoscopic surgery but large and impacted calculi may cause failures. If one uses pneumatic lithotripsy during laparoscopic management of CBD calculi one can achieve 100% stone clearance irrespective of size, degree of hardness and impaction. This study evaluates the feasibility of using pneumatic lithotripsy for CBD calculi. To our knowledge this is the 1st reported series of using pneumatic lithotripsy for CBD calculi. MATERIAL AND METHODS: From June 2002 to June 2010 96 laparoscopic CBD explorations (LCBDE) were done for CBD calculi. Patients having choledocholithiasis with CBD diameter of >10 mm were taken for LCBDE while in patients with CBD diameter of <10 mm were referred for endoscopic clearance. Additionally ERCP failure cases were also subjected to LCBDE. Rigid nephroscope was used for LCBDE and usually calculi were removed by forceps only. In patients having large, hard &/or impacted calculi pneumatic lithotripsy were used for fragmentation. RESULTS: Out of the 96 patients in 12 (12.5%) cases pneumatic lithotripsy was used for stone fragmentation. Out of these 12 cases 5 (41.6%) were ERCP failure cases. At a mean hospital stay of 2.5 days 100% stone clearance was achieved in all cases with no perioperative complication. CONCLUSION: The present study shows how successfully pneumatic lithotripsy can be used to fragment large, hard &/or impacted CBD calculi. Pneumatic lithotripsy being user friendly easily available can reliably fragment CBD calculi in one session. PMID- 20849990 TI - Current perspectives on the etiology of agnathia-otocephaly. AB - Agnathia-otocephaly, a rare, sporadic and lethal malformation, is characterized by microstomia (small mouth), aglossia (absence of the tongue), agnathia (absence of the lower jaw) and abnormally positioned ears. It is a principal anomaly derived from the first pharyngeal arch as a consequence of failed mesenchymal migration of the maxillary prominence and atrophy in the development of the mandibular prominences. Unfortunately, these patients have poor prognoses and may succumb to death shortly after birth due to respiratory problems if appropriate airway management is not implemented. Difficulties persist in the prenatal diagnosis of agnathia-otocephalic patients. However, two- and three-dimensional ultrasonography, computed tomography and magnetic resonance imaging technologies now offer significant improvements in refining the resolution of distinctive facial anomalies. This complex disorder can be attributed to both genetic and teratogenic causes, in addition to other unidentifiable factors. Furthermore, studies in model organisms, in particular mice, have unraveled potential genetic pathways that may contribute to the etiology. This article highlights current perspectives on agnathia-otocephaly with a focus on the etiological causes and issues concerning prenatal diagnosis, differential diagnosis, prognosis and genetic counseling. Finally, studies using animal models especially genetically engineered mice are described to comprehend the molecular genetic interactions that may occur during the genesis of this intriguing craniofacial birth defect. PMID- 20849991 TI - De novo microduplication at 22q11.21 in a patient with VACTERL association. AB - The non-random association of vertebral defects (V), anorectal malformations (A), cardiac defects (C), tracheoesophageal fistula with esophageal atresia (TE), renal malformations (R), and limb defects (L) is termed VACTERL association. The aim of the present study was to identify microaberrations characterized by a loss or gain of genomic material that contribute to VACTERL association at a genome wide level. Molecular karyotyping was performed in a cohort of 12 patients with anorectal malformations and at least two additional cardinal features of the VACTERL association. A de novo microduplication at chromosomal region 22q11.21 was identified in a patient presenting with three cardinal VACTERL features (V, A, R) and vesicoureteral reflux, penile hypospadias, caudal regression syndrome, and right-sided congenital equinovarus deformity. Chromosomal region 22q11.2 is known for its susceptibility to rearrangements. Associated syndromes include the velo-cardio-facial and DiGeorge deletion syndromes, and the complementary 22q11.2 duplication syndrome. The findings of the present study extend the phenotypic spectrum of the 22q11.2 duplication syndrome, and indicate that it also predisposes to VACTERL association. We discuss the overlap between the phenotypic features of our patient and those reported for other 22q11.2 aberrations, and propose that dosage-sensitive loci for all of these phenotypic features may reside on 22q11.2. PMID- 20849992 TI - Isolation and characterization of temperature and alkaline stable bioflocculant from Agrobacterium sp. M-503. AB - A bacterium isolated from activated sludge of propylene epoxide wastewater was identified as Agrobacterium sp. M-503. It was confirmed to produce bioflocculant with excellent flocculation activity. The yield of the bioflocculant reached 14.9 g/l in batch cultivation with a carbon source conversion of 74.5%. This bioflocculant was temperature and alkaline stable, retaining almost all flocculation activity after being treated at 121 degrees C for 20 minutes or at pH 12.0. It consisted of neutral sugar, uronic acid, aminosugar and protein in weight ratios of 85.0:9.9:2.1:3.0. The active polysaccharide fraction of the bioflocculant was purified to homogeneity by ethanol precipitation, DEAE ion exchange and gel chromatography. Analysis of the purified polysaccharide showed that it consisted of glucose residues and had a molecular weight of 8.1 * 104 Da. Its low molecular weight endowed it with excellent solubility and favorable flocculation activity, especially for small particulates. PMID- 20849993 TI - Purification and biochemical characterization of a nattokinase by conversion of shrimp shell with Bacillus subtilis TKU007. AB - BSN1, a nattokinase, was purified from the culture supernatant of Bacillus subtilis TKU007 with shrimp shell wastes as the sole carbon/nitrogen source. The BSN1 was purified to homogeneity by three-step procedure with a 515-fold increase in specific activity and 12% recovery. The molecular masses of BSN1 determined by SDS-PAGE and gel filtrations were approximately 30 kDa and 28 kDa, respectively. The results of peptide mass mapping showed that four tryptic peptides of BSN1 were identical to the nattokinase from B. subtilis (GenBank accession number gi14422313) with 37% sequence coverage. The N-terminal amino acid sequence of the first 12 amino acids of BSN1 was AQSVPYGISQIK. The optimum pH, optimum temperature, pH stability, and thermal stability of BSN1 were 8, 40 degrees C, pH 4-11, and less than 50 degrees C, respectively. BSN1 was inhibited completely by PMSF, indicating that the BSN1 was a serine protease. Using this method, B. subtilis TKU007 produces a nattokinase/fibrinolytic enzyme and this enzyme may be considered as a new source for thrombolytic agents. PMID- 20849994 TI - Breast cancer cells inhibit spontaneous and bisphosphonate-induced osteoclast apoptosis. AB - Breast cancer metastasizes to bone where it stimulates formation of bone resorbing osteoclasts. Bisphosphonates constitute an important treatment for osteolytic metastases. The goal of this study was to assess the effects of soluble factors produced by breast cancer cells on osteoclast survival and responsiveness to bisphosphonates. Osteoclasts derived from the murine monocytic cell line RAW264.7 or from primary mouse bone marrow were cultured for 24-48 h untreated, with 10% conditioned media (CM) from human (MDA-MB-231) or mouse (4T1) metastatic breast carcinoma cells, or with a pro-survival factor RANKL. Cancer derived factors maintained osteoclast survival at the levels comparable to those observed with RANKL. Alendronate (10-4M) or pamidronate (10-7M) induced osteoclast apoptosis in untreated and, to a smaller extent, in RANKL-treated cultures, resulting in a significant decrease in osteoclast number and size, induction of caspase-3 cleavage and up-regulation of BIM. In the presence of cancer-derived factors, bisphosphonates were ineffective in inducing osteoclast apoptosis, resulting in only modest decrease in osteoclast numbers and not in size. MDA-MB-231 CM prevented bisphosphonate-induced cleavage of caspase-3 and up regulation of BIM. MCSF-neutralizing antibody attenuated the effect of MDA-MB-231 CM by ~50%, but could not fully restore osteoclast responsiveness to alendronate. Inhibition of phospholipase C (PLC)-gamma interfered with MDA-MB-231-induced down regulation of BIM and prevented anti-apoptotic action of cancer-derived factors on osteoclasts. Our data suggest that factors produced by the metastatic breast cancer cells promote osteoclast survival and block the apoptotic effect of bisphosphonates in MCSF and PLC-dependent manner, potentially compromising bisphosphonate effectiveness in the bone metastasis setting. PMID- 20849996 TI - [The hypertextual future of the Annals]. PMID- 20849995 TI - Comparing histological, vascular and molecular responses associated with woven and lamellar bone formation induced by mechanical loading in the rat ulna. AB - Osteogenesis occurs by formation of woven or lamellar bone. Little is known about the molecular regulation of these two distinct processes. We stimulated periosteal bone formation at the ulnar mid-diaphysis of adult rats using a single bout of forelimb compression. We hypothesized that loading that stimulates woven bone formation induces higher over-expression of genes associated with cell proliferation, angiogenesis and osteogenesis compared to loading that stimulates lamellar bone formation. We first confirmed that a single bout of 100 cycles of loading using either a rest-inserted (0.1 Hz) or haversine (2 Hz) waveform (15 N peak force) was non-damaging and increased lamellar bone formation (LBF loading). Woven bone formation (WBF loading) was stimulated using a previously described, damaging fatigue loading protocol (2 Hz, 1.3 mm disp., 18 N peak force). There were dramatic differences in gene expression levels (based on qRT-PCR) between loading protocols that produced woven and lamellar bone. In contrast, gene expression levels were not different between LBF loading protocols using a rest inserted or haversine waveform. Cell proliferation markers Hist4 and Ccnd1 were strongly upregulated (5- to 17-fold) 1 and 3 days after WBF loading, prior to woven bone formation, but not after LBF loading. The angiogenic genes Vegf and Hif1a were upregulated within 1 h after WBF loading and were strongly up on days 1-3 (3- to 15-fold). In sharp contrast, we observed only a modest increase (<2 fold) in Vegfa and Hif1a expression on day 3 following LBF loading. Consistent with these relative differences in gene expression, vascular perfusion 3 days after loading revealed significant increases in vessel number and volume following WBF loading, but not after LBF loading. Lastly, bone formation markers (Runx2, Osx, Bsp) were more strongly upregulated for woven (4- to 89-fold) than for lamellar bone (2-fold), consistent with the differences in new bone volume observed 10 days after loading. In summary, robust early increases both molecularly and histologically for cell proliferation and angiogenesis precede woven bone formation, whereas lamellar bone formation is associated with only a modest upregulation of molecular signals at later timepoints. PMID- 20849998 TI - Drugs involved in drug-facilitated crimes: part I: alcohol, sedative-hypnotic drugs, gamma-hydroxybutyrate and ketamine. A review. AB - SUMMARY: In recent years, there has been a notable increase in the number of reports of drug-facilitated crimes (DFCs). Usually, individuals report that they were robbed or assaulted while incapacitated by drugs. Most often, these cases have involved drugs that have the ability to produce an effect that leaves the victim in a semiconscious or unconscious state. It is reasonable to assume that the purpose of drug-induced incapacitation is probably largely unchanged with time. This covers the full range of property offences (particularly theft) and crimes against the person. What have changed are the drugs themselves: the number; type; their accessibility; effects and detection. The purpose of this review is to explore the different aspects related to the involvement and use of ethanol, sedative-hypnotics drugs, gamma-hydroxybutyrate (GHB) and ketamine in DFCs or offences, which may help people working in this field to expand their knowledge for better understanding of the nature of these crimes or offences. PMID- 20849997 TI - [Influenza A/H1N1v 2009 during pregnancy and breastfeeding: which antiviral to choose?]. AB - SUMMARY: Pregnant women are at increased risk of severe complications associated with H1N1 pandemic influenza. Fever and inflammatory syndrome associated with the infection may also be deleterious for the developing fetus. Therefore, early antiviral treatment is recommended. Oseltamivir and zanamivir are the two therapeutic options available indicated in the treatment of H1N1 influenza; however, limited data is published on their use during pregnancy and lactation. In this review, we will focus on the effects of H1N1 during pregnancy and on data safety of antivirals during pregnancy and lactation. Main health authorities recommendations for H1N1 influenza treatment of pregnant women will also be presented. PMID- 20849999 TI - [Hospital pharmaceutical practice in prison]. AB - SUMMARY: Since 1994, hospital pharmaceutical teams have been in charge of pharmaceutical tasks in "unites de consultation et de soins ambulatoires" (UCSA), which are hospital consulting care units in French prisons. In 2008, pharmaceutical team in Parisian prisons received 6500 prescriptions and prepared 85,000 nominative bags containing drugs. Prisoners were 1.3% to receive treatments against HIV, 8.2% cardiovascular drugs, 7.2% opioid substitution treatments, and 52.9% psychoactive drugs, including 39.3% hypnotics, 40.5% anxiolytics, 11.3% antidepressants and 12.2% neuroleptics. In prison, the dichotomy between somatic and mental care is marked, attitudes of prisoners about their medicines are complex (important claims, embezzlement, etc.) and it is difficult for law defendants to maintain treatment confidentiality and to prepare prison outing in terms of health. To attenuate the heterogeneity of drug distribution systems in French prisons, we propose pharmaceutical analysis of prescriptions and nominative dispensation, computerization in UCSA in coordination with hospitals, a better contribution of prison medical and pharmaceutical staff in hospital "drug committees" and the redaction of pharmaceutical guidelines. Acting in concert with multidisciplinary medical staff in UCSA, pharmaceutical teams have to develop epidemiological studies to improve knowledge in prisoner's health and also prevention and health care in prison. PMID- 20850000 TI - [Place and role of safety pharmacology in drug development]. AB - SUMMARY: Safety pharmacology is a key regulatory step for drug development and approval. Prior to phase I, the effects of a drug candidate should be evaluated and characterized on vital functions (cardiovascular, respiratory and central nervous system) according to good laboratory practice standards. For cardiovascular evaluation, effects on blood pressure and electrocardiogram should be explored with a particular emphasis on ventricular repolarization prolongation, a major risk factor for life-threatening arrhythmias, like "torsades de pointe". Global behaviour, motor activity, reflexes and body temperature should be evaluated in animals. A dedicated study is necessary for respiratory function evaluation. All of these studies should be conducted after single administration of the compound administered by the anticipated clinical route. Dependence potential and abuse liability should be characterized for innovative drugs and/or drugs acting on the central nervous system. Evidence for adverse effects at discovery stage with high throughput systems is becoming a key step of decision-making process for pharmaceutical industry. Therefore, determination of the safety margin, risk/benefit ratio analysis and investigation of adverse effects are major decisional elements for providing safety reassurance to patients. Safety of patients will also be improved through modelling methodologies allowing a safer transposition of experimental pharmacology results to clinical pharmacology. PMID- 20850001 TI - [Technology transfer between academic laboratories and industrial laboratories: licensing]. AB - SUMMARY: The time when academic and industrial research were operating in two separate worlds is now over. Technology transfer from one to the other is now frequent and organized. It starts by filing a patent. Of course, provided the amounts at stake for developing a product, especially in the healthcare field, a non patent-protected invention has virtually no chance of eventually reaching the community. But this is only the first step of a long process which starts by licensing deals of which we will examine the main common clauses. PMID- 20850002 TI - [Results of a satisfaction survey carried out among patients living with the virus of human immunodeficiency (HIV) following therapeutic education sessions]. AB - INTRODUCTION: Within the framework of a quality initiative aiming to improve HIV patients' care in our therapeutic educational unit, and to meet the recommendations of the Haute Autorite de Sante (HAS) regarding the evaluation of educational programs, we carried out a satisfaction survey among patients. Our goal was to identify their needs thanks to the analysis of questionnaires in order to improve their care. PATIENTS AND METHOD: Anonymous questionnaires were proposed and collected for two months during a medical or educational consultation or during a renewal of prescription. All 21 questions related to the organization of our unit, the patients' expectations, the tools used and the quality of life. An appreciation scale at four levels was proposed. RESULTS: Twenty-eight questionnaires were returned out of 60 given out; 96.4% of the patients were satisfied and found the sessions to be beneficial and to answer their needs; 85.7% changed their opinion on HIV and 78.6% altered their behaviour; 89.3% were satisfied by the number of sessions; 96.4% thought that the place, duration and frequency of consultations were adapted, and 89.3% approved the educational tools; 67.8% thought that follow-up pad would be useful. DISCUSSION-CONCLUSION: Patients were satisfied with the educational sessions, which constituted a real place of exchange and support, allowing them to evoke all the difficulties they meet. Any improvements must concern information media given out to patients and the ease of access to educational teams in case of difficulties. PMID- 20850003 TI - Evaluation of indoor residual spraying with the pyrrole insecticide chlorfenapyr against pyrethroid-susceptible Anopheles arabiensis and pyrethroid-resistant Culex quinquefasciatus mosquitoes. AB - Chlorfenapyr is a pyrrole insecticide with a unique non-neurological mode of action. Laboratory bioassays of chlorfenapyr comparing the mortality of pyrethroid-susceptible and -resistant Anopheles gambiae s.s. and Culex quinquefasciatus mosquitoes indicated that operational cross-resistance is unlikely to occur (resistance ratio ranged between 0 and 2.1). Three trials of chlorfenapyr indoor residual spraying were undertaken in experimental huts in an area of rice irrigation in northern Tanzania that supports breeding of A. arabiensis. Daily mosquito collections were undertaken to assess product performance primarily in terms of mortality. In the second trial, 250mg/m(2) and 500mg/m(2) chlorfenapyr were tested for residual efficacy over 6 months. Both dosages killed 54% of C. quinquefasciatus, whilst for A. arabiensis 250mg/m(2) killed 48% compared with 41% for 500mg/m(2); mortality was as high at the end of the trial as at the beginning. In the third trial, 250mg/m(2) chlorfenapyr was compared with the pyrethroid alpha-cypermethrin dosed at 30mg/m(2). Chlorfenapyr performance was equivalent to the pyrethroid against A. arabiensis, with both insecticides killing 50% of mosquitoes. Chlorfenapyr killed a significantly higher proportion of pyrethroid-resistant C. quinquefasciatus (56%) compared with alpha-cypermethrin (17%). Chlorfenapyr has the potential to be an important addition to the limited arsenal of public health insecticides for indoor residual control of A. arabiensis and pyrethroid-resistant species of mosquito. PMID- 20850004 TI - Comparison of artesunate and quinine in the treatment of Sudanese children with severe Plasmodium falciparum malaria. AB - Sixty-six children presenting to Singa hospital, Sudan with different manifestations of severe Plasmodium falciparum malaria were randomly divided into two well-matched groups (33 in each arm) to receive either intravenous artesunate 2.4 mg/kg at 0, 12, and 24 hours, then daily, or intravenous quinine 20mg/kg initially then 10mg/kg three times a day. There was no significant difference in the fever, parasite clearance, and coma resolution times. Three patients died, one in the artesunate and two in the quinine groups. One patient developed hypoglycaemia following quinine infusion. Thus, artesunate can be used for the treatment of severe falciparum malaria. PMID- 20850005 TI - Influenza exits the cell without an ESCRT. AB - Many enveloped viruses depend on the membrane remodeling machinery of their host cells to complete their life cycle. In this issue, Rossman et al. (2010) now demonstrate that influenza virus possesses its own device for releasing nascent virus particles from the plasma membrane, the M2 proton-selective ion channel, which can substitute for the host cell's ESCRT pathway. PMID- 20850006 TI - PARP around the clock. AB - Cells possess internal ~24 hr or circadian clocks that synchronize physiological processes with daily cycles of light and nutrient availability. In this issue, Asher et al. (2010) find that PARP-1 (poly(ADP-ribose) polymerase 1) modifies components of the clock machinery in response to feeding, providing a mechanism for how metabolic rhythms coordinate with circadian rhythms. PMID- 20850007 TI - Decoding chromatin goes high tech. AB - Identifying proteins that recognize histone methylation is critical for understanding chromatin function. Vermeulen et al. (2010) now describe a cutting edge strategy to identify and characterize several nuclear proteins and complexes that recognize five major histone trimethyl marks. PMID- 20850008 TI - Natural killer cell education and tolerance. AB - Natural killer (NK) cells play a key role in the immune response to certain infections and malignancies by direct cytolysis of infected or transformed cells and by secretion of potent immune mediators. NK cells express an array of activating receptors that recognize self-molecules. If not restrained by inhibitory receptors recognizing major histocompatibility complex (MHC) class I proteins on the surface of self cells, NK cells are able to kill normal, healthy cells. Not all NK cells express inhibitory receptors for self-MHC class I; thus, other tolerance mechanisms are necessary to prevent NK cell-mediated autoimmunity. Here we review the major mechanisms of NK cell education and tolerance. PMID- 20850009 TI - Regulation of replication termination by Reb1 protein-mediated action at a distance. AB - DNA transactions driven by long-range protein-mediated inter- and intrachromosomal interactions have been reported to influence gene expression. Here, we report that site-specific replication termination in Schizosaccharomyces pombe is modulated by protein-mediated interactions between pairs of Ter sites located either on the same or on different chromosomes. The dimeric Reb1 protein catalyzes termination and mediates interaction between Ter sites. The Reb1 dependent interactions between two antiparallel Ter sites in cis caused looping out of the intervening DNA in vitro and enhancement of fork arrest in vivo. A Ter site on chromosome 2 interacted pairwise with two Ter sites located on chromosome 1 by chromosome kissing. Mutational inactivation of the major interacting Ter site on chromosome 1 significantly reduced fork arrest at the Ter site on chromosome 2, thereby revealing a cooperative mechanism of control of replication termination. PMID- 20850010 TI - Switch between large hand-over-hand and small inchworm-like steps in myosin VI. AB - Many biological motor molecules move within cells using stepsizes predictable from their structures. Myosin VI, however, has much larger and more broadly distributed stepsizes than those predicted from its short lever arms. We explain the discrepancy by monitoring Qdots and gold nanoparticles attached to the myosin VI motor domains using high-sensitivity nanoimaging. The large stepsizes were attributed to an extended and relatively rigid lever arm; their variability to two stepsizes, one large (72 nm) and one small (44 nm). These results suggest that there exist two tilt angles during myosin-VI stepping, which correspond to the pre- and postpowerstroke states and regulate the leading head. The large steps are consistent with the previously reported hand-over-hand mechanism, while the small steps follow an inchworm-like mechanism and increase in frequency with ADP. Switching between these two mechanisms in a strain-sensitive, ADP-dependent manner allows myosin VI to fulfill its multiple cellular tasks including vesicle transport and membrane anchoring. PMID- 20850011 TI - Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. AB - In response to many apoptotic stimuli, oligomerization of Bax is essential for mitochondrial outer membrane permeabilization and the ensuing release of cytochrome c. These events are accompanied by mitochondrial fission that appears to require Drp1, a large GTPase of the dynamin superfamily. Loss of Drp1 leads to decreased cytochrome c release by a mechanism that is poorly understood. Here we show that Drp1 stimulates tBid-induced Bax oligomerization and cytochrome c release by promoting tethering and hemifusion of membranes in vitro. This function of Drp1 is independent of its GTPase activity and relies on arginine 247 and the presence of cardiolipin in membranes. In cells, overexpression of Drp1 R247A/E delays Bax oligomerization and cell death. Our findings uncover a function of Drp1 and provide insight into the mechanism of Bax oligomerization. PMID- 20850012 TI - Influenza virus M2 protein mediates ESCRT-independent membrane scission. AB - Many viruses utilize host ESCRT proteins for budding; however, influenza virus budding is thought to be ESCRT-independent. In this study we have found a role for the influenza virus M2 proton-selective ion channel protein in mediating virus budding. We observed that a highly conserved amphipathic helix located within the M2 cytoplasmic tail mediates a cholesterol-dependent alteration in membrane curvature. The 17 amino acid amphipathic helix is sufficient for budding into giant unilamellar vesicles, and mutation of this sequence inhibited budding of transfected M2 protein in vivo. We show that M2 localizes to the neck of budding virions and that mutation of the M2 amphipathic helix results in failure of the virus to undergo membrane scission and virion release. These data suggest that M2 mediates the final steps of budding for influenza viruses, bypassing the need for host ESCRT proteins. PMID- 20850013 TI - Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. AB - Foxp3(+) regulatory T (Treg) cells maintain immune homeostasis by limiting different types of inflammatory responses. Here, we report that miR-146a, one of the miRNAs prevalently expressed in Treg cells, is critical for their suppressor function. The deficiency of miR-146a in Treg cells resulted in a breakdown of immunological tolerance manifested in fatal IFNgamma-dependent immune-mediated lesions in a variety of organs. This was likely due to augmented expression and activation of signal transducer and activator transcription 1 (Stat1), a direct target of miR-146a. Likewise, heightened Stat1 activation in Treg cells subjected to a selective ablation of SOCS1, a key negative regulator of Stat1 phosphorylation downstream of the IFNgamma receptor, was associated with analogous Th1-mediated pathology. Our results suggest that specific aspects of Treg suppressor function are controlled by a single miRNA and that an optimal range of Stat1 activation is important for Treg-mediated control of Th1 responses and associated autoimmunity. PMID- 20850014 TI - DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC. AB - Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Mechanistically, the demethylase genes are directly activated by Pou5f1 and Cebpbeta and are indirectly repressed by retinoic acid, which antagonizes Pou5f1 and Cebpbeta. Apc mutants lack retinoic acid as a result of the transcriptional repression of retinol dehydrogenase l1 via a complex that includes Lef1, Groucho2, Ctbp1, Lsd1, and Corest. Our findings imply a model wherein APC controls intestinal cell fating through a switch in DNA methylation dynamics. Wild-type APC and retinoic acid downregulate demethylase components, thereby promoting DNA methylation of key genes and helping progenitors commit to differentiation. PMID- 20850015 TI - Patterning axon targeting of olfactory receptor neurons by coupled hedgehog signaling at two distinct steps. AB - We present evidence for a coupled two-step action of Hedgehog signaling in patterning axon targeting of Drosophila olfactory receptor neurons (ORNs). In the first step, differential Hedgehog pathway activity in peripheral sensory organ precursors creates ORN populations with different levels of the Patched receptor. Different Patched levels in ORNs then determine axonal responsiveness to target derived Hedgehog in the brain: only ORN axons that do not express high levels of Patched are responsive to and require a second step of Hedgehog signaling for target selection. Hedgehog signaling in the imaginal sensory organ precursors thus confers differential ORN responsiveness to Hedgehog-mediated axon targeting in the brain. This mechanism contributes to the spatial coordination of ORN cell bodies in the periphery and their glomerular targets in the brain. Such coupled two-step signaling may be more generally used to coordinate other spatially and temporally segregated developmental events. PMID- 20850016 TI - Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. AB - Trimethyl-lysine (me3) modifications on histones are the most stable epigenetic marks and they control chromatin-mediated regulation of gene expression. Here, we determine proteins that bind these marks by high-accuracy, quantitative mass spectrometry. These chromatin "readers" are assigned to complexes by interaction proteomics of full-length BAC-GFP-tagged proteins. ChIP-Seq profiling identifies their genomic binding sites, revealing functional properties. Among the main findings, the human SAGA complex binds to H3K4me3 via a double Tudor-domain in the C terminus of Sgf29, and the PWWP domain is identified as a putative H3K36me3 binding motif. The ORC complex, including LRWD1, binds to the three most prominent transcriptional repressive lysine methylation sites. Our data reveal a highly adapted interplay between chromatin marks and their associated protein complexes. Reading specific trimethyl-lysine sites by specialized complexes appears to be a widespread mechanism to mediate gene expression. PMID- 20850017 TI - SnapShot: Nuclear receptors II. PMID- 20850018 TI - [One point one-seven-two. We've got the impact factor]. PMID- 20850019 TI - [Presentation]. PMID- 20850020 TI - [COPD and alpha-1-antitrypsin deficiency]. AB - Alpha-1-antitrypsin deficiency (AATD) is the main genetic factor related to the development of emphysema. This protein has numerous variants, some of which are clinically relevant because their anomalous conformation implies that they fail to reach the target organs as they are polymerized in the hepatocyte. The main abnormal variant is PiZ. In a small percentage of individuals, the accumulation of Z polymers in the liver leads to the development of liver disease. The lack of AATD in the lung favors the development of emphysema, since the proteolytic effect of elastases - the main biological function of AATD - is not counteracted. In Spain, approximately 400 persons are diagnosed with severe AATD deficiency, representing less than 10 % of those expected by epidemiological studies. The principal prognostic factor in these patients is forced expiratory volume in one second (FEV(1)), which is affected mainly by exposure to tobacco smoke. Thus, life expectancy in nonsmokers is similar to that in the general population while lung function decreases faster in smokers than in other patients with chronic obstructive pulmonary disease (COPD). The treatment of the lung disease is the same, although exogenous AATD augmentation is indicated when lung function deteriorates. PMID- 20850021 TI - [COPD: bronchial and systemic inflammation]. AB - Chronic obstructive pulmonary disease (COPD) is considered to be an inflammatory disease of the airways, in which there can be low-grade systemic inflammation. The etiology of this disease is multifactorial but is mainly due to an anomalous and amplified inflammatory response to tobacco smoke. This inflammatory response involves innate and acquired immunity. The latter is characterized by a Th1-type (CD8) response and its presence seems to be associated with progression to advanced stages of the disease. Currently, it is unknown whether bronchial and systemic inflammation are related or whether they act as independent compartments. Most of the available data on COPD are drawn from cross-sectional studies and consequently a causal relation between the possible inflammatory mediators and the genetic factors involved in pulmonary and extrapulmonary involvement in this disease cannot be established. Further studies are required that would allow the inflammatory response to be correlated with the distinct COPD phenotypes. PMID- 20850022 TI - [COPD in nonsmokers]. AB - The association of chronic obstructive pulmonary disease (COPD) and smoking is well established. However, an increasing number of studies have reported a not inconsiderable prevalence of COPD among nonsmokers. Therefore, other factors, both endogenous and exogenous, may influence the development of this disease. The present article reviews the influence of possible genetic factors, gender and other respiratory diseases (such as chronic asthma and tuberculosis), as well as environmental pollution and occupational exposure in the development of COPD. PMID- 20850023 TI - [Budesonide/formoterol in the treatment of COPD]. AB - Two large, 12-month clinical trials have been performed with budesonide formoterol in patients with stable COPD and have shown clear data on the efficacy of this combination in improving pulmonary function, symptoms and health-related quality of life and in reducing the number of exacerbations. Before these trials, information was already available on the efficacy of both monocomponents in this disease, although the main clinical data obtained with formoterol and budesonide separately in the treatment of COPD come from the respective branches of these drugs in the two large clinical trials described in the present article. Improvement in pulmonary function variables [forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF)] was always greater with the combination of budesonide-formoterol. The scores obtained in quality of life questionnaires were also more favorable in the combination treatment branches as early as the first week of treatment and persisted at 12 months of follow-up. Improvement in symptoms and in the use of reliever medication was also greater in the combination branch. The frequency of mild and severe exacerbations, as well as the use of oral corticosteroids, was lower in the budesonide-formoterol branch. The time to first exacerbation was also more prolonged in this group. The present review discusses the main findings on the efficacy of the combination of budesonide-formoterol in stable COPD. PMID- 20850024 TI - [Safety of inhaled corticosteroids in COPD]. AB - Inhaled corticosteroids (IC) are used in chronic obstructive pulmonary disease (COPD) as these agents decrease the frequency of exacerbations and halt the impairment in health-related quality of life. The intimate mechanisms supporting their use and the dose that should be employed have not been sufficiently well established. IC have adverse effects that are hardly described in guidelines for the management of COPD and are sometimes not even mentioned. These agents have been related to adverse effects in the upper airways, intraocular hypertension and glaucoma, loss of bone mass and fractures, adrenal suppression and, lately, with pneumonia. The debate on the role of CI in these processes is ongoing. However, given the growing frequency of the use of these drugs, awareness of their potential adverse effects is essential, especially since the pharmacodynamic characteristics of the distinct IC differ widely. PMID- 20850025 TI - Nerve density: a new parameter to evaluate peripheral nerve pathology on ultrasound. Preliminary study. AB - The possibility to realize a quantitative evaluation of nerve density on ultrasound is clinically important to enhance the evaluation of peripheral nerve disorders. We developed software that quantifies the ratio between the hypoechoic and hyperechoic areas of peripheral nerves on ultrasound. Nerve density was defined as (hypoechoic pixels)/(total pixels) and the purpose of our study was to asses if nerve density can be used to differentiate pathologic conditions affecting peripheral nerves. Ultrasound images of peripheral nerves were obtained with a high-frequency probe (17-5 MHz, 288 elements). Sixty-five different patients and (n = 65) controls (age range, 35-81 years; mean 55 years) were prospectively evaluated. Thirty-five patients had carpal tunnel syndrome and 30 patients had neurofibromas. Three radiologists performed a semiautomated evaluation with intra and interobserver agreement. A complete automatic evaluation was performed with no need of intra and interobserver evaluation. With the semiautomated evaluation, mean intraobserver agreement was good (K = 0.85). Interobserver agreements was good as well (reader 1 vs reader 2: k = 0.72; reader 2 vs reader 3: k = 0.80; reader 3 vs reader 1: k = 0.72). Differences among value of nerve density in normal nerves, CTS and neurofibromas were statistically significant (p < 0.0001). There were no statistically significant differences between the results obtained using the automatic or the semiautomatic method. Nerve density is capable of discriminating between normal and pathologic nerves of patients affected by carpal tunnel syndrome or neurofibromas. Moreover, nerve density measure is useful to discriminate between patients with mild and severe CTS. PMID- 20850026 TI - Diagnostic accuracy of ultrasound and 18-F-FDG PET or PET/CT for patients with suspected recurrent papillary thyroid carcinoma. AB - The purpose of this study was to evaluate the diagnostic accuracies of ultrasound (US) and 18-F-FDG positron emission tomography (PET) or PET/computed tomography (CT) for detecting recurrent papillary thyroid carcinoma (PTC) after total thyroidectomy. Our study enrolled 76 postoperative patients who underwent both neck US and PET because of the suspicion of recurrence. The results of US and PET were correlated with the histopathology, the radioactive iodine whole body scan (WBS) or the clinical follow-up results. Among them, 53 patients had recurrent disease (local recurrence, 42; distant metastasis, 3; elevated Tg level, 8) and 23 showed no evidence of disease. From the analysis, US showed higher diagnostic accuracy, sensitivity and specificity compared with those of PET (71.1%, 71.7% and 69.6% vs. 55.3%, 56.6%, and 52.2%). PET added diagnostic information in a limited number of patients with negative results on neck US (3 with neck recurrence and 2 with distant metastasis). PMID- 20850027 TI - Acoustic sizing of an ultrasound contrast agent. AB - Because the properties of ultrasound contrast agent populations after administration to patients are largely unknown, methods able to study them noninvasively are required. In this study, we acoustically performed a size distribution measurement of the ultrasound contrast agent Definity((r)). Single lipid-shelled microbubbles were insonified at 25 MHz, which is considerably higher than their resonance frequency, so that their acoustic responses depended on their geometrical cross sections only. We calculated the size of each microbubble from their measured backscattered pressures. The acoustic size measurements were compared with optical reference size measurements to test their accuracy. Our acoustic sizing method was applied to 88 individual Definity((r)) bubbles to derive a size distribution of this agent. The size distribution obtained acoustically showed a mean diameter (2.5 MUm) and a standard deviation (0.9 MUm) in agreement within 8% with the optical reference measurement. At 25 MHz, this method can be applied to bubble sizes larger than 1.2 MUm in diameter. It was observed that similar sized bubbles can give different responses (up to a factor 1.5), probably because of shell differences. These limitations should be taken into account when implementing the method in vivo. This acoustic sizing method has potential for estimating the size distribution of an ultrasound contrast agent noninvasively. PMID- 20850028 TI - In vitro gene transfer by electrosonoporation. AB - Among the nonviral methods for gene delivery in vitro, electroporation is simple, inexpensive and safe. To upregulate the expression level of transfected gene, we investigated the applicability of electrosonoporation. This approach consists of a combination of electric pulses and ultrasound assisted with gas microbubbles. Cells were first electroporated with plasmid DNA encoding-enhanced green fluorescent protein and then sonoporated in presence of contrast microbubbles. Twenty-four hours later, cells that received electrosonoporation demonstrated a four-fold increase in transfection level and a six-fold increase in transfection efficiency compared with cells having undergone electroporation alone. Although electroporation induced the formation of DNA aggregates into the cell membrane, sonoporation induced its direct propulsion into the cytoplasm. Sonoporation can improve the transfer of electro-induced DNA aggregates by allowing its free and rapid entrance into the cells. These results demonstrated that in vitro gene transfer by electrosonoporation could provide a new potent method for gene transfer. PMID- 20850029 TI - Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review. AB - Associations have been found between various micronutrients and cardio-metabolic outcomes. Vitamin K deficiency has been associated with increased calcification of the main arteries and with insulin resistance. The present study aimed to examine the association between vitamin K intake and cardio-metabolic outcomes including cardiovascular disease, type 2 diabetes and the metabolic syndrome. A systematic review of the literature was performed in January 2010. Nine electronic databases, and trial registers, reference lists of retrieved articles and citations were searched. Intervention, cohort, case-control or cross sectional studies in adults were included if they examined the association between vitamin K levels (dietary intake, biomarkers, supplements) on clinical outcomes relevant to cardio-metabolic disease. Five studies met the inclusion criteria (1 trial, 4 cohort studies). Heterogeneity of designs, exposures/interventions and outcomes meant that meta-analysis was not possible. No associations were found between vitamin K1 intake and coronary heart disease (CHD) (4 cohorts) or stroke (2 cohorts) in multivariate analyses. No differences were seen in the prevalence of diabetes in a trial of vitamin K1 supplementation. Two cohorts examined the effects of vitamin K2 intake on the incidence of CHD; both found significant associations where higher vitamin K2 intake was associated with fewer CHD events. Few studies have examined the effects of vitamin K intake on clinical outcomes relevant to cardio-metabolic disorders. None of the studies used biomarkers. Currently there is no evidence for an effect of vitamin K1, but results for vitamin K2 look promising. Further prospective studies are required to confirm these findings. PMID- 20850030 TI - First year update--and more to come. PMID- 20850031 TI - A wake-up call for Canadian Radiology: A message from the president of the Canadian Association of Radiologists. PMID- 20850032 TI - Case of the month #165: Swine-origin influenza A (H1N1) viral pneumonia presenting as crazy-paving on computed tomography: case report and literature review. PMID- 20850033 TI - Dietary polyphenols: focus on resveratrol, a promising agent in the prevention of cardiovascular diseases and control of glucose homeostasis. AB - Plants continuously produce an extraordinary variety of biologically active low molecular-mass compounds. Among them, resveratrol (3,5,4'-trihydroxystilbene) is endowed with significant positive activities by protecting against cardiovascular diseases and preventing the development and progression of atherosclerosis. Furthermore, the molecule significantly ameliorates glucose homeostasis in obese mice. These beneficial effects have driven considerable interest towards resveratrol molecular activities, and intensive efforts for the identification of the stilbene targets have been made. The molecule shows a pleiotropic mode of action. Particularly, its cellular targets are crucial for cell proliferation and differentiation, apoptosis, antioxidant defence and mitochondrial energy production. The complexity of resveratrol activities might account for its effectiveness in ameliorating multifactorial processes, including the onset and/or progression of several degenerative diseases such as myocardial infarction, atherosclerosis and type 2 diabetes. This article reports the actions of resveratrol on cardiovascular diseases and the molecular bases of its activity. We also discuss recent data on the effect of resveratrol on glucose homeostasis and obesity. Finally, the relevance of the stilbene use in the development of new pharmacological strategies is evaluated. PMID- 20850035 TI - Italian osteopathy--an exciting European example. PMID- 20850036 TI - Lessons from the conference: "Highlighting Massage Therapy in Complementary and Integrative Medicine". PMID- 20850034 TI - Guidelines on myocardial revascularization. PMID- 20850037 TI - Highlighting Massage Therapy in CIM Conference: a massage therapist's perspective. PMID- 20850038 TI - How much time is required to modify a fascial fibrosis? AB - SUMMARY: The perception of what appears to be connective tissue fibrosis, and its consequent modification during therapy, is a daily experience for most manual therapists. The aim of this study was to evaluate the time required to modify a palpatory sensation of fibrosis of the fascia in correlation with changes in levels of patient discomfort in 40 subjects with low back pain utilizing the Fascial Manipulation technique. This study evidenced, for the first time, that the time required to modify an apparent fascial density differs in accordance with differences in characteristics of the subjects and of the symptoms. In particular, the mean time to halve the pain was 3.24 min; however, in those subjects with symptoms present from less than 3 months (sub-acute) the mean time was lesser (2.58 min) with respect to the chronic patients (3.29 min). Statistically relevant (p < 0.05) differences were also evidenced between the specific points treated. PMID- 20850039 TI - The effects of manual treatment on rounded-shoulder posture, and associated muscle strength. AB - SUMMARY: A relationship between pectoralis minor muscle tightness and rounded shoulder posture (RSP) has been suggested, but evidence demonstrating that treatment aimed at the pectoralis minor affects posture or muscle function such as lower trapezius strength (LTS) remains lacking. In this randomized, blinded, controlled study of the 56 shoulders of 28 healthy participants, the experimental treatment consisting of pectoralis minor soft tissue mobilization (STM) and self stretching significantly reduced RSP compared to the pre-treatment baseline (Friedman test, p<.001) and the control treatment of placebo touch and pectoralis major self-stretching (Mann-Whitney U-test, p<.01). RSP remained significantly reduced 2 weeks after the single treatment. Both control and experimental treatments resulted in increased LTS (Friedman test, p<.01) with no significant difference in LTS noted between treatments (p>.05). This study demonstrated that STM and self-stretching of the pectoralis minor can significantly reduce RSP. PMID- 20850040 TI - Rhythmic exercises in rehabilitation of TBI patients: a case report. AB - SUMMARY: Patients who have sustained traumatic brain injury (TBI) often present with a multiplicity of dysfunctions making rehabilitation challenging. Patients who have taken part in studies of rehabilitation exercises that incorporated monotonous timed auditory cues (using a metronome) following cerebrovascular events demonstrated improvement in gait and motor functions. The purpose of this case report is to describe the efficacy of Rhythmic Exercises with Auditory Cues (REAC) to improve functions in a patient, years after their traumatic brain injury. METHODS: A single case report of a 24-year-old female patient, nine years post hemispherectomy following TBI that resulted in right hemiparesis. The patient was taught to perform REAC exercises at home. These exercises were designed to activate the body while Alternating hands and feet Bilaterally with Cross-midline movements for a short Duration while synchronizing the movements with a metronome as a Rhythm regulator. Outcome measurements included gait and functional assessment and cognitive and psychological instrument scores that were compared pre and post treatment. Clinical improvement was observed in the patient's gait pattern with reduced hip hiking motion and increased cadence. There was a decrease in spasticity in the right arm and leg with some isolated volitional movements of the hand and fingers returning. She also regained sensation in her right arm and leg. Cognitive improvement was demonstrated by increased IQ scores from 78 to 94. PMID- 20850041 TI - Maximal clenching effort influence on the electromyographic activity of the trapezius muscle in healthy subjects. AB - SUMMARY: Alteration of the occlusion and the position of the jaw can affect the muscles of the neck, due to a relationship between the masticatory and cervical systems. Thus, the objective of this study was to verify whether the bite in maximal clenching effort, in centric occlusion, in individuals with clinically normal occlusion, and without a history of dysfunction in the masticatory system, influences the electromyographic activity of the upper trapezius muscle. A total of 19 normal individuals participated in the study, 14 of which were women (average age of 25.4 +/- 4.14 years), and 5 were men (average age of 24.11 +/- 3.28 years). The root mean square (RMS) amplitude and median frequency (MF) of the upper trapezium muscle with 40% and 60% of maximal voluntary contraction were analyzed under pre- and post-maximal clenching effort conditions in centric occlusion. The electromyographic signal was collected with a sampling frequency of 2 kHz and the value in RMS was obtained by a moving window of 200 ms. The paired Student's t-test was used to compare RMS amplitude and MF under pre- and post-maximal clenching effort conditions. The level of significance for each comparison was set to p<0.05. This study concluded that in individuals without a history of dysfunction of the masticatory system, maximum clenching effort in centric occlusion does not alter the electromyographic signal of the upper trapezius. PMID- 20850042 TI - Clinical and MRI findings after high dosage medical exercise therapy in patients with long lasting subacromial pain syndrome: a case series on six patients. AB - SUMMARY BACKGROUND AND PURPOSE: The primary aim of this case series was to investigate the effect of a high dosage medical exercise therapy program on shoulder pain in patients with subacromial pain syndrome. SUBJECTS: Six subjects were assigned to a medical exercise therapy group. METHODS: They received three treatments a week over three months. Outcome measures were descriptions of the subacromial space including supraspinatus tendon diameter, function, pain, and active range of motion in the shoulder girdle. RESULTS: The subjects showed improvement posttest compared to pretest with respect to pain, function, range of motion, and isometric strength. An MRI demonstrated no change in tendon thickness after the treatment. Inflammatory signs such as fluid in the subacromial bursa decreased in some patients. DISCUSSION AND CONCLUSION: In patients with uncomplicated subacromial pain syndrome, high dosage medical exercise therapy might be an efficient treatment approach. The clinical effects might be explained by morphological changes in the subacromial space. PMID- 20850043 TI - Effect of low back pain on postural stability in younger women: influence of visual deprivation. AB - SUMMARY: This study investigated the effect of low back pain (LBP) on body balance during normal and visual deprivation during standing in a LBP group (10 women) and a control group (10 women). A 3-D force plate was used to measure the center of pressure (COP) anteroposterior and mediolateral displacements, and resultant velocity. ANOVA was used to compare situations. LPB group presented higher amplitudes of COP for anterioposterior direction (p<0.01) in conditions of open (3.07 +/- 0.53 cm) and closed eyes (3.70 +/- 0.71 cm) than healthy women (1.39 +/- 0.17 cm and 1.75 +/- 0.36 cm, for open and closed eyes, respectively). Similar results were found for COP involving mediolateralsway. The resultant COP velocity was larger for LBP group (p<0.05) when visual information was removed (3.03 +/- 0.68 m/s and 3.63 +/- 1.33 m/s for LBP and healthy women, respectively). LBP influenced the stability of young women during quiet standing, and the visual deprivation appears to reinforce LBP effects. PMID- 20850044 TI - Influence of forward head posture on scapular upward rotators during isometric shoulder flexion. AB - SUMMARY: We assessed the effects of forward head posture in the sitting position on the activity of the scapular upward rotators during loaded isometric shoulder flexion in the sagittal plane. Healthy volunteers (n = 21; 11 men, 10 women) with no history of pathology participated in the study. Subjects were instructed to perform isometric shoulder flexion with the right upper extremity in both the forward head posture (FHP) and neutral head posture (NHP) while sitting. Surface electromyography (EMG) was recorded from the upper trapezius, lower trapezius, and serratus anterior muscles. Dependent variables were examined by 2 (posture)*3 (muscle) repeated measures analysis of variance. Significantly increased EMG activity in the upper trapezius and lower trapezius and significantly decreased EMG activity in the serratus anterior were found during loaded isometric shoulder flexion with FHP. Thus, FHP may contribute to work-related neck and shoulder pain during loaded shoulder flexion while sitting. These results suggest that maintaining NHP is advantageous in reducing sustained upper and lower trapezius activity and enhancing serratus anterior activity as compared with FHP during loaded shoulder flexion. PMID- 20850045 TI - The effect of patellar taping on joint reaction forces during squatting in subjects with Patellofemoral Pain Syndrome (PFPS). AB - SUMMARY INTRODUCTION: The mechanisms of pain reduction have not completely been established following patellar taping in subjects with patellofemoral pain syndrome (PFPS); although it might be related to alteration in the kinetics of the patellofemoral joint. METHODS: Patellofemoral Joint Reaction Force (PFJRF) of eighteen subjects with PFPS and eighteen healthy subjects as controls were assessed by a motion-analysis system and one force plate. This procedure was performed on the affected knee of subjects with PFPS, before, during and finally after patellar taping during unilateral squatting. A similar procedure was also performed on the unaffected knees of both groups. RESULTS: The mean values of PFJRF prior to taping (2025N, SD 347N) were decreased significantly following a period of taping (1720N, SD 303N) (P<0.05). There were no significant differences between the mean values of PFJRF among controls (1922N, SD 398N) and subjects with PFPS prior to taping (P>0.05) which might be due to small sample size in both groups and large variability observed in the study. INTERPRETATION: Decreased values of PFJRF may explain the mechanism of pain reduction following patellar taping in subjects with PFPS. PMID- 20850046 TI - The influence of age and physical activity on the pressure sensitivity of soft tissues of the musculoskeletal system. AB - SUMMARY BACKGROUND: The pressure sensitivity of soft tissues is defined as the slightest pressure causing pain. Sex, movement system illnesses, pain ailments may influence the pressure sensitivity. However, there have been few studies on factors determining the level of pressure sensitivity of skeletal muscles. OBJECTIVE: The authors have determined to study the influence of age and physical activity on the pressure sensitivity of skeletal muscles. METHODS: The examination of pressure sensitivity of trigger points and muscle insertions was carried out using algometry. RESULTS: 76 volunteers (38 students and 38 individuals aged 50-75) participated in the study. The differences in pressure sensitivity between students and people aged 50-75 were not statistically significant. Pressure sensitivity of students differed depending on their level of physical activity. CONCLUSIONS: The level of physical activity influenced the pressure sensitivity of skeletal muscles. Age did not significantly influence pressure sensitivity. PMID- 20850047 TI - Referred pain areas of active myofascial trigger points in head, neck, and shoulder muscles, in chronic tension type headache. AB - SUMMARY: Our aim was to analyze the differences in the referred pain patterns and size of the areas of those myofascial trigger points (TrPs) involved in chronic tension type headache (CTTH) including a number of muscles not investigated in previous studies. Thirteen right handed women with CTTH (mean age: 38 +/- 6 years) were included. TrPs were bilaterally searched in upper trapezius, sternocleidomastoid, splenius capitis, masseter, levator scapulae, superior oblique (extra-ocular), and suboccipital muscles. TrPs were considered active when both local and referred pain evoked by manual palpation reproduced total or partial pattern similar to a headache attack. The size of the referred pain area of TrPs of each muscle was calculated. The mean number of active TrPs within each CTTH patient was 7 (95% CI 6.2-8.0). A greater number (T = 2.79; p = 0.016) of active TrPs was found at the right side (4.2 +/- 1.5) when compared to the left side (2.9 +/- 1.0). TrPs in the suboccipital muscles were most prevalent (n = 12; 92%), followed by the superior oblique muscle (n =11/n = 9 right/left side), the upper trapezius muscle (n = 11/n = 6) and the masseter muscle (n = 9/n=7). The ANOVA showed significant differences in the size of the referred pain area between muscles (F = 4.7, p = 0.001), but not between sides (F = 1.1; p = 0.3): as determined by a Bonferroni post hoc analysis the referred pain area elicited by levator scapulae TrPs was significantly greater than the area from the sternocleidomastoid (p = 0.02), masseter (p = 0.003) and superior oblique (p = 0.001) muscles. Multiple active TrPs exist in head, neck and shoulder muscles in women with CTTH. The referred pain areas of TrPs located in neck muscles were larger than the referred pain areas of head muscles. Spatial summation of nociceptive inputs from multiple active TrPs may contribute to clinical manifestations of CTTH. PMID- 20850048 TI - Diagnosis and treatment of posterior interosseous nerve syndrome using soft tissue manipulation therapy: a case study. AB - SUMMARY: Peripheral nerve entrapments of the upper and lower extremity are commonly seen in practice. Chronically repetitive movement patterns lead to constriction of the nerve due to the development of local fibrosis within the soft tissues surrounding the nerve which also affects nerve traction, mobility, and function. A case is presented of a patient with motor weakness in the wrist and hand in order to illustrate the diagnosis and treatment of posterior interosseous nerve (PIN) syndrome. Using Active Release Techniques Soft Tissue Management and Peripheral Nerve Release Systems) the patient's symptomatology was resolved. Soft tissue-based management in conjunction with neural gliding may be beneficial in the conservative management of PIN syndrome. Further research into the pathophysiology of nerve entrapments will have immediate impact on the management of neuropathies and likely result in emphasizing conservative management and rehabilitation rather than surgical intervention particularly in cases not involving denervation or paralysis. PMID- 20850049 TI - Chains, trains and contractile fields. PMID- 20850050 TI - Muscle fascia and force transmission. AB - SUMMARY: This paper reviews the major intramuscular extracellular matrix (IM-ECM) structures (endomysium, perimysium and epimysium) and their possible mechanical contributions to muscle functions. The endomysium appears to provide an efficient mechanism for transmission of contractile forces from adjacent muscle fibres within fascicles. This coordinates forces and deformations within the fascicle, protects damaged areas of fibres against over-extension, and provides a mechanism whereby myofibrils can be interrupted to add new sarcomeres during muscle growth without loss of contractile functionality of the whole column. Good experimental evidence shows that perimysium and epimysium are capable in some circumstances to act as pathways for myofascial force transmission. However, an alternative role for perimysium is reviewed, which involves the definition of slip planes between muscle fascicles which can slide past each other to allow large shear displacements due to shape changes in the whole muscle during contraction. As IM ECM is continually remodelled so as to be mechanically adapted for its roles in developing and growing muscles, control of the processes governing IM-ECM turnover and repair may be an important avenue to explore in the reduction of fibrosis following muscle injury. PMID- 20850051 TI - Compensatory behavior of the postural control system to flexion-relaxation phenomena. AB - SUMMARY: Laxity of the passive tissues of the spine during prolonged spinal flexion has been shown to disturb spinal stability. This study investigated the effects of short periods of static lumbar flexion and short rest periods on the flexion-relaxation angle for the erector spinae muscles in 36 healthy female college students. The surface electromyographic activity of the erector spinae muscles was measured in three states before the onset of creep, immediately after 7 min of static lumbar flexion, and after a 10 min rest. The results showed that 7 min of static lumbar flexion will produce relaxation of the erector spinae muscles that occurs at greater absolute lumbar and trunk angles, during the forward bending activity (P<0.05), while the corresponding relative angles did not change before and after creep. The results also indicate that postural compensations are dominant over the muscular compensations for load sharing in flexion-relaxation phenomena of asymptomatic healthy participants. This further highlights the importance of postural modulation in the control of movement and preservation of skeletal stability. CLINICAL RELEVANCE: Considering spinal posture in the upright condition, and its changes by phenomena such as creep, can reduce postural injuries by instructing subjects to approach a more vertical posture, after periods of bending, to compensate the stretching effects of the tissues and thus regaining the normal muscular activity pattern. PMID- 20850052 TI - Simple geometry in complex organisms. AB - SUMMARY: Many cultures throughout history have used the regularities of numbers and patterns as a means of describing their environment. The ancient Greeks believed that just five archetypal forms--the 'platonic solids'--were part of natural law, and could describe everything in the universe because they were pure and perfect. The formation of simple geometric shapes through the interactions of physical forces, and their development into more complex biological structures, supports a re-appreciation of these pre-Darwinian laws. The self-assembly of molecular components at the nano-scale, and their organization into the tensegrities of complex organisms is explored here. Hierarchies of structure link the nano and micro realms with the whole organism, and have implications for manual therapies. PMID- 20850053 TI - Alexithymia and emotional awareness in anorexia nervosa: time for a shift in the measurement of the concept? AB - The present study compared 35 patients with anorexia nervosa (AN) with an age matched control group using the Toronto Alexithymia Scale (TAS-20; a self-report instrument) and the Levels of Emotional Awareness Scale (LEAS; a performance based instrument). Depression and anxiety have been shown to account for elevated levels of alexithymia in AN, and an elevated level of perfectionism might affect self-reporting in general. The AN-group reported a higher level of alexithymia on the TAS-20 compared to the control group, a difference that disappeared after controlling for depression or anxiety (but not for perfectionism). The findings suggest that the AN-patients believe that they have difficulties in identifying and reporting emotions, but actually perform as well as the control group when confronted with the task of identifying and reporting their emotions according to LEAS. It might be time to rethink the measurement of alexithymia. Maybe, similar to assessment of personality disorders, it should not be assessed when patients are depressed, or it should be assessed through instruments and modalities that are not sensitive to the mood state of the patient. PMID- 20850054 TI - Media images and female body dissatisfaction: the moderating effects of the Five Factor traits. AB - OBJECTIVE: The purpose of this study was to examine how the Five-Factor personality traits moderated the effects of exposure to idealized images on body dissatisfaction in women. METHOD: Sixty-four college women completed the NEO-PI and the Eating Disorder Inventory and were then randomly exposed to images of either thin fashion models or heavier, ("plus-sized") models. Following presentation of the stimuli, participants completed a second body esteem measure, which was the dependent variable. RESULTS: Women high in neuroticism showed significantly greater shifts in body esteem following exposure to media images than did less neurotic women, feeling more dissatisfied with their bodies after viewing idealized images and more satisfied with their bodies after viewing heavier women. Each of the other traits was associated with more favorable self appraisals following exposure to the idealizing images. CONCLUSIONS: Of the Five Factor traits, the harmful effects of idealized images seem to be limited to women with relatively higher levels of neuroticism. These results suggest that the harmful effects of media images may not be as pervasive as is widely believed. PMID- 20850055 TI - Early patterns of food intake in an adolescent weight loss trial as predictors of BMI change. AB - PURPOSE: To determine whether baseline intake or initial changes in intake of fruits (F), vegetables (V), snack foods (SF), and reduced-calorie snack foods (RCSF) during standard behavioral weight loss treatment predict BMI reductions among overweight adolescents. Given conflicting messages between child and adult weight loss interventions, the role of RCSF in adolescent weight control was of particular interest. METHODS: Seventy-two adolescents, 13-16 years old, participating in a 16-week behavioral weight loss trial with diet records at baseline and 4 weeks were included. Height and weight were measured at 0 and 16 weeks. Frequency of intake of F, V, SF, and RCSF were obtained from 7-day food records at 0 and 4 weeks. RESULTS: Male gender, higher initial frequency of intake of V and increased frequency of intake of F and RCSF over the first 4 weeks of treatment accounted for 43% of the variance in BMI reduction at 16 weeks (p<.001). CONCLUSIONS: Early changes in eating habits, including increased frequency of intake of F and RCSF may promote greater adolescent BMI reductions. PMID- 20850056 TI - Primary and secondary control over eating behaviors. AB - The relationships between subjective control, body image, and eating behaviors were examined within the framework of the Optimization in Primary and Secondary Control model (OPS model; Heckhausen, 1999). This model characterizes control as an adaptive and strategic process in which the target of control includes internal as well as external states, and in which the purpose is either to facilitate goal pursuit by engaging with the goal or managing the consequences of goal failure by disengaging from the goal. A convenience sample of 180 Australian women (age: M=26.49, SD=5.03) completed the Optimization of Primary and Secondary Control Scale (OPS scale Heckhausen, 1999), as well as measures of attitudinal and behavioral factors comprising Stice's (1994) dual-pathway model of bulimia. A series of path analyses revealed that the control strategies involved in goal engagement are directly associated with increased dietary restraint and purging, whereas the control strategies involved in goal disengagement are indirectly associated with these factors, and with negative affect, by way of reduced body dissatisfaction and reduced frequency of appearance comparisons. These results suggest that goal engagement strategies, which are typically adaptive in other contexts, are associated with potentially hazardous attitudes and behaviors in the context of the body. The results also suggest that an ability to disengage from body weight goals is associated with a reduced likelihood of developing disordered eating. PMID- 20850057 TI - An investigation of the relationship between fear of negative evaluation and bulimic psychopathology. AB - The current study examined fear of negative evaluation (FNE), the core fear associated with social anxiety, in the context of the dual pathway model of the etiology of bulimia nervosa. Our primary aim was to improve the understanding of the development of bulimic psychopathology. We investigated the relationships between FNE, the risk factors of the dual pathway model and bulimic symptoms using path analysis in a sample of female undergraduates (N=210). The inclusion of FNE increased the predictive ability of the model to account for 49% of the variance in bulimic symptoms compared to previous findings in which the model accounted for 33% of the variance. Additionally, FNE was related to several risk factors of the dual pathway model including the pressure to be thin, thin-ideal internalization and negative affect, as well as contributing directly to bulimic symptoms. These findings suggest that FNE may increase the risk for developing established risk factors of the model, as well as bulimic symptoms, and that targeting FNE in prevention programs may be useful in circumventing this serious disorder. PMID- 20850058 TI - A multidimensional measure of core beliefs relevant to eating disorders: preliminary development and validation. AB - Core beliefs associated with eating disorders are likely to be multidimensional, and may not be adequately captured by existing measures. The current study aimed to develop such a measure and examine its relationship to eating disorder symptoms, anxiety, depression and putative diagnoses of their related disorders. Core belief items were rated by 500 female participants aged 18-65, who also completed self-report measures of eating disorder symptomatology, depression, anxiety, and self esteem. Factor analysis revealed five subscales, with themes related to (a) self loathing, (b) unassertive/inhibited, (c) high standards for self, (d) demanding and needing help and support and (e) abandoned/deprived. Thirty two items were selected for a final scale, the Eating Disorder Core Beliefs Questionnaire (ED-CBQ). The ED-CBQ subscales showed adequate internal consistency and construct (convergent and discriminant) validity. Self loathing appeared to be particularly associated with putative eating disorder diagnosis, while abandoned/deprived was more characteristic of putative anxiety and depression diagnoses. The findings suggest that negative core self beliefs relevant to those with an eating disorder are a multidimensional construct and that self loathing as a core belief merits further research and clinical attention. PMID- 20850059 TI - An obesity provoking behaviour negatively influences young normal weight subjects' health related quality of life and causes depressive symptoms. AB - In many parts of the world the prevalence of a sedentary lifestyle in combination with high consumption of food has increased, which contributes to increased risk for becoming overweight. Our primary aim was, in an intervention, to examine the influence on health related quality of life (HRQoL) and mood in young normal weight subjects of both sexes, when adopting an obesity provoking behaviour by increasing the energy intake via fast food and simultaneously adopting a sedentary lifestyle. A secondary aim was to follow-up possible long-term effects on HRQoL and mood 6 and 12 months after this short-term intervention. In this prospective study, 18 healthy normal weight subjects (mean age 26+/-6.6 years), mainly university students were prescribed doubled energy intake, and maximum 5000 steps/day, during 4 weeks. An age and sex matched control group (n=18), who were asked to have unchanged eating habits and physical activity, was recruited. Before and after the intervention questionnaires including Short Form-36, Hospital Anxiety Depression scale, Center of Epidemiological Studies Depression scale, Sense of Coherence and Mastery scale were completed by the subjects in the intervention group and by the controls with 4 weeks interval. Six and 12 months after the intervention the subjects underwent the same procedure as at baseline and the controls completed the same questionnaires. During the intervention, subjects in the intervention group increased their bodyweight and developed markedly lower physical and mental health scores on Short Form-36 as well as depressive symptoms while no changes appeared in the controls. The increase of depressive symptoms was associated with increases of energy intake, body weight and body fat. When followed up, 6 and 12 months after the intervention, physical and mental health had returned completely to baseline values, despite somewhat increased body weight. In conclusion, adopting obesity provoking behaviour for 4 weeks decreases HRQoL and mood in young normal weight subjects. The effect is temporary and when followed up 6 and 12 months after the short-term intervention no remaining influence is found. PMID- 20850060 TI - Picky eating during childhood: a longitudinal study to age 11 years. AB - Picky eating is a common disorder during childhood often causing considerable parental anxiety. This study examined the incidence, point prevalence, persistence and characteristics of picky eating in a prospective study of 120 children and their parents followed from 2 to 11 years. At any given age between 13% and 22% of the children were reported to be picky eaters. Incidence declined over time whereas point prevalence increased indicating that picky eating is often a chronic problem with 40% having a duration of more than 2 years. Those with longer duration differed from those with short duration having more strong likes and dislikes of food and not accepting new foods. Parents of picky eaters were more likely to report that their children consumed a limited variety of foods, required food prepared in specific ways, expressed stronger likes and dislikes for food, and threw tantrums when denied foods. They were also more likely to report struggles over feeding, preparing special meals, and commenting on their child's eating. Hence, picky eating is a prevalent concern of parents and may remain so through childhood. It appears to be a relatively stable trait reflecting an individual eating style. However no significant effects on growth were observed. PMID- 20850061 TI - Food-related Stroop interference in obese and normal-weight individuals: behavioral and electrophysiological indices. AB - The primary objective of the present study was to investigate differences in the attentional processing of food-related words in a Stroop task, as assessed by means of behavioral (reaction times) and electrophysiological (P200 and P300 amplitudes) indices, between obese and normal-weight individuals. Results revealed a P200 bias to food-related words in obese participants, which was not seen in normal-weight participants. This indicates that, in an early, automatic stage of information processing, obese participants already tend to engage more attention towards food-related stimuli than to neutral stimuli. With respect to reaction times and P300 scores, as alleged indices of more conscious maintained attention, a general food-related bias was observed, with no between-group differences. Further, in the obese group, significant positive correlations were observed between the food-related reaction time bias, food craving, and external eating, whereas in the normal-weight group, food craving scores correlated positively with P200/P300 amplitude biases. It can be concluded that obese individuals display an enhanced automatic, preconscious attentional processing of food-related stimuli, and this can be regarded as an initial expression of a greater responsiveness to food cues. In the current food-abundant environment, such a heightened food cue-responsiveness might contribute substantially to the tendency to overeat. PMID- 20850062 TI - The prediction of preschool children's weight from family environment factors: gender-linked differences. AB - The main objective of this study was to test an explanatory model predicting preschool girls' and boys' body weight from certain child variables (food intake, sedentary behaviors, and eating habits), as well as family variables (interaction during mealtime and level of family financial resources allocated to meeting children's eating needs). A randomized stratified subsample of parents was selected from a larger study (Quebec Longitudinal Study of Child Development, QLSCD-1998-2002), with a breakdown of 581 girls and 611 boys of 4 years of age. Children's skin fold ratio, weight, height, and Body Mass Index (BMI) were recorded. Questionnaires were administered to parents (usually the mother). Using structural equation modeling (SEM) separately for girls and boys, the family environment model of healthy weight development was tested. Results yielded a good fit of the model for both genders. For boys, significant predictors of body weight in the model were family food insecurity and conflicts during mealtime. Healthy eating was predicted by food insecurity, mealtime conflicts, and sedentary behaviors. Mealtime conflicts predicted sedentary behaviors. For girls, none of the variables predicted body weight, however food insecurity predicted less healthy eating. These results outline the importance of prevention and intervention within families with young children. PMID- 20850063 TI - Examining the relationship between dietary restraint and binge eating: differential effects of major and minor stressors. AB - This study sought to examine the complex interactive impact of major stress and minor stressors on the relation between dietary restraint and binge eating. Participants were 497 undergraduate females who completed an online questionnaire that included measures of binge eating (modified version of the bulimia scale of the Eating Disorder Inventory-2; EDI-2), major life stressors (the Social Readjustment Rating Scale; SRRS), minor stressors (Daily Stress Inventory; DSI), and dietary restraint (Restraint Scale; RS). A hierarchal linear regression revealed a significant three-way interaction among dietary restraint, life event stress, and daily stress that accounted for a significant proportion of the variance in binge eating above and beyond all main effects and two-way interactions. Findings suggested that the interactive relationship among dietary restraint and daily stress is present only under conditions of high life event stress. Overall, the relationship between dietary restraint and binge eating appears to be quite complex and dependent upon differential levels of daily and life event stressors. PMID- 20850064 TI - Having a personal weight goal that mismatches healthy weight recommendations increases the likelihood of using unhealthy behaviors among a representative population-based sample of adolescents. AB - Free living populations adopt practices designed to maintain or influence their weight. These practices include at least two components: a personal weight goal and use of a variety of behaviors to reach this personal weight goal. Personal weight goals can either concur (match) or not concur (mismatch) with recommendations that a health professional might stipulate for achieving a healthy weight status. The variety of behaviors used to achieve a personal weight goal can be thought of as inherently healthy, unhealthy, or disordered. We examined associations between matched vs. mismatched personal weight goals and the frequency of use of different types of weight-related behaviors among adolescents. Measures included whether or not personal weight goals matched or mismatched aims that should be pursued given current weight status and self reported frequency of use of behaviors from a representative population-based sample of adolescents (n=2, 346, 51% female; 93.3% complete data). Sex-specific multilevel logistic and ordinal regression analyses showed that pursuing a mismatched personal weight goal increases the likelihood of using unhealthy behaviors across sexes. This association is however not significant for healthy and disordered behaviors. We conclude that there is an association between pursuing a mismatched personal weight goal and the use of unhealthy behaviors but not with healthy or disordered behaviors. PMID- 20850065 TI - The associations between two facets of narcissism and eating disorder symptoms. AB - The current study sought to examine the relationships between two facets of narcissism (vulnerable and grandiose) and eating disorder symptoms. Based upon previous research (Davis, Claridge, & Cerullo, 1997), it was predicted that the vulnerable narcissism facet would be more strongly associated with eating disorder symptoms because of the tendency for vulnerable narcissists to base their self-worth on their appearance (Zeigler-Hill, Clark, & Picard, 2008). The hypotheses were tested cross-sectionally in a sample of 355 male and female undergraduate students. Results generally conformed to prediction, in that vulnerable narcissism tended to be positively correlated with eating disorder symptoms, and this relationship was partially mediated by self-worth that is contingent upon physical appearance. Our findings are consistent with the notion that vulnerable narcissism is a risk factor for eating disorder symptoms because it is associated with a drive to improve self-worth through the enhancement of physical appearance. PMID- 20850066 TI - Mindfulness mediates the relation between disordered eating-related cognitions and psychological distress. AB - The present study investigated whether mindfulness mediates the relation between disordered eating-related cognitions and negative psychological outcomes within a non-clinical college sample. Disordered eating-related cognitions were positively associated with general psychological ill-health and emotional distress in interpersonal contexts and inversely related to mindfulness. Mindfulness, which was also inversely related to general psychological ill-health and emotional distress, was found to partially mediate the relations between disordered eating related cognitions and the two predicted variables. PMID- 20850067 TI - Anxiety mediates the relationship between sleep onset latency and emotional eating in minority children. AB - This study examined associations between sleep onset latency and emotional eating in a minority sample of children. A cross-sectional school-based study of sleep, psychological constructs, diet and physical activity was conducted in 6 public and private schools in Los Angeles County. An ethnically diverse sample of 356 third through fifth graders completed confidential self-report surveys. Multilevel regression (MLM) analyses were conducted to study associations while controlling for gender, ethnicity, and the random effect of school. Girls made up 57% of the total sample, which was predominantly Latino (42.6%), followed by African Americans (21.6%) and Asians (19.2%). MLM revealed that there were significant associations between sleep onset latency and emotional eating (p=.030), depressive symptomology (p<.0001) and trait anxiety (p<.0001). Sobel's test for mediation showed that trait anxiety (p=.011) but not depressive symptomology (p=.141) was a mediator of the relationship between sleep onset latency and emotional eating. Thereby providing a mechanism through which sleep onset latency is related to emotional eating. These findings suggest that sleep onset latency is associated with increased anxiety, depressive symptoms, and emotional eating. Although causal inferences cannot be drawn from this cross sectional data, future studies should examine the possibility that problems falling asleep could lead to emotional dysregulation that in turn leads to emotional eating. Emotional eating may be one avenue by which sleep disturbances lead to overweight and obesity. PMID- 20850068 TI - Is human seasonality implicated in the risk profile for obesity? AB - Although seasonality might once have been a successful energy conservation strategy for people living in temperate regions, this physiological phenomenon may now foster accumulating annual weight gain and thereby feature in the risk profile for obesity. We tested the hypothesis that seasonality relates to BMI, and that this association is mediated by a preference for carbohydrates and the tendency to binge eat. In a sample of men and women, gender significantly moderated the relationship between seasonality and BMI. In men, the relationship was positive, but these two variables did not co-vary in women. Reasons why seasonality is positively associated with BMI only in men are not immediately apparent. It is possible that other gender-specific risk factors for overeating may contribute to these findings. PMID- 20850070 TI - Borderline personality and weight divergence in adulthood. AB - Borderline personality disorder (BPD) is an Axis II dysfunction characterized by extremist thinking (i.e., black/white thinking and thinking in absolutes). In keeping with this cognitive style, and based upon our clinical observations, we wondered whether a possible behavioral marker of extremism, weight divergence (i.e., a large difference between lowest and highest weights in adulthood), might be associated with BPD. Among 95 women psychiatric inpatients, we explored lowest adult weight, current weight, and highest adult weight as well as BPD using two self-report measures for the disorder, the borderline personality disorder scale of the Personality Diagnostic Questionnaire-4 (PDQ-4) and the Self-Harm Inventory (SHI). Results indicated statistically significantly correlations between increasing weight divergence and both BPD measures. Further analyses indicated that this relationship was not explained by overall body size or history of binge eating behavior. Findings suggest that, among psychiatric inpatients, weight divergence in adulthood may be a potential indicator of BPD. PMID- 20850071 TI - Current topics in anesthesia for head and neck surgery. Foreword. PMID- 20850069 TI - Dietary intervention promoting high intakes of fruits and vegetables: short-term effects on eating behaviors in overweight-obese postmenopausal women. AB - OBJECTIVE: To compare changes in eating behaviors in response to two dietary interventions: one focusing on restrictive messages to limit consumption of high fat foods (LOFAT) and the other one based on non-restrictive messages to increase consumption of fruits and vegetables (HIFV). METHODS: Sixty-eight overweight obese postmenopausal women were randomly assigned to one of the two 6-month dietary interventions that included three group sessions and ten individual sessions with a dietitian. Anthropometric variables and eating behaviors were measured at baseline, 3months and 6months. RESULTS: Body weight decreased significantly in both groups at 6months compared to baseline (LOFAT: -3.5+/ 2.9kg; HIFV: -1.6+/-2.9kg). At 6months, dietary restraint score was higher in the LOFAT group compared to the HIFV group (12.7+/-4.2 vs 10.5+/-4.9; p<0.05). Disinhibition and hunger decreased significantly in the HIFV group after 6months while only hunger decreased in the LOFAT group. CONCLUSION: A weight loss approach based on increasing fruit and vegetable consumption leads to a significant weight loss and is associated with a decrease in disinhibition and hunger without any increase in dietary restraint. PMID- 20850072 TI - Current topics in anesthesia for head and neck surgery. Preface. PMID- 20850073 TI - Jet ventilation for surgical interventions in the upper airway. AB - The clinical applications of jet ventilation (JV) in ear, nose, and throat surgery can be best understood by the characteristics that distinguish this form of ventilation from conventional positive pressure ventilation. By definition, JV is based on the application of gas portions under high pressure through an unblocked catheter into the airway, which is open to the ambient air. Beneficial opportunities arise in JV, which otherwise are not available in regular ventilation. PMID- 20850074 TI - Anesthetic considerations for transoral robotic surgery. AB - During the past decade, robotic surgery has been progressively incorporated into the mainstream of cardio-thoracic and abdominopelvic surgery. With the recent US Food and Drug Administration approval of transoral robotic surgery (TORS) for the treatment of all benign tumors and select malignant tumors of the head and neck, robotic surgery has established its place in otolaryngologic surgery. Given the multispecialty applications and widespread use of robotic surgery, there exists a need for anesthesiologists to familiarize themselves with robotic surgery. This article focuses on TORS and the goal of which is to provide the anesthesiologist with a foundation for caring for the TORS patient in the perioperative period. PMID- 20850075 TI - Electromyographic (EMG) neuromonitoring in otolaryngology-head and neck surgery. AB - Intraoperative neuromonitoring (IONM) is a relatively recent advance in electromyography (EMG) applied to otolaryngology-head and neck surgery. Its purpose is to allow real-time identification and functional assessment of vulnerable nerves during surgery. The nerves most often monitored in head and neck surgery are the motor branch of the facial nerve (VII), the recurrent or inferior laryngeal nerves (X), the vagus nerve (X), and the spinal accessory nerve (XI), with other cranial lower nerves monitored less frequently. Morbidity from trauma to these nerves is significant and obvious, such as unilateral facial paresis. Although functional restorative surgery is usually considered to repair the effects of such an insult, the importance of preventing nerve injury in head and neck surgery is obvious. This article focuses on the anesthetic considerations pertinent to IONM of peripheral cranial nerves during otolaryngologic-head and neck surgery. The specific modality of IONM is EMG, both spontaneous and evoked. PMID- 20850076 TI - Anesthesia, sleep, and upper airway collapsibility. AB - Anesthesia and sleep both predispose to upper airway obstruction through state induced reductions in pharyngeal dilator muscle activation and lung volume. The tendencies are related in patients with obstructive sleep apnea commonly presenting with difficulties in airway management in the perioperative period. This is a period of great potential vulnerability for such patients because of compromise of the arousal responses that protect against asphyxiation during natural sleep. Careful preoperative evaluation and insightful perioperative observation are likely to identify patients at risk. A significant proportion of patients will have previously undiagnosed obstructive sleep apnea and anesthesiologists are well placed to identify this potential. Patients with known or suspected obstructive sleep apnea need careful postoperative management, particularly while consciousness and arousal responses are impaired. Specific follow-up of suspected cases is needed to ensure that the sleep-related component of the problem receives appropriate care. PMID- 20850077 TI - Regional anesthesia for office-based procedures in otorhinolaryngology. AB - Local and topical anesthetic techniques have long been used for office-based procedures in otorhinolaryngology. There are numerous advantages to using local and topical anesthesia for office-based procedures, including a shorter recovery period, decreased health care cost, and the maintenance of a conscious patient who can communicate with the surgeon and maintain his or her own airway during the procedure. In this manuscript, we review the local and topical anesthetic techniques that can be used for otorhinolaryngic procedures including anesthesia of the external face, ear, nose, oral cavity, nasopharynx, oropharynx, hypopharynx, and larynx. PMID- 20850078 TI - Laryngeal mask airways in ear, nose, and throat procedures. AB - The use of laryngeal mask airway (LMA) and its variants in ear, nose, and throat procedures have been extensively described in case reports, retrospective reviews, and randomized clinical trials. The LMA has developed a considerable following because of its lack of tracheal stimulation, which can be a considerable advantage in ear, nose, and throat (ENT) procedures. The incidence of coughing on emergence has been shown to be lower with the LMA than with the endotracheal tube (ETT). Although other approaches to smooth emergence have been described, few would argue that it is as easy to achieve a smooth emergence with an ETT as with an LMA. Although patients certainly exist for whom the LMA is contraindicated, many will experience better results with the LMA because of the features delineated in this article. PMID- 20850079 TI - Laser surgery and fire hazards in ear, nose, and throat surgeries. AB - Operating room fires are rare but can be devastating. These fires can occur during almost any surgical procedure but are more likely during airway surgery, during head and neck surgery, and if volatile flammable liquids are used. Each team in the operating room (ie, anesthesia, surgery, and nursing) has special expertise and responsibility in preventing and responding to a fire. Fires can be prevented by ongoing education and an interdisciplinary discussion of risks and responsibilities prior to each high-risk case. PMID- 20850080 TI - Anesthesia for functional endoscopic sinus surgery: a review. AB - Functional endoscopic sinus surgery has become one of the most common head and neck procedures performed. Proper anesthetic management is essential for a successful outcome. Different anesthesia techniques are discussed that include: local versus general anesthesia, LMA versus ETT, inhaled anesthesia versus TIVA. The anesthetic plan should be tailored taking into consideration patient comorbidities, the surgeon and anesthesiologist experience, and individual preference. Specific anesthetic goals are to ensure the best possible surgical field and stable cardiovascular and respiratory status during the surgery, emergence of anesthesia, and upon recovery. PMID- 20850081 TI - Anesthesia for pediatric airway surgery: recommendations and review from a pediatric referral center. AB - Pediatric airway surgery presents many significant challenges to the anesthesia provider. The clinical experience of the Massachusetts Eye and Ear Infirmary serves as a guide in this review to describe the clinical reasoning and perioperative management of the pediatric patient needing airway surgery, with specific emphasis on diagnostic procedures, trauma, laryngotracheal reconstruction, juvenile recurrent respiratory papillomatosis, and adenotonsillectomy. PMID- 20850082 TI - Review of anesthesia for middle ear surgery. AB - Special considerations for middle ear surgery include a bloodless surgical field, attention to patient head positioning, facial nerve monitoring, and management of postoperative nausea and vomiting. Middle ear surgery can be done under local or general anesthesia; each has advantages and disadvantages. PMID- 20850083 TI - Adult laryngotracheal surgery. AB - The human larynx plays a pivotal role in airway protection, respiration, and phonation. Laryngeal disorders can be divided into two categories, benign lesions and malignant lesions. Most benign lesions are treatable with surgery and speech therapy, whereas the malignant lesions require more invasive surgery as well as radiation and chemotherapy. Preoperative assessment and anesthesia management for adult laryngotracheal surgery are reviewed. PMID- 20850084 TI - Applications of ultrasonography in ENT: airway assessment and nerve blockade. AB - This article presents a comprehensive narrative review of the published literature relating to ultrasound imaging relevant to anesthesia for ear, nose, and throat (ENT) surgery. The review comprises 2 main subject areas: the use of ultrasonography related to assessment and management of the airway, and the use of ultrasonography related to nerve blockade for ENT surgery. The relevant sonoanatomy and suitable probe placement are illustrated in relation to applicable regional anatomy (they are not discussed). The possible value of the use of ultrasonography to improve existing clinical practice in these areas is explored. PMID- 20850085 TI - Anesthetic considerations and surgical caveats for awake airway surgery. AB - The evolution of novel techniques for the treatment of laryngeal pathology has led to a significant expansion of the role of diagnostic assessment and the range of laryngeal procedures performed. These procedures typically benefit from an anesthetic approach that diverges from a standard general endotracheal or laryngeal mask airway-based inhalational anesthetic. The shared airway, need for intraoperative assessment of vocal cord function, risk of airway fire, and desire for rapid emergence and discharge are all important factors. In this article the authors undertake a collaborative anesthesia-surgical discussion of anesthetic management for airway procedures that are optimally performed with a spontaneously breathing, cooperative patient. An overview of pharmacologic approaches to airway anesthesia and cooperative sedation, followed by a discussion on the surgical requirements and anesthetic goals of commonly performed procedures, are presented. PMID- 20850086 TI - Interventional fellowship in structural and congenital heart disease for adults. AB - Training for structural and adult congenital heart disease interventions remains undeveloped. With the advent of recent percutaneous interventions for the treatment of structural and valvular heart disease, such as transcatheter aortic and pulmonary valve implantation, mitral valve repair, and the expansion of shunt closure procedures, there is a clear need to define the training requirements for this category of procedures. The training needs to be aligned with the goals and priorities of a basic or advanced level and be categorized into acquired and congenital. This document will define the training needs and knowledge base for the developing field of structural heart disease intervention. PMID- 20850087 TI - Clinical and angiographic risk assessment in patients with left main stem lesions. AB - Percutaneous coronary intervention of unprotected left main stem lesions has been shown to be a suitable alternative to cardiac surgery in selected patients, emphasizing the need for appropriate risk stratification prior to selection of revascularization modality. Several risk models based on clinical and angiographic variables have been developed to guide patient selection, each of which has significant limitations. This paper reviews contemporary and newly proposed risk models for patients undergoing left main stem revascularization. PMID- 20850088 TI - Acceptance, panic, and partial recovery the pattern of usage of drug-eluting stents after introduction in the U.S. (a report from the American College of Cardiology/National Cardiovascular Data Registry). AB - OBJECTIVES: Review the use of drug-eluting stents (DES) to evaluate changes in use. BACKGROUND: The DES were approved after several small studies in carefully selected patients showed dramatic reduction in in-stent restenosis. The DES were then rapidly adopted into routine practice. In 2006, 3 years after introduction, serious concerns regarding long-term safety were raised. METHODS: We queried the American College of Cardiology/National Cardiovascular Data Registry (ACC/NCDR) CathPCI Registry. The percentage of DES used through mid-2009 was reviewed overall and in subgroups of patients categorized by lesion type, clinical factors, insurance, and hospital characteristics. Multivariable logistic models relating these covariates to DES usage were constructed for 3 relevant time intervals. RESULTS: A total of 2,247,647 coronary stent procedures were analyzed. By 2005 over 90% of first stents placed were DES. Safety concerns arising in 2006 reduced DES use to 64% of first stent placed. After publication of salutary outcomes data in 2008, usage increased to 76% by mid-2009. The logistic models demonstrated decreased likelihood of DES usage in patients with: 1) ST-segment elevation myocardial infarctions; and 2) no medical insurance. The DES usage increased for in-stent restenosis. Hospital characteristics were not associated with significant differences in DES usage. CONCLUSIONS: There was rapid adoption of DES into U.S. clinical practice. Concern for late stent thrombosis in 2006 significantly altered DES use with reductions seen in subgroups at risk for thrombosis and patients with no insurance. These rapid cyclic changes after DES introduction reinforce the need for continuous, timely reporting of outcomes data after the introduction of new technologies. PMID- 20850089 TI - Thrombosis of second-generation drug-eluting stents in real practice results from the multicenter Spanish registry ESTROFA-2 (Estudio Espanol Sobre Trombosis de Stents Farmacoactivos de Segunda Generacion-2). AB - OBJECTIVES: This study sought to evaluate second-generation drug-eluting stent (DES) thrombosis in clinical practice. BACKGROUND: First-generation DES are associated with a significant incidence of late thrombosis. There is paucity of data regarding real practice late thrombosis incidence and predictors with second generation DES, zotarolimus-eluting stent (ZES), and everolimus-eluting stents (EES). METHODS: A prospective, large-scale, non-industry-linked multicenter registry was designed. Complete clinical-procedural data and systematic follow-up of all patients treated with these stents was reported in a dedicated registry supported by the Spanish Working Group on Interventional Cardiology. RESULTS: From 2005 to 2008, 4,768 patients were included in 34 centers: 2,549 treated with ZES, and 2,219 with EES. The cumulative incidence of definite/probable thrombosis for ZES was 1.3% at 1 year and 1.7% at 2 years and for EES 1.4% at 1 year and 1.7% at 2 years (p = 0.8). The increment of definite thrombosis between the first and second year was 0.2% and 0.25%, respectively. In a propensity score analysis, the incidence remained very similar. Ejection fraction (adjusted hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.95 to -0.99; p = 0.008), stent diameter (adjusted HR: 0.37; 95% CI: 0.17to 0.81; p = 0.01) and bifurcations (adjusted HR: 2.1; 95% CI: 1.14 to 3.7; p = 0.02) emerged as independent predictors of thrombosis. In the subgroup of patients with bifurcations, the use of ZES was independently associated with a higher thrombosis rate (adjusted HR: 4; 95% CI: 1.1 to 13; p = 0.03). CONCLUSIONS: In a real practice setting, the incidence of thrombosis at 2 years with ZES and EES was low and quite similar. The incidence of very late thrombosis resulted lower than was reported in registries of first-generation DES. In the subset of bifurcations, the use of ZES significantly increased the risk of thrombosis. PMID- 20850090 TI - Frequency of major noncardiac surgery and subsequent adverse events in the year after drug-eluting stent placement results from the EVENT (Evaluation of Drug Eluting Stents and Ischemic Events) Registry. AB - OBJECTIVES: This study sought to determine the frequency of noncardiac surgery and adverse post-operative events among patients who recently received a drug eluting stent (DES) following noncardiac surgery. BACKGROUND: Little is known about frequency of and risks associated with noncardiac surgery after DES implantation. METHODS: In the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry, consecutive patients who underwent attempted stent placement at 42 hospitals between July 2004 and September 2005 were enrolled and followed for 1 year. In this study, we analyzed patients who received >= 1 DES to determine the frequency of noncardiac surgery and cardiac death, myocardial infarction, or stent thrombosis in the following week. RESULTS: Among 4,637 DES recipients, 206 (4.4%) underwent major noncardiac surgery in the following year (median days to surgery: 179 [interquartile range 112 to 266 days; range 13 to 360 days]). Overall, stent use averaged 1.5 per patient. The most frequent operations were orthopedic (36%), abdominal (31%), and vascular (20%). Compared with patients who did not undergo surgery, those who did were older, more likely to be women, and have had a prior stroke; the frequencies of prior myocardial infarction, prior coronary artery bypass graft, and diabetes were similar, as were left ventricular ejection fraction and indication for percutaneous coronary intervention. In the 7 days after surgery, 4 patients had a cardiac death, myocardial infarction, or stent thrombosis (1.9% [exact 95% confidence interval (CI): 0.5% to 4.9%]). The risk of the composite outcome was increased 27-fold in the week following noncardiac surgery compared with any other week after stent implantation (hazard ratio [HR]: 27.3 [95% CI: 10.0 to 74.2], p < 0.001). CONCLUSIONS: The frequency of major noncardiac surgery in the year after DES placement is >4%. Although the overall risk of adverse outcomes was less than previously reported when surgery is performed months after DES placement, it is significantly increased in the week after major noncardiac surgery. PMID- 20850091 TI - Local delivery versus intracoronary infusion of abciximab in patients with acute coronary syndromes. AB - OBJECTIVES: We investigated whether local abciximab delivery to the site of intracoronary thrombus is more effective than intracoronary bolus infusion in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention and downstream clopidogrel administration. BACKGROUND: The intracoronary route of administration does not allow an optimal contact between the plaque components and abciximab, which is rapidly washed out by the coronary flow. METHODS: A total of 50 patients with ACS and a significant lesion in the culprit artery indicative of local thrombosis were randomly assigned to receive local intracoronary delivery of abciximab through a dedicated perfusion catheter or intracoronary infusion through the guiding catheter. The primary end point was the change in thrombus score after angioplasty by optical coherence tomography. RESULTS: After the intervention, the mean percentage change of the thrombus score was significantly higher among patients of the local delivery group compared with those of the intracoronary infusion group (33.8% vs. 3.9%, p = 0.002). Post procedural corrected Thrombolysis in Myocardial Infarction frame count was shorter in the local delivery group compared with the intracoronary infusion group (15.3 +/- 10.2 vs. 21.1 +/- 9.9, p = 0.049). Procedure-related myocardial infarction was observed in 10% and 43% of patients in the local delivery and intracoronary infusion groups, respectively (p = 0.018). At 1 year, MACE were observed in 5.9% and 27.2% of patients in the local delivery and intracoronary infusion groups, respectively (p = 0.046). CONCLUSIONS: Local intracoronary delivery of abciximab by means of a dedicated perfusion catheter reduces thrombus burden with the potential to improve coronary microcirculation. PMID- 20850092 TI - Intracoronary glycoprotein IIb/IIIa inhibitors from questioning the logic to weighing the data. PMID- 20850093 TI - Percutaneous coronary intervention in native vessels with angiographically visible thrombus temporal trends and impact of drug-eluting stents. AB - OBJECTIVES: The aim of our study was to evaluate the temporal trends in outcomes following percutaneous coronary intervention in lesions with angiographically visible thrombus and to assess the impact of drug-eluting stents (DES) on long term outcomes. BACKGROUND: Percutaneous coronary intervention in the presence of angiographically visible thrombus is associated with worse clinical outcomes. Whether recent advances in devices and adjunctive pharmacotherapy have made any significant impact on clinical outcomes is unknown. Moreover, concerns have been raised about the safety of DES in thrombotic lesions. METHODS: We conducted a retrospective analysis of 6,227 consecutive patients who had angiographically visible thrombus. Patients were grouped into 3 eras depending on the dominant interventional strategy of that time: early stent era (1990 to 1996), bare-metal stent era (1997 to 2003), and DES era (2003 to 2006). RESULTS: Procedural success rates, although much improved, have remained unchanged in the last 2 cohorts (43%, 85%, 86%; p < 0.001). Adjusted in-hospital mortality (4.7%, 3.0%, 3.6%; p < 0.001), and major adverse cardiovascular events (7.8%, 5.0%, 5.3%; p < 0.001) decreased modestly. During long-term follow-up, mortality and the combined end point of death or myocardial infarction were similar in the 3 cohorts; but the combined end point of death, myocardial infarction, or target lesion revascularization (p < 0.001) was lower in the 2 most recent eras. CONCLUSIONS: There has been a marked improvement in procedural success accompanied by a reduction in in-hospital mortality and major adverse cardiac event rates. Importantly, the introduction of DES has not been associated with a greater risk of death or myocardial infarction among patients with angiographically visible thrombus. PMID- 20850094 TI - Intracoronary thrombus a sticky problem. PMID- 20850095 TI - New universal definition of myocardial infarction applicable after complex percutaneous coronary interventions? AB - OBJECTIVES: This study aimed to characterize myocardial infarction after percutaneous coronary intervention (PCI) based on cardiac marker elevation as recommended by the new universal definition and on the detection of late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR). It is also assessed whether baseline inflammatory biomarkers are higher in patients developing myocardial injury. BACKGROUND: Cardiovascular magnetic resonance accurately assesses infarct size. Baseline C-reactive protein (CRP) and neopterin predict prognosis after stent implantation. METHODS: Consecutive patients with baseline troponin (Tn) I within normal limits and no LGE in the target vessel underwent baseline and post-PCI CMR. The Tn-I was measured until 24 h after PCI. Serum high-sensitivity CRP and neopterin were assessed before coronary angiography. RESULTS: Of 45 patients, 64 (53 to 72) years of age, 33% developed LGE with infarct size of 0.83 g (interquartile range: 0.32 to 1.30 g). A Tn-I elevation >99% upper reference limit (i.e., myocardial necrosis) (median Tn-I: 0.51 MUg/l, interquartile range: 0.16 to 1.23) and Tn-I > 3* upper reference limit (i.e., type 4a myocardial infarction [MI]) occurred in 58% and 47% patients, respectively. LGE was undetectable in 42% and 43% of patients with periprocedural myocardial necrosis and type 4a MI, respectively. Agreement between LGE and type 4a MI was moderate (kappa = 0.45). The levels of CRP or neopterin did not significantly differ between patients with or without myocardial injury, detected by CMR or according to the new definition (p = NS). CONCLUSIONS: This study reports the lack of substantial agreement between the new universal definition and CMR for the diagnosis of small-size periprocedural myocardial damage after complex PCI. Baseline levels of CRP or neopterin were not predictive for the development of periprocedural myocardial damage. PMID- 20850096 TI - Magnetic resonance imaging and troponin elevation following percutaneous coronary intervention: new insights into myocyte necrosis and scar formation. PMID- 20850097 TI - Patent foramen ovale closure with the SeptRx device initial experience with the first "In-Tunnel" device. AB - OBJECTIVES: The purpose of this study was to evaluate the safety and effectiveness of the SeptRx patent foramen ovale (PFO) closure device (SeptRx, Inc., Fremont, California). BACKGROUND: A PFO is a relatively common remnant of the fetal circulation that can be associated with cryptogenic stroke, transient ischemic attack, migraine, or decompression sickness. Percutaneous PFO closure with different devices has been performed for many years. However, most of the common devices leave a relatively large amount of material in the left and right atria. The SeptRx PFO device (SeptRx, Inc.) is the first PFO closure device designed to fit directly into the pocket of the PFO. METHODS: From July 2006 to May 2007, 13 patients between 18 and 65 years of age with a history of cryptogenic stroke or transient ischemic attack were included into this first-in man trial. All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months. Follow-up was done at 1 and 6 months after procedure with transesophageal echocardiography and transcranial Doppler. RESULTS: In 11 of 13 patients, PFO closure with the SeptRx device was successfully performed. In 2 patients, PFO closure with this device was not possible due to the anatomy of the PFO; 1 device was retrieved before release, and the other was recaptured with a snare. After 30 days, 6 of the 11 PFOs were closed; after 6 months, all were closed. No adverse events occurred. CONCLUSIONS: The SeptRx PFO closure device appears to be safe and effective. The advantage of this occluder is that there is only minimal foreign material on the left and right sides of the interatrial septum. This is the first such "in-tunnel" PFO closure device. PMID- 20850098 TI - Patent foramen ovale closure using a bioabsorbable closure device: safety and efficacy at 6-month follow-up. AB - OBJECTIVES: The aim of this study was to assess the mid-term safety and efficacy of percutaneous patent foramen ovale (PFO) closure using a bioabsorbable device (BioSTAR, NMT Medical, Boston, Massachusetts). BACKGROUND: Closure of PFO in patients with cryptogenic stroke has proven to be safe and effective using different types of permanent devices. METHODS: All consecutive patients who underwent percutaneous PFO closure with the bioabsorbable closure device between November 2007 and January 2009 were included. Residual shunt was assessed using contrast transthoracic echocardiography. RESULTS: Sixty-two patients (55% women, mean age 47.7 +/- 11.8 years) underwent PFO closure. The in-hospital complications were a surgical device retrieval in 2 patients (3.2%), device reposition in 1 (1.6%), and a minimal groin hematoma in 6 patients (9.7%). The short-term complications at 1-month follow-up (n = 60) were a transient ischemic attack in the presence of a residual shunt in 1 patient and new supraventricular tachycardia in 7 patients (11.3%). At 6-month follow-up (n = 60), 1 patient without residual shunt developed a transient ischemic attack and 1 developed atrial fibrillation. A mild or moderate residual shunt was noted in 51.7%, 33.9%, and 23.7% after 1-day, 1-month, and 6-month follow-up, respectively. A large shunt was present in 8.3%, 3.4%, and 0% after 1-day, 1-month, and 6-month follow up. CONCLUSIONS: Closure of PFO using the bioabsorbable device is associated with a low complication rate and a low recurrence rate of embolic events. However, a relatively high percentage of mild or moderate residual shunting is still present at 6-month follow-up. PMID- 20850099 TI - Reparative effects of allogeneic mesenchymal precursor cells delivered transendocardially in experimental nonischemic cardiomyopathy. AB - OBJECTIVES: This study set out to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal precursor cells (MPC) delivered by multisegmental, transendocardial implantation in the setting of nonischemic cardiomyopathy (NICM). BACKGROUND: Prospectively isolated MPC have shown capacity to mediate cardiovascular repair in myocardial ischemia. However, their efficacy in NICM remains undetermined. METHODS: Mesenchymal precursor cells were prepared from ovine bone marrow by immunoselection using the tissue nonspecific alkaline phosphatase, or STRO-3, monoclonal antibody. Fifteen sheep with anthracycline induced NICM were assigned to catheter-based, transendocardial injections of allogeneic MPC (n = 7) or placebo (n = 8), under electromechanical mapping guidance. Follow-up was for 8 weeks, with end points assessed by cardiac magnetic resonance, echocardiography, and histology. RESULTS: Intramyocardial injections were distributed similarly throughout the left ventricle in both groups. Cell transplantation was associated with 1 death late in follow-up, compared with 3 early deaths among placebo animals. Left ventricular end-diastolic size increased in both cohorts, but MPC therapy attenuated end-systolic dilation and stabilized ejection fraction, with a nonsignificant increase (37.3 +/- 2.8% before, 39.2 +/- 1.4% after) compared with progressive deterioration after placebo (38.8 +/- 4.4% before, 32.5 +/- 4.9% after, p < 0.05). Histological outcomes of cell therapy included less fibrosis burden than in the placebo group and an increased density of karyokinetic cardiomyocytes and myocardial arterioles (p < 0.05 for each). These changes occurred in the presence of modest cellular engraftment after transplantation. CONCLUSIONS: Multisegmental, transendocardial delivery of cell therapy can be achieved effectively in NICM using electromechanical navigation. The pleiotropic properties of immunoselected MPC confer benefit to nonischemic cardiac disease, extending their therapeutic potential beyond the setting of myocardial ischemia. PMID- 20850100 TI - Aortic regurgitation after cardiac catheterization. PMID- 20850101 TI - Iatrogenic renal artery dissection uncommon complication during aortic endovascular repair. PMID- 20850102 TI - Carotid artery stenting lessons From CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial). PMID- 20850103 TI - Training on the use of transendocardial delivery of biologics for cardiac regeneration. PMID- 20850104 TI - Imagination is stronger than knowledge. PMID- 20850106 TI - Using the Brink score to predict postpartum anal incontinence. AB - OBJECTIVE: To evaluate whether antepartum pelvic floor muscle strength, as measured by the Brink scale, predicts postpartum anal incontinence. STUDY DESIGN: This prospective cohort study of primigravid women used validated questionnaires and standardized pelvic examinations to evaluate subjects during the third trimester and at 2 postpartum time points. RESULTS: Of the initial 129 subjects, 102 and 81 completed 2 week and 6 month postpartum visits. 35% had cesarean deliveries. The antepartum prevalence of fecal incontinence (14%) did not differ significantly from the postpartum (17% at 2 weeks, 11% at 6 months). However, the prevalence of flatal incontinence fell from antepartum (65%) to postpartum (47% at 2 weeks, P = .001; 49% at 6 months, P = .012). Mean Brink score decreased postpartum; no correlations were found between Brink score and questionnaire scores. CONCLUSION: Anal incontinence symptoms are common in the third trimester of a first pregnancy and may regress or resolve after delivery. Brink score did not predict postpartum anal incontinence. PMID- 20850105 TI - A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness. AB - Congenital stationary night blindness (CSNB) is a nonprogressive retinal disorder that can be associated with impaired night vision. The last decade has witnessed huge progress in ophthalmic genetics, including the identification of three genes implicated in the pathogenicity of autosomal-recessive CSNB. However, not all patients studied could be associated with mutations in these genes and thus other genes certainly underlie this disorder. Here, we report a large multigeneration family with five affected individuals manifesting symptoms of night blindness. A genome-wide scan localized the disease interval to chromosome 15q, and recombination events in affected individuals refined the critical interval to a 10.41 cM (6.53 Mb) region that harbors SLC24A1, a member of the solute carrier protein superfamily. Sequencing of all the coding exons identified a 2 bp deletion in exon 2: c.1613_1614del, which is predicted to result in a frame shift that leads to premature termination of SLC24A1 (p.F538CfsX23) and segregates with the disorder under an autosomal-recessive model. Expression analysis using mouse ocular tissues shows that Slc24a1 is expressed in the retina around postnatal day 7. In situ and immunohistological studies localized both SLC24A1 and Slc24a1 to the inner segment, outer and inner nuclear layers, and ganglion cells of the retina, respectively. Our data expand the genetic basis of CSNB and highlight the indispensible function of SLC24A1 in retinal function and/or maintenance in humans. PMID- 20850107 TI - Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease. AB - Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient. PMID- 20850108 TI - Improving the climate safety of workers in Almeria-type greenhouses in Spain by predicting the periods when they are most likely to suffer thermal stress. AB - The humidex and wind-chill indices were used to determine the periods in which labourers working in Almeria-type greenhouses in southeastern Spain are most likely to suffer conditions able to induce heat and cold stress. Over 500,000 pieces of data for wet and dry bulb temperatures and relative humidity, recorded over a period in excess of five years by a weather station located in an Almeria type greenhouse containing a grass crop, were used in the calculation of these indices. The wind-chill index results showed cold stress never to be a problem, but the humidex index results showed that conditions under which heat stress could develop were common in the warmer months. A clock diagram was produced showing the hours when heat stress is likely to occur in each month of the year. This information could be used to improve the conditions of labourers working in this type of greenhouse; some ways of reducing their exposure to heat stress inducing conditions are discussed. PMID- 20850109 TI - Occupational musculoskeletal and mental health: Significance of rationalization and opportunities to create sustainable production systems - A systematic review. AB - This literature review aims to identify occupational musculoskeletal and mental health effects of production system rationalization as well as organizational level measures that may improve health outcome ("modifiers" in this review). A short review of the effect of ergonomic interventions is included as background and rationalization is discussed as a theoretical concept. Indicator variables for occupational musculoskeletal and mental health and related risk factors are presented. Variables with a generalized format were allowed in the literature searches (e.g., job satisfaction and absenteeism were accepted as risk factor and health indicator, respectively), suitable for the research fields of work sociology, organization science, human resource management (HRM) and economics research. One hundred and sixty-two studies of rationalization effects on health and risk factors and 72 organization-level modifier results were accepted into the final database. Entries were sorted by rationalization strategy and work life sector, and trends in outcome (positive, mixed, no effect, or negative effect on health and risk factors) were determined. Rationalizations have a dominant negative effect on health and risk factors (57% negative, 19% positive); the most negative effects were found for downsizing and restructuring rationalizations in general (71 studies negative, 13 positive) and for the health care sector in particular (36 studies negative, 2 positive). The rationalization strategy High Performance Work System (HPWS) was associated with the highest fraction positive outcome studies (6 of 10 studies). Other rationalization strategies (lean practices, parallel vs. serial production and mechanization level) reported intermediate results, in part dependent on work life sector, but also on the year when studies were carried out. Worker participation, resonant management style, information, support, group autonomy and procedural justice were modifiers with favourable influence on outcome. It is concluded that production system rationalization represents a pervasive work life intervention without a primary occupational health focus. It has considerable and mostly negative influence on worker health, but this can be reduced by attention to modifiers. The results create a basis for new priorities in ergonomic intervention research. PMID- 20850110 TI - Carboxymethylated cyclosophoraose as a novel chiral additive for the stereoisomeric separation of some flavonoids by capillary electrophoresis. AB - A carboxymethylated cyclosophoraose (CM-Cys) was synthesized by the chemical modification of neutral Cys, which was isolated from Rhizobium trifolii TA-1. CM Cys was successfully applied as a novel chiral selector for the separation of some flavonoids including catechin, 3,5,7,3',4'-pentahydroxyflavanone, hesperidin, hesperetin, isosakuranetin, naringenin, naringin, and eriodictyol. The effects of pH, chiral additive concentration, and temperature on resolution and migration time were also studied. PMID- 20850111 TI - Purification and characterization of a thermostable alpha-amylase produced by the fungus Paecilomyces variotii. AB - An alpha-amylase produced by Paecilomyces variotii was purified by DEAE-cellulose ion exchange chromatography, followed by Sephadex G-100 gel filtration and electroelution. The alpha-amylase showed a molecular mass of 75 kDa (SDS-PAGE) and pI value of 4.5. Temperature and pH optima were 60 degrees C and 4.0, respectively. The enzyme was stable for 1 h at 55 degrees C, showing a t50 of 53 min at 60 degrees C. Starch protected the enzyme against thermal inactivation. The alpha-amylase was more stable in alkaline pH. It was activated mainly by calcium and cobalt, and it presented as a glycoprotein with 23% carbohydrate content. The enzyme preferentially hydrolyzed starch and, to a lower extent, amylose and amylopectin. The K(m) of alpha-amylase on Reagen(r) and Sigma(r) starches were 4.3 and 6.2 mg/mL, respectively. The products of starch hydrolysis analyzed by TLC were oligosaccharides such as maltose and maltotriose. The partial amino acid sequence of the enzyme presented similarity to alpha-amylases from Bacillus sp. These results confirmed that the studied enzyme was an alpha amylase ((1->4)-alpha-glucan glucanohydrolase). PMID- 20850112 TI - Left-right coding of past and future in language: the mental timeline during sentence processing. AB - The metaphoric mapping theory suggests that abstract concepts, like time, are represented in terms of concrete dimensions such as space. This theory receives support from several lines of research ranging from psychophysics to linguistics and cultural studies; especially strong support comes from recent response time studies. These studies have reported congruency effects between the dimensions of time and space indicating that time evokes spatial representations that may facilitate or impede responses to words with a temporal connotation. The present paper reports the results of three linguistic experiments that examined this congruency effect when participants processed past- and future-related sentences. Response time was shorter when past-related sentences required a left-hand response and future-related sentences a right-hand response than when this mapping of time onto response hand was reversed (Experiment 1). This result suggests that participants can form time-space associations during the processing of sentences and thus this result is consistent with the view that time is mentally represented from left to right. The activation of these time-space associations, however, appears to be non-automatic as shown by the results of Experiments 2 and 3 when participants were asked to perform a non-temporal meaning discrimination task. PMID- 20850113 TI - [Should we modify our therapeutic behavior as a consequence of the 2009 revision of the ESH/ESC guidelines for the management of arterial hypertension]. AB - The recent publication in November 2009 of the revision of the European guidelines on hypertension management by the European Society of hypertension has aroused great interest. It has included the results of new important studies on hypertension, reinforcing the evidence on which the recommendations of the 2007 ESH/ESC guidelines were based. However, some of the recommendations that were firmly established until now are reconsidered. This dual aspect can generate some relevant doubts in clinical practice, even more so if we consider that some recommendations are opposite to other recently published guidelines. The presentation of a frequently appearing clinical case, as a hypertensive and diabetic female patient >65 years old, provides us the opportunity to analyze and interpret new recommendations, in comparison to the previous ones and to establish the best clinical action approach in the daily practice. In addition to the changes in the management of diabetic patients, some especially relevant aspects of the revised guide are updated, for example, subclinical injury of the target organ and its affect on cardiovascular risk stratification, how to manage those patients with high normal blood pressure values and other cardiovascular risk factors, the "new" blood pressure goals, as well as the objectives and the treatments under specific conditions such as the elderly population and the associated cardiovascular disease. PMID- 20850114 TI - Age estimation in subadult Egyptian remains. AB - In anthropological analyses of past populations, it is very important to be able to accurately reconstruct the palaeodemographic profile in order to interpret infant mortality as an indicator of the environmental, social and cultural conditions. There are various methods to evaluate the age of immature individuals but some of these methods are strongly influenced by the different rates of skeletal development observed in populations from various geographical areas and/or from various time periods, as well as between the sexes. Clearly, there is a need for adopting a method of estimation of age at death, which will be the one most suitable for analysing the particular skeletal sample. In this study we investigated subadults from the Egyptian osteological collection housed in the Museum of Anthropology and Ethnography of the University of Turin. For each individual, the age at death was estimated based on the degree of eruption and mineralisation of the teeth. Then the estimated age at death was correlated with the measurements of the long bones and ilium. We showed that greater regularity and constancy of rates of skeletal growth could be assessed with measurements, alternative to using maximum length of diaphysis. Moreover, using alternative characters, it was possible to markedly increase the number of individuals whose age at death could be estimated. Our study also showed the need to use a reference sample consistent with the sample being analysed and, which was derived from similar biological-environmental context. Therefore, our proposed method can be used for the estimation of age at death in pre/protohistorical populations from the Mediterranean region. PMID- 20850115 TI - Protective effect of deferoxamine on experimental spinal cord injury in rat. AB - OBJECTIVE: To observe the protective effect of deferoxamine on experimental spinal cord injury (SCI) in rats. METHODS: Sprague-Dawley rats were randomly divided into the following four groups. CONTROL GROUP: rats were performed laminectomy only; SCI group: rats were performed laminectomy with SCI; DFO group: rats were injected intraperitoneally a bolus of 100mg/kg deferoxamine after SCI; vehicle group: rats were injected intraperitoneally 0.9% saline after SCI. The SCI of animal model was made by using a modified Allen's method on T(10). Six rats of each group were sacrificed at 4h after injured, and the levels of free iron and malondialdehyde (MDA) of involved spinal cord segments were measured by bleomycin assay and the thiobarbituric acid (TBA) separately. The recovery of function was assessed by Modified Tarlov's scale and inclined plane method at 7, 14, 21d after SCI. The histologic changes of the damaged spinal cord were also examined at 7d after SCI. RESULTS: Following SCI, the levels of free iron and MDA were increased significantly and the Modified Tarlov's score and inclined plane angles decreased in SCI group and vehicle group. In DFO group, the levels of free iron and MDA were not increased, but the Modified Tarlov's score and inclined plane angles decreased, the histological findings were improved as well. CONCLUSION: Deferoxamine can reduce the levels of free iron and lipid peroxidation, and improve the hind limb functional status of rats with spinal cord injury. PMID- 20850116 TI - Consequences of non-fatal electrical injury: findings of community-based national survey in Bangladesh. AB - This study was designed to document the consequences of electrical injury in Bangladesh. A community-based cross-sectional survey was conducted from January to December 2003. Nationally representative data were collected from 171,366 rural and urban households, comprising a total of 819,429 population. Face-to face interview was chosen as a data collection method. The overall rate of electrical injury was 73.7 per 100,000 population-year. The rate of permanent disability due to electrical injury in Bangladesh was 0.366 per 100,000 population-year. Among the total 604 non-fatal electrical injuries in the survey, 282 (46.7%) had suffered from temporary disabilities for different durations. A total of 172 students were injured from electrical injury and among them 139 (80.8%) missed school for different durations due to their illness. Mean duration of absence from school was 9.72 days (SD+/-10.98), ranging from 1 to 45 days. Among the working people average duration of work loss was 10.56 days (SD+/ 14.98), ranging from 1 to 90 days. About 39% of the total patients with electrical injury were contributors to their family income. For each family the expenditure for each seriously injured patient due to electrical injury was USD 271. Electrical Injury is a major cause of morbidity in Bangladesh. It is responsible for significant loss of school days and work days and creating serious health and economic hardship for the inflicted families. A nationwide prevention program needs to be developed to address this problem. PMID- 20850117 TI - Pulmonary fat embolism after reamed and unreamed nailing of femoral fractures. AB - BACKGROUND: To determine whether reamed or unreamed intramedullary nailing of femoral fractures results in higher incidence of pulmonary fat embolism, three different methods of intramedullary nailing were compared in sheep. To analyze the presence of bone marrow fat embolism in pulmonary arteries, histological evaluation was undertaken using a quantitative computer-assisted measurement system. METHODS: In this experimental model of 27 female Swiss alpine sheep, an osteotomy of the proximal femur was conducted in each animal. Then, the animals were divided into three groups according to the method of treatment: two different reamed intramedullary nailing techniques and an unreamed nailing technique were used. In the first group "ER" (experimental reamer; n=9), the nail was inserted after reaming with an experimental reamer; in the second group "CR" (conventional reamer; n=7), the intramedullary nail was inserted after reaming with the conventional AO-reamer. In the third group "UN" (unreamed; n=8) unreamed nailing was performed. During the operation procedure intramedullary pressure was measured in the distal fragment. After sacrificing the animals, quantitative histological analyses of bone marrow fat embolism in pulmonary arteries were done using osmium tetroxide fixation and staining of the fat. RESULTS: The measurement of intramedullary pressure showed significantly lower values for reamed nailing than for the unreamed technique. The quantitative histological evaluation of lung vessels concerning bone marrow fat embolism revealed a statistically significant difference between reamed and unreamed insertion of the nail: 7.77%+/-6.93 (ER) and 6.66%+/-5.61 (CR) vs. 16.25%+/-10.05 (UN) (p<0.05) of the assessed lung vessels were filled with fat emboli. However, no difference was found between the traditional and experimental reamer. CONCLUSIONS: Intramedullary nailing after reaming is a safe procedure with low systemic embolisation when compared to the unreamed insertion of the nail. PMID- 20850118 TI - Volume to density relation in adult human bone tissue. AB - Uniformity of tissue mineralisation is a strongly debated issue, due to its relation with bone mechanical behaviour. Bone mineral density (BMD) is measured in the clinical practice and is applied in computational application to derive material properties of bone tissue. However, BMD cannot identify if the variation in bone density is related to a modification of tissue mineral density (TMD), a change in bone volume or a combination of the two. This study was aimed to investigate whether TMD can be assumed as a constant in adult human bone (trabecular and cortical). A total number of 115 cylindrical bone specimens were collected. An inter-site analysis (96 specimens, 2 donors) was performed on cortical and trabecular specimens extracted from different anatomical sites. An intra-site study (19 specimens, 19 donors) was performed on specimens extracted from femoral heads. Bone volume fraction (BV/TV) was computed by means of a micro computed tomography. Furthermore, ash density (rho(ash)) was measured. TMD was computed as the ratio between rho(ash) and BV/TV. It was found that the TMD of trabecular (1.24 +/- 0.16 g/cm(3)) and cortical (1.19 +/- 0.06 g/cm(3)) bone were not statistically different (p=0.31). Furthermore, the linear regression between rho(ash) and BV/TV was statistically significant (r(2)=0.99, p<0.001). Intra- and inter-site analyses demonstrated that the mineral distribution was independent of the extraction site. The present study suggests that TMD can be assumed reasonably constant in non-pathological adult bone tissue. Consequently, it is suggested that TMD can be managed as a constant in computational models, varying only BV in relation to clinical densitometric analysis. PMID- 20850119 TI - A novel approach for quantitative peptides analysis by selected electron transfer reaction monitoring. AB - Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) with selective reaction monitoring (SRM) is a selective and sensitive method for quantitation of peptides. SRM is achieved via MS/MS utilizing collision-induced dissociation (CID) while monitoring unique precursor-product ion transitions. Low energy CID tandem mass spectrometry has been, by far, the most common method used to dissociate peptide ions for sequence analysis. However, collisional scattering of product ions in CID results in decreased intensity of the primary product ion. The lower intensity of the targeted product ion can lead to a reduction in the sensitivity of a quantitative method that uses SRM. Electron transfer dissociation (ETD) is a fragmentation method that is complementary to CID. During the ETD reaction for doubly protonated peptides ([M+2H](2+)), there is a significant shift toward nondissociative electron transfer (ET) product species ([M+2H](+)). We utilized that particular defect in ETD to develop a new quantitative method for monitoring the transition of unique precursors ([M+2H](2+)) to charge-reduced ions ([M+2H](+)). We refer to this method as selective electron transfer reaction monitoring (SETRM). In ESI-MS, trypsin digested peptides tend to generate doubly protonated peptide precursors. We found that SETRM was more suitable than SRM for these doubly charged tryptic peptides with nano-LC-MS/MS. The quantitative capabilities of SETRM provide a more sensitive way of performing quantitative experiments using the same instrument, thereby improving the application of electron transfer dissociation in proteomics. PMID- 20850120 TI - An automatic system for multidimensional integrated protein chromatography. AB - An automatic system for multidimensional integrated protein chromatography was designed for simultaneous separation of multiple proteins from complex mixtures, such as human plasma and tissue lysates. This computer-controlled system integrates several chromatographic columns that work independently or cooperatively with one another to achieve efficient high throughputs. The pipelines can be automatically switched either to another column or to a collection container for each UV-detected elution fraction. Environmental contamination is avoided due to the closed fluid paths and elimination of manual column change. This novel system was successfully used for simultaneous preparation of five proteins from the precipitate of human plasma fraction IV (fraction IV). The system involved gel filtration, ion exchange, hydrophobic interaction, and heparin affinity chromatography. Human serum albumin (HSA), transferrin (Tf), antithrombin-III (AT-III), alpha 1-antitrypsin (alpha1-AT), and haptoglobin (Hp) were purified within 3 h. The following recovery and purity were achieved: 95% (RSD, 2.8%) and 95% for HSA, 80% (RSD, 2.0%) and 99% for Tf, 70% (RSD, 2.1%) and 99% for AT-III, 65% (RSD, 2.0%) and 94% for alpha1-AT, and 50% (RSD, 1.0%) and 90% for Hp. The results demonstrate that this novel multidimensional integrated chromatography system is capable of simultaneously separating multiple protein products from the same raw material with high yield and purity and it has the potential for a wide range of multi-step chromatography separation processes. PMID- 20850121 TI - High throughput qualitative analysis of polyphenols in tea samples by ultra-high pressure liquid chromatography coupled to UV and mass spectrometry detectors. AB - The analysis of polyphenols in tea extracts is important due to their potential health benefits. Therefore, efficient and high throughput analytical methods have been developed for the separation of seven predominant polyphenols, also known as catechin derivatives, present in tea extracts. Columns packed with sub-2-MUm particles operating at elevated pressure (UHPLC strategy) were selected to improve chromatographic performance. The potential of UHPLC-UV was demonstrated with baseline resolution of all standard catechins in only 30 s using a 50-mm column packed with 1.7-MUm particles. When dealing with real samples such as tea extracts, however, longer columns of up to 150 mm in length were employed to enhance the separation of catechin derivatives and other constituents within the tea samples while maintaining an acceptable analysis time. Two strategies based on 2-D experiments were proposed to clearly identify catechins. Firstly, a liquid liquid extraction procedure was added prior to the UHPLC-UV analysis to decrease the complexity of the sample. Secondly, UHPLC was coupled to ESI-MS/MS to attain sufficient sensitivity and selectivity between catechin derivatives and other constituents of tea extract. These two strategies were found extremely promising as a clear discrimination of catechins from the matrix could be attained. PMID- 20850122 TI - Analysis of thyroid hormones in raw and treated waste water. AB - An analytical method for the quantification of thyroid hormones (3,5,3',5' tetraiodo-L-thyronine, 3,3',5-triiodo-L-thyronine, 3,3',5'-triiodothyronine, 3,5 diiodothyronine, 3,3'-diiodothyronine) in different water matrices has been developed. The method, consisting of solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), was validated for tap and surface water as well as raw and treated waste water. The limits of quantifications (LOQs) were lowest in tap water, where they ranged from 1.1 to 13.3 ng L(-1), and highest in raw wastewater (10.5-84.9 ng L(-1)). Of the target analytes 3,5,3',5'-tetraiodo-L-thyronine (T(4)) could be quantified in the influent and effluent of a waste water treatment plant (WWTP) in Finland. The study showed that despite a relatively high removal rate during treatment (66%), part of the incoming T(4) will reach the aquatic environment and, due to the high endocrine activity of this compound, further studies are needed in order to assess its environmental fate and impact on natural ecosystems. PMID- 20850123 TI - Permanent gold nanoparticle coatings on polyelectrolyte multilayer modified capillaries for open-tubular capillary electrochromatography. AB - This paper reports on a new strategy to coat fused silica capillaries through ionic adsorption of gold nanoparticles (AuNPs) on a polyelectrolyte multilayer (PEM) modified capillary wall. The coating was constructed in situ by alternating rinses with positively charged poly(diallydimethylammonium chloride), negatively charged poly(sodium-4-styrenesulfonate), and positively charged AuNPs. After self assembly of n-octadecanethiol onto the surface of AuNPs, the modified capillary was investigated as a new medium for the separation of neutral analytes and proteins in open-tubular capillary electrochromatography (OT-CEC). The surface coverage of the capillary wall was increased using the high density of AuNPs which were dynamically capped with 4-dimethylaminopyridine (DMAP). The chromatographic performance of the column coated with positively charged AuNPs was remarkably improved compared with a column modified with negatively charged AuNPs. The coating was robust over more than 810 runs in this study and also showed high stability against 0.01 M NaOH, 0.01 M HCl, and electrolyte concentrations up to 70 mM. The run-to-run, day-to-day, and capillary-to capillary reproducibilities of electroosmotic flow were satisfying with relative standard deviation values of less than 1% in all cases. The AuNP-coated PEM modified capillary column not only showed good performance for neutral analytes but also was suitable for the analysis of both basic and acidic proteins. PMID- 20850124 TI - Iminodiacetic acid-modified magnetic poly(2-hydroxyethyl methacrylate)-based microspheres for phosphopeptide enrichment. AB - Magnetic non-porous hydrophilic poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) microspheres prepared by the dispersion polymerization and modified with iminodiacetic acid (IDA) were employed for the IMAC separation of phosphopeptides. Fe(3+) and Ga(3+) ions immobilized on IDA-modified magnetic microspheres were used for the enrichment of phosphopeptides from the proteolytic digests of two model proteins differing in their physico-chemical properties and phosphate group content: porcine pepsin A and bovine alpha-casein. The optimum conditions for phosphopeptide adsorption and desorption in both cases were investigated and compared. The phosphopeptides separated from the proteolytic digests were analyzed by matrix-assisted laser desorption/ionization time-of flight mass spectrometry. The ability of the prepared Fe(3+)- and Ga(3+)-IDA modified magnetic microspheres to capture phosphopeptides from complex mixtures was shown on an example of bovine milk proteolytic digest. PMID- 20850125 TI - Ring-opening metathesis polymerization-derived monolithic anion exchangers for the fast separation of double-stranded DNA fragments. AB - Ring-opening metathesis polymerization- (ROMP) derived monoliths were prepared from 5-norborn-2-enemethyl bromide (NBE-CH(2)Br) and tris(5-norborn-2 enemethoxy)methylsilane ((NBE-CH(2)O)(3)SiCH(3)) within the confines of surface silanized borosilicate columns (100*3 mm I.D.), applying Grubbs' first generation benzylidene-type catalyst [RuCl(2)(PCy(3))(2)(CHPh)]. Monoliths were converted into weak anion exchangers via reaction with diethyl amine. The resulting monolithic anion exchangers demonstrated a very good potential for the anion exchange separation of nucleic acids applying a phosphate buffer (0.05 mol/L, pH 7) and NaCl (1.0 mol/L) as a gradient former. Fast and efficient separations, indicated by sharp and highly symmetric analyte peaks, were established. Except for the 267 and 298 base pair fragments, the eleven fragments of a ds-pUC18 DNA Hae III digest were baseline separated within ~8 min. Nineteen fragments of a ds pBR322 Hae III digest were separated within ~12 min. There, only the 192 and 213 base pair fragments and the 458, 504 and 540 base pair fragments coeluted. A ds pUC18 DNA Hae III digest was used as a control analyte in evaluating the influence of organic additives on the mobile phase such as methanol and acetonitrile on nucleic acid separation. Methanol, and even better, acetonitrile improved the separation efficiency and shortened the analysis time. PMID- 20850127 TI - Tunable photoluminescence in monodisperse silica spheres. AB - The nanometer-scale luminescent monodisperse silica spheres have been prepared by a water/oil (W/O) microemulsion method and the size of these spheres changed with the different concentrations of 3-aminopropyltriethoxysilane (APTES). The luminescent monodisperse silica spheres at the submicrometer scale have been prepared via Stober method and the particles size increased with the increase of the amino concentrations. After calcination, all silica spheres do not change obviously in size. The annealed silica spheres contain C impurities and O defects, which resulted in the luminescence of silica spheres. The spheres showed variations in emission due to the different size and the concentration of organosiloxane precursors. Therefore, the emission can be tuned finely via the change of organosiloxane precursor and the size of samples. PMID- 20850126 TI - Preparation and evaluation of carbon coated alumina as a high surface area packing material for high performance liquid chromatography. AB - The retention of polar compounds, the separation of structural isomers and thermal stability make carbonaceous materials very attractive stationary phases for liquid chromatography (LC). Carbon clad zirconia (C/ZrO(2)), one of the most interesting, exhibits unparalleled chemical and thermal stability, but its characteristically low surface area (20-30 m(2)/g) limits broader application as a second dimension separation in two-dimensional liquid chromatography (2DLC) where high retentivity and therefore high stationary phase surface area are required. In this work, we used a high surface area commercial HPLC alumina (153 m(2)/g) as a support material to develop a carbon phase by chemical vapor deposition (CVD) at elevated temperature using hexane vapor as the carbon source. The loading of carbon was varied by changing the CVD time and temperature, and the carbon coated alumina (C/Al(2)O(3)) was characterized both physically and chromatographically. The resulting carbon phases behaved as a reversed phase similar to C/ZrO(2). At all carbon loadings, C/Al(2)O(3) closely matched the unique chromatographic selectivity of carbon phases, and as expected the retentivity was increased over C/ZrO(2). Excess carbon - the amount equivalent to 5 monolayers--was required to fully cover the oxide support in C/Al(2)O(3), but this was less excess than needed with C/ZrO(2). Plate counts were 60,000-76,000/m for 5 MUm particles. Spectroscopic studies (XPS and FT-IR) were also conducted; they showed that the two materials were chemically very similar. PMID- 20850128 TI - Electrophoretic deposition of TiO2 and composite TiO2-MnO2 films using benzoic acid and phenolic molecules as charging additives. AB - Electrophoretic deposition (EPD) method has been developed for the fabrication of TiO(2) and MnO(2) films. Benzoic acid and phenolic molecules, such as 4 hydroxybenzoic acid, 3,5-dihydroxybenzoic acid, gallic acid, salicylic acid and salicylic acid sodium salt were investigated as charging additives for the EPD of TiO(2) and MnO(2) particles. The deposition yield has been studied as a function of the additive concentration and deposition time for cathodic deposits obtained from the suspensions, containing benzoic acid, 4-hydroxybenzoic acid, 3,5 dihydroxybenzoic acid and anodic deposits prepared from the suspensions, containing gallic acid and salicylic acid sodium salt. The results obtained for the phenolic molecules with different number of OH groups were analyzed and compared with corresponding experimental data for benzoic acid without OH groups. The adjacent OH groups, as well as adjacent OH and COOH groups bonded to the aromatic ring of the phenolic molecules were beneficial for adsorption of the molecules on oxide particles. The adsorption mechanisms involved the interaction of COOH groups and OH groups of the organic molecules with metal ions on the particle surfaces and complexation. Gallic acid was shown to be an effective charging additive, which provided stabilization of TiO(2) and MnO(2) particles in the suspensions and enabled their deposition. It was shown that composite TiO(2) MnO(2) films can be obtained using gallic acid as a common dispersing agent for TiO(2) and MnO(2). The Ti/Mn ratio in the composite films was varied in the range of 0-1.3. The thickness of the films was varied in the range of 0-10 MUm. The mechanisms of particle charging and deposition were discussed. PMID- 20850129 TI - Physicochemical studies on the interaction of serum albumin with pulmonary surfactant extract in films and bulk bilayer phase. AB - Functionality, structure and composition of the adsorbed films of bovine lipid extract surfactant (BLES), in the absence and presence of bovine serum albumin (BSA), at the air-buffer interface was characterized through surface tension, atomic force microscopy and time of flight secondary ion mass spectrometric methods. Gel and fluid domains of BLES films were found to be altered significantly in the presence of BSA. Differential scanning calorimetric studies on BLES dispersions in presence of BSA revealed that the perturbations of the lipid bilayer structures were significant only at higher amount of BSA. FTIR studies on the BLES dispersions in buffer solution revealed that BSA could affect the lipid head-group hydrations in bilayer as well as the methylene and methyl vibration modes of fatty acyl chains of the phospholipids present in BLES. Serum albumin could perturb the film structure at pathophysiological concentration while higher amount of BSA was required in perturbing the bilayer structures. The studies suggest a connected perturbed bilayer to monolayer transition model for surfactant inactivation at the alveolar-air interface in dysfunctional surfactants. PMID- 20850130 TI - Role of hydration and water coordination in micellization of Pluronic block copolymers. AB - Raman, attenuated total reflectance FTIR, near-infrared spectroscopy, and DFT calculations have been used in a study of aqueous solutions of three tri-block copolymers poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) or PEO PPO-PEO with commercial names Pluronic PE6200, PE6400 and F68. It is shown that the process of micellization as a response to increased temperature is reflected in the hydroxyl stretching region of infrared and Raman spectra, which contains information both about restructuring of water and changes of polymer chains in polymer/water aggregates. Raman spectra exhibit differences between individual Pluronics even at temperatures below the critical micellization temperature (CMT). According to the attenuated total reflection (ATR) FTIR spectra, the same five water coordination types defined by the number of donated/accepted hydrogen bonds are present in interacting water as in bulk water. It indicates that models considering mixed states of water with different hydrogen bonding environments provide appropriate descriptions of bound water both below and above the CMT. Above the CMT, aggregate hydration increases in the order PE6400 < PE6200 < F68, although that does not fully correspond to the EO/PO ratio, and points to the differences in microstructure of aggregates formed by each copolymer. This study relates nanoscale phenomena (hydrophobic and hydrophilic hydration) with the mesoscale phenomenon of micellization. PMID- 20850131 TI - Facile preparation of fluorescence-encoded microspheres based on microfluidic system. AB - The fluorescence-encoded microspheres were prepared by the simple and controllable microfluidic device for the first time. The polycaprolactone (PCL) microspheres were encoded with different quantum dots (QDs) at various ratios, and the fluorescence was decoded successfully. The designed fluorescence encoding method was easily manipulated, and generated the uniform microspheres with different size. This research demonstrated a very facile and promising technique for fluorescence encoding over traditional methods. PMID- 20850132 TI - Adsorption of surfactant-rich stickies onto mineral surfaces. AB - "Stickies" are tacky species, present in recycled paper and coated broke, derived from coating formulations, adhesives etc. They impact negatively on paper quality and cause web runnability problems by deposit build-up. To sustain recycling, stickies are controlled by adsorbing them onto minerals added to the recycled stock. We report isotherms for a fatty acid ester defoamer and an acrylic acid ester copolymer adsorbing from colloidal suspension onto various talcs and modified calcium carbonates. We used commercial preparations of the fatty acid ester defoamer and acrylic acid ester copolymer to provide a simple analogue to the industrial process. The modified calcium carbonates are hydrophilic with anionic and cationic sites present. Adsorption isotherms for low surface area modified calcium carbonate conform to the Langmuir model, while those for high surface area modified calcium carbonate reflect a two stage process involving the formation of a monolayer over the mineral surface and subsequent partial aggregation. Talc platelets display hydrophilic edges and hydrophobic surfaces. Adsorption onto them appears to involve three stages; specifically, a hydrophilic interaction between hydrophilic groups on the molecules and the talc edges, followed by hydrophobic interactions between the molecules and the talc surfaces, and finally by formation of multilayers. PMID- 20850133 TI - Effect of an antioxidant drink on homocysteine levels in Alzheimer's patients. AB - BACKGROUND: A large body of evidence supports a role of oxidative stress in Alzheimer disease (AD) and in cerebrovascular disease. Blood levels of homocysteine may be increased in AD and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, plasma total homocysteine (tHcy) concentration may be influenced by administration of polyphenols. OBJECTIVE: To determine the effect of an antioxidant beverage rich in polyphenols on the plasmatic levels of tHcy in Alzheimer's patients. DESIGN, SETTING, AND PATIENTS: A multicenter, randomized, double-blind controlled clinical trial of polyphenols supplementation in 100 subjects (52 of control group, 24 AD patients in initial phase and 24 AD patients in moderate phase) (Mini-Mental State Examination scores between 14 and 26, inclusive). Fasting plasma concentrations of tHcy, folate and vitamin B(12) were measured before (Ti) and after (Tf) the ingestion of the beverage. The study was conducted at clinical research places of the Catholic University San Antonio and University Hospital Virgen de la Arrixaca of Murcia (Spain). INTERVENTION: Participants of the three groups were randomly assigned to 2 groups of the same size: 50% treated with antioxidant beverage rich in polyphenols and 50% treated with an identical placebo beverage. Subjects consumed 1 brick (200 mL/day) of antioxidant drink or placebo drink for 8 months. RESULTS: Higher tHcy levels were observed in the AD moderate phase patients (Ti:12.65+/-1.21 MUmol/L) than in the AD initial phase patients (Ti:9.13+/-1.24 MUmol/L) and in the control group (Ti:9.86+/-0.77 MUmol/L). Lower folate levels were observed in the AD moderate phase patients (Ti:8.20+/-1.29 ng/mL) than in the AD initial phase patients (Ti:9.41+/-1.56 ng/mL) and in the control group (Ti:12.32+/-0.67 ng/mL). Antioxidant drink vs placebo drink attenuated the tHcy increase in the control group (Tf values of 11.74+/-0.45 vs 15.63+/-1.79 MUmol/L) and AD patients, especially in the moderate phase (Tf: 10.49+/-0.73 vs 16.58+/-2.73 MUmol/L). CONCLUSIONS: The regular ingestion of polyphenols contained in an antioxidant beverage may decrease tHcy plasmatic concentrations in Alzheimer's patients. PMID- 20850134 TI - Cerebral microbleeds and vascular cognitive impairment. AB - MRI manifestations of small vessel diseases including white matter hyperintensities and lacunes have been recognized as potential substrates of vascular cognitive impairment for many years. Cerebral microbleeds (CMBs)--small, perviascular haemorrhages seen as small, well-demarcated, hypointense, rounded lesions on MRI sequences sensitive to magnetic susceptibility effects--are also now recognized as an imaging marker for small vessel pathology, but their clinical impact on cognition remains uncertain. CMBs are present in about a third of patients with ischaemic stroke, and in a high proportion of patients with Alzheimer's disease, cerebral amyloid angiopathy, and vascular dementia. They have also been increasingly found in normal elderly populations, particularly using sequences optimized for their detection. Some recent studies have suggested an effect of CMBs on cognition, which could relate directly to focal damage to or dysfunction of adjacent brain tissues; alternatively, CMBs may be a more general marker for the severity of small vessel pathology related to hypertension or cerebral amyloid angiopathy. CMBs may therefore play a role in understanding the underlying mechanisms of vascular cognitive impairment, in diagnosis, and in assessing its severity and prognosis; this review considers recent evidence on this topic. PMID- 20850135 TI - Posterior reversible encephalopathy syndrome following measles vaccination. AB - Due to recent domestic measles outbreaks in Japan, the Japanese government has mandated measles vaccination at ages 14 and 17 since April 2008. Since then, the number of people receiving measles vaccination has increased in Japan. Measles vaccination may cause serious neurological complications including encephalopathy, although the incidence is very low. We report here an adult case of posterior reversible encephalopathy syndrome (PRES) and myeloradiculoneuropathy following measles vaccination. Brain MRI demonstrated typical findings of PRES, high intensity signals in the occipital lobes on FLAIR imaging, isointensity signals on diffusion weighted imaging, with an increase in the apparent diffusion coefficient (ADC). Vasoconstriction mainly in the posterior cerebral arteries was detected by MRA. Physicians should keep in mind the possible occurrence of PRES and myeloradiculoneuropathy following measles vaccination. PMID- 20850136 TI - Neuroanatomical and neuropsychological features of elderly euthymic depressed patients with early- and late-onset. AB - BACKGROUND: Whether or not cognitive impairment and brain structure changes are trait characteristics of late-life depression is still disputed. Previous studies led to conflicting data possibly because of the difference in the age of depression onset. In fact, several lines of evidence suggest that late-onset depression (LOD) is more frequently associated with neuropsychological deficits and brain pathology than early-onset depression (EOD). To date, no study explored concomitantly the cognitive profile and brain magnetic resonance imaging (MRI) patterns in euthymic EOD and LOD patients. METHOD: Using a cross-sectional design, 41 remitted outpatients (30 with EOD and 11 with LOD) were compared to 30 healthy controls. Neuropsychological evaluation concerned working memory, episodic memory, processing speed, naming capacity and executive functions. Volumetric estimates of the amygdala, hippocampus, entorhinal and anterior cingulate cortex were obtained using both voxel-based and region of interest morphometric methods. White matter hyperintensities were assessed semiquantitatively. RESULTS: Both cognitive performance and brain volumes were preserved in euthymic EOD patients whereas LOD patients showed a significant reduction of episodic memory capacity and a higher rate of periventricular hyperintensities compared to both controls and EOD patients. CONCLUSION: Our results support the dissociation between EOD thought to be mainly related to psychosocial factors and LOD that is characterized by increasing vascular burden and episodic memory decline. PMID- 20850137 TI - Neuroimaging in Susac's syndrome: focus on DTI. AB - BACKGROUND: Susac's syndrome is an underdiagnosed disease that is thought to occur mainly in young women. It is characterized by the triad of hearing loss, branch retinal artery occlusions, and encephalopathy with predominantly cognitive and psychiatric symptoms. Treatment consists of immunosuppressive therapy. Focal ischemic lesions in the central portion of the corpus callosum detectable by conventional MRI ("snowballs") are a typical feature of Susac's syndrome. The appearance of these lesions is not, however, correlated with the type and severity of the neuropsychological deficits. METHODS: Nine patients with Susac's syndrome, four men and five women, were investigated using Diffusion Tensor Imaging (DTI), a non-invasive technique for the detection of macro- and microstructural impairment of fiber integrity on the basis of normal values for the fractional anisotropy (FA). Patients were compared to a group of 83 healthy controls on a voxel-by-voxel basis. Several regions of interest were defined. RESULTS: Impairment of fiber integrity was found in every patient. As compared to the controls, every patient showed disruption of fiber integrity in the genu of the corpus callosum. Reduction of FA was found particularly in the prefrontal white matter. CONCLUSION: The type and severity of the encephalopathic symptoms in Susac's syndrome are much better represented by the prefrontal FA reductions detected by DTI than by the mostly sparse white matter abnormalities seen on conventional MRI. The fiber damage in the genu seems to be specific for patients with Susac's syndrome. PMID- 20850138 TI - Capillary CAA and perivascular Abeta-deposition: two distinct features of Alzheimer's disease pathology. AB - Cerebral amyloid angiopathy (CAA) is frequently seen in Alzheimer's disease (AD) cases and represents one of its histopathological hallmarks. CAA is characterized by amyloid beta-protein (Abeta) deposits within vessel walls. In addition to arteries and veins capillaries can also be affected. Abeta deposition into the capillary wall is, thereby, known as capillary CAA (capCAA) and strongly associated with the apolipoprotein E APOEepsilon4 allele as a risk factor. Abeta deposits along the pericapillary glia limitans are described as pericapillary Abeta (pericapAbeta: synonymous with pericapillary CAA in other studies). Here, we studied the relationship between pericapAbeta and capCAA in 58 human autopsy cases. Although pericapAbeta and capCAA were more frequently found in AD cases compared to controls and although they exhibited a correlation to one another, detailed analysis revealed that there is a significant number of cases with pericapAbeta lacking capCAA and vice versa. Moreover, single capillaries show either both pathologies or pericapAbeta or capCAA only. There was no local association between these pathologies when analyzing multiple capillaries in each given case. Moreover, pericapAbeta predominantly exhibited Abeta(42) whereas capCAA contained both Abeta(42) and Abeta(40). These differences as well as differences in the related astroglial reaction indicate that pericapAbeta and capCAA are not directly linked. PericapAbeta appears to represent initial Abeta accumulation along the glia limitans that is involved in the perivascular drainage of apoE and Abeta regardless of the APOE genotype whereas capCAA could be explained by a limited transendothelial clearance of apoE4-Abeta complexes compared to apoE2/3-Abeta complexes. PMID- 20850139 TI - Is endothelial dysfunction of cerebral small vessel responsible for white matter lesions after chronic cerebral hypoperfusion in rats? AB - Cerebral white matter (WM) lesions contribute to cognitive impairment and motor dysfunction in the elderly. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are two important adhesion molecules that are upregulated during endothelial activation. Data from recent studies have suggested that ICAM-1 levels are related to progression of white matter hyperintensities (WMH) on MRI. In the present study, we hypothesized that ICAM-1 and VCAM-1 are involved in the endothelial dysfunction and the subsequent WM lesions after chronic cerebral hypoperfusion. Rats underwent bilateral common carotid artery ligation. They were divided into the lipoic acid group and the saline (vehicle) group. RT-PCR and double immunofluorescence for ICAM-1, VCAM-1, endothelial cells (staining positive for von Willebrand factor, vWF), reactive astrocytes (GFAP staining) and activated microglia/macrophages/(CD11b/c staining) were analyzed at baseline and at 1, 3, 7, 14 and 28 days after hypoperfusion. The severity of the WM lesions in the corpus callosum, internal capsule, and external capsule of both hemispheres was graded by luxol fast blue staining. RT-PCR and double immunofluorescence analysis of white matter from rats that had received lipoic acid (100mg/kg/day) for 28 days exhibited markedly reduced expression of ICAM-1 and VCAM-1 over endothelial cells compared with that of rats receiving saline. In the rats treated with lipoic acid, the WM lesions after chronic cerebral hypoperfusion were significantly less severe, and the number of reactive astrocytes and activated microglia/macrophages (CD11b/c staining) were also significantly lower as compared with the saline-treated rats. These findings indicate that endothelial dysfunction plays a critical role in overexpression of ICAM-1 and VCAM-1, glial cell activation and WM lesions after chronic cerebral hypoperfusion and suggest the potential value of lipoic acid as a therapeutic tool in cerebrovascular WM lesions. Our results also provide support for endothelial activation being involved in early pathogenesis of WM lesions and suggest that therapies that stabilize the endothelium may have a role in preventing WM lesions progression. PMID- 20850141 TI - Leaflet suspension to the contralateral annulus to address restriction or tethering-induced mitral and tricuspid regurgitation in children: results of a case-control study. AB - OBJECTIVES: Acceptable coaptation cannot always be obtained using standard repair techniques. We assessed the safety and mid-term results using a novel technique to address leaflet retraction or tethering in children with type III mitral or tricuspid regurgitation as an addition to standard valve repair techniques. METHODS: Forty children were included, 36 for the mitral valve and 4 for the tricuspid valve, with a mean age of 11.3 +/- 3.9 years. A polypropylene suture was placed on the free edge of the retracted or tethered leaflet segment and anchored to the atrial side of the opposite annulus. This avoided valve replacement in all patients. An additional 40 children were matched for age, etiology, leaflet retraction or tethering, and surgery in which the suspension stitch was not used and constituted the control group. RESULTS: The mean aortic crossclamp and cardiopulmonary bypass time was 36 +/- 9 and 57 +/- 9 minutes, respectively. No early or late deaths occurred. At discharge, no patient had more than mild regurgitation with a gradient of 4.4 +/- 2.4 mm Hg in the mitral position and 2 +/- 1.75 mm Hg in the tricuspid position. The results were not significantly different than those of the control group. During a follow-up of 37.7 +/- 18.4 months, 3 patients required reoperation for mitral valve replacement in the suspension stitch group and 2 within the control group. At echocardiography of the remaining patients, the repair remained stable, with no suspension suture breakage. CONCLUSIONS: This suspension technique improved coaptation and resulted in avoidance or delay of valve replacement in patients with type III regurgitation, with an acceptable transvalvular gradient in most patients that did not significantly increase with growth. PMID- 20850143 TI - Precise evaluation of bilateral pulmonary artery banding for initial palliation in high-risk hypoplastic left heart syndrome. AB - OBJECTIVES: In patients with high-risk hypoplastic left heart syndrome (HLHS), the Norwood operation (NW) in the neonatal period still results in high mortality compared with other cardiac surgery. Bilateral pulmonary artery banding (bPAB), a very effective initial procedure for HLHS, for which the specific evaluation is as yet unsatisfactory, was performed, and we report our findings in the present study. METHODS: We have performed bPAB since 2006. A total of 17 patients with HLHS or a variant underwent bPAB before the NW. Echocardiography was performed between bPAB and the NW, and the flow acceleration just after bPAB and before NW was evaluated. Before the NW, a catheter examination was also performed. RESULTS: bPAB was performed at 6.6 +/- 0.6 days of age, and the NW at 130 +/- 88 days. The patients' mean body weight (BW) was 2.5 +/- 0.4 kg at bPAB and 4.0 +/- 1.1 kg at the NW. The length of the tape for bPAB was 9.9 +/- 0.6 mm in the right pulmonary artery (RPA) and 9.4 +/- 0.6 mm in the left (LPA) because the RPA was usually wider than the LPA. The tape width was 2 mm in all cases. The catheter examination was performed at 95 +/- 85 days after bPAB. The arterial oxygen saturation (SaO2) was 71% +/- 8.6%. Multivariate regression analysis revealed that SaO2 was estimated well using 4 factors: the banding size of the RPA, BW at bPAB, BW at NW, and BW in the period between bPAB and catheter examination (R2 = 0.79). Echocardiography just after bPAB showed that the blood flow at the bPAB had accelerated to 3.0 +/- 0.8 m/s in the RPA and 3.3 +/- 0.8 m/s in the LPA (P = .004). The estimated pressure gradient was 39.2 +/- 17.6 mm Hg in the RPA and 46.1 +/- 23.0 mm Hg in the LPA (P = .006). The blood flow at bPAB was accelerated to 3.7 +/- 0.7 m/s in the RPA and 4.0 +/- 0.6 m/s in the LPA before NW (P = .013). The estimated pressure gradient was 62.6 +/- 27.6 mm Hg in the RPA and 56.1 +/- 19.6 mm Hg in the LPA before NW (P = .014). The catheter examination revealed mean wedge pressures of 18.0 +/- 7.2 mm Hg for the RPA and 16.2 +/- 4.3 mm Hg for the LPA. The operative mortality rate was 0%. One patient required a repeat operation to adjust the bPAB, and prolonged pleural effusion was observed in 1 case. CONCLUSIONS: The postoperative SaO2 after bPAB correlated closely with the banding size and BW at bPAB, NW and during the period after bPAB. Because the mean PA pressure before NW was low enough for single ventricular circulation, the bPAB in this study was an effective option for high-risk patients undergoing HLHS or a variant. We believe the bPAB sizes used were suitable and were determined as follows: BW plus 7 mm for the LPA and BW plus 7.5 mm for the RPA. PMID- 20850144 TI - Determinants of outcome after surgical treatment of pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. AB - OBJECTIVES: Identification of variables influencing surgical outcome in patients treated for pulmonary atresia with ventricular septal defect and major aortopulmonary collateral arteries. METHODS: A total of 90 consecutive patients (median age, 12 months; range, 20 days to 35 years), who had primarily undergone either 1-stage unifocalization (n = 69) or palliation to promote native pulmonary arterial development (n = 21), were studied. Chromosome 22q11 deletion had occurred in 37% of the cases. Ventricular septal defect closure was accomplished in 70 patients (78%), with a mean postoperative right/left ventricular pressure ratio of 0.48 +/- 0.14. RESULTS: The rate of 14-year survival, freedom from conduit reintervention, and freedom from percutaneous intervention on the pulmonary arteries was 75%, 46%, and 52%, respectively. At a median interval of 95 months (range, 1.5-164 months), the right/left ventricular pressure ratio did not differ significantly from early postoperatively. Univariate analysis showed that an absence of confluent intrapericardial pulmonary arteries favorably affected the postoperative right/left ventricular pressure ratio after ventricular septal defect closure (P = .04). Kaplan-Meier estimates showed age of 30 days or younger (P = .0004) and weight of 3 kg or less (P = .0004) at unifocalization and chromosome 22q11 deletion (P = .001) significantly affected survival. Chromosome 22q11 deletion was significantly associated with mortality, even in the Cox regression model (hazard ratio, 8.26; P = .003). Finally, ventricular septal defect closure during single-stage and single/multiple-stage procedures significantly correlated with both early (P = .0013 and P < .00001, respectively) and overall (P = .013 and P = .0007, respectively) survival. CONCLUSIONS: The results of surgery were satisfactory and durable, despite the need for repeated percutaneous or surgical reinterventions. The outcomes were negatively affected by neonatal age and low body weight and positively affected by simultaneous or staged ventricular septal defect closure. Finally, chromosome 22q11 deletion remained an independent variable affecting survival. PMID- 20850146 TI - Histopathological predictors of renal function decrease after laparoscopic radical nephrectomy. AB - PURPOSE: Radical nephrectomy is inevitably associated with a variable renal function decrease. We assessed the association of histopathological parameters in nonneoplastic renal parenchyma with the renal function decrease after radical nephrectomy. MATERIALS AND METHODS: We evaluated 32 male and 17 female patients with a mean age of 55.9 years who underwent laparoscopic radical nephrectomy. Using the Cockcroft-Gault formula we calculated the estimated glomerular filtration rate preoperatively and at last followup at a mean of 19.7 months. The study end point was the percent change in the estimated glomerular filtration rate from baseline, defined as (absolute change/baseline) * 100. Three histological features in the nonneoplastic parenchyma were assessed by a renal pathologist, including global glomerulosclerosis, arteriosclerosis and interstitial fibrosis/tubular atrophy. For glomerulosclerosis assessment the percent of affected glomeruli was determined. Arteriosclerosis or the extent of arterial luminal occlusion was graded into 4 groups, including 1-0% to 5%, 2-6% to 25%, 3-26% to 50% and 4-greater than 50%. However, due to small patient numbers groups 1 and 2, and 3 and 4 were condensed, and AS was statistically evaluated as 0% to 25% or greater than 25%. Interstitial fibrosis/tubular atrophy was evaluated as absent/present. RESULTS: The mean estimated glomerular filtration rate decreased 31% from 122 to 85 ml/minute/1.73 m(2) after surgery (p < 0.0001). The percent change in the estimated glomerular filtration rate was associated with glomerulosclerosis extent (p = 0.034). For each 10% increase in glomerulosclerosis the estimated glomerular filtration rate decreased by 9% from baseline. The extent of arteriosclerosis or the presence of interstitial fibrosis/tubular atrophy did not correlate with the estimated glomerular filtration rate decrease. CONCLUSIONS: Glomerulosclerosis severity in nonneoplastic parenchyma can predict the rate of renal function decrease after radical nephrectomy. This histopathological parameter should be assessed in all tumor nephrectomy specimens, given that preserving renal function is important for quality of life and clinical outcome in patients with renal cancer. PMID- 20850147 TI - Editorial comment. PMID- 20850148 TI - Percutaneous biopsy of primary tumor in metastatic renal cell carcinoma to predict high risk pathological features: comparison with nephrectomy assessment. AB - PURPOSE: As treatment options evolve for metastatic renal cell carcinoma, there is a need for predictive information to help guide therapy. We assessed the accuracy of percutaneous primary tumor biopsy for metastatic renal cell carcinoma by comparing biopsy findings to final nephrectomy pathology in patients undergoing cytoreductive nephrectomy. MATERIALS AND METHODS: Using an institutional database we reviewed the records of patients who underwent percutaneous primary tumor biopsy before cytoreductive nephrectomy. In patients who underwent biopsy elsewhere pathology findings were re-reviewed at our institution. Differences in accuracy based on biopsy technique, imaging modality and biopsy period were determined by chi-square analysis. RESULTS: We identified 166 patients who underwent percutaneous biopsy of the primary tumor before cytoreductive nephrectomy between 1991 and 2007, and had data available for review. Median pathological tumor size was 9.1 cm (range 3 to 32). Median time from biopsy to surgery was 46 days (range 6 to 717). Of 104 patients in whom biopsy was assigned a Fuhrman nuclear grade 33 (31.7%) had the same grade in the nephrectomy specimen, including 74 of 109 (67.9%) when considering only high or low grade. Grade change by more than 2 points was seen in 18 of 104 patients (17.3%). Sarcomatoid features were present in 34 of 166 nephrectomy specimens (20.5%) but only 4 (11.8%) were identified preoperatively. CONCLUSIONS: In patients with metastatic renal cell carcinoma percutaneous renal biopsy has poor accuracy to assess Fuhrman nuclear grade or sarcomatoid features. Physicians should use caution when using biopsy data to guide therapy. PMID- 20850149 TI - Should the patient with positive margins after radical prostatectomy receive adjuvant radiation? PMID- 20850150 TI - Editorial comment. PMID- 20850151 TI - Editorial comment. PMID- 20850152 TI - Hexaminolevulinate guided fluorescence cystoscopy reduces recurrence in patients with nonmuscle invasive bladder cancer. AB - PURPOSE: We assessed the impact that improved detection of nonmuscle invasive bladder cancer with hexaminolevulinate fluorescence cystoscopy may have on early recurrence rates. MATERIALS AND METHODS: This prospective, randomized study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence. All patients underwent white light cystoscopy and mapping of lesions, followed by transurethral resection of the bladder when indicated. Patients in the fluorescence group also received intravesical hexaminolevulinate solution at least 1 hour before cystoscopy to induce fluorescence of cancerous lesions, and underwent additional inspection with blue light before and after transurethral resection of the bladder. Adjuvant intravesical therapy was based on risk. Followup cystoscopy at 3, 6 and 9 months was conducted with white light. RESULTS: Detection was performed as a within patient comparison in the fluorescence group. In this group 286 patients had at least 1 Ta or T1 tumor (intent to treat). In 47 patients (16%) at least 1 of the tumors was seen only with fluorescence (p = 0.001). During the 9-month followup (intent to treat) there was tumor recurrence in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the white light group (p = 0.026). The relative reduction in recurrence rate was 16%. CONCLUSIONS: Hexaminolevulinate fluorescence cystoscopy significantly improves the detection of Ta and T1 lesions and significantly reduces the rate of tumor recurrence at 9 months. PMID- 20850153 TI - PCA3 molecular urine test for predicting repeat prostate biopsy outcome in populations at risk: validation in the placebo arm of the dutasteride REDUCE trial. AB - PURPOSE: We determined the performance of PCA3 alone and in the presence of other covariates as an indicator of contemporaneous and future prostate biopsy results in a population with previous negative biopsy and increased serum prostate specific antigen. MATERIALS AND METHODS: Urine PCA3 scores were determined before year 2 and year 4 biopsies from patients in the placebo arm of the REDUCE trial, a prostate cancer risk reduction study evaluating men with moderately increased serum prostate specific antigen results and negative biopsy at baseline. PCA3, serum prostate specific antigen and percent free prostate specific antigen results were correlated with biopsy outcome via univariate logistic regression and ROC analyses. Multivariate logistic regression was also performed including these biomarkers together with prostate volume, age and family history. RESULTS: PCA3 scores were measurable from 1,072 of 1,140 subjects (94% informative rate). PCA3 scores were associated with positive biopsy rate (p <0.0001) and correlated with biopsy Gleason score (p = 0.0017). PCA3 AUC of 0.693 was greater than serum prostate specific antigen (0.612, p = 0.0077 vs PCA3). The multivariate logistic regression model yielded an AUC of 0.753 and exclusion of PCA3 from the model decreased AUC to 0.717 (p = 0.0009). PCA3 at year 2 was a significant predictor of year 4 biopsy outcome (AUC 0.634, p = 0.0002), whereas serum prostate specific antigen and free prostate specific antigen were not predictive (p = 0.3281 and 0.6782, respectively). CONCLUSIONS: PCA3 clinical performance was validated in the largest repeat biopsy study to date. Increased PCA3 scores indicated increased risk of contemporaneous cancers and predicted future biopsy outcomes. Use of PCA3 in combination with serum prostate specific antigen and other risk factors significantly increased diagnostic accuracy. PMID- 20850155 TI - Editorial comment. PMID- 20850156 TI - Editorial comment. PMID- 20850157 TI - Application of bioassays in toxicological hazard, risk and impact assessments of dredged sediments. AB - Given the potential environmental consequences of dumped dredged harbour sediments it is vital to establish the potential risks from exposure before disposal at sea. Currently, European legislation for disposal of contaminated sediments at sea is based on chemical analysis of a limited number of well-known contaminants for which maximum acceptable concentrations, action levels (ALs), have been set. The present paper addresses the issue of the applicability of in vitro and in vivo bioassays for hazard, risk and local impact assessment of dredged polluted sediments to be disposed of at sea. It discusses how and to what extent selected bioassays can fill in the gaps left open by chemical analysis and the way in which the bioassays may contribute to the present licensing system for disposal. Three different purposes for application were distinguished: the most basic application (A) is a rapid determination of the hazard (potential toxicity) of dredged sediments which is then compared to ALs in a licensing system. As with chemical analysis on whole sediment extracts, the bioavailability of the chemicals is not taken into account. As in vitro assays with sediment extracts are not sensitive to matrix effects, a selection of specific in vitro bioassays can be suitable fast and standardized additions for the licensing system. When the outcome of (A) does not convincingly demonstrate whether the sediment is clean enough or too polluted, further bioanalysis can help the decision making process (B). More aspects of the mostly unknown complex chemical mixtures are taken into account, including the bioavailability and chronic toxicity focusing on ecologically relevant endpoints. The ecotoxicological pressure imposed by the dredged sediments can be quantified as the potentially affected fraction (PAF) based on chemical or biological analysis of levels of contaminants in sediment or biota. To validate the predicted risk, the actual impact of dumped harbour sediments on local ecosystems (C) can be determined using a dedicated set of in vitro and in vivo bioassays as well as bio-indicators selected based on the information obtained from (A) and (B) and on the characteristics of the local ecosystem. Conversely, the local sediment impact assessment (C) can direct fine tuning of the selection of chemical and bioassay analyses and for setting safe levels in the licensing system. It is concluded that in vitro and in vivo bioassays and biological indicators are useful tools in the process of hazard, ecotoxicological risk and impact assessment of dredged harbour sediments, provided they are consciously chosen and quality criteria for assay performance are defined. PMID- 20850158 TI - Misclassification of subjects with insulin resistance and associated cardiovascular risk factors by homeostasis model assessment index. Utility of a postprandial method based on oral glucose tolerance test. AB - Different methods are available for assessing insulin sensitivity in the fasting state. However, insulin resistance (IR) is initially a postprandial disturbance; and usually, when basal (fasting) disturbance appears, the process has been in progress for some time. Our aim was to investigate if a postprandial measurement, performing an oral glucose tolerance test (OGTT), is more sensitive than fasting values. We wished to identify early IR states in healthy, nonobese individuals and ascertain if this situation was associated with other cardiovascular risk factors. A total of 90 nonobese, nondiabetic, and nonsmoker individuals were studied. They were divided into 3 groups according to IR state--group 1: non-IR- homeostasis model assessment of IR (HOMA(IR)) and insulin sensitivity index of Matsuda-De Fronzo (ISI-Mat) were normal (HOMA(IR) <3.2 and ISI-Mat >4.0); group 2: with IR post-OGTT (ISI-Mat <=4.0 and HOMA(IR) <3.2); and group 3: subjects with IR in basal conditions (HOMA(IR) >=3.2). An intravenous glucose tolerance test to compare both indices was also performed. In 14.4% of subjects, the fasting HOMA(IR) values failed to identify IR (false-negative results). The ISI Mat values were better correlated than HOMA(IR) (r = 0.875, P = .0001 and r = 0.631, P = .0001, respectively) with insulin sensitivity index obtained with intravenous glucose tolerance test. Subjects with IR had higher prevalence of a cluster of cardiovascular risk factors than non-IR subjects. These data show that that a significant percentage of subjects were misclassified with HOMA(IR). Early identification of IR by OGTT was associated with other cardiovascular risk factors. The OGTT is a simple method that could be applied to accurately identify IR subjects in the general population. PMID- 20850159 TI - Resveratrol and genistein as adenosine triphosphate-depleting agents in fat cells. AB - Resveratrol and genistein are plant-derived compounds known to exert pleiotropic effects in many cell types, including adipocytes. However, the effects of these compounds on the energetic status of fat cells are unknown. The present study aimed to determine whether resveratrol and genistein influence adenosine triphosphate (ATP) levels in freshly isolated rat adipocytes. To determine the effects of resveratrol and genistein on adipocyte ATP content, cells were exposed to insulin and glucose or insulin and alanine without tested compounds or with 6.25 to 50 MUmol/L resveratrol or genistein. Resveratrol substantially reduced glucose- and alanine-derived ATP in adipocytes. This was not due to the inhibition of glucose transport because the influence of the test compound on insulin-stimulated glucose uptake by adipocytes appeared to be stimulatory. Moreover, resveratrol reduced both alanine oxidation and mitochondrial membrane hyperpolarization. It was also demonstrated that preincubation of cells with resveratrol slightly diminished ATP levels despite the withdrawal of the tested compound from the buffer. The genistein effect was accompanied by attenuation of the mitochondrial membrane hyperpolarization. The compound failed to significantly affect insulin-stimulated glucose uptake by fat cells. Similarly to resveratrol, preincubation of adipocytes with genistein slightly reduced ATP in cells exposed to glucose and insulin. Results of the present study revealed the potent ability of resveratrol to reduce ATP in rat adipocytes, whereas genistein appeared to be less effective. It is suggested that both tested compounds diminish adipocyte ATP via attenuation of the metabolic activity of mitochondria. Because numerous cellular events are strongly ATP dependent, the ATP-depleting effects of resveratrol and genistein may have pleiotropic consequences for adipocyte functions. PMID- 20850160 TI - Dimeric antioxidant and cytotoxic triterpenoid saponins from Terminalia ivorensis A. Chev. AB - Three saponins, including two dimeric triterpenoid glucosides possessing an unusual skeleton, ivorenosides A and B, and a monomeric triterpenoid saponin (ivorenoside C), together with the known sericoside, were isolated from the bark of Terminalia ivorensis. Their structures were established on the basis of 1D and 2D NMR data, chemical methods and tandem MS-MS spectrometry as a dimer of beta-D glucopyranosyl-18,19-seco-2alpha,3beta,19,19,24-pentahydroxyolean-12-en-28-oate and beta-D-glucopyranosyl-2alpha,3beta,19alpha,24-tetrahydroxyolean-12-en-28-oate (ivorenoside A, 1), a dimer of beta-D-glucopyranosyl-18,19-seco-24-carboxyl 2alpha,3beta,19,19-tetrahydroxyolean-12-en-28-oate and beta-D-glucopyranosyl 2alpha,3beta,19alpha,24-tetrahydroxyolean-12-en-28-oate (ivorenoside B, 2) and beta-D-glucopyranosyl-2alpha,3beta,19beta,24-tetrahydroxyolean-11-oxo-olean-12-en 28-oate (ivorenoside C, 3). Ivorenosides A and B are the first examples in nature of dimeric triterpenoid saponins with a 18,19-seco E ring of one of the two units. These isolated compounds were evaluated for their antioxidant properties and further for their cytotoxic activity against four human cancer cell lines. Ivorenoside B and C exhibited scavenging activity against DPPH and ABTS(+) radicals with IC(50) values comparable with that of the standard drug Trolox and ivorenoside A showed antiproliferative activity against MDA-MB-231 and HCT116 human cancer cell lines with IC(50) values of 3.96 and 3.43 MUM, respectively. PMID- 20850161 TI - Efficacy and safety of chloroquine for treatment in patients with uncomplicated Plasmodium vivax infections in endemic countries. AB - Chloroquine (CQ) is a relatively inexpensive drug for treatment of malaria. If efficacy of CQ is still assumed, then it should be indicated in malaria treatment policies as the drug of choice for uncomplicated Plasmodium vivax malaria in endemic countries with resource constraints. The objective of this review is to summarize the existing evidence on the relative efficacy and safety of CQ in treating patients with uncomplicated P. vivax malaria in endemic countries. We searched online data bases (PUBMED, MEDLINE, EMBASE, The Cochrane Library) and the reference lists of the retrieved articles. Fifteen randomized controlled trials (n=6215) assessing the relative efficacy and safety of CQ for treatment of uncomplicated P. vivax malaria were included. CQ monotherapy was compared to CQ plus primaquine (PQ), artemisinin/artemether, artemisinin based combination therapy, quinine, CQ plus tafenoquine, chlorguanil plus dapsone, azithromycin, or placebo. Treatment efficacy was not significantly different between the CQ monotherapy group and that of the CQ with PQ 14 day group at 28 day follow-up (55/711, 7.7% vs 35/712, 4.9%; P=0.16). Evidence from the trials identified for this review draw a fairly clear conclusion about the relative efficacy and safety of CQ for treating uncomplicated P. vivax malaria infection. However, further research in this field with well powered, randomized, non-inferiority design, using the standardized protocol is needed. PMID- 20850162 TI - A simple and general method for determining the protein and nucleic acid content of viruses by UV absorbance. AB - UV spectra of viruses are complicated by overlapping protein and RNA absorbance and light scattering. We describe and validate methodology for estimating RNA and protein concentration from such spectra. Importantly, we found that encapsidation did not substantially affect RNA absorbance. Combining absorbance data with a known T number, we confirmed that brome mosaic virus packages about 3100 nucleotides/capsid, consistent with its genome. E. coli-expressed hepatitis B virus (HBV) packages host RNA based on capsid charge and volume. We examined HBV capsid protein (Cp183, +15 charge) and a less basic mutant (Cp183-EEE, +12 charge) that mimics a phosphorylated state. Cp183-EEE packaged ~3450 nucleotides per T=4 capsid and Cp183 packaged ~4800 nucleotides, correlating to the size of HBV's RNA pre-genome and mature DNA genome, respectively. The RNA:protein charge ratio (about 1.4 phosphates per positive charge) was consistent with that of other ssRNA viruses. This spectroscopic method is generalizable to any virus-like particle. PMID- 20850163 TI - Functional characterization of Kaposi's sarcoma-associated herpesvirus small capsid protein by bacterial artificial chromosome-based mutagenesis. AB - A systematic investigation of interactions amongst KSHV capsid proteins was undertaken in this study to comprehend lesser known KSHV capsid assembly mechanisms. Interestingly the interaction patterns of the KSHV small capsid protein, ORF65 suggested its plausible role in viral capsid assembly pathways. Towards further understanding this, ORF65-null recombinant mutants (BAC-?65 and BAC-stop65) employing a bacterial artificial chromosome (BAC) system were generated. No significant difference was found in both overall viral gene expression and lytic DNA replication between stable monolayers of 293T-BAC36 (wild-type) and 293T-BAC-ORF65-null upon induction with 12-O-tetradecanoylphorbol 13-acetate, though the latter released 30-fold fewer virions to the medium than 293T-BAC36 cells. Sedimentation profiles of capsid proteins of ORF65-null recombinant mutants were non-reflective of their organization into the KSHV capsids and were also undetectable in cytoplasmic extracts compared to noticeable levels in nuclear extracts. These observations collectively suggested the pivotal role of ORF65 in the KSHV capsid assembly processes. PMID- 20850164 TI - Nonstructural protein 1alpha subunit-based inhibition of NF-kappaB activation and suppression of interferon-beta production by porcine reproductive and respiratory syndrome virus. AB - Induction of type I interferon (IFN-alpha/beta) is an early antiviral response of the host, and porcine reproductive and respiratory syndrome virus (PRRSV) has been reported to downregulate the IFN response during infection in cells and pigs. We report that the PRRSV nonstructural protein 1alpha (Nsp1alpha) subunit of Nsp1 is a nuclear-cytoplasmic protein distributed to the nucleus and contains a strong suppressive activity for IFN-beta production that is mediated through the retinoic acid-inducible gene I (RIG-I) signaling pathway. Nsp1alpha suppressed the activation of nuclear factor (NF)-kappaB when stimulated with dsRNA or tumor necrosis factor (TNF)-alpha, and NF-kappaB suppression was RIG-I dependent. The suppression of NF-kappaB activation was associated with the poor production of IFN-beta during PRRSV infection. The C-terminal 14 amino acids of the Nsp1alpha subunit were critical in maintaining immunosuppressive activity of Nsp1alpha for both IFN-beta and NF-kappaB, suggesting that the newly identified zinc finger configuration comprising of Met180 may be crucial for inhibitory activities. Nsp1alpha inhibited IkappaB phosphorylation and as a consequence NF kappaB translocation to the nucleus was blocked, leading to the inhibition of NF kappaB stimulated gene expression. Our results suggest that PRRSV Nsp1alpha is a multifunctional nuclear protein participating in the modulation of the host IFN system. PMID- 20850165 TI - The pathogenesis of Rift Valley fever virus in the mouse model. AB - Detailed studies describing the pathogenesis of Rift Valley fever (RVF) virus (RVFV) in the mouse model are lacking. A fully characterized small animal model of RVF is needed to evaluate potential vaccines and therapeutics. In this study, we characterized the pathogenesis of RVFV throughout the disease course in mice. Infection produced high-titer viremia and demonstrated RVFV tropism for a variety of tissue and individual cell types. Overwhelming infection of hepatocytes, accompanied by apoptosis, was a major consequence of infection. The majority of mice died or were euthanatized between days 3 and 6 postinfection with severe hepatitis. The remaining mice effectively cleared virus from the liver and blood, but exhibited neuroinvasion and developed panencephalitis. In addition, we characterized a number of other virological, clinicopathological, and histopathological features of RVFV infection in mice. The mouse model therefore mimics both the acute-onset hepatitis and delayed-onset encephalitis that are dominant features of severe human RVF. PMID- 20850166 TI - The impact of cemented layers and hardpans on oxygen diffusivity in mining waste heaps: a field study of the Halsbrucke lead-zinc mine tailings (Germany). AB - This article reports fibre-optic oxygen measurements on a reactive mine waste heap located in the polymetallic sulphide mine district of Freiberg in south eastern Germany. The heaped material consists of sulphide-bearing tailings from a processing plant of a lead-zinc mine. Mine waste material was deposited in the water phase after separation of mining ores in a flotation process. The tailing impoundment is partly covered with coarse sand and topsoil. Oxygen profiles were monitored during one year at eleven locations showing different physical and mineralogical compositions. At each location a borehole was drilled where the optic sensors were installed at 2-5 different depths. After installation the oxygen profiles were monitored seven times during one year from 2006-2007 and three to five oxygen profiles at each location were obtained. Oxygen measurements were accompanied by physical, chemical and mineralogical data of the tailing material. Additionally, a detailed mineralogical profile was analysed at a location representative for the central part of the heap, where the cemented layers show lateral continuity. Results showed that cemented layers have a significant influence on natural attenuation of the toxic As and Pb species owing to their capacity of water retention. The measured oxygen profiles are controlled by the zone of active pyrite weathering as well as by the higher water content in the cemented layers which reduces gaseous atmospheric oxygen supply. In contrast, gypsum bearing hardpans detected at three other locations have no detectable influence on oxygen profiles. Furthermore, the grain size distribution was proved to have a major effect on oxygen diffusivity due to its control on the water saturation. Temporal changes of the oxygen profiles were only observed at locations with coarse sediment material indicating also an important advective part of gas flux. PMID- 20850167 TI - Comparison of laboratory methodologies for evaluating radiostrontium diffusion in soils: planar-source versus half-cell methods. AB - A planar-source method, initially designed to obtain diffusion coefficients in compacted clay, is adapted here to determine the apparent diffusion coefficient (D(a)) of radiostrontium in soils representative of the Spanish territory. Experiments were carried out by varying the moisture content (F(moist)), and bulk dry density (rho(bulk)) of the soil samples, in order to study the influence of these soil packing parameters on D(a) values. The moisture in the soil samples was established as the percentage of occupancy of each soil's field capacity (OFC). For a similar OFC, D(a) values in the examined soils ranged by approximately one order of magnitude (e.g. from 6.2 * 10(-)(11) to 6.5 * 10( )(12)m(2)s(-)(1), at 100% of OFC; from 3.0 * 10(-)(11) to 3.8 * 10(-)(12)m(2)s( )(1), at 60% of OFC). For a given soil, D(a) values increased when water content was increased. F(moist), and tortuosity (tau) explained D(a) variability, with R(2) values usually over 0.9. However, no good simple or multiple regressions between the soil packing parameters and D(a) were obtained with the whole dataset of all soils, which indicated that soil sorption capacity affects the diffusion of reactive radionuclides in soils. The inclusion of calculated K(d) values in the multiple regressions improved the correlations in all cases. Finally, D(a) values were compared with those obtained by the application of a half-cell method. The values of D(a) obtained by the planar-source methods were systematically lower than the half-cell ones, with a good correlation between the D(a) derived from both methods (R(2)=0.98). PMID- 20850168 TI - The effect of humic acids on the cytotoxicity of silver nanoparticles to a natural aquatic bacterial assemblage. AB - The effect of a terrestrial humic acid (HA) and a river HA on the cytotoxicity of silver nanoparticles (AgNPs) to natural aquatic bacterial assemblages (0 MUM, 2.5 MUM and 5 MUM) was measured with spread plate counting. The effect of HA (20 and 40 ppm) on the cytotoxicity of AgNPs ranging in size between 15 and 25 nm was tested in the presence and in the absence of natural sunlight. The experiment was a full factorial, completely randomized design and the results were analyzed using the General Linear Model in SAS. LSMEANS was used to separate the means or combinations of means. Significant main effects of all independent variables, plus interaction effects in all cases except HA/LI and HA/AgNPs/LI were observed. The toxicity of AgNPs to natural aquatic bacterial assemblages appears to be concentration dependent for concentrations between 0 MUM and 5 MUM. The data indicate that the light exposure inhibited viability more than the darkness exposure. The HA treatment groups in the presence of light showed greater reduced viability count compared to darkness exposure groups. The inhibition of bacterial viability counts by AgNPs exposure was less in the light treatment groups containing a terrestrial HA compared to that with a river HA. Difference in the extent of reactive oxygen species formation and adsorption/binding of AgNPs was speculated to account for the observed phenomenon. PMID- 20850169 TI - Effect of swine manure dilution on ammonia, hydrogen sulfide, carbon dioxide, and sulfur dioxide releases. AB - Animal manure is a significant source of environmental pollution and manure dilution in barn cleaning and slurry storage is a common practice in animal agriculture. The effect of swine manure dilution on releases of four pollutant gases was studied in a 30-day experiment using eight manure reactors divided into two groups. One group was treated with swine manure of 6.71% dry matter and another with manure diluted with water to 3.73% dry matter. Ammonia release from the diluted manure was 3.32 mg min(-1)m(-2) and was 71.0% of the 4.67 mg min( 1)m(-2) from the undiluted manure (P<0.01). Because the ammonia release reduction ratio was lower than the manure dilution ratio, dilution could increase the total ammonia emissions from swine manure, especially in lagoons with large liquid surface areas. Carbon dioxide release of 87.3 mg min(-1)m(-2) from the diluted manure was 56.4% of the 154.8 mg min(-1)m(-2) from the undiluted manure (P<0.01). Manure dry matter was an important factor for carbon dioxide release from manure. No differences were observed between the treatments (P>0.05) for both hydrogen sulfide and sulfur dioxide releases. Therefore, dilution could also significantly increase the total releases of hydrogen sulfide and sulfur dioxide to the environment because dilution adds to the total manure volume and usually also increases the total gas release surface area. PMID- 20850170 TI - Mercury contamination in spotted seatrout, Cynoscion nebulosus: an assessment of liver, kidney, blood, and nervous system health. AB - Marine fishes in South Florida (Florida Keys-Florida Bay-Everglades region) accumulate higher concentrations of mercury (Hg) in their tissues than similar fishes from other areas of the southeastern U.S., though it is not known whether these elevated levels affect fish health. In this study, we used quantifiable pathological and biochemical indicators to explore Hg-associated differences in marine fish from South Florida, where Hg contamination is high, and from Indian River Lagoon, Florida, which served as a reference area. Hg concentrations in all tissues of mature spotted seatrout (Cynoscion nebulosus) from South Florida were significantly higher than those from Indian River Lagoon and were within the threshold range of those in studies where effects of Hg exposure have been observed. The distribution of Hg among tissues followed the same trend in both areas, with the greatest concentration in kidney tissue, followed by liver, muscle, brain, gonad, and red blood cells. Blood-plasma biochemistry showed that concentrations of iron, inorganic phosphate, lactate dehydrogenase, and aspartate aminotransferase were significantly less in South Florida. Also, fructosamine and alkaline phosphatase were significantly less in South Florida. Liver histology revealed that pyknosis/necrosis, interstitial inflammation, and bile duct hyperplasia were found only in seatrout from South Florida, and steatosis/glycogen was more frequently found in Indian River Lagoon specimens. In renal tissue, interstitial inflammation, glomerular dilatation and thickening, and tubular degeneration and necrosis were more frequently found in South Florida specimens. Changes in the liver cytoskeleton and morphology may explain some of the differences in blood parameters between study areas. Neurochemical analyses showed that brain N-methyl-d-aspartic acid (NMDA) receptors (but not those of muscarinic cholinergic receptors, monoamine oxidase, or acetylcholinesterase) were significantly less in fish from South Florida than from Indian River Lagoon. These findings provide compelling evidence that elevated Hg could cause quantifiable pathological and biochemical changes that might influence the health of spotted seatrout and could also affect other marine fish species. PMID- 20850171 TI - Purification and characterization of 'Trimarin' a hemorrhagic metalloprotease with factor Xa-like Activity, from Trimeresurus malabaricus snake venom. AB - In the present study, we describe the purification and characterization of a metalloprotease 'trimarin' from Trimeresurus malabaricus snake venom. Trimarin is a single-chain basic protein, with a molecular mass of 29.6kDa. Trimarin showed proteolytic activity towards casein and fibrinogen, which was irreversibly inhibited by EDTA and 1,10-phenanthroline. The metal ion associated with trimarin was found to be Zn(2+). Trimarin exhibited pharmacological activities including hemorrhage, myotoxicity, procoagulant and factor Xa-like activities. The hemorrhage and myotoxicity correlated with degradation of extracellular protein components type-IV collagen and fibronectin. Myotoxicity due to muscle tissue necrosis was substantiated with increased serum CK activity. Trimarin showed procoagulant activity with reduced re-calcification time of citrated human plasma. Trimarin shortened the activated partial thromboplastin time (aPTT) and prothrombin time (PT), suggesting its involvement in common pathway of blood coagulation. Trimarin coagulated the citrated human plasma in the absence of CaCl(2), but it was lacking thrombin like activity as it did not clot the purified fibrinogen. Remarkably, the enzyme clotted the factor X deficient human plasma, suggesting that trimarin has factor Xa-like activity. Thus, trimarin may play a key role in the pathophysiological conditions that occur during T. malabaricus envenomation, and may be used as a biological tool to explore many facets of hemostasis. PMID- 20850172 TI - Inter-individual variability of effect of 7 low molecular weight antithrombin dependent anticoagulants studied in vitro with calibrated automated thrombography. AB - INTRODUCTION: Low-molecular-weight heparins (LMWHs) and fondaparinux are antithrombin dependent anticoagulant drugs considered to need no laboratory monitoring because of their reputedly predictable anticoagulant effect. However it has been suggested in the literature the existence of an inter-individual variability in response to LMWHs that would be not fully attributable to pharmacokinetics causes. MATERIAL AND METHODS: In order to separate pharmacokinetic from pharmacodynamics effects we studied in 12 platelet-depleted plasmas from normal donors the inhibitory effect on TG determined with the CAT of added UFH, 5 LMWHs and 2 oligosaccharides with anti-Xa activity only. RESULTS: A concentration-dependent inhibition of thrombin generation was found with all molecules tested. The concentration-response relation was very different when the concentrations were expressed in anti-Xa unit but became very similar when expressed in anti-thrombin units regarding LMWHs. Most importantly, we noticed a large inter-individual variability of the inhibitory effects with all molecules tested, UFH and LMWHs alike. The IC40 value varied at least twofold between the highest and the lowest responder. For any given anti-Xa level of any heparin and of pentasaccharide the inhibition of the ETP showed scattering of around 25%. CONCLUSION: In contrast to what is generally assumed the inter-individual variation of the in vitro pharmacodynamics response is equally high for UFH and any LMWH (~25%) and even for the synthetic pentasaccharide. This questions the rationale for standard dosage, the more so as in clinical practice pharmacokinetic variation (e.g. due to body weight) will add to this pharmacodynamic variability. PMID- 20850173 TI - Localization of c-kit and stem cell factor (SCF) in ovarian follicular epithelium of a lizard, Podarcis s. sicula. AB - We performed an immunohistochemical study to determine the immunolocalization of c-kit and stem cell factor (SCF) in ovarian follicles during the reproductive cycle of the lizard, Podarcis s. sicula. Follicles were serially cut and used for histological and histochemical characterization and also for immunohistochemical detection of both c-kit and SCF. C-kit and SCF were localized in the follicles with a differing pattern with regard to the stage of sexual cycle or the cell type forming the follicular epithelium (granulosa). In pre-reproductive follicles, where the granulosa consists of three main different cytotypes, the c kit receptor was prevalently localized on the plasmalemma of small cells, although some pyriform and intermediate cells also appeared positive. C-kit was also localized in the theca. In pre-reproductive follicles, SCF was markedly observed in the cytoplasm of some pyriform cells. Small cells and theca also stained moderately positive, whereas the intermediate cells were mostly negative. In reproductive follicles, where granulosa cells are morphologically rearranged, c-kit was observed in small cells and in some thecal elements, while SCF was weakly immunostained. At the site of follicular layer invaginations evident c kit/SCF immunostaining was observed in the granulosa epithelium and in the theca. These observations suggest that the expression of c-kit and SCF changes as a function of follicular development and may reflect the involvement of this system in the maturation of the oocyte. PMID- 20850174 TI - Correlates of the preoperative level of CA125 at presentation of ovarian cancer. AB - OBJECTIVE: CA125 at presentation of ovarian cancer carries important prognostic significance; but, other than tumor characteristics, little is known about factors that influence CA125 levels. We examined the effect of epidemiologic variables and tumor features on CA125 at diagnosis and their effects on survival. METHODS: CA125 levels before treatment, tumor features, and questionnaire data from 805 women with ovarian cancer receiving care at Partners Hospitals were recorded. CA125 values were log-normalized and generalized linear, logistic, or Cox proportional hazards models used to identify predictors of CA125 and influence on survival in the subset of women with invasive, nonmucinous tumors. RESULTS: The importance of histology, grade, stage, laterality, and presence of ascites on CA125 level was confirmed. For nonmucinous invasive cancers, Jewish ethnicity, parity, prior breast cancer, and family history of breast or ovarian cancer predicted higher CA125, and greater body mass index (BMI), recurrent yeast infections, colitis, and appendectomy predicted lower CA125. A quadratic model best described the relationship between CA125 and age with lower levels in youngest and oldest women. In multivariate modeling, stage, ascites, and prior breast cancer were the strongest predictors of high CA125 and appendectomy and yeast infections strongest predictors of low CA125. A model with these variables plus CA125 revealed high CA125 remains a predictor of poorer survival. CONCLUSIONS: Ovarian tumor features and presence of ascites are key determinants of CA125 at diagnosis, but epidemiologic features such as BMI, parity, prior breast cancer, and history of inflammatory conditions of the genitourinary or gastrointestinal tracts may also play a role. PMID- 20850175 TI - The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients. AB - OBJECTIVES: The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families. METHODS: Unselected Jewish women with EC who were diagnosed from January 1982 to January 2008 were genotyped for the predominant mutations in Jewish individuals in BRCA1 (185delAG, 5382InsC, Tyr978X) BRCA2 (6174delT), MSH2 (A636P, 324delCA) and MSH6 (c.3984_3987dup). RESULTS: Overall, 289 Jewish women with EC were included, the majority (217-75%) were Ashkenazim. Mean age at diagnosis was 62.6 +/- 12 years, the most common histopathology was type I (endometrioid carcinoma) (80.4% of participants) with 29 having type II (Uterine papillary serous and clear cell cancer) Most patients (85.4%) had stage 1 disease by the FIGO staging. Five women (1.7%-2.3% of the Ashkenazim) carried either the BRCA1*185delAG (n = 4) or BRCA2*6174delT (n = 1) mutations, a rate similar with that of the general Ashkenazi population. Notably, none of 34 women with type II EC carried any BRCA1/BRCA2 mutations. Four (1.8%) and three (1.4%) of the 217 Ashkenazim patients harbored the c.3984_3987dup, A636P, MSH6 and MSH2 mutations, respectively, and 1/72 (1.4%) of the non-Ashkenazi patients harbored the 324delCA MSH2 mutation. Three of 42 (7.1%) women with EC diagnosed < 50 years carried either BRCA1 MSH6 or MSH2 mutations. CONCLUSIONS: Our data do not support screening for BRCA1/2 mutations in consecutive EC patients. PMID- 20850176 TI - Identification of aneuploidy-tolerating mutations. AB - Aneuploidy causes a proliferative disadvantage in all normal cells analyzed to date, yet this condition is associated with a disease characterized by unabated proliferative potential, cancer. The mechanisms that allow cancer cells to tolerate the adverse effects of aneuploidy are not known. To probe this question, we identified aneuploid yeast strains with improved proliferative abilities. Their molecular characterization revealed strain-specific genetic alterations as well as mutations shared between different aneuploid strains. Among the latter, a loss-of-function mutation in the gene encoding the deubiquitinating enzyme Ubp6 improves growth rates in four different aneuploid yeast strains by attenuating the changes in intracellular protein composition caused by aneuploidy. Our results demonstrate the existence of aneuploidy-tolerating mutations that improve the fitness of multiple different aneuploidies and highlight the importance of ubiquitin-proteasomal degradation in suppressing the adverse effects of aneuploidy. PMID- 20850177 TI - Service personnel move to NHS mental health inpatient care. PMID- 20850178 TI - Omsk haemorrhagic fever. AB - Omsk haemorrhagic fever is an acute viral disease prevalent in some regions of western Siberia in Russia. The symptoms of this disease include fever, headache, nausea, severe muscle pain, cough, and moderately severe haemorrhagic manifestations. A third of patients develop pneumonia, nephrosis, meningitis, or a combination of these complications. The only treatments available are for control of symptoms. No specific vaccine has been developed, although the vaccine against tick-borne encephalitis might provide a degree of protection against Omsk haemorrhagic fever virus. The virus is transmitted mainly by Dermacentor reticulatus ticks, but people are mainly infected after contact with infected muskrats (Ondatra zibethicus). Muskrats are very sensitive to Omsk haemorrhagic fever virus. The introduction of this species to Siberia in the 1930s probably led to viral emergence in this area, which had previously seemed free from the disease. Omsk haemorrhagic fever is, therefore, an example of a human disease that emerged owing to human-mediated disturbance of an ecological niche. We review the biological properties of the virus, and the epidemiological and clinical characteristics of Omsk haemorrhagic fever. PMID- 20850179 TI - Effects of two offshore gas platforms on soft-bottom benthic communities (northwestern Adriatic Sea, Italy). AB - The macrozoobenthos living around two offshore gas platforms, Barbara NW (pB) and Calipso (pC) located in the northwestern Adriatic Sea were investigated for three years after their construction to detect eventual effects due to the platforms. The sampling stations were spaced at increasing distance from the platforms up to 1000 m. Both multivariate and univariate analysis showed an initial defaunation (short-term effect) at pB and within a 120 m radius at pC. A general recovery in terms of abundance, species richness and diversity was observed for the benthic communities after one year. During the third monitoring year a mussel mound developed at both the platforms (longer-term effect) extending up to 30 m from pC, whereas similar soft-bottom communities were found at all the other distances. The geographical position plays an important role in the "timing" of the above effects. Moreover, despite the different environmental features, a 3 year monitoring plan can be effective to evaluate the potential impact on benthic communities of offshore gas platforms in the north-central Adriatic Sea. PMID- 20850180 TI - A neurospheroid network-stamping method for neural transplantation to the brain. AB - Neural transplantation therapy using neural stem cells has received as potential treatments for neurodegenerative diseases. Indeed, this therapy is thought to be effective for replacement of degenerating neurons in restricted anatomical region. However, because injected neural stem cells integrate randomly into the host neural network, another approach is needed to establish a neural pathway between selective areas of the brain or treat widespread degeneration across multiple brain regions. One of the promising approaches might be a therapy using pre-made neural network in vitro by the tissue engineering technique. In this study, we engineered a three-dimensional (3D) tissue with a neuronal network that can be easily manipulated and transplanted onto the host brain tissue in vivo. A polydimethylsiloxane microchamber array facilitated the formation of multiple neurospheroids, which in turn interconnected via neuronal processes to form a centimeter-sized neurospheroid network (NSN). The NSN was transferable onto the cortical surface of the brain without damage of the neuronal network. After transfer onto the cortical tissue, the NSN showed neural activity for more than 8 days. Moreover, neurons of the transplanted NSN extended their axons into the host cortical tissue and established synaptic connections with host neurons. Our findings suggest that this method could lay the foundation for treating severe degenerative brain disease. PMID- 20850181 TI - Mother reports of maternal support following child sexual abuse: Preliminary psychometric data on the Maternal Self-report Support Questionnaire (MSSQ). AB - OBJECTIVE: Maternal support is an important factor in predicting outcomes following disclosure of child sexual abuse; however, definition of the construct has been unclear and existing measures of maternal support are utilized inconsistently and have limited psychometric data. The purpose of this study was to develop a reliable and valid mother-report measure for assessing maternal support following the disclosure of child sexual abuse. METHODS: Data from 2 very similar samples of mother-child pairs seeking forensic evaluation following the discovery of child sexual abuse were combined, resulting in a final sample of 246. RESULTS: Exploratory factor analysis resulted in two reliable 7-item factors labeled "Emotional Support" and "Blame/Doubt," each of which had acceptable internal consistency. Analyses with a child-report measure of general maternal support the construct validity of the MSSQ. Concurrent validity analyses revealed unique relations with maternal ratings of child behavior problems and case characteristic data. CONCLUSIONS: The study resulted in the development of a brief, easily scored self-report measure of maternal support with reasonable preliminary psychometric properties that could easily be utilized in other studies of sexually abused children. PRACTICE IMPLICATIONS: Adoption of this promising measure in future research will reduce the lack of cross-study measurement comparability that has characterized the maternal support literature to date, increase the feasibility of expanding upon current literature on maternal support, and may produce important information leading to clinical and theoretical innovation. PMID- 20850182 TI - The overlap of witnessing partner violence with child maltreatment and other victimizations in a nationally representative survey of youth. AB - OBJECTIVE: To examine the co-occurrence of witnessing partner violence with child maltreatment and other forms of victimization. METHOD: Data are from the National Survey of Children's Exposure to Violence (NatSCEV), a nationally representative telephone survey of the victimization experiences of 4,549 youth aged 0-17. RESULTS: Witnessing partner violence (WPV) is very closely associated with several forms of maltreatment and exposure to other forms of family violence in this sample, with adjusted OR ranging from 3.88 to 9.15. WPV is also significantly associated with a wide variety of other forms of victimization, with OR ranging from 1.43 to 7.32. More than 1/3 (33.9%) of youth who witnessed partner violence had also been maltreated in the past year, compared with 8.6% of non-witnesses. For lifetime data, more than half (56.8%) of WPV youth had also been maltreated. Neglect and custodial interference were most closely associated with WPV. CONCLUSIONS: These data support the poly-victimization model, indicating that many youth experience multiple forms of victimization. They also indicate that the various forms of family violence are especially closely linked. PRACTICE IMPLICATIONS: These results provide new urgency to calls to better integrate services to adult and child victims of family violence. For example, screening to identify the needs of child witnesses could be done in domestic violence shelters, and screening to identify the needs of adult victims could be done in child protective service settings. PMID- 20850183 TI - A prospective examination of the role of childhood sexual abuse and physiological asymmetry in the development of psychopathology. AB - OBJECTIVE: Recent literature has emphasized the simultaneous assessment of multiple physiological stress response systems in an effort to identify biobehavioral risk factors of psychopathology in maltreated populations. The current study assessed whether an asymmetrical stress response, marked by activation in one system and a blunted response in another system, predicted higher levels of psychopathology over time. METHODS: Data were collected from an ongoing, prospective study of females with a substantiated history of childhood sexual abuse (n=52) and a non-abused comparison group (n=77). Childhood sexual abuse was determined at the initial study visit. Vagal tone and cortisol were measured 7 years later to assess physiological response to a laboratory stressor across these systems. Depressive symptoms and antisocial behaviors were assessed 6 years after the completion of the laboratory stressor. RESULTS: Structural equation modeling indicated that a prior history of childhood sexual abuse predicted an asymmetrical physiological response to stress in late adolescence. In turn, this asymmetrical response predicted both higher levels of depression and antisocial behaviors in young adulthood. CONCLUSIONS: Childhood sexual abuse may sensitize females to respond to moderate daily stressors in a manner that places them at higher risk for experiencing depressive symptoms and antisocial behaviors over time. PRACTICE IMPLICATIONS: The management of mild to moderate stress in the everyday lives of maltreated females may be a particularly useful point of intervention in order to protect against later psychopathology. PMID- 20850184 TI - Peripheral blood invariant natural killer T cells throughout pregnancy and in preeclamptic women. AB - Invariant natural killer T (iNKT) cells are implicated in the pathogenesis of several diseases. They influence both innate and adaptive immune responses through their capacity to rapidly produce large quantities of cytokines upon activation. During pregnancy maternal immunity is biased towards type 2 cytokine production to regulate type 1 cytokines that could be harmful for the developing fetus. This shift to type 2 cytokines does not occur in preeclamptic women and there is an exaggerated maternal inflammatory response which is dangerous for both mother and baby. We have therefore investigated the numbers, phenotype and functional activity of iNKT cells throughout pregnancy and in women diagnosed with preeclampsia. We demonstrate that the numbers of iNKT cells in the peripheral blood do not change between the first, second and third trimesters of pregnancy, but the cells become activated and less able to produce the type 1 cytokine IFNgamma. However, iNKT cells are unchanged in preeclamptic women, when compared to normal pregnancy, suggesting that these cells are not primary players in the pathogenesis of the disease. PMID- 20850185 TI - Psychopathy, PCL-R, and MAOA genotype as predictors of violent reconvictions. AB - The Revised Psychopathy Checklist (PCL-R) has shown a moderate association with violence. The efficacy of PCL-R in varying monoamine oxidase A (MAOA) genotypes is, however, unexamined. The aim of this study was to investigate the effect of PCL-R and psychopathy on the risk for violent reconvictions among 167 MAOA genotyped alcoholic offenders. Violent reconvictions and PCL-R scores among violent offenders were assessed after a 7-year non-incarcerated follow-up. Regression analysis was used to evaluate the alcohol exposure and age-adjusted effect of PCL-R score and psychopathy on the risk for reconvictions among differing MAOA genotypes. Results suggest that the PCL-R total score predicts impulsive reconvictions among high-activity MAOA offenders (6.8% risk increase for every one-point increase in PCL-R total score, P = 0.015), but not among low activity MAOA offenders, whereas antisocial behavior and attitudes predicted reconvictions in both genotypes (17% risk increase among high-activity MAOA offenders and 12.8% increase among low-activity MAOA offenders for every one point increase in factor 2 score). Both narcissistic self-image with related interpersonal style (factor 1 score) and psychopathy (PCL-R >= 30) failed to predict future violence. Results suggest that the efficacy of PCL-R is altered by MAOA genotype, alcohol exposure, and age, which seems important to note when PCL R is used for risk assessments that will have legal or costly preventive work consequences. PMID- 20850186 TI - A preliminary study to understand the effect of Fasciola hepatica tegument on naive macrophages and humoral responses in an ovine model. AB - Fasciola hepatica, the liver fluke, is a highly evolved endo-parasite that uses various mechanisms to evade the host immune system. The immunosuppressive capabilities of the parasite's excretory/secretory products have been well demonstrated by previous independent studies. However, the role of the parasite's tegument in the immune responses remains to be investigated. In this study, the effect of the tegument and other fractions of adult F. hepatica (excretory/secretory, liver fluke homogenate and liver fluke homogenate without tegument) in the activation of naive macrophages in vitro was investigated using an ovine model. In addition, an immunoproteomic approach was used to investigate the characteristics of humoral antibody responses developed in sheep against the tegument fraction. The results indicated significantly increased arginase expression in macrophages incubated with the tegument and excretory/secretory fractions. Two dimensional gel electrophoresis of the tegument demonstrated approximately 100 protein spots, with only four of these spots were highly reactive with the positive serum as determined by 2-DE immunoblotting. These results give a preliminary indication that the liver fluke tegument may play role in avoiding hosts' protective immune responses against itself. PMID- 20850187 TI - Membrane attack complex of complement is not essential for immune mediated demyelination in experimental autoimmune neuritis. AB - Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P selectin. PMID- 20850188 TI - Gating and permeation of kainate receptors: differences unveiled. AB - Kainate receptors (KARs) represent, together with alpha-amino-3-hydroxy-5-methyl 4-isoxazolepropionic acid (AMPA) and N-methyl D-aspartate (NMDA) receptors, one of the three families of ionotropic glutamate receptors. Recent advances in the study of their biophysical properties have revealed a surprising diversity. KAR mediated excitatory postsynaptic currents (EPSCs) are often much slower than AMPA receptor-mediated EPSCs, and this is probably due to the slow deactivation rate of KARs containing the GluK4 or GluK5 subunits. By contrast, GluK3-containing receptors, unlike other AMPA/kainate receptors, desensitize faster at low agonist concentrations, making these receptors insensitive to glutamate spillover from neighboring synapses. Moreover, KARs have a wide range of sensitivities to intracellular polyamines and consequently of voltage dependent activation. Finally, newly discovered associated proteins, such as Neto1 and 2, have marked effects on receptor properties, increasing further the potential diversity of KAR functional properties. Altogether, this functional diversity of KARs could have profound consequences on their ability to shape synaptic transmission under physiological and pathological conditions. PMID- 20850189 TI - Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. AB - Investigations of synaptic transmission and plasticity in mouse models of Huntington's disease (HD) demonstrate neuronal dysfunction long before the onset of classical disease indicators. Similarly, recent human studies reveal synaptic dysfunction decades before predicted clinical diagnosis in HD gene carriers. These studies guide premanifest tracking of disease and the development of treatment assessment tools. New discoveries of mechanisms underlying early neuronal dysfunction, including elevated pathogenic extrasynaptic NMDA receptor signaling, reduced synaptic connectivity and loss of brain-derived neurotrophic factor (BDNF) support have led to pharmacological interventions that can reverse or delay phenotype onset and disease progression in HD mice. Further understanding the primary effects of gene mutations associated with late-onset neurodegeneration should translate to novel treatments for HD families and guide therapeutic strategies for other neurodegenerative diseases. PMID- 20850191 TI - Antimicrobial action of essential oil vapours and negative air ions against Pseudomonas fluorescens. AB - The aim of this study was to investigate the antibacterial activity of essential oil (in liquid as well as in vapour phase) and negative air ions (NAI) against Pseudomonas fluorescens. The combined effect of NAI with essential oil vapour was also investigated to determine kill time and morphological changes in bacterial cells. The MIC of Cymbopogon citratus (0.567 mg/ml), Mentha arvensis (0.567 mg/ml), Mentha piperita (1.125 mg/ml) and Eucalyptus globulus (2.25 mg/ml) was studied via the agar dilution method. To estimate the antibacterial activity of essential oils in the vapour phase, agar plates inoculated with P. fluorescens were incubated with various concentrations of each essential oil vapour and zone of inhibition was recorded. Further, in order to assess the kill time, P. fluorescens inoculated agar plates were exposed to selected bactericidal essential oil vapour and NAI, separately, in an air-tight chamber. A continuous decrease in bacterial count was observed over time. A significant enhancement in the bactericidal action was observed by exposure to the combination of essential oil vapour and NAI as compared to their individual action. Scanning electron microscopy was used to study the alteration in morphology of P. fluorescens cells after exposure to C. citratus oil vapour, NAI, and combination of C. citratus oil vapour and NAI. Maximum morphological deformation was found due to the combined effect of C. citratus oil vapour and NAI. This study demonstrates that the use of essential oils in the vapour phase is more advantageous than the liquid phase. Further the antibacterial effect of the essential oil vapours can be significantly enhanced by the addition of NAI. The work described here offers a novel and efficient approach for control of bacterial contamination that could be applied for food stabilization practices. PMID- 20850190 TI - Healthcare services for Japanese elderly long-staying in Thailand from the perspective of the patient and healthcare providers: a survey study. AB - Long-stay refers to a long visit abroad by retired middle-aged and older people. This study describes the attitudes/opinions of elderly Japanese long-staying subjects and healthcare providers in Thailand. Two cross-sectional questionnaire surveys were conducted in Chiang Mai Province, Thailand. Questionnaires were sent to a sample recruited from a self-help group of Japanese elders in Thailand (n = 68) and to Thai healthcare providers (n = 101). About half of the Japanese subjects routinely used a Thai medical service, although only 15% had been admitted to the hospital. Half of the Japanese subjects thought the quality of Thai medical services was high. Many elderly Japanese subjects were unable to speak either English or Thai, leading to communication difficulties. About 80% of healthcare professionals found no difference between caring for elderly Japanese subjects and people from Thailand. Most healthcare providers agreed that Japanese language training should be available to medical staff as translators were not always available. Healthcare providers agreed with the Thai government policy promoting long-stays. The most recognized obstacle in caring for Japanese long stay elderly was the language barrier. More research on Japanese elders staying abroad is needed to promote effective communication between Japanese elderly and other ethnic healthcare professionals. PMID- 20850192 TI - Detection of the sour-rot pathogen Geotrichum candidum in tomato fruit and juice by using a highly specific monoclonal antibody-based ELISA. AB - Geotrichum candidum is a common soil-borne fungus that causes sour-rot of tomatoes, citrus fruits and vegetables, and is a major contaminant on tomato processing equipment. The aim of this work was to produce a monoclonal antibody and diagnostic assay for its detection in tomato fruit and juice. Using hybridoma technology, a cell line (FE10) was generated that produced a monoclonal antibody belonging to the immunoglobulin class M (IgM) that was specific to G. candidum and the closely related teleomorphic species Galactomyces geotrichum and anamorphic species Geotrichum europaeum and Geotrichum pseudocandidum in the G. geotrichum/G. candidum complex. The MAb did not cross-react with a wide range of unrelated fungi, including some likely to be encountered during crop production and processing. The MAb binds to an immunodominant high molecular mass (> 200 kDa) extracellular polysaccharide antigen that is present on the surface of arthroconidia and hyphae of G. candidum. The MAb was used in a highly specific enzyme-linked immunosorbent assay (ELISA) to accurately detect the fungus in infected tomato fruit and juice. Specificity of the ELISA was confirmed by sequencing of the internally transcribed spacer (ITS) 1-5.8S-ITS2 rRNA-encoding regions of fungi isolated from naturally-infected tomatoes. PMID- 20850193 TI - Increased iron in HCV infection: collateral damage or antiviral defense? PMID- 20850194 TI - Health care prioritization in ageing societies: influence of age, education, health literacy and culture. AB - OBJECTIVES: To examine how Chinese people in Hong Kong view health care prioritization and to compare the findings with those from a United Kingdom survey. METHODS: A cross-sectional opinion survey was conducted in Hong Kong and 1512 participants were interviewed. RESULTS: Data show that the highest rankings were accorded to "treatment for children" and "high technology services." Services for the elderly, whether in the community or in hospitals, and including end-of-life care, were ranked among the lowest. This view was also shared by healthcare professionals. Compared with the UK findings, there are stark contrasts in the low ranking of end-of-life care and the high ranking of high technology services among the HK population. CONCLUSIONS: It is evident that most people would give priority to the young over the old in distributing a given amount of healthcare services. To meet the needs of ageing societies and to meet the needs of all users equitably, health care policy needs to acknowledge constraints and the needs for prioritization. Both the public and professionals should engage with policy makers in formulating a policy based on cost benefit considerations as well as overall societal view of prioritization that is not based on age alone. PMID- 20850196 TI - Early localized morphea mimicking an acquired port-wine stain. AB - Port-wine stains (PWS) and morphea are distinct conditions that are easily recognized and diagnosed in pediatric patients. Rarely, early localized morphea may mimic an acquired PWS. We present 4 such cases, in two of which the initial clinical impression of acquired PWS was thought to be confirmed by histopathology. A diagnosis of morphea was made approximately 6 months to 3 years after the onset of the acquired PWS. Clinicians should be aware that an apparent acquired PWS may be an early manifestation of localized morphea and continue to monitor these lesions. PMID- 20850197 TI - Hand hygiene in rural Indonesian healthcare workers: barriers beyond sinks, hand rubs and in-service training. AB - Few attempts to increase healthcare workers' hand hygiene compliance have included an in-depth analysis of the social and behavioural context in which hand hygiene is not undertaken. We used a mixed method approach to explore hand hygiene barriers in rural Indonesian healthcare facilities to develop a resource appropriate adoption of international guidelines. Two hospitals and eight clinics (private and public) in a rural Indonesian district were studied for three months each. Hand hygiene compliance was covertly observed for two shifts each in three adult wards at two hospitals. Qualitative data were collected from direct observation, focus group discussions and semistructured in-depth and informal interviews within healthcare facilities and the community. Major barriers to compliance included longstanding water scarcity, tolerance of dirtiness by the community and the healthcare organisational culture. Hand hygiene compliance was poor (20%; 57/281; 95% CI: 16-25%) and was more likely to be undertaken after patient contact (34% after-patient contact vs 5% before-patient contact, P<0.001) and 'inherent' opportunities associated with contacts perceived to be dirty (49% 'inherent' vs 11% 'elective' opportunities associated with clean contacts, P<0.001). Clinicians frequently touched patients without hand hygiene, and some clinicians avoided touching patients altogether. The provision of clean soap and water and in-service training will not overcome strong social and behavioural barriers unless interventions focus on long term community education and managerial commitment to the provision of supportive working conditions. PMID- 20850195 TI - Nck1 and Grb2 localization patterns can distinguish invadopodia from podosomes. AB - Invadopodia are matrix-degrading ventral cell surface structures formed in invasive carcinoma cells. Podosomes are matrix-degrading structures formed in normal cell types including macrophages, endothelial cells, and smooth muscle cells that are believed to be related to invadopodia in function. Both invadopodia and podosomes are enriched in proteins that regulate actin polymerization including proteins involved in N-WASp/WASp-dependent Arp2/3 complex activation. However, it is unclear whether invadopodia and podosomes use distinct mediators for N-WASp/WASp-dependent Arp2/3-complex activation. We investigated the localization patterns of the upstream N-WASp/WASp activators Nck1 and Grb2 in invadopodia of metastatic mammary carcinoma cells, podosomes formed in macrophages, and degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells. We provide evidence that Nck1 specifically localizes to invadopodia, but not to podosomes formed in macrophages or degradative structures formed in Src-transformed fibroblasts and PMA stimulated endothelial cells. In contrast, Grb2 specifically localizes to degradative structures formed in Src-transformed fibroblasts and PMA-stimulated endothelial cells, but not invadopodia or podosomes formed in macrophages. These findings suggest that distinct upstream activators are responsible for N WASp/WASp activation in invadopodia and podosomes, and that all these ventral cell surface degradative structures have distinguishing molecular as well as structural characteristics. These patterns of Nck1 and Grb2 localization, identified in our study, can be used to sub-classify ventral cell surface degradative structures. PMID- 20850198 TI - Epidemiology and risk factors of catheter-associated bloodstream infections among intensive care unit patients: an experience from a tertiary care hospital in Thailand. PMID- 20850199 TI - Molecular-level removal of proteinaceous contamination from model surfaces and biomedical device materials by air plasma treatment. AB - Established methods for cleaning and sterilising biomedical devices may achieve removal of bioburden only at the macroscopic level while leaving behind molecular levels of contamination (mainly proteinaceous). This is of particular concern if the residue might contain prions. We investigated at the molecular level the removal of model and real-life proteinaceous contamination from model and practical surfaces by air plasma (ionised air) treatment. The surface-sensitive technique of X-ray photoelectron spectroscopy (XPS) was used to assess the removal of proteinaceous contamination, with the nitrogen (N1s) photoelectron signal as its marker. Model proteinaceous contamination (bovine serum albumin) adsorbed on to a model surface (silicon wafer) and the residual proteinaceous contamination resulting from incubating surgical stainless steel (a practical biomaterial) in whole human blood exhibited strong N1s signals [16.8 and 18.5 atomic percent (at.%), respectively] after thorough washing. After 5min air plasma treatment, XPS detected no nitrogen on the sample surfaces, indicating complete removal of proteinaceous contamination, down to the estimated XPS detection limit 10ng/cm(2). Applying the same plasma treatment, the 7.7at.% nitrogen observed on a clinically cleaned dental bur was reduced to a level reflective of new, as-received burs. Contact angle measurements and atomic force microscopy also indicated complete molecular-level removal of the proteinaceous contamination upon air plasma treatment. This study demonstrates the effectiveness of air plasma treatment for removing proteinaceous contamination from both model and practical surfaces and offers a method for ensuring that no molecular residual contamination such as prions is transferred upon re-use of surgical and dental instruments. PMID- 20850200 TI - [Levosulpiride in the management of functional dyspepsia and delayed gastric emptying]. AB - Levosulpiride is a sulpiride isomer that exerts its prokinetic action through a dual mechanism: 1) as a D(2) dopamine receptor antagonist and 2) as a serotonin 5HT(4) receptor agonist, conferring this drug with a cholinergic effect. At a dosage of 25mg three times daily, levosulpiride accelerates gastric and gallbladder emptying. Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia, while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists. The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D(2) dopamine antagonists. Therefore, this drug is a useful therapeutic option in the management of patients with functional dyspepsia, as well as in those with delayed gastric emptying. PMID- 20850201 TI - [Cardiac safety of cinitapride]. PMID- 20850202 TI - [Frailty criteria in the elderly: a pilot study]. AB - OBJECTIVE: To measure the frailty of people 75 years or over and who live in their own homes based on Fried's criteria and modified by Avila-Funes. DESIGN: Pilot study of cross-sectional design. SITE: Primary Health Care Centres (7) in the city of Lleida. PARTICIPANTS: A probabilistic sample was selected for every stratum. The total sample was 323 individuals. PRIMARY MEASUREMENTS: Socio demographic characteristics, measurement of the five frailty criteria (involuntary lose of weight, low energy or exhaustion, slow mobility, muscle weakness, low physical activity), and geriatric assessment scales (Charlson Index, Pfeiffer's Test, Katz Index, Lawton and Brody Index, MNA Test and CES-D scale). RESULTS: The prevalence of frailty was 8.5%. Factors associated with frailty were, female sex and low monthly income. It was observed that if the frailty increases, there is deterioration of cognitive status, activities of daily living and nutritional status. There is also higher morbidity. Frailty criteria scores showed a significant correlation with geriatric assessment scales scores. CONCLUSIONS: The prevalence of frailty in elderly people is similar to those in other studies that have used the same criteria. The measurement of frailty criteria in this study demonstrates a better ability for transcription of results. A frailty study using specific markers enhances prevention and improvement of new intervention programs. PMID- 20850204 TI - Anticancer activity of N-bis(trifluoromethyl)alkyl-N'-(polychlorophenyl) and N' (1,2,4-triazolyl) ureas. AB - A number of N-bis(trifluoromethyl)alkyl-N'-substituted ureas have been synthesized and evaluated for their in vitro anticancer activity against the human cancer cell lines at the National Cancer Institute (NCI, USA). Marked activity was shown for compounds 4a and 5a. The most sensitive cell lines relative to the tested compounds were: 4a UO-31 (renal cancer, logGI(50) -5.62), HS 578T (breast cancer, logGI(50) -5.50), 5a HCC-2998 (colon cancer, logGI(50) 5.94), NCI-H322M (lung cancer, logGI(50) -5.75) and PC-3 (prostate cancer, logGI(50) -5.66). PMID- 20850205 TI - Structure-based optimization and biological evaluation of human 20alpha hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors. AB - The tertiary structure of the Leu308Val mutant of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5 substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K(i) = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3alpha-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC(50) value equal to 100 nM. PMID- 20850206 TI - A V-shaped ligand 2,6-bis(2-benzimidazolyl)pyridine and its picrate Mn(II) complex: synthesis, crystal structure and DNA-binding properties. AB - A V-shaped ligand 2,6-bis(2-benzimidazolyl)pyridine (bbp) and its picrate Mn(II) complex have been synthesized and characterized by elemental analysis, molecular conductivities, (1)H NMR, IR, UV-vis spectra and X-ray single crystal diffraction. The crystal structure of [Mn(bbp)(2)](pic)(2).2DMF is six coordinated forming a distorted octahedron. The DNA-binding properties of the two compounds were investigated by electronic absorption spectra, fluorescence spectra and viscosity measurements. The experimental results suggest that the two compounds bind to DNA in an intercalation mode. The main reason of the DNA binding behaviors may be the large coplanar aromatic rings in the V-shaped ligand. As compared to the DNA-binding affinities of the two compounds, the Mn(II) complex is stronger than bbp. This may be due to the V-shaped angle changed. PMID- 20850207 TI - QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids. AB - Naphthylisoquinoline alkaloids have attracted considerable interest because of their intriguing structure, their unique biosynthetic origin, and their biological activities against several pathogens causing tropical diseases. Their promising pharmacologic properties make them suitable lead structures for new agents, in particular against malaria. Since these natural products are not easy to isolate in sufficient quantities or to synthesize stereoselectively, quantitative structure-activity relationship studies were accomplished to find new antiplasmodial analogs that are structurally related to the naturally occurring naphthylisoquinoline alkaloids, but more easily accessible, more active against Plasmodium falciparum, and, last but not least, less toxic. We report on the synthesis of several simplified compounds by a Suzuki coupling between the naphthalene and the isoquinoline moieties and on their activities against different pathogens causing infectious diseases. Some structures were found to exhibit excellent--and selective--activities against P. falciparum in vitro. PMID- 20850208 TI - [Clinical and etiological aspects of uveitis: a retrospective study of 121 patients referred to a tertiary centre of ophthalmology]. AB - PURPOSE: Uveitis consists of a large group of diseases characterized by intraocular inflammation involving the uveal tract. This heterogeneity makes the diagnosis and the treatment of uveitis frequently challenging. The purpose of this study was to describe the various clinical and etiologic aspects of uveitis, through the new standardized uveitis classification and the use of modern investigations for its diagnostic work-up. METHODS: The medical records of 121 new patients with uveitis referred to our tertiary ophthalmologic centre between January 2002 and December 2006 were retrospectively reviewed. Uveitis associated to human immunodeficiency virus and secondary to exogenous endophthalmitis were excluded. All patients had a complete ophthalmological examination and appropriate clinical and paraclinical examination. The diagnosis was established according to the recent international criteria. RESULTS: One hundred and twenty one patients were included. The four main etiologies were: toxoplasmosis (14%), sarcoidosis (11.6%), spondylarthritis or HLA B27-associated uveitis (13.2%) and Herpes virus infections (9.1%) that represented almost half of the uveitis causes (47.9%). Various diseases constituted the remaining causes of the uveitis (20.9%). Uveitis remained unexplained in the remaining 36 patients (29.7%). Overall, associated systemic diseases were diagnosed in 35.5% of our uveitis patients (34 patients), associated infectious conditions in 26.4% (32 patients) and specific ocular diseases in 8.3% (12 patients). CONCLUSION: Despite a limited number of patients, our study showed an etiologic distribution similar to that of the main series reported in the literature. Nevertheless, we observed an elevated frequency of sarcoidosis and systemic diseases, which emphasizes a management that takes into account standardized clinical and paraclinical criteria and the usefulness of a collaboration with the internist. PMID- 20850209 TI - [Cytokines and T cell differentiation in systemic sclerosis]. AB - The physiopathology of systemic sclerosis remains unclear within a complex interaction between vasculopathy, perivascular inflammatory infiltrate, extensive tissue fibrosis and auto-immune manifestations. Chronology between vascular disease and adjacent inflammatory cell infiltration is still not yet clarified. There is growing evidence that T cell activation and its cytokine expression play a key role in vascular impairment occurrence and collagen dysregulation. Nevertheless, cytokine descriptions are mainly limited to blood and tissue measurement and the T cells differentiation analysis restricted to the Th1/Th2 balance. The purpose of this review is to establish an exhaustive cartography of cytokines involved in T cell differentiation, regarding the recent advance in T lymphocyte differentiation, including Th9, Th17, Th22 and regulatory T cells (Treg) pathways. This review will focus on Th17, Th22 and Treg differentiation, corresponding to the equilibrium between inflammation and tolerance. Finally, regarding published results in systemic sclerosis, T cells participation appears to be more a Th1/Th2 co-expression than an exclusive Th1 or Th2 polarization. Also, a possible Th22/Treg imbalance is suggested, leading to a Th22 overexpression and likely to tissue inflammation genesis. PMID- 20850210 TI - [Visceral leishmaniasis: an update]. AB - During the last decade, visceral leishmaniasis has been reconsidered in its epidemiology and strategies for diagnosis, treatment and prevention. This vectorial disease, responsible for more than 50,000 deaths each year across India, East Africa, South America, the Mediterranean area, Central Asia and China, is currently spreading over new territories. This formerly rural disease has even reached cities in South America. This spreading is caused by environmental changes due to global warming or human activity, and by the movement of workers and refugees. As a consequence, the burden of HIV/Leishmania coinfection is increasing in many developing countries even though effective antiretroviral therapy has led to a marked decrease in its incidence in Europe. The disease is now handled differently than it was 10 years ago: PCR has become the most accurate tool for diagnosis and follow-up in developed countries, and field diagnostic tools have been developed (antigenuria, rK39 dipstick). While resistance to antimoniate has appeared in India and Europe, new therapies have been evaluated such as miltefosine, the first oral therapy, or short treatment with liposomal amphotericin B. In France, liposomal amphotericin B has supplanted antimoniate meglumine because of better tolerance and shorter hospitalization duration. Protecting dogs through immunization or collars impregnated with deltamethrin proved effective to prevent zoonotic leishmaniasis due to Leishmania infantum. PMID- 20850211 TI - Oral nutrition in labour: 'whose choice is it anyway?' A review of the literature. AB - OBJECTIVE: to identify factors affecting women's oral nutrition in labour. DESIGN: literature review (1988-2009). SETTING: Westernised maternity care settings. PARTICIPANTS: women, midwives, obstetricians, anaesthetists and hospitals. MEASUREMENTS AND FINDINGS: when addressing labour stages, the risk categorisation of women and maternal/fetal birthing outcomes, there was a lack of consistent evidence identifying adverse outcomes for mothers/infants when oral nutrition in labour had occurred. KEY CONCLUSIONS: little evidence exists to support the continuance of restrictive practices around oral nutrition in labour for all women. Women's choice is impacted by health practitioners' opinions, experience and practice methods and policy (or lack thereof). Policies are not reflective of current evidence. IMPLICATIONS FOR PRACTICE: women's choices and desires regarding oral nutrition in labour need to be addressed. Clear guidelines/policies need to be established based on current evidence. Midwives need greater exposure to research, as well as involvement in policy development and implementation. PMID- 20850212 TI - Low postnatal care rates in two rural counties in Anhui Province, China: perceptions of key stakeholders. AB - OBJECTIVE: to explore the perceptions of stakeholders on postnatal care and to describe the rate of postnatal home visits in two rural counties in Anhui Province, China. DESIGN: this was a mixed methods study which uses mainly qualitative methods including focus group discussions, in- depth interviews and key informant interviews. A household survey of postpartum women was used to calculate the rates of postnatal home visits. SETTING: two rural counties in Anhui Province, China. PARTICIPANTS: qualitative study participants: officials responsible for maternal health care at county level, health providers at township and village level and maternal health-care users. Household survey participants: 2326 women who gave birth in the two counties from January 2005 to December 2006. FINDINGS: the survey of postpartum women revealed that only 4.2% and 4.5% of women received one or more postnatal visits at home in County A and County B. Qualitative interviews revealed a range of perceived reasons for this low rate of provision and utilisation of postnatal care, including: inadequate funding for maternal health care; limited human resources; lack of transport in township hospitals; and limited value placed on postnatal care by women and providers. In addition, where services were provided, a number of factors were likely to restrict health providers from delivering high-quality postnatal health service, such as: weak skills and knowledge of staff; inadequate in-service training; lack of equipment in township hospitals; and poor supervision and monitoring. KEY CONCLUSIONS: the rate of postnatal visits was extremely low in two counties in rural China. Understaffing and inadequate funding are the main factors that affect provision of postnatal health care. IMPLICATIONS FOR PRACTICE: more emphasis should be attached to political support and funding for postnatal care. Research into feasible ways to provide quality postnatal care needs to be conducted. PMID- 20850213 TI - Postural balance under normal and altered sensory conditions in normal-weight and overweight children. AB - BACKGROUND: little or no research has been done in the overweight child on the relative contribution of multisensory information to maintain postural stability. Therefore, the purpose of this study was to investigate postural balance control under normal and experimentally altered sensory conditions in normal-weight versus overweight children. METHODS: sixty children were stratified into a younger (7-9yr) and an older age group (10-12yr). Participants were also classified as normal-weight (n=22) or overweight (n=38), according to the international BMI cut-off points for children. Postural stability was assessed during quiet bilateral stance in four sensory conditions (eyes open or closed, normal or reduced plantar sensation), using a Kistler force plate to quantify COP dynamics. Coefficients of variation were calculated as well to describe intra individual variability. FINDINGS: removal of vision resulted in systematically higher amounts of postural sway, but no significant BMI group differences were demonstrated across sensory conditions. However, under normal conditions lower plantar cutaneous sensation was associated with higher COP velocities and maximal excursion of the COP in the medial-lateral direction for the overweight group. Regardless of condition, higher variability was shown in the overweight children within the 7-9yr old subgroup for postural sway velocity, and more specifically medial-lateral velocity. INTERPRETATION: in spite of these subtle differences, results did not establish any clear underlying sensory organization impairments that may affect standing balance performance in overweight children compared to normal-weight peers. Consequently, it is believed that other factors account for overweight children's functional balance deficiencies. PMID- 20850214 TI - Atrazine is not readily mineralised in 24 temperate soils regardless of pre exposure to triazine herbicides. AB - Mineralisation of atrazine in soil has been shown to depend on previous exposure of the herbicide. In this study, 24 Danish soils were collected and screened for potential to mineralise atrazine. Six soils were chosen, because they had never been exposed to atrazine, whereas 18 soils were chosen because of their history of application of atrazine or the related compound terbuthylazine. None of the 24 soils revealed a mineralisation potential of more than 4% of the added atrazine within a 60 day timeframe. In an atrazine adapted French soil, we found 60% mineralisation of atrazine in 30 days. Cattle manure was applied in order to boost the microbial activity, and a 2-3% increase in the atrazine mineralisation was found in some of the temperate soils, while in the highly adapted French soil it caused a 5% reduction. PMID- 20850215 TI - Effect of enoxaparin and aspirin on hemodynamic disturbances after global cerebral ischemia in rats. AB - STUDY AIM: Whether patients benefit from anticoagulation or anti-platelet agents when subjected to global ischemia is controversial. In this study we assessed the effect of enoxaparin and aspirin on hemodynamic disturbances following global ischemia in rats. METHODS: Twenty-minute global ischemia was induced by four vessel occlusion in Sprague-Dawley rats. Enoxaparin (1.5 mg/kg, i.v.) was administered 4 min before or after ischemia, and aspirin (40 mg/kg, i.p.) was administered twice, 18 and 1.5 h before ischemia. Parietal cortical cerebral blood flow was measured in real time with a laser Doppler flowmeter, and activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured. Three phenomena of hemodynamic disturbance: no-reflow, hyperperfusion, and hypoperfusion, were assessed after 20-min global ischemia. RESULTS: No significant differences in PT values were found; in contrast, the APTT values were shortened markedly by 20-min ischemia, which indicated activation of the endogenous coagulation system. The shortened APTT was markedly prevented by enoxaparin administered before ischemia. No-reflow was partly mitigated by administration of enoxaparin or aspirin before ischemia. Hypoperfusion was almost fully blocked by aspirin, and the hypoperfusion value was increased and hypoperfusion duration was shortened by enoxaparin administered 4 min before or after ischemia. CONCLUSION: These results indicate that enoxaparin and aspirin have protective effects against cerebral hemodynamic disturbances induced by global ischemia in rats. PMID- 20850216 TI - Monthly variation of Dermatophagoides allergens and its influence on respiratory allergy in a high altitude environment (Quito, 2800 m a.s.l. in Andean Ecuador). AB - BACKGROUND: Seasonal variation of Dermatophagoides allergens and its influence in allergic respiratory airway diseases has not been investigated in Andean cities. The objective of this study was to evaluate those parameters in a city located in the Andean mountains. METHODS: Der p1 and Der f1 were measured in dust samples from mattresses in 13 houses in Quito (2800 m above sea level). Samples were collected monthly from August 2004 to July 2005. Patients presenting to a local outpatient allergy clinic with asthma and rhinitis and isolated allergy to Dermatophagoides were analysed to determine if a correlation existed between seasonal Der allergen levels and the number of patients presenting with allergies. RESULTS: High levels of dust mites and humidity were observed throughout the year. The highest geometrical mean values of allergens were detected in April (Der p1, 10.15 MUg/g) and May (Der f1, 13.03 MUg/g), whilst the lowest levels were detected in August (Der p1, 4.26 MUg/g), and September (Der f1, 1.4 MUg/g). Of the 361 patients examined, 182 were allergic to Dermatophagoides, (45.6% asthmatics, 97.8% rhinitics, and 43.4% with both diseases). Patient presentation spiked in August, and from February to May. However, there was not a significant correlation between mite allergen concentrations and humidity or the number of patients presenting with allergies. CONCLUSIONS: Dust samples from mattresses in Quito revealed high concentrations of Der p1 and Der f1. We observed a trend towards increased presentation of asthmatic and rhinitic patients in the months with highest levels of allergens. PMID- 20850217 TI - An angular compounding technique using displacement projection for noninvasive ultrasound strain imaging of vessel cross-sections. AB - Strain is considered to be a useful indicator of atherosclerotic plaque vulnerability. This study introduces an alternative for a recently introduced strain imaging method that combined beam steered ultrasound acquisitions to construct radial strain images of transverse cross-sections of superficial arteries. In that study, axial strains were projected in the radial direction. Using the alternative method introduced in this study, axial displacements are projected radially, followed by a least squares estimation of radial strains. This enables the use of a larger projection angle. Consequently, fewer acquisitions at smaller beam steering angles are required to construct radial strain images. Simulated and experimentally obtained radio-frequency data of radially expanding vessel phantoms were used to compare the two methods. Using only three beam steering angles (-30 degrees , 0 degrees and 30 degrees ), the new method outperformed the older method that used seven different angles and up to 45 degrees of beam steering: the root mean squared error was reduced by 38% and the elastographic signal- and contrast-to-noise ratios increased by 1.8 dB and 4.9 dB, respectively. The new method was also superior for homogeneous and heterogeneous phantoms with eccentric lumens. To conclude, an improved noninvasive method was developed for radial strain imaging in transverse cross sections of superficial arteries. PMID- 20850220 TI - Attentional and emotional mechanisms related to pain as predictors of chronic postoperative pain: a comparison with other psychological and physiological predictors. AB - The present prospective longitudinal study on chronic postoperative pain was conducted to assess the predictive power of attentional and emotional variables specifically assumed to augment pain, such as pain hypervigilance, pain-related anxiety, pain catastrophizing and attentional biases to pain. Their relevance was determined in comparison with other psychological and physiological predictors (depression, anxiety, somatization, cortisol reactivity, pain sensitivity). In 84 young male patients the predictor variables were assessed one day before surgery (correction of chest malformation). Postoperative outcome (subjective pain intensity and pain-related disability) was assessed three (N=84) and six months (N=78) after surgery. Patients were classified into good and poor outcome groups. Patients with high pain intensity three (25%) or six months (14%) after surgery, differed significantly from those low in pain with regard to their preoperative performance in the dot-probe task (high attentional bias towards positive words). A sizeable portion (54%) of patients still felt disabled due to pain after three months and a few patients after six months (13%). These patients were those with high preoperative ratings in the Pain Vigilance and Awareness Questionnaire. The few subjectively disabled patients after six months could be identified in addition by low pressure pain and high cold pain thresholds before surgery. An attentional bias towards positive stimuli prior to surgery may indicate a maladaptive coping style, which avoids necessary confrontation with pain and predisposes patients to chronic postoperative pain. Lasting subjectively felt pain-related disability occurs predominantly in patients with high levels of pain hypervigilance before surgery. PMID- 20850222 TI - In vitro selection and differentiation of ivermectin resistant cyathostomin larvae. AB - Cyathostomins are considered to be the primary helminth pathogen of horses and macrocyclic lactones (ML) are the most frequently used anthelmintics. Therefore, ML resistance is a serious threat for the control of these parasites. In the present study ivermectin resistant cyathostomin L3 were in vitro selected, using a reiterative larval migration inhibition assay (rLMIA) and differentiated by reverse line blot (RLB). Larvae were obtained from two populations, one from a never treated, free-roaming horse population in the nature reserve Oostvaardersplassen (OVP) and the other from regularly ivermectin-treated ponies of Utrecht University (UU). In the rLMIA the proportion of larvae that migrated increased with each passage, demonstrating that the applied procedure indeed selects for larvae the least susceptible for ivermectin. This was further supported by the fact that glutamate addition to this procedure reversed the selection effect, which also suggests that glutamate-gated chloride channels (GluCls) play a role in the ivermectin resistance of the selected L3. In both populations the predominant species were Cyathostomum catinatum, Cylicostephanus longibursatus and Cylicocyclus nassatus. After in vitro selection in the rLMIA in the presence of ivermectin the predominant species became C. catinatum in both larval populations, while C. nassatus disappeared in the never treated OVP larval population but not in the regularly ivermectin-exposed UU population. It is concluded that the rLMIA and RLB can be used to study anthelmintic resistance in cyathostomin populations and to study differences and changes in species composition between populations with different anthelmintic exposure histories. PMID- 20850223 TI - Variants in estrogen receptor alpha gene are associated with phenotypical expression of obsessive-compulsive disorder. AB - Compelling data from animal and clinical studies suggest that sex steroids may play a role in the etiopathology of obsessive-compulsive disorder (OCD). The aim of this study was to investigate whether variants in estrogen receptor genes ESR1 and ESR2 may contribute to the genetic susceptibility to OCD, through a case control association study using an extensive linkage disequilibrium-mapping approach. Twenty tag single-nucleotide polymorphisms (tagSNPs) covering the ESR2 region and nine tagSNPS from regions of ESR1 reported to be related to transcriptional control were genotyped in 229 OCD patients and 279 controls. SNP association and haplotype analysis were performed. The association of these genes and OCD subphenotypes was tested, considering early-onset OCD, comorbid tic and affective disorders, and OCD symptom dimensions. No significant difference in the distribution of alleles or genotypes was detected between controls and OCD subjects. Nevertheless, on analyzing OCD subphenotypes, SNP rs34535804 in ESR1 and a five SNPs haplotype, located at the 5' end of intron 1 of ESR1, were associated with the presence of contamination obsessions and cleaning compulsions. Specifically, carriers of the ACCCG haplotype, a combination of functional alleles related to higher ER alpha expression, showed a reduced risk of suffering from these symptoms. Our results suggest that the ESR1 gene may contribute to the genetic vulnerability to certain OCD manifestations. The dissection of OCD into more homogeneous subphenotypes may well help to identify susceptibility genes for the disorder. PMID- 20850221 TI - Neonatal colon insult alters growth factor expression and TRPA1 responses in adult mice. AB - Inflammation or pain during neonatal development can result in long-term structural and functional alterations of nociceptive pathways, ultimately altering pain perception in adulthood. We have developed a mouse model of neonatal colon irritation (NCI) to investigate the plasticity of pain processing within the viscerosensory system. Mouse pups received an intracolonic administration of 2% mustard oil (MO) on postnatal days 8 and 10. Distal colons were processed at subsequent timepoints for myeloperoxidase (MPO) activity and growth factor expression. Adult mice were assessed for visceral hypersensitivity by measuring the visceromotor response during colorectal distension. Dorsal root ganglion (DRG) neurons from adult mice were retrogradely labeled from the distal colon and calcium imaging was used to measure transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) responses to acute application of capsaicin and MO, respectively. Despite the absence of inflammation (as indicated by MPO activity), neonatal exposure to intracolonic MO transiently maintained a higher expression level of growth factor messenger RNA (mRNA). Adult NCI mice displayed significant visceral hypersensitivity, as well as increased sensitivity to mechanical stimulation of the hindpaw, compared to control mice. The percentage of TRPA1-expressing colon afferents was significantly increased in NCI mice, however they displayed no increase in the percentage of TRPV1 immunopositive or capsaicin-sensitive colon DRG neurons. These results suggest that early neonatal colon injury results in a long-lasting visceral hypersensitivity, possibly driven by an early increase in growth factor expression and maintained by permanent changes in TRPA1 function. PMID- 20850224 TI - Predictors of psychosis severity in individuals with primary stimulant addictions. AB - The goal of this study is to define the factors that could contribute to the development, severity, and persistence of psychotic symptoms in individuals with stimulant addiction. We hypothesize that particular drug use variables may contribute to the severity of psychiatric symptoms. Thirty-seven stimulant users, abstinent for >30 days were recruited from the community. Previous drug use and current and past psychiatric symptoms were assessed using validated objective rating scales and several self-report questionnaires. Age at first use of the stimulant drug was inversely related to the Beck Anxiety Inventory score, and the subjects with more than 5 years duration of chronic use exhibited greater severity of symptoms on the PANSS Positive and General Scales and total score. The method of drug administration, duration of abstinence, latency from first use to regular use, and prior solicitation of treatment were not related to PANSS total and subscale scores or other clinical variables. Severity of psychosis appears to be related to earlier and longer exposure to stimulants, consistent with a "threshold" effect of stimulant use on the development of psychotic symptoms. The association may also suggest a critical developmental period that is most susceptible to the deleterious effects of stimulant exposure. PMID- 20850225 TI - In utero anaphylaxis. AB - Late fetal demise and hypoxic-ischemic neurologic injury after previously normal in utero development remain devastating outcomes of pregnancy, for which no cause is identified in many cases. Based on a case encountered, I propose that some of these incidents may be due to in utero anaphylaxis to food antigens that cross the placenta. Potential allergens to which pregnant women are exposed can be transported across the placenta, and the fetus is capable of producing IgE, the antibody responsible for anaphylaxis in humans. Whether this IgE is antigen specific is controversial with some studies indicating the ability to generate IgE to food antigens prenatally. Indirect evidence for in utero production of specific IgE is the high percentage of food reactions that occur on the first postnatal exposure to the food. I propose that some cases of stillbirth and prenatal hypoxic-ischemic injury may be due to in utero anaphylaxis. PMID- 20850226 TI - Color stability of ground beef packaged in a low carbon monoxide atmosphere or vacuum. AB - Ground beef was either packaged in an atmosphere of 0.4% CO, 30% CO2, and 69.6% N2 (CO-MAP) or vacuum. After storage (48 h, 2-3 degrees C), packages of CO-MAP and vacuum were opened and overwrapped with polyvinyl chloride. Other CO-MAP and vacuum packages were left intact. Packages were initially displayed for 7 days (2 3 degrees C). Intact packages were further displayed up to 35 days before being opened and displayed (1 or 3 days). Intact CO-MAP packaged ground beef was always more red than intact vacuum-packaged ground beef. Color was relatively stable for both types of intact packages over 35 days of display. Upon opening CO-MAP packaged ground beef, the red color decreased slower than in ground beef from vacuum packages. PMID- 20850227 TI - Core classification of head and neck squamous cell carcinomas: correlations between morphology, DNA ploidy and HPV infection. AB - AIMS: The study intended to reveal whether HPV infection is reflected by nuclear morphology and DNA cytometry parameters in head and neck squamous cell carcinomas (HNSCC). METHODS: In total, 39 HNSCC were selected for reanalysis by histomorphology applying the core classification, DNA cytometry and HPV detection. For the core classification, HE sections were assessed by a score system to evaluate the nuclear size, the mitosis size, their variabilities and the presence of tripolar or tetrapolar mitoses. HPV was analyzed by consensus PCR followed by a hybridization method for virus typing. Static DNA cytometry was applied on single cell suspension focusing particularly on the parameters DNA modal value, DNA index peak, DNA index mean, 2c deviation index and 5c exceeding rate. Statistical analysis was done by T-test or Fisher's exact test. RESULTS: The analysis revealed that HPV positive HNSCC had significantly smaller nuclei than HPV negative cases. Increasing values of the nuclear size and mitosis size were significantly associated with higher indices of the DNA cytometry analysis. CONCLUSIONS: The study confirms that the core classification can provide information on the ploidy of HNSCC and that HPV positive tumors represent a distinct morphological and genetic carcinoma subtype. PMID- 20850228 TI - [Spontaneous uterine rupture after myomectomy. Case report and review of the literature]. AB - Uterine rupture after myomectomy is rare but serious. It can occur before onset of labor and compromise vital maternofoetal outcome. We report the case of a uterine rupture at 25-week gestation in a 38-year-old primiparous woman after myomectomy and we will present a review of the literature concerning obstetric outcome after myomectomy. PMID- 20850229 TI - [Culture and susceptibility testing of mycobacteria with VersaTREK]. AB - OBJECTIVES: Our laboratory of microbiology use the VersaTREK/ESP Culture System II for the isolation of mycobacteria. In this study, we evaluate this system for the analysis carried out between April 2009 and March 2010. METHOD: The Myco bottles are supplemented with growth supplements and an antimicrobial agent solution prior to inoculation with the specimen. The technology of the VersaTREK/ESP Culture System II is based on the detection of headspace pressure changes within a sealed bottle. It monitors changes in either gas production or gas consumption due to microbial growth. A special algorithm has been developed for detection of very slow growing mycobacteria. The bottles are incubated during 42 days. Meanwhile a solid medium is inoculated too. All specimen types can be analysed with this system. RESULTS: Compared to solid culture, the time needed for detection of positive cultures was significantly shorter for the VersaTREK with a good recovery rate. For isolates recovered in both systems, mean time of detection is respectively 19.1 and 35.6 days for liquid and solid cultures. Mycobacteria identification may be determined using nucleic acid probs directly in Myco VersaTREK or in the solid medium. The susceptibility test of Mycobacteria tuberculosis complex is obtained between six and 13 days for rifampin, isoniazid, ethambutol, streptomycin and pyrasinamide. CONCLUSION: This system offers a faster diagnosis and is an alternative to other instruments using liquid culture. PMID- 20850230 TI - [Comparative serologic proteome analysis of Staphylococcus aureus and S. epidermidis exoproteins in prosthetic joint infections]. AB - AIM OF THE STUDY: Staphylococci such as Staphylococcus aureus and S. epidermidis are the most frequently pathogens associated to prosthesis joint infections (PJI), counting for 75% among the isolated bacteria. In this study, we identified PJI-related antigens using two-dimensional immunoblots of S. aureus and S. epidermidis exoproteins probed with serum samples from patients with confirmed PJIs. We further analysed by ELISA tests the response of patients to the identified proteins. PATIENTS AND METHODS: Secreted proteins from Mu50 strain (S. aureus) and RP62A strain (S. epidermidis) were separated by 2D gel electrophoresis and analyzed by western blot with serum samples from patients with confirmed S. aureus and S. epidermidis PJIs. Recombinant proteins corresponding to the identified proteins were expressed and screened with an in house ELISA to evaluate their interest for the diagnosis of S. aureus and S. epidermidis PJIs. RESULTS: Fifty-two antigenic exoproteins were identified: 42 belonging to Mu50 strain, and 10 to RP62A strain. Twenty-two proteins were identified as S. aureus specific. Among these proteins, five were most frequently recognized by patients with S. aureus PJI. CONCLUSION: Our results showed that few exoproteins were antigenic by RP62A strain compared to Mu50 strain. We identified five antigenic and S. aureus specific proteins, which may contribute to diagnosis, prevention and treatment of these infections. PMID- 20850232 TI - Avian pathogenic Escherichia coli MT78 invades chicken fibroblasts. AB - Avian pathogenic Escherichia coli (APEC) are responsible for extraintestinal diseases, called colibacillosis, in avian species. The most severe manifestation of the disease is colisepticemia that usually starts at the respiratory tract and may result in bird death. However, it is not yet clear how APEC cross the respiratory epithelium and get into the bloodstream. In this work, we studied the interaction between 8 APEC strains (UEL31, UEL17, UEL13, UEL29, MT78, IMT5155, IMT2470, A2363) and a chicken non-phagocytic cell, the fibroblast CEC-32 cell line. We investigated the association profile, the invasion capability, the cytotoxicity effect and the induction of caspase-3/7 activation in an attempt to understand the way the pathogen gains access to the host bloodstream. Association to cells was determined after 1 h of infection, while cell invasion was determined after 4 and 24 h of infection. The cytotoxic effect of bacterial infection was measured by lactate dehydrogenase (LDH) release and the activation of the apoptotic program was verified by caspase-3/7 activation. Also, the presence of genes for adhesins, invasins and other related virulence-associated factors was verified by PCR. All bacterial strains showed similarity in relation to adhesion, LDH release and caspase-3/7 activation. However, one APEC strain, MT78, showed high invasion capability, comparable to the invasive Salmonella typhimurium strain SL1344. Since an APEC strain was capable of invading non phagocytic cells in vitro, the same may be happening with the epithelial cells of the avian respiratory tract in vivo. CEC-32 monolayers can also provide a useful experimental model to study the molecular mechanisms used by APEC to invade non phagocytic cells. PMID- 20850231 TI - Assessing sleep in opioid dependence: a comparison of subjective ratings, sleep diaries, and home polysomnography in methadone maintenance patients. AB - OBJECTIVES: Comparisons of subjective and objective sleep measures have shown discrepancies between reported sleep and polysomnography (PSG) in non-drug dependent individuals with and without insomnia. Sleep may affect behavioral and physiologic aspects of drug abuse and dependence; patients in methadone maintenance therapy (MMT) for opioid dependence frequently report sleep problems. Whether subjective sleep reflects objective sleep in MMT patients is unknown. We undertook these analyses to establish the correlations among subjective and objective sleep measures in MMT patients. METHODS: We compared one week of daily sleep diaries, one night of home PSG, a questionnaire completed the morning after PSG, and the Pittsburgh Sleep Quality Inventory (PSQI) as well as demographics and drug use measures in 62 MMT patients with disturbed sleep (PSQI score > 5). RESULTS: Subjective and objective sleep durations were similar in this sample; average sleep times for the diary, morning questionnaire, and PSG were 340, 323, and 332 min, respectively. Average diary sleep time, subjective ratings of feeling rested, and PSG sleep efficiency were correlated significantly with PSQI score. Age was inversely correlated with PSG sleep time. Participants whose urine toxicology showed benzodiazapine use reported significantly longer sleep times on the morning questionnaire. CONCLUSIONS: Objective sleep measures confirm subjective measures in MMT patients with disturbed sleep. The high prevalence of sleep complaints in this population likely reflects pathology rather than sleep misperception. Both objective and subjective measures are useful in research and clinical settings for assessing sleep in opioid-dependent patients. PMID- 20850233 TI - Treatment of a nephrotic syndrome by endoscopic removal of a villous adenoma of the duodenum. AB - We report the case of a patient diagnosed with a villous adenoma of the duodenum showing high degree dysplasia who developed a nephrotic syndrome (NS) due to a membranous nephropathy (MN), demonstrated by renal biopsy. Only the endoscopic resection of the duodenal adenoma could control the NS. The first manifestation of a MN is often the development of a NS. Up to 20% of patients older than 65 years who develop a MN have cancer. Tumours most often identified are those of lung, prostate and digestive tract. A renal biopsy is required to identify this type of nephropathy. If a diagnosis of MN is made, an associated tumour should be looked for. PMID- 20850234 TI - Heartbeat-related distension and displacement of the thoracic aorta in healthy volunteers. AB - PURPOSE: To test our hypothesis that distension and displacement in various segments of the healthy thoracic aorta are significant and can be predicted based on clinical characteristics. MATERIALS AND METHODS: Sixty-one Caucasian volunteers without cardiovascular disease (49 +/- 16 years, range 19-82; 28 men, 33 women) divided into two age groups (A: <50, B: >= 50 years) underwent 1.5-T MRI. ECG-gated dynamic data sets were acquired at five locations perpendicular to the thoracic aorta. Aortic distension and Centre of Mass (CoM) displacement were determined as percentages of diastolic aortic diameter. A multiple linear regression model including age group, gender, location, mean arterial blood pressure, heart rate and body mass index was tested. RESULTS: Mean aortic distension averaged over all locations was 11.2 +/- 4.1% (age group A) and 6.7 +/ 3.3% (age group B), mean displacement 15.1 +/- 8.3% (A) and 11.0 +/- 6.2% (B). Systolic and diastolic aortic diameter and CoM position significantly differed at all locations (p<0.001). Distension and displacement could be predicted based on the regression model (p<0.001). Age group A and women exhibited significantly greater distension and displacement compared to age group B (p<0.001) and men (p<0.01), respectively. Distension increased, displacement decreased from proximal to distal. CONCLUSION: Distension and translational displacement are significant at all levels of the thoracic aorta and can be predicted based on clinical characteristics. PMID- 20850235 TI - Elimination of chemical shift artifacts of thoracic spine with contrast-enhanced FLAIR imaging with fat suppression at 3.0 T. AB - The purpose of this study was to assess the effect of chemical shift artifacts and fat suppression between contrast-enhanced T1-weighted fast spin-echo (FSE) sequence with fat suppression and contrast-enhanced T1-weighted fluid attenuated inversion recovery (FLAIR) sequence with fat suppression in magnetic resonance imaging (MRI) of the thoracic spine at 3.0T. Forty patients, who underwent MRI examination, were recruited and analyzed both qualitatively and quantitatively. Due to chemical shift artifacts in the T1-weighted FSE, 14 of the patients were found to be of non-diagnostic value. On the contrary, in 11 of those 14 patients, no chemical shift artifacts were observed in the T1-weighted FLAIR sequence. Regarding the efficiency of fat suppression, both sequences achieved successful fat suppression. Consequently, the use of T1-weighted FLAIR fat suppression after contrast administration sequence seems to eliminate or significantly reduce image quality deterioration stemming from chemical shift artifacts in thoracic spine examinations. PMID- 20850236 TI - Diffusion tensor fiber tractography of the olfactory tract. AB - Magnetic resonance diffusion tensor imaging with fiber tracking is used for 3 dimensional visualization of the nervous system. Peripheral nerves and all cranial nerves, except for the olfactory tract, have previously been visualized. The olfactory tracts are difficult to depict with diffusion-weighted imaging due to the high sensitivity to susceptibility artifacts at the base of the skull. Here we report an optimized single-shot diffusion-weighted echo planar imaging sequence that can visualize the olfactory tracts with fiber tracking. Five healthy individuals were examined, and the olfactory tracts could be fiber tracked with the diffusion-weighted sequence. For comparison and as a negative control, an anosmic patient was examined. No olfactory tracts were visualized on T2-weighted nor diffusion-weighted fiber tracking images. Measuring diffusion in the olfactory tracts promise to facilitate the identification of different hyposmic and anosmic conditions. PMID- 20850237 TI - Brain oscillatory activity during motor imagery in EEG-fMRI coregistration. AB - The purpose of the present work was to investigate the correlation between topographical changes in brain oscillatory activity and the blood oxygenation level-dependent (BOLD) signal during a motor imagery (MI) task using electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) coregistration. EEG was recorded in 7 healthy subjects inside a 1.5 T MR scanner during the imagination of the kinesthetic experience of movement. A Fast Fourier Transform was applied to EEG signal in the rest and active conditions. We used the event-related-synchronization (ERS)/desynchronization (ERD) approach to characterize where the imagination of movement produces a decrease in alpha and beta power. The mean alpha map showed ERD decrease localized over the contralateral sensory motor area (SM1c) and a light desynchronization in the ipsilateral sensory motor area (SM1i); whereas the mean beta map showed ERD decrease over the supplementary motor area (SMA). fMRI showed significant activation in SMA, SM1c, SM1i. The correlation is negative in the contralateral side and positive in the ipsilateral side. Using combined EEG-fMRI signals we obtained useful new information on the description of the changes in oscillatory activity in alpha and beta bands during MI and on the investigation of the sites of BOLD activity as possible sources in generating these rhythms. By correlating BOLD and ERD/ERS we may identify more accurately which regions contribute to changes of the electrical response. PMID- 20850238 TI - Keyhole and zero-padding approaches for reduced-encoding diffusion tensor imaging of the mouse brains. AB - Keyhole diffusion tensor imaging (keyhole DTI) was previously proposed in cardiac imaging to reconstruct DTI maps from the reduced phase-encoding images. To evaluate the feasibility of keyhole DTI in brain imaging, keyhole and zero padding DTI algorithms were employed on in vivo mouse brain. The reduced phase encoding portion, also termed as the sharing rate, was varied from 50% to 90% of the full k-space. Our data showed that zero-padding DTI resulted in decreased fractional anisotropy (FA) and decreased mean apparent diffusion coefficient (mean ADC) in white matter (WM) regions. Keyhole DTI showed a better edge preservation on mean ADC maps but not on FA maps as compared to the zero-padding DTI. When increasing the sharing rate in keyhole approach, an underestimation of FA and an over- or underestimation of mean ADC were measured in WM depending on the selected reference image. The inconsistency of keyhole DTI may add a challenge for the wide use of this modality. However, with a carefully selected directive diffusion-weighted image to serve as the reference image in the keyhole approach, this study demonstrated that one may obtain DTI indices of reduced encoding images with high consistency to those derived with full k-space DTI. PMID- 20850239 TI - Denoising 3D MR images by the enhanced non-local means filter for Rician noise. AB - The non-local means (NLM) filter removes noise by calculating the weighted average of the pixels in the global area and shows superiority over existing local filter methods that only consider local neighbor pixels. This filter has been successfully extended from 2D images to 3D images and has been applied to denoising 3D magnetic resonance (MR) images. In this article, a novel filter based on the NLM filter is proposed to improve the denoising effect. Considering the characteristics of Rician noise in the MR images, denoising by the NLM filter is first performed on the squared magnitude images. Then, unbiased correcting is carried out to eliminate the biased deviation. When performing the NLM filter, the weight is calculated based on the Gaussian-filtered image to reduce the disturbance of the noise. The performance of this filter is evaluated by carrying out a qualitative and quantitative comparison of this method with three other filters, namely, the original NLM filter, the unbiased NLM (UNLM) filter and the Rician NLM (RNLM) filter. Experimental results demonstrate that the proposed filter achieves better denoising performance over the other filters being compared. PMID- 20850240 TI - Influence of attention focus on neural activity in the human spinal cord during thermal sensory stimulation. AB - Perceptions of sensation and pain in healthy people are believed to be the net result of sensory input and descending modulation from brainstem and cortical regions depending on emotional and cognitive factors. Here, the influence of attention on neural activity in the spinal cord during thermal sensory stimulation of the hand was investigated with functional magnetic resonance imaging by systematically varying the participants' attention focus across and within repeated studies. Attention states included (1) attention to the stimulus by rating the sensation and (2) attention away from the stimulus by performing various mental tasks of watching a movie and identifying characters, detecting the direction of coherently moving dots within a randomly moving visual field and answering mentally-challenging questions. Functional MRI results spanning the cervical spinal cord and brainstem consistently demonstrated that the attention state had a significant influence on the activity detected in the cervical spinal cord, as well as in brainstem regions involved with the descending analgesia system. These findings have important implications for the detection and study of pain, and improved characterization of the effects of injury or disease. PMID- 20850241 TI - Arterial spin labeling MRI for assessment of perfusion in native and transplanted kidneys. AB - PURPOSE: To apply a magnetic resonance arterial spin labeling (ASL) technique to evaluate kidney perfusion in native and transplanted kidneys. MATERIALS AND METHODS: This study was compliant with the Health Insurance Portability and Accountability Act and approved by the institutional review board. Informed consent was obtained from all subjects. Renal perfusion exams were performed at 1.5 T in a total of 25 subjects: 10 with native and 15 with transplanted kidneys. A flow-sensitive alternating inversion recovery (FAIR) ASL sequence was performed with respiratory triggering in all subjects and under free-breathing conditions in five transplant subjects. Thirty-two control/tag pairs were acquired and processed using a single-compartment model. Perfusion in native and transplanted kidneys was compared above and below an estimated glomerular filtration rate (eGFR) threshold of 60 ml/min per 1.73 m2 and correlations with eGFR were determined. RESULTS: In many of the transplanted kidneys, major feeding vessels in the coronal plane required a slice orientation sagittal to the kidney. Renal motion during the examination was observed in native and transplant subjects and was corrected with registration. Cortical perfusion correlated with eGFR in native (r=0.85, P=.002) and transplant subjects (r=0.61, P=.02). For subjects with eGFR >60 ml/min per 1.73 m2, native kidneys demonstrated greater cortical (P=.01) and medullary (P=.04) perfusion than transplanted kidneys. For subjects with eGFR <60 ml/min per 1.73 m2, native kidneys demonstrated greater medullary perfusion (P=.04) compared to transplanted kidneys. Free-breathing acquisitions provided renal perfusion measurements that were slightly lower compared to the coached/triggered technique, although no statistical differences were observed. CONCLUSION: In conclusion, FAIR-ASL was able to measure renal perfusion in subjects with native and transplanted kidneys, potentially providing a clinically viable technique for monitoring kidney function. PMID- 20850242 TI - Reduced field-of-view diffusion-weighted imaging of the brain at 7 T. AB - Ventral and rostral regions of the brain are of emerging importance for the MRI characterization of early dementia, traumatic brain injury and epilepsy. Unfortunately, standard single-shot echo planar diffusion-weighted imaging of these regions at high fields is contaminated by severe imaging artifacts in the vicinity of air-tissue interfaces. To mitigate these artifacts and improve visualization of the temporal and frontal lobes at 7 T, we applied a reduced field-of-view strategy, enabled by outer volume suppression (OVS) with novel quadratic phase radiofrequency (RF) pulses, combined with partial Fourier and parallel imaging methods. The new acquisition greatly reduced the level of artifacts in six human subjects (including four patients with early symptoms of dementia). PMID- 20850243 TI - Composite MR image reconstruction and unaliasing for general trajectories using neural networks. AB - In rapid parallel magnetic resonance imaging, the problem of image reconstruction is challenging. Here, a novel image reconstruction technique for data acquired along any general trajectory in neural network framework, called "Composite Reconstruction And Unaliasing using Neural Networks" (CRAUNN), is proposed. CRAUNN is based on the observation that the nature of aliasing remains unchanged whether the undersampled acquisition contains only low frequencies or includes high frequencies too. Here, the transformation needed to reconstruct the alias free image from the aliased coil images is learnt, using acquisitions consisting of densely sampled low frequencies. Neural networks are made use of as machine learning tools to learn the transformation, in order to obtain the desired alias free image for actual acquisitions containing sparsely sampled low as well as high frequencies. CRAUNN operates in the image domain and does not require explicit coil sensitivity estimation. It is also independent of the sampling trajectory used, and could be applied to arbitrary trajectories as well. As a pilot trial, the technique is first applied to Cartesian trajectory-sampled data. Experiments performed using radial and spiral trajectories on real and synthetic data, illustrate the performance of the method. The reconstruction errors depend on the acceleration factor as well as the sampling trajectory. It is found that higher acceleration factors can be obtained when radial trajectories are used. Comparisons against existing techniques are presented. CRAUNN has been found to perform on par with the state-of-the-art techniques. Acceleration factors of up to 4, 6 and 4 are achieved in Cartesian, radial and spiral cases, respectively. PMID- 20850244 TI - Ultrafast MRI of the fetus: an increasingly important tool in prenatal diagnosis of congenital anomalies. AB - OBJECTIVE: To demonstrate the additional utility of ultrafast magnetic resonance imaging (MRI) of the fetus in the evaluation of sonographically detected or equivocal fetal congenital anomalies. MATERIAL AND METHODS: Twenty five pregnant women with ultrasound detected fetal congenital anomalies underwent ultrafast fetal MRI. RESULTS: MRI findings altered the diagnosis of two cases of giant arachnoid cyst and sizable interhemispheric cyst associated with agenesis of the corpus callosum. MRI added additional findings of occult spinal diastematomyelia in two out of four cases of Chiari/meningocele malformation. MRI revealed impaired sulcation and unilateral cleft palate in suspected case of Walker Warburg syndrome. In the remaining 18 cases MRI confirmed the diagnosis of Meckel Gruber syndrome in three cases, hydronephrosis in six cases, cerebral ventriculomegaly in five cases, isolated omphalocele in three cases and findings suggestive of aneuploidy in the last case. CONCLUSION: Ultrasound is the screening method of choice for evaluation of the fetus. Ultrafast MRI is a complementary adjunctive modality with excellent tissue contrast that can image the fetus in multiple planes and add information in sonographically detected or equivocal congenital anomalies that may be significant to establish definitive accurate diagnosis and hence adequate management and counseling. PMID- 20850245 TI - Inflammatory imaging with ultrasmall superparamagnetic iron oxide. AB - The purpose of this study was to investigate the usefulness and feasibility of magnetic resonance imaging (MRI) with ultrasmall superparamagnetic iron oxide (USPIO) (USPIO-enhanced MRI) for imaging inflammatory tissues. First, we investigated the relationship between the apparent transverse relaxation rate (R2*) and the concentration of USPIO by phantom studies and measured the apparent transverse relaxivity (r2*) of USPIO. Second, we performed animal experiments using a total of 30 mice. The mice were divided into five groups [A (n=6), B (n=6), C (n=6), sham control (n=6), and control (n=6)]. The mice in Groups A, B, C and control were subcutaneously injected with 0.1 ml of turpentine oil on Day 0, while those in the sham control group were subcutaneously injected with 0.1 ml of saline. The mice in Groups A, B, C and sham control were intraperitoneally injected with 200 MUmol Fe per kilogram body weight of USPIO (28 nm in diameter) immediately after the first MRI study on Days 3, 5, 7 and 7, respectively, and those in the control group were not injected with USPIO. The second and third MRI studies were performed at 24 and 48 h after USPIO administration, respectively. The maps of R2* were generated from the apparent transverse relaxation time (T2*) weighted images with six different echo times. The phantom studies showed that there was a linear relationship between R2* and the concentration of USPIO (r=0.99) and the r2* value of USPIO was 105.7 mM(-1) s(-1). There was a significant increase of R2* in inflammatory tissues in Group C at 24 h after USPIO administration compared with the precontrast R2* value. Our results suggest that USPIO-enhanced MRI combined with R2* measurement is useful for detecting inflammatory tissues. PMID- 20850246 TI - Quantification of microporosity in fruit by MRI at various magnetic fields: comparison with X-ray microtomography. AB - Microstructure determines the mechanical and transport properties of fruit tissues. One important characteristic of the microstructure is the relative volume fraction of gas-filled intercellular spaces, i.e., the tissue microporosity. Quantification of this microporosity is fundamental for investigating the relationship between gas transfer and various disorders in fruit. We present a new method for quantifying the apparent microporosity using magnetic resonance imaging (MRI). The method is based on the differences in magnetic susceptibility between gas-filled intercellular spaces and their environment inside fruit tissues. It was tested at two different magnetic fields (1.5 and 0.2 T) on apple and tomato fruit. The method was validated by comparing the MRI results with estimation of local tissue porosity using X-ray microtomography experiments. MRI was shown to be effective in determining the distribution of apparent microporosity in fruit. PMID- 20850247 TI - Identification of nontuberculous mycobacterial infection by IS6110 and hsp65 gene analysis on lung tissues. AB - The clinical, histologic, and radiographic presentations of nontuberculous mycobacterial (NTM) lung disease are usually indistinguishable from those of reactivated pulmonary tuberculosis (TB), so it remains a great challenge for the clinician to make treatment decisions for patients with old TB and a positive culture result for NTM. This study investigated whether the mycobacterial specific heat shock protein 65 (hsp65) and Mycobacterium tuberculosis (MTB) specific IS6110 gene would present in pulmonary lesions of patients with NTM pulmonary infection. Formalin-fixed and paraffin-embedded (FFPE) tissue blocks of 24 patients with NTM infections treated at the hospital from 1998 to 2008 were included. Mycobacterial hsp65 gene was amplified in 20 of the 24 patients, and the species identified by sequencing was consistent with corresponding culture results in 12 of these patients. MTB-specific IS6110 gene was detected in 3 of the 7 patients who had old TB and a subsequent diagnosis of fibrocavitary NTM lung disease. Polymerase chain reaction (PCR) analysis of hsp65 gene also confirmed the presence of MTB genes in 2 of these 3 patients. Our results indicate that PCR amplification and sequencing of the mycobacterial hsp65 gene is a sensitive assay for identification of NTM species in FFPE materials. However, consistent results of PCR analysis, microbiology study, histologic manifestations, radiology, and clinical presentation are important for correct diagnosis of NTM pulmonary infection. The presence of MTB gene in patients with fibrocavitary NTM lung lesions poses a clinical dilemma for deciding concurrent treatment TB and NTM infection. PMID- 20850248 TI - Differentiation of Trypanosoma cruzi and Trypanosoma rangeli of Colombia using minicircle hybridization tests. AB - Although Trypanosoma rangeli is harmless for humans, it is a serious problem since it may be confused with diagnosis of Trypanosoma cruzi, the etiologic agent of Chagas disease. Both parasites overlap geographically, share antigenic protein, and are able to infect the same Triatominae vector and vertebrate host, including human. Our objective was to differentiate T. cruzi and T. rangeli isolates from Colombia based on polymerase chain reaction (PCR) amplification of the minicircles followed by appropriate hybridization tests with selected DNA probes and restriction fragment length polymorphism (RFLP) analysis. We worked with highly characterized T. cruzi and T. rangeli isolates from different biologic origins and geographic areas of Colombia, and they were analyzed by RFLP and PCR amplification of variable region of minicircles and Southern blot analysis. Our results and experimental conditions demonstrate the usefulness of PCR amplification of the minicircles followed by Southern blot analysis to differentiate T. cruzi from T. rangeli, which can be highly important to improve diagnosis of Chagas disease. PMID- 20850249 TI - Escherichia coli producing KPC-2 carbapenemase: first report in Brazil. PMID- 20850250 TI - Diagnostic value of an enzyme-linked immunospot assay for interferon-gamma in genitourinary tuberculosis. AB - The aim of this study was to evaluate the diagnostic performance of an enzyme linked immunospot (ELISPOT) assay for interferon-gamma in patients with suspected genitourinary tuberculosis (TB). A total of 30 patients with suspected genitourinary TB at the National Taiwan University Hospital, Taipei, Taiwan, were prospectively enrolled from January 2007 to December 2009, and 12 of whom had positive urine culture for Mycobacterium tuberculosis. Frequency and dysuria were the most common symptoms noted in 6 (50.0%) and 4 (33.3%) patients, respectively. Pyuria was the most common finding of urinalysis noted in 11 (91.7%) patients. Six (50.0%) patients had positive acid-fast stain in urine. Among the 30 patients, 13 patients had positive ELISPOT assay. Eleven patients with positive ELISPOT assay had culture-confirmed TB, and the remaining 2 patients without evidence of active TB had positive ELISPOT assay. The overall sensitivity, specificity, positive predictive value, and negative predictive value for genitourinary TB diagnosis by the ELISPOT assay were 91.7% (95% confidence interval [CI], 59.8-99.6%), 88.9% (95% CI, 63.9-98.1%), 84.6% (95% CI, 53.7 97.3%), and 94.1% (95% CI, 69.2-96.7%), respectively. In conclusion, ELISPOT assay can provide useful support in diagnosing genitourinary TB. PMID- 20850252 TI - An intra-cardiac mass incidentally detected by computed tomography with bolus injection of intravenous contrast: intra-cardiac filling defect. PMID- 20850251 TI - Detection of Helicobacter rodentium-like DNA in the liver tissue of patients with chronic liver diseases by polymerase chain reaction-denaturing gradient gel electrophoresis and DNA sequence analysis. AB - Many Helicobacter spp. were isolated from the stomach, intestinal tract, and liver of different animals and humans. The association between Helicobacter spp. and hepatobiliary diseases, including hepatocellular carcinoma, was thoroughly examined, indicating a potential role of the bacteria in the progression toward cancer. In our work, we screened 97 liver biopsies from patients with chronic liver diseases for the presence of Helicobacter spp. DNA. With the use of genus specific polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and subsequent sequencing, we found that the majority of Helicobacter spp. DNA detected was similar to Helicobacter rodentium DNA (71%). The DNA of other detected Helicobacter spp. was similar to Helicobacter pylori DNA. This is the first indication of H. rodentium-like DNA presence in human liver tissue. We also conclude that PCR-DGGE is a useful screening method for assigning species designation and heterogeneity. PMID- 20850253 TI - Hypokalemia-induced ventricular fibrillation. PMID- 20850254 TI - Field-induced therapeutic hypothermia for neuroprotection after out-of hospital cardiac arrest: a systematic review of the literature. AB - BACKGROUND: Emergency Medical Services (EMS) has started to embrace the early use of therapeutic hypothermia as standard treatment to improve neurological recovery in out-of hospital cardiac arrest (OHCA) survivors. OBJECTIVE: We conducted a systematic review to provide an overall description of the current literature on the use of therapeutic hypothermia in OHCA and to identify possible gaps in the literature. METHODS: Comprehensive searches of MEDLINE, PubMed, CINAHL, and ISI Web of Science from 1950 to March 2009, and EMBASE from 1988 to March 2009 were performed. Bibliographies of selected articles were hand searched. Two reviewers independently selected studies on the basis of three inclusion criteria. Two additional independent reviewers assessed selected studies for quality. RESULTS: Of more than 800 screened citations, a total of 11 published studies were included in the systematic review. Three studies were conducted in the United States, three in Finland, and one each in Australia, France, Germany, Austria, and Norway. Four of the studies were pilot clinical trials that provided prehospital mild therapeutic hypothermia during active cardiopulmonary resuscitation. The remaining seven studies performed cooling after return of spontaneous circulation. Significant differences in research methodology and outcome measures were noted. Eight studies scored poor for quality. CONCLUSIONS: The use of mild therapeutic hypothermia is gaining acceptance within the EMS community. It seems that hypothermia can be efficiently induced in the prehospital environment. There is a need for more research in this area to understand the effectiveness and timing of early therapeutic hypothermia in the prehospital environment. PMID- 20850255 TI - Acute abdomen associated with organophosphate poisoning. AB - BACKGROUND: Pesticides are extensively used in developed and developing countries. OBJECTIVES: The present study was designed to evaluate the clinical course of patients with carbamate or organophosphate poisoning presenting to a University-based emergency department (ED). METHODS: All consecutive patients admitted to our ED due to intoxication with carbamate or organophosphate compounds over a 2-year period were enrolled prospectively. RESULTS: A total of 49 consecutive patients (26 females) were diagnosed with carbamate or organophosphate poisoning in the 24-month study period. The mean age of the patients was 32+/-13.1 years (range 16-70 years). Signs and symptoms most frequently noted in patients with organophosphate or carbamate poisoning were perspiration, vomiting, and bronchorrhea. Abdominal pain was reported by 65.3% of the patients. Abdominal ultrasonography was performed in 22 patients who complained of abdominal pain as a leading symptom. Among these, 63.6% were found to have abdominal free fluid. Pancreatitis and peritonitis developed in one case. Atropine treatment was administered for approximately 24-36h, with a mean total dose of 13.75+/-6.75mg. Pralidoxime was administered to 70.9% of patients with organophosphate poisoning, but was not used in patients intoxicated with carbamates. Endotracheal intubation and mechanical ventilatory support were required in 14.2% of the patients. Mean duration of mechanical ventilation was 3.7+/-2.2 days. The overall mortality rate was 10.2%. CONCLUSION: Patients with a diagnosis of organophosphate poisoning should be screened for acute abdomen. The findings in our study suggest that these patients should undergo routine abdominal ultrasonography, especially in cases with abdominal pain along with other abdominal complaints. PMID- 20850256 TI - Delayed visceral bleeding from liver injury after cardiopulmonary resuscitation. AB - BACKGROUND: Visceral injury is a life-threatening complication of cardiopulmonary resuscitation (CPR); however, the clinical significance has been masked by the lethal outcome of out-of-hospital cardiac arrest (OHCA). OBJECTIVE: The objective is to share our experience of successful treatment of OHCA patients with serious, CPR-related visceral complications. CASE REPORTS: We report two cases of cardiac origin OHCA with liver injury exacerbated by heparinization during mechanical circulatory support. Although both patients presented with delayed massive liver bleeding (intrahepatic or peritoneal) that compromised hemodynamic status, one patient was successfully treated by selective transcatheter arterial embolization and the other by a surgical procedure. CONCLUSION: Preventive measures such as careful CPR, as well as interventional or surgical repair after the early diagnosis of visceral injury, are required to improve the outcome in some cases of OHCA. PMID- 20850257 TI - Moving forward to improve medication adherence. PMID- 20850258 TI - Women's cognitive and affective reactions to breast cancer survivor stories: a structural equation analysis. AB - OBJECTIVE: Compare the immediate affective and cognitive reactions to cancer survivor stories about mammography and breast cancer vs. a didactic, informational approach. METHODS: Participants (N=489) were African American women age 40 years and older (mean=61). Most had <=high school education (67%), annual household income <=$20,000 (77%), and a prior mammogram (89%). Participants completed surveys before and after watching the narrative or informational video. We used structural equation modeling to examine the large number of inter-related latent constructs. RESULTS: Women who watched the narrative video experienced more positive and negative emotions, found it easier to understand the video, had more positive evaluations of the video, reported stronger identification with the message source (i.e., perceived similarity, trust, liking), and were more engaged with the video. CONCLUSION: Narratives elicited immediate reactions consistent with theorized pathways of how communication affects behavior. Future studies should examine whether and how these immediate outcomes act as mediators of the longer term effects of narratives on affect, cognitions, and behavior. PRACTICE IMPLICATIONS: Stories of other women's experiences may be more powerful than a didactic presentation when encouraging African American women to get a mammogram. PMID- 20850260 TI - Les bebes du thalidomide. PMID- 20850259 TI - Organizational factors associated with the use of contingency management in publicly funded substance abuse treatment centers. AB - A promising area within technology transfer studies is the identification of organizational factors that influence the adoption of treatment innovations. Although studies have identified organizational factors associated with the adoption of pharmacological innovations, few studies have examined organizational factors in the adoption of psychosocial innovations, among which contingency management (CM) is a significant practice. Using data from a sample (N = 318) drawn from the population of publicly funded treatment centers in the United States, this study modeled organizational factors falling in the domains of structural characteristics, workforce variables, values and norms, and patient characteristics associated with the use of CM. Organizations were more likely to use CM if they embrace a supportive therapeutic approach, are research friendly, offer only outpatient levels of care, or serve drug-court patients. Implications for studying the diffusion and implementation of evidence-based psychosocial interventions are discussed. PMID- 20850261 TI - [Treatment of limbs lymphedema]. AB - The treatment of lymphedema aims to reduce the volume and prevent infectious and joints mobility complications. This treatment rarely cure and is usually symptomatic; thus it should be continued throughout the life. The erysipelas and lymphangitis are common complications of lymphedema. Erysipela is always of streptococcal origin and requires systemic antibiotics. The risk of recurrent erysipelas on lymphedema is high. In case of large swelling associated with significant dermal sclerosis, it may lead to decrease joint mobility and functional impairment. The skin cares, manual lymph drainage, compression therapy with bandages and exercises are the four pillars of the complex decongestive therapy of limb lymphedema. Compression is the most important treatment. Lymphedema can be improved by only bandages, but a sustained improvement of lymphedema cannot be seen without bandages. The effectiveness of treatment must be evaluated by objective methods, measuring the perimeters of members or volumes. The management of lymphedema includes three phases: attack or initial treatment that aims to reduce volume of the lymphedema and maintenance phase to maintain the result and finally withdrawal phase. In the attack phase, we use complex decongestive therapy, mainly multilayer inelastic bandaging and manual lymphatic drainage (MLD). In the maintenance phase, we use elastic compression (stockings or sleeves) possibly associated with MLD. At all stages skin care and exercises are used. Adjuvant treatments may be useful (intermittent pneumatic compression, drug treatment). Surgery is rarely used except for genital lymphedema. The therapeutic management of lymphedema is difficult but has a variety of techniques. The complex decongestive therapy is very effective to restore a better quality of life even though it does not provide a cure for lymphedema. PMID- 20850262 TI - [Cicatricial pemphigoid, mucous membrane pemphigoid]. AB - Mucous membrane pemphigoid belongs to the family of sub-epidermal bullous diseases and is clinically characterized by mucosal involvement leading to fibrosis and scarring. Cutaneous involvement is unfrequent and oral mucosa and conjunctivas are the most frequently involves mucosa. Treatment relies on anti inflammatory and immunosuppressive drugs. The main goal is the limitation of the fibrosing potential of the autoimmune deposits within various mucous membranes. PMID- 20850263 TI - [Secondary limb lymphedema]. AB - Lymphedema is related to congenital lymphatic abnormality (primary forms) or acquired (secondary forms) after lesions of lymphatic system. Upper to limb secondary lymphedema after breast cancer treatment is the most frequent in France. The first worldwide cause is lymphatic filariosis. Secondary lymphedema is related to adverse effects after cancer treatment including surgery with lymph nodes excision associated with radiotherapy: breast, melanoma for upper limb, cervical, uterine, prostate, bladder cancer, melanoma for lower limb. At lymphedema onset, deep venous thrombosis and recurrent cancer should be investigated. Rare causes of lymphedema are also reported: rheumatic diseases (rheumatoid arthritis), Kaposi sarcoma, retroperitoneal fibrosis, immunosuppressive agent (sirolimus). PMID- 20850264 TI - [Adult respiratory distress syndrome occurring during leptospirosis]. PMID- 20850265 TI - [Digital necrosis related to gemcitabine]. PMID- 20850266 TI - [Is lymphedema an unmanageable disease?]. PMID- 20850267 TI - Family caregiver perspectives on symptoms and treatments for patients dying from complications of cystic fibrosis. AB - CONTEXT: Most patients with advanced cystic fibrosis (CF) die from respiratory failure and experience distressing symptoms as lung disease progresses. Little has been reported about symptom management and the continuation of disease specific treatments near the end of life for patients with CF. OBJECTIVE: We aimed to describe symptom prevalence, symptom management, and frequency of use of disease-specific treatments for patients dying from complications of CF. METHODS: We conducted semistructured interviews about end-of-life care in CF with bereaved family caregivers and asked questions about symptoms and treatments. RESULTS: Twenty-seven caregivers answered questions about symptoms and treatments. Caregivers reported that distressing symptoms were common during the last week of life, including dyspnea (100%), fatigue (96%), anorexia (85%), anxiety (74%), pain (67%), and cough (56%). Most caregivers felt that symptom control was "somewhat good." Many reported that medical providers "did the best they could" to manage symptoms but four (15%) recalled no physician inquiry about symptoms. Caregivers expressed beliefs that symptoms could not be controlled and described concerns about side effects and potential for hastening death with the use of opioids and anxiolytics. Patients received numerous disease-specific treatments, and caregivers described many of them as uncomfortable but necessary. CONCLUSIONS: Distressing symptoms are common in dying CF patients, and disease specific treatments also cause discomfort. Many family caregivers have low expectations for symptom control. This exploratory research can be used to inform clinical interventions to improve symptom management for patients with advanced CF. PMID- 20850269 TI - A mathematical model for Cantor coding in the hippocampus. AB - Recent studies suggest that the hippocampus is crucial for memory of sequentially organized information. Cantor coding in hippocampal CA1 is theoretically hypothesized to provide a scheme for encoding temporal sequences of events. Here, in order to investigate this Cantor coding in detail, we construct a CA1 network model consisting of conductance-based model neurons. It is assumed that CA3 outputs temporal sequences of spatial patterns to CA1. We examine the dependence of output patterns of CA1 neurons on input time series by taking each output and combining it with an input sequence. It is shown that the output patterns of CA1 were hierarchically clustered in a self-similar manner according to the similarity of input temporal sequences. The population dynamics of the network can be well approximated by a set of contractive affine transformations, which forms a Cantor set. Furthermore, it is shown that the performance of the encoding scheme sensitively depends on the interval of input sequences. The bursting neurons with NMDA synapses are effective for encoding sequential input with long (over 150 ms) intervals while the non-bursting neurons with AMPA synapses are effective for encoding input with short (less than 30 ms) intervals. PMID- 20850268 TI - Health status and coping strategies among older parent-carers of adults with intellectual disabilities in an Australian sample. AB - BACKGROUND: Older parent-carers in Australia are the subject of increasing policy and practice attention due to concerns about their ongoing ability to care in the light of their own ageing and the ageing of their adult son or daughter. This paper examines health status and the coping strategies of a group of older Australian parents caring for an adult son or daughter with intellectual disabilities. METHOD: Health status using the SF-12 (Ware, Snow, Kosinski, & Gandek, 1993), caring stress using the CADI (Nolan, Grant, & Keady, 1998), and coping strategies using the CAMI (Nolan et al., 1998) were assessed in 64 older parent-carers of adults with intellectual disabilities. RESULTS: The self reported health status of this sample of older parent-carers did not differ significantly from Australian population norms, with one exception. That is, the younger parent-carers in the sample (55-64 years) reported significantly poorer mental health. Better health was associated with having a partner, a larger and close support network of family, friends and neighbours, and a lower care-load. Overall, the study participants identified both satisfaction as well as stress associated with caring, a finding that runs counter to the common perception that being a carer is overwhelmingly burdensome. Common sources of stress were feeling helpless or not in control, and poor professional support. Analysis of older parent-carers coping strategies suggests that self-reliance, whether by choice or necessity, was the norm. CONCLUSIONS: The health status of older parent-carers may present less cause for concern than anecdotal reports suggest. That said, the strong self-reliance particularly of the older carers presents a challenge to service providers seeking to engage those whose situation appears to warrant support from the service system. PMID- 20850270 TI - Factorial trial found mixed evidence of effects of pre-notification and pleading on response to Web-based survey. AB - OBJECTIVES: To evaluate the effectiveness of pre-notification and pleading invitations in Web surveys by embedding a randomized controlled trial (RCT) in a Web-based survey. STUDY DESIGN AND SETTING: E-mail addresses of 569 authors of published maternal health research were randomized in a 2*2 factorial trial of a pre-notification vs. no pre-notification e-mail and a pleading vs. a non-pleading invitation e-mail. The primary outcome was completed response rate, and the secondary outcome was submitted response rate (which included complete and partial responses). RESULTS: Pleading invitations resulted in 5.0% more completed questionnaires, although this difference did not reach statistical significance [odds ratio (OR) 1.23; 95% confidence interval (CI): 0.86, 1.74; P=0.25]. Pre notification did not increase the completion rate (OR 1.04; 95% CI 0.73, 1.48; P=0.83). Response was higher among authors who had published in 2006 or later (OR 2.07; 95% CI: 1.43, 2.98; P=0.001). There was some evidence that pre-notification was more effective in increasing submissions from authors with recent publications (P=0.04). CONCLUSION: The use of a "pleading" tone to e-mail invitations may increase response to a Web-based survey. Authors of recently published research are more likely to respond to a Web-based survey. PMID- 20850271 TI - Age effects on voxel-based relaxometry used for epileptic patients. AB - PURPOSE: T2 voxel-based relaxometry (VBR) is a technique that allows for a quantitative, unbiased analysis of T2 relaxation time across the whole brain. Previous studies have shown that this technique is effective for clinical analysis of single patients; however, the effects of age normal age-related changes on these data were unknown. Our study was therefore designed to assess the effect of normal aging on VBR data. METHODS: A linear regression with age as a predictor of T2 was run in both a (1) whole-brain voxel-based manner to determine regions which showed significant age-related change and subsequently (2) on a selection of regions-of-interest to allow for a more detailed analysis of the trends. RESULTS: T2 estimates showed a significant increase with age in the frontal lobe white matter and a significant decrease with age in the putamen with region-of-interest and voxel-based regressions (p<0.05). There was also a general trend for T2 to decrease in inferior temporal lobe grey matter in the voxel-based regression. CONCLUSIONS: Age causes changes in T2 relaxation time in healthy control subjects, with increases being observed in frontal lobe white matter and decreases in the putamen. These changes should be accounted for when interpreting single subject VBR data. PMID- 20850272 TI - Is reduced ornithine-delta-aminotransferase activity the cause of vigabatrin associated visual field defects? AB - BACKGROUND: A gabaergic antiepileptic drug, vigabatrin (VGB), is known to induce bilateral concentric visual field defects (VFD) in 30-40% of treated patients. Although the clinical and electrophysiological features of VFDs are well documented, the mechanism of retinal toxicity is still unclear. PURPOSE: To determine if low basal ornithine-delta-aminotranspherase (OAT) activity is implicated in the etiology of VGB retinotoxicity, resulting in a phenotype of a mild form of gyrate atrophy. METHODS: Assays of OAT activity in lymphocytes and GABA-transaminase activity in platelets were performed, and plasma levels of GABA, ornithine, lysine, glutamic acid and glutamine were measured, and visual fields were examined. A total of 47 subjects, aged 14-78 years, were examined. Twenty-one epileptic patients were off VGB more than 1 year; 11 patients with VGB induced VFD and 10 with normal visual fields. Ten epileptic patients were on current VGB therapy more than 1 year; four patients with VGB-induced VFD and six with normal visual fields. The results were compared with those of 10 epilepsy patients taking tiagabine and six patients who suffered from gyrate atrophy (GA) or were obligate carriers of the disease. RESULTS: In patients who had stopped VGB and who had VFDs, OAT activity was significantly reduced as compared with those who had normal visual fields (77.4pmol P5C/min/mgPro vs. 181.9pmol P5C/min/mgPro, p=0.002). In patients with ongoing VGB therapy, no difference was found between the patients with and without VFDs (149.4pmol P5C/min/mgPro vs. 159.1pmol P5C/min/mgPro). CONCLUSIONS: : The results suggest that VGB retinotoxicity might be associated with elevated retinal ornithine mediated by low basal OAT activity. PMID- 20850273 TI - Correlated covariates in ANCOVA cannot adjust for pre-existing differences between groups. PMID- 20850274 TI - Prevalence of metabolic syndrome among patients with schizophrenia in Japan. AB - AIMS: In an Asian population, the criteria for metabolic syndrome (MetS) are different from those for Western populations. The aim of this study was to assess the MetS prevalence among patients with schizophrenia or schizoaffective disorder in Japan. METHODS: We recruited patients (n=1186), aged 54.8+/-14.8 (mean+/-SD) years old with the DSM-IV diagnosis of schizophrenia or schizoaffective disorder who were admitted to seven psychiatric hospitals using a cross-sectional design. MetS prevalence was assessed by three different definitions, including the adapted National Cholesterol Education Program Adult Treatment Panel (ATP III-A). Comparative analysis was performed with schizophrenic subjects and 886 participants from the Iwaki Health Promotion Project 2008 as representative of general population. RESULTS: The overall MetS prevalence based on the ATP III-A definition was 27.5%, with 29.8% in male and 25.3% in female patients. In a logistic regression model with age and body mass index as covariates, being schizophrenic was a significant independent factor (odds ratio=2.00 for males, 2.13 for females) in the development of MetS under the ATP III-A definition. The difference of MetS prevalence between patients and the general population was observed for those under 60 years of age. CONCLUSIONS: Patients with schizophrenia or schizoaffective disorder in Japan had high prevalence of MetS compared to the general population, and was most apparent for those under 60 years of age. The MetS in schizophrenic patients should be carefully monitored to minimize the risks. PMID- 20850275 TI - Galantamine augmentation of long-acting injectable risperidone for cognitive impairments in chronic schizophrenia. AB - BACKGROUND: Galantamine, a reversible cholinesterase inhibitor with effects on nicotinic receptors, has shown mixed effects on cognitive impairments in patients with schizophrenia. Given these mixed results we examined whether galantamine compared to adjunctive placebo may improve cognitive functions in patients treated concomitantly with a long acting atypical antipsychotic. METHOD: The parent study was a 52-week double-blind, randomized study of treatment with long acting injectable risperidone 25mg or 50mg every two weeks. Adjunctive galantamine or placebo treatment was administered from Month 6 to 12. Outcome measures were neurocognitive, psychopathology, social and quality of life functions. Patients were randomized to blinded galantamine up to 24mg/day or matching placebo tablets. All patients were maintained on their randomized long acting injectable risperidone regimen for the duration of the trial. RESULTS: 32 patients were included in the intent-to-treat analysis. No statistically significant differences were found for Attention Vigilance, Declarative Memory, Processing Speed, Reasoning/Problem Solving, Working Memory domains and the Neurocognitive Composite Score. Group specific analysis showed a statistically significant group interaction (p=0.043) with the Social Cognition domain showing in the galantamine group significantly lower scores at endpoint than placebo patients. The PANSS general psychopathology subscale showed significantly higher scores in the galantamine group at endpoint (p=0.05). ANCOVA model for within treatment group comparisons showed a significant increase of 7.3 points for the total PANSS score for the galantamine group. CONCLUSION: Galantamine showed no ameliorative effects on cognitive measures in this 6month, double-blind study of patients with schizophrenia treated with an assured and stable antipsychotic medication delivery system. Galantamine may not be an appropriate augmentation agent for cognitive impairments in patients with schizophrenia at the dose used. PMID- 20850277 TI - Increased parahippocampal and lingual gyrification in first-episode schizophrenia. AB - OBJECTIVE: Cerebral gyrification is attributed to a large extent to genetic and intrauterine/perinatal factors. Hence, investigating gyrification might offer important evidence for disturbed neurodevelopmental mechanisms in schizophrenia. As an extension of recent ROI analyses of gyrification in schizophrenia the present study is the first to compare on a node-by-node basis mean curvature as a sensitive parameter for the identification of local gyrification changes of the whole cortex in first-episode schizophrenia. METHODS: A group of 54 patients with first-episode schizophrenia according to DSM-IV and 54 age and gender matched healthy control subjects were included. All participants underwent high resolution T1-weighted MRI scans on a 1.5 T scanner. Mean curvature was calculated dividing the sum of the principal curvatures by two at each point of the curved surface as implemented in the Freesurfer Software package. Statistical cortical maps were created to estimate gyrification differences between groups based on a clustering approach. RESULTS: A significantly increased gyrification was observed in first-episode schizophrenia patients relative to controls in a right parahippocampal-lingual cortex area. The cluster encompassed a surface area of 750 mm2. A further analysis of cortical thickness of this cluster demonstrated concurrent significant reduced cortical thickness of this area. CONCLUSIONS: This is the first study to reveal an aberrant gyrification of the medial surface in first-episode schizophrenia. This finding is in line with substantial evidence showing medial temporal lobe abnormalities in schizophrenia. The present morphometric data provide further support for an early disruption of cortical maturation in schizophrenia. PMID- 20850276 TI - Use of neuroanatomical pattern regression to predict the structural brain dynamics of vulnerability and transition to psychosis. AB - BACKGROUND: The at-risk mental state for psychosis (ARMS) has been associated with abnormal structural brain dynamics underlying disease transition or non transition. To date, it is unknown whether these dynamic brain changes can be predicted at the single-subject level prior to disease transition using MRI-based machine-learning techniques. METHODS: First, deformation-based morphometry and partial-least-squares (PLS) was used to investigate patterns of volumetric changes over time in 25 ARMS individuals versus 28 healthy controls (HC) (1) irrespective of the clinical outcome and (2) according to illness transition or non-transition. Then, the baseline MRI data were employed to predict the expression of these volumetric changes at the individual level using support vector regression (SVR). RESULTS: PLS revealed a pattern of pronounced morphometric changes in ARMS versus HC that affected predominantly the right prefrontal, as well as the perisylvian, parietal and periventricular structures (p<0.011), and that was more pronounced in the converters versus the non converters (p<0.010). The SVR analysis facilitated a reliable prediction of these longitudinal brain changes in individual out-of training cases (HC vs ARMS: r=0.83, p<0.001; HC vs converters vs non-converters: r=0.83, p<0.001) by relying on baseline patterns that involved ventricular enlargements, as well as prefrontal, perisylvian, limbic, parietal and subcortical volume reductions. CONCLUSIONS: Abnormal brain changes over time may underlie an elevated vulnerability for psychosis and may be most pronounced in subsequent converters to psychosis. Pattern regression techniques may facilitate an accurate prediction of these structural brain dynamics, potentially allowing for an early recognition of individuals at risk of developing psychosis-associated neuroanatomical changes over time. PMID- 20850278 TI - Addressing global health security in Eastern Mediterranean countries by increasing regional cooperation on zoonotic diseases. PMID- 20850279 TI - Reduced thalamic volume observed across different subgroups of autism spectrum disorders. AB - We measured the thalamic volumes of 38 subjects with autism spectrum disorders (ASD), including autism, Asperger's disorder, and pervasive developmental disorder not otherwise specified, and 16 matched healthy controls. Thalamic volume in all ASD subgroups was significantly smaller compared with volume in the control subjects. PMID- 20850280 TI - Thermodynamics studies on tyrosine-hydantoin drug-cetyltrimethylammonium bromide mixed micellar system. AB - In the present paper, we report the micellization, aggregation behavior and thermodynamics of a cationic surfactant viz. cetyltrimethylammonium bromide (CTAB) in absence and presence of tyrosine-hydantoin (TH) drug. The solution behavior of the mixture of CTAB and TH drug has been determined using conductivity, surface tension, UV-visible and fluorescence spectroscopic methods. A strong interaction between the two amphiphiles is indicated from the above measurements. The critical micelle concentration (cmc) of CTAB is found to decrease with increase in the amount of TH in the mixture. The cmc values obtained by these methods are in good agreement with each other. The critical micelle concentration, aggregation number and standard free energy changes of aggregation of the surfactant (CTAB) in aqueous solution in absence and presence of TH are evaluated at different temperatures (294, 303 and 318K). The aggregation number is obtained by the steady-state fluorescence spectroscopic method. Thermodynamic parameters (the standard Gibbs energy change of micellization, DeltaG degrees (m), the standard enthalpy change of micellization, DeltaH degrees (m), the standard entropy change of micellization, DeltaS degrees (m), the standard Gibbs (transfer) energy, (DeltaG degrees (m))(tr)' , and the excess free energy change of micellization, DeltaG(ex)) have been evaluated. The negative values of standard Gibbs energy change indicate spontaneous micellization and synergism. The interaction parameter, beta(m), activity coefficients (f(1), f(2)) have been evaluated, and using these data we evaluated excess Gibbs energies, which indicate the spontaneity and the stability of the mixed micelles. PMID- 20850281 TI - Binary mixing of micelles using Pluronics for a nano-sized drug delivery system. AB - Pluronics with different structural compositions and properties are used for several applications, including drug delivery systems. We developed a binary mixing system with two Pluronics, L121/P123, as a nano-sized drug delivery carrier. The lamellar-forming Pluronic L121 (0.1 wt%) was incorporated with Pluronic P123 to produce nano-sized dispersions (in case of 0.1 and 0.5 wt% P123) with high stability due to Pluronic P123 and high solubilization capacity due to Pluronic L121. The binary systems were spherical and less than 200-nm diameter, with high thermodynamic stability (at least 2 weeks) in aqueous solution. The CMC of the binary system was located in the middle of the CMC of each polymer. In particular, the solubilization capacity of the binary system (0.1/0.1 wt%) was higher than mono-systems of P123. The main advantage of binary systems is overcoming limitations of mono systems to allow tailored mixing of block copolymers with different physicochemical characteristics. These nano-sized systems may have potential as anticancer drug delivery systems with simple preparation method, high stability, and high loading capacity. PMID- 20850282 TI - [In memoriam: Victor Courtecuisse, 1928-2010]. PMID- 20850283 TI - [Juvenile Gougerot Sjogren syndrome: report of 3 cases]. AB - Gougerot Sjogren syndrome is rare during childhood. Diagnosis in adult patients is usually based on sets of criteria combining clinical, serological, and salivary gland histopathological findings. In the pediatric age group, clinical manifestations might be different from the adult form. We report on 3 cases of childhood Gougerot Sjogren syndrome. PMID- 20850284 TI - [Acute inflammatory polyradiculoneuropathy and membranous glomerulonephritis following Epbstein-Barr virus primary infection in a 12-year-old girl]. AB - Acute inflammatory polyradiculoneuropathy, or Guillain-Barre syndrome (GBS), is characterized by peripheral nerve demyelination, which leads to rapidly progressive weakness, loss of sensation, and loss of deep tendon reflexes. It is a prototype of postinfectious autoimmune disease, whose pathophysiology is well described in the forms provoked by certain bacteria (molecular mimicry with Campylobacter jejuni), but remains unclear for the forms related to other organisms (cytomegalovirus, Epstein-Barr virus and other herpes group viruses, Mycoplasma pneumoniae). Glomerular lesions can be associated with the neurological symptoms and have also been described after various infections, independently of any signs of polyradiculoneuropathy. We report the observation of a 12-year-old girl who presented with Guillain-Barre syndrome with facial diplegia, ataxia, and intracranial hypertension following Epstein-Barr virus (EBV) primary infection. During the course of the neurological disease, membranous glomerulonephritis (MGN) was diagnosed. The neurological impairment was regressive within 6 months after intravenous immunoglobulin treatment followed by intravenous then oral corticosteroid administration. Viremia remained high more than 6 months after the onset of symptoms. Glomerulopathy progressed independently and finally required immunosuppressant medication with cyclosporine. EBV might be the factor that triggered the autoimmune disorders, as previously reported for systemic lupus erythematosus and multiple sclerosis in children. To the best of our knowledge, this association of 3 conditions (GBS, MGN, and EBV primary infection) has never been reported in the literature. PMID- 20850285 TI - Home mechanical ventilation in chest wall disease should aim at full correction of PaCO(2). PMID- 20850286 TI - Smoking cessation and development of respiratory health in smokers screened with normal spirometry. AB - BACKGROUND: Case-finding of chronic obstructive pulmonary disease (COPD) using spirometry may deter people with normal lung function from stopping smoking. The objective of this study was to observe the percentage of smokers screened with normal lung function that quit smoking. METHODS: As part of a study on early detection of COPD, 518 smokers were screened with normal lung function (post bronchodilator FEV(1)/FVC >= 70%). They were invited for a follow-up measurement after an average of 2.4 years. Non-smoking was validated by carbon monoxide (<10 ppm), and respiratory health related quality of life was measured with the Clinical COPD Questionnaire (CCQ). RESULTS: A total of 255 participants were followed up (49%). The point prevalence rate of non-smoking at follow-up was 18% (N = 47), and 9% assuming that all non-respondents were smokers. This rate was not lower than the expected rate of quitting in the Dutch population (8-9%) and primary "care as usual" in smokers screened with abnormal lung function (10%; p > 0.05 for all comparisons). The average decline in post-bronchodilator FEV(1) was 26 mL/year, which was unrelated to smoking status at follow-up. Non-smokers showed a clinically meaningful and statistically significant (p < 0.001) improvement in CCQ respiratory symptoms (-0.96) and total score (-0.51). CONCLUSIONS: Our results do not suggest that early detection of airflow limitation to motivate smoking cessation reduces the rate of quitting in smokers shown to have normal lung function. Such smokers should be advised to quit smoking on the grounds that they are likely to improve their respiratory health in the short term and reduce their risk for smoking related diseases in the long term. PMID- 20850287 TI - Selective digestive decontamination reduces ventilator-associated tracheobronchitis. PMID- 20850288 TI - Smoking prevalence, behaviours, and cessation among individuals with COPD or asthma. AB - BACKGROUND: Smoking prevalence, behaviours, physician counselling regarding smoking cessation, and smoking cessation medications were evaluated among male and female smokers with COPD and asthma compared to the general smoking population. METHODS: Data from the large, nationally representative Canadian Community Health Survey (CCHS) was used (for 2003 CCHS, n = 134,072). All data were based on self-report, including the presence of COPD and asthma which were defined by health-professional diagnosis. Nicotine addiction was assessed by the Fagerstrom Test for Nicotine Dependence. RESULTS: In 2003, 32.8% of individuals with COPD, 21.0% with asthma, and 22.1% without COPD or asthma were current smokers. After adjusting for sociodemographic and smoking behaviour confounders, among current smokers, greater odds of high or very high nicotine addiction were observed among women with versus without COPD (OR = 2.49, 95% CI = 1.41-4.39), and among women with versus without asthma (OR = 1.74, 95% CI = 1.01-2.99), but no associations were seen among men. Smokers with COPD and asthma were no more likely to have received physician counselling regarding smoking cessation, nor smoking cessation pharmacotherapy compared to the general smoking population. CONCLUSIONS: Gender differences were observed in the association between COPD and asthma and higher nicotine addition levels in current smokers. These findings could in part explain population trends showing that COPD and asthma are increasing more rapidly in women. Physician counselling and pharmacotherapy for smoking cessation do not appear to be received more frequently among individuals with COPD or asthma compared to the general smoking population, despite the greater vulnerability of such patients to smoking effects. PMID- 20850289 TI - Sensing substrate rigidity by mechanosensitive ion channels with stress fibers and focal adhesions. AB - Cell motility, spreading, proliferation and differentiation are critically influenced by substrate rigidity. To sense substrate rigidity, cells apply traction forces to cell-substrate adhesions via actin stress fibers (SFs) and measure mechanical responses of the substrate. Besides mechanosensitive adaptor proteins, mechanosensitive (MS) channels are involved in the substrate rigidity sensing. MS channels located at or near focal adhesions (FAs) convert the rigidity-dependent stress generated in SF/FA system into the level of cytoplasmic Ca(2+) concentration ([Ca(2+)]cyt) by locally altering their Ca(2+) permeability. Besides by external forces, cells spontaneously generate rigidity-dependent localized [Ca(2+)]cyt increases, implicating MS channels as intrinsic force measurement system. This mechanism may contribute to not only substrate rigidity sensing but also regulation of cell migration. PMID- 20850290 TI - Dynamics of cell-cell and cell-matrix interactions in morphogenesis, regeneration and cancer. PMID- 20850291 TI - Food waste impact on municipal solid waste angle of internal friction. AB - The impact of food waste content on the municipal solid waste (MSW) friction angle was studied. Using reconstituted fresh MSW specimens with different food waste content (0%, 40%, 58%, and 80%), 48 small-scale (100-mm-diameter) direct shear tests and 12 large-scale (430 mm * 430 mm) direct shear tests were performed. A stress-controlled large-scale direct shear test device allowing approximately 170-mm sample horizontal displacement was designed and used. At both testing scales, the mobilized internal friction angle of MSW decreased considerably as food waste content increased. As food waste content increased from 0% to 40% and from 40% to 80%, the mobilized internal friction angles (estimated using the mobilized peak (ultimate) shear strengths of the small-scale direct shear tests) decreased from 39 degrees to 31 degrees and from 31 degrees to 7 degrees , respectively, while those of large-scale tests decreased from 36 degrees to 26 degrees and from 26 degrees to 15 degrees , respectively. Most friction angle measurements produced in this study fell within the range of those previously reported for MSW. PMID- 20850292 TI - Noncovalently functionalized multi-wall carbon nanotubes in aqueous solution using the hydrophobin HFBI and their electroanalytical application. AB - A novel noncovalent approach was developed for the functionalization of multi wall carbon nanotubes (MWNTs) using the hydrophobin, HFBI. Owing to the amphipathic nature, HFBI can be adopted onto the surface of MWNTs to form HFBI MWNTs nanocomposite with good dispersion in water. The HFBI-MWNTs nanocomposite was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and water contact angle measurements (WCA). Furthermore, a glucose biosensor was developed based on HFBI-MWNTs by a one-step casting method. The resulting biosensor displayed high sensitivity, wider linear range, low detection limit, and fast response for glucose detection, which implicated that the HFBI-MWNTs nanocomposite film holds great promise in the design of electrochemical devices, such as sensors and biosensors. PMID- 20850293 TI - Translocation of bio-functionalized magnetic beads using smart magnetophoresis. AB - We demonstrate real time on-chip translocation of bio-functionalized superparamagnetic beads on a silicon surface in a solution using a magnetophoresis technique. The superparamagnetic beads act as biomolecule carriers. Fluorescent-labeled Atto-520 biotin was loaded to streptavidin-coated magnetic beads (Dynabead((r)) M-280) by means of ligand-receptor interactions. The magnetic pathways were patterned lithographically such that semi-elliptical Ni(80)Fe(20) elements were arranged sequentially for a few hundred micrometers in length. An external rotating magnetic field was used to drive translational forces on the magnetic beads that were proportional to the product of the field strength and its gradient. The translational force at the curving edge of the pathway element of 6 MUm diameter was calculated to be ~1.2 pN for an applied field of 7.9 kA m(-1). However, the force at the flat edge was calculated to be ~0.16 pN. The translational force was larger than the drag force and thus allowed the magnetic beads to move in a directional way along the curving edge of the pathway. However, the force was not sufficient to move the beads along the flat edge. The top and bottom curving edge semi-elliptical NiFe pathways were obliquely-arranged on the left and right sides of the converging site, respectively. This caused a central translational force that allowed the converging and diverging of the Atto-520 biotin loaded streptavidin magnetic beads at a particular site. PMID- 20850294 TI - Bioelectrocatalytic determination of nitrite ions based on polyaniline grafted nanodiamond. AB - Polyaniline chains were grafted onto nanodiamond (PANI-g-ND) through electrochemical polymerization of aniline in the presence of amine functionalized ND. A robust and effective composite film comprising PANI-g-ND/gold particles was subsequently prepared. Cytochrome c was successfully immobilized onto PANI-g ND/Au film. Field emission scanning electron microscope (FESEM) image of PANI-g ND/Au reveals the presence of fibrous PANI embedded into ND galleries with uniformly distributed Au clusters (~1 MUm). Direct electrochemistry and electrocatalysis of cyt c were investigated. PANI-g-ND/Au film showed an obvious direct electron transfer between cyt c and the underlying electrode. Cyclic voltammograms revealed that PANI-g-ND/Au/cyt c exhibited an excellent electrocatalysis towards the detection of nitrite ions. Differential pulse voltammetry of PANI-g-ND/Au/cyt c revealed a wide linear concentration range (0.5 MUM-3 mM) for current responses, sensitivity (88.2 MUA/mM) and low detection limit (0.16 MUM) towards the electrochemical detection of nitrite ions. PMID- 20850295 TI - Using light to control signaling cascades in live neurons. AB - Understanding the complexity of neuronal biology requires the manipulation of cellular processes with high specificity and spatio-temporal precision. The recent development of synthetic photo-activatable proteins designed using the light-oxygen-voltage and phytochrome domains provides a new set of tools for genetically targeted optical control of cell signaling. Their modular design, functional diversity, precisely controlled activity and in vivo applicability offer many advantages for investigating neuronal function. Although designing these proteins is still a considerable challenge, future advances in rational protein design and a deeper understanding of their photoactivation mechanisms will allow the development of the next generation of optogenetic techniques. PMID- 20850296 TI - Quality of pathology reports for advanced ovarian cancer: are we missing essential information? An audit of 479 pathology reports from the EORTC-GCG 55971/NCIC-CTG OV13 neoadjuvant trial. AB - OBJECTIVE: To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. METHODS: Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. RESULTS: All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non academic). Quality of reports differs significantly by country. CONCLUSION: This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy. PMID- 20850297 TI - MexTAg mice exposed to asbestos develop cancer that faithfully replicates key features of the pathogenesis of human mesothelioma. AB - Animal models provide an important tool for investigating the biology of cancer and for testing the efficacy of novel treatments. Here we describe several aspects of the transgenic MexTAg mouse that develops asbestos-induced mesothelioma. Targeted expression of the TAg transgene causes mesothelioma to develop more rapidly after asbestos exposure in wild-type mice with 100% incidence compared to 30% incidence in wild-type mice. MexTAg mice do not develop spontaneous mesothelioma and exhibit a very low incidence of other tumours. Here we show that TAg does not affect the aggressiveness or rate of progression of the mesotheliomas, suggesting that the oncogene alters only the rate at which disease is initiated. The instillation of an alternative inflammatory agent, thioglycollate, did not induce mesotheliomas, demonstrating acute inflammation is not sufficient for tumour development in MexTAg mice. We found that neither the age of a mouse at the time of exposure nor its gender were prognostic factors. MexTAg mice with mesotheliomas respond to treatment with a cytotoxic drug in a similar way to that of patients with mesothelioma, demonstrating the validity of the model. We also show that long-term treatment with a COX-2 inhibitor prior to the development of disease does not have a survival benefit, suggesting that this is not a useful cancer prevention therapy for asbestos-exposed individuals. The model is robust and suitable for testing a wide variety of protocols and a range of translational studies. PMID- 20850298 TI - Multi stage high rate biomethanation of poultry litter with self mixed anaerobic digester. AB - A multi stage high rate biomethanation process with novel self mixed anaerobic digester (SMAD) was developed in the present study to reduce the hydraulic residence time (HRT), increase the volatile solids (VS) loading rate, improve the VS destruction efficiency and enhance the methane yield. Specific design features of SMAD were useful in mixing the digester contents without consuming power and de-alienated the problem of scum formation. In the first phase, poultry litter having 10% total solids (TS) was subjected to high rate biomethanation in multi stage configuration (SMAD-I and II in series with UASB reactor). It was observed that gross VS reduction of 58%, gross methane yield of 0.16 m3 kg(-1) (VS reduced) and VS loading rate of 3.5 kg VS m(-3) day(-1) at HRT of 13 days was obtained. In the second phase SMAD-II was bypassed from the process scheme keeping the other parameters same as in the first phase. The results obtained were not as encouraging as in the first phase. The study showed that multi stage configuration with SMAD design improved the anaerobic digestion process efficiency of poultry litter. PMID- 20850299 TI - Design, synthesis, and biological evaluation of 4-(5-nitrofuran-2-yl)prop-2-en-1 one derivatives as potent antitubercular agents. AB - Based on stereoelectronic feature analysis using density functional theory (DFT) at B3LYP/3-21*G level, a series of 4-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives with low LUMO energies (<-0.10eV); concentrated over the nitro group, furan moiety and alpha,beta-unsaturated carbonyl bridge were envisaged as potential antitubercular agents. The target compounds were prepared by condensation of 5-nitro-2-furaldehyde with various ketones under acidic condition. The compounds were evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv and their cytotoxicity in VERO cell line. Several synthesized compounds showed good antitubercular activity of <5MUM along with low cytotoxicity. In particular, compound ((E)-3-(5-nitrofuran-2-yl)-1-(4 (piperidin-1-yl)phenyl)prop-2-en-1-one) (3v) was found to be very potent (MIC: 0.19MUM) with good selectivity index (MIC(90)/CC(50): >1800). Thus, this study shows the potential of stereoelectronic property analysis in developing improved nitroaromatics as antitubercular agents. PMID- 20850300 TI - Discovery and optimization of a new class of potent and non-chiral indole-3 carboxamide-based renin inhibitors. AB - Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin-angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC(50) value of 2nM. PMID- 20850301 TI - Inhibitors of the tyrosine kinase EphB4. Part 3: identification of non benzodioxole-based kinase inhibitors. AB - Starting from the initial bis-anilinopyrimidine 1, good potency against EphB4 was retained when benzodioxole at C-4 was replaced by an indazole. The key interactions of the indazole with the protein were characterised by crystallographic studies. Further optimisation led to compound 20, a potent inhibitor of the EphB4 and Src kinases with good pharmacokinetics in various preclinical species and high fraction unbound in plasma. Compound 20 may be used as a tool for evaluating the potential of EphB4 kinase inhibitors in vivo. PMID- 20850302 TI - Synthesis and biological evaluation of indolyl glyoxylamides as a new class of antileishmanial agents. AB - A series of indolylglyoxylamide derivatives have been synthesized and evaluated in vitro against amastigote form of Leishmania donovani. Compound 8c has been identified as the most active analog of the series with IC(50) value of 5.17MUM and SI value of 31.48, and is several folds more potent than the standard drugs sodium stilbogluconate and pentamidine. PMID- 20850303 TI - Bernthsen synthesis, antimicrobial activities and cytotoxicity of acridine derivatives. AB - The condensation reaction of diphenylamine with 2-oxo-2H-(substituted chromen)-4 yl acetic acid in presence of anhydrous zinc chloride afford 4-(acridine-9 ylmethyl)-2H-(substituted chromen)-2-one. The synthesized compounds were characterized by spectral studies and elemental analysis and screened for their in vitro antibacterial activity against Staphylococcus aureus, Staphylococcus pyogenes (gram +ve), Escherichia coli, Pseudomonas aeruginosa (gram -ve) and antifungal activity against Aspergillus niger and anticancer activity (HL-60, Hep 2 & HEK293T) by MTT assay. Chloro substituted compounds showed antimicrobial and anticancer activity with IC(50) values in the low micromolar range. PMID- 20850305 TI - Inhibitory activity of four demethoxy fluorinated anthracycline analogs against five human-tumor cell lines. AB - Four anthracycline analogs synthesized in our laboratory were evaluated in comparison with adriamycin (doxorubicin) for their growth-inhibitory effect against five human-tumor cell lines, including lung carcinoma, colon adenocarcinoma, breast adenocarcinoma, melanoma, and glioblastoma. The compounds included 4-demethoxy-7-O-(2,6-dideoxy-2-fluoro--l-talopyranosyl)daunomycinone (2), its 3',4'-diacetate (1), its 14-bromo derivative 3, and its 14-hydroxy analog, namely 4-demethoxy-7-O-(2,6-dideoxy-2-fluoro-alpha-l talopyranosyl)adriamycinone (4). Compounds 1, 2, and 3 showed moderate cytotoxic effect in most of the cell lines, while compound 4 had a strong effect, comparable to or better than that of adriamycin in most of the cell lines. PMID- 20850304 TI - Synthesis and SAR studies of 1,4-benzoxazine MenB inhibitors: novel antibacterial agents against Mycobacterium tuberculosis. AB - Menaquinone is an essential component of the electron transport chain in many pathogens and consequently enzymes in the menaquinone biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. In order to identify leads that target MenB, the 1,4-dihydroxy-2-naphthoyl-CoA synthase from Mycobacterium tuberculosis, a high-throughput screen was performed. Several 1,4-benzoxazines were identified in this screen and subsequent SAR studies resulted in the discovery of compounds with excellent antibacterial activity against M. tuberculosis H37Rv with MIC values as low as 0.6MUg/ml. The 1,4-benzoxazine scaffold is thus a promising foundation for the development of antitubercular agents. PMID- 20850306 TI - Discovery of the inhibitors of tumor necrosis factor alpha with structure-based virtual screening. AB - Tumor necrosis factor alpha (TNF-alpha) has been considered as one of the attractive drug targets for allergic diseases including asthma. We have been able to identify five novel TNF-alpha inhibitors with a drug-design protocol involving the structure-based virtual screening and in vitro cell-based assay for antagonistic activity. Because the newly discovered inhibitors are structurally diverse and have the desirable physicochemical properties as a drug candidate, they deserve a further investigation as anti-asthmatic drugs. The interactions of the identified inhibitors in the binding site of TNF-alpha dimer are addressed in detail to understand the mechanisms for the stabilization of the inactive dimeric form of TNF-alpha. PMID- 20850307 TI - Design and synthesis of KNT-127, a delta-opioid receptor agonist effective by systemic administration. AB - We have reported previously the novel delta-opioid agonist, SN-28, which was more potent in in vitro assays than the prototype delta-agonists, TAN-67 and SNC-80. However, when administered by subcutaneous injection, this compound showed no analgesic effect at dosages greater than 30mg/kg in the acetic acid writhing test. We speculated that SN-28 was not effective in the test because the presence of the charged ammonium groups prevented its penetration through the blood-brain barrier. On the basis of our proposal, we designed the novel delta-agonist, KNT 127, which was effective with systemic administration. PMID- 20850308 TI - Synthesis of novel pyrrole and pyrrolo[2,3-d]pyrimidine derivatives bearing sulfonamide moiety for evaluation as anticancer and radiosensitizing agents. AB - Pyrroles and pyrrolo[2,3-d]pyrimidines were reported to act as potent anticancer agents, in this work, a series of novel 2-substituted-3-cyano-4-phenyl-pyrrole 5, 6, 11-18, and 5-phenyl-pyrrolo[2,3-d]pyrimidine derivatives 7-10, 19-24 bearing either sulfathiazole or sulfapyridine were synthesized. The structures of these compounds were confirmed by elemental analysis, IR, (1)H NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro cytotoxicity against liver and breast cancer cell line (HEPG2 and MCF7). Most of the screened compounds showed interesting cytotoxic activities compared with the used reference drug (doxorubicin). The radiosensitizing ability of some of the synthesized compounds was studied and the results showed an increase in the cell killing effect of gamma-radiation after combination with the tested compounds. PMID- 20850309 TI - Design, synthesis and activity of benzothiazole-based inhibitors of NO production in LPS-activated macrophages. AB - Series of benzothiazoles were synthesized and evaluated their inhibitory activities for NO production in lipopolysaccharide-activated macrophages. The most potent compound was the indole-containing benzothiazole 3c with 4.18MUM of IC(50). The mechanistic study suggested that benzothiazoles inhibited NO production by the suppression of iNOS protein and mRNA expression. They also suppressed the expression of COX-2 through the NF-kappaB inactivation. PMID- 20850310 TI - Efficient synthesis and biological evaluation of some 2,4-diamino-furo[2,3 d]pyrimidine derivatives. AB - The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with ammonia to give ethyl 3,4-dihydro-6 methyl-4-oxo-2-arylamino-furo[2,3-d]pyrimidine-5-carboxylate 3. Further reaction of 3 with POCl(3) and various amines generated ethyl 4-alkylamino-2-arylamino-6 methyl-furo[2,3-d]pyrimidine-5-carboxylate 5 in good yields. Their structures were confirmed by (1)H NMR, EI-Ms, IR and elemental analysis. Compound 5b was further analyzed by single crystal X-ray diffraction. Compound 5 exhibited cytotoxicity against two lung cancer cell lines. For example, compound 5a showed the best inhibition activities against A459 with IC(50) 0.8MUM. PMID- 20850311 TI - Indole alkaloids from Ervatamia hainanensis with potent acetylcholinesterase inhibition activities. AB - Through bioassay-guided fractionation and chromatography technique, eight indole alkaloids were furnished from the stems of Ervatamia hainanensis. All isolates were evaluated for acetylcholinesterase (AChE) inhibition activities, in which compounds 1 and 3 exhibited the same level of activities as galantamine, a marketed cholinesterase inhibitor for the treatment of Alzheimer's disease. Discussion about the relationships between structure and activity of these alkaloids was also presented. PMID- 20850312 TI - Bombesin derivative radiolabeled with technetium-99m as agent for tumor identification. AB - A bombesin derivative was successfully radiolabeled in high labeling yield. Biodistribution studies and scintigraphic images in Ehrlich tumor-bearing mice were performed. This compound showed high accumulation in tumor tissue with high tumor-to-muscle and tumor-to-blood ratios. Thus, (99m)Tc-HYNIC-Bombesin((7-14)) could be used as an agent for tumor diagnosis. PMID- 20850313 TI - Discovery of a potent tubulin polymerization inhibitor: synthesis and evaluation of water-soluble prodrugs of benzophenone analog. AB - Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1, a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3.HCl (l valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3.HCl intravenously, with rapid clearance of 3.HCl indicating the effective cleavage of prodrug. Compound 3.HCl (CKD-516) has now been progressed to phase 1 clinical trial. PMID- 20850314 TI - Delivering a hydrophobic anticancer drug for photodynamic therapy by amorphous formulation. AB - An amorphous formulation of hypocrellin A for photodynamic therapy is reported which can provide stable aqueous dispersion of such hydrophobic photosensitizers. In vitro studies have demonstrated the active uptake of amorphous formulation of hypocrellin A into the mitochondria of tumor cells. Compared with Tween-80 micelle embedded hypocrellin A, low dark-toxicity but similar light-toxicity of the amorphous one to drug impregnated tumor cells was observed. Thus, the potential of using amorphous formulation of hypocrellin A as drug delivery system for photodynamic therapy has been demonstrated. PMID- 20850315 TI - Molecular docking and structure-activity relationship studies on benzothiazole based non-peptidic BACE-1 inhibitors. AB - A similarity search on the structural analogs of an inhibitor of BACE-1 with IC(50) 2.8MUM, which contained a P1 benzothiazole group together with a triazine ring linked by a secondary amine group, was described in this Letter and some more potent inhibitors against BACE-1 were identified. The most potent compound 5 (IC(50)=0.12MUM) increases the inhibitory potency by 24 folds. Our results suggest that a pyrrolidinyl side group at the P3' and P4' of the inhibitors are favored for strong inhibition and a small aromatic group at the P4 position is also essential to the potency. PMID- 20850316 TI - A novel ACTA1 mutation resulting in a severe congenital myopathy with nemaline bodies, intranuclear rods and type I fibre predominance. AB - We describe a severe congenital myopathy patient of Xhosa native African origin with a novel de novo p.Gly152Ala skeletal muscle alpha-actin gene (ACTA1) mutation, who died at 6 months of age. The muscle pathology demonstrated abundant cytoplasmic and intranuclear rods, core-like areas and the unusual feature of larger type I than type II fibres. Our results further expand the phenotypes associated with ACTA1 mutations and provide support for the hypothesis that the structural abnormalities seen are a pathological continuum dependent on the precise mutation and biopsy location. Our results also demonstrate the likely world-wide distribution of de novo mutations in this gene. PMID- 20850317 TI - Dystrophin-deficient zebrafish feature aspects of the Duchenne muscular dystrophy pathology. AB - Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. As in humans, zebrafish dystrophin is initially expressed at the peripheral ends of the myofibres adjacent to the myotendinous junction and gradually shifts to non junctional sites. Dystrophin-deficient zebrafish larvae are characterised by abundant necrotic fibres being replaced by mono-nucleated infiltrates, extensive fibrosis accompanied by inflammation, and a broader variation in muscle fibre cross-sectional areas. Muscle progenitor proliferation cannot compensate for the extensive skeletal muscle loss. Live imaging of dystrophin-deficient zebrafish larvae documents detaching myofibres elicited by muscle contraction. Correspondingly, the progressive phenotype of dystrophin-deficient zebrafish resembles many aspects of the human disease, suggesting that specific advantages of the zebrafish model system, such as the ability to undertake in vivo drug screens and real time analysis of muscle fibre loss, could be used to make novel insights relevant to understanding and treating the pathological basis of dystrophin-deficient muscular dystrophy. PMID- 20850318 TI - Respiratory management of congenital myasthenic syndromes in childhood: Workshop 8th December 2009, UCL Institute of Neurology, London, UK. PMID- 20850319 TI - In vitro reconstitution of the functional interplay between MCAK and EB3 at microtubule plus ends. AB - The kinesin-13 family member mitotic centromere-associated kinesin (MCAK) is a potent microtubule depolymerase. Paradoxically, in cells it accumulates at the growing, rather than the shortening, microtubule plus ends. This plus-end tracking behavior requires the interaction between MCAK and members of the end binding protein (EB) family, but the effect of EBs on the microtubule destabilizing activity of MCAK and the functional significance of MCAK accumulation at the growing microtubule tips have so far remained elusive. Here, we dissect the functional interplay between MCAK and EB3 by reconstituting EB3 dependent MCAK activity on dynamic microtubules in vitro. Whereas MCAK alone efficiently blocks microtubule assembly, the addition of EB3 restores robust microtubule growth, an effect that is not dependent on the binding of MCAK to EB3. At the same time, EB3 targets MCAK to growing microtubule ends by increasing its association rate with microtubule tips, a process that requires direct interaction between the two proteins. This EB3-dependent microtubule plus-end accumulation does not affect the velocity of microtubule growth or shortening but enhances the capacity of MCAK to induce catastrophes. The combination of MCAK and EB3 thus promotes rapid switching between microtubule growth and shortening, which can be important for remodeling of the microtubule cytoskeleton. PMID- 20850320 TI - Shapes of krill swarms and fish schools emerge as aggregation members avoid predators and access oxygen. AB - Many types of animals exhibit aggregative behavior: birds flock, bees swarm, fish shoal, and ungulates herd. Terrestrial and aerial aggregations can be observed directly, and photographic techniques have provided insights into the behaviors of animals in these environments and data against which behavioral theory can be tested. Underwater, however, limited visibility can hamper direct observation, and understanding of shoaling remains incomplete. We used multibeam sonar to observe three-dimensional structure of Antarctic krill shoals acoustically. Shoal size and packing density varied greatly, but surface area:volume ratios (roughnesses) were distributed narrowly about ~3.3 m(-1). Shoals of clupeid fish (e.g., sardine, anchovy) from geographically and oceanographically diverse locations have very similar roughnesses. This common emergent shape property suggests common driving forces across diverse ecosystems. Group behavior can be complex, but a simple tradeoff--that we model--in which individual fish and krill juggle only their access to oxygen-replete water and exposure to predation can explain the observed shoal shape. Decreasing oxygen availability in a warming world ocean may impact shoal structure: because structure affects catchability by predators and fishers, understanding the response will be necessary for ecological and commercial reasons. PMID- 20850322 TI - Human muscle spindles act as forward sensory models. AB - Modern theories of motor control incorporate forward models that combine sensory information and motor commands to predict future sensory states. Such models circumvent unavoidable neural delays associated with on-line feedback control. Here we show that signals in human muscle spindle afferents during unconstrained wrist and finger movements predict future kinematic states of their parent muscle. Specifically, we show that the discharges of type Ia afferents are best correlated with the velocity of length changes in their parent muscles approximately 100-160 ms in the future and that their discharges vary depending on motor sequences in a way that cannot be explained by the state of their parent muscle alone. We therefore conclude that muscle spindles can act as "forward sensory models": they are affected both by the current state of their parent muscle and by efferent (fusimotor) control, and their discharges represent future kinematic states. If this conjecture is correct, then sensorimotor learning implies learning how to control not only the skeletal muscles but also the fusimotor system. PMID- 20850321 TI - Cholinergic enhancement augments magnitude and specificity of visual perceptual learning in healthy humans. AB - Learning through experience underlies the ability to adapt to novel tasks and unfamiliar environments. However, learning must be regulated so that relevant aspects of the environment are selectively encoded. Acetylcholine (ACh) has been suggested to regulate learning by enhancing the responses of sensory cortical neurons to behaviorally relevant stimuli. In this study, we increased synaptic levels of ACh in the brains of healthy human subjects with the cholinesterase inhibitor donepezil (trade name: Aricept) and measured the effects of this cholinergic enhancement on visual perceptual learning. Each subject completed two 5 day courses of training on a motion direction discrimination task, once while ingesting 5 mg of donepezil before every training session and once while placebo was administered. We found that cholinergic enhancement augmented perceptual learning for stimuli having the same direction of motion and visual field location used during training. In addition, perceptual learning with donepezil was more selective to the trained direction of motion and visual field location. These results, combined with previous studies demonstrating an increase in neuronal selectivity following cholinergic enhancement, suggest a possible mechanism by which ACh augments neural plasticity by directing activity to populations of neurons that encode behaviorally relevant stimulus features. PMID- 20850323 TI - A catalytic role for Mod5 in the formation of the Tea1 cell polarity landmark. AB - Many systems regulating cell polarity involve stable landmarks defined by internal cues. In the rod-shaped fission yeast Schizosaccharomyces pombe, microtubules regulate polarized vegetative growth via a landmark involving the protein Tea1. Tea1 is delivered to cell tips as packets of molecules associated with growing microtubule ends and anchored at the plasma membrane via a mechanism involving interaction with the membrane protein Mod5. Tea1 and Mod5 are highly concentrated in clusters at cell tips in a mutually dependent manner, but how the Tea1-Mod5 interaction contributes mechanistically to generating a stable landmark is not understood. Here, we use live-cell imaging, FRAP, and computational modeling to dissect dynamics of the Tea1-Mod5 interaction. Surprisingly, we find that Tea1 and Mod5 exhibit distinctly different turnover rates at cell tips. Our data and modeling suggest that rather than acting simply as a Tea1 receptor or as a molecular "glue" to retain Tea1, Mod5 functions catalytically to stimulate incorporation of Tea1 into a stable tip-associated cluster network. The model also suggests an emergent self-focusing property of the Tea1-Mod5 cluster network, which can increase the fidelity of polarized growth. PMID- 20850324 TI - Artificial night lighting affects dawn song, extra-pair siring success, and lay date in songbirds. AB - Associated with a continued global increase in urbanization, anthropogenic light pollution is an important problem. However, our understanding of the ecological consequences of light pollution is limited. We investigated effects of artificial night lighting on dawn song in five common forest-breeding songbirds. In four species, males near street lights started singing significantly earlier at dawn than males elsewhere in the forest, and this effect was stronger in naturally earlier-singing species. We compared reproductive behavior of blue tits breeding in edge territories with and without street lights to that of blue tits breeding in central territories over a 7 year period. Under the influence of street lights, females started egg laying on average 1.5 days earlier. Males occupying edge territories with street lights were twice as successful in obtaining extra pair mates than their close neighbors or than males occupying central forest territories. Artificial night lighting affected both age classes but had a stronger effect on yearling males. Our findings indicate that light pollution has substantial effects on the timing of reproductive behavior and on individual mating patterns. It may have important evolutionary consequences by changing the information embedded in previously reliable quality-indicator traits. PMID- 20850325 TI - An external focus of attention enhances balance learning in older adults. AB - Studies with young adults have shown that an external focus of attention (i.e., on the movement effect) results in more effective motor learning and greater automaticity than an internal focus (i.e., on one's own body movements). The present study examined whether instructions inducing an external versus internal attentional focus would differentially affect the learning of a balance task in 32 older adults (24 females and 8 males, mean age: 69.4 years), divided equally, by number and gender, into two groups. The task required participants to stand on a balance platform (stabilometer) tilting to the left and right, and to try to keep the platform as close to horizontal as possible during each 30-s trial. The external focus group was instructed to concentrate on keeping markers on the platform horizontal, while the internal focus group was instructed to concentrate on keeping their feet horizontal. The dependent variable was time in balance (i.e., platform movements within +/- 5 degrees ). Participants performed 10 practice trials on day 1, with focus reminders given before each trial. Learning was assessed by a retention test, consisting of five trials without instructions, performed 1 day later. The external focus group outperformed the internal focus group in retention [F(4, 120)=3.46, p=.01]. The results demonstrate that the learning benefits of an external attentional focus are generalizable to older learners. PMID- 20850326 TI - Time-to-contact measures capture modulations in posture based on the precision demands of a manual task. AB - The integration between posture and manual control while performing fitting tasks of varying difficulty was investigated. Participants fit a block into either a small (high precision) or large (low precision) opening while standing on a force plate. Postural time-to-contact was used to quantify changes in posture that occurred during the fitting movement. Results suggest that posture became more stabilized when fitting through the small opening (postural time-to-contact values were higher) compared to when fitting through the large opening. Additionally, when fitting through the small opening, individuals modulated sway based on the instantaneous demands of the task. Specifically, time-to-contact was lower towards the end of a fitting movement (as the individual prepared to fit the block through the opening) compared to the beginning of the movement. These results suggest that the dynamics of postural sway are constantly changing based on the constraints of a concurrent task. PMID- 20850327 TI - A meta-analysis of hamstring autografts versus bone-patellar tendon-bone autografts for reconstruction of the anterior cruciate ligament. AB - The objective of this study was to evaluate the effectiveness of hamstring (HT) autografts versus bone-patellar tendon-bone (BPTB) autografts for reconstruction of the anterior cruciate ligament (ACL). We searched the Cochrane Library, MEDLINE, EMBASE and the Chinese Biomedicine Database (CBM) for published randomised clinical trials (RCTs) relevant to ACL reconstruction comparing HT and BPTB autografts. Data analyses were performed with Cochrane Collaboration's RevMan 5.0. A total of 23 reports of 19 randomised controlled trials (RCTs) (1643 patients) met the inclusion criteria. Outcomes favouring BPTB autografts were found in terms of KT-1000 arithmometer values, negative rates of Lachman tests and negative rates of Pivot tests. Outcome measures that favoured HT autografts included anterior knee pain, kneeling pain and extension loss. There was no statistical difference of postoperative graft failure. Overall, postoperative complications of the knee joint were lower for HT autografts than for BPTB autografts, and BPTB autografts were superior to HT autografts in resuming stability of the knee joint, but four-strand HT combined with application of the modern endobutton HT graft-fixation technique could increase knee-joint stability. PMID- 20850328 TI - The radiographic predictors of symptom severity in advanced knee osteoarthritis with varus deformity. AB - Information concerning the abilities of radiographic parameters to predict the symptoms of advanced osteoarthritis (OA) of the knee would be valuable, because plain knee radiographs are used as one of the primary tools for the selection of treatment modalities. We aimed to identify the radiographic predictors of symptom severity in patients with varus knee OA advanced enough to warrant total knee arthroplasty (TKA). In 341 knees with primary varus OA warranting TKA, pertinent radiographic features of the medial and lateral tibiofemoral joint (TFJ), and the patellofemoral joint (PFJ) were assessed separately and scored. In addition, TF alignment was assessed on standing full-limb radiographs. Symptoms and functions were evaluated using WOMAC pain and function scores. In the univariate analyses with generalized estimating equations (GEE), multiple radiographic features (subluxation of the TFJ, overall severity of the medial TFJ, and degree of TF varus alignment) were associated with poorer WOMAC function scores, whereas only the degree of TF varus alignment was associated with poorer WOMAC pain scores. None of radiographic parameters in the PFJ or lateral TFJ (except TFJ subluxation) was associated with WOMAC scores. Multivariate analyses revealed that the degree of TF varus alignment was the strongest predictor of poorer WOMAC pain and function scores. We propose that extent of TF varus malalignment should be considered as the primary indicator of objective disease severity when selecting treatment options for patients with advanced knee OA. PMID- 20850329 TI - In vitro anti-rotavirus activity of polyphenol compounds isolated from the roots of Glycyrrhiza uralensis. AB - We evaluated the ability of six polyphenols isolated from the roots of Glycyrrhiza uralensis to inactivate rotaviruses, specially G5P[7] and G8P[7]. Upon finding that all polyphenols possessed anti-rotavirus activity, we evaluated whether these properties were attributable to direct inhibition of the binding of rotavirus to cells and/or to inhibition of viral replication. Using the virucidal assay, we found that all six compounds directly inhibited rotavirus binding, with activity being dependent on the type of virus. The 50% effective inhibitory concentrations (EC(50)) of the six compounds were 18.7-69.5 MUM against G5P[7] and 14.7-88.1 MUM against G8P[7], respectively. Five of the six compounds inhibited hemagglutination activity. Moreover, the CPE inhibition assay showed that five compounds inhibited viral replication with EC(50) values of 12.1-24.0 MUM against G5P[7] and 12.0-42.0 MUM against G8P[7], respectively. RT-PCR showed that the compounds suppressed viral RNA synthesis in TF-104 cells. Interestingly, the anti-rotavirus activities of four compounds were attributable to inhibition of both viral absorption and viral replication. These results suggest that compounds isolated from the roots of G. uralensis may be potent anti-rotavirus agents in vivo, acting by inhibiting both viral absorption and viral replication. PMID- 20850330 TI - Dosimetry of gamma chamber blood irradiator using Gafchromic EBT film. AB - Gafchromic films are increasingly being used for dosimetry in medical and industrial applications of ionizing radiation because of their favorable characteristics such as self developing in nature, easy to handle, dose rate independent response, insensitivity to normal room lights, high resolution and insensitivity to variation in the environment conditions. The dosimetry measurements using Gafchromic EBT film, Fricke dosimeter and thermoluminescence (TL) dosimeter were carried out on gamma blood irradiators to establish the suitability of Gafchromic EBT film in such applications. The dose rates determined by Gafchromic EBT film, Fricke dosimeter and TL dosimeter powder are found in good agreement to one another within the uncertainty of measurement. The two-dimensional dose distributions determined using Gafchromic EBT film reflects the expected dose distribution inside the sample compartment of the blood irradiator. The results of this study establish Gafchromic EBT film a suitable dosimeter for routine dosimetry on gamma blood irradiators. PMID- 20850331 TI - Numerical modeling of the gamma-gamma density tool responses in horizontal wells with an axial asymmetry. AB - A signal of a spectrometric gamma-gamma density tool in specific borehole conditions has been numerically calculated. Transport of gamma rays, from a point (137)Cs gamma source situated in a borehole tool, through rock media to detectors, has been simulated using a Monte Carlo code. The influence of heterogeneity of the rock medium surrounding the borehole on the signal of the detectors has been examined. This heterogeneity results from the presence of an interface between two different geological layers, parallel to the borehole wall. The above conditions may occur in horizontal logging, when the borehole is drilled along the boundary of geological layers. It is possible to assess the distance from the boundary on the basis of the responses of the gamma-gamma density tool, using the classic interpretation "spine & ribs" procedure. The effect of different densities of the bordered layers on the tool response has been analyzed. The presented calculations show the wide possibilities of numerical modeling of the complex borehole geometry and solving difficult interpretation problems in nuclear well logging. PMID- 20850332 TI - Symbiotic interactions between arbuscular mycorrhizal (AM) fungi and male papaya plants: its status, role and implications. AB - Experiments were conducted to study the arbuscular mycorrhizal (AM) status and its role in P-uptake through assay of root phosphatases activities in four varieties of male Carica papaya L. viz. CO-1, CO-2, Honey Dew and Washington during flowering stages. In the present study, mean total root colonization of AM fungi recorded peak increase in flowering stage-II while mean root phosphatase (acid and alkaline) activities recorded peak increase in flowering stage-I. Unlike root colonization and root phosphatase activities, spore density did not exhibit any definite patterns and recorded a narrow range of fluctuation during different flowering stages of male C. papaya. The study brought out the fact that root colonization and spore density of AM fungi along with root phosphatase activities varied significantly within the four varieties of male C. papaya plants during each flowering stage. The study also recorded consistently higher acid root phosphatase activity than alkaline root phosphatase activity under P deficient, acidic soil conditions during all flowering stages of male C. papaya plants. Studies revealed that the root colonization of AM fungi influenced root phosphatase activities (acid and alkaline) positively and significantly during all flowering stages of male C. papaya plants. A total of twelve species of AM fungi belonging to five genera viz. Acaulospora, Dentiscutata, Gigaspora, Glomus, and Racocetra were recovered from the rhizosphere of male C. papaya plants. PMID- 20850333 TI - Utility of leaf senescence-associated gene homologs as developmental markers in common wheat. AB - Senescence is the final stage of development in plant tissues. In the senescence process, many senescence-associated genes (SAGs) are reportedly transcriptionally up-regulated. Here, we reported the isolation of nine wheat SAG cDNA clones named TaSAG1 to TaSAG9, and evaluated the usefulness of the SAG homologs for wheat developmental molecular markers based on their expression patterns. The nine wheat SAGs were identified in wheat EST libraries based on their homology to rice SAGs. All wheat SAG transcripts were up-regulated during natural senescence as well as during dark-induced senescence in seedling leaves. However, the expression patterns of wheat SAGs in the flag leaf did not necessarily correspond to those in seedling leaves during senescence. The nine wheat SAGs also showed variable expression patterns in developing and ripening seeds. The transcript accumulation patterns of TaSAG5 and TaSAG6 increased linearly during the period examined in the flag leaf and seed, and are therefore available as molecular markers to respectively evaluate the degree of wheat flag leaf senescence and seed maturation. Transcript accumulation levels of the six SAGs were increased before apparent necrotic cell death of seeding leaves exhibiting wheat hybrid necrosis. These results suggested that necrotic cell death in wheat hybrid necrosis could be closely related not only to senescence but also to defense responses. PMID- 20850334 TI - Comparative analysis of Arabidopsis zinc finger-containing glycine-rich RNA binding proteins during cold adaptation. AB - Among the three zinc finger-containing glycine-rich RNA-binding proteins, named AtRZ-1a, AtRZ-1b, and AtRZ-1c, in the Arabidopsis thaliana genome, AtRZ-1a has previously been shown to enhance cold and freezing tolerance in Arabidopsis. Here, we determined and compared the functional roles of AtRZ-1b and AtRZ-1c in Arabidopsis and Escherichia coli under cold stress conditions. AtRZ-1b, but not AtRZ-1c, successfully complemented the cold sensitivity of E. coli BX04 mutant cells lacking four cold shock proteins. Domain deletion and site-directed mutagenesis showed that the zinc finger motif of AtRZ-1b is important for its complementation ability, and that the truncated N- and C-terminal domains of AtRZ 1b and AtRZ-1c harbor the complementation ability. Despite an increase in transcript levels of AtRZ-1b and AtRZ-1c under cold stress, overexpression or loss-of-function mutations did not affect seed germination or seedling growth of Arabidopsis under cold stress conditions. AtRZ-1b and AtRZ-1c proteins, being localized to the nucleus, have been shown to bind non-specifically to RNA sequences in vitro, in comparison to AtRZ-1a that is localized to both the nucleus and the cytoplasm and binds preferentially to G- or U-rich RNA sequences. Taken together, these results demonstrate that the three AtRZ-1 family members showing different cellular localization and characteristic nucleic acid-binding property have a potential to contribute differently to the enhancement of cold tolerance in Arabidopsis and E. coli. PMID- 20850335 TI - Percutaneous aortic valve replacement: valvuloplasty studies in vitro. AB - OBJECTIVE: Valvuloplasty of the aortic valve is currently used in selected patients for severe calcified aortic valve disease, but clinical effectiveness is low and complication rate remains high. In this study, the total particle load after valvuloplasty and the embolization risk of calcific debris into the coronary arteries was analyzed in an in vitro model. METHODS: Three highly calcified human aortic leaflets have been sutured into a porcine annulus (N = 9). Both coronary arteries were separated and each was anastomized to a silicon line, which was drained off into a measuring beaker. Then valvuloplasty was performed (Thyshak II, 20 mm, 1.5 atm). After removal of the balloon, 100ml of sodium chloride solution irrigated the ascending aorta. After passing through the separated coronary arteries, the solution was filtered (filter size 0.45 MUm), dried, and the total amount of particles was analyzed microscopically. RESULTS: Nine experiments were analyzed. After valvuloplasty, all hearts showed a median of 18 particles larger than 1mm in the coronary arteries (range 0-307). The amount of particles smaller than 1mm was 6574 (median, range 2207-14200). In five cases, coronary arteries were completely occluded by bulky particles. CONCLUSION: This study demonstrated a large amount of calcific particles after valvuloplasty with a consequently high risk for coronary embolic events in case of highly calcified aortic valves. In times of valvuloplasty rediscovering as part of transcatheter valve implantation, the risk of embolization should be taken into consideration and filtering techniques have to be developed. PMID- 20850336 TI - Anomalous left coronary artery from the pulmonary artery illustrated before and after surgical correction in adult. PMID- 20850337 TI - Quality of life after anterior mediastinal mass resection: a prospective study comparing open with robotic-assisted thoracoscopic resection. AB - OBJECTIVE: To prospectively evaluate quality of life (QoL) evolution after robotic-assisted thoracoscopic or open anterior mediastinal tumour resection with the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire-C30 and the lung cancer-specific module, LC-13. METHODS: From January 2004 to December 2008, QoL was prospectively recorded in all patients undergoing surgery for mediastinal tumours. A total of 14 patients underwent thoracoscopic resection using the da Vinci robotic system (Intuitive Surgical, Inc., Mountain View, CA, USA), and 22 patients open resection through sternotomy. Questionnaires were administered before surgery and 1, 3, 6 and 12 months, postoperatively, with response rates of 100%, 86.1%, 94.4%; 75.0% and 86.1%, respectively. RESULTS: Both approaches had comparable preoperative patients' characteristics and QoL subscales. Open resection by sternotomy was characterised by a significant decrease in general functioning 1 month after surgery (physical functioning p=0.001, role functioning p=0.001, and social functioning p=0.044). Patients also complained of increased thoracic pain in the first 3 months after surgery (p=0.017). After a da Vinci robotic resection QoL scores approximated baseline preoperative values 1 month after surgery, with the exception of increase in thoracic and shoulder pain the first 3 months after surgery (p=0.028 and 0.029, respectively). CONCLUSIONS: Numerous techniques have been published with different degrees of invasiveness, generating the existing controversy as to which is the best surgical approach for anterior mediastinal tumours. The high burden of decreased physical functioning reported after sternotomy is not seen after a da Vinci robotic-assisted thoracoscopic resection. The initial experience and postoperative QoL data are excellent and, therefore, the da Vinci robot will stay our future technique of choice for the treatment of resectable mediastinal tumours smaller than 4 cm on imaging techniques. PMID- 20850338 TI - Symptomatic giant aneurysms of the sinus of Valsalva. PMID- 20850339 TI - Increasing photostability and water-solubility of carotenoids: synthesis and characterization of beta-carotene-humic acid complexes. AB - Carotenoids are a group of phytochemicals that are recognized as playing an important role in the prevention of several degenerative diseases due to their antioxidant activity. The low water-solubility and poor photostability of beta carotene, a potentially important dietary antioxidant, prompted us to investigate beta-carotene complexes able to increase its water solubility as well as its photostability in aqueous solution. In this work we have used humic acid in order to synthesize beta-carotene-humic acid complexes in different ratios. Complexes were characterized by FT-IR and DSC. beta-Carotene determination were performed by HPLC and antioxidant activity of beta-carotene, humic acid and the complexes were determined by the TEAC method. The formulation beta-carotene-humic acid 2:1 showed the highest photostability and water solubility. The antioxidant activity of the complexes was about 20 times lower than "free" beta-carotene, suggesting a decreased chemical reactivity of the carotenoid in the complex. We showed that complexation of beta-carotene with humic acids was able to increase its water solubility and photostability, and to affect the antioxidant activity of beta carotene after inclusion in HAs. This work provides a useful tool to avoid antioxidants photodegradation and oxidation by radicals, thus maintaining their biological activity. PMID- 20850340 TI - PERK in beta cell biology and insulin biogenesis. AB - PERK (EIF2AK3) was originally discovered as a major component of the unfolded protein response (UPR). PERK deficiency results in permanent neonatal diabetes, which was initially thought to be caused by a failure to regulate ER stress in insulin-secreting beta cells, culminating in beta cell death. However, subsequent studies found that low beta cell mass was a result of reduced cell proliferation, rather than increased apoptosis. Genetic and cellular studies of Perk-deficient beta cells showed that PERK was crucially required for ER functions including proinsulin trafficking and quality control, unrelated to the ER stress pathway. Under normal physiological conditions, changes in ER calcium levels, mediated by glucose and other insulin secretagogues, regulate PERK activity for the purpose of controlling insulin biogenesis. PMID- 20850341 TI - Imaging mass spectrometry data reduction: automated feature identification and extraction. AB - Imaging MS now enables the parallel analysis of hundreds of biomolecules, spanning multiple molecular classes, which allows tissues to be described by their molecular content and distribution. When combined with advanced data analysis routines, tissues can be analyzed and classified based solely on their molecular content. Such molecular histology techniques have been used to distinguish regions with differential molecular signatures that could not be distinguished using established histologic tools. However, its potential to provide an independent, complementary analysis of clinical tissues has been limited by the very large file sizes and large number of discrete variables associated with imaging MS experiments. Here we demonstrate data reduction tools, based on automated feature identification and extraction, for peptide, protein, and lipid imaging MS, using multiple imaging MS technologies, that reduce data loads and the number of variables by >100*, and that highlight highly-localized features that can be missed using standard data analysis strategies. It is then demonstrated how these capabilities enable multivariate analysis on large imaging MS datasets spanning multiple tissues. PMID- 20850342 TI - Dimethyl isotope labeling assisted de novo peptide sequencing. AB - Here, we explore a de novo sequencing strategy in which we combine Lys-N protein digestion with differential isotopic dimethyl labeling to facilitate the (de novo) identification of multiply charged peptides in ESI-MS, both under CID and ETD conditions. For a large fraction of the Lys-N generated peptides, all primary amines are present at the N-terminal lysine, enabling specific labeling of the N terminus. Differential derivatization of only the peptide N-terminus in combination with the simultaneous fragmentation of the corresponding isotopologues allows the straightforward distinction of N-terminal fragments from C-terminal and internal fragments. Furthermore, also singly and multiply charged N-terminal fragments can easily be distinguished due to the mass differences of the isotope labeled fragment pairs. As a proof of concept, we applied this approach to proteins isolated from an avocado fruit, and were able to partially de novo sequence and correctly align, with green plant homologues, a previously uncharacterized avocado ascorbate peroxidase. PMID- 20850343 TI - Characterization of unknown compounds from stainless steel plates in matrix assisted laser desorption/ionization mass spectrometry. AB - Peaks originating from unknown compounds on stainless steel plates used in matrix assisted laser desorption/ionization (MALDI) mass spectrometers are observed around m/z 304.3, 332.3, 360.4, and 388.4 regardless of the matrix and/or solvent, and are even observed with bare plates. These peaks were characterized using three different types of MALDI-MS instrumentation: MALDI-TOF MS, MALDI TOF/TOF MS, and MALDI-FTMS. The fragmentation data from MALDI-TOF/TOF MS and accurate mass determination by MALDI-FTMS enabled identification of the chemical formulae and structures. The unknown compounds are, in fact, likely benzylalkylmethylammonium salts, as confirmed by closely matching fragmentation patterns with a commercially available benzalkonium chloride. PMID- 20850344 TI - Helicobacter pylori infection: protective against increased interdialytic weight gain in asymptomatic hemodialysis patients? AB - OBJECTIVE: Infection with Helicobacter pylori, which induces persistent and uncontrolled gastric inflammation leading to decreased appetite, might be protective against obesity. There is a close relationship between interdialytic weight gain (IDWG) and nutritional parameters, confirming the role of IDWG as a marker of calorie and protein intake in hemodialysis (HD) patients. Hypothesis of the present study was that infection with H pylori in subjects with uremia might cause inflammation, diminished appetite, anorexia, and decreased IDWG. DESIGN: A cross-sectional study was conducted. SETTINGS: This trial involved HD patients from a state hospital. METHODS: Demographic, laboratory, and clinical parameters were collected. All patients were clinically stable and euvolemic and their average IDWG percent was calculated. Malnutrition inflammation score, spKt/V, and normalized protein equivalent of total nitrogen appearance were determined. Patients were asked to rate their appetite status from 1 to 5 on a Likert scale (very good, good, fair, poor, and very poor appetite, respectively). An H pylori infection was detected by the H pylori stool antigen (HpSA) in all the patients. RESULTS: HpSA was positive in 18 (30%) patients. None of the demographic and laboratory parameters differed between patients infected with HpSA and the noninfected patients. Stepwise linear regression analysis of independent factors related with IDWG% revealed that daily urine output (beta = -0.432, P < .0001), serum phosphorus (beta = +0.343, P = .004), and hemoglobin (beta = +0.358, P = .003) were related with IDWG%. CONCLUSIONS: Infection with H pylori is not related with IDWG% and nutritional parameters in HD patients. PMID- 20850345 TI - Dietary phosphate assessment in dialysis patients. AB - Malnutrition is known to be highly prevalent in patients with kidney disease. It is associated with poor clinical prognosis and can result from restricted dietary protein-energy intake. The issue is also compounded by protein wasting that occurs in dialysis patients. In countering malnutrition, an adequate protein intake is essential but limited by its phosphate content. Therefore, an accurate assessment of nutritional status and intake is an important part of the therapeutic strategy for patients on dialysis. Assessing dietary phosphate intake is not straight forward, with many confounding factors requiring consideration. Interview and diet diaries are the preferred means by which dietary intake can be estimated. However, it is evident that these estimates can vary considerably and are subject to underreporting. Moreover, the use of phosphates as additives and their omission from available nutrient databases are significant contributors to this variation and underestimation. This review highlights the main limitations in assessing dietary phosphate intake and introduces the concept of monitoring changes in dietary habit (appetite) as a proxy for dietary protein and energy intake. This review discusses the use of monitoring dietary habit in trials, with phosphate binders as a simple tool to address the possibility that changes to dietary habits may influence phosphate binder efficacy. PMID- 20850346 TI - Reply to Drs Brezinski et al. PMID- 20850347 TI - Transthoracic echocardiography in the intensive care unit for the diagnosis of right-ventricle endocarditis. PMID- 20850349 TI - Iatrogenic mitral valve injury during aortic valve replacement: importance of intraoperative transesophageal echocardiography. PMID- 20850350 TI - 2-dimensional echocardiography and M-mode Doppler of the interatrial septum for assessment of left ventricular diastolic function. PMID- 20850348 TI - A prospective, randomized, double-blind trial of 3 regimens for sedation and analgesia after cardiac surgery. AB - OBJECTIVE: The aim of this study was to evaluate cardiac risk as a consideration for selecting postoperative sedation and analgesia regimens used for cardiac surgical patients requiring cardiopulmonary bypass and early extubation. DESIGN: An observer-blind, randomized, controlled trial. SETTING: A tertiary referral medical center involving an intensive care unit. PARTICIPANTS: One hundred forty five adults requiring elective cardiac surgery. INTERVENTIONS: Patients were stratified preoperatively as low, moderate, or high cardiac risk based on established criteria and then assigned to 1 of 3 postoperative regimens: propofol infusion beginning at 25 MUg/kg/min and morphine boluses (P), fentanyl infusion beginning at 2 MUg/kg/h and midazolam boluses (F), or propofol and fentanyl infusions beginning at 25 MUg/kg/min and 0.5 MUg/kg/h (PF), respectively. MEASUREMENTS AND MAIN RESULTS: Postoperative regimen P was associated with a significantly reduced time to extubation (median value, 264 minutes; p = 0.05) compared with F (295 minutes) but not PF (278 minutes) in patients characterized as low cardiac risk. The time to extubation did not differ among regimens in patients of moderate/high cardiac risk. CONCLUSION: Patients with low cardiac risk undergoing cardiac surgery had statistically significantly shorter times to extubation with propofol infusion and intermittent morphine than a fentanyl infusion and intermittent midazolam. These differences were not sustained in patients considered at higher cardiac risk. The time to extubation after cardiac surgery may further improve if postoperative sedation and analgesia are not administered uniformly to all patients but selected based on individual characteristics. PMID- 20850351 TI - Intraoperative infusion of S(+)-ketamine enhances post-thoracotomy pain control compared with perioperative parecoxib when used in conjunction with thoracic paravertebral ropivacaine infusion. AB - OBJECTIVE: The authors explored the use of continuous postoperative subpleural paravertebral ropivacaine alone combined with intraoperative S(+)-ketamine or perioperative parecoxib as a new approach to pain control after major thoracotomy. DESIGN: A randomized study. SETTINGS: A single university hospital. PARTICIPANTS: Eighty patients underwent elective thoracotomy under general anesthesia. METHODS: Study patients were assigned to 1 of 3 groups: group K (n = 27) received intraoperative S(+)-ketamine (0.5 mg/kg as a preincisional bolus followed by a continuous infusion 400 MUg/kg/h), group P (n = 27) received perioperative parexocib (40 mg before extubation and 12 hours postoperatively), and group C (n = 26) served as the control group. At the end of surgery, all patients received a subpleural paravertebal infusion of ropivacaine. MEASUREMENTS AND MAIN RESULTS: Pain was assessed by visual analog scores and supplemental morphine consumption with PCA up to 48 hours postoperatively. The duration of stay and postoperative functional parameters also were collected. Compared with ropivacaine alone, S(+)-ketamine significantly reduced pain scores at rest and during movement at 4, 12, 24, and 48 hours postoperatively. Moreover, at 24 and 48 hours, pain was less after S(+)-ketamine compared with parexocib. S(+) ketamine also reduced morphine needs in comparison to placebo at 4, 12, 24, and 48 hours and in comparison to parexocib at 48 hours after thoracotomy. There were no differences in parameters for lung or bowel function, mobilization time, or ICU and hospital stay. CONCLUSIONS: In patients with thoracotomy, postoperative paravertebral ropivacaine combined with intraoperative S(+)-ketamine provided better early postoperative pain relief than ropivacaine and perioperative parexocib or ropivacaine alone. PMID- 20850352 TI - Sudden infant and perinatal unexplained death: are we moving forward yet? AB - Autonomic nervous system and cardiac conducting system dysfunctions have been proposed to be implied in the pathogenesis of sudden infant death syndrome (SIDS). However, most clinicians and even pathologists lack experience with detailed examination of the brainstem and cardiac conducting system and may not recognize lesions within those systems that potentially could be crucial factors in the sudden unexpected perinatal and infant death. Recent anatomical, pathological, and bacteriological studies in SIDS confirm that the multidisciplinary approach provides the best approach to the challenging problems of SIDS and sudden unexplained perinatal death. PMID- 20850353 TI - Left ventricular mesenchymal hamartoma, a new hamartoma of the heart. AB - Primary neoplasms of the heart are rare. Benign entities in adult populations include myxoma, fibroma, lipoma, hamartoma of mature myocytes, and vascular hamartoma. The most common pediatric cardiac neoplasm is the rhabdomyoma. We report a 22-year-old female with a primary left ventricle tumor composed of multiple mature mesenchymal tissues, including mature cardiac myocytes, smooth muscle, fibroblasts, fat, blood vessels including a hemangioma like area, and nerve fibers. The various elements were disorganized, but well differentiated, and showed little mitotic activity, which are features suggestive of a hamartoma. Unlike a cardiac fibroma, which may entrap myocardium at the periphery of the lesion, the present case demonstrated all tissue elements throughout the tumor mass. We suggest that this lesion is sufficiently different from those hamartomas previously described to warrant a new designation, for which we propose the title cardiac mesenchymal hamartoma. PMID- 20850354 TI - Visualizing the functional diversification of CD8+ T cell responses in lymph nodes. AB - CD8(+) T cell responses generate effector cells endowed with distinct functional potentials but the contribution of early events in this process is unclear. Here, we have imaged T cells expressing a fluorescent reporter for the activation of the interferon-gamma (IFN-gamma) locus during priming in lymph nodes. We have demonstrated marked differences in the efficiency of gene activation during stable T cell-dentritic cell (DC) contacts, influenced in part by signal strength. Imaging the first cell division, we have demonstrated that heterogeneity in T cell functional potential was largely apparent as T cells initiated clonal expansion. Moreover, by analyzing the fate of single activated T cells ex vivo, we have provided evidence that these early differences resulted in clonal progenies with distinct functional properties. Thus, the early set of T cell-DC interactions in lymph nodes largely contribute to the heterogeneity of T cell responses through the generation of functionally divergent clonal progenies. PMID- 20850355 TI - The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. AB - Hematopoietic stem cells (HSCs) and their lympho-hematopoietic progeny are supported by microenvironmental niches within bone marrow; however, the identity, nature, and function of these niches remain unclear. Short-term ablation of CXC chemokine ligand (CXCL)12-abundant reticular (CAR) cells in vivo did not affect the candidate niches, bone-lining osteoblasts, or endothelial cells but severely impaired the adipogenic and osteogenic differentiation potential of marrow cells and production of the cytokines SCF and CXCL12 and led to a marked reduction in cycling lymphoid and erythroid progenitors. HSCs from CAR cell-depleted mice were reduced in number and cell size, were more quiescent, and had increased expression of early myeloid selector genes, similar to the phenotype of wild-type HSCs cultured without a niche. Thus, the niche composed of adipo-osteogenic progenitors is required for proliferation of HSCs and lymphoid and erythroid progenitors, as well as maintenance of HSCs in an undifferentiated state. PMID- 20850357 TI - Statins and postoperative renal function. PMID- 20850358 TI - Sleep, dreaming, and mental health: a review of historical and neurobiological perspectives. AB - Theories as to the function of sleep and dreaming and their relationship to emotions have been studied since the beginning of recorded history. Earliest historical records show the predominant view to be that dreams were considered divine in origin and only later did dream theory become linked with the functioning of the brain, perhaps most famously in psychoanalytic theory. The development of sleep laboratory techniques ushered in a new era of the dream study and their relationship to mental health. In this review we outline the history of theories about the genesis and function of dreams and sleep and their relationship to mental illness from ancient mythic and religious views to the first tentative scientific approaches to the ascendency of psychoanalysis and ultimately to the modern era of neuroscience. PMID- 20850356 TI - Integrin-induced PIP5K1C kinase polarization regulates neutrophil polarization, directionality, and in vivo infiltration. AB - Neutrophils are important in innate immunity and acute inflammatory responses. However, the regulation of their recruitment to sites of inflammation has not been well characterized. Here, we investigated the kinase PIP5K1C and showed that PIP5K1C deficiency impaired neutrophil recruitment because of an adhesion defect. PIP5K1C regulated the adhesion through facilitating RhoA GTPase and integrin activation by chemoattractants. Integrins could induce polarization of an isoform of PIP5K1C, PIP5K1C-90, in neutrophils through intracellular vesicle transport independently of exogenous chemoattractant. PIP5K1C-90 polarization was required for polarized RhoA activation at uropods and provided an initial directional cue for neutrophil polarization on the endothelium. Importantly, the polarization was also required for circumventing the inhibition of lamellipodium formation by RhoA so that neutrophils could form leading edges required for transendothelial migration. Because integrins are not known to regulate neutrophil polarization, our study revealed a previously underappreciated role of integrin signaling in neutrophil regulation. PMID- 20850359 TI - Transmission of methicillin resistant Staphylococcus aureus among pigs during transportation from farm to abattoir. AB - The prevalence of methicillin resistant Staphylococcus aureus (MRSA) in pigs at abattoirs is higher than in pigs sampled on farms. This study investigated whether MRSA negative pigs can become MRSA positive during transportation from the farm to the abattoir after exposure to other pigs and environmental sources of MRSA. Nasal swabs were collected from four batches of pigs during loading at the farm, on arrival at the abattoir and after stunning. Environmental wipes were taken from lorries after transporting pigs and from lairages after holding pigs. All pigs (n=117) tested MRSA negative before transportation. On arrival at the abattoir, 12/117 (10.3%) pigs in two batches tested MRSA positive. In lorries that tested positive after transportation, the prevalence of MRSA positive pigs was 21.1%, whereas no MRSA was detected in pigs that had been transported in lorries that tested negative after transportation. At stunning, all batches and 70/117 (59.8%) pigs tested MRSA positive. Pigs can become MRSA positive in the short period of time during transportation from the farm to stunning at the abattoir. PMID- 20850360 TI - 3D gradient coil design for open MRI systems. AB - Existing gradient coil design methods typically require some predetermined surface to be specified upon which the precise locations of coil windings are optimised with respect to gradient homogeneity and other measures of coil performance. In contrast, in this paper an analytic inverse method is presented for the theoretical design of 3D gradient coils in which the precise 3D geometry of the coils is obtained as part of the optimisation process. This method has been described previously for cylindrical whole-body gradients and is extended here for open MRI systems. A 3D current density solution is obtained using Fourier series combined with Tikhonov regularisation. The examples presented involve a minimum power penalty function and an optional shielding constraint. A discretised set of 3D coil windings is obtained using an equi-flux streamline seeding method. Results for an unshielded example display a concentration of windings within the portion of the coil volume nearest the imaging region and looped return path windings taken away from this region. However, for a shielded example the coil windings are found to lie almost exclusively on biplanar surfaces, suggesting that this is the optimum geometry for a shielded minimum power open coil. PMID- 20850361 TI - In vivo multisite oximetry using EPR-NMR coimaging. AB - Coimaging employing electron paramagnetic resonance (EPR) imaging and MRI is used for rapid in vivo oximetry conducted simultaneously across multiple organs of a mouse. A recently developed hybrid EPR-NMR coimaging instrument is used for both EPR and NMR measurements. Oxygen sensitive particulate EPR probe is implanted in small localized pockets, called sites, across multiple regions of a live mouse. Three dimensional MRI is used to generate anatomic visualization, providing precise locations of implant sites. The pO2 values, one for every site, are then estimated from EPR measurements. To account for radio frequency (RF) phase inhomogeneities inside a large resonator carrying a lossy sample, a generalization of an existing EPR data model is proposed. Utilization of known spectral lineshape, sparse distribution, and known site locations reduce the EPR data collection by more than an order of magnitude over a conventional spectral spatial imaging, enhancing the feasibility of in vivo EPR oximetry for clinically relevant models. PMID- 20850362 TI - Observation of NMR noise from solid samples. AB - We demonstrate that proton NMR noise signals, i.e. NMR spectra without excitation by radio frequency, can be obtained from solid samples. Experimental results are shown for static and magic-angle spinning conditions. In addition, a tuning procedure based on the probes' NMR noise characteristics and similar to the one described previously for liquids probes can also be used to optimize signal-to noise ratios in 1H-MAS experiments. PMID- 20850363 TI - Comparison of pQCT-based measures of radial bone geometry and apparent trabecular bone structure using manufacturer and in-house-developed algorithms. AB - Peripheral quantitative computed tomography (pQCT) provides noninvasive densitometric and morphometric measures of total, trabecular, and cortical bone compartments. Skeletal changes over time can be determined by repeated measurements. Image thickness of 2.5mm is thought to be advantageous with respect to test-retest reliability through interrogation of a significant tissue volume. However, the error associated with slight shifts in image location is unknown. The primary purpose of this study was to determine the effects of positional variability around the 4% site on radial bone measures. The secondary objective was to compare different software algorithms for estimating the same bone characteristics. Eight left cadaveric forearms (aged 65-88 yr) were imaged at 0.5 mm intervals around the 4% site of the radial bone using pQCT (10 slices; in plane resolution: 0.2 * 0.2mm; thickness: 2.5mm; Stratec XCT2000L. We used the manufacturer's software (Stratec v6.0B) to determine the total bone mineral density (BD_tot), total bone mineral content (BMC_tot), total bone area (Area_tot), trabecular bone mineral density (BD_trab), trabecular bone mineral content (BMC_trab), and trabecular bone area (Area_trab) from each image. For comparison, in-house-developed software was also used to analyze Area_tot and Area_trab at the 4% site. The in-house software also produced measures of apparent trabecular structure, including number (App.Tb.N), thickness (App.Tb.Th), and spacing (App.Tb.Sp), quantified using 2 different stereological approaches: the parallel-plate method using trabecular perimeter lengths and mean intercept length analysis. The effect of slice position was assessed using a 1 way repeated-measures analysis of variance (ANOVA). Reliability of nonsignificant slice distances around the 4% site was determined using intraclass correlation coefficients (ICCs). One-way repeated-measures ANOVA was used to compare measures of similar bone characteristics at the 4% site. Bland-Altman plots were created to assess the level of agreement between pairs of algorithms quantifying comparable apparent trabecular structure. Area_tot and Area_trab differed significantly at greater than or equal to 1.0mm proximal and greater than or equal to 0.5mm distal to the 4% site. BMC_tot and BMC_trab differ significantly greater than or equal to 1.5mm proximally (for both) and greater than or equal to 2.0 and 1.0mm distally, respectively. BD_tot differed significantly at greater than or equal to 1mm proximal and distal to the 4% site. BD_trab did not differ among the 10 slices. For images acquired at the 4% site, and 0.5mm more proximally, reliability was excellent (ICC=0.98 to 0.99). Although the in-house software yielded a higher value for Area_tot and Area_trab at the 4% site (p<0.05), no systematic bias was observed. The parallel-plate method yielded higher values for App.Tb.N and lower values for App.Tb.Th (p<0.05), with no systematic bias. App.Tb.Sp values were smaller using the parallel-plate method, and the difference in methods increased as App.Tb.Sp values increased. Statistically, tolerance for repositioning around the 4% site of the radial bone is least for measures of bone area and greatest for BD_trab. On repeated measures, a proximal shift of 0.5mm will not influence the results. PMID- 20850364 TI - A hip analysis protocol for pediatric bone densitometry: the Iowa Bone Development Study. AB - Pediatric proximal femur dual-energy X-ray absorptiometry (DXA) scans present analytic challenges because of the lack of standard points of reference in the growing skeleton. The Iowa Bone Development Study (IBDS) developed a modified pediatric-specific proximal femur analysis protocol using Hologic software. Serial DXA measurements were obtained for 214 children at approximate ages 5, 8, 11, and 13 yr. Standard analysis procedures as described by the manufacturer (Hologic default) were compared with the IBDS protocol. The IBDS protocol yielded lower but more stable results for bone area, bone mineral content (BMC), and bone mineral density for total hip, femoral neck, trochanter, and intertrochanter as a result of more precisely controlling the regions of interest. Linear regression models with body size, age, and gender as predictors were developed to examine variation in measurements. Coefficients of determination (R(2)) with the IBDS protocol were greater for each time point, demonstrating that the modified protocol was better aligned with body size. Similarly, Spearman correlation coefficients between total hip and hip subregions were consistently higher for BMC and bone area with the IBDS protocol with differences more notable among younger children. The IBDS protocol provides a reproducible method for evaluating pediatric proximal femur DXA scans during growth. PMID- 20850365 TI - Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy. AB - Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy. PMID- 20850367 TI - Prevalence of select infectious agents in inflammatory aural and nasopharyngeal polyps from client-owned cats. AB - Benign, inflammatory polyps may affect the nasopharynx and auditory canal of cats. It has been proposed that inflammation induced by infectious disease agents could trigger polyp formation. The objective of this pilot study was to determine the prevalence of feline herpesvirus-1 (FHV-1), feline calicivirus (FCV), Mycoplasma species, Bartonella species and Chlamydophila felis nucleic acids in polyp tissues collected from 30 clinically affected cats. Samples collected from the tympanic bulla from 12 clinically normal cats were also assayed. DNA or RNA of some of the target agents were amplified from samples from 25% of normal cats and 33% of affected cats; however, statistical associations were not detected for individual agent results or grouped results. The study documents that common oropharyngeal or blood borne agents can be detected in the tympanic bullae of normal cats. Failure to consistently amplify RNA or DNA of the select agents from polyp tissues suggests the agents studied were not directly associated with the pathogenesis of this syndrome in the cats tested. Alternately, the inflammatory response may have cleared microbial nucleic acids to undetectable levels by the time of sample collection. PMID- 20850366 TI - A chaperone cascade sorts proteins for posttranslational membrane insertion into the endoplasmic reticulum. AB - Tail-anchored (TA) proteins are posttranslationally inserted into either the endoplasmic reticulum (ER) or the mitochondrial outer membrane. The C-terminal transmembrane domains (TMDs) of TA proteins enable their many essential cellular functions by specifying the membrane target, but how cells process these targeting signals is poorly understood. Here, we reveal the composition of a conserved multiprotein TMD recognition complex (TRC) and show that distinct TRC subunits recognize the two types of TMD signals. By engineering mutations in a mitochondrial TMD, we switch over its TRC subunit recognition, thus leading to its misinsertion into the ER. Biochemical reconstitution with purified components demonstrates that TRC tethers and enzymatically activates Get3 to selectively hand off ER-bound TA proteins to Get3. Thus, ER-bound TA proteins are sorted at the top of a TMD chaperone cascade that culminates with the formation of Get3-TA protein complexes, which are recruited to the ER membrane for insertion. PMID- 20850368 TI - Comparison of measured acoustic power results gained by using three different methods on an ultrasonic low-frequency device. AB - The theme of this work is characterization of an ultrasonic low-frequency device, driven at an excitation frequency of around 25 kHz at different electrical excitation levels by using three different methods as proposed in IEC 61847 and IEC 61088 standards. The first method is based on the electromechanical characterization of the device. It consists of measuring the input electrical impedance around the excitation frequency in the unloaded and loaded conditions at a low level excitation voltage of 1 V. The equivalent RLC electrical circuit parameters of an unloaded and loaded device are determined in an anechoic tank and in a vessel at different immersion depths and tip positions in a complex geometry. The electroacoustic efficiency factor of the method is determined by knowing the real part of the radiation resistance and mechanical loss resistance which are transformed into an equivalent RLC electrical circuit of the transducer. The second method consists of measuring the spatial pressure distribution of an ultrasonic device near pressure release boundary in an anechoic tank. The acoustic reciprocity principle is used to determine the derived acoustic power of an equivalent point source in the form of radially oscillating sphere at the excitation frequency. The third method is based on the measurement of power dissipated in a restricted volume of water by using a calorimetric method. Some of the suggested methods are complicated to apply in the high energy ultrasonic devices whose size is much lower than the wavelength in the loading medium due to the occurrence of strong cavitation activity and influence of the sonotrode tip position in the complex standing wave field. However, the measured acoustic power found by using the three suggested methods is compared by means of the electroacoustic efficiency factor defined for each considered method. In the electromechanical characterization, which is made at low electrical excitation levels (applied electrical power of 1 mW at the series resonance frequency), the calculated maximum electroacoustic efficiency factor is around 48% when the influence of standing waves pattern on the radiation resistance is small. It is approximately the same as the one obtained by measuring the derived acoustic power in an anechoic tank (43%) without cavitation activity in front of the tip. When a strong cavitation activity is present in the loading medium, the bubble cloud has a significant influence on the derived acoustic power which is then dispersed in a broad frequency range and the electroacoustic efficiency factor of the method decreases down to 2%. A significant growth of the input electrical impedance magnitude at the excitation frequency is observed when the cavitation activity is present in front of the tip and when it is compared with the impedance magnitude measured at lower excitation levels without cavitation. The power dissipated in the loading medium almost linearly depends on the applied electrical power, with saturation at higher excitation levels. In the linear operating mode the electroacoustic efficiency factor of the calorimetric method (48%) is comparable with the efficiency factors of two other methods. In the nonlinear operating mode, it is larger (71%) due to a significant amount of heat energy released during the cavitation process. PMID- 20850369 TI - A comparative study of Lrrk2 function in primary neuronal cultures. AB - OBJECTIVE: To assess the contribution of wild-type, mutant and loss of leucine rich repeat kinase-2 (LRRK2; Lrrk2) on dendritic neuronal arborization. BACKGROUND: LRRK2 mutations are recognized as the major genetic determinant of susceptibility to Parkinson's disease for which a cellular assay of Lrrk2 mutant function would facilitate the development of targeted molecular therapeutics. METHODS: Dendritic neuronal arborization (neurite length, branching and the number of processes per cell) was quantified in primary hippocampal and midbrain cultures derived from five lines of recombinant LRRK2 mice, including human BAC wild-type and mutant overexpressors (Y1699C and G2019S), murine knock-out and G2019S knock-in animals. RESULTS: Neuronal arborization in cultures from BAC Lrrk2 wild-type animals is comparable to non-transgenic littermate controls, despite high levels of human transgene expression. In contrast, primary neurons from both BAC mutant overexpressors presented with significantly reduced neuritic outgrowth and branching, although the total number of processes per cell remained comparable. The mutant-specific toxic gain-of-function observed in cultures from BAC mutant mice may be partially rescued by staurosporine treatment, a non specific kinase inhibitor. In contrast, neuronal arborization is far more extensive in neuronal cultures derived from murine knock-out mice that lack endogenous Lrrk2 expression. In Lrrk2 G2019S knock-in mice, arguably the most physiologically relevant system, neuritic arborization is not impaired. CONCLUSIONS: Impairment of neuritic arborization is an exaggerated, albeit mutant specific, consequence of Lrrk2 over-expression in primary cultures. The phenotype and assay described provides a means to develop therapeutic agents that modulate the toxic gain-of-function conferred by mutant Lrrk2. PMID- 20850370 TI - Swallowing outcomes following Intensity Modulated Radiation Therapy (IMRT) for head & neck cancer - a systematic review. AB - PURPOSE: A systematic review to establish what evidence is available for swallowing outcomes following IMRT for head and neck cancer. METHODS: Online electronic databases were searched to identify papers published in English from January 1998 to December 2009. Papers were independently appraised by two reviewers for methodological quality, method of swallowing evaluation and categorized according to the World Health Organisation's International Classification of Health Functions. The impact of radiation dose to dysphagia aspiration risk structures (DARS) was also evaluated. RESULTS: Sixteen papers met the inclusion criteria. The literature suggests that limiting the radiation dose to certain structures may result in favourable swallowing outcomes. Methodological limitations included variable assessment methods and outcome measures and heterogeneity of patients. There are only limited prospective data, especially where pre-treatment measures have been taken and compared to serial post-treatment assessment. CONCLUSIONS: Few studies have investigated the impact of IMRT on swallow function and the impact on everyday life. Initial studies have reported potential benefits but are limited in terms of study design and outcome data. Further well designed, prospective, longitudinal swallowing studies including multidimensional evaluation methods are required to enable a more comprehensive understanding of dysphagia complications and inform pre-treatment counselling and rehabilitation planning. PMID- 20850371 TI - Comorbidity in head and neck cancer: a critical appraisal and recommendations for practice. AB - Comorbidity, the presence of additional illnesses unrelated to the tumor, has a significant impact on the prognosis of patients with head and neck cancer. In these patients, tobacco and alcohol abuse contributes greatly to comorbidity. Several instruments have been used to quantify comorbidity including Adult Comorbidity Evaluation 27 (ACE 27), Charlson Index (CI) and Cumulative Illness Rating Scale. The ACE 27 and CI are the most frequently used indices. Information on comorbidity at the time of diagnosis can be abstracted from patient records. Self-reporting is less reliable than record review. Functional status is not a reliable substitute for comorbidity evaluation as a prognostic measure. Severity as well as the presence of a condition is required for a good predictive instrument. Comorbidity increases mortality in patients with head and neck cancer, and this effect is greater in the early years following treatment. In addition to reducing overall survival, many studies have shown that comorbidity influences disease-specific survival negatively, most likely because patients with high comorbidity tend to have delay in diagnosis, often presenting with advanced stage tumors, and the comorbidity may also prompt less aggressive treatment. The impact of comorbidity on survival is greater in younger than in older patients, although it affects both. For specific tumor sites, comorbidity has been shown to negatively influence prognosis in oral, oropharyngeal, laryngeal and salivary gland tumors. Several studies have reported higher incidence and increased severity of treatment complications in patients with high comorbidity burden. Studies have demonstrated a negative impact of comorbidity on quality of life, and increased cost of treatment with higher degree of comorbidity. Our review of the literature suggests that routine collection of comorbidity data will be important in the analysis of survival, quality of life and functional outcomes after treatment as comorbidity has an impact on all of the above. These data should be integrated with tumor-specific staging systems in order to develop better instruments for prognostication, as well as comparing results of different treatment regimens and institutions. PMID- 20850372 TI - Influence of genetic polymorphisms on frequency of micronucleated buccal epithelial cells in leukoplakia patients. AB - Micronuclei (MN) are extensively used as an indicator of chromosomal damage and early biomarker of cancer risk. The genetic host factors are known to influence the level of chromosomal alterations consequently affecting MN frequencies. Hence, in the present study, we investigated the extent of chromosomal damage by analyzing micronucleated cell (MNC) frequency in exfoliated buccal epithelial cells (BEC) and its possible relationship with genetic polymorphisms in patients with oral leukoplakia (OL). The study group comprised of habit-free (NHC, n=39), habit controls (HC, n=62) and OL patients (n=66). Micronucleus assay was carried out to determine the MNC frequency and the genotyping was performed by PCR-RFLP for metabolizing (CYP1A1, GSTM1, GSTT1, GSTP1) and DNA repair (hOGG1, XRCC1, XPD) genes. The correlation between MNC frequency and genetic polymorphisms was analyzed. We found significant increase in overall MNC frequency in OL patients as compared to habit-matched controls (p=0.01). The higher proportion of multiple micronucleated cells (>5 MN per cell) indicate increased DNA damage in the buccal mucosa of OL patients than the controls (p=0.004). The polymorphic alleles of XPD751 and hOGG1 showed significant association with total MNC frequency in OLs (p=0.034 and p=0.03 respectively). In conclusion, the extent of chromosomal damage in target tissues is higher in patients with OL. MNC frequency in combination with genetic polymorphisms in DNA repair genes may serve as better predicator of risk. PMID- 20850373 TI - Posttraumatic growth: a novel concept in oral cavity cancer care? AB - Recently the importance of posttraumatic growth (PTG), a phenomenon of positive psychological growth beyond baseline values, has been discovered in the field of oncology. An evidence based review of the literature regarding PTG was performed, both to support its understanding and to consider its application within the research field of oral cavity (OC) cancer. A Pubmed, Medline, PsycINFO search from the earliest date until April 2010 was carried out. Full articles meeting the inclusion and exclusion criteria were reviewed. The search yielded 852 papers, 91 'potentially relevant papers' and 29 'effective papers', the latter of which formed the basis of this review. PTG was assessed in twenty-eight studies with the Posttraumatic Growth Inventory and in only one study with the Perceived Benefits Scale (PBS). PTG in cancer patients has been reported in five main domains (i) appreciation of life, (ii) relating to others, (iii) increased personal sense, (iv) sense of new possibilities and (v) positive spiritual change. Socio-demographic factors, stressor characteristics and coping strategies influence and predict the development PTG. In the past decade an increasing interest in the concept of PTG in the field of oncology has emerged. This evidence based review presents PTG to the research community in the field of OC cancer, appraises its modification capacity of the treatment outcome in other cancer research fields and hypothesizes its eventual benefit in the field of OC cancer research. PMID- 20850374 TI - Expression of EMMPRIN in adenoid cystic carcinoma of salivary glands: correlation with tumor progression and patients' prognosis. AB - Extracellular matrix metalloproteinase inducer (EMMPRIN) plays a critical role in the progression of malignancies by stimulating expression of metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) in stromal cells. However, the expression of EMMPRIN in adenoid cystic carcinoma (ACC) of salivary glands, and its correlation with patients' prognosis have never been investigated thus far. In the present study, the expression of EMMPRIN was examined in 72 ACCs and 20 normal salivary gland tissues by immunohistochemistry. The expression of MMP 2, MMP-9, VEGF, Ki-67 index, and microvessel density (MVD) labeled by CD31 were also assessed by immunohistochemistry in ACCs. The positivity of EMMPRIN in ACCs was 62.5%, which was significantly higher than that in normal salivary gland tissues (P<0.01). EMMPRIN expression was positively correlated with tumor size, histotypes, clinical stage, perineural invasion, vascular invasion, metastasis, expression of MMP-2, MMP-9, VEGF, Ki-67 index, and MVD (P<0.05), but not with gender, age, tumor site or recurrence (P>0.05). Multivariate analysis showed that EMMPRIN expression, Ki-67 index, and solid histotype had an independent prognostic effect on overall survival (P<0.05). According to our findings, EMMPRIN might actively be involved in the growth, angiogenesis, invasion and metastasis of ACCs. Measurement of EMMPRIN may be helpful in predicting patients' prognosis and understanding the malignant behaviors of ACCs. PMID- 20850375 TI - Antibiotic resistance in the environment: a link to the clinic? AB - The emergence of resistance to all classes of antibiotics in previously susceptible bacterial pathogens is a major challenge to infectious disease medicine. The origin of the genes associated with resistance has long been a mystery. There is a growing body of evidence that is demonstrating that environmental microbes are highly drug resistant. The genes that make up this environmental resistome have the potential to be transferred to pathogens and indeed there is some evidence that at least some clinically relevant resistance genes have originated in environmental microbes. Understanding the extent of the environmental resistome and its mobilization into pathogenic bacteria is essential for the management and discovery of antibiotics. PMID- 20850376 TI - Synthesis, spectroscopic, thermal and biological activity studies on triazine metal complexes. AB - The coordination behaviour of the triazine ligand with NNO donation sites, derived from 3-benzyl-7-hydrazinyl-4H-[1,3,4]thiadiazolo[2,3c][1,2,4]triazin-4 one (HL), towards some metal ions namely Mn(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) are reported. The metal complexes are characterized based on elemental analyses, IR, (1)H NMR, solid reflectance, magnetic moment, molar conductance and thermal analyses (TG, DTG and DTA). The ionization constants of the organic ligand under investigation as well as the stability constants of its metal chelates are calculated spectrophotometrically at 25 degrees C. The chelates are found to have octahedral geometrical structures. The ligand (HL) and its binary chelates are subjected to thermal analyses (TG, DTG and DTA) and the different activation thermodynamic parameters are calculated from their corresponding DTG curves to throw more light on the nature of changes accompanying the thermal decomposition process of these compounds. The synthesized ligand and its metal complexes were found to have biological activity against the desert locust Schistocerca gregaria (Forsk.) (Orthoptera - Acrididae) and its adult longevities. PMID- 20850377 TI - Natural intragenotypic and intergenotypic HCV recombinants are rare in southwest China even among patients with multiple exposures. AB - BACKGROUND: Both intragenotypic and intergenotypic hepatitis C virus (HCV) recombinants were recently identified, whereas the frequency of HCV recombinants in circulation in certain parts of the world remains uncertain. OBJECTIVES: To assess the frequency of natural intragenotypic and intergenotypic HCV recombinants in southwest China and that of multitypic HCV infection, which is the prerequisite factor for recombination. STUDY DESIGN: Comparison of the genotyping results based on core-envelope 1 and non-structural 5B sequence phylogenetic analyses to detect the possible recombinants. Multitypic HCV infection was detected by colony analysis of the core-envelope 1 region. RESULTS: There was no discrepancy between genotyping results based on the core-envelope 1 and non-structural 5B regions in 243 sera from 222 patients, including 107 samples from 92 intravenous drug users, 26 samples from 20 hemodialysis patients, and 110 samples from 110 other patients. Multitypic HCV carriage was identified in 9 (47.4%) of the 19 patients with multiple exposures who were randomly selected, and 11 (45.8%) of the 24 specimens. There were 26 repeatedly exposed patients who had more than one HCV RNA positive sera at different time points, but neither of their HCV subtypes had switched over time. CONCLUSION: Although the high frequency of multitypic HCV infection was identified in patients with multiple exposures, intergenotypic or intragenotypic recombination remains an infrequent event in southwest China; thus, routine genotyping with more than one subgenomic region for clinical use is not warranted. PMID- 20850378 TI - Frequent presence of incomplete HPV16 E7 ORFs in lung carcinomas: memories of viral infection. AB - BACKGROUND: HPV16 E6/E7 oncoproteins are critical for cervical carcinogenesis. The corresponding oncogenes are also detected in head and neck cancer, but in lung cancer their presence is strongly debated. PCR-based detection protocols amplify different target sequences. OBJECTIVES: To examine the frequency of different length HPV16 E7 segments in lung carcinomas. STUDY DESIGN: We designed four different amplification schemes for the detection of overlapping segments of the HPV16 E7 ORF, all suitable for specific HPV detection in cervical carcinoma. In two schemes, the entire E7 ORF was targeted while in the remaining schemes internal, smaller sequences were targeted. In total, 76 specimens were used; 29 lung carcinoma specimens, 16 non-cancerous lung tissue specimens from the same patients and 31 bronchial washings from different lung cancer patients. RESULTS: Amplification of the entire HPV16 E7 ORF, using two protocols, demonstrated the absence of the specific HPV16 E7 sequences (74 samples either tested negative by the first PCR protocol or false positive by the second, based on sequencing or AvaII or PvuII digestion). However, both schemes targeting smaller E7 segments revealed the frequent presence of HPV16 E7 sequences in lung carcinoma specimens (14/23 positive by either scheme). CONCLUSIONS: HPV16 E7 sequences are frequently observed in lung carcinomas. Decreasing the size of PCR-target sequences increases the detection frequency, possibly indicating the presence of incomplete viral ORFs. Restriction endonuclease analysis is critical for verifying the reliability of the detection of these sequences. PMID- 20850379 TI - Immuno-reactive proteins from Mycobacterium immunogenum useful for serodiagnosis of metalworking fluid hypersensitivity pneumonitis. AB - Metalworking fluid-associated hypersensitivity pneumonitis (MWF-HP) is a pulmonary disease caused by inhaling microorganisms present in the metalworking fluids used in the industrial sector. Mycobacterium immunogenum is the main etiological agent. Among the clinical, radiological and biological tools used for diagnosis, serological tests are important. The aim of this study was to identify immunogenic proteins in M. immunogenum and to use recombinant antigens for serological diagnosis of MWF-HP. Immunogenic proteins were detected by two dimensional Western blot and candidate proteins were identified by mass spectrometry. Recombinant antigens were expressed in Escherichia coli and tested by enzyme-linked immunosorbent assay (ELISA) with the sera of 14 subjects with MWF-HP and 12 asymptomatic controls exposed to M. immunogenum. From the 350 spots visualized by two-dimensional gel electrophoresis with M. immunogenum extract, 6 immunogenic proteins were selected to be expressed as recombinant antigens. Acyl CoA dehydrogenase antigen allowed for the best discrimination of MWF-HP cases against controls with an area under the receiver operating characteristics (ROC) curve of 0.930 (95% CI=0.820-1), a sensitivity of 100% and a specificity of 83% for the optimum threshold. Other recombinant antigens correspond to acyl-CoA dehydrogenase FadE, cytosol aminopeptidase, dihydrolipoyl dehydrogenase, serine hydroxymethyltransferase and superoxide dismutase. This is the first time that recombinant antigens have been used for the serodiagnosis of hypersensitivity pneumonitis. The availability of recombinant antigens makes it possible to develop standardized serological tests which in turn could simplify diagnosis, thus making it less invasive. PMID- 20850380 TI - Predacious bacteria, Bdellovibrio with potential for biocontrol. AB - Bacteria of the genus of Bdellovibrio are highly motile Gram-negative predators of other Gram-negative bacteria causing lysis of their prey. Here we report results of studies on the interactions of Bdellovibrio with species of Alcaligenes, Campylobacter, Erwinia, Escherichia, Helicobacter, Pseudomonas, Legionella, and Shigella in agar lower, liquid media and cells attached to a surface. Helicobacter pylori was studied employing both actively growing and viable but nonculturable (VBNC) cells. The majority of the bacterial strains tested were found to be susceptible to Bdellovibrio. A significant observation was that Bdellovibrio attacked both actively growing and VBNC H. pylori, that phenomenon has never been reported. The results indicate that bdellovibrios have potential as biocontrol agents. PMID- 20850382 TI - Are US results for assisted reproduction better than the rest? Is it a question of competence or policies? AB - A comparison of nationally published 2006 data from the USA, UK and Australia and New Zealand (ANZ) was performed. Although live births/cycle was higher in USA, live birth/embryo transferred was significantly higher in ANZ (18.2%) compared with both USA and UK (13.8%) (P<0.001). The multiple rates were significantly lower in ANZ (12.0%) compared with USA (30.7%) and UK (25.2%) (P<0.001). The incidence of oocyte donation was significantly higher in the USA (11.1%) than in ANZ (2.8%) and UK (3.9%) (P<0.001). There was significantly higher cycle cancellation in USA (11.5%) compared with the UK (6.8%) and ANZ (9.5%) (P<0.001). The incidence of frozen embryo transfer cycles was significantly higher in ANZ (59%) compared with both UK (24%) and USA (22%) (P<0.001). The total live birth rate from fresh and frozen cycles for the same year was significantly higher in ANZ at 32.0% compared with the UK at 28.8% (P<0.001) with half the multiple rate. It is argued that the USA's higher success rates are explained by policy (transferring higher number of embryos) and selection issues (cancelling or avoiding poor responders) rather than being a matter of clinical competence. PMID- 20850383 TI - Peanut-allergic subjects and their peanut-tolerant siblings have large differences in peanut-specific IgG that are independent of HLA class II. AB - We enrolled 53 peanut-allergic subjects and 64 peanut-tolerant full siblings, measured peanut-specific IgG and IgE, determined HLA class II at high resolution, and analyzed DRB1 alleles by supertypes. Peanut-specific IgG and IgE were elevated in the peanut-allergic subjects (p<0.0001) but did not stratify with HLA alleles, haplotypes, or supertypes. There were no significant differences in HLA class II between the peanut-allergic and peanut-tolerant siblings but there was an increased frequency of DRB1*0803 in both sets of siblings compared to unrelated controls (p(c)=4.5*10-9). Furthermore, we identified 14 sibling pairs in which the peanut-allergic and the peanut-tolerant siblings have identical HLA class II and again found an elevation of anti-peanut IgG in the peanut-allergic subjects (p<0.0001). In conclusion, although DRB1*0803 may identify a subset of families with increased risk of peanut allergy, differences in peanut-specific immunoglobulin production between peanut-allergic subjects and their peanut tolerant siblings are independent of HLA class II. PMID- 20850381 TI - Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial. AB - BACKGROUND: Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. METHODS: Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m2 doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m2 dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. FINDINGS: 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0.82, 95% CI -1.31 to -0.33; end-systolic dimension: 0.57, 0.21-0.93) but not for those who also received dexrazoxane (-0.41, -0.88 to 0.06; 0.15, -0.20 to 0.51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0.47, 0.46-0.48) and thickness-to-dimension ratio (0.66, 0.64-0.68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0.04) for left ventricular fractional shortening at 5 years in girls (1.17, 0.24-2.11), but not in boys (-0.10, -0.87 to 0.68). Similarly, subgroup analysis showed dexrazoxane protection (p=0.046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1.15, 0.44-1.85), but not in boys (0.19, -0.42 to 0.81). With a median follow-up for recurrence and death of 8.7 years (range 1.3-12.1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0.99). INTERPRETATION: Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long term cardioprotective effects in girls than in boys. FUNDING: US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis. PMID- 20850384 TI - Down regulation of Fc and complement receptors on B cells in rheumatoid arthritis. AB - B cell tolerance is regulated by receptors that modulate B cell receptor signaling, such as Fc gamma receptor IIb (FcgammaRIIb; CD32b) and complement receptors (CR) 1 and 2. Deficiency in these receptors may contribute to autoimmunity. To address this we have investigated the receptor expression in healthy individuals in comparison with rheumatoid arthritis (RA) patients. In healthy subjects we found that women had overall lower FcgammaRIIb expression on B cells than men that significantly decreased with age. RA patients had fewer FcgammaRIIb, CR1 and CR2 positive B cells and decreased receptor expressions compared to healthy subjects. Further, the RA B cells displayed a significantly increased proliferative response when cultured with interleukin-2 in vitro. In summary, the dysregulated B cells in RA are associated with lower FcgammaRIIb, CR1 and CR2 levels. The reduced FcgammaRIIb expression on B cells in women may influence the increased frequency of autoimmunity in women. PMID- 20850385 TI - Postoperative interictal epileptiform discharge within 1 month is associated with seizure recurrence after anterior temporal lobectomy. AB - To investigate the relationship of interictal epileptiform discharges (IEDs) within 1 month of anterior temporal lobectomy (ATL) to seizure outcome, we reviewed data for 202 (107 left ATL, 95 right ATL) patients who had undergone ATL for mesial temporal epilepsy. Postoperative EEGs within 30 days and other preoperative variables were analyzed to examine the significant factors that determine freedom from disabling seizures. IEDs were noted in 29 (22.3%) of the 130 patients without seizures for 2 years after ATL compared with 31 (43.1%) of the 72 patients with recurrent seizures (P = 0.002). Postoperative IEDs remained an independent predictive factor for seizure outcome by logistic regression (adjusted OR = 2.38, 95% CI = 1.18-4.81, P = 0.016, 2 years postoperatively; adjusted OR = 2.22, 95% CI = 1.03-4.82, P = 0.043, 5 years postoperatively) and Cox hazard regression analysis (adjusted HR = 1.76, 95% CI = 1.18-2.62, P = 0.006) after controlling for other predicting factors (unilateral hippocampal atrophy, history of febrile seizures, and IQ scores). In this study, IEDs on the EEG obtained soon after surgery were associated with postoperative seizure recurrence. These results can be used in the assessment of risk of seizure recurrence after ATL. PMID- 20850387 TI - Using patient history to distinguish between patients with non-epileptic and patients with epileptic events. AB - Information obtained during psychological evaluations of 93 patients with epileptic events (EEs) and 63 with nonepileptic events (NEEs) was used to test the relative contributions of multiple risk factors to prediction of NEEs during video/EEG monitoring. The best group of independent predictors of NEEs comprised: (1) age at first spell, (2) symptoms of a psychiatric diagnosis other than anxiety or depression, (3) marital instability, (4) symptoms of an anxiety disorder other than panic disorder, and (5) years of education. Report of childhood abuse or neglect and taking psychotropic medication correlated with most of the other risk factors for NEEs. It may not be necessary to gather data on all of the variables shown to be associated with NEEs. Although there is a high prevalence of risk factors for psychopathology in patients with EEs, it is lower compared with that of patients with NEEs, and patients with EEs are less likely to report multiple risk factors. PMID- 20850388 TI - Neuroimaging changes in mesial temporal lobe epilepsy are magnified in the presence of depression. AB - OBJECTIVE: The aim of this study was to investigate differences in gray matter volume between patients with mesial temporal lobe epilepsy (MTLE) with and without depression using voxel-based morphometry. METHOD: We included 48 adults with refractory MTLE (31 women, 39.18 +/- 8.4 years) and 96 healthy controls (75 women, 37.11 +/- 8.9 years). For the psychiatric evaluation, the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Axis I, was used for the diagnosis of depression, and the Beck Depression Inventory, for the determination of symptom intensity. All patients underwent an MRI scan. Patients were separated into two groups: those with MTLE with depression (n = 24) and those with MTLE without depression (n = 24). We performed voxel-based morphometric analysis, comparing patients with controls using the t test. RESULTS: The number of areas of gray matter volume loss was higher in patients with MTLE with depression than in those with MTLE without depression. CONCLUSIONS: The evidence of more widespread gray matter volume loss in patients with MTLE and depression calls our attention to the importance of timely recognition and treatment of depression in patients with MTLE and also to the bidirectional relationship between the two disorders and their frequent co occurrence. PMID- 20850386 TI - Functional MRI is a valid noninvasive alternative to Wada testing. AB - Partial removal of the anterior temporal lobe (ATL) is a highly effective surgical treatment for intractable temporal lobe epilepsy, yet roughly half of patients who undergo left ATL resection show a decline in language or verbal memory function postoperatively. Two recent studies demonstrate that preoperative fMRI can predict postoperative naming and verbal memory changes in such patients. Most importantly, fMRI significantly improves the accuracy of prediction relative to other noninvasive measures used alone. Addition of language and memory lateralization data from the intracarotid amobarbital (Wada) test did not improve prediction accuracy in these studies. Thus, fMRI provides patients and practitioners with a safe, noninvasive, and well-validated tool for making better informed decisions regarding elective surgery based on a quantitative assessment of cognitive risk. PMID- 20850389 TI - Central serotonin 1A receptor binding in temporal lobe epilepsy: a [carbonyl (11)C]WAY-100635 PET study. AB - We performed positron emission tomography using [carbonyl-(11)C]WAY-100635, a serotonin 1A (5-HT(1A)) receptor antagonist, in 13 patients with temporal lobe epilepsy (TLE) and in 13 controls. 5-HT(1A) receptor distribution mapping allowed correct lateralization of the epileptogenic temporal lobe in all patients. 5 HT(1A) receptor binding potential (BP(ND)) was significantly reduced in almost all temporal regions of the epileptogenic lobe. Compared with controls, the patients had significantly decreased BP(ND) values in the hippocampus, parahippocampal gyrus, and amygdala. The asymmetry index (AI), which characterizes the interhemispheric asymmetry in BP(ND), was significantly higher in patients than in controls in most regions. Depression scores were not significantly correlated with BP(ND) or AI values. Our data provide further evidence of functional changes in the serotonergic system in TLE. Molecular imaging of the 5-HT(1A) receptor may help to define the in vivo neurochemistry of TLE, and may provide a valuable tool in the noninvasive presurgical assessment of patients with medically refractory TLE. PMID- 20850390 TI - Intradiscal injection therapy for degenerative chronic discogenic low back pain with end plate Modic changes. AB - BACKGROUND CONTEXT: The effect of intradiscal steroid therapy for patients with degenerative chronic discogenic low back pain remains an issue of debate. PURPOSE: To evaluate the effect of various intradiscal injection regimens for patients with degenerative chronic discogenic low back pain and end plate Modic changes. STUDY DESIGN: Double-blind, randomized, controlled, prospective clinical study. PATIENT SAMPLE: One hundred twenty patients with discogenic low back pain and end plate Modic changes on magnetic resonance imaging (MRI) who received discography but were unwilling to accept surgical operation. OUTCOME MEASURES: Pain and function were determined by the visual analog scale (VAS) and the Oswestry Disability Index (ODI) assessment. METHODS: Patients who received diagnostic discography for suspected degenerative discogenic low back pain were recruited. A total of 120 patients with positive discography and end plate Modic changes at a single level were enrolled in the study and allocated into Groups A and B according to the type of Modic changes on MRI. Then, the patients in Groups A and B were randomized into three subgroups, respectively. Intradiscal injection of normal saline was performed in Subgroups A1 and B1, intradiscal injection of diprospan was performed in Subgroups A2 and B2, and intradiscal injection of a mixed solution of diprospan+songmeile (cervus and cucumis polypeptide) was performed in Subgroups A3 and B3. The clinical outcome of each patient was evaluated and recorded by using the VAS and ODI at 3 and 6 months after the procedure. RESULTS: The subgroups were comparable with respect to gender, age, pain, and percentage disability. Neither VAS pain scores nor Oswestry function scores of the patients within Group A had any improvement at 3 or 6 months after saline injection, but both of them improved significantly at the two time points after diprospan and diprospan+songmeile injection, respectively. Meanwhile, the latter two injection protocols led to no significant difference in pain relief and functional recovery. Similar results were obtained in patients within Group B. Furthermore, no difference of the improvement of VAS pain scores or Oswestry function scores was found between the patients within Group A and within Group B at different time points after various interventions. CONCLUSION: Intradiscal injection of corticosteroids could be a short-term efficient alternative for discogenic low back pain patients with end plate Modic changes on MRI who were still unwilling to accept surgical operation when conservative treatment failed. PMID- 20850391 TI - Comparing robot-assisted with conventional laparoscopic hysterectomy: impact on cost and clinical outcomes. AB - OBJECTIVE: To compare clinical and economic outcomes (hospital costs) in women undergoing laparoscopic hysterectomy performed with and without robotic assistance in inpatient and outpatient settings. METHODS: Using the Premier hospital database, we identified women >18 years of age with a record of minimally invasive hysterectomy performed in 2007 to 2008. Univariable and multivariable analyses examined the association between robot-assisted hysterectomy and adverse events, hospital costs, surgery time, and length of stay. RESULTS: Of 36,188 patient records analyzed from 358 hospitals, 95% (n = 34,527) of laparoscopic hysterectomies were performed without robotic assistance. Inpatient and outpatient settings did not differ substantively in frequency of adverse events. For cardiac, neurologic, wound, and vascular complications, frequencies were <1% for robot and non-robot procedures. In inpatient and outpatient settings alike, use of robotic assistance was consistently associated with statistically significant, higher per-patient average hospital costs. Inpatient procedures with and without robotic assistance cost $9640 (95% confidence interval [CI] = $9621, $9659) versus $6973 (95% CI = $6959, $6987), respectively. Outpatient procedures with and without robotic assistance cost $7920 (95% CI = $7898, $7942) versus $5949 (95% CI = $5932, $5966), respectively. Inpatient surgery times were significantly longer for robot-assisted procedures, 3.22 hours (95% CI = 3.21, 3.23) compared with non-robot procedures at 2.82 hours (95% CI = 2.81, 2.83). Similarly, outpatient surgery times with robot averaged 2.99 hours (95% CI = 2.98, 3.00) versus 2.46 hours (2.45, 2.47) for non-robot procedures. CONCLUSION: Our findings reveal little clinical differences in perioperative and postoperative events. This, coupled with the increased per-case hospital cost of the robot, suggests that further investigation is warranted when considering this technology for routine laparoscopic hysterectomies. PMID- 20850392 TI - Travelling with cystic fibrosis: recommendations for patients and care team members. AB - There are no European Guidelines on issues specifically related to travel for people with cystic fibrosis (CF). The contributors to these recommendations included 30 members of the ECORN-CF project. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Executive Agency of Health and Consumers of the European Union and the Christiane Herzog Foundation. The main goal of this paper is to provide patient-oriented advice that complements medical aspects by offering practical suggestions for all aspects involved in planning and taking a trip. The report consists of three main sections, preparation for travel, important considerations during travel and at the destination, and issues specific to immunocompromised travellers. People with CF should be encouraged to consult with their CF centre prior to travel to another country. The CF centre can advise on the necessary preparation for travel, the need for vaccinations, essential medications that should be brought on the trip and also provide information relating to CF care in the region and plan of action in case of an emergency. PMID- 20850393 TI - A novel mixed-mode solid phase extraction for simultaneous determination of melamine and cyanuric acid in food by hydrophilic interaction chromatography coupled to tandem mass chromatography. AB - Utilizing a solid phase extraction column (MCT) containing mixed hydrophilic functional gel and cation exchange sorbent, a sensitive and rapid HPLC-MS/MS method for simultaneously determining the residues of melamine (MEL) and cyanuric acid (CYA) in human foodstuffs was developed. MEL and CYA in egg, pork, liver, kidney and pork, shrimp, sausage casing, honey, soybean milk, soybean powder and dairy product were extracted using acetonitrile/water, defatted with hexane and isolated using MCT solid phase extraction column. The residues were separated upon a hydrophilic interaction liquid chromatography (HILIC) column and analyzed by electrospray ionization under negative-positive switched mode on a triplequadrupole mass spectrometry. The selected reaction monitoring was performed on [M+H](+) of m/z 127.9 to provide the transition of 127>85 and 127>68 (MEL) while the [M-H](-) of m/z 127.1 was selected as the precursor ion for CYA resulting in product ions m/z 85 and 42. Isotope labeled internal standard ((15)N(3)-MEL and (13)C(3)-CYA) and matrix-matched calibration were both used to observe the recovery to be 70.0-129.6% and 70.0-128.9% with RSD of 1.4-23.3% and 1.5-21.7% for MEL and CYA, respectively (n=6). All the LODs and LOQs of MEL and CYA were less than 39.4 and 99.1MUgkg(-1), respectively, in 18 matrices, which were sensitive enough for quantitative analysis. This method has been proven effective in simultaneous determination of melamine and cyanuric acid when inspecting unknown and positive samples. PMID- 20850394 TI - LC-MS/MS method development and validation for the determination of polymyxins and vancomycin in rat plasma. AB - Simple, sensitive and robust liquid chromatography-tandem mass spectrometer (LC MS/MS) methods were developed and validated for the determination of lipopeptide polymyxins and glycopeptide vancomycin in rat plasma. The effect of trichloroacetic acid (TCA) concentration on sample recoveries (peak area of sample recovered from plasma/peak area of sample from neat solvent solutions) was studied and an optimized concentration of 30% TCA were determined that gives the best sample recovery for the peptides from rat plasma. The effect of the TCA concentration on the chromatographic behavior of peptides was studied on a Phenomenex Jupiter C18 5MU 300A 50mm*2mm column using a mobile phase with a pH of 2.8. Other than protein precipitation, TCA also acted as ion pairing reagent and was only present in the samples but not in the mobile phases. The data demonstrated that by increasing the TCA concentration, the analyte retention and sensitivity were improved. The absence of TCA in mobile phase helped to reduce the ion source contamination and to achieve good reproducibility. The plasma method was linearly calibrated from 5 to 5000ng/mL for polymyxins with precisions to be of 2.3-10.8%, and accuracies to be 91.7-107.4% for polymyxin B1, B2, E1, E2, respectively. For vancomycin the calibration is from 1 to 5000ng/mL with precisions to be of 7.8-10.3 and accuracies to be 96.2-102.0%. The LLOQs corresponding with a coefficient of variation less than 20% were 7.5, 18.1, 7.3, 5.0 and 1.0ng/mL for polymyxin B1, B2, E1, E2 and vancomycin, respectively. PMID- 20850395 TI - Dyslipidemia in renal disease: causes, consequences and treatment. AB - The prevalence of chronic renal insufficiency and its complications, including dyslipidemia, is increasing. Although the characteristics of dyslipidemia in chronic renal insufficiency and its pathophysiology are well known, its cardiovascular and renal impact and the most effective therapeutic approach are poorly defined. PMID- 20850396 TI - Trauma and the endocrine system. AB - The endocrine system may be the target of different types of trauma with varied consequences. The present article discusses trauma of the hypothalamic-pituitary axes, adrenal glands, gonads, and pancreas. In addition to changes in circulating hormone levels due to direct injury to these structures, there may be an endocrine response in the context of the stress caused by the trauma. PMID- 20850398 TI - Use of the dual plunger for creating negative pressure in 10 ml syringe for fat aspiration in Coleman fat transfer procedure. PMID- 20850397 TI - [Taking of position in relationship to the protocol of the current treatment of thyroid nodules and differentiated thyroid cancer]. PMID- 20850399 TI - Use of the interposed nerve graft to reduce differences in functional muscle transfer outcome arising from variability in motor input. AB - Regulation of functional muscle transfer outcome by means of an interposed nerve graft: The gold standard treatment of chronic unilateral facial palsy is a functional muscle transfer (FMT) reinnervated by a branch of the contralateral facial nerve via a cross-facial nerve graft, but clinical outcome varies from underactivity to overactivity of the transferred muscle. Work in an animal model has established that the magnitude of donor motor input received by heterotopically transferred muscle correlates with reinnervation and force production, the corollary being that standardising donor motor input could standardise outcome. We hypothesise that a 'low-capacity' interposed nerve graft could deliver a fixed motor input to an FMT despite variable motor input, thereby standardising force production and clinical outcome. To test this hypothesis, we compared reinnervation and force production by FMTs reinnervated with different sized motor inputs via high- and low-capacity interposed nerve grafts. Force production was measured in vivo after recovery of transplanted muscle, and reinnervation quantified by both nerve morphometry and intramuscular immunohistochemical staining for protein gene product 9.5. Both reinnervation and force production data suggest that outcome correlates with donor motor nerve magnitude only when a high-capacity interposed nerve graft is used, this correlation being lost when using a low-capacity interposed nerve graft. The implications for human facial reanimation surgery are discussed. PMID- 20850400 TI - Invited commentary. PMID- 20850401 TI - Paediatric ride-on mower related injuries and plastic surgical management. AB - Lawnmower related injuries cause significant morbidity in children and young teenagers. The 'ride-on' mowers which are more powerful than the 'walk behind' mowers are becoming increasingly popular. The incidence and severity of injuries from either type of lawnmower appears to be steadily rising as is the burden placed on local plastic surgical and emergency services in managing the care of these patients. The aims of the study were to demonstrate changing trends in lawnmower-related injuries to children presenting to a single unit over a ten year period and to identify any association between injury severity and machine subtype ('ride-on' versus 'walk-behind'). Hospital databases, theatre records and medical case notes were reviewed retrospectively of all patients under the age of 16 treated for lawnmower related injuries over a 10 year period from July 1998 to June 2008. Data gathered included patient demographics, injury site and severity, management (type and number of surgical procedures), length of hospital stay and outcome. Injury severity score was also calculated for each case. Controlling for estimated regional population changes, there was a significant increase in the number of ride-on mower related accidents in the time period 2003-2008, compared to the time period 1998-2003. Ride-on injuries had significantly higher injury severity scores, longer hospital stays and were more likely to involve amputations as compared with walk-behind injuries. Children can sustain significant injuries with unsafe lawnmower use. The current study demonstrates the increasing incidence of ride-on mower related injuries in children and identifies a greater morbidity associated with such injuries. Such presentations place intense demands on local plastic surgical services. PMID- 20850402 TI - Genetic analysis of the SNPforID 34-plex ancestry informative SNP panel in Tunisian and Libyan populations. AB - A total of 149 unrelated and healthy individuals comprising: Tunisian Berbers, Tunisians with Andalusian origin and Libyans were typed with the SNPforID 34-plex ancestry informative marker (AIM) SNP panel. Results of 31 of the 34 SNPs are presented and no deviations from Hardy-Weinberg equilibrium were observed after Bonferroni correction (p=0.00161) except rs722098 (p=0.0000). Comparisons of allele frequencies showed high divergence values between North Africans and Europeans (delta>30%) in markers: rs4540055 (allele A) and rs16891982. Our study adds data that can be used as training set genotypes for future ancestry investigations in forensic cases and suggests these AIM-SNPs can successfully differentiate North Africans and Mediterranean Europeans. PMID- 20850403 TI - Population genetic data for 15 STR loci (PowerPlex 16 kit) in Nicaragua. PMID- 20850404 TI - Odontoid fractures anterior screw fixation: a continuous series of 36 cases. AB - INTRODUCTION: Fracture of the odontoid process represents 5 to 15% of cervical spine fractures. Anterior screw fixation is the reference technique in unstable posterior oblique or horizontal odontoid fracture. OBJECTIVE: We describe results with an original anterior screw fixation technique using a curved thoraco-lumbar pedicle awl to facilitate intra-operative reduction. PATIENTS AND METHODS: This is a retrospective study of 36 consecutive patients who underwent anterior screw fixation for odontoid process fracture. Mean age was 70.3 years. Twenty six patients had type II and 10 type III fracture on the Anderson-D'Alonzo classification. On the Roy-Camille classification, there were 34 posterior oblique fractures and two horizontal fractures. There were no anterior oblique fractures. Bony union was assessed on CT-scan at 3 months. We describe the surgical technique, which used a 4.5mm cannulated cancellous lag screw in all cases. RESULTS: Mean follow-up was 3 years (range, 4 months to 8 years). No intra operative complications were observed. Union rate was 95% and the average time to union was 5 months (3 to 6 months). DISCUSSION: Anterior screw fixation is a common surgical treatment for posterior oblique and horizontal odontoid process fractures. We detail a reliable and reproducible intra-operative reduction maneuver to obtain a good union rate without complications. LEVEL OF EVIDENCE: Level IV. Retrospective therapeutic study. PMID- 20850405 TI - Bilateral clavicle fracture external fixation. AB - Fractures of the middle third of the clavicle are frequent and their conservative treatment ends in bone union in nearly 95% of cases. Surgical treatment is unanimously indicated with open fractures or in cases of cutaneous damage, neurovascular complications, and impaction of the shoulder stump syndromes. We report herein a case of bilateral fractures of the clavicle that required double stabilization with an external fixator following major cutaneous damage appearing after the initial conservative management. The intraoperative discovery of Propionibacterium acnes infection and bone union obtained within the classical time frame, with a satisfactory functional result, all retrospectively proved the soundness of this indication. PMID- 20850406 TI - Second primary lung malignancy in head and neck cancer patients. AB - INTRODUCTION: Second primary lung cancer (SPLC) is generally of poor prognosis in patients presenting with head and neck cancer. METHODS: Between January 2000 and June 2008, 39 patients with head and neck squamous-cell carcinoma (HNSCC) patients diagnosed with SPLC were included. RESULTS: Fourteen SPLC were classified as synchronous and 25 as metachronous. SPLC and HNSCC staging correlated (P=0.0496). Patients with metachronous tumor showed longer median overall survival than those with synchronous tumor (92.9 months versus 15.7 months; Hazard ratio (HR), 0.323; 95% CI, 0.042-0.559; P=0.0045). In the subgroup of 11 patients with SPLC diagnosed more than 5 years after HNSCC, prognosis was better (128.1 versus 29.7 months; HR, 0.288; 95% CI, 0.053-0.353; P<0.0001). DISCUSSION: In the present study, in contrast to the literature, improved prognosis and survival were found in the subgroup in which SPLC developed more than 12 months after initial HNSCC diagnosis, and even more specifically in that in which SPLC developed more than 5 years after initial HNSCC diagnosis. CONCLUSION: SPLC in HNSCC is generally described as unequivocally aggressive and of poor prognosis. Metachronous SPLC, however, especially when diagnosed more than 5 years after HNSCC, was clearly associated with better prognosis. PMID- 20850408 TI - Facile synthesis of metal-chelating magnetic nanoparticles by exploiting organophosphorus coupling. AB - A new method is described for facile synthesis of metal-chelating magnetic nanoparticles by simply mixing iron oxide nanoparticles with a bifunctional organophosphorus compound, N-(phosphonomethyl)iminodiacetic acid (PM-IDA), in aqueous solution. On charging with nickel ions, the PM-IDA functionalized iron oxide nanoparticles exhibited high His-tag protein binding capacity (0.21 and 0.58 mg/mg for His-tagged green fluorescent protein and chloramphenicol acetyltransferase, respectively) and were successfully used to purify these proteins from bacterial cell extracts to high purity in a single step. Although other synthetic schemes for metal-chelating magnetic nanoparticles have been reported, the method described here is markedly simpler and involves only low cost reagents. PMID- 20850410 TI - Detection of DNA mutations by fluorescence resonance energy transfer-based preferential homoduplex formation assay. AB - Molecularly targeted agents for cancer therapy are recognized as being effective and are gaining in popularity. However, the efficacy of the agents depends on the status of the targeted molecule such as the number of molecules expressed, activity, and mutation. Therefore, the use of companion diagnostics for investigating the status of the targeted molecule prior to therapy is highly important. We developed a simple and cost-effective somatic mutation detection method called the fluorescence resonance energy transfer-based preferential homoduplex formation assay (FRET-PHFA). By using double-stranded labeled DNA and fluorescence measurement with thermal control, this method provides higher reproducibility, easier handling, less risk for contamination, shorter assay time (only ~15min), and less cost compared with conventional PHFA. Here we report the evaluation of FRET-PHFA on the detection of multiallelic KRAS mutations in codons 12 and 13 compared with the TheraScreen clinical diagnostics kit. We found that FRET-PHFA detected KRAS mutations (1.25-50%) from all cell line DNA titration samples. PMID- 20850409 TI - Mass balance analysis of contaminated heparin product. AB - A quantitative analysis of a recalled contaminated lot of heparin sodium injection U.S. Pharmacopeia (USP) was undertaken in response to the controversy regarding the exact nature of the contaminant involved in the heparin (HP) crisis. A mass balance analysis of the formulated drug product was performed. After freeze-drying, a 1-ml vial for injection afforded 54.8+/-0.3 mg of dry solids. The excipients, sodium chloride and residual benzyl alcohol, accounted for 11.4+/-0.5 and 0.9+/-0.5 mg, respectively. Active pharmaceutical ingredient (API) represented 41.5+/-1.0 mg, corresponding to 75.7 wt% of dry mass. Exhaustive treatment of API with specific enzymes, heparin lyases, and/or chondroitin lyases was used to close mass balance. HP represented 30.5+/-0.5 mg, corresponding to 73.5 wt% of the API. Dermatan sulfate (DS) impurity represented 1.7+/-0.3 mg, corresponding to 4.1 wt% of API. Contaminant, representing 9.3+/ 0.1 mg corresponding to 22.4 wt% of API, was found in the contaminated formulated drug product. The recovery of contaminant was close to quantitative (95.6-100 wt%). A single contaminant was unambiguously identified as oversulfated chondroitin sulfate (OSCS). PMID- 20850411 TI - High-throughput evaluation of the critical micelle concentration of detergents. AB - Determination of the critical micelle concentration (CMC) value of detergents routinely used in biological applications is necessary to follow possible changes due to different buffer compositions (e.g., temperature, pH) such as those in solutions that are used for protein activity assays or crystallization. Here we report a method to determine the CMC values of detergents through a fast and robust assay that relies on the fluorescence of Hoechst 33342 using a 96-well plate reader. Furthermore, this assay provides the possibility and sensitivity to measure the CMC of detergent mixtures. The examples described here emphasize the potential and applicability of this assay and demonstrate that analysis of the physicochemical parameters of detergents can now be investigated in virtually every laboratory. PMID- 20850412 TI - Ceramide-induced activation of cytosolic NADH/cytochrome c electron transport pathway: An additional source of energy for apoptosis. AB - We have investigated whether increase in the oxidation rate of exogenous cytochrome c (cyto-c), induced by long-chain ceramides, might be due to an increased rate of cytosolic NADH/cyto-c electron transport pathway. This process was identified in isolated liver mitochondria and has been studied in our laboratory for many years. Data from highly specific test of sulfite oxidase prove that exogenous cyto-c both in the absence and presence of ceramide cannot permeate through the mitochondrial outer membrane. However, the oxidation of added NADH, mediated by exogenous cyto-c and coupled to the generation of a membrane potential supporting the ATP synthesis, can also be stimulated by ceramide. The results obtained suggest that ceramide molecules, by increasing mitochondrial permeability, with the generation of either raft-like platforms or channels, may have a dual function. They can promote the release of endogenous cyto-c and activate, with an energy conserving process, the oxidation of cytosolic NADH either inducing the formation of new respiratory contact sites or increasing the frequency of the pre-existing porin contact sites. In agreement with the data in the literature, an increase of mitochondrial ceramide molecules level may represent an efficient strategy to activate and support the correct execution of apoptotic program. PMID- 20850413 TI - Cysteine 351 is an essential nucleophile in catalysis by Porphyromonas gingivalis peptidylarginine deiminase. AB - Peptidylarginine deiminase (PAD), which catalyzes the deimination of the guanidino group from peptidylarginine residues, belongs to a superfamily of guanidino group modifying enzymes that have been shown to produce an S alkylthiouronium ion intermediate during catalysis. Thiol-directed reagents iodoacetamide and iodoacetate inactivate recombinant PAD, and substrate protects the enzyme from inactivation. Activity measurements together with peptide mapping by mass spectrometry of PAD modified in the absence and presence of substrate demonstrated that cysteine-351 is modified by iodoacetamide. The pK(a) value of the cysteine residue, 7.7+/-0.2 as determined by iodoacetamide modification, agrees well with a critical pK value identified in pH rate studies. The role of cysteine-351 in catalysis was tested by site-directed mutagenesis in which the cysteine was replaced with serine to eliminate the proposed nucleophilic interaction. Binding studies carried out using fluorescence spectrometry established the structural integrity of the C351S PAD. However, the C351S PAD variant was catalytically inactive, exhibiting <0.01% wild-type activity. These results indicate that Cys 351 is a nucleophile that initiates the enzymatic reaction. PMID- 20850414 TI - The testis-specific VAD1.3/AEP1 interacts with beta-actin and syntaxin 1 and directs peri-nuclear/Golgi expression with bipartite nucleus localization (BNL) sequence. AB - VAD1.3 (AEP1), a novel testis-specific gene, was first isolated from the testis of a retinol-treated vitamin-A-deficient (VAD) rat model. It is expressed at the acrosomal region of spermatids from postnatal day 25. VAD1.3 immunoreactivity is present in rat, human, monkey and porcine spermatids and spermatozoa, suggesting that VAD1.3 may play a role in acrosome formation. However, direct evidence on the detailed sub-cellular localization of the VAD1.3 protein in the acrosome and how VAD1.3 is involved in acrosome formation remains largely unknown. Here, we isolated and identified VAD1.3 interacting proteins by immunoprecipitation followed by mass spectrometry, and determined the functional motifs of VAD1.3 that were important for its specific sub-cellular location in vitro. We found that VAD1.3 bound to syntaxin 1 and beta-actin proteins in vitro. Immunogold electron microscopic study localized VAD1.3 immunoreactivity to the acrosome membranes and matrix, and colocalized it with the beta-actin protein. The full length GFP-VAD (1-3601) and GFP-VAD (1-730) fusion proteins that contain the bipartite nucleus localization (BNL) signal were located in the peri nucleus/Golgi of the transfected cells. In addition, the GFP signal colocalized with the endoplasmic reticulum marker and the syntaxin 1 protein in the transfected HeLa and GC-2spd cells. The C-terminal GFP-VAD (1770-3601) was expressed in the nucleus. Taken together, VAD1.3 interacts with beta-actin and syntaxin 1 in vitro. The BNL signal may mediate the peri-nuclei localization of the protein that may interact with syntaxin 1 and beta-actin for acrosome formation in spermatogenesis. PMID- 20850415 TI - The bacterial effector Cif interferes with SCF ubiquitin ligase function by inhibiting deneddylation of Cullin1. AB - Cycle inhibiting factor (Cif) is one of the effectors delivered into epithelial cells by enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC) via the type III secretion system (TTSS). Cif family proteins, which inhibit host cell-cycle progression via mechanisms not yet precisely understood, are highly conserved among EPEC, EHEC, Yersinia pseudotuberculosis, Photorhabdus luminescens and Burkholderia pseudomallei. Levels of several proteins relevant to cell-cycle progression are modulated by Cullin-RING ligases (CRLs), which in turn are activated by conjugation and deconjugation of NEDD8 to Cullins. Here we show that Cif interacts with NEDD8 and interferes with SCF (Skp1-Cullin1-F-box protein) complex ubiquitin ligase function. We found that neddylated Cullin family proteins accumulated and ubiquitination of p27 decreased in cells infected with EPEC. Consequently, Cif stabilized SCF substrates such as CyclinD1, Cdt1, and p27, and caused G1 cell cycle arrest. Using time-lapse-imaging of fluorescent ubiquitination-based cell cycle indicator (Fucci)-expressing cells, we were able to monitor cell-cycle progression during EPEC infection and confirmed the arrest of infected cells at G1. Our in vitro and in vivo data show that Cif-NEDD8 interaction inhibits deneddylation of Cullins, suppresses CRL activity and induces G1 arrest. We thus conclude that the bacterial effector Cif interferes with neddylation-mediated cell-cycle control. PMID- 20850416 TI - VEGF secretion during hypoxia depends on free radicals-induced Fyn kinase activity in mast cells. AB - Mast cells (MC) have an important role in pathologic conditions such as asthma and chronic obstructive pulmonary disease (COPD), where hypoxia conduce to deleterious inflammatory response. MC contribute to hypoxia-induced angiogenesis producing factors such as vascular endothelial growth factor (VEGF), but the mechanisms behind the control of hypoxia-induced VEGF secretion in this cell type is poorly understood. We used the hypoxia-mimicking agent cobalt chloride (CoCl2) to analyze VEGF secretion in murine bone marrow-derived mast cells (BMMCs). We found that CoCl2 promotes a sustained production of functional VEGF, able to induce proliferation of endothelial cells in vitro. CoCl2-induced VEGF secretion was independent of calcium rise but dependent on tetanus toxin-sensitive vesicle associated membrane proteins (VAMPs). VEGF exocytosis required free radicals formation and the activation of Src family kinases. Interestingly, an important deficiency on CoCl2-induced VEGF secretion was observed in Fyn kinase-deficient BMMCs. Moreover, Fyn kinase was activated by CoCl2 in WT cells and this activation was prevented by treatment with antioxidants such as Trolox and N acetylcysteine. Our results show that BMMCs are able to release VEGF under hypoxic conditions through a tetanus toxin-sensitive mechanism, promoted by free radicals-dependent Fyn kinase activation. PMID- 20850417 TI - Sustained levels of progesterone prior to the onset of cerebral ischemia are not beneficial to female mice. AB - Female gender, which is abolished following ovariectomy and reproductive senescence, is associated with improved outcome following cerebral stroke. Estrogen replacement partially restores this benefit of the female gender but the effect of progesterone in hormone-deficient animals is currently unknown. We evaluated various outcomes following middle cerebral artery occlusion (MCAO) in ovariectomised female mice, with a physiologically relevant restoration of progesterone levels. Ovariectomised female mice had significantly elevated plasma (P=<0.05) and brain progesterone levels (P=<0.01) following implantation of a 21 day release pellet (50mg) compared with mice that received placebo implants 7 days prior to undergoing 60 min MCAO. Assessment of well-being (body weight recovery) and neurological score at 24h and 48h post-MCAO indicated that MCAO significantly worsened outcome compared with sham-operated mice but progesterone had no effect. MCAO resulted in a substantial lesion formation and a significant increase (P<0.05) in ipsilateral brain water content, both of which were not affected by progesterone treatment. Furthermore, there was no significant alteration in ipsilateral Aquaporin-4 (AQP4) expression following MCAO or progesterone treatment. The present study indicates that sustained physiologically relevant levels of progesterone prior to cerebral ischemia neither benefited nor worsened outcomes in previously ovariectomised female mice. PMID- 20850418 TI - Extending visual dominance over touch for input off the body. AB - Vision tends to dominate over touch in the majority of experimental situations, particularly when visual information is presented on, or near to, the body. We combined two visual dominance paradigms in order to investigate crossmodal interactions between vision and touch for stimuli on versus off the body: 1) The Colavita visual dominance effect, which has recently been extended to vision and touch, and 2) The rubber hand illusion, which has often been used to probe visuotactile interactions. Specifically, we investigated whether moving a visual stimulus off the participant's body would affect visual dominance, and how this dominance would be mediated by the presence/absence of a rubber hand (given the rubber hand illusion provides a way of extending the representation of one's own body in space). Participants made speeded detection/discrimination responses to a random sequence of visual-only, tactile-only, and visuotactile targets. While participants responded near-perfectly on the unimodal target trials, their performance on the visuotactile target trials was deleteriously affected by the simultaneous presentation of a visual stimulus on (as opposed to away from) their body. In particular, when the visual stimulus was presented to their fingertip, participants failed to respond to far more of the tactile than visual stimuli on bimodal trials. The magnitude of this visual dominance effect decreased significantly when the visual stimulus was moved off the body. When a rubber hand was placed at the off-body location, a similar (albeit reduced) visual dominance effect was observed in both positions. These results therefore suggest that visuotactile interactions are strongest when visual stimuli are presented on a body (no matter whom that body, or body-part, belongs to). PMID- 20850419 TI - Alterations of NMDA receptor subunits NR1, NR2A and NR2B mRNA expression and their relationship to apoptosis following transient forebrain ischemia. AB - Glutamate excitotoxicity mediated by NMDA receptor activation plays a key role in many aspects of ischemic brain injury, but the expression of NMDA receptor subunits NR1, NR2A and NR2B mRNA and their relationship to apoptosis is still unclear. In this study, we applied in situ hybridization and TUNEL staining to investigate the expression of NMDA receptor subunit mRNA and apoptosis in hippocampus of rats after transient forebrain ischemia. The results showed that in the CA1 region, NR1 mRNA expression was significantly increased following ischemia-reperfusion (IR), reaching peak levels at IR 24h, and then gradually decreasing until IR 7 days. NR2A and NR2B mRNA expression dropped to lowest levels at IR 6h and IR 12h, respectively, and then started to recover. The mRNA expression of both NR2A and NR2B then increased to peak levels at IR 48h, followed by a sustained decline until IR 7 days. In the CA3 region and dentate gyrus the range of variation in mRNA expression was significantly reduced gradually. At IR 24h, apoptosis-positive cells were observed mainly in the CA1 region. The number of apoptosis-positive cells continuously grew and showed a dramatic increase at IR 48h and peaked at IR 72h. Then, the number of apoptosis positive cells started to decrease, but at IR 7 days the apoptosis-positive cells still remained. These results indicate that the alterations of NMDA receptor subunit mRNA expression may contribute to the ischemic apoptosis of hippocampus after transient forebrain ischemia. PMID- 20850420 TI - Differential effects of adenosine A1 receptor on pain-related behavior in normal and nerve-injured rats. AB - This study investigated the effects of N6-cyclopentyladenosine (CPA), a potent and selective adenosine A1 receptor (A1R) agonist in normal and nerve-injured rats and mechanisms of its action by behavioral tests and electrophysiological technique. The results showed: (1) In normal rats, intraperitoneal administration of CPA (1mg/kg) increased paw withdrawal latencies, in a way blocked by a selective A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 3mg/kg, i.p.), but had no influence on the threshold of mechanical stimulation. (2) In rats with neuropathic pain induced by spinal nerve ligation (SNL), CPA reduced thermal hyperalgesia and mechanical allodynia, which could last 6h and 10h, respectively (n=6/group, P<0.05). Both of the effects could be blocked by pretreatment of DPCPX intraperitoneally. (3) The baseline of C-fiber but not A fiber evoked field potentials was depressed by spinal application of CPA (0.01 mM), and this effect was prevented by application of DPCPX (0.02 mM) 30 min before CPA. (4) Spinal application of CPA depressed long-term potentiation (LTP) of A- and C-fiber evoked field potentials, and both the depression could be blocked by pretreatment of DPCPX 30 min before CPA. These results suggested that the activation of A1R has different influences on normal and neuropathic rats probably due to the absence and presence of central sensitization in spinal dorsal horn. PMID- 20850421 TI - Baicalein inhibits nuclear factor-kappaB and apoptosis via c-FLIP and MAPK in D GalN/LPS induced acute liver failure in murine models. AB - The hepatoprotective effects and molecular mechanisms of baicalein on acute liver failure induced by d-galactosamine (d-GalN)/lipopolysaccharides (LPS) were investigated in vivo. Mice were administered with different doses of baicalein (50, 100 or 150mg/kg, p.o.) 1h before injection of d-GalN (700mg/kg)/LPS (10MUg/kg) and then sacrificed 6h after treatment with d-GalN/LPS. Pretreatment with baicalein prevented d-GalN/LPS-induced liver damage by preventing associated increases of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and by reducing serum tumor necrosis factor alpha (TNF-alpha), nitric oxide (NO) or inducible nitric oxide synthase (iNOS) expressions. The molecular mechanisms involved in baicalein-induced inhibition of d-GalN/LPS-caused apoptosis were associated with the protection of mitochondria, increasing the Bcl 2/Bax ratio, blocking the release of cytochrome c, and suppressing the phosphorylation of IkappaBalpha, ERK and JNK. Moreover, baicalein activated c FLIP(L), XIAP and cIAP2 proteins, potentially blocking the recruitment of NF kappaB signaling molecules. The results support the investigation of baicalein as a therapeutic candidate for acute liver apoptosis or injury and indicate that baicalein might inhibit liver apoptosis by mediating one or more of these pathways. PMID- 20850422 TI - Occurrence of molecular abnormalities of cell cycle in L132 cells after in vitro short-term exposure to air pollution PM(2.5). AB - To improve the knowledge of the underlying mechanisms implying in air pollution Particulate Matter (PM)-induced lung toxicity in humans, we were interested in the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation in the L132 target human lung epithelial cell model. The most toxicologically relevant physical and chemical characteristics of air pollution PM(2.5) collected in Dunkerque, a French highly-industrialized sea-side city, were determined. L132 cells were exposed during 24, 48 and 72h to Dunkerque City's PM(2.5) (i.e. Lethal Concentration (LC)(10)=18.84MUgPM/mL or 5.02MUgPM/cm(2); LC(50)=75.36MUgPM/mL or 20.10MUgPM/cm(2)), TiO(2) and desorbed PM (i.e. dPM; EqLC(10)=15.42MUg/mL or 4.11MUgPM/cm(2); EqLC(50)=61.71MUg/mL or 16.46MUgPM/cm(2)), benzene (7MUM) or Benzo[a]Pyrene (B[a]P; 1MUM). Dunkerque City's PM(2.5) altered the gene expression and/or the protein concentration of several key cell cycle controllers from TP53-RB gene signaling pathway (i.e. P53; BCL2; P21; cyclin D1, cyclin-dependent kinase 1; retinoblastoma protein) in L132 cells, thereby leading to the occurrence of cell proliferation and apoptosis together. The activation of the critical cell cycle controllers under study might be related to PM-induced oxidative stress, through the possible involvement of covalent metals in redox systems, the metabolic activation of organic chemicals by enzyme-catalyzed reactions, and phagocytosis. Taken together, these results might ask the critical question whether there is a balance or, in contrast, rather an imbalance between the cell proliferation and the apoptosis occurring in PM-exposed L132 cells, with possible consequences in term of PM-induced lung tumorgenesis. PMID- 20850423 TI - Serum levels of vaspin and visfatin in patients with coronary artery disease Kozani study. AB - BACKGROUND: The association of novel adipokines, vaspin and visfatin, with atherosclerosis is still obscure. The present study aimed to investigate the relationship of those adipokines with the existence as well as the extent of coronary artery disease (CAD), suggesting a link between adiposity and atherosclerosis. METHODS: We enrolled a total of 108 patients with angiographically proven stable, asymptomatic CAD and 65 healthy controls (HC) without cardiovascular diseases. The severity of CAD was assessed using coronary angiography by the Gensini score. Clinical parameters, glycemic and lipid profile, high-sensitivity CRP (hsCRP), vaspin and visfatin levels were assayed. RESULTS: Serum levels of vaspin were significantly lower in subjects with CAD [0.91 (0.44-1.29) ng/ml] than healthy controls [1.42 (0.96-2.42) ng/ml] (p = 0.009). Inversely, visfatin (p = 0.016) and hsCRP (p < 0.001) levels were considerably up-regulated in CAD vs HC group. Multivariate analysis demonstrated decreased vaspin and increased visfatin levels to correlate with CAD presence, independent of other cardiovascular risk factors (p < 0.05). Standard multiple regression revealed HDL, LDL-C and vaspin to be independent determinants of Gensini score (R2 = 0.189, p = 0.019). Notably, statin-free patients had even lower vaspin levels compared to statin users (p = 0.018). CONCLUSIONS: Decreased vaspin and increased visfatin serum levels were observed in asymptomatic patients with CAD. Low vaspin concentrations seemed to correlate with CAD severity. PMID- 20850424 TI - Circulating fluorocytes at the first attack of acute intermittent porphyria: a missing link in the pathogenesis. AB - BACKGROUND: Acute intermittent porphyria (AIP) is an autosomal dominant disorder of the haem biosynthesis resulting from a partial deficiency of hydroxymethylbilane synthase (HMBS) with incomplete penetrance. By conventional means, it is able to identify asymptomatic mutation carrier by molecular diagnosis, but one cannot reliably predict an acute porphyric attack. The presence of fluorescent red cells (fluorocytes) in AIP is probably under recognized since AIP is a hepatic porphyria and not associated with photosensitivity. METHODS: We used an automatic image acquisition platform to detect the circulating fluorocytes at 700 nm emission in a diabetic AIP patient during acute attack. We screened the patient and her family members for the mutation on HMBS, urine porphobilinogen and circulating fluorocytes. RESULTS: The patient was heterozygous for a disease-causing mutation on HMBS and several bright circulating fluorocytes were detected. We showed evidence that protoporphyrin contributed to the erythrocyte auto-fluorescence. Interestingly, asymptomatic mutation carriers with increased urine porphobilinogen did not have circulating fluorocytes. All mutation-negative family members revealed no circulating fluorocytes. CONCLUSION: Sudden decrease in plasma glucose concentration might invoke acute attack of AIP and appearance of circulatory fluorocytes. Potential of detecting fluorocytes as screening test or for predicting an acute attack of AIP in diabetes is worth investigating. PMID- 20850425 TI - IL-7 and lymphopenia. AB - Interleukin-7 (IL-7) is a growth and anti-apoptotic factor for T-lymphocytes, with potential for clinical use in the treatment of immunodeficiencies due to loss of T-cells. Lymphopenia induced by disease (HIV infection, hemodialysis or Idiopathic CD4+ lymphopenia) or by treatment (high dose chemotherapy or depleting antibodies) for cancer or auto-immune diseases results in increased circulating levels of IL-7 which decline with T-cell recovery, however, the mechanism of such response remains to be elucidated. Furthermore, IL-7 is a major player in the regulation of peripheral T-cell homeostasis and as such is an important candidate cytokine for therapy aimed at improving T-cell reconstitution following lymphopenia. Anti- IL-7 is on the other hand proposed to treat conditions where IL-7 may play a more direct role in pathogenesis such as autoimmune disease like Rheumatoid Arthritis, Multiple Sclerosis or Inflammatory Bowel disease. PMID- 20850426 TI - Post-discharge changes in NT-proBNP and quality of life after acute dyspnea hospitalization as predictors of one-year outcomes. AB - AIMS: The association of serial NT-proBNP changes and poor quality of life (QOL) with progressive heart failure (HF) and clinical outcomes in emergency department dyspnea patients is poorly understood. METHODS AND RESULTS: The predictive value of changes in NT-proBNP and QOL (Minnesota Living with Heart Failure scale) from baseline to 30-day follow-up was examined for all-cause 1-year mortality and HF hospitalization. Patients with an initially elevated NT-proBNP (>=300 ng/L) which persisted at 30-days (no >=25% decrease) were at high risk of death or HF hospitalization (HR=6.36, 95%CI=3.04-13.28). Combined with sustained poor QOL, these subjects with persistently elevated NT-proBNP were at highest mortality risk or HF hospitalization (HR=8.75, 95%CI=3.62-21.16). CONCLUSIONS: Dyspnea patients with elevated NT-proBNP concentrations and no improvement in either NT proBNP or QOL at 30-days are at high risk of mortality and HF hospitalization. These data highlight the value of serial biomarker measurements combined with serial evaluations for QOL. PMID- 20850427 TI - Sample evaporation from pierceable cups: still an important source of analytical error. AB - BACKGROUND: We illustrate the impact of sample evaporation on analytical results in laboratory practice and highlight preventive measures. METHODS: Plasma (n=10) was analysed for glucose, Na(+), HCO(3)(-) and calcium on six different sample configurations at 5 time points within 2h. RESULTS: With time glucose, Na(+) and calcium values increased and HCO(3)(-) values decreased in a clinically significant way. CONCLUSIONS: Analytical error due to evaporation may be significant, but can be reduced with optimal sample handling. A pierceable cover does not prevent loss of HCO(3)(-). PMID- 20850428 TI - Analytical performances of the Diazyme ADA assay on the Cobas(r) 6000 system. AB - OBJECTIVE: To evaluate the analytical performance of the Diazyme ADA assay on the Cobas(r) 6000 system for pleural fluid samples analysis. DESIGN AND METHODS: Imprecision, linearity, calibration curve stability, interference, and correlation studies were completed. RESULTS: The Diazyme ADA assay demonstrated excellent precision (CV<4%) over the analytical measurement range (0.5-117 U/L). Bilirubin above 50 MUmol/L and haemoglobin above 177 MUmol/L interfered with the test, inducing a negative and a positive interference respectively. The Diazyme ADA assay correlated well with the Giusti method (r(2)=0.93) but exhibited a negative bias (~ -30%). CONCLUSIONS: The Diazyme ADA assay on the Cobas(r) 6000 system represents a rapid, accurate, precise and reliable method for determination of ADA activity in pleural fluid samples. PMID- 20850429 TI - Costal 2 interactions with Cubitus interruptus (Ci) underlying Hedgehog-regulated Ci processing. AB - Extracellular Hedgehog (Hh) proteins alter cellular behaviours from flies to man by regulating the activities of Gli/Ci family transcription factors. A major component of this response in Drosophila is the inhibition of proteolytic processing of the latent transcriptional activator Ci-155 to a shorter Ci-75 repressor form. Processing is thought to rely on binding of the kinesin-family protein Cos2 directly to Ci-155 domains known as CDN and CORD, allowing Cos2 associated protein kinases to phosphorylate Ci-155 efficiently and create a binding site for an E3 ubiquitin ligase complex. Here we show that the last three zinc fingers of Ci-155 also bind Cos2 in vitro and that the zinc finger region, rather than the CDN domain, functions redundantly with the CORD domain to promote Hh-regulated Ci-155 proteolysis in wing discs. We also find evidence for a unique function of Cos2 binding to CORD. Cos2 binding to CORD, but not to other regions of Ci, is potentiated by nucleotides and abrogated by the nucleotide binding variant Cos2 S182N. Removal of the CORD region alone enhances processing under a variety of conditions. Most strikingly, CORD region deletion allows Cos2 S182N to stimulate efficient Ci processing. We deduce that the CORD region has a second function distinct from Cos2 binding that inhibits Ci processing, and that Cos2 binding to CORD relieves this inhibition. We suggest that this regulatory activity of Cos2 depends on a specific nucleotide-bound conformation that may be regulated by Hh. PMID- 20850430 TI - The novel isoflavone derivatives inhibit RANKL-induced osteoclast formation. AB - Isoflavones are compounds structurally similar to the mammalian estrogens and have received considerable attention for their preventive actions on bone loss. Here, we synthesized the novel isoflavone derivatives and examined their activities in bone cells. We found that the novel isoflavone derivatives markedly inhibited the receptor activator of nuclear factor kappa B ligand (RANKL) plus macrophage colony stimulating factor (M-CSF)-induced osteoclastic differentiation from bone marrow stromal cells and RAW264.7 macrophage cells. Treatment of RAW264.7 macrophages with RANKL-induced extracellular signal-regulated kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) phosphorylation. However, RANKL induced p38 and JNK but not ERK phosphorylation was attenuated by isoflavone derivatives. Furthermore, RANKL-mediated increase of p65 phosphorylation at Ser536, NF-kappaB-specific DNA-protein complex formation and kappaB-luciferase activity was inhibited by isoflavone derivatives. On the other hand, isoflavone derivatives did not affect the cell proliferation and differentiation of human cultured osteoblasts. Our data suggest that the novel isoflavone derivatives inhibit osteoclastogenesis from bone marrow stromal cells and macrophage cells via attenuation of RANKL-induced p38, JNK and NF-kappaB activation. PMID- 20850432 TI - Hepatic growth factor (HGF) inhibits cigarette smoke extract induced apoptosis in human bronchial epithelial cells. AB - Low concentrations of cigarette smoke induced DNA damage and repair without leading to apoptosis in human bronchial epithelial cells. Higher concentrations of cigarette smoke, however, could induce either apoptosis or necrosis. The current study demonstrated that 15% cigarette smoke extract (CSE) induced apoptosis as evidenced by DNA content profiling (17.8+/-2.1% vs 10.2+/-1.6% of control, p<0.05), LIVE/DEAD staining (60.2+/-2.1% viable cells in CSE-treated vs 86.5+/-2.3% in control cells, p<0.05), and COMET assay (24.3+/-0.6% of Apoptotic Index in the cells treated with CSE vs 4.7+/-0.6% of control, P<0.05). Hepatocyte growth factor (HGF) significantly blocked the cigarette smoke-induced apoptosis as shown by DNA profiling (10.8+/-1.5% of CSE+HGF, p<0.05), LIVE/DEAD staining (78.5+/-1.2% in CSE+HGF treated cells, p<0.05), and COMET assay (Apoptotic Index: 10.0+/-0.8% in CSE+HGF treated cells, P<0.05). This protective effect of HGF on CSE-induced apoptosis was abolished by PI3K inhibitors, wortmannin and LY294002, and by introduction of the dominant negative AKT into the cells. Furthermore, CSE plus HGF could induce phosphorylation of AKT Thr 308 and the pro-apoptotic protein, BAD. These results suggest that HGF modulates cell survival in response to cigarette smoke exposure through the PI3K/AKT signaling pathway. PMID- 20850431 TI - A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3(-/-) cells. AB - Juvenile neuronal ceroid lipofuscinosis (JNCL) is a pediatric lysosomal storage disorder characterized by accumulation of autofluorescent storage material and neurodegeneration, which result from mutations in CLN3. The function of CLN3, a lysosomal membrane protein, is currently unknown. We report that CLN3 interacts with cytoskeleton-associated nonmuscle myosin-IIB. Both CLN3 and myosin-IIB are ubiquitously expressed, yet mutations in either produce dramatic consequences in the CNS such as neurodegeneration in JNCL patients and Cln3(-/-) mouse models, or developmental deficiencies in Myh10(-/-) mice, respectively. A scratch assay revealed a migration defect associated with Cln3(-/-) cells. Inhibition of nonmuscle myosin-II with blebbistatin in WT cells resulted in a phenotype that mimics the Cln3(-/-) migration defect. Moreover, inhibiting lysosome function by treating cells with chloroquine exacerbated the migration defect in Cln3(-/-). Cln3(-/-) cells traversing a transwell filter under gradient trophic factor conditions displayed altered migration, further linking lysosomal function and cell migration. The myosin-IIB distribution in Cln3(-/-) cells is elongated, indicating a cytoskeleton defect caused by the loss of CLN3. In summary, cells lacking CLN3 have defects that suggest altered myosin-IIB activity, supporting a functional and physical interaction between CLN3 and myosin-IIB. We propose that the migration defect in Cln3(-/-) results, in part, from the loss of the CLN3 myosin-IIB interaction. PMID- 20850433 TI - Skilled reaching training promotes astroglial changes and facilitated sensorimotor recovery after collagenase-induced intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) is the most devastating type of stroke and a leading cause of disability and mortality worldwide. Although rehabilitation improves recovery after ICH the cellular mechanisms involved are poorly understood. We decided to examine if skilled (SK) and unskilled (US) training after sham or intracerebral hemorrhage (ICH) surgeries would induce GFAP+ astrocytic changes and whether these modifications can be associated with functional improvement. A 4-week course of motor training, involving either skilled and unskilled training began seven days after surgery; sensorimotor recovery was evaluated using Staircase, ladder walk and cylinder tests. Histological and morphometric analyses were used to assess GFAP+ cell bilaterally in forelimb sensorimotor cortex and dorsolateral striatum. All behavioral tests showed that ICH-SK rats experienced a greater degree of recovery when compared to ICH no task or ICH-US groups; no behavioral differences were found among all sham groups. Astrocytic density was increased in all analyzed structures for ICH no task, ICH-SK and ICH-US rats. Morphological analysis revealed an increased number of primary processes in ipsilateral (to lesion) sensorimotor cortex for all ICH groups. Present results also revealed that both ICH and SK induced an increased length of GFAP+ primary process; there was a further increase in length processes for ICH-SK group in sensorimotor cortex and ipsilateral striatum. We suggest that skilled reaching is an effective intervention to promote astrocytic plasticity and recovery after ICH. PMID- 20850434 TI - Olfactory ensheathing glia: repairing injury to the mammalian visual system. AB - The visual system is widely used as a model in which to study neurotrauma of the central nervous system and to assess the effects of experimental therapies. Adult mammalian retinal ganglion cell axons do not normally regenerate their axons for long distances following injury. Trauma to the visual system, particularly damage to the optic nerve or central visual tracts, causes loss of electrical communication between the retina and visual processing areas in the brain. After optic nerve crush or transection, axons degenerate and retinal ganglion cells (RGCs) are lost over a period of days. To promote and maintain axonal growth and connectivity, strategies must be developed to limit RGC death and provide regenerating axons with permissive substrates and a sustainable growth milieu that will ultimately provide long term visual function. This review explores the role olfactory glia can play in this repair. We describe the isolation of these cells from the olfactory system, transplantation to the brain, gene therapy and the possible benefits that these cells may have over other cellular therapies to initiate repair, in particular the stimulation of axonal regeneration in visual pathways. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20850435 TI - Juvenile and adult olfactory ensheathing cells bundle and myelinate dorsal root ganglion axons in culture. AB - Olfactory ensheathing cells (OEC), which normally associate closely with but do not myelinate axons in situ, myelinate axons in the adult mammalian spinal cord. They are of clinical interest as candidate cells for autologous transplantation but the ability of OEC to myelinate axons in vitro has been controversial. To clarify this issue, we isolated OEC from olfactory bulbs (OB) of juvenile and adult rats expressing GFP and analyzed their ability to myelinate axons. Using a well-defined assay for myelination of dorsal root ganglia (DRG) axons in culture, we found that OEC from juvenile pups associated with and then myelinated DRG axons. OEC assembled into bundles with the axons by 1week and required more than a week before myelination on axons was detected. In contrast, rat Schwann cells did not bundle axons and they formed P0(+) and MBP(+) myelin segments after as little as 1week. Most of the OEC in culture exhibited staining for calponin, a marker that was not found on Schwann cells in culture, whereas in both OEC and Schwann cell populations nearly all cells were positive for p75NTR and GFAP. These results confirm previous reports showing only subtle immunological differences between Schwann cells and OEC. Besides differences in the rate of myelination, we detected two additional functional differences in the interactions of OEC and Schwann cells with DRG axons. First, the diameter of OEC generated myelin was greater than for Schwann cell myelin on DRG axons. Second, OEC but not Schwann cells myelinated DRG axons in the absence of vitamin C. OEC isolated from adult OB were also found to bundle and myelinate DRG axons but the latter occurred only after incubation times of at least 3weeks. The results indicate that adult OEC require longer incubation times than juvenile OEC to myelinate axons and suggest that patterns of myelination by OEC and Schwann cells are distinguishable at least on axons in vitro. This article is part of a Special Issue entitled: Understanding olfactory ensheathing glia and their prospect for nervous system repair. PMID- 20850436 TI - Hymenolepis diminuta: the effects of infection on transepithelial ion transport and tight junctions in rat intestines. AB - In this study, we examine the effect of Hymenolepis diminuta on ion transport in the ileum and on tight junctions in the ileum and colon of rats. We also evaluate the effect of H. diminuta on C-fiber endings in the ileum, the direct habitat of H. diminuta, before and after mechanical stimulation and pharmacological modification by capsaicin (C-fiber irritant). Wistar rats were orally infected with five cysticercoids of H. diminuta. Using a modified Ussing chamber, electrophysiological parameters of the ileum were measured (transepithelial electrical potential difference and transepithelial electrical resistance) as well as the deposition of occludin (a tight junction protein) in the ileum and colon of the rats 8, 16, 25, 35, 40 and 60 days post infection. We observed a significant reduction in transepithelial electrical potential difference in the ileum of rats infected with H. diminuta. In both the ileum and colon of rats infected with H. diminuta we also observed a decrease in occludin deposition, which indicates leakage of tight junctions, correlating with the decrease in transepithelial electrical resistance of these tissues. The application of capsaicin confirmed the hypothesis that H. diminuta in rats affects the C-fiber sensory receptors, causing changes in ion transport in the ileum. The results of the performed electrophysiological and immunohistochemical examinations indicate hymenolepidosis-related changes in the active transport of ions and the passive movement of ions. PMID- 20850437 TI - TAZ interacts with zonula occludens-1 and -2 proteins in a PDZ-1 dependent manner. AB - The transcriptional coactivator TAZ recognizes L/PPxY motifs in transcription factors like Runx1/2 through its WW domain. We show that the first PDZ domain of zona occludens-1 (ZO-1) and 2 (ZO-2) interacts with the carboxy-terminal PDZ binding motif of TAZ. Deletion of this motif abrogates binding. ZO-2 colocalizes with TAZ in the nucleus of MDCK cells and ZO-2 expression alters TAZ localization in human embryonic kidney cells. Luciferase assays demonstrate ZO-2 inhibition of TAZ-mediated transactivation. We propose that zonula occludens is a negative regulator of TAZ and suggest that selected tight junction proteins control nuclear translocation and activity of TAZ. PMID- 20850438 TI - Patterns of ovarian and luteal activity in captive and wild Canada lynx (Lynx canadensis). AB - Canada lynx face some unique breeding restrictions, which may have implications for population viability and captive management. The goal of this study was to improve our understanding of basic reproductive physiology in Canada lynx. Using fecal hormone metabolite analysis, we established normative patterns of fecal estrogen (fE) and progestagen (fP) expression in captive and wild female Canada lynx. Our results indicate that Canada lynx have persistent corpora lutea, which underlie their uncharacteristic fP profiles compared to other felids. Thus, fP are not useful for diagnosing pregnancy in Canada lynx. We also found that Canada lynx are capable of ovulating spontaneously. Captive females had higher concentrations of fE and fP than wild females. Both populations exhibit a seasonal increase in ovarian activity (as measured by fE) between February and April. Finally, there was evidence of ovarian suppression when females were housed together. PMID- 20850439 TI - Corticotropin-releasing factor regulates the development in the direct developing frog, Eleutherodactylus coqui. AB - Direct developing frogs lack a free-living larval phase, such that miniature adults hatch directly from the eggs. Even under such extreme reorganization of the ancestral biphasic developmental pattern, direct developers still undergo thyroid hormone (TH)-dependent post-embryonic development. Hypothalamic regulation of TH synthesis and release plays a central role in controlling the timing of metamorphosis in biphasic developers. In particular, the neuropeptide corticotropin-releasing factor (CRF) regulates TH in tadpoles, but in adults, both thyrotropin-releasing hormone (TRH) and CRF regulate TH. Because direct developers lack a tadpole stage, it was not clear whether hypothalamic regulation of TH would be tadpole-like or adult-like prior to hatching. To test this, we injected pre-hatching Eleutherodactylus coqui daily with CRF, TRH or astressin (a CRF receptor blocker). CRF but not TRH significantly accelerated the developmental rate compared to controls. Astressin-treated animals showed a near complete developmental arrest, which confirmed that development requires CRF. To support the idea that CRF acts to regulate development in E. coqui via thyroid physiology, we showed the TH-direct response gene TRbeta is up-regulated 24 and 48 h after CRF injection. In addition, treatment with 50 nM T3 (triiodothyronine, the active form of TH) increased the developmental rate similar to CRF injections. Our results extend the evidence for a cryptic metamorphosis in direct developers by showing that neuroendocrine signaling is conserved between biphasic and direct developers. Furthermore, the conserved neuroendocrine regulation implies that changes at the peripheral level of hormone action underlie the evolution of the radically divergent development in direct developers. PMID- 20850440 TI - Isolation and characterization of a mRNA encoding a novel insulin receptor (IR) subtype, IR2, from rainbow trout (Oncorhynchus mykiss) and patterns of expression of the four IR subtypes, IR1-IR4, in tissues and during embryonic development. AB - Insulin (INS) plays a critical role in the growth, development, and metabolism of vertebrates. In this study, a cDNA encoding a novel insulin receptor (IR) subtype was isolated, cloned, and sequenced from the liver of rainbow trout. A 1525-bp cDNA encoding a partial amino acid sequence of the beta-subunit including the transmembrane domain, the tyrosine kinase domain, and the 3' untranslated region (UTR) was obtained and designated IR2 based on comparison with known IR subtypes, including the three previously reported IR subtypes of trout. Trout IR2 shares 90.0%, 82.8%, and 84.3% nucleotide identity with previously characterized trout IR1, IR3 and IR4, respectively. Quantitative real-time PCR revealed that the four IR mRNAs were differentially expressed, both in terms of distribution among tissues as well as in terms of abundance within selected tissues of juvenile trout. IR1 mRNA was most abundant in spleen, liver, kidney, and muscle (white, red and cardiac), but least abundant in adipose. IR3 mRNA was most abundant in liver, spleen, kidney, and pancreas; in other tissues, levels of IR3 mRNA were uniformly abundant. By contrast, levels of IR2 and IR4 mRNA were uniformly abundant in most tissues, except in spleen where levels of IR4 were significantly lower. All IR subtypes were detected over the course of embryonic development. In head and tail regions, levels of IR2 and IR3 mRNA declined from pre-hatch (29 days post-fertilization, dpf) to post-hatch (68-90 dpf), whereas levels of IR1 and IR4 remained relatively unchanged. These findings contribute to our understanding of the evolution, distribution, and function of insulin receptors. PMID- 20850441 TI - Characterization of ionic currents and electrophysiological properties of goldfish somatotropes in primary culture. AB - Growth hormone release in goldfish is partly dependent on voltage-sensitive Ca(2+) channels but somatotrope electrophysiological events affecting such channel activities have not been elucidated in this system. The electrophysiological properties of goldfish somatotropes in primary culture were studied using the whole-cell and amphotericin B-perforated patch-clamp techniques. Intracellular Ca(2+) concentration ([Ca(2+)]i) of identified somatotropes was measured using Fura-2/AM dye. Goldfish somatotropes had an average resting membrane potential of -78.4 +/- 4.6 mV and membrane input resistance of 6.2 +/- 0.2 GOmega. Voltage steps from a holding potential of -90 mV elicited a non-inactivating outward current and transient inward currents at potentials more positive than 0 and -30 mV, respectively. Isolated current recordings indicate the presence of 4-aminopyridine- and tetraethylammonium (TEA) sensitive K(+), tetrodotoxin (TTX)-sensitive Na(+), and nifedipine (L-type)- and omega-conotoxin GVIA (N-type)-sensitive Ca(2+) channels. Goldfish somatotropes rarely fire action potentials (APs) spontaneously, but single APs can be induced at the start of a depolarizing current step; this single AP was abolished by TTX and significantly reduced by nifedipine and omega-conotoxin GVIA. TEA increased AP duration and triggered repetitive AP firing resulting in an increase in [Ca(2+)]i, whereas TTX, nifedipine and omega-conotoxin GVIA inhibited TEA-induced [Ca(2+)]i pulses. These results indicate that in goldfish somatotropes, TEA sensitive K(+) channels regulate excitability while TTX-sensitive Na(+) channels together with N- and L-type Ca channels mediates the depolarization phase of APs. Opening of voltage-sensitive Ca(2+) channels during AP firing leads to increases in [Ca(2+)]i. PMID- 20850442 TI - Transdermal delivery of corticosterone in terrestrial amphibians. AB - Stressors elicit allostatic responses that allow animals to cope with changing and challenging environments and also cause release of glucocorticoid hormones (GCs). Compared to other vertebrate classes, relatively little is known about amphibian behavioral and physiological responses to GCs. To understand the effects of elevated plasma GCs in amphibians, exogenous application of GCs is necessary, but traditional methods to elevate GCs require handling and/or anesthesia which themselves are stressors. A less invasive alternative successfully used in birds and reptiles utilizes transdermal delivery by applying GCs via a dermal patch. We asked whether dermal patches containing corticosterone (CORT, the main GC in amphibians) would elevate plasma CORT in terrestrial salamanders and frogs. We explored the use of the dermal patch to deliver CORT in an acute, sustained, and repeated manner. Patches adhered well to the amphibians' moist skin and were easily removed to regulate the time course of CORT delivery. Application of CORT treated patches elevated plasma CORT concentrations compared to vehicle patches in all species. Patches delivered physiological levels of plasma CORT in ecologically relevant time frames. Repeated application and removal of CORT patches were used to simulate exposure to repeated stressors. Application of patches did not represent a stressor because plasma CORT concentrations were similar between animals that received vehicle patches and untreated animals. Thus, transdermal delivery of GCs represents a potentially useful tool to better understand amphibian allostatic responses to stressors, and perhaps amphibian population declines. PMID- 20850443 TI - Reversed hatching order, body condition and corticosterone levels in chicks of southern rockhopper penguins (Eudyptes chrysocome chrysocome). AB - In altricial and semi-altricial species, asynchronous hatching gives the first chicks to hatch an initial advantage over other siblings and often leads to the elimination of the smallest chicks. Both baseline corticosterone and acute stress induced corticosterone levels have been shown to be higher in food deprived chicks than in chicks fed ad libitum. However, first-hatched chicks have also been shown to exhibit higher corticosterone levels than last-hatched chicks, suggesting an influence of the initial differences between eggs on corticosterone levels. We subjected single-chicks of southern rockhopper penguins Eudyptes chrysocome chrysocome to a standardised capture-stress protocol. In this species having very dimorphic two-egg clutches, we examined whether corticosterone levels were different between the two chick categories and tested for the effect of body condition controlled by the chick category. Neither body sizes, nor corticosterone levels differed between A- and B-chicks at 18 days. In contrast to baseline corticosterone levels, acute stress-induced levels of corticosterone were negatively correlated to body condition: chicks with a good body condition had lower acute stress-induced levels of corticosterone than chicks with a poor condition, whatever the chick category. Our results do not support the idea that initial differences in egg characteristics could drive the difference in corticosterone levels between siblings. On the contrary, they show that the A-egg of rockhopper penguins has, when reared alone, the same intrinsic potential to develop into a fledged chick as the B-egg. Later differences in body condition appear to lead to variation in the acute stress-induced levels of corticosterone. PMID- 20850444 TI - At least two expressed genes for transcription factors Pitx2 and Rpx are present in common carp and are upregulated during winter acclimatization. AB - The mechanisms of seasonal acclimatization in eurythermal fish such as common carp are not fully understood. Here, we concentrate on the regulation of pituitary factors, as this organ was shown to be highly affected by seasonal changes. We cloned and sequenced two different cDNAs for each of the transcription factors Pitx2 and Rpx, known to play a role in pituitary development. We show that these genes are conserved throughout evolution, to different degrees depending on the specific domain considered. Finally, we show that the cDNAs for both factors are clearly up-regulated during the winter season, in sharp contrast to other regulators such as Pit1 or pituitary hormone genes such as prolactin (prl) and growth hormone (gh). Our results suggest that increased expression of Pitx2 and Rpx contributes to seasonal adaptation of common carp to winter conditions. PMID- 20850445 TI - Glucokinase activation induces potent hypoglycemia without recruiting insulin and inhibits food intake in chicken. AB - Glucose homeostasis exhibits several peculiarities in chickens (in short, presence of high glycemia and resistance to high doses of exogenous insulin). Though the full chicken glucokinase gene sequence is still lacking, several results suggest its existence. The functionality of chicken glucokinase (GK) has been further investigated using an activator of mammalian GK (GKA). In vitro, GKA decreased GK's S0.5(a) in a glucose-dependent manner in liver homogenates from either fasted or fed chickens; it also increased GK Vmax(a) in homogenates from fed chickens. In vivo, acute oral GKA administration (10-100 mg/kg) induced a potent and dose dependent hypoglycemic effect in fed chickens (starting between 15 and 45 min with a maximum effect at 40 mg/kg, P<0.0001). At this dose, plasma insulin levels showed erratic and minor changes in the early times (an increase at 5 min and a decrease at 10 min, P<0.05). At 90 min, when hypoglycemia had developed plasma insulin levels decreased under controls and plasma pancreatic glucagon levels increased over controls. Also at 40 mg/kg, GKA transiently inhibited food intake at about 3h (P<0.0001). In conclusion, GKA is a potent activator of chicken GK evidencing that the structure and the activity of chicken GK are similar to those of mammalian GK. At variance with results obtained in mammals, the potent GKA hypoglycemic action appears to rely mostly on an effect on liver GK in chicken. This fits with previous results and further support the hypothesis of a "deficient coupling" between Beta-cell metabolism and insulin release in this species. PMID- 20850446 TI - Serum, plasma, and dried blood spot high-sensitivity C-reactive protein enzyme immunoassay for population research. AB - C-reactive protein (CRP) is used as a biomarker of morbidity and mortality risk in studies of population health, and is essential to interpretation of several micronutrient biomarkers. There is thus a need for a robust high-sensitivity CRP (hsCRP) measurement method for large-scale, non-clinical studies. We developed an efficient, inexpensive assay suitable for quantifying CRP across the physiological range using any blood specimen type. The ELISA uses readily available monoclonal antibodies to measure CRP in serum, plasma, or dried blood spots (DBS) made from venous or capillary blood. Assay performance was evaluated by standard methods, including comparison with a previously described assay. Effects of specimen type were tested by measuring CRP in 52 matched serum, plasma, and venous and capillary dried blood spot specimens. Long- and short-term CRP stability were evaluated. Assessments of assay limits of detection, linearity, recovery, imprecision, and concordance with an established method (Pearson correlation=0.988, n=20) demonstrated the validity of the new assay. CRP measurements in serum, plasma, and DBS had Pearson correlations from 0.974 to 0.995, n=52, but CRP in serum was on average 1.6 times (SD 0.37) higher than in DBS. CRP was stable in frozen serum for up to 34 months, but DBS CRP declined quickly with exposure to ambient temperatures, and across long-term storage at 20 degrees C. This hsCRP assay is a robust and inexpensive tool designed for use in large-scale population health research. Our results indicate that DBS CRP is less stable than previously reported. PMID- 20850447 TI - Label-free monitoring of antibody-antigen interactions using optical microchip biosensors. AB - A rapid, label-free optical biosensor system for sensitive monitoring of bio molecular interactions in real-time is presented. SpectroSens sensor chips are based on integrated planar Bragg gratings sensitive to localised changes in refractive index. Bio-molecule recognition is imparted by functionalisation of the sensing surface with antibodies against targets of interest. In this study, antibodies against selected proteins were oriented with recombinant Protein A/G, which was covalently immobilised to the sensor chip via amine coupling to a glutaraldehyde-activated silane layer. Immunoassays for the detection of rabbit IgG and ovalbumin proteins as model antibody-antigen interaction systems were performed. Binding of complementary antigens to respective antibody functionalised sensors manifested as changes in wavelength of light reflected from the optical sensors. Quantitative binding kinetics with detection sensitivities in the mid ng/ml range were obtained for both antigens using this planar, two-dimensional surface coating. Data presented demonstrate the suitability of SpectroSens sensors as a valuable tool in life science research and development for monitoring bio-specific interactions, protein concentration determination and antibody selection; the optical integration and analytical characteristics of these sensors suggest that they may find numerous applications in bio-pharmaceutical development and clinical diagnostics. PMID- 20850448 TI - Changes in the reproductive biology of Biomphalara glabrata infected with different doses of Echinostoma paraensei miracidia. AB - The egg-laying rate, number of egg masses, number of eggs/mass, number of eggs hatched/snail and egg viability of Biomphalaria glabrata exposed to different doses (5 and 50) of Echinostoma paraensei miracidia were analyzed as indicators of reproductive activity. Polystyrene plates were placed in aquariums containing the snails and every other day for four weeks after infection the plates were removed to count the number of egg masses and eggs laid. After this, the plates were numbered individually and placed in new aquariums free of snails and the egg masses were observed daily to determine the hatching rate. On average there was an increase in the parameters evaluated in the infected snails in relation to the controls (uninfected snails), except for egg viability, which was significantly lower in the groups infected with 50 miracidia. These findings indicate that when infected, this host snail is able to increase its reproductive activity, suggesting an ecological strategy to maintain the species. PMID- 20850449 TI - Effect of starvation upon baculovirus replication in larval Bombyx mori and Heliothis virescens. AB - The progression of baculovirus (BmNPV, BmCysPD, AcMNPV or AcAaIT) infection in larval Bombyx mori and Heliothis virescens (1st, 3rd or 5th instar) was investigated following various starvation regimes. When the larvae were starved for 12 or 24h immediately following inoculation, the median lethal time to death (LT(50)) was delayed by 9.5-19.2h in comparison to non-starved controls. This corresponded to a delay of 10-23% depending upon the larval stage and virus that was used for inoculation. When a 24h-long starvation period was initiated at 1 or 2 days post inoculation (p.i.), a statistically significant difference in LT(50) was not found indicating that the early stages of infection are more sensitive to the effects of starvation. Viral titers in the hemolymph of 5th instar B. mori that were starved for 24h immediately following inoculation were 10-fold lower (p<0.01) than that found in non-starved control larvae. Histochemical analyses indicated that virus transmission was reduced in 5th instar B. mori that were starved for 24h immediately following inoculation in comparison to non-starved control larvae. In general, the mass of larvae that were starved immediately after inoculation was 30% lower than that of non-starved control insects. Our findings indicate that starvation of the larval host at the time of baculovirus exposure has a negative effect on the rate baculovirus transmission and pathogenesis. PMID- 20850450 TI - How does the shape of the cardiac action potential control calcium signaling and contraction in the heart? PMID- 20850451 TI - Analysis of cardiac myosin binding protein-C phosphorylation in human heart muscle. AB - A unique feature of MyBP-C in cardiac muscle is that it has multiple phosphorylation sites. MyBP-C phosphorylation, predominantly by PKA, plays an essential role in modulating contractility as part of the cellular response to beta-adrenergic stimulation. In vitro studies indicate MyBP-C can be phosphorylated at Serine 273, 282, 302 and 307 (mouse sequence) but little is known about the level of MyBP-C phosphorylation or the sites phosphorylated in heart muscle. Since current methodologies are limited in specificity and are not quantitative we have investigated the use of phosphate affinity SDS-PAGE together with a total anti MyBP-C antibody and a range of phosphorylation site-specific antibodies for the main sites (Ser-273, -282 and -302). With these newly developed methods we have been able to make a detailed quantitative analysis of MyBP-C phosphorylation in heart tissue in situ. We have found that MyBP-C is highly phosphorylated in non-failing human (donor) heart or mouse heart; tris and tetra-phosphorylated species predominate and less than 10% of MyBP-C is unphosphorylated (0, 9.3 +/- 1%: 1P, 13.4 +/- 2.7%: 2P, 10.5 +/- 3.3%: 3P, 28.7 +/- 3.7%: 4P, 36.4 +/- 2.7%, n=21). Total phosphorylation was 2.7 +/- 0.07 mol Pi/mol MyBP-C. In contrast in failing heart and in myectomy samples from HCM patients the majority of MyBP-C was unphosphorylated. Total phosphorylation levels were 23% of normal in failing heart myofibrils (0, 60.1 +/- 2.8%: 1P, 27.8 +/- 2.8%: 2P, 4.8 +/- 2.0%: 3P, 3.7 +/- 1.2%: 4P, 2.8 +/- 1.3%, n=19) and 39% of normal in myectomy samples. The site-specific antibodies showed a distinctive distribution pattern of phosphorylation sites in the multiple phosphorylation level species. We found that phosphorylated Ser-273, Ser-282 and Ser-302 were all present in the 4P band of MyBP-C but none of them were significant in the 1P band, indicating that there must be at least one other site of MyBP-C phosphorylation in human heart. The pattern of phosphorylation at the three sites was not random, but indicated positive and negative interactions between the three sites. Phosphorylation at Ser-282 was not proportional to the number of sites available. The 2P band contained 302 but not 273; the 3P band contained 273 but not 302. PMID- 20850452 TI - Resident vascular progenitor cells. AB - Homeostasis of the vessel wall is essential for maintaining its function, including blood pressure and patency of the lumen. In physiological conditions, the turnover rate of vascular cells, i.e. endothelial and smooth muscle cells, is low, but markedly increased in diseased situations, e.g. vascular injury after angioplasty. It is believed that mature vascular cells have an ability to proliferate to replace lost cells normally. On the other hand, recent evidence indicates stem/progenitor cells may participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. It was found that all three layers of the vessels, the intima, media and adventitia, contain resident progenitor cells, including endothelial progenitor cells, mesenchymal stromal cells, Sca-1+ and CD34+ cells. Data also demonstrated that these resident progenitor cells could differentiate into a variety of cell types in response to different culture conditions. However, collective data were obtained mostly from in vitro culture assays and phenotypic marker studies. There are many unanswered questions concerning the mechanism of cell differentiation and the functional role of these cells in vascular repair and the pathogenesis of vascular disease. In the present review, we aim to summarize the data showing the presence of the resident progenitor cells, to highlight possible signal pathways orchestrating cell differentiation toward endothelial and smooth muscle cells, and to discuss the data limitations, challenges and controversial issues related to the role of progenitors. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". PMID- 20850453 TI - alpha-actinin is required for the proper assembly of Z-disk/focal-adhesion-like structures and for efficient locomotion in Caenorhabditis elegans. AB - The actin binding protein alpha-actinin is a major component of focal adhesions found in vertebrate cells and of focal-adhesion-like structures found in the body wall muscle of the nematode Caenorhabditis elegans. To study its in vivo function in this genetic model system, we isolated a strain carrying a deletion of the single C. elegans alpha-actinin gene. We assessed the cytological organization of other C. elegans focal adhesion proteins and the ultrastructure of the mutant. The mutant does not have normal dense bodies, as observed by electron microscopy; however, these dense-body-like structures still contain the focal adhesion proteins integrin, talin, and vinculin, as observed by immunofluorescence microscopy. Actin is found in normal-appearing I-bands, but with abnormal accumulations near muscle cell membranes. Although swimming in water appeared grossly normal, use of automated methods for tracking the locomotion of individual worms revealed a defect in bending. We propose that the reduced motility of alpha-actinin null is due to abnormal dense bodies that are less able to transmit the forces generated by actin/myosin interactions. PMID- 20850454 TI - Chemoenzymatic synthesis, inhibition studies, and X-ray crystallographic analysis of the phosphono analog of UDP-Galp as an inhibitor and mechanistic probe for UDP galactopyranose mutase. AB - UDP (uridine diphosphate) galactopyranose mutase (UGM) is involved in the cell wall biosynthesis of many pathogenic microorganisms. UGM catalyzes the reversible conversion of UDP-alpha-D-galactopyranose into UDP-alpha-D-galactofuranose, with the latter being the precursor of galactofuranose (Galf) residues in cell walls. Glycoconjugates of Galf are essential components in the cell wall of various pathogenic bacteria, including Mycobacterium tuberculosis, the causative agent of tuberculosis. The absence of Galf in humans and its bacterial requirement make UGM a potential target for developing novel antibacterial agents. In this article, we report the synthesis, inhibitory activity, and X-ray crystallographic studies of UDP-phosphono-galactopyranose, a nonhydrolyzable C-glycosidic phosphonate. This is the first report on the synthesis of a phosphonate analog of UDP-alpha-D-galactopyranose by a chemoenzymatic phosphoryl coupling method. The phosphonate was evaluated against three bacterial UGMs and showed only moderate inhibition. We determined the crystal structure of the phosphonate analog bound to Deinococcus radiodurans UGM at 2.6 A resolution. The phosphonate analog is bound in a novel conformation not observed in UGM-substrate complex structures or in other enzyme-sugar nucleotide phosphonate complexes. This complex structure provides a structural basis for the observed micromolar inhibition towards UGM. Steric clashes, loss of electrostatic stabilization between an active-site arginine (Arg305) and the phosphonate analog, and a 180 degrees flip of the hexose moiety account for the differences in the binding orientations of the isosteric phosphonate analog and the physiological substrate. This provides new insight into the ability of a sugar-nucleotide-binding enzyme to orient a substrate analog in an unexpected geometry and should be taken into consideration in designing such enzyme inhibitors. PMID- 20850456 TI - The structures and physicochemical properties of organic cofactors in biocatalysis. AB - Many crucial biochemical reactions in the cell require not only enzymes for catalysis but also organic cofactors or metal ions. Here, we analyse the physicochemical properties, chemical structures and functions of organic cofactors. Based on a thorough analysis of the literature complemented by our quantitative characterisation and classification, we found that most of these molecules are constructed from nucleotide and amino-acid-type building blocks, as well as some recurring cofactor-specific chemical scaffolds. We show that, as expected, organic cofactors are on average significantly more polar and slightly larger than other metabolites in the cell, yet they cover the full spectrum of physicochemical properties found in the metabolome. Furthermore, we have identified intrinsic groupings among the cofactors, based on their molecular properties, structures and functions, that represent a new way of considering cofactors. Although some classes of cofactors, as defined by their physicochemical properties, exhibit clear structural communalities, cofactors with similar structures can have diverse functional and physicochemical profiles. Finally, we show that the molecular functions of the cofactors not only may duplicate reactions performed by inorganic metal cofactors and amino acids, the cell's other catalytic tools, but also provide novel chemistries for catalysis. PMID- 20850455 TI - Cellular architecture of Treponema pallidum: novel flagellum, periplasmic cone, and cell envelope as revealed by cryo electron tomography. AB - High-resolution cryo electron tomography (cryo-ET) was utilized to visualize Treponema pallidum, the causative agent of syphilis, at the molecular level. Three-dimensional (3D) reconstructions from 304 infectious organisms revealed unprecedented cellular structures of this unusual member of the spirochetal family. High-resolution cryo-ET reconstructions provided detailed structures of the cell envelope, which is significantly different from that of Gram-negative bacteria. The 4-nm lipid bilayer of both outer membrane and cytoplasmic membrane resolved in 3D reconstructions, providing an important marker for interpreting membrane-associated structures. Abundant lipoproteins cover the outer leaflet of the cytoplasmic membrane, in contrast to the rare outer membrane proteins visible by scanning probe microscopy. High-resolution cryo-ET images also provided the first observation of T. pallidum chemoreceptor arrays, as well as structural details of the periplasmically located cone-shaped structure at both ends of the bacterium. Furthermore, 3D subvolume averages of periplasmic flagellar motors and flagellar filaments from living organisms revealed the novel flagellar architectures that may facilitate their rotation within the confining periplasmic space. Our findings provide the most detailed structural understanding of periplasmic flagella and the surrounding cell envelope, which enable this enigmatic bacterium to efficiently penetrate tissue and to escape host immune responses. PMID- 20850457 TI - Enhancing the stability and solubility of the glucocorticoid receptor ligand binding domain by high-throughput library screening. AB - The human glucocorticoid receptor ligand-binding domain (hGR-LBD) is an important drug target for the treatment of various diseases. However, the low intrinsic stability and solubility of hGR-LBD have rendered its purification and biophysical characterization difficult. In order to overcome these problems, we have stabilized hGR-LBD by a combination of random mutagenesis and high throughput screening using fluorescence-activated cell sorting (FACS) with enhanced green fluorescent protein (eGFP) as folding reporter. Two plasmid encoded gene libraries of hGR-LBD fused to the egfp gene were expressed in Escherichia coli, followed by eight rounds of FACS screening, in each of which 10(8) cells were analyzed. The hgr-lbd mutants isolated by this approach contained numerous amino acid exchanges, and four beneficial ones (A605V, V702A, E705G, and M752T) were followed up in detail. Their characterization showed that the fluorescence of hGR-LBD-eGFP fusions is correlated linearly with the stability and solubility of hGR-LBD in the absence of eGFP. When combined, the four exchanges increased the thermal stability of hGR-LBD by more than 8 degrees C and enhanced its purification yield after expression in E. coli by about 26 fold. The introduction of three beneficial exchanges into the homologous ligand binding domain of mouse enabled its X-ray structure determination at high resolution, which showed how the exchanges stabilize the protein and revealed atomic details that will guide future drug design. Our results demonstrate that large eGFP fusion libraries can be screened by FACS with extreme sensitivity and efficiency, yielding stabilized eukaryotic proteins suitable for biophysical characterization and structure determination. PMID- 20850459 TI - The contribution of a covalently bound cofactor to the folding and thermodynamic stability of an integral membrane protein. AB - The factors controlling the stability, folding, and dynamics of integral membrane proteins are not fully understood. The high stability of the membrane protein bacteriorhodopsin (bR), an archetypal member of the rhodopsin photoreceptor family, has been ascribed to its covalently bound retinal cofactor. We investigate here the role of this cofactor in the thermodynamic stability and folding kinetics of bR. Multiple spectroscopic probes were used to determine the kinetics and energetics of protein folding in mixed lipid/detergent micelles in the presence and absence of retinal. The presence of retinal increases extrapolated values for the overall unfolding free energy from 6.3 +/- 0.4 kcal mol(-1) to 23.4 +/- 1.5 kcal mol(-1) at zero denaturant, suggesting that the cofactor contributes 17.1 kcal mol(-1) towards the overall stability of bR. In addition, the cooperativity of equilibrium unfolding curves is markedly reduced in the absence of retinal with overall m-values decreasing from 31.0 +/- 2.0 kcal mol(-1) to 10.9 +/- 1.0 kcal mol(-1), indicating that the folded state of the apoprotein is less compact than the equivalent for the holoprotein. This change in the denaturant response means that the difference in the unfolding free energy at a denaturant concentration midway between the two unfolding curves is only ca 3-6 kcal mol(-1). Kinetic data show that the decrease in stability upon removal of retinal is associated with an increase in the apparent intrinsic rate constant of unfolding, k(u)(H2O), from ~1 * 10(-16) s(-1) to ~1 * 10(-4) s(-1) at 25 degrees C. This correlates with a decrease in the unfolding activation energy by 16.3 kcal mol(-1) in the apoprotein, extrapolated to zero SDS. These results suggest that changes in bR stability induced by retinal binding are mediated solely by changes in the activation barrier for unfolding. The results are consistent with a model in which bR is kinetically stabilized via a very slow rate of unfolding arising from protein-retinal interactions that increase the rigidity and compactness of the polypeptide chain. PMID- 20850460 TI - 5-HT2C receptor regulation of defensive responses in the rat dorsal periaqueductal gray. AB - Activation of 5-HT2C receptors in limbic structures such as the amygdala and hippocampus increases anxiety. Indirect evidence obtained with non-selective 5 HT2C-interacting drugs suggests that the same may occur in the dPAG, a brainstem region consistently implicated in the genesis/regulation of panic attacks. In this study we used more selective agonists and antagonists to unveil the role played by dPAG 5-HT2C receptors in the regulation of anxiety- and panic-related defensive behaviors. Our results showed that intra-dPAG microinjection of the endogenous agonist 5-HT (20 nmol) or the 5-HT2C receptor agonists MK-212 (1 and 10 nmol) and RO-600175 (40 nmol) significantly increased inhibitory avoidance acquisition in rats tested in the elevated T-maze, suggesting an anxiogenic effect. 5-HT, but not the two 5-HT2C receptor agonists, inhibited escape performance. In the elevated T-maze, inhibitory avoidance and escape responses have been related to generalized anxiety and panic attacks, respectively. The behavioral effects caused by 5-HT and MK-212 were fully blocked by previous local microinjection of the 5-HT2C receptor antagonist SB-242084. Intra-dPAG injection of MK-212 also failed to affect escape expression in another test relating this behavior to panic, the electrical stimulation of the dPAG. Overall, the results indicate that 5-HT2C receptors in the dPAG are preferentially involved in the regulation of defensive behaviors related to anxiety, but not panic. This finding extends to the dPAG the prominent role that has been attributed to 5-HT2C receptors in anxiety generation. PMID- 20850458 TI - Propensities of aromatic amino acids versus leucine and proline to induce residual structure in the denatured-state ensemble of iso-1-cytochrome c. AB - Histidine-heme loop formation in the denatured state of a protein is a sensitive means for probing residual structure under unfolding conditions. In this study, we use a host-guest approach to investigate the relative tendencies of different amino acids to promote residual structure under denaturing conditions. The host for this work is a 6-amino-acid insert of five alanines, followed by a lysine engineered immediately following a unique histidine near the N-terminus of yeast iso-1-cytochrome c. We substitute the fourth alanine in this sequence HAAAXAK (with X=Trp, Phe, Tyr, and Leu). The effects of proline are tested with substitutions at positions 1 and 5 in the insert (HPAAAAK and HAAAAPK, respectively). Thermodynamic studies on His-heme loop formation in 3 M guanidine hydrochloride reveal significant stabilization of residual structure by aromatic amino acids, particularly Trp and Phe, and minimal stabilization of residual structure by Leu. Prolines slightly disfavor His-heme loop formation, presumably due to enhanced chain stiffness. Kinetic studies reveal that much of the change in His-heme loop stability for the aromatic amino acids is caused by a slowdown in the rate of His-heme loop breakage, indicating that residual structure is preferentially stabilized in the closed-loop form of the denatured state. PMID- 20850461 TI - Exposure to a high-fat diet decreases sensitivity to Delta9-tetrahydrocannabinol induced motor effects in female rats. AB - Arachidonic acid, a fatty acid component of neuronal cell membranes, forms the backbone of endogenous ligands of the endocannabinoid system. The lipid nature of this system may make it particularly susceptible to changes in fat content of the diet, which may, in turn, affect endocannabinoid tone and subsequent changes in receptor expression or activity. The latter would also be expected to affect responses to exogenous cannabinoids. The purpose of the present study was to determine the effects of a high-fat diet on sensitivity to the pharmacological effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC). Male and female Long Evans rats were fed either a diet of standard rodent chow or chow enhanced with corn oil. Subsequently, they were repeatedly assessed for Delta(9)-THC-induced hypomobility, catalepsy and hypothermia. Female rats that received the high-fat diet beginning in adolescence or in adulthood became significantly less sensitive to the effects of Delta(9)-THC on motor behavior, but not its hypothermic effects, with faster development of decreased sensitivity in female rats that began the high-fat diet as adults. In contrast, diet-induced differences either did not occur, or were less pronounced, in male rats of both ages. After acute injection, brain and blood levels of Delta(9)-THC and its two primary metabolites were similar regardless of diet. Combined with the fact that diet differentially affected only some of the measures, these results suggest that pharmacokinetic differences cannot fully account for the effects of the high-fat diet on response to Delta(9)-THC. Further, these results suggest that dietary fat content may represent an important consideration in predicting the effects of marijuana in females. PMID- 20850463 TI - Chronic URB597 treatment at adulthood reverted most depressive-like symptoms induced by adolescent exposure to THC in female rats. AB - We have recently shown that chronic THC administration in adolescent female rats induces subtle but lasting alterations in the emotional circuit ending in depressive-like behaviour at adulthood. Here we describe other relevant depressive-like symptoms present in these animals. Adult female rats pretreated with THC display passive coping strategy towards acute stressful situations as demonstrated by their behaviours in the first session of the forced swim test, develop a profound anhedonic state as demonstrated by the reduced consumption of palatable food and present a decrease in social functioning. Besides the emotional symptoms, adolescent exposure to THC induced a significant deficit in object recognition memory. Since it has been reported that deficits in adult hippocampal neurogenesis may underlie the cognitive dysfunction seen in depression, we then survey cell proliferation in the dentate gyrus of the hippocampus. Adolescent THC exposure significantly reduced the number of BrdU positive cells in THC-treated rats as well as hippocampal volume. We suggest that this complex depressive-like phenotype is triggered by a long-lasting decrease in CB1 receptor functionality in specific brain regions. To test whether an increase in the endocannabinoid signalling could ameliorate the depressive phenotype, adult female rats pre-exposed to THC were injected with URB597 (0.3mg/kg ip) and then tested in behavioural assays. URB597 was able to reverse most depressive like symptoms induced by adolescent THC exposure such as the passive coping strategy observed in THC exposed animals in the forced swim test as well as anhedonia and the reduced social activity. These results support a role for the endocannabinoid system in the neurobiology of depression and suggest the use of URB597 as a new therapeutic tool with antidepressant properties. PMID- 20850462 TI - Evaluation of the D3 dopamine receptor selective agonist/partial agonist PG01042 on L-dopa dependent animal involuntary movements in rats. AB - The substituted 4-phenylpiperazine D3 dopamine receptor selective antagonist PG01037 ((E)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)but-2-enyl)-4-(pyridin-2 yl)benzamide) was reported to attenuate L-dopa-associated abnormal involuntary movements (AIMs) in unilaterally lesioned rats, a model of L-dopa-dependent dyskinesia in patients with Parkinson's Disease (Kumar et al., 2009a). We now report that PG01042 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin 3-yl)benzamide), which is a D3 dopamine receptor selective agonist for adenylyl cyclase inhibition and a partial agonist for mitogenesis, is also capable of attenuating AIMs scores. The intrinsic activity of PG01037 and PG01042 were determined using a) a forskolin-dependent adenylyl cyclase inhibition assay and b) an assay for agonist-associated mitogenesis. It was observed that the in vivo efficacy of PG01042 increased when administered by intraperitoneal (i.p.) injection simultaneously with L-dopa/benserazide (8 mg/kg each), as compared to a 60 min or 30 min pretreatment. PG01042 was found to attenuate AIM scores in these animals in a dose dependent manner. While PG01042 did not effectively inhibit SKF 81297-dependent AIMs, it inhibited apomorphine-dependent AIM scores. Rotarod studies indicate that PG01042 at a dose of 10 mg/kg did not adversely affect motor coordination of the unilaterally lesioned rats. Evaluation of lesioned rats using a cylinder test behavioral paradigm indicated that PG01042 did not dramatically attenuate the beneficial effects of L-dopa. These studies and previously published studies suggest that both D3 dopamine receptor selective antagonists, partial agonists and agonists, as defined by an adenylyl cyclase inhibition assay and a mitogenic assay, are pharmacotherapeutic candidates for the treatment of L-dopa-associated dyskinesia in patients with Parkinson's Disease. PMID- 20850464 TI - Chronic treatment with the alpha2-adrenoceptor antagonist fluparoxan prevents age related deficits in spatial working memory in APP*PS1 transgenic mice without altering beta-amyloid plaque load or astrocytosis. AB - Locus coeruleus degeneration and reduced central noradrenaline content is an early feature of Alzheimer's disease. In transgenic mouse models of Alzheimer's disease-like pathology, lesioning the locus coeruleus exacerbates beta-amyloid (Abeta) pathology, neuroinflammation and memory deficits. Here we aimed to determine whether chronic treatment with the alpha(2)-adrenoceptor antagonist fluparoxan, that enhances noradrenaline release, can prevent the onset of Alzheimer's-like pathology and memory deficits in APP/PS1 transgenic mice (TASTPM). Fluparoxan (1mg/kg/day) was administered to TASTPM and wild type mice from 4 to 8 months of age. Memory was assessed at 4 and 8 months of age using the Morris water maze and contextual fear conditioning and at monthly intervals during the duration of treatment using the object recognition and spontaneous alternation task. Abeta plaque load and astrocytosis were measured at 4 and 8 months of age by immunohistochemistry. Fluparoxan treatment prevented age-related spatial working memory deficits in the spontaneous alternation task but not spatial reference memory deficits in the Morris water maze. Abeta plaque load and astrocytosis were unaltered by fluparoxan treatment in TASTPM mice. The findings suggest that fluparoxan treatment selectively prevent the decline of forms of memory where noradrenaline plays an integral role and that this beneficial effect is not due to altered Abeta plaque pathology or astrocytosis. PMID- 20850465 TI - Superior voice recognition in a patient with acquired prosopagnosia and object agnosia. AB - Anecdotally, it has been reported that individuals with acquired prosopagnosia compensate for their inability to recognize faces by using other person identity cues such as hair, gait or the voice. Are they therefore superior at the use of non-face cues, specifically voices, to person identity? Here, we empirically measure person and object identity recognition in a patient with acquired prosopagnosia and object agnosia. We quantify person identity (face and voice) and object identity (car and horn) recognition for visual, auditory, and bimodal (visual and auditory) stimuli. The patient is unable to recognize faces or cars, consistent with his prosopagnosia and object agnosia, respectively. He is perfectly able to recognize people's voices and car horns and bimodal stimuli. These data show a reverse shift in the typical weighting of visual over auditory information for audiovisual stimuli in a compromised visual recognition system. Moreover, the patient shows selectively superior voice recognition compared to the controls revealing that two different stimulus domains, persons and objects, may not be equally affected by sensory adaptation effects. This also implies that person and object identity recognition are processed in separate pathways. These data demonstrate that an individual with acquired prosopagnosia and object agnosia can compensate for the visual impairment and become quite skilled at using spared aspects of sensory processing. In the case of acquired prosopagnosia it is advantageous to develop a superior use of voices for person identity recognition in everyday life. PMID- 20850466 TI - Pathway modeling of microarray data: a case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP). AB - Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data. PMID- 20850467 TI - Texture segmentation: do the processing units on the saliency map increase with eccentricity? AB - The saliency map is a computational model and has been constructed for simulating human saliency processing, e.g. pop-out target detection (e.g. Itti & Koch, 2000). In this study the spatial structure on the saliency map was investigated. It is proposed that the saliency map is structured into processing units whose size is increasing with retinal eccentricity. In two experiments the distance between a target in the stimulus and an irrelevant structure in the mask was varied systematically. Our findings had two main points. Firstly, in texture segmentation tasks the saliency signals from two texture irregularities interfere, when these irregularities appear within a critical spatial distance. Second, the critical distances increase with target eccentricity. The eccentricity-dependent critical distances can be interpreted as crowding effects. It is assumed that additionally to the target eccentricity, also the strength of a saliency signal can determine the spatial area of its impairing influence. PMID- 20850468 TI - Exploitation of natural geometrical regularities facilitates target detection. AB - We have evolved to operate within a dynamic visual world in which natural visual signals are not random but have various statistical regularities. Our rich experience of the probability structure of these regularities could influence visual computation. Considering that spatiotemporal regularity, co-linearity and co-circularity are common geometrical regularities in natural scenes, we explored how our visual system exploits these regularities to achieve accurate and efficient representations of the external world. By measuring human contrast detection performance of a briefly presented foveal target embedded in dynamic stimulus sequences (comprising six short bars appearing consecutively towards the fovea) imitating common regularity structures, we found that both contrast sensitivity and reaction time for target detection was facilitated by predictable spatiotemporal stimulus structure. Qualitatively consistent with natural image analysis that co-linearity is a stronger statistical feature than co-circularity, the facilitation in target detection was more evident for predictable stimulus sequences following a co-linear path than a co-circular path. Control experiments further showed that response bias and uncertainty reduction could not fully account for our observation. It seems that our visual system exploits geometrical natural regularities to facilitate the interpretation of incoming visual signals, such as constraining interpretation on the basis of contextual priors. PMID- 20850469 TI - Locations of serial reach targets are coded in multiple reference frames. AB - Previous work from our lab, and elsewhere, has demonstrated that remembered target locations are stored and updated in an eye-fixed reference frame. That is, reach errors systematically vary as a function of gaze direction relative to a remembered target location, not only when the target is viewed in the periphery (Bock, 1986, known as the retinal magnification effect), but also when the target has been foveated, and the eyes subsequently move after the target has disappeared but prior to reaching (e.g., Henriques, Klier, Smith, Lowy, & Crawford, 1998; Sorrento & Henriques, 2008; Thompson & Henriques, 2008). These gaze-dependent errors, following intervening eye movements, cannot be explained by representations whose frame is fixed to the head, body or even the world. However, it is unknown whether targets presented sequentially would all be coded relative to gaze (i.e., egocentrically/absolutely), or if they would be coded relative to the previous target (i.e., allocentrically/relatively). It might be expected that the reaching movements to two targets separated by 5 degrees would differ by that distance. But, if gaze were to shift between the first and second reaches, would the movement amplitude between the targets differ? If the target locations are coded allocentrically (i.e., the location of the second target coded relative to the first) then the movement amplitude should be about 5 degrees . But, if the second target is coded egocentrically (i.e., relative to current gaze direction), then the reaches to this target and the distances between the subsequent movements should vary systematically with gaze as described above. We found that requiring an intervening saccade to the opposite side of 2 briefly presented targets between reaches to them resulted in a pattern of reaching error that systematically varied as a function of the distance between current gaze and target, and led to a systematic change in the distance between the sequential reach endpoints as predicted by an egocentric frame anchored to the eye. However, the amount of change in this distance was smaller than predicted by a pure eye-fixed representation, suggesting that relative positions of the targets or allocentric coding was also used in sequential reach planning. The spatial coding and updating of sequential reach target locations seems to rely on a combined weighting of multiple reference frames, with one of them centered on the eye. PMID- 20850470 TI - Commuting physical activity and prevalence of metabolic disorders in Poland. AB - OBJECTIVES: The aim of this study was to examine the relationship between walking or cycling to work and prevalence of metabolic syndrome (MetS) and its components. METHODS: Cross-sectional analysis of 6401 randomly selected individuals (3297 men and 3104 women) aged 20-74 years, who participated in the National Multicentre Health Survey WOBASZ, Poland (2002-2005). Commuting physical activity (PA) was assessed by asking about type and time spent on transportation to/from work using an interviewer-administered questionnaire. Weight, height, waist circumference (WC), blood pressure (BP), fasting plasma glucose (FPG), triglycerides (TG) and high-density cholesterol, (HDL-C) were measured by standard methods. MetS was defined according to the NCEP-ATP III and IDF criteria. RESULTS: Active commuting was associated with decreased likelihood of abdominal obesity (WC>=94 cm), lower HDL-C and elevated TG in men and abdominal obesity (WC>=80 cm) in women. In a subgroup of postmenopausal women (n=317) active commuting was favourably associated with abdominal obesity, low HDL-C and elevated FPG. Prevalence of MetS was significantly lower among those who spent above 30 min/day daily on walking/cycling to work than among other gender subgroups. CONCLUSION: Increasing of commuting PA level may have an important influence on reducing the prevalence of metabolic disorders. PMID- 20850471 TI - Fractionation, partial characterization and bioactivity of water-soluble polysaccharides and polysaccharide-protein complexes from Pleurotus geesteranus. AB - Fractionation and purification of mushroom polysaccharides is a critical process for mushroom clinical application. After a hot-water treatment, the crude Pleurotus geesteranus (PG) was further fractionated into four fractions (PG-1, 2, -3, -4) using gradient precipitation with water and ammonia sulphate. By controlling the initial polymer concentration and ratio of solvents, this process produced PG fractions with high chemical uniformity and narrow Mw distribution without free proteins. Structurally, PG-1 and PG-2 are pure homopolysaccharide mainly composed of glucose; and PG-3 and PG-4 are heteropolysaccharide-protein complexes. PG-2, a high M(w) fraction mainly composed of glucose presented significant cytotoxicity at the concentration of 200 and 100 MUg/ml to human breast cancer cells. Here, we report a new mushroom polysaccharides extraction and fractionation method, with which we produced four fractions of PG with PG-2 appearing effective anti-tumour activity. PMID- 20850472 TI - Bioactivities of water-soluble polysaccharides from Jisongrong mushroom: anti breast carcinoma cell and antioxidant potential. AB - Polysaccharides were extracted from Jisongrong mushroom. Jisongrong polysaccharides was a water-soluble compound. Its molecular weight was about 7.4*10(4) Da. HPLC analysis showed that this polysaccharides was composed of mannose, ribose, rhamnose, glucose, xylose, galactose and arabinose in the molar contents of 3.3, 17.3, 6.0, 12.4, 98.4 and 2.1 MUM, respectively. In the range of 2800-3500 cm(-1), peaks at 2958 and 3407 cm(-1) belonging to -C-H of -CH2 groups, were observed in polysaccharides. When Jisongrong polysaccharides were orally administrated to rats for 2 months, level of lipid peroxidation products and activities of antioxidant enzymes in the blood were significantly decreased and enhanced compared to control rats. Moreover, Jisongrong polysaccharides still markedly inhibited cancer cells proliferation. These results suggested that Jisongrong polysaccharides possess a strong antioxidant and antitumour activities. PMID- 20850473 TI - Functional characterization of the CC chemokine RANTES from Pekin duck (Anas platyrhynchos). AB - RANTES (Regulated upon Activation, Normal T-cell Expressed and Secreted) is a key pro-inflammatory cytokine that belongs to the CC-group of chemokines. The present study was carried out to functionally characterize the previously identified RANTES homologue in domestic duck (GenBank Accession No. AY641435). Recombinant duck RANTES was expressed in Escherichia coli-based and HEK293T cell-based systems. A tRNA supplementation strategy was required to express the protein in E. coli due to the presence of rare codons. In biological assays using HEK293T cell-expressed protein, RANTES was found to mediate chemotaxis of DT-40 chicken B cells and primary duck splenocytes at a concentration of 0.505MUg/ml (0.6MUM). Immunostaining of the migrated splenocytes using anti-duck CD4 and CD8 monoclonal antibodies and subsequent flow cytometric analysis showed enhanced chemotaxis of CD8+ cells. The recombinant RANTES exhibited in vitro antiviral activity by inhibiting infection of chicken embryo fibroblast cells with duck enteritis virus (DEV) at the same concentration. The effect could be neutralized by rabbit anti duck RANTES polyclonal serum. The mechanism seems to be direct on viral particles as evidenced by the need for co-incubation of RANTES with DEV prior to the infection for antiviral activity, and also by the enhanced binding of DEV to E. coli expressed purified RANTES on ELISA-based assays. Our results show that the duck RANTES has overlapping biological properties with its mammalian orthologue, and also has possible functional cross-reactivity with chicken immune cells indicated by the chemotaxis of DT-40 cells. PMID- 20850474 TI - European Antibiotic Awareness Day 2010: why doesn't promoting antibiotic awareness always work? PMID- 20850475 TI - Can we use electronic prescribing to reduce prescription errors for antibiotics? PMID- 20850476 TI - A new tip-recording method to test scorpion pecten chemoresponses to water soluble stimulants. AB - On the ventral surface of all scorpions are jointed appendages called pectines, which possess thousands of sensory sensilla. Researchers have electrophysiologically examined these peg sensilla in the past, providing evidence for their chemosensitivity and intra-peg synaptic interactions. However, limits to extracellular recording and chemical stimulation have impeded further research. In this study, we develop and apply a new tip-recording technique for stimulating and recording peg neurons. Relative to previous methods in pecten electrophysiology, this technique allows for very fast and efficient data assembly. Using it, we captured sensilla chemoresponses to aqueous stimulants. We see utility in this method for advancing our understanding of sensory physiology; specifically, we suggest this technique may be useful for physiological assays on scorpion and other arthropod chemoreceptors, such as insect and crustacean gustatory sensilla. PMID- 20850478 TI - Adenoviral vectors stimulate innate immune responses in macrophages through cross talk with epithelial cells. AB - Although adenovirus vectors (Ads) have been widely utilized for gene delivery, their clinical application has been hampered by host immune responses. It has been shown that macrophages can induce inflammatory response against Ads in vivo, but they are not easily activated by Ads in vitro, suggesting their activation requires interaction with other cells. In this study, we investigated the interaction between macrophages and epithelial cells during Ad infection. Ad infection of the macrophage-epithelial cell co-culture resulted in rapid and drastic changes in the cell culture such as decrease in pH within 24h, indicating macrophage activation. Ad infected co-culture showed several characteristics of inflammation including cytotoxicity, induction of pro-inflammatory cytokines, and generation of nitric oxide and reactive oxygen species. These signs of macrophage activation and inflammation were observed exclusively in the co-culture and were absent or significantly weaker in the macrophage mono-culture suggesting that there was a synergistic response by the interaction between macrophages and epithelial cells. We found that inhibition of NF-kappaB activation significantly reduced the inflammatory responses in the co-culture. Furthermore, we show that only the macrophages adjacent to epithelial cells were activated during Ad infection demonstrating that the interaction between macrophages and epithelial cells are crucial for Ad-induced inflammatory response. PMID- 20850477 TI - TL and CD8alphaalpha: Enigmatic partners in mucosal immunity. AB - The intestinal mucosa represents a large surface area that is in contact with an immense antigenic load. The immune system associated with the intestinal mucosa needs to distinguish between innocuous food antigens, commensal microorganisms, and pathogenic microorganisms, without triggering an exaggerated immune response that may lead to excessive inflammation and/or development of inflammatory bowel disease. The thymus leukemia (TL) antigen and CD8alphaalpha are interacting surface molecules that are expressed at the frontline of the mucosal immune system: TL is expressed in intestinal epithelial cells (IEC) whereas CD8alphaalpha is expressed in lymphocytes, known as intraepithelial lymphocytes, that reside in between the IEC. In this review we discuss the significance of the interaction between TL and CD8alphaalpha in mucosal immunity during health and disease. PMID- 20850479 TI - Identification of the structural proteins of VP1 and VP2 of a novel mud crab dicistrovirus. AB - Mud crab dicistrovirus (MCDV), a newly identified single-stranded positive RNA virus, is an important pathogen that causes serious economic losses to mud crab aquaculture. In this study, MCDV was purified, and three structural proteins of MCDV were separated by SDS-PAGE. The N-terminal 15 amino acids were sequenced and aligned with the main structural proteins of other dicistrovirus. The three structural proteins were named VP1, VP2 and VP3. Monoclonal antibodies (MAbs) against the two main structural proteins, VP1 and VP2, were prepared, and the two structural proteins were then identified using these MAbs. The results of Western blot analyses demonstrated that five MAbs recognised VP1 and two recognised VP2. The results of immunogold transmission electron microscopy (IEM) revealed that the epitopes of the two structural proteins recognised by the MAbs were located at the outer surface of the virions, which suggested that the two structural proteins are MCDV capsid proteins. The identification of the two structural proteins of MCDV is useful for studying their functions, as well as the mechanism of infection and the pathogenesis of MCDV. PMID- 20850480 TI - Characterization of Atp1a3 mutant mice as a model of rapid-onset dystonia with parkinsonism. AB - Rapid-onset dystonia with parkinsonism (RDP) or DYT12 dystonia is a rare form of primary, generalized dystonia. Patients do not present with any symptoms until triggered by a physiological stressor. Within days, patients will show both dystonia and parkinsonism. Mutations resulting in a loss of function in the ATP1A3 gene have been identified as the cause of RDP. ATP1A3 encodes the alpha3 subunit of the Na(+)/K(+)-ATPase, which is exclusively expressed in neurons and cardiac cells. We have previously created a line of mice harboring a point mutation of the Atp1a3 gene (mouse homolog of the human ATP1A3 gene) that results in a loss of function of the alpha3 subunit. The Atp1a3 mutant mice showed hyperactivity, spatial learning and memory deficits, and increased locomotion induced by methamphetamine. However, the full spectrum of the motor phenotype has not been characterized in the mutant mice and it is not known whether triggers such as restraint stress affect the motor phenotype. Here, we characterized the motor phenotype in normal heterozygous Atp1a3 mutant mice and heterozygous Atp1a3 mutant mice that have been exposed to a restraint stress. We found that this type of trigger induced significant deficits in motor coordination and balance in the mutant mice, characteristic of other genotypic dystonia mouse models. Furthermore, stressed mutant mice also had a decreased thermal sensitivity and alterations in monoamine metabolism. These results suggest that the Atp1a3 mutant mouse models several characteristics of RDP and further analysis of this mouse model will provide great insight into pathogenesis of RDP. PMID- 20850481 TI - ZBP-89 enhances Bak expression and causes apoptosis in hepatocellular carcinoma cells. AB - ZBP-89 can enhance tumor cells to death stimuli. However, the molecular mechanism leading to the inhibitory effect of ZBP-89 is unknown. In this study, 4 liver cell lines were used to screen for the target of ZBP-89 on cell death pathway. The identified Bak was further analyzed for its role in ZBP-89-mediated apoptosis. The result showed that ZBP-89 significantly and time-dependently induced apoptosis. It significantly upregulated the level of pro-apoptotic Bak. ZBP-89 targeted a region between -457 and -407 of human Bak promoter to stimulate Bak expression based on the findings of Bak promoter luciferase report gene assay and electrophoretic mobility shift assay. ZBP-89-induced Bak increase and ZBP-89 mediated apoptosis were markedly suppressed by Bak siRNA, confirming that Bak was specifically targeted by ZBP-89 to facilitate apoptosis. In conclusion, this study demonstrated that ZBP-89 significantly induced apoptosis of HCC cells via promoting Bak level. PMID- 20850482 TI - Mutagenesis of Propionibacterium acnes and analysis of two CAMP factor knock-out mutants. AB - P. acnes is a skin commensal that is frequently associated with inflammatory diseases such as acne vulgaris. Despite the availability of the genome sequence functional studies on P. acnes are scarce due to a lack of methods for genetic manipulation of this bacterium. Here we present an insertional mutagenesis approach for the inactivation of specific P. acnes genes. The gene of interest can be disrupted and replaced with an erythromycin-resistance cassette by employing homologous recombination. We used this method to generate knock-out mutants of camp2 (PPA0687) and camp4 (PPA1231), encoding CAMP factor homologs with predicted co-hemolytic activities. The successful inactivation of the two genes was confirmed by PCR and Western blotting experiments using specific anti CAMP2/CAMP4 sera. The Deltacamp2 but not the Deltacamp4 mutant exhibited reduced hemolytic activity in the CAMP reaction with sheep erythrocytes, indicating that CAMP2 is the major active co-hemolytic factor of P. acnes. The biological relevance of the CAMP factors remains unclear as disruption of camp2 or camp4 did not significantly alter the transcriptome response of HaCaT cells to P. acnes. The here presented insertional mutagenesis approach will facilitate future studies on P. acnes. PMID- 20850483 TI - A simplified method for detecting pathogenic Yersinia enterocolitica in slaughtered pig tonsils. AB - The aim of this study was to collect preliminary data on the carriage of pathogenic Yersinia enterocolitica in slaughtered pigs in France and to test a simplified method for detecting these strains from tonsils. From January to March 2009, 900 tonsil swabs were taken from pigs at one slaughterhouse in Brittany, France. The swabs were vortexed in 10 ml PSB broth, then 1 ml was added to 9 ml ITC broth. The media were incubated for 48 h at 25 degrees C. The PSB enrichment broth was streaked on CIN plates and the ITC enrichment broth on SSDC plates. In addition to the ISO 10273 method, we also streaked ITC enrichment broth on CIN plates. The plates were incubated for 24h at 30 degrees C, and we then streaked a maximum of four typical colonies per plate onto a plate containing chromogenic medium (YeCM), for the isolation of pathogenic Y. enterocolitica isolates. In parallel, biochemical assays were carried out to confirm the identification of the isolates as Yersinia and to determine biotype. After passage on a YeCM plate and biochemical tests, 380 strains were confirmed to be pathogenic Y. enterocolitica. Finally, with the ISO 10273 method, 9.1% (CI(95%) [5.8-12.4]) of tonsil swabs and 60% (CI(95%) [45.4-74.6]) of the batches were positive. With the ITC-CIN method, 14.0% (CI95% [10.7-17.3]) of the tonsil swabs and 68.9% (CI(95%) [54.3-83.5]) of the batches were positive. Identification as pathogenic Y. enterocolitica was confirmed for 97.0% of the typical colonies obtained on the chromogenic medium, YeCM. The most prevalent biotype was biotype 4 (80.5% of the isolates), followed by biotype 3. This study demonstrates that the ITC-CIN method, followed by streaking on YeCM, may be an effective approach to the isolation of pathogenic Y. enterocolitica from tonsil swabs and the recovery of positive samples. This method is less time-consuming than the ISO 10273 method and reduces the number of biochemical tests required for the confirmation of Yersinia identification, through the use of YeCM. PMID- 20850484 TI - Repressors vs. low- and high-anxious coping styles: EEG differences during a modified version of the emotional Stroop task. AB - In this study of 49 undergraduate university women, those exhibiting a repressive coping style - characterized by defensiveness against negative emotions - were compared to women with low-anxious and high-anxious coping styles during neutral and negative versions of a computerized emotional Stroop task (EST). Using Weinberger, Schwartz, and Davidson's (1979) approach, the present study implemented the Marlowe-Crowne Social Desirability and the Spielberger Trait Anxiety scales for selection. Participants viewed neutral or negative words during the EST but responded to the color of the word. Analysis of continuous EEG recordings for the negative vs. neutral words revealed that the repressor group differed significantly from the other two groups in many aspects but that low- vs. high-anxious groups differed in fewer aspects. Based upon Eysenck and Derakshan's (1997) model, repressor women appear to differ from low- and high anxious women by utilizing an inhibitory process to avoid perceiving low intensity threatening stimuli. PMID- 20850485 TI - Discovery of a steroid 11alpha-hydroxylase from Rhizopus oryzae and its biotechnological application. AB - To overcome the chemically laborious stereo- and regioselective hydroxylation steps in the pharmaceutical production of corticosteroids and progestogens, certain fungal species, e.g. Rhizopus spp. and Aspergillus spp., are employed to perform the 11alpha-hydroxylation of the steroid skeleton, thereby significantly simplifying steroid drug production. Here we report for the first time the identification and expression of a fungal 11alpha-steroid hydroxylase, CYP509C12. The newly identified cytochrome P450, which is one of the 48 putative CYP genes in Rhizopus oryzae, was induced in the fungus by progesterone. By functionally expressing CYP509C12 in recombinant fission yeast, we were able to determine that its substrate spectrum includes progesterone as well as testosterone, 11 deoxycorticosterone, and 11-deoxycortisol, with the hydroxylations taking place predominantly at 11alpha and 6beta positions of the steroid ring system. To increase the 11alpha-hydroxylation activity of CYP509C12 in recombinant fission yeast, its natural redox partner, the R. oryzae NAD(P)H-dependent reductase, was coexpressed. The coexpression improved electron transfer to CYP509C12 and thus an increase in productivity from 246 to 300 MUM hydroxyPg d(-1) was observed, as well as a 7-fold increase of rate of hydroxyprogesterone formation within the linear phase of transformation. This newly developed strain displayed total bioconversion of progesterone into 11alpha-hydroxyprogesterone and small amounts of 6beta-hydroxyprogesterone within the first 6h of incubation with progesterone as substrate, hence demonstrating its potential for biotechnological application. PMID- 20850486 TI - Boosting native promoter activities with non-adjacent response-element multimers. AB - Effective gene therapy requires regulated gene expression and vector safety. We developed a strategy to exponentially increase native promoter activity while retaining inherent regulation by inserting multi-copy response elements (REs) into non-adjacent locations. For the hepatocyte nuclear factor (HNF) 4alpha dependent Hnf1a (MODY3) gene, HNF4alpha stimulation increased from 5- to 90-fold by inserting 3 additional HNF4alpha REs (H4REs). Constructing a promoter with two 4xH4REs 0.25kb apart by duplicating the 4xH4RE fragment increased stimulation to >1000-fold. HNF4alpha-induced protein expression by the duplicate 4xH4RE Hnf1a promoter was comparable to a viral promoter. Converting the two Apolipoprotein C3 (ApoC3) H4REs spaced 0.61kb apart to 4xH4REs achieved a similar result. Increasing spacing to 2.1kb with non-promoter DNA abolished the augmentation. Finally, converting the HNF1alpha RE of the HNF4A (MODY1) P2 promoter to 4xH1RE and adding a second 4xH1RE 0.84kb upstream increased HNF1alpha stimulation from 26- to >200-fold. Deleting intervening DNA to produce 0.23-kb spacing increased stimulation to >500-fold. Spaced multi-copy RE motifs is a novel strategy for engineering promoters that boosts activity far beyond other techniques. Augmentation of three promoters suggests that this approach is potentially applicable to other promoters for gene therapy and might obviate the need for viral promoters. PMID- 20850487 TI - Improved DNA vaccination by skin-targeted delivery using dry-coated densely packed microprojection arrays. AB - HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 +/- 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer. Associated with this efficient delivery of the vaccine into the vicinity of the professional antigen presenting cells, we achieved superior antibody responses and statistically equal protection rate against an HSV-2 virus challenge, when compared with the mice immunized with intramuscular injection using needle and syringe, but with less than 1/10th of the delivered antigen. PMID- 20850489 TI - Acetyl-CoA deficit in brain mitochondria in experimental thiamine deficiency encephalopathy. AB - Several pathologic conditions are known to cause thiamine deficiency, which induce energy shortages in all tissues, due to impairment of pyruvate decarboxylation. Brain is particularly susceptible to these conditions due to its high rate of glucose to pyruvate-driven energy metabolism. However, cellular compartmentalization of a key energy metabolite, acetyl-CoA, in this pathology remains unknown. Pyrithiamine-evoked thiamine deficiency caused no significant alteration in pyruvate dehydrogenase and 30% inhibition of alpha-ketoglutarate dehydrogenase activities in rat whole forebrain mitochondria. It also caused 50% reduction of the metabolic flux of pyruvate through pyruvate dehydrogenase, 78% inhibition of its flux through alpha-ketoglutarate dehydrogenase steps, and nearly 60% decrease of intramitochondrial acetyl-CoA content, irrespective of the metabolic state. State 3 caused a decrease in citrate and an increase in alpha ketoglutarate accumulation. These alterations were more evident in thiamine deficient mitochondria. Simultaneously thiamine deficiency caused no alteration of relative, state 3-induced increases in metabolic fluxes through pyruvate and alpha-ketoglutarate dehydrogenase steps. These data indicate that a shortage of acetyl-CoA in the mitochondrial compartment may be a primary signal inducing impairment of neuronal and glial cell functions and viability in the thiamine deficient brain. PMID- 20850488 TI - Locus coeruleus galanin expression is enhanced after exercise in rats selectively bred for high capacity for aerobic activity. AB - The neuropeptide galanin extensively coexists with norepinephrine in locus coeruleus (LC) neurons. Previous research in this laboratory has demonstrated that unlimited access to activity wheels in the home cage increases mRNA for galanin (GAL) in the LC, and that GAL mediates some of the beneficial effects of exercise on brain function. To assess whether capacity for aerobic exercise modulates this upregulation in galanin mRNA, three heterogeneous rat models were tested: rats selectively bred for (1) high intrinsic (untrained) aerobic capacity (High Capacity Runners, HCR) and (2) low intrinsic aerobic capacity (Low Capacity Runners, LCR) and (3) unselected Sprague-Dawley (SD) rats with and without free access to running wheels for 3 weeks. Following this exercise protocol, mRNA for tyrosine hydroxylase (TH) and GAL was measured in the LC. The wheel running distances between the three models were significantly different, and age contributed as a significant covariate. Both selection and wheel access condition significantly affected GAL mRNA expression, but not TH mRNA expression. GAL was elevated in exercising HCR and SD rats compared to sedentary rats while LCR rats did not differ between conditions. Overall running distance significantly correlated with GAL mRNA expression, but not with TH mRNA expression. No strain differences in GAL or TH gene expression were observed in sedentary rats. Thus, intrinsic aerobic running capacity influences GAL gene expression in the LC only insofar as actual running behavior is concerned; aerobic capacity does not influence GAL expression in addition to changes associated with running. PMID- 20850490 TI - A cross-sectional analysis of reported corporate environmental sustainability practices. AB - The concept of sustainability evolved throughout the 1970s and 1980s, but was formally described by the 27 principles of the Rio Declaration on Environment and Development in 1992. Despite the passage of nearly 20years, to date there are no uniform set of federal rules, regulations, or guidelines specifically governing the environmental aspects of sustainability practices or related requirements in the United States. In this benchmark analysis, we have collected information on the sustainability programs of the five largest US companies in each of the 26 industrial sectors [based on the Forbes Global 2000 through 2009 (n=130)]. For each company, we reviewed the most recent corporate sustainability, citizenship, or responsibility report, limiting our scope to environmental components, if available. Ten criteria were identified and analyzed, including leadership, reporting, external review, certification, and individual components of environmental sustainability programs. With respect to the prevalence of sustainability components between various business sectors, we found that the Drugs and Biotechnology (87%), Household and Personal Products (87%) and Oil and Gas Operations (87%) industries had the most comprehensive environmental sustainability programs. Using the nine components of environmental sustainability as a benchmark, we identified four key components as the characteristics of the most comprehensive environmental sustainability programs. These were (1) empowering leadership with a commitment to sustainability (80%), (2) standardized reporting (87%), (3) third-party evaluation of the sustainability programs (73%), and (4) obtaining ISO 14001 certification (73%). We found that many firms shaped their own definition of sustainability and developed their associated sustainability programs based on their sector, stakeholder interests, products or services, and business model. We noted an emerging area that we have called product sustainability - one in which toxicologists and environmental scientists can play a vital role helping to ensure that a manufactured item will indeed be considered acceptable for distribution now, as well as in the coming years. Numerous examples or case studies are presented. PMID- 20850491 TI - A knowledge-based search engine to navigate the information thicket of nanotoxicology. AB - The risk assessment of nano-sized materials (NM) currently suffers from great uncertainties regarding their putative toxicity for humans and the environment. An extensive amount of the respective original research literature has to be evaluated before a targeted and hypothesis-driven Environmental and Health Safety research can be stipulated. Furthermore, to comply with the European animal protection legislation in vitro testing has to be preferred whenever possible. Against this background, there is the need for tools that enable producers of NM and risk assessors for a fast and comprehensive data retrieval, thereby linking the 3Rs principle to the hazard identification of NM. Here we report on the development of a knowledge-based search engine that is tailored to the particular needs of risk assessors in the area of NM. Comprehensive retrieval of data from studies utilising in vitro as well as in vivo methods relying on the PubMed database is presented exemplarily with a titanium dioxide case study. A fast, relevant and reliable information retrieval is of paramount importance for the scientific community dedicated to develop safe NM in various product areas, and for risk assessors obliged to identify data gaps, to define additional data requirements for approval of NM and to create strategies for integrated testing using alternative methods. PMID- 20850492 TI - l-histidine induces state-dependent memory deficit in mice mediated by H(1) receptor. AB - This study investigated the role of H(1) receptor in the state-dependent memory deficit induced by l-histidine (LH) in mice using Trial 1/2 protocol in the elevated plus-maze (EPM). The test was performed for two consecutive days: Trial 1 (T1) and Trial 2 (T2). Before both trials, mice received a combined injection i.p. of saline+saline (SAL/SAL), 500 mg/kg L-histidine+saline (LH/SAL), 500 mg/kg L-histidine+16 mg/kg chlorpheniramine (LH/CPA) or saline+16 mg/kg chlorpheniramine (SAL/CPA). The trials were performed in the EPM 10 min after the last injection. Each animal was placed in the center of the maze facing the open arm and had five minutes to explore it. On both days, test sessions were videotaped. The behavioral measures were scored from videotape. Data were analyzed based on Analysis of Variance (ANOVA) and the Fisher's LSD test. The data showed no effects on anxiety since there was no difference between the SAL/SAL and the other groups in Trial 1, respectively, open arm entries (OAE), open arm time (OAT) and their percentages (%OAE and %OAT). During Trial 2, OAE, OAT, %OAE and %OAT were reduced in mice treated with SAL/SAL, LH/CPA and SAL/CPA, while the group LH/SAL did not show any difference in these measures. No significant changes were observed in enclosed arm entries (EAE), an EPM index of general exploratory activity. Thus, it can be suggested that LH induces emotional memory deficit and the treatment with chlorpheniramine was able to revert this effect, suggesting this action of LH was mediated by the H(1) receptor. PMID- 20850493 TI - Risperidone-induced hiccups in a youth with Down syndrome. PMID- 20850494 TI - Grass pea and neurolathyrism: farmers' perception on its consumption and protective measure in North Shewa, Ethiopia. AB - Neurolathyrism in Ethiopia is caused by food dependency on grass pea (Lathyrus sativus L.). In the study area, a large proportion of the farmers are growing grass pea since it can withstand harsh environments. Socio-economic factors (poverty; lack of money to buy other food legumes) and environmental problems (such as water logging and frost hazards) influence consumption of grass pea. Most of the respondents have the idea that some chemical contained in grass pea causes a health problem. Different processing and preparation methods are used to prepare grass pea into different food forms. The major processing methods include washing and soaking, as the farmers apply these methods mainly because they assume that the chemical that causes lathyrism, scientifically known as beta-ODAP (beta-N-oxalyl-L-alpha,beta-diaminopropionic acid) is reduced through washing and soaking. The farmers adopt different strategies to avoid the problem of lathyrism such as avoiding consumption of grass pea in the form that they suspect to cause the problem, blending/mixing with other crops, applying different processing/detoxification methods. Since grass pea is consumed with a fear of lathyrism, future research should concentrate either on developing grass pea varieties with safe level of beta-ODAP content or improving the traditional/indigenous processing methods. PMID- 20850495 TI - Involvement of the epidermal growth factor receptor in Pb2+-induced activation of cPLA2/COX-2 genes and PGE2 production in vascular smooth muscle cells. AB - Lead (Pb2+) is one of the most common heavy metal pollutants, which can cause chronic cardiovascular diseases. To clarify the mechanism by which Pb2+ induces inflammatory reactions, we examined the expression of inflammatory genes including encoding cyclooxygenase-2 (COX-2), cytosolic phospholipase A2 (cPLA2), and their down stream product prostaglandin E2 (PGE2) in CRL1999 cells that is a vascular smooth muscle cell line from human aorta. The expression of COX-2/cPLA2 genes and PGE2 secretion was increased markedly after cells were exposed to 1 MUM Pb2+. PD098059, a MEK inhibitor, suppressed Pb2+-mediated inflammatory reactions; this indicates the involvement of the phosphorylation of extracellular signal regulated kinases 1 and 2 (ERK1/2). Furthermore, Pb2+-induced activation of the COX-2/cPLA2 genes was inhibited by both epidermal growth factor receptor (EGFR) inhibitors (AG1478 and PD153035) and EGFR siRNA. Short-term stimulation with Pb2+ induced EGFR phosphorylation at the Tyr residue (position, 1173). Importantly, overexpression of EGFR resulted in a significant potentiation effect on Pb2+ induced gene expression. Taken together, our results indicate that 1 MUM Pb2+ can induce PGE2 secretion by upregulating the transcription of COX-2/cPLA2 genes. EGFR is the key target in the plasma membrane responsible for transmitting Pb2+ signals in order to trigger downstream inflammatory cascades. PMID- 20850496 TI - Protease inhibitors and proteolytic signalling cascades in insects. AB - Proteolytic signalling cascades control a wide range of physiological responses. In order to respond rapidly, protease activity must be maintained at a basal level: the component zymogens must be sequentially activated and actively degraded. At the same time, signalling cascades must respond precisely: high target specificity is required. The insects have a wide range of trapping- and tight-binding protease inhibitors, which can regulate the activity of individual proteases. In addition, the interactions between component proteases of a signalling cascade can be modified by serine protease homologues. The suicide inhibition mechanism of serpin family inhibitors gives rapid turnover of both protease and inhibitor, but target specificity is inherently broad. Similarly, the TEP/macroglobulins have extremely broad target specificity, which suits them for roles as hormone transport proteins and sensors of pathogenic virulence factors. The tight-binding inhibitors, on the other hand, have a lock-and-key mechanism capable of high target specificity. In addition, proteins containing multiple tight-binding inhibitory domains may act as scaffolds for the assembly of signalling complexes. Proteolytic cascades regulated by combinations of different types of inhibitor could combine the rapidity of suicide-inhibitors with the specificity lock-and-key inhibitors. This would allow precise control of physiological responses and may turn out to be a general rule. PMID- 20850497 TI - PKCdelta is a positive regulator of chondrogenesis in chicken high density micromass cell cultures. AB - We aimed to elucidate the role of the Ca-independent PKC isoenzyme PKCdelta in the regulation of spontaneous in vitro chondrogenesis occurring in a 6-day-long culturing period in chicken limb bud-derived high density cell cultures (HDC). PKCdelta expression and activity were detectable throughout the entire culturing period with a peak on days 2 and 3, when most of the chondroblasts differentiate. To inhibit the activity of PKCdelta, either the natural compound rottlerin was transiently applied to the culture medium of HDC in 2.5, 5 or 10 MUM concentrations, or gene silencing was performed by using PKCdelta shRNA. Rottlerin significantly reduced the overall PKC activity in enzyme activity assays of cell-free samples of untreated control HDC, probably via the inhibition of PKCdelta. On the contrary, we were unable to detect any consistent change of PKC enzyme activity assayed in samples of HDC treated with rottlerin during culturing. PKCdelta gene silencing resulted in a significantly lower PKC activity. Both rottlerin and PKCdelta shRNA caused a severe reduction in cartilage formation, furthermore protein and phospho-protein levels of Sox9, the key transcription factor of chondrogenesis, were also significantly decreased. Rottlerin lowered, while PKCdelta gene silencing elevated the phosphorylation status of ERK1/2. Our data suggest that PKCdelta stimulates chondrogenesis via influencing Sox9 and ERK1/2 phosphorylation, but the inhibition of cartilage formation in the rottlerin-treated HDC is probably PKCdelta independent and rottlerin might have different effects when applied to cells or to an in vitro enzyme activity assay. PMID- 20850498 TI - "Protoisochores" in certain archaeal species are formed by replication-associated mutational pressure. AB - This report shows that isochore-like structures can be found not only in warm blooded animals, some reptiles, fishes and yeast, but also in certain archaeal species. In perfectly shaped isochore-like structures (in "protoisochores") from Sulfolobus acidocaldarius and Thermofilum pendens genomes the difference in 3GC levels between genes from different "protoisochores" is about 30%. In these archaeal species GC-poor "protoisochores" are situated near the origin of replication, while GC-rich "protoisochores" are situated near the terminus of replication. There is a strong linear dependence between position of a gene and its 3GC level in S. acidocaldarius (an average difference in 3GC per 100,000 base pairs is equal to 3.6%). Detailed analyses of nucleotide usage biases in genes from leading and lagging strands led us to the suggestion that 3GC in genes situated near terminus of replication grows due to higher rates of thymine oxidation producing T to C transitions in lagging strands. PMID- 20850499 TI - Proteomic study of calpain interacting proteins during skeletal muscle aging. AB - Aging is associated with a progressive and involuntary loss of muscle mass also known as sarcopenia. This condition represents a major public health concern. Although sarcopenia is well documented, the molecular mechanisms of this condition still remain unclear. The calcium-dependent proteolytic system is composed of calcium-dependent cysteine proteases named calpains. Calpains are involved in a large number of physiological processes such as muscle growth and differentiation, and pathological conditions such as muscular dystrophies. The aim of this study was to determine the involvement of this proteolytic system in the phenotype associated with sarcopenia by identifying key proteins (substrates or regulators) interacting with calpains during muscle aging. Immunoprecipitations coupled with proteomic analyses and protein identification by mass spectrometry have been undertaken. Reverse co-immunoprecipitation, cellular colocalisation by confocal microscopy and calpain-dependent in vitro proteolysis of several of the identified proteins have been also carried out. We identified ATP synthase subunit alpha and alpha actinin 3 as key partners of calpains during muscle aging. Such interactions would suggest that calpains are implicated in many processes altered during aging including cytoskeletal disorganisation and mitochondrial dysfunction. PMID- 20850500 TI - Insights into the fatty acid chain length specificity of the carboxylesterase PA3859 from Pseudomonas aeruginosa: A combined structural, biochemical and computational study. AB - The open reading frame PA3859 of Pseudomonas aeruginosa encodes an intracellular carboxylesterase belonging to a group of microbial enzymes (EC 3.1.1.1) that catalyze the hydrolysis of aliphatic and aromatic esters with a broad substrate specificity. With few exceptions, for this class of enzymes, belonging to the alpha/beta-hydrolase fold superfamily, very little information is available regarding their biochemical activity and in vivo function. The X-ray crystal structure of recombinant PA3859 has been determined for two crystal forms (space groups P2(1) and P2(1)2(1)2). The kinetic properties of the enzyme were studied using p-nitrophenyl esters as substrates and data fitted to a surface dilution mixed micelle kinetic model. Enzymatic assays and computational docking simulations, pinpointed the enzyme's preference for esters of palmitic and/or stearic acids and provided insights into the enzyme-substrate favorable binding modes. PMID- 20850501 TI - Differential involvement of rat sperm choline glycerophospholipids and sphingomyelin in capacitation and the acrosomal reaction. AB - Rat spermatozoa main lipid classes and their fatty acids were studied to assess their possible changes in capacitation and the acrosomal reaction (AR), induced in vitro. Capacitation-associated protein tyrosine phosphorylation, and the efflux of 30% of the total cholesterol from gametes to the medium, took place concomitantly with the release of a similar percentage, i.e., a larger amount, of the total phospholipid, mostly after hydrolysis of the major choline glycerophospholipids (CGP). Main medium lipid metabolites after capacitation were lyso-CGP and polyenoic fatty acids typical of CGP (22:4n-9, 22:5n-6), as free fatty acids (FFA). The AR, induced by a calcium ionophore, resulted in further phospholipid loss, but the produced metabolites remained in the gametes. CGP decrease in AR accounted for some additional FFA and lyso-CGP, but mostly for (22:5n-6-rich) diglycerides. Hydrolysis of sphingomyelins (SM) to ceramides also occurred, mostly affecting species with very long chain polyenoic fatty acids. Quantitatively, CGP and SM were the lipid classes decreasing the most after capacitation and AR, respectively. The massive cholesterol and phospholipid loss from the gametes during capacitation is thus associated with protein phosphorylation, a function that has been located to the sperm tail. The lipid metabolites produced during AR, by accumulating in the gamete heads, could be implicated in sperm-oocyte interactions. PMID- 20850502 TI - Reduced-intensity conditioning with Fludarabin, oral Busulfan, and thymoglobulin allows long-term disease control and low transplant-related mortality in patients with hematological malignancies. AB - OBJECTIVE: The development of reduced-intensity conditioning regimens rather than myeloablative regimens for allogeneic stem cell transplantation has led to decreased treatment-related mortality and increased use of this treatment modality, especially in older patients with hematological malignancies. No randomized controlled trials have been performed resulting in determining effectiveness on phase II studies, which rarely report on long-term survival. MATERIALS AND METHODS: In an attempt to address this limitation, we analyzed a single-center cohort of 100 consecutive patients with hematological malignancies undergoing allogeneic stem cell transplantation from a human leukocyte antigen matched related donor with median follow-up of 60 months. The reduced-intensity conditioning regimen consisted of oral Busulfan, rabbit anti-thymocyte globulin, and Fludarabin. RESULTS: Median age was 50 years (range, 18-64 years). The incidences of acute and chronic graft-vs.-host disease were 43% and 81%, respectively. The probability of nonrelapse mortality at 1 and 5 years was 15% and 25%, respectively. Nonrelapse mortality was adversely associated with acute graft-vs.-host disease (hazard ratio = 6; p = 0.0002). Of the 52 patients with measurable disease, 37 (71%) achieved a response. Relapse/progression occurred at a median of 11 months (range 1-52 months) in 21 patients, for a cumulative incidence of 22%. The probability of overall survival and progression-free survival at 5 years were 60% and 54%, respectively. Overall survival and progression-free survival were favorably influenced by having had previous autologous stem cell transplantation and a low CD34(+) cell dose. Overall survival, progression-free survival, and nonrelapse mortality improved over time in this cohort of patients. CONCLUSIONS: These results are encouraging for populations different in term of age, diagnosis, and disease status. PMID- 20850503 TI - NGF protects dorsal root ganglion neurons from oxaliplatin by modulating JNK/Sapk and ERK1/2. AB - The involvement of the Mitogen-Activated Protein Kinases (MAPKs) family in platinum derivative-induced peripheral neuropathy has already been demonstrated. In particular, it has been evidenced that in Dorsal Root Ganglion (DRG) neurons prolonged exposure to oxaliplatin (OHP) induces early activation of p38 and ERK1/2, which mediate neuronal apoptosis, while the neuroprotective action of JNK/Sapk is downregulated by the drug treatment. In this study, the exposure of OHP-treated neurons to a neuroprotective stimulus, represented by a high dose of NGF, counteracts OHP-induced neuronal mortality. This effect was achieved by restoring the MAPK activation existing in untreated control cells. Increased viability occurred also after the administration of retinoic acid (RA), a pro differentiative agent able to activate both JNK/Sapk and ERK1/2. The use of specific chemical inhibitors of MAPKs confirms the importance of this class of proteins for the neuroprotective pathway, since they reverse the protective effect. In summary, our findings assess the validity of MAPKs as the target of neuroprotective therapies during chemotherapeutic treatment. Moreover they also describe a double role for ERK1/2, depending on cellular stimulation, since it mediates neuronal apoptosis after OHP exposure. However, it is also important, as is JNK/Sapk, in preserving the correct cellular differentiation that is pivotal for neuronal survival. PMID- 20850504 TI - Fos proteins are not prerequisite for osmotic induction of vasopressin transcription in supraoptic nucleus of rats. AB - While it is well known that osmotic stimulation induces the expression of Fos family members in the supraoptic nucleus (SON), it is unclear whether the induced protein products are involved in the regulation of the gene transcription of arginine vasopressin (AVP). In the present study, we examined the in vivo correlation between changes in AVP gene transcription and expression of the various Fos family members in the SON after acute osmotic stimuli. The data demonstrated that the peak of AVP transcription (measured by intronic in situ hybridization) observed 15min after an injection of hypertonic saline preceded the expression of Fos proteins, which became detectable at 30min and peaked at 120min. Electrophoretic mobility shift assay showed that the expressed Fos proteins bound to the composite AP-1/CRE-like site in the AVP promoter. These data suggest that Fos proteins in the SON induced by acute osmotic stimuli could affect AVP gene transcription by binding to the AVP promoter, but they are not prerequisite for the induction of AVP gene transcription. PMID- 20850505 TI - Identification of high risk DISC1 protein structural variants in patients with bipolar spectrum disorder. AB - In a large Scottish pedigree, a balanced translocation t (1;11)(q42.1;q14.3) disrupting the DISC1 and DISC2 genes segregates with major mental illness, including schizophrenia and depression. A frame-shift carboxyl-terminal deletion was reported in DISC1 in an American family with schizophrenia, but subsequently found in two controls. Herein, we test one hypothesis utilizing a large scale case-control mutation analysis: uncommon DISC1 variants are associated with high risk for bipolar spectrum disorder. We have analyzed the regions of likely functional significance in the DISC1 gene in 504 patients with bipolar spectrum disorder and 576 ethnically similar controls. Five patients were heterozygous for ultra-rare protein structural variants not found in the 576 controls (p=0.02, one sided Fisher's exact test) and shown to be ultra-rare by their absence in a pool of 10,000 control alleles. In our sample, ultra-rare (private) protein structural variants in DISC1 are associated with an estimated attributable risk of about 0.5% in bipolar spectrum disorder. These data are consistent with: (i) the high frequency of depression in the large Scottish family with a translocation disrupting DISC1; (ii) linkage disequilibrium analysis demonstrating haplotypes associated with relatively small increases in risk for bipolar disorder (<3-fold odds ratio). The data illustrate how low/moderate risk haplotypes that might be found by the HapMap project can be followed up by resequencing to identify protein structural variants with high risk, low frequency and of potential clinical utility. PMID- 20850506 TI - Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro. AB - The hippocampus is a prominent structure to study mechanisms of learning and memory at the cellular level. Long-term potentiation (LTP) as well as long-term depression (LTD) are the major cellular models which could underlie learning and memory formation. LTP and LTD consist of at least two phases, an early protein synthesis-independent transient stage (<4 h; E-LTP, E-LTD) as well as a prolonged phase (>4 h; L-LTP, L-LTD) requiring the synthesis of new proteins. It is known that during E-LTP the further induction of longer lasting LTP is precluded. However, if E-LTP is transformed into L-LTP, the same synapses now allow the induction of LTP again. We reproduced the LTP-results first and then investigated whether hippocampal LTP or LTD also prevents the establishment of subsequent LTD induction in the same synaptic input. We show that the prior induction of LTP or LTD does not prevent a short-term depression (STD) but occludes LTD in apical dendrites of CA1 neurons in hippocampal slices in vitro during the early phase of LTP or LTD. However, LTD can again be induced in addition to STD after the establishment of L-LTP or L-LTD, that is about 4 h after the induction of the first event in the same synaptic input. We suggest that the neuronal input preserves the capacity for STD immediately after an initial potentiation or depression, but for the onset of additional longer lasting LTD in the same synaptic input, the establishment of the late plasticity form of the preceding event is critical. PMID- 20850507 TI - Working memory performance and thalamus microstructure in healthy subjects. AB - Research on the neural basis of working memory (WM) has generally focused on cortical regions, specifically frontal and parietal areas. Comparatively, evidence of a possible involvement of deep gray matter structures, that are parts of cortico-cortical circuits linking anterior and posterior cortical areas, is far less clear. The goal of the present study is to test the hypothesis that individual structural variations within deep gray matter structures may affect the cortical networks involved in WM. To this aim, a large sample (n=181) of healthy subjects underwent a high-resolution structural magnetic resonance imaging (MRI) and a diffusion tensor imaging (DTI) scan protocol. Data of micro- (mean diffusivity, MD) and macro- (volume) structural variations of six bilateral deep gray matter structures (thalamus, caudate nucleus, putamen, hippocampus, amygdala and pallidum) and lateral ventriculi volume were analyzed in association with score in a WM (the so-called n-back task) and other neuropsychological tasks. Results showed that increased MD of bilateral thalami was the only structural parameter that significantly correlated with reduced WM performance. In particular, a voxel-by-voxel analysis revealed that the greater percentage of voxels showing significant anticorrelation between WM score and MD values were localized in those thalamic nuclei projecting to prefrontal and posterior parietal cortices. Results highlight the specific involvement of thalamus microstructure, not volume, in modulating WM performance, possibly by regulating the connections among cortical areas that are recruited during WM tasks. PMID- 20850508 TI - From the vascular microenvironment to neurogenesis. AB - In response to injury, the function of the adult mammalian central nervous system (CNS) is repaired by angiogenesis and neurogenesis. The proliferation, differentiation and migration of the neural progenitor cells (NPCs) are regulated by several components of the vascular microenvironment within the neural stem cell niche. Vascular endothelial cells (VECs), which make up blood vessels, as well as extracellular components, affect neurogenesis directly via contacting with NPCs. Additionally, soluble factors from the vascular system that are released into the CNS enhance neurogenesis in the form of paracrine signaling. The purpose of this mini-review is to highlight the roles of the vascular microenvironment as a mediator in promoting neurogenesis. PMID- 20850509 TI - Variation in aggressive behaviour in the poeciliid fish Brachyrhaphis episcopi: population and sex differences. AB - Aggression is often positively correlated with other behavioural traits such as boldness and activity levels. Comparisons across populations can help to determine factors that promote the evolution of such traits. We quantified these behaviours by testing the responses of wild-caught poeciliid fish, Brachyrhaphis episcopi, to mirror image stimuli. This species occurs in populations that experience either high or low levels of predation pressure. Previous studies have shown that B. episcopi from low predation environments are less bold than those that occur with many predators. We therefore predicted that fish from high predation populations would be more aggressive and more active than fish from low predation populations. However, we found the opposite - low predation fish approached a mirror and a novel object more frequently than high predation fish suggesting that 'boldness' and aggression were higher in low predation populations, and that population-level boldness measures may vary depending on context. When tested individually, low predation fish inspected their mirror image more frequently. Females, but not males, from low predation sites were also more aggressive towards their mirror image. Variation in female aggression may be driven by a trade-off between food availability and predation risk. This suggests that the relationship between aggression and boldness has been shaped by adaptation to environmental conditions, and not genetic constraints. PMID- 20850510 TI - Seasonal variation of reproductive success under female philopatry and male biased dispersal in a common vole population. AB - Variation of reproductive success, an important determinant of the opportunity for sexual selection, is an outcome of competition within one sex for mating with members of the other sex. In promiscuous species, males typically compete for access to females, and their reproductive strategies are strongly related to the spatial distribution of females. I used 10 microsatellite loci and the mtDNA control region to determine seasonal differences in the reproductive success of males and females of the common vole (Microtus arvalis), one of the most numerous mammals in Europe. The sex-related spatial structure and bias in dispersal between genders were also assessed. Standardized variance of the reproductive success of females did not vary seasonally due to the continuity of female philopatry throughout the breeding season and to the constancy of the number of females reproducing successfully in each season. The males are the dispersing sex, undergoing both natal and breeding dispersal. Their standardized variance of reproductive success was significantly higher than that for females in July, when only two males monopolized 80% of the females in the population and when variance of male reproductive success was highest (I(m)=7.70). The seasonally varying and high standardized variance of male reproductive success may be explained by male male competition for matings, coupled with seasonal changes in the age structure of the population. PMID- 20850511 TI - An expanded role for the dorsal auditory pathway in sensorimotor control and integration. AB - The dual-pathway model of auditory cortical processing assumes that two largely segregated processing streams originating in the lateral belt subserve the two main functions of hearing: identification of auditory "objects", including speech; and localization of sounds in space (Rauschecker and Tian, 2000). Evidence has accumulated, chiefly from work in humans and nonhuman primates, that an antero-ventral pathway supports the former function, whereas a postero-dorsal stream supports the latter, i.e processing of space and motion-in-space. In addition, the postero-dorsal stream has also been postulated to subserve some functions of speech and language in humans. A recent review (Rauschecker and Scott, 2009) has proposed the possibility that both functions of the postero dorsal pathway can be subsumed under the same structural forward model: an efference copy sent from prefrontal and premotor cortex provides the basis for "optimal state estimation" in the inferior parietal lobe and in sensory areas of the posterior auditory cortex. The current article corroborates this model by adding and discussing recent evidence. PMID- 20850513 TI - Current focusing sharpens local peaks of excitation in cochlear implant stimulation. AB - Cochlear implant (CI) users' spectral resolution is limited by the number of implanted electrodes, interactions between the electrodes, and the underlying neural population. Current steering has been proposed to increase the number of spectral channels beyond the number of physical electrodes, however, electric field interactions may limit CI users' access to current-steered virtual channels (VCs). Current focusing (e.g tripolar stimulation) has been proposed to reduce current spread and thereby reduce interactions. In this study, current steering and current focusing were combined in a four-electrode stimulation pattern, i.e quadrupolar virtual channels (QPVCs). The spread of excitation was measured and compared between QPVC and Monopolar VC (MPVC) stimuli using a forward masking task. Results showed a sharper peak in the excitation pattern and reduced spread of masking for QPVC stimuli. Results from the forward masking study were compared with a previous study measuring VC discrimination ability and showed a weak relationship between spread of excitation and VC discriminability. The results suggest that CI signal processing strategies that utilize both current steering and current focusing might increase CI users' functional spectral resolution by transmitting more channels and reducing channel interactions. PMID- 20850512 TI - Endbulb synaptic depression within the range of presynaptic spontaneous firing and its impact on the firing reliability of cochlear nucleus bushy neurons. AB - The majority of auditory nerve fibers exhibit prominent spontaneous activity in the absence of sound. More than half of all auditory nerve fibers in CBA mice have spontaneous firing rates higher than 20 spikes/s, with some fibers exceeding 100 spikes/s. We tested whether and to what extent endbulb synapses are depressed by activity between 10 and 100 Hz, within the spontaneous firing rates of auditory nerve fibers. In contrast to rate-dependent depression seen at rates >100 Hz, we found that the extent of depression was essentially rate-independent (~35%) between 10 and 100 Hz. Neither cyclothiazide nor gamma-d-glutamylglycine altered the rate-independent depression, arguing against receptor desensitization and/or vesicle depletion as major contributors for the depression. When endbulb synaptic transmission was more than half-blocked with the P/Q Ca(2+) channel blocker omega-agatoxin IVA, depression during 25 and 100 Hz trains was significantly attenuated, indicating P/Q Ca(2+) channel inactivation may contribute to low frequency synaptic depression. Following conditioning with a 100 Hz Poisson train, the EPSC paired-pulse ratio was increased, suggesting a reduced release probability. This in turn should reduce subsequent depletion based synaptic depression at higher activation rates. To probe whether this conditioning of the synapse improves the reliability of postsynaptic responses, we tested the firing reliability of bushy neurons to 200 Hz stimulation after conditioning the endbulb with a 25 Hz or 100 Hz stimulus train. Although immediately following the conditioning train, bushy cells responded to minimal suprathreshold stimulation less reliably, the firing reliability eventually settled to the same level (<50%) regardless of the presence or absence of the preconditioning. However, when multiple presynaptic fibers were activated simultaneously, the postsynaptic response reliability did not drop significantly below 90%. These results suggest that single endbulb terminals do not reliably trigger action potentials in bushy cells under "normal" operating conditions. We conclude that the endbulb synapses are chronically depressed even by low rates of spontaneous activity, and are more resistant to further depression when challenged with a higher rate of activity. However, there seems to be no beneficial effect as assessed by the firing reliability of postsynaptic neurons for transmitting information about higher rates of activity. PMID- 20850514 TI - Vaccinium arctostaphylos, a common herbal medicine in Iran: molecular and biochemical study of its antidiabetic effects on alloxan-diabetic Wistar rats. AB - AIM OF THE STUDY: The purpose of this study was to define antidiabetic effects of fruit of Vaccinium arctostaphylos L. (Ericaceae) which is traditionally used in Iran for improving of health status of diabetic patients. MATERIALS AND METHODS: Firstly, we examined the effect of ethanolic extract of Vaccinium arctostaphylos fruit on postprandial blood glucose (PBG) after 1, 3, 5, 8, and 24h following a single dose administration of the extract to alloxan-diabetic male Wistar rats. Also oral glucose tolerance test was carried out. Secondly, PBG was measured at the end of 1, 2 and 3 weeks following 3 weeks daily administration of the extract. At the end of treatment period the pancreatic INS and cardiac GLUT-4 mRNA expression and also the changes in the plasma lipid profiles and antioxidant enzymes activities were assessed. Finally, we examined the inhibitory activity of the extract against rat intestinal alpha-glucosidase. RESULTS: The obtained results showed mild acute (18%) and also significant chronic (35%) decrease in the PBG, significant reduction in triglyceride (47%) and notable rising of the erythrocyte superoxide dismutase (57%), glutathione peroxidase (35%) and catalase (19%) activities due to treatment with the extract. Also we observed increased expression of GLUT-4 and INS genes in plant extract treated Wistar rats. Furthermore, in vitro studies displayed 47% and 56% inhibitory effects of the extract on activity of intestinal maltase and sucrase enzymes, respectively. CONCLUSIONS: Findings of this study allow us to establish scientifically Vaccinium arctostaphylos fruit as a potent antidiabetic agent with antihyperglycemic, antioxidant and triglyceride lowering effects. PMID- 20850515 TI - Anti-oxidation activity of the crude polysaccharides isolated from Polygonum cillinerve (Nakai) Ohwi in immunosuppressed mice. AB - AIM OF THE STUDY: Polygonum cillinerve (Nakai) Ohwi is commonly used in China for over 2000 years. Previous research has shown that the crude polysaccharides extracted from Polygonum cillinerve (Nakai) Ohwi (PCCP) have the scavenging free radicals and anti-tumor activities in vitro. In present study, PCCP were further approached the perspective of their anti-oxidation in immunosuppressed mice. METHODS AND MATERIALS: ICR mice were treated firstly with cyclophosphamide (CY, 150 mg/kg), 1 day later, treated with different dosages of PCCP or saline solution once daily for 21 days. Twenty-four hours later for the last drug administration, the animals were weighed, and then killed by decapitation. The liver, spleen, and thymus indices were investigated, and the biochemical parameters were evaluated for various tissues (liver, heart, and kidney). RESULTS: The administration of PCCP with gavage was able to overcome the cyclophosphamide-induced immunosuppression, and significantly to raise the TOC, CAT, SOD, and GSH-Px level. It also raised the liver, spleen, and thymus indices, and decreased the MDA level in mice. CONCLUSIONS: PCCP possess the pronounced free radical-scavenging and antioxidant activities, and could play an important role in the prevention of oxidative damage in immunological system. PMID- 20850516 TI - Respiratory chain cysteine and methionine usage indicate a causal role for thiyl radicals in aging. AB - The identification of longevity-related structural adaptations in biological macromolecules may yield relevant insights into the molecular mechanisms of aging. In screening fully sequenced animal proteomes for signals associated with longevity, it was found that cysteine depletion in respiratory chain complexes was the by far strongest predictor on the amino acid usage level to co-vary with lifespan. This association was though restricted to aerobic animals, whereas anaerobic animals showed variable cysteine accumulation. By contrast, methionine accumulation, a prominent feature of mitochondrially encoded proteins affording competitive antioxidant protection, was not predictive of longevity, but rather paralleled aerobic metabolic capacity. Hence, the easily oxidized sulfur containing amino acids cysteine (a thiol) and methionine (a thioether) show doubly diametrical behaviour in two central paradigms of respiratory oxidative stress. From this comparison, it is concluded that only the one-electron oxidation of thiols to thiyl radicals contributes to aging, whereas other forms of sulfur oxidation, especially even-electron oxidation of both thiols and thioethers, are less critically involved, presumably as their consequences may be much more easily repaired. Thiyl radicals may yet act as chain-transfer agents to entail an irreversible intramembrane cross-linking ("plastination") of some of the a priori most hydrophobic and insoluble proteins known, the respiratory chain complexes. PMID- 20850517 TI - Imaging analysis of the gliadin direct effect on tight junctions in an in vitro three-dimensional Lovo cell line culture system. AB - Tight junctions play a pivotal role in maintaining the integrity of the intestinal barrier. Their alteration is involved in the pathogenesis of celiac disease. Our aim was to investigate the gliadin effect on the tight junction proteins in an in vitro three-dimensional cell culture model through imaging analyses. Lovo multicellular spheroids were treated with enzymatically digested (PT) gliadin 500 MUg/mL and its effect on actin, occludin and zonula occludens-1, was evaluated by means of confocal laser microscopy, transmission electron microscopy and image capture analysis. Compared to untreated spheroids, PT gliadin-treated ones showed enlargement of the paracellular spaces (9.0+/-6.9 vs. 6.2+/-1.7 nm, p<0.05) at transmission electron microscopy and tight junction protein alterations at confocal microscopy and image analyses. In untreated cell cultures thickness of the fluorescence contour of actin, zonula occludens-1 and occludin appeared significantly larger and more intense than in the treated ones. In occludin planimetric analysis the lengths of the integral uninterrupted cellular contour appeared longer in untreated than in PT-gliadin treated spheroids (71.8+/-42.8 vs. 23.4+/-25.9 MUm, p<0.01). Our data demonstrated that tight junction proteins are directly damaged by gliadin as shown by means of quantitative imaging analysis. PMID- 20850518 TI - Effects of 4-tert-octylphenol on the testes and seminal vesicles in adult male bank voles. AB - The present study was designed to evaluate the effects of 4-tert-octylphenol (OP) on male testes and seminal vesicles of bank vole. Adult males kept under long or short photoperiod were orally administered OP (200mg/kg bw) for 30 or 60 days. Treatment for 30 days had no discernible effect on the parameters examined. Treatment for 60 days adversely influenced weights and histological structure of the testes and seminal vesicles. In these tissues, expression of 3beta hydroxysteroid dehydrogenase and androgen receptor and testosterone levels were reduced, whereas expression of aromatase and estrogen receptor alpha and estradiol levels were increased. The alterations were more evident in voles kept in long photoperiod. Taken together, it is suggested that adverse changes in bank vole reproductive tissues induced by long-term OP-exposure result from disturbed androgen and estrogen synthesis and action. Moreover, there might be a subtle difference in the sensitivity to OP between voles kept in different light conditions. PMID- 20850520 TI - Pregnancy loss and eye malformations in offspring of F344 rats following gestational exposure to mixtures of regulated trihalomethanes and haloacetic acids. AB - Chlorination of drinking water yields hundreds of disinfection by-products (DBPs). Among the DBPs, four trihalomethanes (THMs; chloroform, bromodichloromethane, chlorodibromomethane, bromoform) and five haloacetic acids (HAAs; chloroacetic, dichloroacetic, trichloroacetic, bromoacetic, and dibromoacetic acid) are U.S. EPA regulated. We assessed the combined toxicity of these DBPs. F344 rats were treated with mixtures of the four THMs (THM4), the five HAAs (HAA5), or nine DBPs (DBP9; THM4+HAA5). Mixtures were administered in 10% Alkamuls((r)) EL-620 daily by gavage on gestation days 6-20. Litters were examined postnatally. All three mixtures caused pregnancy loss at >= 613 MUmol/kg/day. In surviving litters, resorption rates were increased in groups receiving HAA5 at 615 MUmol/kg/day and DBP9 at 307 MUmol/kg/day. HAA5 caused eye malformations (anophthalmia, microphthalmia) at >= 308 MUmol/kg/day. Thus, both HAAs and THMs contributed to DBP9-induced pregnancy loss. The presence of THMs in the full mixture, however, appeared to reduce the incidence of HAA-induced eye defects. PMID- 20850519 TI - Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity? AB - Human exposures to organophosphate insecticides are ubiquitous. Although regarded as neurotoxicants, increasing evidence points toward lasting metabolic disruption from early-life organophosphate exposures. We gave neonatal rats chlorpyrifos, diazinon or parathion in doses devoid of any acute signs of toxicity, straddling the threshold for barely-detectable cholinesterase inhibition. Organophosphate exposure during a critical developmental window altered the trajectory of hepatic adenylyl cyclase/cyclic AMP signaling, culminating in hyperresponsiveness to gluconeogenic stimuli. Consequently, the animals developed metabolic dysfunction resembling prediabetes. When the organophosphate-exposed animals consumed a high fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared to unexposed rats on the same diet. At the same time, the high fat diet ameliorated many of the central synaptic defects caused by organophosphate exposure, pointing to nonpharmacologic therapeutic interventions to offset neurodevelopmental abnormalities, as well as toward fostering dietary choices favoring high fat intake. These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes. PMID- 20850521 TI - Organophosphorous pesticide exposures and sperm quality. AB - Many Americans are exposed to low levels of organophosphorous (OP) pesticides. It is unclear whether these exposures impact sperm production. We investigated whether there was an association between urinary OP insecticide metabolites and sperm concentration and motility in newly married men from a rural area of eastern People's Republic of China. Ninety-four cases and 95 controls were included based on their median residual value of sperm concentration and motility after adjusting for relevant covariates. Their urine was analyzed for six dialkylphosphate (DAP) compounds. After adjustment for demographic and exposure variables, the odds of being a case were greater (odds ratio=1.30, 95% confidence interval 1.02-1.65) in men with higher urinary concentrations of dimethylphosphate (DMP) compared to men with lower levels. No significant differences between cases and controls were found among the other DAP concentrations. DMP exposure and sperm concentration and motility should be explored further in environmental exposure studies. PMID- 20850522 TI - Rapid and sensitive detection of Enterobacter sakazakii by cross-priming amplification combined with immuno-blotting analysis. AB - Enterobacter sakazakii is a widespread and life-threatening bacterium especially in polluted powdered infant milk formula. Several methods have been developed for detection of E. sakazakii such as physiological and biochemical methods, PCR and loop-mediated isothermal amplification. However, these procedures were disadvantages due to a long assay time, low sensitivity or the use of toxic reagents. Our method of cross-priming amplification (CPA) under isothermal conditions combined with immuno-blotting analysis made the whole detection procedure more sensitivity and lower time-consuming. A set of specific displacement primers, cross primers and testing primers were designed based on six specific sequences in E. sakazakii 16S-23S rDNA internal transcribed spacer. Under isothermal condition at 63 degrees C for 60 min, the specific amplification and hybridization steps were processed simultaneously. The specificity of the CPA was tested in panel of 54 different bacterial strains and 236 milk powder products. Two red signal lines were developed on the BioHelix Express strip in all of positive E. sakazakii strains, and only one signal line was demonstrated by non- E. sakazakii bacterial strains. The limit of decetion of CPA was 6.3 +/- 2.7277 fg for the genomic DNA, 88 +/- 8.7892 cfu/ml for pure bacterial culture, and 3.2 +/- 2.0569 cfu per 100 g milk powder with pre enrichment. The current study demonstrated that the assay method of CPA combined with immuno-blotting analysis was a specific and sensitive detection for the rapid detection of E. sakazakii. PMID- 20850523 TI - A Saccharomyces cerevisiae strain unable to store neutral lipids is tolerant to oxidative stress induced by alpha-synuclein. AB - Parkinson disease is a neurodegenerative pathology that has been linked to several genetic mutations of the SNCA gene encoding the pro-oxidant alpha synuclein protein. The budding yeast Saccharomyces cerevisiae is a valuable model for studying the cellular and molecular mechanisms of alpha-synuclein toxicity. Indeed heterologous expression of alpha-synuclein is toxic to wild-type yeast and exhibits the main features of damage caused to mammalian neurons, including an increase in neutral lipid storage (triglycerides and steryl esters, embedded into lipid droplets). To address the significance of this accumulation, we forced alpha-synuclein production in a strain unable to synthesize triglycerides and steryl esters. Surprisingly, the inability to store neutral lipids rendered the cells more tolerant to alpha-synuclein. Our results indicate that the level of alpha-synuclein toxicity is correlated with fatty acid synthase activity and intracellular redox status. PMID- 20850524 TI - HDL-associated paraoxonase-1 can redistribute to cell membranes and influence sensitivity to oxidative stress. AB - Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated serum enzyme thought to make a major contribution to the antioxidant capacity of the lipoprotein. In previous studies, we proposed that HDL promoted PON1 secretion by transfer of the enzyme from its plasma membrane location to HDL transiently anchored to the hepatocyte. This study examined whether PON1 can be transferred into cell membranes and retain its enzymatic activities and functions. Using Chinese hamster ovary and human endothelial cells, we found that recombinant PON1 as well as PON1 associated with purified human HDL was freely exchanged between the external medium and the cell membranes. Transferred PON1 was located in the external face of the plasma membrane of the cells in an enzymatically active form. The transfer of PON1 led to a gain of function by the target cells, as revealed by significantly reduced susceptibility to oxidative stress and significantly increased ability to neutralize the bacterial virulence agent 3-oxo C(12)-homoserine lactone. The data demonstrate that PON1 is not a fixed component of HDL and suggest that the enzyme could also exert its protective functions outside the lipoprotein environment. The observations may be of relevance to tissues exposed to oxidative stress and/or bacterial infection. PMID- 20850525 TI - Chronic atrazine exposure causes disruption of the spontaneous locomotor activity and alters the striatal dopaminergic system of the male Sprague-Dawley rat. AB - The herbicide atrazine (ATR) is widely used around the world, and is a potential toxicant of the dopaminergic systems. Nigrostriatal and mesolimbic systems are the two major dopaminergic pathways of the central nervous system; they play key roles mediating a wide array of critical motor and cognitive functions. We evaluated the effects of exposing male rats for one year to 10 mg ATR/kg B.W. on these systems using motor and cognitive tasks and measuring monoamine content in the striatum, nucleus accumbens, prefrontal cortex, and hypothalamus. ATR administration resulted in impaired motor coordination and greater spontaneous locomotor activity only after 10 to 12 months of exposure. Chronic exposure to 10 mg ATR decreased striatal dopamine, but had no effect on accumbal, hypothalamic or cortical monoamine content. Chronic ATR exposure caused discrete changes in learning tasks that involve either the striatum or the nucleus accumbens. These results indicate that chronic exposure to ATR preferentially targets the nigrostriatal dopaminergic pathway, in comparison to the other dopaminergic pathways evaluated in this study, inducing behavioral and neurochemical alterations. In order to unveil the full extent of atrazine's effects on the nervous system, other neurochemical systems should be considered in future studies. PMID- 20850526 TI - Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma. AB - In this review, we highlight recent literature concerning the signaling mechanisms underlying the development of two neural birth defects, holoprosencephaly and coloboma. Holoprosencephaly, the most common forebrain defect, occurs when the cerebral hemispheres fail to separate and is typically associated with mispatterning of embryonic midline tissue. Coloboma results when the choroid fissure in the eye fails to close. It is clear that Sonic hedgehog (Shh) signaling regulates both forebrain and eye development, with defects in Shh, or components of the Shh signaling cascade leading to the generation of both birth defects. In addition, other intercellular signaling pathways are known factors in the incidence of holoprosencephaly and coloboma. This review will outline recent advances in our understanding of forebrain and eye embryonic pattern formation, with a focus on zebrafish studies of Shh and retinoic acid pathways. Given the clear overlap in the mechanisms that generate both diseases, we propose that holoprosencephaly and coloboma can represent mild and severe aspects of single phenotypic spectrum resulting from aberrant forebrain development. This article is part of a Special Issue entitled Zebrafish Models of Neurological Diseases. PMID- 20850527 TI - Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica. AB - The aim of the present study was to evaluate the effect of release rate from ordered mesoporous silica materials on the rate and extent of absorption of the poorly soluble drug fenofibrate. Three ordered mesoporous silica materials with different pore diameter (7.3 nm, 4.4 nm and 2.7 nm) were synthesized and loaded with fenofibrate via impregnation. Release experiments were conducted under sink conditions and under supersaturating conditions in biorelevant media, simulating the fasted and the fed state. Subsequently, all silica-based formulations were evaluated in vivo (rat model). The release experiments under sink conditions indicated a clear increase in release rate with increasing pore size. However, under supersaturating conditions (FaSSIF), the, pharmaceutical performance (in terms of both the degree and duration of supersaturation), increased with decreasing pore size. The same trend was observed in vivo (fasted state): the area under the plasma concentration-time profile amounted to 102 +/- 34 MUMh, 86 +/- 19 MUMh and 20 +/- 13 MUMh for the materials with pore diameter of 2.7 nm, 4.4 nm and 7.3 nm, respectively. The results of this, study demonstrate that a decrease in drug release rate - and thus, a decrease of the rate at which supersaturation is created - is beneficial to the absorption of fenofibrate. PMID- 20850528 TI - CD3 mAb treatment ameliorated the severity of the cGVHD-induced lupus nephritis in mice by up-regulation of Foxp3+ regulatory T cells in the target tissue: kidney. AB - Teff/Treg imbalance orchestrated the onset and the progression of the lupus nephritis in a DBA/2->B6D2F1 murine model with cGVHD. In this paper, we first used 145-2C11 Ab to treat these human SLE-like diseased animals. The results showed that short-term low-dose anti-CD3 antibody treatment induced a significant remission of established proteinuria, production of autoantibodies, immune complex deposition and renal parenchyma lesions in lupus nephritic mice. Of note, we found a robust up-regulation of Foxp3 mRNA expression in the target tissue: kidney from mice with anti-CD3 antibody treatment compared to those with control IgG treatment. Likewise, an increased renal mRNA abundance for IL-10 was also observed in anti-CD3 antibody treated mice. In contrast, genes associated with inflammation and fibrosis as well as cytokines related to effector T cell responses were down-regulated by anti-CD3 mAb treatment. These findings suggested that short-term low-dose anti-CD3 antibody treatment might induced an IL-10 secreting Foxp3(+) regulatory T cells in this cGVHD target tissue: kidney, that suppressed the activation of effector T cells (Th1, Th2 and Th17), thus ameliorating the severity of the lupus nephritis in mice. PMID- 20850529 TI - The new immunosuppressant PLNPK prolongs allograft survival in mice. AB - The pentapeptide PLNPK (Pro-Leu-Asn-Pro-Lys) is extracted from the spleen. Preliminary studies have shown that PLNPK could inhibit T lymphocyte transformation and antibody production. In the present study, we detected the inhibitory effect of PLNPK on one-way mixed leukocyte reaction (MLR) in vitro and observed the effect of PLNPK on the duration of allograft survival in mouse models of skin or cardiac transplantation. Pathological damage and T cell infiltration of the grafts were also detected. Results showed that PLNPK could significantly inhibit T lymphocyte proliferation, with an optimized inhibition of 40%. Also PLNPK could significantly prolong the mean survival time of skin allograft and cardiac allograft, producing survival rates of 42% and 38.7%, respectively. PLNPK at a dose of 200 MUg/kg/d or 100 MUg/kg/d could significantly suppress ConA-induced T cell proliferation and T cell IL-2 secretion in transplant recipient mice, compared to the saline group (P<0.05). This information suggests that PLNPK can effectively antagonize transplant rejection, possibly by reducing IL-2 secretion by T cells and inhibiting T cell proliferation and activation. PMID- 20850530 TI - The A1 receptor agonist R-Pia reduces the imbalance between cerebral glucose metabolism and blood flow during status epilepticus: could this mechanism be involved with neuroprotection? AB - It is well known that the uncoupling between local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF), i.e. decrease in LCBF rates with high LCGU, is frequently associated with seizure-induced neuronal damage. This study was performed to assess if the neuroprotective effect of the adenosinergic A(1) receptor agonist R-N-phenylisopropyladenosine (R-Pia) injected prior to pilocarpine is able to reduce the uncoupling between LCGU and LCBF during status epilepticus (SE). Four groups of rats were studied: Saline, Pilo, R-Pia+Saline and R-Pia+Pilo. For LCGU and LCBF studies, rats were subjected to autoradiography using [(14)C]-2-deoxyglucose and [(14)C]-iodoantypirine, respectively. Radioligands were injected 4 h after SE onset. Neuronal loss was evaluated by Fluorojade-B (FJB) at two time points after SE onset (24 h and 7 days). The results showed a significant increase in LCGU in almost all brain regions studied in the Pilo and R-Pia+Pilo groups compared to controls. However, in R-Pia pretreated rats, the uncoupling between LCGU and LCBF was moderated in a limited number of structures as substantia nigra pars reticulata and hippocampal formation rather in favor of hyperperfusion. Significant increases in LCBF were observed in the entorhinal cortex, thalamic nuclei, mammillary body, red nucleus, zona incerta, pontine nucleus and visual cortex. The neuroprotective effect of R Pia assessed by FJB showed a lower density of degenerating cells in the hippocampal formation, piriform cortex and basolateral amygdala. In conclusion our data shows that the neuroprotective effect of R-Pia was accompanied by a compensatory metabolic input in brain areas involved with seizures generation. PMID- 20850531 TI - Apoptosis-inducing factor mediates dopaminergic cell death in response to LPS induced inflammatory stimulus: evidence in Parkinson's disease patients. AB - We show that intranigral lipopolysaccharide (LPS) injection, which provokes specific degeneration of DA neurons, induced caspase-3 activation in the rat ventral mesencephalon, which was mostly associated with glial cells. In contrast, nigral DA neurons exhibited AIF nuclear translocation in response to LPS. A significant decrease of the Bcl-2/Bax ratio in nigral tissue after LPS injection was observed. We next developed an in vitro co-culture system with the microglial BV2 and the DA neuronal MN9D murine cell lines. The silencing of caspase-3 or AIF by small interfering RNAs exclusively in the DA MN9D cells demonstrated the key role of AIF in the LPS-induced death of DA cells. In vivo chemical inhibition of caspases and poly(ADP-ribose)polymerase-1, an upstream regulator of AIF release and calpain, proved the central role of the AIF-dependent pathway in LPS-induced nigral DA cell death. We also observed nuclear translocation of AIF in the ventral mesencephalon of Parkinson's disease subjects. PMID- 20850532 TI - Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model. AB - Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson's disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons. PMID- 20850533 TI - Associations of the correlates of protection and implication on the statistical power for demonstrating non-inferiority: application of a re-sampling method on a large phase III influenza vaccine clinical trial. AB - BACKGROUND: In the later stage of the clinical development of new vaccines it is required to demonstrate their efficacy with the immunogenicity measures established as correlates for disease protection. Evaluation of interpandemic trivalent influenza vaccines is commonly assessed by three immunogenicity measures for each strain in different age groups: Seroprotection, Seroconversion and Geometric Mean Titers. US and European guidelines with respect to this topic have been issued for the licensure of new influenza vaccines. The statistical power of comparative trials, which consider these endpoint variables, could be affected to the extent that these measures are correlated. Results from a large non-inferiority trial in the clinical development of a novel cell-derived influenza vaccine have been analyzed with the aim of evaluating how statistical dependency between the above-mentioned three immunogenicity measures might affect the power to demonstrate non-inferiority. METHODS: The statistical non inferiority criteria, which were met in the trial, were applied to different subsets (n=250, n=370 and n=500) using a re-sampling method from the original dataset (re-samples=10,000). RESULTS: The measures of immunogenicity were highly correlated, and the fulfillment or failure of any of the non-inferiority criteria for a specific measure partially predicted the same outcome for the other measures. Due to this dependency within each strain, the levels of power obtained by re-sampling methods were always higher than those obtained by theoretical calculations, which were based on the assumptions of independency between the three measures of immunogenicity. Seroconversion and Geometric Mean Ratio (GMR) showed a higher correlation. A failure in the fulfillment of the non-inferiority criteria for GMR predicted the failure for Seroconversion in >76% of cases. CONCLUSIONS: The correlation between different measures of immunogenicity should be taken into account when evaluating statistical power for non-inferiority in influenza vaccine trials and in establishing sample sizes. Statistical approaches that include either all three measures of immunogenicity or both Seroconversion and the ratio of GMTs as co-primary non-inferiority endpoints might create redundancy and could increase the probability of not meeting at least one non inferiority criterion by chance, due to multiplicity. PMID- 20850534 TI - Adverse events following influenza A (H1N1) 2009 monovalent vaccines reported to the Vaccine Adverse Event Reporting System, United States, October 1, 2009 January 31, 2010. AB - The United States (US) influenza A (H1N1) 2009 monovalent (2009-H1N1) vaccination program began in October 2009. Reports to the vaccine adverse event reporting system (VAERS), a US spontaneous reporting system, were reviewed to identify potential rare events or unusual adverse event (AE) patterns after 2009-H1N1 vaccination. The adverse event profile after 2009-H1N1 vaccine in VAERS (~10,000 reports) was consistent with that of seasonal influenza vaccines, although the reporting rate was higher after 2009-H1N1 than seasonal influenza vaccines, this may be, at least in part, a reflection of stimulated reporting. Death, Guillain Barre syndrome and anaphylaxis reports after 2009-H1N1 vaccination were rare (each <2 per million doses administered). PMID- 20850535 TI - Dendritic cells devoid of IL-10 induce protective immunity against the protozoan parasite Trypanosoma cruzi. AB - In diverse models of microbial infections, protection is improved by immunization with dendritic cells (DC) loaded with whole pathogen lysate. However, pathogens that modulate DC function as a way to evade immunity may represent a challenge for these vaccination strategies. Thus, DC must be instructed in a particular manner to circumvent this issue and drive an effective immune response. Trypanosoma cruzi or its molecules alter DC function and, as we demonstrated, this phenomenon is associated with the parasite-driven stimulation of IL-10 production by DC. Here, we show that DC from IL-10-deficient mice pulsed in vitro with trypomastigote lysate secreted increased amounts of Th1-related cytokines and stimulated higher allogeneic and antigen-specific lymphocyte responses than their wild-type counterparts. In a model of DC-based immunization, these antigen pulsed IL-10-deficient DC conferred protection against T. cruzi infection to recipient mice. Efficient immunity was associated with enhanced antigen-specific IFN-gamma production and endogenous DC activation. We illustrate for the first time a DC-based vaccination against T. cruzi and evidence the key role of IL-10 produced by sensitizing DC in inhibiting the induction of protection. These results support the rationale for vaccination strategies that timely suppress the effect of specific cytokines secreted by antigen presenting DC. PMID- 20850536 TI - Effect of a combination DNA vaccine for the prevention and therapy of Trypanosoma cruzi infection in mice: role of CD4+ and CD8+ T cells. AB - Chagas disease is a major public health problem, with about 10 million infected people, and DNA vaccines are a promising alternative for the control of Trypanosoma cruzi, the causing agent of the disease. We tested here a new DNA vaccine encoding a combination of two leading parasite antigens, TSA-1 and Tc24, for the prevention and therapy of T. cruzi infection. Immunized Balb/c mice challenged by T. cruzi presented a significantly lower parasitemia and inflammatory cell density in the heart compared to control mice. Similarly, the therapeutic administration of the DNA vaccine was able to significantly reduce the parasitemia and inflammatory reaction in acutely infected Balb/c and C57BL/6 mice, and reduced cardiac tissue inflammation in chronically infected ICR mice. Therapeutic vaccination induced a marked increase in parasite-specific IFNgamma producing CD4(+) and CD8(+) T cells in the spleen as well as an increase in CD4(+) and CD8(+) T cells in the infected cardiac tissue. In addition, some effect of the DNA vaccine could still be observed in CD4-knockout C57BL/6 mice, which presented a lower parasitemia and inflammatory cell density, but not in CD8 deficient mice, in which the vaccine had no effect. These results indicate that the activation of CD8(+) T cells plays a major role in the control of the infection by the therapeutic DNA vaccine, and to a somewhat lesser extent CD4(+) T cells. This observation opens interesting perspectives for the potentiation of this DNA vaccine candidate by including additional CD8(+) T cell antigens/epitopes in future vaccine formulations. PMID- 20850537 TI - Experimental autoimmune encephalomyelitis as a testing paradigm for adjuvants and vaccines. AB - Experimental autoimmune encephalomyelitis (EAE) is an experimental model for multiple sclerosis. EAE can be induced by inoculation with central nervous system (CNS) proteins or peptides emulsified in complete Freund's adjuvant. Protection from EAE, enhancement of EAE or subclinical priming for EAE can occur as a result of either live viral infection or DNA immunization with molecular mimics of CNS proteins or peptides. Here we review the published data describing modulation of EAE through administration of various CNS proteins/peptides introduced via live virus or plasmid DNA and modulation of EAE through choice of adjuvant (immunostimulating agents). PMID- 20850538 TI - Overview of expression of hepatitis B surface antigen in transgenic plants. AB - Hepatitis B virus (HBV), a pathogen for chronic liver infection, afflicts more than 350 million people world-wide. The effective way to control the virus is to take HBV vaccine. Hepatitis B surface antigen (HBsAg) is an effective protective antigen suitable for vaccine development. At present, "edible" vaccine based on transgenic plants is one of the most promising directions in novel types of vaccines. HBsAg production from transgenic plants has been carried out, and the transgenic plant expression systems have developed from model plants (such as tobacco, potato and tomato) to other various plant platforms. Crude or purified extracts of transformed plants have been found to conduct immunological responses and clinical trials for hepatitis B, which gave the researches of plant-based HBsAg production a big boost. The aim of this review was to summarize the recent data about plant-based HBsAg development including molecular biology of HBsAg gene, selection of expression vector, the expression of HBsAg gene in plants, as well as corresponding immunological responses in animal models or human. PMID- 20850539 TI - Vessel-specific role of sphingosine kinase 1 in the vasoconstriction of isolated basilar arteries. AB - Sphingosine-1-phosphate (S1P) constricts cerebral arteries through S1P(3) receptor stimulation. Because the activity of the key S1P-synthesizing enzyme, sphingosine kinase (SPK), can be stimulated by agonists of various G protein coupled receptors, it is likely that S1P also acts as a second messenger for other vasoconstrictors. We investigated the effect of SPK inhibitors and SPK gene deletion on the contractile responses of isolated vessels to vasoactive agonists and KCl-induced depolarization. Basilar and femoral arteries of rat, mounted in a wire myograph, were incubated with dimethylsphingosine (DMS), 2-(p hydroxyanilino)-4-(p-chlorophenyl) thiazole (Compound 2) or FTY720, and exposed to KCl, 5-hydroxytryptamine (5-HT), S1P or phenylephrine (PE). Vasomotor responses in basilar artery were decreased by DMS, Compound 2 and FTY720, while they were not affected in femoral artery. Basilar arteries from SPK1(-/-) mice exhibited weaker vasoconstriction to both KCl and agonists (S1P and the prostanoid U46619) when compared to either wild type (WT) or SPK2(-/-). In contrast, in mesenteric resistance arteries, neither the contraction to KCl nor the maximum contraction to PE and S1P significantly differed among WT, SPK1(-/-) and SPK2(-/-). Quantitative analysis of SPK mRNA (reverse transcription and real time polymerase chain reaction) in mouse arteries showed 40-80-fold higher SPK1 expression in cerebral arteries than in aorta or mesenteric arteries. SPK1 critically modulates the reactivity of cerebral vasculature to vasoconstrictors. S1P plays a specific role as modulator of cerebral blood flow, potentially acting either directly outside vascular smooth muscle cells on S1P(3) receptors, or indirectly after being generated inside the cell in response to vasoconstrictors. PMID- 20850541 TI - Casein kinase 2 and microtubules control axon initial segment formation. AB - The axon initial segment (AIS) is a unique axonal subdomain responsible for the generation of the neuronal action potential and the maintenance of the axon dendritic functional polarity. Despite its importance, the mechanisms controlling AIS development and maintenance remain largely unknown. Here we show that the AIS microtubule cytoskeleton is composed of a pool of more stable, detergent resistant, microtubules. This AIS specific characteristic is conferred by the presence of CK2, an important regulator of microtubule stability, in the AIS during its development and maturation. We show that CK2alpha and CK2alpha' subunits concentrate at the AIS from its initial development, at the same time as pIkappaBalpha and ankyrinG. CK2 pharmacological inhibition or suppression of CK2alpha expression with nucleofected interference RNAs modifies microtubule characteristics throughout the neuron, changes KIF5C distribution, and impairs its own concentration at the AIS, as well as that of ankyrinG, ankyrinG-GFP, pIkappaBalpha and voltage gated sodium channels. Moreover, CK2alpha concentration at the AIS depends on IkappaBalpha phosphorylation by IKK and ankyrinG. In conclusion, our results demonstrate a mutual dependence of CK2, ankyrinG and pIkappaBalpha for their concentration at the axon initial segment, which is related to the specific characteristics of microtubules at the AIS. PMID- 20850540 TI - Intracellular signaling and hepatocellular carcinoma. AB - Liver cancer is the fifth most common cancer and the third most common cause of cancer related death in the world. The recent development of new techniques for the investigations of global change in the gene expression, signaling pathways and wide genome binding has provided novel information for the mechanisms underlying liver cancer progression. Although these studies identified gene expression signatures in hepatocellular carcinoma, the early steps of the development of hepatocellular carcinomas (HCC) are not well understood. The development of HCC is a multistep process which includes the progressive alterations of gene expression leading to the increased proliferation and to liver cancer. This review summarizes recent progress in the identification of the key steps of the development of HCC with the focus on early events of carcinogenesis and on the role of translational and epigenetic alterations in the development of HCC. Quiescent stage of the liver is supported by several tumor suppressor proteins including p53, Rb and C/EBPalpha. Studies with chemical models of liver carcinogenesis and with human HCC have shown that the elevation of gankyrin is responsible for the elimination of these three proteins at early steps of carcinogenesis. Later stages of progression of the liver cancer are associated with alterations in many signaling pathways including translation which leads to epigenetic silencing/activation of many genes. Particularly, recent reports suggest a critical role of histone deacetylase 1, HDAC1, in the development of HCC through the interactions with transcription factors such as C/EBP family proteins. PMID- 20850542 TI - Structure modeling from small angle X-ray scattering data with elastic network normal mode analysis. AB - Computational algorithms to construct structural models from SAXS experimental data are reviewed. SAXS data provides a wealth of information to study the structure and dynamics of biological molecules, however it does not provide atomic details of structures. Thus combining the low-resolution data with already known X-ray structure is a common approach to study conformational transitions of biological molecules. This review provides a survey of SAXS modeling approaches. In addition, we will discuss theoretical backgrounds and performance of our approach, in which elastic network normal mode analysis is used to predict reasonable conformational transitions from known X-ray structures, and find alternative conformations that are consistent with SAXS data. PMID- 20850543 TI - Young's modulus of peritubular and intertubular human dentin by nano-indentation tests. AB - The local Young modulus of dry dentin viewed as a hierarchical composite was measured by nano-indentation using two types of experiments, both in a continuous stiffness measurement mode. First, tests were performed radially along straight lines running across highly mineralized peritubular dentin sections and through less mineralized intertubular dentin areas. These tests revealed a gradual decrease in Young's modulus from the bulk of the peritubular dentin region where modulus values of up to ~40-42GPa were observed, down to approximately constant values of ~17GPa in the intertubular dentin region. A second set of nano indentation experiments was performed on the facets of an irregular polyhedron specimen cut from the intertubular dentin region, so as to probe the modulus of intertubular dentin specimens at different orientations relative to the tubular direction. The results demonstrated that the intertubular dentin region may be considered to be quasi-isotropic, with a slightly higher modulus value (~22GPa) when the indenting tip axis is parallel to the tubular direction, compared to the values (~18GPa) obtained when the indenting tip axis is perpendicular to the tubule direction. PMID- 20850545 TI - Structural basis for reversible and irreversible inhibition of human cathepsin L by their respective dipeptidyl glyoxal and diazomethylketone inhibitors. AB - Cathepsin L plays a key role in many pathophysiological conditions including rheumatoid arthritis, tumor invasion and metastasis, bone resorption and remodeling. Here we report the crystal structures of two analogous dipeptidyl inhibitor complexes which inhibit human cathepsin L in reversible and irreversible modes, respectively. To-date, there are no crystal structure reports of complexes of proteases with their glyoxal inhibitors or complexes of cathepsin L and their diazomethylketone inhibitors. These two inhibitors - inhibitor 1, an alpha-keto-beta-aldehyde and inhibitor 2, a diazomethylketone, have different groups in the S1 subsite. Inhibitor 1 [Z-Phe-Tyr (OBut)-COCHO], with a K(i) of 0.6nM, is the most potent, reversible, synthetic peptidyl inhibitor of cathepsin L reported to-date. The structure of the inhibitor 1 complex was refined up to 2.2A resolution. The structure of the complex of the inhibitor 2 [Z-Phe-Tyr (t Bu)-diazomethylketone], an irreversible inhibitor that can inactivate cathepsin L at MUM concentrations, was refined up to 1.76A resolution. These two inhibitors have substrate-like interactions with the active site cysteine (Cys25). Inhibitor 1 forms a tetrahedral hemithioacetal adduct, whereas the inhibitor 2 forms a thioester with Cys25. The inhibitor 1 beta-aldehyde group is shown to make a hydrogen bond with catalytic His163, whereas the ketone carbonyl oxygen of the inhibitor 2 interacts with the oxyanion hole. tert-Butyl groups of both inhibitors are found to make several non-polar contacts with S' subsite residues of cathepsin L. These studies, combined with other complex structures of cathepsin L, reveal the structural basis for their potency and selectivity. PMID- 20850546 TI - Amorphous calcium carbonate in the shells of adult Unionoida. AB - Shells of adult individuals from two different bivalve families, Hyriopsis cumingii and Diplodon chilensis patagonicus, were studied by Micro-Raman spectroscopy and Focussed Ion Beam-assisted TEM. The shells contain amorphous calcium carbonate in a zone at the interface between the periostracum and the prismatic layer. In this area, the initial prism structures protrude from the inner periostracum layer and it is demonstrated that these structures systematically consist of highly disordered and amorphous calcium carbonate. Within this zone, ordered and disordered areas are intermingled discounting the existence of a crystallization front and favouring models of domainal crystallization processes via so-called mesocrystals. These observations are the first documentation of the use of amorphous calcium carbonate as a precursor phase by adult mollusc species and lend further support to hypotheses postulating widespread use of amorphous phases as building material of skeletal tissue in biology. PMID- 20850544 TI - The utility of geometrical and chemical restraint information extracted from predicted ligand-binding sites in protein structure refinement. AB - Exhaustive exploration of molecular interactions at the level of complete proteomes requires efficient and reliable computational approaches to protein function inference. Ligand docking and ranking techniques show considerable promise in their ability to quantify the interactions between proteins and small molecules. Despite the advances in the development of docking approaches and scoring functions, the genome-wide application of many ligand docking/screening algorithms is limited by the quality of the binding sites in theoretical receptor models constructed by protein structure prediction. In this study, we describe a new template-based method for the local refinement of ligand-binding regions in protein models using remotely related templates identified by threading. We designed a Support Vector Regression (SVR) model that selects correct binding site geometries in a large ensemble of multiple receptor conformations. The SVR model employs several scoring functions that impose geometrical restraints on the Calpha positions, account for the specific chemical environment within a binding site and optimize the interactions with putative ligands. The SVR score is well correlated with the RMSD from the native structure; in 47% (70%) of the cases, the Pearson's correlation coefficient is >0.5 (>0.3). When applied to weakly homologous models, the average heavy atom, local RMSD from the native structure of the top-ranked (best of top five) binding site geometries is 3.1A (2.9A) for roughly half of the targets; this represents a 0.1 (0.3)A average improvement over the original predicted structure. Focusing on the subset of strongly conserved residues, the average heavy atom RMSD is 2.6A (2.3A). Furthermore, we estimate the upper bound of template-based binding site refinement using only weakly related proteins to be ~2.6A RMSD. This value also corresponds to the plasticity of the ligand-binding regions in distant homologues. The Binding Site Refinement (BSR) approach is available to the scientific community as a web server that can be accessed at http://cssb.biology.gatech.edu/bsr/. PMID- 20850547 TI - Molecular characterization and functional analysis of MyD88 in Chinese soft shelled turtle Trionyx sinensis. AB - Myeloid differentiation factor 88 (MyD88) is one of the key adaptor proteins to signal transduction that triggers downstream cascades involved in innate immunity. In this study, the MyD88 gene from Chinese soft-shelled turtle (Trionyx sinensis) (tMyD88) was identified, representing the fist example from reptile species. The tMyD88 has a 894-bp ORF and encodes a polypeptide of 297 amino acids including a typical death domain (DD) at the N-terminus and a conservative Toll/IL-1R (TIR) domain at the C-terminus. It was expressed at high levels in spleen, blood, lungs and liver, but marginal in kidneys and intestines of turtles challenged with live cells of Aeromonas hydrophila, as determined by real-time PCR. RAW 264.7 cells transfected with pcDNA-tMyD88 showed higher NF-kappaB activity than the vector control (673.78 vs 410.72, P < 0.05). Expression of proinflammatory cytokines IL-1beta and TNF-alpha was also significantly higher in RAW 264.7 cells transfected with pcDNA-tMyD88 than those having pcDNA3.1 control vector (P < 0.01). These results indicate that tMyD88 might possess an important role in defense against microbial infection in Chinese soft-shelled turtles similar to that in mammals. PMID- 20850548 TI - Distinct differences in the pattern of hemodynamic response to happy and angry facial expressions in infants--a near-infrared spectroscopic study. AB - Recognition of other people's facial expressions of emotion plays an important role in social communication in infants as well as adults. Evidence from behavioral studies has demonstrated that the ability to recognize facial expressions develops by 6 to 7 months of age. Although the regions of the infant brain involved in processing facial expressions have not been investigated, neuroimaging studies in adults have revealed that several areas including the superior temporal sulcus (STS) participate in the processing of facial expressions. To examine whether the temporal area overlying the STS is responsible for the processing of facial expressions in infants, near-infrared spectroscopy (NIRS) was used to measure the neural activity in the temporal area overlying the STS as infants looked at happy and angry faces. NIRS provides a non invasive means of estimating cerebral blood flow in the human brain and does not require severe constraints of head-movement. According to the International 10-20 system for EEG electrode placement, the measurement area was located in the bilateral temporal area centered at positions T5 and T6, which correspond to the STS. The time-course of the average change in total-Hb concentration revealed a clear difference in the pattern of hemodynamic responses to happy and angry faces. The hemodynamic response increased gradually when infants looked at happy faces and was activated continuously even after the disappearance of the face. In contrast, the hemodynamic responses for angry faces increased during the presentation of angry faces, then decreased rapidly after the face disappeared. Moreover, the left temporal area was significantly activated relative to the baseline when infants looked at happy faces, while the right temporal area was significantly activated for angry faces. These findings suggest hemispheric differences in temporal areas during the processing of positive and negative facial expressions in infants. PMID- 20850549 TI - Instantaneous and causal connectivity in resting state brain networks derived from functional MRI data. AB - BACKGROUND: Most neuroimaging studies of resting state networks have concentrated on functional connectivity (FC) based on instantaneous correlation in a single network. In this study we investigated both FC and effective connectivity (EC) based on Granger causality of four important networks at resting state derived from functional magnetic resonance imaging data - default mode network (DMN), hippocampal cortical memory network (HCMN), dorsal attention network (DAN) and fronto-parietal control network (FPCN). METHODOLOGY/PRINCIPLE FINDINGS: A method called correlation-purged Granger causality analysis was used, not only enabling the simultaneous evaluation of FC and EC of all networks using a single multivariate model, but also accounting for the interaction between them resulting from the smoothing of neuronal activity by hemodynamics. FC was visualized using a force-directed layout upon which causal interactions were overlaid. FC results revealed that DAN is very tightly coupled compared to the other networks while the DMN forms the backbone around which the other networks amalgamate. The pattern of bidirectional causal interactions indicates that posterior cingulate and posterior inferior parietal lobule of DMN act as major hubs. The pattern of unidirectional causal paths revealed that hippocampus and anterior prefrontal cortex (aPFC) receive major inputs, likely reflecting memory encoding/retrieval and cognitive integration, respectively. Major outputs emanating from anterior insula and middle temporal area, which are directed at aPFC, may carry information about interoceptive awareness and external environment, respectively, into aPFC for integration, supporting the hypothesis that aPFC-seeded FPCN acts as a control network. CONCLUSIONS/SIGNIFICANCE: Our findings indicate the following. First, regions whose activities are not synchronized interact via time-delayed causal influences. Second, the causal interactions are organized such that cingulo-parietal regions act as hubs. Finally, segregation of different resting state networks is not clear cut but only by soft boundaries. PMID- 20850551 TI - Conserved and variable architecture of human white matter connectivity. AB - Whole-brain network analysis of diffusion imaging tractography data is an important new tool for quantification of differential connectivity patterns across individuals and between groups. Here we investigate both the conservation of network architectural properties across methodological variation and the reproducibility of individual architecture across multiple scanning sessions. Diffusion spectrum imaging (DSI) and diffusion tensor imaging (DTI) data were both acquired in triplicate from a cohort of healthy young adults. Deterministic tractography was performed on each dataset and inter-regional connectivity matrices were then derived by applying each of three widely used whole-brain parcellation schemes over a range of spatial resolutions. Across acquisitions and preprocessing streams, anatomical brain networks were found to be sparsely connected, hierarchical, and assortative. They also displayed signatures of topo physical interdependence such as Rentian scaling. Basic connectivity properties and several graph metrics consistently displayed high reproducibility and low variability in both DSI and DTI networks. The relative increased sensitivity of DSI to complex fiber configurations was evident in increased tract counts and network density compared with DTI. In combination, this pattern of results shows that network analysis of human white matter connectivity provides sensitive and temporally stable topological and physical estimates of individual cortical structure across multiple spatial scales. PMID- 20850550 TI - MRI reveals differential regulation of retinal and choroidal blood volumes in rat retina. AB - The retina is nourished by two unique (retinal and choroidal) circulations. The lack of depth-resolved blood volume (BV) imaging techniques hampers investigation of vascular-specific regulation of the retina in vivo. This study presents a high resolution, laminar-specific magnetic resonance imaging (MRI) study to image retinal and choroidal BVs, their responses to physiologic challenges in normal and Royal-College-of-Surgeons (RCS) rats (a model of retinal degeneration). Retinal and choroidal BVs were imaged by MRI (30*30*800 MUm) with intravascular administration of monocrystalline iron oxide nanocolloid (MION) contrast agent. Relative baseline BV and BV changes due to physiologic challenges were calculated in normal and RCS rat retinas. BV-MRI revealed two well-resolved retinal and choroidal vascular layers located on either side of the retina and an intervening avascular layer. The ratio of choroidal:retinal BV in normal rats at baseline was 9.8+/-3.2 in control rat retinas (N=7). Hyperoxia decreased retinal BV (-51+/ 17%, p<0.05) more than choroidal BV (-28+/-14%), and hypercapnia increased retinal BV (52+/-11%, p<0.01) more than choroidal BV (12+/-11%). BV-MRI in degenerated retinas of RCS rats (N=7) revealed thinning of the avascular layer and an increase in relative baseline retinal and choroidal BVs. Only hypercapnia induced BV changes in the retinal vasculature of RCS rats were significantly different (smaller) from controls (p<0.05). These findings suggest that BV in both retinal vasculatures is regulated. The relative baseline BV in both vasculatures increased in retinal degeneration. BV-MRI provides clinically relevant data that may prove useful for early detection and longitudinal probing of retinal diseases, and could complement optical imaging techniques. PMID- 20850552 TI - Neurofeedback training of the upper alpha frequency band in EEG improves cognitive performance. AB - In this study, the individually determined upper alpha frequency band in EEG (electroencephalogram) was investigated as a neurofeedback parameter. Fourteen subjects were trained on five sessions within 1 week by means of feedback dependent on the current upper alpha amplitude. On the first and fifth session, cognitive ability was tested by a mental rotation test. As a result, eleven of the fourteen subjects showed significant training success. Individually determined upper alpha was increased independently of other frequency bands. The enhancement of cognitive performance was significantly larger for the neurofeedback group than for a control group who did not receive feedback. Thus, enhanced cognitive control went along with an increased upper alpha amplitude that was found in the neurofeedback group only. PMID- 20850553 TI - Effect of scanner in asymmetry studies using diffusion tensor imaging. AB - The purpose of this study was to evaluate the effects of longitudinal drift in scanner hardware, inter-scanner variability (bias) and scanner upgrade on asymmetries of diffusion properties using longitudinal data obtained on two scanners of the exact same model at one institution. A total of 224 normal subjects (63 females and 161 males) were included in this study. Each subject was scanned twice, at an interval of about 1 year (mean interval=1.0+/-0.11 years, range=0.6-1.3 years), using two 3.0-T scanners of the exact same model. Both scanners were simultaneously upgraded during the study period (159 subjects underwent a follow-up scan before upgrade, and the remaining 65 subjects underwent a follow-up scan after upgrade). The subjects were divided into 4 groups according to the combination of scanners used. With the use of tract-based spatial statistics (TBSS), we investigated the effects of scanner drift and inter scanner variability (bias) on asymmetries of fractional anisotropy (FA) and mean diffusivity (MD). We also investigated the effect of scanner upgrade on FA and MD asymmetries. The voxel-wise analyses revealed a number of regions with significant longitudinal changes in FA and MD asymmetries in the groups where baseline and follow-up images were obtained on different scanners. Even with scanners of the exact same model, inter-scanner variability (bias) significantly affected FA and MD asymmetries, which were relatively stable within the same scanner. Scanner upgrade had a small effect on FA and MD asymmetries. The results indicate that the use of multiple scanners increases variability of DTI asymmetry measurements, and can affect the results of cross-sectional and especially longitudinal DTI asymmetry studies. PMID- 20850554 TI - Anatomical and temporal architecture of theory of mind: a MEG insight into the early stages. AB - Representation of others' actions and mental states leads to the activation of several brain networks: the mentalizing and the "mirror neuron" systems as well as a "low level" social perception component. However, respective activations of the regions belonging to these networks remain unknown with respect to chronometrical data when static drawing stimuli are presented. To determine anatomical and temporal characteristics of theory of mind processes, magnetic signals were measured in 21 subjects during a validated nonverbal attribution of intentions task. Minimum norm estimation provides chronometric and localization data showing that regions known to be involved in the mentalizing, "mirror neuron" and social perception networks have simultaneous activations between 100 and 700 ms post-stimulus, a period which may be thought as corresponding to early stages of social processes. Among some regions, different profiles as well as modulations regarding experimental conditions suggest functional distinctions between these structures, pleading for a cooperative nature of these networks. While the left temporo-parietal area and superior temporal sulcus seem more specialized in social cues coding, we demonstrate that their right homologues, as well as the right inferior parietal cortex, are preferentially recruited during attribution of intentions stimuli compared to scenarios based on physical causality from 200 to 600 ms. PMID- 20850555 TI - Parsing decision making processes in prefrontal cortex: response inhibition, overcoming learned avoidance, and reversal learning. AB - Reversal learning refers to the ability to inhibit or switch responding to an object when the object-reward contingency changes. Deficits in this process are related to social abnormalities, impulsiveness, and a number of psychiatric disorders. A range of neural regions play a role in this process, including dorsolateral prefrontal cortex (dlPFC), dorsomedial prefrontal cortex (dmPFC), and inferior frontal gyrus (IFG). However, determining the specific functional contribution of each region has proved difficult, in part because reversal learning involves multiple cognitive subprocesses such as error detection, inhibiting responding to formerly rewarded stimuli, and overcoming avoidance of previously punished stimuli. We used fMRI and an experimental task adapted from a recent neurochemical study in marmosets to parse neural responding to subprocesses of reversal learning during choice and feedback trial components. Error-feedback processing was associated with increased activity in dmPFC, dlPFC, and IFG whether participants were overcoming avoidance, inhibiting responding, or performing classic response reversal. Reduced activity in medial prefrontal cortex (mPFC) was associated with error-feedback processing for response inhibition but not overcoming avoidance. Conversely, there was significantly greater activity in anterior dmPFC during error-feedback processing in overcoming avoidance compared to response inhibition. A conjunction analysis confirmed that a striking overlap in activity was observed across the three conditions in IFG, dlPFC, and dmPFC. The results are consistent with conceptualizations of IFG function that emphasize modulating stimulus-response maps rather than purely response inhibition. The approach has implications for models of prefrontal function and neurocognitive perspectives on a range of behavioural abnormalities associated with impairments in decision making. PMID- 20850556 TI - Accelerated trace eyeblink conditioning after cortisol IV-infusion. AB - Impairing effects of cortisol on learning performance have been shown in human trace eyeblink conditioning. As the effect is observed from 30 min to hours after administration, a genomic action of cortisol is assumed. Here we report rapid cortisol effects that were observed during the first 10 min after cortisol administration in humans. Young healthy males (n=24) received the cortisol synthesis inhibitor metyrapone (1.5 g per os) to avoid interference of the endogenous pulsatile secretion of cortisol. Next, 2mg cortisol or placebo was infused intravenously, immediately before the trace conditioning task. The probability of the conditioned eyeblink responses was assessed electromyographically during the trace eyeblink conditioning task (unconditioned stimulus: corneal air puff, 10 psi, 50 ms; conditioned stimulus: binaural pure tone, 7 dB, 1000 Hz, 400 ms; empty interval between CS and US: 550 ms). Cortisol resulted in a faster increase of conditioning (p=.02), reaching a comparable level to placebo later on. This result extends the well-known effects of stress on the quality and amount of learning by showing that cortisol also affects the speed of learning. We propose that cortisol accelerates trace eyeblink conditioning via a fast, non-genomic mechanism. This fast action of cortisol is part of the adaptive strategy during the early stress response. PMID- 20850557 TI - Targeting erbB receptors. AB - Our work is concerned with the origins and therapy of human cancers. Members of the epidermal growth factor receptor (EGFR) family of tyrosine kinases, also known as erbB or HER receptors, are over expressed and/or activated in many types of human tumors and represent important therapeutic targets in cancer therapy. Studies from our laboratory identified targeted therapy as a way to treat cancer. Rational therapeutics targeting and disabling erbB receptors have been developed to reverse the malignant properties of tumors. Reversal of the malignant phenotype, best seen with disabling the HER2 receptors using monoclonal antibodies is a distinct process from that seen with blocking of ligand binding to cognate receptors as has been done for EGFr receptors. Here we review the mechanisms of action deduced from a number of approaches developed in our laboratory and elsewhere, including monoclonal antibodies, peptide mimetics, recombinant proteins and small molecules. The biochemical and biological principles which have been uncovered during these studies of disabling HER2 homomeric or HER2-EGFr heteromeric receptors will help the development of novel and more efficient therapeutics targeting erbB family receptors. PMID- 20850558 TI - Intrinsic nitric oxide-stimulatory activity of lipoteichoic acids from different Gram-positive bacteria. AB - Lipoteichoic acid (LTA) is a structural component of the cell walls of Gram positive bacteria. Similar to lipopolysaccharide (LPS) which is expressed in Gram negative bacteria, LTA exhibits immunostimulatory properties. Frequently observed positive response of LTA in the Limulus amebocyte lysate (LAL) assay has been interpreted as a sign of LPS contamination, raising doubts about the intrinsic immune activities of LTA. Regarding many similarities in immunobiological and physicochemical properties of LTA and LPS, we hypothesized that similar to LPS, the LAL reactivity of LTA might be due to its ability to bind to LAL. Our data confirm the positivity of Bacillus subtilis, Staphylococcus aureus, Streptococcus faecalis and Streptococcus pyogenes LTAs in the LAL test. The estimates of suspected LPS content were 605, 10.3, 6.2 and 127 pg/MUg LTA, respectively. The effectiveness of LTAs to induce the NO production in rat peritoneal cells was remarkably higher than that of equivalent concentrations of reference LPS (Escherichia coli). The LPS-induced NO was inhibited by polymyxin B (PMX), the IC(50) of PMX:LPS concentration ratio (pg:pg) being 1050:1. Many fold higher concentrations of PMX were needed to partially suppress the NO-augmenting effects of LTAs, applied at concentrations representing the equivalents of LPS. Transposed to the concentrations of LTAs per se, the IC(50)s of the PMX:LTA ratios (MUg:MUg) ranged from 0.3:1 (S. aureus) to 7.5:1 (B. subtilis). It is concluded that LTA is not necessarily contaminated with LPS. The results prove the intrinsic immunostimulatory properties of LTAs of Gram-positive bacteria. The positive response of LTA in the LAL assay results from its capacity to bind to LAL. In addition, LTA binds with high affinity to PMX. PMID- 20850559 TI - Testosterone modulates pituitary vasotocin receptor expression and adrenal activity in osmotically stressed chicken. AB - Regulation of arginine vasotocin (AVT), avian neurohypophyseal hormone, is an important component of the hypothalamo-pituitary-adrenal axis. Changes in plasma osmolality levels and sex steroids are known to affect AVT gene expression. The present study reports the effect of water deprivation and testosterone treatment independently, as well as simultaneously, on the pituitary vasotocin receptor VT2R expression and adrenal steroidogenic activity in sexually immature male chicken (Gallus gallus). Birds were divided into four groups- control, water deprived (WD), testosterone injected (TE) and TE treated water deprived (TE+WD). WD decreased and TE treatment alone or in combination with WD (TE+WD) increased VT2R expression compared to the control. Expression of pro-opiomelanocortin (POMC) was also studied since this gene is a polypeptide precursor of ACTH and is under the negative feedback of adrenal corticoids. TE treatment as well as WD separately or when coupled together decreased the POMC mRNA expression in the pituitary but stimulated adrenal steroidogenic activity. Further, VT2R expression decreased in TE+WD compared to TE group, but it was not different from the vehicle treated control group suggesting that the suppressive effect of WD on VT2R expression was inhibited by the stimulatory effect of testosterone. Similarly, although both TE and WD decreased POMC expression and increased steroidogenic activity, no further decrease or increase in these parameters was observed when these two (WD and TE) treatments were combined together. Although, the exact mechanism is not clear, data indicate a stimulatory action of testosterone on VT2R expression and adrenal function despite a decreased expression of POMC mRNA. Results also suggest that testosterone treatment to sexually immature birds, in addition to its effect on hypothalamic AVT neurons (earlier study) and pituitary VT2R expression (present study), masks or inhibits osmotic stress-induced alterations in pituitary-adrenal activity. PMID- 20850560 TI - Herbivorous reptiles and body mass: effects on food intake, digesta retention, digestibility and gut capacity, and a comparison with mammals. AB - Differences in the allometric scaling between gut capacity (with body mass, BM1.00) and food intake (with BM0.75) should theoretically result in a scaling of digesta retention time with BM0.25 and therefore a higher digestive efficiency in larger herbivores. This concept is an important part of the so-called 'Jarman Bell principle' (JBP) that explains niche differentiation along a body size gradient in terms of digestive physiology. Empirical data in herbivorous mammals, however, do not confirm the scaling of retention time, or of digestive efficiency, with body mass. Here, we test these concepts in herbivorous reptiles, adding data of an experiment that measured food intake, digesta retention, digestibility and gut capacity in 23 tortoises (Testudo graeca, T. hermanni , Geochelone nigra, G. sulcata, Dipsochelys dussumieri) across a large BM range (0.5-180 kg) to a literature data collection. While dry matter gut fill scaled to BM1.07 and dry matter intake to BM0.76, digesta mean retention time (MRT) scaled to BM0.17; the scaling exponent was not significantly different from zero for species > 1 kg. Food intake level was a major determinant of MRT across reptiles and mammals. In contrast to dietary fibre level, BM was not a significant contributor to dry matter digestibility in a General Linear Model. Digestibility coefficients in reptiles depended on diet nutrient composition in a similar way as described in mammals. Although food intake is generally lower and digesta retention longer in reptiles than in mammals, digestive functions scale in a similar way in both clades, indicating universal principles in herbivore digestive physiology. The reasons why the theoretically derived JBP has little empirical support remain to be investigated. Until then, the JBP should not be evoked to explain niche differentiation along a body size axis in terms of digestive physiology. PMID- 20850562 TI - What's in a name? The argument for changing the name of IAEMS and its affiliated societies. AB - We identify trends over the past decades in membership in societies affiliated with the International Association of Environmental Mutagen Societies (IAEMS), and we also highlight findings in a recent review by Claxton et al. [Environ Health Perspect, in press] regarding the numbers of papers published per year using genetic toxicology assays. These analyses reveal a decline or at best a static level of membership in IAEMS-affiliated societies, as well as a decline in the number of papers published per year using genetic toxicology assays-with the exception of those using comet assays, which already have begun to plateau. In contrast, toxicogenomics and computational toxicology are becoming increasingly prominent relative to environmental mutagenesis research in most research institutes, reflecting the ascendancy of these areas of environmental toxicology. We conclude that changing the name of IAEMS and its affiliated societies to reflect these changes might enhance membership and publication by welcoming a broader range of scientists into these societies. Although various names are possible, we think that changing the name of these societies to "Environmental Genomics Society" may help to make our societies more attractive to a broader range of scientists, resulting in an increase in membership and an acceleration of the incorporation of genomic methods into environmental research. PMID- 20850561 TI - Natural killer T cells: innate lymphocytes positioned as a bridge between acute and chronic inflammation? AB - Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In this review, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their early recruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation. PMID- 20850563 TI - SCN5A mutations in atrial fibrillation. PMID- 20850564 TI - R231C mutation in KCNQ1 causes long QT syndrome type 1 and familial atrial fibrillation. AB - BACKGROUND: Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K(+) channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF). However, KCNQ1 mutation pleiotropy, which is capable of expressing both LQT1 and FAF, has not been demonstrated for a discrete KCNQ1 mutation. The genotype-phenotype relationship for a family with FAF suggests a possible association with the LQT1 p.Arg231Cys-KCNQ1 (R231C-Q1) mutation. OBJECTIVE: The purpose of this study was to determine whether R231C-Q1 also can be linked to FAF. METHODS: The R231C-Q1 proband with AF underwent genetic testing for possible mutations in 10 other AF-linked genes plus KCNH2 and SCN5A. Sixteen members from five other R231C-positive LQT1 families were genetically tested for 21 single nucleotide polymorphisms (SNPs) to determine if the FAF family had discriminatory SNPs associated with AF. R231C-Q1 was expressed with KCNE1 (E1) in HEK293 cells, and Q1E1 currents (I(Q1E1)) were analyzed using the whole-cell patch-clamp technique. RESULTS: Genetic analyses revealed no additional mutations or discriminatory SNPs. Cells expressing WT-Q1 and R231C-Q1 exhibited some constitutively active I(Q1E1) and smaller maximal I(Q1E1) compared to cells expressing WT-Q1. CONCLUSION: Constitutively active I(Q1E1) and a smaller peak I(Q1E1) are common features of FAF-associated and LQT1-associated mutations, respectively. These data suggest that the mixed functional properties of R231C-Q1 may predispose some families to LQT1 or FAF. We conclude that R231C is a pleiotropic missense mutation capable of LQT1 expression, AF expression, or both. PMID- 20850565 TI - Trigger-specific risk factors and response to therapy in long QT syndrome type 2. AB - BACKGROUND: Cardiac events in patients with long QT syndrome type 2 (LQT2) are predominately associated with sudden arousal. However, exercise-induced events also occur in this population. OBJECTIVE: The purpose of this study was to test the hypothesis that risk factors show a trigger-specific association with cardiac events in LQT2 patients. METHODS: The study population consisted of 634 genetically confirmed LQT2 patients from the U.S. portion of the International LQTS Registry. Multivariate Cox proportional hazards regression analysis was used to determine the independent contribution of clinical and genetic risk factors to the first occurrence of trigger-specific cardiac events, categorized as arousal, exercise-induced, and nonarousal/nonexercise, from birth through age 40 years. RESULTS: Study patients experienced 204 cardiac events during follow-up, of which 44% were associated with arousal triggers, 13% with exercise activity, and 43% with nonexercise/nonarousal triggers. Risk factors for arousal-triggered cardiac events included gender (female:male > 13 years: hazard ratio [HR] 9.10, P < .001) and the presence of pore-loop mutations (HR 2.19, P = .009). In contrast, non pore-loop transmembrane mutations were the predominant risk factor for exercise triggered events (HR 6.84, P < .001), whereas gender was not a significant risk factor for this endpoint. Nonexercise/nonarousal events were associated with heterogeneous causes. Risk factors for this endpoint included gender, mutation location and type, and prolonged QTc (>= 500 m) Beta-blocker therapy was associated with a pronounced reduction in the risk for exercise-triggered events (HR 0.29, P < .01) but had a nonsignificant effect on the risk for arousal and nonexercise/nonarousal events. CONCLUSION: The study findings suggest that management of patients with the LQT2 genotype should use a trigger-specific approach to risk assessment and medical therapy. PMID- 20850566 TI - Contribution of microarray data to the advancement of knowledge on the Mycobacterium tuberculosis interactome: use of the random partial least squares approach. AB - Following the central dogma of molecular biology, where data flows from gene to protein through transcript, information on gene expression provides information on the functional state of an organism. Microarray technology arose to measure the expression level of thousands of genes simultaneously. These vast amounts of data generated at all levels of biological organization help to identify co expressed genes, which may reveal proteins interacting in a complex or acting in the same pathway without direct physical contact. Discovering associations of regulatory patterns of characterized proteins with those of hypothetical proteins may identify functional relationships between them and facilitate the characterization of proteins of unknown function. Here we make use of the random partial least squares regression technique (r-PLS) to trace connections between co-expressed genes in Mycobacterium tuberculosis using data downloaded from public microarray databases. We generated the overall topology of a microbial co expression network with the exact complexity of the model. This approach provides a general method for generating a co-expression network of an organism for the purpose of systems-level analyses. PMID- 20850567 TI - Outcome instruments to measure frailty: a systematic review. AB - Frailty is one of the greatest challenges for healthcare professionals. The level of frailty depends on several interrelated factors and can change over time while different interventions seem to be able to influence the level of frailty. Therefore, an outcome instrument to measure frailty with sound clinimetric properties is needed. A systematic review on evaluative measures of frailty was performed in the databases PubMed, EMBASE, Cinahl and Cochrane. The results show numerous instruments that measure the level of frailty. This article gives a clear overview of the content of these frailty instruments and describes their clinimetric properties. Frailty instruments, however, are often developed as prognostic instruments and have also been validated as such. The clinimetric properties of these instruments as evaluative outcome measures are unclear. PMID- 20850568 TI - Anti-fibrillin-1 autoantibodies in normal pregnancy and recurrent pregnancy loss. AB - PROBLEM: The aim of this study was to investigate anti-fibrillin-1 autoantibody in patients with a history of recurrent pregnancy loss (RPL) and during normal pregnancy. METHOD OF STUDY: Anti-fibrillin-1 IgG and IgM antibodies were measured by a home made ELISA in serum samples of 48 medically and obstetrically normal pregnant women, classified to three trimester groups, 15 female patients with RPL and 26 healthy non-pregnant women classified to two control subgroups: (a) women who had already had at least one previous successful pregnancy and (b) women who had never been pregnant. Differences in anti-fibrillin-1 autoantibodies between the groups were analyzed for statistical significance (P<0.05) with one-way analysis of variance (ANOVA) and multiple comparison test - Post Hoc test, Least Significant Difference method. RESULTS: Anti-fibrillin-1 IgM autoantibodies were significantly decreased in the second and third trimester pregnant women compared to the nulligravida controls. RPL patients had significantly increased anti fibrillin-1 IgM antibody compared to control group (a). CONCLUSION: Fibrillin-1 degradation seems to be decreased during the second and third trimester of normal pregnancy. Increased anti-fibrillin-1 IgM antibodies in RPL patients may be a secondary phenomenon of increased fibrillin-1 degradation and contribute to the pathogenesis of pregnancy losses. PMID- 20850569 TI - Systemic lupus erythematosus: clinical presentations. AB - Systemic lupus erythematosus is a complex multisystem autoimmune disease that affects 1 in 2000 adult women in the United Kingdom. Lupus affects Afrocaribbeans and South Asians more frequently and more severely than white British. The disease can affect almost any part of the body and is characterised by remission and relapses. It is most common in women of reproductive age but can present at any age from 1 to 90 years and in men, but the diagnosis is probably missed in some men. It is important to distinguish active lupus features due to inflammatory and thrombotic mechanisms from chronic damage and to be aware that infection is an important trigger that may co-exist or mimic lupus activity. The disease is associated with a variety of autoantibodies that can help in making the diagnosis. Monitoring the disease is usually done using a clinical disease activity index such as the BILAG index, anti-dsDNA antibodies, C3 and C4 levels. Anti-C1q antibodies may have a role in monitoring the disease and in predicting those at risk of renal involvement or flare. The prognosis depends on the organs involved. There is an increased risk of premature atherosclerosis as a complication of lupus and this and infection are the most common causes of death in lupus patients. PMID- 20850570 TI - Recent insights into the role and molecular mechanisms of the autoimmune regulator (AIRE) gene in autoimmunity. AB - Since many years immunologists have being tried to answer the tantalizing enigma of immunological tolerance. Complex mechanisms in both thymus (central tolerance) and peripheral lymphoid organs (peripheral tolerance) underly lymphocyte tolerance and its maintenance. The genesis of autoimmunity involves environmental and genetic mechanisms, both contributing to the disruption and deregulation of central and peripheral tolerance, allowing autoreactive pathogenetic T and B-cell clones arising. Among genetic factors the autoimmune regulator (AIRE) gene is one of the best candidates to understand the complex scenario of autoimmunity. Autoimmune polyendocrinopathy syndrome type 1 is a rare autosomal recessive disease caused by mutations in the AIRE gene. Therefore, the disorder has certainly been a powerful model to address the question concerning how a tolerant state is achieved or maintained and to explore how it has gone lost in the context of autoimmunity. AIRE has been proposed to function as a 'non classical' transcription factor, strongly implicated in the regulation of organ-specific antigen expression in thymic epithelial cells and in the imposition of T cell tolerance, thus regulating the negative selection of autoreactive T cell clones. A plethora of proposal have been suggested for AIRE's potential mechanism of action, thus regulating the negative selection of autoreactive T cells. In this review recent discoveries are presented into the role and molecular mechanisms of the AIRE protein in APECED and other autoimmune diseases. PMID- 20850571 TI - The impact of human pregnancy on perceptual responses to chemoreflex vs. exercise stimulation of ventilation: a retrospective analysis. AB - We examined the impact of human pregnancy on breathlessness intensity at matched levels of ventilation (VE) during isoxic hyperoxic CO2 rebreathing and incremental cycle exercise tests in 21 healthy women in the third trimester (TM3) and again ~5 months post-partum (PP). Pregnancy had no significant (P > 0.05) effect on the slope or threshold of the breathlessness intensity-VE relationship during both exercise and rebreathing. By contrast, the slope of the breathlessness intensity-VE relationship was significantly higher, while the threshold of this relationship was consistently lower during rebreathing vs. exercise (both P < 0.05), regardless of pregnancy status (P > 0.05). As a result, breathlessness intensity was markedly higher at any given VE (e.g., by ~4 Borg units at 40 L/min) during rebreathing vs. exercise, regardless of pregnancy status. Inter-subject variation in breathlessness intensity-VE slopes during exercise was not associated with inter-subject variation in breathlessness intensity-VE slopes during rebreathing or with increased central chemoreflex responsiveness during pregnancy (both P > 0.05). In conclusion, the intensity of perceived breathlessness for a given VE depends, at least in part, on the nature and source of increased central respiratory motor command output, independent of pregnancy status; and pregnancy-induced increases in activity-related breathlessness cannot be easily explained by increased central chemoreflex responsiveness. PMID- 20850572 TI - Ethical arguments relevant to the use of GM crops. AB - The Nuffield Council on Bioethics (NCOB) has published two reports (1999 and 2004) on the social and ethical issues involved in the use of genetically modified crops. This presentation summarises their core ethical arguments. Five sets of ethical concerns have been raised about GM crops: potential harm to human health; potential damage to the environment; negative impact on traditional farming practice; excessive corporate dominance; and the 'unnaturalness' of the technology. The NCOB examined these claims in the light of the principle of general human welfare, the maintenance of human rights and the principle of justice. It concluded in relation to the issue of 'unnaturalness' that GM modification did not differ to such an extent from conventional breeding that it is in itself morally objectionable. In making an assessment of possible costs, benefits and risks, it was necessary to proceed on a case-by-case basis. However, the potential to bring about significant benefits in developing countries (improved nutrition, enhanced pest resistance, increased yields and new products) meant that there was an ethical obligation to explore these potential benefits responsibly, to contribute to the reduction of poverty, and improve food security and profitable agriculture in developing countries. NCOB held that these conclusions were consistent with any practical precautionary approach. In particular, in applying a precautionary approach the risks associated with the status quo need to be considered, as well as any risks inherent in the technology. These ethical requirements have implications for the governance of the technology, in particular mechanisms for enabling small-scale farmers to express their preferences for traits selected by plant breeders and mechanisms for the diffusion of risk-based evaluations. PMID- 20850573 TI - Cell free expression put on the spot: advances in repeatable protein arraying from DNA (DAPA). AB - We have previously described the 'DNA array to protein array' (DAPA) method for microarraying of proteins expressed by cell-free systems in situ on the array surface. In this technique, a DNA array on one slide acts as the template for generating a protein array on a second slide, mediated by a cell free lysate between the two juxtaposed slides. Here we explore the feature of the repeatability of the technology, in which the same DNA array is reused several times, and use the method to generate a microarray of 116 diverse proteins. The capabilities of DAPA technology in comparison with other protein array methods are discussed. PMID- 20850574 TI - Subchondral bone loss following orthodontically induced cartilage degradation in the mandibular condyles of rats. AB - Osteoarthritis (OA) is a degenerative joint disease generally characterized by progressive cartilage degradation and subchondral bone changes. Subchondral bone changes have been proposed to initiate or accompany with cartilage degradation in OA. The purpose of this study was to characterize cartilage damage, subchondral bone remodeling, and the possible mechanism involved in these morphological changes in our reported rat model with OA-like lesions in the mandibular condyle. In experimental groups, the dental occlusion was orthodontically disturbed. By histological analysis, transmission electron microscopy (TEM), micro-CT scanning and serum tests, changes in condylar cartilage and subchondral bone were analyzed at 8 and 12 weeks after treatment. The mRNA and protein levels of bone pro resorptive and pro-formative factors by chondrocytes were investigated. Increased degraded cartilage areas and obvious cartilage calcification were observed in 8- and 12-week treated (EXP) groups compared to the age-matched controls. Subchondral bone loss, characterized as decreased bone mineral density (BMD), bone volume fraction (BV/TV) and trabecular thickness (Tb.Th), but increased trabecular separation (Tb.Sp), was observed in the 12-week but not the 8-week EXP group, respectively, versus their age-matched controls. The subchondral bone loss in the 12-week EXP group was accompanied with decreased new bone formation rate, but increased serum carboxy terminal telopeptides (CTXs), and increased osteoclast numbers and proportion of surface area in the subchondral bone regions. Increased mRNA and protein levels of M-CSF, VEGF, RUNX and RANKL/OPG ratio, but decreased OPG, were found in condylar cartilage in the 12-week EXP group versus its age-matched controls, and those of RANKL/OPG ratios were significantly higher in the 12-week EXP group than the 8-week EXP. In addition, increased mRNA levels of VEGF, RUNX and RANKL/OPG ratio, but decreased OPG, were also found in condylar cartilage in the 8-week EXP group versus its age-matched controls (All P<0.05). This study demonstrated that obvious subchondral bone loss followed cartilage degradation in the mandibular condyles in the present rat models and suggested that the imbalance of chondrocyte-secreted regulatory factors within the degraded cartilage may play a role in the osteoclastogenesis, and thus leading to the subchondral bone loss in OA. PMID- 20850575 TI - The role of the calcitonin receptor in protecting against induced hypercalcemia is mediated via its actions in osteoclasts to inhibit bone resorption. AB - Despite the therapeutic value of calcitonin in treating bone disease, a biological role of endogenous calcitonin is controversial. Having previously demonstrated that the CTR has a biological role in protecting against calcium stress using a global CTRKO mouse model, the purpose of this study was to determine whether the protection conferred by the CTR during induced hypercalcemia is mediated via CTR expression on osteoclasts. Mice were generated, in which the CTR was deleted specifically within osteoclasts (OCL-CTRKOs) and compared with mice in which the CTR was deleted globally (global CTRKOs). Significantly, peak serum calcium levels following induced hypercalcemia were >18% higher in global-CTRKOs and OCL-CTRKOs than controls (P<0.01) due to increased bone resorption (P<0.05). Peak serum calcium levels relative to controls were greater in global-CTRKO males than OCL-CTRKO males (P<0.001), which may, at least in part, be due to increased reabsorption of calcium in the kidney (P<0.01). Controls for all analyses were sex-matched littermates with normal CTR expression. In conclusion, the CTR protects against hypercalcemia predominantly via its inhibitory action on osteoclasts. PMID- 20850576 TI - The societal burden of poor persistence to treatment of osteoporosis in Sweden. AB - OBJECTIVES: Poor persistence to prescribed treatment regimens is a well documented health problem. The issue is of particular importance in treatment of chronic diseases, such as osteoporosis. The objective of this study was to estimate the annual societal burden of real-world persistence to treatment of osteoporosis in Sweden. A second aim was to estimate the monetary net benefit of improved persistence. METHODS: The annual societal burden was evaluated in relation to perfect persistence to a five-year treatment duration and performed using a published Markov model by Strom and colleagues. The target population was extracted from the Swedish Prescribed Drug Register and based on all treatment naive patients who started therapy of primary osteoporosis in Sweden during 2009. Five hypothetical interventions were investigated, with improvements in the persistent proportion of between 10% and 50%. RESULTS: Annually, a total of 1018 fractures were estimated to be caused by non-persistence to treatment of osteoporosis in Sweden. These fractures resulted in a substantial waste of health care resources related to morbidity (?26 million annually) and a loss, in total, of 771 quality-adjusted life-years (QALYs). Using a societal willingness-to-pay for a QALY of ?60000, the total annual societal burden, incorporating both monetary consequences and health effects, was estimated at ?62.76 million. Given current Swedish cost-effectiveness guidelines, between approximately ?225 and ?1130 could be spent per patient to increase persistence, depending on the level of improvement (between 10% and 50%). CONCLUSIONS: The total annual societal burden of current, real-world persistence was estimated at ?63 million. The estimated additional fracture-related costs associated with poor persistence were larger than the current total annual expenditure on all osteoporosis medications in Sweden. Poor persistence to treatment of osteoporosis should consequently be acknowledged as an important and costly health problem, and be taken into account when evaluating osteoporosis interventions. PMID- 20850577 TI - Alteration of contraction-to-rest ratio to optimize trabecular bone adaptation induced by dynamic muscle stimulation. AB - Disuse osteopenia has shown to decrease bone mineral density and compromise bone's integrity, i.e., in aging population and long-term functional disuse. The degree of attenuation of trabecular bone loss and deterioration of its microarchitecture is closely dependent on the mechanical loading parameters within the regimen. Dynamic muscle stimulation as a preventive countermeasure for disuse osteopenia has been shown to be effective. The objective of this study is to determine whether the contraction-to-rest ratio is a crucial parameter to affect the skeletal adaptive responses under a functional disuse environment. Fifty-six skeletally matured Sprague-Dawley rats were divided into seven groups for the 4-week experiment: baseline control, age-matched control, hindlimb suspended (HLS), and HLS plus muscle stimulation with a contraction-to-rest ratio of 1/4, 2/8, 4/6, and 2/28 s. Muscle stimulation was carried out for total of 10 min/day, 5 days/week, for 4 weeks. Trabecular bone in the distal femurs was analyzed with microcomputed tomography and histomorphometry. HLS alone for 4-week resulted in a 25-45% trabecular bone loss in the distal femur. Dynamic muscle stimulation, applied at 50 Hz frequency, with a 2/8 s contraction-to-rest ratio demonstrated significant attenuation of trabecular bone loss against the 4-week disuse, with up to +74% in bone volume fraction, +164% in connectivity, +20% in trabecular number, and -18% in spacing (p<0.05). Stimulation with 1/4 and 4/6 also showed similar effects but with lesser percentage differences when comparing to the HLS animals. Similarly, histomorphometric analysis showed partial enhancement in mineralizing surface and mineral apposition rate. The results suggested the potentials of dynamic muscle stimulation in regulating skeletal adaptive responses and illustrated the effects of optimized contraction-to-rest in mitigation of bone loss, in which 2/8 s has shown maximal adaptive response among all tested ratios. PMID- 20850579 TI - Mechanical, biochemical and morphometric alterations in the femur of mdx mice. AB - The bone tissue abnormalities observed in patients with Duchenne muscular dystrophy are frequently attributed to muscle weakness. In this condition, bones receive fewer mechanical stimuli, compromising the process of bone modeling. In the present study we hypothesize that other factors inherent to the disease might be associated with bone tissue impairment, irrespective of the presence of muscle impairment. Mdx mice lack dystrophin and present cycles of muscle degeneration/regeneration that become more intense in the third week of life. As observed in humans with muscular dystrophy, bone tissue abnormalities were found in mdx mice during more intense muscle degeneration due to age. Under these circumstances, muscle deficit is probably one of the factors promoting these changes. To test our hypothesis, we investigated the changes that occur in the femur of mdx mice at 21 days of age when muscle damage is still not significant. The mechanical (structural and material) and biochemical properties and morphometric characteristics of the femur of mdx and control animals were evaluated. The results demonstrated a lower strength, stiffness and energy absorption capacity in mdx femurs. Higher values for structural (load and stiffness) and material (stress, elastic modulus and toughness) properties were observed in the control group. Mdx femurs were shorter and were characterized by a smaller cortical area and thickness and a smaller area of epiphyseal trabecular bone. The hydroxyproline content was similar in the two groups, but there was a significant difference in the Ca/P ratios. Thermogravimetry showed a higher mineral matrix content in cortical bone of control animals. In conclusion, femurs of mdx mice presented impaired mechanical and biochemical properties as well as changes in collagen organization in the extracellular matrix. Thus, mdx mice developed femoral osteopenia even in the absence of significant muscle fiber degeneration. This weakness of the mdx femur is probably due to genetic factors that are directly or indirectly related to dystrophin deficiency. PMID- 20850580 TI - Sclerostin antibody increases bone mass by stimulating bone formation and inhibiting bone resorption in a hindlimb-immobilization rat model. AB - Sclerostin monoclonal antibody (Scl-Ab) has been shown to increase bone mass and bone strength by stimulating bone formation in an ovariectomy-induced bone loss rat model. The purpose of this study was to determine the effects of Scl-Ab in a rat immobilization/disuse model in which there was both a decrease in bone formation and an increase in bone resorption. Ten-month-old female Sprague Dawley rats were divided into normal weight-bearing (normal-loaded, NL) and right hindlimb-immobilization (under-loaded, UL) groups. Both NL and UL rats were treated with vehicle or Scl-Ab at 5 or 25 mg/kg, twice per week for 4 weeks. Trabecular and cortical bone histomorphometric analyses were performed on the proximal tibial metaphysis (PTM) and tibial shaft (TS). Compared to NL controls, UL rats had reduced body and muscle weights, increased bone marrow fat cells in the PTM, increased trabecular bone resorption and periosteal mineral apposition rate (MAR) as well as decreased trabecular MAR and bone formation rate (BFR/BS). In NL bones, treatment with Scl-Ab significantly increased bone formation and decreased bone resorption, resulting in increased trabecular and cortical bone mass. In UL trabecular bone, treatment with Scl-Ab at 5 or 25 mg/kg induced significant and dose-dependent increases in trabecular bone volume and thickness, mineralized surfaces (MS/BS), MAR and BFR/BS, and a significant decrease in eroded surface (Er.S/BS) compared with UL controls. In UL cortical bone, Scl-Ab treatment induced significant increases in cortical width, periosteal and endocortical MS/BS, MAR and BFR/BS, and significant decreases in endocortical Er.S/BS compared with UL controls. Taken together, these findings suggest that antibody-mediated blockade of sclerostin represents a promising new therapeutic approach for the anabolic treatment of immobilization-induced osteopenia. PMID- 20850581 TI - Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide. AB - The immunoregulatory properties of mesenchymal stem cells (MSC) have been demonstrated on a wide range of cells. Here, we describe the modulatory effects of mouse bone marrow-derived MSC on BV2 microglia proliferation rate, nitric oxide (NO) production and CD40 expression. Mouse bone marrow MSC were co-cultured with BV2 cells at various seeding density ratios and activated with lipopolysaccharide (LPS). We show that MSC exert an anti-proliferative effect on microglia and are potent producers of NO when stimulated by soluble factors released by LPS-activated BV2. MSC suppressed proliferation of both untreated and LPS-treated microglia in a dose-dependent manner, significantly reducing BV2 proliferation at seeding density ratios of 1:0.2 and 1:0.1 (p<.05). Co-culturing MSC with BV2 cells at different ratios revealed interesting dynamics in NO production. A high number of MSC significantly increases NO in co-cultures whilst a lower number reduces NO. The increased NO levels in co-cultures may be MSC derived, as we also show that activated BV2 cells stimulate MSC to produce NO. Cell-cell interaction is not a requirement for this effect as soluble factors released by activated BV2 cells alone do stimulate MSC to produce high levels of NO. Although NO is implicated as a mediator for T cell proliferation, it does not appear to play a major role in the suppression of microglia proliferation. Additionally, MSC reduced the expression of the microglial co-stimulator molecule, CD40. Collectively, these regulatory effects of MSC on microglia offer insight into the potential moderating properties of MSC on inflammatory responses within the CNS. PMID- 20850582 TI - ExTech 2009 SI. PMID- 20850583 TI - Fundamentals and applications of needle trap devices: a critical review. AB - The needle trap device (NTD) is an extraction trap that contains a sorbent inside a small needle, through which fluid can be actively drawn into and out of by a gas-tight syringe or pump, or analytes can be introduced passively to the trap by diffusion. The needle trap (NT) is a potentially solventless sampling technique/sample preparation and introduction device. Both fluid-borne analytes and particles can be trapped inside the needle and then adsorbed analytes are desorbed in an inlet of analytical instrument and introduced for identification and quantification. The fluid may be either gaseous or liquid. The objectives of this critical review are to summarize the theory of the sampling process for both active and passive time-average extraction modes in addition to outlining the evolution of the technology and main applications. PMID- 20850584 TI - Novel pressurized solvent extraction vessels for the analysis of polychlorinated biphenyl congeners in avian whole blood. AB - Persistent organic pollutants remain a serious threat to many food-chain systems. New pollutants continue to emerge. The present study has created novel extraction vessels which are compatible with readily available commercial instrumentation to validate the analysis of one class of persistent organic pollutants, polychlorinated biphenyls (PCBs), in avian blood. The volumes used can be reasonably sampled without sacrificing individuals, or comprising breeding or migratorial success. The procedure consists of the pressurized solvent extraction (PSE) of analytes in a novel PSE extraction vessel. The new extraction cell contains a 38-cm long, coiled, re-packable, in situ clean-up column. Lipid elimination, using Florisil, occurs within the coiled region of the extraction vessel, eliminating the requirement for post extraction clean-up. For development, 0.2 g samples of chicken whole blood have been used. Extract volumes are reduced from (30 to 10) cm(3), compared to unmodified systems. The new PSE vessel with its integrated clean-up method showed satisfactory performance for the analysis of ten environmentally relevant PCB congeners in chicken whole blood samples with recoveries in the range of (70-130)%. Detection limits using gas chromatography coupled with large volume injection ion-trap mass spectrometry (GC LVI-ITMS-MS) were in the range of (0.05-0.5) ng g(-1). The relative standard deviations for all congeners investigated were better than 5%. This is the first PSE validation to have been conducted on unaltered whole blood samples. PMID- 20850585 TI - Determination of cyanide exposure by gas chromatography-mass spectrometry analysis of cyanide-exposed plasma proteins. AB - Exposure to cyanide can occur in a variety of ways, including exposure to smoke from cigarettes or fires, accidental exposure during industrial processes, and exposure from the use of cyanide as a poison or chemical warfare agent. Confirmation of cyanide exposure is difficult because, in vivo, cyanide quickly breaks down by a number of pathways, including the formation of both free and protein-bound thiocyanate. A simple method was developed to confirm cyanide exposure by extraction of protein-bound thiocyanate moieties from cyanide-exposed plasma proteins. Thiocyanate was successfully extracted and subsequently derivatized with pentafluorobenzyl bromide for GC-MS analysis. Thiocyanate levels as low as 2.5 ng mL(-1) and cyanide exposure levels as low as 175 MUg kg(-1) were detected. Samples analyzed from smokers and non-smokers using this method showed significantly different levels of protein-bound thiocyanate (p<0.01). These results demonstrate the potential of this method to positively confirm chronic cyanide exposure through the analysis of protein-bound cyanide in human plasma. PMID- 20850578 TI - Integrins and bone metastasis: integrating tumor cell and stromal cell interactions. AB - Integrins on both tumor cells and the supporting host stromal cells in bone (osteoclasts, new blood vessels, inflammatory cells, platelets and bone marrow stromal cells) play key roles in enhancing bone metastasis. Tumor cells localize to specific tissues through integrin-mediated contacts with extracellular matrix and stromal cells. Integrin expression and signaling are perturbed in cancer cells, allowing them to "escape" from cell-cell and cell-matrix tethers, invade, migrate and colonize within new tissues and matrices. Integrin signaling through alphavbeta3 and VLA-4 on tumor cells can promote tumor metastasis to and proliferation in the bone microenvironment. Osteoclast (OC) mediated bone resorption is a critical component of bone metastasis and can promote tumor growth in bone and alphavbeta3 integrins are critical to OC function and development. Tumors in the bone microenvironment can recruit new blood vessel formation, platelets, pro-tumor immune cells and bone marrow stromal cells that promote tumor growth and invasion in bone. Integrins and their ligands play critical roles in platelet aggregation (alphavbeta3 and alphaIIbbeta3), hematopoietic cell mobilization (VLA-4 and osteopontin), neoangiogenesis (alphavbeta3, alphavbeta5, alpha6beta4, and beta1 integrin) and stromal function (osteopontin and VLA-4). Integrins are involved in the pathogenesis of bone metastasis at many levels and further study to define integrin dysregulation by cancer will yield new therapeutic targets for the prevention and treatment of bone metastasis. PMID- 20850586 TI - An alternative method for analysis of food taints using stir bar sorptive extraction. AB - The determination of taints in food products currently can involve the use of several sample extraction techniques, including direct headspace (DHS), steam distillation extraction (SDE) and more recently solid phase microextraction (SPME). Each of these techniques has disadvantages, such as the use of large volumes of solvents (SDE), or limitations in sensitivity (DHS), or have only been applied to date for determination of individual or specific groups of tainting compounds (SPME). The use of stir bar sorptive extraction (SBSE) has been evaluated as a quantitative screening method for unknown tainting compounds in foods. A range of commonly investigated problem compounds, with a range of physical and chemical properties, were examined. The method was optimised to give the best response for the majority of compounds and the performance was evaluated by examining the accuracy, precision, linearity, limits of detection and quantitation and uncertainties for each analyte. For most compounds SBSE gave the lowest limits of detection compared to steam distillation extraction or direct headspace analysis and in general was better than these established techniques. However, for methyl methacrylate and hexanal no response was observed following stir bar extraction under the optimised conditions. The assays were carried out using a single quadrupole GC-MS in scan mode. A comparison of acquisition modes and instrumentation was performed using standards to illustrate the increase in sensitivity possible using more targeted ion monitoring or a more sensitive high resolution mass spectrometer. This comparison illustrated the usefulness of this approach as an alternative to specialised glassware or expensive instrumentation. SBSE in particular offers a 'greener' extraction method by a large reduction in the use of organic solvents and also minimises the potential for contamination from external laboratory sources, which is of particular concern for taint analysis. PMID- 20850587 TI - Highly sensitive chiral analysis of amino acids by in-line single drop microextraction and capillary electrophoresis with laser-induced fluorescence detection. AB - A highly sensitive method for chiral analysis of amino acids by in-line single drop microextraction (SDME) and chiral capillary electrophoresis (CE) with laser induced fluorescence (LIF) detection was developed. In SDME, a drop of a basic aqueous acceptor phase covered with a thin organic layer was formed at the tip of a capillary by simple combination of sample-handling sequences of a CE apparatus. Then fluorescein isothiocyanate (FITC)-derivatized amino acids in an acidic donor solution were enriched into the drop through the organic layer. The enriched enantiomers were then resolved using a dual chiral selector of beta-cyclodextrin (beta-CD) and sodium taurodeoxycholate (STC). Here, in addition to serving as a labeling reagent providing high fluorescence signal, hydrophobic FITC was primarily used as a modifier aiding the extraction of zwitterionic amino acids by blocking the amino groups and increasing the hydrophobicity, yielding 220 times increase in extraction efficiency. Several hundred-fold enrichments were achieved with 10 min SDME, yielding LODs of 30-60 pM and enabling direct analysis of d-AAs in a 99% enantiomeric excess mixture. In view of no additional modification of the existing commercial CE instrument, this method without stirring can be easily realized using known operations. When a microstirrer was customized to the CE instrument several thousand-fold enrichments could be obtained with LODs in the low picomolar range of 1-3 pM. PMID- 20850588 TI - Analysis of terpenes in white wines using SPE-SPME-GC/MS approach. AB - Terpenes contribute to some white wines aroma, especially these produced from Muscat grapes and others aromatic ones of high terpene contents (Gewurtztramminer, Traminer, Huxel, Sylvaner). Terpenes are present in wine in free and bound (in a form of glycosides) forms. Analyses of bound terpenes are usually performed using solid phase extraction after hydrolysis of glycosides. A new method for determination of terpenes from wine, focused on determination of terpenes released after acidic hydrolysis, based on solid phase extraction (SPE) followed by solid phase microextraction (SPME) was developed. Non-polar (free) and polar (bound terpenes) fractions were separated on 500 mg C18 cartridges. Bound terpenes were sampled using SPME immediately after acidic hydrolysis in non equilibrium conditions. Application of combined SPE-SPME approach allowed quantification of selected terpenes in lower concentrations than in SPE approach and added a selectivity to the method, which enabled detection of compounds non detectable in SPE extracts. Results obtained by SPE and SPE-SPME approach were correlated for free terpenes and those released after acid hydrolysis 20 white wines obtained from different grape varieties (R(2)=0.923). Although developed for wine terpenes analysis, SPE followed by SPME approach has a great potential in analysis of other bound wine flavor compounds, especially those potent odorants present in trace amounts. PMID- 20850589 TI - Methane preconcentration in a microtrap using multiwalled carbon nanotubes as sorbents. AB - The GC monitoring of green house gases is a challenging task because the concentration of organic species such as methane are relatively low (ppm to ppb) and their analysis requires some level of preconcentration. Since methane is highly volatile, it is not easily retained on conventional sorbents. In this paper we present multiwalled carbon nanotubes (MWNTs) as an effective sorbent for a microtrap designed for methane preconcentration. Its performance was compared to other commercially available carbon based sorbents, and it was found to be the most effective sorbent in terms of breakthrough volume and enthalpy of adsorption. PMID- 20850590 TI - Laser ablation single-collector inductively coupled plasma mass spectrometry for lead isotopic analysis to investigate evolution of the Bilbilis mint. AB - This work explores the performance of laser ablation-inductively coupled plasma mass spectrometry using different types of single-collector devices (sector field and time-of-flight instrumentation) for lead isotopic analysis of bronze coins, minted in the ancient city of Bilbilis. The aim of the study was achieving sufficient discrimination power to reveal similarities and differences for coins originating from different historical periods, and to obtain information on the possible source of the lead ores used in their production, while restricting the damage inflicted to the samples such that it is not visible to the naked eye. It was found that satisfactory results (RSD in the 0.15-0.30% range for (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios) could be finally obtained, despite the noisy nature of signals generated upon ablation of the highly inhomogeneous coins, by means of a methodology based on: (a) selection of the line profiling ablation mode; (b) use of a dual pass spray chamber that permits the simultaneous introduction of a solution (containing thallium of known isotopic composition), thus resulting in a wet plasma that showed an increased robustness towards matrix effects and (c) detection using a TOF-ICPMS unit, which proved to be much better suited to deal with the transient signals obtained, while being also sufficiently sensitive to obtain good counting statistics, owing to the high lead level (average around 5%) present in the samples. Moreover, under these conditions, the simultaneous aspiration of the thallium spike permitted accurate correction for mass discrimination, such that it was not necessary to use external matrix matched standards for calibration. PMID- 20850591 TI - Comparing roadsoils pollution patterns extracted by MOLMAP and classical three way decomposition methods. AB - A recent approach based on self-organizing maps (SOMs) to extract patterns from three-way data, named MOLMAP, was applied in a four-seasons study on soil pollution and its results compared with three different conventional approaches: Parallel factor analysis (PARAFAC), matrix augmented principal components analysis (MA-PCA) and Procrustes rotation. Each sampling season comprised 92 roadsoil samples and 12 analytical variables (Cd, Co, Cu, Cr, Fe, Mn, Ni, Pb, Zn, loss on ignition, pH and humidity). It was found that all techniques yielded highly similar results as the samples became organized in two major groups, each with a differentiated pollution pattern. This confirmed MOLMAP as a reliable option to handle environmental three-way datasets and to extract accurate pollution patterns. PMID- 20850592 TI - Synthetic approaches to parabens molecularly imprinted polymers and their applications to the solid-phase extraction of river water samples. AB - In this paper we describe the synthesis, characterisation and use of two distinct molecularly imprinted polymers (MIPs) prepared using esters of p-hydroxybenzoic acid (parabens) as templates: one MIP was synthesised by precipitation polymerisation using a semi-covalent molecularly imprinting strategy with methyl paraben as the template/target (MIP 1); the second MIP was prepared in monolithic form through a conventional non-covalent molecular imprinting strategy, with butyl paraben as the template (MIP 2). MIP 1 recognized methyl paraben, showed cross-selectivity for other parabens analytes used in the study and higher affinity towards these compounds than did a non-imprinted control polymer. Similarly, MIP 2 demonstrated higher affinity towards paraben analytes than a non imprinted control polymer. For the analysis of environmental water samples, a solid-phase extraction (SPE) protocol was developed using MIP 2 as sorbent, and results were compared to a SPE using a commercial sorbent (Oasis HLB). With MIP 2 as sorbent and butyl paraben as target, when percolating 500 mL of river water spiked at 1 MUg L(-1) through the SPE cartridge, and using 1 mL of isopropanol as cleaning solvent, a higher recovery of butyl 4-hydroxybenzoate (butyl paraben) and a cleaner chromatogram where achievable when using the MIP compared to the commercial sorbent. PMID- 20850593 TI - Measurement of diffuse reflectance from combinatorial samples. AB - Using a luminescence spectrometer as a platform, a system of fibre-optic probes was created that allows full colour characterisation, fluorescence and phosphorescence spectra to be recorded in diffuse reflectance and in transmission from thick or thin film arrays of combinatorial samples of diameter down to 2 mm and from liquids. An integrating sphere is not required and the method is more versatile than the instrument's fibre-optic plate reader which has conjoined fibre bundles set at a fixed angle. Incident and detected light is routed via separate optical fibre bundles which remain stationary above or below a two-axis table. The validation and calibration are described. A library of 25 members was scanned for both diffuse reflectance (colour) and fluorescence in less than an hour. The method thus combines techniques that conventionally rely on different instruments and makes them amenable for high throughput libraries. PMID- 20850595 TI - What is not working in working memory? PMID- 20850594 TI - Development and characterization of a magnetic bead-quantum dot nanoparticles based assay capable of Escherichia coli O157:H7 quantification. AB - The development and characterization of a magnetic bead (MB)-quantum dot (QD) nanoparticles based assay capable of quantifying pathogenic bacteria is presented here. The MB-QD assay operates by having a capturing probe DNA selectively linked to the signaling probe DNA via the target genomic DNA (gDNA) during DNA hybridization. The signaling probe DNA is labeled with fluorescent QD(565) which serves as a reporter. The capturing probe DNA is conjugated simultaneously to a MB and another QD(655), which serve as a carrier and an internal standard, respectively. Successfully captured target gDNA is separated using a magnetic field and is quantified via a spectrofluorometer. The use of QDs (i.e., QD(565)/QD(655)) as both a fluorescence label and an internal standard increased the sensitivity of the assay. The passivation effect and the molar ratio between QD and DNA were optimized. The MB-QD assay demonstrated a detection limit of 890 zeptomolar (i.e., 10(-21) mol L(-1)) concentration for the linear single stranded DNA (ssDNA). It also demonstrated a detection limit of 87 gene copies for double stranded DNA (dsDNA) eaeA gene extracted from pure Escherichia coli (E. coli) O157:H7 culture. Its corresponding dynamic range, sensitivity, and selectivity were also presented. Finally, the bacterial gDNA of E. coli O157:H7 was used to highlight the MB-QD assay's ability to detect below the minimum infective dose (i.e., 100 organisms) of E. coli O157:H7 in water environment. PMID- 20850596 TI - [A homage to Sleim Ammar]. PMID- 20850597 TI - [Validation of the French version of the Sociocultural Attitudes Towards Appearance Scale-3 (SATAQ-3)]. AB - INTRODUCTION: Body image literature suggests that the sociocultural environment contributes to the development and maintenance of body dissatisfaction and eating disorders by conveying thin standards of thinness. Three main sources of sociocultural influences were highlighted: family, peers and media. These three sources of pressure can lead to the internalization of messages about the importance of thinness and beauty. Among the various sources of sociocultural influences, media appear to be the most powerful communicator of these standards. Thompson et al. [Intern J Eat Disord 35 (2004) 293-304] developed a multidimensional questionnaire to assess the sociocultural influence of media on appearance: The Sociocultural Attitudes Towards Appearance Scale-3 (SATAQ-3). The SATAQ-3 is a 30-item scale composed of Likert-items in five points (1: completely disagree; 5: completely agree) including four subscales: information, pressures, internalization-general and internalization-athlete. This scale is used in Anglo Saxon research, notably in clinical populations presenting eating disorder pathologies. People with eating disorders generally show higher scores on these four subscales. OBJECTIVE: The present study is to validate the French version of the SATAQ-3. METHOD: The sample consisted of 818 teenagers from private and public middle schools aged an average of 16.8 +/- 1.2 years old, with an average body mass index (BMI) of 20.7 +/- 2.9. Participants completed two questionnaires: the body shape questionnaire (BSQ) assessing body dissatisfaction, in particular worries about weight and body shape, and the SATAQ-3. We carried out the translation of the SATAQ-3 in parallel back-translation. First, two French speaking people translated the English version into French. Then, two English speakers translated the French version without the assistance of the original version. Thereafter, the two English-language versions (original version and version obtained by back-translation) were compared in order to ensure that there were no errors of meaning in the French version. RESULTS: A factorial analysis of the SATAQ-3 was conducted on the 818 subjects through extraction of the main components method with the extraction's rule of the curve for the Eigen values; the data was transformed through Varimax rotation. The factorial analysis showed five factors with Eigen values greater than 1 (11.3; 2.6; 2.1; 1.6; 1.07). The factors were then composed of the items presenting substantial saturation, greater than or equal to 0.5. Since only one item (20) presented saturation on factor 5, the four-factor solution was retained. These four factors accounted for 17.7, 16.3, 9.7 and 14.8% of the overall variance, respectively. This four-factor solution explains 58.5% of the total variance. The oblique rotation analysis underlined moderate to strong correlations between the four factors (0.3 to 0.66). The four factors of the factorial analysis correspond to the four subscales of the initial American study: pressures (Cronbach's alpha=0.89), information (Cronbach's alpha=0.87), internalization-athlete (Cronbach's alpha=0.82), internalization-general (Cronbach's alpha=0.92). The four subscales are positively correlated with the BSQ (0.26 to 0.55). The correlation for age and BMI indicates a very low association between these two variables and the SATAQ-3 subscales, with only one significant correlation (SATAQ-3 pressures and BMI=0.14; p<0.05). Results of a regression analysis showed that body dissatisfaction (BSQ) was predicted by pressures (beta=0.37, t=10.2; p<0.0001), internalization-general (beta=0.29, t=8.1; p<0.0001). This model accounted for 38.1% of the variance of body dissatisfaction. DISCUSSION: This study shows elements of satisfactory validity for the French version of the SATAQ-3. Indeed, as for the original scale validation, the current factorial analysis revealed four factors corresponding to the four subscales developed by the authors along with similar alpha values. Research relating to the risk factors in the development of body image disturbances and eating disorders are important given their implications for future strategies of intervention and prevention. Anglo Saxon research identified media as a powerful and influential communicator concerning sociocultural standards of beauty. Because of the lack of French studies on this subject, the newly validated SATAQ-3 could provide a means for exploring new issues related to eating disorders in this population. Implications of the SATAQ-3 are multiple, particularly to detect "risk groups" and to prevent body image disturbance and eating behaviours. The current results provide a means for research on media influence, notably in French clinical samples with eating disorders. PMID- 20850598 TI - [Neuro-anatomic activations of prepotent responses in schizophrenia in Hayling's task]. AB - OBJECTIVES: In schizophrenia, alteration in the prefrontal cortex can induce some deficiencies of the executive functions, and among them errors in inhibition of prepotent responses. This type of inhibitory processes was called "restraint function" by Hasher et al. It implies a conscious and voluntary inhibition which demands attentional resources. Among the tasks exploring this function, the Hayling completion sentence task (Burgess and Shallice) appears to be the most specific. Moreover, healthy subjects performing this task in functional magnetic resonance imaging (fMRI) show activation of the prefrontal cortex. In this study, we investigated inhibitory processes in schizophrenic patients using two versions of the Hayling completion sentence task, a behavioural version and an fMRI version in order to assess both performance levels and brain correlates of inhibitory processes. METHODS: Forty-eight schizophrenic participants according to DSM-IV, (mean age: 32.8, S.D. 7.7), stabilized for at least one month, receiving antipsychotic medication and with IQ higher than 70 (mean: 96.86, S.D. 20.67) and education level (mean: 11.15, S.D. 3.26) participated in the behavioural study. They were matched on age (mean: 33.8, S.D. 7.6) and education level (mean: 12.28, S.D. 2.87) with thirty-two healthy controls. Nineteen of schizophrenic participants (mean age: 33, S.D. 6.9 and IQ: 99, S.D. 10.74) were assessed by an fMRI adaptation of the Hayling task, matched with 12 controls (mean: 33.9, S.D. 7.3). All the participants had to perform the Hayling task and a speed accuracy task. The Hayling task consists in sentences for which the last word is missing. In the initiation condition, the participants had to complete the sentence with the appropriate word, whereas in inhibition condition the participants had to complete the sentence with inappropriate and unrelated words. RESULTS: Compared to controls, schizophrenics showed an increased number of errors in the inhibition of prepotent responses associated with increased reaction times, even when considering information processing speed. fMRI results showed fairly similar frontal activations in both groups. Nevertheless, schizophrenic patients presented principally large activations in dorsolateral and ventrolateral frontal cortex, the superior frontal sulcus, the frontal pole and the premotor cortex, and stronger activations (bilateral) in the posterior parietal cortex. Control subjects demonstrated a network of deactivated brain regions whereas the schizophrenics did not. DISCUSSION: Our results are in favour of poorer efficacy of restraint function, sometimes comprising impairment of inhibitory processes inducing errors in schizophrenics. This deficiency might be considered as insufficiency in attentional resources and/or in working memory. Hence patients cannot simultaneously restrain prepotent response and find appropriate controlled strategy for correct completion of the task. Moreover, bilateral patterns of parietal hyperactivation and absence of patterns of deactivation seem also in favour of an attentional hypothesis. The Hayling task might be interesting for assessment of inhibitory processes in schizophrenia. PMID- 20850599 TI - [Workaholism: between illusion and addiction]. AB - Workaholism surfaced some years ago as a veritable addiction in the wide sense of the term, dependence. It differs from other sorts of dependence in that it is very often viewed in a positive perspective in the sense that it conveys to the person concerned the illusion of well-being, as well as a motivation and dedication in their professional activity. During the past 30 years, several authors have attempted to define this concept and to determine its characteristics. Robinson believes that workaholics have an approach to life whereby their work feeds on time, energy and physical activity. This provokes consequences that affect their physical health and interpersonal relationships. They have a tendency to live in the future rather than in the present. For Scott, Moore and Micelli , the compulsion for work is not necessarily viewed as being detrimental to one's health. Spence and Robbins highlight the notion of the pleasure experienced at work in their theoretical approach. The prevalence of the dependence on work is estimated at between 27 and 30% in the general population. It is correlated to the number of hours of work per week and tends to be higher as annual revenue increases. The sex ratio is 1, and the parents of children 5 to 18 years of age are the most susceptible to considering themselves workaholics. The physical and psychological consequences of professional exhaustion are characterized primarily by the decrease in self-esteem, symptoms of fatigue, anxiety, depression, irritability and the manifestation of physical problems including cardiovascular ailments, as evidenced by hypertension, as well as heart and kidney complications. All the theoretical point of views, from the psychoanalytical models to the contemporary models, highlight self esteem as being the centerpiece of the question regarding the problem of workaholism. In fact, the narcissism articulated from the sociological evolution of our western way of life permits us to delineate the psychic identity of the individual better, and therefore, to understand this reconstructive attempt of one's self better. In characterizing the personality traits of workaholic individuals, the doctor/therapist is required to deal with this new form of dependence as early as possible, in order to anticipate and avert the numerous personal, professional, social, relational and sanitary complications. Faced with this large prevalence of dependence on work, it seems important to us to look for a symptomatology that would emanate a signal of workaholism so as to envisage and propose to workaholic patients a specific course of action that would be adapted to their needs. PMID- 20850600 TI - [Validation of the French version of the expanded Brief Psychiatric Rating Scale with anchor BPRS-E(A)]. AB - INTRODUCTION: The Brief Psychiatric Rating Scale was initially developed as a rapid method to assess symptom change in psychiatric inpatients of various diagnoses. The original version was expanded to an 18-item version and thereafter to a 24-item version to increase sensitivity to a broader range of psychotic and affective symptoms. The latest version of the expanded 24- item BPRS provides probe questions and detailed anchor points for the ratings for each item. LITERATURE FINDINGS: Studies have shown the expanded and anchored 24-item BPRS to be a sensitive and effective measure of psychiatric symptoms with good interrater reliability that can be maintained over time. To our knowledge, there are eight published papers including factor analyses of the BPRS-E(A). While many similarities are evident between these studies, inconsistencies are apparent that may have been due to sample size, characteristics and / or methodological differences in the factor analysis computation. Among these studies, six provided a four-factor solution. There was no French version of this scale available. METHODS: After its translation into French and back translation, we investigated the validity of the French BPRS-E(A) version. We carried out a component analysis on the data of 111 participants of various diagnoses, mostly hospitalised for a first psychotic episode, yielding to a three-factor solution (positive symptoms- disorganisation; depression-anxiety and negative symptoms). RESULTS: A good internal consistency and interrater reliability were found. These results confirm the psychometric value of the BPRS-E(A) in its French version. We compared those findings to earlier reports; similarities and differences are discussed. PMID- 20850601 TI - [The Alexithymia Questionnaire for Children (AQC): French translation and validation study in a convenience sample of 80 children]. AB - INTRODUCTION: Alexithymia refers to a specific disturbance in psychic functioning characterized by a limited ability to identify and communicate one's feelings. Development of specific rating scales and notably the well-validated 20-item Toronto alexithymia Scale (TAS-20) have allowed the study of alexithymia in numerous samples of clinical or non-clinical subjects. Recently, Rieffe et al. [Pers and Individ Differ 40 (2006) 123-133] have developed an alexithymia questionnaire for children (AQC) basing on the TAS-20. The AQC comprised 20 items divided into three subscales: difficulty-identifying feelings (DIF), difficulty describing feelings (DDF) and externally-oriented thinking (EOT). Using a sample of 740 children and the Dutch version of the AQC the three-factor structure of alexithymia was found, using confirmatory factorial analysis, but the EOT factor showed low factor loadings and reliability. OBJECTIVE: The aim of the study was to present the French version of the AQC and to assess the psychometric properties of this version. METHODS: Eighty children recruited from a convenience sample were included in the study. There were 43 boys and 37 girls with a mean age of 11.81 (SD = 1.99, range: 9-16). The validity and the reliability of the AQC were studied using a confirmatory factorial analysis (CFA), the determination of the Cronbach alpha coefficient, and the calculation of the correlations between each item and the total score. RESULTS: Adequation parameters of the CFA showed that the 3-factor solution of the AQC was adequate (chi 2/df = 1.27, RMSEA = .039) although the EOT factor had low factor loadings. The Cronbach alpha coefficient was 0.64 and 15 items had significant correlations with the total score. CONCLUSION: The three-factor model of the AQC was reported for the French version of scale but the EOT factor had low validity. This result confirms the recent study using the Dutch version of the AQC. Moreover, several studies using foreign versions of the TAS-20 reported low reliability of the EOT factor. Thus, other studies are necessary to explore the reliability of the EOT factor of the French version of the AQC, and it's recommended to use only the total score of the AQC instead of the sub-scores. PMID- 20850602 TI - [Neurological soft signs in pervasive developmental disorders]. AB - BACKGROUND: Many studies have focused on specific motor signs in autism and Asperger's syndrome, but few has been published on the complete range of neurological soft signs (NSS) in children with pervasive developmental disorder (PDD). Scarce are the studies evaluating NSS in children suffering from PDD not otherwise specified (PDDNOS). METHODS: This study compared performance of 11 autistic children (AD) and 10 children with PDDNOS, with controls matched on age, sex and cognitive performance on Krebs et al.'s NSS scale. Because of the duration of the assessments and specific difficulties encountered in managing some items, an adaptation of the scale had to be made during a pilot study with the agreement of the author. To be eligible, patients had to meet the following inclusion criteria: an age range of 6-16 years, a diagnosis of autistic disorder or PDDNOS based on the DSM IV criteria (American Psychiatric Association 1994). The autism diagnostic interview-revised (ADI-R) was used in order to confirm the diagnosis and to evaluate the association of the symptoms to the severity of the NSS. The childhood autism rating scale (CARS) was completed for the patients in order to evaluate symptoms at the time of the NSS examination. Cognitive ability was assessed with Raven's progressive matrices. Were excluded patients with: history of cerebral palsy, congenital anomaly of the central nervous system, epilepsy, known genetic syndrome, tuberous sclerosis, neurofibromatosis, antecedent of severe head trauma, Asperger's syndrome, obvious physical deformities or sensory deficits that would interfere with neurological assessment, deep mental retardation and recent or chronic substance use or abuse. Healthy controls shared the same exclusion criteria, with no personal history of neurological, psychiatric disorder or substance abuse, no family history of psychiatric disorder and normal or retardation in schooling. All study procedures were approved by the local Ethics Committee (Comite d'ethique, Razi Hospital), according to the declaration of Helsinki. RESULTS: There was no difference between patients and controls with respect to sex, age and cognitive function. All children had an IQ higher than 81. Significant differences were found between AD children and control group in the motor integration function and sensory integration function. Different NSS scores were significantly higher in the PDDNOS group than in controls: the total scores, motor coordination, motor integration function, sensory integration and abnormal movements. Lower performance in motor coordination skills was associated with higher ADI-R communication score in the AD group. No relationship was found between NSS and CARS' total sore. CONCLUSION: This study confirms the impaired neurological functioning in autistic as well as PDDNOS children. The association of motor impairment with autistic symptoms highlights the argument that motor control problems can be part of the autism spectrum disorders. The lack of relationship between NSS and intellectual aptitude in the clinical sample provides new elements for the neurodevelopment model of the autism spectrum. PMID- 20850603 TI - [In Alzheimer's disease, the clinical expression of behavioral and psychological signs and symptoms is early and specific of neuropathological stages]. AB - INTRODUCTION: The early diagnosis of Alzheimer's disease is a new challenge. This study concerns 50 patients, 34 females (68 %) and 16 males (32 %) with Alzheimer (AD), according to NINCDS-ADRDA diagnostic criteria. OBJECTIVES: To systematically evaluate in all patients behavioral and psychological signs and symptoms of dementia (BPSSD), according to the stage of AD, with the patients of our population separated into two MMS groups. METHODS: The first group was composed of patients with an MMS score from 10 to 20 (eight males and 19 females). Patients of the second group had an MMS score between 21 and 28 (eight males and 19 females). The Neuro-Psychiatric Inventory (NPI) was used to collect information on the presence of BPSSD in AD patients. NPI scores were correlated to the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog) that permits evaluation of the severity of cognitive impairment in AD patients. Before starting the study, all patients gave their informed consent to participate in the study of BPSSD in AD. Statistical treatment of data was performed using STATVIEW. RESULTS: Our study demonstrates that BPSSD are present not only in early but also in moderate stages of AD. As cognitive impairment, BPSSD are an integrate part of the clinical picture. With a frequency of 74 % for the whole population, "anxiety" represented the more predominant BPSSD for all our patients at all stages of AD. At the very early stages of AD, BPSSD appeared to precede cognitive disorders. CONCLUSION: The symptomatic association of "depression", "agitation", and "irritability of mood" may remain in a steady state for a few months before the appearance of verbal episodic memory impairment, which is characteristic of hippocampus involvement. "Irritability" seems to specifically characterise the initial phase of AD. On the other hand, two BPSSD are characteristic of the late stages of AD: "sleep disorder" and "hallucinations". PMID- 20850604 TI - [Source monitoring: general presentation and review of literature in schizophrenia]. AB - SOURCE MONITORING FRAMEWORK: Source monitoring refers to the ability to remember the origin of information. Three source monitoring processes can be distinguished: external source monitoring, internal or self-monitoring and reality monitoring (i.e. discrimination between internal and external sources of information). Source monitoring decisions are based on memory characteristics recorded such as perceptions, contextual information or emotional reactions and heuristic or more controlled judgement processes. BRAIN STRUCTURES: Several studies suggested that specific structures in the prefrontal and the mediotemporal lobes are the main areas implicated in source monitoring. ASSESSMENT: A typical source monitoring paradigm includes an items generation stage and a second stage of recognition of items (old versus new) and identification of their sources: external (usually the examiner) or internal (the subject). Several indices can be calculated based on the raw data such as the number of false alarms, attribution biases or discrimination indexes. To date, there is no standardized source monitoring task and differences in the type of items used (words, pictures), in the cognitive or emotional effort involved or in the delay between the two test stages, contribute to the heterogeneity of results. FACTORS INFLUENCING SOURCE MONITORING: Factors such as age (either very young or very old) and emotions influence source monitoring performances. Influence of gender was not properly explored, whereas the role of IQ and selective attention is still debated. SOURCE MONITORING DEFICITS IN NEUROLOGICAL DISORDERS: Source monitoring deficits are observed mainly in disorders affecting frontotemporal areas, such as frontal trauma, Alzheimer's disease or frontotemporal dementia. SOURCE MONITORING AND SCHIZOPHRENIA: Source monitoring errors (e.g. external misattribution of self-generated information) are observed in schizophrenia and seem to correlate with positive symptomatology, in particular auditory hallucinations, thought intrusion and alien control symptoms. These results are of particular interest in clinical research because source monitoring is one of the rare cognitive tests showing a correlation with the positive dimension. Source monitoring deficits have been proposed as a potential explanation for the positive symptoms and some, but not all studies lent support to this hypothesis. Heterogeneity of studied samples, in particular different criteria to define hallucinating subjects (e.g. currently versus anytime during their lives), could explain the discordant results. SOURCE MONITORING IN PSYCHIATRIC DISORDERS WITHIN THE SCHIZOPHRENIC SPECTRUM: Source monitoring impairments were observed in pharmacological models of psychosis, in first degree relatives of schizophrenic patients, and also in the general population associated with schizotypal dimensions. These results support a relationship between source monitoring deficits and some of the symptomatic dimensions of the schizophrenic spectrum but still await replication. SOURCE MONITORING AND OTHER PSYCHIATRIC DISORDERS: Some studies found source monitoring deficits in other psychiatric conditions such as mania or obsessive-compulsive disorder. Thus, those studies suggest that source monitoring deficits may be not specific to schizophrenia. CONCLUSION: Source monitoring competencies are critical for good (i.e. adapted) everyday functioning. Source monitoring deficits have been suggested as a potential explanation for some (or all) positive psychotic symptoms. However, to date, methodological inconsistencies (especially with regard to test design and choice of subjects' samples) have precluded firm, definite conclusions. PMID- 20850605 TI - [Levels of emotional awareness in alcohol-dependent patients and abstinent alcoholics]. AB - BACKGROUND: Deficits in the communication and identifying of feelings are usually observed in addiction disorders. These dysfunctions vary according to the type of addiction and are particularly marked for alcoholic subjects. The prevalence of alexithymia evolves in a nearly linear manner according to the severity and the duration of the disorder. As the duration of alcoholism and the quantity of alcohol that is consumed increase, so will the subjects' scores of alexithymia. In addition, certain authors have observed a decrease in alexithymia in abstinent subjects. Subjects having been abstinent for a long period of time were more alexithymic than those having been abstinent for a shorter period of time. However, other studies failed to confirm these findings and did not observe an increase in the levels of alexithymia in polydrug patients. It seems however that the measures of alexithymia obtained using self evaluation tools (TAS 20) lack in precision due to the fact that, even though the subject is supposed to have a deficit in the identifying and the verbalisation of his emotional states, he is asked to do his own evaluation of the said emotional states. Hence, other tools such as the level of emotional awareness scale (LEAS) offer another approach to the measuring of alexithymia, based on the everyday situations and integrated in a general model of the differentiation of emotional states (or of emotional awareness). DESIGN OF STUDY: The purpose of the study is to describe the level of emotional differentiation of alcoholic subjects, and to evaluate the development of the emotional processes following alcohol cessation. Our sample consists of 88 subjects distributed in three groups: a group of alcoholic participants who are in the process of quitting alcohol (33 subjects), a group of alcoholic participants that have been abstinent for more than 6 months (20 subjects) and a group of control participants (35 subjects). The prevalence of alexithymia is estimated by the Toronto alexithymia scale (TAS 20) which measures three factors: the difficulty to identify one's feelings (TAS 1), the difficulty to express one's feelings (TAS 2), and thoughts which are directed towards the outside world (TAS 3). The levels of emotional consciousness are estimated by the LEAS which establishes 20 scenarios in order to measure three scores: emotional consciousness "for oneself" (LEAS 1), emotional consciousness "for others" (LEAS 2) and a total score (total LEAS). RESULTS: The results show a different level of emotional awareness and alexithymia between the three groups of participants. The alcoholic participants are less conscious of their feelings and have more difficulties identifying and expressing their feelings than the control subjects. With regards to the evolution of the emotional deficit linked to alcohol withdrawal, the abstinent subjects obtain weaker scores of alexithymia than the alcoholic subjects. However, abstinent subjects continue to present more difficulties expressing their feelings than control subjects (TAS 2). On the other hand, abstinent subjects' levels of emotional awareness are once again comparable to those of control subjects. Finally, the analysis of the correlations does not show any link between the scores of alexithymia and the scores of emotional consciousness, and this for all of the groups studied. Our major result concerns the recovery of the emotional deficit of abstinent subjects (global score of TAS 20 and the score of emotional consciousness), which underlines the importance of the implementation of therapeutic protocols that focus on the emotional awareness of alcoholic subjects. PMID- 20850606 TI - [The problems with the use of benzodiazepines in elderly patients]. AB - Benzodiazepines (BZD) are widely used to treat anxiety and insomnia in elderly patients. The interest of this prescription is discussed in this article. The discussion is based on the pharmacological properties and adverse effects of BZDs in the elderly. The conclusions are that BZDs should be rarely prescribed in this population; many patients treated by BZDs should be withdrawn and therapeutic strategies, other than BZDs, should be considered to treat anxiety and insomnia in these patients. Problems posed by BZD in the aged patient are both of a pharmacodynamic and pharmacokinetic order. In comparison to young adult users, BZD users among the aged are essentially women; the latter take these medications during important periods in their lives and often have a strong comorbidity, such as cardiovascular or rhumatological problems or even psychiatric problems, such as depression or panic disorders. Aged patients who take BZD at high doses can also consume other drugs, such as alcohol, and often have a psychiatric history. Some important side effects are associated with the use of BZD; essentially concerning falls, and it has been noticed for some years that problems posed by aged car drivers can be enhanced by BZD. It is difficult to know if continual users of BZD really have an advantage over other users. However, instruments, such as an indicator in the form of an algorithm, have been developed to identify the appropriateness of prescribing BZD to elderly patients. It is obvious that it is essential, whenever possible, to have a recourse strategy for cessation, and as much as possible to use BZD with a short half-life that are not oxidised, i.e. essentially BZD that are not metabolised in the strictest sense of the term, such as lorazepam or temazepam. Daily doses must be extremely limited and duration of use should not exceed two or three months in young patients. PMID- 20850607 TI - [Hallucinations, consciousness and psychosis]. PMID- 20850608 TI - Cervical esophageal duplication cyst: case report and review of the literature. AB - Cervical esophageal duplication cysts are rare congenital anomalies that can be successfully managed surgically. These anomalies are rare causes of upper airway obstruction. We present here a case of a cervical esophageal duplication cyst in an infant, along with a review of the literature concerning this anomaly. PMID- 20850609 TI - Intrauterine rectovaginal tear during a manual attempt to rotate a neonate. AB - Intrauterine rectovaginal tears in neonates are a rare and life-threatening complication of abnormal presentation during labor. Two previous cases have been presented in the literature, of which one had a fatal outcome. The authors present a third case of a severe rectovaginal intrauterine tear that had a favorable outcome. PMID- 20850610 TI - Lumbocostovertebral syndrome with associated VACTERL anomaly. AB - Lumbocostovertebral syndrome is a rare clinical association syndrome rarely accompanied by associated VACTERL anomalies. Only one similar case has been reported previously. We describe the second case, where a male neonate born at 38 weeks of gestation had an unusually high number of congenital anomalies including thoracic hemivertebrae with kyphoscoliosis, a high anorectal malformation, dextrocardia with an atrial septal defect, renal pelvic pyelectasis, hypospadias, and congenital talipes equinovarus. PMID- 20850611 TI - Extrarenal Wilms tumor in children with unfavorable histology: a case report. AB - Extrarenal Wilms tumor is extremely rare, and only 25 cases in children have been reported to date in Japan. A 2-year-old girl presented with a large left lower quadrant abdominal mass. Abdominal computed tomography revealed a retroperitoneal tumor located below the left kidney. At laparotomy, the tumor was encapsulated without evidence of metastasis to other abdominal organs. Pathologic diagnosis of the tumor was extrarenal Wilms tumor with diffuse anaplasia. After complete tumor resection, chemotherapy was administered according to the treatment protocol (Regimen I) of the Japan Wilms Tumor Study Group. Cyclophosphamide and etoposide were administered in combination with vincristine and doxorubicin. Two years after treatment, the patient has had no evidence of recurrence. PMID- 20850612 TI - Severe gastric damage caused by button battery ingestion in a 3-month-old infant. AB - Ingestion of a button battery has been considered a serious problem, causing necrosis and perforation, when impacted in the esophagus. However, such batteries in the stomach rarely cause any harm to the gastric wall, which is regarded as evidence supporting the use of conservative treatment. We present the rare case of a 3-month-old infant with severe gastric wall injury caused by a button battery lodged in the stomach. The present case suggests that button batteries located in the stomach should be removed as soon as possible, especially in infants. PMID- 20850613 TI - Granulomatous appendicitis in a 12-year-old boy. AB - Isolated granulomatous inflammation of the appendix is extremely rare, and its etiology is still unknown. We describe a 12-year-old boy with isolated granulomatous appendicitis where the etiology could not be clarified despite infectious criteria such as high fever and gastroenteritis. Children with epithelioid granulomatous appendicitis have a good prognosis following appendectomy. PMID- 20850614 TI - Giant ossifying malignant thymoma in a child. AB - We present the first reported case of an ossifying pediatric thymoma. Our patient was diagnosed with a massive thymoma replacing the whole of the left thoracic cavity. Percutaneous biopsy was attempted 3 times followed by an open incisional biopsy and adjuvant chemotherapy. Complete resection required a median sternotomy and a "trap door" thoracotomy after the tumor failed to respond to chemotherapy. Histology confirmed World Health Organization type B1 lymphocyte-rich thymoma, Masaoka stage I, with extensive osseous metaplasia. PMID- 20850615 TI - OK-432 therapy for chylous pleural effusion or ascites associated with lymphatic malformations. AB - OK-432 therapy is effective for the treatment of macrocystic lymphatic malformations (LMs), but the optimal management of patients with microcystic LMs associated with large chylous pleural effusions or chylous ascites is not resolved. We performed thoracoscopic- or laparoscopic-guided injection of OK-432 for 2 patients with diffuse microcystic LMs accompanied by refractory chylous pleural effusion or chylous ascites. Both cases responded well to OK-432 therapy with improvement/resolution of fluid collections and associated symptoms. We recommend the use of OK-432 therapy as a promising treatment for microcystic LMs with functionally significant lymphatic fluid collections. PMID- 20850616 TI - Outcomes of multigestational pregnancies affected by congenital diaphragmatic hernia. AB - BACKGROUND/PURPOSE: The prognosis for multiple vs singleton pregnancies affected by congenital diaphragmatic hernia (CDH) is not known. To improve the counseling of families with multiple gestation pregnancies complicated by CDH, we examined outcomes of a consecutive series of CDH cases occurring in multiple gestation pregnancy referrals. METHODS: Clinical characteristics and morbidity and mortality data were gathered for a consecutive series of infants with CDH from 16 multiple gestation pregnancies. Outcomes were compared to a cohort of 91 patients with CDH from singleton pregnancies. Multivariate regression was also used in an attempt to determine whether multiple gestation pregnancy was independently predictive of subsequent long-term adverse outcomes. RESULTS: Four pregnancies were lost to follow-up, and 1 underwent selective reduction. Overall mortality for live-born multiple gestation fetuses affected by CDH was 30% and was 8% for unaffected siblings. No pregnancy was concordant. Clinical features were not different between the case series and control infants, except median gestational age at delivery, which was significantly lower for the multigestational infants (34 [range, 32-36] vs 38 [range, 28-41] weeks) (P = .02). Long-term morbidity was comparable between cases and controls. CONCLUSIONS: In terms of mortality, outcomes of multigestational pregnancies affected by CDH are no worse than for CDH pregnancies in general. Long-term risk may depend more on CDH severity rather than the presence of multiple fetuses. PMID- 20850617 TI - Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. AB - PURPOSE: The purpose of the study was to evaluate the neurodevelopmental outcome in infants with congenital diaphragmatic hernia (CDH). METHODS: Between June 2004 and September 2007, 41 CDH survivors were prospectively enrolled in an interdisciplinary follow-up program. Neurodevelopmental status was evaluated using the Bayley Scales of Infant Development II (prior 2006, n = 9), the Bayley Scales of Infant Development III (after 2006, n = 27), or the Wechsler Preschool and Primary Scale of Intelligence III (children older than 4 years, n = 5). Scores were grouped as average, mildly delayed, and severely delayed by standard deviation intervals (115-85, 71-84, <70), and mixed if average and mildly delayed in either cognitive or language. RESULTS: Median age at last assessment was 24 months (range, 6-62). Average, mixed, mildly delayed, and severely delayed scores for neurocognitive and language skills were found in 49%, 19%, 17%, and 15%, respectively. Psychomotor scores were normal, mildly delayed, and severely delayed in 46%, 23%, and 31%, respectively. Autism was present in 7%. Abnormal muscle tonicity was found in 51% (49% hypotonic, 2% hypertonic). Multivariate risk factors for borderline or delayed neurodevelopmental, neurocognitive, and/or psychomotor outcome were intrathoracic liver position (P = .02), presence of a right-sided CDH (P = .02), extracorporeal membrane oxygenation need (P < .001), Gore-Tex patch repair (P = .02), O(2) requirement at 30 days of life (P < .01), and hypotonicity (P < .01). CONCLUSIONS: The prospective evaluation in an interdisciplinary follow-up program uncovered striking morbidities in neurodevelopmental status in approximately half of the CDH infants. The most common neurologic sequelae are neuromuscular hypotonicity and psychomotor dysfunction. Patient-specific factors are important determinants of adverse neurologic outcome. PMID- 20850618 TI - Initial surgical and pain management outcomes after Nuss procedure. AB - PURPOSE: The purpose of this article was to report surgical and pain management outcomes of the initial Nuss procedure experience at the Children's Hospital of Wisconsin (Milwaukee) and to place this experience in the context of the published literature. METHODS: The initial 118 consecutive Nuss procedures in 117 patients were retrospectively reviewed with approval of the Children's Hospital of Wisconsin human rights review board. Patient, surgical, complication, and pain descriptors were collected for each case. Statistical methods for comparison of pain strategies included the Kolmogorov-Smirnov test for normality, 1-way repeated measures analysis of variance, and paired t tests. RESULTS: Patient, surgical, and complication descriptors were comparable to other large series. Complication rates were 7% early and 25% late. Epidural success rate was 96.4%. There was 1 episode of recurrence 2 years postbar removal (n = 114). CONCLUSIONS: The institution of the Nuss procedure provides a highly desired result with significant complication rates. The ideal approach would deliver this result with lower risk. A pain service-driven epidural administration of morphine or hydromorphone with local anesthetic provides excellent analgesia for patients after Nuss procedure. The success of epidural analgesia is independent of catheter site and adjunctive medications. Ketorolac was an effective breakthrough medication. PMID- 20850619 TI - Physical outcome and quality of life after total esophagogastric dissociation in children with severe neurodisability and gastroesophageal reflux, from the caregiver's perspective. AB - BACKGROUND/PURPOSE: The objective of this study is to retrospectively assess the surgical outcome and the quality of life (QOL) from the caregiver's perspective after total esophagogastric dissociation in neurologically impaired (NI) children with gastroesophageal reflux (GOR). METHODS: Based on O'Neill questionnaire, a QOL questionnaire was designed, which was completed by the caregivers recording the child's well being and caregiver's satisfaction preprocedure, immediately (6 months), and long-term postprocedure (median, 21 months; range, 4-38). Statistical analysis was done using Kruskal-Wallis Test and Dunn's multiple comparisons test. RESULTS: Twenty-three children underwent surgery between 2003 and 2008; 19 families participated. Ease of feeding improved significantly both immediately and long term. Statistically significant improvements were also seen in comfort and ability of the child to enjoy life, frequency of medical visits, vomiting, retching, and choking. Postoperatively, caring for the child became easier, and the caregiver's frustration in caring improved statistically, but the caregiver's overall QOL did not improve significantly. CONCLUSIONS: Total esophagogastric dissociation has huge positive impact on the physical well being of the NI children experiencing GOR. The overall view of the procedure is one of success surpassing all expectations. Therefore, it should be considered alongside other antireflux procedures in NI children. PMID- 20850620 TI - Late-onset hypertrophic pyloric stenosis: definition of diagnostic criteria and algorithm for the management. AB - BACKGROUND AND PURPOSE: Gastric outlet obstruction (GOO) may be caused by various congenital and acquired conditions in children. The authors report 11 cases of GOO caused by muscular hypertrophy of the pylorus, which was proven histologically in 7. They describe this entity as "late-onset hypertrophic pyloric stenosis (HPS)," define the diagnostic criteria of the disease, and produce an algorithm for its management. MATERIALS AND METHODS: The medical records of patients with GOO treated from 1999 and 2009 were retrospectively reviewed. Patients with infantile HPS and GOO secondary to corrosive ingestion or neoplasm were not included. Age, sex, family history, presenting symptoms and signs, radiologic methods and findings, type of management, histopathologic features, and outcome were noted for each patient. RESULTS: Eleven patients (4 male, 7 female) ranging in age from 2 to 8 years (mean, 3.6 years) were included in the study. The symptoms were nonbilious vomiting (n = 11), abdominal pain (n = 4), and weight loss (n = 2). Abdominal ultrasound (n = 6) and upper gastrointestinal contrast studies were obtained (n = 11). Gastroscopy revealed complete (n = 6) or partial (n = 5) obstruction of the pylorus. Balloon dilatation of the pylorus was performed in 5 cases and repeated in 3 cases. Conservative treatment was initially attempted in 11 patients. Two patients with chronic gastritis and Helicobacter pylori (n = 2) were treated with amoxicillin clavulanic acid, clarithromycin, and lansoprazole. A Billroth I procedure was performed in 7 cases. Hypertrophied pyloric muscle was noted in 7 patients and chronic gastritis in 2. The postoperative course was uneventful. CONCLUSION: Hypertrophic pyloric stenosis is rarely seen after infancy. Analysis of our results and review of the literature prompted us to redescribe this entity as "late-onset HPS" and define the diagnostic criteria. Late-onset HPS is probably an acquired disease of unknown etiology. The management of late-onset HPS has been summarized in an algorithm, which will also be useful in the treatment of GOO in children caused by etiologies other than classical infantile HPS. PMID- 20850621 TI - Serum and tissue transforming [corrected] growth factor beta1 in children with biliary atresia. AB - BACKGROUND: Biliary atresia (BA) is an infantile disorder characterized by the obstruction of a portion or the entirety of the extrahepatic bile ducts, leading to hepatic fibrosis and loss of liver function. The gold standard for diagnosing and grading fibrosis is liver biopsy, but there are many groups searching for noninvasive biomarkers that could replace and/or complement this procedure. METHODS AND MATERIALS: In this study, we evaluated serum and tissue transforming growth factor beta1 (TGFbeta1) and aspartate aminotransferase [AST]-to-platelet ratio index (APRI) in patients with BA at the time of diagnosis and at liver transplantation and correlated these data with tissue collagen density, to verify if they could act as biomarkers for BA. RESULTS: At the time of diagnosis, TGFbeta1 levels were highly variable in BA patients. However, serum values at transplantation were significantly decreased (13.75 +/- 3.68 ng/mL) as compared to controls (34.36 +/- 9.35 ng/mL) (P = .01). No correlation was found between serum TGF1beta1 and collagen density in both groups analyzed. Serum TGFbeta1 showed no correlation with APRI at diagnosis. At the time of liver transplantation, all patients had low serum TGFbeta1 and variable APRI, although all higher than 2.0. However, when platelet count was used, an inverse correlation with serum TGFbeta1 was observed at the time of diagnostics (r(2) = 0.749; P = .03). CONCLUSIONS: Our findings suggest that at the time of diagnosis the fibrogenic process is active, with higher levels of TGFbeta1, whereas later on, there is scar tissue, with reduced TGFbeta1 expression. Although our results should be confirmed in larger sets of patients with BA, the lack of TGFbeta1 at the time of liver transplantation may have important consequences for the patient because it is a pleiotropic molecule, responsible for many functions in the body, mainly those related to immune response and cell growth. PMID- 20850622 TI - Increased susceptibility to liver damage from pneumoperitoneum in a murine model of biliary atresia. AB - HYPOTHESIS: We hypothesized that livers with biliary atresia (BA) are more susceptible to the harmful effects of a high-pressure CO(2) pneumoperitoneum (PP) than healthy livers. METHODS: A murine model of BA was used in this experiment. Mice were divided into 6 groups: (1) control Balb/c; (2) control Balb/c, CO(2) PP; (3) control BA; (4) BA-sham; (5) BA, CO(2)-PP; and (6) BA, air-PP. Mice from groups 2, 5, and 6 underwent an 8-mm Hg-PP for 60 minutes. Liver samples were collected for histology, colorimetry, and flow cytometry analysis 18 to 24 hours after the procedure. Markers of apoptosis were investigated as indicators of acute cell damage. RESULTS: We observed a statistically significant higher rate of apoptosis in livers with BA exposed to a prolonged CO(2)-PP or air-PP compared with control groups. There were no significant differences between groups 1 and 2, or between groups 5 and 6. CONCLUSIONS: In this animal model, we have shown that livers with BA are more susceptible than healthy livers to injury by a prolonged PP. This injury was caused by both CO(2) and air-PP, implying that it is the direct result of pressure. These results may have implications for the success of minimally invasive Kasai procedures. PMID- 20850623 TI - Focal nodular hyperplasia in children: clinical features and current management practice. AB - BACKGROUND: Although nonoperative management is an accepted practice for most adults with focal nodular hyperplasia (FNH), questions remain about the safety and feasibility of this strategy in children. Our aim was to review the clinical features of children with FNH and determine current management patterns. METHODS: We reviewed records of all children and adolescents with FNH managed at our institution from 1999 to 2009 and performed a MEDLINE search to identify all published cases of FNH in the pediatric population. RESULTS: A total of 172 patients with FNH were identified, including 11 at our institution. The median age at diagnosis was 8.7 years and 66% were female. Median tumor size was 6 cm, and 25% had multiple lesions. Thirty-six percent were symptomatic at presentation. Twenty-four percent had a history of malignancy. Management included resection (61%), biopsy followed by observation (21%), and observation alone (18%). Indications for resection included symptoms (48%), inability to rule out malignancy (24%), tumor growth (15%), and biopsy-proven concurrent malignancy (9%). CONCLUSIONS: Although FNH is a benign lesion that is typically managed nonoperatively in adults, most children with FNH currently undergo resection because of symptoms, increasing size, or inability to confidently rule out malignancy. PMID- 20850624 TI - Surgical separation of shared liver with cotton tourniquets in conjoined twins: simple and effective hemostasis. AB - OBJECTIVE: Surgical separation of the fused liver is extremely risky and sometimes life-threatening in conjoined twins because of the potential risks of hypovolemia and hemorrhagic shock. METHODS: Three pairs of symmetrical conjoined twins sharing fused livers were successfully separated by using a simple but effective local blockade measure without disturbing the portal circulation. RESULTS: The volume of intraoperative blood loss was minimal, and no major complications occurred. All the separated babies survived the procedure and remained healthy, both physically and mentally, after discharge. Two babies died of pneumonia associated with their preexisting cardiac defects. CONCLUSIONS: Cotton tourniquets temporally and securely blocked the local blood supply to the narrow gap dissecting interface with minimal interference with the remaining segments, in addition to orienting the transection of the fused liver and minimizing blood loss from the liver dissection. PMID- 20850625 TI - Gastroschisis: a national cohort study to describe contemporary surgical strategies and outcomes. AB - BACKGROUND: Information on adoption of newer surgical strategies for gastroschisis and their outcomes is largely limited to hospital-based studies. The aim of this study was to use a new UK national surveillance system to identify cases and thus to describe the contemporary surgical management and outcomes of gastroschisis. METHODS: We conducted a national cohort study using the British Association of Paediatric Surgeons Congenital Anomalies Surveillance System to identify cases between October 2006 and March 2008. RESULTS: All 28 surgical units in the United Kingdom and Ireland participated (100%). Data were received for 95% of notified cases of gastroschisis (n = 393). Three hundred thirty-six infants (85.5%) had simple gastroschisis; 45 infants (11.5%) had complex gastroschisis. For 12 infants (3.0%), the type of gastroschisis could not be categorized. Operative primary closure (n = 170, or 51%) and staged closure after a preformed silo (n = 120, or 36%) were the most commonly used intended techniques for simple gastroschisis. Outcomes for infants with complex gastroschisis were significantly poorer than for simple cases, although all deaths occurred in the simple group. CONCLUSIONS: This study provides a comprehensive picture of current UK practice in the surgical management of gastroschisis. Further follow-up data will help to elucidate additional prognostic factors and guide future research. PMID- 20850626 TI - Dollars and sense of interval appendectomy in children: a cost analysis. AB - PURPOSE: Although initial nonoperative management of focal, perforated appendicitis in children is increasingly practiced, the need for subsequent interval appendectomy remains debated. We hypothesized that cost comparison would favor continued nonoperative management over routine interval appendectomy. METHODS: Decision tree analysis was used to compare continued nonoperative management with routine interval appendectomy after initial success with nonoperative management of perforated appendicitis. Outcome probabilities were obtained from literature review and cost estimates from the Kid's Inpatient Database. Sensitivity analyses were performed on the 2 most influential variables in the model, the probability of successful nonoperative management and the costs associated with successful observation. Monte Carlo simulation was performed using the range of cost estimates. RESULTS: Costs for continued nonoperative observation were estimated at $3080.78 as compared to $5034.58 for the interval appendectomy. Sensitivity analysis confirms a cost savings for nonoperative management as long as the likelihood of successful observation exceeds 60%. As the cost of nonoperative management increased, the required probability for its success also increased. Using wide distributions for both probability estimates as well as costs, Monte Carlo simulation favored continued observation in 75% of scenarios. CONCLUSION: Continued nonoperative management has a cost advantage over routine interval appendectomy after initial success with conservative management in children with focal, perforated appendicitis. PMID- 20850627 TI - Hirschsprung-associated enterocolitis develops independently of NOD2 variants. AB - BACKGROUD/PURPOSE: Hirschsprung-associated enterocolitis (HAEC) represents a cause for significant pre- and postoperative morbidity and mortality in Hirschsprung disease (HD). Although multiple studies on HAEC have been performed and several mechanisms have been presumed, the pathogenesis of this condition remains unclear. As changes in colonic mucosal defense are key factors suggested in both Crohn's disease (CD) and HAEC pathogenesis, the aim of the current study was to investigate genetic alterations in the most important susceptibility gene for Crohn's enterocolitis (NOD2) to see whether carriers of polymorphisms within the NOD2 gene are predisposed to the development of HAEC. METHODS: Genotyping for the NOD2 variants in exon 4 (p.Arg702Trp [rs2066844]), exon 8 (p.Gly908Arg [rs2066845]), and exon 11 (p.1007fs [rs2066847]) was performed in 52 white children with HD (41 boys, 11 girls), 152 healthy controls, and 152 children with CD (onset of disease <17 years; mean, 11.8 years). Seventeen patients with HD (32.7%) were carriers of a RET germline mutation, 35 children (67.3%) had short segment disease, and 17 (32.7%) had long segment disease. RESULTS: Ten children (19.2%) with HD were heterozygous carriers of at least one NOD2 variant vs 17 (11.2%) in the healthy control group and 69 (45.4%) in the CD cohort. Hirschsprung-associated enterocolitis was observed in 7 children (13.5%), with 4 having short segment HD and 3 with long segment HD; but none of them were carriers of NOD2 variants. CONCLUSION: Our study shows that NOD2 variants described to be causatively associated with CD do not predispose to the development of HAEC. As data on the molecular basis of HAEC are limited, the distinct mechanisms involved in the pathogenesis of this complication remain unclear. PMID- 20850628 TI - Clinical characteristics and treatment of perianal abscess and fistula-in-ano in infants. AB - PURPOSE: The aims of this study were to evaluate the clinical characteristics of perianal abscess and fistula-in-ano in infants and to identify factors that affected the clinical outcomes. METHOD: The authors retrospectively reviewed the clinical data of 112 infants who were treated for perianal abscess and fistula-in ano by a single pediatric surgeon from January 2006 to December 2008. RESULTS: All patients were male and the mean age of infants presented to our hospital was 6.0 +/- 4.5 months. One hundred one patients (90.2%) had 1 or 2 perianal lesions, and 76 (67.9%) had lesions at the 3 and/or 9-o'clock directions. The use of oral antibiotics did not improve or aggravate the lesions in 29 of 37 cases. Ninety seven patients (86.6%) were cured by conservative treatment with a mean duration of 5.2 +/- 3.9 months from the onset of the disease to the cure. The mean age of curing was 9.0 +/- 4.9 months. Feeding formula change showed improvement of stooling in 38 (62.3%) of 61 patients but did not affect the duration of conservative treatment. Multiple linear analysis revealed that the presence of multiple lesions was a significant independent variable (P = .001) for the duration of conservative treatment, but age of the onset and location of the lesion were not. Twelve patients (10.7%) underwent fistulectomy at a mean age of 15.0 +/- 5.1 months. None of the patients had recurrences after operation for the mean follow-up period of 23.7 +/- 11.7 months. CONCLUSION: Conservative treatment of perianal abscess and fistula-in-ano has an excellent outcome and could be the first choice of treatment of these diseases. PMID- 20850629 TI - Laparoscopic treatment of rectovaginal fistulas. Feasibility, technical details, and functional results of a rare anorectal malformation. AB - INTRODUCTION: Rectovaginal fistulas are a rare variety of anorectal malformations. Eight patients with this anomaly among 420 children with anorectal malformations were treated in our center. We used a laparoscopic approach in 5 of the children. The aim of this study is to define the feasibility and technical details of laparoscopy in the treatment of these patients as compared with those treated by posterior sagittal anorectoplasty (PSARP) and to evaluate the preliminary results. METHODS: Three patients were treated with a PSARP starting February 2000 (group 1 [GI]). The laparoscopic approach (laparoscopic treatment [LT]) was used in the next 5 girls starting in November 2002 (group 2 [G2]). All patients were operated on by the authors. In LT cases, we used 3 ports. The rectum was dissected laparoscopically, and the fistula was transected. An assisted anorectal pull-through was then performed using a minimal perineal incision. Clinical features, age at operation, associated anomalies, ratio/sacrum (sacral ratio [SR]), distal colostogram, operative findings, complications, urinary continence, voluntary bowel movements, constipation, soiling, and requirements of bowel management program were analyzed. Patients older than 3 years and 6 months and with more than 3 months after colostomy closure were included in the analysis of functional results. RESULTS: The mean age at the time of operation was 21.8 months. Urogenital anomalies were seen in 6 (75%) of the 8 girls. Two patients had SRs less than 0.6. Only 3 patients in each group were considered for evaluation of functional results. Mean age was 67 months in 3 (G1) and 64 months in 3 (G2) patients. All 6 patients were continent of urine. Only 1 in G1 had an SR less than 0.6. Voluntary bowel movements were present in 1 patient in G1 and 2 in G2. One patient in G1 had severe constipation and grade 2 soiling requiring bowel management program (SR <0.6), and 1 patient in G2 had occasional soiling. CONCLUSIONS: Laparoscopy allowed an optimal view of the pelvis and helped to achieve a low dissection of the fistula. Although the number of patients in this study is few, functional results with LT seem to be comparable to the open PSARP approach when done by experienced pediatric surgeons. The laparoscopic approach may be considered as an option for the treatment of this rare anomaly. PMID- 20850630 TI - Use of anorectal manometry for evaluation of postoperative results of patients with anorectal malformation: a study from Kuwait. AB - PURPOSE: The objective of this study is to use anorectal manometry for functional assessment of early postoperative results after corrective surgery for anorectal malformations (ARMs) in children and compare manometric observations with age matched controls. Parents were counseled and management strategies were planned according to the manometric assessments. METHODS: From August 2005 to September 2009, 32 patients who underwent surgery for ARM were assessed postoperatively with anorectal manometry using a water-perfused anorectal motility catheter to record anal canal length or high-pressure zone, resting pressure of anal canal (RP), and rectoanal inhibitory reflex (RAIR). These patients were divided in 2 groups (infants, <1 year; children, >1 year) according to the age at the time of performance of anorectal manometry that was done at 6 months or later following stoma closure or anoplasty. RESULTS: Out of these 32 patients, high anomaly was present in 13, whereas 19 had low type of defect. Manometric anal canal length of the children with high and low ARM was 2.10 +/- .44 and 2.25 +/- .53 cm, respectively, which was significantly shorter than that of their age-matched controls(P < .05). In patients with high ARM, RP in infants (17 +/- 7.7 mm of Hg) and children (21 +/- 9.4 mm of Hg) was lower than that of controls (RP in infants = 42.43 +/- 8.19 mm of Hg, RP in children = 43.43 +/- 8.79 mm of Hg, P < .001). In patients with low ARM, RP in infants (34 +/- 8.6 mm of Hg, P = .002) and children (26 +/- 9.9 mm of Hg, P = .001) was lower than that in controls. Presence of RAIR was demonstrated in 5 (38.4%) of 13 patients with high ARM and in 11 (57.9%) of 19 cases with low ARM. Parental counseling was done after this early evaluation, and management strategies like bowel management program and biofeedback training were planned according to the results of the tests. CONCLUSION: Our anorectal manometric results suggest that patients with ARM had short anal canal with lower RP and impaired RAIR, which could affect the ultimate functional outcome in these patients. Thus, postoperative anorectal manometric evaluation of the patients with ARM can give more realistic information about future continence and might help in planning future treatment strategies like bowel management program or biofeedback training. PMID- 20850631 TI - Diagnosis and follow-up in constipated children: should we use ultrasound? AB - PURPOSE: We investigated the efficacy of ultrasound in determining megarectum and fecal load and the response to treatment in constipation and tried to specify objective criteria in this study. METHODS: A total of 66 cases were queried and divided into 2 groups as constipated (n = 35; mean age, 6.8 +/- 2.9 years) and control (n = 31; mean age, 8.4 +/- 3.8 years) according to Rome III criteria. After the clinical evaluation, pelvic ultrasonography (US) was performed by 2 separate radiologists. The bladder capacity and the transverse rectal diameter were measured with a full bladder. Then the rectal diameter and rectal anterior wall thickness were measured, and the presence of fecal load in the rectum and sigmoid colon was recorded with an empty bladder. The examination and ultrasound were repeated after treatment for a month in these patients. RESULTS: Comparison of the US measurements of the 2 radiologists performing the US tests did not show any interobserver difference (r = 0.981; P < .001). We therefore believe our results are objective and reproducible. We found a positive correlation between the rectal diameters and the age, height, weight, and bladder capacity. The posturination mean rectal diameter was thicker in the constipated group (3.02 +/- 1.04 cm) than in the control group (1.98 +/- 0.64 cm) (P < .001). The cutoff point of rectal diameter for a diagnosis of constipation was determined as 2.44 cm (71% sensitive; 76% specific; area under curve, 0.825; P < .001). The rectal anterior wall thickness and fecal load were higher in the constipated patients (P < .001). There was a significant decrease in the constipation score and fecal load after treatment for a month (P < .001), but the rectal diameter had not reached normal limits yet despite the decrease (2.71 +/- 0.77 cm) (P > .05). CONCLUSION: The use of US helps in making a correct diagnosis and in the follow up with objective criteria and also convinces the patient and the family that the treatment needs to be continued. PMID- 20850632 TI - Segmental multicystic dysplastic kidney in children: clinical presentation, imaging finding, management, and outcome. AB - PURPOSE: The aim of the study was to assess the presentation, imaging findings, management, and outcome of segmental multicystic dysplastic kidney (MCDK) in children. MATERIALS AND METHODS: Six patients with segmental MCDK were diagnosed and observed at our hospital. We reviewed the medical records to collect data on initial symptoms, results of imaging studies, associated urinary tract anomalies, operation, and outcome. RESULTS: Three patients had abnormal prenatal ultrasound and were diagnosed by further postnatal imaging; they were asymptomatic after birth. The other 3 children presented with a renal mass, recurrent urinary tract infection, or urinary incontinence. Five patients had associated ipsilateral or contralateral urinary tract abnormalities, including vesicoureteral reflux, ureterocele, duplex collecting system, ureteropelvic junction stenosis, and ectopic ureter. Lower tract reconstruction was performed in 3, and open biopsy was done in 1 child. None underwent partial or total nephrectomy, and all had involution of the cysts for a mean of 40 months. CONCLUSIONS: Most of the cases occur in the upper pole of a duplex kidney and often involute spontaneously without significant complication. The clinical presentation and imaging findings depend on the associated anomalies and complications. Although the latter may require surgery to resolve, segmental MCDK itself rarely requires resection. PMID- 20850633 TI - The effect of CO2 pneumovesicum on upper urinary tract. AB - OBJECTIVE: Pneumovesicum allows minimal invasive intravesical surgeries. The possible deleterious effect of intravesical CO(2) pressure is not known. We assessed the effect of CO(2) pneumovesicum on the urinary tract and renal function. METHODS: Pneumovesicum was established and maintained with CO(2) at 10 mm Hg in 10 sows. Cohen cross-trigonal reimplantation was carried out on the left ureter by a vesicoscopic approach. The right ureter was cannulated and served as control. CO(2) pneumovesicum was maintained for 2 hours. Color Doppler measurements of the upper urinary tract and blood sampling were carried out 30 minutes before and 2 hours after establishing pneumovesicum, and 30 minutes after releasing the pneumovesicum. RESULTS: Compared with the preoperative values, the bilateral anteroposterior diameters of the renal pelves increased significantly after 2 hours of the pneumovesicum (P < .05). Thirty minutes after release of the pneumovesicum, the anteroposterior diameters decreased and showed no statistically significant difference compared with the preoperative values. No air embolus was detected in the ureters, renal pelves, renal veins, or renal arteries on either side 2 hours after establishing the pneumovesicum. There was no statistically significant change in arterial or venous blood flow. There was no significant change in the urea and creatinine levels 2 hours after establishing the pneumovesicum. CONCLUSION: CO(2) pneumovesicum at a pressure of 10 mm Hg for 2 hours did not result in any demonstrable deleterious effect. PMID- 20850634 TI - Sex cord-stromal tumors of the testis in children. A clinicopathologic report from the Italian TREP project. AB - PURPOSE: Testicular sex cord-stromal tumors (SCSTs) are very rare in children and include a variety of neoplasms with different clinical features and biologic behavior. Aim of the study was to report the clinical findings and results observed in a series of patients with testicular SCST, registered in a multi institutional Italian network on rare tumors in children and adolescents. MATERIALS AND METHODS: The records of 11 patients, enrolled in 6 Italian centers from January 2000 to December 2008, were reviewed. The Children's Oncology Group (COG) staging system was adopted. Chemotherapy was recommended in patients with incomplete surgery or metastatic disease. RESULTS: A testicular mass was the most common symptom. All patients underwent primary removal of the tumor; orchiectomy with high ligation of spermatic cord was performed in 7 and tumor enucleation in 4. At histology, 4 patients had Leydig cell tumors, 4 juvenile granulosa cell tumors, 1 Sertoli cell tumor, 1 incompletely differentiated SCST, and 1 SCST with an intermediate pattern Sertoli cell tumor/mixed form. The histology of 8 of 11 cases was reviewed and investigated through immunohistochemical stains. Ten children were in stage I; 1 patient, who did not undergo hemiscrotectomy after enucleation through a transscrotal access, was considered stage II. All the patients are in first complete remission (mean follow-up, 59 months; range, 8 94). CONCLUSIONS: Our experience confirmed the rarity of testicular SCST. They have to be considered in the differential diagnosis of testicular solid masses, taking into account that hormonal signs are present in a minority of cases. All patients were cured with surgery alone. The sparing surgery represented a choice in selected cases. PMID- 20850635 TI - Perioperative surgical findings in congenital and acquired undescended testis. AB - PURPOSE: Perioperative surgical findings in congenital and acquired undescended testis (UDT) were prospectively assessed. METHODS: We included all boys with congenital or acquired UDT who underwent orchidopexy at our hospital between January 2006 and August 2009. Perioperatively, we scored the position and volume of the testis, the insertion of the gubernaculum, the patency of the processus vaginalis, and the obtained position. RESULTS: We included 69 boys (aged 0.9-14.6 years) with 76 congenital UDT and 28 boys (aged 2.2-18.5 years) with 30 acquired UDT. In the congenital group, the testis was in intracanalicular position in 55 cases (72%), whereas in the acquired UDT group, this was in 11 cases (37%; P < .001). The insertion of the gubernaculum was at the bottom of the scrotum in 13 cases (17%) of the congenital UDT group and in 12 cases (40%) of the acquired UDT group (P < .05). The processus vaginalis was open in 63 cases (83%) of the congenital and in 9 cases (30%) of the acquired UDT group (P < .001). CONCLUSION: Compared to congenital UDT, acquired UDT are more likely to be situated in the superficial inguinal pouch, to have a normal insertion of the gubernaculums, and to have a closed processus vaginalis. PMID- 20850637 TI - A case of renal cell carcinoma after successful treatment of Wilms tumor. AB - This case report documents the eighth reported case of renal cell carcinoma (RCC) occurring after treatment of Wilms tumor. Although secondary malignancies after treatment of Wilms tumors are not infrequent, RCC as the second malignancy is rare. We discuss a 17-year-old girl whose RCC was diagnosed 12.5 years after diagnosis of a Wilms tumor. In addition, we review the literature on the subject. Renal cell carcinoma has been proposed as a consequent of chemoradiation; however, a genetic susceptibility must be considered. Because it is routine to assess the functional status of the remaining solitary kidney by annual ultrasonography, we recommend assessing for the presence of secondary renal malignancies and perhaps continuing routine ultrasounds long-term. PMID- 20850638 TI - Kaposiform hemangioendothelioma of the choledochus. AB - Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular neoplasm that mainly occurs during childhood. Although KHE may involve various organs, involvement of the choledochus has not been reported. We report a case of KHE in a 5-month-old male infant. The patient was admitted with icterus and acholic stool. Contrast computed tomography revealed a vascular tumor in the hepatic portal region causing biliary obstruction. Excision of the extrahepatic duct and hepatoportoenterostomy were performed successfully, and he has been well during 3 years of postoperative follow-up. PMID- 20850639 TI - Diffuse infantile hemangiomatosis of the ileum presenting with multiple perforations: a case report and review of the literature. AB - Hemangiomas of the small intestine are rare, accounting for only 0.05% of all intestinal neoplasms (Jarvi et al. J Pediatr Gastroenterol Nutr. 2008;46:593 597). The jejunum is the most common site of involvement in the small intestine (Levy et al. Am J Roentgenol. 2001;177:1073-1081). Small bowel hemangiomas are most commonly manifested by gastrointestinal bleeding, abdominal pain, obstruction, or intussusception. There are very few reported cases in the literature of hemangiomatosis presenting with perforation, and only 1 previously reported case of perforation in the ileum. We present a rare case of a 5-week-old female with diffuse hemangiomatosis of the ileum presenting with multiple ileal perforations and peritonitis. PMID- 20850640 TI - Mesenteric leiomyosarcoma in a 13-year-old boy. AB - Mesenteric leiomyosarcoma occurs most commonly in middle-aged individuals. Primary tumors of the mesentery are uncommon in pediatric and adolescent patients, and primary mesenteric leiomyosarcoma is particularly rare. Accurate preoperative diagnosis of mesenteric soft tumor is generally difficult. We describe a case of leiomyosarcoma arising from the ileal mesentery in a 13-year old boy. The diagnosis was based on histopathologic evaluation using immunohistochemical staining and gene analysis. PMID- 20850641 TI - Unilateral breast mass in an infant: a rare presentation of spontaneously regressing myofibromatosis. AB - Breast tumors are very rare in infants. We describe a 4-month-old female infant who presented with a firm and painless right breast mass. It was first noticed at the age of 1 month and then gradually increased in size. Further physical examination and imaging studies revealed other subcutaneous masses and lytic bone lesions. True-cut biopsy from the breast lesion was consistent with infantile myofibromatosis. Infantile myofibromatosis is a group of uncommon mesenchymal tumors that tend to occur in infancy and regress spontaneously, as demonstrated in our case. Surgical excision of such lesion might have led to permanent loss of breast tissue. The report discusses the clinical, radiological, and pathologic features, in addition to the previously described treatment options for this condition. PMID- 20850642 TI - Renal leiomyoma in a child: a rare renal tumor. AB - Renal leiomyoma is a rare benign smooth muscle tumor of the kidney. Most cases are reported in adults, with very few cases described in children. We report a case of right renal leiomyoma in a 6-year-old boy which was suspected of being a Wilms tumor. Contrast-enhanced computed tomography could not differentiate leiomyoma in the kidney, and the mass was diagnosed as a Wilms tumor. Right radical nephrectomy was performed. Diagnosis of renal leiomyoma could only be achieved after histopathologic examination and immunohistochemistry. We recommend that total nephrectomy has to be done in most cases of pediatric renal tumors to avoid the risk of malignancy. There may be a role for nephron sparing surgery, provided the tumor is small, and one has a strong suspicion for the lesion being benign. PMID- 20850643 TI - Treatment of flaring of the costal arch after the minimally invasive pectus excavatum repair (Nuss procedure) in children. AB - Flaring of the costal arch may be part of the pectus excavatum deformity. This aspect will in rare cases be even worsen after the Nuss repair. This remaining deformity can be treated with a minimal subperichondral partial resection of the costal arch cartilage. In 5 patients, this additional technique regained good to excellent results. PMID- 20850644 TI - Familial recurrence of gastroschisis: literature review and data from the population-based birth registry "Mainz Model". AB - BACKGROUND: Familial forms of gastroschisis are considered rare. A search for these forms in a population-based birth registry in 1993 found a recurrence risk of 3.5% among first-degree relatives. Since then, similar investigations in population-based registries have led to contradictory results. METHODS: A search of the population-based birth registry "Mainz Model" for familial cases of gastroschisis and a systematic review of the literature were performed. RESULTS: The Mainz Model database yielded 1 familial recurrence out of 27 gastroschisis cases. From the literature, 37 affected families could be retrieved. Among 412 gastroschises from population-based registries, 10 familial recurrences have been found. These translate into a recurrence risk of 2.4%, with a strong tendency toward underestimation. CONCLUSION: The existing data support the hypothesis that familial recurrence of gastroschisis is much more likely than previously thought. PMID- 20850645 TI - Computed tomographic diagnosis of midgut volvulus in a 5-year-old child. PMID- 20850646 TI - Transanoproctoplasty: a 21-year review. AB - BACKGROUND: Transanal anorectoplasty was developed through the 1980s by the senior author (AB) as an alternative approach to posterior sagittal anorectoplasty for the management of imperforate anus. This study evaluates this surgical approach and its longer-term results. METHODS: Case notes of all patients treated from 1984 to 2005 were reviewed. Operative procedures, colostomy requirement, complications, and long-term outcome were recorded. Patients were grouped according to the status of the pelvic floor, the location of the rectal fistula, and the sacral ratio. RESULTS: A total of 245 patients (175 male, 70 female) underwent transanal anorectoplasty. The perineum was well formed in 208 patients (85%), moderately formed in 15 (6%), and poorly formed in 22 (9%) patients. Two hundred three patients (82.8%) had a visible perineal or vulval fistula, 24 (9.8%) had a prostatic urethral fistula, whereas 18 (7.4%) had a bulbourethral fistula. Overall, 6 patients (2.5%) had wound infection or breakdown. As continence is age related, 32 patients were excluded from the study. Of the remaining 212 patients, 182 are continent with no soiling or only minimal staining. Thirty patients born with a poor perineum are incontinent. CONCLUSION: Transanal anorectoplasty is a safe procedure with limited morbidity. It is sphincter sparing and permits accurate placement of the rectum with its internal sphincter within the anal canal. The anus lies accurately placed at the center of the external anal sphincter muscle complex. Given a well-performed surgical intervention, eventual continence relates to the original anatomy and neurology of the pelvic floor. Transanal anorectoplasty should be regarded as an alternative rather than as a substitute to posterior sagittal anorectoplasty for reconstruction of most forms of imperforate anus. PMID- 20850647 TI - Bilateral clear cell sarcoma of the kidney. PMID- 20850648 TI - Disparities in pediatric surgical care in Puerto Rico: a call for action. PMID- 20850649 TI - Predictive and prognostic value of preoperative symptoms in the surgical treatment of pulmonary aspergilloma. AB - BACKGROUND: Surgical resection is widely accepted as the treatment of choice for pulmonary aspergilloma (PA). However, the technique involved ranks among the most challenging in thoracic surgery and remains associated with considerable morbidity and mortality. To improve the outcomes, it is essential to establish clear recommendations for optimal timing of surgery and selection of patients. To facilitate this, we analyzed the impact of preoperative clinical factors on the results of treatment. METHODS: Medical records of patients treated surgically for PA between 1979 and 2007 were retrospectively reviewed for clinical variables of potential impact on the surgical outcome with emphasis on preoperative symptoms. RESULTS: Sixty-four patients, including 22 cases of simple aspergilloma and 42 cases of complex aspergilloma were enrolled in the study. Univariable analysis followed by multivariable logistic regression identified weight loss and massive hemoptysis as risk factors for postoperative morbidity [odds ratio (OR) = 8.856, P = 0.006 and OR = 6.9, P = 0.021, respectively]. Ten-year cumulative survival in simple aspergilloma and complex aspergilloma was 88.3% and 70.6%, respectively (P = 0.042). Multivariable analysis by Cox proportional hazard model showed that younger age and lack of massive hemoptysis were independent favorable prognostic factors [hazard ratio (HR) = 1.13, P = 0.0004 and HR = 4.71, P = 0.0319, respectively). CONCLUSION: Massive hemoptysis is an independent unfavorable predictive and prognostic factor in the surgical treatment of PA. We believe that in operable cases, early surgical resection may be recommended even in asymptomatic patients. This strategy may prevent development of life-threatening symptoms and offers a realistic chance of permanent cure with acceptable mortality and morbidity. PMID- 20850650 TI - Are randomized trials the best way to judge the efficacy of surgical procedures? PMID- 20850651 TI - Randomized clinical trials for new surgical operations: square peg in a round hole? PMID- 20850652 TI - Regression of "fixed" pulmonary vascular resistance in heart transplant candidates after unloading with ventricular assist devices. PMID- 20850653 TI - The first Blalock-Taussig shunt. PMID- 20850654 TI - New clinically applicable method for visualizing adjacent lung segments using an infrared thoracoscopy system. AB - OBJECTIVE: Our objective was to attempt a clinical trial of segmentectomy using the infrared thoracoscopy system after intravenous injection of indocyanine green. PATIENTS AND METHODS: A total of 8 patients with lung lesions were investigated (5 with primary lung cancer, 2 with metastatic lung tumor, and 1 with inflammatory change). All were scheduled to undergo segmentectomy and had been confirmed to have no allergy to iodine or indocyanine green. Informed consent was obtained from all patients. We identified the dominant pulmonary artery supplying the target segment using reconstructed computed tomography images. The dominant pulmonary artery of the target segment was ligated, and after we had observed the lung using the infrared thoracoscopy system after intravenous injection of indocyanine green (3.0 mg/kg), and marked the white-to blue transitional zone by electrocautery, we performed segmentectomy. RESULTS: Average operation time was 150 +/- 62.1 minutes, and bleeding volume was 68.8 +/- 30.5 mL. Under infrared thoracoscopy, the area with a normal blood supply became stained blue 13 seconds after injection of indocyanine green. Maximum staining intensity was attained 28 seconds after dye injection, and the observation duration was 3.5 minutes. A well-defined color zonation was observed in all patients. We had enough time to mark it. No complications attributable to infrared thoracoscopy after intravenous injection of indocyanine green were encountered. CONCLUSIONS: Infrared thoracoscopy with indocyanine green makes it possible to identify the target lung segment easily and quickly without the need for inflation. This method will be especially useful for cases associated with severe emphysema or when surgery offers a limited view, as is the case with video assisted thoracic surgery. PMID- 20850656 TI - The effect of regionalization on outcome in pulmonary lobectomy: a Canadian national study. AB - OBJECTIVE: To examine the effect of regionalization of thoracic surgery services in Canada by evaluating change over time in hospital volumes of pulmonary lobectomy and its impact on length of stay and in-hospital mortality. METHODS: Data on pulmonary lobectomy between 1999 and 2007 were abstracted from the Canadian Institute for Health Information Discharge Abstract Database. In hospital mortality was analyzed by logistic regression, and log-transformed length of stay was analyzed by linear regression. Cross-sectional analysis of hospital volume, in-hospital mortality, and length of stay was performed, controlling for clustering. Within-hospital changes in annual volume on outcome was analyzed using multivariable logistic regression, controlling for Charlson comorbidity index and other confounders. RESULTS: Of 19,732 patients, 10, 281 (52%) were male, with an average age of 63.3 years. There was a 45% (95% confidence interval, 21-61; P = .001) relative risk reduction in in-hospital mortality with a 19% reduction in length of stay (95% confidence interval, 12-25; P < .0001). On comparison of volume between hospitals, an increase of 20 cases was associated with a 15% relative risk reduction (95% confidence interval, 9-19; P < .0001) in in-hospital mortality and a 5% relative decrease (95% confidence interval, 3-7; P < .001) in length of stay. Within hospitals there was a nonsignificant relationship between volume and in-hospital mortality. CONCLUSIONS: In-hospital mortality and length of stay for lobectomies have decreased in Canada. In multivariate analysis, volume was associated with improved in-hospital mortality, but there was no reduction in mortality when volume was increased within a given hospital. However, the proportion of patients treated in high-volume centers has increased over time, inferring the importance of high-volume centers in improved outcomes. This supports regionalization policies for pulmonary lobectomy. PMID- 20850658 TI - The trans-subclavian retrograde approach for transcatheter aortic valve replacement: single-center experience. AB - OBJECTIVE: Aortic valve disease is the most common acquired valvular heart disease in adults. With the increasing elderly population, the proportion of patients with symptomatic aortic stenosis who are unsuitable for conventional surgery is increasing. Transcatheter aortic valve implantation has rapidly gained credibility as a valuable alternative to surgery to treat these patients; however, they often have severe iliac-femoral arteriopathy, which renders the transfemoral approach unusable. We report our experience with the trans subclavian approach for transcatheter aortic valve implantation using the CoreValve (Medtronic CV Luxembourg S.a.r.l.) in 6 patients. METHODS: In May 2008 to September 2009, 6 patients (mean age of 82 +/- 5 years), with symptomatic aortic stenosis and no reasonable surgical option because of excessive risk, were excluded from percutaneous femoral CoreValve implantation because of iliac femoral arteriopathy. These patients underwent transcatheter aortic valve implantation via the axillary artery. Procedures were performed by a combined team of cardiologists, cardiac surgeons, and anesthetists in the catheterization laboratory. The CoreValve 18F delivery system was introduced via the left subclavian artery in 6 patients, 1 with a patent left internal thoracic to left anterior descending artery graft. RESULTS: Procedural success was obtained in all patients, and the mean aortic gradient decreased 5 mm Hg or less immediately after valve deployment. One patient required implantation of a permanent pacemaker. One patient required a subclavian covered stent implantation to treat a postimplant artery dissection associated with difficult surgical hemostasis. One patient was discharged in good condition but died of pneumonia 40 days after the procedure. All patients were asymptomatic on discharge, with good mid-term prosthesis performance. CONCLUSIONS: Transcatheter aortic valve implantation via a surgical subclavian approach seems safe and feasible, offering a new option to treat select, inoperable, and high-risk patients with severe aortic stenosis and peripheral vasculopathy. PMID- 20850660 TI - Effect of radial artery or saphenous vein conduit as a second graft on late clinical outcome after coronary artery bypass grafting surgery. PMID- 20850661 TI - Contrast media dose, angiography timing, and acute renal failure after coronary operations. PMID- 20850663 TI - Susceptibility of endodontic pathogens to antibiotics in patients with symptomatic apical periodontitis. AB - INTRODUCTION: The aim of this study was to evaluate susceptibility of predominant endodontic pathogens isolated from teeth with symptomatic apical periodontitis to most commonly prescribed antibiotics. METHODS: Among 58 patients with symptomatic apical periodontitis, 47 and 11 cases were caused by primary and secondary root canal infection, respectively. The microbial samples were taken either from the root canals (35 cases) or by aspiration from apical abscesses (23 cases). Culture methods were used to identify the microorganisms present in the samples. Antibiotic susceptibilities of all isolates were evaluated by using the E-test method. RESULTS: Microorganisms were isolated from 49 of the 58 samples studied and included facultative and obligate anaerobes. Streptococci and obligate anaerobes were the predominant microorganisms in cases of primary infection. Enterococcus faecalis dominated in cases of secondary infection. All tested microorganisms were highly sensitive to penicillin G, amoxicillin, and ampicillin. Susceptibilities to clindamycin and erythromycin were 73.8% and 54.7%, respectively. About 40% of the isolates were resistant to tetracycline. More than 50% of all anaerobes were resistant to metronidazole. All E. faecalis isolates were resistant to clindamycin. CONCLUSIONS: Based on the study results, penicillin and amoxicillin are suitable antibiotics for treatment of endodontic infection when conventional root canal treatment alone is insufficient. Clindamycin could be advised for penicillin-allergic patients with primary endodontic infections. PMID- 20850664 TI - Apical root canal microbiota as determined by reverse-capture checkerboard analysis of cryogenically ground root samples from teeth with apical periodontitis. AB - INTRODUCTION: Bacteria located in the apical root canal system potentially participate in the pathogenesis of apical periodontitis. Detection and identification of apical bacteria can be compromised because of limitations in conventional sampling and identification procedures. This study identified several bacterial taxa in the apical and middle/coronal segments of primarily infected root canal system by using pulverized root segments and a culture independent molecular method. METHODS: Seventeen extracted teeth with attached apical periodontitis lesions were sectioned to obtain 2 root fragments (apical and middle/coronal segments). Root fragments were cryogenically ground, and DNA was extracted from samples. After multiple displacement amplification, DNA from samples was used as template in a reverse-capture checkerboard hybridization assay targeting 28 bacterial taxa. RESULTS: Bacterial DNA was detected in all samples. The most prevalent taxa in the apical root canal system were Olsenella uli (76.5%), Prevotella baroniae (71%), Porphyromonas endodontalis (65%), Fusobacterium nucleatum (53%), and Tannerella forsythia (47%). O. uli, P. endodontalis, and Propionibacterium acnes were as frequently detected in apical samples as they were in middle/coronal samples. P. baroniae, T. forsythia, and F. nucleatum were found more frequently in the apical part of the canal as compared with matched coronal segments. Streptococcus species were more prevalent in middle/coronal samples. The median and mean of shared bacterial taxa between matched apical and middle/coronal segments were 27% and 41%, respectively. CONCLUSIONS: Several candidate endodontic pathogens were very prevalent in the apical root canal system. The apical microbiota was usually complex and differed in species composition when compared with the microbiota of middle/coronal samples from the same tooth. PMID- 20850665 TI - Cone-beam computed tomography study of root and canal morphology of maxillary first and second molars in an Indian population. AB - INTRODUCTION: The aim of this study was to investigate the root and canal morphology of maxillary first and second molars in an Indian population by using cone-beam computed tomography (CBCT). METHODS: Maxillary first (n = 220) and second (n = 205) molars were collected from an indigenous Indian population and scanned by using a CBCT scanner at a constant slice thickness of 125 MUm/slice. Volume rendering and multiplanar volume reconstruction were performed. The number of root canals was examined, and root canal system configurations were classified by using historical and contemporary classifications. RESULTS: Single-rooted first and second molars commonly showed types I, IV (0.5%) and type III (1%) canal systems, respectively. Buccal roots of two-rooted first molars showed 2 canal systems, type I and type IV, whereas second molars with 2 roots showed wide variations in canal anatomy. The most common canal morphology in the mesiobuccal roots of three-rooted first and second molars was type I (51.8% and 62%, respectively), followed by type IV (38.6% and 50%, respectively). The distobuccal and palatal roots of first and second molars showed predominantly type I canal morphology. Additional canal types were identified in 2.2% and 9.3% of the first and second molars, respectively. CONCLUSIONS: The root number, morphology, and canal morphology of Indian maxillary molars showed features that were different from both Caucasian and Mongoloid traits. CBCT is an exciting and clinically useful tool in studying root canal morphology. PMID- 20850666 TI - Platelet-rich fibrin increases proliferation and differentiation of human dental pulp cells. AB - INTRODUCTION: Platelet-rich fibrin (PRF) by Choukroun's technique is derived from an autogenous preparation of concentrated platelets without any manipulation. When delicately pressed between 2 gauzes, the PRF clot becomes a strong membrane with high potential in clinical application. However, the effect of PRF on dental pulp cells (DPCs) remains to be elucidated. This study was to determine the biological effects of PRF on DPCs. METHODS: PRF samples were obtained from 6 healthy volunteers. Human DPCs were derived from healthy individuals undergoing extraction for third molars. Cell proliferation resulting from PRF was evaluated by colorimetric assay. Western blot was used to evaluate the expression of osteoprotegerin (OPG). Alkaline phosphatase (ALP) activity was examined by substrate assay. RESULTS: PRF did not interfere with cell viability of DPCs (P > .05). DPCs were observed to attach at the edges of PRF by phase-contrast microscopy. PRF was found to increase DPC proliferation during 5-day incubation period (P < .05). PRF was found to increase OPG expression in a time-dependent manner (P < .05). ALP activity was also significantly up-regulated by PRF (P < .05). CONCLUSIONS: PRF was demonstrated to stimulate cell proliferation and differentiation of DPCs by up-regulating OPG and ALP expression. These findings might serve as a basis for preclinical studies that address the role of PRF in reparative dentin formation. PMID- 20850667 TI - Hypoxia enhances the angiogenic potential of human dental pulp cells. AB - INTRODUCTION: Trauma can result in the severing of the dental pulp vessels, leading to hypoxia and ultimately to pulp necrosis. Improved understanding of mechanisms underlying the response of dental pulp cells to hypoxic conditions might lead to better therapeutic alternatives for patients with dental trauma. The purpose of this study was to evaluate the effect of hypoxia on the angiogenic response mediated by human dental pulp stem cells (DPSCs) and human dental pulp fibroblasts (HDPFs). METHODS: DPSCs and HDPFs were exposed to experimental hypoxic conditions. Hypoxia-inducible transcription factor-1alpha (HIF-1alpha) was evaluated by Western blot and immunocytochemistry, whereas vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) expression was evaluated by enzyme-linked immunosorbent assay. YC-1, an inhibitor of HIF-1alpha, was used to evaluate the functional effect of this transcriptional factor on hypoxia-induced VEGF expression. Conditioned medium from hypoxic and normoxic pulp cells was used to stimulate human dermal microvascular endothelial cells (HDMECs). HDMEC proliferation was measured by WST-1 assay, and angiogenic potential was evaluated by a capillary sprouting assay in 3-dimensional collagen matrices. RESULTS: Hypoxia enhanced HIF-1alpha and VEGF expression in DPSCs and HDPFs. In contrast, hypoxia did not induce bFGF expression in pulp cells. YC-1 partially inhibited hypoxia-induced HIF-1alpha and VEGF in these cells. The growth factor milieu of hypoxic HDPFs (but not hypoxic DPSCs) induced endothelial cell proliferation and sprouting as compared with medium from normoxic cells. CONCLUSIONS: Collectively, these data demonstrate that hypoxia induces complex and cell type-specific pro-angiogenic responses and suggest that VEGF (but not bFGF) participates in the revascularization of hypoxic dental pulps. PMID- 20850668 TI - Quantitative ultrastructural analysis of the neurofilament 200-positive axons in the rat dental pulp. AB - INTRODUCTION: Previous studies have suggested that myelinated axons lose their myelin and become thinner in their peripheral course to the target organ. In this study, we investigated the morphologic changes of pulpal myelinated axons between their root portion (radicular pulp) and their terminal area (peripheral pulp). METHODS: Sections of pulp of the rat upper molar teeth were immunostained for the marker of myelinated axons neurofilament (NF) 200. The proportion of NF200+ myelinated and unmyelinated fibers and their sizes were analyzed by using quantitative electron microscopy. RESULTS: The axon area, myelin thickness, and fraction of NF200+ myelinated axons of all NF200+ axons were significantly lower in peripheral than in radicular pulp. In addition, large unmyelinated axons were frequently observed in peripheral pulp. CONCLUSIONS: These results suggest that pulpal innervation originates predominantly from myelinated axons, and the myelinated axons undergo extensive morphologic changes during their course from the radicular to the peripheral pulp. PMID- 20850669 TI - Effect of hydration on the strain gradients in dental hard tissues after heat and cold application. AB - INTRODUCTION: This study was aimed to investigate the thermal strain gradients on dental hard tissues to localized heat and cold applications, applied to assess the vitality of pulp. The role of hydration on the thermal strain distribution within the enamel, dentin, and dentino-enamel junction (DEJ) was examined by using a digital moire interferometry. METHODS: Extracted bovine incisors were prepared, and high-frequency diffraction gratings were replicated on one surface. Heat (120 degrees C-140 degrees C) and cold (-50 degrees C) stimuli were applied on the external surface, and the strain patterns were recorded and analyzed for the first 3 seconds. The specimens were tested under fully hydrated and partially dehydrated conditions (72 hours at 24 degrees C, 60% relative humidity). RESULTS: Distinct thermal strain gradient was observed in the enamel, dentin, and DEJ after the application of heat and cold stimuli. Application of both heat and cold resulted in significantly higher strains in the partially dehydrated teeth than in the fully hydrated teeth (P < .05). There was only a marginal increase in strains at the location of application of stimuli in hydrated teeth. The DEJ in both the fully hydrated and partially dehydrated teeth showed the highest strains. CONCLUSIONS: There was a marked difference in the thermal strain gradients within dental hard tissues after the application of heat/cold stimuli, depending on the level of tissue hydration. The findings from this study highlighted the role of free water and structural characteristics of enamel, dentin, and DEJ in dissipating the thermal strains in the tooth. PMID- 20850670 TI - A phosphate-buffered saline intracanal dressing improves the biomineralization ability of mineral trioxide aggregate apical plugs. AB - INTRODUCTION: Recently, it was shown that the biomineralization process promoted by the interaction of mineral trioxide aggregate (MTA) with dentin in phosphate buffered saline (PBS) positively influenced the push-out bond strength of the cement. This study investigated if the use of a PBS intracanal dressing promotes the biomineralization process of MTA apical plugs using an ex vivo apexification model. METHODS: White MTA was introduced into single-rooted teeth with standardized artificially created open apices to form 5-mm-thick apical plugs. The specimens were randomly divided into the following three groups of 10 samples each: group 1: the remaining canal space was filled with PBS as an intracanal dressing; group 2: the root segments were introduced in plastic vials containing floral foams with 20 mL of PBS; and group 3: the root segments were placed in the floral foams with 20 mL of PBS and a PBS intracanal dressing was used. After 2 months, the samples were processed for scanning electron microscopic observations. Data were analyzed by using the Kruskall-Wallis test. RESULTS: In group 1, the formation of an interfacial layer (IL) with intratubular mineralization (ITM) was more evident at the cervical third; however, no mineralization was revealed at the apical third. In group 2, there was no IL and/or ITM formation at the cervical third, but samples denoted IL and ITM formation at the apical third. Group 3 displayed the formation of IL and ITM at the different levels. CONCLUSION: It was concluded that the use of a PBS intracanal dressing promotes the biomineralization process at the inner side of MTA apical plugs. PMID- 20850671 TI - Effects of electropolishing surface treatment on the cyclic fatigue resistance of BioRace nickel-titanium rotary instruments. AB - INTRODUCTION: This study evaluated the influence of electropolishing surface treatment on the number of cycles to fracture of BioRace rotary nickel-titanium endodontic instruments. METHODS: BioRace size BR5C instruments with or without electropolishing surface treatment were used in an artificial curved canal under rotational speed of 300 rpm until fracture. Fractured surfaces and the helical shafts of fractured instruments were analyzed by scanning electron microscopy (SEM). RESULTS: Polished instruments displayed a significantly higher number of cycles to fracture when compared with nonpolished instruments (P < .001). Actually, the number of cycles to fracture of a polished BR5C instrument was 124% higher than that of a nonpolished instrument. SEM analysis showed that the fractured surface of both polished and nonpolished BR5C instruments had ductile morphologic characteristics. Evaluation of the separated fragments after cyclic fatigue testing showed the presence of microcracks near the fracture surface. Polished instruments exhibited fine cracks that assumed an irregular path (zigzag crack pattern), whereas nonpolished instruments showed cracks running along the machining grooves. CONCLUSIONS: Electropolishing surface treatment of BioRace endodontic instruments significantly increased the cyclic fatigue resistance. PMID- 20850672 TI - Human periodontal ligament cell response to a newly developed calcium phosphate based root canal sealer. AB - OBJECTIVES: The aim of this study was to investigate the cellular effects of newly developed calcium phosphate-based sealers (CAPSEAL I and II) using cultured human periodontal ligament cells (HPDLCs) compared with epoxy resin sealer (AH26; Dentsply, DeTrey, Konstanz, Germany), zinc oxide eugenol [ZOE] sealer (extended working time [EWT]; Kerr Corporation, Orange, CA), and CPC sealer (Sankin apatite sealer; Sankin-kogyo, Tokyo, Japan). METHODS: Cell viability by -(4,5 dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide assay, cell attachment by scanning electron microscopy, osteoblastic differentiation and inflammatory mediators by reverse-transcriptase polymerase chain reaction, Western blotting, and alizarin red staining were evaluated. RESULTS: The cytotoxicities of CAPSEAL I and II were less than those of AH 26 and EWT after 1 and 14 days. Cells on CAPSEAL I and II were spread better as compared with those on other sealers. Mineralization after 14 days and the expression of osteoblastic differentiation markers such as alkaline phosphate and osteonectin messenger RNA increased in CAPSEAL I- and II-exposed HPDLCs after 1 and 3 days, whereas the production of inflammatory mediators, including cyclooxygenase-2, inducible nitric oxide synthetase, and reactive oxygen species (ROS), were lower than in other sealers. CONCLUSIONS: These results suggest that both CAPSEAL I and II show less cytotoxicity and inflammatory mediators compared with other sealers and have the potential to promote bone regeneration as root canal sealers. PMID- 20850673 TI - The effect of needle-insertion depth on the irrigant flow in the root canal: evaluation using an unsteady computational fluid dynamics model. AB - INTRODUCTION: The aim of this study was to evaluate the effect of needle insertion depth on the irrigant flow inside a prepared root canal during final irrigation with a syringe and two different needle types using a Computational Fluid Dynamics (CFD) model. METHODS: A validated CFD model was used to simulate irrigant flow from either a side-vented or an open-ended flat 30-G needle positioned inside a prepared root canal (45 .06) at 1, 2, 3, 4, or 5 mm short of the working length (WL). Velocity, pressure, and shear stress in the root canal were evaluated. RESULTS: The flow pattern in the apical part of the root canal was similar among different needle positions. Major differences were observed between the two needle types. The side-vented needle achieved irrigant replacement to the WL only at the 1-mm position, whereas the open-ended flat needle was able to achieve complete replacement even when positioned at 2 mm short of the WL. The maximum shear stress decreased as needles moved away from the WL. The flat needle led to higher mean pressure at the apical foramen. Both needles showed a similar gradual decrease in apical pressure as the distance from the WL increased. CONCLUSIONS: Needle-insertion depth was found to affect the extent of irrigant replacement, the shear stress on the canal wall, and the pressure at the apical foramen for both needle types. PMID- 20850674 TI - The effect of cervical preflaring using different rotary nickel-titanium systems on the accuracy of apical file size determination. AB - INTRODUCTION: An exact determination of the apical root canal diameter is crucial for correct cleaning and shaping of a root canal. The aim of this study was to investigate the discrepancies of the initial apical root canal diameter and the diameter that is measured by the initial apical file (IAF) after cervical flaring using current rotary nickel-titanium systems. METHODS: Mesiobuccal canals of 40 extracted mandibular molars were randomly assigned to four groups. In the first group, root canals were not flared. Root canals of the other groups were preflared using FlexMaster (VDW, Munich, Germany), ProTaper (Dentsply, Konstanz, Germany), or RaCe (FKG Dentaire, Genf, Switzerland) instruments. The tooth length was determined by inserting an ISO 06 K-file to the apical foramen. The working length (WL) was set 1 mm short of the apical foramen. File sizes were increased after binding sensation was felt at the WL. Transversal sections of the WL regions were examined under stereomicroscope, and the diameter of the root canal and the IAF at WL were assessed. RESULTS: Canals preflared with RaCe instruments had the lowest discrepancy between the apical root canal diameter and the IAF diameter (15.7 +/- 9.7 MUm) followed by ProTaper (22.2 +/- 11.0 MUm) and FlexMaster (35.0 +/- 17.2 MUm). CONCLUSIONS: Preflaring of root canals prevents underestimation of the actual apical root canal diameter. The type of instruments used for preflaring show differences on the accuracy of IAF determination. Preflaring with larger tapered instruments leads to a more accurate apical sizing, and this information is crucial concerning the appropriate final diameter for complete apical shaping. PMID- 20850675 TI - Antimicrobial activity of maleic acid and combinations of cetrimide with chelating agents against Enterococcus faecalis biofilm. AB - INTRODUCTION: Chelating agents, such as EDTA or citric acid, can be incorporated into irrigants in order to provide different properties in a single compound. Maleic acid has recently been proposed as an alternative irrigant to EDTA given its better smear layer removal and biocompatibility; however, its antimicrobial activity is not known. The purpose of the present study was therefore to evaluate the in vitro capacity of maleic acid in eradicating Enterococcus faecalis biofilms and to evaluate the combinations of cetrimide with maleic acid, citric acid, and EDTA. METHODS: E. faecalis biofilms were grown in the MBEC high throughput device (Innovotech; Edmonton, Alberta, Canada) for 24 hours and exposed to the irrigating solutions for 30 seconds and 1 and 2 minutes. "Eradication" was defined as 100% bacterial kill. The Student t test was used to compare the efficacy of the irrigant combinations. RESULTS: Maleic acid eradicated E. faecalis biofilms at a concentration of 0.88% after 30 seconds and at 0.11% after 2 minutes of contact time. When combined with 0.2% cetrimide, it eradicated the biofilms at all three times of exposure. The combination of 0.2% cetrimide with either 15% EDTA or 15% citric acid gave 100% bacterial kill after one minute of contact with the biofilms. CONCLUSIONS: Maleic acid showed antimicrobial activity against E. faecalis biofilm both alone or in association with cetrimide from 30 seconds onward and the combination of EDTA and citric acid with cetrimide eradicated biofilm after 1 minute of contact. PMID- 20850676 TI - Influence of the diameter and taper of root canals on the removal efficiency of Thermafil Plus plastic carriers using ProTaper Retreatment Files. AB - INTRODUCTION: This study aimed to investigate the influence of canal shape on the time required for the removal of Thermafil Plus plastic carriers (Dentsply Tulsa Dental, Tulsa, OK) using ProTaper Retreatment Files (Dentsply Maillefer, Ballaigues, Switzerland). METHODS: Sixty simulated J-shaped canals in resin blocks were divided into six groups prepared differently in terms of apical size (25/04 or 35/06) and coronal enlargement (no coronal enlargement, using a K3 orifice opener [SybronEndo, Orange, CA] 25/08, or using Gates-Glidden drills [Mani, Tochigi, Japan] #1-4) and were filled with a Thermafil Plus of the same carrier size (size 25 or 35). The carriers were removed using ProTaper D1, D2, and D3 in a crown-down sequence, and removal time was measured. A similar experiment was performed using extracted mandibular incisors prepared to 25/04 with or without coronal enlargement using Gates-Glidden drills (n = 10 each). RESULTS: Simulated canals coronally enlarged with Gates-Glidden drills required a significantly longer removal time than other groups of identical apical size (p < 0.05). When groups with similar coronal enlargement were compared, those apically prepared to 35/06 required a significantly longer removal time than those prepared to 25/04 (p < 0.05). Coronally enlarged incisors also required a significantly longer removal time than those without coronal enlargement (p < 0.05). CONCLUSIONS: Canals with a larger diameter and/or taper required more time for the removal of Thermafil Plus plastic carriers. PMID- 20850677 TI - Medication with calcium hydroxide improved marginal adaptation of mineral trioxide aggregate apical barrier. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of calcium hydroxide premedication on the marginal adaptation of the mineral trioxide aggregate (MTA) apical barrier. METHODS: Forty single-rooted teeth were prepared and apically resorbed using sulfuric acid for 4 days. Teeth were allocated into two groups according to whether calcium hydroxide was placed in the canals for 1 week (medicated group) or not (nonmedicated group) before placing a 4-mm MTA apical plug in the canals. The roots were mounted on aluminum stubs, the root apex was viewed from the top under scanning electron microscopy, and the maximum distance between MTA and the surrounding dentin was measured. RESULTS: The mean gap widths in the medicated and nonmedicated groups were 70.2 MUm and 130.0 MUm, respectively (p < 0.05). CONCLUSIONS: Calcium hydroxide treatment improves marginal adaptation of the MTA apical plug. PMID- 20850678 TI - Comparative physicochemical and biocompatible properties of radiopaque dicalcium silicate cement and mineral trioxide aggregate. AB - INTRODUCTION: The purpose of this study was to comparatively examine physicochemical and biocompatible properties of 20 wt% bismuth oxide (Bi(2)O(3)) containing dicalcium silicate cement and white-colored mineral trioxide aggregate (WMTA). METHODS: The radiopacity, setting time, diametral tensile strength, pH value, morphology, and phase composition of the cements with and without Bi(2)O(3) were measured after mixing powders with water. Cement biocompatibility was evaluated by incubating the cement specimens with MG63 human osteoblast-like cells. RESULTS: The addition of Bi(2)O(3) to the cement led to a significant increase (p < .05) in the setting time of 24 minutes. It was accompanied by a small decrease in the pH value but without adversely affecting diametral tensile strength. The radiopacity value of the Bi(2)O(3)-containing cement was equivalent to 7.3 mm of aluminum, which was significantly higher (p < 0.05) than pure cement without Bi(2)O(3) (1.1 mm of aluminum) but lower (p < .05) than WMTA (9.3 mm of aluminum). However, it was greater than 3 mm of aluminum, which is the value recommended by ISO 6876/2001 standards. MG63 cell viability cultured on Bi(2)O(3) containing cement was higher than that cultured on WMTA at all culture times. CONCLUSIONS: The dicalcium silicate cement with 20 wt% Bi(2)O(3) showed shortened setting time and good biocompatibility and thus may have the potential to be a root-end filling material alternative to MTA. PMID- 20850679 TI - Biomechanical responses of endodontically treated tooth implant-supported prosthesis. AB - INTRODUCTION: This study was designed to investigate the biomechanical interactions in endodontically treated tooth implant-supported prosthesis with variations in implant system and load type by using the nonlinear finite element (FE) approach. METHODS: The computed tomography (CT), micro-CT image process, and computer-aided design systems were integrated to construct the FE models containing 1-, 2-, and 3-piece implants splinted to the second premolar. Realistic interface conditions within the implant system were simulated by using frictional contact elements, and mechanical responses in terms of von Mises stress were computed for all models. RESULTS: The simulated results indicated that splinting an endodontically treated tooth to a neighbor implant decreased stress values in dentin and post but increased stress of implant and bone. The oblique occlusal forces increased the stress values relative to those of axial analogs. A splinted system with a 2-piece implant increased stress on the bone and decreased stress on the prosthesis compared with that of the 1-piece implant. CONCLUSIONS: Splints with 1-piece implant prosthesis, without eccentric occlusal contacts, have better mechanical responses than those of 2- or 3-piece implants when connected to an endodontically treated tooth restored with post core and crown. PMID- 20850680 TI - Scanning electron microscopic analysis of the integrity of the root-end surface after root-end management using a piezoelectric device: a cadaveric study. AB - INTRODUCTION: The introduction of piezoelectric instruments in endodontic surgery allowed clinicians to manage the bone tissue with precision reducing the risk of damaging soft tissues. Although such instruments can also be used to prepare root end cavity, few information is available on the effect of piezosurgery on dentine. This cadaveric study investigated the integrity of root apices after root-end cavity preparation by piezoelectric instruments at different device settings. METHODS: Fifty maxillary anterior teeth underwent endodontic treatment and apical resection in situ. Ten teeth were used as control. Retrograde cavities were prepared in 40 teeth (10 per group). In three groups, the piezoelectric device was set at constant vibration mode (CV), and three power levels were used. In another experimental group (n = 10), vibration + pulsation mode (VP) was selected, and low power was used. Each root was duplicated and analyzed by scanning electron microscopy for the presence of cracks and marginal chipping. RESULTS: The number of cracks was significantly higher in the VP group, whereas no significant difference was found among CV groups. No difference between groups was found for crack type. The VP group showed a significantly poorer quality of cavity margin respect to the CV groups. CONCLUSION: Constant vibration mode is recommended for retrograde preparation with piezosurgery. PMID- 20850681 TI - Tissue reaction to silver nanoparticles dispersion as an alternative irrigating solution. AB - INTRODUCTION: Nanomaterials have been used to create new consumer products as well as applications for life sciences and biotechnology. The aim of this study was to evaluate the tissue response to implanted polyethylene tubes filled with fibrin sponge embedded with silver nanoparticles dispersion. METHODS: Thirty rats received individually 4 polyethylene tubes filled with sponge embedded in 47 ppm, 23 ppm silver nanoparticles dispersion, 2.5% sodium hypochlorite, or with no embedding as control. The observation periods were 7, 15, 30, 60, and 90 days. After each period of time, 6 animals were killed, and the tubes and surrounding tissue were removed, fixed, and prepared to be analyzed in light microscope with glycol methacrylate embedding, 3-MUm serial cutting, and hematoxylin-eosin stain. Qualitative and quantitative evaluations of the reactions were performed. RESULTS: Both materials caused moderate reactions at 7 days. The response was similar to the control on the 15th day with 23 ppm silver nanoparticles dispersion and 2.5% sodium hypochlorite and on the 30th day with 47 ppm silver nanoparticles dispersion. CONCLUSIONS: It was possible to conclude that silver nanoparticles dispersion was biocompatible especially in a lower concentration. PMID- 20850682 TI - Readability of educational materials for endodontic patients. AB - INTRODUCTION: Vocabulary and writing style have been shown to affect the readability of patient-education materials. Readability is generally defined as the ease of understanding or comprehension because of the style of writing. Microsoft Word software (Microsoft Corporation, Bellevue, WA) can quantify and report readability statistics, providing both the Flesch Reading Ease score and the Flesch-Kincaid Grade Level score of selected documents. METHODS: This study evaluated the readability of 22 endodontic patient education web sites and 15 endodontic patient education brochures. The web sites and brochures were arbitrarily selected based on availability, reputation of the source, and relevance to endodontic patients. RESULTS: The Flesch Reading Ease score and the Flesch-Kincaid Grade Level score were determined for the 37 selected materials. The Flesch Reading Ease scores varied between 44.4 and 76.6, and the Flesch Kincaid Grade Level scores ranged between 4.5 and 10.6. CONCLUSIONS: These findings remind practitioners that some patients may have difficulty reading some endodontic educational materials. PMID- 20850683 TI - Lateral periodontal cysts arising in periapical sites: a report of two cases. AB - INTRODUCTION: The lateral periodontal cyst is an uncommon odontogenic developmental lesion and chiefly arises in the alveolar bone between the roots of a pair of erupted teeth or lateral to a tooth root. Two atypical cases of the lateral periodontal cyst occurring in periapical sites are reported. METHODS: Both lesions presented as an incidental radiographic finding, appearing as an apical radiolucency with well-circumscribed sclerotic borders. One lesion, initially suspected to be of pulpal origin, persisted after endodontic therapy; the other case was first considered to be an odontogenic keratocyst. A biopsy was performed on each patient for lesional identity. RESULTS: Histopathologic assessment of each lesion was consistent with a lateral periodontal cyst and revealed thin, nonkeratinized epithelial linings containing nodular plaques and clear cells. The cyst walls were thickened and had minimal inflammation. CONCLUSIONS: The featured cases show that the lateral periodontal cyst is not always confined to the interradicular region and can masquerade as a lesion of endodontic origin. Aberrant cases warrant long-term surveillance. PMID- 20850684 TI - Mandibular first molar having an unusual mesial root canal morphology with contradictory cone-beam computed tomography findings: a case report. AB - INTRODUCTION: The objective of this article is to highlight the importance of having a thorough knowledge about the root canal anatomy and the possibility of misleading findings in the cone-beam computed tomography (CBCT) images. METHODS: This case report presents the endodontic management of a right mandibular first molar with 2 roots and 2 canals. A CBCT imaging was performed to ascertain this rare root canal anatomy. RESULTS: The clinical and radiographic diagnosis of the existence of a single root canal within the mesial root of mandibular first molar did not correlate with the CBCT findings. CONCLUSIONS: The confirmative diagnosis should be based on cognitive deduction of the clinical picture and intelligent interpretation of radiologic information. PMID- 20850685 TI - Palatogingival groove: endodontic-periodontal management--case report. AB - This report presents a case of a maxillary lateral incisor with a deep palatogingival groove extending up to the root apex with severe periodontal destruction. Despite an apparently poor prognosis, the tooth was successfully managed by endodontic and surgical periodontal therapy. The rationale behind the treatment modalities is also discussed. PMID- 20850686 TI - Management of invasive cervical resorption: observations from three private practices and a report of three cases. AB - Invasive cervical resorption (ICR) is a type of external resorption that is not well understood or well known in the dental community. It is often misdiagnosed, leading to improper treatment or unnecessary loss of the tooth. Treatment may involve the periodontium as well as the tooth and pulp, and management can be complex. Early diagnosis and appropriate treatment are the keys to a successful outcome. This article discusses the decision-making process and management of ICR, with emphasis on the restorative aspects of treatment. Three treatment cases are presented that include nonsurgical and surgical approaches, with recalls of 4, 8, and 9.5 years. PMID- 20850687 TI - Brucellosis as a Transboudary Infection of Animals and Humans which Needs to be Managed by Cooperative Efforts of Different Countries. Introduction. PMID- 20850688 TI - Diagnostic and vaccine chapter. AB - The first report in this chapter describes the development of a killed composite vaccine. This killed vaccine is non-infectious to humans, other animals, and the environment. The vaccine has low reactivity, is non-abortive, and does not induce pathomorphological alterations to the organs of vaccinated animals. The second report of this chapter describes the diagnostic value of a competitive enzyme linked immunosorbent assay for detecting Brucella-specific antibodies and its ability to discriminate vaccinated cattle from infected cattle. The results indicated that the competitive enzyme-linked immunosorbent assay is more sensitive than traditional tests for detecting antibodies to Brucella abortus in naturally and experimentally infected cattle. PMID- 20850689 TI - Epidemiology chapter. AB - This chapter outlines the epidemiology of brucellosis in the Russian Federation and in five countries bordering Russia. Since the Soviet Union's dissolution, Russia and the newly formed independent republics have failed to maintain policies to control brucellosis and other zoonotic diseases. Many of these republics, due to weak animal control and prevention systems and dangerous food preparation practices, are still burdened with the human cost of brucellosis. The final summary of this section provides an example of the successful transboundary cooperative efforts between Arizona and Mexico, which could be applied to the situation between Russia and the bordering independent republics. PMID- 20850690 TI - Bridging the gap, pioneering the future. PMID- 20850691 TI - Soft tissue Rosai-Dorfman disease: 29 new lesions in 18 patients, with detection of polyomavirus antigen in 3 abdominal cases. AB - Soft tissue Rosai-Dorfman disease (STRDD) is rare, previously reported only as single cases and few series. Simian virus 40 (SV40), a polyomavirus, has been identified in lymphoid processes and has a controversial role in neoplasia etiology. Occasional cytoplasmic pink granular inclusions and nuclear changes led us to explore a viral etiology. Only unpublished STRDD from our files with adequate material, soft tissue location, and diagnostic confirmation were included. Immunohistochemistry and follow-up were obtained. Eighteen STRDD patients, 4 male and 14 female, had 29 lesions; 5 with 2 or more lesions. Ages ranged from 8 to 81 years (mean 42.6 years and median 42.5 years). Soft tissue Rosai-Dorfman disease locations include trunk or proximal extremity (n = 19), distal extremity (n = 5), "abdominal" (n = 3), face (n = 1), and unknown subcutaneous site (n = 1). Sizes ranged from 0.5 to 13.7 cm (median, 2.4 cm). Previous disease included lymphoma, buttocks injection site, diabetes and hypothyroidism, and radiation for chronic dermopathy. No patients had a preceding or concurrent known viral infection; none had lymphadenopathy at present. None were known to be immunocompromised. Soft tissue Rosai-Dorfman disease was rapidly progressing. Initial pathologic diagnosis ranged from Rosai-Dorfman disease or inflammatory pseudotumor to inflammatory malignant fibrous histiocytoma. Grossly STRDDs were multilobulated, tan-yellow, and firm; morphologically, circumscribed, and subcutaneous-based. All had sheets of polygonal histiocytes with abundant pale eosinophilic cytoplasm, emperipolesis, plasma cells, and lymphocytes scattered and within clusters. Focal spindle cell change and mild pleomorphism were each observed in 3 patients; 2 had focal necrosis, none with mitoses. Small granular pink cytoplasmic inclusions and nuclear viral-like changes were observed. By immunohistochemistry, all STRDDs were positive for S100 protein, negative for CD1a, Epstein-Barr virus, and latent membrane protein, yet 3 (all abdominal, 1 multicentric) of the 9 studied were focally positive for cytoplasmic and nuclear SV40 polyomavirus. All were treated by local excision. Follow-up on 14 patients older than 8 to 16 years revealed recurrence in 3 patients with persistent multiple lesions, one with abdominal location. There were no metastases or death from disease. Soft tissue Rosai-Dorfman disease is a rapidly evolving, mostly solitary and nonrecurrent trunk and proximal extremity subcutaneous lesion in middle-aged females. More than one third can have persistent multicentric disease. It is important to recognize STRDD, to separate it from malignancy. Epstein-Barr virus/latent membrane protein was negative but polyomavirus was positive in 3 patients with abdominal STRDD, one with multicentric persistent disease. The relationship of polyomavirus to the evolution of abdominal STRDD should be further explored. PMID- 20850692 TI - Hepatocellular carcinoma arising in association with von-Meyenburg's complexes: an incidental finding or precursor lesions? A clinicopatholigic study of 4 cases. AB - Biliary hamartomas or von-Meyenburg complexes form part of a spectrum of ductal plate malformation that includes polycystic liver disease, congenital hepatic fibrosis, and Caroli disease. These lesions are known to have neoplastic transformation. Development of intrahepatic cholangiocarcinoma is well described in these complexes. Rarely, hepatocellular carcinomas (HCCs) have been seen in association with bile duct hamartomas, however; it is not clear whether development of HCC is an epiphenomenon unrelated to the precursor lesion or biliary hamartomas may progress to liver cancers. We herein report 4 interesting cases of hepatitis C virus-, alcohol-, and nonalcoholic fatty liver disease associated end-stage liver disease with coexisting HCC and multiple large von Meyenburg complexes. PMID- 20850693 TI - Prognostic significance of vascular endothelial growth factor, basic fibroblastic growth factor, and microvessel density and their relation to cell proliferation in B-cell non-Hodgkin's lymphoma. AB - Vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor (b FGF) have been described as essential cytokines in the regulation of angiogenesis. Their elevation has been associated with an unfavorable outcome in different neoplasms. However, their role in angiogenesis and proliferation in B cell non-Hodgkin's lymphoma (B-NHL) is unclear. Seventy cases of B-NHL besides 5 cases with reactive lymphadenitis were collected randomly and classified according to World Health Organization classification, Ann Arbor staging. They were subjected to immunostaining using VEGF, b-FGF, CD34, and Ki67 markers. There were a positive correlation between the proliferation and aggressiveness of the tumor as measured with Ki67 and both VEGF and b-FGF, and this was reflected on the stromal increase in microvessel density as measured by CD34. In conclusion, as the tumor becomes more aggressive, it also becomes independent of stromal paracrine factors by the establishment of an autocrine VEGF and b-FGF stimulation that can increase its angiogenesis and proliferation. PMID- 20850694 TI - Cutaneous angiomyxoma and pilomatricoma: a new combination. AB - Superficial angiomyxomas are rare benign tumors that typically present as a solitary lesion or as a component of Carney complex and rarely have been associated with other lesions. In this article, we report 3 cases of an unusual association of superficial angiomyxoma with pilomatricoma. This combination has never been described in the literature. The 3 patients presented with variable sized pedunculated, asymptomatic skin papules overlying firm deeply situated nodules. Histopathologic examination demonstrated that the superficial pedunculated lesion is a superficial angimyxoma with underlying pilomatricoma. Thorough clinical examination failed to reveal any further lesions. We present a rare and unique combination of angiomyxoma and pilomatricoma. This combination may be incidental, representing collision tumors or etiologically related. PMID- 20850695 TI - Podoplanin, a novel marker for seminoma: A comparison study evaluating immunohistochemical expression of podoplanin and OCT3/4. AB - Podoplanin, a 38-kd membrane glycoprotein of podocytes, is the human homologue of mouse protein, aggrus, a 44-kd sialoglycoprotein; the latter has recently been reported in testicular seminomas but not in embryonal carcinomas, suggesting that it may be a specific marker for seminomas. The physiologic role of podoplanin has yet to be determined and its function in tumors is not well characterized. In this study we investigate the utility of podoplanin expression in the diagnosis of testicular germ cell tumors. Sixty-eight cases of testicular mixed germ cell tumors were analyzed using a polyclonal antibody and compared to the results for OCT3/4. Stained sections were graded semiquantitatively as follows: negative (no expression), 1+ (mild intensity), 2+ (moderate intensity), 3+ (intense staining). Diffuse cytoplasmic expression of podoplanin with membrane accentuation was seen in the seminoma component of all cases. Lymphocytes and interstitial cells were negative. In mixed germ cell tumors, podoplanin identified small clusters of seminoma cells lying adjacent to nonseminomatous components. Focal staining was present in one third of cases of choriocarcinoma. There was no significant staining of any nontrophoblastic, nonseminomatous elements. In contrast to OCT3/4, podoplanin does not stain embryonal carcinoma. The availability of a marker for seminoma will enable better recognition and distinction from embryonal carcinoma, particularly in nongonadal sites. The identification by podoplanin of seminoma cells lying adjacent to foci of embryonal carcinoma gives credence to the hypothesis that the latter arise from seminomas as part of a process of "differentiation." PMID- 20850696 TI - Chagas disease and gynecologic neoplasias. AB - The inflammation caused by Trypanosoma cruzi produces irritation and cell proliferation and may contribute to the development of cancer. The objective was to determine the occurrence of gynecologic neoplasia (GN) and demographic characteristics in patients with Chagas disease (CD). We used protocols of 671 autopsies between 1976 and 2008. The patients were divided into 3 groups: with GN and CD, only with CD, and only with GN. The 2 diseases were observed in 4.5% of patients with a mean age of 47.6 years and who were predominantly white. The megaesophagus and megacolon were more frequent in the group with only CD. The most common benign neoplasm was uterine leiomyoma, and malignant, carcinoma of the cervix. We conclude that the epidemiological profile of patients with CD and GN was similar to the other groups, and the CD was found not to be a risk factor or protective against the development of GN. PMID- 20850697 TI - Cystic paraganglioma of the anterior mediastinum. AB - Paraganglioma of the mediastinum is an extremely uncommon neoplasm, and the concurrent finding of cystic changes has yet to be reported in the literature. We report a case of a 43-year-old man presenting with chest pain and left arm paresthesias. Imaging studies revealed a well-defined cystic lesion located in the anterior mediastinum, with the patient undergoing subsequent surgical resection of the mass. Grossly, the heterogenous mass measured 6.0 * 3.6 * 1.7 cm, with prominent cystic spaces and scattered solid areas. Microscopic examination revealed pseudocystic spaces with proliferation of large epithelioid cells with abundant eosinophilic cytoplasm, moderate pleomorphic nuclei, and prominent nucleoli, in a nested pattern of growth along the cysts walls. Immunohistochemical stains showed strong positivity for chromogranin, synaptophysin, and CD56 in the epithelioid cells, with negative staining for cytokeratin AE1/AE3, confirming the diagnosis of paraganglioma. S-100 was positive in the intervening sustentacular cells throughout the tumor. Cystic paraganglioma of the anterior mediastinum is a rare neoplasm, which , to our knowledge, has not yet been reported in the English literature, and should be added to the differential diagnosis of cystic lesions of the mediastinum. PMID- 20850698 TI - Current status of cytology laboratories in anatomic pathology departments. AB - Details of cytology work in 103 US histology laboratories (histolabs) and in 200 from 18 other countries are presented. Data from 1345 additional US cytology practices surveyed from 1985 to 2004 are also included. The average annual workload in 130 histolabs from the United States and 12 other countries combined is 32 200 cases. The average annual workload in 173 histolabs from Spain and 5 Hispano-American countries is 20 000 cytology cases, a workload that is significantly lower (P < .0005) than that in US laboratories. Gynecologic cases, with an average of 1.2 slides each, represent 79% of all cytology accessions in all laboratories. The average annual workload per cytotechnologist (CT) is 6600 cases; this number is not significantly different between countries (P > .10 to P > .75) and is significantly correlated (P < .0008) with the laboratories' total workloads. In the United States, the average annual productivity per CT is 6700 cases with 1.8 slides each, for a daily screening of 55 to 60 slides. The annual benchmark is from 7900 to 8700 cases, equivalent to 14 300 to 15 000 slides per each full-time CT position. The benchmark per cytology aide is 17 000 to 20 000 cases. The number of CTs per histolab is significantly correlated (P < .0002) with its workload. In the United States, there is an average of 4 CTs and 2.7 cytology aides per laboratory, and the cytology tasks completed by the histology staff average 4.1 hours daily. The average turnaround time for cytology cases in the United States is approximately 6 calendar days, with 90% of all cases signed out between 7 and 8 calendar days. In addition to the productivity benchmarks, the pathology leadership must address the ergonomic conditions of the work when filling a new CT position because muscular discomfort caused by the microscopy work is a common occurrence. PMID- 20850699 TI - Vascular plexiform leiomyoma mimicking uterine tumor resembling ovarian sex cord tumor. AB - Leiomyomata are common benign smooth muscle neoplasms with a usually easily recognizable histologic pattern. However, there is a wide variety of subtypes described in the literature, characterized by predominance of a particular distinct histologic pattern. Here we describe a case of a highly vascular leiomyoma with a prominent plexiform pattern and cords and tubules of epithelioid cells that mimics a uterine tumor resembling an ovarian sex cord tumor. PMID- 20850700 TI - Perianal mammary-type myofibroblastoma. AB - We report a unique case of an extramammary mammary-type myofibroblastoma of the perianal region. The patient was a 40-year old female with no significant past history, who presented with a right side painless perianal mass. Gross examination of the excised mass showed a well-circumscribed, apparently encapsulated, nodular mass weighing 30 g and measuring 5 cm. in the greatest dimension. The cut surface showed solid, yellow homogenous tissue. Microscopically, the neoplasm was composed of bland spindled cells generally arranged into short fascicles with abundant myxoid stroma. The cells stained strongly for desmin and CD34. To our knowledge, a review of the literature discloses only ten cases of extramammary, mammary-type myofibroblastoma. PMID- 20850701 TI - Endolymphatic sac tumor with von Hippel-Lindau disease: report of a case with analysis of von Hippel-Lindau gene and review. AB - Endolymphatic sac tumors (ELSTs) are very rare and locally aggressive low-grade neoplasm of endolymphatic system origin, which are associated with von Hippel Lindau (VHL) disease. Evidence suggests that the specific VHL alteration influences the phenotype. Because of the rarity of ELSTs, only a small number of cases have been subjected to molecular genetic analysis. The correlation between ELSTs and the genotype of VHL remains unclear. Herein, we reported a case of ELST with VHL gene analysis who presented with a family history of VHL disease. The radiologic, histologic, and immunohistochemical features of the tumor were typical of ELST. Using the polymerase chain reaction-single-strand conformation polymorphism sequencing techniques, a germline mutation was identified as IVS1 + 1G->A at position 553 + 1. The mutation found in this case has not been previously reported in ELSTs. It is hoped that the study would contribute to a better understanding of ELSTs and the correlation between ELSTs and the genotype of VHL. PMID- 20850702 TI - Basal cell carcinoma of the prostate gland: a case report and brief review of the basal cell proliferations of the prostate gland. AB - Basal cell proliferations within the prostate gland encompass a group of benign and malignant entities. Although basal cell hyperplasia is a common finding, basal cell carcinoma of the prostate gland is a rare tumor that can be mistaken by a benign condition and represents a diagnostic problem in genitourinary pathology. We report a case of basal cell carcinoma in a previously healthy 65 year-old man with urinary symptoms and low prostate-specific antigen. The microscopic findings are presented and the use of immunohistochemical markers classifying basal cell lesions of the prostate discussed. PMID- 20850703 TI - Early-stage mycosis fungoides variants: case-based review. AB - Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. The diagnosis of classic MF is based on a combination of clinical presentation, histopathology, and T-cell monoclonality detected by molecular studies. However, the diagnosis can be difficult in cases of early MF because of the subtle nature of histologic findings and, in cases of variants of MF, because of the unusual clinical and/or pathologic features. In this review, we presented the most frequent variants of MF at early stage including hypopigmented, folliculotropic, pagetoid reticulosis, unilesional, granulomatous, and ichthyosis forms. This case based clinicopathologic review provides the notion that a comprehensive clinicopathologic correlation is of substantial importance to render the diagnosis of MF. In addition, we discuss the role of molecular studies, which are highly sensitive and recently more applicable to routinely processed skin biopsy specimens in the diagnosis of MF. PMID- 20850704 TI - WITHDRAWN: Attention and spatial stimulus coding in the Simon task: A rejoinder to van der Lubbe and Abrahamse (in press). AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 20850705 TI - Hydrodynamic permeability of aggregates of porous particles with an impermeable core. AB - A hydrodynamic permeability of membranes built up by porous cylindrical or spherical particles with impermeable core is investigated. Different versions of a cell method are used to calculate the hydrodynamic permeability of the membranes. Four known boundary conditions, namely, Happel's, Kuwabara's, Kvashnin's and Cunningham/Mehta-Morse's, are considered on the outer surface of the cell. Comparison of the resulting hydrodynamic permeability is undertaken. A possible jump of a shear stress at the fluid-membrane interface, its impact on the hydrodynamic permeability is also investigated. New results related to the calculated hydrodynamic permeability and the theoretical values of Kozeny constant are reported. Both transversal and normal flows of liquid with respect to the cylindrical fibers that compose the membrane are studied. The deduced theoretical results can be applied for the investigation of the hydrodynamic permeability of colloidal cake layers on the membrane surface, the hydrodynamic permeability of woven materials. PMID- 20850706 TI - A comparative analysis of core needle biopsy and final excision for breast cancer: histology and marker expression. AB - BACKGROUND: Core needle biopsy (CNB) is used increasingly not only to diagnose breast cancer, but to determine tumor histology, grade and marker expression, select neoadjuvant therapy, and predict sentinel lymph node status. Thus, we undertook this study to evaluate the accuracy of CNB as a predictor of breast cancer histology and marker expression. METHODS: We identified 209 Breast Cancer Registry cases with a preoperative CNB and reviewed all clinicopathologic data for accuracy. Statistical analysis was performed with statistical software. RESULTS: CNB unequivocally showed cancer in 93%. Exact tumor histology concordance was 86%. Ductal carcinoma in situ on CNB was upgraded to invasive cancer in 23%. Concordance was substantial for estrogen receptor expression (88%, kappa = .71), but kappa values were less than .6 for tumor grade, mitotic rate, progesterone receptor (PR), Ki-67, HER-2/neu, and p53 expression. CONCLUSIONS: Reliance on CNB grade and marker expression for critical decision making may be inadvisable. Further study is warranted to optimize breast cancer patient care. PMID- 20850707 TI - "Component separation" technique and panniculectomy for repair of incisional hernia. AB - BACKGROUND: Primary incisional hernia repair is rarely successful, with recurrence rates ranging from 18% to 62%. We describe the integration of "components separation" herniorrhaphy with panniculectomy. METHODS: Twenty-two patients were treated. Standard panniculectomies and component separation were performed. Intravesical pressure was measured preoperatively, intraoperatively, and postoperatively. Measurement variations were compared using the Wilcoxon test. Complications or hernia recurrence were evaluated. The clinical appearance of the abdomen was subjectively evaluated by patients. RESULTS: Secure abdominal defect closure with midline approximation of the fascia was achieved in all patients. No major early complications occurred. Hernia recurred in 1 patient (4.5%). Intra-abdominal pressure increased in all the patients in our series but remained well below the danger level. Fifteen patients were fully satisfied with the appearance of their abdomen, whereas 7 were satisfied. CONCLUSIONS: Abdominal component separation provides a reliable autologous reconstructive option. Hernia repair combined with abdominoplasty provides functional and esthetic benefits. PMID- 20850708 TI - A rare complication of intraabdominal hydatid disease: gastric fistula and recurrent gastric bleeding. AB - Intra-abdominal hydatid disease is a type of echinococcosis. This silent disease becomes symptomatic with serious complications. A 50-year-old woman presented with abdominal pain and recurrent hematemesis. A computed tomographic scan demonstrated a large retrogastric hydatid cyst and suggested gastric fistula. An emergent laparotomy was performed, and gastric fistula of the intraperitoneal hydatid cyst and arterial bleeding around the fistula were demonstrated intraoperatively. Clinical course, complications, and management of intra abdominal hydatid disease are discussed. PMID- 20850709 TI - A multi-institutional study of the Family Conference Objective Structured Clinical Exam: a reliable assessment of professional communication. AB - BACKGROUND: To test the value of a simulated Family Conference Objective Structured Clinical Exam (OSCE) for resident assessment purposes, we examined the generalizability and construct validity of its scores in a multi-institutional study. METHODS: Thirty-four first-year (PG1) and 27 third-year (PG3) surgery residents (n = 61) from 6 training programs were tested. The OSCE consisted of 2 cases (End-of-Life [EOL] and Disclosure of Complications [DOC]). At each program, 2 clinicians and 2 standardized family members rated residents using case specific tools. Performance was measured as the percentage of possible score obtained. We examined the generalizability of scores for each case separately. To assess construct validity, we compared PG1 with PG3 performance using repeated measures multivariate analysis of variance (MANOVA). RESULTS: The relative G coefficient for EOL was .890. For DOC, the relative G-coefficient was .716. There were no significant performance differences between PG1 and PG3 residents. CONCLUSIONS: This OSCE provides reliable assessments suitable for formative evaluation of residents' interpersonal communication skills and professionalism. PMID- 20850710 TI - Carney complex: Clinical and genetic 2010 update. AB - First described in the mid 1980s, Carney complex is a rare dominantly heritable multiple endocrine neoplasia syndrome that affects endocrine glands as the adrenal cortex, the pituitary and the thyroid. It is associated with many other nonendocrine tumors, including cardiac myxomas, testicular tumors, melanotic schwannoma, breast myxomatosis, and abnormal pigmentation or myxomas of the skin. The Carney complex gene 1 was identified 10 years ago as the regulatory subunit 1A of protein kinase A (PRKAR1A) located at 17q22-24. An inactivating heterozygous germ line mutation of PRKAR1A is observed in about two-thirds of Carney complex patients. This last decade many progresses have been done in the knowledge of this rare disease and its genetics. This review outlines the current state of this knowledge on Carney complex. PMID- 20850711 TI - Intensive physical activity increases peripheral blood dendritic cells. AB - We analyzed the frequency and absolute numbers of circulating myeloid and plasmacytoid DCs in peripheral blood and evaluated their maturation status to test the hypothesis that significant physical stress to the body might induce measurable changes in DCs subsets, phenotype and function, which would complete existing knowledge about the response of the cellular immune system to an acute exercise in top sportsmen. We evaluated the heart rate and draw blood samples before and after the physical load in 18 profesional ice-hockey players. We observed an increase in leukocytes numbers with a predominant increase in the population of DCs and lymphocytes after exercise. Both myeloid and plasmacytoid DCs increased significantly. We found a correlation between the increase of peripheral blood DCs and serum epinephrine and norepinephrine levels. Increase in peripheral blood DCs also correlates with the extent of heart rate elevation during exercise. PMID- 20850712 TI - Acute graft-vs.-host disease correlates with the disparity for the PECAM-1 S536N polymorphism only in the HLA-B44-like positive Tunisian recipients of HSCs. AB - GVHD is the major cause of mortality after HLA-identical HSCT. Such complication has been widely linked to donor/recipient disparity for minor histocompatibility antigens (MiHAgs). PECAM-1 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who undergone HLA-identical HSCT between 2000 and 2009. Genotyping of the three selected PECAM-1 polymorphisms (rs668, rs12953 and rs1131012) was performed with SSP-PCR method. Univariate analyses showed that grades II-IV acute GVHD were considerably linked to the non-identity for rs12953 only in HLA-B44 like positive patients (p=0.010, OR=10.000). Multivariate analysis for chronic GVHD showed that this outcome may be affected only by the adulthood and the conditioning regimen. Our findings support the previously reported data suggesting a significant association between the PECAM-1 disparity and the risk of acute GVHD. PMID- 20850713 TI - [Analysis of the quality of surgical treatment of colorectal cancer, in 2008. A national study]. AB - OBJECTIVE: A national study conducted for the Spanish Association of Surgeons with the aim of analysing the surgical treatment of colorectal cancer (CRC) in Spain and to compare it with scientific literature. MATERIAL AND METHODS: A multicentre, descriptive, prospective and longitudinal study of patients with CRC who were treated by elective surgery. A total of 50 hospitals in 15 Autonomous Regions took part, with 496 treated cases in 2008. A total of 88 variables were collected. RESULTS: The median age was 72 years, increase in ASA III patients; correct preoperative studies, 4% with no staging in the rectum. There was a tendency not to use the colon cleansing or to do it only one day. The percentage of complications is within the ranges in the literature, with the exception of surgical wound infections (19%). Mean of resected lymph nodes: 13.2; 4.3% no mesorectal resection. Mechanical anastomosis: 80.8%, 65.9% of the operations performed by a colorectal surgeon. Preoperative radiotherapy in 43.5% of rectal cancers. Chemotherapy: 32.9%. Laparoscopy: 35.1% of cases, conversion rate 13.8%. Use of antibiotics: 37.1%, blood transfusion: 20.6% and parenteral nutrition: 26.5%. CONCLUSIONS: Surgical treatment of CRC in Spain has a level of quality and peri-operative results similar to the rest of Europe. Compared to previous studies, it was observed that there were advances in preparation of the patient, preoperative studies, imaging techniques, and improvements in surgical techniques with adoption of mesorectal excision, appropriate lymphadenectomies and preservation of sphincters. There are areas for improvement, such as a reduction in surgical wound infections, increase use of protective stoma, appropriate use of antibiotics, parenteral nutrition or neoadjuvants and complete colonoscopies. PMID- 20850715 TI - [Malnutrition in internal medicine: The importance of a great unknown]. PMID- 20850714 TI - When the brain remembers, but the patient doesn't: converging fMRI and EEG evidence for covert recognition in a case of prosopagnosia. AB - The role of the occipito-temporal cortex in visual awareness remains an open question and with respect to faces in particular, it is unclear to what extent the fusiform face area (FFA) may be involved in conscious identification. An answer may be gleaned from prosopagnosia, a disorder in which familiar faces are no longer recognized. This impairment has sometimes been reported to be associated with implicit processing of facial identity, although the neural substrates responsible for unconscious processing remain unknown. In this study, we addressed these issues by investigating the functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) responses to familiar and unfamiliar faces in a well-known prosopagnosic patient (P.S.). Our fMRI results show that faces known prior to the onset of prosopagnosia produce an increase in activation in the lateral fusiform gyrus encompassing the FFA, as well as the right middle frontal gyrus, when compared to unknown faces. This effect is not observed with photographs of celebrities dating after the onset of prosopagnosia. Furthermore, electrophysiological responses show that previously familiar faces differ from unfamiliar ones at around 550 msec. Since covert processing of familiarity is associated with activation in FFA, this structure does not appear to be sufficient to produce awareness of identity. Furthermore, the results support the view that FFA participates in face individuation. PMID- 20850716 TI - Laparoendoscopic single-site and natural orifice surgery in gynecology. AB - OBJECTIVE: To evaluate the current literature on the use of single port and natural orifice surgery in gynecology. DESIGN: Appraisal of articles published on the use of this technology in gynecology. RESULT(S): Most reports on single port and natural orifice surgery are case reports or case series. However, most have reported successful outcomes such as diagnostic or extirpative gynecologic procedures. The main limitation is the availability of instrumentation to successfully accomplish the task. CONCLUSION(S): Single port and natural orifice surgery offers the potential for advancing the minimally invasive approach to gynecologic surgery. PMID- 20850717 TI - Dizygotic twin pregnancy after transfer of one embryo. AB - OBJECTIVE: To consider the risk of intercourse without contraception during infertility treatment. DESIGN: Case report. SETTING: Leiden University Medical Center. PATIENT(S): An infertile couple underwent IVF for tubal pathology. INTERVENTION(S): Transfer of one embryo during a natural cycle. MAIN OUTCOME MEASURE(S): Human leukocyte antigen typing, histochemical analysis of the fetal membranes, neonatal and maternal clinical outcomes. RESULT(S): A dizygotic twin pregnancy was confirmed after birth by human leukocyte antigen typing of both fetuses and mother and by histochemical analysis of the dividing fetal membranes. This suggests a pregnancy of concurrent IVF and spontaneous conception. Pregnancy was complicated by preeclampsia and intrauterine growth retardation of both fetuses. CONCLUSION(S): We state that couples should abstain from intercourse without contraception during infertility treatment to prevent multiple gestation and its related complications for mother and fetuses. PMID- 20850718 TI - Predictive factors of failure in management of ectopic pregnancy with single-dose methotrexate: a general population-based analysis from the Auvergne Register, France. AB - In a general population setting, the existence of a learning curve for treatment of ectopic pregnancy with single-dose methotrexate has been demonstrated, because a significant decrease in failure rate can be achieved over time. Despite this finding, the risk of single-dose methotrexate failure increases significantly in patients with initial hCG levels>1,300 IU/L and/or in women who report having ever used combined oral contraception before pregnancy. PMID- 20850719 TI - Organizational determinants of patient-centered fertility care: a multilevel analysis. AB - OBJECTIVE: To identify organizational determinants of positive patient experiences with fertility care, with the goal of improving patient centeredness of care. DESIGN: Cross-sectional survey. SETTING: One large university clinic and 12 medium-sized fertility clinics in the Netherlands. PATIENT(S): Three hundred and sixty-nine couples receiving medically assisted reproduction in one of the participating clinics between March and May 2008. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Organizational determinants of patients' experiences with patient centeredness in fertility care. RESULT(S): Of the patients during the relevant period, 78% of the women and 76% of their partners participated in the study. Infertile couples who have a lead physician, have access to an electronic personal health record, or see trained fertility nurses have more positive experiences with aspects of patient-centered care, like continuity of care and partner involvement. Moreover, receiving a treatment other than in vitro fertilization was negatively associated with the perceived patient centeredness of care. The identified determinants explained 5.1% to 22.4% of the total variance. CONCLUSION(S): This study provides organizational determinants of patients' experiences with fertility care on numerous facets of patient centeredness. These organizational determinants can be used as valuable tools to enable clinics to provide a more positive patient experience. PMID- 20850720 TI - Embryo disposition: choices made by patients and donor oocyte recipients. AB - OBJECTIVE: To compare final embryo disposition between patients and donor oocyte recipients. DESIGN: Retrospective study. SETTING: Private infertility practice. PATIENT(S): Patients undergoing IVF with embryo cryopreservation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Final cryopreserved embryo disposition. RESULT(S): A total of 1,262 patients using autologous oocytes had 5,417 embryos cryopreserved. A majority either used their embryos (39%) or continued storage (35%). Of 364 patients, who did not use their remaining 1,406 embryos, 77 (21%) donated 290 embryos to other infertile couples, 41 (11%) donated 160 embryos for research, and 246 (68%) discarded 956 embryos. Concurrently, 272 donor oocyte recipients had 1,233 embryos cryopreserved. A majority either used their embryos (40%) or continued storage (23%). Of 110 recipients that did not use their remaining 455 embryos, 62 (56%) donated 280 embryos to other infertile couples, 6 (6%) donated 31 embryos for research, and 42 (38%) discarded 144 embryos. CONCLUSION(S): In our patient population, a higher proportion of patients with infertility ultimately used or stored their cryopreserved embryos for future reproduction compared with donor oocyte recipients. However, recipients were much more likely to donate to other infertile couples and less likely to discard their remaining embryos compared with patients. PMID- 20850721 TI - The impact on ovarian reserve after laparoscopic ovarian cystectomy versus three stage management in patients with endometriomas: a prospective randomized study. PMID- 20850722 TI - Birth defects after assisted reproductive technologies in China: analysis of 15,405 offspring in seven centers (2004 to 2008). AB - This first large-scale report of birth defects in 15,405 offspring conceived by assisted reproductive technologies in China found infants born after IVF alone to have a birth defect frequency comparable to that in the general Chinese population; rates were nonsignificantly higher in infants conceived with use of intracytoplasmic sperm injection compared with those conceived after IVF alone. PMID- 20850723 TI - Claudin-11 expression increased in spermatogenic defect in human testes. AB - Expression of claudin-11, which builds up blood-testis barrier (BTB), was increased in decreased spermatogenesis, including in hypospermatogenesis, spermatocytic and maturation arrest, and Sertoli cell only (SCO) testes. Increased claudin-11 immunoreactivity was observed at the inter-Sertoli tight junctions in maturation arrest and in the cytoplasm of Sertoli cells in SCO. The late spermatogenic wave may negatively regulate claudin-11 gene activation and the subcellular localization of claudin-11 in Sertoli cells, thus altering the BTB in the human testis. PMID- 20850724 TI - Protective effects of montelukast on ischemia-reperfusion injury in rat ovaries subjected to torsion and detorsion: biochemical and histopathologic evaluation. AB - OBJECTIVE: To reveal the effects of montelukast as an antioxidant and tissue protective agent and study the biochemical and histopathologic changes in experimental ischemia and ischemia-reperfusion (I/R) injury in rat ovaries. DESIGN: Experimental study. SETTING: Experimental surgery laboratory in a university department. ANIMAL(S): Forty-eight rats with experimentally induced ovarian torsion. INTERVENTION(S): Group 1: sham; Group 2: ovarian ischemia; Group 3: a 30-hour period of ischemia followed by a 3-hour reperfusion. Groups 4 and 5: rats administered 10 and 20 mg/kg doses of montelukast before a half-hour of ischemia, then ovarian ischemia applied; after a 3-hour period of ischemia, the bilateral ovaries removed. Groups 6 and 7: 3-hour period of ovarian ischemia applied, then 2.5 hours after the ischemia induction, rats given montelukast. Group 8: sham operation and 20 mg/kg of montelukast; at the end of a 3-hour period of ischemia, 3-hours of reperfusion continued. MAIN OUTCOME MEASURE(S): Measurement of ovarian tissue concentrations of superoxide dismutase (SOD), glutathione (GSH), lipid peroxidation (LPO) and myeloperoxidase (MPO) activity; and histopathologic examination of all ovarian rat tissue. RESULT(S): Montelukast treatment normalized changes of LPO and MPO and stimulated an overproduction of endogenous SOD and GSH. The results of the histologic parameters showed that treatment with montelukast in the I/R group of rats ameliorated the development of ischemia and reperfusion tissue injury. CONCLUSION(S): Montelukast at different doses attenuates ovarian I/R-induced ovary tissue injury in rats. PMID- 20850725 TI - Hormonal and ultrasound markers of ovarian function in a woman with a balanced 1;11 translocation. AB - OBJECTIVE: To present a case of a poor responder woman with a rare balanced autosomal translocation. DESIGN: Case report. SETTING: Infertility center in a university teaching hospital. PATIENT(S): A 34-year-old white woman with primary infertility. INTERVENTION(S): Laboratory and ultrasound evaluation, karyotype analysis, ovarian stimulation with gonadotropins. MAIN OUTCOME MEASURE(S): Markers of ovarian reserve and ovarian response to gonadotropin stimulation. RESULT(S): The patient was a carrier of a balanced translocation (1;11) (q23;p11.2). The hormone ovarian reserve markers (FSH, anti-Mullerian hormone, inhibin B) were within the normal range. The antral follicle count (AFC) was measured twice and only in one occasion did it reach the lower limit of the normal range. Furthermore, the patient had regular menstrual cycles. However, ovarian response to the administration of a maximal dose FSH was extremely poor. CONCLUSION(S): Patients with balanced autosomal translocations should be counseled regarding their increased risk for poor response even if markers of ovarian reserve are in the range of normality. PMID- 20850727 TI - Cellular senescence in usual type uterine leiomyoma. PMID- 20850728 TI - New insights of osmoregulatory system changes in ovarian hyperstimulation syndrome. AB - This study evaluated the osmoregulatory system changes in 39 patients with severe ovarian hyperstimulation syndrome. Plasma osmolality (Posm) less or more than 280 mOsm/kg body weight were associated with inappropriate antidiuretic hormone secretion syndrome and hypovolemia, respectively. PMID- 20850729 TI - Aberrant expression of the pluripotency marker SOX-2 in endometriosis. AB - Expression of the pluripotency factors SOX-2, OCT-4, KLF-4, and NANOG was analyzed by quantitative real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence microscopy in the endometrium, myometrium, and endometriotic tissue of 36 patients. Aberrant expression of SOX-2 may indicate a stem cell origin of endometriosis, whereas the presence of all progenitor markers in endometrial tissue marks the endometrium as a potential source for induced pluripotent stem cell generation. PMID- 20850730 TI - Primary amenorrhea in four adolescents revealed 5alpha-reductase deficiency confirmed by molecular analysis. AB - OBJECTIVE: To determine the genetic cause of primary amenorrhea. DESIGN: Case series. SETTING: Pediatric endocrinology, endocrinology, and gynecology departments of academic hospitals. PATIENT(S): Three adolescents and one young woman 46, XY patients with srd5A2 gene mutations. MAIN OUTCOME MEASURE(S): Genetic analysis of srd5A2. RESULT(S): We report four srd5A2 gene mutations in three adolescents and one young woman with 46,XY primary amenorrhea. All presented clitoromegaly and two presented hypospadias; all had been reared as females. Virilization of the external genitalia was noted in the pubertal period in all four patients. Three were maintained in the female sex of rearing by personal choice, and the fourth switched gender. We identified the homozygous substitutions p.L55Q (exon 1), p.Q56R (exon 1), and p.N193S (exon 4), in patients 1, 2, and 3, respectively. Patient 4 had compound heterozygous mutations, a new c.34delG (exon 1) associated with p.R246W (exon 5). All patients had high plasma T levels (ranges, 16.2-23.2 nmol/L; normal female teenage range, 0.35-2 nmol/L). CONCLUSION(S): Our data clearly demonstrate that 5alpha-reductase deficiency should be considered in XY adolescents with primary amenorrhea and no breast development associated with virilization at puberty and high plasma T. Positive parental consanguinity should reinforce the diagnostic orientation. PMID- 20850731 TI - Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study. AB - This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products. PMID- 20850732 TI - Enough is enough! Patients who do not conceive on 600 IU/d of gonadotropins show no improvement from an additional 150 IU of LH activity. AB - Studies have suggested that supplemental LH improves outcomes in assisted reproductive technology (ART) cycles. In this retrospective review, an additional 150 IU of LH activity did not improve ART outcomes in women undergoing a second round of IVF/ intracytoplasmic sperm injection (ICSI) after an initial failed cycle using 600 IU of gonadotropins. PMID- 20850733 TI - Learning curve of transvaginal ultrasound for the diagnosis of endometriomas assessed by the cumulative summation test (LC-CUSUM). AB - A specific statistical tool (the cumulative summation test for learning curve or LC-CUSUM) was used to monitor the learning curve of four trainees for the diagnosis of endometriomas by transvaginal ultrasound. A large intertrainee variability in the learning curves was found, justifying a tailored training to learn this diagnosis. PMID- 20850734 TI - Evaluation of a urinary test as a diagnostic tool of a nonprogressive pregnancy. AB - OBJECTIVE: To evaluate the performance of a one-step test detecting intact hCG and free beta-hCG isoforms in the urine of pregnant women to diagnose an abnormal pregnancy. DESIGN: Prospective study. SETTING: Emergency gynecology departments in teaching hospitals. PATIENT(S): Five hundred twenty-six patients were enrolled, 272 who were not pregnant and 254 who were pregnant. INTERVENTION(S) AND MAIN OUTCOME MEASURE(S): Semiquantitative determination of intact urinary hCG of supposedly not pregnant and pregnant women with vaginal bleeding and/or vaginal pain between 5 and 8 weeks of amenorrhea. RESULT(S): The sensitivity and specificity of the urine test for diagnosing nonpregnancy were, respectively, 100% (252/252) and 100% (272/272). The sensitivity and specificity of the urine test for diagnosing ectopic pregnancy (EP) were, respectively, 97% (32/33) and 83% (142/171). The negative predictive value is 99.3% (142/143). The sensitivity and specificity or the urine test for diagnosing miscarriage were, respectively, 89.6% (43/48) and 83% (142/171). The negative predictive value is 96.6% (142/147). CONCLUSION(S): Abnormal pregnancy, such as an EP or a miscarriage, can be rapidly detected with the one-step test for intact hCG and free beta-hCG isoforms. If ultrasound cannot confirm the localization and/or evolution of a pregnancy, using this test reduces medical supervision and repeated quantification of hCG. PMID- 20850736 TI - Randomized, blinded comparison of transgastric, transcolonic, and laparoscopic peritoneoscopy for the detection of peritoneal metastases in a human cadaver model. AB - BACKGROUND: Natural orifice transluminal endoscopic surgery peritoneoscopy may be able to replace laparoscopic peritoneoscopy (LAP) for staging of GI malignancies if it is proven to be equally accurate and safe. OBJECTIVE: To compare transgastric peritoneoscopy (TGP) and transcolonic peritoneoscopy (TCP) to LAP, pairwise, in a randomized, blinded (to location and number of beads) human cadaver model with simulated peritoneal metastases. DESIGN: Metastases were simulated by 2.5-mm, color-coded beads, which were placed into the peritoneal cavity via an open approach. In previous porcine experiments, LAP resulted in a yield of 95%. By using a noninferiority design with a margin of equivalence of 15%, we needed a sample size of 34 beads for 80% power. Randomization was performed for number and location of beads. Eighteen experiments were performed on 6 fresh-frozen human cadavers. SETTING: Experimental surgical laboratory. INTERVENTION: LAP, TGP, and TCP were performed in randomized order by one of two surgeons/endoscopists blinded for location and number of beads. MAIN OUTCOME MEASUREMENTS: Number of beads detected and touched. RESULTS: LAP found and touched 33 beads (yield 97%), TGP 26 beads (76%; difference in yield vs LAP was 20.5 [95% CI, -26.3 to -9.27]), and TCP 29 beads (85%; difference in yield vs LAP was -11.8 [95% CI, -14.6 to 4.98]). Beads that were missed were mostly located at the inferior liver surface: TGP missed 6 of 9 of these beads (67%), TCP 4 of 9 (44%). LIMITATIONS: Cadaver model. CONCLUSION: In this prospective, blinded, comparative trial in a human cadaver model, TCP was comparable to LAP in detecting simulated metastases. TGP was inferior to LAP. Future development should focus on improved visualization of the inferior surface of the liver. PMID- 20850737 TI - An improved particle swarm optimization algorithm for reliability problems. AB - An improved particle swarm optimization (IPSO) algorithm is proposed to solve reliability problems in this paper. The IPSO designs two position updating strategies: In the early iterations, each particle flies and searches according to its own best experience with a large probability; in the late iterations, each particle flies and searches according to the fling experience of the most successful particle with a large probability. In addition, the IPSO introduces a mutation operator after position updating, which can not only prevent the IPSO from trapping into the local optimum, but also enhances its space developing ability. Experimental results show that the proposed algorithm has stronger convergence and stability than the other four particle swarm optimization algorithms on solving reliability problems, and that the solutions obtained by the IPSO are better than the previously reported best-known solutions in the recent literature. PMID- 20850738 TI - Survivorship of the native hip joint after percutaneous repair of acetabular fractures in the elderly. AB - Our purpose was to examine survivorship of the native hip joint in patients ages 60 and over who underwent percutaneous reduction and fixation of acetabular fractures. A retrospective review at a University Level I Trauma Center was performed. Our institutional trauma database was reviewed. Patients aged 60 or older treated with percutaneous reduction and fixation of acetabular fractures between 1994 and 2007 were selected. 79 consecutive patients with 80 fractures were identified. Rate of conversion to total hip arthroplasty were used to construct a Kaplan-Meier curve showing survivorship of the native hip joint after treatment. 75 fractures had adequate clinical follow-up with a mean of 3.9 years (range 0.5-11.9 years). Average blood loss was 69 cc and there were no postoperative infections. 19/75 (25%) were converted to total hip arthroplasty at a mean time of 1.4 years after the index procedure. Survivorship analysis demonstrated a cumulative survival of 65% at 11.9 years of follow-up. There were no conversions to arthroplasty beyond 4.7 years postoperatively. There were no statistically significant associations between conversion to arthroplasty and age, sex, closed vs. limited open reduction, and simple vs. complex fracture pattern. Percutaneous fixation is a viable treatment option for patients age 60 or greater with acetabular fractures. Rates of conversion to total hip arthroplasty are comparable to open treatment methods and if conversion is required, soft tissues are preserved for future surgery. PMID- 20850739 TI - The influence of compression on the healing of experimental tibial fractures. AB - PURPOSE: Experimental studies of the effects of various mechanical conditions and stimuli on bone healing have disclosed an improvement potential in bone fracture mineralization and biomechanical properties. We therefore evaluated the effect of a clinically practicable application of a mechanical compressive interfragmentary stimulus on the healing of experimental tibial diaphyseal fractures. METHODS: Sixty Male rats received a standardized tibial shaft osteotomy stabilized with a unilateral external fixator with a zero interfragmentary distance, and then randomly assigned to the compression (N=20), control (N=20) or distraction (N=20) group. From days 4 to day 14, the external fixator was either tightened (compression group) or loosened (distraction group) once daily to gradually induce a total axial displacement of the external fixator pin clamps of 1.25 mm. Evaluation at 30 and 60 days post-osteotomy included radiography, dual-energy X ray absorptiometry (DXA), quantitative CT and mechanical testing. RESULTS: All fractures healed radiographically with sparse callus. At 60 days, the compression and control groups exhibited significantly less amount of mineralized callus in terms of DXA measured callus area and bone mineral content (BMC) compared to the distraction group. These groups also demonstrated a smaller volume of low mineralized bone tissue (callus) and a larger volume of highly mineralized bone tissue (cortical bone) measured by QCT than in the distraction group. Both mechanical strength and stiffness was significantly higher in the compression and control groups than in the distraction group at 60 days. DISCUSSION: Compression did not enhance fracture healing in terms of mineralization, bending strength, or stiffness at the time of union, compared with the control condition. The compression and control groups exhibited improved healing in terms of mechanical strength and stiffness and a more mature callus mineralization compared with the distraction group. PMID- 20850740 TI - Quantitative assessment of impaired postevacuation brain re-expansion in bilateral chronic subdural haematoma: possible mechanism of the higher recurrence rate. AB - INTRODUCTION: Recurrence of chronic subdural haematoma (CSDH) occurs in up to 30% of patients. The rate of recurrence is higher in bilateral versus unilateral CSDH and the reason for this has not been fully elucidated. There are few quantitative studies of temporal changes in brain re-expansion after haematoma evacuation. The aim of this study is to use a simple volumetric image analysis method to quantify temporal changes of postoperative brain re-expansion in unilateral and bilateral CSDH. METHODS: We reviewed computed tomography (CT) scans of 20 consecutive patients (16 men, 4 women; median age, 73.5 years) with CSDH (unilateral, n=10; bilateral, n=10) who underwent surgery (burr hole drainage on one or both sides) at our institutions during the period from June 2006 to August 2008. Haematoma volume was quantified preoperatively and on postoperative days 14 and 30 by computer-based image analysis (PACS Web 1000 System) of CT scans. We then calculated the brain re-expansion rate (BRR) for postoperative days 14 and 30. RESULTS: Haematoma volume remained significantly higher (p<0.001) in bilateral versus unilateral CSDHs at both postoperative time points, and the BRR was significantly greater (p<0.001) in unilateral versus bilateral CSDH at both time points. CONCLUSION: Results of this quantitative analysis provide definitive evidence for a poor BRR in bilateral compared to unilateral CSDH. This impairment may result in shifting of the brain and shearing of blood vessels, resulting in a higher recurrence rate. PMID- 20850741 TI - Haematological indices as surrogate markers of factors affecting mortality after hip fracture. AB - This study investigated the relationship between different components of the full blood count, such as haemoglobin (Hb), total white cell count, total lymphocyte count on admission and total neutrophil count as possible surrogate markers of conditions that lead to increased mortality in hip-fracture patients. A total of 791 patients were studied with 81.2% being females. The 1-year mortality was 26.4%(32.9% in males compared with 24.9% in females). A significant increase in mortality was seen in anaemic patients, especially with Hb 80-100 g l(-1) (1-year mortality was 49.2%, p-value < 0.001) and patients with lymphocyte count <= 1.1 * 10(9) l(-1) (33.2% mortality, p-value < 0.0001). There was no relationship between total white cell count or neutrophil count and mortality. This information clearly suggests that Hb and total lymphocyte counts may be surrogate markers for increased mortality after a hip fracture and can be used for audit purposes to adjust for different case mixes between groups. PMID- 20850742 TI - Systemic fat embolism and the patent foramen ovale--a prospective autopsy study. AB - A fat embolism is a known and common complication of blunt force injuries, especially pelvic and long bones fractures. The aim of this study was to determine the importance of a patent foramen ovale (PFO) in developing systemic fat embolism (SFE) and eventually fat embolism syndrome (FES) in patients suffering from orthopaedic blunt injuries and consequent lung fat embolism. The sample was divided: 32 subjects with a sealed foramen ovale (SFO), and 20 subjects with a PFO. In our sample, there was no difference in either the incidence of renal fat embolism in subjects with PFO compared to those with SFO (Fisher's exact test 0.228, p=0.154) or in the grade of renal fat embolism (Pearson Chi-square 2.728, p=0.435). However, there was a statistically significant correlation between the grade of lung fat embolism and the number of fractured bones for the whole sample (Spearman's rho 0.271, p=0.052), but no correlation between the grade of lung fat embolism and the ISS or NISS (Pearson correlation 0.048, p=0.736, and 0.108, p=0.445, respectively). In our study, the presence of fat emboli in the kidney, i.e. SFE, could effectively be predicted by the grade of lung fat embolism (the moderate and slight grades of lung fat embolism were better predictors than the massive one: logistic regression - Wald. Coeff.=11.446, p=0.003, Wald. Coeff.=10.553, p=0.001, and Wald. Coeff.=4.128, p=0.042), and less effectively by presence of PFO (Wald. Coeff.=2.850, p=0.091). This study pointed out that lung and SFE are not pure biomechanical events, so the role of a PFO is not crucial in developing a lung fat embolism into a systemic embolism: the fat embolism is more of a biochemical and pathophsyiological event, than a biomechanical one. The appearance of a patent foramen ovale associated with a systemic fat embolism should be less emphasised: maybe arteriovenous shunts and anastomosis between the functional and nutritive, i.e. systemic circulation of lungs play a more important role in developing a SFE than a PFO. PMID- 20850743 TI - Surgical treatment of unstable pelvic fracture in children: long term results. AB - Paediatric pelvic fractures are rare lesions. In the literature still controversy exists regarding the management of these injuries. The sequelae of these types of lesions has been described. We report the management and long term outcome of 8 patients with paediatric pelvic fractures treated in our institution. Associated injuries to the Risser's growth nuclei are described that has not been previously reported. Anatomical reduction of the displaced fracture should be considered to minimise the risk of long term functional impairment. PMID- 20850744 TI - Combined use of the cardiofemoral index and middle cerebral artery Doppler velocimetry for the prediction of fetal anemia. AB - OBJECTIVE: To assess the accuracy of the combined use of the cardiofemoral index (CFI) and the middle cerebral artery peak systolic velocity (MCA-PSV), converted to multiples of the median (MoM), as noninvasive means to detect severe fetal anemia. METHOD: We measured CFI and MCA-PSV MoM in 37 fetuses just before their first (n=37), second (n=22), and third (n=14) cordocenteses and transfusions. Then, using 2 different criteria for severe fetal anemia detection (Hb deficit >=7 g/dL and hemoglobin level <=0.55 of MoM), we assessed their hemoglobin status during cordocentesis and the accuracy of CFI and MCA-PVS was determined. RESULTS: At the first cordocentesis the mean hemoglobin level was 8.5+/-3.6 g/dL and 15 fetuses (40.5%) had hydrops. In a total of 81 fetal evaluations, 58 (71.6%) of the CFIs and 34 (42.0%) of the MCA-PSV MoM measurements were abnormal. The result of one of these tests was abnormal in 65 evaluations (80.3%) and the results of both tests were abnormal in 27 evaluations (33.3%). All fetuses diagnosed as being severely anemic by at least one of the hemoglobin criteria during cordocentesis had an abnormal result by at least one of the noninvasive tests. Before the second and third transfusions, the combined use of the CFI and MCA-PSV MoM predicted severe fetal anemia with 100% sensitivity. When the CFI and MCA-PSV MoM measurements were normal, the negative likelihood ratio was zero. CONCLUSION: When associated, CFI and MCA-PSV MoM were accurate predictors of severe fetal anemia. PMID- 20850745 TI - Comparison of the pain experienced by infertile women undergoing hysterosalpingo contrast sonography or radiographic hysterosalpingography. AB - OBJECTIVE: To evaluate the pain and cause of pain experienced by women undergoing hysterosalpingography (HSG) and contrast hysterosalpingo sonography (HyCoSy) with air in a saline solution for the assessment of uterine and tubal patency. METHOD: In this prospective study, 121 infertile women undergoing these 2 procedures measured the pain incurred using a digital/analog scale (1-10). We looked for correlations between pain level and variables pertaining to the procedures. Vagal effects and their persistence were also recorded. RESULTS: The pain was less during HSG (median, 5) than during HyCoSy (median, 7). It was greater than menstrual pain for 38.8% of participants during HSG and for 70.5% of participants during HyCoSy. There was no correlation between pain and difficult catheter passage, degree of tubal obstruction, volume of contrast medium injected, or presence of IgG antibodies to Chlamydia when these variables were studied for HyCoSy alone. However, the strong correlation between pain score and volume of contrast medium injected during each procedure seems to explain the significantly higher pain levels during HyCoSy (P<0.001). In 65.3% and 57.8% of participants, respectively, the pain disappeared immediately after the HSG or HyCoSy. Only mild vagal effects were recorded following both procedures, in 0.8% of participants after HSG and 2.5% of participants after HyCoSy. CONCLUSION: Hysterosalpingo contrast sonography is similar to HSG regarding rapidity of pain disappearance, and infrequency and moderation of vagal effects, but the level of pain is slightly higher, probably due to the greater volume of medium injected. PMID- 20850746 TI - Agreement, reliability, and bias in measurement: Commentary on Bland and Altman (1986; 2010). PMID- 20850747 TI - Immobilization stress induces endothelial dysfunction by oxidative stress via the activation of the angiotensin II/its type I receptor pathway. AB - OBJECTIVE: Psychological stress has been shown to contribute to the development of atherosclerosis; however its underlying mechanism has not been clearly elucidated. We here studied the mechanism by which immobilization stress causes endothelial dysfunction with specific aim of identifying the role of angiotensin II and its type I (AT(1)) receptor signaling pathway. METHODS AND RESULTS: Rats (n=30) were subjected to immobilization stress (120 min/day) for 14 days using a restrainer. During immobilized period, rats were orally administrated with or without the angiotensin converting enzyme (ACE) inhibitor ramipril (3 mg/kg/day, n=10) or AT(1) receptor inhibitor losartan (9 mg/kg/day, n=10). Immobilization significantly increased systolic blood pressure and decreased acetylcholine induced ex vivo relaxation of arteries compared with those of control animals (n=10). Immobilization increased the plasma levels of angiotensin II and ACE activity that were inhibited by treatment with ramipril, but not losartan. Furthermore, immobilization increased the plasma level of malondialdehyde and expression of gp91(phox) and Rho-associated kinase-1 in arteries, and decreased the arterial eNOS mRNA and oxidized products of NO (nitrite plus nitrate). These functional and biochemical alterations induced by immobilization were significantly reversed by administration of ramipril or losartan. CONCLUSIONS: Immobilization stress induces vascular oxidative stress by activating the angiotensin II/AT(1) receptor signaling pathway, thereby provoking endothelial dysfunction which can contribute to the development of atherosclerosis and hypertension. PMID- 20850748 TI - Risk factors and peripheral arterial disease; a plea for objective measurements. PMID- 20850750 TI - Predictive equations to estimate spinal loads in symmetric lifting tasks. AB - Response surface methodology is used to establish robust and user-friendly predictive equations that relate responses of a complex detailed trunk finite element biomechanical model to its input variables during sagittal symmetric static lifting activities. Four input variables (thorax flexion angle, lumbar/pelvis ratio, load magnitude, and load position) and four model responses (L4-L5 and L5-S1 disc compression and anterior-posterior shear forces) are considered. Full factorial design of experiments accounting for all combinations of input levels is employed. Quadratic predictive equations for the spinal loads at the L4-S1 disc mid-heights are obtained by regression analysis with adequate goodness-of-fit (R(2)>98%, p<0.05, and low root-mean-squared-error values compared with the range of predicted spine loads). Results indicate that intradiscal pressure values at the L4-L5 disc estimated based on the predictive equations are in close agreement with available in vivo data measured under similar loadings and postures. Combinations of input (posture and loading) variable levels that yield spine loads beyond the tolerance compression limit of 3400 N are identified using contour plots. Ergonomists and bioengineers, faced with the dilemma of using either complex but more accurate models on one hand or less accurate but simple models on the other hand, have thereby easy-to-use predictive equations that quantifies spinal loads and risk of injury under different occupational tasks of interest. PMID- 20850749 TI - Aortic valve disease and gamma-glutamyltransferase: accumulation in tissue and relationships with calcific degeneration. AB - OBJECTIVE: Degenerative aortic valve disease is characterized by some of the histological features of atherosclerotic lesions. Gamma-glutamyltransferase (GGT) has been recently implicated in pathogenesis of atherosclerosis, as well as in modulation of cells involved in calcium metabolism. We aimed to evaluate the possible implication of this enzyme activity in aortic valve disease. METHODS: GGT immunohistochemistry was performed on valve leaflets of 64 patients with aortic valve stenosis undergoing valve replacement. Fractional GGT activity in plasma and tissue was analysed in a subgroup of cases by molecular exclusion chromatography. RESULTS: A close association was found between tissue extracellular GGT staining and lipid deposits (p<0.0001). GGT was expressed by CD68-positive cells around neovessels, as well as by MMP-9- and TRAP-positive multinucleated cells in the vicinity of bone metaplasia areas. Total plasma GGT levels were associated with low HDL-c (p=0.028) and high triglycerides (p=0.017). Total GGT activity in tissue was negatively correlated with the extent of valves calcification (p=0.03). Both serum and tissue GGT levels were negatively associated with severity of valve stenosis, as judged by peak transvalvular pressure gradients (p<0.0003 and p<0.002, respectively). CONCLUSIONS: Accumulation of GGT activity inside the lipid component of valves leaflets suggests a common mechanism of lesion shaping underlying both atherosclerosis and degenerative aortic valve disease. Moreover, the finding of GGT expression in cells with an osteoclast-like phenotype, and its negative correlation with both valves calcification and degree of valvular stenosis lend additional support to the recently envisaged involvement of GGT in the homeostasis of calcified tissues. PMID- 20850752 TI - Novel lap test determines the mechanics of delamination between annular lamellae of the intervertebral disc. AB - Delamination between lamellae of the annulus fibrosus is a crucial stage of intervertebral disc herniation, and to better understand the mechanics of the delamination process, a novel lap test was devised. Specimens consisting of two adjacent, naturally bonded lamellae were obtained from the cervical region of frozen porcine spines. They were cut into specimens nominally 3.5mm wide by 7 mm long and tabs of the deep and superficial layers were removed from opposite ends of the specimens so that a 4.5-5.0mm long intact interface remained between the lamellae. Specimens were mounted in a BioTester tensile instrument using BioRake attachments having 5 sharpened points side-by-side, and they were strained at 2%/s. Force-time curves were obtained and, using tracking software, a detailed map was made of the time course of the displacements within the specimens. Extensibility of the lamellae themselves was found to substantially complicate interpretation of the data. The experiments, together with mathematical analyses and finite element models, show that much of the shear load is transferred between lamellae at the ends of the bonded region, a finding of clinical importance. The inter-lamellae bond was found to have a peak strength of 0.30 +/- 0.05 N/mm of specimen width (not to be confused with lap length), and the remarkable ability to carry substantial load even when lamellae had displaced up to 10mm relative to each other. PMID- 20850753 TI - Identification and determination of inorganic anions in real extracts from pre- and post-blast residues by capillary electrophoresis. AB - Fast, selective, and sensitive analysis of inorganic anions is compulsory for the identification of explosives in post-blast or environmental samples. For the last twenty years, capillary electrophoresis (CE) has become a valuable alternative to ion chromatography (IC) for the analysis of inorganic-based explosives because of its low running costs and its simplicity of use. This article focuses on the development and validation of a CE method for the simultaneous analysis of 10 anions (chloride, nitrite, nitrate, thiosulphate, perchlorate, chlorate, thiocyanate, carbonate, sulphate, and phosphate) which can be found in post-blast residues, plus for the first time azide anion, possibly present in the composition of detonators, and the internal standard (formate) in 20 min total runtime. Intermediate precisions were 2.11% for normalized areas and 0.72% for normalized migration times. Limits of detection close to 0.5 ppm for all anions were obtained with the use of preconcentration techniques, thanks to a fast and simple sample preparation allowing the analysis of a large variety of matrices with the developed generic CE method. The matrix effects were statistically studied for the first time in the explosive field for different matrices, containing interfering anions and cations, sometimes at high levels. In fact, no significant matrix effect occurred (tests with blank matrix extracts of soil, cloth, glass, plastic, paper, cotton, and metal). Finally, analyses of real post blast residues and real detonator extracts were performed. The CE results were compared with those obtained with the IC method used routinely and showed excellent correlation. PMID- 20850754 TI - Chromatographic retention behaviour of n-alkylbenzenes and pentylbenzene structural isomers on porous graphitic carbon and octadecyl-bonded silica studied using molecular modelling and QSRR. AB - The retention behaviour of a series of 15 n-alkylbenzenes and pentylbenzene structural isomers and benzene were investigated using porous graphitic carbon (PGC) and octadecyl-bonded silica (ODS) stationary phases. Shorter chain n alkylbenzenes and benzene (n=0-6), and all the pentylbenzene isomers were more strongly retained on ODS, although the selectivity was greater with PGC. For the pentylbenzene analytes the degree of branching in the alkyl chain at the position adjacent to the aromatic ring affects retention on PGC, with higher retention in less branched molecules. Molecular modelling studies have provided new insights into the geometry of aromatic pi-pi stacking interactions in retention on PGC. For alkylbenzenes with high branching at the position adjacent to the ring, the preferred geometry of association with the surface is with the branched chain directed away from the surface, a geometry not seen in the other alkylbenzenes. The most energetically favoured orientation for interaction between analytes and the PGC surface was found to be cofacial for toluene and ethylbenzene, whereas for other analytes this interaction was in a face-edge orientation. The alternative geometry of association observed with both toluene and ethylbenzene may explain the enhanced retention of these two analytes on PGC compared with their longer chain analogues. Quantitative structure-retention relationships revealed the importance of compactness in analyte structure during retention on PGC, with decreased compactness (associated with longer chain length and reduced chain branching) improving retention. PMID- 20850755 TI - Influence of temperature and reducing conditions on the sorption of sulfate on magnetite. AB - The reactivity of aqueous sulfate toward magnetite was studied between 50 and 275 degrees C as a function of pH and the redox conditions. Under oxidizing conditions, we did not observe redox reactions and the sorption of aqueous sulfate is promoted under acidic conditions when the magnetite surface is positively charged. The effect of temperature on this retention is moderate but complex. From 50 to 125 degrees C the sorption edge is shifted toward low pH values, according to the variation of the point of zero charge. Above 125 degrees C, the effect of temperature is inverted, leading to a shift to basic pH values and an increase of the sorbed quantity. This inversion of the temperature effect is interpreted as related to changes in the nature of the complexes formed, correlated to the evolution of speciation of dissolved S(VI) species. Under reducing conditions (2bar hydrogen), sulfate is involved in redox reactions, likely as a consequence of the catalytic effect of the sorption that enhances the H(2)-sulfate reaction, producing sulfides in the gaseous, liquid, and solid phases. However, this effect is better evidenced at 125 degrees C than at 275 degrees C, illustrating the importance of surface speciation, assumed to change with temperature. PMID- 20850756 TI - Scalable fabrication of superhydrophobic hierarchical colloidal arrays. AB - Here we report a scalable bottom-up technology for assembling hierarchical colloidal arrays with superhydrophobic surface. Non-close-packed (NCP) colloidal multilayers, which facilitate the formation of more hydrophobic surface than close-packed arrays due to a higher fraction of entrapped air in between colloidal particles, are first fabricated by a simple spin-coating technology. Uniform silica nanoparticles are then assembled on the NCP microsphere arrays by a second spin-coating process. After surface functionalization of silica particles with fluorosilane, the resulting hierarchical colloidal arrays exhibit superhydrophobic surface with high apparent water contact angle (159 degrees ) and low contact angle hysteresis (4.7 degrees ). The experimental results on both the wettability and contact angle hysteresis can be qualitatively explained by adapting the Cassie's model. This spin-coating-based colloidal self-assembly technology is compatible with standard microfabrication and enables large-scale production of superhydrophobic coatings that could find important technological applications ranging from self-cleaning diffractive optics to microfluidic devices. PMID- 20850757 TI - Interfacial properties and structure stability of the gp41 tryptophan-rich peptide from HIV-1. AB - The HIV-1 envelope glycoprotein 41 (gp41) undergoes large-scale conformational changes in order to induce the fusion of the virus and cell membranes. Thus, we investigated a possible structure transit at the air-water interface for the tryptophan-rich peptide of gp41 (gp41W). The synthetic peptide (KWASLWNWFNITNWLWYIK), corresponding to gp41W, shows interfacial properties on pure water and Tris buffer at pH 8.5. Isotherm measurements and Brewster angle microscopy (BAM) imaging showed that the behavior of the peptide monolayer was dependent on the subphase composition. A homogenous film was formed on buffer during the peptide monolayer compression, while the appearance of condensed domains on pure water could indicate the oligomerization of gp41W during the surface pressure increase. Polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) showed that, whatever the subphase, gp41W adopts an alpha helix structure at the air-water interface and does not transit for any other structure even at high surface pressures. PMID- 20850758 TI - Word learning and phonetic processing in preschool-age children. AB - Consonants and vowels have been shown to play different relative roles in different processes, including retrieving known words from pseudowords during adulthood or simultaneously learning two phonetically similar pseudowords during infancy or toddlerhood. The current study explores the extent to which French speaking 3- to 5-year-olds exhibit a so-called "consonant bias" in a task simulating word acquisition, that is, when learning new words for unfamiliar objects. In Experiment 1, the to-be-learned words differed both by a consonant and a vowel (e.g., /byf/-/duf/), and children needed to choose which of the two objects to associate with a third one whose name differed from both objects by either a consonant or a vowel (e.g., /dyf/). In such a conflict condition, children needed to favor (or neglect) either consonant information or vowel information. The results show that only 3-year-olds preferentially chose the consonant identity, thereby neglecting the vowel change. The older children (and adults) did not exhibit any response bias. In Experiment 2, children needed to pick up one of two objects whose names differed on either consonant information or vowel information. Whereas 3-year-olds performed better with pairs of pseudowords contrasting on consonants, the pattern of asymmetry was reversed in 4 year-olds, and 5-year-olds did not exhibit any significant response bias. Interestingly, girls showed overall better performance and exhibited earlier changes in performance than boys. The changes in consonant/vowel asymmetry in preschoolers are discussed in relation with developments in linguistic (lexical and morphosyntactic) and cognitive processing. PMID- 20850759 TI - Effectiveness and cost-effectiveness of blood pressure screening in adolescents in the United States. AB - OBJECTIVE: To compare the long-term effectiveness and cost-effectiveness of 3 approaches to managing elevated blood pressure (BP) in adolescents in the United States: no intervention, "screen-and-treat," and population-wide strategies to lower the entire BP distribution. STUDY DESIGN: We used a simulation model to combine several data sources to project the lifetime costs and cardiovascular outcomes for a cohort of 15-year-old U.S. adolescents under different BP approaches and conducted cost-effectiveness analysis. We obtained BP distributions from the National Health and Nutrition Examination Survey 1999-2004 and used childhood-to-adult longitudinal correlation analyses to simulate the tracking of BP. We then used the coronary heart disease policy model to estimate lifetime coronary heart disease events, costs, and quality-adjusted life years (QALY). RESULTS: Among screen-and-treat strategies, finding and treating the adolescents at highest risk (eg, left ventricular hypertrophy) was most cost effective ($18000/QALY [boys] and $47000/QALY [girls]). However, all screen-and treat strategies were dominated by population-wide strategies such as salt reduction (cost-saving [boys] and $650/QALY [girls]) and increasing physical education ($11000/QALY [boys] and $35000/QALY [girls]). CONCLUSIONS: Routine adolescents BP screening is moderately effective, but population-based BP interventions with broader reach could potentially be less costly and more effective for early cardiovascular disease prevention and should be implemented in parallel. PMID- 20850760 TI - Exercise: it isn't just child's play when it comes to managing type 1 diabetes. PMID- 20850761 TI - Beighton score: a valid measure for generalized hypermobility in children. AB - OBJECTIVE: To evaluate the validity of the Beighton score as a generalized measure of hypermobility and to measure the prevalence of hypermobility and pain in a random population of school age children. STUDY DESIGN: Prospective study of 551 children attending various Dutch elementary schools participated; 47% were males (258) and 53% (293) females, age range was 6 to 12 years. Children's joints and movements were assessed according to the Beighton score by qualified physiotherapists and by use of goniometry measuring 16 passive ranges of motion of joints on both sides of the body. RESULTS: More than 35% of children scored more than 5/9 on the Beighton score. Children who scored high on the Beighton score also showed increased range of motion in the other joints measured. Moreover 12.3% of children had symptoms of joint pain, and 9.1% complained of pain after exercise or sports. Importantly, this percentage was independent of the Beighton score. There were no significant differences in Beighton score for sex in this population. CONCLUSION: The Beighton score, when goniometry is used, is a valid instrument to measure generalized joint mobility in school-age children 6 to 12 years. No extra items are needed to improve the scale. PMID- 20850762 TI - Docosahexaenoic Acid and Amino Acid Contents in Pasteurized Donor Milk are Low for Preterm Infants. AB - OBJECTIVE: To evaluate whether pasteurized donor human milk meets the nutritional needs of preterm infants in terms of free fatty acid and amino acid contents. STUDY DESIGN: Milk samples were prospectively collected from 39 donors to the Mothers' Milk Bank of Ohio. The fatty acid and amino acid compositions in donor milk samples were measured before and after pasteurization, and values were compared with previously published findings and preterm infant nutrition guidelines. The nutritional adequacy of donor milk for preterm infants was based on estimated daily intake of 150 mL/kg. Statistical significance was adjusted to account for multiple comparisons. RESULTS: Pasteurization did not appreciably affect donor milk composition. Docosahexaenoic acid level (0.1 mol wt %), and concentrations of glycine, aspartate, valine, phenylalanine, proline, lysine, arginine, serine, and histidine in donor milk were all significantly lower than previously reported concentrations in milk. CONCLUSIONS: Donor milk is not substantially affected by pasteurization, but has low concentrations of docosahexaenoic acid and amino acids. Targeted nutritional supplementation of human donor milk for feeding preterm infants might be warranted. PMID- 20850763 TI - Parental bonding after preterm birth: child and parent perspectives in the Helsinki study of very low birth weight adults. AB - OBJECTIVE: To examine whether parenting behavior recalled by very low birth weight (VLBW) adults or their parents differs from that of term-born control subjects or their parents. STUDY DESIGN: A total of 164 VLBW and 172 control adults (mean age 22.5 years, SD 2.2) assessed retrospectively the parenting behavior of their parents by the Parental Bonding Instrument, which includes dimensions of care, protectiveness, and authoritarianism. A subgroup of 190 mothers and 154 fathers assessed their own parenting behavior by the Parent Behavior Inventory, which includes dimensions of supportive and hostile parenting. RESULTS: The VLBW women assessed their mothers as more protective and authoritarian than the control women. The VLBW and control men did not differ from each other. Both mothers and fathers of the VLBW adults assessed their own parenting as more supportive than those of the control subjects. CONCLUSIONS: Preterm birth at VLBW may promote a more protective, as well as more supportive, parenting style. PMID- 20850764 TI - Can children accurately report their own heights and weights, and why should we care? PMID- 20850765 TI - Anorectal motility abnormalities in children with encopresis and chronic constipation. AB - OBJECTIVE: To evaluate the response to rectal distension in children with chronic constipation and children with chronic constipation and encopresis. STUDY DESIGN: We studied 27 children, aged 3 to 16 years, with chronic constipation; 12 had encopresis. Anorectal motility was measured with a solid state catheter. When the catheter was located in the internal sphincter, the balloon was inflated to 60 mL with air. RESULTS: There were no differences in age, sex distribution, and duration of constipation in the two groups. Comparing groups, anorectal manometry showed no differences in the resting sphincter pressure, recovery pressure, the lowest relaxation pressure, and percent relaxation. However, time to maximum relaxation, time to recovery to baseline pressure, and duration of relaxation were significantly higher in patients with constipation and encopresis, compared with patients who had constipation alone. CONCLUSIONS: There may be an imbalance in neuromuscular control of defecation in constipated patients with encopresis that results in incontinence as a consequence of the increased time to recovery and duration of relaxation of the internal anal sphincter. PMID- 20850766 TI - The impact of environmental and genetic factors on neonatal late-onset sepsis. AB - OBJECTIVE: To assess the genetic contribution to late-onset sepsis in twins in the newborn intensive care unit. STUDY DESIGN: A retrospective cohort analysis of twins born from 1994 to 2009 was performed on data collected from the newborn intensive care units at Yale University and the University of Connecticut. Sepsis concordance rates were compared between monozygotic and dizygotic twins. Mixed effects logistic regression analysis was performed to determine the impact of selected nongenetic factors on late-onset sepsis. The influence of additive genetic and common and residual environmental effects were analyzed and quantified. RESULTS: One hundred seventy monozygotic and 665 dizygotic twin pairs were analyzed, and sepsis identified in 8.9%. Mean gestational age and birth weight of the cohort was 31.1 weeks and 1637 grams, respectively. Mixed-effects logistic regression determined birth weight (regression coefficient, -0.001; 95% CI, -0.003 to 0.000; P = .028), respiratory distress syndrome (regression coefficient, 1.769; 95% CI, 0.943 to 2.596; P < .001), and duration of total parenteral nutrition (regression coefficient, 0.041; 95% CI, 0.017 to 0.064; P < .001) as significant nongenetic factors. Further analysis determined 49.0% (P = .002) of the variance in liability to late-onset sepsis was due to genetic factors alone, and 51.0% (P = .001) the result of residual environmental factors. CONCLUSIONS: Our data support significant genetic susceptibility to late-onset sepsis in the newborn intensive care unit population. PMID- 20850767 TI - Heparin-binding EGF-like growth factor promotes intestinal anastomotic healing. AB - BACKGROUND: We have accumulated multiple lines of evidence supporting the ability of HB-EGF to protect the intestines from injury and to augment the healing of partial-thickness scald burns of the skin. The aim of the current study was to investigate the role of heparin-binding EGF-like growth factor (HB-EGF) in intestinal anastomotic wound healing. MATERIALS AND METHODS: HB-EGF (-/-) knockout (KO) mice (n=42) and their HB-EGF (+/+) wild type (WT) counterparts (n=33), as well as HB-EGF transgenic (TG) mice (n=26) and their (WT) counterparts (n=27), underwent division and reanastomosis of the terminal ileum. In addition, WT mice (n=21) that received enteral HB-EGF (800 MUg/kg) underwent the same operative procedure. Anastomotic bursting pressure was measured at 3 and 6 d postoperatively. Tissue sections were stained with hematoxylin and eosin to assess anastomotic healing, and Picrosirus red to assess collagen deposition. Immunohistochemistry using anti-von Willebrand factor antibodies was performed to assess angiogenesis. Complications and mortality were also recorded. RESULTS: HB EGF KO mice had significantly lower bursting pressures, lower healing scores, higher mortality, and higher complication rates postoperatively compared with WT mice. Collagen deposition and angiogenesis were significantly decreased in KO mice compared with WT mice. Conversely, HB-EGF TG mice had increased anastomotic bursting pressure, higher healing scores, lower mortality, lower complication rates, increased collagen deposition, and increased angiogenesis postoperatively compared with WT mice. WT mice that received HB-EGF had increased bursting pressures compared with non-HB-EGF treated mice. CONCLUSION: Our results demonstrate that HB-EGF is an important factor involved in the healing of intestinal anastomoses. PMID- 20850768 TI - No synergistic effect of carbon monoxide and oxygen during static gaseous persufflation preservation of DCD livers. AB - OBJECTIVE: The benefit of carbon monoxide and/or oxygen as applied by controlled, continuous gaseous persufflation during liver preservation on postischemic graft recovery was investigated in an isolated rat liver model. METHODS: Livers from male Wistar rats were retrieved 30 min after cardiac arrest of the donor and subjected to 18 h of cold storage. Some grafts were subjected to gaseous persufflation during static cold storage either with pure oxygen or with CO dissolved in oxygen. Graft integrity was assessed thereafter upon warm reperfusion in vitro. RESULTS: Oxygen persufflation significantly reduced cellular enzyme loss and metabolic recovery (bile production and ATP recovery) upon reperfusion by about 50%. The effect was associated with a reduction of vascular perfusion resistance, mitigated gene up-regulation of the mitochondrial stress protein GRP 75, and improved mitochondrial ultra-structure. Similar results were obtained by persufflation with CO in oxygen, while no additive benefit of CO and oxygen could be seen in our model. CONCLUSION: Hepatocellular injury of cold stored liver grafts can be notably reduced by gaseous ex vivo application of oxygen with or without additional admixture of CO to the isolated organ but no superiority or additive effect is seen with respect to persufflation with oxygen. PMID- 20850769 TI - Outcome differences between gastroschisis repair methods. AB - BACKGROUND: Gastroschisis is a congenital abdominal wall defect that is repaired with either a primary closure or staged closure. The outcome of these infants may differ because of different closure techniques. In addition to the usual markers of parenteral nutrition (PN) use and length of stay (LOS) as outcome measures, we examined the duration of postoperative acidosis and positive fluid balance as markers for postoperative stress associated with these two techniques. METHODS: A retrospective review of newborns with gastroschisis was conducted at a free standing children's hospital from 2002 to 2008. The demographic data, gestational age, birth weight, operative reports, days on PN, LOS, duration of postoperative acidosis and fluid balances were reviewed. Data were analyzed using the Fisher's exact test or unpaired t test. RESULTS: Thirty-two infants with gastroschisis were identified. One was excluded from analysis due to incomplete follow-up. The patients were classified as either primary closure (n = 8) or staged repair (n = 23). There was one death in our series. Patients who underwent primary closure had significantly older gestational age and higher birth weight. Primary closure is associated with significantly less duration of postoperative metabolic acidosis and fewer days with positive fluid balance. Patients who had primary repair also had less parenteral nutrition use and shorter length of hospitalization, though not statistically significant. Gastroschisis with associated intestinal atresia was more likely to be repaired with staged closures. CONCLUSIONS: There are physiologic advantages to primary repair of gastroschisis that can lead to better outcome, but the indications for the choices of closure technique remain unclear. Primary closure should be used when possible. PMID- 20850770 TI - Drug metabolism in hemorrhagic shock: pharmacokinetics of selective markers of cytochrome-P450 2C9, 2D6, and 3A4 enzyme activities in a porcine model. AB - BACKGROUND: Cytochrome-P450 enzymes metabolize most administered drugs. A variety of clinical conditions affect the CYP system. However, the effect of hemorrhagic shock on CYP-mediated drug metabolism in clinical setting or in clinically applicable in-vivo models is largely unknown. Simultaneous administration of multiple CYP enzyme-selective drugs is a technique to ascertain a population's metabolic profile with a limited number of subjects. MATERIALS AND METHODS: Pigs were used as experimental animals as they possess CYP functionality similar to humans. Three probe drugs (dextromethorphan [CYP2D6], flurbiprofen [CYP2C9], and midazolam [CYP3A4]; doses: 0.5, 0.25, and 0.5 mg/kg, respectively) were administered intravenously to six Yorkshire-crossbred pigs in healthy state. Hemorrhagic shock was induced in six (four from healthy group after a 7-d washout period and two additional) pigs and the same doses of probe drugs were administered after a 14-h resuscitation phase. Blood samples were collected periodically in both phases and analyzed for parent drugs and metabolites (dextrorphan, 4'-hydroxy-flurbiprofen and 1'-hydroxy-midazolam) to calculate pharmacokinetic parameters. A comprehensive set of biochemical and physiologic markers of shock was also recorded. RESULTS: No changes in parent drug clearances were observed post-shock. Extensive metabolite formation with apparent higher exposure to total (conjugated and unconjugated) dextrorphan (p = 0.08), 4' hydroxy-flurbiprofen (p = 0.11) and 1'-hydroxy-midazolam (p = 0.09) were observed post-shock. CONCLUSIONS: The metabolic capacity of CYP enzymes did not appear to be severely hindered in resuscitative phase of hemorrhagic shock. Diminished renal secretory function caused by hemorrhagic shock may be the cause of metabolite accumulation in plasma. PMID- 20850771 TI - Phenylephrine induces early and late cardioprotection through mitochondrial permeability transition pore in the isolated rat heart. AB - BACKGROUND: The aim of this study was to investigate the role of mitochondrial permeability transition pore (mPTP) in cardioprotection afforded by phenylephrine pretreatment in early and late phases. METHODS: Rat hearts were isolated and perfused with Krebs buffer in Langendorff preparation and subjected to 30 min regional ischemia followed by 60 min of reperfusion. Phenylephrine as a selective alpha1-adrenoceptor agonist and atractyloside as a specific opener of the mPTP were used. Seven groups (n = 6) of rats were randomly studied: (I) control: surgical procedure was performed with no ischemia/reperfusion, (II) ischemia/reperfusion: hearts underwent regional ischemia/reperfusion, (III) early phenylephrine: phenylephrine (50 MUM) was perfused for 5 min prior to ischemia/reperfusion, (IV) late phenylephrine: rats were treated with phenylephrine (10 mg/kg, i.p) 24 h prior to ischemia/reperfusion, (V) early phenylephrine+atractyloside: hearts were perfused with phenylephrine as in group III and then atractyloside (20 mM) 5 min before reperfusion for 20 min, (VI) late phenylephrine+atractyloside: hearts were treated with phenylephrine as in group IV and then received atractyloside (20 mM), 5 min before reperfusion for 20 min, (VII) atractyloside-IR group: hearts were perfused with atractyloside (20 mM) 5 min before reperfusion for 20 min. RESULTS: Compared with ischemia/reperfusion group, perfusion of phenylephrine in early and late phases decreased myocardial infarct size (% of ischemia zone), reduced creatine kinase-MB (CK-MB) in the coronary effluent, and improved cardiac function. Administration of atractyloside abolished cardioprotective effects of phenylephrine in both early and late phases and returned infarct size, CK-MB and cardiac function to levels as seen in ischemia/reperfusion group. CONCLUSION: These results suggest that administration of atractyloside as a specific opener of the mPTP abolishes phenylephrine-induced early and late cardioprotection in the isolated rat hearts. PMID- 20850772 TI - In utero gene delivery using chitosan-DNA nanoparticles in mice. AB - BACKGROUND: In utero gene transfer is a novel therapy for monogenic disorders diagnosed in the fetus. Enhanced biosafety alternatives to viral vectors include non-viral transfer agents such as chitosan. The purpose of this study was to evaluate in vitro and in utero gene transfer of reporter gene (GFP) using chitosan as a transfer vehicle. MATERIALS AND METHODS: IN VITRO STUDIES: 1. Chitosan colloidal suspensions were prepared, and particle stability in murine amniotic fluid (AF) was determined. 2. Chitosan-reporter gene (EGFP) constructs were prepared and protection from endogenous digestion in AF was measured by gel electrophoresis. 3. Transfection efficiency (by chitosan-EGFP) of HEK293T cells was determined in varying proportions of medium and AF. In utero studies: Amniotic sacs of time-mated CD-1 mice were injected with chitosan-pEGFP (12.5 MUg DNA) on G17. Pups and their dams were sacrificed and tissues were examined for transgene presence and expression. RESULTS: Chitosan formed stable aggregates in AF. Although AF decreased in vitro transfection efficiency, in vivo transfection by amniotic injection achieved short-term transgene expression in pup lung and intestine. CONCLUSIONS: In utero delivery of chitosan-EGFP results in postnatal gene expression, and shows promise for non-viral gene transfer in animal models of fetal gene therapy. PMID- 20850773 TI - Emulsified isoflurane preconditioning protects against liver and lung injury in rat model of hemorrhagic shock. AB - BACKGROUND: Isoflurane has demonstrated protective effects against ischemia/reperfusion injury in some organs. In this study, using the hemorrhagic shock model, we investigated whether emulsified isoflurane preconditioning protected against liver and lung injury caused by massive surgical blood loss. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into five groups: a control group, a hemorrhagic shock (HS) group, an intralipid (IL) group, an isoflurane (Iso) group, and an emulsified isoflurane (E-Iso) group. Saline, intralipid, isoflurane, or emulsified isoflurane were administered over 15 min. Forty-five min after injection, hemorrhage was initiated in the experimental group. Four h after resuscitation alanine aminotransferase (ALT), protein and white blood cell (WBC) in bronchoalveolar lavage fluid (BAL), and the liver and lung histopathology were measured. The malondialdehyde (MDA) and superoxide dismutase (SOD) in the liver and lung mitochondria were tested. The survival was also observed in hemorrhagic shocked rats. RESULTS: Emulsified isoflurane enhanced survival and decreased ALT, protein and WBC in BAL, liver and lung apoptosis, and the histologic score. It also decreased MDA and increased SOD activity in mitochondria. In the IL group, liver mitochondrial SOD activity increased, while ALT, liver apoptosis and histological score decreased. In the Iso group liver and lung mitochondrial SOD activity increased, while liver and lung apoptosis decreased. CONCLUSION: Emulsified isoflurane preconditioning has a protective effect against liver and lung injury as well as improving the survival in hemorrhagic shock. The potential mechanisms involved are the inhibition of cell death and improvement of antioxidation in mitochondria. PMID- 20850774 TI - Interposition of a reversed jejunal segment enhances intestinal adaptation in short bowel syndrome: an experimental study on pigs. AB - BACKGROUND: Interposition of a reversed intestinal segment as a factor facilitating intestinal adaptation has been experimentally investigated. Controversy exists about its efficacy in terms of body weight improvement, direction of luminal changes, and underlying mechanisms. This study aims to provide a comprehensive approach. METHODS: The pigs were randomly allocated to two groups: (1) short bowel (SB) group (n=8) and (2) short bowel reverse jejunal segment (SB-RS) group (n=8). On postoperative d 3, 30, and 60, intestinal transit time was measured; body weight and serum albumin were measured on baseline, as well as on postoperative d 30 and 60. After sacrifice, histopathologic and immunohistochemical (PCNA, activated caspase-3) evaluation followed. RESULTS: Transit time was numerically longer in SB-RS group at all time points; the difference reached statistical significance on d 60. No statistically significant differences were observed concerning body weight or serum albumin. In the SB-RS group, a statistically significant increase in muscle thickness, crypt depth, villus height, and PCNA immunostaining, and a decrease in caspase-3 positive (+) cell count were documented both at the jejunal and ileal level. CONCLUSIONS: The reversed jejunal segment seemed able to enhance intestinal adaptation at a histopathologic level, as well as to favorably modify transit time. These putatively beneficial actions were not reflected upon body weight. The decrease in apoptosis was caspase-3-dependent. PMID- 20850775 TI - Predicting exocrine insufficiency following pancreatic resection. PMID- 20850776 TI - The effect of chronically increased intra-abdominal pressure on rectus abdominis muscle histology an experimental study on rabbits. AB - BACKGROUND: The aim of this study was to specify the histologic response of the rectus abdominis muscle of the rabbit, to the chronically increased intra abdominal pressure. MATERIALS AND METHODS: Forty-five New Zealand white rabbits were divided into three groups. In all groups, a rubber bag was implanted into the peritoneal cavity. In group A (n=15) the bags were kept empty. In group B (n=15) the bags were filled with normal saline in order to achieve an intra abdominal pressure of over 12 mmHg. This pressure was kept at this level for 8 wk. In group C (n=15) the intra-abdominal rubber bags were filled with lead covered by silicone, equiponderant to the mean weight of the normal saline insufflated in group B. After 8 wk we took biopsies of the rectus abdominis muscle and counted the proportion of the different types of muscular fibers (type I, IIA, and IIB/X). RESULTS: Significant difference was found in the proportion of the three types of muscle fibers. Intra-abdominal hypertension led to an increase in type I fibers (P=0.008). No difference was noticed between groups A and C. CONCLUSIONS: The histologic response to the increased intra-abdominal pressure was an increase in type I muscle fibers. Charging with lead did not cause any significant change in the proportion of muscular fibers. PMID- 20850777 TI - Effect of preconditioned hyperbaric oxygen and ozone on ischemia-reperfusion induced tourniquet in skeletal bone of rats. AB - BACKGROUND: The aim of the study was to investigate effect of I/R injury on bone tissue and protective role of hyperbaric oxygen precondition (HBO-PC) and ozone precondition (O(3)-PC) on I/R injury by using biochemical analysis. MATERIALS AND METHODS: Thirty-two rats were included in study. The animals were divided into four equal groups: sham operation, I/R, I/R+HBO and I/R+O(3). One session of 60 min, 3 ATA, 3-4 L/min, 100% oxygenation was defined as one dose of HBO. First dose of HBO was administrated 72 h before ischemia. Subsequent, one-dose of HBO administrated per 12 hours until ischemia time (total seven doses); 0.7 mg/kg ozone/oxygen mixture intraperitoneally was defined as one dose of ozone. First dose of O(3) was administered 72 h before ischemia (total four doses). I/R model was induced in anesthetized rats by unilateral (right) femoral artery clipping for 2 h followed by 22 h of reperfusion. The right tibia and were harvested. Tissue was assayed for levels of malondialdehyde (MDA) and protein carbonyl (PCO), activities of superoxide dismutase (SOD), and glutathione peroxidase (GSH Px). RESULTS: MDA and PCO levels were increased in I/R group. SOD activity was increased; GSH-Px activity was decreased in I/R group. MDA and PCO levels were decreased, SOD and GSH-Px activities were increased in both HBO+I/R and O(3)+I/R groups. CONCLUSION: It has been shown that levels of MDA and PCO in bone were increased followed by 2 h of ischemia and 22 h of reperfusion period. Ozone-PC and HBO-PC has protective effect against skeletal bone I/R injury by decreasing levels of MDA and PCO, increasing activities of SOD and GSH-Px in rats. PMID- 20850778 TI - Remote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial. AB - BACKGROUND: Remote perconditioning has been proved to reduce myocardial infarction and improve ventricular function in vivo. This study aims to determine the protection of remote perconditioning against cardiac reperfusion injury in patients undergoing valve replacement. METHODS: Eighty-one patients admitted for selective valve replacement were divided into three groups randomly. Control patients (con. n = 27) underwent sham placement of the tourniquet around the right thigh without inflation; the remote preconditioning group (pre. n = 26) received three cycles of 4/4 min right lower limb ischemia and reperfusion after induction of anesthesia, the limb ischemia was induced by the tourniquet inflated to 600 mmHg; the remote perconditioning group (per. n = 28) received the same stimulus immediately after aortic cross-clamping. Venous blood samples were obtained preoperatively, 5 min before declamping, 30 min, 4, 12, and 72 h after declamping for detecting troponin I (cTnI) concentration. The clinical data of inotrope requirement, drainage, ventilation. and intensive care time were routinely recorded. RESULTS: The remote perconditioning group had significantly lower release of cTnI 5 min before declamping (con. versus pre. versus per., 0.15 +/- 0.10 versus 0.13 +/- 0.08 versus 0.10 +/- 0.04 ng/mL, P = 0.050) and 30 min after declamping (con. versus pre. versus per., 0.40 +/- 0.24 versus 0.41 +/- 0.40 versus 0.24 +/- 0.13 ng/mL, P = 0.043). Less incidence of defibrillation were observed in the remote perconditioning groups. CONCLUSIONS: Remote perconditioning, which is induced by transient lower limb ischemia after aortic cross-clamping, reduces myocardial injury over cardioplegia in adults undergoing selective valve replacement. PMID- 20850779 TI - Minimally invasive renal auto-transplantation: the first report. AB - BACKGROUND: Regarding transplant surgery, the minimally invasive revolution was started in 1995 by laparoscopic living donor nephrectomy (L-LDN). In 2006, we made the first report on a minimally invasive technique for kidney transplantation; restricted to a 7-9 cm transverse incision targeted on the anastomotic area of the iliac vessels, and with the meticulously prepared kidney placed in a fitting, retroperitoneal pouch lateral to the skin incision. MATERIALS AND METHODS: By combining "hand-assisted laparoscopic nephrectomy" and "minimally invasive kidney transplantation" - using the same incision (7-8 cm) for hand-assistance, kidney harvesting, and transplantation - we have during 2009 conducted "minimally invasive renal auto-transplantation" in two patients. RESULTS: In both cases, the postoperative course was uneventful. When examined 3 mo postoperatively, both auto-transplants were shown to have excellent function by renal scintigraphy. CONCLUSIONS: Renal auto-transplantation, a traditionally major surgical procedure, can be made minimally invasive by a similar incision as that used for L-LDN. Taking into regard the highly traumatic conventional incisions, we expect the generally proven minimally invasive benefits to be considerable. PMID- 20850780 TI - Protection against severe intestinal ischemia/reperfusion injury in rats by intravenous resveratrol. AB - BACKGROUND: Repetitive enteral or intraperitoneal administration of resveratrol at high doses has recently been found to protect the small intestine against acute ischemia/reperfusion (I/R) injury. In the present work, the protective potential of solvent-free continuous intravenous infusions of small amounts of resveratrol was studied in a model of severe intestinal I/R injury. MATERIALS AND METHODS: Mesenteric ischemia was induced in male Wistar rats (six animals/group) by superior mesenteric artery occlusion (SMAO, 90 min) and reperfusion (120 min) by reopening of the microvascular clamp. Resveratrol (0.056 or 0.28 mg/kg) was continuously perfused into the jugular vein (0.014 or 0.07 mg/kg * h) starting 30 min before SMAO; an SMAO control group and sham groups (no SMAO) receiving either 0.9% NaCl solution or resveratrol (0.28 mg/kg) were included. During the experimental procedure, isotonic saline was given at a systolic blood pressure below 90 mmHg, and several parameters including those of biomonitoring and blood gas analysis were measured. Small intestine injury was assessed macroscopically, from released plasma enzyme activities, from the tissue contents of thiobarbituric acid-reactive substances and hemoglobin, from the tissue myeloperoxidase activity, and histopathologically. RESULTS: Resveratrol at only 0.056 mg/kg significantly decreased the macroscopic damage score, the tissue myeloperoxidase activity, the hemoglobin content, the histopathologic score, and the plasma glutamate-pyruvate transaminase activity, but it did not improve the systemic and metabolic parameters. Instead, during reperfusion, significantly higher volumes of saline were administered to animals receiving the polyphenol, although resveratrol did not significantly affect any parameters in sham-operated animals. CONCLUSIONS: Low doses of intravenously administered resveratrol considerably protected the rat small intestine against severe I/R injury, despite some adverse effects on blood pressure under these conditions. PMID- 20850782 TI - Esophageal perforation in children: a review of one institution's experience. AB - BACKGROUND: The current approach to esophageal perforation treatment in children has shifted towards conservative management. However, the consensus of what constitutes conservative management is unclear, with various therapies and protocols described, including the need for various decompression and drainage procedures. Our institution utilizes conservative management with minimal intervention guided by the patient's clinical course. The purpose of this study is to report our management and add to the growing evidence for conservative management of esophageal perforation in children. METHODS: We performed a retrospective chart review of all patients with an ICD-9 diagnosis of esophageal perforation from January 1995 to July 2009. Patients with postoperative anastomotic leaks with drains in place were excluded, although patients with anastomotic leaks that were not controlled by drains were included. Data collected included patient demographics, etiology, diagnosis, treatment, complications, and outcome. RESULTS: Eight patients were identified who met inclusion criteria. Mean age was 28 mo (1 d-10 y), and the average time from causative event to diagnosis was 1.4 d (0-2 d). The etiology for esophageal perforation included esophagoscopy with dilation (n = 4), button battery ingestion (n = 1), coin ingestion (n = 1), nasogastric tube placement (n = 1), and leak after stricture resection (n = 1). All the patients were treated conservatively without primary surgery or thoracic drainage, and the mean time to perforation healing was 10.2 d (1-24 d). The average length of antibiotic therapy was 10 d (0-26 d). Enteral nutrition was utilized in five patients, and total parenteral nutrition (TPN) was utilized in five patients. No patient developed a new-onset esophageal stricture. CONCLUSION: Conservative management, guided by the patient's clinical course, with antibiotics and nutritional support is a safe and effective treatment for esophageal perforations in children. PMID- 20850781 TI - Hypobaric hypoxia exacerbates the neuroinflammatory response to traumatic brain injury. AB - OBJECTIVE: To determine the inflammatory effects of time-dependent exposure to the hypobaric environment of simulated aeromedical evacuation following traumatic brain injury (TBI). METHODS: Mice were subjected to a blunt TBI or sham injury. Righting reflex response (RRR) time was assessed as an indicator of neurologic recovery. Three or 24 h (Early and Delayed groups, respectively) after TBI, mice were exposed to hypobaric flight conditions (Fly) or ground-level control (No Fly) for 5 h. Arterial blood gas samples were obtained from all groups during simulated flight. Serum and cortical brain samples were analyzed for inflammatory cytokines after flight. Neuron specific enolase (NSE) was measured as a serum biomarker of TBI severity. RESULTS: TBI resulted in prolonged RRR time compared with sham injury. After TBI alone, serum levels of interleukin-6 (IL-6) and keratinocyte-derived chemokine (KC) were increased by 6 h post-injury. Simulated flight significantly reduced arterial oxygen saturation levels in the Fly group. Post-injury altitude exposure increased cerebral levels of IL-6 and macrophage inflammatory protein-1alpha (MIP-1alpha), as well as serum NSE in the Early but not Delayed Flight group compared to ground-level controls. CONCLUSIONS: The hypobaric environment of aeromedical evacuation results in significant hypoxia. Early, but not delayed, exposure to a hypobaric environment following TBI increases the neuroinflammatory response to injury and the severity of secondary brain injury. Optimization of the post-injury time to fly using serum cytokine and biomarker levels may reduce the potential secondary cerebral injury induced by aeromedical evacuation. PMID- 20850783 TI - Invasive lobular breast cancer: does grade matter? PMID- 20850784 TI - Arterially delivered mesenchymal stem cells prevent obstruction-induced renal fibrosis. AB - BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for the treatment of renal disease. While MSCs have been shown to accelerate recovery and prevent acute renal failure in multiple disease models, the effect of MSC therapy on chronic obstruction-induced renal fibrosis has not previously been evaluated. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent renal artery injection of vehicle or fluorescent-labeled human bone marrow-derived MSCs immediately prior to sham operation or induction of left ureteral obstruction (UUO). One or 4 wk later, the kidneys were harvested and the renal cortex analyzed for evidence of stem cell infiltration, epithelial-mesenchymal transition (EMT) as evidenced by E cadherin/alpha-smooth muscle actin (alpha-SMA) expression and fibroblast specific protein (FSP+) staining, renal fibrosis (collagen content, Masson's trichrome staining), and cytokine and growth factor activity (ELISA and real time RT-PCR). RESULTS: Fluorescent-labeled MSCs were detected in the interstitium of the kidney up to 4 wk post-obstruction. Arterially delivered MSCs significantly reduced obstruction-induced alpha-SMA expression, FSP+ cell accumulation, total collagen content, and tubulointerstitial fibrosis, while simultaneously preserving E cadherin expression, suggesting that MSCs prevent obstruction-induced EMT and renal fibrosis. Exogenous MSCs reduced obstruction-induced tumor necrosis factor alpha (TNF-alpha) levels, but did not alter transforming growth factor-beta1 (TGF beta1), vascular endothelial growth factor (VEGF), interleukin-10 (IL-10), fibroblast growth factor (FGF), or hepatocyte growth factor (HGF) expression. CONCLUSIONS: Human bone marrow-derived MSCs remain viable several weeks after delivery into the kidney and provide protection against obstruction-induced EMT and chronic renal fibrosis. While the mechanism of MSCs-induced renal protection during obstruction remains unclear, our results demonstrate that alterations in TNF-alpha production may be involved. PMID- 20850785 TI - Autologous transplantation of ischemically injured kidneys in pigs. AB - BACKGROUND: Expansion of the organ donor pool can be obtained through novel interventions attenuating ischemic acute kidney injury, which will enable the use of kidneys that suffered prolonged ischemia. In basic science, new therapeutic targets are identified that should be tested in a relevant large animal model before use in human kidney transplantation. MATERIALS AND METHODS: The current paper provides a detailed description of the technique of autologous transplantation of ischemically injured kidneys in pigs with special emphasis on perioperative care. RESULTS: The animal model was validated by showing that renal function after transplantation was proportional to the duration of warm ischemia before organ recovery. The extent of renal dysfunction was reproducible following kidney transplantations with the same warm ischemia time. CONCLUSIONS: Our experience may reduce the learning curves of other research groups taking an interest in the model and improve preclinical testing of novel interventions that modulate renal ischemia and reperfusion injury in kidney transplantation. PMID- 20850786 TI - Vitamin D status of morbidly obese bariatric surgery patients. AB - BACKGROUND: Abnormal vitamin D levels are common in bariatric surgery patients. The incidence of deficiencies and the response to therapy is not accurately delineated. The purpose of this study was to define the vitamin D status of patients who undergo either a malabsorptive (gastric bypass) or restrictive (adjustable gastric band) bariatric surgery both prior to and after surgery. METHODS: A retrospective analysis was performed on patients to undergo bariatric surgery from July 2002 to February 2007. Serum levels of vitamin D (Vit D), parathyroid hormone (PTH), and calcium were analyzed. RESULTS: Mean patient age was 45 y; 82% of patients were women. Of 127 total patients, 84% were Vit D deficient preoperatively. These patients had a higher preoperative body mass index (BMI) than those with normal Vit D levels on initial assessment (BMI 44 versus 50 kg/m(2), P < 0.01). A correlation was found between preoperative BMI and Vit D (r(2) = 0.12, P < 0.01) and PTH levels (r(2) = 0.07, P < 0.01). One year following gastric bypass surgery, 20% of patients with elevated PTH levels had normal Vit D levels. The incidence of observed deficiencies for adjustable gastric band versus gastric bypass did not differ statistically at any interval. CONCLUSIONS: Morbidly obese patients seeking bariatric surgery are often deficient in Vit D, a fact that should be accounted for when evaluating the impact of bariatric surgery on Vit D levels. Elevated BMI and increasing degrees of obesity may be risk factors for both Vit D deficiency and secondary hyperparathyroidism. Despite normal Vit D levels, some gastric bypass patients continue to show elevated levels of PTH. PMID- 20850787 TI - Hepatosplanchnic vasoregulation and oxygen consumption during selective aortic blood flow reduction and reperfusion. AB - BACKGROUND: Several studies have shown that the distribution of cardiac output to the intra-abdominal organs may vary during low-flow states. In this study, we developed an experimental model to selectively reduce the abdominal aortic blood flow in order to assess the initial impact of selective hepatosplanchnic hypoperfusion on regional blood flow redistribution. METHODS: Eight anesthetized and mechanically ventilated mongrel dogs were subjected to aortic blood flow reduction with an occluder in a stepwise manner by 50% and 100% for 45 min. After the ischemic period, the occluder was released, and animals were observed for an additional 45 min. Systemic hemodynamics were evaluated through a Swan-Ganz and arterial catheters, and gastrointestinal tract perfusion was evaluated by portal vein and hepatic arterial blood flows measurements (ultrasonic flowprobe). Intestinal O2-derived variables, intestinal mucosal (tonometric)-arterial and tonometric-(end-tidal-carbon-dioxide) gradients (Dt-apCO2 and Dt-EtpCO2) were also calculated. RESULTS: No significant changes in systemic and regional oxygen consumption were observed during the 50% reduction of aortic blood flow. On the other hand, both microregional pCO2 gradients (Dt-apCO2 e Dt-EtpCO2) showed a significant increase during this period. Aortic occlusion was associated with a marked reduction of systemic and regional oxygen delivery and consumption. During the reperfusion, no significant improvement in the tonometry-based pCO2 gradients was observed, in spite of the partial reestablishment of blood flow to the hepatosplanchnic territory. CONCLUSION: During selective intra-abdominal low flow, a proportional reduction in the splanchnic and hepatic blood flows occurs. A selective reduction of approximately 50% in splanchnic oxygen delivery was not associated with significant changes in macroregional markers of hypoperfusion. In this situation, tonometry-based pCO2 gradients can be used for the assessment of hepatosplanchnic perfusion and histologic changes. PMID- 20850788 TI - Importance of EPC-K1 in ischemia and reperfusion injury. PMID- 20850789 TI - Heme oxygenase-1 mediates the protective effects of ischemic preconditioning on mitigating lung injury induced by lower limb ischemia-reperfusion in rats. AB - BACKGROUND: Lower limb ischemia-reperfusion (I/R) imposes oxidative stress, elicits inflammatory response, and subsequently induces acute lung injury. Ischemic preconditioning (IP), a process of transient I/R, mitigates the acute lung injury induced by I/R. We sought to elucidate whether the protective effects of IP involve heme oxygenase-1 (HO-1). METHODS: Adult male rats were randomized to receive I/R, I/R plus IP, I/R plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquet high around each thigh for 3 h followed by reperfusion for 3 h. To achieve IP, three cycles of bilateral lower limb I/R (i.e., ischemia for 10 min followed by reperfusion for 10 min) were performed. IP was performed immediately before I/R. After sacrifice, degree of lung injury was determined. RESULTS: Histologic findings, together with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that I/R induced acute lung injury. I/R also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E(2) concentrations), imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations), and up-regulated HO-1 expression in lung tissues. IP significantly enhanced HO-1 up-regulation and, in turn, mitigated oxidative stress, inflammatory response, and acute lung injury induced by I/R. In addition, the protective effects of IP were counteracted by SnPP. CONCLUSIONS: The protective effects of IP on mitigating acute lung injury induced by lower limb I/R are mediated by HO-1. PMID- 20850790 TI - Incidence of complications following colectomy with mesenteric closure versus no mesenteric closure: does it really matter? AB - BACKGROUND: There remains strong opinion but very little data to support the way that the resultant mesenteric defect is handled following colectomy. Despite case reports of internal hernias and subsequent bowel obstruction requiring operative intervention, no larger series have evaluated this question. MATERIALS AND METHODS: Retrospective review of elective right and left/sigmoid colectomies during the period from 2004 to 2007. Patients were stratified by the method of handling the mesenteric defect (open versus closed), with the primary endpoint of complications potentially directly attributable to the closure or failure to close the mesenteric defect. Preoperative and intraoperative risk factors were also analyzed as covariables. RESULTS: One hundred thirty-three patients (76 male; 57 female; mean age 59+/-15 years) with a median follow-up of 39.5 mo were identified. Thirty-six percent underwent a right hemicolectomy, 33% sigmoidectomy, 11% left hemicolectomy, 9% low anterior resection, and 5% ileocectomy. Overall, 24% of the surgeries were done laparoscopically and 52% had their mesenteric defect closed. The overall complication rate was 27.8% and eight patients (6%) developed a postoperative complication near the mesenteric defect (anastomotic leakage or small bowel obstruction). By multivariate analysis, mesenteric defect closure was the only significant factor identified with the development of complications near the mesenteric defect (OR=5.5; 95% CI 1.069 28.524, P=0.041). No other preoperative or intraoperative factors were found to have an impact on the complication rate. CONCLUSION: Closure of the mesenteric defect was associated with a higher rate of complications, and demonstrated no benefit in abdominal colectomy. PMID- 20850791 TI - Testosterone-down-regulated Akt pathway during cardiac ischemia/reperfusion: a mechanism involving BAD, Bcl-2 and FOXO3a. AB - BACKGROUND: Lower levels of myocardial Akt activity in males are associated with a higher incidence of heart failure and worsened cardiac function after ischemia/reperfusion (I/R). While Akt activation by estrogen provides cardioprotection in females, no information exists regarding the effect of testosterone on the myocardial Akt pathway following I/R. We hypothesized that following I/R: (1) endogenous testosterone will decrease myocardial Akt activation in male hearts; (2) endogenous testosterone will mediate downstream signals of Akt, including Bad, Bcl-2, and FOXO3a; (3) administration of exogenous testosterone will recapitulate negative effects on the Akt pathway in castrated male hearts. METHODS AND RESULTS: Rat hearts from age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide, castrated males with chronic 5alpha-dihydrotestosterone (DHT) implantation, or acute testosterone infusion (ATI) (n = 9/group) were subjected to I/R (Langendorff). Castration or flutamide treatment significantly up-regulated myocardial Akt activation, increased downstream apoptosis-regulatory molecules p Bad, Bcl-2, p-FOXO3a, but reduced Fas-L, consistent with decreased myocardial injury in male hearts following I/R. ATI administration, but not chronic DHT, reversed these effects on Akt signaling associated with further exacerbated cardiac dysfunction in castrated males. Notably, lower levels of MnSOD were observed in male hearts, and castration or flutamide treatment restored myocardial MnSOD expression to the levels of females in male hearts after I/R. CONCLUSION: Our study represents the initial evidence of testosterone-induced down-regulation of the Akt pathway in male hearts following I/R, thereby mediating cardiac injury through decreased p-Bad, reduced ratio of Bcl-2/Bax in the cytoplasm, and increased FOXO3a in the nucleus. PMID- 20850792 TI - Development of an acellular bioengineered matrix with a dominant vascular pedicle. AB - BACKGROUND: This study assessed the feasibility of creating a tissue engineering platform by decellularization of fasciocutaneous tissue. MATERIALS AND METHODS: A fasciocutaneous flap based upon the superficial inferior epigastric artery was harvested from the abdominal wall of 8-wk-old male Sprague-Dawley rats. All cellular components were removed by sequential treatment with sodium azide, DNAse, and sodium deoxycholate. The degree of decellularization was qualitatively assessed by histology and quantitatively assessed by spectrophotometry. Persistence of relevant extracellular matrix proteins was shown following staining with orcein and hematoxylin. The duration of circuit patency was determined by continuous perfusion with a peristaltic perfusion pump. RESULTS: Gross and histologic examination demonstrated removal of cellular constituents with preservation of tissue matrix architecture, including macrochannels and microchannels. This was confirmed by the application of spectrophotometry to DNA isolates, which showed that the decellularized flap retained 4.04 ng/MUL DNA, compared with the non-processed control, which retained 37.03 ng/MUL DNA, and the acellular control, which was read as having 0.65 ng/MUL DNA. The extracellular matrix of vessel walls was shown to remain intact. Peristaltic perfusion of the cannulated pedicle inflow channel with phosphate buffered saline at a rate of 200 MUL/min confirmed circuit patency for 6 h. CONCLUSION: Fasciocutaneous flaps harvested with an intact vascular pedicle and associated tissue vascular network can be successfully decellularized and perfused ex vivo. This methodology, which is scalable to human size tissues, provides promise as a technique for the production of customizable engineered tissues. PMID- 20850794 TI - Historical notes on the World Federation of Neurology Research Group on Aphasia and Cognitive Disorders (RGACD). AB - A brief history of the establishment and the activities of the WFN Research Group on Aphasia and Cognitive disorders is presented, based on the archives of the group. The purpose is to achieve continuity between the past and present and to document the collective memories of the activities of the group, hereby strengthening its future. PMID- 20850793 TI - Frequency and prognostic impact of antibodies to aquaporin-4 in patients with optic neuritis. AB - BACKGROUND: Antibodies to aquaporin-4 (AQP4-Ab) are found in 60-80% of patients with neuromyelitis optica (NMO), a severely disabling inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the optic nerves and spinal cord. OBJECTIVE: To assess the frequency of AQP4-Ab in patients with optic neuritis (ON), and to investigate the prognostic implications of AQP4-Ab seropositivity in such patients. PATIENTS AND METHODS: AQP4-Ab serum levels were determined in 224 individuals from Austria, Denmark, France, Germany, Italy, and Turkey using a newly developed fluorescence immunoprecipitation assay employing recombinant human AQP4. RESULTS: AQP4-Ab were detectable in 8/139 (5.8%) patients with acute monosymptomatic optic neuritis (AMON) and in 10/17 (58.8%) patients with established NMO and a last relapse of acute ON (NMO/ON), but not in 32 patients with multiple sclerosis or in 36 healthy controls. At last examination, 4/8 (50%) seropositive AMON patients had met the criteria for NMO but 0/128 seronegative AMON patients. Disease severity differed significantly between seropositive and seronegative AMON. Complete bilateral or unilateral blindness occurred in six AQP4-Ab positive patients, but only in one AQP4-Ab negative patient. AQP4-Ab levels did not vary between seropositive AMON and NMO/ON and did not correlate with disease severity. Female gender, a relapsing course, and concomitant autoimmunity were associated with AQP4-Ab seropositive status and risk of developing NMO. CONCLUSION: AQP4-Ab is relatively rare among patients with AMON, but if present it predicts a high rate of conversion to NMO within one year. PMID- 20850795 TI - Neurocognitive deficits and personality traits among euthymic patients with mood disorders in late life. AB - BACKGROUND: Previous studies revealed that acute depressive episodes are associated with both cognitive deficits and modified personality patterns in late life. Whether or not these psychological changes are present after remission remains a matter of debate. To date, no study provided concomitant assessment of cognition and psychological functions in this particular clinical setting. METHOD: Using a cross-sectional design, 58 remitted outpatients (36 with unipolar early-onset depression (EOD) and 22 with bipolar disorder (BD)) were compared to 62 healthy controls. Assessment included detailed neurocognitive measures and evaluation of the five factor personality dimensions (NEO-Personality Inventory). RESULTS: Group comparisons revealed significant slower processing speed, working and episodic memory performances in BD patients. EOD patients showed cognitive abilities comparable to those of elderly controls. In NEO PI assessment, both BD and EOD patients displayed higher Depressiveness facet scores. In addition, the EOD but not BD group had lower Extraversion factor, and Warmth and Positive Emotion facet scores than controls. CONCLUSIONS: After remission from acute affective symptoms, older BD patients show significant impairment in several cognitive functions while neuropsychological performances remained intact in elderly patients with EOD. Supporting a long-lasting psychological vulnerability, EOD patients are more prone to develop emotion-related personality trait changes than BD patients. PMID- 20850796 TI - Natural history and medical treatment of cognitive dysfunction after spontaneous subarachnoid haemorrhage: review of current literature with respect to aneurysm treatment. AB - Aneurysmal subarachnoid haemorrhage (aSAH) has the highest mortality and morbidity among all types of stroke. Unfortunately, cognitive dysfunction remains a major problem to those who survive the acute crisis. Most studies focused on patients after microsurgical clipping, which turned out to be different from the modern patient cohorts. With the widespread introduction of endovascular surgery as the first choice of treatment, there was a hope that post-aSAH cognitive dysfunction could be markedly reduced. However, data showed that post-aSAH cognitive dysfunction remained a major burden to the survivors of our modern patient cohort that returned to the community more than nine months after the initial haemorrhage. There is, therefore, a need to further understand its pathophysiology and natural history, and to develop effective treatment strategy. The results are encouraging and further clinical studies are indicated. Collaborations between cognitive scientists, neurologists and neurosurgeons are essential to advance the understanding of the problem. PMID- 20850797 TI - Blood-brain barrier and cerebral small vessel disease. AB - Increasing evidence from neuro and retinal imaging, neuropathology, epidemiology and experimental models suggests that the primary underlying initiating cause of cerebral small vessel disease is the derangement of the blood-brain barrier. This may start some years before the first symptoms, leads to the small vessel structural changes (vessel wall thickening, disorganisation and eventual breakdown) and perivascular changes (oedema, enlarged perivascular spaces, tissue damage interpreted as "infarcts") and is fundamentally different to traditional "ischaemic" mechanisms, although small vessel occlusion due to thrombus formation on damaged vessel walls may be a late secondary phenomenon. Space limits a detailed discussion of the epidemiology and experimental evidence, so this brief review will focus on neuroimaging evidence and summarise the appearances, risk factors and associations of different components of cerebral small vessel disease as identified on imaging, discuss potential causes and, in particular, the evidence that disordered blood-brain barrier precipitates or worsens progression of cerebral small vessel disease. This mechanism may also play a role in other common disorders of ageing such as Alzheimer's disease. PMID- 20850798 TI - Particular aspects in patients with coronary heart disease and vascular cognitive impairment. AB - Among the patients with cognitive vascular impairment, a particular group is represented by those who have concomitant cerebrovascular and coronary heart disease (CHD). The clinical evolution of some of these patients is dominated apparently by the progressive cognitive impairment and sometimes psychotic episodes and not by evident clinical stroke and/or symptoms of their heart disease, so that they receive the diagnosis of Alzheimer's disease or of a psychiatric disease. Most of these patients have a severe evolution, particularly if their cardiovascular disease is not recognized and die unexpectedly. In the author's clinical experience, the systematic cardiovascular examination in all patients hospitalized with the diagnosis of dementia or cognitive impairment, even if they did not have previously been diagnosed with cerebrovascular and/or coronary heart disease, disclosed in many instances the presence of severe but apparently silent cardiovascular disorders characterized always by concomitant severe CHD and significant large vessel disease of the brain. It is important to emphasize the particular situation in which the progressive cognitive impairment associated or not with psychiatric manifestations could mask severe cardio- and cerebrovascular disorders, which could further be worsened by symptomatic psychiatric treatment, and which evolution is to "unexpected" cardiovascular death. PMID- 20850799 TI - An immunohistochemical study of ubiquitin in the skin of sporadic amyotrophic lateral sclerosis. AB - Ubiquitin (UB)-immunoreactive filamentous inclusions, absent in normal cases and in any other disorder, have been found in patients with amyotrophic lateral sclerosis (ALS) and it has been suggested that they may be characteristic of this disorder. However, there has been no study of UB in ALS skin. We made a quantitative immunohistochemical study of the expression of UB in the skin from 19 patients with sporadic ALS and 19 control subjects. The proportion of UB positive (UB+) cells in the epidermis in ALS patients was significantly higher (p<0.001) than in controls. There was a significant positive relationship (r=0.92, p<0.001) between the proportion and duration of illness in ALS patients. The optical density of UB+ cells in the epidermis in ALS patients is markedly stronger (p<0.001) than in controls. There was a significant positive relation (r=0.58, p<0.01) between the immunoreactivity and duration of illness in ALS patients. These data suggest that changes of UB in ALS skin are related to the disease process and that metabolic alterations of UB may take place in the skin of patients with ALS. PMID- 20850800 TI - New development in diagnosis of vascular cognitive impairment. AB - Despite availability of harmonized criteria for the investigation of patients with presumed "vascular cognitive impairment (VCI)" there exists no clear definition of VCI. The challenge lies in the definition of those vascular components being responsible for the cognitive-behavioural decline of elderly patients. We advocate the use of longitudinal brain MRI studies to establish what type and extent of lesion progression parallels cognitive deterioration in elderly patients who often present with a plethora of diffuse and focal brain abnormalities that may or may not contribute to their cognitive phenotype. So far, a temporal relationship between lesion progression and cognitive decline has been established only for two types of "vascular" abnormalities. The most convincing evidence exists for confluent white matter lesions, less, but clearly supportive data are available for lacunes. All other brain abnormalities including microbleeds, loss of brain volume due to vascular processes or ultrastructural brain changes as seen with new imaging techniques need to be further explored in terms of their pathological correlates, rates of progression and their relationship to cognitive functioning. Such data are the pre-requisite to further develop the currently vague concept of VCI to a clearly defined diagnostic entity. PMID- 20850801 TI - Preliminary results of anatomic lung resection using energy-based tissue and vessel coagulative fusion technology. AB - OBJECTIVES: Mechanical stapling devices have been established as the mainstay of therapy in the selective isolation and division of bronchial and vascular structures during anatomic lung resection. Few data are available regarding the application of energy-based tissue fusion technology during anatomic lung resection. In the present study, we evaluated the use of energy-based instruments for the division of the pulmonary arterial and venous branches during anatomic lung resection. METHODS: Anatomic lung resection (segmentectomy or lobectomy) was performed using energy-based coagulative fusion technology. A low-profile jaw can be used to facilitate dissection in both open and video-assisted thoracic surgery cases, applying a seal 6 mm wide by 22 mm in length. Two energy applications were applied to the arterial and venous branches before vessel division. RESULTS: The bipolar tissue fusion system was used in 211 patients between 2008 and 2010 (104 lobectomies and 107 anatomic segmentectomies). Initially, we used a device with a smaller, curved jaw (n = 12), producing a 3.3- to 4.7-cm seal. No arterial dehiscences and 2 partial venous dehiscences that were recognized and controlled intraoperatively occurred. For the remaining cases, we used a new device with a larger jaw that applied a seal 6 mm wide by 22 mm in length. No arterial or venous dehiscences (vessel size range, 0.4-1.2 cm) occurred. CONCLUSIONS: The bipolar tissue fusion system provided safe and reliable control of pulmonary arterial and venous branches during anatomic lung resection. The use of energy based tissue fusion technology represents a reasonable alternative to mechanical stapling devices during anatomic lung resection. PMID- 20850803 TI - Myocardial infarction in rats causes partial impairment in insulin response associated with reduced fatty acid oxidation and mitochondrial gene expression. AB - OBJECTIVE: Myocardial infarction leads to contractile dysfunction. In patients with diabetes, impaired contractility has been associated with the loss of insulin effects and mitochondrial dysfunction. We assessed cardiac insulin sensitivity and mitochondrial and contractile function in rats after ligation of the left coronary artery. METHODS: At 2 weeks after left coronary artery ligation, we performed echocardiography in vivo and assessed the substrate use and insulin response in the isolated working heart and the regulation of insulin (Akt, glucose transporter type 4) and mitochondrial signaling (p38 mitogen activated protein kinase, peroxisome proliferator-activated receptor-gamma coactivator 1alpha, mitochondrial transcription factor A) using polymerase chain reaction and Western blotting. RESULTS: The infarcted hearts were dilated and had a reduced ejection fraction (ejection fraction < 50%). The basal glucose oxidation was preserved, but the fatty acid oxidation was significantly reduced. Insulin's effect on substrate oxidation was significantly impaired for both the decrease in fatty acid oxidation and the increase in glucose oxidation. However, insulin-stimulated glucose uptake was normal in the infarcted hearts, consistent with normal insulin-induced phosphorylation of Akt and unchanged mRNA expression of glucose transporter type 4. The impaired oxidative response to insulin was associated with reduced mRNA expression of the genes regulating fatty acid oxidation (long-chain-acyl-coenzyme A dehydrogenase, carnitine palmitoyltransferase 1, peroxisome proliferator-activated receptor-alpha) and mitochondrial biogenesis (mitochondrial transcription factor A). Although mRNA expression of the mitochondrial master regulator peroxisome proliferator activated receptor-gamma coactivator 1alpha was normal in the infarcted hearts, the protein expression of its post-transcriptional activator, p38 mitogen activated protein kinase, was significantly reduced. CONCLUSIONS: Myocardial infarction in rats caused partial insulin resistance at the level of substrate oxidation, which was associated with mitochondrial and cardiac contractile dysfunction. Mitochondrial dysfunction was characterized by a reduced capacity to oxidize fatty acids and might have resulted from impaired mitochondrial biogenesis through the lack of p38 mitogen-activated protein kinase. PMID- 20850804 TI - The Mosaic porcine bioprosthesis: role of age on clinical performance in aortic position. AB - BACKGROUND: The Mosaic bioprosthesis is a third-generation stented porcine bioprosthesis combining physiologic fixation and alpha-amino oleic acid antimineralization treatment to improve durability and hemodynamic function. This single-center study reports on the performance of the Mosaic bioprosthesis in patients 65 years of age or less and patients older than 65 years at implantation. METHODS: Between 1994 and 1999, 88 younger patients (mean age, 58 years) and 167 older patients (mean age, 72 years) were enrolled in this prospective nonrandomized clinical trial. Follow-up visits were performed after 30 days, 6 months, and annually. Cumulative follow-up was 751 patient-years in the younger group and 1223 patient-years in the older group. RESULTS: Mean systolic gradient increased significantly to 17.0 and 14.7 mm Hg in younger and older patients, respectively, at their latest follow-up (P < .001). Effective orifice area values decreased significantly to 1.8 and 1.6 cm(2) (P < .001). Overall, effective orifice area values were significantly higher in younger patients (P < .001). Transvalvular regurgitation increased over time (P < .001) but remained mild or less in more than 95% of the patients. Freedom from adverse events at latest follow-up in younger and older patients, respectively, were as follows: structural valve deterioration, 85.7% and 86.2% (P < .05); endocarditis, 87.5% and 98.5% (P < .01); valvular thrombosis, 98.8% and 97.1% (not significant); and explantation, 68.9% and 77.9% (P < .01). CONCLUSIONS: Hemodynamic performance is similar in both groups. In the younger patients the incidence of structural valve disease, endocarditis, valve-related reoperation, and explantation is higher. The incidence in structural valve deterioration in the younger patients tends to be similar or lower compared with that seen in the literature. PMID- 20850806 TI - Repair of major congenital cardiac defects in low-birth-weight infants: is delay warranted? AB - OBJECTIVES: Few studies have described the survival of low-birth-weight infants weighing less than 1.5 kg at operation for a cardiac malformation. Our goal was to determine if body weight at surgery affects survival. METHODS: This was a retrospective cohort study using outcome data from the Pediatric Cardiac Care Consortium between 1982 and 2006. RESULTS: We reviewed the outcomes of 450 consecutive infants with a cardiac anomaly and a birth weight of less than 1.5 kg, and weight of less than 2.5 kg at surgery. Of these, 179 patients had undergone surgery with a weight of less than 1.5 kg and 271 patients weighed 1.5 to 2.5 kg at surgery. The 30-day survival rate was 83% for cohort 1 and 86% for cohort 2. For patients not requiring cardiopulmonary bypass, the 30-day survival rate was 86% for cohort 1 and 92% for cohort 2. For patients requiring cardiopulmonary bypass, the 30-day survival rate was 69% for cohort 1 and 73% for cohort 2. No notable improvement in the outcomes occurred over time. CONCLUSIONS: For low-birth-weight infants (weight < 1.5 kg) undergoing a major cardiac procedure, the survival of infants weighing less than 1.5 kg at surgery is comparable to that of infants who weighed 1.5 to 2.5 kg. We conclude that, in our series, weight was not an independent risk factor for mortality, and, therefore, operative delay because of patient weight might be unwarranted. PMID- 20850809 TI - Coil spring fiducial markers placed safely using navigation bronchoscopy in inoperable patients allows accurate delivery of CyberKnife stereotactic radiosurgery. AB - OBJECTIVES: CyberKnife stereotactic body radiosurgery is a potentially curative option for medically inoperable Stage I lung cancer. Fiducial marker placement in or near the tumor is required. Transthoracic placement using computed tomography guidance has been associated with a high risk of iatrogenic pneumothorax. Electromagnetic navigation bronchoscopy offers a safer method of placing markers; however, previous studies using linear markers have shown at least a 10% dislocation rate. We describe the use of coil-spring fiducial markers placed under moderate sedation in an outpatient bronchoscopy suite. METHODS: A total of 52 consecutive nonoperative patients with isolated lung tumors underwent fiducial placement using electromagnetic navigation bronchoscopy. Of the 52 patients, 4 received 17 linear fiducial markers, and 49 patients with 56 tumors received 217 coil-spring fiducial markers. The procedures were considered successful if the fiducial markers had been placed in or near the tumors and had remained in place without migration, allowing radiosurgery without the need for additional fiducial markers. RESULTS: A total of 234 fiducial markers were successfully deployed in 52 patients with 60 tumors (mean diameter 23.7 mm). Of these 60 tumors, 35 (58%) were adjacent to the pleura. At CyberKnife planning, 8 (47%) of 17 linear fiducial markers and 215 (99%) of 217 coil-spring fiducial markers (P = .0001) were still in place. Of the 4 patients with linear fiducial markers, 2 required additional fiducial placements; none of the patients with coil fiducial markers required additional procedures. Three pneumothoraces (5.8%) occurred in peripheral lesions (2 were treated with a pig-tail chest tube and 1 with observation only). CONCLUSIONS: Deployment of coil spring fiducial markers using navigation bronchoscopy can safely be performed with the patient under moderate sedation with almost no migration and a 5.8% rate of pneumothorax. PMID- 20850810 TI - Severe bilateral hydronephrosis and hydroureter secondary to bladder tuberculosis. PMID- 20850811 TI - Assessment of lithogenic risk in children based on a morning spot urine sample. AB - PURPOSE: The Bonn Risk Index has been used to evaluate the risk of urinary calcium oxalate stone formation. According to the original method, risk should be determined based on 24-hour urine collection. We studied whether the Bonn Risk Index could be measured in spot urine samples and which part of the day is most suitable for this purpose. MATERIALS AND METHODS: We collected total and fractionated 24-hour urine (in a 6-hour nocturnal portion and 9 consecutive 2 hour diurnal samples) in 42 children and adolescents with calcium oxalate urolithiasis and 46 controls. Bonn Risk Index values determined from each of the urine fractions were compared to those obtained from related 24-hour urine collections. RESULTS: Both groups exhibited similar circadian patterns of Bonn Risk Index values. Median Bonn Risk Index for the nighttime portion of urine in the stone group was 1.4 times higher than that obtained from the total 24-hour urine. The morning hours between 08:00 and 10:00 showed the peak lithogenic risk, and this fraction had the highest sensitivity and selectivity regarding discrimination between stone formers and healthy subjects. The afternoon hours demonstrated lower and less fluctuating crystallization risk. Despite diurnal fluctuations in Bonn Risk Index, there was still a well-defined cutoff between the groups. CONCLUSIONS: Bonn Risk Index determined from urine samples collected between 08:00 and 10:00 appears optimal in separating stone formers from healthy subjects, and appears as useful as the value determined from 24-hour urine collection. Investigation of this diurnal sample simplifies diagnosis in pediatric stone disease without loss of clinical information. PMID- 20850812 TI - Vesicoureteral reflux and primary bladder neck dysfunction in children: urodynamic evaluation and randomized, double-blind, clinical trial on effect of alpha-blocker therapy. AB - PURPOSE: Primary bladder neck dysfunction has been under diagnosed as a treatable cause of vesicoureteral reflux. We evaluated the effect of prazosin administration on vesicoureteral reflux resolution and urodynamic parameters in children with idiopathic primary reflux and primary bladder neck dysfunction. MATERIALS AND METHODS: A total of 62 children (mean +/- SD age 7.9 +/- 2.4 years) with documented vesicoureteral reflux and urodynamics proved primary bladder neck dysfunction were randomized to receive either 0.025 mg/kg alpha-blocker (prazosin, 40 patients) or placebo (22) nightly for 1 week with a subsequent increase to 2 divided doses. Patients were followed for 12 months with clinical evaluation and uroflowmetry performed every 2 months, and each patient underwent complete urodynamic study at 6-month intervals. RESULTS: In the placebo group no uroflowmetry or urodynamic parameter changed significantly at 1-year followup. A 60% decrease in reflux grade was observed in the treatment group compared to 17% in the placebo group. Mean maximal detrusor pressure, post-void residual and opening time were significantly decreased in both followup sessions in the prazosin group (p <0.05). Average flow rate improved from 4.30 to 12.80 ml per second at 6 months and to 13.10 ml per second at 12 months (both p <0.05). CONCLUSIONS: Special attention should be given to secondary causes of vesicoureteral reflux (such as primary bladder neck dysfunction, an underdiagnosed entity in children), since conventional treatment will most likely fail if these conditions are not addressed promptly. In this study prazosin was effective therapy for children with vesicoureteral reflux and primary bladder neck dysfunction. PMID- 20850813 TI - Staged nephrectomy versus bilateral laparoscopic nephrectomy in patients with autosomal dominant polycystic kidney disease. AB - PURPOSE: In patients with autosomal dominant polycystic kidney disease we compared the outcome of bilateral laparoscopic nephrectomy at a single operation vs staged nephrectomy, including 1 during transplantation and the other via laparoscopic unilateral nephrectomy. MATERIALS AND METHODS: We reviewed the records of patients with autosomal dominant polycystic kidney disease requiring renal transplantation and native bilateral nephrectomy. We compared transplantation with ipsilateral nephrectomy to transplantation alone and then compared unilateral to bilateral laparoscopic native nephrectomy. Indications included pain, infection, bleeding and compressive symptoms. RESULTS: We followed 42 patients, including 16 with transplantation and nephrectomy, 22 with transplantation alone and 4 awaiting transplantation. In those with transplantation vs transplantation with nephrectomy there were no differences in median age (48.3 vs 53.3 years, p = 0.178) or greatest kidney length (19.5 vs 20.9 cm, p = 0.262). Operative time (208 vs 236 minutes, p = 0.104), estimated blood loss (200 vs 250 ml, p = 0.625), hospital discharge creatinine (1.60 vs 1.50 mg/dl, p = 0.491) and complications were similar. We separately compared 24 bilateral and 18 unilateral laparoscopic native nephrectomies, and noted similarities in median age (52.0 vs 56.3 years, p = 0.281) and kidney length (19.5 vs 19.8 cm, p = 0.752). Bilateral nephrectomy showed greater estimated blood loss (125 vs 50 ml, p = 0.001) and operative time (302.8 vs 170.2 minutes, p <0.001). There were 4 open conversions, 9 perioperative complications at bilateral surgery and 1 complication after unilateral surgery. Median followup in the unilateral and bilateral groups was 13.3 vs 35.9 months (p = 0.015). CONCLUSIONS: Renal transplantation and ipsilateral native nephrectomy carry no significant additional morbidity compared to that of renal transplantation alone. Staged unilateral laparoscopic nephrectomy was superior to the bilateral procedure in perioperative outcome. PMID- 20850814 TI - Urinary tract schistosomiasis. PMID- 20850815 TI - Bacterial virulence factors are associated with occurrence of acute pyelonephritis but not renal scarring. AB - PURPOSE: We evaluated the influence of patient factors and virulence factors of uropathogenic Escherichia coli on the occurrence of acute pyelonephritis and subsequent renal parenchymal scarring. MATERIALS AND METHODS: We evaluated 80 boys and 45 girls 1 to 180 months old with febrile urinary tract infections who underwent renal scan to diagnose acute pyelonephritis and followup dimercapto succinic acid scintigraphy at least 6 months later. Urinalysis, white blood cell count, uropathogenic E. coli genotype and vesicoureteral reflux were measured. Voiding cystourethrogram was investigated after acute pyelonephritis was confirmed by renal scan and acute inflammation subsided, about 2 to 4 weeks later. RESULTS: Acute pyelonephritis was significantly more likely to develop in children with urinary tract infections and persistent fever before and after hospitalization, elevated C-reactive protein or positive renal ultrasound findings. E. coli strains with the papG II and iha genes were significantly more likely to occur in patients with acute pyelonephritis. Patients with a fever for more than 3 days and C-reactive protein levels greater than 90.8 mg/l were significantly more likely to have renal scarring. Age was not an independent predictor of acute pyelonephritis, but modified the effect of virulence factors on the development of acute pyelonephritis. CONCLUSIONS: Bacterial virulence factors and host factors are associated with the occurrence of acute pyelonephritis. Host factors such as patient age and vesicoureteral reflux severity modify the influence of virulence factors, although only host factors are associated with the occurrence of renal scarring. PMID- 20850817 TI - Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection. AB - PURPOSE: We determined the incidence of antegrade emission after primary retroperitoneal lymph node dissection in a large contemporary cohort. Our secondary purpose was to evaluate the fertility rate in this population. MATERIALS AND METHODS: We queried the testicular cancer database at our institution from January 1, 2000 to December 31, 2005 and identified all 280 patients who underwent primary retroperitoneal lymph node dissection. Of these patients we contacted 176, and questioned them about ejaculatory and fertility status at 3 to 9 years of followup. RESULTS: Of 176 patients who underwent primary retroperitoneal lymph node dissection 171 (97%) reported preserved antegrade emission. Of the 135 men who underwent a nerve sparing procedure 134 (99%) could ejaculate, as could 33 of 37 (89%) who underwent nonnerve sparing surgery. An attempt to father children was reported by 64 men, of whom 47 (73.4%) were successful. Three other patients fathered children via in vitro fertilization. CONCLUSIONS: Most men who undergo modern primary retroperitoneal lymph node dissection maintain antegrade emission and ejaculation. PMID- 20850816 TI - Microvesicle induction of prostate specific gene expression in normal human bone marrow cells. AB - PURPOSE: Transfer of genetic material from cancer cells to normal cells occurs via microvesicles. Cell specific phenotypes can be induced in normal cells by the transfer of material in microvesicles, leading to genetic changes. We report the identification and expression of prostate specific genes in normal human marrow cells co-cultured with human prostate cancer cells. MATERIALS AND METHODS: We harvested prostate tissue from 11 patients with prostate cancer. In 4 cases prostate tissue was co-cultured across from human marrow for 2 or 7 days but separated from it by a 0.4 MUM polystyrene membrane. In 5 cases conditioned medium from patient cancer tissue was collected and ultracentrifuged, and microvesicles were collected for co-culture (3) and vesicle characterization (3). Explanted human marrow was harvested from cultures and RNA extracted. Real-time reverse transcriptase-polymerase chain reaction was done for select prostate specific genes. RESULTS: Marrow exposed to human prostate tumor or isolated microvesicles in culture in 4 and 3 cases, respectively, showed at least 2-fold or greater prostate gene expression than control marrow. In 1 case in which normal prostate was co-cultured there were no prostate gene increases in normal marrow. CONCLUSIONS: Prostate cancer tumor cells co-cultured with human bone marrow cells induce prostate specific gene expression. The proposed mechanism of transfer of genetic material is via microvesicles. This represents an opportunity for novel therapeutic agents, such as antibodies, to block microvesicle release from cancer cells or for agents that may block cells from accepting microvesicles. PMID- 20850818 TI - Should routine pyeloureterostomy be advocated in adult kidney transplantation? A prospective study of 283 recipients. AB - PURPOSE: Ureteroneocystostomy surgical techniques have been repeatedly debated in the medical literature, in contrast to pyeloureterostomy, which is merely considered a salvage procedure. We assessed urological complications and their management after routine pyeloureterostomy in adult kidney transplantation cases. MATERIALS AND METHODS: We performed a 2-center, uncontrolled, prospective study from January to December 2007. We compared results in 151 consecutive kidney transplantations with routine pyeloureterostomy (group 1) and in 129 procedures with extravesical anti-reflux ureteroneocystostomy (group 2). Perioperative ureteral stenting was done on demand in each group. Major complications included complex leakage, stenosis and surgical revision. Transient leakage or obstruction less than 15 days in duration were considered minor complications. RESULTS: Recipients in group 1 were more likely to undergo ureteral stenting on demand than those in group 2 (68.9% vs 21.7%). The incidence of overall complications was similar in groups 1 and 2 (9.3% and 13.2%, respectively, p = 0.15), although the major complication rate was higher in group 2. Group 1 recipients had a tendency to require long-term ureteral stenting more often. The only recipient with ureteral necrosis in group 1 was treated with surgical resection and repeat end-to-end ureteroureterostomy. In each group no graft was lost due to urological complications or their management. CONCLUSIONS: Routine pyeloureterostomy is a safe technique that may be a valuable alternative to ureteroneocystostomy for adult renal transplantation. It does not preclude further open re-intervention. Its main advantages include a significant decrease in the risk of surgical re intervention, the opportunity to perform further endourological procedures on the allograft urinary system and the avoidance of vesicoureteral reflux. PMID- 20850819 TI - External validation of a virtual reality transurethral resection of the prostate simulator. AB - PURPOSE: Virtual reality surgical simulation is an emerging technology that may eventually fill the gaps in surgical education created by changes in our medical system. We assessed the construct validity of a commercially available, virtual reality transurethral prostate resection simulator. MATERIALS AND METHODS: Participants performed 2, 5-minute transurethral prostate resection exercises on a standardized virtual reality prostate. Data from the first exercise were discarded. Simulator based metrics from the second exercise were tabulated, including tissue resected in gm, number of cuts, coagulation time, number of coagulation attempts, tissue per cut in gm and blood loss. Complications were recorded. Performance metrics were compared between groups based on urological training level and prior real-world experience with transurethral prostate resection. RESULTS: A total of 35 participants with varied levels of transurethral prostate resection experience completed the exercise. Several performance metrics had statistically significant correlations with urology training level and prior experience with transurethral prostate resection. There was a positive correlation of all measures of experience with mass resected, mass resected per cut and blood loss. Number of cuts correlated significantly with transurethral prostate resection experience in the previous year. Complications were present in most groups with medical students more likely to encounter external urethral sphincter and rectal injuries. CONCLUSIONS: We report the construct validity of a commercially available, virtual reality transurethral prostate resection simulator. The more experienced participants resected more tissue in a more efficient manner but with increased blood loss. Further investigations are needed before the widespread application of transurethral prostate resection simulators for training, certification and accreditation. PMID- 20850820 TI - Long-term results of sacral neuromodulation with the tined lead procedure. AB - PURPOSE: We present long-term followup data on the outcome of sacral neuromodulation using the tined lead procedure. MATERIALS AND METHODS: We conducted a single center study including all patients who received an implantable neurostimulator between 2002 and 2005 using the tined lead technique. Treatment efficacy was evaluated by comparing the data of a 3-day voiding diary filled out in May 2009 to the data before the onset of sacral neuromodulation treatment (baseline). Clinical success was defined as more than 50% improvement in at least 1 of the relevant voiding diary parameters. RESULTS: A total of 64 patients underwent implantation with an implantable neurostimulator using the tined lead procedure. Mean followup was 53 months (range 35 to 77). Five patients died of causes unrelated to sacral neuromodulation and they were not included in analysis. The implantable neurostimulator was removed from 7 patients and 3 stopped using the neurostimulator. Voiding diary analysis showed that 38 of 59 patients (64%) were successfully treated. There were 21 patients (33%) who underwent a surgical revision due to an adverse event and 1 (1.6%) who underwent lead revision because of suspected lead migration. CONCLUSIONS: Sacral neuromodulation with the tined lead procedure is a safe and effective treatment for patients with overactive bladder symptoms or urinary retention. PMID- 20850821 TI - Nonneurogenic voiding disorders in children and adolescents: clinical and videourodynamic findings in 4 specific conditions. AB - PURPOSE: We determined if there were any unique findings regarding specific clinical manifestations and videourodynamics among our patients with nonneurogenic voiding disorders. MATERIALS AND METHODS: A cohort of 237 normal children with lower urinary tract symptoms were evaluated by videourodynamics and uroflow/electromyogram, and divided into 4 groups based on the specific urodynamic findings 1) dysfunctional voiding (active electromyogram during voiding with or without detrusor overactivity), 2) idiopathic detrusor overactivity disorder (detrusor overactivity on urodynamics but quiet electromyogram during voiding), 3) detrusor underutilization disorder (willful infrequent but otherwise normal voiding) and 4) primary bladder neck dysfunction. Association of lower urinary tract symptoms, urinary tract infection, vesicoureteral reflux and abnormal urodynamic parameters within each condition was compared. RESULTS: The only strong correlation between a particular symptom and a specific condition was between hesitancy and primary bladder neck dysfunction. Urgency was reported to some degree with all 4 conditions. The most common abnormal urodynamic finding was detrusor overactivity, which was seen in 91% of patients with dysfunctional voiding. The highest detrusor pressures were seen in dysfunctional voiding during voiding and in idiopathic detrusor overactivity disorder during detrusor overactivity. Vesicoureteral reflux was seen in a third of children with dysfunctional voiding or idiopathic detrusor overactivity disorder, in all 8 boys with a history of urinary tract infection and in 51% of patients with febrile or recurrent urinary tract infections with lower urinary tract symptoms when not infected. Bilateral vesicoureteral reflux and bowel dysfunction were most common in dysfunctional voiding. CONCLUSIONS: On objective urodynamic assessment pediatric nonneurogenic voiding dysfunction can essentially be divided into 4 specific conditions. These conditions have distinct urodynamic features that distinguish them from each other, as opposed to their clinical features (particularly lower urinary tract symptoms), which frequently overlap and are not as defining as they are often presumed to be. PMID- 20850822 TI - Laparoendoscopic single site live donor nephrectomy: initial experience. AB - PURPOSE: We present our initial experience in 40 patients undergoing laparoendoscopic single site donor nephrectomy. MATERIALS AND METHODS: We prospectively collected data on 40 consecutive patients. A single access GelPOINTTM device was inserted into the abdomen through a 4 to 5 cm periumbilical incision. We used a bariatric camera with a right angle attachment for the light cord to maximize triangulation. Parameters analyzed included warm ischemia time, operative time, estimated blood loss, visual analog pain score, time to recipient creatinine less than 3 mg/dl, and recipient creatinine at discharge home, and 3 and 6 months. RESULTS: A total of 38 left and 2 right donor nephrectomies were performed. Complete laparoendoscopic single site donor nephrectomy was successful in 38 cases. One left and 1 right case were converted to a hand assisted approach. Average +/- SD body mass index was 26.1 +/- 5.2 kg/m(2). Mean operative time to allograft extraction was 93.5 +/- 27.5 minutes and mean total operative time was 166.7 +/- 33.8 minutes. Average estimated blood loss was 106.7 +/- 93.5 cc. Mean warm ischemia time was 3.96 +/- 0.72 minutes. Mean hospital stay was 1.77 +/- 0.43 days and median time to recipient creatinine less than 3.0 mg/dl was 54.2 +/- 110.3 hours. Mean recipient creatinine at discharge home, and at 3 and 6 months was 1.48 +/- 0.67, 1.29 +/- 0.38 and 1.19 +/- 0.34 mg/dl, respectively. Complications included hyponatremia in 1 patient, wound infection in 1, and a grade III laceration in an allograft that was sustained during extraction. CONCLUSIONS: Our initial experience with laparoendoscopic single site donor nephrectomy is encouraging. This approach to kidney donation without an extra-umbilical incision could become particularly relevant to minimize morbidity in young, healthy organ donors. PMID- 20850823 TI - Editorial comment. PMID- 20850825 TI - Management strategies for Mayer-Rokitansky-Kuster-Hauser related vaginal agenesis: a cost-effectiveness analysis. AB - PURPOSE: The optimal method for neovagina creation in patients with vaginal agenesis is controversial. Progressive perineal dilation is a minimally invasive method with high success rates. However, the economic merits of progressive perineal dilation compared to surgical vaginoplasty are unknown. MATERIALS AND METHODS: We performed a Markov based cost-effectiveness analysis of 3 management strategies for vaginal agenesis-progressive perineal dilation with and without subsequent vaginoplasty, and up-front vaginoplasty. Cost data were drawn from the Pediatric Health Information System database (2004 to 2009) for inpatient procedures and from governmental cost data (2009) for outpatient procedures and clinical followup. Other model parameters were derived from a systematic literature review and comparison with other congenital and acquired pediatric and/or adolescent gynecologic conditions. Bounded and probabilistic sensitivity analyses were used to assess model stability. RESULTS: Including all procedures, equipment and physician visits, progressive perineal dilation had a mean cost of $796, while vaginoplasty cost $18,520. Up-front vaginoplasty was strongly dominated at any age, ie was more expensive but no more effective than other options. In cases of progressive perineal dilation failure the incremental cost effectiveness ratio of progressive perineal dilation with subsequent vaginoplasty was $1,564 per quality adjusted life-year. Only the utility weights of life after treatment impacted model outcomes, while frequency of followup and probability of treatment success did not. CONCLUSIONS: Initial progressive perineal dilation followed by vaginoplasty in cases of dilation failure is the most cost-effective management strategy for vaginal agenesis. Initial vaginoplasty was less cost effective than initial progressive perineal dilation in 99.99% of simulations. PMID- 20850826 TI - Editorial comment. PMID- 20850827 TI - Long-term results of a staged approach: continent urinary diversion in preparation for renal transplantation. AB - PURPOSE: We provide the long-term results of renal transplantation into continent urinary intestinal reservoirs as a planned 2-stage procedure. MATERIALS AND METHODS: Between November 1990 and January 2009, 18 patients underwent cadaveric or living related renal transplantation into continent urinary reservoirs (continent cutaneous diversion 16, orthotopic substitution 2). All patients were prospectively followed. RESULTS: Of these patients 15 are currently free of dialysis. At a mean followup of 89.2 months (range 2 to 188) 13 patients had a serum creatinine ranging from 0.6 to 3.1 mg/dl (mean 1.49) after the first transplantation. Two patients underwent a second transplantation 12 and 122 months after loss of the transplant for renal vein thrombosis and chronic allograft dysfunction, respectively. Two additional patients had to resume hemodialysis 62 and 109 months after renal transplantation. The second transplantation was delayed mainly due to compliance problems. One patient died of fulminant septicemia after laparotomy elsewhere for bowel obstruction with normal renal function before that episode. The continence mechanism needed correction in 3 patients, and 2 further revisions were required for ureteral kinking and lymphocele. The patients with orthotopic substitution (2) voided to completion and showed complete continence. All patients with cutaneous diversion were continent day and night with easy catheterization. CONCLUSIONS: This study is among the largest single series to date of renal transplantation into continent urinary diversions. Long-term followup confirms that this approach is a safe and socially well accepted treatment option in carefully selected patients. PMID- 20850828 TI - Holmium laser ablation versus photoselective vaporization of prostate less than 60 cc: long-term results of a randomized trial. AB - PURPOSE: We evaluated the long-term results and durability of photoselective vaporization and holmium laser ablation as surgical treatment of small to medium prostates in a prospective, randomized study in men with obstructive benign prostatic hyperplasia. MATERIALS AND METHODS: From March 2005 to April 2007 we randomly allocated 109 patients with a prostate gland of less than 60 cc to prostate photoselective vaporization (52) or holmium laser ablation (57) and evaluated them 1, 2 and 3 years postoperatively. Functional followup included measurement of maximum urinary flow rate, post-void residual urine, International Prostate Symptom Score, quality of life, International Index of Erectile Function and prostate specific antigen. RESULTS: Mean +/- SD preoperative prostate volume was 33.1 +/- 14.5 and 37.3 +/- 13.6 in the laser ablation and vaporization groups, respectively. All functional parameters improved significantly compared to baseline values in each group. There was no difference in International Prostate Symptom Score, quality of life, maximum urinary flow rate, post-void residual urine or percent of prostate specific antigen decrease between the 2 groups 1, 2 and 3 years postoperatively. At 3-year followup International Prostate Symptom Score had improved by 70.5%, quality of life had improved by 69.4%, maximum urinary flow rate had increased by 164% and post-void residual urine had decreased by 81% in the holmium laser ablation group. In the photoselective vaporization group International Prostate Symptom Score improved by 64.1%, quality of life improved by 65.5%, maximum urinary flow rate increased by 189% and post-void residual urine decreased by 79.5%. The overall re-treatment rate was 15.8% for holmium laser ablation vs 19.3% for photoselective vaporization. CONCLUSIONS: Prostate photoselective vaporization and holmium laser ablation are effective surgical treatments for benign prostatic hyperplasia. Postoperative functional improvements were significant and durable, and equivalent in the 2 groups. The 2 techniques have a similar complication rate. PMID- 20850829 TI - Baseline erectile function alters the cavernous nerve quantity and distribution around the prostate. AB - PURPOSE: We clarified the distribution of neuronal nitric oxide synthase positive nerve fibers around the prostate and factors contributing to fiber quantity. MATERIALS AND METHODS: We investigated 46 hemispheres of 23 nonnerve sparing radical prostatectomy specimens from patients with available preoperative International Index of Erectile Function and maximum penile circumferential change data. We performed immunohistochemical staining with neuronal nitric oxide synthase antibody, and divided the prostatic hemisphere into 6 zones to assess the distribution of neuronal nitric oxide synthase positive nerve fibers at the apex, midportion and base of the prostate. Multivariate analysis of the quantity of overall neuronal nitric oxide synthase positive nerve fibers used the variables of specimen weight, patient age, body mass index, International Index of Erectile Function and maximum penile circumferential change. A maximum penile circumferential change of 20 mm or less was considered objective erectile dysfunction. RESULTS: Median patient age was 68 years (range 57 to 74). Median International Index of Erectile Function-erectile function domain score was 12 (range 0 to 24) and median maximum penile circumferential change was 25.0 mm (range 2.70 to 38.3). Of the neuronal nitric oxide synthase positive nerve fibers 65% were distributed in a 3 to 5 o'clock sextant (p <0.001). Logistic regression analysis revealed that maximum penile circumferential change was the single significant variable (p = 0.019). The fiber count was greater in the objective erectile dysfunction group (median 1,500, range 382 to 2,760) than in the nonerectile dysfunction group (median 649, range 156 to 2,916) (p = 0.009). The fiber count was significantly different between the 2 groups in the 3 to 6 o'clock area, especially at the apex. CONCLUSIONS: Baseline erectile function greatly impacts cavernous nerve quantity and distribution. Cavernous nerve preservation in the neurovascular bundle, especially at the apex, is still essential for patients with erectile dysfunction. PMID- 20850830 TI - Impact of a laparoscopic renal surgery mini-fellowship program on postgraduate urologist practice patterns at 3-year followup. AB - PURPOSE: To assist practicing urologists incorporate laparoscopic renal surgery into their practice we established a 5-day mini-fellowship program with a mentor, preceptor and a potential proctor at our institution. We report the impact of our mini-fellowship program at 3-year followup. MATERIALS AND METHODS: A total of 106 urologists underwent laparoscopic ablative (44) or laparoscopic reconstructive (62) renal surgery training. The 1:2 teacher-to-attendee experience included tutorial sessions, hands-on inanimate and animate skills training, and clinical case observations. Participants were asked to complete a detailed questionnaire on laparoscopic practice patterns 1, 2 and 3 years after the mini-fellowship. RESULTS: The questionnaire response rate at 1 to 3 years was 77%, 65% and 68%, respectively. Of responders 72%, 71% and 71% performed laparoscopic renal surgery at 1 to 3 years, respectively. Of the 106 participants 32 (39%) had previous laparoscopic experience, including 78% who responded to the questionnaire at 3 years. Of those surgeons there was an increase in the practice of laparoscopic radical nephrectomy (88% vs 72%), nephroureterectomy (56% vs 13%), pyeloplasty (40% vs 6%) and partial nephrectomy (32% vs 6%) at 3 years. Of the 106 participants 74 (70%) were laparoscopy naive, including 48 (65%) who responded to the questionnaire at 3 years. The take rate in this group was 76%, 52%, 34% and 23% for laparoscopic radical nephrectomy, nephroureterectomy, pyeloplasty and partial nephrectomy, respectively. Of the participants 90% indicated that they would recommend this training to a colleague. CONCLUSIONS: An intensive 5-day laparoscopic ablative and reconstructive renal surgery course enabled postgraduate urologists to effectively introduce and expand the volume and breadth of their laparoscopic renal surgery practice. PMID- 20850831 TI - Randomized, placebo controlled study of electrical stimulation with pelvic floor muscle training for severe urinary incontinence after radical prostatectomy. AB - PURPOSE: We evaluated electrical stimulation combined with pelvic floor muscle training for urinary incontinence after radical prostatectomy in a randomized controlled study. MATERIALS AND METHODS: A total of 56 men with severe urinary incontinence (more than 200 gm daily), mean +/- SD age 66.6 +/- 6.2 years, were randomized to an active treatment group (26) or a sham group (30). All patients performed pelvic floor muscle training preoperatively and continued throughout the study. For active stimulation 50 Hz square waves of 300 MUs pulse duration and a 5 seconds on, 5 seconds off duty cycle were applied for 15 minutes twice daily with an anal electrode. Sham stimulation was limited to 3 mA with a 2 seconds on, 13 seconds off duty cycle. RESULTS: In the active group 8 (36%), 14 (63%), 18 (81%) and 19 (86%) patients were continent (22) vs 1 (4%), 4 (16%), 11 (44%) and 17 (86%) in the sham group (25) (leakage less than 8 gm daily) after 1, 3, 6 and 12 months, respectively. There was a significant difference in the number of continent patients between the groups at 1, 3 and 6 months (p = 0.0161, p = 0.0021 and p = 0.0156, respectively). The time to achieve continence was significantly shorter in the active group (2.71 +/- 2.6 months) than in the sham group (6.82 +/- 3.9 months, p = 0.0006). Changes in the amount of leakage, the International Consultation on Incontinence Questionnaire-Short Form score and the King's Health Questionnaire score were significantly larger in the active group at 1 month but there was no difference at 12 months. CONCLUSIONS: Electrical stimulation resulted in earlier recovery of continence in patients with urinary incontinence after radical prostatectomy. PMID- 20850832 TI - Estimating the number of vasectomies performed annually in the United States: data from the National Survey of Family Growth. AB - PURPOSE: While hospital discharge and ambulatory surgery registries provide accurate estimates of female sterilization procedures, current estimates of male sterilization rates are lacking since these procedures are done in many settings. Population based data are used to estimate annual sterilization numbers. MATERIALS AND METHODS: We analyzed data on 4,928 men and 7,643 women from the 2002 National Survey of Family Growth. We determined the year of vasectomy in men and the year of tubal ligation in women who reported a history of surgical sterilization. After accounting for the complex survey design of the National Survey of Family Growth we calculated the estimated number of individuals who underwent surgical sterilization in the United States. RESULTS: A total of 141 men reported vasectomy, representing an overall 6% prevalence in National Survey of Family Growth survey population, while 1,173 women (16%) reported tubal ligation. Using National Survey of Family Growth data an estimated 175,000 to 354,000 vasectomies were done yearly from 1998 to 2002. In the same period the National Survey of Family Growth estimated that 546,000 to 789,000 tubal ligations were done annually in the United States. This compares closely to the 596,000 to 687,000 tubal ligations calculated using ambulatory surgery and hospital discharge data from a similar period. CONCLUSIONS: The estimated annual number of tubal ligations from the National Survey of Family Growth is in line with the current literature using hospital discharge and ambulatory surgery registries, suggesting the accuracy of the method of estimating surgical sterilization numbers. This suggests that the National Survey of Family Growth may be used to provide an estimate of vasectomy use in the United States. PMID- 20850833 TI - Percutaneous tibial nerve stimulation effects on detrusor overactivity incontinence are not due to a placebo effect: a randomized, double-blind, placebo controlled trial. AB - PURPOSE: This is a prospective, double-blind, placebo controlled study, based on an original placebo technique, performed to evaluate the efficacy of percutaneous tibial nerve stimulation in female patients with detrusor overactivity incontinence. MATERIALS AND METHODS: A total of 35 female patients presenting with detrusor overactivity incontinence that did not respond to antimuscarinic therapy were randomly assigned to percutaneous tibial nerve stimulation or to a control group. The percutaneous tibial nerve stimulation group (18 patients) was treated with 12 percutaneous tibial nerve stimulation sessions. The control group (17 patients) received an original placebo treatment using a 34 gauge needle placed in the medial part of the gastrocnemius muscle. The sessions lasted for 30 minutes and were performed 3 times weekly as percutaneous tibial nerve stimulation sessions. All patients were evaluated with bladder diaries as well as quality of life scores before and after treatment. Patients showing a reduction in urge incontinence episodes greater than 50% were considered responders. RESULTS: Some patients (1 in the percutaneous tibial nerve stimulation group and 2 in the placebo group) did not complete the study for reasons not related to the technique. Of 17 patients in the percutaneous tibial nerve stimulation group 12 (71%) and of 15 in placebo group 0 were considered responders according to the previously reported definition (p <0.001). Improvement in the number of incontinence episodes, number of voids, voided volume and incontinence quality of life score were statistically significant in the percutaneous tibial nerve stimulation group but not in the placebo group. CONCLUSIONS: Percutaneous tibial nerve stimulation can be considered an effective treatment for detrusor overactivity incontinence with 71% of patients considered responders, while none of those treated with placebo was considered a responder. The relevance of a placebo effect seems to be negligible in this patient population. PMID- 20850834 TI - Semen quality remains stable during the chronic phase of spinal cord injury: a longitudinal study. AB - PURPOSE: In a longitudinal study we examined changes in semen quality with time during the chronic phase of spinal cord injury. MATERIALS AND METHODS: Included in this study were 87 men with spinal cord injury who underwent 2 or more semen retrieval procedures with a minimum of 3 years between the first and last procedures. Patients were selected from our database of 500 with spinal cord injury who were volunteers enrolled in the Male Fertility Research Program of the Miami Project to Cure Paralysis from January 1, 1991 through April 31, 2009. Semen was collected by masturbation, penile vibratory stimulation or electroejaculation. Semen analysis was done according to WHO criteria. We used a statistical generalized linear mixed model to analyze changes in sperm concentration, total sperm count, total motile sperm count and sperm motility with time. RESULTS: Mean patient age was 30.1 years (range 16 to 48) and mean time after injury at the initial sperm retrieval procedure was 7.1 years (range 1 to 26). Sperm concentration decreased slightly with time but all other parameters were unchanged, including total sperm count, indicating a stable, null pattern in measures with time. CONCLUSIONS: Semen quality does not show clinically significant progressive changes during years after injury in men with spinal cord injury. This information is relevant for urologists who counsel these patients on family planning. Also, routine sperm freezing for fertility preservation is not indicated in this patient population. PMID- 20850835 TI - Functional brainstem changes in response to bladder function alteration elicited by surgical reduction in bladder capacity: a functional magnetic resonance imaging study. AB - PURPOSE: Our previous results revealed a positive correlation between bladder dysfunction and cortical arousals in children with enuresis. This finding implied an interrelationship between bladder dysfunction and brainstem dysfunction. Thus, we used an animal model to characterize brainstem functional changes in response to altered bladder function. MATERIALS AND METHODS: Adult male New Zealand rabbits weighing 3.0 to 3.5 kg underwent surgical bladder volume reduction (12) or sham operation (12). We performed conventional fill cystometry and brainstem functional magnetic resonance imaging in each group 4 weeks postoperatively. During scanning bladder stimulation was provided by bladder filling up to 70% of maximum capacity. We then compared brainstem activation area(s). RESULTS: Results revealed voiding dysfunction in animals with altered bladder function. Bladder function was markedly altered in the reduced bladder volume vs the sham operated group, mainly as significantly increased maximum voiding detrusor pressure (mean +/- 1 SD 24.4 +/- 7.0 vs 0.16.5 +/- 7.2 cm water, p <0.05) and markedly decreased cystometric bladder volume (mean 35.3 +/- 8.2 vs 71.6 +/- 12.9 ml, p <0.05). Functional magnetic resonance imaging results revealed activation of 2 brainstem regions, including in 1) the ventrolateral periaqueductal gray and 2) the dorsolateral pons, in response to bladder distention. Activation in the ventrolateral periaqueductal gray was significantly decreased in the reduced bladder vs the sham operated group with a corresponding decrease in signal size (25% vs 83.3%, signal size 0.7 +/- 1.4 vs 3.3 +/- 2.1 mm(2)). There was no significant difference in activation of the dorsolateral pons between the groups (83.3% vs 91.7%, signal size 3.7 +/- 2.4 vs 0.4.7 +/- 3.0 mm(2)). CONCLUSIONS: Functional derangement in brainstem micturition centers can be evoked by bladder dysfunction. In response to bladder dysfunction the ventrolateral periaqueductal gray shows deactivation during bladder distention, suggesting that it has an important role in bladder dysfunction biofeedback. PMID- 20850836 TI - Patient centered outcomes in prostate cancer treatment: predictors of satisfaction up to 2 years after open radical retropubic prostatectomy. AB - PURPOSE: Few groups have examined satisfaction after prostate cancer treatment. We determined 1) predictors of satisfaction between 3 months and 2 years after open radical retropubic prostatectomy, and 2) whether these factors are time dependent. MATERIALS AND METHODS: This prospective cohort study included 1,542 men who underwent radical retropubic prostatectomy from October 2000 to July 2008. The primary outcome was satisfaction self-assessed at 3, 6, 12 and 24 months. We used multivariate logistic regression and repeated measures analysis to determine predictors of satisfaction, adjusting for demographic and clinical characteristics. RESULTS: Median followup was 24 months. About 93% of the men were satisfied. On multivariate analysis men were significantly less satisfied at 3 months when the urinary catheter was indwelling for 3 weeks or greater (OR 0.23, 95% CI 0.10-0.54), or they required intervention for anastomotic stricture (OR 0.23, 95% CI 0.11-0.49) or experienced 4-point or greater worsening in American Urological Association symptom score (OR 0.26, 95% CI 0.13-0.49). At 6 months worsening urinary function (OR 0.34, 95% CI 0.13-0.88) and biochemical failure (OR 0.15, 95% CI 0.05-0.43) were significantly associated with satisfaction. Worsening sexual function became significant at 12 and 24 months. These associations were confirmed on repeated measures analysis. CONCLUSIONS: Most men were satisfied after radical retropubic prostatectomy. Satisfaction determinants showed a nonsignificant trend toward time dependence. Postoperative factors, such as the duration of indwelling Foley catheterization, were associated with short-term satisfaction while sexual and urinary function, and biochemical failure were associated with long-term satisfaction. Based on high satisfaction rates open radical retropubic prostatectomy is an excellent treatment for prostate cancer. PMID- 20850837 TI - The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis. AB - PURPOSE: We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis. MATERIALS AND METHODS: We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years. RESULTS: We divided (CCTTT)n alleles into short-10 or fewer, intermediate-11 or 12 and long-13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011). CONCLUSIONS: Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels. PMID- 20850838 TI - Temporal morphological and functional impact of complete urinary diversion on the bladder: a model of bladder disuse in rats. AB - PURPOSE: Urinary diversion has been used as a surgical option for some bladder diseases. We developed a urinary diversion model in the rat and examined the effects of urinary diversion on the bladder. MATERIALS AND METHODS: We distributed female Sprague-Dawley(r) rats into age matched control, sham urinary diversion and urinary diversion groups. Each group was subsequently evaluated 1 or 8 weeks after urinary diversion or sham operation. Diversion was done by surgical disconnection of the ureters from the bladder and implantation to the uterine cervix. Conscious cystometry was examined. Bladders were harvested for histological examination and quantification of smooth muscle, urothelium and collagen. Vaginal histology was assessed. Bladder muscarinic and purinergic receptor expression was examined. RESULTS: All rats survived the urinary diversion procedure. Bladder weight decreased in the diversion group. Cystometry showed decreased intercontractile interval and voided volume in the urinary diversion group compared to those in the control and sham operated groups. Compliance was decreased in diverted rats. Smooth muscle and urothelium were decreased as a percent of total bladder cross-sectional area. Collagen increased in 1 and 8-week diverted rats vs controls. Histological examination of the vaginal wall revealed mild swelling in 2 rats. Urinary diversion caused decreased muscarinic 3 and ligand gated purinergic 1 receptor expression but no change in muscarinic 2 or ligand gated purinergic 2 receptors. CONCLUSIONS: Creating a urinary diversion model by ureterovaginostomy in the rat is feasible. Urinary diversion causes distinct functional and morphometric bladder alterations. PMID- 20850839 TI - Prostatic involution after intraprostatic injection of cobra toxin. AB - PURPOSE: We evaluated the comparative effects of intraprostatic injection of cobra cardiotoxin D and botulinum toxin type A on prostate structure in the rat model. MATERIALS AND METHODS: A total of 18 Sprague-Dawley(r) rats weighing 500 to 600 gm received a single 0.1 ml injection of saline (6), botulinum toxin type A (6) or the cardiotoxin D (6) component of cobra (Naja naja atra) toxin in the right and left ventral lobes of the prostate. At 14 days the rats were sacrificed. The prostate glands were harvested, weighed and processed for immunohistochemical and morphological studies. RESULTS: Prostate glands injected with cardiotoxin D showed significantly decreased weight compared to that of prostates injected with botulinum toxin type A and the saline control. Prostatic atrophy in the glandular component with flattening of the epithelial lining was seen histologically in rats that received botulinum toxin and cardiotoxin D. Each group injected with cardiotoxin D and botulinum toxin showed a significant increase in the number of apoptotic cells compared with controls while only the botulinum toxin group showed a significant increase in the number of proliferating cells. Only rats injected with botulinum toxin had body weight loss. CONCLUSIONS: Our study shows that intraprostatic injection of cobra cardiotoxin D induces prostatic atrophy and leads to a decrease in prostatic weight greater than that of intraprostatic injection of botulinum toxin type A. No systemic effects, such as decreased body weight, were noted after cardiotoxin D injection. Further studies are warranted but the statistically significant decrease in the number of proliferating cells implies a prolonged effect of cardiotoxin D. PMID- 20850840 TI - Expression of estrogen related proteins in hormone refractory prostate cancer: association with tumor progression. AB - PURPOSE: Despite increasing evidence that estrogen signaling has a key role in prostate cancer development and progression, few studies have focused on the estrogen pathway in the transition from hormone sensitive to hormone refractory tumors. We investigated the expression of proteins related to androgen and estrogen metabolism in paired prostate cancer samples collected before androgen deprivation therapy and after hormonal relapse. MATERIALS AND METHODS: The study included 55 patients treated for prostate cancer only with androgen deprivation therapy and in whom tissue was available before treatment induction and after recurrence. Immunohistochemistry was performed using tissue microarray with antibodies directed against androgen receptor, phosphorylated androgen receptor, estrogen receptor alpha, estrogen receptor beta, 5alpha-reductase 1 and 2, aromatase, BCAR1 and the proliferation marker Ki67. RESULTS: Compared to hormone sensitive samples, tissues collected after hormonal relapse were characterized by increased expression of Ki67, androgen receptor, phosphorylated androgen receptor (p <0.001) and BCAR (p = 0.03), and by lower staining for 5alpha-reductase 2 (p = 0.002), estrogen receptor beta (p = 0.016) and aromatase (p <0.001). Shorter time to hormonal relapse was associated with high expression of aromatase and BCAR1 on diagnostic biopsy, together with low staining for estrogen receptor alpha in stromal cells. Overall survival was significantly shorter when tissues collected after relapse showed a high proliferation index and low estrogen receptor alpha expression. CONCLUSIONS: Results revealed dysregulation of proteins involved in androgen pathways, and in estrogen synthesis and signaling during the development of hormone refractory prostate cancer. PMID- 20850841 TI - Pharmacological inhibition of cyclin dependent kinases causes p53 dependent apoptosis in renal cell carcinoma. AB - PURPOSE: We evaluated the effect of roscovitine (Sigma-Aldrich(r)), a pharmacological inhibitor of cyclin dependent kinase, on renal cell carcinoma cell lines in vitro. MATERIALS AND METHODS: We exposed several renal cell carcinoma cell lines to roscovitine and examined apoptotic signaling pathways using immunoblotting and immunohistochemistry. RESULTS: As expected, roscovitine caused dose and time dependent inhibition of cyclin dependent kinase 2 autophosphorylation, and of cyclin dependent kinase mediated Pol II phosphorylation in the ACHN (p53-wt) and 786-O (p53 inactive) renal cell carcinoma cell lines (ATCC(r)). Roscovitine also induced apoptosis in each cell line within a narrow concentration range (about 10 MUg/ml). Apoptosis induction was more efficient in ACHN than in 786-O cells and at least partly due to p53 activity. In ACHN cells roscovitine induced apoptosis was associated with p21 induction, and decreased Akt1, XIAP and phospho-Rb expression. These changes also depended on p53 and were not present (p21) or showed a different dose pattern (Akt1, XIAP and phospho-Rb) in 786-O cells. Partial restoration of roscovitine induced apoptosis in 786-O cells by the Mdm-2 inhibitor nutlin-3 (Sigma-Aldrich) suggests that the inactivating mutation of VHL in these cells and its destabilizing effect on p53 are responsible for the decreased sensitivity to apoptosis. CONCLUSIONS: Our data extend previous studies documenting the pro apoptotic effect of roscovitine and to our knowledge show for the first time that this activity is restricted to a narrow dose range in renal cell carcinoma cells and partly depends on p53. Thus, roscovitine is a novel potential chemotherapy in a subset of patients with renal cell carcinoma if a narrow therapeutic window is used. These data also provide insight into the role of VHL mutation and p53 in the renal cell carcinoma response to therapeutic cyclin dependent kinase manipulation. PMID- 20850842 TI - Cardiac glycosides decrease prostate specific antigen expression by down regulation of prostate derived Ets factor. AB - PURPOSE: While cardiac glycosides are the mainstay of congestive heart failure treatment, early studies showed that pharmacological doses of cardiac glycosides inhibited prostate cancer cell line proliferation. We evaluated the mechanisms of cardiac glycosides, including digoxin, digitoxin and ouabain (Sigma(r)), on prostate specific antigen gene expression in vitro. MATERIALS AND METHODS: We cultured LNCaP cells (ATCC(r)) and used them to determine the effect of cardiac glycosides on prostate derived Ets factor and prostate specific antigen expression. We determined prostate derived Ets factor and prostate specific antigen expression by reverse transcription-polymerase chain reaction, immunoblot, transient gene expression assay or enzyme-linked immunosorbent assay. RESULTS: Noncytotoxic doses (100 nM) of cardiac glycosides for 24 hours inhibited prostate specific antigen secretion by LNCaP cells. Reverse transcriptase polymerase chain reaction and immunoblot revealed that cardiac glycosides significantly down-regulated prostate specific antigen and prostate derived Ets factor expression. Transient gene expression assays showed that prostate derived Ets factor over expression enhanced prostate specific antigen promoter activity. However, prostate specific antigen and prostate derived Ets factor gene promoter activity was attenuated when LNCaP cells were treated with 100 nM cardiac glycosides. When LNCaP cells were treated with 25 nM digitoxin or digoxin for 60 hours, prostate specific antigen secretion decreased by 30%. CONCLUSIONS: Results suggest that cardiac glycoside inhibition of prostate specific antigen gene expression may be caused by the down-regulation of prostate derived Ets factor gene expression. When cells were chronically treated with digoxin or digitoxin at concentrations close to or at therapeutic plasma levels, prostate specific antigen secretion decreased. This phenomenon merits further study to determine whether it occurs in men on cardiac glycoside therapy. PMID- 20850843 TI - Comparison of responsiveness of validated outcome measures after surgery for stress urinary incontinence. AB - PURPOSE: We compared the responsiveness of several validated incontinence, pelvic floor and quality of life outcome measures in women undergoing surgery for stress urinary incontinence to assist investigators in selecting appropriate outcomes in future trials of stress urinary incontinence therapy. MATERIALS AND METHODS: This is an ancillary analysis of data from a multicenter, randomized trial comparing tension-free vaginal tape and transobturator slings. All patients were asked to complete outcome measures at baseline and again 1 year postoperatively, including Incontinence Severity Index, Pelvic Floor Distress Inventory-Short Form 20, Pelvic Floor Impact Questionnaire-Short Form 7, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire 12, SF-12(r) and a 3-day bladder diary. They also completed the Patient Global Index of Improvement at 1 year. We assessed the responsiveness of each outcome measure by calculating a standardized response mean and performing receiver operator characteristics curve analysis. RESULTS: Incontinence Severity Index, Pelvic Floor Distress Inventory-Short Form 20, Urinary Distress Inventory-Short Form, Pelvic Floor Impact Questionnaire Short Form 7 and Urinary Impact Questionnaire-Short Form 7 showed excellent responsiveness (standardized response mean >=1.0). Using receiver operator characteristics curve data the bladder diary had the greatest ability to discriminate patients who did vs did not improve (area under the curve 0.97). Incontinence Severity Index, Pelvic Floor Distress Inventory-Short Form 20 and Urinary Distress Inventory-Short Form also showed strong responsiveness according to these data (area under the curve greater than 0.7). CONCLUSIONS: In this study of women undergoing mid urethral sling surgery for stress urinary incontinence the greatest responsiveness was noted on Incontinence Severity Index, Pelvic Floor Distress Inventory-Short Form 20, Urinary Distress Inventory-Short Form and bladder diary. Thus, they may be preferable as primary outcome measures in trials of stress urinary incontinence treatment. PMID- 20850844 TI - Identification of source of a marine oil-spill using geochemical and chemometric techniques. AB - The current work aimed to identify the source of an oil spill off the coast of Maranhao, Brazil, in September 2005 and effect a preliminary geochemical survey of this environment. A combination of bulk analytical parameters, such as carbon isotope (delta(13)C) and Ni/V ratios, and conventional fingerprinting methods (High Resolution Gas Chromatography and Mass Spectrometry) were used. The use of bulk methods greatly speeded source identification for this relatively unaltered spill: identification of the likely source was possible at this stage. Subsequent fingerprinting of biomarker distributions supported source assignment, pointing to a non-Brazilian oil. Steranes proved the most useful biomarkers for sample correlation in this work. Distribution patterns of environmentally more resilient compound types, such as certain aromatic structures, proved inconclusive for correlation, probably in view of their presence in the background. PMID- 20850845 TI - Bioconcentration of selected endocrine disrupting compounds in the Mediterranean mussel, Mytilus galloprovincialis. AB - The occurrence of three endocrine disrupting compounds, 4-n-nonylphenol, triclosan and bisphenol A, was investigated in different bivalves originating from the Aegean Sea (Greece). The bioconcentration potential of these compounds was studied using the Mediterranean mussel (Mytilus galloprovincialis). Tissue samples were extracted by sonication. Analysis was performed by gas chromatography-mass spectrometry. According to the field survey results, the average concentrations of 4-n-nonylphenol, triclosan and bisphenol A, were 158, 461 and 404 ng g(-1) (dry weight), respectively. During 28 days of exposure at 300 ng L(-1), the tissue concentrations of compounds were constantly increased. Steady state was not observed up to the end of the experiment. Kinetic bioconcentration factors varied from 1.7 (4-n-nonylphenol and triclosan) to 4.5 L g(-1) (bisphenol A). Following exposure, mussels were relocated to clean water for 28 days. This experiment revealed that depuration rates for all of the target compounds were lower than uptake rates. The biological half-lives of each compound ranged between 12 days (triclosan) and 26 days (bisphenol A). PMID- 20850846 TI - Association of the clusterin gene polymorphisms with type 2 diabetes mellitus. AB - The association of the clusterin (CLU) gene polymorphism (single nucleotide polymorphisms [SNPs] 1-4: rs1532278, rs1532277, rs2279590, and rs2279591, respectively) with type 2 diabetes mellitus was examined using a population of the Funagata study (n [male-female] = 1631 [741:884]; age, 62.0 +/- 12.1 years), a Japanese community-based study. Single nucleotide polymorphisms 1 to 3 were significantly associated with hemoglobin A(1c) levels (P = .0154, .0021, and .0006, respectively) and diabetes (.0310, .0170, and .0021, respectively). A case control association study of SNP 3 with diabetes by multiple logistic regression analysis showed a significant association of genotype AA (the at-risk genotype) with an odds ratio (OR) of 2.33 (P = .0039) independently of age and sex. The association was marginally validated by a study with another Japanese community based sample, the Takahata Study (n [male-female] = 2.948 [1333:1615]; age, 63.0 +/- 10.2 years) (OR, 1.59; P = .0595; chi(2)P = .0264). When the 2 samples were combined, the association became more significant (OR, 1.75; P = .0025). In subjects with the non-at-risk genotypes, the insulin resistance index- homeostasis model assessment of insulin resistance (HOMA-R)--increased significantly (P < .0001) and the insulin secretion index--HOMA-beta--appeared to decrease (P = .1803 and .0097, respectively, for the genotypes AG and GG) as the glucose tolerance progressed toward diabetes (normal glucose tolerance to glucose intolerance to diabetes). However, in subjects with the at-risk genotype, HOMA-R and HOMA-beta showed a significant increase already in the subjects with normal glucose tolerance (P = .0239 and .0305, respectively); and as the glucose tolerance progressed toward diabetes, HOMA-R stayed approximately the same, whereas HOMA-beta decreased significantly (P = .0332). The CLU gene was associated with diabetes, probably through an increase in insulin resistance primarily and through an impairment of insulin secretion secondarily. PMID- 20850847 TI - Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans. AB - In diabetes mellitus and sepsis, low erythrocyte glutathione (GSH) concentrations are found. Whether this is caused by lowered GSH production has not been clarified. To obtain insight in the relationship between erythrocyte GSH concentrations and GSH production, GSH kinetics were measured in healthy male volunteers during 4 different clamps (low-dose or medium-dose insulin [100 or 400 pmol/L] and euglycemia or hyperglycemia [5 or 12 mmol/L]) in a control setting (n = 6; all 4 clamps in the same subject) or after systemic administration of lipopolysaccharide (to mimic sepsis) (4 groups of n = 6; each clamp in a different subject). Hyperinsulinemia decreased erythrocyte GSH concentration (P = .042), but did not affect fractional synthetic rate (FSR) of GSH. Hyperglycemia did not affect erythrocyte GSH concentration, but decreased FSR of GSH (P = .025). Lipopolysaccharide decreased erythrocyte GSH concentration (P < .001), but increased FSR of erythrocyte GSH (P = .035). Depending on the metabolic circumstances, we found either stable GSH concentrations with lower production rates or decreased levels with either no change or an increase in production rate. Based upon these data, it seems inappropriate to infer conclusions about changes in synthesis rate of GSH from changes in its concentration. PMID- 20850848 TI - Preliminary evaluation of the Moyo chart-a novel, low-cost, weight-for-height slide chart for the improved assessment of nutritional status in children. AB - The Moyo chart is a novel weight-for-height slide chart. We explore the hypothesis that it improves accuracy, speed and ease of nutritional assessment compared with traditional lookup tables. In a crossover randomised controlled trial, 61 medical students in Ethiopia diagnosed hypothetical cases of severe acute malnutrition, moderate acute malnutrition and normal nutrition in children. Mean accuracy of nutritional status diagnosis was 83.2% using the Moyo chart and 76.1% using lookup tables (P = 0.011). There was a trend towards a reduced time per correct diagnosis using the Moyo chart and 78% of participants preferred using it. These preliminary results suggest that the Moyo chart may aid frontline health workers classifying child nutritional status. PMID- 20850849 TI - Evaluation of antibacterial soap in the management of lymphoedema in Leogane, Haiti. AB - In areas endemic for lymphatic filariasis, progression of lymphoedema is associated with recurrent bacterial acute dermatolymphangioadenitis (ADLA). The role of antibacterial soap in preventing ADLA is unknown. In a randomized double blinded clinical trial in Leogane, Haiti, lymphoedema patients washed affected legs with antibacterial (n = 97) or plain soap (n = 100). Reported ADLA incidence (by recall) before the study was 1.1 episodes per person-year, compared to 0.40 assessed during the 12-month study. ADLA incidence was significantly associated with age, illiteracy and lymphoedema stage, but not with soap type. Washing with soap, regardless of its antibacterial content, can help decrease ADLA incidence. (ClinicalTrials.gov identifier number NCT00139100.). PMID- 20850850 TI - An amphotericin B-based drug for treating experimental Leishmania major infection. AB - There is an urgent need for a non-toxic and low-cost treatment for cutaneous leishmaniasis. We synthesised and tested in vivo an amphotericin B poly(methacrylic acid) drug (AmB-PMA) that had previously shown in-vitro activity against Leishmania major and L. donovani parasites. Efficacy was determined using L. major footpad infection in 30 non-healing BALB/c mice. Three subcutaneous injections of AmB-PMA at days 7, 14 and 21 post-infection resulted in a reduction of ~80% in lesion size by day 35 post-infection in 18 treated mice compared with six untreated controls, and complete healing of lesions by day 50 with no lesion relapse seen at day 80 post-infection in six treated mice. Healing was associated with decreased IL-10 (P=0.002) and increased IFN-gamma (P=0.005) in the footpad. PMID- 20850851 TI - Easy-to-make sump suction or drain system. PMID- 20850852 TI - Wrapping of the omental pedicle flap around esophagogastric anastomosis after esophagectomy for esophageal cancer. AB - BACKGROUND: Esophagogastrectomy for esophageal cancer is the standard surgical treatment as a curative measure or for palliation. Esophagogastric anastomotic leakage and stricture are common life-threatening postoperative complications (more so if the leakage occurs in the chest), and the success of the anastomosis created in the reconstruction of the resected esophagus can highly influence morbidity and mortality. METHODS: A prospective, randomized study was undertaken on 291 patients treated for carcinoma of the esophagus between January 2004 and December 2008. The study excluded 36 patients (12%) who were inoperable. Patients were assigned to 2 treatment groups that consisted of 128 patients in group A and 127 patients in group B according to a restricted, permuted block randomization plan. Patients in group A underwent an esophagogastrectomy with wrapping of the pedicle omental flap around the esophagogastric anastomosis. Group B patients underwent an esophagogastrectomy with only a stapled technique. RESULTS: Of all 255 patients who received an esophagogastric anastomosis, 226 (89%) were discharged from the hospital within 15 days of operation. There was no significant difference between these 2 groups in regard to the incidence of pulmonary complications, abdominal or thoracic infections, and days of hospital stay. Anastomotic leaks occurred in a single patient from group A (1%) and in 7 patients from group B (6%). In group A, 33 patients underwent transhiatal esophagogastrectomy and 95 had thoracic esophagogastrectomy, which resulted in an anastomotic leakage in 1 (3%) and 0 (0%) patients, respectively. In group B, 42 patients had transhiatal esophagogastrectomy and 85 had thoracic esophagogastrectomy, which resulted in anastomotic leakage in 5 (12%) and 2 (2%) patients, respectively. The leakage ratio of group B was significant greater than that of group A (P < .05). Two patients were excluded during the evaluation of the benign stricture due to hospital mortality. Anastomotic strictures were noted in 8 patients from group A (6%) and 20 patients from group B (16%), and the difference in the incidence of anastomotic strictures between these 2 groups was statistically significant (P < .05). CONCLUSION: Wrapping of the pedicle omental flap around the esophagogastric stapled anastomosis site decreases the incidence of anastomotic leakage and stricture rate after esophagectomy for esophageal cancer, thereby decreasing the morbidity and mortality of the procedure. PMID- 20850853 TI - Thyroid surgery with the new harmonic scalpel: a prospective randomized study. AB - BACKGROUND: Despite their safety and effectiveness in thyroid surgery, the previous harmonic scalpel instruments are considered large and cumbersome by several surgeons. An innovative technical improvement of the device has been made available since 2008. The objective of this study was to compare the results of total thyroidectomy using the new harmonic scalpel (FOCUS) with that with the previously available device (HARMONIC ACE). METHODS: A prospective randomized study of all total thyroidectomies between February and July 2008 was conducted. Patients (n = 90) were randomized to undergo total thyroidectomy with FOCUS (group A, n = 45) or HARMONIC ACE (group B, n = 45). RESULTS: No significant differences were identified between the 2 groups in terms of demographics, reoperative thyroid surgery, thyroid gland weight and diameter, pathologic diagnosis, preoperative and postoperative serum PTH and calcium levels, postoperative complications, duration of hospital stay, and final outcome. The mean operative time was less in group A than group B (63 +/- 7 min vs 76 +/- 8 min, P = .009). CONCLUSION: The new harmonic scalpel is a useful adjunct to the armamentarium of the thyroid surgeon. It is safe, effective, and hand friendly, offering great capabilities for delicate tissue grasping and dissection. Use of this device decreased operative time compared with the previously available instrument. PMID- 20850854 TI - Micropulsed diode laser therapy: evolution and clinical applications. AB - Many clinical trials have demonstrated the clinical efficacy of laser photocoagulation in the treatment of retinal vascular diseases, including diabetic retinopathy. There is, however, collateral iatrogenic retinal damage and functional loss after conventional laser treatment. Such side effects may occur even when the treatment is appropriately performed because of morphological damage caused by the visible endpoint, typically a whitening burn. The development of the diode laser with micropulsed emission has allowed subthreshold therapy without a visible burn endpoint. This greatly reduces the risk of structural and functional retinal damage, while retaining the therapeutic efficacy of conventional laser treatment. Studies using subthreshold micropulse laser protocols have reported successful outcomes for diabetic macular edema, central serous chorioretinopathy, macular edema secondary to retinal vein occlusion, and primary open angle glaucoma. The report includes the rationale and basic principles underlying micropulse diode laser therapy, together with a review of its current clinical applications. PMID- 20850855 TI - Adult Refsum disease: a form of tapetoretinal dystrophy accessible to therapy. AB - Adult Refsum disease is characterized by an elevated plasma phytanic acid level and high concentrations of phytanic acid in a variety of tissues. Besides tapetoretinal degeneration, additional symptoms are anosmia, skeletal malformations, chronic polyneuropathy, cerebellar ataxia, sensorineural hearing loss, ichthyosis, and cardiac abnormalities. A diet low in phytanic acid ameliorates polyneuropathy and ataxia and slows or even stops the other manifestations. In order to be able to apply dietary therapy, as many patients as possible (even better if all of them are) have to be identified at an early stage. The ophthalmologist plays a crucial role in achieving this goal because of the early manifestation of the tapetoretinal degeneration. PMID- 20850856 TI - Frequency, course, and impact of correctable visual impairment (uncorrected refractive error). AB - Uncorrected refractive error has been identified by the World Health Organization (WHO) as one of the priorities for Vision 2020 and a frequent cause of visual impairment. In the past, only the terms presenting visual impairment (PVI) and visual impairment after best refractive correction (BCVI) were used, so that PVI also included BCVI cases. In the more recent literature, visual impairment has been subdivided into two mutually exclusive entities: that which is correctable by refraction (which we now term correctable visual impairment, CVI) and that which cannot be corrected by refraction due to ocular or neurological disease (which we now term non-correctable visual impairment, NCVI, and which is identical to BCVI). PVI remains a useful concept as it includes both types of impairment. Although CVI is reported to be the major form of visual impairment worldwide, its impacts are not yet well understood. CVI has a higher prevalence among vulnerable groups such as older people, less well educated people and those living alone or in rural areas. Systematic data on barriers to refractive correction remain scant, but these may be present at the individual level, within the health service context, or at a social level. Our review indicates that research on CVI is at a relatively early stage and that more detailed research, particularly determining whether it has impacts on independent living and quality of life, is needed before CVI can be justifiably prioritized in health policy. PMID- 20850857 TI - Polypoidal choroidal vasculopathy: a review. AB - More than a quarter century has passed since the original description of polypoidal choroidal vasculopathy (PCV) in 1982 as a peculiar hemorrhagic disorder involving the macula characterized by recurrent subretinal pigment epithelial bleeding. In the ensuing years, numerous reports have described the expanded clinical spectrum of this entity. PCV is the principal vascular composition of patients of pigmented races experiencing neovascular maculopathies, particularly African Americans and Asians. This form of neovascularization is now known to occur in white patients with or without concomitant drusen, and the site of involvement has extended from the peripapillary area to the peripheral fundus. Indocyanine green angiography has made detection of these abnormal vascular changes more reliable and definitive. More precise diagnosis has also led to a better understanding of specific clinical features that distinguish PCV from more typical proliferations of abnormal choroidal vessels. We review the nature of PCV, including its genetic basis, demographic features, histopathology, clinical manifestations, natural course, response to treatments, and the histopathological and genetic bases. We emphasize multimodal ophthalmic imaging of these vessels, in particular fluorescein and indocyanine green angiography and optical coherence tomography. PMID- 20850858 TI - HIV-1 Gag p17 presented as virus-like particles on the E2 scaffold from Geobacillus stearothermophilus induces sustained humoral and cellular immune responses in the absence of IFNgamma production by CD4+ T cells. AB - We have constructed stable virus-like particles displaying the HIV-1 Gag(p17) protein as an N-terminal fusion with an engineered protein domain from the Geobacillus stearothermophilus pyruvate dehydrogenase subunit E2. Mice immunized with the Gag(p17)-E2 60-mer scaffold particles mounted a strong and sustained antibody response. Antibodies directed to Gag(p17) were boosted significantly with additional immunizations, while anti-E2 responses reached a plateau. The isotype of the induced antibodies was biased towards IgG1, and the E2-primed CD4+ T cells did not secrete IFNgamma. Using transgenic mouse model systems, we demonstrated that CD8+ T cells primed with E2 particles were able to exert lytic activity and produce IFNgamma. These results show that the E2 scaffold represents a powerful vaccine delivery system for whole antigenic proteins or polyepitope engineered proteins, evoking antibody production and antigen specific CTL activity even in the absence of IFNgamma-producing CD4+ T cells. PMID- 20850859 TI - Tethered virions are intermediates in the assembly and release of HIV-1 particles. AB - Vpu enhances HIV-1 release by suppressing CD317-mediated tethering of virions to the cell surface. In HeLa H1 cells, Vpu(+) infection produces significant amounts of tethered virions, although efficient virus release requires Vpu. We have analyzed membrane targeting and assembly of newly synthesized Gag in infected HeLa H1 cells by quantitative pulse-chase assays in both Vpu(+) and DeltaVpu virus backgrounds and in the presence and absence of CD317. Our results show that formation of tethered virions precedes release of viruses to the culture medium in the Vpu(+) infection, and CD317 knockdown reduces tethering in both Vpu(+) and DeltaVpu virus backgrounds. Significantly, our results indicate that tethered Vpu(+) viruses represent precursors for extracellular viruses, and Vpu thus appears to reverse tethering in HeLa H1 cells after budding. PMID- 20850860 TI - Immunoprotection against influenza H5N1 virus by oral administration of enteric coated recombinant Lactococcus lactis mini-capsules. AB - Edible vaccines that can be made widely available and easily administered could bring great benefit to the worldwide battle against pandemic viral infections. They can be used not only for the vaccination of humans and domesticated animals, but also for wild herds and live stock which are otherwise difficult to vaccinate. In this study, we report the development of an edible mini-capsule form of live, non-persisting, recombinant Lactococcus lactis (L. lactis) vaccine against the highly virulent influenza H5N1 strain. Recombinant L. lactis-based H5N1 HA antigen expression constructs were made and shown to be able to induce higher levels of HA-specific serum IgG and fecal IgA antibody production after oral administration. The vectors were then formulated into a mini-capsule dosage form and fed to mouse. Four doses of oral administration rendered complete protection of the mouse against lethal challenges of H5N1 virus. PMID- 20850861 TI - Occurrence of androgens and progestogens in wastewater treatment plants and receiving river waters: comparison to estrogens. AB - Research has shown that exposure to androgens and progestogens can cause undesirable biological responses in the environment. To date, however, no detailed or direct study of their presence in wastewater treatment plants has been conducted. In this study, nine androgens, nine progestogens, and five estrogens were analyzed in influent and final effluent wastewaters in seven wastewater treatment plants (WWTPs) of Beijing, China. Over a period of three weeks, the average total hormone concentrations in influent wastewaters were 3562 (Wujiacun WWTP)-5400 ng/L (Fangzhuang WWTP). Androgens contributed 96% of the total hormone concentrations in all WWTP influents, with natural androgen (androsterone: 2977+/-739 ng/L; epiandrosterone: 640+/-263 ng/L; and androstenedione: 270+/-132 ng/L) being the predominant compounds. The concentrations of synthetic progestogens (megestrol acetate: 41+/-25 ng/L; norethindrone: 6.5+/-3.3 ng/L; and medroxyprogesterone acetate: 6.0+/-3.2 ng/L) were comparable to natural ones (progesterone: 66+/-36 ng/L; 17alpha,20beta dihydroxy-4-progegnen-3-one: 4.9+/-1.2 ng/L; 21alpha-hydroxyprogesterone: 8.5+/ 3.0 ng/L; and 17alpha-hydroxyprogesterone: 1.5+/-0.95 ng/L), probably due to the wide and relatively large usage of synthetic progestogens in medical therapy. In WWTP effluents, androgens were still the dominant class accounting for 60% of total hormone concentrations, followed by progestogens (24%), and estrogens (16%). Androstenedione and testosterone were the main androgens detected in all effluents. High removal efficiency (91-100%) was found for androgens and progestogens compared with estrogens (67-80%), with biodegradation the major removal route in WWTPs. Different profiles of progestogens in the receiving rivers and WWTP effluents were observed, which could be explained by the discharge of a mixture of treated and untreated wastewater into the receiving rivers. PMID- 20850862 TI - Photodegradation of the antibiotics nitroimidazoles in aqueous solution by ultraviolet radiation. AB - The objective of this study was to analyze the efficacy of ultraviolet (UV) radiation in the direct photodegradation of nitroimidazoles. For this purpose, i) a kinetic study was performed, determining the quantum yield of the process; and ii) the influence of the different operational variables was analyzed (initial concentration of antibiotic, pH, presence of natural organic matter compounds, and chemical composition of water), and the time course of total organic carbon (TOC) concentration and toxicity during nitroimidazole photodegradation was studied. The very low quantum yields obtained for the four nitroimidazoles are responsible for the low efficacy of the quantum process during direct photon absorption in nitroimidazole phototransformation. The R(254) values obtained show that the dose habitually used for water disinfection is not sufficient to remove this type of pharmaceutical; therefore, higher doses of UV irradiation or longer exposure times are required for their removal. The time course of TOC and toxicity during direct photodegradation (in both ultrapure and real water) shows that oxidation by-products are not oxidized to CO(2) to the desired extent, generating oxidation by-products that are more toxic than the initial product. The concentration of nitroimidazoles has a major effect on their photodegradation rate. The study of the influence of pH on the values of parameters E (molar absorption coefficient) and k'(E) (photodegradation rate constant) showed no general trend in the behavior of nitroimidazoles as a function of the solution pH. The components of natural organic matter, gallic acid (GAL), tannic acid (TAN) and humic acid (HUM), may act as promoters and/or inhibitors of OH. radicals via photoproduction of H(2)O(2). The effect of GAL on the metronidazole (MNZ) degradation rate markedly differed from that of TAN or HUM, with a higher rate at low GAL concentrations. Differences in MNZ degradation rate among waters with different chemical composition are not very marked, although the rate is slightly lower in wastewaters, mainly due to the UV radiation filter effect of this type of water. PMID- 20850863 TI - Release of antibiotic resistant bacteria and genes in the effluent and biosolids of five wastewater utilities in Michigan. AB - The purpose of this study was to quantify the occurrence and release of antibiotic resistant genes (ARGs) and antibiotic resistant bacteria (ARB) into the environment through the effluent and biosolids of different wastewater treatment utilities including an MBR (Membrane Biological Reactor) utility, conventional utilities (Activated Sludge, Oxidative Ditch and Rotatory Biological Contactors-RBCs) and multiple sludge treatment processes (Dewatering, Gravity Thickening, Anaerobic Digestion and Lime Stabilization). Samples of raw wastewater, pre- and post-disinfected effluents, and biosolids were monitored for tetracycline resistant genes (tetW and tetO) and sulfonamide resistant gene (Sul I) and tetracycline and sulfonamide resistant bacteria. ARGs and ARB concentrations in the final effluent were found to be in the range of ND(non detectable)-2.33 * 10(6) copies/100 mL and 5.00 * 10(2)-6.10 * 10(5) CFU/100 mL respectively. Concentrations of ARGs (tetW and tetO) and 16s rRNA gene in the MBR effluent were observed to be 1-3 log less, compared to conventional treatment utilities. Significantly higher removals of ARGs and ARB were observed in the MBR facility (range of removal: 2.57-7.06 logs) compared to that in conventional treatment plants (range of removal: 2.37-4.56 logs) (p < 0.05). Disinfection (Chlorination and UV) processes did not contribute in significant reduction of ARGs and ARB (p > 0.05). In biosolids, ARGs and ARB concentrations were found to be in the range of 5.61 * 10(6)-4.32 * 10(9) copies/g and 3.17 * 10(4)-1.85 * 10(9) CFU/g, respectively. Significant differences (p < 0.05) were observed in concentrations of ARGs (except tetW) and ARB between the advanced biosolid treatment methods (i.e., anaerobic digestion and lime stabilization) and the conventional dewatering and gravity thickening methods. PMID- 20850864 TI - AsIII oxidation by Thiomonas arsenivorans in up-flow fixed-bed reactors coupled to As sequestration onto zero-valent iron-coated sand. AB - The combined processes of biological As(III) oxidation and removal of As(III) and As(V) by zero-valent iron were investigated with synthetic water containing high As(III) concentration (10 mg L(-1)). Two up-flow fixed-bed reactors (R1 and R2) were filled with 2 L of sieved sand (d = 3 +/- 1 mm) while zero-valent iron powder (d = 76 MUm; 1% (w/w) of sand) was mixed evenly with sand in R2. Thiomonas arsenivorans was inoculated in the two reactors. The pilot unit was studied for 33 days, with HRT of 4 and 1 h. The maximal As(III) oxidation rate was 8.36 mg h( 1) L(-1) in R1 and about 45% of total As was removed in R2 for an HRT of 1 h. A first order model fitted well with the As(III) concentration evolution at the different levels in R1. At the end of the pilot monitoring, batch tests were conducted with support collected at different levels in R1. They showed that bacterial As(III) oxidation rate was correlated with the axial length of reactor, which could be explained by biomass distribution in reactor or by bacterial activity. In opposition, As(III) oxidation rate was not stable in R2 due to the simultaneous bacterial As(III) oxidation and chemical removal by zero-valent iron and its oxidant products. However, a durable removal of total As was realized and zero-valent iron was not saturated by As over 33 days in R2. Furthermore, the influence of zero-valent iron and its oxidant corrosion products on the evolution of As(III)-oxidizing bacteria diversity was highlighted by the molecular fingerprinting method of PCR-DGGE using aoxB gene as a functional marker of aerobic As(III) oxidizers. PMID- 20850865 TI - Interrelationship between exposure to PCDD/Fs and hypertension in metabolic syndrome in Taiwanese living near a highly contaminated area. AB - Metabolic syndrome (MetS) consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease. There is a positive correlation between exposure to persistent organic pollutants and MetS. We examine the association between PCDD/Fs and MetS components in 1490 non-diabetic persons living near a highly dioxin-contaminated area. We used factor analysis, with a set of core variables considered central features of MetS and PCDD/Fs, to group similar risk factors. Serum PCDD/Fs were positively and significantly correlated with the number of MetS components. Four risk factors-lipidemia, blood pressure, body size, and glycemia-accounted for 72.6% of the variance in the 10 core factors, and PCDD/Fs were linked to MetS through shared correlations with high blood pressure. After adjusting for confounding factors, we found that diastolic blood pressure (beta=0.018; p=0.006), glucose (beta=0.013; p=0.046), and waist circumference (beta=0.721; p=0.042) significantly increased with increasing serum PCDD/F levels. We found significant trends for associations between metabolic syndrome and serum low-chlorinated PCDD/Fs. The highest quintiles of 2,3,4,7,8-PeCDF, 1,2,3,6,7,8-HxCDF and 2,3,7,8-TCDD had the top three adjusted ORs (95% CI) of 3.5 (1.9-6.3), 2.9 (1.7-4.9) and 2.8 (1.6-4.9), respectively. We also found a slight monotonic relationship between serum PCDD/Fs and the prevalence of MetS, especially when the serum dioxin level was higher than 25.4pg WHO(98)-TEQ(DF)g(-1) lipid (the fourth Quintile). We hypothesize that high-dose exposure to PCDD/Fs is a blood pressure-related factor that raises MetS risk. PMID- 20850866 TI - Probing Hg evasion from surface waters of two Chinese hyper/meso-eutrophic reservoirs. AB - Measurements of water/air exchange flux of gaseous elemental mercury (GEM) were conducted in a hyper-eutrophic reservoir and a meso-eutrophic reservoir in southwest China in both warm and cold seasons by using a dynamic flux chamber (DFC) method coupled with an automatic gaseous Hg analyzer. Both strong diurnal and seasonal variations of GEM fluxes were observed. The diurnal cycle of the GEM flux was more pronounced during sunny days compared to cloudy and rainy days, which highlights the effect of solar intensity on the GEM flux. GEM fluxes in warm seasons were considerably higher (2.5 to 4.1 times higher) than in cold seasons, which was attributed to the combined factors including meteorological factors, water quality parameters and water Hg concentrations. Clear variation in GEM fluxes was observed between the two reservoirs. Mean GEM fluxes in the hyper eutrophic reservoir (WJD) (3.2-20.1 ng m(-2)h(-1)) were significantly higher than those in the meso-eutrophic reservoir (SFY) (0.6-4.4 ng m(-2)h(-1)). Evasion of Hg played a distinct role in the mass balance of Hg in the two reservoirs. In WJD, evasion was the second most important mechanism for Hg losses from the reservoir (17.5% of the total losses); whereas in SFY, loss of Hg via volatilization constituted an extremely little portion to the total losses of Hg (0.8%). PMID- 20850867 TI - Montelukast might improve compliance with subcutaneous immunotherapy treatments in patients with allergic asthma. PMID- 20850868 TI - Capturing the peer context: developmental issues, statistical methods, and new directions. PMID- 20850869 TI - Countdown to 2015: assessment of official development assistance to maternal, newborn, and child health, 2003-08. AB - BACKGROUND: Achievement of high coverage of effective interventions and Millennium Development Goals (MDGs) 4 and 5A requires adequate financing. Many of the 68 priority countries in the Countdown to 2015 Initiative are dependent on official development assistance (ODA). We analysed aid flows for maternal, newborn, and child health for 2007 and 2008 and updated previous estimates for 2003-06. METHODS: We manually coded and analysed the complete aid activities database of the Organisation for Economic Co-operation and Development for 2007 and 2008 with methods that we previously developed to track ODA. By use of newly available data for donor disbursement and population estimates, we revised data for 2003-06. We analysed the degree to which donors target their ODA to recipients with the greatest maternal and child health needs and examined trends over the 6 years. FINDINGS: In 2007 and 2008, US$4.7 billion and $5.4 billion (constant 2008 US$), respectively, were disbursed in support of maternal, newborn, and child health activities in all developing countries. These amounts reflect a 105% increase between 2003 and 2008, but no change relative to overall ODA for health, which also increased by 105%. Countdown priority countries received $3.4 billion in 2007 and $4.1 billion in 2008, representing 71.6% and 75.6% of all maternal, newborn, and child health disbursements, respectively. Targeting of ODA to countries with high rates of maternal and child mortality improved over the 6-year period, although some of these countries persistently received far less ODA per head than did countries with much lower mortality rates and higher income levels. Funding from the GAVI Alliance and the Global Fund to Fight AIDS, Tuberculosis and Malaria exceeded core funding from multilateral institutions, and bilateral funding also increased substantially between 2003 and 2008, especially from the USA and the UK. INTERPRETATION: The increases in ODA to maternal, newborn, and child health during 2003-08 are to be welcomed, as is the somewhat improved targeting of ODA to countries with greater needs. Nonetheless, these increases do not reflect increased prioritisation relative to other health areas. FUNDING: Partnership for Maternal, Newborn, and Child Health on behalf of the Countdown to 2015 Initiative. PMID- 20850870 TI - Improving aid for maternal, newborn, and child health. PMID- 20850871 TI - Trophoblast invasion: assessment of cellular models using gene expression signatures. AB - Invasive, extravillous trophoblasts (EVT) of the human placenta are critically involved in successful pregnancy outcome since they remodel the uterine spiral arteries to increase blood flow and oxygen delivery to the placenta and the developing fetus. To gain more insights into their biological role different primary cell culture models are commonly utilised. However, access to early placental tissue may be limited and primary trophoblasts rapidly cease proliferation in vitro impairing genetic manipulation. Hence, trophoblastic cell lines have been widely used as surrogates to study EVT function. Although the cell lines share some molecular markers with their primary counterpart, it is unknown to what extent they recapitulate the invasive phenotype of EVT. Therefore, we here report the first thorough GeneChip analyses of SGHPL-5, HTR 8/SVneo, BeWo, JEG-3 and the novel ACH-3P trophoblast cells in comparison to previously analysed primary villous cytotrophoblasts (CTBs) and extravillous trophoblasts (EVTs). Analyses of approximately 14,000 commonly expressed genes revealed that EVTs most closely resemble CTBs with considerable differences to the group of choriocarcinoma cells (JEG-3, BeWo, ACH-3P) and the group of SV40 Large T Antigen-selected cell types (SGHPL-5, HTR-8/SVneo). Similarly, analyses of 912 genes discriminating EVT from CTB, or 370 EVT-specific genes did not unravel a particular cell line with close similarity to any of the primary cell types, although molecular signatures common to EVT and each group of cell lines could be identified. Considering the diversity of mRNA expression patterns it is suggested that molecular studies in trophoblast cell lines require verification of the critical steps in an appropriate primary model system. PMID- 20850872 TI - Effects of Healthy Families New York on the promotion of maternal parenting competencies and the prevention of harsh parenting. AB - OBJECTIVES: This paper examines the effectiveness of the Healthy Families New York (HFNY) home visiting program in promoting parenting competencies and preventing maladaptive parenting behaviors in mothers at risk for child abuse and neglect. METHODS: The study used microlevel observational assessments of mother child interactions in the third wave of a randomized controlled trial to evaluate whether mothers who received home visiting services were more likely to exhibit positive parenting and less likely to display negative parenting behaviors than those who did not receive these services. Women were randomly assigned during pregnancy or shortly after the birth of the target child to an intervention group that was offered home visiting services or a control group that was given referrals to other services. At Year 3, 522 mother and child pairs were systematically observed while they interacted in semistructured tasks presenting varied parenting challenges. The study also sought to replicate a finding from Year 2, which revealed that program effects on harsh parenting were stronger among young, first-time mothers who were randomly assigned during pregnancy (the High Prevention Opportunity subgroup) than among the other mothers (the Limited Prevention Opportunity subgroup). RESULTS: Results indicate that HFNY was effective in fostering positive parenting, such as maternal responsivity and cognitive engagement. With respect to negative parenting, HFNY mothers in the High Prevention Opportunity subgroup were less likely than their counterparts in the control group to use harsh parenting, while no differences were detected for the Limited Prevention Opportunity subgroup. CONCLUSION: HFNY was successful in promoting positive parenting among mothers at risk for child abuse and neglect, which may reflect the program's strength-based approach. The replication of the High Prevention Opportunity subgroup as a moderator of program effects on harsh parenting further suggests that HFNY may be more useful for preventing the initiation rather than the recurrence of child abuse and neglect. PRACTICE IMPLICATIONS: To optimize service delivery, HFNY should continue to focus on enhancing parent-child interactions, prioritize HFNY services for young, first time mothers who are offered the program during pregnancy, and investigate effective strategies to reduce negative parenting practices among the Limited Prevention Opportunity subgroup. PMID- 20850873 TI - Predicting long-term outcomes for women physically abused in childhood: contribution of abuse severity versus family environment. AB - OBJECTIVE: Child physical abuse (CPA) has been associated with adverse adult psychosocial outcomes, although some reports describe minimal long-term effects. The search for the explanation for heterogeneous outcomes in women with CPA has led to an examination of a range of CPA-related factors, from the severity of CPA incidents to the childhood family environment. This study compares several models for predicting adult outcomes: a multidimensional CPA severity scale, the presence or absence of CPA, family environment, and childhood stresses. METHODS: The effect of CPA on adult outcomes was examined among 290 community-dwelling women raised in 2-parent families. Standardized measures and a focused interview were used to collect data, with siblings as collateral informants. RESULTS: Comparison of a multidimensional CPA severity scale to a dichotomous measure of the presence or absence of CPA showed that the severity scale did not have greater predictive value for adult outcomes than the dichotomous measure. Childhood family environment scales considerably attenuated the predictive value of the dichotomous measure of CPA, exerting a greater mediating effect on outcomes than did childhood stresses. CONCLUSIONS: The specific characteristics of a CPA experience may be less important than the occurrence of CPA and the woman's childhood family environment for predicting long-term psychosocial outcomes. PRACTICE IMPLICATIONS: The presence of child physical abuse is substantial and continues to increase, but the clinical significance of abuse on adult outcomes is unclear. The findings of the current study lend credence to the idea that family stresses and resources other than CPA may be crucial in understanding long-term effects in women. Hence treatment and support for victims of CPA might benefit from clinicians' exploration of the family environment. PMID- 20850874 TI - Self-concept, emotion and memory performance in schizophrenia. AB - The "self-reference effect" describes better memory for material someone has related to one's self previously. Schizophrenia can affect aspects of the inner self such as own thoughts or actions. Schizophrenia symptoms, therefore, might not only have an influence on the self-concept, including the self-attribution of positive or negative personality traits, but also reduce the self-reference effect. 15 schizophrenia patients and 15 matched healthy controls were asked to decide on positive and negative personality traits across three separate conditions: self-evaluation, other evaluation (of an intimate person), and during a lexical control task, respectively. An unannounced recognition task followed. Patients revealed a negative bias in the evaluation of themselves and of the well known other person. The reference to a person (oneself, close other) increased later recognition performance. However, patients with schizophrenia revealed an overall decreased recognition performance. The amount of patients' passivity symptoms, i.e., an increase in the permeability of their "self-other boundary", correlated negatively with their recognition performance for previously self referred characteristics and traits referred to the intimate other. This was not the case for lexically processed stimuli or an increase of negative symptoms. Our data underline the necessity of taking into account symptom subgroups when dealing with specific cognitive dysfunctions in schizophrenia. PMID- 20850875 TI - Identification and characterization of immune complexes in the cerebrospinal fluid of patients with spinal cord schistosomiasis. AB - The pathogenesis of neuroschistosomiasis is largely unknown. Available evidence suggests that it depends on the presence of parasite eggs in the nervous tissue and on the host's immune response. We investigated the presence of immune complexes (ICs) in the cerebrospinal fluid (CSF) of four patients with spinal cord schistosomiasis (SCS), and performed their characterization. ICs containing soluble egg antigen of Schistosoma mansoni (SEA) were found in the CSF of all the SCS patients. To our knowledge, this is the first evidence of ICs containing schistosomal antigens in the CSF of patients with SCS. Further studies are necessary to confirm our findings and investigate the possible roles of ICs in the pathogenesis of this disease. PMID- 20850876 TI - Does exposure to testosterone significantly alter endogenous metabolism in the marine mussel Mytilus galloprovincialis? AB - Mussels (Mytilus galloprovincialis) were exposed to different concentrations of testosterone (T: 20, 200 and 2000ng/L) in a semi-static water regime (1-day dosing intervals) for up to 5 days in an attempt to see whether endogenous steroid levels and steroid metabolism were altered by exogenous exposure to testosterone. Whole tissue levels of total testosterone (free+esterified) sharply increased in a concentration-dependent manner, from 2ng/g in controls to 290ng/g in organisms exposed to the highest concentration. In contrast, levels of free testosterone were only significantly elevated at the high-exposure group (5-fold increase with respect to controls). Increased activity of palmitoyl CoA:testosterone acyltransferase (ATAT) was detected in organisms exposed to the highest concentration of testosterone, while those exposed to low and medium concentrations showed significant alterations in their polyunsaturated fatty acid profiles. The obtained results suggest that esterification of the excess of T with fatty acids might act as a homeostatic mechanism to maintain endogenous levels of free T stable. Interestingly, a decrease in CYP3A-like activity was detected in T-exposed mussels together with a significant decrease in the metabolism of the androgen precursor androstenedione to dihydrotestosterone (5alpha-DHT). Overall, the work contributes to the better knowledge of androgen metabolism in mussels. PMID- 20850877 TI - Functional outcome and depression in the elderly with or without fatigue. AB - We evaluated the influence of fatigue on functional outcomes and depression in older people. Fatigue was measured using the fatigue severity scale (FSS). Activity of daily living function was assessed using the functional independence measurement (FIM), the geriatric depression inventory (GDI) was used to assess depression. The average FSS score was 5.66 +/- 1.03 for subjects in the fatigue group, with 50 patients (40.3%) having FSS scores >= 4 points. Significant relationships were found between fatigue and GDI (p<0.001, r = 0.363) and FIM (p<0.04, r = -0.183). Binary logistic regression analysis identified GDI as a significant predictor of fatigue (p < 0.001). We found that 40.3% of older people had fatigue. Fatigue showed a significant correlation with depression and functional status. These findings emphasize the need for careful clinical screening of both fatigue and depression in older individuals. PMID- 20850878 TI - Influence of regular exercise on subjective sense of burden and physical symptoms in community-dwelling caregivers of dementia patients: a randomized controlled trial. AB - With an aim to improve quality of life in caregivers of dementia patients, we examined the effect of regular exercise on caregivers' sense of burden and their physical symptoms. Participants were 31 elderly caregivers living with older patients diagnosed with Alzheimer's-type dementia. They were randomly assigned to either the intervention group, who were prescribed regular exercise with moderate intensity: 3 metabolic equivalents (3METs), 3 times per week for 12 weeks, or the control group, who did not receive any prescription. In the intervention group, significant reductions in the Zarit caregiver burden interview (ZBI) score and in the frequency of feeling fatigued, and an improvement in quality of sleep were observed at follow-up (p < 0.05), while no such changes were observed in the control group. These results suggest that obtaining sustainable habit of moderate exercise may improve quality of life in caregivers of demented patients. PMID- 20850880 TI - Angiographic evidence of progressive lumen narrowing over 2 years following drug eluting stent implantation. AB - BACKGROUND: Questions persist regarding the ability of drug-eluting stents (DES) to inhibit intimal growth in the long-term. METHODS: We prospectively enrolled 766 lesions treated with DES that underwent angiographic examination at 6 months and 2 years after stenting. Lesions with 6-month restenosis (>50% of visual stenosis) were excluded. The primary end point was quantitative change in minimal lumen diameter (MLD) according to serial angiography of the segment (in-segment), the stented region (in-stent) and both edges. Late loss, defined as MLD change, was categorized as early (between post-procedure and 6 months), delayed (between 6 months and 2 years), or overall (between post-procedure and 2-years). RESULTS: MLD progressively decreased in both the in-stent and edge regions at both 6 months and 2 years (p<0.001 in all paired analyses). In-segment MLD decreased from a median 2.27 mm (interquartile range; 1.98, 2.62) at post-procedure to 2.18 mm (1.86, 2.47; p < 0.001 with post-procedure) at 6 months, and to 2.02 mm (1.66, 2.37; p<0.001 with 6 months) at 2 years. Late loss was 0.0 6 mm (-0.05, 0.26) in the early phase, 0.09 mm (-0.01, 0.28) in the delayed phase, and 0.20mm (0.03, 0.50) overall. Two-year angiographic restenosis occurred in 54 (7.0%) lesions, and 65 (8.5%) underwent target lesion revascularization over a median follow-up of 52.5 months. CONCLUSION: Serial angiographic analysis showed that DES lumen diameter progressively narrowed over 2 years post-procedure. However, the incidence of target lesion revascularization was relatively low due to the small amount of late loss in the delayed phase. PMID- 20850879 TI - Vocally disruptive behavior (VDB) in the institutionalized elderly: a naturalistic multiple case report. AB - Employing a naturalistic multiple case study approach, we investigated the current clinical practice in the treatment and care of VDB among a convenience sample of 85 patients cared for in specialized old age psychiatric clinics and nursing homes in French and German-speaking Switzerland. We wished to clinically characterize VDB patients, to identify common approaches used to treat VDB in everyday practice, and to explore how the efficiency of the interventions employed was judged by the responsible carers. Data were collected by means of a questionnaire. Most patients with VDB in this study had dementia, of whom 75% had at least one current or premorbid psychiatric disorder and 25% had premorbid personality disorder. A majority of patients received multiple psychosocial care interventions that were often judged to be effective, but the potential of psychosocial interventions is underused. Many patients did not receive psychotropic medication specifically targeted at VDB, but about 70% of all prescriptions were judged to have positive effects. Premorbid psychiatric and personality disorders or traits are likely candidates to be entered into the etiopathogenic equation of VDB and set a new frame for approaches used to treat these underlying disorders. PMID- 20850881 TI - One-year clinical outcome after treatment of bare-metal stent in-stent restenosis with the paclitaxel-eluting stent in an unselected cohort. PMID- 20850882 TI - Spatial modelling of the between-herd infection dynamics of bovine virus diarrhoea virus (BVDV) in dairy herds in Denmark. AB - According to the current literature BVDV-infected neighbours probably impose a high risk of infection of susceptible cattle herds. In the present study, the objective was to evaluate the risk of a dairy herd changing infection status (from not having persistently infected (PI) animals to having PI-animals) in relation to location and infection status of neighbouring cattle herds in Denmark. In total, 7921 dairy herds were included in the analysis of spatial and non-spatial risk factors. The spatial risk factors were derived based on the cattle herds in the neighbourhood (N=36,639 cattle herds). The neighbourhood was defined as the first order neighbouring cattle herds using a Delauney triangularization. In total, 13.3% of the dairy herds changed herd status to PI herds during the study period that lasted from January 1, 1995, to June 30, 1996. The risk of becoming a PI-herd was negatively associated with the mean distance to the neighbouring herds (OR=0.7 for an increase of 1 km). Presence of PI-herds in the neighbourhood increased the risk of becoming a PI-herd (OR=1.37, 1.40, 1.70 for 1, 2, >=3 PI-herds in the neighbourhood). Increasing herd size increased the risk of becoming a PI-herd (OR=3.9 for an increase of 10 cows). Regional differences were seen. PMID- 20850883 TI - Postoperative radiotherapy and concomitant temozolomide for elderly patients with glioblastoma. AB - BACKGROUND: The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GB) when compared to postoperative RT alone in patients up to 65 years of age. In older patients, RT alone has remained the standard of care because there is concern that radiochemotherapy causes excess toxicity and is less efficacious in this population, but no randomized trials have been reported. We retrospectively assessed feasibility, toxicity and outcome in elderly patients treated at a single institution with RT and concomitant TMZ. PATIENT AND METHODS: Between 04/1999 and 9/2009, 51 patients >=65 years (median age 70 years, range 65-84) with GB were treated by RT (total dose 60 Gy in 30 fractions) and concomitant TMZ (75 mg/m(2)/day throughout RT). Biopsy only had been performed in 23 patients (45.1%), 15 patients (29.4%) had undergone partial resection, and 13 patients (25.5%) macroscopically complete resection. Adjuvant TMZ was applied in 10 of 51 patients. RESULTS: Median overall survival (OS) and progression-free survival (PFS) were 11.5 (95% CI, 6.7-16.3) and 5.5 months (95% CI, 3.7-7.3 months), respectively, in the total cohort. After complete resection, partial resection and biopsy, median OS was 27.4, 15.5 and 7.9 months (p=0.002), respectively. In multivariate Cox proportional hazards regression models extent of resection (p<0.0001) and Karnofsky's performance score (p=0.002) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 30 patients (59%). Five patients (10%) discontinued RT because of disease progression (n=4) or toxicity (pneumonia, n=1). Another 16 patients interrupted concomitant chemotherapy (cytopenia: 9; pneumonia: 2; transaminase elevation: 2; rash: 3). CONCLUSION: RT with concomitant TMZ is a feasible regimen with acceptable toxicity in elderly patients. The promising outcome in patients with good performance status and patients with gross total resections are notable. PMID- 20850884 TI - Comparison of phenotypic (Biolog System) and genotypic (random amplified polymorphic DNA-polymerase chain reaction, RAPD-PCR, and amplified fragment length polymorphism, AFLP) methods for typing Lactobacillus plantarum isolates from raw vegetables and fruits. AB - The diversity of 72 isolates of Lactobacillus plantarum, previously identified from different raw vegetables and fruits, was studied based on phenotypic (Biolog System) and genotypic (randomly amplified polymorphic DNA-polymerase chain reaction, RAPD-PCR, and amplified fragment length polymorphism, AFLP) approaches. A marked phenotypic and genotypic variability was found. Eight clusters were formed at the similarity level of 92% based on Biolog System analysis. The most numerous clusters grouped isolates apart from the original habitat. Almost all isolates fermented maltose, D,L-lactic acid, N-acetyl-D-mannosamine and dextrin, and other typical carbon sources which are prevalent in raw vegetables and fruits. None of the isolates fermented lactose and free amino acids. At high values of linkage distance, two main clusters were obtained from both UPGMA (unweighted pair group with arithmetic average) dendrograms of RAPD-PCR and AFLP analyses. The two clusters mainly separated isolates from tomatoes and carrots from those isolated from pineapples. At 2.5 linkage distance, a high polymorphism was found and several sub-clusters were formed with both analyses. In particular, AFLP allowed the differentiation of 55 of the 72 isolates of L. plantarum. The discriminatory power of each technique used was calculated through the Simpson's index of diversity (D). The values of the D index were 0.65, 0.92 and 0.99 for Biolog System, RAPD-PCR and AFLP analyses, respectively. PMID- 20850885 TI - Distinct pharmacodynamics of insulin glargine and insulin detemir: crossover comparison in Type 1 and Type 2 diabetic patients on basal-bolus regimen. AB - We compared blood glucose profile when glargine or detemir was injected once daily before dinner in combination with pre-meal insulin lispro by a crossover design. Glargine showed lower post-dinner and bedtime glucose levels in Type 1 diabetes, and lower pre-dinner and post-dinner glucose levels in Type 2 diabetes than detemir. PMID- 20850886 TI - Diagnostic accuracy of FibroScan and comparison to liver fibrosis biomarkers in chronic viral hepatitis: a multicenter prospective study (the FIBROSTIC study). AB - BACKGROUND & AIMS: The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the accuracy of FibroScan(r) and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR >= F2) in patients with chronic viral hepatitis. METHODS: A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. RESULTS: The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan(r) examinations). The overall accuracy of FibroScan(r) was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77-0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72-0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0-60% of patients (cirrhosis) and 9-30% of patients (significant fibrosis). CONCLUSIONS: The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis. PMID- 20850888 TI - UJA-3DFD: a program to compute the 3D fractal dimension from MRI data. AB - This work presents a computer program for computing the 3D fractal dimension (3DFD) from magnetic-resonance images of the brain. The program is based on an algorithm that calculates the 3D box counting of the entire volume of the brain, and also of its 3D skeletonization. The validity and accuracy of the software has been confirmed using solids with well-known 3DFD values. The usefulness of the program developed is demonstrated by its successful characterization of several neurodegenerative diseases. PMID- 20850887 TI - Renal and circulatory dysfunction in cirrhosis: current management and future perspectives. AB - Chronic liver diseases are amongst the top leading causes of death in Europe as well as in other areas of the world. Chronic liver diseases are characterized by unrelenting progression of liver inflammation and fibrosis over a prolonged period of time, usually more than 20 years, which may eventually lead to cirrhosis. Advanced cirrhosis leads to a complex syndrome of chronic liver failure which involves many different organs besides the liver, including the brain, heart and systemic circulation, adrenal glands, lungs, and kidneys. The high morbidity and mortality secondary to chronic liver failure is due to complications related to the dysfunction of these organs, either alone or, more frequently, in combination. Understanding the mechanisms leading to organ dysfunction is crucial to the development of strategies for treatment and prevention of complications of cirrhosis. This article reviews our current knowledge, as well as future perspectives, on the management of circulatory and renal dysfunction in chronic liver failure. PMID- 20850889 TI - Apical TLR ligation of intestinal epithelial cells drives a Th1-polarized regulatory or inflammatory type effector response in vitro. AB - Intestinal epithelial cells (IEC) separate the mucosal immune system from the external milieu. Under inflammatory conditions, Toll-like receptor (TLR) expression by IEC is increased. In a transwell co-culture model immune modulation by IEC upon TLR ligation was studied. Human IEC (HT-29 and T84) grown on filters were apically or basolaterally exposed to TLR4 or TLR9 ligands and co-cultured with CD3/CD28-activated healthy donor PBMC in the basolateral compartment. TLR4 ligation of IEC (HT-29) enhanced the production of TNF-alpha and IEC-derived MDC and decreased numbers of Foxp3(+) regulatory T cells. Neutralization of TSLP abrogated TLR4-induced TNF-alpha secretion. In contrast, apical TLR9 ligation of IEC (HT-29 and T84) enhanced IFN-gamma and IL-10 secretion and increased the number of activated T(h)1 cells. The increase in IFN-gamma secretion depended on the presence of IEC. Furthermore, CD14 expression on monocytes was reduced coinciding with enhanced intracellular IL-10 and decreased TNF-alpha production. However, basolateral TLR9 ligand exposure of HT-29 cells resulted in enhanced IFN gamma, IL-6 and TNF-alpha, while IL-10 secretion remained unaltered. TLR4 and TLR9 ligands reduced IL-13 secretion in presence and absence of apically exposed IEC and enhanced IL-12 secretion in presence of IEC. These data suggest that TLR4 ligation of IEC drives an inflammatory, while apical TLR9 ligation drives a regulatory T(h)1 effector immune response in vitro in a polarized manner. IEC may be important modulators of the mucosal effector immune response. PMID- 20850890 TI - Cytokine production by human odontoblast-like cells upon Toll-like receptor-2 engagement. AB - Recent studies have suggested that odontoblasts are involved in the dental pulp immune response to oral pathogens that invade human dentin during the caries process. How odontoblasts regulate the early inflammatory and immune pulp response to Gram-positive bacteria, which predominate in shallow and moderate dentin caries, is still poorly understood. In this study, we investigated the production of pro- and anti-inflammatory cytokines by odontoblast-like cells upon engagement of Toll-like receptor (TLR) 2, a pattern recognition molecule activated by Gram-positive bacteria components. We used a highly sensitive Milliplex((r)) kit for detecting cytokines released by cells stimulated with lipoteichoic acid (LTA), a cell wall component of Gram-positive bacteria, or with the potent TLR2 synthetic agonist Pam2CSK4. We found that odontoblasts produce the pro-inflammatory cytokines interleukin (IL)-6 and CXCL8, as well as the immunosuppressive cytokine IL-10 in response to TLR2 agonists. GM-CSF, IFNgamma, IL-1beta, IL-2, IL-4, IL-5, IL-7, IL-12(p70), IL-13 and TNF-alpha were not detected. These data indicate that TLR2 activation in human odontoblasts selectively induces production of mediators known to influence positively or negatively inflammatory and immune responses in pathogen-challenged tissues. We suggest that these molecules might be important in regulating the fine tuning of the pulp response to Gram-positive bacteria which enter dentin during the caries process. PMID- 20850891 TI - Host defence against Staphylococcus aureus biofilms by polymorphonuclear neutrophils: oxygen radical production but not phagocytosis depends on opsonisation with immunoglobulin G. AB - Bacterial biofilms are increasingly recognised as a major cause of persistent infection and destructive inflammatory processes. In patients with biofilm infection, massive infiltration of leukocytes, particularly polymorphonuclear neutrophils is seen, and previous in vitro studies showed that PMN were able to phagocytose Staphylococcus aureus biofilms. We now addressed the question whether opsonisation of biofilms with immunoglobulin G and complement enhances the efficiency of phagocytosis, as it has been shown for "free-living" planktonic bacteria and other particulate materials. We found that incubation of biofilms with normal human serum resulted in IgG binding and in complement activation with deposits on the biofilm of C3bi. This "opsonisation", however, did not affect the adherence of PMN to the biofilms nor did it enhance degranulation or phagocytosis. The clearance of biofilms, however, was increased, and the oxygen radical production by the PMN depended critically on the coating of biofilms with IgG. PMID- 20850892 TI - The biosynthesis of flavonoids is enhanced similarly by UV radiation and root zone salinity in L. vulgare leaves. AB - Flavonoids have recently been suggested to have the potential to serve as antioxidants other than effective UV attenuators in photoprotection. Here, we tested the hypothesis that flavonoids accumulate in response to "excess light" in the presence or in the absence of UV radiation. In a UV exclusion experiment, we grew Ligustrum vulgare plants outdoors under 30% or 100% sunlight irradiance, by cutting-off the whole UV waveband. These plants were also exposed to UV irradiance or supplied with 125 mM NaCl at the root zone. Leaves of plants under 100% sunlight irradiance suffered from excess light, which was exacerbated greatly by root zone salinity stress. Salinity stress repressed the activities of antioxidant enzymes, particularly in full sunlight, and led to severe leaf oxidative damage. Dihydroxy B-ring-substituted flavonoids, namely quercetin 3-O- and luteolin 7-O-glycosides, accumulated steeply in response to sunlight irradiance in the absence of UV radiation. UV radiation and root zone NaCl increased, to a similar degree, the concentration of these flavonoids, which have a great potential to scavenge various forms of reactive oxygen. Treatment-induced changes in leaf phenylpropanoid concentration affected antioxidant activities to a greater extent than the UV-screening capacities of leaf extracts. Early responses to an abrupt increase in sunlight irradiance included a steep increase in the concentrations of quercetin derivatives and cyanidin 3-O-glucoside, with the latter negligibly absorbing in the UV-spectral region. In contrast, effective UV attenuators, such as hydroxycinnamates and monohydroxy B-ring flavonoids, were unresponsive to the light treatments. Overall, these findings lead to the hypothesis that flavonoids may have an important antioxidant function in photoprotection. This hypothesis is further corroborated by the large distribution of quercetin and luteolin derivatives in the vacuoles of mesophyll, not only in the corresponding compartments of epidermal cells, but also in full sunlight-treated leaves in the absence of UV radiation. Future experiments aimed at evaluating the relative contribution of flavonoids within the complex antioxidant defense systems operating in the leaf are needed to help conclusively address the relevance of their antioxidant functions in photoprotection. PMID- 20850893 TI - Bone mineral density in children with moderate to severe atopic dermatitis. AB - BACKGROUND: Low bone mineral density (BMD) has been reported in 30.4% of adult patients with atopic dermatitis (AD). OBJECTIVE: The aim of this study was to determine the prevalence of low BMD in children with moderate to severe AD and to investigate the relation between BMD and corticosteroid and cyclosporine therapy. METHODS: Lumbar spine BMD was measured by dual-energy X-ray absorptiometry in 60 children (age 5-16 years) with moderate to severe AD. BMD (in g/cm(2)) was expressed in Z-scores, the number of SD above or below the mean value of an age- and sex-matched reference population. In children, low BMD was defined as a Z score less than -2. Information on lifestyle parameters and bone fractures were collected by use of a standardized questionnaire. The cumulative dose of corticosteroids and cyclosporine therapy was calculated for the previous 5-year period. RESULTS: Three patients (5%) had low BMD; one patient (1.7%) had osteoporosis. The observed prevalence of low BMD in this study (6.7%; 95% confidence interval 1.8%-16.2%) does not differ from the expected prevalence of low BMD in the general population (P = .06). Overall, use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD (Z-score). When children received additional systemic treatment (oral corticosteroids and/or cyclosporine) in the previous 5 years, BMD decreased, although the decrease was not statistically significant. Correction for lifestyle parameters did not change these associations. LIMITATIONS: The number of patients studied was limited. The cumulative dose of corticosteroids and cyclosporine therapy was only registered for the previous 5 years, and relatively low amounts of topical corticosteroids were used. The definition of low BMD differs between adults (Z-score < -1) and children (Z-score < -2). Because there is no Dutch BMD reference population for children, normative BMD references were obtained from a different population (US children). CONCLUSIONS: Low BMD did not occur more frequently in this population of children with moderate to severe AD compared with the general population. Use of topical corticosteroids in the previous 5 years was not associated with a decrease in BMD. PMID- 20850894 TI - Surgeon's garb and infection control: what's the evidence? AB - Surgical site infections are an important complication resulting from surgery. Before the 20th century a significant number of surgeries resulted in death from sepsis. One of the rituals resulting from efforts to reduce infection is the donning of surgical garb. A large body of literature has developed on the efficacy of these specialized garments. The available evidence for the efficacy of each individual garb at reducing surgical site infections will be explored. The relevance of this evidence to the outpatient dermatologic surgery setting will also be discussed. PMID- 20850895 TI - Assessment of the long-term safety and effectiveness of etanercept for the treatment of psoriasis in an adult population. AB - BACKGROUND: Etanercept is well tolerated and effective in moderate to severe plaque psoriasis. However, effectiveness and safety data beyond 2.5 years have not been reported. OBJECTIVE: We sought to assess the effectiveness and safety profile of up to 4 years of etanercept therapy in psoriasis. METHODS: We analyzed prospective data from previous trials and open-label extensions, including 506 patients who initiated etanercept therapy in either of two phase III trials. Patients received etanercept, 25 mg twice weekly, 50 mg weekly, or 50 mg twice weekly, depending on which trial therapy was started. Dosage adjustments were allowed in open-label extensions, but no patients exceeded 50 mg twice weekly. Outcomes included change from baseline for the static Physician Global Assessment and Dermatology Life Quality Index scores. Exposure-adjusted adverse event (AE) rates were calculated. RESULTS: In all, 75.9% (95% confidence interval 67.9-84.0) and 27.8% (95% confidence interval 19.3-36.2) maintained Dermatology Life Quality Index response (>= 5-point improvement from baseline) and static Physician Global Assessment response (clear or almost clear) at 48 months, respectively. AE and serious AE rates were 243.5 and 7.8 events per 100 patient-years, respectively. No serious AE rates exceeded 1.0 event per 100 patient-years. Overall infection and serious infection rates were 96.9 and 0.9 events per 100 patient-years, respectively. No cases of tuberculosis or lymphoma were reported. LIMITATIONS: Effectiveness data were limited to static Physician Global Assessment and Dermatology Life Quality Index scores. Analysis of AE rates was limited to available comparator databases. CONCLUSION: Etanercept demonstrated sustained effectiveness and a favorable safety profile with no cumulative toxicity for up to 4 years, representing, to our knowledge, the longest published study on etanercept use in psoriasis to date. PMID- 20850896 TI - Risk factors for multidrug-resistant bacterial infection among patients with tuberculosis. AB - Given that anti-tuberculosis medication itself has antibacterial activity and that broad-spectrum antibiotics are frequently used, the emergence of multidrug resistant (MDR) bacteria among patients being treated for tuberculosis (TB) is likely. We used a case-control design to study the clinical predictors of MDR bacterial infection among TB patients. Both cases and controls were selected from among patients who were diagnosed and treated as having TB between 1 January 1996 and 31 August 2006. TB patients with MDR bacterial infection were included as cases and those with non-MDR bacterial infection were included as controls. Multiple logistic regression analysis was performed to elucidate the risk factors for MDR bacterial infection. During the study period 3667 patients were diagnosed with, and treated for, TB. A total of 123 experienced episodes of bacterial infection, of whom 59 (48.0%) were infected by an MDR strain at least once. The presence of chronic renal failure [adjusted odds ratio (OR): 4.96; 95% confidence interval (CI): 1.37-18.01] and the use of antimicrobials other than typical anti TB drugs within three months (adjusted OR: 4.37; 95% CI: 1.74-10.95) were independent risk factors for MDR bacterial infection. Bacterial infection in TB patients is commonly multidrug resistant. Clinicians should be aware of the possibility of MDR bacterial infection among TB patients with chronic renal failure or recent use of other antimicrobials. PMID- 20850897 TI - Innate resistance to sporicides and potential failure to decontaminate. AB - Bacterial spores are frequently intrinsically resistant to biocides and only a number of alkylating and oxidising biocides are sporicidal under certain conditions. Activity against spores is affected by several key factors such as concentration, exposure time, soiling, and the types of surface to be treated. Sporicidal efficacy is usually achieved after an exposure time of several minutes with a high concentration of a biocide. Failure to understand these factors will result in decreased sporicide activity and spore survival. Sporicides in healthcare settings are used for surface disinfection and for the high level disinfection of certain medical devices (e.g. endoscopes). With efficacy data in mind, sporicidal activity should be achieved for the disinfection of medical devices where both high concentration and long exposure time occur. However, for the disinfection of environmental surfaces, high concentration is not recommended, nor is long exposure time achievable. In this case, sporicidal activity is severely reduced and spore survival following treatment is to be expected and contributes to the explanation of spore persistence on surfaces. PMID- 20850898 TI - Decolonisation for early control of an outbreak of vancomycin-resistant Enterococcus faecium in a geriatric rehabilitation care facility. PMID- 20850899 TI - Twenty-four-hour observational study of hospital hand hygiene compliance. AB - This observational study measured healthcare workers' (HCWs'), patients' and visitors' hand hygiene compliance over a 24h period in two hospital wards using the 'five moments of hand hygiene' observation tool. Hand hygiene is considered to be the most effective measure in reducing healthcare-associated infections but studies have reported suboptimal levels of compliance. Most studies have used random observational time-periods for data collection and this has been criticised. We monitored a total of 823 hand hygiene opportunities (HCWs, N=659; patients and visitors, N=164). Among HCWs, compliance was 47% for doctors, 75% for nurses, 78% for allied health professionals, and 59% for ancillary and other staff (P<0.001). There was no difference in compliance between patients and visitors (56% vs 57%, P=0.87). Hand hygiene compliance varied depending on which of the five moments of hygiene HCWs had undertaken (P<0.001), with compliance before an aseptic task being 100% (3/3); after body fluid exposure 93% (86/93); after patient contact 80% (114/142); before patient contact 68% (196/290); and after contact with surroundings 50% (65/129). Lower levels of compliance were found for HCWs working during the early shift (P<0.001). For patients and visitors there was no evidence of an association between moments of hygiene and compliance. Levels of compliance were higher compared with previous reported estimates. Medical staff had the lowest level of compliance and this continues to be a concern which warrants specific future interventions. PMID- 20850900 TI - Currently available sporicides for use in healthcare, and their limitations. AB - Clostridium difficile has been recognised for some time as a pathogen which can contaminate the environment and which is associated with secondary spread via this route. Unfortunately many of the disinfectants currently used in healthcare environments are inactive against this organism. For example, alcohol-containing hand rubs do not have sporicidal activity and some quaternary ammonium compounds and detergents may even encourage sporulation. European standards have been developed to allow a standardised methodology for testing the efficacy of disinfectants, but no European standard exists for testing products against C. difficile in medical environments. Most laboratories use an adapted version of EN 13704 which was designed for food, domestic and industrial applications. It is important when testing a disinfectant that it is tested under dirty as well as clean conditions and that the disinfectant is adequately neutralised. Some of the currently available biocides have good activity against C. difficile although relatively long contact times are sometimes required and this may not accurately reflect in-use practises. Other agents have very little activity against C. difficile even after a contact time of 1h. It has to be recognised that testing activity against C. difficile is technically very challenging and therefore there can be large interlaboratory variations in results. When interpreting data, it is essential to scrutinise the methodology used in detail. PMID- 20850901 TI - Lower arterial catheter-related infection in brachial than in femoral access. AB - Recent guidelines do not establish a recommendation about the arterial catheter site to minimize the arterial catheter-related infection risk. In this prospective and observational study, we found a higher arterial catheter-related infection in 1085 arterial femoral sites than in 141 arterial brachial sites (5.08 vs 0 per 1000 catheter-days, respectively; odds ratio, 6.18; 95% confidence interval: 1.11-infinite; P = .02). Thus, arterial brachial access should be used in preference to femoral access. PMID- 20850903 TI - Genetic variants in PSEN2 and correlation to CSF beta-amyloid42 levels in AD. AB - Beta-amyloid 42 (Abeta42) concentrations in cerebrospinal fluid (CSF) are significantly decreased in Alzheimer's disease (AD). The aim of this study was to correlate genetic variability in presenilin 2 (PSEN2) in relation to Abeta42 concentrations and to confirm association of apolipoprotein E (APOE) alleles E4/E4 genotype with lower CSF Abeta42. Haplotype analysis of PSEN2 and APOE genotyping were performed in 175 Alzheimer's disease patients, as defined by clinical diagnosis and Abeta42 levels. One distinct haploblock in PSEN2 was detected and the frequent haplotypes were analyzed using 4 tagging single nucleotide polymorphisms (SNPs). We found an association between haplotype 2 and higher CSF Abeta42 concentrations (p = 0.021) and lower Abeta42 concentrations in haplotype 5 carriers (p < 0.001). APOE E4/E4 carriers had lower Abeta42 levels (p = 0.009). Additive regression analysis showed an association of Abeta42 level with APOE genotype (p = 0.024), haplotype 4 (p = 0.064), and haplotype 5 (p = 0.04), whereas gender, age at onset and Mini Mental State Examination (MMSE) remained insignificant. Using CSF Abeta42 as a biomarker we replicated genetic influences in APOE and observed a significant influence of a new haplotype in PSEN2. A better understanding of genetic influences on biomarkers like CSF Abeta42 might help to stratify patients and develop specific treatment strategies. PMID- 20850904 TI - [Quality of life and its association with the severity of fecal incontinence]. AB - BACKGROUND: Wexner's score is widely used to assess the severity of fecal incontinence (FI). The 36-item short form health survey (SF-36) and the Fecal Incontinence Quality of Life Scale (FIQLS), a disease-specific scale, are instruments measuring quality of life that have been validated into Spanish. AIM: To evaluate quality of life in patients with FI by using the FIQL and SF-36 scales to correlate the results with the Wexner's score. METHODS: Wexner's score, SF-36 and FIQLS were completed by 73 patients. The cut-off point for severity, as previously published, was 9 (Wexner's score <9=mild FI; Wexner's score >=9=severe FI). RESULTS: the scores for all SF-36 sub-scales were lower in patients with FI than in the healthy Spanish population (p<0.001). The mental component of the SF 36 correlated with the subscales of "behavior" and "embarrassment" of the FIQLS (p<0.05). Wexner's score correlated with all the domains of the FIQLS (p<0.01). The results for all the domains of the FIQLS were lower for the Wexner >= 9 group than for the Wexner <9 group (p<0.001). There was no significant correlation between Wexner's score and the SF-36. Age, urge and daily FI, comorbidity and anorectal surgery worsened different aspects of quality of life measured by the FIQLS. CONCLUSIONS: quality of life measured by the SF-36 and FIQLS was substantially impaired in patients with FI. The severity of FI correlated with FIQLS. Other factors such as age, type and frequency of FI should be considered when evaluating quality of life. PMID- 20850902 TI - Attenuated long-term Arc expression in the aged fascia dentata. AB - One prominent component of aging is a defect in memory stabilization. To understand how the formation of enduring memories is altered in the aged brain, long-term markers of the biological events that may mediate memory consolidation were used to examine the activity dynamics of hippocampal circuits over extended intervals. The immediate early gene Arc, which is implicated in both durable memory and synaptic plasticity, is expressed in the fascia dentata (FD) for long periods following behavioral experience. To test the hypothesis that aging alters long-term Arc transcription in the FD, a region critical for spatial memory and impaired with progressive age, young and aged rats explored a novel environment twice, separated by an 8-hour interval, and FD Arc transcription was assessed. Relative to young rats, (a) fewer granule cells in the aged FD transcribe arc 8 hours after spatial exploration, and (b) this decrease is correlated with impaired spatial memory. These findings are consistent with behavioral evidence of age-related decline in hippocampal-dependent memory processing long after an event is to be remembered, and reaffirm the integral role of the FD in the neural circuits supporting durable memory. PMID- 20850905 TI - [Incidence and characteristics of pancreatic cystic neoplasms]. AB - INTRODUCTION: Cystic neoplasms (CN) of the pancreas represent 10% of cystic lesions and 1% of pancreatic tumors. Mucinous cystic neoplasm (MCN), serous cystadenoma (SC) and intraductal papillary mucinous neoplasm (IPMN) are cystic neoplasms and represent more than 90% of these types of lesion. Few series have been published on these lesions, especially in Spain. AIM: To evaluate the incidence, characteristics and survival of patients with cystic neoplasms attended in our hospital in the last 12 years. PATIENTS AND METHOD: A retrospective analysis was carried out in all patients diagnosed with CN between January 1997 and December 2008. Diagnosis was made by abdominal computed tomography, pancreatic-magnetic resonance imaging and/or endoscopic ultrasonography. Sex, age, year of diagnosis, symptoms, tumoral location and size, type of surgery, pathology, and survival were evaluated. RESULTS: A total of 117 patients were analyzed. The mean age was 63+/-14 years and 56% were women. Eighty-eight patients had IPMN, 21 had SC and eight had MCN. Fifty-six per cent were diagnosed in the last 4 years, 42.7% were diagnosed as an incidental finding and 19% had a history of acute pancreatitis. The most frequent location was the pancreatic head (53%). The mean imaging size was 32mm. Surgical resection was performed in 69.2% of the patients. Twenty-three percent of the tumors were malignant, 30% were carcinoma in situ and 70% were invasive. Thirteen percent of the patients died; of these 93.3% had invasive carcinoma. Five-year survival was 94.7% in SC, 76% in IPMN and 60% in MCN. CONCLUSIONS: CN were mainly identified as incidental findings, although acute pancreatitis is another possible cause. The most frequent tumor in our environment is IPMN. Surgical treatment of IPMN and MCN, at the right moment, may be useful to prevent the development of pancreatic carcinoma. PMID- 20850906 TI - [Iron deficiency anemia and use of intravenous iron in digestive disease]. PMID- 20850907 TI - [Acute toxic hepatitis due to drinking water]. AB - Toxic-induced liver disease is uncommon, although the true proportion of cases of hepatotoxicity is unknown, as this entity is underdiagnosed and underreported. The main reasons why toxic-induced liver disease goes unnoticed is the lack of pathognomonic data and the lack of spontaneous reporting by doctors and pharmacists. In some cases, the toxic substance can leave its "signature" in the form of clinical semiology suggestive of an underlying toxic cause. We present a case of hepatotoxicity induced by drinking water (chlorinated), which produced a reactive metabolites syndrome (trihalomethanes from the reaction of chlorine with organic products). Although the clinical presentation was typical, the case posed a diagnostic challenge for the various professionals involved. PMID- 20850908 TI - [Solitary fibrous tumor of the abdomen. A rare neoplasm of vascular origin]. AB - Solitary fibrous tumor (formerly known as hemangiopericytoma) is a rare soft tissue neoplasm, most frequently arising from the retroperitoneum and lower extremities. We present two cases of retroperitoneal solitary fibrous tumors diagnosed after surgical removal. We provide a literature review showing the basic clinical, pathologic and therapeutic features of these tumors. PMID- 20850909 TI - [Relationship between exercising and physical and cognitive function indicators. Comparison of results with age]. AB - BACKGROUND: Gerontology research shows the importance of physical exercise for active aging. This study demonstrates the relationship between the practice of aerobic exercise, and physical fitness (muscle strength, respiratory capacity and motor speed) and cognitive performance (memory and visual-perceptual speed) and analyzes whether age is a modulating factor of this relationship. MATERIAL AND METHODS: The sample included 690 subjects with an age range of 30-85 years. The level of physical exercise was assessed using self-report form. Two sub-scales were used for the evaluation of cognitive performance: Digit Span Backwards and Digit Symbol (both are sub-scales of the Wechsler Adult Intelligence Scale- WAIS). The physical fitness was assessed using bio-behavioral measurements (strength, lung capacity, speed). To test the combined effect of exercise and age on the two variables (physical fitness and cognitive performance) two separate factorial analysis of variance were performed (procedure--general linear model: Univariate). RESULT: The most significant result showed that scores on cognitive performance is a function of the intensity of the physical activity (F = 4.8; P < 0.002). With regard to physical fitness, its relationship with physical exercise is also significant (F = 4.10; P<0.007) as well as the interaction between exercise and age (F = 2.2; P<0.001). CONCLUSIONS: The intensity in achieving aerobic exercise is associated with physical fitness and cognitive performance. Age has a specific weight in the association between exercise and physical fitness, this effect is higher in the older age groups (65-74 and 75-85 years for 30-49 and 50-64 years). These data suggest the compensatory effect of exercise on decline in old age. PMID- 20850910 TI - Structure-activity relationship studies of acridones as potential antipsoriatic agents. 2. Synthesis and antiproliferative activity of 10-substituted hydroxy-10H acridin-9-ones against human keratinocyte growth. AB - A series of 10-substituted hydroxy-10H-acridin-9-ones were synthesized and studied as potential antipsoriatic agents. The antiproliferative activity of the novel derivatives, which can be considered as aza-analogues of the antipsoriatic drug anthralin, was determined using the human keratinocyte cell line HaCaT. Structure-activity relationships with respect to the nature of the N-substituent at the acridone scaffold were delineated. Release of lactate dehydrogenase (LDH) was used to exclude non-specific cytotoxic effects. As compared to anthralin, N substitution of the acridone scaffold in the target compounds provided agents devoid of radical producing properties, which was documented by their ineffectiveness to interact with the free radical 2,2-diphenyl-1-picrylhydrazyl. This was in excellent agreement with the data obtained from the LDH assay in which the novel compounds did not induce membrane damage. Benzyl substitution at the 10-position yielded keratinocyte growth inhibitory activity in the low micromolar range. The most potent inhibitor of keratinocyte hyperproliferation was compound 8a having an N-methyl group and a 1,3-dihydroxy arrangement at the acridone scaffold, with an IC(50) value comparable to that of anthralin. PMID- 20850911 TI - New octahydroquinazoline derivatives: synthesis and hypotensive activity. AB - Several novel 1-(4-chlorophenyl)-7,7-dimethyl-1,2,3,4,5,6,7,8-octahydro-5-oxo-3 (substitutedphenyl)quinazoline derivatives (2-21) structurally similar to prazosin, were prepared using Mannich reaction of 3-(4-chlorophenylamino)-5,5 dimethyl-2-cyclohexenone (1) with different aromatic amines in the presence of formaline. The structures of the quinazoline derivatives were established using elemental and spectral analyses. Compounds 18, 20 and 21 were found to possess a high hypotensive effect through their expected alpha(1)-blocking activity like the clinically used drug prazosin but with advantageous of being did not cause reflex tachycardia and having prolonged duration of action when tested in adrenaline-induced hypertension in anaesthetized rats. PMID- 20850912 TI - Synthesis, DNA binding and cleavage activity of macrocyclic polyamines bearing mono- or bis-acridine moieties. AB - Two acridine-pendant cyclen (1,4,7,10-tetraazacyclododecane) derivatives 1 and 2 were synthesized, and their DNA interactions have been systematically investigated by UV absorption, fluorescence titration, viscosity measurement, DNA melting and gel electrophoresis experiments. The results showed that acridine cyclen derivatives could bind to DNA in intercalative mode, and bis-acridine 2 has higher DNA binding ability than that of mono-acridine 1. Moreover, both compounds exhibited preferential interactions with G-rich DNA sequences. Their copper(II) complexes could cleave DNA without the existence of other additives under physiological conditions through an oxidative pathway. PMID- 20850913 TI - [Systemic and autoimmune manifestations in myelodysplastic syndromes]. AB - Myelodysplastic syndromes (MDS) can be associated with systemic or autoimmune diseases. Vasculitides (leucocytoclastic, periarteritis nodosa, micropolyangeitis, Wegener's granulomatosis), relapsing polychondritis, and Sweet's syndrome are the most commonly reported. Refractory anemia with excess of blasts (RAEB), transformed RAEB evolving to an acute leukemia, and chronic myelomonocytic leukemia (CMML) are preferentially associated with these vasculitides or systemic diseases. Corticosteroids are generally effective. Immunosuppressive drugs expose these patients to infectious complications and increase the risk of transformation into acute leukemia. Occurrence of relapsing polychondritis in a patient older than 60years is associated with a myelodysplastic syndrome in 40% of the cases. Sweet's syndrome is associated in 10% of the cases with acute myeloid leukemia and MDS. Polyarthritis or oligoarthritis with systemic manifestations that include fever, skin rash, and more rarely serositis or haemolytic anemia can occur contemporarily to a MDS. Behcet's disease with intestinal involvement has been reported in patients presenting with trisomy 8 associated MDS. Pathogenic mechanisms underlying the association between MDS and autoimmune or systemic disorders remain to be elucidated. PMID- 20850914 TI - [Epigastric mass]. PMID- 20850915 TI - Understanding the optimal learning environment in palliative care. AB - The learning experiences of student nurses undertaking clinical placement are reported widely, however little is known about the learning experiences of health professionals undertaking continuing professional development (CPD) in a clinical setting, especially in palliative care. The aim of this study, which was conducted as part of the national evaluation of a professional development program involving clinical attachments with palliative care services (The Program of Experience in the Palliative Approach [PEPA]), was to explore factors influencing the learning experiences of participants over time. Thirteen semi structured, one-to-one telephone interviews were conducted with five participants throughout their PEPA experience. The analysis was informed by the traditions of adult, social and psychological learning theories and relevant literature. The participants' learning was enhanced by engaging interactively with host site staff and patients, and by the validation of their personal and professional life experiences together with the reciprocation of their knowledge with host site staff. Self-directed learning strategies maximised the participants' learning outcomes. Inclusion in team activities aided the participants to feel accepted within the host site. Personal interactions with host site staff and patients shaped this social/cultural environment of the host site. Optimal learning was promoted when participants were actively engaged, felt accepted and supported by, and experienced positive interpersonal interactions with, the host site staff. PMID- 20850916 TI - After praise and encouragement: emotional support strategies used by birth doulas in the USA and Canada. AB - OBJECTIVE: to describe in detail the emotional support techniques employed by birth doulas during labour. DESIGN: grounded theory methodology was utilised in collecting and analysing interviews given by doulas and mothers who had doula care. By using both informants, a clearer picture of what constitutes emotional support by doulas emerged. PARTICIPANTS: 10 mothers from three different states in the Midwestern USA and 30 doulas from 10 different states and two Canadian provinces were interviewed. Two doulas worked in hospital-based programmes whereas the others had independent practices. Doulas usually attended births in hospitals where medical attendants spent little focused time with the mother. FINDINGS: nine different strategies were distinguished. Four strategies (reassurance, encouragement, praise, explaining) were similar to those attributed to nurses in published research. Five were original and described as only being used by doulas (mirroring, acceptance, reinforcing, reframing, debriefing). CONCLUSIONS: emotional support by professional birth doulas is more complex and sophisticated than previously surmised. Mothers experienced these strategies as extremely meaningful and significant with their ability to cope and influencing the course of their labour. IMPLICATIONS FOR PRACTICE: the doula's role in providing emotional support is distinct from the obstetric nurse and midwife. Professional doulas utilise intricate and complex emotional support skills when providing continuous support for women in labour. Application of these skills may provide an explanation for the positive 'doula effect' on obstetric and neonatal outcomes in certain settings. PMID- 20850917 TI - Renal complications in transfusion-dependent beta thalassaemia. AB - Increased survival in patients with beta thalassaemia major (TM) allowed for several morbidities to manifest. Renal manifestations of the disease and its treatment have been poorly evaluated. There is evidence, mainly from studies in the paediatric population, of tubular dysfunction and glomerular filtration rate abnormalities in this patient population. Long-term outcomes of these changes, however, have not been prospectively investigated. The pathogenesis of these abnormalities could be attributed to iron overload, too aggressive iron removal, and/or the underlying anaemia. These changes seem to be nonprogressive, resolve spontaneously in most part, or may require iron chelator dose modifications. Relative iron depletion may explain renal function changes attributed to chelation therapy; thus, sudden removal of iron or overchelation should be avoided. Future studies should aim to evaluate the natural history of kidney function in TM patients to help understand the mechanisms and long-term sequelae of the observed renal changes. PMID- 20850918 TI - The influence of organizational context on quality improvement and patient safety efforts in infection prevention: a multi-center qualitative study. AB - Patient safety is a healthcare priority worldwide, with most hospitals engaging in activities to improve care quality, safety and outcomes. Despite these efforts, we have limited understanding of why quality improvement efforts are successful in some hospitals and not others. Using data collected as part of a multi-center study, we closely examined quality improvement efforts and the implementation of recommended practices to prevent central line-associated bloodstream infections (CLABSI) in U.S. hospitals. We compare and contrast the experiences among hospitals to better understand 'how' and 'why' certain hospitals were more successful with practice implementation when taking into consideration specific aspects of the organizational context. This study reveals that among a number of hospitals that focused on implementing practices to prevent CLABSI, the experience and outcomes varied considerably despite using similar implementation strategies. Moreover, our findings provide important insights about how and why different quality improvement strategies might perform across organizations with differing contextual characteristics. PMID- 20850919 TI - Overcoming gendered and professional hierarchies in order to facilitate escalation of care in emergency situations: the role of standardised communication protocols. AB - It has been suggested that as many as 23,000 in-hospital cardiac arrests in the UK could be prevented with earlier detection and intervention (Hodgetts et al., 2002). Cases of 'failure to rescue' are often linked with difficulties relaying and interpreting information across occupational and professional boundaries. Standardised communication protocols have been recommended as a means of enabling the transmission of concise, salient information, licensing and empowering the individual to overcome established hierarchies in speaking out and asking for help. This paper critically examines the current discourse around such protocols. We find that there is a paucity of evidence regarding the complex relationship between social contexts, individual applications of these protocols and short- and long-term impact on safety and 'failure to rescue' rates. The paper highlights the complexities of the underlying power dynamics that are located within gendered and occupational hierarchies and explores the role of standardised communication protocols as a potential boundary object. The paper discusses the potential for these protocols to inter-relate and act as a mediating boundary object between nursing and medical staff, enabling understanding and sharing of cultural context. PMID- 20850920 TI - From places to flows. International secondary migration and birth outcomes. AB - Research on the health status of international migrants to industrialised countries in general, and on perinatal outcomes in particular, has assumed an interpretative model based on primary migration, characterised by one permanent cross-border movement from the migrant's country of birth. However, many migrants experience more complex migration patterns that may also be associated with human health. Secondary migration, defined as a migration from a country of residence other than the country where the immigrant was born, has been growing during the last two decades, favoured by globalisation. The purpose of this study was to examine the association between secondary migration and preterm birth (PTB) and infant birthweight at term (BW) using a Canadian official immigration database to build a cohort of immigrants to Ontario, Canada, who obtained their permanent residence in the years 1985-2000. The study population comprised 320,398 singleton live infants born to immigrant women during 1988-2007. Primary and secondary migrants were categorised according to whether they were born in an industrialised country or not. Secondary migrants were further subdivided according to whether the country from which they migrated to Canada was industrialised or not. We found that compared to primary migrants, secondary migrants to Canada born in non-industrialised countries had lower odds of PTB and higher mean BW at term. However, such a protective effect was not observed among secondary migrants born in industrialised countries. In a cross-classified multilevel model restricted to secondary migrants, 5.2% of the variation in birthweight was explained by migrants' countries of birth and 0.8% by migrants' countries of last permanent residence. These findings are consistent with the so called healthy migrant effect, implying that selective migration from non industrialised countries is associated with protective individual characteristics. PMID- 20850921 TI - Evaluation of quality of life among the caregivers of asthmatic children: the new IFABI-R questionnaire. AB - BACKGROUND: The health-related quality of life (HRQoL) of asthmatic children and their caregivers is correlated to management of the disease and the presence of certain morbidity indicators. The integral assessment of paediatric asthma must include the evaluation of HRQoL among the caregivers, although existing questionnaires only partially assess the dimensions of this aspect. The present study describes a new questionnaire for evaluating HRQoL among the caregivers, comprising three dimensions (functional, emotional, and socio-occupational). MATERIAL AND METHODS: The study involves two phases. A total of 81 patients between 3 and 9 years of age and their caregivers participated in the first phase, involving a qualitative and psychometric study of the preliminary version of the questionnaire (IFABI). A total of 137 patients between 2 and 17 years of age and their caregivers participated in the second phase, in which the revised version of the questionnaire (IFABI-R) was developed and subjected to psychometric evaluation. RESULTS: First phase: The IFABI showed important reliability and internal consistency (Cronbach alpha=0.93), concurrent validity requiring improvement, and a scantly clear internal structure. Second phase: The IFABI-R showed important reliability and internal consistency (Cronbach alpha=0.90), adequate concurrent validity, and a three-dimensional structure whose three factors correspond to the three dimensions of the questionnaire. CONCLUSIONS: The good psychometric results obtained with the IFABI-R justify its use in paediatric asthmatic patients. The questionnaire is currently being scaled, and its sensitivity to change is being assessed. PMID- 20850922 TI - Relation of perimenstrual asthma with disease severity and other allergic co morbidities--the first report of perimenstrual asthma prevalence in Saudi Arabia. AB - BACKGROUND: Perimenstrual asthma (PMA) has been documented in 30-40% of asthmatic women; however, there have been few epidemiological investigations of PMA in practice. OBJECTIVES: Determination of the prevalence of perimenstrual asthma in a sample of female Saudi asthmatic patients, and to study the relation of PMA to asthma severity, aspirin-induced asthma and to other allergic co-morbidities. STUDY DESIGN: Data were analysed from all female asthmatic patients followed up in the unit from January 2008 to May 2009 who were not pregnant, not on oral contraceptive pills, not menopausal, nor had had a hysterectomy. They were asked about exacerbation of their asthma state regarding worsening of symptoms, need for more rescue medications and even visits to emergency room just before or in the first days of menstruation, or both. Moreover, relation with aspirin-induced asthma and other associated allergic co-morbidities recorded in their medical files with prevalence of PMA was reported. RESULTS: The prevalence was found to be 8.2%. Asthma severity was found to be significantly related to PMA (p<0.0001). Aspirin-induced asthma and allergic co-morbidities were more prone to occur in cases with PMA than other studied asthmatics. CONCLUSION: We have found a low prevalence of PMA in Saudi women of fertile age compared to other studies published. Study findings support the hypothesis that PMA is related to asthma severity. PMID- 20850923 TI - Differentiation of neural precursor cell-derived oligodendrocyte progenitor cells following transplantation into normal and injured spinal cords. AB - Demyelination contributes to the functional deficits after spinal cord injury (SCI). Therefore, remyelination may be an important strategy to facilitate repair after SCI. Oligodendrocyte precursor cells (OPCs) are immature oligodendrocytes and can differentiate into myelin-forming cells of central nervous system under certain conditions. OPC transplantation is an attractive approach for the treatment of demyelinating diseases. In this study, we transplanted OPCs expressing green fluorescent protein (GFP-OPCs) into normal and injured rat spinal cords to evaluate the differentiation of transplanted OPCs in vivo. Unfortunately, the grafted GFP-OPCs, in spinal cord whether normal or injured, were all differentiated into astrocytes, but not oligodendrocytes. Our further study indicated that inflammatory environment might not be the key factor influencing the differentiation of OPCs. Some spinal cord components, such as bone morphogenetic proteins (BMPs), were the major factors that induced OPCs to differentiate into astrocytes. The three types of BMP receptor (BMPRIA, IB and II) could all be detected in OPCs, and the astroglial differentiation of OPCs induced by spinal cord homogenate extract (SCHE) in vitro could be blocked partly by noggin, an antagonist of BMP. These results suggested that the BMPR signal transduction pathway might be one of the key factors which determine the differentiation direction of engrafted OPCs in spinal cord. PMID- 20850924 TI - MDM2 antagonist Nutlin-3 enhances bortezomib-mediated mitochondrial apoptosis in TP53-mutated mantle cell lymphoma. AB - This study demonstrated a pronounced synergistic growth-inhibitory effect of an MDM2 inhibitor Nutlin-3 and a proteasome inhibitor bortezomib in mantle cell lymphoma (MCL) cells regardless of TP53 mutant status and innate bortezomib sensitivity. In the mutant TP53 MCL cells which are intrinsically resistant to bortezomib, the combination of Nutlin-3/bortezomib synergistically induced cytotoxicity through the mitochondrial apoptotic pathway mediated by transcription-independent upregulation of NOXA, sequestration of MCL-1, activation of BAX, BAK, caspase-9 and -3. In the bortezomib sensitive wild-type TP53 MCL cells, the Nutlin-3/bortezomib combination caused G0/G1 cell cycle arrest followed by the increase in apoptosis induction. These findings indicate potential therapeutic efficacy of Nutlin-3/bortezomib combination for the treatment of chemorefractory MCL. PMID- 20850925 TI - Free-standing graphene by scanning transmission electron microscopy. AB - Free-standing graphene sheets have been imaged by scanning transmission electron microscopy (STEM). We show that the discrete numbers of graphene layers enable an accurate calibration of STEM intensity to be performed over an extended thickness and with single atomic layer sensitivity. We have applied this calibration to carbon nanoparticles with complex structures. This leads to the direct and accurate measurement of the electron mean free path. Here, we demonstrate potentials using graphene sheets as a novel mass standard in STEM-based mass spectrometry. PMID- 20850926 TI - Prevalence of coccidial infection in sheep and goats in northeastern China. AB - The prevalence of coccidial infection in sheep and goats was examined in Heilongjiang Province, northeastern China between January 2007 and June 2009. A total of 508 faecal samples (309 from sheep and 199 from goats) were collected from eight sheep and goat rearing administrative regions. Oocysts in faecal samples were detected using a flotation technique, sporulated and identified to species based on morphological features of the sporulated oocysts. The overall prevalence of coccidial infection was 90.9% (462/508), with prevalence of 92.9% (287/309) for sheep and 87.9% (175/199) for goats. 13 species of Eimeria were identified, namely, E. bakuensis, E. faurei, E. parva, E. ahsata, E. crandallis, E. granulosa, E. intricata, E. pallida, E. christenseni, E. caprina, E. alijevi, E. apsheronica and E. arloingi. In sheep, the most common Eimeria species were E. ahsata (67.2%), E. parva (59.9%) and E. bakuensis (44.3%). In goats, the more prevalent species were E. christenseni (78.3%), E. alijevi (73.7%), E. caprina (62.3%) and E. arloingi (44.6%). Concurrent infection with two to eight species was common. However, no clinical symptoms were observed in the examined sheep and goats. The results of the present investigation have implications for the control of coccidial infections in sheep and goats in northeastern China. PMID- 20850927 TI - Analysis of multiyear studies in horses in Kentucky to ascertain whether counts of eggs and larvae per gram of feces are reliable indicators of numbers of strongyles and ascarids present. AB - Increasing levels of anthelmintic resistance in equine nematodes have led to recommendations of more sustainable anthelmintic treatment protocols with emphasis on parasite surveillance and diagnosis, rather than prophylactic calendar-based treatments. This requires knowledge of the diagnostic test performance of techniques for counts of eggs per gram of feces (EPG) as well as methods for culturing, counting and identifying third stage (L(3)) strongyle larvae per gram of feces (LPG). For horses, such information does not exist in the published literature. The aim of this study was to examine the relationship between worm count and fecal egg count (FEC) data for strongyle and Parascaris equorum infections as well as larval culture counts for diagnosing Strongylus spp. infections. Necropsy data from 693 horses used for critical or controlled tests, including information on total worm counts, fecal egg counts (FEC) and larval culture results collected at the University of Kentucky over a period of 50 years were analyzed. Sensitivity, specificity, positive and negative predictive values, and receiver operator characteristic (ROC) curves were generated for the larval cultures and ascarid egg counts. For the strongyle egg counts, potential FEC cutoff values for treatment were evaluated statistically by comparing the total strongyle worm counts below and above chosen cutoff values. All tests had high positive predictive values (>0.95), but moderate negative predictive values (<0.70). The negative predictive values of the larval counts were negatively affected by increasing egg count levels. Strongyle FEC cutoff values up to the level of 500 EPG yielded significantly higher strongyle worm counts in the treatment group, whereas no differences were found at higher cutoffs. This supports usage of cutoffs for treatment in the 0-500 EPG range. Altogether, the present study yields unique and useful information of widely used methods for parasite surveillance and diagnosis in equine establishments. PMID- 20850928 TI - Cellular response in semi-intensively cultured sea bream gills to Ergasilus sieboldi (Copepoda) with emphasis on the distribution, histochemistry and fine structure of mucous cells. AB - Light and ultrastructure studies were carried out on gill of sea bream, Sparus aurata L., naturally infected with Ergasilus sieboldi (Copepoda) to assess pathology and host cell responses. Thirty S. aurata were examined, and 23 (74%) were infected, the intensity of infection ranging from 3 to 50 parasites per host. The copepod encircled gill lamellae with its second antennae, occluded arteries, compressed the epithelium, provoked hyperplasia and haemorrhage, and often caused tissue disruption. Adjacent to the site of attachment, rodlet cells (RCs), mast cells (MCs) and mucous cells were observed. In parasitized fish, mucous cells were more abundant in infected gills than in uninfected (t-test, P<0.01), while no significant differences were encountered in the numbers of RCs and MCs between gill of infected and uninfected fish (t-test, P>0.01). In both infected and uninfected gill, the RCs were within the primary lamella and also sometimes occurred in secondary lamella. In healthy and infected gill, MCs were free within the connective tissue inside and outside the blood vessels of the primary lamellae and made close contact with vascular endothelial cells. Infected and uninfected gill mucous cells stained positively for neutral muco-substances (PAS positive). In all sea bream, gill mucous cells presented a central or eccentric electron-dense core within the mucus granules. PMID- 20850929 TI - Molecular identification and pathology of Anisakis pegreffii (Nematoda: Anisakidae) infection in the Mediterranean loggerhead sea turtle (Caretta caretta). AB - Nematodes of genus Anisakis spp. parasitize a wide range of marine hosts with marine mammals (mainly cetaceans) serving as definitive hosts, while fish, squid and other invertebrates serve as paratenic or intermediate hosts. Sea turtles can act as accidental or paratenic hosts for Anisakis spp. larvae, harbouring third stage larvae unable to complete their life cycle in an ectothermic vertebrate. Post-mortem examination of 96 loggerhead sea turtles (Caretta caretta) stranded along the Italian coast of the Mediterranean Sea showed infection by Anisakis larvae Type I from 4 of 6 locations that were identified as belonging to Anisakis pegreffii by sequence analyses of the mtDNA cox2. Thirteen turtles (11 males and 2 females) were infected with A. pegreffii. Larvae were detected through gross necroscopy from 7 turtles, while in other 6 positive loggerhead sea turtles A. pegreffii larvae were revealed by histopathology. Pathological changes associated with A. pegreffii larvae in the stomach and intestine included necrosis and granulomatous response compatible with larvae migration. The role of the loggerhead sea turtle as an accidental host in the life cycle of this nematode is also discussed. This study is the first description of pathological changes associated with A. pegreffii in a sea turtle. PMID- 20850930 TI - Standardization of the larval migration inhibition test for the detection of resistance to ivermectin in gastro intestinal nematodes of ruminants. AB - Resistance to anthelmintics is an increasing problem in sheep, goat and cattle industries worldwide. For parasite management on farms reliable methods for the detection of resistance are required and it is important that tests give comparable, reproducible and reliable results in different laboratories. The ability of the larval migration inhibition test (LMIT), to detect ivermectin resistance in cattle and sheep nematodes has been evaluated through ring testing in up to six different laboratories in Europe, supported by an EU sixth Framework Project (PARASOL). Third stage larvae of Ostertagia ostertagi, Cooperia oncophora, and Haemonchus contortus with a known resistance status were obtained from faecal cultures of experimentally infected calves and sheep. Following a series of ring tests using identical protocols, reproducible results were obtained within and between participating laboratories. In all tests dose response curves with R(2) values >0.90 were obtained by all laboratories. Resistance ratios of 8.3 and 8.4 were found when susceptible and IVM-resistant isolates of C. oncophora and H. contortus were compared and differences in the EC(50) values were highly significant (p<0.0001). Protocols for the LMIT and the preparation of ivermectin solutions are described in a supplementary file. PMID- 20850931 TI - Fleshflies in the flesh: epidemiology, population genetics and control of outbreaks of traumatic myiasis in the Mediterranean Basin. AB - Although the damaging effects on healthy tissues of its developing larvae were first described in 1770, the fleshfly Wohlfahrtia magnifica remains a serious pest for the livestock industry. Wohlfahrtiosis, the severe myiasis caused by this fly, is a grave problem in terms of both the animal welfare and economic loss. This review highlights important aspects of the biology, pest status, epidemiology, population genetic structure, economics and control of W. magnifica and wohlfahrtiosis, with an emphasis on recent outbreaks in Greece and Morocco and fly population dynamics in the Mediterranean Basin. Potential areas for future studies on genetics, host tolerance, in vitro rearing, field behaviour and range expansion of the species are also discussed. PMID- 20850933 TI - Bovine besnoitiosis: epidemiological and clinical aspects. AB - Bovine besnoitiosis, due to the cyst-forming apicomplexan Besnoitia besnoiti, is widespread in Africa, in Asia and in the south of Europe. This infection leads to major economic losses in cattle production with a decrease in milk production, transient of definitive sterility of bulls and mortality. Since its emergence in Europe (Germany, Spain and Centre of France), more attention has been given to this infection during the last 10 years, including the recent development of serological methods for diagnosis. The life cycle of B. besnoiti remains a mystery: the definitive host is unknown and the transmission routes are poorly understood. B. besnoiti is thought to be transmitted mainly by hematophagous insects. This paper presents a review of what is currently known of the epidemiology of bovine besnoitiosis and the key manifestations of the disease. It highlights the urgent need for research programs to improve efficient and sustainable control methods. PMID- 20850932 TI - Onchocerca armillata contains the endosymbiotic bacterium Wolbachia and elicits a limited inflammatory response. AB - Human onchocerciasis, also known as River Blindness, is a debilitating disease caused by the filarial nematode Onchocerca volvulus. Many, but not all, filarial nematodes carry within their tissues endosymbiotic, Rickettsia-like bacteria of the genus Wolbachia. Onchocerca spp. infections in cattle offer the most relevant, analogous host-parasite model system. West African cattle are commonly co-infected with four Onchocerca spp.; two of these are Wolbachia-positive (Onchocerca gutturosa and Onchocerca ochengi), and the remainder are of unknown Wolbachia status (Onchocerca dukei and Onchocerca armillata). Previous studies have suggested that worm survival is dependent on this bacterium. O. armillata, an abundant parasite of African cattle that has received little attention, is a primitive species that may lack Wolbachia. The objectives of this study were to determine if O. armillata carries Wolbachia and to provide preliminary descriptions of the host inflammatory cell environment around the adult worms. The findings may support or refute the hypothesis that a prime contribution of Wolbachia is to permit long-term survival and reproduction of certain Onchocerca spp. (including O. volvulus in humans). O. armillata adult worms were found in the aorta of 90.7% of cattle (n=54) slaughtered at an abattoir in Ngaoundere, Adamawa Region, Cameroon. The presence of Wolbachia in O. armillata was confirmed by a specific anti-Wolbachia surface protein antibody detected using a peroxidase conjugate (immunohistochemistry) and PCR for detection of Wolbachia-specific sequences within DNA extracts from frozen worms. Tissue sections stained with haematoxylin and eosin showed the host cell response to be dominated by macrophages and fibroblasts. This is unusual compared with nodule-dwelling Wolbachia-positive Onchocerca spp., where the host response is typically characterised by granulocytes, and suggests that the mechanisms for worm survival employed by this species (which is probably motile) may differ. PMID- 20850934 TI - Fatal infections in a captive Pithecia irrorata (primate) by Porocephalus sp. (Pentastomida). AB - This work presents a case of sudden death of a non-human adult male primate, which belongs to the National Primate Center (CENP - Ananindeua - Para - Brazil). The specimen was necropsied, and the anatomicopathologic exam showed a great collection of clotted blood in the right thoracic cavity, forming a mold. The aorta revealed an extensive lesion in its intima with a disruption area in its tissue. In the lungs, three encapsulated parasites were observed in subpleural location, specifically in the diaphragmatic, right apical and accessory lobes, measuring 05 mm diameter, which revealed a C-form by transparency analysis, characteristic of the nymphal stage of Pentastomida. Two cysts were dissected and the parasites demonstrated structural and morphometric patterns compatible with the nymph of Porocephalus. Histologically, encapsulated parasites were observed in the lungs, with inflammatory reaction in the underlying parenchyma, presence of exudate composed of fibrin, macrophages, detaching the eosinophils and presenting no granulomatous reaction. The aortic adventitial tissue presented development of granulation tissue, deposit of fibroid material in its margins, prevalence of eosinophils and free blood. The macroscopic and microscopic alterations in the aorta, as well as the presence of nymphs of Pentastomida in the lungs are data that base the hypothesis that the aortic lesion was responsible for the fatal picture of internal hemorrhage, and this picture was due to the migratory process of Pentastomida. PMID- 20850935 TI - Life cycle of the camel tick Hyalomma dromedarii (Acari: Ixodidae) under field conditions in Northern Sudan. AB - Engorged Hyalomma dromedarii females were placed for development in shade and sun (open non-shaded site) in April, August and December for two successive years. Engorged nymphs were also placed at the same sites in January, March, May, June, July and August. Preoviposition periods ranged between 9.8 and 11.7 days in the shade but longer in the sun in December (14.7 days). Egg production index was higher in August (0.72) than in April and December (0.46 and 0.39, respectively) in shade and in August compared to December in the sun (0.65 and 0.29, respectively). In shade and in sun, the prehatching periods were longer in December (50.7 and 48.2 days) than in April and August (25.6 and 29.0 days). Percentage hatchability ranged between 82 to 94.1% and 56.2 and 58.9% in the shade and sun, respectively. Number of eggs laid and eggs hatched were positively correlated with females' engorgement weights. There were high mortality rates of females in the sun and most of the eggs desiccated. Slight increased ambient and soil temperatures increased egg production, shortened preoviposition periods and decreased hatchability while increased humidity shortened preoviposition and prehatching periods and increased hatchability. Nymphal-adult moulting periods were long in January (20.7 days in the shade and 14.4 days in the sun) and short in August in the shade (7.8 days) while they were only 6 days in May and June in the sun. High numbers moulted in all months in the shade (ranges 23.3-29.5 nymphs). The mean mortality of engorged nymphs in the shade was very low. However, in the sun mortality was high (12.9-30 nymphs). Premoulting periods were negatively correlated with ambient temperature but positively correlated with humidity. In the shade, mean number of nymphs moulting increased with increased mean ambient temperature, humidity and rainfall. PMID- 20850936 TI - Acute kidney injury and the burned patient: Progression and outcomes. PMID- 20850937 TI - Distribution of molecular breast cancer subtypes among Tunisian women and correlation with histopathological parameters: a study of 194 patients. AB - According to the immunohistochemical test of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (Her-2), breast cancer can be divided into 4 molecular subtypes: luminal A, luminal B, Her-2, and basal like. The purpose of this study is to correlate these subtypes with clinicopathological features. We have selected from the files of our Pathology Department 194 breast carcinomas which had already been studied for ER, PR, and Her-2, diagnosed between January 2008 and October 2009. The cases were classified into 4 molecular subtypes. The clinicopathological characteristics of each subtype were compared. The luminal A subtype was the most prevalent (51.5%). The basal-like and Her-2 subtypes were significantly correlated to a large tumor size, a high tumor grade, and a high-volume nodal involvement (>=4). On multivariate analysis, patients with the Her-2 and basal-like subtypes were 4.2 (95% CI, 1.3-13.5) times more likely to have developed metastases in four or more lymph nodes than those with luminal tumors. Our analysis revealed that the Her-2 and basal-like subtypes are correlated with factors associated with a poor prognosis. The luminal A subtype is the commonest subtype, showing that breast cancer in Tunisia has no aggressive phenotype. PMID- 20850938 TI - [Inheritance in erythropoietic protoporphyria]. AB - Erythropoietic protoporphyria (EPP) is an inherited disorder of heme biosynthesis that results from an accumulation of protoporphyrin IX in erythroid cells, plasma, skin and liver. EPP leads to acute photosensitivity and, in about 2% of patients, liver disease. EPP is a complex syndrome in which two genes are independently involved: FECH and ALAS2. More than 96% of unrelated EPP patients have ferrochelatase (FECH) deficiency (MIM 177000). Four percent of them present with autosomal recessive inheritance with two mutated FECH alleles. In dominant cases (95%) the inheritance of a common hypomorphic IVS3-48C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold. The frequency of the IVS3-48C allele differs widely from the Japanese (45%), to Black West Africans (<1%) populations. These differences in the frequency of this single common SNP account for the prevalence of overt EPP in different countries and for the absence of EPP in Black Africans. The phylogenic origin of the IVS3 48C haplotypes strongly suggests that the IVS3-48C allele arose from a single recent mutational event that occurred 60 Kyears ago. Acquired somatic mutation of FECH secondary to myeloid disease may also exceptionally cause EPP (<1%). Finally, about 4% of unrelated EPP patients have X-linked dominant protoporphyria (XLDPP) (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene leading to an increased erythroid heme biosynthesis and subsequently an accumulation of protoporphyrin without any FECH deficiency. PMID- 20850939 TI - Protective immune responses induced by in ovo immunization with recombinant adenoviruses expressing spike (S1) glycoprotein of infectious bronchitis virus fused/co-administered with granulocyte-macrophage colony stimulating factor. AB - Infectious bronchitis virus (IBV) causes tremendous economic losses associated with production inefficiencies and mortality in poultry industry worldwide. In the present report, the recombinant adenoviruses expressing chicken granulocyte macrophage colony stimulating factor (GM-CSF) and S1 gene of nephropathogenic IBV were constructed and characterized. Then, the immunological efficacy and protection against homologous IBV challenge were assessed in specific pathogen free (SPF) chickens. The results showed that the chickens vaccinated in ovo with rAd-S1, rAd-GM-S1 (GM-CSF fused with S1 using glycine linkers) and rAd-GM-CSF plus rAd-S1 (co-administered) developed specific anti-IBV HI antibodies. Moreover, the fusion of the GM-CSF markedly increased spleen cell proliferation and IFN-gamma production while mild increased in IL-4 production, which demonstrated the enhancement of cell-mediated immune responses. Following challenge with IBV, the chickens in the group vaccinated with rAd-S1 fused or co administered with GM-CSF had fewer nephropathic lesions and showed 100% protection as compared to that of rAd-S1 alone which showed 70% protection. It indicated that the single dose in ovo vaccination of the GM-CSF fused or co administered with S1 of IBV could enhance significantly the humoral, cellular immune responses and provide complete protection against nephropathogenic IBV challenge. This finding may provide basic information for effective in ovo vaccines design against IBV. PMID- 20850940 TI - Early human development: neonatal tumours: vascular tumours. AB - Vascular tumours (haemangiomas and malformations) are common tumours of infancy and childhood. They represent a group of mostly benign conditions, which present early, can grow rapidly and be symptomatic or disfiguring. There are various management options, with different cosmetic and functional outcomes. Haemangiomas and vascular malformations have different clinical courses which dictate respective management; differentiating them is key. Haemangiomas are generally self-limiting after initial proliferation; generally management is conservative. Symptoms can call for treatment. Options include laser, steroids, chemotherapy and surgery. Propanolol, the newest modality of treatment, may have a dramatic effect in problematic lesions. Vascular malformations are a less common group of heterogenous lesions, with some overlap between entities. They do not involute. Treatment options include laser therapy, sclerotherapy, embolisation, and surgery. Emerging therapies include photodynamic therapy and angiogenesis inhibitors. This review will outline the evidence for the various modalities in managing these conditions. PMID- 20850942 TI - 5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant. AB - 5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most prevalent inborn error of folate metabolism, and has variable clinical manifestations from asymptomatic to severe psychomotor retardation, microcephalus and seizure. In untreated infantile cases, it predominantly affects the central nervous system, which is sometimes fatal. On the other hand, peripheral nerve involvement is uncommon. We present a severe infantile case of MTHFR deficiency that manifested unilateral phrenic nerve palsy with communicating hydrocephalus, developmental delay and died at 11months of age. An enzymatic study confirmed MTHFR deficiency with residual activity of 0.75% of mean control values in cultured fibroblasts. Mutation analysis of the MTHFR gene revealed homozygous, tandem missense mutations c.[446G>T; 447C>T] in exon 3 of the MTHFR gene converting glycine to valine (Gly149Val). In MTHFR deficiency, betaine may improve the symptoms if started immediately after birth by reducing the level of serum homocysteine and increasing that of methionine. Our results show that we should be aware of possible inborn errors of folate metabolism such as MTHFR deficiency, in infants with unexplained developmental delay manifesting rapidly progressive polyneuropathy. PMID- 20850941 TI - Endometrial gene expression of acute phase extracellular matrix components following estrogen disruption of pregnancy in pigs. AB - In pigs, administration of estrogen to gilts on Days 9 and 10 of pregnancy causes conceptus fragmentation and death between Days 15 and 18 of gestation. Conceptus degeneration is associated with breakdown of the microvilli surface glycocalyx on the lumenal epithelium (LE). We previously identified endometrial expression of inter-alpha-trypsin inhibitor (ITI) and hyaluronic acid (HA), which are key components of extracellular matrix (ECM), during the period of conceptus attachment to the uterine surface in the pig. Tumor necrosis factor-alpha inducible protein-6 (TNFAIP6) serves as a linker for ECM expansion and is stimulated by prostaglandin E (PGE). We hypothesized that early estrogen administration alters the normal ECM components forming glycocalyx on the LE. Bred gilts (4 gilts/trt/day) were treated with either 5mg estradiol cypionate (E) or corn oil (CO) on Days 9 and 10 of gestation. The uterus was surgically removed on either Days 10, 12, 13, 15 and 17 of gestation and endometrial tissue snap frozen in liquid nitrogen. Endometrial tumor necrosis factor-alpha (TNF), TNFAIP6, interleukin 6 (IL6), and inter-alpha-trypsin inhibitor heavy chains (ITIH) were detected during early pregnancy thereby indicating all components for maintenance of the extracellular glycocalyx are present in the endometrium of pigs. However, only gene expression of ITIH2 was suppressed by E-treatment. TNFAIP6 protein was detected across all days of gestation but was not affected by E-treatment. The present study demonstrates that while the pig endometrium expresses key components of ECM only ITIH2 gene expression was altered by E treatment. A decrease in ITIH2 could lead to the possible loss of the uterine glycocalyx leading to conceptus degeneration; however, other factors may be involved with the loss of glycocalyx during implantation in the pig following E treatment. PMID- 20850943 TI - Characterization of honeybee venom by MALDI-TOF and nanoESI-QqTOF mass spectrometry. AB - The aim of the study was to comprehensively characterize different honeybee venom samples applying two complementary mass spectrometry methods. 41 honeybee venom samples of different bee strains, country of origin (Poland, Georgia, and Estonia), year and season of the venom collection were analyzed using MALDI-TOF and nanoESI-QqTOF-MS. It was possible to obtain semi-quantitative data for 12 different components in selected honeybee venom samples using MALDI-TOF method without further sophisticated and time consuming sample pretreatment. Statistical analysis (ANOVA) has shown that there are qualitative and quantitative differences in the composition between honeybee venom samples collected over different years. It has also been demonstrated that MALDI-TOF spectra can be used as a "protein fingerprint" of honeybee venom in order to confirm the identity of the product. NanoESI-QqTOF-MS was applied especially for identification purposes. Using this technique 16 peptide sequences were identified, including melittin (12 different breakdown products and precursors), apamine, mast cell degranulating peptide and secapin. Moreover, the significant achievement of this study is the fact that the new peptide (HTGAVLAGV+Amidated (C-term), M(r)=822.53Da) has been discovered in bee venom for the first time. PMID- 20850944 TI - The impact of dietary and tooth-brushing habits to dental caries of special school children with disability. AB - The daily oral activities may severely influence oral health of children with disabilities. In this survey, we analyzed the impact of dietary and tooth brushing habits to dental caries in special school children with disabilities. This cross-sectional survey investigated 535 special school children with disabilities aged 6-12 years, 60.93% males, 39.07% females from 10 special schools in Taiwan. Oral examinations were carried out by dentists with a Kappa score of their inter-examiner agreement exceeding 0.8. Data on demographics, diet, and tooth-brushing habits of children with disabilities were collected using a standardized questionnaire completed by parents/caregivers. More than three quarters of the participants were combined with severe or profound disability. Children with profound severity in disability had a higher percentage (67.37%) in teeth-brushing by parents/caregivers compared to those children with mild/moderate severity in disability which had a higher percentage (81.60%) in teeth-brushing by themselves. Children whose teeth were brushed by parents/caregivers had a better dental health, and lower caries prevalence. The main risk factors related to decayed teeth of children with disabilities are frequency of sweets intake, ability to brush teeth and with plaque or not. The dental health education, prevention program and periodical oral check-up to children with disabilities and their parents/caregivers should be reinforced. Brushing skill should be taught to children according to their type, severity and individual characteristics of disability. PMID- 20850946 TI - Left ventricular reverse remodeling in percutaneous and surgical aortic bioprostheses: an echocardiographic study. AB - BACKGROUND: Surgical aortic valve replacement (SAVR) is the definitive proven therapy for patients with severe aortic stenosis who have symptoms or decreased left ventricular (LV) function. The development of transcatheter aortic valve implantation (TAVI) offers a viable and "less invasive" option for the treatment of patients with critical aortic stenosis at high risk with conventional approaches. The main objective of this study was the comparison of LV hemodynamic and structural modifications (reverse remodeling) between percutaneous and surgical approaches in the treatment of severe aortic stenosis. METHODS: Fifty eight patients who underwent TAVI with the CoreValve bioprosthetic valve were compared with 58 patients with similar characteristics who underwent SAVR. Doppler echocardiographic data were obtained before the intervention, at discharge, and after 6-month to 12-month follow-up. RESULTS: Mean transprosthetic gradient at discharge was lower (P<.003) in the TAVI group (10+/-5 mm Hg) compared with the SAVR group (14+/-5 mm Hg) and was confirmed at follow-up (10+/ 4 vs 13+/-4 mm Hg, respectively, P<.001). Paravalvular leaks were more frequent in the TAVI group (trivial to mild, 69%; moderate, 14%) than in the SAVR group (trivial to mild, 30%; moderate, 0%) (P<.0001). The incidence of severe prosthesis-patient mismatch (PPM) was significantly lower (P<.004) in the TAVI group (12%) compared with the SAVR group (36%). At follow-up, LV mass and LV mass indexed to height and to body surface area improved in both groups, with no significant difference. In patients with severe PPM, only the TAVI subgroup showed significant reductions in LV mass. LV ejection fraction improved at follow up significantly only in TAVI patients compared with baseline values (from 50.2+/ 9.6% to 54.8+/-7.3%, P<.0001). CONCLUSIONS: Hemodynamic performance after TAVI was shown to be superior to that after SAVR in terms of transprosthetic gradient, LV ejection fraction, and the prevention of severe PPM, but with a higher incidence of aortic regurgitation. Furthermore, LV reverse remodeling was observed in all patients in the absence of PPM, while the same remodeling occurred only in the TAVI subgroup when severe PPM was present. PMID- 20850945 TI - Accuracy and reproducibility of strain by speckle tracking in pediatric subjects with normal heart and single ventricular physiology: a two-dimensional speckle tracking echocardiography and magnetic resonance imaging correlative study. AB - BACKGROUND: Myocardial strain is a sensitive measure of ventricular systolic function. Two-dimensional speckle-tracking echocardiography (2DSE) is an angle independent method for strain measurement but has not been validated in pediatric subjects. The aim of this study was to evaluate the accuracy and reproducibility of 2DSE-measured strain against reference tagged magnetic resonance imaging measured strain in pediatric subjects with normal hearts and those with single ventricles (SVs) of left ventricular morphology after the Fontan procedure. METHODS: Peak systolic circumferential strain and longitudinal strain (LS) in segments (n = 16) of left ventricles in age-matched and body surface area-matched 20 healthy and 12 pediatric subjects with tricuspid atresia after the Fontan procedure were measured by 2DSE and tagged magnetic resonance imaging. Average (global) and regional segmental strains measured by the two methods were compared using Spearman's and Bland-Altman analyses. RESULTS: Global strains measured by 2DSE and tagged magnetic resonance imaging demonstrated close agreements, which were better for LS than circumferential strain and in normal left ventricles than in SVs (95% limits of agreement, +0.0% to +3.12%, -2.48% to +1.08%, -4.6% to +1.8%, and -3.6% to +1.8%, respectively). There was variability in agreement between regional strains, with wider limits in apical than in basal regions in normal left ventricles and heterogeneity in SVs. Strain values were significantly (P < .05) higher in normal left ventricles than in SVs except for basal LS, which were similar in both cohorts. The regional strains in normal left ventricles demonstrated an apicobasal magnitude gradient, whereas SVs showed heterogeneity. Reproducibility was the most robust for images obtained with frame rates between 60 and 90 frames/sec, global LS in both cohorts, and basal strains in normal left ventricles. CONCLUSIONS: Strains measured by 2DSE agree with strain measured by magnetic resonance imaging globally but vary regionally, particularly in SVs. Global strain may be a more robust tool for cardiac functional evaluation than regional strain in SV physiology. The reliability of 2DSE-measured strain is affected by the frame rate, the nature of strain, and ventricular geometry. PMID- 20850947 TI - Pitfalls in diagnosing PFO: characteristics of false-negative contrast injections during transesophageal echocardiography in patients with patent foramen ovales. AB - BACKGROUND: Contrast injections during transesophageal echocardiography for patent foramen ovale (PFO) detection may be false negative. The characteristics of false-negative injections were studied retrospectively. METHODS: Contrast transesophageal echocardiography was analyzed for the presence or absence of two characteristics: leftward bulging of the interatrial septum and dense contrast filling of the region of the right atrium adjacent to the interatrial septum. RESULTS: Two hundred forty-seven injections were administered to 14 patients with PFOs, and 130 (53%) were false negative. The absence of either characteristic during a single injection resulted in low sensitivity for PFO detection of 7%. When the two characteristics were present at the same time, the sensitivity for PFO detection after a single injection was as high as 95%. CONCLUSIONS: The simultaneous presence of both leftward bulging of the interatrial septum and dense contrast filling of the region in the right atrium, adjacent to the interatrial septum, is a prerequisite for PFO detection, and if either characteristic is missing, the injection is inconclusive. PMID- 20850949 TI - A familial spontaneous epileptic feline strain: a novel model of idiopathic/genetic epilepsy. AB - A spontaneous epileptic model of cats has not been described previously. Recently, we identified familial epileptic cats and investigated their clinical features. These epileptic cats are healthy except for the presence of recurrent seizures that are typically a focal limbic seizure with secondary generalization. Furthermore, generalized seizures were induced by vestibular stimulation in some cats. This spontaneous epileptic cat strain may be a valuable model for idiopathic/genetic epilepsy. PMID- 20850948 TI - Immunotargeting of insulin reactive CD8 T cells to prevent diabetes. AB - Insulin is one of the earliest targeted autoantigens in the immune destruction of insulin-producing beta cells by autoreactive CD4 and CD8 T cells in type 1 diabetes. In this study, we used Non-obese diabetic (NOD) transgenic T cells engineered to express MHC class I-insulin peptide complexes linked to a T cell activation component (InsCD3-zeta), to target insulin-reactive CD8 T cells. We showed that activated, but not naive, InsCD3-zeta CD8 T cells killed diabetogenic insulin-reactive CD8 target cells in vitro, inducing antigen-specific cell death mediated via both the release of perforin and the Fas-Fas ligand pathway. In vivo, InsCD3-zeta CD8 T cells migrated to the pancreatic lymph nodes of NOD mice after adoptive transfer. Concomitant with this, infiltration of CD8 T cells was also reduced in the pancreatic islets. Finally, in vivo, we showed that diabetes induced by adoptive transfer of insulin-reactive T cells was reduced following injection of activated InsCD3-zeta CD8 T cells. Furthermore, young NOD mice injected with InsCD3-zeta CD8 T cells developed a lower incidence and delayed onset of diabetes. Thus, using this novel system we have demonstrated that InsCD3 zeta CD8 T cells can directly kill insulin-reactive CD8 T cells in vitro and by targeting insulin-specific CD8 T cells early in the course of disease alter the progression of spontaneous diabetes in vivo in NOD mice. PMID- 20850950 TI - EEG spectral power and negative symptoms in at-risk individuals predict transition to psychosis. AB - INTRODUCTION: EEG power in the delta, theta and beta1 bands has been shown to be positively correlated with negative symptoms in first episode psychotic patients. The present study investigates this correlation in an "at risk mental state for psychosis" (ARMS) with the aim to improve prediction of transition to psychosis. METHODS: Thirteen ARMS patients with later transition to psychosis (ARMS-T) and fifteen without (follow-up period of at least 4 years) (ARMS-NT) were investigated using spectral resting EEG data (of 8 electrodes over the fronto central scalp area placed according to the 10-20 system) and summary score of the Scale for the Assessment of Negative Symptoms (SANS). Linear regressions were used to evaluate the correlation of SANS and EEG power in seven bands (delta, theta, alpha1, alpha2, beta1, beta2, beta3) in both ARMS groups and logistic regressions were used to predict transition to psychosis. Potentially confounding factors were controlled. RESULTS: ARMS-T and ARMS-NT showed differential correlations of EEG power and SANS in delta, theta, and beta1 bands (p<.05): ARMS T showed positive and ARMS-NT negative correlations. Logistic regressions showed that neither SANS score nor EEG spectral power alone predicted transition to psychosis. However, SANS score in combination with power in the delta, theta, beta1, and beta2 bands, respectively, predicted transition significantly (p<.03). CONCLUSIONS: ARMS-T and ARMS-NT show differential correlations of SANS summary score and EEG power in delta, theta, and beta bands. Prediction of transition to psychosis is possible using combined information from a negative symptom scale and EEG spectral data. PMID- 20850951 TI - The Schizophrenia Caregiver Quality of Life questionnaire (S-CGQoL): development and validation of an instrument to measure quality of life of caregivers of individuals with schizophrenia. AB - OBJECTIVE: This study aims to validate a self-administered, multidimensional QoL instrument based on the point of view of caregivers of individuals with schizophrenia. METHODS: Data were collected through the departments of six psychiatric hospitals in France (n=246). The item reduction and validation processes were based on both item response theory and classical test theory. RESULTS: The S-CGQoL contains 25 items describing seven dimensions (Psychological and Physical Well-Being; Psychological Burden and Daily Life; Relationships with Spouse; Relationships with Psychiatric Team; Relationships with Family; Relationships with Friends; and Material Burden). The seven-factor structure accounted for 74.4% of the total variance. Internal consistency was satisfactory; Cronbach's alpha coefficients ranged from 0.79 to 0.92 in the whole sample. The scalability was satisfactory, with INFIT statistics falling within an acceptable range. In addition, the results confirmed the absence of DIF and supported the invariance of the item calibrations. CONCLUSION: The S-CGQoL is a self administered QoL instrument that presents satisfactory psychometric properties and can be completed in 5 min, thereby fulfilling the goal of brevity sought in research and clinical practice. PMID- 20850952 TI - Clozapine treatment associated with increased risk of acute myeloid leukemia (AML). PMID- 20850953 TI - Immune responses induced by Pelargonium sidoides extract in serum and nasal mucosa of athletes after exhaustive exercise: modulation of secretory IgA, IL-6 and IL-15. AB - The evidence that exhaustive exercise may compromise the immune response is mainly confirmed by upper respiratory tract infections which are probably related to the decrease in secretory immunoglobulin A in the upper airway mucosa and/or profile changes of systemic cytokines as well as local cytokines of the upper respiratory tract. An extract from Pelargonium sidoides roots is currently used to treat infections in the upper airways. The aim of the present study was to evaluate the action of this herbal medicine on the immune response of athletes submitted to an intense running session by analyzing the production of immunoglobulin A in their saliva and of cytokines both locally and systemically, using a placebo as control. The results show that Pelargonium sidoides extract modulates the production of secretory immunoglobulin A in saliva, both interleukin-15 and interleukin-6 in serum, and interleukin-15 in the nasal mucosa. Secretory immunoglobulin A levels were increased, while levels of IL-15 and IL-6 were decreased. Based on this evidence, we suggest that this herbal medicine can exert a strong modulating influence on the immune response associated with the upper airway mucosa in athletes submitted to intense physical activity. PMID- 20850954 TI - Apigenin inhibits hepatoma cell growth through alteration of gene expression patterns. AB - Apigenin, a common plant flavonoid, has been shown to possess anti-tumor properties; however, the underlying molecular mechanisms are still not completely understood. In the present study, we investigated the effects of apigenin on human hepatoma Huh7 cell proliferation, cell cycle distribution, apoptosis, and colony formation in vitro, as well as on the tumorigenicity of Huh7 cells in vivo. To get more insight into the mechanism of apigenin action, we performed genome-wide expression profiling of apigenin-treated Huh7 cells using cDNA microarrays (Agilent Whole Human Genome Oligo Microarray) that contain 41,000 genes. Ten of the most differentially expressed genes (?5-fold changes) were selected for further evaluation by quantitative RT-PCR (qPCR) and Western blot analyses. Notably, apigenin (5-20 MUg/ml) remarkably inhibited Huh7 cell proliferation and colony formation as compared to the vehicle control, which was in a dose-dependent manner. Accompanying with the decreased growth, apigenin treated cells showed a cell cycle arrest at G2/M phase and an increased rate of apoptosis. Moreover, the xenografts derived from Huh7 cells were significantly (p<0.05) retarded by the delivery of apigenin (50 MUg/mouse/day) relative to the control counterparts. Gene expression profile analysis revealed that 1336 genes were up-regulated and 428 genes were down-regulated by apigenin. The down regulation of interleukin-4 receptor and ubiquitin specific protease 18 and the up-regulation of SLC27A3 and chemokine (C-C motif) receptor 2 were further confirmed by the qPCR and Western blot results. In conclusion, apigenin exhibits inhibitory effects on hepatoma cell growth, which is likely mediated through alteration of gene expression profiles. PMID- 20850955 TI - Bacopa monnieri modulates endogenous cytoplasmic and mitochondrial oxidative markers in prepubertal mice brain. AB - Bacopa monnieri (BM) an herb, found throughout the Indian subcontinent in wet, damp and marshy areas is used in Ayurvedic system of medicine for improving intellect/memory, treatment of anxiety and neuropharmacological disorders. Although extensively given to children as a memory enhancer, no data exists on its ability to modulate neuronal oxidative stress in prepubertal animal models. Hence in this study, we examined if dietary intake of BM leaf powder has the propensity to modulate endogenous markers of oxidative stress, redox status (reduced GSH, thiol status), response of antioxidant defenses (enzymic), protein oxidation and cholinergic function in various brain regions of prepubertal (PP) mice. PP mice maintained on a BM-enriched diet (0.5 and 1%) for 4 weeks showed a significant diminution of basal oxidative markers (malondialdehyde levels, reactive species generation, hydroperoxide levels and protein carbonyls) in both cytoplasm and mitochondria of all brain regions. This was accompanied with enhanced reduced glutathione, thiol levels and elevated activities of antioxidant enzymes (catalase, glutathione peroxidase, superoxide dismutase). Significant reduction in the activity of acetyl cholinesterase enzyme in all brain regions suggested the potential of BM leaf powder to modulate cholinergic function. Further evidence that dietary intake of BM leaf powder confers the prepubertal brain with additional capacity to cope up with neurotoxic prooxidants was obtained by exposing cortical/cerebellar synaptosomes of normal and BM fed mice to 3-nitropropionic acid (3-NPA). While synaptosomes from control mice exhibited a concentration related lipid peroxidation and ROS generation, synaptosomes obtained from BM fed mice showed only a marginal induction at the highest concentration clearly suggesting their increased resistance to 3-NPA-induced oxidative stress. Collectively these data clearly indicate the potential of Bacopa monnieri to modulate endogenous markers of oxidative stress in brain tissue of PP mice. Based on these results, it is hypothesized that dietary intake of BM leaf powder confers neuroprotective advantage and is likely to be effective as a prophylactic/therapeutic agent for neurodegenerative disorders involving oxidative stress. PMID- 20850956 TI - Escin exerts synergistic anti-inflammatory effects with low doses of glucocorticoids in vivo and in vitro. AB - Escin, a natural mixture of triterpenoid saponins isolated from the seed of the horse chestnut (Aesculus hippocastanum), had been demonstrated to possess anti edematous and anti-inflammatory effects. The present study was designed to investigate whether escin exhibits synergistic anti-inflammatory effects when combined with glucocorticoids. The carrageenan-induced paw edema and pleuritis in bilaterally adrenalectomized rats were used to investigate the anti-inflammatory effects of escin and glucocorticoid alone or combined. The carrageenan-induced paw edema was inhibited only when escin and corticosterone (Cort) were administered together. Co-administration of escin with Cort significantly reduced the volume of exudates and the number of white blood cells of exudates in bilaterally adrenalectomized rats with pleuritis, but treatment with escin or Cort alone at a suboptimal concentration did not show any effect on the pleuritis rats. After the murine macrophagic RAW264.7 cells stimulated by lipopolysaccharide (LPS), they were treated with escin, Cort or escin and Cort. Then nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) of cell culture supernatants were analyzed. Escin or Cort markedly reduced the content of NO, TNF-alpha and IL-1beta secreted by LPS stimulated RAW264.7 macrophage cells. The combination of suboptimal concentrations of escin with Cort, which alone could not markedly inhibit the release of inflammatory factors, inhibited the secretion of NO, TNF-alpha and IL 1beta in LPS-stimulated RAW264.7 macrophage cells. The findings suggest escin can synergize with glucocorticoids to enhance their anti-inflammatory effect. PMID- 20850957 TI - First report of an anti-tumor, anti-fungal, anti-yeast and anti-bacterial hemolysin from Albizia lebbeck seeds. AB - A monomeric 5.5-kDa protein with hemolytic activity toward rabbit erythrocytes was isolated from seeds of Albizia lebbeck by using a protocol that involved ion exchange chromatography on Q-Sepharose and SP-Sepharose, hydrophobic interaction chromatography on Phenyl-Sepharose, and gel filtration on Superdex 75. It was unadsorbed on both Q-Sepharose and SP-Sepharose, but adsorbed on Phenyl Sepharose. Its hemolytic activity was fully preserved in the pH range 0-14 and in the temperature range 0-100 degrees C, and unaffected in the presence of a variety of metal ions and carbohydrates. The hemolysin reduced viability of murine splenocytes and inhibited proliferation of MCF-7 breast cancer cells and HepG2 hepatoma cells with an IC50 of 0.21, 0.97, and 1.37 MUM, respectively. It impeded mycelial growth in the fungi Rhizoctonia solani with an IC50 of 39 MUM but there was no effect on a variety of other filamentous fungi, including Fusarium oxysporum, Helminthosporium maydis, Valsa mali and Mycosphaerella arachidicola. Lebbeckalysin inhibited growth of Escherichia coli with an IC50 of 0.52 MUM. PMID- 20850958 TI - Antigen-specific immunotherapy of autoimmune and allergic diseases. AB - Nearly a century has passed since the first report describing antigen-specific immunotherapy (antigen-SIT) was published. Research into the use of antigen-SIT in the treatment of both allergic and autoimmune disease has increased dramatically since, although its mechanism of action is only slowly being unravelled. It is clear though, from recent studies, that success of antigen-SIT depends on the induction of regulatory T (T reg) cell subsets that recognise potentially disease-inducing epitopes. The major challenge remaining for the widespread use of antigen-SIT is to safely administer high doses of immunodominant and potentially pathogenic epitopes in a manner that induces T cell tolerance rather than activation. This review illustrates that intelligent design of treatment agents and strategies can lead to the development of safe and effective antigen-SIT. PMID- 20850959 TI - Indacaterol once-daily is equally effective dosed in the evening or morning in COPD. AB - Indacaterol is a novel, inhaled, long-acting beta(2)-agonist providing 24-h bronchodilation with once-daily (o.d.) dosing in patients with COPD. In this double-blind, incomplete block crossover study, patients with moderate-to-severe COPD were randomised to receive three treatment cycles from: indacaterol 300 MUg o.d. dosed PM or AM, salmeterol 50 MUg twice daily or placebo, each for 14 days. Trough FEV(1) was measured 24 h after indacaterol, and 12 h after salmeterol. Ninety-six patients (mean age: 64 years; post-bronchodilator FEV(1) 57% predicted, FEV(1)/FVC 55%) were randomised; 83 completed. After 14 days, the difference vs. placebo in trough FEV(1) for PM indacaterol was 200 mL (p < 0.001 [primary analysis]) and for AM indacaterol was 200 mL (p < 0.001). Compared with salmeterol, trough FEV(1) for PM indacaterol was 110 mL higher (p < 0.001), and for AM indacaterol was 50 mL higher (p = NS). Over 14 days, vs. placebo, both PM and AM indacaterol improved the % of nights with no awakenings (by 11.9 and 8.1 points; p < 0.01); the % of days with no daytime symptoms (by 6.7 and 5.5 points; p < 0.05); and the % of days able to perform usual activities (by 6.7 and 7.8 points; p < 0.05). Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00615030. PMID- 20850960 TI - CdSe/ZnS quantum dots based electrochemical immunoassay for the detection of phosphorylated bovine serum albumin. AB - A CdSe/ZnS quantum dot (QD) based electrochemical immunoassay of phosphorylated bovine serum albumin (BSA-OP) as a protein biomarker is presented. The QDs were used as labels for amplifying electrochemical signals and were conjugated with a secondary anti-phosphoserine antibody in a heterogeneous sandwich immunoassay. In this assay, the model phosphorylated protein BSA-OP was added to the primary BSA antibody coated polystyrene microwells, and then the QD labeled anti phosphoserine antibody was added for completing immunorecognition. Finally, the bound QD was dissolved in an acid-dissolution step and was detected by electrochemical stripping analysis. The measured current responses were proportional to the concentration of BSA-OP. Under optimal conditions, the voltammetric response was linear over the range of 0.5-500 ngmL(-1) of BSA-OP, with a detection limit of 0.5 ngmL(-1). It also shows good reproducibility with a relative standard deviation of 8.6%. This QD-based electrochemical immunoassay offers great promise for simple and cost-effective analysis of protein biomarkers. PMID- 20850961 TI - Molecular switching fluorescence based high sensitive detection of label-free C reactive protein on biochip. AB - A novel detection technique on biochip for the quantification of label-free C reactive protein (CRP) based on molecular switching of fluorescence (MSF) is demonstrated by total internal reflection fluorescence microscopy. It alters fluorescence intensity of fluoreseinamine isomer 1 (FAI) upon binding with its specific ligand, O-phosphorylethanolamine (PEA). In the MSF-based detection, FAI was used as an ink, printed on a 3-glycidoxypropyl-trimethoxysilane (GPTS)-coated glass coverslip. With the addition of GPTS conjugated PEA solution to the FAI printed coverslip, the fluorescence intensity was remarkably decreased. Addition of CRP increased fluorescence intensity linearly in the range of 800 aM to 500 fM (R=0.997). The MSF-based biochip assay for the estimation of CRP in human sera showed ~200 times increased detection sensitivity in less than a third of the time to obtain results using a conventional enzyme-linked immunosorbent assay. This biochip detection is a promising new technique for the quantification of CRP molecules from trace amounts of clinical samples. PMID- 20850962 TI - Biocatalysts by evolution. AB - Proteins evolve by iterative cycles of mutation, selection and amplification. Analogous evolutionary strategies are being profitably exploited in the laboratory to generate and optimize biocatalysts for diverse biotechnological applications. In this review, we summarize recent efforts to improve this process by creating more effective protein libraries and more efficient screening/selection schemes. Targeted mutagenesis using simplified amino acid alphabets, statistical analyses of sequence-function-stability relationships, and neutral mutational drift have emerged as powerful tools for generating useful molecular diversity, while new techniques for controlling selection stringency and microfluidic methods for screening large populations of molecules promise to facilitate exploration of sequence space. Enzyme engineers interested in creating novel biocatalysts for abiological reactions are sure to profit from these advances. PMID- 20850963 TI - Oscillatory control of signalling molecules. AB - The emergence of biological function from the dynamic control of cellular signalling molecules is a fundamental process in biology. Key questions include: How do cells decipher noisy environmental cues, encode these signals to control fate decisions and propagate information through tissues? Recent advances in systems biology, and molecular and cellular biology, exemplified by analyses of signalling via the transcription factor Nuclear Factor kappaB (NF-kappaB), reveal a critical role of oscillatory control in the regulation of these biological functions. The emerging view is that the oscillatory dynamics of signalling molecules and the epigenetically regulated specificity for target genes contribute to robust regulation of biological function at different levels of cellular organisation through frequency-dependent information encoding. PMID- 20850964 TI - Neural basis of social status hierarchy across species. AB - Social status hierarchy is a ubiquitous principle of social organization across the animal kingdom. Recent findings in social neuroscience reveal distinct neural networks associated with the recognition and experience of social hierarchy in humans, as well as modulation of these networks by personality and culture. Additionally, allelic variation in the serotonin transporter gene is associated with prevalence of social hierarchy across species and cultures, suggesting the importance of the study of genetic factors underlying social hierarchy. Future studies are needed to determine how genetic and environmental factors shape neural systems involved in the production and maintenance of social hierarchy across ontogeny and phylogeny. PMID- 20850965 TI - Nonapeptide mechanisms of social cognition, behavior and species-specific social systems. AB - Nonapeptide functions have been explored in a diverse literature that has burgeoned in recent years, particularly in relation to affiliation, bonding and human social cognition. However, brain distributions of the oxytocin-like and vasopressin-like peptides are fundamentally similar across all vertebrate animals, including many species that do not exhibit social bonds, grouping, or even parent-offspring interaction. Hence, unifying principles extend beyond, and may even constrain, nonapeptide effects on social cognition and behavior. Conversely, nonapeptide receptor distributions are highly species-specific, suggesting almost limitless functional variation. Drawing on the vast recent literature, we here present a phylogenetically integrated review of both ubiquitous vertebrate features and species diversity, highlighting important nonapeptide effects on socially relevant physiology, sensorimotor integration, assignment of valence, and functional connectivity. PMID- 20850967 TI - Electron tomography of the supramolecular structure of virus-infected cells. AB - Visualizing the viral life cycle in the host challenges us to extend our understanding of the viral infection mechanism. Three-dimensional images obtained by advanced electron tomographic imaging techniques, if resolved to molecular resolution, are helpful for bridging the atomic structural information of proteins to cellular events. Characteristic large structures appear in virus infected host cells through the life cycle of various viruses. These structures are likely to provide clues to understanding viral infection mechanisms, such as how viruses move in host cells, how they are assembled, how they egress and how they spread cell-to-cell. Here we review recent advances in the studies of the molecular architecture of virus machinery involved in the mechanism of virus infection using comprehensive electron tomographic imaging techniques. PMID- 20850968 TI - Preparation of capacitor's electrode from sunflower seed shell. AB - Series of nanoporous carbons are prepared from sunflower seed shell (SSS) by two different strategies and used as electrode material for electrochemical double layer capacitor (EDLC). The surface area and pore-structure of the nanoporous carbons are characterized intensively using N2 adsorption technique. The results show that the pore-structure of the carbons is closely related to activation temperature and dosage of KOH. Electrochemical measurements show that the carbons made by impregnation-activation process have better capacitive behavior and higher capacitance retention ratio at high drain current than the carbons made by carbonization-activation process, which is due to that there are abundant macroscopic pores and less interior micropore surface in the texture of the former. More importantly, the capacitive performances of these carbons are much better than ordered mesoporous carbons and commercial wood-based active carbon, thus highlighting the success of preparing high performance electrode material for EDLC from SSS. PMID- 20850966 TI - Basal ganglia contributions to motor control: a vigorous tutor. AB - The roles of the basal ganglia (BG) in motor control are much debated. Many influential hypotheses have grown from studies in which output signals of the BG were not blocked, but pathologically disturbed. A weakness of that approach is that the resulting behavioral impairments reflect degraded function of the BG per se mixed together with secondary dysfunctions of BG-recipient brain areas. To overcome that limitation, several studies have focused on the main skeletomotor output region of the BG, the globus pallidus internus (GPi). Using single-cell recording and inactivation protocols these studies provide consistent support for two hypotheses: the BG modulates movement performance ('vigor') according to motivational factors (i.e. context-specific cost/reward functions) and the BG contributes to motor learning. Results from these studies also add to the problems that confront theories positing that the BG selects movement, inhibits unwanted motor responses, corrects errors on-line, or stores and produces well learned motor skills. PMID- 20850969 TI - Expansion of SAR studies on triaryl bis sulfone cannabinoid CB2 receptor ligands. AB - We report further expansion of the structure activity relationship (SAR) on the triaryl bis sulfone class of compounds (I), which are potent CB(2) receptor ligands with excellent selectivity over the CB(1) receptor. This study was extended to B ring changes, followed by simultaneous optimization of the A-, B-, and C-rings. Compound 42 has excellent CB(2) potency, selectivity and rat exposure. PMID- 20850970 TI - Novel thiazolidinedione derivatives with anti-obesity effects: dual action as PTP1B inhibitors and PPAR-gamma activators. AB - Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC(50) values in a low micromolar range. Compound 18l, the lowest, bore an IC(50) of 1.3 MUM. In a peroxisome proliferator-activated receptor-gamma (PPAR gamma) promoter reporter gene assay, 18l was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 18l as an anti-obesity and hypoglycemic agent was evaluated in a mouse model system. Compound 18l significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA without overt toxic effects. PMID- 20850971 TI - Property based optimization of delta-lactam HDAC inhibitors for metabolic stability. AB - The novel delta-lactam based HDAC inhibitor, KBH-A118 (3) shows a good HDAC enzyme and cancer cell growth inhibitory activities but has undesirable pharmacokinetics profiles because of instability in mouse liver microsome. To improve metabolic stability, various analogues were prepared with substituents on aromatic ring of cap group and various chain lengths between the cap group and delta-lactam core. The newly prepared analogues showed moderate to potent in vitro activities. Among them six compounds (8a, 8e, 8j, 8n, 8t, and 8v) were evaluated on mouse liver microsome assay and it turned out that the microsomal stabilities were dependent on lipophilicity and the number of the rotatable bonds. Finally, the animal pharmacokinetic profiles of 8e displayed improving oral exposure and oral bioavailability. PMID- 20850972 TI - Rational design of novel pyrrolidine derivatives as orally active neurokinin-3 receptor antagonists. AB - The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic. PMID- 20850973 TI - Novel CGRP receptor antagonists from central amide replacements causing a reversal of preferred chirality. AB - A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range. PMID- 20850974 TI - A new truncating MPZ mutation associated with a very mild CMT1 B phenotype. AB - We have investigated a 34-year-old female who had mild clinical and electrophysiological features of demyelinating peripheral neuropathy. She presented a novel frameshift mutation (V160fsX3) in the exon 4 of the Myelin Protein Zero (MPZ) gene. Clinical and genetic studies performed on her family revealed the same mutation in her oligosymptomatic mother and sister. Our report expands the number of MPZ mutations and indicates that mutations in exon 4 may cause a mild Charcot-Marie-Tooth type 1B phenotype. PMID- 20850975 TI - 168th ENMC International Workshop: outcome measures and clinical trials in Charcot-Marie-Tooth disease (CMT). PMID- 20850976 TI - The photographic knee pain map: locating knee pain with an instrument developed for diagnostic, communication and research purposes. AB - Pain maps are used to determine the location of pain. Knee pain maps have previously been described, but only one study has reported on reliability and none report validity. The present study describes the generation of a photographic knee pain map (PKPM) together with its validity and reliability. A photographic representation of a pair of knees was chosen by 26 patients, (66.7%) from a group of 39. The selected photograph was modified and a template of anatomical zones was generated. The opinions of 25 independent subject matter experts were canvassed and validity ratios calculated for these zones, ranged from 0.28 to 0.84. Hypothetical comparisons were made between the PKPM and an alternative knee pain map, in a cross-sectional group of 26 patients (35 knees). Convergent patterns of validity were found where hypothesised. Reliability was determined using a different cohort of 44 patients (58 knees) who completed the PKPM before and after a sampling delay. Four of these patients were excluded with a short sampling delay. Calculated agreement of test-retest reproducibility was fair to good. All of the completed PKPM (151 knees) were then subject to further analysis where inter-rater reproducibility was good to very good and intra-rater reproducibility was very good. The PKPM is readily accessible to patients with low completion burden. It is both valid and reliable and we suggest it can be used in both clinical and research settings. Further studies are planned to explore its predictive ability as a diagnostic tool. The PKPM can be found at www.photographickneepainmap.com. PMID- 20850977 TI - The synthesis and biologic evaluation of anti-platelet and cytotoxic beta nitrostyrenes. AB - Our previous studies demonstrated that two cytotoxic beta-nitrostyrene derivatives, 3,4-methylenedioxy-beta-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy beta-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of beta-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC(50)<=0.7 MUM) without significant cytotoxicity on a human cancer cell line (up to 20 MUM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents. PMID- 20850978 TI - Small molecules targeting the interaction between HIV-1 integrase and LEDGF/p75 cofactor. AB - The search of small molecules as protein-protein interaction inhibitors represents a new attractive strategy to develop anti-HIV-1 agents. We previously reported a computational study that led to the discovery of new inhibitors of the interaction between enzyme HIV-1 integrase (IN) and the nuclear protein lens epithelium growth factor LEDGF/p75.(1) Herein, we describe new findings about the binding site of LEDGF/p75 on IN employing a different computational approach. In this way further structural requirements, helpful to disrupt LEDGF/p75-IN binding, have been identified. The main result of this work was the exploration of a relevant hydrophobic region. So we planned the introduction of suitable and simple chemical modifications on our previously reported 'hit' and the new synthesized compounds were subjected to biological tests. The results obtained demonstrate that the hydrophobic pocket could play a key role in improving inhibitory efficacy thus opening new suggestions to design active ligands. PMID- 20850979 TI - Cytoskeletal organization of bee ovarian follicles during oogenesis. AB - The germ cells in the germarium of the bee meroistic polytrophic ovarian cysts remain interconnected by cytoplasmic bridges as a result of incomplete cell division. These intercellular bridges form a distribution pathway for the substances that initially determine which of the cystocytes will become oocyte and later conduct the products synthesized by the nurse cells to the oocyte. In the present work, the presence and distribution of cytoskeleton components, actin and tubulin were studied in ovaries of queens of Apis mellifera and Scaptotrigona postica, two eusocial species, using antibody against alpha- and beta-tubulin and FITC-phalloidin, aiming to shed light on the role of these cytoskeleton elements in oogenesis. The immunofluorescent preparations were analyzed by laser scanning confocal microscopy. F-actin was detected in the intercellular bridges of both species. The tubulin distribution in cell cytoplasm of A. mellifera and S. postica also displayed similar pattern. The role of these elements in the oogenetic events responsible for both cell support and motility is discussed. PMID- 20850980 TI - A novel electron paramagnetic resonance spin-probe technique demonstrates the relation between the production of hydroxyl radicals and ischemia-reperfusion injury. AB - OBJECTIVE: Many previous studies have suggested an increase in hydroxyl radical (OH) production after myocardial ischemia-reperfusion; however, traditional techniques have not been able to conclusively prove this phenomenon. We investigated whether the production of OH was increased during myocardial reperfusion using a novel electron paramagnetic resonance (EPR) technique using an OH-specific spin probe. An OH scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), was used to examine the relationship between OH production and post ischemic functional recovery or the degree of myocardial injury. METHODS: We used an isolated rabbit-heart preparation perfused with support-rabbit blood, and the heart was reperfused after normothermic global ischemia. Heart samples were reacted with the OH-specific spin probe, 4-hydroxy-2,2,6,6-tetramethyl-piperidine N-oxyl (hydroxyl-TEMPO). The rate of decay of the EPR signal showed OH production. We investigated the rate of EPR signal decay and cardiac function. RESULTS: The rate of signal decay was significantly increased just after reperfusion compared with that of pre-ischemia (2.00*10(-2)+/-0.77*10(-2)min(-1) vs 0.11*10(-2)+/-0.02*10(-2)min(-1), p<0.01). Administration of MCI-186 reduced the rate of decay to 0.86*10(-2)+/-0.14*10(-2)min(-1) just after reperfusion (p<0.01). Cardiac function was significantly improved 60 min after reperfusion using MCI-186 compared without MCI-186 (left ventricular developed pressure was 95+/-9 mm Hg vs 60+/-6 mm Hg and the first derivative of the left ventricular pressure (dP/dt) was 1843+/-200 mm Hg s(-1) vs 1182+/-127 mm Hg s(-1)). CONCLUSIONS: A novel EPR spin-probe technique demonstrated the relation between the production of OH and ischemia-reperfusion injury. We confirmed that OH production influenced cardiac function and myocardial ischemia-reperfusion injury. PMID- 20850982 TI - Port implantation into the aortic arch: an unusual complication requiring urgent cardiac surgery. PMID- 20850981 TI - Failure of noninvasive ventilation after lung surgery: a comprehensive analysis of incidence and possible risk factors. AB - OBJECTIVE: Noninvasive ventilation has been successfully used after thoracic surgery. However, noninvasive ventilation fails in about 20% of patients. The aim of the study was to analyze episodes of noninvasive ventilation failure and to assess possible risk factors, while taking into account the performance of fiberoptic bronchoscopy for secretion management. METHODS: From January 2006 to June 2008, the use of noninvasive ventilation was prospectively recorded after thoracic surgery. Data were retrospectively abstracted from charts, including the number of fiberoptic bronchoscopies performed. Risk factors associated with noninvasive ventilation failure were evaluated using logistic regression analysis to estimate odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS: During the study period, 664 patients were admitted in the intensive care unit (ICU) after lung resection or pulmonary thromboendarterectomy. A total of 135 patients underwent noninvasive ventilation (20.3%). As many as 40 of these 135 patients needed to be intubated (29.6%) and represented the noninvasive ventilation failure group. Patients with noninvasive ventilation failure had more fiberoptic bronchoscopies performed compared with patients with noninvasive ventilation success: 3 (1-5) versus 1 (0-3); p = 0.0008. Four independent variables were associated with noninvasive ventilation failure during the first 48 h of appliance: increased respiratory rate (OR: 4.17 (1.63-10.67); increased Sequential Organ Failure Assessment (SOFA) score (OR: 3.05 (1.12-8.34); number of fiberoptic bronchoscopies performed (OR: 1.60 (1.01-2.54); and number of hours spent on noninvasive ventilation (OR: 1.06 (1.01-1.11). Nosocomial pneumonia was the leading cause of respiratory complications and occurred in 21 and 6 patients with and without noninvasive ventilation failure, respectively (53% vs 6%; p < 0.0001). Patients in the failure group had a higher mortality rate (20% vs 0%; p < 0.0001). CONCLUSIONS: Noninvasive ventilation failure is associated with higher mortality, but is merely a marker of progression of a more severe disease. This may at least indicate the need for caution in some patients. Interestingly, increased use of fiberoptic bronchoscopies during noninvasive ventilation appliance was identified as a risk factor of failure. PMID- 20850983 TI - Single T factors predict survival of patients with resected stage-IIB non-small cell lung cancers. AB - OBJECTIVE: In the seventh edition of TNM Classification of Malignant Tumours (TNM) staging, the stage-IIB category for lung cancer is comprised of four factors: lymph-node metastasis, chest-wall invasion, large tumor size (> 7 cm), and same-lobe nodules. Tumors are further classified into eight sub-categories based on each TN factor or factor combinations. This study evaluated the prognostic value of each TN factor or combinations for resected stage-IIB non small-cell lung cancer (NSCLC). METHODS: We retrospectively studied 186 consecutive patients who had resections for NSCLC at Chiba University Hospital and were diagnosed as stage IIB according to the seventh edition of TNM staging. RESULTS: Five-year survivals for each stage IIB were: T2bN1M0 = 47 +/- 12% (+/- standard error); T3 (chest-wall invasion; N0M0) = 59 +/- 7%; T3 (large tumor> 7 cm)=72 +/- 11%; T3 (same-lobe nodules) = 78 +/- 5%; T3 (invasion + > 7 cm)=44 +/- 16%; T3 (invasion+same-lobe nodules) = 25 +/- 22%; T3 (>7cm+same-lobe nodules) = 0%; and T3 (invasion + > 7 cm +same-lobe nodules)=0%. Among the four single factors, same-lobe nodules had the best prognoses, whereas T2bN1M0 had the worst prognoses. Comparing cases with single factors and multiple factors that decided stage IIB, cases with multiple factors had poorer prognoses (P=0.02). CONCLUSION: The stage-IIB category is comprised of eight sub-categories, with either single factors or factor combinations; these sub-categories have different prognoses. The worst survivals were for cases with T2bN1M0 as a single factor or for cases with multiple factors, although these represented a small proportion of resected stage-IIB NSCLC cases. PMID- 20850984 TI - Does stentless aortic valve implantation increase perioperative risk? A critical appraisal of the literature and risk of bias analysis. AB - Stentless aortic valve replacement has potential benefits in terms of valve hemodynamics and clinical outcomes, although these may be offset by greater technical complexity of implantation with longer cardiopulmonary bypass and cross clamp times compared with stented valves. Meta-analyses of the small number of published randomized trials have been limited by their lack of critical synthesis of the literature, including evaluation of the Risk of Bias. Our objective was to determine whether stentless aortic valves increase perioperative risk of mortality. We also examined secondary clinical outcomes of neurological, renal and respiratory complications as well as hemodynamic changes reported by studies following implantation of the two types of aortic prosthesis. The methodology used to answer this question was a rigorous meta-analysis of randomized controlled trials, using bias-assessment techniques designed to address limitations of conventional meta-analysis. Our findings show that many of the existing randomized trials have a high or uncertain risk of bias. Analysis of studies with low risk of bias reveals that stentless valves do not increase perioperative risk in terms of 30-day mortality and morbidity though neither do they exhibit benefits in hemodynamics or clinical outcomes compared with stented valves. Larger, more stringent randomized studies would be required to identify any robust clinical difference. PMID- 20850985 TI - Left anterior descending artery to pulmonary artery fistula: a rare cause of cardiac arrest. PMID- 20850986 TI - Iron deficiency, but not underfeeding reduces the secretion of interferon-gamma by mitogen-activated murine spleen cells. AB - Interferon-gamma (IFN-gamma), a cytokine primarily secreted by T and natural killer cells regulates cell-mediated and innate immunity. Iron deficiency, a public health problem in children impairs immune function. To determine whether reduced IFN-gamma contributes to impaired immunity, we measured IFN-gamma in supernatants of activated (2.5 MUg/ml concanavalin A, 50 ng/ml anti-CD3 antibody) spleen cells from control (C), iron-deficient (ID), pair-fed (PF), and iron replete mice for 3 (R3) and 14 days (R14) (11-12/group). Except for iron content, the low iron (5 ppm) and control (50 ppm) diets had identical composition. Mean indices of iron status after 51 days of feeding were as follows: C=PF~R14>R3>ID (p<0.01). Iron deficiency, but not pairfeeding reduced IFN-gamma concentration in mitogen-treated cells by 30-43% (p<0.05); iron repletion improved it. Reduced IFN gamma was not simply due to differences in IL-12 (IFN-gamma inducer), percentage of CD3+ T cells, or impaired cell proliferation because these indices were not always decreased. It was likely due to a defect in T cell activation that leads to IFN-gamma gene expression. IFN-gamma positively correlated with indicators of iron status, body, and thymus weights (r=0.238-0.472; p<0.05). Reduced IFN-gamma secretion during iron deficiency may affect response to infections. PMID- 20850987 TI - Dizziness in a patient with a right atrial mass. PMID- 20850989 TI - Uncalibrated arterial pulse cardiac output measurements in patients with moderately abnormal left ventricular function. AB - OBJECTIVE: The aim of the study was to evaluate the accuracy and precision of the Vigileo/FloTrac system (Edwards Lifesciences, Irvine, CA) when compared with the intermittent cardiac output and continuous cardiac output measurements obtained from pulmonary arterial catheters in patients with moderately abnormal left ventricular function undergoing elective coronary artery bypass graft surgery. DESIGN: A prospective, observational study. SETTING: Tertiary university hospital. PARTICIPANTS: Twenty patients with moderately abnormal left ventricular function undergoing coronary artery bypass graft surgery were enrolled. MEASUREMENTS AND RESULTS: Data were collected before the induction of anesthesia (T1), after the induction of anesthesia (T2), before cardiopulmonary bypass with an open chest (T3), after cardiopulmonary bypass (T4), after sternal closure (T5), on intensive care unit admission (T6), and at 6 hours (T7) and 12 hours after surgery (T8). A total of 360 data measurements were collected; the mean bias between intermittent cardiac output (ICO) and arterial pressure cardiac output (APCO) was -0.50 +/- 1.72 L/min, and the percentage error (PE) was 37.00%. The mean difference between CCO and APCO was -0.06 +/- 1.84 L/min, and the PE was 37.80%. The correlation between DeltaICO and DeltaAPCO was r = 0.7; the correlation between DeltaCCO and DeltaAPCO was r = 0.73. In the intraoperative period, the mean bias between ICO and APCO was -0.41 +/- 1.75 L/min, and the PE was 40.87%. The mean difference between CCO and APCO was -0.18 +/- 1.90 L/min, and the PE was 41.48%. In the postoperative period, the mean bias between ICO and APCO was -0.56 +/- 1.70 L/min, and the PE was 34.43%. The mean difference between CCO and APCO was -0.36 +/- 1.76 L/min, and the PE was 34.87%. CONCLUSIONS: In cardiac surgical patients with moderately abnormal left ventricular function, the Vigileo/FloTrac 2nd generation software sensor device showed mild intraoperative and postoperative agreement when compared with a pulmonary arterial catheter. PMID- 20850990 TI - Attention and time constraints in perceptual-motor learning and performance: instruction, analogy, and skill level. AB - We sought to gain more insight into the effects of attention focus and time constraints on skill learning and performance in novices and experts by means of two complementary experiments using a table tennis paradigm. Experiment 1 showed that skill-focus conditions and slowed ball frequency disrupted the accuracy of experts, but dual-task conditions and speeded ball frequency did not. For novices, only speeded ball frequency disrupted accuracy. In Experiment 2, we extended these findings by instructing novices either explicitly or by analogy (implicit motor learning technique). Explicitly instructed novices were less accurate in skill-focused and dual-task conditions than in single-task conditions. Following analogy instruction novices were less accurate in the skill focused condition, but maintained accuracy under dual-task conditions. Participants in both conditions retained accuracy when ball frequency was slowed, but lost accuracy when ball frequency was speeded, suggesting that not attention, but motor dexterity, was inadequate under high temporal constraints. PMID- 20850991 TI - Sex differences play a role in cardiac endoplasmic reticulum stress (ERS) and ERS initiated apoptosis induced by pressure overload and thapsigargin. AB - Excessive endoplasmic reticulum stress (ERS) triggers myocardial apoptosis. Sex differences appear to be an important determinant in the occurrence of stress and apoptosis through many pathways, but the roles of sex differences in the cardiac ERS and ERS-initiated apoptosis are largely unknown. In the present study, we investigated the in vivo role of sex differences in the cardiac ERS and apoptosis elicited by ascending aortic banding surgery or thapsigargin (Thap) injection using male and female C57BL/6 JAX mice. The surgery significantly increased the expression levels of cardiac glucose-regulated protein (GRP)78 and CCAAT/enhancer binding protein homology protein (CHOP) protein, increased the myocardial apoptosis and decreased the sarcoplasmic reticulum Ca(2+)-ATPase isoform (SERCA)2 immunoreactivity in the male mice relative to female mice. Furthermore, during ERS induction using Thap, myocardial apoptosis and the expression levels of cardiac GRP78, inositol-requiring enzyme (Ire)1alpha and tumor necrosis factor receptor-associated factor (TRAF)2 were significantly increased in male mice relative to female mice. Sex differences significantly affected the above results. Our data suggest that sex differences affected the response of myocardial tissues in dealing with cardiac ERS and further result of ERS, apoptosis, at least in part through the regulation of SERCA2, CHOP, Ire1alpha and TRAF2. PMID- 20850992 TI - Expression of allograft inflammatory factor-1 (AIF-1) in acute cellular rejection of cardiac allografts. AB - BACKGROUND: To date, there are no good biomarkers for diagnosing and predicting the progression of cardiac allograft rejection. Previous studies have shown a correlation of allograft inflammatory factor-1 (AIF-1) to human cardiac allograft rejection; however these studies were limited in sample size and did not address whether AIF-1 could be used as a biomarker in diagnosing and predicting the progression of cardiac allograft rejection. METHODS: Using immunohistochemistry, AIF-1 expression was determined in cardiomyocytes (CMCs), mononuclear cells (MNCs) and Quilty lesions in 192 allograft endomyocardial biopsies and 37 heart specimens from nontransplant patients with diverse heart diseases. RESULTS: AIF-1 was found in both cardiac allografts and hearts with other cardiac diseases. In cardiac allografts, expression levels of AIF-1 in both CMCs and MNCs directly correlated with the severity of cardiac cellular rejection. AIF-1 expression was also elevated in Quilty B lesions, but not in Quilty A lesions. The rejection grade in subsequent biopsies increased in biopsies that had low-grade rejection with high CMC AIF-1 scores or Quilty B lesions. CONCLUSION: AIF-1 was expressed in both CMCs and MNCs in hearts with various adverse conditions including but not limited to heart transplantation. In cardiac transplantation, AIF-1 was associated with the severity of cardiac allograft rejection and Quilty B lesions, which could predict subsequent increases in rejection grade. Thus, AIF-1 shows promise that it can be a potential biomarker for cardiac allograft rejection. PMID- 20850993 TI - Transplantation of tissue-engineered cartilage for the treatment of osteochondritis dissecans in the elbow: outcomes over a four-year follow-up in two patients. PMID- 20850995 TI - The unstable painful shoulder (UPS) as a cause of pain from unrecognized anteroinferior instability in the young athlete. AB - HYPOTHESIS: The etiology of shoulder pain in the overhead athlete is often difficult to determine. This study hypothesized that (1) instability can present in a purely painful form, without any apparent history of instability, but with anatomic lesions indicative of instability, termed unstable painful shoulder (UPS), and that (2) arthroscopic shoulder stabilization is effective. MATERIALS AND METHODS: The study evaluated 20 patients (mean age, 22 +/- 8 years) at a mean of 38 months postoperatively (range, 24-69 months). Inclusion criteria were painful shoulder with lesions indicative of instability on imaging or at surgery, minimum 2-year follow-up. Exclusion criteria were recognized instability, other associated pathologies, and previous shoulder surgery. RESULTS: Patients were young, hyperlax athletes who complained of deep, anterior shoulder pain and denied any instability. Pain was reproduced with the arm in an anterior apprehension position and relieved by a relocation test; however, no actual apprehension was experienced. Patients often had glenohumeral laxity and hyperlaxity. Lesions indicative of instability confirmed that at least 1 unapparent shoulder subluxation occurred. The Rowe, Walch-Duplay, and University of California, Los Angeles scores improved significantly (P < .05); 19 patients (95%) were satisfied, and 15 (75%) returned to their previous level of sports. DISCUSSION: The diagnosis of UPS is often missed but is important to consider in the young hyperlax athlete. Soft tissue and/or bony lesions consistent with instability are necessary to confirm the diagnosis. Arthroscopy certainly deserves a significant place in this form of anteroinferior instability because it allows both the assessment of lesions (ie, diagnosis) and a satisfactory functional result and return to sport. PMID- 20850994 TI - Clinical evaluation of acromioclavicular joint pathology: sensitivity of a new test. AB - BACKGROUND: A prospective study was established to assess the sensitivity of the newly described Bell-van Riet (BvR) test for isolated AC pathology, and compare with 4 commonly used clinical tests. MATERIALS AND METHODS: The BvR test is essentially the cross-adduction test, with the addition of attempted elevation against resistance. In a positive test, this results in some pain and the inability of the patient to maintain the arm in the adducted and elevated position against resistance. Fifty-eight patients with isolated AC joint symptoms were assessed in random order with the BvR test and 4 other tests. A corticosteroid and local anaesthetic injection was administered into the AC joint space. The BvR test and 4 other tests were then repeated following the injection. After the injection, a symptom free clinical examination was used as a measure of truly positive tests. RESULTS: The BvR test showed a sensitivity of 98%. All 4 other tests were less sensitive. CONCLUSION: The BvR test is a highly sensitive test in patients presenting with isolated AC related symptoms, and demonstrates AC joint pathology better than other accepted tests. PMID- 20850996 TI - Treatment of heterotopic ossification of the elbow following burn injury: recommendations for surgical excision and perioperative prophylaxis using radiation therapy. AB - BACKGROUND: Heterotopic ossification (HO) is reported to occur in 0.1-3.3% of elbows after a severe burn, and can significantly limit elbow motion and upper extremity function. METHODS: The study included 9 patients (11 elbows) treated by the senior author (TW). The surgical technique consisted of making multiple small surgical approaches to remove heterotopic ossification (without raising cutaneous flaps) and concomitantly releasing the elbow capsule and skin contracture. Perioperative radiation therapy was performed to decrease heterotopic ossification recurrence. Outcome measures included postoperative elbow range of motion and Mayo Elbow Performance Score. RESULTS: The average amount of body surface area burned was 54% (range, 10-86%) and mean time from injury to elbow surgery was 416 days (range, 175-860). All elbows had some degree of direct involvement with the thermal injury. Preoperative arc of motion averaged 39 degrees in flexion/extension and 78 degrees in supination/pronation. Four elbows had complete ankylosis in the flexion/extension plane and 1 had only 5 degrees of motion. At last follow-up, arc of motion in flexion/extension averaged 116 degrees and 139 degrees in supination/pronation, an improvement of 77 degrees and 61 degrees , respectively. One recurrence of HO required re excision. CONCLUSION: We recommend this multiple-approach surgical technique for treatment of heterotopic ossification and elbow contracture after burn injury, along with perioperative radiation therapy to decrease recurrence. Our surgical approach and treatment resulted in significant gains in elbow motion and upper extremity function with few complications. PMID- 20850997 TI - Hand-held dynamometer testing of the internal and external rotator musculature based on selected positions to establish normative data and unilateral ratios. AB - HYPOTHESIS: Objective documentation is needed of shoulder internal and external rotator strength using hand-held dynamometry in selected positions commonly used in a clinic. We compared strength measures and unilateral ratios between gender, limbs (dominant, nondominant), and 3 testing positions. We hypothesized that men would be stronger than women, the dominant shoulder would be stronger than the nondominant shoulder, and the seated neutral (0 degrees adduction) and seated 30 degrees abduction, 30 degrees scaption, 30 degrees diagonal (30 degrees -30 degrees -30 degrees ) positions would be stronger than the prone at 90 degrees 90 degrees position. MATERIALS AND METHODS: Three positions (prone at 90 degrees , seated at neutral, and seated at 30 degrees -30 degrees -30 degrees ) were evaluated in 181 individuals using hand-held dynamometry. Three separate 3-factor (limb by position by gender) analyses of variance were conducted on internal rotation, external rotation, and unilateral ratios. RESULTS: Although the dominant limb was significantly stronger (P < .001) than the nondominant for internal rotation, there was no difference for external rotation. The external rotators demonstrated significantly greater strength in the prone at 90 degrees position compared with the seated at neutral (P = .001) and seated at 30 degrees 30 degrees -30 degrees (P = .002) positions. The internal rotators demonstrated significantly greater (P = .036) strength in the neutral position than in the prone at 90 degrees position for the women. The unilateral ratio of external rotators/internal rotators ranged from 86% to 99%. For the women, the prone at 90 degrees ratio was significantly greater than seated at neutral (P = .001) and seated at 30 degrees -30 degrees -30 degrees (P = .001) positions. Moderate strength relationships (r = 0.506 to 0.572) were revealed between body mass and all strength measures. DISCUSSION: The results of this study provide evidence to interpret normative data, bilateral comparisons and unilateral ratios of the internal/external rotators in the 3 selected positions. CONCLUSION: Because there are no differences between the seated at neutral and 30 degrees -30 degrees -30 degrees positions and the advantages it offers, we recommend the 30 degrees -30 degrees -30 degrees position for testing and the initiation of rehabilitation. PMID- 20850999 TI - Symptomatic elastofibroma in young baseball pitchers: report of three cases. PMID- 20850998 TI - Interclinician and intraclinician variability in the mechanics of the pivot shift test for posterolateral rotatory instability (PLRI) of the elbow. AB - HYPOTHESIS: Posterolateral rotatory instability (PLRI) of the elbow results from injury to the lateral collateral ligament complex from trauma or iatrogenic injury. The lateral pivot-shift test (PST) is standard for diagnosing PLRI, but its subjectivity affects diagnosis and makes it difficult to train young surgeons. A well-controlled investigation has not been done to quantify interclinician and intraclinician variability in PST mechanics in the intact and unstable elbow. The authors predict that there exist differences in PST mechanics between clinicians. MATERIALS AND METHODS: Five unpaired elbow specimens underwent PST intact and after sequential sectioning of lateral stabilizing ligaments. Multiple PST trials were performed on each specimen by 3 clinicians (1 expert, 2 in-training) while 3-dimensional motion and loads were recorded. Intraclinician and interclinician variability were analyzed. RESULTS: Mean supination torque, valgus torque, and axial force were 3.6 +/- 1.9 Nm, 5.6 +/- 3.1 Nm, and -8.3 +/- 15.7 N, respectively. Mean radial head displacement was 13.7 +/- 4.6 mm. There were no significant differences in these measures after sequential ligament sectioning. One surgeon (in-training 2) applied significantly greater axial compressive forces across the elbow joint (5-9 N difference). Variability of axial force (380% +/- 473%) was greater than that of supination torque (20% +/- 11%), valgus torque (14% +/- 4%), and radial head displacement (8% +/- 6%; P < .05 for analysis of variance). DISCUSSION: The clinicians performed the PST consistently and with comparable loads, with the exception of axial compressive force across the radiohumeral joint, which varied across clinicians by 1 to 2 pounds (5-9 N). CONCLUSION: This study suggests that the PST is a mechanically reproducible clinical examination, despite differing levels of training in performing the maneuver. With the exception of axial force, PST mechanics are highly repeatable for a given surgeon applying the test on a single specimen. PMID- 20851000 TI - Outcome of ankle arthrodesis using a transfibular approach. AB - Variable union rates in ankle arthrodesis using different surgical techniques have been reported in the biomedical literature. However, the advantages of a transfibular approach with sagittal splitting of the fibula have not been widely reported, even though the technique is well known and even described in surgical textbooks. We analyzed outcomes in our practice for all patients who underwent ankle arthrodesis. Over a 5-year period, 2 surgeons using the same transfibular approach performed 26 ankle arthrodeses in 25 patients. The medical records and radiographs of the patients were reviewed for duration of hospital admission, time to union, and complications. All (100%) of the ankle fusions progressed to solid union in a mean postoperative duration of 4.5 +/- 1.8 months (range, 2-10 months), and the only clinically significant complication involved 1 patient with suspected complex regional pain syndrome, who responded to treatment and recovered fully. PMID- 20851001 TI - Femoral head allograft for tibiotalocalcaneal fusion using a cup and cone reamer technique. AB - End-stage degenerative joint disease of the hindfoot with large structural bone deficits is a complex problem encountered by the foot and ankle surgeon. Surgical treatment of this condition often requires tibiotalocalcaneal fusion with use of structural allograft bone. In this article, we describe a technique in which an acetabular reamer is used to create a concave surface for placement of a convex femoral head allograft. This "cup-and-cone" technique provides a congruent area for placement of the allograft, thereby increasing stability of the graft during preparation and placement of an intramedullary nail, while maximizing bone-to bone surface contact at the arthrodesis site. PMID- 20851002 TI - Asymptomatic synovial chondromatosis of the ankle: an incidental finding. AB - Synovial chondromatosis is an uncommon, benign lesion of nodular cartilaginous neoplastic development of the synovium that can lead to loose bodies and arthritic degeneration if left untreated. Although very rare, malignant transformation to chondrosarcoma can occur. Primary and secondary forms of synovial chondromatosis also exist, and each has distinct clinical, radiographic, and histologic characteristics. In this article, we describe a case of extensive primary synovial chondromatosis of the ankle that was asymptomatic until just before presentation, and that was treated by means of open synovectomy with excision of the osteochondromatous lesions within the joint. PMID- 20851003 TI - The optimized evaluation of diabetic foot infection by dual isotope SPECT/CT imaging protocol. AB - Sequential Tc-99m hydroxymethylene-diphosphonate (HDP) 3-phase bone (BS) and In 111 leukocyte scanning (WBCS) have been frequently used to evaluate the diabetic foot, as nonosteomyelitis BS uptake is repeatedly observed and osteomyelitis (OM) in WBCS is often uncertain without BS correlation. Additionally, both modalities are limited in lesion localization because of low resolution and lack of anatomic details. We investigated a method that combined BS/WBCS, and if needed, WBCS/bone marrow scanning (BMS) using SPECT/CT to accurately diagnose/localize infection in a practical protocol. Blood flow/pool images were obtained followed by WBC reinjection and next day dual isotope (DI) BS/WBCS planar and SPECT/CT. BMS/WBCS SPECT/CT (step 2 DI) was obtained on the following day when images were suspicious for mid/hindfoot OM. Diagnosis accuracy and confidence were judged for the various imaging combinations. Diagnosis was classified as OM, soft tissue infection (STI), both OM/STI, and other/no bony pathology by microbiology/pathology or follow-up. Distinction between various diagnostic categories and overall OM diagnostic accuracy in 213 patients were higher for DI than WBCS or BS alone, and for DI SPECT/CT than DI planar or SPECT only. Diagnostic confidence/lesion site was significantly higher for DI SPECT/CT than other comparative imaging methods. In a group of 97 patients with confirmed microbiologic/pathologic diagnosis, similar results were attained. Step 2 DI SPECT/CT performed in 67 patients further improved diagnostic accuracy/confidence. DI SPECT/CT is a highly accurate modality that considerably improves detection and discrimination of STI and OM while providing precise anatomic localization in the diabetic foot. This combined imaging technique promises to beneficially impact diabetic patient care. PMID- 20851004 TI - The use of collagen injections in the treatment of metatarsalgia: a case report. AB - Metatarsalgia is an increasingly common condition seen in the outpatient setting. A number of conservative and surgical management options are available for this condition. We present an interesting case that was unsuccessfully treated with'dermal filler.' To our knowledge, we have not found any published material in peer-reviewed journals documenting the use of collagen injections in the treatment of metatarsalgia. The authors feel that the lesson learned from this case should be highlighted for other foot and ankle surgeons. PMID- 20851005 TI - Autogenous bone graft harvest using reamer irrigator aspirator (RIA) technique for tibiotalocalcaneal arthrodesis. AB - Tibiotalocalcaneal arthrodesis is a technically demanding procedure that can be associated with a high number of complications, including nonunion. Bone grafting is commonly used in arthrodesis procedures to decrease the risk of nonunion. In this article, we describe a technique that uses a reamer-irrigator-aspirator (RIA) method for procurement of autogenous bone graft for use in tibiotalocalcaneal arthrodesis fixated with a retrograde intramedullary nail. Using the RIA technique, autogenous bone graft can be readily obtained without the need for additional incisions and dissection, thereby minimizing the need for additional sources of bone graft. PMID- 20851006 TI - Individual differences in tolerance to shift work--a systematic review. AB - Shift work tolerance is a term describing the ability to adapt to shift work without adverse consequences. In this paper we systematically review literature published investigating the relation between individual differences such as age, gender, personality, morningness/eveningness as well as biological variables and different measures of shift work tolerance from 1998 till 2009. A total of 60 articles were included in this review, of which ten studies were classified as longitudinal, while the rest were classified as cross-sectional. Overall, the studies indicate that young age, male gender, low scores on morningness, high scores on flexibility and low scores on languidity, low scores on neuroticism, high scores on extraversion and internal locus of control and some genetic dispositions are related to higher shift work tolerance. More longitudinal studies, especially concerning personality, are needed to make conclusions about the predictive power of individual differences for shift work tolerance. PMID- 20851007 TI - Fungal rhinosinusitis caused by Scedosporium apiospermum in a cat. AB - A 3-year-old neutered male Bengal cat with a history of chronic mucopurulent bilateral nasal discharge and sneezing was diagnosed with severe fungal rhinosinusitis. A diagnosis was obtained after computer tomography imaging, histopathological examination and fungal culture. The mold Scedosporium apiospermum was identified as the aetiological agent. To our knowledge, this case is the first description of a rhinitis or sinusitis caused by this agent in a cat. Aggressive surgical debridement combined with topical and systemic antifungal therapy was performed. Unfortunately, the treatment resulted only in a partial remission of signs. PMID- 20851008 TI - Infectious causes for feline upper respiratory tract disease--a case-control study. AB - The aim of this case-control study was to investigate the prevalence of microorganisms in group-living cats with clinical signs of upper respiratory tract disease (URTD), in in-contact cats and in cats in groups without URTD problems. Samples were taken from the ventral conjunctival fornix for analysis of feline herpesvirus-1 (FHV), Mycoplasma felis and Chlamydiaceae using a real-time polymerase chain reaction technique. The oropharynx was sampled for bacteriological culture and viral isolation. Specific infectious agents were identified in 11/20 (55%) of the case households, in 7/20 (35%) of the cats with clinical signs and in 3/20 (15%) of the control households, in 3/40 (7.5%) of the cats. Chlamydiae and M felis were only detected from case households, both from cats with URTD and from in-contact cats. The difference in prevalence between case and control households was statistically significant for M felis (P=0.047). The presence of M felis in cat groups was thus associated with clinical signs of URTD. PMID- 20851009 TI - [Improving the continuous care process in primary care during weekends and holidays: redesigning and FMEA]. AB - OBJECTIVE: To describe a project carried out in order to improve the process of Continuous Health Care (CHC) on Saturdays and bank holidays in Primary Care, area number 4, Madrid. The aim of this project was to guarantee a safe and error-free service to patients receiving home health care on weekends. MATERIALS AND METHOD: The urgent need for improving CHC process was identified by the Risk Management Functional Unit (RMFU) of the area. In addition, some complaints had been received from the nurses involved in the process as well as from their patients. A SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis performed in 2009 highlighted a number of problems with the process. As a result, a project for improvement was drawn up, to be implemented in the following stages: 1. Redesigning and improving the existing process. 2. Application of failure mode and effect analysis (FMEA) to the new process. 3. Follow up, managing and leading the project. 4. Nurse training. 5. Implementing the process in the whole area. 6. CHC nurse satisfaction surveys. RESULTS: After carrying out this project, the efficiency and level of automation improved considerably. Since implementation of the process enhancement measures, no complaints have been received from patients and surveys show that CHC nurse satisfaction has improved. By using FMEA, errors were given priority and enhancement steps were taken in order to: Inform professionals, back-up personnel and patients about the process. Improve the specialist follow-up report. Provide training in ulcer patient care. CONCLUSION: The process enhancement, and especially its automation, has resulted in a significant step forward toward achieving greater patient safety. FMEA was a useful tool, which helped in taking some important actions. Finally, CHC nurse satisfaction has clearly improved. PMID- 20851010 TI - Infection control: the case for horizontal rather than vertical interventional programs. AB - The authors define two types of infection control interventions: horizontal, in which all infections at any site are reduced; and vertical, in which only specific organisms are targeted. We suggest that horizontal programs should form the platform of all infection control programs and the key question should be, what is the incremental value of a new vertical program? PMID- 20851012 TI - Gruppo Italiano di Studio sulle Infezioni Gravi - GISIG 3: controversial issues of severe bacterial infections due to multidrug-resistant Gram-positive bacteria: introduction by the National Coordinators. PMID- 20851011 TI - Methicillin-resistant Staphylococcus aureus: the superbug. AB - Over the last decade, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged as serious pathogens in the nosocomial and community setting. Hospitalization costs associated with MRSA infections are substantially greater than those associated with methicillin-sensitive S. aureus (MSSA) infections, and MRSA has wider economic effects that involve indirect costs to the patient and to society. In addition, there is some evidence suggesting that MRSA infections increase morbidity and the risk of mortality. Glycopeptides are the backbone antibiotics for the treatment of MRSA infections. However, several recent reports have highlighted the limitations of vancomycin, and its role in the management of serious infections is now being reconsidered. Several new antimicrobials demonstrate in vitro activity against MRSA and other Gram-positive bacteria. Data from large surveys indicate that linezolid, daptomycin, and tigecycline are almost universally active against MRSA. This review will briefly discuss the epidemiology, costs, outcome, and therapeutic options for the management of MRSA infections. PMID- 20851013 TI - Consensus document on controversial issues in the treatment of complicated skin and skin-structure infections. AB - BACKGROUND: Complicated skin and skin-structure infections (cSSSI), including surgical site infections (SSI), cellulitis, and abscesses, have been extensively studied, but controversial issues still exist. CONTROVERSIAL ISSUES: The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for the following controversial issues: (1) What is the efficacy of topical negative pressure wound treatment as compared to standard of care in the treatment of severe surgical site infections, i.e., deep infections, caused by Gram-positive microorganisms? (2) Which are the most effective antibiotic therapies in the treatment of cSSSI, including SSI, due to methicillin-resistant staphylococci? Results are presented and discussed. METHODS: A systematic literature search using the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and www.clinicaltrials.gov databases of randomized controlled trials and/or non randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method was used for grading quality of evidence. An analysis of the studies published between 1990 and 2008 is presented and discussed in detail. PMID- 20851014 TI - Human immunodeficiency virus disease in Jordan--data from the National AIDS Program from 1986 until 2008. PMID- 20851016 TI - Absence of consistent association between human leukocyte antigen-I and -II alleles and human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis risk in an HTLV-1 French Afro-Caribbean population. AB - OBJECTIVES: Human T-cell lymphotropic virus type 1 (HTLV-1) infection leads to the risk of developing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in less than 5% of cases. The mechanism of disease progression in HAM/TSP remains unknown. A significant role of certain human leukocyte antigen (HLA) genotypes in determining the risk of HAM/TSP has been reported in Japan, where the HLA-A*02 gene has been found to be associated with a lower HTLV-1 provirus load and with protection from HAM/TSP, whereas HLA-DRB1*0101 has been found to be associated with an increased susceptibility to HAM/TSP. The aim of the present case-control study was to investigate the HLA class I and class II allele distribution in HTLV-seropositive French Afro-Caribbean individuals, originating from the French West Indies. METHODS: Associations with HLA class I (A and B) and class II (DRB1 and DQB1) alleles were tested in 123 HAM/TSP patients and 85 asymptomatic HTLV-1 carriers. HLA typing was undertaken on genomic DNA extracted from peripheral blood leukocytes. RESULTS: In our cohort, no significant effect on either the risk of developing HAM/TSP or HTLV-1 provirus load was found for HLA class I or class II, including HLA-A*02 (p=0.43). CONCLUSIONS: Our findings are in contrast to those in the Japanese population, however the literature on HLA associations in HTLV-1 infections across different populations over the past decade have reported conflicting results and this suggests strong ethnic disparities. PMID- 20851015 TI - Oral fluid for the serological and molecular diagnosis of measles. AB - OBJECTIVES: Since measles presents mostly in children, a non-invasive sample collection technique such as oral fluid sampling would be very useful in the early detection of measles RNA and antibodies. The aim of this study was to validate the detection of anti-measles IgM and measles virus RNA in oral fluid and to make a comparison with the gold standard methods of ELISA using serum (Enzygnost((r)) anti-Measles IgM) and in-house nested reverse transcriptase polymerase chain reaction (RT-PCR) using nasopharyngeal secretions. METHODS: Three samples each from 73 measles-positive and 44 measles-negative subjects (serum, oral fluid, and nasopharyngeal secretions) were analyzed. RESULTS: The anti-measles IgM ELISA (MicroImmune) on oral fluid was validated against the IgM ELISA (Siemens) for serum and this resulted in a sensitivity of 92% and specificity of 100%. A molecular nested RT-PCR using oral fluid was validated against the standard assay on nasopharyngeal secretions and gave a sensitivity of 100% and specificity of 100%. CONCLUSIONS: The results confirm that both serological and molecular oral fluid assays are suitable for routine use. The use of oral fluid samples for the detection of measles virus may encourage patients, general practitioners, and pediatricians to participate in the Belgian measles surveillance system and other epidemiological studies in the framework of the World Health Organization elimination program. PMID- 20851017 TI - Mean platelet volume predicts embolic complications and prognosis in infective endocarditis. AB - OBJECTIVES: This study was designed to examine the change in mean platelet volume (MPV) over the course of infective endocarditis (IE) and also the association between MPV and complications including embolic events in IE. METHODS: Forty patients (26 male, mean age 46+/-15 years) who were hospitalized with a diagnosis of IE at the Department of Cardiology, Erciyes University, from March 2005 to August 2008, were retrospectively evaluated. The diagnosis of IE was made clinically and was confirmed with Duke's criteria. The erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hs-CRP), and MPV were measured before treatment and periodically during the follow-up period, until discharge. RESULTS: There were 27 cases of native valve endocarditis and 13 of prosthetic valve endocarditis. While 31 patients were treated medically, an operation was performed in nine patients because of unsuccessful medical therapy. On admission, mean MPV was 10.8+/-1.1 fl, ESR was 82+/-26mm/h, and hs-CRP was 110+/-72mg/l. Seven patients died: one intraoperatively, three patients postoperatively, and three patients during medical treatment. With the exception of these seven patients, ESR and hs-CRP were significantly reduced in all patients at discharge compared to levels at hospitalization (ESR 82+/-26 to 32+/-22, p=0.001 and hs-CRP 110+/-72 to 25+/-15, p=0.001). Similarly, we detected a significant decrease in MPV from hospitalization to discharge, i.e., from the active period of the disease to recovery (10.8+/-1.1 to 9.7+/-0.8 fl, p=0.002). In addition, MPV was found to be significantly higher in patients with observed embolic complications (11.5 vs. 10.3 fl, p=0.001), other complications (11.0 vs. 10.2 fl, p=0.001), and death (11.1 vs. 10.4 fl, p=0.005). CONCLUSION: MPV can be used as an activity criterion in IE, like ESR and hs-CRP. Also, high MPV is associated with a poor prognosis and adverse outcomes, and predicts complications including embolic events. PMID- 20851018 TI - The relationship between leukemoid reaction and perinatal morbidity, mortality, and chorioamnionitis in low birth weight infants. AB - OBJECTIVES: Neonatal leukemoid reaction (NLR) is relatively rare and considered as a white blood cell (WBC) count >=50*10(9)/l . The aim of this study was to investigate the association of NLR with neonatal morbidity and mortality and maternal chorioamnionitis in low birth weight infants. METHODS: In this case controlled retrospective study, the medical records of 1200 newborn infants with a birth weight <2500g admitted to the neonatal unit over a period of 5 years were reviewed. The infants who developed features of NLR (n=17, 1.4%) formed the study group, while the remainder without NLR, matched for gestational age and birth weight (n=123), formed the control group. A chart review was performed and salient demographic, clinical, and laboratory data abstracted. A statistical analysis was subsequently performed on this data. RESULTS: The mean WBC and absolute neutrophil counts of infants with NLR were significantly higher than those in the control group. The peak time of NLR was at 7.9+/-3.6 (interquartile range (IQR) 1-30) days and on average it improved within 4.1+/-1.95 (IQR 2-9) days. It was noted that those infants with NLR were mostly born by vaginal delivery and their mothers had a higher rate of early rupture of the membranes and chorioamnionitis. NLR was associated with a 4-fold increase in sepsis, 20 fold increase in intraventricular hemorrhage, 54-fold increase in bronchopulmonary dysplasia, and 6-fold increase in mortality. In the study group, those infants whose mothers had chorioamnionitis had a higher rate of early rupture of the membranes and they developed sepsis and intraventricular hemorrhage more often than those whose mothers did not have clinical chorioamnionitis. CONCLUSIONS: In low birth weight newborn infants, NLR is significantly associated with sepsis, intraventricular hemorrhage, bronchopulmonary dysplasia, and a high mortality rate. Also, those infants with NLR are more likely to be born to mothers with chorioamnionitis and they face sepsis and intraventricular hemorrhage more often. PMID- 20851019 TI - Unusual multicentric angiomyolipoma of knee joint and soft tissue foot. AB - To report unusual occurrence of angiomyolipoma at intraarticular location with another lesion in the same side foot. A 12-year-old girl was referred to us after initial inconclusive work-up done elsewhere for swelling of left knee joint. There was a 15 * 12 cm swelling in the knee joint partially encasing patella while also a similar hourglass shaped swelling measuring 9 * 4 cm was noted in the same side foot. After clinical and radiological evaluation an excision biopsy was planned for both sites. The specimen sent for histopathological evaluation revealed angiomyolipoma with identical characteristics in the two locations and was HMB45 immunostain negative. Patient was evaluated for possibility of tuberous sclerosis but there was no contributory evidence. Angiomyolipoma is typically a solitary renal tumor with rare occurrence at musculoskeletal sites. Multicentric variety is still infrequent. Intraarticular occurrence of angiomyolipoma presents a diagnostic challenge not only in terms of unfamiliarity but also unusual presentation with absence of characteristic immunostaining and multicentricity requiring careful exclusion of other lesions that may require a more radical approach for treatment. PMID- 20851020 TI - Traditional cardiovascular risk factors in rheumatoid arthritis: a meta-analysis. AB - OBJECTIVE: Rheumatoid arthritis is associated with increased cardiovascular morbidity and mortality. We performed a systematic review of the literature and a meta-analysis to look for differences in the prevalence of traditional cardiovascular risk factor between RA patients and controls. METHODS: Medline database was searched to identify studies evaluating the prevalence of traditional cardiovascular risk factors in rheumatoid arthritis patients and controls. Studies were selected and reviewed by two investigators. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated through the use of Chi2 and I2 statistics. RESULTS: Fifteen case-control studies with a total of 2956 patients and 3713 controls met the inclusion criteria. The prevalence of smoking was increased in RA patients in comparison with controls: OR (95%CI) 1.56 (1.35-1.80) (P < 0.00001). The prevalence of hypertension did not differ: OR (95% CI) 1.09 (0.91-1.31) (P = 0.35). The prevalence of diabetes mellitus was increased in RA: OR (95%CI) 1.74 (1.22-2.50) (P = 0.003). The prevalence of hypercholesterolemia did not differ: OR (95%CI) 0.84 (0.67-1.04) (P = 0.11). HDL cholesterol levels were lower in RA patients: weighted mean difference -17.72 mg/dl (-18.35 - -17.08) (P < 0.00001). Significant heterogeneity among studies was found for diabetes mellitus and HDL cholesterol levels. CONCLUSIONS: Some traditional cardiovascular risk factors, such as smoking, diabetes mellitus or lower HDL cholesterol levels, appear more prevalent in rheumatoid arthritis patients and could contribute to the increased cardiovascular morbidity and mortality observed in rheumatoid arthritis. PMID- 20851021 TI - The placebo effect in rheumatology: new data. AB - The placebo effect is often poorly understood or confused with evaluation bias or spontaneous improvement, particularly when study inclusion criteria select patients at the peak of their symptoms. Cerebral imaging studies have confirmed that the placebo effect exists, although it is now known to involve a combination of conditioned reflexes and reward anticipation. The magnitude of the placebo effect can be evaluated by randomly dividing patients into three groups, one of which receives no treatment at all; by crossover studies; or by the newly developed open-hidden study design. This last design has established that rebound effects can occur after placebo discontinuation, and other experiments have shown that anxiety is associated with a weaker placebo response. This anti-placebo effect of anxiety, similar to the nocebo effect, may involve the release of cholecystokinin. The strength of the placebo effect varies across procedures and joints. A marked placebo effect can be seen in rheumatology patients, as shown recently by two high-quality double-blind studies that found no difference between vertebroplasty and a sham procedure. Effective blinding is crucial both to obtain a strong placebo effect and to separate an intrinsic effect from a placebo effect. Beliefs of the patients and physicians regarding the active drug and the existence and strength of the placebo effect could also be usefully evaluated throughout clinical studies. PMID- 20851022 TI - The calcium controversy. PMID- 20851023 TI - Smoking habits influence pain and functional and psychiatric features in fibromyalgia. AB - OBJECTIVE: Numerous epidemiologic data have shown that smoking may play a role in the disease manifestations or severity of chronic musculoskeletal pain. The authors of the present study investigated the effect of smoking on clinical features such as pain, fatigue, functional impairment, and psychiatric features in the Korean population with fibromyalgia syndrome (FMS). METHODS: A total of 336 patients with FMS were consecutively enrolled from 10 medical centers which participated in the Korean national fibromyalgia survey. Smoking was divided into current smokers and non-smokers. Instruments of FMS assessment included tender points, Fibromyalgia Impact questionnaire (FIQ), 36-item Medical Outcomes Study Short-Form Health Survey (SF-36), Brief Fatigue Inventory (BFI), Brief Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI)-1 and STAI-2, and social family support and social friend support. Statistical analyses included Chi square test, Fisher's exact test, Mann-Whitney U test, and multivariate logistic regression analysis. RESULTS: Thirty-three patients (9.8%) out of 336 participants were current smokers. The number of tender points (P=0.037), BFI (P=0.026), general health of SF-36 (P=0.028), BDI (P=0.014), syncope (P=0.024), and reflex sympathetic dystrophy (P=0.003) showing significance between current smokers and non-smokers were not associated with smoking habits after adjustment. The significance of the number of tender points (P=0.009), scores of total tender points (P=0.032), BDI (P=0.038), general weakness (P=0.047), and reflex sympathetic dystrophy (P=0.011) was observed between randomized non-smokers (n=55) and smokers (n=33). In addition, the number of tender points (P=0.027, OR=1.379) was associated with smoking status after adjustment. The analysis between randomized non-smokers (n=45) and smokers (n=22) in female FMS patients showed that BDI in FMS was associated with smoking status (P=0.023, OR=1.077) after logistic regression analysis. CONCLUSIONS: This study revealed that smoking habits may, in part, influence pain or functional and psychiatric features in FMS patients. The impact of smoking on clinical features in FMS should be assessed in a larger study population. PMID- 20851024 TI - Whipple's disease endocarditis following anti-TNF therapy for atypical rheumatoid arthritis. PMID- 20851025 TI - Blood vessels, a potential therapeutic target in rheumatoid arthritis? AB - New micro-vessels formation within synovium and macro-vessels endothelial damage with atheroma are two major features of rheumatoid arthritis, the former related to the articular involvement of the disease, the latter to its main systemic complication. The similarities between pannus development and solid tumors growth, and the efficacy of anti-angiogenic treatments in oncology, opened the perspective of directly targeting angiogenesis in arthritis. Nevertheless, despite the success of different anti-angiogenic therapeutic strategies in many arthritis experimental models, the application in human disease is still lacking. Recent data suggest that synovial neoangiogenesis and macro-vessels endothelial damage might be two linked phenomena. While synovial angiogenesis seems to be detrimental to endothelial damage repair, even anti-angiogenic treatments might paradoxically aggravate macro-vascular disease, especially in the context of uncontrolled inflammation. These elements induce to further explore the interconnections between inflammation and angiogenesis on one side and between micro- and macro-vascular diseases on the other, in order to establish the proper way to therapeutically target blood vessels in rheumatoid arthritis. PMID- 20851027 TI - Roles of vessel growth factors in bone development and repair. PMID- 20851026 TI - Why should rheumatologists evaluate the impact of rheumatoid arthritis on sexuality? PMID- 20851028 TI - Biopsychosocial complexity is correlated with psychiatric comorbidity but not with perceived pain in complex regional pain syndrome type 1 (algodystrophy) of the knee. AB - AIM: The aim of this study was to compare the characteristics of patients suffering from complex regional pain syndrome type 1 ([CRPS], also known as reflex sympathetic dystrophy or algodystrophy) of the knee with those of a matched group of patients experiencing post-traumatic knee pain. The comparisons looked at biopsychosocial complexity (simple versus complex), psychiatric comorbidity and pain intensity. METHODS: Cross-sectional, single-centre, case control study using the INTERMED scale, psychiatric diagnostic tools (ICD-10) and visual analogue pain scale. Contingency table and Chi2 tests. One-way analysis of variance for continuous dependent variables. Difference between groups: Tukey's variance test, after the event. For nominal dependent variables, multivariate logistic analysis. RESULTS: Biopsychosocial complexity did not differ between the two groups (p = 0.7). The "complex" patients displayed significantly more psychiatric comorbidity (odds ratio 2.94, 95% confidence interval 1.1-7.8, p < 0.01), independently of whether or not CRPS was present. The pain perceived varied with biopsychosocial complexity only in the control group. The "complex" control patients reported more pain than the "simple" control patients (p < 0.05). The perceived intensity of pain was not different between the "simple" and "complex" patients with CRPS. CONCLUSIONS: Biopsychosocial complexity was comparable between the two groups, and was strongly associated with the presence of psychiatric comorbidity. However, unlike with other pain syndromes, with CRPS the intensity of the perceived pain did not vary with biopsychosocial complexity. Early identification of "complex" patients could make it possible to quickly institute targeted management for both groups of patients. PMID- 20851029 TI - Role for imaging studies in ankylosing spondylitis. AB - Although the diagnosis and structural monitoring of ankylosing spondylitis relies classically on standard radiography, recent classification criteria and recommendations issued by the ASAS-OMERACT working group give considerable weight to modern imaging methods, most notably magnetic resonance imaging (MRI). MRI and, more recently, ultrasonography, yield three major benefits: they ensure the early diagnosis of ankylosing spondylitis in the absence of radiographic sacroiliitis, they provide therapeutic guidance at any time during the course of the disease, and they supply objective information on the degree of inflammation and response to treatment. Prospective longitudinal studies are under way to determine the respective roles for MRI and ultrasonography in the diagnosis and monitoring of axial and peripheral forms of ankylosing spondylitis. The introduction of whole-body MRI, new MRI sequences and positron emission tomography can be expected to further benefit the diagnosis of ankylosing spondylitis. PMID- 20851030 TI - Microparticles and inflammatory joint disease. PMID- 20851031 TI - The association of common variable immune deficiency with idiopathic inflammatory myopathies. PMID- 20851032 TI - Tocilizumab in a patient with ankylosing spondylitis and Crohn's disease refractory to TNF antagonists. PMID- 20851034 TI - Landscape and children's health: old natures and new challenges for the preventorium. AB - Preventoria were established in the early part of the twentieth century at fresh air sites away from cities for the purposes of rest cures for children, usually for those who were at risk of contracting tuberculosis. This paper discusses preventoria in relation to their general landscapes, and outlines the types of landscapes in which preventoria are found, namely woods and forests, ocean, rivers and lakes, and agricultural settings. The preventorium movement is placed in historical landscape context, with urban planning, national parks, and other nineteenth century trends. Fresh air was the driving force of both treatment and locations of preventoria and sanatoria. Current movements in child health to combat obesity and 'nature-deficit-disorder' also call for greater engagement with fresh air, and stress the therapeutic value of natural landscape. Australia's oldest preventorium is examined as a case study of preventoria and the challenges which old preventoria are facing today to re-invent themselves in predominantly rural landscapes. PMID- 20851033 TI - Multi-organ autonomic dysfunction in Parkinson disease. AB - Both pathologic and clinical studies of autonomic pathways have expanded the concept of Parkinson disease (PD) from a movement disorder to a multi-level widespread neurodegenerative process with non-motor features spanning several organ systems. This review integrates neuropathologic findings and autonomic physiology in PD as it relates to end organ autonomic function. Symptoms, pathology and physiology of the cardiovascular, skin/sweat gland, urinary, gastrointestinal, pupillary and neuroendocrine systems can be probed by autopsy, biopsy and non-invasive electrophysiological techniques in vivo which assess autonomic anatomy and function. There is mounting evidence that PD affects a chain of neurons in autonomic pathways. Consequently, autonomic physiology may serve as a window into non-motor PD progression and allow the development of mechanistically based treatment strategies for several non-motor features of PD. End-organ physiologic markers may be used to inform a model of PD pathophysiology and non-motor progression. PMID- 20851035 TI - Root hair systems biology. AB - Plant functional genomic studies have largely measured the response of whole plants, organs and tissues, resulting in the dilution of the signal from individual cells. Methods are needed where the full repertoire of functional genomic tools can be applied to a single plant cell. Root hair cells are an attractive model to study the biology of a single, differentiated cell type because of their ease of isolation, polar growth, and role in water and nutrient uptake, as well as being the site of infection by nitrogen-fixing bacteria. This review highlights the recent advances in our understanding of plant root hair biology and examines whether the root hair has potential as a model for plant cell systems biology. PMID- 20851036 TI - The roots of a new green revolution. AB - A significant increase in shoot biomass and seed yield has always been the dream of plant biologists who wish to dedicate their fundamental research to the benefit of mankind; the first green revolution about half a century ago represented a crucial step towards contemporary agriculture and the development of high-yield varieties of cereal grains. Although there has been a steady rise in our food production from then onwards, the currently applied technology and the available crop plants will not be sufficient to feed the rapidly growing world population. In this opinion article, we highlight several below-ground characteristics of plants such as root architecture, nutrient uptake and nitrogen fixation as promising features enabling a very much needed new green revolution. PMID- 20851037 TI - Increased Langerhan cell density and corneal nerve damage in diabetic patients: role of immune mechanisms in human diabetic neuropathy. AB - AIM/HYPOTHESIS: Immune mechanisms have been proposed to play a role in the development of diabetic neuropathy. We employed in vivo corneal confocal microscopy (CCM) to quantify the presence and density of Langerhans cells (LCs) in relation to the extent of corneal nerve damage in Bowman's layer of the cornea in diabetic patients. METHODS: 128 diabetic patients aged 58 +/- 1 yrs with a differing severity of neuropathy based on Neuropathy Deficit Score (NDS-4.7 +/- 0.28) and 26 control subjects aged 53 +/- 3 yrs were examined. Subjects underwent a full neurological evaluation, evaluation of corneal sensation with non-contact corneal aesthesiometry (NCCA) and corneal nerve morphology using corneal confocal microscopy (CCM). RESULTS: The proportion of individuals with LCs was significantly increased in diabetic patients (73.8%) compared to control subjects (46.1%), P = 0.001. Furthermore, LC density (no/mm(2)) was significantly increased in diabetic patients (17.73 +/- 1.45) compared to control subjects (6.94 +/- 1.58), P = 0.001 and there was a significant correlation with age (r = 0.162, P = 0.047) and severity of neuropathy (r = -0.202, P = 0.02). There was a progressive decrease in corneal sensation with increasing severity of neuropathy assessed using NDS in the diabetic patients (r = 0.414, P = 0.000). Corneal nerve fibre density (P < 0.001), branch density (P < 0.001) and length (P < 0.001) were significantly decreased whilst tortuosity (P < 0.01) was increased in diabetic patients with increasing severity of diabetic neuropathy. CONCLUSION: Utilising in vivo corneal confocal microscopy we have demonstrated increased LCs in diabetic patients particularly in the earlier phases of corneal nerve damage suggestive of an immune mediated contribution to corneal nerve damage in diabetes. PMID- 20851038 TI - Cytokinin signaling and transcriptional networks. AB - The cytokinin signaling pathway consists of a phosphorelay mechanism that is initiated by binding of cytokinin to histidine kinase receptors and culminates with the transcription of cytokinin-responsive genes in the nucleus. Type-B response regulators (ARR) encode transcription factors that act as major players in the transcriptional activation of cytokinin-responsive genes, among which are many transcription factors. In this review, we highlight the transcriptional networks regulated by cytokinin that have been identified and their roles in the regulation of a subset of the many developmental and physiological processes regulated by this plant hormone. PMID- 20851039 TI - Regulation of the nuclear activities of brassinosteroid signaling. AB - Brassinosteroids (BRs) are important plant growth hormones that largely rely on transcription factors (TFs) to regulate a variety of plant physiological/developmental processes. Past genetic and biochemical studies have identified two key TFs and interacting partners that play major roles in regulating many BR-responsive genes, while genome-wide microarray experiments have discovered at least 50 BR-regulated TFs. However, little is known how these TFs function or whether additional TFs are involved in BR signaling. In the past few years, genetic studies and yeast one/two-hybrid screens coupled with microarray and chromatin immunoprecipitation experiments not only revealed new roles of the key regulatory TFs but also implicated additional TFs and other nuclear proteins in regulating the nuclear activities of BR signaling in Arabidopsis and rice. PMID- 20851040 TI - The perception of gibberellins: clues from receptor structure. AB - The discovery of GID1, a soluble receptor for gibberellins (GAs), has revealed new insights into how GA is perceived. X-ray analysis has demonstrated similarities in the tertiary structure of GID1 to hormone sensitive lipase (HSL), and the GA-binding pocket of GID1 corresponds to the active site of HSL. X-ray analysis has also revealed the structural basis of the GA-GID1 interaction, and evolutionary aspects of GID1 have been discovered by comparison to GID1 from non flowering plants. Recent studies have also demonstrated the complexity of GA signaling in Arabidopsis, which is mediated by three GID1 and five DELLA proteins. Finally, mechanistic and structural similarities for hormone signaling are compared for GA, auxin and abscisic acid, three hormones where the receptor protein structure was recently described. PMID- 20851041 TI - Genomic evolution of Vibrio cholerae. AB - Vibrio cholera, the causal agent of cholera, also occupies an autochthonous aquatic inhabitant. The current, seventh cholera pandemic is linked to O1 El Tor biotype and O139 serogroups. In the last decades, we have witnessed a shift involving genetically and phenotypically varied pandemic clones in Asia and Africa. Recent comparative genomic studies have identified a large 'mobilome', or composed of mobile genomic islands in V. cholerae. All seventh pandemic isolates have highly related genome sequences, but they can be differentiated by set of these genomic islands. A consequence of the extensive lateral gene transfer is that classically important diagnostic markers, such as serotype and biotype, are not reliable and new methods based on genomic sequences are required. PMID- 20851042 TI - Vibrational spectroscopy: can density functional theory cope with highly electronegative atoms? AB - Vibrational properties of molecules composed solely of highly electronegative atoms are studied by means of density functional methods. Performance of different combinations of exchange and correlation functionals is tested. It is demonstrated that certain functionals can successfully simulate infrared spectra of systems containing only fluorine, oxygen and nitrogen. PMID- 20851043 TI - Design, synthesis, growth and characterization of 4-methoxy-4'-dimethylamino benzylidene aniline (MDMABA): a novel third order nonlinear optical material. AB - Synthesis, growth, X-ray crystal structure and characterization of a novel third order nonlinear optical material, 4-methoxy-4'-dimethylamino-benzylidene aniline (MDMABA), are reported for the first time. The asymmetric unit of MDMABA compound contains two crystallographically independent molecules (A and B), and they exist in the E-configuration. The structural perfection of the grown crystal is analyzed by high-resolution X-ray diffraction rocking curve analysis. The functional groups present in MDMABA are investigated by FTIR and FT-Raman spectral analyses. The placement of the protons is determined using HNMR spectrum. The range and percentage of optical transmission were ascertained by recording UV-vis-NIR spectrum. Thermal and mechanical properties are reported. Dielectric study shows that the dielectric constant of the crystal varies with frequency and temperature. The third order nonlinear optical absorption coefficient of the MDMABA crystal is determined by the Z-scan technique. PMID- 20851044 TI - Spectrofluorometric study of iron removal from bovine lactoferrin by ethylenediamminetetraacetic acid. AB - The kinetics of iron removal from the two metal binding sites of the bovine lactoferrin by ethylenediaminetetraacetic acid (EDTA) was investigated at pH 7.5 and 33 degrees C. Solutions were buffered at pH 7.5 by 0.15 M Tris-HCl. Pseudo first-order rate constants as a function of ligand concentration were measured for iron removal from diferric lactoferrin and from N- and C-terminal monoferric lactoferrin. Diferric lactoferrin showed simple saturation behavior while both the monoferric forms showed a two-term dependence of kobs on ligand concentration that signifies two pathways for iron removal under the conditions applied. Moreover, the results show that the N-terminal site is more labile towards iron removal by EDTA than the C-terminal site. PMID- 20851045 TI - An ensemble method based on uninformative variable elimination and mutual information for spectral multivariate calibration. AB - Based on the combination of uninformative variable elimination (UVE), bootstrap and mutual information (MI), a simple ensemble algorithm, named ESPLS, is proposed for spectral multivariate calibration (MVC). In ESPLS, those uninformative variables are first removed; and then a preparatory training set is produced by bootstrap, on which a MI spectrum of retained variables is calculated. The variables that exhibit higher MI than a defined threshold form a subspace on which a candidate partial least-squares (PLS) model is constructed. This process is repeated. After a number of candidate models are obtained, a small part of models is picked out to construct an ensemble model by simple/weighted average. Four near/mid-infrared (NIR/MIR) spectral datasets concerning the determination of six components are used to verify the proposed ESPLS. The results indicate that ESPLS is superior to UVEPLS and its combination with MI-based variable selection (SPLS) in terms of both the accuracy and robustness. Besides, from the perspective of end-users, ESPLS does not increase the complexity of a calibration when enhancing its performance. PMID- 20851047 TI - A 5-year prospective cohort study on health-related quality of life in patients with narcolepsy. AB - OBJECTIVE: To evaluate the 5-year variation of health-related quality of life (HRQoL) and mood symptoms in a cohort of patients with narcolepsy. METHODS: Adults attending the Sleep Centre of the Department of Neurological Sciences, University of Bologna in 1997 and meeting the International Classification of Sleep Disorders-Revised criteria for the diagnosis of narcolepsy were eligible. Included patients self-administered the Medical Outcome Short Form-36 (SF-36) and the Zung depression scale (ZDS) prospectively in 1998 and 2003. RESULTS: There was no significant difference between 1998 and 2003 measures of SF-36 and ZDS in the 54 patients included. About 25% of them showed moderate or severe mood symptoms in both observations. ZDS score (inversely) and duration of disease (directly) explained a percentage of variance of role physical, vitality (VT), social functioning (SF) and role emotional. At the second observation VT and SF had a further percentage of variance explained by excessive daytime sleepiness (EDS) and age at onset. Self-reported diabetes frequency doubled after 5 years (from 7% to 17%). CONCLUSIONS: Patients with narcolepsy show a stable impairment of HRQoL in a 5-year period with respect to Italian normative data. Mood status and EDS negatively influence their HRQoL while disease duration has a positive influence. PMID- 20851046 TI - Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep. AB - OBJECTIVE: To compare heart rate variability (HRV) changes in patients with restless legs syndrome (RLS) and in healthy subjects, and to evaluate HRV before and after treatment with pramipexole in RLS patients. METHODS: A prospective, polysomnographic, single-blind, placebo-controlled study was performed in 23 patients with RLS and 10 healthy subjects. Basal spectral analysis of HRV and phasic heart rate (HR) changes during PLMS were compared between the two groups and, within the RLS group, before and after treatment with placebo or pramipexole. RESULTS: No differences were found in the basal sympathovagal balance outside of PLMS between RLS and controls and, in the RLS group, before and after treatment. The amplitude of PLMS-related HR changes was higher in patients than in controls. Treatment with pramipexole decreased the number of PLMS and normalized the increased PLMS-related HR response in RLS subjects. CONCLUSIONS: The repetitive abnormal autonomic response to PLMS might play a role in the increased cardiovascular risk proposed for RLS patients. Pramipexole reduced the number of PLMS and the amplitude of the autonomic response to residual PLMS, without effects on the tonic sympathovagal regulation. D3 receptors in the sympathetic pre-ganglionic neurons of the spinal intermediolateral columns might be a target of pramipexole. The normalization of the HR response could be relevant in reducing the risk of cardiovascular diseases and associated autonomic dysfunctions in patients with RLS. PMID- 20851048 TI - Restless legs syndrome mothers and attention-deficit/hyperactivity disorder children: what happened between them? PMID- 20851049 TI - Yawning cannot cause significant temperature decreases in humans. PMID- 20851050 TI - Influence of indoor factors in dwellings on the development of childhood asthma. AB - Asthma has become the most common, childhood chronic disease in the industrialized world, and it is also increasing in developing regions. There are huge differences in the prevalence of childhood asthma across countries and continents, and there is no doubt that the prevalence of asthma was strongly increasing during the past decades worldwide. Asthma, as a complex disease, has a broad spectrum of potential determinants ranging from genetics to life style and environmental factors. Environmental factors are likely to be important in explaining the regional differences and the overall increasing trend towards asthma's prevalence. Among the environmental conditions, indoor factors are of particular interest because people spend more than 80% of their time indoors globally. Increasing prices for oil, gas and other sources of primary energy will further lead to better insulation of homes, and ultimately to reduced energy costs. This will decrease air exchange rates and will lower the dilution of indoor air mass with ambient air. Indoor air quality and potential health effects will therefore be an area for future research and for gaining a better understanding of asthma epidemics. This strategic review will summarize the current knowledge of the effects of a broad spectrum of indoor factors on the development of asthma in childhood in Western countries based on epidemiological studies. In conclusion, several epidemiological studies point out, that indoor factors might cause asthma in childhood. Stronger and more consistent findings are seen when exposure to these indoor factors is assessed by surrogates for the source of the actual toxicants. Measurement-based exposure assessments for several indoor factors are less common than using surrogates of the exposure. These studies, however, mainly showed heterogeneous results. The most consistent finding for an induction of asthma in childhood is related to exposure to environmental tobacco smoke, to living in homes close to busy roads, and in damp homes where are visible moulds at home. The causing agents of the increased risk of living in damp homes remained uncertain and needs clarification. Exposure to pet-derived allergens and house dust mites are very commonly investigated and thought to be related to asthma onset. The epidemiological evidence is not sufficient to recommend avoidance measures against pet and dust mites as preventive activities against allergies. More research is also needed to clarify the potential risk for exposure to volatile and semi-volatile organic compounds due to renovation activities, phthalates and chlorine chemicals due to cleaning. PMID- 20851051 TI - A review of the clinical evidence for exercise in osteoarthritis of the hip and knee. AB - Osteoarthritis (OA) is a chronic joint disease with the hip and knee being commonly affected lower limb sites. Osteoarthritis causes pain, stiffness, swelling, joint instability and muscle weakness, all of which can lead to impaired physical function and reduced quality of life. This review of evidence provides recommendations for exercise prescription in those with hip or knee OA. A narrative review was performed. Conservative non-pharmacological strategies, particularly exercise, are recommended by all clinical guidelines for the management of OA and meta-analyses support these exercise recommendations. Aerobic, strengthening, aquatic and Tai chi exercise are beneficial for improving pain and function in people with OA with benefits seen across the range of disease severities. The optimal exercise dosage is yet to be determined and an individualized approach to exercise prescription is required based on an assessment of impairments, patient preference, co-morbidities and accessibility. Maximising adherence is a key element dictating success of exercise therapy. This can be enhanced by the use of supervised exercise sessions (possibly in class format) in the initial exercise period followed by home exercises. Bringing patients back for intermittent consultations with the exercise practitioner, or attendance at "refresher" group exercise classes may also assist long-term adherence and improved patient outcomes. Few studies have evaluated the effects of exercise on structural disease progression and there is currently no evidence to show that exercise can be disease modifying. Exercise plays an important role in managing symptoms in those with hip and knee OA. PMID- 20851052 TI - LH (as HCG) and FSH surges for final oocyte maturation: sometimes it takes two to tango? AB - Until now, clinicians have been relying solely on LH activity-dependent triggering of final oocyte maturation and thus taken it for granted that the natural midcycle FSH surge is biologically redundant. However, it is time to question this paradigm. Evidence from clinical studies hint that in a yet-to-be defined subset of patients, dual LH and FSH surge is advantageous compared with LH-only surge in the form of human chorionic gonadotrophin (HCG) trigger. Dual surge can be triggered by a bolus of gonadotrophin-releasing hormone agonist causing a flare-up of both endogenous LH and FSH, resembling the natural midcycle surge of gonadotrophins. HCG given in parallel secures adequate exposure to LH activity. Further research is needed to characterize the patients in whom FSH surge is needed for proper resumption of the oocyte meiotic process. PMID- 20851053 TI - Impact of commercials on food preferences of low-income, minority preschoolers. AB - OBJECTIVE: To determine whether fruit and vegetable (FV) commercials have an impact on preschool children's preferences for specific FV. DESIGN: A year of extensive formative assessment was conducted to develop 2 30-second commercials: "Judy Fruity" promoted apples and bananas and "Reggie Veggie" promoted broccoli and carrots. The commercials were embedded into a 15-minute TV program. Fruit and vegetable preferences were assessed before and after 4 exposures to each of the commercials. SETTING: Four Head Start centers in Houston, Texas. PARTICIPANTS: One hundred eighty-three preschool children (39% African American; 61% Hispanic American). MAIN OUTCOME MEASURES: Assessment of whether FV preferences were significantly higher in the treatment group than the control group, controlling for baseline FV preferences, age, race, and intervention dose in the model. ANALYSIS: A general linear model was used. RESULTS: There was a significantly higher preference for broccoli and carrots (P = .02) in the intervention group compared to the control group after multiple exposures to the vegetable commercial. CONCLUSIONS AND IMPLICATIONS: Data suggest that commercials promoting vegetables may be an effective strategy to influence young children's preferences for vegetables. This may not be the case with fruit preferences, which are already high in this age group. PMID- 20851054 TI - Patient and caregiver perspectives on seizure prediction. AB - One of the goals of the Fourth International Workshop on Seizure Prediction was to provide an opportunity for patients with epilepsy and their caregivers to voice their perspectives on seizure prediction and related matters toward the goal of influencing the design of solutions. In an attempt to fulfill this goal, a survey of patients and caregivers, who often make or influence patient choices, was conducted on issues pertaining to living with epilepsy, epilepsy treatments, seizure prediction, and the use of implantable devices for the control of seizures. The results of this survey are reported here. PMID- 20851055 TI - Distance delivery of mindfulness-based cognitive therapy for depression: project UPLIFT. AB - This study evaluated the efficacy of a newly developed, home-based depression intervention for people with epilepsy. Based on mindfulness-based cognitive therapy (MBCT), the eight-session, weekly intervention was designed for group delivery via the Internet or telephone. Forty participants were randomly assigned to intervention or waitlist. Depressive symptoms and other outcomes were measured at baseline, after intervening in the intervention group (~8 weeks), and after intervening in the waitlist group (~16 weeks). Depressive symptoms decreased significantly more in the intervention group than the waitlist group; Internet and telephone did not differ. This effect persisted over the 8 weeks when those waitlisted received the intervention. Knowledge/skills increased significantly more in the intervention than the waitlist group. All other changes, though not significant, were in the expected direction. Findings indicate that distance delivery of group MBCT can be effective in reducing symptoms of depression in people with epilepsy. Directions for future research are proposed. PMID- 20851056 TI - Epilepsy-associated stigma in Zambia: what factors predict greater felt stigma in a highly stigmatized population? AB - Epilepsy-associated stigma in Africa has been described largely in terms of enacted stigma or discrimination. We conducted a study of 169 adults with epilepsy attending epilepsy clinics in Zambia's Lusaka or Southern province using a three-item instrument (maximum score = 3). Potential determinants of felt stigma including age, gender, education, wealth, disclosure status (meaning whether or how their community members knew of their condition), seizure type (generalized vs partial), seizure frequency, the presence of visible epilepsy associated stigmata, personal contagion beliefs, and community contagion beliefs. The median stigma score was 2.5, suggesting some ceiling effect in the instrument. People with epilepsy who believed their condition to be contagious, who thought their community believed epilepsy to be contagious, and whose condition had been revealed to their community against their wishes reported more felt stigma. Community and clinic-based educational campaigns to dispel contagion beliefs are needed. PMID- 20851057 TI - Association between substance use disorder status and pain-related function following 12 months of treatment in primary care patients with musculoskeletal pain. AB - The goal of this study was to examine relationships between substance use disorder (SUD) history and 12-month outcomes among primary care patients with chronic noncancer pain (CNCP). Patients were enrolled in a randomized trial of collaborative care intervention (CCI) versus treatment as usual (TAU) to improve pain-related physical and emotional function. At baseline, 72 of 362 patients (20.0%) had a history of SUD. Compared to CNCP patients without SUD, those with comorbid SUD had poorer pain-related function and were more likely to meet criteria for current major depression and posttraumatic stress disorder (all P values <.05). Logistic regression analyses were conducted to examine whether SUD status was associated with clinically significant change over 12 months in pain related function (30% reduction in Roland Morris Disability Questionnaire Score). The overall model was not significant in the CCI group. However, within the TAU group, participants with a SUD history were significantly less likely to show improvements in pain-related function (OR = .30, 95% CI = .11-.82). CNCP patients with comorbid SUD reported greater functional impairment at baseline. Patients with SUD who received usual care were 70% less likely to have clinically significant improvements in pain-related function 12 months postbaseline, and SUD status did not impede improvement for the CCI group. PERSPECTIVE: Chronic noncancer pain patients with a history of a substance use disorder (SUD) report poorer pain-related functioning and are less likely to experience clinically significant improvements from usual pain treatment. Providers should assess for SUD status and provide more intensive interventions for these patients. PMID- 20851059 TI - Does catastrophic midline failure of upper thoracic lamina screws violate the spinal canal? A cadaveric biomechanical analysis using two lamina screw techniques. AB - BACKGROUND CONTEXT: Lamina screws have been reported to be a biomechanically sound alternative to pedicle screws in the proximal thoracic spine. However, concerns have been raised that midline failure may result in a spinal canal breach. PURPOSE: To evaluate the catastrophic failure of proximal thoracic lamina screws using two techniques for lamina screw purchase. STUDY DESIGN: Biomechanical study with human cadaveric vertebrae. PATIENT SAMPLE: Not applicable. OUTCOME MEASURES: Not applicable. METHODS: Nineteen fresh-frozen T1 T2 vertebrae were Dual energy X-ray absorptiometry scanned for bone mineral density. Caliper measurements of lamina thickness and lateral mass width for bicortical purchase were obtained. Ten specimens had right-to-left 26-mm lamina screws inserted entirely within the length of the lamina (unicortical). Nine specimens had right-to-left 42-mm lamina screws inserted as to extend the length of the lamina and breach the cortex behind the first and second ribs (bicortical). All screws were placed by experienced spine surgeons under fluoroscopic visualization using 4.5-mm cervicothoracic screws. Insertional torque was recorded while placing all implants and reported in "in-lbs." Tensile loading to failure was performed with the force oriented in the parasagittal plane along the vertebral midline. Pullout loading was applied at a rate of 0.25 mm/s using an MTS 858 MiniBionix II System (MTS Systems, Inc., Minneapolis, MN, USA) with the maximum pullout strength (POS) recorded in Newtons. Video fluoroscopy was performed during midline pullout to evaluate screw failure and ascertain spinal canal breach. After testing, all specimens were visually inspected for spinal canal breach. RESULTS: Neither the unicortical nor the bicortical lamina screws violated the spinal canal during catastrophic midline failure. The ventral lamina cortex remained intact for both the lamina screw techniques. All of the unicortical lamina screws resulted in dorsal avulsion of the spinous process and lamina. All nine bicortical lamina screws separated the dorsal lamina from the ventral but were able to maintain lateral mass purchase. The peak insertional torque for both lamina screw techniques was not significantly different (p = .20). However, bicortical lamina screw POS (584.8 +/ 150.2 N) was significantly greater than unicortical lamina screw POS (455.6 +/- 100.2 N) (p = .04). Bone mineral density showed a moderate correlation with unicortical (r = 0.67) and bicortical (r = 0.47) lamina screw POS. CONCLUSION: Our results suggest that catastrophic midline failure of lamina screws does not violate the spinal canal. Of the two techniques tested, bicortical lamina screws have a biomechanical advantage. Lamina screws present a viable option for instrumenting the proximal thoracic spine. PMID- 20851058 TI - Combination drug therapy for chronic pain: a call for more clinical studies. AB - Chronic pain is a debilitating clinical condition associated with a variety of disease entities including diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. For many general practitioners and specialists, managing chronic pain has become a daunting challenge. As a modality of multidisciplinary chronic pain management, medications are often prescribed in combinations, an approach referred to as combination drug therapy (CDT). However, many medications for pain therapy, including antidepressants and opioid analgesics, have significant side effects that can compound when used in combination and impact the effectiveness of CDT. To date, clinical practice of CDT for chronic pain has been based largely on clinical experiences. In this article, we will focus on (1) the scientific basis and rationales for CDT, (2) current clinical data on CDT, and (3) the need for more clinical studies to establish a framework for the use of CDT. PERSPECTIVE: More preclinical, clinical, and translational studies are needed to improve the efficacy of combination drug therapy that is an integral part of a comprehensive approach to the management of chronic pain. PMID- 20851060 TI - Monitoring of periodic anaerobic digestion with flow-through array of miniaturized ion-selective electrodes. AB - In the last few years Electronic tongues (ETs) based on various sensor arrays were applied to the monitoring of various fermentation processes, as devices capable of fast, inexpensive, automated and on-line control. In this work a novel application of ET is proposed--flow-through array of miniaturized ion-selective electrodes (ISEs) was used for the analysis of samples obtained during anaerobic digestion (methane fermentation) performed in periodic conditions. The samples were classified according to their Chemical Oxygen Demand (COD) and Volatile Fatty Acid (VFA) content. Moreover, for this application a novel design of ISEs was developed, which is fully compatible with flow-through modules for sensor measurements. PMID- 20851061 TI - In vitro activity of temocillin against planktonic and sessile Burkholderia cepacia complex bacteria. AB - Burkholderia cepacia complex (Bcc) bacteria are opportunistic respiratory pathogens which are particularly difficult to eradicate from the lungs of cystic fibrosis (CF) patients because of their innate resistance to antimicrobials and their capacity to form biofilms. The goal of the present study was to evaluate the bacteriostatic and bactericidal activities of temocillin against planktonic and sessile Bcc bacteria. 37 strains belonging to 17 Bcc species were tested. 75.7% of the strains were susceptible when grown planktonically (minimal inhibitory concentration <16 MUg/ml). The minimal bactericidal concentrations were higher than 128 MUg/ml for most strains. No remarkable differences in resistance between exponentially growing planktonic cells and 4 h old biofilms were observed: when grown in a biofilm, 59.5% of the strains were susceptible. After treating 24 h biofilms with a concentration of 10*MIC, only a minor reduction was seen in the number of sessile cells, indicating a limited bactericidal activity against biofilms. Our data indicate that temocillin has a good bacteriostatic in vitro activity against planktonic and 4 h old biofilms, but seems of limited use to eradicate 24 h old biofilms. PMID- 20851062 TI - Simultaneous two-dimensional HPLC determination of free D-serine and D-alanine in the brain and periphery of mutant rats lacking D-amino-acid oxidase. AB - A fully automated two-dimensional HPLC system combining a microbore-ODS column and a narrowbore-enantioselective column was designed and validated, and the amounts of D-serine (D-Ser) and D-alanine (D-Ala) in various tissues and physiological fluids of Long-Evans agouti/SENDAI (LEA/Sen) rats lacking D-amino acid oxidase (DAO) were determined. Intra- and inter-day precision was less than 4.3% and accuracy ranged between 99.9 and 104%. LEA/Sen rats were reported to lack DAO in their kidneys and expected to be a novel mutant animal lacking DAO, however, the amounts of D-amino acids in the LEA/Sen rats have not been investigated. In the present study, the intrinsic amounts of D-Ser and D-Ala, which are neuromodulators of the N-methyl-D-aspartate (NMDA) receptors, were determined in seven brain tissues, four peripheral tissues, plasma and urine of the LEA/Sen rats and compared to those of the control (Wistar and SD) rats having normal DAO activity. The levels of D-Ser in the tissues and physiological fluids of the LEA/Sen rats were significantly higher than those of the Wistar and SD rats except for the frontal brain regions. Concerning D-Ala, the amounts in the tissues and physiological fluids of the LEA/Sen rats were drastically increased compared to those of the Wistar and SD rats. These results indicate that the intrinsic amounts of D-Ser and D-Ala in the tissues of rats are regulated by DAO, and that LEA/Sen rats would be useful for the study of NMDA receptor-related diseases in which DAO is implicated. PMID- 20851063 TI - Measurement of cortisol, cortisone, prednisolone, dexamethasone and 11 deoxycortisol with ultra high performance liquid chromatography-tandem mass spectrometry: Application for plasma, plasma ultrafiltrate, urine and saliva in a routine laboratory. AB - We describe an ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC MS/MS) method suitable for a routine laboratory to determine endogenous and exogenous glucocorticoids in plasma, plasma ultrafiltrate, urine and saliva in a single analytical run. After addition of a multi-analyte internal standard, a standardised sample preparation procedure with solid phase extraction followed, before injecting into a tandem mass spectrometer with positive mode electron spray ionisation and multiple reactant monitoring acquisition. The chromatography time was 3min. The limit of quantitation for cortisol and cortisone in plasma was 3.75nmol/L and linearity extended to 2000nmol/L. The limit of quantitation for cortisol in plasma ultrafiltrate and saliva was 0.6nmol/L. The limit of quantitation for 11-deoxycortisol and prednisolone was 5nmol/L and for dexamethasone 1nmol/L. The intra-assay CV was <5% and the inter assay CV <10% for all analytes in all matrices. Comparison with an immuno-assay (IA) plasma cortisol method resulted in a regression equation of UHPLC=0.79*IA+31.12 with R(2)=0.960 (p<0.0001). Comparison with a high performance liquid chromatography (HPLC) cortisol method yielded a regression equation of UHPLC=1.06*HPLC+9.82, R(2)=0.992 (p<0.0001). The simultaneous measurement of endogenous and exogenous glucocorticoids contributed to patient care in cases with dexamethasone and metyrapone dynamic tests and unsuspected therapeutic glucocorticoid use. PMID- 20851064 TI - Does prenatal healthcare improve child birthweight outcomes in Azerbaijan? Results of the national Demographic and Health Survey. AB - This paper evaluates the effectiveness of prenatal healthcare in Azerbaijan on improving child birthweight using the 2006 Azerbaijan Demographic and Health Survey, a nationally representative survey of reproductive aged women. Two measures of prenatal health utilization are used to measure healthcare input-the number of prenatal visits and the quality index of health care. Endogeneity in prenatal healthcare utilization is controlled by 2SLS regression. Selection bias of probability of child being weighed is controlled by a binomial probit regression. We found that prenatal healthcare does improve child birthweight. The results of the 2SLS suggest that an additional prenatal visit increases birthweight by about 26g, or approximately 0.8% of the raw mean of birthweight in the country. Likewise, a unit increase in quality of prenatal healthcare increases birthweight by 21g or by approximately 1.3% of the birthweight. In general, the magnitude of prenatal care impact in Azerbaijan is comparable with that in other countries. PMID- 20851065 TI - Dynamic contrast-enhanced magnetic resonance imaging: definitive imaging of placental function? AB - The placenta constitutes a complex circulatory interface between the mother and fetus, but the relationship between the maternal and fetal circulation is still very difficult to study in vivo. There is growing evidence that magnetic resonance imaging (MRI) is useful and safe during pregnancy, and MRI is increasingly used for fetal and placental anatomical imaging. MRI functional imaging is now a modern obstetric tool and has the potential to provide new insights into the physiology of the human placenta. Placental perfusion has been studied during the first pass of an MR contrast agent, by arterial spin labeling, diffusion imaging, T1 and T2 relaxation time measurement using echo-planar imaging, and by a combination of magnetization transfer with established stereological methods. The BOLD (blood oxygen level-dependent) effect offers new perspectives for functional MRI evaluation of the placenta. PMID- 20851066 TI - Biomechanical analysis of sutures used for mesh fixation in the donor area after removal of the rectus abdominis muscle. AB - BACKGROUND: The use of synthetic mesh for abdominal wall closure after removal of the rectus abdominis is established but not standardised. This study compares two forms of mesh fixation: a simple suture, which fixes the mesh to the edges of the defect on the anterior rectus abdominis fascia; and total fixation, which incorporates the fasciae of the internal oblique, external oblique and transverse muscles in the suture, anchoring the mesh in the position of the removed muscle. METHOD: A total of 16 fresh cadavers were dissected. Two sutures were compared: simple and total. Three different sites were analysed: 5 cm above, 5 cm below and at the level of the umbilicus. The two sutures compared were tested in each region using a standardised technique. All sutures were performed with nylon 0, perpendicular to the linea alba. Each suture was secured to a dynamometer, which was pulled perpendicularly towards the midline until the rupture of the aponeurosis. 'Rupture resistance' was measured in kilogram force. The mean among the groups was compared using the paired Student's t-test to a significance level of 1% (p<0.01). RESULTS: The mean rupture resistance of the total suture was 160% higher than that of the simple suture. CONCLUSION: The total suture includes the external oblique, internal oblique and transverse fasciae, which are multi directional, and creates a much higher resistance when compared with the simple suture. Total suture may reduce the incidence of bulging and hernias of the abdominal wall after harvesting the rectus abdominis muscle, but comparative clinical studies are necessary. PMID- 20851067 TI - The island pedicled anterolateral thigh (pALT) flap via the lateral subcutaneous tunnel for recurrent ischial ulcers. AB - Chronic recurrent ischial sores are an important cause of morbidity in paraplegics and geriatric patients. Compared to sacral and trochanteric ulcers, ischial sores are the most difficult to treat, with a low success rate following conservative therapy and a high recurrence rate after surgical treatment. We report the use of the pedicled anterolateral thigh (pALT) flap for reconstruction of a chronic ischial sore. The free ALT flap has an established role in reconstruction in the head and neck and extremities. However, there are few reports concerning its clinical applications for regional reconstruction. As a pedicled flap, it has been used in the primary reconstruction of the perineum, groin, anterior abdominal wall, thigh and ischium. We present the first reported case of a paraplegic man with a recurrent ischial sore treated successfully with an island pALT flap inset via a lateral subcutaneous approach. We discuss the indications and its role as a simple and reliable secondary reconstructive option in the treatment of recurrent ischial ulcers after first-line loco-regional surgical options have been exhausted. PMID- 20851068 TI - Pyoderma gangrenosum of the breast: a diagnosis not to be missed. AB - Pyoderma gangrenosum (PG) is a non-infectious purulent ulcerative disease triggered mainly by chronic inflammatory bowel disease, monoclonal gammapathy, polyarthritis and haematological malignancies; exceptionally, it can be triggered by surgery alone. When PG is associated with fever, it can mimic infectious cellulitis. When it is located on the breast, unnecessary and deleterious surgical debridement may be performed. We present two cases of PG of the breast. The first is a postoperative PG and the second was associated with acute myeloid leukaemia - both led to unnecessary surgery. Several elements may have helped to make the diagnosis: nipples little affected by PG, symmetrical lesions on both breasts, other similar lesions elsewhere on the body, resistance to wide spectrum antibiotherapy, complete blood count abnormalities and negativity of bacterial culture. We propose an index to help the surgeon in his decision to realise a surgical debridement or to postpone it and consider the diagnosis of PG. PMID- 20851069 TI - Luer lock drain bottles. A simple and practical device for fat harvesting. PMID- 20851070 TI - Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. AB - Adipose tissue-derived stem cells (ADSCs) have shown potential for the treatment of nerve injuries. Most previous efforts have aimed at stimulating regeneration by using neural-differentiation protocols, but the potential of undifferentiated ADSCs to enhance axonal growth as well as their ability to transdifferentiate in situ have been poorly investigated. In this study, using a rat sciatic nerve model we show that ADSCs, transplanted in an artificial nerve conduit, stimulate axonal outgrowth from the proximal nerve stump and evoke greater Schwann cell (SC) proliferation/intrusion in the distal stump. To track the fate of the transplanted cells, we used green fluorescent protein (GFP)-labelling and polymerase chain reaction (PCR) for the detection of the sex determining region Y (SRY) gene in the donor male cells. Both methods indicated a lack of significant quantities of viable cells 14 days after transplantation. These results suggest that any regenerative effect of transplanted ADSCs is more likely to be mediated by an initial boost of released growth factors and/or by an indirect effect on endogenous SCs activity. Future studies need to address long-term cell survival in tissue-engineered nerve conduits to improve the neuroregenerative potential of ADSCs. PMID- 20851071 TI - Type 2 diabetes in younger adults: clinical characteristics, diabetes-related complications and management of risk factors. AB - AIM: To describe the clinical characteristics and risk factors of adults <35 years with type 2 diabetes (T2DM). METHODS: Observational study of 185 younger adults attending a specialist diabetes clinic. RESULTS: In this cohort 65% were female, 51% Caucasian, 43% South Asian. Characteristics at presentation: age 24 +/- 5.5 years, BMI 33 +/- 7.6 kg/m(2) and HbA1c 9.0% +/- 2.3. Follow up of 3.2 +/ 2.8 years with a diabetes duration of 4.5 +/- 3.6 years. HbA1c had improved compared with diagnosis (8.3 +/- 2.2% vs. 9.0% +/- 2.3%, p<0.0001), but 63% still had an HbA1c>7%. Oral anti-diabetic drugs were used in 72%, insulin alone in 19% and both in 26%. 41% had a BP >= 140/80 mmHg, 78% total cholesterol >4 mmol/l, 63% LDL >2 mmol/l, 56% triglycerides >1.7 mmol/l. From diagnosis only the cholesterol and LDL improved significantly, with a modest increase in primary prevention therapy (statin 12-26%, p<0.0001, anti-hypertensives 16-29%, p<0.0001, aspirin 8-12%, p=0.18). 13% had retinopathy, 21% microalbuminuria. 46% had not been reviewed within the past year. CONCLUSIONS: This group represents an extreme phenotype with a high prevalence of insufficiently treated metabolic risk factors. There is need for tailored management strategies to engage and aggressively manage this high-risk group. PMID- 20851072 TI - Prospective isolation of clonogenic mantle cell lymphoma-initiating cells. AB - Here, we have prospectively isolated and characterized, for the first time, clonogenic cells with self-renewal capacities from mantle cell lymphoma (MCL), a particularly deadly form of non-Hodgkin's lymphoma (NHL). Self-renewal and tumorigenic activities were enriched in MCL cell fractions that lacked expression of the prototypic B-cell surface marker, CD19. CD45+CD19- cells represented a relatively small fraction of the total MCL tumor cells; however, they recapitulated the heterogeneity of original patient tumors on transplantation into immunodeficient mice. As few as 100 of these cells displayed self-renewal capacities in secondary and tertiary recipient mice by in vivo limiting dilution assays. Similar to leukemic stem cells, CD45+CD19- MCL cells also displayed a quiescent status as determined by dye efflux assays. In summary, this study is the first to isolate subpopulations of MCL cells that have self-renewal and tumorigenic capacities. Identification and characterization of MCL-ICs are important first steps toward understanding how self-renewal and tumorigenicity are regulated in MCL and designing targeted therapies against MCL-ICs will ultimately lead to improved outcomes for MCL patients. PMID- 20851073 TI - Comments on: muscle fatty infiltration in rotator cuff tears: descriptive analysis of 1,688 cases by B. Melis, C. Nemoz and G. Walch, published in 10.1016/j.otsr. 2009.05.001. PMID- 20851074 TI - Shelf arthroplasties long-term outcome: influence of labral tears. A prospective study at a minimal 16 years' follows up. AB - INTRODUCTION: Osteoarthritis lesions extent and dysplasia severity (negative vertical center edge [CE] angle) are recognized as unfavorable criteria for the survival of shelf arthroplasties performed for correcting hip dysplasia. Labral tears have recently been described on dysplastic hips, indicating beginning osteoarthritis and worsening the risk of instability. HYPOTHESIS: The labral tears identified in the course of shelf arthroplasty procedures for correction of hip dysplasia carry a predictive value for the survival of this operation. OBJECTIVES: Evaluate this hypothesis at the intermediate term in a long-term prospective observational study. PATIENT AND METHODS: Eighteen adult patients (18 dysplastic hips) having undergone shelf arthroplasty were included consecutively in a continuous prospective study. At the time the shelf arthroplasty was performed, a hip arthroscopic exam was carried out to search for and resect a labral tear if necessary. Fifteen patients were reviewed with a minimum follow-up of 16 years. Two patients died and one patient was lost to follow-up. RESULTS: During arthroscopic exploration, 10 hips presented labral tears (55.6%). At a mean follow-up of 16.3 years (range, 16-18 years), eight hips underwent hip arthroplasty. Of these hips, only one did not present a labral tear. The seven other hips had a tear of the labrum (p<0.001). The overall survival rate was 41.3%; it was 83.3% for hips with no labral tear and 15.2% for hips with a lesion of the labrum (p=0.048). DISCUSSION AND CONCLUSION: Labral tears had a negative impact on the outcome of shelf arthroplasty for hip dysplasia. This lesion therefore warrants being sought using appropriate exploration techniques (MRI or CT-arthrography) before shelf arthroplasty surgery. The existence of a preoperative labral tear does not seem to cast doubt on shelf arthroplasty itself. However, it should be identified so as to set objectives and expectations: long-term survival is significantly lower in the presence of a labral tear. It seems preferable to repair this type of lesion with arthroscopic guidance during shelf arthroplasty to prevent a potential source of residual pain, keeping in mind that secondary resection will be more difficult after covering the lesion. LEVEL OF EVIDENCE: Level 3 prospective observational prognostic study. PMID- 20851075 TI - Tarsal tunnel syndrome and flexor hallucis longus tendon hypertrophy. AB - Tarsal tunnel syndrome (TTS) defines an entrapment neuropathy of the posterior tibial nerve or one of its branches, within the tarsal tunnel. Numerous etiologies have been described explaining this entrapment, including trauma, space-occupying lesions, foot deformities, etc. We present an unreported cause of a space-occupying lesion in the etiology of TTS, namely the combination of a hypertrophic long distally extended muscle belly of the flexor hallucis longus and repetitive ankle motion. Surgical debulking of the muscle belly in the posterior ankle compartment resolved all symptoms. PMID- 20851076 TI - Distal leg fractures: How critical is the fibular fracture and its fixation? AB - INTRODUCTION: Extra-articular distal tibia fractures include a tibial fracture line located partially or totally in the metaphyseal bone and a fibular fracture in variable areas or sometimes absent. There is no consensus in the literature on the conduct to address the fibula fracture. The main objective of this study was to assess its impact on tibial reduction and union. HYPOTHESIS: Fibular fixation plays a positive role in reducing tibial displacement and improving mechanical stability of the entire lesion. MATERIAL AND METHODS: This study was based on the multicenter observational group of the 2009 SOFCOT symposium, i.e., 142 metaphyseal fractures of the tibia. The fibula was intact in 10 cases and fractured in 132. In the three main categories of surgical treatment for the tibia (nailing, plating, external fixation) (126 fractures), the fibular lesion was not treated in 79 cases (61%) in this series, nine were treated with intramedullary pinning, and 38 with plate and screw fixation. RESULTS: There was no statistical relation between the anatomic situation of the diaphysis and the anatomic type of the fibular fracture or between the anatomic type of the fibular fracture and its situation compared to the tibial fracture line. The intertubercular and neck fractures were type A1 or B1 (P<0.001) and were combined to a tibia fracture with a torsional component; the medial-diaphyseal and subtubercular fractures were associated with tibial fracture lines with a simple transversal or comminution or metaphyseal-diaphyseal component (P<0.032). The rate of pseudarthrosis of the fibular fracture was 4.7% at 1 year; in all these cases, fibular treatment had been conservative. All treatments combined, the tibial axes were statistically better corrected when the fibula was treated with fixation. In four of the 11 cases of axial tibial malunion, the primary fibular fixation caused or worsened them. DISCUSSION: The present clinical series provides results similar to the biomechanical studies. The consequences of fibular fixation perpetuating a tibia reduction abnormality or on the contrary the absence of fibular fixation appeared as probable factors of residual reduction defects, lack of stability of the tibiofibular complex, and tibia non union. LEVEL OF EVIDENCE: Level IV (prospective cohort study). PMID- 20851077 TI - Radiographic preoperative templating of extra-offset cemented THA implants: how reliable is it and how does it affect survival? AB - INTRODUCTION: Securing femoral offset should in theory improve hip stability and abductor muscles moment arms. As problems arise mainly in case of originally increased offset (>40 mm), a range of extra-offset stems is available; the exact impact in terms of fixation, however, is not known. HYPOTHESIS: Extra-offset stems should more reliably reestablish original femoral offsets exceeding 40 mm than standard femoral components, limiting instability risk without possible adverse effect on fixation. OBJECTIVE: To compare the ability of five commonly available femoral stem designs to restitute offset exceeding 40 mm, and to assess function and cement fixation at a minimum 6 years' follow-up in a stem conceived to reproduce such offset. PATIENTS AND METHODS: A continuous series of 74 total hip replacements (THR) in hips with increased (>40 mm) femoral offset was studied. All underwent preoperative X-ray templating on ImagikaTM software to assess offset reproduction by five models of stem: four standard, and one Lubinus SP2TM extra-offset stem. A retrospective clinical and X-ray study was conducted with a minimum 6 years' follow-up on the Lubinus SP2TM 117 degrees stems used to try to reproduce offset in the 74 THRs. RESULTS: Apart from the increased (>40 mm) offset, the cervicodiaphyseal angle was consistently <135 degrees , <130 degrees in 60 femurs (81%) and <125 degrees in 45 (60%). Planning showed the four standard stems to induce (>5mm femoral offset reduction in 50-83% of cases, versus only 25% with the Lubinus SP2TM 117 degrees ). All 74 hips received Lubinus SP2TM 117 degrees stems: at a mean 78 months FU (range, 70-94 mo), their mean Postel-Merle d'Aubigne score was 17+/-1.8 (range, 13-18). Five of the 74 THRs underwent surgical revision: three cases of loosening, in which the stem was replaced, and two of instability, without change of stem. Loosening was not related to offset reproduction quality; two of the three cases were due to initial cementing defect, and the third occurred in a femur with previous history of two osteotomies. There were four cases of dislocation (5.4%: two primary, which were not operated on, and two recurrent, managed by acetabular revision), despite good reproduction of the preoperative offset in three of the four cases. Mean 7-year implant survivorship was 95.1% (+/-4.8). DISCUSSION AND CONCLUSION: The anatomic form of the LubinusTM SP2 117 degrees should in theory provide a uniform cement mantle. Survivorship, however, is less good than for regular offset versions (126 degrees or 135 degrees ). On the other hand, it does reproduce anatomy in case of >40mm offset, providing extra offset of more than 51mm. The slightly shorter survivorship requires more long-term surveillance. LEVEL OF EVIDENCE: Level IV, retrospective study. PMID- 20851078 TI - In healthy subjects, the sitting position can be used to validate the postural effects induced by wearing a lumbar lordosis brace. AB - AIM OF THE STUDY: To assess the validity of the sitting position when testing lumbar braces for the maintenance of lordosis. PATIENTS AND METHODS: Twelve young adult subjects participated in the experiment, in which they were seated on force platform. The four experimental conditions (with or without a brace and with or without enforced lordosis) were chosen in order to distinguish between the roles played by lordosis and the brace, respectively. The trajectories of the centre of pressure (CP) were analyzed and compared, in order to assess postural orientation and stabilisation processes. RESULTS: Although no effect was seen in terms of orientation, our data showed that use of a lumbar brace led to a notable reduction in CP displacement along the mediolateral and anteroposterior axes. Lordosis barely affected postural performance and only an increase in the mean CP velocity was observed. Lastly, an analysis of variance failed to reveal an interaction between the "lordosis" and "brace" factors. CONCLUSION: A lumbar brace (in the absence or presence of lordosis) helps subjects to improve their sitting performance. In contrast to previous studies based on the standing posture, the fact that significant differences were found as a function of brace wear emphasises the discriminant power of the sitting position. This task should therefore be applied more widely in the development of more appropriate, validated equipment for lower back pain sufferers. PMID- 20851079 TI - Oral delivery of a DNA vaccine against tuberculosis using operator-repressor titration in a Salmonella enterica vector. AB - Attenuated Salmonella enterica offers a vaccine delivery route that has the benefits of enhanced immunogenicity and oral delivery. The majority of immunization studies have been conducted to deliver recombinant proteins, expressed from a gene that is either chromosomally integrated or carried on a low or medium-copy number plasmid. There are, however, an increasing number of reports demonstrating the delivery of DNA vaccines, but the high-copy number plasmids that are preferentially used for this application are unstable in Salmonella. Here, we use the Operator-Repressor Titration (ORT) plasmid maintenance system in Salmonella enterica serovar Typhimurium to deliver a high copy number plasmid expressing the Mycobacterium tuberculosis gene mpt64 to mice. MPT64 expression was detected in phagocytes using immunofluorescence microscopy following Salmonella-mediated delivery of the DNA vaccine. The indicative CD8+ responses measured by antigen-specific IFN-gamma were higher from the live bacterial vector than from injected plasmid DNA, and a reduction in the pulmonary bacterial load was seen following an aerogenic challenge. This illustrates the potential of live attenuated Salmonella as oral tuberculosis vaccine vectors. PMID- 20851080 TI - A clinical trial to evaluate the safety and immunogenicity of the LEISH-F1+MPL-SE vaccine when used in combination with sodium stibogluconate for the treatment of mucosal leishmaniasis. AB - Adult patients with mucosal leishmaniasis (ML) were enrolled in a randomized, double-blind, placebo-controlled, dose-escalating clinical trial and were randomly assigned to receive three injections of either the LEISH-F1+MPL-SE vaccine (consisting of 5, 10, or 20 MUg recombinant Leishmania polyprotein LEISH F1 antigen+25 MUg MPL((r))-SE adjuvant) (n=36) or saline placebo (n=12). The study injections were given subcutaneously on Days 0, 28, and 56, and the patients were followed through Day 336 for safety, immunological, and clinical evolution endpoints. All patients received standard chemotherapy with sodium stibogluconate starting on Day 0. The vaccine was safe and well tolerated, and induced both humoral and cell-mediated immune responses. Furthermore, intracellular cytokine staining showed an increase in the proportion of memory LEISH-F1-specific IL-2(+) CD4 T-cells after vaccination, which was associated with clinical cure. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in patients with ML. PMID- 20851082 TI - HSV-1 amplicon vectors that direct the in situ production of foot-and-mouth disease virus antigens in mammalian cells can be used for genetic immunization. AB - HSV-1 amplicon vectors encoding heterologous antigens were capable to mediate in situ generation of protein synthesis and to generate a specific immune response to the corresponding antigens. In this study, foot-and-mouth disease (FMD) virus antigens were used to generate a genetic vaccine prototype. The amplicons were designed to provide a high safety profile as they do not express any HSV-1 genes when packaged using a helper virus-free system, and they are able to encapsidate several copies of the transgene or allow the simultaneous expression of different genes. Virus-like particles were produced after cell processing of the delivered DNA. Inoculation of mice with 5 * 10(5) transducing units of amplicon vectors resulted in FMDV-specific humoral responses in the absence of adjuvants, which were dependent on the in situ de novo production of the vector-encoded antigens. Challenge of mice vaccinated with these amplicons with a high dose of live virus, resulted in partial protection, with a significant reduction of viremia. This work highlights the potential use of a HSV-1 amplicon vector platform for generation of safe genetic vaccines. PMID- 20851081 TI - Vaccine preventable diseases in returned international travelers: results from the GeoSentinel Surveillance Network. AB - Vaccine preventable diseases (VPDs) threaten international travelers, but little is known about their epidemiology in this group. We analyzed records of 37,542 ill returned travelers entered into the GeoSentinel Surveillance Network database. Among 580 (1.5%) with VPDs, common diagnoses included enteric fever (n=276), acute viral hepatitis (n=148), and influenza (n=70). Factors associated with S. typhi included VFR travel (p<0.016) to South Central Asia (p<0.001). Business travel was associated with influenza (p<0.001), and longer travel with hepatitis A virus (p=0.02). 29% of those with VPDs had pre-travel consultations. At least 55% of those with VPDs were managed as inpatients, compared to 9.5% of those with non-VPDs. Three deaths occurred; one each due to pneumococcal meningitis, S. typhi, and rabies. VPDs are significant contributors to morbidity and potential mortality in travelers. High rates of hospitalization make them an attractive target for pre-travel intervention. PMID- 20851083 TI - Needle-free jet injection of small doses of Japanese encephalitis DNA and inactivated vaccine mixture induces neutralizing antibodies in miniature pigs and protects against fetal death and mummification in pregnant sows. AB - Japanese encephalitis (JE) virus causes abortion and stillbirth in swine, and encephalitis in humans and horses. We have previously reported that immunogenicity of a DNA vaccine against JE was synergistically enhanced in mice by co-immunization with a commercial inactivated JE vaccine (JEVAX) under a needle-free injection system. Here, we found that this immunization strategy was also effective in miniature pigs. Because of the synergism, miniature pigs immunized twice with a mixture of 10 MUg of DNA and a 1/100 dose of JEVAX developed a high neutralizing antibody titer (1:190 at 90% plaque reduction assay). Even using 1 MUg of DNA, 3 of 4 pigs developed neutralizing antibodies. Following challenge, all miniature pigs with detectable neutralizing antibodies were protected against viremia. Pregnant sows inoculated with 10 or 1 MUg of DNA mixed with JEVAX (1/100 dose) developed antibody titers of 1:40-1:320. Following challenge, fetal death and mummification were protected against in DNA/JEVAX immunized sows. PMID- 20851084 TI - CD40 ligand expressed in adenovirus can improve the immunogenicity of the GP3 and GP5 of porcine reproductive and respiratory syndrome virus in swine. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has recently caused heavy economic losses in swine industry worldwide. Current vaccination strategies only provide a limited protective efficacy, thus immune modulators are being considered to enhance the effectiveness of PRRSV vaccines. In this study, the recombinant adenoviruses expressing porcine CD40 ligand (CD40L) and GP3/GP5 of PRRSV were constructed and the immune responses were examined in pigs. The results showed that rAd-CD40L-GP35 (co-expressing CD40L and GP3-GP5) or rAd-GP35 (expressing GP3-GP5) plus rAd-CD40L (expressing CD40L) could provide significant higher specific anti-PRRSV ELISA antibody and neutralizing antibody. And the levels of proliferative responses of peripheral blood mononuclear cells (PBMC), IFN-gamma and IL-4 were markedly increased in rAd-CD40L-GP35 and rAd-CD40L plus rAd-GP35 groups than those in rAd-GP35 group. Following homologous challenge with Chinese isolate of the North-American genotype of PRRSV, pigs inoculated with recombinant rAd-CD40L-GP35 and rAd-CD40L plus rAd-GP35 showed lighter clinical signs and lower viremia, as compared to those in rAd-GP35 group. It indicated that porcine CD40L could effectively increase humoral and cell-mediated immune responses of GP3 and GP5 of PRRSV. Porcine CD40L might be used as an attractive adjuvant or immunotargeting strategies to enhance the PRRSV subunit vaccine responses in swine. PMID- 20851085 TI - Rotavirus incidence and genotype distribution before and after national rotavirus vaccine introduction in Belgium. AB - RotarixTM was introduced into the Belgian market in 2006 and RotaTeqTM in 2007, quickly reaching more than 85% vaccine coverage of all newborns in Belgium. The incidence of rotavirus gastroenteritis has been monitored in the Gasthuisberg University Hospital (GUH), Belgium since 1986, and since 1999 the genotypes of circulating rotavirus strains have been determined. The average percentage of rotavirus positive cases out of all hospitalized gastro-enteritis cases tested (>95% of these cases are younger than 5 years old) at the GUH between 1986 and 2006 was 19.0%. This percentage dropped to 12.4%, 9.6% and 6.4% in the three seasons post vaccine introduction (2006-2009), which is a decline of 34.7%, 49.4% and 66.3% respectively. In addition the rotavirus season was found to be shortened and delayed. The prevalence of the G2 genotype sharply increased in the 2006-2007 rotavirus season compared to the previous seasons and remained high (30 40%) in the 2007-2008 and 2008-2009 seasons. Rotavirus vaccines have strongly reduced the number of children hospitalized due to a rotavirus infection at the GUH; it is however unclear if the predominance of G2 genotypes is related to the vaccine introduction, or if this is attributable to normal genotype fluctuations. Continued surveillance will be pivotal to answer this question in the future. PMID- 20851086 TI - Study designs for timely estimation of influenza vaccine effectiveness using European sentinel practitioner networks. AB - European sentinel practitioner influenza surveillance networks represent a simple and feasible framework to conduct observational studies providing rapid and repeated influenza vaccine effectiveness estimates. The minimum requirements for those studies should be to correctly ascertain vaccination status, to include laboratory-confirmed influenza as outcome and to collect variables to control for confounding. Various study designs are possible including the screening method, computerised cohort and case control studies using various control groups. Selecting the study design is a compromise between methodological constraints, availability and ease of access to data sources and resources available. Results from practitioner-based studies complement other pieces of evidence (e.g. immunogenicity studies, vaccine efficacy, surveillance data) to assess the effect of influenza vaccination in the population. PMID- 20851087 TI - Effectiveness of rotavirus vaccine in preventing hospitalization due to rotavirus gastroenteritis in young children in Connecticut, USA. AB - Rotavirus vaccine was recommended for use in US infants to prevent rotavirus gastroenteritis (RGE) in February 2006. This matched case control study assessed the effectiveness of rotavirus vaccine in preventing hospitalization of young. Cases were vaccine-eligible children 8 weeks-3 years of age, hospitalized due to laboratory-confirmed RGE. Cases (n=42) were matched to 2 control groups: (a) hospitalized controls (n=80): children hospitalized for reasons other than RGE, matched to the cases by age and time of presentation and (b) community controls (n=73): non-hospitalized children matched by age and medical practice. Adjusted vaccine effectiveness against hospitalization with RGE in vaccine eligible children receiving at least one dose of vaccine was 94.3% (95% C.I.: 55.4%-99.3%; p=0.006) for hospitalized controls and 96.9% (95% C.I.: 59.4%-99.8%; p=0.008) for community controls. PMID- 20851088 TI - Acceptability of HPV vaccination among young adults aged 18-30 years--a population based survey in Sweden. AB - Acceptability of human papillomavirus (HPV) vaccination seems to be high in the Western world but fewer data are available for men than for women. There are also concerns that HPV vaccination might lead young people to change their healthcare related behaviours. We investigated these issues in a population-based survey performed in Sweden during January-May, 2007, just after HPV vaccination had been licensed. A total of 10567 men and women aged 18 to 30 years participated. The intention to accept HPV vaccination among these young adults was relatively high but could likely be improved with higher awareness of HPV-related diseases as well as of the safety and efficacy of vaccines in general. Also, the cost of the vaccine needs to be affordable. Even though few young adults stated their healthcare-related behaviours would change after HPV vaccination, a significant number were uncertain, suggesting a need for continued educational efforts when HPV-vaccinating this group. PMID- 20851089 TI - Immunogenicity and protective efficacy of a DNA vaccine against Venezuelan equine encephalitis virus aerosol challenge in nonhuman primates. AB - A study to evaluate the immunogenicity and protective efficacy of a Venezuelan equine encephalitis virus (VEEV) DNA vaccine in an aerosol model of nonhuman primate infection was performed. Cynomolgus macaques vaccinated with a plasmid expressing the 26S structural genes of VEEV subtype IAB by particle-mediated epidermal delivery (PMED) developed virus-neutralizing antibodies. No serum viremia was detected in two out of three macaques vaccinated with the VEEV DNA after aerosol challenge with homologous virus, while one displayed a low viremia on a single day postchallenge. In contrast, all three macaques vaccinated with empty vector DNA developed a high viremia that persisted for at least 3 days after challenge. In addition, macaques vaccinated with the VEEV DNA had reduced febrile reactions, lymphopenia, and clinical signs of disease postchallenge as compared to negative control macaques. Therefore, although the sample size was small in this pilot study, these results indicate that a VEEV DNA vaccine administered by PMED can at least partially protect nonhuman primates against an aerosol VEEV challenge. PMID- 20851090 TI - Considerations in the design of vaccines that induce CD8 T cell mediated immunity. AB - The protective capacity of many currently used vaccines is based on induction of neutralizing antibodies. Many pathogens, however, have adapted themselves in different ways to escape antibody-based immune protection. In particular, for those infections against which conventional neutralizing antibody-based vaccinations appear challenging, CD8 T-cells are considered to be promising candidates for vaccine targeting. The design of vaccines that induce robust and long-lasting protective CD8 T-cell responses however imposes new challenges, as many factors such as kinetics and efficiency of antigen-processing and presentation by antigen presenting cells, T-cell repertoire and cytokine environment during T cell priming contribute to the specificity and functionality of CD8 T-cell responses. In the following, we review the most prominent aspects that underlie CD8 T-cell induction and discuss how this knowledge may help to improve the design of efficient CD8 T-cell inducing vaccines. PMID- 20851091 TI - DNA vaccine delivery by densely-packed and short microprojection arrays to skin protects against vaginal HSV-2 challenge. AB - There is an unmet medical need for a prophylactic vaccine against herpes simplex virus (HSV). DNA vaccines and cutaneous vaccination have been tried for many applications, but few reports combine this vaccine composition and administration route. We compared DNA administration using the NanopatchTM, a solid microprojection device coated with vaccine comprised of thousands of short (110 MUm) densly-packed projections (70 MUm spacing), to standard intramuscular DNA vaccination in a mouse model of vaginal HSV-2 infection. A dose-response relationship was established for immunogenicity and survival in both vaccination routes. Appropriate doses administered by NanopatchTM were highly immunogenic and enabled mouse survival. Vaginal HSV-2 DNA copy number day 1 post challenge correlated with survival, indicating that vaccine-elicited acquired immune responses can act quickly and locally. Solid, short, densely-packed arrays of microprojections applied to the skin are thus a promising route of administration for DNA vaccines. PMID- 20851092 TI - Headspace analyses of 2H labeling of acetone: enabling studies of fatty acid oxidation in vivo. AB - We demonstrate that one can measure low levels of 2H labeling (e.g., <0.025% excess 2H) by exchanging hydrogen (deuterium) in water with acetone and subjecting samples to gas chromatography-pyrolysis-isotope ratio mass spectrometry. This analytical method circumvents the need to use typical off-line reduction methods that convert water to hydrogen gas prior to isotope ratio mass spectrometry or the need to purchase extra peripheral devices that would permit the direct analysis of water labeling. This method enables routine measurements of fatty acid oxidation in rodents; that is, one administers a 2H-labeled fatty acid(s) and then quantifies the production of 2H-labeled water. PMID- 20851093 TI - Potency determinations of acetylcholinesterase inhibitors using Ellman's reaction based assay in screening: Effect of assay variants. AB - In primary drug discovery screenings and potency determinations of active acetylcholinesterase (AChE) inhibitors, different variations of the Ellman's reaction-based assay are extensively applied. However, these are prone to produce variable results. Here we studied how assay variants differing in the order of reagent addition and substrate concentrations influence potency measurements of AChE inhibitors. Three model compounds were used: tacrine, physostigmine, and a newly reported inhibitor, 1-[5-[4-[(hexahydro-1H-azepin-1-yl)carbonyl]-1 piperidinyl]-1,3,4-thiadiazol-2-yl]-2-pyrrolidinone. Different patterns of potency changes related to the different inhibition mechanisms of the compounds were detected. Recognizing this, better judgment can be applied when publishing results and selecting optimal screening assays. PMID- 20851094 TI - N-Terminal sequencing by mass spectrometry through specific fluorescamine labeling of alpha-amino groups before tryptic digestion. AB - We present a single-step procedure for the specific mass labeling of unblocked protein N termini. We show that the dye fluorescamine, which is commonly assumed to require mildly alkaline conditions for undergoing a nonspecific reaction with alpha- and epsilon-amino groups associated with amino acids, in fact shows a specific reaction only with alpha-amino groups present at protein N termini when mildly acidic conditions are used. We use this finding to label, identify, and sequence the trypsinolysis-derived N-terminal peptide of lysozyme, using only mass spectrometry, to illustrate how this method could be used with other proteins. PMID- 20851095 TI - The synthesis of pABA: Coupling between the glutamine amidotransferase and aminodeoxychorismate synthase domains of the bifunctional aminodeoxychorismate synthase from Arabidopsis thaliana. AB - Aminodeoxychorismate (ADC) synthase in plants is a bifunctional enzyme containing glutamine amidotransferase (GAT) and ADC synthase (ADCS) domains. The GAT domain releases NH(3) from glutamine and the ADCS domain uses NH(3) to aminate chorismate. This enzyme is involved in folate (vitamin B9) biosynthesis. We produced a stable recombinant GAT-ADCS from Arabidopsis. Its kinetic properties were characterized, and activities and coupling of the two domains assessed. Both domains could operate independently, but not at their optimal capacities. When coupled, the activity of one domain modified the catalytic properties of the other. The GAT activity increased in the presence of chorismate, an activation process that probably involved conformational changes. The ADCS catalytic efficiency was 10(4) fold higher with glutamine than with NH(4)Cl, indicating that NH(3) released from glutamine and used for ADC synthesis did not equilibrate with the external medium. We observed that the GAT activity was always higher than that of ADCS, the excess of NH(3) being released in the external medium. In addition, we observed that ADC accumulation retro-inhibited ADCS activity. Altogether, these results indicate that channeling of NH(3) between the two domains and/or amination of chorismate are the limiting step of the whole process, and that ADC cannot accumulate. PMID- 20851096 TI - Oxygen activation by P450(cin): Protein and substrate mutagenesis. AB - A conserved threonine found in the majority of cytochromes P450 (P450s) has been implicated in the activation of dioxygen during the catalytic cycle. P450(cin) (CYP176A) has been found to be an exception to this paradigm, where the conserved threonine has been replaced with an asparagine. Prior studies with a P450(cin) N242A mutant established that the Asn-242 was not a functional replacement for the conserved threonine but was essential for the regio- and stereocontrol of the oxidation of cineole. To explore further how P450(cin) controls the activation of the dioxygen in the absence of the conserved threonine, two concurrent lines of investigation were followed. Modification of P450(cin) indicated that the Thr-243 was not involved in controlling the protonation of the hydroperoxy species. In addition, the N242T mutant did not enhance the rate and/or efficiency of catalytic turnover of cineole by P450(cin). In parallel experiments, the substrate cineole was modified by removing the ethereal oxygen to produce camphane or 2,2-dimethylbicyclo[2.2.2]octane (cinane). An analogous experiment with P450(EryF) showed that a hydroxyl group on the substrate was vital, and in its absence catalytic turnover was effectively abolished. Catalytic turnover of P450(cin) with either of these alternative substrates (camphane or cinane) revealed that in the absence of the ethereal oxygen there was still a significant amount of coupling of the NADPH-reducing equivalents to the formation of oxidised product. Again the substrate itself was not found to be important in controlling oxygen activation, in contrast to P450(EryF), but was shown to be essential for regio- and stereoselective substrate oxidation. Thus, it still remains unclear how dioxygen activation in the catalytic turnover of cineole by P450(cin) is controlled. PMID- 20851097 TI - Bacterial sulfite-oxidizing enzymes. AB - Enzymes belonging to the Sulfite Oxidase (SO) enzyme family are found in virtually all forms of life, and are especially abundant in prokaryotes as shown by analysis of available genome data. Despite this fact, only a limited number of bacterial SO family enzymes has been characterized in detail to date, and these appear to be involved in very different metabolic processes such as energy generation from sulfur compounds, host colonization, sulfite detoxification and organosulfonate degradation. The few characterized bacterial SO family enzymes also show an intriguing range of structural conformations, including monomeric, dimeric and heterodimeric enzymes with varying numbers and types of redox centres. Some of the bacterial enzymes even catalyze novel reactions such as dimethylsulfoxide reduction that previously had been thought not to be catalyzed by SO family enzymes. Classification of the SO family enzymes based on the structure of their Mo domain clearly shows that three distinct groups of enzymes belong to this family, and that almost all SOEs characterized to date are representatives of the same group. The widespread occurrence and obvious structural and functional plasticity of the bacterial SO family enzymes make this an exciting field for further study, in particular the unraveling of the metabolic roles of the three enzyme groups, some of which appear to be associated almost exclusively with pathogenic microorganisms. PMID- 20851098 TI - Indolicidin action on membrane permeability: carrier mechanism versus pore formation. AB - Indolicidin, a 13-residue cationic peptide with extremely high tryptophan content, exhibits broad-spectrum antimicrobial as well as hemolytic activity. To gain insight into the mechanism of indolicidin action on membrane permeability, liposome leakage induced by this peptide was studied by using various probes with vesicles of different lipid compositions. In liposomes containing negatively charged lipids, indolicidin induced rather unselective permeabilization. By contrast, the peptide appeared to be selective in provoking leakage of neutral, egg phosphatidylcholine (PC) liposomes: it effectively induced the release of negatively charged fluorescent dyes, carboxyfluorescein (CF), calcein and sulforhodamine B, but was unable to induce the leakage of a neutral compound, glucose, and that of positively charged doxorubicin. Moreover, organic anions, such as fatty acids, were found to suppress the indolicidin-induced CF leakage of egg PC liposomes. Based on these results, we concluded that indolicidin facilitates the dye release from uncharged lipid vesicles not by formation of membrane pores as it is generally accepted for the majority of antimicrobial peptides but rather via translocation of dye molecules across the membrane in the form of dye-peptide complexes, i.e. indolicidin operates as an organic anion carrier. This conclusion was supported by observing the formation of complexes between indolicidin and pyrenebutyrate in solution. The indolicidin analog having only one arginine was ineffective in pyrenebutyrate binding and CF transport. The mode of action proposed here for indolicidin can be related to that previously postulated for oligoarginine derivatives which are able to carry organic anions across liposomal and bulk phase membranes [Sakai N. & Matile S. J. Am. Chem. Soc. 2003, 125:14348-14356]. The newly identified mechanism of peptide ionophoric activity in uncharged lipid membranes may be involved in hemolytic action of indolicidin via induction of plasma membrane permeability for important anionic metabolites which disturbs regulation of osmotic balance ultimately leading to erythrocyte membrane rupture. PMID- 20851099 TI - Apolipoprotein E LDL receptor-binding domain-containing high-density lipoprotein: a nanovehicle to transport curcumin, an antioxidant and anti-amyloid bioflavonoid. AB - Curcumin is an antioxidant and anti-inflammatory bioflavonoid that has been recently identified as an anti-amyloid agent as well. To make it more available in its potent form as a potential amyloid disaggregation agent, we employed high density lipoproteins (HDL), which are lipid-protein complexes that transport plasma cholesterol, to transport curcumin. The objective of this study was to employ reconstituted HDL containing human apoE3 N-terminal (NT) domain, as a vehicle to transport curcumin. The NT domain serves as a ligand to mediate binding and uptake of lipoprotein complexes via the low-density lipoprotein receptor (LDLr) family of proteins located at the cell surface. Reconstituted HDL was prepared with phospholipids and recombinant apoE3-NT domain in the absence or presence of curcumin. Non-denaturing polyacrylamide gel electrophoresis indicated that the molecular mass and Stokes' diameter of HDL bearing curcumin were ~670kDa and ~17nm, respectively, while electron microscopy revealed the presence of discoidal particles. Fluorescence emission spectra of HDL bearing (the intrinsically fluorescent) curcumin indicated that the wavelength of maximal fluorescence emission (lambda(max)) of curcumin was ~495nm, which is highly blue shifted compared to lambda(max) of curcumin in solvents of varying polarity (lambda(max) ranging from 515-575nm) or in aqueous buffers. In addition, an enormous enhancement in fluorescence emission intensity was noted in curcumin containing HDL compared to curcumin in aqueous buffers. Curcumin fluorescence emission was quenched to a significant extent by lipid-based quenchers but not by aqueous quenchers. These observations indicate that curcumin has partitioned efficiently into the hydrophobic milieu of the phospholipid bilayer of HDL. Functional assays indicated that the LDLr-binding ability of curcumin-containing HDL with apoE3-NT is similar to that of HDL without curcumin. Taken together, we report that apoE-containing HDL has a tremendous potential as a 'nanovehicle' with a homing device to transport curcumin to target sites. PMID- 20851100 TI - Cholesterol depletion enhances adrenergic signaling in cardiac myocytes. AB - Cardiac myocytes endogenously express alpha and beta adrenergic receptors, prototypes of the G-protein coupled receptor superfamily. Depending upon the dose of norepinephrine (agonist) exposure, hypertrophy and apoptosis are initiated by differential induction of two discrete constituents of the transcription factor AP-1, i.e., FosB and Fra-1. We explored differential adrenergic signaling as a paradigm for understanding how cholesterol dictates cells to choose hypertrophy or apoptosis. For this, we used fosB and fra-1 promoter-reporter constructs for monitoring adrenergic signaling. We show that cholesterol depletion enhances norepinephrine-mediated signaling in cardiac myocytes. Importantly, this increased signaling is reduced to original level upon cholesterol replenishment. We used specific ligands for alpha and beta adrenergic receptors and show that the enhanced signaling upon cholesterol depletion is a combined effect of both alpha and beta adrenergic receptors. These results constitute the first report demonstrating the effect of cholesterol on adrenergic signaling using a direct end-point gene expression. PMID- 20851101 TI - Heparin-derived oligosaccharides interact with the phospholamban cytoplasmic domain and stimulate SERCA function. AB - The association between the cardiac transmembrane proteins phospholamban and sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) regulates the active transport of Ca(2+) into the sarcoplasmic reticulum (SR) lumen and controls the contraction and relaxation of the heart. Heart failure (HF) and cardiac hypertrophy have been linked to defects in Ca(2+) uptake by the cardiac SR and stimulation of calcium transport by modulation of the PLB-SERCA interaction is a potential therapy. This work is part of an effort to identify compounds that destabilise the PLB-SERCA interaction in well-defined membrane environments. It is shown that heparin derived oligosaccharides (HDOs) interact with the cytoplasmic domain of PLB and consequently stimulate SERCA activity. These results indicate that the cytoplasmic domain of PLB is functionally important and could be a valid target for compounds with drug-like properties. PMID- 20851102 TI - 2-deoxyglucose sensitizes melanoma cells to TRAIL-induced apoptosis which is reduced by mannose. AB - While melanoma cell lines use aerobic glycolysis, addition of a competitive inhibitor such as 2-deoxyglucose (2DG) by itself achieved only modest killing. To overcome high levels of pro-survival proteins in melanoma cells, 2DG or glucose deprivation (GD) was combined with tumor necrosis factor-related apoptosis inducing-ligand (TRAIL). TRAIL treatment by itself also only induced modest killing, but combining TRAIL with 2DG or GD triggered a synergistic pro-apoptotic response in melanoma lines but not melanocytes. In melanoma cells, there was cleavage of caspases 3, 8 and Bid. Killing by combination treatments was completely blocked by a pan-caspase inhibitor, z-VAD. Mechanistically, 2DG and GD enhanced surface levels for both death receptors (DR4 and DR5); which was accompanied by reductions in levels of Mcl-1, Bcl-2 and survivin. Mannose pre treatment reduced enhanced killing by combination treatments, accompanied by reduced DR5 levels. These results indicate melanoma cells in which there is altered glucose-related metabolomics can be exploited by interfering with glucose metabolism in combination with TRAIL; thereby overcoming the notorious death resistance of melanoma. Thus, a new therapeutic window is open for future clinical trials using agents targeting the glucose-related metabolome, in combination with agents triggering death receptors in patients with melanoma. PMID- 20851103 TI - Thickness sensing of hMSCs on collagen gel directs stem cell fate. AB - Mechanically compliant substrate provides crucial biomechanical cues for multipotent stem cells to regulate cellular fates such as differentiation, proliferation and maintenance of their phenotype. Effective modulus of which cells sense is not only determined by intrinsic mechanical properties of the substrate, but also the thickness of substrate. From our study, it was found that interference from underlying rigid support at hundreds of microns away could induce significant cellular response. Human mesenchymal stem cells (hMSCs) were cultured on compliant biological gel, collagen type I, of different thickness but identical ECM composition and local stiffness. The cells sensed the thin gel (130 MUm) as having a higher effective modulus than the thick gel (1440 MUm) and this was reflected in their changes in morphology, actin fibers structure, proliferation and tissue specific gene expression. Commitment into neuronal lineage was observed on the thin gel only. Conversely, the thick gel (1440 MUm) was found to act like a substrate with lower effective modulus that inhibited actin fiber polymerization. Stem cells on the thick substrate did not express tissue specific genes and remained at their quiescent state. This study highlighted the need to consider not only the local modulus but also the thickness of biopolymer gel coating during modulation of cellular responses. PMID- 20851104 TI - ADAM15 expression is downregulated in melanoma metastasis compared to primary melanoma. AB - In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma. We further demonstrate that IFN-gamma and TGF-beta downregulate ADAM15 protein levels in melanoma cells. To investigate the role of ADAM15 in melanoma progression, we overexpressed ADAM15 in melanoma cells. Importantly, overexpression of ADAM15 in melanoma cells reduced the migration, invasion and the anchorage dependent and independent cell growth of melanoma cells. In summary, the downregulation of ADAM15 plays an important role in melanoma progression and ADAM15 act as a tumorsuppressor in melanoma. PMID- 20851105 TI - Identification and characterization of a transcriptional regulator, SucR, that influences sucCD transcription in Corynebacterium glutamicum. AB - We have identified and characterized a novel transcriptional regulator that binds to the promoter region of succinyl-CoA synthetase (sucCD) in Corynebacterium glutamicum. Using biotin-labeled DNA affinity beads, we identified a DeoR-type transcriptional regulator, SucR (Cg0146), which is a protein consisting of 282 amino acids with a mass of 31 kDa and RamB (Cg0444). The results of electrophoretic mobility shift assays verified that these regulators specifically bind to the sucCD promoter region. The putative SucR binding region extends from position -155 to -146 (a 10 bp sequence, ACTCTAGGGG) relative to the transcriptional start point of the sucCD operon. The expression level of sucCD in a sucR deletion mutant was seven times higher than that in wild-type cells grown on acetate. The increase in succinyl-CoA synthetase levels caused by inactivation of sucR. These assays revealed that SucR acts as a repressor of sucCD expression during acetate metabolism. PMID- 20851106 TI - SP1 acts as a key factor, contributes to upregulation of ADAM23 expression under serum deprivation. AB - ADAM23 modulates many cellular functions, alteration of expression causes a number of tumor types; however, the mechanisms controlling ADAM23 expression remain unknown. Here we have identified a SP1 binding site (-202/-190) that binds SP1 at the proximal promoter of human ADAM23 gene; furthermore, serum deprivation enhances open chromatin accessibility and help expose the SP1 binding site; finally, SP1 binding recruits RNA polymerase II, which in turn results in upregulation of endogenous ADAM23 expression. Therefore, the present study delineates the fundamental elements of a core promoter structure that will be helpful for future studies of the regulation of ADAM23 gene. PMID- 20851107 TI - Resveratrol prevents RANKL-induced osteoclast differentiation of murine osteoclast progenitor RAW 264.7 cells through inhibition of ROS production. AB - The bone protective effects of resveratrol have been demonstrated in several osteoporosis models while the underlying mechanism is largely unclear. In the present study, we evaluated the effects of resveratrol on differentiation and apoptosis of murine osteoclast progenitor RAW 264.7 cells. We found that resveratrol at non-toxic concentrations dose-dependently inhibited RANKL-induced osteoclast differentiation and induced apoptosis. Resveratrol has been shown to be an activator of Sirt1, a NAD(+) dependent protein deacetylase, and has been demonstrated to mimic estrogen. However, we found that although Sirt1 protein was abundantly expressed in RAW264.7 cells, the specific Sirt1 inhibitor EX-527 could not attenuate the inhibition of osteoclastogenesis mediated by resveratrol. Also, the effects of resveratrol could not be attenuated by ICI-182780, a high affinity estrogen receptor antagonist. The central role of reactive oxygen species (ROS) in RANKL-induced osteoclast differentiation has recently been clarified. We found that resveratrol suppressed RANKL-induced ROS generation in a concentration dependent manner. We postulate that the direct inhibitory effects of resveratrol on osteoclastogenesis are mediated via inhibition of ROS generation. PMID- 20851109 TI - CaMKII phosphorylates serine 10 of p27 and confers apoptosis resistance to HeLa cells. AB - Protein phosphatase (PP) 6 is a serine threonine phosphatase which belongs to the PP2A subfamily of protein phosphatases. PP6 has been implicated in the control of apoptosis. A dominant negative form PP6 (DN-PP6) mutant cDNA was prepared and transfected into HeLa cells to investigate the regulation of apoptosis. HeLa cells expressing DN-PP6 showed increased resistance to apoptosis induced by TNF and cycloheximide. CaMKII phosphorylation and the expression of p27 were increased in DN-PP6 transfectants. Transient expression or activation of CaMKII increased the expression of p27. Furthermore, CaMKII phosphorylated serine 10 of p27, which induces the translocation of p27 from nucleus to cytoplasm and increases the stability of p27. Overexpression of wild type but not the S10A mutant p27 cDNA increased the expression of Bcl-xL and conferred apoptosis resistance to HeLa cells. These results indicated that PP6 and CaMKII regulated apoptosis by controlling the expression level of p27. PMID- 20851108 TI - Regulation of ryanodine receptors by sphingosylphosphorylcholine: involvement of both calmodulin-dependent and -independent mechanisms. AB - Sphingosylphosphorylcholine (SPC), a lipid mediator with putative second messenger functions, has been reported to regulate ryanodine receptors (RyRs), Ca2+ channels of the sarco/endoplasmic reticulum. RyRs are also regulated by the ubiquitous Ca2+ sensor calmodulin (CaM), and we have previously shown that SPC disrupts the complex of CaM and the peptide corresponding to the CaM-binding domain of the skeletal muscle Ca2+ release channel (RyR1). Here we report that SPC also displaces Ca2+-bound CaM from the intact RyR1, which we hypothesized might lead to channel activation by relieving the negative feedback Ca2+CaM exerts on the channel. We could not demonstrate such channel activation as we have found that SPC has a direct, CaM-independent inhibitory effect on channel activity, confirmed by both single channel measurements and [3H]ryanodine binding assays. In the presence of Ca2+CaM, however, the addition of SPC did not reduce [3H]ryanodine binding, which we could explain by assuming that the direct inhibitory action of the sphingolipid was negated by the simultaneous displacement of inhibitory Ca2+CaM. Additional experiments revealed that RyRs are unlikely to be responsible for SPC-elicited Ca2+ release from brain microsomes, and that SPC does not exert detergent-like effects on sarcoplasmic reticulum vesicles. We conclude that regulation of RyRs by SPC involves both CaM-dependent and -independent mechanisms, thus, the sphingolipid might play a physiological role in RyR regulation, but channel activation previously attributed to SPC is unlikely. PMID- 20851110 TI - Nuclear orphan receptor Nor-1 contributes to depressive behavior in the Wistar Kyoto rat model of depression. AB - The current study explored the effects of prolonged antidepressant treatment on mRNA levels of two nuclear receptors in specific brain regions of an animal model of depression, the Wistar-Kyoto (WKY) rat. Both nuclear receptors have been implicated in the development or treatment of depression. The expression of nuclear orphan receptor-1 (Nor-1), a member of the NR4A nuclear orphan receptor family, is induced by electroconvulsive shock, an effective treatment for depression. Deficit in the levels or function of the glucocorticoid receptor (GR) found in depressed patients has been causally implicated in depression, as this deficit is normalized by antidepressant treatments. Baseline levels of amygdalar Nor-1 and GR mRNA were higher in the WKYs compared to the comparison control Sprague-Dawley rats (SD). Prolonged treatment with the antidepressant desipramine (DMI) decreased the expression of both transcripts in the WKY strain concomitantly with decreased immobility in the forced swim test (FST) of depressive behavior. Using short hairpin RNA (shRNA) targeted against Nor-1, we investigated the direct contribution of elevated Nor-1 expression in the amygdala of WKY to their exaggerated depressive behavior in the FST. After validating the shRNA targeting of Nor-1 in vitro, Nor-1 shRNA containing vector was infused intracerebroventricularly, using a linear polyethylenimine (PEI)-containing in vivo gene delivery system. Repeated administration of Nor-1 shRNA ameliorated the depressive behavior of WKYs in the FST and decreased amygdalar Nor-1 mRNA levels without affecting GR mRNA levels. These data demonstrate that brain region specific changes in GR expression in response to DMI are strain dependent and that elevated amygdalar Nor-1 expression can contribute to depressive behavior in the WKY model of depression. PMID- 20851111 TI - The transcriptional control of female puberty. AB - The initiation of mammalian puberty requires a sustained increase in pulsatile release of gonadotrophin releasing hormone (GnRH) from the hypothalamus. This increase is brought about by coordinated changes in transsynaptic and glial neuronal communication, consisting of an increase in neuronal and glial stimulatory inputs to the GnRH neuronal network and the loss of transsynaptic inhibitory influences. GnRH secretion is stimulated by transsynaptic inputs provided by excitatory amino acids (glutamate) and at least one peptide (kisspeptin), and by glial inputs provided by growth factors and small bioactive molecules. The inhibitory input to GnRH neurons is mostly transsynaptic and provided by GABAergic and opiatergic neurons; however, GABA has also been shown to directly excite GnRH neurons. There are many genes involved in the control of these cellular networks, and hence in the control of the pubertal process as a whole. Our laboratory has proposed the concept that these genes are arranged in overlapping networks internally organized in a hierarchical fashion. According to this concept, the highest level of intra-network control is provided by transcriptional regulators that, by directing expression of key subordinate genes, impose genetic coordination to the neuronal and glial subsets involved in initiating the pubertal process. More recently, we have begun to explore the concept that a more dynamic and encompassing level of integrative coordination is provided by epigenetic mechanisms. PMID- 20851112 TI - Physical activity, but not environmental complexity, facilitates HPA axis response habituation to repeated audiogenic stress despite neurotrophin mRNA regulation in both conditions. AB - Stress exacerbates several physical and psychological disorders. Voluntary exercise can reduce susceptibility to many of these stress-associated disorders. In rodents, voluntary exercise can reduce hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to various stressors as well as upregulate several brain neurotrophins. An important issue regarding voluntary exercise is whether its effect on the reduction of HPA axis activation in response to stress is due to the physical activity itself or simply the enhanced environmental complexity provided by the running wheels. The present study compared the effects of physical activity and environmental complexity (that did not increase physical activity) on HPA axis habituation to repeated stress and modulation of brain neurotrophin mRNA expression. For six weeks, male rats were given free access to running wheels (exercise group), given 4 objects that were repeatedly exchanged (increased environmental complexity group), or housed in standard cages. On week 7, animals were exposed to 11 consecutive daily 30-min sessions of 98-dBA noise. Plasma corticosterone and adrenocorticotropic hormone were measured from blood collected directly after noise exposures. Tissue, including brains, thymi, and adrenal glands was collected on Day 11. Although rats in both the exercise and enhanced environmental complexity groups expressed higher levels of BDNF and NGF mRNA in several brain regions, only exercise animals showed quicker glucocorticoid habituation to repeated audiogenic stress. These results suggest that voluntary exercise, independent from other environmental manipulations, accounts for the reduction in susceptibility to stress. PMID- 20851113 TI - The effects of acupuncture on the brain networks for emotion and cognition: an observation of gender differences. AB - Acupuncture modulates brain activity at the limbic-paralimbic-neocortical network (LPNN) and the default mode network (DMN). Since these brain networks show gender differences when mediating emotional and cognitive tasks, we thus hypothesize that women and men may also respond differently to acupuncture procedure at these brain regions. In order to test this hypothesis, we retrieved the data of 38 subjects, 19 females and 19 males, who had brain fMRI during acupuncture from previous studies and reanalyzed them based on sex status. Deactivation at the LPNN/DMN during needle manipulation of acupuncture was more extensive in females than in males, particularly in the posterior cingulate (BA31), precuneus (BA7m) and angular gyrus (BA39). The functional correlations between the right BA31 and pregenual cingulate (BA32), hippocampus or contralateral BA31 were significantly stronger in females than in males. The angular gyrus (BA39) was functionally correlated with BA31 in females; in contrast, it was anticorrelated with BA31 in males. Soreness, a major component of the psychophysical responses to needle manipulation, deqi, was correlated in intensity with deactivation of the angular gyrus in females; no such relationships were observed in males. In contrast to lesser deactivation at the LPNN/DMN networks, needle manipulation during acupuncture induced greater activation at the secondary somatosensory cortex and stronger functional connectivity with the anterior-middle cingulate (BA32/24) in males than in females. Our study suggests that brains with sex dimorphism may process the acupuncture stimulation differently between women and men. PMID- 20851114 TI - Development of a high resolution melting method for the detection of genetic variations in Long QT Syndrome. AB - BACKGROUND: Inherited Long QT Syndrome (LQTS) is a cardiac channelopathy associated with a high risk of sudden death. The prevalence has been estimated at close to 1:2000. Due to large cohorts to investigate, the size of the 3 prevalent mutated genes, and the presence of a large spectrum of private mutations, mutational screening requires an extremely sensitive and specific scanning method. METHODS: Efficiency of high resolution melting (HRM) analysis was evaluated for the most prevalent LQTS-causing genes (KCNQ1, KCNH2) using control DNAs and DNAs carrying previously identified gene variants. A cohort of 34 patients with a suspicion of LQTS was further blindly screened. To evaluate HRM sensitivity, this cohort was also screened using an optimized DHPLC strategy. RESULTS: HRM analysis was successfully optimized for KCNQ1 but optimisation of KCNH2 was more laborious as only 3 KCNH2 exons could be finally optimized. Remaining KCNH2 exons were analysed by direct sequencing. This molecular approach, which combined HRM and direct sequencing, was applied on the cohort of 34 cases and 9 putative mutations were identified. Using this approach, molecular investigation was completed faster and cheaper than using DHPLC strategy. CONCLUSIONS: This HRM/sequencing procedure represents an inexpensive, highly sensitive and high-throughput method to allow identification of mutations in the coding sequences of prevalent LQTS genes. PMID- 20851115 TI - Preventive effects of rutin on lysosomal enzymes in isoproterenol induced cardio toxic rats: biochemical, histological and in vitro evidences. AB - This study was aimed to evaluate the preventive effect of rutin on lysosomal enzymes in isoproterenol induced cardio toxic rats. Male albino Wistar rats were pretreated with rutin (80 mg/kg) daily for a period of 42 days. After the pretreatment period, isoproterenol (100 mg/kg) was subcutaneously injected to rats at an interval of 24 h for two days. The activity of serum creatine kinase MB and the levels of serum troponins T and I and the activities of serum and heart lysosomal enzymes (beta-glucuronidase, beta-N-acetylglucosaminidase, beta galactosidase, cathepsin-B and D) were increased significantly (P<0.05) in isoproterenol induced cardio toxic rats. Isoproterenol induced cardio toxic rats also resulted in decreased stability of membranes, which was reflected by decreased activities of beta-glucuronidase and cathepsin-D in mitochondrial, nuclear, lysosomal and microsomal fractions. Pretreatment with rutin daily for a period of 42 days to isoproterenol induced cardio toxic rats prevented the changes in the activities of these enzymes. Oral treatment with rutin (80 mg/kg) to normal rats did not show any significant effect in all the biochemical parameters studied. Histopathology of myocardium showed the preventive effects of rutin in isoproterenol induced cardio toxic rats. In vitro study also confirmed the mechanism of action of rutin. Thus, the results of our study show that rutin protects the lysosomal membrane against isoproterenol induced cardiac damage. The observed effects are due to the free radical scavenging, antioxidant and membrane stabilizing properties of rutin. PMID- 20851116 TI - Statins inhibited erythropoietin-induced proliferation of rat vascular smooth muscle cells. AB - Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [3H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect. PMID- 20851117 TI - Pharmacological characterization of the cannabinoid CB1 receptor PET ligand ortholog, [3H]MePPEP. AB - MePPEP ((3R,5R)-5-(3-methoxy-phenyl)-3-((R)-1-phenyl-ethylamino)-1-(4 trifluoromethyl-phenyl)-pyrrolidin-2-one) is an inverse agonist shown to be an effective PET ligand for labeling cannabinoid CB1 receptors in vivo. [11C]MePPEP and structurally related analogs have been reported to specifically and reversibly label cannabinoid CB1 receptors in rat and non-human primate brains, and [11C]MePPEP has been used in human subjects as a PET tracer. We have generated [3H]MePPEP, an ortholog of [11C]MePPEP, to characterize the molecular pharmacology of the cannabinoid CB1 receptor across preclinical and clinical species. [3H]MePPEP demonstrates saturable, reversible, and single-site high affinity binding to cannabinoid CB1 receptors. In cerebellar membranes purified from brains of rat, non-human primate and human, and cells ectopically expressing recombinant human cannabinoid CB1 receptor, [3H]MePPEP binds cannabinoid CB1 receptors with similar affinity with K(d) values of 0.09 nM, 0.19 nM, 0.14 nM and 0.16 nM, respectively. Both agonist and antagonist cannabinoid ligands compete [3H]MePPEP with predicted rank order potency. No specific binding is present in autoradiographic sections from cannabinoid CB1 receptor knockout mouse brains, demonstrating that [3H]MePPEP selectively binds cannabinoid CB1 receptors in native mouse tissue. Furthermore, [3H]MePPEP binding to anatomical sites in mouse and rat brain is comparable to the anatomical profiles of [11C]MePPEP in non human primate and human brain in vivo, as well as the binding profiles of other previously described cannabinoid CB1 receptor agonist and antagonist radioligands. Therefore, [3H]MePPEP is a promising tool for translation of preclinical cannabinoid CB1 receptor pharmacology to clinical PET ligand and cannabinoid CB1 receptor inverse agonist therapeutic development. PMID- 20851118 TI - Excitation properties of the right cervical vagus nerve in adult dogs. AB - Vagus nerve stimulation (VNS) is an approved treatment for epilepsy and depression, and it is currently under investigation for applications in Alzheimer's disease, anxiety, heart failure, and obesity. However, the mechanism(s) by which VNS has its effects are not clear, and the stimulation parameters for obtaining therapeutic outcomes appear highly variable. The purpose of this study was to quantify the excitation properties of the right cervical vagus nerve in adult dogs anesthetized with propofol and fentanyl. Input-output curves of the right cervical vagus nerve compound action potential and laryngeal muscle electromyogram were measured in response to VNS across a range of stimulation parameters: amplitudes of 0.02-50mA, pulsewidths of 10, 50, 100, 200, 300, 500, and 1,000MUs, frequencies of 1-2Hz, and train lengths of 20 pulses with 3 different electrode configurations: monopolar cathode, proximal anode/distal cathode, and proximal cathode/distal anode. Electrode configuration and stimulation waveform (monophasic vs. asymmetric charge-balanced biphasic) did not affect the threshold or recruitment of the vagal nerve fibers that were activated. The rheobase currents of A- and B-fibers were 0.4mA and 0.7mA, respectively, and the chronaxie of both components was 180MUs. Pulsewidth had little effect on the normalized threshold difference between activation of A- and B-fibers. The results provide insight into the complement of nerve fibers activated by VNS and guidance to clinicians for the selection of optimal stimulation parameters. PMID- 20851119 TI - The puzzle box as a simple and efficient behavioral test for exploring impairments of general cognition and executive functions in mouse models of schizophrenia. AB - Deficits in executive functions are key features of schizophrenia. Rodent behavioral paradigms used so far to find animal correlates of such deficits require extensive effort and time. The puzzle box is a problem-solving test in which mice are required to complete escape tasks of increasing difficulty within a limited amount of time. Previous data have indicated that it is a quick but highly reliable test of higher-order cognitive functioning. We evaluated the use of the puzzle box to explore executive functioning in five different mouse models of schizophrenia: mice with prefrontal cortex and hippocampus lesions, mice treated sub-chronically with the NMDA-receptor antagonist MK-801, mice constitutively lacking the GluA1 subunit of AMPA-receptors, and mice over expressing dopamine D2 receptors in the striatum. All mice displayed altered executive functions in the puzzle box, although the nature and extent of the deficits varied between the different models. Deficits were strongest in hippocampus-lesioned and GluA1 knockout mice, while more subtle deficits but specific to problem solving were found in the medial prefrontal-lesioned mice, MK 801-treated mice, and in mice with striatal overexpression of D2 receptors. Data from this study demonstrate the utility of the puzzle box as an effective screening tool for executive functions in general and for schizophrenia mouse models in particular. PMID- 20851120 TI - Stimulus-secretion coupling by high-affinity IgE receptor: new developments. AB - Stimulation of mast cells through their high affinity IgE receptor (FcepsilonRI) leads to the secretion of pre- and neoformed soluble mediators through vesicular carriers. This process is highly regulated in order to adapt the secretion of these potentially dangerous factors to the physiological needs. This regulation requires numerous essential effectors that are necessary to transmit the initial signal of FcepsilonRI aggregation and couple it to the sophisticated secretory machinery of membrane fusion. Studies in recent years have led to the discovery of a series of new effector molecules that link FcepsilonRI to secretion. We describe here some of the new developments that have allowed to obtain a clearer picture of stimulus/secretion coupling in mast cells. PMID- 20851121 TI - Dietary keto-acid feed-back on pituitary activity in gilthead sea bream: effects of oral doses of AKG. A proteomic approach. AB - The influence of a daily oral dose of alpha-ketoglutarate (AKG, 0.1 g/kg body weight), an intermediate metabolite in the Krebs cycle and a dietary additive, on the pituitary proteome of gilthead sea bream was determined by two-dimensional electrophoresis (2-DE). A high-resolution map of the sea bream pituitary proteome was generated. Proteins with a modified expression between Controls and AKG treated fish were further analysed by MALDI-TOF/TOF-MS and liquid chromatography combined with a nanoelectrospray (LC-MS/MS). The main changes in the proteome induced by AKG treatment were grouped. Metabolic proteins up-regulated with AKG supplementation included fructose-bis-phosphate aldolase, glyceraldehyde phosphate dehydrogenase and malate dehydrogenase, all related to glucose metabolism (p<0.000). Protein folding related up-regulation with AKG supplementation included two isoforms of heat shock proteins as well as cyclophylin and chaperonin (p<0.000). An unexpected form of apolipoprotein-A-1 with lower molecular weight (15-16 kDa) was evidenced as being highly abundant in the pituitary proteome of Controls, yet it was down-regulated by AKG treatment. Finally, proteins found to be associated with regeneration of neural function namely cofilin and Vat-protein were up-regulated after AKG supplementation. The only hormone to be modified by AKG treatment was somatolactin, which was significantly down-regulated cf. Controls. In summary, these results provide evidence of a potential endocrine/metabolic regulatory loop activated by AKG supplementation. PMID- 20851122 TI - Lesions of orexin neurons block conditioned place preference for sexual behavior in male rats. AB - The hypothalamic neuropeptide orexin (hypocretin) mediates reward related to drugs of abuse and food intake. However, a role for orexin in sexual reward has yet to be investigated. Orexin neurons are activated by sexual behavior, but endogenous orexin does not appear to be essential for sexual performance and motivation in male rats. Therefore, the goal of the current study was to test the hypothesis that orexin is critically involved in processing of sexual reward in male rats. First, it was demonstrated following exposure to conditioned contextual cues associated with sexual behavior in a conditioned place preference paradigm that cFos expression is induced in orexin neurons, indicating activation of orexin neurons by cues predicting sexual reward. Next, orexin-cell specific lesions were utilized to determine the functional role of orexin in sexual reward processing. Hypothalami of adult male rats were infused with orexin-B-conjugated saporin, resulting in greater than 80% loss of orexin neurons in the perifornical dorsomedial and lateral hypothalamus. Orexin lesions did not affect expression of sexual behavior, but prevented formation of conditioned place preference for a sexual behavior paired chamber. In contrast, intact sham-treated males or males with partial lesions developed a conditioned place preference for mating. Orexin lesioned males maintained the ability to form a conditioned place aversion to lithium chloride-induced visceral illness, indicating that orexin lesions did not disrupt associative contextual memory. Overall, these findings suggest that orexin is not essential for sexual performance or motivation, but is critical for reward processing and conditioned cue-induced seeking of sexual behavior. PMID- 20851123 TI - Methionine transport in the malaria parasite Plasmodium falciparum. AB - The intraerythrocytic malaria parasite, Plasmodium falciparum, derives amino acids from the digestion of host cell haemoglobin. However, it also takes up amino acids from the extracellular medium. Isoleucine is absent from adult human haemoglobin and an exogenous source of isoleucine is essential for parasite growth. An extracellular source of methionine is also important for the normal growth of at least some parasite strains. In this study we have characterised the uptake of methionine by P. falciparum-infected human erythrocytes, and by parasites functionally isolated from their host cells by saponin-permeabilization of the erythrocyte membrane. Infected erythrocytes take up methionine much faster than uninfected erythrocytes, with the increase attributable to the flux of this amino acid via the New Permeability Pathways induced by the parasite in the erythrocyte membrane. Having entered the infected cell, methionine is taken up by the intracellular parasite via a saturable, temperature-dependent process that is independent of ATP, Na(+) and H(+). Substrate competition studies, and comparison of the transport of methionine with that of isoleucine and leucine, yielded results consistent with the hypothesis that the parasite has at its surface one or more transporters which mediate the flux into and out of the parasite of a broad range of neutral amino acids. These transporters function most efficiently when exchanging one neutral amino acid for another, thus providing a mechanism whereby the parasite is able to import important exogenous amino acids in exchange for surplus neutral amino acids liberated from the digestion of host cell haemoglobin. PMID- 20851124 TI - Development of ultra-sensitive soybean peroxidase-based CL-ELISA for the determination of human thyroglobulin. AB - Serum thyroglobulin (Tg) is a main marker of thyroid cancer relapses after total or near-total thyroidectomy of patients with differentiated thyroid carcinoma. In this study, we developed a chemiluminescent enzyme-linked immunosorbent assay (CL ELISA) for detecting Tg in human serum. Soybean peroxidase (SbP) in combination with 3-(10'-phenothiazinyl)propane-1-sulfonate (SPTZ) and 4-morpholinopyridine (MORPH) and horseradish peroxidase (HRP) with p-iodophenol (PIP) were used as detection systems in the sandwich CL-ELISA. Comparison of these two systems showed that a lower detection limit (LOD) of CL-ELISA with SbP/SPTZ/MORPH was 10 times lower than for the immunoassay with HRP/PIP. The LOD value for SbP-based CL ELISA of 0.2 ng/mL was identical to LOD value typical of CL-ELISA Immulite kit produced with alkaline phosphatase. The sensitivity of Tg CL-ELISA using SbP/SPTZ/MORPH completely satisfies the requirements of modern endocrinology. Comparative study of clinical serum specimens assayed by the SbP-based CL-ELISA (x) and Immulite kit (y) for detecting Tg showed a good correlation between these two immunoassays (y=1.15 x -0.14, R=0.99). The obtained results open good perspectives for use of SbP/SPTZ/MORPH system in the development of ultra sensitive immunoassays. PMID- 20851126 TI - Structural and biochemical studies elucidate the mechanism of rhamnogalacturonan lyase from Aspergillus aculeatus. AB - We present here the first experimental evidence for bound substrate in the active site of a rhamnogalacturonan lyase belonging to family 4 of polysaccharide lyases, Aspergillus aculeatus rhamnogalacturonan lyase (RGL4). RGL4 is involved in the degradation of rhamnogalacturonan-I, an important pectic plant cell wall polysaccharide. Based on the previously determined wild-type structure, enzyme variants RGL4_H210A and RGL4_K150A have been produced and characterized both kinetically and structurally, showing that His210 and Lys150 are key active-site residues. Crystals of the RGL4_K150A variant soaked with a rhamnogalacturonan digest gave a clear picture of substrate bound in the -3/+3 subsites. The crystallographic and kinetic studies on RGL4, and structural and sequence comparison to other enzymes in the same and other PL families, enable us to propose a detailed reaction mechanism for the beta-elimination on [-,2)-alpha-l rhamno-(1,4)-alpha-d-galacturonic acid-(1,-]. The mechanism differs significantly from the one established for pectate lyases, in which most often calcium ions are engaged in catalysis. PMID- 20851127 TI - Structural determinants for improved stability of designed ankyrin repeat proteins with a redesigned C-capping module. AB - Designed ankyrin repeat proteins (DARPins) that specifically bind to almost any target can be obtained by ribosome display or phage display from combinatorial libraries. Although DARPins are already very stable molecules, molecular dynamics simulations, equilibrium denaturation experiments, structural studies, and recent NMR experiments suggested that the unfolding of the original C-terminal capping repeat (C-cap), taken from a natural ankyrin repeat protein, limits the stability of the initial DARPin design. Several point mutations had been introduced to optimize the C-cap and were shown to indeed further increase the stability of DARPins. We now determined crystal structures of DARPins with one or three full consensus internal repeats (NI(1)C or NI(3)C) between an N-terminal capping repeat and mutants of the C-cap. An NI(1)C mutant, in which the C-cap was only extended by three additional helix-forming residues, showed no structural change but reduced B-factors in the C-cap. An NI(3)C C-cap mutant carrying five additional mutations in the interface to the preceding repeat, previously designed by using the consensus sequence as a guide, showed a rigid-body movement of the C-cap towards the internal repeat. This movement results in an increased buried surface area and a superior surface complementarity and explains the improved stability in equilibrium unfolding, compared to the original C-cap. A C cap mutant with three additional mutations introducing suitably spaced charged residues did not show formation of salt bridges, explaining why its stability was not increased further. These structural studies underline the importance of repeat coupling for stability and help in the further design of this protein family. PMID- 20851125 TI - Structure-based analysis of Toxoplasma gondii profilin: a parasite-specific motif is required for recognition by Toll-like receptor 11. AB - Profilins promote actin polymerization by exchanging ADP for ATP on monomeric actin and delivering ATP-actin to growing filament barbed ends. Apicomplexan protozoa such as Toxoplasma gondii invade host cells using an actin-dependent gliding motility. Toll-like receptor (TLR) 11 generates an innate immune response upon sensing T. gondii profilin (TgPRF). The crystal structure of TgPRF reveals a parasite-specific surface motif consisting of an acidic loop, followed by a long beta-hairpin. A series of structure-based profilin mutants show that TLR11 recognition of the acidic loop is responsible for most of the interleukin (IL)-12 secretion response to TgPRF in peritoneal macrophages. Deletion of both the acidic loop and the beta-hairpin completely abrogates IL-12 secretion. Insertion of the T. gondii acidic loop and beta-hairpin into yeast profilin is sufficient to generate TLR11-dependent signaling. Substitution of the acidic loop in TgPRF with the homologous loop from the apicomplexan parasite Cryptosporidium parvum does not affect TLR11-dependent IL-12 secretion, while substitution with the acidic loop from Plasmodium falciparum results in reduced but significant IL-12 secretion. We conclude that the parasite-specific motif in TgPRF is the key molecular pattern recognized by TLR11. Unlike other profilins, TgPRF slows nucleotide exchange on monomeric rabbit actin and binds rabbit actin weakly. The putative TgPRF actin-binding surface includes the beta-hairpin and diverges widely from the actin-binding surfaces of vertebrate profilins. PMID- 20851128 TI - DHPC strongly affects the structure and oligomerization propensity of Alzheimer's Abeta(1-40) peptide. AB - Alzheimer's disease (AD) is thought to depend on the deleterious action of amyloid fibrils or oligomers derived from beta-amyloid (Abeta) peptide. Out of various known Abeta alloforms, the 40-residue peptide Abeta(1-40) occurs at highest concentrations inside the brains of AD patients. Its aggregation properties critically depend on lipids, and it was thus proposed that lipids could play a major role in AD. To better understand their possible effects on the structure of Abeta and on the ability of this peptide to form potentially detrimental amyloid structures, we here analyze the interactions between Abeta(1 40) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC). DHPC has served, due to its controlled properties, as a major model system for studying general lipid properties. Here, we show that DHPC concentrations of 8 mM or higher exert dramatic effects on the conformation of soluble Abeta(1-40) peptide and induce the formation of beta-sheet structure at high levels. By contrast, we find that DHPC concentrations well below the critical micelle concentration present no discernible effect on the conformation of soluble Abeta, although they substantially affect the peptide's oligomerization and fibrillation kinetics. These data imply that subtle lipid-peptide interactions suffice in controlling the overall aggregation properties and drastically accelerate, or delay, the fibrillation kinetics of Abeta peptide in near-physiological buffer solutions. PMID- 20851129 TI - Three-dimensional structure of the M-region (bare zone) of vertebrate striated muscle myosin filaments by single-particle analysis. AB - The rods of anti-parallel myosin molecules overlap at the centre of bipolar myosin filaments to produce an M-region (bare zone) that is free of myosin heads. Beyond the M-region edges, myosin molecules aggregate in a parallel fashion to yield the bridge regions of the myosin filaments. Adjacent myosin filaments in striated muscle A-bands are cross-linked by the M-band. Vertebrate striated muscle myosin filaments have a 3-fold rotational symmetry around their long axes. In addition, at the centre of the M-region, there are three 2-fold axes perpendicular to the filament long axis, giving the whole filament dihedral 32 point group symmetry. Here we describe the three-dimensional structure obtained by a single-particle analysis of the M-region of myosin filaments from goldfish skeletal muscle under relaxing conditions and as viewed in negative stain. This is the first single-particle reconstruction of isolated M-regions. The resulting three-dimensional reconstruction reveals details to about 55 A resolution of the density distribution in the five main nonmyosin densities in the M-band (M6', M4', M1, M4 and M6) and in the myosin head crowns (P1, P2 and P3) at the M-region edges. The outermost crowns in the reconstruction were identified specifically by their close similarity to the corresponding crown levels in our previously published bridge region reconstructions. The packing of myosin molecules into the M-region structure is discussed, and some unidentified densities are highlighted. PMID- 20851131 TI - Atorvastatin treatment affects atrial ion currents and their tachycardia-induced remodeling in rabbits. AB - AIMS: Atrial fibrillation (AF) leads to electrical atrial remodeling including alterations of various ion channels early after arrhythmia onset. The beneficial effects of statins in AF treatment due to their influence on oxidative stress and inflammation are discussed. Our hypothesis was that statins might also alter atrial ion currents and their early tachycardia-induced remodeling. MAIN METHODS: Effects of an atorvastatin treatment (7 days) on atrial ion currents and their tachycardia-induced alterations were studied in a rabbit model of tachycardia induced electrical remodeling (rapid atrial pacing (600 min) for 24 and 120 h). Ion currents (L-type calcium channel [I(Ca,L)], transient outward current [I(to)]) were measured using whole cell patch clamp method and were compared with previous experiments in untreated but also tachypaced animals. KEY FINDINGS: Atorvastatin treatment alone decreased I(Ca,L) similar to rapid atrial pacing alone, currents were also further reduced by additional atrial tachypacing. I(to) and its pacing-induced down-regulation after 24 h were not influenced by atorvastatin treatment. However, I(to) was still reduced after 120 h in atorvastatin-treated animals and did not return to control values as expected. SIGNIFICANCE: The present study establishes that an atorvastatin treatment can affect atrial ion currents and their tachycardia-induced remodeling in a rabbit model. These results show that-amongst other positive effects on oxidative stress and inflammation-the impact of statins on ion currents and their tachycardia induced alterations might also play a role in "upstream" treatment of AF with HMG CoA reductase inhibitors. PMID- 20851130 TI - Internalizing cancer antibodies from phage libraries selected on tumor cells and yeast-displayed tumor antigens. AB - A number of approaches have been utilized to generate antibodies to cancer cell surface receptors that can be used as potential therapeutics. A number of these therapeutic approaches, including antibody-drug conjugates, immunotoxins, and targeted nucleic acid delivery, require antibodies that not only bind receptor but also undergo internalization into the cell upon binding. We previously reported on the ability to generate cancer cell binding and internalizing antibodies directly from human phage antibody libraries selected for internalization into cancer cell lines. While a number of useful antibodies have been generated using this approach, limitations include the inability to direct the selections to specific antigens and to identify the antigen bound by the antibodies. Here we show that these limitations can be overcome by using yeast displayed antigens known to be associated with a cell type to select the phage antibody output after several rounds of selection on a mammalian cell line. We used this approach to generate several human phage antibodies to yeast-displayed EphA2 and CD44. The antibodies bound both yeast-displayed and mammalian cell surface antigens, and were endocytosed upon binding to mammalian cells. This approach is generalizable to many mammalian cell surface proteins, results in the generation of functional internalizing antibodies, and does not require antigen expression and purification for antibody generation. PMID- 20851132 TI - Effects of pantoprazole in experimental acute pancreatitis. AB - AIMS: Oxidative stress with free radicals plays a crucial role in acute pancreatitis (AP). Pantoprazole (PPZ), widely used as a proton pump inhibitor, possesses reactivity towards hydroxyl radicals. The aim of the study was to examine the effect of PPZ on the course of experimental AP. MAIN METHODS: Mild AP was induced in rats by caerulein (n=12). Severe AP was induced by infusion of glycodeoxycholic acid (10mM) into the pancreatic duct combined with caerulein (n=12). Both AP models were randomized to PPZ treatment (20mg/kg at baseline and after 12h) or placebo. Control animals received Ringer solution (n=6) without AP induction. After 24h severity of AP was examined by histology, enzyme levels, edema and inflammatory markers (myeloperoxidase, protein profiling). Furthermore, CD62P and CD31 for leukocyte and platelet activation were investigated. KEY FINDINGS: Histology showed that PPZ treatment reduced tissue infiltration of inflammatory cells and acinar cell necrosis in severe AP. After PPZ treatment CD62P expression in mild AP and CD31 expression in severe pancreatitis decreased, indicating an inhibition of platelet activation. In mild and severe AP, PPZ significantly decreased amylase, LDH, edema and myeloperoxidase activity. Protein profile of pancreatic juice and serum revealed different spectra and less pancreatic juice proteins in PPZ treated groups indicating less acinar cell leakage. SIGNIFICANCE: PPZ possesses anti-inflammatory in vivo properties and attenuates the course of AP. This is mediated via a reduced expression of inflammatory and adhesive proteins with a consecutive decrease in platelet and leukocyte activation as key steps in the pathogenesis of AP. PMID- 20851133 TI - Attenuation of cadmium-induced testicular injury in metallothionein-III null mice. AB - AIMS: In order to evaluate the role of metallothionein (MT)-III in cadmium (Cd) induced testicular toxicity, we examined the sensitivity of MT-III null mice to severe testicular injury caused by Cd. MAIN METHODS: Male MT-III null mice, MT I/II null mice and wild-type mice were given a subcutaneous injection of CdCl(2) (15MUmol/kg). The testis was collected from each mouse at 6, 12 and 24h after Cd administration. KEY FINDINGS: Testicular hemorrhages by evaluating morphology, hemoglobin content and histological parameters in the 3 types of mice were elevated by Cd injection in a time-dependent manner. The degree of hemorrhage in Cd-injected MT-I/II null mice was similar to that in the wild-type mice. In contrast, hemorrhage in the MT-III null mice was attenuated compared with that in wild-type mice and MT-I/II null mice. Cd levels, MT-I and MT-II mRNA levels and Cd-binding molecules in the testis were similar between MT-III null mice and wild type mice. In microarray analysis, high expression of purine-nucleoside phosphorylase 2 (Pnp2), retinal degeneration 3 (Rd3), and cadherin-like 24 (Cdh24) was revealed in the testis of MT-III null mice under normal or Cd-treated conditions. SIGNIFICANCE: MT-III null mice were found to show attenuation of Cd induced severe testicular toxicity. These results suggest the lack of MT-III contributes to protection of testis from Cd. In addition, regulation of Pnp2, Rd3, and Cdh24 mRNA levels may involve the sensitivity of MT-III null mice to Cd. PMID- 20851134 TI - Accumulation of true single strand breaks and AP sites in base excision repair deficient cells. AB - Single strand breaks (SSBs) are one of the most frequent DNA lesions caused by endogenous and exogenous agents. The most utilized alkaline-based assays for SSB detection frequently give false positive results due to the presence of alkali labile sites that are converted to SSBs. Methoxyamine, an acidic O-hydroxylamine, has been utilized to measure DNA damage in cells. However, the neutralization of methoxyamine is required prior to usage. Here we developed a convenient, specific SSB assay using alkaline gel electrophoresis (AGE) coupled with a neutral O hydroxylamine, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (OTX). OTX stabilizes abasic sites (AP sites) to prevent their alkaline incision while still allowing for strong alkaline DNA denaturation. DNA from DT40 and isogenic polymerase beta null cells exposed to methyl methanesulfonate were applied to the OTX-coupled AGE (OTX-AGE) assay. Time-dependent increases in SSBs were detected in each cell line with more extensive SSB formation in the null cells. These findings were supported by an assay that indirectly detects SSBs through measuring NAD(P)H depletion. An ARP-slot blot assay demonstrated a significant time-dependent increase in AP sites in both cell lines by 1mM MMS compared to control. Furthermore, the Pol beta-null cells displayed greater AP site formation than the parental DT40 cells. OTX use represents a facile approach for assessing SSB formation, whose benefits can also be applied to other established SSB assays. PMID- 20851137 TI - In vivo uptake and acute immune response to orally administered chitosan and PEG coated PLGA nanoparticles. AB - Nanoparticulate drug delivery systems offer great promise in addressing challenges of drug toxicity, poor bioavailability and non-specificity for a number of drugs. Much progress has been reported for nano drug delivery systems for intravenous administration, however very little is known about the effects of orally administered nanoparticles. Furthermore, the development of nanoparticulate systems necessitates a thorough understanding of the biological response post exposure. This study aimed to elucidate the in vivo uptake of chitosan and polyethylene glycol (PEG) coated Poly, DL, lactic-co-glycolic Acid (PLGA) nanoparticles and the immunological response within 24 h of oral and peritoneal administration. These PLGA nanoparticles were administered orally and peritoneally to female Balb/C mice, they were taken up by macrophages of the peritoneum. When these particles were fluorescently labelled, intracellular localisation was observed. The expression of pro-inflammatory cytokines IL-2, IL 6, IL-12p70 and TNF-alpha in plasma and peritoneal lavage was found to remain at low concentration in PLGA nanoparticles treated mice as well as ZnO nanoparticles during the 24 hour period. However, these were significantly increased in lipopolysaccharide (LPS) treated mice. Of these pro-inflammatory cytokines, IL-6 and IL-12p70 were produced at the highest concentration in the positive control group. The anti-inflammatory cytokines IL-10 and chemokines INF-gamma, IL-4, IL-5 remained at normal levels in PLGA treated mice. IL-10 and INF-gamma were significantly increased in LPS treated mice. MCP-1 was found to be significantly produced in all groups in the first hours, except the saline treated mice. These results provide the first report to detail the induction of cytokine production by PLGA nanoparticles engineered for oral applications. PMID- 20851136 TI - Activation of brain somatostatin 2 receptors stimulates feeding in mice: analysis of food intake microstructure. AB - We recently reported that the oligosomatostatin receptor agonist, ODT8-SST increases food intake in rats via the somatostatin 2 receptor (sst(2)). We characterized ingestive behavior following intracerebroventricular (icv) injection of a selective sst(2) agonist in freely fed mice during the light phase. The sst(2) agonist (0.01, 0.03, 0.1, 0.3 or 1MUg/mouse) injected icv under short inhalation anesthesia dose-dependently increased cumulative light phase food intake over 4h compared to vehicle with a 3.1-times increase at 1MUg/mouse (p<0.05). Likewise, the sst(2,3,5) agonist octreotide (0.3 or 1MUg/mouse) dose dependently increased 4-h food intake, whereas selective sst(1) or sst(4) agonists at 1MUg/mouse did not. In vehicle-treated mice, high fat diet increased caloric intake/4h by 2.8-times compared to regular diet (p<0.05) and values were further increased 1.4-times/4h by the sst(2) agonist. Automated continuous assessment of food intake established a 6.6-times higher food intake during the dark phase due to increased number of meals, meal size, meal duration and rate of ingestion compared to non-treated mice during the light phase. During the first 4h post icv sst(2) agonist injection, mice had a 57% increase in number of meals with a 60% higher rate of ingestion, and a 61% reduction in inter-meal intervals, whereas meal sizes were not altered compared to vehicle. These data indicate that the activation of brain sst(2) receptors potently stimulates the light phase ingestive behavior under basal or high fat diet-stimulated conditions in mice. The shortened inter-meal interval suggests an inhibitory effect of the sst(2) agonist on "satiety", whereas "satiation" is not altered as indicated by normal meal size. PMID- 20851138 TI - Enzyme sequence similarity improves the reaction alignment method for cross species pathway comparison. AB - Pathway-based information has become an important source of information for both establishing evolutionary relationships and understanding the mode of action of a chemical or pharmaceutical among species. Cross-species comparison of pathways can address two broad questions: comparison in order to inform evolutionary relationships and to extrapolate species differences used in a number of different applications including drug and toxicity testing. Cross-species comparison of metabolic pathways is complex as there are multiple features of a pathway that can be modeled and compared. Among the various methods that have been proposed, reaction alignment has emerged as the most successful at predicting phylogenetic relationships based on NCBI taxonomy. We propose an improvement of the reaction alignment method by accounting for sequence similarity in addition to reaction alignment method. Using nine species, including human and some model organisms and test species, we evaluate the standard and improved comparison methods by analyzing glycolysis and citrate cycle pathways conservation. In addition, we demonstrate how organism comparison can be conducted by accounting for the cumulative information retrieved from nine pathways in central metabolism as well as a more complete study involving 36 pathways common in all nine species. Our results indicate that reaction alignment with enzyme sequence similarity results in a more accurate representation of pathway specific cross-species similarities and differences based on NCBI taxonomy. PMID- 20851135 TI - DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer. AB - Genetic somatic alterations are fundamental hallmarks of cancer. In addition to point and other small mutations targeting cancer genes, solid tumors often exhibit aneuploidy as well as multiple chromosomal rearrangements of large fragments of the genome. Whether somatic chromosomal alterations and aneuploidy are a driving force or a mere consequence of tumorigenesis remains controversial. Recently it became apparent that not only genetic but also epigenetic alterations play a major role in carcinogenesis. Epigenetic regulation mechanisms underlie the maintenance of cell identity crucial for development and differentiation. These epigenetic regulatory mechanisms have been found substantially altered during cancer development and progression. In this review, we discuss approaches designed to analyze genetic and epigenetic alterations in colorectal cancer, especially DNA fingerprinting approaches to detect changes in DNA copy number and methylation. DNA fingerprinting techniques, despite their modest throughput, played a pivotal role in significant discoveries in the molecular basis of colorectal cancer. The aim of this review is to revisit the fingerprinting technologies employed and the oncogenic processes that they unveiled. PMID- 20851140 TI - Sociodemographic and economic determinants of overweight and obesity in female food-aid users in France (the ABENA study 2004-2005). PMID- 20851139 TI - The effects of dose and repeated administration on the longer-term hypophagia produced by amphetamine in rats. AB - Rats are hypophagic approximately 1-3 and 13-27h after receiving amphetamine (2.0mg/kg). This study examined how these short- and longer-term phases of hypophagia were affected by repeated administration of different amphetamine doses. Throughout eight five-day tests, the rats could lever press for food pellets for 1-hour periods beginning every three hours. On test day 1, the rats were treated with saline, and on test day 3, they were treated with a dose of amphetamine. Across tests, for one group, treatment on day 3 alternated between 0.0 (saline) and 0.5mg/kg amphetamine; for a second, group treatment on day 3 alternated between 1.0 and 2.0mg/kg amphetamine; and for a third group, treatment on day 3 was always 1.0mg/kg amphetamine. The patterns of food intake following day 1 saline and day 3 treatment were compared. Short-term food intake was abolished by 0.5, 1.0, and 2.0mg/kg amphetamine, and no tolerance was observed to this effect. Longer-term hypophagia was produced by 1.0 and 2.0 but not by 0.5mg/kg. Tolerance to longer-term hypophagia was seen when 1.0mg/kg alone was used as the day 3 treatment, but not when 1.0 and 2.0mg/kg were alternated across tests as the day 3 treatment. Short- and longer-term hypophagia were dissociated by threshold doses for elicitation and by differential tolerance. Occasional receipt of a higher amphetamine dose may sometimes increase the longer-term hypophagia produced by a lower dose. PMID- 20851141 TI - Intelligent obesity interventions using Smartphones. PMID- 20851142 TI - Reproductive health of young adults with physical disabilities in the U.S. AB - OBJECTIVE: Previous research shows reduced cervical and breast cancer screening among women with physical disabilities. However, other indicators of reproductive health have been largely ignored. We aimed to compare the reproductive health of young adults in the U.S. with and without physical disabilities in a nationally representative sample. METHODS: Data are from 13,819 respondents aged 18-26 who participated in Waves I (1994-1995) and III (2001-2002) of the National Longitudinal Study of Adolescent Health (Add Health). Using logistic regression, we examined associations between physical disability and multiple reproductive health indicators including sexually transmitted infection (STI) testing, STI diagnosis, receipt of a gynecologic exam, and cervical cancer screening. Analyses were stratified by sex and adjusted for the complex study design. RESULTS: We identified 5.8% of respondents as having a physical disability. In multivariate analyses, females with physical disabilities had lower odds of having a Pap smear in the past 12 months than females without disabilities (OR=0.77; 95% CI: 0.61, 0.97). Physical disability was not associated with other reproductive health indicators among females or males. CONCLUSION: We found few differences in examined reproductive health indicators of young adults with and without physical disabilities, but findings suggest differences in some screening services that merit additional study. PMID- 20851143 TI - A computational neuroscience approach to schizophrenia and its onset. AB - Computational neuroscience integrate-and-fire attractor network models can be used to understand the factors that alter the stability of cortical networks in the face of noise caused for example by neuronal spiking times. A reduction of the firing rates of cortical neurons caused for example by reduced NMDA receptor function (present in schizophrenia) can lead to instability of the high firing rate attractor states that normally implement short-term memory and attention, contributing to the cognitive and negative symptoms of schizophrenia. Reduced cortical inhibition caused by a reduction of GABA neurotransmission (present in schizophrenia) can lead to instability of the spontaneous firing states of cortical networks, leading to a noise-induced jump to a high firing rate attractor state even in the absence of external inputs, contributing to the positive symptoms of schizophrenia. We consider how effects occurring at the time of late adolescence including synaptic pruning, decreases in grey matter volume, and changes in GABA-mediated inhibition and dopamine may contribute to the onset in some individuals of schizophrenia at this time. PMID- 20851144 TI - Resilience and adaptive aspects of stress in neurobehavioral development. PMID- 20851146 TI - The threshold of insulin-induced hypophagia is lower in chicks selected for low rather than high juvenile body weight. AB - Chicks genetically selected for low juvenile body weight had a lower threshold of central insulin-induced decreased food and water intake and whole blood glucose concentration than those selected for juvenile high body weight. Plasma corticosterone concentration was increased but not differently between lines. Therefore, selection may have affected insulin sensitivity which may have then contributed to their hypo- and hyperphagia and differential body weights. PMID- 20851147 TI - Abnormal whole-brain functional connection in amnestic mild cognitive impairment patients. AB - Amnestic mild cognitive impairment (aMCI) patients are thought to be particularly vulnerable to convert to clinical AD where functional disconnection is a major feature of the cortical neuropathology. However, the presence and extent of whole brain connectivity disturbances is largely unknown in aMCI patients. Twenty-six aMCI patients and eighteen matched healthy subjects were evaluated at baseline and at mean 20 months follow up. Temporal correlations between spatially distinct regions were evaluated by using longitudinal resting-state fMRI. Compared to normal aging controls, patterns of abnormal interregional correlations in widely dispersed brain areas were identified in the patients, which also changed with disease progression. These disturbances were found particularly in subcortical regions and frontal cortex. Importantly, significantly decreased negative functional connection may be specifically associated with the development of aMCI patients. This suggests a compensatory mechanism is underway where local processing deficits are offset by recruitment of more dispersed cortical regions. In addition, the presence of this increased connectivity is seen to eventually weaken with disease progression. The results suggest that patterns of whole-brain functional connection may be a useful risk marker for conversion to AD in aMCI patients. PMID- 20851145 TI - Identifying key features of early stressful experiences that produce stress vulnerability and resilience in primates. AB - This article examines the complex role of early stressful experiences in producing both vulnerability and resilience to later stress-related psychopathology in a variety of primate models of human development. Two types of models are reviewed: Parental Separation Models (e.g., isolate-rearing, peer rearing, parental separations, and stress inoculation) and Maternal Behavior Models (e.g., foraging demands, variation in maternal style, and maternal abuse). Based on empirical evidence, it is argued that early life stress exposure does not increase adult vulnerability to stress-related psychopathology as a linear function, as is generally believed, but instead reflects a quadratic function. Features of early stress exposure including the type, duration, frequency, ecological validity, sensory modality, and developmental timing, within and between species, are identified to better understand how early stressful experiences alter neurobiological systems to produce such diverse developmental outcomes. This article concludes by identifying gaps in our current knowledge, providing directions for future research, and discussing the translational implications of these primate models for human development and psychopathology. PMID- 20851148 TI - UMB-3, a novel rabbit monoclonal antibody, for assessing MU-opioid receptor expression in mouse, rat and human formalin-fixed and paraffin-embedded tissues. AB - BACKGROUND: The immunohistochemical localization of the MU-opioid receptor (MOR, MOP) has been studied in detail in mouse and rat brain using a variety of polyclonal antibodies. However, biochemical analysis of the MOR signaling complex in vivo has been hampered by the lack of suitable monoclonal antibodies for efficient immunoprecipitation of the receptor protein from native sources. Moreover, previous immunohistochemical investigations were restricted to frozen sections from perfusion-fixed rodent brain, largely due to the limited availability of MOR antibodies that effectively stain paraffin-embedded tissues. METHODS: Here, we extensively characterized the novel rabbit monoclonal anti-MOR antibody UMB-3 using transfected cells and MOR-deficient mice. UMB-3 was also subjected to a comparative immunohistochemical study of formalin-fixed, paraffin embedded mouse and rat organ samples as well as human normal and neoplastic tissues. RESULTS: Specificity of UMB-3 was demonstrated by detection of a broad band migrating at M(r) 70,000-80,000 in immunoprecipitates from crude brain homogenates of MOR+/+ mice but not of MOR-/- mice; cell surface staining of MOR transfected cells; translocation of MOR receptor immunostaining after agonist exposure; distinct immunostaining of neuronal cell bodies and fibers in MOR expressing brain regions; absence of staining in MOR-deficient mice; and abolition of tissue immunostaining by preadsorption of UMB-3 with its immunizing peptide. CONCLUSIONS: The rabbit monoclonal antibody UMB-3 is an excellent tool for immunoprecipitation of MOR from native sources as well as for immunohistochemical staining of MOR in paraffin-embedded tissue samples of rodent and human origin. PMID- 20851149 TI - Distinct distribution of GLUT4 and insulin regulated aminopeptidase in the mouse kidney. AB - The physiological importance of the insulin responsive glucose transporter GLUT4 in adipocytes and muscle in maintaining glucose homeostasis is well established. A key protein associated with this process is the aminopeptidase IRAP which co localizes with GLUT4 in specialized vesicles, where it plays a tethering role. In this study, we investigated the distribution of both GLUT4 and IRAP in the kidney to gain insights into the potential roles of these proteins in this organ. Both IRAP and GLUT4 immunostaining was observed in the epithelial cells of the proximal and distal tubules and thick ascending limbs in the cortex, but very little overlap between GLUT4 and IRAP immunoreactivity was observed. GLUT4 staining was consistent with a vesicular localization, whereas IRAP staining was predominantly on the luminal surface. In the principal cells of the inner medulla collecting duct (IMCD), IRAP immunoreactivity was detected throughout the cell, with limited overlap with the vasopressin responsive water channel aquaporin-2 (AQP-2). AQP-2 levels were observed to be two-fold higher in IRAP knockout mice. Based on our results, we propose that GLUT4 plays a role in shunting glucose across epithelial cells. In the kidney cortex, IRAP, in concert with other peptidases, may be important in the generation of free amino acids for uptake, whereas in the principal cells of the inner medulla IRAP may play a localized role in the regulation of vasopressin bioactivity. PMID- 20851150 TI - APM/CD13 and FOS in the hypothalamus of monosodium glutamate obese and food deprived rats. AB - Protein (western blotting) and gene (PCR) expressions, catalytic activity of puromycin-insensitive membrane-bound neutral aminopeptidase (APM/CD13) and in situ regional distribution of CD13 and FOS immunoreactivity (ir) were evaluated in the hypothalamus of monosodium glutamate obese (MSG) and/or food deprived (FD) rats in order to investigate their possible interplay with metabolic functions. Variations in protein and gene expressions of CD13 relative to controls coincided in the hypothalamus of MSG and MSG-FD (decreased 2- to 17-fold). Compared with controls, the reduction of hypothalamic CD13 content reflected a negative balance in its regional distribution in the supraoptic, paraventricular, periventricular and arcuate nuclei. CD13-ir increased in the supraoptic nucleus in MSG (2.5-fold) and decreased in the paraventricular nucleus (2-fold) together with FOS-ir (1.5 fold) in FD. In MSG-FD, FOS-ir decreased (7-fold) in the paraventricular nucleus, while CD13-ir decreased in the periventricular (5.6-fold) and the arcuate (3.7 fold) nuclei. It was noteworthy that all these changes of CD13 were not related to catalytic activity of APM. Data suggested that hypothalamic CD13 plays a role in the regulation of energy metabolism not by means of APM enzyme activity. PMID- 20851151 TI - Relaxin inhibits early steps in vascular inflammation. AB - Increased expression of endothelial adhesion molecules, high levels of the monocyte chemoattractant protein-1 (MCP-1) and enhanced VLA4 integrin/VCAM-1 and CCR-2/MCP-1 interactions are initial steps in vascular inflammation. We sought to determine whether relaxin, a potent vasodilatory and anti-fibrotic agent, mitigates these early events compromising endothelial integrity. The effect of relaxin coincubation on the TNF-alpha-stimulated expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin; the MCP-1 expression by human umbilical vein endothelial cells (HUVEC) and human aortic smooth muscle cells (HAoSMC); as well as on direct monocyte-endothelium cell adhesion was quantified by ELISA or adhesion assay. CCR-2 and PECAM expression on HUVEC and THP-1 monocytes was investigated by FACS analysis. Relaxin treatment suppressed significantly TNF alpha-induced upregulation of VCAM-1 and PECAM, CCR-2, and MCP-1 levels and direct monocyte adhesion to HUVEC. Our findings identify relaxin as a promising inhibitory factor in early vascular inflammation. By attenuating the upregulation of VCAM-1, key adhesion molecule in early vascular inflammation, and of MCP-1, a chemokine pivotal to monocyte recruitment, relaxin decreased initial monocyte endothelium contact. This may be of relevance for the prevention and treatment of atherosclerosis and of other pro-inflammatory states. PMID- 20851152 TI - Validation of ATP luminometry for rapid and accurate titration of Mycoplasma hyopneumoniae in Friis medium and a comparison with the color changing units assay. AB - Limited reports are available on the growth response of Mycoplasma hyopneumoniae in Friis medium and the routinely used color changing units (CCU) assay has not yet been profoundly compared with other titration methods. Firstly, growth kinetics of 7 diverse M. hyopneumoniae isolates were followed by ATP luminometry in five Friis medium batches. Secondly, results of the CCU and ATP assays were compared hereby evaluating the methods. Growth curves of all isolates had log, stationary and senescence phases, and reached similar maximal titres when cultured in the same batch of Friis medium. Doubling times (Tds) of the isolates grown in slowly shaken cultures varied between 4.8 and 7.8 h. Maximal titres, Tds, growth phase in which the phenol red indicator turned from red to yellow due to acidification by mycoplasmal metabolism, and the length of the stationary phase varied depending on the Friis medium batch. The effect of static vs. shaking culture conditions on the Td depended on the isolate. ATP and CCU assays obtained similar growth curves, but when maximal levels were reached the CCU titre dropped earlier than the ATP titre. During log phase, CCU and ATP titres were strongly linearly linked. We developed a model enabling transformation of ATP into CCU titres or vice versa. The calculated amount of ATP per CCU (1.77 amol ATP/ml) indicated that the CCU assay likely underestimates the actual cell concentration. When titres were determined as means of 3 measurements, the ATP assay was 7 times more accurate and had 11-fold lower outliers than the CCU assay. Unlike the CCU assay, luminometry only requires one measurement to obtain sufficient accuracy. It was concluded that the ATP assay constitutes a valuable robust alternative for reproducible real-time titre assessment of freshly grown M. hyopneumoniae cultures. It is faster, more accurate and time, work and cost efficient compared to the CCU assay. The assay is preferred to better standardise and describe M. hyopneumoniae cultures used in various experiments. PMID- 20851153 TI - A novel homologous dominant selection marker for genetic transformation of Penicillium chrysogenum: overexpression of squalene epoxidase-encoding ergA. AB - Genetic engineering requires genetic selection markers. For generation of biosafe strains in industrial applications, homologous dominant selection markers allowing "self-cloning" are best suited but scarce. Here we describe a novel homologous dominant genetic selection system for the filamentous fungus Penicillium chrysogenum based on overexpression of the P. chrysogenum squalene epoxidase-encoding ergA gene, which confers resistance against terbinafine. Terbinafine (TRB) is a potent antifungal drug used in therapy of fungal infections. Overexpression of ergA was driven by the P. chrysogenum endoxylanase xylP promoter that is highly inducible by xylose. The suitability of the novel selection marker cassette for genetic manipulation was proven by its use for targeted deletion of the transcription factor nosA in P. chrysogenum. NosA deficiency did not affect growth rates on solid or in liquid media, conidiation in light or darkness, and resistance to hydrogen peroxide. However, NosA deficiency significantly decreased penicillin productivity. As TRB inhibits the growth of a variety of fungal species, this novel selection marker is expected to be suitable for genetic engineering of diverse fungal species. PMID- 20851154 TI - Rapid quantification of intracellular PHA using infrared spectroscopy: an application in mixed cultures. AB - Fourier transform infrared (FT-IR) spectroscopy is proposed for a method for rapid quantification of polyhydroxyalkanoates (PHA) in mixed culture bacterial systems. Spectra from 122 samples from a wide range of PHA production systems were studied. The spectra were collected in a library that was used to calibrate a partial least squares (PLS) model linking FT-IR spectra with PHA content in the biomass. The library of spectra contained samples with a range of total PHA content (0.03-0.58 w/w) as well as varying compositions (poly-(3-hydroxyvalerate) (3HV) content of 0-63% in Cmol basis). A robust PLS model was developed using calibration data from a diverse range of systems and PHA content. Coupling this model with FT-IR spectra has been shown to be applicable for predicting PHA content in mixed culture production systems. The method was used to reliably determine PHA content in biomass from a new, independent PHA production system with a standard error of prediction (RMSEP) value of 0.023 w/w, despite the complexity of the matrices. This method reduces the analytical time for PHA quantification down to under 30 min (5 min handling time was achieved when FT-IR equipment was immediately available), and eliminates hazardous waste by-products. The work has demonstrated a level of accuracy and reproducibility in quantifying PHA in mixed culture systems similar to that obtained from the GC analytical technique. Further work is required to enable the use of the method to analyze crystallinity related factors that may be useful towards quantifying poly-(3 hydroxybutyrate) and poly-(3-hydroxyvalerate) (3HB/3HV) composition. The method has been shown to be suitable for rapid quantification in large scale applications and in its present form is reliable for routine process monitoring. PMID- 20851155 TI - Development of highly-sensitive microbial biosensors by mutation of the nahR regulatory gene. AB - NahR, a transcriptional regulator for naphthalene degradation in response to salicylate, is a central element in the microbial biosensor for detection of naphthalene and salicylate. To maximize the sensitivity of the biosensor, we have chosen a rational design of highly-sensitive microbial biosensors by introducing site directed mutagenesis to nahR gene. Eight single mutants (N169A, N169C, N169K, N169S, R248H, R248M, R248Q, and R248Y) were made at residues 169 and 248 known as the central inducer-recognition and the C-terminal multimerization domain. The effects of these mutations were examined by monitoring expression of a firefly luciferase (luc) reporter gene under the control of NahR. We found that all mutants at residues 248 and N169C show increased sensitivity (maximum ~50 fold) compared to wild type, respectively. R248M shows response even at toxic concentration, 5mM. The results show the feasibility and potential versatility of mutational approach for the development of the highly-sensitive microbial biosensors. PMID- 20851156 TI - Target-specific delivery of peptide-based probes for PET imaging. AB - Positron emission tomography (PET) is one of the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with various diseases. The principal goal of PET imaging is to visualize, characterize, and measure biological processes at the cellular, subcellular, and molecular level in living subjects with non-invasive procedures. PET imaging takes advantage of the traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of disease. During the last decade, advances in molecular biology have revealed an increasing number of potential molecular targets, including peptide receptors and peptide-related biomolecules. With the help of sophisticated bioconjugation and radiolabeling techniques, numerous peptide-based agents have been developed and evaluated for delivery of PET radionuclides to the specific molecular targets in preclinical and clinical studies. As compared to macromolecules, such as proteins or antibodies, low molecular-weight peptides have their distinctive advantages and predominantly demonstrate their favorable pharmacokinetics for in vivo PET applications. This review summarizes the criteria of peptide-based PET probes design, the selection of radioisotopes, labeling methods, and provides an overview of the current status and trends in the development of target-specific peptide-based probes with respect to their unique PET imaging applications. PMID- 20851157 TI - Subtyping weight-preoccupied overweight/obese women along restraint and negative affect. AB - Previous clustering analysis performed among samples of bulimic or binge eating women have consistently yielded two subtypes (Dietary and Dietary-Depressive). The present study verifies whether this clustering solution could be replicated among weight-preoccupied overweight/obese women and compares the different clusters on personality-, eating- and weight-related variables. Cluster analysis was performed along dietary restraint and negative affect among a sample of 156 overweight/obese weight-preoccupied women. Results failed to replicate the original two-cluster solution, rather evidencing a three-cluster solution (Dietary, Depressive, Low-Dietary/Low-Depressive). Also, dietary restraint did not appear to be a core feature for all weight-preoccupied overweight/obese women as it is for eating-disordered women since only one group presented dietary restraint. The presence of a pure Depressive group and a pure Dietary group showed that dietary restraint and negative affect may act independently among our sample. In term of clinical severity, the Dietary group, even in the absence of high negative affect, occupied an intermediate position between the Low Dietary/Low-Depressive and the Depressive group, the most impaired one, in accordance with previous studies. It thus suggests that other factors beside negative affect can contribute to eating and psychological impairment among overweight/obese women. PMID- 20851158 TI - A strawberry by any other name would smell as sweet, green, fruity and buttery. Multisensory cognition of a food aroma. AB - This brief report presents illustrative findings from the first implementation for recognition of an aroma of individualised analysis of cognition as normed discriminations. Two assessors compared mixtures of four odorants with a fresh strawberry in overall aroma, its intensity and balance, and in the smell of each odorant conceptualised in their own words. By the second session, each assessor's judgments of overall likeness of a mixture to strawberry focused on one of the six mental processes tested. One assessor acquired a configural conceptualisation of all the odorants as smelling the same as strawberry. The other asssessor learnt to rate strawberriness by conceptualising the four odorants separately in judgments of both intensity and balance. Even this modest amount of data provides insights into mental mechanisms by which an individual perceives the complex profile of odorants released by a familiar material. PMID- 20851159 TI - Chimerism studies with quantitative real-time PCR in stem cell recipients with acute myeloid leukemia. AB - OBJECTIVE: Chimerism is well-established for surveillance of acute myeloid leukemia (AML) patients after allogeneic hematopoietic stem cell transplantation (HSCT), but interpretation of the results and techniques is not standardized. MATERIALS AND METHODS: We correlated chimerism in 75 AML patients (38 male, 37 female) who underwent myeloablative (n = 36)/reduced (n = 39) allo-HSCT with the risk of relapse and survival. Chimerism was evaluated by quantitative real-time polymerase chain reaction for donor/recipient specific polymorphisms/Y-specific sequences. RESULTS: After HSCT, 40 patients (53%) achieved stable complete donor chimerism (>= 99.0% of donor alleles), while 35 (47%) failed to achieve stable donor chimerism. Thirty-one patients (41%) showed decreasing donor alleles after having first achieved complete donor chimerism. To investigate the kinetics of mixed chimerism, patients were separated whether they showed subsequent increasing or decreasing donor alleles. Subsequent decrease of donor alleles was associated with relapses in 17 of 18 cases (94%), while no patient with subsequent increasing donor alleles relapsed (p < 0.001). Patients with mixed chimerism and increasing donor alleles had better 2-year disease-free survival (85%) than those with decreasing donor alleles (0%; p < 0.001). CONCLUSIONS: The kinetics of mixed chimerism as assessed by quantitative real-time polymerase chain reaction is an important prognostic predictor in the post-transplantation period of AML patients. PMID- 20851160 TI - MCE special issue on signalling and regulation of GPCRs. PMID- 20851161 TI - Up-regulation of GABA transporters and GABA(A) receptor alpha1 subunit in tremor rat hippocampus. AB - The loss of GABAergic neurotransmission has been closely linked with epileptogenesis. The modulation of the synaptic activity occurs both via the removal of GABA from the synaptic cleft and by GABA transporters (GATs) and by modulation of GABA receptors. The tremor rat (TRM; tm/tm) is the parent strain of the spontaneously epileptic rat (SER; zi/zi, tm/tm), which exhibits absence-like seizure after 8 weeks of age. However, there are no reports that can elucidate the effects of GATs and GABA(A) receptors (GABARs) on TRMs. The present study was conducted to detect GATs and GABAR alpha1 subunit in TRMs hippocampus at mRNA and protein levels. In this study, total synaptosomal GABA content was significantly decreased in TRMs hippocampus compared with control Wistar rats by high performance liquid chromatography (HPLC); mRNA and protein expressions of GAT-1, GAT-3 and GABAR alpha1 subunit were all significantly increased in TRMs hippocampus by real time PCR and Western blot, respectively; GAT-1 and GABAR alpha1 subunit proteins were localized widely in TRMs and control rats hippocampus including CA1, CA3 and dentate gyrus (DG) regions whereas only a wide distribution of GAT-3 was observed in CA1 region by immunohistochemistry. These data demonstrate that excessive expressions of GAT-1 as well as GAT-3 and GABAR alpha1 subunit in TRMs hippocampus may provide the potential therapeutic targets for genetic epilepsy. PMID- 20851162 TI - Protein kinase A activators produce a short-term, but not long-term, increase in respiratory-drive transmission at the hypoglossal motor nucleus in vivo. AB - Synaptic plasticity is an intrinsic and conserved feature of neuronal activity that has been most extensively studied in the context of learning and memory in Aplysia and the mammalian hippocampus. However, the intracellular mechanisms underlying plasticity at motor nuclei, influencing motor behaviour, are less well studied. In vitro experiments in neonatal rodents indicate that protein kinase A (PKA) modulates respiratory-drive transmission at the hypoglossal motor nucleus (HMN), which innervates the genioglossus muscle of the tongue. We hypothesised that PKA activators at the HMN would increase genioglossus activity in vivo, whereas a PKA inhibitor would suppress activity indicative of constitutive PKA activation. Since PKA activators are importantly involved in models of long-term augmentation of neuronal activity following massed stimulation [16], we also hypothesised that application of PKA activators to the HMN would produce long term facilitation of genioglossus activity. Experiments were performed in 25 isoflurane-anaesthetised, tracheotomised, spontaneously breathing adult rats. Microdialysis perfusion of 8-Br-cAMP (direct PKA activator) into the HMN increased genioglossus activity compared to baseline levels with artificial cerebrospinal fluid (P<0.001). Application of forskolin (indirect PKA activator) had a similar effect (P<0.002). Genioglossus activity progressively decreased back to baseline during a 90-min washout with artificial cerebrospinal fluid, demonstrating a lack of long-term facilitation of genioglossus activity. Similar to massed application of 8-Br-cAMP to the HMN, intermittent application produced a short-term (P<0.001), but not long-term, increase in genioglossus activity in vivo. Application of Rp-8-Cl-cAMPS (PKA inhibitor) did not decrease genioglossus activity, indicating a lack of constitutive PKA activation. PMID- 20851163 TI - Effects of single and group housing conditions and alterations in social and physical contexts on amphetamine-induced behavioral sensitization in rats. AB - Repeated administration of amphetamine (AMPH) can produce behavioral sensitization. However, whether contextual elements and housing conditions influence AMPH-induced behavioral sensitization remains uncertain. This study was designed to examine the effects of housing conditions (single- vs. group-housed) and different contextual changes, including social (with two other co-drug partners) and physical (novel box) context changes, on AMPH-induced behavioral sensitization. During the training phase, all rats were exposed for 7 days to AMPH (1mg/kg, intraperitoneally) in a Locometer chamber, with the exception of animals tested for the effects of physical context changes trained in a novel box. Following a 7-day withdrawal phase, all rats received an AMPH (0.5mg/kg) challenge, and locomotor activity in a Locometer box was recorded before and after AMPH injection during the testing phase. Under group housing conditions, animals exposed to a different physical environment between the training and testing phases or accompanying co-drug partners during the training phase exhibited decreased AMPH-induced locomotor sensitization. In contrast, single housing conditions did not have an inhibitory effect on AMPH-induced behavioral sensitization after manipulations of the physical and social contexts. These results suggest that under group housing conditions, both physical and social context changes can attenuate AMPH-induced behavioral sensitization. The possible neural mechanisms underlying the involvement of different housing conditions in AMPH-induced behavioral sensitization are discussed. PMID- 20851164 TI - Early impact of 5-HTTLPR polymorphism on the neural correlates of sadness. AB - Healthy adults carrying the short (S) allele of the human serotonin transporter gene linked polymorphism (5-HTTLPR) show increased amygdala activation during visual processing of emotionally negative stimuli compared to healthy adults homozygous for the long (L) allele. To determine whether abnormal brain responses during negative emotion appear early in life in S allele carriers, functional magnetic resonance imaging (fMRI) was used to measure brain activity during a transient state of sadness in children carrying the S allele (S group) or homozygous for the L allele (L group). Blood-oxygen-level dependent (BOLD) signal changes were measured while subjects viewed blocks of neutral film excerpts and sad film excerpts. During the sad condition (relative to the neutral condition), there was significantly greater activation in the S group compared to the L group in brain regions known to be involved in normal sadness and major depression. Given that the 5-HTTLPR polymorphism has been associated with mood disorders, it is plausible that the abnormal pattern of regional brain activity detected here, in children carrying the S allele, increases susceptibility to emotional dysregulation and depressive symptoms. PMID- 20851165 TI - Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia. AB - Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Abeta-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Abeta-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0-I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia. PMID- 20851166 TI - Neuromelanin inhibits CXCL10 expression in human astroglial cells. AB - Increasing evidence indicates neuroinflammation is instrumental in the pathogenesis of Parkinson's disease (PD). In PD, there is selective degeneration of neuromelanin (NM)-containing dopamine neurons. Neuromelanin is predominantly cytoprotective within dopaminergic neurons, whereas, NM released from damaged neurons activates microglia. However, the effects of NM on astroglial cells remain largely unknown. Astroglia are essential to neuronal homeostasis and responsive to injury, in part, through secretion of chemokines, including interferon gamma inducible protein-10 (CXCL10). Thus, we used an in vitro approach to identify the effects of NM on TNFalpha-induced CXCL10 expression in human astroglial cells. TNFalpha-induced CXCL10 expression was inhibited in NM exposed cells. Additionally, TNFalpha-induced NF-kB activation was inhibited by NM. Given that CXCL10 expression is NF-kB-dependent in human astroglial cells, these findings suggest that NM may inhibit CXCL10 expression, in part, through an NF-kB-dependent mechanism. While the in vivo consequences of NM mediated effects on astroglial CXCL10 expression remain to be fully elucidated, insights obtained in this study further our understanding of the effects of NM on inflammatory signaling in human astroglial cells. PMID- 20851167 TI - Effects of berberine on 6-hydroxydopamine-induced neurotoxicity in PC12 cells and a rat model of Parkinson's disease. AB - Protoberberine isoquinoline alkaloids including berberine inhibit dopamine biosynthesis and aggravate l-DOPA-induced cytotoxicity in PC12 cells. In this study, the effects of berberine on 6-hydroxydopamine (6-OHDA)-induced cytotoxicity in PC12 cells and on unilateral 6-OHDA-lesioned rats were investigated. In PC12 cells, berberine at 10 and 30MUM associated with 6-OHDA (10, 20, and 50MUM) enhanced cytotoxicity at 48h compared to 6-OHDA alone, indicated by an increase in apoptotic cell death. In addition, treatment with berberine (5 and 30mg/kg, i.p.) for 21 days in 6-OHDA-lesioned rats markedly depleted tyrosine hydroxylase-immunopositive cells in the substantia nigra as compared to berberine-untreated rats. Further, the levels of dopamine and norepinephrine were also significantly decreased by berberine administration (5 and 30mg/kg) in the striatal regions of 6-OHDA-lesioned rats. These results suggested that berberine aggravated 6-OHDA-induced cytotoxicity in PC12 cells, and led to the degeneration of dopaminergic neuronal cells in the substantia nigra of 6-OHDA-lesioned rats. It is, therefore, suggested that the use of long term l-DOPA therapy with isoquinoline derivatives including berberine may need to be examined for the presence of adverse symptoms. PMID- 20851168 TI - Right temporal-lobe contribution to the retrieval of family relationships in person identification. AB - We previously reported a patient who exhibited a peculiar form of delusional misidentification. She had a selective deficit in retrieving family relationships between herself and her daughters and husband (i.e., she misidentified her daughters as her sisters and her husband as her father) despite being able to retrieve their names and faces and some person-specific semantic information (e.g., occupation). Based on this finding, the present positron emission tomography study was designed to elucidate the brain mechanisms underlying the retrieval of family relationships in healthy individuals. We found that the right inferior temporal gyrus, in which hypoperfusion was detected in the patient we had reported, was significantly activated during the retrieval of family relationships compared with names and occupations. These findings indicate that the retrieval of the relationships between oneself and one's family members may require a specific cognitive process dissociated from the retrieval of names and other person-specific semantic information. PMID- 20851170 TI - 5-Lipoxygenase in mouse cerebellar Purkinje cells. AB - It has been suggested that the enzymatic pathway of 5-lipoxygenase (5-LOX) influences brain functioning and pathobiology. The mRNAs for both the enzyme 5 LOX and its activating protein FLAP have been found in the cerebellum. In this work, we investigated the cellular expression of 5-LOX in the adult mouse cerebellar cortex. We used the in situ mRNA hybridization assay, immunocytochemistry, laser capture microdissection, and our previously developed method for assaying the DNA methylation status of a putative mouse 5-LOX promoter. Since both 5-LOX mRNA in situ hybridization signal and FLAP immunoreactivity co-localize with calbindin 28 kD immunoreactivity (a Purkinje cell marker) but not with S-100beta immunoreactivity (a Bergmann glia marker), the suggestion is that the 5-LOX pathway is expressed in cerebellar Purkinje cells. We found that methylation in the sites targeted by methylation-sensitive restriction endonucleases AciI and HinP1I but not BstUI and HpaII was greater in DNA samples obtained from a high-5-LOX-expressing cerebellar region (Purkinje cells) versus a low-5-LOX-expressing region (the molecular cell layer), suggesting a possible epigenetic contribution to the cell-specific 5-LOX expression in the cerebellum. We propose that Purkinje cell-localized 5-LOX and FLAP expression may be involved in the cerebellar synthesis of leukotrienes and/or could influence the Dicer-mediated microRNA formation and processes of neuroplasticity. PMID- 20851169 TI - Increased delivery of TAT across an endothelial monolayer following ischemic injury. AB - There is a great need for the development of vehicles capable of delivering therapeutic cargoes across the blood-brain barrier (BBB) and into brain cells. Cell-penetrating peptides (CPPs), such as TAT, present one such solution, and have been used successfully in vivo to deliver neuroprotective cargoes to the brain in models of stroke and seizure. However, a significant discrepancy exists in the literature, as other groups have not had the same success. One commonality between the successful studies is a compromised BBB. In this study, we hypothesized that ischemic injury increases the transport of TAT across an endothelial monolayer (comprised of bEnd.3 cells) in vitro and, consequently, increases TAT-mediated delivery into astrocytes on the other side. In the 24h following in vitro ischemia (oxygen-glucose deprivation), transendothelial electrical resistance (TEER) significantly decreased, indicating disruption of BBB integrity. Concomitantly, the transport of a green fluorescent protein (GFP) TAT fusion protein significantly increased, and the transduction of GFP-TAT into astrocytes cultured on the other side of the endothelial monolayer significantly increased. These results explain why TAT-mediated delivery of therapeutic cargoes is successful in the ischemic brain but not in the uninjured brain with an intact BBB, highlighting the necessity for continued development of delivery vehicles. We conclude that although TAT may not be an efficient vehicle for trans-BBB delivery across an intact BBB, it may have utility in clinical situations when the BBB is disrupted. PMID- 20851171 TI - An improved counterselectable marker system for mycobacterial recombination using galK and 2-deoxy-galactose. AB - Counterselectable markers are powerful tools in genetics because they allow selection for loss of a genetic marker rather than its presence. In mycobacteria, a widely used counterselectable marker is the gene encoding levan sucrase (sacB), which confers sensitivity to sucrose, but frequent spontaneous inactivation complicates its use. Here we show that the Escherichia coli galactokinase gene (galK) can be used as a counterselectable marker in both Mycobacterium smegmatis and Mycobacterium tuberculosis. Expression of E. coli galK, but not the putative M. tuberculosis galK, conferred sensitivity to 2-deoxy-galactose (2-DOG) in both M. smegmatis and M. tuberculosis. We tested the utility of E. coli galK as a counterselectable marker in mycobacterial recombination, both alone and in combination with sacB. We found that 0.5% 2-DOG effectively selected recombinants that had lost the galK marker with the ratio of galK loss/galK mutational inactivation of approximately 1:4. When we combined galK and sacB as dual counterselectable markers and selected for dual marker loss on 0.2% 2-DOG/5% sucrose, 98.6-100% of sucrose/2-DOG resistant clones had undergone recombination, indicating that the frequency of mutational inactivation of both markers was lower than the recombination frequency. These results establish a new counterselectable marker system for use in mycobacteria that can shorten the time to generate unmarked mutations in M. smegmatis and M. tuberculosis. PMID- 20851172 TI - The reproductive-cell cycle theory of aging: an update. AB - The Reproductive-Cell Cycle Theory posits that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence. Since reproduction is the most important function of an organism from the perspective of the survival of the species, if reproductive-cell cycle signaling factors determine the rate of growth, determine the rate of development, determine the rate of reproduction, and determine the rate of senescence, then by definition they determine the rate of aging and thus lifespan. The theory is able to explain: 1) the simultaneous regulation of the rate of aging and reproduction as evidenced by the fact that environmental conditions and experimental interventions known to extend longevity are associated with decreased reproductive-cell cycle signaling factors, thereby slowing aging and preserving fertility in a hostile reproductive environment; 2) two phenomena that are closely related to species lifespan-the rate of growth and development and the ultimate size of the animal; 3). the apparent paradox that size is directly proportional to lifespan and inversely proportional to fertility between species but vice versa within a species; 4). how differing rates of reproduction between species is associated with differences in their lifespan; 5). why we develop aging-related diseases; and 6). an evolutionarily credible reason for why and how aging occurs-these hormones act in an antagonistic pleiotrophic manner via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence (dyosis). In essence, the Reproductive-Cell Cycle Theory can explain aging in all sexually reproductive life forms. PMID- 20851173 TI - Growth hormone, insulin and aging: the benefits of endocrine defects. AB - Longevity of mice can be increased by spontaneous or experimentally induced mutations that interfere with the biosynthesis or actions of growth hormone (GH), insulin-like growth factor 1 (IGF-1), or insulin in the adipose tissue. The effects of GH resistance and deficiency of GH (along with thyrotropin and prolactin) on aging and lifespan are the most pronounced and best established of these mutations. Potential mechanisms linking these endocrine deficits with delayed aging and extended longevity include increased stress resistance, alterations in insulin and mammalian target of rapamycin (mTOR) signaling and metabolic adjustments. Physiological relationships deduced from the extreme phenotypes of long-lived mouse mutants appear to apply broadly, encompassing genetically normal ("wild-type") mice and other mammalian species. The role of GH in the control of human aging continues to be hotly debated, but recent data indicate that reduced somatotropic signaling provides protection from cancer and other age-related diseases and may promote old age survival. PMID- 20851174 TI - The interplay of descriptor-based computational analysis with pharmacophore modeling builds the basis for a novel classification scheme for feruloyl esterases. AB - One of the most intriguing groups of enzymes, the feruloyl esterases (FAEs), is ubiquitous in both simple and complex organisms. FAEs have gained importance in biofuel, medicine and food industries due to their capability of acting on a large range of substrates for cleaving ester bonds and synthesizing high-added value molecules through esterification and transesterification reactions. During the past two decades extensive studies have been carried out on the production and partial characterization of FAEs from fungi, while much less is known about FAEs of bacterial or plant origin. Initial classification studies on FAEs were restricted on sequence similarity and substrate specificity on just four model substrates and considered only a handful of FAEs belonging to the fungal kingdom. This study centers on the descriptor-based classification and structural analysis of experimentally verified and putative FAEs; nevertheless, the framework presented here is applicable to every poorly characterized enzyme family. 365 FAE related sequences of fungal, bacterial and plantae origin were collected and they were clustered using Self Organizing Maps followed by k-means clustering into distinct groups based on amino acid composition and physico-chemical composition descriptors derived from the respective amino acid sequence. A Support Vector Machine model was subsequently constructed for the classification of new FAEs into the pre-assigned clusters. The model successfully recognized 98.2% of the training sequences and all the sequences of the blind test. The underlying functionality of the 12 proposed FAE families was validated against a combination of prediction tools and published experimental data. Another important aspect of the present work involves the development of pharmacophore models for the new FAE families, for which sufficient information on known substrates existed. Knowing the pharmacophoric features of a small molecule that are essential for binding to the members of a certain family opens a window of opportunities for tailored applications of FAEs. PMID- 20851175 TI - Glaucocalyxin A induces apoptosis in human leukemia HL-60 cells through mitochondria-mediated death pathway. AB - Glaucocalyxin A (GLA) is a biologically active ent-kauranoid diterpenoid isolated from Rabdosia japonica var. glaucocalyx, a traditional Chinese medicinal herb, which has been shown to inhibit tumor cell proliferation. However, the mechanism underlying GLA-induced cytotoxicity remains unclear. In this study, we focused on the effect of GLA induction on apoptosis, the mitochondria-mediated death pathway and the accumulation of reactive oxygen species (ROS) in human leukemia cells (HL 60). GLA could induce a dose-dependent apoptosis in HL-60 cells as characterized by cell morphology, DNA fragmentation, activation of caspase-3, -9 and an increased expression ratio of Bax/Bcl-2. The mitochondrial membrane potential (Deltapsi(m)) loss and cytochrome c release from mitochondria to cytosol were observed during the induction. Moreover, GLA caused a time- and dose-dependent elevation of intracellular ROS level in HL-60 cells, and N-acetyl-l-cysteine (NAC, a well-known antioxidant) could block GLA-induced ROS generation and apoptosis. These data suggest that GLA induces apoptosis in HL-60 cells through ROS-dependent mitochondrial dysfunction pathway. PMID- 20851176 TI - Running exercise protects the substantia nigra dopaminergic neurons against inflammation-induced degeneration via the activation of BDNF signaling pathway. AB - Parkinson's disease (PD) is characterized by a progressive and selective loss of dopaminergic (DA) neurons in the substantia nigra (SN). Although the etiology of PD remains unclear, neuroinflammation has been implicated in the development of PD. Running exercise (Ex) promotes neuronal survival and facilitates the recovery of brain functions after injury. Therefore, we hypothesize that Ex protects the DA neurons against inflammation-induced injury in the SN. An intraperitoneal lipopolysaccharide (LPS, 1 mg/kg) injection induced microglia activation in the SN within hours, followed by a reduction in the number of DA neurons. LPS reduced the level of dopamine in the striatum and impaired the performance of motor coordination. Furthermore, the levels of the brain-derived neurotrophic factor (BDNF) were reduced in the SN by the LPS treatment. Four weeks of Ex before LPS treatment completely prevented the LPS-induced loss of DA neurons, reduction of dopamine levels and dysfunction of motor movement. Ex did not change the LPS induced status of microglia activation or the levels of cytokines/chemokines, but restored the levels of LPS-reduced BDNF-TrkB signaling molecules. Blocking the action of BDNF, through its receptor TrkB antagonist, abolished the Ex-induced protection against LPS-induced DA neuron loss. Intrastriatal perfusion of BDNF alone was sufficient to counteract the LPS-induced DA neuron loss. Altogether, our results show that Ex protects DA neurons against inflammation-induced insults. The neuroprotective effects of Ex are not due to the modulation of inflammation status, but rather to the activation of the BDNF-TrkB signaling pathway. PMID- 20851177 TI - Developmental origins of the metabolic syndrome: body clocks and stress responses. AB - The prevalence of the metabolic syndrome, which represents a spectrum of metabolic and cardiovascular disorders, continues to increase at an alarming rate in contemporary society. Inadequate responses of an individual to environmental challenges such as unbalanced diet or lack of physical exercise during their life course has been recognised to increase risk of this pathological condition. Recent evidence suggests that this may involve alterations in the settings of the circadian clock system, which consists of oscillating molecular pacemakers found not only in the hypothalamic region of the brain but also in most peripheral tissues, and of the hypothalamic-pituitary-adrenal (HPA) axis which regulates stress responses. These two systems are now known to interact to produce an integrated response to environmental challenges. In this review, we highlight the importance of environmental cues during early development in establishing the homeostatic set-points of the circadian clock and HPA stress systems. These effects can operate within the normal range and are not in themselves pathological, but can nevertheless affect an individual's response to environmental challenges in adult life and thus their risk of the metabolic syndrome. PMID- 20851178 TI - Characterization of maternal transfer of decabromodiphenyl ether (BDE-209) administered to pregnant Sprague-Dawley rats. AB - To evaluate maternal transfer of decabromodiphenyl ether (BDE-209), Sprague Dawley rats were given daily oral doses of 5 MUmol/kgb.w. BDE-209 in peanut oil from gestation day (GD) 7 to postpartum day (PD) 4. BDE-209 was increased temporally in maternal blood, placenta, fetuses and neonates. Furthermore, more BDE-209 was found in neonate whole-body samples obtained during lactational period (PD 4) than in that of fetal whole-body samples during pregnancy GD 15 and 21. Overall an increase was observed over time for nona-BDE levels in maternal blood and placenta, but these congeners were decreased in fetuses or neonates. Slight changes were observed for octa-BDEs in both maternal blood and placenta while a significant decrease was observed in the fetuses or neonates for BDE-196 and 198/203. These results demonstrated that BDE-209 and its metabolites can transport to the placenta and milk, and eventually enter the fetuses and/or the neonates. PMID- 20851179 TI - Noble metal targeting of thioredoxin reductase--covalent complexes with thioredoxin and thioredoxin-related protein of 14 kDa triggered by cisplatin. AB - Palladium (Pd), platinum (Pt), and gold (Au) are noble metals, two of which have established medical use. Pt has anticancer efficacy, predominantly as cisplatin, whereas the gold compound auranofin is used against arthritis. Both compounds inhibit the selenoprotein thioredoxin reductase (TrxR), but Pd has not been studied in this regard. Using salts of Pd, Pt, and Au as well as cisplatin and auranofin we found that Pd and Au were strikingly more potent inhibitors of recombinant TrxR1 than Pt. The TrxR-related nonselenoprotein glutathione reductase in pure form (but less so in a cellular context), as well as cellular thioredoxin (Trx) activities, were inhibited by the gold salt KAuCl(4) but were little affected by auranofin or the other compounds. In an analysis of three cancer cell lines, the extent of inhibition of TrxR activity and decrease in cell viability depended upon the choice of both noble metal and ligand and also seemed independent of p53 status. During treatment of cells with cisplatin, covalent complexes of TrxR1 with either Trx1 or TRP14 (Trx-related protein of 14kDa) were formed, as verified by Western blot analyses and mass spectrometry. These results reveal that Au and Pd are strong inhibitors of TrxR, but Pt and cisplatin trigger highly specific cellular effects on the Trx system, including covalent cross linking of TrxR1 with Trx1 and TRP14. PMID- 20851180 TI - Reduction of elevated plasma globotriaosylsphingosine in patients with classic Fabry disease following enzyme replacement therapy. AB - Fabry disease is treated by two-weekly infusions with alpha-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against alpha-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients. PMID- 20851181 TI - Marinobufagenin is an upstream modulator of Gadd45a stress signaling in preeclampsia. AB - Preeclampsia (PE) is a hypertensive disorder of pregnancy, in which marinobufagenin (MBG), a circulating cardiotonic steroid, is increased. The Gadd45a stress sensor protein is an upstream modulator of the pathophysiological changes observed in PE. However, the effects of MBG on Gadd45a stress signaling remain unknown. We examined the expression of Gadd45a, the sFlt-1 receptor, and p38, as well as caspase 3 and 8 activities in placental samples from four groups of rats. These were: normal pregnant (NP, n=8); pregnant rats which received weekly injections of desoxycorticosterone acetate and 0.9% saline as their drinking water (PDS, n=9); normal pregnant rats injected with MBG (NPM, n=8); and PDS rats injected with resibufogenin (RBG), an in vivo antagonist of MBG (PDSR, n=8). Utilizing human cytotrophoblast (CTB) cells, we examined the effect of MBG on these stress signaling proteins in vitro. Placental Gadd45a expression, caspase 3 and 8 activities, sFlt-1 concentrations, and sFlt-1 receptor expression were significantly higher in PDS and NPM compared to NP and PDSR rats. Gadd45a protein was significantly upregulated in the CTB cells when MBG was present in concentrations >=1nM. Treatment with MBG (>=1nM) also significantly arrested cell cycle progression and activated the expression of the Gadd45a-mediated stress signaling proteins. Inhibition of Gadd45a through RNAi-mediation attenuated MBG induced CTB cell stress signaling. In conclusion, MBG is involved in the alteration in Gadd45a stress signaling both in vivo and in vitro and RBG prevents these changes when administered in vivo. PMID- 20851182 TI - Systematic expression and loss-of-function analysis defines spatially restricted requirements for Drosophila RhoGEFs and RhoGAPs in leg morphogenesis. AB - The Drosophila leg imaginal disc consists of a peripheral region that contributes to adult body wall, and a central region that forms the leg proper. While the patterning signals and transcription factors that determine the identity of adult structures have been identified, the mechanisms that determine the shape of these structures remain largely unknown. The family of Rho GTPases, which consists of seven members in flies, modulates cell adhesion, actomyosin contractility, protrusive membrane activity, and cell-matrix adhesion to generate mechanical forces that shape adult structures. The Rho GTPases are ubiquitously expressed and it remains unclear how they orchestrate morphogenetic events. The Rho guanine nucleotide exchange factors (RhoGEFs) and Rho GTPase activating proteins (RhoGAPs), which respectively activate and deactivate corresponding Rho GTPases, have been proposed to regulate the activity of Rho signaling cascades in specific spatiotemporal patterns to orchestrate morphogenetic events. Here we identify restricted expression of 12 of the 20 RhoGEFs and 10 of the 22 Rho RhoGAPs encoded in Drosophila during metamorphosis. Expression of a subset of each family of RhoGTPase regulators was restricted to motile cell populations including tendon, muscle, trachea, and peripodial stalk cells. A second subset was restricted either to all presumptive joints or only to presumptive tarsal joints. Depletion of individual RhoGEFs and RhoGAPs in the epithelium of the disc proper identified several joint-specific genes, which act downstream of segmental patterning signals to control epithelial morphogenesis. Our studies provide a framework with which to understand how Rho signaling cascades orchestrate complex morphogenetic events in multi-cellular organisms, and evidence that patterning signals regulate these cascades to control apical constriction and epithelial invagination at presumptive joints. PMID- 20851184 TI - Production of human beta-actin and a mutant using a bacterial expression system with a cold shock vector. AB - Actin is the most abundant protein in the cytoplasm of most eukaryotic cells and is involved in a variety of cellular functions. It has been difficult to produce actin in bacterial expression systems in good yields. In this study, we developed a new simple method for the production of recombinant actin in Escherichia coli cells. Human beta-actin was successfully expressed using a cold shock vector, pCold, in the bacterial expression system. The expressed beta-actin (hexahistidine-tagged) was separated with a Ni-chelating resin, followed by a polymerization/depolymerization cycle or column chromatography with the Ni chelating resin. The purified recombinant beta-actin showed a normal polymerization ability compared with beta-actin purified from human platelets. We produced a recombinant mutant actin with a Gly-168Arg mutation in the system and confirmed that it exhibited an impaired polymerization ability. The system developed in this study will provide a useful method for the production of actin isoforms and their mutants. PMID- 20851185 TI - On-column refolding purification of DT389-hIL13 recombinant protein expressed in Escherichia coli. AB - Protein refolding is a bottleneck in the production of therapeutic proteins from inclusion bodies. In recent years, several studies have described on-column refolding of recombinant proteins. DT389-hIL13 is a recombinant protein that targets the glioma. In our study, the recombinant protein DT389-hIL13 was expressed in Escherichia coli (E. coli). The isolated inclusion bodies were refolded using size exclusion chromatography (SEC) and further purified using anion exchange chromatography. Three different methods of SEC on-column refolding were studied. In vitro tests on U251 cells showed that the recombinant protein could effectively inhibit the proliferation of U251 cells, especially the protein refolded by urea and pH gradient method. The half-maximal inhibitory concentration (IC50) of 0.887 nM was achieved with this new method, unlike an IC50 of 11.4 nM achieved in the non-gradient method. PMID- 20851183 TI - Gene signatures in hepatocellular carcinoma (HCC). AB - Primary hepatocellular carcinoma (HCC) is a significant human cancer globally, with poor prognosis. New and efficacious therapy strategies are needed as well as new biomarkers for early detection of at-risk patients. In this review, we discuss select microarray studies of human HCCs, and propose a gene signature that has promise for clinical/translational application. This gene signature combines the proliferation cluster of genes and the hepatic cancer initiating/stem cell gene cluster for identification of HCCs with poor prognosis. Evidence from cell-based assays identifies the existence of a mechanistic link between these two gene clusters, involving the proliferation cluster gene polo like kinase 1 (PLK1). We propose that PLK1 is a promising therapy target for HCC. PMID- 20851186 TI - A high-throughput protein refolding screen in 96-well format combined with design of experiments to optimize the refolding conditions. AB - Production of correctly folded and biologically active proteins in Escherichiacoli can be a challenging process. Frequently, proteins are recovered as insoluble inclusion bodies and need to be denatured and refolded into the correct structure. To address this, a refolding screening process based on a 96 well assay format supported by design of experiments (DOE) was developed for identification of optimal refolding conditions. After a first generic screen of 96 different refolding conditions the parameters that produced the best yield were further explored in a focused DOE-based screen. The refolding efficiency and the quality of the refolded protein were analyzed by RP-HPLC and SDS-PAGE. The results were analyzed by the DOE software to identify the optimal concentrations of the critical additives. The optimal refolding conditions suggested by DOE were verified in medium-scale refolding tests, which confirmed the reliability of the predictions. Finally, the refolded protein was purified and its biological activity was tested in vitro. The screen was applied for the refolding of Interleukin 17F (IL-17F), stromal-cell-derived factor-1 (SDF-1alpha/CXCL12), B cell-attracting chemokine 1 (BCA-1/CXCL13), granulocyte macrophage colony stimulating factor (GM-CSF) and the complement factor C5a. This procedure identified refolding conditions for all the tested proteins. For the proteins where refolding conditions were already available, the optimized conditions identified in the screening process increased the yields between 50% and 100%. Thus, the method described herein is a useful tool to determine the feasibility of refolding and to identify high-yield scalable refolding conditions optimized for each individual protein. PMID- 20851187 TI - Crystal structure of a dimeric archaeal cleavage and polyadenylation specificity factor. AB - Proteins of the metallo-beta-lactamase (MbetaL) fold form a large superfamily of metallo-hydrolase/oxidoreductases. Members of this family are found in all three domains of life and are involved in a variety of biological functions related to hydrolysis, redox processes, DNA repair and uptake, and RNA processing. We classified the archaeal homologs of this superfamily based on sequence similarity and characterized a subfamily of the Cleavage and Polyadenylation Specificity Factor (CPSF) with an uncommon domain composition: in addition to an extended MbetaL domain, which accommodates the active site for RNA cleavage, this group has two N-terminal KH domains. Here, we present the crystal structure of a member of this group from Methanosarcina mazei. It reveals a dimerization mode of the MbetaL domain that has not been observed before and suggests that RNA is bound across the dimer interface, recognized by the KH domains of one monomer, and cleaved at the active site of the other. PMID- 20851188 TI - Focal issue on hybrid imaging. PMID- 20851189 TI - Challenges to attention: a continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. AB - Maintaining attention and performance over time is an essential part of many activities, and effortful cognitive control is required to avoid vigilance decrements and interference from distraction. Regions at or near right middle frontal gyrus (Brodmann's area (BA) 9), as well as in other prefrontal and parietal areas, are often activated in studies of sustained attention (e.g., Cabeza and Nyberg, 2000; Kim et al., 2006; Lim et al., 2010). This activation has often been interpreted as representing the engagement of cognitive control processes. However, such studies are typically implemented at one level of task difficulty, without an experimental manipulation of control demands. The present study used the distractor condition sustained attention task (dSAT), which has been used extensively in animals to determine the role of neuromodulator systems in attentional performance, to test the hypotheses that BA 9 is sensitive to changes in the demand for cognitive control and that this sensitivity reflects an increased engagement of attentional effort. Continuous arterial spin labeling (ASL) was used to measure neural activity in sixteen healthy, young adults performing a sustained attention task under standard conditions and under a distraction condition that provided an experimental manipulation of demands on cognitive control. The distractor impaired behavioral performance and increased activation in right middle frontal gyrus. Larger increases in right middle frontal gyrus activity were associated with greater behavioral vulnerability to the distractor. These findings indicate that while right middle frontal gyrus regions are sensitive to demands for attentional effort and control, they may not be sufficient to maintain performance under challenge. In addition, they demonstrate the sensitivity of ASL methods to variations in task demands, and suggest that the dSAT may be a useful tool for translational cross-species and clinical research. PMID- 20851190 TI - Evidence of disrupted functional connectivity in the brain after combat-related blast injury. AB - Non-impact blast-related mild traumatic brain injury (mTBI) appears to be present in soldiers returning from deployments to Afghanistan and Iraq. Although mTBI typically results in cognitive deficits that last less than a month, there is evidence that disrupted coordination of brain activity can persist for at least several months following injury (Thatcher et al., 1989, 2001). In the present study we examined whether neural communication may be affected in soldiers months after blast-related mTBI, and whether coordination of neural function is associated with underlying white matter integrity. The investigation included an application of a new time-frequency based method for measuring electroencephalogram (EEG) phase synchronization (Aviyente et al., 2010) as well as fractional anisotropy measures of axonal tracts derived from diffusion tensor imaging (DTI). Nine soldiers who incurred a blast-related mTBI during deployments to Afghanistan or Iraq were compared with eight demographically similar control subjects. Despite an absence of cognitive deficits, the blast-related mTBI group exhibited diminished EEG phase synchrony of lateral frontal sites with contralateral frontal brain regions suggesting diminished interhemispheric coordination of brain activity as a result of blast injury. For blast injured (i.e., blast-related mTBI) soldiers we found that EEG phase synchrony was associated with the structural integrity of white matter tracts of the frontal lobe (left anterior thalamic radiations and the forceps minor including the anterior corpus callosum). Analyses revealed that diminished EEG phase synchrony was not the consequence of combat-stress symptoms (e.g., post-traumatic stress and depression) and commonly prescribed medications. Results provide evidence for poor coordination of frontal neural function after blast injury that may be the consequence of damaged anterior white matter tracts. PMID- 20851192 TI - Spatially distributed patterns of oscillatory coupling between high-frequency amplitudes and low-frequency phases in human iEEG. AB - Spatially distributed coherent oscillations provide temporal windows of excitability that allow for interactions between distinct neuronal groups. It has been hypothesized that this mechanism for neuronal communication is realized by bursts of high-frequency oscillations that are phase-coupled to a low-frequency spatially distributed coupling oscillation. This mechanism requires multiple physiologically different interacting sources, one generating the low-frequency coupling oscillation and the others generating phase-coupled high-frequency oscillations. Using human intracranial EEG (iEEG) data, we provide evidence for multiple oscillatory patterns, as characterized on the basis of their spatial maps (topographies) and their frequency spectra. In fact, we show that the spatial maps for the coupling oscillations are much more widespread than the ones for the associated phase-coupled bursts. Second, in the majority of the patterns of phase-amplitude coupling (PAC), phase-coupled bursts of high-frequency activity are synchronized across brain areas. Third and last, working memory operations affect the PAC strength in a heterogeneous way: in some PAC patterns, working memory operations increase their strength, whereas in others they decrease it. PMID- 20851191 TI - A reproducible evaluation of ANTs similarity metric performance in brain image registration. AB - The United States National Institutes of Health (NIH) commit significant support to open-source data and software resources in order to foment reproducibility in the biomedical imaging sciences. Here, we report and evaluate a recent product of this commitment: Advanced Neuroimaging Tools (ANTs), which is approaching its 2.0 release. The ANTs open source software library consists of a suite of state-of the-art image registration, segmentation and template building tools for quantitative morphometric analysis. In this work, we use ANTs to quantify, for the first time, the impact of similarity metrics on the affine and deformable components of a template-based normalization study. We detail the ANTs implementation of three similarity metrics: squared intensity difference, a new and faster cross-correlation, and voxel-wise mutual information. We then use two fold cross-validation to compare their performance on openly available, manually labeled, T1-weighted MRI brain image data of 40 subjects (UCLA's LPBA40 dataset). We report evaluation results on cortical and whole brain labels for both the affine and deformable components of the registration. Results indicate that the best ANTs methods are competitive with existing brain extraction results (Jaccard=0.958) and cortical labeling approaches. Mutual information affine mapping combined with cross-correlation diffeomorphic mapping gave the best cortical labeling results (Jaccard=0.669+/-0.022). Furthermore, our two-fold cross-validation allows us to quantify the similarity of templates derived from different subgroups. Our open code, data and evaluation scripts set performance benchmark parameters for this state-of-the-art toolkit. This is the first study to use a consistent transformation framework to provide a reproducible evaluation of the isolated effect of the similarity metric on optimal template construction and brain labeling. PMID- 20851193 TI - Parkinson's disease tremor-related metabolic network: characterization, progression, and treatment effects. AB - The circuit changes that mediate parkinsonian tremor, while likely differing from those underlying akinesia and rigidity, are not precisely known. In this study, to identify a specific metabolic brain network associated with this disease manifestation, we used FDG PET to scan nine tremor dominant Parkinson's disease (PD) patients at baseline and during ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS). Ordinal trends canonical variates analysis (OrT/CVA) was performed on the within-subject scan data to detect a significant spatial covariance pattern with consistent changes in subject expression during stimulation-mediated tremor suppression. The metabolic pattern was characterized by covarying increases in the activity of the cerebellum/dentate nucleus and primary motor cortex, and, to a less degree, the caudate/putamen. Vim stimulation resulted in consistent reductions in pattern expression (p<0.005, permutation test). In the absence of stimulation, pattern expression values (subject scores) correlated significantly (r=0.85, p<0.02) with concurrent accelerometric measurements of tremor amplitude. To validate this spatial covariance pattern as an objective network biomarker of PD tremor, we prospectively quantified its expression on an individual subject basis in independent PD populations. The resulting subject scores for this PD tremor-related pattern (PDTP) were found to exhibit: (1) excellent test-retest reproducibility (p<0.0001); (2) significant correlation with independent clinical ratings of tremor (r=0.54, p<0.001) but not akinesia-rigidity; and (3) significant elevations (p<0.02) in tremor dominant relative to atremulous PD patients. Following validation, we assessed the natural history of PDTP expression in early stage patients scanned longitudinally with FDG PET over a 4-year interval. Significant increases in PDTP expression (p<0.01) were evident in this cohort over time; rate of progression, however, was slower than for the PD-related akinesia/rigidity pattern (PDRP). We also determined whether PDTP expression is modulated by interventions specifically directed at parkinsonian tremor. While Vim DBS was associated with changes in PDTP (p<0.001) but not PDRP expression, subthalamic nucleus (STN) DBS reduced the activity of both networks (p<0.05). PDTP expression was suppressed more by Vim than by STN stimulation (p<0.05). These findings suggest that parkinsonian tremor is mediated by a distinct metabolic network involving primarily cerebello-thalamo-cortical pathways. Indeed, effective treatment of this symptom is associated with significant reduction in PDTP expression. Quantification of treatment-mediated changes in both PDTP and PDRP scores can provide an objective means of evaluating the differential effects of novel antiparkinsonian interventions on the different motor features of the disorder. PMID- 20851195 TI - A new method based on ICBM152 head surface for probe placement in multichannel fNIRS. AB - We propose a new probe placement method for multichannel functional Near Infrared Spectroscopy (fNIRS) based on the ICBM152 template, the most commonly used reference brain for neuroimaging. Our method is based on the use of a physical model of the ICBM152 head surface as reference scalp and its validity is supported by previous investigations of cranio-cerebral correlation. The method, intended for fNIRS group studies, dispenses with the use of individual MRI scan and digitizing procedure for each participant. The present approach offers a fast, simple, reproducible and straightforward method to place the probes on the head surface according to the MNI coordinates of the regions of interest with an average measurement error similar to those of previous methods. This ensures that fNIRS results can be readily compared within the neuroimaging community, both across studies and techniques. PMID- 20851194 TI - Impaired error-likelihood prediction in medial prefrontal cortex in schizophrenia. AB - The cognitive impairment in individuals with schizophrenia includes deficits of working memory in dorsolateral prefrontal cortex and deficits of performance monitoring in medial prefrontal cortex (MPFC). Recent work suggests a more general role for MPFC in predicting the outcome of actions and then evaluating those predictions. Here we investigate, in individuals with schizophrenia, two specific effects associated with this role: the error likelihood effect (occurring on trials with correct performance, but features that predict a high probability of errors), and the error unexpectedness effect (occurring on trials with an error, but features that predict errors are of low probability). In a rapid event-related fMRI design with a modified version of the change-signal task, a cue incidentally predicting error likelihood was encoded into working memory by participants in order to perform a secondary delayed match-to-sample task. There were four key findings: (1) individuals with schizophrenia exhibited poorer working memory performance and reduced error signals in MPFC; (2) even in control and schizophrenia subgroups matched on working memory performance, the schizophrenia subgroup showed a deficit in error-likelihood prediction in MPFC at the time of the predictive cue; (3) the schizophrenia subgroup also showed a deficit in evaluative error-unexpectedness activity when errors were committed; and (4) a mediation analysis indicated that error-likelihood predictions successfully explained error-unexpectedness evaluations in both controls and patients. Collectively, these findings suggest that individuals with schizophrenia have a disturbance in the evaluation of outcomes that is the result of a primary deficit in the prediction of error likelihood in MPFC. PMID- 20851196 TI - Early time points perfusion imaging. AB - The aim was to investigate the feasibility of making relative cerebral blood flow (rCBF) maps from MR images acquired with short TR by measuring the initial arrival amount of Gd-DTPA evaluated within a time window before any contrast agent has a chance to leave the tissue. We named this rCBF measurement technique utilizing the early data points of the Gd-DTPA bolus the "early time points" method (ET), based on the hypothesis that early time point signals were proportional to rCBF. Simulation data were used successfully to examine the ideal behavior of ET while monkey's MRI results offered encouraging support to the utility of ET for rCBF calculation. A better brain coverage for ET could be obtained by applying the Simultaneous Echo Refocusing (SER) EPI technique. A recipe to run ET was presented, with attention paid to the noise problem around the time of arrival (TOA) of the contrast agent. PMID- 20851197 TI - Intermediate templates guided groupwise registration of diffusion tensor images. AB - Registration of a population of diffusion tensor images (DTIs) is one of the key steps in medical image analysis, and it plays an important role in the statistical analysis of white matter related neurological diseases. However, pairwise registration with respect to a pre-selected template may not give precise results if the selected template deviates significantly from the distribution of images. To cater for more accurate and consistent registration, a novel framework is proposed for groupwise registration with the guidance from one or more intermediate templates determined from the population of images. Specifically, we first use a Euclidean distance, defined as a combinative measure based on the FA map and ADC map, for gauging the similarity of each pair of DTIs. A fully connected graph is then built with each node denoting an image and each edge denoting the distance between a pair of images. The root template image is determined automatically as the image with the overall shortest path length to all other images on the minimum spanning tree (MST) of the graph. Finally, a sequence of registration steps is applied to progressively warping each image towards the root template image with the help of intermediate templates distributed along its path to the root node on the MST. Extensive experimental results using diffusion tensor images of real subjects indicate that registration accuracy and fiber tract alignment are significantly improved, compared with the direct registration from each image to the root template image. PMID- 20851198 TI - Cerebral activation is correlated to regional atrophy of the spinal cord and functional motor disability in spinal cord injured individuals. AB - Recovery of function following lesions in the nervous system requires adaptive changes in surviving circuitries. Here we investigate whether changes in cerebral activation are correlated to spinal cord atrophy and recovery of functionality in individuals with incomplete spinal cord injury (SCI). 19 chronic SCI individuals and 7 age-comparable controls underwent functional magnetic resonance imaging (fMRI) while performing rhythmic dorsiflexion of the ankle. A significant negative correlation was found between the activation in the ipsilateral motor (M1) and bilateral premotor cortex (PMC) on one hand and the functional ability of the SCI participants measured by the clinical motor score on the other. There was no significant correlation between activation in any other cerebral area and the motor score. Activation in ipsilateral somatosensory cortex (S1), M1 and PMC was negatively correlated to the width of the spinal cord in the left-right direction, where the corticospinal tract is located, but not in the antero posterior direction. There was a tendency for a negative correlation between cerebral activation in ipsilateral S1, M1 and PMC and the amplitude of motor evoked potentials in the tibialis anterior muscle elicited by transcranial magnetic stimulation, but this did not reach statistical significance. There was no correlation between motor score or spinal cord dimensions and the volume of the cortical motor areas. The observations show that lesion of descending tracts in the lateral part of the spinal cord results in increased activation in ipsilateral motor and sensory areas, which may help to compensate for the functional deficit following SCI. PMID- 20851199 TI - Patch-based segmentation using expert priors: application to hippocampus and ventricle segmentation. AB - Quantitative magnetic resonance analysis often requires accurate, robust, and reliable automatic extraction of anatomical structures. Recently, template warping methods incorporating a label fusion strategy have demonstrated high accuracy in segmenting cerebral structures. In this study, we propose a novel patch-based method using expert manual segmentations as priors to achieve this task. Inspired by recent work in image denoising, the proposed nonlocal patch based label fusion produces accurate and robust segmentation. Validation with two different datasets is presented. In our experiments, the hippocampi of 80 healthy subjects and the lateral ventricles of 80 patients with Alzheimer's disease were segmented. The influence on segmentation accuracy of different parameters such as patch size and number of training subjects was also studied. A comparison with an appearance-based method and a template-based method was also carried out. The highest median kappa index values obtained with the proposed method were 0.884 for hippocampus segmentation and 0.959 for lateral ventricle segmentation. PMID- 20851200 TI - Response of engineered cartilage to mechanical insult depends on construct maturity. AB - Injury to articular cartilage leads to degenerative changes resulting in a loss of mechanical and biochemical properties. In engineered cartilage, the injury response of developing constructs is unclear. OBJECTIVE: To characterize the cellular response of tissue-engineered constructs cultured in chemically-defined medium after mechanical insult, either by compression-induced cracking, or by cutting, as a function of construct maturity. METHODS: Primary immature bovine articular chondrocytes (4-6 weeks) were encapsulated in agarose hydrogel (2%, 30 millioncells/mL) and cultured in chemically-defined medium supplemented with Transforming growth factor (TGF)-beta3 (10ng/mL, first 2 weeks). At early (5 days) and late (35 days) times in culture, subsets of constructs were exposed to mechanical overload to produce a crack in the tissue or were exposed to a sharp wound with a perpendicular cut. Constructs were returned to culture and allowed to recover in static conditions. Mechanical and biochemical properties were evaluated at 2-week intervals to day 70, and cellular viability was assessed at 2 week intervals to day 85. RESULTS: Constructs injured early in culture recovered their mechanical stiffness back to control values, regardless of the mode of injury. Later in culture, when constructs exhibited properties similar to those of native cartilage, compression-induced cracking catastrophically damaged the bulk matrix of the tissue and resulted in permanent mechanical failure with persistent cell death. No such detrimental outcomes were observed with cutting. Biochemical content was similar across all groups irrespective of mode or time of injury. CONCLUSIONS: Unlike native cartilage, engineered cartilage constructs exhibit a reparative capacity when the bulk integrity of the developing tissue is preserved after injury. PMID- 20851201 TI - Effect of self-assembling peptide, chondrogenic factors, and bone marrow-derived stromal cells on osteochondral repair. AB - OBJECTIVE: The goal of this study was to test the ability of an injectable self assembling peptide (KLD) hydrogel with or without chondrogenic factors (CF) and allogeneic bone marrow stromal cells (BMSCs) to stimulate cartilage regeneration in a full-thickness, critically-sized, rabbit cartilage defect model in vivo. We used CF treatments to test the hypotheses that CF would stimulate chondrogenesis and matrix production by cells migrating into acellular KLD (KLD+CF) or by BMSCs delivered in KLD (KLD+CF+BMSCs). DESIGN: Three groups were tested against contralateral untreated controls: KLD, KLD+CF, and KLD+CF+BMSCs, n=6-7. Transforming growth factor-beta1 (TGF-beta1), dexamethasone, and insulin-like growth factor-1 (IGF-1) were used as CF pre-mixed with KLD and BMSCs before injection. Evaluations included gross, histological, immunohistochemical and radiographic analyses. RESULTS: KLD without CF or BMSCs showed the greatest repair after 12 weeks with significantly higher Safranin-O, collagen II immunostaining, and cumulative histology scores than untreated contralateral controls. KLD+CF resulted in significantly higher aggrecan immunostaining than untreated contralateral controls. Including allogeneic BMSCs+CF markedly reduced the quality of repair and increased osteophyte formation compared to KLD-alone. CONCLUSIONS: These data show that KLD can fill full-thickness osteochondral defects in situ and improve cartilage repair as shown by Safranin-O, collagen II immunostaining, and cumulative histology. In this small animal model, the full thickness critically-sized defect provided access to the marrow, similar in concept to abrasion arthroplasty or spongialization in large animal models, and suggests that combining KLD with these techniques may improve current practice. PMID- 20851202 TI - Comparison of BLOKS and WORMS scoring systems part II. Longitudinal assessment of knee MRIs for osteoarthritis and suggested approach based on their performance: data from the Osteoarthritis Initiative. AB - INTRODUCTION: There are two widely used scoring systems for knee magnetic resonance imaging (MRI) in osteoarthritis (OA) and the strengths and weaknesses of each system in terms of ease of use and association with known risk factors and outcomes are unknown. OBJECTIVE: To compare Whole Organ Magnetic Resonance Imaging Score (WORMS) and Boston Leeds Osteoarthritis Knee Score (BLOKS) scales using longitudinal MRI and X-ray data. METHODS: In the Osteoarthritis Initiative (OAI), knee radiographs, long limb films for alignment and MRI's were acquired in the interval from 0 to 24 months follow-up. OAI MRI's from baseline and 24 months were read separately using BLOKS and WORMS scales. X-rays were scored semiquantitatively for joint space loss and long limb films were measured for alignment angle. We evaluated which of the WORMS or BLOKS cartilage loss scores best correlated with joint space loss on the X-ray and which was best predicted by varus malalignment on long limb film. To examine the validity of bone marrow lesion (BML) and meniscal scales, we tested which of WORMS or BLOKS baseline scores for BML or meniscus best predicted cartilage loss from baseline to 24 months. We critically evaluated strengths and weaknesses of each scoring system also. RESULTS: Of 113 knees read longitudinally, 33 showed any cartilage loss using BLOKS and 30 using WORMS with high agreement between the scales. In the medial compartment, both BLOKS and WORMS picked up only 42% of the knees with X ray joint space loss with similar specificity (88 vs 86%). Varus knees were more likely to be a risk factor for medial cartilage loss in BLOKS [adj odds ratio (OR) 5.9 (95% confidence intervals (CIs) 1.5, 24.0)] than in WORMS [adj OR 2.1 (95% CI 0.7, 6.3)]. WORMS BML scores predicted cartilage loss more strongly than any BLOKS BML variables and some BLOKS BML measures did not affect risk of cartilage loss at all. However, across the range of scores, meniscal tear scores in BLOKS predicted cartilage loss better for each abnormality than did WORMS meniscal tear scores and the meniscal signal abnormality scored in BLOKS but not in WORMS, predicted cartilage loss. BLOKS took longer and was more difficult to score longitudinally especially for BML scores. CONCLUSION: In a comparison of instruments limited by small numbers of knees compared, BLOKS meniscal score was preferable to WORMS meniscal scale in predicting cartilage loss most likely because it includes potentially important pathology missed by WORMS. On the other hand, BML scoring in WORMS was preferable in that it better predicted later cartilage loss, was easier to score and did not include potentially extraneous measures. Neither method was definitively better for cartilage scoring. PMID- 20851204 TI - Combined itraconazole-pentoxifylline treatment promptly reduces lung fibrosis induced by chronic pulmonary paracoccidioidomycosis in mice. AB - Fibrosis is a severe and progressive sequel of many pulmonary diseases, has no effective therapy at present and, consequently, represents a serious health problem. In Latin America, chronic pulmonary paracoccidioidomycosis (PCM) is one of the most important, prevalent and systemic fungal diseases that allows the development of lung fibrosis, with the additional disadvantage that this sequel may appear even after an apparently successful course of antifungal therapy. In this study, was propose the pentoxifylline as complementary treatment in the pulmonary PCM due to its immunomodulatory and anti-fibrotic properties demonstrated in vitro and in vivo in liver, skin and lung. Our objective was to investigate the possible beneficial effects that a combined antifungal (Itraconazole) and immunomodulatory (Pentoxifylline) therapy would have in the development of fibrosis in a model of experimental chronic pulmonary PCM in an attempt to simulate the naturally occurring events in human patients. Two different times post-infection (PI) were chosen for starting therapy, an "early time" (4 weeks PI) when fibrosis was still absent and a "late time" (8 weeks PI) when the fibrotic process had started. Infected mice received the treatments via gavage and were sacrificed during or upon termination of treatment; their lungs were then removed and processed for immunological and histopathologic studies in order to assess severity of fibrosis. When pulmonary paracoccidioidomycosis had evolved and reached an advanced stage of disease before treatment began (as normally occurs in many human patients when first diagnosed), the combined therapy (itraconazole plus pentoxifylline) resulted in a significantly more rapid reduction of granulomatous inflammation and pulmonary fibrosis, when compared with the results of classical antifungal therapy using itraconazole alone. PMID- 20851203 TI - Sulfur mustard-induced pulmonary injury: therapeutic approaches to mitigating toxicity. AB - Sulfur mustard (SM) is highly toxic to the lung inducing both acute and chronic effects including upper and lower obstructive disease, airway inflammation, and acute respiratory distress syndrome, and with time, tracheobronchial stenosis, bronchitis, and bronchiolitis obliterans. Thus it is essential to identify effective strategies to mitigate the toxicity of SM and related vesicants. Studies in animals and in cell culture models have identified key mechanistic pathways mediating their toxicity, which may be relevant targets for the development of countermeasures. For example, following SM poisoning, DNA damage, apoptosis, and autophagy are observed in the lung, along with increased expression of activated caspases and DNA repair enzymes, biochemical markers of these activities. This is associated with inflammatory cell accumulation in the respiratory tract and increased expression of tumor necrosis factor-alpha and other proinflammatory cytokines, as well as reactive oxygen and nitrogen species. Matrix metalloproteinases are also upregulated in the lung after SM exposure, which are thought to contribute to the detachment of epithelial cells from basement membranes and disruption of the pulmonary epithelial barrier. Findings that production of inflammatory mediators correlates directly with altered lung function suggests that they play a key role in toxicity. In this regard, specific therapeutic interventions currently under investigation include anti-inflammatory agents (e.g., steroids), antioxidants (e.g., tocopherols, melatonin, N acetylcysteine, nitric oxide synthase inhibitors), protease inhibitors (e.g., doxycycline, aprotinin, ilomastat), surfactant replacement, and bronchodilators. Effective treatments may depend on the extent of lung injury and require a multi faceted pharmacological approach. PMID- 20851205 TI - Peroxynitrite stimulates pulmonary artery endothelial and smooth muscle cell proliferation: involvement of ERK and PKC. AB - BACKGROUND: There is evidence that peroxynitrite is generated in pulmonary hypertension and we have therefore investigated whether peroxynitrite can cause proliferation of pulmonary artery cells. METHODS: Bovine pulmonary artery endothelial (PAEC) and smooth muscle cells (PASMC) were exposed to peroxynitrite solution or to the peroxynitrite generating compound, 3-morpholinosydnonimine (SIN-1). Vascular cell proliferation was determined by cell count and (3)H thymidine incorporation. Protein biochemistry was by western blot analysis. RESULTS: Transient exposure to peroxynitrite stimulated the proliferation of PASMC (peroxynitrite 0.2 nM-2 MUM) and PAEC (peroxynitrite 0.2 MUM). Peroxynitrite 0.2 MUM stimulated DNA synthesis in PASMC cell by 200 +/- 22% and in PAEC by 137 +/- 4%. DNA synthesis in PAEC and PASMC was also stimulated by the peroxynitrite generator SIN-1 2 MUM. Cell proliferation was accompanied by activation of ERK, which peaked at 15 min and remained elevated for 12 h in PASMC. However peroxynitrite at the concentrations used in this study did not activate the stress pathways p38 mitogen activated protein kinase (MAPK) or Jun N terminal kinase (JNK). Peroxynitrite-induced proliferation and ERK phosphorylation in PASMC were abolished by the peroxynitrite scavenger ebselen 5 MUM. Peroxynitrite-induced proliferation and extracellular signal-regulated kinase (ERK) phosphorylation in PASMC was prevented by selective inhibitors of MAP kinase kinase (MEK) (U0126 5 MUM, PD98059 50 MUM), Raf-1 (Raf-1 kinase inhibitor 10 MUM), Ras (FPT II and FPT III 10 MUM) and protein kinase C (PKC) (GF109203X 10 MUM). Inhibition of EGF or PDGF receptor signaling using AG-1296, AG-1478 or imatinib prevented peroxynitrite-induced cell proliferation and ERK phosphorylation in PASMC. CONCLUSION: Peroxynitrite can stimulate proliferation of pulmonary artery cells, involving ERK, PKC and EGF or PDGF receptors. PMID- 20851206 TI - A second form of Sox11 homologue identified in the orange-spotted grouper Epinephelus coioides: analysis of sequence and mRNA expression patterns. AB - Sox genes, a family of genes related to the mammalian sex-determining region Y (SRY) gene, are found throughout the animal kingdom, and involved in diverse developmental processes including sex determination and neurogenesis. Previously, we have identified one sox11 homologue, sox11b, from the ovary of the orange spotted grouper. In the present study, another sox11 homologue, sox11a, was cloned from the brain. The orange-spotted grouper Sox11a contained the signature features of mammalian SOX11 homologues except the Pro-Glu rich region, was clustered with Sox11a homologues of other teleosts in the phylogenetic tree, and shared higher homologies with Sox11 of other species than the duplicated copy Sox11b. Interestingly, significant conservation was observed in the 3'UTR of sox11a but not sox11b transcripts when compared with mammalian Sox11 homologues. The expression of sox11a mRNA was detected in a wide range of tissues, with higher abundances in the central nervous system. During embryogenesis and larval development, the expression of sox11a mRNA remained at considerably high levels at all stages examined, from newly fertilized eggs, through organogenesis, to the larvae 18days posthatching. Together, these results indicated that the orange spotted grouper sox11a was evolutionarily more conserved than sox11b, and may play important roles in neurogenesis, embryogenesis, and larval development. PMID- 20851207 TI - A practical method for transforming free-text eligibility criteria into computable criteria. AB - Formalizing eligibility criteria in a computer-interpretable language would facilitate eligibility determination for study subjects and the identification of studies on similar patient populations. Because such formalization is extremely labor intensive, we transform the problem from one of fully capturing the semantics of criteria directly in a formal expression language to one of annotating free-text criteria in a format called ERGO annotation. The annotation can be done manually, or it can be partially automated using natural-language processing techniques. We evaluated our approach in three ways. First, we assessed the extent to which ERGO annotations capture the semantics of 1000 eligibility criteria randomly drawn from ClinicalTrials.gov. Second, we demonstrated the practicality of the annotation process in a feasibility study. Finally, we demonstrate the computability of ERGO annotation by using it to (1) structure a library of eligibility criteria, (2) search for studies enrolling specified study populations, and (3) screen patients for potential eligibility for a study. We therefore demonstrate a new and practical method for incrementally capturing the semantics of free-text eligibility criteria into computable form. PMID- 20851209 TI - Methodological concerns in usability evaluation of software prototypes. PMID- 20851208 TI - Exposing the cancer genome atlas as a SPARQL endpoint. AB - The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. PMID- 20851210 TI - Patients with celiac disease and B-cell lymphoma have a better prognosis than those with T-cell lymphoma. AB - BACKGROUND & AIMS: Celiac disease (CD) is associated with an increased risk of lymphoma. However, relatively few studies have assessed the outcome of patients diagnosed with both CD and lymphoma. We evaluated the temporal association between lymphoma and CD, along with clinical presentation, response to therapy, and prognosis. METHODS: Patients diagnosed with both CD and lymphoma were identified retrospectively in a tertiary referral center. Clinical characteristics and survival were analyzed. RESULTS: Sixty-three patients (36 men) were identified who had been diagnosed with lymphoma and CD. Thirty-six (57%) were diagnosed with CD before they were diagnosed with lymphoma. The most common histologic entity was diffuse, large, B-cell lymphoma, which affected 18 (29%) patients. Complete information for staging was available in 59 patients; 24 (38%) had stage IV disease. Only chemotherapy or only radiation therapy was used for 43 (68%) and 11 (17%) patients, respectively. The 5- and 10-year cumulative survival rates for the entire cohort were 58% and 39%, respectively. Survival of patients with T-cell lymphoma was shorter than for all other lymphomas (119.4 vs 22.8 mo; P = .02). CONCLUSIONS: CD is associated with B- and T-cell lymphomas. Patients with B-cell lymphomas had a better prognosis than those with T-cell lymphoma. Therapy is unsatisfactory for enteropathy-type T-cell lymphoma. PMID- 20851212 TI - Image of the month. Mycobacterium avium complex enteritis. PMID- 20851214 TI - Duodenal perforation by an inferior vena cava filter. PMID- 20851211 TI - Liver disease in the HIV-infected individual. AB - Since the advent of effective antiretroviral therapy (ART) for human immunodeficiency virus-1 (HIV), there has been a substantial decrease in deaths related to acquired immunodeficiency syndrome (AIDS). However, in the ART era, liver disease is now the most common non-AIDS-related cause of death among HIV infected patients, accounting for 14%-18% of all deaths in this population and almost half of deaths among hospitalized HIV-infected patients. Just as the burden of non-AIDS morbidity and mortality has changed in the ART era, the types of liver disease the clinician is likely to encounter among these patients have changed as well. This review will discuss the causes of liver disease in the HIV infected population in the ART era, including chronic hepatitis C virus, chronic hepatitis B virus, medication-related hepatotoxicity, alcohol abuse, nonalcoholic fatty liver disease, and AIDS-related liver diseases. PMID- 20851213 TI - Natural history of potential celiac disease in children. AB - BACKGROUND & AIMS: The presence of celiac disease-associated autoantibodies (antiendomysium and antitissue transglutaminase [anti-TG2]) with normal jejunal mucosa indicate potential celiac disease. We performed a prospective, 3-year cohort study to determine the natural history of potential celiac disease in children. METHODS: The study included 106 children with potential celiac disease, based on serology analysis and normal duodenal architecture. All but 2 carried the HLA-DQ2 and/or DQ8 haplotype. In all children, every 6 months, growth, nutritional parameters, celiac disease serology, and autoimmunity were investigated. In biopsies, gammadelta intraepithelial-, CD3-, and lamina propria CD25-positive cells were counted; duodenal deposits of anti-TG2 immunoglobulin A were detected. Biopsy analysis was repeated after 2 years on patients with persistent positive serology and/or symptoms. RESULTS: Celiac disease was detected primarily in first-degree relatives and patients with autoimmune disorders (40.6%). A gluten-free diet was prescribed to 20/106 patients because of symptoms, which were relieved in only 11. Eighty-nine of the 106 patients entered the follow-up study, with normal daily consumption of gluten. During the follow-up antibodies disappeared in 14.6% and fluctuated in 32.6%. Villous atrophy was observed in 12/39 patients (30.8%) who underwent a repeat biopsy. CONCLUSIONS: Most children with potential celiac disease remain healthy. After 3 years, approximately 33% of patients develop villous atrophy. Intestinal deposits of anti-TG2 IgA identify children at risk for villous atrophy. PMID- 20851215 TI - Morgagni's hernia. PMID- 20851216 TI - Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms. AB - BACKGROUND & AIMS: Little information is available about the clinico-pathologic characteristics of pancreatic branch duct intraductal papillary mucinous neoplasm (Br-intraductal papillary mucinous neoplasm [IPMN]) because of difficulties in diagnosis based on radiologic and tissue information. We investigated the natural history of Br-IPMN using imaging and surgical pathology data from patients. METHODS: Data were collected from patients admitted to a single tertiary referral institution from January 2000 to March 2009 (median follow up of 27.9 months); 201 patients were diagnosed with Br-IPMN with an initial cyst less than 30 mm without main pancreatic duct dilatation or mural nodules. The patients were followed for more than 3 months and examined by computed tomography (CT) at least twice. RESULTS: The mean size of the patients' initial cysts was 14.7 mm; the mean cyst growth rate was 1.1 mm/year. Thirty-five patients received surgery during follow up and 8 were confirmed to have malignant cysts. The malignant cysts were greater in final size than nonmalignant cysts (24.3 mm vs 16.9 mm; P = .003); they also grew by a greater percentage (69.8% vs 19.4%; P = .046) and at a greater rate (4.1 mm vs 1.0 mm/year; P = .001). The actuarial 5-year risk of malignancy was 41.6% in the group that received surgery and 10.9% for all patients. Cysts that grew more than 2 mm/year had a higher risk of malignancy (5 year risk = 45.5% vs 1.8%; P < .001). CONCLUSIONS: In combination with cyst size and the presence of mural nodules, cyst growth rate could be used to predict malignancy in patients with Br-IPMN. PMID- 20851217 TI - Image of the month. Endocytoscopy-based detection of focal high-grade intraepithelial neoplasia in colonic polyps. PMID- 20851218 TI - A mitochondrial ubiquitin ligase MITOL controls cell toxicity of polyglutamine expanded protein. AB - Expansion of a polyglutamine tract in ataxin-3 (polyQ) causes Machado-Joseph disease, a late-onset neurodegenerative disorder characterized by ubiquitin positive aggregate formation. Several lines of evidence demonstrate that polyQ also accumulates in mitochondria and causes mitochondrial dysfunction. To uncover the mechanism of mitochondrial quality-control via the ubiquitin-proteasome pathway, we investigated whether MITOL, a novel mitochondrial ubiquitin ligase localized in the mitochondrial outer membrane, is involved in the degradation of pathogenic ataxin-3 in mitochondria. In this study, we used N-terminal-truncated pathogenic ataxin-3 with a 71-glutamine repeat (DeltaNAT-3Q71) and found that MITOL promoted DeltaNAT-3Q71 degradation via the ubiquitin-proteasome pathway and attenuated mitochondrial accumulation of DeltaNAT-3Q71. Conversely, MITOL knockdown induced an accumulation of detergent-insoluble DeltaNAT-3Q71 with large aggregate formation, resulting in cytochrome c release and subsequent cell death. Thus, MITOL plays a protective role against polyQ toxicity, and thereby may be a potential target for therapy in polyQ diseases. Our findings indicate a protein quality-control mechanism at the mitochondrial outer membrane via a MITOL mediated ubiquitin-proteasome pathway. PMID- 20851219 TI - Modelling proteins: conformational sampling and reconstruction of folding kinetics. AB - In the last decades biomolecular simulation has made tremendous inroads to help elucidate biomolecular processes in-silico. Despite enormous advances in molecular dynamics techniques and the available computational power, many problems involve long time scales and large-scale molecular rearrangements that are still difficult to sample adequately. In this review we therefore summarise recent efforts to fundamentally improve this situation by decoupling the sampling of the energy landscape from the description of the kinetics of the process. Recent years have seen the emergence of many advanced sampling techniques, which permit efficient characterisation of the relevant family of molecular conformations by dispensing with the details of the short-term kinetics of the process. Because these methods generate thermodynamic information at best, they must be complemented by techniques to reconstruct the kinetics of the process using the ensemble of relevant conformations. Here we review recent advances for both types of methods and discuss their perspectives to permit efficient and accurate modelling of large-scale conformational changes in biomolecules. This article is part of a Special Issue entitled: Protein Dynamics: Experimental and Computational Approaches. PMID- 20851220 TI - Microstructures and rheological properties of tilapia fish-scale collagen hydrogels with aligned fibrils fabricated under magnetic fields. AB - Tilapia fish-scale type I atelocollagen hydrogels with aligned fibril structures were fabricated under a strong magnetic field of 6 or 12 T using two different methods. In the first method, a solution of acid-soluble collagen was neutralized with phosphate buffer saline and maintained in the magnetic field at 28 degrees C for 3h. Under these conditions fibrogenesis occurs, and a hydrogel is formed. The hydrogel was subsequently crosslinked with ethyl-dimethylcarbodiimide (EDC). In the second method, the hydrogels were formed as described above, but in the absence of an applied magnetic field. Only after being crosslinked with EDC were these gels exposed to the magnetic field (28 degrees C for 3h). Both methods led to alignment of the collagen fibrils perpendicular to the magnetic direction, the extent of which depended on the duration of magnetic treatment. Even after EDC treatment, collagen fibrils can align, indicating that crosslinking has taken place within fibrils. Both sorts of aligned hydrogels exhibited similar rheological properties with higher storage and loss moduli than were observed with unoriented gels. The hydrogels treated at 6 T had the best rheological properties. The decrease in tangent angle phase delta indicated that the ratio of elasticity to viscosity was greater in the crosslinked than in the non crosslinked hydrogels. Atomic force microscopy images showed that magnetic treatment had no effect on the nanostructure of collagen fibrils. Differential scanning calorimetry measurements indicated that collagen hydrogels with and without magnetic treatment had the same denaturation temperature, 48 degrees C, while EDC crosslinking increased the denaturation temperature to 62 degrees C. PMID- 20851221 TI - Assessment of protein domain fusions in human protein interaction networks prediction: application to the human kinetochore model. AB - In order to understand how biological systems function it is necessary to determine the interactions and associations between proteins. Some proteins, involved in a common biological process and encoded by separate genes in one organism, can be found fused within a single protein chain in other organisms. By detecting these triplets, a functional relationship can be established between the unfused proteins. Here we use a domain fusion prediction method to predict these protein interactions for the human interactome. We observed that gene fusion events are more related to physical interaction between proteins than to other weaker functional relationships such as participation in a common biological pathway. These results suggest that domain fusion is an appropriate method for predicting protein complexes. The most reliable fused domain predictions were used to build protein-protein interaction (PPI) networks. These predicted PPI network models showed the same topological features as real biological networks and different features from random behaviour. We built the PPI domain fusion sub-network model of the human kinetochore and observed that the majority of the predicted interactions have not yet been experimentally characterised in the publicly available PPI repositories. The study of the human kinetochore domain fusion sub-network reveals undiscovered kinetochore proteins with presumably relevant functions, such as hubs with many connections in the kinetochore sub-network. These results suggest that experimentally hidden regions in the predicted PPI networks contain key functional elements, associated with important functional areas, still undiscovered in the human interactome. Until novel experiments shed light on these hidden regions; domain fusion predictions provide a valuable approach for exploring them. PMID- 20851222 TI - The central role of the skeleton in chronic diseases. PMID- 20851223 TI - Parental involvement laws and parent-daughter communication: policy without proof. PMID- 20851224 TI - Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review. AB - The effect of obesity on drug metabolism and pharmacokinetics is poorly understood, and this is particularly true in regard to contraceptive steroids. This article will review the known and theoretical physiologic and pharmacologic interactions between obesity and contraceptive steroids. PMID- 20851225 TI - Obstetrician-gynecologist physicians' beliefs about emergency contraception: a national survey. AB - BACKGROUND: Although emergency contraception (EC) is available without a prescription, women still rely on doctors' advice about its safety and effectiveness. Yet little is known about doctors' beliefs and practices in this area. STUDY DESIGN: We surveyed 1800 US obstetrician-gynecologists. Criterion variables were doctors' beliefs about EC's effects on pregnancy rates, and patients' sexual practices. We also asked which women are offered EC. Predictors were demographic, clinical and religious characteristics. RESULTS: Response rate was 66% (1154/1760). Most (89%) believe EC access lowers unintended pregnancy rates. Some believe women use other contraceptives less (27%), initiate sex at younger ages (12%) and have more sexual partners (15%). Half of physicians offer EC to all women (51%), while others offer it never (6%) or only after sexual assault (6%). Physicians critical of EC, males and religious physicians were more likely to offer it never or only after sexual assault (odds ratios 2.1-12). CONCLUSION: Gender, religion and divergent beliefs about EC's effects shape physicians' beliefs and practices. PMID- 20851226 TI - How commonly do US abortion clinics offer contraceptive services? AB - BACKGROUND: About half of US women having abortions have already had at least one prior abortion. Facilitating access to contraception may help these women avoid subsequent unintended pregnancies. Information is needed to document the availability of contraceptive services in abortion care settings in the United States. STUDY DESIGN: Data for this cross-sectional mixed-methods study were collected between December 2008 and September 2009 and come from two sources: 15 semistructured telephone interviews and 173 structured questionnaires administered to a nationally representative sample of eligible facilities. Respondents were administrators at large (400+ abortions per year), nonhospital facilities that provide abortion services in the United States. RESULTS: Virtually all (96%) abortion clinics incorporate contraceptive education into abortion care, and the three most common methods reported to be distributed are the birth control pill (99%), the vaginal ring (61%) and Depo-Provera (58%). Almost one-third reported being able to offer post-abortion intrauterine device insertion. Most facilities (82%) accept some form of insurance for either contraceptive or abortion services, and those with a broader family planning focus are significantly more likely to do so. Administrators at the majority of facilities (56%) report that patients most commonly do not pay additional fees for contraceptive services because they are included in the cost of abortion services. CONCLUSION: Although almost all large, non-hospital abortion providers in the United States are able to provide some level of contraceptive care to their abortion patients, the degree to which they are able to do so is influenced by a wide range of factors. PMID- 20851227 TI - Patterns of contraceptive use before and after an abortion: results from a nationally representative survey of women undergoing an abortion in France. AB - BACKGROUND: Using a large national survey of women undergoing an abortion in France, we explore their contraceptive use surrounding an abortion. STUDY DESIGN: The study comprised a representative sample of 7541 women undergoing an abortion in 2007. We compared their use of contraception before and after the abortion and examined the factors associated with the prescription of a very effective method (IUD, hormonal methods) after the procedure. RESULTS: Sixty-six percent of women were using contraception in the month they conceived. A third of women reported the same use of contraception before and after the abortion, 54% were prescribed a more effective method, while 14% changed to a less effective or no method at all. After the abortion, 77% of women were prescribed a very effective contraceptive. CONCLUSIONS: Abortion offers an opportunity to improve contraceptive uptake and a chance for providers to adjust their prescriptions according to the difficulties women experience in their use of contraceptives. PMID- 20851228 TI - Uptake and adherence to long-acting reversible contraception post-abortion. AB - BACKGROUND: This study aimed to increase use of long-acting reversible contraceptive (LARC) methods by women post-abortion. STUDY DESIGN: Ten-week intervention at a public abortion clinic involving free access to three LARC methods (DMPA, LNG-IUS, Multiload Cu375); posters promoting LARC; updated information for clinic staff. OUTCOME MEASURES: change in the proportion of women choosing LARC prior to and during the intervention; rate of follow-up and method retention at 6 weeks and at 6 months post-abortion. RESULTS: Use of post-abortion LARC increased significantly from 44% at baseline (226/510) to 61% (310/510) during the intervention (p<.001). Use of LNG-IUS increased almost sixfold from 6% to 36%. Follow-up rates were 71% at 6 weeks (221/310) and 74% at 6 months (184/249). Method retention was 89% at 6 weeks (197/221) and 86% at 6 months (159/184). CONCLUSION: Uptake of LARC by women post-abortion can be achieved by increasing access to these methods - by eliminating cost and raising awareness and benefits of long-acting methods among both clinicians and patients. PMID- 20851229 TI - Operative management of intrauterine device complications: a case series report. AB - BACKGROUND: There is limited information about the number of intrauterine device (IUD) users requiring operative intervention for device-related complications. This is an evaluation of cases requiring in-hospital operative intervention for IUD perforations, removals and pregnancy-related complications. STUDY DESIGN: Large retrospective case series of patients who received operative management of IUD complications. RESULTS: Charts of patients from 15 hospitals in two health care systems from 2000 to 2007 were reviewed and outcomes of 276 women are reported. There were 95 operative IUD removals for perforations (including 60 levonorgestrel-releasing intrauterine systems), 157 operative procedures for inability to remove an IUD in the office, and 42 pregnancy-related complications that were managed in the operating room. Ectopic pregnancy was the most common diagnosis among pregnant women (23 of 42 pregnant women, 54.8%). CONCLUSION: The majority of operative procedures were performed for intrauterine IUDs, most of which were appropriately positioned IUDs with missing or short strings. In-office techniques for obtaining analgesia and dilation as well as appropriate devices for removal of T-shaped IUDs should make this practice rare. PMID- 20851230 TI - Endometrial safety of a novel monophasic combined oral contraceptive containing 0.02 mg ethinylestradiol and 2 mg chlormadinone acetate administered in a 24/4 day regimen over six cycles. AB - BACKGROUND: This study was conducted to examine whether small doses of ethinylestradiol (EE, 0.02 mg) and chlormadinone acetate (CMA, 2 mg) administered in a novel 24/4-day regimen during six cycles would suffice to suppress proliferation and to cause secretory changes in the endometrium. STUDY DESIGN: This Phase II, randomized (two assessment groups), single-center, open, uncontrolled, multiple-dosing study treated 59 female subjects. The subjects underwent three endometrial biopsies: one pretreatment, one during medication (either at Cycle 3 or Cycle 6) and one during the first post-treatment cycle. RESULTS: The study revealed that 0.02 mg EE/2 mg CMA effectively transformed the endometrium from a proliferative state into a secretory or inactive state after three (90% of subjects) and six (76% of subjects) medication cycles. The mean endometrial thickness decreased markedly from 10.2 (SD+/-3.0) mm (pretreatment) to an unfavorable level for the nidation of a blastocyst [5.3 (SD+/-2.1) and 4.1 (SD+/-2.2) mm in Medication Cycles 3 and 6, respectively]. Correspondingly, estradiol and progesterone levels decreased during treatment. In the post treatment cycle, endometrial biopsy and ultrasound evaluation as well as sex hormone levels suggested a quick return to fertility. There were no signs of hyperplasia, endometrial polyps, neoplasia or other detrimental histopathological changes at any time during the trial. Treatment-related adverse events (AEs) were reported by 22 (37%) of 59 subjects and were reported most commonly in Cycle 1, decreasing continuously thereafter. No AEs led to discontinuation of the trial medication and there were no serious AEs. CONCLUSIONS: The 24/4-day regimen of 0.02 mg EE/2 mg CMA provided effective and reversible endometrial effects with secretory transformation or suppression without inducing pathological changes. PMID- 20851231 TI - A combined oral contraceptive containing 30 mcg ethinyl estradiol and 3.0 mg drospirenone does not impair endothelium-dependent vasodilation. AB - BACKGROUND: Ethinyl estradiol (EE) increases endothelium-dependent vasodilation in young women, but certain progestins paired with EE in combination oral contraceptive pills (OCPs) have been shown to antagonize the vasodilatory effects of EE. Therefore, the purpose of this study was to investigate how endothelial function, serum biomarkers and resting blood pressures change across an OCP cycle in women using a monophasic OCP formulation containing the progestin drospirenone. STUDY DESIGN: Twelve women were studied during two hormone phases of their OCP cycle: once at the end of 3 weeks of active pills (30 mcg EE and 3.0 mg drospirenone) and once at the end of a week of placebo pills (no exogenous hormones) RESULTS: Endothelium-dependent vasodilation was greater during the active phase compared to the placebo phase (p<.001). In contrast, there was no difference in endothelium-independent dilation between hormone phases. CONCLUSION: These data suggest that the combination of 30 mcg EE and 3.0 mg drospirenone used in the active phase of this OCP increases endothelium-dependent vasodilation compared to a placebo phase. PMID- 20851232 TI - A randomized, double-blind, noninferiority study to compare two regimens of levonorgestrel for emergency contraception in Nigeria. AB - BACKGROUND: Unplanned pregnancies are common in Nigeria. Much of the unplanned pregnancies is due to low contraceptive prevalence and high contraceptive user failure rates. High user failure rates suggest the important role of emergency contraception to prevent unplanned pregnancy. STUDY DESIGN: Randomized, controlled, double-blind, multicenter, noninferiority trial comparing efficacy and side effects of two emergency contraceptive regimens up to 5 days after unprotected intercourse among 3022 Nigerian women: levonorgestrel administered in two doses of 0.75 mg given 12 h apart and levonorgestrel administered in a single dose of 1.5 mg. RESULTS: Efficacy was similar between the treatment groups; post treatment pregnancy proportions were 0.57% in the two-dose regimen vs. 0.64% in the single-dose regimen (risk difference 0.07% (95% CI -0.50 to 0.64). The majority of women menstruated the first day of expected menses and the groups did not differ regarding reported side effects. CONCLUSIONS: This study shows the simplified emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen among Nigerian women. PMID- 20851233 TI - The effects of mifepristone on the expressions of osteopontin, interleukin-6 and leukemia inhibitory factor in the villi of early pregnant women. AB - BACKGROUND: The autocrine, paracrine and hormonal effects of osteopontin (OPN), leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) suggest that these cytokines may play key roles at the maternal-fetal interface. This study was performed to determine the effects of mifepristone on OPN, LIF and IL-6 mRNA and protein expressions in the villi in early pregnancy. STUDY DESIGN: Twenty-nine healthy women seeking termination of pregnancy up to 40 days' gestation were recruited. The study group (n=14) was given 150 mg mifepristone 24 h before vacuum aspiration. The control group (n=15) was not given any treatment prior to vacuum aspiration. Villi were collected, and immunohistochemical analysis and real-time reverse transcription PCR (RT-PCR) were used to detect the locations and the expression levels of OPN, IL-6 and LIF mRNA. RESULTS: In the study group, the expression level of OPN protein in the villous trophoblast and stoma cells was significantly lower (p<.01), while the expression levels of IL-6 and LIF protein were significantly higher than those in the control group (p<.01, p<.05, respectively). Compared with the control group, the relative expression of OPN mRNA was significantly lower (p=.001) and the IL-6 and LIF mRNA expression levels were significantly higher in the study group (p=.003 and p<.001, respectively). CONCLUSION: OPN, IL-6 and LIF may have critical roles in human pregnancy maintenance. These three factors may be involved in the immunological reaction initiated by mifepristone. PMID- 20851235 TI - Re: Better than nothing or savvy risk-reduction practice: the important of withdrawal. PMID- 20851234 TI - Spermatotoxicity of a protein isolated from the root of Achyranthes aspera: a comparative study with gossypol. AB - BACKGROUND: A previous study showed that 50% ethanolic extracts of the roots of Achyranthes aspera possess spermatotoxic effects. STUDY DESIGN: A 58-kDa protein (Ap) was isolated, and its spermatotoxic effects were studied in comparison with gossypol. Ap (25 mg/kg body weight a day) and gossypol (40 mg/kg body weight a day) were administered orally to Swiss male albino mice for 35 days. Sperm motility, sperm count, sperm abnormality, toxicity markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) in the liver and serum, testicular activities of hydroxyl methyl glutaryl CoA reductase (HMG CoA reductase), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), 17beta-hydroxysteroid dehydrogenase(17beta-HSD), glucose-6-phosphate dehydrogenase, cholesterol level and serum testosterone were assayed. Spermicidal action of the proteolytic digests of Ap was also studied in vitro. RESULTS: Treated mice showed significant spermatotoxicity. Significant differences were also observed in the testicular activities of HMG CoA reductase, 3beta-HSD, 17beta-HSD and glucose-6-phosphate dehydrogenase and in the levels of cholesterol and serum testosterone. The nontoxic nature of Ap was indicated by the insignificant alterations in the activities of AST and ALT. Ap possessed spermicidal activity even after proteolysis. CONCLUSION: The 58-kDa protein isolated from A. aspera possesses spermatotoxic effects comparable to gossypol. PMID- 20851236 TI - Update on the cost-effectiveness of contraceptives in the United States. PMID- 20851238 TI - Author response to the commentary "Evaluating research on abortion and mental health". PMID- 20851242 TI - Chronic fatigue syndrome: going viral? PMID- 20851241 TI - Equity as a shared vision for health and development. PMID- 20851243 TI - Tobacco use in the USA. PMID- 20851244 TI - Levels and trends in child mortality, 1990-2009. PMID- 20851245 TI - The benefits of educating women. PMID- 20851246 TI - Japan's new global health policy: 2011-2015. PMID- 20851247 TI - Tuberculosis control is crucial to achieve the MDGs. PMID- 20851249 TI - Jeff Waage--building a coalition of disciplines for global health. PMID- 20851250 TI - Costs of eliminating HIV in South Africa have been underestimated. PMID- 20851251 TI - Misoprostol use in the community to reduce maternal death. PMID- 20851252 TI - Towards better science and programmes. PMID- 20851254 TI - Misoprostol use in the community to reduce maternal death. PMID- 20851255 TI - Triglyceride-mediated pathways and coronary heart disease. PMID- 20851256 TI - Triglyceride-mediated pathways and coronary heart disease. PMID- 20851258 TI - Triglyceride-mediated pathways and coronary heart disease. PMID- 20851259 TI - Drug manufacturing in Africa. PMID- 20851261 TI - Not all renal cysts are created equal. PMID- 20851260 TI - Increased educational attainment and its effect on child mortality in 175 countries between 1970 and 2009: a systematic analysis. AB - BACKGROUND: In addition to the inherent importance of education and its essential role in economic growth, education and health are strongly related. We updated previous systematic assessments of educational attainment, and estimated the contribution of improvements in women's education to reductions in child mortality in the past 40 years. METHODS: We compiled 915 censuses and nationally representative surveys, and estimated mean number of years of education by age and sex. By use of a first-differences model, we investigated the association between child mortality and women's educational attainment, controlling for income per person and HIV seroprevalence. We then computed counterfactual estimates of child mortality for every country year between 1970 and 2009. FINDINGS: The global mean number of years of education increased from 4.7 years (95% uncertainty interval 4.4-5.1) to 8.3 years (8.0-8.6) for men (aged >=25 years) and from 3.5 years (3.2-3.9) to 7.1 years (6.7 -7.5) for women (aged >=25 years). For women of reproductive age (15-44 years) in developing countries, the years of schooling increased from 2.2 years (2.0-2.4) to 7.2 years (6.8-7.6). By 2009, in 87 countries, women (aged 25-34 years) had higher educational attainment than had men (aged 25-34 years). Of 8.2 million fewer deaths in children younger than 5 years between 1970 and 2009, we estimated that 4.2 million (51.2%) could be attributed to increased educational attainment in women of reproductive age. INTERPRETATION: The substantial increase in education, especially of women, and the reversal of the gender gap have important implications not only for health but also for the status and roles of women in society. The continued increase in educational attainment even in some of the poorest countries suggests that rapid progress in terms of Millennium Development Goal 4 might be possible. FUNDING: Bill & Melinda Gates Foundation. PMID- 20851263 TI - Surgery in the multimodality treatment of sinonasal malignancies. PMID- 20851264 TI - Maximizing efficiency and impact in effectiveness and services research. PMID- 20851265 TI - Collaborative depression care: history, evolution and ways to enhance dissemination and sustainability. AB - OBJECTIVE: To describe the history and evolution of the collaborative depression care model and new research aimed at enhancing dissemination. METHOD: Four keynote speakers from the 2009 NIMH Annual Mental Health Services Meeting collaborated in this article in order to describe the history and evolution of collaborative depression care, adaptation of collaborative care to new populations and medical settings, and optimal ways to enhance dissemination of this model. RESULTS: Extensive evidence across 37 randomized trials has shown the effectiveness of collaborative care vs. usual primary care in enhancing quality of depression care and in improving depressive outcomes for up to 2 to 5 years. Collaborative care is currently being disseminated in large health care organizations such as the Veterans Administration and Kaiser Permanente, as well as in fee-for-services systems and federally funded clinic systems of care in multiple states. New adaptations of collaborative care are being tested in pediatric and ob-gyn populations as well as in populations of patients with multiple comorbid medical illnesses. New NIMH-funded research is also testing community-based participatory research approaches to collaborative care to attempt to decrease disparities of care in underserved minority populations. CONCLUSION: Collaborative depression care has extensive research supporting the effectiveness of this model. New research and demonstration projects have focused on adapting this model to new populations and medical settings and on studying ways to optimally disseminate this approach to care, including developing financial models to incentivize dissemination and partnerships with community populations to enhance sustainability and to decrease disparities in quality of mental health care. PMID- 20851266 TI - Treatment research for children and youth exposed to traumatic events: moving beyond efficacy to amp up public health impact. AB - OBJECTIVE: Population-based demands for trauma services have accelerated interest in the rapid deployment of efficacious interventions to address the diverse mental health consequences of traumatic experiences. However, optimal strategies for supporting either implementation or dissemination of trauma-focused interventions within healthcare or mental healthcare systems are underdeveloped. METHODS: This work offers suggestions for adapting treatment research parameters in order to advance the science on the implementable and practical use of trauma focused interventions within a public health framework. To this end, we briefly examine the current status of research evidence in this area and discuss efficacy and effectiveness treatment research parameters with specific attention to the implications for developing the research base on the implementation and dissemination of effective trauma practices for children and adolescents. RESULTS: Examples from current studies are used to identify approaches for developing, testing and enhancing strategies to roll out effective treatment practices in real-world settings. CONCLUSIONS: New approaches that reflect the contexts in which these practices are implemented may enhance the feasibility, acceptability, replicability and sustainability of trauma treatments and services, and thus improve outcomes for a broader population of youth and families. PMID- 20851268 TI - Association between major depression, depressive symptoms and personal income in US adults with diabetes. AB - OBJECTIVE: Although the association between diabetes and depression outcomes has been well studied, very little is known about the association between depression and personal income in adults with diabetes. We examined the association between major depression, number of depressive symptoms and personal income among individuals with diabetes. METHODS: We used the two-stage Heckman procedure to estimate adjusted personal income by major depression status and number of depressive symptoms for 1818 adults with diabetes from the nationally representative 2006 Medical Expenditure Panel Survey. STATA V.10 was used for statistical analysis to account for the complex survey design. RESULTS: In a fully adjusted model with major depression as a binary variable, major depression was associated with $2838 lower personal income. In a separate model with depressive symptoms as a continuous variable, each additional symptom was associated with $1235 lower personal income. Compared with being white/non Hispanic, being black/non-Hispanic (-$4640) was associated with decreased personal income. Compared with excellent health status, fair health status ( $12,172) and poor health status (-$13,835) were associated with lower income. Relative to private insurance, public insurance only (-$8413) and being uninsured (-$9600) were associated with decreased income. CONCLUSIONS: Among adults with diabetes, major depression and depressive symptoms are associated with lower personal income, after adjusting for relevant confounders. This finding suggests that aggressively diagnosing and treating depression as well as keeping people free of depressive symptoms can have huge human capital savings over the employment lifetime of individuals with diabetes and depression. PMID- 20851267 TI - Efficiency in mental health practice and research. AB - Limited financial resources, escalating mental health-related costs and opportunities for capitalizing on advances in health information technologies have brought the theme of efficiency to the forefront of mental health services research and clinical practice. In this introductory article to the journal series stemming from the 20th NIMH Mental Health Services Research Conference, we first delineate the need for a new focus on efficiency in both research and clinical practice. Second, we provide preliminary definitions of efficiency for the field and discuss issues related to measurement. Finally, we explore the interface between efficiency in mental health services research and practice and the NIMH strategic objectives of developing improved interventions for diverse populations and enhancing the public health impact of research. Case examples illustrate how perspectives from dissemination and implementation research may be used to maximize efficiencies in the development and implementation of new service delivery models. Allowing findings from the dissemination and implementation field to permeate and inform clinical practice and research may facilitate more efficient development of interventions and enhance the public health impact of research. PMID- 20851270 TI - Depressive mood and quality of life in functional gastrointestinal disorders: differences between functional dyspepsia, irritable bowel syndrome and overlap syndrome. AB - OBJECTIVE: To investigate the differences in depressive mood and quality of life in patients with between functional dyspepsia (FD), irritable bowel syndrome (IBS), and FD-IBS overlap as diagnosed based on Rome III criteria. METHODS: The subjects completed a questionnaire based on Rome III criteria, the Beck Depressive Inventory (BDI) including Cognitive Depression Index (CDI) for depressive mood evaluation and the 36-item Short Form general health survey (SF 36) for quality of life assessment. Upper gastrointestinal endoscopy and colonoscopy were performed to exclude organic disease. RESULTS: Of 279 subjects, 70 and 124 subjects were diagnosed as FD and IBS, respectively. FD-IBS overlap patients (n=42) and FD alone patients (n=28) showed higher BDI scores than normal subjects (n=127) (P<.001 and P=.02, respectively), whereas that of IBS alone patients (n=82) did not show difference (P=.17). All the SF-36 subscores of the FD-IBS overlap patients were significantly lower than normal subjects (P<.05). CONCLUSIONS: Depressive mood was significantly related to FD and FD-IBS overlap but not to IBS based on Rome III criteria. FD-IBS overlap patients have worse quality of life than FD-alone and IBS-alone patients. PMID- 20851269 TI - Family factors are associated with psychological distress and smoking status in chronic obstructive pulmonary disease. AB - OBJECTIVE: The objective of this study was to test three hypotheses in a sample of individuals with chronic obstructive pulmonary disease (COPD): (1) unsupportive family relationships are associated with psychological distress, (2) psychological distress is associated with smoking status and (3) unsupportive family relationships are indirectly associated with smoking status via psychological distress. METHOD: Cross-sectional data were collected via self report questionnaires completed by 455 individuals with COPD who had at least a 10-pack-year smoking history. The hypotheses were tested with structural equation modeling. RESULTS: All three hypotheses were supported. Unsupportive family relationships were associated with psychological distress (beta=.67, P<.001), psychological distress was associated with smoking status (beta=.40, P<.001), and unsupportive family relationships were indirectly associated with smoking status via psychological distress (beta=.27, P<.001). CONCLUSION: Results of this study suggest that family relationships are an important factor to include in future longitudinal research that attempts to elucidate social and psychological influences on smoking behavior. PMID- 20851271 TI - Psychological and neuroendocrinological characteristics associated with depressive symptoms in breast cancer patients at the initial cancer diagnosis. AB - OBJECTIVE: Breast cancer patients can have biopsychosocial changes induced by distress related to the cancer diagnosis. This study investigated psychological characteristics and hypothalamic-pituitary-adrenal (HPA) axis function associated with depressive symptoms in breast cancer patients at the initial diagnosis. METHOD: Seventy-eight breast cancer patients were enrolled, and 61 patients were included in the final analysis. Patients were evaluated concerning psychological adjustment to cancer diagnosis, self-concept and depressive symptoms and given a dexamethasone suppression test before the main surgical treatment. RESULTS: Self concept scale scores and fighting spirit factor scores of the Korean version of the Mental Adjustment to Cancer (KMAC) scale showed inverse correlations. Anxious preoccupation (AP) factor scores of the KMAC scale positively correlated with depressive symptom scores. Depressive symptom scores were significantly correlated with postdexamethasone serum cortisol levels. In multiple regression analysis, postdexamethasone serum cortisol and the KMAC-AP factor score had significant partial effects in the final model. CONCLUSION: Hypothalamic pituitary-adrenal axis dysfunction and anxious coping to cancer diagnosis may be associated with depressive symptoms in breast cancer patients before treatment. Based on this analysis, we recommend psychotherapeutic interventions to increase adaptive mental coping strategy and to ameliorate psychological distress. Screening for HPA axis dysfunction and provision of depression treatment may prevent breast cancer patients from developing depressive symptoms. PMID- 20851272 TI - Pain complaints in a sample of psychiatric inpatients. AB - OBJECTIVE: We examined the prevalence of pain and pain severity in a sample of psychiatric inpatients. Currently, scant information exists about which patient groups are most affected by pain. METHODS: Pain was assessed in 416 psychiatric inpatients using the brief pain inventory. Patients were characterized by applying DSM-IV criteria and obtaining self-reports of adverse childhood experiences. RESULTS: Of psychiatric inpatients, 31.0% reported having substantial pain. Women with posttraumatic stress disorder (PTSD) had the highest prevalence of substantial pain among all psychiatric inpatients and a significantly higher rate compared to women without PTSD (49% vs. 28%, P=.02). Pain was significantly associated with adverse childhood experiences in both men and women. CONCLUSION: Within a group of psychiatric inpatients, pain is associated with PTSD in women and with adverse childhood experiences in both men and women. Attention should therefore be paid towards such high-risk groups and the consequences that the pain might entail for physical and mental health. PMID- 20851273 TI - Reducing suicides through an alliance against depression? AB - BACKGROUND: Since 2003, the Regensburg Alliance Against Depression, the regional partner of the German Alliance Against Depression, has been conducting a four level intervention program to improve early detection and treatment of patients with depression, which was successfully piloted in the framework of the German Research Network on Depression and Suicidality. METHODS: After 5 years of campaign, the suicide rates before and after the intervention were evaluated in comparison with two control regions and with the German overall rate. FINDINGS: The results show that only the suicide rate in Regensburg fell significantly during the intervention period. The drop in the suicide rate was due to a significant decrease in male suicides. INTERPRETATION: An intensive community based campaign could be effective in lowering suicide rates. Especially, the combination of continuing medical educations (CMEs) for general practitioners focusing on 'male depression' and low-threshold campaigns for the general public seems to reach male depressive patients. PMID- 20851274 TI - Receipt of preventive medical care and medical screening for patients with mental illness: a comparative analysis. AB - BACKGROUND: There has been long-standing concern about the delivery of preventive and screening services to patients with mental illness. OBJECTIVE: We aimed to examine whether the quality of preventive care received by patients with mental health conditions differs from that received by individuals who have no comparable mental disorder. Our hypothesis was that patients with mental illness would be in receipt of lower quality or lower frequency of preventive care. METHOD: Studies that examined the quality of care in those with and without comorbid mental illness were reviewed and comparative data extracted. By using only comparative studies we hope to ascertain whether inequalities in care existed by virtue of psychiatric diagnoses (or closely affiliated factors). RESULTS: We identified 26 studies that examined preventive care in individuals with vs. without psychiatric illness. From these eligible studies, 61 comparisons were documented across 13 health care domains. These included mammography, cervical smears, vaccinations, cholesterol screening, lifestyle counseling, colonoscopy. Twenty-seven comparisons revealed inferior preventive health care in those with mental illness, but 10 suggested superior preventive health care and 24 reached inconclusive findings. Inferior preventive care was most apparent in those with schizophrenia and in relation to osteoporosis screening, blood pressure monitoring, vaccinations, mammography and cholesterol monitoring. CONCLUSIONS: We conclude there is strong evidence to suggest that the quality of preventive and screening services received by patients with mental illness is often lower, but occasionally superior to that received by individuals who have no comparable mental disorder. More work must be done to improve the quality of medical and preventive care for individuals with mental illness. PMID- 20851275 TI - Do the PHQ-8 and the PHQ-2 accurately screen for depressive disorders in a sample of pregnant women? AB - OBJECTIVE: The aim of this study was to assess the psychometric properties of the Patient Health Questionnaire (PHQ)-8, and the PHQ-2, a two-item version of the PHQ, respectively, in pregnancy. These screeners were compared to a structured diagnostic interview in a cohort of pregnant women attending prenatal care. Based upon studies documenting high sensitivity and specificity on the PHQ-8 and PHQ-2 in the general adult population, we hypothesized that both instruments would be effective in this population. METHODS: Two hundred eighteen women, 13 of them depressed, were given the Composite International Diagnostic Interview and the PHQ-8 before 17 weeks of pregnancy. Receiver Operating Characteristic curves determined optimal thresholds and sensitivity and specificity were calculated using both dimensional and categorical approaches. Agreement between the PHQ-2 and PHQ-8 was measured using Cohen's kappa. RESULTS: Optimal cutoffs for the PHQ 8 and PHQ-2 were 11 and 4, respectively. Using these cutoffs, the PHQ-8 had a sensitivity of 77% and a specificity of 62% while the PHQ-2 had a sensitivity of 62% and a specificity of 79%. The categorical method of scoring the PHQ-8 yielded a sensitivity of 54% and a specificity of 84%. CONCLUSIONS: In our sample, the PHQ-8 and PHQ-2 performed almost equally in detecting probable major depressive disorder in a sample of pregnant women. The categorical scoring method for the PHQ-8 had lower sensitivity but slightly higher specificity than the dimensional version. We found the PHQ-8 and PHQ-2 to have lower sensitivity and specificity in our pregnant population as compared to findings in nonpregnant populations; however, characteristics of our sample and choice of diagnostics instrument could explain these discrepant findings. PMID- 20851276 TI - Comparison of patients with and without mental disorders treated for suicide attempts in the emergency departments of four general hospitals in Shenyang, China. AB - OBJECTIVE: Compare the sociodemographic and psychological characteristics of suicide attempters admitted to emergency departments of general hospitals in China that do and do not meet diagnostic criteria for mental disorders. METHODS: The Structured Clinical Interview for DSM-IV, the Suicide Ideation Scale, the Hamilton Depression Rating Scale and a quality of life measure were administered to 239 consecutive suicide attempters who were treated in the emergency departments of four randomly selected general hospitals in Shenyang. RESULTS: Among the enrolled subjects, 166 (69.5%) met diagnostic criteria for a current mental disorder. Among these 166 subjects, 62.7% had mood disorders, 14.5% had anxiety disorders, 10.8% had psychotic disorders and 3.6% had substance use disorders. The 73 suicide attempters without a mental disorder were younger, had higher levels of impulsiveness and were more likely to have ideas about being rescued. Multivariate logistic regression analysis identified the following independent predictors of having a current psychiatric disorder in the suicide attempters: female gender (OR=3.67, 95% CI=1.23-10.91), more than 6 years of formal education (OR=1.19, 95% CI=1.04-1.36), a higher score on the suicide ideation scale (OR=1.01, 95% CI=1.00-1.03), a higher score on Hamilton depression rating scale (OR=1.26, 95% CI=1.16-1.37) and a lower score on the quality of life scale (OR=0.75, 95% CI=0.63-0.90). CONCLUSION: The prevalence of psychiatric disorders in suicide attempters in emergency departments of urban China is lower than that reported in most western countries. Suicide attempters with and without mental illnesses are distinct on a number of important dimensions. Mental health assessment and appropriate discharge planning for patients treated in emergency departments for suicide attempts are crucial components of comprehensive suicide prevention efforts. PMID- 20851277 TI - Successful treatment of comorbid obsessive-compulsive disorder with aripiprazole in three patients with bipolar disorder. AB - Data on the efficacy of aripiprazole in obsessive-compulsive disorder (OCD), compared to data on the efficacy of other atypical antipsychotics, are inadequate. This report presents the successful treatment of concurrent OCD with aripiprazole in three patients with bipolar disorder (BD). Assessments performed with the Yale-Brown Obsessive-Compulsive Scale revealed significant reductions in OCD symptoms. Aripiprazole may be a beneficial psychotropic agent for the treatment of BD and OCD comorbidity, which is an important problem in clinical practice. PMID- 20851278 TI - A case of methamphetamine use disorder treated with the antibiotic drug minocycline. AB - Methamphetamine (METH) use is one of the major public health concerns worldwide. Long-term use of METH induces not only dependence but also psychosis which is associated with METH-induced brain damage, including neuroinflammation produced by activated microglia. We report the case of a female patient whose psychotic symptoms in METH use disorder were successfully improved by anti-inflammatory drug minocycline therapy. Although the precise mechanism(s) underlying the efficacy of minocycline in METH use disorder are currently unclear, minocycline appears to be a good candidate for future investigation clinical trials for medication development in METH using populations. PMID- 20851279 TI - A case of schizophrenia with dysphagia successfully treated by a multidimensional approach. AB - Dysphagia in patients with psychiatric illnesses contributes to morbidities and mortalities. It is, however, an overlooked problem in clinical practice. We report a patient of schizophrenia with dysphagia who was successfully treated using a multidimensional approach, which included medication adjustment, swallowing training and diet modification. PMID- 20851281 TI - Reversible escitalopram-induced hypothyroidism. AB - Some drugs can cause alterations in the concentration of thyroid hormones in blood even without clinical signs of dysfunction or pathology of the thyroid gland. Apart from the well-known relationship between depression and hypothalamic pituitary-thyroid (HPT) axis, and the impact of selective serotonin reuptake inhibitors (SSRIs) on thyroid indices, hypothyroidism is a very rare adverse effect of SSRI treatment. However, the case presented here demonstrates that escitalopram may have the potential to induce hypothyroidism without any significant clinical signs and symptoms. Therefore, the possibility of SSRI induced asymptomatic hypothyroidism presented here may help clinicians in this regard. PMID- 20851280 TI - Anti-retroviral therapy-induced status epilepticus in "pseudo-HIV serodeconversion". AB - Diligence in the interpretation of results is essential as information gained from the psychiatric patient's history might often be restricted. Nonobservance of established guidelines may lead to a wrong diagnosis, induce a false therapy and result in life-threatening situations. Communication errors between hospitals and doctors and uncritical acceptance of prior diagnoses add substantially to this problem. We present a patient with alcohol-related dementia who received anti-retroviral therapy that promoted a non-convulsive status epilepticus. HIV serodeconversion was considered after our laboratory result yielded a HIV negative status. Critical review of previous diagnostic investigations revealed several errors in the diagnosis of HIV infection leading to a "pseudo serodeconversion." Finally, anti-retroviral therapy could be discontinued. PMID- 20851282 TI - Risperidone induced stuttering. AB - Stuttering as a side effect of antipsychotics is rare. There are a few case reports of antipsychotic-induced stuttering, namely, chlorpromazine, levomepromazine, trifluoperazine, fluphenazine, olanzapine and clozapine. Risperidone is commonly used as an atypical antipsychotic. It is licensed for both acute and chronic psychosis and mania. There is only one documented case report mentioned on risperidone induced stuttering. One case report of risperidone-induced stuttering is now described. Stuttering is a rare side effect and requires a high index of suspicion for diagnosis. Further study and research to identify the neurophysiological and psychological processes behind adult onset stuttering and identification of the processes involved in risperidone induced stuttering would help our understanding further. PMID- 20851283 TI - Drug interaction between carbapenems and extended-release divalproex sodium in a patient with schizoaffective disorder. AB - BACKGROUND: Clinicians prescribing divalproex sodium (DVX) are well aware of its potential to cause a drug-drug interaction. One specific interaction occurs between the carbapenem antibiotics and DVX resulting in decreased valproic acid (VPA) levels immediately following the initiation of this antibiotic class. OBJECTIVE/METHOD: We describe a case of a 46 year-old Caucasian male who had an undetectable VPA level following treatment with carbapenems. RESULTS: On admission the patient's VPA level was 115 MUg/ml; however, a routine VPA level on day 19 of his hospitalization returned a value of 16 MUg/ml. At this point, he had received a total of 15 days of carbapenem antibiotics for treatment of lower leg cellulitis. His DVX dose was increased to a maximum of 6g daily, twice his home dose, but it did not produce a therapeutic VPA concentration. The patient was lost to follow-up before an outpatient VPA level was drawn. CONCLUSION: Our case report is the first to document this drug-drug interaction in a patient diagnosed with schizoaffective disorder, bipolar type. PMID- 20851285 TI - Treatment-resistant depression prior to the diagnosis of cryptococcal meningitis: a case report. AB - Comorbidity of chronic infectious disorders is one of the common causes of treatment-resistant depression. Depression may alter some aspects of immunity that can contribute to the development of infection. Here we describe an elderly male with treatment-resistant depression. Ten months after antidepressants were administered, he was found to have cryptococcal meningitis. After successful treatment of the central nervous system infection, his depressive symptoms improved apparently. A possible interaction between depression and cellular immunity was discussed. Physicians should be cautious about the risk of opportunistic infection in patients with depression, especially in immunocompromised condition. PMID- 20851284 TI - Multiple pulmonary thromboembolism and severe depression. AB - INTRODUCTION: Depression is known to have a bidirectional relationship with cardiovascular disease. Severe major depression associated with psychomotor retardation and immobility can be a risk factor for pulmonary embolism; the reverse pathway has not been reported. CASE REPORT: We report a case of a 61-year old man diagnosed with multiple pulmonary thromboembolism finally attributed to a right pulmonary artery intraluminal sarcoma. One month after the onset of presenting symptoms, the patient suddenly developed an episode of severe, melancholic depression, which remitted in six weeks under treatment with venlafaxine 225 mg/day. DISCUSSION: Pathophysiological mechanisms implicated in the development of depression in our patient might resemble those postulated for post-myocardial infarction depression; in line with the "vascular depression" hypothesis, cerebral damage in the limbic circuitry caused by transient hypoxia, an inflammatory response or both may have contributed. CONCLUSION: Multiple pulmonary thromboembolism seems to have a bidirectional relationship with major depression, in a similar way as myocardial infarction does. PMID- 20851286 TI - Effects of exposure to a 128-mT static magnetic field on glucose and lipid metabolism in serum and skeletal muscle of rats. AB - BACKGROUND AND AIMS: Increasing environmental pollution may participate in the growing incidence of metabolic disorders. Static magnetic fields (SMFs) are an emerging environmental health issue due to increased exposure in residential and commercial areas; however, their metabolic effects in serum and skeletal muscle are largely unknown. The aim of this study was to investigate the effect of SMF exposure on glucose and lipid metabolism in serum and skeletal muscles of rats. METHODS: Twelve 6- to 7-week-old male Wistar rats were randomly divided into two groups: rats exposed to 128 mT SMF and sham-exposed rats. This moderate-intensity exposure was performed for 1 h/day for 15 consecutive days. RESULTS: Animals exposed to 128 mT SMF displayed significant changes in both glucose (i.e., increases in plasma glucose and lactate and decrease in plasma insulin levels) and lipid (i.e., increases in plasma glycerol, cholesterol and phospholipids but not triglyceride levels) metabolism. During intraperitoneal glucose tolerance tests, SMF-exposed rats displayed significantly higher hyperglycemia compared to sham-exposed rats despite similar insulin levels in both groups. In tissues, SMF exposure induced significant alterations in enzyme activities only in glycolytic muscles and caused a significant decrease in quadriceps and liver glycogen content together with increased phospholipid levels. CONCLUSIONS: This study provides evidence that subacute SMF exposure of moderate intensity induces important alterations of glucose and lipid metabolisms, which deserve further investigations to evaluate long-term consequences. PMID- 20851287 TI - Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. AB - BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Aberrant activation of sonic hedgehog (Shh) signaling pathway plays important roles in tumorigenesis and progression of several tumors. Cyclopamine, an important inhibitor of Shh signaling pathway, can induce cell apoptosis. However, the mechanisms underlying cyclopamine-induced apoptosis are not well understood. The aim of this study is to determine the expression of the Shh signaling pathway components in HCC and to investigate the mechanisms underlying cyclopamine-induced apoptosis in HCC cells. METHODS: Shh signaling components (Shh, Ptch, Smo and Gli-1) expression levels were evaluated by immunohistochemistry on tissue microarrays containing 98 HCCs with paired adjacent noncancerous liver tissues. The relationships between sonic hedgehog signal pathway and clinicopathological factors were analyzed in HCC. Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptosis was detected by flow cytometry. mRNA and protein levels were analyzed by RT-PCR and Western blot, respectively. RESULTS: Shh, Ptch, Smo and Gli-1 were overexpressed in HCC tissues compared with paired adjacent noncancerous liver tissue. Activated Shh signaling pathway was associated with tumor size, capsular invasion and vascular invasion in HCC. Cyclopamine remarkably decreased cell viability, induced apoptosis and downregulated Bcl-2 expression in HCC cells. CONCLUSIONS: Shh signaling pathway plays an important role in HCC tumorigenesis and progression, indicating that Shh signaling pathway is a potential therapeutic target for HCC. Cyclopamine induces apoptosis through downregulating Bcl-2 in HCC. PMID- 20851288 TI - Selected South African honeys and their extracts possess in vitro anti Helicobacter pylori activity. AB - BACKGROUND AND AIMS: Eradication of Helicobacter pylori by triple therapy often results in a failure rate of 10-20%; thus, there is a need to seek alternative treatments. The aim of this study was to screen selected South African honeys for their anti-H. pylori activity, to extract the antimicrobial components using organic solvents and to determine the minimum inhibitory concentrations (MICs) of the extracts. METHODS: Three locally produced honeys from different regions in South Africa were screened for anti-H. pylori activity at four different concentrations using the agar well diffusion technique. Subsequently, Pure honey was extracted using n-hexane, diethyl ether, chloroform and ethyl acetate; extracts were also examined for anti-H. pylori activity by agar well diffusion method. The MICs of the three most active extracts were determined both by visual inspection and spectrophotometric analysis at 620 nm using the broth microdilution method. The results were analyzed by one-way ANOVA at 95% significance level. RESULTS: All honeys demonstrated anti-H. pylori activity and were most active at 75% v/v. The positive control (clarithromycin) recorded a zone diameter of 18.0 +/- 7.4 mm not significantly different (p >0.05) from honeys at 75% v/v and solvent extracts. Chloroform extract recorded the lowest MIC(95) values that ranged from 0.156-5% v/v confirming this extract to be the most active. CONCLUSION: All honeys demonstrated anti-H. pylori activity at concentrations >=10%, as did the solvent extracts. Therefore, these honeys and solvent extracts possess potential compounds with therapeutic activity that could be further exploited as lead molecules in the treatment of H. pylori infections. PMID- 20851289 TI - Effects of orally administered bacteria carrying HIF-1alpha gene in an experimental model of intestinal ischemia. AB - BACKGROUND AND AIMS: Bactofection is delivery of therapeutic genes into target cells using bacteria penetrating the target cell membrane and releasing the gene into the cell. Hypoxia-inducible factor 1alpha (HIF-1alpha) represents a potential therapeutic gene to be used for gene delivery in ischemic diseases. The aim of this study was to prove the effects of bacteria-mediated transfer of hypoxia-inducible factor 1alpha (HIF-1alpha) in an experimental model of intestinal ischemia in rats. METHODS: Male Wistar rats with a surgically induced ischemia of colon (cecum) or sham-operated rats were treated by per os application of E. coli carrying therapeutic genes. After 1 week, samples were taken for measurement of oxidative stress markers and expression analyses. RESULTS: According to our observation, there were no signs or symptoms of ongoing ischemia in gastrointestinal tissue. Interestingly, all experimental groups treated by bacteria, regardless of their ability to invade cells or the presence of HIF-1alpha gene, showed decreased levels of vascular endothelial growth factor (VEGF) compared to control groups. Similarly, all treatment groups showed increased hematocrit. CONCLUSIONS: We conclude ineffectiveness of the bacterial gene delivery system. However, the effect of bacteria themselves was obvious. HIF 1 can be activated hypoxia-independently by the action of pathogenic bacteria in the rat intestine. We hypothesize that therapeutic bacterial strain used may compete with siderophore-expressing bacteria present in the gut of rats to force them out and prevent their ability to activate HIF-1 in a hypoxia-independent manner. This phenomenon should be analyzed in detail in further studies. PMID- 20851290 TI - Assessment of CXCL12 (SDF-1alpha) polymorphisms and its serum level in posttransfusion occult HBV-infected patients in Southeastern Iran. AB - BACKGROUND: Occult hepatitis B infection (OBI) is defined as a form of hepatitis in which, despite absence of detectable HBsAg, HBV-DNA is present in peripheral blood of patients. The main aim of this study was to determine an association between polymorphisms in +801 of CXCL12 (SDF-1alpha) and its serum level in OBI patients. METHODS: In this experimental study, plasma samples of 3700 blood donors were tested for HBsAg and anti-HBc by ELISA. The HBsAg(-)/anti-HBc(+) samples were selected and screened for HBV-DNA by PCR. HBV-DNA positive samples assigned as OBI cases and PCR-RFLP techniques were performed to examine the CXCL12 (SDF-1alpha) polymorphisms. The serum level of CXCL12 (SDF-1alpha) was also analyzed by ELISA. RESULTS: Of 3700 blood samples, 352 (9.5%) were HBsAg/anti-HBc(+) and HBV-DNA was detected in 57/352 (16.1%) of HBsAg(-)/anti HBc(+) samples. Our results showed a significant difference in genotypes and alleles of +801 region of CXCL12 (SDF-1alpha). However, the serum level of CXCL12 (SDF-1alpha) was decreased in OBI patients but was not significant. Our results also showed that the alleles of +801 region of CXCL12 (SDF-1alpha) were also not associated with serum level of the chemokine. CONCLUSIONS: The polymorphisms in +801 region of CXCL12 (SDF-1alpha) are possibly related to OBI. PMID- 20851291 TI - Association between angiotensin II type 1 receptor gene polymorphism and metabolic syndrome in a young female Iranian population. AB - BACKGROUND AND AIMS: The overall prevalence of obesity and metabolic syndrome (MetS) is increasing among children and adolescents and can predispose to type II diabetes mellitus and cardiovascular disease. There are reported associations between an angiotensin II type I receptor gene polymorphism (AT(1)R/A1166C) with hypertension, myocardial infarction, insulin resistance and cardiovascular disease risk. In the present study, we aimed to investigate whether the AT(1)R/A1166C polymorphism was associated with MetS among adolescent Iranian girls. METHODS: A total of 350 adolescent girls aged 15-17 years from high schools and different educational zones of Mashhad city participated in this population-based, genetic association study. Of these individuals, 101 patients had MetS (defined by the NCEP-ATP III criteria); the remaining 249 age-matched girls were considered as the control group. All subjects were genotyped for the AT(1)R/A1166C polymorphism using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Frequencies of the AA, AC and CC genotypes were 164 (65.9%), 80 (32.1%) and 5 (2.0%) in the control group and 79 (78.2%), 20 (19.8%) and 2 (2.0%) in patients, which were not consistent with the Hardy-Weinberg equilibrium (p <0.05 and p <0.001, respectively). Frequency of the AT(1)R C allele was found to be significantly lower in patients compared with controls (p <0.05). CONCLUSIONS: Our findings suggested that the 1166C allele of AT(1)R gene may be associated with a decreased risk of MetS in adolescent Iranian females. PMID- 20851292 TI - Polymorphisms of superoxide dismutase, glutathione peroxidase and catalase genes in patients with post-transplant diabetes mellitus. AB - BACKGROUND AND AIMS: Post-transplant diabetes mellitus (PTDM) is a metabolic disorder that develops in response to a relative insulin deficiency in patients after organ transplantation treated with immunosuppressive drugs. Several studies have suggested that oxidative stress may be associated with diabetes and its complications. The aim of this study was to examine the association of polymorphisms in superoxide dismutase, catalase and glutathione peroxidase genes with PTDM in patients after kidney transplantation. METHODS: The study included 159 patients receiving kidney transplants. PTDM was diagnosed in 21 patients. RESULTS: Analyzing the C599T (Pro200Leu) polymorphism in the GPX1 gene PTDM was diagnosed in 8.45% of patients with CC genotype, 13.43% with CT and in 28.57% with TT. Allele T was significantly more frequent among patients with PTDM compared to patients without PTDM (OR = 2.14, 95% CI = 1.11-4.12, p = 0.024). There were no associations between SOD1, SOD2 and CAT polymorphisms and PTDM. CONCLUSIONS: The present results suggest that Pro200Leu polymorphism of the GPX1 gene may be associated with the risk of PTDM development in renal graft recipients. PMID- 20851293 TI - Is carnosinase 1 gene (CNDP1) polymorphism associated with chronic kidney disease progression in children and young adults? results of a family-based study. AB - BACKGROUND AND AIMS: The aim of the study was to investigate the role of the D18S880 microsatellite polymorphism of carnosinase 1 gene (CNDP1), which encodes serum carnosinase, in the development and progression of chronic kidney disease (CKD) of nondiabetic etiology. METHODS: We applied two different approaches. First, a family-based study was carried out comprising 109 patients with CKD caused by chronic glomerulonephritis (GN) or tubulointerstitial nephritis (IN) and their 218 healthy parents using the transmission/disequilibrium test. CNDP1 polymorphism and serum carnosinase activity were determined in all subjects. Serum carnosinase activity was also measured in 20 healthy controls. Second, we performed a case-control study to determine whether polymorphism in CNDP1 gene and other factors influence the progression of renal impairment. RESULTS: Preferential transmission of the 5 allele of CNDP1 polymorphism from heterozygous parents to their offspring with CKD caused by GN was found. There was no association between that polymorphism and the loss of glomerular filtration rate. Serum carnosinase activity was significantly higher in CKD patients than in controls. CONCLUSION: This study found no association between the CNDP1 polymorphism and increased risk for development of CKD caused by IN. However, the polymorphism can influence CKD caused by GN. The progression rate of CKD does not depend on this polymorphism. The increased serum carnosinase activity in the CKD patients may suggest its role in the pathomechanism of the disease. PMID- 20851294 TI - Six-minute walk distance predicts 30-day readmission in hospitalized heart failure patients. AB - BACKGROUND AND AIMS: Identification of patients with heart failure (HF) at high risk of hospital readmission is critical to refine processes for reducing readmission rates. We hypothesized that patients with higher 6-min walk (6MW) distance at the time of hospital discharge are at low risk for early readmission. METHODS: We prospectively enrolled 265 patients admitted with HF and left ventricular systolic dysfunction. 6MW testing was administered prior to discharge. Multivariate logistic regression analysis was performed to determine the relationship between 6MW distance and 30-day readmission, stratifying by <=400 m and >400 m. RESULTS: Two hundred ten patients underwent 6MW testing prior to discharge. Patients with 6MW >400 m had a 30-day readmission rate of 15.9%, whereas patients with 6MW <=400 m had a 30-day readmission rate of 30.3% (p = 0.016). Patients requiring readmission within 30 days had a median 6MW of 30 m, whereas patients not requiring readmission at 30 days walked 338 m (p = 0.012). 6MW distance predicted freedom from readmission at 30 days (OR: 0.435, 95% CI 0.21-0.9, p = 0.025). Other independent predictors of 30-day readmission included history of gout (0.117, 0.021-0.637, p = 0.013), use of angiotensin-converting enzyme inhibitor or accepted alternative (0.372, 0.169-0.820, p = 0.014) and blood urea nitrogen level (1.019, 1.003-1.035, p = 0.020). CONCLUSIONS: Low 6MW distance predicts early hospital readmission in patients with HF. Programs seeking to produce systems that are effective in reducing early hospital readmission may desire to incorporate 6MW testing during HF hospital care. PMID- 20851295 TI - Folic Acid and vitamin B12 supplementation improves coronary flow reserve in elderly subjects with vitamin B12 deficiency. AB - BACKGROUND AND AIMS: Major cardiovascular risk factors including hyperhomocysteinemia are frequently associated with decreased coronary flow reserve (CFR), an important physiological parameter of the coronary circulation. This study was designed to determine whether folate (5 mg) and vitamin B12 (500 MUg) supplementation in elderly patients with vitamin B12 deficiency improved CFR, while reducing homocysteine levels. METHODS: Forty-four patients aged >65 years showing serum vitamin B12 concentrations <180 mg/dL were randomized to take either oral folate (5 mg) plus vitamin B12 (500 MUg) supplementation (n = 24) or placebo (n = 20) for 8 weeks. The study course consisted of two visits: visit 1 (pretreatment) included the baseline assessment of laboratory profile and CFR values with trans-thoracic Doppler echocardiography. Visit 2 was scheduled 8 weeks later to repeat CFR and laboratory tests after therapy. RESULTS: In the treatment arm, oral supplementation with folate and vitamin B12 significantly improved total cholesterol, serum folate, serum vitamin B12, homocysteine, and insulin resistance. At 8 weeks, the treatment group had a significant increase from baseline in CFR values (baseline: 1.7 +/- 0.2; postttreatment: 2.1 +/- 0.2, p <0.001) that was not seen in the placebo group (baseline: 1.6 +/- 0.2; posttreatment: 1.6 +/- 0.2; P = ns). CONCLUSIONS: In this study of elderly subjects with vitamin B12 deficiency, supplementation with folate and vitamin B12 was associated with a significant improvement in CFR values. PMID- 20851296 TI - Typical leptin fall is mitigated by breastfeeding in female infants. AB - BACKGROUND AND AIMS: Programming of the nutritional and hormonal status of offspring occurs mostly during the gestational and breastfeeding periods. Several studies have reported that breastfed children are more protected from developing obesity in adult life; however, the mechanism that explains this phenomenon is not clear. We undertook this study to evaluate if weight, gender or feeding mode (breastfed or formula-fed) affects leptin levels (during the first 3 months after birth) in a cohort of term newborns, the Breastfeeding Cohort. METHODS: A cohort of 99 term newborns divided into four groups according to gender and feeding type: breastfed female, formula-fed female, breastfed male and formula-fed male were studied. Feeding mode was freely chosen by the parents. Blood sampling for glucose, insulin and leptin was performed at birth and after 3 months. RESULTS: No differences were found among the groups for maternal age, marital status, educational and socioeconomic level, maternal occupation, and prenatal care. No statistically significant differences were found for weight, length or body mass index at birth among the four groups. There were differences in leptin with a higher level in girls (0.907 +/- 0.332) than boys (0.663 +/- 0.351; p <0.001) at birth and at 3 months (0.618 +/- 0.225, 0.464 +/- 0.195; p <0.0001). A decrease in leptin levels from birth to 3 months was observed in all groups with the exception of breastfed females (0.849 +/- 0.352-0.672 +/- 0.222, p = NS). CONCLUSIONS: In our study, breastfed females were protected from this fall in serum leptin levels. Our findings support further studies on the long-term effects of breastfeeding. PMID- 20851297 TI - G1359A polymorphism in the cannabinoid receptor-1 gene is associated with metabolic syndrome in the Chinese Han population. AB - BACKGROUND AND AIMS: Recent studies suggest that endocannabinoids modulate food intake and lipogenesis through cannabinoid receptor-1 (CNR1). This study aims to determine the association between G1359A polymorphism of CNR1 and metabolic syndrome (MetS) in the Chinese Han population. METHODS: A total of 382 subjects at risk for MetS and 136 healthy subjects from Tianjin, China were genotyped for the G1359A polymorphism of CNR1 using TaqMan assay. Anthropometric measurements and serum analyses were done for body mass index (BMI), waist circumference, blood pressure, serum triglycerides (TG), serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and plasma insulin levels. RESULTS: GG genotype of CNR1 has a higher incidence in MetS subjects than in control subjects. Logistic regression analysis shows that the GG genotype was significantly associated with the increased risk of developing MetS (OR 2.204, 95% CI 1.277-3.803, p = 0.005). Compared with CNR1 GG genotype in MetS subjects, CNR1 GA and AA genotypes in subjects with MetS had relatively lower levels of BMI, waist circumference, homeostasis model assessment of insulin resistance (HOMA-IR) and TG. CONCLUSIONS: Results suggest that the G1359A polymorphism of the CNR1 gene may contribute to MetS susceptibility in the Chinese Han population. PMID- 20851299 TI - G6PD Deficiency as a predisposing factor for attention deficit/hyperactivity disorder: a hypothesis. PMID- 20851298 TI - Quantitative assessment of the effect of hepatic lipase gene polymorphism on the risk of coronary heart disease. AB - BACKGROUND AND AIMS: The human hepatic lipase (LIPC) is a glycoprotein member of the lipase superfamily that has attracted considerable attention as a candidate gene for coronary heart disease (CHD) based on its enzyme function as a key factor in lipoprotein catabolism pathways. In the past decade, a number of case control studies have been carried out to investigate the relationship between the LIPC polymorphisms and CHD. However, studies on the association between LIPC polymorphisms and CHD remain conflicting. METHODS: To derive a more precise estimation of the relationship, a meta-analysis of 11,906 cases and 13,273 controls from 18 published case-control studies was performed. RESULTS: Overall, the summary odds ratio of CHD was 0.87 (95% confidence interval: 0.66-1.15) and 1.03 (95% confidence interval: 0.98-1.07) for LIPC -250A and -514T alleles, respectively. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, source of controls, no evidence of any gene disease association was obtained. CONCLUSIONS: Our result suggest that the G 250A, C-514T polymorphisms of LIPC gene are not associated with CHD susceptibility. PMID- 20851300 TI - Decreased 1-25 dihydroxyvitamin D(3) concentration in peripheral blood serum of patients with thyroid cancer. PMID- 20851302 TI - Neurocysticercosis: changes after 25 years of medical therapy. PMID- 20851304 TI - Polyphenol content and health benefits of raisins. AB - The health benefits of grapes and wine have been studied and publicized extensively, but dried grapes (raisins, including "sultanas" and "currants") have received comparatively little attention. The purpose of the review was to summarize the polyphenol, phenolic acid, and tannin (PPT) composition of raisins; predict the likely bioavailability of the component PPT; and summarize the results of human intervention studies involving raisins. The most abundant PPTs are the flavonols, quercetin and kaempferol, and the phenolic acids, caftaric and coutaric acid. On a wet weight basis, some PPTs, such as protocatechuic and oxidized cinnamic acids, are present at a higher level in raisins compared to grapes. In human intervention studies, raisins can lower the postprandial insulin response, modulate sugar absorption (glycemic index), affect certain oxidative biomarkers, and promote satiety via leptin and ghrelin. However, only limited numbers of studies have been performed, and it is not clear to what extent the PPT component is responsible for any effects. More research is required to establish the bioavailability and health effects of the PPT component of raisins, the effects of raisins on health biomarkers in vivo in humans, and how these effects compare to grapes and wine. PMID- 20851305 TI - Reproducibility and relative validity of a food frequency questionnaire to assess intake of dietary flavonol and flavone in Chinese university campus population. AB - Epidemiologic studies have shown that populations that consume more fruits and vegetables have lower incidences of some diseases. These health effects have largely been attributed to flavonoid intake and bioavailability. However, no published data on the estimated flavonol and flavone intake of Chinese adults are currently available. Considering reports that food frequency questionnaires (FFQs) have been shown to provide good measurements of energy, macronutrient, and micronutrient intakes, we hypothesized that FFQ may be used to estimate intake of dietary flavonol and flavone. The two 7-day 24-hour dietary recalls (24-HDRs) and plasma levels were used as reference criteria. A total of 128 subjects each completed two 7-day 24-HDR and 2 FFQs, and 92 subjects donated 2 plasma samples. Pearson correlation coefficients and the agreement of quartile categorization between the FFQ and each reference instrument were conducted. Pearson correlation coefficients between 2 FFQs were 0.62 for flavonol and 0.65 for flavone and ranged from 0.48 (quercetin) to 0.63 (luteolin) (all P < .05). Pearson correlation coefficients between FFQ and 24-HDR were 0.62 for flavonol and 0.68 for flavone and ranged from 0.36 (quercetin) to 0.63 (luteolin) (all P < .05). Between the FFQ and plasma samples, Pearson correlation coefficients were 0.52 for flavonol and 0.41 for flavone and ranged from 0.32 (quercetin) to 0.44 (kaempferol) (all P < .05). The complete and partial agreement by quartiles ranged from 70% to 89%. The findings indicate that administering FFQ is a reliable and accurate method of assessing dietary intake of flavonol and flavone. PMID- 20851306 TI - Poor diet quality and food habits are related to impaired nutritional status in 13- to 18-year-old adolescents in Jeddah. AB - In recent decades, diets have changed rapidly in the Kingdom of Saudi Arabia (KSA) because the Western diet is replacing the traditional Arabic diet. This has resulted in an alarming increase in the number of overweight and obese children and adolescents in KSA. It is well documented that lifestyle is strongly associated with the development of obesity. Nevertheless, this remains to be demonstrated in adolescents from a rapidly developing country in the Middle East such as Saudi Arabia. This study tested the hypothesis that the new current dietary habits are related to the increase in overweight and obese Saudi Arabian adolescents. In 2006, a cross-sectional study was conducted among 239 adolescents (13-18 years old) who were selected by cluster sampling from schools in Jeddah, KSA. The nutritional status was assessed by anthropometric and biochemical parameters at the Saudi German Hospitals Group, Jeddah. Dietary habits were evaluated by a 3-day dietary recall (food diary) and a food frequency questionnaire. The mean age of the participants was 15.5 +/- 2.5 years. The mean body mass index was 27.43 +/- 4.61 kg/m(2). A total of 44.6% of the adolescents were overweight, and 56.6%, 30.5%, and 13.0% of energy was derived from carbohydrates, fats, and proteins, respectively. Compared with the Dietary Reference Intake, carbohydrate and fat intakes were higher, and calcium, iron, and zinc intakes were lower. Higher cholesterol and lower hemoglobin levels were found in 30.5% and 53.6% of the adolescents, respectively. In summary, increased weight status of 13- to 18-year-old Saudi adolescents was related to their inadequate dietary habits. This indicates the importance of rapidly promoting a healthier lifestyle among Saudi Arabian adolescents. PMID- 20851307 TI - The content of docosahexaenoic acid in serum phospholipid is inversely correlated with plasma homocysteine levels in patients with end-stage renal disease. AB - Patients with end-stage renal disease (ESRD) have a high morbidity and mortality from cardiovascular disease. An elevated homocysteine level is an independent predictor of cardiovascular events in patients with ESRD. Interestingly, some studies have found an inverse relationship between the content of marine n-3 polyunsaturated fatty acids (PUFAs) and homocysteine levels, but data are ambiguous. In patients with ESRD, we hypothesized that serum phospholipid n-3 PUFA content would inversely correlate with homocysteine levels in plasma and that supplementation with n-3 PUFA would reduce plasma homocysteine levels. In a double-blind, randomized, controlled design, 206 patients with documented cardiovascular disease and treated with hemodialysis for a minimum of 6 months were randomized to treatment with daily supplement of 1.7 g n-3 PUFA or placebo (olive oil) for 3 months. The content of n-3 PUFA in serum phospholipids and homocysteine levels in plasma were measured at baseline and after 3 months of intervention. A dietary questionnaire was filled out at baseline, and study participants were divided into groups of low, intermediate, and high fish intake. Docosahexaenoic acid was inversely correlated with homocysteine at baseline (coefficient = -0.161; P = .03). Homocysteine was not related to self-reported fish intake. Supplementation with n-3 PUFA did not reduce homocysteine levels compared with placebo (mean +/- SD difference, -0.3 +/- 7.8 versus 0.3 +/- 7.1; P = .58). The content of docosahexaenoic acid in serum phospholipids is inversely correlated with plasma homocysteine levels, and supplementation with n-3 PUFA does not reduce homocysteine levels in patients with ESRD. PMID- 20851308 TI - Randomized, controlled trial promotes physical activity and reduces consumption of sweets and sodium among overweight and obese adults. AB - The present study sought to assess the impact of an intervention to reduce weight and control risk factors of noncommunicable chronic diseases in overweight or obese adults who are users of primary and secondary healthcare units of the public health system of Pelotas, Brazil. We hypothesized that individuals who received an educational intervention regarding how to lose weight and prevent other noncommunicable chronic disease risk factors through nutrition would lose weight and acquire active habits during leisure time more frequently than individuals under regular care. Two hundred forty-one participants from the Nutrition Outpatient Clinic of the Medical Teaching Hospital of the Federal University of Pelotas, Brazil, aged 20 years or older and classified as overweight or obese were randomly allocated to either the intervention group (IG; n = 120) or control group (CG; n = 121). The IG received individualized nutritional care for 6 months, and the CG received individualized usual care of the health services. Intention-to-treat analyses showed that at 6 months, mean fasting glycemia and daily consumption of sweet foods and sodium were reduced, and the time spent on physical leisure activity was increased in IG. Analysis of adherence to the protocol of the study revealed that individuals from IG had lost more in body weight, waist circumference, and fasting glucose compared to the CG. Leisure time physical activity increased in IG. Individuals adhered equally to the dietetic recommendations, irrespective of the nutrition approach that was used. PMID- 20851309 TI - Validity and reliability of an omega-3 fatty acid food frequency questionnaire for first-generation Midwestern Latinas. AB - This study tested the hypothesis that a culturally developed omega-3 (n-3) fatty acid food frequency questionnaire (FFQ) could be an accurate instrument to capture n-3 fatty acid food intakes of first-generation Midwestern Latinas. The goal of the study was to assess validity and test-retest reliability of an FFQ to estimate total n-3 fatty acid (total n-3), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) intakes. An n-3 FFQ was developed and pilot tested. Two FFQs and 3 nonconsecutive 24-hour recalls were collected from 162 participants. Pearson correlation and paired t test were used to test the hypothesis. Correlation of the 2 FFQs was 0.71 for total n-3, 0.65 for ALA, 0.74 for EPA, and 0.54 for DHA (P < .01). The means of the 2 FFQs and of the 24-hour recalls were not significantly different for total n-3 and ALA (P > .05), but were significantly different for EPA and DHA. The n-3 FFQ had acceptable reliability, validated only total n-3 and ALA, and provided relevant findings about the n-3 eating habits of Midwestern Latinas. PMID- 20851310 TI - Milk-derived proteins and minerals alter serum osteocalcin in prepubertal boys after 7 days. AB - We have previously shown that at equal protein content, milk, but not meat, decreased bone turnover in boys. This suggested that milk-derived components are important for bone metabolism. In the present study, we hypothesized that milk derived proteins (whey and casein) affect bone turnover during growth depending on the content of milk minerals (calcium and phosphorus). This was a randomized, parallel, double-blind study. Eight-year-old boys (n = 57) received 1 of 4 milk drinks: whey protein with low or high content of minerals, or casein protein with low or high content of minerals. The amount of whey and casein was identical to their content in 1.5 L of milk. We measured serum osteocalcin (sOC), bone specific alkaline phosphatase, and C-terminal telopeptides of type I collagen (immunoassay) and estimated dietary intake (3-day weighed food record) at baseline and after 7 days. Only sOC was significantly affected by the treatments (P < .05). There was a significant interaction between milk-derived proteins and minerals with regard to sOC (P = .01). The intake of milk drinks containing whey increased sOC at the low content of minerals, whereas it decreased sOC at the high content of minerals (P < .05). In contrast, milk drinks containing casein increased sOC both at the low and at the high contents of minerals. In conclusion, whey and casein (corresponding to their content in 1.5 L of milk) differently affect sOC in 8-year-old boys depending on the content of milk minerals, but do not seem to affect other markers for bone turnover. PMID- 20851311 TI - No meaningful association of neighborhood food store availability with dietary intake, body mass index, or waist circumference in young Japanese women. AB - The affordability of food is considered as an important factor influencing people's diet and hence health status. The objective of this cross-sectional study was to test the hypothesis that neighborhood food store availability is associated with some aspects of dietary intake and thus possibly with body mass index (BMI) and waist circumference in young Japanese women. Subjects were 989 female Japanese dietetic students 18 to 22 years of age. Neighborhood food store availability was defined as the number of food stores within a 0.5-mile (0.8-km) radius of residence (meat stores, fish stores, fruit and vegetable stores, confectionery stores/bakeries, rice stores, convenience stores, and supermarkets/grocery stores). Dietary intake was estimated using a validated, comprehensive self-administered diet history questionnaire. No association was seen between any measure of neighborhood food store availability and dietary intake, except for a positive association between confectionery and bread availability (based on confectionery stores/bakeries, convenience stores, and supermarkets/grocery stores) and intake of these items (P for trend = .02). Further, no association was seen for BMI or waist circumference, except for an inverse relationship between availability of convenience stores and BMI and a positive relationship between store availability for meat (meat stores and supermarkets/grocery stores) and fish (fish stores and supermarkets/grocery stores) and waist circumference. In conclusion, this study of young Japanese women found no meaningful association between neighborhood food store availability and dietary intake, BMI, or waist circumference, with the exception of a positive relationship between availability and intake for confectionery and bread. PMID- 20851312 TI - Serum selenium levels in cirrhotic patients are not influenced by the disease severity index. AB - Selenium (Se) is an antioxidant element that protects against cellular damage by reactive oxygen species. Therefore, total serum Se concentration may reflect protection during the development of cirrhosis, an oxidative stress-related disease. We hypothesized that serum Se levels are diminished in cirrhotic patients due to their enhanced oxidative stress, and serum Se levels are reduced the most in patients with the highest severity of cirrhosis. A case-control study was performed to determine whether cirrhosis is associated with changes in serum Se levels. Blood samples from 30 healthy controls and 93 cirrhotic patients were analyzed for total serum Se by hydride generation atomic absorption spectrometry. The Child-Pugh index score was used to evaluate the severity of liver disease. The mean serum Se concentration was significantly lower in patients vs controls (0.721 +/- 0.239 vs 0.926 +/- 0.241 MUmol/L; P = .001). Mean serum Se levels were not significantly lower in patients with higher severity of cirrhosis (0.691 +/- 0.229 vs 0.755 +/- 0.255 MUmol/L; P = .144). A positive and significant correlation was found between age and serum Se levels in patients (r = 0.277, P = .007). Patients showed significant sex differences in serum Se level (higher in male) and severity index (higher in female). The significantly decreased serum Se level in patients indicates that the Se component of the antioxidant system is severely impaired in cirrhosis. However, serum Se levels were not influenced by the severity of the disease. PMID- 20851313 TI - The butanol fraction of Eclipta prostrata (Linn) increases the formation of brain acetylcholine and decreases oxidative stress in the brain and serum of cesarean derived rats. AB - Eclipta prostrata has been used as a traditional medicinal plant to prevent dementia and to enhance memory in Asia. Its potential as a nootropic and as an antioxidant have been reported in mice. We hypothesized that Eclipta may affect the formation of neurotransmitters and the inhibition of oxidative stress. Charles River cesarean-derived rats (male, 180 +/- 10 g) were fed experimental diets supplemented with 0 mg (control), 25 mg (E25), 50 mg (E50), or 100 mg (E100) of a freeze-dried butanol fraction of E prostrata per kilogram of diet for 6 weeks. The acetylcholine level was significantly increased by 9.6% and 12.1% in the brains of E50 and E100 groups, respectively, as compared with the control group that was fed standard diet alone. The acetylcholine esterase activity was significantly increased by 13.1% and 19.7% in the brains of E50 and E100 groups, respectively, compared with the control group. Monoamine oxidase-B activity was significantly decreased by 10.5% in the brains of the E100 group, and the superoxide radical level was significantly reduced by 9.4% in the serum of the E100 group compared with the control group. Superoxide dismutase activity was significantly increased by 9.6% and 11.6% in the serum of E50 and E100 groups, respectively, compared with the control group. These results clearly demonstrate the effects of E prostrata on the formation of acetylcholine in the brain and the inhibition of oxidative stress in the brain and serum of rats. These findings may have implications for preventing dementia and enhancing memory function in humans. PMID- 20851314 TI - Quiz page October 2010: Anemia in a patient newly transferred from peritoneal dialysis to hemodialysis. PMID- 20851315 TI - Predicting acute kidney injury after cardiac surgery: how to use the "crystal ball". PMID- 20851316 TI - Urinary biomarkers in acute kidney injury: ready for prime time? PMID- 20851317 TI - Sexual dysfunction in CKD. PMID- 20851318 TI - Cognitive impairment in CKD: no longer an occult burden. PMID- 20851319 TI - Cost-effectiveness of screening for and treating albuminuria in individuals without diabetes or hypertension: are we moving beyond the evidence? PMID- 20851322 TI - Coercion and procedural justice in psychiatric care: state of the science and implications for nursing. AB - Coercive treatment regimens have increased in variety and intensity over the past decade and include such options as outpatient commitment (OPC) and mental health courts. The intimate involvement of nurses in coerced treatment situations in both inpatient and outpatient settings necessitates a closer examination of its effects. OPC presumably offers greater flexibility and freedom for consumers than lengthy inpatient stays but also extends the state's control over their lives beyond the institution. Although OPC has been shown to decrease rates of rehospitalization and violence, it also is associated with increased levels of perceived coercion. The relationship of the perception of coercion to treatment outcomes is complex and not clearly understood. The goal of OPC is treatment adherence and ultimately increased quality of life, but research has produced conflicting results in those areas. Numerous episodes of OPC may have a cumulative effect on the perception of coercion and contribute to treatment avoidance. However, there is evidence that the perception of coercion can be mitigated by procedural justice that is demonstrated by fairness, patient inclusion in the process, and benevolence on the part of authority figures. Implications for nursing practice and research concerning coercion, procedural justice, and OPC are discussed. PMID- 20851321 TI - The SeniorWISE study: improving everyday memory in older adults. AB - We tested whether at-risk older adults receiving memory training showed better memory self-efficacy, metamemory, memory performance, and function in instrumental activities of daily living than participants receiving a health promotion training comparison condition. We followed participants for 26 months. The sample was mostly female (79%) and Caucasian (71%), with 17% Hispanics and 12% African Americans; average age was 75 years, and average education was 13 years. The memory training group made greater gains on global cognition and had fewer memory complaints, but both groups generally maintained their performance on the other cognitive measures and instrumental activities of daily living (IADLs) throughout the 24-month study period. Black and Hispanic participants made greater gains than Whites did on some memory performance measures but not on memory self-efficacy. The unexpected finding that minority elders made the largest gains merits further study. This study contributed to the knowledge base of geropsychiatric nursing by providing evidence for an effective psychosocial intervention that could be delivered by advanced practice nurses. PMID- 20851323 TI - A systematic review of the relationship of diabetes mellitus, depression, and missed appointments in a low-income uninsured population. AB - The purpose of this systematic literature review was to determine the relationship between the diagnosis of diabetes and depression and missed appointments in a low-income, uninsured, racially heterogeneous, adult population. Research demonstrates that individuals with diabetes have an increased incidence of depression across socioeconomic and racial groups. Low income individuals have an increased prevalence of depression. The cost and burden of diabetes are greatly increased among individuals with both diabetes and depression versus diabetes alone. The prevalence and effects of diabetes and depression in a low-income, uninsured, racially heterogeneous population have not been determined. Further research to explore the relationship of diabetes, depression, and missed appointments in this vulnerable population is needed before effective treatment models can be developed. Longitudinal studies are also needed to determine the cause and effect between diabetes and depression among all populations. PMID- 20851324 TI - Developing a psychosocial rehabilitation treatment mall: an implementation model for mental health nurses. AB - The psychosocial rehabilitation "treatment mall" is a widely accepted method of providing active treatment to patients with serious mental illnesses in psychiatric hospital settings. As a multidisciplinary endeavor, it is important that all clinical disciplines are involved in the development and operation of treatment malls. However, related to their roles as both clinicians and as milieu managers, nurses are crucial in both the development and implementation of such malls. Current literature fails to adequately highlight the role nurses and nursing staff play in treatment malls. Using the treatment mall at Memphis Mental Health Institute as an exemplar, a mall implementation model will be discussed specifically focusing on intra- and interdisciplinary nursing practice. PMID- 20851325 TI - Seen as core: a Delphi consensus study of essential elements of mental health nursing care in Ireland. AB - Continued ambiguity about the scope of mental health nursing is harmful to the discipline's identity and to patients' interests. Using a Delphi survey design, consensus was achieved on a set of 70 items representing core elements of mental health nursing among a sample of 150 mental health nurses working in Ireland. Items achieving consensus in Round 3 of the survey were composed of 28 clinical phenomena (framed as client problems), 18 direct and 12 indirect nursing interventions, and 12 nursing-sensitive outcomes of care. Mental health nurses accepted responsibility across a broad range of outcomes apart from those linked to physical care, the one domain of care rejected by participants. The findings portray mental health nursing as a psychosocial enterprise, encompassing both phenomenological and diagnosis-related elements. PMID- 20851326 TI - Facades of suffering: clients' photo stories about mental illness. AB - In this article, photo stories are examined that were the result of working with photography as a therapeutic instrument dealing with suffering in mental health care settings. The purpose is to describe the role of facades in the process of suffering and acceptance. Clients took photographs, talked about them in group meetings, and exhibited them to a broader audience. Their photo stories were analyzed using a mixed-methods model. Data from two narrative approaches (semiotics and hermeneutics) were compared with information from other informants and official records to find discrepancies between the photo story and the real life context. Although facades are usually perceived as an obstacle for personal growth, the visual narratives revealed that facades can function as an alternative to common acceptance strategies, such as facing one's losses and reconciliation. Facades can create a distance between the person and the suffering. We conclude that visual narratives can reveal and foster agency in clients. PMID- 20851327 TI - HIV/AIDS-associated stigma among Afro-Caribbean people living in the United States. AB - Estimates of AFRO-CARIBBEAN people living with HIV/AIDS are questionable because this population is unwilling to be tested or disclose their status, fearing stigmatization. The purpose of this study was to explore attitudes about HIV/ AIDS-associated stigma for churchgoing Afro- Caribbean people in the United States. Two focus groups of mothers and daughters were convened. The research question was How do young people your age feel about having a friend who is HIV positive? and How do mothers feel about their daughters having a friend who is HIV-positive? Information from mothers and daughters was evaluated separately through content analysis. Results are discussed. PMID- 20851329 TI - Intervention found. PMID- 20851331 TI - Where are the systematic reviews in transfusion medicine? A study of the transfusion evidence base. AB - Transfusion medicine has become a large and complex specialty. Although there are now systematic reviews covering many aspects of transfusion, these span a large number of clinical areas and are published across more than a hundred different medical journals, making it difficult for transfusion medicine practitioners and researchers to keep abreast of the current high-level evidence. In response to this problem, NHS Blood and Transplant's Systematic Review Initiative (SRI) has produced a comprehensive overview of systematic reviews in transfusion medicine. A systematic search (to December 2009) and screening procedure were followed by the appraisal of systematic reviews according to predefined inclusion criteria. The 340 eligible systematic reviews were mapped to 10 transfusion intervention groups and 14 topic groups within clinical medicine. Trends in the systematic review literature were examined and gaps in the literature described. The spread of systematic reviews across clinical areas was found to be very uneven, with some areas underreviewed and others with multiple systematic reviews on the same topic, making the identification of the best evidence for current transfusion practice a continuing challenge. References and links to all systematic reviews included in this overview can be freely accessed via the SRI's new online database, the Transfusion Evidence Library (www.transfusionguidelines.org). PMID- 20851332 TI - Keys to open the door for blood donors to return. AB - Because of demographic changes, the worldwide shortage of blood will likely be aggravated in the foreseeable future. Hence, the retention of already active blood donors (BDs) is becoming more and more important. Moreover, a substantial increase in blood donations could be achieved by a relatively small increase in BD return. Blood donation services are therefore well advised to understand their BDs' motivations to become regular and committed BDs and to consider this in planning BD retention programs. Focusing on the published literature of the last decade, we summaries some key recommendations in considering BD retention strategies. Whereas starting a career as a BD is mainly driven by external stimuli, becoming a committed BD needs a well-developed identity role; that is, a BD with a high level of intrinsic motivation. Active communications with the BD right from the beginning, introducing distinct measures to support the development of a BD's distinct identity, increasing convenience of the blood donation process, having well-trained and motivated staff, applying distinct measures to reduce anxiety as well as adverse events, making BDs satisfied with their blood donation experience, appropriate use of incentives, quickly recapturing temporarily deferred BDs, and appealing to BDs' personal motivations and moral norms--all of these are major keys to achieving this important aim. PMID- 20851330 TI - Clinical trial opportunities in Transfusion Medicine: proceedings of a National Heart, Lung, and Blood Institute State-of-the-Science Symposium. AB - The use of blood products to support patients undergoing the large variety of medical and surgical interventions requiring such support has continued to escalate very significantly over time. Relevantly, significant practice variation in the use of blood products exists among practitioners and institutions, largely because of the lack of robust clinical trial data, in many instances, which are critical for providing practitioners with evidence-based guidelines for appropriate blood product utilization. Recognizing this gap, the National Heart, Lung, and Blood Institute recently established a State-of-the-Science Symposium to help define areas of clinical trial research that would enhance the opportunity for developing appropriate practice guidelines for both Transfusion Medicine and Hemostasis/Thrombosis. Such a Symposium was held in September 2009 to identify important clinical trial research issues in these 2 subject areas of endeavor. The aims of this Symposium were to specifically identify phase 2 and 3 clinical trials that, if conducted over the next 5 to 10 years, could impact the treatment of patients with hemostatic and other disorders as well as to optimize the use of blood products in patients who need such interventions. This article reports on the deliberations that were held relating to the various clinical trial concepts developed by 7 Transfusion Medicine subcommittees. This Symposium generated a rich assortment of clinical trial proposals that will undergo further refinement before final implementation into pilot or full randomized clinical trials. The various proposals identified many opportunities for clinical trial research and most importantly underscored the ongoing need for well-developed evidence-based clinical trial research in the field of Transfusion Medicine. PMID- 20851333 TI - Transfusion-related acute lung injury (TRALI): A Canadian blood services research and development symposium. AB - Since the first description of transfusion-related acute lung injury (TRALI) more than 2 decades ago, we have only recently begun to learn how this disorder may occur and how to prevent it. Scientists from around the world have made great strides in identifying the possible causes of this condition. Blood banks and transfusion services have risen to the challenges of prevention. Recent introduction of restricting most plasma products to those obtained from male donors only has greatly reduced the incidence of TRALI worldwide. Scientists have recently identified the gene and protein for the human neutrophil antigen-3a associated with most mortality due to TRALI, and this presents an opportunity for a screening assay to prevent future TRALI-associated deaths. Finally, animal models of TRALI have provided insight into the possible mechanisms of this disorder and can be used to explore potential treatment modalities. PMID- 20851334 TI - Tibor Jack Greenwalt: Father of Transfusion Medicine. AB - Tibor J. Greenwalt (1914-2005) was, as much as anyone, the Father of Transfusion Medicine. He was founder of the Blood Center of Wisconsin, the first member of the American Association of Blood Banks, founding editor of Transfusion, chair of the National Research Council's Committee on Blood and Transfusion, national medical director of the American Red Cross Blood Services, and president of the International Society of Blood Transfusion. He wrote 200 papers and 25 books, describing erythroblastosis fetalis as an immune hemolytic anemia, new blood groups and antigens, the effects of hepatitis testing on blood safety, better ways to store red cell, and much more. He worked until days before his death at age 91, ending a 63-year career with 5 papers in press. PMID- 20851335 TI - Repetitive elements and genome instability. PMID- 20851336 TI - Harnessing biology to produce inorganic materials. PMID- 20851337 TI - Making it easier to regulate protein stability. AB - The ability to induce degradation of a protein of interest is a powerful experimental tool used to ascertain protein function. Iwamoto et al. (2010) describe a method that allows reversible and dose-dependent modulation of the stability of any target protein. PMID- 20851338 TI - Creating designer laccases. AB - High redox potential laccases from white-rot fungi are recalcitrant to engineering. Mate et al. (2010) employed directed evolution to improve the activity and expression level of the fungal laccase from basidiomycete PM1, followed by rational design to restore thermostability lost during evolution, resulting in a highly active and stable enzyme. PMID- 20851339 TI - A group I intron riboswitch. AB - Riboswitches are mRNA-based elements that regulate gene expression via binding of a specific ligand. Breaker and coworkers have now discovered a novel type of regulatory RNA motif that acts by c-di-GMP-dependent control of a self-splicing group I intron ribozyme (Lee et al., 2010). PMID- 20851340 TI - Phospholipid membranes as regulators of localized activity. AB - In a recent article, Tsuji and Yoshikawa (2010) report that the interaction of long DNA with phospholipids on the surface of aqueous microdroplets can lead to changes of the DNA conformation, and as consequence, to a remarkable alteration of the DNA's transcriptional activity. PMID- 20851341 TI - A family of pyrazinone natural products from a conserved nonribosomal peptide synthetase in Staphylococcus aureus. AB - Each year in the United States, infections by methicillin-resistant Staphylococcus aureus (MRSA) are responsible for ~19,000 deaths and result in $3 $4 billion of health care costs. Because skin colonization is a major risk factor for S. aureus infection, identifying novel small molecules produced by S. aureus can lead to new molecular insights into its ability to colonize and infect the host and new targets for antibacterial intervention. Here, we report that a nonribosomal peptide synthetase conserved across S. aureus and other skin associated staphylococci encodes a family of three pyrazinone natural products. These molecules likely result from the synthesis and release of a dipeptide aldehyde, its spontaneous cyclization to a dihydropyrazinone, and subsequent oxidation to a pyrazinone. As an unexpected family of small molecule natural products from the pathogen S. aureus, the pyrazinones may open a new window into the interspecies interactions that underlie the poorly understood process of skin colonization. PMID- 20851342 TI - Halogen bonds form the basis for selective P-TEFb inhibition by DRB. AB - Cdk9, the kinase of the positive transcription elongation factor b, is required for processive transcription elongation by RNA polymerase II. Cdk9 inhibition contributes to the anticancer activity of many Cdk inhibitors under clinical investigation and hence there is interest in selective Cdk9 inhibitors. DRB (5,6 dichlorobenzimidazone-1-beta-D-ribofuranoside) is a commonly used reagent for Cdk9 inhibition in cell biology studies. The crystal structures of Cdk9 and Cdk2 in complex with DRB reported here describe the molecular basis for the DRB selectivity toward Cdk9. The DRB chlorine atoms form halogen bonds that are specific for the Cdk9 kinase hinge region. Kinetic and thermodynamic experiments validate the structural findings and implicate the C-terminal residues of Cdk9 in contributing to the affinity for DRB. These results open the possibility to exploit halogen atoms in inhibitor design to specifically target Cdk9. PMID- 20851343 TI - Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. AB - To probe increased O-GlcNAc levels as an independent mechanism governing insulin resistance in 3T3-L1 adipocytes, a new class of O-GlcNAcase (OGA) inhibitor was studied. 6-Acetamido-6-deoxy-castanospermine (6-Ac-Cas) is a potent inhibitor of OGA. The structure of 6-Ac-Cas bound in the active site of an OGA homolog reveals structural features contributing to its potency. Treatment of 3T3-L1 adipocytes with 6-Ac-Cas increases O-GlcNAc levels in a dose-dependent manner. These increases in O-GlcNAc levels do not induce insulin resistance functionally, measured using a 2-deoxyglucose (2-DOG) uptake assay, or at the molecular level, determined by evaluating levels of phosphorylated IRS-1 and Akt. These results, and others described, provide a structural blueprint for improved inhibitors and collectively suggest that increased O-GlcNAc levels, brought about by inhibition of OGA, does not by itself cause insulin resistance in 3T3-L1 adipocytes. PMID- 20851344 TI - Elevation of Global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis. AB - The O-GlcNAc modification is proposed to be a nutrient sensor with studies suggesting that global increases in O-GlcNAc levels cause insulin resistance and impaired glucohomeostasis. We address this hypothesis by using a potent and selective inhibitor of O-GlcNAcase, known as NButGT, in a series of in vivo studies. Treatment of rats and mice with NButGT, for various time regimens and doses, dramatically increases O-GlcNAc levels throughout all tissues but does not perturb insulin sensitivity or alter glucohomeostasis. NButGT also does not affect the severity or onset of insulin resistance induced by a high-fat diet. These results suggest that pharmacological increases in global O-GlcNAc levels do not cause insulin resistance nor do they appear to disrupt glucohomeostasis. Therefore, the protective benefits of elevated O-GlcNAc levels may be achieved without deleteriously affecting glucohomeostasis. PMID- 20851345 TI - Acyldepsipeptide antibiotics induce the formation of a structured axial channel in ClpP: A model for the ClpX/ClpA-bound state of ClpP. AB - In ClpXP and ClpAP complexes, ClpA and ClpX use the energy of ATP hydrolysis to unfold proteins and translocate them into the self-compartmentalized ClpP protease. ClpP requires the ATPases to degrade folded or unfolded substrates, but binding of acyldepsipeptide antibiotics (ADEPs) to ClpP bypasses this requirement with unfolded proteins. We present the crystal structure of Escherichia coli ClpP bound to ADEP1 and report the structural changes underlying ClpP activation. ADEP1 binds in the hydrophobic groove that serves as the primary docking site for ClpP ATPases. Binding of ADEP1 locks the N-terminal loops of ClpP in a beta hairpin conformation, generating a stable pore through which extended polypeptides can be threaded. This structure serves as a model for ClpP in the holoenzyme ClpAP and ClpXP complexes and provides critical information to further develop this class of antibiotics. PMID- 20851346 TI - Structural studies of a peptide with immune modulating and direct antimicrobial activity. AB - The structure and function of the synthetic innate defense regulator peptide 1018 was investigated. This 12 residue synthetic peptide derived by substantial modification of the bovine cathelicidin bactenecin has enhanced innate immune regulatory and moderate direct antibacterial activities. The solution state NMR structure of 1018 in zwitterionic dodecyl phosphocholine (DPC) micelles indicated an alpha-helical conformation, while secondary structures, based on circular dichroism measurements, in anionic sodium dodecyl sulfate (SDS) and phospholipid vesicles (POPC/PG in a 1:1 molar ratio) and simulations revealed that 1018 can adopt a variety of folds, tailored to its different functions. The structural data are discussed in light of the ability of 1018 to potently induce chemokine responses, suppress the LPS-induced TNF-alpha response, and directly kill both Gram-positive and Gram-negative bacteria. PMID- 20851348 TI - Metabolomic identification of the target of the filopodia protrusion inhibitor glucopiericidin A. AB - Identifying the targets of bioactive compounds is a major challenge in chemical biological research. Here, we identified the functional target of the natural bioactive compound glucopiericidin A (GPA) through metabolomic analysis. We isolated GPA while screening microbial samples for a filopodia protrusion inhibitor. Interestingly, GPA alone did not inhibit filopodia protrusion, but synergistically inhibit protrusion with the mitochondrial respiration inhibitor, piericidin A (PA). These results suggested that GPA might inhibit glycolysis. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) provided strong evidence that GPA suppresses glycolysis by functionally targeting the glucose transporter. GPA may therefore serve as a glucose transporter chemical probe. Simultaneous inhibition of both glycolysis and mitochondrial respiration dramatically decreased intracellular ATP levels, indicating that GPA inhibits ATP dependent filopodia protrusion with PA. Our results represent a challenge of molecular target identification using metabolomic analysis. PMID- 20851347 TI - A general chemical method to regulate protein stability in the mammalian central nervous system. AB - The ability to make specific perturbations to biological molecules in a cell or organism is a central experimental strategy in modern research biology. We have developed a general technique in which the stability of a specific protein is regulated by a cell-permeable small molecule. Mutants of the Escherichia coli dihydrofolate reductase (ecDHFR) were engineered to be degraded, and, when this destabilizing domain is fused to a protein of interest, its instability is conferred to the fused protein resulting in rapid degradation of the entire fusion protein. A small-molecule ligand trimethoprim (TMP) stabilizes the destabilizing domain in a rapid, reversible, and dose-dependent manner, and protein levels in the absence of TMP are barely detectable. The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system. PMID- 20851349 TI - Selective and sensitive monitoring of caspase-1 activity by a novel bioluminescent activity-based probe. AB - The role of caspase-1 in inflammation has been studied intensely over recent years. However, the research of caspase-1 has remained difficult mainly due to the lack of sensitive and selective tools to monitor not only its abundance but also its activity. Here we present a bioluminescent activity-based probe (ABP) for caspase-1, developed by the Reverse Design concept, where chemically optimized protease inhibitors are turned into selective substrate ABPs. The probe exhibits excellent selectivity for caspase-1 and ~1000-fold increase in sensitivity compared to available fluorogenic peptidic caspase-1 substrates. Moreover, we have been able to monitor and quantify specific caspase-1 activity directly in cell lysates. The activity correlated well with processing of prointerleukin-1beta and prointerleukin-18 in phorbol 12-myristate 13-acetate (PMA)-stimulated cells. A detectable caspase-1 activity was present also in nonstimulated cells, consistent with processing of constitutively expressed prointerleukin-18. PMID- 20851350 TI - The quaternary organization and dynamics of the molecular chaperone HSP26 are thermally regulated. AB - The function of ScHSP26 is thermally controlled: the heat shock that causes the destabilization of target proteins leads to its activation as a molecular chaperone. We investigate the structural and dynamical properties of ScHSP26 oligomers through a combination of multiangle light scattering, fluorescence spectroscopy, NMR spectroscopy, and mass spectrometry. We show that ScHSP26 exists as a heterogeneous oligomeric ensemble at room temperature. At heat-shock temperatures, two shifts in equilibria are observed: toward dissociation and to larger oligomers. We examine the quaternary dynamics of these oligomers by investigating the rate of exchange of subunits between them and find that this not only increases with temperature but proceeds via two separate processes. This is consistent with a conformational change of the oligomers at elevated temperatures which regulates the disassembly rates of this thermally activated protein. PMID- 20851352 TI - Laboratory evolution of high-redox potential laccases. AB - Thermostable laccases with a high-redox potential have been engineered through a strategy that combines directed evolution with rational approaches. The original laccase signal sequence was replaced by the alpha-factor prepro-leader, and the corresponding fusion gene was targeted for joint laboratory evolution with the aim of improving kinetics and secretion by Saccharomyces cerevisiae, while retaining high thermostability. After eight rounds of molecular evolution, the total laccase activity was enhanced 34,000-fold culminating in the OB-1 mutant as the last variant of the evolution process, a highly active and stable enzyme in terms of temperature, pH range, and organic cosolvents. Mutations in the hydrophobic core of the evolved alpha-factor prepro-leader enhanced functional expression, whereas some mutations in the mature protein improved its catalytic capacities by altering the interactions with the surrounding residues. PMID- 20851351 TI - Dual-color click beetle luciferase heteroprotein fragment complementation assays. AB - Understanding the functional complexity of protein interactions requires mapping biomolecular complexes within the cellular environment over biologically relevant time scales. Herein, we describe a set of reversible multicolored heteroprotein complementation fragments based on various firefly and click beetle luciferases that utilize the same substrate, D-luciferin. Luciferase heteroprotein fragment complementation systems enabled dual-color quantification of two discrete pairs of interacting proteins simultaneously or two distinct proteins interacting with a third shared protein in live cells. Using real-time analysis of click beetle green and click beetle red luciferase heteroprotein fragment complementation applied to beta-TrCP, an E3-ligase common to the regulation of both beta-catenin and IkappaBalpha, GSK3beta was identified as a candidate kinase regulating IkappaBalpha processing. These dual-color protein interaction switches may enable directed dynamic analysis of a variety of protein interactions in living cells. PMID- 20851353 TI - Pre-hospital provider recognition of intimate partner violence. AB - The leading risk factor of morbidity and mortality in Victorian women aged between 15 and 45 years is intimate partner violence (IPV) (approximately 8 times than that of smoking). Paramedics are frequently the first point of contact for victims of IPV. Due to this unique viewpoint, paramedics have the advantage of potentially identifying and reporting IPV, which can then result in early intervention. This article will summarise the literature regarding pre-hospital provider knowledge of IPV. PMID- 20851354 TI - Dental age estimation in Egyptian children, comparison between two methods. AB - The need to estimate age of living individuals is becoming increasingly more important in both forensic science and clinical dentistry. The study of the morphological parameters of teeth on dental radiographs of adult humans is more reliable than most other methods for age estimation. Willems and Cameriere methods are newly presented methods. The aim of this work was to evaluate the applicability of using these methods for Egyptian children. Digitalized panoramas taken from 286 Egyptian children (134 boys, 152 girls) with age range from 5 to 16 years were analyzed. The seven left permanent mandibular teeth were evaluated using the two methods. The results of this research showed that dental age estimated by both methods was significantly correlated to real age. However, Willems method was slightly more accurate (98.62%) compared to Cameriere method (98.02%). Therefore, both methods can be recommended for practical application in clinical dentistry and forensic procedures on the Egyptian population. PMID- 20851355 TI - One model of healthcare provision lessons learnt through clinical governance. AB - AIM: Clinical Governance describes a systematic approach to maintaining and improving the quality of patient care. Risk management includes a themes analysis of clinical incidents and positive interventions with the resulting information disseminated to staff through personal performance plans, and publication and development training workshops. Our model of healthcare provision utilises doctors, nurses and paramedics to assess individuals in custody and this paper discusses the implementation of clinical risk management within this setting. METHOD: A description of the model of healthcare provision, together with a themes analysis was undertaken for all clinical incidents received by the clinical team. Each incident receives an individual response and is discussed within the clinical risk management committee. From the review of each event, learning outcomes are identified and the information captured on a database. The information is analysed for reoccurring themes and further measures are introduced to ensure a high standard of healthcare provision to all counties. FINDINGS: Of the 86,184 patient/detainee episodes from 11 county forces, from January 2009-December 2009, 159 clinical incidents and positive interventions were generated. These were categorised into Clinical Near Misses--39, Prescribing issues--38, Health and Safety matters--13, Organisational matters--23, Positive Interventions--21 and Professional issues--25. CONCLUSION: Risk management, with a regular review of clinical incidents is an essential part of clinical governance especially when working in a multidisciplinary team providing safe and effective custody healthcare. This analysis contributes to the knowledge base in clinical forensic medicine and supports the importance of identifying educational requirements for staff, working in a multiagency partnership and continuous monitoring of the quality of care for detainees. PMID- 20851356 TI - The socio-demographic profile of hanging suicides in Ireland from 1980 to 2005. AB - This paper provides a comparison of the socio-demographic profile of hanging suicides and suicides by other means in Ireland from January 1st 1980 to December 31st 2005. Data on 9674 suicides occurring in that time frame was provided by the Central Statistics Office of Ireland (CSO). 4031 (42%) of these deaths involved suicide by 'hanging, suffocation or strangulation' (HSS), with the remainder being suicides by other means. Binary logistic regressions were used to examine six potential risk factors for suicide across the two groups: Gender, marital status, employment in the agricultural sectors, residential location (urban/rural) and age were entered in Block 1 of the analysis, with year of death (pre 1994 vs. post 1994) added in a second block. Results indicate that those dying through hangings were statistically more likely to be male (OR=3.1, 95% CI=2.8-3.5), single (OR=1.3, 95% CI=1.2-1.4), rural-dwelling (OR=1.1, 95% CI=1.0 1.2), agri-employed (OR=1.3, 95% CI=1.1-1.4) and to have died since 1994 (OR=2.3, 95% CI=2.1-2.5). The magnitude of the group effect was moderate for all but the gender and time period comparisons. Hanging suicide victims (m=37.7, sd=16.7) were also significantly younger than other suicide victims (mean=42.72, sd=16.7), although the size of the effect was small (r=.16). Overall the six variables explained 6% of the variance in the criterion variable. PMID- 20851357 TI - Calcaneus radiograph as a diagnostic tool for sexual dimorphism in Egyptians. AB - Measurements of calcaneus have been shown to be sexually dimorphic in American whites and blacks, Italians and South African whites and blacks. Since the validity of discriminant function equation in sex determination is population specific, the aim of the present study was to derive similar equations for the calcanei of Egyptians. Lateral radiographs of the ankles of 204 Egyptians aged 20 70 were analyzed with regards to sexual dimorphism, consisting of 104 males and 100 females. X-ray films were obtained from Minia Forensic Department. Six measurements were taken for every calcaneal X-ray film, three linear and three angular measurements. Data were analyzed by SPSS version 17, An independent samples t-test and discriminant function analysis were done. All linear measurements, but not angular, showed significant sexual differences. Maximum length was found to be the most sexually dimorphic (90.2%). Combination of maximum length with minimum height gave the same result of all linear measurements (92.6%) which was more than given by individual variables (81.4 90.2%). PMID- 20851358 TI - Elder homicide in the north of Portugal. AB - INTRODUCTION: The increasing average life expectancy leads to population aging, and growing numbers in the elder population, a population that suffers from great vulnerability. Therefore, a rise in elder homicide is expected. This phenomenon has not been thoroughly described in Portugal. This study aims to analyse and characterize elder homicide, in order to achieve a better understanding of this form of violence. MATERIAL AND METHODS: We conducted a retrospective study, reviewing autopsy reports along with data regarding circumstances of death of suspected homicides occurring between 1992 and 2007 (n = 78), whose victims were 65 years old or above, autopsied in the medical-legal services of the north of Portugal. RESULTS: During this period, an overall of 615 suspected homicides occurred, 13% being perpetrated against elders. The age range of the victims was 65-96 years, with an average of 74 years; 58% of them were males and 45% were married. In 61% of the documented cases, the perpetrator was known to the victim, and a family member in 36%. A considerable number of deaths occurred at the victim's residence and in a rural scenario, the motive being robbery in 51% of the documented cases. The supposed perpetrator ran away from the scene in 64% of the cases. The most frequent mechanisms of death were blunt force trauma (31%), followed by stabbing (22%) and gunshot wounds (21%). Fatal wounds were observed mainly in the head (55%) and thorax (35%). CONCLUSIONS: In the north of Portugal, elder homicide seems to be uncommon. This study suggests an association between elder homicide and robbery, in which elders, due to their vulnerability, are a preferential target. Contrary to other reports worldwide, there were no cases of death in nursing homes, possibly due to underreport or misidentification. In a large number of the cases, it wasn't possible to collect all the necessary data, due to lack of information regarding circumstances of the events. PMID- 20851359 TI - Unintentional carbon monoxide poisoning in Northwest Iran: a 5-year study. AB - This paper describes the epidemiology of unintentional carbon monoxide (CO) poisoning in Northwest Iran between 2003 and 2008. Data were obtained from the records of the main provider of emergency medical transportation and from death certificate reports of the Legal Medicine Organization. During the study period, a total of 3078 hospital admissions were recorded against which 346 deaths were due to unintentional CO related poisoning caused by gas appliances in the homes. The ratio of unintentional CO related poisoning cases in relation to all poisonings was 11.6%. With regard to gender differences, non-fatal CO poisoning was higher in females than males, whereas actual fatalities were higher in males than females. Non-fatal CO poisoning was most prevalent in adults aged between 20 and 49 years, whereas the age specific death rate was highest for those over 60 years. The highest frequency of both non-fatal poisonings and actual fatalities occurred in the month January. The results suggest that CO poisoning has a high prevalence in this geographic region, with elderly adults being at the greatest risk, especially during the winter season. This represents a serious, but often neglected area of public health, and Health Authorities should be encouraged to promote public awareness against the dangers of CO exposure. This paper reviews the data and evidence surrounding the issue of CO poisoning and makes recommendations that a range of agencies and authorities should be involved in setting stricter standards and environmental legislations in this respect. PMID- 20851360 TI - Exploring the limits for the survival of DNA in blood stains. AB - It is generally recognized that usable DNA may be retained in dry biological stains for years. We have explored the environmental limits for this property. Air-dried blood stains were incubated at different conditions of relative humidity (RH) and temperature. The quality of the extracted DNA was assessed by the ability to amplify 273 bp and 1600 bp DNA fragments by PCR, and by quantitative estimation of a 147 bp DNA fragment using real time PCR. Despite the fact that the availability of water is important for processes that degrade DNA, no significant difference was observed in the stability of DNA at 50%, 80% or 93% RH at room temperature or at 35 degrees C, and even the 1600 bp fragment was amplifiable after one year. Microbial growth was not observed at these conditions and the number of template molecules did not drop significantly over time. At 100% RH, however, microbial growth was observed after varying amounts of time. This may explain the decreased stability of DNA observed at these conditions. Even so, the 273 bp fragment was amplifiable for at least 3 months, and the 1600 bp fragment for at least two months. Microbial growth was not observed at higher temperatures (45-65 degrees C) at 100% RH, and the 1600 bp fragment was amplifiable after eight months at 45 degrees C, but only survived for one month at 55 degrees C or 65 degrees C. Thus DNA remains amplifiable in blood stains for many months, even at extreme RH and temperatures up to 45 degrees C. Even in humid climates the average RH is usually not more than 80% and RH rarely exceeds 93%; therefore we conclude that normal climatic conditions are not critical for the long time survival of DNA in untreated blood stains. PMID- 20851361 TI - Fatal accidental asphyxia in a jack-knife position. AB - Accidental death from postural or positional asphyxia takes place when the abnormal position of the victim's body compromises the process of respiration. Diagnosis is largely made by circumstantial evidence supported by absence of any other significant pathology or trauma explaining death. This case report is about a 50-year-old male who had been drinking the previous night and was found dead in the morning inside a tire repair shop. His jack-knifed body had been encompassed, buttocks-down, within the hollow core made by 3 big tires stacked on top of each other. The author was called to the scene of death and had hands-on encounter with the body in-situ where scene photographs were taken. Apart from a blood alcohol of 290 mg/100 ml, marked congestion of the face, petechial hemorrhages on the conjunctivae and lung edema and congestion, autopsy findings were unremarkable. Abrasions on shoulders, lateral aspects of arms and posterior aspects of lower legs indicated friction with internal rims of tires while slipping down. There were no other injuries or pathology to account for his death. Death was determined to be due to accidental postural asphyxia secondary to intoxication by alcohol. PMID- 20851362 TI - Infantile asphyxia due to aberrant uvula--an anatomic misadventure. AB - A case of unexpected death of an infant with an abnormally elongated uvula is presented. The child, born prematurely, was recovering from protracted treatment in hospital, including surgical interventions and periods of ventilation support necessitating recurrent intubations and anesthesia. She was discharged home in good general health, affected by episodes of cough, and was found dead in her crib a week later. The proximity of the aberrant uvula to the vocal cords may have caused intermittent laryngospasm, with subsequent symptoms of cough and airway obstruction, ending in a fatal outcome. Recurrent airway irritation may have contributed to uvular hypertrophy, due to inflammatory and reactive changes. It is pertinent for the pathologist to thoroughly examine the structures of the pharynx, and the uvula in particular, in any case of pediatric death suspected to result from asphyxia or sudden infant death syndrome (SIDS). PMID- 20851363 TI - Re intoxication with Qaat, Catha edulis L. PMID- 20851364 TI - Association of squamous cell carcinoma of the larynx and chronic lymphoid leukemia. AB - INTRODUCTION: The association of squamous cell carcinoma of the larynx and chronic lymphocytic leukemia (CLL) is exceptional. We report an observation of this association and present the therapeutic problems as well as the effects on prognosis. OBSERVATION: Direct laryngoscopy showed a tumor of the right hemilarynx, with the biopsy concluding in moderately differentiated keratinizing squamous cell carcinoma. The patient had a total laryngectomy, with bilateral lymph node evidement. The anatomopathological examination of the operative specimen demonstrated infiltration of the larynx and squamous cell carcinoma adenopathies and CLL. It was decided to monitor the chronic lymphoid leukemia, classified as Binet stage B. The synchronous or metachronous onset of a second cancer in a patient with CLL is more frequent than in the general population. The synchronous association of squamous cell carcinoma of the larynx and CLL has been described only rarely. The therapeutic strategy should focus first on the cancer with the shortest survival rate. The prognosis is more negative in an association of cervicofacial squamous cell carcinoma and leukemia than in a single cervicofacial cancer. PMID- 20851365 TI - Outpatient management of patients following pulmonary embolism. AB - Pulmonary embolus is a common reason for hospitalization and requires close follow-up and management in the office setting. The main issues facing the clinician include determination of the appropriate anticoagulation regimen, how long to anticoagulate, and whether an evaluation for hypercoagulable states is indicated. The decisions will depend on individual patient factors and assessment of the risks and benefits for that patient. PMID- 20851366 TI - Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. AB - PURPOSE: To report a case series of patients with the nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw-a form of jaw osteonecrosis that does not manifest with necrotic bone exposure/mucosal fenestration. METHODS: Among 332 individuals referred to 5 clinical centers in Europe because of development of jawbone abnormalities after or during exposure to bisphosphonates, we identified a total of 96 patients who presented with the nonexposed variant of osteonecrosis. Relevant data were obtained via clinical notes; radiological investigations; patients' history, and referral letters. RESULTS: The most common clinical feature of nonexposed osteonecrosis was jaw bone pain (88/96; 91.6%); followed by sinus tract (51%), bone enlargement (36.4%); and gingival swelling (17.7%). No radiological abnormalities were identified in 29.1% (28/96) of patients. In 53.1% (51/96) of the patients; nonexposed osteonecrosis subsequently evolved into frank bone exposure within 4.6 months (mean; 95% confidence interval; 3.6-5.6). CONCLUSIONS: Clinicians should be highly vigilant to identify individuals with nonexposed osteonecrosis, as the impact on epidemiological data and clinical trial design could be potentially significant. Although the present case series represents approximately 30% of all patients with bisphosphonates associated osteonecrosis observed at the study centers, further population-based prospective studies are needed to obtain robust epidemiological figures. PMID- 20851367 TI - Hepatitis C virus and cocaine-induced rhabdomyolysis. PMID- 20851368 TI - An IRIS to remember. PMID- 20851369 TI - Acute onset of dyspnea in an HIV patient. PMID- 20851370 TI - Placental pathology in asphyxiated newborns meeting the criteria for therapeutic hypothermia. AB - OBJECTIVE: We sought to describe placental findings in asphyxiated term newborns meeting therapeutic hypothermia criteria and to assess whether histopathologic correlation exists between these placental lesions and the severity of later brain injury. STUDY DESIGN: We conducted a prospective cohort study of the placentas of asphyxiated newborns, in whom later brain injury was defined by magnetic resonance imaging. RESULTS: A total of 23 newborns were enrolled. Eighty seven percent of their placentas had an abnormality on the fetal side of the placenta, including umbilical cord lesions (39%), chorioamnionitis (35%) with fetal vasculitis (22%), chorionic plate meconium (30%), and fetal thrombotic vasculopathy (26%). A total of 48% displayed placental growth restriction. Chorioamnionitis with fetal vasculitis and chorionic plate meconium were significantly associated with brain injury (P = .03). Placental growth restriction appears to significantly offer protection against the development of these injuries (P = .03). CONCLUSION: Therapeutic hypothermia may not be effective in asphyxiated newborns whose placentas show evidence of chorioamnionitis with fetal vasculitis and chorionic plate meconium. PMID- 20851372 TI - Structure-function relationships using spectral-domain optical coherence tomography: comparison with scanning laser polarimetry. AB - PURPOSE: To evaluate and compare the regional relationships between visual field sensitivity and retinal nerve fiber layer (RNFL) thickness as measured by spectral-domain optical coherence tomography (OCT) and scanning laser polarimetry. DESIGN: Prospective cross-sectional study. METHODS: One hundred and twenty eyes of 120 patients (40 with healthy eyes, 40 with suspected glaucoma, and 40 with glaucoma) were tested on Cirrus-OCT, GDx VCC, and standard automated perimetry. Raw data on RNFL thickness were extracted for 256 peripapillary sectors of 1.40625 degrees each for the OCT measurement ellipse and 64 peripapillary sectors of 5.625 degrees each for the GDx VCC measurement ellipse. Correlations between peripapillary RNFL thickness in 6 sectors and visual field sensitivity in the 6 corresponding areas were evaluated using linear and logarithmic regression analysis. Receiver operating curve areas were calculated for each instrument. RESULTS: With spectral-domain OCT, the correlations (r(2)) between RNFL thickness and visual field sensitivity ranged from 0.082 (nasal RNFL and corresponding visual field area, linear regression) to 0.726 (supratemporal RNFL and corresponding visual field area, logarithmic regression). By comparison, with GDx-VCC, the correlations ranged from 0.062 (temporal RNFL and corresponding visual field area, linear regression) to 0.362 (supratemporal RNFL and corresponding visual field area, logarithmic regression). In pairwise comparisons, these structure-function correlations were generally stronger with spectral-domain OCT than with GDx VCC and with logarithmic regression than with linear regression. The largest areas under the receiver operating curve were seen for OCT superior thickness (0.963 +/- 0.022; P < .001) in eyes with glaucoma and for OCT average thickness (0.888 +/- 0.072; P < .001) in eyes with suspected glaucoma. CONCLUSIONS: The structure-function relationship was significantly stronger with spectral-domain OCT than with scanning laser polarimetry, and was better expressed logarithmically than linearly. Measurements with these 2 instruments should not be considered to be interchangeable. PMID- 20851371 TI - The anatomical relationships between the lower eyelid retractors and the lacrimal caruncle: a microscopic study. AB - PURPOSE: To characterize the microscopic relationships between the lower eyelid retractors and the lacrimal caruncle and to define the possible role of the caruncle in the lacrimal drainage process. DESIGN: Observational anatomic study. METHODS: Twelve eyelids with their orbital tissues (6 right and 6 left), fixed in 10% buffered formalin, were studied in 10 Asian cadavers (mean age at death: 77.1 years, age range: 62-92 years). An oblique incision in the harvested tissue specimen passed through the lower eyelid retractors and the lacrimal caruncle. The sliced specimens were stained with Masson's trichrome. RESULTS: In all specimens, the lower eyelid retractors were shown to have direct connections to the lacrimal caruncle at the level of the medial horn of the lower eyelid retractors and to reach the medial rectus capsulopalpebral fascia. At this level, smooth muscle fibers were abundant both in the lower eyelid retractors and in the medial rectus capsulopalpebral fascia, which were symmetrically situated to the caruncle. CONCLUSIONS: The lower eyelid retractors have direct connections to the lacrimal caruncle, at a level that is rich in smooth muscle fibers. These anatomic findings may confer functional advantages to the lacrimal drainage system. PMID- 20851373 TI - Gastric cancer-related information on the Internet: incomplete, poorly accessible, and overly commercial. AB - BACKGROUND: Patients increasingly use the Internet for gastric cancer information. However, the quality of the information is questionable. We evaluated the accuracy, completeness, accessibility, reliability, and readability of gastric cancer websites. METHODS: The Internet was searched for the terms "gastric cancer" or "stomach cancer" using general search engines. Websites were evaluated for completeness (CS) and accuracy (AS) using predefined quality appraisal instruments (QAIs), reliability using an integrity score (IS), readability using the Flesch-Kincaid (FK) grade level, and accessibility using automated accessibility appraisal tools. Site sponsor and the presence of quality labels were noted. RESULTS: Fifty-one websites were evaluated. The mean CS was 100.3 (SD +/-44.9), AS was 107.22 (SD +/-47.9), IS was 15.3 (SD +/-3.7), and the mean readability grade level was 10.4 (SD +/-2.5). Only 5 websites had the minimum mandatory basic accessibility. Commercial sites and sites with quality labels had significantly more accessibility violations. CONCLUSIONS: Internet gastric cancer information is overtly commercial, generally incomplete, and poorly accessible. PMID- 20851374 TI - Evaluation of the use of patient-focused simulation for student assessment in a surgery clerkship. AB - BACKGROUND: The purpose of this study was to evaluate the use of simulated patients in conjunction with anatomic and tissue task-training models to assess skills. METHODS: Faculty reviewed the objectives of the clerkship to identify skills to be acquired. Three cases were developed related to rectal examination, suturing, and inserting intravenous lines and nasogastric tubes. Student scores were based on their ability to gather data from simulated patients and perform procedures on simulation models. RESULTS: A total of 670 students were assessed between 2006 and 2009. Alpha reliability coefficients were .97 for Communication/Interpersonal Skills, .71 for Procedures, and .58 for Data Gathering. Students receiving low ratings from faculty in the clerkship had significantly (P < .001) lower simulation scores. There were significant (P < .001) relationships between scores and grades in other clerkships. CONCLUSIONS: The combination of simulated patients and simulation models yielded reliable scores for procedural and interpersonal skills, and evidence of validity related to clinical ratings. PMID- 20851375 TI - Postoperative falls in the acute hospital setting: characteristics, risk factors, and outcomes in males. AB - BACKGROUND: Hospital falls are an important cause of morbidity in older surgical patients. The objectives of this study were to describe the characteristics, risk factors, and outcomes for postoperative falls. METHODS: A retrospective study was performed on patients who were admitted to the hospital for more than 23 hours after surgery. Patients who fell within 30 days of their surgery were considered to have experienced a postoperative fall. RESULTS: Over 5 years and 9,625 inpatient surgical procedures, 154 patients experienced 190 falls. Injuries resulting from postoperative falls included major injury (hip fracture), less than 1%; injury requiring intervention, 2%; injury not requiring intervention, 27%; and no injury, 70%. Variables associated with postoperative falls included older age, functional dependence, lower albumin level, and higher American Society of Anesthesia score. CONCLUSIONS: One or more postoperative falls occurred in 1.6% of surgical inpatients and can lead to significant morbidity. Recognition of fall risk factors will help design postoperative fall prevention programs by identifying patients at highest risk for postoperative falls. PMID- 20851376 TI - Malignant eccrine spiradenoma: a meta-analysis of reported cases. AB - BACKGROUND: Malignant eccrine spiradenoma is an aggressive sweat gland tumor with poorly understood behavior and no currently accepted therapeutic regimen. METHODS: An individual patient data meta-analysis with Kaplan-Meier survival curves was performed on 72 reported cases of malignant eccrine spiradenoma. RESULTS: In 35 patients with no distant metastasis, local resection resulted in 100% disease-free survival. Of 7 patients with lymph node but no distant metastasis treated with surgical resection and lymph node dissection, 6 patients remained disease-free at final follow-up evaluation. For the 24 cases with confirmed distant metastatic disease, patient survival did not significantly differ between local resection and surgery with adjuvant chemoradiotherapy (P = .8763). CONCLUSIONS: Heightened awareness is recommended among surgeons likely to treat this entity. An aggressive surgical approach is supported in the absence of metastasis. When lymph nodes are not clinically involved, sentinel node may have a role followed by lymph node dissection in patients with a positive node. PMID- 20851377 TI - Once bitten, twice incised: recurrent gallstone ileus. AB - Uncommon causes of small bowel obstruction can provide interesting surgical decision-making challenges. This report describes a patient with recurrent gallstone ileus. According to most current reviews, erring on the side of enterolithotomy alone as the treatment of choice for gallstone ileus appears to be the most appropriate decision. Although a rare scenario, the situation of recurrent gallstone ileus presents an interesting learning opportunity. It is important to keep in mind the need for complete examination of the abdomen. Furthermore, evacuation of any remaining stones from the gallbladder is imperative if possible. Erring on the side of enterolithotomy alone as the treatment of choice for gallstone ileus has been shown to be a safe and effective treatment decision over a single-stage removal of the stone with closure of the cholecystoduodenostomy. PMID- 20851378 TI - [Diabetes and hypokinetic cardiopathy : when to consider mitochondrial disease?]. AB - The association between diabetes mellitus and hypokinetic cardiomyopathy is frequent. We report a case of diabetes and hypokinetic cardiopathy in a 40-year old man which led to the hypothesis of maternally inherited diabetes and deafness (MIDD) due to a mitochondrial disease. This diagnosis was confirmed by genetic testing which showed a DNA A3243G mutation in the mitochondria, the prevalence of which is 1-2% in diabetes mellitus. Cardiac abnormalities are frequent (18-34% of patients depending on the series) and the co-existence of left ventricular hypertrophy and systolic dysfunction is suggestive of this disease. Some authors have proposed co-enzyme Q as a treatment to improve the left ventricular ejection fraction and insulin secretion. PMID- 20851379 TI - [Non invasive methylergometrine test should be carried out after cardiac arrest due to coronary spasm?]. AB - A 59-year-old man was admitted after cardiac arrest with successful reanimation. There was no significant coronary lesion. We conclude to the diagnosis of coronary spasm after the occurrence of a chest pain with anterior ST elevation reversible with intravenous nitrates. One month later, non-invasive methylergometrine test was carried out and complicated by a cardiac arrest due to complete heart block and asystole treated by chest compression, molsidomine and epinephrine. No cardiac event occurred within the following six months. Technique (invasive versus not invasive) and indication of methylergometrine test for the follow-up of severe manifestations of coronary spasm should be better specified in international guidelines. PMID- 20851380 TI - Processing efficiency in anxiety: Evidence from eye-movements during visual search. AB - It is generally held that anxiety is characterized by an attentional bias for threatening information. In recent years there has been an important debate whether these biases reside at the level of attentional selection (threat detection) or attentional processing after threat detection (attentional disengagement). In a visual search task containing emotional facial expressions, eye-movements were examined before and after threat detection in high and low trait anxious individuals to further elucidate the temporal unfolding of attentional bias. Results indicated that high-anxious individuals neither showed facilitated orienting to threat nor impaired disengagement of visual attention from threat. Interestingly, the presence of threat in the visual search display was associated with increased decision times in high-anxious individuals. These results challenge some of the current views on attentional bias to threat but indicate that emotional information reduces processing efficiency in anxiety. PMID- 20851381 TI - Hybrid nanofibrous yarns based on N-carboxyethylchitosan and silver nanoparticles with antibacterial activity prepared by self-bundling electrospinning. AB - Hybrid nanofibrous materials with antibacterial activity consisting of yarns from N-carboxyethylchitosan (CECh) and poly(ethylene oxide) (PEO) that contain 5 wt% or 10 wt% silver nanoparticles (AgNPs) were prepared. This was achieved by electrospinning using formic acid as a solvent and as a reducing agent for silver ions. AgNO3 was used as an Ag(+)-containing salt. Its concentration was selected to be 0.02 mol/L or 0.04 mol/L in order the content of the AgNPs in the electrospun nanofibers to be 5 wt% or 10 wt%, respectively. The self-bundling of the fibers into yarns with a mean diameter of ca. 35 MUm was enabled only by using a grounded needle electrode. The reduction of the silver ions to an elemental silver was evidenced by UV-vis spectroscopy, X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The transmission electron microscopy (TEM) analyses revealed that AgNPs formed at AgNO3 concentration of 0.02 mol/L were with a mean diameter of 4+/-0.5 nm and were distributed uniformly within the fiber. The increase of AgNO3 concentration to 0.04 mol/L led to the preparation of AgNPs with a higher mean diameter and a broader diameter distribution as well as to aggregate formation. The performed studies on the antibacterial activity of CECh/PEO/AgNPs fibrous materials against Staphylococcus aureus showed that at AgNPs content of 5 wt% the mats had bacteriostatic, and at AgNPs content of 10 wt%-bactericidal activity. PMID- 20851382 TI - Isocyanate crosslinked reactive starch nanoparticles for thermo-responsive conducting applications. AB - Hydrophobic nanoparticles and nanocomposite films of 1,4-hexamethylene diisocyanate (HMDI)-modified starch nanoparticles (SNPs) have been synthesized at ambient temperatures. The platelet-like starch nanocrystals become pseudospherical after modification with HMDI and the size increases or decreases depending on diisocyanate concentration compared to the ungrafted particles as revealed by transmission electron microscopy (TEM) results. The obtained nanocrystals were characterized by means of the FT-IR and X-ray diffraction (XRD) techniques. When compared with the hydrophobic performance of the unmodified starch nanocrystals, that of crosslinked starch nanocrystals significantly increased. X-ray diffraction reveals that the crystalline structure of modified starch nanocrystals was preserved. The resulting hydrophobic starch nanoparticles are versatile precursors to the development of nanocomposites. The polyether polyurethane crosslinked with SNPs nanocomposite film exhibited thermo-responsive electrical conductivity. PMID- 20851383 TI - The expression and function of beta-1,4-galactosyltransferase-I in dendritic cells. AB - beta-1,4-Galactosyltransferase-I (GalTI) is unusual among the galactosyltransferase family, which has two isoforms that differ only in the length of their cytoplasmic domains [1]. In this study, we found that both the long and short isoforms of GalTI were expressed in human monocyte-derived dendritic cells (MoDCs), and localized in the cytoplasm near nucleus and cytomembrane. The expression level of GalTI and cellular adhesion ability was increased when DCs continued to mature. We also demonstrated that the cellular adhesion ability of DCs was inhibited by alpha-lactalbumin (alpha-LA) via interference with cell surface GalTI function, suggesting that the adhesion ability was positively correlated with the expression of cell surface long GalTI. alpha-LA also could inhibit DC-T clustering and CD4(+) T cell proliferation. Collectively, the data suggests that GalTI might act as a key adhesion molecular participating in T cells-DCs contacts. PMID- 20851384 TI - The DTH effector response and IL-2 are unaffected by cyclosporine A in autoimmune B6D2F1 mice. AB - Delayed-type hypersensitivity (DTH) is classically defined as inflammation involving activated Th1 cells and cytokine production. DTH paw swelling, along with the cytokines IL-2, IFNgamma, MCP-1 and TNFalpha, were inhibited in Balb/c mice by cyclosporine A (CsA). Surprisingly, the DTH response in the B6D2F1 mice was unaffected by CsA, despite a decrease in TNFalpha and IFNgamma levels. IL-2 levels, however, were not decreased. To determine if the IL-2 production in the B6D2F1 strain is occurring through CD28-mediated costimulation, both CsA and CTLA 4Ig were administered. Paw swelling and IL-2 levels were decreased, indicating a role for costimulation. Co-administration of temsirolimus and CsA also reduced DTH and IL-2 levels in B6D2F1 mice, demonstrating involvement of the mTORC1 pathway. These results indicate that the cell activation pathways responsible for DTH differ with mouse strain. It is important to understand these differences in order to accurately interpret the results using potential therapeutic agents. PMID- 20851385 TI - Cytotoxicity responses to selected ESAT-6 and CFP-10 peptides in tuberculosis. AB - Cytotoxicity responses were studied for the ESAT-6 peptides Esp1, Esp6, Esp7, Esp8, and CFP-10 peptides, Cfp6, Cfp7, Cfp8, Cfp9 (synthetic 20-mer peptides) and the recombinant ESAT-6, CFP-10 proteins. Cytolytic molecules perforin, granzymes A and B, granulysin responses in healthy household contacts (HHC) and pulmonary tuberculosis patients (PTB), were studied by intracellular flow cytometry. Functional cytotoxicity was studied in both the groups for the peptides Esp6 and Cfp8 by an enzyme (lactate dehydrogenase) based assay. The results revealed that cytolytic molecule positive CD4+ and CD8+ T cells were increased in HHC in response to Esp1, Esp6, Cfp8 and Cfp9 immunogenic peptides compared to PTB. Functional cytotoxicity results showed higher cytotoxicity (not statistically significant) to be exhibited by the peptide Esp6 than Cfp8 in the HHC. PMID- 20851388 TI - [Antibiotic treatment in Fournier's gangrene]. PMID- 20851386 TI - Neutralization of interleukin (IL)-10 released by monocytes/macrophages enhances the up-regulatory effect of monocyte/macrophage-derived IL-6 on expressions of IL 6 and MUC1, and migration in HT-29 colon cancer cells. AB - The interactions between monocyte-derived IL-6 and IL-10 in colon cancer are unknown. We continued previous work that showed monocyte/macrophage-derived IL-6 induces IL-6 and MUC1 expression in HT-29 cancer cells, and evaluated if IL-10 present in monocyte/macrophage is involved in this IL-6-mediated effect. We treated HT-29 cells with monocyte/macrophage supernatant following neutralization of monocyte/macrophage-released IL-10. Neutralization markedly enhanced monocyte/macrophage-derived IL-6 effects on HT-29 cells including IL-6 and MUC1 production and cell migration. Double blocking of IL-6 and IL-10 in monocyte/macrophage supernatants abolished this enhancement. Western blot analysis of STAT3 phosphorylation showed that this augmented response in HT-29 cells following IL-10 neutralization is probably mediated through enhanced IL-6 induced phosphorylation (Tyr(705)) of STAT3 proteins. Therefore, monocytes/macrophages have the capacity to release the functionally associated cytokines IL-6 and IL-10 whose interactions can account for the pathogenesis and progression of colon cancer. PMID- 20851389 TI - [Adequate management of postoperative pain in surgery for hemorrhoidal disease]. PMID- 20851390 TI - [Acute heart failure in patients over 70 years of age: Precipitating factors of decompensation]. AB - OBJECTIVES: Heart failure decompensation is the most common reason for hospitalization in persons over 65 years old. There is limited information on the prevalence of precipitating factors of heart failure decompensation in this population. In this study we prospectively examined the factors associated with decompensation of heart failure in patients over 70 years of age. MATERIAL AND METHODS: During the 36 months from January 2006 to December 2008, we included 386 patients over 70 years of age that were admitted through emergencies with these three criteria: Dyspnea (class III or IV of the New Yourk Heart Association), pulmonary edema and echocardiographic data of left ventricular systolic or diastolic dysfunction. RESULTS: The mean age of the patients was 82 years and 58.5% were female. Left ventricular systolic dysfunction was diagnosed in 41.2% of them. We identified one or more precipitating factors of heart failure decompensation in 89.6% of the patients. The most common were atrial tachyarrhythmia (22.3%), respiratory infection (21.2%), severe anemia (17.1%), acute renal failure (12.7%), severe hypoalbuminemia (11.4%) and acute coronary syndrome (9.1%). Fifty-two patients (13.5%) died. The variables independently associated with hospital mortality were acute renal failure, severe hypoalbuminemia, systolic blood pressure <110mmHg, white blood cell count >10.000 per mm3 and valvular heart disease. CONCLUSIONS: In most patients over 70 years of age hospitalized with acute heart failure it is possible to identify one or more precipitating factors of decompensation, some of which are independently associated with hospital mortality. PMID- 20851391 TI - [Thyroid dysfunction in hospital worker population]. AB - INTRODUCTION: The prevalence of thyroid dysfunction (TD) and thyroid autoimmunity (TA) in hospital employees in our country is unknown. OBJECTIVE: To study the prevalence of TD and TA in a group of hospital employees. STUDY SUBJECTS AND METHODS: We studied thyroid function (thyrotropin, TSH, free thyroxine, T4, and free triiodothyronine, T3) and thyroid autoimmunity (anti-thyroglobulin, antiTg and anti-thyroid peroxidase, antiTPO) in 310 adult subjects (18-70 years) from the hospital General, Segovia, Spain during 2007. RESULTS: Eleven subjects (3.5%, 10 women) had previously known TD. Thirty-four subjects (11.0%) were diagnosed of unknown TD, mainly subclinical hypothyroidism (8.4%). Prevalence of total TD was 14.2%. TA was positive in 44 (14.2%) subjects. Both TD (P<0.05) and TA (P<0.05) were associated with female sex, and antiTPO levels were related to the presence of unknown TD (OR 1.007; 95% CI, 1.004-1.010; P<0.001). CONCLUSION: In this population, total prevalence of TD and TA is similar (14%). Increased antiTPO titers are predictors of unknown TD. PMID- 20851392 TI - [Acute chest pain caused by pericardial fat necrosis: a diagnosis to consider in some patients]. PMID- 20851393 TI - An impact source localization technique for a nuclear power plant by using sensors of different types. AB - In a nuclear power plant, a loose part monitoring system (LPMS) provides information on the location and the mass of a loosened or detached metal impacted onto the inner surface of the primary pressure boundary. Typically, accelerometers are mounted on the surface of a reactor vessel to localize the impact location caused by the impact of metallic substances on the reactor system. However, in some cases, the number of accelerometers is not sufficient to estimate the impact location precisely. In such a case, one of useful methods is to utilize other types of sensor that can measure the vibration of the reactor structure. For example, acoustic emission (AE) sensors are installed on the reactor structure to detect leakage or cracks on the primary pressure boundary. However, accelerometers and AE sensors have a different frequency range. The frequency of interest of AE sensors is higher than that of accelerometers. In this paper, we propose a method of impact source localization by using both accelerometer signals and AE signals, simultaneously. The main concept of impact location estimation is based on the arrival time difference of the impact stress wave between different sensor locations. However, it is difficult to find the arrival time difference between sensors, because the primary frequency ranges of accelerometers and AE sensors are different. To overcome the problem, we used phase delays of an envelope of impact signals. This is because the impact signals from the accelerometer and the AE sensor are similar in the whole shape (envelope). To verify the proposed method, we have performed experiments for a reactor mock-up model and a real nuclear power plant. The experimental results demonstrate that we can enhance the reliability and precision of the impact source localization. Therefore, if the proposed method is applied to a nuclear power plant, we can obtain the effect of additional installed sensors. PMID- 20851394 TI - The Trauma and Injury Severity Score (TRISS) revised. AB - BACKGROUND: The Trauma and Injury Severity Score (TRISS) remains the most commonly used tool for benchmarking trauma fatality outcome. Recently, it was demonstrated that the predictive power of TRISS could be substantially improved by re-classifying the component variables and treating the variable categories nominally. This study aims to develop revised TRISS models using re-classified variables, to assess these models' predictive performances against existing TRISS models, and to identify and recommend a preferred TRISS model. MATERIALS AND METHODS: Revised TRISS models for blunt and penetrating injury mechanism were developed on an adult (aged 15 years) sample from the National Trauma Data Bank National Sample Project (NSP), using 5-category variable classifications and weighted logistic regression. Their predictive performances were then assessed against existing TRISS models on the unweighted NSP, National Trauma Data Bank (NTDB), and New Zealand Database (NZDB) samples using area under the Receiver Operating Characteristic curve (AUC) and Bayesian Information Criterion (BIC) statistics. RESULTS: The weighted NSP sample included 1,124,001 adults with blunt or penetrating injury mechanism events and known discharge status, of whom 1,061,709 (94.5%) survived to discharge. Complete information for all TRISS variables was available for 896,212 (79.7%). Revised TRISS models that included main-effects and two-factor interaction terms had superior AUC and BIC statistics to main effects models and existing TRISS models for patients with complete data in NSP, NTDB and NZDB samples. Predictive performance decreased as the number of variables with missing values included within revised TRISS models increased, but model performances generally remained superior to existing TRISS models. DISCUSSION: Revised TRISS models had importantly improved predictive capacities over existing TRISS models. Additionally, they were easily computed, utilised only those variables already collected for existing TRISS models, and could be applied and produce meaningful survival probabilities when one or more of the predictor variables contained missing values. The preferred revised TRISS model included main-effects and two-factor interaction terms and allowed for missing values in all predictor variables. A strong case exists for replacing existing TRISS models in trauma scoring systems benchmarking software with this preferred revised TRISS model. PMID- 20851395 TI - Unintentional injury deaths among adult Finns in 1971-2008. AB - Injuries are a significant public health problem and among the leading causes of death worldwide. In Finland, nearly 1.2 million accidents or assaults lead to physical injury annually. This study examined the nationwide trends in unintentional injury deaths of adults in Finland. For this purpose, we obtained from the Finnish Official Cause-of-Death Statistics (OCDS) the data for persons aged 15 years or older whose deaths occurred in 1971-2008 due to an unintentional injury. A drastic decline occurred in road traffic crashes. The age-standardized death rate (per 100,000 person-years) of men's road traffic crashes was 48 in 1971 but only 10 in 2008. Traffic caused fewer deaths in women than men, but the declining trend in women's death rates was also clear, from 17 in 1971 to 3 in 2008. During the study period, falls became the leading category of men's unintentional injury death, although their rate rose rather slowly from 19 in 1971 to 21 in 2008. Among Finnish women, the rate of fall-induced deaths declined from 32 in 1971 to 16 in 2008. There was a notable rise in men's unintentional alcohol poisoning deaths, especially since 2003. In 2008, alcohol poisonings were the second leading cause of men's injury death (rate 18). The rate of women's deaths due to alcohol poisoning was yet low during the entire study period but its rise was clear, from 1 in 1971 to 5 in 2008. Poisoning deaths caused by other substances also increased: among men their rate was 4 in 1971 and 11 in 2008, and among women 2 in 1971 to 4 in 2008. Between 1998 and 2008, psychotropic drugs, narcotics and opioid analgesics caused the majority of both men's and women's non alcohol poisoning deaths. In conclusion, unintentional injury deaths in road traffic crashes declined steeply among adult Finns during 1971-2008. The rate of fall-induced deaths in Finnish men was rather stable during the study period while in women it clearly declined. In contrast, increase in poisoning deaths due to alcohol and other substances was alarming. Vigorous preventive actions should be initiated to control this development. PMID- 20851396 TI - Trauma and Injury Severity Score (TRISS): is it time for variable re categorisations and re-characterisations? AB - BACKGROUND: Despite its limitations, the Trauma and Injury Severity Score (TRISS) continues to be the most commonly used tool for benchmarking trauma outcome. Since its inception, considerable energy has been devoted to improving TRISS. However, there has been no investigation into the classification or characterisation of the TRISS variables. Using a major nationally representative database, this study aims to explore the adequacy of the existing TRISS model by investigating variable re-categorisations and alternative characterisations in a logistic model used to predict survival in adults after traumatic injury. MATERIALS AND METHODS: Data were obtained from the National Trauma Data Bank National Sample Project (NSP). Each variable in the TRISS model was related to discharge status and various categorisations considered using weighted logistic regression. Categorisations were treated nominally,using a series of indicator variables. For each variable and classification level, the best category combination was ascertained using the Bayesian Information Criterion (BIC). All best 5-category classified TRISS variables were combined, as were all best 10 category classified TRISS variables, and their predictive performance assessed against two conventionally defined TRISS models on the unweighted NSP sample using area under the Receiver Operating Characteristic curve (AUC) and BIC statistics. RESULTS: Overall, the weighted sample included 1,124,001 adults with injury events and known discharge status, of whom 1,061,709 (94.5%) were alive at discharge. When separately related to discharge status, each re-classified TRISS variable yielded a superior BIC statistic to its original specification. When investigating predictive performance, complete information was available for 167,239 (79.9%) adults with blunt and 20,643 (82.3%) adults with penetrating injury mechanisms. AUC and BIC estimates for the re-classified TRISS models were superior to the conventionally defined TRISS models. While having better predictive precision, the complexity associated with the best 10-category model resulted in the best 5-category model being preferred for penetrating mechanism injuries and being negligibly inferior for blunt mechanism injuries. DISCUSSION: Substantial improvements in the predictive power of TRISS were demonstrated by reclassifying the component variables and treating the variable categories nominally. However, before anew TRISS model with updated coefficients can be published, variable interactions and the effect of missing data needs thorough statistical evaluation. PMID- 20851397 TI - Increased mechanosensitivity of cells cultured on nanotopographies. AB - Enhancing cellular mechanosensitivity is recognized as a novel tool for successful musculoskeletal tissue engineering. We examined the hypothesis that mechanosensitivity of human mesenchymal stem cells (hMSCs) is enhanced on nanotopographic substrates relative to flat surfaces. hMSCs were cultured on polymer-demixed, randomly distributed nanoisland surfaces with varying island heights and changes in intracellular calcium concentration, [Ca(2+)](i), in response to fluid flow induced shear stress were quantifide. Stem cells cultured on specific scale nanotopographies displayed greater intracellular calcium responses to fluid flow. hMSCs cultured on 10-20nm high nanoislands displayed a greater percentage of cells responding in calcium relative to cells cultured on flat control, and showed greater average [Ca(2+)](i) increase relative to cells cultured on other nanoislands (45-80nm high nanoislands). As [Ca(2+)](i) is an important regulator of downstream signaling, as well as proliferation and differentiation of hMSCs, this observation suggests that specific scale nanotopographies provide an optimal milieu for promoting stem cell mechanotransduction activity. That mechanical signals and substrate nanotopography may synergistically regulate cell behavior is of significant interest in the development of regenerative medicine protocols. PMID- 20851398 TI - Multi-residue analytical method for human pharmaceuticals and synthetic hormones in river water and sewage effluents by solid-phase extraction and liquid chromatography-tandem mass spectrometry. AB - Pollutants such as human pharmaceuticals and synthetic hormones that are not covered by environmental legislation have increasingly become important emerging aquatic contaminants. This paper reports the development of a sensitive and selective multi-residue method for simultaneous determination and quantification of 23 pharmaceuticals and synthetic hormones from different therapeutic classes in water samples. Target pharmaceuticals include anti-diabetic, antihypertensive, hypolipidemic agents, beta2-adrenergic receptor agonist, antihistamine, analgesic and sex hormones. The developed method is based on solid phase extraction (SPE) followed by instrumental analysis using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) with 30 min total run time. River water samples (150 mL) and (sewage treatment plant) STP effluents (100 mL) adjusted to pH 2, were loaded into MCX (3 cm(3), 60 mg) cartridge and eluted with four different reagents for maximum recovery. Quantification was achieved by using eight isotopically labeled internal standards (I.S.) that effectively correct for losses during sample preparation and matrix effects during LC-ESI MS/MS analysis. Good recoveries higher than 70% were obtained for most of target analytes in all matrices. Method detection limit (MDL) ranged from 0.2 to 281 ng/L. The developed method was applied to determine the levels of target analytes in various samples, including river water and STP effluents. Among the tested emerging pollutants, chlorothiazide was found at the highest level, with concentrations reaching up to 865 ng/L in STP effluent, and 182 ng/L in river water. PMID- 20851400 TI - Sensitizing of pyrene fluorescence by beta-cyclodextrin-modified TiO2 nanoparticles. AB - TiO(2) nanoparticles were synthesized by hydrolysis of tetraisopropyl orthotitanate in an aqueous solution of cyclodextrin. The beta-cyclodextrin modified spherical TiO(2) nanoparticles were water-dispersible and had an average particle diameter of 4.4 +/- 1 nm. Pyrene fluorescence was enhanced by increasing the concentration of beta-cyclodextrin-modified TiO(2) nanoparticle and the sensitization effect was triply stronger than the case of the beta-cyclodextrin only. The increase in a concentration of host (beta-cyclodextrin) changes its microenvironment for guest (pyrene), that is, the interaction of pyrene with apolar cavity of beta-cyclodextrin increases, resulting in enhancement of fluorescence. The sensitization behavior of pyrene fluorescence in the presence of TiO(2) nanoparticles occurs from the increase in the extinction coefficient of pyrene, demonstrating the charge transfer between pyrene and metal oxide nanoparticle. PMID- 20851399 TI - A cost effective, sensitive, and environmentally friendly sample preparation method for determination of polycyclic aromatic hydrocarbons in solid samples. AB - A simple, cost effective, and yet sensitive sample preparation technique was investigated for determining Polycyclic Aromatic Hydrocarbons (PAHs) in solid samples. The method comprises ultrasonic extraction, Stir Bar Sorptive Extraction (SBSE), and thermal desorption-gas chromatography-mass spectrometry to increase analytical capacity in laboratories. This method required no clean-up, satisfied PAHs recovery, and significantly advances cost performance over conventional extraction methods, such as Soxhlet and Microwave Assisted Extraction (MAE). This study evaluated three operational parameters for ultrasonic extraction: solvent composition, extraction time, and sample load. A standard material, SRM 1649 a (urban dust), was used as the solid sample matrix, and 12 priority PAHs on the US Environmental Protection Agency (US EPA) list were analyzed. Combination of non polar and polar solvents ameliorated extraction efficiency. Acetone/hexane mixtures of 2:3 and 1:1 (v/v) gave the most satisfactory results: recoveries ranged from 63.3% to 122%. Single composition solvents (methanol, hexane, and dichloromethane) showed fewer recoveries. Comparing 20 min with 60 min sonication, longer sonication diminished extraction efficiencies in general. Furthermore, sample load became a critical factor in certain solvent systems, particularly MeOH. MAE was also compared to the ultrasonic extraction, and results determined that the 20-min ultrasonic extraction using acetone/hexane (2:3, v/v) was as potent as MAE. The SBSE method using 20 mL of 30% alcohol fortified solution rendered a limit of detection ranging from 1.7 to 32 ng L(-1) and a limit of quantitation ranging from 5.8 to 110 ng L(-1) for the 16 US EPA PAHs. PMID- 20851401 TI - Direct determinations of energetic parameters at chitosan/Cr(VI) interfaces by means of immersion heat-conduction microcalorimetry. AB - Interaction parameters at epichlorohydrin-crosslinked chitosan beads/Cr(VI) interfaces from aqueous solutions was obtained by using immersion heat-conduction microcalorimetry. This technique permits simultaneous determinations of adsorbed amounts and interaction energies. The experimental variables evaluated were pH of the Cr(VI) solutions of 4.0 and 6.0, initial Cr(VI) concentration in solution of 0.50 and 5.00 * 10(-3) mol L(-1) and temperature of 25 and 45 degrees C. The calorimetric results were evaluated using a 2(3) full factorial design. The responses were the adsorption amounts (n(int)), the adsorption energies (Q(int)) and the adsorption enthalpies (Delta(int)H). The results indicated that all thermodynamic responses (adsorption energies and adsorption enthalpies) are all exothermic in nature. The initial Cr(VI) concentration in solution was the most important parameter in all responses evaluated in this study. Polynomial fits have pointed out that almost all interactive effects are statistically important on the values of n(int), Q(int) and Delta(int)H. It is concluded that the thermodynamical aspects of the Cr(VI) adsorption parameters are greatly influenced by the interactive factors and not by temperature changes alone. PMID- 20851403 TI - Controlled synthesis of Pt nanoparticles via seeding growth and their shape dependent catalytic activity. AB - Through a seed-mediated growth route, Pt nanoparticles (NPs) with tunable shape and size were prepared, such as octahedral, cuboctahedral, branched and rice like. Three nanometer Pt NPs were prepared and dispersed in oleyl amine to form seed solution and then Pt precursor (platinum acetylacetonate (Pt(acac)(2))) was added. Under high temperature, oleyl amine as both reducing and protective agents can reduce Pt precursor to Pt atoms which selectively deposit on seeds surface to form variously structured Pt NPs. By adjusting the reactive conditions (the molar ratio of Pt metals from Pt(acac)(2) and seed (PPS), the seed diameter, the addition route of Pt(acac)(2)), the NPs growth could be controlled to fall into kinetic or thermodynamic regime, producing variously shaped NPs. On the basis of observed results, a reaction mechanism in which the resulting NP shape had strong dependence on c/s (c=precursor concentration, s=available deposition surface area) was figured out. The obtained NPs were supported on black carbon to act as Pt/C catalysts for oxidization of methanol and results show that the catalysts from branched NPs had higher catalytic activity and stability than ones from polyhedral NPs. PMID- 20851402 TI - Effect of film thickness and particle size on cracking stresses in drying latex films. AB - The stress at which latex films crack during drying was investigated using beam bending. Two systems were investigated: (i) poly(methyl methacrylate/butyl acrylate) particles cast as thin films to examine the effect of film thickness on cracking film stress and (ii) polystyrene particles dried as drops to investigate the effect of particle size. Results indicated an inverse relationship between film thickness and film stress, whilst film stress was shown to be independent of the original particle size. These outcomes were in good agreement with Tirumkudulu and Russel's theoretical analysis [M.S. Tirumkudulu and W.B. Russel, Langmuir 21 (2005) 4938], albeit the measured stress values were almost twice the theoretical estimation. PMID- 20851404 TI - Effect of heat treatment on CO2 adsorption of KOH-activated graphite nanofibers. AB - In this work, graphite nanofibers (GNFs) were successfully expanded intercalating KOH followed by heat treatment in the temperature range of 700-1000 degrees C. The aim was to improve the CO(2) adsorption capacity of the GNFs by increasing the porosity of GNFs. The effects of heat treatment on the pore structures of GNFs were investigated by N(2) full isotherms, XRD, SEM, and TEM. The CO(2) adsorption capacity was measured by CO(2) isothermal adsorption at 25 degrees C and 1 atm. From the results, it was found that the activation temperature had a major influence on CO(2) adsorption capacity and textural properties of GNFs. The specific surface area, total pore volume, and mesopore volume of the GNFs increased after heat treatment. The CO(2) adsorption isotherms showed that G-900 exhibited the best CO(2) adsorption capacity with 59.2 mg/g. PMID- 20851405 TI - Clogging of microchannels by nano-particles due to hetero-coagulation in elongational flow. AB - We have investigated the phenomenon of flow-induced aggregation in highly concentrated colloidal dispersions exposed to strongly converging flow fields. This phenomenon is relevant not only for classical technical operations like coating, pumping or filtration, but also for the application of concentrated suspensions in upcoming processing technologies based on microfluidic devices. A ring-slit device (gap height 10-25 MUm), which allows for a variation of flow kinematics in a wide range, has been developed in order to investigate this phenomenon. Various polymer dispersions with different particle surface properties have been used as model systems. Our experiments exclude, that channel clogging is due to retention of pre-existing aggregates, fouling or hydrodynamic bridging. Instead, we demonstrate that clogging of the microchannel is induced by hetero-coagulation between primary colloidal particles and micron-sized impurities present at concentrations on the order of 100-1000 ppm. Clogging can occur even if the diameter of these impurities is less than a tenth of the gap height. Aggregation takes place in the converging flow field at the channel entrance, but not in the shear field within the slit. It can be suppressed by appropriate stabilization of the primary particles. PMID- 20851406 TI - Preparation of poly(2-amino thiophenol) nanodiscs by a "combined hard-soft template" approach and characterization. AB - A seed induced chemical oxidative polymerization was used for the preparation of pure poly(2-amino thiophenol) nanodiscs (P2AT-NDs (P)). Two templates, (hard (MCM 41) and soft (beta-napthalene sulfonic acid), were utilized for the preparation of the seed, P2AT nanostructures loaded MCM-41. The field emission scanning electron microscopy reveals nanodisc morphology for P2AT (P). X-ray diffraction, current-potential characteristics and electrochemical impedance spectroscopy were used to evaluate the physicochemical properties of P2AT-ND (P). The P2AT-ND (P) exhibits semicrystalline behaviour, good electron transport and lesser charge transfer resistance at the interface as compared to simple P2AT prepared by conventional chemical route. PMID- 20851407 TI - Particle separation by a moving air-liquid interface in a microchannel. AB - Particle separation is an important topic in microfluidic field and has recently gained significant attention in sample preparations for biological and chemical studies. In this paper, a novel particle separation method was proposed. In this method, the particles were separated by the air-liquid interface in a microchannel. The motion of the air-liquid interface was controlled with a syringe pump. Depending on the air-liquid interface speed, the liquid film thickness and the viscous force on particles were changed and the particles were separated by sizes. We observed the separation of 1.01 MUm particles from the larger particles when the air-liquid interface speed was less than 11 MUm/s, and the separation of both 1.01 MUm and 5.09 MUm particles from the larger particles when the interface speed was between 11 MUm/s and 120 MUm/s. When the speed was higher than 120 MUm/s, the drag force of the liquid flow generated by the advancing interface on particles was so strong that the flow removed all particles off from the bottom channel wall and there were no particles left behind the advancing interface. PMID- 20851408 TI - A strategy of fast reversible wettability changes of WO3 surfaces between superhydrophilicity and superhydrophobicity. AB - As-prepared WO(3) nanostructure films on alumina or tungsten substrates by a facile hydrothermal method exhibit a superhydrophilic property. An effective strategy is proposed to control the wettability of WO(3) films in a reversible manner between superhydrophilicity and superhydrophobicity with a rapid response. By controlling the process of adsorption/desorption of n-dodecanethiol associated with the light-induced plating Ag nano-grains on WO(3) nanostructures, it only takes about 25 min to fulfill the wettability change from superhydrophilicity to superhydrophobicity, and only 30 s to finish the reversed change. Moreover, the contact angles of WO(3) surface can be tuned by controlling the etching time of superhydrophobic WO(3) surfaces in a solution of nitric acid containing 5 mM sodium dodecyl benzene sulfonate. Electrowetting process is successfully demonstrated to trap a water drop onto the superhydrophobic WO(3) surfaces. Considering WO(3) is one of typical electrochromic materials, researches on the effect of coupling between electrowetting and electrochromic properties would be more promising. PMID- 20851409 TI - A review of electrocardiogram filtering. AB - Analog filtering and digital signal processing algorithms in the preprocessing modules of an electrocardiographic device play a pivotal role in providing high quality electrocardiogram (ECG) signals for analysis, interpretation, and presentation (display, printout, and storage). In this article, issues relating to inaccuracy of ECG preprocessing filters are investigated in the context of facilitating efficient ECG interpretation and diagnosis. The discussion covers 4 specific ECG preprocessing applications: anti-aliasing and upper-frequency cutoff, baseline wander suppression and lower-frequency cutoff, line frequency rejection, and muscle artifact reduction. Issues discussed include linear phase, aliasing, distortion, ringing, and attenuation of desired ECG signals. Due to the overlapping power spectrum of signal and noise in acquired ECG data, frequency selective filters must seek a delicate balance between noise removal and deformation of the desired signal. Most importantly, the filtering output should not adversely impact subsequent diagnosis and interpretation. Based on these discussions, several suggestions are made to improve and update existing ECG data preprocessing standards and guidelines. PMID- 20851410 TI - Cannabis and psychometrically-defined schizotypy: use, problems and treatment considerations. AB - Cannabis use is associated with onset of psychosis in individuals vulnerable for developing schizophrenia-spectrum disorders. The present study addressed three knowledge gaps pertaining to this issue: 1) clarifying the incidence of cannabis use in schizotypal individuals, 2) examining how cannabis use is related to psychosocial and physiological problems in schizotypy and interest in treatment, and 3) examining how cannabis use is associated with positive, negative and disorganization features of schizotypy. Scores from a measure of schizotypal traits were used to trichotomize 1665 young adults into schizotypy (top 5% of scorers), non-schizotypy (bottom 50% of scorers) and "unconventional" (scorers within the 50th to 85th percentile) groups. Nearly a quarter of the schizotypy group endorsed cannabis use at least weekly, a rate nearly two to four times that of the other groups. The schizotypy group also reported a much greater frequency of cannabis-related problems compared to the other groups. Despite this, interest in treatment for cannabis use in the schizotypy group was not elevated. Interestingly, 85% of individuals in the schizotypy group reported interest in psychological/psychiatric treatment more generally. Cannabis use was not associated with abnormal patterns of positive or disorganized schizotypy traits in the schizotypy group relative to the other groups. However, cannabis use was associated with lower severity of negative traits. Implications of these results are discussed. PMID- 20851411 TI - Prognostic impact of fascin-1 expression is more significant in advanced colorectal cancer. AB - BACKGROUND: Fascin-1 is not expressed in normal colorectal epithelium, but is up regulated in colorectal cancer. However, its exact biological mechanism remains unknown. The purpose of this study was to investigate the relationship of fascin 1 expression with the clinicopathologic parameters and its prognostic impact in advanced colorectal cancer. MATERIALS AND METHODS: The immunohistochemical stainings for fascin-1, beta-catenin, and Ki-67 labeling index were performed with 126 stage III colorectal cancer specimens. RESULTS: Fascin-1 was found to be expressed in 74 (58.7%) of the 126 colorectal cancer specimens. Five-year survival rate was significantly low, whereas the distant recurrence rate was significantly high in patients with fascin-positive stage III colorectal cancer. There was no significant correlation between fascin-1 expression and clinicopathologic factors such as tumor size, nodal metastasis, pathologic stage, beta-catenin expression, and Ki-67 labeling index. However, fascin-1 expression was an independent prognostic factor in multivariate analysis. Patients with N1 showed no significant difference in 5-y DFS and OS according to the fascin-1 expression (79.0% versus 60.5%, P = 0.113; 86.5% versus 78.8%, P = 0.566). Patients with N2 showed marginal difference in 5-y DFS and significant difference in 5-y OS according to the fascin-1 expression (59.4% versus 32.4%, P = 0.088; 81.2% versus 39.5%, P = 0.002). CONCLUSIONS: This study suggests that fascin-1 expression in colorectal cancer may be clinically useful in predicting distant metastasis and poor survival, and we demonstrated that fascin-1 expression and N stage are significant independent prognostic factors for survival of colorectal cancer patients. PMID- 20851412 TI - The faith of ilioinguinal nerve after preserving, cutting, or ligating it: an experimental study of mesh placement on inguinal floor. AB - BACKGROUND: Postherniorrhaphy chronic pain may be related to the trauma to the regional nerves or prosthetic mesh. This study was aimed to search the objective findings of prosthetic mesh placement on the ilioinguinal nerve in three different nerve treatment patterns with two different mesh types. MATERIALS AND METHODS: Thirty New Zealand rabbits were used. Bilateral ilioinguinal nerves were identified. A 2*1 cm standard polypropylene mesh was laid on the nerve on right side, whereas a same sized lightweight polypropylene was applied on the left after three different nerve treatments were carried out. The nerve was completely preserved in the first group [G1], cut by scissors without a further process in the second [G2], and proximal cut end was ligated with 5/0 polyglactin. Three months after the surgery, bilateral nerve samples were taken from the contiguous nerve segment for light microscopy and electron microscopy. RESULTS: Nerve protection could not prevent microscopic changes entirely. Prosthetic mesh itself seemed to cause histopathologic changes. Overall incidence of histopathologic changes in light microscopy, without taking the nerve treatment pattern into account, was somewhat lower at standard mesh side than that of lightweight mesh side. However this difference did not reach the level of significance (P=0.39). When three groups were evaluated in respect to overall nerve damage without paying attention to mesh type, the highest damage rate was observed in G3 (cut and ligate). When each group was compared separately within itself for histopathologic changes, no differences were observed between heavy and light mesh sides in any group. When the microscopic changes were compared in respect to the different nerve treatment patterns on heavyweight mesh side, the rates were 12.5%, 12.5%, and 33.3%, respectively. On lightweight mesh side, all three groups exhibited similar microscopic finding rates, 37.5%, 25.0%, and 33.3%, respectively. Protection of the nerve resulted in virtually zero neuroma formation after two types of mesh use. Surgical trauma to the nerve was observed to have an obvious potential for neuroma formation. Mesh type did not affect the overall neuroma rate within the whole subject pool; both groups displayed same 40% overall neuroma development rate. The neuroma incidence was in 43.8% G2 and 72.2% in G3, however the difference did not attain level of significance (P=0.09). The highest rate was observed when a lightweight mesh was used after dividing and ligating the nerve. CONCLUSIONS: Light mesh could not provide a protection in subjects whose nerves were injured during surgery. Ligation of the cut end of the nerve also could not be helpful. Nerve protection still seems to be the best way for a nerve-related complaint-free postoperative period. The merit of nerve end implantation into the muscle should also be reconsidered. PMID- 20851413 TI - Effects of pegylated interferon alpha2b on metastasis of hepatocellular carcinoma. AB - OBJECTIVE: Interferon (IFN) has an anti-tumor activity in hepatocellular carcinoma (HCC) via anti-angiogenesis and induction of apoptosis. We have previously reported anti-metastatic effects of IFN combined chemotherapy on the outcome of HCC patients. The aim of this study was to investigate anti-metastatic effects of IFN. METHODS: In vitro, pegylated interferon alpha2b (PEG-IFN-alpha2b) was administered to mouse MH134 cells (mouse HCC cell line, MH134), and anti implantation effects were examined by evaluating the inhibition of cell invasion and cell proliferation. Expressions of vascular endothelial growth factor (VEGF) mRNA were also measured. In vivo, PEG-IFN-alpha2b was subcutaneously administered into MH134 cells and tumor growth was evaluated. In distant metastasis models, PEG-IFN-alpha2b was subcutaneously administered and MH134 cells were injected into the spleen. The number of liver metastases and microvessel densities (MVD) were counted. RESULTS: In vitro, the proliferation of MH134 cells was significantly suppressed by PEG-IFN-alpha2b dose-dependently. MH134 cells added with PEG-IFN-alpha2b exhibited significantly lower levels of invasion potential. In vivo, tumor size in mice treated with PEG-IFN-alpha2b significantly suppressed compared with control mice (mean 0.5 versus 5.0 cm, in diameter, P < 0.05) and also decreased number of liver metastases (19.3 versus 6.0, P < 0.05). Moreover, PEG-IFN-alpha2b significantly suppressed angiogenesis compared with the control. CONCLUSION: PEG-IFN-alpha2b in itself had remarkable anti-metastatic effects via inhibition of angiogenesis and cell adhesions. PMID- 20851414 TI - Impact of complications after surgery for colorectal liver metastasis on patient survival. AB - BACKGROUND: In some patients with colorectal liver metastases it is not clear whether liver resection or isolated liver perfusion is the best treatment option. For instance, the risk of complications after surgery may be so substantial and affect subsequent survival. Aim of the present study is to compare complication occurrence and its effect on survival after liver resection and perfusion. METHODS: Patient records of all 225 patients with colorectal liver metastases treated with liver resection (n = 121) or liver perfusion (n = 104) in the period 1997-2006 were reviewed for complications during the initial hospitalisation until 30 d after discharge, and to assess patient survival until the last hospital visit. Median duration of follow-up was 38 mo for overall survival and 22 mo for survival after surgery. RESULTS: Complications occurred less often in patients undergoing resection than perfusion (29.8% versus 49.0%, X(2) = 8.77, P < 0.01). Postoperative mortality rates were similar in both groups (4.1% and 4.8%, respectively). As expected, long term survival after liver surgery was better in the resection group: at 3 y, 60% of patients survived in the resection group, compared with 22% after liver perfusion (log rank X(2) = 35.29 P < 0.001). However, liver resection patients with postoperative complications, had similar survival as perfusion patients without complications (log rank X(2) = 2.45, p = 0.12). This remained after adjustment for differences between the patient groups at time of surgery. CONCLUSION: Liver resection has superior long-term survival, but survival is significantly reduced by the occurrence of post-surgical complications. When complications occur after liver resection, survival is comparable to patients who underwent uncomplicated liver perfusion. PMID- 20851415 TI - Impact of duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct after pancreaticoduodenectomy. AB - BACKGROUND: A variety of different techniques are established for the management of the pancreatic remnant after partial pancreaticoduodenectomy. Although pancreaticojejunostomy is one of the most favored methods, technical details are still under discussion. We report about a series of duct-to-mucosa pancreaticojejunostomies with total external drainage of the pancreatic duct. PATIENTS AND METHODS: Between 1998 and 2007 257 patients underwent surgical therapy for malignant disease of the pancreas and the periampullary region and for chronic pancreatitis. Of these, 153 partial pancreaticoduodenectomies (85 pylorus preserving resections and 68 Whipple's procedures) were performed. In all of these cases, the pancreatic remnant was drained by a duct-to-mucosa pancreaticojejunostomy with external drainage of the pancreatic duct. Presence of postoperative pancreatic fistula (PPF) was defined according to the International Study Group on Pancreatic Fistula (ISGPF). RESULTS: Postoperative mortality was 1.9%. The incidence of postoperative pancreatic fistula (PPF) was 19.6% according to the ISGPF criteria. Only one patient required re-laparotomy for complications caused by PPF. Patients with PPF had a significantly longer operation time (7.3 h versus 6.6 h; P=0.041). Incidence of PPF was not influenced by histology. In all cases the fistulas resolved under conservative treatment. CONCLUSION: Duct-to mucosa PJ with external drainage is a safe procedure to enteralize the pancreatic stump after partial pancreaticoduodenectomy. PMID- 20851416 TI - Low-cost, locally fabricated simulators: the wave of the future. PMID- 20851417 TI - Use of a modified chitosan-dextran gel to prevent peritoneal adhesions in a rat model. AB - BACKGROUND: Intra-abdominal adhesions are a major cause of morbidity and a significant drain on healthcare resources. Numerous anti-adhesion products have reached clinical use but none has been wholly satisfactory. This study examines the application of a modified chitosan-dextran (CD) gel to the intraperitoneal cavity to reduce adhesion formation. This is a unique synthetic gel, its active ingredients being succinyl chitosan and dextran aldehyde. MATERIALS AND METHODS: Eighty adult male Wistar albino rats were randomized to undergo surgery alone or to receive CD gel at the time of surgery. Control groups using modified dextran only gel were also included. The surgical procedures comprised of laparotomy and either cecal abrasion or anastomotic simulation by enterotomy of the cecum with primary closure. At postoperative d 21 rats were euthanized by CO2 inhalation, and adhesions graded by an investigator blinded to the treatment groups, using a predetermined adhesion measurement score. RESULTS: Adhesions were significantly reduced in the cecal abrasion group with median adhesion scores for the treatment group of 0 versus 3 in the control group (P<0.001, Fisher's exact test). Further reduction in adhesion formation was noted in the enterotomy group with median scores of 2 versus 5 for treatment and control groups respectively (P=0.003, Fisher's exact test). CONCLUSIONS: Chitosan-dextran gel appears to significantly reduce the formation of intra-abdominal adhesions without adversely affecting wound healing. This is a noteworthy advancement in the safe prevention of post operative, intra-abdominal adhesions. PMID- 20851418 TI - Titration of mean airway pressure and FiO2 during high frequency oscillatory ventilation in a porcine model of acute lung injury. AB - BACKGROUND: High frequency oscillatory ventilation (HFOV) is frequently utilized for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). However, precise criteria to titrate mean airway pressure (mPaw) and FiO(2) as the patient's condition improves are lacking. We hypothesized that reducing mPaw and FiO(2) too quickly after reaching target arterial oxygen saturation levels would promote ventilator induced lung injury (VILI). MATERIALS AND METHODS: ALI was induced by instilling 3% Tween 20. Pigs were placed supine and received 30 min of nonprotective ventilation. Pigs were separated into two groups: HFOV constant (HFOVC, n = 3) = constant mPaw and FiO(2) for the duration; HFOV titrated (HFOVT, n = 4) = FiO(2) and/or mPaw were reduced every 30 min if the oxygen saturation remained between 88%-95%. Hemodynamic and pulmonary measurements were made at baseline, after lung injury, and every 30 min during the 6-h study. Lung histopathology was determined by quantifying alveolar hyperdistension, fibrin, congestion, atelectasis, and polymorphonuclear leukocyte (PMN) infiltration. RESULTS: Oxygenation was significantly lower in the HFOVT group compared to the HFOVC group after 6 h. Lung histopathology was significantly increased in the HFOVT group in the following categories: PMN infiltration, alveolar hyperdistension, congestion, and fibrin deposition. CONCLUSIONS: Rapid reduction of mPaw and FiO(2) in our ALI model significantly reduced oxygenation, but, more importantly, caused VILI as evidenced by increased lung inflammation and alveolar hyperdistension. Specific criteria for titration of mPaw and inspired oxygen are needed to maximize the lung protective effects of HFOV while maintaining adequate gas exchange. PMID- 20851419 TI - Continuous hemodiafiltration therapy ameliorates LPS-induced systemic inflammation in a rat model. AB - BACKGROUND: Systemic inflammation can result in multiple organ dysfunction syndrome, a potentially life-threatening condition. Some reports suggest that continuous hemodiafiltration can effectively remove proinflammatory cytokines from circulation during systemic inflammation. In the present study, we investigated whether continuous hemodiafiltration therapy could prevent LPS induced systemic inflammation and improve survival in a rat model. MATERIALS AND METHODS: Male Wistar rats were injected with lipopolysaccharide (LPS; 7.5 mg/kg body weight), and 6 h later were treated with either single-pass hemofiltration (C group), continuous hemofiltration (CHF group), continuous hemodiafiltration (CHDF group), or mock filtration (Control group). We performed histologic examinations of lung and liver tissues, determined serum cytokine levels, and survival rates for each treatment group, and compared cytokine removal between CHF and CHDF therapies. RESULTS: Histologic examination revealed significant reduction in inflammation in lung and liver tissues harvested 24 h after CHDF compared with the Control group. Likewise, LPS-induced serum TNF-alpha and IL-6 levels decreased with continuous hemodiafiltration along with a significant improvement in survival. After 30 min of treatment, both CHF and CHDF removed significant amounts of TNF-alpha and IL-6 from the blood. However, serum cytokine levels measured before and after filtration were not significantly different. CONCLUSIONS: Continuous hemodiafiltration therapy lowered inflammatory cytokines and increased survival rates in a rat model of systemic inflammation. Therefore, continuous hemodiafiltration may be a potential therapy for use against various systemic inflammatory diseases. PMID- 20851420 TI - The emerging role of vitamin D3 in protecting ischemic tissues. PMID- 20851422 TI - Extracorporeal shockwave shows regression of osteoarthritis of the knee in rats. AB - BACKGROUND: This study investigated the effects of extracorporeal shockwave technology (ESWT) in osteoarthritis of the knee in rats. MATERIALS AND METHODS: Thirty-six Sprague-Dawley rats were randomly divided into three groups with 12 rats in each group. Group I was the control group and received neither anterior cruciate ligament transection (ACLT) nor ESWT. In groups II and III, ACLT was performed in left knee and osteoarthritis (OA) was verified at 12 wk. Group II received no ESWT, and group III received ESWT at 12 wk after ACLT. Radiographs and bone mineral density (BMD) were obtained at 0, 12, and 24 wk. The animals were sacrificed at 24 wk. One half of the animals were subjected to bone strength test, and the other half for histomorphologic examination and immunohistochemical analysis. RESULTS: Radiographs of the left knee showed progressive OA changes at 12 and 24 wk in group II, whereas, very subtle OA changes were noted in group I and group III. BMD and bone strength were significantly lower in group II compared with groups I and III, but no difference was noted between group I and group III. The cartilage degradations were significantly higher in group II compared with groups I and III, but no difference was noted between group I and group III. The subchondral bone remodeling was significantly less pronounced in group II compared with groups I and III, but no difference was noted between group I and group III. CONCLUSIONS: Application of ESWT to the subchondral bone of the medial tibia condyle showed regression of osteoarthritis of the knees in rats. PMID- 20851421 TI - High antimetastatic efficacy of MEN4901/T-0128, a novel camptothecin carboxymethyldextran conjugate. AB - The antimetastatic activity of a novel camptothecan conjugate, MEN4901/T-0128, in which 7-ethyl-10-aminopropyloxy-camptothecin (T-2513) is bound to a biodegradable carboxymethyldextran via a Gly-Gly-Gly linker, was observed in this study. High antimetastatic activity of MEN4901/T-0128 was demonstrated in a clinically relevant orthotopic mouse model of human colon cancer. MEN4901/T-0128 and irinotecan were compared for anti-metastatic activity as well as efficacy against the primary tumor. An imageable, metastatic model was made by surgical orthotopic implantation (SOI) of the green fluorescent protein (GFP)-expressing HT-29 tumor in nude mice. MEN4901/T-0128 and irinotecan were administered intravenously at various doses and schedules. MEN4901/T-0128, with treatment beginning on d 49 after SOI, was highly effective on lymph node metastasis as well as against the primary tumor. Both GFP imaging and histology demonstrated a markedly lower metastatic incidence of lymph nodes in all MEN4901/T-0128 treated mice compared with irinotecan-treated and untreated mice. At the most efficacious dose of MEN4901/T-0128, only 1 of 12 animals had lymph node metastasis compared with 19 of 20 in the control group. The present study demonstrates the principle that when a camptothecan is conjugated to an appropriate polymer, the drug can become extremely effective with important clinical potential for antimetastatic therapy, a most urgent need. PMID- 20851423 TI - Brain natriuretic peptide is not reno-protective during renal ischemia reperfusion injury in the rat. AB - BACKGROUND: Acute kidney injury (AKI) occurs in 30% of patients undergoing complex cardiovascular surgery, and renal ischemia-reperfusion (I/R) injury is often a contributing factor. A recent meta-analysis observed that perioperative natriuretic peptide administration was associated with a reduction in AKI requiring dialysis in cardiovascular surgery patients. This study was designed to further clarify the potential reno-protective effect of brain natriuretic peptide (BNP) using an established rat model of renal I/R injury. METHODS: The study comprised three groups (n = 10 kidneys each): (1) control (no injury); (2) I/R injury (45 min of bilateral renal ischemia followed by 3 h of reperfusion); and (3) BNP (I/R injury plus rat-BNP pretreatment at 0.01 MUg/kg/min). Glomerular filtration rate (GFR) and a biomarker of AKI, urinary neutrophil gelatinase associated lipocalin (uNGAL), were measured at baseline and at 30 minute intervals post-ischemia. Groups were compared using two-way repeated measures analysis of variance (mean +/- SD, significance P < 0.05). RESULTS: Baseline GFR measurements for control, I/R, and BNP groups were 1.07 +/- 0.55, 0.88 +/- 0.51, and 1.03 +/- 0.59 mL/min (P = 0.90), respectively. Post-ischemia, GFR was significantly lower in I/R and BNP compared with controls at 30 min, 1.29 +/- 0.97, 0.08 +/- 0.04, and 0.06 +/- 0.05 mL/min (P < 0.01), and remained lower through 3 h, 1.79 +/- 0.44, 0.30 +/- 0.17, and 0.32 +/- 0.12 mL/min (P < 0.01). Comparing I/R to BNP groups, GFR did not differ significantly at any time point. There was no significant difference in uNGAL levels at 1 h (552 +/- 358 versus 516 +/- 259 ng/mL, P = 0.87) or 2 h (1073 +/- 589 versus 989 +/- 218 ng/mL, P = 0.79) between I/R and BNP. CONCLUSIONS: BNP does not reduce the renal injury biomarker, urinary NGAL, or preserve GFR in acute renal ischemia-reperfusion injury. PMID- 20851424 TI - Hereditary and non-hereditary microangiopathies in the young. An up-date. AB - In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur in younger age, below 45 years. Cerebral microangiopathies constitute an appreciable portion of all strokes. In middle aged patients, hereditary cerebral small vessel diseases have to be separated from sporadic degenerative cerebral microangiopathy which is mainly due to a high vascular risk load. Features of the following disorders and details how to differentiate them, are reviewed here, namely CADASIL, MELAS, AD RVLC, HEMID, CARASIL, PADMAL, FABRY, COL4A1-related cerebral small vessel diseases and a Portuguese type of autosomal dominant cerebral small vessel disease (SVDB). The symptomatic overlap of the cerebral microangiopathies include also other distinctive non-hereditary diseases like posterior (reversible) encephalopathy and Susac's syndrome which are also described. Some of the microangiopathies described here are not only seen in the young but also in the elderly. The precise diagnosis has direct therapeutic implications in several of these entities. Cerebral microangiopathies cause recurring strokes and diffuse white matter lesions leading to a broad spectrum of gait disturbances and in most of these disorders cognitive impairment or even vascular dementia in the long term. Often, they also involve the eye, the inner ear or the kidney. Several typical imaging findings from illustrative cases are presented. The order in which these diseases are presented here is not dictated by an inner logic principle, because a genetically or pathophysiologically based classification system of all these entities does not exist yet. Some entities are well established and not unusual, whereas others have only been described in a few cases in total. PMID- 20851426 TI - Case-control studies on ceruloplasmin and superoxide dismutase (SOD1) in neurodegenerative diseases: a short review. AB - This short review describes a series of case-control studies on the concentration and oxidative activity of ceruloplasmin (CP) in serum and the activity of superoxide dismutase (SOD1) in erythrocytes in patients with Alzheimer's disease (AD), Parkinson's disease (PD) and Down's syndrome (DS). The same parameters were re-examined in the PD patients 5 years later. The specific oxidative activity (oxidative activity related to mass) of CP was calculated in PD and DS. In AD and PD the oxidative activity of CP and SOD1 activity was significantly lower in patients than controls. The specific oxidative activity of CP was also significantly lower in PD patients. The difference in all parameters determined was still present 5 years later in PD patients. There was no difference in the concentration or activity of CP in patients with DS and controls. Because of the gene-dose effect (the gene for SOD1 is located on chromosome 21); the SOD1 activity was 50% higher in the patients than the controls. The CP specific oxidative activity and SOD1 activity were found to be significantly lower in the older (>40 years) than the younger DS patients. Whether changes in CP and SOD1 in AD, PD and DS are primary changes or a result of prolonged disease burden needs to be examined. PMID- 20851427 TI - Perioperative statin therapy reduces mortality in normolipidemic patients undergoing cardiac surgery. AB - OBJECTIVE: Statins might have pleiotropic effects, independent of their ability to reduce lipid levels. Recent data have suggested that statins improve early survival and cardiovascular outcomes after coronary artery bypass graft surgery. The effectiveness of statin therapy in normolipidemic cardiac surgery patients is as yet unclear. METHODS: We evaluated 3056 consecutive patients who had undergone cardiac surgery between April 2004 and April 2009. Perioperative statin therapy was defined as continued treatment both before (>= 6 months) and after the index surgery (included as a discharge medication). Hyperlipidemia (HL) was defined as a total cholesterol level greater than 200 mg/dL within 6 months before surgery. Four groups were analyzed: (1) statin-untreated normolipidemic (NL-, n = 1052); (2) statin-treated normolipidemic (NL+, n = 206); (3) statin-untreated hyperlipidemic (HL-, n = 638); and (4) statin-treated hyperlipidemic (HL+, n = 1160) patients. Adjusted hazard ratios accounted for the known preoperative cardiac risk factors. Mortality was ascertained by retrospective database review and the Social Security Death Index. RESULTS: The mean follow-up was 2.2 years. The crude rate of 30-day mortality was 3.0% (32/1052), 0% (0/206), 8.0% (51/638), and 0.7% (8/1160) for the NL-, NL+, HL-, and HL+ groups, respectively. The overall all-cause crude mortality rate was 9.6% (101/1052), 3.9% (8/206), 17.2% (110/638), and 6.5% (75/1160) for the NL-, NL+, HL-, and HL+ groups, respectively. Statin therapy for NL patients undergoing cardiac surgery independently reduced the overall all-cause mortality (adjusted hazard ratio, 0.34; 95% confidence interval, 0.16-0.71; P = .004). CONCLUSIONS: Perioperative statin therapy was associated with reduced mid-term mortality for patients undergoing cardiac surgery, irrespective of their baseline lipid status. This clinical evidence suggests that the beneficial effects of statins might extend beyond their lipid-lowering ability. PMID- 20851432 TI - Editorial comment. PMID- 20851429 TI - One-port retroperitoneoscopic assisted pyeloplasty versus open dismembered pyeloplasty in young children: preliminary experience. AB - PURPOSE: We propose 1-port retroperitoneoscopic assisted pyeloplasty as a minimally invasive approach and compare the results to open dismembered pyeloplasty. MATERIALS AND METHODS: All patients 6 months to 5 years old presenting with ureteropelvic junction obstruction between January 2008 and June 2009 were offered 1-port retroperitoneoscopic assisted pyeloplasty. Age matched patients who underwent open dismembered pyeloplasty during 2007 served as controls. The ureteropelvic junction was isolated retroperitoneoscopically and exteriorized through a single operative trocar. Pyeloplasty was performed in an open fashion with Double-J(r) stenting. Operative time, postoperative pain, surgical complications, hospital stay, ultrasound and mercaptoacetyltriglycine nuclear scan results at 6-month followup were evaluated and compared. Chi-square test and Student's t test were adopted for statistical analysis, with p <0.05 considered statistically significant. RESULTS: A total of 28 children (17 males) with a mean age of 18 months were treated with 1-port retroperitoneoscopic assisted pyeloplasty (18 left side). The control group consisted of 25 patients (11 males) with a mean age of 19 months who underwent open dismembered pyeloplasty (10 left side). Median operative time was 95 minutes (range 70 to 130) in 1-port retroperitoneoscopic assisted pyeloplasty and 72 minutes (58 to 102) in open dismembered pyeloplasty (p <0.05). Median postoperative hospital stay was 2.4 days with the 1-port approach and 6.1 days with the open procedure (p <0.05). Postoperative pain was significantly less in the 1-port group. Skin scar length was 1.4 to 2.9 cm (median 1.7) with 1-port retroperitoneoscopic assisted pyeloplasty and 3.5 to 6.0 cm (4.3) in the open group (p <0.05). CONCLUSIONS: The 1-port retroperitoneoscopic assisted pyeloplasty represents a safe and effective minimally invasive technique to treat hydronephrosis and could be the treatment of choice in young children. The procedure does not require laparoscopic suturing skills, and combines the advantages of open and laparoscopic pyeloplasty. PMID- 20851435 TI - Should the patient with positive margins after radical prostatectomy receive adjuvant radiation? PMID- 20851436 TI - Activated RhoA/Rho kinase impairs erectile function after cavernous nerve injury in rats. AB - PURPOSE: RhoA and rho kinase serve as key regulators of penile vascular homeostasis. The role of RhoA/rho kinase signaling in the penis after cavernous nerve injury has not been fully investigated. We characterized the molecular expression profiles of RhoA/rho kinase signaling that occur in the penis after cavernous nerve injury. We hypothesized that erectile dysfunction after bilateral cavernous nerve injury is accompanied by up-regulation of RhoA/rho kinase activity in the rat penis. MATERIAL AND METHODS: We used 2 groups, including sham operation and bilateral cavernous nerve injury. At 14 days after nerve injury each group underwent cavernous nerve stimulation to determine erectile function at baseline and after intracavernous injection of the rho kinase inhibitor Y 27632 (Tocris Bioscience, Ellisville, Missouri). Penes were assessed at baseline for protein expression of neuronal nitric oxide synthase, RhoA, and rho kinase 1 and 2 by Western blot, immunoreactivity of neuronal nitric oxide synthase, rho kinase 1 and 2, RhoA-guanosine triphosphatase and rho kinase activity. RESULTS: Erectile function was decreased in nerve injured rats. Neuronal nitric oxide synthase protein was significantly decreased while RhoA and rho kinase 2 protein levels were significantly increased in rat penes with nerve injury. Rho kinase 1 protein expression was equivalent. Rho kinase immunoreactivity was qualitatively increased in the corporeal smooth muscle of nerve injured rats. RhoA-guanosine triphosphatase and rho kinase activity was significantly increased in injured rat penes compared to that in sham operated penes. Intracavernous injection of Y 27632 caused a significantly greater increase in intracavernous pressure in nerve injured rats compared to that in sham operated rats, suggesting increased rho kinase activity. CONCLUSIONS: Data suggest that RhoA/rho kinase up-regulation in response to cavernous nerve injury contributes to penile vasculature dysfunction after cavernous nerve injury. Thus, the RhoA/rho kinase pathway may be a suitable target for treating post-radical prostatectomy erectile dysfunction. PMID- 20851437 TI - Diffusion-weighted magnetic resonance imaging in patients with unilateral prostate cancer on extended prostate biopsy: predictive accuracy of laterality and implications for hemi-ablative therapy. AB - PURPOSE: We evaluated the ability of extended prostate biopsy to detect unilateral prostate cancer and assessed the incremental diagnostic benefit of diffusion-weighted magnetic resonance imaging to predict unilateral prostate cancer. MATERIALS AND METHODS: A total of 130 patients with prostate cancer detected by extended pattern prostate biopsy underwent magnetic resonance imaging before radical prostatectomy. Tumor laterality on extended prostate biopsy was compared with the corresponding lobe on the radical prostatectomy specimen. In patients with unilateral prostate cancer on biopsy we calculated the probability of a tumor in the contralateral lobe on magnetic resonance images and calculated area under the receiver operating characteristics curve. We compared the diagnostic accuracy of combined T2-weighted and diffusion-weighted magnetic resonance images to that of T2-weighted magnetic resonance images alone. RESULTS: Of the 130 patients 88 (67.7%) had unilateral disease on extended prostate biopsy. Radical prostatectomy pathology showed that 19% of these patients had unilateral disease but 81% had bilateral disease. Area under the receiver operating characteristics curve of combined diffusion-weighted and T2-weighted magnetic resonance imaging was greater than that of T2-weighted magnetic resonance imaging alone (0.814, 95% CI 0.716-0.889 vs 0.510, 95% CI 0.401-0.618). T2-weighted plus diffusion-weighted magnetic resonance imaging had significantly higher sensitivity (84.1% vs 61.9%, p = 0.003) and specificity (72.0% vs 36.0%, p = 0.004) to predict cancer in the contralateral lobe than T2-weighted magnetic resonance alone. CONCLUSIONS: Extended prostate biopsy cannot accurately determine prostate cancer unilaterality. Diffusion-weighted magnetic resonance combined with T2-weighted magnetic resonance imaging has an incremental diagnostic benefit to predict unilateral prostate cancer. PMID- 20851438 TI - Editorial comment. PMID- 20851439 TI - Editorial comment. PMID- 20851440 TI - The occurrence, spatial and temporal distribution, and environmental routes of tetracycline resistance and integrase genes in Crassostrea virginica beds. AB - Rapid spread of antibiotic resistance genes has placed them under consideration as emerging environmental contaminants. The occurrence and distribution of tetracycline resistance genes (TRG) and integrons (INT) have been monitored for 2 years in seven oyster beds located in the Altamaha River (Georgia, USA) estuary. TRG/INT profiles varied both temporally (p<0.025) and spatially between oysters and their environment (p<0.005) suggesting shifts in sources of contamination and selection of TRG/INT carriers by oysters. The latter was confirmed via analysis of tet(D) and tet(G) distribution between oysters and their environment. Uncommon class 3 integrons dominated the integrons' profile in oysters. The frequency of TRG/INT incidents correlated (R(2) >= 0.9) to (i) dissolved solids, (ii) potential water density, and (iii) turbidity but not to the amount of local precipitation suggesting the watershed as the dominant source of TRG/INT contamination and other than directly rainfall-caused run-offs as its environmental route. PMID- 20851442 TI - The heritability of ocular traits. AB - Heritability is the proportion of phenotypic variation in a population that is attributable to genetic variation among individuals. Many ophthalmic disorders and biometric traits are known to have a genetic basis and consequently much work has been published in the literature estimating the heritability of various ocular parameters. We collated and summarized the findings of heritability studies conducted in the field of ophthalmology. We grouped the various studies broadly by phenotype as follows: refraction, primary open-angle glaucoma, age related macular degeneration (AMD), cataract, diabetic retinopathy, and others. A total of 82 articles were retrieved from the literature relating to estimation of heritability for an ocular disease or biometric trait; of these, 37 papers were concerned with glaucoma, 28 with refraction, 4 with AMD, 5 with diabetic retinopathy, and 4 with cataract. The highest reported heritability for an ophthalmic trait is 0.99 for the phenotype >= 20 small hard drusen, indicating that observed variation in this parameter is largely governed by genetic factors. Over 60% of the studies employed a twin study design and a similar percentage utilized variance components methods and structural equation modeling (SEM) to derive their heritability values. Using modern SEM techniques, heritability estimates derived from twin subjects were generally higher than those from family data. Many of the estimates are in the moderate to high range, but to date the majority of genetic variants accounting for these findings have not been uncovered, hence much work remains to be undertaken to elucidate fully their molecular etiology. PMID- 20851441 TI - Cytotoxic tirucallane C26 triterpenoids from the stem barks of Aphanamixis grandifolia. AB - Five tirucallane type C(26) triterpenoids, accompanied by two known compounds, 3alpha-hydroxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone and 3-oxo 24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, were isolated from the stem barks of Aphanamixis grandifolia. Their structures were established mainly by means of a combination of 1D and 2D NMR spectroscopic and mass spectrometry techniques as 3alpha-hydroxyl-21alpha-methoxy-24,25,26,27-tetranortirucall-7-ene 23(21)-lactone, 3alpha-hydroxy-21beta-methoxy-24,25,26,27-tetranortirucall-7-ene 23(21)-lactone, 3-oxo-21alpha-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21) lactone, 3-oxo-21beta-methoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone, and 3-oxo-21alpha-ethoxy-24,25,26,27-tetranortirucall-7-ene-23(21)-lactone. All isolates were in vitro evaluated for their cytotoxic activities against five tumor cell lines (MCF-7, HeLa, HepG2, SGC-7901 and BGC-823). PMID- 20851443 TI - Control of mineral scale deposition in cooling systems using secondary-treated municipal wastewater. AB - Secondary-treated municipal wastewater (MWW) is a promising alternative to freshwater as power plant cooling system makeup water, especially in arid regions. A prominent challenge for the successful use of MWW for cooling is potentially severe mineral deposition (scaling) on pipe surfaces. In this study, theoretical, laboratory, and field work was conducted to evaluate the mineral deposition potential of MWW and its deposition control strategies under conditions relevant to power plant cooling systems. Polymaleic acid (PMA) was found to effectively reduce scale formation when the makeup water was concentrated four times in a recirculating cooling system. It was the most effective deposition inhibitor of those studied when applied at 10 mg/L dosing level in a synthetic MWW. However, the deposition inhibition by PMA was compromised by free chlorine added for biogrowth control. Ammonia present in the wastewater suppressed the reaction of the free chlorine with PMA through the formation of chloramines. Monochloramine, an alternative to free chlorine, was found to be less reactive with PMA than free chlorine. In pilot tests, scaling control was more challenging due to the occurrence of biofouling even with effective control of suspended bacteria. Phosphorous-based corrosion inhibitors are not appropriate due to their significant loss through precipitation reactions with calcium. Chemical equilibrium modeling helped with interpretation of mineral precipitation behavior but must be used with caution for recirculating cooling systems, especially with use of MWW, where kinetic limitations and complex water chemistries often prevail. PMID- 20851444 TI - QMRA and decision-making: are we handling measurement errors associated with pathogen concentration data correctly? AB - Knowledge of the variability in pathogen or indicator concentrations over time at a particular location (e.g. in drinking water sources) is essential in implementation of concentration-based regulations and in quantitative microbial risk assessment. Microbial enumeration methods, however, are known to yield highly variable counts (even among replicates) and some methods are prone to substantial losses (i.e. only a fraction of the target microorganisms in a sample are observed). Consequently, estimated microorganism concentrations may be biased and only a fraction of the variability that is observed in temporally distributed concentration estimates is due to variability in concentration itself. These issues have often been ignored in the past, and approaches to integrate knowledge about the measurement error associated with enumeration methods into decisions have not been standardized. Here, an existing model that describes variability in microorganism counts as a function of sample volume and the analytical recovery of the enumeration method is expanded to include temporal concentration variability and sample-specific recovery information. This model is used to demonstrate that microorganism counts and analytical recovery are not independent (as has often been assumed), even if the correlation is obscured by other sources of variability in the data. It is also used as an experimental design tool to evaluate strategies that may yield more accurate concentration estimates. Finally, the model is implemented in a Bayesian framework (with a Gibbs sampling algorithm) to quantify temporal concentration variability with appropriate consideration of measurement errors in the data and the analytical recovery of the enumeration method. We demonstrate by simulation that this statistical approach facilitates risk analyses that appropriately model variability in microorganism concentrations given the available data and that it enables decisions based on quantitative measures of uncertainty. PMID- 20851445 TI - A screening level fate model of organic contaminants from advanced water treatment in a potable water supply reservoir. AB - Augmentation of potable water sources by planned indirect potable reuse of wastewater is being widely considered to address growing water shortages. Environmental buffers such as lakes and dams may act as one of a series of barriers to potable water contamination stemming from micropollutants in wastewater. In South-East Queensland, Australia, current government policy is to begin indirect potable reuse of water from reverse osmosis equipped advanced water treatment plants (AWTPs) when the combined capacity of its major storages is at 40% capacity. A total of 15 organic contaminants including NDMA and bisphenol A have been publically reported as detected in recycled water from one of South-East Queensland's AWTPs, while another 98 chemicals were analysed for, but found to be below their detection limit. To assess the natural attenuation in Lake Wivenhoe, a Level III fugacity based evaluative fate model was constructed using the maximum concentrations of these contaminants detected as input data. A parallel aquivalence based model was constructed for those contaminants, such as dichloroacetic acid, dalapon and triclopyr, which are ionised in the environment of Lake Wivenhoe. A total of 247 organic chemicals of interest, including disinfection by-products, pesticides, pharmaceuticals and personal care products, xenoestrogens and industrial chemicals, were evaluated with the model to assess their potential for natural attenuation. Out of the 15 detected chemicals, trihalomethanes are expected to volatilise with concentrations in the outflow from the dam approximately 400 times lower than influent from the AWTPs. Transformation processes in water are likely to be more significant for NDMA and pharmaceuticals such as salicylic acid and paracetamol as well as for caffeine and the herbicides dalapon and triclopyr. For hydrophobic contaminants such as cholesterol and phenolic xenoestrogens such as 4-nonylphenol, 4-t-octylphenol and bisphenol A, equilibrium between water and sediments will not be attained and hence fate processes such as removal in outflow are predicted to become relatively important. PMID- 20851446 TI - Advances in on-line drinking water quality monitoring and early warning systems. AB - Significant advances have been made in recent years in technologies to monitor drinking water quality for source water protection, treatment operations, and distribution system management, in the event of accidental (or deliberate) contamination. Reports prepared through the Global Water Research Coalition (GWRC) and United States Environment Protection Agency (USEPA) agree that while many emerging technologies show promise, they are still some years from being deployed on a large scale. Further underpinning their viability is a need to interpret data in real time and implement a management strategy in response. This review presents the findings of an international study into the state of the art in this field. These results are based on visits to leading water utilities, research organisations and technology providers throughout Europe, the United States and Singapore involved in the development and deployment of on-line monitoring technology for the detection of contaminants in water. PMID- 20851447 TI - Direct observation of solid-phase adsorbate concentration profile in powdered activated carbon particle to elucidate mechanism of high adsorption capacity on super-powdered activated carbon. AB - Decreasing the particle size of powdered activated carbon (PAC) by pulverization increases its adsorption capacities for natural organic matter (NOM) and polystyrene sulfonate (PSS, which is used as a model adsorbate). A shell adsorption mechanism in which NOM and PSS molecules do not completely penetrate the adsorbent particle and instead preferentially adsorb near the outer surface of the particle has been proposed as an explanation for this adsorption capacity increase. In this report, we present direct evidence to support the shell adsorption mechanism. PAC particles containing adsorbed PSS were sectioned with a focused ion beam, and the solid-phase PSS concentration profiles of the particle cross-sections were directly observed by means of field emission-scanning electron microscopy/energy-dispersive X-ray spectrometry (FE-SEM/EDXS). X-ray emission from sulfur, an index of PSS concentration, was higher in the shell region than in the inner region of the particles. The X-ray emission profile observed by EDXS did not agree completely with the solid-phase PSS concentration profile predicted by shell adsorption model analysis of the PSS isotherm data, but the observed and predicted profiles were not inconsistent when the analytical errors were considered. These EDXS results provide the first direct evidence that PSS is adsorbed mainly in the vicinity of the external surface of the PAC particles, and thus the results support the proposition that the increase in NOM and PSS adsorption capacity with decreasing particle size is due to the increase in external surface area on which the molecules can be adsorbed. PMID- 20851448 TI - Submerged anaerobic membrane bioreactor for low-strength wastewater treatment: effect of HRT and SRT on treatment performance and membrane fouling. AB - Three 6-L submerged anaerobic membrane bioreactors (SAnMBRs) with solids retention times (SRTs) of 30, 60 and infinite days were setup for treating synthetic low-strength wastewater at hydraulic retention times (HRTs) of 12, 10 and 8 h. Total COD removal efficiencies higher than 97% were achieved at all operating conditions. Maximum biogas production rate was 0.056 L CH(4)/g MLVSS d at an infinite SRT. A shorter HRT or longer SRT increased biogas production due to increased organic loading rate or enhanced dominancy of methanogenics. A decrease in HRT enhanced growth of biomass and accumulation of soluble microbial products (SMP), which accelerated membrane fouling. A drop in carbohydrate to protein ratio also inversely affected fouling. At 12-h HRT, the effect of SRT on biomass concentration in SAnMBRs was negligible and membrane fouling was controlled by variant surface modification due to different SMP compositions, i.e., higher carbohydrate and protein concentrations in SMP at longer SRT resulted in higher membrane fouling rate. At 8 and 10-h HRTs, infinite SRT in SAnMBR caused highest MLSS and SMP concentrations, which sped up particle deposition and biocake/biofilm development. At longer SRT, lower extracellular polymeric substances reduced flocculation of particulates and particle sizes, further aggravated membrane fouling. PMID- 20851449 TI - Removal of bacterial fecal indicators, coliphages and enteric adenoviruses from waters with high fecal pollution by slow sand filtration. AB - The aim of the present study was to estimate the performance of slow sand filtration (SSF) facilities, including the time needed for reaching stabilization (maturation), operated with surface water bearing high fecal contamination, representing realistic conditions of rivers in many emerging countries. Surface water spiked with wastewater was infiltrated at different pore water velocities (PWV) and samples were collected at different migration distances. The samples were analyzed for phages and to a lesser extent for fecal bacteria and enteric adenoviruses. At the PWV of 50 cm/d, at which somatic phages showed highest removal, their mean log(10) removal after 90 cm migration was 3.2. No substantial differences of removal rates were observed at PWVs between 100 and 900 cm/d (2.3 log(10) mean removal). The log(10) mean removal of somatic phages was less than the observed for fecal bacteria and tended more towards that of enteric adenoviruses This makes somatic phages a potentially better process indicator than Escherichia coli for the removal of viruses in SSF. We conclude that SSF, and by inference in larger scale river bank filtration (RBF), is an excellent option as a component in multi-barrier systems for drinking water treatment also in areas where the sources of raw water are considerably fecally polluted, as often found in many emerging countries. PMID- 20851450 TI - Multi-scale temporal and spatial variation in genotypic composition of Cladophora borne Escherichia coli populations in Lake Michigan. AB - High concentrations of Escherichia coli in mats of Cladophora in the Great Lakes have raised concern over the continued use of this bacterium as an indicator of microbial water quality. Determining the impacts of these environmentally abundant E. coli, however, necessitates a better understanding of their ecology. In this study, the population structure of 4285 Cladophora-borne E. coli isolates, obtained over multiple three day periods from Lake Michigan Cladophora mats in 2007-2009, was examined by using DNA fingerprint analyses. In contrast to previous studies that have been done using isolates from attached Cladophora obtained over large time scales and distances, the extensive sampling done here on free-floating mats over successive days at multiple sites provided a large dataset that allowed for a detailed examination of changes in population structure over a wide range of spatial and temporal scales. While Cladophora borne E. coli populations were highly diverse and consisted of many unique isolates, multiple clonal groups were also present and accounted for approximately 33% of all isolates examined. Patterns in population structure were also evident. At the broadest scales, E. coli populations showed some temporal clustering when examined by year, but did not show good spatial distinction among sites. E. coli population structure also showed significant patterns at much finer temporal scales. Populations were distinct on an individual mat basis at a given site, and on individual days within a single mat. Results of these studies indicate that Cladophora-borne E. coli populations consist of a mixture of stable, and possibly naturalized, strains that persist during the life of the mat, and more unique, transient strains that can change over rapid time scales. It is clear that further study of microbial processes at fine spatial and temporal scales is needed, and that caution must be taken when interpolating short term microbial dynamics from results obtained from weekly or monthly samples. PMID- 20851451 TI - Genetic polymorphism of CYP2D6*2 C->T 2850, GSTM1, NQO1 genes and their correlation with biomarkers in manganese miners of Central India. AB - Manganese (Mn) intoxication is most often regarded as an occupational manifestation and occurs in places such as manganese mines, dry cell battery plants and ceramic industries. In the present study, the influence of genetic polymorphism in cytochrome P450 2D6 (CYP2D6*2), glutathione S-transferase M1 (GSTM1) and NAD(P)H quinone oxidoreductase 1 (NQO1) genes on blood manganese and plasma prolactin concentrations in manganese miners was investigated. Genotyping of CYP2D6*2 C->T 2850 and NQO1 C->T 609 was carried out using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) whereas the genotyping of GSTM1 was carried out by multiplex PCR using beta globin as an internal control. Manganese miners with CYP2D6*2 C->T 2850 variant genotype had relatively low Mn concentration [GM: 21.4+/-8.9 MUg L(-1)] than the subjects with wild (GM: 36.3+/-8.5 MUg L(-1)) and heterozygous (GM: 34.4+/-6.9 MUg L(-1)) genotypes. Miners with CYP2D6*2 variant genotypes showed low prolactin levels (GM: 13.13+/-1.6 ng mL(-1)) compared to the wild (GM: 16.4.4+/-1.5 MUg L(-1)) and heterozygous (GM: 18.7+/-1.6 ng mL(-1)) genotypes. Gene-gene interaction studies also revealed that the subjects with CYP2D6*2 C->T 2850 variant genotypes had low levels of Mn and prolactin. Our new findings suggest that CYP2D6*2 C->T 2850 variant genotypes can regulate plasma prolactin levels in manganese miners of Central India and could be involved in the fast metabolism of blood manganese, compared to wild and heterozygous genotypes. PMID- 20851452 TI - Using the o,p'-DDT/p,p'-DDT ratio to identify DDT sources in China. AB - Dichlorodiphenyltrichloroethane (DDT) has been banned in China for decades, and yet high DDT concentrations are still being detected in the Chinese environment. This might be at least partly due to the current use of dicofol formulation, which contains DDT as an impurity. In this study, a method based on the ratios of two DDT isomers, o,p'-DDT and p,p'-DDT, was established and used to estimate the relative contributions of dicofol formulation and those of technical DDT to overall environmental DDT. Based on this method and field data from the literature, we calculated that dicofol formulation contributed >72% of atmospheric DDT in 2004 in the Taihu Lake region, China, and this value was >84% in summer when dicofol was applied for agricultural purposes. Sediment and soil, however, contained mostly residual DDT from the historical use of technical DDT. In most other regions of China, we found that dicofol contributed to a significant fraction of DDT in air samples. PMID- 20851453 TI - Multimedia fate of petroleum hydrocarbons in the soil: oil matrix of constructed biopiles. AB - A dynamic multimedia fugacity model was used to evaluate the partitioning and fate of petroleum hydrocarbon fractions and aromatic indicator compounds within the soil: oil matrix of three biopiles. Each biopile was characterised by four compartments: air, water, soil solids and non-aqueous phase liquid (NAPL). Equilibrium partitioning in biopile A and B suggested that most fractions resided in the NAPL, with the exception of the aromatic fraction with an equivalent carbon number from 5 to 7 (EC(5-7)). In Biopile C, which had the highest soil organic carbon content (13%), the soil solids were the most important compartment for both light aliphatic fractions (EC(5-6) and EC(6-8)) and aromatic fractions, excluding the EC(16-21) and EC(21-35). Our starting hypothesis was that hydrocarbons do not degrade within the NAPL. This was supported by the agreement between predicted and measured hydrocarbon concentrations in Biopile B when the degradation rate constant in NAPL was set to zero. In all scenarios, biodegradation in soil was predicted as the dominant removal process for all fractions, except for the aliphatic EC(5-6) which was predominantly lost via volatilization. The absence of an explicit NAPL phase in the model yielded a similar prediction of total petroleum hydrocarbon (TPH) behaviour; however the predicted concentrations in the air and water phases were significantly increased with consequent changes in potential mobility. Further comparisons between predictions and measured data, particularly concentrations in the soil mobile phases, are required to ascertain the true value of including an explicit NAPL in models of this kind. PMID- 20851454 TI - Impact of wastewaters and hospital effluents on the occurrence of controlled substances in surface waters. AB - We have investigated the occurrence of controlled drugs in two rivers, two wastewater treatment plants (WWTPs) and five hospital effluents in Taipei, Taiwan, and report here the concentrations of controlled drugs used as prescription medication or drugs of abuse. Of the target drugs, morphine, codeine, methamphetamines and ketamine were observed in significant quantities in hospital effluents, with maximum concentrations of 1240, 378, 260 and 206 ng L( 1), respectively. The other six compounds (including metabolites) were found at trace levels or below the method detection limits. In addition, the high occurrence in river waters of methamphetamine, codeine and ketamine (maximum values 405, 57, and 341 ng L(-1), respectively) indicated the significant prevalence of these controlled drugs. This study demonstrated that effluents from hospitals and clinics and treated WWTP effluents contribute to the controlled substances that eventually reach natural rivers. We hypothesize that the occurrence of controlled drugs in the environment can be attributed to two main sources: (1) substance abuse by individuals and (2) treatment with prescription medication for acute and chronic pain. The presence of these contaminants in the aquatic environment may pose significant risk to aquatic and human life. Further studies are needed for verification and may contribute to the development of sustainable strategies for environmental remediation. PMID- 20851455 TI - Photodegradation of organic contamination in wastewaters by bonding TiO2/single walled carbon nanotube composites with enhanced photocatalytic activity. AB - Bonding TiO(2)/single-walled carbon nanotube (SWCNT) composites have been successfully synthesized through a facile sol-solvothermal technique. The obtained materials were characterized in detail by XRD, FT-IR, Raman and TEM. The results revealed that TiO(2) and SWNCT linked compactly through ester bonds and thus improved their interfaces. Therefore, the recombination of photogenerated electron-hole pairs was inhibited efficiently, which improved the photocatalytic activity. A reasonable mechanism was proposed to explain its formation. The photocatalytic activity was investigated utilizing rhodamine B and nitrobenzene (NB) as models for organic contamination in wastewaters. Experimental results indicated that this bonding composite exhibited higher photocatalytic activity than that of Degussa P25. The excellent photocatalytic activity could be attributed to larger surface area, smaller crystalline size, and especially the ester bonds, which was further confirmed by surface photovoltage spectroscopy. Furthermore, by adding ()OH scavenger tert-butanol, the obvious decrease of NB photodegradation indicated that NB was oxidized primarily by ()OH. The photodegradation products were identified by GC/MS, further indicating that the degradation proceeded via ()OH oxidation. A possible reaction pathway for the degradation of NB was suggested by the evidence presented in this study. PMID- 20851456 TI - Recycling of ash from mezcal industry: a renewable source of lime. AB - Agave bagasse is a byproduct generated in the mezcal industry. Normally it is burned to reduce its volume, then a byproduct is generated in the form of residual ash, which can contaminate the water in rivers and lakes near the production places called "mezcaleras". This report details measurements of the Agave Salmiana fiber transformation after the burning process. The wasted ash was heated at 950 degrees C, and then hydrolyzed. The compounds were indentified using the X-ray diffraction. The images obtained by scanning electron microscope showed all the morphological transformations of the lime through the whole process. Thermal, elemental and morphological characterization of the agave bagasse were done. Experiments showed that 16% of ash was produced in the burning process of agave bagasse (450 degrees C), and 66% of the ash remains after heating (950 degrees C) in the form of calcium oxide. The results show an important renewable source of calcium compounds, due to the high production of agave based beverages in Mexico. PMID- 20851457 TI - Comparative in vivo forefoot kinematics of Homo sapiens and Pan paniscus. AB - The human metatarsophalangeal joints play a key role in weight transmission and propulsion during bipedal gait, but at present, the identification of when a habitual, human-like metatarsi-fulcrimating mechanism first appeared in the fossil record is debated. Part of this debate can be attributed to the absence of certain detailed quantitative data distinguishing human and great ape forefoot form and function. The aim of this study is to quantitatively test previous observations that human metatarsophalangeal joints exhibit greater amounts of dorsal excursion (i.e., dorsiflexion) than those of Pan at the terminal stance phase of terrestrial locomotion. Video recordings were made in order to measure sagittal excursions of the medial metatarsophalangeal joints in habitually shod/unshod adult humans and adult bonobos (Pan paniscus). Results indicate that the human first and second metatarsophalangeal joints usually dorsiflex more than those of bonobos. When timing of maximum excursion of the first metatarsophalangeal joint is coupled with existing plantar pressure data, the unique role of the human forefoot as a key site of leverage and weight transmission is highlighted. These results support hypotheses that significant joint functional differences between great apes and humans during gait underlie taxonomic distinctions in trabecular bone architecture of the forefoot. PMID- 20851458 TI - Measure of microhardness, fracture toughness and flexural strength of N vinylcaprolactam (NVC)-containing glass-ionomer dental cements. AB - OBJECTIVES: To investigate the effects of N-vinylcaprolactam (NVC)-containing terpolymers on the fracture toughness, microhardness, and flexural strength of conventional glass-ionomer cements (GIC). METHODS: The terpolymer of acrylic acid (AA)-itaconic acid (IA)-N-vinylcaprolactam (NVC) with 8:1:1 (AA:IA:NVC) molar ratio was synthesized by free radical polymerization and characterized using (1)H NMR and FTIR. Experimental GIC samples were made from a 50% solution of the synthesized terpolymer with Fuji IX powder in a 3.6:1 P/L ratio. Specimens were mixed and fabricated at room temperature. Plane strain fracture toughness (K(Ic)) was measured in accordance with ASTM Standard 399-05. Vickers hardness was determined using a microhardness tester. Flexural strength was measured using samples with dimensions of 2 mm*2 mm*20 mm. For all mechanical property tests, specimens were first conditioned in distilled water at 37 degrees C for 1 day or 1 week. Fracture toughness and flexural strength tests were conducted on a screw driven universal testing machine using a crosshead speed of 0.5mm/min. Values of mechanical properties for the experimental GIC were compared with the control group (Fuji IX GIC), using one-way ANOVA and the Tukey multiple range test at alpha=0.05. RESULTS: The NVC-modified GIC exhibited significantly higher fracture toughness compared to the commercially available Fuji IX GIC, along with higher mean values of flexural strength and Vickers hardness, which were not significantly different. SIGNIFICANCE: It was concluded that NVC-containing polymers are capable of enhancing clinically relevant properties for GICs. This new modified glass-ionomer is a promising restorative dental material. PMID- 20851459 TI - From kissing to coitus? Sex-of-partner differences in the sexual milestone achievement of young men. AB - Scientific information regarding normative patterns of young men's sexual behavior is insufficient, especially regarding the impact of sex of partner. We explored the age at which 255 young adult men achieved several milestones (e.g., first kiss, manual-genital contact, intercourse) as well as the sequence of milestone achievement and stability in sex-of-partner preferences as a function of sex-of-partner experiences. Mean ages of milestone achievement were consistent with the extant empirical literature. Men with only female partners were younger at first kiss and first relationship, and older at first intercourse than men with only male partners; they also reported an almost universal sequence of milestone achievement and little change in sex-of-partner preferences. Most men with male partners reported increased preference for male partners over time. Men with partners of both sexes tended to demonstrate patterns consistent with the relevant sex-of-partner group. Findings suggested a common male sexual trajectory and sex-of-partner dependent trajectories. PMID- 20851461 TI - Preventing HIV infection: turning the tide for young women. PMID- 20851460 TI - PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. AB - BACKGROUND: Innovative prevention strategies for HIV-1 transmission are urgently needed. PRO2000 vaginal gel was efficacious against HIV-1 transmission in studies in macaques; we aimed to assess efficacy and safety of 2% and 0.5% PRO2000 gels against vaginal HIV-1 transmission in women in sub-Saharan Africa. METHODS: Microbicides Development Programme 301 was a phase 3, randomised, double-blind, parallel-group trial, undertaken at 13 clinics in South Africa, Tanzania, Uganda, and Zambia. We randomly assigned sexually active women, aged 18 years or older (>=16 years in Tanzania and Uganda) without HIV-1 infection in a 1:1:1 ratio to 2% PRO2000, 0.5% PRO2000, or placebo gel groups for 52 weeks (up to 104 weeks in Uganda). Randomisation was done by computerised random number generator. Investigators and participants were masked to group assignment. The primary efficacy outcome was incidence of HIV-1 infection before week 52, which was censored for pregnancy and excluded participants without HIV-1 follow-up data or with HIV-1 infection at enrolment. HIV-1 status was established by rapid tests or ELISA at screening at 12 weeks, 24 weeks, 40 weeks, and 52 weeks, and confirmed in a central reference laboratory. The primary safety endpoint was an adverse event of grade 3 or worse. Use of 2% PRO2000 gel was discontinued on Feb 14, 2008, on the recommendation of the Independent Data Monitoring Committee because of low probability of benefit. This trial is registered at http://isrctn.org, number ISRCTN 64716212. FINDINGS: We enrolled 9385 of 15 818 women screened. 2591 (95%) of 2734 participants enrolled to the 2% PRO2000 group, 3156 (95%) of 3326 in the 0.5% PRO2000 group, and 3112 (94%) of 3325 in the placebo group were included in the primary efficacy analysis. Mean reported gel use at last sex act was 89% (95% CI 86-91). HIV-1 incidence was much the same between groups at study end (incidence per 100 woman-years was 4.5 [95% CI 3.8-5.4] for 0.5% PRO2000 vs 4.3 [3.6-5.2] for placebo, hazard ratio 1.05 [0.82-1.34], p=0.71), and at discontinuation (4.7 [3.8-5.8] for 2% PRO2000 gel, 3.9 [3.0-4.9] for 0.5% PRO2000 gel, and 3.9 [3.1-5.0] for placebo gel). Incidence of the primary safety endpoint at study end was 4.6 per 100 woman-years (95% CI 3.9-5.4) in the 0.5% PRO2000 group and 3.9 (3.2-4.6) in the placebo group; and was 4.5 (3.7-5.5) in the 2% PRO2000 group at discontinuation. INTERPRETATION: Although safe, 0.5% PRO2000 and 2% PRO2000 are not efficacious against vaginal HIV-1 transmission and are not indicated for this use. FUNDING: UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, International Partnership for Microbicides, and Endo Pharmaceuticals Solutions. PMID- 20851462 TI - Variability in the structure of epiphytic assemblages of Posidonia oceanica in relation to human interferences in the Gulf of Gabes, Tunisia. AB - In this study we evaluate whether the pattern of spatial variability of the macro epiphyte assemblages of leaves of Posidonia oceanica differed in relation to anthropogenic interference in the Gulf of Gabes (southern coast of Tunisia). A hierarchical sampling design was used to compare epiphytic assemblages at 5 m depth in terms of abundance and spatial variability at disturbed and control locations. The results indicate that the biomass and mean percentage cover decreased at locations near the point of sewage outlet in comparison to control locations. These losses were related to the distance from the source of disturbance. This study revealed that the diversity is reduced in disturbed locations by the loss of biomass and the mean percentage cover, explained by means of a multiple-stressor model which plays an important role in the macro epiphytes' setting. It is urgent to propose the best management plans to save the remaining P. oceanica meadow in the Gulf of Gabes and its associated epiphytes. PMID- 20851463 TI - Self-assembled fluorescent magnetic nanoprobes for multimode-biomedical imaging. AB - We fabricated multimode nanoprobes for acquisition of biological information at different object levels, i.e., in vivo detection and ex vivo validation for characterizing tumor angiogenesis. Fluorescent magnetic nanoprobes (FMNPs) were synthesized by using amphiphilic pyrenyl polyethylene glycol (Py-PEG) and superparamagnetic MnFe(2)O(4) nanocrystals (MNCs). Py-PEG, which is synthesized by conjugation of hydrophilic PEG with hydrophobic and fluorescent 1 pyrenebutyric acid through an esterification process, is capable of self-assembly and maintaining a high UV fluorescent intensity in aqueous phase. Py-PEG can be used as a fluorescent surfactant that simultaneously and efficiently encapsulates MNCs to exhibit fluorescent and magnetic properties as well as maintaining high water-solubility. Consequently, we proved that our biologically non-toxic FMNPs were prominent multimode imaging probes by showing not only excellent MR sensitivity but also high illumination intensity with strong signal strength under short exposure time of UV light from the extensive imaging studies of in vitro/vivo and ex vivo using orthotopic and xenograft mice models. PMID- 20851464 TI - Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer. AB - Gemcitabine [2', 2'-difluoro-2'-deoxycytidine (dFdC)] is a low molecular weight, deoxycytidine analog inhibiting cellular DNA synthesis. Currently, it is the frontline drug approved by Food and Drug Administration (FDA) for the treatment of pancreatic cancer. However, efforts to use gemcitabine as an anti-cancer agent have been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and intracellular action. Polymer-drug conjugates, in this regard have spawned an approach to improve the cytotoxicity efficiency and bioavailability of gemcitabine by chemical modification. The present study describes the synthesis of a water soluble formulation of PEGylated gemcitabine characterized by FT IR, (1)H NMR and RP-HPLC chromatography. The PEGylated gemcitabine has a prolonged circulation time in plasma as studied in an animal model. This eventually caused a marked improvement in the cytotoxicity and apoptosis-inducing activity in pancreatic cancer cell lines (MIA PaCa 2 and PANC 1). Hence, these findings demonstrate the PEGylated gemcitabine is a desirable approach for therapy by intravenous administration. Successful clinical application of this approach can significantly contribute to the treatment of pancreatic cancer. PMID- 20851465 TI - Role of substance P (SP) and calcitonin gene-related peptide (CGRP) in gibbon-ape leukemia virus (GALV) transduction of CD34+ cells. AB - AIMS: Optimization of transduction condition is an important goal to improve gene transduction. Therefore, we aimed to assess the effect of SP and/or CGRP as novel growth/transducing factors on the efficacy of CD34(+) transduction. METHODS: CD34(+) cells were transduced with Gibbon-Ape-Leukemia virus (GALV), containing Neomycin gene. CD34(+) cells were transduced with GALV presence of SP and/or CGRP. Real Time PCR and colony formation assay (CFU-C) was performed. RESULTS: Viral vectors titration on Hela cells indicated transduction efficiency of 1*10(6)CFU/ml. Real Time PCR of Neo and CFU-C showed stimulatory role of SP on gene transfer 5.9% and 14.84% compared to 3.6% and 12.58% in control group, while opposite role observed for CGRP 0.89% and 7.86%. Both SP and CGRP showed no significant effect in these assays. DISCUSSION: This study showed including of SP in growth factor cocktail is beneficial for CD34(+) transduction, which could be applied to genetic modification procedures. PMID- 20851466 TI - The development and validation of the protective factors survey: a self-report measure of protective factors against child maltreatment. AB - OBJECTIVE: The objective of this study was to evaluate the internal structure of a self-report measure of multiple family-level protective factors against abuse and neglect and explore the relationship of this instrument to other measures of child maltreatment. METHODS: For the exploratory factor analysis, 11 agencies from 4 states administered the Protective Factors Survey (PFS), the Brief Child Abuse Potential Inventory (Ondersma et al., 2005), and another measure to establish content validity (N=249 participants). Exploratory factor analyses were conducted to obtain a small, integrated set of items that tap the targeted protective factors correlated with other theoretically important constructs. Correlations were computed to explore PFS criterion-related validity. Confirmatory factor analyses were conducted on an additional sample of 689 participants from 19 agencies across the United States. RESULTS: Exploratory and confirmatory factor analyses yielded a 4-factor solution, consisting of Family Functioning, Emotional Support, Concrete Support, and Nurturing and Attachment. Four measures were administered to assess constructs that were predicted to correlate negatively with the protective factors: child abuse potential, depression, stress, and maladaptive coping. The PFS was also predicted to correlate positively with adaptive coping such as use of emotional and instrumental social support and positive reframing. Overall, the PFS subscales were significantly related to these measures in the directions predicted. CONCLUSIONS: The PFS is a valid and reliable instrument to measure individual differences in multiple protective factors in families. The measure is an easily administered tool that offers programs an alternative to costly, time-intensive measures. PRACTICE IMPLICATIONS: The PFS offers community-based prevention programs a valid and reliable survey instrument that measures multiple protective factors. The subscales-Family Functioning, Emotional Support, Concrete Supports, and Nurturing and Attachment-can be used by practitioners to understand the service population more fully, inform services, and contribute to the evidence base of a protective factors approach. Practitioners can build on the strengths or protective factors in parents and select services to address areas that are less developed. PMID- 20851468 TI - Spatio-temporal patterns of road traffic noise pollution in Karachi, Pakistan. AB - We studied the spatial and temporal patterns of noise exposure due to road traffic in Karachi City, Pakistan, and found that levels of noise were generally higher during mornings and evenings because of the commuting pattern of Karachi residents. This study found the average value of noise levels to be over 66 dB, which could cause serious annoyance according to the World Health Organization (WHO) outdoor noise guidelines. Maximum peak noise was over 101 dB, which is close to 110 dB, the level that can cause possible hearing impairment according to the WHO guidelines. We found that noise pollution is not an environmental problem reserved for developed countries, but occurs in developing countries as well. For this reason, steps might be required to reduce noise levels caused by road traffic. PMID- 20851467 TI - Lead-induced genotoxicity to Vicia faba L. roots in relation with metal cell uptake and initial speciation. AB - Formation of organometallic complexes in soil solution strongly influence metals phytoavailability. However, only few studies deal with the influence of metal speciation both on plant uptake and genotoxicity. In the present study, Vicia faba seedlings were exposed for 6h in controlled hydroponic conditions to 5 MUM of lead nitrate alone and chelated to varying degrees by different organic ligands. Ethylenediaminetetraacetic acid and citric acid were, respectively, chosen as models of humic substances and low weight organic acids present in natural soil solutions. Visual Minteq software was used to estimate free lead cations concentration and ultimately to design the experimental layout. For all experimental conditions, both micronucleus test and measure of lead uptake by plants were finally performed. Chelation of Pb by EDTA, a strong chelator, dose dependently increased the uptake in V. faba roots while its genotoxicity was significantly reduced, suggesting a protective role of EDTA. A weak correlation was observed between total lead concentration absorbed by roots and genotoxicity (r(2)=0.65). In contrast, a strong relationship (r(2)=0.93) exists between Pb(2+) concentration in exposure media and genotoxicity in the experiment performed with EDTA. Citric acid induced labile organometallic complexes did not demonstrate any significant changes in lead genotoxicity or uptake. These results demonstrate that metal speciation knowledge could improve the interpretation of V. faba genotoxicity test performed to test soil quality. PMID- 20851469 TI - Effects of sewage effluent remediation on body size, somatic RNA: DNA ratio, and markers of chemical exposure in three-spined sticklebacks. AB - Body mass, fork length, RNA:DNA ratio, specific growth rate, and hepatic EROD activity and CYP1A expression, were measured in three-spined sticklebacks in the River Ray (south west England) at sites downstream of an urban waste water treatment works (WWTW) prior to, and following, remediation of the effluent with granular activated carbon (GAC) tertiary treatment. During the same two-year period fish were also sampled from a neighbouring reference river (R. Ock). The WWTW effluent elevated water temperatures and nutrient content in the R. Ray and rendered a direct comparison of fish populations in the two rivers untenable. Instead, the stability of population parameters within each river during matched pre- and post-remediation periods was compared. Stickleback populations in both rivers were annual but fish in the R. Ray spawned earlier and were larger than those in the R. Ock. In the R. Ray fish gained mass throughout the winter months whereas in the R. Ock growth was much reduced during this period. In fish from the R. Ray the somatic RNA:DNA ratio remained elevated during May-November after remediation, rather than declining as in the same period pre-remediation and as was the case for fish in the R. Ock during both periods. The specific growth rate of the first post-remediation generation of sticklebacks in the R. Ray was higher than that of the previous pre-remediation generation. Following remediation there was no decline in hepatic EROD activity or in the abundance of hepatic CYP1A transcripts in fish in the R. Ray suggesting that the primary route of exposure to contaminants for these fish was not via the water column, and that the change in performance of the fish post-remediation was not impeded by continued exposure to contaminants. Both EROD activity and CYP1A expression increased in fish in the R. Ock during the later stages of the study suggesting that the fish in this river were exposed to an unidentified contaminant episode. This may have been linked with the poorer performance of fish in the R. Ock during the post remediation period. The improved performance of fish in the R. Ray suggest that there may be factors in good quality secondary treated sewage effluent which can adversely influence the performance of fish populations, directly or indirectly, and which can be removed by tertiary treatment. PMID- 20851470 TI - Transcriptome analysis of Traf6 function in the innate immune response of zebrafish embryos. AB - TRAF6 is a key player at the cross-roads of development and immunity. The analysis of its in vivo molecular function is a great challenge since severe developmental defects and early lethality caused by Traf6 deficiency in knock-out mice interfere with analyses of the immune response. In this study we have used a new strategy to analyze the function of Traf6 in a zebrafish-Salmonella infectious disease model. In our approach the effect of a Traf6 translation blocking morpholino was titrated down to avoid developmental defects and the response to infection under these conditions was studied using the combination of microarray analysis and whole transcriptome deep sequencing. Transcriptome profiling of the traf6 knock-down allowed the identification of a gene set whose responsiveness during infection is highly dependent on Traf6. Expression trend analysis based on the resulting datasets identified nine clusters of genes with characteristic transcription response profiles, demonstrating Traf6 has a dynamic role as a positive and negative regulator. Among the Traf6-dependent genes was a large set of well known anti-microbial and inflammatory genes. Additionally, we identified several genes which were not previously linked to a response to microbial infection, such as the fertility hormone gene gnrh2 and the DNA-damage regulated autophagy modulator 1 gene dram1. With the use of the zebrafish embryo model we have now analyzed the in vivo function of Traf6 in the innate immune response without interference of adaptive immunity. PMID- 20851471 TI - Anti-Leishmanial activity of homo- and heteroleptic bismuth(III) carboxylates. AB - Bismuth(III) complexes of NSAIDs (Non-Steroidal Anti Inflammatory Drugs) and substituted benzoic acids (o-methoxybenzoic acid, m-methoxybenzoic acid, o nitrobenzoic acid, 3,5-diacetamidobenzoic acid, and 5-[(R/S)-2,3-dihydroxypropyl carbamoyl]-2-pyridine carboxylic acid) have been synthesised and fully characterised. Two new bis-carboxylato bismuth complexes have been characterised by single crystal X-ray diffraction, namely [PhBi(o MeOC(6)H(4)CO(2))(2)(bipy)].0.5EtOH (bipy=2,2'-bipyridine) and [PhBi(C(9)H(11)N(2)O(3)CO(2))(2)(H(2)O)].6H(2)O. All compounds were tested against the parasite Leishmania major promastigotes for their anti-Leishmanial activity and were further assessed for their toxicity to mammalian cells. The NSAID free acids and their bismuth derivatives show negligible anti-Leishmanial activity at concentrations 1.95 to 250 MUg/mL against the promastigotes of L. major whereas in the case of mammalian cells only bismuth complexes of naproxen and mefenamic acid have significant effect at concentration>=250 MUg/mL. The bismuth(III) complexes of substituted benzoic acids show significant anti Leishmanial activity against the promastigotes of L. major V121 at very low concentrations while their respective free carboxylic acids show no effective activity. However, the bismuth compounds inhibit the growth of the mammalian cells at all concentrations studied (1.95 to 500 MUg/mL) following 48 h incubation. The comparatively low toxicity of BiCl(3) and Bi(NO(3))(3), suggests that overall toxicity of bismuth complexes towards the parasite is both ligand and metal dependent. PMID- 20851472 TI - Use of endocanalicular dacryocystorhinostomy with multidiode laser in children. AB - OBJECTIVE: To evaluate the clinical outcome and efficacy of endocanalicular laser dacryocystorhinostomy using a multidiode laser in cases unresponsive to medical therapy, probing or intubation of pediatric nasolacrimal duct obstruction. METHODS: Eight children with nasolacrimal duct obstruction were treated with a multidiode laser. The study was prospective, non-randomized, and noncomparative. The patients, 2 (25%) males and 6 (75%) females, ranged in age from 8 to 13 years (mean 11.25+/-2.43). Surgery was performed under general anesthesia. All procedures were performed using a multidiode laser. The nasal passage was visualized with a 30 degrees nasal video endoscope. In all cases, silicone stents were inserted. The main outcome measure was resolution or improvement of the epiphora and no major laser damage intranasally. Patients were followed for at least 6 months. RESULTS: The endocanalicular laser dacryocystorhinostomy failed in one of the 8 (12.5%) cases, which had been secondary to trauma. The others were due to primary nasolacrimal duct obstruction. External dacryocystorhinostomy was performed on the failed case. None of the cases with primary nasolacrimal duct obstruction had obstruction after the endocanalicular laser dacryocystorhinostomy operation. CONCLUSIONS: Endocanalicular laser dacryocystorhinostomy using a multidiode laser appears to be an effective technique in cases unresponsive to medical therapy, probing or intubation of primary nasolacrimal duct obstruction. PMID- 20851473 TI - Toxic effects of Cr(VI) and Cr(III) on energy metabolism of heterotrophic Euglena gracilis. AB - To assess the toxic effect of Cr on energy metabolism, heterotrophic Euglena gracilis was grown in a medium that prompts high yield biomass and in the presence of different Cr(VI) or Cr(III) concentrations. The cell growth IC50 value was 12 and >250MUM for Cr(VI) and Cr(III), respectively; in these cells chromium was accumulated and a fraction compartmentalized into mitochondria, and synthesis of cysteine and glutathione was induced. Respiration of control isolated mitochondria was strongly inhibited by added Cr(VI) or Cr(III) with L lactate or succinate as substrates. In turn, cellular and mitochondrial respiration, respiratory Complexes I, III and IV, glycolysis and cytosolic NAD(+) alcohol and -lactate dehydrogenases from cells cultured with Cr(VI) were significantly lower than control, whereas AOX and external NADH dehydrogenase activities were unaltered or increased, respectively. Addition of Cr(VI) or Cr(III) to isolated mitochondria or cytosol from control- or Cr(VI)-grown cells induced inhibition of respiration, respiratory Complexes III, IV and AOX, and glycolytic pyruvate kinase; whereas Complex I, external NADH dehydrogenase, and other glycolytic enzymes were unaffected. Protein contents of mitochondrial Complexes I, III, IV and V, and ANT were diminished in Cr(VI)-grown cells. Decreased respiration and glycolysis induced by Cr(VI) resulted in lower cellular ATP content. Results suggested that Cr(VI) cytotoxicity altered gene expression (as widely documented) and hence enzyme content, and induced oxidative stress, but it was also related with direct enzyme inhibition; Cr(III) was also cytotoxic although at higher concentrations. These findings establish new paradigms for chromium toxicity: Cr(VI) direct enzyme inhibition and non-innocuous external Cr(III) toxicity. PMID- 20851474 TI - Can a chronic dental infection be considered a cause of cardiovascular disease? A review of the literature. AB - Cardiovascular diseases (CVD) have a complex etiology determined by risk factors, which are in turn associated to a strong genetic component and to environmental factors. In the biological background for the development of CVD, low-grade chronic inflammation plays a role as a pathogenetic determinant of atherosclerosis. Dental infections have been associated with CVD. Periodontal disease is a chronic infection of the supporting tissues of the tooth that can lead to teeth loss. In recent years, a number of reports have demonstrated the possible relationship between periodontal disease and CVD. Apical periodontitis, on the other hand, is the late consequence of an endodontic infection, which is caused by the persistence of coronal caries and involves the root canal system of the tooth. Most of the time, it is a chronic infection. Some studies have found a correlation between a "composite status" of oral health (eg. caries, tooth loss, periodontal disease) and CVD, but only a few of them have addressed the association between apical periodontitis and CVD. This "state of the art" paper represents the first stage of an incoming study on the relationship between chronic endodontic infection and CVD. PMID- 20851475 TI - Anticoagulation remains underused in prevention of stroke associated with atrial fibrillation: insights from two consecutive national surveys. AB - BACKGROUND: Atrial fibrillation (AF) is a major risk factor of ischemic stroke. We tested whether the adoption of the CHADS(2) score in clinical guidelines has impacted treatment strategies for stroke prevention, and examined how AF affects stroke outcome. METHODS: In the setting of two national surveys [National Acute Stroke Israeli Surveys; all patients hospitalized for stroke in Israel during February-March 2004, and March-April 2007] data of patients with and without AF were analyzed with respect to patient characteristics, use of anticoagulation, stroke severity, clinical course, and long-term outcome. RESULTS: Of 3040 patients with acute ischemic stroke, 586 patients (19%) had a history of AF. Severe strokes on admission were significantly more frequent in patients with AF, as was the proportion of total anterior circulation strokes. Ischemic stroke associated with AF predicted poor outcome at discharge (adjusted OR 1.56; 95%CI 1.24-1.96) and higher mortality rates throughout follow-up. Among patients with a CHADS(2) score >= 2 prior to the index stroke and without known contraindications, 41% received anticoagulation. This proportion increased to only 62% after the index stroke, even after excluding patients with severe disability and no significant increase between 2004 and 2007 was detectable. Increasing age, in-hospital infectious complications, and unfavorable functional status at discharge were independently associated with decreased likelihood of receiving anticoagulation. CONCLUSIONS: In deviation from current recommendations and in spite of the introduction of CHADS(2) criteria, anticoagulation for stroke prevention remains underutilized, despite the particularly poor outcome of strokes associated with AF. PMID- 20851476 TI - Effect of an invasive strategy on in-hospital outcome and one-year mortality in women with non-ST-elevation myocardial infarction. AB - BACKGROUND: Subgroup analyses from randomized studies show inconsistent results regarding an early invasive approach in women with non-ST-elevation myocardial infarction (NSTEMI). We sought to investigate the impact of an invasive strategy in clinical practice, analyzing data from the German Acute Coronary Syndromes registry (ACOS). METHODS: Overall 1986 consecutive women were enrolled in the registry between June 2000 and November 2002 and were divided into two groups: 1215 (61.2%) underwent coronary angiography, 771 (38.8%) received conservative treatment. In the invasive group percutaneous coronary intervention was performed in 40.7% within 48 h and in 16.4% after 48 h, whereas 8.3% underwent coronary artery bypass grafting within hospital stay. RESULTS: In-hospital death (3.2% vs 10.5%, p<0.0001), in-hospital death/myocardial infarction (MI) (7.1% vs 14.9%, p<0.0001) and one-year death (8.1% vs 24%) occurred significantly less often in patients with invasive strategy. After adjustment of the confounding factors in the propensity score analysis the invasive strategy showed no significant benefit for in-hospital death (OR 0.86, 95% CI 0.51-1.44) or death/MI (OR 0.70, 95% CI 0.47-1.04) but remained superior for mortality (OR 0.47, 95% CI 0.3-0.7) and death/MI one year after discharge (OR 0.47, 95% CI 0.33-0.68). CONCLUSIONS: In clinical practice women presenting with NSTEMI have a long-term benefit from an invasive therapeutic strategy with a significant reduction in mortality as well as the composite endpoint of death/MI. PMID- 20851477 TI - Chronotropic incompetence and its relation to exercise intolerance in hypertrophic cardiomyopathy. AB - BACKGROUND: Diminished functional capacity is common in hypertrophic cardiomyopathy (HCM), although the underlying mechanisms are complicated. We studied the prevalence of chronotropic incompetence and its relation to exercise intolerance in patients with HCM. METHODS: Cardiopulmonary exercise testing was performed in 68 patients with HCM (age 44.8 +/- 14.6 years, 45 males). Chronotropic incompetence was defined by chronotropic index (heart rate reserve)/(220-age-resting heart rate) and exercise capacity was assessed by peak oxygen consumption (peak Vo(2)). RESULTS: Chronotropic incompetence was present in 50% of the patients and was associated with higher NYHA class, history of atrial fibrillation, higher fibrosis burden on cardiac MRI, and treatment with beta-blockers, amiodarone and warfarin. On univariate analysis, male gender, age, NYHA class, maximal wall thickness, left atrial diameter, peak early diastolic myocardial velocity of the lateral mitral annulus, history of atrial fibrillation, presence of left ventricular outflow tract obstruction (LVOTO) at rest, and treatment with beta-blockers were related to peak Vo(2). Peak heart rate during exercise, heart rate reserve, chronotropic index, and peak systolic blood pressure were also related to peak Vo(2). On multivariate analysis male gender, atrial fibrillation, presence of LVOTO and heart rate reserve were independent predictors of exercise capacity (R(2) = 76.7%). A cutoff of 62 bpm for the heart rate reserve showed a negative predictive value of 100% in predicting patients with a peak Vo(2) <80%. CONCLUSIONS: Blunted heart rate response to exercise is common in HCM and represents an important determinant of exercise capacity. PMID- 20851478 TI - Validation of an animal model of right ventricular dysfunction and right bundle branch block to create close physiology to postoperative tetralogy of Fallot. AB - BACKGROUND: In the past 5 years a few number of studies and case reports have come out focusing on biventricular (BiV) stimulation for treatment of congenital heart disease related ventricular dysfunction. The few available studies include a diverse group of pathophysiological entities ranging from a previously repaired tetralogy of Fallot (TOF) to a functional single ventricle anatomy. Patient's status is too heterogeneous to build important prospective study. To well understand the implication of prolonged electromechanical dyssynchrony we performed a chronic animal model that mimics essential parameters of postoperative TOF. METHODS: Significant pulmonary regurgitation, mild stenosis, as well as right ventricular outflow tract (RVOT) scars were induced in 15 piglets to mimic repaired TOF. 4 months after hemodynamics and dyssynchrony parameters were compared with a control group and with a population of symptomatic adult with repaired TOF. RESULTS: Comparing the animal model with the animal control group on echocardiography, RV dilatation, RV and LV dysfunction, broad QRS complex and dyssynchrony were observed on the animal model piglets. Moreover, epicardial electrical mapping showed activation consistent with a right bundle branch block. The animal models displayed the same pathophysiological parameters as the post TOF repair patients in terms of QRS duration, pulmonary regurgitation biventricular dysfunction and dyssynchrony. CONCLUSION: This chronic swine model mimics electromechanical ventricular activation delay, RV and LV dysfunction, as in adult population of repair TOF. It does appear to be a very useful and interesting model to study the implication of dyssynchrony and the interest of resynchronization therapy in TOF failing ventricle. PMID- 20851479 TI - The defects in development and apoptosis of cardiomyocytes in mice lacking the transcriptional factor Pax-8. AB - BACKGROUND: Cardiac-specific deletion of ALK3 is lethal in mid-gestation with ventricular septum malformations (VSM). This study was designed to define the Pax 8's role in heart development and cardiomyocyte apoptosis. METHODS: Pathologic changes in the hearts of Pax-8 or ALK3 knockout and wild type control mice were determined by light and electron microscopy. Analysis of cardiomyocyte apoptosis was performed by TUNEL. The effect of Pax-8 gene deficiency on caspase-3 activity was examined after transfecting Pax-8 siRNA into cultured myoblast cell line. RESULTS: Mice with ALK3 or Pax-8 gene knockout but not wild type control animals showed the development of VSM. Increased cardiomyocyte apoptosis was found in homozygotes. Echocardiography showed that Pax-8 homozygote mice developed malfunction of the heart. Furthermore, the caspase-3 activity was significantly higher in the cells treated with Pax-8 siRNA as compared to those treated with negative control siRNA in H9C2 (2-1) cell line. CONCLUSIONS: The Pax-8 gene may play a crucial role in heart development and regulating cardiocyte apoptosis. Knockout of Pax-8 may exert a similar effect on myocardial morphology and apoptosis as those seen in ALK3 knockouts. Furthermore, the ventricular septum malformations could be partially attributed to accelerated cardiomyocyte apoptosis. PMID- 20851480 TI - Corticosteroid administration for patients with coronary artery aneurysms after Kawasaki disease may be associated with impaired regression. AB - INTRODUCTION: Corticosteroid administration in Kawasaki disease (KD) is controversial but accepted as treatment for patients who do not respond to initial treatment. The impact of corticosteroids on evolving coronary artery aneurysms (CAA) and future vascular remodelling is unknown. METHODS AND RESULTS: The clinical history of 80 patients (73% male; median age at diagnosis 2.2 years) seen from 1990 to 2008 with CAAs after KD were reviewed, 19 (24%) of whom received systemic corticosteroids in the acute phase (14 for <= 3 days, 5 for 4+ days). CAA z-scores were assessed at baseline, 2-3 months, and 1 year after the acute phase. Linear regression models adjusted for repeated measures were used to determine the association between change in CAA z-score over time and corticosteroid use, adjusting for patient age at diagnosis, gender, intravenous immunoglobulin use, total days of fever, albumin level, hemoglobin level and platelet count. RESULTS: The corticosteroid treated group had longer duration of fever in the acute phase (median 17 vs. 11 days, p=0.04). Adjusted CAA z-scores at diagnosis, 2-3 months and 1 year follow-up for CAA in the left anterior descending decreased (from +5.5 to +3.5 to +1.9) in those not treated with corticosteroids, but progressed for those treated with corticosteroids (from +7.4 to +17.5 to +15.8), regardless of duration of corticosteroid treatment. Similar results were noted for CAA of the right coronary artery and the left main coronary artery. CONCLUSIONS: The use of corticosteroids in the acute phase of KD for patients with evolving CAAs may be associated with worsening involvement and impaired vascular remodelling and warrants further study. PMID- 20851481 TI - A new telemonitoring system intended for chronic heart failure patients using mobile telephone technology--feasibility study. AB - BACKGROUND: Remote monitoring is one modality of structured care in chronic heart failure. The purpose of this study was to evaluate the feasibility of a new wireless telemonitoring system via a mobile phone network. METHODS: Portable home devices for electrocardiogram, blood pressure, body weight and self-assessment measurements were connected (via Bluetooth) to a personal digital assistant (PDA) that performs automated encrypted transmission via mobile phone. Two telemedical centres were set-up. RESULTS: 30 healthy volunteers were enrolled and followed for 26 days. A total of 4002 single measurements were taken, 133 +/- 37 per person. No data was lost or incorrectly allocated. 880 of 937 (94%) of the ECG recordings had sufficient diagnostic quality for rhythm analysis and single beat measurements. 50 continuous ECG-streams (312 min) without disruption were performed. Total system availability was 96.6%, including that of the mobile phone network. CONCLUSIONS: Mobile phone technology is suitable for continuous and secure medical data transmission. To evaluate the clinical use in chronic heart failure patients, a large multicentre randomized controlled trial (ClinicalTrials.gov Identifier: NCT00543881) was started. PMID- 20851482 TI - Abnormal hyperventilation in patients with hepatic cirrhosis: role of enhanced chemosensitivity to carbon dioxide. AB - BACKGROUND: Patients with hepatic cirrhosis frequently show idiopathic hyperventilation at rest, despite no concomitant cardiopulmonary disease. The aim of the study was to determine whether altered chemosensitivity either to hypoxia or hypercapnia could underlie inappropriate hyperventilation in cirrhotic patients. METHODS: We consecutively recruited 30 biopsy proven cirrhotic patients equally distributed in the three Child's classes A, B and C (age 54 +/- 8 years, mean +/- SD). All patients underwent evaluation of chemosensitivity to hypoxia and to hypercapnia and blood sampling for brain natriuretic peptide, norepinephrine and progesterone, besides full clinical characterization. We also recruited 10 age- and gender-matched healthy controls (age 55 +/- 7 years). RESULTS: Overall, 18 patients (60%) showed an increased chemosensitivity to carbon dioxide (CO(2)), while 8 patients (27%) showed enhanced chemosensitivity to hypoxia. Child's class C patients had lower arterial partial pressure of CO(2) (PaCO(2)), higher rest ventilation, increased chemosensitivity to hypercapnia, plasma level of norepinephrine and serum progesterone levels when compared to class A patients and controls (all p < 0.05). Rest ventilation was positively related to pH (R = 0.41, p = 0.023), chemosensitivity to hypercapnia (R = 0.54, p = 0.002), and progesterone (R = 0.53, p = 0.016) and negatively to PaCO(2) (R = 0.61, p < 0.001), but not to hemoglobin level and chemosensitivity to hypoxia. Chemosensitivity to hypercapnia was positively related to PaCO(2) (R = 0.74, p < 0.001), serum progesterone (R = 0.50, p = 0.016), and to plasma norepinephrine (R = 0.57, p = 0.004). CONCLUSIONS: Enhanced chemosensitivity to hypercapnia was found in more decompensated cirrhotic patients and was associated with sympathetic overactivity and elevated serum progesterone, likely representing a key mechanism underlying the "unexplained" hyperventilation observed in such patients. PMID- 20851483 TI - Short-term metabolic changes achieved by weight loss in hypertensive patients. AB - INTRODUCTION: Glucose and lipid metabolism abnormalities of hypertensive patients are highly relevant due to its increase in cardiovascular risk; moreover, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) have a high risk of new-onset diabetes mellitus (DM) development. The objective of the study was to describe glucose metabolism abnormalities and the impact of mid-term weight loss. METHODS: A six-month prospective, observational and multicentre study of patients with hypertension was conducted. Clinical antecedents, physical examination, blood test and treatments were collected in two separated visits; conventional advice was the only intervention planned. RESULTS: A total of 1957 patients were included, mean age 66.3 (10.9) years and 59.9% males. A previous diagnosis of glucose metabolism alteration was present in 43.9% (25.5% type-2 DM, 14.8% IFG, 1.6% IFG and IGT, 1.0% IGT and 1.0% type-1 DM). An increasing pattern of cardiovascular risk and target organ damage was observed according to the categories of fasting glucose. Oral glucose tolerance test (OGTT) was carried out in 234 patients (11.9%) patients and yielded the diagnosis of IGT in 44.7% or DM in 22.4% of patients with fasting glucose >100mg/dl. Six months follow-up was achieved in 85.9% patients. A slight reduction in fasting glucose was observed in the whole cohort and patients who achieved >= 5% weight loss experienced the highest reduction in fasting glucose, LDL-c and triglycerides; moreover, 15.8% normalized their IFG. CONCLUSIONS: Glucose and lipid metabolism abnormalities are highly prevalent in hypertensive patients and improve with 5% of weight lost at 6 months follow-up. OGTT is not currently extended in daily clinical practise. PMID- 20851485 TI - The value of coverage in the medicare advantage insurance market. AB - This paper examines the impact of coverage on demand for health insurance in the Medicare Advantage (MA) insurance market. Estimating the effects of coverage on demand poses a challenge for researchers who must consider both the hundreds of benefits that affect out-of-pocket costs (OOPC) to consumers, but also the endogeneity of coverage. These problems are addressed in a discrete choice demand model by employing a unique measure of OOPC that considers a consumer's expected payments for a fixed bundle of health services and applying instrumental variable techniques to address potential endogeneity bias. The results of the demand model show that OOPC have a significant effect on consumer surplus and that not instrumenting for OOPC results in a significant underestimate of the value of coverage. PMID- 20851484 TI - Anti-inflammatory effect of hydrogen-rich saline in a rat model of regional myocardial ischemia and reperfusion. AB - INTRODUCTION: To study the possible anti-inflammatory effect of hydrogen-rich saline (H(2) saline) on rat hearts with regional myocardial ischemia and reperfusion (I/R). METHODS: Sixty-six rats were equally randomized to three groups: sham-operated group, I/R group (control group) and I/R plus H(2) saline treatment group. Myocardial I/R was established by occlusion of the left anterior descending (LAD) coronary artery for 30 min and reperfusion for 24 h. RESULTS: H(2) saline treatment attenuated I/R-induced cardiac cell apoptosis, presenting as significant improvement of heart function parameters 24h after reperfusion, including left ventricular systolic pressure (LVSP), left ventricular diastolic pressure (LVEDP), +(dP/dt)max and -(dP/dt)max. It also decreased neutrophil infiltration, 3-nitrotyrosine level, expression of intercellular adhesion molecule 1(ICAM-1) and myeloperoxidase (MPO) activity in the area at risk zones (AAR) of rat hearts subjected to regional myocardial I/R, and attenuated the increase of I/R induced proinflammatory cytokine tumor necrosis factor-alpha (TNF a) and interleukin-1beta (IL-1b) levels in the AAR. CONCLUSION: H(2) saline has an anti-inflammatory effect on rat hearts with regional myocardial I/R. PMID- 20851486 TI - Development of an electronic database for quality assurance of radiotherapy in the International Society of Paediatric Oncology (Europe) high risk neuroblastoma study. AB - Quality assurance of radiotherapy is an important determinant of outcome in some cancers. SIOPEN-R-NET developed a computerised remote data entry system for recording imaging and treatment parameters for its multimodality high risk neuroblastoma study. This will enable investigation of the relationship between radiotherapy quality and local control. PMID- 20851487 TI - Effectiveness of surgery and individualized high-dose hyperfractionated accelerated radiotherapy on survival in clinical stage I non-small cell lung cancer. A propensity score matched analysis. AB - BACKGROUND AND PURPOSE: Surgery is considered the treatment of choice for early stage non-small cell lung cancer (NSCLC). Patients with poor pulmonary function or other comorbidities are treated with radiotherapy. The objective of this investigation is to compare the 3-year survival of two early-stage NSCLC populations treated in two different hospitals, either by surgical resection (lobectomy) or by individualized high-dose accelerated radiotherapy, after matching patients by propensity scoring analysis. METHODS: A retrospective comparative study has been performed on two series of consecutive patients with cytohistological diagnosis of NSCLC, clinically staged IA by means of PET-scan (radiotherapy group) and pathologically staged IA (surgery group). RESULTS: A total of 157 cases were initially selected for the analysis (110 operated and 47 treated by radiotherapy). Patients in the radiotherapy group were older, with higher comorbidity and lower FEV1% with 3-years probability of survival for operated patients higher than that found for patients treated by radiotherapy. After matching by propensity scoring (using age and FEV1%), differences disappear and 3-years probability of survival had no statistical differences. CONCLUSIONS: Although this is a non-randomized retrospective analysis, we have not found 3 years survival differences after matching cases between surgery and radiotherapy. Nevertheless, data presented here support the continuous investigation for non surgical alternatives in this disease. PMID- 20851489 TI - Diversity of Saccharomyces and non-Saccharomyces yeasts in three red grape varieties cultured in the Serrania de Ronda (Spain) vine-growing region. AB - For the first time, an ecological survey of wine yeasts present in grapes growing in two vineyards located in the region of "Serrania de Ronda" (Malaga, southern Spain) has been carried out. During the 2006 and 2007 vintages, grapes from different varieties were aseptically collected and allowed to ferment spontaneously in the laboratory. From a total of 1586 colonies isolated from microvinifications, 1281 were identified according to ITS polymorphisms and their identity confirmed by sequencing of the D1/D2 region of 26S rDNA. Most of the isolates (84%) corresponded to thirteen different non-Saccharomyces species with Kluyveromyces thermotolerans, Hanseniaspora guilliermondii, Hanseniaspora uvarum and Issatchenkia orientalis accounting for 42.7% of the total. Mitochondrial DNA restriction analysis from the Saccharomyces cerevisiae isolates revealed a low diversity since only eleven different profiles were found, nine of them corresponding to local strains and two to commercial ones that had been used in different campaigns and that very likely were disseminated from the winery to the adjacent vineyard. A different distribution of strains was found in the three grape varieties studied. PMID- 20851488 TI - Variations of N-acetylation level of peptidoglycan do not influence persistence of Lactococcus lactis in the gastrointestinal tract. AB - The food-grade Gram-positive bacterium, Lactococcus lactis, is recognized as a potential candidate to deliver proteins of medical interest by mucosal routes. The ability of carrier bacteria to persist and/or to lyse in the gastrointestinal tract needs to be considered to design optimal carrier strains to deliver proteins of interest at the mucosal level. Meyrand et al. (2007) have previously characterized in L. lactis, a peptidoglycan (PG) N-acetylglucosamine deacetylase (PgdA), which activity on PG influences bacterial sensitivity to lysozyme. Inactivation of pgdA gene in this bacterium, led to fully acetylated PG, resulting in a lysozyme-sensitive phenotype, whereas pgdA overexpression led to an increased degree of PG deacetylation, resulting in a lysozyme-resistant phenotype (Meyrand et al., 2007). In order to determine whether variations in L. lactis resistance to host lysozyme may influence its persistence in the GIT and its ability to deliver heterologous proteins in situ, we constructed L. lactis strains with different de-N-acetylation levels and producing a model antigen (the human papillomavirus type-16 E7 protein) and we compared the pharmacokinetics properties of these recombinant strains with that of a wild-type strain producing the same antigen in the GIT of mice. Our results show that there was no correlation between survival, at the ileum level, of bacteria intragastrically administered in mice and bacteria sensitivity or resistance to lysozyme. In addition, analysis of the E7-specific immune response evoked by the three strains after mucosal administration in mice suggest that neither lysozyme-sensitive nor lysozyme-resistant phenotype in L. lactis enhances significantly the potential of this bacterium as mucosal delivery live vector. In conclusion, our results suggest that either pgdA inactivation or pgdA overexpression in L. lactis leading to different levels of PG deacetylation does not confer any advantage in the persistence of this bacterium in the GIT and its ability to enhance host immune responses induced by delivered antigen in situ. PMID- 20851491 TI - Drug-induced liver injury: is it time for genetics to change our clinical practice? PMID- 20851492 TI - Power of the process: evaluating the impact of the Framework Convention on Tobacco Control negotiations. AB - OBJECTIVE: Evaluate the impact of the FCTC negotiations on the diffusion of tobacco control policies. METHODS: Analyzed country characteristics to determine their effects on the frequency, type and strength of tobacco control policies adopted among WHO Member States. Bivariate analyses were conducted for each characteristic to compare the frequency and strength of control policies adopted between pre-negotiation and negotiation periods. Multivariate regression analyses were performed to determine the predictive nature of these variables. RESULTS: The frequency of policy adoption intensified during the years the FCTC negotiations were most intense. The strength of policies adopted also shifted significantly towards policies promoted by WHO. The average strength of policies adopted varied significantly according to country characteristics. All characteristics, with the exception of total and male smoking prevalence, were significantly associated with the number of policy types adopted. CONCLUSIONS: This study suggests that investments in international legal processes can be effective, even when the outcomes are unclear from the start. The FCTC negotiation process coincided with a rise in domestic policy adoption in the direction advocated by WHO. However, there remains a need to improve outreach and diffusion to lower-income countries in tobacco control, as well as other areas of chronic disease control. PMID- 20851493 TI - A golden age for evolutionary genetics? Genomic studies of adaptation in natural populations. AB - Studies of the genetic basis of adaptive changes in natural populations are now addressing questions that date back to the beginning of evolutionary biology, such as whether evolution proceeds in a gradual or discontinuous manner, and whether convergent evolution involves convergent genetic changes. Studies that combine quantitative genetics and population genomics provide a powerful tool for identifying genes controlling recent adaptive change. Accumulating evidence shows that single loci, and in some cases single mutations, often have major effects on phenotype. This implies that discontinuous evolution, with rapid changes in phenotype, could occur frequently in natural populations. Furthermore, convergent evolution commonly involves the same genes. This implies a surprising predictability underlying the genetic basis of evolutionary changes. Nonetheless, most studies of recent evolution involve the loss of traits, and we still understand little of the genetic changes needed in the origin of novel traits. PMID- 20851494 TI - Structural identifiability and indistinguishability analyses of the minimal model and a euglycemic hyperinsulinemic clamp model for glucose-insulin dynamics. AB - Many mathematical models have been developed to describe glucose-insulin kinetics as a means of analysing the effective control of diabetes. This paper concentrates on the structural identifiability analysis of certain well established mathematical models that have been developed to characterise glucose insulin kinetics under different experimental scenarios. Such analysis is a pre requisite to experiment design and parameter estimation and is applied for the first time to these models with the specific structures considered. The analysis is applied to a basic (original) form of the Minimal Model (MM) using the Taylor Series approach and a now well-accepted extended form of the MM by application of the Taylor Series approach and a form of the Similarity Transformation approach. Due to the established inappropriate nature of the MM with regard to glucose clamping experiments an alternative model describing the glucose-insulin dynamics during a Euglycemic Hyperinsulinemic Clamp (EIC) experiment was considered. Structural identifiability analysis of the EIC model is also performed using the Taylor Series approach and shows that, with glucose infusion as input alone, the model is structurally globally identifiable. Additional analysis demonstrates that the two different model forms are structurally distinguishable for observation of both glucose and insulin. PMID- 20851495 TI - Complement mediated hepatocytes injury in a model of autoantibody induced hepatitis. AB - Despite multiple reports on autoantibody-initiated complement activation in autoimmune hepatitis (AIH), how does the humoral immunity contribute to the pathogenesis of AIH remained unclear. In this report, by adoptively transferring a polyclonal rabbit anti-OVA antibody into Hep-OVA Tg mice in which OVA is selectively expressed on the surface of hepatocytes, we found that excessive complement activation initiated by the autoantibody overwhelmed the protection of intrinsic cell surface complement regulators, and induced hepatocytes injury both in vitro and in vivo. The anti-OVA antibody induced hepatic injury in Hep-OVA Tg but not WT C57BL/6 mice as assessed by serum ALT levels and liver histopathology. Immunohistochemical analyses showed that after the antibody administration, there was massive complement activation on anti-OVA IgG coated hepatocytes in Hep-OVA Tg mice, but not in WT mice. Consistent with these results, depleting complement by cobra venom factor (CVF) prior to antibody injections protected Hep-OVA Tg mice from anti-OVA IgG induced hepatic injury. In addition, treating Hep-OVA Tg mice with recombinant mouse decay accelerating factor, a native complement inhibitor, protected them from autoantibody induced hepatitis. These results suggest that complement could play a pivotal role in liver specific autoantibody mediated hepatocyte injury in AIH, and that complement inhibitors could be, in principle, developed as novel therapeutics against AIH. PMID- 20851496 TI - The short chain fatty acid sodium butyrate regulates the induction of CD1a in developing dendritic cells. AB - Dendritic cells (DCs) are professional antigen-presenting cells with attributes for priming/activating T cells and mediating immune responses. Considering the importance of DCs in the initiation of immune responses, it will be of interest to study their mechanisms of regulation. Histone-modifying enzymes, such as histone deacetylases (HDACs), are critical in controlling chromatin organization. The aim of our study was to investigate DC differentiation under the influence of sodium butyrate (NaB), a short chain fatty acid that is a histone deacetylase inhibitor. Monocytes from healthy individuals were differentiated into immature DCs with IL-4 and GM-CSF in the presence or absence of NaB. DC differentiation was evaluated by CD14 and CD1a expression by flow cytometry. We observed that monocytes stimulated to differentiate in the presence of NaB displayed colony formation and dendritic cell morphology, lost CD14 and showed decreased secretion of IL-1beta. The acquisition of CD1a, however, was impaired. Being a natural short chain fatty acid, NaB may regulate CD1a acquisition independently of its HDAC inhibitory activity. We observed that the addition of peroxisome proliferator-activated receptor gamma (PPAR-gamma) antagonist (GW9662) did not reverse NaB effect, suggesting this was not the pathway involved. On the other hand, CD1a can also be induced by toll like receptors 2 (TLR 2) agonists, such as Pam3Cys, and NaB inhibited this effect. Our data suggest that the histone deacetylase inhibitor NaB instead of impairing DC differentiation inhibits the acquisition of CD1a induced both by cytokines and by TLR 2 agonist stimulus. Furthermore, this occurs at the transcriptional level as NaB led to a decrease in mRNA levels of CD1a and upregulation of CD1d. PMID- 20851497 TI - [Intraorbital foreign body]. AB - INTRODUCTION: Perforative intraorbital injuries can be potentially serious, and management depends on the type of projectile and its intraorbital trajectory. Medical imaging is an imperative part of the initial assessment. OBSERVATION: We report the case of a wooden intraorbital foreign body (arrow), with no functional or anatomical consequences, with a remarkable intraorbital trajectory analyzed by CT. DISCUSSION: The two main risks of these injuries are first mechanical, with possible bulb, nerve, muscle or bone complications, and second infectious. The CT scan or better yet MRI imaging provide a detailed analysis of the projectile's intraorbital trajectory in the orbital cavity. Infectious complications are promoted by the fat cells present in the orbit and must be systematically controlled with wide-spectrum antibiotics. PMID- 20851498 TI - [Glaucoma flecks]. PMID- 20851499 TI - Early treatment of cold sores with topical ME-609 decreases the frequency of ulcerative lesions: a randomized, double-blind, placebo-controlled, patient initiated clinical trial. AB - BACKGROUND: Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL. OBJECTIVES: The primary study end point was the prevention of ulcerative HSL lesions. METHODS: In all, 2437 patients with a history of HSL were randomized to self-initiate treatment with ME-609, 5% acyclovir in ME-609 vehicle, or ME-609 vehicle (placebo) at the earliest sign of a cold sore recurrence. Cream was applied 5 times/d for 5 days. A total of 1443 patients experienced a recurrence and initiated treatment with ME-609 (n = 601), acyclovir (n = 610), or placebo (n = 232). RESULTS: Of patients receiving ME-609, 42% did not develop an ulcerative lesion compared with 35% of patients receiving acyclovir in ME-609 vehicle (P = .014) and 26% of patients receiving placebo (P < .0001). In patients with ulcerative lesions, healing times were reduced in the ME 609 and acyclovir groups compared with placebo (P < .01 for both). The cumulative lesion area for all lesions was reduced 50% in patients receiving ME-609 compared with the placebo group (P < .0001). There were no differences among groups in the number of patients with positive herpes simplex virus cultures. The side-effect profile was similar among treatments. LIMITATIONS: The study did not contain a group treated with a topical corticosteroid alone. CONCLUSIONS: ME-609 prevented progression of cold sores to ulcerative lesions and significantly reduced the cumulative lesion area compared with acyclovir and placebo. ME-609 treatment offers additional therapeutic benefit compared with therapy with topical acyclovir alone. PMID- 20851500 TI - Combined approach for extensive maxillectomy: technique and cadaveric dissection. AB - BACKGROUND: Currently described endoscopic techniques for subtotal resections of the maxilla include endoscopic medial maxillectomy and extended endoscopic medial maxillectomy; however, a complete resection of the maxilla is sometimes warranted. We describe a combined transoral and endoscopic technique for total and subtotal maxillectomy in an attempt to decrease the morbidity of traditional approaches. METHODS: Technical note, Feasibility, Human cadaveric dissection. RESULTS: Ten total and subtotal maxillectomies were performed in human specimens without the need of facial incisions or transfixion of the nasal septum. The pterygopalatine and infratemporal fossas were accessed and dissected in all cases. CONCLUSIONS: A combined transoral and endoscopic approach is feasible and can be used in selected patients when other minimally endoscopic techniques are not indicated. The benefits of no facial incisions and/or transfixion of the nasal septum, potential improvement in hemostasis, and visual magnification may help to decrease the morbidity of traditional open approaches. PMID- 20851501 TI - Metastatic neuroblastoma to the mandible: an unusual presentation. AB - Neuroblastoma is an uncommon cause of a mandibular mass. We describe an 8-month old child who presented with loosening of his dentition, poor oral intake, and a large mandibular mass. Thorough radiographic study and subsequent biopsy of the oral lesion revealed the diagnoses of metastatic neuroblastoma. Ultimately, he was successfully treated with surgery and chemotherapy. The unusual presentation and pathophysiology of this malignancy will be reviewed. Neuroblastoma presenting as a mandible mass associated with natal teeth is rare, but it should be considered in the differential diagnosis of pediatric mandibular lesions. PMID- 20851502 TI - Single-shot, low-dose intratympanic gentamicin in Meniere disease: role of vestibular-evoked myogenic potentials and caloric test in the prediction of outcome. AB - OBJECTIVE: The aim of this study was to assess the efficacy and safety of single and low-dose intratympanic gentamicin therapy in patients with Meniere disease and who were monitored both with caloric tests and vestibular-evoked myogenic potentials (VEMPs) to see if VEMPs have an additional role in predicting the efficacy of the drug. STUDY DESIGN: This is a prospective cohort study. SETTING: Tertiary referral center is the study setting. PATIENTS: Twenty-five intractable Meniere disease patients were included as the study group. INTERVENTION(S): Low dose (16 mg/mL), single-shot intratympanic gentamicin was applied. VEMP and caloric test were applied 2 weeks after the application. MAIN OUTCOME MEASURE(S): Safety and efficacy of protocol were evaluated at the sixth month postoperatively with tonal audiogram and visual analog scale, respectively. RESULTS: Mean average pure-tone hearing threshold at 0.5, 1, 2, 4, and 8 kHz was 49.6 and 51.0 dB before and after the application, respectively (P > .05). Mean pretreatment and posttreatment visual analog scale scores of patients were 17.6 mm (10-30 mm) and 74.6 mm (41-100 mm), respectively (P < .01). Posttreatment VEMPs were absent in 17, deteriorated in 2, and not changed in 6 patients. VEMP was a significant predictor of posttreatment visual analog scale score, whereas caloric test was not (P < .01). CONCLUSIONS: Low-dose, single-shot intratympanic gentamicin treatment proved to be effective and safe among intractable Meniere patients. VEMPs obtained at posttreatment second week were significant predictors of patients posttreatment sixth-month dizziness status and vertigo control. PMID- 20851503 TI - Evidence-based applications of mitomycin C in the nose. AB - BACKGROUND: Mitomycin C (MMC) is an antimitotic drug that may, when applied topically, prevent postoperative stenosis. Its use remains controversial. This review aims to provide otolaryngologists with an update of the evidence on the applications of this agent in the nose and sinuses. METHODS: A systematic review was performed. Inclusion criteria were as follows: English literature, original articles, reviews, and case series. Exclusion criteria were as follows: animal and in vitro studies, nonendoscopic and nonsinonasal applications of MMC, and external lacrimal surgery. Studies that used other ways of dilating stenoses in conjunction with MMC were excluded. RESULTS: Out of 48 studies published, 9 fulfilled our inclusion criteria, totaling 322 patients. Eighty-five percent were primary and 15% were revision cases. Follow-up ranged from 1 to 42 months. Main outcome measures used were endoscopic examination, anatomical measurements, radiological scoring systems, dye tests, and subjective symptom resolution. Main overall outcomes from studies where extrapolation of data was feasible were (1) patency rate, which ranged from 63% to 94.4% (mean, 81.3%); (2) adhesions: 5.1% (MMC) vs 15.05 (control); and (3) stenosis: 14.05% (MMC) vs 32.6% (control). CONCLUSIONS: There appears to be a favorable short-term effect of MMC, but no robust evidence regarding long-term prevention of restenosis. Larger homogenous and multicenter randomized trials are needed to assess the long-term effects of MMC in sinonasal surgery. PMID- 20851504 TI - [Primary pancreatic tuberculosis in an immunocompetent patient: first case report in Spain]. AB - Primary pancreatic tuberculosis (PPTB) is an extremely rare entity defined by an isolated pancreatic lesion with microbiological confirmation, in the absence of previously identified tuberculosis (TB) and involvement of any other organ. We report the case of a 47-year-old man referred for abdominal pain and weight loss, in whom several imaging techniques revealed a solid mass in the head of the pancreas. CT-guided fine-needle aspiration cytology was consistent with necrotic granuloma. Intradermic tuberculin reaction was positive, but acid fast bacilli staining was negative in repeat cytology. No additional evidence of TB was found after exhaustive diagnostic work-up. Exploratory laparotomy was proposed for a definitive diagnosis, but cultures grew Mycobacterium tuberculosis at 50 days. The pancreatic lesion disappeared after 4 months of antitubercular therapy. This is the first case report of PPTB in an immunocompetent person in Spain. A high index of suspicion and accurate samples for microbiology are mandatory to avoid unnecessary surgical procedures. PMID- 20851505 TI - [Recommendations for the management of Sorafenib in patients with hepatocellular carcinoma]. PMID- 20851506 TI - [Effectiveness of a preventive intervention strategy based on structured telephone interviews in a working population with a moderate to high cardiovascular risk]. AB - OBJECTIVE: This study assesses the effectiveness of a structured telephone survey on cardiovascular prevention, in modifying lifestyle, on cardiovascular risk parameters, percentage of smoking cessation and overall cardiovascular risk (CVR). DESIGN: Quasi-experimental study of preventive intervention. SETTING: Ibermutuamur (Spanish Accident and Health Insurance Company). Centres established throughout Spain. PARTICIPANTS: A total of 4,792 workers with moderate/high cardiovascular risk who had agreed to be contacted by phone. Subjects with a previous diagnosis of cardiovascular disease and those receiving treatment for hypertension, hypercholesterolemia or diabetes were excluded. INTERVENTION: A final total of 3,085 workers were contacted and were followed up by telephone surveys on the first, fourth and eighth month after the initial check up (CU) in order to emphasise cardiovascular health advice (Group A); we failed to contact 1,707 workers, who only attended the baseline and one year CUs (Group B). PRINCIPAL OUTCOMES: CUs included medical records and physical examination, with two blood pressure measurements, Body Mass Index (BMI), and biochemical parameters. Cardiovascular risk was stratified following the European cardiovascular SCORE. Individuals with a relative risk higher than 4 were also considered as high-risk. All workers were informed about their cardiovascular risk profile (CVRF) and healthy cardiovascular lifestyle measures. They were also given a letter for their General Practitioner (GP) to inform them on the worker's cardiovascular risk level. RESULTS: A total of 71.5% of the workers were over 45 years, 95.0% males, 76.6% manual workers ("Blue Collar") and 69.7% smokers. Both groups showed improvement in lipid parameters, blood pressure, smoking cessation and overall cardiovascular risk in the second CU. There were significant differences in favour of Group A as regards blood pressure, lipids (except HDL cholesterol), BMI, glycaemia, smoking cessation (A: 23.5%/B: 19.44%, P=0.001) and CVR stratum improvement (A: 46.6%/B: 37.7%, P=0.0001). The large majority (85%) of workers read preventive recommendations; 33% knew their risk level and 73% knew their CVRF. 52.9% gave the letter to the GP, which led them to start therapies on diet (47%), hypertension (19.5%), dyslipidaemia (16.7%), diabetes (4.4%) and smoking (2.9%) and no changes were made in 36.5% of cases. CONCLUSIONS: The results of this study suggests that cardiovascular prevention strategy based on structured telephone surveys on high/moderate CVR subjects to promote lifestyle changes could be effective at reducing CVR. A clinical trial is required for confirmation. Sending information on CVRF following routine medial CUs and Primary Care involvement, could contribute to the positive changes observed. PMID- 20851507 TI - [Spontaneous streptococcal arthritis of the pubic symphysis]. AB - Septic arthritis of the pubic symphysis is uncommon, and usually occurs in patients with predisposing conditions (female incontinence surgery, sports). Staphylococcus aureus and Pseudomonas aeruginosa are the main bacteria responsible of these infections. Streptococcal infections of the pubic symphysis are uncommon. We report three cases of streptococcal infections of the pubic symphysis that occurred in the absence of predisposing condition such as surgery or endocarditis. The diagnosis of septic arthritis was difficult, particularly in one patient who underwent an orchidopexy for a suspected of spermatic cord torsion before diagnosis was corrected. All three patients had a favourable outcome after an antibiotic treatment combining amoxicillin and rifampicin. Septic arthritis of the pubic symphysis should be suspected in patients with sudden groin pain, pubic tenderness and fever to avoid traumatic treatments and useless investigations. PMID- 20851508 TI - [Small fibre neuropathy: Diagnostic approach and therapeutic issues, and its association with primary Sjogren's syndrome]. AB - This article reviews the diagnostic issues and the therapeutic management of small fibre neuropathy (SFN), and a detailed literature analysis of its association with primary Sjogren's syndrome (pSS). A diagnosis of SFN should be raised in the presence of diffuse neuropathic painful manifestations (burning sensation, paresthesia, pricking, allodynia or hyperesthesia) and neurovegetative signs. The neurological examination and the electroneuromyogram are usually normal. The diagnosis of SFN can be confirmed by the evidence of decreased intra epidermal nerve fibre density after a skin punch biopsy or the presence of abnormal nonconventional neurophysiological tests exploring the A-delta and C small nerve fibres (laser-evoked potentials, quantitative sensory tests, cutaneous sympathic reflex, autonomic function tests). The association of SFN and pSS has been scarcely evaluated, probably because of its lack of awareness and the low availability of the required diagnostic procedures. According to our literature review, pSS may be present in 9 to 30% of patients with SFN. Conversely, a pure SFN is present in 3 to 9% of patients with pSS where it may represent 25 to 35% of pSS-associated peripheral neuropathies. The treatment of SFN is mainly symptomatic and based on antalgic neuropsychotropic drugs and conventional analgesics. Corticosteroids and immunosuppressive drugs are usually unsuccessful. The effectiveness of intravenous immunoglobulins is only supported by a few case reports. SFN deserves to be separately evaluated among pSS associated peripheral neuropathies. This requires a better availability of the appropriate diagnostic procedures, the investigation of underlying immunopathological mechanisms and the assessment of the new treatments recently proposed in pSS, mainly rituximab. PMID- 20851509 TI - An analysis of the meanings of pre-eclampsia for pregnant and postpartum women and health professionals in Rio Grande do Norte, Brazil. AB - OBJECTIVE: To understand the meanings of pre-eclampsia for pregnant and postpartum women and health-care professionals. DESIGN: a word-association test and semi-structured interviews. SETTING: A maternity hospital located in Natal, Rio Grande do Norte, Brazil that serves pregnant and postpartum women considered to be at high risk. PARTICIPANTS: 51 Pregnant women, 10 postpartum women and 87 health-care professionals completed a word-association test; 18 pregnant women, two postpartum women and 20 health-care professionals for the interviews. MEASUREMENTS AND FINDINGS: Thematic categories based on the word-association test and the interviews were created to help the data analysis. chi(2) test was used to compare the categories raised by both groups in the word-association test to determine the association between the frequencies of these categories. The meanings of pre-eclampsia to pregnant and postpartum women were fear, risk, care and lack of information. To the health-care professionals, the meanings were care, fear, risk, high blood pressure, oedema and proteinuria. The frequencies of the categories 'fear', 'care' and 'risk' were statistically different (chi(2) = 31.84, 14.5, 38.19, respectively; df = 2, p < 0.001) between the group of pregnant and postpartum women and the group of health-care professionals. For the first group, the most significant meanings were fear and risk, compared with care for the second group. The analysis of the interviews confirmed and deepened the results of the word-association test, and also demonstrated that the pregnant and postpartum women had no information about pre-eclampsia. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: There is a gap between how women and health professionals view their experiences of pre-eclampsia. A warm welcome to the health-care facility, with clear explanations about the disease and the procedures to be performed during the visits and hospitalisation would be important aspects for the physical and mental well-being of pregnant and postpartum women. PMID- 20851510 TI - Fabrication, calibration and evaluation of a phosphate ion-selective microelectrode. AB - To conduct the micro-environment study of flocs in an enhanced biological phosphorus removal (EBPR) process, a phosphate ion-selective microelectrode was developed. The cobalt-based microelectrodes have tip diameters of 5-20MUm and respond to all the three forms of phosphate ions, namely, H(2)PO(4)(-), HPO(4)(2 ), and PO(4)(3-). The calibration curve at pH 7.5 had a slope of 31.5mV per decade change of concentration and a R(2) value of 0.99. Other characteristics of this microelectrode, such as response time, interferences from pH, ion strength, DO and other anions were also evaluated. PMID- 20851511 TI - Electrophysiological correlates of the composite face illusion: disentangling perceptual and decisional components of holistic face processing in the human brain. AB - When the bottom halves of two faces differ, people's behavioral judgment of the identical top halves of those faces is impaired: they report that the top halves are different, and/or take more time than usual to provide a response. This behavioral measure is known as the composite face effect (CFE) and has traditionally been taken as evidence that faces are perceived holistically. Recently, however, it has been claimed that this effect is driven almost entirely by decisional, rather than perceptual, factors (Richler, Gauthier, Wenger, & Palmeri, 2008). To disentangle the contribution of perceptual and decisional brain processes, we aimed to obtain an event-related potential (ERP) measure of the CFE at a stage of face encoding (Jacques & Rossion, 2009) in the absence of a behavioral CFE effect. Sixteen participants performed a go/no-go task in an oddball paradigm, lifting a finger of their right or left hand when the top half of a face changed identity. This change of identity of the top of the face was associated with an increased ERP signal on occipito-temporal electrode sites at the N170 face-sensitive component (~160 ms), the later decisional P3b component, and the lateralized readiness potential (LRP) starting at ~350 ms. The N170 effect was observed equally early when only the unattended bottom part of the face changed, indicating that an identity change was perceived across the whole face in this condition. Importantly, there was no behavioral response bias for the bottom change trials, and no evidence of decisional biases from electrophysiological data (no P3b and LRP deflection in no-go trials). These data show that an early CFE can be measured in ERPs in the absence of any decisional response bias, indicating that the CFE reflects primarily the visual perception of the whole face. PMID- 20851512 TI - Further support for active surveillance in the management of low-volume, low grade prostate cancer. PMID- 20851513 TI - Breakages at common fragile sites set boundaries of amplified regions in two leukemia cell lines K562 - Molecular characterization of FRA2H and localization of a new CFS FRA2S. AB - Genome amplification is often observed in human tumors. The breakage-fusion bridge (BFB) cycle is the mechanism that often underlies duplicated regions. Some research has indicated common fragile sites (CFS) as possible sites of chromosome breakages at the origin of BFB cycles. Here we searched two human genome regions known as amplification hot spots for any DNA copy number amplifications by analyzing 21 cancer cell lines to investigate the relationship between genomic fragility and amplification. We identified a duplicated region on a chromosomes der(2) present in the karyotype of two analysed leukemia cell lines K562. The two duplicated regions are organized into large palindromes, which suggests that one BFB cycle has occurred. Our findings show that the three breakpoints are localized in the sequence of three CFSs: FRA2H (2q32.1-q32.2), which here has been characterized molecularly; FRA2S (2q22.3-q23.3), a newly localized aphidicolin inducible CFS; and FRA2G (2q24.3-q31). PMID- 20851514 TI - The use of Apatite IITM to remove divalent metal ions zinc(II), lead(II), manganese(II) and iron(II) from water in passive treatment systems: column experiments. AB - The conventional passive treatments for remediation of acid mine drainage using calcite are not totally efficient in the removal of certain heavy metal ions. Although pH increases to 6-7 and promotes the precipitation of trivalent and some divalent metals as hydroxides and carbonates, the remaining concentrations of some divalent metals ions do not fulfill the environmental regulations. In this study, Apatite IITM, a biogenic hydroxyapatite, is used as an alternative reactive material to remove Zn(II), Pb(II), Mn(II) and Fe(II). Apatite IITM reacted with acid water releasing phosphate and increasing pH up to 6.5-7, inducing metals to precipitate mainly as metal-phosphates: zinc precipitated as hopeite, Zn(3)(PO(4))(2).4H(2)O, lead as pyromorfite, Pb(5)(PO(4))(3)OH, manganese as metaswitzerite, Mn(3)(PO(4))(2).4H(2)O and iron as vivianite, Fe(3)(PO(4))(2).8H(2)O. Thus, metal concentrations from 30 to 75 mg L(-1) in the inflowing water were depleted to values below 0.10 mg L(-1). Apatite IITM dissolution is sufficiently fast to treat flows as high as 50 m/a. For reactive grain size of 0.5-3mm, the treatment system ends due to coating of the grains by precipitates, especially when iron and manganese are present in the solution. PMID- 20851515 TI - Phylogenetic and functional diversity of alkane degrading bacteria associated with Italian ryegrass (Lolium multiflorum) and Birdsfoot trefoil (Lotus corniculatus) in a petroleum oil-contaminated environment. AB - Twenty-six different plant species were analyzed regarding their performance in soil contaminated with petroleum oil. Two well-performing species, Italian ryegrass (Lolium multiflorum var. Taurus), Birdsfoot trefoil (Lotus corniculatus var. Leo) and the combination of these two plants were selected to study the ecology of plant-associated, culturable alkane-degrading bacteria. Hydrocarbon degrading bacteria were isolated from the rhizosphere, root interior and shoot interior and subjected to the analysis of 16S rRNA gene, the 16S and 23S rRNA intergenic spacer region and alkane hydroxylase genes. Furthermore, we investigated whether alkane hydroxylase genes are plasmid located. Higher numbers of culturable, alkane-degrading bacteria were associated with Italian ryegrass, which were also characterized by a higher diversity, particularly in the plant interior. Only half of the isolated bacteria hosted known alkane hydroxylase genes (alkB and cytochrome P153-like). Degradation genes were found both on plasmids as well as in the chromosome. In regard to application of plants for rhizodegradation, where support of numerous degrading bacteria is essential for efficient break-down of pollutants, Italian ryegrass seems to be more appropriate than Birdsfoot trefoil. PMID- 20851516 TI - Characteristics of heavy metals in airborne particulate matter on misty and clear days. AB - This study identified characteristics of heavy metals in ambient total suspended particulates (TSP) and air pollutants (PM(10), CO, NO(x), SO(2) and O(3)) collected on clear and misty days at an urban-residential area and an industrial area in the largest industrial city, Korea, for one-year study period. Average concentrations of TSP at the urban-residential (130 MUg/m(3)) and industrial (141 MUg/m(3)) areas on misty days were 1.9-2.1 (p<0.05) times higher than those on clear days. Concentrations of heavy metals in the TSP from both areas on misty days were significantly (p<0.05) higher than those on clear days. In particular, Pb and Mn concentrations on misty days were 2.4-2.6 (p<0.05) and 1.7-1.8 (p<0.05) times, respectively, higher at both areas as compared to clear days. Clear days showed higher correlations between TSP and heavy metal concentrations than on misty days at both areas. Average concentrations of PM(10), CO and NO(2) simultaneously measured at/near the sampling sites on misty days were significantly (p<0.05) higher than on clear days at both areas. Average O(3) and SO(2) concentrations showed a similar increase pattern at only one area. PMID- 20851517 TI - Discrepancy among acute guideline levels for emergency response. AB - Acute guidance values are tools for public health risk assessment and management during planning, preparedness and response related to sudden airborne release of hazardous chemicals. The two most frequently used values, i.e. Acute Exposure Guidance Levels (AEGL) and Emergency Response Planning Guideline (ERPG), were compared in qualitative and quantitative terms. There was no significant difference between the general level of AEGL and ERPG values, suggesting the two systems are equally precautious. However, the guidance values diverged by a factor of 3 or more for almost 40% of the substances, including many of high production volume. These deviations could be explained by differences in selection of critical effect or critical study and in a few cases differences in interpretation of the same critical study. Diverging guidance values may hamper proper risk communication and risk management. Key factors for broad international acceptance of harmonized values include transparency of the decision process, agreement on definition of toxicological tiers, and a target population including sensitive groups of the general population. In addition, development of purely health based values is encouraged. Risk management issues, such as land use and emergency response planning should be treated separately, as these rely on national legislation and considerations. PMID- 20851518 TI - Variation in quantitative sensory testing and epidermal nerve fiber density in repeated measurements. AB - Quantitative sensory testing (QST) is commonly used to evaluate peripheral sensory function in neuropathic conditions. QST measures vary in repeated measurements of normal subjects but it is not known whether QST can reflect small changes in epidermal nerve fiber density (ENFd). This study evaluated QST measures (touch, mechanical pain, heat pain and innocuous cold sensations) for differences between genders and over time using ENFd as an objective-independent measure. QST was performed on the thighs of 36 healthy volunteers on four occasions between December and May. ENFd in skin biopsies was determined on three of those visits. Compared to men, women had a higher ENFd, a difference of 12.2 ENFs/mm. They also had lower tactile and innocuous cold thresholds, and detected mechanical pain (pinprick) at a higher frequency. Heat pain thresholds did not differ between genders. By the end of the 24-week study, men and women showed a small reduction (p<0.05) in the frequency of sharp mechanical pain evoked by pinprick whereas tactile and thermal thresholds showed no change. This coincided with a small decrease in ENFd, 4.18 ENFs/mm. Variation in measurements over time was large in a fraction of normal subjects. We conclude that most QST measures detect relatively large differences in epidermal innervation (12.2 ENFs/mm), but response to mechanical pain was the only sensory modality tested with the sensitivity to detect small changes in innervation (4.18 ENFs/mm). Since some individuals had large unsystematic variations, unexpected test results should therefore alert clinicians to test additional locations. PMID- 20851520 TI - Assessment of brain responses to innocuous and noxious electrical forepaw stimulation in mice using BOLD fMRI. AB - Functional magnetic resonance imaging (fMRI) using the blood oxygen level dependent (BOLD) contrast was used to study sensory processing in the brain of isoflurane-anesthetized mice. The use of a cryogenic surface coil in a small animal 9.4T system provided the sensitivity required for detection and quantitative analysis of hemodynamic changes caused by neural activity in the mouse brain in response to electrical forepaw stimulation at different amplitudes. A gradient echo-echo planar imaging (GE-EPI) sequence was used to acquire five coronal brain slices of 0.5mm thickness. BOLD signal changes were observed in primary and secondary somatosensory cortices, the thalamus and the insular cortex, important regions involved in sensory and nociceptive processing. Activation was observed consistently bilateral despite unilateral stimulation of the forepaw. The temporal BOLD profile was segregated into two signal components with different temporal characteristics. The maximum BOLD amplitude of both signal components correlated strongly with the stimulation amplitude. Analysis of the dynamic behavior of the somatosensory 'fast' BOLD component revealed a decreasing signal decay rate constant k(off) with increasing maximum BOLD amplitude (and stimulation amplitude). This study demonstrates the feasibility of a robust BOLD fMRI protocol to study nociceptive processing in isoflurane anesthetized mice. The reliability of the method allows for detailed analysis of the temporal BOLD profile and for investigation of somatosensory and noxious signal processing in the brain, which is attractive for characterizing genetically engineered mouse models. PMID- 20851519 TI - NeuPSIG guidelines on neuropathic pain assessment. AB - This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A-beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser-evoked potentials is useful for assessing function of the A-delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended. PMID- 20851521 TI - Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy. AB - Sensory neuropathy (HIV-SN) is a common cause of pain in HIV-infected people. Establishing a diagnosis of HIV-SN is important, especially when contemplating opioid use in high-risk populations. However physical findings of HIV-SN may be subtle, and sensitive diagnostic tools require specialized expertise. We investigated the association between self-report of distal neuropathic pain and/or paresthesias (DNPP) and objective signs of HIV-SN. Data were obtained from the Central Nervous System HIV Antiretroviral Therapy Effects Research (CHARTER) study. Out of 237 participants, 101 (43%) reported DNPP. Signs of HIV-SN were measured by a modified Total Neuropathy Score (TNS), composed of six objective sensory subscores (pin sensibility, vibration sensibility, deep tendon reflexes, quantitative sensory testing for cooling and vibration, and sural sensory amplitude). Self-report of DNPP was associated with all six TNS items in univariate analysis and with four TNS items in multivariate analysis. The sensitivity and specificity of self-report of DNPP in detecting the presence of a sensory abnormality were 52% and 92%, respectively with a PPV of 96% and a NPV of 34%. Increasing intensity of pain measured on a visual analog scale was associated with increasing severity of sensory abnormality. In summary, our results suggest that HIV-infected patients reporting symptoms consistent with HIV SN, such as tingling, pins and needles, or aching or stabbing pain in the distal lower extremities, usually have objective evidence of HIV-SN on neurologic examination or with neurophysiologic testing. This finding holds true regardless of demographic factors, depression or substance use history. PMID- 20851522 TI - Clinical trials in interventional pain management: optimizing chances for success? PMID- 20851523 TI - Neospora caninum infection in stray and farm dogs: seroepidemiological study and oocyst shedding. AB - In a previous study, farm and stray dogs were considered potential high risk populations of Neospora caninum infection in Spain. Consequently, we decided to investigate the significance of N. caninum infection in these populations. Specific antibodies were detected in 120 out of 275 dog sera (43.6%), with titres ranging from 1:50 to 1:800. Differences in seroprevalence between farm (47.5%, 67/141) and stray (39.5%, 53/134) dogs were not significant (P>0.05; chi(2) test), but farm dogs showed significantly higher titres (P<0.01; Student's t test). N. caninum seroprevalence in farm dogs was associated with increasing age (P<0.01; chi(2) test) and dogs with free access to the farm were more likely to be seropositive than controlled-dogs (P<0.05; chi(2) test). The presence of anti N. caninum antibodies was more often detected in dogs from farms with 5-20% N. caninum within-herd seroprevalence (56.9%, 37/65) than those from farms with 0-5% seroprevalence (38%, 23/60) (P<0.05; chi(2) test). We microscopically observed N. caninum-like oocysts in the faeces from one farm dog, but the number of oocysts was very low, and the aetiology could not be confirmed. Also, parasite isolation was attempted from fresh neural tissue from stray dogs but was unsuccessful. PMID- 20851524 TI - Low seroprevalence of Leishmania infantum infection in cats from northern Portugal based on DAT and ELISA. AB - Cats have been considered playing a role in the epidemiology of leishmaniasis caused by Leishmania infantum, an endemic zoonosis in countries of the Mediterranean basin. The present study assessed the prevalence of antibodies to L. infantum in 316 domestic cats from northern Portugal, by means of the direct agglutination test (DAT) and an enzyme-linked immunosorbent assay (ELISA). Seroreactivity to DAT was found in six cats, and nine cats were positive in the ELISA, including the six DAT-positive animals. The overall seroprevalence of Leishmania infection was 2.8%, based on ELISA and DAT. A substantial agreement (99%; kappa value=0.80) was found between DAT and ELISA results. The difference between seroprevalence values in females (0.7%) and males (4.7%) was statistically significant (p=0.045). The age of seropositive cats ranged from 31 to 84 months. Cats with 5-6 years (60-71 months) and 6-7 years (72-83 months) presented the highest level of seropositivity (15.4% and 33.3%, respectively). A significant difference was found comparing the seroprevalences in cats aged less than 24 months (0.0%) and in those with 24 months or more (7.3%) (p=0.022). Seroprevalences in cats living in a rural environment (10.5%) or in urban areas (0.0%) were also found to be significantly different (p<0.001). No significant differences were detected between serological status to Leishmania in pure non European and European or mixed breeds (p=0.442), cats that lived totally indoors and those that had access to outdoors (p=0.412), cats seropositive and seronegative to Toxoplasma gondii (p=0.276), or apparently healthy animals and those with clinical illness (p=0.271). This study is the largest epidemiological investigation performed on feline Leishmania infection in Portugal. The seroprevalence of Leishmania infection was low in cats living in northern Portugal, a region where canine leishmaniasis is endemic. Nevertheless, Leishmania infection must not be underestimated and leishmaniasis may be included in the differential diagnosis of cutaneous or systemic clinical signs in cats. PMID- 20851525 TI - Molecular epidemiology of Giardia duodenalis in an endangered carnivore--the African painted dog. AB - The African painted dog (Lycaon pictus) is an endangered carnivore of sub-Saharan Africa. To assist in conservation efforts a parasitological survey was conducted on wild and captive populations. Faecal samples were collected and examined for the presence of parasites using traditional microscopy techniques. The protozoan Giardia duodenalis was identified at a prevalence of approximately 26% in the wild populations and 62% in the captive population. Molecular characterisation of these isolates using three loci, 18S rRNA, beta-giardin and the glutamate dehydrogenase gene revealed the zoonotic assemblages A and B existed in high proportions in both populations. The dog assemblages C and D were rarely observed. The identification of the zoonotic genotype suggests this species has the potential to act as a reservoir for human infections. Zoonotic transmission may be possible in captive populations due to the close interaction with humans however, in wild populations anthropozoonotic transmission seems more likely. This study is the first to observe G. duodenalis in the African painted dog and to identify a possible emerging disease in this wild carnivore. PMID- 20851526 TI - Trypanosoma evansi: recent outbreaks in Europe. AB - Here, two recent outbreaks of Trypanosoma evansi infection in mainland France and Spain associated with the importation of dromedary camels from the Canary Islands, are reported. The disease is well-known on the Archipelago since 1997 and many efforts have been made towards control and eventual eradication, but some areas still remain affected. Both mainland outbreaks were controlled by means of massive treatments and monthly serological, parasitological and molecular (PCR) evaluations carried out by Valencian Regional Animal Health laboratory and by CIRAD, Montpellier, respectively. Possible causes for the persistence of the parasite in a small area of the Canaries are discussed. T. evansi must be included among the animal health conditions for international trade within the European Union as well as many other countries. Moreover, procedures including diagnosis, curative or preventive treatment and quarantine should be established to insure the status of the animals moving from a country to another. PMID- 20851527 TI - Plasma and milk kinetics of eprinomectin following topical or oral administration to lactating Chinese Holstein cows. AB - Chinese Holstein, bred by mating the Holstein-Friesian to Chinese Yellow Cattle, is a major dairy cattle breed in China. Eprinomectin is widely used in the treatment of nematode and ectoparasite infections in lactating cattle. The pharmacokinetics of eprinomectin in the plasma and milk were determined in Chinese Holstein cows following topical (at 0.5 mg kg(-1)) or oral (at 0.2 mg kg( 1)) administration. For topical administration, the concentrations of eprinomectin in plasma reached peak values (C(max)) of 16.16 +/- 6.02 ng ml(-1) at 3.20 +/- 1.30 days (T(max)). In milk, the C(max) values of 2.28 +/- 0.85 ng ml(-1) were obtained at 3.48 +/- 0.65 days. The MRT values were 5.00 +/- 0.96 days for plasma and 4.65 +/- 0.60 days for milk. The AUC values were 91.00 +/- 25.32 ng d ml(-1) for plasma and 10.53 +/- 1.55 ng d ml(-1) for milk. The ratio of AUC milk/plasma was 0.124 +/- 0.041. Significant differences were found in C(max) and AUC of eprinomectin in plasma between Chinese Holstein and Prim Holstein following topical administration. It was probably due to the lower storage of body fat in Chinese Holstein than in Prim Holstein. For oral administration, the concentrations of eprinomectin reach peak values of 30.02 +/- 5.73 ng ml(-1) at 1.60 +/- 0.55 days in plasma and 3.14 +/- 0.88 ng ml(-1) at 1.40 +/- 0.27 days in milk. The MRT values for plasma and milk were 3.00 +/- 0.46 and 3.18 +/- 0.55 days, respectively. The AUC values were 98.46 +/- 24.75 ng d ml(-1) for plasma and 10.42 +/- 4.22 ng d ml(-1) for milk. The ratio of AUC milk/plasma was 0.104 +/- 0.022. Compared with the topical administration, a significantly shorter MRT of eprinomectin in plasma was obtained following oral administration, which would shorten residue time of this compound in faeces and reduce its ecotoxicological effect. The low exposure of eprinomectin in milk would favor the use of eprinomectin in lactating Chinese Holstein for topical or oral administration. PMID- 20851528 TI - The role of acute pancreatitis in pediatric burn patients. AB - Few publications recognize acute pancreatitis as a complication after large burns, consequently the incidence and outcome acute pancreatitis after burn in children is not well defined. The aim of this study was to determine the incidence, morbidity, and mortality relating to acute pancreatitis in a pediatric burn population and to correlate clinical diagnosis with autopsy findings to determine the incidence of unrecognized pancreatitis. Records of 2699 patients with acute burns were reviewed. Acute pancreatitis was defined as abdominal pain and/or feeding intolerance in addition to a three-fold elevation of amylase and/or lipase. One-hundred twenty-seven burned children served as the control cohort. To assess the presence of autopsy confirmed AP in pediatric burn patients, we evaluated autopsy reports of 78 children who died from burns, looking for reported evidence of pancreatic inflammation, and fat/parenchymal necrosis. Our data show that acute pancreatitis in children has a low incidence after burn. The study included 2699 patients of which 13 were suffering acute pancreatitis (13/2699 = 0.05%). Mortality is significantly higher for the acute pancreatitis group vs. the control group, p < 0.05. Autopsy reports established 11 of 78 patients with evidence of pancreatitis, resulting in an incidence of 0.17% for pancreatitis at autopsy. Although it has low incidence, acute pancreatitis is associated with increased mortality in severely burned pediatric patients, which underlines the importance of increased vigilance in the evaluation and treatment of pancreatitis in burned children. PMID- 20851529 TI - First web space post-burn contracture types: contracture elimination methods. AB - First web space adduction contractures are a common consequence of hand burns. Many reconstructive techniques are used and investigation for more effective methods continues. Effective hand reconstruction usually considers anatomy as its foundation. Based on the experience of over 500 web space contracture elimination cases, three anatomical types of thumb adduction contractures were identified: edge, medial and total. Edge contractures (80% of all thumb adduction contractures) are caused by a fold in which only one sheet is scarred, either the palmar or dorsal surface. The contraction is caused by a trapeze-shaped length deficiency of the scar sheet, which has a surface surplus in width. Reconstruction consists of surface deficiency compensation with trapezoid flap prepared from the non-scarred side and skin-fat tissues of the web space. In most cases, the small scar-fat trapezoid flaps should be prepared from the non-scarred side to cover the donor wounds on both sides of the main flap. Medial contractures (10% of thumb adduction contractures) are caused by the fold, both sheets of which are scarred and have trapeze-shaped surface deficiency in length and surplus in width. Both fold sheets are converted into one or several pairs of trapezoid scar-fat flaps by radial incisions. The oppositely located flaps are transposed towards each other. As a result of the counter flaps transposition, the contracture is eliminated; the web space's shape and depth are restored by the use of flaps alone or in combination with skin grafting. The trapeze-flap plasty is very simple and effective with the length gain of up to 100-200%. Neither flap loss nor re-contracture occurs. Total contractures (about 10% of all) have no fold. Reconstruction consists of the creation of the central zone of the first web space depth with the rectangular subdermal pedicle flap; the wounds on both sides of the flap are skin grafted. The flap sustains normal web depth and prevents the contracture recurrence and skin graft shrinkage. PMID- 20851530 TI - First consumption ever of multiple substances: applying an expert-based taxonomy to a Swiss national sample of adolescents. AB - The use of multiple legal and illegal substances by adolescents is a growing concern in all countries, but since no consensus about a taxonomy did emerge yet, it is difficult to understand the different patterns of consumption and to implement tailored prevention and treatment programs directed towards specific subgroups of the adolescent population. Using data from a Swiss survey on adolescent health, we analyzed the age at which ten legal and illegal substances were consumed for the first time ever by applying a method combining the strength of both automatic clustering and use of substance experts. Results were then compared to 30 socio-economic factors to establish the usefulness of and to validate our taxonomy. We also analyzed the succession of substance first use for each group. The final taxonomy consists of eight groups ranging from non consumers to heavy drug addicts. All but four socio-economic factors were significantly associated with the taxonomy, the strongest associations being observed with health, behavior, and sexuality factors. Numerous factors influence adolescents in their decision to first try substances or to use them on a regular basis, and no factor alone can be considered as an absolute marker of problematic behavior regarding substance use. Different processes of experimentation with substances are associated with different behaviors, therefore focusing on only one substance or only one factor is not efficient. Prevention and treatment programs can then be tailored to address specific issues related to different youth subgroups. PMID- 20851531 TI - Reactivity to in vivo marijuana cues among cannabis-dependent adolescents. AB - INTRODUCTION: Cannabis dependence is a common but poorly understood condition in adolescents. Marijuana craving has been posited as a potential contributing factor to continued use and relapse, but relatively few studies have focused on the measurement of craving and reactivity to marijuana cues. The present work sought to explore reactivity to marijuana cues within this age group. METHODS: Thirty treatment-seeking cannabis-dependent adolescents (age 13-20) completed a cue reactivity session, consisting of exposure to and manipulation of in vivo marijuana cues ("joint" and lighter) and matching neutral cues (pencil and eraser), in counterbalanced order. Subjective craving and physiological reactivity were assessed. RESULTS: Participants demonstrated increased craving and skin conductance reactivity in response to marijuana cues, relative to neutral cues. CONCLUSION: In vivo marijuana cues appear to elicit significant subjective and physiological reactivity among treatment-seeking cannabis dependent adolescents. Further work is needed with a larger sample and with a wider variety of cues. PMID- 20851532 TI - A 5alpha-reductase inhibitor, finasteride, increases differentiation and proliferation of embryonal carcinoma cell-derived-neural cells. AB - Recent advances in stem cell biology have resulted in identifying new agents to differentiate stem cell-derived-neural cells. Different stem cell types have been shown to differentiate into neural cells. It has been shown that P19 line of embryonal carcinoma cells develops into neurons and astroglia after exposure to some hormones such as dehydroepiandrosterone (DHEA). Steroid 5alpha-reductase is a key enzyme in the conversion of several Delta4-3 keto steroids, such as testosterone into their respective 5alpha-reductase derivatives. Finasteride is a 5alpha-reductase inhibitor that inhibits conversion of testosterone to the more potent androgen dihydrotestosterone (DHT). Reduction in DHT and sustaining testosterone levels has an important impact on differentiation and proliferation of embryonal carcinoma cells to neural cells. We hypothesize that finasteride, a 5alpha-reductase inhibitor, will be differentiate embryonal carcinoma cell to the neural cell and increase their proliferation due to the elevation levels of testosterone, a neuroprotective neurosteroid. PMID- 20851533 TI - Hydrogen therapy may reduce the risks related to radiation-induced oxidative stress in space flight. AB - Cosmic radiation is known to induce DNA and lipid damage associated with increased oxidative stress and remains a major concern in space travel. Hydrogen, recently discovered as a novel therapeutic medical gas in a variety of biomedical fields, has potent antioxidant and anti-inflammatory activities. It is expected that space mission activities will increase in coming years both in numbers and duration. It is therefore important to estimate and prevent the risks encountered by astronauts due to oxidative stress prior to developing clinical symptoms of disease. We hypothesize that hydrogen administration to the astronauts by either inhalation or drinking hydrogen-rich water may potentially yield a novel and feasible preventative/therapeutic strategy to prevent radiation-induced adverse events. PMID- 20851534 TI - Intraaxonal uptake and transport of marker proteins: novel ways of tracing peripheral nerve regeneration. AB - Disruption of peripheral nerve continuity occurs after accidents or in obstetrics. Brachial plexus palsy is accompanied by loss of function of the upper extremity. For optimal regeneration, surgical reconstruction should be performed within 6 months after injury. Postoperative monitoring is difficult because reliable diagnostic tools are not available. Here we present a hypothesis how to monitor peripheral nerve regeneration taking into account two intriguing features of nerve repair. First, the nerve itself with its numerous axons has been neglected as transportation pathway hitherto. Second, growth associated proteins are exclusively upregulated during peripheral nerve repair and development providing excellent target molecules. Contrast media could be designed using truncated forms of these proteins. Previous studies showed that peripheral nerves have the ability to incorporate proteins with a size up to 240 kDa. After wounding, growth associated proteins are transported intraaxonally and incorporated into growth cone membranes. We hypothesize that injection of contrast media close to nerve cell bodies or into the end organ of the injured nerve would lead to protein uptake and transport to the injury site. Sprouting of peripheral nerves could be monitored by magnetic resonance imaging or single photon emission computer tomography using adequate tracer-coupled proteins. By this new method, nerve repair could be monitored non-invasively, selectively and repeatedly. Less contrast media at lower price would be needed and only the injured part of the body would be exposed to the diagnostic apparatus. Aberrant nerve repair could be detected easily followed by surgical therapy within the critical time frame of sustained nerve regeneration. PMID- 20851535 TI - Expression of Neuropilin-2 in salivary adenoid cystic carcinoma: its implication in tumor progression and angiogenesis. AB - Neuropilin-2(Nrp2), which is a nontyrosine kinase transmembrane glycoprotein, can promote angiogenesis and is a poor prognostic factor in some human cancers. In the present study, to explore the expression and potential function of Nrp2 in salivary adenoid cystic carcinoma (SACC), immunohistochemistry was used to examine the Nrp2 expression in 50 SACCs and 20 normal salivary gland tissues nearby SACCs. The result showed that immunoreactivity for Nrp2 was detected in 47 of 50 SACCs, and its expression level had significant correlations with microvessel density, tumor size, TMN clinical stage, vascular invasion, and metastasis (P<0.05) of SACCs. In addition, inhibition of Nrp2 function by the receptor-ligand interaction-blocking antibody decreased cell migration, invasion, and angiogenic promotion without influences on the cell proliferation of Acc-3 cells. Taken together, the expression of Nrp2 protein is significantly correlated with tumor progression and angiogenesis in SACCs. These results suggest that Nrp2 may be a potential therapeutic target for SACCs. PMID- 20851536 TI - Review of probiotics for use in bivalve hatcheries. AB - The aquaculture of bivalve molluscs has attained a considerable level of production but it is not enough to cover the demand of worldwide consumers. In the development of this sector, hatcheries play an important role, as suppliers of competent spat of different bivalves, including species with an aquaculture based on natural extraction present. Besides, these installations may help in the recovery of exhausted natural beds and in the obtaining of populations under genetic selection. Unfortunately, the disease outbreaks caused by bacterial pathogens are frequent, with the loss of complete batches, compromising the regular production and the economic viability of the industry. There are many descriptive studies about these outbreaks, but only a few focused on the control of microbiota. The particularities of bivalve aquaculture in hatchery must be taken into account to design methods of control. A common environment is shared by larvae and bacteria, including both beneficial and potentially pathogenic. The filter-feeding behaviour of larvae increases the strong influence of these populations. The classical treatments are directed toward to the complete elimination of bacteria from culture seawater. That objective is unfeasible, because the cultures are not axenic, and undesirable, since some bacteria enhance larval development. Taking into account these considerations, the most promising alternative is the use of probiotic bacteria. In this review we summarize the scientific literature about this subject, considering the particularities of bivalve larval cultures and the need to adapt the concept of probiotic and the strategies to use in marine bivalve hatcheries. PMID- 20851537 TI - Challenges in immunisation against bacterial infection in children. AB - Polysaccharide-encapsulated organisms such as S. pneumoniae, H. influenzae type b and N. meningitidis are the leading causes of serious invasive bacterial diseases and pneumonia in children. The use of conjugate vaccines in developed countries has markedly decreased the burden of disease and mortality from these organisms through direct protection of the immunised and through herd immunity. Although conjugate vaccines are highly immunogenic, antibody levels after immunisation in early infancy wane, leading to the need for programmes which include booster doses. Understanding the generation of long-term immunity could lead to improvements in vaccine formulation and scheduling with the ultimate goal of providing more sustained protection. Prematurity is a risk factor for disease caused by polysaccharide-encapsulated bacteria and the available data indicate that preterm infants should be immunised according to their chronological age to provide early protection. PMID- 20851538 TI - Insights into fetal and neonatal development through analysis of cell-free RNA in body fluids. AB - The use of cell-free nucleic acids in the circulation of pregnant women for noninvasive prenatal diagnosis is arguably one of the hottest current topics in prenatal medicine. Between 1997 and the present era this field has gone from basic research to clinical application for diagnosis of fetal gender and Rhesus D status. Over the next few years it is likely that noninvasive prenatal diagnosis for Down syndrome will also be possible. Here we summarize current and future clinical applications of analyzing cell-free fetal DNA and RNA in both maternal and neonatal body fluids, including maternal plasma, serum, whole blood, amniotic fluid, and neonatal saliva. We describe methods to evaluate normal and abnormal fetal and neonatal development using gene expression microarrays. We also discuss the ways in which differentially-regulated gene lists can advance knowledge of both fetal and neonatal biology, as well as suggest novel possibilities for fetal and neonatal treatment. PMID- 20851540 TI - Preservation of dental evidence following exposure to high temperatures. AB - The success of the Disaster Victim Identification (DVI) process relies upon sufficient post-mortem data being recovered to allow for a meaningful comparison with ante-mortem records of the missing person. Human bodies subjected to prolonged high temperatures, as experienced during the Black Saturday bushfires in Victoria, are often reduced to fragile skeletal elements. The dental structures, however, are the most durable tissues of the body and often survive these prolonged high temperatures. Without protecting the fragile remains at the scene and during transportation to the mortuary, disruption of the skeletal and dental elements may occur. This disruption will result in difficulties in obtaining post-mortem evidence and lead to problems during the reconciliation (formal identification) phase of the investigation. In the two case reports presented to illustrate these problems, there was significant loss and degradation of dental structures at the scene and during transportation to the mortuary. In the first case described, where no protection was afforded to the remains, total loss of all anatomical dental structures occurred. In the second case, where protection of the structures was undertaken, vital dental evidence was preserved. As a result of the experience in this particular DVI incident, where remains were exposed to prolonged high temperature and physical damage, new protocols have been formulated. Adherence to these protocols will maximise the recovery and preservation of dental evidence at the scene and during transportation to the mortuary. PMID- 20851539 TI - Androgens, health and sexuality in women and men. AB - The importance of good sexual function for individuals is well recognised. Testosterone is contributory to a healthy sex life for both women and men. The British Society for Sexual Medicine (BSSM) has initiated and led the development of these guidelines for the assessment of testosterone deficiency in both women and men, for use within the UK and beyond. Clinical awareness of the possibility of testosterone deficiency and the impact this may have on an individual's sexual and somatic function and the need to make sufficient enquiry about the sex life of patients attending a broad spectrum of clinical services is emphasised. The management of testosterone deficiency is outlined in detail for both women and men. PMID- 20851541 TI - Sex determination of early medieval individuals through nested PCR using a new primer set in the SRY gene. AB - One of the first questions asked about excavated human skeletal remains is the sex. As the morphological sex determination is complicated in cases involving fragmentary bones and in skeletons from infants and children, the development of DNA-based techniques has led to improvements in sex determination. This study is focused on sex determination from ancient DNA obtained from 25 skeletons found in Middle Aged burials in western Slovakia. We performed separate amplifications of DXZ4 repetitive satellite sequences on the X chromosome, and SRY gene - testis determined factor on the Y chromosome, using nested PCR. Our results showed that DXZ4 was amplified in the case of 23 individuals. With newly designed internal and external primer sets for SRY detection with internal PCR products in lengths of 102 bp and 85 bp we succeeded in detecting the SRY locus in 9 samples. Finally, the gender was determined in 23 individuals (14 females and 9 males). In 20 samples, the gender was determined by morphological and molecular methods. Sex determination of 17 samples using nested PCR matched the morphological one, providing evidence of the authenticity and ancient origin of the PCR amplifications. The DXZ4/SRY nested PCR method represents a useful technique in sex determination of medieval human remains and it is a critical addition to anthropological studies. PMID- 20851542 TI - Influence of pre-analytical conditions on the interpretation of zopiclone concentrations in whole blood. AB - Zopiclone is a short-acting hypnotic drug used for treatment of insomnia and its stability has been described in some detail. However, data especially on short term pre-analytical stability is missing. This study investigated zopiclone stability differences between spiked and authentic whole blood from subjects dosed with zopiclone. In this way influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized. Nine volunteers participated in the study. Whole blood was obtained before and after oral administration of 10mg Imovane((r)). Aliquots of 1g of authentic and spiked blood were after initial measuring, stored at 20 degrees C during 5 days, 5 or -20 degrees C during 3 months, and zopiclone was measured by gas chromatography with nitrogen phosphorus detection. The results showed no stability differences between authentic and spiked blood but confirmed the very short stability in whole blood at ambient temperature. In summary, the stability was less than 1 day at 20 degrees C, less than 2 weeks at 5 degrees C but stable for 3 months at -20 degrees C. This study demonstrates the importance of controlling pre-analytical conditions from sampling to analysis to avoid misinterpretation of toxicological results. PMID- 20851543 TI - Complex appearance of vascularization in the wrist and finger joints in rheumatoid arthritis patients. PMID- 20851544 TI - BMD measurements of the spine derived from sagittal reformations of contrast enhanced MDCT without dedicated software. AB - PURPOSE: To assess QCT equivalent BMD of the lumbar spine in sagittal reformations of routine abdominal contrast-enhanced MDCT with simple PACS measurement tools and to apply this method to MDCT datasets for differentiating patients with and without osteoporotic vertebral fractures. MATERIALS AND METHODS: Eight postmenopausal women (65+/-5 years) underwent standard QCT to assess BMD of L1-L3. Afterwards routine abdominal contrast-enhanced MDCT images of these women were obtained and apparent BMD of L1-L3 was measured using the sagittal reformations. The MDCT-to-QCT conversion equation for BMD was calculated with linear regression analysis. The conversion equation was applied to vertebral BMD datasets (L1-L3) of 75 postmenopausal women (66+/-4 years). Seventeen of the 75 patients had osteoporotic vertebral fractures. RESULTS: BMD values of contrast enhanced MDCT were on average 56 mg/ml higher than those of standard QCT. A correlation coefficient of r=0.94 (p<0.05) was calculated for the BMD values of MDCT and standard QCT with the conversion equation BMDQCT=0.69*BMDMDCT-11 mg/ml. Accordingly converted BMD values of patients with vertebral fractures were significantly lower than those of patients without vertebral fractures (69 mg/ml vs. 85 mg/ml; p<0.05). Using ROC analysis to differentiate patients with and without vertebral fractures, AUC=0.72 was obtained for converted BMD values (p<0.05). Short- and long-term reproducibility errors for BMD measurements in the sagittal reformations amounted 2.09% and 7.70%, respectively. CONCLUSION: BMD measurements of the spine could be computed in sagittal reformations of routine abdominal contrast-enhanced MDCT with minimal technical and time effort. Using the conversion equation, the acquired BMD data could differentiate patients with and without osteoporotic vertebral fractures. PMID- 20851545 TI - Roles and responsibilities of medical physicists in radiation protection. PMID- 20851546 TI - Genotypic and phenotypic diversity of rhizobia isolated from Lathyrus japonicus indigenous to Japan. AB - Sixty-one rhizobial strains from Lathyrus japonicus nodules growing on the seashore in Japan were characterized and compared to two strains from Canada. The PCR-based method was used to identify test strains with novel taxonomic markers that were designed to discriminate between all known Lathyrus rhizobia. Three genomic groups (I, II, and III) were finally identified using RAPD, RFLP, and phylogenetic analyses. Strains in genomic group I (related to Rhizobium leguminosarum) were divided into two subgroups (Ia and Ib) and subgroup Ia was related to biovar viciae. Strains in subgroup Ib, which were all isolated from Japanese sea pea, belonged to a distinct group from other rhizobial groups in the recA phylogeny and PCR-based grouping, and were more tolerant to salt than the isolate from an inland legume. Test strains in genomic groups II and III belonged to a single clade with the reference strains of R. pisi, R. etli, and R. phaseoli in the 16S rRNA phylogeny. The PCR-based method and phylogenetic analysis of recA revealed that genomic group II was related to R. pisi. The analyses also showed that genomic group III harbored a mixed chromosomal sequence of different genomic groups, suggesting a recent horizontal gene transfer between diverse rhizobia. Although two Canadian strains belonged to subgroup Ia, molecular and physiological analyses showed the divergence between Canadian and Japanese strains. Phylogenetic analysis of nod genes divided the rhizobial strains into several groups that reflected the host range of rhizobia. Symbiosis between dispersing legumes and rhizobia at seashore is discussed. PMID- 20851547 TI - Genetic diversity of native soybean bradyrhizobia from different topographical regions along the southern slopes of the Himalayan Mountains in Nepal. AB - Soybean-nodulating bradyrhizobia are genetically diverse and are classified into different species. In this study, the genetic diversity of native soybean bradyrhizobia isolated from different topographical regions along the southern slopes of the Himalayan Mountains in Nepal was explored. Soil samples were collected from three different topographical regions with contrasting climates. A local soybean cultivar, Cobb, was used as a trap plant to isolate bradyrhizobia. A total of 24 isolates selected on the basis of their colony morphology were genetically characterized. For each isolate, the full nucleotide sequence of the 16S rRNA gene and ITS region, and partial sequences of the nifD and nodD1 genes were determined. Two lineages were evident in the conserved gene phylogeny; one representing Bradyrhizobium elkanii (71% of isolates), and the other representing Bradyrhizobium japonicum (21%) and Bradyrhizobium yuanmingense (8%). Phylogenetic analyses revealed three novel lineages in the Bradyrhizobium elkanii clade, indicating high levels of genetic diversity among Bradyrhizobium isolates in Nepal. B. japonicum and B. yuanmingense strains were distributed in areas from 2420 to 2660 m above sea level (asl), which were mountain regions with a temperate climate. The B. elkanii clade was distributed in two regions; hill regions ranging from 1512 to 1935 m asl, and mountain regions ranging from 2420 to 2660 m asl. Ten multi-locus genotypes were detected; seven among B. elkanii, two among B. japonicum, and one among B. yuanmingense-related isolates. The results indicated that there was higher species-level diversity of Bradyrhizobium in the temperate region than in the sub-tropical region along the southern slopes of the Himalayan Mountains in Nepal. PMID- 20851548 TI - Evaluation of nitrate reductase assay for rapid detection of resistance to second line drugs in Mycobacterium tuberculosis in a tertiary care hospital. AB - The present study evaluated nitrate reductase assay (NRA) for rapid detection of resistance to 5 second-line drugs: kanamycin, ethionamide, ofloxacin, cycloserine, and para-aminosalicylic acid. Eighty-six multidrug-resistant clinical isolates of Mycobacterium tuberculosis were used to compare NRA with proportion method for rapid detection of resistance to second-line drugs. The sensitivity of the NRA for different drugs ranged from 86.4% to 100%, whereas the specificity ranged from 98.4% to 100%. Excellent agreement was found between the 2 tests with respect to their kappa values. For 63% of the isolates, the results were available in 14 days (turnaround time). The NRA is a rapid, accurate, simple, and inexpensive method for detection resistance to second-line drugs. This method may become an appropriate alternative method, especially for the resource poor settings. PMID- 20851549 TI - Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation. AB - Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem. PMID- 20851550 TI - CMY-2, CMY-8b, and DHA-1 plasmid-mediated AmpC beta-lactamases among clinical isolates of Escherichia coli and Klebsiella pneumoniae from a university hospital, Thailand. AB - Between February 2005 and January 2006 in Srinagarind Hospital, Thailand, 44 from 1730 isolates (2.5%) of Escherichia coli and 8 from 982 isolates (0.8%) of Klebsiella pneumoniae were found to produce plasmid-mediated AmpC beta-lactamases (pAmpCs) as detected by a cefoxitin-Hodge test followed by a multiplex polymerase chain reaction (PCR) technique. Fifteen of the 52 pAmpC-producing isolates also produced extended-spectrum beta-lactamases. The ampC genes found in both organisms were bla(CMY-2) (46 isolates), bla(CMY-8b) (4 isolates), and bla(DHA-1) (2 isolates). These genes were present on plasmids. Twenty-five of the 46 CMY-2 producing isolates could transfer cefoxitin resistance to E. coli UB1637 by conjugation. More than 90% of the pAmpC-producing isolates were resistant to cefoxitin, but 80% to 90% of them were susceptible or intermediately susceptible to ceftazidime or cefotaxime. Enterobacterial repetitive intergenic consensus PCR analysis revealed that most isolates were of different strains, indicating the ease of transmission of these resistance determinants. This is the first report of CMY-2, CMY-8b, and DHA-1 beta-lactamases in Thai isolates. PMID- 20851551 TI - Molecular epidemiology and antifungal susceptibility of Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis in Taiwan. AB - Candida parapsilosis was recently reclassified into 3 closely related species, C. parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis. Variation in susceptibility characteristics and prevalence of the 3 genomic species could have therapeutic and epidemiologic implications. The aim of this study is to characterize the genetic and antifungal susceptibility profiles of 97 C. parapsilosis isolates from 71 patients. Among the 71 nonduplicate isolates, 85.9% (61/71) were identified as C. parapsilosis sensu stricto, 5.6% (4/71) as C. metapsilosis, and 8.5% (6/71) as C. orthopsilosis species based on sequences of the internal transcribed spacer (ITS) region. The delineation of these 3 species is concordant with that achieved by pulsed-field gel electrophoresis of BssHII restriction fragments at 75% similarity. Antifungal susceptibility tests showed that most isolates were susceptible to flucytosine, azoles, amphotericin B, and echinocandins, whereas 3 C. metapsilosis isolates from 1 patient showed resistance and susceptible-dose dependence to fluconazole. The C. metapsilosis isolates exhibited significantly higher MIC values to both fluconazole and voriconazole than those of C. parapsilosis sensu stricto and C. orthopsilosis. On the other hand, the C. metapsilosis isolates showed significantly lower MIC values on 24 h to caspofungin than those of C. parapsilosis sensu stricto and C. orthopsilosis. For micafungin, the isolates of C. parapsilosis sensu stricto had significantly higher MIC values on 24 h than those of C. orthopsilosis and C. metapsilosis. Compared to Candida albicans, mutations from proline to alanine were identified on the hot spot 1 of Fks1 in all these C. parapsilosis sensu lato isolates regardless of their MIC levels. Some of the C. orthopsilosis and C. metapsilosis isolates expressed the isoleucine to valine substitution on the hot spot 2 region. However, the amino acid variations in these isolates did not correlate to their MIC values of echinocandin. PMID- 20851552 TI - Benidipine hydrochloride intoxication in a child. PMID- 20851553 TI - Severe tricuspid regurgitation and atrioventicular block caused by blunt thoracic trauma in an elderly woman. AB - BACKGROUND: Symptomatic cardiac injury after blunt chest trauma is relatively rare, and valvular injury is even more rare. The valves most commonly affected are tricuspid. Automobile accidents are mostly responsible for this type of injury. OBJECTIVES: Unlike with the mitral valve, post-traumatic tricuspid heart valve insufficiency is usually well tolerated. Indeed, severe tricuspid regurgitation can resolve spontaneously. CASE REPORT: A 68-year-old woman with no previous cardiac or medical history was brought to our Emergency Department after an automobile accident. She had chest pain and shortness of breath upon admission. Transthoracic echocardiographic examination revealed severe tricuspid regurgitation with rupture of the chordae tendineae and prolapse of the valve cusps into the right atrium during systole. An electrocardiogram was consistent with second-degree Mobitz II atrioventricular block on admission, which subsequently progressed to complete atrioventricular block on day 3. During follow-up with close hemodynamic monitoring, her symptoms disappeared and repeat echocardiography revealed a regression in the severity of tricuspid regurgitation. Operative repair of the tricuspid valve was deemed unnecessary and the patient was discharged with medical therapy on the eighth day after admission. CONCLUSIONS: It is important to be aware of traumatic tricuspid regurgitation after non-penetrating chest trauma. Close follow-up may suffice in some patients with stable hemodynamic conditions, and regression of tricuspid regurgitation can be expected during follow-up. PMID- 20851554 TI - A case of massive delayed acute subdural hematoma. PMID- 20851555 TI - Acquired methemoglobinemia due to application of prilocaine during circumcision. PMID- 20851556 TI - Cancer is an insufficiently recognized risk factor for atrial fibrillation. PMID- 20851557 TI - An unusual presentation of twiddler's syndrome. PMID- 20851558 TI - A wandering spleen presenting as an acute abdomen: case report. AB - BACKGROUND: A wandering spleen, defined as a spleen without peritoneal attachments, is a rare entity characterized by splenic hypermobility due to laxity or maldevelopment of the supporting splenic ligaments. Patients with a wandering spleen may be asymptomatic, or may present with a palpable mass in the abdomen, or with acute, chronic, or intermittent symptoms due to torsion of the wandering spleen. Because early clinical diagnosis is difficult, imaging modalities play an important role in the diagnosis. Treatment should be planned according to the vitality of the spleen. CASE REPORT: A 22-year-old woman presented with an acute abdomen that was found to be due to a wandering spleen with 720 degrees anti-clockwise torsion around the pedicle. CONCLUSIONS: Splenectomy is advocated in the presence of torsion, splenic vein thrombosis, or splenic infarction. Conversely, when a viable wandering spleen is found at laparotomy, detorsion with splenopexy is preferred. PMID- 20851559 TI - The Nonverbal Accommodation Analysis System (NAAS): initial application and evaluation. AB - OBJECTIVE: To describe the development, initial application, and evaluation of the Nonverbal Accommodation Analysis System (NAAS). Grounded in Communication Accommodation Theory, this coding system provides a method for analyzing physician and patient nonverbal accommodation behaviors within medical consultations. METHODS: Video recordings of 45 new visit consultations at a comprehensive cancer center were coded using the NAAS. Inter-rater and intra rater reliability were assessed. For validation purposes, two independent coders rated all consultations for theoretically related constructs. RESULTS: The NAAS demonstrated high levels of reliability. Statistically significant correlations were observed across all 10 behavior categories for both inter-rater and intra rater reliability. Evidence of content and construct validity was also observed. CONCLUSION: The current study presents the initial application and evaluation of a coding system meant for analysis of the nonverbal behavior of physicians and patients within medical consultations. The results of this initial trial and psychometric evaluation provide evidence of the NAAS as a valid and reliable nonverbal accommodation coding system. PRACTICE IMPLICATIONS: The NAAS enables researchers to investigate the way in which physicians and patients manage social distance through nonverbal behavior within medical interactions from a theoretically-informed perspective. Such efforts can aid in the development of communication skill interventions. PMID- 20851560 TI - Effective or ineffective: attribute framing and the human papillomavirus (HPV) vaccine. AB - OBJECTIVE: To experimentally test whether presenting logically equivalent, but differently valenced effectiveness information (i.e. attribute framing) affects perceived effectiveness of the human papillomavirus (HPV) vaccine, vaccine related intentions and policy opinions. METHODS: A survey-based experiment (N=334) was fielded in August and September 2007 as part of a larger ongoing web enabled monthly survey, the Annenberg National Health Communication Survey. Participants were randomly assigned to read a short passage about the HPV vaccine that framed vaccine effectiveness information in one of five ways. Afterward, they rated the vaccine and related opinion questions. Main statistical methods included ANOVA and t-tests. RESULTS: On average, respondents exposed to positive framing (70% effective) rated the HPV vaccine as more effective and were more supportive of vaccine mandate policy than those exposed to the negative frame (30% ineffective) or the control frame. Mixed valence frames showed some evidence for order effects; phrasing that ended by emphasizing vaccine ineffectiveness showed similar vaccine ratings to the negative frame. CONCLUSION: The experiment finds that logically equivalent information about vaccine effectiveness not only influences perceived effectiveness, but can in some cases influence support for policies mandating vaccine use. PRACTICE IMPLICATIONS: These framing effects should be considered when designing messages. PMID- 20851561 TI - Meniscal allograft transplantation without bone blocks: a 5- to 8-year follow-up of 33 patients. AB - PURPOSE: The purpose of this study was to evaluate the functional and radiographic results on a midterm basis, as well as complications, in an initial series of meniscal allograft transplantations performed with suture fixation without any bone block. METHODS: A series of 33 meniscal allograft transplantations were performed at our institution from January 2001 to October 2003. Inclusion criteria were patients with compartmental joint line pain due to a previous meniscectomy. There were 24 men and 9 women with a mean age of 38.8 years (range, 21 to 54 years). The functional outcomes were evaluated by use of Lysholm and Tegner scores at a mean and minimum follow-up of 6.5 years and 5 years, respectively. A visual analog scale for pain was also used. Radiographic assessment included joint space narrowing on the Rosenberg view and magnetic resonance imaging evaluation. RESULTS: The Lysholm and Tegner scores significantly improved from 65.4 to 88.6 (P < .001) and from 3.1 to 5.5 (P < .001), respectively, after surgery. The visual analog scale score significantly dropped from 6.4 to 1.5 (P < .001). The radiographic evaluation did not show any joint space narrowing (P = .38). Meniscal extrusion was a constant finding, averaging 36.3% of total meniscal size. According to the Van Arkel criteria, the survival rate was 87.8% at 6.5 years. The rate of complications was 33%. CONCLUSIONS: This study suggests that this procedure provides significant pain relief and functional improvement in selected symptomatic individuals on a midterm basis. However, there was a high rate of complications (33%) and revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 20851562 TI - Safety analysis of all-inside arthroscopic repair of peripheral triangular fibrocartilage complex. AB - PURPOSE: The purpose of this study was to determine whether an all-inside peripheral triangular fibrocartilage complex (TFCC) repair using the FasT-Fix device (Smith & Nephew Endoscopy, Andover, MA) is safe by measuring the proximity of the anchors to ulnar-sided anatomic structures. METHODS: Eleven fresh-frozen cadaveric wrists were thawed and placed in traction. Under direct arthroscopic visualization, an all-inside arthroscopic peripheral TFCC repair was completed by placing a single FasT-Fix device in a vertical mattress fashion. The wrists were then dissected to visualize the 2 anchors. The distance between these anchors and the flexor carpi ulnaris (FCU), extensor carpi ulnaris (ECU), and dorsal branch of the ulnar sensory nerve (DBUN) were measured with digital calipers and recorded. RESULTS: The peripheral anchor averaged 4.2 mm (range, 0 to 14 mm) from the ECU tendon, 3.8 mm (range, 0 to 9 mm) from the DBUN, and 8.3 mm (range, 1 to 15 mm) from the FCU tendon. The central anchor averaged 9.6 mm (range, 2 to 15 mm) from the ECU tendon, 6.8 mm (range, 1 to 13 mm) from the DBUN, and 7.6 mm (range, 1 to 13 mm) from the FCU tendon. CONCLUSIONS: This study exposes some safety concerns with the all-inside peripheral TFCC repair using the FasT-Fix device, which was found to reside in close proximity to the ECU, FCU, and DBUN. In multiple wrists the anchors were noted to underlie the anatomic structure that we measured, making it possible to pierce these structures with the needle before deployment of the anchor. CLINICAL RELEVANCE: Though technically feasible, all inside arthroscopic repair of the peripheral TFCC risks injury to the ulnar-sided anatomy. PMID- 20851563 TI - Fracture of a cross-linked polyethylene liner: a multifactorial issue. AB - A limited number of reports have detailed the cause of fracture of a highly cross linked polyethylene liner. Typically, the fractures have occurred in a region of thin and/or unsupported polyethylene, in association with superiorly directed edge loading conditions secondary to an excessively inclinated acetabular component. This case report details an unusual fracture mechanism of a 5-mrad cross-linked liner caused by horizontal loading conditions. The report details several factors that were felt to be etiologic including the specific liner locking mechanism. The treatment options are discussed. PMID- 20851564 TI - A systematic review of modern metal-on-metal total hip resurfacing vs standard total hip arthroplasty in active young patients. AB - This systematic review compared 2 treatments for hip disease in active young patients: modern metal-on-metal total hip resurfacing and standard total hip arthroplasty. We conducted a literature search to identify relevant randomized and clinical controlled trials and included 968 patients from 4 trials in our analysis. Our results indicated increased rates of revision, femoral neck fractures, and component loosening among patients who received modern metal-on metal hip resurfacing. No significant differences in the rates of mortality, dislocation, or deep hip joint infection were found between treatment groups. Hip function scores were similar between the 2 groups, but the resurfacing group showed higher activity levels. These results have provided insufficient evidence to determine whether modern metal-on-metal total hip resurfacing offers clinical advantages over standard total hip arthroplasty. PMID- 20851565 TI - Directed air flow to reduce airborne particulate and bacterial contamination in the surgical field during total hip arthroplasty. AB - This study evaluated the use of a system that delivers a small field of local, directed air from a high-efficiency particulate air (HEPA) filter to reduce airborne particulate and airborne bacteria in the surgical field during total hip arthroplasty. Thirty-six patients were randomized into 3 groups: with directed air flow, with the directed air flow system present but turned off, and control. Airborne particulate and bacteria were collected from within 5 cm of the surgical wound. All particulate and bacterial counts at the surgical site were significantly lower in the directed air flow group (P < .001). The directed air flow system was effective in reducing airborne particulate and colony-forming units in the surgical field during total hip arthroplasty. PMID- 20851567 TI - Crack initiation in retrieved cross-linked highly cross-linked ultrahigh molecular-weight polyethylene acetabular liners: an investigation of 9 cases. AB - Nine cross-linked highly cross-linked ultrahigh-molecular weight polyethylene acetabular liners were retrieved at revision surgery. Eight of the liners were fully intact and functional at retrieval. Six cases contained shallow initiated cracks at the root of rim notches; 1 crack had propagated several millimeters. Optical and electron microscopic inspection of the crack surfaces revealed clam shell markings, which are characteristic of fatigue crack initiation. Crack initiation at notches has been identified in reports of catastrophic cross-linked liner failures, with crack initiation sites exhibiting similar morphology and clam shell markings. Thus, we believe that the shallow cracks identified in this case series are precursors to catastrophic rim fracture. The results of this study recommend further investigations to clarify the etiology and prevalence of crack initiation in cross-linked acetabular liners. PMID- 20851566 TI - Measuring functional improvement after total knee arthroplasty requires both performance-based and patient-report assessments: a longitudinal analysis of outcomes. AB - The purpose was to explore the responsiveness of both patient-report and performance-based outcome measures to determine functional changes during the acute and long-term postoperative recovery after total knee arthroplasty (TKA). One hundred patients scheduled for unilateral TKA underwent testing preoperatively and at 1 and 12 months postoperatively using the Delaware Osteoarthritis Profile. All physical performance measures decreased initially after surgery then increased in the long term; however, the perceived function did not follow the same trend, and some showed an increase immediately after surgery. Patient-report measures were variable, with no to small response early, but had excellent long-term responsiveness that was twice as large as performance measures. Patient perception fails to capture the acute functional declines after TKA and may overstate the long-term functional improvement with surgery. PMID- 20851568 TI - Anterior knee pain after total hip arthroplasty in developmental dysplasia. AB - Little has been reported on knee pain after total hip arthroplasty (THA). The purpose of this study was to investigate the incidence and mechanism of knee pain after THA. Two hundred fifty-two patients with hip dysplasia were clinically and radiographically assessed for knee pain before and after THA. Incidences of knee pain and patellofemoral alignment were analyzed with reference to postoperative change in leg length, femoral anteversion, and the femoral offset. Anterior knee pain was present in 16 patients (7.3%). Lateral patellar tilt was increased in all patients with knee pain and significantly larger compared to that seen in patients without knee pain. The increased patellar tilt disappeared within 3 months, but symptoms in 4 patients persisted for more than 3 months. The patellar tilt was significantly related to the amount of leg lengthening. This study demonstrates that THA influences the patellofemoral joint via leg lengthening and causes anterior knee pain. PMID- 20851569 TI - Nurse practitioner-based models of specialist palliative care at home: sustainability and evaluation of feasibility. AB - CONTEXT: Patients with serious medical problems who live at home may not be able to access specialist-level palliative care when the need develops. Nurse practitioner (NP)-based models may be able to increase the availability of specialist care in the community. OBJECTIVES: The aim of this study was to evaluate the financial sustainability and feasibility of two NP-based models in an urban setting. METHODS: In one model, an NP was linked with a social worker (SW) to create a new palliative home care team (PHCT-NP-SW), which would provide consultation and direct care to referred homebound elderly patients with advanced illnesses. In a second model, an NP was assigned to a hospice program (Hospice NP) for the purpose of enhancing the reach and impact of a home care team. The revenue generated by each model was compared with direct costs; the PHCT-NP-SW model also was evaluated for its feasibility and impact on patient-level outcomes. RESULTS: Over a two-year period, the NP in the PHCT-NP-SW model made 350 visits and followed 114 patients at home. Annualized revenue through reimbursement from patient billing offset less than 50% of the NP's salary costs. In contrast, the Hospice-NP model led to a 360% increment in hospice referrals, yielding sufficient new revenue to support this position indefinitely after only seven months. The PHCT-NP-SW model provided numerous interventions that yielded a significant decline in symptom distress during the initial two weeks after referral (P=0.003), 100% compliance with advance care planning, 21% admission rate to hospice, access to other community services, and crisis management. Nonetheless, lack of funding led to closure of this model after the two years. CONCLUSION: This experience suggests that a PHCT-NP-SW model is not sustainable in this urban environment through reimbursement-based revenue, whereas a Hospice NP model for hospice can be sustainable based on the growth of hospice census. The PHCT-NP-SW model appears to offer benefits, and additional efforts are needed to establish the funding mechanisms to sustain such programs, create mixed models of hospice and nonhospice funding, or provide a basis for sustainability through cost reduction. PMID- 20851570 TI - A multidimensional anxiety assessment of adolescents after Typhoon Morakot associated mudslides. AB - The aims of this study were to examine the factor structure, reliability and validity of the Taiwanese version of the Multidimensional Anxiety Scale for Children (MASC-T) in a group of adolescents in mountainous regions worst affected by Typhoon Morakot-associated mudslides. In total, 271 adolescents in grades 7-9 completed the MASC-T and the Chinese version of the Impact of Events Scale Revised (C-IES-R). They also received a diagnostic interview to determine whether they had post-traumatic stress disorder (PTSD). We examined adequacy of the original four-factor structure of the MASC-T using confirmatory factor analysis, as well as its internal reliability, discriminant and predictive validities for PTSD, and convergent validity with the C-IES-R. Results support adequacy of the four-factor structure and internal reliability of the MASC-T in adolescents affected by Typhoon Morakot. Scores for the total MASC-T and subscales significantly discriminated adolescents with PTSD from those without PTSD. However, levels of predictive values for PTSD and the convergent validity with the C-IES-R differed among the MASC-T subscales and the total scale. The physical symptoms and harm avoidance subscales had the highest and lowest predictive accuracies for presence of PTSD, respectively. The MASC-T combined with diagnostic interviews for PTSD and self-report measures for assessing PTSD specific symptoms can be used to evaluate a broad range of anxiety symptoms. PMID- 20851571 TI - Behaving as or behaving as if? Children's conceptions of personified robots and the emergence of a new ontological category. AB - Imagining another's perspective is an achievement in social cognition and underlies empathic concern and moral regard. Imagination is also within the realm of fantasy, and may take the form of imaginary play in children and imaginative production in adults. Yet, an interesting and provocative question emerges in the case of personified robots: How do people conceive of life-like robots? Do people imagine about robots' experiences? If so, do these imaginings reflect their actual or pretend beliefs about robots? The answers to these questions bear on the possibility that personified robots represent the emergence of a new ontological category. We draw on simulation theory as a framework for imagining others' internal states as well as a means for imaginative play. We then turn to the literature on people's and, in particular, children's conceptions of personified technologies and raise the question of the veracity of children's beliefs about personified robots (i.e., are they behaving as or behaving as if?). Finally, we consider the suggestion that such personified technologies represent the emergence of a new ontological category and offer some suggestions for future research in this important emerging area of social cognition. PMID- 20851572 TI - Conceptual change and preschoolers' theory of mind: evidence from load-force adaptation. AB - Prominent theories of preschoolers' theory of mind development have included a central role for changing or adapting existing conceptual structures in response to experiences. Because of the relatively protracted timetable of theory of mind development, it has been difficult to test this assumption about the role of adaptation directly. To gain evidence that cognitive adaptation is particularly important for theory of mind development, we sought to determine whether individual differences in cognitive adaptation in a non-social domain predicted preschoolers' theory of mind development. Twenty-five preschoolers were tested on batteries of theory of mind tasks, executive functioning tasks, and on their ability to adapt their lifting behavior to smoothly lift an unexpectedly heavy object. Results showed that children who adapted their lifting behavior more rapidly performed better on theory of mind tasks than those who adapted more slowly. These findings held up when age and performance on the executive functioning battery were statistically controlled. Although preliminary, we argue that this relation is attributable to individual differences in children's domain general abilities to efficiently change existing conceptual structures in response to experience. PMID- 20851573 TI - Haptic model fabrication for undergraduate and postgraduate teaching. AB - Three series of cone-beam computed tomography (CBCT) patient data sets were obtained. These data were exported into DICOM and MIMICS (Materialise's Interactive Medical Image Control System; Materialise, Leuven, Belgium) and were imported for differentiation of various tissues (bone, teeth, and nerve). After transferring the data to an additive manufacturing machine, three-dimensional (3D) haptic models were fabricated using clear and opaque materials. These models were integrated into phantom heads normally used for education in undergraduate dental education. 3D prototype CBCT-based haptic patient models can be used in undergraduate and postgraduate education. Students can simulate routine standard oral surgical procedures with supervision under 'dry conditions'. Residents can simulate advanced and complex cases before performing the real operation. PMID- 20851574 TI - Dose-dependent protective effect of connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion. AB - Epileptic seizures typically result in delayed neuronal loss secondary to the initial damage and an up-regulation in connexin43 (Cx43). This study investigated the role of Cx43 gap junctions in lesion spread and cell loss following epileptiform activity. Epileptiform injury in hippocampal slice cultures was induced by 48 h exposure to 100 MUM bicuculline methochloride (BMC). During the 24h recovery period following BMC treatment, lesion spread was observed in the CA1. A Cx43 mimetic peptide, applied during either the BMC treatment or recovery periods, produced concentration- and exposure time-dependent neuroprotection, as measured by propidium iodide uptake at the end of the recovery period. During the BMC period, peptide concentrations between 5 and 50 MUM (sufficient to block hemichannels) had a protective effect while a substantial gap junction blockade with 500 MUM peptide exacerbated the lesion. By contrast, all doses applied during the recovery period protected the CA1 region from further damage. The results indicate that while the slices are undergoing excessive neuronal firing and epileptic stress, gap junction communication appears to be essential for tissue survival but hemichannel opening may be damaging. Following epileptiform insult, however, gap junction communication plays a crucial role in the spread of neuronal damage. The findings from this study identify gap junction communication as a potential therapeutic target for epilepsy. PMID- 20851575 TI - UV irradiation induces Snail expression by AP-1 dependent mechanism in human skin keratinocytes. AB - BACKGROUND: Ultraviolet (UV) irradiation from the sun is the major cause of keratinocyte skin cancer. Transcription factor Snail plays an important role in epithelial-to-mesenchymal transition and epithelial tumor formation. OBJECTIVE: The aims of this study are to determine the regulation of Snail expression of ultraviolet (UV) irradiation on Snail expression in human skin in vivo, and the mechanisms by which UV irradiation induces Snail expression, in human keratinocytes. METHODS: Real-time RT-PCR was employed to measure Snail expression in human skin in vivo and cultured human keratinocytes. Luciferase assay and electrophoretic mobility shift assay (EMSA) were employed to investigate transcriptional regulation of the in Snail gene promoter. RESULTS: Ultraviolet (UV) irradiation transiently induces Snail expression in human skin in vivo and cultured human keratinocytes. Snail induction is significantly reduced by specific inhibitors of ERK, p38 or JNK, indicating each of the three major mitogen-activated protein kinase (MAPK) pathways participate in Snail regulation. AP-1 transcription factor complex, a downstream target of MAPK signaling, is required for Snail induction. Inhibition of AP-1 activity by over-expression of dominant-negative c-Jun substantially reduces Snail induction. Analyses of the Snail promoter, revealed the presence of an AP-1 binding site. EMSA assay demonstrated that UV irradiation specifically induced c-Jun binding to this AP-1 site. Mutation of the AP-1-binding site completely blocked protein binding and inhibited UV irradiation-induced Snail promoter activity. CONCLUSION: UV irradiation induces Snail gene expression in human skin keratinocytes. This induction is mediated by MAPK-AP-1 dependent signaling pathway. Elevated expression of Snail in response to chronic UV irradiation in human skin may contribute to UV irradiation-induced skin tumor development. PMID- 20851576 TI - Efficacy of daptomycin combined with rifampicin for the treatment of experimental meticillin-resistant Staphylococcus aureus (MRSA) acute osteomyelitis. AB - Daptomycin exhibits rapid bactericidal activity against Gram-positive organisms, including meticillin-resistant Staphylococcus aureus (MRSA). Daptomycin in combination with rifampicin needs to be assessed in bone infection. An MRSA acute osteomyelitis model was used. Daptomycin and vancomycin were compared, alone or in combination with rifampicin, over 4 days. Surviving bacteria were counted in bone, bone marrow and joint fluid. Vancomycin and daptomycin as single therapies were ineffective, but both combinations were significantly more effective than the corresponding monotherapy. Combination of daptomycin and rifampicin could prevent S. aureus from developing resistance. This combination could be a useful alternative to treat MRSA osteomyelitis at an early stage. PMID- 20851577 TI - High antitrypanosomal activity of plant-derived sulphur-containing amides. AB - Chagas disease, caused by Trypanosoma cruzi, represents an important public health problem in endemic geographic regions in Middle and South America, affecting 15 million infected people. Treatment options are still limited due to the toxicity of available drugs, parasite resistance and poor drug activity during the chronic phase of the disease. In this study, we investigated the in vitro antitrypanosomal activity of 15 tropical plant-derived compounds with the aim of finding new drug candidates. Three novel sulphur-containing amides (methyldambullin, methylgerambullin and sakambullin) showed promising antitrypanosomal activities, with 50% effective concentrations (EC50 values) after 72 h exposure of 1.7, 1.23 and 5.18 MUM, respectively, compared with EC50 values for amphotericin B and benznidazole of 0.71 MUM and 30.89 MUM, respectively. PMID- 20851578 TI - Evaluation of folate conjugated pegylated thermosensitive magnetic nanocomposites for tumor imaging and therapy. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been receiving great attention lately in biomedical applications, such as in magnetic resonance imaging and drug delivery. However, their systemic administration still remains a challenge due to their hydrophobic nature with instances of aggregation leading to fast reticuloendothelial system (RES) uptake. In this study, magnetic nanocomposites with thermosensitive polymer have been investigated. Random polymers of N-isopropylacrylamide (NIPAAM), acrylic acid (AA) and PEGMA have been coated on SPIONs followed by conjugation with folic acid. Particles of ~200 nm and low polydispersity 0.1-0.2 having a critical temperature (T(c)) of 44 degrees C were formed. Thermogravimetric and powder X-ray diffraction studies showed that the nanocomposites were composed of 90% cubic face-centered magnetite. Nearly 76.5% doxorubicin was loaded onto the nanoparticles by diffusion method. Drug release was higher at the hyperthermia temperature (72.42 +/- 5.25% in 48 h) proving the thermoresponsive nature of the polymer. Folate conjugated samples showed a magnetization value of 32 emu/g as well as high r1 and r2 relaxivities in magnetic resonance imaging. R2 weighted images of nanocomposites were darker than the control with 20 MUg/mL as the darkest. At this concentration the magnetic composites showed nearly 95% viability in L929 fibroblast cells. These thermoresponsive nanosystems with pegylated surfaces and size of ~200 nm are therefore highly suitable for in vivo imaging and hyperthermia based drug delivery. PMID- 20851579 TI - [Why a neonatology issue?]. PMID- 20851580 TI - [Exposure of a cohort of newborn infants to tuberculosis in a neonatology service]. AB - INTRODUCTION: A nursery nurse that was working in the neonatology service had been diagnosed with tuberculosis. As a consequence, the newborn infants were in danger of a possible contamination during a 4-month period. METHODOLOGY: One hundred and thirty kids that had been in touch with the nurse were given attention. Prophylactic treatment for three months with isoniazid and rifampicin has been proposed to all families. Each of them was screened with a tuberculin sensitivity test and was given chest radiography initially and after three months. RESULTS: None of the children was initially suspected for tuberculosis. Among the chest radiographies, 97.6% were normal and all the intradermal tuberculin were either negative or in the norm following a vaccination by the Bacillus Calmette-Guerin. In most cases, the treatment tolerance was high. CONCLUSION: A 4-year-long surveillance ensured that no infant was infected. This procedure has established that the risk of transmission by a nurse is low, should it be for newborn babies, as long as guidelines are strictly adhered to. PMID- 20851581 TI - [Subgaleal hematoma in 2 neonates]. AB - Subgaleal hematoma in the newborn infant is rare, occurs early, and often bears serious consequences. We report on 2 subacute cases of bruising of the scalp that occurred following the use of a suction cup. Emergency treatment consisted of a transfusion of packed red blood cells and fresh frozen plasma. Children born by use of vacuum extractor or forceps require careful monitoring by the nursing staff throughout their stay in the maternity unit. PMID- 20851583 TI - Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats. AB - The present study was undertaken to evaluate the protective effect of selenium against arsenic-induced oxidative damage in experimental rats. Males were randomly divided into four groups where the first was served as a control, whereas the remaining groups were respectively treated with sodium selenite (3 mg/kg b.w.), sodium arsenite (5.55 mg/kg b.w.) and a combination of sodium arsenite and sodium selenite. Changes in liver enzyme activities, thiobarbituric acid reactive substances (TBARS) level, antioxidants and reduced glutathione (GSH) contents were determined after 3 weeks experimental period. Exposure of rats to As caused a significant increase in liver TBARS compared to control, but the co-administration of Se was effective in reducing its level. The activities of glutathione peroxidase (GPx) and glutathione-S-transferase (GST) of As-treated group were found lower compared to the control and the Se-treated group. The co administration of Se had an additive protective effect on liver enzyme activities compared to As-treated animals. On the other hand, a significant increase in plasmatic activities of AST, ALT and ALP was observed in As-treated group. The latter was also exhibited a decrease in body weight and an increase in liver weight compared to the control. The co-administration of Se has decreased the activities of AST, AST and ALP and improved the antioxidant status as well. Liver histological studies have confirmed the changes observed in biochemical parameters and proved the beneficial role of Se. To conclude, results suggest that As exposure enhanced an oxidative stress by disturbing the tissue antioxidant defense system, but the Se co-administration protected liver tissues against As intoxication probably owing to its antioxidant properties. PMID- 20851582 TI - Highlights from "Italian Standards of care for Diabetes Mellitus 2009-2010". AB - The Italian Standards for the Treatment of Diabetes Mellitus represent a consensus document of the two Italian scientific diabetes societies (AMD and SID), providing specific recommendations for the diagnosis and treatment of diabetes and its complications. The level of scientific evidence behind every recommendation has been classified in accordance with the National Guidelines Plan. An original processing system was employed: the document prepared by the Editorial Team was published online for 20 days, and the suggestions and criticisms of about 30 persons were evaluated and integrated to those provided by a panel of diabetologists and members of other healthcare professions dedicated to diabetes care, as well as lay members. Lastly, the document was approved by AMD and SID National Steering Committees. In this version, some highlights of the full document (www.siditalia.it; www.aemmedi.it) concerning the main and most representative recommendations on diagnosis and treatment of diabetes and its complications as well as on diabetes care in some specific contexts, are reported. PMID- 20851584 TI - Thirty-year follow-up after Wagner resurfacing hip arthroplasty: Case report. AB - Wagner hip arthroplasty has been used as a resurfacing and thereby bone preserving method for the treatment of disabling osteoarthritis particularly in younger individuals. The underlying rationale was to replace exclusively diseased tissue, to restore anatomy and function and to optimize range of motion and stress transfer to the proximal femur. Wagner's approach was designed to reduce the risk of infection and to make later revisions easier. The technique was however associated with a high revision rate due to early aseptic wear induced component loosening and neck fractures. Nevertheless, we report a case of a 30 years follow-up of a Wagner resurfacing hip arthroplasty. PMID- 20851585 TI - Pharmacological mechanism responsible for the Atractylodes japonica-induced distal colonic contraction in rats. AB - BACKGROUND AND AIM: Atractylodes japonica Koidz (Compositae) has been commonly used to treat the gastrointestinal (GI) disorders in Korean traditional medicine, but its pharmacological roles in the regulation of GI motility have not been clarified yet. METHODS: Atractylodes japonica was sequentially partitioned with MeOH, n-hexane, CHCl(3), EtOAc and n-BuOH saturated with H(2)O, and the effects of Atractylodes japonica extracts on the spontaneous contractility of GI muscle strips prepared from rats were measured. RESULTS: Among five different fractionations, EtOAc extracts of Atractylodes japonica (AJEA) dose-dependently increased the low frequency contraction of distal colon longitudinal muscles (DCLM), and the ED(50) values were revealed to be 1.71*10(-9) g/ml. Among GI tracts, a prominent contractile response to AJEA was observed only in the DCLM. The contractile patterns produced by AJEA remarkably differed from those caused by acetylcholine and 5-HT. 4-DAMP and methoctramine at 0.5 MUM significantly blocked the AJEA (1.0 MUg/ml)-induced contraction of DCLM, but ondansetron, GR113808 and methysergide at 1.0 MUM in combination did not change the AJEA induced DCLM contractions. Acetylethylcholine mustard (5.0 MUM) significantly diminished the AJEA-induced DCLM contractions, whereas p-chlorophenyl alanine (1.0 MUM) did not affect the stimulatory effects of AJEA on the DCLM contractions. CONCLUSION: The present results suggest that AJEA may specifically act on the DCLM among GI smooth muscles, and AJEA-induced DCLM contraction is likely mediated, at least, by activation of ChAT and acetylcholinergic muscarinic receptors. PMID- 20851586 TI - Hypoglycemic activities of A- and B-type procyanidin oligomer-rich extracts from different Cinnamon barks. AB - Procyanidin oligomers in Cinnamon are thought to be responsible for the biological activity in the treatment of diabetes mellitus (DM). To clarify types of procyanidin oligomers in different Cinnamon species and investigate their different effects, the present study investigated procyanidin oligomers in polyphenolic oligomer-rich extracts of three Cinnamon samples by LC-MS methods, and their hypoglycemic activities were detected in vivo and in vitro. The results showed that two of the three samples from Cinnamomum cassia were rich in B-type procyanidin oligomers, and the other sample was rich in A-type procyanidin oligomers. The Cinnamon extracts were administered at doses of 200 and 300 mg/kg body wt. in high-fat diet-fed and low-dose streptozotocin (STZ)-induced diabetic mice for 14 days. The results showed that blood glucose concentrations were significantly decreased in all Cinnamon extract groups compared with the control group (p<0.05). Administration of the Cinnamon extracts significantly increased the consumption of extracellular glucose in insulin-resistant HepG2 cells and normal HepG2 cells compared with the control group. These results suggest that both A- and B-type procyanidin oligomers in different Cinnamon species have hypoglycemic activities and may improve insulin sensitivity in type 2 DM. PMID- 20851588 TI - Inhibition of human drug metabolizing cytochrome P450 enzymes by plant isoquinoline alkaloids. AB - The human cytochrome P450 (CYP) enzymes play a major role in the metabolism of endobiotics and numerous xenobiotics including drugs. Therefore it is the standard procedure to test new drug candidates for interactions with CYP enzymes during the preclinical development phase. The purpose of this study was to determine in vitro CYP inhibition potencies of a set of isoquinoline alkaloids to gain insight into interactions of novel chemical structures with CYP enzymes. These alkaloids (n=36) consist of compounds isolated from the Papaveraceae family (n=20), synthetic analogs (n=15), and one commercial compound. Their inhibitory activity was determined towards all principal human drug metabolizing CYP enzymes: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4. All alkaloids were assayed in vitro in a 96-well plate format using pro-fluorescent probe substrates and recombinant human CYP enzymes. Many of these alkaloids inhibited the CYP3A4 form, with 30/36 alkaloids inhibiting CYP3A4 with at least moderate potency (IC50 < 10 MUM) and 15/36 inhibiting CYP3A4 potently (IC50 < 1 MUM). Among them corydine, parfumine and 8-methyl-2,3,10,11-tetraethoxyberbine were potent and selective inhibitors for CYP3A4. CYP2D6 was inhibited with at least moderate potency by 26/34 alkaloids. CYP2C19 was inhibited by 15/36 alkaloids at least moderate potently, whereas CYP1A2, CYP2B6, CYP2C8, and CYP2C9 were inhibited to a lesser degree. CYP2A6 was not significantly inhibited by any of the alkaloids. The results provide initial structure-activity information about the interaction of isoquinoline alkaloids with major human xenobiotic-metabolizing CYP enzymes, and illustrate potential novel structures as CYP form-selective inhibitors. PMID- 20851587 TI - Predicting cyclooxygenase inhibition by three-dimensional pharmacophoric profiling. Part II: Identification of enzyme inhibitors from Prasaplai, a Thai traditional medicine. AB - Prasaplai is a medicinal plant mixture that is used in Thailand to treat primary dysmenorrhea, which is characterized by painful uterine contractility caused by a significant increase of prostaglandin release. Cyclooxygenase (COX) represents a key enzyme in the formation of prostaglandins. Former studies revealed that extracts of Prasaplai inhibit COX-1 and COX-2. In this study, a comprehensive literature survey for known constituents of Prasaplai was performed. A multiconformational 3D database was created comprising 683 molecules. Virtual parallel screening using six validated pharmacophore models for COX inhibitors was performed resulting in a hit list of 166 compounds. 46 Prasaplai components with already determined COX activity were used for the external validation of this set of COX pharmacophore models. 57% of these components were classified correctly by the pharmacophore models. These findings confirm that the virtual approach provides a helpful tool (i) to unravel which molecular compounds might be responsible for the COX-inhibitory activity of Prasaplai and (ii) for the fast identification of novel COX inhibitors. PMID- 20851589 TI - Novel chemotherapeutic and renal protective effects for the green tea (EGCG): role of oxidative stress and inflammatory-cytokine signaling. AB - BACKGROUND: The green tea catechin, epigallocatechin-gallate (EGCG) is a superb nature's medicine candidate. We evaluated the chemotherapeutic/chemoenhancing effects of EGCG in mice bearing the solid Ehrlich ascites carcinoma (EAC) tumor, and jointly monitored levels of serum C-reactive protein (CRP), lipid peroxidation (as malondialdehyde: MDA) and leukocytosis (LC). Besides, we verified whether; and how then, EGCG would protect against a devastating CP induced nephrotoxicity in rats. In particular, renal proinflammatory (TNF-alpha) and oxidant stress signals have been investigated. RESULTS: (EAC)-bearing mice displayed elevated serum-LC (2-fold), -CRP (11-fold) and -MDA levels (2.7-fold). EGCG (20, 40 mg/kg) significantly shrank tumors (by 48% and 92%, respectively), and reduced LC, CRP and MDA levels. Such responses for CP were less prominent than those of EGCG (40 mg/kg). Further, EGCG (20 mg/kg) markedly augmented such functional and biochemical responses to CP. Correlation studies showed positive association between tumor size and each of CRP (r=0.97) and LC (r=0.83). Additionally; in rats, CP (10 mg/kg) caused a prominent nephrotoxicity that was manifested as deteriorated glomerular filtration rate (GFR, 2-5-fold rise in serum creatinine/urea levels) after 4 days, and unanimous animal fatalities after 7 days. Kidney homogenates from CP-treated rats showed significantly higher MDA- and TNF-alpha-, and -depleted GSH levels. Rats treated with EGCG (50 mg/kg, but not 25 mg/kg) devoid the nephrotoxic effects of CP and their consequences; while their homogenates had appreciably lower MDA and TNF-alpha, and higher GSH levels. Notable correlation was detected between serum creatinine level and each of MDA (r=0.85), TNF-alpha (r=0.85) and GSH (r=-0.81). CONCLUSION: This study shows remarkable cytotoxic/chemoenhancing effects for EGCG and introduces CRP as a predictor of both tumor's progression and responsiveness to chemotherapy. Further, this study is the first to reveal that EGCG can obliterate the lethal CP induced nephrotoxicity. Mechanistically, EGCG acts by suppressing leukocytosis, systemic inflammation, oxidative stress, and their sequelae. PMID- 20851590 TI - Neonatal tolerance under breastfeeding influence. AB - Diseases due to defect in tolerance induction such as allergy, celiac disease, or Type 1 Diabetes develop mostly in childhood indicating the necessity of early intervention for primary prevention. Epidemiological studies report that breastfeeding could protect from these diseases. However, data are controversial and the mechanisms unclear. Experimental data suggest that breastfeeding-induced protection might rely on tolerance induction as long as some criteria are fulfilled. Thus, the tolerogenic potential of breast milk would depend on maternal exposure to common environmental and dietary antigens and the efficiency of antigen transfer across mammary epithelium. Induction of tolerance upon breast milk-mediated antigen transfer will also depend on the presence of immunomodulatory factors in breast milk and of its impact on neonatal gut and immune system maturation. The better understanding of maternal influence on tolerance induction through breastfeeding should allow the development of new strategies to prevent immune-mediated diseases. PMID- 20851591 TI - Contrasting pressure-support ventilation and helium-oxygen during exercise in severe COPD. AB - Helium-oxygen mixtures and pressure-support ventilation have been used to unload the respiratory muscles and increase exercise tolerance in COPD. Considering the different characteristics of these techniques, we hypothesized that helium-oxygen would be more effective in reducing exercise-induced dynamic hyperinflation than pressure-support. We also hypothesized that patients would experience greater increases in respiratory rate and minute ventilation with helium-oxygen than with pressure-support. The hypotheses were tested in ten patients with severe COPD (FEV(1) = 28 +/- 3% predicted [mean +/- SE]) during constant-load cycling (80% maximal workrate) while breathing 30% oxygen-alone, helium-oxygen, and pressure support in randomized order. As hypothesized, helium-oxygen had greater impact on dynamic hyperinflation than did pressure-support (end-exercise; p = 0.03). For the most part of exercise, respiratory rate and minute ventilation were greater with helium-oxygen than with pressure-support (p <= 0.008). During the initial phases of exercise, helium-oxygen caused less rib-cage muscle recruitment than did pressure-support (p < 0.03), and after the start of exercise it caused greater reduction in inspiratory reserve volume (p <= 0.02). Despite these different responses, helium-oxygen and pressure-support caused similar increases in exercise duration (oxygen-alone: 6.9 +/- 0.8 min; helium-oxygen: 10.7 +/- 1.4 min; pressure-support: 11.2 +/- 1.6 min; p = 0.003) and similar decreases in inspiratory effort (esophageal pressure-time product), respiratory drive, pulmonary resistance, dyspnea and leg effort (p < 0.03). In conclusion, helium oxygen reduced exercise-induced dynamic hyperinflation by improving the relationship between hyperinflation and minute ventilation. In contrast, pressure support reduced hyperinflation solely as a result of lowering ventilation. Helium oxygen was more effective in reducing exercise-induced dynamic hyperinflation in severe COPD, and was associated with greater increases in respiratory rate and minute ventilation than pressure-support. PMID- 20851592 TI - Usefulness of TAO model to predict and manage the transformation in soil of carbon and nitrogen forms from West-Africa urban solid wastes. AB - The TAO model of Transformation of Added Organic materials (AOM) calibrated on AOMs and substrates of temperate areas was used to assess the transformations in soil of carbon and nitrogen forms of AOMs: raw materials, selected mixtures and composts from Ouagadougou urban wastes. AOMs were studied in terms of chemical and biochemical contents and for their C and N mineralization during incubations in a typical Ferric Lixisol of the sub-urban agriculture of Ouagadougou. The TAO model was used to predict the transformations of C (very labile, resistant and stable organic C) and N (very labile, resistant and stable organic N, produced and immobilized inorganic N) forms driven by AOM biochemical data. Without any change in calibration formulae, TAO predicted accurately the C transformations and inorganic N production of most of the tested AOMs, with a tendency to slightly overestimate C mineralization of previously well-composted materials and re-mineralization of immobilized N. Complementary adjustments using more complete data from laboratory experiments are suggested, but the model agrees with other data collected in the field and appears as a promising tool to optimise the management of urban wastes in the tropical area as well as for agro industrial organic fertilizers of the temperate zone. This application suggests ways to improve the management of urban wastes aiming to optimize agricultural yields, system sustainability and C sequestration in soil. PMID- 20851593 TI - Evanescent wave fluorescence biosensor combined with DNA bio-barcode assay for platelet genotyping. AB - An evanescent wave fluorescence biosensor was combined with a DNA bio-barcode assay to resolve problems met in detection of poor biologic samples. Human platelet antigen (HPA) genotyping was used as a demonstrator. Our bio-barcode assay was based on magnetic carboxylatex particles and non-magnetic carboxylatex particles, both functionalized with oligonucleotides. It was assessed for detecting 84mer synthetic oligonucleotides as targets. The assay allows to specifically detect single nucleotide polymorphism with a detection limit of 2 pM of target nucleic acids. The fluorescence detection is achieved in 150 s. PMID- 20851594 TI - Hydrophilic modification of polystyrene with hydrophobin for time-resolved immunofluorometric assay. AB - Herein we reported that a hydrophobin film was used as a solid support on the polystyrene surface for immobilizing antibodies in the time-resolved immunofluorometric assay (TR-IFMA). Quartz crystal microbalance with dissipative monitoring (QCM-D), X-ray photoelectron spectroscopy (XPS) and water contact angle (WCA) measurements, as well as atomic force microscope (AFM) were used to characterize the hydrophilic modification of polystyrene surface with Class I hydrophobin isolated from Grifola frondosa (HGFI). The performance of HGFI modified polystyrene was evaluated by TR-IFMA of carcinoembryonic antigen (CEA). QCM-D revealed that HGFI formed an intact monolayer on the polystyrene at pH 5. XPS and WCA measurements showed that self-assembling HGFI could render polystyrene surface hydrophilic for three months. AFM indicated that an end-on antibody monolayer was adsorbed on the HGFI film rather than multilayers on the polystyrene in a side-on orientation. Furthermore, a linear calibration curve (from 5 to 600 ng/mL) of CEA showed HGFI-modified polystyrene had higher detection sensitivity than unmodified ones in TR-IFMA. This present method for modifying polystyrene is simple without severe chemical treatment and may have wide applicability to functionalize other supports for immobilizing biomolecules. PMID- 20851595 TI - Frequency control of cell cycle oscillators. AB - The cell cycle oscillator, based on a core negative feedback loop and modified extensively by positive feedback, cycles with a frequency that is regulated by environmental and developmental programs to encompass a wide range of cell cycle times. We discuss how positive feedback allows frequency tuning, how size and morphogenetic checkpoints regulate oscillator frequency, and how extrinsic oscillators such as the circadian clock gate cell cycle frequency. The master cell cycle regulatory oscillator in turn controls the frequency of peripheral oscillators controlling essential events. A recently proposed phase-locking model accounts for this coupling. PMID- 20851596 TI - Prognostic factors in women treated for ovarian yolk sac tumour: a retrospective analysis of 84 cases. AB - BACKGROUND: Ovarian yolk sac tumour (OYST) is a very rare malignancy arising in young women. Our study aimed to evaluate long-term outcomes and to identify prognostic parameters likely to help make appropriate risk-based decisions about therapy in this disease. METHODS: This retrospective study is based on prospectively recorded OYST cases at the Institut Gustave-Roussy. A univariate analysis using the logrank test evaluated possible associations between survival and patient or disease covariates. The multivariate analysis was performed using the Cox proportional hazard regression method. RESULTS: Between 1976 and 2006, 84 patients were registered. Since 1991, most of the patients have undergone fertility-sparing surgery. With a median follow-up of 71 months, the overall 5 year and event-free survival rates are 84% and 79%, respectively. In the multivariate model only the absence of ascites and a favourable serum AFP decline rate were significantly associated with better overall survival. CONCLUSIONS: Patients with a poor prognosis factor such as an unfavourable serum AFP decline may be considered for aggressive treatment whereas those with good prognostic factors could be given less courses of chemotherapy. PMID- 20851597 TI - Psychometric validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ EN24). AB - AIM: A validation study was conducted to evaluate the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-EN24). This module was designed to assess disease and treatment specific aspects of the quality of life (QoL) of patients with endometrial cancer. METHODS: Two hundred and sixty-eight women with endometrial cancer were recruited in different phases of treatment: after pelvic surgery (Group 1); during adjuvant chemotherapy and/or radiotherapy (Group 2); after completion of treatment (Group 3). Patients completed the EORTC QLQ-C30, the endometrial cancer module and a short debriefing questionnaire. RESULTS: Multi-trait scaling analyses confirmed the hypothesised scale structure of the QLQ-EN24. Internal consistency reliability was good with Cronbach's alpha coefficients ranging from 0.74 to 0.86 (lymphoedema 0.80, urological symptoms 0.75, gastrointestinal symptoms 0.74, body image problems 0.86 and sexual/vaginal problems 0.86). Convergent and discriminant validity did not show any scaling errors for the subscales. The QLQ-EN24 module discriminated well between clinically different groups of patients. All items exhibited a high completion rate with less than 2% missing values except for the sexuality items (19%). CONCLUSION: The validation study supports the reliability, the convergent and divergent validity of the EORTC QLQ-EN24. This newly developed QLQ-EN24 module is a useful instrument for the assessment of the QoL in patients treated for endometrial cancer in clinical trials. PMID- 20851598 TI - High surface area porous carbons prepared from hydrochars by phosphoric acid activation. AB - In the present work, a new route for preparation of high-performance porous carbons under mild conditions was reported. The high surface area (2700 m2/g) and large pore volume (1.98 cm3/g) porous carbons were prepared from hydrochars by conventional phosphoric acid activation method. The hydrochars described here can be obtained from sulfuric acid hydrolysis of rice husk via dehydration, polymerization and carbonization. A specific capacitance of 130 F g(-1) was achieved by using the porous carbon, indicating that the porous carbon prepared by this route has good electrochemical performance. Furthermore, the localized graphitic nature of the porous carbon was proved by X-ray diffraction pattern. PMID- 20851599 TI - Design, synthesis and structure-activity relationship of novel quinoxalin-2 carboxamides as 5-HT3 receptor antagonists for the management of depression. AB - A novel series of quinoxalin-2-carboxamides were designed based on the ligand based approach, employing a three-point pharmacophore model; it consists of an aromatic residue and a linking carbonyl group and a basic nitrogen. The target new chemical entities were synthesized from the key intermediate, quinoxalin-2 carboxylic acid, by coupling it with various amines in the presence of 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 1 hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by spectral data. The target new chemical entities were evaluated for their 5-HT(3) receptor antagonisms in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methyl-5-HT, which was expressed in the form of pA(2) value. All the synthesized compounds showed antagonism towards 5-HT(3) receptor; based on this result, a structure-activity relationship was derived, which reveals that the aromatic residue in 5-HT(3) receptor antagonists may have hydrophobic interaction with 5-HT(3) receptor. Regardless of their antagonistic potentials, all the synthesized molecules were screened for their anti-depressant potentials by using forced swim test in mice model; interestingly none of the tested compounds affect the locomotion of mice in the tested dose levels. Compounds with significant pA(2) values exhibited good anti-depressant like activity as compared to the vehicle-treated group. PMID- 20851600 TI - Synthesis and antifungal activity of benzofuran-5-ols. AB - Benzofuran-5-ol derivatives were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species, and Cryptococcus neoformans. Among them tested, many benzofuran-5-ols showed good antifungal activity. The results suggest that benzofuran-5-ols would be promising antifungal agents. PMID- 20851601 TI - Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro 6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity. AB - We describe the design, synthesis, and structure-activity relationships of triazolobenzodiazepinone CCK1 receptor agonists. Analogs in this series demonstrate potent agonist activity as measured by in vitro and in vivo assays for CCK1 agonism. Our efforts resulted in the identification of compound 4a which significantly reduced food intake with minimal systemic exposure in rodents. PMID- 20851602 TI - Heterobifunctional PEGs: efficient synthetic strategies and useful conjugation methodologies. AB - The desire to develop nanoparticle and liposomal formulations as drug carriers capitalizing on active transport mechanisms requires constant development of novel heterobifunctional polyethyleneglycol (PEG) constructs. Such constructs should be capable of sequentially reacting with extracellular binding ligands and structural components of nanoparticles and/or liposomes. This paper describes two syntheses of heterobifunctional PEGs useful for tethering small molecule ligands to synthetic lysine-bearing polymers. PMID- 20851603 TI - Breastfeeding and prognostic markers in breast cancer. AB - BACKGROUND: Several studies suggest that total breastfeeding time reduces breast cancer risk. The underlying mechanisms are unclear. Whether breastfeeding also affects the prognosis is not yet investigated. A number of tumour characteristics, i.e. histological type of cancer, grade, tumour size, Nottingham prognostic index, vascular invasion and DNA-ploidy, have been demonstrated to be of prognostic value. METHODS: We have searched for a possible link between these prognostic markers and breastfeeding time, age at first child and number of children. 250 women treated for breast cancer have answered a questionnaire. RESULTS: No significant interactions were found possibly with one exception, LVI vs. age at first child. We found, significant correlations between lobular cancer, and thereby also DNA-ploidy, and age at first childbirth. CONCLUSIONS: We have found that lobular cancer (and thereby also diploid tumours) are connected, independently, to age at first childbirth and possibly also to number of children but no other correlations between reproductive data, breastfeeding included, and prognostic markers used in this study were found. PMID- 20851604 TI - Minimally invasive compared to open microdiscectomy for lumbar disc herniation. AB - Before the advent of minimally invasive surgery for microdiscectomy, an open microdiscectomy had been the standard surgical intervention. Minimally invasive techniques have recently become more popular based upon the premise that smaller, less traumatic incisions should afford better recovery times and outcomes. From 2005 to 2008 we analyzed the outcomes of 25 patients who received an open microdiscectomy compared to 20 patients who received a minimally invasive microdiscectomy by the senior author (DC) in the lumbar region for disc herniation. A retrospective analysis was performed by carefully reviewing medical records for perioperative and immediate postoperative outcomes, and clinical follow-up was obtained either in the clinic or by telephone. There were no statistically significant differences between the minimally invasive and open groups in terms of operative time, length of stay, neurological outcome, complication rate, or change in pain score (pain improvement). PMID- 20851605 TI - Temporo-mesial extraventricular neurocytoma and cortical dysplasia in focal temporal lobe epilepsy. AB - We describe a 17-year-old boy with a left extraventricular temporo-mesial neurocytoma associated with cortical dysplasia causing focal pharmacoresistant temporal lobe epilepsy. He presented with a long history of medically refractory, temporal complex partial seizures. MRI showed a left temporo-mesial lesion suspect to be a low-grade tumor. Based on the pre-operative non-invasive neurophysiological studies, the patient underwent a left tailored temporal antero mesial resection. Histopathological examination showed an extraventricular neurocytoma associated with architectural dysplasia (Type 1a) of the temporal pole. The patient was seizure-free at 2 years follow-up. Extraventricular neurocytomas must be considered in the differential diagnosis of the plethora of low-grade tumors associated with focal epilepsy that typically involve the temporal lobe, and are frequently associated with focal cortical dysplasia. PMID- 20851606 TI - Intracranial dural arteriovenous fistula presenting as parkinsonism and cognitive dysfunction. AB - There are few syndromes of parkinsonism with dementia which can be treated. We report two patients with dural arteriovenous fistula (DAVF) who presented with rapidly progressive parkinsonism and cognitive dysfunction. DAVF are rare lesions resulting from abnormal connections between meningeal arteries and dural sinuses. Angiography in both patients revealed DAVF associated with multiple occlusive changes in the dural venous sinus. This report emphasizes the need for a high level of clinical suspicion to diagnose DAVF and consider it as one of the causes of rapidly progressive cognitive dysfunction in patients with parkinsonism. PMID- 20851607 TI - Which dietary and lifestyle behaviours may be important in the aetiology (and prevention) of stroke? AB - Prevention of stroke requires optimal control of causal risk factors. However, only three-quarters of all strokes can be attributable to known causal risk factors. We aimed to identify novel risk factors for acute stroke in 48 patients with acute (<1 week) stroke admitted to Royal Perth Hospital Stroke Unit and 47 controls matched for age and sex from the northeast Perth metropolitan area. Patients and controls were interviewed, and had physical measurements and blood taken. Multiple odds ratios (OR) for risk factors, with 95% confidence intervals (CI), were calculated by unconditional multiple logistic regression. Mediterranean diet (OR: 0.1; 95% CI, 0.02-0.4), increased waist-to-hip ratio (OR 4.0, 95% CI, 1.5-11), physical activity during leisure time (OR 0.2; 95% CI, 0.1 0.9), periodontal disease (OR 6.4; 95% CI, 1.5-27), and acute febrile illness (OR 14; 95% CI, 1.5-127) were associated significantly and independently with ischaemic stroke. These preliminary data suggest that certain dietary and lifestyle behaviours may play as important a role in the aetiology (and prevention) of stroke as other conventional causal risk factors for stroke. However, these associations need confirmation from larger randomised trials given the small sample size of the current study. PMID- 20851608 TI - Management of recurrent Cushing's disease. AB - The management of patients with Cushing's disease remains a major challenge. The remission rate for initial transsphenoidal surgery is reported as 69-94% while the recurrence rate following initially successful transsphenoidal surgery is 2 27%. Treatment options for Cushing's disease after failed initial therapy or recurrence include repeat transsphenoidal surgery, radiotherapy, medical therapy and bilateral adrenalectomy. Management options following unsuccessful initial surgery or recurrence are presented and discussed. PMID- 20851609 TI - Surgical outcome of the endoscopic endonasal approach for non-functioning giant pituitary adenoma. AB - Pituitary adenomas with extensive suprasellar extension are a therapeutic challenge. The efficacy and safety of the endoscopic endonasal approach for non functioning giant pituitary adenoma was evaluated retrospectively. A total of 43 consecutive patients with pituitary adenomas with a suprasellar extension of >20mm underwent tumor resection with a purely endoscopic endonasal approach, and their surgical outcomes were analyzed. At surgery, irrespective of the size and shape of the adenoma, every effort was made to perform intracapsular resection under direct visual control using an angled-lens endoscope. Gross total removal was achieved in 20 out of 43 patients. Postoperatively, 42 patients showed varying improvement of both visual field defects and impaired visual acuity. In two patients who presented with gait disturbance and cognitive dysfunction due to obstructive hydrocephalus, these symptoms were completely resolved. There were no serious operative complications. The results indicate that intracapsular resection via the endoscopic approach can be a safe and effective treatment for giant pituitary adenomas. PMID- 20851610 TI - Renal vein occlusion as a complication of anterior spinal fusion. AB - We report a 41-year-old female with inferior renal vein compression following anterior lumbar interbody fixation and fusion. Traumatic vascular injuries are not uncommon with anterior approaches to the spine; however, compressive vascular injuries are not well described. This report serves to raise the awareness that such injuries may occur due to distortion of normal anatomy. PMID- 20851611 TI - Surgical treatment for brain metastases: Prognostic factors and survival in 309 patients with regard to patient age. AB - Brain metastases are the most common intracranial tumors. Overall, the only accepted prognostic factors are patient age and performance status. However, several other factors are considered before surgery. We performed a retrospective analysis of 309 patients who underwent surgical resection of newly diagnosed brain metastases between 1994 and 2004. Univariate survival analysis revealed age, performance status, extracranial metastases, complete resection, radiotherapy and re-craniotomy as prognostic indicators. Multivariate analysis determined that patient age, performance status, extracranial metastases, radiotherapy and re-craniotomy are independent factors of prolonged survival. We statistically estimated the age threshold separating patients with favorable outcomes from those with unfavorable prognoses. Using the Kaplan-Meier analysis this threshold can be set at 65 years. Multivariate analysis of patients >65 years revealed the presence of co-morbidities, the number of brain metastases, post-operative performance status and radiotherapy as independent prognostic factors. PMID- 20851612 TI - Spinal-cord compression related to pseudohypoparathyroidism. AB - We report a 24-year-old male with pseudohypoparathyroidism and a 6-month history of sensory disturbance in both legs which was associated with difficulty in walking. His physical signs included a short stature, a thick neck, short fourth metacarpals and metatarsals, a spastic paraparesis and sphincteric disturbance. His serum electrolytes included low serum calcium and high serum phosphorus levels. CT reconstruction showed compression of the spinal cord in association with ossified ligamentum flavum at the C2-7 and T9-10 levels. These findings were confirmed by MRI scans. PMID- 20851613 TI - Synthesis, NMR characterization and divergent biological actions of 2'-hydroxy ceramide/dihydroceramide stereoisomers in MCF7 cells. AB - A straightforward method for the simultaneous preparation of (2S,3R,2'R)- and (2S,3R,2'S)-2'-hydroxy-ceramides (2'-OHCer) from (2S,3R)-sphingosine acetonide precursors and racemic mixtures of 2-hydroxy fatty acids (2-OHFAs) is described. The obtained 2'-OH-C4-, -C6-, -C12-, -C16-Cer and 2'-OH-C6-dhCer pairs of diastereoisomers were characterized thoroughly by TLC, MS, NMR, and optical rotation. Dynamic and multidimensional NMR studies provided evidence that polar interfaces of 2'-OHCers are extended and more rigid than observed for the corresponding non-hydroxylated analogs. Stereospecific profile on growth suppression of MCF7 cells was observed for (2'R)- and (2'S)-2'-OH-C6-Cers and their dihydro analogs. The (2'R)-isomers were more active than the (2'S)-isomers (IC(50) ~3 MUM/8 MUM and IC(50) ~8 MUM/12 MUM, respectively), surpassing activity of the ordinary C6-Cer (IC(50) ~12 MUM) and C6-dhCer (IC(50) ~38 MUM). Neither isomer of 2'-OH-C6-Cers and 2'-OH-C6-dhCers was metabolized to their cellular long chain 2'-OH-homologs. Surprisingly, the most active (2'R)-isomers did not influence the levels of the cellular Cers nor dhCers. Contrary to this, the (2'S) isomers generated cellular Cers and dhCers efficiently. In comparison, the ordinary C6-Cer and C6-dhCer also significantly increased the levels of their cellular long chain homologs. These peculiar anabolic responses and SAR data suggest that (2'R)-2'-OHCers/dhCers may interact with some distinct cellular regulatory targets in a specific and more effective manner than their non hydroxylated analogs. Thus, stereoisomers of 2'-OHCers can be potentially utilized as novel molecular tools to study lipid-protein interactions, cell signaling phenomena and to understand the role of hydroxylated sphingolipids in cancer biology, pathogenesis and therapy. PMID- 20851614 TI - Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11beta-hydroxysteroid dehydrogenase 2 inhibitors. AB - Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11beta-hydroxysteroid dehydrogenase (11beta HSD) type 1 and type 2. Whereas inhibition of 11beta-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11beta-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11beta-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11beta-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11beta-HSD1 and 11beta-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11beta-HSD2. The most potent and selective compound is active against human 11beta-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11beta-HSD1. PMID- 20851615 TI - A convenient synthesis and molecular modeling study of novel purine and pyrimidine derivatives as CDK2/cyclin A3 inhibitors. AB - A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC(50) values of 14+/-9 and 13+/-9 MUM, respectively. Additionally, compound 15a showed the highest potency (IC(50)=10+/-6 MUM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores. PMID- 20851616 TI - Detection of erythrocytes in patient with elliptocytosis complicating ITP using atomic force microscopy. AB - The pathological changes of erythrocytes were detected at the nanometer scale, which was important for revealing the onset of diseases, early diagnosis, and effective therapies. Diseases may disturb the morphology and function of erythrocytes at molecular scale. There were dramatic surface deformations in topography of erythrocytes from a patient with elliptocytosis complicating idiopathic thrombocytopenic purpura (ITP). The overall shape and surface membrane of the healthy, pre- and post-therapeutic erythrocytes have been studied by high resolution atomic force microscopy imaging. The results showed that we can detect healthy and pathological erythrocytes by the morphologic parameters of the length, width, ratio of length to width, peak, valley, valley-to-peak, surface fluctuation, and standard deviations of the erythrocytes. Therefore, the morphologic information of erythrocytes is very important indictor for diagnosing the healthy and disease, as well as evaluating therapeutic effect. PMID- 20851617 TI - Endothelial integrity of radial artery grafts harvested by minimally invasive surgery--immunohistochemical studies of CD31 and endothelial nitric oxide synthase expressions: a randomized controlled trial. AB - OBJECTIVE: To compare the endothelial integrity of radial artery grafts harvested by minimally invasive surgery and arteries harvested conventionally for coronary artery bypass surgery (CABG) in 200 participants, who were assigned to interventions by using random allocation. METHODS: An immunohistochemical procedure with monoclonal antibodies was employed to estimate CD31 antigen and endothelial nitric oxide synthase (eNOS) expressions - markers defining endothelial integrity. RESULTS: The CD31 immunostaining revealed that the endothelial cell integrity of the minimally invasive harvested arteries was preserved in 76.1+/-7.4% of the circumference of luminal endothelium, which was similar to results obtained in conventionally harvested grafts (77.2+/-9.8%; not significant). On the other hand, eNOS immunostaining indicated that the endothelial integrity of the minimally invasive harvested grafts was preserved in 75.4+/-10.5% while in conventionally harvested grafts it was reduced to 42.4+/ 14.5% of the total luminal endothelium circumference (P<0.05). CONCLUSIONS: The endothelial integrity of radial artery grafts harvested by minimally invasive surgery is better preserved than in the grafts obtained by the conventional manner. This could play an important role in improving graft patency and might represent a preliminary condition of stable functioning in coronary arterial bypasses. PMID- 20851619 TI - pH dependence of the composition and stability of Mn(III)-bicarbonate complexes and its implication for redox interaction of Mn(II) with photosystemII. AB - Dependence of the electrochemical potential of oxidation of Mn(II) to Mn(III) on logarithm of bicarbonate concentration at different pH is considered. Slope values of the dependence are equal to -60, -120 and -180mV/log C(HCO)3 at pH6.20, 6.50 and 8.35 respectively, that corresponds to binding of one, two and three HCO(3)(-) ligands to Mn(III). Extrapolation of these dependences to log C(HCO)3=0 shows that at pH6.20 complex [Mn(III)HCO(3)](2+) with E(0)=0.99V and K(st)=6.5*10(8)M(-1), at pH6.50 complex [Mn(III)(HCO(3))(2)](+) with E(0)=0.77V and K(st)=3.5*10(12)M(-2), and at pH8.35 complex [Mn(III)(HCO(3))(3)](0) with E(0)=0.67V and K(st)=1.73*10(14)M(-3) are formed. From the dependence of oxidation potential of Mn(II) to Mn(III) on pH at initial concentration of NaHCO(3) equal to 28mM the limits of pH stability of the complexes were determined: pH5.0-6.35 for [Mn(III)HCO(3)](2+), pH6.35-7.0 for [Mn(III)(HCO(3))(2)](+) and pH7.0-8.35 for [Mn(III)(HCO(3))(3)](0). The obtained data may be important for understanding the mechanism of stimulating action of HCO(3)(-) ions on photoinduced electron transfer from Mn(II) to reaction centres of photosystem2 or to reaction centres of anoxygenic photosynthetic bacteria. PMID- 20851618 TI - Minimized extracorporeal circulation system in coronary artery bypass surgery: a 10-year single-center experience with 2243 patients. AB - OBJECTIVE: Coronary artery bypass grafting (CABG) is the gold standard for the surgical therapy of multivessel coronary artery disease. To reduce the side effects, associated with standard extracorporeal circulation (ECC), a concept of minimal extracorporeal circulation (MECC) was devised in our center. We report on our 10-year experience with the MECC for coronary revascularization. METHODS: From January 1998 to August 2009, 2243 patients underwent CABG with MECC in our center. In a retrospective observational study, we analyzed indication, preoperative patient co-morbidity, postoperative clinical course, and perioperative outcome of all patients operated on with MECC. Furthermore, the risk factors for mortality in the MECC group were assessed. RESULTS: Patients showed a mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) of 4.5+/-0.1%. The mean age of the patients was 66.8+/-9.1 years. The overall 30-day mortality after CABG with MECC was 2.3%, ranging from 1.1% for elective to 13.0% for emergent patients and was significantly better than standard ECC. Only 15.3% (n=344) of patients with MECC required intra-operative blood transfusion. Postoperative catecholamine support, red blood cell transfusion, need for hemodialysis, release of creatinine kinase, incidence of stroke, and postoperative delirium were low after MECC revascularization. Ejection fraction below 30% (odds ratio (OR): 5.1), emergent operation (OR: 9.4), and high-dose catecholamine therapy (OR: 2.6) were associated predictors for mortality. CONCLUSION: MECC until now is an established concept and has become an alternative for ECC in routine CABG in our center. The use of the MECC system is associated with low mortality and conversion rate. Excellent survival rates and low transfusion requirements in the perioperative course were achieved. PMID- 20851620 TI - Effects of sex on mechanical embolectomy outcome. AB - Given that women have demonstrated a greater margin of benefit than men from treatment with thrombolytics in certain acute stroke trials, the current study explored whether this sex effect extends to mechanical embolectomy and can be explained by revascularization rate. The study included the 305 patients enrolled in the Mechanical Embolus Removal in Cerebral Ischemia (MERCI) and Multi MERCI trials. Demographic, risk factor, and procedural characteristics were evaluated in women and men. Odds ratios for outcomes by sex were compared in patients with revascularization and those without revascularization, defined as a Thrombolysis in Myocardial Infarction score of 2-3 at the end of the procedure. Outcomes included a modified Rankin Scale (mRS) score of 0-2 and mortality at 90 days, as well as the presence of symptomatic intracranial hemorrhage (sICH). Patient and procedural characteristics did not differ between women and men except for mean age (women, 70.1 years; men, 64.8 years; P = .003), hypertension (women, 78.0%; men, 65.5%; P = .021), and number of vertebrobasilar occlusions (women, 8/159 [5.0%]; men, 20/146 [13.7%]; P = .01). Revascularization was significantly associated with favorable outcomes in both women and men (P < .0001), and rates of favorable outcome, mortality, and sICH did not differ between women and men when the vessel was revascularized. Likewise, mechanical embolectomy with the Merci Retriever was not associated with different outcomes in women and men when the vessel was revascularized. Our data suggest that the sex differences seen in thrombolytic trials might be due to factors other than immediate postprocedural large vessel opening. PMID- 20851622 TI - Accuracy of the new ICD-9-CM code for "drip-and-ship" thrombolytic treatment in patients with ischemic stroke. AB - A new International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code, V45.88, was approved by the Centers for Medicare and Medicaid Services (CMS) on October 1, 2008. This code identifies patients in whom intravenous (IV) recombinant tissue plasminogen activator (rt PA) is initiated in one hospital's emergency department, followed by transfer within 24 hours to a comprehensive stroke center, a paradigm commonly referred to as "drip-and-ship." This study assessed the use and accuracy of the new V45.88 code for identifying ischemic stroke patients who meet the criteria for drip-and ship at 2 advanced certified primary stroke centers. Consecutive patients over a 12-month period were identified by primary ICD-9-CM diagnosis codes related to ischemic stroke. The accuracy of V45.88 code utilization using administrative data provided by Health Information Management Services was assessed through a comparison with data collected in prospective stroke registries maintained at each hospital by a trained abstractor. Out of a total of 428 patients discharged from both hospitals with a diagnosis of ischemic stroke, 37 patients were given ICD-9-CM code V45.88. The internally validated data from the prospective stroke database demonstrated that a total of 40 patients met the criteria for drip-and ship. A concurrent comparison found that 92% (sensitivity) of the patients treated with drip-and-ship were coded with V45.88. None of the non-drip-and-ship stroke cases received the V45.88 code (100% specificity). The new ICD-9-CM code for drip-and-ship appears to have high specificity and sensitivity, allowing effective data collection by the CMS. PMID- 20851621 TI - Periprocedural cilostazol treatment and restenosis after carotid artery stenting: the Retrospective Study of In-Stent Restenosis after Carotid Artery Stenting (ReSISteR-CAS). AB - Restenosis after carotid artery stenting (CAS) is a critical issue. Cilostazol can reduce restenosis after interventions in coronary or femoropopliteal arteries. We investigated whether periprocedural cilostazol treatment was related to the incidence of in-stent restenosis (ISR) or target vessel revascularization (TVR) after CAS. The study group comprised 553 of 580 patients who underwent CAS between April 2003 and August 2006 and were followed for 30 months after the procedure. ISR was defined as stenosis of at least 50% detected on angiography or ultrasonography. TVR was defined as revascularization of the treated carotid artery. During CAS, 207 patients (37.4%) were treated with cilostazol. Over 30 months, ISR occurred in 23 patients (4.2%), TVR occurred in 16 patients (2.9%), and either ISR or TVR occurred in 25 patients (4.5%). The incidence of ISR or TVR was significantly lower in the cilostazol-treated group than in the untreated group (1.4% vs 6.4%; log-rank P = .006). In a multivariate analysis, cilostazol treatment (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.08-0.95; P = .041) and stent diameter (HR, 0.73/1-mm increase; 95% CI, 0.54-0.99; P = .044) were independent factors for the occurrence of ISR or TVR. The incidence of a composite of events, including thromboembolism, hemorrhage, death, and TVR, tended to be lower in the cilostazol-treated group than in the untreated group (15.0% vs 19.9%; log-rank P = .17). Periprocedural cilostazol treatment was associated with lower rates of ISR and retreatment after CAS. A prospective randomized controlled trial is needed to clarify the effect of cilostazol on ISR after CAS. PMID- 20851623 TI - An aneurysm rupturing into a middle cranial fossa arachnoid cyst presenting as an intracystic hemorrhage. AB - We report a case of an aneurysm rupturing into an arachnoid cyst presenting as a confined intracystic hemorrhage. A 37-year-old man with a history of sporadic headaches for several years complained of a headache of several days' duration. Brain computed tomography and magnetic resonance imaging revealed a cystic lesion in the left side of the middle cranial fossa that included a 3-cm-diameter hematoma in the Sylvian fissure without extracystic hemorrhage. Left carotid artery angiography showed an internal carotid artery-posterior communicating artery (IC-PC) aneurysm and an anterior choroidal artery aneurysm. The cyst wall was excised, and the aneurysms were clipped. The bleeding point was the spot at which the IC-PC aneurysm entered the arachnoid cyst. Right oculomotor nerve palsy developed after surgery, but resolved after 3 months. To the best of our knowledge, this is the only fourth report to date in the literature of a confined aneurysm rupturing into an arachnoid cyst. PMID- 20851624 TI - Metabolic syndrome is a risk factor for acute cerebral infarction in a younger elderly Kurashiki population. AB - This study evaluated the association between metabolic syndrome as defined by Japanese criteria and its diagnostic components (visceral obesity, dyslipidemia, hypertension, and impaired glucose tolerance) and acute cerebral infarction in younger elderly (age 50-74 years) and the older elderly (age >=75 years) persons living in the Japanese city of Kurashiki. We studied 73 patients aged >=50 years (44 of them aged >=75 years) admitted to our hospital with acute cerebral infarction and 323 control subjects aged >=50 years (52 aged >=75 years) who underwent medical checkup of the brain in our hospital. Types of cerebral infarction included atherothrombotic (27 patients), lacunar (24 patients), cardioembolic (19 patients), and other types (3 patients). Metabolic syndrome was defined based on the Japanese criteria. In multiple logistic regression analysis, among the 29 younger elderly patients aged 50-74 years, dyslipidemia, hypertension, and impaired glucose tolerance as diagnostic components of metabolic syndrome, and metabolic syndrome itself were significantly related to acute cerebral infarction (adjusted odds ratio [OR], 5.664, 4.869, 3.390, and 3.214, respectively). Among the 44 older elderly patients aged >=75 years, dyslipidemia was significantly related to acute cerebral infarction (OR, 4.193). However, metabolic syndrome was not a significant risk factor for acute cerebral infarction, even when patients with cardioembolic and other types of infarction were excluded. These data suggest that metabolic syndrome as defined by Japanese criteria is an independent risk factor for acute cerebral infarction in the younger elderly, but not the older elderly, Kurashiki population. PMID- 20851625 TI - An unusual case of elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with multiple cerebrovascular risk factors. AB - Here we report a female patient with elderly-onset cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). At age 71, she developed gait disturbance, followed by memory disturbance 1 year later. She had been treated for hypertension and diabetes mellitus for 19 years. There apparently was low penetrance of disease. Magnetic resonance imaging (MRI) findings showed typical features of CADASIL, and the R607C mutation was detected in exon 11 in NOTCH3. This case strongly indicates that CADASIL should be considered when typical findings are observed on MRI even in cases of elderly onset with multiple cerebrovascular risk factors. PMID- 20851626 TI - Brachial artery approach for endovascular treatment of posterior circulation intracranial vascular disease: technique and application in 5 cases. AB - Although the transbrachial artery approach has been well described as an alternative for percutaneous coronary interventions and diagnostic cerebral arteriography, little has been reported regarding the use of this technique for therapeutic neuroendovascular procedures. We highlight the technical applications of this technique during 5 procedures. Three women (age 68, 69, and 83 years) and 1 man (age 79 years) were treated using brachial artery access. Two of the women with complex posterior circulation aneurysms were treated with stent-assisted coil embolization. The third woman presented with a symptomatic occlusion of the basilar artery and underwent intra-arterial thrombolysis and angioplasty, followed at a later date by a second intra-arterial thrombolysis procedure. The male patient presented with recurrent, intractable posterior circulation ischemic events and underwent balloon angioplasty and stenting of a high-grade stenosis of the right vertebral artery. All patients had failed treatment via a transfemoral route and demonstrated significant thoracoaortic and/or iliofemoral tortuosity. Appropriate intracranial vascular access was achieved in all patients, and there were no intraprocedural complications. We conclude that a transbrachial approach may be successfully used for a variety of therapeutic neuroendovascular interventions when a transfemoral route is not available. PMID- 20851627 TI - Significance of magnetic resonance angiography-diffusion weighted imaging mismatch in hyperacute cerebral infarction. AB - Therapeutic results with respect to lesion size were analyzed and compared in patients with hyperacute cerebral infarction with and without major artery lesions on magnetic resonance angiography (MRA) and in those who did and did not receive intravenous (IV) tissue plasminogen activator (t-PA). Of the patients with cerebral infarction who visited the hospital within 3 hours of onset between April 2007 and September 2009, 127 patients with cerebral infarction in the anterior circulation region in whom head magnetic resonance imaging (diffusion weighted imaging [DWI]) or MRA was performed (81 men and 46 women; mean age, 71 +/- 11 years) were enrolled. Major artery lesions (+) were defined as internal carotid artery occlusion and middle cerebral artery (M1/M2 segment) occlusion and >=50% stenosis. Based on the presence or absence of major artery lesions and the size of DWI lesions, the subjects were divided into 3 groups: MRA-DWI mismatch (+) group [major artery lesion (+) and DWI-ASPECTS >=6], MRA-DWI mismatch (-) group [major artery lesion (+) and DWI-ASPECTS <6], and major artery lesion (-) group. IV t-PA was given to 21 of the 64 patients in the MRA-DWI mismatch (+) group, to 1 of the 24 patients in the MRA-DWI mismatch (-) group, and to 9 of the 39 patients in the major artery lesion (-) group. In the MRA-DWI mismatch (+) group (n = 64), the median National Institutes of Health Stroke Scale (NIHSS) score on admission was higher in t-PA-treated patients than in t-PA-untreated patients (15 vs 11). The modified Rankin scale (mRS) score at day 90 after onset was more favorable in t-PA-treated patients (0-2 in 10 patients [48%] and 3-6 in 11 patients [52%]) than in t-PA-untreated patients (0-2 in 12 patients [28%] and 3-6 in 31 patients [72%]). After adjusting for admission NIHSS score, there was a significant difference in outcome (mRS score) between t-PA-treated patients (0-2 in 10 patients [48%] and 3-6 in 11 patients [52%]) and t-PA-untreated patients (0 2 in 3 patients [9%] and 3-6 in 29 patients [91%]) (P = .002). In the MRA-DWI mismatch (-) group (n = 24), mRS scores at day 90 after onset were poor in both t PA-treated (3-6 in 1 patient [100%]) and t-PA-untreated patients (0-2 in 1 patient [4%] and 3-6 in 22 patients [96%]). In the major artery lesion (-) group (n = 39), mRS scores at day 90 after onset were favorable in both t-PA-treated (0 2 in 9 patients [100%]) and t-PA-untreated patients (0-2 in 28 patients [93%] and 3-6 in 2 patients [7%]). When comparing major artery lesions in the MRA-DWI mismatch (+) group, outcomes were more favorable in patients with M1/M2 segment lesions who received t-PA than in those who did not receive t-PA. In the MRA-DWI mismatch (+) group, the prognosis was significantly better for t-PA-treated patients than for t-PA-untreated patients, suggesting that IV t-PA is indicated in patients with MRA-DWI mismatch. PMID- 20851628 TI - Predictors of percutaneous endoscopic gastrostomy tube placement in patients with severe dysphagia from an acute-subacute hemispheric infarction. AB - This study investigated the influence of age, National Institutes of Health Stroke Scale (NIHSS) score, time from stroke onset, infarct location and volume in predicting placement of a percutaneous endoscopic gastrostomy (PEG) tube in patients with severe dysphagia from an acute-subacute hemispheric infarction. We performed a retrospective analysis of a hospital-based patient cohort to analyze the effect of the aforementioned variables on the decision of whether or not to place a PEG tube. Consecutive patients were identified using International Classification of Diseases, Ninth Revision (ICD-9) codes for acute ischemic stroke, Current Procedural Terminology (CPT)-4 codes for a formal swallowing evaluation by a speech pathologist, and procedure codes for PEG placement over a 5-year period from existing medical records at our institution. Only patients with severe dysphagia were enrolled. A total of 77 patients met inclusion criteria; 20 of them underwent PEG placement. The relationship between age (dichotomized; < and >=75 years), time from stroke onset (days), NIHSS score, acute infarct lesion volume (dichotomized; < and >=100 cc), and infarct location (ie, insula, anterior insula, periventricular white matter, inferior frontal gyrus, motor cortex, or bilateral hemispheres) with PEG tube placement were analyzed using logistic regression analysis. In univariate analysis, NIHSS score (P = .005), lesion volume (P = .022), and presence of bihemispheric infarction (P = .005) were found to be the main predictors of interest. After multivariate adjustment, only NIHSS score (odds ratio [OR], 1.15; 90% confidence interval [CI], 1.02-1.29; P = .04) and presence of bihemispheric infarcts (OR, 4.67; 90% CI, 1.58-13.75; P = .018) remained significant. Our data indicates that baseline NIHSS score and the presence of bihemispheric infarcts predict PEG placement during hospitalization from an acute-subacute hemispheric infarction in patients with severe dysphagia. These results require further validation in future studies. PMID- 20851629 TI - Assessment of long-term outcomes for the STRokE DOC telemedicine trial. AB - Telemedicine can provide stroke evaluations in locations with limited available expertise. The reliability of telestroke has been established. Decision making efficacy has been shown in the National Institutes of Health's STRokE DOC trial. No prospective trial has assessed long-term telestroke outcomes, however. In an institutional review board-approved trial (NCT00936455), we contacted patients originally enrolled in the STRokE DOC trial. A telephone script was used to verify consent. Patients were asked standardized questions regarding disposition, modified Rankin Scale (mRS) score, mortality, and recurrent stroke for 2 retrospective time points (6 and 12 months postevent) and one current time point. Blind was maintained. Primary outcome measures of mortality and percent mRS score of 0-1 [%mRS(0-1)] at 6 months are reported. Wilcoxon's rank-sum test was used for continuous variables, and Fisher's exact was used for categorical variables. Of the original 222 participants, 75 patients or surrogates could be contacted. Mean time from enrollment was 3.96 +/- 1.0 years (range, 2.33-5.45 years). Mean National Institutes of Health Stroke Scale (NIHSS) score was 8 +/- 7 (5 +/- 8 for telephone; 12 +/- 8 for telemedicine; P = .002). The rate of intravenous recombinant tissue plasminogen activator (rt-PA) use was 31%. Six-month %mRS(0-1) outcome was not different, at 42%. Mortality after imputation to the entire study sample also was not different, at 18%. There was no difference in the rate of recurrent stroke (P = .61). Some 85% of patients were home at 6 months. This study reports a good 6-month outcome for stroke patients evaluated by telemedicine or telephone. This design is limited by the time since original enrollment and resultant inability to contact participants. Although these findings can add to the limited data on telemedicine outcomes, a prospective trial is needed. PMID- 20851630 TI - Is intravenous thrombolysis useful in carotid artery dissection with tandem occlusion? AB - Cervical artery dissection no longer represents an obstacle for performing intravenous (IV) thrombolysis. This treatment can be used safely for patients with cervical artery dissection, but tandem lesions may be related to poor outcome. We report a patient with an occlusive internal carotid artery (ICA) dissection and middle cerebral artery (MCA) embolus, with collateral circulation through the ophthalmic artery and communicating anterior artery. He underwent IV thrombolysis, with subsequent MCA recanalization and good outcome. In cases of tandem lesions in cervical artery dissection with MCA occlusion, IV thrombolysis is indicated despite the presence of ICA occlusion. Due to the presence of collateral circulation and the composition of the embolus, recanalization of MCA might be possible. PMID- 20851631 TI - Long-term results of medical and surgical therapy for Japanese patients with moderate carotid stenosis. AB - To clarify the efficacy of medication versus carotid endarterectomy (CEA), we investigated cardiovascular events and outcomes in Japanese patients with moderate carotid stenosis. We consecutively registered patients with significant carotid stenosis (50%-79%) measured by digital subtraction angiography (DSA) over 10 years and compared the incidences of stroke, myocardial infarction, and death between treatment groups (surgical group vs medical group). Of 406 registered patients, 163 (108 treated surgically and 55 treated medically) with moderate carotid stenosis were analyzed. Complete follow-up data (mean, 4.2 years) were available for 105 patients in the surgical group (97.2%) and 54 patients in the medical group (98.2%). Surgical treatment was associated with lower incidences of any stroke, myocardial infarction, and death compared with medication. Although the incidence rates differed significantly between CEA and medication in the 66 symptomatic patients, there were no significant differences in the 93 asymptomatic patients. The results of this single-center study in Japanese patients suggest that CEA is an acceptable treatment for patients with symptomatic moderate carotid stenosis, but that CEA for asymptomatic moderate carotid stenosis seems to be less effective in Japanese patients. PMID- 20851632 TI - Chronic kidney disease and carotid atherosclerosis. AB - Chronic kidney disease is an independent risk factor for cardiovascular disease. The association between carotid intima-media thickness (IMT) and chronic kidney disease is controversial, however. In addition, whether renal dysfunction promotes vascular calcification in patients with chronic kidney disease is not clear. The study subjects were 1003 patients aged >=50 years who underwent carotid ultrasonography in our hospital. Kidney function was evaluated based on the estimated glomerular filtration rate (eGFR) and the presence of proteinuria. Patients with end-stage renal failure were excluded. We measured the mean max-IMT (which indicates mean maximal wall thickness) at 12 carotid segments, and examined the characteristics of the maximal plaques by carotid ultrasonography. We evaluated the association between mean max-IMT and eGFR, and also evaluated the clinical factors associated with mean max-IMT and calcification of the maximal plaques. We found that eGFR was significantly correlated with mean max IMT. Reduced eGFR, proteinuria, age, male sex, cardiovascular disease, hypertension, diabetes, and smoking were independently associated with mean max IMT in multiple regression analysis. Kidney function was not associated with calcified plaque. Kidney dysfunction was associated with carotid atherosclerosis in patients with mild or moderate chronic kidney disease. PMID- 20851633 TI - Proteomic biomarker discovery in cerebrospinal fluid for cerebral vasospasm following subarachnoid hemorrhage. AB - Currently, there are no established biomarkers for diagnosing preclinical vasospasm or monitoring its progression. Two areas of extensive biomarker research are neuroimaging and biochemical markers in body fluids, such as cerebrospinal fluid (CSF). We performed a review of studies conducted over the past 2 decades summarizing the science to date and the evolution of CSF biomarkers in subarachnoid hemorrhage (SAH). A Medline search performed using the search terms "subarachnoid hemorrhage marker AND cerebrospinal fluid," limited to the period January 1, 1990 to June 1, 2009, returned 62 references. Abstracts that did not deal primarily with SAH and potential markers in the CSF of humans were excluded, resulting in 27 abstracts. Only articles providing sufficient information for a substantiated analysis were selected. In addition, articles identified in reference lists of individual articles were selected if considered appropriate. Evidence was classified as class I-IV and recommendations were classified as category A-C according to European Federation of Neurological Societies guidelines. We evaluated CSF markers in SAH patients and divided them into 3 categories: A, markers with auspicious value; B, candidate markers; and C, noncandidate markers. Category A markers included tumor necrosis factor (TNF) alpha, soluble tumor necrosis factor receptor I (sTNFR-I), and interleukin (IL)-1 receptor antagonist (IL-1ra), as well as the neurofilament proteins NFL and NfH. Category B markers included apolipoprotein E (ApoE), F2-isoprostane (F2-IsoP), NOx, and the indicators for thrombin activity membrane-bound tissue factor (mTF) and thrombin-antithrombin III complex (TAT) for neurologic outcome prediction, as well as E-selectin, lactate, alpha-II spectrin breakdown products (SBDPs), asymmetric dimethyl-L-arginine (ADMA), and monocyte chemoattractant protein-1 (MCP-1) for vasospasm prognostication. Category C markers included S100B, platelet-derived growth factor (PDGF), YKL-40, chitotriosidase, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL 8. Cytokines and their receptors, as well as neuronal intracellular proteins, seem to be potential markers for outcome determination in patients after SAH. PMID- 20851634 TI - Common carotid artery dissection: a case report and review of the literature. AB - Common carotid artery dissection (CCAD) is a rare and poorly characterized cause of ischemic stroke. We describe a case of multiple cerebral infarcts in a patient with CCAD initially detected by carotid duplex ultrasonography, and review the literature on CCAD. A Medline search from 1960 to the present for cases of CCAD yielded 46 cases. We extracted demographic data, anatomical location, symptoms, neurosonography, neuroradiology, pathological findings, treatment, and outcomes. The mean age of the patients was 48.8 +/- 15.8 years (range, 19-89 years). With our patient, our search found 20 cases of spontaneous CCAD, 11 cases of traumatic CCAD, 4 cases of iatrogenic CCAD, and 12 cases of CCAD associated with aortic arch dissection. The most common presenting neurologic symptoms of CCAD were hemiparesis, decreased consciousness, headache/neck pain, aphasia, and monocular field deficit. The most frequently reported neurosonographic findings included a double lumen, mural thrombus, intraluminal hyperechoic/isoechoic lesion, and intimal flap. Most cases of CCAD were subsequently confirmed with conventional angiography, computed tomography angiography, or magnetic resonance angiography. Treatment differed based on etiology; anticoagulation was used most commonly for spontaneous CCAD, and surgical repair was most often done for traumatic and aortic dissection-associated CCAD. Prognosis was generally good; the majority of patients achieved complete clinical recovery, but 3 died. Our findings indicate that carotid Doppler is a widely accessible, rapid, and noninvasive technique for diagnosing CCAD. Our case and literature review further characterizes the diverse etiologies, clinical course, and radiographic features of CCAD. PMID- 20851635 TI - Isolated hypersomnia due to bilateral thalamic infarcts. AB - We describe a unique patient who developed hypersomnia as the sole presenting symptom of bilateral thalamic infarcts. PMID- 20851636 TI - The revised digital transcutaneous PCO2/SpO2 ear sensor is a reliable noninvasive monitoring tool in patients after cardiac surgery. AB - OBJECTIVE: The aim of this study was to validate the revised SenTec V-Sign 2 sensor (SenTec AG, Therwil, Switzerland) for combined noninvasive continuous assessment of pulse rate, pulse oximetry (SpO(2)), and transcutaneous carbon dioxide tension (PtcCO(2)) in adults after cardiac surgery. DESIGN: A prospective clinical study. SETTING: A single-center university hospital. PARTICIPANTS: Twenty adult patients aged 36 to 84 years after cardiac surgery. INTERVENTIONS: SpO(2) and PtcCO(2) values of three V-Sign 2 sensors (SenTec AG) attached at the earlobe, forehead, and cheek and SpO(2) values of the Nellcor Durasensor (Model DS-100A; Nellcor Puritan Bennett Inc, Pleasanton, CA) were compared with simultaneous measurements of blood gases and end-expiratory carbon dioxide. MEASUREMENTS AND MAIN RESULTS: Measurements were performed during periods of hyper-, normo-, and hypocapnia and then at 30-minute intervals up to 5 hours. Bland-Altman analysis and simple regression analysis were used. RESULTS: The detection failures for PtcCO(2) were 0.3% to 1.3%, for SpO(2) 10% to 25%, and for pulse rate 5% to 10%. The V-Sign 2 earlobe sensor provided the best results. The mean bias and limits of agreement for PtcCO(2ear) and PaCO(2) were 1.1 and 3.4/+5.5 mmHg. The drift of PtcCO(2) was negligible at all locations. The mean bias and limits of agreement of V-Sign SpO(2ear) and SaO(2), as well as V-Sign pulse rate and the electrocardiogram, were -1.7% and -6.8/+3.9% and 1.2 beats/min and -3.3/+5.8 beats/min. End-expiratory carbon dioxide showed a weak correlation with PaCO(2) (r(2) = 0.47). CONCLUSIONS: Transcutaneous capnometry using the revised V-Sign 2 sensor at the earlobe is a reliable monitoring tool during the recovery period of patients after cardiac surgery. This approach has the potential to reduce the number of arterial blood gas samples. PMID- 20851637 TI - Cardiomyocyte survivin protein expression is associated with cell size and DNA content in the failing human heart and is reversibly regulated after ventricular unloading. AB - BACKGROUND: Mechanical support in congestive heart failure (CHF) by a left ventricular assist device (LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways. Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory effect of p16(INK4a) on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored. METHODS: In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the protein expression of survivin, cyclin D1, cdk4, p16(INK4a), and proliferating cell nuclear antigen (PCNA) was immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content. RESULTS: The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4, p16(INK4a), and PCNA was significantly increased in CHF compared with controls and significantly decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and 43.5% to 25.2%, respectively; p < 0.05). All investigated parameters, in particular survivin and cyclin D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content (r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p < 0.05). CONCLUSIONS: These data indicate that survivin is reversibly regulated by ventricular unloading and might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remodelling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes. PMID- 20851638 TI - Association between gastrointestinal symptoms and health-related quality of life after heart transplantation. AB - BACKGROUND: Heart transplantation (HTx) ameliorates the self-perceived health related quality of life (HRQoL) of patients with terminal heart disease; gastrointestinal (GI) symptoms, due to obligatory immunosuppression, may contribute to impaired HRQoL post-HTx. METHODS: In this cross-sectional, exploratory study we aimed to investigate association between GI symptoms and HRQoL. The study consisted of 167 patients who had undergone HTx between 1985 and 2006 in Finland. Short-Form 36 (SF-36) Quality of Life and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires were sent to the patients at the end of 2006 for capturing data on the HRQoL of HTx recipients. RESULTS: Higher or equal SF-36 scores describing the HRQoL dimensions compared with the Finnish age- and gender-matched reference population were as follows: physical functioning, 60.5%; role-physical, 67.5%; bodily pain, 62.6%; general health, 64.0%; vitality, 68.1%; social functioning, 68.1%; role-emotional, 70.0%; and mental health, 70.4%. The prevalence of troublesome GI symptoms (GSRS score >1) per GSRS dimension was 53.9% for diarrhea, 91.0% for indigestion, 60.6% for constipation, 73.4% for abdominal pain, 46.4% for reflux and 95.8% for any GI symptom. Diabetes contributed to the presence of diarrhea (odds ratio [OR]: 3.00; 95% confidence interval [CI]: 1.12 to 8.00), use of prednisolone to indigestion (OR: 3.21; 95% CI: 1.05 to 9.79) and increased age to constipation (OR: 1.04; 95% CI: 1.02 to 1.07). CONCLUSIONS: HRQoL after HTx is relatively good and comparable to the age- and gender-matched reference population. HRQoL is vulnerable to side-effects caused by the obligatory post-HTx immunosuppressive regimen, where GI symptoms play a major but clearly an underestimated role. PMID- 20851639 TI - Evaluation of the lung allocation score in highly urgent and urgent lung transplant candidates in Eurotransplant. AB - BACKGROUND: The purpose of the study was to investigate the impact of the lung allocation score (LAS) on mortality among highly urgent (HU) and urgent (U) lung transplant (LTx) candidates in Eurotransplant (ET) and to identify useful additional parameters (LASplus). METHODS: All adult LTx candidates for whom a first request for HU or U status was made in 2008 in ET were included (N = 317). Patients were followed until LTx, death on the waiting list (WL), delisting, or closure date (i.e., January 10, 2010). The relationship between the LAS/LASplus and waiting list, post-transplant, and overall mortality was assessed with a multivariate regression model. The LAS and LASplus were decomposed into their basic waitlist and post-transplant components. RESULTS: Waiting list mortality rate was 22% and 1-year post-transplant mortality rate was 34%. The waitlist component of the LASplus was significantly associated with waiting list mortality (hazard ratio [HR] 1.91, p = 0.021), whereas the LAS was not (p = 0.063). The post-transplant components of both scores were significantly associated with 1 year post-transplant mortality (LAS: HR 2.69, p = 0.005; LASplus: HR 2.55, p = 0.004). Both scores strongly predicted overall mortality (LAS: HR 1.65, p = 0.008; LASplus: HR 1.72, p = 0.005). CONCLUSION: LAS accurately predicts overall mortality in critically ill transplant candidates and should therefore be considered as the basis for a new lung allocation policy in ET. An adjustment of the original LAS may be indicated to accurately predict waiting list mortality. PMID- 20851640 TI - Endothelin-1 antagonism and nitric oxide augmentation prevents cyclosporine induced vasomotor impairment. AB - BACKGROUND: We previously demonstrated that cyclosporine (CyA) impairs endothelial function as a result of alterations in nitric oxide (NO) and endothelin-1 (ET-1) regulation. Bosentan (BOS), an ET-1 antagonist, and tetrahydrobiopterin (BH4), an eNOS cofactor, may reduce endothelial dysfunction by improving ET-1/NO homeostasis. METHODS: Lewis rats received intraperitoneal injections of CyA with BOS or with BOS+BH4 daily for 2 weeks. Control (Con) animals received saline injections. Thoracic aortic segments were assessed for endothelial-dependent (E(dep)) and -independent (E(ind)) relaxation (E(max%)) after exposure to acetylcholine and sodium nitroprusside. Vessel sensitivity to ET-1-induced vasospasm was evaluated. RESULTS: CyA use resulted in impaired E(dep) vasorelaxation when compared with Con, whereas BOS and BH4 treatment preserved E(dep) vasorelaxation. CyA significantly altered E(ind) vasorelaxation, whereas BOS and BH4 therapy attenuated CyA-induced effects. Compared with Con, CyA and BH4 exposure demonstrated increased sensitivity to ET-1 vasospasm. BOS therapy abrogated the CyA and BH4-induced sensitivity to vasospasm. CyA treatment resulted in higher 8-isoprostane levels compared with Con. CyA-mediated vascular dysfunction is characterized by impaired NO and ET-1 homeostasis. CONCLUSIONS: Our study suggests potential therapeutic strategies to prevent endothelial dysfunction as combined therapy with ET-1 antagonism and NO augmentation completely abrogated CyA-induced vascular injury. PMID- 20851641 TI - Sudden death late post-cardiac transplantation as a consequence of cardiac allograft vasculitis. PMID- 20851642 TI - Web-based curriculum improves residents' knowledge of health care business. AB - BACKGROUND: Curricular options for teaching and evaluating surgery residents' outcomes in systems-based practice are limited. A Web-based curriculum, MDContent, developed collaboratively by experts in business and surgery, provides learning experiences in the business of health care. The purpose of this study is to describe surgery residents' experience and learning outcomes associated with the curriculum. STUDY DESIGN: Twenty-eight PGY3 to 6 general and plastic surgery residents were enrolled in the Web-based curriculum. Twenty-two residents (79%) completed the pretest, 11 modules, the post-test, and the course evaluation by the end of 1 year. The pretest and the post-test were 30-item multiple-choice exams based on a blueprint of the curricular objectives. Descriptive statistics were calculated on course evaluation and module completion data. Paired t-tests were used to compare pre- and post-test performance. Content analysis was performed on course evaluation written responses. RESULTS: Residents' performance on the multiple choice exam improved significantly (p = 0.0001) from the pre-test (mean 59%, SD 12.1) to the post-test (mean 78%, SD 9.4), with an average gain of 19 percentage points. Participants rated their Web-based learning experience as very positive, with a majority of residents agreeing that the content was well organized, relevant, and an excellent learning experience around content not taught elsewhere in medical school or residency. CONCLUSIONS: Participation in a Web-based curriculum on health care business improves surgery residents' knowledge about health care business concepts and principles. Residents with varying levels of interest in health care business provide positive ratings about their learning experience and indications that lessons learned would be applied in their clinical practice. MDContent is a feasible and effective method for teaching and assessing systems-based practice concepts. PMID- 20851643 TI - Surgeon distress as calibrated by hours worked and nights on call. AB - BACKGROUND: The relationships of working hours and nights on call per week with various parameters of distress among practicing surgeons have not been previously examined in detail. STUDY DESIGN: More than 7,900 members of the American College of Surgeons responded to an anonymous, cross-sectional survey. The survey included self-assessment of their practice setting, a validated depression screening tool, and standardized assessments of burnout and quality of life. RESULTS: There was a clear gradient between hours and burnout, with the prevalence of burnout ranging from 30% for surgeons working <60 hours/week, 44% for 60 to 80 hours/week, and 50% for those working >80 hours/week (p < 0.001). When correlated with number of nights on call, burnout exhibited a threshold effect at >=2 nights on call/week (<=1 nights on call/week, 30%; >=2 nights on call/week, 44% to 46%; p < 0.0001). Screening positive for depression rate also correlated strongly with hours and nights on call (both p < 0.0001). Those who worked >80 hours/week reported a higher rate of medical errors compared with those who worked <60 hours/week (10.7% versus 6.9%; p < 0.001), and were twice as likely to attribute the error to burnout (20.1% versus 8.9%; p = 0.001). Not surprisingly, work and home conflicts were higher among surgeons who worked longer hours or had >=2 nights on call. A significantly higher proportion of surgeons who worked >80 hours/week or had >2 nights on call/week would not become a surgeon again (p < 0.0001). CONCLUSIONS: Number of hours worked and nights on call per week appear to have a substantial impact on surgeons, both professionally and personally. These factors are strongly related to burnout, depression, career satisfaction, and work and home conflicts. PMID- 20851644 TI - Hepatitis B genotype C correlated with poor surgical outcomes for hepatocellular carcinoma. AB - BACKGROUND: Genotype B and C are the predominant hepatitis B virus (HBV) strains in Taiwan. We aimed to investigate the role of genotype in HBV-related hepatocellular carcinoma (HCC) after resection. STUDY DESIGN: From October 2005 to November 2008, 64 patients who underwent liver resection for HBV-related HCC were enrolled. HBV genotypes were determined by molecular method. Patient characteristics, biochemical, tumor, and viral factors were evaluated for their prognostic significance. RESULTS: During a mean follow-up of 26.6 +/- 13.2 months, patients infected with genotype C had higher HBV viral load (p = 0.007) and worse disease-free survival rate (p = 0.028) than patients with genotype B. By univariate analysis, genotype C, alanine transaminase >50 U/L, tumor size >=5 cm, and microvascular invasion were associated with tumor recurrence. Further multivariate analysis demonstrated genotype C remained a significant risk factor (p = 0.034). CONCLUSIONS: Genotype C is a strong risk factor for HCC recurrence after resection. More intensive monitoring for recurrence should be considered in patients with genotype C. PMID- 20851645 TI - The learning curve of laparoendoscopic single-site (LESS) cholecystectomy: definable, short, and safe. AB - BACKGROUND: The applications of laparoendoscopic single-site (LESS) surgery, including cholecystectomy, are occurring quickly, although little is generally known about issues associated with the learning curve of this new technique including operative time, conversion rates, and safety. STUDY DESIGN: We prospectively followed all patients undergoing LESS cholecystectomy, and compared operations undertaken at our institutions in cohorts of 25 patients with respect to operative times, conversion rates, and complications. RESULTS: One-hundred fifty patients of mean age 46 years underwent LESS cholecystectomy. No significant differences in operative times were demonstrable between any of the 25-patient cohorts operated on at our institution. A significant reduction in operative times (p < 0.001) after completion of 75 LESS procedures was, however, identified with the experience of a single surgeon. No significant reduction in the number of procedures requiring an additional trocar(s) or conversion to open operations was observed after completion of 25 LESS cholecystectomies. Complication rates were low, and not significantly different between any 25 patient cohorts. CONCLUSIONS: For surgeons proficient with multi-incision laparoscopic cholecystectomy, the learning curve for LESS cholecystectomy begins near proficiency. Operative complications and conversions were infrequent and unchanged across successive 25-patient cohorts, and were similar to those reported for multi-incision laparoscopic cholecystectomy after the learning curve. PMID- 20851646 TI - Centralisation: putting patients first. PMID- 20851649 TI - Augmented mechanical response of muscular thin-fiber receptors in aged rats recorded in vitro. AB - Musculoskeletal pain deteriorates quality of life by disrupting daily activities and is a considerable economic burden to many countries because of the large number of patients. Little is known about the peripheral neural mechanisms of muscular nociception in the aged, although structural and functional changes in the muscle are apparent as a function of age. The aim of the present study was to investigate the activities of aged muscle nociceptors systematically to mechanical, chemical and thermal stimuli, and to compare with the data from young animals. Activities of single C-fibers were recorded from in vitro preparations of extensor digitorum longus muscle-nerve excised from hind legs of aged rats (125-133 weeks). Mechanical threshold measured by a ramp mechanical stimulus in the aged muscle (median; 45.2 mN (IQR; 38.1-59.1 mN), n=29) was significantly lower than that in the younger muscle (median; 65.4 mN (IQR; 46.6-122.0 mN), n=33, p<0.01, Mann-Whitney U-test) reported in our previous study (Taguchi et al., 2005). In addition, the magnitude of the mechanical response during the first 5s of the 10s stimulus was significantly greater in the aged muscle (11.0 spikes (IQR; 6.5-20.5 spikes)) than in the young (7.0 spikes (IQR; 4.0-11.5 spikes), p<0.05, Mann-Whitney U-test). In contrast, the numbers of discharges induced by chemical (pH 5.5, ATP and bradykinin) and thermal (cold and heat) stimuli were not different with the different ages. These results showed an augmented mechanical response in muscle C-afferents in the aged rats. PMID- 20851651 TI - Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients. AB - We report a case of dengue hemorrhagic fever (DHF) complicated by acute myocarditis and review the literature. A 65-year-old woman experienced DHF due to dengue virus serotype 3, complicated with acute myocarditis and acute pulmonary edema. Clinically this masqueraded as acute myocardial infarction, with an electrocardiographically depressed ST segment in precordial leads and elevated serum cardiac-specific troponin I level. Under supportive management, the patient recovered 3 days later. A total of 18 pertinent articles involving 339 dengue affected patients with cardiac complications were found by PubMed search. Clinical manifestations of cardiac complications varied considerably, from self limiting tachy-brady arrhythmia to severe myocardial damage, leading to hypotension and pulmonary edema. Although rare, a fatal outcome was reported in some cases of dengue with cardiac complications. To avoid otherwise preventable morbidity and mortality, physicians should have a high index of suspicion for cardiac complications in patients with dengue illness and should manage this accordingly. PMID- 20851650 TI - Solid-state NMR paramagnetic relaxation enhancement immersion depth studies in phospholipid bilayers. AB - A new approach for determining the membrane immersion depth of a spin-labeled probe has been developed using paramagnetic relaxation enhancement (PRE) in solid state NMR spectroscopy. A DOXYL spin label was placed at different sites of 1 palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine (PSPC) phospholipid bilayers as paramagnetic moieties and the resulting enhancements of the longitudinal relaxation (T1) times of 31P nuclei on the surface of the bilayers were measured by a standard inversion recovery pulse sequence. The 31P NMR spin-lattice relaxation times decrease steadily as the DOXYL spin label moves closer to the surface as well as the concentration of the spin-labeled lipids increase. The enhanced relaxation vs. the position and concentration of spin-labels indicate that PRE induced by the DOXYL spin label are significant to determine longer distances over the whole range of the membrane depths. When these data were combined with estimated correlation times tau(c), the r-6-weighted, time-averaged distances between the spin-labels and the 31P nuclei on the membrane surface were estimated. The application of using this solid-state NMR PRE approach coupled with site-directed spin labeling (SDSL) may be a powerful method for measuring membrane protein immersion depth. PMID- 20851648 TI - Histamine in the regulation of wakefulness. AB - The histaminergic system is exclusively localized within the posterior hypothalamus with projection to almost all the major regions of the central nervous system. Strong and consistent evidence exist to suggest that histamine, acting via H1 and/or H3 receptor has a pivotal role in the regulation of sleep wakefulness. Administration of histamine or H1 receptor agonists induces wakefulness, whereas administration of H1 receptor antagonists promotes sleep. The H3 receptor functions as an auto-receptor and regulates the synthesis and release of histamine. Activation of H3 receptor reduces histamine release and promotes sleep. Conversely, blockade of H3 receptor promotes wakefulness. Histamine release in the hypothalamus and other target regions is highest during wakefulness. The histaminergic neurons display maximal activity during the state of high vigilance, and cease their activity during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The cerebrospinal levels of histamine are reduced in diseased states where hypersomnolence is a major symptom. The histamine deficient L-histidine decarboxylase knockout (HDC KO) mice display sleep fragmentation and increased REM sleep during the light period along with profound wakefulness deficit at dark onset, and in novel environment. Similar results have been obtained when histamine neurons are lesioned. These studies strongly implicate the histaminergic neurons of the TMN to play a critical role in the maintenance of high vigilance state during wakefulness. PMID- 20851652 TI - Diabetes and inflammation: fundamental aspects and clinical implications. AB - AIM: The aim of this paper is to provide the fundamental background of the inflammation theory associated with type 2 diabetes, to discuss the clinical consequences of low-grade inflammation, particularly in terms of cardiovascular risk, and to infer some clinical therapeutic strategies deriving from drugs that already exist or are in development. METHODS: This non-exhaustive work is the result of a Pubmed((r)) research, based on requests including the following keywords: diabetes, inflammation, innate immunity, obesity, reticulum endoplasmic stress, cytokines, endothelial dysfunction. RESULTS: Obesity and type 2 diabetes are linked with a low-grade inflammation state that reflects the activation of innate immunity where metabolic, environmental and genetic factors are implicated. The role of endoplasmic reticulum stress and unfold protein response is underlined. Inflammation markers are predictive for the risk to develop diabetes, and are associated with an increased cardiovascular risk. While lifestyle modifications are followed by an improvement in inflammation markers, treatments inferred from the inflammation theory are of great interest, although quite moderate effects on glycaemic control have been observed with some of them. CONCLUSION: The development of molecules targeting different inflammatory mechanisms could lead in diabetic patients to improvement of both glycaemia and cardiovascular prognosis. PMID- 20851653 TI - Osteochondral plate angiogenesis: a new treatment target in osteoarthritis. AB - Healthy adult joint cartilage contains neither blood vessels nor nerves. Osteoarthritic cartilage, in contrast, may be invaded by blood vessels from the subchondral bone. The mechanisms underlying cartilage angiogenesis in osteoarthritis are unclear but may involve hypertrophic chondrocyte differentiation. Active research is under way to identify the factors involved in cartilage angiogenesis. Here, we discuss the pathophysiological mechanisms of osteoarthritic cartilage angiogenesis based on evidence from a systematic literature review of articles retrieved via PubMed and ISI Web of Knowledge. Our conclusions suggest new research perspectives and treatment options. PMID- 20851654 TI - Relationship between nailfold capillary abnormalities and vestibular dysfunction in systemic sclerosis. AB - OBJECTIVE: To investigate the vestibular dysfunction in a cohort of patients with systemic sclerosis (SSc) and to correlate the findings with disease parameters and microvascular involvement. METHODS: Vestibular affection was assessed in 30 female SSc patients and 29 age-matched healthy females subjects by using the computerized dynamic platform posturography (CDP). Assessment of microvasculature was done by nailfold videocapillaroscopy (NVC). The main clinical correlates of disease, such as renal function, skin, articular and lung involvement, were evaluated by clinical and instrumental investigations. RESULTS: Subtle vestibular dysfunction was detected in 33% of SSc patients. They exhibited significant decrease in their vestibular ratio values compared to controls (P=0.01). There was a statistical significant association of vestibular affection with both Rodnan's skin score and vascular severity score. Moreover a significant association was found between vestibular dysfunction and NVC patterns. On the other hand, no correlation was observed between vestibular impairment with age, disease duration, disease subsets, autoantibodies and the other clinical disease parameters. CONCLUSION: Our results showed an evidence of vestibular impairment in patients with SSc. Vestibular dysfunction positively correlates with vascular severity score as assessed by NVC. PMID- 20851655 TI - Rheumatoid anemia. AB - Rheumatoid anemia is a typical example of anemia of chronic disease. It differs from other forms of anemia, such as iron deficiency anemia or iatrogenic anemia. Rheumatoid anemia is normochromic, normocytic or, less often, microcytic, aregenerative, and accompanied with thrombocytosis. Serum transferrin levels are normal or low, transferrin saturation is decreased, serum ferritin levels are normal or high, the soluble transferrin receptor (sTfR) is not increased (a distinguishing feature with iron deficiency anemia), and the sTfR/log ferritin ratio is lower than 1. This review discusses the prevalence and impact of rheumatoid anemia based on a review of the literature. Iron metabolism, absorption, diffusion, storage, and use by the bone marrow are described using published data on transferrin, ferritin, and hepcidin. Hepcidin is now recognized as a key factor in rheumatoid anemia, in conjunction with the cytokine interleukin-6 (IL-6). Hepcidin is a hormone that lowers serum iron levels and regulates iron transport across membranes, preventing iron from exiting the enterocytes, macrophages, and hepatocytes. In addition, hepcidin inhibits intestinal iron absorption and iron release from macrophages and hepatocytes. The action of hepcidin is mediated by binding to the iron exporter ferroportin. Hepcidin expression in the liver is dependent on the protein hemojuvelin. Inflammation leads to increased hepcidin production via IL-6, whereas iron deficiency and factors associated with increased erythropoiesis (hypoxia, bleeding, hemolysis, dyserythropoiesis) suppress the production of hepcidin. Data from oncology studies and the effects of recombinant human IL-6 support a causal link between IL-6 production and the development of anemia in patients with chronic disease. IL-6 diminishes the proportion of nucleated erythroid cells in the bone marrow and lowers the serum iron level, and these abnormalities can be corrected by administering an IL-6 antagonist. IL-6 stimulates hepcidin gene transcription, most notably in the hepatocytes. Studies involving human hepatocyte exposure to a panel of cytokines showed that IL-6, but not TNFalpha or IL-1, induced the production of hepcidin mRNA. Recent data on hepcidin level variations in patients with rheumatoid arthritis are reviewed. Rheumatoid anemia is best corrected by ensuring optimal control of systemic disease activity. The role for iron supplementation (per os or intravenously) and erythropoietin in the treatment of rheumatoid anemia is discussed. Given the cascade of interactions linking IL-6, hepcidin, and anemia, IL-6 antagonists hold considerable promise for the management of rheumatoid anemia. PMID- 20851656 TI - Dorsal prevertebral lesions in Wegener granulomatosis: report on four cases. AB - Retroperitoneal fibrosis has been reported in several patients with Wegener granulomatosis (WG), but only three isolated cases of dorsal prevertebral lesions, closely resembling fibrosing mediastinitis, have been published so far. We describe four new WG patients (two men, two women), 49-59 years old at diagnosis, with dorsal prevertebral lesions, mainly right-sided, and with adjacent pleural thickening in two. These lesions were detected on computed tomography scans at diagnosis in two patients, and occurred later in the two others. Only one of them had mild back pain. Two patients' lesions were biopsied, revealing granulomatous inflammation. In one patient, the lesion regressed under WG treatment. Lesion size did not change in the remainings. Intralesional calcifications appeared in two. None of the patients had local bone erosion, vascular or neurological complications. These prevertebral lesions might represent a dorsal form of retroperitoneal fibrosis in WG, but usually with a more benign presentation and course. WG should be included in the differential diagnosis of fibrosing mediastinitis (with tuberculosis, neoplastic diseases, sarcoidosis, histiocytosis and inflammatory pseudotumor), which may have a similar radiological appearance. PMID- 20851657 TI - Serious herpes zoster in rheumatoid arthritis under anti-interleukin-6 receptor antibody. PMID- 20851658 TI - Bone changes in spouses having shared lifestyle for 40 years. AB - OBJECTIVES: Spousal concordance has already been observed for several other diseases but it has not yet been studied for bone loss. Our aim was to determine whether or not bone changes were the same within spouses who have shared the same environment for many decades. METHODS: We conducted a prospective study on an average of 5+/-3 years in a single center. We evaluated in the 104 spouses who came at least twice and had more than 1 year of follow-up the changes in bone mineral density (BMD) at femoral neck adjusted on weight and height, and on hormone replacement therapy use and duration for women. Lifestyle characteristics and biological parameters were evaluated at baseline. RESULTS: The mean (+/-SD) baseline age of wives was 63+/-5 years and that of their husbands was 66+/-5 years. They had been living together for 40+/-8 years. Most of the environmental baseline factors were correlated within partners: BMI (r=0.26, P<0.01), 25-OHD(3) (r=0.32, P<0.01), daily calories (r=0.52, P<0.001) and calcium intake (r=0.31, P<0.01), physical activity (r=0.43, P<0.0001). Bone loss was observed in wives ( 0.0023 g/cm(2)/yr, P<0.01) but not in their husbands (0.0016 g/cm(2)/yr, P=0.10). Changes of BMD were not correlated within spouses (r=0.0004, P=0.99). In women, 25-OHD(3) and interactions of tobacco with 25-OHD(3) and calories intake explained 37% of the bone loss variance (P<0.01). CONCLUSION: Environmental factors do not appear to influence changes in bone density in the same manner in subjects of different genders. PMID- 20851659 TI - Management recommendations for knee osteoarthritis: how usable are they? AB - OBJECTIVES: Despite the availability of practice guidelines for the management of knee osteoarthritis, inadequacies in practices of clinicians and patients have been found, leading to suboptimal outcomes. Literature has shown that simply disseminating management recommendations does not lead to adherence. Research suggests that barriers to use should be identified and addressed to improve adherence. The objective of this study was to identify barriers to use of conservative management recommendations for knee osteoarthritis by patients, general practitioners and physiotherapists. METHODS: Following systematic reviews of evidence and guidelines, 12 key management recommendations were elaborated on four themes: medication, exercise, self-management and occupation. Focus groups were separately done with patients with knee osteoarthritis, general practitioners and physiotherapists to assess barriers to the use of recommendations. RESULTS: Patients and general practitioners appeared generally fatalistic with regards to knee osteoarthritis, with physiotherapists being more positive regarding long-term improvement of knee osteoarthritis. For medication, discrepancies were found between recommendations and views of clinicians. Both patients and general practitioners appeared ambivalent towards exercise and activity, recognizing its usefulness but identifying it at the same time as a cause of knee osteoarthritis. Patients and general practitioners appeared to consider weight loss particularly difficult. DISCUSSION/CONCLUSIONS: Barriers specific to each knee osteoarthritis management recommendation and stakeholder group were identified. Recommendations to address these barriers were elaborated. Results of this study can be used to develop implementation strategies to overcome identified barriers, with the goal of facilitating the use of guideline recommendations and improving outcomes. PMID- 20851660 TI - Isolated fibrosis/contracture of the rectus femoris muscle: diagnosis and follow up with sonography. AB - Reported here is a 21-year-old female with isolated contracture of the rectus femoris muscle. Its possible relation to breech positioning, and the role of sonography for its diagnosis and close follow-up are discussed in the light of the relevant literature. PMID- 20851661 TI - Anti-PL7 antisynthetase syndrome under interferon therapy. AB - A 62-year-old woman with a past history of chronic hepatitis C virus infection presented an atypical predominantly painful polymyositis following a flu-like syndrome, persisting despite the withdrawal of PEG-interferon alpha-2b therapy. Clinical assessment, then immunological, electrophysiological and iconographic investigations including myositis antibodies, electromyography, pulmonary functions assessment and thoracic CT-scan found respectively "mechanic hands", arthralgia, presence of antisynthetase anti-PL7 antibody, typical myographic features of hip and shoulder girdles involvement, pulmonary fibrosis and restrictive syndrome features. A deltoid muscle biopsy revealed an unclassified myositis getting closer to anti-J0-1 and connective tissue disease associated myositis featuring: some components of polymyositis, dermatomyositis, and the following peculiar pathological aspects: noncaseous granulomatous infiltrate, endomysial microangiopathy and vascular and sarcolemic deposition of complement membrane attack complex. The diagnosis of interferon induced anti-PL7 antisynthetase syndrome with microangiopathic and granulomatous overlap myositis was retained. A treatment associating intravenous immunoglobulin and moderate tapered oral corticosteroids allowed a complete long-term resolution of myositis and a clear improvement of pulmonary involvement. This case points out the wide range of interferon alpha-associated disorders and call for a precise and detailed immunopathological analysis of myositis, instead of the usual vague classification as idiopathic polymyositis or dermatomyositis about antisynthetase syndrome. PMID- 20851662 TI - Effects of ultrasonic treatment on zeolite synthesized from coal fly ash. AB - The synthesis of zeolites from three samples of fly ash was carried out through a low-temperature (25-60 degrees C) hydrothermal process with a NaOH pre-fusion treatment preceded by sonication. The results were compared with those of conventional hydrothermal syntheses. XRD and SEM investigations demonstrate that the application of ultrasonic treatment facilitates the formation of zeolites at a lower-temperature (25 degrees C) than syntheses not preceded by sonication. No significant difference in type, temperature of crystallization, or amount of zeolites synthesized was noted between the three different samples of fly ash, implying that the chemical composition of fly ash had little influence on the zeolite product within the compositional range of these fly ash precursors. Although there appears to be a correlation between the SiO(2)/Al(2)O(3) ratio of the fly ash and the temperature of zeolite formation by conventional synthesis, no correlation was apparent when ultrasonic pre-treatment was used at low temperatures. PMID- 20851663 TI - A new concept for ferredoxin-NADP(H) oxidoreductase binding to plant thylakoids. AB - During the evolution of photosynthesis, regulatory circuits were established that allow the precise coupling of light-driven electron transfer chains with downstream processes such as carbon fixation. The ferredoxin (Fd):ferredoxin NADP(+) oxidoreductase (FNR) couple is an important mediator for these processes because it provides the transition from exclusively membrane-bound light reactions to the mostly stromal metabolic pathways. Recent progress has allowed us to revisit how FNR is bound to thylakoids and to revaluate the current view that only membrane-bound FNR is active in photosynthetic reactions. We argue that the vast majority of thylakoid-bound FNR of higher plants is not necessary for photosynthesis. We furthermore propose that the correct distribution of FNR between stroma and thylakoids is used to efficiently regulate Fd-dependent electron partitioning in the chloroplast. PMID- 20851665 TI - The missing link for attention pointers: comment on Cavanagh et al. PMID- 20851666 TI - Advances in dissecting endomembrane trafficking with small molecules. AB - Chemical genomics is relatively new to plant biology in academia; however, the ability of this approach to present novel discoveries is being demonstrated clearly. One particularly suitable application of this approach is plant endomembrane trafficking. The rapid and dynamic nature of vesicular trafficking plus genetic redundancy has hampered effective study of this complex network. The ability of small molecules to act quickly to inhibit or arrest vesicular trafficking should permit the association of specific vesicles, especially endosome compartments, with their cargoes, particularly those destined for the plasma membrane. This approach and the large target space presented by the endomembrane trafficking network require the discovery of many new bioactive molecules. Advances in high-throughput chemical screening in plants are making this a reality. However, successful chemical genomic approaches in plants must be coupled with improvements in automated microscopy, image analysis, and target identification. In addition, the ability to correlate specific molecules with complex phenotypic data will be crucial. The data obtained from these experiments will be composed of a matrix of intracellular markers displaying complex chemically induced phenotypes as well as whole plant and perhaps data generated by genomics, proteomics, and metabolomics. In this manner, it should be possible to view endomembrane trafficking and its interactions as a systems-based network. PMID- 20851667 TI - Raman intensity interpretation of pyridine liquid and its adsorption on the Ag electrode via bond polarizabilities. AB - The temporal bond polarizabilities of pyridine adsorbed on the Ag electrode under various applied voltages are obtained from their surface enhanced Raman intensities. In so doing, the delicate bond behaviors of pyridine molecule in the surface enhanced Raman process are well demonstrated, including the effects by the charge transfer and electromagnetic mechanisms. Furthermore, the adsorption effect is well reflected by the bond polarizabilities after relaxation as contrasted with the calculated bond electronic densities in the ground state. The work of pyridine liquid is also shown because its comparison with that under adsorption deepens our understanding of the Raman process. Though the method is semi-classical and simple as contrasted with those based on the quantum chemistry, it indeed offers us a very clear physical picture. This work demonstrates that this approach is quite universal for the Raman active systems even under adsorption as far as their Raman profiles are well measured. PMID- 20851668 TI - Application of photoacoustic infrared spectroscopy in the forensic analysis of artists' inorganic pigments. AB - Fourier-transform photoacoustic infrared (PAIR) spectroscopy has been used in the analysis of 12 inorganic pigments commonly in use by artists today, viz., cobalt blue, ultramarine blue, Prussian blue, azurite, malachite, chromium oxide, viridian, cadmium yellow, chrome yellow, iron oxide, yellow ochre and Mars orange. The authenticity of these 12 commercial pigments was first established by recording their Raman spectra. The subsequent PAIR spectra were highly reproducible and matched well in the mid-IR region with previously published data for these pigments. A number of additional overtone and combination bands were also detected that will prove useful in the identification of the pigments in the future. The PAIR technique is a promising and reliable method for the analysis of inorganic pigments, especially since it involves much simpler preparation than is required for conventional IR measurements. PMID- 20851669 TI - Muscle-afferent projection to the sensorimotor cortex after voluntary movement and motor-point stimulation: an MEG study. AB - OBJECTIVE: To investigate the projection of muscle afferents to the sensorimotor cortex after voluntary finger movement by using magnetoencephalography (MEG). METHODS: The movement-evoked magnetic fields (MEFs) after voluntary index-finger extension were recorded by a 204-channel whole-head MEG system. Somatosensory evoked magnetic fields (SEFs) were recorded after motor-point stimulation was applied to the right extensor indicis muscle by using a pair of wire electrodes. RESULTS: The MEF waveforms were observed at 35.8+/-9.7 ms after movement onset (MEF1). The most concentrated SEFs were identified at 78.7+/-5.6 ms (M70), and the onset latency of M70 was 39.0+/-5.5 ms after motor-point stimulation. The mean locations of the equivalent current dipoles (ECDs) of MEF1 and M70 were significantly medial and superior to that of N20m elicited by median-nerve stimulation. The ECD locations and directions of both MEF1 and M70 were concordant in the axial, coronal and sagittal planes. CONCLUSIONS: MEF1 and M70 might be elicited by muscle-afferent feedback following muscle contraction. In addition, these ECDs may be located in area 4. SIGNIFICANCE: Motor-point stimulation is a useful tool for confirming the projection of muscle-afferent feedback to the sensorimotor cortex after voluntary movement. PMID- 20851670 TI - Chitosan as a condensing agent induces high gene transfection efficiency and low cytotoxicity of liposome. AB - To enhance the transfection efficiency of the cationic liposomes, chitosan was selected as a DNA condensing agent. The particle size of the liposome/chitosan/DNA ternary complexes decreased and the zeta potential increased with the addition of chitosan. The formation of the ternary complexes was identified using agarose gel retardation study. The interaction of the ternary complexes was further confirmed by the decrease of the DNA fluorescence in the presence of [Ru(phen)2dppz](2+). In vitro and in vivo transfection activities of the complexes were determined using green fluorescent protein (GFP) expression in various cell lines and mouse tibial anterior muscle subcutaneously, respectively. Liposome/chitosan/DNA ternary complexes showed improved transfection efficiency in vitro cell culture system in the presence or absence of serum as well as in vivo mouse model system, as compared with liposome/DNA lipoplex. More importantly, the cell toxicity of the ternary complex is lower than that of lipoplex and liposome/poly-l-lysine/DNA ternary complex. The precondensation of DNA with chitosan can be a promising approach to further increase the transfection efficiency of cationic liposomes in clinical application. PMID- 20851671 TI - Optical resolution of n-butyl D- and L-lactates using immobilized lipase catalyst. AB - n-Butyl D- and L-lactates (BuDLa and BuLLa) were incubated with immobilized lipase. (1)H-NMR showed that BuDLa reacted to oligomers, while BuLLa did not react. A mixture containing 90.4% of BuLLa and 9.6% of BuDLa was incubated with the enzyme for 72 h, then distilled. The purity of BuLLa increased to 98.6%. PMID- 20851672 TI - Identification and characterization of a novel fermented substance produced by edible Aspergillus oryzae AO-1 that inhibits DPP-IV activity. AB - We identified a novel fermented substance (FKA) produced by the edible Aspergillus oryzae strain AO-1 that inhibited dipeptidyl peptidase IV (DPP-IV) (IC(50) = 3.41 mg . mL(-1)). HPLC analysis of FKA showed specific one metabolite (WYK-1), which inhibited DPP-IV (IC(50) = 6.98 MUM). WYK-1 was identified as a tetrahydroxyisoquinoline derivative. Interestingly, we examined 60 strains of A. oryzae, AO-1 was the only A. oryzae strain that produces WYK-1. This is the first report that an edible A. oryzae strain produces a DPP-IV inhibitor such as WYK-1. This study also suggests that FKA has applications in the development of novel antihyperglycemic therapeutics or functional foods. PMID- 20851673 TI - Methanogenic pathway and community structure in a thermophilic anaerobic digestion process of organic solid waste. AB - The methanogenic pathway and microbial community in a thermophilic anaerobic digestion process of organic solid waste were investigated in a continuous-flow stirred-tank reactor using artificial garbage slurry as a feedstock. The decomposition pathway of acetate, a significant precursor of CH(4) and a key intermediate metabolite in the anaerobic digestion process, was analyzed by using stable isotopes. A tracer experiment using (13)C-labeled acetate revealed that approximately 80% of the acetate was decomposed via a non-aceticlastic oxidative pathway, whereas the remainder was converted to methane via an aceticlastic pathway. Archaeal 16S rRNA analyses demonstrated that the hydrogenotrophic methanogens Methanoculleus spp. accounted for >90% of detected methanogens, and the aceticlastic methanogens Methanosarcina spp. were the minor constituents. The clone library targeting bacterial 16S rRNA indicated the predominance of the novel Thermotogales bacterium (relative abundance: ~53%), which is related to anaerobic acetate oxidizer Thermotoga lettingae TMO, although the sequence similarity was low. Uncultured bacteria that phylogenetically belong to municipal solid waste cluster I were also predominant in the microflora (~30%). These results imply that the microbial community in the thermophilic degrading process of organic solid waste consists exclusively of unidentified bacteria, which efficiently remove acetate through a non-aceticlastic oxidative pathway. PMID- 20851674 TI - Isocyanate and total inhalable particulate air measurements in the European wood panel industry. AB - INTRODUCTION: It is well known that the use of MDI (methylene diphenyldiisocyanate) as an alternative for formaldehyde-based resins is seen as a responsible option to reduce formaldehyde emissions for CWP (Composite Wood Products) in buildings. However, there are concerns raised regarding the exposure risk of workers. The purpose of this article is to provide the reader with factual information to demonstrate that the use of MDI compared to other agents used in CWP production processes does not pose increased inhalation exposure risks for workers. Personal and area air measurements were carried out at nine Composite Wood Panel plants throughout Europe to assess potential inhalation exposures to MDI and wood dust as Total Inhalable Particulates (TIP). In total, 446 pairs of samples were collected for MDI and TIP of which 283 pairs were personal samples and the remaining 163 pairs were area samples collected at key locations along the production line. This data together with published formaldehyde exposure data has been used to evaluate the exposure safety margin opposite what are considered relevant occupational exposure limits. MATERIAL AND METHODS: The methods used for sampling and analysing MDI and TIP are based on internationally accepted methods, i.e. MDHS 25/3 (or ISO 16702) for MDI, and MDHS 14/3 for TIP. RESULTS: The job functions with an increased exposure profile for TIP were the cleaners, drying operators and quality control staff, and for MDI, the cleaners and quality control staff. The areas with an increased exposure profile for TIP are the conveyor area from OSB blender to former area and the OSB press infeed, and for MDI the OSB weigh belt and OSB former bin area. CONCLUSIONS: The exposure safety margin opposite the selected exposure limits can be ranked as MDI>TIP>formaldehyde (high margin of safety to low margin of safety), indicating that the use of MDI also reduces the exposure risks to workers during production of CWP compared to formaldehyde. By reducing the airborne TIP concentrations, a respiratory sensitiser, MDI workplace concentrations in general can be reduced further. This can be achieved by improving design and/or maintenance and testing programmes of existing control measures, which should be in place already to effectively control exposure to TIP and formaldehyde. The airborne concentration of MDI at workstations situated after pressing (curing) is regarded as extremely low and likely mainly constituted by workplace emissions from elsewhere in the plant. PMID- 20851675 TI - Fishing activity, health characteristics and mercury exposure of Amerindian women living alongside the Beni River (Amazonian Bolivia). AB - Populations in Bolivian Amazonia are exposed to mercury contamination through fish ingestion. A group of 170 Amerindian women living along the banks of the Beni River were examined in order to detect any adverse effects on their health consistent with the toxic effects of mercury. The mercury content of the women's hair (H-Hg) was used as the bio-indicator of mercury exposure. The women answered a 24-h food recall questionnaire on the frequency of their fish consumption. They also underwent a clinical examination with their weight, stature, hemoglobin concentration in blood, and blood pressure being recorded. Significant relationships were found between fishing practices, the frequency of fish consumption and H-Hg levels with mercury contaminated women (H-Hg>5MUg/g) being more likely to present neurological abnormalities (paresthesia, static and dynamic imbalance, poor motor coordination) than non-contaminated women. No relationship was found between blood pressure and mercury levels. Women with higher H-Hg reported more infant deaths than did women with lower levels. A logistic regression analysis which included socio-cultural traits, fish consumption habits and health characteristics was performed in order to determine the risks of contamination. Contaminated women were more likely to belong to those communities pursuing traditional fishing activities; moreover these women tended to be younger and frailer than other. They also exhibited mild neurological abnormalities and reported more infant deaths. These findings should stimulate local communities to take preventive actions directed towards the more "traditional" and vulnerable groups of population. PMID- 20851676 TI - Diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH) and Di(2-ethylhexyl) terephthalate (DEHT) in indoor dust samples: concentration and analytical problems. AB - Possible human health effects of phthalate plasticizers have been intensely discussed during the last decade. Di(2-ethylhexyl) phthalate (DEHP), the phthalate acid ester with the largest production volume worldwide, has been substituted by new compounds like Diisononyl 1,2-cyclohexanedicarboxylic acid (DINCH) or Di(2-ethylhexyl) terephthalate (DEHT) in many applications. There are numerous reports about concentration levels of phthalates in indoor environments, but data on concentrations of these alternative plasticizers are not available yet. Also, the methods for the determination of phthalate substitutes are not yet established. This study presents the results achieved by quantification using different analytical methods. Data on the concentration of DEHT and DINCH in 953 dust samples from German households are presented. These samples were obtained in four different studies conducted from 1997 to 2009. Maximum concentrations of 110 mg DINCH/kg dust and 440 mg DEHT/kg dust were found. Especially the amount of DINCH has increased significantly after the market introduction of this plasticizer in 2002. Up to the beginning of 2006, DINCH was found in 44% of the dust samples. Dust samples collected in 2009 indicate an increased concentration for both softeners. PMID- 20851677 TI - Study of kidney dysfunction in non-silicotic Egyptian workers. AB - Occupational exposure to silica dust could lead to renal alterations in the glomeruli and proximal tubules. In the present study, occupational exposure to silica dust has been examined as a possible risk factor with respect to subclinical signs of kidney dysfunction. One-hundred forty eight exposed workers from a ceramic factory versus 121 controls of matched age, socioeconomic status and smoking habits were included. Data was collected through a questionnaire and clinical examination. There was a high prevalence of renal complaints in the ceramic workers specially the loin pain, dysuria. Crystalluria was significantly higher in the exposed group (12.2%) than the controls (5%). Renal urinary biomarkers including the high-molecular-weight protein albumin (U.Malb); the low molecular-weight protein alpha1-microglobulin (alpha(1)M); the lysosomal enzyme N acetyl-beta-D-glucosaminidase (NAG) urinary excretion of copper (U.Cu) and zinc (U.Zn) have been investigated. Urinary levels of silica and creatinine (U.cr) were estimated. Data from the present study showed a high significant increase in the urinary excretion of all measured urinary parameters in the group of ceramic workers compared with control subjects. There were no significant differences in the means of U.Zn/U.cr, U.Malb/U.cr, and alpha(1)M/U.cr among the four investigated departments of ceramic factory. The significant difference was present mainly between the individual departments and the controls, while, there was significant differences in the means of U.Cu/U.cr, U.NAG/U.cr, and U.silica/U.cr among the four departments and the controls. Among the exposed workers, significant correlation was apparent between work duration and only U.Zn/U.cr (r=0.17, p<0.05), and U.Cu/U.cr (r=0.19, p<0.05), while all measured urinary parameters were significantly correlated with each other. On conclusion silica exposure leads to renal alterations which parallel the change in proteinuria and enzymuria, as well as the increased loss in urine of each of Zn and Cu. Measurement of the levels of urinary zinc and copper may serve as a sensitive indicator of the impaired renal function caused by silica exposure. The corresponding analytes could have potential value as indicators of renal function before the kidney is irreversibly injured and, thus could be suitable as monitoring tools for at-risk persons exposed to silica. Researches should assess whether the current occupational standards for silica adequately protect workers from renal disease or this established standard needs to be revised. PMID- 20851678 TI - Peri-procedural anticoagulation and the incidence of haematoma formation after permanent pacemaker implantation in the elderly. AB - BACKGROUND: Haematoma formation is a recognised complication after permanent pacemaker (PPM) implantation. The contribution of peri-procedural anticoagulation to the risk of haematoma formation is unclear. METHOD: The records of 518 consecutive patients, mean age 76.9+/-9.8 years, receiving their first PPM (2004 2007) in a single tertiary referral centre were reviewed. Follow-up was complete for 506 patients (97.7%) up to six weeks. Haematomas were diagnosed clinically, and further subdivided according to the need for evacuation. RESULTS: There were 27 instances of haematoma formation in 25 patients (4.9%) with 19 requiring drainage or evacuation. Twenty-one of the 25 patients who developed a haematoma had stopped warfarin and received bridging therapeutic anticoagulation pre- and post-PPM. The incidence of haematoma was significantly greater in those receiving peri-operative therapeutic anticoagulation (26.9% vs 0.9%, p<0.001), but was unaffected by the use of anti-platelet therapy. Most haematomas developed in patients whose heparin was recommenced within 24 hours of implantation. The development of haematoma post-PPM increased median hospital stay significantly (p<0.001). The main indication for anticoagulation in these patients was atrial fibrillation (79.5%) and most of these patients had a low to intermediate risk of peri-procedural thromboembolic events. CONCLUSION: Peri-operative therapeutic anticoagulation is associated with more than 25-fold increase in haematoma formation post-pacemaker implantation. The risk-benefit ratio of therapeutic anticoagulation should be carefully considered, particularly in patients with a low risk of thromboembolic events. PMID- 20851679 TI - A clinico-pathological conference on constrictive pericarditis secondary to rheumatoid arthritis: a case report with expert commentary and review of the literature. AB - Constrictive pericarditis is the commonest cardiac complication of rheumatoid arthritis (RA). Two percent of patients with RA develop significant clinical symptoms of pericarditis, which may not correlate with joint disease duration or severity. Symptoms are often vague and non-specific, which frequently delays the diagnosis and subsequent management. Surgical excision of the pericardium is the only definitive treatment option. We present the case of a 60 year-old lady with RA who presented with symptoms due to pericardial constriction and underwent radical pericardectomy. PMID- 20851680 TI - Mycotic aortic aneurysm: A case of an unlikely location and an unlikely pathogen. AB - This is an unusual case of a mycotic aortic aneurysm located in the ascending aorta caused by Neisseria meningitidis. The diagnosis was made using two dimensional (2D) and three-dimensional (3D) transoesophageal echocardiogram (TOE) and cardiovascular magnetic resonance (CMR). Management was with prolonged antibiotics followed by surgical resection. The ascending aorta was replaced with Dacron tube graft. The contribution of multimodality imaging in clearly defining the pathology, its location and directing the timing of surgery, was a striking aspect of this case. PMID- 20851681 TI - Exploring the scope of oncology specialist nurses' practice in the UK. AB - PURPOSE: Revolutionary changes have taken place to nurses' roles and clinical responsibilities over the past decade, leading to new ways of working and higher levels of nursing practice. However, despite the development of nurse-led clinics and services within oncology there has been little formal evaluation. METHODS: A survey of 103 UK oncology specialist nurses was undertaken to explore their scope of practice, with emphasis on nurse-led services. RESULTS: The survey highlighted significant developments within nurses' roles and nurse-led services, although there was a distinct lack of clarity between nurses' titles and their roles/responsibilities. Most nurses had extended their role. However there were significant differences in the nature of clinical practice, such as clinical examination and nurse prescribing. Overall, new roles were greatly valued by the multidisciplinary team, reducing waiting times and providing benefits for patients. However other nurses felt frustrated by deficiencies in infrastructure and support, which often overshadowed potential benefits. CONCLUSIONS: There is a great diversity in oncology specialist nurses' roles; however lack of clarity in titles, training, competencies and responsibilities is creating confusion. Role developments and nurse-led clinics have been ad hoc and poorly evaluated. The introduction of a competency framework, national standards and a system of clinical appraisals seems key to providing increased transparency and vital safeguards for both nurses and patients. Without further exploration and evaluation of nurse-led initiatives it is difficult to fully appreciate their impact on patients, staff and service delivery. PMID- 20851683 TI - Kinase inhibitors for refractory thyroid cancers. PMID- 20851682 TI - Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study. AB - BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0.40, p=0.021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205. PMID- 20851684 TI - Combined PET/MRI: one step further in multimodality imaging. AB - Given the need for sophisticated in vivo detection techniques to better characterize the cellular and subcellular processes in animals and humans, molecular imaging has become an important discipline. Techniques in molecular imaging have developed from stand alone modalities to multimodality methods. Among these, the combination of positron emission tomography (PET) and computed tomography (CT) is a successful imaging method and has become an important tool in clinical practice. Technological approaches that combine magnetic resonance imaging (MRI) with diffuse optical tomography (DOT), fluorescence tomography (FT) and PET have now been introduced. PET/MRI and the resulting combination of molecular, morphological and functional information will pave the way for a better understanding of physiological and disease mechanisms in preclinical and clinical settings. PMID- 20851685 TI - Incidence of asymptomatic meatal stenosis in children following neonatal circumcision. AB - OBJECTIVE: To determine the incidence of meatal stenosis after neonatal circumcision. PATIENTS AND METHODS: Male children (5-10 years old) who had been circumcised during the neonatal period and presented at our pediatric clinic for reasons other than urinary complaints were examined and interviewed regarding urination problems. RESULTS: Of the 132 cases, 27 (20.4%) had severe meatal stenosis (diameter < 5 F). Thickening of the bladder and bilateral hydronephrosis (pyelocaliceal) were found in three cases (11.1%), and a voiding cystourethrogram was performed to reveal vesicoureteral reflux (VUR). One patient had grade II VUR in his right kidney and grade III in his left kidney; another had grade II VUR in both his kidneys. CONCLUSION: These results highlight the importance of follow-up genital examination for all male children who have been circumcised during the neonatal period, to detect possible meatal stenosis. PMID- 20851686 TI - Outcome of hypogammaglobulinemia in children: immunoglobulin levels as predictors. AB - We evaluated 131 children (M=88, F=43) with hypogammaglobulinemia. Data was analyzed mainly for delineating predictor factors for outcome. The distance from the lower limit of normal (-2SD) for any single measurement of immunoglobulins (Ig) was calculated and transformed into Ig scores. Mean age and duration of follow-up were 5.06 +/- 4.05 and 3.7 +/- 3.03 years, respectively. The diagnoses were: 22 CVID, 16 IgA deficiency, 33 transient hypogammaglobulinemia of childhood (THC), 3 selective IgM deficiency and 57 unclassified hypogammaglobulinemia (UCH). Low IgA scores (<-0.124) at presentation were indicative of subsequent development of IgA deficiency or CVID, whereas low IgM score (<-0.038) pointed towards more severe and persistent phenotypes. Combination of low IgM score between 2 and 5 years, impaired antibody response and low B cell counts enabled us to predict persistence of hypogammaglobulinemia beyond 5 years (specificity=90.5% and PPV=94.9%) and chronic lung disease (sensitivity=90.4% and specificity=68.3%). The set of criteria including low IgM scores, impaired antibody response and low B cell counts provided a high predictive value in detecting those with persistent hypogammaglobulinemia. PMID- 20851687 TI - Recurrent seizure-related injuries in people with epilepsy at a tertiary epilepsy center: a 2-year longitudinal study. AB - Though seizure-related injuries (SRIs) among people with epilepsy (PWE) have recently gained much attention in the literature, most studies are retrospective and data are gathered indirectly through questionnaires or medical record documentation. We investigated SRIs and their associated risks in PWE attending a tertiary care center with direct and systematic inquiries during routine clinic follow-up visits over a 2-year period (N = 306). Past SRIs occurred in 54% of all patients, and 24% experienced recurrent SRIs during the study period. On multiple regression analyses, past SRI was associated with tonic-clonic seizures (TCSs) (3.2, 95% CI = 1.7-5.8) and cognitive handicap (4.3, 95% CI 1.5-16.1), and recurrent SRI was associated with TCSs (3.5, 95% CI = 1.6-7.9). Most recurrent SRIs (72%) involved head injury. SRIs are common when assessed systematically in a tertiary care setting, and TCSs represent a risk factor for recurrent SRIs. The potential clinical impact of recurrent SRIs on PWE requires further study. PMID- 20851688 TI - Examining health-related quality of life, adaptive skills, and psychological functioning in children and adolescents with epilepsy presenting for a neuropsychological evaluation. AB - The purpose of this study was to characterize 132 children and adolescents (mean age = 10 years, 11 months) with epilepsy in terms of psychosocial functioning and to determine the extent to which adaptive skills and psychological functioning predict health-related quality of life (HRQOL), above and beyond demographic and epilepsy-specific characteristics. A chart review was conducted to obtain demographic and epilepsy-specific information as well as caregiver responses on the Behavior Assessment System for Children, Second Edition (BASC-2) Parent Report and the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). In addition to Full Scale IQ and age at seizure onset, the BASC-2 Clinical and Adaptive Skills subscales also predicted HRQOL, indicating that this measure may be particularly helpful in predicting HRQOL above and beyond information routinely collected in a medical setting. It is imperative to evaluate children with epilepsy for psychosocial difficulties and diminished HRQOL to ensure the provision of comprehensive quality care and intervention services. PMID- 20851689 TI - Depression in epilepsy: why aren't we treating? AB - Depression is a common and largely untreated comorbidity in patients with epilepsy. Our aim was to examine physician attitudes that may contribute to this treatment gap. We surveyed primary care physicians, neurologists, and psychiatrists chosen from the Ohio State Medical Board registry on the topics of depression in epilepsy, seizures with antidepressant use, and comfort in treating depression in epilepsy. Our data identified fear of increased seizure frequency with antidepressant use as a significant barrier to treatment. There was a clear inverse relationship between the estimated risk of antidepressant-induced seizures and comfort treating depression in epilepsy (P = 0.02), with 52% of primary care physicians identifying this as a reason for not treating depression in this population. Further education of community physicians and neurologists regarding the importance of treating depression in patients with epilepsy and research into the use of antidepressants in this population are indicated. PMID- 20851690 TI - Chronic expanding hematoma after spinal surgery. AB - BACKGROUND CONTEXT: Chronic expanding hematoma after spinal surgery is extremely rare, with no case previously reported in the literature. PURPOSE: To report a rare case of a chronic expanding hematoma of the spine that occurred 24 years after thoracic laminectomy and spinal cord tumor resection. STUDY DESIGN: Case report. METHODS: A 71-year-old man presented with a spinal mass located approximately at the level of the sixth thoracic vertebral body. The patient had undergone thoracic laminectomy with tumor resection 24 years previously. The mass had appeared 5 years after this and had gradually enlarged over 19 years. RESULTS: The tumor was resected en bloc. The lamina and spinous processes had been partially eroded by the tumor at the fifth and sixth thoracic vertebrae, but the dura was intact. Histopathologic examination confirmed the diagnosis of chronic expanding hematoma. The hematoma had not recurred at the 1-year follow up. CONCLUSION: We report herein an extremely rare case of chronic expanding hematoma after spinal surgery. This entity may be considered a late complication after surgery regardless of the number of years that have passed since the index surgery. PMID- 20851691 TI - Pharmacological modulation of the micturition pattern in normal and cyclophosphamide pre-treated conscious rats. AB - In the current study, we wanted to assess the influence of muscarinic receptors, nitric oxide and purinoceptors on the micturition pattern of conscious normal and cyclophosphamide (CYP) pre-treated rats. The micturition parameters were assessed using a metabolic cage. Rats were pre-treated with either saline or CYP, to induce cystitis, followed by treatment with either the muscarinic M1/M3/M5 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine (4-DAMP), the nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl (L-NAME), the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) or a combination of 4-DAMP with PPADS or L-NAME. Voiding volumes per micturition event were significantly lower in CYP pre-treated than in saline pre treated rats. Neither 4-DAMP nor L-NAME had any effect in the normal rats, whereas PPADS reduced the micturition volume per event. In CYP pre-treated rats, 4-DAMP and L-NAME significantly increased voiding volumes per event and micturition frequency, respectively. 4-DAMP dose-dependently reduced the differences in micturition activity between saline and CYP pre-treated rats. We show that cystitis changes the urodynamics in conscious rats and that this change seems to depend on the production of NO and on altered muscarinic receptor effects. The altered muscarinic receptor responses are likely to per se involve NO-mediated mechanisms. PMID- 20851692 TI - Acupuncture from a physiological and clinical perspective. PMID- 20851693 TI - Amperometric sensor for hydrogen peroxide based on direct electron transfer of spinach ferredoxin on Au electrode. AB - A protein-based electrochemical sensor for hydrogen peroxide (H(2)O(2)) was developed by an easy and effective film fabrication method where spinach ferredoxin (Fdx) containing [2Fe-2S] metal center was cross linked with 11 mercaptoundecanoic acid (MUA) on a gold (Au) surface. The surface morphology of Fdx molecules on Au electrodes was investigated by atomic force microscopy (AFM). Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) were employed to study the electrochemical behavior of adsorbed Fdx on Au. The interfacial properties of the modified electrode were evaluated in the presence of Fe(CN)(6)(3-/4-) redox couple as a probe. From CV, a pair of well-defined and quasi-reversible redox peaks of Fdx was obtained in 10mM, pH 7.0 Tris-HCl buffer solution at -170 and -120mV respectively. One electron reduction of the [2Fe 2S](2+) cluster occurs at one of the iron atoms to give the reduced [2Fe-2S](+). The formal reduction potential of Fdx ca. -150mV (vs. Ag/AgCl electrode) at pH 7.0. The electron-transfer rate constant, k(s), for electron transfer between the Au electrode and Fdx was estimated to be 0.12s(-1). From the electrochemical experiments, it is observed that Fdx/MUA/Au promoted direct electron transfer between Fdx and electrode and it catalyzes the reduction of H(2)O(2). The Fdx/MUA/Au electrode displays a linear increase in amperometric current for increasing concentration of H(2)O(2).The sensor calibration plot was linear with r(2)=0.998 with sensitivity approximately 68.24MUAm M(-1)cm(-2). Further, the effect of nitrite on the developed sensor was examined which does not interfere with the detection of H(2)O(2). Finally, the addition of H(2)O(2) on MUA/Au electrode was observed which has no effect on amperometric current. PMID- 20851694 TI - Simultaneous production of immunoaffinity membranes. AB - We simultaneously separated antibodies for transferrin, the third component of complement (C3), haptoglobin and transthyretin by multi-sample non-denaturing two dimensional electrophoresis (2-DE), transferred them to a polyvinylidene difluoride (PVDF) membrane and then stained them using direct blue 71 to obtain membrane-immobilized antibodies. The antigens, transferrin, C3, haptoglobin and transthyretin were specifically bound to the membrane-immobilized antibodies and were eluted only after rinsing the membrane with acid solution. The antigens specifically bound to the membrane-immobilized antibodies were separated by SDS PAGE and identified by peptide mass fingerprinting using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Furthermore, transferrin and transthyretin were trapped and eluted by each membrane-immobilized antibody and detected by MALDI-TOF MS directly without separations. Using membrane-immobilized anti-transferrin antibody, transferrin in flowing blood was directly trapped and analyzed. The results indicated that membrane-immobilized antibodies are simultaneously produced, and that the immunoaffinity membranes can capture specific substances in flowing fluids. PMID- 20851696 TI - Opinion of gastroenterologists towards quality assurance in endoscopy. AB - BACKGROUND: Quality assurance has become an important issue. Many societies are adopting quality assurance programs in order to monitor and improve quality of care. AIM: To assess the opinion of gastroenterologists towards quality assurance on the endoscopy department. METHODS: A survey was sent to all gastroenterologists (n=319) in the Netherlands. It assessed their opinion on a quality assurance program for endoscopy units, including its design, logistics, and content. RESULTS: 200 gastroenterologists (63%) completed the questionnaire. 95% had a positive opinion towards quality assurance and 67% supposed an increase in quality. 28% assumed a negative impact on the time available for patient contact by introducing a quality assurance program and 35% that the capacity would decrease. A negative attitude towards disclosure of results to insurance companies (23%) and media (53%) was reported. Female gastroenterologists were less positive to share the results with other stakeholders (p<0.05). Most important quality measurements were assessment of complications (97%), standardised reporting (96%), and adequate patient information (95%). CONCLUSION: Gastroenterologists have a positive attitude towards quality assurance. However, concerns do exist about time investment and disclosure of results to others. Information provision and procedure characteristics were considered the most important aspects of quality assurance. PMID- 20851697 TI - Population genetic polymorphisms of 17 Y-chromosomal STR loci in South Koreans. AB - Haplotypes and allele frequencies of 17 Y-chromosomal STR loci included in the AmpFlSTR((r)) Yfiler((r)) system were obtained from a sample of 1021 unrelated individuals living in 6 provinces of South Korea. A total of 938 haplotypes were observed in the 1021 individuals studied, of which 885 were unique. The overall haplotype diversity for the 17 Y-STR loci was 0.9998, and the discrimination capacity was 0.9187. We found 11 atypical alleles (null, duplicated, triplicated, and microvariant alleles), that have not previously been reported in South Korean populations. It seems that these 17 loci are useful genetic markers for forensic personal identification and paternity testing in the South Korean population. PMID- 20851695 TI - Targeted nanoagents for the detection of cancers. AB - Nanotechnology has enabled a renaissance in the diagnosis of cancers. This is due, in part to the ability to develop agents bearing multiple functionalities, including those utilized for targeting, imaging, and therapy, allowing for the tailoring of the properties of the nanomaterials. Whereas many nanomaterials exhibit localization to diseased tissues via intrinsic targeting, the addition of targeting ligands, such as antibodies, peptides, aptamers, and small molecules, facilitates far more sensitive cancer detection. As such, this review focuses upon some of the most poignant examples of the utility of affinity ligand targeted nanoagents in the detection of cancer. PMID- 20851698 TI - Launching the Greek forensic DNA database. The legal framework and arising ethical issues. AB - Since the creation of the first national DNA database in Europe in 1995, many European countries have legislated laws for initiating and regulating their own databases. The Greek government legislated a law in 2008, by which the National DNA Database of Greece was founded and regulated. According to this law, only DNA profiles from convicted criminals were recorded. Nevertheless, a year later, in 2009, the law was amended to permit the creation of an expanded database including innocent people and children. Unfortunately, the new law is very vague in many aspects and does not respect the principle of proportionality. Therefore, according to our opinion, it will soon need to be re-amended. Furthermore, prior to legislating the new law, there was no debate with the community itself in order to clarify what system would best suit Greece and what the citizens would be willing to accept. We present the current legal framework in Greece, we highlight issues that need to be clarified and we discuss possible ethical issues that may arise. PMID- 20851700 TI - Minimally invasive locking screw plate fixation of non-articular proximal and distal tibia fractures. AB - Intramedullary nailing of proximal and distal quarter tibia fractures is known to be a challenging procedure due to the metaphyseal enlargement, the reduced contact between implant and cortex and fracture comminution. Therefore, some authors suggest preferring the use of plate internal fixation in the management of these challenging fractures. The purpose of this manuscript is to present and describe our technique of minimally invasive locking plate osteosynthesis in the treatment of extra-articular proximal and distal tibia fractures. Osteosynthesis was performed by means of a locking screw plate system which construct characteristics usually allow immediate weight-bearing and early functional mobilization. This minimally invasive surgical procedure advantageously combines the principles of closed fixation with construct stability. PMID- 20851701 TI - Natural variation in stress response is related to post-stress parental effort in male house sparrows. AB - The central life-history trade-off between current and future reproductive effort seems to be mediated by corticosterone in birds. However, still little is known about how naturally occurring corticosterone levels during an acute stress may influence subsequent parental behavior. In this study we observed the parental behavior of free-living male house sparrows (Passer domesticus) both before and after they were subjected to a standard capture-handling stress. We investigated the relationships between corticosterone levels, pre- and post-stress parental behavior, while we statistically controlled for a number of other variables using a multivariate regression method, the path analysis. We found that males' baseline feeding rate predicted the body mass of the nestlings, indicating that male parental care is directly linked to fitness. Corticosterone levels were not explained by baseline feeding rate, but both baseline and stress-induced corticosterone levels had a negative influence on the males' post-stress feeding behavior. Moreover, males with large bib size had a stronger stress response and lower post-stress feeding rate than small bibbed males. These results indicate that naturally occurring variation in baseline and stress-induced corticosterone levels may influence subsequent parental decisions: individuals mounting a robust stress response are likely to reduce their parental commitment. Parental effort may be regulated in a complex manner, with corticosterone mediating the life history trade-off between current reproduction and survival. However, different resolutions of this trade-off were apparent only following the stress, therefore the ability to modulate the stress response and maintain parental care in stressful situations may be important in life-history evolution. PMID- 20851702 TI - Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus. AB - Major depression is a growing problem worldwide with variation in symptoms and response to treatment. Individual differences in response to stress may contribute to such observed individual variation in behavior and pathology. Therefore, we investigated depressive-like behavior following exposure to repeated social defeat in a rat model of individual differences in response to novelty. Rats are known to exhibit either high locomotor activity and sustained exploration (high responders, HR) or low activity with minimal exploration (low responders, LR) in a novel environment. We measured anhedonia using the sucrose preference test in HR and LR rats following exposure to social defeat stress or in basal, non-defeated conditions. We then compared histone acetylation in the hippocampus in HR and LR defeat and non-defeated rats and measured mRNA levels of histone deacetylases (HDAC) 3, 4, 5, and Creb binding protein (CBP). We found that basally, HR rats consumed more sucrose solution than LR rats, but reduced consumption after exposure to defeat. LR rats' preference was unaffected by social defeat. We found that HR rats had higher levels of histone acetylation on H3K14 and H2B than LR rats in non-stress conditions. Following defeat, this acetylation pattern changed differentially, with HR rats decreasing acetylation of H3K14 and H2B and LR's increasing acetylation of H3K14. Acetylation on histone H4 decreased following defeat with no individual variation. Basal differences in CBP expression levels may underlie the observed acetylation pattern; however we found no significant effects of defeat in levels of HDACs 3, 4, 5 in the hippocampus. PMID- 20851703 TI - Occurrence of Apicomplexa-like structures in the digestive gland of Strombus gigas throughout the Caribbean. AB - The queen conch, Strombus gigas, is a marine resource of ecological and economical importance in the Caribbean region. Given its importance in this region, and the critical status of most populations, the reproductive biology of this species has been studied to support management decisions. It was from these studies that a generalized sporozoan infection was detected. This study describes the geographic distribution of a coccidian (Apicomplexa) parasite infecting the digestive gland of S. gigas throughout the Caribbean. The parasite was present in every location sampled. Based on histological analysis, the parasites from all locations are similar and appear to complete their life cycle within the digestive gland. The highest occurrence of the parasites was registered in samples from Puerto Rico (54 parasites per field) and Martinique (45 parasites per field). The lowest incidence was registered on the Mexican coast of Yucatan peninsula, at Alacranes and Chinchorro with 17 parasites per field. Data showed significant differences among sites (Kruskal Wallis H=106.957; p <= 0.05). The abundance of parasites found in the digestive ducts and in the faeces suggests the liberation of parasites to the environment. A gradual decrease in abundance was found from East to West of the Caribbean sea. PMID- 20851704 TI - Kinetic, thermodynamic, and structural insight into the mechanism of phosphopantetheine adenylyltransferase from Mycobacterium tuberculosis. AB - Phosphopantetheine adenylyltransferase (PPAT) catalyzes the penultimate step in the coenzyme A (CoA) biosynthetic pathway, reversibly transferring an adenylyl group from ATP to 4'-phosphopantetheine (PhP) to form dephosphocoenzyme A. This reaction sits at the branch point between the de novo pathway and the salvage pathway, and has been shown to be a rate-limiting step in the biosynthesis of CoA. Importantly, bacterial and mammalian PPATs share little sequence homology, making the enzyme a potential target for antibiotic development. A series of steady-state kinetic, product inhibition, and direct binding studies with Mycobacterium tuberculosis PPAT (MtPPAT) was conducted and suggests that the enzyme utilizes a nonrapid-equilibrium random bi-bi mechanism. The kinetic response of MtPPAT to the binding of ATP was observed to be sigmoidal under fixed PhP concentrations, but substrate inhibition was observed at high PhP concentrations under subsaturating ATP concentrations, suggesting a preferred pathway to ternary complex formation. Negative cooperativity in the kinetic response of MtPPAT to PhP binding was observed under certain conditions and confirmed thermodynamically by isothermal titration calorimetry, suggesting the formation of an asymmetric quaternary structure during sequential ligation of substrates. Asymmetry in binding was also observed in isothermal titration calorimetry experiments with dephosphocoenzyme A and CoA. X-ray structures of MtPPAT in complex with PhP and the nonhydrolyzable ATP analogue adenosine-5' [(alpha,beta)-methyleno]triphosphate were solved to 1.57 A and 2.68 A, respectively. These crystal structures reveal small conformational changes in enzyme structure upon ligand binding, which may play a role in the nonrapid equilibrium mechanism. We suggest that the proposed kinetic mechanism and asymmetric character in MtPPAT ligand binding may provide a means of reaction and pathway regulation in addition to that of the previously determined CoA feedback. PMID- 20851705 TI - Identification of critical residues for the tight binding of both correct and incorrect nucleotides to human DNA polymerase lambda. AB - DNA polymerase lambda (Pol lambda) is a novel X-family DNA polymerase that shares 34% sequence identity with DNA polymerase beta. Pre-steady-state kinetic studies have shown that the Pol lambda-DNA complex binds both correct and incorrect nucleotides 130-fold tighter, on average, than the DNA polymerase beta-DNA complex, although the base substitution fidelity of both polymerases is 10(-)(4) to 10(-5). To better understand Pol lambda's tight nucleotide binding affinity, we created single-substitution and double-substitution mutants of Pol lambda to disrupt the interactions between active-site residues and an incoming nucleotide or a template base. Single-turnover kinetic assays showed that Pol lambda binds to an incoming nucleotide via cooperative interactions with active-site residues (R386, R420, K422, Y505, F506, A510, and R514). Disrupting protein interactions with an incoming correct or incorrect nucleotide impacted binding to each of the common structural moieties in the following order: triphosphate?base>ribose. In addition, the loss of Watson-Crick hydrogen bonding between the nucleotide and the template base led to a moderate increase in K(d). The fidelity of Pol lambda was maintained predominantly by a single residue, R517, which has minor groove interactions with the DNA template. PMID- 20851707 TI - Conformational characterization of disulfide bonds: a tool for protein classification. AB - BACKGROUND: Throughout evolution, mutations in particular regions of some protein structures have resulted in extra covalent bonds that increase the overall robustness of the fold: disulfide bonds. The two strategically placed cysteines can also have a more direct role in protein function, either by assisting thiol or disulfide exchange, or through allosteric effects. In this work, we verified how the structural similarities between disulfides can reflect functional and evolutionary relationships between different proteins. We analyzed the conformational patterns of the disulfide bonds in a set of disulfide-rich proteins that included twelve SCOP superfamilies: thioredoxin-like and eleven superfamilies containing small disulfide-rich proteins (SDP). RESULTS: The twenty conformations considered in the present study were characterized by both structural and energetic parameters. The corresponding frequencies present diverse patterns for the different superfamilies. The least-strained conformations are more abundant for the SDP superfamilies, while the "catalytic" +/-RHook is dominant for the thioredoxin-like superfamily. The "allosteric" RHSaple is moderately abundant for BBI, Crisp and Thioredoxin-like superfamilies and less frequent for the remaining superfamilies. Using a hierarchical clustering analysis we found that the twelve superfamilies were grouped in biologically significant clusters. CONCLUSIONS: In this work, we carried out an extensive statistical analysis of the conformational motifs for the disulfide bonds present in a set of disulfide-rich proteins. We show that the conformational patterns observed in disulfide bonds are sufficient to group proteins that share both functional and structural patterns and can therefore be used as a criterion for protein classification. PMID- 20851706 TI - Solution structure and phospholipid interactions of the isolated voltage-sensor domain from KvAP. AB - Voltage-sensor domains (VSDs) are specialized transmembrane segments that confer voltage sensitivity to many proteins such as ion channels and enzymes. The activities of these domains are highly dependent on both the chemical properties and the physical properties of the surrounding membrane environment. To learn about VSD-lipid interactions, we used nuclear magnetic resonance spectroscopy to determine the structure and phospholipid interface of the VSD from the voltage dependent K(+) channel KvAP (prokaryotic Kv from Aeropyrum pernix). The solution structure of the KvAP VSD solubilized within phospholipid micelles is similar to a previously determined crystal structure solubilized by a nonionic detergent and complexed with an antibody fragment. The differences observed include a previously unidentified short amphipathic alpha-helix that precedes the first transmembrane helix and a subtle rigid-body repositioning of the S3-S4 voltage sensor paddle. Using (15)N relaxation experiments, we show that much of the VSD, including the pronounced kink in S3 and the S3-S4 paddle, is relatively rigid on the picosecond-to-nanosecond timescale. In contrast, the kink in S3 is mobile on the microsecond-to-millisecond timescale and may act as a hinge in the movement of the paddle during channel gating. We characterized the VSD-phospholipid micelle interactions using nuclear Overhauser effect spectroscopy and showed that the micelle uniformly coats the KvAP VSD and approximates the chemical environment of a phospholipid bilayer. Using paramagnetically labeled phospholipids, we show that bilayer-forming lipids interact with the S3 and S4 helices more strongly than with S1 and S2. PMID- 20851708 TI - Sampling-through-time in birth-death trees. AB - I consider the constant rate birth-death process with incomplete sampling. I calculate the density of a given tree with sampled extant and extinct individuals. This density is essential for analyzing datasets which are sampled through time. Such datasets are common in virus epidemiology as viruses in infected individuals are sampled through time. Further, such datasets appear in phylogenetics when extant and extinct species data is available. I show how the derived tree density can be used (i) as a tree prior in a Bayesian method to reconstruct the evolutionary past of the sequence data on a calender-timescale, (ii) to infer the birth- and death-rates for a reconstructed evolutionary tree, and (iii) for simulating trees with a given number of sampled extant and extinct individuals which is essential for testing evolutionary hypotheses for the considered datasets. PMID- 20851709 TI - Physiological and health consequences of social status in zebrafish (Danio rerio). AB - Social status affects access to food, mates and shelter and has consequences for the physiology of individuals and their health status. In the zebrafish (Danio rerio), an emerging model for studies into animal behavior, the possible consequences of social hierarchy to an individual's physiology and health are unknown. To address this, in this species we assessed the effects of social interaction (for periods of 1-5days) on growth, stress, immune function and reproductive condition. Wide-ranging differences in physiology occurred between the social ranks, some of which were sex-related and time-dependent. In both sexes, dominant fish were larger than subordinates and dominant males had a higher growth rate during the trials. Subordinates had higher plasma cortisol and in males higher telencephalic corticotrophin-releasing hormone, neuropeptide y and glucocorticoid receptor gene expression. Splenic cytokine expression suggested differences in immune status between ranks in both sexes and hematocrit was elevated in subordinate males. In both sexes, dominants and subordinates differed in the expression of genes for various gonadal sex steroid receptors and steroidogenic enzymes and in dominant females the ovary was larger relative to body mass compared with in subordinates. Dominant males had higher plasma 11 ketotestosterone than subordinates and there was an increase in the number of spermatids in their testes over the duration of the study that was not seen in subordinate males. The wide-ranging physiological differences seen between dominant and subordinate zebrafish as a consequence of their social status suggest negative health impacts for subordinates after prolonged durations in those hierarchies. PMID- 20851710 TI - Dienogest, a synthetic progestin, inhibits prostaglandin E2 production and aromatase expression by human endometrial epithelial cells in a spheroid culture system. AB - Prostaglandin E(2) (PGE(2)) is a major mediator in the pathophysiology, and pathogenesis of gynecological diseases associated with abnormal endometrial disease with proliferation and inflammation, such as endometriosis. In this study, we investigated the effect of dienogest, a selective progesterone receptor agonist, on PGE(2) production and the expression of aromatase, an estrogen synthase, in human immortalized endometrial epithelial cells. Compared with monolayer culture, the cells showed enhanced PGE(2) production and expression of the PGE(2) synthases cyclooxygenase-2 (COX-2), and microsomal prostaglandin E(2) synthase-1 (mPGES-1) in a spheroid culture system. Dienogest inhibited PGE(2) production and this effect was reversed by RU486, a progesterone receptor antagonist. Dienogest inhibited the PGE(2) synthases mRNA and protein expression, and the nuclear factor-kappaB activation. Moreover, the suppressive effect of dienogest on PGE(2) production was sustained 24h after the drug was withdrawn. Dienogest but not COX inhibitors inhibited aromatase expression. These results suggest that progesterone receptor activation reduces the gene expressions of COX 2, mPGES-1, and aromatase. Our findings suggest that the pharmacological mechanism of dienogest includes the direct inhibition of PGE(2) synthase and aromatase expression and may contribute to the therapeutic effect on the progression of endometriosis. PMID- 20851711 TI - Gene expression in SK-Mel-28 human melanoma cells treated with the snake venom jararhagin. AB - Alternative approaches to improve the treatment of advanced melanomas are highly needed. The disintegrin domain of metalloproteinases binds integrin receptors on tumor cells, blocking migration, invasion, and metastatization. Previous studies showed that jararhagin, from the Bothrops jararaca snake venom, induces changes in the morphology and viability of SK-Mel-28 human melanoma cells, and decreases the number of metastases in mice injected with pre-treated cells. The purpose of this study was to evaluate the molecular effects of jararhagin on SK-Mel-28 cells and fibroblasts, concerning the expression of integrins, cadherins, caspases, and TP53 genes. Sub-toxic doses of jararhagin were administered to confluent cells. RT-PCR was performed following extraction of total RNA. Jararhagin treatments induced similar morphological alterations in both normal and tumor cells, with higher IC50 values for fibroblasts. Integrin genes were downregulated in untreated cells, except for ITGA6a,b, ITGAv, and ITGB3 which were highly expressed in SK-Mel-28. The integrin expression profiles were not affected by the toxin. However, jararhagin 30ng/MUl upregulated genes TP53, CDKN1A, CDKN2A, CASP3, CASP5, CASP6, CASP8, and E-CDH in SK-Mel-28, and genes ITGB6, ITGB7, CASP3, TP53, and CDKN1B in fibroblasts. Appropriate jararhagin concentration can have apoptotic and suppressant effects on SK-Mel-28 cells, rather than on fibroblasts, and can be used to develop potential anti-cancer drugs. PMID- 20851712 TI - Life-long caloric restriction: Effect on age-related changes in motoneuron numbers, sizes and apoptotic markers. AB - The first purpose of this study was to determine the effect of advanced age (31 months) on the number of motoneurons in the lumbar enlargement of the rat and to determine if motoneurons die via apoptosis with age. The second purpose was to determine if caloric restriction (CR) would attenuate any observed age-related changes in motoneuron numbers or markers of apoptosis and ROS damage. Using immunohistochemistry to identify choline acetyltransferase (ChAT) - positive motoneurons in the ventro-lateral horn larger than 15MUm in diameter and having a clear soma and nucleus were sized and counted. Western blots were used to quantify markers of ROS, apoptosis and autophagy in the ventral horn of the lumbar enlargement. The results suggest that the total number of motoneurons in the rat lumbar enlargement does not significantly decrease with age. Also at the time of sacrifice, aged motoneurons were actively undergoing apoptosis through the intrinsic pathway, in a caspase-dependent manner. CR was able to attenuate the increase in body weight, body weight/muscle mass ratio and the level of activate caspase-3 associated with age. CR also reduced the level of heat shock protein 27, oxoguanine glycosylase 1, cytochrome c and LC3B-I. PMID- 20851713 TI - Intrathecal administration of a gap junction decoupler, an inhibitor of Na(+) K(+)-2Cl(-) cotransporter 1, or a GABA(A) receptor agonist attenuates mechanical pain hypersensitivity induced by REM sleep deprivation in the rat. AB - We studied the hypothesis that some of the spinal mechanisms that are involved in neuropathic hypersensitivity play a role in hypersensitivity induced by REM sleep deprivation (REMSD). Rats with a chronic intrathecal (i.t.) catheter had REMSD of 48h duration that induced hypersensitivity to mechanical stimulation. After REMSD, the animals were treated i.t. with carbenoxolone (a gap junction decoupler), bumetanide (a blocker of Na(+)-K(+)-2Cl(-) cotransporter 1 or NKCC1), muscimol (a GABA(A) receptor agonist), or pretreated intraperitoneally with minocycline (an inhibitor of microglia activation). Previously, all these treatments attenuated neuropathic hypersensitivity. Following REMSD, carbenoxolone, bumetanide and muscimol had a strong antihypersensitivity effect, whereas pretreatment with minocycline failed to prevent development of hypersensitivity. The results suggest that among spinal pain facilitatory mechanisms that are common to REMSD and neuropathy are NKCC1 blocker- and gap junction decoupler-reversible mechanisms. Moreover, there is a net pain inhibitory effect by spinal administration of an exogenous GABA(A) receptor agonist following REMSD as shown earlier in neuropathy. In contrast, activation of spinal microglia may not be as important for the development of hypersensitivity induced by REMSD as following nerve injury. PMID- 20851714 TI - Serpin-1 splicing isoform J inhibits the proSpatzle-activating proteinase HP8 to regulate expression of antimicrobial hemolymph proteins in Manduca sexta. AB - The innate immune system of insects include the Toll pathway, which is mediated by an extracellular serine proteinase cascade. In the tobacco hornworm, Manduca sexta, hemolymph proteinase 8 (HP8) promotes the synthesis of antimicrobial proteins by cleaving proSpatzle, the putative ligand of M. sexta Toll. HP8 has been observed to form a complex in hemolymph with M. sexta serpin-1, which has multiple alternative splicing isoforms. To investigate the regulation of HP8 and its processing of proSpatzle, we characterized the interaction of recombinant HP8 with serpin-1 isoform J (serpin-1J). Recombinant serpin-1J formed an SDS-stable complex with HP8 in vitro. The association rate constant of serpin-1J and HP8 was 1.3*10(4)M(-1)s(-1), with a stoichiometry of inhibition of 5.4. Serpin-1J inhibited the cleavage of proSpatzle by HP8. Injection of serpin-1J into M. sexta larvae resulted in decreased bacteria-induced antimicrobial activity in hemolymph and reduced expression of cecropin, attacin and hemolin mRNA in fat body. Altogether, these results suggest that serpin-1J functions to inhibit HP8 and thereby modulates the concentration of active Spatzle to regulate the Toll pathway response in M. sexta. PMID- 20851716 TI - Antiviral activity of chondroitin sulphate E targeting dengue virus envelope protein. AB - Sulphated glycosaminoglycans such as heparin inhibit the early step of dengue virus infection through interaction with envelope (E) protein. Here, we found that chondroitin sulphate E (CSE), but not CSD, which contains the same degree of sulphation, inhibited dengue virus (DENV) infection of cells with adsorption. CSE significantly reduced infectivity of all dengue virus serotypes to BHK-21 and Vero cells. DENV preferentially bound to CSE immobilised on plastic plates. Also, virus binding to CSE or heparin was cross-inhibited by soluble CSE or heparin. These findings suggested that common carbohydrate determinants on CSE and heparin could be essential epitopes for interaction of DENV, and may be responsible for inhibition of the early steps of DENV infection. A recombinant E protein directly bound heparin and CSE, but not CSD, meaning that interaction of CSE with E protein contributes to the inhibitory action of this glycosaminoglycan. These observations indicate that a specific carbohydrate structure rather than polysulphation or addition of negative charges of the glycosaminoglycan molecule would be necessary for direct binding to DENV E protein. In conclusion, CSE showed antiviral activity as an entry inhibitor targeting E protein of dengue virus. PMID- 20851715 TI - Improved protection against avian influenza H5N1 virus by a single vaccination with virus-like particles in skin using microneedles. AB - To develop a more effective vaccination method against H5N1 virus, we investigated the immunogenicity and protective efficacy after skin vaccination using microneedles coated with influenza virus-like particles containing hemagglutinin derived from A/Vietnam/1203/04 H5N1 virus (H5 VLPs). A single microneedle vaccination of mice with H5 VLPs induced increased levels of antibodies and provided complete protection against lethal challenge without apparent disease symptoms. In contrast, intramuscular injection with the same vaccine dose showed low levels of antibodies and provided only partial protection accompanied by severe body weight loss. Post-challenge analysis suggested that improved protection was associated with lower lung viral titers and enhanced generation of recall antibody secreting cells by microneedle vaccination. Thus, this study provides evidence that skin delivery of H5 VLP vaccines using microneedles designed for self-administration induces improved protection compared to conventional intramuscular immunization. PMID- 20851717 TI - Midazolam reduces the selective activation of the rhinal cortex by contextual fear stimuli. AB - Independent brain circuits appear to underlie different forms of conditioned fear, depending on the type of conditioning used, such as a context or explicit cue paired with footshocks. Several clinical reports have associated damage to the medial temporal lobe (MTL) with retrograde amnesia. Although a number of studies have elucidated the neural circuits underlying conditioned fear, the involvement of MTL components in the aversive conditioning paradigm is still unclear. To address this issue, we assessed freezing responses and Fos protein expression in subregions of the rhinal cortex and ventral hippocampus of rats following exposure to a context, light or tone previously paired with footshock (Experiment 1). A comparable degree of freezing was observed in the three types of conditioned fear, but with distinct patterns of Fos distribution. The groups exposed to cued fear conditioning did not show changes in Fos expression, whereas the group subjected to contextual fear conditioning showed selective activation of the ectorhinal (Ect), perirhinal (Per), and entorhinal (Ent) cortices, with no changes in the ventral hippocampus. We then examined the effects of the benzodiazepine midazolam injected bilaterally into these three rhinal subregions in the expression of contextual fear conditioning (Experiment 2). Midazolam administration into the Ect, Per, and Ent reduced freezing responses. These findings suggest that contextual and explicit stimuli endowed with aversive properties through conditioning recruit distinct brain areas, and the rhinal cortex appears to be critical for storing context-, but not explicit cue footshock, associations. PMID- 20851718 TI - Identification of hyperactive intrinsic amygdala network connectivity associated with impulsivity in abstinent heroin addicts. AB - Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and 15 cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction. PMID- 20851719 TI - Genome-wide RNAi screens in bloodstream form trypanosomes identify drug transporters. AB - An inducible RNA interference (RNAi) library, consisting of a pool of independent stable transformants with 9-fold genome coverage, was constructed in bloodstream form Trypanosoma brucei using an improved transfection protocol. RNAi induction and selection of resistant parasites was performed in the presence of melarsoprol or eflornithine. The former led to the isolation of the adenosine transporter TbAT1, which is known to be involved in melarsoprol uptake, while the latter identified an amino acid transporter, AAT6. Knockdown of AAT6 reduced mRNA levels to 30-35% in independent clones and increased resistance to eflornithine >5-fold. Genome-wide screens with this library allow an unbiased approach to gene discovery, are extremely rapid and do not exclude essential genes. PMID- 20851720 TI - Neurogenesis in the dentate gyrus of the rat hippocampus enhanced by tickling stimulation with positive emotion. AB - Hippocampal neurogenesis is influenced by many factors. In this study, we examined the effect of tactile stimulation (tickling), which induced positive emotion, on neurogenesis in the dentate gyrus (DG) of the hippocampus. Four week old rats were tickled for 5 min/day on 5 consecutive days and received 5-bromo-2' deoxyuridine (BrdU) administration for 4 days from the second tickling day. Then they were allowed to survive for 18 h or 3 weeks after the end of BrdU treatment. Neurogenesis in the DG was compared between the tickled and untickled rats by using immunohistochemistry with anti-BrdU antibody. The result showed that the number of BrdU- and NeuN (neural cell marker)-double positive neurons on 18h as well as 3 weeks of the survival periods was significantly increased in the tickled group as compared with the untickled group. The expression of mRNA of brain-derived neurotrophic factor (BDNF) in the hippocampus of the tickled rats was not altered when compared with the control rats. In conclusion, tickling stimulation which induces positive emotion may affect the generation and survival of new neurons of the DG through the BDNF-independent pathway. PMID- 20851721 TI - Expression of interfering RNAs from an HIV-1 Tat-inducible chimeric promoter. AB - The therapeutic value of antiviral interfering RNAs could be improved by technologies that limit their expression to the infected cell population. The HIV 1 Tat-inducible viral LTR and LTR-containing chimeric promoters have previously been used to drive expression of antiviral RNAs and proteins directed against HIV 1. Here, we characterize an alternative promoter, consisting of a chicken beta actin core promoter fused to the viral TAR element, for the conditional expression of interfering RNAs. This promoter, that we refer to as the CK-TAR promoter, can induce levels of silencing comparable to the viral LTR in response to Tat produced from co-transfected plasmids or during viral replication. While the CK-TAR promoter shows a modest level of basal activity, similar to the viral LTR, it is less responsive to the extracellular stimuli tested including LPS, TNFalpha, and PMA. The CK-TAR promoter is an alternative Tat-inducible promoter with the potential to minimize the risk of vector mobilization and to drive polycistronic expression of interfering RNAs. PMID- 20851722 TI - Structural changes in the SL5 and SL6 leader sequences of HIV-1 RNA following interactions with the viral mGag protein. AB - We previously identified sequences downstream of the SL4 region of HIV-1 RNA that are involved in the recognition of the 5' leader region of HIV-1 RNA by a minimal version of the HIV-1 Gag protein (mGag). These sequences increase the affinity of this interaction, promote Gag multimerization, and enhance formation of an early mGag-RNA complex. Now, we provide protein footprinting results on the +350 to +500 nucleotide region of viral RNA, based on use of different single-stranded and base-paired ribonucleases. Use of the mfold program confirmed the existence of both a stem-loop 5 (SL5), downstream of SL4, and a more complex multi-stem loop structure (SL6). Footprinting analysis using mGag and single-stranded specific nucleases showed almost complete protection of the single-stranded region. In contrast, results obtained with RNase V1, a double-stranded-specific nuclease, suggest that the RNA structure is changed upon protein binding, presumably because of formation of novel and longer stems. Furthermore, RNA footprinting, using viral nucleocapsid protein (NC) and RNase VI, indicate a highly double-stranded structure in several regions. These findings show that viral RNA structure is modified by interaction with proteins, and that NC may possess different chaperone activity in the context of the Gag precursor than in its mature form. PMID- 20851723 TI - Taming PRRSV: revisiting the control strategies and vaccine design. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) continues to be a threat, causing economically significant impacts on the swine industry worldwide. In this article, we share the information related to the Thai PRRSV and review the available options for PRRS control strategies. Unfortunately, the traditional control strategies and conventional vaccines fail to provide sustainable disease control, as they suffer from both antigenic heterogeneity and various immune evasion strategies of PRRSV. Induction of interleukin (IL)-10 following PRRSV infection is believed to be a focal mechanism leading to the unique immunological outcomes and interference of PRRS vaccine efficacy. It is likely that the nucleocapsid protein plays an important role in induction of IL-10 following PRRSV infection. We propose that removal or reduction of the PRRSV-induced, negative immunomodulatory effects especially during the first 2 weeks following infection is essential to establish proper anti-PRRSV immunity. In other word, incorporation of the "taming strategy" will be needed to reduce PRRSV-induced immunomodulatory effects, and to ensure maximal vaccine-induced immunity in the face of viral exposure. Any PRRSV vaccine that can induce cross-protective immunity and simultaneously eliminate the immunoinhibitory effects of PRRSV would be ideal. In addition, tracking of the inhibitory parameters, following the PRRSV challenge should be included in the vaccine testing protocol. Therefore, the future of PRRSV vaccine development relies tremendously on the basic knowledge of host-virus interactions and the communication between the basic and clinical PRRSV research fields. PMID- 20851724 TI - Short term effects of alcohol on appetite in humans. Effects of context and restrained eating. AB - The present study examined further the short-term effects of alcohol on food intake and appetite in women volunteers, testing the extent to which the apparent appetizing effects of alcohol depend on (a) expectations that alcohol had been consumed and (b) disinhibition of dietary restraint. Twenty restrained and 20 unrestrained women consumed a drink preload 30 min before a test meal on four different days, with preloads varying in alcohol content (alcohol or energy matched control) and drink context (alcohol-related - beer or alcohol unrelated - juice). Significantly more energy was consumed following alcohol than no-alcohol, but this effect depended on the drink consumed: least was eaten after the alcohol free juice drink, and most after the same juice drink with added alcohol. There was no evidence that the effect of alcohol on intake was due to disinhibition of restrained eating, nor did alcohol increase liking for the test foods. The change in energy intake at lunch was mainly due to greater intake of energy-rich foods on days when alcohol had been consumed. Alcohol also increased rated appetite once food had been tasted, suggesting alcohol may increase food-related reward. Overall these data suggest that effects of alcoholic drinks represent a complex interaction between physiological effects of alcohol and expectations and associations generated by past experience of alcoholic drinks. PMID- 20851725 TI - Body weight gain in rats consuming sweetened liquids. Effects of caffeine and diet composition. AB - Previous studies show that high-intensity sweeteners can stimulate weight gain in rats. The present studies examined whether caffeine, a stimulant commonly added to beverages consumed by humans, influences intake of saccharin- or glucose sweetened solutions or body weight gain in rats and whether the nature of the maintenance diet influences the effects of caffeine. In two experiments, rats received glucose or saccharin solution mixed with 0.125 mg/g caffeine or no caffeine. Rats consumed significantly more caffeinated than noncaffeinated solutions when they were maintained on a low-fat chow diet (Experiment 1) and when maintained on a sweet, high-fat, high calorie chow diet (Experiment 2). Consumption of saccharin resulted in higher body weight gain in both experiments. Caffeine reversed this effect in Experiment 1 (low-fat diet) but not Experiment 2 (sweet, high-fat diet). The findings extend what is known about the conditions under which consumption of high intensity sweeteners promote energy dysregulation. PMID- 20851726 TI - Food liking, familiarity and expected satiation selectively influence portion size estimation of snacks and caloric beverages in men. AB - We explored the relationship between three food attributes and portion size estimation. Twenty-seven men rated liking, familiarity and expected satiation (ES) of a chocolate bar, muffin, banana, cola, cornflakes, potato chips (crisps), hot chocolate drink and ice-cream, before estimating portion size when hungry and full. Portion estimates correlated with liking ratings in three foods (r = -0.53 to 0.28); with familiarity in two foods (r = -0.30, full only); and with ES in four foods (r <= 0.45). Across foods lower ES ratings tended to correlate with higher portion size estimates. Portion size estimation is influenced by food liking, familiarity and expected satiation. PMID- 20851727 TI - Gender and food, a study of attitudes in the USA towards organic, local, U.S. grown, and GM-free foods. AB - Food choice is influenced by consumer attitudes towards food attributes. This U.S.-based study (n = 601) simultaneously compares attitudes towards selected food attributes of organic, locally grown, U.S. grown, and GM-free food in relation to other food attributes. Exploratory factor analysis identifies underlying constructs that determine, together and separately, female and male food choice decisions. Gendered analysis of the value of food in life and food behaviours (cooking and shopping) support the investigation of the highlighted food attributes. Respondents generally assigned greater importance to the U.S. grown, followed by GM-free, locally grown, and organically produced food attributes in deciding what to eat. Analysis of the female and male subsamples yielded similar factor results. All four main attributes were captured in a single factor, associated with respondents in both the female and male subsamples who are older, have lower incomes, and who are religiously observant. Additionally, among females, this factor was associated with higher education; and among males, living in households with children and/or with partners. Additional studies should further explore the interaction of food attributes now becoming increasingly important and prevalent in current food products. PMID- 20851728 TI - Test-retest reliability and comparison of children's reports with parents' reports of young children's fruit and vegetable preferences. AB - The aim of this study is to investigate the test-retest reliability of a short computerized assessment of young children's fruit (F) and vegetable (V) preferences, and to compare children's responses with their parents' responses. A paper-and-pencil F and V preference and F and V food frequency questionnaire was completed by 194 parents. Data on 139 preschoolers was available for test and retest of F preferences and data on 135 children for V. F and V preference scales were computed, including the ten most commonly consumed F and the ten most commonly consumed V. Alpha reliabilities were good (F = 0.78; V = 0.76) and test retest intraclass correlations were high (ICC for F = 0.74; V = 0.75). Agreement between parents' and children's reports was moderate (F: ICC = 0.48, V: ICC = 0.41). Children reported more often to have never consumed an item, and less often the midcategory "not yummy, not yucky but ok". Covariance analysis indicated differences in agreement by school and mothers' education level with a lower agreement for those of lower social status. A weak, but significant association was found between children's reported preferences and children's consumption (F: r = 0.19, V: r = 0.25). The results are promising, but additional validation is needed in a representative sample and should further explore the sources of disagreements. PMID- 20851729 TI - Sugar alters the level of serum insulin and plasma glucose and the serum cortisol:DHEAS ratio in female migraine sufferers. AB - Early work has highlighted that a large percentage of migraineurs may have an altered glucidic methabolis due to carbohydrate-induced hyperinsulinism. The aim of this study was to assess the effect of sucrose on biomarkers of energy metabolism and utilization in migraineous females. A total of 16 participants (8 = Migraine, 8 = Non-migraine) at the mid-point of their menstrual cycle underwent a 15-h fast prior to ingesting 75 g sucrose dissolved in 175 g water. Blood sampling for the assessment of serum insulin, serum cortisol and serum dehydroepiandrosterone sulfate (DHEAS) and plasma glucose was conducted upon arrival at 09:00 h and then at regular 15-min intervals across a 150-min experimental period. The results showed a significant alteration in serum insulin and plasma glucose following sucrose ingestion in the migraine and non-migraine groups. In addition, significant group differences were observed in the level of serum insulin, serum DHEAS, and the cortisol:DHEAS ratio with migraine participants on average recording a higher sucrose-induced serum insulin level and lower DHEAS level and cortisol:DHEAS ratio when group data was compared. It was concluded that while sucrose consumption may potentiate serum insulin in migraineurs this does not result in the development of sucrose-induced hypoglycemia in migraine or non-migraine participants. PMID- 20851730 TI - Characterization of bioactive compounds from raw and ripe Mangifera indica L. peel extracts. AB - Mango is one of the important tropical fruits in the world. As it is a seasonal fruit, it is processed for various products. During its processing, peel is one of the major byproducts, which is being wasted. Bioactive conserves were extracted using 80% acetone from peels of raw and ripe mango fruits and subjected to acid hydrolysis. The prominent phenolic compounds identified by HPLC were protocatechuic acid, gentisic acid and gallic acid. The phenolic acid derivatives present in acetone extracts of raw and ripe peels were tentatively identified by LC-MS. Gallic acid, syringic acid, mangiferin, ellagic acid, gentisyl protocatechuic acid, quercetin were the phenolic compounds identified in both raw and ripe peels, while raw peel showed the presence of glycosylated iriflophenone and maclurin derivatives also. beta-Carotene was the major carotenoid followed by violaxanthin and lutein. Thus, both raw and ripe mango peel extracts have different phenolic compounds and carotenoids, which will have various pharmaceutical applications. PMID- 20851731 TI - Ameliorative role of conjugated linolenic acid isomers against oxidative DNA damage induced by sodium arsenite in rat model. AB - The present study was undertaken to evaluate the ameliorative role of alpha eleostearic acid and punicic acid, isomers of conjugated linolenic (CLnA) acid, against oxidative stress induced DNA damage. Male albino rats were divided into six groups. Group 1 and 2 were normal control and sodium arsenite treated (Sa; 10 mg/kg BW) control respectively. Group 3-6 were orally treated with different doses of two fatty acids (0.5% and 1.0% of total lipid given for each isomer) along with sodium arsenite (Sa; 10 mg/kg BW). Comet assay of blood leukocytes showed that administration of CLnA reduced DNA damage significantly (P<0.05) which was determined by tail DNA percent and olive tail moment. Results showed that activity of antioxidant enzymes viz. catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) in plasma, liver and erythrocyte lysate decreased and activity of nitric oxide synthase in plasma and liver increased significantly due to oxidative stress generated by sodium arsenite. Administration of CLnA isomers restored all the altered parameters and also reduced lipid peroxidation and leakage of transaminase enzymes from liver to blood due to liver injury. alpha-Eleostearic acid was more efficient antioxidant than punicic acid against oxidative DNA damage. PMID- 20851732 TI - Bacterial metabolic 'toxins': a new mechanism for lactose and food intolerance, and irritable bowel syndrome. AB - Lactose and food intolerance cause a wide range of gut and systemic symptoms, including gas, gut pain, diarrhoea or constipation, severe headaches, severe fatigue, loss of cognitive functions such as concentration, memory and reasoning, muscle and joint pain, heart palpitations, and a variety of allergies (Matthews and Campbell, 2000; Matthews et al., 2005; Waud et al., 2008). These can be explained by the production of toxic metabolites from gut bacteria, as a result of anaerobic digestion of carbohydrates and other foods, not absorbed in the small intestine. These metabolites include alcohols, diols such as butan 2,3 diol, ketones, acids, and aldehydes such as methylglyoxal (Campbell et al., 2005, 2009). These 'toxins' induce calcium signals in bacteria and affect their growth, thereby acting to modify the balance of microflora in the gut (Campbell et al., 2004, 2007a,b). These bacterial 'toxins' also affect signalling mechanisms in cells around the body, thereby explaining the wide range of symptoms in people with food intolerance. This new mechanism also explains the most common referral to gastroenterologists, irritable bowel syndrome (IBS), and the illness that afflicted Charles Darwin for 50 years (Campbell and Matthews, 2005a,b). We propose it will lead to a new understanding of the molecular mechanism of type 2 diabetes and some cancers. PMID- 20851733 TI - Parkinson's disease: insights from non-traditional model organisms. AB - Parkinson's disease (PD) was one of the first neurological disorders to have aspects of the disease modeled faithfully in non-human animal species. A key feature of the disease is a diminished control over voluntary movement and progressive depletion of brain dopamine (DA) levels that stems from the large scale loss of DA-producing neurons. Despite their inherent limitations, rodent and non-human primate models of PD have helped unravel several aspects of PD pathogenesis. Thus, we now have neurotransmitter replacement therapy for PD, and a number of neuroprotective compounds that can be assessed in clinical trials. However, no treatment is currently available that can halt or retard the progressive loss of DA neurons, which underlies PD pathology. Moreover, no therapies can permanently alleviate the clinical features of the disease. The lack of a cure or long-term effective treatment is paralled by our incomplete understanding of the underlying pathomechanisms of the disease. A range of robust, flexible, and complementary animal models will be an invaluable tool with which to unravel the pathogenesis of PD. Here we review the most important contributions made by non-mammalian model organisms. These include zebrafish (Danio rerio), flies (Drosophila melanogaster), anurans (frogs and toads) and nematodes (Caenorhabditis elegans). While it is not anticipated that they will replace rodent and primate-based ones, they offer convenient systems with which to explore the relative contribution made by genetic and environmental factors to PD pathology. In addition, they offer an economic and rapid alternative for testing compounds that target PD. Most importantly, the combined use of these models allow for ongoing research to uncover the basic mechanisms underlying PD pathogenesis. PMID- 20851734 TI - Psychophysiology of spider phobia in 8- to 12-year-old girls. AB - The present investigation focused on late event-related potentials (ERPs) and facial electromyographic (EMG) activity in response to symptom provocation in 8- to 12-year-old spider phobic girls and compared results to those in non-fearful controls. Fourteen patients and 14 controls were presented with phobia-relevant, generally fear-inducing, disgust-inducing and affectively neutral pictures in an EEG/EMG session. ERPs were extracted in the time-windows 340-500ms (P300) and 550 770ms (late positive potential, LPP). Relative to controls, phobics showed enhanced amplitudes of P300 and LPP in response to spider pictures. This result is interpreted to reflect motivated attention to emotionally salient stimuli. Moreover, phobics showed enhanced average facial EMG activity of the levator labii and the corrugator supercilii in response to spider pictures, reflecting the negative valence and disgust relevance of spiders. Additionally, spider phobic girls relative to controls showed higher overall disgust proneness and heightened average facial EMG activity in both muscle regions in response to disgust stimuli, possibly revealing a disgust-based origin of spider phobia in children. These aspects should be considered in psychotherapeutic treatment of childhood spider phobia. PMID- 20851735 TI - Upward spirals of the heart: autonomic flexibility, as indexed by vagal tone, reciprocally and prospectively predicts positive emotions and social connectedness. AB - Vagal tone (VT), an index of autonomic flexibility, is linked to social and psychological well-being. We posit that the association between VT and well-being reflects an "upward spiral" in which autonomic flexibility, represented by VT, facilitates capitalizing on social and emotional opportunities and the resulting opportunistic gains, in turn, lead to higher VT. Community-dwelling adults were asked to monitor and report their positive emotions and the degree to which they felt socially connected each day for 9 weeks. VT was measured at the beginning and end of the 9-week period. Adults who possessed higher initial levels of VT increased in connectedness and positive emotions more rapidly than others. Furthermore, increases in connectedness and positive emotions predicted increases in VT, independent of initial VT level. This evidence is consistent with an "upward spiral" relationship of reciprocal causality, in which VT and psychosocial well-being reciprocally and prospectively predict one another. PMID- 20851736 TI - Active centrum hypothesis: the origin of chiral homogeneity and the RNA-world. AB - I propose a hypothesis on the origin of chiral homogeneity of bio-molecules based on chiral catalysis. The first chiral active centre may have formed on the surface of complexes comprising metal ions, amino acids, other coenzymes and oligomers (short RNAs). The complexes must have been dominated by short RNAs capable of self-reproduction with ligation. Most of the first complexes may have catalysed the production of nucleotides. A basic assumption is that such complexes can be assembled from their components almost freely, in a huge variety of combinations. This assumption implies that "a few" components can constitute "a huge" number of active centre types. Moreover, an experiment is proposed to test the performance of such complexes in vitro. If the complexes were built up freely from their elements, then Darwinian evolution would operate on the assembly mechanism of complexes. For the production of complexes, first their parts had to appear by forming a proper three-dimensional structure. Three possible re-building mechanisms of the proper geometric structure of complexes are proposed. First, the integration of RNA parts of complexes was assisted presumably by a pre-intron. Second, the binding of RNA parts of a complex may give rise to a "polluted" RNA world. Third, the pairing of short RNA parts and their geometric conformation may have been supported by a pre-genetic code. Finally, an evolutionary step-by-step scenario of the origin of homochirality and a "polluted" RNA world is also introduced based on the proposed combinatorial complex chemistry. Homochirality is evolved by Darwinian selection whenever the efficiency of the reflexive autocatalysis of a dynamical combinatorial library increases with the homochirality of the active centres of reactions cascades and the homochirality of the elements of the dynamical combinatorial library. Moreover, the potential importance of phospholipid membrane is also discussed. PMID- 20851737 TI - Diffusion-convection effects on drug distribution at the cell membrane level in a patch-clamp setup. AB - We present a model-based method for estimating the effective concentration of the active drug applied by a pressure pulse to an individual cell in a patch-clamp setup, which could be of practical use in the analysis of ligand-induced whole cell currents recorded in patch-clamp experiments. Our modelling results outline several important factors which may be involved in the high variability of the electric response of the cells, and indicate that with a pressure pulse duration of 1s and diameter of the perfusion tip of 600 MUm, elevated amounts of drug can accumulate locally between the pipette tip and the cell. Hence, the effective agonist concentration at the cell membrane level can be consistently higher than the initial concentration inside the perfusion tubes. We performed finite difference and finite-element simulations to investigate the diffusion/convection effects on the agonist distribution on the cell membrane. Our model can explain the delay between the commencement of acetylcholine application and the onset of the whole-cell current that we recorded on human rhabdomyosarcoma TE671 cells, and reproduce quantitatively the decrease of signal latency with the concentration of agonist in the pipette. Results also show that not only the geometry of the bath chamber and pipette tip, but also the transport parameters of the diffusive and convective phenomena in the bath solution are determinant for the amplitude and kinetics of the recorded currents and have to be accounted for when analyzing patch-clamp data. PMID- 20851738 TI - Non-Gaussian noise-optimized intracellular cytosolic calcium oscillations. AB - We have numerically studied the effect of a particular kind of non-Gaussian colored noise (NGN), characterized by the deviation q from Gaussian noise (q=1), on intracellular cytosolic calcium (Ca(2+)) oscillations. It is found that, as q is increased, the Ca(2+) oscillation regularity increases and reaches a best performance at an optimal q, and then decreases with further increasing q, which represents the occurrence of coherence resonance, i.e., the most regular Ca(2+) oscillations. Similar phenomena occur for different values of noise intensity and correlation time of the NGN. This phenomenon of deviation-optimized Ca(2+) oscillations show that, external non-Gaussian noises of different types can enhance and even optimize the intracellular Ca(2+) oscillations. This result provides new insights into the constructive roles and potential applications of non-Gaussian noises in intracellular cytosolic Ca(2+) oscillations. PMID- 20851739 TI - A hierarchical approach to model parameter optimization for developmental systems. AB - In the context of Systems Biology, computer simulations of gene regulatory networks provide a powerful tool to validate hypotheses and to explore possible system behaviors. Nevertheless, modeling a system poses some challenges of its own: especially the step of model calibration is often difficult due to insufficient data. For example when considering developmental systems, mostly qualitative data describing the developmental trajectory is available while common calibration techniques rely on high-resolution quantitative data. Focusing on the calibration of differential equation models for developmental systems, this study investigates different approaches to utilize the available data to overcome these difficulties. More specifically, the fact that developmental processes are hierarchically organized is exploited to increase convergence rates of the calibration process as well as to save computation time. Using a gene regulatory network model for stem cell homeostasis in Arabidopsis thaliana the performance of the different investigated approaches is evaluated, documenting considerable gains provided by the proposed hierarchical approach. PMID- 20851740 TI - Current profiles of astrocytes from the corpus callosum of newborn and 28-day-old rats. AB - In astrocytes, ion currents are predominantly carried by K(+) ions, and their potassium channel expression changes during development. Here, we studied ion current generated by voltage-ramp protocols in cultured astrocytes from the corpus callosum of newborn (P0) and 28-day-old (P28) rats. Inward currents measured at -140 mV and chord conductances measured from -140 to -75 mV, were smaller in P0-astrocytes than in P28-astrocytes, and in P28-astrocytes were affected by 100 MUM Ba(2+), indicating the presence of an inward rectifier K(+) (Kir) current. On the other hand, P0-astrocytes showed higher outward current measured at 80 mV and a higher chord conductance, between 0 and 80 mV, than P28 astrocytes. The outward current was more potently reduced by 2mM Ba(2+) in P0 astrocytes than in P28-astrocytes, and slightly reduced at both ages using low concentrations of Ba(2+). Moreover, outward current was partially blocked by iberiotoxin in P0-astrocytes, indicating the presence of big-conductance Ca(2+) activated K(+) (BK) channels. In addition, 4-aminopyridine inhibited the outward current in P0- and P28-astrocytes. In summary, P0-astrocytes exhibited the BK current, a major density of delayed rectifier K(+) (K(DR)) current, and a low density of the Kir current, whereas P28-astrocytes presented a major density of Kir current, a low density of the K(DR) current, and the absence of BK current. These results could contribute to a better understanding of the role of K(+) currents in the corpus callosum. PMID- 20851741 TI - NMDA R1 receptor distribution in the cyprid of Balanus amphitrite (=Amphibalanus amphitrite) (Cirripedia, Crustacea). AB - The ontogenetic cycle of the barnacle Balanus amphitrite (=Amphibalanus amphitrite) (Darwin, 1854) includes a cyprid that binds submerged surfaces, metamorphosing into a sessile adult. gamma-Aminobutyric acid (GABA) and GABA receptors have recently been located in its cyprid with a similar pattern to other crustaceans. Since NMDA R1 ionotropic glutamatergic receptors have been identified in crustacean neuromuscular junctions, we have investigated their presence in the B. amphitrite cyprid. The presence of NMDA R1 receptors might indicate a role for glutamate in neuromuscular control in B. amphitrite cyprids, therefore we studied the presence and distribution of the NMDA R1 by immunohistochemistry. Its distribution was observed in the peripheral nervous system and in non-neuronal elements. Actually, NMDA R1 immunoreactivity was detected in thoracic appendages, at the level of neuromuscular junctions, thus suggesting an involvement in motor control functions, as already demonstrated in other crustaceans. Immunoreactivity was also detected in ommatidia cells of the eye, in antennules, and in epidermal cells. The distribution pattern comparable to that of GABAergic molecules could indicate an interrelated agonistic/antagonistic role for these two systems, which could be considered as potential targets of combined antifouling strategies. PMID- 20851742 TI - Simvastatin treatment improves functional recovery after experimental spinal cord injury by upregulating the expression of BDNF and GDNF. AB - The aim of this study was to determine the therapeutic efficacy of simvastatin treatment starting 1 day after spinal cord injury (SCI) in rat and to investigate the underlying mechanism. Spinal cord injury was induced in adult female Sprague Dawley rats after laminectomy at T9-T10. Then additionally with sham group (laminectomy only) the SCI animals were randomly divided into 3 groups: vehicle treated group; 5-mg/kg simvastatin-treated group; and 10-mg/kg simvastatin treated group. Simvastatin or vehicle was administered orally at 1 day after SCI and then daily for 5 weeks. Locomotor functional recovery was assessed during 8 weeks postoperation by performing open-field locomotor test and inclined-plane test. At the end of study, motor evoked potentials (MEPs) and somatosensory evoked potentials (SEPs) were assessed to evaluate the integrity of spinal cord pathways. Then, the animals were killed, and 1-cm segments of spinal cord encompassing the injury site were removed for histopathological analysis. Immunohistochemistry was performed to observe the expression of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) in the spinal cord. Results show that the simvastatin-treated animals showed significantly better locomotor function recovery, better electrophysiological outcome, less myelin loss, and higher expression of BDNF and GDNF. These findings suggest that simvastatin treatment starting 1 day after SCI can significantly improve locomotor recovery, and this neuroprotective effect may be related to the upregulation of BDNF and GDNF. Therefore, simvastatin may be useful as a promising therapeutic agent for SCI. PMID- 20851744 TI - Influence of sex on reinstatement of cocaine-conditioned place preference. AB - To explore sex differences in reinstatement of conditioned place preference, we subjected intact male and female Long Evans rats to an extended conditioned place preference (CPP) paradigm, which included observations of acquisition, extinction, and reinstatement of a preference to cocaine-paired stimuli. In a series of experiments, separate groups of animals were given six 30-min pairings of one chamber with cocaine (3, 5, 10, 15, 20, 25mg/kg) and six of the other with saline on alternate days. Overall, there were no sex differences in acquisition of cocaine CPP at any of the six doses tested (p>0.05). All animals established cocaine CPP at each of the six doses tested during the acquisition test, with the exception of the group of females conditioned with 5mg/kg. Preferences for the cocaine-paired chamber were successfully extinguished for both males and females after an extinction-training period. CPP reinstatement was achieved by the groups of males and females given training and priming doses of 10, 15, 20, and 25mg/kg (p<0.05). Overall, our reinstatement data demonstrate that reinstatement of cocaine CPP is greater for female versus male animals. Females showed a greater magnitude of reinstatement of cocaine CPP when trained and primed with 15 and 25mg/kg as compared to males (p<0.05). Further, at the three highest doses tested (15, 20, and 25mg/kg), females showed a greater magnitude of CPP in the reinstatement phase of CPP compared to that of the initial acquisition phase (p<0.05). The reinstatement data for the males show that the 20mg/kg dose resulted in the highest levels of reinstatement preference for male rats. These results indicate that sex differences in reinstatement to conditioned behavior maybe due, in part, to females forming a stronger association for the salience of the drug and the environment in which it was administered. PMID- 20851743 TI - Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain. AB - For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, tropomyosin receptor kinase A (TrkA) expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release nerve growth factor (NGF), which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that, the earlier therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain. PMID- 20851745 TI - Hypoglycemia induced behavioural deficit and decreased GABA receptor, CREB expression in the cerebellum of streptozoticin induced diabetic rats. AB - Intensive glycemic control during diabetes is associated with an increased incidence of hypoglycemia, which is the major barrier in blood glucose homeostasis during diabetes therapy. The CNS neurotransmitters play an important role in the regulation of glucose homeostasis. In the present study, we showed the effects of hypoglycemia in diabetic and non- diabetic rats on motor functions and alterations of GABA receptor and CREB expression in the cerebellum. Cerebellar dysfunction is associated with seizure generation, motor deficits and memory impairment. Scatchard analysis of [(3)H]GABA binding in the cerebellum of diabetic hypoglycemic and control hypoglycemic rats showed significant (P<0.01) decrease in B(max) and K(d) compared to diabetic and control rats. Real-time PCR amplification of GABA receptor subunit GABA(Aalpha1) and GAD showed significant (P<0.001) down-regulation in the cerebellum of hypoglycemic rats compared to diabetic and control rats. Confocal imaging study confirmed the decreased GABA receptors in hypoglycemic rats. CREB mRNA expression was down-regulated during recurrent hypoglycemia. Both diabetic and non-diabetic hypoglycemic rats showed impaired performance in grid walk test compared to diabetic and control. Impaired GABA receptor and CREB expression along with motor function deficit were more prominent in hypoglycemic rats than hyperglycemic which showed that hypoglycemia is causing more neuronal damage at molecular level. These molecular changes observed during hypo/hyperglycemia contribute to motor and learning deficits which has clinical significance in diabetes treatment. PMID- 20851746 TI - Neuroprotective effect of CPDT on THA-induced cortical motor neuron death in an organotypic culture model. AB - Brain stroke, trauma, and motor neuron disease each can result in cortical motoneuron (CMN) death or impairment. Glutamate excitotoxicity induces motor neuron damage in both acute motor neuron loss and chronic motor neuron degeneration. It is necessary to find effective strategies to protect CMNs from excitotoxicity in a variety of pathological conditions. 5,6-Dihydrocyclopenta-1,2 dithiole-3-thione (CPDT) is one of the phase II enzyme inducers. In our previous report, CPDT was shown to have neuroprotective effects on the spinal cord, by activating the Nrf2/ARE pathway to increase antioxidative capacity. In this study, in order to figure out whether CPDT can prevent CMN's from THA-induced death, we set up an organotypic brain slice culture system. Threo hydroxyaspartate (THA), a glutamate transport inhibitor, was added to the culture medium to induce CMN death by glutamate excitotoxicity. Brain slices were pretreated with CPDT for 48h, then treated with CPDT and THA simultaneously for 3 weeks. We found that pretreatment with CPDT significantly increased CMN survival. Glutamate concentration in the culture medium was significantly greater following THA treatment, whereas no significant decrease was found in the CPDT pretreatment group. However, both Nrf2 and HO-1 protein expression was significantly elevated in the CPDT pretreatment group, and Nrf2 protein translocated to the nucleus after CPDT stimulation. These findings suggest that CPDT can protect CMNs from THA-induced motor neuron death by activating the Nrf2 pathway and increasing HO-1 protein expression. Therefore, increasing antioxidative defense capacity should benefit to upper motor neuron survival following a glutamate excitotoxicity insult. PMID- 20851747 TI - Hypoalgesia in mice lacking aquaporin-4 water channels. AB - Previous studies have demonstrated the involvement of astrocytes in the modulation of pain. The water channel aquaporin-4, which is expressed in astrocytes but not neurons, has also been demonstrated to function in sensory processing, including hearing, vision, and olfaction. In the present study, we investigated a possible role of aquaporin-4 in the processing of nociception by measuring behavioral responses to noxious stimulation in aquaporin-4 knockout mice. Pain thresholds were increased in knockout mice, when compared to wild-type mice, with thermal and chemical stimulation but not mechanical stimulation. Aquaporin-4 knockout mice presented normal locomotor activity and basal skin temperature. Likewise, the electrophysiological recordings showed a significant decrease in the number of dorsal horn neurons sensitive to noxious thermal stimuli in aquaporin-4 knockout mice. Moreover, latencies to thermal stimuli were significantly prolonged in a subset of dorsal horn wide-dynamic-range neurons. Taken together, these results suggest that aquaporin-4 plays a role in the processing of nociception. PMID- 20851748 TI - Involvement of GABAergic transmission in the midbrain ventral tegmental area in the regulation of hippocampal theta rhythm. AB - Previously we indicated that the ventral tegmental area (VTA) may belong to the system regulating hippocampal theta rhythm. In the present study, we aimed at assessing the role of the GABAergic system of the VTA in regulation of hippocampal electric activity. Male Wistar rats received unilateral intra-VTA microinjection of either bicuculline (50ng/0.5MUl, n=9), muscimol (100ng/0.5MUl, n=10) or phaclofen (500ng/0.5MUl, n=9). 1-min tail pinch stimulations were applied at 10-min intervals to evoke theta rhythm episodes in hippocampus. We analysed peak power (P(max)) and corresponding frequency (F(max)) of EEG signal at delta and theta bands. Bicuculline induced theta rhythm in both hippocampi with 0 latency, continuous for ca. 33min. Phaclofen also induced theta but in this group it appeared with latency (17.45+/-3.16min on average), lasted for ca. 33.6min and during this time was interrupted by periods of irregular activity of variable length. Tail pinch was not applied in these groups. Muscimol induced an opposite effect: depression of theta P(max) with simultaneous increase in delta P(max) and a decrease in F(max) delta during episodes of tail pinch-evoked theta. This effect had variable latency and no return to the control EEG could be observed. We propose that GABA activity in the VTA is of tonic character, so that abolition of this mechanism produces immediate effect, i.e. theta induction (strong by GABA(A) and weak by GABA(B) receptors blockade), whereas enhancing the already present GABAergic inhibition causes delayed, prolonged changes expressed as gradual loss of theta synchronisation. PMID- 20851749 TI - New perspectives in cyclic AMP-mediated axon growth and guidance: The emerging epoch of Epac. AB - In the search for a cure to brain and spinal cord injury much has been learned about the inhibitory environment of the central nervous system (CNS), and yet a clinical therapy remains elusive. In recent years great advances have been made in understanding intracellular molecular mechanisms that transduce cell surface receptor-mediated signals that neurons receive from their environment. Many of these signalling pathways share common mechanisms, which presents the possibility that manipulating activities of key cell signalling molecules such as those regulated by 3'-5'-cyclic adenosine monophosphate (cAMP) might allow axons to simultaneously overcome the inhibitory effects of a number of extracellular ligands. The identification of Epac, a novel direct intracellular target for cAMP, has opened up a new avenue of research that is beginning to explain how cAMP can mediate a range of neuronal functions including distinct axon growth and guidance decisions. With current research tools that allow more specific activation of proteins or knock-down of their expression, as well as quantitation of protein activities in live cells, it is already becoming clear that Epac plays highly important roles in the development and function of the nervous system. Here, we focus on emerging evidence that Epac mediates cAMP-regulated axon growth and chemoattraction, and thus represents a novel target for overcoming axon growth inhibition and promoting CNS regeneration. PMID- 20851750 TI - The caper (Capparis L.): ethnopharmacology, phytochemical and pharmacological properties. AB - Caper (Capparis L.), a shrub plant with a large natural distribution, is used in traditional medicines to cure various illnesses. Phytochemicals studies have shown the presence of many beneficial compounds such as spermidine, rutin, quercetin, kaempferol, stigmasterol, campesterol, tocopherols, and carotenoids. Biological studies reveal important antimicrobial, anti-oxidative, anti inflammatory, immunomodulatory and antiviral properties. The presented review summarizes information concerning the morphology, ethnopharmacology, phytochemistry, and biological activities of caper plants. PMID- 20851751 TI - Therapeutic orchids: traditional uses and recent advances--an overview. AB - Orchids have been used as a source of medicine for millennia to treat different diseases and ailments including tuberculosis, paralysis, stomach disorders, chest pain, arthritis, syphilis, jaundice, cholera, acidity, eczema, tumour, piles, boils, inflammations, menstrual disorder, spermatorrhea, leucoderma, diahorrhea, muscular pain, blood dysentery, hepatitis, dyspepsia, bone fractures, rheumatism, asthma, malaria, earache, sexually transmitted diseases, wounds and sores. Besides, many orchidaceous preparations are used as emetic, purgative, aphrodisiac, vermifuge, bronchodilator, sex stimulator, contraceptive, cooling agent and remedies in scorpion sting and snake bite. Some of the preparations are supposed to have miraculous curative properties but rare scientific demonstration available which is a primary requirement for clinical implementations. Incredible diversity, high alkaloids and glycosides content, research on orchids is full of potential. Meanwhile, some novel compounds and drugs, both in phytochemical and pharmacological point of view have been reported from orchids. Linking of the indigenous knowledge to the modern research activities will help to discover new drugs much more effective than contemporary synthetic medicines. The present study reviews the traditional therapeutic uses of orchids with its recent advances in pharmacological investigations that would be a useful reference for plant drug researches, especially in orchids. PMID- 20851752 TI - Medicinal plants useful for treating chronic obstructive pulmonary disease (COPD): current status and future perspectives. AB - Chronic obstructive pulmonary disease (COPD) is a major global health problem. The current therapies are inadequate and have numerous adverse effects. There is an acute need of potential alternative therapies. Medicinal plants are classical and most widespread form of medication for treating various human ailments throughout the world. For COPD also, various plants are practiced in many countries. We have surveyed the literatures for the medicinal plants which are used in obstructive lung diseases such as bronchitis and emphysema. These plants were segregated into two categories. Firstly, the plants which are used for obstructive lung diseases based on various traditional recommendations only. Secondly, the plants or their formulations which have been studied grossly in COPD patients and animal models for their scientific validation. Further, we have described some known cellular and molecular factors involved in COPD and their modulation by plant-derived compounds. Certain future perspectives have also been discussed. PMID- 20851753 TI - Evolution of alternative splicing in newly evolved genes of Drosophila. AB - New gene origination is a fundamental process underlying evolution of biological diversity. Although new genes usually evolve rapidly in sequences, structure and expression, the evolutionary pattern of alternative splicing (AS) in new genes and the molecular mechanisms involved in this alternation remain to be explored. Here, we used the new genes identified in the Drosophila melanogaster lineage to study alternation of AS and the possible functional consequences of these genes. We found that new genes tended to exhibit low degree of AS, though a few new genes were alternatively spliced. Interestingly loss of introns in retroposed new genes can only account for one third of the low-level AS in new genes, while partial gene duplication without AS exons and mutations in the duplicated AS exons/introns together have resulted in two-third AS losses in new genes, indicating that reducing the degree of AS is a general trend in all categories of new genes. Further investigations on tissue expression patterns of these new genes showed that those with AS alternation had a relatively lower expression level, were expressed in fewer tissues and tended to be more likely expressed in testis than their parental genes. All these observations imply that these new genes may have gained diverged structures and expression patterns from their parental genes after AS alternation. PMID- 20851754 TI - Biomarker variance component estimation for exposure surrogate selection and toxicokinetic inference. AB - Biomarkers are useful exposure surrogates given their ability to integrate exposures through all routes and to reflect interindividual differences in toxicokinetic processes. Also, biomarker concentrations tend to vary less than corresponding environmental measurements, making them less-biasing surrogates for exposure. In this article, urinary PAH biomarkers (namely, urinary naphthalene [U Nap]; urinary phenanthrene [U-Phe]; 1-hydroxypyrene [1-OH-Pyr]; and 1-, (2+3)-, 4 , and 9-hydroxyphenanthrene [1-, (2+3)-, 4-, and 9-OH-Phe]) were evaluated as surrogates for exposure to hot asphalt emissions using data from 20 road-paving workers. Linear mixed-effects models were used to estimate the within- and between-person components of variance for each urinary biomarker. The ratio of within- to between-person variance was then used to estimate the biasing effects of each biomarker on a theoretical exposure-response relationship. Mixed models were also used to estimate the amounts of variation in Phe metabolism to individual OH-Phe isomers that could be attributed to Phe exposure (as represented by U-Phe concentrations) and covariates representing time, hydration level, smoking status, age, and body mass index. Results showed that 1-OH-Phe, (2+3)-OH-Phe, and 1-OH-Pyr were the least-biasing surrogates for exposure to hot asphalt emissions, and that effects of hydration level and sample collection time substantially inflated bias estimates for the urinary biomarkers. Mixed-model results for the individual OH-Phe isomers showed that between 63% and 82% of the observed biomarker variance was collectively explained by Phe exposure, the time and day of sample collection, and the hydration level, smoking status, body mass index, and age of each worker. By difference, the model results also showed that, depending on the OH-Phe isomer, a maximum of 6-23% of the total biomarker variance was attributable to differences in unobserved toxicokinetic processes between the workers. Therefore, toxicokinetic processes are probably less influential on urinary biomarker variance than are exposures and observable covariate effects. The methods described in this analysis should be considered for the selection and interpretation of biomarkers as exposure surrogates in future exposure investigations. PMID- 20851755 TI - Paraquat induces cyclooxygenase-2 (COX-2) implicated toxicity in human neuroblastoma SH-SY5Y cells. AB - Paraquat produces dopaminergic pathologies of Parkinson's disease, in which cyclooxygenase-2 (COX-2) is implicated. However, it is unclear whether paraquat induces toxicity within dopaminergic neurons through COX-2. To address this, human neuroblastoma SH-SY5Y cells were treated with paraquat and then the involving mechanism of COX-2 was investigated. We initially examined the involvement of COX-2 in paraquat-induced toxicity. Data suggest that COX-2 is implicated in paraquat-induced reduction of viability in SY5Y cells. Then, to confirm the presence of COX-2 in SY5Y cells, we examined COX-2 mRNA and protein levels, which are regulated by NF-kappaB. Data indicate that paraquat activates NF-kappaB and up-regulates COX-2. We then checked quinone-bound proteins as quinones produced by COX-2 bind to intracellular proteins. Paraquat obviously forms quinone-bound proteins, in particular, quinone-bound DJ-1 and this formation is attenuated by meloxicam. Finally, we investigated antioxidant system including nuclear factor erythroid-related factor 2 (Nrf2), gamma glutamylcysteine synthetase (gammaGCS), and glutathione (GSH) as DJ-1 is linked to Nrf2 and Nrf2 regulates gammaGCS expression and gammaGCS is a GSH synthesis enzyme. Paraquat decreases protein levels of Nrf2 and gammaGCS and intracellular GSH level and these decreases are alleviated by meloxicam. Therefore, collectively, our data indicate that paraquat induces COX-2 implicated toxicity in SY5Y cells. In conclusion, current findings support the idea that paraquat might produce toxicity in dopaminergic neurons through COX-2. PMID- 20851757 TI - Cryopreservation of sweetpotato (Ipomoea batatas) and its pathogen eradication by cryotherapy. AB - Sweetpotato (Ipomoea batatas) ranks as the seventh most important staple crop in the world and the fifth in developing countries after rice, wheat, maize and cassava. Sweetpotato is mainly grown in developing countries, which account for more than 95% of total production of the whole world. Genetic resources, including cultivated varieties and wild species, are a prerequisite for novel sweetpotato breeding in both conventional and genetic engineering programs. Various cryopreservation protocols have been developed for shoot tips and embryogenic tissues. The former explants are preferred for long-term conservation of sweetpotato genetic resources, while the latter are valuable for sweetpotato genetic improvement. This review provides update comprehensive information on cryopreservation of sweetpotato shoot tips and embryogenic tissues. Plant pathogens such as viruses and phytoplasma severely hamper high yield and high quality production of sweetpotato. Thus, usage of pathogen-free planting materials is pivotal for sustainable sweetpotato production. Cryotherapy of shoot tips can efficiently eradicate sweetpotato pathogens such as viruses and phytoplasma. The mechanism behind pathogen eradication by cryotherapy of shoot tips has been elucidated. Pathogen eradication by cryotherapy provides an alternative, efficient strategy for production of pathogen-free plants. In addition, cryopreserved tissues may also be considered to be safer for exchange of germplasm between countries and regions. PMID- 20851756 TI - A bird brain's view of auditory processing and perception. AB - By studying the primary forebrain auditory area of songbirds, field L, using a song-inspired synthetic stimulus and reverse correlation techniques, we found a surprisingly systematic organization of this area, with nearly all neurons narrowly tuned along the spectral dimension, the temporal dimension, or both; there were virtually no strongly orientation-sensitive cells, and in the areas that we recorded, cells broadly tuned in both time and frequency were rare. In addition, cells responsive to fast temporal frequencies predominated only in the field L input layer, suggesting that neurons with fast and slow responses are concentrated in different regions. Together with other songbird data and work from chicks and mammals, these findings suggest that sampling a range of temporal and spectral modulations, rather than orientation in time-frequency space, is the organizing principle of forebrain auditory sensitivity. We then examined the role of these acoustic parameters important to field L organization in a behavioral task. Birds' categorization of songs fell off rapidly when songs were altered in frequency, but, despite the temporal sensitivity of field L neurons, the same birds generalized well to songs that were significantly changed in timing. These behavioral data point out that we cannot assume that animals use the information present in particular neurons without specifically testing perception. PMID- 20851758 TI - Impaired oligodendroglial development by decabromodiphenyl ether in rat offspring after maternal exposure from mid-gestation through lactation. AB - Pregnant Sprague-Dawley rats were given diet containing decabromodiphenyl ether (DBDE) either at 0, 10, 100, or 1000 ppm from gestation day (GD) 10 until day 20 after delivery (PND 20). No significant alterations were observed in maternal and offspring reproductive parameters. At PND 20, serum triiodothyronine concentrations examined in males were slightly reduced at 1000 ppm (84.2% of the control value), and incidence of thyroid follicular cell hypertrophy was increased in both sexes with significant difference in males at 1000 ppm. Diffuse liver cell hypertrophy accompanying increased relative liver weight and increased cytoplasmic eosinophilia of the renal proximal tubules were observed in both sexes with significant difference from 10 ppm in males and females, respectively. At postnatal week 11, serum thyroxine concentrations examined in males were slightly reduced at 1000 ppm (85.9% of the control value), and the incidence of thyroid follicular cell hypertrophy was non-significantly increased from 10 ppm in males. There were reductions in the corpus callosum area and density of 2',3' cyclic nucleotide 3'-phosphodiesterase-immunoreactive oligodendrocytes in the cingulate deep cortex in males from 100 ppm. Conversely, NeuN-immunoreactive neuronal distribution in the hippocampal CA1 was unchanged. This suggests that developmental DBDE-exposure caused irreversible white matter hypoplasia targeting oligodendrocytes from 100 ppm, accompanied with developmental hypothyroidism. The lowest-observed-adverse-effect level of DBDE was determined to be 10 ppm (0.7-2.4 mg/kg-body weight-d). PMID- 20851759 TI - Evaluation of the intramuscular administration of CervarixTM vaccine on fertility, pre- and post-natal development in rats. AB - CervarixTM is a prophylactic human papillomavirus (HPV)-16/18 vaccine for the prevention of cervical cancer. It contains GSK Biologicals' proprietary Adjuvant System AS04. The objective of this study was to investigate the effects of CervarixTM and of AS04 on female fertility and pre- and post-natal development in Sprague Dawley rats. Female rats were injected with vaccine, AS04, or saline 30 days before mating and on Gestation Days 6, 8, 11 and 15. Each dose of vaccine was one-fifth the human dose volume. Treatment of rats with vaccine or AS04 was not associated with any systemic toxicity and had no impact on female fertility. There were no adverse effects on pre- or post-natal development of litters from treated rats, as judged by fetal evaluation at Gestation Day 20, and growth and survival of pups to postnatal Day 25. These results support the use of the vaccine in the targeted human population. PMID- 20851761 TI - Mitochondrial decay is involved in BaP-induced cervical damage. AB - Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon and a potent inducer of carcinogenesis. Many studies have reported that the carcinogenic effects of BaP might be due to its intermediate metabolites and to reactive oxygen species (ROS) that cause oxidative damage to the cells. However, the mechanisms of BaP-induced oxidative damage in cervical tissue are still not clear. We studied these mechanisms in female ICR mice treated with BaP either orally or intraperitoneally by measuring (1) several general biomarkers of oxidative stress in serum, (2) mitochondrial function in the cervix, and (3) the morphology of mitochondria in cervical tissue. BaP treatment (1) significantly lowered levels of vitamins A, C, and E and of glutathione; (2) reduced activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferases; and (3) significantly increased lipid peroxidation levels. In addition, significant increases in the levels of superoxide anion, hydrogen peroxide, and hydroxyl radical were observed. These results were confirmed by morphological changes in mitochondria and by decreases in membrane potential levels and in succinate dehydrogenase and malate dehydrogenase activities. The changes in these biomarkers and mitochondrial damage were BaP-dose-dependent and eventually induced both cell apoptosis and necrosis in cervical tissue. As mitochondria are the major sites of ROS generation, these findings show that mitochondrial decay greatly contributes to BaP-induced cervical damage. PMID- 20851762 TI - The use of thiols by ribonucleotide reductase. AB - Ribonucleotide reductase (RNR) catalyzes the rate-limiting de novo synthesis of 2'-deoxyribonucleotides from the corresponding ribonucleotides and thereby provides balanced deoxyribonucleotide pools required for error-free DNA replication and repair. The essential role of RNR in DNA synthesis and the use of DNA as genetic material has made it an important target for the development of anticancer and antiviral agents. The most well known feature of the universal RNR reaction in all kingdoms of life is the involvement of protein free radicals. Redox-active cysteines, thiyl radicals, and thiol redox proteins of the thioredoxin superfamily play major roles in the catalytic mechanism. The involvement of cysteine residues in catalysis is common to all three classes of RNR. Taking account of the recent progress in this field of research, this review focuses on the use of thiols in the redox mechanism of RNR enzymes. PMID- 20851760 TI - Environmental toxicants and the developing immune system: a missing link in the global battle against infectious disease? AB - There is now compelling evidence that developmental exposure to chemicals from our environment contributes to disease later in life, with animal models supporting this concept in reproductive, metabolic, and neurodegenerative diseases. In contrast, data regarding how developmental exposures impact the susceptibility of the immune system to functional alterations later in life are surprisingly scant. Given that the immune system forms an integrated network that detects and destroys invading pathogens and cancer cells, it provides the body's first line of defense. Thus, the consequences of early life exposures that reduce immune function are profound. This review summarizes available data for pollutants such as cigarette smoke and dioxin-like compounds, which consistently support the idea that developmental exposures critically impact the immune system. These findings suggest that exposure to common chemicals from our daily environment represent overlooked contributors to the fact that infectious diseases remain among the top five causes of death worldwide. PMID- 20851764 TI - Platelet-derived growth factor-induced signaling pathways interconnect to regulate the temporal pattern of Erk1/2 phosphorylation. AB - The biological outcome of Erk1/2 activation is specified by the duration and magnitude of its phosphorylation, as well as its subcellular localization. In the present study, we investigated how the cross-talk between signaling pathways induced by platelet-derived growth factor receptor beta (PDGFRbeta) regulates the temporal pattern of Erk1/2 activation. We demonstrated that Src kinase activity was necessary for rapid Erk1/2 phosphorylation in PDGF-BB-stimulated cells. A delay in the onset of Erk1/2 activation was also observed upon phospholipase C (PLC) inhibition; this effect was found to be mediated by protein kinase C (PKC). In addition, we observed that both the PI3K pathway and RasGAP negatively regulated the strength of Erk1/2 phosphorylation. In contrast, interfering with SHP2 binding to PDGFRbeta did not affect the pattern of Erk1/2 activation. Interestingly, changes in the kinetics and amplitude of Erk1/2 activation were transmitted to the transcriptional level and affected c-fos expression. In conclusion, cross-talk with other PDGFRbeta-induced signaling pathways is important for fine-tuning of the pattern of Erk1/2 activation. PMID- 20851763 TI - Crosstalk between VEGFR2 and muscarinic receptors regulates the mTOR pathway in serum starved SK-N-SH human neuroblastoma cells. AB - Muscarinic acetylcholine receptors (mAchRs) are guanosine nucleotide-binding protein (G protein) coupled receptors that crosstalk with receptor tyrosine kinases (RTKs) to signal mitogenic pathways. In particular, mAchRs are known to couple with RTKs for several growth factors to activate the mammalian target of rapamycin (mTOR)/Akt pathway, a regulator of protein synthesis. The RTK for the vascular endothelial growth factor (VEGF), VEGFR2, can signal protein synthesis but whether it cooperates with mAchRs to mediate mTOR activation has not been demonstrated. Using serum starved SK-N-SH neuroblastoma cells, we show that the muscarinic receptor agonists carbachol and pilocarpine enhance the activation of the mTOR substrate p70 S6 Kinase (S6K) and its target ribosomal protein S6 (S6) in a VEGFR2 dependent manner. Treatments with carbachol increased VEGFR2 phosphorylation, suggesting that mAchRs stimulate VEGFR2 transactivation to enhance mTOR signaling. Inhibitor studies revealed that phosphatidylinositol 3 kinase resides upstream from S6K, S6 and Akt phosphorylation while protein kinase C (PKC) functions in an opposing fashion by positively regulating S6K and S6 phosphorylation and suppressing Akt activation. Treatments with the phosphatase inhibitors sodium orthovanadate and okadaic acid increase S6, Akt and to a lesser extent S6K phosphorylation, indicating that tyrosine and serine/threonine dephosphorylation also regulates their activity. However, okadaic acid elicited a far greater increase in phosphorylation, implicating phosphatase 2A as a critical determinant of their function. Finally, pilocarpine but not carbachol induced a time and dose dependent cell death that was associated with caspase activation and oxidative stress but independent of S6K and S6 activation through VEGFR2. Accordingly, our findings suggest that mAchRs crosstalk with VEGFR2 to enhance mTOR activity but signal divergent effects on survival through alternate mechanisms. PMID- 20851765 TI - Rab7: role of its protein interaction cascades in endo-lysosomal traffic. AB - Protein-protein interaction cascades are crucial for cellular signaling pathways and cell morphogenesis. Membrane traffic along the secretory and endocytic pathways is similarly governed by regulated protein-protein interactions of diverse machineries, which are inter-regulated, assembled and disassembled sequentially to drive membrane budding, vesicle transport, membrane fission and fusion. Rab7, the key regulator in endo-lysosomal trafficking investigated extensively in the past decades, is emerging to govern early-to-late endosomal maturation, microtubule minus-end as well as plus-end directed endosomal migration and positioning, and endosome-lysosome transport through different protein-protein interaction cascades. We summarize here the key protein interaction cascades of Rab7 by focusing on endo-lysosomal trafficking regulated by its interaction with HOPs, RILP, ORP1L, FYCO1 and Mon1/Sand1-CCZ1 complex. PMID- 20851766 TI - RhoH modulates pre-TCR and TCR signalling by regulating LCK. AB - Pre-T-cell receptor (pre-TCR) and TCR signals govern the development of T lymphocytes. RhoH, a hematopoietic-specific and GTPase-deficient member of the RhoGTPase family, is required in the development of T-lymphocytes. Here we found that RhoH binds and modulates LCK, the non-receptor tyrosine kinase crucial in initiating pre-TCR and TCR signallings. In both pre-TCR and TCR signalling transduction, LCK is phosphorylated by CSK to maintain the inactive state of LCK at rest. Upon being activated, CSK phosphorylation is removed and LCK autophosphorylation leads to LCK activation and further phosphorylates ZAP70 to initiate further downstream signalling. At rest, LCK may be recruited to the plasma membrane by RhoH, which also binds CSK, resulting in LCK inactivation. Additionally, the presence of RhoH enhances the inactivation phosphorylation of LCK by CSK. RhoH was found to bind preferentially inactive LCK, indicating that, upon ligand-mediated TCR activation, LCK is dephosphorylated resulting in LCK autoactivation and its release from RhoH. Thus RhoH is a critical part of the microenvironment for maintaining the inactive state of LCK. Furthermore, we found that the reduction of RhoH levels results in LCK autoactivation and constitutive activation of the TCR pathway. Our findings indicate that RhoH is a key adapter protein that maintains LCK in the inactive state, contributing to the regulation of both pre-TCR and TCR signalling during T-cell development. The data also supports a model for ligand-independent signal transduction by pre-TCR. PMID- 20851767 TI - Sn-protoporphyrin inhibits both heme degradation and hemozoin formation in Rhodnius prolixus midgut. AB - Hematophagy is a feeding habit that involves the ingestion of huge amounts of heme. The hematophagous hemipteran Rhodnius prolixus evolved many genetic resources to protect cells against heme toxicity. The primary barrier against the deleterious effects of heme is the aggregation of heme into hemozoin in the midgut lumen. Hemozoin formation is followed by the enzymatic degradation of heme by means of a unique pathway whose end product is dicysteinyl-biliverdin IX-gamma (Rhodnius prolixus biliverdin, RpBv). These mechanisms are complemented by a heme binding protein (RHBP) in the hemolymph that attenuates the pro-oxidant effects of heme. In this work, we show that when insects are fed with blood enriched with a heme analog, Sn-protoporphyrin (SnPP-IX), both hemozoin synthesis and RpBv production are inhibited in a dose-dependent manner. These effects are accompanied by increased oxidative damage to the midgut epithelium and inhibition of oviposition, indicating that hemozoin formation and heme degradation are protective mechanisms that work together and contributed to the adaptation of this insect to successfully feed on vertebrate blood. PMID- 20851768 TI - Inactivation of fibroblast growth factor binding protein 3 causes anxiety-related behaviors. AB - The neurobiological mechanisms of emotional modulation and the molecular pathophysiology of anxiety disorders are largely unknown. The fibroblast growth factor (FGF) family has been implicated in the regulation of many physiological and pathological processes, which include the control of emotional behaviors. The present study examined mice with a targeted deletion of the fgf-bp3 gene, which encodes a novel FGF-binding protein, in animal models relevant to anxiety. To define the behavioral consequences of FGF-BP3 deficiency, we evaluated fgf-bp3 deficient mice using anxiety-related behavioral paradigms that provide a conflict between the desire to explore an unknown area or objects and the aversion to a brightly lit open space. The fgf-bp3-deficient mice exhibited alterations in time spent in the central area of the open-field arena, were less active in the lit areas of a light/dark transition test, and had a prolonged latency to feed during a novelty-induced hypophagia test. These changes were associated with alterations in light-induced orbitofrontal cortex (OFC) activation in an extracellular signal regulated kinase (ERK) pathway-dependent manner. These results demonstrate that FGF-BP3 is a potent mediator of anxiety-related behaviors in mice and suggest that distinct pathways regulate emotional behaviors. Therefore, FGF-BP3 plays a critical role in the regulation of emotional states and in the development of anxiety disorders and should be investigated as a therapeutic target for anxiety disease in humans. PMID- 20851769 TI - Escherichia coli-based production of a tumor idiotype antibody fragment--tetanus toxin fragment C fusion protein vaccine for B cell lymphoma. AB - The unique immunoglobulin idiotype expressed on the surface of B lymphoma cells can be used as an effective antigen in tumor-specific vaccines when fused to immunostimulatory proteins and cytokines. A DNA vaccine encoding for an idiotype antibody single chain Fv (scFv) fragment fused to the Tetanus Toxin Fragment C (TTFrC) has been shown to induce protective anti-tumor responses. Protein-based strategies may be more desirable since they provide greater control over dosage, duration of exposure, and in vivo distribution of the vaccine. However, production of fusion protein vaccines containing complex disulfide bonded idiotype antibodies and antibody-derived fragments is challenging. We use an Escherichia coli-based cell-free protein synthesis platform as well as high-level expression of E. coli inclusion bodies followed by refolding for the rapid generation of an antibody fragment - TTFrC fusion protein vaccine. Vaccine proteins produced using both methods were shown to elicit anti-tumor humoral responses as well as protect from tumor challenge in an established B cell lymphoma mouse model. The development of technologies for the rapid production of effective patient-specific tumor idiotype-based fusion protein vaccines provides opportunities for clinical application. PMID- 20851770 TI - Functional connectivity of the human insular cortex during noxious and innocuous thermal stimulation. AB - The insula plays a key role in brain processing of noxious and innocuous thermal stimuli. The anterior and the posterior portions of the insular cortex are involved in different ways in nociceptive and thermoceptive processing. Therefore, their stimulus-specific functional connectivity may also differ. Here we used functional magnetic resonance imaging (fMRI) to investigate the activity and functional connectivity of insular cortex subregions during noxious and innocuous thermal stimulation. In 11 healthy subjects, psychophysically controlled noxious and innocuous warm and cold stimuli were applied to the left forearm. To differentiate between the subregions of the insular cortex involved in pain processing and those involved in temperature processing, a 2*2 factorial fMRI analysis was performed. Pain processing insular areas (main effect of pain) were detected in bilateral aINS and contralateral pINS. Temperature processing insular areas (main effect of temperature) were also found in bilateral aINS and contralateral pINS. The individual signal time courses from the pain- and temperature processing insular activation clusters were used for calculation and comparison of stimulus-specific functional connectivity of aINS and pINS by means of a correlation analysis. As expected, both aINS and pINS were functionally connected to a large brain network - which predominantly includes areas involved in nociception and thermoception: primary (S1) and secondary (S2) somatosensory cortices, cingulate gyrus, prefrontal cortex (PFC) and parietal association cortices (PA). When statistically compared, during both noxious and innocuous stimulation, aINS was more strongly connected to PFC and to ACC than was pINS; pINS meanwhile was more strongly connected to S1 and to the primary motor cortex (M1). Interestingly, S2 was more strongly connected to aINS than to pINS during painful stimulation but not during innocuous thermal stimulation. We conclude that aINS is more strongly functionally connected to areas known for affective and cognitive processing, whereas pINS is more strongly connected with areas known for sensory-discriminative processing of noxious and somatosensory stimuli. PMID- 20851771 TI - Serotonin transporter binding in the hypothalamus correlates negatively with tonic heat pain ratings in healthy subjects: a [11C]DASB PET study. AB - There is a large body of evidence that the serotonergic system plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) with the serotonin transporter (SERT) tracer [(11)C]DASB to study the relationship between SERT binding in the brain and responses to noxious heat stimulation in a group of 21 young healthy volunteers. Responses to noxious heat stimuli were assessed in a separate psychophysical experiment and included measurements of pain threshold, pain tolerance, and responses to phasic noxious heat stimuli and to a long lasting (7-minute) tonic noxious heat stimulus. PET data were analyzed using both volume-of-interest (VOI) and voxel-based approaches. VOI analysis revealed a significant negative correlation between tonic pain ratings and SERT binding in the hypothalamus (r=-0.59; p=0.008), a finding confirmed by the parametric analysis. The parametric analysis also revealed a negative correlation between tonic pain ratings and SERT binding in the right anterior insula. Measures of regional SERT binding did not correlate with pain threshold or with responses to short phasic suprathreshold phasic heat stimuli. Finally, the VOI analysis revealed a positive correlation between pain tolerance and SERT binding in the hypothalamus (r=0.53; p=0.02) although this was not seen in the parametric analysis. These data extend our earlier observation that cortical 5-HT receptors co-determine responses to tonic but not to phasic pain. The negative correlation between SERT binding in the hypothalamus and insula with tonic pain ratings suggests a possible serotonergic control of the role of these areas in the modulation or in the affective appreciation of pain. PMID- 20851772 TI - Enhanced ICBM diffusion tensor template of the human brain. AB - Development of a diffusion tensor (DT) template that is representative of the micro-architecture of the human brain is crucial for comparisons of neuronal structural integrity and brain connectivity across populations, as well as for the generation of a detailed white matter atlas. Furthermore, a DT template in ICBM space may simplify consolidation of information from DT, anatomical and functional MRI studies. The previously developed "IIT DT brain template" was produced in ICBM-152 space, based on a large number of subjects from a limited age-range, using data with minimal image artifacts, and non-linear registration. That template was characterized by higher image sharpness, provided the ability to distinguish smaller white matter fiber structures, and contained fewer image artifacts, than several previously published DT templates. However, low dimensional registration was used in the development of that template, which led to a mismatch of DT information across subjects, eventually manifested as loss of local diffusion information and errors in the final tensors. Also, low dimensional registration led to a mismatch of the anatomy in the IIT and ICBM-152 templates. In this work, a significantly improved DT brain template in ICBM-152 space was developed, using high-dimensional non-linear registration and the raw data collected for the purposes of the IIT template. The accuracy of inter subject DT matching was significantly increased compared to that achieved for the development of the IIT template. Consequently, the new template contained DT information that was more representative of single-subject human brain data, and was characterized by higher image sharpness than the IIT template. Furthermore, a bootstrap approach demonstrated that the variance of tensor characteristics was lower in the new template. Additionally, compared to the IIT template, brain anatomy in the new template more accurately matched ICBM-152 space. Finally, spatial normalization of a number of DT datasets through registration to the new and existing IIT templates was improved when using the new template. PMID- 20851773 TI - Purification and kinetic characteristics of strombine dehydrogenase from the foot muscle of the hard clam (Meretrix lusoria). AB - Strombine dehydrogenase (SDH, EC 1.5.1.22) from the foot of the hard clam Meretrix lusoria was purified over 470-fold to apparent homogeneity. It has a monomeric structure with a relative molecular mass of 46,000. Two isoenzymes were identified with isoelectric points of 6.83 and 6.88. SDH is heat labile, and has pH and temperature optima of 7.4-7.6 and 45-46 degrees C, respectively. l Alanine, glycine, and pyruvate are the preferred substrates. l-Serine is the third preferred amino acid. Iminodiacetate with the lowest K(i) of SDH at both pH 6.5 and 7.5 was the strongest inhibitor among succinate, acetate, iminodiacetate, oxaloacetate, and l-/d-lactate. The inhibitory activities of succinate at pH 6.5, and iminodiacetate and oxaloacetate at pH 7.5 on the SDH were higher. These inhibitors are either competitive or mixed-competitive inhibitors. Half of the enzymatic activity of SDH was inhibited by 0.2mM Fe(3+) and 0.6mM Zn(2+). PMID- 20851774 TI - Activation of PPARalpha by bezafibrate negatively affects de novo synthesis of sphingolipids in regenerating rat liver. AB - Serine palmitoyltransferase (SPT) is a key enzyme in de novo sphingolipid biosynthesis. SPT activity in liver is up-regulated by pro-inflammatory cytokines, which play an important role in initiation of liver regeneration after partial hepatectomy (PH). The aim of the study was to investigate the impact of a high-fat diet or PPARalpha activation by bezafibrate on the activity and protein expression of SPT in rat liver after PH. The animals were divided into three groups: those fed a standard chow (SD), those fed a high-fat diet (HFD), and those treated with bezafibrate (BF). It has been found that the expression and activity of SPT increased in regenerating liver. This was accompanied by the elevation of plasma NEFA concentration. Moreover, in both diet groups, the content of sphinganine increased. Bezafibrate decreased protein expression of SPT at the 4th and 12th hour, and inhibited SPT activity at the 4th hour after PH. Both, the plasma NEFA concentration and sphinganine content decreased in the groups treated with bezafibrate. We conclude that partial hepatectomy stimulates de novo sphingolipid synthesis. Activation of PPARalpha by bezafibrate negatively affects this process, presumably by decreasing the availability of plasma-borne fatty acids. PMID- 20851775 TI - The neuro-steroid, 5-androstene 3beta,17alpha diol; induces endoplasmic reticulum stress and autophagy through PERK/eIF2alpha signaling in malignant glioma cells and transformed fibroblasts. AB - In this study, we identified a mechanism by which the neuro-steroid, 5-androstene 3beta,17alpha diol (17alpha-AED) induces autophagy in human malignant glioma cells and transformed fibroblasts. 17alpha-AED treatment induced endoplasmic reticulum (ER) stress, identified by the partial activation of an unfolded protein response in T98G, U87MG, U251MG, LN-18, LN-229 and LN-Z308 glioma cell lines. In this regard, there were increased levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and glucose-regulated protein of 78kDa transcripts but no splicing of X-box-binding protein 1 mRNA or processing of activating transcription factor-6 in glioma cells treated with the neuro-steroid. 17alpha-AED induced eukaryotic translational initiation factor 2alpha (eIF2alpha) phosphorylation in glioma cells which correlated with microtubule-associated protein-light chain 3 (LC3) conversion from LC3-I to -II. In transformed murine embryonic fibroblasts (MEFs) that are deficient of eIF2alpha function or T98G glioma cells transfected with a dominant-negative eIF2alpha construct, 17alpha AED induced LC3 conversion was significantly reduced as compared to control cells. Neuro-steroid treatment caused the activation of the eIF2alpha kinase, protein kinase-like ER kinase (PERK) but not other eIF2alpha kinases in glioma cells. Moreover, eIF2alpha phosphorylation and LC3 conversion, in response to 17alpha-AED treatment, was blocked in MEFs that lacked PERK activity. T98G cells transfected with a dominant-negative PERK construct exhibited an attenuated response to neuro-steroid treatment in terms of decreases in: eIF2alpha activation; CHOP expression; the incidence of autophagy; and cytotoxicity. These results demonstrate that ER stress is linked to 17alpha-AED induced autophagy by PERK/eIF2alpha signaling in human malignant glioma cells and transformed fibroblasts. PMID- 20851777 TI - Chlorination treatment of aqueous samples reduces, but does not eliminate, the mutagenic effect of the azo dyes Disperse Red 1, Disperse Red 13 and Disperse Orange 1. AB - The treatment of textile effluents by the conventional method based on activated sludge followed by a chlorination step is not usually an effective method to remove azo dyes, and can generate products more mutagenic than the untreated dyes. The present work evaluated the efficiency of conventional chlorination to remove the genotoxicity/mutagenicity of the azo dyes Disperse Red 1, Disperse Orange 1, and Disperse Red 13 from aqueous solutions. The comet and micronucleus assays with HepG2 cells and the Salmonella mutagenicity assay were used. The degradation of the dye molecules after the same treatment was also evaluated, using ultraviolet and visible absorption spectrum measurements (UV-vis), high performance liquid chromatography coupled to a diode-array detector (HPLC-DAD), and total organic carbon removal (TOC) analysis. The comet assay showed that the three dyes studied induced damage in the DNA of the HepG2 cells in a dose dependent manner. After chlorination, these dyes remained genotoxic, although with a lower damage index (DI). The micronucleus test showed that the mutagenic activity of the dyes investigated was completely removed by chlorination, under the conditions tested. The Salmonella assay showed that chlorination reduced the mutagenicity of all three dyes in strain YG1041, but increased the mutagenicity of Disperse Red 1 and Disperse Orange 1 in strain TA98. With respect to chemical analysis, all the solutions showed rapid discoloration and a reduction in the absorbance bands characteristic of the chromophore group of each dye. However, the TOC was not completely removed, showing that chlorination of these dyes is not efficient in mineralizing them. It was concluded that conventional chlorination should be used with caution for the treatment of aqueous samples contaminated with azo dyes. PMID- 20851778 TI - Binding of huperzine A and galanthamine to acetylcholinesterase, based on ONIOM method. AB - Binding energy calculations of huperzine A (HUP A) and galanthamine (GAL) to the binding pocket of the acetylcholinesterase enzyme (AChE) were studied. It was found that hydrogen bond formation and particular hydrogen pi interactions exhibit the most significant contributions to the binding interaction of HUP A with Trp84 (W84) and Tyr130 (Y130), whereas no hydrogen bond was detected with Y130 of GAL binding. The interaction energies, calculated at the MP2 level between drugs and residues, demonstrate that the attractive interactions between GAL and residues at positions 84 and 130 were less than those for HUP A by 1.6 and 7.7 kcal.mol(-1), respectively. In addition, ONIOM3 results show that the binding energies of HUP A per pocket (-28.4 kcal mol(-1)) are higher than for GAL per pocket (-17.0 kcal.mol(-1)). The detailed understanding of these interactions can be useful for the design of specific inhibitors for the AChE binding site. FROM THE CLINICAL EDITOR: The more efficient and specific inhibition of acetylcholinesterase may provide an enhanced treatment strategy in Alzheimer's disease compared to the currently available inhibitors. This study discusses interactions of the enzyme binding site with two ligands. The results may pave the way to the development of more potent inhibitors. PMID- 20851779 TI - An urgent need to include risk-benefit analysis in clinical trials investigating conjugated linoleic acid supplements in cancer patients. AB - Malnutrition and weight loss are common in patients with cancer, both factors could potentially affect the response and tolerance to treatment, decreased quality of life, and thus associate them with poor survival. Conjugated linoleic acid (CLA) is shown to have beneficial health effects in healthy and disease situations including chemoprotective properties in various experimental cancer models. However, the anticarcinogenic property of CLA in animal and tissue culture models could not be confirmed in the Netherlands Cohort Study on Diet and Cancer and a prospective cohort of Swedish women. Cancer patients are already at increased risk of anorexia and there are evidences that CLA suppresses appetite even in healthy individuals. Risk/benefit analysis of CLA supplementation has never been reported before and it is not clear whether any beneficial anti-tumor effect of CLA prevails over its anti-appetite and/or weight lowering side effect in these patients. I suggest that clinical trials investigating CLA supplements in cancer patients, measure appropriate variables such as food intake, weight, and appetite change to yield preliminary data for future trials. I also suggest that data from previous trials that have administered CLA supplements to cancer patients be re-analyzed retrospectively to attempt to find out any effect from routine nutritional measures such as weight, serum albumin and such as those. PMID- 20851776 TI - Potential applications for cell regulatory factors in liver progenitor cell therapy. AB - Orthotopic liver transplant represent the state of the art treatment for terminal liver pathologies such as cirrhosis in adults and hemochromatosis in neonates. A limited supply of transplantable organs in relationship to the demand means that many patients will succumb to disease before an organ becomes available. One promising alternative to liver transplant is therapy based on the transplant of liver progenitor cells. These cells may be derived from the patient, expanded in vitro, and transplanted back to the diseased liver. Inborn metabolic disorders represent the most attractive target for liver progenitor cell therapy, as many of these disorders may be corrected by repopulation of only a portion of the liver by healthy cells. Another potential application for liver progenitor cell therapy is the seeding of bio-artificial liver matrix. These ex vivo bioreactors may someday be used to bridge critically ill patients to other treatments. Conferring a selective growth advantage to the progenitor cell population remains an obstacle to therapy development. Understanding the molecular signaling mechanisms and micro-environmental cues that govern liver progenitor cell phenotype may someday lead to strategies for providing this selective growth advantage. The discovery of a population of cells within the bone marrow possessing the ability to differentiate into hepatocytes may provide an easily accessible source of cells for liver therapies. PMID- 20851780 TI - Structure and immunomodulatory property relationship in NapA of Borrelia burgdorferi. AB - NapA from Borrelia burgdorferi is a member of the Dps-like protein family with specific immunomodulatory properties; in particular, NapA is able to induce the expression of IL-23 in neutrophils and monocytes, as well as the expression of IL 6, IL-1beta, and transforming growth factor beta (TGF-beta) in monocytes, via Toll-like receptor (TLR) 2. Such an activity on innate immune cells triggers a synovial fluid Th17 response. Here we report the crystal structure of NapA, determined at 2.6A resolution, which shows that the quaternary structure of the protein is that of a dodecamer with 23 symmetry, typical of the proteins of the family. We also demonstrate that the N- and C-terminal tails, which are flexible and not visible in the crystal, are not relevant for its pro-Th17 activity. Based on the crystal structure and on the comparison with the structure of the orthologous protein from Helicobacter pylori, HP-NAP, we hypothesize that the charge distributions on the two proteins' surfaces are responsible for the interaction with TLR2 and for the different behaviors in modulating the immune response. PMID- 20851781 TI - Biochemical monitoring in fenugreek to develop functional food and medicinal plant variants. AB - Many plants used as functional foods or for medicinal purposes have been criticized for their inconsistent physiological effects. Variation in genotype and environmental conditions under which plants are produced can contribute to this inconsistency in biochemical composition. Fenugreek (Trigonella foenum graecum L.) is a medicinal plant that not only can lower blood glucose and cholesterol levels in animals, but also can be used as a forage crop for livestock feed. Seed content for the bioactive compounds diosgenin, galactomannan and 4-hydroxyisoleucine was characterized for ten fenugreek genotypes under rainfed and irrigated conditions. High and low seed yielding genotype/environment combinations were identified that possessed distinct biochemical and seed production traits. In general high seed yielding genotype/environment combinations exhibited a more stable biochemical composition and consisted largely of irrigated fenugreek. This research indicates that comprehensive biochemical analysis of plant products would facilitate the development of more reliable produce for use by the functional food/medicinal plant industry. PMID- 20851785 TI - Closed-loop anesthetic drug concentration estimation using clinical-effect feedback. AB - This letter presents a novel closed-loop approach to anesthetic drug concentration estimation using clinical-effect measurement feedback. Compared with the open-loop prediction used in current target-controlled infusion systems, closed-loop estimation exploits the discrepancy between the measured and predicted clinical effects to make corrections to the drug-concentration estimate, achieving improved robustness against variability in the patient pharmacokinetics and pharmacodynamics. A robust estimator, which processes drug administration and clinical-effect measurements to estimate the plasma- and effect-site drug concentrations, is designed using MU-synthesis theory. Initial proof of principle of the closed-loop estimation is demonstrated using the Monte Carlo simulation of surgical procedures with a wide range of patient models. Closed-loop estimation results in statistically significant reductions in median percentage, median absolute percentage, and maximum absolute percentage drug concentration errors compared to open-loop prediction. PMID- 20851784 TI - Effects of the antiarrhythmic drug dofetilide on transmural dispersion of repolarization in ventriculum. A computer modeling study. AB - Dofetilide is a class-III drug that inhibits the rapid component of the delayed potassium current ( I(Kr)). Experimental studies have shown that the different layers of ventricular muscle present differences in action potential duration (APD) and different responses to class III agents. It has been suggested that it contributes to APD heterogeneity in the ventricles. However, in vivo studies suggest that the strong cellular coupling reduces APD dispersion in intact heart. The aim of this paper is to study the effect of dofetilide on the action potentials (APs) in isolated ventricular cells and on APD dispersion in a strand of ventricular tissue. A mathematical model of dofetilide effects on I(Kr) has been developed and incorporated into the Luo--Rudy dynamic model of ventricular AP. Our results show that dofetilide induces in midmyocardium cells a faster time course inhibition of I(Kr) than in endocardial or epicardial cells, and periods of instability with beat-to-beat APs variability. This behavior could favor temporal dispersion of repolarization between the different cells. The results also indicate that although dofetilide increases, the transmural gradient of APD in the ventricular wall, early afterdepolarizations (EADs) did not appear even under strong uncoupling conditions. However, reduced repolarization reserve favors the induction of EADs, even under normal coupling conditions. PMID- 20851786 TI - Pattern mining of multichannel sEMG for tremor classification. AB - Tremor is defined as the involuntary rhythmic or quasi-rhythmic oscillation of a body part, resulting from alternating or simultaneous contractions of antagonistic muscle groups. While tremor may be physiological, those who have disabling pathological tremors find that performing typical activities for daily living to be physically challenging and emotionally draining. Detecting the presence of tremor and its proper identification are crucial in prescribing the appropriate therapy to lessen its deleterious physical, emotional, psychological, and social impact. While diagnosis relies heavily on clinical evaluation, pattern analysis of surface electromyogram (sEMG) signals can be a useful diagnostic aid for an objective identification of tremor types. Using sEMG system attached to several parts of the patient's body while performing several tasks, this research aims to develop a classifier system that automates the process of tremor types recognition. Finding the optimal model and its corresponding parameters is not a straightforward process. The resulting workflow, however, provides valuable information in understanding the interplay and impact of the different features and their parameters to the behavior and performance of the classifier system. The resulting model analysis helps identify the necessary locations for the placement of sEMG electrodes and relevant features that have significant impact in the process of classification. These information can help clinicians in streamlining the process of diagnosis without sacrificing its accuracy. PMID- 20851787 TI - P- and T-wave delineation in ECG signals using a Bayesian approach and a partially collapsed Gibbs sampler. AB - Detection and delineation of P- and T-waves are important issues in the analysis and interpretation of electrocardiogram (ECG) signals. This paper addresses this problem by using Bayesian inference to represent a priori relationships among ECG wave components. Based on the recently introduced partially collapsed Gibbs sampler principle, the wave delineation and estimation are conducted simultaneously by using a Bayesian algorithm combined with a Markov chain Monte Carlo method. This method exploits the strong local dependency of ECG signals. The proposed strategy is evaluated on the annotated QT database and compared to other classical algorithms. An important feature of this paper is that it allows not only for the detection of P- and T-wave peaks and boundaries, but also for the accurate estimation of waveforms for each analysis window. This can be useful for some ECG analysis that require wave morphology information. PMID- 20851788 TI - In vivo quantitative mapping of myocardial stiffening and transmural anisotropy during the cardiac cycle. AB - Shear wave imaging was evaluated for the in vivo assessment of myocardial biomechanical properties on ten open chest sheep. The use of dedicated ultrasonic sequences implemented on a very high frame rate ultrasonic scanner ( > 5000 frames per second) enables the estimation of the quantitative shear modulus of myocardium several times during one cardiac cycle. A 128 element probe remotely generates a shear wave thanks to the radiation force induced by a focused ultrasonic burst. The resulting shear wave propagation is tracked using the same probe by cross-correlating successive ultrasonic images acquired at a very high frame rate. The shear wave speed estimated at each location in the ultrasonic image gives access to the local myocardial stiffness (shear modulus MU). The technique was found to be reproducible (standard deviation ) and able to estimate both systolic and diastolic stiffness on each sheep (respectively MU(dias) ~ 2 kPa and MU(syst) ~ 30 kPa). Moreover, the ability of the proposed method to polarize the shear wave generation and propagation along a chosen axis permits the study the local elastic anisotropy of myocardial muscle. As expected, myocardial elastic anisotropy is found to vary with muscle depth. The real time capabilities and potential of Shear Wave Imaging using ultrafast scanners for cardiac applications is finally illustrated by studying the dynamics of this fractional anisotropy during the cardiac cycle. PMID- 20851789 TI - Detection of architectural distortion in prior mammograms. AB - We present methods for the detection of sites of architectural distortion in prior mammograms of interval-cancer cases. We hypothesize that screening mammograms obtained prior to the detection of cancer could contain subtle signs of early stages of breast cancer, in particular, architectural distortion. The methods are based upon Gabor filters, phase portrait analysis, a novel method for the analysis of the angular spread of power, fractal analysis, Laws' texture energy measures derived from geometrically transformed regions of interest (ROIs), and Haralick's texture features. With Gabor filters and phase portrait analysis, 4224 ROIs were automatically obtained from 106 prior mammograms of 56 interval-cancer cases, including 301 true-positive ROIs related to architectural distortion, and from 52 mammograms of 13 normal cases. For each ROI, the fractal dimension, the entropy of the angular spread of power, 10 Laws' measures, and Haralick's 14 features were computed. The areas under the receiver operating characteristic curves obtained using the features selected by stepwise logistic regression and the leave-one-ROI-out method are 0.76 with the Bayesian classifier, 0.75 with Fisher linear discriminant analysis, and 0.78 with a single layer feed-forward neural network. Free-response receiver operating characteristics indicated sensitivities of 0.80 and 0.90 at 5.8 and 8.1 false positives per image, respectively, with the Bayesian classifier and the leave-one image-out method. PMID- 20851790 TI - PET image reconstruction using information theoretic anatomical priors. AB - We describe a nonparametric framework for incorporating information from co registered anatomical images into positron emission tomographic (PET) image reconstruction through priors based on information theoretic similarity measures. We compare and evaluate the use of mutual information (MI) and joint entropy (JE) between feature vectors extracted from the anatomical and PET images as priors in PET reconstruction. Scale-space theory provides a framework for the analysis of images at different levels of detail, and we use this approach to define feature vectors that emphasize prominent boundaries in the anatomical and functional images, and attach less importance to detail and noise that is less likely to be correlated in the two images. Through simulations that model the best case scenario of perfect agreement between the anatomical and functional images, and a more realistic situation with a real magnetic resonance image and a PET phantom that has partial volumes and a smooth variation of intensities, we evaluate the performance of MI and JE based priors in comparison to a Gaussian quadratic prior, which does not use any anatomical information. We also apply this method to clinical brain scan data using F(18) Fallypride, a tracer that binds to dopamine receptors and therefore localizes mainly in the striatum. We present an efficient method of computing these priors and their derivatives based on fast Fourier transforms that reduce the complexity of their convolution-like expressions. Our results indicate that while sensitive to initialization and choice of hyperparameters, information theoretic priors can reconstruct images with higher contrast and superior quantitation than quadratic priors. PMID- 20851791 TI - Robust methodology for fractal analysis of the retinal vasculature. AB - We have developed a robust method to perform retinal vascular fractal analysis from digital retina images. The technique preprocesses the green channel retina images with Gabor wavelet transforms to enhance the retinal images. Fourier Fractal dimension is computed on these preprocessed images and does not require any segmentation of the vessels. This novel technique requires human input only at a single step; the allocation of the optic disk center. We have tested this technique on 380 retina images from healthy individuals aged 50+ years, randomly selected from the Blue Mountains Eye Study population. To assess its reliability in assessing retinal vascular fractals from different allocation of optic center, we performed pair-wise Pearson correlation between the fractal dimension estimates with 100 simulated region of interest for each of the 380 images. There was Gaussian distribution variation in the optic center allocation in each simulation. The resulting mean correlation coefficient (standard deviation) was 0.93 (0.005). The repeatability of this method was found to be better than the earlier box-counting method. Using this method to assess retinal vascular fractals, we have also confirmed a reduction in the retinal vasculature complexity with aging, consistent with observations from other human organ systems. PMID- 20851793 TI - Spatiotemporal localization and categorization of human actions in unsegmented image sequences. AB - In this paper we address the problem of localization and recognition of human activities in unsegmented image sequences. The main contribution of the proposed method is the use of an implicit representation of the spatiotemporal shape of the activity which relies on the spatiotemporal localization of characteristic ensembles of feature descriptors. Evidence for the spatiotemporal localization of the activity is accumulated in a probabilistic spatiotemporal voting scheme. The local nature of the proposed voting framework allows us to deal with multiple activities taking place in the same scene, as well as with activities in the presence of clutter and occlusion. We use boosting in order to select characteristic ensembles per class. This leads to a set of class specific codebooks where each codeword is an ensemble of features. During training, we store the spatial positions of the codeword ensembles with respect to a set of reference points, as well as their temporal positions with respect to the start and end of the action instance. During testing, each activated codeword ensemble casts votes concerning the spatiotemporal position and extend of the action, using the information that was stored during training. Mean Shift mode estimation in the voting space provides the most probable hypotheses concerning the localization of the subjects at each frame, as well as the extend of the activities depicted in the image sequences. We present classification and localization results for a number of publicly available datasets, and for a number of sequences where there is a significant amount of clutter and occlusion. PMID- 20851792 TI - A differential geometric approach to automated segmentation of human airway tree. AB - Airway diseases are frequently associated with morphological changes that may affect the physiology of the lungs. Accurate characterization of airways may be useful for quantitatively assessing prognosis and for monitoring therapeutic efficacy. The information gained may also provide insight into the underlying mechanisms of various lung diseases. We developed a computerized scheme to automatically segment the 3-D human airway tree depicted on computed tomography (CT) images. The method takes advantage of both principal curvatures and principal directions in differentiating airways from other tissues in geometric space. A "puzzle game" procedure is used to identify false negative regions and reduce false positive regions that do not meet the shape analysis criteria. The negative impact of partial volume effects on small airway detection is partially alleviated by repeating the developed differential geometric analysis on lung anatomical structures modeled at multiple iso-values (thresholds). In addition to having advantages, such as full automation, easy implementation and relative insensitivity to image noise and/or artifacts, this scheme has virtually no leakage issues and can be easily extended to the extraction or the segmentation of other tubular type structures (e.g., vascular tree). The performance of this scheme was assessed quantitatively using 75 chest CT examinations acquired on 45 subjects with different slice thicknesses and using 20 publicly available test cases that were originally designed for evaluating the performance of different airway tree segmentation algorithms. PMID- 20851794 TI - Human motion tracking by temporal-spatial local gaussian process experts. AB - Human pose estimation via motion tracking systems can be considered as a regression problem within a discriminative framework. It is always a challenging task to model the mapping from observation space to state space because of the high-dimensional characteristic in the multimodal conditional distribution. In order to build the mapping, existing techniques usually involve a large set of training samples in the learning process which are limited in their capability to deal with multimodality. We propose, in this work, a novel online sparse Gaussian Process (GP) regression model to recover 3-D human motion in monocular videos. Particularly, we investigate the fact that for a given test input, its output is mainly determined by the training samples potentially residing in its local neighborhood and defined in the unified input-output space. This leads to a local mixture GP experts system composed of different local GP experts, each of which dominates a mapping behavior with the specific covariance function adapting to a local region. To handle the multimodality, we combine both temporal and spatial information therefore to obtain two categories of local experts. The temporal and spatial experts are integrated into a seamless hybrid system, which is automatically self-initialized and robust for visual tracking of nonlinear human motion. Learning and inference are extremely efficient as all the local experts are defined online within very small neighborhoods. Extensive experiments on two real-world databases, HumanEva and PEAR, demonstrate the effectiveness of our proposed model, which significantly improve the performance of existing models. PMID- 20851795 TI - Multi-objective four-dimensional vehicle motion planning in large dynamic environments. AB - This paper presents Multi-Step A* (MSA*), a search algorithm based on A* for multi-objective 4-D vehicle motion planning (three spatial and one time dimensions). The research is principally motivated by the need for offline and online motion planning for autonomous unmanned aerial vehicles (UAVs). For UAVs operating in large dynamic uncertain 4-D environments, the motion plan consists of a sequence of connected linear tracks (or trajectory segments). The track angle and velocity are important parameters that are often restricted by assumptions and a grid geometry in conventional motion planners. Many existing planners also fail to incorporate multiple decision criteria and constraints such as wind, fuel, dynamic obstacles, and the rules of the air. It is shown that MSA* finds a cost optimal solution using variable length, angle, and velocity trajectory segments. These segments are approximated with a grid-based cell sequence that provides an inherent tolerance to uncertainty. The computational efficiency is achieved by using variable successor operators to create a multiresolution memory-efficient lattice sampling structure. The simulation studies on the UAV flight planning problem show that MSA* meets the time constraints of online replanning and finds paths of equivalent cost but in a quarter of the time (on average) of a vector neighborhood-based A*. PMID- 20851796 TI - Multidisciplinary cancer care: we need to practice what we preach. PMID- 20851797 TI - Mus musculus. PMID- 20851798 TI - Institutional declaration in favour of the development of interdisciplinary cancer care in Spain. PMID- 20851799 TI - Genetic alterations in children and adolescents with acute myeloid leukaemia. AB - Acute Myeloid Leukemia is a clinically and genetically heterogeneous disease, in which cytogenetic aberrations are the most important factors to determine biological behavior and prognosis. More than 20 different chromosomal abnormalities have been identified in a high percentage of children (70-85%) with the novo AML. We reviewed the most frequently found and the impact of these aberrations on prognosis. Differences according to the age of patients and mainly in relation to adult population have been enhanced, although the low incidence of AML in children and the high number of abnormalities make difficult to accurately define the prognosis significance of these aberrations. PMID- 20851800 TI - Candidate genes and potential targets for therapeutics in Wilms' tumour. AB - Wilms' tumour (WT) is the most common malignant renal tumour of childhood. During the past two decades or so, molecular studies carried out on biopsy specimens and tumour-derived cell lines have identified a multitude of chromosomal and epigenetic alterations in WT. In addition, a significant amount of evidence has been gathered to identify the genes and signalling pathways that play a defining role in its genesis, growth, survival and treatment responsiveness. As such, these molecules and mechanisms constitute potential targets for novel therapeutic strategies for refractory WT. In this report we aim to review some of the many candidate genes and intersecting pathways that underlie the complexities of WT biology. PMID- 20851801 TI - The role of magnetic resonance imaging in oncology. AB - Conventional diagnostic magnetic resonance imaging (MRI) techniques have focused on improving the spatial resolution and image acquisition speed (whole-body MRI) or on new contrast agents. Most advances in MRI go beyond morphologic study to obtain functional and structural information in vivo about different physiological processes of tumor microenvironment, such as oxygenation levels, cellular proliferation, or tumor vascularization through MRI analysis of some characteristics: angiogenesis (perfusion MRI), metabolism (MRI spectroscopy), cellularity (diffusion-weighted MRI), lymph node function, or hypoxia [blood oxygen-level-dependent (BOLD) MRI]. We discuss the contributions of different MRI techniques than must be integrated in oncologic patients to substantially advance tumor detection and characterization risk stratification, prognosis, predicting and monitoring response to treatment, and development of new drugs. PMID- 20851802 TI - Optimal adjuvant hormonal therapy in postmenopausal women with hormone-receptor positive early breast cancer: have we answered the question? AB - Adjuvant endocrine therapy is the most important systemic treatment for postmenopausal women with hormone-receptor-positive early breast cancer following surgery. Most trials have shown that the third-generation aromatase inhibitors, anastrozole, letrozole (LET), and exemestane, significantly prolong disease-free survival compared with tamoxifen. However, an overall survival benefit with aromatase inhibitors was observed in only three trials to date, in retrospective analyses from selected groups of patients: sequential analysis in the Austrian Breast & Colorectal Study Group 8, switch analysis in the Intergroup Exemestane Study, and analysis of initial letrozole in Breast International Group 1-98 study. Although the priming effect observed in preclinical models and breast cancer patients provides a rationale for sequencing adjuvant endocrine treatment with tamoxifen and aromatase inhibitors, the optimal strategy for adjuvant endocrine treatment has yet to be determined. This review discusses aromatase inhibitor monotherapy, sequential adjuvant treatment with tamoxifen followed by an aromatase inhibitor, and sequential adjuvant treatment with an aromatase inhibitor followed by tamoxifen. Available data in support of and against each strategy is evaluated. The safety profiles of tamoxifen and aromatase inhibitors is also examined. PMID- 20851803 TI - Revised guidelines for second-look surgery in patients with colon and rectal cancer. AB - Proper indications for a second surgical intervention in patients with colorectal cancer have always been a controversial subject. Surgeons find benefit in a second-look operation where a limited extent of cancer is discovered and resected with negative margins. However, a negative exploratory laparotomy or an intervention that is unable to achieve an R0 resection provides little or no benefit. Unfortunately, this type of intervention may place the patient in a worse condition, leading to morbidity or mortality. This manuscript attempts to define clinical parameters of primary colorectal cancer that are associated with a pattern of recurrence and that can be definitively addressed by second-look surgery. Also, new surgical technologies that may assist in achieving a potentially curative resection of local-regional recurrence are described. Cytoreductive surgery with peritonectomy and perioperative intraperitoneal chemotherapy with hyperthermia is presented as a new treatment option for reoperative surgery. A new management plan utilized in patients at high risk for local-regional recurrence may result in a high likelihood of conversion of a second-look cancer-positive patient to a long-term survivor. PMID- 20851804 TI - Fifty-one Kaposi sarcoma patients. AB - INTRODUCTION: Kaposi sarcoma (KS) is a mesenchymal tumor originating from lymphatic endothelial cells. Immunosuppressive patients have higher risk for KS. HHV-8 has a role in immunopathogenesis of KS. Aim Evaluation of demographical properties with tumor characteristics and treatment modalities of KS. MATERIAL AND METHOD: Histopathologically documented KS patients were evaluated retrospectively. Anti-HIV seroprevalence was also evaluated with patient and tumor characteristics besides treatment regimens. RESULTS: Fifty-one patients were included between September 1998 and February 2009. Male/female ratio was 3.25 (39/12). Median age was 68 (31-94). Lower extremity was the most common site whereas excisional biopsy was the most common diagnostic procedure. Smoking rate was 42.8%. Twenty percent had family history for cancer. Anti- HIV seropositivity rate was 1.9%. Thirty eight percent had local monotherapy, and radiotherapy was most common (26%). Multidisciplinary approach rate was 44%. Most of them had surgery and radiotherapy combination. Two-third of the patients had radiotherapy alone or with other modalities. Rates were as 12% for chemotherapy and 6% for interferon. Vincristine-bleomycin-doxorubicin combination was the most preferred regimen (60%). CONCLUSION: Male patients in the sixth decade seem to have higher risk for KS. Smoking rate was almost as high. Local therapy might be sufficient in most of the patients. However, we may also consider systemic chemotherapy for selected patients, including vincristine, bleomycin and doxorubicin. PMID- 20851805 TI - Repeated liver resection for recurrence of colorectal cancer metastases. AB - BACKGROUND: Resection of liver metastases is accepted as treatment for diverse tumours, implying a survival improvement. Metastases often recur after first hepatectomy and, very few would be potentially resectable. MATERIALS AND METHODS: A retrospective study of 18 patients undergoing repeated hepatectomies (two or more liver resections in the same patient) due to metastases of colorectal cancer between 1988 and 2006 was performed. RESULTS: Thirteen men and five women, mean age 57.55 years, participated. In all patients, repeated liver resection was performed due to recurrence of the metastases. Complications rate after first hepatectomy was 11.1% and after the second 16.6%. Mortality rate was 11.1% after second hepatectomy, and there was no mortality after third hepatectomy. Three- and 5-year survival after colectomy was 88.9% and 77.8%, respectively; after first hepatectomy 3- and 5-year survival was 88.9% and 61.1%, respectively; after second hepatectomy, 3- and 5-year survival was 83.3% and 61.1% respectively; and 3-year survival after third hepatectomy was 67%. CONCLUSION: Repeated resections by expert surgeons for recurrent liver metastases can be safely performed, with low morbidity and mortality rates similar to first hepatectomies. Repeated resections of liver metastases of colorectal cancer improve global survival. PMID- 20851806 TI - Stereotactic body radiation therapy for spinal metastases. AB - The goal of this paper is to expose the clinical results and review of the literature of the treatment of spinal metastases with Stereotactic Body Radiation Therapy (SBRT) presenting one case. A spinal metastases from rectal cancer treated with a single dose of 18Gy is presented. The following physics aspects are exposed: Treatment volume, tumor volume marginal doses and maximum doses in organs at risk. Clinical and radiographic follow up is presented. Local control and pain relief after one year of follow up was excellent. In properly selected patients, the treatment of limited metastatic disease with SBRT appears to be feasible and safe. PMID- 20851807 TI - Pancreaticoduodenectomy for metastasis of uterine leiomyosarcoma to the pancreas. AB - Metastasis of uterine leiomyosarcoma to the pancreas is rare. A 46-year-old woman was diagnosed with uterine leiomyosarcoma and underwent surgery. Thereafter, recurrences in the lung and subsequently in the pancreas were diagnosed. These lesions were resected and diagnosed as metastasis of uterine leiomyosarcoma. We report a rare case of uterine leiomyosarcoma with metastasis to the lung and pancreas, both of which were resected using aggressive surgery. PMID- 20851808 TI - G-CSF for stem cell therapy in acute myocardial infarction: friend or foe? AB - Stem cell-based therapy has emerged as a potential therapeutic option for patients with acute myocardial infarction. The ability of granulocyte colony stimulating factor (G-CSF) to mobilize endogenous stem cells as well as to protect cardiomyocytes at risk via paracrine effects has attracted considerable attention. In the past decade, a number of clinical trials were carried out to study the efficacy of G-CSF in cardiac repair. These trials showed variable outcomes in terms of improved cardiac contractile function and suppressed left ventricular negative remodelling. Critical examinations of these results have raised doubts concerning the effectiveness of G-CSF in modulating functional recovery. However, these cumulative clinical experiences are helpful in the understanding of mechanisms and roles of signalling pathways in regulating homing and engraftment of bone marrow stem cells to the infarcted heart. In this review, we discuss some of the observations that may have influenced the clinical outcomes. Improving strategies that target the critical aspects of G-CSF-driven cardiac therapy may provide a better platform to augment clinical benefits in future trials. PMID- 20851809 TI - Inorganic nitrite and chronic tissue ischaemia: a novel therapeutic modality for peripheral vascular diseases. AB - Ischaemic tissue damage represents the ultimate form of tissue pathophysiology due to cardiovascular disease, which is the leading cause of morbidity and mortality across the globe. A significant amount of basic research and clinical investigation has been focused on identifying cellular and molecular pathways to alleviate tissue damage and dysfunction due to ischaemia and subsequent reperfusion. Over many years, the gaseous molecule nitric oxide (NO) has emerged as an important regulator of cardiovascular health as well as protector against tissue ischaemia and reperfusion injury. However, clinical translation of NO therapy for these pathophysiological conditions has not been realized for various reasons. Work from our laboratory and several others suggests that a new form of NO-associated therapy may be possible through the use of nitrite anion (sodium nitrite), a prodrug which can be reduced to NO in ischaemic tissues. In this manner, nitrite anion serves as a highly selective NO donor in ischaemic tissues without substantially altering otherwise normal tissue. This surprising and novel discovery has reinvigorated hopes for effectively restoring NO bioavailability in vulnerable tissues while continuing to reveal the complexity of NO biology and metabolism within the cardiovascular system. However, some concerns may exist regarding the effect of nitrite on carcinogenesis. This review highlights the emergence of nitrite anion as a selective NO prodrug for ischaemic tissue disorders and discusses the potential therapeutic utility of this agent for peripheral vascular disease. PMID- 20851810 TI - Baicalin increases VEGF expression and angiogenesis by activating the ERR{alpha}/PGC-1{alpha} pathway. AB - AIMS: Baicalin is the major component found in Scutellaria baicalensis root, a widely used herb in traditional Chinese medicine. Although it has been used for thousands of years to treat stroke, the mechanisms of action of S. baicalensis have not been clearly elucidated. In this report, we studied the modulation of angiogenesis as one possible mechanism by investigating the effects of these agents on expression of vascular endothelial growth factor (VEGF), a critical factor for angiogenesis. METHODS AND RESULTS: The effects of baicalin and an extract of S. baicalensis on VEGF expression were tested in several cell lines. Both agents induced VEGF expression in all cells without increasing expression of hypoxia-inducible factor-1alpha (HIF-1alpha). The expression of reporter genes was also activated under the control of the VEGF promoter containing either a functional or a defective HIF response element (HRE). Only minimal effects were observed on reporter activation under the HRE promoter. Instead, both agents significantly induced oestrogen-related receptor (ERRalpha) expression as well as the activity of reporter genes under the control of ERRalpha-binding element. Their ability to induce VEGF expression was suppressed once ERRalpha expression was knocked down by siRNA or ERRalpha-binding sites were deleted in the VEGF promoter. We also found that both agents stimulated cell migration and vessel sprout formation from the aorta. CONCLUSION: Our results implicate baicalin and S. baicalensis in angiogenesis by inducing VEGF expression through the activation of the ERRalpha pathway. These data may facilitate a better understanding of the potential health benefits of these agents in the treatment of cardiovascular diseases. PMID- 20851811 TI - Ex vivo carbon monoxide delivery inhibits intimal hyperplasia in arterialized vein grafts. AB - AIMS: Veins are still the best conduits available for arterial bypass surgery. When these arterialized vein grafts fail, it is often due to the development of intimal hyperplasia (IH). We investigated the feasibility and efficacy of the ex vivo pre-treatment of vein grafts with soluble carbon monoxide (CO) in the inhibition of IH. METHODS AND RESULTS: The inferior vena cava was excised from donor rats and placed as an interposition graft into the abdominal aorta of syngeneic rats. Prior to implantation, vein grafts were stored in cold Lactated Ringer (LR) solution with or without CO saturation (bubbling of 100% CO) for 2 h. Three and 6 weeks following grafting, vein grafts treated with cold LR for 2 h developed IH, whereas grafts implanted immediately after harvest demonstrated significantly less IH. Treatment in CO-saturated LR significantly inhibited IH and reduced vascular endothelial cell (VEC) apoptosis. Electron microscopy revealed improved VEC integrity with less platelet/white blood cell aggregation in CO-treated grafts. The effects of CO in preventing IH were associated with activation of hypoxia inducible factor-1alpha (HIF-1alpha) and an increase in vascular endothelial growth factor (VEGF) expression at 3-6 h after grafting. Treatment with a HIF-1alpha inhibitor completely abrogated the induction of VEGF by CO and reversed the protective effects of CO on prevention of IH. CONCLUSION: Ex vivo treatment of vein grafts in CO-saturated LR preserved VEC integrity perioperatively and significantly reduced neointima formation. These effects appear to be mediated through the activation of the HIF1alpha/VEGF pathway. PMID- 20851812 TI - Antibiotic stewardship programmes--what's missing? AB - Inappropriate antibiotic use and antibiotic resistance are now major global issues. Antimicrobial stewardship programmes are increasingly being used to optimize antibiotic prescribing in acute care. The central tenet of these programmes tends to be policy and guidelines aimed at prescribers. However, rules and guidelines alone may not be sufficient to bring about effective and sustainable optimization of practice. Best practice needs to be positively reinforced by an environment that facilitates and supports optimal prescribing choices, i.e. a 'choice architecture' that makes prudent antibiotic prescribing the path of least resistance. To make prudent antibiotic management an integral part of the behaviour of all healthcare professionals and to bring about quality improvement it is necessary to adopt a whole-system approach. To do this it is necessary first to understand the factors that influence antibiotic management and prescribing. PMID- 20851814 TI - Detection of KPC-2-producing Citrobacter freundii isolates in Spain. PMID- 20851813 TI - German multicentre survey of the antibiotic susceptibility of Bacteroides fragilis group and Prevotella species isolated from intra-abdominal infections: results from the PRISMA study. AB - OBJECTIVES: To determine the susceptibility of Gram-negative anaerobic bacteria of the family Bacteroidaceae from hospitalized patients with intra-abdominal infections (IAIs) to moxifloxacin and other antimicrobial agents with known activity against anaerobes. METHODS: Four hundred and thirty anaerobic bacterial isolates of the family Bacteroidaceae obtained from patients with IAIs were collected from 32 centres in Germany in 2007. MICs were determined using microbroth dilution for the following antimicrobials: ampicillin/sulbactam; ertapenem; meropenem; levofloxacin; moxifloxacin; clindamycin; and metronidazole. EUCAST and CLSI guidelines (for moxifloxacin) were used for interpretation. RESULTS: Overall, metronidazole exhibited the lowest resistance rates against the study isolates (four isolates, 0.9%), while the resistance rate was 4.9% for ampicillin/sulbactam, 5.3% for ertapenem and 4.9% for meropenem. Moxifloxacin showed good activity against most Bacteroides species. Resistance rates ranged between 10% and 22% for the various species except Bacteroides vulgatus, with 59% of isolates being resistant. Clindamycin had only poor activity, with 9%-56% of Bacteroides isolates being resistant. CONCLUSIONS: Resistance among Bacteroides spp. involved in IAIs to antimicrobials with known activity against anaerobes does occur and the resistance rate observed for the carbapenems is a cause of concern. These data emphasize the need not only for periodic monitoring of the susceptibility of anaerobic pathogens to guide empirical treatment but also for species identification and susceptibility testing in selected patients with severe infections involving anaerobic bacteria. PMID- 20851815 TI - Parallel increase in community use of fosfomycin and resistance to fosfomycin in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. AB - OBJECTIVES: To document fosfomycin susceptibility of extended-spectrum beta lactamase-producing Escherichia coli (ESBL-EC), analyse trends in fosfomycin use and investigate fosfomycin resistance in ESBL-EC isolated from urinary tract infections (UTIs). METHODS: Twenty-seven Spanish hospitals participating in the European Antimicrobial Resistance Surveillance Network were requested to collect up to 10 sequential ESBL-EC for centralized susceptibility testing and typing. EUCAST guidelines were followed for antibiotic susceptibility testing, and bla(ESBL) type, phylogroups and O25b serotype were determined by PCR and sequencing. In addition, the trend in fosfomycin resistance among ESBL-EC causing UTIs was determined in 9 of the 27 hospitals. Total fosfomycin use for ambulatory care was established by WHO-recommended methods. RESULTS: A total of 231 ESBL-EC (42.4% CTX-M-15, 34.2% SHV-12 and 23.4% CTX-M-14) were collected. The overall rate of fosfomycin resistance was 9.1%, but varied according to ESBL type (5.6% of CTX-M-14 isolates, 5.1% of SHV-12 and 15.3% of CTX-M-15). Of 67 O25b/B2 isolates, 11 (16.4%) were fosfomycin resistant. Predictors of infection with fosfomycin-resistant ESBL-EC were O25b/phylogroup B2 isolates, female gender and nursing home residence. Among 114 197 UTIs caused by E. coli 4740 (4.2%) were due to ESBL-EC. Fosfomycin resistance increased in these isolates from 4.4% (2005) to 11.4% (2009). The use of fosfomycin grew from 0.05 defined daily doses per 1000 inhabitants per day (1997) to 0.22 (2008), a 340% increase. CONCLUSIONS: Key factors related to increased fosfomycin resistance in ESBL-EC causing UTIs could be the rapid growth in community use of fosfomycin, the widespread distribution of the 025b/B2 E. coli clone and the existence of a susceptible population comprising women residing in nursing home facilities. PMID- 20851816 TI - Rapid detection of vancomycin-non-susceptible Staphylococcus aureus using the spiral gradient endpoint technique. AB - OBJECTIVES: Several methods have been introduced for detection of vancomycin-non susceptible Staphylococcus aureus [heterogeneous vancomycin-intermediate S. aureus (hVISA) and vancomycin-intermediate S. aureus (VISA)]. However, the limitations of these methods can delay appropriate therapy for the patient. This study evaluated the spiral gradient endpoint (SGE) technique for detection of hVISA/VISA. METHODS: The SGE method was evaluated for intra-batch, inter-batch and inter-observer reproducibility in comparison with MICs determined by agar dilution. Three media, Mueller-Hinton agar, brain heart infusion agar and brain heart infusion agar with 5% glucose, were evaluated. The SGE method was compared with agar dilution for correlation of MIC and susceptibility category using control strains, clinical isolates and induced vancomycin-non-susceptible strains. RESULTS: The SGE method had good reproducibility and there was excellent correlation of MICs generated by SGE using brain heart infusion agar with those by agar dilution (r(2) =0.950), with no difference in resistance categories generated by the two methods. All VISA isolates were correctly identified and the method allowed easy identification of hVISA by means of the trailing endpoint. CONCLUSIONS: SGE offers a simple, rapid and cost-effective alternative method for the detection of hVISA/VISA for the routine laboratory. Early recognition of vancomycin-non-susceptible strains can allow the change to appropriate antibiotics, resulting in potentially better patient outcomes. PMID- 20851817 TI - Tissue engineered biological augmentation for tendon healing: a systematic review. AB - INTRODUCTION: Tendon injuries give rise to significant morbidity. In the last few decades, several techniques have been increasingly used to optimize tendon healing. SOURCES OF DATA: We performed a comprehensive search of PubMed, Medline, Cochrane, CINAHL and Embase databases using various combinations of the commercial names of each scaffold and the keywords 'tendon', 'rotator cuff', 'supraspinatus tendon', 'Achilles tendon', 'growth factors', 'cytokines', 'gene therapy', 'tissue engineering', 'mesenchymal' and 'stem cells' over the years 1966-2009. All articles relevant to the subject were retrieved, and their bibliographies were hand searched for further references in the context to tissue engineered biological augmentation for tendon healing. AREAS OF AGREEMENT: Several new techniques are available for tissue-engineered biological augmentation for tendon healing, growth factors, gene therapy and mesenchimal stem cells. AREAS OF CONTROVERSY: Data are lacking to allow definitive conclusions on the use of these techniques for routine management of tendon ailments. GROWING POINTS: The emerging field of tissue engineering holds the promise to use new techniques for tendon augmentation and repair. Preliminary studies support the idea that these techniques can provide an alternative for tendon augmentation with great therapeutic potential. AREAS TIMELY FOR DEVELOPING RESEARCH: The optimization strategies discussed in this article are currently at an early stage of development. Although these emerging technologies may develop into substantial clinical treatment options, their full impact needs to be critically evaluated in a scientific fashion. PMID- 20851818 TI - Left ventricular systolic and diastolic function improve after acute myocardial infarction treated with acute percutaneous coronary intervention, but are not influenced by intracoronary injection of autologous mononuclear bone marrow cells: a 3 year serial echocardiographic sub-study of the randomized-controlled ASTAMI study. AB - AIMS: To clarify long-term changes in global, regional, and diastolic left ventricular (LV) function after intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) in acute myocardial infarction (AMI). METHODS AND RESULTS: In the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) study, 100 patients with anterior ST-elevation myocardial infarction and percutaneous coronary intervention on the left anterior descending artery (LAD) were randomized to receive intracoronary injection of mBMCs or not. Transthoracic echocardiography was performed at baseline, 3, 6, 12 months, and 3 years. Regional LV function was assessed by two-dimensional speckle-tracking echocardiography. From baseline to 3 years, LV ejection fraction changed from 45.7 to 47.5% in the mBMC group, and from 46.9 to 46.8% in the control group (P = 0.87 for difference in change over time between groups). Longitudinal strain in the LAD territory improved from -9.7 to -12.2% in the mBMC group and from -9.9 to -12.8% in the control group (P = 0.45). E/e' decreased from 14.7 to 12.9 in the mBMC group and from 14.8 to 11.9 in the control group (P = 0.31). There were no significant differences between groups in change of LV volumes, global systolic function, regional function, or diastolic function during 3 years follow-up. CONCLUSION: No differences between groups indicating beneficial effect of intracoronary mBMC injection could be identified. Both groups in ASTAMI experienced improvement of global, regional, and diastolic LV function after 3-6 months, with effects sustained at 3 years. PMID- 20851819 TI - Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin. AB - AIMS: Insulin-like growth factor (IGF)-I is a regulator of glucose/fatty acid metabolism and may be involved in the pathophysiology of cardiovascular disease, but it remains unclear whether endogenous IGF-I is associated with the prognosis of heart failure (HF). We investigated whether the IGF axis, the ratio of IGF-I to IGF-binding protein-3 (IGFBP-3), was a predictor of clinical outcomes in HF. The association of IGF axis with serum adiponectin level, a prognostic marker of HF as well as a regulator of glucose/fatty acid metabolism, was also analysed. METHODS AND RESULTS: We measured serum IGF-I and IGFBP-3 in 142 HF patients with left ventricular systolic dysfunction and 63 control subjects. Patients with HF underwent clinical assessment and measurement of adiponectin and B-type natriuretic peptide (BNP). Compared with controls, HF patients showed significantly decreased serum IGF axis values [median (inter-quartile ranges), 0.114 (0.063-0.150) vs. 0.099 (0.052-0.158), P = 0.042]. In HF patients, the log transformed IGF axis values were inversely correlated with the log-transformed serum adiponectin levels (r = -0.35, P < 0.0001) and plasma BNP levels (r = 0.25, P = 0.0028). The IGF axis was lower in patients with New York Heart Association (NYHA) functional class III/IV than those with class I/II [0.071 (0.044-0.145) vs. 0.107 (0.068-0.161), P = 0.022]. Furthermore, a decrease in IGF axis was associated with increased rates of all-cause mortality (P = 0.013), cardiac death (P = 0.035), and a composite of cardiac death and re hospitalization (P = 0.0085). CONCLUSION: Insulin-like growth factor axis is a significant predictor of clinical outcomes in HF and is significantly associated with serum adiponectin levels. PMID- 20851820 TI - Venesection for non-alcoholic fatty liver disease unresponsive to lifestyle counselling--a propensity score-adjusted observational study. AB - BACKGROUND/AIM: To test the short-term clinical usefulness of venesection associated with lifestyle counselling as against counselling alone on insulin resistance and liver enzymes in subjects with non-alcoholic fatty liver disease (NAFLD), using a propensity score approach. METHODS: We carried out a 6- to 8 month observational analysis of 198 NAFLD patients in three Italian referral centres (79 venesection and 119 counselling alone). Insulin resistance was measured by the homeostasis model assessment (HOMA) method. Logistic regression was used to identify factors associated with normal HOMA and normal alanine aminotransferase (ALT) at the end of observation. The results were adjusted for the propensity score to be enrolled in the venesection programme, based on clinical and laboratory data, including common HFE polymorphisms and liver biopsy (available in 161 cases). RESULTS: After adjustment for propensity and changes in BMI, venesection was significantly associated with normal HOMA [all cases: odds ratio (OR) 3.00; 95% confidence interval (CI) 1.51-5.97; cases with histology: OR 2.29; 95% CI 1.08-4.87] and ALT within normal limits (all cases: OR 2.56; 95% CI 1.29-5.10; cases with histology: OR 2.81; 95% CI 1.20-5.24). The results were confirmed in an analysis of 57 pairs matched for propensity, where venesection similarly increased the probability of normal HOMA (OR 3.27; 95% CI 1.16-7.84) and normal ALT (OR 5.60; 95% CI 2.09-15.00). Similar data were obtained in the subset of cases with normal basal ferritin (<350 ng/ml). CONCLUSION: Iron depletion by venesection favours the normalization of insulin resistance and raised liver enzymes in non-haemochromatosis patients with NAFLD. PMID- 20851821 TI - The new Sheffield risk and benefit tables for the elderly. AB - Several charts or tables are used to guide treatment in primary prevention of cardiovascular disease (CVD). These usually relate to patients up to 75 years of age, leaving older patients without guidance. Most also present this information as risk, leaving patients to estimate the benefit of treatment and decide whether it is worthwhile. We present tables to display both CVD risk and benefit from treatment in the elderly. A systematic review identified CVD risk functions for the elderly. The Dubbo study of older patients' 5-year CVD risk equation was deemed most appropriate, due to the population studied, endpoints observed and risk factors recorded. By dichotomizing most risk factors, we produced a new risk table in the form of the original 'Sheffield table'. Risk is calculated by selecting the appropriate table for gender and the appropriate cell from the rows and columns, representing age and risk factor contributors, respectively. Total cholesterol above a cell value corresponds to a 20 or 40% 10-year CVD risk. A simple risk scoring system was then derived from the Dubbo equation. Calculation of risk score requires knowledge of a patient's simple demographics, systolic blood pressure and total and high-density lipoprotein cholesterol. Positive integers corresponding to level of risk for each contributing factor are then added together to give a final risk score. A Markov chain model was produced based on the Dubbo derived risk and relative risk reductions from published meta analyses of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors (statins) and anti-hypertensive treatment. Using this model, individual scores were mapped to likely benefit from treatment in terms of disease free years. Our risk table provides a simple means for calculating risk in the elderly, to two major thresholds, while the benefit table explores the concept of presenting benefit of taking CVD-preventing medication. PMID- 20851822 TI - Acute myocardial infarction after botulinum toxin injection. PMID- 20851823 TI - Catecholaminergic polymorphic ventricular tachycardia: important messages from case reports. PMID- 20851824 TI - Pre-clinical detection of amiodarone-induced acute fibrosing alveolitis by intra thoracic impedance monitor of an implantable cardioverter-defibrillator. AB - A 66-year-old male received an implant of a dual-chamber implantable cardioverter defibrillator (ICD) and was prescribed amiodarone (400 mg/day). The intra thoracic impedance monitor in the ICD antecedently detected amiodarone-induced acute fibrosing alveolitis >3 months prior to clinical symptoms. PMID- 20851825 TI - Germline and somatic mosaicism for a mutation of the ryanodine receptor type 2 gene: implication for genetic counselling and patient caring. AB - We identified a heterozygous p.Arg2401His mutation of RYR2 by sequencing the DNA of a 7-year-old girl who was referred for catecholaminergic polymorphic ventricular tachycardia (CPVT). Using high-resolution melting assay, we have demonstrated a mosaicism for this mutation in her asymptomatic mother which illustrates the benefit of extensive genetic analysis in CPVT, in particular regarding genetic counselling. PMID- 20851826 TI - An amino acid residue in the middle of the fingers subdomain is involved in Neq DNA polymerase processivity: enhanced processivity of engineered Neq DNA polymerase and its PCR application. AB - Neq DNA polymerase is the first archaeal family B DNA polymerase reported to lack uracil recognition function and successfully utilize deaminated bases. We have focused on two amino acid residues (Y515, A523) in the fingers subdomain of Neq DNA polymerase, which were predicted to be located in the middle of the fingers subdomain, based on amino acid sequence alignment of the Neq DNA polymerase with structurally determined archaeal DNA polymerases. Those two residues were replaced by site-directed mutagenesis, and the enzymatic properties of the mutants were analyzed. Here, we show that the A523 residue located in the middle of the fingers subdomain affects the processivity of Neq DNA polymerase. Mutational analysis has allowed us to enhance the protein function as well as understand the function of the residues. One mutant protein, Neq A523R DNA polymerase, exhibited a roughly 3-fold enhanced processivity and extension rate compared to wild type, enabling more efficient PCR. In the presence of uracil, Neq A523R DNA polymerase outperformed Taq DNA polymerase with enhanced specificity and sensitivity. These results suggest that Neq A523R DNA polymerase could be most effectively utilized in real-time PCR using uracil-DNA glycosylase without the risk of carry-over contamination. PMID- 20851827 TI - Psychiatric and somatic health in relation to experience of parental divorce in childhood. AB - BACKGROUND: The outcome of studies about the experience of parental divorce and its effects on mental and physical health differs, a result possibly caused by the use of different questionnaires and instruments, varying length of time since the divorce and divergent drop-out of participants. AIMS: To study the presence of psychiatric records and number of diagnosed somatic and mental healthcare visits in a group of young adults with childhood experience of parental divorce in comparison to a group without this experience. METHODS: The presence of records at public psychiatric clinics and 10 years of administrative healthcare data (somatic and mental) were checked for both groups. RESULTS: Significantly more persons from the divorce group appeared in child and adolescent psychiatric care; this was most pronounced in females. However, there were no significant differences between the groups in the number of persons seeking adult psychiatry or in the number of psychiatric consultations. Experience of parental divorce was not found to be an indicator of larger somatic health problems. CONCLUSION: Experience of parental divorce in childhood is not an indicator of adult psychiatric or somatic need of care. PMID- 20851828 TI - Satisfaction with inpatient treatment for first-episode psychosis among different ethnic groups: a report from the UK AeSOP study. AB - BACKGROUND: There is concern about the level of satisfaction with mental healthcare among minority ethnic patients in the UK, particularly as black patients have more compulsory admissions to hospital. AIMS: To determine and compare levels of satisfaction with mental healthcare between patients from different ethnic groups in a three-centre study of first-onset psychosis. METHOD: Data were collected from 216 patients with first-episode psychosis and 101 caregivers from South London, Nottingham and Bristol, using the Acute Services Study Questionnaire (Patient and Relative Version) and measures of sociodemographic variables and insight. RESULTS: No differences were found between ethnic groups in most domains of satisfaction tested individually, including items relating to treatment by ward staff and number of domains rated as satisfactory. However, logistic regression modelling (adjusting for age, gender, social class, diagnostic category and compulsion) showed that black Caribbean patients did not believe that they were receiving the right treatment and were less satisfied with medication than white patients. Black African patients were less satisfied with non-pharmacological treatments than white patients. These findings were not explained by lack of insight or compulsory treatment. CONCLUSIONS: The study found that black patients were less satisfied with specific aspects of treatment, particularly medication, but were equally satisfied with nursing and social care. Understanding the reasons behind this may improve the acceptability of psychiatric care to black minority ethnic groups. PMID- 20851829 TI - Migrants referring to the Bologna Transcultural Psychiatric Team: reasons for drop-out. AB - BACKGROUND: Recent immigrants face various difficulties in adjusting to western countries and show a high prevalence of mental disorders. Access to a culturally appropriate community mental health centre (CMHC) is crucial for immigrants (Bhui et al., 2007). The Bologna West Transcultural Psychiatric Team (BoTPT, Tarricone et al., 2009) is one of the first projects in Italy that prioritizes cultural competence care. This paper aims to evaluate the effectiveness of this service and to describe what characteristics of patient and psychiatric intervention are related to 'drop-out'. METHOD: All migrants who consecutively attended the BoTPT between 1 July 1999 and 30 June 2008 were included and evaluated at first contact and again six months later. RESULTS: After six months we followed up 162 patients; 32 (17.9%) of these had interrupted treatment. Non-Asian origin, a recent history of migration and not receiving social intervention were the strongest predictors of drop-out cases. CONCLUSION: Psychiatric consultation services to migrants could be made more effective by enhancing: (a) cultural competence, through cultural mediator involvement; and (b) social support from the first psychiatric contact. These two characteristics of psychiatric consultation could be developed from resources ordinarily present in the context of a CMHC and could then become a cost-effective strategy for addressing mental health needs among first-generation immigrants. PMID- 20851830 TI - Social organization in a flatworm: trematode parasites form soldier and reproductive castes. AB - In some of the most complex animal societies, individuals exhibit a cooperative division of labour to form castes. The most pronounced types of caste formation involve reproductive and non-reproductive forms that are morphologically distinct. In colonies comprising separate or mobile individuals, this type of caste formation has been recognized only among the arthropods, sea anemones and mole-rats. Here, we document physical and behavioural caste formation in a flatworm. Trematode flatworm parasites undergo repeated clonal reproduction of 'parthenitae' within their molluscan hosts forming colonies. We present experimental and observational data demonstrating specialization among trematode parthenitae to form distinct soldier and reproductive castes. Soldiers do not reproduce, have relatively large mouthparts, and are much smaller and thinner than reproductives. Soldiers are also more active, and are disproportionally common in areas of the host where invasions occur. Further, only soldiers readily and consistently attack heterospecifics and conspecifics from other colonies. The division of labour described here for trematodes is strongly analogous to that characterizing other social systems with a soldier caste. The parallel caste formation in these systems, despite varying reproductive mode and taxonomic affiliation, indicates the general importance of ecological factors in influencing the evolution of social behaviour. Further, the 'recognition of self' and the defence of the infected host body from invading parasites are comparable to aspects of immune defence. A division of labour is probably widespread among trematodes and trematode species encompass considerable taxonomic, life history and environmental diversity. Trematodes should therefore provide new, fruitful systems to investigate the ecology and evolution of sociality. PMID- 20851831 TI - Mitotic recombination: a genotoxic effect of the antidepressant citalopram in Aspergillus nidulans. AB - This report evaluates the potential of the antidepressant drug citalopram to induce homozygotization of genes previously present in a heterozygous condition, by homologous recombination. In order to address this question, a heterozygous diploid strain of the filamentous fungus Aspergillus nidulans and the homozygotization assay were utilized. Non-cytotoxic concentrations of citalopram (50, 75 and 100 MUmol/L) showed a strong recombinogenic effect in A. nidulans, inducing homozygosis of the diploid strain's nutritional markers. The genetic markers exhibited homozygotization index (HI) rates higher than 2.0 and significantly different from HI control ones. Since citalopram has been previously characterized as a DNA synthesis inhibitor, the recombinogenic potential of this antidepressant in A. nidulans may be associated with the recombinational repair of citalopram-induced DNA strand breaks. PMID- 20851832 TI - Tracking deposition of a 14C-radiolabeled kudzu hairy root-derived isoflavone rich fraction into bone. AB - Hairy roots were induced in four genotypes from three kudzu species (Pueraria montana var. lobata, P. lobata and P. phaseoloides) in vitro using Agrobacterium rhizogenes to stimulate rapid secondary metabolite synthesis. Hairy roots from P. montana var. lobata (United States Department of Agriculture no. PI 434246) yielded the highest puerarin and total isoflavone content and the greatest new biomass per growth cycle among the genotypes evaluated. Hairy roots from this genotype were selected for radiolabeling using (14)C-sucrose as a carbon source. Isoflavones from radiolabeled kudzu hairy root cultures were extracted with 80% methanol, partitioned by solvent extraction, and then subfractionated by Sephadex LH-20 gel filtration. Radiolabeled isoflavones were isolated in a highly enriched fraction, which contained predominantly puerarin, daidzin and malonyl-daidzin and had an average radioactivity of 8.614 MBq/g (232.8 MUCi/g) dry fraction. The (14)C-radiolabeled, isoflavone-rich fraction was orally administered at a dose of 60 mg/kg body weight to male Sprague-Dawley rats implanted with a jugular catheter, a subcutaneous ultrafiltrate probe and a brain microdialysate probe. Serum, interstitial fluid, brain microdialysate, urine and feces were collected using a Culex((r)) Automated Blood Collection System for 24 h. At the end of this period, rats were sacrificed and major tissues were collected. Analysis by a scintillation counter confirmed that a bolus dose of (14)C-radiolabeled, isoflavone-rich kudzu fraction reached bone tissues, which accumulated 0.011%, 0.09% and 0.003% of the administered dose in femur, tibia and vertebrae, respectively. Femurs extracted with 80% methanol were analyzed by high performance liquid chromatography with electrospray ionization-mass spectrometry and were found to contain trace quantities of puerarin, daidzein and puerarin glucuronide. This study demonstrates that kudzu isoflavones and metabolites are capable of reaching bone tissues, where they may contribute to the prevention of osteoporosis and the promotion of bone health. PMID- 20851833 TI - The linker domain of basal transcription factor TFIIB controls distinct recruitment and transcription stimulation functions. AB - RNA polymerases (RNAPs) require basal transcription factors to assist them during transcription initiation. One of these factors, TFIIB, combines promoter recognition, recruitment of RNAP, promoter melting, start site selection and various post-initiation functions. The ability of 381 site-directed mutants in the TFIIB 'linker domain' to stimulate abortive transcription was systematically quantitated using promoter-independent dinucleotide extension assays. The results revealed two distinct clusters (mjTFIIB E78-R80 and mjTFIIB R90-G94, respectively) that were particularly sensitive to substitutions. In contrast, a short sequence (mjTFIIB A81-K89) between these two clusters tolerated radical single amino acid substitutions; short deletions in that region even caused a marked increase in the ability of TFIIB to stimulate abortive transcription ('superstimulation'). The superstimulating activity did, however, not correlate with increased recruitment of the TFIIB/RNAP complex because substitutions in a particular residue (mjTFIIB K87) increased recruitment by more than 5-fold without affecting the rate of abortive transcript stimulation. Our work demonstrates that highly localized changes within the TFIIB linker have profound, yet surprisingly disconnected, effects on RNAP recruitment, TFIIB/RNAP complex stability and the rate of transcription initiation. The identification of superstimulating TFIIB variants reveals the existence of a previously unknown rate-limiting step acting on the earliest stages of gene expression. PMID- 20851835 TI - Protein-protein interaction and pathway databases, a graphical review. AB - The amount of information regarding protein-protein interactions (PPI) at a proteomic scale is constantly increasing. This is paralleled with an increase of databases making information available. Consequently there are diverse ways of delivering information about not only PPIs but also regarding the databases themselves. This creates a time consuming obstacle for many researchers working in the field. Our survey provides a valuable tool for researchers to reduce the time necessary to gain a broad overview of PPI-databases and is supported by a graphical representation of data exchange. The graphical representation is made available in cooperation with the team maintaining www.pathguide.org and can be accessed at http://www.pathguide.org/interactions.php in a new Cytoscape web implementation. The local copy of Cytoscape cys file can be downloaded from http://bio.icm.edu.pl/~darman/ppi web page. PMID- 20851834 TI - TRIP Database: a manually curated database of protein-protein interactions for mammalian TRP channels. AB - Transient receptor potential (TRP) channels are a superfamily of Ca(2+)-permeable cation channels that translate cellular stimuli into electrochemical signals. Aberrant activity of TRP channels has been implicated in a variety of human diseases, such as neurological disorders, cardiovascular disease and cancer. To facilitate the understanding of the molecular network by which TRP channels are associated with biological and disease processes, we have developed the TRIP (TRansient receptor potential channel-Interacting Protein) Database (http://www.trpchannel.org), a manually curated database that aims to offer comprehensive information on protein-protein interactions (PPIs) of mammalian TRP channels. The TRIP Database was created by systematically curating 277 peer reviewed literature; the current version documents 490 PPI pairs, 28 TRP channels and 297 cellular proteins. The TRIP Database provides a detailed summary of PPI data that fit into four categories: screening, validation, characterization and functional consequence. Users can find in-depth information specified in the literature on relevant analytical methods and experimental resources, such as gene constructs and cell/tissue types. The TRIP Database has user-friendly web interfaces with helpful features, including a search engine, an interaction map and a function for cross-referencing useful external databases. Our TRIP Database will provide a valuable tool to assist in understanding the molecular regulatory network of TRP channels. PMID- 20851836 TI - Parent report and direct observation of injection-related coping behaviors in youth with type 1 diabetes. AB - OBJECTIVE: This study evaluated insulin injection coping by parental report and video observation in children 3 to <11 years old with diabetes. METHODS: Caregivers of 61 youth with type 1 diabetes completed the Diabetes Injection Distress-Parent Report Form (DID-PRF); a subsample (n = 19; 30%) submitted video recordings of their children's insulin injections. RESULTS: The DID-PRF demonstrated acceptable internal consistency and moderately correlated with video recordings. Half of parents (n = 31; 51%) reported their child's history of insulin injection distress; 30% reportedly experienced distress >=1 year after diagnosis. Current distress was reported for about half (n = 28) of children. More parent and child coping/distress behaviors was associated with younger child age. Children displayed more injection distress in their first month after diagnosis versus the most recent month. CONCLUSIONS: Diabetes-related injection distress and associated coping behaviors should be further explored; longitudinal data and additional measurement development is warranted. PMID- 20851837 TI - Benign paroxysmal vertigo of childhood: long-term outcome. AB - INTRODUCTION: Benign paroxysmal vertigo (BPV) is characterized by recurrent attacks of dizziness in a healthy child. Complete recovery typically takes place during childhood, and an epidemiological link with migraine has been pointed out. Nevertheless, data concerning long-term patient outcome are scarce. SUBJECTS AND METHODS: We analyzed the clinical data of 17 patients diagnosed with BPV between 1991 and 2008 in our neuropediatric department; we particularly focused on family medical history and long-term patient outcome by reviewing their medical files and by interviewing the families with a standardized questionnaire administered by phone. RESULTS: Thirteen families responded to the questionnaire, performed 1.1 to 24.5 years after onset. Among 10 patients older than 11 years of age, five continue to suffer attacks of vertigo. Median age at recovery was six years. Nine subjects exhibited migraine, including all six aged 15 years or older. There was a first-degree history of migraine in eight out of 13 children. CONCLUSION: BPV may not be a homogeneous condition, as some children have a poorer prognosis than others. The strong link with migraine, already noticed by previous authors, led us to discuss the pathophysiology of this condition. PMID- 20851838 TI - New daily persistent headache and panic disorder. AB - BACKGROUND: New daily persistent headache (NDPH) is a primary chronic daily headache that is generally considered to be difficult to treat. Migraine has been linked to comorbid psychiatric conditions, mainly mood and anxiety disorders, but NDPH has never been linked to psychiatric conditions, and never studied extensively for such an association. CASE: We report nine cases (six women and three men) of patients diagnosed with NDPH and panic disorder who were treated for both conditions. Six of them (66%) had good or excellent responses. CONCLUSION: The spectrum of anxiety disorders, particularly panic disorder, should be considered in NDPH patients. Simultaneous treatment of both disorders may lead to good outcomes. PMID- 20851839 TI - Organ culture of the trigeminal ganglion induces enhanced expression of calcitonin gene-related peptide via activation of extracellular signal-regulated protein kinase 1/2. AB - BACKGROUND AND OBJECTIVE: Clinical and experimental studies have revealed a central role of calcitonin gene-related peptide (CGRP) in primary headaches. The role of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in neuronal and glial cell expression of CGRP- immunoreactivity (-ir) in rat trigeminal ganglia was studied with an organ culture method. EXPERIMENTAL PROCEDURES: Sections of adult rat trigeminal ganglia were cultured for up to 48 hours, examined with immunohistochemistry and quantitative real-time polymerase chain reaction (PCR) assay. Specific antibodies against CGRP, phosphorylated ERK1/2 (pERK1/2), total ERK1/2 (tERK1/2), phosphorylated p38 (pp38), phosphorylated C-Jun-N-terminal protein kinase (pJNK), pro-calcitonin (pro-CT), CGRP receptor activity modifying protein 1 (RAMP1), glutamine synthetase (GS) and pro-CT were used. To explore molecular mechanisms involved in the organ culture-induced CGRP-ir in neurons and glial cells, the effects of the MEK/ERK1/2 inhibitor U0126, its inactive analogue U0124, the p38 inhibitor SB203580 and the JNK inhibitor SP600125 were studied. RESULTS: In fresh ganglia, small- and medium-sized neurons were CGRP-ir while some larger neurons displayed RAMP1-ir. Glial cells were negative to both. After organ culture, neurons showed enhanced CGRP- and RAMP1-ir. In addition, some glial cells were RAMP1- and CGRP-ir. Isolated glial cells and neurons were found to contain CGRP mRNA, and showed pro-CT-ir, suggestive of local formation of CGRP. Neurons and glial cells showed enhanced pERK1/2-ir already after two hours of organ culture and this remained elevated for 48 hours. There was transient pJNK-ir in neurons at two hours, while pp38-ir was not altered. U0126 reduced the enhanced pERK1/2-ir, while U0124 had no such effect; the CGRP-ir in neurons and glial cells was reduced at 48 hours and in parallel the CGRP mRNA expression was lower at 24 hours. CONCLUSION: We suggest that in conditions of elevated CGRP expression, inhibition of ERK1/2 might be an option for novel treatment. PMID- 20851840 TI - Double orifice mitral valve with normal function: an echocardiography and MRI study of a rare finding. PMID- 20851841 TI - Three techniques for integrating data in mixed methods studies. PMID- 20851842 TI - Bitter pills for drug companies. PMID- 20851843 TI - Does intravenous Delta9-tetrahydrocannabinol increase dopamine release? A SPET study. AB - Intravenous (IV) Delta9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5 mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30 min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis. PMID- 20851844 TI - Pool resources to lift children's health services out of "mediocre state". PMID- 20851845 TI - The effect of health, socio-economic position, and mode of data collection on non response in health interview surveys. AB - AIMS: To investigate the relationship between potential explanatory factors (socio-economic factors and health) and non-response in two general population health interview surveys (face-to-face and telephone), and to compare the effects of the two interview modes on non-response patterns. METHODS: Data derives from The Danish Health Interview Survey 2000 (face-to-face interview) and The Funen County Health Survey 2000/2001 (telephone interview). Data on all invited individuals were obtained from administrative registers and linked to survey data at individual level. Multiple logistic regression analyses were used to examine associations between potential explanatory factors and non-response. RESULTS: The overall response rate was higher in the face-to-face interview survey (74.5%) than in the telephone survey (69.2%). Refusal was the most common reason for non response and the same factors were generally associated with non-response in both modes of interview. The non-response rate was high among persons with low socio economic position. No significant associations between health and non-response were found. CONCLUSIONS: Health status does not play a systematic role for non response rates in health interview surveys, but the non-response rate is higher in lower socio-economic groups. Analyses of non-response should be performed to understand the implications of survey findings. PMID- 20851846 TI - Secular trends in muscular fitness among Finnish adolescents. AB - AIM: To investigate secular change over time in health-related muscular fitness and how leisure time physical activity (LTPA), sport club participation, and body mass index are associated with muscular fitness in adolescents. METHODS: Two cross-sectional samples of Finnish 13-16-year-old adolescents were studied in 1976 (n = 643; 312 boys and 331 girls) and in 2001 (n = 579; 308 boys and 271 girls). Muscular fitness index was calculated as the sum of age- and sex-specific z-scores of four tests measuring muscular fitness and agility. Height and weight were also measured. Self-reported weekly frequency of LTPA of at least 30-min duration and regularity of participation in organised sport were obtained by questionnaire. Identical methods were used in 1976 and 2001. RESULTS: Muscular fitness index was higher in 2001 than in 1976 in both boys (by 0.77 points, p = 0.008, effect size d = 0.17, small difference) and girls (1.01 points, p = 0.004, d = 0.20, small difference). Sport club participation, body mass index, and participation in LTPA together explained more of the muscular fitness index variance in 2001 than in 1976 in both boys (coefficient of determination from 0.10 to 0.24) and girls (from 0.25 to 0.40). CONCLUSIONS: The muscular fitness of 13-16-year old adolescents slightly improved over time. Organised LTPA showed a stronger association with muscular fitness in 2001 than in 1976. Due to increased polarisation in fitness, in health promotion more attention should be paid on adolescents' health-related fitness and its association to LTPA. PMID- 20851847 TI - Dietary, social, and environmental determinants of obesity in Kenyan women. AB - AIM: To assess the determinants of overweight and obesity in Kenyan women considered to be undergoing the nutrition transition. METHODS: A nationally representative sample of women (n = 1008) was randomly drawn. Weight, height, waist, and hip circumference were measured. A 24-hour dietary recall was conducted with each participant and a socio-demographic questionnaire completed. Data was analysed by age, education, location, and socioeconomic status. Risk for obesity was calculated while adjusting for age and location. RESULTS: Overweight and obesity (BMI >= 25 kg/m(2)) were highly prevalent in Kenya (43.3%). Urbanisation appears to be an important determinant of obesity since obesity was most prevalent in urban women in the high income group. Women in the high income group (7278 kJ) and in urban areas (7049 kJ) had the highest mean energy intakes. There were also significant urban/rural and income differences in the contribution of macronutrients to energy intake. Total fat intake was 34.5% of energy (E) in urban areas and 29.7% E in rural areas; while carbohydrates contributed 69.9% E in rural areas and 57.4% E in urban areas (p < 0.0001). Overweight was significantly more likely in the highest income group; among households where room density was low; electricity or gas was used for cooking; and households had own tap and/or own flush toilet. CONCLUSIONS: This study suggests that urbanisation and its associated economic advancement as well as changes in dietary habits are among the most important determinants of overweight and obesity in Kenyan women. PMID- 20851848 TI - Longitudinal data for interdisciplinary ageing research. Design of the Linnaeus Database. AB - RATIONALE: To allow for interdisciplinary research on the relations between socioeconomic conditions and health in the ageing population, a new anonymized longitudinal database - the Linnaeus Database - has been developed at the Centre for Population Studies at Umea University. This paper presents the database and its research potential. DESIGN: Using the Swedish personal numbers the researchers have, in collaboration with Statistics Sweden and the National Board for Health and Welfare, linked individual records from Swedish register data on death causes, hospitalization and various socioeconomic conditions with two databases - Betula and VIP (Vasterbottens Intervention Programme) - previously developed by the researchers at Umea University. Whereas Betula includes rich information about e.g. cognitive functions, VIP contains information about e.g. lifestyle and health indicators. POPULATION AND SAMPLE SIZE: The Linnaeus Database includes annually updated socioeconomic information from Statistics Sweden registers for all registered residents of Sweden for the period 1990 to 2006, in total 12,066,478. The information from the Betula includes 4,500 participants from the city of Umea and VIP includes data for almost 90,000 participants. Both datasets include cross-sectional as well as longitudinal information. POTENTIAL: Due to the coverage and rich information, the Linnaeus Database allows for a variety of longitudinal studies on the relations between, for instance, socioeconomic conditions, health, lifestyle, cognition, family networks, migration and working conditions in ageing cohorts. CONCLUSIONS: By joining various datasets developed in different disciplinary traditions new possibilities for interdisciplinary research on ageing emerge. PMID- 20851849 TI - Measurement of action forces and posture to determine the lumbar load of healthcare workers during care activities with patient transfers. AB - Moving patients or other care activities with manual patient handling is characterized by high mechanical load on the lumbar spine of healthcare workers (HCWs). During the patient transfer activity, the caregivers exert lifting, pulling, and pushing forces varying over time with respect to amplitude and direction. Furthermore, the caregivers distinctly change their posture and frequently obtain postures asymmetrical to the median sagittal plane, including lateral bending and turning the trunk. This paper describes a procedure to determine lumbar load during patient transfer supported by measurement techniques and an exemplary application; this methodology represents the basis of a complex research project, the third 'Dortmund Lumbar Load Study (DOLLY 3)'. Lumbar load was determined by simulation calculations using a comprehensive biomechanical model ('The Dortmunder'). As the main influencing factors, the hand forces of the caregiver exerted during typical patient transfers and the posture and movements of the HCW were recorded in laboratory studies. The action forces were determined three-dimensionally with the help of a newly developed 'measuring bed', two different 'measuring chairs', a 'measuring bathtub', and a 'measuring floor'. To capture the forces during transfers in or at the bed, a common hospital bed was equipped with an additional framework, which is attached to the bedstead and connected to the bedspring frame via three-axial force sensors at the four corners. The other measuring systems were constructed similarly. Body movements were recorded using three-dimensional optoelectronic recording tools and video recordings. The posture and force data served as input data for the quantification of various lumbar-load indicators. PMID- 20851850 TI - Domains of awareness in schizophrenia. AB - Patients with schizophrenia are often characterized as lacking insight or awareness into their illness and symptoms, yet despite considerable research, we still lack a full understanding of the factors involved in causing poor awareness. Within schizophrenia, there has been shown to be a fractionation across dimensions of awareness into mental illness: of being ill, of symptoms, and of treatment compliance. Recently, attention has turned to evidence of a fractionation between awareness of illness and of cognitive impairments and functioning. The current study investigated the degree of fractionation across a broad range of domains of function in schizophrenia and how each domain may be associated with neuropsychological functioning, clinical, mood, and demographic variables. Thirty-one mostly chronic stable patients with schizophrenia completed a battery of neuropsychological tests and measures of psychopathology, including mood. Cognitive insight and awareness of illness, symptoms, memory, and behavioral functioning were also measured. Insight and awareness were assessed using a combination of semistructured interview, observer-rated, self-rated, and objective measures, and included measures of the discrepancy between carer and self-ratings of impairment. Results revealed that awareness of functioning in each domain was largely independent and that awareness in each domain was predicted by different factors. Insight into symptoms was relatively poor while insight into cognitive deficits was preserved. Relative to neuropsychological variables, cognitive insight, comprising self-certainty and self-reflexivity, was a greater predictor of awareness. In conclusion, awareness is multiply fractionated and multiply determined. Therapeutic interventions could, therefore, produce beneficial changes within specific domains of awareness. PMID- 20851851 TI - Cortical auditory adaptation in the awake rat and the role of potassium currents. AB - Responses to sound in the auditory cortex are influenced by the preceding history of firing. We studied the time course of auditory adaptation in primary auditory cortex (A1) from awake, freely moving rats. Two identical stimuli were delivered with different intervals ranging from 50 ms to 8 s. Single neuron recordings in the awake animal revealed that the response to a sound is influenced by sounds delivered even several seconds earlier, the second one usually yielding a weaker response. To understand the role of neuronal intrinsic properties in this phenomenon, we obtained intracellular recordings from rat A1 neurons in vitro and mimicked the same protocols of adaptation carried out in awake animals by means of depolarizing pulses of identical duration and intervals. The intensity of the pulses was adjusted such that the first pulse would evoke a similar number of spikes as its equivalent in vivo. A1 neurons in vitro adapted with a similar time course but less than in awake animals. At least two potassium currents participated in the in vitro adaptation: a Na(+)-dependent K(+) current and an apamin-sensitive K(+) current. Our results suggest that potassium currents underlie at least part of cortical auditory adaptation during the awake state. PMID- 20851852 TI - The prenatal origin of hemispheric asymmetry: an in utero neuroimaging study. AB - Anatomical and functional hemispheric lateralization originates from differential gene expression and leads to asymmetric structural brain development, which initially appears in the perisylvian regions by 26 gestational weeks (GWs). In this in vivo neuroimaging study, we demonstrated a predominant pattern of temporal lobe (TL) asymmetry in a large cohort of human fetuses between 18 and 37 GWs. Over two-thirds of fetuses showed a larger, left-sided TL, combined with the earlier appearance of the right superior temporal sulcus by 23 GWs (vs. 25 GWs on the left side), which was also deeper than its left counterpart in the majority of cases (94.2%). Shape analysis detected highly significant differences in the contour of the right and left TLs by 20 GWs. Thus, fetal hemispheric asymmetry can be detected in utero, opening new diagnostic possibilities for the assessment of diseases that are believed to be linked to atypical hemispheric lateralization. PMID- 20851853 TI - The neural organization of semantic control: TMS evidence for a distributed network in left inferior frontal and posterior middle temporal gyrus. AB - Assigning meaning to words, sounds, and objects requires stored conceptual knowledge plus executive mechanisms that shape semantic retrieval according to the task or context. Despite the essential role of control in semantic cognition, its neural basis remains unclear. Neuroimaging and patient research has emphasized the importance of left inferior frontal gyrus (IFG)--however, impaired semantic control can also follow left temporoparietal lesions, suggesting that this function may be underpinned by a large-scale cortical network. We used repetitive transcranial magnetic stimulation in healthy volunteers to disrupt processing within 2 potential sites in this network--IFG and posterior middle temporal cortex. Stimulation of both sites selectively disrupted executively demanding semantic judgments: semantic decisions based on strong automatic associations were unaffected. Performance was also unchanged in nonsemantic tasks -irrespective of their executive demands--and following stimulation of a control site. These results reveal that an extended network of prefrontal and posterior temporal regions underpins semantic control. PMID- 20851854 TI - Overexpression of high-mobility group box 2 is associated with tumor aggressiveness and prognosis of hepatocellular carcinoma. AB - PURPOSE: We investigated the expression of high-mobility group box 2 (HMGB2) in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms. EXPERIMENTAL DESIGN: HMGB2 mRNA levels were measured in 334 HCC patients by real-time reverse transcription-PCR and HMGB2 protein levels in 173 HCC patients by immunohistochemical studies. The HMGB2 expression level was measured by Western blotting for three HCC cell lines. To clarify the precise role of HMGB2 on cell proliferation, we did in vitro analysis with expression vectors and small interfering RNAs. RESULTS: HMGB2 mRNA and protein expression were significantly higher in HCC than in noncancerous surrounding tissues (P < 0.0001) and showed a positive correlation (rho = 0.35, P < 0.001). HMGB2 overexpression was significantly correlated with shorter overall survival time, both at mRNA (P = 0.0054) and protein level (P = 0.023). Moreover, HMGB2 mRNA level was an independent prognostic factor for overall survival in a multivariate analysis (P = 0.0037). HMGB2 knockdown by small interfering RNAs decreased cell proliferation, and overexpression of HMGB2 by expression vectors diminished cisplatin- and etoposide-induced cell death. CONCLUSIONS: Our clinical and in vitro data suggest that HMGB2 plays a significant role in tumor development and prognosis of HCC. These results can partly be explained by altered cell proliferations by HMGB2 associated with the antiapoptotic pathway. PMID- 20851855 TI - A selective annotated bibliography for clinical audiology (1989-2009): books. AB - PURPOSE: This is the 2nd in a series of 3 planned companion articles that present a selected, annotated, and indexed bibliography of clinical audiology publications from 1989 through 2009. METHOD: Research and preparation of the bibliography were based on published guidelines, professional audiology experience, and professional librarian experience. RESULTS: The first article in the series covered reference works. This article focuses on other books. The planned third companion article will present periodicals and online resources. CONCLUSIONS: Audiologists and librarians can use this bibliography to help them identify relevant clinical audiology literature. PMID- 20851856 TI - Optogenetic monitoring of membrane potentials. AB - Over the last decade, researchers in our laboratory have engineered and developed several series of genetically encoded voltage-sensitive fluorescent proteins (VSFPs) by molecular fusion of a voltage-sensing domain operand with different fluorescent reporter proteins. These genetically encoded VSFPs have been shown to provide a reliable optical report of membrane potential from targeted neurons and muscle cells in culture or in living animals. However, these various reporters also exhibit discrepancies in both their voltage-sensing and targeting properties that are essentially related to the intrinsic characteristics of the fluorescent reporter proteins. It is therefore important carefully to select the sensor that is most appropriate for the particular question being investigated experimentally. Here we examine the current state of this subfield of optogenetics, address current limitations and challenges, and discuss what is likely to be feasible in the near future. PMID- 20851857 TI - Protein restriction in the pregnant mouse modifies fetal growth and pulmonary development: role of fetal exposure to {beta}-hydroxybutyrate. AB - Maternal undernutrition during sensitive periods of pregnancy results in offspring predisposed towards the development of a number of diseases of adulthood, including hypertension and diabetes. In order to determine the nature of any gross alterations in fetal growth during early organogenesis, we supplied timed-mated pregnant mice with diets containing 6% protein (6%P), 9% protein (9%P) or 18% protein (18%P; control) from day 0 of pregnancy. At embryonic days 11 (E11), 12 (E12) and 13 (E13), females were killed and fetuses removed. Gross morphological analysis revealed that fetal limb growth was impaired between E11 and E12 in 6%P animals, but this recovered by E13. Likewise, fetal liver growth and lung branching morphogenesis were seen to exhibit an initial growth impairment at E12 followed by a rapid recovery by E13. Coincident with the observed changes in fetal growth, we noted an elevation in maternal hepatic triglyceride content, expression of the ketogenic 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) and circulating plasma beta-hydroxybutyrate (BOHB). In addition, fetal liver Hmgcs2 expression was switched on by E13 in both 6%P- and 9%P-exposed animals. Exogenous BOHB did not influence branching morphogenesis in fetal lung explant cultures; however, we cannot rule out the possibility that this may occur in vivo. In conclusion, we find that disturbance of fetal growth by maternal dietary protein restriction is associated and therefore potentially indicated by changes in maternal and fetal ketone body metabolism. PMID- 20851858 TI - Early response of heat shock proteins to functional overload of the soleus and plantaris in rats and mice. AB - Heat shock proteins (HSPs) are important factors in the response of skeletal muscles to chronic increases or decreases in activation and loading. The purpose of this study was to compare species-, time- and muscle-dependent changes in protein expression of Hsp20, Hsp25, alphaB-crystallin, Hsp72 and Hsp90 in response to functional overload (FO) in rats and mice. We compared protein levels of Hsp20, Hsp25, alphaB-crystallin, Hsp72 and Hsp90 in soleus and plantaris in baseline conditions and following 0.5, 1, 2, 3 and 7 days (rats) or 3 and 7 days (mice) of FO. Baseline levels of all HSPs were higher in rat soleus than plantaris, whereas only baseline expression of Hsp20 was higher in mouse soleus than plantaris. Levels of Hsp72 and Hsp90 were higher in plantaris and soleus of FO than control mice and rats after 3 and 7 days of FO. Protein levels and phosphorylation of Hsp25 in mouse plantaris and soleus were higher than control levels after 3 and 7 days of FO, except for soleus at 3 days. alphaB-crystallin levels were higher in plantaris of FO than control mice after 3 and 7 days of FO and in FO than control rats after 7 days of FO. Heat shock protein 20 was the least responsive, increasing only in 7 day FO rat plantaris compared with control rats. Overall, the results demonstrate that levels of both large and small HSPs increase with FO, suggesting a contributory role during the compensatory hypertrophy response. PMID- 20851860 TI - Differential responses to sympathetic stimulation in the cerebral and brachial circulations during rhythmic handgrip exercise in humans. AB - The sympathetic neural regulation of the cerebral circulation remains controversial. The purpose of the present study was to determine how exercise modulates the simultaneous responsiveness of the cerebral and brachial circulations to 'endogenous' sympathetic activation (cold pressor test). In nine healthy subjects, heart rate (HR) and mean arterial blood pressure (MAP) were continuously measured during cold pressor tests (4 degrees C water) conducted at rest and during randomized bouts of rhythmic handgrip of 10, 25 and 40% of maximal voluntary contraction. Doppler ultrasound was used to examine brachial artery blood flow (FBF) and middle cerebral artery (MCA) mean blood velocity (V mean), and indices of vascular conductance were calculated for the brachial artery (forearm vascular conductance, FVC) and MCA (cerebral vascular conductance index, CVCi). End-tidal PCO2 (P ET.CO2) was evaluated on a breath-by-breath basis. Handgrip evoked increases in HR, FBF, FVC and MCA V mean (P < 0.05 versus rest), while MAP and CVCi were unchanged and P ET.CO2 fell slightly (P < 0.05 versus rest). Increases in MAP and HR during the cold pressor test were similar at rest and during all handgrip trials. Forearm vascular conductance was markedly reduced with the cold pressor test at rest (-45 +/- 8%), but this vasoconstrictor effect was progressively attenuated with increasing exercise intensity (FVC -17 +/- 3% during exercise at 40% of maximal voluntary contraction; P < 0.05). In contrast, the small reduction in CVCi with cold pressor test was similar at rest and during handgrip (approximately -5%). Our data indicate that while the marked vasoconstrictor responses to sympathetic activation in the skeletal muscle vasculature are blunted by handgrip exercise, the modest cerebrovascular responses to a cold pressor test remain unchanged. PMID- 20851861 TI - Cardiovascular strain impairs prolonged self-paced exercise in the heat. AB - It has been proposed that self-paced exercise in the heat is regulated by an anticipatory reduction in work rate based on the rate of heat storage. However, performance may be impaired by the development of hyperthermia and concomitant rise in cardiovascular strain increasing relative exercise intensity. This study evaluated the influence of thermal strain on cardiovascular function and power output during self-paced exercise in the heat. Eight endurance-trained cyclists performed a 40 km simulated time trial in hot (35 degrees C) and thermoneutral conditions (20 degrees C), while power output, mean arterial pressure, heart rate, oxygen uptake and cardiac output were measured. Time trial duration was 64.3 +/- 2.8 min (242.1 W) in the hot condition and 59.8 +/- 2.6 min (279.4 W) in the thermoneutral condition (P < 0.01). Power output in the heat was depressed from 20 min onwards compared with exercise in the thermoneutral condition (P < 0.05). Rectal temperature reached 39.8 +/- 0.3 (hot) and 38.9 +/- 0.2 degrees C (thermoneutral; P < 0.01). From 10 min onwards, mean skin temperature was ~7.5 degrees C higher in the heat, and skin blood flow was significantly elevated (P < 0.01). Heart rate was ~8 beats min(-1) higher throughout hot exercise, while stroke volume, cardiac output and mean arterial pressure were significantly depressed compared with the thermoneutral condition (P < 0.05). Peak oxygen uptake measured during the final kilometre of exercise at maximal effort reached 77 (hot) and 95% (thermoneutral) of pre-experimental control values (P < 0.01). We conclude that a thermoregulatory-mediated rise in cardiovascular strain is associated with reductions in sustainable power output, peak oxygen uptake and maximal power output during prolonged, intense self-paced exercise in the heat. PMID- 20851859 TI - Sharpey-Schafer lecture: gas channels. AB - The traditional dogma has been that all gases diffuse through all membranes simply by dissolving in the lipid phase of the membrane. Although this mechanism may explain how most gases move through most membranes, it is now clear that some membranes have no demonstrable gas permeability, and that at least two families of membrane proteins, the aquaporins (AQPs) and the Rhesus (Rh) proteins, can each serve as pathways for the diffusion of both CO2 and NH3. The knockout of RhCG in the renal collecting duct leads to the predicted consequences in acid base physiology, providing a clear-cut role for at least one gas channel in the normal physiology of mammals. In our laboratory, we have found that surface-pH (pH(S)) transients provide a sensitive approach for detecting CO2 and NH3 movement across the cell membranes of Xenopus oocytes. Using this approach, we have found that each tested AQP and Rh protein has its own characteristic CO2/NH3 permeability ratio, which provides the first demonstration of gas selectivity by a channel. Our preliminary AQP1 data suggest that all the NH3 and less than half of the CO2 move along with H2O through the four monomeric aquapores. The majority of CO2 takes an alternative route through AQP1, possibly the central pore at the four-fold axis of symmetry. Preliminary data with two Rh proteins, bacterial AmtB and human erythroid RhAG, suggest a similar story, with all the NH3 moving through the three monomeric NH3 pores and the CO2 taking a separate route, perhaps the central pore at the three-fold axis of symmetry. The movement of different gases via different pathways is likely to underlie the gas selectivity that these channels exhibit. PMID- 20851862 TI - CD4-positive T-helper cell responses to the PASD1 protein in patients with diffuse large B-cell lymphoma. AB - BACKGROUND: Vaccine development targeting the novel immunogenic Per ARNT Sim Domain containing 1 (PASD1) cancer testis antigen represents an attractive therapeutic approach for the significant number of patients with diffuse large B cell lymphoma who are refractory to conventional treatment. Since CD4-positive T helper cells have crucial roles in promoting and maintaining immune responses to tumor antigens, the presence of a CD4-positive T-helper immune response to the PASD1 antigen in patients with diffuse large B-cell lymphoma was investigated in the current study. DESIGN AND METHODS: Thirty-one patients with diffuse large B cell lymphoma (25 with de novo, five with transformed and one with T-cell-rich B cell lymphoma) were studied. Five immunogenic PASD1 peptides predicted to bind to several major histocompatibiliy complex, class II DR beta 1 alleles were identified using web-based algorithms. Peripheral blood mononuclear cells from patients were used to investigate the immunogenicity of these DR beta 1 restricted peptides in vitro using both gamma-interferon release enzyme-linked immunospot and cytolytic assays. RESULTS: Two of the five PASD1 peptides, PASD1(6) and PASD1(7), were shown to be immunogenic in 14 out of 32 patients studied in a gamma-interferon release assay. CD4-positive T-helper cell lines from two patients raised against PASD1 peptides were able to lyse cell lines derived from hematologic malignancies expressing endogenous PASD1 protein. CONCLUSIONS: This is the first report of a CD4-positive T-helper response to the PASD1 protein in patients with lymphoma. The immunogenic peptides described here represent valuable additional candidates for inclusion in a vaccine to treat patients with PASD1-positive diffuse large B-cell lymphoma whose disease is refractory to conventional therapies. PMID- 20851863 TI - Abnormal modulation of cell protective systems in response to ischemic/reperfusion injury is important in the development of mouse sickle cell hepatopathy. AB - BACKGROUND: Sickle cell disease, a genetic red cell disorder inherited in an autosomal recessive manner, occurs throughout the world. Hepatic dysfunction and liver damage may be present in sickle cell disease, but the pathogenesis of these conditions is only partially understood. DESIGN AND METHODS: Transgenic mice with sickle cell disease (SAD mice) and wild-type mice were exposed to an ischemic/reperfusion stress. The following parameters were evaluated: hematologic profile, transaminase and bilirubin levels, liver histopathology, and mRNA levels of nuclear factor-kappaB p65, endothelial nitric oxide synthase, inducible nitric oxide synthase, heme oxygenase-1 and phosphodiesterase-1, -2, -3, and -4 genes in hepatocytes obtained by laser-capture microdissection. Immunoblotting was used to analyze the expression of the following proteins: nuclear factor-kappaB p65 and phospho-nuclear factor-kappaB p65, heme oxygenase-1, biliverdin reductase, heat shock protein-70, heat shock protein-27 and peroxiredoxin-6. A subgroup of SAD mice was treated with the phosphodiesterase-4 inhibitor rolipram (30 mg/Kg/day by gavage) during the ischemic/reperfusion protocol. RESULTS: In SAD mice the ischemic/reperfusion stress induced liver damage compatible with sickle cell disease hepatopathy, which was associated with: (i) lack of hypoxia-induced nuclear factor-kappaB p65 activation; (ii) imbalance in the endothelial/inducible nitric oxide synthase response to ischemic/reperfusion stress; (iii) lack of hypoxia-induced increased expression of heme oxygenase-1/biliverdin reductase paralleled by a compensatory increased expression of heat shock proteins 70 and 27 and peroxiredoxin-6; and (iv) up-regulation of the phosphodiesterase-1, -2, 3, and -4 genes. In SAD mice the phosphodiesterase-4 inhibitor rolipram attenuated the ischemic/reperfusion-related microcirculatory dysfunction, reduced the inflammatory cell infiltration and induced the heme oxygenase-1/biliverdin reductase cytoprotective systems. CONCLUSIONS: In SAD mice, sickle cell hepatopathy is associated with perturbed nuclear factor-kappaB p65 signaling with an imbalance of endothelial/inducible nitric oxide synthase levels, lack of heme oxygenase-1/biliverdin reductase expression and up-regulation of two novel cytoprotective systems: heat shock protein-27 and peroxiredoxin-6. PMID- 20851864 TI - Late altered organ function in very long-term survivors after allogeneic hematopoietic stem cell transplantation: a paired comparison with their HLA identical sibling donor. AB - BACKGROUND: Hematopoietic stem cell transplantation has become an established procedure worldwide. Severe early and late complications are well described. Little is known about more subtle changes in general health status of very long term survivors. The study objective was to assess health status of very long-term survivors in comparison with their respective human leukocyte antigen-identical sibling donors. DESIGN AND METHODS: Case matched comparison in a cross-sectional cohort was performed in a tertiary university hospital and referral center for hematopoietic stem cell transplantation. Forty-four pairs of recipients and their respective donors with a very long-term (17.5 years median; 11-26 years range) follow up after allogeneic hematopoietic stem cell transplantation were included. A comparative clinical evaluation and examination of routine clinical chemistry tests was carried out. RESULTS: Recipients more frequently had a lower Karnofsky score (P = 0.05), hypertension (P = 0.015) and dyslipidemia (P = 0.002) but were less likely to be smokers (P = 0.016). Recipients showed systematically lower glomerular filtration rates (P < 0.0001), higher liver function tests (P = 0.0004 for Aspartat-Amino-Transferase) and reduced thyroid function (P = 0.002) despite normal or near normal values, and independent of presence or absence of chronic graft-versus-host disease. Indicators of inflammation were more frequent in recipients (9 of 44) with ongoing chronic graft-versus-host disease as measured by higher C-reactive protein (P = 0.001) and higher von Willebrand factor (P = 0.002). Conclusions Clinically very long-term survivors after an allogeneic hematopoietic stem cell transplantation present more frequently with cardiovascular risk factors and with subtle signs of altered organ function compared to their sibling donors. Even minimal ongoing chronic graft-versus-host disease remains associated with elevated laboratory indicators of inflammation. The clinical significance of these findings needs to be defined. PMID- 20851865 TI - SQSTM1-NUP214: a new gene fusion in adult T-cell acute lymphoblastic leukemia. PMID- 20851866 TI - Impact of constitutional polymorphisms in VCAM1 and CD44 on CD34+ cell collection yield after administration of granulocyte colony-stimulating factor to healthy donors. AB - Background The number of CD34(+) cells mobilized from bone marrow to peripheral blood after administration of granulocyte colony-stimulating factor varies greatly among healthy donors. This fact might be explained, at least in part, by constitutional differences in genes involved in the interactions tethering CD34(+) cells to the bone marrow. DESIGN AND METHODS: We analyzed genetic characteristics associated with CD34(+) cell mobilization in 112 healthy individuals receiving granulocyte colony-stimulating factor (filgrastim; 10 MUg/kg; 5 days). RESULTS: Genetic variants in VCAM1 and in CD44 were associated with the number of CD34(+) cells in peripheral blood after granulocyte colony stimulating factor administration (P = 0.02 and P = 0.04, respectively), with the quantity of CD34(+) cells *106/kg of donor (4.6 versus 6.3; P < 0.001 and 7 versus 5.6; P = 0.025, respectively), and with total CD34(+) cells *106 (355 versus 495; P = 0.002 and 522 versus 422; P = 0.012, respectively) in the first apheresis. Of note, granulocyte colony-stimulating factor administration was associated with complete disappearance of VCAM1 mRNA expression in peripheral blood. Moreover, genetic variants in granulocyte colony-stimulating factor receptor (CSF3R) and in CXCL12 were associated with a lower and higher number of granulocyte colony-stimulating factor-mobilized CD34(+) cells/MUL in peripheral blood (81 versus 106; P = 0.002 and 165 versus 98; P=0.02, respectively) and a genetic variant in CXCR4 was associated with a lower quantity of CD34(+) cells *106/kg of donor and total CD34(+) cells *106 (5.3 versus 6.7; P = 0.02 and 399 versus 533; P = 0.01, respectively). Conclusions In conclusion, genetic variability in molecules involved in migration and homing of CD34(+) cells influences the degree of mobilization of these cells. PMID- 20851867 TI - HuMab-7D8, a monoclonal antibody directed against the membrane-proximal small loop epitope of CD20 can effectively eliminate CD20 low expressing tumor cells that resist rituximab-mediated lysis. AB - BACKGROUND: Incorporation of the chimeric CD20 monoclonal antibody rituximab in the treatment schedule of patients with non-Hodgkin's lymphoma has significantly improved outcome. Despite this success, about half of the patients do not respond to treatment or suffer from a relapse and additional therapy is required. A low CD20-expression level may in part be responsible for resistance against rituximab. We therefore investigated whether the CD20-expression level related resistance to rituximab could be overcome by a new group of CD20 mAbs (HuMab-7D8 and ofatumumab) targeting a unique membrane-proximal epitope on the CD20 molecule. DESIGN AND METHODS: By retroviral transduction of the CD20 gene into CD20-negative cells and clonal selection of transduced cells a system was developed in which the CD20-expression level is the only variable. These CD20 transduced cells were used to study the impact of rituximab and HuMab-7D8 mediated complement-dependent cytotoxicity. To study the in vivo efficacy of these mAbs an in vivo imaging system was generated by retroviral expression of the luciferase gene in the CD20-positive cells. RESULTS: We show that HuMab-7D8 efficiently killed CD20(low) cells that are not susceptible to rituximab-induced killing in vitro. In a mouse xenograft model, we observed a comparable increase in survival time between HuMab-7D8 and rituximab-treated mice. Most significantly, however, HuMab-7D8 eradicated all CD20-expressing cells both in the periphery as well as in the bone marrow whereas after rituximab treatment CD20(low) cells survived. CONCLUSIONS: Cells that are insensitive to in vitro and in vivo killing by rituximab as the result of their low CD20-expression profile may be efficiently killed by an antibody against the membrane-proximal epitope on CD20. Such antibodies should, therefore, be explored to overcome rituximab resistance in the clinic. PMID- 20851870 TI - Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. AB - BACKGROUND: Transplantation from an HLA-matched sibling is the treatment of choice for young patients with acquired severe aplastic anemia. For older patients, the acceptable upper age limit for transplantation as first-line treatment varies. The current analysis, therefore, sought to identify age or ages at transplantation at which survival differed. DESIGN AND METHODS: We studied the effect of patients' age, adjusting for other significant factors affecting outcomes, in 1307 patients with severe aplastic anemia after HLA-matched sibling transplantation using logistic and Cox regression analysis. Age categories (<20 years, 20-40 years, >40 years) were determined using Martingale residual plots for overall survival and categories based on differences in survival. RESULTS: Patients aged over 40 years old were more likely to have had immunosuppressive therapy, a poor performance score and a longer interval between diagnosis and transplantation. Neutrophil recovery was similar in all age groups but patients aged over 40 years had a lower likelihood of platelet recovery compared to patients aged less than 20 years (OR 0.45, P=0.01) but not compared to those aged 20-40 years (OR 0.60, P=0.10). Compared to the risk of mortality in patients aged less than 20 years, mortality risks were higher in patients over 40 years old (RR 2.70, P<0.0001) and in those aged 20-40 years (RR 1.69, P<0.0001). The mortality risk was also higher in patients aged over 40 years than in those 20-40 years old (RR 1.60, P=0.008). CONCLUSIONS: Mortality risks increased with age. Risks were also higher in patients with a poor performance score and when the interval between diagnosis and transplantation was longer than 3 months, implying earlier referral would be appropriate when this treatment option is being considered. PMID- 20851868 TI - Viral encephalitis after allogeneic stem cell transplantation: a rare complication with distinct characteristics of different causative agents. AB - BACKGROUND: Limited data are available on characteristics of viral encephalitis in patients after allogeneic stem cell transplantation. DESIGN AND METHODS: We analyzed 2,628 patients after allogeneic stem cell transplantation to identify risk factors and characteristics of viral encephalitis. RESULTS: Viral encephalitis occurred in 32 patients (1.2%, 95% confidence interval 0.8%-1.6%) and was associated with the use of OKT-3 or alemtuzumab for T-cell depletion (P < 0.001) and an increased mortality (P = 0.011) in comparison to patients without viral encephalitis. Detected viruses included human herpesvirus-6 (28%), Epstein Barr virus (19%), herpes simplex virus (13%), JC virus (9%), varicella zoster virus (6%), cytomegalovirus (6%) and adenovirus (3%). More than one virus was identified in 16% of the patients. The median onset time was 106 days after allogeneic stem cell transplantation for the total group of 32 patients, but onset times were shortest in those with human herpesvirus-6 encephalitis and longest in those with JC virus-associated progressive multifocal leukoencephalopathy. The probability of a sustained response to treatment was 63% (95% confidence interval 44%-82%) with a median survival of 94 (95% confidence interval 36-152) days after onset, but significant variation was found when considering different causative viruses. Patients with herpes simplex virus encephalitis had the most favorable outcome with no encephalitis-related deaths. CONCLUSIONS: The use of OKT-3 or alemtuzumab for in vivo T-cell depletion is associated with an increased risk of viral encephalitis after allogeneic stem cell transplantation. Different viruses are frequently associated with distinct characteristics such as onset time, response to treatment and outcome. PMID- 20851871 TI - Polymorphic variation within the VWF gene contributes to the failure to detect mutations in patients historically diagnosed with type 1 von Willebrand disease from the MCMDM-1VWD cohort. PMID- 20851872 TI - Coronary microvascular function in early chronic kidney disease. AB - BACKGROUND: coronary microvascular dysfunction may underlie the high cardiovascular risk associated with chronic kidney disease (CKD), but the effects of CKD on coronary microvasculature function remain uncertain. METHODS AND RESULTS: we assessed myocardial blood flow changes in mild-to-moderate CKD and analyzed the association between creatinine clearance (CrCl) and peak myocardial blood flow and coronary flow reserve (CFR) measured as the ratio of stress to rest perfusion at baseline and at 1 year in 435 nondiabetic individuals who underwent quantitative rest and pharmacological stress positron emission tomography imaging. At baseline, CFR was significantly associated with CrCl (beta per 10 mL/min increase, 0.07; P=0.001). Factors such as age and blood pressure accounted for this association, and it was not significant in adjusted analyses (beta=-0.02, P=0.53). Peak flow was not associated with CrCl in either crude or adjusted analyses (beta per 10 mL/min=-0.02 mL/min per g, P=0.29). Although change in peak flow at 1 year was similar in patients with and without CKD, CrCl was a strong and independent predictor of a higher rate of change in CFR, with a loss of 0.11 CFR units/y (95% confidence interval, 0.01 to 0.20) for each 10 mL/min drop in CrCl (P=0.03). CONCLUSIONS: these findings demonstrate that mild to-moderate CKD is not independently associated with a reduction in peak myocardial flow or CFR and suggests that microvascular changes are unlikely to explain the high cardiovascular mortality in mild to moderate CKD. Loss of CFR, however, may accelerate in mild to moderate CKD. Further studies are needed to determine whether these changes lead to more significant reductions that may reduce peak flows and CFR and contribute to cardiovascular risk in more severe CKD. PMID- 20851873 TI - Coronary branch steal: experimental validation and clinical implications of interacting stenosis in branching coronary arteries. AB - BACKGROUND: fluid dynamic analysis predicts a new concept in coronary physiology that we call "branch steal," whereby stenosis proximal and distal to arterial branching interact with the nonstenotic branch between stenosis that shunts or "steals" flow away from the distal stenotic artery during reactive hyperemia, tested experimentally. METHODS AND RESULTS: in 21 large hounds under surgical anesthesia, proximal and distal left circumflex and obtuse marginal coronary arteries were instrumented with electromagnetic flowmeters, proximal and distal machined Teflon screw-down stenosers with round concentric closing and distal silk-in-tubing sleeve occluders. Baseline reactive hyperemia was recorded after 15-second occlusions of both arteries at baseline and for progressive distal stenosis during each step of progressive proximal stenosis. At each combination of stenosis, a coronary arteriogram was obtained using left Judkins catheters and Philips cine calibrated with modulated transfer function to +/- 0.1 mm accuracy for fluid dynamic analysis of arterial stenosis-branching anatomy. In 324 experiments of parent-child stenosis combinations of the left circumflex artery with an intervening obtuse marginal branch, coronary flow reserve (CFR) calculated by the fluid dynamic model accounting for stenosis-branch interactions and "branch steal" correlated with CFR directly measured by flowmeter (linear regression, CFRartgm=0.18+0.7*CFRflowmtr with Pearson r=0.73). Quantitative arteriography and positron emission tomography perfusion imaging confirmed the concept in clinical examples. CONCLUSIONS: functional severity of anatomically fixed stenosis is not constant, specific, or independent of other stenosis in branching coronary arteries but requires analysis as an integrated component of the entire branching coronary artery tree to guide revascularizations. PMID- 20851874 TI - Hybrid treatment of inferior vena cava obstruction after orthotopic heart transplantation. AB - Caval stenosis with subsequent thrombosis may occur after orthotopic heart transplantation (HT). Management of this complication may include a percutaneous approach or an open surgical one. Here, we report the case of an obstruction and severe thrombosis of the inferior vena cava, following orthotopic HT, that was managed in a hybrid fashion with surgical venous thrombectomy, inferior vena cava stenting, and atrio-caval patch-plasty. PMID- 20851875 TI - Extended right pneumonectomy in an adult with a double aortic arch: a therapeutic dilemma. AB - We report the case of a 69-year-old man presenting with a primary right lung cancer and a complete double aortic arch. An extended right pneumonectomy was successfully performed and the patient remained well at the one-year follow-up. We discuss the surgical approach and the technical considerations imposed by this rare vascular abnormality. PMID- 20851876 TI - Thymic neuroendocrine tumour (carcinoid): clinicopathological features of four patients with different presentation. AB - Thymic carcinoids are aggressive and present at an advanced stage. This article describes the utility of (68)Gallium-1,4,7,10-traazacyclododecane-NI, NII, NIII, NIIII-tetra acetic acid-(D)-Phel1-Tyr3-octreotide positron emission tomography ((68)Ga DOTATOC PET-CT-scan) and clinicopathological features of four thymic carcinoid tumours. Two typical, one atypical, and one large cell neuroendocrine carcinoma (LCNEC) were analysed. There were three males and one female with a mean age of 33 years. Three patients had a stage III and one had a stage II tumour. Preoperative (68)Ga DOTATOC PET-CT-scan of three patients did not show uptake of radiotracer in the tumour. Three patients were disease free at 19-27 months follow-up. The patient with LCNEC developed recurrence in the lumbar vertebrae. There is no locoregional recurrence of tumour in any of our patients. Complete surgical resection of the tumour with invaded adjacent structures, postoperative radiotherapy to the tumour bed helps in obtaining disease free survival. PMID- 20851877 TI - Metabolism of sesamin by cytochrome P450 in human liver microsomes. AB - Metabolism of sesamin by cytochrome P450 (P450) was examined using yeast expression system and human liver microsomes. Saccharomyces cerevisiae cells expressing each of human P450 isoforms (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, and 3A4) were cultivated with sesamin, and monocatechol metabolite was observed in most of P450s. Kinetic analysis using the microsomal fractions of the recombinant S. cerevisiae cells revealed that CYP2C19 had the largest k(cat)/K(m) value. Based on the kinetic data and average contents of the P450 isoforms in the human liver, the putative contribution of P450s for sesamin metabolism was large in the order of CYP2C9, 1A2, 2C19, and 2D6. A good correlation was observed between sesamin catecholization activity and CYP2C9 specific activity in in vitro studies using 10 individual human liver microsomes, strongly suggesting that CYP2C9 is the most important P450 isoform for sesamin catecholization in human liver. Inhibition studies using each anti-P450 isoform specific antibody confirmed that CYP2C9 was the most important, and the secondary most important P450 was CYP1A2. We also examined the inhibitory effect of sesamin for P450 isoform-specific activities and found a mechanism-based inhibition of CYP2C9 by sesamin. In contrast, no mechanism-based inhibition by sesamin was observed in CYP1A2-specific activity. Our findings strongly suggest that further studies are needed to reveal the interaction between sesamin and therapeutic drugs mainly metabolized by CYP2C9. PMID- 20851878 TI - Transcriptional repressor E4-binding protein 4 (E4BP4) regulates metabolic hormone fibroblast growth factor 21 (FGF21) during circadian cycles and feeding. AB - Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding. PMID- 20851879 TI - IGFBP-3 can either inhibit or enhance EGF-mediated growth of breast epithelial cells dependent upon the presence of fibronectin. AB - Progression of breast cancer is associated with remodeling of the extracellular matrix, often involving a switch from estrogen dependence to a dependence on EGF receptor (EGFR)/HER-2 and is accompanied by increased expression of the main binding protein for insulin-like growth factors (IGFBP-3). We have examined the effects of IGFBP-3 on EGF responses of breast epithelial cells in the context of changes in the extracellular matrix. On plastic and laminin with MCF-10A normal breast epithelial cells, EGF and IGFBP-3 each increased cell growth and together produced a synergistic response, whereas with T47D breast cancer cells IGFBP-3 alone had no effect, but the ability of EGF to increase cell proliferation was markedly inhibited in the presence of IGFBP-3. In contrast on fibronectin with MCF-10A cells, IGFBP-3 alone inhibited cell growth and blocked EGF-induced proliferation. With the cancer cells, IGFBP-3 alone had no effect but enhanced the EGF-induced increase in cell growth. The insulin-like growth factor independent effects of IGFBP-3 alone on cell proliferation were completely abrogated in the presence of an EGFR, tyrosine kinase inhibitor, Iressa. Although IGFBP-3 did not affect EGFR phosphorylation [Tyr(1068)], it was found to modulate receptor internalization and was associated with activation of Rho and subsequent changes in MAPK phosphorylation. The levels of fibronectin and IGFBP-3 within breast tumors may determine their dependence on EGFR and their response to therapies targeting this receptor. PMID- 20851880 TI - BMP2-activated Erk/MAP kinase stabilizes Runx2 by increasing p300 levels and histone acetyltransferase activity. AB - Runx2 is a critical transcription factor for osteoblast differentiation. Regulation of Runx2 expression levels and transcriptional activity is important for bone morphogenetic protein (BMP)-induced osteoblast differentiation. Previous studies have shown that extracellular signal-regulated kinase (Erk) activation enhances the transcriptional activity of Runx2 and that BMP-induced Runx2 acetylation increases Runx2 stability and transcriptional activity. Because BMP signaling induces Erk activation in osteoblasts, we sought to investigate whether BMP-induced Erk signaling regulates Runx2 acetylation and stability. Erk activation by overexpression of constitutively active MEK1 increased Runx2 transcriptional activity, whereas U0126, an inhibitor of MEK1/2, suppressed basal Runx2 transcriptional activity and BMP-induced Runx2 acetylation and stabilization. Overexpression of constitutively active MEK1 stabilized Runx2 protein via up-regulation of acetylation and down-regulation of ubiquitination. Erk activation increased p300 protein levels and histone acetyltransferase activity. Knockdown of p300 using siRNA diminished Erk-induced Runx2 stabilization. Overexpression of Smad5 increased Runx2 acetylation and stabilization. Erk activation further increased Smad-induced Runx2 acetylation and stabilization, whereas U0126 suppressed these functions. On the other hand, knockdown of Smad1 and Smad5 by siRNA suppressed both basal and Erk-induced Runx2 protein levels. Erk activation enhanced the association of Runx2 with p300 and Smad1. Taken together these results indicate that Erk signaling increases Runx2 stability and transcriptional activity, partly via increasing p300 protein levels and histone acetyltransferase activity and subsequently increasing Runx2 acetylation by p300. In addition to the canonical Smad pathway, a BMP-induced non Smad Erk signaling pathway cooperatively regulates osteoblast differentiation partly via increasing the stability and transcriptional activity of Runx2. PMID- 20851881 TI - The farnesoid X receptor regulates adipocyte differentiation and function by promoting peroxisome proliferator-activated receptor-gamma and interfering with the Wnt/beta-catenin pathways. AB - The bile acid receptor farnesoid X receptor (FXR) is expressed in adipose tissue, but its function remains poorly defined. Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a master regulator of adipocyte differentiation and function. The aim of this study was to analyze the role of FXR in adipocyte function and to assess whether it modulates PPARgamma action. Therefore, we tested the responsiveness of FXR-deficient mice (FXR(-/-)) and cells to the PPARgamma activator rosiglitazone. Our results show that genetically obese FXR(-/ )/ob/ob mice displayed a resistance to rosiglitazone treatment. In vitro, rosiglitazone treatment did not induce normal adipocyte differentiation and lipid droplet formation in FXR(-/-) mouse embryonic fibroblasts (MEFs) and preadipocytes. Moreover, FXR(-/-) MEFs displayed both an increased lipolysis and a decreased de novo lipogenesis, resulting in reduced intracellular triglyceride content, even upon PPARgamma activation. Retroviral-mediated FXR re-expression in FXR(-/-) MEFs restored the induction of adipogenic marker genes during rosiglitazone-forced adipocyte differentiation. The expression of Wnt/beta catenin pathway and target genes was increased in FXR(-/-) adipose tissue and MEFs. Moreover, the expression of several endogenous inhibitors of this pathway was decreased early during the adipocyte differentiation of FXR(-/-) MEFs. These findings demonstrate that FXR regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARgamma and Wnt/beta-catenin pathways. PMID- 20851882 TI - The loss of Cbl-phosphatidylinositol 3-kinase interaction perturbs RANKL-mediated signaling, inhibiting bone resorption and promoting osteoclast survival. AB - Cbl is an adaptor protein and an E3 ligase that plays both positive and negative roles in several signaling pathways that affect various cellular functions. Tyrosine 737 is unique to Cbl and is phosphorylated by Syk and Src family kinases. Phosphorylated Cbl Tyr(737) creates a binding site for the p85 regulatory subunit of PI3K, which also plays an important role in the regulation of bone resorption by osteoclasts. To investigate the role of Cbl-PI3K interaction in bone homeostasis, we examined the knock-in mice (Cbl(YF/YF)) in which the PI3K binding site in Cbl is ablated due to the mutation in the regulatory tyrosine. We report that in Cbl(YF/YF) mice, despite increased numbers of osteoclasts, bone volume is increased due to defective osteoclast function. Additionally, in ex vivo cultures, mature Cbl(YF/YF) osteoclasts showed an increased ability to survive in the presence of RANKL due to delayed onset of apoptosis. RANKL-mediated signaling is perturbed in Cbl(YF/YF) osteoclasts, and most interestingly, AKT phosphorylation is up-regulated, suggesting that the lack of PI3K sequestration by Cbl results in increased survival and decreased bone resorption. Cumulatively, these in vivo and in vitro results show that, on one hand, binding of Cbl to PI3K negatively regulates osteoclast differentiation, survival, and signaling events (e.g. AKT phosphorylation), whereas on the other hand it positively influences osteoclast function. PMID- 20851883 TI - The active site of oligogalacturonate lyase provides unique insights into cytoplasmic oligogalacturonate beta-elimination. AB - Oligogalacturonate lyases (OGLs; now also classified as pectate lyase family 22) are cytoplasmic enzymes found in pectinolytic members of Enterobacteriaceae, such as the enteropathogen Yersinia enterocolitica. OGLs utilize a beta-elimination mechanism to preferentially catalyze the conversion of saturated and unsaturated digalacturonate into monogalacturonate and the 4,5-unsaturated monogalacturonate like molecule, 5-keto-4-deoxyuronate. To provide mechanistic insights into the specificity of this enzyme activity, we have characterized the OGL from Y. enterocolitica, YeOGL, on oligogalacturonides and determined its three dimensional x-ray structure to 1.65 A. The model contains a Mn(2+) atom in the active site, which is coordinated by three histidines, one glutamine, and an acetate ion. The acetate mimics the binding of the uronate group of galactourono configured substrates. These findings, in combination with enzyme kinetics and metal supplementation assays, provide a framework for modeling the active site architecture of OGL. This enzyme appears to contain a histidine for the abstraction of the alpha-proton in the -1 subsite, a residue that is highly conserved throughout the OGL family and represents a unique catalytic base among pectic active lyases. In addition, we present a hypothesis for an emerging relationship observed between the cellular distribution of pectate lyase folding and the distinct metal coordination chemistries of pectate lyases. PMID- 20851884 TI - Rapid fusion and syncytium formation of heterologous cells upon expression of the FGFRL1 receptor. AB - The fusion of mammalian cells into syncytia is a developmental process that is tightly restricted to a limited subset of cells. Besides gamete and placental trophoblast fusion, only macrophages and myogenic stem cells fuse into multinucleated syncytia. In contrast to viral cell fusion, which is mediated by fusogenic glycoproteins that actively merge membranes, mammalian cell fusion is poorly understood at the molecular level. A variety of mammalian transmembrane proteins, among them many of the immunoglobulin superfamily, have been implicated in cell-cell fusion, but none has been shown to actively fuse cells in vitro. Here we report that the FGFRL1 receptor, which is up-regulated during the differentiation of myoblasts into myotubes, fuses cultured cells into large, multinucleated syncytia. We used luciferase and GFP-based reporter assays to confirm cytoplasmic mixing and to identify the fusion inducing domain of FGFRL1. These assays revealed that Ig-like domain III and the transmembrane domain are both necessary and sufficient to rapidly fuse CHO cells into multinucleated syncytia comprising several hundred nuclei. Moreover, FGFRL1 also fused HEK293 and HeLa cells with untransfected CHO cells. Our data show that FGFRL1 is the first mammalian protein that is capable of inducing syncytium formation of heterologous cells in vitro. PMID- 20851885 TI - Mutational analysis of Saccharomyces cerevisiae Erf2 reveals a two-step reaction mechanism for protein palmitoylation by DHHC enzymes. AB - DHHC protein acyltransferases (PATs) catalyze the palmitoylation of eukaryotic proteins through an enzymatic mechanism that remains largely unexplored. In this study we have combined genetic and biochemical approaches to examine the molecular mechanism of palmitate transfer of the yeast Ras PAT, which is composed of Erf2 and Erf4. The palmitoylation reaction consists of two steps; they are autopalmitoylation of the enzyme to create a palmitoyl-Erf2 intermediate followed by the transfer of the palmitoyl moiety to the Ras substrate. Palmitoyl-CoA serves as the palmitate donor. To elucidate the kinetic properties of the Erf2.Erf4 PAT, we have developed a coupled enzyme assay that monitors the turnover of the palmitoyl-enzyme species indirectly by measuring the rate of CoASH release. Mutational analysis indicates that the DHHC motif constitutes the catalytic core of the enzyme required for autopalmitoylation and palmitoyl transfer to the Ras2 substrate. In the absence of Ras2, the palmitoyl-Erf2.Erf4 complex undergoes a cycle of hydrolysis and re-palmitoylation, implying that in the presence of palmitoyl-CoA, the complex is autopalmitoylated and competent to transfer palmitate to a protein substrate. PMID- 20851886 TI - Leptin receptor (Lepr) is a negative modulator of bone mechanosensitivity and genetic variations in Lepr may contribute to the differential osteogenic response to mechanical stimulation in the C57BL/6J and C3H/HeJ pair of mouse strains. AB - This study investigated the role of leptin receptor (Lepr) signaling in determining the bone mechanosensitivity and also evaluated whether differences in the Lepr signaling may contribute to the differential osteogenic response of the C57BL/6J (B6) and C3H/HeJ (C3H) pair of mouse strains to mechanical stimuli. This study shows that a loading strain of ~2,500 MUepsilon, which was insufficient to produce a bone formation response in B6 mice, significantly increased bone formation parameters in leptin-deficient ob(-)/ob(-) mice and that a loading strain of ~3,000 MUepsilon also yielded greater osteogenic responses in Lepr deficient db(-)/db(-) mice than in wild-type littermates. In vitro, a 30-min steady shear stress increased [(3)H]thymidine incorporation and Erk1/2 phosphorylation in ob(-)/ob(-) osteoblasts and db(-)/db(-) osteoblasts much greater than those in corresponding wild-type osteoblasts. The siRNA-mediated suppression of Lepr expression in B6 osteoblasts enhanced (but in osteoblasts of C3H (the mouse strain with poor bone mechanosensitivity) restored) their anabolic responses to shear stress. The Lepr signaling (leptin-induced Jak2/Stat3 phosphorylation) in C3H osteoblasts was higher than that in B6 osteoblasts. One of the three single nucleotide polymorphisms in the C3H Lepr coding region yielded an I359V substitution near the leptin binding region, suggesting that genetic variation of Lepr may contribute to a dysfunctional Lepr signaling in C3H osteoblasts. In conclusion, Lepr signaling is a negative modulator of bone mechanosensitivity. Genetic variations in Lepr, which result in a dysfunctional Lepr signaling in C3H mice, may contribute to the poor osteogenic response to loading in C3H mice. PMID- 20851887 TI - Experimental validation of the predicted binding site of Escherichia coli K1 outer membrane protein A to human brain microvascular endothelial cells: identification of critical mutations that prevent E. coli meningitis. AB - Escherichia coli K1, the most common cause of meningitis in neonates, has been shown to interact with GlcNAc1-4GlcNAc epitopes of Ecgp96 on human brain microvascular endothelial cells (HBMECs) via OmpA (outer membrane protein A). However, the precise domains of extracellular loops of OmpA interacting with the chitobiose epitopes have not been elucidated. We report the loop-barrel model of these OmpA interactions with the carbohydrate moieties of Ecgp96 predicted from molecular modeling. To test this model experimentally, we generated E. coli K1 strains expressing OmpA with mutations of residues predicted to be critical for interaction with the HBMEC and tested E. coli invasion efficiency. For these same mutations, we predicted the interaction free energies (including explicit calculation of the entropy) from molecular dynamics (MD), finding excellent correlation (R(2) = 90%) with experimental invasion efficiency. Particularly important is that mutating specific residues in loops 1, 2, and 4 to alanines resulted in significant inhibition of E. coli K1 invasion in HBMECs, which is consistent with the complete lack of binding found in the MD simulations for these two cases. These studies suggest that inhibition of the interactions of these residues of Loop 1, 2, and 4 with Ecgp96 could provide a therapeutic strategy to prevent neonatal meningitis due to E. coli K1. PMID- 20851888 TI - Control of redox balance by the stringent response regulatory protein promotes antioxidant defenses of Salmonella. AB - We report herein a critical role for the stringent response regulatory DnaK suppressor protein (DksA) in the coordination of antioxidant defenses. DksA helps fine-tune the expression of glutathione biosynthetic genes and discrete steps in the pentose phosphate pathway and tricarboxylic acid cycle that are associated with the generation of reducing power. Control of NAD(P)H/NAD(P)(+) redox balance by DksA fuels downstream antioxidant enzymatic systems in nutritionally starving Salmonella. Conditional expression of the glucose-6-phosphate dehydrogenase encoding gene zwf, shown here to be under DksA control, increases both the NADPH pool and antioxidant defenses of dksA mutant Salmonella. The DksA-mediated coordination of redox balance boosts the antioxidant defenses of stationary phase bacteria. Not only does DksA increase resistance of Salmonella against hydrogen peroxide (H(2)O(2)), but it also promotes fitness of this intracellular pathogen when exposed to oxyradicals produced by the NADPH phagocyte oxidase in an acute model of infection. Given the role of DksA in the adjustment of gene expression in most bacteria undergoing nutritional deprivation, our findings raise the possibility that the control of central metabolic pathways by this regulatory protein maintains redox homeostasis essential for antioxidant defenses in phylogenetically diverse bacterial species. PMID- 20851889 TI - Inhibition of Bak activation by VDAC2 is dependent on the Bak transmembrane anchor. AB - Bax and Bak are pro-apoptotic factors that are required for cell death by the mitochondrial or intrinsic pathway. Bax is found in an inactive state in the cytosol and upon activation is targeted to the mitochondrial outer membrane where it releases cytochrome c and other factors that cause caspase activation. Although Bak functions in the same way as Bax, it is constitutively localized to the mitochondrial outer membrane. In the membrane, Bak activation is inhibited by the voltage-dependent anion channel isoform 2 (VDAC2) by an unknown mechanism. Using blue native gel electrophoresis, we show that in healthy cells endogenous inactive Bak exists in a 400-kDa complex that is dependent on the presence of VDAC2. Activation of Bak is concomitant with its release from the 400-kDa complex and the formation of lower molecular weight species. Furthermore, substitution of the Bak transmembrane anchor with that of the mitochondrial outer membrane tail anchored protein hFis1 prevents association of Bak with the VDAC2 complex and increases the sensitivity of cells to an apoptotic stimulus. Our results suggest that VDAC2 interacts with the hydrophobic tail of Bak to sequester it in an inactive state in the mitochondrial outer membrane, thereby raising the stimulation threshold necessary for permeabilization of the mitochondrial outer membrane and cell death. PMID- 20851890 TI - Resveratrol inhibits mTOR signaling by promoting the interaction between mTOR and DEPTOR. AB - Resveratrol (RSV) is a naturally occurring polyphenol that has been found to exert antioxidant, anti-inflammatory, and neuroprotective properties. However, how RSV exerts its beneficial health effects remains largely unknown. Here, we show that RSV inhibits insulin- and leucine-stimulated mTOR signaling in C2C12 fibroblasts via a Sirt1-independent mechanism. Treating C2C12 cells with RSV dramatically inhibited insulin-stimulated Akt, S6 kinase, and 4E-BP1 phosphorylation but had little effect on tyrosine phosphorylation of the insulin receptor and activation of the p44/42 MAPK signaling pathway. RSV treatment also partially blocked mTOR and S6 kinase phosphorylation in TSC1/2-deficient mouse embryonic fibroblasts, suggesting the presence of an inhibitory site downstream of TSC1/2. Knocking out PDK1 or suppressing AMP-activated protein kinase had little effect on leucine-stimulated mTOR signaling. On the other hand, RSV significantly increased the association between mTOR and its inhibitor, DEPTOR. Furthermore, the inhibitory effect of RSV on leucine-stimulated mTOR signaling was greatly reduced in cells in which the expression levels of DEPTOR were suppressed by RNAi. Taken together, our studies reveal that RSV inhibits leucine stimulated mTORC1 activation by promoting mTOR/DEPTOR interaction and thus uncover a novel mechanism by which RSV negatively regulates mTOR activity. PMID- 20851891 TI - A novel p53 phosphorylation site within the MDM2 ubiquitination signal: I. phosphorylation at SER269 in vivo is linked to inactivation of p53 function. AB - p53 is a thermodynamically unstable protein containing a conformationally flexible multiprotein docking site within the DNA-binding domain. A combinatorial peptide chip used to identify the novel kinase consensus site RXSPhi(K/D) led to the discovery of a homologous phosphorylation site in the S10 beta-strand of p53 at Ser(269). Overlapping peptide libraries confirmed that Ser(269) was a phosphoacceptor site in vitro, and immunochemical approaches evaluated whether p53 is phosphorylated in vivo at Ser(269). Mutation or phosphorylation of p53 at Ser(269) attenuates binding of the p53-specific monoclonal antibody DO-12, identifying an assay for measuring Ser(269) phosphorylation of p53 in vivo. The mAb DO-12 epitope of p53 is masked via phosphorylation in a range of human tumor cells with WT p53 status, as defined by increased mAb DO-12 binding to endogenous p53 after phosphatase treatment. Phospho-Ser(269)-specific monoclonal antibodies were generated and used to demonstrate that p53 phosphorylation is induced at Ser(269) after irradiation with kinetics similar to those of p53 protein induction. Phosphomimetic mutation at Ser(269) inactivated the transcription activation function and clonogenic suppressor activity of p53. These data suggest that the dynamic equilibrium between native and unfolded states of WT p53 can be modulated by phosphorylation of the conformationally flexible multiprotein binding site in the p53 DNA-binding domain. PMID- 20851892 TI - The archaeal topoisomerase reverse gyrase is a helix-destabilizing protein that unwinds four-way DNA junctions. AB - Four-way junctions are non-B DNA structures that originate as intermediates of recombination and repair (Holliday junctions) or from the intrastrand annealing of palindromic sequences (cruciforms). These structures have important functional roles but may also severely interfere with DNA replication and other genetic processes; therefore, they are targeted by regulatory and architectural proteins, and dedicated pathways exist for their removal. Although it is well known that resolution of Holliday junctions occurs either by recombinases or by specialized helicases, less is known on the mechanisms dealing with secondary structures in nucleic acids. Reverse gyrase is a DNA topoisomerase, specific to microorganisms living at high temperatures, which comprises a type IA topoisomerase fused to an SF2 helicase-like module and catalyzes ATP hydrolysis-dependent DNA positive supercoiling. Reverse gyrase is likely involved in regulation of DNA structure and stability and might also participate in the cell response to DNA damage. By applying FRET technology to multiplex fluorophore gel imaging, we show here that reverse gyrase induces unwinding of synthetic four-way junctions as well as forked DNA substrates, following a mechanism independent of both the ATPase and the strand-cutting activity of the enzyme. The reaction requires high temperature and saturating protein concentrations. Our results suggest that reverse gyrase works like an ATP-independent helix-destabilizing protein specific for branched DNA structures. The results are discussed in light of reverse gyrase function and their general relevance for protein-mediated unwinding of complex DNA structures. PMID- 20851893 TI - Less is more: Neisseria gonorrhoeae RecX protein stimulates recombination by inhibiting RecA. AB - Escherichia coli RecX (RecX(Ec)) is a negative regulator of RecA activities both in the bacterial cell and in vitro. In contrast, the Neisseria gonorrhoeae RecX protein (RecX(Ng)) enhances all RecA-related processes in N. gonorrhoeae. Surprisingly, the RecX(Ng) protein is not a RecA protein activator in vitro. Instead, RecX(Ng) is a much more potent inhibitor of all RecA(Ng) and RecA(Ec) activities than is the E. coli RecX ortholog. A series of RecX(Ng) mutant proteins representing a gradient of functional deficiencies provide a direct correlation between RecA(Ng) inhibition in vitro and the enhancement of RecA(Ng) function in N. gonorrhoeae. Unlike RecX(Ec), RecX(Ng) does not simply cap the growing ends of RecA filaments, but it directly facilitates a more rapid RecA filament disassembly. Thus, in N. gonorrhoeae, recombinational processes are facilitated by RecX(Ng) protein-mediated limitations on RecA(Ng) filament presence and/or length to achieve maximal function. PMID- 20851894 TI - Substrate binding in free methionine-R-sulfoxide reductase. PMID- 20851895 TI - Calcium and iron regulate swarming and type III secretion in Vibrio parahaemolyticus. AB - Here, we probe the response to calcium during growth on a surface and show that calcium influences the transcriptome and stimulates motility and virulence of Vibrio parahaemolyticus. Swarming (but not swimming) gene expression and motility were enhanced by calcium. Calcium also elevated transcription of one of the organism's two type III secretion systems (T3SS1 but not T3SS2) and heightened cytotoxicity toward host cells in coculture. Calcium stimulation of T3SS gene expression has not been reported before, although low calcium is an inducing signal for the T3SS of many organisms. EGTA was also found to increase T3SS1 gene expression and virulence; however, this was demonstrated to be the consequence of iron rather than calcium chelation. Ectopic expression of exsA, encoding the T3SS1 AraC-type regulator, was used to define the extent of the T3SS1 regulon and verify its coincident induction by calcium and EGTA. To begin to understand the regulatory mechanisms modulating the calcium response, a calcium-repressed, LysR type transcription factor named CalR was identified and shown to repress swarming and T3SS1 gene expression. Swarming and T3SS1 gene expression were also demonstrated to be linked by LafK, a sigma(54)-dependent regulator of swarming, and additionally connected by a negative-feedback loop on the swarming regulon propagated by ExsA. Thus, calcium and iron, two ions pertinent for a marine organism and pathogen, play a signaling role with global consequences on the regulation of gene sets that are relevant for surface colonization and infection. PMID- 20851896 TI - Genome sequence of the polymyxin-producing plant-probiotic rhizobacterium Paenibacillus polymyxa E681. AB - Paenibacillus polymyxa E681, a spore-forming, low-G+C, Gram-positive bacterium isolated from the rhizosphere of winter barley grown in South Korea, has great potential for agricultural applications due to its ability to promote plant growth and suppress plant diseases. Here we present the complete genome sequence of P. polymyxa E681. Its 5.4-Mb genome encodes functions specialized to the plant associated lifestyle and characteristics that are beneficial to plants, such as the production of a plant growth hormone, antibiotics, and hydrolytic enzymes. PMID- 20851897 TI - Complete genome sequence of the cellulolytic thermophile Caldicellulosiruptor obsidiansis OB47T. AB - Caldicellulosiruptor obsidiansis OB47(T) (ATCC BAA-2073, JCM 16842) is an extremely thermophilic, anaerobic bacterium capable of hydrolyzing plant-derived polymers through the expression of multidomain/multifunctional hydrolases. The complete genome sequence reveals a diverse set of carbohydrate-active enzymes and provides further insight into lignocellulosic biomass hydrolysis at high temperatures. PMID- 20851898 TI - Characterization of Pgp3, a Chlamydia trachomatis plasmid-encoded immunodominant antigen. AB - Human antibody recognition of Chlamydia trachomatis plasmid-encoded Pgp3 protein is dependent on the native conformation of Pgp3. The structural basis for the conformation dependence and the function of Pgp3 remain unknown. Here, we report that Pgp3 trimerization is required for the recognition of Pgp3 by human antibodies. In a native polyacrylamide gel, Pgp3 purified from a bacterial expression system migrated as stable trimers that were dissociated into monomers only by treatment with urea or sodium dodecyl sulfate (SDS) but not nonionic detergents. Human antibodies recognized trimeric but not monomeric Pgp3, suggesting that Pgp3 is presented to the human immune system as trimers during C. trachomatis infection. The endogenous Pgp3 secreted into the chlamydial outer membrane complex or host cell cytosol is always trimerized. Intact Pgp3 trimers were eluted from the outer membrane complex by a combination of nonionic detergents with reducing agents but not by the presence of either alone. These observations have provided important information for further understanding the role of Pgp3 in chlamydial pathogenesis and potentially optimizing Pgp3 as a subunit vaccine candidate antigen. PMID- 20851899 TI - Predicting plasmid promiscuity based on genomic signature. AB - Despite the important contribution of self-transmissible plasmids to bacterial evolution, little is understood about the range of hosts in which these plasmids have evolved. Our goal was to infer this so-called evolutionary host range. The nucleotide composition, or genomic signature, of plasmids is often similar to that of the chromosome of their current host, suggesting that plasmids acquire their hosts' signature over time. Therefore, we examined whether the evolutionary host range of plasmids could be inferred by comparing their trinucleotide composition to that of all completely sequenced bacterial chromosomes. The diversity of candidate hosts was determined using taxonomic classification and genetic distance. The method was first tested using plasmids from six incompatibility (Inc) groups whose host ranges are generally thought to be narrow (IncF, IncH, and IncI) or broad (IncN, IncP, and IncW) and then applied to other plasmid groups. The evolutionary host range was found to be broad for IncP plasmids, narrow for IncF and IncI plasmids, and intermediate for IncH and IncN plasmids, which corresponds with their known host range. The IncW plasmids as well as several plasmids from the IncA/C, IncP, IncQ, IncU, and PromA groups have signatures that were not similar to any of the chromosomal signatures, raising the hypothesis that these plasmids have not been ameliorated in any host due to their promiscuous nature. The inferred evolutionary host range of IncA/C, IncP-9, and IncL/M plasmids requires further investigation. In this era of high throughput sequencing, this genomic signature method is a useful tool for predicting the host range of novel mobile elements. PMID- 20851901 TI - Crystallographic insights into the pore structures and mechanisms of the EutL and EutM shell proteins of the ethanolamine-utilizing microcompartment of Escherichia coli. AB - The ethanolamine-utilizing bacterial microcompartment (Eut-BMC) of Escherichia coli is a polyhedral organelle that harbors specific enzymes for the catabolic degradation of ethanolamine. The compartment is composed of a proteinaceous shell structure that maintains a highly specialized environment for the biochemical reactions inside. Recent structural investigations have revealed hexagonal assemblies of shell proteins that form a tightly packed two-dimensional lattice that is likely to function as a selectively permeable protein membrane, wherein small channels are thought to permit controlled exchange of specific solutes. Here, we show with two nonisomorphous crystal structures that EutM also forms a two-dimensional protein membrane. As its architecture is highly similar to the membrane structure of EutL, it is likely that the structure represents a physiologically relevant form. Thus far, of all Eut proteins, only EutM and EutL have been shown to form such proteinaceous membranes. Despite their similar architectures, however, both proteins exhibit dramatically different pore structures. In contrast to EutL, the pore of EutM appears to be positively charged, indicating specificity for different solutes. Furthermore, we also show that the central pore structure of the EutL shell protein can be triggered to open specifically upon exposure to zinc ions, suggesting a specific gating mechanism. PMID- 20851900 TI - A Rhodobacter capsulatus member of a universal permease family imports molybdate and other oxyanions. AB - Molybdenum (Mo) is an important trace element that is toxic at high concentrations. To resolve the mechanisms underlying Mo toxicity, Rhodobacter capsulatus mutants tolerant to high Mo concentrations were isolated by random transposon Tn5 mutagenesis. The insertion sites of six independent isolates mapped within the same gene predicted to code for a permease of unknown function located in the cytoplasmic membrane. During growth under Mo-replete conditions, the wild-type strain accumulated considerably more Mo than the permease mutant. For mutants defective for the permease, the high-affinity molybdate importer ModABC, or both transporters, in vivo Mo-dependent nitrogenase (Mo-nitrogenase) activities at different Mo concentrations suggested that ModABC and the permease import molybdate in nanomolar and micromolar ranges, respectively. Like the permease mutants, a mutant defective for ATP sulfurylase tolerated high Mo concentrations, suggesting that ATP sulfurylase is the main target of Mo inhibition in R. capsulatus. Sulfate-dependent growth of a double mutant defective for the permease and the high-affinity sulfate importer CysTWA was reduced compared to those of the single mutants, implying that the permease plays an important role in sulfate uptake. In addition, permease mutants tolerated higher tungstate and vanadate concentrations than the wild type, suggesting that the permease acts as a general oxyanion importer. We propose to call this permease PerO (for oxyanion permease). It is the first reported bacterial molybdate transporter outside the ABC transporter family. PMID- 20851902 TI - A TRAP transporter for pyruvate and other monocarboxylate 2-oxoacids in the cyanobacterium Anabaena sp. strain PCC 7120. AB - In the cyanobacterium Anabaena sp. strain PCC 7120, open reading frames (ORFs) alr3026, alr3027, and all3028 encode a tripartite ATP-independent periplasmic transporter (TRAP-T). Wild-type filaments showed significant uptake of [(14)C]pyruvate, which was impaired in the alr3027 and all3028 mutants and was inhibited by several monocarboxylate 2-oxoacids, identifying this TRAP-T system as a pyruvate/monocarboxylate 2-oxoacid transporter. PMID- 20851903 TI - Cadaverine covalently linked to peptidoglycan is required for interaction between the peptidoglycan and the periplasm-exposed S-layer-homologous domain of major outer membrane protein Mep45 in Selenomonas ruminantium. AB - The peptidoglycan of Selenomonas ruminantium is covalently bound to cadaverine (PG-cadaverine), which likely plays a significant role in maintaining the integrity of the cell surface structure. The outer membrane of this bacterium contains a 45-kDa major protein (Mep45) that is a putative peptidoglycan associated protein. In this report, we determined the nucleotide sequence of the mep45 gene and investigated the relationship between PG-cadaverine, Mep45, and the cell surface structure. Amino acid sequence analysis showed that Mep45 is comprised of an N-terminal S-layer-homologous (SLH) domain followed by alpha helical coiled-coil region and a C-terminal beta-strand-rich region. The N terminal SLH domain was found to be protruding into the periplasmic space and was responsible for binding to peptidoglycan. It was determined that Mep45 binds to the peptidoglycan in a manner dependent on the presence of PG-cadaverine. Electron microscopy revealed that defective PG-cadaverine decreased the structural interactions between peptidoglycan and the outer membrane, consistent with the proposed role for PG-cadaverine. The C-terminal beta-strand-rich region of Mep45 was predicted to be a membrane-bound unit of the 14-stranded beta-barrel structure. Here we propose that PG-cadaverine possesses functional importance to facilitate the structural linkage between peptidoglycan and the outer membrane via specific interaction with the SLH domain of Mep45. PMID- 20851904 TI - Characterization of an archaeal medium-chain acyl coenzyme A synthetase from Methanosarcina acetivorans. AB - Short- and medium-chain acyl coenzyme A (acyl-CoA) synthetases catalyze the formation of acyl-CoA from an acyl substrate, ATP, and CoA. These enzymes catalyze mechanistically similar two-step reactions that proceed through an enzyme-bound acyl-AMP intermediate. Here we describe the characterization of a member of this enzyme family from the methane-producing archaeon Methanosarcina acetivorans. This enzyme, a medium-chain acyl-CoA synthetase designated Macs(Ma), utilizes 2-methylbutyrate as its preferred substrate for acyl-CoA synthesis but cannot utilize acetate and thus cannot catalyze the first step of acetoclastic methanogenesis in M. acetivorans. When propionate or other less favorable acyl substrates, such as butyrate, 2-methylpropionate, or 2-methylvalerate, were utilized, the acyl-CoA was not produced or was produced at reduced levels. Instead, acyl-AMP and PP(i) were released in the absence of CoA, whereas in the presence of CoA, the intermediate was broken down into AMP and the acyl substrate, which were released along with PP(i). These results suggest that although acyl-CoA synthetases may have the ability to utilize a broad range of substrates for the acyl-adenylate-forming first step of the reaction, the intermediate may not be suitable for the thioester-forming second step. The Macs(Ma) structure has revealed the putative acyl substrate- and CoA-binding pockets. Six residues proposed to form the acyl substrate-binding pocket, Lys(256), Cys(298), Gly(351), Trp(259), Trp(237), and Trp(254), were targeted for alteration. Characterization of the enzyme variants indicates that these six residues are critical in acyl substrate binding and catalysis, and even conservative alterations significantly reduced the catalytic ability of the enzyme. PMID- 20851905 TI - The methanogen-specific transcription factor MsvR regulates the fpaA-rlp-rub oxidative stress operon adjacent to msvR in Methanothermobacter thermautotrophicus. AB - Methanogens represent some of the most oxygen-sensitive organisms in laboratory culture. Recent studies indicate that they have developed mechanisms to deal with brief oxygen exposure. MsvR is a transcriptional regulator that has a domain architecture unique to a select group of methanogens. Here, runoff in vitro transcription assays were used to demonstrate that MsvR regulates transcription of the divergently transcribed fpaA-rlp-rub operon in Methanothermobacter thermautotrophicus in addition to transcription from its own promoter. The protein products of the fpaA-rlp-rub operon have previously been implicated in oxidative stress responses in M. thermautotrophicus. Additionally, electrophoretic mobility shift assays (EMSAs) and DNase I footprinting were used to confirm a binding site inferred by bioinformatic analysis. Sequence mutations within these binding sites did not significantly alter EMSA shifting patterns on longer templates but did on shorter 50-bp fragments encompassing only the region containing the binding sites. Footprinting confirmed that the regions protected for the longer mutant templates are at different positions within the intergenic region compared to those seen in the intact intergenic region. Oxidized and reduced preparations of MsvR demonstrated different EMSA binding patterns and regions of protection on the intergenic sequence, suggesting that MsvR may play a role in detecting the redox state of the cell. PMID- 20851906 TI - Seasonal changes of whole root system conductance by a drought-tolerant grape root system. AB - The role of root systems in drought tolerance is a subject of very limited information compared with above-ground responses. Adjustments to the ability of roots to supply water relative to shoot transpiration demand is proposed as a major means for woody perennial plants to tolerate drought, and is often expressed as changes in the ratios of leaf to root area (A(L):A(R)). Seasonal root proliferation in a directed manner could increase the water supply function of roots independent of total root area (A(R)) and represents a mechanism whereby water supply to demand could be increased. To address this issue, seasonal root proliferation, stomatal conductance (g(s)) and whole root system hydraulic conductance (k(r)) were investigated for a drought-tolerant grape root system (Vitis berlandieri*V. rupestris cv. 1103P) and a non-drought-tolerant root system (Vitis riparia*V. rupestris cv. 101-14Mgt), upon which had been grafted the same drought-sensitive clone of Vitis vinifera cv. Merlot. Leaf water potentials (psi(L)) for Merlot grafted onto the 1103P root system (-0.91+/-0.02 MPa) were +0.15 MPa higher than Merlot on 101-14Mgt (-1.06+/-0.03 MPa) during spring, but dropped by approximately -0.4 MPa from spring to autumn, and were significantly lower by -0.15 MPa (-1.43+/-0.02 MPa) than for Merlot on 101-14Mgt (at -1.28+/ 0.02 MPa). Surprisingly, g(s) of Merlot on the drought-tolerant root system (1103P) was less down-regulated and canopies maintained evaporative fluxes ranging from 35-20 mmol vine(-1) s(-1) during the diurnal peak from spring to autumn, respectively, three times greater than those measured for Merlot on the drought-sensitive rootstock 101-14Mgt. The drought-tolerant root system grew more roots at depth during the warm summer dry period, and the whole root system conductance (k(r)) increased from 0.004 to 0.009 kg MPa(-1) s(-1) during that same time period. The changes in k(r) could not be explained by xylem anatomy or conductivity changes of individual root segments. Thus, the manner in which drought tolerance was conveyed to the drought-sensitive clone appeared to arise from deep root proliferation during the hottest and driest part of the season, rather than through changes in xylem structure, xylem density or stomatal regulation. This information can be useful to growers on a site-specific basis in selecting rootstocks for grape clonal material (scions) grafted to them. PMID- 20851907 TI - Echinicola jeungdonensis sp. nov., isolated from a solar saltern. AB - A non-motile and yellow-pigmented bacterium, designated strain HMD3054(T), was isolated from a solar saltern in Jeungdo, Republic of Korea. The major fatty acids of strain HMD3054(T) were iso-C15:0 (31.4 %), anteiso-C15:0 (23.5 %), iso C17:0 3-OH (14.2 %), summed feature 3 (comprising C16:1omega6c and/or C16:1omega7c; 6.9 %) and summed feature 9 (comprising iso-C17:1omega9c and/or 10 methyl C16:0; 6.0 %). The major respiratory quinones were MK-6 and MK-7. The DNA G+C content of strain HMD3054(T) was 46.9 mol%. A phylogenetic tree based on 16S rRNA gene sequences showed that strain HMD3054(T) formed a lineage within the genus Echinicola. Strain HMD3054(T) was closely related to Echinicola vietnamensis KMM 6221(T) (94.3 % 16S rRNA gene sequence similarity) and Echinicola pacifica KMM 6172(T) (94.0 %). On the basis of the evidence presented in this study, strain HMD3054(T) represents a novel species of the genus Echinicola, for which the name Echinicola jeungdonensis sp. nov. is proposed. The type strain is HMD3054(T) ( = KCTC 23122(T) = CECT 7682(T)). PMID- 20851908 TI - Shewanella indica sp. nov., isolated from sediment of the Arabian Sea. AB - A Gram-negative, facultatively anaerobic, rod-shaped, catalase- and oxidase positive bacterium, motile by means of a single polar flagellum and designated strain KJW27(T), was isolated from the marine sediment of Karwar jetty, west coast of India. The strain was beta-haemolytic and grew with 0-10 % (w/v) NaCl, at 10-45 degrees C and at pH 6.5-10, with optimum growth with 2 % (w/v) NaCl, at 37 degrees C and at pH 7.5. The major fatty acids were iso-C15:0 (22.2 %), C17:1omega8c (21 %), summed feature 3 (comprising C16:1omega7c and/or C16:1omega6c; 10.2 %), C16:0 (7.1 %), iso-C13:0 (5.6 %) and C17:0 (4.4 %). The DNA G+C content was 51.2 mol%. Phylogenetic analysis based on 16S rRNA and gyrB gene sequences showed that strain KJW27(T) forms a lineage within the genus Shewanella and is closely related to Shewanella algae ATCC 51192(T) (98.8 %), Shewanella haliotis DW01(T) (98.8 %) and Shewanella chilikensis JC5(T) (98.2 %). Sequence identity with other members of this genus ranges from 92.2 to 96.4 %. The DNA-DNA relatedness of strain KJW27(T) with S. algae ATCC 51192(T), S. haliotis DW01(T) and S. chilikensis JC5(T) was 52, 44 and 33 %, respectively. The phenotypic, genotypic and DNA-DNA relatedness data indicate that strain KJW27(T) should be distinguished from S. algae ATCC 51192(T), S. haliotis DW01(T) and S. chilikensis JC5(T). On the basis of the data presented in this study, strain KJW27(T) represents a novel species, for which the name Shewanella indica sp. nov. is proposed. The type strain is KJW27(T) ( = KCTC 23171(T) = BCC 41031(T) = NCIM 5388(T)). PMID- 20851910 TI - Thioalbus denitrificans gen. nov., sp. nov., a chemolithoautotrophic sulfur oxidizing gammaproteobacterium, isolated from marine sediment. AB - A mesophilic, facultatively anaerobic, autotrophic bacterium, designated strain Su4(T), was isolated from marine sediment. The isolate was able to utilize reduced sulfur compounds including thiosulfate, tetrathionate, sulfur and sulfide but not sulfite as the energy source. Growth occurred under aerobic and denitrifying chemolithoautotrophic conditions in the presence of thiosulfate as an electron donor and bicarbonate as a carbon source. The G+C content of the genomic DNA was 64.5 mol%. Comparative 16S rRNA gene sequence studies showed that strain Su4(T) was clearly affiliated with the class Gammaproteobacteria. The isolate was Gram-negative-staining and rod-shaped, lacked flagella and grew in artificial seawater medium at 10-40 degrees C (optimum 28-32 degrees C) and in 1-5 % (w/v) NaCl (optimum 3 % NaCl). Strain Su4(T) possessed C16:0, C16:1omega7c/iso-C15:0 2-OH and C18:1omega7c/omega9t/omega12t as the major fatty acids. On the basis of phenotypic and phylogenetic analysis, the isolate represents a novel species of a novel genus, for which the name Thioalbus denitrificans is proposed. The type strain is Su4(T) ( = KCTC 5699(T) = JCM 15568(T)). PMID- 20851909 TI - Zhongshania antarctica gen. nov., sp. nov. and Zhongshania guokunii sp. nov., gammaproteobacteria respectively isolated from coastal attached (fast) ice and surface seawater of the Antarctic. AB - Two Gram-negative, motile, aerobic, catalase- and oxidase-positive, rod-shaped strains, designated ZS5-23(T) and ZS6-22(T), were respectively isolated from Antarctic coastal attached (fast) ice and surface seawater samples. Both strains could grow at 4-35 degrees C (optimum 30 degrees C) and in the absence of NaCl. Analyses of 16S rRNA gene sequences revealed that strains ZS5-23(T) and ZS6-22(T) were closely related to each other (99.0 % sequence similarity) and belonged to the class Gammaproteobacteria, with their closest relatives being Spongiibacter and Melitea species (93.1-94.3 % sequence similarity). The predominant cellular fatty acids in both strains were C17:1omega8c, C17:0 and summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH). Genomic DNA G+C contents of strains ZS5 23(T) and ZS6-22(T) were 51.5 and 51.8 mol%, respectively. The DNA-DNA relatedness between strains ZS5-23(T) and ZS6-22(T) was 50.9 %. Strains ZS5-23(T) and ZS6-22(T) could be differentiated from each other and from Spongiibacter and Melitea species by differences in a number of phenotypic properties. Based on the data presented, strains ZS5-23(T) and ZS6-22(T) represent two novel species in a new genus in the class Gammaproteobacteria, for which the names Zhongshania antarctica gen. nov., sp. nov. (the type species) and Zhongshania guokunii sp. nov. are proposed. The type strain of Zhongshania antarctica is ZS5-23(T) ( = KACC 14066(T) = CCTCC AB 209246(T)) and that of Zhongshania guokunii is ZS6 22(T) ( = KACC 14532(T) = CCTCC AB 209247(T)). PMID- 20851911 TI - Altererythrobacter dongtanensis sp. nov., isolated from a tidal flat. AB - A Gram-negative, rod-shaped and non-spore-forming bacterial strain, JM27(T), was isolated from a tidal flat of Dongtan Wetland, Chongming Island, China. The strain formed smooth yellow colonies on R2A plates. Growth occurred at 10-37 degrees C (optimum, 30-37 degrees C), at pH 6.0-10.0 (optimum, pH 7.0-9.0) and in the presence of 0-1 % NaCl (optimum, 0 %). Catalase test was positive and oxidase test was negative. Ubiquinone 10 (Q10) was the major respiratory quinone. C18:0omega7c and C17:1omega6c were the most abundant fatty acids. Diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol were the major polar lipids. The DNA G+C content of strain JM27(T) was 66.4 mol%. The 16S rRNA gene sequence of the isolate showed highest similarity to that of Altererythrobacter marinus H32(T) (96.4 %). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain belonged to the genus Altererythrobacter of the family Erythrobacteraceae of the class Alphaproteobacteria. On the basis of phylogenetic analysis, whole-cell fatty acids, polar lipid compositions, and biochemical and physiological characteristics, strain JM27(T) is proposed to represent a novel species of the genus Altererythrobacter for which the name Altererythrobacter dongtanensis sp. nov. is proposed. The type strain is JM27(T) ( = KCTC 22672(T) = CCTCC AB 209199(T)). PMID- 20851912 TI - Roseovarius indicus sp. nov., isolated from deep-sea water of the Indian Ocean. AB - A taxonomic study was carried out on a novel bacterial strain, designated B108(T), which was isolated from a polycyclic aromatic hydrocarbon (PAH) degrading consortium, enriched from deep-sea water of the Indian Ocean. The isolate was Gram-reaction-negative, rod-shaped and non-motile. Growth of strain B108(T) was observed in 1-15 % (w/v) NaCl and at 10-39 degrees C and it was unable to degrade Tween 80 or gelatin. 16S rRNA gene sequence comparisons showed that strain B108(T) was most closely related to Roseovarius halotolerans HJ50(T) (97.1 % sequence similarity), followed by Roseovarius pacificus 81-2(T) (96.6 %) and Roseovarius aestuarii SMK-122(T) (95.2 %); other species shared <95.0 % sequence similarity. DNA-DNA hybridization tests showed that strain B108(T) had a low DNA-DNA relatedness to R. halotolerans HJ50(T) and R. pacificus 81-2(T) (48+/ 4 % and 44+/-5 %, respectively). The predominant fatty acids were C16:0, C16:0 2 OH, summed feature 8 (C18:1omega7c/omega6c) and C19:0omega8c cyclo, which accounted for 84.2 % of the total cellular fatty acids. The G+C content of the chromosomal DNA was 63.6 mol%. The major respiratory quinone was ubiquinone 10 (Q10). Phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine and some unidentified compounds were detected. These characteristics were in good agreement with those of members of the genus Roseovarius. The pufLM gene was also detected. According to its morphology, physiology, fatty acid composition and phylogenetic position based on 16S rRNA sequence data, the novel strain most appropriately belongs to the genus Roseovarius but can be readily distinguished from known species of this genus. Therefore, strain B108(T) represents a novel species, of the genus Roseovarius, for which the name Roseovarius indicus sp. nov. is proposed. The type strain is B108(T) ( = 2PR52-14(T) = CCTCC AB 208233(T) = LMG 24622(T) = MCCC 1A01227(T)). PMID- 20851913 TI - Rubricoccus marinus gen. nov., sp. nov., of the family 'Rhodothermaceae', isolated from seawater. AB - A coccoid- and amorphous-shaped, non-gliding, reddish bacterium, designated SG 29(T), was isolated from seawater in the western North Pacific Ocean near Japan. The strain was Gram-stain-negative, obligately aerobic, heterotrophic and catalase-positive. Nitrate was reduced to nitrogen and acid was produced from aesculin, turanose, 2-keto-gluconate and arabinose. Growth occurred with 1-5 % NaCl (optimum 2 % NaCl) and at 5-37 degrees C (optimum 20-30 degrees C). The G+C content of genomic DNA was 68.9 mol% (HPLC). The predominant isoprenoid quinone was MK-7 and the major cellular fatty acids (>10 %) were iso C17:1omega9c, C17:1omega8c and iso-C17:0. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SG-29(T) belonged to the phylum Bacteroidetes. The most closely related strain was Rhodothermus obamensis JCM 9785(T), with which the isolate exhibited 86.1 % 16S rRNA gene sequence similarity. On the basis of phenotypic and phylogenetic features, strain SG-29(T) is classified in a novel genus and species within the family 'Rhodothermaceae', for which the name Rubricoccus marinus gen. nov., sp. nov. ( = NBRC 107124(T) = KCTC 23197(T)) is proposed. PMID- 20851914 TI - Jeotgalicoccus nanhaiensis sp. nov., isolated from intertidal sediment, and emended description of the genus Jeotgalicoccus. AB - A novel non-sporulating, non-motile, catalase- and oxidase-positive, strictly aerobic, Gram-positive-staining coccus, strain JSM 077023(T), was isolated from an intertidal sediment sample collected from Naozhou Island in the South China Sea, China. Growth occurred in the presence of 0.5-25 % (w/v) NaCl [optimum, 2-5 % (w/v) NaCl] and at pH 5.5-10.5 (optimum, pH 7.0-8.0) and at 4-45 degrees C (optimum, 30-35 degrees C). The major amino acid constituents of the cell wall were alanine, glycine and lysine. The major cellular fatty acids were anteiso C15:0 and iso-C15:0. The strain contained MK-7 and MK-6 as the predominant respiratory quinones and diphosphatidylglycerol, phosphatidylglycerol and an unidentified phospholipid as the polar lipids. The genomic DNA G+C content of strain JSM 077023(T) was 41.3 mol%. A phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain JSM 077023(T) should be assigned to the genus Jeotgalicoccus and was most closely related to the type strains of Jeotgalicoccus halotolerans (sequence similarity 99.0 %) and Jeotgalicoccus aerolatus (99.0 %), followed by Jeotgalicoccus coquinae (98.6 %) and Jeotgalicoccus psychrophilus (97.4 %). 16S rRNA gene sequence similarities of less than 97 % were observed with other species of the genus Jeotgalicoccus. Levels of DNA-DNA relatedness between strain JSM 077023(T) and the type strains of J. halotolerans, J. aerolatus, J. coquinae and J. psychrophilus ranged from 36.8 to 22.7 %. The combination of phylogenetic analysis, DNA-DNA relatedness values, phenotypic characteristics and chemotaxonomic data supported the suggestion that strain JSM 077023(T) represents a novel species of the genus Jeotgalicoccus, for which the name Jeotgalicoccus nanhaiensis sp. nov. is proposed. The type strain is JSM 077023(T) ( = DSM 23006(T) = KCTC 13714(T)). An emended description of the genus Jeotgalicoccus is also presented. PMID- 20851915 TI - Reichenbachiella faecimaris sp. nov., isolated from a tidal flat, and emended descriptions of the genus Reichenbachiella and Reichenbachiella agariperforans. AB - A taxonomic study was carried out on two bacterial strains, PCP11(T) and PCP104, isolated from a tidal flat of the Yellow Sea, Korea. Comparative 16S rRNA gene sequence studies showed that these strains belonged to the family Cytophagaceae, phylum Bacteroidetes. Strains PCP11(T) and PCP104 shared 99.4 % sequence similarity and were related most closely to Reichenbachiella agariperforans KMM 3525(T) (95.8 and 96.0 % sequence similarity, respectively). Members of the genera Fulvivirga, Roseivirga, Fabibacter and Marinoscillum were the next closest relatives of the new isolates, with sequence similarities <= 91 %. The two isolates were Gram-staining-negative, strictly aerobic, gliding bacteria. They grew in the presence of 1-5 % NaCl, at pH 5.5-8.5 and at 4-35 degrees C. Strains PCP11(T) and PCP104 shared a number of physiological and biochemical properties with Reichenbachiella agariperforans KMM 3525(T), but they differed from this strain in the hydrolysis of biopolymers and in the production of carotenoid and flexirubin-type pigments. Both strains possessed iso-C(15 : 0), summed feature 4 (C(16 : 1)omega7c and/or iso-C(15 : 0) 2-OH) and C(15 : 0) as major cellular fatty acids. The major respiratory quinone was menaquinone 7 (MK-7). The G+C contents of the genomic DNA of strains PCP11(T) and PCP104 were 39.6 and 41.9 mol%, respectively. On the basis of phenotypic data and phylogenetic inference, it is proposed that the two isolates represent a novel species, Reichenbachiella faecimaris sp. nov., with strain PCP11(T) ( = KACC 14523(T) = JCM 16588(T)) as the type strain. Emended descriptions of the genus Reichenbachiella and Reichenbachiella agariperforans are also proposed. PMID- 20851916 TI - Streptococcus rupicaprae sp. nov., isolated from a Pyrenean chamois (Rupicapra pyrenaica). AB - Biochemical and molecular genetic studies were performed on an unknown Gram-stain positive, catalase-negative, coccus-shaped organism isolated from clinical samples of a Pyrenean chamois. The micro-organism was identified as a streptococcal species based on its cellular morphological and biochemical tests. 16S rRNA gene sequence comparison studies confirmed its identification as a member of the genus Streptococcus, but the organism did not correspond to any species of this genus. The nearest phylogenetic relative of the unknown coccus from chamois was Streptococcus ovis (95.9 % 16S rRNA gene sequence similarity). The rpoB and sodA sequence analysis showed sequence similarity values of less than 85.7 % and 83.0 %, respectively, with the currently recognized species of the genus Streptococcus. The novel bacterial isolate was distinguished from S. ovis and other species of the genus Streptococcus using biochemical tests. Based on both phenotypic and phylogenetic findings, it is proposed that the unknown bacterium be classified as a novel species of the genus Streptococcus, Streptococcus rupicaprae sp. nov., with the type strain 2777-2-07(T) ( = CECT 7718(T) = CCUG 59652(T)). PMID- 20851917 TI - Ensifer sojae sp. nov., isolated from root nodules of Glycine max grown in saline alkaline soils. AB - Thirteen bacterial isolates from root nodules of soybean grown in saline-alkaline soils in the Chinese province of Hebei were identified as a unique group in the genus Ensifer based upon BOX-PCR patterns, sequencing analyses of 16S rRNA and housekeeping genes and DNA-DNA hybridization. Phenotypically, positive tests for acid production and negative results for reduction in litmus milk and sensitivity to 50 ug ampicillin ml(-1), as well as some other features, could differentiate the novel group from defined species of the Ensifer-Sinorhizobium group. The novel group had symbiotic gene sequences (nodC and nifH) that were identical or very similar to those of Ensifer (Sinorhizobium) fredii, and formed effective nodules with Glycine max (soybean), Vigna unguiculata and Glycine soja. Based upon the consensus of these analyses, a novel species, Ensifer sojae sp. nov., is proposed, with CCBAU 05684(T) ( = LMG 25493(T) = HAMBI 3098(T)) as the type strain. The DNA G+C content of strain CCBAU 05684(T) was 60.9 mol% (T(m)). PMID- 20851919 TI - Constrictibacter antarcticus gen. nov., sp. nov., a cryptoendolithic micro organism from Antarctic white rock. AB - A Gram-negative, non-spore-forming, ovoid to rod-shaped aerobic or microaerobic bacterium, strain 262-8(T), was isolated from a cavity within white rock collected in Antarctica. Strain 262-8(T) grew at 5-30 degrees C (optimum 25 degrees C), at pH 6-8 (optimum approximately pH 7) and with 0.1-2.0 % (w/v) NaCl (optimum 0.5 % NaCl). The addition of tryptone or yeast extract was essential for growth. Strain 262-8(T) was able to utilize organic compounds such as ribose, pyruvate and succinate in the presence of a low concentration of tryptone. Ubiquinone 10 was the major respiratory quinone. The major fatty acids were C(18 : 1), C(16 : 0) and C(18 : 0). The G+C content of the genomic DNA was 69.8 mol%. Comparative analyses of 16S rRNA gene sequences and physiological characteristics indicated that strain 262-8(T) was a phylogenetically novel bacterium that should be classified in a new genus of the family Rhodospirillaceae, for which the name Constrictibacter antarcticus gen. nov., sp. nov. is proposed. The type strain of the type species is 262-8(T) ( = JCM 16422(T) = ATCC BAA-1906(T)). PMID- 20851920 TI - Paracoccus caeni sp. nov., isolated from sludge. AB - A Gram-negative, non-motile bacterium, designated MJ17(T), was isolated from sludge at the Daejeon sewage disposal plant in South Korea. Comparative 16S rRNA gene sequence analysis showed that strain MJ17(T) belonged to the genus Paracoccus in the family Rhodobacteraceae of the class Alphaproteobacteria. 16S rRNA gene sequence similarities between strain MJ17(T) and type strains of species of the genus Paracoccus were 94.1-97.4 %. The highest similarities were between strain MJ17(T) and Paracoccus homiensis DD-R11(T), Paracoccus zeaxanthinifaciens ATCC 21588(T) and Paracoccus alcaliphilus JCM 7364(T) (97.4, 97.2 and 96.3 %, respectively). Strain MJ17(T) exhibited <22 % DNA-DNA relatedness with P. homiensis KACC 11518(T) and P. zeaxanthinifaciens JCM 21774(T). The G+C content of the genomic DNA was 58.7 mol%. Strain MJ17(T) contained ubiquinone Q-10. The major fatty acids were C(18 : 0) (11.3 %), C(16 : 0) (10.2 %) and summed feature 7 (containing one or more of C(18 : 1)omega7c, C(18 : 1)omega9c and C(18 : 1)omega12t; 54.3 %). Poly-beta-hydroxybutyrate granules are formed. On the basis of phenotypic and genotypic properties and phylogenetic distinctiveness, strain MJ17(T) should be classified in a novel species of the genus Paracoccus, for which the name Paracoccus caeni sp. nov. is proposed. The type strain is MJ17(T) ( = KCTC 22480(T) = JCM 16385(T) = KEMB 9004-001(T)). PMID- 20851921 TI - Osteoclast activity and subtypes as a function of physiology and pathology- implications for future treatments of osteoporosis. AB - Osteoclasts have traditionally been associated exclusively with catabolic functions that are a prerequisite for bone resorption. However, emerging data suggest that osteoclasts also carry out functions that are important for optimal bone formation and bone quality. Moreover, recent findings indicate that osteoclasts have different subtypes depending on their location, genotype, and possibly in response to drug intervention. The aim of the current review is to describe the subtypes of osteoclasts in four different settings: 1) physiological, in relation to turnover of different bone types; 2) pathological, as exemplified by monogenomic disorders; 3) pathological, as identified by different disorders; and 4) in drug-induced situations. The profiles of these subtypes strongly suggest that these osteoclasts belong to a heterogeneous cell population, namely, a diverse macrophage-associated cell type with bone catabolic and anabolic functions that are dependent on both local and systemic parameters. Further insight into these osteoclast subtypes may be important for understanding cell-cell communication in the bone microenvironment, treatment effects, and ultimately bone quality. PMID- 20851922 TI - Metabolic abnormalities in children with asthma. AB - RATIONALE: Childhood asthma and obesity have reached epidemic proportions worldwide, and the latter is also contributing to increasing rates of related metabolic disorders, such as diabetes. Yet, the relationship between asthma, obesity, and abnormal lipid and glucose metabolism is not well understood, nor has it been adequately explored in children. OBJECTIVES: To analyze the relationship between asthma diagnosis and body mass in children across the entire range of weight percentile categories, and to test the hypothesis that early derangement in lipid and glucose metabolism is independently associated with increased risk for asthma. METHODS: Cross-sectional analysis of a representative sample of public school children from a statewide community-based screening program, including a total of 17,994 children, 4 to 12 years old, living in predominantly rural West Virginia, and enrolled in kindergarten, second, or fifth grade classrooms. MEASUREMENTS AND MAIN RESULTS: We analyzed demographics; family history; smoke exposure; parent-reported asthma diagnosis; body mass index; evidence of acanthosis nigricans as a marker for developing insulin resistance; and fasting serum lipid profile including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides. Regardless of their body mass index percentile, children diagnosed with asthma were more likely than children without asthma to have higher triglyceride levels and acanthosis nigricans after controlling for sex differences and smoke exposure. CONCLUSIONS: This study provides the first set of community-based data linking asthma, body mass, and metabolic variables in children. In particular, these findings uniquely describe a statistically significant association between asthma and abnormal lipid and glucose metabolism beyond body mass index associations. PMID- 20851923 TI - Bedside ultrasound assessment of positive end-expiratory pressure-induced lung recruitment. AB - RATIONALE: In the critically ill patients, lung ultrasound (LUS) is increasingly being used at the bedside for assessing alveolar-interstitial syndrome, lung consolidation, pneumonia, pneumothorax, and pleural effusion. It could be an easily repeatable noninvasive tool for assessing lung recruitment. OBJECTIVES: Our goal was to compare the pressure-volume (PV) curve method with LUS for assessing positive end-expiratory pressure (PEEP)-induced lung recruitment in patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). METHODS: Thirty patients with ARDS and 10 patients with ALI were prospectively studied. PV curves and LUS were performed in PEEP 0 and PEEP 15 cm H2O2. PEEP induced lung recruitment was measured using the PV curve method. MEASUREMENTS AND MAIN RESULTS: Four LUS entities were defined: consolidation; multiple, irregularly spaced B lines; multiple coalescent B lines; and normal aeration. For each of the 12 lung regions examined, PEEP-induced ultrasound changes were measured, and an ultrasound reaeration score was calculated. A highly significant correlation was found between PEEP-induced lung recruitment measured by PV curves and ultrasound reaeration score (Rho = 0.88; P < 0.0001). An ultrasound reaeration score of +8 or higher was associated with a PEEP-induced lung recruitment greater than 600 ml. An ultrasound lung reaeration score of +4 or less was associated with a PEEP-induced lung recruitment ranging from 75 to 450 ml. A statistically significant correlation was found between LUS reaeration score and PEEP-induced increase in Pa(O2) (Rho = 0.63; P < 0.05). CONCLUSIONS: PEEP-induced lung recruitment can be adequately estimated with bedside LUS. Because LUS cannot assess PEEP-induced lung hyperinflation, it should not be the sole method for PEEP titration. PMID- 20851924 TI - Rheumatoid arthritis-interstitial lung disease-associated mortality. AB - RATIONALE: Mortality rates from rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are largely unknown. OBJECTIVES: We sought to determine mortality rates from rheumatoid arthritis-associated interstitial lung disease in the United States from 1988 through 2004. METHODS: Using data from the National Center for Health Statistics, we calculated age-adjusted mortality rates from the deaths of persons with rheumatoid arthritis-associated interstitial lung disease, determined the prevalence of interstitial lung disease in all decedents with rheumatoid arthritis, and compared the age and underlying cause of death in these two cohorts of decedents. MEASUREMENTS AND MAIN RESULTS: From 1988 to 2004, there were 39,138,394 deaths in U.S. residents and 162,032 rheumatoid arthritis associated deaths. Of these deaths, 10,725 (6.6%) met criteria for rheumatoid arthritis-associated interstitial lung. Mortality rates from rheumatoid arthritis fell over the course of this study in both women and men. However, mortality rates from rheumatoid arthritis-associated interstitial lung disease increased 28.3% in women (to 3.1 per million persons in 2004) and declined 12.5% in men (to 1.5 per million persons in 2004). Because the rate of decline in rheumatoid arthritis outpaced rheumatoid arthritis-associated interstitial lung disease in men, the prevalence of rheumatoid arthritis-associated interstitial lung disease increased in both sexes over time. CONCLUSIONS: Clinically significant RA-ILD occurs in nearly 10% of the RA population, and is associated with shortened survival and more severe underlying disease. Whereas overall mortality rates for RA have fallen, those associated with RA-ILD have increased significantly in older age groups. PMID- 20851925 TI - Integrated strategies to optimize sputum smear microscopy: a prospective observational study. AB - RATIONALE: Smear-positive tuberculosis (TB) case detection rates are far below targets in most low-income countries. The standard approach to smear microscopy involves sputum collection over multiple days and examination of sputum smears by light microscopy (LM), an insensitive and time-consuming technique. OBJECTIVE: To determine whether two alternative approaches can increase smear-positive case detection by increasing the efficiency (single-specimen microscopy) or sensitivity (light-emitting diode [LED] fluorescence microscopy [FM]) of TB suspect evaluation. METHODS: We enrolled patients with cough of 2 weeks or more admitted to Mulago Hospital in Kampala, Uganda and collected spot and early morning sputum specimens. We compared the diagnostic accuracy of four prespecified strategies based on the number of sputum specimens collected (one specimen versus two specimens) and the type of microscopy (LM versus LED FM) using mycobacterial culture as a reference standard. MEASUREMENTS AND MAIN RESULTS: Two hundred thirty-three of 464 (50%) patients had culture-positive TB. There was no difference in sensitivity between single-specimen and two-specimen strategies when smears were examined with LM (55 vs. 56%; difference, -1%; 95% confidence interval [CI], -5 to +2%) or LED FM (61 vs. 64%; difference, -3%; 95% CI, -7 to +1%). LED FM was more sensitive than LM with both the single-specimen (61 vs. 55%; difference, 6%; 95% CI, 2-10%) and two-specimen strategies (64 vs. 56%; difference, 8%; 95% CI, 3-12%). Findings were similar among the HIV-infected patient subset (n = 321 patients). CONCLUSIONS: In low-income, high TB burden settings, single-specimen microscopy and LED FM, either alone or in combination, could considerably increase identification of smear-positive TB cases. PMID- 20851926 TI - HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. AB - RATIONALE: In aging HIV-infected populations comorbid diseases are important determinants of morbidity and mortality. Pulmonary diseases have not been systematically assessed in the combination antiretroviral therapy (ART) era. OBJECTIVES: To determine the incidence of pulmonary diseases in HIV-infected persons compared with HIV-uninfected persons. METHODS: We analyzed data from the Veterans Aging Cohort Study Virtual Cohort, consisting of 33,420 HIV-infected veterans and 66,840 age, sex, race and ethnicity, and site-matched HIV-uninfected veterans. Using Poisson regression, incidence rates and adjusted incidence rate ratios were calculated to determine the association of HIV with pulmonary disease. The Virtual Cohort was merged with the 1999 Veterans Large Health Survey to adjust for self-reported smoking in a nested sample (14%). MEASUREMENTS AND MAIN RESULTS: Incident chronic obstructive pulmonary disease, lung cancer, pulmonary hypertension, and pulmonary fibrosis, as well as pulmonary infections, were significantly more likely among HIV-infected patients compared with uninfected patients in adjusted analyses, although rates of asthma did not differ by HIV status. Bacterial pneumonia and chronic obstructive pulmonary disease were the two most common incident pulmonary diseases, whereas opportunistic pneumonias were less common. Absolute rates of most pulmonary diseases increased with age, although the relative differences between those with and without HIV infection were greatest in younger persons. Chronic obstructive pulmonary disease and asthma, as well as pulmonary infections, were less likely in those with lower HIV RNA levels and use of ART at baseline. CONCLUSIONS: Pulmonary diseases among HIV infected patients receiving care within the Veterans Affairs Healthcare System in the combination ART era reflect a substantial burden of non-AIDS-defining and chronic conditions, many of which are associated with aging. PMID- 20851927 TI - Dysregulation of p38 and MKP-1 in response to NOD1/TLR4 stimulation in sarcoid bronchoalveolar cells. AB - RATIONALE: Sarcoidosis is a systemic inflammatory disorder characterized by distinct up-regulation of Th1 cytokines, such as tumor necrosis factor (TNF) alpha and IL-12. The mechanism underlying this up-regulation remains unclear. Recognition of microbial moieties through Toll-like or Nod-like receptors evokes sequential activation of mitogen-activated protein kinases (MAPKs), which plays a role in Th1-immune response. OBJECTIVES: To test the hypothesis that dysregulation in MAPK signaling in response to microbial stimulation is important in mediating Th1 response in sarcoidosis. METHODS: Ex vivo cultured bronchoalveolar lavage (BAL) cells isolated from patients with sarcoidosis and control subjects were stimulated with low-dose Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 1 (NOD1) ligands as a model of microbial stimulation, and MAPK signaling and inflammatory response were analyzed. MEASUREMENTS AND MAIN RESULTS: BAL cells from patients with sarcoidosis exhibited higher basal p38 activity, greater p38 phosphorylation, and more robust production of TNF-alpha and IL-12/IL-23p40 on stimulation with NOD1 and TLR4 agonists than cells isolated from control subjects. In contrast, control BAL cells had greater basal extracellular signal-regulated kinase (ERK) activity and NOD1 and TLR4 agonists preferentially activated the ERK pathway. Inhibition of p38, but not ERK, attenuated production of both IL12/IL23p40 and TNF-alpha. Interestingly, stimulation of cells from patients with sarcoidosis with either NOD1 or TLR4 ligand failed to induce MAPK phosphatase 1 (MKP-1). Adenovirus mediated overexpression of MKP-1 attenuated p38 activation and decreased the production of IL12/IL23p40 and TNF-alpha in sarcoid BAL cells. CONCLUSIONS: Our results suggest that enhanced p38 signaling in response to microbial products is caused by abnormal regulation of MKP-1 and contributes to heightened inflammation in sarcoidosis. PMID- 20851928 TI - Regulatory haplotypes in ARG1 are associated with altered bronchodilator response. AB - RATIONALE: beta2-agonists, the most common treatment for asthma, have a wide interindividual variability in response, which is partially attributed to genetic factors. We previously identified single nucleotide polymorphisms in the arginase 1 (ARG1) gene, which are associated with beta2-agonist bronchodilator response (BDR). OBJECTIVES: To identify cis-acting haplotypes in the ARG1 locus that are associated with BDR in patients with asthma and regulate gene expression in vitro. METHODS: We resequenced ARG1 in 96 individuals and identified three common, 5' haplotypes (denoted 1, 2, and 3). A haplotype-based association analysis of BDR was performed in three independent, adult asthma drug trial populations. Next, each haplotype was cloned into vectors containing a luciferase reporter gene and transfected into human airway epithelial cells (BEAS-2B) to ascertain its effect on gene expression. MEASUREMENTS AND MAIN RESULTS: BDR varied by haplotype in each of the three populations with asthma. Individuals with haplotype 1 were more likely to have higher BDR, compared to those with haplotypes 2 and 3, which is supported by odds ratios of 1.25 (95% confidence interval, 1.03-1.71) and 2.18 (95% confidence interval, 1.34-2.52), respectively. Luciferase expression was 50% greater in cells transfected with haplotype 1 compared to haplotypes 2 and 3. CONCLUSIONS: The identified ARG1 haplotypes seem to alter BDR and differentially regulate gene expression with a concordance of decreased BDR and reporter activity from haplotypes 2 and 3. These findings may facilitate pharmacogenetic tests to predict individuals who may benefit from other therapeutic agents in addition to beta(2)-agonists for optimal asthma management. Clinical trial registered with www.clinicaltrials.gov (NCT00156819, NCT00046644, and NCT00073840). PMID- 20851929 TI - RNA interference therapy in lung transplant patients infected with respiratory syncytial virus. AB - RATIONALE: Lower respiratory tract infections due to respiratory syncytial virus (RSV) are associated with development of bronchiolitis obliterans syndrome in lung transplant (LTX) recipients. ALN-RSV01 is a small interfering RNA targeting RSV replication. OBJECTIVES: To determine the safety and explore the efficacy of ALN-RSV01 in RSV infection. METHODS: We performed a randomized, double-blind, placebo-controlled trial in LTX recipients with RSV respiratory tract infection. Patients were permitted to receive standard of care for RSV. Aerosolized ALN RSV01 (0.6 mg/kg) or placebo was administered daily for 3 days. Viral load was determined by quantitative reverse transcriptase-polymerase chain reaction on serial nasal swabs. Patients completed symptom score cards twice daily. Lung function, including the incidence of new-onset or progressive bronchiolitis obliterans syndrome, was recorded at Day 90. MEASUREMENTS AND MAIN RESULTS: We enrolled 24 patients (ALN-RSV01, n = 16; placebo, n = 8); randomization was stratified by ribavirin use. ALN-RSV01 was well tolerated, with no drug-related serious adverse events or post-inhalation perturbations in lung function. Interpretation of viral measures was confounded by baseline differences between the two groups in viral load and time from symptom onset to first dose. Mean daily symptom scores were lower in subjects receiving ALN-RSV01, and the mean cumulative daily total symptom score was significantly lower with ALN-RSV01 (114.7 +/- 63.13 vs. 189.3 +/- 99.59, P = 0.035). At Day 90, incidence of new or progressive bronchiolitis obliterans syndrome was significantly reduced in ALN RSV01 recipients compared with placebo (6.3% vs. 50%, P = 0.027). CONCLUSIONS: ALN-RSV01 was safe and may have beneficial effects on long-term allograft function in LTX patients infected with RSV. Clinical trial registered with www.clinicaltrials.gov (NCT 00658086). PMID- 20851930 TI - Elastic properties of the central airways in obstructive lung diseases measured using anatomical optical coherence tomography. AB - RATIONALE: Our understanding of how airway remodeling affects regional airway elastic properties is limited due to technical difficulties in quantitatively measuring dynamic, in vivo airway dimensions. Such knowledge could help elucidate mechanisms of excessive airway narrowing. OBJECTIVES: To use anatomical optical coherence tomography (aOCT) to compare central airway elastic properties in control subjects and those with obstructive lung diseases. METHODS: After bronchodilation, airway lumen area (Ai) was measured using aOCT during bronchoscopy in control subjects (n = 10) and those with asthma (n = 16), chronic obstructive pulmonary disease (COPD) (n = 9), and bronchiectasis (n = 8). Ai was measured in each of generations 0 to 5 while airway pressure was increased from 10 to 20 cm H(2)O. Airway compliance (Caw) and specific compliance (sCaw) were derived from the transpulmonary pressure (Pl) versus Ai curves. MEASUREMENTS AND MAIN RESULTS: Caw decreased progressively as airway generation increased, but sCaw did not differ appreciably across the generations. In subjects with asthma and bronchiectasis, Caw and sCaw were similar to control subjects and the Pl-Ai curves were left-shifted. No significant differences were observed between control and COPD groups. CONCLUSIONS: Proximal airway elastic properties are altered in obstructive lung diseases. Although central airway compliance does not differ from control subjects in asthma, bronchiectasis, or COPD, Ai is lower in asthma and the Pl-Ai relationship is left-shifted in both asthma and bronchiectasis, suggesting that airways are maximally distended at lower inflating pressures. Such changes reflect alteration in the balance between airway wall distensibility and radial traction exerted on airways by surrounding lung parenchyma favoring airway narrowing. Clinical trial registered with Australian New Zealand Clinical Trials Registry (ACTRN12607000624482). PMID- 20851933 TI - Femoroacetabular impingement: caution is warranted in making imaging-based assumptions and diagnoses. PMID- 20851934 TI - Femoroacetabular impingement: evidence of an established hip abnormality. PMID- 20851935 TI - Consensus interpretation in imaging research: is there a better way? PMID- 20851936 TI - Short-term follow-up recommendations after preoperative breast MR assessment for breast cancer diagnosis: are we lacking a rational basis? PMID- 20851937 TI - The constantly changing field of radiology: maintaining professionalism in an era of electronic communication. PMID- 20851938 TI - Microbubble-enhanced US in body imaging: what role? AB - Contrast agents for ultrasonography (US) comprise microscopic bubbles of gas in an encapsulating shell. They are unique in that they interact with the imaging process, oscillating in response to a low-intensity ultrasound field and disrupting in response to a high-intensity field. New contrast-specific imaging modes allow US to show exquisite vascularity and tissue perfusion in real time and with excellent spatial resolution. In Europe, Asia, and Canada, to name only the most obvious, characterization of focal liver masses is the first and best established use of contrast-enhanced (CE) US, allowing for the noninvasive diagnosis of commonly encountered liver masses with comparable accuracy to that of computed tomography and magnetic resonance studies. CE US is a preferred modality for the difficult task of diagnosis of liver nodules detected on surveillance scans in those at risk for hepatocellular carcinoma. Newer body applications include the guidance of ablative intervention, monitoring activity of bowel inflammation in Crohn disease, characterization of kidney masses, especially cystic renal cell carcinoma, diagnosis of prostate cancer, and monitoring the response of tumors to antivascular drug therapies. Microbubble contrast agents are easy to use and robust; their use poses no risk of nephrotoxicity and requires no ionizing radiation. CE US plays a vital and expanding role that improves management and patient care. PMID- 20851939 TI - Diffusion-weighted MR imaging: pretreatment prediction of response to neoadjuvant chemotherapy in patients with breast cancer. AB - PURPOSE: To evaluate the potential of diffusion-weighted (DW) magnetic resonance (MR) imaging with an apparent diffusion coefficient (ADC) map in the prediction of response to neoadjuvant chemotherapy in patients with breast cancer. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, which waived the informed consent requirement. Fifty-three consecutive women (mean age, 43.7 years; median age, 42.0 years; age range, 24-65 years) with 53 invasive breast cancers (mean diameter, 5.0 cm; median diameter, 4.2 cm; diameter range, 2.0-13.3 cm) who had undergone chemotherapy were included. Both DW MR imaging (b values, 0 and 750 sec/mm(2)) and dynamic contrast material enhanced (DCE) MR imaging were performed at 1.5 T before and after chemotherapy prior to surgery. Mean time from initiation of chemotherapy to posttreatment ADC measurement was 54 days (range, 48-62 days). Average ADC for three regions of interest per tumor on ADC maps was calculated. Patients with a reduction in tumor diameter of at least 30% after chemotherapy at DCE MR imaging were defined as responders. Pretreatment ADCs and percentage increases in ADC after chemotherapy in responders and nonresponders were compared. The best pretreatment ADC cutoff with which to differentiate between responders and nonresponders was calculated with receiver operating characteristic curve analysis. RESULTS: After chemotherapy, 36 (68%) patients were classified as responders, and 17 (32%) were classified as nonresponders. Pretreatment mean ADC ([1.036 +/- 0.015] * 10(-3) mm(2)/sec [standard error]) of responders was significantly lower than that of nonresponders ([1.299 +/- 0.079] * 10(-3) mm(2)/sec) (P = .004). Furthermore, mean percentage ADC increase of responders (47.9% +/- 4.8) was higher than that of nonresponders (18.1% +/- 4.5) (P < .001). The best pretreatment ADC cutoff with which to differentiate between responders and nonresponders was 1.17 * 10( 3) mm(2)/sec, which yielded a sensitivity of 94% (95% confidence interval [CI]: 81%, 99%) and a specificity of 71% (95% CI: 44%, 90%). CONCLUSION: Patients with breast cancer and a low pretreatment ADC tended to respond better to chemotherapy. Prediction of response to neoadjuvant chemotherapy with DW MR imaging might help physicians individualize treatments and avoid ineffective chemotherapy. PMID- 20851940 TI - Multisection CT protocols: sex- and age-specific conversion factors used to determine effective dose from dose-length product. AB - PURPOSE: To determine conversion factors for the new International Commission on Radiological Protection (ICRP) publication 103 recommendations for adult and pediatric patients and to compare the effective doses derived from Monte Carlo calculations with those derived from dose-length product (DLP) for different body regions and computed tomographic (CT) scanning protocols. MATERIALS AND METHODS: Effective dose values for the Oak Ridge National Laboratory phantom series, including phantoms for newborns; 1-, 5-, and 10-year-old children; and adults were determined by using Monte Carlo methods for a 64-section multidetector CT scanner. For each phantom, five anatomic regions (head, neck, chest, abdomen, and pelvis) were considered. Monte Carlo simulations were performed for spiral scanning protocols with different voltages. Effective dose was computed by using ICRP publication 60 and publication 103 recommendations. The calculated effective doses were compared with those derived from the DLP by using previously published conversion factors. RESULTS: In general, conversion factors determined on the basis of Monte Carlo calculations led to lower values for adults with both ICRP publications. Values up to 33% and 32% lower than previously published data were found for ICRP publication 60 and ICRP publication 103, respectively. For pediatric individuals, effective doses based on the Monte Carlo calculations were higher than those obtained from DLP and previously published conversion factors (eg, for chest CT scanning in 5-year-old children, an increase of about 76% would be expected). For children, a variation in conversion factors of up to 15% was observed when the tube voltage was varied. For adult individuals, no dependence on voltage was observed. CONCLUSION: Conversion factors from DLP to effective dose should be specified separately for both sexes and should reflect the new ICRP recommendations. For pediatric patients, new conversion factors specific for the spectrum used should be established. PMID- 20851941 TI - Staging monoclonal plasma cell disease: comparison of the Durie-Salmon and the Durie-Salmon PLUS staging systems. AB - PURPOSE: To investigate the concordance of the Durie-Salmon staging system with the Durie-Salmon PLUS staging system in monoclonal plasma cell disease. MATERIALS AND METHODS: Institutional review board approval was obtained, with waiver of informed consent. Lesions in 403 untreated patients (age range, 21-83 years) with monoclonal gammopathy of undetermined significance (MGUS) (n = 84), solitary plasmacytoma (n = 17), amyloid light-chain amyloidosis (n = 12), and multiple myeloma (MM) (n = 290) were first staged on the basis of the classic Durie-Salmon staging system, which included conventional radiography. After examination with whole-body (WB) magnetic resonance (MR) imaging, lesions in these patients were, in addition, staged by using the Durie-Salmon PLUS staging system. Bone marrow infiltration pattern and focal lesions described as intramedullary, transcortical, and soft-tissue lesions, were assessed. The staging levels of both systems were compared. RESULTS: Of 84 patients with MGUS, lesions in 33 (39%) would have been staged differently with Durie-Salmon PLUS staging system when compared with Durie-Salmon staging system (stage I MM [37%], stage II MM [0%], and stage III MM [2%]). All 17 patients with plasmacytoma showed additional focal lesions or a diffuse infiltration leading to a classification as stage I MM (76%), stage II MM (12%), or stage III MM (12%) with Durie-Salmon PLUS. Of the 149 patients with stage I MM, lesions in 81 (54%) would have been staged differently with the Durie-Salmon PLUS staging system. Of the 21 patients with stage II MM, lesions in 19 (91%) would have been staged differently with Durie Salmon PLUS staging system when compared with the Durie-Salmon staging system. Of the 120 patients with stage III MM, lesions in 72 (60%) would have been staged differently with the Durie-Salmon PLUS staging system. CONCLUSION: Given the fact that the Durie-Salmon and Durie-Salmon PLUS staging systems were concordant in only 45% of all examined patients with monoclonal plasma cell disease, in most cases, treatment decisions depend on the staging system used and, thus, remain a matter of debate. PMID- 20851942 TI - Investigational Vertebroplasty Efficacy and Safety Trial: detailed analysis of blinding efficacy. AB - PURPOSE: To perform a detailed analysis of blinding efficacy in the Investigational Vertebroplasty Efficacy and Safety Trial (INVEST) to determine any factors associated with patient unblinding. MATERIALS AND METHODS: One hundred thirty-one patients were enrolled in this HIPAA-compliant, institutional review board-approved trial and were randomized to vertebroplasty (n = 68) or control intervention (n = 63). At multiple times up to 1 month, patients guessed their treatment allocation (vertebroplasty or control) with a forced-choice response. Patients offered a confidence level (scale, 0-10) for each guess and, when possible, a reason for their guess. Univariable logistic regression models were used to test for an association between baseline characteristics of the patients and correctly guessing their randomized treatment assignment. A two sample t test was used to determine whether change in pain score differed between patients who guessed their treatment was vertebroplasty versus those who guessed their treatment was control intervention. Qualitative reasons for guesses were tabulated according to treatment assignment and guess. RESULTS: Recruitment site was the only baseline factor significantly associated with guessing treatment correctly at 14 days (P < .01). Between the control and vertebroplasty groups, a total of 54 patients offered 64 reasons for their guesses, with 16 (25%) reasons based on procedural experiences. Control patients guessing vertebroplasty had significantly greater pain improvement at days 14 and 30 than did those guessing control (day 14, P = .02; day 30, P < .001). In the vertebroplasty group, no relationship between change in pain and patient guess was noted. CONCLUSION: A number of factors were associated with the ability of patients to guess their treatment allocation correctly-namely, treatment effect (in the control group only), study treatment site, and baseline pain duration. Procedural experiences rarely affected perceived treatment in INVEST. PMID- 20851943 TI - Right coronary MR angiography at 7 T: a direct quantitative and qualitative comparison with 3 T in young healthy volunteers. AB - PURPOSE: To objectively compare quantitative parameters related to image quality attained at coronary magnetic resonance (MR) angiography of the right coronary artery (RCA) performed at 7 T and 3 T. MATERIALS AND METHODS: Institutional review board approval was obtained, and volunteers provided signed informed consent. Ten healthy adult volunteers (mean age +/- standard deviation, 25 years +/- 4; seven men, three women) underwent navigator-gated three-dimensional MR angiography of the RCA at 7 T and 3 T. For 7 T, a custom-built quadrature radiofrequency transmit-receive surface coil was used. At 3 T, a commercial body radiofrequency transmit coil and a cardiac coil array for signal reception were used. Segmented k-space gradient-echo imaging with spectrally selective adiabatic fat suppression was performed, and imaging parameters were similar at both field strengths. Contrast-to-noise ratio between blood and epicardial fat; signal-to noise ratio of the blood pool; RCA vessel sharpness, diameter, and length; and navigator efficiency were quantified at both field strengths and compared by using a Mann-Whitney U test. RESULTS: The contrast-to-noise ratio between blood and epicardial fat was significantly improved at 7 T when compared with that at 3 T (87 +/- 34 versus 52 +/- 13; P = .01). Signal-to-noise ratio of the blood pool was increased at 7 T (109 +/- 47 versus 67 +/- 19; P = .02). Vessel sharpness obtained at 7 T was also higher (58% +/- 9 versus 50% +/- 5; P = .04). At the same time, RCA vessel diameter and length and navigator efficiency showed no significant field strength-dependent difference. CONCLUSION: In our quantitative and qualitative study comparing in vivo human imaging of the RCA at 7 T and 3 T in young healthy volunteers, parameters related to image quality attained at 7 T equal or surpass those from 3 T. PMID- 20851944 TI - Pulmonary mycobacterial disease: diagnostic performance of low-dose digital tomosynthesis as compared with chest radiography. AB - PURPOSE: To compare the diagnostic performance of a low-radiation-dose digital tomosynthesis (DTS) technique with that of conventional radiography in the detection of lung lesions in patients with pulmonary mycobacterial disease. MATERIALS AND METHODS: The institutional review board approved this study, and all patients provided informed consent. In this study, 100 patients (65 study patients, 35 control patients) underwent multidetector computed tomography (CT), chest radiography, and low-dose DTS (effective doses: 3.4, 0.02, and 0.05 mSv, respectively). Two radiologists evaluated radiographs and DTS images for the presence of parenchymal lesions and the number of cavities in each patient; CT served as the reference standard. Wilcoxon signed rank and McNemar tests and kappa statistics were used. RESULTS: The accuracies of DTS and radiography in depicting mycobacterial disease were 97% and 89%, respectively, for observer 1 (P = .039) and 99% and 93%, respectively, for observer 2 (P = .031). The accuracies of DTS and radiography in depicting each lesion type were, respectively, 95% and 77% for bronchiolitis, 92% and 76% for nodules, 86% and 79% for consolidation, and 93% and 70% for cavities. Interobserver agreement with DTS (kappa = 0.62 0.94) was superior to that with radiography (kappa = 0.46-0.62). Of a total of 141 cavities found with CT, means of 27 (19%) cavities at chest radiography and 108 (77%) cavities at DTS (P < .01) were detected by the two observers. CONCLUSION: DTS performed with a low-dose technique is superior to radiography for the detection of lung lesions in patients with pulmonary mycobacterial disease. PMID- 20851946 TI - Case 162: scapulothoracic dissociation. PMID- 20851947 TI - The U.S. Preventive Services Task Force guidelines are not supported by the scientific evidence. PMID- 20851948 TI - Evidence-based advocacy rather than emotion in defense of screening mammography. PMID- 20851949 TI - U.S. Preventive Services Task Force: the unbalanced view. PMID- 20851950 TI - Wise words from Drs Berlin and Hall. PMID- 20851951 TI - Repeat US-guided fine-needle aspiration biopsy of thyroid nodules: some clarifications are needed. PMID- 20851952 TI - MR signal intensity calculations are not reliable for differentiating renal cell carcinoma from lipid poor angiomyolipoma. PMID- 20851953 TI - Curcumin inhibits carcinogen and nicotine-induced Mammalian target of rapamycin pathway activation in head and neck squamous cell carcinoma. AB - Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 +/- 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent. PMID- 20851954 TI - Health risk from the use of roof-harvested rainwater in Southeast Queensland, Australia, as potable or nonpotable water, determined using quantitative microbial risk assessment. AB - A total of 214 rainwater samples from 82 tanks were collected in urban Southeast Queensland (SEQ) in Australia and analyzed for the presence and numbers of zoonotic bacterial and protozoal pathogens using binary PCR and quantitative PCR (qPCR). Quantitative microbial risk assessment (QMRA) analysis was used to quantify the risk of infection associated with the exposure to potential pathogens from roof-harvested rainwater used as potable or nonpotable water. Of the 214 samples tested, 10.7%, 9.8%, 5.6%, and 0.4% were positive for the Salmonella invA, Giardia lamblia beta-giardin, Legionella pneumophila mip, and Campylobacter jejuni mapA genes, respectively. Cryptosporidium parvum oocyst wall protein (COWP) could not be detected. The estimated numbers of Salmonella, G. lamblia, and L. pneumophila organisms ranged from 6.5 * 101 to 3.8 * 102 cells, 0.6 * 100 to 3.6 * 100 cysts, and 6.0 * 101 to 1.7 * 102 cells per 1,000 ml of water, respectively. Six risk scenarios were considered for exposure to Salmonella spp., G. lamblia, and L. pneumophila. For Salmonella spp. and G. lamblia, these scenarios were (i) liquid ingestion due to drinking of rainwater on a daily basis, (ii) accidental liquid ingestion due to hosing twice a week, (iii) aerosol ingestion due to showering on a daily basis, and (iv) aerosol ingestion due to hosing twice a week. For L. pneumophila, these scenarios were (i) aerosol inhalation due to showering on a daily basis and (ii) aerosol inhalation due to hosing twice a week. The risk of infection from Salmonella spp., G. lamblia, and L. pneumophila associated with the use of rainwater for showering and garden hosing was calculated to be well below the threshold value of one extra infection per 10,000 persons per year in urban SEQ. However, the risk of infection from ingesting Salmonella spp. and G. lamblia via drinking exceeded this threshold value and indicated that if undisinfected rainwater is ingested by drinking, then the incidences of the gastrointestinal diseases salmonellosis and giardiasis are expected to range from 9.8 * 10 degrees to 5.4 * 101 (with a mean of 1.2 * 101 from Monte Carlo analysis) and from 1.0 * 101 to 6.5 * 101 cases (with a mean of 1.6 * 101 from Monte Carlo analysis) per 10,000 persons per year, respectively, in urban SEQ. Since this health risk seems higher than that expected from the reported incidences of gastroenteritis, the assumptions used to estimate these infection risks are critically examined. Nonetheless, it would seem prudent to disinfect rainwater for use as potable water. PMID- 20851955 TI - Novel fluorescence-assisted whole-cell assay for engineering and characterization of proteases and their substrates. AB - We have developed a sensitive and highly efficient whole-cell methodology for quantitative analysis and screening of protease activity in vivo. The method is based on the ability of a genetically encoded protease to rescue a coexpressed short-lived fluorescent substrate reporter from cytoplasmic degradation and thereby confer increased whole-cell fluorescence in proportion to the protease's apparent activity in the Escherichia coli cytoplasm. We demonstrated that this system can reveal differences in the efficiency with which tobacco etch virus (TEV) protease processes different substrate peptides. In addition, when analyzing E. coli cells expressing TEV protease variants that differed in terms of their in vivo solubility, cells containing the most-soluble protease variant exhibited the highest fluorescence intensity. Furthermore, flow cytometry screening allowed for enrichment and subsequent identification of an optimal substrate peptide and protease variant from a large excess of cells expressing suboptimal variants (1:100,000). Two rounds of cell sorting resulted in a 69,000 fold enrichment and a 22,000-fold enrichment of the superior substrate peptide and protease variant, respectively. Our approach presents a new promising path forward for high-throughput substrate profiling of proteases, engineering of novel protease variants with desired properties (e.g., altered substrate specificity and improved solubility and activity), and identification of protease inhibitors. PMID- 20851956 TI - Activation of two different resistance mechanisms in Saccharomyces cerevisiae upon exposure to octanoic and decanoic acids. AB - Medium-chain fatty acids (octanoic and decanoic acids) are well known as fermentation inhibitors. During must fermentation, the toxicity of these fatty acids is enhanced by ethanol and low pH, which favors their entrance in the cell, resulting in a decrease of internal pH. We present here the characterization of the mechanisms involved in the establishment of the resistance to these fatty acids. The analysis of the transcriptome response to the exposure to octanoic and decanoic acids revealed that two partially overlapping mechanisms are activated; both responses share many genes with an oxidative stress response, but some key genes were activated differentially. The transcriptome response to octanoic acid stress can be described mainly as a weak acid response, and it involves Pdr12p as the main transporter. The phenotypic analysis of knocked-out strains confirmed the role of the Pdr12p transporter under the control of WAR1 but also revealed the involvement of the Tpo1p major facilitator superfamily proteins (MFS) transporter in octanoic acid expulsion. In contrast, the resistance to decanoic acid is composite. It also involves the transporter Tpo1p and includes the activation of several genes of the beta-oxidation pathway and ethyl ester synthesis. Indeed, the induction of FAA1 and EEB1, coding for a long-chain fatty acyl coenzyme A synthetase and an alcohol acyltransferase, respectively, suggests a detoxification pathway through the production of decanoate ethyl ester. These results are confirmed by the sensitivity of strains bearing deletions for the transcription factors encoded by PDR1, STB5, OAF1, and PIP2 genes. PMID- 20851957 TI - lacZ reporter system for use in Borrelia burgdorferi. AB - Regulation of gene expression is critical for the ability of Borrelia burgdorferi to adapt to different environments during its natural infectious cycle. Reporter genes have been used successfully to study gene regulation in multiple organisms. We have introduced a lacZ gene into B. burgdorferi, and we show that B. burgdorferi produces a protein with detectable beta-galactosidase activity in both liquid and solid media when lacZ is expressed from a constitutive promoter. Furthermore, when lacZ is expressed from the ospC promoter, beta-galactosidase activity is detected only in B. burgdorferi clones that express ospC, and it accurately monitors endogenous gene expression. The addition of lacZ to the repertoire of genetic tools available for use in B. burgdorferi should contribute to a better understanding of how B. burgdorferi gene expression is regulated during the infectious cycle. PMID- 20851958 TI - New insights into the fructosyltransferase activity of Schwanniomyces occidentalis beta-fructofuranosidase, emerging from nonconventional codon usage and directed mutation. AB - Schwanniomyces occidentalis beta-fructofuranosidase (Ffase) releases beta fructose from the nonreducing ends of beta-fructans and synthesizes 6-kestose and 1-kestose, both considered prebiotic fructooligosaccharides. Analyzing the amino acid sequence of this protein revealed that it includes a serine instead of a leucine at position 196, caused by a nonuniversal decoding of the unique mRNA leucine codon CUG. Substitution of leucine for Ser196 dramatically lowers the apparent catalytic efficiency (k(cat)/K(m)) of the enzyme (approximately 1,000 fold), but surprisingly, its transferase activity is enhanced by almost 3-fold, as is the enzymes' specificity for 6-kestose synthesis. The influence of 6 Ffase residues on enzyme activity was analyzed on both the Leu196/Ser196 backgrounds (Trp47, Asn49, Asn52, Ser111, Lys181, and Pro232). Only N52S and P232V mutations improved the transferase activity of the wild-type enzyme (about 1.6-fold). Modeling the transfructosylation products into the active site, in combination with an analysis of the kinetics and transfructosylation reactions, defined a new region responsible for the transferase specificity of the enzyme. PMID- 20851959 TI - Covariation of soil bacterial composition with plant rarity. AB - Rare and common plants are predicted to host different rhizospheric microbes. To evaluate this prediction, we used terminal restriction fragment length polymorphism (T-RFLP) analysis to compare rhizospheric bacteria from eight native grass species whose local abundances in their natural ecosystem spanned a 15-fold range. We observed that locally rare versus common plants are associated with divergent bacterial communities. PMID- 20851961 TI - Stable, site-specific fluorescent tagging constructs optimized for burkholderia species. AB - Several vectors that facilitate stable fluorescent labeling of Burkholderia pseudomallei and Burkholderia thailandensis were constructed. These vectors combined the effectiveness of the mini-Tn7 site-specific transposition system with fluorescent proteins optimized for Burkholderia spp., enabling bacterial tracking during cellular infection. PMID- 20851960 TI - Molecular evidence for multiple infections as revealed by typing of Asaia bacterial symbionts of four mosquito species. AB - The recent increased detection of acetic acid bacteria (AAB) of the genus Asaia as symbionts of mosquitoes, such as Anopheles spp. and Aedes spp., prompted us to investigate the diversity of these symbionts and their relationships in different mosquito species and populations. Following cultivation-dependent and independent techniques, we investigated the microbiota associated with four mosquito species, Anopheles stephensi, Anopheles gambiae, Aedes aegypti, and Aedes albopictus, which are important vectors of human and/or animal pathogens. Denaturing gradient gel electrophoresis (DGGE) analysis based on the 16S rRNA gene revealed the presence of several bacterial taxa, among which Asaia sequences were among the dominant in most of the samples. A collection of 281 Asaia isolates in cell-free media was established from individuals belonging to the four species. The isolates were typed by internal transcribed spacer (ITS)-PCR, tRNA-PCR, BOX-PCR, and randomly amplified polymorphic DNA (RAPD)-PCR, revealing that different Asaia strains are present in different mosquito populations, and even in single individuals. PMID- 20851962 TI - Evolutionary relationships among primary endosymbionts of the mealybug subfamily phenacoccinae (hemiptera: Coccoidea: Pseudococcidae). AB - Mealybugs (Coccoidea: Pseudococcidae) are sap-sucking plant parasites that harbor bacterial endosymbionts within specialized organs. Previous studies have identified two subfamilies, Pseudococcinae and Phenacoccinae, within mealybugs and determined the primary endosymbionts (P-endosymbionts) of the Pseudococcinae to be Betaproteobacteria ("Candidatus Tremblaya princeps") containing Gammaproteobacteria secondary symbionts. Here, the P-endosymbionts of phenacoccine mealybugs are characterized based on 16S rRNA from the bacteria of 20 species of phenacoccine mealybugs and four outgroup Puto species (Coccoidea: Putoidae) and aligned to more than 100 published 16S rRNA sequences from symbiotic and free-living bacteria. Phylogenetic analyses recovered three separate lineages of bacteria from the Phenacoccinae, and these are considered to be the P-endosymbionts of their respective mealybug hosts, with those from (i) the mealybug genus Rastrococcus belonging to the Bacteroidetes, (ii) the subterranean mealybugs, tribe Rhizoecini, also within Bacteroidetes, in a clade sister to cockroach endosymbionts (Blattabacterium), and (iii) the remaining Phenacoccinae within the Betaproteobacteria, forming a well-supported sister group to "Candidatus Tremblaya princeps." Names are proposed for two strongly supported lineages: "Candidatus Brownia rhizoecola" for P-endosymbionts of Rhizoecini and "Candidatus Tremblaya phenacola" for P-endosymbionts of Phenacoccinae excluding Rastrococcus and Rhizoecini. Rates of nucleotide substitution among lineages of Tremblaya were inferred to be significantly faster than those of free-living Betaproteobacteria. Analyses also recovered a clade of Gammaproteobacteria, sister to the P-endosymbiont lineage of aphids ("Candidatus Buchnera aphidicola"), containing the endosymbionts of Putoidae, the secondary endosymbionts of pseudococcine mealybugs, and the endosymbionts of several other insect groups. PMID- 20851963 TI - Granule formation mechanisms within an aerobic wastewater system for phosphorus removal. AB - Granular sludge is a novel alternative for the treatment of wastewater and offers numerous operational and economic advantages over conventional floccular-sludge systems. The majority of research on granular sludge has focused on optimization of engineering aspects relating to reactor operation with little emphasis on the fundamental microbiology. In this study, we hypothesize two novel mechanisms for granule formation as observed in three laboratory scale sequencing batch reactors operating for biological phosphorus removal and treating two different types of wastewater. During the initial stages of granulation, two distinct granule types (white and yellow) were distinguished within the mixed microbial population. White granules appeared as compact, smooth, dense aggregates dominated by 97.5% "Candidatus Accumulibacter phosphatis," and yellow granules appeared as loose, rough, irregular aggregates with a mixed microbial population of 12.3% "Candidatus Accumulibacter phosphatis" and 57.9% "Candidatus Competibacter phosphatis," among other bacteria. Microscopy showed white granules as homogeneous microbial aggregates and yellow granules as segregated, microcolony like aggregates, with phylogenetic analysis suggesting that the granule types are likely not a result of strain-associated differences. The microbial community composition and arrangement suggest different formation mechanisms occur for each granule type. White granules are hypothesized to form by outgrowth from a single microcolony into a granule dominated by one bacterial type, while yellow granules are hypothesized to form via multiple microcolony aggregation into a microcolony segregated granule with a mixed microbial population. Further understanding and application of these mechanisms and the associated microbial ecology may provide conceptual information benefiting start-up procedures for full-scale granular sludge reactors. PMID- 20851964 TI - Changes in ultrastructure and Fourier transform infrared spectrum of Salmonella enterica serovar typhimurium cells after exposure to stress conditions. AB - The effect of exposure to acid (pH 2.5), alkaline (pH 11.0), heat (55 degrees C), and oxidative (40 mM H2O2) lethal conditions on the ultrastructure and global chemical composition of Salmonella enterica serovar Typhimurium CECT 443 cells was studied using transmission electron microscopy and Fourier transform infrared spectroscopy (FT-IR) combined with multivariate statistical methods (hierarchical cluster analysis and factor analysis). Infrared spectra exhibited marked differences in the five spectral regions for all conditions tested compared to those of nontreated control cells, which suggests the existence of a complex bacterial stress response in which modifications in a wide variety of cellular compounds are involved. The visible spectral changes observed in all of the spectral regions, together with ultrastructural changes observed by transmission electron microscopy and data obtained from membrane integrity tests, indicate the existence of membrane damage or alterations in membrane composition after heat, acid, alkaline, and oxidative treatments. Results obtained in this study indicate the potential of FT-IR spectroscopy to discriminate between intact and injured bacterial cells and between treatment technologies, and they show the adequacy of this technique to study the molecular aspects of bacterial stress response. PMID- 20851966 TI - Maximizing capture efficiency and specificity of magnetic separation for Mycobacterium avium subsp. paratuberculosis cells. AB - In order to introduce specificity for Mycobacterium avium subsp. paratuberculosis prior to a phage amplification assay, various magnetic-separation approaches, involving either antibodies or peptides, were evaluated in terms of the efficiency of capture (expressed as a percentage) of M. avium subsp. paratuberculosis cells and the percentage of nonspecific binding by other Mycobacterium spp. A 50:50 mixture of MyOne Tosylactivated Dynabeads coated with the chemically synthesized M. avium subsp. paratuberculosis-specific peptides biotinylated aMp3 and biotinylated aMptD (i.e., peptide-mediated magnetic separation [PMS]) proved to be the best magnetic-separation approach for achieving 85 to 100% capture of M. avium subsp. paratuberculosis and minimal (<1%) nonspecific recovery of other Mycobacterium spp. (particularly if beads were blocked with 1% skim milk before use) from broth samples containing 10(3) to 10(4) CFU/ml. When PMS was coupled with a recently optimized phage amplification assay and used to detect M. avium subsp. paratuberculosis in 50-ml volumes of spiked milk, the mean 50% limit of detection (LOD(50)) was 14.4 PFU/50 ml of milk (equivalent to 0.3 PFU/ml). This PMS-phage assay represents a novel, rapid method for the detection and enumeration of viable M. avium subsp. paratuberculosis organisms in milk, and potentially other sample matrices, with results available within 48 h. PMID- 20851967 TI - Functionality of sortase A in Lactococcus lactis. AB - Lactococcus lactis IL1403 harbors a putative sortase A (SrtA) and 11 putative sortase substrates that carry the canonical LPXTG signature of such substrates. We report here on the functionality of SrtA to anchor five LPXTG substrates to the cell wall, thus suggesting that SrtA is the housekeeping sortase in L. lactis IL1403. PMID- 20851965 TI - Rumen microbial population dynamics during adaptation to a high-grain diet. AB - High-grain adaptation programs are widely used with feedlot cattle to balance enhanced growth performance against the risk of acidosis. This adaptation to a high-grain diet from a high-forage diet is known to change the rumen microbial population structure and help establish a stable microbial population within the rumen. Therefore, to evaluate bacterial population dynamics during adaptation to a high-grain diet, 4 ruminally cannulated beef steers were adapted to a high grain diet using a step-up diet regimen containing grain and hay at ratios of 20:80, 40:60, 60:40, and 80:20. The rumen bacterial populations were evaluated at each stage of the step-up diet after 1 week of adaptation, before the steers were transitioned to the next stage of the diet, using terminal restriction fragment length polymorphism (T-RFLP) analysis, 16S rRNA gene libraries, and quantitative real-time PCR. The T-RFLP analysis displayed a shift in the rumen microbial population structure during the final two stages of the step-up diet. The 16S rRNA gene libraries demonstrated two distinct rumen microbial populations in hay fed and high-grain-fed animals and detected only 24 common operational taxonomic units out of 398 and 315, respectively. The 16S rRNA gene libraries of hay-fed animals contained a significantly higher number of bacteria belonging to the phylum Fibrobacteres, whereas the 16S rRNA gene libraries of grain-fed animals contained a significantly higher number of bacteria belonging to the phylum Bacteroidetes. Real-time PCR analysis detected significant fold increases in the Megasphaera elsdenii, Streptococcus bovis, Selenomonas ruminantium, and Prevotella bryantii populations during adaptation to the high-concentrate (high grain) diet, whereas the Butyrivibrio fibrisolvens and Fibrobacter succinogenes populations gradually decreased as the animals were adapted to the high concentrate diet. This study evaluates the rumen microbial population using several molecular approaches and presents a broader picture of the rumen microbial population structure during adaptation to a high-grain diet from a forage diet. PMID- 20851968 TI - The Rhodococcus opacus PD630 heparin-binding hemagglutinin homolog TadA mediates lipid body formation. AB - Generally, prokaryotes store carbon as polyhydroxyalkanoate, starch, or glycogen. The Gram-positive actinomycete Rhodococcus opacus strain PD630 is noteworthy in that it stores carbon in the form of triacylglycerol (TAG). Several studies have demonstrated that R. opacus PD630 can accumulate up to 76% of its cell dry weight as TAG when grown under nitrogen-limiting conditions. While this process is well studied, the underlying molecular and biochemical mechanisms leading to TAG biosynthesis and subsequent storage are poorly understood. We designed a high throughput genetic screening to identify genes and their products required for TAG biosynthesis and storage in R. opacus PD630. We identified a gene predicted to encode a putative heparin-binding hemagglutinin homolog, which we have termed tadA (triacylglycerol accumulation deficient), as being important for TAG accumulation. Kinetic studies of TAG accumulation in both the wild-type (WT) and mutant strains demonstrated that the tadA mutant accumulates 30 to 40% less TAG than the parental strain (WT). We observed that lipid bodies formed by the mutant strain were of a different size and shape than those of the WT. Characterization of TadA demonstrated that the protein is capable of binding heparin and of agglutinating purified lipid bodies. Finally, we observed that the TadA protein localizes to lipid bodies in R. opacus PD630 both in vivo and in vitro. Based on these data, we hypothesize that the TadA protein acts to aggregate small lipid bodies, found in cells during early stages of lipid storage, into larger lipid bodies and thus plays a key role in lipid body maturation in R. opacus PD630. PMID- 20851969 TI - Salmonella enterica in commercial swine feed and subsequent isolation of phenotypically and genotypically related strains from fecal samples. AB - The purpose of this study was to determine the occurrence and genotypic relatedness of Salmonella enterica isolates recovered from feed and fecal samples in commercial swine production units. Of 275 feed samples, Salmonella was detected in 10 feed samples that originated from 8 of 36 (22.2%) barns, with a prevalence of 3.6% (10/275 samples). In fecal samples, a prevalence of 17.2% was found at the early finishing stage (1,180/6,880 samples), with a significant reduction in prevalence (7.4%) when pigs reached market age (392/5,321 samples). Of the 280 Salmonella isolates systematically selected for further characterization, 50% of the feed isolates and 55.3% of the isolates of fecal origin showed similar phenotypes based on antimicrobial resistance patterns and serogrouping. About 44% of the isolates were multidrug resistant. Pulsed-field gel electrophoresis (PFGE) genotyping grouped the 46 representative isolates into five genotypic clusters, of which four of the clusters consisted of genotypically related isolates recovered from feed and fecal samples. The occurrence of genotypically related and, in some cases, clonal strains, including multidrug resistant isolates in commercially processed feed and fecal samples, suggests the high significance of commercial feed as a potential vehicle of Salmonella transmission. PMID- 20851970 TI - Persistence of Bacteroides species populations in a river as measured by molecular and culture techniques. AB - Given the interest in Bacteroides species as microbial source tracking (MST) markers, and the limited knowledge of the survival of Bacteroides species in the environment, here we examine the survival of Bacteroides fragilis, B. thetaiotaomicron, and environmental species of Bacteroides by use of culture techniques and molecular tools. Two kinds of experiments were performed: (i) on site experiments, in which bacteria were exposed to changes in the levels of several environmental parameters in a river, and (ii) microcosm assays in the laboratory, with controlled temperatures. On-site experiments showed different survival patterns for the cultivable Bacteroides strains. B. fragilis die-off rate was strongly affected by the combined effect of high temperatures and grazing predators, which were more active under warmer conditions. However, the survival rates of cultivable B. thetaiotaomicron and environmental Bacteroides spp. were more affected by dissolved oxygen (DO) concentration in water. Environmental Bacteroides strains survived longer than either type strain, due to better adaptation to environmental conditions. However, the period of their survival was shorter than that observed for fecal coliforms and enterococci, suggesting Bacteroides species as markers of recent fecal pollution. The total Bacteroides species were detected by molecular techniques throughout the experiment in winter, but they were detected on only two or three days in the summer. This indicates that temperature is the main factor affecting DNA degradation, regardless of species. The use of microcosms in the laboratory also pointed to temperature as the main factor affecting Bacteroides survival, regardless of species. However, the conditions in the laboratory may mask the effects of the environmental factors and their interactions. The observed variability in die-off rate as a function of the species analyzed, the experimental conditions, and the methodology used should be taken into consideration in future persistence studies. PMID- 20851971 TI - Genetic transformation and mutagenesis via single-stranded DNA in the unicellular, diazotrophic cyanobacteria of the genus Cyanothece. AB - We describe a genetic system for producing specific gene knockouts in Cyanothece sp. strain PCC 7822 using a single-stranded DNA technique (B. Zorin, P. Hegemann, and I. Sizova, Eukaryot. Cell 4:1264-1272, 2005). The first fully segregated mutant was a DeltanifK mutant, and it was unable to grow on medium lacking combined nitrogen and produced virtually no hydrogen. PMID- 20851973 TI - Isolation of a novel bacteriophage specific for the periodontal pathogen Fusobacterium nucleatum. AB - Fusobacterium nucleatum is a periodontal pathogen that has been directly associated with the development and progression of periodontal disease, a widespread pathology that affects the support tissues of the tooth. We isolated a new bacteriophage (FnpPhi02) that specifically infects this bacterium. Transmission electron microscopy showed that the virion is composed of an icosahedral head and a segmented tail. The size of the phage genome was estimated to be approximately 59 kbp of double-stranded DNA. The morphological features and the genetic characteristics suggest that FnpPhi02 is part of the Siphoviridae family. Using one-step growth and adsorption experiments, the latent period, burst size, and adsorption rate were estimated to be 15 h, 100 infectious units per cell, and 7.5 * 10-10 ml min-1, respectively. A small fragment of phage DNA was cloned and sequenced, showing 93% nucleotide identity with the phage PA6 of Propionibacterium acnes and amino acid identity with fragments of two proteins (Gp3 and Gp4) of this phage. To our knowledge, FnpPhi02 is the first phage described to infect Fusobacterium nucleatum and provides the base for future exploration of phages in the control of periodontal disease. PMID- 20851974 TI - Nonlinear biosynthetic gene cluster dose effect on penicillin production by Penicillium chrysogenum. AB - Industrial penicillin production levels by the filamentous fungus Penicillium chrysogenum increased dramatically by classical strain improvement. High-yielding strains contain multiple copies of the penicillin biosynthetic gene cluster that encodes three key enzymes of the beta-lactam biosynthetic pathway. We have analyzed the gene cluster dose effect on penicillin production using the high yielding P. chrysogenum strain DS17690 that was cured from its native clusters. The amount of penicillin V produced increased with the penicillin biosynthetic gene cluster number but was saturated at high copy numbers. Likewise, transcript levels of the biosynthetic genes pcbAB [delta-(l-alpha-aminoadipyl)-l-cysteinyl-d valine synthetase], pcbC (isopenicillin N synthase), and penDE (acyltransferase) correlated with the cluster copy number. Remarkably, the protein level of acyltransferase, which localizes to peroxisomes, was saturated already at low cluster copy numbers. At higher copy numbers, intracellular levels of isopenicillin N increased, suggesting that the acyltransferase reaction presents a limiting step at a high gene dose. Since the number and appearance of the peroxisomes did not change significantly with the gene cluster copy number, we conclude that the acyltransferase activity is limiting for penicillin biosynthesis at high biosynthetic gene cluster copy numbers. These results suggest that at a high penicillin production level, productivity is limited by the peroxisomal acyltransferase import activity and/or the availability of coenzyme A (CoA)-activated side chains. PMID- 20851975 TI - Cell wall anchoring of the 37-kilodalton oncofetal antigen by Lactobacillus plantarum for mucosal cancer vaccine delivery. AB - The 37-kDa oncofetal antigen (OFA), a tumor immunogen expressed on all mammalian cancers examined to date, was secreted and anchored to the cell wall of Lactobacillus plantarum using homologous signal peptides and LPxTG anchors. Orally administered L. plantarum expressing anchored OFA induced a specific immune response against OFA in mice. PMID- 20851976 TI - Effect of host cells on low- and medium-pressure UV inactivation of adenoviruses. AB - UV disinfection is highly effective against most pathogens, with the exception of the adenoviruses (AD). To date, many studies have focused on low-pressure (LP) UV inactivation of AD, but little is known about the effect of medium-pressure (MP) UV inactivation of AD. Despite numerous studies of LP UV inactivation of AD, extreme variabilities in the LP UV dose requirements of AD had been observed because of differing experimental conditions used, such as the types of cell lines used for AD enumeration. This study therefore investigates the effect of three different host cell lines (PLC/PRF/5, human embryonic kidney 293 [HEK293], and XP17BE) on the LP and MP UV dose requirements of AD serotype 5 (AD5), AD40, and AD41 under similar experimental settings. Results showed that for 4-log inactivation of AD, LP UV and MP UV doses needed to be in the ranges of 123 to 182 mJ/cm2 and 65 to 90 mJ/cm2, respectively, when HEK293 and PLC/PRF/5 cells were used for enumeration. The UV doses required for MP UV inactivation of AD were significantly lower than those required for LP UV inactivation (P value < 0.05). When different cell lines were used for enumeration, UV dose requirements for AD differed. AD were portrayed to be most susceptible to UV (LP UV doses of <57 mJ/cm2 and MP UV doses of <42 mJ/cm2 for 4-log AD inactivation) when the XP17BE cells were used as the host cell. The use of different cell lines for AD enumeration affected LP UV dose results more significantly than MP UV dose results (P value < 0.05). Cell line variability factors for LP UV disinfection (CL(LP)) and MP UV disinfection (CL(MP)) for AD5, AD40, and AD41 enumerated with HEK293, PLC/PRF/5, and XP17BE cells were in the ranges of 1.0 to 3.2 and 1.0 to 2.5, respectively. PMID- 20851972 TI - The spatial factor, rather than elevated CO2, controls the soil bacterial community in a temperate Forest Ecosystem. AB - The global atmospheric carbon dioxide (CO2) concentration is expected to increase continuously over the next century. However, little is known about the responses of soil bacterial communities to elevated CO2 in terrestrial ecosystems. This study aimed to partition the relative influences of CO2, nitrogen (N), and the spatial factor (different sampling plots) on soil bacterial communities at the free-air CO2 enrichment research site in Duke Forest, North Carolina, by two independent techniques: an entirely sequencing-based approach and denaturing gradient gel electrophoresis. Multivariate regression tree analysis demonstrated that the spatial factor could explain more than 70% of the variation in soil bacterial diversity and 20% of the variation in community structure, while CO2 or N treatment explains less than 3% of the variation. For the effects of soil environmental heterogeneity, the diversity estimates were distinguished mainly by the total soil N and C/N ratio. Bacterial diversity estimates were positively correlated with total soil N and negatively correlated with C/N ratio. There was no correlation between the overall bacterial community structures and the soil properties investigated. This study contributes to the information about the effects of elevated CO2 and soil fertility on soil bacterial communities and the environmental factors shaping the distribution patterns of bacterial community diversity and structure in temperate forest soils. PMID- 20851977 TI - Acetic acid bacteria, newly emerging symbionts of insects. AB - Recent research in microbe-insect symbiosis has shown that acetic acid bacteria (AAB) establish symbiotic relationships with several insects of the orders Diptera, Hymenoptera, Hemiptera, and Homoptera, all relying on sugar-based diets, such as nectars, fruit sugars, or phloem sap. To date, the fruit flies Drosophila melanogaster and Bactrocera oleae, mosquitoes of the genera Anopheles and Aedes, the honey bee Apis mellifera, the leafhopper Scaphoideus titanus, and the mealybug Saccharicoccus sacchari have been found to be associated with the bacterial genera Acetobacter, Gluconacetobacter, Gluconobacter, Asaia, and Saccharibacter and the novel genus Commensalibacter. AAB establish symbiotic associations with the insect midgut, a niche characterized by the availability of diet-derived carbohydrates and oxygen and by an acidic pH, selective factors that support AAB growth. AAB have been shown to actively colonize different insect tissues and organs, such as the epithelia of male and female reproductive organs, the Malpighian tubules, and the salivary glands. This complex topology of the symbiosis indicates that AAB possess the keys for passing through body barriers, allowing them to migrate to different organs of the host. Recently, AAB involvement in the regulation of innate immune system homeostasis of Drosophila has been shown, indicating a functional role in host survival. All of these lines of evidence indicate that AAB can play different roles in insect biology, not being restricted to the feeding habit of the host. The close association of AAB and their insect hosts has been confirmed by the demonstration of multiple modes of transmission between individuals and to their progeny that include vertical and horizontal transmission routes, comprising a venereal one. Taken together, the data indicate that AAB represent novel secondary symbionts of insects. PMID- 20851978 TI - Development of an environmental functional gene microarray for soil microbial communities. AB - Functional attributes of microbial communities are difficult to study, and most current techniques rely on DNA- and rRNA-based profiling of taxa and genes, including microarrays containing sequences of known microorganisms. To quantify gene expression in environmental samples in a culture-independent manner, we constructed an environmental functional gene microarray (E-FGA) consisting of 13,056 mRNA-enriched anonymous microbial clones from diverse microbial communities to profile microbial gene transcripts. A new normalization method using internal spot standards was devised to overcome spotting and hybridization bias, enabling direct comparisons of microarrays. To evaluate potential applications of this metatranscriptomic approach for studying microbes in environmental samples, we tested the E-FGA by profiling the microbial activity of agricultural soils with a low or high flux of N2O. A total of 109 genes displayed expression that differed significantly between soils with low and high N2O emissions. We conclude that mRNA-based approaches such as the one presented here may complement existing techniques for assessing functional attributes of microbial communities. PMID- 20851979 TI - Novel activity of Rhodobacter sphaeroides spheroidene monooxygenase CrtA expressed in Escherichia coli. AB - The spheroidene monooxygenase CrtA of Rhodobacter sphaeroides introduces a keto group and/or hydroxy group at the ends of nonnative substrates in Escherichia coli, resulting in the production of novel oxocarotenoids. The heme-containing CrtA is not a P450 enzyme but a new type of oxygenase. PMID- 20851980 TI - Molecular cloning of cyanobacterial pteridine glycosyltransferases that catalyze the transfer of either glucose or xylose to tetrahydrobiopterin. AB - Here, we report cloning of cyanobacterial genes encoding pteridine glycosyltransferases that catalyze glucosyl or xylosyl transfer from UDP-sugars to tetrahydrobiopterin. The genes were cloned by PCR amplification from genomic DNA which was isolated from culture and environmental samples and overexpressed in Escherichia coli for an in vitro activity assay. PMID- 20851981 TI - Dispersion of TiO2 nanoparticle agglomerates by Pseudomonas aeruginosa. AB - Engineered nanoparticles are increasingly incorporated into consumer products and are emerging as potential environmental contaminants. Upon environmental release, nanoparticles could inhibit bacterial processes, as evidenced by laboratory studies. Less is known regarding bacterial alteration of nanoparticles, including whether bacteria affect physical agglomeration states controlling nanoparticle settling and bioavailability. Here, the effects of an environmental strain of Pseudomonas aeruginosa on TiO2 nanoparticle agglomerates formed in aqueous media are described. Environmental scanning electron microscopy and cryogenic scanning electron microscopy visually demonstrated bacterial dispersion of large agglomerates formed in cell culture medium and in marsh water. For experiments in cell culture medium, quantitative image analysis verified that the degrees of conversion of large agglomerates into small nanoparticle-cell combinations were similar for 12-h-growth and short-term cell contact experiments. Dispersion in cell growth medium was further characterized by size fractionation: for agglomerated TiO2 suspensions in the absence of cells, 81% by mass was retained on a 5-MUm-pore-size filter, compared to only 24% retained for biotic treatments. Filtrate cell and agglomerate sizes were characterized by dynamic light scattering, revealing that the average bacterial cell size increased from 1.4 MUm to 1.9 MUm because of nano-TiO2 biosorption. High-magnification scanning electron micrographs showed that P. aeruginosa dispersed TiO2 agglomerates by preferential biosorption of nanoparticles onto cell surfaces. These results suggest a novel role for bacteria in the environmental transport of engineered nanoparticles, i.e., growth-independent, bacterially mediated size and mass alterations of TiO2 nanoparticle agglomerates. PMID- 20851982 TI - Combined transcriptome and proteome analysis of Bifidobacterium animalis subsp. lactis BB-12 grown on xylo-oligosaccharides and a model of their utilization. AB - Recent studies have demonstrated that xylo-oligosaccharides (XOS), which are classified as emerging prebiotics, selectively enhance the growth of bifidobacteria in general and of Bifidobacterium animalis subsp. lactis strains in particular. To elucidate the metabolism of XOS in the well-documented and widely used probiotic strain B. animalis subsp. lactis BB-12, a combined proteomic and transcriptomic approach was applied, involving DNA microarrays, real-time quantitative PCR (qPCR), and two-dimensional difference gel electrophoresis (2D-DIGE) analyses of samples obtained from cultures grown on either XOS or glucose. The analyses show that 9 of the 10 genes that encode proteins predicted to play a role in XOS catabolism (i.e., XOS-degrading and metabolizing enzymes, transport proteins, and a regulatory protein) were induced by XOS at the transcriptional level, and the proteins encoded by three of these (beta-d-xylosidase, sugar-binding protein, and xylose isomerase) showed higher abundance on XOS. Based on the obtained results, a model for the catabolism of XOS in BB-12 is suggested, according to which the strain utilizes an ABC (ATP binding cassette) transport system (probably for oligosaccharides) to bind XOS on the cell surface and transport them into the cell. XOS are then degraded intracellularly through the action of xylanases and xylosidases to d-xylose, which is subsequently metabolized by the d-fructose-6-P shunt. The findings obtained in this study may have implications for the design of a synbiotic application containing BB-12 and the XOS used in the present study. PMID- 20851983 TI - Moderate temperature fluctuations rapidly reduce the viability of Ralstonia solanacearum race 3, biovar 2, in infected geranium, tomato, and potato plants. AB - Most Ralstonia solanacearum strains are tropical plant pathogens, but race 3, biovar 2 (R3bv2), strains can cause bacterial wilt in temperate zones or tropical highlands where other strains cannot. R3bv2 is a quarantine pathogen in North America and Europe because of its potential to damage the potato industry in cooler climates. However, R3bv2 will not become established if it cannot survive temperate winters. Previous experiments showed that in water at 4 degrees C, R3bv2 does not survive as long as native U.S. strains, but R3bv2 remains viable longer than U.S. strains in potato tubers at 4 degrees C. To further investigate the effects of temperature on this high-concern pathogen, we assessed the ability of R3bv2 and a native U.S. strain to survive typical temperate winter temperature cycles of 2 days at 5 degrees C followed by 2 days at -10 degrees C. We measured pathogen survival in infected tomato and geranium plants, in infected potato tubers, and in sterile water. The population sizes of both strains declined rapidly under these conditions in all three plant hosts and in sterile water, and no culturable R. solanacearum cells were detected after five to seven temperature cycles in plant tissue. The fluctuations played a critical role in loss of bacterial viability, since at a constant temperature of -20 degrees C, both strains could survive in infected geranium tissue for at least 6 months. These results suggest that even when sheltered in infected plant tissue, R3bv2 is unlikely to survive the temperature fluctuations typical of a northern temperate winter. PMID- 20851984 TI - Catalytic biomineralization of fluorescent calcite by the thermophilic bacterium Geobacillus thermoglucosidasius. AB - The thermophilic Geobacillus bacterium catalyzed the formation of 100-MUm hexagonal crystals at 60 degrees C in a hydrogel containing sodium acetate, calcium chloride, and magnesium sulfate. Under fluorescence microscopy, crystals fluoresced upon excitation at 365 +/- 5, 480 +/- 20, or 545 +/- 15 nm. X-ray diffraction indicated that the crystals were magnesium-calcite in calcite-type calcium carbonate. PMID- 20851985 TI - Identifying active phage lysins through functional viral metagenomics. AB - Recent metagenomic sequencing studies of uncultured viral populations have provided novel insights into the ecology of environmental bacteriophage. At the same time, viral metagenomes could also represent a potential source of recombinant proteins with biotechnological value. In order to identify such proteins, a novel two-step screening technique was devised for cloning phage lytic enzymes from uncultured viral DNA. This plasmid-based approach first involves a primary screen in which transformed Escherichia coli clones that demonstrate colony lysis following exposure to inducing agent are identified. This effect, which can be due to the expression of membrane-permeabilizing phage holins, is discerned by the development a hemolytic effect in surrounding blood agar. In a secondary step, the clones identified in the primary screen are overlaid with autoclaved Gram-negative bacteria (specifically Pseudomonas aeruginosa) to assay directly for recombinant expression of lytic enzymes, which are often encoded proximally to holins in phage genomes. As proof-of-principle, the method was applied to a viral metagenomic library constructed from mixed animal feces, and 26 actively expressed lytic enzymes were cloned. These proteins include both Gram-positive-like and Gram-negative-like enzymes, as well as several atypical lysins whose predicted structures are less common among known phage. Overall, this study represents one of the first functional screens of a viral metagenomic population, and it provides a general approach for characterizing lysins from uncultured phage. PMID- 20851986 TI - Development of a real-time qPCR method for detection and enumeration of Mycobacterium spp. in surface water. AB - A real-time quantitative PCR method was developed for the detection and enumeration of Mycobacterium spp. from environmental samples and was compared to two other methods already described. The results showed that our method, targeting 16S rRNA, was more specific than the two previously published real-time quantitative PCR methods targeting another 16S rRNA locus and the hsp65 gene (100% versus 44% and 91%, respectively). PMID- 20851987 TI - Use of cellular CRISPR (clusters of regularly interspaced short palindromic repeats) spacer-based microarrays for detection of viruses in environmental samples. AB - It is currently difficult to detect unknown viruses in any given environment. The recent discovery of CRISPR (clusters of regularly interspaced short palindromic repeats) loci within bacterial and archaeal cellular genomes may provide an alternative approach to detect new viruses. It has been shown that the spacer sequences between the direct repeat units of the CRISPR loci are often derived from viruses and likely function as guide sequences to protect the cell from viral infection. The spacer sequences within the CRISPR loci may therefore serve as a record of the viruses that have replicated within the cell. We have cataloged the CRISPR spacer sequences from cellular metagenomic data from high temperature (>80 degrees C), acidic (pH < 4) hot spring environments located in Yellowstone National Park (YNP). We designed a microarray platform utilizing these CRISPR spacer sequences as potential probes to detect viruses present in YNP hot spring environments. We show that this microarray approach can detect viral sequences directly from virus-enriched environmental samples, detecting new viruses which have not been previously characterized. We further demonstrated that this microarray approach can be used to examine temporal changes in viral populations within the environment. Our results demonstrate that CRISPR spacer sequence-based microarrays will be useful tools for detecting and monitoring viruses from diverse environmental samples. PMID- 20851988 TI - Isolation and characterization of the gene cluster for biosynthesis of the thiopeptide antibiotic TP-1161. AB - Recently, we isolated a new thiopeptide antibiotic, TP-1161, from the fermentation broth of a marine actinomycete typed as a member of the genus Nocardiopsis. Here we report the identification, isolation, and analysis of the TP-1161 biosynthetic gene cluster from this species. The gene cluster was identified by mining a draft genome sequence using the predicted structural peptide sequence of TP-1161. Functional assignment of a ~16-kb genomic region revealed 13 open reading frames proposed to constitute the TP-1161 biosynthetic locus. While the typical core set of thiopeptide modification enzymes contains one cyclodehydratase/dehydrogenase pair, paralogous genes predicted to encode additional cyclodehydratases and dehydrogenases were identified. Although attempts at heterologous expression of the TP-1161 gene cluster in Streptomyces coelicolor failed, its identity was confirmed through the targeted gene inactivation in the original host. PMID- 20851989 TI - Xyn10A, a thermostable endoxylanase from Acidothermus cellulolyticus 11B. AB - We cloned and purified the major family 10 xylanase (Xyn10A) from Acidothermus cellulolyticus 11B. Xyn10A was active on oat spelt and birchwood xylans between 60 degrees C and 100 degrees C and between pH 4 and pH 8. The optimal activity was at 90 degrees C and pH 6; specific activity and K(m) for oat spelt xylan were 350 MUmol xylose produced min-1 mg of protein-1 and 0.53 mg ml-1, respectively. Based on xylan cleavage patterns, Xyn10A is an endoxylanase, and its half-life at 90 degrees C was approximately 1.5 h in the presence of xylan. PMID- 20851990 TI - Lactococcal abortive infection protein AbiV interacts directly with the phage protein SaV and prevents translation of phage proteins. AB - AbiV is an abortive infection protein that inhibits the lytic cycle of several virulent phages infecting Lactococcus lactis, while a mutation in the phage gene sav confers insensitivity to AbiV. In this study, we have further characterized the effects of the bacterial AbiV and its interaction with the phage p2 protein SaV. First, we showed that during phage infection of lactococcal AbiV(+) cells, AbiV rapidly inhibited protein synthesis. Among early phage transcripts, sav gene transcription was slightly inhibited while the SaV protein could not be detected. Analyses of other phage p2 mRNAs and proteins suggested that AbiV blocks the activation of late gene transcription, probably by a general inhibition of translation. Using size exclusion chromatography coupled with on-line static light scattering and refractometry, as well as fluorescence quenching experiments, we also demonstrated that both AbiV and SaV formed homodimers and that they strongly and specifically interact with each other to form a stable protein complex. PMID- 20851991 TI - Isolation of a novel Campylobacter jejuni clone associated with the bank vole, Myodes glareolus. AB - Campylobacter jejuni can be isolated from different animal hosts. Various studies have used multilocus sequence typing to look for associations between particular clones of C. jejuni and specific hosts. Here, we describe the isolation of a novel clone (sequence type 3704 [ST-3704]) of C. jejuni associated with the bank vole (Myodes glareolus). PMID- 20851992 TI - In vivo and ex vivo evaluations of bacteriophages e11/2 and e4/1c for use in the control of Escherichia coli O157:H7. AB - This study investigated the effect of bacteriophages (phages) e11/2 and e4/1c against Escherichia coli O157:H7 in an ex vivo rumen model and in cattle in vivo. In the ex vivo rumen model, samples were inoculated with either 103 or 106 CFU/ml inoculum of E. coli O157:H7 and challenged separately with each bacteriophage. In the presence of phage e11/2, the numbers of E. coli O157:H7 bacteria were significantly (P < 0.05) reduced to below the limit of detection within 1 h. Phage e4/1c significantly (P < 0.05) reduced E. coli O157:H7 numbers within 2 h of incubation, but the number of surviving E. coli O157:H7 bacteria then remained unchanged over a further 22-h incubation period. The ability of a phage cocktail of e11/2 and e4/1c to reduce the fecal shedding of E. coli O157:H7 in experimentally inoculated cattle was then investigated in two cattle trials. Cattle (yearlings, n = 20 for trial one; adult fistulated cattle, n = 2 for trial two) were orally inoculated with 10(10) CFU of E. coli O157:H7. Animals (n = 10 for trial one; n = 1 for trial two) were dosed daily with a bacteriophage cocktail of 10(11) PFU for 3 days postinoculation. E. coli O157:H7 and phage numbers in fecal and/or rumen samples were determined over 7 days postinoculation. E. coli O157:H7 numbers rapidly declined in all animals within 24 to 48 h; however, there was no significant difference (P > 0.05) between the numbers of E. coli O157:H7 bacteria shed by the phage-treated or control animals. Phages were recovered from the rumen but not from the feces of the adult fistulated animal in trial two but were recovered from the feces of the yearling animals in trial one. While the results from the rumen model suggest that phages are effective in the rumen, further research is required to improve the antimicrobial effectiveness of phages for the elimination of E. coli O157:H7 in vivo. PMID- 20851994 TI - Engineering of Corynebacterium glutamicum with an NADPH-generating glycolytic pathway for L-lysine production. AB - A sufficient supply of NADPH is a critical factor in l-lysine production by Corynebacterium glutamicum. Endogenous NAD-dependent glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of C. glutamicum was replaced with nonphosphorylating NADP dependent glyceraldehyde 3-phosphate dehydrogenase (GapN) of Streptococcus mutans, which catalyzes the reaction of glyceraldehyde 3-phosphate to 3 phosphoglycerate with the reduction of NADP(+) to NADPH, resulting in the reconstruction of the functional glycolytic pathway. Although the growth of the engineered strain on glucose was significantly retarded, a suppressor mutant with an increased ability to utilize sugars was spontaneously isolated from the engineered strain. The suppressor mutant was characterized by the properties of GapN as well as the nucleotide sequence of the gene, confirming that no change occurred in either the activity or the basic properties of GapN. The suppressor mutant was engineered into an l-lysine-producing strain by plasmid-mediated expression of the desensitized lysC gene, and the performance of the mutant as an l-lysine producer was evaluated. The amounts of l-lysine produced by the suppressor mutant were larger than those produced by the reference strain (which was created by replacement of the preexisting gapN gene in the suppressor mutant with the original gapA gene) by ~70% on glucose, ~120% on fructose, and ~100% on sucrose, indicating that the increased l-lysine production was attributed to GapN. These results demonstrate effective l-lysine production by C. glutamicum with an additional source of NADPH during glycolysis. PMID- 20851996 TI - Transcriptional activation by pRB and its coordination with SWI/SNF recruitment. AB - A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility. Still, potential promoter targets of pRB and its role in normally differentiating osteoblasts remain insufficiently characterized. Here, an early marker of osteoblast differentiation, alkaline phosphatase, is identified as a direct promoter activation target of pRB. One role of pRB on this promoter is to displace the histone lysine demethylase KDM5A, thereby favoring trimethylation of H3K4, a promoter activation mark. A major new aspect of pRB-mediated transcriptional activation revealed in this promoter analysis is its role in recruitment of an activating SWI/SNF chromatin-remodeling complex. SWI/SNF is a critical coordinator of tissue-specific gene expression. In osteoblasts, SWI/SNF complexes containing the BRM ATPase repress osteoblast-specific genes to maintain the precursor state, whereas the alternative ATPase BRG1 distinguishes an activating SWI/SNF complex necessary for RNA polymerase-II recruitment. A switch from BRM to BRG1 on the alkaline phosphatase promoter marks the onset of differentiation and is accomplished in a precise two-step mechanism. Dissociation of BRM-containing SWI/SNF depends on p300, and association of BRG1-containing SWI/SNF depends on pRB. PMID- 20851995 TI - Characterization of bacterial community structure in a drinking water distribution system during an occurrence of red water. AB - The role of bacteria in the occasional emergence of red water, which has been documented worldwide, has yet to be determined. To better understand the mechanisms that drive occurrences of red water, the bacterial community composition and the relative abundance of several functional bacterial groups in a water distribution system of Beijing during a large-scale red water event were determined using several molecular methods. Individual clone libraries of the 16S rRNA gene were constructed for three red water samples and one sample of normal water. Beta-, Alpha-, and Gammaproteobacteria comprised the major bacterial communities in both red water and normal water samples, in agreement with previous reports. A high percentage of red water clones (25.2 to 57.1%) were affiliated with or closely related to a diverse array of iron-oxidizing bacteria, including the neutrophilic microaerobic genera Gallionella and Sideroxydans, the acidophilic species Acidothiobacillus ferrooxidans, and the anaerobic denitrifying Thermomonas bacteria. The genus Gallionella comprised 18.7 to 28.6% of all clones in the three red water libraries. Quantitative real-time PCR analysis showed that the 16S rRNA gene copy concentration of Gallionella spp. was between (4.1 +/- 0.9) * 107 (mean +/- standard deviation) and (1.6 +/- 0.3) * 108 per liter in red water, accounting for 13.1% +/- 2.9% to 17.2% +/- 3.6% of the total Bacteria spp. in these samples. By comparison, the percentages of Gallionella spp. in the normal water samples were 0.1% or lower (below the limit of detection), suggesting an important role of Gallionella spp. in the formation of red water. PMID- 20851993 TI - Detection of protozoan hosts for Legionella pneumophila in engineered water systems by using a biofilm batch test. AB - Legionella pneumophila proliferates in aquatic habitats within free-living protozoa, 17 species of which have been identified as hosts by using in vitro experiments. The present study aimed at identifying protozoan hosts for L. pneumophila by using a biofilm batch test (BBT). Samples (600 ml) collected from 21 engineered freshwater systems, with added polyethylene cylinders to promote biofilm formation, were inoculated with L. pneumophila and subsequently incubated at 37 degrees C for 20 days. Growth of L. pneumophila was observed in 16 of 18 water types when the host protozoan Hartmannella vermiformis was added. Twelve of the tested water types supported growth of L. pneumophila or indigenous Legionella anisa without added H. vermiformis. In 12 of 19 BBT flasks H. vermiformis was indicated as a host, based on the ratio between maximum concentrations of L. pneumophila and H. vermiformis, determined with quantitative PCR (Q-PCR), and the composition of clone libraries of partial 18S rRNA gene fragments. Analyses of 609 eukaryotic clones from the BBTs revealed that 68 operational taxonomic units (OTUs) showed the highest similarity to free-living protozoa. Forty percent of the sequences clustering with protozoa showed >=99.5% similarity to H. vermiformis. None of the other protozoa serving as hosts in in vitro studies were detected in the BBTs. In several tests with growth of L. pneumophila, the protozoa Diphylleia rotans, Echinamoeba thermarum, and Neoparamoeba sp. were identified as candidate hosts. In vitro studies are needed to confirm their role as hosts for L. pneumophila. Unidentified protozoa were implicated as hosts for uncultured Legionella spp. grown in BBT flasks at 15 degrees C. PMID- 20851997 TI - The miR-17-92 cluster of microRNAs confers tumorigenicity by inhibiting oncogene induced senescence. AB - In mammalian cells, activation of oncogenes usually triggers innate tumor suppressing defense mechanisms, including apoptosis and senescence, which are compromised by additional mutations before cancers are developed. The miR-17-92 gene cluster, a polycistron encoding six microRNAs (miRNA), is frequently overexpressed in human cancers and has been shown to promote several aspects of oncogenic transformation, including evasion of apoptosis. In the current study, we show a new role of miR-17-92 in inhibiting oncogenic ras-induced senescence. Further dissection of the miRNA components in this cluster reveals that the miR 17/20a seed family accounts for this antisenescence activity. miR-17 and miR-20a are both necessary and sufficient for conferring resistance to ras-induced senescence by directly targeting p21(WAF1), a key effector of senescence. By contrast, these components are not essential for the ability of miR-17-92 to evade Myc-induced apoptosis. Moreover, disruption of senescence by miR-17-92 or its miR-17/20a components leads to enhanced oncogenic transformation by activated ras in primary human cells. Taken together with previous reports that miR-17-92 inhibits apoptosis by suppressing Pten via the miR-19 components, our results indicate that this miRNA cluster promotes tumorigenesis by antagonizing both tumor-suppressing mechanisms, apoptosis, and senescence, through the activities of different miRNA components encoded in this cluster. PMID- 20851998 TI - A genetic mouse model of adult-onset, pervasive central nervous system demyelination with robust remyelination. AB - Adult-onset demyelinating disorders of the central nervous system represent the most common neurological abnormalities in young adults. Nevertheless, our understanding of disease pathogenesis and recovery in demyelinating disorders remains incomplete. To facilitate investigation into these processes, we have developed a new mouse model system that allows for the induction of dipththeria toxin A subunit expression in adult oligodendrocytes, resulting in widespread oligodendrocyte loss and demyelination of the central nervous system. These mice develop severe ataxia and tremor that correlates with impaired axonal conduction in the spinal cord. Strikingly, these animals fully recover from their motor and physiological defects and display extensive oligodendrocyte replenishment and widespread remyelination. This model system demonstrates the robust reparative potential of myelin in the central nervous system and provides a promising model for the quantitative assessment of therapeutic interventions that promote remyelination. PMID- 20851999 TI - Pharmaceutical waste: as in the Titanic we are only seeing the tip of the iceberg. PMID- 20852000 TI - Effect of kaolin addition on the performance of controlled low-strength material using industrial waste incineration bottom ash. AB - Incineration of industrial waste produces large quantities of bottom ash which are normally sent to secured landfill, but is not a sustainable solution. Use of bottom ash in engineering applications will contribute to sustainability and generate revenue. One way of using the industrial waste incineration bottom ash is in controlled low-strength material (CLSM). Use of bottom ash in CLSM has problems related to bleeding and excessive strength development and so an additive has to be used to control bleeding and strength development. The main objective of this research is to study the effect of kaolin addition on the performance of CLSM made using industrial waste incineration bottom ash. CLSM mixes were made with bottom ash, cement, and refined kaolin. Various tests were performed on the CLSM in fresh and hardened states including compressive strength, water absorption, California bearing ratio (CBR) and the tests for concentration of leachable substances on the bleed and leachate. The compressive strength of CLSM tested ranged from 0.11 to 9.86 MPa. CBR values ranged from 6 to 46, and water absorption values from 12 to 36%. It was shown that the addition of kaolin delayed the initial setting time of CLSM mixtures, reduced bleeding, lowered the compressive strength, and increased the values of water absorption, sorption, and initial surface absorption. The CLSM tested did not have corrosivity. It was shown that the hardened CLSM was non hazardous, and the addition of kaolin increased the concentration of heavy metals and salts in the bleed and leachate. PMID- 20852001 TI - Evaluation of pharmacokinetic interactions between amlodipine, valsartan, and hydrochlorothiazide in patients with hypertension. AB - The steady-state pharmacokinetic (PK) interaction potential between amlodipine (10 mg), valsartan (320 mg), and hydrochlorothiazide (HCTZ; 25 mg) was evaluated in patients with hypertension in a multicenter, multiple-dose, open-label, 4 cohort, parallel-group study. Eligible patients were randomly allocated to the dual combination of valsartan + HCTZ, amlodipine + valsartan, or amlodipine + HCTZ and nonrandomly allotted to amlodipine + valsartan + HCTZ triple combination treatment. After 6 days of treatment with a half-maximal dose of different combinations, patients were up-titrated to the maximal drug doses from day 7 through day 17. PK parameters of corresponding analytes from the triple- and dual treatment groups were estimated on day 17 and compared. Safety and tolerability of all treatments was assessed. The C ( ssmax ) and AUC(0-tau) values of amlodipine or HCTZ remained unaffected when administered with valsartan + HCTZ or valsartan + amlodipine, respectively. On the other hand, valsartan exposure increased by 10% to 25% when coadministered with HCTZ and amlodipine, which is not considered clinically relevant. In conclusion, there were no clinically relevant PK interactions with amlodipine, valsartan, and HCTZ triple combination compared with the corresponding dual combinations. All treatments were safe and well tolerated. PMID- 20852002 TI - Integrated population pharmacokinetics of etanercept in healthy subjects and in patients with rheumatoid arthritis and ankylosing spondylitis. AB - Etanercept pharmacokinetics in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis were assessed separately with distinct models using population pharmacokinetics methods of limited precision. The different model structures and associated significant covariates identified by these earlier methods made it difficult to compare etanercept pharmacokinetics among disease groups. This integrated analysis aimed to establish a framework to evaluate previously established population pharmacokinetic models of etanercept, and to identify consistent and important demographic and disease factors that affected etanercept pharmacokinetics in a diverse population of healthy subjects and patients with RA and AS. In this integrated analysis, cumulative rich and sparse etanercept concentration data from 53 healthy volunteers, 212 patients with RA, and 346 patients with AS were examined and compared using nonlinear mixed effect methodology implemented the in NONMEM VI software package. A more precise estimation method (FOCEi) was employed and compared with the first-order method in population pharmacokinetics model building and evaluation. The integrated analysis found that an optimal population pharmacokinetics model with a 2-compartment structure adequately characterized etanercept pharmacokinetics in all subject groups. Health status or disease type did not significantly affect etanercept pharmacokinetics. In adult patients with RA and AS, age and body weight do not significantly affect etanercept pharmacokinetics. PMID- 20852003 TI - Food effect and biocomparison of two formulations of the dual orexin receptor antagonist almorexant in healthy male subjects. PMID- 20852005 TI - Effect of number of replicate electrocardiograms recorded at each time point in a thorough QT study on sample size and study cost. AB - In a "thorough QT/QTc" (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within-subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost-effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day -1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject-specific (QTcI) formulas. Within-subject and between-subject standard deviations for QTcF obtained by repeated-measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within- and between-subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per-ECG and per-subject costs. PMID- 20852004 TI - A multicenter, randomized, open-label, pharmacokinetics and safety study of pantoprazole tablets in children and adolescents aged 6 through 16 years with gastroesophageal reflux disease. AB - Children with gastroesophageal reflux disease (GERD) may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug's kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged 6 to 11 years (study 1) and 12 to 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar to PK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults. PMID- 20852006 TI - Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation. AB - Raltegravir is an HIV-1 integrase strand transfer inhibitor with potent activity against HIV-1. A prior investigation of raltegravir coadministered with rifampin demonstrated a decrease in plasma concentrations of raltegravir likely secondary to induction of UGT1A1, the enzyme primarily responsible for the metabolism of raltegravir. Little is known regarding the induction of UGT1A1 by rifabutin, an alternate rifamycin. In vitro characterization of the induction potency of rifampin and rifabutin on UGT1A1 was performed. In vitro studies indicate that rifabutin is a less potent inducer of UGT1A1 messenger RNA expression than is rifampin. A fixed-sequence, 2-period, clinical crossover study was conducted to assess the effect of rifabutin on plasma levels of raltegravir: period 1, 400 mg of raltegravir every 12 hours for 4 days; period 2, 400 mg of raltegravir every 12 hours and 300 mg of rifabutin once daily for 14 days. Geometric mean ratio (GMR) (coadministration of rifabutin and raltegravir vs raltegravir alone) of raltegravir area under the concentration-time curve from 0 to 12 hours post dose (AUC(0-12h)) and the 90% confidence interval (CI) was 1.19 (0.86-1.63); GMR of concentration at 12 hours (C(12h)) and 90% CI was 0.80 (0.68-0.94); and GMR of time to maximal concentration (C(max)) and 90% CI was 1.39 (0.87-2.21). Overall, coadministration of rifabutin did not alter raltegravir pharmacokinetics to a clinically meaningful degree. PMID- 20852007 TI - Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. AB - BACKGROUND: Evidence for an association between selenium status and prostate cancer risk is still inconclusive. Anticarcinogenic effects of selenium are supposedly mediated through cellular protective and redox properties of selenoenzymes in vivo. We evaluated the association between serum selenium status and prostate cancer risk in a population with relative low selenium concentrations considering effect modification by genetic variants in selenoprotein genes. MATERIALS AND METHODS: A case-control study of 248 incident prostate cancer cases and 492 matched controls was nested within the EPIC Heidelberg cohort. Baseline blood samples were analyzed for serum selenium and selenoprotein P concentrations and glutathione peroxidase activity. Genotyping was carried out for SEP15 (rs5859, rs540049), SEPP1 (rs3877899, rs7579), GPX1 (rs1050450), and GPX4 (rs713041). Conditional logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: The OR for prostate cancer was 0.89 (95% CI, 0.79-1.01) per 10 MUg/L increase of serum selenium concentration. This association was modified by rs1050450 (C>T) in GPX1 (P(interaction) = 0.03), with carriers of one or two T alleles having a significantly reduced OR of 0.87 (95% CI, 0.76-0.99). Furthermore, there was an association between rs7579 genotype in SEPP1 and prostate cancer risk (OR, 1.72; 95% CI, 0.99-2.98). CONCLUSIONS: Our results support a role of selenium and polymorphisms in selenoenzymes in prostate cancer etiology, which warrants confirmation in future studies. IMPACT: These findings might help to explain biological effects of selenium in prostate cancer development in order to overcome inconsistencies arising from former studies. PMID- 20852008 TI - Associations of folate, vitamin B12, homocysteine, and folate-pathway polymorphisms with prostate-specific antigen velocity in men with localized prostate cancer. AB - BACKGROUND: Vitamin B(12), holo-haptocorrin, and the folate-pathway single nucleotide polymorphisms MTR 2756A>G and SHMT1 1420C>T have been associated with an increased risk of prostate cancer. We investigated whether these and other elements of folate metabolism were associated with prostate-specific antigen (PSA) velocity (PSAV) as a proxy measure of prostate cancer progression in men with localized prostate cancer. METHODS: We measured plasma folate, B(12), holo haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine at diagnosis in 424 men (ages 45-70 years) with localized prostate cancer in a U.K. wide population-based cohort. Thirteen folate-pathway single-nucleotide polymorphisms were genotyped for 311 of these men. Postdiagnosis PSAV (continuous measure and with a threshold set a priori at 2 ng/mL/y) was estimated from repeat PSA measurements. RESULTS: Median follow-up time was 2.5 (range, 0.8-5.6) years. Vitamin B(12), holo-haptocorrin, holo-transcobalamin, total transcobalamin, and total homocysteine were not associated with postdiagnosis PSAV. Folate was associated with an increased risk of PSAV >2 ng/mL/y [odds ratio (OR) per unit increase in log(e) concentration, 1.57; 95% confidence interval (95% CI), 0.98 2.51; P = 0.06]. MTRR 66A>G (rs1801394) was associated with a reduced risk (recessive model OR, 0.33; 95% CI, 0.11-0.97; P = 0.04), and SHMT1 1420C>T (rs1979277) with an increased risk (per-allele OR, 1.49; 95% CI, 0.93-2.37; P = 0.09) of PSAV >2 ng/mL/y. CONCLUSIONS: We found weak evidence that higher folate levels may be associated with faster progression of localized prostate cancer. IMPACT: Long-term follow-up is needed to test associations with metastases and mortality, and the observed genetic effects require replication. PMID- 20852009 TI - Forty years of faster decline in cigarette smoking in California explains current lower lung cancer rates. AB - BACKGROUND: Declining lung cancer rates in California have been attributed to the California Tobacco Control Program, but may reflect earlier declines in smoking. METHODS: Using state-taxed sales and three survey series, we assessed trends in smoking behavior for California and the rest of the nation from 1960 to 2008 and compared these with lung cancer mortality rates. We tested the validity of recent trends in state-taxed sales by projecting results from a model of the 1960 to 2002 data. RESULTS: From 1960 to 2002, the state-taxed sales and survey data are consistent. Californians initially smoked more than the rest of the nation, but cigarette consumption declined earlier, dropping lower in 1971 with an ever widening gap over time. Lung cancer mortality follows a similar pattern, after a lag of 16 years. Introduction of the California Tobacco Control Program doubled the rate of decline in cigarette consumption. From 2002 to 2008, differences in enforcement and tax evasion may compromise the validity of the taxed sales data. In 2010, smoking prevalence is estimated to be 9.3% in California and 17.8% in the rest of the nation. However, in 2008, for the first time, both cigarette price and tobacco control expenditures were lower in California than the rest of the nation, suggesting that the gap in smoking behavior will start to narrow. CONCLUSION: An effective Tobacco Control Program means that California will have faster declines in lung cancer than the rest of the nation for the next 2 decades, but possibly not beyond. IMPACT: Tobacco control interventions need further dissemination. PMID- 20852010 TI - Is discussion of colorectal cancer screening options associated with heightened patient confusion? AB - BACKGROUND: Clinical guidelines recommend offering patients options for colorectal cancer (CRC) screening, but the modalities vary by frequency, accuracy, preparations, discomfort, and cost, which may cause confusion and reduce screening rates. We examined whether patients reported confusion about the options and whether confusion was associated with socio-demographic characteristics, number of options discussed, and adherence. METHODS: Patients ages 50 to 75 years who had visited a clinician within 2 years were randomly selected for a cross-sectional study (n = 6,100). A questionnaire mailed in 2007 asked the following: whether a clinician had ever discussed CRC screening options; which of four recommended tests (i.e., fecal occult blood testing, flexible sigmoidoscopy, colonoscopy, and barium enema) were presented; and whether the options were confusing. Analyses were restricted to respondents who reported discussing one or more screening options (n = 1,707). Weighted frequencies were calculated and multivariate logistic regression was done. RESULTS: The sample was 55.5% female, 15.6% African American, and 83.2% adherent to screening recommendations, and 56.0% had discussed two or more screening options. In adjusted analyses, nonadherent patients reported greater confusion than adherent patients (P < 0.01). Adults who discussed two or more options were 1.6 times more likely to be confused than those who discussed one option [95% confidence interval (CI), 1.08-2.26]. Patients who reported being confused were 1.8 times more likely to be nonadherent to screening than those who did not (95% CI, 1.14-2.75). CONCLUSIONS: Our study provides the first empirical evidence linking multiple options with confusion and confusion with screening adherence. IMPACT: Confusion may act as a barrier to screening and should be considered in public health messages and interventions. PMID- 20852011 TI - Internet-facilitated commercial sexual exploitation of children: findings from a nationally representative sample of law enforcement agencies in the United States. AB - This article explores the variety of ways in which the Internet is used to facilitate the commercial sexual exploitation of children (CSEC) and provides national incidence estimates for the number of arrests involving such technology facilitated crimes in 2006. The National Juvenile Online Victimization Study is a nationally representative longitudinal study of more than 2,500 local, county, state, and federal law enforcement agencies across the United States. The current article utilizes Wave 2 data, which surveyed arrests in 2006 for Internet-related sex crimes against minors. Detailed data were collected via telephone interviews with investigators about 1,051 individual arrest cases. Findings show that an estimated 569 arrests for Internet-facilitated commercial sexual exploitation of children (IF-CSEC) occurred in the United States in 2006. Offenders in IF-CSEC cases fell into two main categories: (1) those who used the Internet to purchase or sell access to identified children for sexual purposes including child pornography (CP) production (36% of cases), and (2) those who used the Internet to purchase or sell CP images they possessed but did not produce (64% of cases). Offenders attempting to profit from child sexual exploitation were more likely than those who were purchasing to have (a) prior arrests for sexual and nonsexual offenses, (b) a history of violence, (c) produced CP, (d) joined forces with other offenders, and (e) involved female offenders. Although the number of arrests for IF-CSEC crimes is relatively small, the victims of these crimes are a high-risk subgroup of youth, and the offenders who try to profit from these crimes are particularly concerning from a child welfare perspective. PMID- 20852012 TI - Reconceptualizing the role of fear of falling and balance confidence in fall risk. AB - OBJECTIVE: This article aimed to critically examine preexisting conceptualizations of the relationship among fear of falling, falls efficacy, and falls and to offer a new theoretical model incorporating findings from the recent literature. METHOD: This is a theoretical article based on a review of preexisting findings pertaining to fear of falling and falls efficacy. RESULTS: Traditional conceptualizations consider avoidance of activity and deconditioning to be mediators in the relationship between fear of falling and falls, but recent findings suggest that this mediational conceptualization may not be accurate. Moreover, the terms falls efficacy and fear of falling are often used interchangeably in the literature, which is conceptually problematic. DISCUSSION: We conclude with the presentation and discussion of an alternative predictive model of fear of falling that incorporates important findings from the recent literature. PMID- 20852013 TI - Acculturation and depressive symptoms among Mexican American elders new to the caregiving role: results from the Hispanic-EPESE. AB - OBJECTIVE: The purpose of this study was to identify characteristics associated with becoming a caregiver among Mexican American (MA) elders and to examine predictors of depressive symptoms among the new caregivers 2 years later. METHOD: Drawn from the Hispanic Established Populations for Epidemiologic Studies of the Elderly (H-EPESE), 152 MA recent caregivers and 2,023 other MAs were compared. Residualized change regression analysis was conducted. RESULTS: At baseline, MAs who had recently become caregivers exhibited a significantly greater number of depressive symptoms compared to those who had not. Controlling for background characteristics, physical health, social support, and baseline depressive symptoms, regression analysis revealed that 2 years later higher acculturation was related to a greater number of depressive symptoms among those who at baseline were new caregivers. DISCUSSION: Better knowledge of the within-group differences among MA elderly caregivers, especially with respect to acculturation, may better inform interventions for this at-risk group. PMID- 20852014 TI - Art groups for marginalized women with breast cancer. AB - Professionally led support groups can significantly reduce distress, trauma symptoms, and pain for women with breast cancer. Despite the known benefits, women with breast cancer from marginalized groups tend not to participate in support groups. It is important to address barriers that prevent their participation and to identify types of support groups that appeal to as wide a range of women as possible. For this study, we interviewed women with breast cancer from marginalized groups in the San Francisco Bay Area (United States). We asked them about social, cultural, and psychological barriers that prevent participation in support groups, and about the potential of art groups to overcome these barriers. Our qualitative analysis of the interviews yielded findings that suggest a model for a type of support group that could make the benefits of support groups available to more women with breast cancer. PMID- 20852015 TI - Home care nurses' provision of support to families of the elderly at the end of life. AB - In this article we describe our study of assistance for family decisions and caregiving by Japanese home care nurses to families of elderly relatives at the end of life. The participants were 31 nurses who had been evaluated as providing good end-of-life care. We carried out semistructured interviews concerning the practice of family support in two cases (cancer and noncancer). We conducted a qualitative analysis using the constant comparative approach and derived several categories inductively. Home care nurses are responsible for (a) estimating the possibility of dying at home, (b) visualizing what is coming and what can be done, (c) proposing where and how the family can say goodbye, (d) building family consensus, (e) coordinating resources, and (f) offering psychological support for end-of-life care. End-of-life family care by home care nurses is a process in which multiple components of care are provided with changing content as death approaches. PMID- 20852016 TI - Psychosocial consequences of false-positive newborn screens for cystic fibrosis. AB - This study was designed to develop a framework for understanding parents' perspectives about the psychosocial consequences of false-positive newborn screening (NBS) results for cystic fibrosis (CF). Through content analysis of interviews with 87 parents of 44 infants, we found that receipt of genetic information through NBS affected parents on intrapersonal and interpersonal levels within a relational family system. Repercussions included wondering about test accuracy, the child's health, and the future; gaining new perspectives and strengthening relationships; questioning paternity; wondering if other relatives had CF/were carriers; searching for the genetic source; sharing genetic information; supporting NBS; and feeling empathy for parents of affected children. We concluded that abnormal NBS results that involve genetic testing can have psychosocial consequences that affect entire families. These findings merit additional investigation of long-term psychosocial sequelae for false-positive results, interventions to reduce adverse iatrogenic outcomes, and the relevance of the relational family system framework to other genetic testing. PMID- 20852017 TI - The bacterial pathogen Xanthomonas oryzae overcomes rice defenses by regulating host copper redistribution. AB - Pathogen effectors are virulence factors causing plant diseases. How the host targets of these effectors facilitate pathogen infection is largely unknown. An effector of Xanthomonas oryzae pv oryzae (Xoo) transcriptionally activates rice (Oryza sativa) susceptibility gene Xa13 to cause bacterial blight disease. Xa13 encodes an indispensable plasma membrane protein of the MtN3/saliva family, which is prevalent in eukaryotes with unknown biochemical function. We show that the XA13 protein cooperates with two other proteins, COPT1 and COPT5, to promote removal of copper from xylem vessels, where Xoo multiplies and spreads to cause disease. Copper, an essential micronutrient of plants and an important element for a number of pesticides in agriculture, suppresses Xoo growth. Xoo strain PXO99 is more sensitive to copper than other strains; its infection of rice is associated with activation of XA13, COPT1, and COPT5, which modulate copper redistribution in rice. The involvement of XA13 in copper redistribution has led us to propose a mechanism of bacterial virulence. PMID- 20852018 TI - Copper transport and bacterial pathogenesis in rice. PMID- 20852020 TI - The Chlorella genome: big surprises from a small package. PMID- 20852019 TI - The Chlorella variabilis NC64A genome reveals adaptation to photosymbiosis, coevolution with viruses, and cryptic sex. AB - Chlorella variabilis NC64A, a unicellular photosynthetic green alga (Trebouxiophyceae), is an intracellular photobiont of Paramecium bursaria and a model system for studying virus/algal interactions. We sequenced its 46-Mb nuclear genome, revealing an expansion of protein families that could have participated in adaptation to symbiosis. NC64A exhibits variations in GC content across its genome that correlate with global expression level, average intron size, and codon usage bias. Although Chlorella species have been assumed to be asexual and nonmotile, the NC64A genome encodes all the known meiosis-specific proteins and a subset of proteins found in flagella. We hypothesize that Chlorella might have retained a flagella-derived structure that could be involved in sexual reproduction. Furthermore, a survey of phytohormone pathways in chlorophyte algae identified algal orthologs of Arabidopsis thaliana genes involved in hormone biosynthesis and signaling, suggesting that these functions were established prior to the evolution of land plants. We show that the ability of Chlorella to produce chitinous cell walls likely resulted from the capture of metabolic genes by horizontal gene transfer from algal viruses, prokaryotes, or fungi. Analysis of the NC64A genome substantially advances our understanding of the green lineage evolution, including the genomic interplay with viruses and symbiosis between eukaryotes. PMID- 20852021 TI - Aspergillus fumigatus flbB encodes two basic leucine zipper domain (bZIP) proteins required for proper asexual development and gliotoxin production. AB - The opportunistic human pathogen Aspergillus fumigatus reproduces asexually by forming a massive number of mitospores called conidia. In this study, we characterize the upstream developmental regulator A. fumigatus flbB (AfuflbB). Northern blotting and cDNA analyses reveal that AfuflbB produces two transcripts predicted to encode two basic leucine zipper domain (bZIP) polypeptides, AfuFlbBbeta (420 amino acids [aa]) and AfuFlbBalpha (390 aa). The deletion of AfuflbB results in delayed/reduced sporulation, precocious cell death, the lack of conidiophore development in liquid submerged culture, altered expression of AfubrlA and AfuabaA, and blocked production of gliotoxin. While introduction of the wild-type (WT) AfuflbB allele fully complemented these defects, disruption of the ATG start codon for either one of the AfuFlbB polypeptides leads to a partial complementation, indicating the need of both polypeptides for WT levels of asexual development and gliotoxin biogenesis. Consistent with this, Aspergillus nidulans flbB(+) encoding one polypeptide (426 aa) partially complements the AfuflbB null mutation. The presence of 0.6 M KCl in liquid submerged culture suppresses the defects caused by the lack of one, but not both, of the AfuFlbB polypeptides, suggesting a genetic prerequisite for AfuFlbB in A. fumigatus development. Finally, Northern blot analyses reveal that both AfuflbB and AfuflbE are necessary for expression of AfuflbD, suggesting that FlbD functions downstream of FlbB/FlbE in aspergilli. PMID- 20852022 TI - Characterization of glycoside hydrolase family 5 proteins in Schizosaccharomyces pombe. AB - In yeast, enzymes with beta-glucanase activity are thought to be necessary in morphogenetic events that require controlled hydrolysis of the cell wall. Comparison of the sequence of the Saccharomyces cerevisiae exo-beta(1,3) glucanase Exg1 with the Schizosaccharomyces pombe genome allowed the identification of three genes that were named exg1(+) (locus SPBC1105.05), exg2(+) (SPAC12B10.11), and exg3(+) (SPBC2D10.05). The three proteins have different localizations: Exg1 is secreted to the periplasmic space, Exg2 is a membrane protein, and Exg3 is a cytoplasmic protein. Characterization of the biochemical activity of the proteins indicated that Exg1 and Exg3 are active only against beta(1,6)-glucans while no activity was detected for Exg2. Interestingly, Exg1 cleaves the glucans with an endohydrolytic mode of action. exg1(+) showed periodic expression during the cell cycle, with a maximum coinciding with the septation process, and its expression was dependent on the transcription factor Sep1. The Exg1 protein localizes to the septum region in a pattern that was different from that of the endo-beta(1,3)-glucanase Eng1. Overexpression of Exg2 resulted in an increase in cell wall material at the poles and in the septum, but the putative catalytic activity of the protein was not required for this effect. PMID- 20852024 TI - The use of SSMD-based false discovery and false nondiscovery rates in genome scale RNAi screens. AB - In genome-scale RNA interference (RNAi) screens, it is critical to control false positives and false negatives statistically. Traditional statistical methods for controlling false discovery and false nondiscovery rates are inappropriate for hit selection in RNAi screens because the major goal in RNAi screens is to control both the proportion of short interfering RNAs (siRNAs) with a small effect among selected hits and the proportion of siRNAs with a large effect among declared nonhits. An effective method based on strictly standardized mean difference (SSMD) has been proposed for statistically controlling false discovery rate (FDR) and false nondiscovery rate (FNDR) appropriate for RNAi screens. In this article, the authors explore the utility of the SSMD-based method for hit selection in RNAi screens. As demonstrated in 2 genome-scale RNAi screens, the SSMD-based method addresses the unmet need of controlling for the proportion of siRNAs with a small effect among selected hits, as well as controlling for the proportion of siRNAs with a large effect among declared nonhits. Furthermore, the SSMD-based method results in reasonably low FDR and FNDR for selecting inhibition or activation hits. This method works effectively and should have a broad utility for hit selection in RNAi screens with replicates. PMID- 20852025 TI - Capillary wells microplate with side optical access. AB - The presence of bubbles in liquid samples residing in microplate wells causes inaccuracies in fluorescence measurements. In addition, pipetting errors, if not adequately managed, can result in misleading data and wrong interpretations of assay results, particularly in the context of high-throughput screening. In this work, the authors describe an adapted design to the capillary wells microplate approach that permits side viewing. They demonstrate a prototype that detects bubbles and pipetting errors during actual assay runs to ensure accuracy in screening. PMID- 20852023 TI - The antiretroviral lectin cyanovirin-N targets well-known and novel targets on the surface of Entamoeba histolytica trophozoites. AB - Entamoeba histolytica, the protist that causes amebic dysentery and liver abscess, has a truncated Asn-linked glycan (N-glycan) precursor composed of seven sugars (Man(5)GlcNAc(2)). Here, we show that glycoproteins with unmodified N glycans are aggregated and capped on the surface of E. histolytica trophozoites by the antiretroviral lectin cyanovirin-N and then replenished from large intracellular pools. Cyanovirin-N cocaps the Gal/GalNAc adherence lectin, as well as glycoproteins containing O-phosphodiester-linked glycans recognized by an anti proteophosphoglycan monoclonal antibody. Cyanovirin-N inhibits phagocytosis by E. histolytica trophozoites of mucin-coated beads, a surrogate assay for amebic virulence. For technical reasons, we used the plant lectin concanavalin A rather than cyanovirin-N to enrich secreted and membrane proteins for mass spectrometric identification. E. histolytica glycoproteins with occupied N-glycan sites include Gal/GalNAc lectins, proteases, and 17 previously hypothetical proteins. The latter glycoproteins, as well as 50 previously hypothetical proteins enriched by concanavalin A, may be vaccine targets as they are abundant and unique. In summary, the antiretroviral lectin cyanovirin-N binds to well-known and novel targets on the surface of E. histolytica that are rapidly replenished from large intracellular pools. PMID- 20852026 TI - Deletion of Pten in pancreatic beta-cells protects against deficient beta-cell mass and function in mouse models of type 2 diabetes. AB - OBJECTIVE: Type 2 diabetes is characterized by diminished pancreatic beta-cell mass and function. Insulin signaling within the beta-cells has been shown to play a critical role in maintaining the essential function of the beta-cells. Under basal conditions, enhanced insulin-PI3K signaling via deletion of phosphatase with tensin homology (PTEN), a negative regulator of this pathway, leads to increased beta-cell mass and function. In this study, we investigated the effects of prolonged beta-cell-specific PTEN deletion in models of type 2 diabetes. RESEARCH DESIGN AND METHODS: Two models of type 2 diabetes were employed: a high fat diet (HFD) model and a db/db model that harbors a global leptin-signaling defect. A Cre-loxP system driven by the rat insulin promoter (RIP) was employed to obtain mice with beta-cell-specific PTEN deletion (RIPcre(+) Pten(fl/fl)). RESULTS: PTEN expression in islets was upregulated in both models of type 2 diabetes. RIPcre(+) Pten(fl/fl) mice were completely protected against diabetes in both models of type 2 diabetes. The islets of RIPcre(+) Pten(fl/fl) mice already exhibited increased beta-cell mass under basal conditions, and there was no further increase under diabetic conditions. Their beta-cell function and islet PI3K signaling remained intact, in contrast to HFD-fed wild-type and db/db islets that exhibited diminished beta-cell function and attenuated PI3K signaling. These protective effects in beta-cells occurred in the absence of compromised response to DNA-damaging stimuli. CONCLUSIONS: PTEN exerts a critical negative effect on both beta-cell mass and function. Thus PTEN inhibition in beta-cells can be a novel therapeutic intervention to prevent the decline of beta-cell mass and function in type 2 diabetes. PMID- 20852027 TI - Effects of PNPLA3 on liver fat and metabolic profile in Hispanic children and adolescents. AB - OBJECTIVE: A genome-wide study of adults identified a variant of PNPLA3 (rs738409) associated with ~twofold higher liver fat. The purpose of this study was to examine the influence of PNPLA3 genotype on liver fat and other related metabolic outcomes in obese Hispanic children and adolescents. RESEARCH DESIGN AND METHODS: Three hundred and twenty-seven Hispanics aged 8-18 years were genotyped for rs738409. One hundred and eighty-eight subjects had measures of visceral (VAT) and subcutaneous (SAT) adipose tissue volume and hepatic (HFF) and pancreatic (PFF) fat fraction by magnetic resonance imaging. One hundred and thirty-nine subjects did not have HFF measures but had extensive measures of insulin sensitivity and fasting lipids. RESULTS: Liver fat in GG subjects was 1.7 and 2.4 times higher than GC and CC (11.1 +/- 0.8% in GG vs. 6.6 +/- 0.7% in GC and 4.7 +/- 0.9% in CC; P < 0.0001), and this effect was observed even in the youngest children (8-10 years of age). The variant was not associated with VAT, SAT, PFF, or insulin sensitivity or other glucose/insulin indexes. However, Hispanic children carrying the GG genotype had significantly lower HDL cholesterol (40.9 +/- 10.9 in CC vs. 37.0 +/- 8.3 in CG vs. 35.7 +/- 7.4 in GG; P = 0.03) and a tendency toward lower free fatty acid levels (P = 0.06). CONCLUSIONS: These results provide new evidence that the effect of the PNPLA3 variant is apparent in Hispanic children and adolescents, is unique to fat deposition in liver as compared with other ectopic depots examined, and is associated with lower HDL cholesterol. PMID- 20852028 TI - Metformin treatment may increase omentin-1 levels in women with polycystic ovary syndrome. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with the metabolic syndrome. Decreased omentin-1 levels are associated with obesity and diabetes. To study the effects of metformin treatment on omentin-1 levels in PCOS subjects and effects of omentin-1 on in vitro migration and angiogenesis. RESEARCH DESIGN AND METHODS: Serum omentin-1 was measured by ELISA. Angiogenesis was assessed by studying capillary tube formation in human microvascular endothelial cells (HMEC 1) on growth factor reduced Matrigel. Endothelial cell migration assay was performed in a modified Boyden chamber. Nuclear factor-kappaB (NF-kappaB) was studied by stably transfecting HMEC-1 cells with a cis-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-kappaB binding sites. Akt phosphorylation was assessed by Western blotting. RESULTS: Serum omentin-1 was significantly lower in PCOS women (P < 0.05). After 6 months of metformin treatment, there was a significant increase in serum omentin-1 (P < 0.01). Importantly, changes in hs-CRP were significantly negatively correlated with changes in serum omentin-1 (P = 0.036). In vitro migration and angiogenesis were significantly increased in serum from PCOS women (P < 0.01) compared with matched control subjects; these effects were significantly attenuated by metformin treatment (P < 0.01) plausibly through the regulation of omentin-1 levels via NF-kappaB and Akt pathways. CRP and VEGF induced in vitro migration, and angiogenesis was significantly decreased by omentin-1. CONCLUSIONS: Increases in omentin-1 levels may play a role but are not sufficient to explain the decreased inflammatory and angiogenic effects of sera from metformin-treated PCOS women. PMID- 20852030 TI - Impact of BMI and the metabolic syndrome on the risk of diabetes in middle-aged men. AB - OBJECTIVE: The existence of an obese subgroup with a healthy metabolic profile and low diabetes risk has been proposed; yet long-term data are lacking. We aimed to investigate associations between combinations of BMI categories and metabolic syndrome and risk of type 2 diabetes in middle-aged men. RESEARCH DESIGN AND METHODS: At age 50, cardiovascular risk factors were assessed in 1,675 participants without diabetes in the community-based Uppsala Longitudinal Study of Adult Men (ULSAM) study. According to BMI/metabolic syndrome status, they were categorized as normal weight (BMI <25 kg/m2) without metabolic syndrome (National Cholesterol Education Program criteria, n = 853), normal weight with metabolic syndrome (n = 60), overweight (BMI 25-30 kg/m2) without metabolic syndrome (n = 557), overweight with metabolic syndrome (n = 117), obese (BMI >30 kg/m2) without metabolic syndrome (n = 28), and obese with metabolic syndrome (n = 60). We investigated the associations between BMI/metabolic syndrome categories at baseline and diabetes incidence. RESULTS: After 20 years, 160 participants had developed diabetes. In logistic regression models adjusting for age, smoking, and physical activity, increased risks for diabetes were observed in the normal weight with metabolic syndrome (odds ratio 3.28 [95% CI] 1.38-7.81; P = 0.007), overweight without metabolic syndrome (3.49 [2.26-5.42]; P < 0.001), overweight with metabolic syndrome (7.77 [4.44-13.62]; P < 0.001), obese without metabolic syndrome (11.72 [4.88-28.16]; P < 0.001), and obese with metabolic syndrome (10.06 [5.19-19.51]; P < 0.001) categories compared with the normal weight without metabolic syndrome category. CONCLUSIONS: Overweight or obese men without metabolic syndrome were at increased risk for diabetes. Our data provide further evidence that overweight and obesity in the absence of the metabolic syndrome should not be considered a harmless condition. PMID- 20852029 TI - Candesartan attenuates diabetic retinal vascular pathology by restoring glyoxalase-I function. AB - OBJECTIVE: Advanced glycation end products (AGEs) and the renin-angiotensin system (RAS) are both implicated in the development of diabetic retinopathy. How these pathways interact to promote retinal vasculopathy is not fully understood. Glyoxalase-I (GLO-I) is an enzyme critical for the detoxification of AGEs and retinal vascular cell survival. We hypothesized that, in retina, angiotensin II (Ang II) downregulates GLO-I, which leads to an increase in methylglyoxal-AGE formation. The angiotensin type 1 receptor blocker, candesartan, rectifies this imbalance and protects against retinal vasculopathy. RESEARCH DESIGN AND METHODS: Cultured bovine retinal endothelial cells (BREC) and bovine retinal pericytes (BRP) were incubated with Ang II (100 nmol/l) or Ang II+candesartan (1 MUmol/l). Transgenic Ren-2 rats that overexpress the RAS were randomized to be nondiabetic, diabetic, or diabetic+candesartan (5 mg/kg/day) and studied over 20 weeks. Comparisons were made with diabetic Sprague-Dawley rats. RESULTS: In BREC and BRP, Ang II induced apoptosis and reduced GLO-I activity and mRNA, with a concomitant increase in nitric oxide (NO(*)), the latter being a known negative regulator of GLO-I in BRP. In BREC and BRP, candesartan restored GLO-I and reduced NO(*). Similar events occurred in vivo, with the elevated RAS of the diabetic Ren-2 rat, but not the diabetic Sprague-Dawley rat, reducing retinal GLO I. In diabetic Ren-2 rats, candesartan reduced retinal acellular capillaries, inflammation, and inducible nitric oxide synthase and NO(*), and restored GLO-I. CONCLUSIONS: We have identified a novel mechanism by which candesartan improves diabetic retinopathy through the restoration of GLO-I. PMID- 20852031 TI - Metabolic syndrome, brain magnetic resonance imaging, and cognition. AB - OBJECTIVE: We explored cognitive impairment in metabolic syndrome in relation to brain magnetic resonance imaging (MRI) findings. RESEARCH DESIGN AND METHODS: We studied 819 participants free of clinical stroke and dementia of the population based Austrian Stroke Prevention Study who had undergone brain MRI, neuropsychological testing, and a risk factor assessment relevant to National Cholesterol Education Program Adult Treatment Panel III criteria-defined metabolic syndrome. High-sensitivity C-reactive protein (hs-CRP) was also determined. RESULTS: Of 819 subjects, 232 (28.3%) had metabolic syndrome. They performed worse than those without metabolic syndrome on cognitive tests assessing memory and executive functioning after adjustment for possible confounders. Stratification by sex demonstrated that metabolic syndrome was related to cognitive dysfunction in men but not in women. Only in men was an increasing number of metabolic syndrome components associated with worse cognitive performance. MRI showed no significant differences in focal ischemic lesions and brain volume between subjects with and without metabolic syndrome, and MRI abnormalities failed to explain impaired cognition. Cognitive performance was most affected in male subjects with metabolic syndrome who also had high hs CRP levels. CONCLUSIONS: Metabolic syndrome exerts detrimental effects on memory and executive functioning in community-dwelling subjects who have not had a clinical stroke or do not have dementia. Men are more affected than women, particularly if they have high inflammatory markers. MRI-detected brain abnormalities do not play a crucial role in these relationships. PMID- 20852032 TI - Characterization of the beta-carotene hydroxylase gene DSM2 conferring drought and oxidative stress resistance by increasing xanthophylls and abscisic acid synthesis in rice. AB - Drought is a major limiting factor for crop production. To identify critical genes for drought resistance in rice (Oryza sativa), we screened T-DNA mutants and identified a drought-hypersensitive mutant, dsm2. The mutant phenotype was caused by a T-DNA insertion in a gene encoding a putative beta-carotene hydroxylase (BCH). BCH is predicted for the biosynthesis of zeaxanthin, a carotenoid precursor of abscisic acid (ABA). The amounts of zeaxanthin and ABA were significantly reduced in two allelic dsm2 mutants after drought stress compared with the wild type. Under drought stress conditions, the mutant leaves lost water faster than the wild type and the photosynthesis rate, biomass, and grain yield were significantly reduced, whereas malondialdehyde level and stomata aperture were increased in the mutant. The mutant is also hypersensitive to oxidative stresses. The mutant had significantly lower maximal efficiency of photosystem II photochemistry and nonphotochemical quenching capacity than the wild type, indicating photoinhibition in photosystem II and decreased capacity for eliminating excess energy by thermal dissipation. Overexpression of DSM2 in rice resulted in significantly increased resistance to drought and oxidative stresses and increases of the xanthophylls and nonphotochemical quenching. Some stress-related ABA-responsive genes were up-regulated in the overexpression line. DSM2 is a chloroplast protein, and the response of DSM2 to environmental stimuli is distinctive from the other two BCH members in rice. We conclude that the DSM2 gene significantly contributes to control of the xanthophyll cycle and ABA synthesis, both of which play critical roles in the establishment of drought resistance in rice. PMID- 20852034 TI - Cannabinoid CB1 receptor is downregulated in clear cell renal cell carcinoma. AB - Several studies in cell cultures and in animal models have demonstrated that cannabinoids have important antitumoral properties. Because many of these effects are mediated through cannabinoid (CB) receptors CB1 and CB2, the study of their expression in human neoplasms has become of great interest in recent years. Fresh and formalin-fixed tissue samples of 20 consecutive clear cell renal cell carcinomas (CCRCCs) were collected prospectively and analyzed for the expression of both CB receptors by using RT-PCR, Western blot (WB), and immunohistochemical techniques. RT-PCR assays demonstrated the expression of mRNA encoding the CB1 in tumor tissue and in adjacent non-neoplastic kidney. Conversely, WB and IHC revealed a marked downregulation of CB1 protein in tumor tissue; CB2 was not expressed. The obtained data suggest a possible implication of the endocannabinoid system in renal carcinogenesis. A posttranscriptional downregulation of CB1 and the absence of expression of CB2 characterize CCRCC. PMID- 20852036 TI - Controls for immunocytochemistry: an update. AB - Immunocytochemistry is a highly productive method in biomedical research used to identify proteins and other macromolecules in tissues and cells. Control samples are required to show label localization is correct, but the understanding and use of immunocytochemistry controls have been inconsistent. A new classification of immunocytochemical controls is proposed that will help in understanding this most important component of the experiment. The three types of controls required for immunocytochemistry are primary antibody controls that show the specificity of the primary antibody binding to the antigen, secondary antibody controls that show the label is specific to the primary antibody, and label controls that show the labeling is the result of the label added and not the result of endogenous labeling. Publications containing immunocytochemical results must give details of how these controls were performed. PMID- 20852035 TI - Overexpression and gender-specific differences of SRC-3 (SRC-3/AIB1) immunoreactivity in human non-small cell lung cancer: an in vivo study. AB - Steroid receptor coactivator-3 (SRC-3) has been reported to be overexpressed in the development and progression of many tumor types. SRC-3 has been detected in several lung cancer cell lines, but its expression and clinical significance in non-small cell lung cancer (NSCLC) remain unclear. In this study, 48 NSCLC tissues were collected and tissue microarrays were performed. The expression of SRC-3 was examined using nickel-intensified IHC. The results showed that of these 48 cases, 18 (37.5%) exhibited high levels of SRC-3 immunoreactivity, 23 (47.9%) exhibited moderate levels of SRC-3 immunoreactivity, and 7 (14.6%) were negative; thus, the total frequency of SRC-3 overexpression was 85.4% (41/48). This SRC-3 overexpression frequency was similar to the overexpression frequency observed for squamous cell carcinoma and adenocarcinoma (82.1% vs 90%) and for metastasis and non-metastasis patients (84.6% vs 85.7%). Data analysis demonstrated a significantly higher overexpression frequency in male patients compared with that in female patients (88.6% vs 76.9%). However, female patients tended to have higher expression levels of SRC-3, as measured by immunoreactivity, than male patients. These results demonstrate a high frequency of SRC-3 overexpression in NSCLC with a gender difference, suggesting that there is a specific role for SRC 3 in the pathogenesis of NSCLC. PMID- 20852038 TI - Exercise in hypertension: do skeletal muscle reflexes make this a dangerous proposition? PMID- 20852037 TI - Site-specific differences in gene expression of secreted proteins in the mouse lung: comparison of methods to show differences by location. AB - Studies on the effects of pulmonary toxicants on the lung often overlook the fact that site-specific changes are likely to occur in response to chemical exposure. These changes can be highly focal and may be undetected by methods that do not examine specific lung regions. This problem is especially acute for studies of the conducting airways. In this study, differential gene expression of secreted proteins in the lung by different methods of collection (whole lung, gross airway microdissection, and laser capture microdissection) and by airway levels (whole lobe, whole airway tree, proximal airways, airway bifurcations, and terminal bronchioles) was examined. Site-specific sampling approaches were combined with methods to detect both gene and corresponding protein expression in different lung regions. Differential expression of mRNA by both airway level and lung region was determined for Clara cell secretory protein, calcitonin gene-related peptide, uteroglobin-related protein 2, surfactant protein A, and surfactant protein C. Therefore, for maximal enrichment of mRNA and maximal ability to identify changes in mRNA levels in the diseased state or in response to chemical exposure, it is critical to choose the appropriate airway region and sample collection method to enrich detection of the transcript(s) of interest. PMID- 20852039 TI - Adenine nucleotide control of coronary blood flow during exercise. AB - The adenine nucleotide hypothesis postulates that the ATP released from red blood cells is broken down to ADP and AMP in coronary capillaries and that ATP, ADP, and AMP act on purinergic receptors on the surface of capillary endothelial cells. Purinergic receptor activation initiates a retrograde conducted vasodilator signal to the upstream arteriole that controls coronary blood flow in a negative feedback manner. A previous study (M. Farias 3rd, M. W. Gorman, M. V. Savage, and E. O. Feigl, Am J Physiol Heart Circ Physiol 288: H1586-H1590, 2005) demonstrated that coronary venous plasma ATP concentration increased during exercise and correlated with coronary blood flow. The present experiments test the adenine nucleotide hypothesis by examining the balance between oxygen delivery (via coronary blood flow) and myocardial oxygen consumption during exercise before and after purinergic receptor blockade. Dogs (n = 7) were chronically instrumented with catheters in the aorta and coronary sinus and a flow transducer around the circumflex coronary artery. During control treadmill exercise, myocardial oxygen consumption increased and the balance between oxygen delivery and myocardial oxygen consumption fell as indicated by a declining coronary venous oxygen tension. Blockade of P1 and P2Y(1) purinergic receptors combined with inhibition of nitric oxide synthesis significantly decreased the balance between oxygen delivery and myocardial oxygen consumption compared with control. The results support the hypothesis that ATP and its breakdown products ADP and AMP are part of a negative feedback control mechanism that matches coronary blood flow to myocardial oxygen consumption at rest and during exercise. PMID- 20852040 TI - The role of collagen in extralobar pulmonary artery stiffening in response to hypoxia-induced pulmonary hypertension. AB - Hypoxic pulmonary hypertension (HPH) causes extralobar pulmonary artery (PA) stiffening, which potentially impairs right ventricular systolic function. Changes in the extracellular matrix proteins collagen and elastin have been suggested to contribute to this arterial stiffening. We hypothesized that vascular collagen accumulation is a major cause of extralobar PA stiffening in HPH and tested our hypothesis with transgenic mice that synthesize collagen type I resistant to collagenase degradation (Col1a1(R/R)). These mice and littermate controls that have normal collagen degradation (Col1a1(+/+)) were exposed to hypoxia for 10 days; some were allowed to recover for 32 days. In vivo PA pressure and isolated PA mechanical properties and collagen and elastin content were measured for all groups. Vasoactive studies were also performed with U 46619, Y-27632, or calcium- and magnesium-free medium. Pulmonary hypertension occurred in both mouse strains due to chronic hypoxia and resolved with recovery. HPH caused significant PA mechanical changes in both mouse strains: circumferential stretch decreased, and mid-to-high-strain circumferential elastic modulus increased (P < 0.05 for both). Impaired collagen type I degradation prevented a return to baseline mechanical properties with recovery and, in fact, led to an increase in the low and mid-to-high-strain moduli compared with hypoxia (P < 0.05 for both). Significant changes in collagen content were found, which tended to follow changes in mid-to-high-strain elastic modulus. No significant changes in elastin content or vasoactivity were observed. Our results demonstrate that collagen content is important to extralobar PA stiffening caused by chronic hypoxia. PMID- 20852042 TI - Baroreceptor and chemoreceptor contributions to the hypertensive response to bilateral carotid occlusion in conscious mice. AB - This study aimed to characterize the role played by baroreceptors and chemoreceptors in the hypertensive response to bilateral carotid occlusion (BCO) in conscious C57BL mice. On the day before the experiments the animals were implanted with pneumatic cuffs around their common carotid arteries and a femoral catheter for measurement of arterial pressure. Under the same surgical approach, groups of mice were submitted to aortic or carotid sinus denervation or sham surgery. BCO was performed for 30 or 60 s, promoting prompt and sustained increase in mean arterial pressure and fall in heart rate. Compared with intact mice, the hypertensive response to 30 s of BCO was enhanced in aortic-denervated mice (52 +/- 4 vs. 41 +/- 4 mmHg; P < 0.05) but attenuated in carotid sinus denervated mice (15 +/- 3 vs. 41 +/- 4 mmHg; P < 0.05). Suppression of peripheral chemoreceptor activity by hyperoxia [arterial partial pressure of oxygen (Pa(O(2))) > 500 mmHg] attenuated the hypertensive response to BCO in intact mice (30 +/- 6 vs. 51 +/- 5 mmHg in normoxia; P < 0.05) and abolished the bradycardia. It did not affect the hypertensive response in carotid sinus-denervated mice (20 +/- 4 vs. 18 +/- 3 mmHg in normoxia; P < 0.05). The attenuation of the hypertensive response to BCO by carotid sinus denervation or hyperoxia indicates that the hypertensive response in conscious mice is mediated by both baro- and chemoreceptors. In addition, aortic denervation potentiates the hypertensive response elicited by BCO in conscious mice. PMID- 20852041 TI - Impaired relaxation of cerebral arteries in the absence of elevated salt intake in normotensive congenic rats carrying the Dahl salt-sensitive renin gene. AB - This study evaluated endothelium-dependent vascular relaxation in response to acetylcholine (ACh) in isolated middle cerebral arteries (MCA) from Dahl salt sensitive (Dahl SS) rats and three different congenic strains that contain a portion of Brown Norway (BN) chromosome 13 introgressed onto the Dahl SS genetic background through marker-assisted breeding. Two of the congenic strains carry a 3.5-Mbp portion and a 2.6-Mbp portion of chromosome 13 that lie on opposite sides of the renin locus, while the third contains a 2.0-Mbp overlapping region that includes the BN renin allele. While maintained on a normal salt (0.4% NaCl) diet, MCAs from Dahl SS rats and the congenic strains retaining the Dahl SS renin allele failed to dilate in response to ACh, whereas MCAs from the congenic strain carrying the BN renin allele exhibited normal vascular relaxation. In congenic rats receiving the BN renin allele, vasodilator responses to ACh were eliminated by nitric oxide synthase inhibition with N(G)-nitro-l-arginine methyl ester, angiotensin-converting enzyme inhibition with captopril, and AT(1) receptor blockade with losartan. N(G)-nitro-l-arginine methyl ester-sensitive vasodilation in response to ACh was restored in MCAs of Dahl SS rats that received either a 3 day infusion of a subpressor dose of angiotensin II (3 ng.kg(-1).min(-1) iv), or chronic treatment with the superoxide dismutase mimetic tempol (15 mg.kg(-1).day( 1)). These findings indicate that the presence of the Dahl SS renin allele plays a crucial role in endothelial dysfunction present in the cerebral circulation of the Dahl SS rat, even in the absence of elevated dietary salt intake, and that introgression of the BN renin allele rescues endothelium-dependent vasodilator responses by restoring normal activation of the renin-angiotensin system. PMID- 20852043 TI - Increased C-reactive protein expression exacerbates left ventricular dysfunction and remodeling after myocardial infarction. AB - We previously reported serum C-reactive protein (CRP) elevation after acute myocardial infarction (MI) to be associated with adverse outcomes including cardiac rupture, left ventricular (LV) remodeling, and cardiac death. Experimental studies have indicated that CRP per se has various biological actions including proinflammatory and proapoptotic effects, suggesting a pathogenic role of CRP in the post-MI remodeling process. We tested the hypothesis that increased CRP expression would exacerbate adverse LV remodeling after MI via deleterious effects of CRP. Transgenic mice with human CRP expression (CRP-Tg) and their transgene-negative littermates (control) underwent left coronary artery ligation. There was no apparent difference in phenotypic features between CRP-Tg and control mice before MI. Although mortality and infarct size were similar in the two groups, CRP-Tg mice showed more LV dilation and worse LV function with more prominent cardiomyocyte hypertrophy and fibrosis in the noninfarcted regions after MI than controls. Histological evaluation conducted 1 wk post-MI revealed a higher rate of apoptosis and more macrophage infiltration in the border zones of infarcted hearts from CRP-Tg mice in relation to increased monocyte chemotactic protein (MCP)-1 expression and matrix metalloproteinase (MMP)-9 activity. Increased CRP expression exacerbates LV dysfunction and promotes adverse LV remodeling after MI in mice. The deleterious effect of CRP on post-MI LV remodeling may be associated with increased apoptotic rates, macrophage infiltration, MCP-1 expression, and MMP-9 activity in the border zone. PMID- 20852044 TI - Contrasting vascular effects caused by loss of Bardet-Biedl syndrome genes. AB - Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, autosomal-recessive disorder associated with several clinical features including obesity, hypertension, and cardiovascular abnormalities. BBS proteins play an important role in the function of cilia, a mechanosensory organelle in endothelial cells, but whether these proteins are directly involved in the regulation of vascular function is unclear. Here, we show that Bbs genes (1-12) are expressed in endothelial and smooth muscle cell lines and tissues enriched in endothelial (lung) and smooth muscle (stomach) cells as well as the aorta. Next, we used aortic rings to examine the vascular function of two BBS mouse models that recapitulate the human phenotype, namely Bbs2(-/-) (obese and normotensive) and Bbs6(-/-) (obese and hypertensive) mice. Interestingly, the endothelium-dependent relaxation (induced by ACh) was significantly enhanced in Bbs2(-/-) but not Bbs6( /-) mice. In contrast, the endothelium-independent relaxation (induced by sodium nitroprusside) was unaltered in both BBS mouse models. In addition, the contractile responses to serotonin and endothelin-1 were attenuated in Bbs2(-/-) but not Bbs6(-/-) mice. Of note, the NO-producing enzymes (eNOS and iNOS) were upregulated in the aorta of Bbs2(-/-) but not Bbs6(-/-) mice. On the other hand, the expression level of membrane subunits of NADPH oxidase (p22(phox) and p47(phox)) in the aorta was decreased in Bbs2(-/-) mice but increased in Bbs6(-/ ) mice. In conclusion, these data implicate Bbs genes in the regulation of vascular function and demonstrate that disrupting Bbs2 and Bbs6 genes affect differentially the vascular function. PMID- 20852045 TI - Epidermal growth factor receptor transactivation by endogenous vasoactive peptides contributes to hyperproliferation of vascular smooth muscle cells of SHR. AB - We showed previously that vascular smooth muscle cells (VMSC) from spontaneously hypertensive rats (SHR) exhibit increased proliferation. The present study was undertaken to examine whether the enhanced levels of endogenous angiotensin (ANG) II and endothelin (ET)-1 contribute to the enhanced proliferation of VSMC from SHR and to further investigate the underlying mechanisms responsible for this response. The enhanced proliferation of VSMC from SHR compared with Wistar-Kyoto (WKY) rats was attenuated by losartan, BQ-123, BQ-788, and AG-1478, inhibitors of AT(1), ET(A), ET(B) and epidermal growth factor (EGF-R) receptors, respectively. In addition, BQ-123 and BQ-788 also attenuated the enhanced production of superoxide anion (O(2)(-)) and NADPH oxidase activity. Furthermore, diphenyleneiodonium (DPI, inhibitor of NADPH oxidase), N-acetyl-L-cysteine (NAC, O(2)(-) scavenger), and PP2 (inhibitor of c-Src) also inhibited the augmented proliferation of VSMC from SHR to WKY levels. In addition, the enhanced phosphorylation of EGF-R in VSMC from SHR compared with WKY was also attenuated by inhibitors of AT(1), ET(A), ET(B), and EGF-R but not by inhibitors of platelet derived growth factor receptor or insulin-like growth factor receptor. Furthermore, the enhanced phosphorylation of ERK1/2 in VSMC from SHR was also attenuated by AT(1), ET(A), ET(B), c-Src, and EGF-R inhibitors. The phosphorylation of c-Src was significantly augmented in VSMC from SHR compared with VSMC from WKY and was attenuated by DPI and NAC. These data suggest that endogenous vasoactive peptides, through increased oxidative stress and resultant activation of c-Src, transactivate EGF-R, which through mitogen-activated protein (MAP) kinase signaling may contribute to the hyperproliferation of VSMC from SHR. PMID- 20852046 TI - Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP. AB - The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O(2)-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O(2) saturation (O(2)Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O(2)Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O(2)Hb (r(2) = 0.86-0.98; P = 0.01), decreases in venous plasma nitrite (r(2) = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r(2) = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r(2) = 0.59; P = 0.07). No relationship was observed with plasma ATP (r(2) = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature. PMID- 20852047 TI - Time course of carotid artery growth and remodeling in response to altered pulsatility. AB - Elucidating early time courses of biomechanical responses by arteries to altered mechanical stimuli is paramount to understanding and eventually predicting long term adaptations. In a previous study, we reported marked long-term (at 35-56 days) consequences of increased pulsatile hemodynamics on arterial structure and mechanics. Motivated by those findings, we focus herein on arterial responses over shorter periods (at 7, 10, and 14 days) following placement of a constrictive band on the aortic arch between the innominate and left carotid arteries of wild-type mice, which significantly increases pulsatility in the right carotid artery. We quantified hemodynamics in vivo using noninvasive ultrasound and measured wall properties and composition in vitro using biaxial mechanical testing and standard (immuno)histology. Compared with both baseline carotid arteries and left carotids after banding, right carotids after banding experienced a significant increase in both pulse pressure, which peaked at day 7, and a pulsatility index for velocity, which continued to rise over the 42-day study despite a transient increase in mean flow that peaked at day 7. Wall thickness and inner diameter also increased significantly in the right carotids, both peaking at day 14, with an associated marked early reduction in the in vivo axial stretch and a persistent decrease in smooth muscle contractility. Glycosaminoglycan content also increased within the wall, peaking at day 14, whereas increases in monocyte chemoattractant protein-1 activity and the collagen to-elastin ratio continued to rise. These findings confirm that pulsatility is an important modulator of wall geometry, structure, and properties but reveal different early time courses for different microscopic and macroscopic metrics, presumably due to the separate degrees of influence of pressure and flow. PMID- 20852048 TI - 2,3',4,5'-Tetramethoxystilbene prevents deoxycorticosterone-salt-induced hypertension: contribution of cytochrome P-450 1B1. AB - Reactive oxygen species (ROS) contribute to various models of hypertension, including deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Recently, we have shown that ROS, generated by cytochrome P-450 1B1 (CYP1B1) from arachidonic acid, mediate vascular smooth muscle cell growth caused by angiotensin II. This study was conducted to determine the contribution of CYP1B1 to hypertension and associated pathophysiological changes produced by DOCA (30 mg/kg) given subcutaneously per week with 1% NaCl + 0.1% KCl in drinking water to uninephrectomized rats for 6 wk. DOCA-salt treatment increased systolic blood pressure (SBP). Injections of the selective inhibitor of CYP1B1, 2,3',4,5' tetramethoxystilbene (TMS; 300 MUg/kg ip every 3rd day) initiated at the 4th week of DOCA-salt treatment normalized SBP and decreased CYP1B1 activity but not its expression in the aorta, heart, and kidney. TMS also inhibited cardiovascular and kidney hypertrophy, prevented the increase in vascular reactivity and endothelial dysfunction, and minimized the increase in urinary protein and K(+) output and the decrease in urine osmolality, Na(+) output, and creatinine clearance associated with DOCA-salt treatment. These pathophysiological changes caused by DOCA-salt treatment and associated increase in vascular superoxide production, NADPH oxidase activity, and expression of NOX-1, and ERK1/2 and p38 MAPK activities in the aorta, heart, and kidney were inhibited by TMS. These data suggest that CYP1B1 contributes to DOCA-salt-induced hypertension and associated pathophysiological changes, most likely as a result of increased ROS production and ERK1/2 and p38 MAPK activity, and could serve as a novel target for the development of agents like TMS to treat hypertension. PMID- 20852049 TI - Myocardial contraction-relaxation coupling. AB - Since the pioneering work of Henry Pickering Bowditch in the late 1800s to early 1900s, cardiac muscle contraction has remained an intensely studied topic for several reasons. The heart is located centrally in our body, and its pumping motion demands the attention of the observer. The contraction of the heart encompasses a complex interplay of mechanical, chemical, and electrical properties, and its function can thus be studied from any of these viewpoints. In addition, diseases of the heart are currently killing more people in the Westernized world than any other disease. When combined with the increasing emphasis of research to be clinically relevant, this contributes to the heart remaining a topic of continued basic and clinical investigation. Yet, there are significant aspects of cardiac muscle contraction that are still not well understood. A big complication of the study of cardiac muscle contraction is that there exists no equilibrium among many of the important governing parameters, which include pre- and afterload, intracellular ion concentrations, membrane potential, and velocity and direction of movement. Thus the classic approach of perturbing an equilibrium or a steady state to learn about the role of the perturbing factor in the system cannot be unambiguously interpreted, since each of the parameters that govern contraction are constantly changing, as well as constantly changing their interaction with each other. In this review, presented as the 54th Bowditch Lecture at Experimental Biology meeting in Anaheim in April 2010, I will revisit several governing factors of cardiac muscle relaxation by applying newly developed tools and protocols to isolated cardiac muscle tissue in which the dynamic interactions between the governing factors of contraction and relaxation can be studied. PMID- 20852050 TI - Femoral artery occlusion increases expression of ASIC3 in dorsal root ganglion neurons. AB - Acid-sensing ion channels (ASICs) in sensory nerves are responsive to increases in the levels of protons in the extracellular medium. Prior studies suggest that the muscle metabolite, lactic acid, plays a role in reflex sympathetic and cardiovascular responses via stimulation of thin muscle afferent nerves. Also, femoral artery occlusion augments the reflex sympathetic nerve response in rats. ASIC3 is a main subtype to appear in sensory nerves in mediating the response induced by increases in protons in the interstitial space of contracting muscles. Thus, in this article, we hypothesized that femoral occlusion increases the expression of ASIC3 in primary afferent neurons innervating muscles, and this contributes to the exaggerated reflex sympathetic responses. Femoral occlusion/vascular insufficiency of the hindlimb muscles was induced by the femoral artery ligation in rats. First, Western blot analysis shows that 24-72 h of femoral artery ligation significantly increased the expression of ASIC3 protein in dorsal root ganglion (optical density, 1.0 +/- 0.07 in control vs. 1.65 +/- 0.1 after 24 h of occlusion, P < 0.05; n = 6 in each group). There were no significant differences for increases in ASIC3 24 and 72 h postocclusion. Second, experiments using fluorescent immunohistochemistry and retrograde labeling technique show that a greater percentage of ASIC3 staining neurons are localized in muscle-innervating dorsal root ganglion neurons after the arterial occlusion (78 +/- 3% in 24 h post occlusion vs. 59 +/- 5% in control, P < 0.05; n = 6 in each group). Third, the reflex responses in renal sympathetic nerve and arterial blood pressure induced by the stimulation of ASIC were examined after an injection of lactic acid into the arterial blood supply of hindlimb muscles of control rats and ligated rats. The results demonstrate that the sympathetic and pressor responses to lactic acid were significantly augmented after femoral occlusion compared with those in the control group. The data of this study suggest that enhanced ASIC3 expression in muscle afferent nerves contributes to the exaggerated reflex sympathetic and pressor responses to lactic acid as seen in arterial occlusion. PMID- 20852051 TI - Cardioprotective PKG-independent NO signaling at reperfusion. AB - Cell models of ischemic preconditioning (IPC) indicate nitric oxide (NO) is involved in protection accruing during reoxygenation but disagree whether it acts through PKG. Using a more relevant intact heart model, we studied isolated rabbit hearts subjected to 30-min coronary artery occlusion/120-min reperfusion. We previously found protection from PKG activator 8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate (CPT-cGMP) at reperfusion was blocked by A(2b) adenosine receptor (A(2b)AR), ERK, or phosphatidylinositol 3-kinase (PI3-kinase) blockers. In this investigation A(2b)AR agonist BAY 60-6583 or CPT-cGMP at reperfusion reduced infarction comparably to IPC. Their protection was abrogated by N(omega)-nitro-l-arginine methyl ester (l-NAME), suggesting a PKG-independent NO synthase in IPC's mediator pathway downstream of PKG and A(2b)AR. NO donor S nitroso-N-acetyl-d,l-penicillamine (SNAP) at reperfusion also protected. This protection was not blocked by PI3-kinase inhibitor wortmannin or ERK antagonist PD-98059, suggesting NO acted downstream of these kinases. Protection from SNAP was not affected by mitochondrial ATP-sensitive K(+) channel closer 5 hydroxydecanoate, PKC antagonist chelerythrine, reactive oxygen species scavenger N-2-mercaptopropionylglycine, or soluble guanylyl cyclase antagonist 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Absence of ODQ effect indicated NO was acting independently of PKG. BAY 58-2667, a soluble guanylyl cyclase activator, was protective, and l-NAME blocked its infarct-sparing effect, indicating a second signaling event dependent on NO generation but independent of PKG. SB216763, a blocker of glycogen synthase kinase-3beta (GSK-3beta), decreased infarct size, and its infarct-sparing effect was not affected by l-NAME, suggesting GSK-3beta acted downstream or independently of NO. Hence, NO signaling occurs in IPC's mediator pathway downstream of Akt and ERK, and its protection is independent of PKG. PMID- 20852052 TI - Activation of NFATc1 is directly mediated by IP3 in adult cardiac myocytes. AB - The Ca(2+)-sensitive nuclear factor of activated T cell (NFAT) transcription factors are implicated in cardiac development and cellular remodeling associated with cardiac disease. In adult myocytes it is not resolved what specific Ca(2+) signals control the activity of different NFAT isoforms in an environment that undergoes large changes of intracellular Ca(2+) concentration with every heart beat. Cardiac myocytes possess the complete inositol 1,4,5-trisphosphate (IP(3))/Ca(2+)-signaling cassette; however, its physiological and pathological significance has been a matter of ongoing debate. Therefore, we tested the hypothesis whether IP(3) receptor activation regulates NFAT activity in cardiac myocytes. We used confocal microscopy to quantify the nuclear localization of NFATc1-green fluorescent protein (GFP) and NFATc3-GFP fusion proteins (quantified as the ratio of nuclear NFAT to cytoplasmic NFAT) in response to stimulation with neurohumoral agonists. In rabbit atrial myocytes, an overnight stimulation with endothelin-1, angiotensin II, and phenylephrine induced nuclear accumulation of NFATc1 that was sensitive to calcineurin inhibitors (cyclosporin A or inhibitor of NFAT-calcineurin association-6) and prevented by the IP(3) receptor inhibitor 2-aminoethoxydiphenyl borate. Furthermore, a direct elevation of intracellular IP(3) with a cell-permeable IP(3) acetoxymethyl ester (10 MUM) induced nuclear localization of NFATc1. With a fluorescence-based in vivo assay, we showed that endothelin-1 also enhanced the transcriptional activity of NFATc1 in atrial cells. The agonists failed to activate NFATc1 in rabbit ventricular cells, which express IP(3) receptors at a lower density than atrial cells. They also did not activate NFATc3, an isoform that is highly influenced by nuclear export processes, in both cell types. Our data show that the second messenger IP(3) is directly involved in the activation of NFATc1 in adult atrial cardiomyocytes. PMID- 20852053 TI - Activation of host tissue trophic factors through JAK-STAT3 signaling: a mechanism of mesenchymal stem cell-mediated cardiac repair. AB - We recently demonstrated a cardiac therapeutic regimen based on injection of bone marrow mesenchymal stem cells (MSCs) into the skeletal muscle. Although the injected MSCs were trapped in the local musculature, the extracardiac cell delivery approach repaired the failing hamster heart. This finding uncovers a tissue repair mechanism mediated by trophic factors derived from the injected MSCs and local musculature that can be explored for minimally invasive stem cell therapy. However, the trophic factors involved in cardiac repair and their actions remain largely undefined. We demonstrate here a role of MSC-derived IL-6 type cytokines in cardiac repair through engagement of the skeletal muscle JAK STAT3 axis. The MSC IL-6-type cytokines activated JAK-STAT3 signaling in cultured C2C12 skeletal myocytes and caused increased expression of the STAT3 target genes hepatocyte growth factor (HGF) and VEGF, which was inhibited by glycoprotein 130 (gp130) blockade. These in vitro findings were corroborated by in vivo studies, showing that the MSC-injected hamstrings exhibited activated JAK-STAT3 signaling and increased growth factor/cytokine production. Elevated host tissue growth factor levels were also detected in quadriceps, liver, and brain, suggesting a possible global trophic effect. Paracrine actions of these host tissue-derived factors activated the endogenous cardiac repair mechanisms in the diseased heart mediated by Akt, ERK, and JAK-STAT3. Administration of the cell-permeable JAK STAT inhibitor WP1066 abrogated MSC-mediated host tissue growth factor expression and functional improvement. The study illustrates that the host tissue trophic factor network can be activated by MSC-mediated JAK-STAT3 signaling for tissue repair. PMID- 20852055 TI - A new sense of protection: role of the Ca2+-sensing receptor in ischemic preconditioning. PMID- 20852054 TI - Myocardial insulin resistance induced by high fat feeding in heart failure is associated with preserved contractile function. AB - Previous studies have reported that high fat feeding in mild to moderate heart failure (HF) results in the preservation of contractile function. Recent evidence has suggested that preventing the switch from fatty acid to glucose metabolism in HF may ameliorate dysfunction, and insulin resistance is one potential mechanism for regulating substrate utilization. This study was designed to determine whether peripheral and myocardial insulin resistance exists with HF and/or a high fat diet and whether myocardial insulin signaling was altered accordingly. Rats underwent coronary artery ligation (HF) or sham surgery and were randomized to normal chow (NC; 14% kcal from fat) or a high-fat diet (SAT; 60% kcal from fat) for 8 wk. HF + SAT animals showed preserved systolic (+dP/dt and stroke work) and diastolic (-dP/dt and time constant of relaxation) function compared with HF + NC animals. Glucose tolerance tests revealed peripheral insulin resistance in sham + SAT, HF + NC, and HF + SAT animals compared with sham + NC animals. PET imaging confirmed myocardial insulin resistance only in HF + SAT animals, with an uptake ratio of 2.3 +/- 0.3 versus 4.6 +/- 0.7, 4.3 +/- 0.4, and 4.2 +/- 0.6 in sham + NC, sham + SAT, and HF + NC animals, respectively; the myocardial glucose utilization rate was similarly decreased in HF + SAT animals only. Western blot analysis of insulin signaling protein expression was indicative of cardiac insulin resistance in HF + SAT animals. Specifically, alterations in Akt and glycogen synthase kinase-3beta protein expression in HF + SAT animals compared with HF + NC animals may be involved in mediating myocardial insulin resistance. In conclusion, HF animals fed a high-saturated fat exhibited preserved myocardial contractile function, peripheral and myocardial insulin resistance, decreased myocardial glucose utilization rates, and alterations in cardiac insulin signaling. These results suggest that myocardial insulin resistance may serve a cardioprotective function with high fat feeding in mild to moderate HF. PMID- 20852056 TI - Individual differences in the heart rate response to activation of the muscle metaboreflex in humans. AB - We tested the hypotheses that the heart rate (HR) response to muscle metaboreflex activation induced by postexercise muscle ischemia (PEMI) varies considerably among subjects and that individual differences in the HR response are associated with differences in cardiac autonomic tone and/or arterial baroreflex function during PEMI. Fifty-one healthy subjects (36 men and 15 women) performed a 1-min isometric handgrip exercise at 50% maximal voluntary contraction, which was followed by a 3.5-min period of imposed PEMI. We estimated cardiac autonomic tone using spectral analysis of beat-to-beat variation in the R-R interval (RRI). In addition, the sensitivity of the arterial baroreflex control of HR (BRS) was evaluated using transfer function analysis of systolic arterial pressure (SAP) and RRI. Although the mean RRI during the PEMI and subsequent recovery period did not differ from the resting value, the variance among the individual differences in RRI between the rest and PEMI periods was significantly greater than between the rest and recovery periods. The changes in RRI elicited by PEMI correlated significantly with changes in the spectral power of the RRI variability in the high-frequency range and the BRS. By contrast, no significant correlation was observed between changes in RRI and changes in mean arterial pressure or the power of the RRI variability in the low-frequency range. This suggests that, in humans, the HR response to PEMI-induced activation of muscle metaboreflex varies considerably from individual to individual and that these differences reflect changes in cardiac parasympathetic tone and spontaneous BRS during PEMI. PMID- 20852057 TI - The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. AB - We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N(omega)-nitro-l-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 MUl in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload. PMID- 20852058 TI - Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes. AB - Many issues remain unresolved concerning how local, subcellular Ca(2+) signals interact with bulk cellular concentrations to maintain homeostasis in health and disease. To aid in the interpretation of data obtained in quiescent ventricular myocytes, we present here a minimal whole cell model that accounts for both localized (subcellular) and global (cellular) aspects of Ca(2+) signaling. Using a minimal formulation of the distribution of local [Ca(2+)] associated with a large number of Ca(2+)-release sites, the model simulates both random spontaneous Ca(2+) sparks and the changes in myoplasmic and sarcoplasmic reticulum (SR) [Ca(2+)] that result from the balance between stochastic release and reuptake into the SR. Ca(2+)-release sites are composed of clusters of two-state ryanodine receptors (RyRs) that exhibit activation by local cytosolic [Ca(2+)] but no inactivation or regulation by luminal Ca(2+). Decreasing RyR open probability in the model causes a decrease in aggregate release flux and an increase in SR [Ca(2+)], regardless of whether RyR inhibition is mediated by a decrease in RyR open dwell time or an increase in RyR closed dwell time. The same balance of stochastic release and reuptake can be achieved, however, by either high frequency/short-duration or low-frequency/long-duration Ca(2+) sparks. The results are well correlated with recent experimental observations using pharmacological RyR inhibitors and clarify those aspects of the release-reuptake balance that are inherent to the coupling between local and global Ca(2+) signals and those aspects that depend on molecular-level details. The model of Ca(2+) sparks and homeostasis presented here can be a useful tool for understanding changes in cardiac Ca(2+ )release resulting from drugs, mutations, or acquired diseases. PMID- 20852059 TI - Effect of peri-infarct pacing early after myocardial infarction: results of the prevention of myocardial enlargement and dilatation post myocardial infarction study. AB - BACKGROUND: Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling. METHODS AND RESULTS: Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction <=35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS <120 ms, were randomized to either control (implantable cardioverter-defibrillator [ICD]) or biventricular pacing with peri infarct LV lead placement (cardiac resynchronization therapy [CRT]-D) arms between 2 and 14 days after the MI. The primary end point-change in LV end diastolic volume (LVEDV) from baseline to 12 months-was not significantly different between the 2 groups (CRT, 10.6+/-27.7 mL; ICD, 11.2+/-31.2 mL; 2 sample t test P>0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, -0.16+/ 0.28; ICD, -0.01+/-0.24, 2-sample t test P=0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P>0.05). CONCLUSIONS: Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year. PMID- 20852060 TI - Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. AB - BACKGROUND: Heart failure (HF) with preserved left ventricular ejection fraction (HFPEF) is the most common form of HF in the older population. Exercise intolerance is the primary chronic symptom in patients with HFPEF and is a strong determinant of their reduced quality of life (QOL). Exercise training (ET) improves exercise intolerance and QOL in patients with HF with reduced ejection fraction (EF). However, the effect of ET in HFPEF has not been examined in a randomized controlled trial. METHODS AND RESULTS: This 16-week investigation was a randomized, attention-controlled, single-blind study of medically supervised ET (3 days per week) on exercise intolerance and QOL in 53 elderly patients (mean age, 70+/-6 years; range, 60 to 82 years; women, 46) with isolated HFPEF (EF >=50% and no significant coronary, valvular, or pulmonary disease). Attention controls received biweekly follow-up telephone calls. Forty-six patients completed the study (24 ET, 22 controls). Attendance at exercise sessions in the ET group was excellent (88%; range, 64% to 100%). There were no trial-related adverse events. The primary outcome of peak exercise oxygen uptake increased significantly in the ET group compared to the control group (13.8+/-2.5 to 16.1+/ 2.6 mL/kg per minute [change, 2.3+/-2.2 mL/kg per minute] versus 12.8+/-2.6 to 12.5+/-3.4 mL/kg per minute [change, -0.3+/-2.1 mL/kg per minute]; P=0.0002). There were significant improvements in peak power output, exercise time, 6-minute walk distance, and ventilatory anaerobic threshold (all P<0.002). There was improvement in the physical QOL score (P=0.03) but not in the total score (P=0.11). CONCLUSIONS: ET improves peak and submaximal exercise capacity in older patients with HFPEF. PMID- 20852061 TI - The will and the ways to becoming an ex-offender. PMID- 20852062 TI - Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. AB - AMP-activated protein kinase (AMPK) is a metabolic sensor involved in intracellular energy metabolism through the control of several homeostatic mechanisms, which include autophagy and protein degradation. Recently, we reported that AMPK activation by resveratrol promotes autophagy-dependent degradation of the amyloid-beta (Abeta) peptides, the core components of the cerebral senile plaques in Alzheimer's disease. To identify more potent enhancers of Abeta degradation, we screened a library of synthetic small molecules selected for their structural similarities with resveratrol. Here, we report the identification of a series of structurally related molecules, the RSVA series, which inhibited Abeta accumulation in cell lines nearly 40 times more potently than did resveratrol. Two of these molecules, RSVA314 and RSVA405, were further characterized and were found to facilitate CaMKKbeta-dependent activation of AMPK, to inhibit mTOR (mammalian target of rapamycin), and to promote autophagy to increase Abeta degradation by the lysosomal system (apparent EC(50) ~ 1 MUM). This work identifies the RSVA compounds as promising lead molecules for the development of a new class of AMPK activating drugs controlling mTOR signaling, autophagy, and Abeta clearance. PMID- 20852063 TI - Efficient nonadhesive ex vivo expansion of early endothelial progenitor cells derived from CD34+ human cord blood fraction for effective therapeutic vascularization. AB - Endothelial progenitor cells (EPCs) have been shown to have therapeutic potential in ischemic disease. However, the number of EPCs for cell therapy is limited. In this study, instead of the typical adherent culture method, we investigated a more efficient, clinically applicable nonadhesive expansion method for early EPCs using cord blood-derived cells to overcome rapid cellular senescence. After a suspension culture of isolated CD34(+) cells in serum-free medium containing each cytokine combination was maintained for 9 d, the number of expanded functional EPCs was assessed by an adherent culture assay. Compared to mononuclear cells, the CD34(+) fraction was superior in its expansion of functional EPCs that could differentiate into acLDL/UEA-1(+) cells without significant cellular senescence, whereas the CD34(-) fraction showed no EPC expansion. Among the cytokine combinations tested for the CD34(+) fraction, a combination (SFIb) consisting of stem cell factor (SCF), FMS-like tyrosine kinase 3 ligand, interleukin-3, and basic fibroblast growth factor resulted in a reproducible 64- to 1468-fold EPC expansion from various cord blood origins. Interestingly, the SFIb combination displayed markedly increased EPC expansion (2.43-fold), with a higher percentage of CD34(+) cells (2.17-fold), undifferentiated blasts (2.38-fold) and CXCR4(+) cells (1.68-fold) compared to another cytokine combination (SCF, thrombopoietin, and granulocyte colony-stimulating factor), although the two cytokine combinations had a similar level of total mononucleated cell expansion (~ 10% difference). Accordingly, the cells expanded in the SFIb combination were more effective in recovery of blood flow and neovascularization in hind-limb ischemia in vivo. Taken together, these results suggest that the nonadhesive serum-free culture conditions of the CD34(+) fraction provide an effective EPC expansion method for cell therapy, and an expansion condition leading to high percentages of CD34(+) cells and blasts is likely important in EPC expansion. PMID- 20852064 TI - The active Zot domain (aa 288-293) increases ZO-1 and myosin 1C serine/threonine phosphorylation, alters interaction between ZO-1 and its binding partners, and induces tight junction disassembly through proteinase activated receptor 2 activation. AB - Vibrio cholerae-derived zonula occludins toxin (Zot) is a multifunctional protein that reversibly disassembles intestinal tight junctions (tjs). Zot structure function analysis has mapped this activity to aa 288-293, named AT1002. AT1002 reduced transepithelial electrical resistance across rat small intestine, ex vivo, as did Zot and its processed mature form, DeltaG. AT1002 increased in vivo permeability to sugar tracers, whereas scrambled control peptides did not. Binding and barrier assays in proteinase activated receptor (PAR)(2)-expressing and PAR(2)-null cells established AT1002 activity to be PAR(2) dependent. Coincident with the increased intestinal permeability, confocal microscopy of AT1002-exposed rat intestinal IEC6 cells revealed displacement of ZO-1 and occludin from intercellular boundaries. In coimmunoprecipitation assays, AT1002 decreased ZO-1-occludin and ZO-1-claudin 1 interactions coincident with PKCalpha dependent ZO-1 serine/threonine phosphorylation. Further, AT1002 increased serine phosphorylation of myosin 1C and, at the same time, transiently diminished its association with ZO-1. The COOH-terminal domain of ZO-1 was required for its association with myosin 1C. These data indicate that the NH(2)-terminal portion of active Zot contains a PAR(2)-activating motif, FCIGRL, that increases PKCalpha dependent ZO-1 and myosin 1C serine/threonine phosphorylation. These modifications provoke selective disengagement of ZO-1 from its binding partners, occludin, claudin 1, and myosin 1C, coincident with opening of tjs. PMID- 20852065 TI - A nonself sugar mimic of the HIV glycan shield shows enhanced antigenicity. AB - Antibody 2G12 uniquely neutralizes a broad range of HIV-1 isolates by binding the high-mannose glycans on the HIV-1 surface glycoprotein, gp120. Antigens that resemble these natural epitopes of 2G12 would be highly desirable components for an HIV-1 vaccine. However, host-produced (self)-carbohydrate motifs have been unsuccessful so far at eliciting 2G12-like antibodies that cross-react with gp120. Based on the surprising observation that 2G12 binds nonproteinaceous monosaccharide D-fructose with higher affinity than D-mannose, we show here that a designed set of nonself, synthetic monosaccharides are potent antigens. When introduced to the terminus of the D1 arm of protein glycans recognized by 2G12, their antigenicity is significantly enhanced. Logical variation of these unnatural sugars pinpointed key modifications, and the molecular basis of this increased antigenicity was elucidated using high-resolution crystallographic analyses. Virus-like particle protein conjugates containing such nonself glycans are bound more tightly by 2G12. As immunogens they elicit higher titers of antibodies than those immunogenic conjugates containing the self D1 glycan motif. These antibodies generated from nonself immunogens also cross-react with this self motif, which is found in the glycan shield, when it is presented in a range of different conjugates and glycans. However, these antibodies did not bind this glycan motif when present on gp120. PMID- 20852066 TI - Induction of long interspersed nucleotide element-1 (L1) retrotransposition by 6 formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct. AB - Long interspersed nucleotide element-1 (L1) is a retroelement comprising about 17% of the human genome, of which 80-100 copies are competent as mobile elements (retrotransposition: L1-RTP). Although the genetic structures modified during L1 RTP have been clarified, little is known about the cellular signaling cascades involved. Herein we found that 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct postulated as a candidate physiological ligand of the aryl hydrocarbon receptor (AhR), induces L1-RTP. Notably, RNA-interference experiments combined with back-transfection of siRNA-resistant cDNAs revealed that the induction of L1-RTP by FICZ is dependent on AhR nuclear translocator-1 (ARNT1), a binding partner of AhR, and the activation of cAMP-responsive element binding protein. However, our extensive analyses suggested that AhR is not required for L1-RTP. FICZ stimulated the interaction of the L1-encoded open reading frame-1 (ORF1) and ARNT1, and recruited ORF1 to chromatin in a manner dependent on the activation of mitogen-activated protein kinase. Along with our additional observations that the cellular cascades for FICZ-induced L1-RTP were different from those of L1-RTP triggered by DNA damage, we propose that the presence of the cellular machinery of ARNT1 mediates L1-RTP. A possible role of ARNT1-mediated L1-RTP in the adaptation of living organisms to environmental changes is discussed. PMID- 20852067 TI - Pancreatic stellate cells produce acetylcholine and may play a role in pancreatic exocrine secretion. AB - The pancreatic secretagogue cholecystokinin (CCK) is widely thought to stimulate enzyme secretion by acinar cells indirectly via activation of the vagus nerve. We postulate an alternative pathway for CCK-induced pancreatic secretion. We hypothesize that neurally related pancreatic stellate cells (PSCs; located in close proximity to the basolateral aspect of acinar cells) play a regulatory role in pancreatic secretion by serving as an intermediate target for CCK and secreting the neurotransmitter acetylcholine (ACh), which, in turn, stimulates acinar enzyme secretion. To determine whether PSCs (i) exhibit CCK-dependent ACh secretion and (ii) influence acinar enzyme secretion, primary cultures of human and rat PSCs were used. Immunoblotting and/or immunofluorescence was used to detect choline acetyltransferase (ACh synthesizing enzyme), vesicular ACh transporter (VAChT), synaptophysin, and CCK receptors 1 and 2. Synaptic-like vesicles in PSCs were identified by EM. ACh secretion by PSCs exposed to 20 pM CCK was measured by LC-MS/MS. Amylase secretion by acini [pretreated with and without the muscarinic receptor antagonist atropine (10 MUM) and cocultured with PSCs] was measured by colorimetry. PSCs express ACh synthesizing enzyme, VAChT, synaptophysin, and CCK receptors; exhibit CCK-dependent ACh secretion; and stimulate amylase secretion by acini, which is blocked by atropine. In conclusion, PSCs express the essential elements for ACh synthesis and secretion. CCK stimulates ACh secretion by PSCs, which, in turn, induces amylase secretion by acini. Therefore, PSCs may represent a previously unrecognized intrapancreatic pathway regulating CCK-induced pancreatic exocrine secretion. PMID- 20852068 TI - Eukaryotic genes of archaebacterial origin are more important than the more numerous eubacterial genes, irrespective of function. AB - The traditional tree of life shows eukaryotes as a distinct lineage of living things, but many studies have suggested that the first eukaryotic cells were chimeric, descended from both Eubacteria (through the mitochondrion) and Archaebacteria. Eukaryote nuclei thus contain genes of both eubacterial and archaebacterial origins, and these genes have different functions within eukaryotic cells. Here we report that archaebacterium-derived genes are significantly more likely to be essential to yeast viability, are more highly expressed, and are significantly more highly connected and more central in the yeast protein interaction network. These findings hold irrespective of whether the genes have an informational or operational function, so that many features of eukaryotic genes with prokaryotic homologs can be explained by their origin, rather than their function. Taken together, our results show that genes of archaebacterial origin are in some senses more important to yeast metabolism than genes of eubacterial origin. This importance reflects these genes' origin as the ancestral nuclear component of the eukaryotic genome. PMID- 20852069 TI - Absence of branches from xylan in Arabidopsis gux mutants reveals potential for simplification of lignocellulosic biomass. AB - As one of the most abundant polysaccharides on Earth, xylan will provide more than a third of the sugars for lignocellulosic biofuel production when using grass or hardwood feedstocks. Xylan is characterized by a linear beta(1,4)-linked backbone of xylosyl residues substituted by glucuronic acid, 4-O-methylglucuronic acid or arabinose, depending on plant species and cell types. The biological role of these decorations is unclear, but they have a major influence on the properties of the polysaccharide. Despite the recent isolation of several mutants with reduced backbone, the mechanisms of xylan synthesis and substitution are unclear. We identified two Golgi-localized putative glycosyltransferases, GlucUronic acid substitution of Xylan (GUX)-1 and GUX2 that are required for the addition of both glucuronic acid and 4-O-methylglucuronic acid branches to xylan in Arabidopsis stem cell walls. The gux1 gux2 double mutants show loss of xylan glucuronyltransferase activity and lack almost all detectable xylan substitution. Unexpectedly, they show no change in xylan backbone quantity, indicating that backbone synthesis and substitution can be uncoupled. Although the stems are weakened, the xylem vessels are not collapsed, and the plants grow to normal size. The xylan in these plants shows improved extractability from the cell wall, is composed of a single monosaccharide, and requires fewer enzymes for complete hydrolysis. These findings have implications for our understanding of the synthesis and function of xylan in plants. The results also demonstrate the potential for manipulating and simplifying the structure of xylan to improve the properties of lignocellulose for bioenergy and other uses. PMID- 20852070 TI - The increased risk of post-transplant diabetes mellitus in peritoneal dialysis treated kidney allograft recipients. AB - BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a common metabolic complication in kidney allograft recipients, significantly contributing to the elevated cardiovascular morbidity after renal transplantation and increased risk of chronic transplant dysfunction. The aim of the present investigation was to evaluate the factors influencing PTDM development. Under particular consideration were the elements, existing before the transplantation, especially the modality of dialysis treatment significance, i.e. haemodialysis (HD) versus peritoneal dialysis (PD). METHODS: Three hundred and seventy-seven consecutive outpatients who underwent renal transplantation (RTx) in our institution between January 2003 and December 2005 were analysed. PTDM was diagnosed according to the current American Diabetic Association/World Health Organization criteria. Statistical inference was conducted by means of univariate methods (one factor versus PTDM) and multivariate methods in frames of generalized linear model. RESULTS: In the study group, 72 patients (23.4%) developed PTDM after RTx (55 HD and 17 PD patients). PTDM incidence at 3, 6 and 12 months was 15.9%, 22.1% and 23.4%, respectively. The mean interval from transplantation to the onset of PTDM was 3.08 +/- 2.73 months. In univariate analysis, the factors associated with the elevated risk of PTDM appearance were older recipient age, positive family history of diabetes, hypertensive nephropathy as end-stage renal disease cause, higher body mass index at transplantation, treatment by PD, and the graft from an older donor. In multivariate verification, statistical significance remained: older recipient age (P < 0.001), positive family history of diabetes (P = 0.002), and treatment by PD (P = 0.007). CONCLUSIONS: Treatment by PD appears to be a possible novel factor, not yet reported, which may increase the risk of PTDM development. PMID- 20852071 TI - Urine output criteria for the diagnosis of early stages of acute kidney injury. Muddying the waters? PMID- 20852072 TI - Extraordinary popular delusions and the madness of crowds: puncturing the epoetin bubble--lessons for the future. AB - Recent trials, and meta-analyses, have cast further doubt on the clinically desirable and safe range for increasing haemoglobin in chronic kidney disease using erythropoiesis-stimulating agents. In this article, I review the current dilemmas we face, suggest key clinical and biological research priorities, and conclude that we need to be brave enough to admit our present shortcomings, and then perhaps adopt a more patient-focused, individualized approach to anaemia management. PMID- 20852074 TI - Temporal gene expression in equine corpora lutea based on serial biopsies in vivo. AB - A biopsy procedure was developed to enable repeated sampling of a single equine corpus luteum (CL) over the course of an estrous cycle. The tissue collected was utilized in characterizing mRNA abundance for genes involved in luteal formation, function, and regression in the cyclic mare. Serial biopsies of CL in cyclic mares (2.7 to 27.5 mg per biopsy) were collected using an ultrasound-guided transvaginal technique. Biopsies were collected from each mare on d 2 and 5 (d 0 = ovulation) of the estrous cycle, and every other day from d 12 through luteolysis. Samples were obtained from 4 mares with normal estrous cycles and 1 mare with a retained CL. The biopsy procedure did not adversely affect luteal size or function, as measured by luteal area and serum concentrations of progesterone. Real-time reverse-transcription PCR was used to quantify steady state mRNA concentrations in each tissue sample obtained. Mean abundance of steroidogenic acute regulatory protein (StAR) mRNA was not different (P = 0.102 to 0.964) on any of the sampling dates, but a trend for mRNA encoding StAR to decrease between d 12 and 14 (P = 0.10) was observed. Values for mRNA encoding StAR were positively correlated to serum concentrations of progesterone on d 5 (R = 0.95; P = 0.05) and 14 (R > 0.99; P < 0.01). Steady-state abundance of mRNA for 3beta-hydroxysteroid dehydrogenase, Delta 5-Delta 4 isomerase (3beta-HSD) declined between d 12 and 14 (P = 0.15). There were positive correlations between mRNA for 3beta-HSD and concentrations of progesterone on d 5 (R = 0.94; P = 0.06) and 12 (R > 0.99; P = 0.05). No difference was detected in abundance of mRNA encoding cyclooxygenase-2 (cox-2; P = 0.340 to 0.840) or caspase-3 (P = 0.517 to 0.882) between any of the sampling dates. A successful luteal biopsy procedure was developed that did not negatively affect luteal function, and abundance of mRNA encoding StAR, 3beta-HSD, cox-2, and caspase-3 was characterized in luteal biopsy tissue collected on d 2, 5, 12, and 14 of the estrous cycle in the mare. PMID- 20852073 TI - Fetal muscle development, mesenchymal multipotent cell differentiation, and associated signaling pathways. AB - Enhancing muscle growth while reducing fat accumulation improves the efficiency of animal production. The fetal stage is crucial for skeletal muscle development. Fetal muscle development involves myogenesis, adipogenesis, and fibrogenesis from mesenchymal multipotent cells (MC), which are negatively affected by maternal nutrient deficiencies. Enhancing myogenesis increases the lean-to-fat ratio of animals, enhancing intramuscular adipogenesis increases intramuscular fat that is indispensible for the superior eating properties of meat because fat is the major contributor to meat flavor. The promotion of fibrogenesis leads to the accumulation of connective tissue, which contributes to the background toughness of meat and is undesirable. Thus, it is essential to regulate MC differentiation to enhance lean growth and improve meat quality. To date, our understanding of mechanisms regulating the lineage commitment of MC is limited. In this review, we first discuss the impact of maternal nutrient deficiency on fetal development, offspring body composition, and meat quality. Because maternal nutrition affects fetal muscle through altering MC differentiation, we then review several important extracellular morphogens regulating MC differentiation, including hedgehog, Wingless and Int (Wnt), and bone morphogenic proteins. Possible involvement of epigenetic modifications associated with histone deacetylases class IIa and histone acetyltransferase, p300, in MC differentiation is also discussed. PMID- 20852075 TI - Cell Biology Symposium: imaging the organization and trafficking of lipolytic effectors in adipocytes. AB - The storage and mobilization of lipid energy are central functions of adipocytes. Lipid energy is stored as triglyceride in lipid droplet structures that are now recognized as bona fide organelles and whose functions are greatly influenced by members of the perilipin family of lipid droplet scaffolds. Recent work indicates that the signaling events underlying fatty acid mobilization involve protein trafficking to a specialized subset of lipid droplets. Furthermore, the core lipolytic machinery is composed of evolutionarily conserved proteins whose functions are conserved in avian and mammalian production species. Lipolysis affects many aspects of animal nutrition and physiology, which can have an important influence on growth efficiency, lactation, and meat quality. This review focuses on recent research that addresses the organization and trafficking of key players in hormone-stimulated lipolysis, and the central role of perilipin1A in adipocyte lipolysis. The review emphasizes recent work from the laboratories of the authors that utilizes imaging techniques to explore the organization and interactions among lipolytic effectors in live cells during lipolytic activation. A mechanistic understanding of lipolysis may lead to new strategies for promoting human and animal health. PMID- 20852077 TI - Citizen complaints and environmental regulation of Michigan livestock operations. AB - Citizen environmental complaints filed against agricultural producers in Michigan were examined to determine farm and community factors influencing citizen complaints and the subsequent response of the farmer. Secondary citizen environmental complaint data were obtained from the Michigan Department of Agriculture from 1998 to 2007 with 1,289 observations. Citizen complaints were grouped into 5 categories: odor, surface water, ground water, combination, and other complaints. Complaints were further classified as nonverified or verified where verified meant that the inspected farm was not complying with relevant generally accepted agricultural and management practices. These data were used to examine how farm characteristics affected the likelihood of a verified complaint. Odor and surface water complaints accounted for 75% of all complaints. A probit regression analysis was used to estimate the probability of a verified complaint as a function of complaint type, farm characteristics, county characteristics, and seasonal factors. Results from the probit regression analysis revealed that larger operations, poultry, and hog farms received more nonverified complaints than other livestock farms. Surface water issues were 17% more likely to be verified complaints compared with odor issues, of which the surface water complaints often originated from sources other than neighbors. In contrast, odor issues were more likely to result from accepted management practices requiring no mitigation. Farms that received a verified citizen complaint were required to mitigate the complaint by implementing corrective practices. A log-level (log Y) regression was used to evaluate how farm characteristics influenced the cost to implement corrective practices on those farms receiving a verified citizen complaint. Costs to implement corrective practices to mitigate verified complaints were greatest for dairy operations and surface water complaints. Corrective practices required to mitigate a surface water complaint were predicted to cost 46% more than an odor complaint with an estimated average cost of $7,442. The most expensive practices were associated with manure incorporation, stream bank fencing, and controlling runoff. PMID- 20852076 TI - Oral administration of Saccharomyces cerevisiae boulardii reduces mortality associated with immune and cortisol responses to Escherichia coli endotoxin in pigs. AB - The effects of active dry yeast, Saccharomyces cerevisiae boulardii (Scb), on the immune/cortisol response and subsequent mortality to Escherichia coli lipopolysaccharide (LPS) administration were evaluated in newly weaned piglets (26.1 +/- 3.4 d of age). Barrows were assigned to 1 of 2 treatment groups: with (Scb; n = 15) and without (control; n = 15) the in-feed inclusion of Scb (200 g/t) for 16 d. On d 16, all piglets were dosed via indwelling jugular catheters with LPS (25 MUg/kg of BW) at 0 h. Serial blood samples were collected at 30-min intervals from -1 to 6 h and then at 24 h. Differential blood cell populations were enumerated hourly from 0 to 6 h and at 24 h. Serum cortisol, IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) concentrations were determined via porcine-specific ELISA at all time points. In Scb-treated piglets, cumulative ADG increased (P < 0.05) by 39.9% and LPS-induced piglet mortality was reduced 20% compared with control piglets. White blood cells, lymphocytes, and neutrophils were increased (P < 0.05) in Scb-treated animals before LPS dosing compared with control piglets before being equally suppressed (P < 0.05) from baseline in both treatments after LPS dosing with a return to baseline by 24 h. Suppression of circulating cortisol concentrations (P < 0.05) was observed in Scb-treated piglets from -1 h to 1 h relative to LPS dosing compared with control animals before both peaked equally and subsequently returned to baseline. Peak production (P < 0.05) of IL-1beta and IL-6 was less in Scb-treated piglets after LPS administration compared with controls before both equally returned to baseline. Peak TNF-alpha production in Scb-treated animals was accelerated 0.5 h and was greater (P < 0.05) than peak production in control piglets, after which both equally returned to baseline. The peak production of IFN-gamma was greater and had increased (P < 0.05) amplitude persistence for 3 h in Scb-treated animals compared with control piglets before both equally returned to baseline. These results highlight the previously unidentified effects of Scb administration on immune and cortisol responses and the subsequent impact on growth and endotoxin-induced mortality in weaned piglets. PMID- 20852078 TI - Galactoglucomannan oligosaccharide supplementation affects nutrient digestibility, fermentation end-product production, and large bowel microbiota of the dog. AB - A galactoglucomannan oligosaccharide (GGMO) obtained from fiberboard production was evaluated as a dietary supplement for dogs. The GGMO substrate contained increased concentrations of oligosaccharides containing mannose, xylose, and glucose, with the mannose component accounting for 35% of DM. Adult dogs assigned to a 6 * 6 Latin square design were fed 6 diets, each containing a different concentration of supplemental GGMO (0, 0.5, 1, 2, 4, and 8%) that replaced dietary cellulose. Total tract DM and OM apparent digestibilities increased (P < 0.001) linearly, whereas total tract CP apparent digestibility decreased (P < 0.001) linearly as dietary GGMO substrate concentration increased. Fecal concentrations of acetate, propionate, and total short-chain fatty acids increased (P <= 0.001) linearly, whereas butyrate concentration decreased (P <= 0.001) linearly with increasing dietary concentrations of GGMO. Fecal pH decreased (P <= 0.001) linearly as dietary GGMO substrate concentration increased, whereas fecal score increased quadratically (P <= 0.001). Fecal phenol (P <= 0.05) and indole (P <= 0.01) concentrations decreased linearly with GGMO supplementation. Fecal biogenic amine concentrations were not different among treatments except for phenylethylamine, which decreased (P < 0.001) linearly as dietary GGMO substrate concentration increased. Fecal microbial concentrations of Escherichia coli, Lactobacillus spp., and Clostridium perfringens were not different among treatments. A quadratic increase (P <= 0.01) was noted for Bifidobacterium spp. as dietary GGMO substrate concentration increased. The data suggest positive nutritional properties of supplemental GGMO when incorporated in a good-quality dog food. PMID- 20852079 TI - Effects of dietary antibiotic growth promoter and Saccharomyces cerevisiae fermentation product on production, intestinal bacterial community, and nonspecific immunity of hybrid tilapia (Oreochromis niloticus female x Oreochromis aureus male). AB - To investigate the effects of a dietary antibiotic growth promoter (florfenicol) and a Saccharomyces cerevisiae fermentation product (DVAQUA) on growth, G:F, daily feed intake, intestinal bacterial community, and nonspecific immunity of hybrid tilapia (Oreochromis niloticus ? * Oreochromis aureus ?), a 16-wk feeding trial was conducted in a recirculating aquaculture system. Four feeding regimens were evaluated: control, dietary florenicol (0.02 g/kg; 16 wk), dietary DVAQUA (0.5 g/kg; 16 wk), and sequential use of florenicol (0.02 g/kg; 8 wk), and DVAQUA (0.5 g/kg; 8 wk). Each regimen had 4 replicate tanks (0.5 * 0.5 * 0.5 m) and each tank contained 12 fish (initial BW: 46.88 +/- 0.38 g). Dietary florfenicol improved growth (P = 0.089), G:F (P = 0.036), and serum complement component concentrations (P < 0.001) of hybrid tilapia. However, the compound decreased the estimated intestinal bacterial count estimated by rpoB quantitative PCR (P < 0.001) and bacterial diversity (visual band numbers, Shannon diversity index, and Shannon equitability index based on 16S rDNA V3 denaturing gradient gel electrophoresis fingerprints) compared with the control. Although sequential use of florfenicol and DVAQUA improved growth and G:F numerically to a similar extent as dietary florfenicol, and increased intestinal bacterial count to normal quantities, the sequential use of florenicol and DVAQUA decreased intestinal bacterial diversity (visual band numbers, Shannon diversity index, and Shannon equitability index) as well as serum complement component concentrations (P < 0.001) compared with their respective use and the control. These findings might be negatively related to disease control and host defense, and the sequential use of florenicol and DVAQUA should be practiced with caution. Feeding DAVQUA to the fish improved nonspecific immunity and increased intestinal bacterial count and bacterial diversity, but further research, including challenge studies, should be conducted before recommendation of DVAQUA supplementation to hybrid tilapia diets. PMID- 20852080 TI - Technical note: Evolution of exit velocity in suckling Brahman calves. AB - The purpose of this study was to assess changes in exit velocity (EV) of Brahman calves from 21 d of age (DOA) to 56 d postweaning (231.30 +/- 1.23 DOA). Spring born calves (n = 308) from 2006 to 2008 were sired by 18 bulls. Exit velocity (m/s) was determined as the rate of speed of a calf traversing 1.83 m after being released from a working chute. Temperament score was determined as the average of EV and pen score 28 d before and at weaning (2006: 173 +/- 2 DOA; 2007: 174 +/- 2 DOA; 2008: 163 +/- 2 DOA). Pen score was determined by separating calves into groups of 3 to 5 animals and scoring their reactivity to a human observer on a scale of 1 (calm, docile, approachable) to 5 (aggressive, volatile, crazy). The number of calves that switched temperament group was determined by ranking calves based on their EV at 21 to 24 DOA, 90 DOA, weaning, and at 56 d postweaning. The GLIMMIX procedure of SAS was used to analyze EV with DOA, birth year and sex as fixed effects, and sire and calf nested within sire included as random effects. Temperament classification (calm, intermediate, temperamental) was modeled as a fixed effect, and the linear regression of traits on DOA investigated. Spearman rank order correlations were determined between EV at 21 to 24 DOA, 90 DOA, weaning, and 56 d postweaning and correlations decreased as the number of days between EV measurements increased. Differences in EV were observed between the 2006 (2.23 +/- 0.057 m/s) compared with the 2007 (1.90 +/- 0.059 m/s) and 2008 (1.83 +/- 0.057 m/s) calves (P < 0.001), but the 2007 and the 2008 calves did not differ (P = 0.75). The random effect of sire approached significance (P = 0.07) and accounted for some of the variation observed. Exit velocity increased as days of age increased (P < 0.001). Exit velocity of temperamental calves increased at a faster rate with age (P < 0.001; estimate of slope = 0.005 +/- 0.0004 m/s daily) compared with intermediate (slope = 0.003 +/- 0.0005 m/s daily; P < 0.001) and calm calves (slope = 0.0007 +/- 0.0005 m/s daily; P < 0.001). Exit velocity is a useful and viable indicator of temperament classification. Results suggest that temperamental calves increase their EV at a faster rate and may be identified before weaning, which may enhance the ability of producers to select against temperamental animals. PMID- 20852081 TI - Use of model super-shedders to define the role of pen floor and hide contamination in the transmission of Escherichia coli O157:H7. AB - Super-shedders, cattle shedding at least 10(4) cfu of Escherichia coli O157:H7 per gram of feces, increase the risks of contaminating the food chain and disseminating the organism through cattle populations. Because detecting super shedders in cattle populations is laborious and time-consuming, a study was conducted to evaluate the role of hide and pen-floor contamination by model super shedders (MSS) in transmission of E. coli O157:H7. Steers (n = 48) negative for E. coli O157:H7 were allocated to 6 pens, with 2 replicate pens per treatment. Treatment A consisted of 3,000 g of feces inoculated with 10(6) cfu/g of a 5 strain mixture of nalidixic acid-resistant E. coli O157:H7 and spread in simulated fecal pats on the pen floor for d 0 through 4 and d 14 through 18. For treatment B, 100 g of the feces per day was spread on the perineum of 1 MSS per pen, and the remaining feces was placed on the pen floor as fecal pats similar to treatment A. Treatment C differed from B in that 50 g of feces was spread on the perineum and 50 g on the brisket of the MSS steer. Fecal samples, perineal swabs (500-cm(2) area around the anus), freshly voided fecal pats and manila rope samples were collected during a 56-d experimental period. More positive rope samples were found in treatments B and C compared with A (P = 0.05), and steers within treatments B and C were 1.3 times more likely (P = 0.05) to shed E. coli O157:H7 in their feces than steers in treatment A. Even though the number of E. coli O157:H7 introduced into pens was similar, results indicate an increased importance of hide compared with pen-floor contamination for transmission of this organism to cattle. Because cattle within treatment B were persistently colonized with E. coli O157:H7, this design should prove suitable for future studies investigating the role of super-shedders in the transmission of E. coli O157:H7. PMID- 20852082 TI - Effects of bovine fatty acid synthase, stearoyl-coenzyme A desaturase, sterol regulatory element-binding protein 1, and growth hormone gene polymorphisms on fatty acid composition and carcass traits in Japanese Black cattle. AB - The quality of fat is an important factor in defining the quality of meat. Fat quality is determined by the composition of fatty acids. Among lipid metabolism related genes, including fatty acid synthesis genes, several genetic variations have been reported in the bovine fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD), sterol regulatory element-binding protein 1 (SREBP1), and GH genes. In the present study, we evaluated the single and epistatic effects of 5 genetic variations (4 SNP and 1 insertion/deletion) in 4 genes (FASN, SCD, SREBP1, and GH) on the fatty acid composition of the longissimus thoracis muscle and carcass and meat quality traits in 480 commercial Japanese Black cattle. Significant single effects of FASN, SCD, and GH(L127V) polymorphisms on the fatty acid composition of the longissimus thoracis muscle were detected. The A293V polymorphism of SCD had the largest effect on myristic acid (C14:0, P < 0.001), myristoleic acid (C14:1, P < 0.001), stearic acid (C18:0, P < 0.001), oleic acid (C18:1, P < 0.001), and MUFA (P < 0.001). Polymorphisms in the FASN, SCD, and SREBP1 genes showed no effect on any meat yield trait. There were no significant epistatic effects on fatty acid composition among pairs of the 3 genes (FASN, SCD, and SREBP1) involved in fatty acid synthesis. No epistatic interactions (P > 0.1) were detected between FASN and SCD for any carcass trait. When the genotypes of 3 markers (FASN, SCD, and GH(L127V)) were substituted from the lesser effect allele to the greater effect allele, the proportion of C18:1 increased by 4.46%. More than 20% of the genetic variance in the C18:1 level could be accounted for by these 3 genetic markers. The present results revealed that polymorphisms in 2 fatty acid synthesis genes (FASN and SCD) independently influenced fatty acid composition in the longissimus thoracis muscle. These results suggest that SNP in the FASN and SCD genes are useful markers for the improvement of fatty acid composition in commercial Japanese Black cattle. PMID- 20852083 TI - Measurement of urinary zearalenone concentrations for monitoring natural feed contamination in cattle herds: On-farm trials. AB - The aims of the present study were to investigate the efficacy of measuring bovine urinary zearalenone (ZEN) concentrations by using a commercially available ELISA method in cattle kept under different feeding conditions to monitor the natural contamination of feeds at the farm level, and to investigate the effects of supplementation of a mycotoxin adsorbent (MA) product in the feed based on urinary ZEN concentration. First, Japanese Black cattle herds kept for breeding (4 herds) and fattening (4 herds) purposes were provided with similar feeding conditions. Then, urinary samples from 5 cows in each herd were collected and analyzed. Second, dairy cows from 1 herd fed with total mixed rations (TMR) were selected. After thorough mixing of the MA (40 g/d) with TMR, the supplemented TMR was fed according to the following schedule: with MA for 2 wk, without MA for 3 wk; then with MA for 2 wk and without MA for 6 wk. Urine samples were collected from cows (n = 6 to 7) and examined before and after each interval. Zearalenone concentrations were measured by the ELISA and liquid chromatography-tandem mass spectrometry methods. The concentration of ZEN and its metabolites was expressed after creatinine (Crea) correction [ZEN or metabolites (pg/mL)/Crea (mg/dL); pg/mg of Crea]. In the first experiment, the urinary concentrations of ZEN and its metabolites were variable in all herds, and significant differences were observed between herds. In 1 fattening herd, in particular, urinary ZEN concentrations were greater (P < 0.001) than in the other 3 herds. This might reflect significant natural ZEN contamination of the feed at the farm level. In Exp. 2, urinary ZEN concentrations displayed peculiar trends after supplementation with MA. After 2 wk of supplementation, a significant decrease of ZEN (P < 0.05) was observed. Zearalenone concentrations remained at a reduced amount during 3 wk without MA supplementation and 2 wk with MA supplementation. When MA was not added to the feed for the next 6 wk, the concentrations increased to the original quantity. These findings indicate the usefulness of measuring concentrations of urinary ZEN and its metabolites not only for monitoring the natural ZEN contamination of cattle feed at the farm level but also for in vivo evaluation of MA function after supplementing feeds with MA. PMID- 20852084 TI - Stiff heart syndrome. AB - Isolated cardiac amyloidosis, or "Stiff Heart Syndrome," is a rare manifestation of amyloidosis. Some degree of cardiac amyloid deposition is common in elderly patients, as reported in prior post-mortem studies; however, isolated cardiac involvement with predominantly cardiac symptoms and no evidence of systemic disease is a rare presentation. Establishing the correct diagnosis, even with the use of extensive testing including amyloid typing, understanding the clinical significance, and management can be challenging in such cases. PMID- 20852085 TI - Impact of diabetic status on the hyperglycemia-induced adverse risk of short term outcomes in hospitalized patients with acute coronary syndromes in the Middle East: findings from the Gulf registry of Acute Coronary Events (Gulf RACE). AB - BACKGROUND: While glucose levels on admission are clearly a much stronger predictor of short term adverse outcomes than diabetes status, there is a paucity of data on how diabetes status impacts the hyperglycemia-induced increased risk. METHODS: 2786 patients admitted to the hospital with acute coronary syndrome (ACS) and diabetic level hyperglycemia (random >11.1 mmol/L or fasting >7 mmol/L) were identified from a Gulf registry of ACS. We divided the cohort into two groups. Those who were previously known to have diabetes mellitus were identified as the known diabetes group, and the non-diabetic group included those without a previous diabetes diagnosis. We used logistic regression models to assess the effect of glycemic status on hospital mortality and other patient outcomes including heart failure, stroke, recurrent ischemia, cardiogenic shock, major bleeding, and ventilation. RESULTS: About two-thirds of the hyperglycemics on admission had been diagnosed previously with diabetes. After adjusting for age, in-hospital mortality was significantly higher in the non-diabetic group (OR: 2.36; 95% CI 1.54-3.61) compared to the diabetic group. As for the other outcomes, known diabetes patients had significantly lower incidences of heart failure, cardiogenic shock, and ventilation compared to non-diabetic patients. CONCLUSION: The effects of hyperglycemia are mitigated by the presence of the chronic diabetic state, and thus, hyperglycemia has a worse effect in those not known to have chronic diabetes. These findings are important and call for further investigation. PMID- 20852087 TI - Research mentor: a web-based resource supporting grantsmanship and scientific publication. PMID- 20852086 TI - Development of sarcoidosis following completion of treatment for hepatitis C with pegylated interferon-{alpha}2a and ribavirin: a case report and literature review. AB - Sarcoidosis is a chronic inflammatory multisystem disease of unknown etiology. We report on a woman, aged 57 years, presenting with typical sarcoidosis occurring two months after completion of a six-month course of interferon-alpha and ribavirin for chronic hepatitis C virus infection. The current observation is interesting with regard to the time elapsed between the occurrence of symptoms and antiviral treatment withdrawal, and spontaneous recovery after ten months of follow-up. Pathophysiological mechanisms involved in the development of antiviral therapy-induced sarcoidosis are discussed. PMID- 20852088 TI - Self-mutilation of tongue and lip in a patient with simple schizophrenia. AB - Self-inflicted lesions that cause mutilation are observed in schizophrenic patients. This case report describes the diagnosis and treatment of simple schizophrenia in a 31-year-old male patient who bit his own tongue and lower lip. The dental treatment proposed included the construction of a splint to prevent new lesions and to allow healing of existing ones. The treatment afforded to avoid tooth extraction before the patient responded to psychiatric drug treatment. The importance of a transdisciplinary approach to self-mutilation due to psychiatric disorders is stressed. The interaction between the two teams, stomatology and psychiatry, was crucial for the improvement of the patient's condition. PMID- 20852089 TI - Rapid reduction of severely elevated serum triglycerides with insulin infusion, gemfibrozil and niacin. AB - The conventional methods of treatment of severe hypertriglyceridemia are dietary restriction and lipid lowering medications, mainly fibric acid derivatives. In the medical literature, use of insulin infusion to treat hypertriglyceridemia has not been highlighted sufficiently. We report a 53-year-old male who presented with a four-day history of epigastric pain. The patient's clinical history was significant for hypertriglyceridemia, type-2 diabetes mellitus with medication noncompliance, obesity, status post-gastric bypass surgery, and alcohol abuse with prior admissions for detoxification. Physical examination revealed mild epigastric tenderness. Laboratory studies revealed severely elevated serum triglyceride (TG) level (8116 mg/dL). Computed tomography (CT) scan of the abdomen exhibited no evidence of pancreatitis. Regular insulin infusion was started at 3 U/h and gradually increased to 7-10 U/h. Dextrose infusion was titrated to avoid hypoglycemia and maintain blood glucose levels below 150 mg/dL. Gemfibrozil and niacin were also started. After 24 hours, his TG levels were decreased to 2501 mg/dL. Insulin infusion was continued for about 48 hours. A low carbohydrate diet excluding simple carbohydrates was given. The patient's serum TG levels normalized over a period of one month. Thus insulin infusion can be considered a safe modality of treatment for rapid reduction of serum TG in addition to fibrates and niacin. PMID- 20852090 TI - Retroperitoneal solitary fibrous tumor-induced hypoglycemia associated with high molecular weight insulin-like growth factor II. AB - A man, aged 65 years, presented with frequent episodes of hypoglycemia and unconsciousness. Hypoglycemia was accompanied by undetectable serum insulin and C peptide levels and a high serum insulin-like growth factor (IGF)-II level. He was found to have a retroperitoneal solitary fibrous tumor. He underwent successful resection of the tumor and had no hypoglycemic episodes after the operation. Immunohistochemical analysis revealed positive immunostaining for IGF-II in tumor cells. The presence of the high-molecular-weight form of IGF-II in the patient's serum was confirmed by immunoblotting, which suggests that his hypoglycemia was due to an increase in the plasma level of IGF-II secreted by the tumor. PMID- 20852091 TI - Recurrent negative pressure pulmonary edema. AB - An African-American man, aged 34 years, underwent an elective uncomplicated right wrist laceration repair while under general anesthesia. Following extubation, the patient developed hypoxemia, tachypnea, shortness of breath, pulmonary rales, frothy sputum, decreased oxygen saturation, and evidence of upper airway obstruction. Chest radiograph showed pulmonary edema. The patient was diagnosed with post-extubation pulmonary edema (aka. negative pressure pulmonary edema [NPPE]) and was treated with intravenous furosemide and oxygen therapy; he improved remarkably within a few hours. Once stabilized, the patient described a similar episode 10 years earlier following surgery for multiple gunshot wounds. Negative pressure pulmonary edema following tracheal extubation is an uncommon (0.1%) and life-threatening complication of patients undergoing endotracheal intubation and general anesthesia for surgical procedures. The common pattern in these cases is the occurrence of an episode of airway obstruction upon emergence from general anesthesia, usually caused by laryngospasm. Patients who are predisposed to airway obstruction may have an increased risk of airway complications upon extubation after general anesthesia. Prevention and early relief of upper airway obstruction should decrease incidence. Recurrent NPPE has not been previously described in the literature. Herein, we describe the first case of recurrent NPPE in the same patient following extubation. PMID- 20852093 TI - Footpad dermatitis in poultry. AB - Footpad dermatitis (FPD) is a condition that causes necrotic lesions on the plantar surface of the footpads in growing broilers and turkeys. This condition not only causes downgrades and condemnations of saleable chicken paws, the portion of the leg below the spur, but is also an animal welfare concern in both the United States and in Europe.. Revenue from chicken paws in 2008 alone was worth $280 million. Harvesting large, unblemished paws has become a priority to poultry companies all over the world. Research on this subject has been ongoing since the 1940s and has looked into many different areas including nutrition, environment, and genetics. Early research looked at nutritional deficiencies such as riboflavin and biotin mainly in turkey poults. This early research was most likely looking at a separate form of dermatitis than what is being investigated now. Recent findings have suggested that there is a myriad of interacting factors that lead to FPD. Litter moisture appears to be the most likely culprit in the onset of this condition. Research has also shown a possible genetic link in the susceptibility to development of FPD lesions. Current chicken paw prices have skyrocketed due to a large export market in Asia. To produce unblemished paws for both increased profit and comply with current animal welfare recommendations, further research is needed to understand how the condition develops and what strategies can be used to prevent it. PMID- 20852092 TI - Oleic acid inhibits stearic acid-induced inhibition of cell growth and pro inflammatory responses in human aortic endothelial cells. AB - Saturated fatty acids (SFAs), significant components of both enteral/parenteral nutritional formulations (including diet), are linked to cardiovascular disease complications, such as atherosclerosis. We investigated whether oleic acid (C18:1n-9) reduces the growth inhibitory and pro-inflammatory effects of the stearic acid (C18:0) in human aortic endothelial cells (HAEC). Stearic acid induced growth inhibition at concentrations less than 50 MUM, whereas higher concentrations invoked cytotoxicity. Stearic acid-induced growth inhibition and cytotoxic effects were eradicated upon cosupplementation with oleic acid (25 MUM). Oleic acid (as low as 5 MUM) also inhibited the stearic acid-induced increase in intercellular adhesion molecule-1 (ICAM-1) expression. Stearic acid induced phosphorylation of nuclear factor-kappa B (NF-kappaB), a transcriptional regulator of ICAM-1, was also reduced by oleic acid. HAECs supplemented with either stearic or oleic acid resulted in cellular incorporation of C18:0 and C18:1n-9, respectively. Stearic acid primarily incorporated into phospholipids without increasing the total fatty acid content in HAECs. In contrast, oleic acid, with or without stearic acid, incorporated into both phospholipids and triglycerides, with a significant increase in total fatty acid amounts in triglycerides. Our data suggest that oleic acid has the ability to reduce the inflammatory effects of long-chain SFAs in HAECs through reducing cellular stearic acid incorporation and NF-kappaB activation. PMID- 20852094 TI - Effect of ozonation on particulate matter in broiler houses. AB - The effects of ozonation on particulate matter were studied on a commercial broiler farm. The farm consisted of 4 identical tunnel-ventilated houses (12.8*152.4 m): 2 houses were treated with O3 (maximum concentration 0.1 ppm) and the other 2 served as control units. The particle size distributions of total suspended particulate (TSP) samples from both control and treated houses were found to have very similar profiles with no statistical difference. The TSP concentrations were significantly higher in treated houses as compared with those in control houses, and the mean of the differences was 5.50 mg/m3. In both treated and control houses, there were substantial vertical TSP concentration gradients and the concentrations decreased with height. At broiler chicken height (0.28 m), TSP concentrations were 13+/-3 mg/m3 in control houses and 17+/-2 mg/m3 in treated houses. At human breathing height (1.55 m), TSP concentrations were 8+/-4 mg/m3 in control houses and 7+/-2 mg/m3 in treated houses. Particle phase NH4+ concentrations were higher in treated houses (ranging from 0.59 to 42.01 mg/m3 with mean=17.49 mg/m3) than in control houses (ranging from 0.34 to 13.55 mg/m3 with mean=4.42 mg/m3). The TSP samples from locations in the vicinity of the farm showed higher concentrations downwind than that upwind, but there were no significant differences observed among different ambient locations for TSP NH4+ concentrations. The results from this study did not show that direct application of ozonation technique has beneficial effects for particulate matter control in broiler houses. PMID- 20852095 TI - Effect of acute heat stress on calcium concentration, proliferation, cell cycle, and interleukin-2 production in splenic lymphocytes from broiler chickens. AB - In the present study, we investigated the effects of acute heat stress on the concentration of free Ca2+ ([Ca2+]i) and markers of cellular immunity in splenic lymphocytes from broiler chickens. Eighty 6-wk-old male broilers were randomly allocated to 2 treatments and exposed to 25 and 35 degrees C (RH, 50+/-5%) for 3 h. We observed that 3 h of heat exposure (35+/-1 degrees C, 50+/-5% RH) increased the body temperature and respiratory rate of broiler chickens significantly, but plasma levels of corticosterone were not changed. Examination of [Ca2+]i and the proliferation of splenic lymphocytes isolated from heat-stressed broiler chickens, using fura-2-acetoxymethyl ester and Cell Counting Kit-8, respectively, showed that acute heat stress caused a significant increase in [Ca2+]i and enhanced concanavalin A-stimulated but not lipopolysaccharide-stimulated lymphocyte proliferation significantly. Flow cytometric analysis of the cell cycle and T-lymphocyte subsets (CD4+ and CD8+) indicated that heat stress promoted the transition of lymphocytes from gap phase 1 to synthesis phase and increased the ratio of CD4+ to CD8+ of T lymphocytes. In addition, acute heat stress enhanced the secretion of interleukin-2 by splenic lymphocytes significantly. These results suggest that the effect of acute heat stress to increase the [Ca2+]i in lymphocytes may be an early event that enhances Con A stimulated T-cell proliferation and interleukin-2 secretion and promotes the transition of T cells from gap phase 1 to synthesis phase. PMID- 20852096 TI - Effect of heat and several additives related to stress levels on fluctuating asymmetry, heterophil:lymphocyte ratio, and tonic immobility duration in White Leghorn chicks. AB - The purpose of this study was to analyze the effects of heat and several additives related to stress on fluctuating asymmetry (groups 1 to 10), heterophil:lymphocyte ratio (groups 1 to 3 and 8 to 10), and tonic immobility duration (groups 1 to 7 and 10) in White Leghorn chicks at 42 d of age. Chicks in group 1 (heat) were reared with temperatures 8 degrees C greater than those of the control group. Groups 2 to 9 consisted of chicks reared with temperatures 8 degrees C greater than those of the control group and addition of capsaicin, allicin, ascorbic acid, tryptophan, brewer's yeast, lactic acid, corticosterone, or cholesterol in diet. Chicks in group 10 (control) were reared with standard temperatures. Heat effect was significant (P<0.05) for the heterophil:lymphocyte ratio, which was greater in heat-stressed chicks without any additives and smaller in control chicks. There were no significant differences for the fluctuating asymmetry and the tonic immobility duration between both groups. Heterophil:lymphocyte ratio for heat-stressed chicks with capsaicin or allicin was significantly lower (P<0.05) than that of heat-stressed chicks without any additives. Capsaicin effect was not significant for the fluctuating asymmetry and the tonic immobility duration, whereas allicin significantly increased fluctuating asymmetry of wing length and tonic immobility duration (P<0.05). The addition of lactic acid or corticosterone resulted in greater fluctuating asymmetry of wing length of heat-stressed chicks (P<0.05). In conclusion, an increased heterophil:lymphocyte ratio was found in heat-stressed chicks without additives, indicating that it is a more reliable indicator of the effect of heat in chicks. In addition, dietary capsaicin or allicin supplementation was effective to alleviate the stress induced by the high temperature, as indicated by a lower heterophil:lymphocyte ratio. PMID- 20852097 TI - Influence of supplemental dietary poultry fat, phytase, and 25 hydroxycholecalciferol on the egg characteristics of commercial layers inoculated before or at the onset of lay with F-strain Mycoplasma gallisepticum. AB - The effects of supplemental dietary poultry fat (PF), phytase (PHY), and 25 hydroxycholecalciferol (D3) on the egg characteristics of commercial layers inoculated with F-strain Mycoplasma gallisepticum (FMG) were investigated in 2 trials. Sham and FMG inoculations were administered at 12 (before lay) and 22 (onset of lay) wk and 4 dietary treatments [basal control diet (BCD); BCD with 0.75% supplemental PF; BCD with 1.50% supplemental PF; BCD with 1.50% supplemental PF, 0.013% PHY, and 0.025% D3] were initiated at 20 wk of age. Percentages of albumen, yolk, and eggshell weights; yolk:albumen ratio; yolk moisture and lipid concentrations; and eggshell weight per unit of surface area were determined at 24, 34, 44, 50, and 58 wk of age. Inoculation with FMG reduced yolk lipid concentration at wk 24 and increased yolk moisture concentration at wk 58. In birds inoculated on wk 22, percentage of yolk weight was lower in those inoculated with FMG compared with those that were sham-inoculated. Yolk:albumen ratio was lower in birds that were FMG-inoculated at 22 wk of age compared with those that were sham-inoculated at the same age or that were FMG-inoculated at 12 wk of age. Percentage of yolk weight was greater in birds inoculated at wk 22 and fed the BCD with 1.50% supplemental PF treatment compared with those inoculated at wk 22 and fed the BCD or BCD with 1.50% supplemental PF, 0.013% PHY, and 0.025% D3 treatments and compared with birds inoculated at wk 12 and fed the BCD with 0.75% supplemental PF treatment. In conclusion, inoculation with FMG before or at the onset of lay caused a decrease in yolk lipid content early in lay but an increase in yolk moisture late in lay, and FMG reduced percentage of yolk weight in birds inoculated on wk 22. Furthermore, when used in combination with added 1.50% PF in birds inoculated on wk 22, supplementary PHY and D3 prevented an increase in percentage of yolk weight that occurred in response to diets supplemented only with 1.50% PF. PMID- 20852098 TI - Genetics and vaccine efficacy: host genetic variation affecting Marek's disease vaccine efficacy in White Leghorn chickens. AB - Marek's disease (MD) is a T-cell lymphoma disease of domestic chickens induced by MD virus (MDV), a naturally oncogenic and highly contagious cell-associated alpha herpesvirus. Earlier reports have shown that the MHC haplotype as well as non-MHC genes are responsible for genetic resistance to MD. The MHC was also shown to affect efficiency of vaccine response. Using specific-pathogen-free chickens from a series of 19 recombinant congenic strains and their 2 progenitor lines (lines 6(3) and 7(2)), vaccine challenge experiments were conducted to examine the effect of host genetic variation on vaccine efficacy. The 21 inbred lines of White Leghorns share the same B*2 MHC haplotype and the genome of each recombinant congenic strain differs by a random 1/8 sample of the susceptible donor line (7(2)) genome. Chickens from each of the lines were divided into 2 groups. One was vaccinated with turkey herpesvirus strain FC126 at the day of hatch and the other was treated as a nonvaccinated control. Chickens of both groups were inoculated with a very virulent plus strain of MDV on the fifth day posthatch. Analyses of the MD data showed that the genetic line significantly influenced MD incidence and days of survival post-MDV infection after vaccination of chickens (P<0.01). The protective indices against MD varied greatly among the lines with a range of 0 up to 84%. This is the first evidence that non-MHC host genetic variation significantly affects MD vaccine efficacy in chickens in a designed prospective study. PMID- 20852099 TI - Evaluation of adiponectin gene expression in the abdominal adipose tissue of broiler chickens: feed restriction, dietary energy, and protein influences adiponectin messenger ribonucleic acid expression. AB - We studied the effects of feed restriction and different energy and protein contents of the diet on BW, abdominal adipose tissue percentage, and adiponectin gene expression in abdominal adipose tissue in broiler chickens. Two experiments were conducted to determine whether feed restriction and dietary energy and protein levels alter adiponectin mRNA abundance in broiler chicks. Body weight and abdominal adipose tissue percentage were recorded and abdominal adipose tissue samples were collected at sampling days. Adiponectin mRNA expression in abdominal adipose tissue was quantitated using real-time quantitative PCR. We found that BW, abdominal adipose tissue percentage, and adiponectin gene expression were decreased in restricted chicks compared with those fed ad libitum at 32 d of age, but feed restriction had no effect on abdominal adipose tissue percentage and adiponectin gene expression at 49 d of age (experiment 1). Body weight was increased significantly in broilers fed on low-energy diets compared with those fed high-energy diets in experiment 1. Also, increasing levels of dietary protein increased BW in broiler chicks in experiment 2. A positive response in adiponectin gene expression and abdominal adipose tissue percentage was achieved by decreasing protein level in the diet of chicks at 32 d of age, but dietary protein had no effect on adiponectin gene expression at 49 d of age (experiment 1). Also, in experiment 2, abdominal adipose tissue percentage increased as dietary protein with fixed level of energy decreased in broiler chickens at 42 and 56 d of age. In experiment 1, increasing dietary energy levels increased adiponectin gene expression and abdominal adipose tissue percentage in chicks at 32 d of age. Also, we showed that dietary energy had an effect on abdominal adipose tissue percentage at 49 d of age. In experiment 2, a high energy diet with a fixed level of protein increased abdominal adipose tissue percentage in chicks at 42 and 56 d of age. Dietary energy and protein levels had no significant effect on adiponectin gene expression in abdominal adipose tissue in broilers. PMID- 20852100 TI - A single nucleotide polymorphism in the parathyroid hormone gene and effects on eggshell quality in chickens. AB - Parathyroid hormone (PTH), released by the parathyroid gland of animals, plays an important role in regulating the metabolism of calcium and phosphate. As a candidate gene for eggshell quality traits, the SNP was screened and its genetic effects on eggshell qualities and levels of serum calcium, phosphate, and PTH were analyzed in this study. Three hundred Houdan hens, an indigenous breed of chicken in France, were used for genotyping and data recording. Of the 3 sets of primers used to amplify the exons, exon 3 was polymorphic and 3 genotypes were identified. Sequencing revealed a nucleotide transition, A2205G (GenBank accession no. NC_006092), which was a synonymous mutation and caused a codon for lysine to change from AAA to AAG. Eggshell percentage and breaking strength for genotypes GG and AG were greater (P<0.05) than for AA, respectively; the total serum calcium for genotype GG was higher than for genotypes AA and AG by 11.8 and 10.1%, respectively; the serum phosphate for genotype GG was greater than genotype AA and AG by 16.7 and 12%, respectively. All genotypes shared the same calcium:phosphate ratio. For serum PTH, genotype GG was approximately 30% higher than genotype AA. Therefore, the SNP A2205G in PTH affected the eggshell percentage and breaking strength, and it may be associated with the variation of serum calcium and PTH level, indicating that the SNP in PTH has the potential for utilization in a MAS program for eggshell quality in chicken. PMID- 20852101 TI - Pharmacokinetics of disodium fosfomycin in broilers and dose strategies to comply with its pharmacodynamics versus Escherichia coli. AB - The objective of this study was to determine, in broilers, which modality of disodium fosfomycin (DF) administration and at what dose the best pharmacokinetic (PK) profile could be obtained, taking as reference a 110 field bacterial strains of Escherichia coli minimum inhibitory concentration survey. The DF was administered via drinking water either ad libitum or at a higher concentration having 1 h of water restriction to build up thirst in the birds (loading dose). Dosages tested were 10, 20, 40, and 80 mg/kg per administration, either once or twice daily. Birds included were 24-d-old Cornish broilers randomly assigned to 16 groups of 200 birds per group and 3 replicates per group. The PK of DF was determined after ad libitum administration of either a single- or double-loading dose or after an initial loading dose followed by ad libitum medication. Also, PK after i.v. administration was studied in separate groups. Serial blood samplings were performed in all groups. Serum obtained was analyzed for DF and a possible active metabolite by means of a microbiological agar diffusion assay. The DF showed a short elimination half-life (approximately 2 h after oral loading administration) with a rapid clearance (1.23 to 1.42 mL/kg per h). Apparent volume of distribution-area under the curve values were also low (10 and 80 mg/kg=0.25 L/kg and 0.22 L/kg, respectively). Considering a minimum inhibitory concentration level that inhibited 90% of total strains of 8 ug/mL for E. coli, it is concluded that single-loading administration at 10, 20, 40, and 80 mg/kg complies poorly with sustained serum concentrations over a dosing interval of 24 h. Doses of 10 and 20 mg/kg twice a day also were insufficient to attain therapeutic concentrations. Useful serum concentrations of DF to treat outbreaks of susceptible E. coli require an initial loading dose of 40 mg/kg, followed by an ad libitum medication of 40 mg/kg 8 h later (80 mg/kg per d). PMID- 20852102 TI - Occurrence of purulent arthritis broilers vertically infected with Salmonella enterica serovar Enteritidis in Korea. AB - Salmonella enterica serovar Enteritidis (Salmonella Enteritidis) has been associated with morbidity and mortality in broiler chickens worldwide. The present study described purulent arthritis of broilers infected with Salmonella Enteritidis and investigated antibiograms and genetic characteristics of Salmonella Enteritidis isolates from epidemiologically related properties such as a hatchery and breeder farm in an attempt to elucidate the source of contamination. Clinical disease and mortality were observed in the affected broiler flock. Mortality was 5.8% until 12 d of age. The birds typically showed lameness with moderately swollen hock joints and footpads. The most prevalent lesions were severely purulent arthritis with polyserositis. Histopathology revealed moderate to severe inflammation in the synovial membrane of leg joints and visceral organs. When the antimicrobial susceptibility test was performed against 7 isolates of Salmonella Enteritidis from broilers, and relevant hatchery and breeder farms by the disk diffusion method using 18 antimicrobial agents, isolates from broiler and breeder farms had the same antibiogram characterized by multiple drug resistance to ampicillin, ceftiofur, cephalothin, gentamycin, nalidixic acid, streptomycin, sulfisoxazole, and tetracycline, whereas isolates from the hatchery were differently resistant to only nalidixic acid. Through the genetic analysis with pulsed-field gel electrophoresis using the restriction enzyme XbaI, Salmonella Enteritidis isolates from both broiler and breeder farms also showed the same PFGE pattern compared with the hatchery isolates resistant to nalidixic acid. As a result, the same PFGE profiles and antibiogram patterns among isolates from broilers and breeder farms provided direct evidence of vertical Salmonella Enteritidis transmission from the contaminated breeder farm to commercial broiler. PMID- 20852103 TI - Expression profiles of genes within a subregion of chicken major histocompatibility complex B in spleen after Marek's disease virus infection. AB - Major histocompatibility complex has previously been shown to influence the resistance of chicken to Marek's disease virus (MDV). However, little is known about expression of other genes in the MHC-I and II pathway after MDV infection. This study aimed at investigating 8 immune-related genes in the MHC core region that affects host responses to MDV. Spleens of infected and age-matched uninfected chickens were removed at 4, 7, 14, 21, and 28 d postinfection for gene expression detection using real-time PCR. Different expression patterns of MHC-I and II pathway genes were observed in the spleen. In the MHC-I pathway, the expression of transporter of antigen protein 1 (TAP1), transporter of antigen protein 2 (TAP2), and transporter of antigen protein-binding protein (TAPBP) genes was significantly increased in the spleen of MDV-infected than that of uninfected chickens. It indicated that host antivirus responses were generated to enhance antigen presentation. However, MHC-II pathway genes showed contrary trends. Classical MHC-II beta chain major gene (BLB2) and nonclassical class II genes [DM alpha chain gene (DMA), DM beta chain gene-1 (DMB1), and DM beta chain gene-2 (DMB2)] had consistent lower transcripts in spleens of MDV-infected than that of uninfected chickens, which reflected that MDV interfered with multiple components of the MHC-II pathway. Overall, expression of most genes in the MHC core region was altered; moreover, the genes in endogenous and exogenous antigen presentation pathways had different expression patterns in the spleen after MDV infection. PMID- 20852104 TI - Salmonella antibiotic-mutant strains reduce fecal shedding and organ invasion in broiler chicks. AB - We investigated the exposure to antibiotics in the production of antibiotic mutant strains of Salmonella. Ten isolates of poultry origin were assayed for antibiotic susceptibilities. One strain of Salmonella Enteritidis, one of Salmonella Heidelberg, and one of Salmonella Typhimurium were selected to induce antimicrobial resistance. Each strain was exposed to high concentrations of streptomycin, rifampicin, and nalidixic acid, respectively. Parent and antibiotic mutant strains were assayed for antibiotic susceptibilities using a commercial microdilution test and the disk susceptibility test. The strains were assessed for virulence genes and evaluated for fecal shedding, cecal colonization, organ invasion, and mean Salmonella counts after inoculation in 1-day-old chicks. The study revealed that exposure to high concentrations of streptomycin produced the antibiotic-mutant strain SE/LABOR/USP/08 and the exposure to rifampicin produced the antibiotic-mutant SH/LABOR/USP/08. These strains showed significantly reduced fecal shedding (P<=0.05) and organ invasion, persisting less than the parental strains and showing no clinical signs in inoculated chicks. High concentrations of nalidixic acid produced the antibiotic-mutant strain ST/LABOR/USP/08, which did not show any differences compared with the parent strain. Likewise, SE/LABOR/USP/08 did not show the expression of plasmid-encoded fimbriae (pefA) and plasmid virulence protein (spvC), suggesting that after exposure to streptomycin, the parent isolate lost the original gene expression, reducing fecal shedding and organ invasion in inoculated chicks. PMID- 20852105 TI - L-arginine and antioxidant vitamins E and C improve the cardiovascular performance of broiler chickens grown under chronic hypobaric hypoxia. AB - Two hundred broiler chicks were randomly assigned to 3 dietary treatments: control [CTL; 3,200 kcal of ME/kg, 23% CP, 1.55% Arg, and 40 IU of vitamin E (VE)/kg of feed], high-Arg (HA; CTL+0.8% Arg), or high-Arg and high antioxidant vitamin diet (AEC; HA+200 IU of VE/kg of feed and 500 mg of vitamin C/L of water). The chicks were housed in wire cages in hypobaric chambers simulating 3,000 m above sea level. From d 28 to 42, clinically healthy birds were selected for cardiovascular performance (n=7 to 12/treatment). After surgery, pulmonary arterial pressure (PAP) and mean arterial pressure (MAP) readings were taken at 180, 120, and 60 s (basal values) before an epinephrine (EPI) challenge and then at 30, 60, 120, 180, 300, 600, and 1,200 s after the challenge, followed by a second EPI challenge with similar sample readings. There were no differences in the basal PAP values among chicken groups. The PAP increased within 30 s after both EPI challenges in all groups. It took 180 s after the first EPI challenge for the CTL chickens to return to the basal PAP values, whereas HA and AEC chickens returned to basal PAP values in 120 s. After the second EPI challenge, it took 60, 180, and 300 s for the AEC, HA, and CTL groups, respectively, to return to basal PAP values. The MAP response pattern to the EPI challenges mimicked that of PAP, but there were no differences among treatments in MAP at any sampling point. Supplemental Arg, VE, and vitamin C did not reduce ascites incidence in hypoxic broilers. In conclusion, supplemental Arg improved the pulmonary vascular performance of hypoxic broiler chickens and its effects were further improved by the addition of the antioxidant VE and vitamin C. Arginine and antioxidant vitamins may have played synergistic roles to increase NO bioavailability and reduce oxidative stress damage, thus improving cardiopulmonary performance. PMID- 20852106 TI - Comparison of hydrated sodium calcium aluminosilicate and yeast cell wall on counteracting aflatoxicosis in broiler chicks. AB - The objective of this research was to determine the efficacy of 2 types of adsorbents [hydrated sodium calcium aluminosilicates (HSCAS) vs. a combination of clay and yeast cell wall] in preventing aflatoxicosis in broilers. A total of 275 one-day-old birds were randomly divided into 11 treatments, with 5 replicate pens per treatment and 5 chicks per pen. The 11 treatments included 3 diets without any adsorbent containing either 0, 1, or 2 mg/kg of aflatoxin B1 (AFB1) plus 8 additional treatments employing 2 dietary levels of AFB1 (1 or 2 mg/kg), 2 different adsorbents [Solis (SO) and MTB-100 (MTB)], and 2 different levels of each absorbent (0.1 and 0.2%) in a 2*2*2 factorial arrangement. Solis is a mixture of different HSCAS and MTB is a combination of clay and yeast cell wall. Feed and water were provided ad libitum throughout the 21-d study period. Body weight gain and feed intake were depressed and relative liver weight was increased in chicks fed AFB1 compared with the positive control (P<0.05). Severe liver damage was observed in chicks fed 2 mg/kg of AFB1 with lesions consistent with aflatoxicosis, including fatty liver and vacuolar degeneration. Serum glucose, albumin, total protein, Ca, P, and alkaline phosphatase concentrations were reduced by AFB1 (P<0.05). The addition of either SO or MTB ameliorated the negative effects of 1 mg/kg of AFB1 on growth performance and liver damage (P<0.05). However, supplemental MTB failed to diminish the negative effects of 2 mg/kg of AFB1, whereas SO was more effective compared with MTB at 2 mg/kg of AFB1 (P<0.05). These data indicate that the HSCAS product effectively ameliorated the negative effect of AFB1 on growth performance and liver damage, whereas the yeast cell wall product was less effective especially at the higher AFB1 concentration. PMID- 20852107 TI - Effects of zinc source and phytate on zinc absorption by in situ ligated intestinal loops of broilers. AB - Two experiments were conducted to investigate the effects of Zn source and phytate on Zn absorption in broilers. In experiment 1, eight different Zn sources, including ZnSO4, Zn Gly chelate, Zn Met chelate, and Zn amino acid C complex with the weak complex strength (Zn AA C), Zn protein B complex with the moderate complex strength (Zn Pro B), and zinc protein A complex with the strong complex strength (Zn Pro A), and the mixtures of ZnSO4 with either Gly or Met (Zn+Gly or Zn+Met, respectively) were used to study the effects of Zn sources on Zn absorption by in situ ligated intestinal loops of broilers. In experiment 2, 3*4 factorial arrangements of treatments involving 3 phytate levels and 4 Zn sources were used to investigate the effect of phytate on Zn absorption. Three molar ratios of phytate to Zn were 0, 2:1, and 10:1, respectively, and 4 Zn sources included ZnSO4, Zn AA C, Zn Pro B, and Zn Pro A, respectively. No differences (P>0.05) were found among the absorption percentages of Zn as Zn+Gly, Zn+Met, and ZnSO4 in 3 intestinal segments. The absorption percentages of Zn as Zn Gly chelate, Zn Met chelate, Zn AA C, Zn Pro B, and Zn Pro A in the duodenum and jejunum were 29 to 129% higher (P<0.05) than those of Zn as ZnSO4, Zn+Gly, and Zn+Met in the following order: Zn Pro A>Zn Pro B>Zn AA C>Zn Gly chelate or Zn Met chelate>ZnSO4, Zn+Met, or Zn+Gly. The changes of Zn absorption as different Zn sources in the ileum were also observed and were similar to those in the duodenum and jejunum. There was a significant interaction (P<0.05) between phytate levels and Zn sources on Zn absorption in 3 intestinal segments. The absorption percentage of Zn as ZnSO4 in the duodenum with a phytate-added group (10:1) was 40% (P<0.05) lower than that of Zn as ZnSO4 without a phytate-added group. With the increasing phytate levels, the changes of Zn absorption as organic Zn sources in 3 intestinal segments were similar to those of ZnSO4 in the duodenum. However, the reduction of Zn absorption as organic Zn sources was lessened with the increasing complex strengths, and the highest absorption of Zn as Zn Pro A was observed. These results indicated that the absorption of Zn as organic Zn was more effective than that of Zn as inorganic Zn. The organic Zn absorption increased with the increasing complex strengths as well. The simple mixture of ZnSO4 with amino acid did not increase Zn absorption. In addition, the phytate could reduce Zn absorption as different Zn sources in 3 intestinal segments. Organic Zn sources could lessen the negative effect of phytate on Zn absorption, and then the absorption of organic Zn, especially Zn Pro A with strong complex strength, was more effective than inorganic Zn under the high levels of phytate. PMID- 20852108 TI - Selenium enrichment of table eggs. AB - Selenium is an essential trace element with a recommended dietary allowance for human adults of 55 MUg/d. However, there is evidence that greater dietary intakes may have possible health benefits, including a reduction in the risk of cancer. Several studies have shown the feasibility of enriching eggs using organic Se and that Se-enriched eggs are an effective way to supplement human diets. However, few studies have examined the response of egg Se concentration to high (>1 MUg/g) dietary organic Se intake by the laying hens. The objective of the current study is to examine the effect of higher dietary organic Se levels on production, egg mass, and egg Se levels. These were assessed by feeding 3 breeds of laying hens (Barred Plymouth Rock, Lohmann Brown, Lohmann White) a basal diet containing 0.3 MUg of Se/g of diet as Na2SeO3. Into this diet, Se yeast (SelenoSource AF 600), an organic source of Se, was added at 1.0, 2.4, or 5.1 MUg of Se/g of diet for 4 wk. Feed consumption, egg production, and egg mass were not affected by the dietary Se concentration in all 3 breeds. Within the range of Se levels employed in the laying hens' diet, egg Se content increased linearly as dietary levels of Se increased. The results of this study indicate that feeding up to 5.1 ug/g of Se will not affect egg production and the welfare of the laying hen and is a practical way of producing Se-enriched eggs for the consumers. PMID- 20852109 TI - Digestible lysine requirements of male broilers from 28 to 42 days of age. AB - Research addressing digestible Lys requirement data of modern broilers from 4 to 6 wk of age is limited. Male broilers (1,632 Ross*Ross TP16 and 3,000 Cobb*Cobb 700) were used in separate experiments to determine the digestible Lys requirements from 28 to 42 d. In each experiment, 2 diets (dilution and summit) consisting of corn, soybean meal, animal protein meal, and peanut meal were formulated to be adequate in all other amino acids. The dilution and summit diets were blended to create 9 titration diets. A control diet formulated to contain corn, soybean meal, and animal protein meal as the primary ingredients was used for comparison with the titration diets. Body weight gain, feed intake, digestible Lys intake, digestible Lys intake:BW gain, feed conversion, mortality, carcass yields, and physiological measurements were assessed during experimentation. Digestible Lys requirements were estimated using a quadratic broken-line model. In experiment 1, the digestible Lys requirement for male Ross*Ross TP16 broilers was determined at 0.988, 1.053, 0.939, and 0.962%, respectively, for BW gain, feed conversion, carcass weight, and total breast meat weight. In experiment 2, the digestible Lys requirement for male Cobb*Cobb 700 broilers ranged from 0.965, 1.012, 1.029, 0.987, and 0.981%, respectively, for 28 to 42-d BW gain, feed conversion, carcass weight, total breast meat weight, and total breast meat yield. Digestible Lys requirements for male Ross*Ross TP16 and Cobb*Cobb 700 broilers were estimated at 1.001 and 0.995%, respectively, based upon averages of live performance and meat yield responses. Both strains required the highest requirement estimate of digestible Lys to optimize feed conversion. PMID- 20852110 TI - Comparative feeding value of extruded and nonextruded wheat and corn distillers dried grains with solubles for broilers. AB - The feeding value of extruded and nonextruded wheat and corn distillers dried grains with solubles (DDGS) for broilers was evaluated in 2 experiments. In experiment 1, male broilers (n=360) housed in battery cages were fed assay diets that included either 15 or 30% wheat or corn DDGS (extruded or not) in relation to a basal diet from d 21 to 28. Birds were killed on d 28 and ileal digesta was collected to establish the apparent ileal digestibility (AID) coefficients of energy and nutrients for test ingredients using the difference method based on 5 cages of 8 birds per diet. In experiment 2, a 42-d study compared the growth performance of broilers fed phase diets including 0, 5, or 10% wheat or corn DDGS, based on 4 pens of 55 birds per diet*sex combination. Diets within phase were formulated to have a similar content of AME, CP, and digestible lysine. Breast meat weight and yield were determined on d 37 by sampling 5 birds per pen. In experiment 1, at 15% inclusion, AID coefficients of most amino acids were higher for corn DDGS than for wheat DDGS (P<0.05). At 30% inclusion, however, there were fewer differences in AID between corn and wheat DDGS. Twin-screw extrusion increased the AID of AA in both corn and wheat DDGS by 10 to 34% (P<0.05). In experiment 2, there was no adverse effect of including corn or wheat DDGS at up to 10% of the diet on pen average daily weight gain, feed disappearance, feed efficiency, breast meat weight, or yield. In conclusion, extrusion increased the feeding value of DDGS. The AID coefficients for amino acids were similar between corn and wheat DDGS. We also confirmed that either corn or wheat DDGS can be included at up to 10% of wheat-based broiler diets without affecting growth performance or breast meat yield. PMID- 20852111 TI - Effects of type and particle size of dietary fiber on growth performance and digestive traits of broilers from 1 to 21 days of age. AB - A trial was conducted to study the effects of type and particle size of dietary fiber on growth performance and digestive traits of broilers from 1 to 21 d of age. There was a negative control diet with 1.54% crude fiber, a positive control diet that included 3% cellulose (CEL), and 4 additional diets arranged factorially that included 3% oat hulls (OH) or sugar beet pulp (SBP) ground through a 0.5- or a 2.0-mm screen. For the entire experimental period, fiber inclusion improved BW gain (P<=0.01) and feed conversion ratio (P<=0.001), but particle size of the fiber source did not affect performance. The relative weight of the gizzard was higher (P<=0.001) with OH and SBP than with CEL or the control diet. Also, gizzard weight decreased (P<=0.001) with a reduction in particle size of the fiber source. Fiber inclusion increased HCl concentration and reduced gizzard pH (P<=0.01), and the effects were more noticeable with OH and SBP than with CEL. Fiber inclusion increased total tract apparent retention of nitrogen (P<=0.001) and soluble ash (P<=0.001) as well as the AMEn of the diet (P<=0.001). All of these effects were in general more pronounced with OH than with CEL, with SBP being intermediate. A reduction in particle size of the OH and SBP improved total tract apparent retention of DM (P<=0.001), nitrogen (P<=0.05), and soluble ash (P<=0.01) as well as the AMEn of the diet (P<=0.05). It is concluded that additional OH and SBP improves gizzard weight and growth performance in young chicks fed low-fiber diets and that the effects are more pronounced with OH than with CEL. Particle size of OH and SBP does not affect broiler performance, but coarse grinding increases gizzard development and reduces nutrient digestibility in young birds. PMID- 20852112 TI - The effects of Saccharomyces cerevisiae extract on the weight of some organs, liver, and pancreatic digestive enzyme activity in breeder hens fed diets contaminated with aflatoxins. AB - The effects of the Saccharomyces cerevisiae extract on some organ, liver, and pancreatic digestive enzymes in breeder hens fed on aflatoxin (AF)-contaminated feed were investigated. Forty-eight 58-wk-old Ross 308 breeder hens were used. The hens were fed diets containing 0 or 100 ug of AF/kg and 0 or 1 g of S. cerevisiae/kg in a 2*2 factorial arrangement of treatments. Although serum alkaline phosphatase levels were significantly higher, serum alkaline aminotransferase (P=0.068) and gamma-glutamyltransferase (P=0.067) levels tended to increase (P<0.05) in hens fed the AF-contaminated diet than those of hens fed the uncontaminated diet. Both AF and S. cerevisiae extract increased (P<0.001) pancreatic amylase activity, but the effect was not additive, resulting in an AF*S. cerevisiae extract interaction (P<0.001). alpha-Amylase activity in duodenum was lower (P<0.001) in hens fed the AF-contaminated diet. Duodenum alpha amylase activity was higher (P=0.024), but jejunum alpha-amylase activity was lower in S. cerevisiae extract-supplemented hens than that of nonsupplemented hens. There was a significant interaction between AF and S. cerevisiae extract on pancreatic and duodenal lipase activity. Pancreatic lipase activity decreased in hens fed the AF-contaminated diet. However, S. cerevisiae supplementation extract minimized this effect of AF on pancreatic lipase activity. Duodenal lipase activity was decreased in hens fed the AF-contaminated diet without S. cerevisiae extract supplementation. However, there were not any significant differences between hens fed the AF-contaminated diet and hens fed the uncontaminated diet after S. cerevisiae extract supplementation. Pancreatic trypsin activity was higher (P=0.044) in hens fed the AF-contaminated diet than that of hens fed the uncontaminated diet. There was a significant interaction between AF and S. cerevisiae extract on pancreatic chymotrypsin activity. It was increased in hens fed the AF-contaminated diet without S. cerevisiae extract supplementation. However, S. cerevisiae extract supplementation counteracted this negative effect of AF on pancreatic chymotrypsin activity. The treatments did not result in any change in duodenal chymotrypsin activity, but S. cerevisiae supplementation decreased (P<0.05) jejunal chymotrypsin activity. In conclusion, our results showed that addition of 1 g/kg of S. cerevisiae extract reduces the toxic effects of AF on pancreatic lipase and chymotrypsin activity. Therefore, it may be useful to supplement feedstuff with S. cerevisiae extract to reduce the effects of AF in laying breeder hens. PMID- 20852113 TI - Growth performance and nutrient utilization of broiler chickens fed diets supplemented with phytase alone or in combination with citric acid and multicarbohydrase. AB - An experiment was conducted to determine the effect of supplementing a corn soybean meal-based diet with phytase alone or in combination with citric acid (CA) or multicarbohydrase, a preparation containing nonstarch polysaccharide degrading enzymes, or both, on growth performance, nutrient utilization, and bone mineralization. A total of 360 one-day-old broiler chicks were assigned to 6 dietary treatments, consisting of 12 pens of 5 birds each, and were fed experimental diets from 1 to 21 d of age. The diets included a positive control (0.46% nonphytate P; 1.1% Ca) and a negative control (NC; 0.26% nonphytate P; 0.89% Ca) without or with phytase (600 U/kg) alone, phytase plus CA (5 g/kg), phytase plus multicarbohydrase (Superzyme OM; 0.6 g/kg), or phytase (Ronozyme P CT) plus CA and multicarbohydrase. Birds fed the positive control diet had higher (P<0.05) BW gain (764 vs. 594 g/21 d) and tibia ash content (50.0 vs. 38.3%) than those fed the NC diet. Phytase improved (P<0.05) BW gain (632 g/21 d), which increased further (P<0.05) to 673 g/21 d for the phytase plus multicarbohydrase diet. In contrast to phytase alone, phytase plus multicarbohydrase supplementation improved (P<0.05) feed conversion ratio of the NC diet from 1.37 to 1.32. Tibia ash content for the NC diet increased (P<0.05) from 38.3 to 42.4% due to phytase addition. Phytase improved (P<0.05) ileal digestibility of P from 29.5 to 43%, and the addition of CA or multicarbohydrase, or both, to a phytase supplemented diet further increased (P<0.05) P digestibility to 51.5, 53.4, and 54.3%, respectively. Phytase addition improved (P<0.05) diet AMEn content from 2,959 to 3,068 kcal/kg, which tended (P<0.06) to increase further with CA (3,150 kcal/kg) or multicarbohydrase (3,142 kcal/kg) addition. No beneficial interactions were detected between CA and multicarbohydrase for all response criteria measured. Results show that addition of multicarbohydrase to the phytase supplemented broiler diets improved nutrient utilization and growth performance. PMID- 20852114 TI - Energy value of wheat dried distillers grains with solubles in roosters, broilers, layers, and turkeys. AB - Four experiments were conducted to measure total tract metabolizability of gross energy (GE), the AME, and AMEn or AME content corrected for a standardized N retention (AMEs) of 10 European wheat dried distillers grains with solubles (DDGS) in roosters, broilers (3 wk old), layers (25 wk old), and growing turkeys (10 wk old). The wheat DDGS were obtained from 7 European ethanol plants and selected to get a large variability in chemical composition. The AME, AMEn, or AMEs of wheat DDGS was obtained according to the difference method. The highest AMEn:GE was obtained for roosters with an average (minimum-maximum) value of 49% (43-55), the lowest in turkeys (43%; 34-50), and intermediate values (47%; 41-57 and 46%; 36-50) in broilers and layers, respectively. Corresponding AMEn values were 10.3 (9.0-11.3), 9.9 (8.5-11.7), 9.6 (7.8-10.5), and 9.6 (7.8-10.5) MJ/kg of DM for roosters, broilers, layers, and turkeys, respectively. The AMEs for N retention equal to 50% of N intake was about 0.6 MJ higher than the corresponding AMEn value. Our data indicate that the AMEn content of wheat DDGS can be predicted from either their acid detergent fiber content (R2=0.79) or the lightness score (L*; R2=0.77) with a common slope but different intercepts for the 4 poultry categories. If dark and overheated samples (L*<50; n=3) with the lowest AMEn:GE ratio and AMEn values are excluded, the average AMEn:GE ratio becomes 51, 49, 48, and 45% in roosters, broilers, layers, and turkeys, respectively, with corresponding AMEn values of 10.7, 10.2, 10.0, and 9.5 MJ/kg of DM that are more representative of a well-controlled process for DDGS preparation. The negative effect of L* on energy value and energy metabolizability indicates that overheating while drying should be minimized to maximize the energy value of wheat DDGS for poultry. Finally, equations for predicting AME values in layers, broilers, or turkeys from the AME values in roosters are proposed. PMID- 20852115 TI - Effects of feeding distillers dried grains with solubles to broilers from 0 to 28 days posthatch on broiler performance, feed manufacturing efficiency, and selected intestinal characteristics. AB - This study evaluated the effect of 2 levels (0 vs. 8%) of distillers dried grains with solubles (DDGS) in a starter broiler diet (0 to 14 d; 45 replicates/treatment) after these same birds were subsequently fed a grower diet (14 to 28 d) with either 0, 7.5, 15, 22.5, or 30% DDGS (9 replicates/treatment). Ross*Ross 308 male broilers were used in this experiment, and evaluation criteria consisted of feed mill parameters, broiler growth, relative liver weight, ileal viscosity, and cecal content count of Clostridium perfringens and Escherichia coli analyzed by both selective media and real-time PCR. Increased inclusion of DDGS resulted in a nonlinear response for production rate (P<0.05), conditioner energy usage (P<0.01), and pellet mill energy usage (P<0.05). Increasing DDGS resulted in a linear decrease in pellet quality (P<0.001) and an increase (P<0.001) in total fines. Inclusion of DDGS decreased (P<0.001) energy usage at the pellet mill and decreased (P<0.05) bulk density of the diets. The DDGS levels fed during the starter phase (0 vs. 8%) had no effect on the broilers at 14 or at 28 d of age. Increasing DDGS inclusion levels during the grower phase resulted in a linear decrease (P<0.001) in BW gain and liver relative weight (P<0.001). A DDGS starter*grower interaction (P<0.05) was observed for feed consumption, in which birds that consumed no DDGS during the starter phase exhibited a decrease in feed consumption with the higher inclusion levels of DDGS during the grower phase, whereas birds that received 8% DDGS during the starter phase were unaffected by DDGS inclusion level in the grower phase. Feed conversion, mortality, ileal viscosity, and cecal C. perfringens and E. coli concentrations were unaffected by DDGS level in the grower diet. The feed intake response suggests a beneficial effect of exposing broiler chicks to DDGS if inclusion levels of 22.5% or higher are to be fed after 14 d of age. However, the data suggest that the young broiler can be negatively affected with inclusion levels of 15% DDGS or higher up to 28 d of age. PMID- 20852116 TI - Epigallocatechin-3-gallate prevents lipid peroxidation and enhances antioxidant defense system via modulating hepatic nuclear transcription factors in heat stressed quails. AB - Epigallocatechin-3-gallate (EGCG), a polyphenol derived from green tea, exerts antioxidant effects. Oxidative stress is one of the consequences of heat stress (HS), which also depresses performance in poultry. This experiment was conducted to elucidate the action mode of EGCG in alleviation of oxidative stress in heat stressed quail (Coturnix coturnix japonica). A total of 180 five-week-old female Japanese quails were reared either at 22 degrees C for 24 h/d (thermoneutral, TN) or 34 degrees C for 8 h/d (HS) for 12 wk. Birds in both environments were randomly fed 1 of 3 diets: basal diet and basal diet added with 200 or 400 mg of EGCG/kg of diet. Each of the 2*3 factorially arranged groups was replicated in 10 cages, each containing 3 quails. Performance variables [feed intake (FI) and egg production (EP)], oxidative stress biomarkers [malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and hepatic transcription factors [nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)] were analyzed using 2-way ANOVA. Exposure to HS caused reductions in FI by 9.7% and EP by 14.4%, increased hepatic MDA level by 84.8%, and decreased hepatic SOD, CAT, and GSH-Px activities by 25.8, 52.3, and 45.5%, respectively (P<0.0001 for all). The hepatic NF-kappaB expression was greater (156 vs. 82%) and Nrf2 expression was lower (84 vs. 118%) for quails reared under the HS environment than for those reared under the TN environment (P<0.0001 for both). In response to increasing supplemental EGCG level, there were linear increases in FI from 29.6 to 30.9 g/d and EP from 84.3 to 90.1%/d, linear decreases in hepatic MDA level from 2.82 to 1.72 nmol/g and Nrf2 expression from 77.5 to 123.3%, and linear increases in hepatic SOD (146.4 to 182.2), CAT (36.2 to 47.1), and GSH-Px (13.5 to 18.5) activities (U/mg of protein) and NF-kappaB expression (149.7 to 87.3%) (P<0.0001 for all). Two-way treatment interactions revealed that the degree of restorations in all response variables was more notable under the HS environment than under the TN environment as supplemental EGCG level was increased. Moreover, levels of oxidative biomarkers were strongly correlated with expressions of hepatic nuclear transcription factors. In conclusion, supplemental EGCG alleviates oxidative stress through modulating the hepatic nuclear transcription factors in heat-stressed quails. PMID- 20852117 TI - Expression analyses and antiviral properties of the Beijing-You and White Leghorn myxovirus resistance gene with different amino acids at position 631. AB - Influenza is a topic of wide public concern, particularly because of the recent emergence of avian flu. The myxovirus resistance (Mx) protein has been shown to have an inhibitory effect on influenza virus and is therefore of great interest. This study examines the Mx protein in 8 local Chinese chicken breeds and 2 exotic chicken breeds. Amino acid 631, found in the Mx GTPase effector domain, was examined in 534 individuals by comparing PCR results, and individuals were separated into the A/A genotype or the G/G genotype, depending on whether amino acid 631 is an Asn or Ser. In the native breed, the frequency of G/G homozygotes is 0.780 (294/377). The Mx expression levels in tissues and chicken embryo fibroblast cells with different genotypes were also studied. The A/A individuals from Beijing-You and White Leghorn breeds had higher Mx expression levels than G/G individuals. The liver, heart, and spleen had higher expression levels than muscle or kidney. The A/A chicken embryo fibroblast cells had higher antiviral activity against vesicular stomatitis virus and Newcastle disease. We provide the first report examining the expression level and antiviral activity of different Mx alleles of nucleotide 2216(S631N) genotypes. This study lays a good foundation for correlative studies examining genotype and antiviral function. PMID- 20852118 TI - Initiating egg production in turkey breeder hens: thyroid hormone involvement. AB - The role of thyroid hormones in the expression of photosensitivity photorefractoriness in female turkeys was investigated through the use of an antithyroidal agent, 6-n-propyl-2-thiouracil (PTU). In experiment 1, females held continuously from hatch on long day lengths (16L:8D; LD) and fed 0.1% PTU from 0 to 16 wk, began laying eggs at 26 wk of age, peaking at 75% hen-day egg production by 29 wk, whereas controls initiated lay 3 wk earlier but only achieved less than 50% hen-day egg production. In experiment 2, PTU treatment from 10 to 18 wk severely suppressed plasma triiodothyronine and thyroxine, as confirmed by RIA. Egg production of PTU and control hens held on LD from hatch began by 23 wk, with PTU hens reaching a substantially greater rate of lay than controls. Eggs were smaller initially in both treatments but exceeded 75 g by 28 wk. In experiment 3, recycled hens on short day lengths (8L:16D) received PTU for 2 wk before LD and 12 wk thereafter; a subset of these hens was killed after 48 h of LD for immunohistochemical analysis of fos-related antigen (FRA) expression in the tuberal hypothalamus as a marker of photoinduced neuronal activity. The PTU treatment completely forestalled egg production until its withdrawal; egg production then rose sharply to control levels before resuming, along with controls, a typical seasonal decline. The PTU treatment did not impair photoinduced FRA expression. Together, these results demonstrate the following: 1) that a period of pharmacological suppression of triiodothyronine and thyroxine can substitute for short day exposure in conferring photosensitivity on juvenile aged turkeys (and is actually superior to short day exposure), 2) that reproductive development does not limit egg production of turkey hens photostimulated as young as approximately 20 wk of age, and 3) that effects of thyroid suppression on photostimulation lie downstream of photoinduced FRA expression. Taken together, these results suggest that there is ample physiological potential to substantially advance the age of photoinduced egg production in commercial flocks. PMID- 20852119 TI - Enzymatic hydrolysis of poultry meal with endo- and exopeptidases. AB - The objective of this research was to determine whether commercial proteases are capable of hydrolyzing denatured poultry by-product proteins that have gone through a rendering process. The material used for this research was low-ash poultry meal obtained from a local poultry processor. Samples of poultry meal were treated with the commercial proteases Alcalase, Flavourzyme, Protamex, and Liquipanol that were added individually or as a combination of 2 proteases, which were incorporated either simultaneously or sequentially. Temperature was controlled during the reaction to the optimal level for each enzyme, and pH was initially adjusted to the most favorable level for each enzyme and was maintained during the course of the reaction by addition of NaOH at established intervals. Consumption of NaOH was used to calculate the degree of hydrolysis. At the end of the hydrolysis, the molecular weight of selected hydrolysates was determined by size exclusion chromatography and by gel electrophoresis. In addition, amino acid analysis was performed on selected hydrolysates. Results show that the sequential treatment with Alcalase and Flavourzyme served best for the preparation of poultry meal hydrolysates with a maximum degree of hydrolysis of 11.1% and the highest hydrolyzable material recovered at 58%, which is attributed to the combined nature of the endo- and exocatalytic action of Alcalase and Flavourzyme, respectively. Hydrolysate with Flavourzyme or the combination of Flavourzyme and Alcalase were both good methods to produce significant amounts of free amino acids. This research shows the feasibility of hydrolyzing poultry by-products that went through a rendering process using different brands of commercial proteases. Findings from this research are important in the preparation of palatants, in which relatively inexpensive hydrolyzed poultry meal could be used to improve the flavor of companion animal food products. PMID- 20852120 TI - Sensory characteristics and consumer preference for chicken meat in Guinea. AB - This study identified the sensory characteristics and consumer preference for chicken meat in Guinea. Five chicken samples [live village chicken, live broiler, live spent laying hen, ready-to-cook broiler, and ready-to-cook broiler (imported)] bought from different locations were assessed by 10 trained panelists using 19 sensory attributes. The ANOVA results showed that 3 chicken appearance attributes (brown, yellow, and white), 5 chicken odor attributes (oily, intense, medicine smell, roasted, and mouth persistent), 3 chicken flavor attributes (sweet, bitter, and astringent), and 8 chicken texture attributes (firm, tender, juicy, chew, smooth, springy, hard, and fibrous) were significantly discriminating between the chicken samples (P<0.05). Principal component analysis of the sensory data showed that the first 2 principal components explained 84% of the sensory data variance. The principal component analysis results showed that the live village chicken, the live spent laying hen, and the ready-to-cook broiler (imported) were very well represented and clearly distinguished from the live broiler and the ready-to-cook broiler. One hundred twenty consumers expressed their preferences for the chicken samples using a 5-point Likert scale. The hierarchical cluster analysis of the preference data identified 4 homogenous consumer clusters. The hierarchical cluster analysis results showed that the live village chicken was the most preferred chicken sample, whereas the ready-to-cook broiler was the least preferred one. The partial least squares regression (PLSR) type 1 showed that 72% of the sensory data for the first 2 principal components explained 83% of the chicken preference. The PLSR1 identified that the sensory characteristics juicy, oily, sweet, hard, mouth persistent, and yellow were the most relevant sensory drivers of the Guinean chicken preference. The PLSR2 (with multiple responses) identified the relationship between the chicken samples, their sensory attributes, and the consumer clusters. Our results showed that there was not a chicken category that was exclusively preferred from the other chicken samples and therefore highlight the existence of place for development of all chicken categories in the local market. PMID- 20852121 TI - Sensory evaluation and consumer acceptance of eggs from hens fed flax seed and 2 different antioxidants. AB - The sensory attributes and consumer acceptance of eggs from flax seed-fed hens were evaluated by trained and untrained panelists. Hens were fed diets containing 0% flax seed (control), 10% flax seed (flax), 10% flax seed+100 IU/kg of vitamin E (flax+alpha-tocopherol), or 10% flax seed+100 mg/kg of butylated hydroxytoluene (BHT) (flax+BHT). Fresh eggs collected within 24 h were hard-boiled, coded, and were offered to trained panelists in 4 testing sessions. Sensory traits evaluated were aroma, flavor, off-flavor, and overall difference. The trained panelists rated flax, flax+alpha-tocopherol, and flax+BHT eggs to be different from control eggs (P<0.001). In a second study, sensory attributes were tested by untrained panelists. The majority (75 to 80%) of the panelists could not distinguish flax seed-fed versus control eggs for aroma and flavor. A consumer preference test was also conducted to gauge end-user response to flax seed-fed eggs. Consumer acceptance testing did not find any significant difference (P>0.05) between control and flax seed-fed eggs. These results suggest that flax seed when incorporated at 10% in the layer diet can produce eggs that are acceptable to untrained panelists and consumers. However, trained panelists are able to detect differences in flavor, aroma, and off-flavor and overall difference in eggs from hens fed flax seed. Antioxidant supplementation (vitamin E, BHT) did not enhance the acceptability of flax seed-fed eggs by trained panelists. PMID- 20852122 TI - Treated fava bean (Vicia faba var. minor) as substitute for soybean meal in diet of early phase laying hens: egg-laying performance and egg quality. AB - The objective of this study was to determine the effect of dietary dehulled micronized fava bean (Vicia faba var. minor) seed on egg production, egg weight, feed conversion ratio, eggshell quality, and egg yolk color. In this trial, 18-wk old laying hens in the early phase of production (ISA Brown) were randomly assigned to 2 groups and fed durum wheat middlings-based diets containing soybean or micronized-dehulled fava bean meal as the main protein source. Eggs were collected and weighed daily. Laying performance, egg quality, and feed conversion ratio were evaluated for 10 wk. The only significant effect detected was for feed intake (P<0.05), which was lower in hens fed the diet containing fava bean than for hens fed soybean meal, without however any negative effects on feed efficiency. None of the egg quality parameters studied were influenced by dietary treatment, except for yolk color score that was reduced in hens fed the fava bean diet (P<0.05). We conclude that dehulled-micronized fava beans in the diet did not have a negative influence on productive performance or egg quality of young brown hens. PMID- 20852124 TI - CSPG4 protein as a new target for the antibody-based immunotherapy of triple negative breast cancer. AB - BACKGROUND: The cell surface proteoglycan, chondroitin sulfate proteoglycan 4 (CSPG4), is a potential target for monoclonal antibody (mAb)-based immunotherapy for many types of cancer. The lack of effective therapy for triple-negative breast cancer (TNBC) prompted us to examine whether CSPG4 is expressed in TNBC and can be targeted with CSPG4-specific mAb. METHODS: CSPG4 protein expression was assessed in 44 primary TNBC lesions, in TNBC cell lines HS578T, MDA-MB-231, MDA-MB-435, and SUM149, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. The effect of CSPG4-specific mAb 225.28 on growth, adhesion, and migration of TNBC cells was tested in vitro. The ability of mAb 225.28 to induce regression of tumor metastases (n = 7 mice) and to inhibit spontaneous metastasis and tumor recurrence (n = 12 mice per group) was tested in breast cancer models in mice. The mechanisms responsible for the antitumor effect of mAb 225.28 were also investigated in the cell lines and in the mouse models. All statistical tests were two-sided. RESULTS: CSPG4 protein was preferentially expressed in 32 of the 44 (72.7%) primary TNBC lesions tested, in TNBC cell lines, and in tumor cells in pleural effusions from 12 metastatic breast cancer patients. CSPG4-specific mAb 225.28 statistically significantly inhibited growth, adhesion, and migration of TNBC cells in vitro. mAb 225.28 induced 73.1% regression of tumor metastasis in a TNBC cell-derived experimental lung metastasis model (mAb 225.28 vs control, mean area of metastatic nodules = 44590.8 vs 165950.8 MUm(2); difference of mean = 121360.0 MUm(2), 95% confidence interval = 91010.7 to 151709.4 MUm(2); P < .001). Additionally, mAb 225.28 statistically significantly reduced spontaneous lung metastases and tumor recurrences in an orthotopic xenograft mouse model. The mechanisms responsible for antitumor effect included increased apoptosis and reduced mitotic activity in tumor cells, decreased blood vessel density in the tumor microenvironment, and reduced activation of signaling pathways involved in cell survival, proliferation and metastasis. CONCLUSIONS: This study identified CSPG4 as a new target for TNBC. The antitumor activity of CSPG4-specific mAb was mediated by multiple mechanisms, including the inhibition of signaling pathways crucial for TNBC cell survival, proliferation, and metastasis. PMID- 20852125 TI - RGS/Gi2alpha interactions modulate platelet accumulation and thrombus formation at sites of vascular injury. AB - Although much is known about extrinsic regulators of platelet function such as nitric oxide and prostaglandin I(2) (PGI(2)), considerably less is known about intrinsic mechanisms that prevent overly robust platelet activation after vascular injury. Here we provide the first evidence that regulators of G-protein signaling (RGS) proteins serve this role in platelets, using mice with a G184S substitution in G(i2alpha) that blocks RGS/G(i2) interactions to examine the consequences of lifting constraints on G(i2)-dependent signaling without altering receptor:effector coupling. The results show that the G(i2alpha)(G184S) allele enhances platelet aggregation in vitro and increases platelet accumulation after vascular injury when expressed either as a global knock-in or limited to hematopoietic cells. Biochemical studies show that these changes occur in concert with an attenuated rise in cyclic adenosine monophosphate levels in response to prostacyclin and a substantial increase in basal Akt activation. In contrast, basal cyclic adenosine monophosphate (cAMP) levels, agonist-stimulated increases in [Ca(++)](i), Rap1 activation, and alpha-granule secretion were unaffected. Collectively, these observations (1) demonstrate an active role for RGS proteins in regulating platelet responsiveness, (2) show that this occurs in a pathway selective manner, and (3) suggest that RGS proteins help to prevent unwarranted platelet activation as well as limiting the magnitude of the normal hemostatic response. PMID- 20852126 TI - Heparin modifies the immunogenicity of positively charged proteins. AB - The immune response in heparin-induced thrombocytopenia is initiated by and directed to large multimolecular complexes of platelet factor 4 (PF4) and heparin (H). We have previously shown that PF4:H multimolecular complexes assemble through electrostatic interactions and, once formed, are highly immunogenic in vivo. Based on these observations, we hypothesized that other positively charged proteins would exhibit similar biologic interactions with H. To test this hypothesis, we selected 2 unrelated positively charged proteins, protamine (PRT) and lysozyme, and studied H-dependent interactions using in vitro and in vivo techniques. Our studies indicate that PRT/H and lysozyme/H, like PF4/H, show H dependent binding over a range of H concentrations and that formation of complexes occurs at distinct stoichiometric ratios. We show that protein/H complexes are capable of eliciting high-titer antigen-specific antibodies in a murine immunization model and that PRT/H antibodies occur in patients undergoing cardiopulmonary bypass surgery. Finally, our studies indicate that protein/H complexes, but not uncomplexed protein, directly activate dendritic cells in vitro leading to interleukin-12 release. Taken together, these studies indicate that H significantly alters the biophysical and biologic properties of positively charged compounds through formation of multimolecular complexes that lead to dendritic cell activation and trigger immune responses in vivo. PMID- 20852127 TI - The pathogenesis of Plasmodium falciparum malaria in humans: insights from splenic physiology. AB - Clinical manifestations of Plasmodium falciparum infection are induced by the asexual stages of the parasite that develop inside red blood cells (RBCs). Because splenic microcirculatory beds filter out altered RBCs, the spleen can innately clear subpopulations of infected or uninfected RBC modified during falciparum malaria. The spleen appears more protective against severe manifestations of malaria in naive than in immune subjects. The spleen-specific pitting function accounts for a large fraction of parasite clearance in artemisinin-treated patients. RBC loss contributes to malarial anemia, a clinical form associated with subacute progression, frequent splenomegaly, and relatively low parasitemia. Stringent splenic clearance of ring-infected RBCs and uninfected, but parasite-altered, RBCs, may altogether exacerbate anemia and reduce the risks of severe complications associated with high parasite loads, such as cerebral malaria. The age of the patient directly influences the risk of severe manifestations. We hypothesize that coevolution resulting in increased splenic clearance of P. falciparum-altered RBCs in children favors the survival of the host and, ultimately, sustained parasite transmission. This analysis of the RBC-spleen dynamic interactions during P falciparum infection reflects both data and hypotheses, and provides a framework on which a more complete immunologic understanding of malaria pathogenesis may be elaborated. PMID- 20852128 TI - Mutation of inhibitory helix-loop-helix protein Id3 causes gammadelta T-cell lymphoma in mice. AB - Human gammadelta T-cell lymphoma is a rare clinicopathologic entity with aggressive course and poor prognosis. The etiology and pathogenesis of gammadelta T-cell lymphoma is unknown. We show here that mice with deficiency in inhibitory helix-loop-helix protein Id3 (Id3(-/-)) developed gammadelta T-cell lymphoma that resembled human gammadelta T-cell lymphoma. The Id3(-/-) mice with lymphoma showed splenomegaly, hepatomegaly, and lymphadenopathy with involvement of bone marrow, thymus, kidney, and lungs between 6 and 15 months of age. Phenotypic analysis revealed that lymphomatous cells were cluster of differentiation (CD)3(+), gammadelta T-cell receptor (TCR)(+), and alphabeta TCR(-), and expressed CD8(+)CD4(-), CD4(+)CD8(-), or a mixture of the two. Id3(-/-) gammadelta T-cell lymphoma used predominantly Vgamma1.1, some Vgamma3, yet no Vgamma2 TCR, and some showed increased levels of the oncogene c-Myc. Strikingly, adoptive transfer of the gammadelta T-cell lymphoma into syngeneic Rag1(-/-) mice resulted in aggressive gammadelta T-cell lymphoma, identical to the Id3(-/-) donor. Thus, our data demonstrate that Id3 regulates the development of gammadelta T-cell lymphoma in mice, raising a possibility of Id3 gene mutation in human gammadelta T-cell lymphoma. Our model will provide a tool for studying the molecular mechanisms and development of human gammadelta T-cell lymphoma. PMID- 20852130 TI - miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. AB - The recent discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation, affecting the immune system. Here, we identify their roles in regulating human plasmacytoid dendritic cell (PDC) activation. miRNA profiling showed the significantly differential expression of 19 miRNAs in PDCs after Toll like receptor 7 (TLR7) stimulation, among which miR-155* and miR-155 were the most highly induced. Although they were processed from a single precursor and were both induced by TLR7 through the c-Jun N-terminal kinase pathway, miR-155* and miR-155 had opposite effects on the regulation of type I interferon production by PDC. Further study indicated that miR-155* augmented interferon alpha/beta expression by suppressing IRAKM, whereas miR-155 inhibited their expression by targeting TAB2. Kinetic analysis of miR-155* and miR-155 induction revealed that miR-155* was mainly induced in the early stage of stimulation, and that miR-155 was mainly induced in the later stage, suggesting their cooperative involvement in PDC activation. Finally, we demonstrated that miR-155* and miR-155 were inversely regulated by autocrine/paracrine type I interferon and TLR7 activated KHSRP at the posttranscriptional level, which led to their different dynamic induction by TLR7. Thus, our study identified and validated novel miRNA protein networks involved in regulating PDC activation. PMID- 20852129 TI - In vivo efficacy of platelet-delivered, high specific activity factor VIII variants. AB - Ectopically expressed, human B-domainless (hB) factor 8 (F8) in platelets improves hemostasis in hemophilia A mice in several injury models. However, in both a cuticular bleeding model and a cremaster laser arteriole/venule injury model, there were limitations to platelet-derived (p) hBF8 efficacy, including increased clot embolization. We now address whether variants of F8 with enhanced activity, inactivation resistant F8 (IR8) and canine (c) BF8, would improve clotting efficacy. In both transgenic and lentiviral murine model approaches, pIR8 expressed at comparable levels to phBF8, but pcBF8 expressed at only approximately 30%. Both variants were more effective than hBF8 in cuticular bleeding and FeCl(3) carotid artery models. However, in the cremaster injury model, only pcBF8 was more effective, markedly decreasing clot embolization. Because inhibitors of F8 are stored in platelet granules and IR8 is not protected by binding to von Willebrand factor, we also tested whether pIR8 was effective in the face of inhibitors and found that pIR8 is protected from the inhibitors. In summary, pF8 variants with high specific activity are more effective in controlling bleeding, but this improved efficacy was inconsistent between bleeding models, perhaps reflecting the underlying mechanism(s) for the increased specific activity of the studied F8 variants. PMID- 20852132 TI - Microsatellite instability detection by high-resolution melting analysis. AB - BACKGROUND: Microsatellite instability (MSI) is an important marker for screening for hereditary nonpolyposis colorectal cancer (Lynch syndrome) as well as a prognostic and predictive marker for sporadic colorectal cancer (CRC). The mononucleotide microsatellite marker panel is a well-established and superior alternative to the traditional Bethesda MSI analysis panel, and does not require testing for corresponding normal DNA. The most common MSI detection techniques fluorescent capillary electrophoresis and denaturing HPLC (DHPLC)-both have advantages and drawbacks. A new high-resolution melting (HRM) analysis method enables rapid identification of heteroduplexes in amplicons by their lower thermal stability, a technique that overcomes the main shortcomings of capillary electrophoresis and DHPLC. METHODS: We investigated the straightforward application of HRM for the detection of MSI in 70 archival CRC samples. HRM analysis for 2 MSI markers (BAT25 and BAT26) was evaluated, and 2 different HRM enabled instruments were compared-the LightCycler(r) 480 (Roche Diagnostics) and the LightScanner(TM) (Idaho Technology). We also determined the analytical sensitivity and specificity of the HRM assay on both instruments using 11 known MSI-positive and 54 microsatellite-stable CRC samples. RESULTS: All MSI-positive samples were detected on both instruments (100% analytical sensitivity). The LightScanner performed better for analytical specificity, giving a combined specificity value of 99.1% compared with 92.3% on the LightCycler 480. CONCLUSIONS: We expanded the application of the HRM analysis method as an effective MSI detection technique for clinical samples. PMID- 20852131 TI - Deletion-based mechanisms of Notch1 activation in T-ALL: key roles for RAG recombinase and a conserved internal translational start site in Notch1. AB - Point mutations that trigger ligand-independent proteolysis of the Notch1 ectodomain occur frequently in human T-cell acute lymphoblastic leukemia (T-ALL) but are rare in murine T-ALL, suggesting that other mechanisms account for Notch1 activation in murine tumors. Here we show that most murine T-ALLs harbor Notch1 deletions that fall into 2 types, both leading to ligand-independent Notch1 activation. Type 1 deletions remove exon 1 and the proximal promoter, appear to be RAG-mediated, and are associated with mRNA transcripts that initiate from 3' regions of Notch1. In line with the RAG dependency of these rearrangements, RAG2 binds to the 5' end of Notch1 in normal thymocytes near the deletion breakpoints. Type 2 deletions remove sequences between exon 1 and exons 26 to 28 of Notch1, appear to be RAG-independent, and are associated with transcripts in which exon 1 is spliced out of frame to 3' Notch1 exons. Translation of both types of transcripts initiates at a conserved methionine residue, M1727, which lies within the Notch1 transmembrane domain. Polypeptides initiating at M1727 insert into membranes and are subject to constitutive cleavage by gamma-secretase. Thus, like human T-ALL, murine T-ALL is often associated with acquired mutations that cause ligand-independent Notch1 activation. PMID- 20852133 TI - Human tissue ownership and use in research: what laboratorians and researchers should know. AB - BACKGROUND: The use of human blood and tissue is critical to biomedical research. A number of treaties, laws, and regulations help to guide the ethical collection of these specimens. However, there are no clearly defined regulations regarding the ownership of human tissue specimens and who can control their fate. CONTENT: This review discusses the existing regulations governing human studies and the necessary components of patient consent. Legal cases that have addressed the issue of ownership of human tissue are reviewed, including recent settlements that have led to the destruction of millions of specimens of patient tissue. The unique regulations that guide the use of tissues collected postmortem are also examined. Potential changes in the future of biomedical research that uses human tissue, including genetic material, are also discussed. SUMMARY: The use of human tissue is directed by numerous laws and regulations. Awareness of these rules and of how and when to obtain meaningful informed consent from patients is essential for laboratorians and researchers, who should also be familiar with situations that have led to lawsuits and in some cases the destruction of valuable human tissue specimens. PMID- 20852134 TI - Electrochemical immunosensor for simultaneous detection of dual cardiac markers based on a poly(dimethylsiloxane)-gold nanoparticles composite microfluidic chip: a proof of principle. AB - BACKGROUND: The emergence of microfluidic immunosensors has provided a promising tool for improving clinical diagnoses. We developed an electrochemical immunoassay for the simultaneous detection of cardiac troponin I (cTnI) and C reactive protein (CRP), based on microfluidic chips. METHODS: The quantitative methodology was based on ELISA in poly(dimethylsiloxane)-gold nanoparticle composite microreactors. CdTe and ZnSe quantum dots were bioconjugated with antibodies for sandwich immunoassay. After the CdTe and ZnSe quantum dots were dissolved, Cd(2+) and Zn(2+) were detected by square-wave anodic stripping voltammetry to enable the quantification of the 2 biomarkers. The 2 biomarkers were measured in 20 human serum samples by using the proposed method and commercially available methods. RESULTS: This immunosensor allowed simultaneous detection of serum cTnI and CRP. The linear range of this assay was between 0.01 and 50 MUg/L and 0.5 and 200 MUg/L, with the detection limits of approximately 5 amol and approximately 307 amol in 30-MUL samples corresponding to cTnI and CRP, respectively. Slopes close to 1 and the correlation coefficient over 0.99 were obtained for both analytes. CONCLUSIONS: This strategy demonstrates a proof of principle for the successful integration of microfluidics with electrochemistry that can potentially provide an alternative to protein detection in the clinical laboratory. PMID- 20852135 TI - Introduction: creativity, psychopathology, and clinical theory. PMID- 20852136 TI - "You, I, we created the poet": Anne Sexton's recorded therapy, November 1963. AB - In 1991, when it was revealed that the psychiatrist Martin Orne had released tapes of his therapy sessions with Anne Sexton to her biographer, mental health professionals expressed concern and outrage. Those who actually listen to the controversial tapes would be curious to find a debate between Sexton and Orne about mental illness, creativity, and therapeutic process. To what extent did Sexton's creative accomplishments point to aspects of her psychiatric progress that might otherwise have been overlooked? While Sexton asserted her achievements and sought affirmation from her psychiatrist, Orne persistently responded by stating that the poetry is not as important as the person. Their different ways of understanding the relationships between poetry and therapeutic process speak volumes about the power of the creative imagination to challenge existing structures of thought, even structures designed to define the psyche itself. PMID- 20852137 TI - Anne Sexton's recorded therapy: commentary on Skorczewski. PMID- 20852138 TI - Listening with a different theory: commentary on Skorczewski. PMID- 20852139 TI - "My story for my better self": love, loss, and working through in the diary of Elizabeth Barrett Browning. AB - An approach to the diary as more than a private record, but a psychologically meaningful act and object, is demonstrated by a close reading of the diary of the English poet Elizabeth Barrett Browning. Attending to both formal and thematic aspects, this study attempts to illustrate the variable uses of diary-keeping, as well as to identify its uses of specific importance to this particular diarist. The more expansive and profound insight thus gained into the poet's life and work points to the potential of a psychoanalytic approach to such uniquely intimate documents. Evidence is offered to support the position that Browning's diary served important integrating functions during a critical period of her life: modulating overwhelming affect, organizing experiences beyond her control, and serving as a concrete symbol of preservation in the face of accumulative painful losses. The diary-keeping was a self-therapeutic endeavor, mediating and metabolizing these losses into a work of mourning as the poet elaborated and memorialized them. PMID- 20852140 TI - Treating patients who are parents: the good grandparent transference and countertransference. AB - Psychoanalysis has paid scant attention to the role of grandparenthood, especially as it may appear in treatment. Clinical material is presented to illustrate the transference-countertransference phenomenon of what will be called the good grandparent; this is not an uncommon occurrence in the treatment of patients who are parents. But while the occurrence of a grandparent transference may occur with some frequency, it is not always recognized as such. When patients require support, mirroring, and general encouragement for their parenting skills, they may be demonstrating a legitimate need that should not be rejected out of hand by the analyst. At the same time, such an apparently benign process may mask negative feelings and fantasies to which we must remain alert. PMID- 20852141 TI - Introduction: how should psychoanalysis adapt to certain challenges of contemporary culture? PMID- 20852142 TI - The analyst's ambivalence about continuing and deepening an analysis. AB - Of the many variables that affect an analyst's capacity to analyze, the analyst's ambivalence about analysis has received minimal attention. A previous paper (Ehrlich 2004) addressed how the analyst's ambivalence manifests itself in reluctance to recommend analysis and address the patient's resistances to the recommendation. The present paper examines the analyst's ambivalence about maintaining and deepening the analytic engagement. More specifically, it explores the analyst's conflicts around maintaining the analytic frame. A detailed clinical example illustrates how the analyst's continued scrutiny of her reluctance to maintain the analytic frame allowed a continuation of the analysis and a deepening of the analytic process. Given the current economic crisis and patients' increased propensity to use concerns about fee and frequency as a mode of resistance, it becomes increasingly important for analysts to recognize how their own ambivalence undermines their capacity to address those resistances effectively. PMID- 20852143 TI - The lure of the symptom in psychoanalytic treatment. AB - Psychoanalysis, which at its core is a search for truth, stands in a subversive position vis-a-vis the contemporary therapeutic culture that places a premium on symptomatic "cure." Nevertheless, analysts are vulnerable to succumbing to the internal and external pressures for the achievement of symptomatic improvement. In this communication we trace the evolution of Freud's thinking about the relationship between the aims of psychoanalysis and the alleviation of symptoms. We note that analysts today may recapitulate Freud's early struggles in their pursuit of symptom removal. We present an account of a clinical consultation in which the analytic pair were ensnared in an impasse that involved the analyst's preoccupation with the intransigence of one of the patient's symptoms. We suggest alternative ways of working with these clinical issues and offer some thoughts on how our own work as analysts and consultants to colleagues has been influenced by our understanding of what frequently occurs when the analyst becomes symptom focused. PMID- 20852151 TI - Medicare bundles medications into ESRD payments. PMID- 20852152 TI - Ulipristal approved for emergency contraception. PMID- 20852150 TI - Use of a TGFbeta type I receptor inhibitor in mouse skin carcinogenesis reveals a dual role for TGFbeta signaling in tumor promotion and progression. AB - Pharmacological inhibitors of the transforming growth factor beta (TGFbeta) type I receptor (ALK5) have shown promise in blocking growth of xenotransplanted cancer cell lines but the effect on a multistage cancer model is not known. To test this, we treated mouse skin with SB431542 (SB), a well-characterized ALK5 inhibitor, during a two-stage skin carcinogenesis assay. Topical SB significantly reduced the total number, incidence and size of papillomas compared with 12-O tetradecanoylphorbol 13-acetate (TPA) promotion alone, and this was linked to increased epidermal apoptosis, decreased proliferation and decreased cutaneous inflammation during promotion. In contrast, the frequency of conversion to squamous cell carcinoma (SCC) was 2-fold higher in papillomas treated with SB. Although there was no difference in tumor cell proliferation in early premalignant lesions, those that formed after SB treatment exhibited reduced squamous differentiation and an altered inflammatory microenvironment similar to SCC. In an inducible epidermal RAS transgenic model, treatment with SB enhanced proliferation and cutaneous inflammation in skin but decreased expression of keratin 1 and increased expression of simple epithelial keratin 18, markers of premalignant progression. In agreement with increased frequency of progression in the multistage model, SB treatment resulted in increased tumor formation with a more malignant phenotype following long-term RAS induction. In contrast to the current paradigm for TGFbeta in carcinogenesis, these results demonstrate that cutaneous TGFbeta signaling enables promotion of benign tumors but suppresses premalignant progression through context-dependent regulation of epidermal homeostasis and inflammation. PMID- 20852153 TI - Acute care hospitals face cuts under inpatient rule. PMID- 20852155 TI - Maximum daily dose of hydrocodone. PMID- 20852156 TI - Characteristics of patients with morbid obesity at an academic medical center. PMID- 20852157 TI - Color-coding process for monitoring medication beyond-use dates. PMID- 20852158 TI - Development of a training program for bar-code-assisted medication administration in inpatient pharmacy. PMID- 20852159 TI - Emergency medicine pharmacy. AB - Emergency medicine pharmacy is in its relative infancy. It is unlike any other area of current clinical practice and encompasses a wide variety of diseases, age groups, and patient populations. Patient care in the ED is provided in a fast paced environment, often by new physicians and nurses, without the benefit of the numerous safety checks that may exist on a more-conventional service. Therefore, the impact of an emergency medicine pharmacy specialist on patient safety could be substantial. New practitioners interested in practicing in this setting should possess an outgoing personality, embrace the speed of flow in the ED, be assertive at identifying potential areas of pharmacy involvement, have solid pharmacy practice skills and knowledge, and have the managerial and leadership qualities necessary to drive the changes needed to provide a safe and optimal level of patient care in the ED. PMID- 20852160 TI - Ewing's sarcoma. AB - PURPOSE: The current treatments of and new therapeutic options for the management of Ewing's sarcoma (ES) are reviewed. SUMMARY: ES is the second most common primary bone malignancy in pediatric patients and is numbered among the cancers that result in the greatest risk of mortality and morbidity in children and young adults. Much progress has been made in the treatment of ES since the disease was first described in the 1920s. With current multimodality treatment including chemotherapy, radiation, and surgery, patients with localized disease have a long term survival rate of approximately 50%. Survival rates for patients with metastatic disease or those with early relapse remain poor. New combinations of cytotoxic agents such as cyclophosphamide, topotecan, irinotecan, and temozolomide have shown efficacy and tolerability in patients with relapsed or refractory disease. To date, the role of high-dose chemotherapy supported by stem cell rescue as a consolidation therapy for high-risk ES tumors has yet to be conclusively determined. Much effort is being invested in treating cancer with targeted therapies, and the EWS-ETS fusion gene would likely provide an important tumor-specific target. Tyrosine kinases (TKs) are overexpressed in human sarcoma tumors, and cell lines may serve as potential targets for new therapies. One TK receptor that is a promising therapeutic target is insulinlike growth factor-1 receptor. CONCLUSION: Treatments for ES include surgery, radiation, and cytotoxic regimens, many of which include vincristine. Treatment for recurrent ES has included topotecan, cyclophosphamide, temozolomide, and irinotecan. Angiogenesis inhibitors, TK inhibitors, and bisphosphonates have also been studied. PMID- 20852161 TI - Hypotension and bradycardia associated with concomitant tizanidine and lisinopril therapy. AB - PURPOSE: A case of severe bradycardia and hypotension associated with concomitant tizanidine and lisinopril therapy is reported. SUMMARY: An 85-year-old man with a chief complaint of profound weakness was admitted to the hospital with a blood pressure reading of 60/32 mm Hg and a heart rate of 37 beats/min. His medical history included type 2 diabetes mellitus, congestive heart failure, gastroesophageal reflux disease, chronic obstructive pulmonary disease, osteoarthritis, restless leg syndrome, benign prostatic hyperplasia, generalized anxiety disorder with depression, and severe chronic back pain for which he was receiving treatment at a pain clinic. Two days before hospital admission, he had been seen at the pain clinic and started on ti-zanidine. Additional medications included acetaminophen, chlorpromazine, citalopram, finasteride, lidocaine patch, lisinopril, metformin, pramipexole, omeprazole, simvastatin, theophylline, diclofenac topical gel, hydrocodone-acetaminophen, and ondansetron. After taking three doses of the newly prescribed tizanidine, he developed severe hypotension and bradycardia. Notable laboratory test values included a serum creatinine concentration of 1.90 mg/dL, a blood urea nitrogen concentration of 21 mg/dL, a serum potassium concentration of 5.5 meq/L, and a serum sodium concentration of 128 meq/L. Upon admission, tizanidine, lisinopril, theophylline, omeprazole, and simvastatin were withheld, and i.v. fluids were administered. The patient's vital signs began to gradually improve. Within 24 hours, the patient's blood pressure and heart rate had improved, as had the previously abnormal laboratory test values. Tizanidine was discontinued, and all of his other preadmission medications were restarted at discharge. CONCLUSION: The addition of tizanidine in a patient receiving long-term treatment with lisinopril was associated with severe hypotension and bradycardia. PMID- 20852162 TI - Decreased plasma efavirenz concentrations in a patient receiving rifabutin. AB - PURPOSE: The case of a patient with decreased plasma efavirenz concentrations during concomitant rifabutin therapy is reported. SUMMARY: A 42-year-old Hispanic man newly diagnosed with acquired immune deficiency syndrome (AIDS) and coinfected with aseptic meningitis and disseminated Mycobacterium avium complex (MAC) received efavirenz-based highly active antiretroviral therapy (HAART). When the patient was admitted to the hospital, his medications included enoxaparin, metformin, ganciclovir, clarithromycin, ethambutol, rifampin, pyrazinamide, isoniazid, pyridoxine, trimethoprim-sulfamethoxazole, dexamethasone, and tenofovir-emtricitabine- efavirenz. Rifampin was changed to rifabutin 450 mg daily due to the potential interaction with rifampin and efavirenz. Clarithromycin was replaced with azithromycin for the treatment of MAC infection, and dexamethasone was gradually decreased over three months. The established therapeutic plasma concentration of efavirenz is 1-4 MUg/mL. After receiving the standard efavirenz dosage of 600 mg daily, the patient had subtherapeutic plasma efavirenz concentrations. To correct these low concentrations, the patient's efavirenz dosage was increased to 800 mg daily; however, his efavirenz concentrations continued to remain subtherapeutic (two concentrations of 0.58 MUg/mL). The patient's viral load decreased slowly while on HAART; however, it only became undetectable 12 days after rifabutin was discontinued. The Drug Interaction Probability Scale demonstrated a probable relationship between the coadministration of rifabutin and the decreased efavirenz concentrations due to the possible induction of efavirenz metabolism by rifabutin. CONCLUSION: A 42 year-old Hispanic man newly diagnosed with AIDS had subtherapeutic efavirenz levels during concomitant treatment with rifabutin. PMID- 20852163 TI - Comparison of International Normalized Ratios provided by two point-of-care devices and laboratory-based venipuncture in a pharmacist-managed anticoagulation clinic. AB - PURPOSE: The International Normalized Ratios (INRs) measured by two point-of-care (POC) devices were compared with those obtained via laboratory-based venipuncture. METHODS: In an outpatient, pharmacist-managed anticoagulation clinic, 52 patients receiving oral warfarin therapy had their INR values measured using two POC devices, i-STAT PT/INR (Abbott Laboratories, Abbott Park, IL) and CoaguChek XS Plus (Roche Diagnostics, Indianapolis, IN). At the same visit, one venous blood sample was collected from each patient for INR measurement by the reference laboratory's instrumentation (STAGO, Diagnostica-Stago, Parsippany, NJ). Accuracy was evaluated by calculating the absolute difference for each set of INR values. Clinical correlation was defined as an INR measurement obtained by the POC devices that would have resulted in the same therapeutic decision as the INR value measured by the reference laboratory's instrumentation. RESULTS: Accuracy was superior with the CoaguChek XS Plus device. The absolute difference (mean +/- S.D.) in the INR measurements obtained using STAGO versus CoaguChek XS Plus was 0.28 +/- 0.31 (p < 0.0001). The absolute difference in INR values measured using STAGO and the i-STAT PT/INR device was 0.51 +/- 0.44 (p < 0.0001). For clinical correlation, 17 (33%) of 52 INR measurements with the CoaguChek XS Plus were sufficiently different from the STAGO-measured INR values to have resulted in a different therapeutic decision (p < 0.001), compared with 28 (54%) of 52 with the i-STAT PT/INR (p < 0.001). CONCLUSION: INR measurements generated by POC devices exhibited positive bias, compared with laboratory-based venipuncture, for INR values at the high end of the INR range. PMID- 20852164 TI - Economic effects of pharmacists on health outcomes in the United States: A systematic review. AB - PURPOSE: A systematic review examining the economic effects of pharmacist provided direct patient care on health outcomes in the United States was conducted. METHODS: A comprehensive literature search was conducted using 13 academic and medical databases. Studies were included in the analysis if they described pharmacist-provided direct patient care, used comparison groups, evaluated economic outcomes, and were conducted in the United States. Outcome results were categorized as (1) favorable, indicating significant improvement as a result of pharmacists' interventions or services, (2) not favorable, indicating significant improvement as a result of nonpharmacist care, (3) mixed, having favorable results on one measure of a study variable but not favorable results or no effect on another, (4) having no effect, indicating no significant difference between pharmacists' interventions or services and the comparison, or (5) unclear, indicating the outcome could not be determined based on presented data. RESULTS: Of the 56,573 citations considered, a total of 126 studies met the criteria for inclusion in this systematic review. Results favoring pharmacist provided care were found in 20 studies (15.9%), mixed results were seen in 53 studies (42.1%), no effect was found in 6 studies (4.8%), and unclear results were found in 47 studies (37.3%). CONCLUSION: A majority of studies examining the economic effects of pharmacist-provided direct patient care in the United States were limited by their partial cost analyses, study design, and other analysis considerations. A majority of the 20 studies that found positive economic benefits examined pharmacists' interventions involving technical methods or multimodal approaches. PMID- 20852165 TI - Use of social media by residency program directors for resident selection. AB - PURPOSE: Pharmacy residency program directors' attitudes and opinions regarding the use of social media in residency recruitment and selection were studied. METHODS: A 24-item questionnaire was developed, pilot tested, revised, and sent to 996 residency program directors via SurveyMonkey.com. Demographic, social media usage, and opinions on social media data were collected and analyzed. RESULTS: A total of 454 residency program directors completed the study (response rate, 46.4%). The majority of respondents were women (58.8%), were members of Generation X (75.4%), and worked in a hospital or health system (80%). Most respondents (73%) rated themselves as either nonusers or novice users of social media. Twenty percent indicated that they had viewed a pharmacy residency applicant's social media information. More than half (52%) had encountered e professionalism issues, including questionable photos and posts revealing unprofessional attitudes, and 89% strongly agreed or agreed that information voluntarily published online was fair game for judgments on character, attitudes, and professionalism. Only 4% of respondents had reviewed applicants' profiles for residency selection decisions. Of those respondents, 52% indicated that the content had no effect on resident selection. Over half of residency program directors were unsure whether they will use social media information for future residency selection decisions. CONCLUSION: Residency program directors from different generations had different views regarding social media information and its use in residency applicant selections. Residency program directors anticipated using social media information to aid in future decisions for resident selection and hiring. PMID- 20852166 TI - Visual compatibility of oritavancin diphosphate with selected coadministered drugs during simulated Y-site administration. AB - PURPOSE: The visual compatibility of the new intravenous antibiotic oritavancin diphosphate with various drugs commonly administered to patients in acute care settings was studied. METHODS: Clinically used concentrations of 37 drugs, including antibiotics, sedatives, analgesics, and cardiovascular agents, were evaluated in 1:1 mixtures with oritavancin concentrations of 0.8, 1.2, and 2 mg/mL. Oritavancin solutions were prepared in 5% dextrose injection and mixed with each test drug solution. The mixtures were then visually observed over a period of four hours at room temperature. The pH of the mixtures was also determined immediately and four hours after mixing. Compatibility was defined as the absence of any color change, haze, fibers, particles, and precipitate. RESULTS: Of the 37 tested drugs, 23 were visually compatible with all three concentrations of oritavancin over the four-hour study period. Drugs formulated at a basic or neutral pH were more likely to be incompatible with oritavancin. CONCLUSION: Oritavancin diphosphate was visually incompatible with many intravenous drugs that are likely to be coadministered in acute care settings. PMID- 20852167 TI - Effects of a new sterile product preparation and delivery process on operational efficiency and cost. AB - PURPOSE: Process changes in a hospital pharmacy's batch preparation of sterile products to reduce product and human resource waste are described. SUMMARY: The pharmacy information system and direct observation were used in the collection of data on the existing i.v. room process, which generated batches of drug products every 12 hours. The daily numbers of doses prepared and doses credited, the percentage of doses credited, the cost of wasted doses, and the number of pharmacy technician hours wasted in the process were recorded. After a change to every-4-hour batch preparation and a modification of the schedule for delivering products to nursing units, data were again collected to determine savings of waste and costs. Fewer doses were prepared daily in the new batch process. The percentage of doses credited daily decreased from 26% to 18%, and pharmacy technician workload decreased by 3.05 hours. The reductions in waste led to a projected annual product cost saving of $122,000 and a workload reduction of 0.5 technician full-time equivalent. CONCLUSION: The implementation of a new i.v. room batch process improved operational efficiency by reducing the production of waste and led to a substantial projected annual cost saving. PMID- 20852168 TI - Report of the ASHP Task Force on Caring for Patients Served by Specialty Suppliers. AB - Task Force recommendations are discussed in more detail in eAppendix A (available at www.ajhp.org). What follows is a brief summary of those recommendations. In very abbreviated terms, the Task Force suggested that ASHP: 1. Consider creating and maintaining a Web resource center on ASHP's website to provide information about restricted drug distributions systems (RDDSs), risk evaluation and mitigation strategies (REMSs), risk assessment and minimization plans (RiskMAPs), and specialty suppliers and products. 2. Provide comprehensive education to members, other health professionals, regulators, third-party payers, patients, and other stakeholders about RDDSs, REMSs, RiskMAPs, and specialty suppliers and products. 3. Develop policies to advocate that a. Pharmacists serve as the institutional leaders in compliance and utilization challenges of safely managing externally supplied medications and related drug administration devices, b. Agencies, organizations, and associations that influence the distribution, sale, and dispensing of medications under these alternative distribution models address issues these models create in continuity of care, reimbursement, and patient safety, c. The Centers for Medicare and Medicaid Services and the Joint Commission develop standards and interpretations that accommodate hospital use of these products and devices when currently available technology (e.g., cold-chain storage, e-pedigree) is used to ensure patient safety, d. Group purchasing organizations negotiate contractual arrangements for specialty pharmaceuticals for both acquisition costs and distribution arrangements, and e. Information technology (IT) be used to resolve issues created by alternative distribution models and that ASHP work with IT vendors to ensure that programs are designed to meet the needs of these evolving models. 4. Quantify through research, perhaps in cooperation with entities such as the Agency for Healthcare Research and Quality, the Institute of Medicine, and the Institute for Safe Medication Practices, the impact of alternative distribution models on financial, safety, clinical, and humanistic patient outcomes. 5. Develop multidisciplinary tools and best practices that assist health care practitioners address the challenges created by alternative distribution models, from patient intake and referral to hospital discharge. PMID- 20852169 TI - A career of making good things happen for patients. PMID- 20852170 TI - The importance of anchors. PMID- 20852171 TI - Nutrition is metabolism. PMID- 20852172 TI - Conjugated bile acids as potential early markers of parenteral nutrition associated liver disease. PMID- 20852173 TI - Central venous catheter infections and antibiotic therapy during long-term home parenteral nutrition. PMID- 20852175 TI - Parenteral fish oil as monotherapy improves lipid profiles in children with parenteral nutrition-associated liver disease. AB - BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS: After 14 weeks of fish oil monotherapy, children had a 24% increase in high density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION: A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia. PMID- 20852176 TI - A new intravenous fat emulsion containing soybean oil, medium-chain triglycerides, olive oil, and fish oil: a single-center, double-blind randomized study on efficacy and safety in pediatric patients receiving home parenteral nutrition. AB - BACKGROUND: SMOFlipid 20% is an intravenous lipid emulsion (ILE) containing soybean oil, medium-chain triglycerides, olive oil, and fish oil developed to provide energy, essential fatty acids (FAs), and long-chain omega-3 FAs as a mixed emulsion containing alpha-tocopherol. The aim was to assess the efficacy and safety of this new ILE in pediatric patients receiving home parenteral nutrition (HPN) compared with soybean oil emulsion (SOE). METHODS: This single center, randomized, double-blind study included 28 children on HPN allocated to receive either SMOFlipid 20% (n = 15) or a standard SOE (Intralipid 20%, n = 13). ILE was administered 4 to 5 times per week (goal dose, 2.0 g/kg/d) within a parenteral nutrition regimen. Assessments, including safety and efficacy parameters, were performed on day 0 and after the last study infusion (day 29). Lipid peroxidation was determined by measurement of thiobarbituric acid reactive substances (TBARS). RESULTS: There were no significant differences in laboratory safety parameters, including liver enzymes, between the groups on day 29. The mean +/- standard deviation changes in the total bilirubin concentration between the initial and final values (day 29 to day 0) were significantly different between groups: SMOFlipid group -1.5 +/- 2.4 umol/L vs SOE group 2.3 +/- 3.5 umol/L, P < .01; 95% confidence interval [CI], -6.2 to -1.4). In plasma and red blood cell (RBC) phospholipids, the omega-3 FAs C20:5omega-3 (eicosapentaenoic acid) and + C22:6omega-3 (docosahexaenoic acid) increased significantly in the SMOFlipid group on day 29. The omega-3:omega-6 FA ratio was significantly elevated with SMOFlipid 20% compared with SOE group (plasma, day 29: 0.15 +/- 0.06 vs 0.07 +/- 0.02, P < .01, 95% CI, 0.04-0.11; and RBC, day 29: 0.23 +/- 0.07 vs 0.14 +/- 0.04, P < .01, 95% CI, 0.04-0.13). Plasma alpha-tocopherol concentration increased significantly more with SMOFlipid 20% (15.7 +/- 15.9 vs 5.4 +/- 15.2 umol/L, P < .05; 95% CI, -2.1 to 22.6). The low-density lipoprotein TBARS concentrations were not significantly different between both groups, indicating that lipid peroxidation did not differ between groups. CONCLUSIONS: SMOFlipid 20%, which contains 15% fish oil, was safe and well tolerated, decreased plasma bilirubin, and increased omega-3 FA and alpha-tocopherol status without changing lipid peroxidation. PMID- 20852177 TI - Prefeeding with omega-3 fatty acids suppresses inflammation following hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock followed by resuscitation stimulates an inflammatory response. This study tests the hypothesis that prefeeding with fish oil rich in omega-3 fatty acids (FAs) will attenuate that response. METHODS: Male Sprague-Dawley rats (n = 60; 350 +/- 30 g) were randomly but unequally assigned to 3 groups: sham (n = 12), control (n = 24), and fish oil (n = 24). In the fish oil group, rat chow was supplemented with fish oil (600 mg/kg/d, 25% omega-3 FA). Control and sham group diets were supplemented with corn oil. Under fluothane, hemorrhagic shock was induced, and arterial pressure was maintained at 25 to 30 mm Hg for 30 minutes. Resuscitation was carried out by giving 21 mL/kg lactated Ringer's solution and returning shed blood to the animal. Half of each group was killed at 30 minutes and at 4 hours postresuscitation. Liver samples were assayed for indicators of inflammation and heat shock protein 25 (Hsp25). Lung edema was measured. RESULTS: All animals survived. At 30 minutes postresuscitation, expression of mRNA for inducible nitric oxide synthase (iNOS) was significantly elevated in the control group but normal in the fish oil group. At 4 hours, expression of mRNA for Hsp25 was significantly increased in the fish oil group. Lung edema index was significantly lower in the fish oil group than in either sham or control groups. CONCLUSIONS: Fish oil prefeeding in a rodent model of hemorrhagic shock was associated with increased liver mRNA expression of Hsp25, reduced liver mRNA expression of iNOS, and decreased lung edema. These findings support the validity of the study hypothesis. PMID- 20852178 TI - Parenteral but not enteral omega-3 fatty acids (Omegaven) modulate intestinal regrowth after massive small bowel resection in rats. AB - BACKGROUND: The purpose of the present study was to evaluate the effects of omega 3 fatty acids (Omegaven) on early intestinal adaptation in rats with short bowel syndrome (SBS). METHODS: Male Sprague-Dawley rats were randomly assigned to 1 of 4 groups: sham rats underwent bowel transection; SBS rats underwent 75% bowel resection; SBS-O omega-3 rats underwent bowel resection and were treated with oral Omegaven given by gavage; and SBS-I omega-3 rats underwent bowel resection and were treated with Omegaven given intraperitoneally. Rats were killed on day 14. Parameters of intestinal adaptation (bowel and mucosal weight, mucosal DNA and protein, villus height and crypt depths, cell proliferation and apoptosis) were determined at time of death. Real-time polymerase chain reaction was used to determine the level of Bax and Bcl-2 messenger RNA (mRNA). Statistical analysis was performed using Kruskal-Wallis test followed by post hoc test, with P < .05 considered statistically significant. RESULTS: Oral omega-3 supplementation did not significantly change intestinal regrowth. In contrast, parenteral omega-3 in rats that underwent resection resulted in higher bowel and mucosal weights, mucosal DNA and protein in ileum, villus height in ileum, crypt depth in jejunum and ileum, and greater rates of cell proliferation in jejunum and ileum compared with SBS animals. The initial decreased levels of apoptosis corresponded with the early decrease in Bax and increase in Bcl-2 mRNA levels. CONCLUSIONS: Parenteral but not enteral Omegaven augments and accelerates structural bowel adaptation in a rat model of SBS. Increased cell proliferation and decreased apoptosis reflect increased cell turnover in Omegaven-treated animals. PMID- 20852180 TI - The impact of glutamine dipeptide-supplemented parenteral nutrition on outcomes of surgical patients: a meta-analysis of randomized clinical trials. AB - OBJECTIVE: To evaluate the impact of glutamine dipeptide-supplemented parenteral nutrition (GLN-PN) on clinical outcomes in surgical patients. METHODS: MEDLINE, EMBASE, Web of Science, and the Cochrane Controlled Clinical Trials Register were searched to retrieve the eligible studies. The studies were included if they were randomized controlled trials that evaluated the effect of GLN-PN and standard PN on clinical outcomes of surgical patients. Clinical outcomes of interest were postoperative morbidity of infectious complication, mortality, length of hospital stay, and cost. Statistical analysis was conducted by RevMan 4.2 software from the Cochrane Collaboration. RESULTS: Fourteen randomized controlled trials (RCTs) (N = 587) were included in this meta-analysis. The results showed that glutamine dipeptide significantly reduced the length of hospital stay by around 4 days in the form of alanyl-glutamine (weighted mean difference [WMD] = -3.84; 95% confidence interval [CI] -5.40, -2.28; z = 4.82; P < .001) and about 5 days in the form of glycyl-glutamine (WMD = -5.40; 95% CI -8.46, -2.33; z = 3.45; P < .001). The overall effect indicated a significant decrease in the infectious complication rates of surgical patients receiving GLN-PN (risk ratio = 0.69; 95% CI 0.50, 0.95; z = 2.26; P = .02). CONCLUSION: GLN-PN was beneficial to postoperative patients by shortening the length of hospital stay and reducing the morbidity of postoperative infectious complications. PMID- 20852179 TI - Effect of recombinant human growth hormone on intestinal absorption and body composition in children with short bowel syndrome. AB - This prospective study aimed to establish the effect of recombinant human growth hormone (rhGH) on intestinal function in children with short bowel syndrome (SBS). Eight children with neonatal SBS were included. All were dependent on parenteral nutrition (PN) for >3 years (range, 3.8-11.6 years), with PN providing >50% of recommended dietary allowance for age (range, 50%-65%). The subjects received rhGH (Humatrope) 0.13 mg/kg/d subcutaneously over a 12-week period. The follow-up was continued over a 12-month period after rhGH discontinuation. Clinical and biological assessments were performed at baseline, at the end of the treatment period, and 12 months after the end of treatment. No side effects related to rhGH were observed. PN requirements were decreased in all children during the course of rhGH treatment. Between baseline and the end of treatment, significant increases were observed in concentrations (mean +/- standard deviation) of serum insulin-like growth factor 1 (103.1 +/- 49.9 ug/L vs 153.5 +/ 82.2 ug/L; P < .01), serum insulin-like growth factor-binding protein 3 (1.7 +/- 0.6 mg/L vs 2.5 +/- 0.9 mg/L; P < .001), and plasma citrulline (16.5 +/- 14.8 umol/L vs 25.2 +/- 18.3 umol/L; P < .05). A median 54% increase in enteral intake (range, 10%-244%) was observed (P < .001) and net energy balance improved significantly (P < .002). It was necessary for 6 children to be maintained on PN or restarted after discontinuation of rhGH treatment, and they remained on PN until the end of the follow-up period. A 12-week high-dose rhGH treatment allowed patients to decrease PN, but only 2 patients could be definitively weaned from PN. Indications and cost-effectiveness of rhGH treatment for SBS pediatric patients need further evaluation. PMID- 20852181 TI - Cisplatin upregulates glutamine transport in human intestinal epithelial cells: the protective mechanism of glutamine on intestinal mucosa after chemotherapy. AB - BACKGROUND: Glutamine (GLN) prevents the intestinal mucosal injury induced by chemotherapy, although the mechanism of this protective action has not yet been elucidated. Amino acid transport across the plasma membrane is essential for supplying enterocytes with amino acids for cellular metabolism. It was hypothesized that chemotherapy stimulates GLN transport, which enables GLN to be used more efficiently as a metabolic fuel. METHODS: A rat model was used to examine the effect of enteral GLN on intestinal mucosal injury induced by intraperitoneal injection of cisplatin (7.0 mg/kg of body weight). The effects of cisplatin on amino acid transport and the expression of messenger RNA and protein were evaluated by real-time polymerase chain reaction and Western blot analysis, respectively, in the human intestinal epithelial cell line Caco-2. The effects of cisplatin on glutaminase activity and intracellular glutathione were also studied. RESULTS: GLN prevented mucosal atrophy induced by cisplatin in rats. In Caco-2 cells, cisplatin significantly increased GLN transport and the expression of GLN transporter ASCT2 messenger RNA and protein. Leucine, but not glutamate, transport significantly increased in the cisplatin-treated group due to the increase in LAT1 (leucine transporter) protein expression. Glutaminase activity and intracellular glutathione increased significantly in the cisplatin-treated group. CONCLUSIONS: Bolus enteral GLN prevents intestinal mucosal injury induced by cisplatin in rats, as demonstrated by increased GLN transport and increased GLN transporter expression after cisplatin administration. PMID- 20852182 TI - Plasma levels of conjugated bile acids in newborns after a short period of parenteral nutrition. AB - BACKGROUND: Patients receiving parenteral nutrition (PN) frequently exhibit liver dysfunction. The authors previously reported that plant sterols of lipid emulsions added to the nutritional solution of newborns receiving PN accumulate in plasma and cell membranes and may contribute to the development of cholestasis. Conjugated bile acids (BA) have been shown to be useful markers of cholestasis. Plasma levels of several BA in newborns were quantified after administration of PN for less than 2 weeks. METHODS: Plasma samples from 15 healthy control infants (CN), 22 patients who had received PN for 3-15 days (T1), and 9 patients scheduled to receive PN (T0) were analyzed. After a simple extraction procedure, plasma BA were analyzed by liquid chromatography-tandem mass spectrometry using a quantitative isotope dilution method. RESULTS: The concentrations of BA did not differ significantly between controls and patients before PN (CN vs T0), with the exception of glycocholic acid (GCA; 2.30 +/- 2.60 uM vs 7.29 +/- 5.39 uM, respectively). There was a significant difference in several BA between controls and patients after PN (2.30 +/- 2.60 uM vs 7.61 +/- 6.46 uM for GCA, respectively; 4.02 +/- 3.49 uM vs 11.88 +/- 11.05 uM for taurocholic acid [TCA], respectively; and 4.81 +/- 3.49 uM vs 13.58 +/- 12.22 uM for taurochenodeoxycholic + taurodeoxycholic + tauroursodeoxycholic acids [TCDCA+TDCA+TUDCA], respectively). CONCLUSIONS: In newborns receiving PN, a short period of PN is associated with an early increase of some conjugated BA. These results suggest that GCA, TCA, and TCDCA+TDCA+TUDCA levels could be used as early markers of PN-related cholestasis. PMID- 20852183 TI - Maximizing calcium and phosphate content in neonatal parenteral nutrition solutions using organic calcium and phosphate salts. AB - BACKGROUND: The provision of high amounts of calcium and phosphate in parenteral nutrition (PN) solution for neonates is important for bone mass accretion. Because of the risk of calcium phosphate precipitation, a well-documented incompatibility for inorganic salts, the concentrations of these electrolytes in PN are generally limited to 5 mmol/L. The aim of this study was to assess the risk of precipitation of calcium phosphate when organic calcium and phosphate salts are used instead of inorganic salts. METHODS: Precipitation curves were determined for inorganic and organic calcium and phosphate salts in a PN solution favorable to precipitation (low concentration of amino acids and glucose) using visual inspection and particle counts. RESULTS: The use of organic phosphate salt was associated with a decreased risk of precipitation of calcium phosphate. No precipitation occurred up to a concentration of 50 mmol/L of calcium and phosphate. In contrast, organic calcium salt only slightly decreased the risk of precipitation. CONCLUSION: Up to 50 mmol/L of organic calcium and phosphate salts can be safely mixed in PN, even in unstable conditions, making it possible to follow the current European recommendations for requirements in neonates. PMID- 20852184 TI - Metabolic vs nutrition support: a hypothesis. AB - It is now generally accepted that early feeding post injury exerts a positive effect on outcome in the critically ill, despite the fact that many of these patients are well nourished or even overnourished on admission. One possible mechanism is that early feeding post injury may have a positive influence on the duration and intensity of the systemic inflammatory response, especially when coupled with intensive insulin therapy to maintain normoglycemia at <150 mg/dL. Current clinical nutrition guidelines recommend early enteral nutrition providing full nutrition requirements in the critically ill patient; however, in the first week post injury, exclusive enteral feeding is typically inadequate, particularly in protein. A potentially new and different therapeutic goal to modulate the systemic inflammatory response might be more effectively accomplished for the first week post injury by hypocaloric feedings (~9-18 kcal/kg or 50%-75% resting metabolic expenditure) principally as intravenous dextrose but with at least 1 g/kg protein as intravenous amino acids to provide early metabolic support. This proposed regime, along with intensive insulin therapy to maintain glucose homeostasis, should promote the protein synthetic component of the postinjury inflammatory response while reducing net protein catabolism. A formal trial of early metabolic support in the acutely injured should be safe, easy to execute, and potentially efficacious, with subsequent improvement in the inflammatory state and, it is hoped, clinical outcomes. PMID- 20852185 TI - Computer-assisted glucose regulation during rapid step-wise increases of parenteral nutrition in critically ill patients: a proof of concept study. AB - BACKGROUND: Early delivery of calories is important in critically ill patients, and the administration of parenteral nutrition (PN) is sometimes required to achieve this goal. However, PN can induce acute hyperglycemia, which is associated with adverse outcome. We hypothesized that initiation of PN using a rapid "step-up" approach, coupled with a computerized insulin-dosing protocol, would result in a desirable caloric intake within 24 hours without causing hyperglycemia. METHODS: In our surgical intensive care unit (ICU), glucose is regulated by a nurse-centered computerized glucose regulation program. When adequate enteral feeding was not possible, PN was initiated according to a simple step-up rule at an infusion rate of 10 mL/h (approximately 10 kcal/h) and subsequently increased by steps of 10 mL/h every 4 hours, provided glucose was <10 mmol/L, until the target caloric intake (1 kcal/kg/h) was reached. All glucose levels and insulin doses were collected during the step-up period and for 24 hours after achieving target feeding. RESULTS: In all 23 consecutive patients requiring PN, mean intake was 1 kcal/kg/h within 24 hours. Of the 280 glucose samples during the 48-hour study period, mean +/- standard deviation glucose level was 7.4 +/- 1.4 mmol/L. Only 4.5% of glucose measurements during the step up period were transiently >=10 mmol/L. After initiating PN, the insulin requirement rose from 1.1 +/- 1.5 units/h to 2.9 +/- 2.5 units/h (P < .001). CONCLUSIONS: This proof of concept study shows that rapid initiation of PN using a step-up approach coupled with computerized glucose control resulted in adequate caloric intake within 24 hours while maintaining adequate glycemic control. PMID- 20852186 TI - Effects of enteral immunonutrition on the maintenance of gut barrier function and immune function in pigs with severe acute pancreatitis. AB - BACKGROUND: This study evaluated the effects of enteral immunonutrition (EIN) supplemented with glutamine, arginine, and probiotics on gut barrier function and immune function in pigs with severe acute pancreatitis (SAP). METHODS: The model was induced by retrograde injection of 5% sodium taurocholate and trypsin via the pancreatic duct. After induction of SAP, 18 pigs were randomly divided into 3 groups, in which either parenteral nutrition (PN), control enteral nutrition (CEN), or EIN was applied for 8 days. Serum and pancreatic fluid amylase concentration was determined. Intestinal permeability (lactulose to mannitol ratio) was measured by high-performance liquid chromatography, and plasma endotoxin was quantified by the chromogenic limulus amebocyte lysate technique. Samples of venous blood and organs were cultured using standard techniques. Pancreatitis severity and villi of ileum were scored according to histopathologic grading. Plasma T-lymphocyte subsets were measured by flow cytometry, and immunoglobulins (Igs) were determined via enzyme-linked immunosorbent assay. RESULTS: There were no significant differences in serum and pancreatic fluid amylases concentrations or in pancreatitis severity between any 2 of the 3 groups. Compared with PN and CEN, EIN significantly decreased intestinal permeability, plasma endotoxin concentration, and the incidence and magnitudes of bacterial translocation, but increased ileal mucosal thickness, villous height, crypt depth, and percentage of normal intestinal villi. Significant differences were found in CD3+, CD4+ lymphocyte subsets, the ratio of CD4+: CD8+ lymphocyte subsets, and serum IgA and IgG, but not IgM, between any 2 of the 3 groups. CONCLUSIONS: EIN maintained gut barrier function and immune function in pigs with SAP. PMID- 20852187 TI - Effects of sesame oil against after the onset of acetaminophen-induced acute hepatic injury in rats. AB - BACKGROUND: Acetaminophen (APAP) is a safe and effective analgesic and antipyretic when used at therapeutic levels. However, an acute or cumulative overdose can cause severe liver injury with the potential to progress to liver failure in humans and experimental animals. Much attention has been paid to the development of an antioxidant that protects against APAP-induced acute hepatic injury. Hence, we aimed to investigate the effect of sesame oil against after the onset of acute hepatic injury in APAP-overdosed rats. METHODS: Male Wistar rats were first given 2 oral doses (1,000 mg/kg each) of APAP (at 0 and 24 hours) and then 1 oral dose of sesame oil (8 mL/kg at 24 hours). RESULTS: After 48 hours, APAP increased aspartate and alanine aminotransferase levels in the rats' serum and centrilobular necrosis in liver tissue. In addition, APAP significantly decreased the rats' glutathione levels and mitochondrial aconitase activity, but increased superoxide anion, hydroxyl radical, and lipid peroxidation levels. Oral sesame oil (8 mL/kg, given at 24 hours) reversed all APAP-altered parameters and protected the rats against APAP-induced acute liver injury. CONCLUSION: We hypothesize that sesame oil acts as a useful agent that maintains intracellular glutathione levels and inhibits reactive oxygen species, thereby protecting rats against after the onset of APAP-induced acute oxidative liver injury. PMID- 20852188 TI - Gamma interferon supplementation for melioidosis. PMID- 20852189 TI - Role of mutations in dihydrofolate reductase DfrA (Rv2763c) and thymidylate synthase ThyA (Rv2764c) in Mycobacterium tuberculosis drug resistance. PMID- 20852190 TI - Unraveling the binding mechanism of trivalent tumor necrosis factor ligands and their receptors. AB - Characterization of the binding of a tumor necrosis factor (TNF) ligand to its receptor(s) is pivotal to understand how these proteins initiate signal transduction pathways. Unfortunately, kinetic elucidation of these interactions is strongly hampered by the multivalent nature of the binding partners. The interaction between TNF-related apoptosis-inducing ligand and its death receptors was analyzed using in-depth applications of surface plasmon resonance technology. Variations in receptor density and sensor chip type allowed us to manipulate the stoichiometry of the formed complex, and the rate constants describing the binding of trimeric TNF-related apoptosis-inducing ligand to only one receptor molecule were determined. Remarkably, the affinity of this trimer-monomer complex is in the picomolar range, and its dissociation very slow. Further analysis showed that the second and third receptor molecules bind with lower affinity to the preformed trimer-monomer complex. This together with results obtained with receptor activator of NF-kappaB ligand and B cell-activating factor strongly suggests that the binding of TNF family ligands to their receptors is initiated via the formation of a trimer-monomer complex that is sufficiently stable to allow binding of two additional receptor molecules. These results suggest that avidity does not play a significant role and thus provide new insight in how TNF ligands form the biologically important complexes with their receptors. PMID- 20852192 TI - British Association for Sexual Health and HIV: framework for guideline development and assessment. AB - This article has been prepared by the Clinical Effectiveness Group (CEG) of the British Association for Sexual Health and HIV (BASHH) to specify the methodology BASHH requires for guideline development and the process of guideline evaluation by the CEG. This replaces the specifications for the development of UK guidelines on the management of sexually transmitted infections and closely related conditions previously published in this journal in 2004 and updated in 2005. PMID- 20852191 TI - Disruption of the chaperonin containing TCP-1 function affects protein networks essential for rod outer segment morphogenesis and survival. AB - Type II Chaperonin Containing TCP-1 (CCT, also known as TCP-1 Ring Complex, TRiC) is a multi-subunit molecular machine thought to assist in the folding of ~ 10% of newly translated cytosolic proteins in eukaryotes. A number of proteins folded by CCT have been identified in yeast and cultured mammalian cells, however, the function of this chaperonin in vivo has never been addressed. Here we demonstrate that suppressing the CCT activity in mouse photoreceptors by transgenic expression of a dominant-negative mutant of the CCT cofactor, phosducin-like protein (PhLP), results in the malformation of the outer segment, a cellular compartment responsible for light detection, and triggers rapid retinal degeneration. Investigation of the underlying causes by quantitative proteomics identified distinct protein networks, encompassing ~ 200 proteins, which were significantly affected by the chaperonin deficiency. Notably among those were several essential proteins crucially engaged in structural support and visual signaling of the outer segment such as peripherin 2, Rom1, rhodopsin, transducin, and PDE6. These data for the first time demonstrate that normal CCT function is ultimately required for the morphogenesis and survival of sensory neurons of the retina, and suggest the chaperonin CCT deficiency as a potential, yet unexplored, cause of neurodegenerative diseases. PMID- 20852193 TI - Diabetes and genital warts: an unhappy coalition. AB - Through clinical practice, it is often perceived that patients with diabetes are more likely to suffer from severe and recalcitrant warts. This study was set up to investigate if genital warts were more common in patients with diabetes and to determine if patients with diabetes and genital warts required more treatment than those without diabetes. Only female patients with diabetes and genital warts were investigated and were compared to the non-diabetic population. Results suggested that patients with diabetes had more extensive warts and recurrences. This study will hopefully further inform the debate surrounding preferential use of quadrivalent human papilloma virus (HPV) vaccine as opposed to bivalent HPV vaccine especially in the setting of a Diabetes Young Person's clinic. PMID- 20852195 TI - Prevalence of hepatitis C virus among users attending a voluntary testing centre in Rio Grande, southern Brazil: predictive factors and hepatitis C virus genotypes. AB - We estimated the prevalence of hepatitis C (HCV) infection and associated risk factors in 750 individuals attending the Voluntary Counseling and Testing Center of Rio Grande (VCT/RG), in Southern Brazil, and identified viral genotypes. Demographic data and risk factors for HCV transmission were also collected and analysed. Anti-HCV antibody-positive individuals were tested for HCV-RNA and genotyped by sequencing the 5' untranslated region of the viral genome. Prevalence estimates of anti-HCV and HCV-RNA were 6% and 5.5%, respectively. We identified genotypes 1 (67%), 2 (2%) and 3 (31%); the latter was more prevalent than in other regions of Brazil. Anti-HCV prevalence in VCT/RG users was similar to previous reports. Age, previous blood transfusion, sexual orientation and injecting drug use were independent predictors of HCV infection. The presence of multiple risk factors was also associated with a higher risk for HCV infection. HCV genotype was not associated with any variable analysed in this study. PMID- 20852194 TI - Risk factors associated with chlamydia and gonorrhoea infection among female sex workers in two Mexico-USA border cities. AB - Female sex workers (FSWs) aged >=18 years without known HIV infection living in Tijuana and Ciudad Juarez, Mexico who had recent unprotected sex with clients underwent interviews and testing for chlamydia and gonorrhoea using nucleic acid amplification. Correlates of each infection were identified with logistic regression. Among 798 FSWs, prevalence of chlamydia and gonorrhoea was 13.0% and 6.4%, respectively. Factors independently associated with chlamydia were younger age, working in Tijuana versus Ciudad Juarez and recent methamphetamine injection. Factors independently associated with gonorrhoea were working in Tijuana versus Ciudad Juarez, using illegal drugs before or during sex, and having a recent male partner who injects drugs. Chlamydia and gonorrhoea infection were more closely associated with FSWs' drug use behaviours and that of their sexual partners than with sexual behaviours. Prevention should focus on subgroups of FSWs and their partners who use methamphetamine and who inject drugs. PMID- 20852196 TI - Prevalence and characteristics of symptomatic and asymptomatic tuboovarian masses in women with HIV: an ultrasonographic study. AB - HIV-positive women with pelvic inflammatory disease have been reported to have an increased prevalence of tuboovarian masses (TOMs). The aim of this study was to assess the prevalence of asymptomatic ultrasonographic TOMs in women with HIV and to identify associated factors in order to formulate a selective ultrasonographic screening strategy. Two-hundred and four HIV outpatients underwent transvaginal ultrasonography. Eight (3.9%) had a diagnosis of TOM (5 were asymptomatic). Two profiles of patients at risk for TOM were identified who could be considered for selective screening strategies: the 'long-term infected' (age>35 years, diagnosis of HIV infection more than 5 years ago, HIV clinical category C, CD4 counts below 200/mm(3), >5 lifetime partners and on antiretroviral therapy) and the 'recently diagnosed with HIV' (African ethnicity, age 25-35, HIV diagnosis in the previous year, >5 lifetime partners, HIV clinical category C and not on antiretroviral therapy). PMID- 20852197 TI - Aetiological agents of urethritis in symptomatic South African men attending a family practice. AB - The objective was to determine the occurrence of four urethral pathogens in urine specimens from symptomatic men using transcription mediated amplification (TMA) assay. Urethral swab and urine specimens from 300 men presenting to a family practitioner were Gram stained and tested for Neisseria gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis and Mycoplasma genitalium using three TMA assays respectively. Except for T. vaginalis, the other recognized pathogens viz. N. gonorrhoeae, C. trachomatis and M. genitalium were detected in significantly larger numbers of patients with urethral discharge than in those with burning on micturition (BOM). The overall prevalences were 16.7% for N. gonorrhoeae, 12.3% C. trachomatis, 8.0% T. vaginalis and 17.3% M. genitalium. With regard to microscopic evidence of urethritis, significant associations were found for N. gonorrhoeae and C. trachomatis, but not for M. genitalium and T. vaginalis. This study demonstrated that in symptomatic men attending family practice, M. genitalium and T. vaginalis are also important aetiological agents of urethritis and hence treatment strategies be they syndromic management or laboratory directed should cover for these causative agents. The microscopic diagnosis of urethritis may not be important for treatment strategies. The current syndromic treatment guidelines for developing countries including South Africa need modification. PMID- 20852198 TI - The fear factor: drivers and barriers to follow-up screening for human papillomavirus-related anal cancer in men who have sex with men. AB - Human papillomavirus (HPV)-related anal cancer incidence is rising in men who have sex with men (MSM). Effective screening strategies exist, but many patients are lost to follow-up (LTF). We studied factors impacting screening compliance to recommended annual screening visits. Retrospective chart review identified MSM with anal dysplasia. MSM were grouped as regular screeners (regular to follow-up [RF]) (>=1 visit/year), lost to follow-up (LTF) (>1 year since previous screening) and LTF who then returned for screening (lost came back [LCB]). From June 2007 to March 2008, subjects completed a questionnaire in-person at the time of screening or via telephone (LTF). Questionnaires were completed after anal dysplasia diagnosis. One hundred and ninety-five MSM were enrolled (96 RF, 50 LTF and 49 LCB). RF were compliant for 4.8 years; LTF were lost for 2.3 years. LCB were previously lost for 5.6 years before returning. Mean knowledge score of screening procedures was larger in RF versus LTF (P < 0.001). MSM with more sexual partners in the past six months were more likely to be LCB versus LTF (P = 0.05). RF were more likely to describe their HPV diagnosis as 'upsetting' (P = 0.003). RF were more likely driven by physical symptoms versus LTF (P = 0.002). MSM with high-grade intraepithelial lesions (HSIL) were more likely to be RF versus those with low-grade intraepithelial lesions (P = 0.001. Positive predictors for screening compliance include an upsetting experience during the HPV diagnosis, physical symptoms driving the initial visit and HSIL. Engaging patients in a firm, salient approach may facilitate follow-up compliance. PMID- 20852199 TI - Multicity HIV seroprevalence in street youth, Ukraine. AB - We conducted the first systematic, community-based, multicity assessment outside the USA of HIV seroprevalence, risk factors and linkage into clinical services among 929 street youth. After city-wide mapping, we used time-location sampling and randomly selected 74 venues in Odesa, Kyiv and Donetsk, Ukraine. Rapid HIV testing with post-test counselling was offered to all eligible youths aged 15-24 years. Overall, 18.4% (95% confidence interval 16.2-20.2) were HIV positive and 85% had previously unknown status. Rates were identical by sex. Subgroups with highest rates included orphans (26%), youths with histories of exchanging sex (35%), sexually transmitted infections (STIs) (37%), injection drug use (IDU) (42%) and needle sharing (49%). Independent predictors, similar across age groups and city, included being orphaned, time on the street, history of anal sex, STIs, exchanging sex, any drug use, IDU and needle sharing. Two-thirds (68%) of HIV positive youths were linked to services. This high-risk population has many immediate needs. PMID- 20852200 TI - Seasonal variation in mortality of Pneumocystis jirovecii pneumonia in HIV infected patients. AB - A seasonal variation in the presentation of Pneumocystis jirovecii pneumonia (PCP) has been reported and a previous study from this centre noted a seasonal variation in mortality rates. This study examined seasonal influences (including climatic factors) within-host factors (clinical and laboratory-derived variables), the infectious burden of P. jirovecii in bronchoalveolar lavage (BAL) fluid, the presence of dihydropteroate synthase (DHPS) mutations in P. jirovecii, variations in knowledge and skills of junior medical staff, and mortality in 547 episodes of PCP occurring in 494 HIV-infected patients. The overall mortality rate was 13.5%. There was a seasonal variation in mortality: highest in autumn (21.2%) and lowest in spring (9.7%), P = 0.047. After adjustment was made for prognostic factors previously identified as being associated with mortality (increasing patient age, second/third episode of PCP, low haemoglobin, low PaO(2), presence of medical co-morbidity and pulmonary Kaposi sarcoma), there was no seasonal association with mortality, P = 0.249. The quantity of P. jirovecii DNA in BAL fluid showed no evidence of seasonal variation, P = 0.67; DHPS mutations were identified with equal frequency in each season and the mortality rate for February and August (when junior medical staff arrive in new posts) was 16.7%, only slightly greater than for other months (13.0%). PMID- 20852201 TI - Universal hepatitis C screening in genitourinary medicine. AB - Our genitourinary (GU) medicine service currently offers all attendees hepatitis C testing, regardless of risk factors. We carried out a retrospective case-note review of all cases of hepatitis C diagnosed in 2008 to determine whether a significant number of these cases would have been missed if screening was targeted at high-risk groups. Twenty-three cases of hepatitis C were diagnosed from approximately 30,000 screening tests, of which 19 were available for study. In all, 53% (10/19) were polymerase chain reaction-negative resolved infection and 47% (9/19) were chronic active hepatitis. All cases of infection had identifiable risk factors for infection with hepatitis C. We are now changing our guidelines to screen only those with identifiable risk factors. PMID- 20852202 TI - National audit of asymptomatic screening in UK genitourinary medicine clinics: case-notes audit. AB - A national audit of screening of asymptomatic patients seen in UK genitourinary medicine clinics in 2009 was conducted against the national guidelines. Data were aggregated by regions and clinics in regions, allowing practice to be compared within and between regions, as well as to national averages and against national guidelines. The case-notes of 4428 patients were audited. Performance was over 80% against the national guidelines for screening of asymptomatic heterosexual men, men who have sex with men (MSM) and women for chlamydial, gonorrhoeal, syphilis and HIV infections. However, the recommended method of endocervical culture for gonorrhoea was performed in only 65% of women, with a further one quarter being screened with endocervical or vulvovaginal nucleic acid amplification tests (NAATs). Although significant NAAT use for gonorrhoea was seen in all groups, testing for gonorrhoea by culture is still recommended as a first-line test on invasive samples. Over 80% of MSM, who were not known to be immune, were screened for hepatitis B. Urethral microscopy was performed in 22% of heterosexual men and 17% of MSM, and cervical microscopy in 12% of women. PMID- 20852203 TI - National audit of asymptomatic screening in UK genitourinary medicine clinics: clinic policies audit. AB - Of clinics responding to the audit, 99 and 97% have policies that are compliant with the British Association for Sexual Health and HIV National Guidelines for testing of asymptomatic men and women for HIV and syphilis, respectively. All clinics offer men, and all but one clinic offer women, screening for chlamydial infection with nucleic acid amplification tests (NAATs), as recommended by the guidelines. However, for gonorrhoea screening one-third of clinics offer men urine or urethral NAATs, and one quarter of clinics offer women endocervical, vulvovaginal or urinary NAATs, and not endocervical culture, and these practices are not compliant with the guidelines. Eight clinics did not specify whether they routinely offer testing for gonorrhoea in women. One-third of clinics routinely perform rectal and oropharyngeal screening for gonorrhoea in men who have sex with men (MSM), but fewer screen for chlamydia, regardless of sexual history which is stated as a determinant of offering screening at these anatomical sites. Finally, one-fifth of clinics offer urethral microscopy to asymptomatic heterosexual men and MSM, and about one half of clinics offer urethral culture for detection of gonorrhoea in asymptomatic women, even though these practices are not compliant with the guidelines. PMID- 20852204 TI - Audit of partner notification for chlamydia infection in the genitourinary medicine clinic at the University Hospital of Hartlepool: 2004-2008. AB - Partner notification is essential for the control of chlamydia infection, which is on the rise. The aim of this study was to assess the performance of partner notification for chlamydia infection in the genitourinary medicine clinic at the University Hospital of Hartlepool, UK from 2004 to 2008. Overall 1.37 partners were declared per index patient, with male patients declaring 1.59 partners and female patients declaring 1.19 partners. For each chlamydia index patient 0.52 partners were screened (38 per cent of declared partners). Fifty-seven percent of the screened patients were positive for chlamydia and this increased from 33% in 2004 to 66% in 2008. The number of index cases needed to interview to get a new positive chlamydia was 3.37 over the study period and varied from 6.74 in 2004 to 2.74 in 2008. This audit highlights the need to improve partner notification for chlamydia infection. PMID- 20852205 TI - Conjunctivitis due to Phthirus pubis: a trap for the unwary. AB - It is not uncommon for patients to present to eye casualties with a red eye and where treatment has already been started by the general practitioner, usually in the form of antibiotic drops or ointment for presumed bacterial/viral conjunctivitis. Occasionally, the diagnosis is not simply a bacterial conjunctivitis and this can only be clarified by close ocular inspection. PMID- 20852206 TI - Severe septic-shock like reaction to co-trimoxazole in an HIV-positive man. AB - Adverse drug reactions occur at a greater frequency in HIV-infected individuals. A 38-year-old Eritrean man was treated with outpatient co-trimoxazole for confirmed Pneumocystis jirovecii pneumonia, but was switched to clindamycin and primaquine due to nausea and vomiting. Following development of methaemaglobinaemia, he was recommenced on prophylactic co-trimoxazole. He was later found moribund with features resembling septic shock and required invasive respiratory support. The diagnosis of a rare, but severe reaction to co trimoxazole did not become apparent until he was rechallenged with prophylactic co-trimoxazole after recovery from his initial severe reaction. In an era of polypharmacy and an increasing availability of novel drugs, this case is a timely reminder to clinicians of the ongoing need for pharmacovigilance, especially in HIV-infected individuals who may have unusual presentations of an adverse drug reaction. PMID- 20852207 TI - An unusual and unsettling place for a worm. AB - A 56-year-old man presented complaining of urinary frequency, passing urine eight times per day, urethral irritation and dysuria. Investigations showed no evidence of urinary tract infection or sexually transmitted infections. Three months later he presented, again complaining of increased urinary frequency and urethral irritation. He brought with him a urine specimen containing a small 'worm', 2 mm in length, identified as a drain fly (or moth fly) larva, of the genus Psychoda (dipterous flies). Psychoda lay eggs in organically polluted water such as sewage plants, sink drains or on decaying vegetables and fruits. Urogenital myiasis may arise from hatching of larvae near the urethral opening and ascending migration along the urethra with consequent urethritis. Following larval identification, ivermectin was prescribed and the man's symptoms improved after six weeks. PMID- 20852208 TI - An unusual testicular lump. AB - A 32-year-old British Asian man presented with what appeared clinically and on ultrasound to be a testicular tumour. However, syphilis serology, histology and detection of Treponema pallidum DNA by polymerase chain reaction confirmed that the lesion was a gumma. Without routine syphilis serology, the correct diagnosis may have been missed. PMID- 20852209 TI - Successful treatment of recurrent and refractory cervical condylomata acuminata with topical 5% imiquimod cream in five patients. PMID- 20852210 TI - Put your books right (PBR). PMID- 20852211 TI - Paromomycin treatment of recalcitrant Trichomonas vaginalis. PMID- 20852212 TI - Reply to: Sampling for Chlamydia trachomatis infection. PMID- 20852213 TI - On humanizing the expert witness: a proposed narrative approach to expert witness qualification. PMID- 20852214 TI - Domestic homicide and homicide-suicide: the older offender. AB - The importance of clarifying the features characteristic of older homicide offenders is highlighted by recent research that indicates an increase in rates of homicides followed by suicides of older perpetrators. In a retrospective study of data from coroners' files on domestic homicides involving individuals killed by an older spouse or family member (65+ years of age) over a 15-year period in Quebec, Canada, we identified several specific offender and victim characteristics and circumstances surrounding the offenses. The homicide was frequently followed by the suicide of the perpetrator. Several victims had pre existing medical illnesses, indicating that the offenses may have been committed by individuals who were caregivers to chronically ill spouses. At the time of the offense, most of the perpetrators had a mental illness, usually depressive disorder, but few had received psychiatric help. The impact of mental illness on domestic homicide-suicide is indicated, underscoring the importance of identifying existing psychopathology. PMID- 20852215 TI - Commentary: Homicide-suicide in older adults--cultural and contextual perspectives. AB - The authors comment on "Domestic Homicide and Homicide-Suicide: The Older Offender" by Bourget et al., who learned that after a domestic homicide in Canada, the older offender frequently commits suicide. The authors comment on the ubiquity of single homicide-suicide across cultures, the incidence of single homicide-suicide in various cultures, the common patterns and differences in single homicide-suicides across cultures, ethnic and gender differences in single homicide-suicide within different cultures, characteristics of the phenomenon of mass murder followed by suicide and ethnic differences within this type of homicide-suicide, and differences in suicidal patterns in different cultures. Suicide and suicide preceded by homicide (single or multiple) are so rare, it is currently impossible to draw any substantive conclusions about the incidence of these phenomena in various contexts; however, ideas for consideration in addressing homicide-suicide are provided. PMID- 20852216 TI - The unique predisposition to criminal violations in frontotemporal dementia. AB - Brain disorders can lead to criminal violations. Patients with frontotemporal dementia (FTD) are particularly prone to sociopathic behavior while retaining knowledge of their acts and of moral and conventional rules. This report describes four FTD patients who committed criminal violations in the presence of clear consciousness and sufficiently intact cognition. They understood the nature of their acts and the potential consequences, but did not feel sufficiently concerned to be deterred. FTD involves a unique pathologic combination affecting the ventromedial prefrontal cortex, with altered moral feelings, right anterior temporal loss of emotional empathy, and orbitofrontal changes with disinhibited, compulsive behavior. These case histories and the literature indicate that those with right temporal FTD retain the capacity to tell right from wrong but have the slow and insidious loss of the capacity for moral rationality. Patients with early FTD present a challenge to the criminal justice system to consider alterations in moral cognition before ascribing criminal responsibility. PMID- 20852217 TI - Commentary: The forensic psychiatry of frontotemporal dementia. AB - The article by Dr. Mendez is a timely contribution to the literature on the study of antisocial behavior associated with frontotemporal dementia. My commentary is focused on the need to take into account the neuroscientific advances involving frontotemporal dementia and the way in which such information may be conceptually helpful in furthering our understanding of forensic psychiatric cases of individuals with frontotemporal dementia. I place particular emphasis on the need to present basic psychiatric-legal aspects of such cases before we attempt to integrate the relevant neuropsychiatric information. I use the cases presented by Dr. Mendez to highlight this important need in forensic neuropsychiatry. With this commentary, I support the view that both theoretical and practical aspects of neuropsychiatric and forensic psychiatric knowledge must be carefully integrated to achieve effective forensic neuropsychiatric assessments. PMID- 20852218 TI - Abnormal attentions toward the British Royal Family: factors associated with approach and escalation. AB - Abnormal approach and escalation from communication to physical intrusion are central concerns in managing risk to prominent people. This study was a retrospective analysis of police files of those who have shown abnormal attentions toward the British Royal Family. Approach (n = 222), compared with communication only (n = 53), was significantly associated with specific factors, most notably serious mental illness and grandiosity. In a sample of those who engaged in abnormal communication (n = 132), those who approached (n = 79) were significantly more likely to evidence mental illness and grandiosity, to use multiple communications, to employ multiple means of communication, and to be driven by motivations that concerned a personal entitlement to the prominent individual. Logistic regression produced a model comprising grandiosity, multiple communications, and multiple means of communication, for which receiver operating characteristic (ROC) analysis gave an area under the curve (AUC) of 0.82. The implications of these findings are discussed in relation to those for other target groups. PMID- 20852219 TI - Commentary: Approaching and stalking public figures--a prerequisite to attack. AB - The concept of studying approaches to public figures (i.e., physical pursuit or stalking) arose as a proxy measure to aid in the development of tools to prevent assassination, a low base rate event. In this commentary, we review the origins of this concept and the historical record of public figure attacks in the United States that formed the empirical basis of the concept, we describe case examples of approaches toward public figures in the United States that did not result in injurious attacks, and we provide a synopsis of our findings on the ways in which communications predict approach. PMID- 20852220 TI - Civil commitment outcomes of incompetent defendants. AB - In Maricopa County, Arizona, most defendants who are found not competent and not restorable (NCNR) are admitted involuntarily to an acute-care inpatient hospital. Many of these patients would most likely not have met the State's usual admission criteria for acute inpatient care had they not been evaluated in relation to a criminal offense. Is this group treated differently from their peers who are not involved in the criminal justice system? We examined records for 293 NCNR admissions, retrospectively, to assess their admission status and the outcomes of their commitment. We compared them to 280 matched cases of patients admitted involuntarily from the community (non-NCNR). The NCNR group met fewer admission criteria and received court-ordered treatment (COT) 22 percent more often than did the non-NCNR patients. The NCNR patients had longer hospital stays despite being found less dangerous to themselves or others than the community sample. Results suggest that NCNR individuals are treated differently from non-NCNR patients. PMID- 20852221 TI - Commentary: Resistance to Jackson v. Indiana--civil commitment of defendants who cannot be restored to competence. AB - Levitt and colleagues provide empirical data and qualitative information that indicate that unrestorable, incompetent defendants are treated differently from ordinary patients in the civil commitment process. This report contributes to the literature suggesting that mentally ill defendants' rights under Jackson v. Indiana are not being respected. The historic developments that have led to problematic implementation of Jackson are reviewed. Increased involvement of the mentally ill in the criminal justice system and civil commitment reform are key factors that have given rise to prosecutors' widespread resistance to implementing Jackson. The current approach to unrestorable, incompetent defendants is outmoded and does not serve public safety. PMID- 20852222 TI - Commentary: civil commitment statutes--40 years of circumvention. AB - There is a longstanding body of literature that describes how states' civil commitment statutes have been stretched or circumvented to accommodate institutional and systemic needs. The paper by Levitt and colleagues provides yet another example of this phenomenon: Arizona's use of its civil commitment statutes to detain unrestorable, incompetent criminal defendants for whom other provisions have not been developed. This commentary provides a brief overview of other examples of the stretching of commitment laws, providing a broader context for viewing the findings of Levitt and colleagues. PMID- 20852223 TI - Folie a deux and the courts. AB - Folie a deux is a condition that presents distinct challenges in the legal system. The authors searched the LexisNexis database for cases involving folie a deux and provide a review of criminal and civil case law involving individuals with the diagnosis. The case surrounding Elizabeth Smart's abduction from her Utah home is highlighted. Folie a deux is a formally recognized mental disorder, although it is intrinsically different from most other primary psychiatric conditions. It can cause considerable confusion among mental health experts and legal professionals alike. It is difficult to make a reliable diagnosis of a condition that is, to date, not well validated. The authors discuss possible directions for future research and suggest methods for examining evaluees with suspected folie a deux. PMID- 20852224 TI - Do protection orders protect? AB - Protection orders are widely used legal interventions intended to reduce the risk of future harm by one person considered to be a threat to another. However, there has been controversy about when and whether such orders are useful. This article is a review of empirical studies of outcomes associated with protection orders and factors associated with violations of the orders. Although protection orders are not a panacea, the results support that they can serve a useful role in threat management. We describe factors to consider before implementing a protection order. PMID- 20852225 TI - Normative versus consequential ethics in sexually violent predator laws: an ethics conundrum for psychiatry. AB - Nineteen states and the federal government have statutes for the civil commitment of sexually violent predators (SVP). The American Psychiatric Association has vigorously opposed SVP laws, citing the abuse of both individual civil rights and of psychiatry in forwarding preventive detention. Those who support the laws underscore that the statutes target highly dangerous sex offenders. There are two different approaches to understanding ethics-based problems and their solutions. The normative approach assumes that there is a universal, intuitive, abstract, correct answer to a given question. However, there is no universal right way to balance the important normative ethic of protecting individual rights with the equally important normative ethic of protecting public safety. A less universal approach, consequential ethics, becomes necessary when abstract normative values conflict and lead to opposing conclusions. In this commentary, we examine and attempt to resolve the conflicting positions raised by the SVP statutes by using consequential versus normative ethics. PMID- 20852226 TI - Disparities in justice and care: persons with severe mental illnesses in the U.S. immigration detention system. AB - As the total number of persons held within the U.S. immigration detention system has grown, the number of detained persons with severe mental illnesses has grown correspondingly. Reports issued by the government, legal and human rights advocates, and the media have brought to light a problematic and growing detention system with pervasive legal and mental health care disparities. Described are the structure and funding of the U.S. immigration detention system, the legal state of affairs for immigration detainees with mental illnesses, and what is known about the present system of mental health care within the U.S. immigration detention system. Attention is given to the paucity of legal protections for immigration detainees with severe mental illnesses, such as no right to appointed legal counsel and no requirement for mental competence before undergoing deportation proceedings. A case example and discussion of potential alternatives to detention highlight the need for wide-ranging reform. PMID- 20852227 TI - Alice in actuarial-land: through the looking glass of changing Static-99 norms. AB - The Static-99, an actuarial rating method, is employed to conduct sexual violence risk assessment in legal contexts. The proponents of the Static-99 dismiss clinical judgment as not empirical. Two elements must be present to apply an actuarial risk model to a specific individual: sample representativeness and uniform measurement of outcome. This review demonstrates that both of these elements are lacking in the normative studies of the Static-99 and its revised version, the Static-99R. Studies conducted since the publication of the Static-99 have not replicated the original norms. Sexual recidivism rates for the same Static-99 score vary widely, from low to high, depending on the sample used. A hypothetical case example is presented to illustrate how the solitary application of the Static-99 or Static-99R recidivism rates to the exclusion of salient clinical factors for identifying sexual dangerousness can have serious consequences for public safety. PMID- 20852228 TI - Combat veterans and the death penalty: a forensic neuropsychiatric perspective. AB - With our nation's present conflicts, a new generation of veterans are returning home, many of whom have substantial psychopathology and are encountering significant barriers in accessing care. Headlines from around the nation reflect that some of these wounded warriors go on to commit offenses that are potentially punishable by death. Existing circumstances speak to the urgency with which the subject of combat veterans with post-traumatic stress disorder (PTSD), traumatic brain injury (TBI), or both facing capital crimes ought to be addressed. This publicity has led to a recent call for a legislatively or judicially enacted, narrow, categorical exclusion for combat veterans who were affected by either PTSD or TBI at the time of their capital offenses. In the present article, we illustrate the reality that combat veterans who commit capital offenses may face execution, summarize legal arguments offered in favor of a categorical exclusion, and provide a neuropsychiatric perspective on PTSD, TBI, and aggression, to help inform further dialogue on this weighty subject. PMID- 20852230 TI - Ruling on social security benefits. PMID- 20852231 TI - Probability matching and strategy availability. AB - Findings from two experiments indicate that probability matching in sequential choice arises from an asymmetry in strategy availability: The matching strategy comes readily to mind, whereas a superior alternative strategy, maximizing, does not. First, compared with the minority who spontaneously engage in maximizing, the majority of participants endorse maximizing as superior to matching in a direct comparison when both strategies are described. Second, when the maximizing strategy is brought to their attention, more participants subsequently engage in maximizing. Third, matchers are more likely than maximizers to base decisions in other tasks on their initial intuitions, suggesting that they are more inclined to use a choice strategy that comes to mind quickly. These results indicate that a substantial subset of probability matchers are victims of "underthinking" rather than "overthinking": They fail to engage in sufficient deliberation to generate a superior alternative to the matching strategy that comes so readily to mind. PMID- 20852232 TI - Implicit sequence learning is represented by stimulus-response rules. AB - For nearly two decades, researchers have investigated spatial sequence learning in an attempt to identify what specifically is learned during sequential tasks (e.g., stimulus order, response order, etc.). Despite extensive research, controversy remains concerning the information-processing locus of this learning effect. There are three main theories concerning the nature of spatial sequence learning, corresponding to the perceptual, motor, or response selection (i.e., central mechanisms underlying the association between stimulus and response pairs) processes required for successful task performance. The present data investigate this controversy and support the theory that stimulus-response (S-R) rules are critical for sequence learning. The results from two experiments demonstrate that sequence learning is disrupted only when the S-R rules for the task are altered. When the S-R rules remain constant or involve only a minor transformation, significant sequence learning occurs. These data implicate spatial response selection as a likely mechanism mediating spatial sequential learning. PMID- 20852233 TI - The temporal contiguity effect predicts episodic memory performance. AB - One way to study the associative processes at work during episodic memory is to examine the order of participant responses, which reveal the strong tendency to transition between temporally contiguous or semantically proximal items on the study list. Here, we assessed the correlation between participants' recall performance and their use of semantic and temporal associations to guide retrieval across nine delayed free recall studies. The size of the participants' temporal contiguity effects predicted their recall performance. When interpreted in terms of two models of episodic memory, these results suggest that participants who more effectively form and retrieve associations between items that occur nearby in time perform better on episodic recall tasks. Sample code may be downloaded as a supplement for this article from http://mc.psychonomic journals.org/content/supplemental. PMID- 20852234 TI - North is up(hill): route planning heuristics in real-world environments. AB - Navigators use both external cues and internal heuristics to help them plan efficient routes through environments. In six experiments, we discover and seek the origin of a novel heuristic that causes participants to preferentially choose southern rather than northern routes during map-based route planning. Experiment 1 demonstrates that participants who are tasked to choose between two equal length routes, one going generally north and one south, show reliable decision preferences toward the southern option. Experiment 2 demonstrates that participants produce a southern preference only when instructed to adopt egocentric rather than allocentric perspectives during route planning. In Experiments 3-5, we examined participants' judgments of route characteristics and found that judgments of route length and preferences for upper relative to lower path options do not contribute to the southern route preference. Rather, the southern route preference appears to be a result of misperceptions of increased elevation to the north (i.e., north is up). Experiment 6 further supports this finding by demonstrating that participants provide greater time estimates for north- than for equivalent south-going routes when planning travel between U.S. cities. Results are discussed with regard to predicting wayfinding behavior, the mental simulation of action, and theories of spatial cognition and navigation. PMID- 20852235 TI - Shared spatial representations for physical locations and location words in bilinguals' primary language. AB - For monolinguals, the Simon effect is eliminated when Simon task trials are intermixed with ones in which participants respond to the words left and right with incompatibly mapped keypresses. For bilingual Dutch/French speakers, this result has been shown to occur when the words are in Dutch (their first and primary language), but not when they are in French. To dissociate the influence of order in which the languages were learned from whether the language was the primary one currently being used, we tested bilinguals who learned Spanish or Vietnamese as their first language but for whom English became their primary language. For both groups, the incompatible location-word mapping influenced performance of the Simon task when the words were in English but not when they were in the first language. These findings indicate that the strength of language, not order of acquisition, is the critical factor. PMID- 20852236 TI - Not just semantics: strong frequency and weak cognate effects on semantic association in bilinguals. AB - To investigate the possibility that knowledge of two languages influences the nature of semantic representations, bilinguals and monolinguals were compared in a word association task. In Experiment 1, bilinguals produced less typical responses relative to monolinguals when given cues with a very common associate (e.g., given bride, bilinguals said "dress" instead of "groom"). In Experiment 2, bilinguals produced responses as typical as those of monolinguals when given cues with high-frequency associates, but not when given cues with low-frequency associates. Bilinguals' responses were also affected, to a certain extent, by the cognate status of the stimulus word pairs: They were more similar to monolinguals' responses when the cue and its strongest associate were both cognates (e.g., minute-second is minuto-segundo in Spanish), as opposed to both being noncognates. Experiment 3 confirmed the presence of a robust frequency effect on bilingual but not on monolingual association responses. These findings imply a lexical locus for the bilingual effect on association responses and reveal the association task to be not quite as purely semantic as was previously assumed. PMID- 20852237 TI - Effects of syntactic prominence on eye movements during reading. AB - Three experiments explored whether patterns of eye movements during reading might help explain syntactic prominence effects that are typically observed using reaction time tasks. Participants read sentences in which target words were in syntactically prominent or syntactically less prominent positions. Across all three experiments, using three types of syntactic prominence manipulations, there were fewer fixations and shorter reading times for words in more prominent positions, indicating that enhanced accessibility of syntactically prominent words is not caused by increased processing time. Rather, syntactic prominence appears to facilitate early encoding/lexical access and sentence integration processes while also, as shown previously, increasing activation of concepts in a comprehender's sentence or discourse representation. We propose that enhanced encoding and sentence integration processes can be attributed to an increase in attentional resources for more prominent concepts, and that this increase derives from readers' immediate sensitivity to informational prominence contours that are signaled by syntax. PMID- 20852238 TI - How readers experience characters' decisions. AB - When people read narratives, they have ample opportunities to encode mental preferences about characters' decisions. In our present project, we examined how readers' preferences for characters' decisions structure their experiences of story outcomes. In Experiment 1, participants read brief stories and explicitly rated which of two potential decisions they thought the characters should make. The actual decision that each character made was either preferred or nonpreferred by readers. By the end of each story, readers learned whether there was a positive or negative outcome to these decisions. Decisions and outcomes either matched (e.g., a preferred decision followed by a positive outcome) or did not match (e.g., a nonpreferred decision followed by a negative outcome). Participants took longer to read outcome sentences when there was a mismatch. In Experiment 2, we replicated this finding with a task that allowed more natural reading. These results provide converging evidence that readers encode responses to characters' decisions and that these responses affect the time course with which they assimilate story outcomes. PMID- 20852239 TI - Processing complex graphemes in handwriting production. AB - Recent studies on handwriting production and neuropsychological data have suggested that orthographic representations are multilevel structures that encode information on letter identity and order, but also on intermediate-grained processing units such as syllables and morphemes. This study on handwriting production examined whether orthographic representations also include a graphemic processing level. French adults wrote words containing an embedded one-, two-, or three-letter grapheme (e.g., a in clavier, ai in prairie, ain in plainte) on a digitizer. The results for letter duration revealed that the timing of movement processing depends on grapheme length (e.g., the duration of a for one-letter graphemes was shorter than that for two-letter graphemes, which, in turn, was shorter than that for three-letter graphemes). Two- and three-letter graphemes start to be processed before we start to write them. The results therefore revealed that orthographic representations also encode information on grapheme complexity. PMID- 20852240 TI - Episodic feeling-of-knowing resolution derives from the quality of original encoding. AB - In recent studies, researchers have argued for adult age-related deficits in the resolution of episodic feeling of knowing (FOK) owing to a decline in inferential processes. In the present study, we introduce the memory constraint hypothesis, which argues that deficits are an outcome of differences in the level of learning. A repetition delay paradigm for a list of paired-associate items showed that repeated presentations at encoding increased memory performance and in turn increased FOK resolution for unrecalled items. Older adults who were given a 48-h delay between encoding and subsequent tests (and FOKs) had equivalent memory performance to younger adults who were given a 7-day delay. In this case, age equivalence arose in FOK resolution except at the lowest levels of recognition in the single-presentation condition. The use of effective strategies during encoding correlated with memory performance and FOKs, even for unrecalled pairs. These results are inconsistent with an inferential-deficit explanation of age deficits in FOK resolution; they point to the importance of original encoding quality as a potent contributor to FOK resolution, and they argue for equating age groups on memory performance when evaluating the episodic FOK resolution of age differences. PMID- 20852241 TI - Culture, gender, and the first memories of black and white American students. AB - A pattern of delayed offset of childhood amnesia in Asian cultures has been attributed to the influence of the collectivist orientation of these cultures. To explore the generality of this finding, black and white American students were compared in two studies. A culture * gender interaction was observed in both studies; black women were approximately 11-16 months older at the time of their first memory than were black men, white women, and white men. In the second study, analyses of memory content indicated that black women were least likely to report personal experiences and most likely to report experiences from family or wider social contexts. Overall, black participants rated their memories as more vivid, but there were culture * gender interactions for ratings of emotional intensity and coherence. We consider multiple influences on age at first memory, including distal influences, gender themes in self-construal, and proximal influences on search criteria. PMID- 20852242 TI - Directed forgetting shares mechanisms with attentional withdrawal but not with stop-signal inhibition. AB - To explore the mechanisms underlying the ability to intentionally forget, the present study combined an item-method directed forgetting paradigm with tasks that measure stop-signal inhibition (Experiments 1 and 2) and inhibition of return (IOR; Experiment 2). Following each study-phase instruction to remember (R) or forget (F), a target was presented centrally (Experiment 1) or to the left or right in the visual periphery (Experiment 2); the target required a speeded response that was sometimes countermanded by a central stop signal. Although stop signal reaction times were unaffected by the preceding memory instruction (or relationship with word-target location), F instructions improved stopping and delayed responses. Replicating previous findings in the literature, significant IOR was observed following F instructions but not following R instructions (Experiment 2). These findings suggest that intentional forgetting is an active cognitive process that more likely engages attentional mechanisms related to orienting than those related to stop-signal inhibition. PMID- 20852243 TI - Component processes underlying future thinking. AB - This study sought to investigate the component processes underlying the ability to imagine future events, using an individual-differences approach. Participants completed several tasks assessing different aspects of future thinking (i.e., fluency, specificity, amount of episodic details, phenomenology) and were also assessed with tasks and questionnaires measuring various component processes that have been hypothesized to support future thinking (i.e., executive processes, visual-spatial processing, relational memory processing, self-consciousness, and time perspective). The main results showed that executive processes were correlated with various measures of future thinking, whereas visual-spatial processing abilities and time perspective were specifically related to the number of sensory descriptions reported when specific future events were imagined. Furthermore, individual differences in self-consciousness predicted the subjective feeling of experiencing the imagined future events. These results suggest that future thinking involves a collection of processes that are related to different facets of future-event representation. PMID- 20852244 TI - Learning to diminish the effects of proactive interference: reducing false memory for young and older adults. AB - Results from two experiments revealed that prior experience with proactive interference (PI) diminished PI's effects for both young and older adults. Participants were given two rounds of experience, with different materials, in a situation that produced PI. Comparisons with a control condition showed that the effects of PI on accuracy and on high-confidence intrusion errors (false memory) were reduced on the second round, as compared with those on the first. Also, the ability of confidence to diagnose accuracy of responding improved across rounds. Effects of prior experience with PI depended on feedback given at the time of test (Experiment 1). At least in part, the diminishment of PI resulted from participants' allocating more attention to interference items during study in the second round than in the first (Experiment 2). Implications of the results for interpreting age differences in PI and false memory are discussed. PMID- 20852245 TI - Chlamydophila abortus as a cause of bovine abortion. PMID- 20852246 TI - Assessing portable blood glucose meters for clinical use in cats in the United Kingdom. AB - The aims of this study were to evaluate six portable blood glucose meters for use in cats in a clinical setting and to identify potential sources of inaccuracy such as the effect of glucose concentration and haematocrit. Excess fluorinated whole-blood samples were obtained and were tested using the six meters and a reference laboratory method. Bland-Altman plots were constructed and an error grid analysis was performed, using a grid adapted in this study for diabetic cats. Error grids are a clinically oriented non-parametric approach to blood glucose data, and are designed to determine whether differences between glucometer and laboratory readings are clinically significant. All the meters studied had the potential to under- or overestimate blood glucose levels to varying degrees throughout the glycaemic range. This variation was not consistent enough to be predictable and correctable. The study failed to demonstrate any link between haematocrit and difference between laboratory and glucometer readings. PMID- 20852247 TI - Efficacy of a spot-on formulation of pyriprole on dogs infested with Sarcoptes scabiei. AB - To determine the efficacy of a 12.5 per cent spot-on formulation of pyriprole (Prac-Tic; Novartis Animal Health) and that of a combination of 10 per cent imidacloprid and 2.5 per cent moxidectin (Advocate; Bayer Animal Health) against Sarcoptes scabiei on dogs, 20 naturally infested adult dogs were ranked according to their pretreatment mite counts, allocated to one of two groups and housed individually in pens. Two spot-on treatments with each product, 30 days apart, were administered. Mite counts and clinical assessments were performed on each dog two days before treatment, and 28, 60 and 90 days after treatment. Efficacy was measured on the basis of the presence or absence of live mites. Except for day 60 following treatment, on which a single dog in the group treated with pyriprole was positive, no live mites were found on the treated dogs during the assessments on days 28, 60 and 90. Thus, efficacy measured on the basis of this finding (day 90 assessment) was 100 per cent. On final assessment, all dogs treated with pyriprole had 100 per cent resolution of papules, but crusts resembling healing lesions were still present on two dogs. Those treated with imidacloprid and moxidectin had 100 per cent resolution of papules and crusts. Hair regrowth, to greater than 90 per cent of pretreatment hair cover, was observed on all 20 dogs. PMID- 20852248 TI - Oestrous expression and relapse back into anoestrus at early postpartum ovulations in fertile dairy cows. AB - A total of 368 ovulations from 92 lactations in 69 cows were analysed to determine the effects of timing of ovulation and signs of oestrus on the fertility of the cows. During the study period of 10 to 13 weeks postpartum, cows ranged from having reached their first ovulation to having reached their fifth. Before ovulation, the cows exhibiting standing oestrus or mounting activity with other oestrous signs were considered to be in oestrus. The total number of anoestrous ovulations was 136 (37 per cent). From the second to fifth ovulations, the percentage of cows expressing ST increased from 10 to 74 per cent, while the percentage of cows with ovulations accompanied by mounting oestrus increased from 1 per cent at the first ovulation to 19 to 24 per cent at subsequent ovulations. Seventeen relapses to anoestrous ovulation occurred in 14 cows that had resumed an oestrous cycle, and sixteen of these relapses were observed at the second to fourth ovulations. Cows exhibiting first oestrus at the third ovulation had a similar number of days open as at the second ovulation, but a significantly fewer number of days open than at the first, fourth or fifth ovulations. These results can be valuable for studying and improving the reproductive performance of high yielding dairy cows. PMID- 20852249 TI - Multiple strains of Mycobacterium avium subspecies hominissuis infections associated with aborted fetuses and wasting in pigs. AB - A herd of pigs being reared for breeding and fattening, in which there had been incidences of abortion and wasting, reduced growth rates and an increase in mortality for the past year, were tested for Mycobacterium infection by pathological examinations, skin test, serology and Mycobacterium culture. In one placenta, and also in the lung tissues of fetuses, Ziehl-Neelsen staining revealed acid-fast bacilli in combination with infiltrations of neutrophils, macrophages and multinucleated giant cells. Acid-fast bacilli were also found in the mesenteric lymph nodes, liver and/or spleen and jejunum of pigs with wasting and in slaughtered animals. The specimen cultures were identified as Mycobacterium avium subspecies hominissuis using IS1245-specific PCR and IS1245 restriction fragment length polymorphism (RFLP). IS1245 RFLP revealed that the herd was infected with multiple M avium subspecies hominissuis strains belonging to at least two different clades. It is suggested that this infection may have played a more important role in the economic losses of the pig farm than had been assumed previously. PMID- 20852250 TI - Exonic mutations in the L2HGDH gene in Staffordshire bull terriers. PMID- 20852251 TI - Possible horse chestnut poisoning in a Cashmere goat. PMID- 20852252 TI - Causes of red squirrel (Sciurus vulgaris) mortality in England. PMID- 20852253 TI - Use of jargon. PMID- 20852254 TI - Identification of Escherichia coli mismatch-specific uracil DNA glycosylase as a robust xanthine DNA glycosylase. AB - The gene for the mismatch-specific uracil DNA glycosylase (MUG) was identified in the Escherichia coli genome as a sequence homolog of the human thymine DNA glycosylase with activity against mismatched uracil base pairs. Examination of cell extracts led us to detect a previously unknown xanthine DNA glycosylase (XDG) activity in E. coli. DNA glycosylase assays with purified enzymes indicated the novel XDG activity is attributable to MUG. Here, we report a biochemical characterization of xanthine DNA glycosylase activity in MUG. The wild type MUG possesses more robust activity against xanthine than uracil and is active against all xanthine-containing DNA (C/X, T/X, G/X, A/X and single-stranded X). Analysis of potentials of mean force indicates that the double-stranded xanthine base pairs have a relatively narrow energetic difference in base flipping, whereas the tendency for uracil base flipping follows the order of C/U > G/U > T/U > A/U. Site-directed mutagenesis performed on conserved motifs revealed that Asn-140 and Ser-23 are important determinants for XDG activity in E. coli MUG. Molecular modeling and molecular dynamics simulations reveal distinct hydrogen-bonding patterns in the active site of E. coli MUG that account for the specificity differences between E. coli MUG and human thymine DNA glycosylase as well as that between the wild type MUG and the Asn-140 and Ser-23 mutants. This study underscores the role of the favorable binding interactions in modulating the specificity of DNA glycosylases. PMID- 20852255 TI - Dual modes of interaction between XRCC4 and polynucleotide kinase/phosphatase: implications for nonhomologous end joining. AB - XRCC4 plays a crucial role in the nonhomologous end joining (NHEJ) pathway of DNA double-strand break repair acting as a scaffold protein that recruits other NHEJ proteins to double-strand breaks. Phosphorylation of XRCC4 by protein kinase CK2 promotes a high affinity interaction with the forkhead-associated domain of the end-processing enzyme polynucleotide kinase/phosphatase (PNKP). Here we reveal that unphosphorylated XRCC4 also interacts with PNKP through a lower affinity interaction site within the catalytic domain and that this interaction stimulates the turnover of PNKP. Unexpectedly, CK2-phosphorylated XRCC4 inhibited PNKP activity. Moreover, the XRCC4.DNA ligase IV complex also stimulated PNKP enzyme turnover, and this effect was independent of the phosphorylation of XRCC4 at threonine 233. Our results reveal that CK2-mediated phosphorylation of XRCC4 can have different effects on PNKP activity, with implications for the roles of XRCC4 and PNKP in NHEJ. PMID- 20852256 TI - Evaluation of mid-upper arm circumference in pre-school children: comparison between NCHS/CDC-2000 and WHO-2006 references. AB - We aimed to evaluate the classification of arm circumference (AC) in pre-school children by using National Center for Health Statistics (NCHS/CDC-2000) and World Health Organization (WHO-2006) references. We evaluated 205 children: weight, height and AC were assessed and the body mass index (BMI) was calculated. The BMI values were classified into Z-scores by the WHO referential. The AC was classified into Z-cores by two references, comparing the whole-sample value and among groups (tercis) of BMI Z-score. The correlation was also evaluated between differences of AC with BMI Z-score. The WHO referential classified the AC in Z scores greater than the NCHS/CDC, which is more specific and less sensitive than the NCHS/CDC for lean children and at the same time more sensitive and less specific for children with overweight. In conclusion, a significant difference in the AC classification occurs according to the referential used. PMID- 20852258 TI - Dissecting endonuclease and exonuclease activities in endonuclease V from Thermotoga maritima. AB - Endonuclease V is an enzyme that initiates a conserved DNA repair pathway by making an endonucleolytic incision at the 3'-side 1 nt from a deaminated base lesion. DNA cleavage analysis using mutants defective in DNA binding and Mn(2+) as a metal cofactor reveals a novel 3'-exonuclease activity in endonuclease V [Feng,H., Dong,L., Klutz,A.M., Aghaebrahim,N. and Cao,W. (2005) Defining amino acid residues involved in DNA-protein interactions and revelation of 3' exonuclease activity in endonuclease V. Biochemistry, 44, 11486-11495.]. This study defines the enzymatic nature of the endonuclease and exonuclease activity in endonuclease V from Thermotoga maritima. In addition to its well-known inosine dependent endonuclease, Tma endonuclease V also exhibits inosine-dependent 3' exonuclease activity. The dependence on an inosine site and the exonuclease nature of the 3'-exonuclease activity was demonstrated using 5'-labeled and internally-labeled inosine-containing DNA and a H214D mutant that is defective in non-specific nuclease activity. Detailed kinetic analysis using 3'-labeled DNA indicates that Tma endonuclease V also possesses non-specific 5'-exonuclease activity. The multiplicity of the endonuclease and exonuclease activity is discussed with respect to deaminated base repair. PMID- 20852257 TI - Infant-feeding patterns and cardiovascular risk factors in young adulthood: data from five cohorts in low- and middle-income countries. AB - BACKGROUND: Infant-feeding patterns may influence lifelong health. This study tested the hypothesis that longer duration of breastfeeding and later introduction of complementary foods in infancy are associated with reduced adult cardiovascular risk. METHODS: Data were pooled from 10 912 subjects in the age range of 15-41 years from five prospective birth-cohort studies in low-/middle income countries (Brazil, Guatemala, India, Philippines and South Africa). Associations were examined between infant feeding (duration of breastfeeding and age at introduction of complementary foods) and adult blood pressure (BP), plasma glucose concentration and adiposity (skinfolds, waist circumference, percentage body fat and overweight/obesity). Analyses were adjusted for maternal socio economic status, education, age, smoking, race and urban/rural residence and infant birth weight. RESULTS: There were no differences in outcomes between adults who were ever breastfed compared with those who were never breastfed. Duration of breastfeeding was not associated with adult diabetes prevalence or adiposity. There were U-shaped associations between duration of breastfeeding and systolic BP and hypertension; however, these were weak and inconsistent among the cohorts. Later introduction of complementary foods was associated with lower adult adiposity. Body mass index changed by -0.19 kg/m(2) [95% confidence interval (CI) -0.37 to -0.01] and waist circumference by -0.45 cm (95% CI -0.88 to -0.02) per 3-month increase in age at introduction of complementary foods. CONCLUSIONS: There was no evidence that longer duration of breastfeeding is protective against adult hypertension, diabetes or overweight/adiposity in these low-/middle-income populations. Further research is required to determine whether 'exclusive' breastfeeding may be protective. Delaying complementary foods until 6 months, as recommended by the World Health Organization, may reduce the risk of adult overweight/adiposity, but the effect is likely to be small. PMID- 20852259 TI - mRNA degradation controls differentiation state-dependent differences in transcript and splice variant abundance. AB - Expression profiling experiments usually provide a static snapshot of messenger RNA (mRNA) levels. Improved understanding of the dynamics of mRNA synthesis and degradation will aid the development of sound bioinformatic models for control of gene expression. We studied mRNA stability in proliferating and differentiated myogenic cells using whole-genome exon arrays and reported the decay rates (half life) for ~7000 mRNAs. We showed that the stability of many mRNAs strongly depends on the differentiation status and contributes to differences in abundance of these mRNAs. In addition, alternative splicing turns out to be coupled to mRNA degradation. Although different splice forms may be produced at comparable levels, their relative abundance is partly determined by their different stabilities in proliferating and differentiated cells. Where the 3'-untranslated region (3'-UTR) was previously thought to contain most RNA stabilizing and destabilizing elements, we showed that this also holds for transcript isoforms sharing the same 3'-UTR. There are two splice variants in Itga7, of which the isoform with an extra internal exon is highly stable in differentiated cells but preferentially degraded in the cytoplasm of proliferating cells. In conclusion, control of stability and degradation emerge as important determinants for differential expression of mRNA transcripts and splice variants. PMID- 20852260 TI - MatrixDB, the extracellular matrix interaction database. AB - MatrixDB (http://matrixdb.ibcp.fr) is a freely available database focused on interactions established by extracellular proteins and polysaccharides. Only few databases report protein-polysaccharide interactions and, to the best of our knowledge, there is no other database of extracellular interactions. MatrixDB takes into account the multimeric nature of several extracellular protein families for the curation of interactions, and reports interactions with individual polypeptide chains or with multimers, considered as permanent complexes, when appropriate. MatrixDB is a member of the International Molecular Exchange consortium (IMEx) and has adopted the PSI-MI standards for the curation and the exchange of interaction data. MatrixDB stores experimental data from our laboratory, data from literature curation, data imported from IMEx databases, and data from the Human Protein Reference Database. MatrixDB is focused on mammalian interactions, but aims to integrate interaction datasets of model organisms when available. MatrixDB provides direct links to databases recapitulating mutations in genes encoding extracellular proteins, to UniGene and to the Human Protein Atlas that shows expression and localization of proteins in a large variety of normal human tissues and cells. MatrixDB allows researchers to perform customized queries and to build tissue- and disease-specific interaction networks that can be visualized and analyzed with Cytoscape or Medusa. PMID- 20852261 TI - The human Pat1b protein: a novel mRNA deadenylation factor identified by a new immunoprecipitation technique. AB - The complex of the yeast Lsm1p-7p proteins with Pat1p is an important mRNA decay factor that is involved in translational shutdown of deadenylated mRNAs and thus prepares these mRNAs for degradation. While the Lsm proteins are highly conserved, there is no unique mammalian homolog of Pat1p. To identify proteins that interact with human LSm1, we developed a novel immunoprecipitation technique that yields virtually pure immunocomplexes. Mass-spec analysis therefore identifies mostly true positives, avoiding tedious functional screening. The method unambiguously identified the Pat1p homolog in HeLa cells, Pat1b. When targeted to a reporter mRNA, Pat1b represses gene expression by inducing deadenylation of the mRNAs. This demonstrates that Pat1b, unlike yPat1p, acts as an mRNA-specific deadenylation factor, highlighting the emerging importance of deadenylation in the mRNA regulation of higher eukaryotes. PMID- 20852262 TI - Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity. AB - Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3' untranslated region of OREBP (OREBP-3'UTR). Furthermore, overexpression of OREBP 3'UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR 717 being most significantly down-regulated. Moreover, increased miR-200b or miR 717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA-3'UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR 200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells. PMID- 20852263 TI - A highly conserved SOX6 double binding site mediates SOX6 gene downregulation in erythroid cells. AB - The Sox6 transcription factor plays critical roles in various cell types, including erythroid cells. Sox6-deficient mice are anemic due to impaired red cell maturation and show inappropriate globin gene expression in definitive erythrocytes. To identify new Sox6 target genes in erythroid cells, we used the known repressive double Sox6 consensus within the epsilony-globin promoter to perform a bioinformatic genome-wide search for similar, evolutionarily conserved motifs located within genes whose expression changes during erythropoiesis. We found a highly conserved Sox6 consensus within the Sox6 human gene promoter itself. This sequence is bound by Sox6 in vitro and in vivo, and mediates transcriptional repression in transient transfections in human erythroleukemic K562 cells and in primary erythroblasts. The binding of a lentiviral transduced Sox6FLAG protein to the endogenous Sox6 promoter is accompanied, in erythroid cells, by strong downregulation of the endogenous Sox6 transcript and by decreased in vivo chromatin accessibility of this region to the PstI restriction enzyme. These observations suggest that the negative Sox6 autoregulation, mediated by the double Sox6 binding site within its own promoter, may be relevant to control the Sox6 transcriptional downregulation that we observe in human erythroid cultures and in mouse bone marrow cells in late erythroid maturation. PMID- 20852265 TI - Clinical, functional and structural determinants of central pain in syringomyelia. AB - The present study aimed to investigate the relationship between neuropathic symptoms (i.e. pain and paraesthesia/dysaesthesia) and structural damage and functional alterations of spinal sensory tracts in patients with syringomyelia. Three-dimensional fibre tracking of the cervical spinal cord (at level C3-C4), electrophysiological assessments of nociceptive (laser-evoked potentials) and non nociceptive (somatosensory-evoked potentials) pathways and quantitative sensory testing were carried out in 37 patients with syringomyelia, 27 with neuropathic pain and 21 controls. Four regions of the body (both hands and shoulders) were systematically examined with laser-evoked potentials and quantitative sensory testing, and somatosensory-evoked potentials were induced from both hands. The diffusion tensor imaging variables investigated included the mean fractional anisotropy, the mean apparent diffusion coefficient and the number of reconstructed nerve fibres of the tracts located within three volumes of interest (full spinal section, anterior cord and posterior cord). Consistent with the results of previous studies, patients with or without neuropathic pain were indistinguishable on the basis of quantitative sensory testing, laser-evoked and somatosensory-evoked potentials and three-dimensional fibre tracking analyses. However, in patients with neuropathic pain, higher average daily pain intensity was correlated with greater structural damage to the spinal cord, as assessed by fractional anisotropy (Spearman's rho = -0.64, P = 0.020) and the number of reconstructed nerve fibres (r = -0.75; P = 0.020) of the full spinal cord. The number of reconstructed nerve fibres was negatively correlated with two neuropathic dimensions, i.e. 'deep spontaneous pain' (r = -0.59, P = 0.040) and 'paraesthesia/dysaesthesia' (i.e. pins and needles/tingling) (r = -0.67, P = 0.020), suggesting that various pain descriptors have distinct underlying mechanisms. Patients with both spontaneous and evoked pain clearly differed from patients with spontaneous pain only. Patients with spontaneous pain only had more severe spinal cord damage, and the correlation between average daily pain intensity and fractional anisotropy of the full spinal cord was particularly strong in this subgroup of patients (Spearman's rho = -0.93, P = 0.008). By contrast, patients with both spontaneous and evoked pain had not only less structural spinal cord damage, but also better preserved spinothalamic and lemniscal tracts on quantitative sensory testing and electrophysiological testing. These data showed, for the first time, a direct relationship between central neuropathic pain and objective markers of spinal cord damage, and confirmed the clinical relevance of 3D fibre tracking for the sensory assessment of patients with a spinal cord lesion. PMID- 20852264 TI - A novel cerebello-ocular syndrome with abnormal glycosylation due to abnormalities in dolichol metabolism. AB - Cerebellar hypoplasia and slowly progressive ophthalmological symptoms are common features in patients with congenital disorders of glycosylation type I. In a group of patients with congenital disorders of glycosylation type I with unknown aetiology, we have previously described a distinct phenotype with severe, early visual impairment and variable eye malformations, including optic nerve hypoplasia, retinal coloboma, congenital cataract and glaucoma. Some of the symptoms overlapped with the phenotype in other congenital disorders of glycosylation type I subtypes, such as vermis hypoplasia, anaemia, ichtyosiform dermatitis, liver dysfunction and coagulation abnormalities. We recently identified pathogenic mutations in the SRD5A3 gene, encoding steroid 5alpha reductase type 3, in a group of patients who presented with this particular phenotype and a common metabolic pattern. Here, we report on the clinical, genetic and metabolic features of 12 patients from nine families with cerebellar ataxia and congenital eye malformations diagnosed with SRD5A3-congenital disorders of glycosylation due to steroid 5alpha-reductase type 3 defect. This enzyme is necessary for the reduction of polyprenol to dolichol, the lipid anchor for N-glycosylation in the endoplasmic reticulum. Dolichol synthesis is an essential metabolic step in protein glycosylation. The current defect leads to a severely abnormal glycosylation state already in the early phase of the N-glycan biosynthesis pathway in the endoplasmic reticulum. We detected high expression of SRD5A3 in foetal brain tissue, especially in the cerebellum, consistent with the finding of the congenital cerebellar malformations. Based on the overlapping clinical, biochemical and genetic data in this large group of patients with congenital disorders of glycosylation, we define a novel syndrome of cerebellar ataxia associated with congenital eye malformations due to a defect in dolichol metabolism. PMID- 20852266 TI - What are the causes of pre-existing dementia in patients with intracerebral haemorrhages? AB - In intracerebral haemorrhage, the most frequent underlying vasculopathies are cerebral amyloid angiopathy and hypertensive vasculopathy. Although both are associated with cognitive impairment, no study has focused on pre-existing dementia in patients with intracerebral haemorrhage. Therefore, we aimed to determine prevalence and mechanisms of pre-existing dementia in a large cohort of patients with an intracerebral haemorrhage. In a cohort of 417 patients, we evaluated the cognitive status before intracerebral haemorrhage with the Informant Questionnaire on Cognitive Decline in the Elderly. The cut-off to diagnose cognitive impairment with no dementia was 53 and 64 for pre-existing dementia. We determined factors associated with pre-existing dementia in multivariate analyses in the overall cohort and among patients with lobar only or deep only intracerebral haemorrhages. We performed post-mortem examinations when possible. Of 417 patients (median age 72 years, interquartile range 58-79), 58 (14%; 95% CI 11-18%) patients had cognitive impairment with no dementia and 65 had pre-existing dementia (16%; 95% CI 12-19%). In lobar intracerebral haemorrhage, the prevalence was 23%, and factors associated with pre-existing dementia were increasing age (odds ratio: 1.09 per year; 95% CI 1.02-1.15), having <8 years of education (odds ratio: 8.37; 95% CI 1.91-36.65) and increasing cortical atrophy (odds ratio: 3.34 per step; 95% CI 1.40-7.96). The five autopsied patients had Alzheimer's disease with cerebral amyloid angiopathy. In deep intracerebral haemorrhage, factors associated with pre-existing dementia were presence of old territorial vascular lesions (odds ratio: 4.52; 95% CI 1.18 17.42) and increasing severity of leucoaraiosis (odds ratio: 4.11 per step; 95% CI 1.73-9.75); the autopsied patient had small-vessel disease without Alzheimer's disease. These findings support the fact that pre-existing dementia is frequent in patients with intracerebral haemorrhage and may be the consequence of two different mechanisms: neurodegeneration with Alzheimer's disease and cerebral amyloid angiopathy in lobar intracerebral haemorrhage versus vascular process in deep intracerebral haemorrhage. These findings may contribute to the improvement of prevention and management of patients with intracerebral haemorrhages. PMID- 20852267 TI - International intercomparisons of integrating radon/thoron detectors with the NIRS radon/thoron chambers. AB - Intercomparisons of radon/thoron detectors play an important role not only for domestic radon/thoron survey but also for international or interregional discussion about radon/thoron mapping in dwellings as well as that in the soil. For these purposes, it is necessary to improve and standardise technical methods of measurement and to verify quality assurance by intercomparisons between laboratories. Therefore, the first thoron international intercomparison was provided at the NIRS (National Institute of Radiological Sciences, Japan) thoron chamber with a 150 dm(3) inner volume. In addition, a second intercomparison of radon detectors was conducted at NIRS with a 24.4 m(3) inner volume walk-in radon chamber. Only etched-track detectors were used during thoron intercomparison as well as three types for the radon intercomparison: etched-track, charcoal and electret. In general, 45 % results for thoron experiment do not differ more than 20 % from the reference value of thoron concentration and 69 % for radon. PMID- 20852268 TI - Integrase inhibitors in the treatment of HIV-1 infection. AB - Agents active against HIV type 1 (HIV-1) that target the viral integrase by inhibiting the strand transfer step of integration have now entered the clinical arena. Raltegravir is the first in this new class. Clinical trials in treatment experienced and in treatment-naive patients have shown that raltegravir containing regimens have potent antiretroviral activity and are well tolerated. Drug resistance emerges relatively frequently in patients who fail therapy and is associated with mutations in the gene encoding the integrase enzyme. Although such mutations often confer cross-resistance to other integrase inhibitors, newer agents in development, such as S/GSK1349572, show promise as potential second generation integrase inhibitors. Given their potency, safety and novel mechanism of action, integrase inhibitors represent an important advance in HIV-1 therapy. PMID- 20852269 TI - Differential impact of the HIV-1 non-nucleoside reverse transcriptase inhibitor mutations K103N and M230L on viral replication and enzyme function. AB - OBJECTIVES: We wished to study the resistance profile of etravirine, a novel non nucleoside reverse transcriptase inhibitor (NNRTI) active against common human immunodeficiency virus type-1 (HIV-1) drug-resistant strains. METHODS: We compared the effects of K103N, the most prevalent NNRTI resistance mutation, and M230L on enzyme function, virus replication and extent of biochemical inhibition by etravirine, efavirenz and nevirapine. RESULTS: Growth kinetics analyses in cord blood mononuclear cells (CBMCs) demonstrated that K103N-containing virus replicated as well as wild-type (WT) virus and that the M230L-containing virus was severely impaired in replication ability in the absence of NNRTIs. K103N containing viruses replicated well in the presence of efavirenz and nevirapine, while virus containing M230L displayed substantial replication in the presence of all NNRTIs tested. RNA-dependent DNA polymerase assays using a heterogeneous HIV 1 RNA template and purified recombinant WT or mutated reverse transcriptase enzymes revealed that the fold change (FC) for etravirine was 0.7 for K103N and 8 for M230L. K103N and M230L conferred high-level resistance to both efavirenz (FC=39 and 15.3, respectively) and nevirapine (FC=43.5 and 33), confirming that M230L confers cross-resistance to both drugs while K103N-containing viruses remain susceptible to etravirine. In enzymatic assays, the K103N mutation was associated with moderate reductions in the efficiency of 3' DNA end-directed RNA template cleavage, while comparable efficiency to WT enzyme was observed with regard to minus-strand strong stop DNA synthesis and polymerase processivity. CONCLUSIONS: These properties help to explain differences in the evolution and prevalence of these two NNRTI mutations. PMID- 20852270 TI - DNA methylase modifications and other linezolid resistance mutations in coagulase negative staphylococci in Italy. AB - BACKGROUND: Despite 10 years of clinical use, linezolid resistance in Staphylococcus aureus and coagulase-negative staphylococci (CoNS) is still a rare phenomenon. This study reports the mechanisms of resistance and strain types seen in clusters of linezolid-resistant CoNS from two different hospitals in Italy during the period 2008-09. METHODS: Genes associated with linezolid resistance were subjected to molecular analysis and isolates were characterized by PFGE macrorestriction analysis using SmaI. RESULTS: Thirty-three linezolid-resistant isolates of methicillin-resistant CoNS comprising Staphylococcus epidermidis (24), Staphylococcus hominis (5) and Staphylococcus simulans (4) were studied. The isolates showed varying levels of linezolid resistance. Almost all isolates for which linezolid MICs were 64 mg/L possessed point mutations in domain V of 23S rRNA, while isolates for which the MICs were 256 mg/L expressed methylase activity at position A2503 mediated by the cfr gene. Overall, the isolates showed reduced susceptibility to vancomycin (MICs 1-2 mg/L) and 11 of the 33 isolates showed no susceptibility to teicoplanin. These strains were also resistant to chloramphenicol (28 of 33), lincomycin (24 of 33), erythromycin (17 of 33) and quinupristin/dalfopristin (13 of 33). S. epidermidis isolates, showing mutations or methylase modifications, belonged to different PFGE profiles and to two different sequence types (ST2 and ST23), in which the cfr gene was carried on a plasmid of ~50 kb. CONCLUSIONS: Clinical CoNS strains with resistance to linezolid and other second-line antibiotics, as well as reduced susceptibility to glycopeptides, have emerged in Italy. PMID- 20852271 TI - Treatment of acute cough/lower respiratory tract infection by antibiotic class and associated outcomes: a 13 European country observational study in primary care. AB - OBJECTIVES: Acute cough/lower respiratory tract infection (LRTI) is one of the commonest reasons for consulting and antibiotic prescribing. There are theoretical reasons why treatment with particular antibiotic classes may aid recovery more than others, but empirical, pragmatic evidence is lacking. We investigated whether treatment with a particular antibiotic class (amoxicillin) was more strongly associated with symptom score resolution and time to patients reporting recovery than each of eight other antibiotic classes or no antibiotic treatment for acute cough/LRTI. METHODS: Clinicians recorded history, examination findings, symptom severity and antibiotic treatment for 3402 patients in a 13 country prospective observational study of adults presenting in 14 primary care research networks with acute cough/LRTI. 2714 patients completed a symptom score daily for up to 28 days and recorded the day on which they felt recovered. A three-level autoregressive moving average model (1,1) model investigated logged daily symptom scores to analyse symptom resolution. A two-level survival model analysed time to reported recovery. Clinical presentation was controlled for using clinician-recorded symptoms, sputum colour, temperature, age, co morbidities, smoking status and duration of illness prior to consultation. RESULTS: Compared with amoxicillin, no antibiotic class (and no antibiotic treatment) was associated with clinically relevant improved symptom resolution (all coefficients in the range -0.02 to 0.01 and all P values greater than 0.12). No antibiotic class (and no antibiotic treatment) was associated with faster time to recovery than amoxicillin. CONCLUSIONS: Treatment by antibiotic class was not associated with symptom resolution or time to recovery in adults presenting to primary care with acute cough/LRTI. PMID- 20852272 TI - Rifaximin modulates the colonic microbiota of patients with Crohn's disease: an in vitro approach using a continuous culture colonic model system. AB - OBJECTIVES: Rifaximin, a rifamycin derivative, has been reported to induce clinical remission of active Crohn's disease (CD), a chronic inflammatory bowel disorder. In order to understand how rifaximin affects the colonic microbiota and its metabolism, an in vitro human colonic model system was used in this study. METHODS: We investigated the impact of the administration of 1800 mg/day of rifaximin on the faecal microbiota of four patients affected by colonic active CD [Crohn's disease activity index (CDAI > 200)] using a continuous culture colonic model system. We studied the effect of rifaximin on the human gut microbiota using fluorescence in situ hybridization, quantitative PCR and PCR-denaturing gradient gel electrophoresis. Furthermore, we investigated the effect of the antibiotic on microbial metabolic profiles, using (1)H-NMR and solid phase microextraction coupled with gas chromatography/mass spectrometry, and its potential genotoxicity and cytotoxicity, using Comet and growth curve assays. RESULTS: Rifaximin did not affect the overall composition of the gut microbiota, whereas it caused an increase in concentration of Bifidobacterium, Atopobium and Faecalibacterium prausnitzii. A shift in microbial metabolism was observed, as shown by increases in short-chain fatty acids, propanol, decanol, nonanone and aromatic organic compounds, and decreases in ethanol, methanol and glutamate. No genotoxicity or cytotoxicity was attributed to rifaximin, and conversely rifaximin was shown to have a chemopreventive role by protecting against hydrogen peroxide-induced DNA damage. CONCLUSIONS: We demonstrated that rifaximin, while not altering the overall structure of the human colonic microbiota, increased bifidobacteria and led to variation of metabolic profiles associated with potential beneficial effects on the host. PMID- 20852273 TI - Has decolonization played a central role in the decline in UK methicillin resistant Staphylococcus aureus transmission? A focus on evidence from intensive care. AB - The UK has seen a dramatic reduction in methicillin-resistant Staphylococcus aureus (MRSA) infection and transmission over the past few years in response to the mandatory MRSA bacteraemia surveillance scheme. Healthcare institutions have re-enforced basic infection control practice, such as universal hand hygiene, contact precautions and admission screening; however, the precipitous decline suggests other contributing factors. The intensive care unit (ICU), with its high endemic rates and complex patient population, is an important reservoir for seeding MRSA around the hospital and has understandably been at the forefront of MRSA control programmes. Recent studies from the UK and elsewhere have identified decolonization with agents such as chlorhexidine and mupirocin as having an important and perhaps underappreciated role in reducing ICU MRSA transmission, although evidence is incomplete and no prospective randomized studies have been performed. Chlorhexidine particularly is being recommended in the ICU for an increasing number of indications, including decolonization, universal patient bathing, oropharyngeal antisepsis in ventilated patients and vascular catheter insertion sites. Likewise, although there is little published evidence on decolonization efficacy or practice on UK general wards, it is now recommended for all MRSA-colonized patients and uptake is probably widespread. The recent observation that MRSA strains carrying the antiseptic resistance genes qacA/B can be clinically resistant to chlorhexidine raises a note of caution against its unfettered use. The dissemination of chlorhexidine-resistant MRSA would have implications for the decolonization of individual patients and for preventing transmission. PMID- 20852274 TI - Investing in primary care as the bridge for transitional care. PMID- 20852275 TI - Renal manifestations of Henoch-Schonlein purpura in a 6-month prospective study of 223 children. AB - OBJECTIVE: To assess the risk factors for developing Henoch-Schonlein purpura nephritis (HSN) and to determine the time period when renal involvement is unlikely after the initial disease onset. DESIGN: A prospective study of 223 paediatric patients to examine renal manifestations of Henoch-Schonlein purpura (HSP). The patient's condition was monitored with five outpatient visits to the research centre and urine dipstick testing at home. RESULTS: HSN occurred in 102/223 (46%) patients, consisting of isolated haematuria in 14%, isolated proteinuria in 9%, both haematuria and proteinuria in 56%, nephrotic-range proteinuria in 20% and nephrotic-nephritic syndrome in 1%. The patients who developed HSN were significantly older than those who did not (8.2+/-3.8 vs 6.2+/ 3.0 years, p<0.001, CI for the difference 1.1 to 2.9). Nephritis occurred a mean of 14 days after HSP diagnosis, and within 1 month in the majority of cases. The risk of developing HSN after 2 months was 2%. Prednisone prophylaxis did not affect the timing of the appearance of nephritis. The risk factors for developing nephritis were age over 8 years at onset (OR 2.7, p=0.002, CI 1.4 to 5.1), abdominal pain (OR 2.1, p=0.017, CI 1.1 to 3.7) and recurrence of HSP disease (OR 3.1, p=0.002, CI 1.5 to 6.3). Patients with two or three risk factors developed nephritis in 63% and 87% of cases, respectively. Laboratory tests or blood pressure measurement at onset did not predict the occurrence of nephritis. CONCLUSION: The authors recommend weekly home urine dipstick analyses for the first 2 months for patients with HSP. Patients with nephritis should be followed up for more than 6 months as well as the patients with HSP recurrence. PMID- 20852276 TI - The association of sugar-sweetened beverage consumption and inadequate physical activity with overweight and obesity in school-going children and adolescents in Pakistan. PMID- 20852277 TI - Child-protection medical assessments: the need for a uniform service model. PMID- 20852278 TI - Parenteral nutrition for neonates and children: a mixed bag. PMID- 20852279 TI - What price 90 seconds: is 'Call Connect' a disservice to 999 callers? PMID- 20852280 TI - Simulation training improves ability to manage medical emergencies. AB - OBJECTIVE: In the case of an emergency, fast and structured patient management is crucial for a patient's outcome. Every physician and graduate medical student should possess basic knowledge of emergency care and the skills to manage common emergencies. This study determines the effect of a simulation-based curriculum in emergency medicine on students' abilities to manage emergency situations. METHODS: A controlled, blinded educational trial of 44 final-year medical students was carried out at Frankfurt Medical School; 22 students completed the former curriculum as the control group and 22 the new curriculum as the intervention group. The intervention consists of simulation-based training with theoretical and simulation-based training sessions in realistic encounters based on the Basic Life Support (BLS), Advanced Cardiac Life Support (ACLS) and adapted Advanced Trauma Life Support (ATLS) training. Further common emergencies were integrated corresponding to the course objectives. All students faced a performance-based assessment in a 10 station Objective Structured Clinical Examination (OSCE) using checklist rating within a maximum of 4 months after completion of the intervention. RESULTS: The intervention group performed significantly better at all of the 10 OSCE stations in the checklist rating (p<0.0001 to p=0.016). CONCLUSIONS: The simulation-based intervention offers a positively evaluated possibility to enhance students' skills in recognising and handling emergencies. Additional studies are required to measure the long-term retention of the acquired skills, as well as the effect of training in healthcare professionals. PMID- 20852282 TI - Best evidence topic reports. BET 1: Should venous sample be used instead of capillary sample for estimation of blood glucose in patients with shock? PMID- 20852284 TI - Best evidence topic reports. BET 2: Should I use 2.5 mg or 5 mg nebulised salbutamol in acute exacerbations of COPD? PMID- 20852285 TI - Best evidence topic reports. BET 3: Can throat examination distinguish between bacterial and viral infective agents? PMID- 20852286 TI - Best evidence topic reports. BET 4: Does it matter whether a chest drain is aimed upwards or downwards for the optimum drainage of fluid or air from the pleural cavity? PMID- 20852288 TI - Midterm experience with implantable cardioverter-defibrillators in children and young adults. AB - AIMS: This single-centre study was undertaken to review our experience with implantable cardioverter-defibrillator (ICD) implantation in children with relatively different aetiologies. METHODS AND RESULTS: We retrospectively reviewed the records of the paediatric patients who underwent ICD implantation between October 2001 and December 2008. The data of these patients were collected by reviewing the patients' medical records and computerized departmental pacemaker databases. A total of 28 patients who underwent ICD implantation during this period were included in this study. The median age was 12 years and median weight was 32 kg. Most of the patients had ion-channel diseases (n = 13) or cardiomyopathy (n = 11). Devices were implanted for either secondary (n = 22) or primary (n = 6) prevention. The selected ICD generator type was single chamber in 22 patients, dual chamber in 5 patients, and biventricular in 1. Nineteen patients received 122 shocks. Fifteen of 22 patients (68.2%) from the secondary prevention group and 2 of 6 patients (33.3%) from the primary prevention group experienced at least one appropriate shock during a median period of 11.3 months (range: 4 days-6.5 years). Forty-two inappropriate shocks were delivered in seven (31.8%) patients from the secondary prophylaxis group during a median period of 11.3 months. The most important reason for inappropriate shocks was T-wave oversensing. In six patients, lead-related acute or chronic complications occurred. CONCLUSION: The ICD was safe and effective in interrupting malignant arrhythmias in children and adolescents with a high risk of sudden cardiac death. However, the occurrence of lead complications is significant. The incidence of therapies delivered by the device, with appropriate and inappropriate shocks, was high and interfered with the quality of life. The most important reason for inappropriate shocks was T-wave oversensing. Careful programming is mandatory to reduce the inappropriate shocks. PMID- 20852289 TI - Inpatient vs. elective outpatient cardiac resynchronization therapy device implantation and long-term clinical outcome. AB - AIMS: It remains unclear whether cardiac resynchronization therapy (CRT) device implantation during inpatient (IP) hospitalization affords the same benefit as elective outpatient (OP) implantation. We hypothesized that IPs undergoing CRT device implantation during acute hospitalization may have worse outcomes compared with elective OP implantation. METHODS AND RESULTS: We retrospectively separated patients undergoing CRT implants at Massachusetts General Hospital into OP (n= 196) and IP (n = 105) cohorts. Long-term outcomes, measured as heart failure (HF) hospitalization, all-cause mortality, ventricular assist device placement, or heart transplant over a 2-year follow-up period, were estimated by the Kaplan Meier method. Propensity scores were generated to balance the baseline co morbidities between IP and OP. Baseline age, gender, left ventricular ejection fraction, and aetiology of cardiomyopathy were comparable between OP and IP (66.8 +/- 11.8 vs. 67.5 +/- 13.4 years, 78 vs. 84% males, 24 vs. 23%, and 39 vs. 50% ischaemic, P = NS). Inpatients had greater burden of diabetes mellitus (40 vs. 27%, P = 0.028), renal insufficiency (47 vs. 25%, P< 0.001), and right ventricular dysfunction (54 vs. 39%, P = 0.026) compared with OPs. At 2-year follow-up, IP implant was associated with greater risk of HF hospitalization (HR 1.6, 95% CI 1.03-2.48, P = 0.038) compared with elective OP implants. After propensity score adjustment, there was no statistically significant difference in HF hospitalization between the IP and OP groups (HR 1.031, 95% CI 0.61-1.78, P = 0.91). CONCLUSION: Compared with OP CRT implants, IPs are at increased risk for recurrent HF hospitalization; however, the increased risk is attributable to greater co-morbidities in the IP population. PMID- 20852290 TI - The effect of left ventricular pacing site on cardiac resynchronization therapy outcome and mortality: the results of a PROSPECT substudy. AB - AIMS: Left ventricular pacing site (LV-PS) was prospectively collected to test the influence of the anatomical LV-PS on the outcome of cardiac resynchronization therapy (CRT) and mortality. METHODS AND RESULTS: Four hundred and twenty-six patients with standard indications for CRT underwent echocardiographic and clinical evaluation before and after CRT implantation. The LV-PS was determined from fluoroscopy using the clockwise principle (CP). The LV-PS was categorized into three prospectively defined groups: between 3 and 5 o'clock and longitudinal basal/mid-position (Group A, 'optimal'); between 12 and 2 o'clock and longitudinal mid-apical anterior position (Group B, 'non-optimal'); and all other (Group C, 'other'). Of 333 patients, followed for 0.9 years (mean), adequate images were available to define the LV-PS. Left ventricular pacing site was Group A for 118 patients, Group B for 56, and Group C for 159. The three groups were comparable regarding gender, aetiology, and NYHA class; however, patients in Group A were younger. No relation was found between the LV-PS groups and CRT outcome or all-cause mortality. However, further exploratory subanalyses suggest that LV-PS may impact outcomes in non-ischaemic patients, those with left bundle branch block, and when LV-PS is apical in location. CONCLUSION: Using the CP to define anatomical LV-PS, no relation was found between the LV-PS groups and CRT outcome and mortality. Exploratory analyses warrant further studies. PMID- 20852291 TI - Cardiac resynchronization therapy implantation following transcatheter aortic valve implantation. PMID- 20852292 TI - A study of blood soluble P-selectin, fibrinogen, and von Willebrand factor levels in idiopathic and lone atrial fibrillation. AB - AIMS: A prothrombotic state with elevated levels of soluble P-selectin (sP-sel), fibrinogen, von Willebrand factor (vWf), and other haemostatic indices has been reported in some patients with atrial fibrillation (AF). Whether these changes are due to AF itself or coexistent cardiovascular diseases remains a matter of debate. Therefore, in the present study, the differences in plasma levels of sP sel, fibrinogen, and vWf between patients with idiopathic/lone AF and sex-, age-, and risk factor-matched controls were investigated to determine whether AF itself might be associated with a hypercoagulable state. METHODS AND RESULTS: Ninety consecutive patients (63 males, 54.1 +/- 10.1 years) with idiopathic AF were studied, 60 (43 males, 48.8 +/- 7.5 years) of whom were diagnosed as lone AF. Plasma sP-sel and vWf were measured by enzyme-linked immunosorbent assay. Plasma fibrinogen was measured by chromometry. These indices in AF patients were compared with those in sex-, age- and risk factor-matched controls. Compared with the controls, patients with idiopathic AF had higher levels of sP-sel (AF vs. control: 33.4 +/- 7.4 vs. 29.2 +/- 6.5 ng/mL, P < 0.001) and fibrinogen (AF vs. control: 3.3 +/- 0.9 vs. 3.0 +/- 0.6 g/L, P = 0.02), but not vWf, whether with the adjustment of covariates or not. As for those < 60 years, between lone AF and age-matched controls, significant difference existed in the levels of sP-sel (AF vs. control: 34.5 +/- 7.3 vs. 30.2 +/- 7.3 ng/mL, P = 0.002), but not in those of fibrinogen and vWf, whether with the adjustment of covariates or not. CONCLUSIONS: Both platelet activation and abnormal changes in coagulation were suggested in idiopathic AF and a platelet activation state in lone AF. This supports the notion that AF per se contributes to a state of hypercoagulation. PMID- 20852293 TI - Multiple marker approach to risk stratification in patients with stable coronary artery disease. AB - AIMS: multimarker approaches for risk prediction in coronary artery disease have remained inconsistent. We assessed multiple biomarkers representing distinct pathophysiological pathways in relation to cardiovascular events in stable angina. METHODS AND RESULTS: we investigated 12 biomarkers reflecting inflammation [C-reactive protein, growth-differentiation factor (GDF)-15, neopterin], lipid metabolism (apolipoproteins AI, B100), renal function (cystatin C, serum creatinine), and cardiovascular function and remodelling [copeptin, C terminal-pro-endothelin-1, mid-regional-pro-adrenomedullin (MR-proADM), mid regional-pro-atrial natriuretic peptide (MR-proANP), N-terminal-pro-B-type natriuretic peptide (Nt-proBNP)] in 1781 stable angina patients in relation to non-fatal myocardial infarction and cardiovascular death (n = 137) over 3.6 years. Using Cox proportional hazards models and C-indices, the strongest association with outcome for log-transformed biomarkers in multivariable-adjusted analyses was observed for Nt-proBNP [hazard ratio (HR) for one standard deviation increase 1.65, 95% confidence interval (CI) 1.28-2.13, C-index 0.686], GDF-15 (HR 1.59, 95% CI 1.25-2.02, C-index 0.681), MR-proANP (HR 1.46, 95% CI 1.14-1.87, C index 0.673), cystatin C (HR 1.39, 95% CI 1.10-1.75, C-index 0.671), and MR proADM (HR 1.63, 95% CI 1.21-2.20, C-index 0.668). Each of these top single markers and their combination (C-index 0.690) added predictive information beyond the baseline model consisting of the classical risk factors assessed by C-index and led to substantial reclassification (P-integrated discrimination improvement <0.05). CONCLUSION: comparative analysis of 12 biomarkers revealed Nt-proBNP, GDF 15, MR-proANP, cystatin C, and MR-proADM as the strongest predictors of cardiovascular outcome in stable angina. All five biomarkers taken separately offered incremental predictive ability over established risk factors. Combination of the single markers slightly improved model fit but did not enhance risk prediction from a clinical perspective. PMID- 20852294 TI - Bilateral mammary artery vs. single mammary artery grafting: promising early results: but will the match finish with enough players? PMID- 20852295 TI - Flavanols and cardiovascular disease prevention. AB - Diet is a major lifestyle factor in the primary and secondary prevention of numerous chronic diseases, including myocardial infarction, stroke, and diabetes. Epidemiological studies suggest that the beneficial cardiovascular health effects of diets rich in fruits and vegetables are in part mediated by their flavonoid content, with particular benefits provided by one member of this family, the flavanols. This concept is supported by findings from small-scale intervention studies with surrogate endpoints including endothelium-dependent vasodilation, blood pressure, platelet function, and glucose tolerance. Mechanistically, short term effects on endothelium-dependent vasodilation following the consumption of flavanol-rich foods, as well as purified flavanols, have been linked to an increased nitric oxide bioactivity in healthy humans, and those with increased cardiovascular risk. The critical biological target(s) for flavanols have yet to be identified and the extent to which these acute results are important in the context of long-term human health is unknown. While flavanols represent a promising class of food components with respect to their ability to lower cardiovascular risk the flavanol-rich foods used in many trials have been poorly defined with respect to their flavanol content and flavanol-isomer profile; several studies have lacked appropriate controls, and the long-term randomized controlled intervention trials with flavanol-rich foods are missing. Thus, while the literature regarding flavanols and vascular health is encouraging, more in depth and well-controlled clinical and experimental studies are needed to better define the potential protective vascular effects of these nutrients and their therapeutic value in cardiovascular medicine. PMID- 20852296 TI - Outcomes in patients with cardiovascular implantable electronic devices and bacteremia caused by Gram-positive cocci other than Staphylococcus aureus. AB - BACKGROUND: Infection is a serious complication of cardiovascular implantable electronic device (CIED) placement and requires device removal for attempted cure. METHODS AND RESULTS: We studied the rate, risk factors, and outcomes of CIED infection in 74 consecutive patients with bacteremia caused by Gram-positive cocci (GPC) other than Staphylococcus aureus between 2001 and 2007. CIED infection was defined as the presence of signs of infection at the generator site, lead vegetations seen on echocardiography, or microbiological growth from device cultures. Twenty-two (30%) of 74 patients with non-S aureus GPC bacteremia had CIED infections. Coagulase-negative staphylococci (CoNS) accounted for 73% of CIED infections. The rate of CIED infection in patients with CoNS bacteremia was almost 2-fold that of non-CoNS GPC bacteremia (36% versus 20%, P = 0.13). The number of leads, the presence of abandoned leads, and prior generator replacement were associated with CIED infection. Among 33 patients without identifiable CIED infection at initial evaluation who did not undergo device removal, 5 (15%) had relapsing bacteremia within 12 weeks of completing antibiotic therapy. CoNS accounted for all relapses, and none had evidence of CIED infection at relapse. CONCLUSIONS: Patients with a CIED and bacteremia caused by GPC other than S aureus frequently had evidence of underlying CIED infection on clinical evaluation that included transesophageal echocardiography. This was particularly true among those with CoNS bacteremia. No evidence of underlying CIED infections was identified in the subgroup of patients who did not have manifestations of CIED infection on initial evaluation but subsequently had relapsing bacteremia caused by CoNS. PMID- 20852297 TI - A ZASP missense mutation, S196L, leads to cytoskeletal and electrical abnormalities in a mouse model of cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a primary disease of the heart muscle associated with sudden cardiac death secondary to ventricular tachyarrhythmias and asystole. However, the molecular pathways linking DCM to arrhythmias and sudden cardiac death are unknown. We previously identified a S196L mutation in exon 4 of LBD3-encoded ZASP in a family with DCM and sudden cardiac death. These findings led us to hypothesize that this mutation may precipitate both cytoskeletal and conduction abnormalities in vivo. Therefore, we investigated the role of the ZASP4 mutation S196L in cardiac cytoarchitecture and ion channel biology. METHODS AND RESULTS: We generated and analyzed transgenic mice with cardiac-restricted expression of the S196L mutation. We also performed cellular electrophysiological analysis on isolated S196L cardiomyocytes and protein protein interaction studies. Ten month-old S196L mice developed hemodynamic dysfunction consistent with DCM, whereas 3-month-old S196L mice presented with cardiac conduction defects and atrioventricular block. Electrophysiological analysis on isolated S196L cardiomyocytes demonstrated that the L-type Ca(2+) currents and Na(+) currents were altered. The pull-down assay demonstrated that ZASP4 complexes with both calcium (Ca(v)1.2) and sodium (Na(v)1.5) channels. CONCLUSIONS: Our findings provide new insight into the mechanisms by which mutations of a structural/cytoskeletal protein, such as ZASP, lead to cardiac functional and electric abnormalities. This work represents a novel framework to understand the development of conduction defects and arrhythmias in subjects with cardiomyopathies, including DCM. PMID- 20852298 TI - Atrial coronary arteries in areas involved in atrial fibrillation catheter ablation. AB - BACKGROUND: The proximity to vascular structures is a limiting factor during radiofrequency ablation. However, little or no attention has been given to the atrial arterial circulation during the development of atrial fibrillation (AF) catheter ablation techniques. METHODS AND RESULTS: We examined the atrial arterial circulation in areas involved in AF ablation in 24 heart specimens by colored resin injection and careful dissection. The sinus node artery (SNA) arose from the circumflex artery in 42% of case; proximal to the LA appendage in 29%, crossing the left atrium (LA) anterior wall; and after the LA appendage in the remaining 13%, crossing the mitral isthmus and passing close to the left pulmonary veins (PVs), the LA roof, and the right superior PV. In 58%, the SNA arose from the right coronary artery. Major arteries (>= 1 mm in external diameter) were found in the mitral isthmus in 54%, at the LA roof in 54%, and at the LA anterior wall in 29%. Around the left PV ostia, there were areas with major arteries in up to 37% (at the roof and inferior segments) and around the right PV ostia in up to 29% (at the roof segment). CONCLUSIONS: Major atrial coronary arteries, including the SNA, were commonly found in the areas involved in AF ablation and could cause difficulties in obtaining transmural lesions and electric isolation or even lead to ischemic sinus node or atrial dysfunction. PMID- 20852300 TI - Impact of intracranial extension on survival in stage IV nasopharyngeal carcinoma: identification of a subset of patients with better prognosis. AB - OBJECTIVE: T-stage is an imperfect prognostic indicator for patients with nasopharyngeal carcinoma. We evaluated the effect of extent of intracranial involvement on survival after conventional radiotherapy in patients with Stage T4 nasopharyngeal carcinoma. METHODS: We conducted a retrospective analysis of the results of computed tomography, magnetic resonance imaging and treatment outcomes in 84 consecutive patients with Stage T4 nasopharyngeal carcinoma during the period September 1993 to December 2002 in Taiwan. The patients were subcategorized into those who had limited intracranial involvement (primary nasopharyngeal tumors with involvement of the unilateral cavernous sinus or the parasellar region only) or extensive involvement (extension of the tumors to the bilateral cavernous sinus or the parasellar region, into the orbit and the ethmoid sinus anteriorly, or to the prepontine region and the posterior cranial fossa). RESULTS: Extensive intracranial involvement was found in 51.2% of the patients. Among these patients, the 5-year rate of overall survival after conventional radiotherapy was only 3.4%. In contrast, the 5-year survival among patients with limited intracranial involvement was 42.9%. This difference was significant (P < 0.001). In the multivariate analysis, extensive intracranial involvement, advanced age and a nodal status of N3 correlated with poor overall survival (all P < 0.05). CONCLUSIONS: Among patients with T4 nasopharyngeal carcinoma, better treatment outcomes were associated with limited intracranial involvement. We conclude that a subdivision of Stage T4 nasopharyngeal carcinoma disease based on the extent of intracranial involvement would provide better prognostic information. PMID- 20852299 TI - A prospective comparison of cardiac imaging using intracardiac echocardiography with transesophageal echocardiography in patients with atrial fibrillation: the intracardiac echocardiography guided cardioversion helps interventional procedures study. AB - BACKGROUND: The Intracardiac Echocardiography Guided Cardioversion Helps Interventional Procedures study evaluated the concordance of intracardiac echocardiography (ICE) with transesophageal echocardiography (TEE) in patients with atrial fibrillation (AF). METHODS AND RESULTS: Patients with AF undergoing right heart catheterization underwent left atrium (LA) and interatrial septal (IAS) imaging by TEE and ICE. A blinded comparison of the 2 modalities was performed at a core laboratory. Ninety-five patients aged 58 +/- 12 years completed the study. The LA was profiled in all patients with both techniques, and concordance for image quality was 96%. LA appendage (LAA) imaging was achieved in 85% with ICE and 96% with TEE. There was no difference in the presence of spontaneous echo contrast between ICE and TEE during LA imaging, but there was a trend toward a greater incidence in the LAA with TEE (P = 0.109). Intracardiac thrombus was uncommonly seen (TEE, 6.9%; ICE, 5.2%). The concordance for the presence or absence of thrombus was 97% in the LA and 92% in the LAA, but the latter was detected more frequently with TEE. IAS imaging was achieved in 91% with ICE and in 97% with TEE (P = 0.177). Concordance for patent foramen ovale and atrial septal aneurysms was 100% and 96%, respectively. A negative ICE examination was associated with absence of dense echo contrast or thrombus on TEE in 86%. CONCLUSIONS: This study provides validation for the use of ICE for LA and IAS imaging. ICE imaging was less sensitive compared to TEE for LAA thrombus identification. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00281073. PMID- 20852301 TI - De-identification procedure and sample quality of the post-clinical test samples at the bio-repository of the National Cancer Center Hospital (NCCH) in Tokyo. AB - We established our bio-repository in October 2002. One of the unique aspects of our bio-repository is that it is based on post-clinical test samples. Although the post-clinical test sample-based storage is beneficial because ample clinical information is available for each sample and samples are to be refreshed regularly, many bio-bankers are hesitant to store them because of the possible problems of de-identification procedures and sample quality. Currently, we have two different types of sample, not de-identified status and de-identified status. Most of the samples for storage are not de-identified status. A portion of the samples are transferred to new tubes before and after being frozen, without clinical patient identifications and the status is de-identified. This tube transfer is the only de-identification procedure in our bio-repository so far. After a procedure of de-identification, these samples are stored. The de identified samples are collected under various project-based schemes. The quality standards of our samples are established by two factors: pre-analytical quality control efforts, and record keeping of sample history by sample tracking system. All the samples have been phlebotomized under strict control of pre-analytical requirements. By record keeping of sample history with the sample tracking system, we can tell the exact temperature and elapsed time in various situations since the phlebotomy procedure or on arrival at the clinical laboratory. In this article, we will disclose how we have dealt with the de-identification procedure and sample quality. PMID- 20852302 TI - Neurotrauma and the RUB: where tragedy meets ethics and science. AB - Decompressive craniectomy is a technically straightforward procedure whereby a large section of the cranium is temporarily removed in cases where the intracranial pressure is dangerously high. While its use has been described for a number of conditions, it is increasingly used in the context of severe head injury. As the use of the procedure increases, a significant number of patients may survive a severe head injury who otherwise would have died. Unfortunately some of these patients will be left severely disabled; a condition likened to the RUB, an acronym for the Risk of Unacceptable Badness. Until recently it has been difficult to predict this outcome, however an accurate prediction model has been developed and this has been applied to a large cohort of patients in Western Australia. It is possible to compare the predicted outcome with the observed outcome at 18 months within this cohort. By using predicted and observed outcome data this paper considers the ethical implications in three cases of differing severity of head injury in view of the fact that it is possible to calculate the RUB for each case. PMID- 20852303 TI - Access to investigational medicinal products for minors in Europe: ethical and regulatory issues in negotiating children's access to investigational medicines. AB - Patients who search for a better treatment, an increased quality of life, or even a chance to preserve life itself may claim to have an interest in accessing investigational medicinal products (IMP), particularly when no validated treatment for their disease or condition exists. For many, awaiting the uncertain and time-consuming process of converting an IMP into an approved drug may not appear a realistic option, as prognoses may be grim and a dramatic outcome may seem hard to avert. Gaining access to an IMP, however, often proves to be a difficult enterprise with a highly uncertain outcome. In addition, the process of seeking access to IMP is surrounded by various ethical issues that will be explored in this article. This paper explores the ethical concerns in two potential tracks of seeking access to IMP for minors: on an individual basis, or collectively, as a patient organisation. In this discourse, several unique ethical and regulatory concerns related to the direct negotiation of access to IMP for minor patients are identified, with a focus on product safety, the recruitment of research subjects, the unnoticed entry of market mechanisms in the recruitment of research subjects, and the sidelining of third parties in the recruitment process. The paper concludes with a concise reflection on the way forward. The quest for access to investigational drugs is particularly relevant to paediatric practice, in which a significant share of the drugs prescribed has never been tested in children or labelled for use in the paediatric population. PMID- 20852304 TI - Unconscious conflict of interest: a Jewish perspective. AB - In contemporary medicine, it is not always obvious whether the acceptance of a benefit constitutes a conflict of interest. A particular area of controversy has been the impact of small gifts or other benefits from pharmaceutical companies on physicians' behaviour. Typically, in such cases, the gift is not an explicit reward for cooperation; the physician does not perceive the gift as an attempt to influence his or her judgement; and the reward is relatively minor. Under these circumstances, physicians are generally of the view that acceptance of gifts will not affect their behaviour, notwithstanding findings from social psychology and neuroscience that the impact of gifts is often unconscious, shaping action without a person's awareness. Here, we draw on traditional texts of Jewish law pertaining to the prohibition of taking a gift to illustrate recognition by the ancients of unconscious conflicts of interest, and their approach to dealing with the problem. PMID- 20852305 TI - Mortality in small geographical areas and proximity to air polluting industries in the Basque Country (Spain). AB - OBJECTIVES: To study the association between proximity to air polluting industrial facilities and mortality in the Basque Country (Spain) in the 1996 2003 period. METHODS: A cross-sectional ecological study with 1465 census sections (CS) as units of analysis with a mean population of 1257 inhabitants. Association of CS mortality with proximity of industries of the European Pollutant Emission Register was studied by type of industrial activity and adjusted for social deprivation. Two distance thresholds (1 km and 2 km) were used as proxies for exposure in a 'near versus far' analysis. Causes of mortality studied were: all causes; tracheal, bronchial, and lung cancer; haematological tumours; ischaemic heart disease; cerebrovascular diseases; chronic diseases of the lower respiratory tract; and breast cancer (in women). Poisson's generalised linear mixed models (GLMM) with two random effects (heterogeneity and structured spatial variability) were used in a fully Bayesian environment. RESULTS: Men living in sections within 1 km from energy production industries had greater mortality from tracheal, bronchial, and lung cancer [CI(90%) 6% to 53%] as compared with people living further. Women had greater mortality from ischaemic heart disease [CI(90%) 1% to 17%] and respiratory illness [CI(90%) 1% to 24%] within 2 km from metal-processing industries. On the contrary, within the 1 km buffer from mineral industries, mortality was lower for all causes [CI(90%) -20% to -6%] and for ischaemic heart disease [CI(90%) -40% to -10%] in women, and from respiratory diseases in men [CI(90%) -39% to -4%], while it was greater for breast cancer in women [CI(90%) 2% to 28%] within the 2 km buffer. CONCLUSIONS: Analysis of mortality by census sections is a helpful exploratory tool for investigating environmental risk factors and directing actions to sites and risk factors with a greater impact on health. Further epidemiological and environmental investigations around metal-processing and energy-producing plants are required. PMID- 20852306 TI - Glyphosate drift promotes changes in fitness and transgene gene flow in canola (Brassica napus) and hybrids. AB - BACKGROUND AND AIMS: With the advent of transgenic crops, genetically modified, herbicide-resistant Brassica napus has become a model system for examining the risks and potential ecological consequences of escape of transgenes from cultivation into wild compatible species. Escaped transgenic feral B. napus and hybrids with compatible weedy species have been identified outside of agriculture and without the apparent selection for herbicide resistance. However, herbicide (glyphosate) exposure can extend beyond crop field boundaries, and a drift-level of herbicide could function as a selective agent contributing to increased persistence of transgenes in the environment. METHODS: The effects of a drift level (0.1 * the field application rate) of glyphosate herbicide and varied levels of plant competition were examined on plant fitness-associated traits and gene flow in a simulated field plot, common garden experiment. Plants included transgenic, glyphosate-resistant B. napus, its weedy ancestor B. rapa, and hybrid and advanced generations derived from them. KEY RESULTS: The results of this experiment demonstrate reductions in reproductive fitness for non-transgenic genotypes and a contrasting increase in plant fitness for transgenic genotypes as a result of glyphosate-drift treatments. Results also suggest that a drift level of glyphosate spray may influence the movement of transgenes among transgenic crops and weeds and alter the processes of hybridization and introgression in non agronomic habitats by impacting flowering phenology and pollen availability within the community. CONCLUSIONS: The results of this study demonstrate the potential for persistence of glyphosate resistance transgenes in weedy plant communities due to the effect of glyphosate spray drift on plant fitness. Additionally, glyphosate drift has the potential to change the gene-flow dynamics between compatible transgenic crops and weeds, simultaneously reducing direct introgression into weedy species while contributing to an increase in the transgenic seed bank. PMID- 20852308 TI - Are evaluated respiratory service developments implemented into clinical practice? AB - INTRODUCTION: Evaluation of the way in which respiratory care is delivered is increasingly recognised to be an important area for research. When service developments are reported, it is not always clear whether they are subsequently implemented within the reporting institution, and if not why not. METHODS: 3281 abstracts from three specialist journals and one general journal were reviewed, and 36 reported evaluated service developments identified. The authors of each of these were approached to determine whether the reported service developments were in use in their institution. RESULTS: 30 of the 36 authors responded (83%). 10 reports were of sharing care with nurses and five with other health professionals, and the remainder involved new technologies, education, patient information or guideline implementation. 15/30 had implemented the reported development into practice, 11 of which were implemented immediately. Delays were due to staffing, funding and organisational issues. 10/15 studies were not put into practice, the main reason being that the key person had left. Four respondents embarked upon further study to confirm their preliminary published findings. CONCLUSIONS: Reports of apparently positive service developments are only implemented in approximately one-half of institutions reporting the development. In a third of cases, non-implementation reflects the original authors believing that further study is necessary to confirm effectiveness. PMID- 20852307 TI - Comparison of three approaches to model grapevine organogenesis in conditions of fluctuating temperature, solar radiation and soil water content. AB - BACKGROUND AND AIMS: There is increasing interest in the development of plant growth models representing the complex system of interactions between the different determinants of plant development. These approaches are particularly relevant for grapevine organogenesis, which is a highly plastic process dependent on temperature, solar radiation, soil water deficit and trophic competition. METHODS: The extent to which three plant growth models were able to deal with the observed plasticity of axis organogenesis was assessed. In the first model, axis organogenesis was dependent solely on temperature, through thermal time. In the second model, axis organogenesis was modelled through functional relationships linking meristem activity and trophic competition. In the last model, the rate of phytomer appearence on each axis was modelled as a function of both the trophic status of the plant and the direct effect of soil water content on potential meristem activity. KEY RESULTS: The model including relationships between trophic competition and meristem behaviour involved a decrease in the root mean squared error (RMSE) for the simulations of organogenesis by a factor nine compared with the thermal time-based model. Compared with the model in which axis organogenesis was driven only by trophic competition, the implementation of relationships between water deficit and meristem behaviour improved organogenesis simulation results, resulting in a three times divided RMSE. The resulting model can be seen as a first attempt to build a comprehensive complete plant growth model simulating the development of the whole plant in fluctuating conditions of temperature, solar radiation and soil water content. CONCLUSIONS: We propose a new hypothesis concerning the effects of the different determinants of axis organogenesis. The rate of phytomer appearance according to thermal time was strongly affected by the plant trophic status and soil water deficit. Furthermore, the decrease in meristem activity when soil water is depleted does not result from source/sink imbalances. PMID- 20852309 TI - Risk behaviours among internet-facilitated sex workers: evidence from two new datasets. AB - Sex workers have historically played a central role in STI outbreaks by forming a core group for transmission and due to their higher rates of concurrency and inconsistent condom usage. Over the past 15 years, North American commercial sex markets have been radically reorganised by internet technologies that channelled a sizeable share of the marketplace online. These changes may have had a meaningful impact on the role that sex workers play in STI epidemics. In this study, two new datasets documenting the characteristics and practices of internet facilitated sex workers are presented and analysed. The first dataset comes from a ratings website where clients share detailed information on over 94,000 sex workers in over 40 cities between 1999 and 2008. The second dataset reflects a year-long field survey of 685 sex workers who advertise online. Evidence from these datasets suggests that internet-facilitated sex workers are dissimilar from the street-based workers who largely populated the marketplace in earlier eras. Differences in characteristics and practices were found which suggest a lower potential for the spread of STIs among internet-facilitated sex workers. The internet-facilitated population appears to include a high proportion of sex workers who are well-educated, hold health insurance and operate only part time. They also engage in relatively low levels of risky sexual practices. PMID- 20852310 TI - Association of Mycoplasma genitalium with balanoposthitis in men with non gonococcal urethritis. AB - OBJECTIVE: To determine whether Mycoplasma genitalium is associated with balanitis and/or posthitis in a previous study of the role of M genitalium in men with acute non-gonococcal urethritis (NGU). METHODS: In a previous study of men with acute NGU, the existence of balanitis and/or posthitis was recorded. Chlamydia trachomatis, M genitalium and ureaplasmas were sought in urethral swabs and urine using a direct fluorescent antibody test and in-house PCR, an in-house PCR and a culture method, respectively. Men were treated with doxycycline or erythromycin. RESULTS: M genitalium was associated significantly (p = 0.01) with balanitis and/or posthitis in 114 men with acute NGU. This association persisted when there was control for C trachomatis and urethral discharge (p = 0.021, OR 4.1, 95% CI 1.2 to 13.5). C trachomatis and ureaplasmas were not associated with balanitis and/or posthitis. CONCLUSION: Detection of M genitalium in men with acute NGU was associated significantly with balanitis and/or posthitis. The association is biologically plausible and may have a role in HIV-1 transmission and susceptibility. PMID- 20852311 TI - HIV infection and sexual behaviour in primary and secondary infertile relationships: a case--control study in Kigali, Rwanda. AB - OBJECTIVE: To compare the prevalence of sexually transmitted infections (STIs) (including HIV) and of high-risk sexual behaviour in the following three groups: primary infertile relationships, secondary infertile relationships and fertile relationships. Primary infertility is here defined as never having conceived before, secondary infertility as infertility subsequent to having conceived at least once. DESIGN: Unmatched case--control study. METHODS: Sexually active infertile women aged 21-45 years presenting at an infertility clinic of the Kigali Teaching Hospital, Rwanda and their male partners were invited to participate. Fertile controls who had recently delivered were recruited from the community. In a face-to-face interview, participants were asked about sociodemographic characteristics and their sexual behaviours, and tested for HIV and STIs. RESULTS: Between November 2007 and May 2009, 312 women and 254 partners in infertile relationships and 312 women and 189 partners in fertile relationships were enrolled. Involvement in a secondary infertile relationship was associated with HIV infection after adjusting for sociodemographic covariates for women (adjusted OR (AOR) = 4.03, 95% CI 2.4 to 6.7) and for men (AOR = 3.3, 95% CI 1.8 to 6.4). Involvement in a primary infertile relationship, however, was not. Secondary infertile women were more likely to have engaged in risky sexual behaviour during their lifetime compared with primary infertile and fertile women. Men in primary and secondary infertile relationships more often reported multiple partners in the past year (AOR = 5.4, 95% CI 2.2 to 12.7; AOR = 7.1, 95% CI 3.2 to 15.8, respectively). CONCLUSIONS: Increased HIV prevalence and risky sexual behaviour among infertile couples is driven by secondary infertility. Infertile couples, and especially those with secondary infertility, should be targeted for HIV prevention programmes and their fertility problems should be addressed. PMID- 20852312 TI - Physical fitness, but not muscle strength, is a risk factor for death in amyotrophic lateral sclerosis at an early age. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder mainly characterised by motor symptoms. Extensive physical activity has been implicated in the aetiology of ALS. Differences in anthropometrics, physical fitness and isometric strength measured at 18-19 years were assessed to determine if they are associated with subsequent death in ALS. METHOD: Data on body weight and height, physical fitness, resting heart rate and isometric strength measured at conscription were linked with data on death certificates in men born in 1951 1965 in Sweden (n=809 789). Physical fitness was assessed as a maximal test on an electrically braked bicycle ergometer. Muscle strength was measured as the maximal isometric strength in handgrip, elbow flexion and knee extension in standardised positions, using a dynamometer. Analyses were based on 684 459 (84.5%) men because of missing data. A matched case control study within this sample was performed. The population was followed until 31 December 2006, and 85 men died from ALS during this period. RESULTS: Weight adjusted physical fitness (W/kg), but not physical fitness per se, was a risk factor for ALS (OR 1.98, 95% CI 1.32 to 2.97), whereas resting pulse rate, muscle strength and other variables were not. CONCLUSIONS: Physical fitness, but not muscle strength, is a risk factor for death at early age in ALS. This may indicate that a common factor underlies both fitness (W/kg) and risk of ALS. PMID- 20852313 TI - Orientation to time as a guide to the presence and severity of cognitive impairment in older hospital patients. AB - BACKGROUND: Testing of orientation to time is an important part of mental status examination. The validity of errors in different aspects of temporal orientation was examined in older hospital patients as a guide to the presence of dementia or delirium and as a measure of the severity of dementia, as defined by the Global Deterioration Scale. METHODS: Inpatients and outpatients attending an acute hospital underwent independent assessments by two doctors on the same day to determine orientation to time and cognitive status. Optimum cut-offs for error scores on the different aspects of temporal orientation were calculated to maximise the sum of sensitivity and specificity for detection of dementia or delirium. RESULTS: Of the 262 patients assessed, 62 (23.7%) had dementia or delirium. The best cut-offs for detection of these disorders were: any error in identifying the year, month, day of the month or day of the week; and an error of more than 1 h in identifying the time of day. Failure to identify the year correctly was the most valuable single sign of dementia or delirium (sensitivity 86% and specificity 94%); failure to identify either year or month correctly was 95% sensitive and 86.5% specific for the detection of cognitive impairment. Severity of temporal disorientation, measured using a number of approaches, was strongly associated with severity of dementia. CONCLUSION: Disorientation to time is a useful guide to the presence and severity of dementia or delirium in older hospital patients. Failure to identify the year or month correctly is a sufficiently sensitive and specific indicator of dementia or delirium to warrant more detailed cognitive assessment in this population. PMID- 20852314 TI - The effect of visual impairment on quality of life of children aged 3-16 years. AB - BACKGROUND: It is well known that visual impairment (VI) has a detrimental effect on Quality of Life (QoL) in adults. Little is known about the effects of VI in childhood. AIMS: To evaluate the effects of VI on QoL of children. To the authors' knowledge, this is the first study containing a comparison arm for children with VI. METHODS: QoL in children with VI (n=24, age 10.13+/-2.89, 18 male, 6 female) was compared with an age-matched comparison group (n=24, age 9.83+/-2.81, 18 male, 6 female) using the Low Vision Quality of Life Questionnaire. Factors (distance and near visual acuity and age) that could be used as predictors of QoL were assessed. These were measured with standard clinical tests. RESULTS: Children with VI had significantly lower QoL scores than the comparison group (p<0.001), resulting in a 35.6% reduction in total QoL score. QoL scores in children with VI were correlated with distance and near visual acuity (p<0.05). 38% of the variance could be predicted by these factors and age. CONCLUSIONS: Consideration of the effects of this reduced QoL must be made. Further studies are needed to establish the benefit to QoL of different habilitation strategies. PMID- 20852315 TI - Diagnosis and management of ophthalmological features in patients with mucopolysaccharidosis. AB - Ocular pathology is common in patients with mucopolysaccharidosis (MPS), a hereditary lysosomal storage disorder, where the eye as well as other tissues accumulate excessive amounts of glycosaminoglycans. Despite genetic and phenotypic heterogeneity within and between different types of MPS, the disease symptoms and clinical signs often manifest during the first 6 months of life with increasing head size, recurrent infections, umbilical hernia, growth retardation and skeletal problems. Typical ocular features include corneal clouding, ocular hypertension/glaucoma, retinal degeneration and optic nerve atrophy. Visual deterioration and sensitivity to light may substantially reduce the quality of life in MPS patients, particularly when left untreated. As an early intervention, haematopoietic stem cell transplantation and/or enzyme replacement therapy are likely to improve patients' symptoms and survival, as well as visual outcome. Thus, it is of utmost importance to ensure proper detection and accurate diagnosis of MPS at an early age. It is of fundamental value to increase awareness and knowledge among ophthalmologists of the ocular problems affecting MPS patients and to highlight potential diagnostic pitfalls and difficulties in patient care. This review provides insight into the prevalence and severity of ocular features in patients with MPS and gives guidance for early diagnosis and follow-up of MPS patients. MPS poses therapeutic challenges in ocular management, which places ophthalmologists next to paediatricians at the forefront of interventions to prevent long-term sequelae of this rare but serious disease. PMID- 20852316 TI - Rapid assessment of avoidable blindness in three counties, Jiangxi Province, China. AB - BACKGROUND: A survey was undertaken in 2007 to assess the prevalence and causes of blindness and visual impairment in people aged >= 50 years in three different counties in Jiangxi, South East China (Gao'an, Xin'gan and Wan'zai). The counties were purposively selected to assess the impact of established non-governmental organisation activities in two counties (Gao'an and Xin'gan) compared with a third county (Wan'zai) without such a programme. METHODS: Clusters of 50 people aged >= 50 years were sampled with a probability proportional to the size of the population. Because of differences in expected prevalence and resources available for conducting the surveys, the total sample size varied from 4699 in Gao'an (94.0% response rate) to 3834 in Xin'gan (95.9%) and 2861 (95.4%) in Wan'zai. Households within clusters were selected through random walk sampling. Visual acuity (VA) was measured with a tumbling 'E' chart. Ophthalmologists examined people with VA< 6/18 in either eye. RESULTS: The prevalence of blindness (VA< 3/60 in the better eye with available correction) was similar in Gao'an (1.5%, 95% CI 1.1% to 1.8%), Xin'gan (1.8%, 1.4% to 2.2%) and Wan'zai (1.6%, 1.2% to 2.1%), and the prevalence of visual impairment (VA< 6/18 and >= 6/60) was approximately fourfold higher. Cataract was the leading cause of blindness in each of the three counties, while uncorrected refractive error was the dominant cause of visual impairment. The majority of blindness was avoidable in Gao'an (84.3%), Xin'gan (71.0%) and Wan'zai (71.7%). CONCLUSIONS: The prevalence of blindness in the three counties in Jiangxi, China was lower than expected, yet most of the blindness and visual impairment was avoidable, indicating that the prevalence could be reduced further through adequate programme planning and implementation. PMID- 20852317 TI - Evaluation of tear samples for Herpes Simplex Virus 1 (HSV) detection in suspected cases of viral keratitis using PCR assay and conventional laboratory diagnostic tools. AB - BACKGROUND: Herpes Simplex Virus (HSV) keratitis is a leading cause of corneal blindness. Definitive laboratory diagnosis is essential for timely management. Collection of corneal scrapings in patients with advanced epithelial keratitis and corneal thinning poses perforation risks; tear fluid is a feasible and convenient alternative but has not been widely evaluated for HSV detection. METHODS: Tear fluid alone (229) or along with corneal scrapings (153) from patients of suspected herpetic keratitis was tested for HSV-1 antigen by indirect immunofluorescence assay, virus isolation in Hep 2 cells and PCR to amplify the 111bp region of the thymidine kinase (tk) coding gene and the 144bp region from the DNA polymerase coding gene of HSV. RESULTS: HSV 1 antigen was detected in 31/229 (13.53%) tear specimen and 35/153 (22.87%) corneal scrapings in immunofluorescence assay; virus was isolated from 12/229 (5.2%) tear and 17/153 (11.11%) corneal scrapings, and PCR was positive for both the genes in 32/229 (13.97%) tear specimen and 56/153 (36.66%) corneal scrapings. CONCLUSION: Corneal scrapings yielded a significantly better HSV positivity than tears in both the PCR assay (p<0.0005) and immunofluorescence assay. PCR was much more sensitive than immunofluorescence and virus isolation. However, tears should be tested for definitive laboratory diagnosis of HSV infection whenever corneal scraping collection is not possible. PMID- 20852318 TI - Stereotactic low-voltage x-ray irradiation for age-related macular degeneration. AB - The IRay stereotactic low-voltage x-ray irradiation treatment system for age related macular degeneration consists of a low voltage x-ray tube, an eye tracking system, a robotically controlled delivery system, a coupling device to facilitate tracking and stabilisation, a graphical user interface and gating software. Low-voltage x-rays are delivered in a series of three spots to the macula in a non-invasive manner through the inferior pars plana. These beams are designed to overlap on the centre of the macula. Each beam delivers one-third of the total dose, such that the total macula dose is three times an individual beam's dose. The device is designed to run off standard domestic electrical power, and no special shielding is necessary for the room. This system has been validated in Monte Carlo simulations, human cadaver eye studies, pre-clinical animal studies and in a phase I clinical trial. PMID- 20852319 TI - Orbital development in survivors of retinoblastoma treated by enucleation with hydroxyapatite implant. AB - AIMS: To determine the impact of enucleation with hydroxyapatite implant on bony orbital development in survivors of retinoblastoma (RB) by measuring orbital volume based on CT imaging. METHODS: The authors used CT images obtained at a median age of 6 years to measure orbital volume of RB and contralateral orbits in 18 patients who underwent enucleation with hydroxyapatite implant for RB. Comparison of the orbital volume of RB and contralateral orbits was done using the Wilcoxon rank sum test. RESULTS: The mean age at diagnosis and operation was 29+/-23 months, and the mean follow-up was 49+/-31 months. The mean volume difference between RB and contralateral orbits was 0.93+/-1.13 cm(3). RB orbits with hydroxyapatite implant were statistically significantly smaller than contralateral orbits (p=0.002). The age at operation was significantly negatively correlated with orbital volume difference (p=0.033). Orbital volume differences for children treated by enucleation before the age of 12 months were also statistically significantly larger than those treated later. (p=0.03). CONCLUSION: Significant orbital growth retardation remained after enucleation, even with a hydroxyapatite implant for the RB orbit. Orbital growth retardation was correlated with operation age and also more prominent in children treated in the first year of life. PMID- 20852320 TI - The psychosocial effects of adult strabismus: a review. AB - Correction of adult strabismus is not a cosmetic procedure but one that restores normality to an individual's appearance that has been altered by a disease process. Two fundamental principles underpinning facial attractiveness are symmetry and averageness-manifest strabismus affects both of these giving an unconscious signal of poor genetic history. The presence of manifest strabismus adversely affects many aspects of patients' lives including finding a partner, job prospects and interaction with peers, and may manifest more seriously as psychiatric disorders. Surgical correction has been shown to be safe and effective for the functional problems of strabismus in adults but the hugely positive effects on the psychosocial aspects are only now becoming apparent. The advent of a new adult strabismus specific quality-of-life questionnaire and its subsequent validation will make this quantification of improvement easier. The wider medical community and the public at large should be made aware of the benefits of corrective strabismus surgery in adults. PMID- 20852321 TI - The case for recycling and adapting anti-tobacco mass media campaigns. AB - Effective mass media campaigns are hard to come by. A delicate blend of art and science is required to ensure content is technically accurate as well as being creatively engaging for the target audience. However, the most expensive component of a media campaign is not its development but its placement at levels that allow smokers to see, engage and respond to its content. This paper uses two examples to illustrate the process of adapting existing effective material to maximise the expenditure of precious resources on the placement of material. PMID- 20852322 TI - Malaysian and Thai smokers' beliefs about the harmfulness of 'light' and menthol cigarettes. AB - OBJECTIVE: This study explored the extent to which Malaysian and Thai smokers believe "light" and menthol cigarettes are less harmful than "regular" cigarettes and the correlates of these beliefs. METHODS: The study used data from wave 1 of the International Tobacco Control Southeast Asia Survey. 2006 adult smokers (95.3% male) from Malaysia and 2000 adult smokers (94.5% male) from Thailand were interviewed face to face in 2005. RESULTS: 29% of Malaysian respondents reported currently smoking light cigarettes and 14% menthols, with 19% agreeing that lights are less harmful and 16% agreeing that menthols are less harmful. 38% of Thai respondents reported currently smoking light cigarettes and 19% menthols, with 46% agreeing that lights are less harmful and 35% agreeing that menthols are less harmful. Malaysian smokers reporting current use of light or menthol cigarettes were more likely to believe that they are less harmful. Reported use of lights did not relate to beliefs for Thai respondents. The belief that light and/or menthol cigarettes are less harmful was strongly related to the belief that they have smoother smoke. CONCLUSIONS: The experience of smoother smoke is likely to produce some level of belief in reduced harm, regardless of how brands are labelled and whether or not Federal Trade Commission FTC/International Organisation for Standardisation tar, nicotine and carbon monoxide yield figures are used. PMID- 20852323 TI - Exploring differences in smokers' perceptions of the effectiveness of cessation media messages. AB - OBJECTIVE: To examine which types of cessation-focused advertisements are associated with perceived advertisement effectiveness among smokers and to assess whether key smoker characteristics (ie, cigarette consumption, desire to quit and past quit attempts) influence perceived effectiveness of different types of cessation ads. METHODS: We used data from the New York Media Tracking Survey Online, a web survey of 7060 adult smokers in New York. Participants were exposed to four categories of cessation ads: (1) why to quit--graphic images, (2) why to quit--testimonial, (3) how to quit and (4) anti-industry. Perceived ad effectiveness was measured with a four-item scale assessing the degree to which participants thought the ads made them stop and think, grabbed their attention, were believable and made them want to quit smoking. We categorised smokers based on cigarette consumption, desire to quit and past quit attempts. We used multivariable analyses to examine how smoker characteristics and category of cessation ads predict perceived ad effectiveness. RESULTS: Ads using the 'why to quit' strategy with either graphic images or personal testimonials were perceived as more effective than the other ad categories. Smokers who had less desire to quit or had not tried quitting in the past 12 months responded significantly less favourably to all types of cessation ads tested. Greater cigarette consumption was also associated with lower perceived effectiveness, but this association was smaller in magnitude. CONCLUSIONS: Tobacco control programmes that utilise cessation-focus advertising should focus relatively more on ads that adopt the 'why to quit' strategy with either graphic images or personal testimonials. PMID- 20852324 TI - Adolescents' awareness of, and involvement with, illicit tobacco in the UK. PMID- 20852325 TI - 'Carcinogens in a puff': smoking in Hong Kong movies. AB - Smoking scenes in movies, exploited by the tobacco industry to circumvent advertisement bans, are linked to adolescent smoking. Recently, a Hong Kong romantic comedy Love in a puff put smoking at centre stage, with numerous smoking scenes and words that glamourise smoking. Although WHO has issued guidelines on reducing the exposure of children to smoking in movies, none is adopted in Hong Kong. Comprehensive tobacco control strategies are urgently needed to protect young people in Hong Kong from cigarette promotion in movies. PMID- 20852326 TI - The association between home smoking restrictions and youth smoking behaviour: a review. AB - OBJECTIVE: To review the available evidence for home smoking restrictions as a useful tool in the prevention of youth smoking and to make recommendations for further research. METHODS: A PubMed search (1 January 1990 to 26 January 2010) identified studies involving youth <=18 years using extensive criteria. In all, 17 studies relating home smoking restrictions to youth smoking behaviour were identified from titles, abstracts or the full text, as required. Two additional articles were identified by other means. KE, NS and EG reviewed the studies. Differences in interpretation were resolved by discussion, with EG making final decisions. RESULTS: Of the 19 studies, 16 (including the only 2 longitudinal studies) showed at least marginal evidence of an association of home smoking restrictions with reduced adolescent smoking behaviours. Associations were more numerous and stronger in homes without adult smokers, suggesting that even in such homes, lack of a smoke-free home may undermine the parental value of not smoking. Definitions of home smoking rules, adolescent smoking behaviour and treatment of parental smoking varied widely among studies. It is recommend that future research: (1) contrast smoke-free homes for everyone against all others, (2) included an interaction term for parental smoking and having a smoke-free home, or conduct separate analyses for homes with and without parental or other adults smokers and (3) examine early and later stages of the smoking uptake continuum. CONCLUSIONS: While the evidence is suggestive for an effect, further research is required to establish causality using longitudinal designs. PMID- 20852328 TI - Right atrial lipoma in patient with Cowden syndrome. AB - Primary cardiac tumors are rarest form of cancer and the lipoma represent about 8% of these tumors. Cowden disease is a rare autosomal dominant disorder, associated to a germline mutation of the PTEN gene, characterized by multiple hamartomas and an increased risk of breast, thyroid and endometrial carcinomas. For the first time, we describe a right atrial lipoma in a patient affected by Cowden syndrome. The patient suffered of some episodes of atrial flutter. The echocardiogram showed a cardiac mass, suggestive of lipoma with cardiac magnetic resonance images. Right atrial mass was completely resected and the histological examination confirmed the diagnosis of lipoma. The patient was discharged from hospital without any complications. PMID- 20852327 TI - Chylomicron- and VLDL-derived lipids enter the heart through different pathways: in vivo evidence for receptor- and non-receptor-mediated fatty acid uptake. AB - Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36(-/-)), and double knock-out (hLpL0/Cd36(-/-)-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 +/- 3.8; hLpL0, 36.2 +/- 3.5; Cd36(-/-), 57.7 +/- 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 +/- 1.4 nmol/g, p < 0.05). Myocardial VLDL triglyceride (TG) uptake was reduced in the hLpL0 (31 +/- 6%) and Cd36(-/-) (47 +/- 4%) mice with an additive reduction in the DKO (64 +/- 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of beta-actin-MerCreMer/LpL(flox/flox) mice. Induced loss of LpL increased TG levels >10-fold and reduced HDL by >50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by ~70% and retinyl ester by ~50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins. PMID- 20852329 TI - Cyanoacrylate-sealed Donati suture for wound closure after cardiac surgery in obese patients. AB - The majority of wound infections after median sternotomy in obese patients are triggered by the breakdown of skin suture and subsequent seepage of skin flora into the deeper tissue layers. In a prospective study, 90 patients (body mass index >=30) who had cardiac surgery via median sternotomy were enrolled. In 45 patients, skin closure was performed according to the Donati technique (vertical interrupted mattress suture) and sealed with octylcyanoacrylate (group A). In 45 patients, intracutaneous running technique without sealed was performed (group B). The endpoint was wound infection within 90 days. Degree of obesity and other risk factors for wound infection were equally distributed between groups A and B (all P>0.05). In group A only two superficial infections occurred, whereas in group B there were nine wound infections including two deep infections (P=0.026). In 10 of 11 infections (both groups) coagulase-negative staphylococci were isolated. In eight of 11 wound infections the caudal third of the incision was affected. Intertrigo in inframammary skin folds was found in 20.0% (18/90) of all patients but in 63.6% (seven of 11) of cases with infection. We conclude, that cyanoacrylate-sealed Donati suture is superior to intracutaneous suture technique since it offers tension-resistant closure with immediate microbial barrier properties. PMID- 20852330 TI - Surgical management of bronchopulmonary typical carcinoid tumors: an institutional experience. AB - Bronchopulmonary typical carcinoid tumors are well known as low-grade malignant tumors with fairly benign behaviors; however, distant metastasis after complete resection and multiple carcinoid tumors in the resected lungs have been sporadically reported. Lesser resections are preferred including lung-sparing surgery, while the importance of major surgical resections is also emphasized. For better understanding of bronchopulmonary typical carcinoid tumors, we reviewed our institutional experience. Eight patients with bronchopulmonary typical carcinoid tumors underwent complete pulmonary resection. Various perioperative variables and postoperative survival were investigated retrospectively. All patients were alive after surgery. Seven patients received more than a lobectomy and one underwent a segmentectomy for a peripheral small nodule. In all patients, systemic nodal dissection was performed. In one patient who received a lobectomy for a peripheral nodule, multiple carcinoid tumors were found in the resected specimen. No patients received any adjuvant chemotherapy or radiotherapy after pulmonary resection. In one patient, tumors recurred at the bronchial stump and in the liver approximately five years after complete pulmonary resection. Despite a small number of cases, our study supported the idea that bronchopulmonary typical carcinoid tumors might require major surgical procedures and that complete pulmonary resection of typical carcinoid tumors could expect long-term survival. PMID- 20852331 TI - Right ventricular recovery after cervical extra corporeal membrane oxygenation in a four-month-old male leading to left Berlin Heart Excor assistance. AB - A 4-month-old male with cardiogenic shock was implanted with cervical extracorporeal membrane oxygenation (ECMO). He had a biventricular heart failure associated to multiple organ failure (MOF). Right ventricular (RV) function and MOF recovered during five days ECMO leading to left ventricular assistance device (LVAD) implantation. This case shows the advantages of the double bridge strategy providing intervention time for complications refractory to VAD implantation and evaluation time of right and left ventricular function for potential mono- or bi VAD implantation. Furthermore, there are no reports describing this strategy in young children leading to RV function recovery and its advantage. PMID- 20852332 TI - Early diagnosis of lung cancer using a SAFE-3000 autofluorescence bronchoscopy. AB - The aim of the study was to evaluate the double modality working of a new autofluorescence videobronchoscope SAFE-3000 for the detection and localization of precancerous and malignant lesions. From April to May 2009, 168 patients underwent SAFE-3000 bronchoscopy using 'Twin Mode' and 'Multiple Image Xposition (MIX)' technologies. The study considers only 97 patients with morphological alterations (visual score 2 or 3) of mucosa; four bronchial biopsies (two for every modality) have been performed on every patient. Histological diagnosis of the 388 biopsies revealed normal mucosa in 11 patients, four benign lesions, 27 precancerous lesions and 55 malignant lesions. The sensitivity of the 'Twin Mode' and 'MIX' techniques in the characterization of premalignant and malignant lesions was 96% vs. 100%. The specificity was 60% in both of these technologies. SAFE-3000 autofluorescence bronchoscopy allows an early diagnosis of preneoplastic or neoplastic lesions according to the careful analysis of the bronchial mucosa, due to the complementarity of two modalities 'Twin Mode' and 'MIX'. Based on the relationship between the bronchoscopic goal and the histological results the MIX method contributes more of the new endoscopic technique findings. PMID- 20852333 TI - Off-pump Y-graft coronary artery bypass in a patient with situs inversus totalis. AB - Situs inversus is the mirror image of situs solitus. Situs inversus with dextrocardia is termed 'situs inversus totalis'. Since situs inversus totalis is a rare condition, there are a only a few reports about off-pump coronary artery bypass (OPCAB) in these patients. A 67-year-old man with a diagnosis of situs inversus totalis and three-vessel disease, underwent an elective surgical revascularization. The operation consisted of an OPCAB using a total arterial composite Y-graft. The right internal mammary artery (RIMA) and the left radial artery (RA) were harvested as pedicles and they were anastomized as Y-grafts. Three distal anastomoses were performed: the RIMA to the anterior descending artery and the RA sequentially to the obtuse marginal branch and the posterior descending artery. The peculiarity of OPCAB no-touch with a composite graft in a patient with situs inversus totalis consisted in the mirroring of the whole surgical set-up and of the surgical strategy. The surgery as well as the postoperative period were uneventful. This case report shows the feasibility of OPCAB 'no-touch' with composite arterial grafting in a patient with situs inversus totalis. PMID- 20852335 TI - A multi-view approach to cDNA micro-array analysis. AB - Microarray has emerged as a powerful technology that enables biologists to study thousands of genes simultaneously, therefore, to obtain a better understanding of the gene interaction and regulation mechanisms. This paper is concerned with improving the processes involved in the analysis of microarray image data. The main focus is to clarify an image's feature space in an unsupervised manner. In this paper, the Image Transformation Engine (ITE), combined with different filters, is investigated. The proposed methods are applied to a set of real-world cDNA images. The MatCNN toolbox is used during the segmentation process. Quantitative comparisons between different filters are carried out. It is shown that the CLD filter is the best one to be applied with the ITE. PMID- 20852334 TI - Molecular genetics evidence for the in vivo roles of the two major NADPH dependent disulfide reductases in the malaria parasite. AB - Malaria-associated pathology is caused by the continuous expansion of Plasmodium parasites inside host erythrocytes. To maintain a reducing intracellular milieu in an oxygen-rich environment, malaria parasites have evolved a complex antioxidative network based on two central electron donors, glutathione and thioredoxin. Here, we dissected the in vivo roles of both redox pathways by gene targeting of the respective NADPH-dependent disulfide reductases. We show that Plasmodium berghei glutathione reductase and thioredoxin reductase are dispensable for proliferation of the pathogenic blood stages. Intriguingly, glutathione reductase is vital for extracellular parasite development inside the insect vector, whereas thioredoxin reductase is dispensable during the entire parasite life cycle. Our findings suggest that glutathione reductase is the central player of the parasite redox network, whereas thioredoxin reductase fulfils a specialized and dispensable role for P. berghei. These results also indicate redundant roles of the Plasmodium redox pathways during the pathogenic blood phase and query their suitability as promising drug targets for antimalarial intervention strategies. PMID- 20852336 TI - Compact extreme learning machines for biological systems. AB - In biological system modelling using data-driven black-box methods, it is essential to effectively and efficiently produce a parsimonious model to represent the system behaviour. The Extreme Learning Machine (ELM) is a recent development in fast learning paradigms. However, the derived model is not necessarily sparse. In this paper, an improved ELM is investigated, aiming to obtain a more compact model without significantly increasing the overall computational complexity. This is achieved by associating each model term to a regularized parameter, thus insignificant ones are automatically unselected, leading to improved model sparsity. Experimental results on biochemical data confirm its effectiveness. PMID- 20852337 TI - An improved multi-label classification method and its application to functional genomics. AB - In this paper, a multi-label classification method based on label ranking and delicate boundary Support Vector Machine (SVM) is proposed for solving the functional genomics applications. Firstly, an improved probabilistic SVM with delicate decision boundary is used as scoring approach to obtain a proper label rank. Secondly, an instance-dependent thresholding strategy is proposed to decide classification results. A d-folds validation approach is utilised to determine a set of target thresholds for all training samples as teachers, then an appropriate instance-dependent threshold for each testing instance is obtained by applying k-Nearest Neighbours (KNN) strategy on this teacher threshold set. PMID- 20852338 TI - Predicting three-dimensional structure of protein fragments from dihedral angle propensities and molecular dynamics. AB - Incorporating the existing knowledge of protein structural preferences, e.g., amino acid angle frequencies, in structure prediction have proven to be less successful with smaller peptides. In this work, we compare the effectiveness of backbone angle propensity libraries derived from two protein data sets: one consisting of proteins of unrestricted lengths; the second containing proteins ranging in size from 40 to 75 residues. Model structures for 29 target peptides are predicted using a threading algorithm and their stability evaluated using in vacuo molecular dynamics simulations. Structures derived from the data set consisting of smaller proteins outperformed those developed from that unrestricted by protein length. PMID- 20852340 TI - [Some reasons to carry on and improve mortality data in Italy]. PMID- 20852339 TI - Proteomic-based screening of miRNAs metabolic pathway targeting. AB - The analysis of miRNA expression profile is powerful support to screen new disease biomarkers. One miRNA can control the expression of several different protein mRNAs. Lack of knowledge about the process of target recognition is a weak point in the development of reliable computational tools for miRNA target selection. Here we present a novel integrative approach for to predict potential miRNA target. It is a workflow founded on integration proteomic and miRNA information. The software has been tested on a sample of proteomic data obtained from samples of mouse subjected to the effect of Environmental Cigarette Smoke (ECS). PMID- 20852341 TI - [Colorectal cancer: if the actual trend persists, the gap between north and south will disappear in 2019]. PMID- 20852342 TI - [The National Prevention Programme 2010-2012]. PMID- 20852343 TI - [Smoking cessation with the help of community pharmacists]. AB - AIM: To investigate the outcome of a protocol for smoking cessation used in the practice of the community pharmacies. DESIGN: Observational descriptive study of a non pharmacological intervention, without parallel control. SETTING AND PARTICIPANTS: Urban community pharmacies in the province of Trieste (n=60). Data have been collected by 31 pharmacists representing 31 pharmacies (52%). MAIN OUTCOME MEASURES: Outcome of a brief intervention aimed to promote the use of nicotine replacement (NRT) or to refer to a smoking cessation clinic. RESULTS: Data of 905 smokers have been analysed: 16.1% (CI 95%: 11.6%-20.5%) purchased NRT and 11.1% (CI 95%: 7.8%-14.5%) accepted to be referred to a smoking cessation clinic. The assessment of the degree of motivation to stop smoking and of the degree of nicotine dependence, according to West, is highly associated to the outcome of the intervention. CONCLUSION: The study encourages the use of no smoking programs in the community pharmacies. Intervention must be short and simple. West's assessment system is useful and reliable for smokers' evaluation and for decisions regarding the therapeutic strategy of smoking cessation. PMID- 20852344 TI - [Mortality and morbidity cohort study of residents in the neighbourhood of Milazzo industrial area (Sicily)]. AB - OBJECTIVE: The municipality of Pace del Mela, together with Milazzo and San Filippo del Mela, has been recognized as a contaminated site of national concern. The purpose of the present study is to evaluate the health status of subjects resident in the Gabbia district, which is close to the industrial areas of both, Pace del Mela and Milazzo. SETTING AND PARTICIPANTS: All streets and addresses of the area of interest have been identified, taking into account their changes in name over time. The cohort of subjects who lived in the area for any period of time from September 1st, 1984, through December 31st, 2007 has been reconstructed by manual consultation of the Registrar Office files. Standardized mortality ratios, specific for cause, age class, gender and calendar period, have been computed using as reference the Sicilian population. Standardised incidence ratios, based on regional hospital discharge files, have been computed for the years 2001-2007. The cohort is constituted by 457 subjects, 230 men and 227 women. Ascertainment of vital status has not been possible for 39 subjects, corresponding to 8.5% of the cohort. RESULTS: Observed mortality for all causes and for all cancers is consistent with expected figures (62 observed vs 63 expected and 14 observed vs 15 expected, respectively). Observed cancer morbidity is inferior to the corresponding expected figure (SIR=0.49, CI 95%: 0.31-0.79). CONCLUSION: The health profile of the Gabbia district population, as estimated from mortality and hospital discharge records, does not show major departures from expected figures. PMID- 20852345 TI - [Mortality from asbestos-related causes and incidence of pleural mesothelioma among former asbestos cement workers in San Filippo del Mela (Sicily)]. AB - OBJECTIVES: The present paper estimates the burden of asbestos-related disease among asbestos-cement production workers of the Sacelit plant that operated in San Filippo del Mela (Province of Messina) from 1958 through 1993. SETTING AND PARTICIPANTS: The cohort was enumerated by the local committee of formerly exposed workers, with whom a collaboration was set up. The cohort includes 198 subjects with complete individual anagraphic information, out of 231 previous workers identified by the committee. A record-linkage with the Sicilian centre of the National mesothelioma registry enabled estimation of mesothelioma incidence for the years 1998-2008. Standardised proportionate mortality (SPMR) for asbestos related causes was computed for the years 1986-2009. Sicilian Region constituted the reference population. The rationale for using SPMR rather than standardized mortality ratio (SMR) was a consequence for the lack of company files from which to obtain dates of start and termination of employment, and thus to compute person-years of observation, following the guidelines of the international scientific literature. RESULTS: Standardised incidence ratio (SIR) for mesothelioma in the overall cohort was 251 (4 observed, 0.02 expected). Proportionate mortality analysis among male subjects showed significant increases for pneumoconiosis (SPMR 80.1, 5 observed), lung cancer (SPMR 2.81, 10 observed) and pleural neoplasms (SPMR 19.4, 2 observed). CONCLUSIONS: Notwithstanding limitations in cohort reconstruction, for which the proportion of eligible subjects was 87.5% of those detected by the local committee, and the lack of information on duration of employment, it was possible to estimate a significant increase of the incidence of pleural mesothelioma with respect to Sicilian population. Also mortality from asbestos-related causes was in excess with respect to the regional reference population. PMID- 20852346 TI - [Health surveillance for subjects with past occupational exposure to asbestos: the experience of Local Health Unit Messina 5 (Sicily)]. AB - OBJECTIVE: In the framework of the World Health Organization (WHO)-Istituto superiore di sanita (ISS) joint research project "Cohort studies in areas of high environmental risk in Sicily", since 2007 a working group ISS-Local Health Unit Messina 5 (AUSL ME5) assessed the issue emerged during the course of a health monitoring program launched in 2003, dedicated to former employees of an asbestos cement factory, and their relatives (378 subjects, 119 ex employees and 259 relatives). METHODS: Communication about the health risks linked to previous exposure to asbestos, diagnostic tools for asbestos-related diseases, available preventive measures (stopping smoking tobacco, avoiding further exposure to respiratory irritants, prophylaxis of any intercurrent respiratory diseases) were focused. The working group discussed the whole structure of the activity in progress, and identified the difficulties emerged in previous years. RESULTS AND CONCLUSIONS: The authors developed a health plan that could be useful in similar Sicilian contexts with public health problems due to past activities with asbestos. PMID- 20852347 TI - [Acute effects of air pollution in Brindisi (Italy): a case-crossover analysis]. AB - OBJECTIVE: To evaluate the association between daily air pollutant concentration and daily data regarding mortality and hospital admissions among residents of Brindisi (Southern Italy) in the years 2003-2006. DESIGN: The association between the time series of daily mortality (2003-2005) and hospital admissions (2003 2006) and the time series of daily pollutant concentration were analyzed using a case-crossover method and a conditional logistic regression. Bi-directional control periods were selected using a time-stratified approach. Models include mean temperature, relative humidity, influence of epidemics, summer decrease of resident population and holidays as confounders. Specific models with the following variables: cause of death or hospital admission, gender, age and season have been fitted. As hazard periods the following lags have been considered: single lag (from 0 to five) and cumulative lag (lag 0-1 for mortality and 0-3 for hospital admissions). MAIN OUTCOME MEASURES: A total of 1,792 subjects deceased of all natural causes (including cardiovascular and respiratory causes) and 6,925 hospital admissions for acute conditions (cardiac, cerebrovascular and respiratory diseases) were considered. PM10, NO2 and CO daily pollutant concentration series were examined. RESULTS: PM10 was associated with mortality from all natural causes (10.36%; 95% CI 1.83-19.61 at lag 0-1). The risk was more pronounced for cardiovascular mortality (14.35%; 95% CI 2.11; 28.07 at lag 1). The association with hospitalization for cerebrovascular diseases was statistically significant for PM10 among females (13.4%; 95% CI 1.7; 26.4 at lag 4) and elderly over 75 years old (13.6%; 95% CI 0.4; 28.6 at lag 4). In specific population groups, increased mortality and hospital admissions have been associated with NO2. CONCLUSION: This study found strong and consistent associations between outdoor air pollution (coming from both industrial emissions and urban traffic) and short-term increases in both mortality and morbidity. Precautionary measures should be taken. PMID- 20852348 TI - ["Bridge Coding" ICD-9, ICD-10 and effects on mortality statistics]. AB - OBJECTIVE: This study evaluates the impact of the introduction of ICD-10 on mortality statistics in Italy. DESIGN: "Bridge-Coding" analysis carried out by a working group that has coded a number of death certificates using both ICD-9 and ICD-10 versions. In 2006, a training project was launched in order to allow the group to standardize the coding procedures. SETTING: The study was carried out by professionals from the following regions: Emilia-Romagna, Veneto, Tuscany, Liguria; and from the towns of Biella and Milan. The analysis included 74,525 Death Certificates produced in the aforementioned areas. RESULTS: A limited variability was observed for the most important groups of diseases (diseases of the circulatory system and neoplasms), with low impact on mortality statistics. The variability was higher for "minor" diseases like infectious and respiratory diseases, and dementia. The variability was similar but not identical to that observed in other national and international studies. The "Bridge-Coding" analysis has a local impact. Furthermore, changes depending on the variation in the selection rules are impossible to predict or to correct with the trans-coding procedure. CONCLUSIONS: In some cases, the changes determined by the implementation of ICD-10 are not completely corrected by the transcoding procedure, even applying appropriate Comparability Ratios (CR) from "Bridge Coding" analysis like this. Studies on respiratory diseases, or dementia and some neoplasms require new coding procedures in only one ICD version. Quality and accuracy of the compilation of death certificates have more effect than a correct coding, though more casual and less evaluable by means of comparability studies like this one. PMID- 20852349 TI - [Health of immigrants in Italy: increasing evidences and forgotten issues in the epidemiological research]. AB - To obtain a broad picture of epidemiological studies on health of immigrants in Italy, we analyzed abstracts presented at the last five annual meetings of the Italian Epidemiological Association (AIE), and abstracts on PubMed published in 2000-2009 (including also clinical studies). Studies at AIE meetings mainly used electronic archives of health records to investigate the overall health profile of immigrants, or specifically women and perinatal health; these surveys are then rarely published on scientific journals. By contrast, several areas addressed in the literature (infectious diseases, accidents, lifestyles, mental health, pediatric diseases, allergic diseases) are almost absent in recent AIE meetings. If Italian epidemiologists claim a role as technical support to policy makers, they should probably invest more in what has recently become the most important and debated issue in the Italian society. PMID- 20852350 TI - [TNM classification of malignant tumours, VII edition 2009. Changes and practical effects on cancer epidemiology]. AB - The seventh edition of TNM classification of malignant tumours has been published by the International Union against Cancer in late 2009 and it is now available also in Italian language. This new edition introduces some major revisions and several updates of cancer staging rules. New criteria based on pathological details, biological assessment of lesions and new prognostic groupings have been established. Clinicians, pathologists, epidemiologists have now the chance to get familiar with those novelties, that are expected to be of great help in a moment like the present one, when strong evolutions occur in the strategies of diagnosis and of treatment of cancer. PMID- 20852351 TI - Significant enhancement of the sensing characteristics of In2O3 nanowires by functionalization with Pt nanoparticles. AB - We report a significant enhancement in the gas sensing properties of In(2)O(3) nanowires by functionalizing their surfaces with Pt nanoparticles. For Pt functionalization, In(2)O(3)-Pt core-shell nanowires are synthesized by the sputtering deposition of Pt layers on bare In(2)O(3) nanowires. Next, continuous Pt shell layers are transformed into Pt nanoparticles of cubic phase by heat treatment. In an O(2) gas sensing test, the Pt-functionalized In(2)O(3) nanowires reveal exceptionally higher sensitivity and faster response than bare In(2)O(3) nanowires. PMID- 20852352 TI - Nanoscale memory devices. AB - This article reviews the current status and future prospects for the use of nanomaterials and devices in memory technology. First, the status and continuing scaling trends of the flash memory are discussed. Then, a detailed discussion on technologies trying to replace flash in the near-term is provided. This includes phase change random access memory, Fe random access memory and magnetic random access memory. The long-term nanotechnology prospects for memory devices include carbon-nanotube-based memory, molecular electronics and memristors based on resistive materials such as TiO(2). PMID- 20852353 TI - CuO based inorganic-organic hybrid nanowires: a new type of highly sensitive humidity sensor. AB - The organic surfactant template method has been widely used for the preparation of CuO nanorods, nanotubes and nanowires. However, the surfactants in this system have no effect on the properties of the final products because they are flushed away. In this work, we used this method to synthesize a novel type of inorganic organic hybrid nanowire via the hybridization between CuO and amphiphilic oligomer octadecyl, polyethylene glycol di-butenetrioate (O-B-EG-B). Here O-B-EG B, as a structure director, was not flushed away but remained in the prepared hybrid nanowires because it was bound around CuO or entrapped in interior CuO. The hybrid nanowires showed CuO cores and P(O-B-EG-B) shells when the concentration of O-B-EG-B was 0.4 mg ml(-1), but exhibited P(O-B-EG-B) cores and CuO shells when the concentration of O-B-EG-B was 4.0 mg ml(-1). We found that the hybrid nanowires with P(O-B-EG-B) cores and CuO shells could sense a slight change in the relative humidity (RH) and respond by rapidly changing their conductivity. The resistance changed by about two orders of magnitude within the humidity range from 5% to 83.8%. Moreover, a humidity sensor based on this type of nanowire not only showed long-term stability but also exhibited excellent reversibility to moisture changes in air. PMID- 20852354 TI - Integrin-targeting thermally cross-linked superparamagnetic iron oxide nanoparticles for combined cancer imaging and drug delivery. AB - We report multifunctional nanoparticles that are capable of cancer targeting and simultaneous cancer imaging and therapy. The nanoparticles are composed of cyclic arginine-glycine-aspartic acid (cRGD) peptide ligand bioconjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) that enable loading of the anticancer drug doxorubicin (Dox). The cyclic RGD-conjugated TCL SPION (cRGD_TCL-SPION) had a mean hydrodynamic size of 34 +/- 8 nm with approximately 0.39 wt% of cyclic RGD attached to the surface of the nanoparticles. The cRGD_TCL-SPION exhibited preferential binding towards target cancer cells (U87MG, integrin alpha(v)beta(3)+) when analyzed by T(2)-weighted magnetic resonance (MR) imaging. When Dox was loaded onto the polymeric coating layers of cRGD_TCL-SPION via ionic interaction, the resulting Dox-loaded cRGD_TCL SPION (Dox@cRGD_TCL-SPION) showed much higher cytotoxicity in U87MG cells than Dox@TCL-SPION lacking cRGD (IC(50) value of 0.02 uM versus 0.12 uM). These results suggest that Dox@cRGD_TCL-SPION has potential for use as an integrin targeted, combined imaging and therapeutic agent. PMID- 20852355 TI - Transient photoconductivity and femtosecond nonlinear optical properties of a conjugated polymer-graphene oxide composite. AB - A water soluble conjugated thiophene polymer, sodium salt of poly[2-(3 thienyl)ethoxy-4-butylsulfonate] (TPP), and graphene oxide (GO) composite film (GO-TPP) device was prepared. Transient photoconductivity measurements were carried out on the GO-TPP composite film using 150 ns laser pulses of 527 nm wavelength. Highly efficient photocurrent generation was observed from the GO-TPP film. The relationships of the film photoconductivity, photocurrent decay time and electron decay times with the incident light intensity were investigated. The photoconductive gain of the film was determined to be greater than 40% and to be independent of the light intensity. Furthermore, the femtosecond nonlinear optical properties of the GO-TPP film were measured using 800 nm femtosecond laser pulses and the composite film exhibited high nonlinear absorption and nonlinear refraction coefficients. PMID- 20852357 TI - Site-selective synthesis of in situ Ni-filled multi-walled carbon nanotubes using Ni(salen) as a catalyst source. AB - The synthesis of Ni-filled multi-walled carbon nanotubes was performed by atmospheric pressure chemical vapor deposition with propane on Si at 850 degrees C using a simple mixture of (N, N'-bis(salicylidene)-ethylenediiminato) nickel(II), commonly known as Ni(salen), and a conventional photoresist. Analysis of the carbon nanotubes using scanning electron microscopy together with high resolution transmission electron microscopy show that the nanotubes have grown by a tip-growth mechanism and exhibit a multi-walled structure with partial Ni filling. The high quality of the Ni-filled nanotubes is evidenced by Raman spectroscopy. The magnetic properties of Ni-filled nanotubes were analyzed using a superconducting quantum interference device which revealed their ferromagnetic behavior with large coercivity. A scalable as well as site-selective growth of high quality Ni-filled carbon nanotubes is achieved by a simple photolithographic method. PMID- 20852356 TI - Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes. AB - A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems. PMID- 20852358 TI - Effects of pravastatin on cellular ultrastructure and hemorheology in rats after traumatic head injury. AB - Pravastatin has neuroprotective effects against aging but its role in brain injury remains unclear. This study evaluated the effects of pravastatin on the ultrastructural changes and hemorheological parameters in rats after traumatic brain injury (TBI) of right parietal cortical contusion by a controlled weight dropping method. There were three groups: (I) Sham operated group; (II) TBI + vehicle (saline) group; and (III) TBI + pravastatin group. Right parietal craniectomy was performed in all groups. In TBI + pravastatin group, pravastatin was administered orally at a dose of 1 mg/kg every day for 7 days starting at 24 hours after the injury. Plasma viscosity, erythrocyte deformability and erythrocyte aggregation were measured from blood samples of all rats on 2nd, 7th and 15th days. At the same time electron microscopic study was done on designated days for groups II and III. Treatment with pravastatin markedly increased aggregation amplitude and gammaIsc max values and significantly decreased erythrocyte deformability but did not change plasma viscosity in 2 weeks time. Ultrastructural parameters such as perinuclear edema, mitochondrial swelling and intraneuronal vacuoles were detected in lower degree in the statin group when compared to the saline group, especially decreased demyelinization and endothelial detachment was prominent. As a result, the hyperviscosity state with increased erythrocyte aggregation and decreased erythrocyte deformability induced by pravastatin in this study was accompanied by an improvement of the ultrastructural findings in TBI. This hyperviscosity state may be a compensatory mechanism to increase the oxygenation of the injured tissue by inducing the release of antiaggregant and vasodilatory substances by increasing shear stress. Therefore, we suggest that prolonged pravastatin usage may exert affirmative effects on traumatic brain injury conditions by increasing blood viscosity. PMID- 20852359 TI - Does ambient temperature affect exercise-induced changes in the main determinants of blood rheology? AB - To ascertain the effects of environmental temperature on blood rheology, ten subjects performed two exercise trials, in random order, at approximately 60% VO(2) max for 45-min. One trial was conducted in thermoneutral environment (20 +/ 1 degrees C), while the other was performed in hot dry condition (36 +/- 1 degrees C). Venous blood was removed at rest; following exercise and recovery. Blood was measured for lactate, haematocrit, and hemoglobin, while plasma was measured for viscosity, and fibrinogen. Plasma volume changes were estimated from Hct and Hb readings. Exercise was followed by a significant (P < 0.05) reduction in plasma volume in both test trials. Lactate increased significantly (P < 0.05) following exercise with no difference being observed between trials. When post exercise raw data were not adjusted for plasma volume changes, a significant increase (P < 0.05) in plasma viscosity (PV) and plasma fibrinogen (Fb) was found with no difference between thermoneutral and hot trials. When the raw data post exercise for PV and Fb were adjusted for plasma volume changes, no significant difference between rest and post exercise was demonstrated. Rheological variables returned to the pre-exercise level at the end of recovery. In conclusion, vigorous exercise transiently increased PV and Fb, and the added heat stress did not affect these responses more than exercise alone. The mechanism responsible for the increase in PV and Fb in response to vigorous exercise appears to be related to plasma shifts from intravascular to the extravascular spaces rather than plasma volume loss. PMID- 20852360 TI - The low-dose combination preparation Vertigoheel activates cyclic nucleotide pathways and stimulates vasorelaxation. AB - Vertigo of various and often unknown aetiologies has been associated with and attributed to impaired microvascular perfusion in the inner ear or the vertebrobasilar system. Vertigoheel is a low-dose combination preparation of proven value in the symptomatic treatment of vertigo. In the present study we tested the hypothesis that Vertigoheel's anti-vertiginous properties may in part be due to a vasodilatory effect exerted via stimulation of the adenylate and/or guanylate cyclase pathways. Thus, the influence of Vertigoheel or its single constituents on synthesis and degradation of cyclic nucleotides was measured. Furthermore, vessel myography was used to observe the effect of Vertigoheel on the vasoreactivity of rat carotid arteries. Vertigoheel and one of its constituents, Anamirta cocculus, stimulated adenylate cyclase activity, while another constituent, Conium maculatum, inhibited phosphodiesterase 5, suggesting that the individual constituents of Vertigoheel contribute differentially to a synergistic stimulation of cyclic nucleotide signalling pathways. In rat carotid artery rings, Vertigoheel counteracted phenylephrine-induced tonic vasoconstriction. The present data demonstrate a vasorelaxant effect of Vertigoheel that goes along with a synergistic stimulation of cyclic nucleotide pathways and may provide a mechanistic basis for the documented anti-vertiginous effects of this combination preparation. PMID- 20852361 TI - Vancomycin and to lesser extent tobramycin have vasomodulatory effects in experimental endotoxemia in the rat. AB - BACKGROUND: Antibiotic treatment represents a key component of therapy for severe sepsis. Apart from their antimicrobial efficacy, when choosing antibiotics in septic conditions, vasomodulatory effects should also be taken into account. OBJECTIVES: Aim of this study was to evaluate the vasomodulatory effects of vancomycin (VANCO) and tobramycin (TOBRA) in experimental endotoxemia by using intravital microscopy (IVM) of the intestinal microcirculation and measurements of the arterial contractility in vitro. METHODS: Endotoxemia was induced in rats by intravenous administration of lipopolysaccharide (LPS). VANCO or TOBRA were given immediately after LPS administration. Intestinal functional capillary density (FCD) and leukocyte-endothelial interactions were evaluated by IVM 2 hrs after LPS challenge. The effects of the antibiotics on the motility of aortal rings were examined in vitro. RESULTS: Leukocyte adhesion was significantly potentiated in the LPS group and in both antibiotic groups as compared to control group. Roller flow in V1 and V3 venules increased in antibiotic treated groups as compared to untreated LPS animals. FCD in the longitudinal muscular and mucosal layers decreased significantly in either endotoxemia or antibiotics treated rats. However, administration of VANCO ameliorated FCD in endotoxemic rats. Both antibiotics, in higher concentration, produced moderate relaxation of the arterial smooth muscle. CONCLUSION: Tobramycin and vancomycin did not affect the interaction between leukocytes and microvascular endothelium while vancomycin increased functional capillary density in the intestinal wall. Both antibiotics had direct relaxing effects on the vascular smooth muscle. Therefore, vancomycin and to lesser extent tobramycin may influence vascular tone and thereby affect microcirculation in endotoxemia and sepsis. PMID- 20852362 TI - Dithiothreitol revisited in red cells: a new head for an old hat. AB - In the present article the authors make an approach over the applications of dithiothreitol (DTT) in its different clinical-laboratory, potential and up-to date sources. Dithiothreitol is a chemical reagent with a wide actuation spectrum not only from a laboratorial view but also from a therapeutic standpoint, more clinical and practical. DTT (i) is frequently used in a variety of experiences that involve proteins or peptides, protecting sulfhydryl groups from oxidation and reducing disulfide bonds between cysteines; (ii) is also used in the study of disulfide exchange reactions of protein disulfides; (iii) is able to keep glutathione in the reduced state; (iv) acts as an "antidote" enabling the activity of detoxification systems; (v) participates in cellular mechanisms such as vesiculation, cell morphology, signal transduction pathways (hormone-'like' role), etc.; (vi) can be used in the treatment approach of diseases like cystinosis or medical conditions resulting from ion or metal toxicity. In erythrocytes, there's literature pointing that DTT may trigger changes on the normal discoid shape following metabolic depletion, and additionally modulate the exovesiculation kinetics as demonstrated by us. The present article dissects in detail recent findings in our Unit concerning the DTT influence on human erythrocytes. PMID- 20852363 TI - Heart rate variability is related to impaired haemorheology in older women with type 2 diabetes. AB - Impaired heart rate variability (HRV)and haemorheology are independently associated with cardiovascular disease and diabetic complications. The aim of the present study was to investigate the relationships between parameters of HRV,and red blood cell (RBC) aggregation and deformability, in older women with type 2 diabetes. Twenty women (age 69 +/- 2 yr) with uncomplicated type 2 diabetes and twenty controls (age 69 +/- 3 yr) participated in the study. Beat-to-beat cardiac (RR) intervals over 5 min were analysed for HRV parameters in the time and frequency domains. Blood was sampled for RBC deformability, as well as RBC aggregation in two suspending mediums: haematocrit adjusted plasma and 3% dextran 70. RBC aggregation was increased and HRV was impaired for those with type 2 diabetes when compared with control. RBC aggregation was negatively related to low frequency power of HRV, and was positively related to high frequency power of HRV, for subjects with type 2 diabetes. RBC deformability was positively related to HRV only for those with type 2 diabetes. Impaired haemorheology is associated with reduced HRV in older women with type 2 diabetes, suggesting changes in the microcirculation may result in impaired modulation of cardiac cycles. PMID- 20852364 TI - Alzheimer's disease: more than amyloid. AB - CONTEXT: The etiology of Alzheimer's disease (AD) is inconclusive. Treatments targeting amyloid have largely been unsuccessful. There is increasing evidence that vasculopathy may play an important pathogenic role in AD. OBJECTIVE: Longitudinal measurements of whole blood viscosity (WBV) using a computer assisted hemorheologic protocol and characterization of microvascular abnormalities using computer-assisted intravital microscopy (CAIM) are two objective methods adopted in this laboratory to noninvasively quantify vasculopathy in AD patients. A correlation of increased disease severity with worsened vasculopathy would further bolster a cause and effect relationship. A case report (Case 1) is presented to illustrate the usefulness of following an AD patient with these noninvasive techniques to correlate disease progression with vasculopathy. DESIGN: Patients were selected from a private practice setting who met the Diagnostic and Statistical Manual of Mental Disorders criteria for AD. The RheologTM, a computer-assisted scanning rheometer, was used to obtain longitudinal measurements of WBV. The microvascular abnormalities in the bulbar conjunctiva were quantified using a severity index (SI, scale 0-15). The patient was observed over a 4 year period from 2005 to 2008. CONCLUSION: This case study shows a correlation of disease progression in an AD patient with worsened vasculopathy. It illustrates the usefulness of WBV and CAIM as tools to quantify vasculopathy in AD patients and additionally suggests a pathogenetic role vasculopathy may play in concert with the amyloid hypothesis. PMID- 20852367 TI - Costs of hemodialysis and kidney transplantation in Sudan: a single center experience. AB - INTRODUCTION. End-stage renal disease is a serious illness with major consequences in both health and healthcare expenditures. The growing number of patients with end-stage renal disease in developing countries will consume a greater proportion of healthcare budget. We aimed to assess the costs of hemodialysis and kidney transplantation in a renal care center in Sudan. MATERIALS AND METHODS. We conducted a cross-sectional study to estimate the costs of kidney transplantation and compare those with the costs of hemodialysis per year. We enrolled 78 patients on regular hemodialysis for at least 2 years and 33 kidney transplant patients on regular follow-up at Gezira Hospital for Renal Diseases and Surgery in Sudan. RESULTS. The annual cost of hemodialysis was found to be US $ 6847.00. The total cost of the first year after transplantation was US $ 14 825.04 and the cost of kidney transplantation after the first year was US $ 10 651.00. The total hospitalization days and absence from work were less in the transplant group. Conclusions. Hemodialysis in Sudan is less expensive than transplantation. PMID- 20852366 TI - Why do we need chronic kidney disease screening and which way to go? AB - Dialysis and transplantation are life-saving but very expensive treatments. Current increases in the number of hemodialysis centers, machines, shifts, and kidney transplantations cannot keep pace with the increasing number of end-stage renal disease patients globally. The only way to decrease the incidence of end stage renal disease is identifying patients with low glomerular filtration rate. The risk groups to be targeted, the expected outcomes, and the tests to be ordered are reviewed in this article. The ways that it is possible to make a screening program sustainable and likely cost-efficient model is discussed. It seems the high-risk target population for chronic kidney disease screening in our country can be those with diabetes mellitus, hypertension, hyperlipidemia, age over 40 years, and obesity (possibly abdominal obesity). Macroalbuminuria check in addition to serum creatinine measurement in high-risk population may look a practical approach to initiate a national program. PMID- 20852368 TI - Protective effect of grape seed extract on gentamicin-induced acute kidney injury. AB - INTRODUCTION. This study was designed to determine the protective effect of red grape seed extract (RGSE) on gentamicin-induced nephrotoxicity in rats. MATERIALS AND METHODS. Thirty male Wistar rats were divided into 3 groups to receive RGSE, for 60 days followed by intraperitoneal injection of saline solution (as placebo) for 8 days (group 1); RGSE followed by gentamicin for 8 days (group 2); and gentamicin without pre-medication of RGSE (group 3). Oral RGSE, 40 mg/kg/d, and intraperitoneal injection of gentamicin, 100 mg/kg/d, were administered in these groups of rats. Blood and urine samples were collected on days 0 and 68 of the study. Then, the kidneys were removed for pathologic examination. RESULTS. On day 68, serum creatinine and blood urea nitrogen concentrations were highest in group 3, which was significantly higher than in group 1 (P = .001 and P = .004, respectively), while slightly higher than in group 2 (P = .30 and P = .50, respectively). Fractional excretion of sodium was not significantly different between the three groups. Histopathological evaluation showed that rats in group 3 had significantly higher degrees of severe acute tubular necrosis and interstitial mononuclear cell infiltration than the rats in groups 1 and 2 (P < .001). CONCLUSIONS. This animal study suggests that pretreatment with RGSE protects against gentamicin-induced acute kidney injury as evident on tissue histology. However, this was not accompanied with significant improvement in biochemical markers of kidney injury. PMID- 20852369 TI - Effect of levamisole in steroid-dependent nephrotic syndrome. AB - INTRODUCTION. Childhood idiopathic nephrotic syndrome is characterized by frequent relapsing courses or steroid dependency. Levamisole is a popular drug for treatment of these patients. The purpose of this study was to evaluate levamisole in children with steroid-dependent nephrotic syndrome. MATERIALS AND METHODS. We retrospectively studied 304 children with a diagnosis of steroid dependent nephrotic syndrome or frequently relapsing nephrotic syndrome. The mean age at the time of diagnosis was 4.84 years. Following induction of complete remission with steroid therapy based on the International Study of Kidney Disease in Children's protocol and when they were taking alternative days of steroid, 2.5 mg/kg of levamisole was administered. RESULTS. The steroid dose was significantly decreased (mean reduction of 0.39 +/- 0.46 g to 0.33 +/- 0.38 g) after treatment with levamisole (P < .001). The number of relapses also significantly decreased (mean reduction of 0.92 +/- 0.98 episodes to 1.07 +/- 1.20 relapses per year; P < .001). The 14.5-month administration of levamizole had a sensitivity of 67.5% and a specificity of 71.9% to reach a dose reduction of more than 50% in steroid therapy. The duration of levamizole treatment was associated with more than 50% reduction in the number of relapses (P < .001). A 14.5-month treatment with levamizole had a sensitivity of 62.3% and a specificity of 63.6% to reach a relapse reduction of more than 50%. CONCLUSIONS. Levamisole appears to be effective in prolonging the duration of remission and decreasing the steroid dose in children with steroid-dependent nephrotic syndrome. PMID- 20852370 TI - Technetium Tc 99m dimercaptosuccinic acid renal scintigraphy in children with acute pyelonephritis: correlation with other imaging tests. AB - INTRODUCTION. Urinary tract infection is the most common serious bacterial infection in children. The aim of this study was to compare the value of different laboratory and imaging techniques in detecting renal involvement in acute pyelonephritis. MATERIALS AND METHODS. In a cross-sectional study of patients 1 month to 14 years of age diagnosed with urinary tract infection were examined with systemic inflammatory markers, renal ultrasonography, voiding cystourethrography (VCUG), and technetium Tc 99m dimercaptosuccinic acid ((99m)Tc DMSA) renal scintigraphy. A total of 1467 pediatric patients were eligible for treatment of pyelonephritis. Evaluations included a complete blood count, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), urinalysis, urine culture, and measurement of serum blood urea nitrogen and creatinine levels. RESULTS. The results of (99m)Tc-DMSA scans were normal in 20.2%, mild decreased cortical uptake in 45.0%, moderate decreased cortical uptake in 12.3%, severe decreased cortical uptake in 12.0%, and decreased cortical function plus irregularity or scar formation in 10.5%. Voiding cystourethrography showed vesicoureteral reflux in 25.9%. The sensitivity of (99m)Tc-DMSA for prediction of vesicoureteral reflux was 84.1% with a negative predictive value of 80.6%. Significant differences were found in the level of blood leukocyte count (P = .03), urine leukocyte count (P = .003), ESR (P = .008), and age (P = .04) between patients with normal and abnormal (99m)Tc-DMSA scan results. CONCLUSIONS. We found that in patient with clinical signs of pyelonephritis, (99m)Tc-DMSA renal scintigraphy can detect pyelonephritis more accurately than the other inflammatory and imaging tests. PMID- 20852371 TI - Interleukin-4 gene polymorphisms in type 2 diabetic patients with nephropathy. AB - INTRODUCTION. The impact of several environmental and genetic factors on diabetes mellitus and its complications is well documented. It has also been established that cytokines play key roles in the pathogenesis of nephropathy. Polymorphisms of the -590 region of interleukin (IL)-4 are associated with the regulation of expression of this gene. In this study, we aimed to find polymorphisms of this region in nephropathic type 2 diabetic patients. MATERIALS AND METHODS. Peripheral blood samples were collected from 100 type 2 diabetic patients with nephropathy and 150 healthy controls. DNA was extracted and a polymerase chain reaction-restricted fragment length polymorphism technique was performed to examine polymorphisms in the -590 region of the IL-4 gene. RESULTS. Our results showed a significant difference between the C/C, T/C, and T/T genotypes and the C and T alleles of the -590 region of IL-4 in nephropathic patients in comparison with the healthy controls. CONCLUSIONS. Results of this study suggest that the functional gene polymorphisms of IL-4 play an important role in the pathogenesis of diabetic nephropathy in patients with type 2 diabetes mellitus. PMID- 20852372 TI - Screening for asymptomatic kidney disease in high-risk population of Urmia, Iran. AB - INTRODUCTION. Screening programs for chronic kidney disease (CKD) are deemed to be cost effective only when they are limited to high-risk groups. We screened a sample of high-risk population of Urima, Iran. MATERIALS AND METHODS. As a pilot study for a national project, we enrolled 905 participants who had at least one risk factor for CKD (including hypertension, diabetes mellitus, or a family history of CKD). The study population was selected from among patients with Dm or hypertension and family members of those with CKD in Urima urban area and 2 randomly selected neighbor rural areas. Urine dipstick tests were done and blood sample was obtained to detect proteinuria and measure serum creatinine concentration, respectively. RESULTS. A total of 607 participants (67.1%) were enrolled from rural areas and 298 (32.9%) from the urban area. The mean serum creatinine level was 1.27 +/- 0.60 mg/dL. A high serum creatinine level was demonstrated in 343 participants (37.9%), and 212 (23.4%) were demonstrated to have proteinuria. There was a significant correlation between serum creatinine level and urinary protein excretion (P = .001). There were no significant differences between rural and urban subgroups in terms of proteinuria (P = .42) and serum creatinine level (P = .08). CONCLUSIONS. The prevalence of a high creatinine level (37.9%) is so high in the high-risk population of Urmia. Our most important goal of implementing this preliminary study was to assess probable limitations and problems of performing an extensive national screening program for CKD in the future. PMID- 20852373 TI - Association of Helicobacter pylori infection and serum albumin in patients on hemodialysis. AB - INTRODUCTION. Helicobacter pylori infection in gastric mucosa may cause systemic inflammatory reaction. We investigated the inflammatory effect of H pylori infection on nutritional factors such as serum albumin in hemodialysis patients and influence of eradication of H pylori on this association. MATERIALS AND METHODS. Ninety-eight patients on hemodialysis were divided into 2 groups according to H pylori infection. Eradication of H pylori, 8 weeks after treatment, was confirmed by urease breath test and H pylori stool antigen. Serum albumin, lipid profile, and metabolite levels were checked before and after 8 weeks and 6 months of eradication of H pylori. RESULTS. Thirty-nine patients (39.8%) were infected with H pylori. There were no significant differences between the two groups in age, dialysis duration, serum albumin, serum creatinine, blood urea nitrogen, hemoglobin, serum calcium, serum phosphorus, and lipid profile. Thirty-seven patients with H pylori completed the treatment period. Eradication was successful in 30 patients (81.1%). Eight weeks and 6 months after anti-H pylori drug therapy, the mean serum albumin level significantly decreased from 4.2 mg/dL to 3.6 mg/dL (P < .001) and 3.7 mg/dL (P < .001), respectively. Significant decreases were seen in serum cholesterol (P = .001), blood urea nitrogen (P = .005), and serum calcium level (P = .03) and a significant increase in hemoglobin level (P = .02). CONCLUSIONS. Our study did not demonstrate nutritional benefits after H pylori eradication treatment, as the level of nutritional markers reduced. This relationship needs to be confirmed by further prospective studies. PMID- 20852374 TI - Noninvasive stool antigen assay for screening of Helicobacter pylori infection and assessing success of eradication therapy in patients on hemodialysis. AB - INTRODUCTION. Helicobacter pylori infection can be diagnosed by biopsy-based or noninvasive methods. Our aim was to identify H pylori-positive patients on hemodialysis by the noninvasive method of H pylori stool antigen (HPSA) and investigate its diagnostic accuracy for assessment of the eradication of infection after treatment in comparison with urea breath test (UBT). MATERIALS AND METHODS. Serology, HPSA, and UBT were performed on 87 hemodialysis patients. Infection with H pylori was confirmed if at least 2 tests were positive. Patients with H pylori infection received a 2-week course of triple therapy. To evaluate success of eradication HPSA and UBT were done after 8 weeks. RESULTS. Eighty seven patients were enrolled in the study, of whom 39 (44.8%) were proved to have H pylori infection. The HPSA was positive in the stool specimens of 37 patients (42.5%) and the serology test was positive in 39 (44.8%). The HPSA had a 87.1% sensitivity and a 93.7% specificity for detection of H pylori infection. Thirty seven patients completed the treatment period. Success of H pylori eradication was documented in 30 of the 37 patients (81.1%) based on UBT. After the treatment, the HPSA was negative in 32 of 37 of the stool specimens (86.4%), showing a 42.8% sensitivity and a 93.3% specificity to detect the failure of eradication of H pylori. CONCLUSIONS. Helicobacter pylori stool antigen assay is a noninvasive reliable tool to screen H pylori infection before therapy and assess the success of eradication in patients on hemodialysis. PMID- 20852375 TI - Effect of omega-3 fatty acid on oxidative stress in patients on hemodialysis. AB - INTRODUCTION. Oxidative stress in patients with chronic kidney failure, particularly in hemodialysis patients, has been suggested to have a major role in the pathogenesis of atherosclerosis. We evaluated omega-3 fatty acids supplementation effects on oxidative and antioxidant factors in hemodialysis patients. MATERIALS AND METHODS. In a clinical trial, patients on hemodialysis were divided into 2 groups in order to receive either omega-3 fatty aid capsule, 1 g 3 times a day, or placebo for 2 months. The two groups were comparable in terms of sex distribution, age, medications, diabetes mellitus, hemoglobin level, serum ferritin, and serum albumin. Blood samples taken from patients before and at the end of the study period were examined for oxidative stress markers including malondialdehyde, glutathione peroxidase, superoxide dismutase, and ferric reducing antioxidant power. RESULTS. Seventy-five hemodialysis patients were divided into the omega-3 group (n = 37) and the control group (n = 38). Before the treatment period, the two groups were comparable in the malondialdehyde, glutathione peroxidase, superoxide dismutase, and ferric reducing antioxidant power levels. In the patients who received omega-3 fatty acids, antioxidant factors including glutathione peroxidase, superoxide dismutase, and ferric reducing antioxidant power were significantly increased after two months (P = .02, P = .02, and P = .01, respectively); however, there was no significant changes in the control group in these markers. Malondialdehyde levels were significantly reduced after the study period only in the omega-3 group (P = .007). CONCLUSIONS. The present study revealed that the supplementation with omega-3 fatty acids may result in better antioxidation status in patients on maintenance hemodialysis. PMID- 20852376 TI - Effect of high-flux versus low-flux dialysis membranes on parathyroid hormone. AB - INTRODUCTION. Hyperparathyroidism is a common finding in patients with renal insufficiency and parathyroid hormone (PTH) is considered a uremic toxin responsible for many of the abnormalities of the uremic state and bone disease. The aim of this study was to investigate the influence of permeability of low flux versus high-flux dialysis membranes on intact PTH during hemodialysis in children. MATERIALS AND METHODS. Forty-four children aged between 4 and 13 years old on regular hemodialysis were enrolled in a prospective study. Low-flux polysulfone membranes were used for at least 6 months and then the patients were switched to use high-flux polysulfone membranes for 3 months. Serum electrolytes and intact PTH before and after dialysis were compared before and after changes in dialysis membrane. RESULTS. At the end of the 3-month use of high-flux filters, predialysis intact PTH level (49.40 +/- 19.64 ng/dL) showed a highly significant decline (P < .001) compared to the predialysis intact PTH (21.67 +/- 4.85 ng/dL) with low-flux membranes at the start of the study. Intact PTH level correlated negatively with serum ionized calcium and positively with serum phosphorus levels only in the predialysis samples with the use of low-flux but not high-flux filters. CONCLUSIONS. In children, high-flux dialysis membranes are more efficient in removal of intact PTH, one of the middle-sized uremic toxins, than low-flux membranes. PMID- 20852377 TI - Guide wire migration during femoral vein catheterization. AB - Central vein catheterization is a routine and relatively safe procedure in critically ill patients. Complications with this procedure depend to the site of catheterization and the skill of the operator. In addition to the common complications with femoral vein catheterization there are some rare usually preventable side effects related to guide wire and catheter. In our patient who underwent femoral catheterization for acute hemodialysis, we report migration of guide wire through the systemic circulation from the femoral vein to the jugular vein. This is a very rare complication that is a human error and is totally preventable by doing the procedure by a skilled doctor and considering the standards described for central vein catheter insertion. PMID- 20852378 TI - Extranodal diffuse large B-cell lymphoma confined to liver in a kidney transplant recipient. AB - Posttransplant lymphoproliferative disorder (PTLD) is a well-documented complication that arises as a result of immunosuppression in the setting of solid organ or bone marrow transplantation. The disorder may be subtle and/or extranodal. We report a patient with extranodal lymphoma following kidney transplantation who had successful treatment with surgery and chemotherapy. PMID- 20852379 TI - Nephroquiz 5: a 51-year-old man with kidney failure. PMID- 20852380 TI - Re: renal involvement in patients with hepatitis C virus infection. PMID- 20852385 TI - HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. AB - JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2 dependent MPN. PMID- 20852386 TI - Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. AB - Dense deposit disease (DDD) is a severe renal disease characterized by accumulation of electron-dense material in the mesangium and glomerular basement membrane. Previously, DDD has been associated with deficiency of factor H (fH), a plasma regulator of the alternative pathway (AP) of complement activation, and studies in animal models have linked pathogenesis to the massive complement factor 3 (C3) activation caused by this deficiency. Here, we identified a unique DDD pedigree that associates disease with a mutation in the C3 gene. Mutant C(3923DeltaDG), which lacks 2 amino acids, could not be cleaved to C3b by the AP C3-convertase and was therefore the predominant circulating C3 protein in the patients. However, upon activation to C3b by proteases, or to C3(H2O) by spontaneous thioester hydrolysis, C(3923DeltaDG) generated an active AP C3 convertase that was regulated normally by decay accelerating factor (DAF) but was resistant to decay by fH. Moreover, activated C(3b923DeltaDG) and C3(H2O)(923DeltaDG) were resistant to proteolysis by factor I (fI) in the presence of fH, but were efficiently inactivated in the presence of membrane cofactor protein (MCP). These characteristics cause a fluid phase-restricted AP dysregulation in the patients that continuously activated and consumed C3 produced by the normal C3 allele. These findings expose structural requirements in C3 that are critical for recognition of the substrate C3 by the AP C3 convertase and for the regulatory activities of fH, DAF, and MCP, all of which have implications for therapeutic developments. PMID- 20852387 TI - HGF upregulation contributes to angiogenesis in mice with keratinocyte-specific Smad2 deletion. AB - TGF-beta signaling can promote tumor formation and development or suppress it, depending on the cellular context and tumor stage. A potential target of this dual effect of TGF-beta is HGF, as TGF-beta can inhibit or promote its expression, although the mechanisms underlying this are largely unknown. In the present study, we found that mice with keratinocyte-specific deletion of the TGF beta signaling mediator Smad2 (referred to herein as K5.Smad2(-/-) mice), which have increased susceptibility to squamous cell carcinomas (SCCs), exhibited angiogenesis associated with epithelial overexpression of HGF and endothelial activation of the HGF receptor c-Met. Application of a c-Met inhibitor abrogated angiogenesis, suggesting that HGF overexpression plays a major role in angiogenesis associated with epithelial Smad2 loss. On the Hgf promoter, Smad2 was mainly associated with transcriptional corepressors, whereas Smad4 was mainly associated with the transcriptional coactivator CREB-binding protein (CBP/p300). Smad2 loss caused increased binding of Smad4 and CBP/p300 to the Hgf promoter. Consistent with this, knocking down Smad2 in human keratinocytes caused increased levels of HGF, which were abrogated by concomitant knockdown of Smad3 and Smad4. Importantly, the incidence of HGF-positive human SCC was high in cases with Smad2 loss and lower when Smad4 was also lost. We therefore conclude that Smad2 loss causes HGF upregulation via loss of Smad2-mediated transcriptional repression and enhanced Smad3/4-mediated transactivation. Since Smad2 is often downregulated in human SCCs, our data suggest a therapeutic strategy of blocking HGF/c-Met activation for Smad2-deficient SCCs. PMID- 20852390 TI - Roles of the ubiquitin-proteosome system in neurogenesis. AB - The ubiquitin-proteosome system (UPS) is a non-lysosomal proteolysis system involved in the degradation of irrelevant/misfolded intracellular proteins. The protein substrates of this system are tagged by ubiquitin in sequential reactions that target them for proteasome-dependent destruction. In the developing central nervous system, ubiquitin-mediated proteolysis has recently emerged as an important player in the regulation of neural progenitor proliferation, cell specification, neuronal differentiation, maturation, and migration. E3 ubiquitin ligases are crucial components in the UPS because they provide the specificity that determines which substrates are targeted for ubiquitin-dependent proteolysis. In this review, we discuss the molecular mechanisms of the UPS, focusing primarily on the roles of E3 ligases and their substrates in sequential steps of neurogenesis. PMID- 20852391 TI - The virtual reality of clinical education through simulation. PMID- 20852388 TI - Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that is caused by mutations at two loci, polycystin 1 (PKD1) and polycystin 2 (PKD2). It is characterized by the formation of multiple cysts in the kidneys that can lead to chronic renal failure. Previous studies have suggested a role for hyperactivation of mammalian target of rapamycin (mTOR) in cystogenesis, but the etiology of mTOR hyperactivation has not been fully elucidated. In this report we have shown that mTOR is hyperactivated in Pkd1-null mouse cells due to failure of the HGF receptor c-Met to be properly ubiquitinated and subsequently degraded after stimulation by HGF. In Pkd1-null cells, Casitas B lineage lymphoma (c-Cbl), an E3-ubiquitin ligase for c-Met, was sequestered in the Golgi apparatus with alpha3beta1 integrin, resulting in the inability to ubiquitinate c-Met. Treatment of mouse Pkd1-null cystic kidneys in organ culture with a c-Met pharmacological inhibitor resulted in inhibition of mTOR activity and blocked cystogenesis in this mouse model of ADPKD. We therefore suggest that blockade of c-Met is a potential novel therapeutic approach to the treatment of ADPKD. PMID- 20852389 TI - PPARgamma-induced cardiolipotoxicity in mice is ameliorated by PPARalpha deficiency despite increases in fatty acid oxidation. AB - Excess lipid accumulation in the heart is associated with decreased cardiac function in humans and in animal models. The reasons are unclear, but this is generally believed to result from either toxic effects of intracellular lipids or excessive fatty acid oxidation (FAO). PPARgamma expression is increased in the hearts of humans with metabolic syndrome, and use of PPARgamma agonists is associated with heart failure. Here, mice with dilated cardiomyopathy due to cardiomyocyte PPARgamma overexpression were crossed with PPARalpha-deficient mice. Surprisingly, this cross led to enhanced expression of several PPAR regulated genes that mediate fatty acid (FA) uptake/oxidation and triacylglycerol (TAG) synthesis. Although FA oxidation and TAG droplet size were increased, heart function was preserved and survival improved. There was no marked decrease in cardiac levels of triglyceride or the potentially toxic lipids diacylglycerol (DAG) and ceramide. However, long-chain FA coenzyme A (LCCoA) levels were increased, and acylcarnitine content was decreased. Activation of PKCalpha and PKCdelta, apoptosis, ROS levels, and evidence of endoplasmic reticulum stress were also reduced. Thus, partitioning of lipid to storage and oxidation can reverse cardiolipotoxicity despite increased DAG and ceramide levels, suggesting a role for other toxic intermediates such as acylcarnitines in the toxic effects of lipid accumulation in the heart. PMID- 20852392 TI - Patient agitation and dexmedetomidine. PMID- 20852393 TI - Plain talk about employment contracts. PMID- 20852396 TI - Treatment strategies for atrial fibrillation. PMID- 20852398 TI - Guide to care for patients. About vaccines. PMID- 20852399 TI - Dermal fillers: help patients put their best face forward. PMID- 20852400 TI - Unwanted sex: health and risk behaviors in college women. PMID- 20852402 TI - Tightening conflict-of-interest policies: the impact of 2005 ethics rules at the NIH. AB - PURPOSE: To determine both the intended and unintended effects of the National Institutes of Health (NIH) 2005 ethics rules by examining changes in publishing rates and the frequency of external relationships among NIH scientists. METHOD: After identifying eligible intramural scientists and administrators from institutes' Web pages and central directories, a mailed survey was administered to 900 NIH research faculty between October 2008 and January 2009 (response rate 70.1%). RESULTS: Eighty percent of respondents believed the NIH ethics rules were too restrictive. Whereas 45% of respondents believed the rules positively impacted the public's trust in the NIH, 77% believed the rules hindered the NIH's ability to complete its mission. Implementation of the ethics rules significantly decreased self-reported government-industry relationships among NIH faculty (from 51.8% to 33.2%, P < .01), including significant drops in consulting (33.1% to 7.8%, P < .01) and scientific advisory board membership (31.5% to 16.0%, P < .01), both of which may be allowed under the new regulations in restricted situations with increased oversight. The policy had limited impact on NIH faculty participation in nonindustrial professional service roles and had no detectable change in publishing behavior (5.29 articles per researcher per year from 2002 2005 versus 5.26 from 2005-2008, P = .88). CONCLUSIONS: The NIH ethics rules accomplished much of what they were intended to do, limiting relationships with industry while maintaining NIH researchers' association with external scientific and professional organizations. However, the rules negatively affected personnel morale and the perceived progress of research. PMID- 20852403 TI - Despite CD4 cell count rebound the higher initial costs of medical care for HIV infected patients persist 5 years after presentation with CD4 cell counts less than 350 MUl. AB - We determined that for HIV patients presenting with CD4 cell counts less than 350 MUl the initial higher costs of care persisted over 5 years. Fifty-nine percent of new patients between 1 April 1998 and 1 April 2003 had CD4 cell counts less than 350 MUl. Mean first year total costs ($19 917 $Cdn) were 2.5 times higher than for presentations with CD4 cell counts more than 350 MUl ($7840). Total annual costs of care subsequently decreased to $15 663 by year 5, but still remained higher ($8883) than those with CD4 cell counts more than 350 MUl despite a median CD4 cell count increase from 134 to 464 MUl. PMID- 20852404 TI - The MMP1 (-16071G/2G) single nucleotide polymorphism associates with the HAART related lipodystrophic syndrome. AB - OBJECTIVE: Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in extracellular matrix remodelling and adipocyte differentiation and are inhibited by antiretrovirals. MMPs and TIMPs and their single nucleotide polymorphisms (SNPs) might contribute to the HAART-related lipodystrophic syndrome pathogenesis. DESIGN AND SETTING: Cross-sectional study in a university based outpatient clinic. PATIENTS AND METHODS: Two hundred and sixteen HIV infected patients on extended HAART were studied. Serum MMPs (1, 2, 3, 8, 9, 10, 13) and TIMPs (1, 2, 4) were measured by ELISA microarrays. MMP1 (-16071G/2G) SNP was also genotyped. Lipodystrophic syndrome was diagnosed by a clinical scale validated by fat dual energy X-ray absorptiometry. RESULTS: Eighty-two patients (38.0%) showed lipodystrophic syndrome, mostly lipoatrophy. The 2G/2G MMP1 SNP genotype was more frequent among lipodystrophic syndrome patients (41.3 vs. 20.5%, odds ratio, 2.73; 95% confidence interval, 1.41-5.29; chi2 = 9.62, P = 0.002 for HIV-infected patients with and without lipodystrophic syndrome respectively). Carriers of this genotype had higher serum levels of MMP1 compared with those with the 1G/1G (P = 0.02). Higher MMP1 (P = 0.022) and lower TIMP4 (P = 0.038) serum levels were observed while comparing HIV patients with and without lipodystrophic syndrome. MMP1 2G carriage (P = 0.0008), TIMP4 lower serum levels (P = 0.02), treatment with stavudine (P < 0.0001), treatment with zidovudine (P = 0.006) and absence of hepatitis C virus coinfection (P = 0.002) were associated with lipodystrophic syndrome by logistic regression. CONCLUSION: MMP1 SNP, which induced increased serum levels of this protein, was associated with lipodystrophic syndrome. PMID- 20852405 TI - To what extent is the HIV epidemic in southern India driven by commercial sex? A modelling analysis. AB - BACKGROUND: In south India, general population HIV prevalence estimates range from 0.5 to 3%. To focus HIV prevention efforts, it is important to understand whether HIV transmission is driven by commercial sex. METHODS: A dynamic HIV/sexually transmitted infection transmission model was parameterized using data from Belgaum and Mysore in south India. Fits to sexually transmitted infection/HIV data from female sex workers (FSWs) and their clients for each district were obtained. Model HIV/herpes simplex virus-2 (HSV-2) prevalence projections for the general population were cross-validated against empirical estimates not used to fit model. The model estimated the proportion of incident HIV/HSV-2 infections due to HIV/HSV-2 transmission between FSWs/clients, their noncommercial partners and other low-risk partnerships. The relative impact of a generic intervention targeting different partnerships was explored. RESULTS: The model's general population HIV/HSV-2 prevalence projections agreed well with empirical estimates. Recent increases in condom use resulted in decreasing HIV epidemics in both settings. For men, most incident HIV/HSV-2 infections (>90%) directly result from commercial sex, whereas for women most are due to bridging infections from clients of FSWs (80-90%) with the remainder mainly due to commercial sex. Less than 1.5% of incident infections are due to low-risk partnerships. Intervention impact is maximized through targeting commercial sex but substantial impact could also be achieved through targeting noncommercial partners of clients. DISCUSSION: In southern India, HIV transmission could be driven by FSWs and their clients. While efforts to reduce HIV transmission due to commercial sex must continue, prevention programmes should also consider strategies to prevent transmission from clients to their noncommercial partners. PMID- 20852406 TI - Adenomatoid spindle cell thymomas: a clinicopathological and immunohistochemical study of 20 cases. AB - Twenty cases of adenomatoid spindle cell thymomas are presented. The patients are 13 males and 7 females between 7 and 82 years of age (mean: 55 y). Clinically, all patients presented with symptoms of chest pain and shortness of breath. Radiologically, an anterior mediastinal mass was discovered, and complete surgical resection was performed in all of the patients. Grossly, the tumors were described as well-defined solid tumor masses surrounded by membranous tissue, which at cut surface show a light tan homogenous surface. Areas of necrosis, hemorrhage, and/or cystic degeneration were not observed in any of the cases. Histologically, all tumors showed similar histological features and were characterized by the presence of a spindle cellular proliferation with an "adenomatoid-like" appearance, which at higher magnification showed the presence of cells with a signet-ring cell-like appearance. Rare mitotic figures were seen in some cases. Seven tumors showed transcapsular invasion, whereas 13 cases were encapsulate. Immunohistochemical studies showed positive staining for broad spectrum keratin and keratin 7 with only scattered cells positive for calretinin and epithelial membrane antigen. Other markers including S-100 protein, desmin, smooth muscle actin, and alpha-feto protein were negative. Follow-up information ranging from 4 to 96 months (average: 32.3 mo) was obtained in 17 patients showing that all patients were alive. The cases herein described highlight the importance of recognizing this unusual pattern of spindle cell thymomas to avoid misdiagnosis with other tumors, namely, when dealing with small mediastinoscopic biopsies. PMID- 20852408 TI - Encapsulated well-differentiated follicular-patterned thyroid carcinomas do not play a significant role in the fatality rates from thyroid carcinoma. PMID- 20852409 TI - Neostigmine versus sugammadex: which, when, and how much? PMID- 20852410 TI - Active, personalized, and balanced coagulation management saves lives in patients with massive bleeding. PMID- 20852411 TI - Bupropion for depression in schizophrenia. AB - OBJECTIVES: The catecholaminergic theory of depression assumes dysfunctional neurotransmission of dopamine and norepinephrine. Therefore, the antidepressant bupropion, a dual dopamine and norepinephrine reuptake inhibitor, might be a valuable treatment option also in schizophrenic patients with major depressive episodes. However, reports on induced psychotic symptoms in depressed patients questioned its use in patients with psychotic spectrum lifetime diagnoses. Here, we report on treatment experiences with bupropion in patients with schizophrenia with respect to antidepressive efficacy, safety, and tolerability. METHODS: We report on a consecutive series of depressed patients with psychotic spectrum lifetime diagnoses who received bupropion extended release for a period of 6 weeks in addition to stable doses of antipsychotic agents (N = 5). The psychometric scales Positive and Negative Syndrome Scale, Scale for the Assessment of Negative Symptoms, Calgary Depression Scale for Schizophrenia, Hamilton Depression Scale, and Extrapyramidal Symptoms Scale were applied. RESULTS: All patients experienced significant improvements of their major depressive episodes. Psychotic positive symptoms remained stably absent, whereas both negative symptoms and global psychopathology considerably improved. The treatment was generally well tolerated; however, subtle electroencephalographic deteriorations were observed. CONCLUSIONS: This case series suggests safe and effective antidepressive treatment with bupropion in patients with schizophrenic disorders, if stable antipsychotic medication and electroencephalographic monitoring are provided. Further randomized studies involving a control group are necessary. PMID- 20852412 TI - Systemic weakness after therapeutic injections of botulinum toxin a: a case series and review of the literature. AB - The use of intramuscular injections of Botulinum neurotoxin A (BoNT-A) is common in the treatment of hypertonicity and movement disorders. Although most side effects are mild, systemic effects, manifested by generalized weakness distant from the site of injection, have been reported. Previously reported occurrences are discussed, and 3 new cases of patients, who developed systemic weakness after administration of BoNT-A (Botox), despite having tolerated similar injections on several previous occasions, are presented. A review of the literature and reported cases indicate that risk of developing systemic effects does not seem to be related to dose based on body weight. It may be more likely that risk for systemic effects is related to total injection dose and injection frequency. The results of our 3 patients would indicate that injections of greater than 600 units of Botox with follow-up injections occurring every 3 months may lead to an increased risk. We would recommend careful consideration of reinjection frequency if injections of greater than 600 units of Botox are given. Reduction in systemic side effects may occur if reinjection frequency occurs in intervals of 4 months or greater in these individuals. PMID- 20852413 TI - The effect of a clinically practical exercise on levodopa bioavailability and motor response in patients with Parkinson disease. AB - OBJECTIVE: The aim of the study was to investigate the potential effect of short, moderate intensity (<=70% maximum heart rate) cyclette exercise on levodopa (LD)/dopa decarboxylase inhibitor bioavailability and motor response in a subgroup of Parkinson disease (PD) patients presenting a moderate-to-severe delay in fasting morning LD dose absorption and matched motor response. METHODS: Ten patients underwent an oral LD instrumental kinetic-dynamic test based on simultaneous serial measurements of plasma LD concentrations, finger tapping motor effects, dyskinesia ratings plus Unified Parkinson Disease Rating Scale Motor Section (section III) evaluation after ingestion of their usual fasting first morning LD dose, on 2 occasions, 2 weeks apart, according to an intrasubject randomized cross-over design: once receiving their oral LD test dose immediately before a 15-minute cycling and once at seated rest. The main LD pharmacokinetic variables were time to peak, peak plasma concentration, and the area under the 4-hour plasma concentration-time curve. The main LD pharmacodynamic variables were the latency, duration of the motor effect elicited by the LD test dose, and the area under the 4-hour tapping effect-time curve. RESULTS: The LD pharmacokinetics and pharmacodynamics did not differ between the 2 sessions. CONCLUSIONS: We found no significant effect of a moderate, clinically practical exercise on LD rate and extent of absorption and matched motor response in a subgroup of patients with delayed LD kinetic-dynamic effect. PMID- 20852414 TI - Should we change our lipid management strategies to focus on non-high-density lipoprotein cholesterol? AB - PURPOSE OF REVIEW: Despite aggressive low-density lipoprotein cholesterol lowering, patients continue to be at significant risk of cardiovascular events. Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel guidelines, non-HDL-C was introduced as a secondary target of therapy. RECENT FINDINGS: A combined post-hoc analysis of data from two prospective, randomized trials assessing the role of statins in patients with established coronary heart disease showed that on-treatment levels of non-HDL-C were more closely associated with cardiovascular outcomes than levels of low density lipoprotein cholesterol. A recent meta-analysis of the relationship between non-HDL-C reduction and coronary heart disease risk showed that most lipid-modifying drugs used as monotherapy have a 1 : 1 relationship between percentage non-HDL-C lowering and percentage coronary heart disease reduction. In the European Prospective Investigation Into Cancer and Nutrition-Norfolk prospective population study (n = 21,448), participants with high non-HDL-C levels were at increased coronary heart disease risk independently of their low density lipoprotein cholesterol levels. SUMMARY: Because non-HDL-C appears to be superior for risk prediction beyond low-density lipoprotein cholesterol, future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies. There is an increased need to have non-HDL C reported on routine lipid panels, especially because it would be at no added cost. PMID- 20852415 TI - Therapy for acute high-risk pulmonary embolism: thrombolytic therapy and embolectomy. AB - PURPOSE OF REVIEW: Acute pulmonary embolism remains associated with high morbidity and mortality rates despite currently available therapeutic options. This review outlines the most recent changes in this field and summarizes the main indications for thrombolytic therapy and surgical or catheter-based embolectomy in patients with high-risk pulmonary embolism. RECENT FINDINGS: There have been no major advances in therapy for high-risk pulmonary embolism over the past few years. The main change concerns risk stratification, which now classifies patients as high risk versus intermediate or low risk, replacing the former terminology of acute massive, submassive or nonmassive pulmonary embolism. Risk stratification is now oriented toward evaluation of the risk of early pulmonary embolism-related death. Thrombolysis is the mainstay of therapy in high risk pulmonary embolism. Surgical embolectomy has become more frequent, due to the reduction in mortality risk associated with this technique. However, it remains limited to patients unsuitable for thrombolysis. Catheter-based embolectomy is reserved for situations in which neither thrombolysis nor surgical embolectomy is possible. SUMMARY: Thrombolytic treatment should be first-line therapy in patients with high-risk pulmonary embolism presenting with cardiogenic shock and/or persistent arterial hypotension, with very few absolute contraindications. Both surgical and catheter pulmonary embolectomy are valuable therapeutic options in patients in whom thrombolysis is absolutely contraindicated or has failed. PMID- 20852416 TI - Management guidelines for penetrating abdominal trauma. AB - PURPOSE OF REVIEW: Patients with penetrating abdominal trauma are at risk of harboring life-threatening injuries. Many patients are in need of emergent operative intervention. However, there are clearly patients who can be safely managed nonoperatively. This review evaluates the literature to identify management guidelines for patients with penetrating abdominal trauma. RECENT FINDINGS: Accumulating evidence supports nonoperative management of patients with stab wounds to the thoracoabdominal region, the back, flank, and anterior abdomen. Furthermore, select patients with gunshot wounds can be safely managed nonoperatively. SUMMARY: Shock, evisceration, and peritonitis warrant immediate laparotomy following penetrating abdominal trauma. Thoracoabdominal stab wounds should be further evaluated with chest X-ray, ultrasonography, and laparoscopy or thoracoscopy. Wounds to the back and flank should be imaged with CT scanning. Anterior abdominal stab wound victims can be followed with serial clinical assessments. The majority of patients with gunshot wounds are best served by laparotomy; however, select patients may be managed expectantly. PMID- 20852417 TI - Management of peripheral arterial injury. AB - PURPOSE OF REVIEW: Significant changes in the management of patients, with possible or documented injuries to peripheral arteries, have occurred over the last 20 years. RECENT FINDINGS: Based on recent military experience, it is likely that the use of tourniquets by civilian emergency medical services systems will increase. Evaluation in the emergency center will continue to rely on a careful physical examination and measurement of an ankle-brachial index (ABI) or arterial pressure index (API). Patients without 'hard signs' of an arterial injury and an API or ABI less than 0.9 should undergo arteriography in the trauma room with a digital subtraction device, in radiology by computed tomography arteriography, which is rapidly replacing conventional arteriography, or surgeon-performed arteriography in the operating room. A temporary intraluminal arterial shunt is indicated in patients with unstable fractures in the extremity or in near exsanguinated patients needing 'damage control'. A saphenous vein interposition graft is the conduit of choice when segmental resection of an injured artery is necessary. Measurement of postarterial repair compartment pressure is the most definitive way to determine the need for fasciotomy in an injured extremity. SUMMARY: The care of patients with injured peripheral arteries has remained the same in some areas; however, lessons from the battlefield, new imaging technology, the safety of nonoperative management, use of temporary intraluminal shunts, and better recognition of postrepair compartment syndromes have had a significant impact on current management. PMID- 20852418 TI - Evidence-based therapies for upper extremity dysfunction. AB - PURPOSE OF REVIEW: The diversity of interventions aimed at improving upper extremity dysfunction is increasing. This article reviews the effectiveness of different therapeutic approaches that have been published in 2009 and 2010. Evidence is based on randomized controlled trials, systematic reviews, and meta analyses. RECENT FINDINGS: Application of constraint-induced movement therapy in acute stroke patients was not more effective than a control intervention, and a more intense therapy may even be harmful. Botulinum toxin injections do not only reduce spasticity but, in children, also improve motor functions if combined with occupational therapy. Strength training improves arm function but not necessarily activities of daily living. Bilateral arm training is as effective as other interventions. Extrinsic feedback and sensory training may further improve motor functions. Mirror therapy was particularly effective for patients with initial hand plegia. SUMMARY: For some interventions (e.g. constraint-induced movement therapy, botulinum toxin), efficacy is evident, for others (e.g. mental practice, virtual reality), well designed studies with sufficient numbers of patients are needed. The ultimate goal still is to develop evidence-based therapies for all different degrees of motor impairment. PMID- 20852419 TI - The logopenic variant of primary progressive aphasia. AB - PURPOSE OF REVIEW: The aim is to explore the evolution of the logopenic variant of primary progressive aphasia as a distinct clinical entity and to outline recent advances that have clarified its clinical characteristics, neural underpinnings, and potential genetic and pathological bases. This is particularly relevant as researchers attempt to identify clinico-pathological relationships in subtypes of primary progressive aphasia in hopes of utilizing language phenotype as a marker of underlying disease. RECENT FINDINGS: Recent work has served to refine and expand upon the clinical phenotype of the logopenic variant. Logopenic patients show a unique pattern of spared and impaired language processes that reliably distinguish this syndrome from other variants of progressive aphasia. Specifically, they exhibit deficits in naming and repetition in the context of spared semantic, syntactic, and motor speech abilities. Further, there is a growing body of evidence indicating a possible link between the logopenic phenotype and specific pathological and genetic correlates. SUMMARY: Findings indicate that the logopenic variant is a distinct subtype of progressive aphasia that may hold value as a predictor of underlying pathology. Additional research, however, is warranted in order to further clarify the cognitive-linguistic profile and to confirm its relation to certain pathological and genetic processes. PMID- 20852420 TI - What's new in new technologies for upper extremity rehabilitation? AB - PURPOSE OF REVIEW: The field of new technologies for upper-limb rehabilitation is exploding. The review presents new trends and studies of effectiveness from recent literature regarding robots, virtual reality and telerehabilitation for neurorehabilitation of the upper limb. RECENT FINDINGS: There appears to be a greater focus on technological developments than on clinical trials or studies to evaluate the mechanisms behind the effectiveness of these systems. Developments are most abundant in the field of robotics. However, the first well designed and powered randomized-controlled trial on robot rehabilitation has appeared, confirming that the effectiveness of robot therapy lies in the number of repetitions provided. There is a move towards studies in populations other than stroke, particularly cerebral palsy with a few studies on multiple sclerosis and traumatic brain injury. There is also an increasing trend for the use of robotic devices as evaluation tools. SUMMARY: Despite the fact that new technologies are based on knowledge from motor control and learning literature and that they provide an exciting potential for varied rehabilitation, recent evidence suggests that the only contribution to clinical practice currently is the provision of intensive, repetitive movements. PMID- 20852421 TI - Robot-assisted rehabilitation of hand function. AB - PURPOSE OF REVIEW: Initial work on robot-assisted neurorehabilitation for the upper extremity aimed primarily at training, reaching movements with the proximal sections of the upper extremity. However, recent years have seen a surge in devices dedicated to hand function. This review describes the state of the art and the promises of this novel therapeutic approach. RECENT FINDINGS: Numerous robotic devices for hand function with various levels of complexity and functionality have been developed over the last 10 years. These devices range from simple mechanisms that support single joint movements to mechanisms with as many as 18 degrees-of-freedom (DOF) that can support multijoint movements at the wrist and fingers. The results from clinical studies carried out with eight out of 30 reported devices indicate that robot-assisted hand rehabilitation reduces motor impairments of the affected hand and the arm, and improves the functional use of the affected hand. SUMMARY: The current evidence in support of the robot assisted hand rehabilitation is preliminary but very promising, and provides a strong rationale for more systematic investigations in the future. PMID- 20852422 TI - Not all rickets is vitamin D deficiency. AB - Although vitamin D deficiency is a common cause of rickets, other types of rickets, including hereditary forms, must be considered in the differential diagnosis. The patient described here presented for evaluation of bowing of his lower extremities, and was ultimately diagnosed with X-linked hypophosphatemic rickets, a disorder caused by renal wasting of phosphate that occurs as a result of a mutation in the PHEX gene. PMID- 20852423 TI - Oral immunotherapy for food allergy. AB - PURPOSE OF REVIEW: Food allergy is a difficult clinical problem for which no disease-modifying therapy currently exists. RECENT FINDINGS: The daily administration of graded allergen doses through oral immunotherapy (OIT) is one promising experimental approach to the development of a clinically available treatment. Although the concept of oral immunologic tolerance is not new, OIT as a treatment for food allergy is innovative. Over the last few years, several groups of investigators have begun to demonstrate safety and varying degrees of efficacy and immune modulation in uncontrolled pilot studies of OIT. Rigorously designed trials are currently underway and important unanswered questions remain. SUMMARY: OIT for food allergy holds promise for patients with food allergy but additional research is necessary before this approach is ready for clinical use. PMID- 20852425 TI - Varicocele repair for treatment of androgen deficiency. AB - PURPOSE OF REVIEW: The association between varicocele and male infertility is well established. Modern artery and lymphatic-sparing techniques of varicocele repair have been shown to significantly enhance semen quality and increase pregnancy rates. However, the effect of varicocele on testosterone production is less well defined and the possible association with androgen deficiency is controversial. Data regarding the effects of varicocelectomy on serum testosterone levels are limited and conflicting. RECENT FINDINGS: Few studies in the past 18 months have assessed the impact of varicocele repair on serum testosterone levels. The limited data available are culled from a diverse patient population with the goal of evaluating other primary outcome parameters and thus provide a challenge for drawing definitive conclusions. One of the more interesting recent studies uses a rat model of varicocele and varicocelectomy to assess changes in intratesticular testosterone levels. SUMMARY: Although the impact of varicocele on testosterone production is not well understood and the utility of varicocelectomy to prevent or reduce deterioration in Leydig cell function remains unproven, recent data suggest an adverse effect of varicocele and possible benefit of repair. Further human clinical studies are warranted to better define these relationships. PMID- 20852424 TI - DNA mismatch repair and infertility. AB - PURPOSE OF REVIEW: To highlight the significance of the abnormal DNA repair mechanism in male infertility. RECENT FINDINGS: DNA repair defects cause a variety of spermatogenic defects in mouse models. Evidence is accumulating to demonstrate the importance of DNA repair defects in human nonobstructive azoospermia. Epigenetic changes may also play a crucial role in infertility. SUMMARY: The DNA in the cell needs to be constantly repaired to ensure fidelity of DNA replication, to maintain genome stability and to ensure propagation of species. The DNA repair and recombination machineries are highly conserved across the species and inactivation of these pathways may lead to replication and recombination errors. This review summarizes the different types of DNA lesions and DNA repair pathways, particularly focusing on highly conserved meiotic regulators, the DNA mismatch repair proteins. Targeted deletions of some of these proteins result in infertility and predisposes to tumor in mutant mouse models. There is evidence for loss of some of these proteins in human male infertility. Because defective DNA repair is associated with a mutator phenotype, the risk of transmission to the offspring of these otherwise infertile men conceived using an assisted reproductive technology needs further evaluation. PMID- 20852426 TI - Vasectomy reversal versus IVF with sperm retrieval: which is better? AB - PURPOSE OF REVIEW: This paper will describe why this review is timely and relevant. Over the past two decades, treatment options for couples with reconstructible obstructive azoospermia have improved tremendously. Advances in assisted reproductive technologies (ART), specifically sperm retrieval techniques for intracytoplasmic sperm injection coupled with in-vitro fertilization, as well as refinements in microsurgical reconstruction have led to improved outcomes and cost-effectiveness. Providing the most up-to-date care based on the most recent data allows for better patient outcomes and satisfaction. RECENT FINDINGS: Microsurgical reconstruction of the vas has remained a cost-effective, reliable and effective means of restoring fertility in the majority of men who have previously undergone vasectomy when the reconstruction is performed by an experienced microsurgeon. However, there are specific instances in which sperm retrieval/IVF/ICSI may be a more appropriate treatment modality as ART techniques continue to improve. SUMMARY: Data comparing surgical reconstruction versus sperm retrieval/ICSI/IVF are neither randomized nor homogenous. Therefore, a comprehensive understanding of the factors that can affect outcomes, overall cost, and the morbidity associated with each treatment modality, respective of the institution providing the treatment, is strongly recommended. PMID- 20852427 TI - Burn injury caused by hand sanitizing gel. PMID- 20852428 TI - Extended multidrug-resistant Stenotrophomonas maltophilia septicemia in a severely burnt patient. PMID- 20852429 TI - Postoperative pyoderma gangrenosum after elective abdominoplasty: a case report and review of the literature. AB - Pyoderma gangrenosum (PG) is a relatively uncommon disease that can present after a bevy of inciting events, ranging from posttraumatic and postoperative states to association with a number of systemic inflammatory disorders. Various classification schemes have been described to further delineate the underlying cause, including ulcerative, pustular, vegetative, bullous, peristomal, and pathergic forms of PG. Pathergic PG develops at the site of a previous trauma. Described here is a case report of a patient with progressive PG after an elective abdominoplasty. Regardless of the cause, the most important concept in management of patients with this disorder is early recognition, which often mandates a high clinical index of suspicion. Although many different treatment regimens have been described in the literature, the consensus opinion is centered on conservative and prompt administration of antiinflammatory medications, often in the form of exogenous corticosteroid therapy. PMID- 20852430 TI - Changing patterns in electrical burn injuries in a developing country: should prevention programs focus on the rural population? AB - In the developing world, the incidence of electrical injuries has increased in the past few years. This study attempts to identify the causative and demographic risk factors that can help in formulating a targeted prevention program. The study was conducted prospectively and retrospectively from 2004 to 2009. Eighty four consecutive patients with electrical burn injuries were analyzed for their demographic profile, age, sex, occupation, rural-urban distribution, mode of injury, and place of injury. The patients were asked to fill out a questionnaire regarding their awareness about electrical burn injuries, and the results were tabulated. The age of presentation ranged from 3 to 61 years. The most frequently affected age group was the second decade of life (33.3%). Of 84 patients studied, 71 were male and 13 female. Fifty-nine patients were from the urban area, while 25 were from the surrounding rural area. Students including children and adolescents were the most common affected single group (22.5%). Contact with live wire or contact with an object that was in contact with a live wire (secondary contact) accounted for 43 of 84 cases (51%). Home was the most common location where injury occurred (51.2%). Twenty-one of 59 cases (35.6%) reported from the urban area and 3 of 25 cases (12%) from the rural area had specific knowledge about prevention of electrical burn injury. Forty-one patients (69.4%) from the urban area and 22 (88%) from the rural area believed that adequate information regarding electrical burn injury was not available. Thirty-six patients (61%) from the urban area and 24 (96%) from the rural area believed that they would have behaved differently if the information had been available. The authors recommend that prevention programs should be modified to cater to the specific needs of the younger age groups and the rural population. PMID- 20852431 TI - Spectral endoscopic imaging: the multiband system for enhancing the endoscopic surface visualization. AB - In the past few years, newly developed procedures and technologies have improved endoscopic recognition of the gastrointestinal tract. In particular, narrow band imaging, multiband imaging, and contrast enhancement make possible the "real time," on demand recognition of the gastrointestinal mucosa during the endoscopic examination. These imaging techniques have been designed to enhance visualization of the vascular network and surface texture of the mucosa in an effort to improve tissue characterization, differentiation, and diagnosis. These techniques are considered as potential alternatives to chromoendoscopy because they provide contrast enhancement of tissue surface structures. This review focuses on data published on multiband imaging system. We report the technological basis of the system and speculate on its applications. Therefore, PubMed was searched for articles published up to 31 October 2009 using, in combination, these terms: "multiband imaging," "band imaging," "endoscopy," "high-resolution," "gastrointestinal," "FICE," "magnification," "spectral endoscopic images," "computed virtual chromoendoscopy." The reference list of articles identified in the initial PubMed search was reviewed for further relevant publications. Abstracts of communications presented to the most relevant international meetings and congresses were also included in this review. We did not carry out meta analyses and reviewed only articles published in English. PMID- 20852432 TI - Repeatability of retrobulbar blood flow velocity measured using color Doppler imaging in the Indianapolis Glaucoma Progression Study. AB - PURPOSE: Determine the repeatability of color Doppler imaging (CDI) measurements in patients with open-angle glaucoma (OAG). PATIENTS AND METHODS: We performed a cross-sectional, observational study of OAG patients participating in the Indianapolis Glaucoma Progression Study. Retrobulbar blood flow velocities and Pourcelot's vascular resistance index (RI) measured with CDI were examined. Two baseline measurements were obtained 1 to 2 weeks apart at the same time of day for all participants. Peak systolic and end diastolic blood flow velocities (PSV/EDV) were measured in the ophthalmic (OA), central retinal (CRA), and nasal and temporal short posterior ciliary arteries (N/TPCA) and RI was calculated. Intraclass correlation coefficient (ICC) between the 2 baselines was calculated. RESULTS: One hundred and sixteen patients with OAG [mean age 65.9 y (SD 10.9 y), 60% female] were examined in both baseline visits. In the OA, the intraobserver ICC for the PSV, EDV, and RI were all above 0.82. In the CRA, the intraobserver ICC for the PSV and RI were both above 0.8, whereas the EDV was 0.64. The intraobserver ICC in the N/TPCA for the PSV, EDV, and RI ranged from 0.71 to 0.88. The interobserver ICC was similar to the intraobserver ICC for the OA and the CRA but was lower than 0.7 in the EDV and RI of the T/NPCA. CONCLUSIONS: Blood flow velocities and calculated vascular resistance of the OA, CRA, and PCAs conducted within 2 weeks in patients with OAG are repeatable. Intraobserver CDI measurements were found more reproducible than interobserver CDI analysis. PMID- 20852433 TI - Comparative study of 3 techniques to detect a relative afferent pupillary defect. AB - PURPOSE: To compare the standard method of testing for a relative afferent pupillary defect (RAPD) using the Standard Swinging Flashlight Method (S-SFM) with 2 novel techniques, to evaluate the validity and reproducibility of each method, and to validate the clinical significance of detecting more subtle RAPDs by correlating the extent of glaucoma damage with the presence or absence of an RAPD as assessed by each method. PATIENTS AND METHODS: In this prospective, observational study 101 consecutive patients (68 diagnosed glaucoma patients, 20 glaucoma suspects including ocular hypertensives, and 13 controls) were screened for the presence or absence of an RAPD using the S-SFM, Magnifier-Assisted Swinging Flashlight Method (MA-SFM), and Ophthalmoscopic Swinging Flashlight Method . Humphrey visual field mean deviation (MD) of each eye and the intereye differences in MD and Disc damage likelihood score (DDLS) and intereye difference in DDLS were calculated. Sensitivities for each method (S-SFM, MA-SFM, and Ophthalmoscopic Swinging Flashlight Method) were calculated at increasing levels of change in DDLS and MD. Weighted kappa scores were calculated for agreement between tests. RESULTS: MA-SFM is the most sensitive method for determining an RAPD in terms of both intereye difference in DDLS and intereye differences in MD at all levels of change. Weighted kappa scores revealed substantial agreement between tests for the same method, and moderate to substantial agreement among the observers. CONCLUSIONS: This study confirms results of our earlier study suggesting that swinging flashlight test modified with magnification (MA-SFM) can provide a simple, inexpensive, reproducible method of detecting an RAPD. PMID- 20852434 TI - Relation between the volume of the lake and intraocular pressure reduction after nonfiltering glaucoma surgery: a spectral-domain anterior segment optical coherence tomography study. AB - PURPOSE: To assess the relationship between the volume of the "lake" measured by spectral-domain anterior segment optical coherence tomography and the intraocular pressure (IOP) reductions after modified deep sclerectomy (D-lectomy). METHODS: We measured the 3-dimensional volume of the lake 3 to 6 months after D-lectomy using spectral-domain anterior segment optical coherence tomography in 37 eyes of 37 consecutive outpatients and compared the volume with the ratio of the IOP reduction 3 and 6 months after D-lectomy. RESULTS: The mean volume of the lake was 2.00 +/- 1.98 mm, and the mean IOP reductions 3 and 6 months after D-lectomy were 33.2% and 35.9%, respectively. The correlations between the 3-dimensional volume of the lake and the ratio of the IOP reduction at 3 and 6 months were poor, and their correlation coefficients were as small as r=-0.073 (P=0.669) and r=-0.094 (P=0.593), respectively. The IOP reductions in eyes with (N=14) and without (N=23) the filtering bleb were 38.2% and 30.1% at 3 months, and 39.9% and 33.2% at 6 months, respectively. The IOP reduction in eyes with no bleb also did not correlate with the volume of the lake at 3 months (r=0.007, P=0.98) and 6 months (r=0.02, P=0.92). CONCLUSIONS: The correlation between the volume of the lake and the rate of IOP reduction was poor after D-lectomy. Thus, the transscleral outflow to the subconjunctival space may be a minor factor in the mechanism of IOP reduction after D-lectomy. PMID- 20852435 TI - Effect of instrument orientation on the accuracy of intraocular pressure measurements in human cadaveric eyes: manometric evaluation of the model 30 classic Pneumatonometer and Tono-Pen XL. AB - PURPOSE: To determine the effects of probe orientation on the accuracy of intraocular pressure (IOP) measurements obtained with pneumatonometry (Model 30 Classic Pneumatonometer, Reichert Ophthalmic Instruments, Depew, NY) and with a handheld electronic tonometer (Tono-Pen XL, Reichert Ophthalmic Instruments, Depew, NY). MATERIALS AND METHODS: Six enucleated human eyes were obtained fewer than 24 hours postmortem. IOP was maintained at 10, 20, and 30 mm Hg, sequentially, via liquid column manometry. At each IOP setpoint, the eyes were positioned to mimic a sitting, supine, and prone patient. Pneumatonometry was performed in the sitting and supine orientations. Tono-Pen measurements were performed in the sitting, supine, and prone orientations. Accuracy was analyzed using multifactor repeated measures analysis of variance, and one-sample t tests. RESULTS: At all IOP setpoints, for both instruments, probe orientation had no significant effect on the IOP measurement (pneumatonometer P=0.58; Tono-Pen P=0.85). At all 3 setpoints (10, 20, and 30 mm Hg) the pneumatonometer overestimated IOP (P<0.0001; P<0.0001; P=0.005, respectively). The Tono-Pen overestimated IOP at the 10 mm Hg setpoint (P<0.0001), but underestimated IOP at the 20 and 30 mm Hg setpoints (P=0.03; P<0.0001, respectively). CONCLUSIONS: Under experimental conditions, probe orientation had no significant effect on IOP measurements for either instrument, suggesting that both can be used without correction in the tested orientations. In enucleated human cadaveric eyes, the pneumatonometer overestimated IOP at all setpoints. The handheld electronic tonometer overestimated IOP at 10 mm Hg, but underestimated IOP at the higher setpoints. It is unknown if these findings are generalizable to human eyes in vivo. PMID- 20852436 TI - Normal tension glaucoma in patients with obstructive sleep apnea/hypopnea syndrome. AB - PURPOSE: To determine the prevalence of normal tension glaucoma (NTG) in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) and further investigate whether the severity of OSAHS would increase the risk of glaucoma. PATIENTS AND METHODS: Two hundred fifty-six participants were consecutively admitted for polysomnographic exam to diagnose OSAHS. All participants, then underwent a complete ophthalmologic evaluation, including best-corrected visual acuity, intraocular pressure, slit lamp biomicroscopy, gonioscopy, fundoscopy, automated visual field (VF), and retinal nerve fiber layer (RNFL) evaluation. RESULTS: A total of 247 participants were enrolled in the study. Two hundred nine patients were OSAHS and 38 participants were classified as the normal group. Among the OSAHS patients, NTG was found in 12 patients with a prevalence of 5.7%, which was higher than that in the normal group (P=0.003). In the NTG patients, 1 was in the mild, 3 were in the moderate, and 8 were in the severe OSAHS group. There was no glaucoma patient in the normal group. The prevalence of NTG in moderate/severe OSAHS patients was 7.1%, significantly higher (P=0.033) than that in normal/mild OSAHS patients. The mean saturation of oxygen and lowest saturation of oxygen correlated with the average thickness of RNFL in the OSAHS patients. CONCLUSIONS: Patients with OSAHS had a high prevalence of NTG, especially in patients with moderate and severe OSAHS. The severity of OSAHS inversely correlated with retinal nerve fiber layer thickness. Clinicians need to consider the possibility of glaucoma in patients with moderate and severe OSAHS. PMID- 20852437 TI - Reproducibility of retinal nerve fiber layer thickness measurements using spectral domain optical coherence tomography. AB - PURPOSE: To evaluate the reproducibility of the peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained by Spectralis spectral domain optical coherence tomography (OCT) (Heidelberg Engineering, Heidelberg, Germany) in normal and glaucoma participants. METHODS: Participants were recruited from a university-based clinic. Peripapillary RNFL thickness measurements were repeated 3 times during the same visit using the follow-up function. One eye of each participant was randomly selected for statistical analysis. Reproducibility was evaluated using within-subject standard deviation (Sw), coefficient of variation (CV), and intraclass correlation coefficient (ICC). Spearman rank correlation coefficient analyses were used to assess the correlation of the standard deviation of the 3 measurements for each participant with the RNFL thickness value. RESULTS: Forty-five normal participants and 33 glaucoma patients were included in the study. The CVs ranged from 1.45% [overall global (G)] to 2.59% [temporal quadrant (T)] in normal eyes and from 1.74% (G) to 3.22% (T) in the glaucomatous eyes. ICCs ranged from 0.977 (T) to 0.990 (G and inferior-nasal sector) in normal eyes and from 0.983 (T) to 0.997 (inferior quadrant) in glaucomatous eyes. Sw were from 1.34 MUm (G) to 2.39 MUm (superior-temporal and inferior-temporal sectors) in normal eyes and from 1.14 MUm (G) to 2.25 MUm (superior-nasal sector) in the glaucomatous eyes. There were no significant correlations between RNFL thickness values and the measurement variability for each participant. CONCLUSIONS: Spectralis OCT shows excellent reproducibility for measuring the peripapillary RNFL thickness values in both healthy and glaucoma participants. PMID- 20852439 TI - Optic nerve head morphology assessed by laser scanning tomography in normal Japanese subjects. AB - PURPOSE: To study the optic disc characteristics using the Heidelberg Retina Tomograph (HRT) II in normal Japanese subjects. METHODS: A total of 1060 eyes of 530 normal subjects with reliable HRT images, who participated in the community health checkup in the city of Akita, Japan, were included in the study. Optic disc parameters were obtained using the HRT II. Sex, age, height, weight, blood pressure, ocular perfusion pressure, hemoglobin A1c status, intraocular pressure, and disc area with HRT parameters were assessed using correlation and multiple regression analysis. RESULTS: Disc area and cup area averaged 2.04+/-0.44 mm (mean+/-standard deviation) and 0.51+/-0.34 mm, respectively. There were no significant differences in parameters between right and left eyes. Males had significantly greater cup area, cup volume, cup/disc ratio than females (P<0.001) and smaller rim area and rim volume. Disc area was strongly correlated with all HRT parameters. Age had moderate correlations with several tomographic parameters in multiple regression analysis, whereas blood pressure, ocular perfusion pressure, intraocular pressure, hemoglobin A1c, height, and weight had weak or no correlations. CONCLUSIONS: This study provided a range of normal HRT II optic disc parameters for Japanese subjects. Compared with data from studies on other races, the mean disc area and cup area of Japanese subjects were between that of African Americans and white subjects. Given the significant differences between males and females, a normative database of HRT II variables should be established by sex. PMID- 20852438 TI - Measurement of adherence to brimonidine therapy for glaucoma using electronic monitoring. AB - PURPOSE: To assess the patient adherence and behavior with brimonidine twice daily (bid) or 3 times daily (tid) in patients used to topical glaucoma medication. PATIENTS AND METHODS: Seventy-five patients with glaucoma or ocular hypertension were enrolled in a prospective, observational cohort study. Consenting patients were randomly assigned to brimonidine bid or tid and received conventional brimonidine eye drops with attached electronic monitoring devices for 4 weeks. Patients were not explicitly informed on the compliance monitoring. RESULTS: The study was completed by 67 patients (89%). In 65 patients (97%), at least 1 dosing interval exceeded 24 hours. The mean adherence rates were better in the brimonidine bid group (72 +/- 19% vs. 62 +/- 16%, P=0.04), although dosing frequency was higher in the tid group (1.9 +/- 0.5 vs. 1.4 +/- 0.4 per day; P<0.001). On average medication coverage was 70% for the bid group and 67% for the tid group; 19 patients (28%) had a coverage rate above 75%, 42 patients (63%) 50% to 75%, and 6 (9%) below 50%. Patients with normal-tension glaucoma had lower coverage rates than patients with primary open-angle glaucoma and ocular hypertension (P<0.05). Data also showed that on average 20% of the glaucoma medication was wasted owing to inefficient drug delivery by using more than 1 drop per dosing. CONCLUSIONS: Individual adherence with brimonidine was highly variable and pharmacologically insufficient for more than two-third of the patients. Special attention should be paid to compliance of patients with normal tension glaucoma. Our findings underline the need to improve individual adherence and drug delivery in topical glaucoma therapy. PMID- 20852440 TI - Ahmed glaucoma valve implantation for neovascular glaucoma after vitrectomy for proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the safety and efficacy of Ahmed Glaucoma Valve implantation (AGVI) for the management of neovascular glaucoma (NVG) associated with proliferative diabetic retinopathy (PDR) in the vitrectomized eyes. PATIENTS AND METHODS: We reviewed the medical records of patients with NVG associated with PDR who underwent AGVI for intraocular pressure (IOP) control and compared the surgical outcome according to vitrectomy history. The main outcome measures were: postoperative IOP control, visual acuity, and complications. Success was defined as an IOP of <=21 mm Hg and >=6 mm Hg, without further glaucoma surgery or loss of light perception and devastating complications. RESULTS: A total of 73 patients (73 eyes) were included: 42 patients with vitrectomy history before AGVI (vitrectomized group) and 31 patients without vitrectomy history (nonvitrectomized group). The cumulative probabilities of success after AGVI were 89.9% and 83.8% after 1 year, 74.8% and 74.7% after 2 years, and 62.5% and 68.5% after 3 years for the vitrectomized group and the nonvitrectomized group, respectively (P=0.9309). Cox proportional hazards regression showed the intraocular silicone oil tamponade as a risk factor for the surgical failure (odds ratio=4.543, P=0.047). Final visual acuity improved or stabilized in 33 patients (78.6%) in the vitrectomized group and 18 patients (58.1%) in the nonvitrectomized group. Complications were comparable between the groups, but surgical interventions were needed for 5 patients (11.9%) in the vitrectomized group. CONCLUSION: Despite some complications that necessitate surgical intervention, the AGVI is a safe and effective procedure that enables successful IOP control and vision preservation in patients with NVG associated with vitrectomy for the PDR. PMID- 20852442 TI - Influence of ocular pulse amplitude on ocular response analyzer measurements. AB - PURPOSE: To evaluate if the ocular pulse amplitude (OPA) (the difference between systolic and diastolic intraocular pressure) is associated with the measurement variability of IOPg [Goldmann-correlated intraocular pressure (IOP)], IOPcc (corneal compensated IOP), corneal hysteresis (CH), and corneal resistance factor (CRF) obtained from the ocular response analyzer (ORA). METHODS: Sixty normal participants and 60 glaucoma patients were included. In 1 randomly selected eye in each participant, 4 repeated measurements were obtained with the ORA (Reichert Inc, Depew, NY) followed by OPA measurement by dynamic contour tonometry (Pascal; Swiss Microtechnology AG, Port, Switzerland). The repeatability of IOPg (a mathematically derived value with strong correlation with Goldmann applanation pressure measurement), IOPcc (a mathematically derived measurement less affected by corneal biomechanical properties), CH, and CRF were calculated. The associations between age, refraction, keratometry, central corneal thickness, axial length, OPA, and ORA measurements variability were evaluated with univariate and multivariate regression analyses. RESULTS: The repeatability of IOPg, IOPcc, CRF, and CH were 4.08 (95% confidence interval: 3.06-5.09) mm Hg, 4.72 (3.54-5.89) mm Hg, 2.14 (1.61-2.68) mm Hg, 2.35 (1.77-2.94) mm Hg, respectively, for the normal group; and 4.18 (3.75-4.61) mm Hg, 5.56 (4.99-6.14) mm Hg, 2.17 (1.95-2.40) mm Hg, 2.78 (2.50-3.07) mm Hg, respectively, for the glaucoma group. Within-subject variances of IOPg and IOPcc, but not CRF and CH, were positively correlated with OPA. No association was found between age, refraction, keratometry, central corneal thickness, axial length, and the measurement variability of ORA. CONCLUSIONS: The measurement reliability of ORA was only moderate. Eyes with large OPA were associated with high IOP measurement variability. Taking average of multiple repeated measurements is important for reliable measurement of ORA. PMID- 20852441 TI - Corticosteroids versus NSAIDs on intraocular pressure and the hypertensive phase after Ahmed glaucoma valve surgery. AB - PURPOSE: To compare the effect of topical steroids versus nonsteroidal anti inflammatory drugs on intraocular pressure (IOP) and the hypertensive phase (HP) after Ahmed glaucoma valve surgery. PATIENTS AND METHODS: Prospective, randomized, double-masked controlled trial. Twenty-eight consecutive consenting patients scheduled for Ahmed glaucoma valve surgery were randomized to receive either postoperative topical dexamethasone or ketorolac. The main outcome measure was IOP. Secondary outcomes included incidence of HP, visual acuity, number of glaucoma medications, postoperative complications, and subsequent procedures. RESULTS: The mean postoperative IOP (in mm Hg) in the ketorolac versus dexamethasone arms respectively was as follows: 8.8+/-4.7 versus 10.0+/-4.5 at week 1 (P=0.500); 10.7+/-6.7 versus 17.5+/-10.4 at week 2 (P=0.053); 11.0+/-6.5 versus 18.0+/-7.3 at week 4 (P=0.013); 14.8+/-8.6 versus 17.5+/-5.2 at week 6 to 8 (P=0.323); and 14.8+/-9.6 versus 17.8+/-7.5 at week 10 to 12 (P=0.374). Four patients (31%) in the ketorolac arm versus 8 patients (53%) in the dexamethasone arm exhibited the HP (P=0.276). Wound leak was the most severe complication and there were 3 cases (23%) in the ketorolac group versus nil in the steroid group (P=0.087). Conjunctival retraction was observed in 8 patients (62%) in the ketorolac arm versus 2 patients (13%) in the dexamethasone arm (P=0.016). CONCLUSIONS: Mean IOP was greater at all time points postoperatively in the steroid group with the difference between groups statistically significant at week 4. The nonsteroidal anti-inflammatory drug group showed greater wound healing problems. PMID- 20852443 TI - Resolution of lymphoma-associated open-angle glaucoma by rituximab. AB - PURPOSE: To report a patient who developed open-angle glaucoma, secondary to bilateral perilimbal conjunctival lymphoid infiltrates without intraocular involvement that resolved after treatment with systemic rituximab. METHODS: Observational case report. RESULTS: Review of historic, clinical, and photographic data of a 67-year-old woman with non-Hodgkin lymphoma of the axillary and cervical lymph nodes and bilateral perilimbal conjunctival lymphoid infiltrates who presented for treatment of uncontrolled chronic open-angle glaucoma on maximum medical therapy. The elevated intraocular pressures and conjunctival lesions resolved after treatment of the systemic lymphoma with rituximab. The patient was followed for a period of 6 years without recurrence of the conjunctival lesions, with low normal intraocular pressures without progressive optic nerve damage off all glaucoma treatments. CONCLUSIONS: Open angle glaucoma can result as a consequence of isolated conjunctival lymphoid tumors and can resolve with successful treatment of lymphoid lesions. The mechanism of glaucoma may be obstruction of aqueous outflow to the episcleral and conjunctival veins either by compression from a mass effect or direct infiltration that is relieved with resolution of the conjunctival lymphoid lesions. We believe this is a unique presentation of glaucoma associated with lymphoid tumors that has not been reported earlier. PMID- 20852444 TI - High blood pressure prevalence and control in a middle-aged French population and their associated factors: the MONA LISA study. AB - AIMS: This work aims to assess high blood pressure (BP) prevalence and control and their associated factors in a population-based study conducted in three French areas: the Urban Community of Lille and the districts of Bas-Rhin and Haute-Garonne, between 2005 and 2007. METHODS: Participants were randomly recruited from electoral rolls after stratification on sex, 10-year age group (35 74 years) and town size. BP was measured by trained medical staff following standardized procedures. High BP was defined as BP at least 140/90 mmHg and/or taking antihypertensive drugs or following a specific diet. BP below 140/90 mmHg among treated individuals was considered adequately controlled (<130/80 mmHg among diabetics). RESULTS: Four thousand eight hundred and twenty-five participants were recruited (mean age 55.5 +/- 11.3 years). The prevalence of high BP was greater in men (47%) than in women (35%). Antihypertensive treatment concerned 80% of the hypertensive individuals with most often a combination therapy. Control rates concerned only 38% of women and 22% of men and decreased with age. Metabolic risk factors and aging were independently associated with high BP prevalence as were low educational level and alcohol consumption. Diabetes and high cardiovascular risk were strong independent predictors of uncontrolled BP. The use of multiple drug treatment did not predict a better control. CONCLUSIONS: Hypertension is frequent in France, particularly in the age group 55-74 years. Control rates remain low, particularly in high-risk, older and diabetic individuals. Intensified efforts are required to improve lifestyle, awareness of the condition, and use of appropriate and well tolerated combination therapy. PMID- 20852445 TI - Common variants in or near FGF5, CYP17A1 and MTHFR genes are associated with blood pressure and hypertension in Chinese Hans. AB - OBJECTIVES: Recent genome-wide association studies have identified a number of variants influencing blood pressure. We aimed to examine whether these associations can be replicated in Chinese. METHODS: We genotyped eight of these variants (in or near FGF5, CYP17A1, MTHFR, ZNF652, PLCD3, ATP2B1, c10orf107) in a population-based cohort of Chinese Hans (N = 3210). Logistics regression and generalized linear analyses were applied to test for association of each variant with hypertension risk and blood pressure (BP), BMI, waistline and high sensitivity C-reactive protein (hsCRP), respectively. RESULTS: Six variants showed directionally consistent association with blood pressure and risk of hypertension, of which four (FGF5, two in CYP17A1, MTHFR) reached significance. The associations were most pronounced for FGF5-rs16998073 [SBP: beta = 1.97 mmHg/allele, P = 0.0006; DBP: beta = 0.95 mmHg/allele, P = 0.0008, hypertension: odds ratio (OR) 1.36/allele, P = 0.0001]. Effect size of FGF5-rs16998073 on SBP and hypertension were significantly more pronounced in Han Chinese compared to white Europeans. None of these variants was associated with BMI, waistline or hsCRP that are the well established risk factors for hypertension. The genetic risk score, calculated as the sum of BP-increasing alleles of FGF5-rs16998073, CYP17A1-rs11191548, CYP17A1-rs1004467 and MTHFR-rs17367504, was significantly associated with increased SBP (1.16 mmHg/allele, P = 9.01E-5), DBP (0.51 mmHg/allele, P = 4.40E-4) and hypertension risk (OR = 1.22/allele, P = 2.74E-7). CONCLUSION: Variants in or near FGF5, CYP17A1 and MTHFR contributed to variation in BP and hypertension risk. Effect sizes of these three loci tended to be larger in Chinese than in white Europeans, but more studies with larger sample size are required for a definitive conclusion. PMID- 20852446 TI - Age-related and blood pressure-independent reduction in aortic stiffness after kidney transplantation. AB - OBJECTIVES: Aortic stiffness is a novel cardiovascular risk factor in patients with chronic kidney disease (CKD). The purpose of the present study is to examine whether there is a blood pressure-independent improvement in aortic stiffness 3 months after successful kidney transplantation (KTx), and whether this improvement is age-dependent. METHOD: In this prospective, longitudinal observational study, we studied hemodynamic and biological parameters prior to and 3 months after a KTx in 52 stage 5 CKD patients. Aortic stiffness was measured by carotido-femoral pulse wave velocity (c-f PWV) and enhanced central wave reflection was evaluated by the heart rate-adjusted central augmentation index (AIx) by means of arterial tonometry. Endothelin-1, L-arginine, asymmetric dimethylarginine (biomarkers of endothelial dysfunction), pentosidine (advanced glycation end-products) and mineral metabolism parameters were also measured. RESULTS: After adjusting for the reduction in mean blood pressure, c-f PWV decreased significantly from 12.1 +/- 3.3 to 11.6 +/- 2.3 m/s (P < 0.05). In an analysis stratified by age, this improvement was only present in patients older than 50 years of age as compared with patients younger than 50 years of age (-5.5 +/- 2.2 vs. 2.1 +/- 1.9%, P < 0.05). AIx decreased from 22 +/- 11 to 14 +/- 13% (P < 0.01), but this reduction was not age-dependent. We also observed a similar degree of improvement in the biomarker levels of endothelial dysfunction and pentosidine in both groups. CONCLUSION: This study shows for the first time that there is an age-dependent improvement in aortic stiffness after KTx. These observations suggest that older patients may have an added cardiovascular risk reduction after a successful KTx. PMID- 20852447 TI - Role of CYP2C9 genetic variants for salt sensitivity and the regulation of the renin-angiotensin-aldosterone system in normotensive men. AB - OBJECTIVE: Cytochrome P450 (CYP) 2C9 gene polymorphisms have been implicated in regulation of the renin-angiotensin-aldosterone system (RAAS) and salt sensitivity in hypertensive patients. We tested the relevance of CYP2C9 genotypes for regulation of plasma renin activity (PRA), plasma aldosterone concentrations and blood pressure (BP) in response to changes in salt intake in normotensive individuals. METHODS: Three hundred and ten normotensive men (mean age 24.9 +/- 0.1) were studied after a standardized low = 20 mmol/day or high = 220 mmol/day sodium intake for 7 days. Individuals were classified as salt sensitive when the mean arterial BP was more than 3 mmHg higher after high compared with low-salt exposure. RESULTS: CYP2C9*2 and CYP2C9*3 alleles were not associated with salt sensitivity status or BP phenotypes; CYP2C9*2 had no effect on PRA or plasma aldosterone. CYP2C9*3 carriers showed a significantly lower PRA compared with CYP2C9*1/*1 individuals in the overall study cohort (high salt: 0.39 +/- 0.05 vs. 0.62 +/- 0.04 ng/ml per h, P = 0.009; low salt: 2.19 +/- 0.27 vs. 2.87 +/- 0.13 ng/ml per h, P = 0.013). Salt-sensitive CYP2C9*3 carriers exhibited the lowest PRA values and significantly lower 24 h sodium excretion rates during high-salt intake (P = 0.005 vs. CYP2C9*1/*1). Lower plasma aldosterone concentrations were only observed in salt-resistant CYP2C9*3 carriers under low salt (P = 0.039). CONCLUSION: The present study confirms an association between CYP2C9 polymorphism and activity of the RAAS. Specifically, we detected an overall effect of CYP2C9*3 on lower PRA, but not on salt-sensitive BP regulation in normotensive men. Further studies are needed to analyze the long-term effects of CYP2C9*3 for salt sensitivity and hypertensive diseases. PMID- 20852448 TI - Isolated clinic hypertension: diagnostic criteria based on 24-h blood pressure definition. AB - OBJECTIVE: The use of diagnostic criteria based on 24-h ambulatory blood pressure (BP) values could improve prognostic value by incorporating night BP, minimize biases and improve the diagnostic reproducibility of isolated clinic hypertension (ICH). We estimate the 24-h BP cut-off points that best discriminate and predict the two diagnostic thresholds of mean daytime BP for ICH (135/85 and 130/80 mmHg). METHODS: Cross-sectional, comparative, multicentre study in 6176 untreated hypertensive patients, whose BP was measured by ambulatory BP monitoring. ICH was defined with an office BP of >=140/>=90 mmHg and a daytime BP of <135/<85 mmHg (ICH1) or <130/80 mmHg (ICH2). Sensitivity, specificity, positive likelihood ratio (LR+), odds ratio (OR), error rate, predictive values, kappa values and 95% confidence interval were calculated for each possible cut-off point for ICH1 and ICH2. RESULTS: One thousand eight hundred and seven patients (29.2%) and 960 patients (15.5%) met ICH1 and ICH2 criteria, respectively. The 24-h BP cut-off points that best predict ICH1 and ICH2 are less than 132/82 mmHg (sensitivity: 93.6%, specificity: 94.3%, LR+: 16.6, OR: 1367.1, error rate: 5.9, kappa 0.86) and less than 127/77 mmHg (sensitivity: 90.8%, specificity: 97.4%, LR+: 34.6, OR: 1041.5, error rate: 3.6,kappa 0.86), respectively. These values achieved the best balance of sensitivity and specificity, together with the highest values of LR+ and OR and the lowest error rate. CONCLUSION: The 24-h BP cut-off point that best predicts the daytime criterion of less than 135/85 and less than 130/80 mmHg are 132/82 and 127/77 mmHg, respectively. These 24-h cut-off points may add value to ambulatory blood pressure monitoring for both diagnostic and management future decisions. PMID- 20852449 TI - Measurement of vasoactive metabolites (hydroxyeicosatetraenoic and epoxyeicosatrienoic acids) in uterine tissues of normal and compromised human pregnancy. AB - BACKGROUND: Preeclampsia and intrauterine growth restriction define two disorders of a multifactorial etiology that compromise maternal and fetal well being as well as cardiovascular health in later life. Many of the overt symptoms of preeclampsia are attributable to the systemic endothelial dysfunction observed in the uteroplacental and systemic circulation, leading to a generalized vasoconstriction, hypertension and inadequate placental perfusion. Mounting evidence implicates nonprostanoid eicosanoids, epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) in the control of vascular function and dysfunction. OBJECTIVE: To determine whether levels of EETs and HETEs are altered in preeclampsia and intrauterine growth restriction compared with normal term pregnancy. METHODS: An analytical liquid chromatography-tandem mass spectrometry profiling method was utilized in order to analyze differential levels of EETs and HETEs in intrauterine tissues of term nonlaboring, laboring and preeclamptic women as well as women with a growth-restricted pregnancy. RESULTS: Placentae of preeclamptic women contained significantly (P < 0.05) larger amounts of 5-HETE, 12-HETE and 15-HETE known to possess either vasoconstrictive or proinflammatory actions. Laboring tissues were characterized by significantly higher (P < 0.05) EET levels in the amnion compared with the other clinical groups. EET and HETE levels in preeclampsia and intrauterine growth restriction were positively correlated (P < 0.05), whereas in normal and laboring pregnancies, EETs and HETEs were negatively correlated. CONCLUSION: Increased production of 5-HETE, 12-HETE and 15-HETE metabolites in preeclamptic placentae indicates an important role for this family of eicosanoids in the cause of this disease. PMID- 20852450 TI - Static and dynamic accommodation measured using the WAM-5500 Autorefractor. AB - PURPOSE: This study was undertaken to compare static and dynamic accommodation measurements using the Grand Seiko WR-5500 (WAM) in young, phakic subjects. METHODS: Fifteen subjects, aged 20 to 28 years (23.8 +/- 0.58 years; mean +/- SD years) participated. Accommodation was stimulated with printed text presented at various distances. In static mode, three measurements were taken for each stimulus amplitude. In dynamic mode, 5-Hz recordings were started, and subjects alternately looked through a transparent near chart and focused on a letter chart at 6 m for 5 seconds and then focused on the near letter chart for 5 seconds for a total of 30 seconds. After smoothing the raw data, the highest three individual values recorded in each 5-s interval of focusing at near were averaged for each stimulus amplitude. Analysis of variance and Bland-Altman analysis were used to compare the static and dynamic measurements. A calibration was performed with +3.00 to -10.00 D trial lenses behind an infrared filter, in 1.00 D steps in 5 of the 15 subjects. RESULTS: Stimulus-response graphs from static and dynamic modes were not significantly different in the lower stimulus range (<5.00 D, p = 0.93), but differed significantly for the higher stimulus amplitudes (p = 0.0027). One of the 15 subjects showed a significant difference between the static and dynamic modes. Corresponding pupil diameter could be recorded along with the accommodation responses for the subjects, and pupil diameter decreased with increasing stimulus demand. Calibration curves for static and dynamic measurements were not significantly different from the 1:1 line or from each other (p = 0.32). CONCLUSIONS: Slight differences between the dynamically and statically recorded response amplitudes were identified. This is attributed to differences in the accommodative responses in this population and not to the instrument performance. Dynamic measurement of accommodation and pupil constriction potentially provides additional useful information on the accommodative response other than simply the response amplitude. PMID- 20852451 TI - Evaluation of extractants and precipitants in tear film proteomic analyses. AB - PURPOSE: To determine the efficiency of several protein extraction or precipitation treatments used in proteomic analyses. METHODS: Tear samples were taken from each eye of 40 normal subjects using glass microcapillaries. Tear volume was measured followed by storage at -86 degrees C. Lotrafilcon B contact lenses were fitted and worn for 14 days, followed by removal and storage at -86 degrees C. Tear samples from each eye within a subject were randomly assigned to either one of four chemical treatments (acetone, trichloroacetic acid, urea, and trifluoroacetic acid/acetonitrile [TFA/ACN]) or no chemical treatment in groups of 10. Contact lens samples were subjected to the same treatments as tear samples for each subject, with a second treatment preceding the first. Protein concentrations were quantified by Bradford assay. RESULTS: For tear samples, a significant reduction in total protein was observed when subjected to any of the four treatments studied compared with those samples left untreated. A positive relationship was noted between protein concentration and tear volume for treated, untreated, and combined tear samples. For contact lens samples, there was a significant reduction in the amount of deposited protein removed when comparing acetone, trichloroacetic acid, and urea with TFA/ACN. A second extraction from contact lenses assigned to the urea and TFA/ACN groups yielded a significant amount of additional protein compared with the amount removed initially. CONCLUSIONS: Tear samples subjected to any of the evaluated chemical treatments provided significantly less protein than untreated samples. For contact lenses, TFA/ACN extraction provided the highest yield of available protein out of the four treatments evaluated. PMID- 20852452 TI - Is the pediatric quality of life inventory valid for use in preschool children with refractive errors? AB - PURPOSE: To determine the psychometric validity of the pediatric quality of life inventory (PedsQL 4.0) in assessing the impact of refractive errors on health related quality of life (HRQoL) in preschool children in Singapore. METHODS: Parents of toddlers (aged 25 to 48 months) and young children (49 to 72 months) completed the PedsQL 4.0, an HRQoL scale as part of population-based trial in Singapore. The outcome measures were the overall score, and the "physical"; "emotional"; "social"; and "school" functioning subscales. Rasch analysis was used to validate the PedsQL 4.0. RESULTS: Parents of 939 (48.9%) toddlers and 982 (51.1%) young children completed the PedsQL 4.0 survey. The overall mean (+/ standard deviation) spherical equivalence for the right eye was 0.47 +/- 1.13 diopter (D) for toddlers and 0.74 +/- 1.22 D for young children. One hundred forty-nine (15.9%) toddlers and 90 (9.2%) young children were considered myopic (>=-0.50 D). Most participants (n = 1286, 89.6%) had presenting visual acuity 6/9 or better. Rasch analysis showed evidence of disordered category thresholds and poor person-item targeting for both groups. The separation reliability was 0.00 for toddlers and 0.03 for young children, indicating there was no variance in both samples. The PedsQL 4.0 overall and subscale scores displayed substantial multidimensionality as the variance values explained by the measures was <25% in both groups. A minimum value of 60% is usually considering acceptable. CONCLUSIONS: The PedsQL 4.0 in its current state is not a valid psychometric scale to effectively evaluate the impact of refractive errors on HRQoL in preschool children in Singapore. PMID- 20852454 TI - Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics. AB - BACKGROUND: Studies in antenatal care clinics suggest that lower genital tract infections (LGTI) may be associated with adverse pregnancy outcomes (APO). We sought to characterize antenatal care patterns and determine whether LGTI are independently associated with preterm birth and/or low-birth weight among a high risk public sexually transmitted diseases (STD) clinic population. METHODS: Electronic STD clinic medical records and state birth records were matched for 730 pregnant women age 13 to 49 tested for 5 treatable LGTI (bacterial vaginosis, chlamydia, gonorrhea, early syphilis, and trichomoniasis) in a case-control analysis. Cases were women with preterm and/or low-birth weight newborns; controls were women without APO. The association between LGTI and APO was assessed using logistic regression. RESULTS: Although pregnant women attending STD clinics reported high risk behaviors and were found to have high rates of LGTI (55%), most of these women were engaged in antenatal care (85%). Of the pregnant women, 22% experienced an APO (7% preterm birth, 4% low birth weight, and 12% preterm birth and low birth weight). In multivariate analyses, chlamydia was associated with low-birth weight (adjusted odds ratio [aOR]: 2.07, 95% confidence interval [CI]: 1.01-4.24), and gonorrhea was associated with preterm birth (aOR: 2.01, 95% CI: 1.02-3.97), particularly when diagnosed during the first trimester (aOR: 2.95, 95% CI: 1.30-6.70). CONCLUSIONS: Our findings confirm the association of some LGTI with APO and suggest that timing of LGTI screening may affect outcomes. STD clinic visits represent a critical opportunity to target interventions aimed at improving pregnancy outcomes. PMID- 20852453 TI - Perceived financial need and sexual risk behavior among urban, minority patients following sexually transmitted infection diagnosis. AB - BACKGROUND: Previous studies have shown that racial/ethnic and gender disparities in human immunodeficiency virus (HIV)/sexually transmitted infections (STI) may be due in part to factors such as poverty and income-inequality. Little has been published in the HIV/STI literature on the effect of the perception of having unmet basic needs on sexual risk behavior. METHODS: Data on perceived financial need and sexual risk were collected as part of a behavioral intervention aimed at promoting STI partner notification and reducing sexual behavior among minority patients presenting for care at 1 of 2 STI treatment centers in Brooklyn, NY, between January 2002 and December 2004. Data from 528 participants collected at the 6-month follow-up visit were used for the current study. RESULTS: Forty-three percent of participants were categorized as having unmet needs. Those with unmet needs were more likely to report unprotected anal or vaginal sex (unprotected anal or vaginal intercourse [UAVI]; 62%) versus those who had met needs (53%). This association was significant (adjusted odds ratio=1.28; 95% confidence interval=1.04-1.53), after controlling for age, sex, site of recruitment, intervention group membership, and country of origin. Stratified analyses indicated that, in the group that did not receive the intervention, there was a statistically significant interaction between sex and basic needs such that women with unmet needs were more likely to report any UAVI (78%) than those with met needs (54%) (adjusted odds ratio=1.18; 95% confidence interval=1.07-1.24). No such relationship was detected for men in this sample. CONCLUSIONS: The significant association between perceived unmet needs and UAVI appears to be particularly relevant for women. These findings provide preliminary evidence that HIV/STI intervention components that seek to directly deal with issues of reduction in partner conflict might be beneficial to women with high perceived unmet basic needs, and for whom a potential dissolution of a relationship may represent a further loss in ability to meet basic needs. PMID- 20852456 TI - Infection control: everybody's business. PMID- 20852455 TI - Longitudinal associations among relationship factors, partner change, and sexually transmitted infection acquisition in adolescent women. AB - OBJECTIVES: New sex partners put adolescents at increased risk for sexually transmitted infections (STIs), even when these sex partners are nonoverlapping. Although the risk of partner change is well described, little is known about its antecedents. We prospectively examined associations between relationship characteristics, partner change, and subsequent STI during intervals of "serial monogamy." METHODS: As part of a longitudinal study, 332 adolescent women were interviewed and tested for gonorrhea, chlamydia, and trichomonas every 3 months for up to just over 6 years. Interviews covered partner-specific relationship characteristics and sexual behaviors. The quarterly interval, a 3-month period bracketed by interviews and STI testing, was the unit of analysis. We examined associations among relationship factors, partner change, and subsequent STI using a series of mixed regression models, controlling for age, STI at Time 1, and condom nonuse. RESULTS: Age, lower relationship quality, and lower levels of partner closeness to friends and family predicted partner change from Time 1 to Time 2. In turn, partner change was associated with acquisition of a new STI at Time 2. Although relationship factors did not exert a direct effect on STI at Time 2, they improved partner change-STI model fit. Similar patterns were seen with each organism. CONCLUSION: Relationship factors drive partner change, which in turn contributes to STI acquisition. STI prevention research may need to focus on the relationship antecedents to partner change, in addition to the partner change itself. PMID- 20852457 TI - The pathogenesis of infection and immune response. AB - An understanding of the pathogenesis of infection, and the complex and fascinating 'relationship', or interaction, between the infecting organism and the host are advantageous when caring for patients with infections/infectious diseases, particularly as many of the clinical features of infection are as a consequence of the defence mechanisms mounted by the immune system. This article aims to provide a brief overview of the pathogenesis of infection, explaining how the two branches of the immune system, the innate/natural immune response, and the adaptive/acquired immune response, mount an attack against invading bacteria. Reference is made to bacteria such as Staphylococcus aureus, Clostridium difficile, Streptococcus pyogenes, Neisseria meningitidis and Mycobacterium tuberculosis, and their effect on the human host and the immune response, through the processes of attachment/entry, evasion of host defences, replication, and damage to the host. PMID- 20852458 TI - Developing decontamination strategies and monitoring tools. AB - Decontamination within the healthcare setting plays a significant role in reducing the risk of healthcare-associated infections. This article will examine decontamination from hand hygiene to sterilization of instruments and discuss how hazard analysis at critical control points (HACCP) can be used to monitor and record practice, ensuring that consistent standards are based on recommended guidelines, the law and policies. PMID- 20852459 TI - The impact of workload on hygiene compliance in nursing. AB - The objective of this research was to clarify whether external factors (e.g. ward capacity, level of nursing intensity) had an influence on nursing staff compliance with hand hygiene guidelines. The study was conducted at a German hospital (450 beds). Quantitative data were collected prospectively in six trial phases (E1-E6) starting in June 2007 and ending in May 2008. Included in the study were ten hospital departments: four surgical wards, four internal medicine departments, and two interdisciplinary intensive care units. In six participant observation trials, nursing staff were monitored for the disinfection of hands. Narrative interviews were conducted immediately after the observation with those who did not disinfect their hands in accordance with national guidelines. Observations and interviews were unannounced, taking place at different times. The collected data was analysed on subsequent categorization after summarizing the core statements (content analysis). The statistical relevance of staff compliance to the rate of used ward capacity could be proved using a multifactorial regression model (P=0.011). Workload factors (e.g. maximum ward capacity, severity of patient cases) have an impact on staff compliance with hand hygiene guidelines, even where non-compliance contradicts the personal level of professional training. PMID- 20852461 TI - Talking 'bout my generation. PMID- 20852460 TI - A journey too far? PMID- 20852462 TI - Airway management for nurses:emergency assessment and care. AB - Within the hospital environment patients can deteriorate rapidly and for many different reasons. Maintaining a patient's breathing is the main priority in any emergency situation--although achieving airway control can be difficult. All health professionals need to be able to safely undertake airway management and the key to the management of an airway is through a thorough assessment, to firstly ensure whether the airway is patent or not. This article will discuss airway management--both acute and chronic--as well as associated nursing care. PMID- 20852464 TI - In too deep: understanding, detecting and managing DVT. AB - Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious health and social care problem of the developed world, affecting 1 in 1000 adults every year, and with an annual financial overhead of approximately L640 million. The nature of DVT means that often the condition can go unrecognized until the thrombus becomes an embolus. The pathogenesis of DVT continues to be based on Virchow's triad, which attributes VTE to 'hypercoagulability', 'stasis' and 'intimal injury'. The diagnosis of DVT is often the result of a number of tests performed either sequentially or in combination before mechanical and/or chemical treatment is embarked on. Creating public awareness of DVT and PE is the best way to prevent this condition. Nurses are in an ideal position to discuss the importance of lifestyle changes and other related measures to prevent DVT. PMID- 20852463 TI - Recognition and treatment of anaphylaxis in hospital. AB - Anaphylaxis is a life-threatening, generalized or systemic hypersensitivity reaction characterized by rapidly developing airway, and/or breathing, and/or circulation compromise, usually associated with skin and mucosal changes. Summoning expert help, positioning the patient appropriately, administering high flow oxygen, and administering adrenaline by intramuscular injection are the key initial treatment and management options. This article draws on the literature, including published guidelines, to discuss the recognition and treatment of anaphylaxis in hospital. PMID- 20852465 TI - Venous thromboembolism prophylaxis: the role of the nurse. AB - Venous thromboembolism is the most common preventable cause of hospital death, with surgical and medical patients at a significantly increased risk. It is estimated that, without prophylaxis, it occurs in 20% of general medical and surgical patients, and 40-60% of orthopaedic patients. It accounts for 25-times greater mortality than meticillin resistant Staphylococcus aureus (MRSA). Despite overwhelming evidence advocating the routine use of thromboprophylaxis, provision is persistently deficient. It has been demonstrated that involvement of the nursing profession in initiatives to improve provision is important and effective. Recent years have seen the nursing profession continue to evolve and take the lead in a number of areas of preventive medicine, and to develop specialist nursing roles. The authors believe that this drive must be harnessed so that the profession can enact the routine provision of thromboprophylaxis to patients. PMID- 20852467 TI - Nursing considerations in patients with vaginitis. AB - Vaginitis is defined as an inflammation of the vagina. It can result in symptoms of any or all of the following: discharge, itching and pain, and often irritation or infection of the vulva. There is no specific cause for vaginitis, and many other conditions can cause the symptoms. Vaginitis is a distressing condition that affects many women of reproductive age and beyond, and encompasses candidiasis (also known as thrush), bacterial vaginosis, and trichomoniasis. It can occur in a single episode, or recur throughout a woman's lifetime. Some women will seek medical help, but many more self-treat with over-the-counter medications, suspecting the recurrence of Candida in particular. This article aims to explore the causes, signs and symptoms, and treatments of vaginitis to provide nurses with the necessary background information to feel more confident in dealing with women's health issues. PMID- 20852466 TI - The role of the community stroke rehabilitation nurse. AB - There is strong evidence for early supported discharge (ESD) following stroke, but there is no evidence on how these services should be organized or the best models of care. ESD teams rarely include a community stroke rehabilitation nurse. A service development project was undertaken in Portsmouth Hospitals NHS Trust's community stroke rehabilitation team to identify and explore the unique contributions of community stroke rehabilitation nurses in an established ESD team. When the team was set up, the nurses had inpatient stroke rehabilitation skills, but no community experience. This novel approach, which involved taking specialist hospital nurses into the community, meant there was a steep learning curve and, unfortunately, there were no role models to support their development. During these early days, it became apparent that intensive stroke rehabilitation within an interdisciplinary ESD team required effective and timely nursing intervention, the development of skills to support interdisciplinary working and a greater understanding of the roles of all team members. Locally and nationally, questions were being asked pertaining to the nurses' role, which precipitated this project. Through a series of journal club sessions, the interdisciplinary team reviewed the evidence base of the nurse role in stroke rehabilitation. The team were able to evaluate findings against current practice. The project confirmed that the community stroke rehabilitation nurse provides a unique and fundamental role to the team that strengthens the model of interdisciplinary teamworking. PMID- 20852468 TI - 'Have a nice day': consumerism, compassion and health care. AB - Plans to implement a quality measurement framework that will rate nurses according to the level of care and compassion they demonstrate have been proposed and discussed in a number of Department of Health documents. From September 2010 degree-level nursing students in Wales will receive regular feedback on their communication skills and whether they are exhibiting sufficient levels of compassion. This article examines the reasons why there have been such moves by both politicians and health professionals to demonstrate, in quantifiable terms, that they are able to measure something that is frequently contextual and subject to individual interpretation. It explores how these moves have been influenced by the disclosure of unacceptable standards of care by the Patients Association report and the enquiry into Mid-Staffordshire NHS Foundation Trust. It also discusses how the adoption of targets to evaluate care and compassion seems to reflect a market-driven and bureaucratic approach to health care that has resulted in a system in which measurability and outcome are considered the most important indicator of quality. PMID- 20852469 TI - Health professionals' views on sexual information following MI. AB - Following myocardial infarction (MI), patients often have unanswered questions about resuming sexual activity. Coronary care nurses can play an important role in counselling. However, this sensitive area is frequently neglected in nursing practice. This article discusses patient and nurse perceptions of such discussions and explores ways to increase nurses' awareness, so that they might offer sexual counselling to patients post-MI. Health professionals representing 18 Swedish coronary care units answered two open-ended questions, and their answers were analysed and categorized by content. Two main categories were identified: 'Difficulties and challenges' and 'Future needs'. These two categories were further divided into sub-categories respectively: 'Information flow', 'Patients' responsibility', 'Information to partners' and 'Cooperating with other experts'; and 'Preparing information tools' and 'Highlighting sexual issues'. It was found that when sexual concerns arise, contact with medical social workers, urologists and gynaecologists is scarce. It was also found that the current written information is insufficient. Responsibility currently falls on patients to ensure that both they and their partners have been adequately informed regarding any sexual concerns. It is essential that health professionals are well-educated and have the necessary skills to inform patients and their partners about sexual issues following MI. PMID- 20852471 TI - Can high-impact nursing actions result in enhanced patient care? PMID- 20852472 TI - Patient safety in the NHS: the tides of change. AB - John Tingle discusses the Department of Health's recent report on the review of arm's-length bodies (ALBs), particularly in relation to the National Patient Safety Agency (NPSA) which, along with several other ALBs, is set to be abolished. PMID- 20852473 TI - Advance care planning: the role of the nurse. AB - Advance care planning is a process designed to enable patients to discuss and record their values and treatment preferences to inform future care in the event that they lose decision-making capacity. Current law provides for the appointment of a proxy decision-maker under a Lasting Power of Attorney, or advance decisions for treatment refusal. A further option is a statement of wishes to record the values and views to be used to inform the determination of best interests. Nurses can play an invaluable role in facilitating open and frank discussion. PMID- 20852474 TI - Writing for professional publication. Part 1: Motivation. AB - Writing for professional publication can be a daunting prospect, but, with a little effort and the right motivation, it can be a rewarding and career enhancing experience. And the good news is, it's not as difficult as it may sound. In this first part of a series of articles on writing for professional publication, John Fowler, an experienced nursing lecturer and author, discusses perhaps the most important factor in seeing your work published: motivation. Forthcoming issues will explore different aspects of publication and include advice and practical tips. PMID- 20852475 TI - Regulating support workers. PMID- 20852476 TI - Is pressure ulcer prevention given the priority it deserves? AB - In England, the Chief Nursing Officer of the Department of Health has raised the stakes with regard to pressure ulcer prevention, by putting it into the 'high impact actions' arena. It is probably true to say that this has prompted a flurry of activity around 'Root Cause Analysis' of incidents of pressure damage. The process involves senior nurses, and possibly risk managers, investigating why patients developed category three and four ulcers. There will have been recurrent themes, such as failure to check the patient's skin or pressure ulcer risk on admission to professional care. If such checks are not carried out, there is no baseline from which real causation can be deduced. PMID- 20852477 TI - The impact of nurses' values on the prevention of pressure ulcers. AB - Values are perceived to be a key determinant of people's behaviour and actions. There is a limited amount of research into the value that nurses place on the prevention of pressure ulcers, but past studies have suggested that nurses place a low value on pressure ulcer prevention. This article describes a study that was undertaken to ascertain what value nurses place on pressure ulcer prevention. The participants in this study (n=16) were recruited from the non-acute adult medical wards of 14 hospitals of one NHS trust and a local university. Data were gathered via semi-structured interviews, then transcribed and analysed via Straussian grounded theory. The findings of this study show that the value that nurses place on pressure ulcer prevention is important because all nurses attempt to work in line with the value that they place on pressure ulcer prevention. The nurses who place a high value on pressure ulcer prevention appear to be more proactive and determined to deliver care that protects the care of their patients' skin. However, the findings suggest that the efforts of nurses to prevent pressure ulcers are often impeded by environmental factors like bed management, and the differing values placed on ulcer prevention by colleagues. It also shows that interventions to protect the skin of patients are often undertaken by healthcare assistants and students because nurses are too busy carrying out other tasks. PMID- 20852478 TI - Bridging the theory-practice gap in pressure ulcer prevention. AB - Pressure ulcers are a largely preventable problem, but the incidence can impact negatively on the ability of the health service to deliver effective and quality care. Pressure ulcers commonly occur in the very old, the malnourished and those with acute illness. As pressure ulcers most commonly occur in the hospital setting, this can increase both length of stay and costs to the health service. As a result, prevention and management strategies should be core components in the strategic planning of healthcare services. This article discusses the importance of education and knowledge in pressure ulcers, and the onus of the nurse to put theory into practice in order to prevent this problem. PMID- 20852479 TI - Does honey have a role in paediatric wound management? AB - Topical honey treatment has been shown to possess antimicrobial properties, promote autolytic debridement, stimulate growth of wound tissues to hasten healing, and to start the healing process in dormant wounds, stimulating anti inflammatory activity that rapidly reduces pain, oedema and exudate production. This article provides an overview of the use of honey as a medicinal substance, particularly its use in wound treatment, and reviews the published data concerning honey as a form of complementary and alternative medicine in paediatric wound management. The literature reviewed was found by searching the PubMed, BIOSIS, and ISI Web of Science databases for the term honey. Exclusion criteria were articles where honey was used in a mixture with other therapeutic substances. PMID- 20852480 TI - The effects of silver dressings on chronic and burns wound healing. AB - Silver (Ag) has been thought to improve wound healing and reduce instances of associated infections for many years. There are centuries-old records of silver being used in wound treatment, but the past two decades in particular have seen an increasing clinical application of silver-impregnated wound dressings and as such, have seen the number of research articles similarly increase. The majority of these articles focus on the positives and potential negatives (e.g. the toxicity of silver as a heavy metal) of using silver-impregnated dressings in the clinical management of wounds. This article examines the potential advantages and disadvantages of using silver in the management of chronic and burn wounds, and provides a physiological understanding of the body's response to silver absorption. The author also attempts to critically appraise the opposing literature related to the clinical relevance of microbial kill-time and the volume of silver contained in dressings, while investigating the efficacy of silver-impregnated dressings in the management of burns and chronic wounds. In order to collect literature relevant to this review, the author searched CINAHL, Medline, BMJ, Medscape, Journal of Advanced Nursing, the Electronic Medicines Compendium (EMC), and the Cochrane Library, using the terms silver, silver sulfadiazine, impregnated, wound, burn, dressing, review, quantative, efficacy, in vitro, in vivo, nanocrystalline, toxicity, infection, microbial kill-time, and comparison. PMID- 20852481 TI - Time for training. PMID- 20852482 TI - Female sexual dysfunction: reality or disease-mongering? PMID- 20852483 TI - Psychiatric side effects of non-psychiatric drugs. AB - Psychiatric side effects of non-psychiatric drugs are poorly studied. This article describes how to identify and manage the psychiatric side effects of some commonly prescribed medicines that are known to cause such problems. PMID- 20852484 TI - Approaches to improving antibiotic management. AB - New information is available to improve antibiotic outcomes in severe sepsis where increasing resistance and reducing novel compound development make reaching the right decisions ever more difficult and important. PMID- 20852485 TI - Aspirin sensitivity and the nose. AB - There is a well-recognized association of aspirin sensitivity, aspirin-induced asthma, nasal polyposis or sinusitis, known as Samter's triad. This article outlines the pathogenesis and clinical features of this condition and reviews current management options. PMID- 20852486 TI - Bearing couples in total hip arthroplasty. AB - Total hip arthroplasty is a well-established treatment for arthritis of the hip. The choice of bearing couple used for articulation should be tailored to the patient. This article reviews the history of different bearing surfaces, and outlines the advantages and disadvantages that may influence their use. PMID- 20852487 TI - Sorafenib in hepatocellular carcinoma. AB - Sorafenib, a small molecule multikinase inhibitor, is the standard of care in the USA and Europe for the treatment of advanced hepatocellular carcinoma. This article reviews its development from the basis of molecular hepatocarcinogenesis to phase III trials and discusses the future for sorafenib in hepatocellular carcinoma. PMID- 20852488 TI - Cranial computed tomography 1: technical aspects for clinicians. AB - The importance of cranial computed tomography in the diagnosis and follow up of intracranial pathology cannot be underestimated. Clinicians at every level should have a basic understanding of this technique. This first of two articles looks at the technical strengths and weaknesses of cranial computed tomography, and cranial anatomy. PMID- 20852489 TI - Evaluating trainee doctors' educational use of a personal digital assistant: a pilot study. AB - In recent times, health-care providers in the western world have embraced modern technology to advance patient care. Ease and speed of access to modern technologies has enhanced the quality of medical education and provided a valuable new adjunct to workplace-based learning. PMID- 20852490 TI - Diversity, equal opportunities and human rights. AB - Equality and diversity are central to education and health services, in terms of both employment and service delivery. Clinical teachers need to be able to support students and trainees around equality issues, have the confidence to challenge discriminatory practice and provide an inclusive and safe learning and teaching environment. PMID- 20852491 TI - The 'missing piece' sign: distant migration of a patellar tendon cerclage wire. PMID- 20852492 TI - Systemic granulomatous disease and syndrome of inappropriate antidiuretic hormone. PMID- 20852493 TI - Peter Lowe: a father figure of the Royal College of Physicians and Surgeons of Glasgow. PMID- 20852496 TI - Should epidural analgesia be used in free flap transfer? PMID- 20852497 TI - Managing the media 2: a guide for the foundation year doctor. PMID- 20852498 TI - Radiology of acute shoulder injuries. PMID- 20852500 TI - An ethical dilemma on call. PMID- 20852499 TI - Orbital swelling: a simplified guide. PMID- 20852501 TI - So you want to be ... a rheumatologist. PMID- 20852503 TI - Biofilm maturity studies indicate sharp debridement opens a time- dependent therapeutic window. AB - OBJECTIVE: To investigate the hypothesis that newly formed wound biofilms (or bioburdens) are more susceptible to antimicrobial treatment. METHOD: Four separate and distinct models were performed by four separate biofilm research laboratories to evaluate the resistance of biofilms to antimicrobial treatments over time. These included a drip-flow biofilm model along with a hydrodebridement study, a porcine skin punch biopsy ex vivo model, a mouse chronic wound model and clinical longitudinal debridement study. RESULTS: All four models showed that, within the first 24 hours, the biofilm community was more susceptible to the selected antibiotics, and after maturing for up to 48 hours became increasingly tolerant. In each model, there was at least a 24-hour period in which the biofilms were more resistant to antibiotics. Each of the models utilised showed a significant decrease in the resistance of the biofilm/ burden to gentamicin for up to 24 hours with a confidence interval of at least 95%. The resistance increased in each of the models by 48 hours and reached original resistance levels by 72 hours. CONCLUSION: These data suggest the principles of biofilm based wound care, along with the use of serial debridement to continually remove mature biofilm, followed by biofilm wound management strategies, including topical antibiotics while the bioburden is still immature and more susceptible, are valid. PMID- 20852504 TI - Molecular diagnosis of Raoultella planticola infection of a surgical site. AB - Raoultella planticola has been rarely diagnosed in clinical specimens. A case of a polymicrobial surgical site infection primarily caused by R. planticola in a 66 year-old Caucasian male with a fractured left tibia after an open reduction internal fixation of his left ankle is described and confirms this organism to be an opportunistic human pathogen. This pathogen was diagnosed with rapid clinical molecular pathogen diagnostic methods, which allowed an appropriate therapy to be implemented, thereby improving prognosis. PMID- 20852505 TI - Prevalence of diabetic foot syndrome and its risk factors in the UK. AB - OBJECTIVE: To determine the prevalence of diabetic foot syndrome (DFS) and its risk factors (diabetic neuropathy, peripheral vascular disease, open wounds and mycoses of the feet) at GP practices in the UK in 2008. METHOD: We searched the IMS Disease Analyzer database, which stores representative information on approximately 4.2 million patients. All documented diagnoses of diabetes mellitus in 2008, based on either ICD-10 (international classification of diseases) codes or free text comments from doctors, were analysed. RESULTS: Data from 34,198 patients with type 2 diabetes (47.1% female, mean age 66.1 years [SD 15.1], mean diabetes duration 7.4 years [SD 5.1]) and 2,576 patients with type 1 diabetes (43.2% female, mean age 39.2 years [SD: 18.0], diabetes duration 11.0 years [SD: 6.1]) were analysed. DFS was registered in 7.6% (95% CI: 6.6-8.6) of patients with type 1 diabetes and 8.5% (95% CI: 8.2-8.8) with type 2 diabetes. Many more patients were at high risk of developing DFS, with diabetic neuropathy, diabetic angiopathy, foot mycoses and/or open wounds of the feet. CONCLUSION: Results from this analysis of one of the large representative databases show that even though the prevalence of DFS among patients with diabetes mellitus is relatively low, the prevalence of its main risk factors is high. Preventive efforts should target these risk factors. PMID- 20852506 TI - Living with wound-associated pain: impact on the patient and what clinicians really think. AB - OBJECTIVE: To gain an insight into current practice and practitioner opinions on the recognition and management of wound-associated pain as compared with that previously presented in the literature. METHOD: Delegates who attended Wound Expo 2009 and participated in the interactive learning workshops held in the wound pain educational zone were surveyed. This was therefore a convenience sample. All participants signed a consent form prior to the interactive voting session to allow their anonymous responses to be used. The survey consisted of questions that had been devised to generate a clearer insight into current practice and opinion on wound-associated pain. Questions were posed during the workshop (displayed in a PowerPoint presentation) and attendees were given 10 seconds per question to select their preferred responses, each using an individual electronic interactive voting panel. All responses were recorded electronically and the data were subsequently analysed. RESULTS: The survey identified a number of positive approaches used by the delegates in their assessment of wound-associated pain. These include a high level of continuous assessment, an awareness of the wide range of pain assessment tools available and an acknowledgement of the need for a multiprofessional approach to pain management. CONCLUSION: The findings highlight the issues clinicians face in the recognition, assessment and management of wound associated pain during their everyday practice. Although many of these issues are difficult to resolve entirely, a fundamental element is that the patient's experiences must be assessed and documented in a consistent and informed manner, and then appropriate management actions taken. PMID- 20852507 TI - CONSORT 2010 statement: updated guidelines can improve wound care. AB - There is a growing need to add to the evidence base in wound care. Randomised controlled trials (RCTs) are one methodological approach for this. The CONSORT statement, which provides guidance on how to conduct a rigorous RCT, was updated earlier this year. Implementation of the Consort statement will clarify to the reader what exactly was done in the RCT, to whom and when. In this way, practitioners and health-care providers can determine its validity. The Consort statement has the potential to play a crucial role in influencing the quality of research and clinical practice, and so to improve wound care. The benefits of Consort 2010 are clear; the challenge is for clinicians and researchers to use it. PMID- 20852508 TI - Human skin allografts as a useful adjunct in the treatment of purpura fulminans. AB - OBJECTIVE: The aim of this report is to discuss the role of human skin allografts in surgical coverage procedures for patients with purpura fulminans. METHOD: We describe cases of purpura fulminans in three adults and one infant treated at our burns unit between October 2006 and January 2008. RESULTS: The application of cryopreserved human skin allografts allowed us to obtain immediate wound closure after necrosis excision and enabled our team to subsequently perform autografts on favourable graft recipient sites. CONCLUSION: Recourse to human skin allografts must be considered a pertinent therapeutic option in patients with purpura fulminans. PMID- 20852510 TI - Hydroxyurea-induced foot ulcer in a case of essential thrombocythaemia. AB - OBJECTIVE: To illustrate the association between hydroxyurea and the development of ulcers. METHOD: A case study is presented, in which histological changes, mean corpuscular volume (MCV) and transcutaneous oxygen tension (TcPO2) were all measured and analysed, both during hydroxyurea treatment and following it's discontinuation. RESULTS: Two months following the cessation of hydroxyurea therapy, the patient's ulcer had healed completely. Biopsy specimens taken before and after its discontinuation showed a considerable improvement in vascularity, with a capillary density 6.28 times higher after discontinuation of the drug. TcPO2 was just 8mmHg at the first measurement, and this increased to 65mmHg at the second. CONCLUSION: These findings suggest deficient neovascularisation and circulation during hydroxyurea treatment. Changes in MCV also appeared to have an effect on the progress of wound healing, which supports the hypothesis that macroerythrocytosis may be involved in the development of these rare ulcers, via impairment of the microcirculatory rheology. PMID- 20852511 TI - Ranking palliative and end-of-life care. AB - It is easy to be sceptical about tables that rank services but there is also something quite intriguing about rankings-with an inevitable curiosity about who made it to the top of the table. It is with this in mind that I read a report entitled The Quality of Death: Ranking End-of-Life Care Across the World (Economist Intelligence Unit, 2010). PMID- 20852512 TI - A L30 million pledge for children's palliative care leads to a race against the clock to secure funding. AB - The government recently announced that up to L30 million would be made available to the children's palliative care sector in England, on the condition that the money is spent by March 2011. The challenge now is to ensure this money is spent on sustainable projects to develop children's palliative care before time runs out. PMID- 20852513 TI - Evaluating the impact of education on knowledge and confidence in delivering psychosocial end-of-life care. AB - Psychosocial care has been identified as an area of high priority in the UK. At a local level, staff cited a lack of knowledge and understanding of the key features of psychosocial care, resulting in low confidence in delivering effective psychosocial care. The aim of this evaluation was to review the impact of education on the knowledge and confidence of hospice staff in delivering effective psychosocial care. Qualitative and quantitative data was collected in order to facilitate consideration of the impact of education. Nine participants from the multiprofessional team completed the training programme. Findings demonstrated an increase in confidence scores for all participants linked with an increased understanding of psychosocial care. Audio-taping and observation of an interaction were found to be valuable when applying theory, and participants reported a change in their practice. The results suggest that attendance on the 3 day programme has increased the health professionals' understanding of psychosocial care and their confidence in providing psychosocial care in the clinical setting. PMID- 20852514 TI - Medical error in the hospice setting: exploring the perspectives of management staff. AB - This study explores the experiences of health professionals in managerial roles at various levels in child and adult hospice care in northern England, studying perspectives around managing medical error, the issues that arise, and the challenges faced. A multicentred, descriptive, exploratory design was adopted. The sample comprised 10 hospice managers (five deputy and five senior managers) from four hospices (two adult and two children's) in the north of England. Participants took part in individual semi-structured interviews, which lasted between 45-60 minutes each. Interviews were transcribed and analysed by a team of three researchers, including two health psychologists and one nurse using a qualitative analytic framework. Emerging themes appeared to be inter-related and were ultimately linked to two meta-concepts; underpinning and fundamental to the data, these issues were intrinsically tied to all emerging themes. Primary themes were defined by their explanatory power and regularity. Primary themes highlighted the impact of managing error on management teams at a professional and personal level, the challenges for error management in hospice settings, the use of error management tools, and the conceptualization of blame in these settings. The strong influence of the health-care setting in which an error takes place on the outcomes of an error event for the health professional, managers, health-care organizations, and ultimately patients was evident. PMID- 20852515 TI - What does respite care mean for palliative care service users and carers? Messages from a conceptual mapping. AB - Over the coming years, as an ageing population with multiple chronic illnesses increases, the number of carers and paid carers is set to decrease. There is, therefore, an urgent need to understand what types of services are most supportive in helping to sustain caring relationships. Respite care is frequently mentioned as a key factor in supporting family carers and improving their quality of life but there is a lack of research to support its efficacy. This paper will present a conceptual map of respite care in order to promote a greater understanding of the multiple tensions that the palliative care respite literature reveals. As learning more about carer's needs and the complexities of the caring relationship develops, it is an appropriate time to map the key messages from the literature to help us understand what respite care does actually mean to palliative care service users and carers. PMID- 20852516 TI - Developing nurse independent prescribing in a specialist palliative care setting. AB - Nurse independent prescribing (NIP) has been at the centre of government policy in the UK to improve patient care. Clinical nurse specialists (CNSs) are key workers in the delivery of specialist palliative care services, and NIP enables them to improve the quality of care their patients receive. However, there are known barriers that prevent qualified NIPs from prescribing, including lack of NIP policies in organizations and difficulties in ensuring ongoing mentoring and support. This article describes how an NIP policy was developed and introduced within an independent specialist palliative care setting (hospice community team). The process undertaken by the NIP policy team is described as well as approaches to overcoming potential and actual barriers. Challenges in creating a NIP policy are explored, including such issues as managing off-label prescribing, obtaining peer support and securing insurance cover. As CNSs often work independently, it was felt important to provide mentoring following qualification by senior medical staff in order to gain confidence in their new roles in NIP. Wider influences, such as initiatives to increase care of patients in the community and 7-day working by CNSs are also considered. This article aims to support other health care providers, both in the independent and national health sectors, who plan to deliver the NIP agenda. Barriers to NIP must be addressed in order to achieve success and to ensure specialist palliative care nurses trained in NIP are able to put their extended skills into practice. PMID- 20852517 TI - Reviewing the evidence for prescribing steroids for non-specific symptoms in patients with advanced cancer. AB - his article sets out to review the evidence for prescribing steroids for non specific symptoms experienced by patients with advanced carcinoma. Factors influencing the prescription of steroids, for example, drug interactions and their side effects are explored. Furthermore the importance of including patients in prescribing decisions and promoting adherence is discussed. The evidence shows that the benefit of steroids is felt within a week of commencement but is usually not sustained much beyond two weeks. In practice there appears to be inconsistent prescribing and monitoring of steroids, creating a need for a change of practice to promote high quality care for patients. PMID- 20852520 TI - Dying at home: access should be equitable. AB - For a document that is wholly based on statistics, the recent report from the National End of Life Care Intelligence Network (NEoLCIN) on variations in place of death in England (NEoLCIN, 2010) is fascinating reading. It highlights the differences across the country in where people die and challenges assumptions about what can and can't be achieved for people who want to die at home. Too often we judge effectiveness on the basis of the individual case. This report helps us to look beyond personal experience and individual services. It sets a benchmark against which to judge how health and social care services are supporting people to die at home. PMID- 20852521 TI - Treating shingles (herpes zoster) in the older person. AB - Shingles is a common problem and will affect a fifth of the population at some time in their lives (Opstelten, 2005). It may occur at any age but the incidence and severity of the condition increases with age (Johnson et al, 2008). It is therefore likely that community nurses, in their day-to-day work with older people, will encounter the problem. If they are able to recognize it and arrange treatment in the earlier stages of its development, they will be in the position of helping to speed the resolution of the rash and reduce the debilitating consequences that may follow, in particular in the form of post-herpetic pain, which may affect the patient for weeks, months or even years after the active stage is over, visual complications following ophthalmic herpes zoster or zoster encephalitis that may be fatal. Apart from pain and future of the patient, the condition may require the disruptive and expensive option of hospital admission. The possibility of the introduction of a new vaccine, that would reduce the incidence of shingles, will also be discussed. PMID- 20852522 TI - Challenging times for skin diseases and the elderly. AB - Over the past three years the British Skin foundation has awarded over L2.2 million to research projects looking at a huge/multitude of different skin diseases in the UK. It is a lot of money but research is expensive and there remains a long way to go before many of these skin diseases are fully understood. Awareness of skin disease remains one of our biggest issues. There are such a vast number of skin diseases, it would be impossible for any medical professional to understand them all. Nonetheless, there a few skin diseases that tend to affect the elderly more frequently than others, so it is worth keeping an eye out for the symptoms of them while at work. PMID- 20852523 TI - District nurse role in end-stage COPD: a review. AB - District Nurses (DNs) are core providers of end-stage care in the community but appear to have little contact with patients suffering from non-malignant diseases, such as chronic obstructive pulmonary disease (COPD). This review found limited literature describing the role of DNs in end-stage COPD care, and the studies that did touch on the subject restricted their discourse to the frequency of interaction. A clear bias of end-of-life services to patients with malignancy was noted, as well as a call for community services to extend care to all end stage patients regardless of underlying disease. In addition, there was a further call for DNs to apply a more holistic approach to care, as described in the literature. Finally, it was clear that while ongoing community intervention is necessary for end-stage COPD patients, support and training is essential to equip DNs to care for these vulnerable patients. PMID- 20852524 TI - The Long Term Conditions Delivery Support (LTC DS) Team. AB - The LTC DS Team is a small, NHS-funded organization with one team member based in each of the ten Strategic Health Authority regions around the country. Over the past few years, the direction and focus of our work has had a few twists and turns, not least of all owing to the recent change in government. Our remit is, broadly speaking, to support the implementation of government policy, and we do this by supporting service improvement and innovation for people with long-term conditions, with an emphasis on neurology. PMID- 20852525 TI - Medicine management: pharmacokinetic update for community nurses. AB - Medication management is a major part of nursing practice. Ensuring safety in medication management is all the more important in the community, where patients are not under constant observation of a health-care professional. One of the prime factors in maintaining safety with medication is establishing and maintaining adequate and safe drug levels in the body. Before drugs can have an effect, they are acted upon by the body; these processes change the drug, mainly to enhance its removal from the body. Study of these processes is called pharmacokinetics and includes the processes of absorption, distribution, metabolism and excretion. Pharmacokinetic processes determine the time of onset and duration of drug action. In turn drug pharmacokinetics is affected by concordance with medication regimes and systemic illness; factors which may render the medication useless or toxic. This article introduces the reader to the principles of pharmacokinetics and shows the link between pharmacokinetics and disease and administration of multiple drugs (polypharmacy). With an aim to equip the community nurse with a better understanding of how to recognize and foresee problems associated with medication management. PMID- 20852526 TI - Regulation of herbal medicines. AB - Complementary and alternative medicine is an increasingly popular form of health intervention used by millions of people in the UK each year. The demand for such therapies has seen their use grow and many have been adopted by district nurses as a supplement to the treatment and care they provide their patients. The use of complementary and alternative medicine is largely unregulated and this has led to increasing call for more effective regulation to ensure patient safety. Of particular concern recently has been the need to regulate the use of herbal medicines. This article considers the proposals for the reform of herbal medicines and professional and legal implications for district nurses who use complementary and alternative medicine in their practice. PMID- 20852527 TI - Recognition and treatment of anaphylaxis in the community. AB - Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction characterized by rapidly developing airway and/or breathing and/or circulation compromise usually associated with skin and mucosal changes. Calling 999 for an ambulance, positioning the patient appropriately and administering adrenaline intramuscularly are the key initial treatment and management options. The aim of this article is to discuss the recognition and treatment of anaphylaxis in the community. PMID- 20852529 TI - Consent and capacity: a guide for district nurses. AB - The Mental Capacity Act 2005, which came into force in 2007, sought to provide a statutory framework to facilitate empowerment and provide protection to individuals who lack capacity. District nurses must be aware of the legislation regarding mental capacity (Nursing and Midwifery Council, 2008) and understand how and when they may need to assess decision-making capacity. The article explores the legal and ethical issues surrounding consent, and seeks to inform district nurses as to the guidelines used in assessing a person's capacity to consent, along with best interests policy. PMID- 20852530 TI - Drug use variations. AB - Medications play a large part in today's health-care delivery. Indeed, it is this centrality to health care that has fuelled various debates about the cost and benefits of different drugs, especially expensive medicines associated with cancer treatments and multiple sclerosis (MS). Undoubtedly, medications have been responsible for improved patient outcomes for treatable conditions, however, funding of medications can impact upon the available resources for other health services. In an attempt to understand medication usage in the UK, Professor Sir Mike Richards (Department of Health, 2010) examined the extent and potential causes of international variations in medication usage. The data revealed considerable variation both between countries and within countries regarding the treatment of different diseases. PMID- 20852531 TI - Tissue viability 2010 -2015:from good to great. AB - This paper explores the challenges of the changing face of the NHS with specific relation to the challenges for community-based tissue viability services following the publication of government documents that identify the need to provide a quality service for all patients in health-care settings. Patients receiving care in the community is paramount to the success of the NHS going forward; service redesign, improvements in quality, outcome tracking, seamless discharge and patient satisfaction/responsibilities has been heralded as the core prerequisites of successful services. Tissue viability is a relatively young specialism, with most services being nurse led and established less than 15 years. It is argued that in order to continue to be successful as a specialism, tissue viability has to challenge traditional patient and nursing beliefs and values. PMID- 20852532 TI - Is wound management training in primary care good enough? PMID- 20852533 TI - An interview with Jacqui Fletcher. PMID- 20852534 TI - Innovative solutions to daily challenges. AB - Today's clinicians face the daunting task of finding the best cost-effective and clinically appropriate solutions to ever complex wounds. The right combination of dressings help to maintain a moist environment, successfully manage exudate levels and reduce complications. This article seeks to explore the fundamental issues behind successful dressing choice and the new products that are becoming available for use as tools in the ongoing wound care initiative. In particular, the antimicrobial dressing Cutimed(r) Sorbact(r) used in conjunction with the exudate management properties of Cutimed(r) Siltec(r) and Cutisorb(r) Ultra by BSN medical will be examined with the commencement of three clinical evaluations. PMID- 20852535 TI - The Lindsay Leg Club Foundation: update. PMID- 20852536 TI - Achieving effective outcomes: monitoring the effectiveness of the Softform Premier Active (TM) mattress. AB - The identification of pressure-relieving mattresses to achieve positive clinical outcomes for patients and financial considerations for organizations is a challenge for health-care staff. This article reports on an audit undertaken within a primary care trust to determine the clinical and cost effectiveness of the Softform(r) Premier Active mattress. Preliminary results have been previously published (Stephen-Haynes, 2009) and are presented here in full. PMID- 20852537 TI - A new era for WCAUK. PMID- 20852538 TI - Chronic leg ulceration in the community: changing the focus. AB - Compression therapy is considered the gold standard for healing chronic venous leg ulceration, and impressive healing rates are achievable for many patients. Unfortunately, this condition is chronic, characterized by frequent recurrences and, for some patients, ulcer healing may never occur. Within community services, commissioners of nursing services tend to focus on complete ulcer healing within a defined timescale as quality indicators. The challenge, therefore, will be for community nurses to demonstrate alternative but equally effective patient-centred outcome measures for nursing interventions when healing is delayed or does not occur. The current government health policy encourages active patient involvement in treatment, with an emphasis on self-care/management for patients with chronic conditions. Self-management interventions, such as the Expert Patient Programme (Department of Health, 2001) for chronic conditions, have been positively evaluated and have demonstrated considerable benefits for patients in terms of pain reduction and improved psychosocial wellbeing. This article briefly discusses the outcomes of such interventions and suggests that nurse-led self care programmes could be adapted for leg ulcer patients in order to provide alternative outcome measures for nursing interventions when ulcer healing may not be achievable. This article also gives an overview of current innovations developed to encourage patient involvement and self-care in this client group. PMID- 20852539 TI - Safer cut: revelations of surgical harm through a national database. PMID- 20852540 TI - Can we cure rheumatoid arthritis? PMID- 20852541 TI - We need time for training. PMID- 20852542 TI - Assessment and treatment of trigeminal neuralgia. AB - Patients with trigeminal neuralgia, a rare facial neuropathic pain, present to both medical and dental specialists. International guidelines on diagnosis and management of trigeminal neuralgia provide a useful framework for this article. PMID- 20852543 TI - Guillain-Barre syndrome: a review. AB - Guillain-Barre syndrome is an autoimmune disease which is a common cause of acute neuromuscular paralysis and should be suspected in all patients with unexplained motor weakness. Specific management strategies are more effective if given early in the course of the disease. PMID- 20852544 TI - Spontaneous intracerebral haemorrhage: a clinical review. AB - This article provides a clinical overview of spontaneous intracerebral haemorrhage, focusing on clinical aspects of the aetiology, diagnosis and management (both in the emergency department and in a critical care environment) of this important and devastating condition. PMID- 20852545 TI - Dramatic parasomnias: recognition and treatment. AB - As each of the many parasomnias requires its own specific treatment, confusion between them can have serious consequences. By recognizing their distinctive features, misdiagnosis can be avoided and the appropriate management decided. PMID- 20852546 TI - The Limberg flap in sacrococcygeal pilonidal sinus disease. AB - Pilonidal sinus disease can sometimes pose a surgical challenge because of prolonged wound healing problems and recurrence rates. This article describes a simple transposition flap which can be used for pilonidal sinus disease by general surgeons with good results. PMID- 20852547 TI - Cranial computed tomography 2: use in clinical practice. AB - The importance of cranial computed tomography in the diagnosis and follow up of intracranial pathology cannot be underestimated. Clinicians at every level should have a basic understanding of this technique. This second part discusses the practical use of computed tomography in the clinical setting. PMID- 20852548 TI - Surgical education: the new curriculum and training in the UK. AB - Surgical education in the UK has been changing in the past two decades, as a result of the Calman reforms and Modernising Medical Careers. The surgical curriculum has been planned to promote global competence development and based on modern concepts of adult learning. PMID- 20852549 TI - Involving patients in clinical education. AB - The interdependent relationship between the clinical teacher, the learner and the patient is a vital part of clinical education. Changing health services and patient expectations have stimulated the need for teachers to consider patients' rights and needs as active participants and partners in clinical teaching. PMID- 20852550 TI - Cerebral venous sinus thrombosis: a diagnosis not to be missed. PMID- 20852551 TI - Crohn's disease and enterovesical fistulae: common things are common. PMID- 20852552 TI - Nocturia, enuresis and snoring: an unusual combination in an adult? PMID- 20852553 TI - Sir Gordon Gordon-Taylor: master surgeon in peace and war. PMID- 20852554 TI - We need time for training. PMID- 20852555 TI - Lithium enabling use of clozapine in a patient with pre-existing neutropenia. PMID- 20852556 TI - Analgesia for total knee arthroplasty. PMID- 20852557 TI - Information governance: a guide for the foundation year doctor. PMID- 20852558 TI - The applied anatomy of rectal examination. PMID- 20852559 TI - Radiology of acute injuries to the hand and fingers. PMID- 20852560 TI - Diagnosis and management of degenerative neck pain. PMID- 20852561 TI - Discharge summaries: a guide for foundation doctors. PMID- 20852562 TI - So you want to be...a geriatrician. PMID- 20852563 TI - Without science, we are nothing. PMID- 20852564 TI - Improving care: the power of the pen. PMID- 20852566 TI - The Leg Club model: a survey of staff and members' perceptions of this model of care. AB - OBJECTIVE: To determine the Leg Club members' perceptions of the Leg Club as a model for delivery of service. METHOD: An explorative qualitative approach was used. All members and staff at two Leg Clubs in the UK were invited to participate. They were asked to nominate five key words that described their views of the Leg Club model of care. The researcher and a research supervisor then counted them and decided on categories. Members' themes were verified by 10 randomly chosen Leg Club members and staff themes by five randomly chosen staff. RESULTS: All of the 85 Leg Club members and 15 staff approached agreed to take part. Categories identified for the Leg Club members were: sociability, enabling, knowledge and experience, interpersonal relationships, caring and quality. Categories identified for Leg Club staff were: camaraderie, education, empowerment, sociability and tiredness. CONCLUSION: These results indicate that the community Leg Club environment provides benefits in addition to those of guidelines, wound care expertise and evidence-based care. While the small sample size limits the generalisability of these exploratory data, the results identify the positive views of Leg Club members and highlights the need for further research. Similar data is not available for other health care delivery methods, so this also warrants further exploration. PMID- 20852565 TI - Flammacerium in the formation and stabilisation of eschar in chronic wounds. AB - OBJECTIVE: To determine the effectiveness of Flammacerium, a topical treatment used in the treatment of burns, in the stabilisation of necrosis in non-healing wounds. The therapy is designed to prevent the risk of infection, stop necrosis from spreading and improve the patient's quality of life. METHOD: This retrospective survey involved patients with necrotic, non-healing wounds who had been treated with Flammacerium. In all cases, debridement was contraindicated. Available data on wound evolution were collected. RESULTS: Ninety-nine patient files were analysed and the wound aetiologies included in the survey were classified as arterial (n=42), malignant (n=5), pressure ulcers (n=30), traumatic wounds (n=10) and other wounds (n=12). The formation of a leather-like eschar induced by topical use of Flammacerium improved pain management, decreased exudate levels and malodour, and had a positive effect on quality of life, increasing patient comfort, participation in social activity and psychological wellbeing. Following application of the cream, an eschar develops that strongly adheres to wound edges. By preventing the necrosis from spreading, this gave the practitioners more time to prepare for subsequent treatment, including skin grafting. CONCLUSION: Flammacerium seems to be effective in the stabilisation of necrosis in non-healing wounds in which debridement is contraindicated. However, this study is limited by its retrospective nature. A prospective study will hopefully confirm and strengthen these results. PMID- 20852567 TI - Quality of nursing care from the perspective of patients with leg ulcers. AB - OBJECTIVE: To investigate and analyse the quality of nursing care in a primary care setting from the perspective of patients with leg ulcers and determine the subjective importance that patients attach to various aspects of quality of care. METHOD: All of the patients with leg ulcers at 15 primary care centres in the south east of Sweden were invited to participate. They were given the short version of the Quality from the Patient's Perspective questionnaire (QPP) to fill in. This included a number of closed and open questions relating to their perceptions of the quality of their nursing care and the importance of this care to them. RESULTS: Overall, the patients in this study perceived that the quality of nursing care was high. However, important areas for improvement were revealed, including the need for an increase in patient-focused care, continuity of care and better pain relief. CONCLUSION: To address the weak points highlighted by the study, we recommend that nurses explore patient perceptions of pain in greater detail and invite patients take a more active role in the management of their leg ulcers. PMID- 20852568 TI - Ward nurses' use of wound dressings before and after a bespoke education programme. AB - A survey of ward nurses in medical, surgical, orthopaedic and rehabilitation specialties in relation to their care of wounds and their choice and use of wound dressings was carried out in May and August 2009 at St Mary's Hospital. Isle of Wight, UK. The objectives were to find out the distribution of wound types, and their characteristics, that were treated by ward nurses in the hospital, and to assess clinical practice in the use of wound dressings, before and after a bespoke programme of education and training. A visual framework to aid the ward nurses in the choice of dressings and frequency of change was introduced after the May 2009 survey. Following the nurses' education and training programme a repeat survey, using the same methodology, was conducted in August 2009. In the initial survey, 172 wounds were included (mean number of wounds per patient 1.64) and in the repeat one, 159 (mean number of wounds per patient 1.54). In both phases of the survey, the most common wound type was pressure ulcers, followed by surgical wounds; over 60% of the wounds were pressure ulcers, of which around half were category 1, and one-third were category 2. No category 4 ulcers were recorded. About one-third of the wounds had a duration of more than 21 days. On average, wound dressings were left in place for between two and three days, with 35% of dressings being changed on a daily basis. The mean cost of dressings per wound per week was observed to be lower in the repeat survey than in the initial one (L9.02 and L11.23 respectively). The number of undesirable reasons for changing the dressing was lower in the second phase than the first. The methodology of the surveys provided meaningful and valuable results over a short timescale, and increased understanding of wound types, their characteristics, and clinical practice. The surveys showed that data that can be collected in a short period using a simple tool can yield complex and revealing data trends. They also showed that an education programme followed by a re-survey can improve practice and reduce the costs of wound care. PMID- 20852569 TI - TGF-beta in wound healing: a review. AB - TGF-beta, a growth factor involved in various stages of the wound healing process, exists in three different isoforms. Experimental models have shown these isoforms to be functionally different and one of them, TGF-beta3, has the potential to reduce scarring in clinical practice. This literature review explores the role of TGF- in wound healing, examining the research to date. PMID- 20852570 TI - Management of a complex wound in a person with spinal cord injury and mental illness. AB - This paper highlights the important nexus between physical and mental health by examining a case concerning a patient with a lower spinal cord injury and mental illness who subsequently developed two pressure ulcers. It examines how clinicians can benefit from looking beyond typical assumptions when caring for an individual with complex needs in the community setting. In such circumstances, the need for a holistic and collaborative approach to wound care is vital. This involves taking into account the individual's mental health care needs, which can be overlooked in the first instance. Recommendations for clinical practice centre on involving the patient in his or her dietary, psychological and physical care, thereby helping to build resilience to any mental health problems and promoting a positive physical recovery. PMID- 20852571 TI - [Physicians in the frontier research - what role?]. PMID- 20852572 TI - Metabolic syndrome, inflammation and atherosclerosis - the role of adipokines in health and in systemic inflammatory rheumatic diseases. AB - Cardiovascular (CV) events are among the leading causes of morbidity and mortality in patients with inflammatory rheumatic diseases. It has been hypothesized that, in addition to the traditional CV risk factors, inflammation is a major contributor to atherogenesis. Metabolic syndrome (MetS) stands for a cluster of risk factors associated with insulin resistance and increased abdominal fat. Inflammation and MetS are intimately linked. Inflammatory biomarkers are frequently elevated in people with MetS and, conversely, the prevalence of MetS is higher in patients with chronic inflammatory rheumatic diseases, such as Rheumatoid Arthritis and Systemic Lupus Erythematosus. Inflammatory cytokines impair insulin sensitivity and can induce an adverse lipoprotein profile as seen in MetS. Furthermore, the presence of MetS correlates with increased subclinical atherosclerosis, major adverse CV events and death, making an important contribution to the CV burden in inflammatory diseases. Adipose tissue has recently emerged as an active organ that produces and secretes numerous mediators - adipokines - particularly relevant in energy homeostasis, inflammation, immune regulation and angiogenesis. These mediators arise as a potential link between MetS, inflammation and atherogenesis. Understanding the complex regulation and function of adipokines in health and disease is a priority since it may lead to new preventive and therapeutic interventions aiming to decrease CV risk. PMID- 20852573 TI - Central auditory processing in patients with systemic lupus erythematosus. AB - Systemic Lupus Erythematosus (SLE) patients can also present neuropsychiatric disorders, such as impaired memory and attention. Central auditory processing depends on a great number of skills controlled by the central nervous system. OBJECTIVE: To characterize the performance of SLE patients, with and without neuropsychiatric disorders (NP), in central auditory processing tests. PATIENTS AND METHODS: A prospective controlled study of Dichotic Speech and Temporal Processing Tests was carried out at a tertiary teaching Institution. Three groups were formed with 20 individuals each, totalizing sixty women with age varying from 18 to 48 years: Group I - SLE patients without neuropsychiatric disorders; Group II - SLE patients with neuropsychiatric disorders as well; and Group III - age and gender matched healthy controls. RESULTS: Dichotic Speech Test showed similar results for patients in Group I and for healthy controls; however, most of the patients in Group II presented impaired performance with great variability of response. SLE patients (Groups I and II) presented a significantly lower performance in Temporal Processing tests than controls. CONCLUSION: SLE patients especially those with neuropsychiatric disorders presented impaired central auditory processing, which may contribute to the memory and attention impairment. PMID- 20852574 TI - Effect of wrist involvement on median nerve electrophysiology in juvenile idiopathic arthritis. AB - OBJECTIVES: Localized compression of the median nerve due to wrist arthritis is a frequently reported complication in adult patients with rheumatoid arthritis. However, in only two cases median nerve compression has been reported in juvenile idiopathic arthritis (JIA) patients. In this study, we aimed to assess the effect of wrist involvement on median nerve electrophysiology in JIA patients. PATIENTS AND METHODS: Thirty-three patients fulfilling the diagnostic criteria for JIA according to the International League of Associations for Rheumatology and twenty three healthy controls were enrolled. All subjects underwent a thorough neuromuscular examination and median and ulnar nerve conduction studies. The presence of wrist arthritis was noted. Complete blood count, erythrocyte sedimentation rate, C reactive protein, renal/liver function tests were measured. RESULTS: Sensory examination and provocative tests for CTS were normal both in patient and control groups. Age, height and electrophysiological data of the subjects were compared within three groups: JIA patients with wrist arthritis, those without wrist arthritis and healthy controls. None of the electrophysiological data of median nerve revealed significant differences between groups. CONCLUSIONS: In the light of our preliminary results, the median nerve seems not to be affected due to wrist involvement in patients with JIA. PMID- 20852575 TI - Mortality and functional impairment after hip fracture - a prospective study in a Portuguese population. AB - OBJECTIVES: Osteoporotic hip fractures (HF) are a major cause of morbidity and mortality with increasing familial, social and economic repercussions. The objectives of this paper were to evaluate the status vitae at 6 and 12 months of a cohort of patients with an osteoporotic HF and the risk factors for 12-month mortality as well as to evaluate the functional outcome and the overall health perception of these patients. PATIENTS AND METHODS: We conducted a 12-month follow-up evaluation of a cohort of 184 patients older than 65 years admitted to our centre with a non-pathological osteoporotic HF from January 1st to December 31st 2007. Baseline data collection was performed in the first 72 hours after admission and, 12 months later, a second evaluation was conducted, by telephone in order to ascertain their status vitae and functional status. The magnitude of sex--specific, age-adjusted associations between potential prognostic factors and mortality was estimated using hazard ratios (HR) and respective 95% confidence intervals (95%CI), calculated using Cox's proportional hazards model. RESULTS: It was possible to ascertain the status vitae in 164 (89.1%) patients. Overall 12 months mortality was 26.8% (48.3% in males and 22.2% in females). Mortality was higher in patients that became bedridden, were unable to walk again, were admitted to a hospital during the follow-up for any cause and who became dependent in their daily living activities. After discharge, physical therapy and ability to walk again were associated with a lower risk of death. Most of the patients reported a decline of their overall health-related quality of life. More than 75% of patients became totally dependent after HF. CONCLUSION: This study reinforces the HF poor outcome. Twelve-month mortality rates were similar to the estimates obtained in other studies, although the 6-month's mortality was higher. Physical deterioration and loss of independence in activities of daily living were evident in this study and constituted major factors for low self-esteem and deterioration of quality of life. Our findings may constitute an evidence for action in this particular population, with an active search for means to improve the outcome of HF in these patients. PMID- 20852576 TI - [Behcet's disease - Infliximab in the treatment of mucocutaneous manifestations]. AB - Behcet's disease (BD) is chronic, relapsing and multisystem inflammatory disorder, whose diagnosis is essentially clinical. In recent studies, the antagonists of tumor necrosis factor alpha have shown good results in the treatment of mucocutaneous manifestations of BD. The authors describe three cases of BD with serious mucocutaneous involvement treated with infliximab. CLINICAL CASE 1: A 16-year-old female patient with an 8-year history of severe bipolar aphtosis. A rapid clinical response to biological therapy was verified, with partial and total remission of ulcers at 2nd and 6th week of treatment, respectively. CLINICAL CASE 2: A 56-year-old female patient with chronic nodular panniculitis of lower limbs, arthralgias and orogenital ulceration. After 6 weeks of treatment with infliximab, a complete clinical remission was observed. CLINICAL CASE 3: A 50-year-old female with a 15-year history of relapsing oropharyngeal ulceration. A good clinical response to biologic therapy was observed. At 22nd week it was interrupted because frequent dental abscesses. In our experience, infliximab is an effective therapeutic alternative that should be considered in the presence of mucocutaneous manifestations resistant to conventional therapies. PMID- 20852577 TI - [Osteoporotic fractures in pregnancy - conjunction of factors?]. AB - Pregnancy-associated osteoporosis is rare and self--limiting. We report two clinical cases, with beginning of back pain during a 1st pregnancy. In the 1st case, the pain became severe after a fall, and she had other risk factors of fracture, like low calcium intake, and a treatment with thyroid hormones for weight loss. In the 2nd case, we did not find any. Both were diagnosed of osteoporosis by bone densitometry and radiology (multiple vertebral compression fractures). They had a favorable progression with life-style measures, calcium and vitamin D supplementation, and oral biphosphonate in the 2nd case. Nevertheless, both still suffer the impact. PMID- 20852578 TI - [Hip arthritis in an young adult - a diagnosis to consider]. AB - Osteoarthritis is the most common articular degenerative disease and can be classified as primary or secondary. The last one must be excluded in the context of a young adult. Optimal management requires early diagnosis and awareness of the risk factors (more importantly "modifiable" ones) that can affect the prognosis. The authors present a case of a young man who complaint about mechanical groin pain because degenerative changes on hip joint. After patient assessment it was encountered ultrasonographic typical images of gout in the context of asymptomatic hyperuricemia. PMID- 20852579 TI - [Hip pain in young adults - a case report and review of the literature]. AB - A painful hip in a young adult may have its origin in different aetiologies, and both clinical history and physical examination are crucial for diagnostic guidance. The authors describe the case of a 28 year-old male, amateur football player, suffering from insidious progressive left cruralgia, with nocturnal and prolonged high-impact loading activities exacerbation, resulting in significant impairment of exercise tolerance, gait and other daily activities. He had a transitory response to non-steroid anti-inflammatory drugs. Besides slight limitation of hip internal rotation and an antalgic gait pattern, physical examination was normal. Laboratory tests and conventional X-ray of the left hip were normal. CT and MRI depicted findings compatible with an osteoid osteoma in the femoral cervico-cephalic transition and signs of a potential "cam" type femoro-acetabular impingement. The adopted therapeutic strategy consisted on radiofrequency excision of the nidus of osteoid, with complete clinical recovery after 6 months. PMID- 20852580 TI - [Two cases of Nail-Patella Syndrome (hereditary arthro-onychodisplasia)]. PMID- 20852581 TI - [Osteopokilosis]. PMID- 20852582 TI - [Giant rheumatoid synovial cyst of the shoulder]. PMID- 20852583 TI - Thyroid gland: Early adjustment of levothyroxine treatment in pregnancy. PMID- 20852584 TI - Pediatrics: Supplements: when will vitamin D have its day in the sun? PMID- 20852585 TI - Diabetes: Finding and treating gestational diabetes mellitus-does it help? PMID- 20852586 TI - Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. AB - Hypovitaminosis D is a prevalent disorder in developing countries. Clinical manifestations of hypovitaminosis D include musculoskeletal disorders, such as nonspecific muscle pain, poor muscle strength and low BMD, as well as nonmusculoskeletal disorders, such as an increased risk of respiratory infections, diabetes mellitus and possibly cardiovascular diseases. In developing countries, the prevalence of hypovitaminosis D varies widely by and within regions; prevalence ranges between 30-90%, according to the cut-off value used within specific regions, and is independent of latitude. A high prevalence of the disorder exists in China and Mongolia, especially in children, of whom up to 50% are reported to have serum 25-hydroxyvitamin D levels <12.5 nmol/l. Despite ample sunshine throughout the year, one-third to one-half of individuals living in Sub Saharan Africa and the Middle East have serum 25-hydroxyvitamin D levels <25 nmol/l, according to studies published in the past decade. Hypovitaminosis D is also prevalent in children and the elderly living in Latin America. Risk factors for hypovitaminosis D in developing countries are similar to those reported in Western countries and include extremes of age, female sex, winter season, dark skin pigmentation, malnutrition, lack of sun exposure, a covered clothing style and obesity. Clinical trials to assess the effect of vitamin D supplementation on classical and nonclassical clinical outcomes in developing countries are needed. PMID- 20852587 TI - Genetic causes and treatment of isolated growth hormone deficiency-an update. AB - Isolated growth hormone deficiency is the most common pituitary hormone deficiency and can result from congenital or acquired causes, although the majority of cases are idiopathic with no identifiable etiology. Known genes involved in the genetic etiology of isolated growth hormone deficiency include those that encode growth hormone (GH1), growth-hormone-releasing hormone receptor (GHRHR) and transcription factor SOX3. However, mutations are identified in a relatively small percentage of patients, which suggests that other, yet unidentified, genetic factors are involved. Among the known factors, heterozygous mutations in GH1 remain the most frequent cause of isolated growth hormone deficiency. The identification of mutations has clinical implications for the management of patients with this condition, as individuals with heterozygous GH1 mutations vary in phenotype and can, in some cases, develop additional pituitary hormone deficiencies. Lifelong follow-up of these patients is, therefore, recommended. Further studies in the genetic etiology of isolated growth hormone deficiency will help to elucidate mechanisms implicated in the control of growth and may influence future treatment options. Advances in pharmacogenomics will also optimize the treatment of isolated growth hormone deficiency and other conditions associated with short stature, for which recombinant human growth hormone is a licensed therapy. PMID- 20852588 TI - CtsR, the Gram-positive master regulator of protein quality control, feels the heat. AB - Protein quality networks are required for the maintenance of proper protein homeostasis and essential for viability and growth of all living organisms. Hence, regulation and coordination of these networks are critical for survival during stress as well as for virulence of pathogenic species. In low GC, Gram positive bacteria central protein quality networks are under the control of the global repressor CtsR. Here, we provide evidence that CtsR activity during heat stress is mediated by intrinsic heat sensing through a glycine-rich loop, probably in all Gram-positive species. Moreover, a function for the recently identified arginine kinase McsB is confirmed, however, not for initial inactivation and dissociation of CtsR from the DNA, but for heat-dependent auto activation of McsB as an adaptor for ClpCP-mediated degradation of CtsR. PMID- 20852589 TI - CLASP1, astrin and Kif2b form a molecular switch that regulates kinetochore microtubule dynamics to promote mitotic progression and fidelity. AB - Accurate chromosome segregation during mitosis requires precise coordination of various processes, such as chromosome alignment, maturation of proper kinetochore microtubule (kMT) attachments, correction of erroneous attachments, and silencing of the spindle assembly checkpoint (SAC). How these fundamental aspects of mitosis are coordinately and temporally regulated is poorly understood. In this study, we show that the temporal regulation of kMT attachments by CLASP1, astrin and Kif2b is central to mitotic progression and chromosome segregation fidelity. In early mitosis, a Kif2b-CLASP1 complex is recruited to kinetochores to promote chromosome movement, kMT turnover, correction of attachment errors, and maintenance of SAC signalling. However, during metaphase, this complex is replaced by an astrin-CLASP1 complex, which promotes kMT stability, chromosome alignment, and silencing of the SAC. We show that these two complexes are differentially recruited to kinetochores and are mutually exclusive. We also show that other kinetochore proteins, such as Kif18a, affect kMT attachments and chromosome movement through these proteins. Thus, CLASP1-astrin-Kif2b complex act as a central switch at kinetochores that defines mitotic progression and promotes fidelity by temporally regulating kMT attachments. PMID- 20852590 TI - P-cadherin expression as a prognostic biomarker in a 3992 case tissue microarray series of breast cancer. AB - P-cadherin is a calcium-dependent cell-cell adhesion glycoprotein. P-cadherin expression is restricted to the myoepithelial cells in normal breast tissue, and aberrant staining has also been described in invasive tumors. Several small studies have reported P-cadherin as a marker of poor outcome in breast cancer patients but its prognostic significance in relation to other variables has not been established in a large series of breast cancers. A tissue microarray was constructed from 3992 cases of invasive breast carcinoma, and P-cadherin expression was evaluated using immunohistochemistry. Median follow-up was 12.5 years. The immunohistochemistry-based definitions of cancer subtypes were luminal (ER+ or PR+/HER2-), luminal/HER2+ (ER+ or PR+/HER2+), HER2+ (ER-/PR-/HER2+), and basal (ER-/PR-/HER2-/CK5/6+ or EGFR+). Clinical covariate and biomarker associations were assessed using contingency tables, and Pearson's chi(2) or Fisher's exact test. Survival associations were assessed using Kaplan-Meier plots, logrank and Breslow tests, and Cox proportional hazards regression analysis. P-cadherin was expressed in 34.8% (1290/3710, 50% cut point) of cases. P-cadherin staining was strongly associated with HER2+ and basal carcinoma subtypes (P<0.0005). P-cadherin-positive patients showed significantly poorer short-term (0-10 years) overall survival, disease-specific survival, distant relapse-free interval, and locoregional relapse-free interval in univariable models (P<0.05). In multivariable Cox models containing standard clinical covariates and cancer subtypes, P-cadherin did not show independent prognostic value. P-cadherin expression was positively associated with histological grade, chemotherapy, Ki-67, EGFR, CK5/6, p53, YB-1, and HER2 expression (P<0.002), and negatively associated with age at diagnosis, ER, PR, and Bcl-2 expression (P<0.0005). This study shows the value of P-cadherin as a marker of poor prognosis. The large sample size of this series clarifies contradictory findings of many smaller studies. P-cadherin positivity is associated with high-grade tumor subtypes and well-established markers of poor prognosis, and may represent a promising antibody therapeutic target. PMID- 20852591 TI - Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma. AB - Cellular angiofibroma represents a rare benign mesenchymal tumor, occurring mainly in the superficial soft tissue of the genital region. The involvement of 13q14 in some cases confirmed the morphological suggested link with spindle cell lipoma and mammary-type myofibroblastoma. We analyzed the clinicopathological and immunohistochemical features of 25 cases, and performed in a number of cases additional molecular studies. There were 17 female and 8 male patients (age ranged from 27 to 83 years); females tended to be younger. A marked predilection for the vulva (n=13) was observed, and neoplasms in males were predominantly located in the inguinal region (n=4), and one case each in the scrotum, perianal, the knee, and the upper eyelid. The tumors arose most commonly in the superficial soft tissue and were well circumscribed in all but two cases. The tumor size ranged from 1 to 9 cm. All lesions were composed of spindle-shaped cells associated with numerous small- to medium-sized blood vessels; however, a broad morphological variation with foci of lipogenic differentiation in nine cases and sarcomatous transformation in one case was found. By immunohistochemistry, 11 out of 22 cases expressed CD34. A focal reaction for alpha-smooth muscle actin was observed in 9 out of 22 cases, and two cases each stained weak and focally positive for epithelial membrane antigen and CD99. In all seven cases tested, a monoallelic deletion of RB1 was detected by FISH analysis. Follow-up, available in 14 patients, showed neither local recurrence nor metastasis. In conclusion, we affirm the link between cellular angiofibroma, spindle cell lipoma, and mammary type myofibroblastoma, showing a spectrum of one entity with morphological variations dependent on anatomic location. PMID- 20852592 TI - Clonal X-chromosome inactivation suggests that splenic cord capillary hemangioma is a true neoplasm and not a subtype of splenic hamartoma. AB - Splenic hamartoma is a rare tumor-like lesion composed of structurally disorganized red pulp elements. It has been hypothesized that two other splenic lesions, cord capillary hemangioma and myoid angioendothelioma, may fall within the spectrum of splenic hamartoma, simply representing morphological variants. In this study, we compared the vascular and stromal composition of cord capillary hemangioma and myoid angioendothelioma with those of classical hamartoma. In addition, we assessed the clonal vs polyclonal nature of the lesions in nine female cases by performing clonality analysis for X-chromosome inactivation at the human androgen receptor locus (HUMARA) on laser-assisted microdissected samples. In 15 of 17 cases, increased reticulin and/or collagen content was observed. The classical hamartoma cases showed a vasculature predominantly composed of CD8+ CD31+ CD34- splenic sinuses, whereas cases of cord capillary hemangioma and myoid angioendothelioma contained many CD8- CD31+ CD34+ cord capillaries, but very little CD8+ vasculature. All cases lacked expression of D2 40 and Epstein Barr virus-encoded RNA. All cases showed a proliferation index of <=5% by Ki-67. Cases of classical hamartoma lacked significant perisinusoidal expression of collagen IV and low-affinity nerve growth factor receptor. Both markers were variably expressed in the other lesions. Increased CD163-positive histiocytes were found in four cases (three cord capillary hemangiomas and one myoid angioendothelioma). HUMARA analysis was informative in all nine tested cases, of which three cases showed a non-random X-chromosome inactivation pattern, indicating clonality. All three clonal cases were cord capillary hemangiomas. Our study has shown that in spite of considerable morphologic heterogeneity and overlapping features, classical hamartoma and cord capillary hemangioma and myoid angioendothelioma are different in terms of their vascular and stromal composition. Clonality analysis supports a true neoplastic origin for the cord capillary hemangioma. A larger study using additional immunohistochemical and molecular studies is necessary to further evaluate the biological significance of the current findings. PMID- 20852594 TI - Hierarchical clustering analysis of pathologic and molecular data identifies prognostically and biologically distinct groups of colorectal carcinomas. AB - This work has evaluated the potential superiority of a morphomolecular classification based on the combination of clinicopathologic and molecular features of colorectal cancers. A cohort of 126 colorectal carcinomas was investigated by unsupervised hierarchical clustering analysis to combine 13 routinely assessed clinicopathologic features and all five molecular markers recently suggested by Jass' classification to distinguish four molecular subtypes of sporadic colorectal carcinomas. Survival analysis was assessed by a Cox proportional hazards model. A clear separation into three prognostically significant groups was identified: cluster A and cluster C were associated with good prognosis and cluster B with poor prognosis (P=0.006). Clinicopathologic and molecular features of cluster A and cluster B tumors were strongly concordant with colorectal cancer profiles characterized by microsatellite instability or by chromosomal instability, respectively. The clinicopathologic features of cluster C tumors were suggestive of a less aggressive disease than cluster B tumors. Genetically, they appeared intermediate between cluster A and cluster B tumors, as they were mainly microsatellite stable tumors showing high levels of both MGMT methylation and loss of heterozygosity. Chromosomal instability was significantly lower in cluster C than in cluster B tumors. A more accurate tumor classification should combine the prognostic power of clinicopathologic parameters with molecular biomarkers that provide information regarding the natural history of the cancer. Hierarchical clustering seems to be a useful, promising and powerful tool for further translational studies and should lead us to define a diagnostic and prognostic signature for different carcinomas. PMID- 20852593 TI - Gastric cardiac carcinomas involving the esophagus are more adequately staged as gastric cancers by the 7th edition of the American Joint Commission on Cancer Staging System. AB - The aim of this study was to compare the 7th with the 6th edition of the American Joint Commission on Cancer Staging System for prognostic stratification of gastric cardiac carcinomas involving the esophagus. We retrospectively compared differences in pathological stages with patient survival between the 7th and the 6th staging systems in 142 consecutive resection cases of this cancer. Patient median age was 65 years. The male-female ratio was 3.3. The epicenter of all tumors was within 5 cm below the gastroesophageal junction. The median tumor size was 5.0 cm. Most tumors (79%) were typical adenocarcinomas and the rest showed uncommon histology types. Using the guidelines for gastric cancer, this group of cancer was better stratified by the 7th than the 6th edition of the staging system, especially for pathological nodal (pN) and overall stage pIIIC. Patients with celiac axis nodal disease had the 5-year survival rate worse than those staged at pN3A and pIIIA. Patients staged at pT3 and pN3B had the 5-year survival rate worse than those at pM1 and pIV. We showed that the overall stage of gastric cardiac carcinomas was better stratified by gastric than by esophageal cancer grouping. We conclude that these tumors are better stratified with the 7th than the 6th edition of the gastric staging system, especially for pIII cancers, and better staged by the new gastric than esophageal cancer staging system. We propose that the staging of these tumors be reverted to gastric grouping and combine pT3 and pN3B into the overall stage pIV. PMID- 20852595 TI - Stem cell markers (cytokeratin 15, cytokeratin 19 and p63) in in situ and invasive cutaneous epithelial lesions. AB - The inherent longetivity of stem cells causes them to be susceptible to multiple genetic hits. Thus, it is not surprising that stem cells are implicated in the etiopathogenesis of select cutaneous neoplasms. However, most studies to date are restricted to the use of a single marker (p63, cytokeratin-15 or cytokeratin-19) and do not appear to compare distribution of stem cell markers in a spectrum of cutaneous in situ versus invasive epithelial malignancies. In this study, we evaluate expression of cytokeratin-15, cytokeratin-19, and p63 in a series of primary cutaneous epithelial lesions that include actinic keratosis (n=29), squamous cell carcinoma in situ (n=30), bowenoid papulosis (n=15) and squamous cell carcinoma, well differentiated (n=29) in order to evaluate the role of stem cell marker expression in the grading and development of in situ and invasive malignancies. For cytokeratin-15, expression was retained in actinic keratosis (38%), squamous cell carcinoma in situ (53%) and bowenoid papulosis (60%) but appeared to be lost in squamous cell carcinoma (3%) with statistically significant differences observed between groups that retained versus those that did not (P<0.05 for all three); for cytokeratin-19, patchy yet basal expression was noted in actinic keratosis (21%), patchy and suprabasal expression was noted in squamous cell carcinoma in situ (37%), bowenoid papulosis (13%) and squamous cell carcinoma (24%) with no statistically significant differences between groups; for p63, expression was retained in actinic keratosis (90%), squamous cell carcinoma in situ (87%), bowenoid papulosis (60%) and squamous cell carcinoma (100%) with no statistically significant differences between groups. In summary, our findings expand the neoplasms which involve stem cells to include cutaneous epithelial malignancies. Differential localization of each of these markers argues in favor of stem cell heterogeneity. PMID- 20852596 TI - Arterial stiffness, wave reflections, and diabetes: a bidirectional relationship? PMID- 20852598 TI - Electrocardiography plus limited echocardiography in young, newly identified, hypertensives: some considerations. PMID- 20852601 TI - Hunting down heterogeneity. PMID- 20852602 TI - Messy biology and the origins of evolutionary innovations. AB - Biological messiness relates to infidelity, heterogeneity, stochastic noise and variation--both genetic and phenotypic--at all levels, from single proteins to organisms. Messiness comes from the complexity and evolutionary history of biological systems and from the high cost of accuracy. For better or for worse, messiness is inherent to biology. It also provides the raw material for physiological and evolutionary adaptations to new challenges. PMID- 20852603 TI - Judit Puskas. PMID- 20852605 TI - Bioinorganic chemistry: electrons in Fe-S protein assembly. PMID- 20852606 TI - DNA replication: changing faces, trading places. PMID- 20852607 TI - Biomaterials: spider strength and stretchability. PMID- 20852608 TI - The role of physiological heterogeneity in microbial population behavior. AB - As the ability to analyze individual cells in microbial populations expands, it is becoming apparent that isogenic microbial populations contain substantial cell to-cell differences in physiological parameters such as growth rate, resistance to stress and regulatory circuit output. Subpopulations exist that are manyfold different in these parameters from the population average, and these differences arise by stochastic processes. Such differences can dramatically affect the response of cells to perturbations, especially stress, which in turn dictates overall population response. Defining the role of cell-to-cell heterogeneity in population behavior is important for understanding population-based research problems, including those involving infecting populations, normal flora and bacterial populations in water and soils. Emerging technological breakthroughs are poised to transform single-cell analysis and are critical for the next phase of insights into physiological heterogeneity in the near future. These include technologies for multiparameter analysis of live cells, with downstream processing and analysis. PMID- 20852609 TI - A systematic approach to protein glycosylation analysis: a path through the maze. AB - Protein glycosylation is an important post-translational modification. It is a feature that enhances the functional diversity of proteins and influences their biological activity. A wide range of functions for glycans have been described, from structural roles to participation in molecular trafficking, self-recognition and clearance. Understanding the basis of these functions is challenging because the biosynthetic machinery that constructs glycans executes sequential and competitive steps that result in a mixture of glycosylated variants (glycoforms) for each glycoprotein. Additionally, naturally occurring glycoproteins are often present at low levels, putting pressure on the sensitivity of the analytical technologies. No universal method for the rapid and reliable identification of glycan structure is currently available; hence, research goals must dictate the best method or combination of methods. To this end, we introduce some of the major technologies routinely used for structural N- and O-glycan analysis, describing the complementary information that each provides. PMID- 20852610 TI - Heterogeneity in the chemistry, structure and function of plant cell walls. AB - Higher plants resist the forces of gravity and powerful lateral forces through the cumulative strength of the walls that surround individual cells. These walls consist mainly of cellulose, noncellulosic polysaccharides and lignin, in proportions that depend upon the specific functions of the cell and its stage of development. Spatially and temporally controlled heterogeneity in the physicochemical properties of wall polysaccharides is observed at the tissue and individual cell levels, and emerging in situ technologies are providing evidence that this heterogeneity also occurs across a single cell wall. We consider the origins of cell wall heterogeneity and identify contributing factors that are inherent in the molecular mechanisms of polysaccharide biosynthesis and are crucial for the changing biological functions of the wall during growth and development. We propose several key questions to be addressed in cell wall biology, together with an alternative two-phase model for the assembly of noncellulosic polysaccharides in plants. PMID- 20852613 TI - Anisotropies in cortical tension reveal the physical basis of polarizing cortical flows. AB - Asymmetric cell divisions are essential for the development of multicellular organisms. To proceed, they require an initially symmetric cell to polarize. In Caenorhabditis elegans zygotes, anteroposterior polarization is facilitated by a large-scale flow of the actomyosin cortex, which directs the asymmetry of the first mitotic division. Cortical flows appear in many contexts of development, but their underlying forces and physical principles remain poorly understood. How actomyosin contractility and cortical tension interact to generate large-scale flow is unclear. Here we report on the subcellular distribution of cortical tension in the polarizing C. elegans zygote, which we determined using position- and direction-sensitive laser ablation. We demonstrate that cortical flow is associated with anisotropies in cortical tension and is not driven by gradients in cortical tension, which contradicts previous proposals. These experiments, in conjunction with a theoretical description of active cortical mechanics, identify two prerequisites for large-scale cortical flow: a gradient in actomyosin contractility to drive flow and a sufficiently large viscosity of the cortex to allow flow to be long-ranged. We thus reveal the physical requirements of large scale intracellular cortical flow that ensure the efficient polarization of the C. elegans zygote. PMID- 20852614 TI - Laser cooling of a diatomic molecule. AB - It has been roughly three decades since laser cooling techniques produced ultracold atoms, leading to rapid advances in a wide array of fields. Laser cooling has not yet been extended to molecules because of their complex internal structure. However, this complexity makes molecules potentially useful for a wide range of applications. For example, heteronuclear molecules possess permanent electric dipole moments that lead to long-range, tunable, anisotropic dipole dipole interactions. The combination of the dipole-dipole interaction and the precise control over molecular degrees of freedom possible at ultracold temperatures makes ultracold molecules attractive candidates for use in quantum simulations of condensed-matter systems and in quantum computation. Also, ultracold molecules could provide unique opportunities for studying chemical dynamics and for tests of fundamental symmetries. Here we experimentally demonstrate laser cooling of the polar molecule strontium monofluoride (SrF). Using an optical cycling scheme requiring only three lasers, we have observed both Sisyphus and Doppler cooling forces that reduce the transverse temperature of a SrF molecular beam substantially, to a few millikelvin or less. At present, the only technique for producing ultracold molecules is to bind together ultracold alkali atoms through Feshbach resonance or photoassociation. However, proposed applications for ultracold molecules require a variety of molecular energy-level structures (for example unpaired electronic spin, Omega doublets and so on). Our method provides an alternative route to ultracold molecules. In particular, it bridges the gap between ultracold (submillikelvin) temperatures and the ~1-K temperatures attainable with directly cooled molecules (for example with cryogenic buffer-gas cooling or decelerated supersonic beams). Ultimately, our technique should allow the production of large samples of molecules at ultracold temperatures for species that are chemically distinct from bialkalis. PMID- 20852615 TI - Asterless is a scaffold for the onset of centriole assembly. AB - Centrioles are found in the centrosome core and, as basal bodies, at the base of cilia and flagella. Centriole assembly and duplication is controlled by Polo-like kinase 4 (Plk4): these processes fail if Plk4 is downregulated and are promoted by Plk4 overexpression. Here we show that the centriolar protein Asterless (Asl; human orthologue CEP152) provides a conserved molecular platform, the amino terminus of which interacts with the cryptic Polo box of Plk4 whereas the carboxy terminus interacts with the centriolar protein Sas-4 (CPAP in humans). Drosophila Asl and human CEP152 are required for the centrosomal loading of Plk4 in Drosophila and CPAP in human cells, respectively. Depletion of Asl or CEP152 caused failure of centrosome duplication; their overexpression led to de novo centriole formation in Drosophila eggs, duplication of free centrosomes in Drosophila embryos, and centrosome amplification in cultured Drosophila and human cells. Overexpression of a Plk4-binding-deficient mutant of Asl prevented centriole duplication in cultured cells and embryos. However, this mutant protein was able to promote microtubule organizing centre (MTOC) formation in both embryos and oocytes. Such MTOCs had pericentriolar material and the centriolar protein Sas-4, but no centrioles at their core. Formation of such acentriolar MTOCs could be phenocopied by overexpression of Sas-4 in oocytes or embryos. Our findings identify independent functions for Asl as a scaffold for Plk4 and Sas-4 that facilitates self-assembly and duplication of the centriole and organization of pericentriolar material. PMID- 20852616 TI - Hybrid nanoscale inorganic cages. AB - Cage structures exhibit inherent high symmetry and beauty, and both naturally occurring and synthetic molecular-scale cages have been discovered. Their characteristic high surface area and voids have led to their use as catalysts and catalyst supports, filtration media and gas storage materials. Nanometre-scale cage structures have also been synthesized, notably noble-metal cube-shaped cages prepared by galvanic displacement with promising applications in drug delivery and catalysis. Further functionality for nanostructures in general is provided by the concept of hybrid nanoparticles combining two disparate materials on the same system to achieve synergistic properties stemming from unusual material combinations. We report the integration of the two powerful concepts of cages and hybrid nanoparticles. A previously unknown edge growth mechanism has led to a new type of cage-structured hybrid metal-semiconductor nanoparticle; a ruthenium cage was grown selectively on the edges of a faceted copper(I) sulphide nanocrystal, contrary to the more commonly observed facet and island growth modes of other hybrids. The cage motif was extended by exploiting the open frame to achieve empty cages and cages containing other semiconductors. Such previously unknown nano-inorganic cage structures with variable cores and metal frames manifest new chemical, optical and electronic properties and demonstrate possibilities for uses in electrocatalysis. PMID- 20852617 TI - Nucleation geometry governs ordered actin networks structures. AB - Actin filaments constitute one of the main components of cell cytoskeleton. Assembled into bundles in filopodia or in stress fibres, they play a pivotal role in eukaryotes during cell morphogenesis, adhesion and motility. The bundle emergence has been extensively related to specific actin regulators in vivo. Such dynamic modulation was also highlighted by biochemical reconstitution of the actin-network assembly, in bulk solution or with biomimetic devices. However, the question of how geometrical boundaries, such as those encountered in cells, affect the dynamic formation of highly ordered actin structures remains poorly studied. Here we demonstrate that the nucleation geometry in itself can be the principal determinant of actin-network architecture. We developed a micropatterning method that enables the spatial control of actin nucleation sites for in vitro assays. Shape, orientation and distance between nucleation regions control filament orientation and length, filament-filament interactions and filopodium-like bundle formation. Modelling of filament growth and interactions demonstrates that basic mechanical and probabilistic laws govern actin assembly in higher-order structures. PMID- 20852618 TI - Unusual infrared-absorption mechanism in thermally reduced graphene oxide. AB - Infrared absorption of atomic and molecular vibrations in solids can be affected by electronic contributions through non-adiabatic interactions, such as the Fano effect. Typically, the infrared-absorption lineshapes are modified, or infrared forbidden modes are detectable as a modulation of the electronic absorption. In contrast to such known phenomena, we report here the observation of a giant infrared-absorption band in reduced graphene oxide, arising from the coupling of electronic states to the asymmetric stretch mode of a yet-unreported structure, consisting of oxygen atoms aggregated at the edges of defects. Free electrons are induced by the displacement of the oxygen atoms, leading to a strong infrared absorption that is in phase with the phonon mode. This new phenomenon is only possible when all other oxygen-containing chemical species, including hydroxyl, carboxyl, epoxide and ketonic functional groups, are removed from the region adjacent to the edges, that is, clean graphene patches are present. PMID- 20852619 TI - High proton conduction in grain-boundary-free yttrium-doped barium zirconate films grown by pulsed laser deposition. AB - Reducing the operating temperature in the 500-750 degrees C range is needed for widespread use of solid oxide fuel cells (SOFCs). Proton-conducting oxides are gaining wide interest as electrolyte materials for this aim. We report the fabrication of BaZr(0.8)Y(0.2)O(3-delta) (BZY) proton-conducting electrolyte thin films by pulsed laser deposition on different single-crystalline substrates. Highly textured, epitaxially oriented BZY films were obtained on (100)-oriented MgO substrates, showing the largest proton conductivity ever reported for BZY samples, being 0.11 S cm(-1) at 500 degrees C. The excellent crystalline quality of BZY films allowed for the first time the experimental measurement of the large BZY bulk conductivity above 300 degrees C, expected in the absence of blocking grain boundaries. The measured proton conductivity is also significantly larger than the conductivity values of oxygen-ion conductors in the same temperature range, opening new potential for the development of miniaturized SOFCs for portable power supply. PMID- 20852620 TI - Molecular manipulator driven by spatial variation of liquid-crystalline order. AB - Collective long-range interactions between micrometre-sized impurities in liquid crystals result from the elastic distortion of the liquid-crystalline order. For substantially smaller polymeric impurities, what is relevant is not the elastic interaction between them but the coupling between the scalar nematic order parameter S and the polymer concentration phi. This coupling originates from local molecular interactions, but becomes long ranged because the total polymer concentration is conserved over the whole sample. Here, we propose a new mechanism by which the spatial variation of S generates a force, mediated by the coupling between S and phi, that transports nanoscale polymeric impurities. We have designed a prototype of a molecular manipulator that moves molecules along spatial variations of the scalar order parameter, modulated in a controlled manner by spot illumination of an azobenzene-doped nematic phase with ultra violet light. We also demonstrate the use of the manipulator for the measurement of the anisotropic diffusion constant of a polymer in the nematic phase. The manipulator can control the spatial variation of the polymer concentration, thus showing promise for use in the design of hybrid soft materials. PMID- 20852621 TI - Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. AB - During fasting, mammals maintain normal glucose homeostasis by stimulating hepatic gluconeogenesis. Elevations in circulating glucagon and epinephrine, two hormones that activate hepatic gluconeogenesis, trigger the cAMP-mediated phosphorylation of cAMP response element-binding protein (Creb) and dephosphorylation of the Creb-regulated transcription coactivator-2 (Crtc2)--two key transcriptional regulators of this process. Although the underlying mechanism is unclear, hepatic gluconeogenesis is also regulated by the circadian clock, which coordinates glucose metabolism with changes in the external environment. Circadian control of gene expression is achieved by two transcriptional activators, Clock and Bmal1, which stimulate cryptochrome (Cry1 and Cry2) and Period (Per1, Per2 and Per3) repressors that feed back on Clock-Bmal1 activity. Here we show that Creb activity during fasting is modulated by Cry1 and Cry2, which are rhythmically expressed in the liver. Cry1 expression was elevated during the night-day transition, when it reduced fasting gluconeogenic gene expression by blocking glucagon-mediated increases in intracellular cAMP concentrations and in the protein kinase A-mediated phosphorylation of Creb. In biochemical reconstitution studies, we found that Cry1 inhibited accumulation of cAMP in response to G protein-coupled receptor (GPCR) activation but not to forskolin, a direct activator of adenyl cyclase. Cry proteins seemed to modulate GPCR activity directly through interaction with G(s)alpha. As hepatic overexpression of Cry1 lowered blood glucose concentrations and improved insulin sensitivity in insulin-resistant db/db mice, our results suggest that compounds that enhance cryptochrome activity may provide therapeutic benefit to individuals with type 2 diabetes. PMID- 20852622 TI - Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia. AB - Pneumonia remains the leading cause of death from infection in the US, yet fundamentally new conceptual models underlying its pathogenesis have not emerged. We show that humans and mice with bacterial pneumonia have markedly elevated amounts of cardiolipin, a rare, mitochondrial-specific phospholipid, in lung fluid and find that it potently disrupts surfactant function. Intratracheal cardiolipin administration in mice recapitulates the clinical phenotype of pneumonia, including impaired lung mechanics, modulation of cell survival and cytokine networks and lung consolidation. We have identified and characterized the activity of a unique cardiolipin transporter, the P-type ATPase transmembrane lipid pump Atp8b1, a mutant version of which is associated with severe pneumonia in humans and mice. Atp8b1 bound and internalized cardiolipin from extracellular fluid via a basic residue-enriched motif. Administration of a peptide encompassing the cardiolipin binding motif or Atp8b1 gene transfer in mice lessened bacteria-induced lung injury and improved survival. The results unveil a new paradigm whereby Atp8b1 is a cardiolipin importer whose capacity to remove cardiolipin from lung fluid is exceeded during inflammation or when Atp8b1 is defective. This discovery opens the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia. PMID- 20852623 TI - Opioid inhibition of N-type Ca2+ channels and spinal analgesia couple to alternative splicing. AB - Alternative pre-mRNA splicing occurs extensively in the nervous systems of complex organisms, including humans, considerably expanding the potential size of the proteome. Cell-specific alternative pre-mRNA splicing is thought to optimize protein function for specialized cellular tasks, but direct evidence for this is limited. Transmission of noxious thermal stimuli relies on the activity of N-type Ca(V)2.2 calcium channels in nociceptors. Using an exon-replacement strategy in mice, we show that mutually exclusive splicing patterns in the Ca(V)2.2 gene modulate N-type channel function in nociceptors, leading to a change in morphine analgesia. Exon 37a (e37a) enhances MU-opioid receptor-mediated inhibition of N type calcium channels by promoting activity-independent inhibition. In the absence of e37a, spinal morphine analgesia is weakened in vivo but the basal response to noxious thermal stimuli is not altered. Our data suggest that highly specialized, discrete cellular responsiveness in vivo can be attributed to alternative splicing events regulated at the level of individual neurons. PMID- 20852624 TI - Muscarinic receptors induce LTD of NMDAR EPSCs via a mechanism involving hippocalcin, AP2 and PSD-95. AB - Although muscarinic acetylcholine receptors (mAChRs) and NMDA receptors (NMDARs) are important for synaptic plasticity, learning and memory, the manner in which they interact is poorly understood. We found that stimulation of muscarinic receptors, either by an agonist or by the synaptic release of acetylcholine, led to long-term depression (LTD) of NMDAR-mediated synaptic transmission. This form of LTD involved the release of Ca2+ from IP3-sensitive intracellular stores and was expressed via the internalization of NMDARs. Our results suggest that the molecular mechanism involves a dynamic interaction between the neuronal calcium sensor protein hippocalcin, the clathrin adaptor molecule AP2, the postsynaptic density enriched protein PSD-95 and NMDARs. We propose that hippocalcin binds to the SH3 region of PSD-95 under basal conditions, but it translocates to the plasma membrane on sensing Ca2+; in doing so, it causes PSD-95 to dissociate from NMDARs, permitting AP2 to bind and initiate their dynamin-dependent endocytosis. PMID- 20852625 TI - Synapses with short-term plasticity are optimal estimators of presynaptic membrane potentials. AB - The trajectory of the somatic membrane potential of a cortical neuron exactly reflects the computations performed on its afferent inputs. However, the spikes of such a neuron are a very low-dimensional and discrete projection of this continually evolving signal. We explored the possibility that the neuron's efferent synapses perform the critical computational step of estimating the membrane potential trajectory from the spikes. We found that short-term changes in synaptic efficacy can be interpreted as implementing an optimal estimator of this trajectory. Short-term depression arose when presynaptic spiking was sufficiently intense as to reduce the uncertainty associated with the estimate; short-term facilitation reflected structural features of the statistics of the presynaptic neuron such as up and down states. Our analysis provides a unifying account of a powerful, but puzzling, form of plasticity. PMID- 20852626 TI - Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. AB - Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB1 cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB1 receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy. PMID- 20852627 TI - Coordinate control of gene expression noise and interchromosomal interactions in a MAP kinase pathway. AB - In the Saccharomyces cerevisiae pheromone-response pathway, the transcription factor Ste12 is inhibited by two mitogen-activated protein (MAP)-kinase responsive regulators, Dig1 and Dig2. These two related proteins bind to distinct regions of Ste12 but are redundant in their inhibition of Ste12-dependent gene expression. Here we describe three functions for Dig1 that are non-redundant with those of Dig2. First, the removal of Dig1 results in a specific increase in intrinsic and extrinsic noise in the transcriptional outputs of the mating pathway. Second, in dig1Delta cells, Ste12 relocalizes from the nucleoplasmic distribution seen in wild-type cells into discrete subnuclear foci. Third, genome wide insertional chromatin immunoprecipitation studies revealed that Ste12 dependent genes have increased interchromosomal interactions in dig1Delta cells. These findings suggest that the regulation of gene expression through long-range gene interactions, a widely observed phenomenon, comes at the cost of increased noise. Consequently, cells may have evolved mechanisms to suppress noise by controlling these interactions. PMID- 20852628 TI - Ubiquitylation of the amino terminus of Myc by SCF(beta-TrCP) antagonizes SCF(Fbw7)-mediated turnover. AB - The SCFFbw7 ubiquitin ligase mediates growth-factor-regulated turnover of the Myc oncoprotein. Here we show that SCFbeta-TrCP binds to Myc by means of a characteristic phosphodegron and ubiquitylates Myc; this results in enhanced Myc stability. SCFFbw7 and SCFbeta-TrCP can exert these differential effects through polyubiquitylation of the amino terminus of Myc. Whereas SCFFbw7 with the Cdc34 ubiquitin-conjugating enzyme specifically requires lysine 48 (K48) of ubiquitin, SCFbeta-TrCP uses the UbcH5 ubiquitin-conjugating enzyme to form heterotypic polyubiquitin chains on Myc. Ubiquitylation of Myc by SCFbeta-TrCP is required for Myc-dependent acceleration of cell cycle progression after release from an arrest in S phase. Therefore, alternative ubiquitylation events at the N terminus can lead to the ubiquitylation-dependent stabilization of Myc. PMID- 20852629 TI - O2 regulates stem cells through Wnt/beta-catenin signalling. AB - Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (<5% O2) have revealed strong regulatory links between O2 availability and functions of stem and precursor cells. Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O2 gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1alpha (HIF-1alpha), a principal mediator of hypoxic adaptations, modulates Wnt/beta catenin signalling in hypoxic embryonic stem (ES) cells by enhancing beta-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/beta-catenin activity is closely associated with low O2 regions in the subgranular zone of the hippocampus, a key NSC niche. Hif-1alpha deletion impairs hippocampal Wnt dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/beta-catenin signalling in the subgranular zone. O2 availability, therefore, may have a direct role in stem cell regulation through HIF-1alpha modulation of Wnt/beta-catenin signalling. PMID- 20852630 TI - Identification of a co-activator that links growth factor signalling to c-Jun/AP 1 activation. AB - The AP-1 transcription factor c-Jun is essential for cellular proliferation in many cell types, but the molecular link between growth factors and c-Jun activation has been enigmatic. In this study we identify a previously uncharacterized RING-domain-containing protein, RACO-1 (RING domain AP-1 co activator-1), as a c-Jun co-activator that is regulated by growth factor signalling. RACO-1 interacted with c-Jun independently of amino-terminal phosphorylation, and was both necessary and sufficient for c-Jun/AP-1 activation. Growth factor-mediated stimulation of AP-1 was attributable to MEK/ERK-dependent stabilization of RACO-1 protein. Stimulation of the MEK/ERK pathway strongly promoted Lys 63-linked ubiquitylation of RACO-1, which antagonized Lys 48-linked degradative auto-ubiquitylation of the same Lys residues. RACO-1 depletion reduced cellular proliferation and decreased expression of several growth associated AP-1 target genes, such as cdc2, cyclinD1 and hb-egf. Moreover, transgenic overexpression of RACO-1 augmented intestinal tumour formation triggered by aberrant Wnt signalling and cooperated with oncogenic Ras in colonic hyperproliferation. Thus RACO-1 is a co-activator that links c-Jun to growth factor signalling and is essential for AP-1 function in proliferation. PMID- 20852631 TI - A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. AB - Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (P(trend) = 2.3 * 10-9 to P(trend) = 3.9 * 10-7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17-1.35; rs2363956 HR = 0.84, 95% CI 0.80 0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor-negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75-0.92, P(trend) = 0.0003) and an association with estrogen receptor-positive disease in the opposite direction (OR = 1.07, 95% CI 1.01-1.14, P(trend) = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (P(trend) = 1 * 10-7) to P(trend) = 8 * 10-5; rs2363956 per-allele OR = 0.80, 95% CI 0.74-0.87, P(trend) = 1.1 * 10-7 PMID- 20852632 TI - A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. AB - Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2). Here, we report on nine additional candidate loci (defined as having P <= 10-4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P <= 5 * 10-8 (8q24, P = 8.0 * 10 15 and 2q31, P = 3.8 * 10-14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 * 10-8 and 17q21, P = 1.4 * 10-7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development. PMID- 20852633 TI - Common variants at 19p13 are associated with susceptibility to ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 * 10-4 and P = 6 * 10-4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 * 10-9 and P = 4 * 10-11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development. PMID- 20852634 TI - Quantitative comparison of genome-wide DNA methylation mapping technologies. AB - DNA methylation plays a key role in regulating eukaryotic gene expression. Although mitotically heritable and stable over time, patterns of DNA methylation frequently change in response to cell differentiation, disease and environmental influences. Several methods have been developed to map DNA methylation on a genomic scale. Here, we benchmark four of these approaches by analyzing two human embryonic stem cell lines derived from genetically unrelated embryos and a matched pair of colon tumor and adjacent normal colon tissue obtained from the same donor. Our analysis reveals that methylated DNA immunoprecipitation sequencing (MeDIP-seq), methylated DNA capture by affinity purification (MethylCap-seq), reduced representation bisulfite sequencing (RRBS) and the Infinium HumanMethylation27 assay all produce accurate DNA methylation data. However, these methods differ in their ability to detect differentially methylated regions between pairs of samples. We highlight strengths and weaknesses of the four methods and give practical recommendations for the design of epigenomic case-control studies. PMID- 20852636 TI - The structure and mechanism of the Mycobacterium tuberculosis cyclodityrosine synthetase. AB - The Mycobacterium tuberculosis enzyme Rv2275 catalyzes the formation of cyclo(L Tyr-L-Tyr) using two molecules of Tyr-tRNA(Tyr) as substrates. The three dimensional (3D) structure of Rv2275 was determined to 2.0-A resolution, revealing that Rv2275 is structurally related to the class Ic aminoacyl-tRNA synthetase family of enzymes. Mutagenesis and radioactive labeling suggests a covalent intermediate in which L-tyrosine is transferred from Tyr-tRNA(Tyr) to an active site serine (Ser88) by transesterification with Glu233 serving as a critical base, catalyzing dipeptide bond formation. PMID- 20852635 TI - Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications. AB - Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression. PMID- 20852637 TI - An aminotransferase branch point connects purine catabolism to amino acid recycling. AB - Although amino acids are known precursors of purines, a pathway for the direct recycling of amino acids from purines has never been described at the molecular level. We provide NMR and crystallographic evidence that the PucG protein from Bacillus subtilis catalyzes the transamination between an unstable intermediate ((S)-ureidoglycine) and the end product of purine catabolism (glyoxylate) to yield oxalurate and glycine. This activity enables soil and gut bacteria to use the animal purine waste as a source of carbon and nitrogen. The reaction catalyzed by (S)-ureidoglycine-glyoxylate aminotransferase (UGXT) illustrates a transamination sequence in which the same substrate provides both the amino group donor and, via its spontaneous decay, the amino group acceptor. Structural comparison and mutational analysis suggest a molecular rationale for the functional divergence between UGXT and peroxisomal alanine-glyoxylate aminotransferase, a fundamental enzyme for glyoxylate detoxification in humans. PMID- 20852638 TI - Direct observation of single-charge-detection capability of nanowire field-effect transistors. AB - A single localized charge can quench the luminescence of a semiconductor nanowire, but relatively little is known about the effect of single charges on the conductance of the nanowire. In one-dimensional nanostructures embedded in a material with a low dielectric permittivity, the Coulomb interaction and excitonic binding energy are much larger than the corresponding values when embedded in a material with the same dielectric permittivity. The stronger Coulomb interaction is also predicted to limit the carrier mobility in nanowires. Here, we experimentally isolate and study the effect of individual localized electrons on carrier transport in InAs nanowire field-effect transistors, and extract the equivalent charge sensitivity. In the low carrier density regime, the electrostatic potential produced by one electron can create an insulating weak link in an otherwise conducting nanowire field-effect transistor, modulating its conductance by as much as 4,200% at 31 K. The equivalent charge sensitivity, 4 * 10(-5) e Hz(-1/2) at 25 K and 6 * 10(-5) e Hz(-1/2) at 198 K, is orders of magnitude better than conventional field-effect transistors and nanoelectromechanical systems, and is just a factor of 20-30 away from the record sensitivity for state-of-the-art single-electron transistors operating below 4 K (ref. 8). This work demonstrates the feasibility of nanowire-based single electron memories and illustrates a physical process of potential relevance for high performance chemical sensors. The charge-state-detection capability we demonstrate also makes the nanowire field-effect transistor a promising host system for impurities (which may be introduced intentionally or unintentionally) with potentially long spin lifetimes, because such transistors offer more sensitive spin-to-charge conversion readout than schemes based on conventional field-effect transistors. PMID- 20852640 TI - Elegance and empiricism. AB - C60 was discovered in 1985 but it took five years to confirm that this famous molecule was spherical. Chris Toumey revisits a debate that highlighted different approaches to science. PMID- 20852639 TI - Hybrid superconductor-quantum dot devices. AB - Advances in nanofabrication techniques have made it possible to make devices in which superconducting electrodes are connected to non-superconducting nanostructures such as quantum dots. The properties of these hybrid devices result from a combination of a macroscopic quantum phenomenon involving large numbers of electrons (superconductivity) and the ability to control single electrons, offered by quantum dots. Here we review research into electron transport and other fundamental processes that have been studied in these devices. We also describe potential applications, such as a transistor in which the direction of a supercurrent can be reversed by adding just one electron to a quantum dot. PMID- 20852641 TI - Optical rectification and field enhancement in a plasmonic nanogap. AB - Metal nanostructures act as powerful optical antennas because collective modes of the electron fluid in the metal are excited when light strikes the surface of the nanostructure. These excitations, known as plasmons, can have evanescent electromagnetic fields that are orders of magnitude larger than the incident electromagnetic field. The largest field enhancements often occur in nanogaps between plasmonically active nanostructures, but it is extremely challenging to measure the fields in such gaps directly. These enhanced fields have applications in surface-enhanced spectroscopies, nonlinear optics and nanophotonics. Here we show that nonlinear tunnelling conduction between gold electrodes separated by a subnanometre gap leads to optical rectification, producing a d.c. photocurrent when the gap is illuminated. Comparing this photocurrent with low-frequency conduction measurements, we determine the optical frequency voltage across the tunnelling region of the nanogap, and also the enhancement of the electric field in the tunnelling region, as a function of gap size. The measured field enhancements exceed 1,000, consistent with estimates from surface-enhanced Raman measurements. Our results highlight the need for more realistic theoretical approaches that are able to model the electromagnetic response of metal nanostructures on scales ranging from the free-space wavelength, lambda, down to ~lambda/1,000, and for experiments with new materials, different wavelengths and different incident polarizations. PMID- 20852642 TI - Structural basis for 16S ribosomal RNA cleavage by the cytotoxic domain of colicin E3. AB - The toxin colicin E3 targets the 30S subunit of bacterial ribosomes and cleaves a phosphodiester bond in the decoding center. We present the crystal structure of the 70S ribosome in complex with the cytotoxic domain of colicin E3 (E3-rRNase). The structure reveals how the rRNase domain of colicin binds to the A site of the decoding center in the 70S ribosome and cleaves the 16S ribosomal RNA (rRNA) between A1493 and G1494. The cleavage mechanism involves the concerted action of conserved residues Glu62 and His58 of the cytotoxic domain of colicin E3. These residues activate the 16S rRNA for 2' OH-induced hydrolysis. Conformational changes observed for E3-rRNase, 16S rRNA and helix 69 of 23S rRNA suggest that a dynamic binding platform is required for colicin E3 binding and function. PMID- 20852643 TI - Structural basis of HIV-1 resistance to AZT by excision. AB - Human immunodeficiency virus (HIV-1) develops resistance to 3'-azido-2',3' deoxythymidine (AZT, zidovudine) by acquiring mutations in reverse transcriptase that enhance the ATP-mediated excision of AZT monophosphate from the 3' end of the primer. The excision reaction occurs at the dNTP-binding site, uses ATP as a pyrophosphate donor, unblocks the primer terminus and allows reverse transcriptase to continue viral DNA synthesis. The excision product is AZT adenosine dinucleoside tetraphosphate (AZTppppA). We determined five crystal structures: wild-type reverse transcriptase-double-stranded DNA (RT-dsDNA) AZTppppA; AZT-resistant (AZTr; M41L D67N K70R T215Y K219Q) RT-dsDNA-AZTppppA; AZTr RT-dsDNA terminated with AZT at dNTP- and primer-binding sites; and AZTr apo reverse transcriptase. The AMP part of AZTppppA bound differently to wild-type and AZTr reverse transcriptases, whereas the AZT triphosphate part bound the two enzymes similarly. Thus, the resistance mutations create a high-affinity ATP binding site. The structure of the site provides an opportunity to design inhibitors of AZT-monophosphate excision. PMID- 20852644 TI - Structure of the cholera toxin secretion channel in its closed state. AB - The type II secretion system (T2SS) is a macromolecular complex spanning the inner and outer membranes of Gram-negative bacteria. Remarkably, the T2SS secretes folded proteins, including multimeric assemblies such as cholera toxin and heat-labile enterotoxin from Vibrio cholerae and enterotoxigenic Escherichia coli, respectively. The major outer membrane T2SS protein is the 'secretin' GspD. Cryo-EM reconstruction of the V. cholerae secretin at 19-A resolution reveals a dodecameric structure reminiscent of a barrel, with a large channel at its center that contains a closed periplasmic gate. The GspD periplasmic domain forms a vestibule with a conserved constriction, and it binds to a pentameric exoprotein and to the trimeric tip of the T2SS pseudopilus. By combining our results with structures of the cholera toxin and T2SS pseudopilus tip, we provide a structural basis for a possible secretion mechanism of the T2SS. PMID- 20852645 TI - The 2009 pandemic H1N1 neuraminidase N1 lacks the 150-cavity in its active site. AB - Influenza A virus neuraminidase can be classified into groups 1 and 2 on the basis of its primary structure. The main structural feature of group 1 neuraminidase is an extra cavity in the active site, the 150-cavity. Here we present the crystal structure of neuraminidase from the 2009 pandemic H1N1 influenza strain. In contrast to other characterized N1 neuraminidases, which are all members of group 1, 2009 H1N1 neuraminidase does not have a 150-cavity. PMID- 20852646 TI - Escherichia coli RecBC helicase has two translocase activities controlled by a single ATPase motor. AB - E. coli RecBCD is a DNA helicase with two ATPase motors (RecB, a 3'->5' translocase, and RecD, a 5'->3' translocase) that function in repair of double stranded DNA breaks. The RecBC heterodimer, with only the RecB motor, remains a processive helicase. Here we examined RecBC translocation along single-stranded DNA (ssDNA). Notably, we found RecBC to have two translocase activities: the primary translocase moves 3'->5', whereas the secondary translocase moves RecBC along the opposite strand of a forked DNA at a similar rate. The secondary translocase is insensitive to the ssDNA backbone polarity, and we propose that it may fuel RecBCD translocation along double-stranded DNA ahead of the unwinding fork and ensure that the unwound single strands move through RecBCD at the same rate after interaction with a crossover hot-spot indicator (Chi) sequence. PMID- 20852647 TI - The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. AB - Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis. S1P(1) signaled through the kinase mTOR and antagonized the function of transforming growth factor-beta mainly by attenuating sustained activity of the signal transducer Smad3. S1P(1) function was dependent on endogenous sphingosine kinase activity. Notably, two seemingly unrelated immunosuppressants, FTY720 and rapamycin, targeted the same S1P(1) and mTOR pathway to regulate the dichotomy between T(H)1 cells and T(reg) cells. Our studies establish an S1P(1)-mTOR axis that controls T cell lineage specification. PMID- 20852648 TI - Validation of two ribosomal RNA removal methods for microbial metatranscriptomics. AB - The predominance of rRNAs in the transcriptome is a major technical challenge in sequence-based analysis of cDNAs from microbial isolates and communities. Several approaches have been applied to deplete rRNAs from (meta)transcriptomes, but no systematic investigation of potential biases introduced by any of these approaches has been reported. Here we validated the effectiveness and fidelity of the two most commonly used approaches, subtractive hybridization and exonuclease digestion, as well as combinations of these treatments, on two synthetic five microorganism metatranscriptomes using massively parallel sequencing. We found that the effectiveness of rRNA removal was a function of community composition and RNA integrity for these treatments. Subtractive hybridization alone introduced the least bias in relative transcript abundance, whereas exonuclease and in particular combined treatments greatly compromised mRNA abundance fidelity. Illumina sequencing itself also can compromise quantitative data analysis by introducing a G+C bias between runs. PMID- 20852650 TI - Dimensions of human ejaculated spermatozoa in Papanicolaou-stained seminal and swim-up smears obtained from the Integrated Semen Analysis System (ISAS((r))). AB - Objective measurements are required for computer-aided sperm morphometric analysis (CASMA) machines to distinguish normal from abnormal sperm heads. The morphometric characteristics of spermatozoa in 72 samples of semen and of spermatozoa from 72 other semen samples after swim-up were quantified by the semi automated Integrated Sperm Analysis System (ISAS) computer-aided system, which measured the sperm head parameters length (L), width (W), area (A), perimeter (P), acrosomal area (Ac), and the derived values L/W and P/A. For each man a homogeneous population of distributions characterized seminal spermatozoa (7 942 cells: median values L 4.4 MUm, W 2.8 MUm, A 9.8 MUm(2), P 12.5 MUm, Ac 47.5%, L/W 1.57, P/A 1.27), and there was no significant difference in within- and among individual variation. Different men could have spermatozoa of significantly different dimensions. Head dimensions for swim-up spermatozoa from different men (4 812 cells) were similar to those in semen, differing only by 2%-5%. The values of L, W and L/W fell within the limits given by the World Health Organization (WHO). Although these samples were not biologically matched, linear mixed-effects statistical analyses permitted valid comparison of the groups. A subpopulation of 404 spermatozoa considered to fit the stringent criteria of WHO 'normal' seminal spermatozoa from both semen and swim-up were characterized by median values (and 95% confidence intervals) of L, 4.3 MUm (3.8-4.9), W, 2.9 MUm (2.6-3.3), A, 10.2 MUm(2) (8.5-12.2), P, 12.4 MUm (11.3-13.9), Ac, 49% (36-60), L/W, 1.49 (1.32 1.67) and P/A, 1.22 (1.11-1.35). These median values fall within the 95th centile confidence limits given by WHO, but the confidence intervals for L and W were larger. Although these differences in head dimensions among men and after swim-up could be detected by CASMA, the small differences make it unlikely that technicians would be able to distinguish them. The values could be used as default sperm head values for the CASMA machine used here. PMID- 20852649 TI - Scanless two-photon excitation of channelrhodopsin-2. AB - Light-gated ion channels and pumps have made it possible to probe intact neural circuits by manipulating the activity of groups of genetically similar neurons. What is needed now is a method for precisely aiming the stimulating light at single neuronal processes, neurons or groups of neurons. We developed a method that combines generalized phase contrast with temporal focusing (TF-GPC) to shape two-photon excitation for this purpose. The illumination patterns are generated automatically from fluorescence images of neurons and shaped to cover the cell body or dendrites, or distributed groups of cells. The TF-GPC two-photon excitation patterns generated large photocurrents in Channelrhodopsin-2 expressing cultured cells and neurons and in mouse acute cortical slices. The amplitudes of the photocurrents can be precisely modulated by controlling the size and shape of the excitation volume and, thereby, be used to trigger single action potentials or trains of action potentials. PMID- 20852652 TI - Control of APN/CD13 and NEP/CD10 on sperm motility. AB - Aminopeptidase N (APN/CD13) and neutral endopeptidase (NEP/CD10) are enzymes present in human sperm cells and involved in regulation of sperm motility of noncapacitated spermatozoa. We investigated the involvement of APN/CD13 and NEP/CD10 in motility and in kinematic parameters of human capacitated spermatozoa. Sperm cells isolated by a discontinuous Percoll gradient (40%-80%) followed up by swim-up techniques were incubated with the APN/CD13-specific inhibitor, leuhistin (100 MUmol L(-1)), and the NEP/CD10-specific inhibitor, thiorphan (1 MUmol L(-1)). The complete inhibition of both APN/CD13 and NEP/CD10 improved sperm motility. Spermatozoa incubated with the APN/CD13-specific inhibitor leuhistin showed asymmetrical trajectories, whereas sperm trajectories were more regular after treatment with the NEP/CD10-specific inhibitor thiorphan. In conclusion, APN/CD13 and NEP/CD10 modulate the motility of capacitated spermatozoa, although each of the enzymes seems to participate in the control of different aspects of sperm motility. Therefore, both inhibitors may be useful for sperm activation at different functional stages of spermatozoa. PMID- 20852651 TI - Effects of ethanol on the tonicity of corporal tissue and the intracellular Ca2+ concentration of human corporal smooth muscle cells. AB - Heavy alcohol consumption is associated with an increased risk of erectile dysfunction (ED); however, the acute effects of ethanol (EtOH) on penile tissue are not fully understood. We sought to investigate the effects of EtOH on corporal tissue tonicity, as well as the intracellular Ca(2+) concentration ([Ca(2+)](i)) and potassium channel activity of corporal smooth muscle. Strips of corpus cavernosum (CC) from rabbits were mounted in organ baths for isometric tension studies. Electrical field stimulation (EFS) was applied to strips precontracted with 10 MUmol L(-1) phenylephrine as a control. EtOH was then added to the organ bath and incubated before EFS. The [Ca(2+)](i) levels were monitored by the ratio of fura-2 fluorescence intensities using the fura-2 loading method. Single-channel and whole-cell currents were recorded by the conventional patch clamp technique in short-term cultured smooth muscle cells from human CC tissue. The corpus cavernosal relaxant response of EFS was decreased in proportion to the concentration of EtOH. EtOH induced a sustained increase in [Ca(2+)](i) in a dose dependent manner, Extracellular application of EtOH significantly increased whole cell K(+) currents in a concentration-dependent manner (P < 0.05). EtOH also increased the open probability in cell-attached patches; however, in inside-out patches, the application of EtOH to the intracellular aspect of the patches induced slight inhibition of Ca(2+)-activated potassium channel (KCa) activity. EtOH caused a dose-dependent increase in cavernosal tension by alterations to [Ca(2+)](i). Although EtOH did not affect KCa channels directly, it increased the channel activity by increasing [Ca(2+)](i). The increased corpus cavernosal tone caused by EtOH might be one of the mechanisms of ED after heavy drinking. PMID- 20852653 TI - Twists and turns on the way to progress in metastatic castrate-resistant prostate cancer. PMID- 20852654 TI - Loss of microRNAs in thymus perturbs invariant NKT cell development and function. AB - microRNAs (miRNAs) are small noncoding RNAs that mediate RNA interference to suppress protein expression at the translational level. Accumulated evidence indicates that miRNAs play critical roles in various biological processes and disease development, including autoimmune diseases. Invariant natural killer T (iNKT) cells are an unusual CD1d-restricted subset of thymus-derived T cells that are potent regulators of diverse immune responses. Our previous studies with the mouse model of bone marrow-specific Dicer deletion suggest the involvement of Dicer-dependent miRNAs in the development and function of iNKT cells. In the present study, to further dissect the functional levels of Dicer-dependent miRNAs in regulating iNKT cell development, we generated a mouse model with the Dicer deletion in the thymus. Our data indicate that lack of miRNAs following the deletion of Dicer in the thymus severely interrupted the development and maturation of iNKT cells in the thymus and significantly decreased the number of iNKT cells in the peripheral immune organs. miRNA-deficient peripheral iNKT cells display profound defects in activation and cytokine production upon alpha galactosylceramide (alpha-GalCer) stimulation. Our results demonstrate a critical role of the miRNA-dependent pathway in the thymus in the regulation of iNKT cell development and function. PMID- 20852656 TI - Excision and end-to-end anastomotic urethroplasty in the management of post traumatic urethral stricture disease: experience and challenges in a Nigerian teaching hospital. AB - AIMS AND OBJECTIVES: The study aims to assess the outcome of excision and end-to end anastomotic urethroplasty in the management of post traumatic urethral stricture in at one of the teaching hospitals in Nigeria. MATERIALS AND METHODS: All cases of post traumatic urethral stricture disease managed by excision and end to end anastomosis between January 2000 and December 2006 were retrospectively studied. The data collected included the patients age, cause of stricture, location, length and the outcome of surgery. RESULTS: A total of 47 patients excision and end to end anastomotic urethroplasty were carried out during the period. Twenty patients (42.6%) had bulbar stricture and 27 (57.4%) had pelvic fracture urethral distraction stricture involving the posterior urethra. There was a 100% success rate in the 20 patients with bulbar urethral stricture at a minimum follow up of 1 year while the success rate for the 27 patients with posterior urethral stricture was 70.4%. Complications included one case each of perineal wound infection and of urethrocutaneous fistula which were managed conservatively. CONCLUSION: Excision and end to end anastomotic urethroplasty gives excellent results for the treatment of short segment post traumatic bulbar strictures and should be used as the primary treatment for such strictures. PMID- 20852657 TI - In-situ pinning for Slipped Capital Femoral Epiphysis in blacks: experience in a regional orthopaedic centre. AB - BACKGROUND: Slipped Capital Femoral Epiphysis (SCFE) is the commonest pathology affecting the adolescent hip with an incidence of approximately 2 per 100,000 population. Blacks are more commonly affected than Caucasians. Of many treatment options available, in-situ-pinning appears to be the most widely employed. AIMS AND OBJECTIVES: To determine the epidemiological pattern and the outcome of in situ pinning for slipped capital femoral epiphysis in Nigerian adolescents. PATIENTS AND METHODS: This is a six-year retrospective review of all the cases of slipped capital femoral epiphysis treated by in-situ pinning between 1st January 1998 and 31st December 2003 at the National Orthopaedic Hospital, Igbobi, Lagos, Nigeria. RESULTS: Thirty-one patients with 35 affected hips were managed with in situ pinning during the period of review. Twenty-one females (67.7%) and 10 males (32.3%) with a F:M ratio of 2.1:1 were affected. The mean age for all the patients was 12.45 years (range 6 - 16; SD +/- 1.79). The most common presenting complaint was hip pain seen in 48.4% of cases. Satisfactory results were obtained in 13 hips (37%) while the results in the remaining 22 hips were unsatisfactory. The most common complication was limb length discrepancy. CONCLUSION: This study shows that SCFE is not an uncommon condition in orthopaedic practice in Nigeria. The high rate of unsatisfactory results is associated with the severity of the slips and the unavailability of image intensifier at the time of surgery. PMID- 20852658 TI - Comparative effect of tube drain on post operative inflammatory complications of impacted mandibular third molar surgery College Hospital, Ibadan, Nigeria. AB - BACKGROUND AND OBJECTIVES: Swelling, pain and trismus are acute reversible inflammatory complications of impacted mandibular third molar (M3) surgery. They contribute to the deterioration of quality of life and loss of several useful working hours. This study aimed to investigate whether the use of a surgical drain following M3 surgery can minimise these inflammatory complications. PATIENTS AND METHODS: Eighty consecutive patients who gave consent were enrolled into the study. Patients were assigned into two groups (drain and no drain) by systematic sampling method which was modified to ensure matching of patients by age, sex and spatial relationship of the impacted mandibular third molar. The patients in the drain group (n=40) had a Foley's catheter drain inserted into the wound after the surgical procedure while the patients in the no drain group (n=40) had their wound closed without the use of drain. All patients had primary wound closure with 3.0 black silk sutures after the procedure. Demographic data, cheek dimension and maximal mouth opening were recorded before the procedure. Pain, swelling and trismus were evaluated in the two groups at 24 hours, 48 hours and 7th day after surgery. RESULTS: Post operative swelling and visual analogue scale score for pain were comparatively lesser in the drain group patients. The maximal interincisal distance was also more in the drain group patients. CONCLUSION: The findings from this study indicated that there is a significant benefit of using a surgical drain in minimising postoperative oedema, pain and trismus following surgical removal of impacted mandibular third molar. PMID- 20852655 TI - Ten years of Nature Reviews Neuroscience: insights from the highly cited. AB - To celebrate the first 10 years of Nature Reviews Neuroscience, we invited the authors of the most cited article of each year to look back on the state of their field of research at the time of publication and the impact their article has had, and to discuss the questions that might be answered in the next 10 years. This selection of highly cited articles provides interesting snapshots of the progress that has been made in diverse areas of neuroscience. They show the enormous influence of neuroimaging techniques and highlight concepts that have generated substantial interest in the past decade, such as neuroimmunology, social neuroscience and the 'network approach' to brain function. These advancements will pave the way for further exciting discoveries that lie ahead. PMID- 20852659 TI - Argyrophilic nucleolar organiser region (AgNOR) study of some odontogenic cyst epithelium. AB - AIMS AND OBJECTIVES: This study compared the biologic activity of three different cyst types and assessed the value of the AgNOR technique as an aid to diagnosis. BACKGROUND: The nucleolar organiser region (NORs) reflect replicatory activities within the cells. It has been found to be of diagnostic value in the prediction of the biologic behaviour of some tumors and even oral epithelial dysplasia. MATERIALS AND METHODS: Thirty histologically diagnosed H & E sections of cystic lesions consisting of ten (10) radicular, ten (10 dentigerous and ten (10) odontogenic kerotocysts were randomly selected from the record of biopsy services of the Lagos University Teaching Hospital. The paraffin blocks of the selected sections were retrieved for AgNOR staining. For each cyst type the mean and standard deviation of AgNORs/100 cells was calculated and compared with other cyst types using an analysis of variance and student's t-tests. RESULTS: RESULTS of this study show a statistically significant higher means AgNORs cyst. (p = 0.0016; p = 0.00049 and respectively). However, no statistically significant difference in mean AgNOR score/cell was found when the radicular and dentigerous cysts were compared. CONCLUSION: These variations reflect the difference in the proliferation rate of the odontogenic keratocyst, radicular and dentigerous cysts. PMID- 20852660 TI - Knowledge and practice of standard precautions among health care workers in the Federal Medical Centre, Asaba, Delta State, Nigeria. AB - AIMS AND OBJECTIVES: Health care workers (HCWs) are exposed to blood and other body fluids in the course of their day to day activities in the health care setting. Standard precautions are designed to reduce the risk of transmission of microorganisms from both recognized and unrecognised sources. This study is to determine the knowledge and practice of standard precautions among health care workers in Federal Medical Centre, Asaba, Delta State, Nigeria. SUBJECTS AND METHODS: This descriptive, cross sectional study was carried out among Health Care workers in Federal Medical Centre Asaba, Delta State. A total population of all the doctors and laboratory workers was used while the nurses were selected using a stratified sampling method. A semi-structured, self-administered questionnaire was the tool for data collection. RESULTS: A total of 167 respondents participated in this study. The mean age of the HCWs was 36.9 +/- 6.8 years made up of 47 (28.1%) doctors, 100 (59.9%) nurses and 20 (12.0%) laboratory workers. There were more females (65.3%) than males (34.7%) in the study. One hundred and thirty seven (82.0%) respondents had heard about standard precautions. Only 63 (37.7%) of them had correct knowledge of it. There was fair practice and adherence to the standard precautions by those who knew of it. CONCLUSION: Findings from this study emphasised the need for intensive enlightenment programme to educate health care workers on various aspects of standard precautions and infection control programmes and policies. PMID- 20852661 TI - Domestic refuse management practice in Sokoto: the effect of health education. AB - AIMS AND OBJECTIVES: Domestic refuse remains a major environmental concern in large cities around the world. Its management also continues to be a major challenge. The aim of this study was to assess the effect of health education on the knowledge, attitude and practices of domestic refuse management (DRM) among community members in Sokoto metropolis. MATERIALS AND METHODS: A quasi experimental study design was employed to investigate two sampled (intervention and control groups) population of 225 subjects in the study areas. RESULTS: The mean knowledge score (%) of the study subjects was high and similar (p=0.82), in both the intervention and control groups at baseline, but differed significantly (p<0.0001) at post-intervention. The mean attitude score (%) was high and similar (p=0.38), in both the intervention and control groups at baseline, but differed significantly (p=0.008) at post intervention. The mean observed practice score (%) was low and similar (p=0.42), in both the intervention and control groups at baseline, but differed significantly (p<0.0001) at post-intervention. CONCLUSION: This study has identified the underlying problem of our DRM system to be inherent in the practice component in the triangulation of knowledge, attitude and practice of DRM. The implications of the study findings for healthcare policy, planning and implementation cannot be over-emphasised. PMID- 20852662 TI - Assessment of violence against women in Kano metropolis, Nigeria. AB - BACKGROUND: Violence against women, in its various forms, is endemic in communities and countries around the world, cutting across class, education, race, age, religious and national boundaries. AIMS AND OBJECTIVES: This descriptive cross-sectional study was conducted to identify various forms of gender based violence affecting women in Kano metropolis, determine factors responsible for gender based violence and use this to suggest ways of preventing gender based violence. SUBJECTS AND METHODS: Respondents for this study were selected from the eight metropolitan Local Government Areas of Kano State, Nigeria. Six hundred adult males and females were selected through a multi-stage sampling technique by the use of questionnaire as the data tool. RESULTS: More than three quarters 436 (75.7%) of the respondents knew that women are subjected to various forms of verbal abuse in their homes by their spouses. Deprivation of assess to health care and education was identified by 454 (78.8%) and 490 (85.15) respondents as challenges faced by women at homes. Majority of the respondents 498 (86.4%) identified financial reason, four hundred and forty (76.4%) respondents mentioned unfaithfulness and three-quarters 434 (75.3%) of the respondents said refusal of sexual advance is a reason for violence activities witnessed by women in their respective homes. There was a statistically significant relationship in opinion of male and female on coercion of wife for sexual activities when she is tired and when she is not in the mood (p value=0.0000). CONCLUSION: Government and Non Governmental organisation should intensify activities to promote awareness and advocacy on violence against women. Involvement of males in all programmes relating to violence against women should be done especially since the perpetrators in most cases are men. PMID- 20852663 TI - Influence of maternal height on mode of delivery in Nigerian women. AB - AIMS AND OBJECTIVES: To determine the influence of maternal height on the mode of delivery even when matched for maternal characteristics. The study is a prospective cohort study comparing the mode of delivery in 57 short stature women (d"150 cm) with age and parity-matched, taller control women (n = 57). MATERIALS AND METHODS: A total of 114 parturients were studied, 57 of whom had a height of 150 cm or lower and constituted the study group, while the other 57 taller women were matched with respect to parity (i.e. belonging to same parity group of either nulliparity, para 1-3, para 4+) and maternal age group (i.e. <20, 20-34, 35+ years) to the shorter women and constituted the control group. Patients were also matched by gestational age (28-37 weeks, 38-42 weeks, 42+ weeks) and birth weight (<2500g, 2500-3999g, 4000+) groupings. RESULTS: Caesarean section rate in the short women was higher (42.1%) than in taller women (21.1%), P= 0.016, as was the incidence of cephalopelvic disproportion (35.5% versus 10.3% respectively, P = 0.010). Nevertheless, neonatal outcome remains good; the 5-min Apgar score <7 was 21.1% versus 15.8% respectively, P =0.469, while the stillbirth rate was 10.5% versus 7.0), P = 0.508. CONCLUSION: Short stature is independently associated with an increased risk of intrapartum caesarean section in Nigerian women and advocate early recourse to caesarean section to avoid undue delay. PMID- 20852664 TI - Malpractice and medicolegal issues in radiology practice: knowledge base for residency trainees and trainers. AB - BACKGROUND: Medical malpractice is a global problem of professional negligence resulting in damage or harm to a patient due to deviation from accepted standards of practice. Radiology service delivery to patients from all the four major medical disciplines and the ever increasing imaging arsenal potentially increase the incidence of adverse events in radiology. It is pertinent therefore, that radiology practitioners become conversant with the regulatory role of the medical malpractice system in the protection of the right of patients. AIMS AND OBJECTIVES: To document the knowledge base of medical malpractice in current literature in order to arouse the awareness of radiology residency trainees and trainers to this all-important professional practising issue. MATERIALS AND METHODS: Literature materials on medical malpractice in general and Radiology in particular were reviewed. Four illustrative case reports from past experiences were highlighted. Discussion was carried out on the historical perspective, classes, defendant status, legal requirements and prevention of medical malpractice. RESULTS: Discovery of x-ray in 1895 shifted focus of medical malpractice matters to Radiology. Practically all imaging techniques, including US, CT, MRI have been subject of malpractice lawsuits. Cognitive and perceptual diagnostic errors constitute 70% of malpractice cases against radiologists. CONCLUSION: Adequate professional training, informed consent by the patient and improved doctor-patient relationship are basic to standard medical practice. PMID- 20852665 TI - Choroid plexus papilloma in a Nigerian child: a case report. AB - Choroid plexus papilloma is a rare but known cause of hydrocephalus among children. We report the case of an 8 month old girl who clinically was thought to have post-infective Hydrocephalus. Cranial CT however showed an associated intra ventricular tumour which after surgical resection was reported as a Choroid plexus papilloma. This is the first time such a case is being diagnosed at our hospital and very few cases have been documented in literature from sub-Saharan Africa. This case highlights the available treatment and good prognosis that is possible with Choroid plexus papilloma. It also highlights the need for a high index of suspicion for less common causes of an enlarging head especially when the clinical picture is not typical as demonstrated in our patient. The seeming rarity of this disease in our environment may be partly due to the limited availability of CT scanners in many centres and the paucity of Neuroradiologist and Neurosurgeons in sub-Saharan Africa. PMID- 20852666 TI - Flapless guided implant surgery: a case report and review of literature. AB - Dental implant surgery has traditionally been done through raising flaps, until recently when flapless surgery was advocated. The major challenges of implant placement include correct implant localisation / angulations and osseointegration. In this regard, many types of surgical guides have been proposed. This is a case report of implant placement using flapless guided surgery with a simple surgical guide. A 31 year old female with missing right maxillary canine and left 1st premolar was treated in a private hospital in Lagos, Nigeria. Two implants (BASIC: Bio Anatomical System Implant Corporation USA) with titanium-oxidised surface were proposed for placement. The patient was treated according to the protocol in the BASIC treatment manual. In summary, it involved design and fabrication of a surgical guide and flapless guided implant surgery. This minimally invasive flapless procedure offered less chair time with no complication. The accompanying 3 month osseointegrating period offered a comfortable post surgical period for the patient without compromised treatment outcome. The design technique involved the use of a periapical (P.A) radiograph, impression casts, P.A film overlay. All of which are affordable in a developing environment. PMID- 20852667 TI - Tree diversity promotes insect herbivory in subtropical forests of south-east China. AB - 1.Insect herbivory can strongly affect ecosystem processes, and its relationship with plant diversity is a central topic in biodiversity-functioning research. However, very little is known about this relationship from complex ecosystems dominated by long-lived individuals, such as forests, especially over gradients of high plant diversity.2.We analysed insect herbivory on saplings of 10 tree and shrub species across 27 forest stands differing in age and tree species richness in an extraordinarily diverse subtropical forest ecosystem in China. We tested whether plant species richness significantly influences folivory in these highly diverse forests or whether other factors play a more important role at such high levels of phytodiversity.3.Leaf damage was assessed on 58 297 leaves of 1284 saplings at the end of the rainy season in 2008, together with structural and abiotic stand characteristics.4.Species-specific mean damage of leaf area ranged from 3% to 16%. Herbivory increased with plant species richness even after accounting for potentially confounding effects of stand characteristics, of which stand age-related aspects most clearly covaried with herbivory. Intraspecific density dependence or other abiotic factors did not significantly influence overall herbivory across forest stands.5.Synthesis.The positive herbivory-plant diversity relationship indicates that effects related to hypotheses of resource concentration, according to which a reduction in damage by specialized herbivores might be expected as host plant concentration decreases with increasing plant diversity, do not seem to be major determinants for overall herbivory levels in our phytodiverse subtropical forest ecosystem. We discuss the potential role of host specificity of dominant herbivores, which are often expected to show a high degree of specialization in many (sub)tropical forests. In the forest system we studied, a much higher impact of polyphagous species than traditionally assumed might explain the observed patterns, as these species can profit from a broad dietary mix provided by high plant diversity. Further testing is needed to experimentally verify this assumption. PMID- 20852668 TI - California annual grass invaders: the drivers or passengers of change? AB - The dominance of invasive species is often assumed to reflect their competitive superiority over displaced native species. However, invasive species may be abundant because of their greater tolerance to anthropogenic impacts accompanying their introduction. Thus, invasive species can either be the drivers or passengers of change.We distinguish between these two possibilities in California grasslands currently dominated by Mediterranean annuals (exotics) and subjected to livestock grazing since European settlement. We focused on native annual grasses and forbs, an understudied species-rich component of the California flora, and Mediterranean annual grasses, currently dominant and among the first non-native plants introduced to the area.We established a field experiment with fenced and unfenced blocks in a cattle pasture. We measured concentrations of limiting resources (nitrogen, phosphorus, light and soil moisture) in monoculture plots as an index of competitive ability (i.e. R*). We then quantified grazing impacts on biomass and seed production in grazed vs. ungrazed monoculture plots. Finally, we measured biomass and seed production of each species competing in mixture plots, in the presence and absence of grazers.We found that native and exotic species did not differ in R* indices of competitive ability, i.e. concentrations of limiting resources in ungrazed native monoculture plots did not differ from concentrations in ungrazed exotic monoculture plots. By contrast, exotic annuals suffered less from grazing than native annuals, perhaps reflecting their longer evolutionary history with cattle grazing. Consistent with these results, native and exotic annuals were equally abundant in ungrazed mixtures, but exotic species overwhelmingly dominated grazed mixtures.Species able to draw down nitrogen and light to lower levels in monocultures (i.e. those with lower R* values) dominated biomass and seeds in mixed plots without grazers. However, R* did not predict the relative abundance of species in grazed plots. Moreover, the relative abundance of species in mixtures did not correlate with grazing impacts on their monocultures, implying that grazing alters inter-specific competitive dynamics.Synthesis. We demonstrate that the displacement of native annuals by Mediterranean annual grasses in California may largely have been driven by cattle grazing. PMID- 20852669 TI - Optimal management of sarcopenia. AB - Sarcopenia is the progressive generalized loss of skeletal muscle mass, strength, and function which occurs as a consequence of aging. With a growing older population, there has been great interest in developing approaches to counteract the effects of sarcopenia, and thereby reduce the age-related decline and disability. This paper reviews (1) the mechanisms of sarcopenia, (2) the diagnosis of sarcopenia, and (3) the potential interventions for sarcopenia. Multiple factors appear to be involved in the development of sarcopenia including the loss of muscle mass and muscle fibers, increased inflammation, altered hormonal levels, poor nutritional status, and altered renin-angiotensin system. The lack of diagnostic criteria to identify patients with sarcopenia hinders potential management options. To date, pharmacological interventions have shown limited efficacy in counteracting the effects of sarcopenia. Recent evidence has shown benefits with angiotensin-converting enzyme inhibitors; however, further randomized controlled trials are required. Resistance training remains the most effective intervention for sarcopenia; however, older people maybe unable or unwilling to embark on strenuous exercise training programs. PMID- 20852671 TI - Risk of "silent stroke" in patients older than 60 years: risk assessment and clinical perspectives. AB - With the increasing size of the elderly population and evolving imaging technology, silent brain infarction (SBI) has garnered attention from both the public and the physicians. Over 20% of the elderly exhibit SBI, and the prevalence of SBI increases steadily with age, ie, 30%-40% in those older than 70 years. Well-known cardiovascular risk factors such as hypertension has been identified as a risk factor of SBI (odds ratio [OR] = 3.47) Besides this, blood pressure (BP) reactivity to mental stress, morning BP surges, and orthostatic BP changes have been demonstrated to contribute to the presence of SBI. Further, a metabolic syndrome not only as a whole syndrome (OR =2.18) but also as individual components could have an influence on SBI. Increased C-reactive protein and interleukin-6, coronary artery disease, body mass index, and alcohol consumption have also been associated with SBI. The ORs and possible mechanisms have been discussed in this article. Overt stroke, dementia, depression, and aspiration pneumonia were all associated with SBI. (overt stroke: hazard ratio [HR] =1.9, 95% confidence interval [CI]: 1.2-2.8; dementia: HR =2.26, 95% CI: 1.09-4.70). We also looked into their close relationship with SBI in this review. PMID- 20852670 TI - Levodopa in the treatment of Parkinson's disease: an old drug still going strong. AB - After more than 40 years of clinical use, levodopa (LD) remains the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Compared with other available dopaminergic therapies, dopamine replacement with LD is associated with the greatest improvement in motor function. Long-term treatment with LD is, however, often complicated by the development of various types of motor response oscillations over the day, as well as drug-induced dyskinesias. Motor fluctuations can be improved by the addition of drugs such as entacapone or monoamine oxidase inhibitors, which extend the half-life of levodopa or dopamine, respectively. However, dyskinesia control still represents a major challenge. As a result, many neurologists have become cautious when prescribing therapy with LD. This review summarizes the available evidence regarding the use of LD to treat PD and will also address the issue of LD delivery as a critical factor for the drug's propensity to induce motor complications. PMID- 20852672 TI - Aripiprazole for late-life schizophrenia. AB - Antipsychotics are frequently used in elderly patients to treat a variety of conditions, including schizophrenia. While extensively studied for their impact in younger populations, there is comparatively limited evidence about the effectiveness of these agents in older patients. Further complicating this situation are the high co-morbidity rates (both psychiatric and medical) in the elderly; age-related changes in pharmacokinetics leading to a heightened proclivity for adverse effects; and the potential for multiple, clinically relevant drug interactions. With this background in mind, we review diagnostic and treatment-related issues specific to elderly patients suffering from schizophrenia and other psychotic conditions, focusing on the potential role of aripiprazole. PMID- 20852674 TI - Actual status of veralipride use. AB - During the climacteric period, several symptoms exist that motivate women to seek medical advice; one of the most common is the hot flush, which presents in 75% 85% of these during a variable time span. For the treatment of hot flush, several non-hormonal treatments exist; among them, veralipride has shown to be a useful treatment of vasomotor symptoms during the climacteric period. In recent times, several medical societies have discredited its use. The purpose of this review, therefore, is to define a measured position in relation to the use of this drug. On completion of this review, it was possible to conclude that this drug has an antidopaminergic mechanism of action. The recommended schedule is: 100 mg/day for 20 days, with 10 days drug free. Since the risk of undesirable secondary effects such as galactorrhea, mastodynia, and extrapyramidal can increase with use, no more than 3 treatment cycles are recommended. This drug has a residual effect that can allow drug-free intervals, which permit a longer time between schedules. PMID- 20852675 TI - A Computerized Asthma Outcomes Measure Is Feasible for Disease Management. AB - OBJECTIVE: To develop and test an online assessment referred to as the ASTHMA-CAT (computerized adaptive testing), a patient-based asthma impact, control, and generic health-related quality of life (HRQOL) measure. STUDY DESIGN: Cross sectional pilot study of the ASTHMA-CAT's administrative feasibility in a disease management population. METHODS: The ASTHMA-CAT included a dynamic or static Asthma Impact Survey (AIS), Asthma Control Test, and SF-8 Health Survey. A sample of clinician-diagnosed adult asthmatic patients (N = 114) completed the ASTHMA CAT. Results were used to evaluate administrative feasibility of the instrument and psychometric performance of the dynamic AIS relative to the static AIS. A prototype aggregate (group-level) report was developed and reviewed by care providers. RESULTS: Online administration of the ASTHMA-CAT was feasible for patients in disease management. The dynamic AIS functioned well compared with the static AIS in preliminary studies evaluating response burden, precision, and validity. Providers found reports to be relevant, useful, and applicable for care management. CONCLUSION: The ASTHMA-CAT may facilitate asthma care management. PMID- 20852676 TI - Adapting a Family-Based HIV Prevention Program for HIV-Infected Preadolescents and Their Families: Youth, Families and Health Care Providers Coming Together to Address Complex Needs. AB - This article describes a family-based HIV prevention and mental health promotion program specifically designed to meet the needs of perinatally-infected preadolescents and their families. This project represents one of the first attempts to involve perinatally HIV-infected youth in HIV prevention efforts while simultaneously addressing their mental health and health care needs. The program, entitled CHAMP+ (Collaborative HIV Prevention and Adolescent Mental Health Project-Plus), focuses on: (1) the impact of HIV on the family; (2) loss and stigma associated with HIV disease; (3) HIV knowledge and understanding of health and medication protocols; (4) family communication about puberty, sexuality and HIV; (5) social support and decision making related to disclosure; and (6) parental supervision and monitoring related to sexual possibility situations, sexual risk taking behavior and management of youth health and medication. Findings from a preliminary evaluation of CHAMP+ with six families are presented along with a discussion of challenges related to feasibility and implementation within a primary health care setting for perinatally infected youth. PMID- 20852673 TI - Advantages of dietary, exercise-related, and therapeutic interventions to prevent and treat sarcopenia in adult patients: an update. AB - Sarcopenia is the loss of skeletal muscle mass and function with aging. Although the term sarcopenia was first coined in 1989, its etiology is still poorly understood. Moreover, a consensus for defining sarcopenia continues to elude us. Sarcopenic changes in the muscle include losses in muscle fiber quantity and quality, alpha-motor neurons, protein synthesis rates, and anabolic and sex hormone production. Other factors include basal metabolic rate, increased protein dietary requirements, and chronic inflammation secondary to age-related changes in cytokines and oxidative stress. These changes lead to decreased overall physical functioning, increased frailty, falls risk, and ultimately the loss of independent living. Because the intertwining relationships of these factors are complex, effective treatment options are still under investigation. The published data on sarcopenia are vast, and this review is not intended to be exhaustive. The aim of this review is to provide an update on the current knowledge of the definition, etiology, consequences, and current clinical trials that may help address this pressing public health problem for our aging populations. PMID- 20852677 TI - A COMPARATIVE EVALUATION OF TWO INTERVENTIONS FOR EDUCATOR TRAINING IN HIV/AIDS IN SOUTH AFRICA. AB - The purpose of this study was to compare two different methods to teach educators about HIV/AIDS. Sixty educators were selected from eight schools in KwaZulu-Natal Province, South Africa, to undergo HIV/AIDS training using an interactive CD-ROM intervention. Another sixty educators from other schools were selected to undergo a two-day Care & Support Training Programme provided by the Department of Education. The outcomes both before and after the interventions were measured by surveying the educators' knowledge and attitudes related to HIV/AIDS, as well as their self-efficacy with respect to dealing with HIV/AIDS in the classroom setting. Both interventions resulted in significant changes in knowledge and attitudes as well as in the self-efficacy with respect to ability to teach about HIV/AIDS and to deal with classroom situations involving HIV and blood. The Care & Support Training Programme proved superior in enhancing basic knowledge about HIV, and the CD-ROM was superior in teaching about HIV transmission risks. PMID- 20852678 TI - Characterization of an Anisotropic Hydrogel Tissue Substrate for Infusion Testing. AB - Artificial tissue models that capture specific transport properties are useful for investigating physical phenomena important to drug delivery. In this study, an in vitro tissue model was developed and characterized with the goal of mimicking aligned tissue. An anisotropic porous medium was developed by the construction of a 1% agarose hydrogel implanted with different volume fractions (~ 5, 10, and 20%) of 10-MUm-diameter glass fibers. The developed substrate was able to capture anisotropic transport after the direct infusion of a macromolecular tracer, Evans blue albumin (EBA). To further characterize the test substrate, the diffusion tensor of water was measured by diffusion tensor imaging, and the ratios of the diffusivities in the directions parallel and perpendicular to the glass fibers were 1.16, 1.20, and 1.26 for 5, 10, and 20% fiber volume fractions, respectively. The hydraulic conductivity was estimated by the measurement of pressure gradients across samples under controlled microflow conditions in the direction parallel to implanted fibers. The hydraulic conductivities at various hydrogel concentrations without fibers and in a 1% hydrogel with various fiber volume fractions were measured; for example, K(||) = 1.20 * 10(-12) m(4) N(-1) s(-1) (where K(||) is the conductivity component in the direction parallel to the glass fibers) for 20% fiber volume fractions. Also, EBA distributions were fit to porous medium transport models to estimate hydraulic conductivity in the direction perpendicular to glass fibers. The estimated ratio of directional hydraulic conductivity, K(||)/K(?) (where K(?) is the conductivity component in the direction perpendicular to the glass fibers), ranged from approximately 3 to 5, from 6 to 10, and from 40 to 90 for 5, 10, and 20% fiber volume fractions, respectively. These agarose hydrogel models provided convenient media for quantifying infusion protocols at low flow rates. PMID- 20852679 TI - Changes in American children's time - 1997 to 2003. AB - Over the six-year period between 1997 and 2003 broad social changes occurred in the United States: welfare rules changed, the nation's school policies were overhauled, America was attacked by terrorists, and American values shifted in a conservative direction. Changes in children's time were consistent with these trends. Discretionary time declined. Studying and reading increased over the period, whereas participation in sports declined, suggesting that the increased emphasis on academics at the school level has altered children's behavior at home as well. Increased participation in religious and youth activities and declines in outdoor activities may reflect changes in parental values and security concerns. The results suggest continuation of the upward trend in reading and studying from the 1980s and early 1990s, but increased religious attendance and youth group participation rather than increased participation in sports characterized this recent period. PMID- 20852681 TI - Response to letter by Hadjiev and Mineva. PMID- 20852682 TI - Normal Total WBC and Operative Delay in Appendicitis. PMID- 20852683 TI - Hemorrhagic Fever in california. PMID- 20852684 TI - Acetaminophen toxicity: when to consult the transplant surgeon. PMID- 20852685 TI - Ectopic pregnancy. PMID- 20852687 TI - Ciguatera fish poisoning. PMID- 20852686 TI - Treating influenza in the emergency department. PMID- 20852688 TI - Acute gamma hydroxybutyrate toxicity. PMID- 20852689 TI - The call for academic departments of emergency medicine throughout the university of california. PMID- 20852690 TI - Gamma-Hydroxybutyrate (GHB) With-Drawal. PMID- 20852691 TI - Emerging infections in 2001. PMID- 20852692 TI - Evaluation of documentation practices of sexual assault nurse examiners. PMID- 20852693 TI - The impact of global warming and air pollution on patient visits in the emergency department. PMID- 20852694 TI - Clinical findings in patients with splenic injuries: are injuries to the left lower chest important? PMID- 20852695 TI - Outbreak of datura ingestion at a juvenile correctional facility. PMID- 20852696 TI - EMS Adherence to a Pre-hospital Cervical Spine Clearance Protocol. AB - PURPOSE: To determine the degree of adherence to a cervical spine (c-spine) clearance protocol by pre-hospital Emergency Medical Services (EMS) personnel by both self-assessment and receiving hospital assessment, to describe deviations from the protocol, and to determine if the rate of compliance by paramedic self assessment differed from receiving hospital assessment. METHODS: A retrospective sample of pre-hospital (consecutive series) and receiving hospital (convenience sample) assessments of the compliance with and appropriateness of c-spine immobilization. The c-spine clearance protocol was implemented for Orange County EMS just prior to the April-November 1999 data collection period. RESULTS: We collected 396 pre-hospital and 162 receiving hospital data forms. From the pre hospital data sheet, the percentage deviation from the protocol was 4.0% (16/396). Only one out of 16 cases that did not comply with the protocol was due to over immobilization (0.2%). The remaining 15 cases were under immobilized, according to protocol. Nine of the under immobilized cases (66%) that should have been placed in c-spine precautions met physical assessment criteria in the protocol, while the other five cases met mechanism of injury criteria. The rate of deviations from protocol did not differ over time. The receiving hospital identified 8.0% (13/162; 6/l6 over immobilized, 7/16 under immobilized) of patients with deviations from the protocol; none was determined to have actual c spine injury. CONCLUSION: The implementation of a pre-hospital c-spine clearance protocol in Orange County was associated with a moderate overall adherence rate (96% from the pre-hospital perspective, and 9250 from the hospital perspective. p = .08 for the two evaluation methods). Most patients who deviated from protocol were under immobilized. but no c-spine injuries were missed. The rate of over immobilization was better than previously reported, implying a saving of resources. PMID- 20852697 TI - Physostigmine as an antidote. PMID- 20852698 TI - Reperfusion Strategies for Acute Myocardial Infarction: Mechanical vs. Thrombolytic Therapy. PMID- 20852700 TI - Triage and ED Overcrowding: Two Cases of Unexpected Outcome. PMID- 20852699 TI - Bioterrorism. PMID- 20852701 TI - Quinapril overdose-induced renal failure. PMID- 20852702 TI - Utility of the CORD ECG Database in Evaluating ECG Interpretation by Emergency Medicine Residents. AB - OBJECTIVES: Electrocardiograph (ECG) interpretation is a vital component of Emergency Medicine (EM) resident education, but few studies have formally examined ECG teaching methods used in residency training. Recently, the Council of EM Residency Directors (CORD) developed an Internet database of 395 ECGs that have been extensively peer-reviewed to incorporate all findings and abnormalities. We examined the efficacy of this database in assessing EM residents' skills in ECG interpretation. METHODS: We used the CORD ECG database to evaluate residents at our academic three-year EM residency. Thirteen residents participated, including four first-year, four second-year, and five third-year residents. Twenty ECGs were selected using 14 search criteria representing a broad range of abnormalities, including infarction, rhythm, and conduction abnormalities. Exams were scored based on all abnormalities and findings listed in the teaching points accompanying each ECG. We assigned points to each abnormal finding based on clinical relevance. RESULTS: Out of a total of 183 points in our clinically weighted scoring system, first-year residents scored an average of 99 points (54.1%) [91-119], second-year residents 111 points (60.4%) [97-126], and third-year residents 130 points (71.0%) [94-150], p = 0.12. Clinically relevant abnormalities, including anterior and inferior myocardial infarctions, were most frequently diagnosed correctly, while posterior infarction was more frequently missed. Rhythm abnormalities including ventricular and supraventricular tachycardias were most frequently diagnosed correctly, while conduction abnormalities including left bundle branch block and atrioventricular (AV) block were more frequently missed. CONCLUSION: The CORD database represents a valuable resource in the assessment and teaching of ECG skills, allowing more precise identification of areas upon which instruction should be further focused or individually tailored. Our experience suggests that more focused teaching of conduction abnormalities and posterior infarctions may be beneficial. The CORD database should be considered for incorporation into an ECG curriculum during residency training. PMID- 20852703 TI - Syphilis Testing in Emergency Department Patients Treated for Other STDs. PMID- 20852705 TI - A case of imported malaria in california: an overview of a globally widespread disease. PMID- 20852704 TI - When looking at a non-contrast head CT, what actually appears white in an acute hemorrhagic stroke? PMID- 20852706 TI - Holding on to your kids: a report on car seat safety in san francisco. PMID- 20852707 TI - Overcrowding in U.S. EDS: A Critical Condition. PMID- 20852708 TI - Flexible bedside monitoring and assisted consultation in rural emergency departments. PMID- 20852709 TI - Abstracts from the CAL/ACEP Scientific Assembly, Long Beach, CA 2002. PMID- 20852710 TI - Regarding CaJEM July 2001's "We Told You So" President's Message. PMID- 20852711 TI - The effects of the FDA warning on the use of droperidol by u.s. Emergency physicians. AB - OBJECTIVES: To determine if emergency physicians' (EP) use of droperidol has changed since the United States Food and Drag Administration (FDA) warning of December 2001 concerning QT interval prolongation, torsade de pointes, and sudden death; and to query EP opinions regarding droperidol before and after the FDA warning and regarding potential alternative drugs. METHODS: An internet-based survey was designed with questions regarding droperidol use in the emergency department (ED). Data collected included EP demographics, use of droperidol before and after the FDA warning, use of alternative drugs, and incidence of arrhythmias. A representative sample of EPs were contacted by e-mail and asked to complete the survey. RESULTS: A total of 2,000 e-mails resulted in 506 (25%) completed surveys. There was no second mailing. Responders' average years practicing was 12.6 +/- 9.2. EP responders worked in private/community (n=278, 55%), academic/county (n=187, 37%), and HMO (n=41, 8%) hospitals. The. majority (n=455, 90%) used droperidol and were aware of the FDA warning (n=460, 91%). Droperidol was no longer available at 122 (24%) of the respondents' EDs as a result of the FDA warning. Prior to the FDA warning, EPs who had used droperidol used it as an antiemetic (n=408, 90%), for control of agitation (n=330, 73%), for treatment of headache (n=247, 54%), and for treatment of vertigo (n=106, 23%). After the FDA warning, 387 (85%) of EPs reported their use of droperidol had decreased or ceased altogether, and 68 (15%) always obtained an electrocardiogram prior to administration. Of those who used droperidol for agitation, 137 (42%) felt there were no other drugs with greater efficacy. Haloperidol was the most cited alternative agent (n=260, 79%) followed by benzodiazepines (n=223, 68%). Of those who used droperidol for antiemesis, 116 (28%) felt there were no other drugs with greater efficacy than droperidol; promethazine was the most cited alternative agent (n=260, 64%). Two (0.4%) EPs reported arrhythmias in patients who received droperidol. Only 37 (8%) EPs reported they were unconcerned with potential loss of droperidol from the market. CONCLUSION: Based on this survey, EP use of droperidol has decreased dramatically as a result of the FDA warning. However, EPs believe that there are few or no alternative antiemetic drugs that have an improved adverse effect profile. PMID- 20852713 TI - Welcome. PMID- 20852712 TI - I Can't Believe It's Not Toothpaste! Poison Control Center Calls Regarding Dental and Oral-Care Products. AB - BACKGROUND: A cluster of incidents in which non-tooth-paste products were used to brush teeth prompted a review of all calls to one Poison Control Center (PCC) regarding exposures to dental and oral-care products to determine if any resulted in significant toxicity. METHODS: Retrospective review of 65,849 calls to one PCC during one calendar year. All inquiries about exposures to substances used as dental or oral-care products were analyzed by a single reviewer for reported adverse effects; including hospital admission or PCC referral for emergent medical evaluation. RESULTS: 798 calls involved exposure to dental or oral-care products, comprising 1.21 % of all calls received. Toothbrushing incidents with non-toothpaste products (122 cases) did not result in any significant recognized toxicity. Twenty-four patients were either referred for emergent medical evaluation (14) or were admitted to the hospital (10). In 23 of these patients (96%), the toxic agent was either an over-the-counter analgesic or a local anesthetic used to treat dental pain. CONCLUSIONS: Among PCC calls received regarding dental and oral-care products, over-the-counter analgesics and local anesthetics used for dental pain resulted in the most frequent need for emergent medical evaluation or for hospital admission. PMID- 20852714 TI - Phenobarbital for alcohol withdrawal: rapid patient disposition. PMID- 20852716 TI - Landmark trial starts. PMID- 20852715 TI - Overcrowding in emergency departments: effects on patients. PMID- 20852717 TI - NANOROBOTS FOR MICROFACTORIES TO OPERATIONS IN THE HUMAN BODY AND ROBOTS PROPELLED BY BACTERIA. AB - The exploitation of the properties at the nanoscale enables novel nanorobotic based instrumented platforms and techniques. Here, some unique interdisciplinary examples from our research laboratory are briefly described providing some insights about the possibilities and the huge potentials of nanorobotics with main areas of applications in medicine and bioengineering, including supporting new robotic platforms for micro- and nano-manufacturing and high-throughput automatic operations at the nanoscale. For several applications where specifications cannot be met using modern technologies, especially at such small scales, a highly interdisciplinary approach integrating biological components in engineered systems becomes an essential part of the development process. PMID- 20852718 TI - Minor Groove Interactions between Polymerase and DNA: More Essential to Replication than Watson-Crick Hydrogen Bonds? PMID- 20852719 TI - Politics or Economics? International Migration during the Nicaraguan Contra War. AB - The issue of whether Central Americans in the United States are 'political' or 'economic' migrants has been widely debated, yet little empirical research has informed the controversy. Earlier studies have relied primarily on cross sectional aggregate data. In order to overcome these limitations we draw on recent surveys conducted in five Nicaraguan communities by the Latin American Migration Project. Using retrospective data, we reconstruct a history of a family's migration to the United States and Costa Rica from the date of household formation to the survey date and link these data to national-level data on GDP and Contra War violence. While out migration to both Costa Rica and the United States is predicted by economic trends, US-bound migration was more strongly linked to the level of Contra War violence independent of economic motivations, especially in an interactive model that allows for a higher wartime effect of social networks. We conclude that elevated rates of Nicaraguan migration to the United States during the late 1980s and early 1990s were a direct result of the US-Contra intervention. The approach deployed here - which relates to the timing of migration decisions to macro-level country trends - enables us to address the issue of political versus economic motivations for migration with more precision than prior work. PMID- 20852720 TI - Structure and Base Pairing Properties of a Replicable Nonpolar Isostere for Deoxyadenosine. AB - We report the synthesis, structure, and pairing properties in DNA of an isostere for deoxyadenosine which lacks all hydrogen-bonding functionality on the Watson Crick pairing edge. A deoxyribo-nucleoside derivative of 4-methylbenzimidazole (1), which was recently shown to be inserted into DNA by Klenow DNA polymerase (Morales, J. C.; Kool, E. T. Nature Struct. Biol.1998, 5, 950), is prepared from 1-chloro-2-deoxy-3,5-bis-O-p-toluoyl-alpha-D-erythro-pentofuranose. The X-ray crystal structure of the nucleoside confirms that the compound is a close steric match for deoxyadenosine (2), although the methylbenzimidazole base is in the syn glycosidic orientation in the crystal. In D(2)O solution, 1H NMR studies show that 1 and 2 have similar (60% vs 70% S) sugar conformations and anti glycosidic orientations. Compound 1 is incorporated into a 12mer oligodeoxynucleotide and its base pairing properties in duplexes assessed by thermal denaturation. The results show that 1 has low affinity for the four natural bases but displays a stronger preference for being situated opposite a nonpolar difluorotoluene nucleoside analogue of thymine (3). The structural similarities of 1 and 2, combined with recent polymerase studies, add support to the hypothesis that steric complementarity plays an important role in base pair replication by polymerase enzymes and that Watson-Crick hydrogen bonds are not absolute requirements. Compound 1 should have significant utility as a probe of the importance of electrostatic effects in protein-DNA and protein-nucleotide binding as well as in DNA replication. PMID- 20852721 TI - Selective and Stable DNA Base Pairing without Hydrogen Bonds. PMID- 20852723 TI - Kyol Goeu ('Wind Overload') Part I: A Cultural Syndrome of Orthostatic Panic among Khmer Refugees. AB - Certain cultural syndromes seem to increase the risk of panic attacks by generating catastrophic cognitions about symptoms of autonomic arousal. These schemas create a constant anxious scanning of the body, hence facilitating, maintaining, and producing panic. As a case in point, a Khmer fainting syndrome,'wind overload' (kyol goeu), results in dire expectations concerning the autonomic symptoms experienced upon standing, thus contributing to the high rate of orthostatically induced panic observed in this population. PMID- 20852722 TI - Physiology and Endocrinology of the Ovarian Cycle in Macaques. AB - Macaques provide excellent models for preclinical testing and safety assessment of female reproductive toxicants. Currently, cynomolgus monkeys are the predominant species for (reproductive) toxicity testing. Marmosets and rhesus monkeys are being used occasionally. The authors provide a brief review on physiology and endocrinology of the cynomolgus monkey ovarian cycle, practical guidance on assessment and monitoring of ovarian cyclicity, and new data on effects of social housing on ovarian cyclicity in toxicological studies. In macaques, cycle monitoring is achieved using daily vaginal smears for menstruation combined with cycle-timed frequent sampling for steroid and peptide hormone analysis. Owing to requirements of frequent and timed blood sampling, it is not recommended to incorporate these special evaluations into a general toxicity study design. Marmosets lack external signs of ovarian cyclicity, and cycle monitoring is done by regular determinations of progesterone. Cynomolgus and marmoset monkeys do not exhibit seasonal variations in ovarian activity, whereas such annual rhythm is pronounced in rhesus monkeys. Studies on pair- and group-housed cynomolgus monkeys revealed transient alterations in the duration and endocrinology of the ovarian cycle followed by return to normal cyclicity after approximately six months. This effect is avoided if the animals had contact with each other prior to mingling. These experiments also demonstrated that synchronization of ovarian cycles did not occur. PMID- 20852724 TI - Case notes and clinicians: Galen's "Commentary" on the Hippocratic "Epidemics" in the Arabic tradition. AB - Galen's "Commentaries" on the Hippocratic "Epidemics" constitute one of the most detailed studies of Hippocratic medicine from antiquity. The Arabic translation of the "Commentaries" by Hunayn ibn Ishaq (d. c. 873) is of crucial importance because it preserves large sections now lost in Greek, and because it helped to establish an Arabic clinical literature. The present contribution investigate the translation of this seminal work into Syriac and Arabic. It provides a first survey of the manuscript tradition, and explores how physicians in the medieval Muslim world drew on it both to teach medicine to students, and to develop a framework for their own clinical research. PMID- 20852726 TI - What Costs Do Reveal and Moving Beyond the Cost Debate: Reply to Einstein and McDaniel (in press). AB - Einstein et al., (2005) predicted no cost to an ongoing task when a prospective memory task meet certain criteria. Smith et al. (2007) used prospective memory tasks that met these criteria and found a cost to the ongoing task, contrary to Einstein et al.'s prediction. Einstein and McDaniel (in press) correctly note that there are limitations to using ongoing task performance as a measure of the processes that contribute to prospective memory performance, however, the alternatives suggested by Einstein and McDaniel all focus on ongoing task performance and therefore do not move beyond the cost debate. This article describes why the Smith et al. findings are important, provides recommendations for issues to consider when investigating cost, and discusses individual cost measures. Finally, noting the blurry distinction between Einstein and McDaniel's description of the reflexive associative processes and preparatory attentional processes and difficulties in extending the multiprocess view to nonlaboratory tasks, suggestions are made for moving beyond the cost debate. PMID- 20852725 TI - Studying a population undergoing nutrition transition: a practical case study of dietary assessment in urban South African adolescents. AB - The South African Medical Research Council food frequency questionnaire (FFQ) and protocol was used to determine food intake in 83 adolescents from the Birth To Twenty study. The FFQ was piloted on a small group (n=8). Specific problems which resulted in overestimation of energy intake were identified. The protocol was modified and administered to the remainder of the adolescents and their caregivers. Reasonable energy intakes were obtained, and time spent completing the FFQ was reduced. The modified protocol was more successful in determining habitual food intake although it would benefit from validation against other dietary intake techniques. PMID- 20852727 TI - Response to Commentary on "Agricultural exposures and gastric cancer risk in Hispanic farm workers in California" (Mills, P.K., and Yang, R.C., Environmental Research (2007) 104, 282-289). PMID- 20852728 TI - Steroidal regulation of uterine miRNAs is associated with modulation of the miRNA biogenesis components Exportin-5 and Dicer1. AB - MicroRNAs (miRNAs) are small, non-coding RNA molecules which post transcriptionally regulate gene expression. We have previously demonstrated that within the uterus, miRNA expression is under steroidal control and that disruption of Dicer1, the enzyme which generates mature miRNAs, leads to abnormalities in the development and function of the female reproductive tract. Despite the apparent importance of miRNAs and the enzymes which lead to their generation, little to no information exists on the mechanisms which regulate the expression of this system in the female reproductive tract. The objective of the current study was to examine steroidal regulation of the miRNAs biogenesis enzymes, Drosha, Dgcr8, Exportin-5 and Dicer1 in the mouse uterus. The results of this study indicate that estrogen and progesterone significantly increased Exportin-5 mRNA expression while only progesterone increased Dicer1 expression. We conclude from these studies that the miRNA biogenesis components Drosha, Dgcr8, Exportin-5 and Dicer1 are expressed in the mouse uterus and that Exportin 5 and Dicer1 appear to be the major steroid regulated components in the miRNA biogenesis pathway. These observations suggest that in addition to steroids modulating miRNA expression at the level of transcription, they may also influence miRNA expression by regulating the expression of the miRNA biogenesis components necessary for their processing to the mature cytoplasmic form. PMID- 20852729 TI - Fabrication Methods and Performance of Low-Permeability Microfluidic Components for a Miniaturized Wearable Drug Delivery System. AB - In this paper, we describe low-permeability components of a microfluidic drug delivery system fabricated with versatile micromilling and lamination techniques. The fabrication process uses laminate sheets which are machined using XY milling tables commonly used in the printed-circuit industry. This adaptable platform for polymer microfluidics readily accommodates integration with silicon-based sensors, printed-circuit, and surface-mount technologies. We have used these methods to build components used in a wearable liquid-drug delivery system for in vivo studies. The design, fabrication, and performance of membrane-based fluidic capacitors and manual screw valves provide detailed examples of the capability and limitations of the fabrication method. We demonstrate fluidic capacitances ranging from 0.015 to 0.15 MUL/kPa, screw valves with on/off flow ratios greater than 38 000, and a 45* reduction in the aqueous fluid loss rate to the ambient due to permeation through a silicone diaphragm layer. PMID- 20852730 TI - Fluid Flow Induced Calcium Response in Bone Cell Network. AB - In our previous work, bone cell networks with controlled spacing and functional intercellular gap junctions had been successfully established by using microcontact printing and self assembled monolayers technologies [Guo, X. E., E. Takai, X. Jiang, Q. Xu, G. M. Whitesides, J. T. Yardley, C. T. Hung, E. M. Chow, T. Hantschel, and K. D. Costa. Mol. Cell. Biomech. 3:95-107, 2006]. The present study investigated the calcium response and the underlying signaling pathways in patterned bone cell networks exposed to a steady fluid flow. The glass slides with cell networks were separated into eight groups for treatment with specific pharmacological agents that inhibit pathways significant in bone cell calcium signaling. The calcium transients of the network were recorded and quantitatively evaluated with a set of network parameters. The results showed that 18alpha-GA (gap junction blocker), suramin (ATP inhibitor), and thapsigargin (depleting intracellular calcium stores) significantly reduced the occurrence of multiple calcium peaks, which were visually obvious in the untreated group. The number of responsive peaks also decreased slightly yet significantly when either the COX 2/PGE(2) or the NOS/nitric oxide pathway was disrupted. Different from all other groups, cells treated with 18alpha-GA maintained a high concentration of intracellular calcium following the first peak. In the absence of calcium in the culture medium, the intracellular calcium concentration decreased slowly with fluid flow without any calcium transients observed. These findings have identified important factors in the flow mediated calcium signaling of bone cells within a patterned network. PMID- 20852731 TI - Differentiating ASD from DLD in Toddlers. AB - Until recently children with autism spectrum disorders (ASD) were rarely diagnosed before the age of 3 to 4 years. But a major thrust of current research has been to lower the age of identification, due in part to evidence supporting the effectiveness of early intervention. Late talkers -- toddlers who appear to be developing normally but do not begin speaking, acquire words very slowly, and do not begin combining words at the typical ages --are also typically seen in their second year or early in the third year of life. This report presents the findings of a comparison of toddlers who received clinical diagnoses of ASD and those who were clinically diagnosed as DLD in order to examine the patterns of behavior in the second and third years of life in these two groups. Findings suggest that, when matched on expressive language level, toddlers with ASD and DLD are similar, and less skilled than toddlers with TD, in their use of gaze to regulate interactions, their ability to share emotions with others, to engage in back-and-forth interactions, their rate of communication, and the range of sounds and words produced. The children with DLD were similar to those with TD, and higher than those with ASD, in terms of their nonverbal cognitive skills, use of gestures to communicate, use of pretend play, and ability to respond to language. Children with DLD did show some weaknesses in interpersonal skills -- such as sharing affect, using gaze, and initiating communication. However, their ability to engage in pretend play, use gestures to communicate and respond to language are sufficient to differentiate them from age-mates with ASD. The clinical implications of these findings are discussed. PMID- 20852732 TI - Differential Survivorship of Invasive Mosquito Species in South Florida Cemeteries: Do Site-Specific Microclimates Explain Patterns of Coexistence and Exclusion? AB - Within 2 yr of the arrival of the invasive container mosquito Aedes albopictus (Skuse), the previously dominant invasive mosquito Aedes aegypti (L.) disappeared from many Florida cemeteries. At some cemeteries, however, Ae. aegypti populations seem stable despite Ae. albopictus invasion. We sought to understand this variation in the outcome (exclusion, coexistence) of this invasion, given that previous experiments show that Ae. albopictus is the superior larval competitor. We tested experimentally the hypothesis that climate-dependent egg survivorship differs between exclusion and coexistence cemeteries and that differences in invasion outcome are associated with microclimate. Viability of eggs oviposited in the laboratory and suspended in vases at six cemeteries was significantly greater for Ae. aegypti than for Ae. albopictus, and greater in 2001 than in 2006. Cemeteries differed significantly in egg survivorship of Ae. albopictus, but not of Ae. aegypti, which is consistent with the hypothesis that Ae. albopictus suffers site-specific, climate-driven egg mortality that mitigates the competitive superiority of larval Ae. albopictus. Principal component (PC) analysis of microclimate records from vases during the experiments yielded three PCs accounting for >96% of the variance in both years of experiments. Multivariate analysis of variance of the three PCs revealed significant microclimate differences among the six cemeteries and between exclusion versus coexistence cemeteries. Stepwise logistic regression of egg survivorship versus microclimate PCs yielded significant fits for both species, and twice as much variance explained for Ae. albopictus as for Ae. aegypti in both years. Higher mortalities in 2006 were associated with high average daily maximum temperatures in vases, with lethal thresholds for both species at ~40 degrees C. From 1990 to 2007, vase occupancy by Ae. albopictus increased and that by Ae. aegypti decreased, with increasing seasonal precipitation at one well-sampled cemetery. Results support the hypothesis that locally variable climate-driven mortality of Ae. albopictus eggs contributes to patterns of exclusion of, or coexistence with, Ae. aegypti. PMID- 20852733 TI - Visualizing Fluorescence: Using a Homemade Fluorescence "Microscope" to View Latent Fingerprints on Paper. AB - We describe an inexpensive handheld fluorescence imager (low-magnification microscope), constructed from poly(vinyl chloride) pipe and other inexpensive components for use as a teaching tool to understand the principles of fluorescence detection. Optical filters are used to select the excitation and emission wavelengths and can be easily interchanged to accommodate different fluorescent samples. As a demonstration, we used the fluorescence imager to view lawsone-dyed fingerprints on paper, which fluoresce red when illuminated with green light. This emission can be seen by viewing the sample through the instrument by eye, or the fluorescence can be captured by a camera. The entire imager can be built for less than $300. PMID- 20852735 TI - Corrigendum. PMID- 20852736 TI - Cyclosporine G Analysis and Monitoring by High-Pressure Liquid Chromatography. PMID- 20852737 TI - Histiocytic Lymphoma in Renal Transplant Patients Receiving Cyclosporine. PMID- 20852734 TI - Expression of pax6 and sox2 in adult olfactory epithelium. AB - The olfactory epithelium maintains stem and progenitor cells that support the neuroepithelium's life-long capacity to reconstitute after injury. However, the identity of the stem cells--and their regulation--remain poorly defined. The transcription factors Pax6 and Sox2 are characteristic of stem cells in many tissues, including the brain. Therefore, we assessed the expression of Pax6 and Sox2 in normal olfactory epithelium and during epithelial regeneration after methyl bromide lesion or olfactory bulbectomy. Sox2 is found in multiple kinds of cells in normal epithelium, including sustentacular cells, horizontal basal cells, and some globose basal cells. Pax6 is co-expressed with Sox2 in all these, but is also found in duct/gland cells as well as olfactory neurons that innervate necklace glomeruli. Most of the Sox2/Pax6-positive globose basal cells are actively cycling, but some express the cyclin-dependent kinase inhibitor p27(Kip1), and are presumably mitotically quiescent. Among globose basal cells, Sox2 and Pax6 are co-expressed by putatively multipotent progenitors (labeled by neither anti-Mash1 nor anti-Neurog1) and neuron-committed transit amplifying cells (which express Mash1). However, Sox2 and Pax6 are expressed by only a minority of immediate neuronal precursors (Neurog1- and NeuroD1-expressing). The assignment of Sox2 and Pax6 to these categories of globose basal cells is confirmed by a temporal analysis of transcription factor expression during the recovery of the epithelium from methyl bromide-induced injury. Each of the Sox2/Pax6-colabeled cell types is at a remove from the birth of neurons; thus, suppressing their differentiation may be among the roles of Sox2/Pax6 in the olfactory epithelium. PMID- 20852738 TI - Early Function of Heart, Liver, and Kidney Allografts Following Combined Procurement. PMID- 20852739 TI - Stimuli, reinforcers, and the persistence of behavior. AB - This article reviews evidence from basic and translational research with pigeons and humans suggesting that the persistence of operant behavior depends on the contingency between stimuli and reinforcers, and considers some implications for clinical interventions. PMID- 20852740 TI - The LIM Protein Zyxin Binds CARP-1 and Promotes Apoptosis. AB - Zyxin is a dual-function LIM domain protein that regulates actin dynamics in response to mechanical stress and shuttles between focal adhesions and the cell nucleus. Here we show that zyxin contributes to UV-induced apoptosis. Exposure of wild-type fibroblasts to UV-C irradiation results in apoptotic cell death, whereas cells harboring a homozygous disruption of the zyxin gene display a statistically significant survival advantage. To gain insight into the molecular mechanism by which zyxin promotes apoptotic signaling, we expressed an affinity tagged zyxin variant in zyxin-null cells and isolated zyxin-associated proteins from cell lysates under physiological conditions. A 130-kDa protein that was co isolated with zyxin was identified by microsequence analysis as the Cell Cycle and Apoptosis Regulator Protein-1 (CARP-1). CARP-1 associates with the LIM region of zyxin. Zyxin lacking the CARP-1 binding region shows reduced proapoptotic activity in response to UV-C irradiation. We demonstrate that CARP-1 is a nuclear protein. Zyxin is modified by phosphorylation in cells exposed to UV-C irradiation, and nuclear accumulation of zyxin is induced by UV-C exposure. These findings highlight a novel mechanism for modulating the apoptotic response to UV irradiation. PMID- 20852741 TI - Influence of dendrimer surface charge on the bioactivity of 2-methoxyestradiol complexed with dendrimers. AB - We report the complexation of a potential anticancer agent 2-methoxyestradiol (2 ME) with generation 5 (G5) poly(amidoamine) dendrimers having different surface functional groups for therapeutic applications. The complexation experiment shows that approximately 6-8 drug molecules can be complexed with one dendrimer molecule regardless the type of the dendrimer terminal groups. The bioactivity of 2-ME complexed with dendrimers was found to be significantly dependent on the surface charge of G5 dendrimers. In vitro cell biological assays show that amine, hydroxyl, and acetamide-terminated G5 dendrimers with positive, slightly positive, and close to neutral surface charges, respectively are able to deliver 2-ME to inhibit cancer cell growth. In contrast, 2-ME complexed with carboxyl terminated G5 dendrimers with negative surface charges does not show its inherent bioactivity. Further molecular dynamics simulation studies show that the compact structure of carboxylated G5 dendrimers complexed with 2-ME does not allow the release of the drug molecules even at a pH of 5.0, which is the typical pH value in lysosome. Our findings indicate that the surface modification of dendrimers with different charges is crucial for the development of formulations of various anticancer drugs for therapeutic applications. PMID- 20852742 TI - Family-Based HIV Preventive Intervention: Child Level Results from the CHAMP Family Program. AB - Social indicators suggest that African American adolescents are in the highest risk categories of those contracting HIV/AIDS (CDC, 2001). The dramatic impact of HIV/AIDS on urban African American youth have influenced community leaders and policy makers to place high priority on programming that can prevent youth's exposure to the virus (Pequegnat & Szapocznik, 2000). Program developers are encouraged to design programs that reflect the developmental ecology of urban youth (Tolan, Gorman-Smith, & Henry, 2003). This often translates into three concrete programmatic features: (1) Contextual relevance; (2) Developmental groundedness; and (3) Systemic Delivery. Because families are considered to be urban youth's best hope to grow up and survive multiple-dangers in urban neighborhoods (Pequegnat & Szapocznik, 2000), centering prevention within families may ensure that youth receive ongoing support, education, and messages that can increase their capacity to negotiate peer situations involving sex.This paper will present preliminary data from an HIV/AIDS prevention program that is contextually relevant, developmentally grounded and systematically-delivered. The collaborative HIV/AIDS Adolescent Mental Health Project (CHAMP) is aimed at decreasing HIV/AIDS risk exposure among a sample of African American youth living in a poverty-stricken, inner-city community in Chicago. This study describes results from this family-based HIV preventive intervention and involves 88 African American pre-adolescents and their primary caregivers. We present results for the intervention group at baseline and post intervention. We compare post test results to a community comparison group of youth. Suggestions for future research are provided. PMID- 20852743 TI - Rural Community Characteristics, Economic Hardship, and Peer and Parental Influences in Early Adolescent Alcohol Use. AB - The study explores how differences in rural community contexts relate to early adolescent alcohol use. Data were gathered from 1,424 adolescents in the sixth through eighth grades in 22 rural Northern Plains communities, as well as 790 adults, parents, teachers, and community leaders. Multilevel modeling analyses revealed that community supportiveness, as perceived by adolescents, but not adults, was associated with less lifetime and past month alcohol use, and for past month use, this relationship was stronger than perceived peer drinking or parental closeness. Perceived peer drinking and parental closeness were not associated with past month use. Adolescents experiencing family economic strain did not report greater lifetime or past month use, but living in a disadvantaged community was associated with greater past month use. Relatively affluent adolescents reported greater past month use when living in a poor community than did poorer adolescents, highlighting relationship complexity between economic disadvantage and alcohol use. PMID- 20852744 TI - The assessment and treatment of prosodic disorders and neurological theories of prosody. AB - In this article, we comment on specific aspects of Peppe (Peppe, 2009). In particular, we address the assessment and treatment of prosody in clinical settings and discuss current theory on neurological models of prosody. We argue that in order for prosodic assessment instruments and treatment programs to be clinical effective, we need assessment instruments that: (1) have a representative normative comparison sample and strong psychometric properties; (2) are based on empirical information regarding the typical sequence of prosodic acquisition and are sensitive to developmental change; (3) meaningfully subcategorize various aspects of prosody; (4) use tasks that have ecological validity; and (5) have clinical properties, such as length and ease of administration, that allow them to become part of standard language assessment batteries. In addition, we argue that current theories of prosody processing in the brain are moving toward network models that involve multiple brain areas and are crucially dependent on cortical communication. The implications of these observations for future research and clinical practice are outlined. PMID- 20852745 TI - Muscarinic receptor antagonist and an alpha-adrenergic agonist are required in combination to provide stable mydriasis following intravitreal injection in mice. AB - Tropicamide (muscarinic receptor antagonist) and phenylephrine (alpha-adrenergic receptor agonist) are commonly used to dilate the pupils by topical application. These two eye drops are often used, singly or in combination, to dilate the pupil and perform acute light-evoked physiological experiments (electroretinography, for example), before and after intravitreal injections of pharmacological agents, as an assay for their affect on retinal activity. This study wanted to determine whether treatment with one of these drugs, or with both, is most effective in maintaining mydriasis after intravitreal injections. Changes in pupillary dilation before and after intravitreal injection of balanced salt solution (0.5 ul) were recorded. Phenylephrine (alpha-adrenergic agonist) and tropicamide (muscarinic agonist) when combined, but not singly, produced full and stable pupillary dilation following intravitreal injections. Re-instillation of topical mydriatics after intravitreal injections was required for maximal pupillary dilation. A combination of a muscarinic receptor antagonist and an alpha adrenergic agonist is required for stable mydriasis following intravitreal injection. PMID- 20852746 TI - Liver X Receptors as Therapeutic Targets for Managing Cholesterol: Implications for Atherosclerosis and Other Inflammatory Conditions. AB - Atherosclerosis is a disease characterized by excess cholesterol and inflammation in the blood vessels. The liver X receptors (alpha and beta) are members of the nuclear hormone receptor family that are activated by endogenous cholesterol metabolites. These receptors are widely expressed with a tissue distribution that includes the liver, intestine and macrophage. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. More recently, they have also been shown to inhibit the inflammatory response in macrophages. These functions are accomplished through direct regulation of gene transcription. Herein, we will describe the key benefits and potential risks of targeting the LXRs for the treatment of atherosclerosis. PMID- 20852747 TI - Suppression of heart NF-kappaB p65 expression by jugular vein injection of RNAi in mice. AB - The nuclear factor-kappaB (NF-kappaB) in cardiac vascular endothelial cells (type II VEC) is a key factor that activates delayed xenograft rejection (DXR), and therefore inhibition of NF-kappaB gene expression may alleviate post-transplant rejection. siRNA technology was used to inhibit NF-kappaB p65 gene expression in ICR mice. After jugular vein injection of siRNA/in vivo-jetPEI complex, fluorescence levels of FAM-labeled siRNA in hearts and lungs were much higher after jugular vein injection than tail vein injection, suggesting more efficient siRNA delivery to the heart through the jugular vein. The amount of FAM fluorescence of hearts increased to the highest level between 48 and 72 hours after injection, and decreased gradually 1 week after injection. A minimum dose of 6 nmol NF-kappaB p65 siRNA and a siRNA/in vivo-jetPEI ratio of 6 (N/P = 6) were required for in vivo siRNA-mediated gene silencing in the heart. Under these conditions, application of siRNA/in vivo-jetPEI complexes from the jugular vein successfully suppressed NF-kappaB p65 expression in the heart. The same strategy can be applied to heart transplant animal models to protect against NF-kappaB gene-related type II VEC activation and xenograft rejection. PMID- 20852748 TI - Influence of GABA-acting drugs on morphine-induced hyperthermia in rats. AB - A major inhibitory neurotransmitter of the nervous system, GABA (gamma aminobutyric acid), is involved in mammalian thermoregulation. The present study investigated the influence of GABAergic neurotransmission-enhancing drugs, in a model of morphine-induced hyperthermia in conscious rats. We used body temperature assays to examine the effects of GABA-acting drugs on morphine induced hyperthermia. In rats, low doses of morphine injected i.p. produced significant hyperthermia in a body temperature assay that was significantly attenuated upon pretreatment with GABA-acting drugs. These results suggest the existence of opioidergic-GABAergic interactions in a complex process of thermoregulation. PMID- 20852749 TI - Antidiarrheal evaluation of the ethanol extract of Musanga cecropioides stem bark. AB - The ethnomedicinal uses of Musanga cecropioides R. Apud Tedlie (Cecropiaceae) as a hypotensive agent have been scientifically investigated and reported. This work examines its effect on various models of diarrhea based on the ethnomedicinal use of the plant for this indication. The stem bark of the plant, used locally by soaking in gin (alcoholic), was treated with absolute ethanol and the extract screened for antidiarrheal activity using the castor oil-induced diarrhea and small intestinal motility models in mice. Its effects on the isolated rat ileum were also investigated. In the castor oil-induced diarrhea, the extract at 100, 200, and 400 mg/kg significantly (P < 0.05 at all doses) showed dose-related antidiarrheal effects as indicated by reduction in the number and weight of fecal material produced. The extract at all doses used also significantly (P < 0.05, P < 0.0001 and P < 0.0001 at 100, 200, and 400 mg/kg doses, respectively) decreased the intestinal motility of the treated mice as compared to controls and inhibited acetylcholine-induced contractions (P < 0.0001). In the isolated rat ileum the extract at 5 and 10 mg/mL, remarkably inhibited acetylcholine induced contractions, indicating a probable antimuscarinic effect of the extract. The results obtained confirmed that the stem bark of M cecropioides has antidiarrheal activity as used in folkloric medicine. PMID- 20852750 TI - Effect of gastric emptying and entero-hepatic circulation on bioequivalence assessment of ranitidine. AB - The aim of study was to compare the bioavailability of ranitidine obtained from either Ranitidine (300 mg tablet; LPH(r) S.C. LaborMed Pharma S.A. Romania: the test formulation) and Zantac(r) (300 mg tablet; GlaxoSmithKline, Austria: the reference formulation). Twelve, Romanian, healthy volunteers were enrolled in the study. An open-label, two-period, crossover, randomized design was used. Plasma levels of ranitidine were determined using the validated, high-pressure liquid chromatography (HPLC) method. The physiologically motivated time-delayed model was used for the data evaluation and a paired Student's t-test and Schuirmann's two one-sided tests were carried out to compare parameters. Nonmodeling parameters (AUC(t), AUC, C(max), T(max)) were tested by the paired Student's t test and the 90 confidence intervals of the geometric mean ratios were determined by Schuirmann's tests. Paired Student's t-test showed no significant differences between nonmodeling and modeling parameters. The results of the Schuirmann's tests however indicated significant statistical differences with reference to AUC(t), AUC, C(max), T(max) and other modeling parameters, especially MT(c) and tau(c). Schuirmann's tests revealed significant bioequivalence between ranitidine formulations using the modeling parameters MRT and n. The presented model can be useful as an additional tool to assess drug bioequivalence, by screening for disruptive parameters. PMID- 20852751 TI - Arterial blood pressure and aortic responses in obese, age-grouped Zucker rats. AB - Endothelial dysfunction is one of the many proposed mechanisms of hypertension and it may justify, at least in part, the increased blood pressure of hypertensive subjects. Nevertheless, the exact mechanisms involved in the hypertensive condition of obese Zucker rats are unclear. In this study, we measured the arterial blood pressure (tail cuff method) of four groups of seven, female, obese Zucker rats each. The rats of groups 1-4 were 9-12, 15-18, 21-24 and 27-30 weeks old respectively. We also evaluated the responses of aortic rings to KCl, methoxamine and acetylcholine, in these animals. Aortic rings were successively exposed to 80 mM KCl and to methoxamine (10(-8)-10(-5) M). The endothelium-dependent relaxation to acetylcholine (10(-9)-10(-5) M) was also established in the methoxamine-precontracted tissue (precontraction close to 80% of the maximum effect of methoxamine). A clear increase in the arterial blood pressure was observed when the age of these animals increased. The contractile responses to KCl and methoxamine were lower in the aortic rings of rats with increased arterial blood pressure. The response to acetylcholine was lower in the rings from 15-18, 21-24 and 27-30 weeks old rats, than in the younger groups. In conclusion, obese Zucker rats develop hypertension and endothelial dysfunction. Nevertheless, the arterial contractions elicited by depolarization or by alpha(1) adrenoceptor stimulation decrease in aged, obese Zucker rats. PMID- 20852752 TI - A prospective study on the pattern of medication use for schizophrenia in the outpatient pharmacy department, Hospital Tengku Ampuan Rahimah, Selangor, Malaysia. AB - Schizophrenia is a chronic psychiatric disorder and pharmacotherapy plays a major role in its management. The 1950s and early 1960s saw milestones in the introduction of psychotropic drugs in clinical practice. A review of drug prescriptions in different settings provides an insight into the pattern of drug use, identifies drug-related problems and may be used to compare recommended guidelines with actual practice. This effort led to the evaluation of the drug prescribing pattern of antipsychotics in patients attending the psychiatric clinic at a government hospital. The data from 371 antipsychotic medication prescriptions that included 200 prescriptions for schizophrenia were collected during one month (1rst-31rst August 2008) at the outpatient pharmacy department. The mean age of patients was 35.0 years (SD = 1.131), with a male to female ratio of 2:1. The most widely used oral antipsychotic was haloperidol (16.3%) while the most common depot preparation prescribed was zuclopenthixol decanoate (8.8%). The daily dose of the average antipsychotic prescribed in this clinic was 342.06 mg equivalent of chlorpromazine. There was no relation between the doses received and ethnicity of the patient (Malay, Chinese or Indian). However, there was a significant relationship between the prescribed dose and patient age (P < 0.042). Nearly 32% of the schizophrenia patients were prescribed with atypical antipsychotics such as olanzapine (10.8%), risperidone (10.0%), quetiapine (7.6%) and clozapine (3.2%). Monotherapy was given to 73.0% of the schizophrenia patients. The majority of patients also received antidepressants. To conclude, this study gave evidence that physicians had a strong preference for monotherapy with conventional antipsychotic drugs while the use of atypical drugs was less prevalent. PMID- 20852753 TI - Depletion of serum zinc in ischemic stroke patients. AB - The pathogenesis of a number of diseases like cardiovascular diseases, cancer and neurological disorders, has been associated with changes in the balance of certain trace elements. In this study we aimed at investigating the levels of trace elements like calcium, copper, iron and zinc, in ischemic stroke patients in comparison with healthy controls. Serum samples were collected from 256 ischemic stroke patients and 180 healthy, age and sex matched controls. Trace element levels were detected using commercially available kits and an Auto Analyzer (ChemWell 2910, Awareness Technology, US). The concentrations of calcium, copper and iron were not significantly different in patients when compared to healthy controls. The concentration of zinc was significantly lower in stroke patients (P = 0.001) as compared to normal subjects. To conclude, patients with acute ischemic stroke have reduced levels of serum zinc. Zinc may represent an independent risk factor for stroke and therefore a possible target for prevention. Additional studies are needed to further examine the role of zinc in the pathogenesis of stroke. PMID- 20852754 TI - Gateways to clinical trials. AB - A-3309, Abobotulinumtoxin A, Adalimumab, AIDSVAX gp120 B/E, ALVAC E120TMG, Atorvastatin calcium; Bepridil, Bevacizumab; Candesartan cilexetil, Capecitabine, Cetuximab, Clopidogrel; Dapagliflozin, Dasatinib, Denosumab, Dexmedetomidine hydrochloride, Diacetylmorphine, Diannexin, Docetaxel, Dutasteride; Entecavir, Eplerenone, Erlotinib hydrochloride, Escitalopram oxalate, Everolimus, Ezetimibe; Fesoterodine fumarate, Flagellin.HuM2e, Fluzone; Glimepiride/rosiglitazone maleate; Hyaluronic acid-paclitaxel bioconjugate; IDX-184, Imatinib mesylate, Infliximab, Insulin glargine, Irbesartan; JX-594; Landiolol, Latrunculin B, Levocetirizine dihydrochloride, Liraglutide, Lyprinol; Metformin, Metronidazole/tetracycline hydrochloride/bismuth biskalcitrate, Mipomersen sodium, Mycophenolic acid sodium salt; Nalfurafine hydrochloride, Nilotinib hydrochloride monohydrate; Paclitaxel nanoparticles, Paclitaxel poliglumex, Peginterferon alfa-2a, Peginterferon alfa-2b, Perospirone hydrochloride, Pimavanserin tartrate, Pirfenidone, Pitavastatin calcium, Prasterone, Prasugrel, Pregabalin, Ranelic acid distrontium salt, Ranibizumab, Remimazolam, Risedronate, Rosuvastatin calcium; Silodosin, Silybin phosphatidylcholine complex, Sirolimus eluting stent, Sitagliptin phosphate monohydrate, Sorafenib, Sunitinib malate; Tadalafil, Tamsulosin hydrochloride, Technosphere/insulin, Telmisartan, Temsirolimus, Teriparatide, Thymalfasin, Ticagrelor, Toltedorine-XR, Tramadol-XR, Triphosadenine, Trospium-XR; Val8-GLP-1(7-37)OH, Valsartan, Vardenafil hydrochloride hydrate, Varenicline tartrate, Velaglucerase alfa; Zoledronic acid monohydrate. PMID- 20852760 TI - Structure and luminescence properties of a well-known macrometallocyclic trinuclear Au(I) complex and its adduct with a perfluorinated fluorophore showing cooperative anisotropic supramolecular interactions. AB - The structure and luminescence properties of a well-known trinuclear Au(i) imidazolate complex are determined for the first time along with its interaction with the organic pi acid perfluoronaphthalene in the solid state and solution. PMID- 20852761 TI - Robust photocatalytic water reduction with cyclometalated Ir(III) 4-vinyl-2,2' bipyridine complexes. AB - Novel [Ir(C^N)(2)(N^N)](+) complexes with N^N ligands containing vinyl groups were synthesized resulting in quintupled turn-over numbers for the photocatalytic hydrogen production compared to the analogous non-vinyl compounds. PMID- 20852762 TI - Excellent performance of Pt0 on high nitrogen-containing carbon nanotubes using aniline as nitrogen/carbon source, dispersant and stabilizer. AB - Novel high nitrogen-containing carbon nanotubes (NC-CNT) (14% N) as catalyst support have been successfully prepared using aniline as a dispersant to CNT and as a source for both carbon and nitrogen coated on the surface of the CNT. PMID- 20852763 TI - Efficient CuAAC click formation of functional hemoglobin bis-tetramers. AB - A cross-linked hemoglobin bis-tetramer with oxygenation properties appropriate for a red cell substitute is produced by CuAAC conjugation of a dialkyne and two equivalents of an azide of beta,beta-cross-linked hemoglobin. The latter is formed efficiently by the aminolysis of the 3,5-dibromosalicylate ester of the beta-82-beta'-82-bis trimesyl amide of human hemoglobin A with (4 aminomethyl)benzyl azide. PMID- 20852764 TI - A new supramolecular sulfonated polyimide for use in proton exchange membranes for fuel cells. AB - Uracil-terminated telechelic sulfonated polyimides (SPI-U) were transformed into noncovalent network membranes through biocomplementary hydrogen bonding recognition in the presence of an adenine-based crosslinking agent. SPI-U membrane exhibited dramatically improved methanol permeability, oxidative stability, proton conductivity, and selectivity relative to those of the standard SPI. PMID- 20852765 TI - A novel electrochemiluminescence strategy for ultrasensitive DNA assay using luminol functionalized gold nanoparticles multi-labeling and amplification of gold nanoparticles and biotin-streptavidin system. AB - Luminol functionalized gold nanoparticles were used as labels for electrochemiluminescence signal amplification and an ultrasensitive, highly selective, convenient, low cost DNA detection strategy was developed. PMID- 20852766 TI - Electrochemical detection of insertion/deletion mutations based on enhanced flexibility of bulge-containing duplexes on electrodes. AB - Ferrocene-modified DNA probes formed fully matched duplexes and bulge-containing ones with wild-type and insertion/deletion-type complements of clinical importance, respectively. Cyclic voltammetry measurements revealed that the bulge containing duplexes showed an increased flexibility compared to the fully matched duplexes. The difference in the bending elasticity could be read out electrochemically by square wave voltammetry. PMID- 20852767 TI - A simple physical model for the simultaneous rationalisation of melting points and heat capacities of ionic liquids. AB - The analysis of potential energy surfaces of ion pairs within the framework of an anharmonic oscillator model allows rationalization and prediction of melting points (T(mp)) and heat capacities (C(p)) of ionic liquids (ILs) comprising di- and trialkylimidazolium or tetraalkylphosphonium cations and weakly coordinating BF(4), PF(6), or Tf(2)N anions. Multiple short contacts between the counterions are demonstrated to be typical for the imidazolium based ILs. Differences in the types of contacts result in moderate changes of melting points of the ILs, comparable with differences in T(mp) experimentally determined for the same crystal. The theoretical evaluation of IL heat capacities additionally requires a consideration of conformational behaviour of the corresponding cations. A similar conformational composition of 1-butyl-3-methylimidazolium hexafluorophosphate and tetrafluoroborate at ambient temperature is demonstrated by the combined DFT vibrational spectroscopy approach. A rough proportionality of C(p) to 1/T(mp) of ionic liquids is suggested, provided that the conformational composition of the ILs does not change on crystal-to-liquid transition. PMID- 20852768 TI - Colloidal synthesis of inorganic fullerene nanoparticles and hollow spheres of titanium disulfide. AB - The synthesis of inorganic fullerene (IF) nanoparticles and IF hollow spheres of titanium disulfide by a simple colloidal route is reported. The injection temperature of the titanium precursor into the solvent mixture was found to be important in controlling the morphology. PMID- 20852769 TI - Electrophilic functionalization of well-behaved manganese monoanions supported by m-terphenyl isocyanides. AB - The m-terphenyl isocyanides CNAr(Mes2) and CNAr(Dipp2) support five-coordinate, isocyanide/carbonyl monoanions of manganese. For CNAr(Dipp2), a bis-isocyanide anion is available that is remarkably well behaved upon reaction with electrophiles. Most notable is the formation of an unprecedented chloride substituted metallostannylene. PMID- 20852770 TI - IRMPD spectroscopy of protonated S-nitrosocaptopril, a biologically active, synthetic amino acid. AB - S-Nitrosocaptopril, a biologically active S-nitrosothiol, is generated as protonated species and isolated in the gas phase by electrospray ionization coupled to Fourier Transform Ion Cyclotron Resonance (FT-ICR) or ion-trap mass spectrometry. The structural and IR spectroscopic characterization of protonated S-nitrosocaptopril (SNOcapH(+)) is aided by the comparative study of the parent species lacking the NO feature, namely protonated captopril. The study is accomplished by methodologies based on tandem mass spectrometry, namely by energy resolved collision-induced dissociation and infrared multiple-photon dissociation (IRMPD) spectroscopy, backed by density functional theory calculations. IRMPD spectra have been obtained both in the 1000-1900 cm(-1) fingerprint range, using a beamline of the infrared free electron laser (IR-FEL) at the Centre Laser Infrarouge d'Orsay (CLIO), and in the O-H and N-H stretching region (2900-3700 cm(-1)) using the tunable IR radiation of a tabletop parametric oscillator/amplifier (OPO/OPA) laser source. The structural features of the ion have been ascertained by comparison of the experimental IRMPD spectra with the IR transitions calculated for the lowest energy isomers. Evidence is obtained that protonation occurs at the amide carbonyl oxygen which is found to be the thermodynamically most basic site. However, SNOcapH(+) is present as a thermally equilibrated mixture of low-energy structures, with a major contribution of the most stable isomer characterized by a trans relationship of the positively charged OH group with respect to the carboxylic acid functionality on the adjacent proline ring and by an anti conformation at the S-N (partial) double bond, though the energy difference with the analogous trans-syn isomer is less than 1 kJ mol(-1). The highly diagnostic N-O stretching mode has been unambiguously identified, which may be regarded as an informative probe for S nitrosation features in more complex, biologically active molecules. PMID- 20852771 TI - Mutanobactin A from the human oral pathogen Streptococcus mutans is a cross kingdom regulator of the yeast-mycelium transition. AB - The recent investigation of a gene cluster encoding for a hybrid PKS-NRPS metabolite in the oral pathogen Streptococcus mutans UA159 yielded evidence that this natural product might play an important role regulating a range of stress tolerance factors. We have now characterized the major compound generated from this gene cluster, mutanobactin A, and demonstrated that this secondary metabolite is also capable of influencing the yeast-mycelium transition of Candida albicans. PMID- 20852773 TI - Monitoring of a flame retardant (tetrabromobisphenol A) toxicity on different microalgae assessed by flow cytometry. AB - Microalgae are key organisms in aquatic ecosystems. Emergent pollutants like the tetrabromobisphenol A (TBBPA) are potential threat for these primary producers at the base of the trophic chain. The effects of this flame retardant on three microalgae (Pseudokirchneriella subcapitata, Nitzschia palea and Chlamydomonas reinhardtii) commonly observed in freshwater ecosystems were studied using a flow cytometer. Each species was exposed to 1.8, 4.8, 9.2, 12.9 and 16.5 umol L-1 of TBBPA for 72 h. After staining with fluorescein diacetate (FDA), viable cells were discriminated in flow cytogram according to the chlorophyll autofluorescence and the intracellular enzyme activity (esterase) to assess the sensitivity of microalgae to the TBBPA with multi-parametric analysis. For P. subcapitata and N. palea, growth inhibitions of viable cells were lower when the viability was assessed with chlorophyll autofluorescence in comparison with esterase activity. These results are related to the appearance of cells presenting optimal chlorophyll fluorescence without intracellular esterase activity after exposure to TBBPA. Abundance increase of these cells was higher in N. palea than in P. subcapitata. No similar trends were observed in C. reinhardtii populations due to the very high mortality of this microalgal species exposed to TBBPA. PMID- 20852774 TI - Diversity and functional properties of bistable pigments. AB - Rhodopsin and related opsin-based pigments, which are photosensitive membrane proteins, have been extensively studied using a wide variety of techniques, with rhodopsin being the most understood G protein-coupled receptor (GPCR). Animals use various opsin-based pigments for vision and a wide variety of non-visual functions. Many functionally varied pigments are roughly divided into two kinds, based on their photoreaction: bistable and monostable pigments. Bistable pigments are thermally stable before and after photo-activation, but monostable pigments are stable only before activation. Here, we review the diversity of bistable pigments and their molecular characteristics. We also discuss the mechanisms underlying different molecular characteristics of bistable and monostable pigments. In addition, the potential of bistable pigments as a GPCR model is proposed. PMID- 20852775 TI - Semiconductor-mediated photodegradation of pollutants under visible-light irradiation. AB - The semiconductor and the surface-adsorbed antenna molecule (dyes or other color species) can constitute efficient photochemical systems for environmental remediation. The major advantage of these systems is that they are able to achieve the degradation of organic pollutants by using visible light from the sun as energy and O(2) in the air as the oxidant under ambient conditions. In this tutorial review, the unique mechanistic characteristics, the constitution of photodegradation systems and their performance are described. The involved radical reactions during the degradation are also discussed. PMID- 20852776 TI - Pharmacologically active compounds in the environment and their chirality. AB - Pharmacologically active compounds including both legally used pharmaceuticals and illicit drugs are potent environmental contaminants. Extensive research has been undertaken over the recent years to understand their environmental fate and toxicity. The one very important phenomenon that has been overlooked by environmental researchers studying the fate of pharmacologically active compounds in the environment is their chirality. Chiral drugs can exist in the form of enantiomers, which have similar physicochemical properties but differ in their biological properties such as distribution, metabolism and excretion, as these processes (due to stereospecific interactions of enantiomers with biological systems) usually favour one enantiomer over the other. Additionally, due to different pharmacological activity, enantiomers of chiral drugs can differ in toxicity. Furthermore, degradation of chiral drugs during wastewater treatment and in the environment can be stereoselective and can lead to chiral products of varied toxicity. The distribution of different enantiomers of the same chiral drug in the aquatic environment and biota can also be stereoselective. Biological processes can lead to stereoselective enrichment or depletion of the enantiomeric composition of chiral drugs. As a result the very same drug might reveal different activity and toxicity and this will depend on its origin and exposure to several factors governing its fate in the environment. In this critical review a discussion of the importance of chirality of pharmacologically active compounds in the environmental context is undertaken and suggestions for directions in further research are made. Several groups of chiral drugs of major environmental relevance are discussed and their pharmacological action and disposition in the body is also outlined as it is a key factor in developing a full understanding of their environmental occurrence, fate and toxicity. This review will be of interest to environmental scientists, especially those interested in issues associated with environmental contamination with pharmacologically active compounds and chiral pollutants. As the review will outline current state of knowledge on chiral drugs, it will be of value to anyone interested in the phenomenon of chirality, chiral drugs, their stereoselective disposition in the body and environmental fate (212 references). PMID- 20852777 TI - Phenol biosensor based on hydrogel microarrays entrapping tyrosinase and quantum dots. AB - This paper describes the use of microarray-based biosensor system for the determination of phenol. Microarrays based on poly(ethylene glycol)(PEG) hydrogel were prepared by photopatterning of a solution containing PEG diacrylate (PEG DA), photoinitiator, tyrosinase, and CdSe/ZnS quantum dots (QDs). During photo induced crosslinking, tyrosinase and QDs were entrapped within the hydrogel microarrays, making the hydrogel microarray fluorescent and responsive to phenol. The entrapped tyrosinase could carry out enzyme-catalyzed oxidation of phenol to produce quinones, which subsequently quenched the fluorescence of QDs within hydrogel microarray. The fluorescence intensity of the hydrogel microarrays decreased linearly according to phenol concentration and the detection limit of this system was found to be 1.0 MUM. The microarray system presented in this study could be combined with a microfluidic device as an initial step to create a phenol-detecting "micro-total-analysis-system (MU-TAS)". PMID- 20852778 TI - Designing late-transition metal catalysts for olefin insertion polymerization and copolymerization. AB - The innovation of polyolefin with unique architecture, composition and topology continues to inspire polymer chemists. An exciting recent direction in the polyolefin field is the design of new catalysts based on late-transition metals. In this review, we highlight recent developments in rationally designing late transition metal catalysts for olefin polymerization. The examples described in this review showcase the power of the design of well-defined late-metal catalysts for tailored polyolefin synthesis, which may usher in a new era in the polymer industry. PMID- 20852779 TI - Hexagonal mesocrystals formed by ultra-thin tungsten oxide nanowires and their electrochemical behaviour. AB - Hexagonal mesocrystals formed by tungsten oxide nanowires have been synthesized using a solvothermal method without any template. The selected area electron diffraction (SAED) analysis of the regular hexagonal mesocrystal demonstrates that the nanowires are highly ordered. Electrochemical behaviour of the mesocrystals has been evaluated by cyclic voltammograms. PMID- 20852780 TI - Fast synthesis of ultra-thin ZnSnO3 nanorods with high ethanol sensing properties. AB - Ultra-thin 3 nm ZnSnO(3) nanorods were successfully prepared, which not only exhibit high sensitivity to ethanol at relatively low temperature, but also good selectivity. PMID- 20852781 TI - Synthesis of C-furanosides from a D-glucal-derived cyclopropane through a ring expansion/ring-contraction sequence. AB - gem-Dibromocyclopropane 1, prepared from tri-O-benzyl-D-glucal, undergoes thermal and silver-promoted ring expansion in the presence of alcohols to give substituted oxepines. With further heating, ring contraction to highly substituted tetrahydrofurans follows. These represent C-furanosides, potentially useful as precursors to C-nucleosides and other carbohydrate mimics. PMID- 20852782 TI - Rhodium-catalyzed domino heterocyclization and [(3+2)+2] carbocyclization: construction of fused tricycloheptadienes. AB - A rhodium-catalyzed domino heterocyclization and formal [(3+2)+2] carbocyclization reaction of readily available diyne-enones and alkynes was developed. PMID- 20852783 TI - Pd(0)-Catalyzed carbonylation of 1,1-dichloro-1-alkenes, a new selective access to Z-alpha-chloroacrylates. AB - A novel and fully chemo- and stereoselective three component strategy leading to Z-alpha-chloroacrylates by a Pd(0)-catalyzed reaction of CO (1 atm) with 1,1 dichloro-1-alkenes and various alcohols is disclosed. This catalytic approach compares favourably with the Wittig type strategies as alpha-chloroacrylates of pure Z configuration are obtained in high yield. PMID- 20852784 TI - Fabrication of freestanding honeycomb films with through-pore structures via air/water interfacial self-assembly. AB - Highly ordered freestanding honeycomb films with asymmetric through-pore structures were prepared from polystyrene/gold-nanoparticles (PS/AuNPs) nanocomposite at an air/water interface using a one-step interfacial self assembly method. PMID- 20852785 TI - From unexpected reactions to a new family of ionic co-crystals: the case of barbituric acid with alkali bromides and caesium iodide. AB - Pressing solid barbituric acid with KBr to prepare samples for IR spectroscopy leads to the formation of an ionic co-crystal, in which the co-former is a classical ionic salt; co-crystal formation is also obtained with the other alkali bromides (LiBr, NaBr, RbBr and CsBr) and with caesium iodide. The simultaneous presence of alkali and halide ions affects the dissolution properties of barbituric acid in water. PMID- 20852786 TI - A sensitive aptasensor for adenosine based on the quenching of Ru(bpy)(3)(2+) doped silica nanoparticle ECL by ferrocene. AB - A reusable signal on aptasensor for adenosine based on the quenching of Ru-SNPs electrochemiluminescence by ferrocene was developed. PMID- 20852787 TI - Anatase TiO(2) nanosheets with exposed (001) facets: improved photoelectric conversion efficiency in dye-sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) are fabricated based on anatase TiO(2) nanosheets (TiO(2)-NSs) with exposed {001} facets, which were obtained by a simple one-pot hydrothermal route using HF as a morphology controlling agent and Ti(OC(4)H(9))(4) as precursor. The prepared samples were characterized by scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, UV-vis absorption spectroscopy and N(2) adsorption-desorption isotherms. The photoelectric conversion performances of TiO(2)-NSs solar cells are also compared with TiO(2) nanoparticles (TiO(2) NPs) and commercial-grade Degussa P25 TiO(2) nanoparticle (P25) solar cells at the same film thickness, and their photoelectric conversion efficiencies (eta) are 4.56, 4.24 and 3.64%, respectively. The enhanced performance of the TiO(2)-NS solar cell is due to their good crystallization, high pore volume, large particle size and enhanced light scattering. The prepared TiO(2) nanosheet film electrode should also find wide-ranging potential applications in various fields including photocatalysis, catalysis, electrochemistry, separation, purification and so on. PMID- 20852788 TI - Facile synthesis of free-standing CeO(2) nanorods for photoelectrochemical applications. AB - Free-standing CeO(2) nanorods with different morphology grew directly on Ti substrates via an electrochemical assembly process, and their absorption edges show a remarkable red-shift to the visible region. Moreover, photoelectrochemical cell (PEC) measurements demonstrate these CeO(2) nanorods exhibit a photovoltaic response under visible light illumination (lambda>= 390 nm). PMID- 20852789 TI - Amine-catalyzed (3+n) annulations of 2-(acetoxymethyl)buta-2,3-dienoates with 1,n bisnucleophiles (n = 3-5). AB - A tertiary amine-catalyzed formal (3+n) annulation of 2-(acetoxymethyl)buta-2,3 dienoate with 1,n-binucleophiles has been developed, which provides a facile entry to heterocyclic compounds. The mechanism, involving tandem S(N)2'-S(N)2' substitution and Michael addition, has also been established. PMID- 20852790 TI - Facile nucleophilic substitution of sulfonyl oxime ethers: an easy access to oxime ethers, carbonyl compounds and amines. AB - Sulfonyl oxime ethers undergo facile nucleophilic substitutions with various nucleophiles to yield the corresponding oxime ethers which provide an easy access to amines and carbonyl compounds. PMID- 20852791 TI - Fluorinase mediated chemoenzymatic synthesis of [(18)F]-fluoroacetate. AB - A novel preparation of sodium [(18)F]-fluoroacetate is described where 5'-[(18)F] fluoro-5'-deoxyadenosine is generated by a fluorinase catalysed reaction of S adenosyl-l-methionine (SAM) with no carrier added [(18)F]-fluoride and then oxidation to [(18)F]-fluoroacetate by a Kuhn-Roth oxidative degradation. PMID- 20852792 TI - Regio- and stereoselective copper-catalyzed beta-borylation of allenoates by a preactivated diboron. AB - A mild and efficient copper-catalyzed borylation of electron deficient allenoates using an sp(2)-sp(3) mixed hybridized diboron regioselectively installs a boron moiety on the beta-position with exclusive (Z)-double bond geometry. PMID- 20852793 TI - Metal binding to a zinc-finger peptide: a comparison between solution and the gas phase. AB - Solution-phase spectroscopy and mass spectrometry are used to probe interactions between divalent metal ions and a synthetic Cys(2)His(2) zinc-finger peptide (vCP1). Both methods provide the same order of binding affinity, zinc >= cobalt ? copper ? calcium. Collision-cross-section measurements show that both apo and holo forms are compact. This is corroborated by molecular-dynamics simulations. PMID- 20852794 TI - Amphiphilic photo-isomerisable phosphanes for aqueous organometallic catalysis. AB - Water-soluble phosphanes were tagged with a light-responding diazo group. Upon UV exposure, the diazo-isomerisation led to phosphane morphology change, resulting in an increase in the reaction rate of an aqueous palladium-catalysed cleavage reaction. PMID- 20852795 TI - Suppression of spin-spin coupling in nitroxyl biradicals by supramolecular host guest interactions. AB - The use of supramolecular architectures to control the spatially dependent spin exchange (spin communication) between two covalently linked radical centers (biradical) has been explored. Cucurbit[8]uril, through supramolecular steric effect, completely suppresses spin exchange between two adjacent radical centers in a biradical. PMID- 20852796 TI - Steam-stable hydrophobic ITQ-29 molecular sieve membrane with H(2) selectivity prepared by secondary growth using Kryptofix 222 as SDA. AB - A neutral framework cation-free hydrophobic ITQ-29 molecular sieve membrane with hydrogen selectivity was prepared on porous alpha-Al(2)O(3) supports by using Kryptofix 222 as organic structure directing agent through secondary growth method. PMID- 20852797 TI - Intracellular degradation of low-density lipoprotein probed with two-color fluorescence microscopy. AB - The intracellular vesicle-mediated degradation of extracellular cargo is an essential cellular function. Using two-color single particle tracking fluorescence microscopy, we have probed the intracellular degradation of low density lipoprotein (LDL) in living cells. To detect degradation, individual LDL particles were heavily labeled with multiple fluorophores resulting in a quenched fluorescent signal. The degradation of the LDL particle then resulted in an increase in fluorescence. Endocytic vesicles were fluorescently labeled with variants of GFP. We imaged the transient colocalization of LDL with endocytic vesicles while simultaneously measuring the intensity of the LDL particle as an indicator of degradation. These studies demonstrate that late endosomes are active sites of degradation for LDL. Measurement of the time from colocalization with lysosome-associated membrane protein 1 (LAMP1) vesicles to degradation suggests that LAMP1-vesicles initiate the degradative event. Observing degradation as it occurs in living cells makes it possible to describe the complete endocytic pathway of LDL from internalization to degradation. More generally, this research provides a model for the intracellular degradation of extracellular cargo and a method for its study in living cells. PMID- 20852798 TI - Characterization of liposomes formed by lipopolysaccharides from Burkholderia cenocepacia, Burkholderia multivorans and Agrobacterium tumefaciens: from the molecular structure to the aggregate architecture. AB - The microstructure of liposomes formed by the lipopolysaccharides (LPS) derived from Burkholderia cenocepacia ET-12 type strain LMG 16656, Burkholderia multivorans strain C1576 and Agrobacterium tumefaciens strain TT111 has been investigated by a combined experimental strategy, including dynamic light scattering (DLS), small-angle neutron scattering (SANS) and electron paramagnetic resonance (EPR). The results highlight that the LPS molecular structure determines, through a complex interplay of hydrophobic, steric and electrostatic interactions, the morphology of the aggregates formed in aqueous medium. All the considered LPS form liposomes that in most cases present a multilamellar arrangement. The thickness of the hydrophobic domain of each bilayer and the local ordering of the acyl chains are determined not only by the molecular structure of the LPS glycolipid portion (lipid A), but also, indirectly, by the bulkiness of the saccharidic portion. In the case of a long polysaccharidic chain, such as that of the LPS derived from Burkholderia multivorans, liposomes coexist with elongated micellar aggregates, whose population decreases if a typical phospholipid, such as dioleoyl phosphatidylethanolamine (DOPE) is introduced in the liposome formulation. The effect of temperature has also been considered: for all the considered LPS an extremely smooth transition of the acyl chain self-organization from a gel to a liquid crystalline phase is detected around 30-35 degrees C. In the biological context, our results suggest that the rich biodiversity of LPS molecular structure could be fundamental to finely tune the structure and functional properties of the outer membrane of Gram negative bacteria. PMID- 20852799 TI - Is beta-homo-proline a pseudo-gamma-turn forming element of beta-peptides? An IR and VCD spectroscopic study on Ac-beta-HPro-NHMe in cryogenic matrices and solutions. AB - In order to test the pseudo-gamma-turn forming capability of beta-homo-proline (beta(3)-HPro) 2-[(2S)-1-acetylpyrrolidin-2-yl]-N-methylacetamide (Ac-beta(3) HPro-NHMe) was synthesized and its potential energy landscape was investigated by infrared (IR) and vibrational circular dichroism (VCD) spectroscopy combined with density functional calculations. Based upon a comparison between experimental and computed spectra three different pseudo-gamma-turn-like trans conformers and a cis conformer were identified in low-temperature Ar and Kr matrices. The computations in agreement with the observations reveal that, in contrast to its alpha-Pro analogue, the room-temperature abundance of the cis conformer is significant, falling above 10% in the isolated phase. Furthermore, solution-phase vibrational spectra and computations show that the cis conformer is predominant in polar solvents. This result indicates that beta(3)-HPro is significantly less apt to form pseudo-gamma-turns when compared to the gamma-turn forming tendency of alpha-proline. The present study also shows that the interpretation of solution-phase VCD spectra of flexible molecules should be done with extra caution. PMID- 20852800 TI - Bipolar redox behaviour, field-effect mobility and transistor switching of the low-molecular azo glass AZOPD. AB - We present electrochemical and spectroelectrochemical data for the bipolar azo compound N,N'-diphenyl-N,N'-bis[4-(phenylazo)phenyl]-4,4'diaminobiphenyl (AZOPD) demonstrating reversible bipolar redox behaviour with a bandgap of 2.1 eV. The reduced species formed upon two-electron transfer can be described as bis(radical anion) as was confirmed by comparison with a reference compound with only one azo chromophore. Hole and electron transport behaviour in amorphous films was demonstrated by the fabrication of organic field-effect transistors using gold and magnesium contacts, respectively. The transistors are sensitive to light due to E-Z photoisomerization. PMID- 20852802 TI - Hydrogen saturation stabilizes vacancy-induced ferromagnetic ordering in graphene. AB - Density functional theory calculations are performed to explore vacancy-induced magnetism in graphene. The hydrogen saturation not only stabilizes the vacancy structure but also induces distinct magnetic coupling depending on the defect distribution: weak magnetic coupling between defects on different sublattices and strong coupling between defects on the same sublattice. Ferromagnetic ordering has to be accompanied with a semiconducting property. The interaction integral J between defective spins decreases linearly with the increase of the distance between them. Based on the 2D Ising model and Monte Carlo simulations, the possible highest Curie temperature T(c) of defective graphene is predicted to be lower than 500 K. PMID- 20852801 TI - Integrative genome-wide approaches in embryonic stem cell research. AB - Embryonic stem (ES) cells are derived from blastocysts. They can differentiate into the three embryonic germ layers and essentially any type of somatic cells. They therefore hold great potential in tissue regeneration therapy. The ethical issues associated with the use of human embryonic stem cells are resolved by the technical break-through of generating induced pluripotent stem (iPS) cells from various types of somatic cells. However, how ES and iPS cells self-renew and maintain their pluripotency is still largely unknown in spite of the great progress that has been made in the last two decades. Integrative genome-wide approaches, such as the gene expression microarray, chromatin immunoprecipitation based microarray (ChIP-chip) and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) offer unprecedented opportunities to elucidate the mechanism of the pluripotency, reprogramming and DNA damage response of ES and iPS cells. This frontier article summarizes the fundamental biological questions about ES and iPS cells and reviews the recent advances in ES and iPS cell research using genome-wide technologies. To this end, we offer our perspectives on the future of genome-wide studies on stem cells. PMID- 20852803 TI - Electronic effects in iridium C-H borylations: insights from unencumbered substrates and variation of boryl ligand substituents. AB - Experiment and theory favour a model of C-H borylation where significant proton transfer character exists in the transition state. PMID- 20852804 TI - Cationic intermediates in Friedel-Crafts acylation: structural information from theory and experiment. AB - Experimentally-determined intramolecular and intermolecular deuterium kinetic isotope effects and computational studies imply three possible kinetic scenarios for the Friedel-Crafts acylation of xylene. The influence of the structural and energetic properties of the pi-complexes and sigma-complex upon the observed isotope effects is explored. PMID- 20852805 TI - Microporous polyimide networks with large surface areas and their hydrogen storage properties. AB - Microporous polyimide networks with BET surface areas up to 1407 m(2) g(-1) and pore size distribution of 4-8 A were synthesized. The respective effect of surface area and affinity between hydrogen molecule and polyimides on hydrogen storage properties were investigated. PMID- 20852806 TI - Ligand dimerization programmed by hybridization to study multimeric ligand receptor interactions. AB - Oligomerization of receptors induced or stabilized by polyvalent ligands is a fundamental mechanism in cellular recognition and signal transduction. Herein we report a general approach to encode complex peptide macrocycles with peptide nucleic acid (PNA) tags and program their oligomerization through hybridization as exemplified with a ligand binding to oligomeric DR5, a receptor of TRAIL cytokine. PMID- 20852807 TI - Mechanistic studies of the 'blue' Cu enzyme, bilirubin oxidase, as a highly efficient electrocatalyst for the oxygen reduction reaction. AB - The 'blue copper' enzyme bilirubin oxidase from Myrothecium verrucaria shows significantly enhanced adsorption on a pyrolytic graphite 'edge' (PGE) electrode that has been covalently modified with naphthyl-2-carboxylate functionalities by diazonium coupling. Modified electrodes coated with bilirubin oxidase show electrocatalytic voltammograms for the direct, four-electron reduction of O(2) by bilirubin oxidase with up to four times the current density of an unmodified PGE electrode. Electrocatalytic voltammograms measured with a rapidly rotating electrode (to remove effects of O(2) diffusion limitation) have a complex shape (an almost linear dependence of current on potential below pH 6) that is similar regardless of how PGE is chemically modified. Importantly, the same waveform is observed if bilirubin oxidase is adsorbed on Au(111) or Pt(111) single-crystal electrodes (at which activity is short-lived). The electrocatalytic behavior of bilirubin oxidase, including its enhanced response on chemically-modified PGE, therefore reflects inherent properties that do not depend on the electrode material. The variation of voltammetric waveshapes and potential-dependent (O(2)) Michaelis constants with pH and analysis in terms of the dispersion model are consistent with a change in rate-determining step over the pH range 5-8: at pH 5, the high activity is limited by the rate of interfacial redox cycling of the Type 1 copper whereas at pH 8 activity is much lower and a sigmoidal shape is approached, showing that interfacial electron transfer is no longer a limiting factor. The electrocatalytic activity of bilirubin oxidase on Pt(111) appears as a prominent pre-wave to electrocatalysis by Pt surface atoms, thus substantiating in a single, direct experiment that the minimum overpotential required for O(2) reduction by the enzyme is substantially smaller than required at Pt. At pH 8, the onset of O(2) reduction lies within 0.14 V of the four-electron O(2)/2H(2)O potential. PMID- 20852808 TI - Yttria-zirconia coatings studied by grazing-incidence small-angle X-ray scattering during in situ heating. AB - The morphology of sol-gel derived dip-coated yttria-doped zirconia films containing variable amounts of yttria has been studied using in situ grazing incidence small-angle X-ray scattering (GISAXS) whilst heated incrementally to 1000 degrees C. A procedure to analyse in situ GISAXS data has been devised which allows a quantitative analysis of time-dependent GISAXS data tracing processes such as chemical reactions or manufacturing procedures. To achieve this, the relative positions of the Yoneda peak and the through beam are used to fix the vertical q scale when the sample thickness is subject to fluctuations due to chemical reactions or deposition processes. A version of Beaucage's unified model with a structure factor from Hosemann's model for paracrystals describes the yttria-zirconia film data best. It is interpreted in terms of particles forming from a polymeric gel network and subsequently agglomerating into larger units subject to Ostwald ripening as both size and average separation distance of the scattering objects increase. The sample with the highest yttria content shows progressive surface roughening from 850 degrees C which may indicate the onset of chemical segregation. PMID- 20852809 TI - Building biomimetic membrane at a gold electrode surface. AB - This article describes efforts to build a model biological membrane at a surface of a gold electrode. In this architecture, the membrane may be exposed to static electric fields on the order of 10(7) to 10(8) V m(-1). These fields are comparable in magnitude to the static electric field acting on a natural biological membrane. The field may be conveniently used to manipulate organic molecules within the membrane. By turning a knob on the control instrument one can deposit or lift the membrane from the gold surface. Electrochemical techniques can be used to control the physical state of the film while the infrared reflection absorption spectroscopy (IRRAS), surface imaging by STM and AFM and neutron scattering techniques can be employed to study conformational changes of organic molecules and their ordering within the membrane. This is shown on examples of membranes built of a simple zwitterionic phospholipid such as 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) and a mixed membrane composed of DMPC and cholesterol. The results illustrate the tremendous effect of cholesterol on the membrane structure. Two methods of membrane deposition at the electrode surface, namely by unilamellar vesicles fusion and using the Langmuir Blodgett technique, are compared. Applications of these model systems to study interactions of small antibiotic peptides with lipids are discussed. PMID- 20852810 TI - Photo- and vapor-responsive conducting microwires based on Pt...Pt interactions. AB - The ordered [Pt(CN-tBu)(2)(CN)(2)] semiconducting microwires have been prepared on substrates based on solvent evaporation or dip-and-pull approaches and were found to display photo- and vapor-responsive conducting characteristics. PMID- 20852811 TI - Lewis acid activation of molybdenum nitrides for alkyne metathesis. AB - The substantial kinetic barrier to molybdenum nitride-alkyne metathesis is facilitated by precomplexation of the borane Lewis acid B(C(6)F(5))(3), providing convenient access to metathesis-active molybdenum alkylidynes. Spectroscopic and X-ray structural analysis suggest Mo=N bond weakening upon borane complexation. PMID- 20852812 TI - Structural changes in the water tetramer. A combined Monte Carlo and DFT study. AB - The heat capacity curve of the water tetramer has been calculated at various levels of theory and over a broad range of temperatures, T = 50-200 K. Parallel tempering and multiple-histogram Monte Carlo methods have been used and combined with the Density Functional Theory calculations of intra-cluster interactions via the Boltzmann-reweighting approach. It is demonstrated that such a combination can yield well converged thermodynamic data even for a modest number of sample configurations, which makes the methodology particularly appropriate for the inclusion of quantum chemistry calculations in Monte Carlo simulations. The B97-1 exchange-correlation functional has been used in the present work together with augmented correlation-consistent basis sets of atomic orbitals up to triple-zeta quality. A structural change has been detected in the water tetramer in the temperature range considered. It is demonstrated that the change corresponds to the onset of rotations of the water molecules around hydrogen bonds with an almost rigid skeleton of the cluster (square cycle) conserved. PMID- 20852813 TI - Multicomponent sulfides as narrow gap hydrogen evolution photocatalysts. AB - A series of mixed crystals composed of Cu(2)ZnSnS(4), Ag(2)ZnSnS(4) and ZnS was prepared by co-precipitation of the corresponding metal ions in aqueous sodium sulfide followed by annealing in a sulfur atmosphere. Ideal solid solutions of Cu(2)ZnSnS(4) and Ag(2)ZnSnS(4) with a kesterite structure ((Cu(x)Ag(1 x))(2)ZnSnS(4) (0 <=x<= 1)) were successfully obtained by this procedure, as confirmed by their X-ray diffraction (XRD) patterns and energy-diffuse X-ray (EDX) analyses. On the other hand, the solubility of ZnS in these kesterite compounds was found to be limited: the upper limit of the ratio of ZnS to (Cu(x)Ag(1-x))(2)ZnSnS(4) was less than 0.1, regardless of the Cu-Ag ratio in (Cu(x)Ag(1-x))(2)ZnSnS(4). Based on the results for dependence of their photoabsorption properties on atomic compositions, a plausible band structure is discussed. Evaluation of the photocatalytic activity for H(2) evolution of these mixed crystals from an aqueous solution containing S(2-) and SO(3)(2-) ions upon loading Ru catalysts under simulated solar radiation (AM 1.5) revealed that active compounds for this reaction should contain both dissolved ZnS and Ag components. The dissolved ZnS in (Cu(x)Ag(1-x))(2)ZnSnS(4) gave upward shifts of their conduction band edges. Moreover, the presence of Ag in the solid solution provided n-type conductivity, leading to efficient migration of photogenerated electrons to the surface to induce water reduction into H(2). PMID- 20852814 TI - Quantum mechanical mechanisms of inelastic and reactive H + D(2)(v = 0, j = 2) collisions. AB - This article analyses the mechanisms of inelastic and reactive H + D(2)(v = 0, j = 2) collisions that result in highly vibrationally excited products when the collision energy is 1.70 eV. The analytical method is entirely quantum mechanical and focuses on correlations between the polarization of the reactant molecule and the direction of product scattering. Two viewpoints are used. The "intrinsic" viewpoint reveals the reactant polarizations that lead to the largest cross section at each value of the scattering angle (the angle between the reactant approach and product-recoil directions); the "extrinsic" viewpoint reveals how the dependence of the collision cross section on the scattering angle changes when the reactant polarization is fixed at each one of a set of experimentally feasible alternatives. Comparison of processes correlating with the same range of impact parameters is also used, to facilitate isolation and identification of directional effects. When products are scattered in the backward and sideways regions, the results for inelastic and reactive collisions are rather similar. When products are scattered in the forward region, the results for inelastic and reactive collisions are clearly different: a side-on collision geometry that largely increases the inelastic cross section hardly affects the reactive cross section. This feature is the quantum mechanical signature of the so-called "tug of-war" mechanism. PMID- 20852820 TI - Enantioselective conjugate addition of boronic acids to enones catalyzed by O monoacyltartaric acids. AB - We have found that O-monoacyltartaric acids catalyze asymmetric conjugate addition of boronic acids to enones with good enantioselectivity, and the 3,5 di(tert-butyl)benzoyl group provides the best results among the acyl groups examined. PMID- 20852821 TI - The structure of Au(6)Y(+) in the gas phase. AB - The geometric and electronic structure of the Au(6)Y(+) cation is studied by gas phase vibrational spectroscopy combined with density functional theory calculations. The infrared photodissociation spectrum of Au(6)Y(+).Ne is measured in the 95-225 cm(-1) energy range and exhibits two characteristic absorption bands at 181 cm(-1) and 121 cm(-1). Based on DFT/BP86 quantum chemical calculations, the infrared spectrum is assigned to the lowest energy species found, an eclipsed C(3v) geometry. The 3D structure of Au(6)Y(+) is considerably different from those previously found for both the neutral Au(6)Y (quasi-planar circular geometry) and the anionic Au(6)Y(-) (planar D(6h) symmetry). The different geometries are related to different electronic structures in agreement with 2D and 3D phenomenological shell models for metal clusters. PMID- 20852822 TI - Factors affecting temporal and spatial variations of microcystins in Gonghu Bay of Lake Taihu, with potential risk of microcystin contamination to human health. AB - A field survey of the seasonal variation of microcystin (MC) concentration was performed in Gonghu Bay (a total of 15 sampling sites) of Lake Taihu from January to December 2008. Microcystis spp. biomass and intra-/extracellular MCs were significantly correlated with water temperature, suggesting the importance of temperature in cyanobacterial blooming in the lake. Higher MC concentration was found in summer and autumn, and peaks of Microcystis biomass and intra /extracellular MC concentrations were all present in October. Spatially, risk of MCs was higher in littoral zones than in the pelagic area. There were significant correlations between N or P concentrations, and Microcystis biomass or MC content, suggesting that N and P levels affected MC production through influencing Microcystis biomass. Intra-/extracellular MCs and Microcystis biomass had negative exponential relationships with TN:TP, and the maximum values all occurred when TN:TP was <25. Multivariate analyses by PCCA indicated that intra- and extracellular MC concentrations had better correlations with biological factors (such as Microcystis biomass and chl-a) than with physicochemical factors. The maximum MC concentration reached up to 17 micrograms/L MC-LReq, considerably higher than the drinking water safety standard (1 micrograms/L) recommended by the WHO. So it is necessary to take measures to reduce the exposure risk of cyanobacterial toxins to human beings. PMID- 20852823 TI - An unusual presentation of a mixed epithelial and stromal tumor in an elderly male. AB - Mixed epithelial and stromal tumors (MESTs) of the kidney are rare renal neoplasms characterized by mixed cystic and solid components. These tumors are typically present in middle-aged women as a flank mass, or as a cause of flank pain or hematuria. We outline the case of an older male who presented with an enlarging abdominal mass causing symptoms that suggested a partial small bowel obstruction. Management of the patient and a brief review are discussed. PMID- 20852824 TI - Reinduction of hormone sensitivity to goserelin following chemotherapy with vinorelbine in castration-resistant prostate cancer. AB - Primary androgen ablation leads to symptomatic improvement and a reduction in prostate-specific antigen (PSA) serum levels in patients with advanced prostate cancer, but all patients eventually become refractory to hormone therapy with progression of the disease and a life expectancy of about a year. We describe a patient who developed castration resistance, was treated with vinorelbine, and continues to be progression free on therapy with luteinizing hormone releasing hormone agonists alone, more than 2.5 years following cessation of treatment with vinorelbine. PMID- 20852825 TI - Correlation of color Doppler with multidetector CT angiography findings in carotid artery stenosis. AB - The aim of this paper was to examine the correlation between the Color Doppler ultrasound (CD-US) and multidetector CT angiography (MDCTA) diagnostic methods, and to define the degree and extent of stenosis in patients with internal carotid artery stenosis. This was a cross-sectional study with a consecutive series of patients. All US examinations were always carried out by the same physician angiologist, while all CT examinations were always carried out by the same physician-radiologist. Both worked independently from each other. The stenosis area was measured at the narrowest point by NASCET criteria for US/CT. Peak systolic velocity (PSV) over 210 cm/sec and end diastolic velocity (EDV) over 110 cm/sec criteria were applied for stenoses with lumen narrowed over 70%, while PSV under 130 cm/sec and EDV under 100 cm/sec criteria were applied for those with lumen narrowed under 70%. A total of 124 carotid arteries were observed; namely, 89 narrowed and 68 surgically treated. All patients were reviewed by US and then by MDCTA; patients with 70-99% stenosis underwent surgery. The correlation coefficient between stenosis degree measured by US and MDCTA was 0.922; p < 0.01. The average difference between US and MDCTA diagnostic methods was 3% (Z = 1.438, p > 0.05). The US and CT matching level for stenoses from 70 to 99% was very high (kappa = 0.778, p < 0.01). In conclusion, there is a highly significant statistical correlation among both diagnostic methods when measuring stenosis degree and extent. US is more dependent on the physician, while MDCTA is more objective and independent from the physician. We think it would be appropriate to undertake an MDCTA exam for those patients who are candidates for carotid endarterectomy. PMID- 20852826 TI - Dissection of the interplay between class I PI3Ks and Rac signaling in phagocytic functions. AB - Phagocytes, like neutrophils and macrophages, are specialized cells evolved to clear infectious pathogens. This function resides at the core of innate immunity and requires a series of concerted events that lead first to migration to the infected tissue and then to the killing of the invading pathogens. Molecular mechanisms underlying these processes are starting to emerge and point to the interplay between two families of crucial proteins: the PI3K lipid kinases and the Rac GTPases. This review focuses on how these two protein families contribute to migration, phagocytosis, and reactive oxygen species production, as well as their epistatic and feedback relations that finely tune these crucial aspects of the immune response. PMID- 20852827 TI - The melanocortin system in control of inflammation. AB - Melanocortin peptides, the collective term for alpha-, beta-, and gamma melanocyte-stimulating hormone (alpha-, beta-, gamma-MSH) and adrenocorticotropic hormone (ACTH), are elements of an ancient modulatory system. Natural melanocortins derive from the common precursor pro-opiomelanocortin (POMC). Five receptor subtypes for melanocortins (MC1-MC5) are widely distributed in brain regions and in peripheral cells. Melanocortin receptor activation by natural or synthetic ligands exerts marked anti-inflammatory and immunomodulatory effects. The anticytokine action and the inhibitory influences on inflammatory cell migration make melanocortins potential new drugs for treatment of inflammatory disorders. Effectiveness in treatment of acute, chronic, and systemic inflammatory disorders is well documented in preclinical studies. Further, melanocortins are promising compounds in neuroprotection. This review examines the main signaling circuits in anti-inflammatory and immunomodulatory actions of melanocortins, and the potential therapeutic use of these molecules. PMID- 20852828 TI - Radiotherapeutic strategies in the management of low-risk prostate cancer. AB - Prostate cancer is the most common nonskin malignancy among men in the United States. Since the introduction of screening with prostate-specific antigen (PSA), most patients are being diagnosed at an early stage with low-risk disease. For men with low-risk prostate cancer, there exists an array of radiotherapeutic strategies that are effective and well tolerated, such as external-beam radiotherapy and brachytherapy. In recent years, there have been tremendous advances in the field of radiation oncology that have transformed the way radiation is used to treat prostate cancer, such as intensity-modulated radiotherapy, image-guided radiotherapy, and stereotactic radiotherapy. It is now feasible to deliver high doses of radiation to the target volume with improved precision and spare more of the neighboring tissues from potentially damaging radiation. Disease outcomes are generally excellent in low-risk prostate cancer. Improvements are expected with further integration of innovative technologies in radiation delivery, tumor imaging, and target localization. PMID- 20852829 TI - Therapeutic potential of 5-HT2C receptor ligands. AB - Serotonin 2C receptors are G protein-coupled receptors expressed by GABAergic, glutamatergic, and dopaminergic neurons. Anatomically, they are present in various brain regions, including cortical areas, hippocampus, ventral midbrain, striatum, nucleus accumbens, hypothalamus, and amygdala. A large body of evidence supports a critical role of serotonin 2C receptors in mediating the interaction between serotonergic and dopaminergic systems, which is at the basis of their proposed involvement in the regulation of mood, affective behavior, and memory. In addition, their expression in specific neuronal populations in the hypothalamus would be critical for their role in the regulation of feeding behavior. Modulation of these receptors has therefore been proposed to be of interest in the search for novel pharmacological strategies for the treatment of various pathological conditions, including schizophrenia and mood disorders, as well as obesity. More precisely, blockade of serotonin 2C receptors has been suggested to provide antidepressant and anxiolytic benefit, while stimulation of these receptors may offer therapeutic benefit for the treatment of psychotic symptoms in schizophrenia and obesity. In addition, modulation of serotonin 2C receptors may offer cognitive-enhancing potential, albeit still a matter of debate. In the present review, the most compelling evidence from the literature is presented and tentative hypotheses with respect to existing controversies are outlined. PMID- 20852830 TI - Why is the New York Times writing so much about Alzheimer's disease therapies? PMID- 20852831 TI - Physical work demands, hypertension status, and risk of ischemic heart disease and all-cause mortality in the Copenhagen Male Study. AB - OBJECTIVE: Increased risk of ischemic heart disease (IHD) mortality from high physical work demands has been observed among men with low physical fitness and leisure time physical activity. We tested whether hypertensive men are at a particularly high risk of IHD mortality when exposed to high physical work demands. METHOD: We carried out a 30-year follow-up of the Copenhagen Male Study of 5249 gainfully employed men aged 40-59 years. Of these, 274 men with a history of myocardial infarction or prevalent symptoms of angina pectoris or intermittent claudication were excluded from the follow-up. Men were classified as having hypertension when any of the following factors was present: (i) treatment for hypertension, (ii) a systolic blood pressure of >160 mm Hg, or (iii) a diastolic blood pressure of >90 mm Hg. Physical work demands were determined by two self reported questions. RESULTS: Of the eligible study population, 587 men (11.9%) died due to IHD. Hypertensive men had more than a doubled risk of IHD mortality [hazard ratio (HR) 2.16, 95% confidence interval (95% CI) 1.80-2.59]. Cox analyses--adjusted for age, smoking, alcohol, body mass index, diabetes, physical fitness, leisure time physical activity, and social class--showed that high physical work demands were associated with an increased risk of IHD and all-cause mortality among normotensive men (N=4127, HR 1.36, 95% CI 0.96-1.92 and HR 1.24, 95% CI 1.06-1.44, respectively), but not among the hypertensive men (N=808, HR 1.07, 95% CI 0.63-1.81 and HR 1.07, 95% CI 0.80-1.42, respectively) using men with low physical work demands as the reference. CONCLUSION: Compared to normotensive men, hypertensive men did not have a higher risk of IHD or all-cause mortality from high physical work demands. PMID- 20852832 TI - Physical workload and accelerated occurrence of lumbar spine diseases: risk and rate advancement periods in a German multicenter case-control study. AB - OBJECTIVE: In a German multicenter case-control study of lumbar disc diseases, we calculated risk and rate advancement periods (RAP) for physical workload. METHODS: Patients aged 25-70 years with clinically and radiologically verified lumbar disc herniation (286 males, 278 females) or symptomatic lumbar disc narrowing (145 males, 206 females) were compared with population control subjects (453 males and 448 females). For this analysis, all manual handling of objects of about >=5 kg and postures with trunk inclination of >=20 degrees , as assessed by technical experts, were included in the calculation of cumulative lumbar load, determined by biomechanical model calculations. Logistic regression analysis was applied to calculate RAP, adjusted for region. RESULTS: We found a steep positive dose-response relationship between age and lumbar disc narrowing among men as well as women; however, we did not find a monotonic increase in lumbar disc herniation risk with age. As a monotonic increase in disease risk with age constitutes a fundamental assumption underlying the RAP concept, we restricted our RAP analysis to cases with symptomatic lumbar disc narrowing. Among men, there was a positive dose-response relationship between the cumulative lumbar load and the acceleration of lumbar disc narrowing. In the highest exposure category, a RAP of 28.0 years [95% confidence interval (95% CI) 9.7-46.3 years] was found. Among women, the RAP was 8.8 years (95% CI 2.4-15.2 years) in the highest exposure category. CONCLUSION: This study emphasizes the conceptual importance of risk acceleration - causation not only comprises the occurrence of a disease (that without a specific exposure would not have occurred at all) but also the accelerated occurrence of a disease (that without exposure would have occurred later in life). PMID- 20852833 TI - [Emergency mission documentation in simulated care. Video-based error analysis]. AB - BACKGROUND: The aim of this study was to examine documentation quality in physician staffed emergency medical services (EMS). This study compared simulated on-site care with the associated patient records written by EMS physicians. METHODS: For this study two standardized simulated case scenarios, ST segment elevation myocardial infarction (STEMI) and major trauma with traumatic brain injury were designed by an expert committee. Overall 29 EMS teams each consisting of 1 EMS physician and 2 paramedics ran through the scenarios on high fidelity patient simulators and each scenario was videotaped. The scenarios were stopped after 12 min for STEMI and after 14 min for major trauma independent of the actions carried out and each EMS physician then had 10 min to document this initial phase on standardized protocol sheets. The videotaped scenarios were analyzed by two independent investigators. Documentation of predefined contents and all drug dosages were checked against the simulated on-site care. The data were evaluated and classified as correct, incorrect or missing documentation although action performed. RESULTS: Written consent for data analysis was provided by 28 teams. Overall 20 parameters and actions in the STEMI scenario and 16 in the major trauma scenario as well as all drug dosages were evaluated. For the scenario STEMI 469 actions were analyzed of which 271 (58%) were correct, 94 (20%) incorrect and 104 (22%) had missing documentation. A total of 140 medications were administered of which 31 (22%) were documented incorrectly and 14 (10%) were not documented. For major trauma 401 actions were analyzed of which 244 (61%) were correct, 101 (25%) incorrect and 56 (14%) had missing documentation. In this scenario the teams administered 138 medications of which 31 (22%) were documented incorrectly and 16 (12%) were not documented. Infused amounts of crystalloids and colloids were mostly documented correctly in this case (35 correct /6 incorrect/8 not documented). Documentation of several clinical parameters was carried out predominantly correctly, e.g. initial blood pressure (STEMI: 25/2/1, major trauma: 21/4/2) and initial ECG rhythm (STEMI: 27/0/1, major trauma: 26/0/1). Documentation of other clinically relevant parameters was often performed incorrectly: 12-lead ECG in STEMI (5/9/12) and capnometry in major trauma (9/4/7). No team used a pain scale to assess the level of pain in the STEMI scenario but 12 EMS physicians documented an accordant value (numerical rating scale) on the patient records. Furthermore some parameters could be identified where documentation was mostly missing although they were measured, e.g. onset of symptoms in STEMI (5/4/15) and reduced level of consciousness and bradypnea in major trauma (9/2/17). CONCLUSION: Patient safety can be reduced if relevant preclinical data are not transmitted correctly to the admitting hospital. Therefore there is a need to improve documentation quality in EMS. Electronic documentation, training of EMS staff and quality management programs might offer solutions. Because of the small sample size further studies are needed to evaluate the validity of these results. PMID- 20852834 TI - [Life-threatening macroglossia following cleft palate palatoplasty]. AB - The case of a 13-month-old child who developed a life-threatening macroglossia with airway obstruction following palatoplasty for a cleft palate is reported. As direct laryngoscopy was not feasible a laryngeal mask (LM) was inserted to secure the airway. Under fiber optic guidance an endotracheal tube was then introduced via the LM. In this article the incidence, pathophysiology, clinical dynamics, options for emergency anesthesia management and organizational implications of this rare but typical complication in the field of oral and craniomaxillofacial surgery are reported. PMID- 20852835 TI - [Successful cardiopulmonary resuscitation in prone position]. AB - In certain surgical positions standard cardiopulmonary resuscitation (CPR) cannot be carried out. It is sometimes impossible or time-consuming to establish a supine position without increasing the no-flow-time and therefore creating a negative outcome of the patient. The case of CPR in a prone position during an emergency evacuation of a cerebellar hematoma is reported. The resuscitation was initiated in the prone position to decrease the no-flow-time. This was very effective because the return of spontaneous circulation (ROSC) started before turning the patient to the supine position. Resuscitation in the prone position in this case was equally as effective as in the traditional supine position. PMID- 20852836 TI - [Emergency response management near the tracks of the public railway network: special aspects of missions connected with the German national railway system]. AB - Emergency response management and rescue operations concerning the railway network in Germany need special attention and implementation in several ways. The emergency response concerning the German national railway network managed by Deutsche Bahn AG is subject to various rules and regulations which have to be followed precisely. Only by following these rules and procedures is the safety of all emergency staff at the scene ensured. The German national railway network (Deutsche Bahn AG) provides its own emergency response control center, which specializes in managing its response to emergencies and dispatches an emergency response manager to the scene. This person serves as the primary Deutsche Bahn AG representative at the scene and is the only person who is allowed to earth the railway electrical power lines. This article will discuss different emergency situations concerning railway accidents and the emergency medical response to them based on a near collision with a high speed train during a rescue mission close to the railway track. Injury to personnel could only be avoided by chance and luck. The dangers and risks for rescue staff are specified. Furthermore, the article details practical guidelines for rescue operations around the German national railway track system. PMID- 20852838 TI - PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). AB - Platelets have been regarded as static cells that do not move once they adhere to a matrix. The present study explored, whether platelets are able to migrate. In contrast to the current opinion, we found that platelets were mobile, able to migrate over a surface, and transmigrate through a transwell membrane and endothelium toward a source of stromal cell-derived factor 1 (SDF-1). Platelet migration was stimulated by SDF-1, which led to the downstream activation and phosphorylation of Wiskott-Aldrich syndrome protein. SDF-1 signaling and subsequent platelet migration could be inhibited by CXCR4-receptor blocker AMD3100, pertussis toxin, inhibition of phosphoinositol 3-kinase (PI3 kinase) with LY294002 or wortmannin, and disruption of actin polymerization with cytochalasin B. The potential of platelets to migrate in an SDF-1-mediated fashion may redefine the role of platelets in the pathophysiology of vascular inflammation, subsequent atherosclerotic degeneration, and vascular regeneration. PMID- 20852839 TI - Variables affecting leakage past endotracheal tube cuffs: a bench study. AB - PURPOSE: Leakage of oral secretions past endotracheal tubes (ETT) has been implicated in ventilator associated pneumonia. The aim of this bench study was to compare the ability of current generation ETT cuffs to prevent fluid leakage and to determine the specific mechanical ventilator settings that affect movement of fluid across an inflated ETT cuff. METHODS: Using a 2.3-cm internal diameter (ID) tracheal model and simulated ventilatory support, we evaluated the impact of cuff pressure (20 and 30 cmH(2)O), positive end-expiratory pressure/continuous positive airway pressure (PEEP/CPAP, 0-15 cmH(2)O), peak inspiratory pressure (PIP, 15-45 cmH(2)O), and mode of ventilation (volume control, volume assist/control, pressure control, pressure assist/control, and CPAP) on leakage of fluid past the ETT cuffs of 16 ETTs. The tracheal model was configured in the vertical position with 35 ml of vitaminwater((r)) on top of the inflated ETT cuff and mechanically ventilated. Fluid leakage past the cuff was determined by calculating the volume change in the tracheal model after each 30-min ventilation period. Initially five 8.0-mm-ID ETTs of each manufacturer type were evaluated at baseline ventilator settings. Tubes allowing a consistent leak within two SD of the mean leakage for the five tubes were numbered in consecutive order. A single tube from this group was then randomly selected for detailed evaluation. RESULTS: Cuff leakage varied among ETT types (p < 0.0001); median leak volume 6.0 ml (0.6 15.1) across all tubes under all conditions. Cuff leakage was inversely related to PEEP level, cuff pressure, and PIP except when PEEP was set at 15 cmH(2)O (all p < 0.0001). In addition, cuff leak varied among modes (p = 0.035). CONCLUSION: Cuff leakage varies greatly among ETT types and is affected by cuff pressure, PEEP, PIP, and mode. PMID- 20852840 TI - Prognostic impact of high-flow nasal cannula oxygen supply in an ICU patient with pulmonary fibrosis complicated by acute respiratory failure. PMID- 20852841 TI - Case report: delayed pleural effusion by femoral cooling catheter. PMID- 20852842 TI - A new hamstring test to complement the common clinical examination before return to sport after injury. AB - PURPOSE: The aim was to introduce and evaluate the reliability and validity of an active hamstring flexibility test as a complement to common clinical examination when determining safe return to sport after hamstring injury. METHODS: Eleven healthy subjects (28 years) were tested on repeated occasions, and 11 athletes (21 years) with MRI-verified acute hamstring strain were tested when common clinical examination revealed no signs of remaining injury, i.e. there was no differences between the legs in palpation pain, manual strength tests, and passive straight leg raise. Flexibility, i.e. highest range of motion of three consecutive trials, was calculated from electrogoniometer data during active ballistic hip flexions and conventional passive slow hip-flexions in a supine position. A VAS-scale (0-100) was used to estimate experience of insecurity during active tests. RESULTS: No significant test-retest differences were observed. Intra-class correlation coefficients ranged 0.94-0.99 and coefficients of variation 1.52-4.53%. Active flexibility was greater (23%) than passive flexibility. In the athletes, the injured leg showed smaller (8%) active, but not passive, flexibility than the uninjured leg. Average insecurity estimation was 52 (range 28-98) for the injured and 0 for the uninjured leg, respectively. CONCLUSION: The new test showed high reliability and construct validity; furthermore, it seems to be sensitive enough to detect differences both in active flexibility and in insecurity after acute hamstring strains at a point in time when the commonly used clinical examination fails to reveal injury signs. Thus, the test could be a complement to the common clinical examination before the final decision to return to sport is made. PMID- 20852843 TI - Clinical outcome using a ligament referencing technique in CAS versus conventional technique. AB - PURPOSE: Computer-assisted surgery (CAS) for total knee arthroplasty (TKA) has become increasingly common over the last decade. There are several reports including meta-analyses that show improved alignment, but the clinical results do not differ. Most of these studies have used a bone referencing technique to size and position the prosthesis. The question arises whether CAS has a more pronounced effect on strict ligamentous referencing TKAs. METHODS: We performed a prospective cohort study comparing clinical outcome of navigated TKA (43 patients) with that of conventional TKA (122 patients). Patients were assessed preoperatively, and 2 and 12 months postoperatively by an independent study nurse using validated patient-reported outcome tools as well as clinical examination. RESULTS: At 2 months, there was no difference between the two groups. However, after 12 months, CAS was associated with significantly less pain and stiffness, both at rest and during activities of daily living, as well as greater overall patient satisfaction. CONCLUSION: The present study demonstrated that computer navigated TKA significantly improves patient outcome scores such as WOMAC score (P=0.002) and Knee Society score (P=0.040) 1 year after surgery in using a ligament referencing technique. Furthermore, 91% were extremely or very satisfied in the CAS TKA group versus 70% after conventional TKA (P=0.007). PMID- 20852844 TI - Efficient strategy for controlling postoperative hemorrhage in total knee arthroplasty. AB - PURPOSE: The objective of the present study was to compare the intraoperative use of tranexamic acid (TNA) plus intra-articular diluted-epinephrine (DEP) with preoperative autologous blood donations and transfusions in reducing an allogeneic blood transfusion (ABT) in primary unilateral total knee arthroplasty (TKA). METHODS: Patients (n=133) treated with unilateral primary TKA were divided into three groups retrospectively: patients administered autologous blood transfusions were assigned to group A (n=51); patients administered preoperative injections of TNA and postoperative intra-articular injections of DEP were assigned to group B (n=42); and patients treated with the drain-clamp method in addition to injections of TNA and DEP were assigned to group C (n=40). The rate of avoidance of ABTs, postoperative blood loss, and complications (DVT/PE, skin problems) were examined. RESULTS: The differences among the three groups were not significant in terms of the proportion of patients requiring no ABTs (94% in group A, 93% in group B and 95% in group C, n.s.). The total blood loss calculated was 1,140+/-451 ml, 852+/-343 ml, and 850+/-296 ml, respectively (group B>A, group C>A, P=0.0009). The significant complications were not observed in three groups. CONCLUSION: The results of the study showed that the TNA plus DEP combination exerted a comparable effect with preoperative autologous blood transfusion in avoiding ABTs in unilateral primary TKA. Considering several problems of preoperative autologous blood donation, the use of TNA plus DEP is recommended. In addition, it is highly possible that allogeneic blood transfusions can be avoided for patients with preoperative Hb values>=10.5 using the method described in this study, and the need for preoperative autologous blood donations can be decreased. PMID- 20852846 TI - Stabilization for chronic sternoclavicular joint instability. AB - We present a surgical reconstruction technique for chronic unstable sternoclavicular (SC) joint utilizing the tendon of sternocleidomastoid (SCM) muscle and additional augmentation utilizing the palmaris longus free tendon graft to secure the medial end of the clavicle to the first rib. This double stabilization procedure may strengthen the SC joint fixation for the chronic SC joint instability. PMID- 20852845 TI - Hybrid fixation: evaluation of a novel technique in adult osteochondritis dissecans of the knee. AB - PURPOSE: Treatment of osteochondritis dissecans of the adult knee requires bone and cartilage integration of the loose fragment. Screw fixation provides primary stability but does not guarantee bony consolidation. Additional biological fixation using osteochondral grafts-hybrid fixation-could improve fragment integration. METHODS: The study included seven patients [median age 21 years (15 29)] who underwent surgery for Bedouelle IIB or III osteochondritis dissecans of the medial femoral condyle. The technique involved metal screw fixation of the fragment. Mosaicplasty grafts were then press-fitted through the fragment. Cancellous autograft was utilized in the cases of subchondral bone loss. Patients were followed up clinically and radiologically (Hughston score). Screws were removed arthroscopically at 3 months and the cartilage graded using the International Cartilage Repair Society score. Fragment integration was evaluated by MRI Arthrogram (4 patients). RESULTS: Median follow-up was 27 months (7-35). Median clinical Hughston score was 2 (0-3) preoperatively and 4 (2-4) postoperatively. Median radiological Hughston score was 3 (2-4) and 4 (3-4). During arthroscopic removal of metalwork, osteochondritis fragments were well integrated in all cases. The International Cartilage Repair Society score was I in one patients, II in five, and III in one. Postoperative MRI arthrograms confirmed that cartilage and bone integration was complete. CONCLUSIONS: Isolated screw fixation of osteochondritis dissecans in adults provides poor bony integration. Mosaicplasty is an alternative but does not retain normal condylar anatomy. The hybrid fixation technique adds a biological "booster" to osteochondritis fixation, with excellent short-term outcome. Further studies are required to investigate the long-term results. PMID- 20852847 TI - Membrane fluidity and fatty acid comparisons in psychrotrophic and mesophilic strains of Acidithiobacillus ferrooxidans under cold growth temperatures. AB - Psychrotrophic strains of Acidithiobacillus ferrooxidans have an important role in metal leaching and acid mine drainage (AMD) production in colder mining environments. We investigated cytoplasmic membrane fluidity and fatty acid alterations in response to low temperatures (5 and 15 degrees C). Significant differences in membrane fluidity, measured by polarization (P) of 1,6-diphenyl 1,3,5-hexatriene (DPH), were found where the psychrotrophic strains had a significantly more rigid membrane (P range = 0.41-0.45) and lower transition temperature midpoints (T (m) = 2.0 degrees C) and broader transition range than the mesophilic strains (P range = 0.38-0.39; T (m) = 2.0-18 degrees C) at cold temperatures. Membrane remodeling was evident in all strains with a common trend of increased unsaturated fatty acid component in response to lower growth temperatures. In psychrotrophic strains, decreases in 12:0 fatty acids distinguished the 5 degrees C fatty acid profiles from those of the mesophilic strains that showed decreases in 16:0, 17:0, and cyclo-19:0 fatty acids. These changes were also correlated with the observed changes in membrane fluidity (R (2) = 63-97%). Psychrotrophic strains employ distinctive modulation of cytoplasmic membrane fluidity with uncommon membrane phase changes as part of their adaptation to the extreme AMD environment in colder climates. PMID- 20852849 TI - Flow field-flow fractionation with multiangle light scattering detection for the analysis and characterization of functional nanoparticles. AB - Chemical modifications of nanoparticles (NPs) are often necessary to improve their features as spectroscopic tracers or chemical sensors, or to increase water solubility and biocompatibility of NPs for applications in nano-biotechnology. The description of newly designed functional NPs is rapidly expanding. However, the full exploitation of technologies based on functional NPs requires accurate, precise, and rugged methods for their analysis and characterization. When quality control protocols for industrial NP production are required, these methods must be applied on a routine basis. Since many properties of functional NPs are size dependent, particle size distribution analysis provides fundamental information. The actual presence and distribution of functional groups in the NPs as well as their chemical features in the nanodispersed state are also fundamental aspects to be additionally analyzed. However, all these tasks cannot be afforded by a single method. Separation methods are necessary to isolate the newly synthesized NPs from the reagents in solution, and then coupled methods can characterize the isolated NPs. Flow field-flow fractionation (F4) is increasingly used as a mature separation method to size-sort and isolate NPs for their further analysis or size characterization by multiangle light scattering (MALS) detection. In this work, firstly the application of F4-MALS to different types of functional NPs is concisely overviewed. We then illustrate our recent applications of F4-MALS coupled with spectroscopic methods for the analysis and characterization of functional NPs. We finally provide an outlook of what we believe are the trends to make F4 soon become the required method in routine-based analytical platforms for quality control protocols of industrial-scale, functional NP production. PMID- 20852848 TI - The effects of nociceptin/orphanin FQ receptor agonist Ro 64-6198 and diazepam on antinociception and remifentanil self-administration in rhesus monkeys. AB - RATIONALE: The synthetic nonpeptide NOP (nociceptin/orphanin FQ peptide) receptor agonist Ro 64-6198 produces antinociception in rhesus monkeys. In rodents, it has much more variable effects on pain responses, but has response rate-increasing effects on punished operant behavior and decreases drug reward. OBJECTIVES: The aim of this study was to compare Ro 64-6198 with the benzodiazepine diazepam in tests of analgesia, drug self-administration, and response-increasing effects in rhesus monkeys. RESULTS: Ro 64-6198 (0.001-0.01 mg/kg, i.v.) produced antinociception against an acute noxious stimulus (50 degrees C water) in the absence of sedation, whereas diazepam (0.32-3.2 mg/kg, i.v.) did not have analgesic effects without sedation. Diazepam (1.0-5.6 mg/kg, i.v.) and the largest dose of Ro 64-6198 (0.32 mg/kg, i.v.) decreased lever pressing maintained by intravenous self-administration of the mu-opioid agonist, remifentanil, but neither effect could be distinguished from sedative effects. Although neither drug consistently increased responding during nonreinforcement, such effects were observed more frequently following diazepam administration. The effects of Ro 64 6198 on lever pressing were blocked by the NOP-receptor antagonist, J-113397, but not by the benzodiazepine antagonist, flumazenil. CONCLUSIONS: These findings suggest that the effects of Ro 64-6198 on operant lever pressing are mediated by NOP receptors and that larger doses are required to impact operant behavior when compared directly with those that produce antinociception. Therefore, the present findings support previous literature suggesting NOP receptors are a viable target for pain management. PMID- 20852850 TI - Porous monoliths: sorbents for miniaturized extraction in biological analysis. AB - In this review the focus is on application of porous monoliths to miniaturized extraction of biological analysis, with emphasis on porous monolithic materials and different miniaturized extraction formats. The general approaches used to synthesize organic polymer and silica monolithic materials are highlighted, and their properties and applicability are described and compared. Several extraction formats, including in-tube microextraction, chip-based microextraction, tip-based microextraction, among others, are reviewed in depth. PMID- 20852851 TI - DNA microarrays for visual detection of human pathogenic microorganisms based on tyramine signal amplification coupled with gold label silver stain. AB - The utility of DNA microarrays is severely limited by their restricted sensitivity. Tyramine signal amplification (TSA) coupled with gold label silver stain (GLSS) was introduced in DNA microarrays for visual detection of human pathogenic microorganisms. First, a TSA system was introduced to the microarrays after the microarrays were prepared and hybridized with biotinylated targets. This procedure leads to large amounts of biotin-conjugated tyramine depositing at the site of enzyme reaction under HRP catalysis. Second, streptavidin-nanogold was introduced and accumulated by specific binding of biotin and streptavidin. Finally, silver staining was performed. The images of the spots were scanned with a visible light scanner and quantified with ArrayVision 7.0 software. Detection conditions were systematically optimized. Then the sensitivity among TSA coupled with GLSS, GLSS, and TSA coupled with Cy3 was compared. The optimized conditions were: streptavidin-HRP (1 mg mL(-1)) dilution 1:1500, biotin-tyramine dilution 1:200 (+0.5% H(2)O(2)), streptavidin-nanogold dilution 1:100 (all diluted in 1 * PBS + 1% BSA) and silver stain time of 10 min. The sensitivity of TSA coupled with GLSS was 100-fold higher than that of GLSS, and was identical with that of TSA coupled with Cy3. Meanwhile, the specificity of the microarrays were not affected. This implied that TSA coupled with GLSS was a sensitive visual detection method and would be an ideal alternative to fluorescence-based detection for DNA microarrays. PMID- 20852852 TI - The biphenyl-carboxylate derivative ABD328 is a novel orally active antiresorptive agent. AB - We previously described a novel series of biphenyl carboxylic acid derivatives which have potent antiresorptive effects in vitro and in vivo and do not affect osteoblast function. However, none of the previous compounds showed oral activity, probably because they were esters, which would be expected to be metabolized very rapidly. Here, we tested whether derivatives where the ester link was replaced by a ketone link were orally active. Compounds were tested in murine osteoclast and osteoblast cultures and in the mouse ovariectomy (OVX) model of osteoporosis. The ketones were at least as potent at inhibiting osteoclast formation and RANKL signaling in vitro as the esters and did not inhibit osteoblast differentiation or function. The basic ketone-linked compound ABD68 was only partially able to inhibit OVX-induced bone loss at an oral dose of 20 mg/kg daily. Substitutions on the phenyl rings increased the potency of the compounds in vitro and may prevent metabolism of the compounds in vivo. The most promising derivative, ABD328, completely prevented OVX-induced bone loss when administered by intraperitoneal injection at 3 mg/kg daily. Furthermore, ABD328 was also able to fully prevent OVX-induced bone loss when given orally at 10 mg/kg daily. The results indicate that biphenyl carboxylates like ABD328 are oral candidate drugs for the treatment of diseases characterized by increased bone resorption, such as postmenopausal osteoporosis. PMID- 20852854 TI - Intracranial findings of Hunter syndrome. PMID- 20852853 TI - Impacts of percutaneous nephrolithotomy on the estimated glomerular filtration rate during the first few days after surgery. AB - Long-term effects of percutaneous nephrolithotomy (PCNL) on renal function have been evaluated in many studies but there are little data on the renal effects of PCNL immediately after surgery in human patients. The aim of this study was to evaluate estimated glomerular filtration rate (GFR) during the first few days after PCNL. From July to September 2008, we gathered preoperative and postoperative serum creatinine data of all the patients who underwent PCNL at our center. Children and patients who received transfusion during surgery were excluded. Creatinine clearance was estimated by Cockcroft-Gault equation and was used to estimate GFR. 94 patients met the inclusion criteria. The mean +/- SD of creatinine clearance by Cockcroft-Gault equation was 87.5 +/- 32.2 cc/min before operation. It decreased to 85.5 +/- 29.4 cc/min, 77.0 +/- 26.8 cc/min and 75.9 +/ 25.0 cc/min at 6, 24 and 48 h after operation and then increased slightly to 81.9 +/- 26.4 cc/min 72 h after operation. Renal GFR decreases immediately after PCNL reaches a nadir 48 h after operation, and then, increases slowly. It seems advisable to avoid factors that can bear a negative influence on renal function during the early postoperative period such as nephrotoxic drugs, contrast agents, shock wave lithotripsy and Re-PCNL. PMID- 20852855 TI - Adrenal and renal corticomedullary junction iron deposition in red cell aplasia. AB - Iron deposition can occur in the kidneys as a result of hemolysis or extensive iron overload from transfusions. With T2* MRI, renal iron deposition can be visualized. In this report, renal corticomedullary junction iron deposition is noted using T2* MRI in a boy with red cell aplasia. The renal corticomedullary junction iron deposition is an indication of the severity of his iron overload. This is an unusual finding and brings clinical attention to the boy's renal function for further evaluation. PMID- 20852856 TI - Torsion of a splenule. PMID- 20852857 TI - Annular pancreas in a toddler. PMID- 20852858 TI - Impact of the Ki-67 proliferation index on response to peptide receptor radionuclide therapy. AB - PURPOSE: The role of the Ki-67 tumour proliferation index (PI) in predicting the efficacy of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic tumours (GEP-NET) remains undetermined. This single-centre analysis focused on the potential therapeutic impact of this immunohistochemical parameter. METHODS: A total of 81 consecutive GEP-NET patients treated with (177)Lu-DOTA-octreotate (mean activity of 7.9 GBq per cycle, usually four treatment cycles at standard intervals of 3 months) were retrospectively analysed. Both an evaluable PI and tumour response (modified SWOG criteria) were required for patient inclusion. RESULTS: Response of tumours with a PI of <=20% (partial response 40%, minor response 15%, stable disease 34%, progressive disease 11%) was comparable in all PI subsets, including those with a PI of 20%. However, G3 tumours (PI > 20%) showed progression in 71% of patients. CONCLUSION: Response to PRRT is consistent over the PI range of <=20% (G1 + G2). Contrary to preliminary previous suggestions, a PI of 15% or 20% should not preclude candidates from somatostatin receptor-targeted radiotherapy. PMID- 20852859 TI - Contribution of the anterior longitudinal ligament to ossification and growth of the vertebral body: an immunohistochemical study using the human fetal lumbar vertebrae. AB - Using 15 mid-term human fetuses, we examined the role of the spine anterior and posterior longitudinal ligaments (ALL, PLL) in ossification of the lumbar vertebral body. By 18 weeks, a pair of calcified tissue or cortical walls had developed on the anterior and posterior sides of the ossification center. These calcified cortical walls were more highly eosinophilic than trabecular or woven bone in the ossification center. Vimentin-positive osteoblasts were arranged in line along the outer surface of the walls. However, few CD68-positive osteoclasts were evident around the walls, suggesting that the calcification in the walls was similar to periosteal ossification. The anterior cortical wall was connected tightly with the ALL by fiber bundles, but the posterior wall was separated from the PLL by the basivertebral (central) vein and loose tissues. Notably, by 30 weeks, the anterior cortical wall had become attached to and incorporated into the ALL. Thus, the ALL seemed to act as an active periosteum for ossification. Although our materials were limited in number and stage, we hypothesized that, in contrast to the PLL, the mature anterior cortical wall corresponds to a calcified fibrocartilage adjacent to the ALL and forms a bone-ligament interface maintaining an ossification potential. PMID- 20852861 TI - Phylogeny, genealogy and the Linnaean hierarchy: a logical analysis. AB - Phylogenetic terms (monophyly, polyphyly, and paraphyly) were first defined in the context of a phylogenetic tree. However, reproduction is the background process that largely determines phylogeny. To establish a connection between genealogy and phylogeny, definitions of phylogenetic terms are presented and studied within a genealogical context. The correctness of the definitions is corroborated with results that show they satisfy the appropriate properties in the context of a phylogenetic tree. In an application of the definitions, a formal analysis shows why the monophyletic condition makes a Linnaean hierarchy entirely monotypic. PMID- 20852860 TI - Novel small molecule drugs inhibit tumor cell metabolism and show potent anti tumorigenic potential. AB - BACKGROUND: Rapidly dividing tumor cells have an increased demand for nutrients to support their characteristic unabated growth; this demand is met by an increased availability of nutrients such as amino acids through vasculogenesis and by the enhanced cellular entry of nutrients through the upregulation of specific transporters. Deprivation of intracellular amino acids or block of amino acid uptake has been shown to be cytotoxic to many established human cancer cell lines in vitro and in human cancer xenograft models. RESULTS: In this paper, we provide evidence that the two small molecule oxyphenisatine analogs TOP001 and TOP216 exert their anti-cancer effect by affecting tumor cell metabolism and inducing intracellular amino acid deprivation, leading to a block of cell proliferation. GCN2-mediated phosphorylation of eIF2alpha as well as mTOR pathway inhibition supports the above notion. In addition, these novel anti-cancer compounds inhibit DNA and protein synthesis and induce apoptosis in a broad spectrum of cancer cell lines. In vivo, the compounds induce tumor stasis and regression in mouse xenograft models of human breast, prostate, ovarian and pancreatic cancer, both when administered intravenously and orally. CONCLUSION: In conclusion, these small molecules, built on a 1,3-dihydroindole-2-one scaffold, elicit strong anti-proliferative and cytotoxic activity, and importantly, a strong anti-tumorigenicity is observed in in vivo xenograft models of human breast, ovary, prostate and pancreatic cancers encouraging the translation of this class of compounds into the clinic. PMID- 20852863 TI - [Molecular pathology of plasma cell neoplasms]. AB - Plasma cell myeloma (PCM) and related immunosecretory disorders are a group of B cell proliferations with a wide clinical and prognostic spectrum, characterized by the production of monoclonal immunoglobulin by immortalized plasma cells. Recent years have seen an explosion in knowledge on the genetic basis and biology of these diseases, followed by improved clinical risk stratification and the introduction of novel therapeutic concepts, such as treatment with proteasome inhibitors or immunomodulatory substances. PCM is a common malignancy, accounting for approximately 10% of all hematological neoplasms. There is good evidence to support a multistep transformation process in plasma cell neoplasms, which corresponds to clinically discernible disease stages. Monoclonal gammopathy of unknown significance is a common asymptomatic precursor lesion for PCM which carries an approximately 1% annual risk for progression. Terminal disease stages are characterized by increasing genetic complexity and independence from bone marrow stromal cells and show a rapidly increasing tumour load with severe clinical symptoms. Modern diagnostics of plasma cell neoplasms require inclusion of clinical, morphological, immunophenotypical and cytogenetic features to allow for individual risk assessment and therapy planning. PMID- 20852865 TI - [Familial thyroid carcinomas]. AB - Approximately 5% of differentiated thyroid carcinomas with follicular cell differentiation, papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) and 25-30% of medullary thyroid carcinoma (MTC) are hereditary. They occur either as part of a defined syndrome or are confined to the thyroid gland. Compared to their sporadic non-hereditary counterparts hereditary thyroid carcinomas generally develop earlier and regularly show multifocal tumour growth. With the exception of familial MTC, which is preceded by neoplastic C cell hyperplasia, no precursor lesions of hereditary thyroid carcinoma are known. In strong correlation with the localisation of the germline mutation of the RET protooncogene, familial MTC shows a distinct clinical course which allows precise clinical decision-making for prophylactic thyroidectomy to prevent invasive MTC. According to current knowledge prophylactic thyroidectomy of all other types of hereditary thyroid carcinoma is not justified. PMID- 20852864 TI - [Morphological and molecular pathology of lung cancer]. AB - Lung carcinoma is the most frequent cause of cancer death in Germany. It is characterized by a considerable morphological complexity that has been reduced by clinicians to the distinction between small cell (SCLC) and non-small cell carcinoma (NSCLC). Underpinned by the possibilities of more differentiated tumor therapy, the classification of lung cancer has undergone a re-evaluation, some essential developments of which are summarized in this article. SCLC and NSCLC do not only differ in gene expression and genetic alterations but also in the ploidy level: SCLC is typically hypodiploid, NSCLC often hyperdiploid/near-triploid. Immunohistochemical analysis is meanwhile standard and includes in particular the markers p63, TTF-1, CK5/6, CK7, CD56/NCAM, synaptophysin, chromogranin and Ki67. A new interdisciplinary classification of adenocarcinoma differentiates between preinvasive, minimally invasive and invasive lesions. Lending new weight to the predominantly histological growth patterns it includes information on molecular genetic alterations such as EGFR mutations. PMID- 20852866 TI - Focal therapy in urologic oncology: maximizing organ function and oncologic disease control. PMID- 20852867 TI - Mechanisms of song production in the Australian magpie. AB - Australian magpies (Gymnorhina tibicen) are notable for their vocal prowess. We investigated the syringeal and respiratory dynamics of vocalization by two 6 month-old males, whose songs had a number of adult features. There was no strong lateral syringeal dominance and unilateral phonation was most often achieved by closing the syringeal valve on the contralateral side of the syrinx. Unlike other songbirds studied, magpies sometimes used an alternative syringeal motor pattern during unilateral phonation in which both sides of the syrinx are partially adducted and open to airflow. Also, in contrast to most other songbirds, the higher fundamental frequency during two-voice syllables was usually generated on the left side of the syrinx. Amplitude modulation, a prominent feature of magpie song, was produced by linear or nonlinear interactions between different frequencies which may originate either on opposite sides of the syrinx or on the same side. Pulse tones, similar to vocal fry in human speech, were present in some calls. Unlike small songbirds, the fundamental of the modal frequency can be as low as that of the pulse tone, suggesting that large birds may have evolved pulse tones to increase acoustic diversity, rather than decrease the fundamental frequency. PMID- 20852868 TI - Indications for thoracoscopic repair of congenital diaphragmatic hernia in neonates. AB - PURPOSE: We reviewed 26 consecutive cases of congenital diaphragmatic hernia (CDH) prospectively to establish selection criteria for successful thoracoscopic CDH repair (TR). METHODS: Five preoperative deaths were excluded, leaving 21 subjects. TR was only considered once pulmonary hypertension (PH) improved on echocardiography, and if cardiopulmonary status was stable in the decubitus position in the neonatal intensive care unit (NICU) under conventional mechanical or high-frequency oscillatory ventilation (HFOV) with/without nitric oxide (NO) for at least 10 min as a marker for tolerating surgery and manual ventilation was possible for transfer to the operating room. All other patients had open repair (OR). RESULTS: 8/21 had TR and 13/21 had OR. There were significant differences between TR and OR for prenatal diagnosis (37.5 vs. 84.6%, p < 0.05) and earlier surgery (1.4 +/- 0.8 vs. 2.5 +/- 1.1 days after birth, p < 0.05), respectively. Intraoperative HFOV was required in all OR and 3 TR (p < 0.01). NO was required in 1 TR and 10 OR (p < 0.01). Organ herniation was significantly less in TR (50 vs. 100%, p < 0.01 for stomach; 0 vs. 54%, p < 0.05 for liver). Three TR required conversion to OR because of technical difficulties. One OR died from deteriorating PH. CONCLUSIONS: Our selection criteria for TR would appear to be safe and reasonable. PMID- 20852869 TI - Choledochal cyst and systemic lupus erythematosus. AB - A 16-year-old female with systemic lupus erythematosus was diagnosed with choledochal cyst. As high-dose steroids had been prescribed for CNS lupus, surgery was performed under steroid cover. Despite postoperative pneumonia and wound infection, she is well 2 years later. There is no similar report in the literature. PMID- 20852870 TI - Comparison of the new high sensitive cardiac troponin T with myoglobin, h-FABP and cTnT for early identification of myocardial necrosis in the acute coronary syndrome. AB - BACKGROUND: We sought to determine the performance of the new high sensitivity cardiac troponin T assay (TnThs) for early diagnosis of myocardial infarction in patients with suspected acute coronary syndrome (ACS) and compare it with the fourth generation cTnT assay, myoglobin and heart-type fatty acid binding protein (h-FABP). METHODS: Ninety-four patients with diagnosis of suspected ACS without ST-segment elevation admitted to our chest pain unit were included. Patients were divided according to time from onset of symptoms to presentation into an early presenter group (<4 h) and a late presenter group (>=4 h). A median of six samples (range 2-8) were available per patient. The diagnostic performance of TnThs was assessed using ROC analysis. Areas under the curve (AUC) of baseline and follow-up results of TnThs, cTnT, myoglobin, and h-FABP were compared using c statistics. RESULTS: The TnThs assay allows an excellent prediction of non-ST segment elevation myocardial infarction (non-STEMI) at presentation, particularly among late presenters. A follow-up sample improves diagnostic performance in a time-dependent manner. The AUC of TnThs was superior to cTnT at all time points. The performance of TnThs was at least as good as myoglobin and h-FABP at presentation and during follow-up. CONCLUSIONS: A baseline sample of TnThs allows an earlier prediction of non-STEMI than the less sensitive and precise fourth generation cTnT assay. Probably, this excellent performance of TnThs at baseline and follow-up could obviate the need for other early markers of necrosis in future. PMID- 20852871 TI - Rosuvastatin induces apoptosis in CD4(+)CD28 (null) T cells in patients with acute coronary syndromes. AB - AIMS: CD4(+)CD28(null) cells represent an aggressive and long-living T cell subpopulation, capable of infiltrating atheromatous plaque, leading to destabilisation and resulting in acute coronary syndromes (ACS). The aim of this study was to evaluate whether statins decrease the number of circulating CD4(+)CD28(null) T cells by apoptosis in patients with ACS. METHODS AND RESULTS: Patients with troponin-positive ACS (n = 35) without cholesterol lowering drugs were randomised to placebo (n = 17) or rosuvastatin 20 mg (n = 18) once daily for 6 weeks. CD4(+)CD28(null) T cell abundance (>1%) was distributed equally among the two groups at entry (n = 10 per group). Within 72 h rosuvastatin treatment significantly reduced mean CD4(+)CD28(null) T cell numbers (37 * 106/L vs. placebo 122 * 106/L, n = 20, P = 0.041), IFN-gamma production (62.6 vs. 101.5%, P = 0.049) and increased apoptosis of these T cells (63.4 vs. 12.3%, P < 0.001). The intrinsic mitochondria-dependent pathway measured by the anti-apoptotic protein expression of B cell lymphoma 2 (BCL-2) was significantly down-regulated (mean fluorescence intensity 16.08 vs. placebo 43.34, P < 0.001). CONCLUSIONS: The down-regulation of anti-apoptotic BCL-2 expression by statins induces apoptosis in CD4(+)CD28(null) T cells. Targeting CD4(+)CD28(null) T cells in ACS statins could provide one further therapeutic strategy to prevent acute life threatening coronary events. PMID- 20852872 TI - Drug-eluting versus bare-metal stents in ST-segment elevation myocardial infarction: a mortality analysis from the EUROTRANSFER Registry. AB - AIM: To assess the patterns of drug-eluting stent (DES) and bare-metal stent (BMS) implantation and associated real-life outcomes in patients with ST-segment elevation myocardial infarction (STEMI) transferred for primary percutaneous coronary intervention (PCI). METHODS: Data were gathered for 1,650 consecutive STEMI patients transferred for primary PCI from hospital networks in seven countries of Europe from November 2005 to January 2007. We identified 1,428 patients with >=1 stent implanted (86.5%). DES were implanted in 382 patients (26.8%) and BMS in 1,046 patients (73.2%) of 1,428 who received stent. RESULTS: High variability in DES use among countries participating in the registry (range from 6.8 to 72.1%) was observed. The use of DES in STEMI declined during the fourth quarter of 2006 through the first quarter of 2007. In the assessed population, age, previous PCI, systolic and diastolic pressures on admission, clopidogrel before admission, left anterior descending artery as the infarct related artery, and thrombus aspiration device use were identified as the independent predictors of DES implantation. Use of DES was associated with significantly lower rates of ischemic events during follow-up (1-year mortality: BMS vs. DES: 6.7% vs. 3.1%; p = 0.014), but observed difference was no longer significant after adjustment for propensity score (adjusted OR (95% CI): 0.55 (0.28-1.06); p = 0.07). CONCLUSIONS: In this large, prospective European registry, the presence of large geographical and temporal variation of DES utilization in STEMI in Europe was confirmed. DES in STEMI appear to be as safe as BMS, with similar mortality after adjustment for potential confounders and trend toward lower 1-year mortality in patients treated with DES. PMID- 20852873 TI - First implantation of the CE-marked transcatheter Sapien pulmonic valve in Europe. PMID- 20852874 TI - Cor triatriatum dexter: rare case of neonatal cyanosis. PMID- 20852875 TI - A histamine H2 receptor blocker ameliorates development of heart failure in dogs independently of beta-adrenergic receptor blockade. AB - Histamine has a positive inotropic effect on ventricular myocardium and stimulation of histamine H2 receptors increases the intracellular cAMP level via Gs protein, as dose stimulation of beta-adrenergic receptors, and worsens heart failure. To test whether a histamine H2 receptor blocker had a beneficial effect in addition to beta-adrenergic receptor blockade, we investigated the cardioprotective effect of famotidine, a histamine H2 receptor blocker, in dogs receiving a beta-blocker. We induced heart failure in dogs by rapid ventricular pacing (230 beats/min). Animals received no drugs (control group), famotidine (1 mg/kg daily), carvedilol (0.1 mg/kg daily), or carvedilol plus famotidine. Both cardiac catheterization and echocardiography were performed before and 4 weeks after the initiation of pacing. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks of pacing. In the control group, the left ventricular ejection fraction (LVEF) was decreased after 4 weeks compared with before pacing (71 +/- 2 vs. 27 +/- 2%, p < 0.05) and mean pulmonary capillary wedge pressure (PCWP) was increased (8 +/- 1 vs. 19 +/- 3 mmHg). Famotidine ameliorated the decrease of LVEF and increase of PCWP, while the combination of carvedilol plus famotidine further improved both parameters compared with the carvedilol groups. These beneficial effects of famotidine were associated with a decrease of the myocardial cAMP level. Histamine H2 receptor blockade preserves cardiac systolic function in dogs with pacing-induced heart failure, even in the presence of beta-adrenergic receptor blockade. This finding strengthens the rationale for using histamine H2 blockers in the treatment of heart failure. PMID- 20852876 TI - Unusual form of superficial spreading squamous cell carcinoma of cervix involving the endometrium, bilateral tubes and ovaries: a case report with literature review. AB - OBJECTIVE: Although the majority of metastatic ovarian tumors arise within the female genital tract, squamous cell carcinoma of the cervix is a rare form of metastases to the bilateral ovaries by endometrial and transtubal spreading. CASE: A 53-year-old woman was referred to the oncology clinic with postmenopausal bleeding. On vaginal examination, a 3 cm tumor arising from the cervix was inspected. Multiple cervical biopsies and endocervical curettage revealed large cell, non-keratinized squamous cell cervix carcinoma. Radical hysterectomy and bilateral salpingo-oophorectomy were performed. Bilateral pelvic and para-aortic lymph nodes were also removed. The final pathology report revealed endometrial, focal myometrial, bilateral tubal mucosal, fimbrial and bilateral ovarian squamous cell carcinoma involvement. Pelvic and para-aortic nodes were free from metastases. CONCLUSION: Although the incidence of ovarian metastases of adenocarcinoma of the cervix is significantly higher, squamous cell carcinoma may also metastasize to the ovaries by endometrial and transtubal spreading in the absence of lymph node involvement. Especially in young patients for whom preservation of the ovaries is supposed, gross intraoperative inspection of the radical hysterectomy specimen and endometrium should be done and ovaries should be evaluated carefully. PMID- 20852877 TI - Paroxysmal dysarthria and ataxia in multiple sclerosis and corresponding magnetic resonance imaging findings. AB - Paroxysmal dysarthria (PD) and paroxysmal dysarthria-ataxia (PDA) syndromes are uncommon symptoms of the neurological dysfunction in multiple sclerosis (MS). We describe two patients who had clinically definite MS presented with symptomatic PD and PDA syndromes, respectively, related to demyelinating lesions. In one patient, the PD symptom was the initial manifestation of an acute episode. In the other patient, the episode of dysarthria was accompanied by ataxia disorders. Both patients had midbrain lesions at or below the level of the right red nucleus on magnetic resonance imaging (MRI), confirming that this area is critically involved. Both responded well to carbamazepine (CBZ). PMID- 20852878 TI - Current approach to seronegative myasthenia. AB - The group of patients with weakness or fatigue who have electrophysiological evidence of neuromuscular transmission defects, but no antibodies against either acetyl choline receptor or muscle specific kinase, need special evaluation and therapeutic consideration. Such seronegative patients may have low affinity antibodies but may also be late onset of a congenital myasthenic syndrome. This review discuss the practical approach toward the condition of seronegative myasthenia. PMID- 20852879 TI - Neuromuscular disorders and 2010: recent advances. AB - This short review summarises the research articles related to neuromuscular disorders published in the Journal of Neurology over the last year from May 2009 to July 2010. PMID- 20852880 TI - Comparison in eccentric exercise-induced muscle damage among four limb muscles. AB - This study tested the hypothesis that changes in indirect markers of muscle damage following maximal eccentric exercise would be smaller for the knee extensors (KE) and flexors (KF) compared with the elbow flexors (EF) and extensors (EE). A total of 17 sedentary men performed five sets of six maximal isokinetic (90 degrees s(-1)) eccentric contractions of EF (range of motion, ROM: 90 degrees -0 degrees , 0 = full extension), EE (55 degrees -145 degrees ), KF (90 degrees -0 degrees ), and KE (30 degrees -120 degrees ) using a different limb with a 4-5-week interval in a counterbalanced order. Changes in maximal isometric and concentric isokinetic strength, optimum angle, limb circumference, ROM, plasma creatine kinase activity and myoglobin concentration, muscle soreness, and echo-intensity of B-mode ultrasound images before and for 5 days following exercise were compared amongst the four exercises using two-way repeated-measures ANOVA. All variables changed significantly following EF, EE, and KF exercises, but KE exercise did not change the optimum angle, limb circumference, and echo-intensity. Compared with KF and KE, EF and EE showed significantly greater changes in all variables, without significant differences between EF and EE. Changes in all variables were significantly greater for KF than KE. For the same subjects, the magnitude of change in the dependent variables following exercise varied among the exercises. These results suggest that the two arm muscles are equally more susceptible to muscle damage than leg muscles, but KF is more susceptible to muscle damage than KE. The difference in the susceptibility to muscle damage seems to be associated with the use of muscles in daily activities. PMID- 20852881 TI - Effect of heliox on heart rate kinetics and dynamic hyperinflation during high intensity exercise in COPD. AB - Respiratory mechanical abnormalities in patients with chronic obstructive pulmonary disease (COPD) may impair cardiodynamic responses and slow down heart rate (HR) kinetics compared with normal resulting in reduced convective oxygen delivery during exercise. We reasoned that heliox breathing (79% helium-21% oxygen) and the attendant reduction of operating lung volumes should accelerate HR kinetics in the transition from rest to high-intensity exercise. Eleven male ambulatory patients with clinically stable COPD undertook constant work-rate cycle testing at 80% of each individuals' maximum work capacity while breathing room air (RA) or heliox (HX), randomly. Mean response time (MRT) for HR and dynamic end-expiratory lung volume (EELV) were measured. Resting EELV was not affected by HX breathing, while exercise EELV decreased significantly by 0.23 L at isotime during HX breathing compared with RA. During HX breathing, MRT for HR significantly accelerated (p = 0.002) by an average of 20 s (i.e., 17%). Speeded MRT for HR correlated with indices of reduced lung hyperinflation, such as EELV at isotime (r = 0.88, p = 0.03), and with improved exercise endurance time (r = 0.64, p = 0.03). The results confirm that HX-induced reduction of dynamic lung hyperinflation is associated with consistent improvement in indices of cardio circulatory function such as HR kinetics in the rest-to-exercise transition in COPD patients. PMID- 20852882 TI - Short-term unilateral leg immobilization alters peripheral but not central arterial structure and function in healthy young humans. AB - Short-term leg immobilization is an acute model of inactivity, which induces vascular deconditioning. The present study was conducted to determine if short term leg immobilization induced alterations in central and peripheral conduit artery structure (diameter and compliance), function (resting blood flow and mean wall shear rate), and peripheral flow-mediated dilation. Healthy participants (n = 7 women and n = 8 men) were studied before and after 12 days of unilateral leg immobilization. Carotid artery structure and function were unaltered with immobilization indicating that the unilateral immobilization did not have a detectable effect on this representative central artery. In contrast, peripheral measures of arterial structure at the common femoral and popliteal arteries showed significant reductions in both the immobilized and non-immobilized limbs but to a greater extent in the immobilized limbs. Specifically, femoral and popliteal artery compliance and femoral artery diameter were reduced in both the immobilized and the non-immobilized limb (p < 0.05) while popliteal artery diameter was reduced only in the immobilized leg. Popliteal artery flow-mediated dilation, an indicator of peripheral artery function, was increased in the immobilized limb, which parallels reports in paralyzed limbs of spinal-cord injured individuals. The time course of vascular alterations with inactivity likely follows a sequence of adaptations in arterial structure and function reflecting differing initial flow patterns, and arterial wall composition, and diverse hemodynamic stimuli within different blood vessels. PMID- 20852883 TI - Outcomes of non-anatomic liver resection for hepatocellular carcinoma in the patients with liver cirrhosis and analysis of prognostic factors. AB - PURPOSE: In the east countries, patients with hepatocellular carcinoma (HCC) are usually associated with varied degrees of liver cirrhosis, and anatomic resection is therefore limited to use, especially in those with severe liver cirrhosis. This study aims to evaluate the clinical value of non-anatomic resection in HCC patients with cirrhosis. METHODS: Seventy-seven consecutive HCC patients with cirrhosis underwent non-anatomic liver resection in Tongji Hospital from January 2003 to December 2006. The clinical data, severity of liver cirrhosis, and survival rates of these patients were retrospectively evaluated, and the prognostic factors were analyzed. RESULTS: One-, 2-, and 3-year overall and disease-free survival rates of this cohort of patients were 78%, 68%, 56%, and 66%, 58%, 55%, respectively. The hospital mortality and morbidity were 0% and 24.7%, respectively. The 1-, 2-, and 3-year overall survival rates were 85.7%, 77.1%, and 74.3% in the patients with mild cirrhosis, 81.5%, 63%, and 48.1% in the patients with moderate cirrhosis, and 60.0%, 53.3%, and 26.7% in the patients with severe cirrhosis, respectively. There was a significant difference among the patients with different grades of cirrhosis (P = 0.001). Multivariate and univariate analyses revealed that severity of cirrhosis, tumor diameter larger than 5 cm, and vascular invasion were independent prognostic factors. CONCLUSIONS: Non-anatomic liver resection for HCC could yield comparable outcomes with anatomic resection in the patients with mild cirrhosis or tumors diameter smaller than 5 cm. Severity of cirrhosis is an independent factor worsening long time survival. Non-anatomic resection is a safe and effective surgical modality in the treatment of HCC patients with cirrhosis. PMID- 20852884 TI - Polyploidy origin of wheatgrass Douglasdeweya wangii (Triticeae, Poaceae): evidence from nuclear ribosomal DNA internal transcribed spacer and chloroplast trnL-F sequences. AB - To study hybrid speciation in wheatgrass Douglasdeweya wangii and to investigate the evolutionary pattern of nuclear ribosomal DNA (nrDNA) internal transcribed spacer sequences (ITSs) in allotetraploids, DNA sequence variation of ITSs and chloroplast trnL-F sequences from D. wangii and its putative donors were analyzed. The ITSs revealed that D. wangii had an StP genome composition. Most accessions of D. wangii had one parental ITS copy in their genome, one accession had two parental ITSs. The trnL-F sequences revealed an especially close relationship of Pseudoroegneria to all D. wangii individuals included, and the two accessions of Pseudoroegneria tauri (PI401324 and PI401331) were maternal candidates of the studied D. wangii individuals. Both of ITS and trnL-F trees suggested multiple origins and recurrent hybridization of D. wangii. Thus, the results suggested that: (1) the St and P genome in allotetraploid D. wangii were donated by Pseudoroegneria and Agropyron, respectively;(2) Pseudoroegneria was the maternal donor of D. wangii, and P. tauri 26 (accession PI401324) and P. tauri 27 (accession PI401331) were most likely the potential candidates of maternal donors; (3) D. wangii individuals studied here showed multiple origins and experienced recurrent hybridization; and (4) bidirectional interlocus concerted evolution of ITSs had occurred in most D. wangii accessions, while in one accession concerted evolution among homeologous loci did not occur. PMID- 20852885 TI - Melanoma, Darwinian medicine and the inner world. AB - INTRODUCTION: A diverse range of human diseases, including allergy, asthma, autoimmune disease, cancer and chronic neurologic diseases, notably multiple sclerosis and endogenous depression, is becoming more prevalent in industrialized countries. It has been postulated that environmental factors associated with improved standards of hygiene play a leading role in this process since the immune system seems to need extrinsic challenges for its proper maturation. THE INNER WORLD: An added dimension has now emerged--the impact on disease of the inner world, principally the numerous endogenous retroviruses (HERVs) within the human genome. Taking melanoma as an example, we propose a framework for understanding how a complex infectious and immunological background can induce or inhibit expression of a HERV-related disease process. The central role of a failure to induce or to maintain certain populations of self-specific CD8(+) T cells mediating immune surveillance, the expression of HERV-encoded peptides on affected cells and pathological mechanisms directly attributable to HERV proteins are discussed. CONCLUSIONS: The presented concepts explain events preceding the clinical manifestation of diseases by several years and provide a rationale for the use of currently available vaccines to protect against certain HERV-induced diseases, especially melanoma. Criteria for establishing the causal role of HERVs in a given disease are proposed. PMID- 20852886 TI - Identification and characterization of a serine protease inhibitor with two trypsin inhibitor-like domains from the human hookworm Ancylostoma duodenale. AB - Protease inhibitors play important roles in the parasitic nematodes' survival within their host, in the development and reproduction of the parasites. The present study described the isolation, identification, and characterization of a novel member of the Ascaris family of serine protease inhibitors, designated AduTIL-1, from the human hookworm Ancylostoma duodenale. AduTIL-1 is composed of a signal sequence and two trypsin inhibitor-like (TIL) domains, which showed the highest similarity with OdmCRP, a putative serine protease inhibitor with two TIL domains in Oesophagostomum dentatum. Each TIL domain of the AduTIL-1 was expressed in Escherichia coli, and their inhibitory activities against serine proteases from animals and human were characterized, respectively. Both of the two TIL domains inhibited human neutrophil elastase and pancreatic trypsin, but different in effectiveness. Although the first TIL domain of AduTIL-1 inhibited bovine pancreatic chymotrypsin (Ki=18.0 nM), both of the two domains showed no inhibitory activity against the human pancreatic chymotrypsin. Immunohistochemical studies demonstrated that AduTIL-1 was localized in esophagus, intestine, and cuticular surface of the adult worms. These results suggested that AduTIL-1 may be involved in the survival of A. duodenale in host by targeting related digestive enzymes and neutrophil elastase. PMID- 20852887 TI - A new gonad-infecting species of Philometra (Nematoda: Philometridae) from the red cusk-eel Genypterus chilensis (Osteichthyes: Ophidiidae) off Chile. AB - A new nematode species, Philometra genypteri sp. n. (Philometridae), is described from male and female specimens found in the ovary of red cusk-eel, Genypterus chilensis (Guichenot) (Ophidiidae, Ophidiiformes), from the eastern South Pacific Ocean off the coast of northern Chile. Based on light and scanning electron microscopy examination, the new species differs from most other gonad-infecting Philometra spp. in the length of spicules (126-135 MUm), a gubernaculum with dorsal lamella-like structures on its distal end, and the number and arrangement of genital papillae in the male. From a few congeneric, gonad-infecting species with unknown males, it can be distinguished by some morphological and biometrical features found in gravid female (absence of caudal projections, length of first stage larvae or oesophagus, moderately developed anterior oesophageal inflation) and by the host type (fish family) and geographical distribution. P. genypteri is the first philometrid species reported from a fish belonging to the order Ophidiiformes and the second nominal species of Philometra recorded from marine fishes of the eastern South Pacific. PMID- 20852888 TI - Litomosoides pardinasi n. sp. (Nematoda, Onchocercidae) from two species of cricetid rodents in northern Patagonia, Argentina. AB - Seventy-seven cricetid rodents, corresponding to six different species, deposited at the Mammal Collection at Centro Nacional Patagonico, Puerto Madryn, Chubut, were examined for parasites. Litomosoides pardinasi n. sp. is described parasitizing the pleural and abdominal cavities of Phyllotis xanthopygus (Phyllotini) and the abdominal cavity of Oligoryzomys longicaudatus (Oryzomynii) in the northern Patagonia, Argentina. The new species is included in the carinii group, characterized by the presence of a right spicule with a dorsal heel and a terminal cap well cuticularized; left spicule composed with a handle longer or as long as the blade, and the blade constituted by a cuticularized distal filament. Litomosoides pardinasi n. sp. possesses a buccal capsule tubular with an anterior enlargement, and a smooth cavity; four labial and two dorsal cephalic papillae; vulva posterior to the esophagus-intestinal junction; male tail with three to five pairs of symmetric postcloacal papillae; female tail slender; vagina globular and small. This is the first record for a filarioid in a Phyllotini rodent and the southernmost record of any filarioid species worldwide. PMID- 20852889 TI - Flight behavior of adult Culicoides oxystoma and Culicoides maculatus under different temperatures in the laboratory. AB - The flight behavior of adult Culicoides biting midges is associated with their likelihood to reach nearby host animals and spread diseases. Therefore, evaluating the effects of atmospheric factors on the flight performances of these insects is important for understanding the spread of diseases in various circumstances. We evaluated the effects of different temperatures on the flight behavior of Culicoides oxystoma and Culicoides maculatus under laboratory conditions. The flight activities for both species particularly increased in the range between 10 degrees C and 20 degrees C, while the activities under 10 degrees C were very limited for both species. The temperature when one half of the proportion of insects had flown was estimated to be 18.1 degrees C for C. oxystoma and slightly higher than the value of 17.4 degrees C for C. maculatus by fitting sigmoid curves. However, the wide 95% confidence interval observed for C. maculatus did not statistically justify the difference. The flight behavior of adult Culicoides biting midges was highly influenced by temperature. Our results would be of use for modeling studies or geographical analyses of diseases transmitted by these insects. PMID- 20852890 TI - Screening the Schistosoma mansoni transcriptome for genes differentially expressed in the schistosomulum stage in search for vaccine candidates. AB - Schistosomiasis affects more than 200 million people worldwide; another 600 million are at risk of infection. The schistosomulum stage is believed to be the target of protective immunity in the attenuated cercaria vaccine model. In an attempt to identify genes up-regulated in the schistosomulum stage in relation to cercaria, we explored the Schistosoma mansoni transcriptome by looking at the relative frequency of reads in EST libraries from both stages. The 400 genes potentially up-regulated in schistosomula were analyzed as to their Gene Ontology categorization, and we have focused on those encoding-predicted proteins with no similarity to proteins of other organisms, assuming they could be parasite specific proteins important for survival in the host. Up-regulation in schistosomulum relative to cercaria was validated with real-time reverse transcription polymerase chain reaction (RT-PCR) for five out of nine selected genes (56%). We tested their protective potential in mice through immunization with DNA vaccines followed by a parasite challenge. Worm burden reductions of 16 17% were observed for one of them, indicating its protective potential. Our results demonstrate the value and caveats of using stage-associated frequency of ESTs as an indication of differential expression coupled to DNA vaccine screening in the identification of novel proteins to be further investigated as potential vaccine candidates. PMID- 20852891 TI - Construction, purification, and evaluation of multivalent DNA vaccine against Schistosoma japonicum. AB - DNA vaccine encoding a multivalent antigen is a novel approach of protective immunization. Four Schistosoma japonicum candidate antigen genes, glyceraldehyde 3-phosphate dehydrogenase (SjGAPDH), 23 kDa transmembrane protein (Sj23), 14 kDa fatty-acid binding protein (SjFABP) and 26 kDa glutathione-S-transferase (Sj26), are recombined into two pieces of fusion genes SjFABP.Sj23 and Sj26.SjGAPDH, respectively. Tetravalent DNA vaccine pVIVO2-SjFABP.Sj23/Sj26.SjGAPDH is constructed by co-expressing these two fusion genes. The super-coiled DNA vaccines for large-scale clinic application were purified by sequential chromatographies including group separation chromatography and affinitive chromatographies. The purified DNA vaccines were evaluated for in vivo and in vitro transfection assay. The immunoprotective properties of the different kinds of constructed DNA vaccines were appraised by pharmacological trials. The pharmacological trials results showed that tetravalent DNA vaccine has higher protective efficiency than other tested DNA vaccines. PMID- 20852892 TI - The molecular basis of autosomal recessive diseases among the Arabs and Druze in Israel. AB - The Israeli population mainly includes Jews, Muslim and Christian Arabs, and Druze In the last decade, data on genetic diseases present in the population have been systematically collected and are available online in the Israeli national genetic database ( http://www.goldenhelix.org/server/israeli ). In the non-Jewish population, up to 1 July 2010, the database included molecular data on six diseases relatively frequent in the whole population: thalassemia, familial Mediterranean fever (FMF), cystic fibrosis, deafness, phenylketonuria and congenital adrenal hyperplasia, as well as data on 195 autosomal recessive diseases among Muslim Israeli Arabs, 11 among the Christian Arabs and 31 among Druze. A single mutation was characterized in 149 out of the 238 rare disorders for which the molecular basis was known. In many diseases, mutation had never been observed in any other population and was present in one family only suggesting that it occurred as a de novo event. In other diseases, the mutation was present in more than one community or even in other populations such as Bedouins from the Arab peninsula or Christians from Lebanon. In the 89 other disorders, more than one mutation was characterized either in the same gene or in more than one gene. While it is probable that most of these cases represent random events in some cases such as Bardet Biedl among the Bedouins, the reason may be a selective advantage to the heterozygotes. PMID- 20852893 TI - Rare variation at the TNFAIP3 locus and susceptibility to rheumatoid arthritis. AB - Genome-wide association studies (GWAS) conducted using commercial single nucleotide polymorphisms (SNP) arrays have proven to be a powerful tool for the detection of common disease susceptibility variants. However, their utility for the detection of lower frequency variants is yet to be practically investigated. Here we describe the application of a rare variant collapsing method to a large genome-wide SNP dataset, the Wellcome Trust Case Control Consortium rheumatoid arthritis (RA) GWAS. We partitioned the data into gene-centric bins and collapsed genotypes of low frequency variants (defined here as MAF <= 0.05) into a single count coupled with univariate analysis. We then prioritized gene regions for further investigation in an independent cohort of 3,355 cases and 2,427 controls based on rare variant signal p value and prior evidence to support involvement in RA. A total of 14,536 gene bins were investigated in the primary analysis and signals mapping to the TNFAIP3 and chr17q24 loci were selected for further investigation. We detected replicating association to low frequency variants in the TNFAIP3 gene (combined p = 6.6 * 10(-6)). Even though rare variants are not well-represented and can be difficult to genotype in GWAS, our study supports the application of low frequency variant collapsing methods to genome-wide SNP datasets as a means of exploiting data that are routinely ignored. PMID- 20852894 TI - Does the early frog catch the worm? Disentangling potential drivers of a parasite age-intensity relationship in tadpoles. AB - The manner in which parasite intensity and aggregation varies with host age can provide insights into parasite dynamics and help identify potential means of controlling infections in humans and wildlife. A significant challenge is to distinguish among competing mechanistic hypotheses for the relationship between age and parasite intensity or aggregation. Because different mechanisms can generate similar relationships, testing among competing hypotheses can be difficult, particularly in wildlife hosts, and often requires a combination of experimental and model fitting approaches. We used field data, experiments, and model fitting to distinguish among ten plausible drivers of a curvilinear age intensity relationship and increasing aggregation with host age for echinostome trematode infections of green frogs. We found little support for most of these proposed drivers but did find that the parsimonious explanation for the observed age-intensity relationship was seasonal exposure to echinostomes. The parsimonious explanation for the aggregated distribution of parasites in this host population was heterogeneity in exposure. A predictive model incorporating seasonal exposure indicated that tadpoles hatching early or late in the breeding season should have lower trematode burdens at metamorphosis, particularly with simulated warmer climates. Application of this multi-pronged approach (field surveys, lab experiments, and modeling) to additional parasite-host systems could lead to discovery of general patterns in the drivers of parasite age-intensity and age-distribution relationships. PMID- 20852895 TI - Birds help plants: a meta-analysis of top-down trophic cascades caused by avian predators. AB - The tritrophic interactions between plants, herbivores and avian predators are complex and prone to trophic cascades. We conducted a meta-analysis of original articles that have studied birds as predators of invertebrate herbivores, to compare top-down trophic cascades with different plant responses from different environments and climatic areas. Our search found 29 suitable articles, with a total of 81 separate experimental study set-ups. The meta-analysis revealed that plants benefited from the presence of birds. A significant reduction was observed in the level of leaf damage and plant mortality. The presence of birds also positively affected the amount of plant biomass, whereas effects on plant growth were negligible. There were no differences in the effects between agricultural and natural environments. Similarly, plants performed better in all climatic areas (tropical, temperate and boreal) when birds were present. Moreover, both mature plants and saplings gained benefits from the presence of birds. Our results show that birds cause top-down trophic cascades and thus they play an integral role in ecosystems. PMID- 20852896 TI - Assessing survival in a multi-population system: a case study on bat populations. AB - In long-lived animals, adult survival is among the most important determinants of population dynamics. Although it may show considerable variation both in time and among populations and sites, a single survival estimate per species is often used in comparative evolutionary studies or in conservation management to identify threatened populations. We estimated adult survival of the isabelline serotine bat Eptesicus isabellinus using capture-recapture data collected on six maternity colonies scattered over a large area (distance 8-103 km) during periods varying from 8 to 26 years. We modelled temporal and inter-colony variations as random effects in a Bayesian framework and estimated mean annual adult survival of females on two scales and a single survival value across all colonies. On a coarse scale, we grouped colonies according to two different habitat types and investigated the effect on survival. A difference in adult survival was detected between the two habitat types [posterior mean of annual survival probability 0.71; 95% credible interval (CI) 0.51-0.86 vs. 0.60; 0.28-0.89], but it was not statistically supported. On a fine scale, survival of the six colonies ranged between 0.58 (95% CI 0.23-0.92) and 0.81 (0.73-0.88), with variation between only two colonies being statistically supported. Overall survival was 0.72 (95% CI 0.57-0.93) with important inter-colony variability (on a logit scale 0.98; 95% CI 0.00-8.16). Survival varied temporally in a random fashion across colonies. Our results show that inference based solely on single colonies should be treated with caution and that a representative unbiased estimate of survival for any species should ideally be based on multiple populations. PMID- 20852897 TI - Advances, shortcomings, and recommendations for wind chill estimation. AB - This article discusses briefly the advances made and the remaining short-comings in the "new" wind chill charts adopted in the US and Canada in 2001. A number of indicated refinements are proposed, including the use of whole body models in the computations, verification of heat exchange coefficients by human experiments, reconsideration of "calm" wind conditions, reconsideration of frostbite threshold levels, the inclusion of cold-related pain and numbness in the charts, etc. A dynamic numerical model is applied to compare the effects of wind speeds, on the one hand, and air temperatures, on the other, on the steady-state exposed facial and bare finger temperatures. An apparent asymmetry is demonstrated, favoring the effects of wind speeds over those of air temperatures for an identical final facial temperature. This asymmetry is reversed, however, when SI unit changes in these quantities are considered. PMID- 20852898 TI - Determining optimal clothing ensembles based on weather forecasts, with particular reference to outdoor winter military activities. AB - Military and civil defense personnel are often involved in complex activities in a variety of outdoor environments. The choice of appropriate clothing ensembles represents an important strategy to establish the success of a military mission. The main aim of this study was to compare the known clothing insulation of the garment ensembles worn by soldiers during two winter outdoor field trials (hike and guard duty) with the estimated optimal clothing thermal insulations recommended to maintain thermoneutrality, assessed by using two different biometeorological procedures. The overall aim was to assess the applicability of such biometeorological procedures to weather forecast systems, thereby developing a comprehensive biometeorological tool for military operational forecast purposes. Military trials were carried out during winter 2006 in Pokljuka (Slovenia) by Slovene Armed Forces personnel. Gastrointestinal temperature, heart rate and environmental parameters were measured with portable data acquisition systems. The thermal characteristics of the clothing ensembles worn by the soldiers, namely thermal resistance, were determined with a sweating thermal manikin. Results showed that the clothing ensemble worn by the military was appropriate during guard duty but generally inappropriate during the hike. A general under-estimation of the biometeorological forecast model in predicting the optimal clothing insulation value was observed and an additional post processing calibration might further improve forecast accuracy. This study represents the first step in the development of a comprehensive personalized biometeorological forecast system aimed at improving recommendations regarding the optimal thermal insulation of military garment ensembles for winter activities. PMID- 20852899 TI - Fatal "hypertensive" intracerebral hemorrhage associated with a cerebral cavernous angioma: case report. PMID- 20852900 TI - The posterior subtemporal keyhole approach combined with the transchoroidal approach to the ambient cistern: microsurgical anatomy and image-guided quantitative analysis. AB - PURPOSE: The aim of this study is to describe microsurgical anatomy and to quantitatively analyze exposure using the posterior subtemporal keyhole (PSK) approach combined with the transchoroidal keyhole (TCK) approach to the ambient cistern. METHODS: We determined the proper location of craniotomy of such combined keyhole approach on 16 sides of cadaver heads. The PSK approach and the TCK approach were performed in the same minicraniotomy to observe microanatomic features and to quantitatively measure exposure limits of the ambient cistern and related structures using image-guided system. RESULTS: Some superficial and bone landmarks could be used to find the proper location of such combined minicraniotomy. In the PSK approach, the exposure distances of the trigeminal nerve and the anterior portion of the P2 segment (P2a) were 10.02 +/- 0.76 mm and 16.32 +/- 2.02 mm, respectively. The superior, inferior, anterior, and posterior exposure limit of brainstem from the intersection point of the lateral mesencephalic sulcus and pontomesencephalic sulcus was 7.5 +/- 0.19 mm, 11.04 +/- 0.27 mm, 15.72 +/- 0.52 mm, and 10.16 +/- 0.38 mm, respectively. In the TCK approach, the vertical distances between the taenia fimbriae and the lateral geniculate body without and with mild caudal retraction of the hippocampus were 5.28 +/- 0.46 mm and 11.18 +/- 0.57 mm, respectively. The linear exposure distances of the posterior portion of the P2 segment (P2p) or P3 segment were 12.14 +/- 1.88 mm. Except of one case, the P2p could be exposed using the TCK approach. The midpoint of the medial edge of the parahippocampal gyrus on the coronal magnetic resonance images provides landmark to choose the appropriate approach. CONCLUSIONS: The PSK combined with the TCK approach can simultaneously expose the lower and upper ambient cistern in a proper minicraniotomy. PMID- 20852901 TI - Pre-existing chiasma syndromes do not entirely remit following transsphenoidal surgery for pituitary adenomas. AB - BACKGROUND: It is not known whether following transsphenoidal surgery for pituitary adenomas the vision of patients with preoperative chiasma syndromes (CS) does improve to the degree of vision of patients without preoperative CS. OBJECTIVE: The purpose of this study is to answer the question above. METHODS: Pertinent data of a successive series of patients operated transsphenoidally for the first time for pituitary adenoma were retrospectively analysed. RESULTS: Of the 304 patients, 35.1% presented preoperatively with CS. The median visual acuity (VA) of these patients improved significantly from preoperative (right eye, 0.63 (0; 1.25); left eye, 0.56 (0; 1.4)) to postoperative (right eye, 0.8 (0; 1.25); left eye, 0.74 (0; 1.25)). The median number of impaired quadrants of the binocular visual fields (VF) improved significantly from preoperative (2 (0; 8)) to postoperative CS (0 (0; 4)). In patients without preoperative CS, postoperative vision (VA as well as VF) remained unchanged. Postoperatively, VA of patients with preoperative CS remained significantly lower than that of patients without preoperative CS (right eye, 0.96 (0.2; 1.4); left eye, 0.94 (0.05; 1.4)). Postoperatively, the number of impaired quadrants of the binocular VF of patients with preoperative CS remained significantly higher than in patients without preoperative CS (0 (0; 1)). CONCLUSION: In this unselected patient series, the vision (VA as well as VF) of patients with preoperative CS did not improved postoperatively to the degree of the vision of patients without preoperative CS. Thus, in patients with adenomatous chiasma compression transsphenoidal surgery may be indicated before CS develops. PMID- 20852903 TI - Two novel begomoviruses belonging to different lineages infecting Rhynchosia minima. AB - Rhynchosia minima is a host for several begomoviruses, both in the Old World and the New World. In Cuba, a whitefly-transmitted disease causing yellow mosaic symptoms, suggested to be of viral origin, was described more than 30 years ago in R. minima, but no information about the nature of the viruses infecting this weed in this country is available to date. Here, we report the detection of isolates of two novel begomovirus species infecting R. minima in Cuba, which we proposed be named Rhynchosia golden mosaic Havana virus (RhGMHaV) and Rhynchosia rugose golden mosaic virus (RhRGMV). The highest nucleotide sequence identities of RhGMHaV and RhRGMV DNA-A were with isolates of Rhynchosia golden mosaic virus (78.7%) and Sida golden mosaic virus (87.5%), respectively. Phylogenetic analysis demonstrated that these novel viruses belong to two different lineages of New World begomoviruses. PMID- 20852902 TI - Running wheel activity restores MPTP-induced functional deficits. AB - Wheel-running and treadmill running physical exercise have been shown to alleviate parkinsonism in both laboratory and clinical studies. MPTP was administered to C57/BL6 mice using two different procedures: (a) administration of a double-dose regime (MPTP 2 * 20 or 2 * 40 mg/kg, separated by a 24-h interval), vehicle (saline 5 ml/kg) or saline (vehicle 2 * 5 ml/kg), and (b) administration of a single-dose weekly regime (MPTP 1 * 40 mg/kg) or saline (vehicle 1 * 5 ml/kg) repeated over 4 consecutive weeks. For each procedure, two different physical exercise regimes were followed: (a) after the double-dose MPTP regime, mice were given daily 30-min periods of wheel-running exercise over 5 consecutive days/week or placed in a cage in close proximity to the running wheels for 3 weeks. (b) Mice were either given wheel-running activity on 4 consecutive days (30-min periods) or placed in a cage nearby for 14 weeks. Behavioral testing was as follows: (a) after 3 weeks of exercise/no exercise, mice were tested for spontaneous motor activity (60 min) and subthreshold L-Dopa (5 mg/kg)-induced activity. (b) Spontaneous motor activity was measured on the fifth day during each of the each of the first 5 weeks (Tests 1-5), about 1 h before injections (first 4 weeks), and continued on the 5th days of the 6th to the 14th weeks (Tests 6-14). Subthreshold L-Dopa (5 mg/kg)-induced activity was tested on the 6th, 8th, 10th, 12th and 14th weeks. (b) Mice from the single-dose MPTP weekly regime were killed during the 15th week and striatal regions taken for dopamine analysis, whereas frontal and parietal cortex and hippocampus were taken for analysis of brain-derived neurotrophic factor (BDNF). It was shown that in both experiments, i.e., the double-dose regime and single-dose weekly regime of MPTP administration, physical activity attenuated markedly the MPTP-induced akinesia/hypokinesia in both the spontaneous motor activity and restored motor activity completely in subthreshold L-Dopa tests. Running wheel activity attenuated markedly the loss of dopamine due to repeated administrations of MPTP. BDNF protein level in the parietal cortex was elevated by the MPTP insult and increased further by physical exercise. Physical running wheel exercise alleviated both the functional and biomarker expressions of MPTP-induced parkinsonism. PMID- 20852904 TI - Kaposi's sarcoma-associated herpesvirus load in asymptomatic contacts of Cuban epidemic KS patients. AB - To evaluate the pathogenic mechanisms and transmission routes involved in KSHV infection in 22 Cuban individuals who maintained close contact with epidemic KS patients, real-time PCR was used to quantify KSHV-DNA in clinical samples of plasma, saliva and peripheral blood mononuclear cells (PBMC). KSHV-DNA was detected in 72.7% (16/22) of the contacts. The highest levels of KSHV load were detected in saliva, followed by PBMC (average log copies/100 ng DNA = 1.28 and 1.12), while significantly lower levels were detected in plasma (average log copies/ml = 0.37). Two of three intra-domiciliary and two serodiscordant sexual contacts of AIDS-KS patients were infected with KSHV. The rate of KSHV-DNA detection in saliva and PBMC samples in men who have sex with men (MSM) was significantly higher than in heterosexuals (HT) (p = 0.014). MSM were more likely to harbor KSHV-DNA in saliva when compared with HT individuals (OR 4.33; 95% CI 1.117-16.8). These results emphasize that, in Cuba, KSHV horizontal transmission through saliva may occur, although homosexual behavior may predispose an individual to KSHV acquisition. Even in the absence of disease, KSHV could cause an asymptomatic systemic infection in individuals who maintain close contact with AIDS-KS patients. PMID- 20852905 TI - Oral supplementation with carbohydrate- and branched-chain amino acid-enriched nutrients improves postoperative quality of life in patients undergoing hepatic resection. AB - The long-term outcomes of branched-chain amino acid (BCAA) administration in patients undergoing hepatic resection remain unclear. The aim of this study is to assess the impact of oral supplementation with BCAA-enriched nutrients on postoperative quality of life (QOL) in patients undergoing liver resection. A prospective randomized clinical trial was conducted in 96 patients undergoing hepatic resection. Patients were randomly assigned to receive BCAA supplementation (AEN group, n = 48) or a conventional diet (control group, n = 48). Postoperative QOL and short-term outcomes were regularly and continuously evaluated in all patients using a short-form 36 (SF-36) health questionnaire and by measuring various clinical parameters. This study demonstrated a significant improvement in QOL after hepatectomy for liver neoplasm in the AEN group based on the same patients' preoperative SF-36 scores (P < 0.05). Perioperative BCAA supplementation preserved liver function and general patient health in the short term for AEN group patients compared to those not receiving the nutritional supplement. BCAA supplementation improved postoperative QOL after hepatic resection over the long term by restoring and maintaining nutritional status and whole-body kinetics. This study was registered at http://www.clinicaltrials.gov (registration number: NCT00945568). PMID- 20852906 TI - Novel amino acids indices based on quantum topological molecular similarity and their application to QSAR study of peptides. AB - A new source of amino acid (AA) indices based on quantum topological molecular similarity (QTMS) descriptors has been proposed for use in QSAR study of peptides. For each bond of the chemical structure of AA, eight electronic properties were calculated using the approaches of bond critical point and theory of atom in molecule. Thus, for each molecule a data matrix of QTMS descriptors (having information from both topology and electronic features) were calculated. Using four different criterion based on principal component analysis of the QTMS data matrices, four different sets of AA indices were generated. The indices were used as the input variables for QSAR study (employing genetic algorithm-partial least squares) of three peptides' data sets, namely, angiotensin-converting enzyme inhibitors, bactericidal peptides and the peptides binding to the HLA A*0201 molecule. The obtained models had better prediction ability or a comparable one with respect to the previously reported models. In addition, by using the proposed indices and analysis of the variable important in projection, the active site of the peptides which plays a significant role in the biological activity of interest, was identified. PMID- 20852907 TI - Dietary glycine protects from chemotherapy-induced hepatotoxicity. AB - Hepatotoxic side effects of neoadjuvant chemotherapy for colorectal liver metastases increase perioperative morbidity and mortality. Glycine protects liver from injury in various animal models. Thus, this study was designed to assess its effect on liver after chemotherapy. Sprague-Dawley rats (200-220 g) were fed a synthetic diet containing 5% glycine for 5 days. Subsequently, chemotherapy (FOLFIRI: irinotecan, folinic acid and fluorouracil, or FOLFOX: oxaliplatin, folinic acid and fluorouracil) was administered at standard doses. Transaminases, histology, immunohistochemistry and in vivo microscopy were used to index liver injury, to monitor intrahepatic microperfusion and activation of Kupffer cells. Glycine significantly decreased transaminases after chemotherapy to 25-50% of control values (p < 0.05). Microvesicular steatosis was significantly reduced from 18.5 +/- 3.4 and 57.1 +/- 8.6% in controls to 9.5 +/- 1.8 and 37.7 +/- 4.4% after FOLFIRI and FOLFOX, respectively. Furthermore, phagocytosis of latex beads was reduced by about 50%, while leukocyte adherence in central and midzonal subacinar zones decreased to 60-80% after glycine (p < 0.05). Glycine significantly reduced expression of inducible nitric oxide synthase after chemotherapy, while hepatic microcirculation was increased (p < 0.05). This study shows for the first time that glycine reduces chemotherapy-induced liver injury. The underlying mechanisms most likely include Kupffer cells and an improved intrahepatic microperfusion. PMID- 20852908 TI - Electroacupuncture enhances cell proliferation and neuronal differentiation in young rat brains. AB - To investigate the effect of electroacupuncture on cell proliferation and differentiation in young rat hippocampus, postnatal day-14 rats were assigned randomly to control, ketamine anesthesia, nonacupoint, or acupoint electroacupuncture groups. Electroacupuncture was applied at bilateral acupoints (Quchi, Waiguan, Huantiao, and Zusanli) 30 min daily for 7 successive days. The proliferation and neuronal differentiation of proliferated surviving cells in the dentate gyrus were evaluated at 4 weeks after last stimulation. The stimulatory effect of electroacupuncture on cell proliferation had a long-lasting effect, as indicated by the increased phosphor-histone H3-positive cells. The number of proliferated and survival cells, indicated by BrdU labeling, was highest in the electroacupuncture group. The number of newly differentiated neurons, as indicated by BrdU/NeuN double labeling, was significantly higher in the electroacupuncture group than in any of the other groups. This finding provides a theoretical basis for the clinical application of acupuncture to cerebral injury rehabilitation in children. PMID- 20852909 TI - Serotonin transporter and saitohin genes in risk of Alzheimer's disease and frontotemporal lobar dementia: preliminary findings. AB - Serotonergic transmission impairment and abnormal phosphorylation of tau protein have been implicated in the physiopathology of Alzheimer's disease (AD) and frontotemporal lobar dementia (FTLD). Associations between a functional polymorphism (5-HTTLPR), in the promoter region of the serotonin transporter gene, and susceptibility to sporadic AD and FTLD have been reported. A polymorphism (Q7R) in saitohin gene inside the microtubule-associated protein tau gene has also been related to dementia. To determine the possible role of the two polymorphisms in susceptibility to AD and FTLD, we performed a case-control study collecting 218 Italian sporadic dementia patients and 54 controls. We found a significant excess of 5-HTTLPR short alleles and an interaction between 5-HTTLPR and Q7R polymorphisms in demented subjects. Our study confirms the role of 5 HTTLPR as a potential susceptibility factor for sporadic dementia in the Italian population, and suggests a possible interaction between 5-HTTLPR and Q7R polymorphisms in neurodegenerative diseases. PMID- 20852910 TI - Ultra-low-level laser therapy. AB - A growing number of laboratory and clinical studies over the past 10 years have shown that low-level laser stimulation (633 or 670 nm) at extremely low power densities (about 0.15 mW/cm(2)), when administered through a particular emission mode, is capable of eliciting significant biological effects. Studies on cell cultures and animal models as well as clinical trials give support to a novel therapeutic modality, which may be referred to as ultra low level laser therapy (ULLLT). In cultured neural cells, pulsed irradiation (670 nm, 0.45 mJ/cm(2)) has shown to stimulate NGF-induced neurite elongation and to protect cells against oxidative stress. In rats, anti-edema and anti-hyperalgesia effects following ULLL irradiation were found. Clinical studies have reported beneficial effects (also revealed through sonography) in the treatment of musculoskeletal disorders. The present paper reviews the existing experimental evidence available on ULLLT. Furthermore, the puzzling issue of the biophysical mechanisms that lie at the basis of the method is explored and some hypotheses are proposed. Besides presenting the state-of-the-art about this novel photobiostimulation therapy, the present paper aims to open up an interdisciplinary discussion and stimulate new research on this subject. PMID- 20852911 TI - Homeorhetic adaptation to lactation: comparative transcriptome analysis of mammary, liver, and adipose tissue during the transition from pregnancy to lactation in rats. AB - Tissue-specific shifts in a dam's metabolism to support fetal and neonatal growth during pregnancy and lactation are controlled by differential expression of regulatory genes. The goal of this study was to identify a more detailed cohort of genes in mammary, liver, and adipose tissue that are transcriptionally controlled during the pregnancy to lactation evolution and explore the relationship of these genes to core clock genes. Total RNA was isolated from mammary, liver and adipose tissues collected from rat dams on day 20 of pregnancy (P20) and day 1 of lactation (L1) and gene expression was measured using Rat 230 2.0 Affymetrix GeneChips. Gene functional analysis revealed that pathway associated metabolism (carbohydrate, amino acid, lipid, cholesterol, protein) were enriched (P < 0.001) in the mammary gland during P20 to L1 transition. Approximately 50% of the genes associated with solute transport, as well as lipogenesis were up-regulated in the mammary gland during P20 to L1 transition compared to 10% in liver and 15% in adipose tissue. Genes engaged in conveying glucose (INSR, GLUT1, GLUT4, SGLT1, and SGLT2), bicarbonate (SLC4), sodium (SLC9), zinc (SLC30), copper (SLC31), iron (SLC40) in tandem with rate-limiting lipogenic genes (ACACA, FASN, PRLR, SREBP2, THRSP) were specifically enriched in the mammary gland during the P20 to L1 evolution. Our results provide insight into a cross-tissue transcriptional repertoire that is associated with homeorhetic adaptation needed to support lactation, and at the onset of lactation the mammary gland becomes a factory for macromolecular biosynthesis through inducing genes participating in nutrient transfer and lipid biosynthesis. PMID- 20852912 TI - Finite-size corrections to scaling behavior in sorted cell aggregates. AB - Cell sorting is a widespread phenomenon pivotal to the early development of multicellular organisms. In vitro cell sorting studies have been instrumental in revealing the cellular properties driving this process. However, these studies have as yet been limited to two-dimensional analysis of three-dimensional cell sorting events. Here we describe a method to record the sorting of primary zebrafish ectoderm and mesoderm germ layer progenitor cells in three dimensions over time, and quantitatively analyze their sorting behavior using an order parameter related to heterotypic interface length. We investigate the cell population size dependence of sorted aggregates and find that the germ layer progenitor cells engulfed in the final configuration display a relationship between total interfacial length and system size according to a simple geometrical argument, subject to a finite-size effect. PMID- 20852913 TI - Vibrational entropy and the structural organization of proteins. AB - In this paper we analyze the vibrational spectra of a large ensemble of non homologous protein structures by means of a novel tool, that we coin Hierarchical Network Model (HNM). Our coarse-grained scheme accounts for the intrinsic heterogeneity of force constants displayed by protein arrangements and also incorporates side chain degrees of freedom. Our analysis shows that vibrational entropy per unit residue correlates with the content of secondary structure. Furthermore, we assess the individual contribution to vibrational entropy of the novel features of our scheme as compared with the predictions of state-of-the-art network models. This analysis highlights the importance of properly accounting for the intrinsic hierarchy in force strengths typical of the different atomic bonds that build up and stabilize protein scaffolds. Finally, we discuss possible implications of our findings in the context of protein aggregation phenomena. PMID- 20852914 TI - A pilot study on using eye tracking to understand assessment of surgical outcomes from clinical photography. AB - Appearance changes resulting from breast cancer treatment impact the quality of life of breast cancer survivors, but current approaches to evaluating breast characteristics are very limited. It is challenging, even for experienced plastic surgeons, to describe how different aspects of breast morphology impact overall assessment of esthetics. Moreover, it is difficult to describe what they are looking for in a manner that facilitates quantification. The goal of this study is to assess the potential of using eye-tracking technology to understand how plastic surgeons assess breast morphology by recording their gaze path while they rate physical characteristics of the breasts, e.g., symmetry, based on clinical photographs. In this study, dwell time, transition frequency, dwell sequence conditional probabilities, and dwell sequence joint probabilities were analyzed across photographic poses and three observers. Dwell-time analysis showed that all three surgeons spent the majority of their time on the anterior-posterior (AP) views. Similarly, transition frequency analysis between regions showed that there were substantially more transitions between the breast regions in the AP view, relative to the number of transitions between other views. The results of both the conditional and joint probability analyses between the breast regions showed that the highest probabilities of transitions were observed between the breast regions in the AP view (APRB, APLB) followed by the oblique views and the lateral views to complete evaluation of breast surgical outcomes. PMID- 20852916 TI - Ischemic maculopathy following intravitreal bevacizumab for refractory diabetic macular edema. AB - A 58-year-old male presented with decreased visual acuity from persistent diffuse diabetic macular edema despite multiple interventions including laser photocoagulation and intravitreal triamcinolone acetonide injections. Following treatment with 1.25 mg of intravitreal bevacizumab, reduction in macular leakage was shown by fluorescein angiography and resolution of edema was shown by optical coherence tomography (OCT); however, visual acuity deteriorated and fluorescein angiograms demonstrated progressive enlargement of the foveal avascular zone (FAZ), which had shown no abnormalities before the injection. Despite normalisation of macular thickness on OCT and cessation of leakage on angiography, visual acuity remained at the same level until 6 months of follow up. Intravitreal bevacizumab must be used with caution in patients with chronic, persistent diabetic macular edema. Disruption of the fragile fine foveal network of capillaries with induction of macular ischemia may result following treatment even if there are no pre-existing defects in the FAZ and may be responsible for non-improvement or decrease in visual acuity. PMID- 20852917 TI - JAGGED LATERAL ORGAN (JLO) controls auxin dependent patterning during development of the Arabidopsis embryo and root. AB - The plant hormone auxin plays a role in virtually every aspect of plant growth and development. Temporal and spatial distribution of auxin largely depends on the dynamic expression and subcellular localization of the PIN auxin-efflux carrier proteins. We show here that the Arabidopsis thaliana JAGGED LATERAL ORGAN (JLO) gene, a member of the LATERAL ORGAN BOUNDARY DOMAIN (LBD) gene family, is required for coordinated cell division during embryogenesis. JLO promotes expression of several PINFORMED (PIN) genes during embryonic and root development. Inducible JLO misexpression reveals that JLO activity is sufficient for rapid and high level PIN1 and PIN3 transcription. Genes of the PLETHORA (PLT) family respond to auxin and direct PIN expression, but PLT genes were severely underexpressed in jlo mutants. JLO controls embryonic patterning together with the auxin dependent MONOPTEROS/BODENLOS pathway, but is itself only mildly auxin inducible. We further show that all known auxin responses in the root require JLO activity. We thereby identify JLO as a central regulator of auxin distribution and signaling throughout plant development. PMID- 20852919 TI - Can prevalence of apolipoprotein E epsilon 4 allele explain the geographical variation of coronary heart disease mortality rates in Western Europe? PMID- 20852918 TI - Two cotton Cys2/His2-type zinc-finger proteins, GhDi19-1 and GhDi19-2, are involved in plant response to salt/drought stress and abscisic acid signaling. AB - Cotton (Gossypium hirsutum) often encounters abiotic stress such as drought and high salinity during its development, and its productivity is significantly limited by those adverse factors. To investigate the molecular adaptation mechanisms of this plant species to abiotic stress, we identified two genes encoding Di19-like Cys2/His2 zinc-finger proteins in cotton. GFP fluorescence assay demonstrated that GhDi19-1 and GhDi19-2 are two nuclear-localized proteins. Quantitative RT-PCR and Northern blot analyses revealed that mRNA accumulation of both GhDi19-1 and GhDi19-2 was significantly promoted by salinity and drought. Expression of GUS gene driven by the GhDi19-1 and GhDi19-2 promoters, respectively, was intensively induced in cotyledons under NaCl and mannitol stresses. Overexpression of GhDi19-1 and GhDi19-2 in Arabidopsis resulted in the seedlings displaying hypersensitivity to high salinity and abscisic acid (ABA). Seed germination and seedling growth of the transgenic Arabidopsis were dramatically inhibited by salinity and ABA, compared with wild type. In addition, expression levels of the ABA-responsive genes ABF3, ABF4, ABI5 and KIN1 were also remarkably altered in the transgenic plants under ABA treatment. Collectively, our results suggested that both GhDi19-1 and GhDi19-2 may be involved in response to salt/drought stress and ABA signaling during early stages of plant development. PMID- 20852920 TI - BNIP3 induces IL6 and calcineurin/NFAT3 hypertrophic-related pathways in H9c2 cardiomyoblast cells. AB - Ischemia/reperfusion injury causes cardiomyocyte apoptosis, ventricular remodeling, leading to a dilated heart. Hypoxia is one of the causes involved in ischemia damage, and BNIP3 is a hypoxia-inducible marker and also a sensor to induce mitochondria-dependent apoptosis. Recent reports discussed ablating BNIP3 can restrain cardiomyocytes apoptosis and post-infarction remodeling. BNIP3 is a crucial therapeutic target. However, the BNIP3-induced hypertrophy aspect is rarely investigated. Here, we transiently transfected BNIP3 plasmids into H9c2 cardiomyoblast cells to evaluate the molecular signaling and hypertrophy markers using Western blot. We measured the cell size change using actin staining. We disclose that BNIP3 overexpression induced an increase in cell size, activated the pathological-related hypertrophy signaling pathways, such as IL6-MEK5-ERK5, IL6-JAK2-STAT1/3, calcineurin/NFAT3 and p38beta MAPK resulting in the fetal genes, ANP and BNP expressing. Concluding above, BNIP3 acts as a pathological hypertrophy inducer, which might be a potential therapeutic target for heart damage prevention. PMID- 20852921 TI - Usability evaluation of mobile medical treatment carts: another explanation by information engineers. AB - Healthcare services integration is a critical task as it attempts to reform the user practices. In response to the request of facilities upgrade, we perform a usability evaluation of the mobile medical treatment carts (MMTC) installed in the Emergency Medicine Department of our healthcare enterprise. A survey conducted in August 2006 identified that our experimental area needs some improvements to support the MMTC adoption. For example, the MMTC can accompany with several popular nursing care items. Follow-up several undertaken investigations indicated that our expectation of the MMTC solution had been reached. Given the evident heterogeneity of viewpoints, it is imperative for a healthcare enterprise to broadly ascertain the requirements of end users before investing in any information technologies. PMID- 20852922 TI - Saccadic latency in hepatic encephalopathy: a pilot study. AB - Hepatic encephalopathy is a common complication of cirrhosis. The degree of neuro psychiatric impairment is highly variable and its clinical staging subjective. We investigated whether eye movement response times-saccadic latencies-could serve as an indicator of encephalopathy. We studied the association between saccadic latency, liver function and paper- and pencil tests in 70 patients with cirrhosis and 31 patients after liver transplantation. The tests included the porto systemic encephalopathy (PSE-) test, critical flicker frequency, MELD score and ammonia concentration. A normal range for saccades was established in 31 control subjects. Clinical and biochemical parameters of liver, blood, and kidney function were also determined. Median saccadic latencies were significantly longer in patients with liver cirrhosis when compared to patients after liver transplantation (244 ms vs. 278 ms p < 0.001). Both patient groups had prolonged saccadic latency when compared to an age matched control group (175 ms). The reciprocal of median saccadic latency (MU) correlated with PSE tests, MELD score and critical flicker frequency. A significant correlation between the saccadic latency parameter early slope (sigma(E)) that represents the prevalence of early saccades and partial pressure of ammonia was also noted. Psychometric test performance, but not saccadic latency, correlated with blood urea and sodium concentrations. Saccadic latency represents an objective and quantitative parameter of hepatic encephalopathy. Unlike psychometric test performance, these ocular responses were unaffected by renal function and can be obtained clinically within a matter of minutes by non-trained personnel. PMID- 20852923 TI - Pentraxin 3 values during normal pregnancy. AB - Pentraxin 3 (PTX3) is an inflammatory molecule that has been reported to be a promising early biomarker for subsequent preeclampsia. The levels of PTX3 vary during pregnancy and it is thus a need to establish reference intervals during normal pregnancy. Repeated blood samples were collected from 52 healthy pregnant females. The samples were divided according to collection time into the following groups: week 7-17, week 17-24, week 24-28, week 28-31, week 31-34, week 34-38, before delivery and after delivery. The samples were analyzed for PTX3 with a sandwich ELISA and the 2.5 and 97.5 percentiles for each sample period was calculated. There was a continuous increase of serum PTX3 as pregnancy progressed. The increase was most evident after week 31 with the highest levels just before delivery. PMID- 20852924 TI - Treatment with recombinant Hsp72 suppresses collagen-induced arthritis in mice. AB - Although the level of heat shock protein (Hsp72) has been shown to be enhanced in rheumatoid arthritis (RA) synovial tissues and RA synovial fluid, it remains unclear what role extracellular Hsp72 plays in the pathogenesis of RA. This study was conducted to investigate the effects of recombinant human Hsp72 on collagen induced arthritis (CIA) when administered therapeutically and elucidate its underlying mechanism. We demonstrated that recombinant Hsp72 significantly reduced disease severity. Hsp72-treated animals displayed significantly less cartilage and bone destruction than that in the controls. Hsp72 treatment also reduced the expression of tumor necrosis factor alpha and interleukin 6 in the sera. Furthermore, Hsp72 treatment significantly inhibited activation of nuclear factor kappa B (NF-kappaB) in synovial tissues of CIA mice. These findings suggest that recombinant Hsp72 effectively suppressed synovial inflammation and the development and progress of CIA, which is mediated through the reduction of production of proinflammatory cytokines and the suppression of activation of NF kappaB pathway. PMID- 20852925 TI - Induction of cytopathic effects and apoptosis in Spodoptera frugiperda cells by the HIV-1 Env glycoprotein signal peptide. AB - The loss of CD4(+) T-cells in human immunodeficiency virus-infected individuals has been attributed not only to dysregulation of immune cell function but also direct and indirect killing mechanisms of both infected and bystander cells. This process proceeds through both necrotic and programmed cell death pathways. Several human immunodeficiency virus type 1 (HIV-1) gene products have been linked to the induction of cell death and apoptosis associated with virus infection. These include the Nef, Tat, Vpr, and Vpu proteins as well as the viral envelope glycoprotein. Our results now indicate that the signal peptide of HIV-1 is also involved in the induction of cytopathic effects leading to cell death. We have shown here that expression of HIV-1 gp120 or vesicular stomatitis virus G glycoprotein with the HIV-1 Env signal peptide resulted in a rapid induction of cytopathicity and cell death in S. frugiperda cells, whereas removal or replacement of the signal peptide ameliorated those effects. Further, our results show that cell death is induced, at least in part, through apoptotic pathways as characterized by evidence of nuclear condensation and DNA fragmentation, as well as by the activation of host-cell caspase activity. Our results indicate that the signal peptide of HIV-1 Env itself thus has a direct role in cellular cytotoxicity and the triggering of cell death pathways. PMID- 20852927 TI - Sleeping site selection of Francois's langur (Trachypithecus francoisi) in two habitats in Mayanghe National Nature Reserve, Guizhou, China. AB - Sleeping site selection is an important aspect of the behavioral biology of primates. Comparison of different habitats for the same species in this context enhances understanding of their adaptation to altered environments. We collected data on sleep-related behaviors for 6 groups of Francois's langur (Trachypithecus francoisi) in two habitats, in Mayanghe National Nature Reserve, Guizhou, China. Regardless of habitat, all sleeping sites were located in areas of steep terrain of >=60 degrees . In undisturbed habitat, sleeping sites were located only in evergreen broadleaf forest with rock caves and crevices surrounded mainly by a vegetation layer of shrub + rock. In disturbed habitat, sleeping sites were also located in mixed evergreen and deciduous broadleaf forest and in grassland, including rock caves, crevices, and pits, surrounded mainly by arbor + shrub and shrub + rock. Wild food availability was higher in undisturbed habitat than disturbed habitat, but food abundance around sleeping sites was lower. Water sources included river and seasonal gully or pond. There was strong positive correlation between use of sleeping sites away from the river valley and occurrence of seasonal water sources. The number of sleeping sites varied across groups, numbering 6, 7, and 10 for three specific groups. Few sleeping sites were used all year round. Six consecutive nights was the longest recorded run. Francois's langurs' sleeping habits differed between two habitats. In undisturbed habitat, minimizing predation risk appeared to predominate, expressed by choosing steep terrain, open visual field, and inconspicuous presleeping behavior. In disturbed habitat, along with predation avoidance, food resources may strongly influence sleeping site selection, as demonstrated by the richer food abundance and greater foraging activity around the site. Finally, water resources may influence choice of sites distant from the river; such sites were used less frequently during water shortages. PMID- 20852926 TI - Genome scan for spelling deficits: effects of verbal IQ on models of transmission and trait gene localization. AB - Dyslexia is a complex learning disability with evidence for a genetic basis. Strategies that may be useful for dissecting its genetic basis include the study of component phenotypes, which may simplify the underlying genetic complexity, and use of an analytic approach that accounts for the multilocus nature of the trait to guide the investigation and increase power to detect individual loci. Here we present results of a genetic analysis of spelling disability as a component phenotype. Spelling disability is informative in analysis of extended pedigrees because it persists into adulthood. We show that a small number of hypothesized loci are sufficient to explain the inheritance of the trait in our sample, and that each of these loci maps to one of four genomic regions. Individual trait models and locations are a function of whether a verbal IQ adjustment is included, suggesting mediation through both IQ-related and unrelated pathways. PMID- 20852928 TI - Role of supramolecular cellulose structures in enzymatic hydrolysis of plant cell walls. AB - The study of biomass deconstruction by enzymatic hydrolysis has hitherto not focussed on the importance of supramolecular structures of cellulose. In lignocellulose fibres, regions with a different organisation of the microfibrils are present. These regions are called dislocations or slip planes and they are known to be more susceptible to various forms of degradation such as acid hydrolysis. Traditionally the cellulose within these regions has been assumed to be amorphous, but in this study it is shown by use of polarized light microscopy that dislocations are birefringent. This indicates that they have a crystalline organisation. Dislocations may be entry points for endoglucanases. Using a fluorescent labelled endoglucanase combined with confocal fluorescence microscopy, it is shown that the enzyme selectively binds to dislocations during the initial phase of the hydrolysis. Using a commercial cellulase mixture on hydrothermally treated wheat straw, it was found that the fibres were cut into segments corresponding to the sections between the dislocations initially present, as has previously been observed for acid hydrolysis of softwood pulps. The results indicate that dislocations are important during the initial part of enzymatic hydrolysis of cellulose. The implications of this phenomenon have not yet been recognized or explored within cellulosic biofuels. PMID- 20852929 TI - Transactional associations between youths' responses to peer stress and depression: the moderating roles of sex and stress exposure. AB - This study examined transactional associations between responses to peer stress and depression in youth. Specifically, it tested the hypotheses that (a) depression would predict fewer effortful responses and more involuntary, dysregulated responses to peer stress over time; and (b) fewer adaptive and more maladaptive responses would predict subsequent depression. Youth (M age = 12.41; SD = 1.19; 86 girls, 81 boys) and their maternal caregivers completed semi structured interviews and questionnaires at three annual waves. Multi-group comparison path analyses were conducted to examine sex and stress-level differences in the proposed reciprocal-influence model. In girls and in youth exposed to high levels of peer stress, maladaptive stress responses predicted more depressive symptoms and adaptive stress responses predicted fewer depressive symptoms at each wave. These findings suggest the utility of preventive interventions for depression designed to enhance the quality of girls' stress responses. In boys, depression predicted less adaptive and more maladaptive stress responses, but only at the second wave. These findings suggest that interventions designed to reduce boys' depressive symptoms may help them develop more adaptive stress responses. PMID- 20852930 TI - Evaluation of exposure to the airborne asbestos in an asbestos cement sheet manufacturing industry in Iran. AB - Iran imports nearly 55,000 tons of Chrysotile asbestos per year and asbestos cement (AC) plants contribute nearly 94% of the total national usage. In the present study, airborne asbestos concentrations during AC sheet manufacturing were measured. The fiber type and its chemical composition were also evaluated by scanning electron microscopy (SEM), with energy-dispersive X-ray analysis. Airborne total fiber concentrations of 45 personal samples were analyzed by phase contrast microscopy. The results have highlighted that 15.5% of samples exceed the threshold limit value (TLV) established the American Conference of Governmental Industrial Hygienists, which is 0.1 fiber per milliliter (f/ml). Personal monitoring of asbestos fiber levels indicated a ranged from 0.02 +/- 0.01 to 0.16 +/- 0.03 f/ml. The geometrical mean was 0.05 +/- 1.36 f/ml, which is considerably lower than the TLV. SEM data demonstrate that the fibrous particles consisted, approximately, of Chrysotile (55.89%) and amphiboles (44.11%). We conclude that the industrial consumption of imported Chrysotile asbestos is responsible for the high airborne amphibole asbestos levels in the AC sheet industry. More research is needed to improve characterization of occupational exposures by fiber size and concentration in a variety of industries. PMID- 20852931 TI - New insights into the distribution of WXG100 protein secretion systems. AB - Protein secretion is an important aspect of bacterial interaction with the environment. The WXG100 secretion system is a poorly understood pathway for the secretion of members of the WXG100 protein family in Firmicutes and Actinobacteria, notably Mycobacteria. This pathway has also been termed the Type VII secretion system but there are semantic problems with this nomenclature. This Perspective reviews the phylum level distribution of WXG100 secretion systems and presents comparative genomic evidence that these systems are present in several Chloroflexi and in some members of the phyla Cyanobacteria, Lentisphaerae, Proteobacteria (notably Helicobacter pylori) and Verrucomicrobiae. These findings have implications for the nomenclature of the WXG100 secretion pathway. PMID- 20852932 TI - The violence triad and common single precipitants to psychiatric patient assaults on staff: 16-year analysis of the Assaulted Staff Action Program. AB - Psychiatric patient assaults are a serious community health hazard. Risk management strategies to identify common single precipitants have had limited value and this limitation has resulted in the emergence of multiple determinant studies. This 16-year retrospective study of assault precipitants in one, public sector mental health-care system assessed single common, immediate precipitants; the multiple clinical precipitants of history of violence, personal victimization, and substance use disorder (the violence triad); and both combined. Denial of services, acute psychoses, and excess sensory stimulation were the most common single precipitants. The multicomponent violence triad yielded greater association with subsequent assault than single precipitants. The combination of the violence triad and single precipitants did not yield statistically significant greater associations. Discussion of the clinical risk management implication, and methodological issues are presented. PMID- 20852933 TI - Metabolic investigations prevent liver transplantation in two young children with citrullinemia type I. AB - Acute liver failure may be caused by a variety of disorders including inborn errors of metabolism. In those cases, rapid metabolic investigations and adequate treatment may avoid the need for liver transplantation. We report two patients who presented with acute liver failure and were referred to our center for liver transplantation work-up. Urgent metabolic investigations revealed citrullinemia type I. Treatment for citrullinemia type I avoided the need for liver transplantation. Acute liver failure as a presentation of citrullinemia type I has not previously been reported in young children. Although acute liver failure has occasionally been described in other urea cycle disorders, these disorders may be underestimated as a cause. Timely diagnosis and treatment of these disorders may avoid liver transplantation and improve clinical outcome. Therefore, urea cycle disorders should be included in the differential diagnosis in young children presenting with acute liver failure. PMID- 20852934 TI - Cerebrospinal fluid alterations of the serotonin product, 5-hydroxyindolacetic acid, in neurological disorders. AB - Although patients with low cerebrospinal fluid (CSF) serotonin metabolite levels have been reported, inborn errors of the rate-limiting enzyme of serotonin synthesis (tryptophan hydroxylase, TPH) have not been described so far. In this study we aimed to evaluate CSF alterations of the serotonin metabolite 5 hydroxyindolacetic acid (5-HIAA) in patients with neurological disorders and to explore a possible TPH deficiency in some of them. A total of 606 patients (286 males, 320 females, mean age 4 years and 6 months, SD 5 years and 7 months) underwent CSF analysis of neurotransmitter metabolites by reverse phase high performance liquid chromatography. Results were compared with values established in a control population. Patients' medical records were reviewed to determine diagnosis and clinical features. A primary defect of biogenic amines was genetically investigated in indicated patients. Low 5-HIAA was seen in 19.3%. Of these, 22.2% showed inborn errors of metabolism (mitochondrial disorders being the most frequent at 10.2% of low 5-HIAA patients) and neurogenetic conditions. Other relatively frequent conditions were pontocerebellar hypoplasia (4.3%), Rett syndrome (4.3%), and among congenital nonetiologically determined conditions, epilepsy including epileptic encephalopathies (26.4%), leukodystrophies (6.8%), and neuropsychiatric disturbances (4.2%). Mutational analysis of the TPH2 gene, performed in five candidate patients, was negative. Although frequency of secondary alteration of 5-HIAA was relatively high in patients with neurological disorders, this finding was more frequently associated with some neurometabolic disorders, epileptic encephalopathies, and neuropsychiatric disturbances. No inborn errors of TPH were found. Due to serotonin's neurotrophic role and to ameliorate symptoms, a supplementary treatment with 5-hydroxytriptophan would seem advisable in these patients. PMID- 20852935 TI - Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. AB - Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-alpha-D glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems. PMID- 20852936 TI - Case report: Long-term outcome post-heart transplantation in a woman with Fabry's disease. AB - Fabry's disease is an X-linked recessive disorder that results from the deficiency of alpha-galactosidase A and causes the accumulation of globotriaosylceramide (Gb3) in different tissues. It leads to a rare form of cardiomyopathy which may be complicated by end-stage heart failure and need to heart transplant. Our group described the first case of heart transplant in a woman with cardiomyopathy secondary to Fabry's disease about 12 years ago. There was uncertainty in regards to the possibility of recurrence of the disease as previously documented in kidney transplant recipients and long-term outcomes. In this report, 14 years after transplant, this woman is still alive and there is no evidence of Fabry's disease in any of the endomyocardial biopsies. Heart transplantation can be recommended for Fabry's patients with end-stage cardiomyopathy. PMID- 20852937 TI - S-adenosylhomocysteine hydrolase deficiency: two siblings with fetal hydrops and fatal outcomes. AB - This paper reports the clinical and metabolic findings in two sibling sisters born with fetal hydrops and eventually found to have deficient S adenosylhomocysteine hydrolase (AHCY) activity due to compound heterozygosity for two novel mutations, c.145C>T; p.Arg49Cys and c.257A>G; p.Asp86Gly. Clinically, the major abnormalities in addition to fetal hydrops (very likely due to impaired synthetic liver function) were severe hypotonia/myopathy, feeding problems, and respiratory failure. Metabolic abnormalities included elevated plasma S adenosylhomocysteine, S-adenosylmethionine, and methionine, with hypoalbuminemia, coagulopathies, and serum transaminase elevation. The older sister died at age 25 days, but the definitive diagnosis was made only retrospectively. The underlying genetic abnormality was diagnosed in the second sister, but treatment by means of dietary methionine restriction and supplementation with phosphatidylcholine and creatine did not prevent her death at age 122 days. These cases extend the experience with AHCY deficiency in humans, based until now on only the four patients previously identified, and suggest that the deficiency in question may be a cause of fetal hydrops and developmental abnormalities of the brain. PMID- 20852938 TI - Achieving consistent image quality with dose optimization in 64-row multidetector computed tomography prospective ECG gated coronary calcium scoring. AB - To evaluate the clinical value of a body mass index (BMI) based tube current (mA) selection method for obtaining consistent image quality with dose optimization in MDCT prospective ECG gated coronary calcium scoring. A formula for selecting mA to achieve desired image quality based on patient BMI was established using a control group (A) of 200 MDCT cardiac patients with a standard scan protocol. One hundred patients in Group B were scanned with this BMI-dependent mA for achieving a desired noise level of 18 HU at 2.5 mm slice thickness. The CTDIvol and image noise on the ascending aorta for the two groups were recorded. Two experienced radiologists quantitatively evaluated the image quality using scores of 1-4 with 4 being the highest. The image quality scores had no statistical difference (P = 0.71) at 3.89 +/- 0.32, 3.87 +/- 0.34, respectively, for groups A and B of similar BMI. The image noise in Group A had linear relationship with BMI. The image noise in Group B using BMI-dependent mA was independent of BMI with average value of 17.9 HU and smaller deviations for the noise values than in Group A (2.0 vs. 2.9 HU). There was a 35% dose reduction with BMI-dependent mA selection method on average with the lowest effective dose being only 0.35 mSv for patient with BMI of 18.3. A quantitative BMI-based mA selection method in MDCT prospective ECG gated coronary calcium scoring has been proposed to obtain a desired and consistent image quality and provide dose optimization across patient population. PMID- 20852939 TI - Application of genotype MTBDRplus in rapid detection of the Mycobacterium tuberculosis complex as well as its resistance to isoniazid and rifampin in a high volume laboratory in Southern China. AB - The alarmingly worsening epidemics of drug-resistant tuberculosis (TB) call urgent need for a simple method for the rapid detection of drug-resistant TB in clinical settings. In an attempt to establish a rapid procedure for laboratory diagnosis of TB and investigate the local TB epidemiology, molecular line probe assay of the Genotype MTBDRplus was used to identify Mycobacterium tuberculosis complex (MTBC) and detect mutations conferring resistance to two most active first-line drugs against TB: Rifampin and Isoniazid. 96 acid-fast bacillus (AFB) smear- positive sputums and 18 PCR-positive non-sputum specimens have been determined for the MTBC and resistance to Rifampin and Isoniazid. The MTBC detection rates in two sources of specimens were 93.8% (90/96) and 77.8% (14/18) respectively. The overall drug resistance (Rifampin or Isoniazid) occurred in 34.6% (36/104). Resistance to rifampin (RMP) was 28.8% (30/104) and 25% (26/104) was to Isoniazid (INH), in which high level drug resistance accounted for 88.5% (23/26) and low level drug resistance accounted for 7.7% (2/26). Multidrug resistance (MDR), defined as resistant to both RMP and INH, was found in 19.2% (20/104) of clinical samples, which was double that of official statistics. In addition, 63.3% (19/30) RMP-resistant mutations were identified in the region of RopB 530-533 and 57.9% (11/19) were the S531L mutation. 84.6% (22/26) of resistance to INH was mediated by Kat S315T1 mutations which conferred the high level resistance to INH. The Genotype MTBDRplus line probe assay is a suitable and applicable method for establishing the rapidness in detection of drug resistant TB in clinical laboratory. It will be a valuable addition to the conventional TB diagnostic approaches. PMID- 20852940 TI - Molecular characterization of antigen B2 subunit in two genotypes of Echinococcus granulosus from Indian bubaline isolates, its stage specific expression and serological evaluation. AB - Echinococcus granulosus is a parasitic helminth which affects both man and animals. During infection with larval stage of the organism secretory and membrane-bound (S/M) proteins play a meaningful role for evasion of immune system. Antigen B (AgB) is one of them. Present investigation has defined sequence diversity of AgB2 subunit of cattle and buffalo isolates of the organism. A total of 55 isolates were screened by polymerase chain reaction based single stranded conformation polymorphism (PCR-SSCP). Subsequently, six conformers could be detected. Based on predicted amino acid sequences of 90 amino acid residues, three clusters could be deduced. Sequence information of two buffalo isolates was homologous to AgB4 indicating gene switching phenomenon in between closely related isoforms. Numerical value of Tajima's D test proved negative selection pressure. Using artificial neural network (ANN), B cell linear epitope and stretches of agretope were predicted. Three clusters could be defined on the basis of B cell linear epitope. Out of three clusters, two showed more than 50% binding propensity with same MHCII alleles whereas, cluster 3 exhibited binding propensity with other MHCII alleles (DRB1_1501, DRB1_1502). Relative expression of AgB2 was more in active cysts (1.636 +/- 0.092) followed by degenerating (0.449 +/- 0.037) and calcified (0.255 +/- 0.008). This result suggested that relative expression of AgB2 declines with progression of the disease. Using recombinant AgB2 sensitivity, specificity and accuracy of the ELISA test was 96.7, 94.7 and 95.9%, respectively. No cross reactivity was found with common cestode and trematode infected cattle and buffalo because cross reactive antigen was expressed intracellularly. Finally, this was concluded that AgB2 is the suitable immunological marker for detection, diagnosis and progression of the disease. PMID- 20852941 TI - Molecular cloning and characterization of lactate dehydrogenase gene 1 in the silkworm, Bombyx mori. AB - Lactate dehydrogenase (LDH) catalyzes the reduction of pyruvate into lactate and constitutes a major checkpoint of anaerobic glycolysis. Recently, LDH draws a great deal of attention for its potential to be used as a novel diagnostic and therapeutic target for various diseases, including cancer and malaria. Insect LDHs have been mainly identified from fruit fly and mosquitoes, but not from silkworm. In this study, a novel LDH homologue, designated as BmLDH1, was firstly identified and characterized from the silkworm, Bombyx mori. The BmLDH1 cDNA contains an open reading frame of 996 bp, and encodes a protein of 331 amino acid residues with calculated molecular mass of 36 kDa. Sequence comparison showed BmLDH1 is a highly conserved protein. RT-PCR revealed BmLDH1 is transcripted in all tissues and in all developmental stages tested, indicating its essential roles for silkworm physiology and development. The BmLDH1 gene was subcloned and expressed in E. coli, and was further characterized by Western blot and Mass Spectrometry. The expressed protein contained the LDH activity, and could be inhibited by reduced glutathione in vitro. Immunofluoresence showed that the BmLDH1 was located in the cytoplasm. The cloned BmLDH1 sequence was deposited in the GenBank (accession number EU334850). PMID- 20852943 TI - DSM diagnosis and beyond: on the need for a hermeneutically-informed biopsychosocial framework. AB - While often dubbed "the bible of contemporary psychiatry" and widely hailed as providing "a benchmark" for the profession, on closer inspection the DSM is seen to be shot through with philosophical assumptions that restrict its theoretical cogency and limit it clinical efficacy. Hence, in the interests of enhanced patient-care it is important to think critically about the DSM, with a view to maximising its diagnostic strengths while minimising its weaknesses. The critical analysis undertaken in the present paper underscores the importance of not construing the DSM as a self-contained diagnostic tool but of viewing it, rather, as an indispensable component in a more comprehensive, multidimensional diagnostic process. More specifically, the contention is that the DSM's diagnostic limitations evoke a biopsychosocial framework of application as their necessary corrective, notwithstanding the entrenched tendency to construe these approaches as oppositional. Further, it is contended that a hermeneutically informed biopsychosocial template has particular advantages as an integrating framework. PMID- 20852942 TI - Base excision repair genes XRCC1 and APEX1 and the risk for prostate cancer. AB - Prostate cancer is the second cause of cancer death in Brazilian men. One of the relevant phenomena to the inherited susceptibility is the presence of allelic variants in genes involved with the DNA repair pathway. The aim of this study was to analyze the frequencies of prevalent, heterozygous and rare genotypes of the base excision repair genes APEX1 and XRCC1 in a case-control study and relate the genotypes with tumoral aggressiveness. DNA from peripheral blood of 172 patients and 172 controls were analyzed by RFLP-PCR method. The polymorphisms were also evaluated in relation to clinical and pathological parameters. The OR (Odds Ratio) and confidence interval (CI = 95%) were used in the association study and the Chi-square and ANOVA tests for the evaluation of histopathological parameters. The rare genotypes frequencies of the gene APEX1 increased the risk for the development of prostate cancer (OR = 1.68 95% CI 1.10-2.58). No association was found for the gene XRCC1 (OR = 0.82 95% CI 0.53-1.27). The combined analysis for both genes did not show association with this neoplasia (OR = 1.27 95% CI 0.79-20.5). The relationship of XRCC1 and APEX1 genotypes with cancer aggressiveness through the correlation with histopathological parameters, did not find any association. Our results suggest that the polymorphism in the gene APEX1 may be indicated as a potential marker for prostate cancer risk. PMID- 20852944 TI - A whisper-game perspective on the family communication of DNA-test results: a retrospective study on the communication process of BRCA1/2-test results between proband and relatives. AB - Objective of this paper is to study how DNA-test result information was communicated and perceived within families. A retrospective descriptive study in 13 probands with a BRCA1/2 unclassified variant, 7 with a pathogenic mutation, 5 with an uninformative result, and in 44, 14, and 12 of their 1st and 2nd degree relatives respectively. We examined differences and correlations between: (a) information actually communicated (b) probands' perception, (c) relatives' perception. The perception consisted of recollections and interpretations of both their own and their relatives' cancer-risks, and heredity-likelihood (i.e. likelihood that cancer is heritable in the family). Differences and low correlations suggested few similarities between the actually communicated information, the probands' and the relatives' perception. More specifically, probands recalled the communicated information differently compared with the actually communicated information (R = .40), and reinterpreted this information differently (R = .30). The relatives' perception was best correlated with the proband's interpretation (R = .08), but this perception differed significantly from their proband's perception. Finally, relatives reinterpreted the information they received from their proband differently (R = .25), and this interpretation was only slightly related with the original message communicated by the genetic counsellor (R = .15). Unclassified-variants were most frequently misinterpreted by probands and relatives, and had the largest differences between probands' and relatives' perceptions. Like in a children's whisper-game, many errors occur in the transmission of DNA-test result information in families. More attention is required for how probands disseminate information to relatives. Genetic counsellors may help by supporting the probands in communicating to relatives, e.g. by providing clear summary letters for relatives. PMID- 20852945 TI - What I wish I'd known before surgery: BRCA carriers' perspectives after bilateral salipingo-oophorectomy. AB - We retrospectively studied BRCA carriers with a history of prophylactic bilateral salingo-oophorectomy (PBSO) regarding: (1) their post-operative symptoms, (2) their recollection of pre-operative conversations with their health care providers regarding possible surgical side-effects and (3) what information they would have found helpful to have before surgery. Female BRCA carriers seen through the Yale Cancer Genetic Counseling Program who had PBSO were invited to participate in a questionnaire that assessed their recall of information they received pre-operatively compared with their post-operative knowledge and symptoms related to menopause, cognitive changes, loss of fertility, cancer risks, osteoporosis, heart disease, vasomotor symptoms, urogenital symptoms, sexuality and body image. The questionnaire also elicited written feedback from participants regarding their decision to have PBSO, what they wished they had known before surgery, advice for other BRCA carriers considering this surgery and advice for health care providers who counsel women about PBSO. Two hundred and ninety female BRCA carriers were invited to participate and 113 (39.0%) indicated they were interested. Of those, 99 (87.6%) returned their questionnaire and 98 (86.7%) responses were included in the analysis. The mean age at PBSO was 45.5 years (range: 32-63 years). The five most common "frequent" or "very frequent" post-surgical symptoms were: vaginal dryness (52.1%), changes in interest in sex (50.0%), sleep disturbances (46.7%), changes in sex life (43.9) and hot flashes (42.9%). The majority of women would have found it helpful to have more information regarding the impact of this surgery on their sex life (59.2%), the availability of sex counseling (57.1%) and the risk of coronary heart disease (57.1%). This study illustrates that while health care providers are discussing selected side effects of PBSO, women undergoing this surgery have other concerns that should be addressed. This information provides insights into the informational needs of BRCA carriers considering PBSO. PMID- 20852946 TI - PALB2: a novel inactivating mutation in a Italian breast cancer family. AB - Rare germline monoallelic mutations in PALB2 confer a relative risk of breast cancer of 2 to 4-times. To better define the role of PALB2 in breast cancer susceptibility in Italian breast or breast-ovarian cancer families we screened 95 index cases negative for BRCA1/BRCA2 germline mutations. The mutational analysis of the PALB2 gene in a index case of an high risk breast cancer family, has identified a frameshift mutation (c.1517delG) in the exon 4 that leads to the formation of a stop codon, 12 residues downstream of the mutation (Leu451X). The mutation was identified in a woman 52 year old with an infiltrating ductal breast carcinoma and in two of the three sisters without breast cancer. Our results confirmed that PALB2 could be a susceptibility gene for familial breast cancer also in Italian population. PMID- 20852947 TI - Communicating genetic risk information within families: a review. AB - This review of family communication of genetic risk information addresses questions of what the functions and influences on communication are; what, who and how family members are told about genetic risk information; what the impact for counsellee, relative and relationships are; whether there are differences by gender and condition; and what theories and methodologies are used. A systematic search strategy identified peer-reviewed journal articles published 1985-2009 using a mixture of methodologies. A Narrative Synthesis was used to extract and summarise data relevant to the research questions. This review identified 33 articles which found a consistent pattern of findings that communication about genetic risk within families is influenced by individual beliefs about the desirability of communicating genetic risk and by closeness of relationships within the family. None of the studies directly investigated the impact of communication on counsellees or their families, differences according to gender of counsellee or by condition nor alternative methods of communication with relatives. The findings mainly apply to late onset conditions such as Hereditary Breast and Ovarian Cancer. The most frequently used theory was Family Systems Theory and methods were generally qualitative. This review points to multifactorial influences on who is communicated with in families and what they are told about genetic risk information. Further research is required to investigate the impact of genetic risk information on family systems and differences between genders and conditions. PMID- 20852949 TI - Further research on Xyrem(r)/sodium oxybate treatment of patients with obstructive sleep apnea is needed. PMID- 20852948 TI - Determinants of physiologic 18F-FDG uptake in brown adipose tissue in sequential PET/CT examinations. AB - PURPOSE: The aim of this study was to assess independent predictors of 2-deoxy-2 [(18)F]fluoro-D-glucose ((18)F-FDG) uptake in brown adipose tissue (BAT) in patients undergoing repeated positron emission tomography (PET)/computed tomography (CT) scans. PROCEDURES: Eight hundred forty-eight (mean age 50.9 +/- 16 years) patients in whom PET/CT scan was repeated (mean interval 5 +/- 1.5 months) constituted the study group. (18)F-FDG uptake in characteristic areas of BAT, with CT density of adipose tissue, greater than background soft-tissue activity was considered as evidence of BAT uptake. Both distribution and maximum standardized uptake values (SUVmax) were registered. Clinical and anamnestic data were collected for each patient. RESULTS: (18)F-FDG uptake in BAT was present in 8.6% patients at first scan. Independent predictors of presence of uptake were age (younger), gender (female), body mass index (lower), and maximum outdoor temperature (lower). Age was the only independent predictor of BAT (18)F-FDG uptake distribution, while SUVmax was related to both age and outdoor temperature. Independent determinants of persistence of BAT (18)F-FDG uptake at second PET/CT were outdoor temperature at time of second scan and extension of metabolically active BAT at first scan. CONCLUSIONS: Age, body mass index, and outdoor temperature are significant determinants of BAT evidence at (18)F-FDG PET/CT. Moreover, extension of BAT and outdoor temperature are the strongest determinants of persistence of BAT evidence on (18)F-FDG PET/CT in repeated scan. PMID- 20852951 TI - In-silico oncology: an approximate model of brain tumor mass effect based on directly manipulated free form deformation. AB - PURPOSE: The present work introduces a novel method for approximating mass effect of primary brain tumors. METHODS: The spatio-temporal dynamics of cancerous cells are modeled by means of a deterministic reaction-diffusion equation. Diffusion tensor information obtained from a probabilistic diffusion tensor imaging atlas is incorporated into the model to simulate anisotropic diffusion of cancerous cells. To account for the expansive nature of the tumor, the computed net cell density of malignant cells is linked to a parametric deformation model. This mass effect model is based on the so-called directly manipulated free form deformation. Spatial correspondence between two successive simulation steps is established by tracking landmarks, which are attached to the boundary of the gross tumor volume. The movement of these landmarks is used to compute the new configuration of the control points and, hence, determines the resulting deformation. To prevent a deformation of rigid structures (i.e. the skull), fixed shielding landmarks are introduced. In a refinement step, an adaptive landmark scheme ensures a dense sampling of the tumor isosurface, which in turn allows for an appropriate representation of the tumor shape. RESULTS: The influence of different parameters on the model is demonstrated by a set of simulations. Additionally, simulation results are qualitatively compared to an exemplary set of clinical magnetic resonance images of patients diagnosed with high-grade glioma. CONCLUSIONS: Careful visual inspection of the results demonstrates the potential of the implemented model and provides first evidence that the computed approximation of tumor mass effect is sensible. The shape of diffusive brain tumors (glioblastoma multiforme) can be recovered and approximately matches the observations in real clinical data. PMID- 20852952 TI - Role of diffusion-weighted MR imaging in assessing malignant versus benign skull base lesions. AB - PURPOSE: This study was done to assess the role of diffusion-weighted magnetic resonance (MR) imaging in assessing malignant versus benign skull lesions. MATERIALS AND METHODS: A retrospective analysis was undertaken of 45 patients (26 male, 19 female; age range 14-68 years, mean age 39 years) with skull-base lesions. Diffusion-weighted MR images were acquired with a b-factor of 500 and 1,000 s/mm(2) using single-shot echoplanar imaging. Apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC value of the lesion was calculated. RESULTS: The mean ADC value of malignant tumours was (1.002 +/- 0.21) * 10(-3) mm(2)/s and that of benign tumours was (1.63 +/- 0.29) * 10(-3) mm(2)/s. There was a statistically significant difference (p=0.001) in the ADC value of malignant skull-base tumours versus benign lesions. Selection of (1.3) * 10( 3)mm(2)/s as a threshold value of ADC for differentiating benign from malignant tumours yielded the best result, with an accuracy of 94%, sensitivity of 94%, specificity of 93%, positive predictive value of 93%, negative predictive value of 94% and area under the curve of 0.932. CONCLUSIONS: We conclude that diffusion weighted MR imaging is a promising, noninvasive approach that can be used to characterise skull-base lesions in that it can help differentiate malignant tumours from benign lesions and evaluate the pathological grading of malignant tumours. PMID- 20852953 TI - Critical issues in radiology requests and reports. AB - PURPOSE: This study evaluated the appropriateness and accuracy of 500 radiology requests and their matched reports in order to identify recurring errors in both areas. MATERIALS AND METHODS: A randomly chosen sample consisting of 167 computed tomography (CT), 166 ultrasonography (US) and 167 radiographic examinations were collected and analysed according to national referral guidelines and to the principles of justification and optimisation (Law no. 187/2000). RESULTS: We identified a high rate of inappropriate requests (27.6%) and requests lacking a clinical question (22%). There was good precision in the anamnestic data (80.6%) and in the formulation of the diagnostic question (76.8%). Almost all requests were handwritten, and 12.5% lacked the referring physician's stamp and/or signature. No report mentioned the clinical information received or the equipment used. The use of contrast medium was always reported. Conclusions were reported in 9.8% of these reports. When further investigation would have been necessary, the radiologist omitted to report this in 60% of cases. CONCLUSIONS: Some important weaknesses emerged, especially regarding requests for radiological examinations (22% lacked the clinical question, 27.6% were inappropriate), potentially limiting the effectiveness of the diagnostic process and leading to negative effects on the correct risk management process. There emerges a need for better collaboration between clinicians and radiologists. PMID- 20852954 TI - Ultrasound-guided aspiration and ethanol sclerotherapy for treating endometrial cysts. AB - PURPOSE: The authors sought to evaluate the effectiveness of ultrasound (US) guided aspiration and ethanol sclerotherapy in treating endometrial cysts and adopt this procedure as an alternative to surgery. MATERIALS AND METHODS: Fifty consecutive patients with an average age of 25.2 years [standard deviation (SD) 6.5; range 16-40 years) and US diagnosis of endometrial cyst who were pregnant or presenting with high anaesthesia risk, adhesions or who refused surgery underwent US-guided aspiration of a total of 54 endometrial cysts (40 with transabdominal approach and the remaining 14 with transvaginal approach) and ethanol sclerotherapy. RESULTS: The procedure was successful in all patients. Follow-up imaging was carried out at 12 h, 24 h, 15 days, 3 months, 6 months and 12 months. After 12 months, four patients (8%) showed recurrence, three of whom opted for a second session of US-guided aspiration and ethanol sclerotherapy. CONCLUSIONS: US guided aspiration and sclerotherapy with 95% ethanol provides a valid alternative to surgery in treating endometrial cysts. PMID- 20852955 TI - B3 breast lesions determined by vacuum-assisted biopsy: how to reduce the frequency of benign excision biopsies. AB - PURPOSE: The aim of this study was to identify parameters allowing differentiation among the diverse group of B3 lesion at stereotactic vacuum assisted biopsy (VAB) to identify patients with a low risk of cancer and who can therefore be referred for follow-up rather than surgery and thus reduce the number of unnecessary surgical procedures. MATERIALS AND METHODS: Among 608 VAB procedures performed for nonpalpable ultrasound (US)-occult mammographic abnormality, 102 cases of B3 were included in this study. Mammographic lesion type, lesion size, Breast Imaging Reporting and Data System (BIRADS) category, number of specimens per lesion and presence of atypia were retrospectively analysed. Results were compared with histological findings at surgery (53 cases) or mammographic findings during follow-up (49 cases). Statistical analysis was performed with univariate analysis (chi-square test), and statistical significance was set at p<0.05. RESULTS: The majority of cases were depicted as isolated microcalcifications (82.3%), were smaller than 10 mm (80.4%), had a low level of radiological suspicion (64.7%) and had 11 or more cores sampled (94.1%). Atypia at VAB was reported in 60 of 102 cases (58.8%). Carcinoma was found at excision in 5/60 (8%) B3 lesions with atypia and in no B3 lesions without atypia (p=0.146). Cancer at surgery was more frequent among cases of isolated microcalcifications (p=0.645), cases with high radiological suspicion (p=0.040) and those with a smaller number of cores sampled (borderline significant p=0.064). CONCLUSIONS: On the basis of our experience, the presence or absence of atypia in our series proved to be the reliable criterion to prompt or avoid surgery in cases with a VAB finding of B3 lesion. This criterion may therefore be adopted in practice to more accurately select patients for surgery. PMID- 20852956 TI - Preliminary experience with abdominal dual-energy CT (DECT): true versus virtual nonenhanced images of the liver. AB - PURPOSE: The aim of this work was to compare the quality and noise of true non enhanced (TNE) and virtual non-enhanced (VNE) images in patients undergoing dual energy computed tomography (DECT) of the liver. MATERIALS AND METHODS: Twenty consecutive patients (mean age 54.7+/-19.9 years) prospectively underwent abdominal DECT to assess the liver using a triphasic protocol consisting of precontrast, arterial-phase and portal-phase acquisitions. Exclusion criteria were allergy to iodinated contrast material, impaired renal function and a body mass index (BMI) >35 kg/m(2). The DE portal-phase acquisition was performed with automatic dose modulation (CARE Dose 4D). Nonionic iodinated contrast material (Iomeron 400) was administered at 0.625 gI/kg with a flow rate of 3.5 ml/s. Axial VNE images were reconstructed based on the portal data set using a collimation and an increment of 5 mm and were compared with TNE images reconstructed with the same parameters. The average image quality and noise were analysed by two radiologists in separate reading sessions. RESULTS: No statistically significant difference (p>0.05) in image quality was observed between VNE (4.00+/-0.85) and TNE images (4.35+/-0.58). A sufficient diagnostic quality was found in 95.0% (19/20) of VNE images and in 100% of TNE images. No statistically significant difference (p<0.05) was observed in the average image noise of VNE (9.5+/-0.7) and TNE (12.3+/-1.1) images. CONCLUSIONS: Abdominal DECT allows acquisition of liver VNE images with similar image quality and lower noise than TNE. Nevertheless, a few technical limitations related to the small field of view of the second detector in patients with a high BMI and heterogeneous iodine subtraction restrict the application of this technique to selected patients only. PMID- 20852957 TI - Multislice CT in congenital bronchopulmonary malformations in children. AB - Congenital bronchopulmonary malformations encompass a wide spectrum of pathologies involving the lungs, trachea and bronchi, pulmonary vessels, and oesophagus. These developmental lesions are often isolated, but the association of two or more anomalies is not infrequent. Contrast-enhanced multidetector computed tomography (MDCT), thanks to multiplanar and 3D reconstructions, allows for detailed studies of these malformations, achieving better accuracy compared with conventional techniques such as chest X-ray, fluoroscopy, ventilation and perfusion scintigraphy and ultrasonography. MDCT is characterised by fast data acquisition and does not require sedation in the majority of cases. The main drawbacks of MDCT are the use of ionising radiation and - in many cases -contrast media. Recently, improved CT scanners and optimised CT protocols have made available to children all the benefits of MDCT, thanks to a significant reduction in radiation dose and an improved risk-benefit ratio. The aim of our paper was to evaluate MDCT in children with bronchopulmonary malformations by reporting our experience (about 2,400 studies in 30 months with a 64-slice MDCT scanner) and comparing it with the available literature. PMID- 20852958 TI - Effect of an oral anxiolytic medication and heart rate variability on image quality of 64-slice MDCT coronary angiography. AB - PURPOSE: The aim of the study was to investigate the relationship between image quality in 64-slice multidetector computed tomography (MDCT) and patients' preimaging anxiety status and heart rate variability (HRV), and to evaluate the efficacy of an orally administered anxiolytic medication on HRV and image quality. MATERIALS AND METHODS: Sixty patients [14 women, 46 men; mean age 52.53 +/- 10.55 (SD), range 33-78 years] were studied. Anxiety levels were assessed with the State-Trait Anxiety Inventory 60 min before the procedure. The participating patients were randomly assigned to one of the two study groups: a control group (no medication administered for anxiety reduction) and an anxiolytic medication group, with 30 patients in each group. The presence of motion artefacts and image quality for each coronary artery segment were evaluated using a four-point grading system. To estimate HRV, the duration of each heartbeat during MDCT data acquisition was measured in each patient. RESULTS: A moderate correlation was found between HRV during MDCT scanning and the mean image quality for all coronary segments (r=0.47, p<0.01). There was an association between HRV and state anxiety scores in all cases (r=0.370, p<0.01). HRV in the patients who received alprazolam was statistically significantly lower than in controls (p<0.05). The average image quality in patients who used alprazolam was also statistically significantly higher than in controls (p<0.05). CONCLUSIONS: The most important finding in our study is that oral premedication to reduce anxiety is also effective in decreasing HRV and improves image quality. Therefore, we suggest that using alprazolam in addition to a beta-blocker may improve image quality in patients undergoing MDCT coronary angiography (MDCT-CA). Anxiolytic usage may improve image quality by lowering the HRV in selected cases where administration of a beta-blocker is contraindicated. We also suggest that further studies in larger series are required to validate this finding. PMID- 20852959 TI - Diagnostic accuracy of 64-slice CT in evaluating coronary artery bypass grafts and of the native coronary arteries. AB - PURPOSE: Our aim was to evaluate the accuracy, sensitivity and specificity of 64 slice multidetector computed tomography (MDCT) in the assessment of occlusions and stenoses of arterial and venous bypass grafts and disease progression in the native vessels distal to the graft, and to compare the results with those of conventional coronary angiography. MATERIALS AND METHODS: We enrolled 78 individuals (45 men, 33 women; mean age 59) and evaluated 213 bypass grafts using a 64-slice MDCT scanner. All patients underwent conventional coronary angiography with a mean time interval between the two examinations of 2 days. RESULTS: One patient was excluded due to arrhythmia during the examination. The 212 bypass grafts in the remaining 77 patients (98.7%) consisted of 115 (54%) venous grafts and 97 (46%) arterial grafts. In the 115 venous grafts, MDCT showed a sensitivity, specificity and accuracy of 100% in evaluating occluded grafts and a sensitivity of 94.4%, specificity of 98.4% and accuracy of 96.9% in evaluating significant stenoses. In evaluating occluded arterial grafts, sensitivity was 83.3%, specificity 100% and accuracy 98.9%, whereas in evaluating stenoses of arterial grafts, sensitivity was 100%, specificity 97.7% and accuracy 98%. CONCLUSIONS: Sensitivity, specificity and accuracy in evaluating native coronary vessels distal to the graft allow for a complete assessment of the surgical and native circulation. The examination appears therefore to be exhaustive in ruling out or confirming the presence of diseased vessels in the postoperative follow up. PMID- 20852960 TI - Clinical Risk Management in radiology. Part II: applied examples and concluding remarks. AB - With the aim of providing a clearer understanding of the tools used for evaluating risk in the radiological setting and how they are applied, this second part presents two practical examples. The first is a proactive analysis applied to CT, whereas the second is a reactive analysis performed following a sentinel event triggered by a CT study allocated to the wrong patient in the RIS-PACS system. PMID- 20852961 TI - Clinical Risk Management in radiology. Part I: general background and types of error and their prevention. AB - The present contribution, presented as an Editorial, addresses the issue of patient safety in Radiology: this topic, of great current National and Regional interest, has stimulated a strong focus on accidents and mistakes in medicine, together with the diffusion of procedures for Risk Management in all health facilities. The possible sources of incidents in the radiological process are exposed, due to human errors and to system errors connected both to the organization and to the dissemination of Information Technology in the Radiological world. It also describes the most common methods and tools for risk analysis in health systems, together with some application examples presented in Part II. PMID- 20852962 TI - Malignant small-bowel neoplasms: spectrum of disease on MR imaging. AB - Malignant neoplasms of the small bowel are among the rarest types of cancer, accounting for only 2% of all gastrointestinal neoplasms. Owing both to the intrinsic difficulty of common radiographic and endoscopic methods in visualising the entire small bowel and the lack of typical physical findings, a delay in diagnosis is common. Recently, magnetic resonance (MR) imaging has become a widely accepted imaging modality in the study of suspected small-bowel neoplasms due to its ability to depict, without exposure to ionising radiation and with excellent soft-tissue contrast, intraluminal disorders in conjunction with mural, extraparietal and regional abnormalities. The aim of this pictorial review is to illustrate the MR appearance of malignant small-bowel neoplasms. PMID- 20852964 TI - Intracochlear schwannoma presenting as diffuse cochlear enhancement: diagnostic challenges of a rare cause of deafness. AB - Intracochlear schwannoma is a rare, treatable, cause of unilateral hearing loss. Due to the small size, position, and variable clinical and imaging features, diagnosis presents a significant challenge and is often delayed. We present a case of a patient with an intracochlear schwannoma presenting as a diffuse enhancement of the cochlea, mimicking an infectious or inflammatory process. The absence of focal nodularity in this lesion on multiple high-resolution MRI examinations led to a delay of over 3 years from the patient's initial presentation to surgical diagnosis. Clinical history and examination, imaging features, pathologic findings, and surgical management options are described. PMID- 20852963 TI - Role of magnetic resonance spectroscopic imaging ([1H]MRSI) and dynamic contrast enhanced MRI (DCE-MRI) in identifying prostate cancer foci in patients with negative biopsy and high levels of prostate-specific antigen (PSA). AB - PURPOSE: The purpose of this study was to evaluate the role of magnetic resonance spectroscopic imaging (MRSI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in detecting tumour foci in patients with elevated prostate specific antigen (PSA) and negative transrectal ultrasonography (TRUS)-guided biopsy. MATERIALS AND METHODS: This prospective randomised trial was conducted on 150 patients who underwent [1H]MRSI and DCE-MRI and targeted biopsies of suspicious areas on MRI associated with random biopsies. RESULTS: After the second biopsy, the diagnosis of prostate adenocarcinoma was made in 64/150 cases. On a per-patient basis, MRSI had 82.8% sensitivity, 91.8% specificity, 88.3% positive predictive value (PPV), 87.8% negative predictive value (NPV) and 85.7% diagnostic accuracy. The sensitivity, specificity, PPV, NPV and accuracy for DCE MRI was 76.5%, 89.5%, 84.5%, 83.7% and 82%, respectively. The combination of MRSI and DCE-MRI yielded 93.7% sensitivity, 90.7% specificity, 88.2% PPV, 95.1% NPV and 90.9% accuracy in detecting prostate carcinoma. CONCLUSIONS: The combined study with [1H]MRSI and DCE-MRI showed promising results in guiding the biopsy of cancer foci in patients with an initial negative TRUS-guided biopsy. PMID- 20852965 TI - A cost-benefit analysis of bariatric surgery on the South Plains region of Texas. AB - The regional economic burdens of obesity have not been fully quantified. This study incorporated bariatric surgery demographics collected from a large university hospital with regional economic and employment data to evaluate the cost of obesity for the South Plains region of Texas. Data were collected from patients who underwent laparoscopic gastric bypass and laparoscopic banding between September 2003 and September 2005 at Texas Tech University Health Sciences Center. A regional economic model estimated the economic impact of lost productivity due to obesity. Comparisons of lost work days in the year before and after surgery were used to estimate the potential benefit of bariatric surgery to the South Plains economy. Total output impacts of obesity, over $364 million, were 3.3% of total personal income; total labor income impacts neared $60 million: the losses corresponded to $2,389 lost output and $390 lost labor income per household. Obesity cost the South Plains over 1,977 jobs and decreased indirect business tax revenues by over $13 million. The net benefit of bariatric surgery was estimated at $9.9 billion for a discount rate of 3%, $5.0 billion for a discount rate of 5%, and $1.3 billion for a discount rate of 10%. Potential benefits to the South Plains economy of performing bariatric surgery more than outweigh its costs. PMID- 20852966 TI - Association of dental fluorosis with polymorphisms of estrogen receptor gene in Chinese children. AB - Dental fluorosis (DF) is one of the important performances of endemic fluorosis. Some studies indicated that estrogen receptor (ESR) gene polymorphisms were associated with bone metabolism-related diseases. Therefore, it is possible that the variation in ESR genotypes will be associated with DF status. A case-control study was conducted among children aged 8-12 years with (n = 75) or without (n = 165) DF in China to investigate the relationship between ESR gene polymorphisms and DF. Gene polymorphisms were genotyped using the PCR-RFLP procedure. Children carrying R allele of ER RsaI had significantly increased risk of DF (Odds ratio (OR) = 1.821; 95% confidence interval (CI), 1.013-3.274) compared to children carrying r allele of ER RsaI in endemic fluorosis villages. For children with high-loaded fluoride status, carrying X allele of ESRalpha XbaI had a significantly decreased risk of DF (OR = 0.542; 95% CI, 0.314-0.936) compared to carrying x allele. This study provides the first evidence of an association between polymorphisms in the ESR gene with DF in high-fluoride-exposed populations. Further studies are needed to confirm the association. PMID- 20852967 TI - Studies on scavenger receptors under experimental hypercholesterolemia: modulation on selenium supplementation. AB - Scavenger receptors (SR) are the cell surface proteins that can bind and internalize modified lipoproteins. Because ox-LDL seems to play a key role in foam cell formation during atherogenesis, SR may be critical for pathogenesis of atherosclerosis. The present study was aimed to study the effect of selenium (Se) supplementation on SR, i.e., SRB1 and CD36 under experimental hypercholesterolemia. Male Sprague Dawley rats were divided into three groups and fed on the control diet, high cholesterol diet (HCD), and HCD + Se, respectively, for a period of 4 months. Selenium and reactive oxygen species (ROS) levels were estimated in serum and liver respectively. mRNA expression using RT-PCR and protein expression using ELISA were analyzed for SRB1 and CD36 receptors. Selenium levels decreased whereas ROS levels increased under experimental hypercholesterolemic state. Selenium supplementation (1 ppm), however, diminished the HCD-induced ROS levels. Furthermore, the protein expression of SRB1 was significantly reduced in HCD group in comparison to the control group. On the other hand, HCD-induced increase in CD36 mRNA and protein expression decreased significantly on Se supplementation. In conclusion, CD36 receptors seem to play a pro-atherogenic role under hypercholesterolemic state. Selenium supplementation, in addition, might prove to be a therapeutically valuable approach in near future to limit the adverse effect of hypercholesterolemia. PMID- 20852968 TI - Mechanism of low-frequency ultrasound in opening blood-tumor barrier by tight junction. AB - The clinical chemotherapy of brain tumors has been limited by the blood-tumor barrier (BTB). Low-frequency ultrasound (LFU) in combination with microbubbles might be a useful method for local drug delivery. However, the underlying mechanism remains unclear. In this study, we asked whether LFU changed the permeability of BTB by regulating the tight junction-related proteins. The permeability of BTB was evaluated by Evans blue dye, and the protein and mRNA expression levels of tight junction-related proteins claudin-5, occludin, and ZO 1 were determined by immunohistochemical staining, RT-PCR, and western blot assays. We found that the permeability of BTB increased significantly after LFU exposure in the presence of Optison. The mRNA and protein expression levels of claudin-5, occludin, and ZO-1 decreased significantly at 3 h, restored gradually and nearly recovered after 12 h. The correlation between the increase of BTB permeability and the reduction of tight junction-related proteins suggests that LFU combined with microbubbles may be involved in the opening of the BTB by the tight junction-related proteins. PMID- 20852969 TI - Two novel homozygous SACS mutations in unrelated patients including the first reported case of paternal UPD as an etiologic cause of ARSACS. AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay, more commonly known as ARSACS, is an early-onset cerebellar ataxia with spasticity, amyotrophy, nystagmus, dysarthria, and peripheral neuropathy. SACS is the only gene known to be associated with the ARSACS phenotype. To date, 55 mutations have been reported; of these, only five in Italian patients. We found two novel homozygous nonsense mutations in the giant exon of SACS gene in two unrelated patients with classical ARSACS phenotype. Characterization of the homozygous nature of the mutations through genotyping of the parents, quantitative DNA analysis and indirect STS studies permitted us to confirm in one of the cases that uniparental isodisomy of the paternal chromosome 13 carrying the mutated SACS gene played an etiologic role in the disease. PMID- 20852970 TI - Phencyclidine (PCP)-induced disruption in cognitive performance is gender specific and associated with a reduction in brain-derived neurotrophic factor (BDNF) in specific regions of the female rat brain. AB - Phencyclidine (PCP), used to mimic certain aspects of schizophrenia, induces sexually dimorphic, cognitive deficits in rats. In this study, the effects of sub chronic PCP on expression of brain-derived neurotrophic factor (BDNF), a neurotrophic factor implicated in the pathogenesis of schizophrenia, have been evaluated in male and female rats. Male and female hooded-Lister rats received vehicle or PCP (n=8 per group; 2 mg/kg i.p. twice daily for 7 days) and were tested in the attentional set shifting task prior to being sacrificed (6 weeks post-treatment). Levels of BDNF mRNA were measured in specific brain regions using in situ hybridisation. Male rats were less sensitive to PCP-induced deficits in the extra-dimensional shift stage of the attentional set shifting task compared to female rats. Quantitative analysis of brain regions demonstrated reduced BDNF levels in the medial prefrontal cortex (p<0.05), motor cortex (p<0.01), orbital cortex (p<0.01), olfactory bulb (p<0.05), retrosplenial cortex (p<0.001), frontal cortex (p<0.01), parietal cortex (p<0.01), CA1 (p<0.05) and polymorphic layer of dentate gyrus (p<0.05) of the hippocampus and the central (p<0.01), lateral (p<0.05) and basolateral (p<0.05) regions of the amygdaloid nucleus in female PCP-treated rats compared with controls. In contrast, BDNF was significantly reduced only in the orbital cortex and central amygdaloid region of male rats (p<0.05). Results suggest that blockade of NMDA receptors by sub chronic PCP administration has a long-lasting down-regulatory effect on BDNF mRNA expression in the female rat brain which may underlie some of the behavioural deficits observed post PCP administration. PMID- 20852971 TI - Primary primitive neuroectodermal tumor of the urinary bladder: a case report and literature review. AB - Primitive neuroectodermal tumor (PNET) arising in the urinary bladder is extremely rare. Here, we report a case of primary PNET of the urinary bladder in an aged Asian man that showed an aggressive clinical course. A 74-year-old man presented with frequency, dysuria, and gross hematuria. Pelvic computed tomography showed a mass in the urinary bladder. Microscopically, the tumor revealed sheets of uniform, small, round, blue cells, and immunohistochemical examination demonstrated primary PNET of the urinary bladder. Palliative chemotherapy was administered. After three courses of chemotherapy, his disease progressed and he died 4 months after diagnosis. PMID- 20852972 TI - Ceramic-on-ceramic total hip arthroplasty: incidence of instability and noise. AB - BACKGROUND: Alternative bearing materials in THA have been developed to reduce the incidence of osteolysis. Alumina-on-alumina bearings exhibit extremely low wear rates in vitro, but concerns exist regarding component impingement with the potential for dislocation and the occurrence of noise. QUESTIONS/PURPOSES: We determined generation of squeaking and the relationship between squeaking and component position. METHODS: We prospectively entered 436 alumina-on-alumina, cementless, primary THAs in 364 patients into our institutional database. All procedures were performed with the same surgical technique and the same implant. We obtained Harris Hip scores and a noise questionnaire and assessed radiographic component position and loosening. We determined the difference in abduction angle between squeakers and nonsqueakers. Minimum followup was 2 years (average, 3.5 years; range, 2.0-6.2 years). RESULTS: The mean Harris hip score increased from 51.9 preoperatively to 94.4 at latest followup. Six hips underwent reoperation: four hips (1.1%) for dislocation and two (0.53%) for periprosthetic fracture after trauma. The incidence of noise of any type was 11%, with the most common type of noise being clicking or snapping. Squeaking was reported by 1.9% of patients, with no patient being revised for this phenomenon. We found no association between component position and squeaking. CONCLUSIONS: At average 3 years followup, 98% of ceramic-on-ceramic THAs did not require a revision, with 1.1% of hips having been revised for dislocation. Fewer than 2% of patients reported hearing an audible squeak, with no association found between component position and squeaking. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20852973 TI - Acetabular UHMWPE survival and wear changes with different manufacturing techniques. AB - BACKGROUND: Polyethylene wear may be affected by the type of polyethylene resin, manufacturing technique, degree of thermal stabilization, and sterilization technique. QUESTIONS/PURPOSES: We therefore compared femoral head penetration into the PE and cup survival using the same cup system with different PE resins, manufacturing, and sterilization techniques. METHODS: Our study group consisted of 1912 THAs performed using the same uncemented cup and identical 28-mm cobalt chrome heads. The polyethylene varied as follows: Group 1 (94 cups), GUR 4150 resin, ram-extruded, sterilized in air, no barrier packaging; Group 2 (74 cups), same as Group 1 but sterilized in argon; Group 3 (75 cups), Himont 1900 resin, compression-molded bar stock, sterilized in argon, no barrier packaging; Group 4 (620 cups), same as Group 3 except with barrier packing; Group 5 (711 cups), GUR 1050 resin, compression-molded bar stock, sterilized in argon gas with barrier packaging; and Group 6 (338 cups), GUR 1050 resin, compression-molded bar stock, sterilized in argon with barrier packaging, irradiated with 50 kGy, heated below melting temperature, machined, and finally placed in nonbarrier packaging with gas plasma sterilization. Minimum followup was 2 years (average, 7 years; range, 2-17 years). RESULTS: Femoral head penetration averaged 0.05 mm per year for Groups 5 and 6 and was substantially lower than for Groups 1 to 4. Cup survival was higher at seven years in Groups 3, 4, and 5, and at 10 years in group 4 when compared to groups 1, 2, and 3. CONCLUSIONS: We observed lower FHP rates and higher cup survival with polyethylene machined from direct compression-molded bar stock, sterilized in argon gas, with barrier packaging. LEVEL OF EVIDENCE: Level III Therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20852974 TI - Improving cup positioning using a mechanical navigation instrument. AB - BACKGROUND: Although surgical navigation reduces the rate of malpositioned acetabular cups in total hip arthroplasty (THA), its use has not been widely adopted. As a result of our perceived need for simple and efficient methods of navigation, we developed a mechanical navigation device for acetabular cup orientation. QUESTIONS/PURPOSES: We assessed accuracy of cup orientation (mean error of cup inclination and anteversion) of a novel mechanical navigation device, percentage of outliers, length of operation, and compared the results with a series of CT-based computer-assisted THAs. METHODS: Cup orientation of 70 THAs performed using the mechanical navigation device was compared with a historical control group of 146 THAs performed using CT-based computer navigation. Postoperative cup orientation was measured using a validated two dimensional/three-dimensional matching method. An outlier was defined outside a range of +/- 10 degrees from the planned inclination and/or anteversion. RESULTS: Using the mechanical navigation device, we observed a decrease in the errors of inclination (1.3 degrees +/- 3.4 degrees [range, -6.6 degrees to 8.2 degrees ] versus 3.5 degrees +/- 4.2 degrees [-12.7 degrees to 6.9 degrees ]), errors of anteversion (1.0 degrees +/- 4.1 degrees [-8.8 degrees to 9.5 degrees ] versus 3.0 degrees +/- 5.8 degrees [-11.8 degrees to 19.6 degrees ]), percentages of outliers (0% versus 9.6%), and length of operation (112 +/- 22 [78-184] minutes versus 132 +/- 18 [90-197] minutes) compared with CT-based navigation. CONCLUSIONS: Compared with CT-based surgical navigation, navigation of acetabular cup orientation using a mechanical device can be performed in less time, lower mean errors, and minimal equipment. PMID- 20852975 TI - Biographical sketch: Sir John Charnley MD, 1911-1982. AB - This biographical sketch of Sir John Charnley corresponds to the historic text, The Classic: The Bonding of Prostheses to Bone by Cement, available at DOI 10.1007/s11999-010-1545-8 . PMID- 20852976 TI - Psychological determinants and outcomes of sedentary and physical activity behaviours. PMID- 20852978 TI - The Damocles Syndrome: where we are today. PMID- 20852977 TI - Effect of dietary fiber of "Rihane" barley grains and azoxymethane on serum and liver lipid variables in Wistar rats. AB - The aim of the present study is to evaluate the effects of diet enriched with dietary fiber of barley variety "Rihane" and azoxymethane on serum and liver lipid variables in male rats. Forty male rats were divided into four groups and fed on control diet or experimental diet that contained control enriched with dietary fiber of barley variety "Rihane". Animals were injected with saline (controls) or azoxymethane (20 mg/kg body weight s.c.) at 7 and 8 weeks of age. The experimental diet significantly decreased cholesterol level compared with the control diet. Rats fed with BR diet significantly increased the serum high density lipoprotein (HDL) cholesterol and significantly decreased low-density lipoprotein (LDL) cholesterol concentrations. The experimental diet decreased the atherogenic index (p < 0.05) compared with the control diet. Whereas the azoxymethane induced a significant increase of liver lipid, serum LDL and triglyceride concentrations, but it caused a significant reduction of HDL. Consequently, the ratio of HDL/TC decreased significantly compared with the control (p < 0.05). Accordingly, these results indicated that the diet enriched with dietary fiber of barley variety "Rihane" could be effective in decreasing the atherogenic risk factors in rats whereas the use of the azoxymethane as colon specific carcinogen substance altered the lipid metabolism. PMID- 20852979 TI - Predicting health literacy among English-as-a-second-Language older Chinese immigrant women to Canada: comprehension of colon cancer prevention information. AB - Inadequate health literacy has been identified as a barrier to the utilization of health-care services, including cancer screening. This study examined predictors of health literacy among 106 older Chinese immigrant women to Canada and how colon cancer information presented in their first versus second language affected health literacy skill. Only 38.7% of the women had adequate health literacy based on Short Test of Functional Health Literacy for Adults, and 54.3% had adequate comprehension of the colon cancer information. Comprehension of the cancer information was significantly lower among women who received the information in English compared with those who received the information in Chinese. Age, acculturation, self-reported proficiency reading English, and education were significant predictors of health literacy but varied depending on the measure of health literacy used and language of the information. Presentation of cancer prevention information in one's first rather than second language improves health literacy but does not eliminate comprehension difficulties for older ESL Chinese immigrants. PMID- 20852981 TI - Photorhabdus temperata subsp. stackebrandtii subsp. nov. (Enterobacteriales: Enterobacteriaceae). AB - The bacterial symbiont of the entomopathogenic nematode Heterorhabditis bacteriophora strain GPS11 was characterized by 16S rRNA gene sequence and physiological traits. The phylogenetic tree built upon 16S rRNA gene sequences clustered the GPS11 bacterial isolate with Photorhabdus temperata strains which have been previously isolated from Heterorhabditis species. The phylogenetic tree further identified four subgroups in P. temperata, and the relationships among these subgroups were confirmed by gyrase subunit B (gyrB) gene sequence analysis. The subgroup containing the GPS11 bacterial isolate differs from other subgroups in sequences of 16S rRNA and gyrB gene, physiological traits, nematode host species, and geographic origin. Therefore, the subgroup comprising the GPS11 bacterial isolate is proposed here as a new subspecies: Photorhabdus temperata subsp. stackebrandtii subsp. nov. (type strain GPS11). The type strain has been deposited in ATCC and DSMZ collections. PMID- 20852980 TI - Aniline-induced tryptophan production and identification of indole derivatives from three purple bacteria. AB - Growth on aniline by three purple non-sulfur bacteria (Rhodospirillum rubrum ATCC 11170, Rhodobacter sphaeroides DSM 158, and Rubrivivax benzoatiliticus JA2) as nitrogen, or carbon source could not be demonstrated. However in its presence, production of indole derivatives was observed with all the strains tested. At least 14 chromatographically (HPLC) distinct peaks were observed at the absorption maxima of 275-280 nm from aniline induced cultures. Five major indoles were identified based on HPLC and LC-MS/MS analysis. While tryptophan was the major common metabolite for all the three aniline induced cultures, production of indole-3-acetic acid was observed with Rvi. benzoatilyticus JA2 alone, while indole-3-aldehyde was identified from Rvi. benzoatilyticus JA2 and Rba. sphaeroides DSM 158. Indole-3-ethanol was identified only from Rsp. rubrum ATCC 1170 and anthranilic acid was identified from Rba. sphaeroides DSM 158. PMID- 20852982 TI - Monogeneans from Epinephelus chlorostigma (Val.) (Perciformes: Serranidae) off New Caledonia, with the description of three new species of diplectanids. AB - Gill monogeneans from the brownspotted grouper Epinephelus chlorostigma (Val.) collected in deep water off the coral barrier reef of New Caledonia, South Pacific, comprise seven species. These include the ancyrocephalid Haliotrema sp., the capsalid Allobenedenia cf. epinepheli Yamaguti, 1968, and five diplectanids, namely Pseudorhabdosynochus epinepheli (Yamaguti, 1938), reported in a previous paper, P. cyanopodus Sigura & Justine, 2008 and P. podocyanus Sigura & Justine, 2008, two species originally described from E. cyanopodus Richardson, P. stigmosus n. sp., P. exoticoides n. sp. and Diplectanum femineum n. sp. P. stigmosus is characterised by a sclerotised vagina with a straight primary canal, large ovoid primary chamber and spherical secondary chamber. P. exoticoides is a highly aberrant species, with a thick-walled male quadriloculate organ and a discoid sclerotised vagina with an exceptional structure. Interestingly, P. exoticoides resembles P. exoticus Sigura & Justine, 2008, a species from E. cyanopodus, and P. stigmosus resembles P. cyanopodus and P. podocyanus, also both from E. cyanopodus, suggesting close relationships between the diplectanid faunae of these two fish species. D. femineum belongs to a group of diplectanids, provisionally classified as 'Diplectanum' Diesing, 1858, which all share a small funnel-shaped male copulatory organ. In contrast to other members of this group which have no sclerotised vagina, D. femineum has a sclerotised vagina with the same organisation as those of species of Pseudorhabdosynochus Yamaguti, 1958. This suggests that the species of 'Diplectanum' from groupers are closer to Pseudorhabdosynochus than suggested by the structure of the male organs. PMID- 20852983 TI - Species of Neohaliotrema Yamaguti, 1965 (Monogenea: Ancyrocephalidae) from the pomacentrid Abudefduf vaigensis (Quoy & Gaimard) off Pulau Langkawi, Malaysia, with a revised diagnosis of the genus and a key to its species. AB - Four new and one unidentified species of Neohaliotrema Yamaguti, 1965 were obtained from the gills of the Indo-Pacific sergeant Abudefduf vaigensis (Quoy & Gaimard) off Pulau Langkawi, Malaysia. The five species, N. malayense n. sp., N. bombini n. sp., N. andamanense n. sp., N. parvum n. sp. and an unidentified Neohaliotrema sp. (similar to N. macracanthum Zhukov, 1976), are described and distinguished based mainly on features of the haptor. Species of this genus are divisible into two groups, the 'maomao group', with two pairs of morphometrically modified 'marginal' hooks and a fenestrated haptor, and the 'gracile group', with morphologically similar marginal hooks and an entire haptor. With the exception of N. bombini n. sp., the species described fit within the 'maomao group'. It is suggested that the more complex Neohaliotrema species of the 'maomao group' have modified hooks 1 and 2 on a haptoral 'isthmus' between two large apertures, i.e. 'windows', whereas the less complex species lacking these features are those of the 'gracile group'. Neohaliotrema spp. have only a single pair of pigmented eye spots. A fenestrated haptor is unique to the Neohaliotrema spp. of the 'maomao group'. The generic diagnosis of Neohaliotrema is amended to include new data and a key to its known species is presented. PMID- 20852984 TI - Tantulocarida (Crustacea) from the Southern Ocean deep sea, and the description of three new species of Tantulacus Huys, Andersen & Kristensen, 1992. AB - During the expedition ANT XIX/3 meiofauna samples were collected from the German research vessel Polarstern near the Shackleton Fracture Zone. During sorting of the samples 86 tantulus larvae were found. Extensive examination of the larvae revealed a high diversity of tantulocaridans in the Southern Ocean deep sea (33 species). A remarkable proportion of these were new species of Tantulacus Huys, Andersen & Kristensen, 1992. The present paper reports the discovery of three new Antarctic tantulocarids which are referred to Tantulacus. The affiliation of T. longispinosus n. sp., T. karolae n. sp. and T. dieteri n. sp. to Tantulacus is straightforward: all representatives of the Tantulocarida are characterised by the presence of 1-2 slender setae on the endopod of the second to fifth thoracopods, but in none of the hitherto described genera, other than Tantulacus, are these elements modified. Tantulacus hoegi Huys, Andersen & Kristensen, 1992 and the three new species share the possession of a distal rigid spine on the endopod of the second to fifth thoracopods as a synapomorphy and thus can be readily distinguished from other tantulocaridans. This is the first record of free-living sediment-inhabiting tantulus larvae from this area, although this probably reflects the degree of undersampling. PMID- 20852985 TI - Redescription of the male and description of the female of Ixodes abrocomae Lahille, 1916 (Acari: Ixodidae). AB - The male of Ixodes abrocomae Lahille, 1916 (Acari: Ixodidae) is redescribed and the female described for the first time from specimens collected on the rodents Abrothrix longipilis (Waterhouse), A. olivaceous (Waterhouse) and Phyllotis xanthopygus (Waterhouse) at Coquimbo, Chile. The males of I. abrocomae are peculiar in having the combination of the following features: length and width less than 2 mm and 1 mm, respectively; hypostome notched with two rows of stout denticles and several small internal denticles; article II of the palpi with two conspicuous dorsal setae; coxa I with two subequal spurs; coxae II-IV with a single spur plus an indication of a second spur; and a scutum with long, scattered hairs except for the glabrous postero-median field which reaches to the marginal fold. The females of I. abrocomae are peculiar in possessing a combination of: a pointed hypostome, with a 3/3 dentition of flared denticles; a long, narrow scutum with few 'hairs' and with punctations which are especially numerous in the posterior region; a triangular basis capituli, with oval porose areas lacking definitive borders and separated by the width of one area, and a sinuous posterior margin with small cornuae; one spur on coxae I-IV; and conspicuous setae on the interno-dorsal face of palpal article II and the ventral face of article I. Sequences of 16S rDNA were identical for male and female I. abrocomae, but differ by 3.8% and 5.5% from sequences of their closest relatives, I. stilesi Neumann, 1911 and I. sigelos Keirans, Clifford & Corwin, 1976, respectively. Characters enabling the separation of I. abrocomae from Ixodes spp. distributed in the southwestern Neotropics are presented. Records of I. abrocomae in different climatic areas and on different, widely distributed rodent hosts indicate that this species may be present beyond its known Chilean territorial range (Regions III and IV). PMID- 20852986 TI - PROFILE: Tatiana Alexandrovna Timofeeva (1944-2010). PMID- 20852988 TI - A PCR-based marker for a locus conferring aroma in vegetable soybean (Glycine max L.). AB - Vegetable soybean (Glycine max L.) is an important economic and nutritious crop in South and Southeast Asian countries and is increasingly grown in the Western Hemisphere. Aromatic vegetable soybean is a special group of soybean varieties that produce young pods containing a sweet aroma, which is produced mainly by the volatile compound 2-acetyl-1-pyrroline (2AP). Due to the aroma, the aromatic vegetable soybean commands higher market prices and gains wider acceptance from unfamiliar consumers. We have previously reported that the GmAMADH2 gene encodes an AMADH that regulates aroma (2AP) biosynthesis in soybeans (Arikit et al. 2010). A sequence variation involving a 2-bp deletion in exon 10 was found in this gene in all investigated aromatic varieties. In this study, a codominant PCR based marker for the aroma trait in soybeans was designed based on the 2-bp deletion in GmAMADH2. The marker was verified in five aromatic and five non aromatic varieties as well as in F(2) soybean population segregating for aroma. The aromatic genotype with the 2-bp deletion was completely associated with the five aromatic soybean varieties as well as the aromatic progeny of the F(2) population with seeds containing 2AP. Similarly, the non-aromatic genotype was associated with the five non-aromatic varieties and non-aromatic progeny. The perfect co-segregation of the marker genotypes and aroma phenotypes confirmed that the marker could be efficiently used for molecular breeding of soybeans for aroma. PMID- 20852989 TI - GLP-1 signaling preserves cardiac function in endotoxemic Fischer 344 and DPP4 deficient rats. AB - Glucagon-like peptide-1 (GLP-1) is rapidly cleaved by widely expressed dipeptidyl peptidase-4 (DPP4) enzyme. Both DPP4 inhibitors and GLP-1 analogue are being developed as a novel class of oral antihyperglycemic agent in the treatment of diabetes. However, the benefits of both agents on the cardiovascular function of endotoxemic animals remains poorly understood. In this study, the cardiac function of wild-type and DPP4-deficient rats was evaluated by pressure-volume loops in control and 4 h after lipopolysaccharide (LPS, 10 mg/kg, i.v.) treatment. LPS-induced suppression of cardiovascular function in wild-type rats was associated with a significant reduction in cardiac cAMP level, phosphorylation of phospholamban, and attenuation of aortic contractile response to phenylephrine. DPP4-deficient rats had better preservation of cardiovascular function than wild-type rats during endotoxemia, which was correlated with a more prominent elevation of GLP-1 signaling. These findings coincided with the pretreatment of GLP-1 analogue, exendin-4, where the deterioration of cardiovascular function during endotoxemia was significantly reversed in wild type rats. Furthermore, the benefit of DPP4 deficiency or GLP-1 analogue not only preserved cardiovascular function but also alleviated multiple organ injury and improved survival rate during endotoxemia. In summary, this study demonstrated that the resistance to LPS in DPP4-deficient rats seems to be derived from the higher GLP-1 production, and exendin-4 prevents cardiac dysfunction in wild-type rats with endotoxemia. This study proves that GLP-1 agonists or DPP4 inhibitor may possibly be used as a preventive or even as a novel therapeutic agent in septic shock. PMID- 20852987 TI - NF-kappaB/Rel proteins and the humoral immune responses of Drosophila melanogaster. AB - Nuclear Factor-kappaB (NF-kappaB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for understanding host responses to microbial infections. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-kappaB mediated immune responses. Drosophila combats pathogens through humoral and cellular immune responses. These humoral responses are well characterized and are marked by the robust production of a battery of anti-microbial peptides. Two NF-kappaB signaling pathways, the Toll and the IMD pathways, are responsible for the induction of these antimicrobial peptides. Signal transduction in these pathways is strikingly similar to that in mammalian TLR pathways. In this chapter, we discuss in detail the molecular mechanisms of microbial recognition, signal transduction and NF-kappaB regulation, in both the Toll and the IMD pathways. Similarities and differences relative to their mammalian counterparts are discussed, and recent advances in our understanding of the intricate regulatory networks in these NF-kappaB signaling pathways are also highlighted. PMID- 20852990 TI - The many roles of vision during walking. AB - Vision can improve bipedal upright stability during standing and locomotion. However, during locomotion, vision supports additional behaviors such as gait cycle modulation, navigation, and obstacle avoidance. Here, we investigate how the multiple roles of vision are reflected in the dynamics of trunk control as the neural control problem changes from a fixed to a moving base of support. Subjects were presented with either low- or high-amplitude broadband visual stimuli during standing posture or while walking on a treadmill at 1 km/h and 5 km/h. Frequency response functions between visual scene motion (input) and trunk kinematics (output) revealed little or no change in the gain of trunk orientation in the standing posture and walking conditions. However, a dramatic increase in gain was observed in trunk (hip and shoulder) horizontal displacement from posture to locomotion. Such increases in gain may be interpreted as an increased coupling to visual scene motion. However, we believe that the increased gain reflects a decrease in stability due to a change of the control problem from standing to locomotion. Indeed, keeping the body upright with the use of vision during walking is complicated by the additional locomotor processes at work. Unlike during standing, vision plays many roles during locomotion, providing information for upright stability as well as body position relative to the external environment. PMID- 20852991 TI - Neural control of the lips differs for young and older adults following a perturbation. AB - Aging impairs the control of many skilled movements including speech. The purpose of this paper was to investigate whether young and older adults adapt to lower lip perturbations during speech differently. Twenty men (10 young, 26 +/- 3 years of age; 10 older, 60 +/- 9 years of age) were requested to repeat the word ("papa") 300 times. In 15% of the trials, the subjects experienced a mechanical perturbation on the lower lip. Displacement and neural activation (EMG) of the upper and lower lips were evaluated. Perturbations to the lower lip caused a greater increase in the maximum displacement of the lower lip for older adults compared with young adults (34.7 +/- 19% vs. 13.4 +/- 17%; P=0.017). Furthermore, young adults exhibited significantly greater 30-100 Hz normalized EMG power for the lower lip compared to the upper lip (P<0.005). In young adults, changes from normal to perturbed trials in the 30-50 Hz frequency band of the EMG were negatively correlated to the changes from normal to perturbed trials in the lower lip maximum displacement (R (2) =0.48; P=0.025). It is concluded that young adults adapt better to lower lip perturbations compared with older adults and that the associated neural activation strategy of the involved muscle is different for the two age groups. PMID- 20852993 TI - Degradation of cresols by phenol-acclimated aerobic granules. AB - High-strength cresol isomers were treated with phenol-acclimated granules in batch experiments. The aerobic granules effectively metabolized cresol isomers at concentrations up to 1,500 mg l(-1). The modified Haldane kinetic model, used to assess the kinetic behavior during cresol degradation by granule cells, yielded a high maximum specific growth rate (1.13-1.45 h(-1)) and inhibition constant (617 952 mg l(-1)). The microbial community structure, which was stable under cresol stress, was principally composed of genera Bacillus, Acinetobacter, Corynebacterium, and Nocardioides. Enzyme assay results suggest simultaneous expression of ortho- and meta-cleavage pathways during cresol degradation. Under high cresol concentrations, however, cresol isomers were largely degraded via the meta-cleavage pathway, likely attributable to the activity of Bacillus. The aerobic granular sludge system is a promising biotechnology for degrading wastewater containing high-strength cresols. PMID- 20852992 TI - Cortical neurons combine visual cues about self-movement. AB - Visual cues about self-movement are derived from the patterns of optic flow and the relative motion of discrete objects. We recorded dorsal medial superior temporal (MSTd) cortical neurons in monkeys that held centered visual fixation while viewing optic flow and object motion stimuli simulating the self-movement cues seen during translation on a circular path. Twenty stimulus configurations presented naturalistic combinations of optic flow with superimposed objects that simulated either earth-fixed landmark objects or independently moving animate objects. Landmarks and animate objects yield the same response interactions with optic flow; mainly additive effects, with a substantial number of sub- and super additive responses. Sub- and super-additive interactions reflect each neuron's local and global motion sensitivities: Local motion sensitivity is based on the spatial arrangement of directions created by object motion and the surrounding optic flow. Global motion sensitivity is based on the temporal sequence of self movement headings that define a simulated path through the environment. We conclude that MST neurons' spatio-temporal response properties combine object motion and optic flow cues to represent self-movement in diverse, naturalistic circumstances. PMID- 20852994 TI - Enhanced reductive degradation of methyl orange in a microbial fuel cell through cathode modification with redox mediators. AB - A model azo dye, methyl orange (MO), was reduced through in situ utilization of the electrons derived from the anaerobic conversion of organics in a microbial fuel cell (MFC). The MO reduction process could be described by a pseudo first order kinetic model with a rate constant of 1.29 day(-1). Electrochemical impedance spectroscopic analysis shows that the cathode had a high polarization resistance, which could decrease the reaction rate and limit the electron transfer. To improve the MO reduction efficiency, the cathode was modified with redox mediators to enhance the electron transfer. After modification with thionine, the polarization resistance significantly decreased by over 50%. As a consequence, the MO decolorization rate increased by over 20%, and the power density was enhanced by over three times. Compared with thionine, anthraquinone 2, 6-disulfonate modified cathode has less positive effect on the MFC performance. These results indicate that the electrode modification with thionine is a useful approach to accelerate the electrochemical reactions. This work provides useful information about the key factors limiting the azo dye reduction in the MFC and how to improve such a process. PMID- 20852995 TI - Cloning, purification, and characterization of beta-galactosidase from Bacillus licheniformis DSM 13. AB - The gene encoding homodimeric beta-galactosidase (lacA) from Bacillus licheniformis DSM 13 was cloned and overexpressed in Escherichia coli, and the resulting recombinant enzyme was characterized in detail. The optimum temperature and pH of the enzyme, for both o-nitrophenyl-beta-D: -galactoside (oNPG) and lactose hydrolysis, were 50 degrees C and 6.5, respectively. The recombinant enzyme is stable in the range of pH 5 to 9 at 37 degrees C and over a wide range of temperatures (4-42 degrees C) at pH 6.5 for up to 1 month. The K(m) values of LacA for lactose and oNPG are 169 and 13.7 mM, respectively, and it is strongly inhibited by the hydrolysis products, i.e., glucose and galactose. The monovalent ions Na(+) and K(+) in the concentration range of 1-100 mM as well as the divalent metal cations Mg2(+), Mn2(+), and Ca2(+) at a concentration of 1 mM slightly activate enzyme activity. This enzyme can be beneficial for application in lactose hydrolysis especially at elevated temperatures due to its pronounced temperature stability; however, the transgalactosylation potential of this enzyme for the production of galacto-oligosaccharides (GOS) from lactose was low, with only 12% GOS (w/w) of total sugars obtained when the initial lactose concentration was 200 g/L. PMID- 20852996 TI - Cloning and characterization of a rhamnose isomerase from Bacillus halodurans. AB - Whole-genome sequence analysis of Bacillus halodurans ATCC BAA-125 revealed an isomerase gene (rhaA) encoding an L-rhamnose isomerase (L-RhI). The identified L RhI gene was cloned from B. halodurans and over-expressed in Escherichia coli. DNA sequence analysis revealed an open reading frame of 1,257 bp capable of encoding a polypeptide of 418 amino acid residues with a molecular mass of 48,178 Da. The molecular mass of the purified enzyme was estimated to be ~48 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and 121 kDa by gel filtration chromatography, suggesting that the enzyme is a homodimer. The enzyme had an optimal pH and temperature of 7 and 70 degrees C, respectively, with a k(cat) of 8,971 min-1 and a k(cat)/K(m) of 17 min-1mM-1 for L-rhamnose. Although L-RhIs have been characterized from several other sources, B. halodurans L-RhI is distinguished from other L-RhIs by its high temperature optimum (70 degrees C) with high thermal stability of showing 100% activity for 10 h at 60 degrees C. The half-life of the enzyme was more than 900 min and ~25 min at 60 degrees C and 70 degrees C, respectively, making B. halodurans L-RhI a good choice for industrial applications. This work describes one of the most thermostable L-RhI characterized thus far. PMID- 20852997 TI - Immune thrombocytopenic pupura-induced reversible posterior leukoencephalopathy successfully treated by rituximab. PMID- 20852998 TI - A case of ITP with cauda equina syndrome. PMID- 20852999 TI - Outpatient treatment with intravenous antimicrobial therapy and oral levofloxacin in patients with febrile neutropenia and hematological malignancies. AB - The purpose of this study was to evaluate outcomes such as success of the initial therapy, failure of outpatient treatment, and death in outpatient treatment during intravenous antimicrobial therapy in patients with febrile neutropenia (FN) and hematological malignancies. In addition, clinical and laboratory data and the Multinational Association for Supportive Care of Cancer index (MASCC) were compared with failure of outpatient treatment and death. In a retrospective study, we evaluated FN following chemotherapy events that were treated initially with cefepime, with or without teicoplanin and replaced by levofloxacin after 48 h of defervescence in patients with good general conditions and ANC>500/mm3. Of the 178 FN episodes occurred in 126 patients, we observed success of the initial therapy in 63.5% of the events, failure of outpatient treatment in 20.8%, and death in 6.2%. The success rate of oral levofloxacin after defervescence was 99% (95 out of 96). Using multivariate analysis, significant risks of failure of outpatient treatment were found to be smoking (odds ratio (OR) 3.14, confidence interval (CI) 1.14-8.66; p=0.027) and serum creatinine levels>1.2 mg/dL (OR 7.97, CI 2.19-28.95; p=0.002). With regard to death, the risk found was oxygen saturation by pulse oximetry<95% (OR 5.8, IC 1.50-22.56; p=0.011). Using the MASCC index, 165 events were classified as low risk and 13 as high risk. Failure of outpatient treatment was reported in seven (53.8%) high-risk and 30 (18.2%) low-risk episodes (p=0.006). In addition, death occurred in seven (4.2%) low-risk and four (30.8%) high-risk events (p=0.004). Ours results show that MASCC index was able to identify patients with high risk. In addition, non-smoking, serum creatinine levels<=1.2 mg/dL, and oxygen saturation by pulse oximetry>=95% were protection factors. PMID- 20853000 TI - Reactivation of a silenced minimal Mutator transposable element system following low-energy nitrogen ion implantation in maize. AB - In maize, Mutator transposable elements are either active or silenced within the genome. In response to environmental stress, silenced Mutator elements could be reactivated, leading to changes in genome structure and gene function. However, there is no direct experimental evidence linking environmental stress and Mutator transposon reactivation. Using a maize line that contains a single inactive MuDR and a lone nonautonomous Mutator element, a Mu1 insertion in the recessive reporter allele a1-mum2 in an inactive Mutator background, we directly assessed Mutator reactivation following low-energy nitrogen ion implantation. We observed that N(+) implantation decreased cytosine methylation in MuDR terminal inverted repeats and increased expression of mudrA and mudrB. Both changes were associated with increased transpositional activity of MuDR through reactivation of the inactive minimal Mutator transposable element system. This study provides direct evidence linking environmental stress agents and Mutator transposon mobilization in maize. In addition, the observed changes to DNA methylation suggest a new mechanism for mutations by low-energy ion implantation. PMID- 20853001 TI - Distribution of cerebral blood flow in the caudate nucleus, lentiform nucleus and thalamus in patients with carotid artery stenosis. AB - OBJECTIVE: To investigate the influence of internal carotid artery (ICA) stenosis on the distribution of blood flow to the caudate nucleus, lentiform nucleus, and thalamus. METHODS: We studied 18 healthy control subjects, 20 patients with a unilateral asymptomatic ICA stenosis, and 15 patients with a recently symptomatic unilateral ICA stenosis. The contribution of the ICAs and the basilar artery to the perfusion of the deep brain structures was assessed by perfusion territory selective arterial spin labeling (ASL) MRI. Differences were tested with a two tailed Fishers' exact test. RESULTS: The caudate nucleus was predominantly supplied with blood by the ipsilateral ICA in all groups. In 4 of the 15 (27%) the symptomatic patients, the caudate nucleus partially received blood from the contralateral ICA, compared to none of the 18 healthy control subjects (p = 0.03). The lentiform nucleus and the thalamus were predominantly supplied with blood by the ipsilateral ICA and basilar artery respectively in all groups. CONCLUSION: In patients with a symptomatic ICA stenosis, the caudate nucleus may be supplied with blood by the contralateral ICA more often than in healthy controls. PMID- 20853002 TI - Intrathecal baclofen therapy: complication avoidance and management. AB - PURPOSE: Intrathecal baclofen (ITB) therapy is an accepted treatment modality for spasticity and dystonia. Several complications related to ITB have been described, including mechanical malfunctions, infections, cerebrospinal fluid fistula, and baclofen withdrawal or overdose. In this study, we present our institutional experience with ITB therapy, emphasizing complication avoidance and lessons learned. METHODS: The charts of 87 patients treated with ITB therapy were retrospectively reviewed. The primary surgical technique, complication type and timing, method of treatment, and outcome were analyzed. RESULTS: Thirteen out of 76 (17.1%) patients primarily treated at our department had 25 complications. The first complication occurred 17.5-30.9 months (mean 24.2+/-6.7) after the pump implantation. Additional four patients with pumps placed elsewhere had six complications and were subsequently treated by our group. The main complications were: catheter fracture (11), subcutaneous fluid collection (5), lumbar wound/CSF infection (3), lumbar catheter or connector protrusion (3), pump malfunction (3), distal catheter migration outside the thecal sac (2), and baclofen withdrawal (1). Of the patients in the NYULMC group, six were treated by a single surgical procedure, six underwent multiple surgical procedures, and one was managed conservatively. In retrospect, changing the surgical technique, or adding an abdominal binder may have prevented 17 complications (54.8%). There were two deaths that were unrelated to the ITB therapy. CONCLUSION: ITB therapy is associated with complications, many of which require additional surgery. Some of these complications are avoidable by adhering to a strict surgical technique and a proper criterion for patient selection. PMID- 20853003 TI - Serial assessment of knee joint moments in posterior cruciate ligament and posterolateral corner reconstructed patients during a turn running task. AB - INTRODUCTION: During post-operative rehabilitation for posterior cruciate ligament (PCL) reconstruction, flexion is limited to 90 degrees for the first 6 weeks, and hamstring strengthening is initiated at 3 months because of static stability. The posterolateral corner sling (PLCS) procedure is frequently performed with PCL reconstruction to help alleviate posterolateral rotator instability, and it is possible, during this procedure, to damage the dynamic motion and to over-constrain the knee. MATERIALS AND METHODS: For the patients group, PCL and PLCS reconstructions were performed simultaneously, and all reconstructed patients had stable knees and showed no complications. A motion analysis system was used to measure and calculate kinematic and kinetic data for seven patients after PCL and PLCS reconstruction (patients group) and seven normal subjects (control group) during a turn running task. The study was conducted on two groups at both 3 months (return to daily activity) and 6 months (return to light sports) post-operation. At 6 months after surgery, the dial test was also performed to observe the static rotational stability. RESULTS: Compared to the control group, the patients group showed a decreased extension moment ( 1.15 +/- 0.46 vs. -3.51 +/- 0.69 Nm/kg, p = 0.000), a decreased valgus moment ( 1.36 +/- 0.72 vs. -2.15 +/- 0.54 Nm/kg, p = 0.041) and a decreased external rotational moment (-0.15 +/- 0.11 vs. -0.37 +/- 0.10 Nm/kg, p = 0.002) 3 months post-operatively. However, these results approximated to the normal control, and the patients group showed an improved extension moment (-2.95 +/- 0.67 Nm/kg, p = 0.188), valgus moment (-1.73 +/- 0.58 Nm/kg, p = 0.359) and external rotational moment (-0.30 +/- 0.09 Nm/kg, p = 0.325) at 6 months post-operatively. A static rotational stability revealed a similar or over-constrained state compared with the contralateral knee, and no patient showed rotational instability. CONCLUSIONS: PCL-PLCS reconstructed patients were reluctant to engage in, or lacked strength for, daily rotational activities. Therefore, we must consider more active and systematic co-contraction exercise of the hamstring and quadriceps and rehabilitation program about rotation that is not adverse to the static stability in PCL-PLCS reconstructed patients for early return to daily activities. PMID- 20853004 TI - Comparison of optical low-coherence reflectometry and applanation ultrasound biometry on intraocular lens power calculation. AB - BACKGROUND: The aim of the study was to determine whether the innovative non contact optical low-coherence reflectometry method utilized by the Lenstar LS 900(r) agrees sufficiently with applanation ultrasound A-scan technique in routine biometric measurement and intraocular lens power calculation to replace it. METHODS: Twenty-two patients hospitalized at our eye clinic undergoing cataract surgery were assigned to have five consecutive measurements of axial length by two examiners in a single session using applanation ultrasound and the Lenstar. The applanation ultrasound intraocular lens power calculation was based on automated keratometry and applanation ultrasound axial length measurements. The Lenstar intraocular lens power calculation was based on its measurement of keratometry and axial length. Bland-Altman analysis was used to assess interobserver repeatability of applanation ultrasound and the Lenstar as well as agreement between the Lenstar and applanation ultrasound for axial length measurement and intraocular lens power calculation. RESULTS: Thirty-two eyes of 22 patients were analyzed. In 95% of the observations, predicted refractive error corresponded to -0.26 +/- 0.62 D and 0.01 +/- 0.20 D obtained with applanation ultrasound and the Lenstar, respectively. CONCLUSIONS: Based on excellent repeatability of the Lenstar and acceptable repeatability of applanation ultrasound, two techniques may be used interchangeably. The predicted refractive error of +/- 0.20 D in 95% of the observations has never been achieved. Optical low-coherence reflectometry might become a new standard method for biometric measurement needed for intraocular lens-power calculation in patients with cataract. PMID- 20853005 TI - Incidence of endophthalmitis after 20-gauge vs 23-gauge vs 25-gauge pars plana vitrectomy. AB - PURPOSE: To compare endophthalmitis rates after 20-gauge versus 23-gauge versus 25-gauge pars plana vitrectomy (PPV) in 2007-2008, and compare the rates with those of 2005-2006. METHODS: Multicenter study including all patients who developed endophthalmitis following PPV performed by any of the authors during 2005-2008, and all patients who developed endophthalmitis following PPV at Penn State College of Medicine and Bascom Palmer Eye Institute during 2005-2008. The endophthalmitis rates after 20-gauge, 23-gauge and 25-gauge PPV during 2007-2008 were compared to those from 2005-2006. RESULTS: The endophthalmitis incidence during 2007-2008 was 1/4,403 (0.02%) for 20-gauge PPV, 1/3,362 (0.03%) for 23 gauge PPV, and 1/789 (0.13%) for 25-gauge PPV. There is no significant difference among these rates between any two of the three groups. Compared with the endophthalmitis rates among the same group of surgeons during 2005-2006, the 2007 2008 endophthalmitis rates following 20-gauge and 23-gauge PPV were stable, and the rate following 25-gauge PPV was marginally lower (p = 0.056; odds ratio = 0.15; 95% CI: (0.003, 1.03)). CONCLUSIONS: There was no significant difference in the 2007-2008 rates of endophthalmitis following 20-gauge versus 23-gauge versus 25-gauge PPV; among the same group of surgeons, the 2007-2008 rate of endophthalmitis following 25-gauge PPV was marginally lower than the 2005-2006 rate. PMID- 20853006 TI - Thermomechanical stability of sclera after glyceraldehyde crosslinking. AB - PURPOSE: Recently, glyceraldehyde-induced crosslinking was proposed by us for the treatment of progressive myopia, increasing significantly the biomechanical rigidity of sclera. The aim of the present study was to investigate the changes in thermo-mechanical stability after scleral glyceraldehyde crosslinking, allowing a better evaluation of the efficacy of crosslinking. METHODS: One hundred and twenty six porcine eyes were retrieved from the local abattoir. Using hot saline solution, the threshold shrinkage temperature (Ts) was determined for both equatorial scleral strips and whole eye globes incubated with glyceraldehyde for 4 days. Untreated control samples and specimens crosslinked with formaldehyde for 4 days were tested for comparison. In the globes, a small 6 mm limbus parallel scleral strip was excised 5 mm behind the limbus to allow extrusion of the vitreous, facilitating heat-induced globe contraction. After heat exposure, the eyes were examined histologically by light microscopy. RESULTS: There was significant Maillard browning of the sclera after incubation with glyceraldehyde. The contraction temperature determined in the glyceraldehyde group was 78 degrees C for both scleral strips and globes, in the formaldehyde group 88 degrees C for scleral strips and 92 degrees C for globes, and in non-crosslinked controls 62 degrees C for scleral strips and 68 degrees C for globes. Interestingly, the eye balls contracted in an implosion-like manner, leading to an abrupt reduction in eye volume by about one third. On light microscopy, scleral thickening, heat denaturation of collagen fibers, and loss of birefringence were noted. CONCLUSIONS: Scleral collagen crosslinking by glyceraldehyde proved very efficient in increasing the scleral thermomechanical stability by at least 10 degrees C in Ts, stabilizing the eye shape and preventing the shrinkage of the eye in all dimensions. There is hope that, in a similar manner, glyceraldehyde crosslinking can stabilize the scleral collagen crosslinks and eye shape in myopia, stopping progression of scleral thinning and stretching. PMID- 20853007 TI - The effect of vitamin A on renal damage following acute pyelonephritis in children. AB - Animal studies suggest that administration of vitamin A to rats with experimental urinary tract infection decreases the frequency of renal scars (Kavukcu et al., BJU Int 83(9):1055-1059, 1999). The aim of this study was to determine the effect of vitamin A on the rate of permanent renal damage in children with acute pyelonephritis. Fifty children, median age of 24 months (range 2-144), with first time pyelonephritis verified by an uptake defect on acute dimercaptosuccinic acid (DMSA) scan were included in the study and randomly allocated to the case or control groups. All were given intravenous ceftriaxone for 10 days followed by oral cephalexin for 3 months. Cases in addition were given a single intramuscular dose of vitamin A, 25,000 U for infants below 1 year of age and 50,000 U for older children. At the repeat DMSA scan after 3 months, five of 25 cases (20%) and 17 of 25 controls (68%) had abnormal findings (p = 0.001). In conclusion, administration of vitamin A was associated with a significantly lower rate of permanent renal damage. PMID- 20853008 TI - Survey of sleeping position recommendations for prematurely born infants. AB - The risk of sudden infant death syndrome is increased in prematurely born infants compared to those born at term, particularly if they are either slept prone or on their side. The aim of this study was to determine whether a national campaign "Time to get back to sleep" had influenced the recommendations made by neonatal practitioners regarding the sleeping position for prematurely born babies prior to and after neonatal unit discharge. A questionnaire survey was sent to all UK neonatal units, of which 90% responded. The results were compared to those of a survey carried out prior to the national campaign. Analysis of the responses demonstrated that there was no significant difference in the proportion of units which recommended supine sleeping at least 1-2 weeks before discharge (78% versus 83%). Still, a minority of units provided written information for staff (26% versus 33%), but a greater proportion of units provided written information for parents (95% versus 90%, p = 0.047). All units recommended supine sleeping following discharge, and compared to the results of the previous survey, a smaller proportion of units additionally recommended side sleeping after discharge (8% versus 17%, p =0.01) and a greater proportion actively discouraged prone sleeping (62% versus 38%, p < 0.0001). CONCLUSIONS: The majority but, importantly, not all neonatal units are giving appropriate recommendations regarding sleeping position following neonatal unit discharge. These results highlight that further education of neonatal staff regarding appropriate sleeping position for prematurely born babies remains imperative. PMID- 20853009 TI - Development of an efficient gene targeting system in Colletotrichum higginsianum using a non-homologous end-joining mutant and Agrobacterium tumefaciens-mediated gene transfer. AB - The hemibiotrophic ascomycete Colletotrichum higginsianum is the casual agent of anthracnose disease of cruciferous plants. High efficiency transformation by Agrobacterium tumefaciens-mediated gene transfer has been established for this fungus. However, targeted gene mutagenesis through homologous recombination rarely occurs in C. higginsianum. We have identified and disrupted the C. higginsianum homologue of the human Ku70 gene, ChKU70, which encodes a protein that plays a role in non-homologous end-joining for repair of DNA breaks. chku70 mutants showed a dramatic increase in the frequency of integration of introduced exogenous DNA fragments by homologous recombination without any detectable phenotypic defects. This result demonstrates that the chku70 mutant is an efficient recipient for targeted gene mutagenesis in C. higginsianum. We have also developed a novel approach [named direct repeat recombination-mediated gene targeting (DRGT)] for targeted gene disruption through Agrobacterium tumefaciens mediated gene transfer. DRGT utilizes homologous recombination between repeated sequences on the T-DNA flanking a partial fragment of the target gene. Our results suggest that DRGT in the chku70 mutant background could be a useful tool for rapid isolation of targeted gene disruptants in C. higginsianum. PMID- 20853010 TI - Clinical impact of endoscopic papillectomy for benign-malignant borderline lesions of the major duodenal papilla. AB - BACKGROUND AND PURPOSE: The present study retrospectively analyzed the clinical impact of endoscopic papillectomy on the selection of a treatment strategy for patients with benign-malignant borderline lesions of the major duodenal papilla. PATIENTS AND METHODS: Between November 1995 and July 2009, 28 patients were selected for endoscopic papillectomy. The clinical impact of endoscopic papillectomy was assessed. Snare resection was performed in a radical fashion. RESULTS: An endoscopic papillectomy was technically feasible in all patients. En bloc excision was achieved in 22 cases (79%). The final histopathological diagnoses of the endoscopic specimen were 17 adenoma (61%), 7 carcinoma in adenoma (25%), and 4 adenocarcinoma (14%). Two out of the four adenocarcinoma cases were referred for surgery. The other two patients with negative margins have not experienced recurrences during the follow-up period. A residual tumor was detected in 1 out of 17 cases (6%) of adenoma and 2 out of 7 cases (29%) of carcinoma in adenoma. CONCLUSIONS: Endoscopic papillectomy is therefore considered to be an effective treatment for patients with a benign-malignant borderline lesion of the major duodenal papilla. This method also has an important clinical impact because it provides an accurate diagnosis, aids in the selection of an appropriate treatment strategy, and reduces unnecessary surgery. PMID- 20853011 TI - Do symplasmic networks in cambial zones correspond with secondary growth patterns? AB - The plasmodesmal (PD) network in the cambial zone of Arabidopsis thaliana hypocotyls was analysed using electron microscopy and dye-coupling studies and compared to those of internodes of Populus nigra and Solanum lycopersicum. In all species, PD densities and frequencies undergo alterations in topologically successive cambial walls reflecting species-specific patterns of PD degradation and PD insertion during cell development. Longitudinal PD fission is responsible for an abrupt increment of PD numbers in specific walls of the youngest derivatives at the xylem and/or phloem side. Here, PDs seem to mediate positional signalling to control tissue fate and early cell determination. PD numbers at all cambial interfaces of A. thaliana correspond to those of the herbaceous tomato, but are higher with the woody poplar. This suggests a positive correlation between PD frequencies and the rapidity of cell division activity. Photoactivated green fluorescent protein (26 kDa) did not diffuse through cambial PDs of A. thaliana. This is in keeping with the common size exclusion limit (SEL) of 8-10 kDa observed for PDs at the youngest interfaces of tomato and poplar which may mediate diffusive exchange of developmental signals of equal molecular size. The regular growth patterns in internodal cambial zones of poplar and tomato result from synchronized cell division activity of neighbouring initials. A. thaliana hypocotyls have an irregular mode of secondary growth. Here, signalling through PDs in misaligned radial walls between non-homologous derivatives may control tissue development. The observed organizational differences between the cambia cast doubts on the suitability of A. thaliana as a model plant for cambial research. PMID- 20853012 TI - Expression analysis of sugarcane shaggy-like kinase (SuSK) gene identified through cDNA subtractive hybridization in sugarcane (Saccharum officinarum L.). AB - Identification of genes whose expression enables plants to adapt to any kind of stresses is integral to developing stress tolerance in crop plants. In this study, PCR-based cDNA suppression subtractive hybridization technique was used to construct sugarcane salt (NaCl) stress specific forward and reverse subtracted cDNA library. For this, mRNAs were pooled from the shoot and root tissues stressed with NaCl (200 mM) for various time intervals (0.5 to 18 h). Sequencing the clones from the forward subtracted cDNA library, we identified shaggy-like protein kinase (hereafter referred as sugarcane shaggy-like protein kinase, SuSK; NCBI GenBank EST database Acc: FG804674). The sequence analysis of the SuSK revealed homology to Arabidopsis thaliana shaggy-related protein kinase delta (E value, 1e(-108)), dzeta and iota. Alignment of the catalytic domain sequence of GSK-3/shaggy-like kinase with partial sequence of SuSK performed using ClustalW tool indicated kinase active-site signature sequence. Spatial and temporal transcript expression profiling of the SuSK gene based on Real-Time PCR revealed significant induction of transcript expression in response to short-term salt (NaCl 200 mM) or polyethylene glycol-8,000 (PEG; 20% w/v) induced osmotic stress in leaves and shoots of sugarcane plants. The transcript expression increased progressively under salt stress and reached to 1.5-fold of the control up to 8 h treatment. In response to PEG stress, the transcript expression increased by 1.5 fold over the control in 2-h treatment in leaf, whereas in shoots, the expression remained unchanged in response to the various treatments. Differences in growth parameters, relative water content, and membrane damage rate were statistically insignificant in the short-term salt or PEG-stressed plants as compared to the control, non-stressed plants. Expression analysis revealed the differential and temporal regulation of this gene under salt and PEG stress and that its early induction may indicate involvement in stress signaling. PMID- 20853014 TI - Swabbing for respiratory viral infections in older patients: a comparison of rayon and nylon flocked swabs. AB - The purpose of this study was to compare the sampling efficacy of rayon swabs and nylon flocked swabs, and of oropharyngeal and nasopharyngeal specimens for the detection of respiratory viruses in elderly patients. Samples were obtained from patients 60 years of age or above who were newly admitted to Sorlandet Hospital Arendal, Norway. The patients were interviewed for current symptoms of a respiratory tract infection. Using rayon swabs and nylon flocked swabs, comparable sets of mucosal samples were harvested from the nasopharynx and the oropharynx. The samples were analysed using real-time polymerase chain reaction (PCR) methods. A total of 223 patients (mean age 74.9 years, standard deviation [SD] 9.0 years) were swabbed and a virus was recovered from 11% of the symptomatic patients. Regardless of the sampling site, a calculated 4.8 times higher viral load (95% confidence interval [CI] 1.3-17, p = 0.017) was obtained using the nylon flocked swabs as compared to the rayon swabs. Also, regardless of the type of swab, a calculated 19 times higher viral load was found in the samples from the nasopharynx as compared to the oropharynx (95% CI 5.4-67.4, p < 0.001). When swabbing for respiratory viruses in elderly patients, nasopharyngeal rather than oropharyngeal samples should be obtained. Nylon flocked swabs appear to be more efficient than rayon swabs. PMID- 20853015 TI - Differences between methicillin-resistant Staphylococcus aureus bacteremic isolates harboring type IV and type V staphylococcal cassette chromosome mec genes based on prior patient healthcare exposure. AB - This observational study enrolled adult patients with bacteremia due to methicillin-resistant Staphylococcus aureus (MRSA) who were treated at the emergency department of a teaching hospital from 2001 to 2007. MRSA isolates with type IV and type V staphylococcal cassette chromosome mec (SCCmec) genes (SCC IV/V-MRSA) were included in the final analysis. Healthcare-associated SCC IV/V MRSA (HA-SCC IV/V-MRSA) and community-acquired SCC IV/V-MRSA (CA-SCC IV/V-MRSA) were defined as the identification of an SCC IV/V-MRSA isolate from a patient with and without healthcare-associated risk factors, respectively. Thirty-four cases of CA-SCC IV/V-MRSA (20 SCCmec type IV, 14 SCCmec type V) and 81 cases of HA-SCC IV/V-MRSA (59 SCCmec type IV, 22 SCCmec type V) bacteremia were identified. Vascular device-associated infections were a significant infection source in HA-SCC IV/V-MRSA bacteremia cases. SCCmec type IV HA-SCC IV/V-MRSA isolates (3.4%) were significantly less likely to carry the Panton-Valentine leukocidin (PVL) gene than SCCmec type IV CA-SCC IV/V-MRSA isolates (35.0%, p = 0.001). The 90-day cumulative probability of survival was 76% for patients with CA-SCC IV/V-MRSA bacteremia and 66% for patients with HA-SCC IV/V-MRSA bacteremia (p = 0.247, by the Wilcoxon rank-sum test). Significant differences in antimicrobial susceptibility were observed between bacterial isolates from patients with CA-SCC IV/V-MRSA bacteremia and HA-SCC IV/V-MRSA bacteremia. PMID- 20853016 TI - Quantification and significance of fluid shear stress field in biaxial cell stretching device. AB - A widely used commercially available system for the investigation of mechanosensitivity applies a biaxial strain field to cells cultured on a compliant silicone substrate membrane stretched over a central post. As well as intended substrate strain, this device also provides a fluid flow environment for the cultured cells. In order to interpret the relevance of experiments using this device to the in vivo and clinical situation, it is essential to characterise both substrate and fluid environments. While previous work has detailed the substrate strain, the fluid shear stresses, to which bone cells are known to be sensitive, are unknown. Therefore, a fluid structure interaction computational fluid dynamics model was constructed, incorporating a finite element technique capable of capturing the contact between the post and the silicone substrate membrane, to the underside of which the pump control pressure was applied. Flow verification experiments using 10-MUm-diameter fluorescent microspheres were carried out. Fluid shear stress increased approximately linearly with radius along the on-post substrate membrane, with peak values located close to the post edge. Changes in stimulation frequency and culture medium viscosity effected proportional changes in the magnitude of the fluid shear stress (peak fluid shear stresses varied in the range 0.09-3.5 Pa), with minor effects on temporal and spatial distribution. Good agreement was obtained between predicted and measured radial flow patterns. These results suggest a reinterpretation of previous data obtained using this device to include the potential for a strong role of fluid shear stress in mechanosensitivity. PMID- 20853017 TI - Understanding the role of tumor stem cells in glioblastoma multiforme: a review article. AB - It has been hypothesized that cancer stem cells (CSC) may account for the pathogenesis underlying various tumors, including GBM. Markers of these CSCs can be potentially used as therapeutic targets. In this review, we discuss the most recent information regarding CSCs, their molecular biology and their potential role in GBM. PMID- 20853018 TI - Analysis of transforming growth factor beta receptor expression and signaling in higher grade meningiomas. AB - TGF-beta receptors (TGF-betaRs) inhibit growth of many cell types. Loss of TGF betaRs or its signaling components have been found in several human malignancies. The expression and the role of TGF-betaRs in regulating anaplastic meningioma growth has not been studied. Real time PCR found TGF-beta RIII expression significantly lower in five grade III compared to eight grade I and eight grade II tumors (P = 0.0481). By western blot analysis, TGF-betaRI was detected in the four fetal and adult leptomeninges, all 18 grade I, 14 grade II and six grade III meningiomas. TGF-betaRII was detected in none of the leptomeninges, 55% of grade I, 71% of grade II and weak to negative in five of six the grade III meningiomas analyzed. TGF-betaRIII immunoreactivity was not detected in the fetal meninges but was detected in 94% of grade I, 70% of grade II and 67% grade III tumors. Phospho-SMAD 3 and Smad 7 were detected in nearly all tumors. TGF-beta1 had no effect on PDGF-BB stimulation of DNA synthesis in six of seven WHO grade II and the grade III cells. It produced an increase in phosphorylation of SMAD 3 and p38MAPK in two of four and p44/42MAPK in three of four grade II cells showing no change in DNA synthesis after treatment. Thus, only attenuated TGF-betaRIII expression and TGFB growth inhibition may occur in select higher grade meningiomas. Nonetheless, restoring TGF-beta inhibition of meningioma cell proliferation may be an important objective in the design of new chemotherapies for these tumors. PMID- 20853019 TI - FACT-MNG: tumor site specific web-based outcome instrument for meningioma patients. AB - To formulate Functional Assessment of Cancer Therapy-Meningioma (FACT-MNG), a web based tumor site-specific outcome instrument for assessing intracranial meningioma patients following surgical resection or stereotactic radiosurgery. We surveyed the relevant literature available on intracranial meningioma surgery and subsequent outcomes (38 papers), making note of which, if any, QOL/outcome instruments were utilized. None of the surgveyed papers included QOL assessment specific to tumor site. We subsequently developed questions that were relevant to the signs and symptoms that characterize each of 11 intracranial meningioma sites, and incorporated them into a modified combination of the Functional Assessment of Cancer Therapy-Brain (FACT-BR) and SF36 outcome instruments, thereby creating a new tumor site-specific outcome instrument, FACT-MNG. With outcomes analysis of surgical and radiosurgical treatments becoming more important, measures of the adequacy and success of treatment are needed. FACT-MNG represents a first effort to formalize such an instrument for meningioma patients. Questions specific to tumor site will allow surgeons to better assess specific quality of life issues not addressed in the past by more general questionnaires. PMID- 20853020 TI - Chronic kidney diseases of uncertain etiology (CKDue) in Sri Lanka: geographic distribution and environmental implications. AB - The increase in the number of chronic kidney disease (CKD) patients from the north central region of Sri Lanka has become a environmental health issue of national concern. Unlike in other countries where long-standing diabetes and hypertension are the leading causes of renal diseases, the majority of CKD patients from this part of Sri Lanka do not show any identifiable cause. As the disease is restricted to a remarkably specific geographical terrain, particularly in the north central dry zone of the country, multidisciplinary in-depth research studies are required to identify possible etiologies and risk factors. During this study, population screening in the prevalent region and outside the region, analysis of geoenvironmental and biochemical samples were carried out. Population screening that was carried out using a multistage sampling technique indicated that the point prevalence of CKD with uncertain etiology is about 2-3% among those above 18 years of age. Drinking water collected from high-prevalent and non endemic regions was analyzed for their trace and ultratrace element contents, including the nephrotoxic heavy metals Cd and U using ICP-MS. The results indicate that the affected regions contain moderate to high levels of fluoride. The Cd contents in drinking water, rice from affected regions and urine from symptomatic and non-symptomatic patients were much lower indicating that Cd is not a contributing factor for CKD with uncertain etiology in Sri Lanka. Although no single geochemical parameter could be clearly and directly related to the CKD etiology on the basis of the elements determined during this study, it is very likely that the unique hydrogeochemistry of the drinking water is closely associated with the incidence of the disease. PMID- 20853021 TI - Dexamethasone-induced FKBP51 expression in peripheral blood mononuclear cells could play a role in predicting the response of asthmatics to treatment with corticosteroids. AB - BACKGROUND: Corticosteroids (CSs) are the preferred anti-inflammatory therapy for the treatment of asthma, but the responses of asthmatics to CSs are known to vary. It has thus become important to discover reliable markers in predicting responses to CSs. METHODS: We performed time-series microarrays using a murine model of asthma after a single dose of dexamethasone, based on the assumption that the gene showing a greater change in response to CSs can also be a potential marker for that finding. We then evaluated the clinical meaning of the gene discovered in the microarray experiments. RESULTS: We found that the expression of FK506 binding protein 51 gene (FKBP51) in lung tissue markedly increased after dexamethasone treatment in a murine model of asthma. We then measured dexamethasone-induced FKBP51 expression in peripheral blood mononuclear cells (PBMCs) in asthmatics. Dexamethasone-induced FKBP51 expression in PBMCs was significantly higher in severe asthmatics compared with mild-to-moderate asthmatics treated with inhaled CSs. In addition, we found that dexamethasone induced FKBP51 expression in PBMCs was inversely correlated with improvement in lung function after treatment with orally administered prednisolone in six steroid-naive asthmatics. CONCLUSION: Dexamethasone-induced FKBP51 expression in PBMCs may be a reliable and practical biomarker in predicting the response to CSs in asthmatics. PMID- 20853023 TI - Demonstration and evaluation of a peer-delivered, individually-tailored, HIV prevention intervention for HIV-infected MSM in their primary care setting. AB - Employing HIV-infected peer counselors in secondary prevention interventions for MSM is appealing for scalable interventions. One-hundred-seventy-six HIV-infected MSM at their primary care facility participated in a secondary HIV-prevention study delivered by HIV-infected MSM peers. Of those who entered the intervention and completed the initial intake, 62% completed all four of the intervention sessions, and 93% completed at least one. While there was no overall change in transmission risk behavior (TRB) for the whole sample, among those who reported HIV TRB at baseline (n = 29), there were significant reductions in TRB over the next year. Themes that emerged in qualitative exit interviews conducted with a subset of participants centered on peer counselor quality, intervention implications, and intervention experience. This demonstration project provides initial evidence for the ability to recruit HIV-infected MSM in care into a peer based intervention study, and shows how a peer-based intervention can be delivered in the context of HIV care. PMID- 20853022 TI - Differential olfactory identification in children with autism and Asperger's disorder: a comparative and longitudinal study. AB - Key theories of autism implicate orbitofrontal cortex (OFC) compromise, while olfactory identification (OI) deficits are associated with OFC dysfunction. This study aimed to complete a 5-year follow-up of children with high-functioning autism (HFA) who previously lacked the normal age-OI association; and compare unirhinal-OI in children with HFA, Asperger's disorder (ASP), and controls. While both HFA and controls had improved birhinal-OI at follow-up, reduced OI in some HFA participants suggested OFC deterioration and heterogeneous OFC development. Unirhinal-OI was impaired in HFA but not ASP relative to controls, suggesting orbitofrontal compromise in HFA but integrity in ASP. Differing IQ-OI relationships existed between HFA and ASP. Findings support the hypothesis of separate neurobiological underpinnings in ASP and HFA, specifically differential orbitofrontal functioning. PMID- 20853024 TI - Isolation, culture, and verification of human sweat gland epithelial cells. AB - Human sweat gland epithelial cells (SGECs) have been isolated and grown in vitro, However, slow proliferation makes the culture of these cells extremely difficult. The present study was carried out to explore the modified culture medium for SGECs in vitro. Full-thickness skin samples were minced (1 mm(3)) and digested overnight with type II collagenase. The gland coils were removed under an inverted phase-contrast microscope. An adherent culture method was used to isolate and culture SGECs. Staining with hematoxylin and eosin was performed, followed by observation of the morphologic features of these cells. Immunofluorescence staining with antibodies to cytokeratins CK7, CK18, and CK19 and carcinoembryonic antigen (CEA) was performed to verify the presence of SGECs. Growth curves by MTT were created for cells grown in serum-free keratinocyte medium and in modified keratinocyte medium containing 2.5% fetal bovine serum (FBS). One week after culturing, the cells grew well and were polygonal or irregular in shape by inverted phase contrast microscopy. Cell fusion, with a characteristic paving-stone arrangement, reached 100% after approximately 3 weeks in culture. Immunofluorescence staining indicated expression of CK7, CK18, CK19, and CEA. Compared with SGECs grown in serum-free keratinocyte medium, the proliferation of SGECs grown in modified culture medium with low concentration of FBS at days 6, 9, and 12 was significantly accelerated (p < 0.05). This study suggests that keratinocyte medium supplemented with 2.5% FBS is effective and suitable for the culture of SGECs. PMID- 20853025 TI - A framework for the automatic generation of surface topologies for abdominal aortic aneurysm models. AB - Patient-specific abdominal aortic aneurysms (AAAs) are characterized by local curvature changes, which we assess using a feature-based approach on topologies representative of the AAA outer wall surface. The application of image segmentation methods yields 3D reconstructed surface polygons that contain low quality elements, unrealistic sharp corners, and surface irregularities. To optimize the quality of the surface topology, an iterative algorithm was developed to perform interpolation of the AAA geometry, topology refinement, and smoothing. Triangular surface topologies are generated based on a Delaunay triangulation algorithm, which is adapted for AAA segmented masks. The boundary of the AAA wall is represented using a signed distance function prior to triangulation. The irregularities on the surface are minimized by an interpolation scheme and the initial coarse triangulation is refined by forcing nodes into equilibrium positions. A surface smoothing algorithm based on a low pass filter is applied to remove sharp corners. The optimal number of iterations needed for polygon refinement and smoothing is determined by imposing a minimum average element quality index with no significant AAA sac volume change. This framework automatically generates high-quality triangular surface topologies that can be used to characterize local curvature changes of the AAA wall. PMID- 20853026 TI - Three-dimensional cardiac tissue image registration for analysis of in vivo electrical mapping. AB - A method is presented for registering 3D cardiac tissue images to reference data, for the purpose of analyzing recorded electrical activity. Following left ventricular in vivo electrical mapping studies in pig hearts, MRI is used to define a reference geometry in the tissue segment around the recording electrodes. The segment is then imaged in 3D using a high-resolution serial imaging microscopy technique. The tissue processing required for this introduces segment-wide distortion. Piecewise-smooth maps are used to correct the tissue distortion and register the 3D images with the reference MRI data. The methods are validated and techniques for identifying the preferred maps are proposed. Recorded electrical activation is shown to map reliably onto cardiac tissue structure using this registration method. PMID- 20853028 TI - Effect of different heat treatments and disinfectants on the survival of Prototheca zopfii. AB - Bovine mastitis caused by the yeast-like alga Prototheca zopfii represents a serious veterinary problem and may result in heavy economic losses to particular dairy farms. The purpose of this study was to evaluate the survival of 50 isolates of P. zopfii in milk subjected to different heat treatments and the survival of further 106 P. zopfii isolates after exposure to three classes of teat disinfectants: iodine (Dipal), quaternary ammonium compounds (Teat), and dodecylbenzenesulphonic acid (Blu-gard). Of the 50 isolates tested for thermal tolerance, 29 (58%) survived heat treatment at 62 degrees C for 30 s and 13 (26% of all isolates) of those survived after heat treatment at 72 degrees C for 15 s. None of the 106 isolates were able to withstand the in-use concentrations of the three disinfectants tested. The highest disinfectant concentrations that permitted survival of at least one isolate were dilutions: 1:1,000 for Dipal (survival rate of 52.8-57.5%), 1:100 for Teat (88.7-90.6%), and 1:10 for Blu-gard (100%). No differences in the survival rates of P. zopfii were observed with respect to the duration of exposure to disinfectant. The results of this study support the previous findings that P. zopfii may resist high-temperature treatments, including that applied in the high-temperature, short-time (HTST) pasteurization process. The obtained data also demonstrate the efficacy of the three classes of teat disinfectants against P. zopfii, with the efficacy of iodine being most pronounced. The study emphasizes the necessity of using higher temperatures in the pasteurization of raw milk to kill the Prototheca algae, as well as the particular suitability of the iodine for the control procedures of protothecal mastitis. PMID- 20853027 TI - Three-dimensional quantitative micromorphology of pre- and post-implanted engineered heart valve tissues. AB - There is a significant gap in our knowledge of engineered heart valve tissue (EHVT) development regarding detailed three-dimensional (3D) tissue formation and remodeling from the point of in vitro culturing to full in vivo function. As a step toward understanding the complexities of EHVT formation and remodeling, a novel serial confocal microscopy technique was employed to obtain 3D microstructural information of pre-implant (PRI) and post-implant for 12 weeks (POI) EHVT fabricated from PGA:PLLA scaffolds and seeded with ovine bone-marrow derived mesenchymal stem cells. Custom scaffold fiber tracking software was developed to quantify scaffold fiber architectural features such as length, tortuosity, and minimum scaffold fiber-fiber separation distance and scaffold fiber orientation was quantified utilizing a 3D fabric tensor. In addition, collagen and cellular density of ovine pulmonary valve leaflet tissue were also analyzed for baseline comparisons. Results indicated that in the unseeded state, scaffold fibers formed a continuous, oriented network. In the PRI state, the scaffold showed some fragmentation with a scaffold volume fraction of 7.79%. In the POI specimen, the scaffold became highly fragmented, forming a randomly distributed short fibrous network (volume fraction of 2.03%) within a contiguous, dense collagenous matrix. Both PGA and PLLA scaffold fibers were observed in the PRI and POI specimens. Collagen density remained similar in both PRI and POI specimens (74.2 and 71.5%, respectively), though the distributions in the transmural direction appeared slightly more homogenous in the POI specimen. Finally, to guide future 2D histological studies for large-scale studies (since acquisition of high-resolution volumetric data is not practical for all specimens), we investigated changes in relevant collagen and scaffold metrics (collagen density and scaffold fiber orientation) with varying section spacing. It was found that a sectioning spacing up to 25 MUm (for scaffold morphology) and 50 MUm (for collagen density) in both PRI and POI tissues did not result in loss of information fidelity, and that sectioning in the circumferential or radial direction provides the greatest preservation of information. This is the first known work to investigate EHVT microstructure over a large volume with high resolution and to investigate time evolving in vivo EHVT morphology. The important scaffold fiber structural changes observed provide morphological information crucial for guiding future structurally based constitutive modeling efforts focused on better understanding EHVT tissue formation and remodeling. PMID- 20853029 TI - Combined therapy against murine-disseminated infection by Fusarium verticillioides. AB - Using a murine model of disseminated infection by two strains of Fusarium verticillioides, we have evaluated the efficacy of high doses of amphotericin B (AMB) (3 mg/kg of body weight/day), voriconazole (VRC) (60 mg/kg of body weight/day), posaconazole (PSC) (100 mg/kg of body weight/day), and the combinations of AMB plus VRC or PSC. In general, our results were very modest. Neither combination was superior to the respective monotherapies. VRC alone and in combination with AMB was able to prolong survival but not to reduce tissue burden, and AMB plus PSC was able to reduce fungal load in organs but not to prolong survival. PMID- 20853030 TI - A Comparison of the LigaSure and harmonic scalpel in thyroid surgery: a single institution review. AB - BACKGROUND: During the last few years, many surgeons have begun to utilize the LigaSure device or Harmonic scalpel to perform thyroid surgery. Several papers have demonstrated the benefits of these devices compared with traditional hand tying techniques. The purpose of this study was to examine our institution's experience with the LigaSure device and Harmonic scalpel during thyroid surgery and to compare mean operative times and complications associated with each device. METHODS: A retrospective chart review was performed on all patients who underwent thyroid surgery using the LigaSure device or Harmonic scalpel at a single institution between December 2005 and August 2009. Charts were reviewed for patient demographics, mean operative time, length of stay, and complications, such as transient recurrent laryngeal nerve injury, hypocalcemia, and hematoma formation. RESULTS: A total of 231 patients were included in the study, of whom 123 underwent total thyroidectomy and 108 underwent lobectomy. There was a significant decrease in the operative time for both thyroidectomies and lobectomies when the Harmonic scalpel was utilized. In regard to complications, there was no statistically significant difference in the number of transient and permanent recurrent laryngeal nerve injuries, percentage of patients developing hypocalcemia, or rate of hematoma development. CONCLUSION: In this study, there was no difference in the rate of complications between the two devices. However, the use of the Harmonic scalpel significantly decreased operative time for both thyroidectomies and thyroid lobectomies compared with the LigaSure device. PMID- 20853031 TI - Operative salvage for retroperitoneal nodal recurrence in colorectal cancer: a systematic review. AB - BACKGROUND: Retroperitoneal nodal recurrence after curative resection of colorectal cancer is an uncommon and challenging problem. The evidence for salvage surgery is limited and remains controversial, particularly when major vascular structures are involved. Some reports have demonstrated a survival benefit after metachronous resection of retroperitoneal metastasis with and without concomitant aortic resection. We conducted a systematic review of the literature to find evidence in favor of or against salvage surgery. METHODS: Electronic searches of the MEDLINE, Cochrane, and EMBASE database were performed. Additional papers were identified by a manual search of the references from the key articles. Only peer-reviewed articles published in the English language were evaluated. RESULTS: A total of nine suitable studies were identified: three case reports and six larger series, of which one was a case-control study. Including our case reports, the total number of patients who underwent surgical resection that are available for review was 110. Median overall survival was between 34 and 44 months and median disease-free survival between 17 and 21 months. Concomitant resection of major vessels with graft replacement was feasible with survival ranging from 19 months to 18 years. There was no reported mortality associated with surgical salvage of retroperitoneal recurrence and the overall morbidity was 17-33%. CONCLUSIONS: The current literature suggests that more aggressive surgical treatment of retroperitoneal nodal recurrence in CRC has acceptable morbidity and may be associated with an improved survival in well-selected patients. PMID- 20853032 TI - ASBrS and ASO: a new partnership begins. PMID- 20853033 TI - Presidential Address: 2010. The American Society of Breast Surgeons. There's no "boring" in breast surgery!! PMID- 20853034 TI - Complication rates of radiation on tissue expander and autologous tissue breast reconstruction. AB - BACKGROUND: To evaluate risk factors for complications of tissue expander/implant and autologous tissue breast reconstructions and determine if radiation increases complication rates. MATERIALS AND METHODS: We performed a retrospective review of patients who underwent mastectomy plus autologous tissue or expander/implant reconstruction at the Cleveland Clinic. Univariate and multivariate analysis were performed in each group to evaluate for risk factors for complications. A complication was considered major if it required reoperation. A predictive model was used to compare the 2 groups to one another. RESULTS: A total of 1037 patients were included in the study. In the tissue expander/implant population, there was a total complication rate of 31.8% and overall major complication rate of 24.4%. Radiation increased the major complication rate from 21.2 to 45.4%. However, 70.1% of the radiated patients ultimately had a successful implant-based reconstruction while an additional 10.3% went on to have autologous reconstruction. Age and body mass index (BMI) > 30 also led to higher major complication rates in tissue expander/implant reconstruction while smoking, hypertension, and chemotherapy had no impact. In the autologous reconstruction group, there was a total complication rate of 31.5% and a major complication rate of 19.7%. There was no statistically significant difference between the radiated and nonradiated autologous tissue reconstructions with major complication rates of 17.9 and 20.5%, respectively. BMI > 30 was the only significant factor leading to higher major complications in the autologous reconstructions. CONCLUSION: Total complication rates were similar between tissue expander and autologous reconstructions. Increased major complication rates in patients with tissue expander reconstructions occurred in those with radiation, but was still successful in the majority of patients. Radiation had no influence on autologous tissue reconstruction major complication rates. PMID- 20853035 TI - Impact of breast density on the presenting features of malignancy. AB - PURPOSE: To determine the relationship between breast density, presenting features and molecular subtype of cancer, and surgical treatment received. METHODS: Retrospective review of a prospectively maintained database. Eligible patients had stage 1-3 cancer, were treated between 1/2005 and 6/2007, and had estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) measurements and films available for review. Density was classified at presentation as 1-4 using the Breast Imaging Reporting and Data System (BI-RADS) classification. RESULTS: 1,323 patients were included. Significant differences across the four density groups were present in age, race, multicentricity/focality, and presence of an extensive intraductal component (EIC). When density was combined into two groups, after adjustment for age, only an EIC and mammographically occult cancer were significantly more common in the dense groups. Extremely dense breasts (BI-RADS density 4) more commonly had luminal A tumors (p = 0.05), lobular cancers (p = 0.03), multicentricity (p = 0.02), and occult tumors (p < 0.0001). Greater density was associated with increased mastectomy use, with 61% of the extremely dense group having mastectomy versus 43% of those of lesser density (p = 0.01). CONCLUSIONS: Cancers in extremely dense breasts occur in younger women, are more often mammographically occult, and appear to be phenotypically different from those arising in other density groups. The more common use of mastectomy may be related to these features, although density itself is not a selection criterion for mastectomy. PMID- 20853036 TI - Five-year outcome of patients classified in the "unsuitable" category using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Panel guidelines for the application of accelerated partial breast irradiation: an analysis of patients treated on the American Society of Breast Surgeons MammoSite(r) Registry trial. AB - PURPOSE: We applied the ASTRO Consensus Panel (CP) guidelines for the application of accelerated partial breast irradiation (APBI) to patients treated with this technique on the ASBS MammoSite(r) registry trial to determine potential differences in outcome of patients classified in the "unsuitable" category. METHODS: Of 1,449 cases treated with APBI on the registry trial, 176 fit the criteria for the unsuitable category: 130 cases were <50 years of age, 13 had positive margins, 38 had positive nodes, 6 had tumors >3 cm, and 9 had an EIC >3 cm. Rates of ipsilateral breast tumor recurrence (IBTR) and regional nodal failure (RNF) were assessed. Median follow-up was 53.6 months. RESULTS: The 5 year actuarial rate of IBTR for unsuitable cases was 5.25% (RNF rate was 0.63%). By comparison, the 5-year actuarial IBTR rates for various subsets of patients were: all 1,449 cases, 3.89% (p = 0.2365); all 1,449 cases excluding unsuitable cases [n =1,273] (3.6%, p =0.1683); invasive only cases [n = 1,255] (3.86%, p = 0.2464); and invasive only cases excluding unsuitable invasive cases [n =1,105] (3.89%, p = 0.2396). On univariate analysis for variables potentially associated with IBTR in all 1,255 cases with invasive cancer (including age, tumor size, nodal status, overall stage, margin status, ER status, presence of an EIC, and ASTRO unsuitable category), only negative ER (-) status was associated with the 5 year rate of IBTR (p = 0002). No other variable (including unsuitable CP designation) was associated with IBTR. CONCLUSIONS: The ASTRO CP guideline designation of unsuitable did not differentiate a subset of patients with a significantly worse rate of IBTR when treated with the MammoSite(r) breast brachytherapy catheter to deliver APBI. PMID- 20853037 TI - Regional management of breast cancer. Highlights from the 11th Annual Meeting of the American Society of Breast Surgeons, Las Vegas, NV. PMID- 20853038 TI - Controversies in breast surgery. PMID- 20853039 TI - Early results from a novel quality outcomes program: the American Society Of Breast Surgeons' Mastery of Breast Surgery. AB - BACKGROUND: In 2008, the American Society for Breast Surgeons launched its Mastery in Breast Surgery Pilot Program to demonstrate feasibility of a Web-based tool for breast surgeons to document and monitor quality outcomes. METHODS: Participating surgeons report performance of three quality measures for breast procedures: Was a needle biopsy performed to evaluate the breast lesion before the procedure? Was the surgical specimen oriented? For nonpalpable lesions localized with image guidance, was there intraoperative confirmation of removal? Data are collected through the American Society for Breast Surgeons' Web-based software using a secure server and encrypted identification numbers. Surgeon demographic/practice characteristic data were collected, and logistic regression models were used to identify factors that affected quality measures. RESULTS: From October 2008 to December 2009, a total of 696 surgeons entered data for 28,798 breast procedures. Participants were diverse in years in practice, geographic location, practice setting and type, and proportion of practice made up of breast procedures. Delivery of "optimal care" (defined as delivery of all quality measures for which there was no valid clinical reason for nonperformance) was high for all surgeon demographic/practice characteristics, ranging from 81% to 94%. Statistically significant differences in delivery of quality measures were observed within all physician demographic/practice characteristic variables, but many absolute differences were small. CONCLUSIONS: The high level of participation and volume of breast procedures for which quality measure data was entered demonstrate this is a feasible means of collecting quality performance data. Future development will include identifying/developing additional quality measures and establishing evidence-based benchmarks for care on the basis of data collected. PMID- 20853040 TI - How I do it: oncoplastic breast-conservation surgery. PMID- 20853041 TI - Nipple-areolar complex-sparing mastectomy: feasibility, patient selection, and technique. AB - BACKGROUND: We assessed the feasibility, patient selection, and technique of nipple-areolar complex (NAC)-sparing mastectomy. This dynamic article includes a video that demonstrates that sentinel node biopsy or axillary dissection can be performed through the mastectomy incisions or through a separate axillary incision. METHODS: The University of Texas M. D. Anderson Cancer Center initiated a prospective study investigating the feasibility of performing NAC-sparing mastectomy in the setting of prophylaxis and breast cancer treatment. Patients selected were at low risk for skin/NAC necrosis and NAC involvement with tumor. RESULTS: Preliminary results of 54 breasts that underwent NAC-sparing mastectomy showed a NAC necrosis rate of 7.2%. One patient who underwent NAC-sparing prophylactic mastectomy was found to have ductal carcinoma-in-situ that was not present at the nipple base. At a median follow-up of 15 months, there has been no NAC recurrence, which is similar to other reported series of 0% to 2%. Results were comparable with other small prospective series. CONCLUSIONS: NAC-sparing mastectomy can be performed effectively while maintaining NAC viability. The risk of leaving residual breast tissue or occult tumor with the NAC is probably low if margin assessment is performed at the base or central core of the NAC. Long-term follow-up is forthcoming on these procedures. To achieve optimal cosmetic results with oncologic safety, NAC-sparing mastectomy should only be performed in carefully selected patients. PMID- 20853042 TI - Surgeon-read screening mammography: an analysis of 11,948 examinations. AB - INTRODUCTION: Mammography was pioneered by surgeons but is now the domain of radiologists. With ever-increasing cost pressures it must be examined whether interpretation of mammography by clinicians and radiation technologists is comparable to that of breast radiologists. We present the largest series of surgeon-read screening mammography to date. METHODS: All mammography performed between 2003 and 2009 at a comprehensive breast centre was recorded prospectively. First assessment was by a radiation technologist and consensus established after second reading by a breast surgeon, who took responsibility for the reading. Data recorded were: age, hormonal replacement therapy, prior breast surgery, indications for mammography and outcomes. Outcomes were classified based using the Breast Imaging Reporting and Data System (BIRADS). Indeterminate lesions were imaged further or underwent tissue acquisition. All BIRADS 5 lesions underwent tissue acquisition. RESULTS: Of 11,948 mammograms, 538 were reported as indeterminate/compatible with malignancy; 240 biopsies were performed, and 87 cancers diagnosed. In 40-49-year-old women (4,956 mammograms), the recall rate was 4.2%, the biopsy rate was 1.6%, the malignancy rate of biopsy was 23.7% and the cancer diagnosis rate was 3.6/1,000 examinations; for 50-69-year-old women these figures were 6,546, 4.7, 2.2, 44.1% and 10.0/1,000, respectively, and in women older than 70 years, they were 446, 5.6, 3.4, 33.3% and 11.2/1,000, respectively. Of all cancers, 32.2% were non-invasive; of invasive cancers, 49.1% were 10 mm or less in diameter and 75% were node negative. CONCLUSIONS: These results are similar to those in high-quality organized screening programs. The role of breast surgeons in mammography interpretation should be expanded. PMID- 20853043 TI - Use of preoperative magnetic resonance imaging for invasive lobular cancer: good, better, but maybe not the best? AB - BACKGROUND: Invasive lobular cancer (ILC) of the breast is difficult to diagnose clinically and radiologically. It is hoped that preoperative magnetic resonance imaging (MRI) can improve evaluation of extent of disease. METHODS: Patients diagnosed with ILC at a single institution from 2001 to 2008 who underwent clinical breast examination (CBE), mammography, ultrasound, and MRI were studied retrospectively. Concordance between tumor size on imaging/CBE and pathologic size was defined as size within +/- 0.5 cm. Pearson correlation coefficients (R) were calculated for each modality. Local recurrence and re-excision rates were compared with those patients with ILC who did not undergo preoperative MRI. RESULTS: Seventy patients with ILC had all imaging modalities, including CBE, performed preoperatively. The sensitivity for detection of ILC by MRI was 99%. MRI-based tumor size was concordant with pathologic tumor size in 56% of tumors. MRI overestimated tumor size by >0.5 cm in 31% of tumors. Correlation of tumor size on imaging with final pathology was better for MRI (R = 0.75) than for mammography (R = 0.65), CBE (R = 0.63), or ultrasound (R = 0.45, all P < 0.01). Preoperative MRI was associated with lower reoperation rates for close/positive margins (P > 0.05). CONCLUSIONS: For ILC, MRI has better sensitivity of detection and correlation with tumor size at pathology than CBE, mammography, or ultrasound. However, 31% of cases are overestimated by MRI, and correlation remains only at 0.75. The select use of MRI for preoperative estimation of tumor size in ILC is supported by our data, but the need for improvement and refinement of imaging remains. PMID- 20853044 TI - Use of breast MRI surveillance in women at high risk for breast cancer: a single institutional experience. AB - INTRODUCTION: The study aim is to investigate indications for breast magnetic resonance imaging (MRI) screening for high-risk women and to determine outcomes, correlation with routine imaging, and adherence to current guidelines for use. METHODS: We identified 200 patients undergoing 275 breast MRIs for high-risk surveillance from 2005 to 2008. Data collected included patient characteristics, need for additional imaging and/or biopsy, correlation with routine imaging, and outcomes. Gail scores were calculated for patients without hereditary breast cancer syndromes or previous chest radiation. Descriptive statistics were utilized for data summary. RESULTS: Two hundred patients underwent 275 breast MRIs for high-risk surveillance (mean age 45 years, range 18-76 years). Indications included BRCA mutation (n =21), history of chest radiation (n = 10), and perceived high risk (n =169). The mean Gail score for the latter group was 25% (range 10-46%); 32 (16%) patients had Gail score <20%. Of 275 MRIs, 49 (18%) required additional imaging and 21 (8%) prompted biopsy. Of 21 biopsies, 4 were malignant; 2 were also visible on routine imaging performed concurrently with breast MRI. The false-positive rate for breast MRI screening in our cohort of high-risk patients was 23%. CONCLUSION: The rate of cancer detection in high-risk patients undergoing breast MRI at our institution is similar to that of large, multicenter trials. Sixteen percent of patients undergoing breast MRI did not meet high-risk criteria. Because the need for additional imaging and biopsy remains high, further investigation is necessary to determine if this strategy is cost effective. PMID- 20853045 TI - Are percutaneous biopsy rates a reasonable quality measure in breast cancer management? AB - BACKGROUND: Utilization of percutaneous needle biopsy (PNB) has been proposed as a quality measure of breast cancer care. We evaluated rates and reasons for failure of patients undergoing PNB as the initial diagnostic procedure for evaluation of breast pathology. METHODS: We performed a retrospective review of sequential patients undergoing image-guided PNB and open surgical excisional breast biopsies from January 2006 to July 2009 at our institution. Factors associated with failure to undergo a percutaneous approach were analyzed. RESULTS: During the study period, 1196 breast biopsies were performed; 87 (7.3%) were open surgical biopsies, and 1109 (92.7%) were PNB. Imaging used for percutaneous guidance or needle localization was ultrasound in 58.9%, mammogram in 40.0%, and magnetic resonance imaging (MRI) in 0.9%. Open surgical excisional biopsy was associated with mammographic guidance (P < .001), location in the central or lower inner quadrant of the breast (P = .002), BIRADS score of 1 or 6 (P < .001), or calcifications as target (P < .001). There were no differences in rates of PNB by age, size of lesion, or breast density. Reasons for failure of PNB were technical (calcifications not visualized, proximity to implant, etc.) in 86.2% of cases. No reason was documented in 10.3%, and 3.4% of patients refused a percutaneous approach. CONCLUSIONS: The majority of patients in this series underwent PNB as an initial diagnostic approach. Most percutaneous failures are due to technical reasons. PNB rates are a reasonable quality measure in breast cancer care. Documentation of failure to meet this benchmark should be stringently monitored. PMID- 20853046 TI - Impact of preoperative breast MRIs on timing of surgery and type of intervention in newly diagnosed breast cancer patients. AB - BACKGROUND: We sought to evaluate the effect of preoperative breast magnetic resonance imaging (BMRI) on the wait time to surgery and to what extent it affects the surgical management plan initially considered. METHODS: From April 2007 to April 2009, a total of 147 newly diagnosed breast cancer patients who underwent surgery as initial treatment at Marvelle Koffler Breast Centre at Mount Sinai Hospital, Toronto, Ontario, Canada, met the inclusion criteria and were divided into two groups: those who had BMRI (n =71) and those who did not (n = 76). Time to surgery was calculated from the day core biopsy result was available to the date surgery was carried out. Time span between initial surgical consult and the day of the surgery day was also calculated. Change was defined as conversion from conservative to radical surgery and/or unilateral to bilateral procedures. RESULTS: Overall waiting period between histologic diagnosis and treatment was 34.2 days (BMRI group 36.0 days vs. non-BMRI group 32.3 days, P =0.15); and between date surgical management was propose and date of surgery (BMRI group 24.2 days vs. non-BMRI group 22.5 days, P =0.38). Additional workup resulted in seven otherwise occult malignant lesions that required change. Ten percent of patients who underwent BMRI had change in surgical management. The mastectomy rate was higher among those with preoperative BMRI (initial 12% vs. final 26%, P =0.8), but this was not statistically significant. CONCLUSIONS: Preoperative BMRI did not delay surgical treatment or correlate with a higher rate of radical treatment. PMID- 20853047 TI - Does blue dye contribute to success of sentinel node mapping for breast cancer? AB - BACKGROUND: We sought to evaluate the utilization of blue dye in addition to radioisotope and its relative contribution to sentinel lymph node (SLN) mapping at a high-volume institution. METHODS: Using a prospectively maintained database, 3,402 breast cancer patients undergoing SLN mapping between 2002 and 2006 were identified. Trends in utilization of blue dye and results of SLN mapping were assessed through retrospective review. Statistical analysis was performed with Student t test and chi-square analysis. RESULTS: 2,049 (60.2%) patients underwent mapping with dual technique, and 1,353 (39.8%) with radioisotope only. Blue dye use decreased gradually over time (69.8% in 2002 to 48.3% in 2006, p < 0.0001). Blue dye was used significantly more frequently in patients with lower axillary counts, higher body mass index (BMI), African-American race, and higher T stage, and in patients not undergoing skin-sparing mastectomy. There was no difference in SLN identification rates between patients who had dual technique versus radiocolloid alone (both 98.4%). Four (0.8%) of 496 patients who had dual mapping and a positive SLN had a blue but not hot node as the only involved SLN. None of these four had significant counts detected in the axilla intraoperatively. Nine (0.4%) of 2,049 patients who had dual mapping had allergic reactions attributed to blue dye. CONCLUSIONS: Blue dye use has decreased with increasing institutional experience with SLN mapping. In patients with adequate radioactive counts in the axilla, blue dye is unlikely to improve the success of sentinel node mapping. PMID- 20853048 TI - Sentinel lymph node biopsy is precise after primary systemic therapy in stage II III breast cancer patients. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) without axillary lymph node dissection (ALND) in SLN negative patients is a standard of care for most breast cancer patients. SLNB for axillary staging after primary systemic therapy (PST) is still under discussion because of possibly reduced accuracy, while data are lacking. The purpose of this study was to evaluate the accuracy of SLNB after PST. MATERIALS AND METHODS: A total of 185 breast cancer patients were treated with PST; 160 patients received preoperative chemotherapy, and 25 patients received preoperative endocrine therapy. Thus, 143 of 160 patients with preoperative chemotherapy and 22 of 25 patients with preoperative endocrine therapy were eligible for evaluation. The combination of blue dye and radioactive tracer was used for identification of SLNs. All patients received SLNB and axillary lymph node dissection (ALND). Pathologic assessment of SLNs was performed and compared to non-SLN status. RESULTS: Pathologic complete response rates and breast conserving therapy rates were 15.4 and 78.3% in the preoperative chemotherapy group and 0 and 77.3% in the preoperative endocrine therapy group, respectively. Identification rate, sensitivity, overall accuracy, and false negative rate were 81.1% (116 of 143), 91.7% (55 of 60), 95.7% (111 of 116), and 8.3% (5 of 60) in the preoperative chemotherapy group and 77.3% (17 of 22), 90.0% (9 of 10), 94.1% (16 of 17), and 10.0% (1 of 10) in the preoperative endocrine therapy group, respectively. DISCUSSION: SLNB after primary systemic therapy is accurate, and the results are comparable to those of primary SLNB. SLNB after PST could spare ALND in up to 40% of patients with primary positive axillary lymph nodes and should be considered as a standard for axillary staging in those patients. PMID- 20853049 TI - Delays in time to treatment and survival impact in breast cancer. AB - BACKGROUND: Time interval from diagnosis of breast cancer to treatment has been promulgated as one factor that can be used to evaluate cancer care quality. It remains controversial, however, whether a delay to treatment impacts survival. The purpose of this study was to evaluate whether delays from diagnosis to initial treatment in breast cancer impacts survival. MATERIALS AND METHODS: A retrospective review of patients undergoing breast cancer treatment between August 2005 and December 2008 in a comprehensive, multidisciplinary breast oncology program was undertaken. Two hospital systems were included: a county hospital (CH) treating a primarily minority, indigent population and a university hospital (UH) treating a primarily Caucasian, insured population. Interval to treatment, calculated from date of diagnosis to surgery, chemotherapy, or radiation treatment, and overall survival was compared between the two groups. RESULTS: A total of 1337 patients were included; 634 patients were treated in the CH and 703 in the UH. Interval to treatment was longer in the CH compared with the UH (53.4 +/- 2.0 vs 33.2 +/- 1.2 days; mean +/- standard error of the mean [SEM], P < .0001). Patients treated at the CH had overall worse survival (P = .02); however, this difference did not hold true when controlled for stage. Additionally, when time to treatment was analyzed as an individual variable for all patients, there was no impact on survival. CONCLUSIONS: Interval from diagnosis to treatment of breast cancer within the same cancer center was longer at the CH than the UH. There was, however, no effect on overall survival. Time to treatment may not be a meaningful indicator of cancer care quality. PMID- 20853050 TI - Factors associated with variance in compliance with a sentinel lymph node dissection quality measure in early-stage breast cancer. AB - BACKGROUND: Guidelines recommend sentinel lymph node dissection (SLND) for patients with clinical stage I/IIA/IIB breast cancer; however, a significant fraction of patients do not undergo this procedure. We sought to identify factors associated with noncompliance with the SLND benchmark in early-stage breast cancer. MATERIALS AND METHODS: All patients with an initial diagnosis of Stage I/IIA/IIB invasive breast carcinoma who were treated between 2004 and 2007 with records in the California Cancer Registry were evaluated. Odds ratios evaluating receipt of SLND were compared for sex, age, stage, socioeconomic status (SES), race/ethnicity, surgery type, year of diagnosis, and hospital cancer program approval from the American College of Surgery (ACOS). RESULTS: Of 55,207 patients identified, 66% underwent SLND. On multivariable analyses, patients were significantly less likely to undergo SLND if they were >65 years of age, stage IIA or IIB, of lower socioeconomic status, of nonwhite race/ethnicity, treated with total mastectomy, treated during 2004-2005, or at a non-ACOS approved institution. CONCLUSIONS: SLND use in California has increased over time; however, only two-thirds of eligible patients undergo this recommended procedure. Using SLND as a quality measure demonstrates significant disparities that have implications not only for patient and provider education, but also for health care policy and reform. PMID- 20853051 TI - Micrometastatic disease and isolated tumor cells as a predictor for additional breast cancer axillary metastatic burden. AB - BACKGROUND: Our study aims were to investigate breast cancer patients with micrometastases or isolated tumor cells (ITCs) in sentinel lymph nodes (SLNs) to determine the rate of non-SLN metastasis and axillary recurrences, and to compare actual non-SLN metastasis rates with those predicted by the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram. METHODS: We identified 116 stage I to III breast cancer patients who underwent sentinel lymph node biopsy and had micrometastases or ITCs (<2-mm deposits). Patients underwent completion axillary lymph node dissection (ALND) (group 1) or had no further axillary surgery (group 2). P < 0.05 was considered statistically significant. RESULTS: Of 116 patients with micrometastases or ITCs in SLNs, 55 (47%) underwent completion ALND (group 1), and 61 (53%) had no further axillary surgery (group 2). The rate of non-SLN metastases in group 1 patients was 9 (16%) of 55, which was significantly less than that predicted by the MSKCC nomogram (median 30%, P < 0.001). Patient age, race, tumor histology, tumor grade, estrogen receptor/Her-2neu status, and lymphovascular invasion did not differ significantly between group 1 patients with positive non-SLNs and those with negative non-SLNs (P > 0.05 for each), but patients with positive non-SLNs had larger tumors (P < 0.001). No patient in group 1 experienced an axillary recurrence, while only one patient (1.6%) in group 2 experienced axillary recurrence. CONCLUSIONS: The actual rate of positive non-SLNs for breast cancer patients with SLN micrometastases or ITCs who underwent completion ALND was significantly less than that predicted by the MSKCC nomogram. The rate of axillary recurrence is negligible, regardless of the extent of axillary staging. PMID- 20853052 TI - Molecular detection of micrometastatic breast cancer in histopathology-negative axillary lymph nodes fails to predict breast cancer recurrence: a final analysis of a prospective multi-institutional cohort study. AB - BACKGROUND: To address the clinical relevance of molecular detection of occult breast cancer in sentinel lymph nodes and nonsentinel axillary lymph nodes (ALN), we initiated the Minimally Invasive Molecular Staging of Breast Cancer (MIMS) trial, a multi-institutional prospective cohort study. This trial represents the first prospective cohort study in which a multimarker, real-time reverse transcription polymerase chain reaction (RT-PCR) analysis was applied to the detection of breast cancer micrometastases in ALN. MATERIALS AND METHODS: Sentinel and/or nonsentinel ALN from 501 breast cancer subjects with T1-T3 primary tumors were analyzed by standard histopathology and multimarker, real time RT-PCR analysis. Seven breast cancer-associated genes (mam, mamB, PIP, CK19, muc1, PSE, and CEA) known to be overexpressed in metastatic breast cancer compared with control lymph nodes were used. Follow-up data were collected for 5 years. RESULTS: Of the 501 breast cancer subjects enrolled, 348 were node negative and completed the 5-year follow-up. Of these patients (n = 94), 27% demonstrated evidence of molecular overexpression. The 5-year relapse-free survival rate was 95.4% (95% confidence interval [95% CI], 92.4-97.2%). No single gene or combination of study genes was predictive of recurrence. CONCLUSIONS: The genes in this study panel failed to be predictive of clinical relapse. This may be a function of several factors: the low event rate at 5 years, the particular gene set, the methodology used for detection/analysis or that our original hypothesis was wrong and that the presence of positive marker signal by real-time RT-PCR is not associated with a worsened clinical outcome. PMID- 20853053 TI - Scapulothoracic bursitis as a significant cause of breast and chest wall pain: underrecognized and undertreated. AB - OBJECTIVES: Pain is one of the most commonly reported breast complaints. Referred pain from inflammation of the shoulder bursa is often overlooked as a cause of breast pain. The objective of this study is to evaluate the role of shoulder bursitis as a cause of breast/chest pain. METHOD: An IRB-approved retrospective review from July 2005 to September 2009 identified 461 patients presenting with breast/chest pain. Cases identified with a trigger point in the medial aspect of the ipsilateral scapula were treated with a bursitis injection at the point of maximum tenderness. The bursitis injection contains a mixture of local anesthetic and corticosteroid. Presenting complaint, clinical response and associated factors were recorded and treated with descriptive statistics. RESULTS: Average age of the study group was 53.4 +/- 12.7 years, and average BMI was 30.4 +/- 7.4. One hundred and three patients were diagnosed with shoulder bursitis as the cause of breast pain and received the bursitis injection. Most cases (81/103 or 78.6%) presented with the breast/chest as the site of most significant discomfort, where 8.7% (9/103) had the most severe pain at the shoulder, 3.9% (4/103) at the axilla and 3.9% (4/103) at the medial scapular border. Of the treated patients, 83.5% (86/103) had complete relief of the pain, 12.6% (13/103) had improvement of symptoms with some degree of residual pain, and only 3.9%(4/103) did not respond at all to the treatment. The most commonly associated factor to the diagnosis of bursitis was the history of a previous mastectomy, present in 27.2% (28/103) of the cases. CONCLUSIONS: Shoulder bursitis represents a significant cause of breast/chest pain (22.3% or 103/461) and can be successfully treated with a local injection at site of maximum tenderness in the medial scapular border. PMID- 20853054 TI - Breast conservation in women with multifocal-multicentric breast cancer: is it feasible? AB - BACKGROUND: The incidence of preoperatively identified multifocal and multicentric breast cancer is rising with improved sensitivity of imaging modalities. Based on retrospective, historic data, breast conservation in women with multiple tumors has been discouraged because of high rates of local regional recurrence (LRR). These studies, however, do not extrapolate to contemporary practice as they do not incorporate the use of modern therapies and surgical techniques. This study is designed to evaluate the feasibility of breast conservation in women with multiple breast primaries. MATERIALS AND METHODS: We retrospectively reviewed the charts of 22 women who underwent breast conservation surgery for 2 or more synchronous, ipsilateral cancers between 1998 and 2008. We extracted data including tumor size, nodal staging, receptor status, adjuvant therapies administered, and local-regional recurrence. RESULTS: A total of 22 patients were identified. Average follow up is 3.5 years. One patient (4.5%) experienced an in-breast recurrence. Both initial tumors in this patient were invasive ductal carcinoma, ER/PR, negative and HER2 positive. Time to LRR was 2.5 years. CONCLUSIONS: Our data are consistent with those of recent studies in which multifocal/multicentric local regional recurrence in multicentric/multifocal breast is equivalent to that seen in women with unifocal cancer. The single local recurrence in this study occurred in a premenopausal women with ER/PR- disease who were HER2+. Prior retrospective studies have identified ER/PR- and HER2 overexpression as independent risk factors for recurrence following breast conservation. Additional prospective trials are warranted to better assess the oncologic safety of breast conservation in this population. PMID- 20853055 TI - Increase in contralateral prophylactic mastectomy: echoes of a bygone era? Surgical trends for unilateral breast cancer. AB - OBJECTIVES: Surgical therapy for invasive breast cancer includes breast conservation therapy (BCT), unilateral mastectomy (UM), or bilateral mastectomy, including contralateral prophylactic mastectomy (CPM) with or without reconstruction (+/- R). The goal of this study was to determine factors associated with CPM. METHODS: A breast cancer database collected from 2000 through 2008 was retrospectively reviewed. Treatment groups analyzed included BCT, UM +/- R, and CPM +/- R. Variables were compared using ANOVA F-tests and chi square tests. Multivariate analysis was performed using logistic regression. RESULTS: A total of 1,391 patients underwent surgery for invasive breast cancer: 69% BCT, 21% UM, and 10% bilateral mastectomy. Of those undergoing bilateral mastectomy, 30% had bilateral cancer and were excluded from analysis. The rate of CPM increased significantly from 0 to 20% (p < 0.001), whereas the rate of UM remained relatively stable. Factors associated with CPM included younger age, significant family history, genetic testing, positive BRCA gene mutation, and preoperative magnetic resonance imaging (MRI). Tumor characteristics associated with CPM included positive axillary lymph node metastases and triple-negative disease (ER-/PR-/HER2 normal). Breast reconstruction was more common among women who underwent CPM (p < 0.001). On multivariate regression comparing BCT with CPM, younger age, larger tumors, multifocal disease, and MRI significantly predicted CPM. Comparing UM with CPM, only age and genetic testing significantly predicted CPM. CONCLUSIONS: The rate of bilateral mastectomy for unilateral breast cancer is increasing. This is particularly true for younger patients with strong family history. The availability of breast reconstruction may play a role and the effects of stage and multifocal disease needs further exploration. PMID- 20853056 TI - Pure tubular carcinoma and axillary nodal metastases. AB - BACKGROUND: Pure tubular carcinoma of the breast is a rare subtype with a low incidence of axillary lymph node metastases. The aim of this study was to determine the frequency of axillary lymph node metastasis in patients with pure tubular carcinoma. METHODS: We identified patients diagnosed with tubular carcinoma from 1987 to 2009 from our institution's tumor registry. Pathology slides were reviewed, and pure tubular carcinoma was defined as >= 90% tubule formation, low nuclear grade, and rare to no mitoses. Medical records were reviewed for clinicopathologic data including tumor size, number of positive and negative axillary lymph nodes, treatment, and recurrence. RESULTS: We identified 105 cases of pure tubular carcinoma of the breast in 103 patients. Median tumor size was 0.8 (range 0.1-1.8) cm. Nodal staging was performed in 93 cases (89%). Five patients (5.4%) had positive lymph nodes, and two patients (2.2%) had isolated tumor cells. All patients with lymph node metastases had tumors >0.8 cm in size. At 5.2 years' follow-up, no patients have developed recurrence or metastases, or have died from breast cancer. CONCLUSIONS: Axillary lymph node metastases are not common in small pure tubular carcinomas. Nodal staging may be omitted in small pure tubular carcinomas. PMID- 20853058 TI - Single-center long-term follow-up after intraoperative radiotherapy as a boost during breast-conserving surgery using low-kilovoltage x-rays. AB - BACKGROUND: Intraoperative radiotherapy (IORT) during breast-conserving surgery as a boost followed by whole-breast radiotherapy is increasingly used. METHODS: Between February 2002 and December 2008, a total of 197 patients were treated with IORT as a boost (20 Gy, 50 kV x-rays; Intrabeam System, Carl Zeiss Surgical, Oberkochen, Germany) during breast-conserving surgery, followed by whole-breast radiotherapy (46-50 Gy). Systemic therapy was provided according to the St. Gallen consensus. Patients were recalled every 6-12 months for follow-up. Findings were scored according to the LENT-SOMA scale. RESULTS: Median age was 61.8 (range 30-84) years, and median follow-up was 37 (range 5-91) months. There were T1, T2, and Tx tumors in 129, 67, and 1 patients, respectively, and N0, N1, N2, and N3 disease in 144, 36, 15, and 2 patients, respectively. Until December 2009, 5 local invasive relapses, 1 local ductal carcinoma-in-situ, 1 axillary relapse, 6 secondary cancers, and 11 distant metastases were seen, resulting in a 5-year disease-free survival of 81.0% and an overall survival of 91.3%. Local relapse-free survival (invasive cancers) at 3 and 5 years was 97.0%. After a follow-up of 5 years (n =58), only 8 patients (13.8%) had chronic skin toxicities, and 2 patients (3.4%) had a marked increase in density (fibrosis III), while 62.0% had no/barely palpable fibrosis 0-I. Other toxicities observed included severe pain (n = 4, 6.9%), retraction (n =17, 29.3%), edema of the breast (n =1, 1.7%), and lymphedema in general (n =2, 3.4%). CONCLUSIONS: After IORT as a tumor bed boost with low-kilovoltage x-rays followed by whole-breast radiotherapy, low local recurrence and chronic toxicity rates were seen after 5 year follow-up. PMID- 20853057 TI - Trends in and outcomes from sentinel lymph node biopsy (SLNB) alone vs. SLNB with axillary lymph node dissection for node-positive breast cancer patients: experience from the SEER database. AB - BACKGROUND: Complete axillary lymph node dissection (ALND) after a positive sentinel lymph node biopsy (SLNB) remains the standard practice. As nodal surgery has long been considered a staging procedure without a clear survival benefit, the need for ALND in all patients is debatable. The purpose of this study was to examine differences in survival for patients undergoing SLNB alone versus SLNB with complete ALND. METHODS: Patients with breast cancer who underwent SLNB and were found to have nodal metastases were identified from the Surveillance, Epidemiology, and End Results database (1998-2004). Clinicopathologic and outcomes data were examined for patients who underwent SLNB alone versus SLNB with ALND. RESULTS: We identified 26,986 patients with disease-positive lymph nodes; 4,425 (16.4%) underwent SLNB alone, and 22,561 (83.6%) underwent SLNB with ALND. Patients were significantly more likely to undergo SLNB alone if they were older (median 59 years old) or if the tumor was low grade and estrogen receptor positive. From 1998 to 2004, the proportion of patients with micrometastasis in the sentinel lymph nodes who underwent SLNB alone increased from 21.0 to 37.8% (P < 0.001). At a median follow-up of 50 months, there were no statistically significant differences in overall survival (OS) between patients who underwent SLNB alone versus complete ALND. CONCLUSIONS: There is an increasing trend toward omitting ALND in patients with micrometastatic nodal disease identified by SLNB. Compared with SLNB alone, completion ALND does not seem to be associated with improved survival for breast cancer patients with micrometastasis in the sentinel lymph nodes. PMID- 20853059 TI - Health-related quality of life after breast-conserving surgery and intraoperative radiotherapy for breast cancer using low-kilovoltage X-rays. AB - BACKGROUND: Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach during breast-conserving surgery (BCS). IORT can be used either as a tumor bed boost followed by external-beam radiotherapy (EBRT) or as a single treatment. In a matched-pair study, we assessed quality of life (QoL) in 69 patients with early breast cancer treated with BCS and/or IORT and/or EBRT. METHODS: Patients were matched for age and time since BCS. IORT was provided with 50 kV x-rays (Intrabeam) delivering 20 Gy at the applicator surface. EBRT (46 to 50 Gy in 2-Gy fractions in the IORT with EBRT group, and 56 Gy in 2-Gy fractions in the EBRT group) was initiated after completion of wound healing and/or chemotherapy. The mailed questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 and BR23, FACT-F, HADS, Body Image Scale, and Rosenberg Self-Esteem Scale. At 18 to 70 months' follow-up (median 47 months), all patients were disease free. RESULTS: We found only a few differences between the three groups. There was a trend toward more pain (mean +/- standard deviation; 42.8 +/- 32.9 vs. 27.5 +/- 34.7) and reduced QoL (57.6 +/- 20.7 vs. 70.3 +/- 23.9) after IORT with EBRT compared with EBRT, respectively. IORT patients reported comparable QoL (70.3 +/- 23.0), and less breast symptoms and body image concerns compared to EBRT (8.6 +/- 12.3 vs. 19.2 +/- 23.8, and 1.7 +/- 3.3 vs. 3.4 +/- 4.4, respectively). IORT alone resulted in significantly fewer breast symptoms (8.6 +/- 12.3; P = 0.012) and less pain (23.9 +/- 24.5, P = 0.041) compared with IORT with EBRT (26.1 +/- 27.6; 42.8 +/- 32.9, respectively). CONCLUSIONS: Patients with early breast cancer after BCS and IORT with or without EBRT present with comparable QoL like patients receiving EBRT without a boost. IORT patients show the lowest rate of breast symptoms. PMID- 20853060 TI - Long-term follow-up study of a prospective multicenter sentinel node trial: molecular detection of breast cancer sentinel node metastases. AB - BACKGROUND: This prospective multicenter sentinel lymph node (SLN) trial investigated whether molecular analysis would improve the detection of SLN metastases and their prognostic value. We report mammaglobin quantitative real time polymerase chain reaction (qRT-PCR) results and clinical outcome for 547 patients (mean follow-up 7 years). METHODS: Breast cancer patients (excluding stage IV disease or palpable nodes) were enrolled from 1996 to 2005 at 16 institutional review board-approved sites. Alternate 2-mm serial sections of each SLN were examined by hematoxylin and eosin staining with or without immunohistochemistry at multiple levels or blinded and assayed by Taqman qRT-PCR according to previously established thresholds. RESULTS: Mammaglobin remains a highly specific (99%), sensitive (97% primary tumor; 82% N1 SLN) marker for breast cancer. Mammaglobin SLN expression was associated with other prognostic factors, was detected in most patients with distant recurrence (48 of 79; 61%), and was associated with decreased recurrence-free survival (log rank P < 0.0001). Molecular analysis upstaged 13% (52 of 394) node-negative (N0) patients who exhibited a significantly lower distant recurrence-free survival compared to node negative, PCR-negative patients (80 vs. 91%; P < 0.04). N0 patients with PCR positive SLN were 3.4 times more likely to experience relapse than PCR-negative patients (odds ratio 3.4; 95% confidence interval 1.6-7.1; P = 0.001). However, molecular staging failed to predict most of the N0 patient recurrences (25 of 34) and was not a statistically significant independent predictor of distant recurrence. CONCLUSIONS: To our knowledge, these data are the first to prospectively compare PCR detection of SLN metastases with long-term outcome in breast cancer patients. Molecular staging of SLN detected clinically significant disease missed by standard pathology. Further refinement and optimization of molecular staging is indicated to improve clinical utility. PMID- 20853061 TI - Ten-year experience with hematoma-directed ultrasound-guided (HUG) breast lumpectomy. AB - BACKGROUND: Pain, patient inconvenience, vasovagal symptoms, scheduling problems, wire malposition, and a positive margin rate of 40-75% are problems commonly associated with needle localized biopsy (NLBB). Despite these issues, NLBB is still the primary means of identifying nonpalpable lesions in the breast. We hypothesized that the hematoma-directed ultrasound-guided (HUG) procedure for intraoperative localization of nonpalpable lesions would allow for lumpectomy without the downfalls of needle localization and decrease the high positive margin rate with NLBB. METHODS: This is a retrospective study from January 2000 to October 2009. Electronic chart review identified lumpectomy procedures performed in the clinic and operating room. These patients underwent preoperative core-biopsy diagnosis by ultrasound (US) or stereotactic means. When excision was necessary needle localization or HUG was planned. A multifrequency linear array transducer was used intraoperatively for the HUG procedures, and a block of tissue surrounding the hematoma was removed. RESULTS: Localization procedures were performed in 455 patients: 126 (28%) via needle localization and 329 (72%) via HUG. The previous core-biopsy site in 100% of patients was successfully excised using HUG: 152 of 329 (46%) were benign and 177 of 329 (54%) were malignant. Margins were positive in 42 of these 177 cases (24%). was successful in 100% of patients: 88 of 126 (70%) were benign and NLBB 38 of 126 (30%) were malignant; margins were positive in 18 of these 38 (47%). Margin positivity was significantly higher for NLBB than HUG (P = 0.045, Fisher exact). CONCLUSIONS: This 10-year experience, representing the largest to date, suggests that HUG is more accurate in localizing nonpalpable lesions than NLBB. Compared with the additional painful procedure of NLBB, HUG is more time and cost-efficient. Preoperative needle core biopsy is not only the minimally invasive diagnostic procedure of choice, but also becomes the localization procedure when excisional biopsy is necessary. PMID- 20853062 TI - Triple-negative breast cancers: unique clinical presentations and outcomes. AB - BACKGROUND: Triple-negative (TN) breast cancers lack estrogen receptor (ER), progesterone receptor (PR), and HER2/neu amplification (HER2). Few studies have been dedicated to characterizing this subset of cancer. MATERIALS AND METHODS: Retrospective review of a prospectively collected database of patients treated for invasive breast cancer at a single institution. Three tumor marker groups were compared: TN [ER-/PR-/HER2-], HER2+ [ERx/PRx/HER2+], and ER+ [ER+/PRx/HER2 ]. RESULTS: Over 8 years, 123 TN, 210 HER2+, and 728 ER+ patients were identified. On average, TN patients were younger (mean age TN 59.7, HER2+ 62.0, ER+ 64.5 years, P = 0.0001). They were referred for genetic testing more frequently (17% TN, 10% HER2+, 10% ER+, P = 0.055) and were most likely to have a BRCA mutation identified if tested (24% TN, 10% HER2+, 4% ER+, P = 0.019). TN tumors were larger (mean size 2.1 cm TN, 2.0 cm HER2+, 1.8 cm ER+, P = 0.031) and most commonly detected by breast exam (54% TN, 43% HER2+, 42% ER+, P = 0.025). Lymph node involvement was least common with TN tumors (21% TN, 37% HER2+, 32% ER+, P = 0.013), and angiolymphatic invasion was less common for TN than HER2+ (18% TN, 24% HER2+, 15% ER+, P = 0.006). TN patients had significantly higher local or regional recurrence (5.7% TN, 2.9% HER2+, 1.0% ER+, P = 0.001), and the worst 5-year overall survival, although this did not reach statistical significance (85% +/- 6% TN, 94% +/- 2% HER2+, 91% +/- 2% ER+). CONCLUSIONS: TN breast cancers are associated with unique patient presentations, tumor characteristics, and clinical outcomes of which clinicians and investigators should be aware. PMID- 20853063 TI - Phylogenetic relationships of true butterflies (Lepidoptera: Papilionoidea) inferred from COI, 16S rRNA and EF-1alpha sequences. AB - The molecular phylogenetic relationships among true butterfly families (superfamily Papilionoidea) have been a matter of substantial controversy; this debate has led to several competing hypotheses. Two of the most compelling of those hypotheses involve the relationships of (Nymphalidae + Lycaenidae) + (Pieridae + Papilionidae) and (((Nymphalidae + Lycaenidae) + Pieridae) + Papilionidae). In this study, approximately 3,500 nucleotide sequences from cytochrome oxidase subunit I (COI), 16S ribosomal RNA (16S rRNA), and elongation factor-1 alpha (EF-1alpha) were sequenced from 83 species belonging to four true butterfly families, along with those of three outgroup species belonging to three lepidopteran superfamilies. These sequences were subjected to phylogenetic reconstruction via Bayesian Inference (BI), Maximum Likelihood (ML), and Maximum Parsimony (MP) algorithms. The monophyletic Pieridae and monophyletic Papilionidae evidenced good recovery in all analyses, but in some analyses, the monophylies of the Lycaenidae and Nymphalidae were hampered by the inclusion of single species of the lycaenid subfamily Miletinae and the nymphalid subfamily Danainae. Excluding those singletons, all phylogenetic analyses among the four true butterfly families clearly identified the Nymphalidae as the sister to the Lycaenidae and identified this group as a sister to the Pieridae, with the Papilionidae identified as the most basal linage to the true butterfly, thus supporting the hypothesis: (Papilionidae + (Pieridae + (Nymphalidae + Lycaenidae))). PMID- 20853064 TI - Systems-level analysis of gene expression data revealed NR0B2/SHP as potential tumor suppressor in human liver cancer. AB - Nuclear receptors (NRs) play pivotal roles in cell growth, proliferation, differentiation and homeostasis. Recent progress demonstrates that NR is tightly linked to human disease such as cancer, diabetes and obesity. Here we explore NR expression profiles in human tissue using systematic approaches. NR gene profiles reveal that individual NR has its own gene expression signature depending on tissue type. Of many organs, NRs expression is enriched in liver. Expression of many NRs was significantly changed in liver cancer. Notably, NR0B2/SHP expression level was significantly decreased in human liver cancer but not in normal liver. In addition, expression of SHP is well associated with good prognosis. SHP gene network analysis based on microarray data in liver cancer shows that SHP regulates cell proliferation and metabolism related gene sets. Our systematic approaches suggest that loss of SHP expression in liver might be key genetic events during hepatocarcinogenesis. PMID- 20853065 TI - Update in medical education. PMID- 20853066 TI - Medical care needs of returning veterans with PTSD: their other burden. AB - BACKGROUND: There has been considerable focus on the burden of mental illness (including post-traumatic stress disorder, PTSD) in returning Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans, but little attention to the burden of medical illness in those with PTSD. OBJECTIVES: (1) Determine whether the burden of medical illness is higher in women and men OEF/OIF veterans with PTSD than in those with No Mental Health Conditions (MHC). (2) Identify conditions common in those with PTSD. DESIGN: Cross-sectional study using existing databases (Fiscal Year 2006-2007). SETTING: Veterans Health Administration (VHA) patients nationally. PATIENTS: All 90,558 OEF/OIF veterans using VHA outpatient care nationally, categorized into strata: PTSD, Stress Related Disorders, Other MHCs, and No MHC. MEASUREMENTS: (1) Count of medical conditions; (2) specific medical conditions (from ICD9 codes, using Agency for Health Research and Quality's Clinical Classifications software framework). MAIN RESULTS: The median number of medical conditions for women was 7.0 versus 4.5 for those with PTSD versus No MHC (p<0.001), and for men was 5.0 versus 4.0 (p<0.001). For PTSD patients, the most frequent conditions among women were lumbosacral spine disorders, headache, and lower extremity joint disorders, and among men were lumbosacral spine disorders, lower extremity joint disorders, and hearing problems. These high frequency conditions were more common in those with PTSD than in those with No MHC. CONCLUSIONS: Burden of medical illness is greater in women and men OEF/OIF veteran VHA users with PTSD than in those with No MHC. Health delivery systems serving them should align clinical program development with their medical care needs. PMID- 20853067 TI - Plant oil bodies: novel carriers to deliver lipophilic molecules. AB - Oil bodies (OBs) are specialised organelles ubiquitously detected in plant oil seeds, which serve as lipid storage compartments. OBs consist of a hydrophobic core of triacylglycerol (TAGs), surrounded by a monolayer of phospholipids (PLs) embedded with some specific proteins with a size ranging from 0.5 to 2 MUm. In this work, we report an easy method to reconstitute OBs starting from their constituents and to encapsulate lipophilic molecules, i.e. the fluorescent fluorescein isothiocyanate (FITC) and carboxyfluorescein (CF), into reconstituted OBs. This methods allowed us to produce OBs 4- to 10-fold smaller (50-200 nm) than the native one and to obtain a good recovery (about 40%) of both the fluorescent compounds used in the present work. The properties of reconstituted OBs were investigated by a combination of Brewster angle microscopy, scanning force microscopy, zeta-potential techniques. OBs were stable and formed ordered monolayers when patterned on hydrophobic substrates whereas they showed a higher tendency to aggregate into larger, coalescing OBs when were deposited onto hydrophilic substrates or at the air/water interface. Furthermore, we verified the uptake of FITC-loaded OBs by the MCF-7 breast cancer cell line. Our results indicated that OBs could be envisaged as novel carriers to deliver hydrophobic bioactive compounds. PMID- 20853068 TI - Value-added production of nisin from soy whey. AB - The objective of this study was to evaluate the potential of low/negative value soy whey (SW) as an alternative, inexpensive fermentation substrate to culture Lactococcus lactis subsp. lactis for nisin production. Initially, a microtiter plate assay using a Bioscreen C Microbiology Plate Reader was used for rapid optimization of culture conditions. Various treatments were examined in efforts to optimize nisin production from SW, including different methods for SW sterilization, ultrasonication of soy flake slurries for possible nutrient release, comparison of diluted and undiluted SW, and supplementation of SW with nutrients. In subsequent flask-based experiments, dry bacterial mass and nisin yields obtained from SW were 2.18 g/L and 619 mg/L, respectively, as compared to 2.17 g/L and 672 mg/L from a complex medium, de Man-Rogosa-Sharpe broth. Ultrasonication of soybean flake slurries (10% solid content) in water prior to production of SW resulted in ~2% increase in biomass yields and ~1% decrease in nisin yields. Nutrient supplementation to SW resulted in ~3% and ~7% increase in cell and nisin yields, respectively. This proof-of-concept study demonstrates the potential for use of a low/negative value liquid waste stream from soybean processing for production of a high-value fermentation end product. PMID- 20853069 TI - Blood-born tissue factor in cardiovascular disease: where are we now? PMID- 20853070 TI - Predictors of the early outcome in elderly patients with ST elevation myocardial infarction treated with primary angioplasty: a single center experience. AB - Elderly patients are under-represented in trials assessing strategies of early coronary revascularization in acute myocardial infarction, though they are the fastest growing segment of our population. The aims of the present investigation, performed in 357 elderly (>=75 years) patients with ST elevation myocardial infarction (STEMI) submitted to primary percutaneous coronary intervention (PCI) consecutively admitted to our Intensive Cardiac Care Unit (ICCU) from 1 January 2006 to 31 December 2009, were as follows: (a) to identify predictors for in-ICCU mortality among clinical, angiographic and metabolic factors and (b) to evaluate whether there are gender-related differences in management, outcome and in the metabolic and inflammatory responses to acute myocardial ischemia. At multivariable backward stepwise logistic regression analysis, the following variables were independent predictors for in-ICCU mortality in the overall population: age (OR 1.15; 95% CI 1.05-1.27; p < 0.003), admission glycemia (OR 2.24; 95% CI 1.41-3.56; p < 0.001), left ventricular ejection fraction (LVEF) (OR 0.92; 95% CI 0.88-0.97; p < 0.001), primary PCI failure (OR 4.70; 95% CI 1.70 12.98; p < 0.003). In elderly STEMI patients submitted to primary PCI, early mortality can be related to age, hemodynamic derangement (as indicated by LVEF), the rate of procedural success, and increased glucose values. No gender-related differences in management were detectable in our series. Our data strongly suggest that, in elderly patients in the acute phase of STEMI, since hyperglycemia is a modifying factor, glucose values deserve a more intensive treatment. Further studies, performed specifically in elderly STEMI patients, should be addressed to identify the glucose cut-off values able to influence the outcome. PMID- 20853071 TI - Natriuretic peptides in heart failure: where we are, where we are going. AB - Tremendous advances have been made in understanding the pathophysiology and treatment of congestive heart failure (CHF). However, diagnosis still remains difficult, even with a comprehensive physical examination. Symptoms such as dyspnea are non-specific and poorly sensitive indicators for early CHF that can be largely undetected. The discovery of natriuretic peptides (BNP) as diagnostic biomarkers has been one of the most critical advances for heart failure diagnosis. Therefore, both B-type and N-terminal pro-B-type have potential role in the diagnosis of heart failure, as well as in prognostic risk assessment. A single determination of BNP at any time during the progression of chronic HF provides a clinically useful tool for risk stratification. The hypothesis that repeated measurements might carry prognostic information beyond a single measure was confirmed in different settings. One of the main interests is given to the values of repeated determinations for monitoring progression of disease, and for the evaluation of the clinical effects of medical therapy. Nevertheless, despite thousands of papers describing their potential utility, current guidelines have not endorsed the highest level of recommendation for their use, in part, because the application in clinical practice is often limited for the absence of well codified cut off. Recently, European guidelines emphasized the role of natriuretic peptides as potential laboratory markers. In the near future, algorithm building will take into consideration clinical and echocardiographic parameters as well as NP measurements, and this may lead to a correct diagnosis and identification of patients at high risk. The purpose of this review is to discuss the clinical approaches and future applications of natriuretic peptides in heart failure and coronary disease. PMID- 20853073 TI - Functional characterization of stem cell activity in the mouse mammary gland. AB - Any portion of the mouse mammary gland is capable of recapitulating a clonally derived complete and functional mammary tree upon transplantation into an epithelial divested mammary fat-pad of a recipient host. As such, it is an ideal model tissue for the study somatic stem cell function. This review will outline what is known regarding the function of stem/progenitor cells in the mouse mammary gland, including how progenitor populations can be functionally defined, the evidence for and potential role of selective DNA strand segregation, and the role of the niche in maintaining and controlling stem cell function. PMID- 20853074 TI - Prognostic significance of survivin and caspase-3 immunohistochemical expression in patients with diffuse large B-cell lymphoma treated with rituximab and CHOP. AB - Survivin is an inhibitor of apoptosis whose expression may be associated with inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated without rituximab. Caspase-3 is the final caspase of the apoptotic cascade and its pattern of expression may also be related to patients' outcome. In this study we investigated immunohistochemical expression of survivin and caspase-3 (CPP32) in 57 patients with DLBCL treated with rituximab and CHOP (R-CHOP). According to previously published criteria, we separately analyzed correlation of different types of survivin expression with patients' outcome. Nuclear survivin was expressed in only 26% of cases, cytoplasmic survivin was expressed in 81% of cases while application of immunoreactivity scoring system yielded 58% of survivin positive cases. Caspase-3 was expressed in 77% of cases. There were no significant correlations between any type of survivin expression and response to treatment or survival of the patients. The expression of caspase-3 was also not associated with patients' outcome. We conclude that survivin and caspase-3 have no significant prognostic significance in patients with DLBCL treated with R CHOP. PMID- 20853072 TI - The potential of adipose stem cells in regenerative medicine. AB - Adipose stem cells (ASCs) are an attractive and abundant stem cell source with therapeutic applicability in diverse fields for the repair and regeneration of acute and chronically damaged tissues. Importantly, unlike the human bone marrow stromal/stem stem cells (BMSCs) that are present at low frequency in the bone marrow, ASCs can be retrieved in high number from either liposuction aspirates or subcutaneous adipose tissue fragments and can easily be expanded in vitro. ASCs display properties similar to that observed in BMSCs and, upon induction, undergo at least osteogenic, chondrogenic, adipogenic and neurogenic, differentiation in vitro. Furthermore, ASCs have been shown to be immunoprivileged, prevent severe graft-versus-host disease in vitro and in vivo and to be genetically stable in long-term culture. They have also proven applicability in other functions, such as providing hematopoietic support and gene transfer. Due to these characteristics, ASCs have rapidly advanced into clinical trials for treatment of a broad range of conditions. As cell therapies are becoming more frequent, clinical laboratories following good manufacturing practices are needed. At the same time as laboratory processes become more extensive, the need for control in the processing laboratory grows consequently involving a greater risk of complications and possibly adverse events for the recipient. Therefore, the safety, reproducibility and quality of the stem cells must thoroughly be examined prior to extensive use in clinical applications. In this review, some of the aspects of examination on ASCs in vitro and the utilization of ASCs in clinical studies are discussed. PMID- 20853075 TI - The role of viral infections in the development of dilated cardiomyopathy. AB - Enteroviruses (EVs) are the most frequent pathogens in myocarditis and in the subsequently developing dilated cardiomyopathy as well. Furthermore, persistence of other viruses might play a pathogenic role in the evolution from myocarditis to dilated cardiomyopathy. Explanted heart of 28 patients, who underwent heart transplantation were screened for EV, AdV3 and HHV6 sequences in order to assess the incidence of cardiac viral infection that may be implicated in the pathogenesis of cardiomyopathy, and estimate viral distribution in the myocardium. Viral sequences were extracted from five different regions of the hearts. Nested PCR was used to amplify conservative regions of AdV3, HHV6 and EVs. Histological examination was performed on routinely processed myocardial samples. AdV3 was verified in one fourth of the patients. ADV3 and HHV6 sequences coexisted in one case with inflammatory cardiomyopathy. Some patients had more than one positive area of their heart. AdV3 positive right ventricular samples were double in amount compared to the left ones. None of the patients had positive result for EV. This is the first occasion to identify AdV3 (a mainly respiratory infective virus) sequence in explanted hearts of cardiomyopathy patients. Though the clinical importance of our results is still unclear, AdV3 could be a new member of the viral group with possible pathogenic effect on the myocardium. Regional distribution of viral sequence location confirmed that the right ventricular wall as a biopsy sampling site might be adequate for endomyocardial biopsy pro diagnostic purposes. PMID- 20853076 TI - Involvement of c-Ski oncoprotein in carcinogenesis of cholangiocacinoma induced by Opisthorchis viverrini and N-nitrosodimethylamine. AB - Opisthorchiasis is the major public health problem in the endemic areas of Thailand and Laos because Opisthorchis viverrini infection causes serious hepatobiliary diseases including CCA. The molecular mechanism of the CCA carcinogenesis induced by the infection remains obscure. To reveal the potential genes and signaling pathways to involve in the carcinogenesis, the present study investigated the expression of c-Ski, an oncogene, and two TGF-beta signaling pathway relative genes, TGF-beta and Smad4, during the development of CCA induced by O. viverrini infection in hamster model, and in human opisthorchiasis associated CCA. The results showed that the expression of c-Ski gene was greatly up-regulated during the carcinogenesis of CCA in hamster model. The overexpression of c-Ski was confirmed by immunohistological staining result which showed the increased expression of c-Ski protein in cytoplasm of the epithelial lining of hepatic bile ducts. Moreover, the immunohistological staining of the specimens of human opisthorchiasis associated CCA revealed the up-regulated expression of c-Ski and Smad4 proteins in the cytoplasm of the epithelial lining of hepatic bile ducts and stomal fibrosis respectively. The expression of TGF beta and Smad4 were up-regulated, which expression kinetics was time-dependent of CCA development. These results suggest that c-Ski is likely involved in the carcinogenesis of CCA induced by O. viverrini infection through regulating TGF beta signaling pathway. PMID- 20853077 TI - Different characteristics of mitochondrial microsatellite instability between uterine leiomyomas and leiomyosarcomas. AB - Uterine leiomyomas are benign tumors of the uterus that arise clonally from smooth muscle cells of the myometrium and are the most common reason for hysterectomies. The aim of this study was to evaluate mitochondrial microsatellite instability (mtMSI) in uterine leiomyomas and leiomyosarcomas to clarify the molecular pathogenetic distinction between these tumors. DNA was isolated from paired normal and tumoral tissues in 50 patients with uterine leiomyomas and 14 patients with leiomyosarcomas. mtMSI was analyzed by using eight microsatellite markers. Our result showed that mitochondrial microsatellite instability was not found in all uterine leiomyomas. However, 3 (21.4%) of 14 patients with leiomyosarcomas had mtMSI and the frequencies of mtMSI in these tumors were significantly different (p < 0.01). Distinctive characteristics of mitochondrial genetic instability in uterine leiomyomas and leiomyosarcomas suggested the potential of mtMSI as a marker for differential diagnosis between them. PMID- 20853078 TI - Nucleometric study of anisonucleosis, diabetes and oxidative damage in liver biopsies of orthotopic liver transplant recipients with chronic hepatitis C virus infection. AB - Anisonucleosis is defined as a morphological manifestation of nuclear injury characterized by variation in the size of the cell nuclei. It has been described in variety of benign conditions and is most pronounced in dysplasia and malignancy. To better understand the pathogenesis of anisonucleosis in liver diseases, this study focused on hepatocyte anisonucleosis in biopsies of liver transplant recipients who developed recurrent chronic hepatitis C virus (HCV) infection. Post transplant surveillance liver biopsy specimens were evaluated employing light microscopy, immunohistochemistry, digital image analysis, and nucleometry for histopathological analyses, measurement of nuclear size, and quantification of tissue expression of oxidative marker 8-hydroxy 2'deoxyguanosine (8-OHdG). Our aim in this study was to determine whether there were any independent associations between hepatocyte anisonucleosis and various clinicopathological parameters. These features included patient age, body mass index, gender, race, donor age, live versus cadaveric donor status, history of diabetes mellitus, history of tacrolimus and cyclosporine therapy, duration post transplant and parameters of hepatitis activity index, fibrosis index, steatosis, and oxidative tissue damage in formalin fixed paraffin embedded (FFPE) liver biopsies as determined by immunohistochemistry using 8-OHdG, an indicator of hydroxyl radical mediated tissue damage. Our findings suggested that in liver transplant recipients with recurrent chronic HCV infection, hepatocyte anisonucleosis is more pronounced in individuals with diabetes mellitus (p = 0.0016), and among those who have heightened hepatic expression of the oxidative damage marker 8-OHdG (p = 0.0053). Further studies are necessary to determine whether anisonucleosis is an independent marker for diabetes or oxidative damage. PMID- 20853079 TI - Implication of RAF and RKIP genes in urinary bladder cancer. AB - RKIP has been shown to regulate the RAS-RAF-MEK-ERK kinase cascade acting as modulator of apoptosis and metastasis in prostate cancer. Our goal was to examine the expression of the RAF (A-RAF, B-RAF and RAF-1) and RKIP genes in urinary bladder cancer. Microarray analysis and qPCR was employed to investigate the expression of RAF and RKIP, in 30 patients with transitional cell carcinoma (TCC) of the urinary bladder vs. the corresponding levels of adjacent normal tissue. Computational analysis was also performed on Gene Expression Omnibus (GEO) datasets, to unravel differences in the expression of RAF or RKIP between tumor and control samples, and between superficial and muscle invasive tumors. Microarray analysis revealed >2-fold expression of BRAF and RKIP in T2, T3, grade III tumors vs. controls. B-RAF over-expression was verified by qPCR in pT1, grade III tumors vs. their normal counterparts (p = 0.016). qPCR revealed a significant RKIP reduction in TCC vs. normal tissue (p = 0.002 and p < 0.001 for T1, grade II and Ta-T1, grade III, respectively); All RAF genes were positively correlated among each other (A-RAF/B-RAF, p = 0.003; A-RAF/RAF-1, p < 0.001; B-RAF/RAF-1, p = 0.050), whereas B-RAF was negatively correlated with RKIP in TCC (p = 0.050). Further computational analysis revealed different expression profiles for the genes of interest, among muscle invasive carcinomas, superficial TCCs, cystectomy specimens and normal tissue. The reduced RKIP mRNA levels in TCC and the elevated levels of B-RAF in pT1, grade III tumors vs. normal tissue, corroborate that these genes are involved in the pathogenesis of urinary bladder cancer. PMID- 20853081 TI - [Priority to whom? Prioritizing in the public health system]. PMID- 20853080 TI - Increased NDRG1 expression is associated with advanced T stages and poor vascularization in non-small cell lung cancer. AB - N-myc downstream regulated gene 1 (NDRG1) is a member of the N-myc downstream regulated gene family which belongs to the alpha/beta hydrolase superfamily. Earlier studies have shown its association with inhibition of tumor metastasis. However, its function in malignant tumors is not fully enunciated. Recently there was increasing evidence that NDRG1 is involved in stress responses. In the current study, we examined the expression of NDRG1 and its correlation with clinicopathological factors and microvessel density (MVD) in non-small cell lung cancer (NSCLC) using immunohistochemistry (IHC). NDRG1 expression in NSCLC (71/115, 61.7%) was higher than that in normal lung tissues (32/115, 27.8%) (p < 0.05). NDRG1 expression in NSCLC cells was found in cytoplasm (63/115, 54.8%), nuclear (24/115, 20.9%) and cell membrane (13/115, 11.3%). NDRG1 expression in NSCLC with advanced T stages (T2-4) (63/84, 75.0%) was significantly higher than that with T1 stage (8/31, 25.8%) (P < 0.05). No other clinicopathological factors including lymph node metastasis were found to be associated with NDRG1 expression (p > 0.05). Moreover increased NDRG1 expression was associated with lower MVD in NSCLC (P < 0.05). MVD in adenocarcinoma (33.4 +/- 8.4/HP) was significantly higher than that in squamous cell carcinoma (SCC) (19.3 +/- 8.1/HP) (P < 0.05). No other clinicopathological factors were associated with MVD in NSCLC (p > 0.05). The present findings indicate an increase of NDRG1 expression with the progress of tumour extent which may be due to unbalanced tumor oxygenation on account of poor vascularization in NSCLC. PMID- 20853082 TI - [Ethical basis of priority setting in healthcare]. AB - The debate about priorities in healthcare has also started in Germany. Because of the special moral significance of health and healthcare, priority setting in healthcare also involves ethical issues. After clarifying the relationship between priority setting and rationing, I first discuss whether it is ethically acceptable or even mandated to set priorities in healthcare. If this first question is answered with "yes", the following question is how the priorities can be determined in an ethically defensible way. I will try to show that it is impossible to justify priorities in healthcare within a liberal theory of justice that is neutral towards substantive conceptions of the good life. We rather need a deliberative decision process about how we want to live in the face of illness, suffering, and death. Only by reference to a substantial concept of a good life is it possible to define and justify healthcare priorities. A national priority setting commission could play an important role in stimulating this deliberation and developing general recommendations according to which criteria and procedures priorities should be set in the German healthcare system. The application of this general framework requires the cooperation of medical scientific and physician organizations. PMID- 20853083 TI - [Priorization in healthcare. An important duty, an unnecessary luxury, or playing with fire? A sociomedical point of view]. AB - While setting priorities in healthcare has been discussed internationally for about 25 years, attempts to even start a discussion in Germany have failed for more than a decade. On the contrary, the topic was and still is actively suppressed. In this respect, one helpful mechanism is to deliberately or carelessly confuse prioritization with rationing, a German taboo-word. The national healthcare debate again and again neglects the question on what to spend Germany's still very considerable resources. This helps our health politicians to continue to live the postulate that everybody should have immediate, unrestricted access to all medically indicated healthcare. Attempts to distinguish between priority setting and rationing as two entirely distinct programs based on prioritization models from Sweden, England, and Oregon/USA are presented. While discussing possible objects, levels, criteria, ethics, and normative implications of priority setting in healthcare, recent recommendations of a permanent vaccination committee (STIKO) are used as an example. PMID- 20853084 TI - [Priority setting in healthcare. What can Germany learn from other countries?]. AB - Internationally, priority setting has been debated since the late 1980s, partly only regarding underlying principles, but partly with real implications for the benefit basket. Whereas all approaches reviewed (Norway, Sweden, Denmark, Oregon, The Netherlands, New Zealand) are convincing, those that relied on public consensus and left the priority-setting principles to the discretion of individual healthcare professionals had no effect as early prioritization efforts in the Scandinavian countries show. Prioritization approaches that have relied on concrete lists of indication-treatment pairs (for example, in the U.S. state of Oregon across all areas of care and in Sweden the form of guidelines within indication groups) have led to changes but not always to the expected results: expenditure was only moderately reduced but the provision of care has become more transparent. Regardless of the differences between the various countries, they have several things in common: a heated public debate, a very long implementation timeline, and the lack of a (much feared) prioritization according to age, gender, or social status. Recently, priority setting has been seen as complementary to health technology assessments, guidelines, and quality assurance, all with their own focuses. PMID- 20853085 TI - [Aspects of health economic evaluations as a contribution to the priority-setting debate in Germany]. AB - Decision-making in healthcare is a priority-setting process. Tools used in health economic evaluation support decision-making by outlining complex interdependences, simulating short- and long-term consequences, and quantifying formal comparisons of health technologies. Key elements in health economic evaluations are patient-relevant outcomes and cost parameters. Costing of healthcare services is demanding and reflects only an approximation to reality, particularly in Germany, as the reimbursement schemes neither fully provide all details nor the different costing perspectives. Hence, in order to obtain uniform and cross-indication applicable cost parameters, a German standard cost dataset is necessary. In addition, patient-relevant and indication-specific sets of outcomes parameters should be agreed upon in order to also enable a reliable clinical product development. Economic aspects could be applied in a two-step decision-making approach, where initially the anticipated indication-specific technical efficiency level in terms of cost per adjusted life years would be assessed from a health system perspective. The second step would employ prioritization based on indication-relevant outcomes and ranking criteria in the individual patient decision situation. Health economic evaluations are relevant tools to support prioritization of health technologies, both on an individual as well as public health level. PMID- 20853086 TI - [The acceptance of personal responsibility as a criterion in assigning health care benefits. An empirical study]. AB - In order to accomplish broad acceptance of priority setting in healthcare, a public debate seems essential, in particular, including the preferences of the general public. In Germany, objections to public involvement are to some extent based on the perception that individuals have an inherent personal bias and cannot represent interests other than their own. The following excerpt from a more comprehensive study reports on the acceptance of personal responsibility as a criterion for prioritizing. A mixed-methods design is used for combining a qualitative interview study and a quantitative survey representative of the German public. Both the interview study and the survey demonstrate that behavior that is harmful to one's health is generally accepted as a criterion for posteriorizing patients, mostly regardless of self interest. In addition, the interview study shows reasons for acceptance or refusal of the self-inflicted behavior criterion. PMID- 20853087 TI - [Teleconferences for national surveillance of infectious diseases and public health events in Germany. Evaluation after three quarters in 2009]. AB - Public health threats are increasingly triggered by events which span across international, national and state level jurisdictions. Innovative surveillance methods are needed to ensure adequate and timely response to such threats. In January 2009 the Department of Infectious Disease Epidemiology at the Robert Koch Institute (RKI) established a system of weekly telephone conferences with all competent authorities of the German federal states to identify, discuss and respond to infectious disease events in real-time. A regular and structured platform was developed for use between participants from state level public health authorities, the military and the RKI. During the first three quarters, 46 infectious diseases were covered, including mandatory reports of measles and meningococcal meningitis and outbreaks of cowpox, which does not have to be notified in Germany. Results of a targeted evaluation and a consistently high attendance rate both indicate that the teleconference has met additional needs for supplemental information exchange among participants. The telephone conference has proven to be a useful resource for rapid and direct communication, coordination and evaluation of signals for public health events in Germany. PMID- 20853088 TI - [Acute ethanol intoxication among children and adolescents in Hamburg, Germany]. AB - By using an anonymous postcard reporting system, data of n=358 children, adolescents, and young adults who were treated in 26 emergency departments because of acute alcohol intoxication were collected. The aim of this study was to estimate the prevalence of acute alcohol intoxications in Hamburg, compare these data with the official hospital diagnosis register, and analyze the circumstances that led to the intoxication. A total of 358 cases were reported by the postcard system. Age ranged from 11-21 years, with 64.5% being 14-17 years old. Data were collected in the municipal area of Hamburg during the calendar year of 2008. The percentage of female patients was 65.6% in the age group from 11-17 years and decreased in the age group of patients being 18 years and older. A vast majority of patients were admitted by ambulance and were reported as being a"first offender". On average, male patients showed a higher level of blood alcohol when being admitted (2.02 0/00) than female patients (1.76 0/00). The older the age group, the higher the blood alcohol level. Among drinking circumstances, the situation"drank together with friends" was most frequently reported. In comparison with the official hospital diagnosis register, prevalence was 31.6% higher. This could mean that the prevalence reported in the official hospital diagnosis register is an underestimation of the actual case numbers. PMID- 20853089 TI - [Validation of a syndromic surveillance system of acute respiratory tract diseases in preschools of Schleswig-Holstein (SHARE)]. AB - To obtain reliable, regionalized, and timely data for the spread of seasonal influenza in various age groups, which are preferentially affected by the influenza virus, a syndromic surveillance system for acute respiratory tract infections in Schleswig-Holstein (SHARE) was established in preschools and nurseries starting in 2006. The Schleswig-Flensburg district with 12 of 114 preschools and nurseries and 850 of 5,750 supervised children served as a pilot district. The weekly rates of sickness absenteeism correlated most strongly with the onset of seasonal influenza and with population density during the first half of the year. Mean annual sickness absenteeism levels of above 6% occurred more frequently above a population density of 200 inhabitants/km(2) than below this density (relative risk 2.50, 95% confidence interval 1.18-5.32). By analysis of the receiver-operating characteristic curve, the diagnostic performance of the SHARE system as a classifier for seasonal influenza was determined. The sensitivity was 83% and the specificity was 79% when sickness absence rates exceeded 5%. The performance of the SHARE system correlated with the size of the kindergarten. In 2008, 13 of 15 districts of Schleswig-Holstein participated with 157 of 1,684 kindergarten and 10,300 of 113,000 children. The evaluation for 2008 confirmed that the SHARE system is suitable for the surveillance of seasonal influenza at the district and state levels. PMID- 20853090 TI - [Morbidity and healthcare differences between insured in the statutory ("GKV") and private health insurance ("PKV") in Germany. Review of empirical studies]. AB - BACKGROUND: It has rarely been analyzed whether there are differences in Germany concerning morbidity and healthcare between insured by statutory health insurance (Gesetzliche Krankenversicherung, GKV) and insured by private health insurance (Private Krankenversicherung, PKV). In addition, the available studies are very scattered and no review has been published yet. The study presented here aims at closing this gap and at discussing recommendations for future analyses. METHODS: By searching for publications in the Medline and PubMed databanks, only a very few studies could be identified in this manner Thus, our search was extended to include a number of German institutes and organizations working in the field of public health and health systems research. In addition, we checked all references listed in the relevant publications. RESULTS: A total of 18 relevant publications could be identified; however, just four of them were found via Medline and PubMed. The empirical analyses show that the GKV insured are often less healthy than the PKV insured, and that they more often go to primary care physicians. A potential disadvantage of GKV insured concerning healthcare can be seen in regard to new, innovative drugs, organ transplantations, financial burden due to co payments, waiting times, and communication between patient and physician. CONCLUSION: Most studies show that there are large differences between GKV insured and PKV-insured, concerning health status as well as healthcare. However, due to methodological weaknesses, some of these results are difficult to interpret. More studies focusing on specific age groups (e.g., children) are needed, and the methodological standard (e.g., statistical control for other factors such as income, distinction between different subgroups of insured) must also be raised. Finally, systematic differences between GKV and PKV should be considered in all analyses comparing these two schemes, such as differences in the availability of data concerning healthcare. PMID- 20853091 TI - [Terminal care in the form of sedation at the end of life. Current medical ethics recommendations and further need for discussion]. PMID- 20853092 TI - [Parvovirus B19. Position of the Blood Working Group of the Federal Ministry of Health]. PMID- 20853093 TI - [Orthopoxviruses: infections in humans. Position of the Blood Working Group of the Federal Ministry of Health]. PMID- 20853094 TI - [Human cytomegalovirus (HCMV). Position of the Blood Working Group of the Federal Ministry of Health]. PMID- 20853095 TI - [Indoor air guide values for benzyl alcohol]. AB - The German Working Group on Indoor Air Guidelines of the Federal Environment Agency and the States' Health Authorities is issuing indoor air guide values to protect public health. For health evaluation of benzyl alcohol in indoor air valid inhalation studies are missing. Following subchronic oral exposure to 800 mg benzyl alcohol/kg body weight and day neurotoxicity was observed in rats. Accounting for data gaps by a factor of 2 and extrapolating to continuous exposure by applying a factor of 2 the lowest adverse effect level for chronic exposure (LAELchron) is assessed as 200 mg benzyl alcohol/kg b. w. and day. By applying an interspecies factor of 10, an intraspecies factor of 10, a path-to path-extrapolation and a modifying factor of 2 referring to the special physiology of children (higher breathing rate compared to adults) a health hazard guide value (RW II) of 4 mg benzyl alcohol/m3 indoor air and a health precaution guide value (RW I) of 0.4 mg benzyl alcohol/m3 are derived. PMID- 20853096 TI - Prey-tracking behavior in the invasive terrestrial planarian Platydemus manokwari (Platyhelminthes, Tricladida). AB - Platydemus manokwari is a broadly distributed invasive terrestrial flatworm that preys heavily on land snails and has been credited with the demise of numerous threatened island faunas. We examined whether P. manokwari tracks the mucus trails of land snail prey, investigated its ability to determine trail direction, and evaluated prey preference among various land snail species. A plastic treatment plate with the mucus trail of a single species and a control plate without the trail were placed side by side at the exit of cages housing P. manokwari. All trials were then videotaped overnight. The flatworms moved along plates with mucus trails, but did not respond to plates without trails, blank control (distilled water), or with conspecific flatworm trails. When presented at the midpoint of a snail mucus trail, the flatworms followed the trail in a random direction. The flatworms showed a preference when choosing between two plates, each with a mucus trail of different land snail species. Our results suggest that P. manokwari follows snail mucus trails based on chemical cues to increase the chance of encountering prey; however, trail-tracking behavior showed no directionality. PMID- 20853097 TI - Immortal time bias and survival in patients who self-monitor blood glucose in the Retrolective Study: self-monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes (ROSSO). AB - AIMS/HYPOTHESIS: In the February 2006 issue of Diabetologia, the observational Retrolective Study: Self-monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes (ROSSO) reported a 51% reduction in the risk of all-cause mortality in patients with type 2 diabetes who performed self-monitoring of blood glucose (SMBG). However, these impressive benefits conflict with results from observational studies and randomised controlled trials. We aimed to show that these findings are caused by a flawed design that introduced immortal time bias. METHODS: We illustrate the bias in the ROSSO study and demonstrate that it is large enough to completely explain the apparently protective effect of SMBG on all-cause mortality. RESULTS: In the ROSSO study, patients were classified as exposed to SMBG for their whole follow-up time if they performed self-monitoring for at least 1 year during the study period. Thus, the time between cohort entry and the date after 1 year self-monitoring was performed is unavoidably 'immortal' for patients with SMBG. Patients had to survive at least 1 year to be classified as exposed to this intervention and were artificially 'protected' from death. Based on published information, the total amount of misclassified immortal person time in the SMBG group is at least 5,082 of 9,248 person-years at risk (55%). After re-classification of immortal person-time as unexposed, the unadjusted relative risk changed from 0.59 to 1.95. CONCLUSIONS/INTERPRETATION: The apparently protective effect of SMBG on all-cause mortality observed in the ROSSO study is completely explained by immortal time bias. PMID- 20853098 TI - Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat. AB - AIMS/HYPOTHESIS: Impaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model. METHODS: DP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose-mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf beta (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR. RESULTS: The HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered. CONCLUSIONS/INTERPRETATION: Improved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect. PMID- 20853099 TI - State-level women's status and psychiatric disorders among US women. AB - PURPOSE: Although greater gender equality at the state-level is associated with fewer depressive symptoms in women after controlling for individual-level confounders, the extent to which state-level women's status is related to psychiatric disorders in women and gender differences in psychopathology has never been examined. We examined these associations in the current report. METHODS: We used data from the National Epidemiologic Survey on Alcohol and Related Conditions (n=34,653), a national probability sample of US adults. Respondents completed structured diagnostic assessments of DSM-IV psychiatric disorders. We used generalized estimating equations to examine associations between four state-level indicators of women's status (political participation, employment/earnings, social/economic autonomy, and reproductive rights) and odds of 12-month mood and anxiety disorders among women. We also tested whether women's status predicted the magnitude of gender differences in psychiatric disorders. RESULTS: State-level political participation, employment/earnings, and social/economic autonomy were unrelated to odds of 12-month mood and anxiety disorders among women. However, the prevalence of major depression and post traumatic stress disorder was lower in states where women have greater reproductive rights (OR 0.93-0.95), controlling for individual-level risk factors. None of the women's status indicators predicted gender differences in mood and anxiety disorder prevalence. CONCLUSIONS: State-level women's status was largely unrelated to mood and anxiety disorders in women or to gender differences in these disorders. Investigation of social factors that play a role in shaping the distribution of individual-level risk factors that are associated with gender disparities in psychiatric disorders represents an important avenue for future research. PMID- 20853100 TI - Risk factors for poor work functioning of persons with schizophrenia in rural China. AB - BACKGROUND: The long-term work performance of persons with schizophrenia in the community is unclear. This study examined the status of long-term work functioning and the predictors of poor work status among patients with schizophrenia in a Chinese rural area. METHODS: A 10-year follow-up investigation (1994-2004) of a cohort (n = 510) of persons with schizophrenia was conducted in Xinjin County, Chengdu, China. RESULTS: Compared with baseline data, work functioning of patients with schizophrenia deteriorated after 10 years. The rates of not working increased significantly from 12.0% in 1994 to 23.0% in 2004. Bivariate analyses showed that the poor work functioning in 2004 was significantly associated with male gender, older age, older age of first onset, higher level of education, longer duration of illness, lower family economic status, lack of caregivers, poor work status in 1994, living in shabby or unstable house, marked symptoms, and higher score on the Social Disability Screening Schedule (SDSS). In multiple logistic regression analyses, higher score of SDSS and poor work status in 1994 were identified as unique predictors of poor work status in 2004. CONCLUSION: The status of work functioning of persons with schizophrenia decreased over the course of the illness. The risk factors for poor work functioning and specific socio-cultural environment should be considered in planning community mental health services and rehabilitation for these patients. PMID- 20853101 TI - Similar prefrontal cortical activities between general fluid intelligence and visuospatial working memory tasks in preschool children as revealed by optical topography. AB - General fluid intelligence (gF) is a major component of intellect in both adults and children. Whereas its neural substrates have been studied relatively thoroughly in adults, those are poorly understood in children, particularly preschoolers. Here, we hypothesized that gF and visuospatial working memory share a common neural system within the lateral prefrontal cortex (LPFC) during the preschool years (4-6 years). At the behavioral level, we found that gF positively and significantly correlated with abilities (especially accuracy) in visuospatial working memory. Optical topography revealed that the LPFC of preschoolers was activated and deactivated during the visuospatial working memory task and the gF task. We found that the spatio-temporal features of neural activity in the LPFC were similar for both the visuospatial working memory task and the gF task. Further, 2 months of training for the visuospatial working memory task significantly increased gF in the preschoolers. These findings suggest that a common neural system in the LPFC is recruited to improve the visuospatial working memory and gF in preschoolers. Efficient recruitment of this neural system may be important for good performance in these functions in preschoolers, and behavioral training using this system would help to increase gF at these ages. PMID- 20853102 TI - The effects of error augmentation on learning to walk on a narrow balance beam. AB - Error augmentation during training has been proposed as a means to facilitate motor learning due to the human nervous system's reliance on performance errors to shape motor commands. We studied the effects of error augmentation on short term learning of walking on a balance beam to determine whether it had beneficial effects on motor performance. Four groups of able-bodied subjects walked on a treadmill-mounted balance beam (2.5-cm wide) before and after 30 min of training. During training, two groups walked on the beam with a destabilization device that augmented error (Medium and High Destabilization groups). A third group walked on a narrower beam (1.27-cm) to augment error (Narrow). The fourth group practiced walking on the 2.5-cm balance beam (Wide). Subjects in the Wide group had significantly greater improvements after training than the error augmentation groups. The High Destabilization group had significantly less performance gains than the Narrow group in spite of similar failures per minute during training. In a follow-up experiment, a fifth group of subjects (Assisted) practiced with a device that greatly reduced catastrophic errors (i.e., stepping off the beam) but maintained similar pelvic movement variability. Performance gains were significantly greater in the Wide group than the Assisted group, indicating that catastrophic errors were important for short-term learning. We conclude that increasing errors during practice via destabilization and a narrower balance beam did not improve short-term learning of beam walking. In addition, the presence of qualitatively catastrophic errors seems to improve short-term learning of walking balance. PMID- 20853104 TI - Construction of a xylose-metabolizing yeast by genome integration of xylose isomerase gene and investigation of the effect of xylitol on fermentation. AB - A yeast with the xylose isomerase (XI) pathway was constructed by the multicopy integration of XI overexpression cassettes into the genome of the Saccharomyces cerevisiae MT8-1 strain. The resulting yeast strain successfully produced ethanol from both xylose as the sole carbon source and a mixed sugar, consisting of xylose and glucose, without any adaptation procedure. Ethanol yields in the fermentation from xylose and mixed sugar were 61.9% and 62.2% of the theoretical carbon recovery, respectively. Knockout of GRE3, a gene encoding nonspecific aldose reductase, of the host yeast strain improved the fermentation profile. Not only specific ethanol production rates but also xylose consumption rates was improved more than twice that of xylose-metabolizing yeast with the XI pathway using GRE3 active yeast as the host strain. In addition, it was demonstrated that xylitol in the medium exhibits a concentration-dependent inhibition effect on the ethanol production from xylose with the yeast harboring the XI-based xylose metabolic pathway. From our findings, the combination of XI-pathway integration and GRE3 knockout could be result in a consolidated xylose assimilation pathway and increased ethanol productivity. PMID- 20853103 TI - The use of opioids at the end of life: knowledge level of pharmacists and cooperation with physicians. AB - PURPOSE: What is the level of knowledge of pharmacists concerning pain management and the use of opioids at the end of life, and how do they cooperate with physicians? METHODS: A written questionnaire was sent to a sample of community and hospital pharmacists in the Netherlands. The questionnaire was completed by 182 pharmacists (response rate 45%). RESULTS: Pharmacists were aware of the most basic knowledge about opioids. Among the respondents, 29% erroneously thought that life-threatening respiratory depression was a danger with pain control, and 38% erroneously believed that opioids were the preferred drug for palliative sedation. One in three responding pharmacists did not think his/her theoretical knowledge was sufficient to provide advice on pain control. Most pharmacists had working agreements with physicians on euthanasia (81%), but fewer had working agreements on palliative sedation (46%) or opioid therapy (25%). Based on the experience of most of responding pharmacists (93%), physicians were open to unsolicited advice on opioid prescriptions. The majority of community pharmacists (94%) checked opioid prescriptions most often only after dispensing, while it was not a common practice among the majority of hospital pharmacists (68%) to check prescriptions at all. CONCLUSIONS: Although the basic knowledge of most pharmacists was adequate, based on the responses to the questionnaire, there seems to be a lack of knowledge in several areas, which may hamper pharmacists in improving the quality of care when giving advice to physicians and preventing or correcting mistakes if necessary. If education is improved, a more active role of the pharmacist may improve the quality of end-of-life pharmacotherapy. PMID- 20853105 TI - Fluorescence spectral characteristics of the supernatants from an anaerobic hydrogen-producing bioreactor. AB - Microbial products formed in biological wastewater treatment systems are closely related to system performance and status, and many of them have fluorescence spectral characteristics. In this work, the fluorescence spectral characteristics of the supernatants from an anaerobic hydrogen-producing bioreactor were studied using three-dimensional excitation-emission matrix (EEM) fluorescence spectroscopy. Since the components of the microbial products are complex, the parallel factor analysis (PARAFAC) method was used to extract the real spectra from the overlapped spectra. Two principal components were identified from the EEM spectra. The peaks at excitation-emission maxima of 280/350 and 350/440 nm were, respectively, attributed to the fluorescence of proteins and NADH. Their real concentrations were quantified using the PARAFAC coupled with the second order calibration method. Results show that the formation rate of proteins was correlated to the production rate of hydrogen and volatile fatty acids, as well as the substrate degradation rate. A close correlation between the hydrogen partial pressure and the two fluorophores was found out. This study provides a reliable and convenient approach, which could be potentially used for monitoring the wastewater treatment reactor performance through measuring the fluorescence spectra of the supernatant. PMID- 20853106 TI - Engineered polyketide biosynthesis and biocatalysis in Escherichia coli. AB - Polyketides are important bioactive natural products biosynthesized by bacteria, fungi, and plants. The enzymes that synthesize polyketides are collectively referred to as polyketide synthases (PKSs). Because many of the natural hosts that produce polyketides are difficult to culture or manipulate, establishing a universal heterologous host that is genetically tractable has become an important goal toward the engineered biosynthesis of polyketides and analogues. Here, we summarize the recent progresses in engineering Escherichia coli as a heterologous host for reconstituting PKSs of different types. Our increased understanding of PKS enzymology and structural biology, combined with new tools in protein engineering, metabolic engineering, and synthetic biology, has firmly established E. coli as a powerful host for producing polyketides. PMID- 20853107 TI - Mature seed-derived callus of the model indica rice variety Kasalath is highly competent in Agrobacterium-mediated transformation. AB - We previously established an efficient Agrobacterium-mediated transformation system using primary calli derived from mature seeds of the model japonica rice variety Nipponbare. We expected that the shortened tissue culture period would reduce callus browning--a common problem with the indica transformation system during prolonged tissue culture in the undifferentiated state. In this study, we successfully applied our efficient transformation system to Kasalath--a model variety of indica rice. The Luc reporter system is sensitive enough to allow quantitative analysis of the competency of rice callus for Agrobacterium-mediated transformation. We unexpectedly discovered that primary callus of Kasalath exhibits a remarkably high competency for Agrobacterium-mediated transformation compared to Nipponbare. Southern blot analysis and Luc luminescence showed that independent transformation events in primary callus of Kasalath occurred successfully at ca. tenfold higher frequency than in Nipponbare, and single copy T-DNA integration was observed in ~40% of these events. We also compared the competency of secondary callus of Nipponbare and Kasalath and again found superior competency in Kasalath, although the identification and subsequent observation of independent transformation events in secondary callus is difficult due to the vigorous growth of both transformed and non-transformed cells. An efficient transformation system in Kasalath could facilitate the identification of QTL genes, since many QTL genes are analyzed in a Nipponbare * Kasalath genetic background. The higher transformation competency of Kasalath could be a useful trait in the establishment of highly efficient systems involving new transformation technologies such as gene targeting. PMID- 20853108 TI - Performance of hand-held whole-breast ultrasound based on BI-RADS in women with mammographically negative dense breast. AB - OBJECTIVE: To assess the performance of breast ultrasound based on BI-RADS final assessment categories in women with mammographically negative dense breast. METHODS: Of 3,820 cases with mammographically negative dense breast and subsequent hand-held bilateral whole-breast ultrasound, a total of 1,507 cases in 1,046 women who had biopsy or at least 2-year follow-up ultrasound constituted the basis of this retrospective study. Cancer rate of each sonographic BI-RADS category was determined and medical audit was performed separately in screening general, screening-treated, and diagnostic group. RESULTS: A total of 43 cases (2.9%) were confirmed as malignancy. Cancer rate among BI-RADS categories was significantly different (p < 0.0001). Among three groups, the cancer rate was significantly different (p < 0.0001) and the highest in diagnostic group (15.8%, 22 of 139). Abnormal interpretation rate, PPV of biopsy performed, cancer detection rate, and rate of early stage cancer, and the size of invasive cancer were significantly different among three groups and the highest in diagnostic group. Regarding cancer characteristics, the proportion of advanced cancer was the highest in diagnostic group. CONCLUSION: Breast ultrasound based on BI-RADS as an adjunctive to negative mammography can be useful for predicting malignancy in women with dense breast. PMID- 20853109 TI - Signal characteristics of focal bone marrow lesions in patients with multiple myeloma using whole body T1w-TSE, T2w-STIR and diffusion-weighted imaging with background suppression. AB - OBJECTIVE: This study analyses the diagnostic potential of Diffusion-Weighted Imaging with Background Suppression (DWIBS) in the detection of focal bone marrow lesions from multiple myeloma. The signal and contrast properties of DWIBS are evaluated in correlation with the serum concentration of M-component (MC) and compared with established T1- and T2-weighted sequences. METHODS: Data from 103 consecutive studies in 81 patients are analysed retrospectively. Signal intensities and apparent Diffusion Coefficients (ADC) of 79 focal lesions in the lumbar spine or pelvis of 38 patients are determined and contrast-to-noise-ratio (CNR) is calculated. Data from patients with low (<20 g/L) and high (>20 g/dL) MC are evaluated separately. RESULTS: Signal intensities of focal myeloma lesions on T2w-STIR vary significantly depending on the MC, which leads to a loss in CNR in patients with high MC. No signal variation is observed for T1w-TSE and DWIBS. The CNR values provided by DWIBS in patients with high MC are slightly higher than those of T2w-STIR. ADC values in patients with low MC are significantly higher than in patients with high MC. CONCLUSION: Whole-body DWIBS has the potential to improve the conspicuity of focal myeloma lesions and provides additional biological information by ADC quantification. PMID- 20853110 TI - Posterior fossa tumors in children with neurofibromatosis type 1 (NF1). PMID- 20853111 TI - Study of brain growth in children--a new approach to volume measurements using MRI-reconstructed 3D neuroimaging. AB - OBJECTIVE: The three-dimensional (3D) reconstructed neuroimages are currently available to analyze brain structure. It provides a new tool for clinical evaluation and academic research on brain. However, there are several methods for processing 3D images. In this article, we present a technique that utilizes a work station and a software program to process reconstructed 3D neuroimages after magnetic resonance imaging (MRI) scanning. METHODS: The brain volumes of 50 normal children aged between 3 months and 12 years and 11 months were measured by 3D neuroimages reconstructed from regular MRI scans. These results were then analyzed statistically against the growth curve. RESULTS: The regression curve of cortical growth was y = 39.317Ln(x) + 631.31, R (2) = 0.1318. The regression curve of white matter growth was y = 81.754Ln(x) + 186.07, R(2) = 0.5675. The regression curve of whole brain growth was y = 121.07Ln(x) + 817.738, R (2) = 0.4077. Current studies show that at the postnatal stage, the cortex grows mainly between birth and 4 years of age. At the same time, the postnatal development of the brain depends mainly on the growth of white matter from birth through adolescence. CONCLUSIONS: This study presents the basic data from a study of children's brains using reconstructed 3D brain images. A 3D reconstructed neuroimage provides a new tool for neurological and psychological in vivo research of the brain. Based on the techniques we introduce here, the clinician may evaluate the growth of the brain in a more efficient and precise manner. PMID- 20853112 TI - Disabling Parkinsonism following brief exposure to lithium carbonate in amyotrophic lateral sclerosis. PMID- 20853113 TI - Disease activity in idiopathic intracranial hypertension: a 3-month follow-up study. AB - Idiopathic intracranial hypertension (IIH) is a disorder of raised intracranial pressure (ICP) in the absence of identifiable pathology. The purpose of this study was to evaluate the clinical presentation and monitor a 3-month course using frequent optical coherence tomography (OCT) evaluations, visual field testings and lumbar opening pressure measurements. A longitudinal study of 17 patients with newly diagnosed IIH and 20 healthy overweight controls were included in the study. Peripapillary retinal nerve fiber layer thickness (RNFLT) and retinal thickness (RT) measurements (Stratus OCT-3, fast RNFL 3.4 protocol), and Humphrey visual field testing were evaluated at regular intervals. Repeat lumbar puncture was performed at final visit (n = 13). The diagnostic delay was 3 months and initial symptoms were headache (94%), visual blurring (82%) and pulsatile tinnitus (65%). Complete clinical remission was achieved in 65%, partial in 29% and unchanged symptoms in 6%. Total average RNFLT and RT decreased significantly during the follow-up period (p < 0.0001 and p < 0.0001, respectively). Changes in RNFLT and RT correlated with improvements in visual field mean deviation (MD) (RNFLT: p = 0.006; RT: p = 0.03) and pattern standard deviation (PSD) (RNFLT: p = 0.002; RT: p = 0.003). In patients with weight-loss >3.5% of BMI, ICP decreased significantly (p = 0.0003). In patients with weight loss <3.5% of BMI, changes in ICP were insignificant (p = 0.6). OCT combined with visual field testing may be a valuable objective tool to monitor IIH patients and the short term IIH outcome is positive. Weight-loss is the main predictor of a favorable outcome with respect to CSF pressure. PMID- 20853114 TI - Bilateral uveal melanoma in an arc welder. AB - PURPOSE: To report sequential bilateral uveal melanoma in an arc welder. METHODS: Case report. RESULTS: A 57-year-old Caucasian male, with a 15-year profession of arc welding, was found to have an iridociliary mass in his left eye (OS), measuring 14 * 10 * 4 mm, and proven on fine needle aspiration biopsy to be spindle B-cell melanoma. A coincidental small choroidal nevus was observed in the right eye (OD). There was no ocular melanocytosis. Plaque radiotherapy was applied OS, with regression of the iridociliary melanoma. Four years later, the choroidal nevus OD enlarged into melanoma measuring 8 * 7 * 2.7 mm and was treated successfully with plaque radiotherapy. There was no evidence of systemic metastasis at 56-month follow-up. CONCLUSION: Arc welding is a known environmental risk for unilateral uveal melanoma, and possibly predisposed our patient to bilateral uveal melanoma. PMID- 20853115 TI - Response to: Comparison of higher-order aberration and optical quality after Epi LASIK and LASIK for myopia. PMID- 20853116 TI - Role of keratan sulphate (sulphated poly -N-acetyllactosamine repeats) in keratoconic cornea, histochemical, and ultrastructural analysis. AB - AIMS: Keratan sulphate (KS) is the predominant glycosaminoglycan (GAG) present in the corneal stroma where it is thought to regulate collagen fibril diameter. In this study we investigated the distribution of KS in normal and keratoconic corneas. METHODS: Four normal, one mild, and four severe keratoconic corneas were used for the study. Distribution of keratan sulphate proteoglycans (KS-PG) was investigated using a primary monoclonal antibody (5-D-4) that recognizes disulphated disaccharides in the poly-N-acetyllactosamine repeats of KS. The immuno-reactivity of 5-D-4 was analyzed by immunohistochemistry and immuno electron microscopy. RESULTS: Immuno-histochemistry showed diffuse 5-D-4 staining in keratoconic cornea compared to the punctuate staining in normal corneas. In the single cornea with mild keratoconus, immunogold microscopy revealed a very high density of KS-PG staining, especially in the posterior stroma, compared to severe keratoconic and normal cornea. The amount of KS-PG in the stroma in severe keratoconus was slightly less compared to the normal cornea. In the mild keratoconic cornea, a higher quantity of KS-PG was present around the keratocytes. In severe keratoconic corneas, a higher quantity of KS-PG was present within the keratocytes compared to normal cornea. CONCLUSIONS: The finding of an altered expression of KS in our keratoconic corneas, in particular the strong expression of KS in keratocytes, is in keeping with reports of an altered expression of proteoglycan metabolism in keratoconus. KS-PG plays an important role in stromal collagen fibril assembly and a dysregulation of KS-PG synthesis or catabolism could explain changes in collagen fibril spacing and diameter, which we have reported elsewhere. PMID- 20853117 TI - The effects of the intraocular dye brilliant blue G (BBG) mixed with varying concentrations of glucose on retinal function in an isolated perfused vertebrate retina. AB - BACKGROUND: During vitreoretinal surgery, vital dyes such as brilliant blue G (BBG) are used to visualize anatomical structures. By adding glucose to a concentration of 5%, many surgeons try to achieve a dye mixture heavier than water to facilitate staining of the ILM without preceding fluid-air exchange. However, the intraocular use of high glucose concentrations is critical. This study investigated the effect of 0.4 ml BBG (Brilliant PeelTM 0.25 mg/ml, Fluoron, Ulm, Germany) mixed with various glucose concentrations on the retina in an pseudo in vivo model METHODS: Bovine retinas were isolated and superfused with an oxygen saturated nutrient solution, and the electroretinogram (ERG) was recorded. BBG mixed with 0.05 ml/0.1 ml/0.15 ml glucose 40% was applied epiretinally. ERG recovery was monitored for 75 minutes. 1 mM aspartate was added to the nutrient solution to obtain a-waves. RESULTS: After application of BBG/0.05 ml 40% glucose, a non-significant decrease of the b-wave amplitude was recorded (11.2%). In contrast, higher glucose concentrations showed a significant decrease of the b-wave (23.40% at 0.1 ml glucose, 26% at 0.15 ml glucose). The a wave amplitudes showed no significant change at the end of the washout for all concentrations. CONCLUSIONS: The clinically used mixture of BBG and glucose seems to be safe up to a concentration of 5%. However, higher concentrations of glucose starting from 10% showed strong evidence of a toxic effect on the retinal function and should be avoided. PMID- 20853118 TI - Prevalence and characteristics of hepatitis B and C virus infections in treatment naive HIV-infected patients. AB - In HIV-infected treatment-naive patients, we analyzed risk factors for either chronic hepatitis B (HBV) infection, occult HBV infection (OHBV) or a positive hepatitis C (HCV) serostatus. A total of 918 patients of the RESINA-cohort in Germany were included in this study. Before initiating antiretroviral therapy, clinical parameters were collected and blood samples were analyzed for antibodies against HIV, HBV and HCV, HBs antigen and viral nucleic acids for HIV and HBV. Present or past HBV infection (i.e. HBsAg and/or anti-HBc) was found in 43.4% of patients. HBsAg was detected in 4.5% (41/918) and HBV DNA in 6.1% (34/554), resulting in OHBV infection in 2.9% (16/554) of patients. OHBV infection could not be ruled out by the presence of anti-HBs (50.1%) or the absence of all HBV seromarkers (25%). A HCV-positive serostatus was associated with the IVDU transmission route, non-African ethnicity, elevated liver parameters (ASL or GGT) and low HIV viral load. Replicative HBV infection and HCV-positive serostatus both correlated with HIV resistance mutations (P = 0.001 and P = 0.028). HBV and HCV infection are frequent co-infections in HIV treatment-naive patients. These co-infections influence viral evolution, clinical parameters and serological markers. Consequently, HIV patients should routinely be tested for HBV and HCV infection before initiating HIV treatment. OHBV infection constituted almost half of all HBV infections with detectable HBV DNA. Due to a lack of risk factors indicating OHBV infection, HBV diagnosis should not only include serological markers but also the detection of HBV DNA. PMID- 20853119 TI - Quantification of intraoral pressures during nutritive sucking: methods with normal infants. AB - We report quantitative measurements of ten parameters of nutritive sucking behavior in 91 normal full-term infants obtained using a novel device (an Orometer) and a data collection/analytical system (Suck Editor). The sucking parameters assessed include the number of sucks, mean pressure amplitude of sucks, mean frequency of sucks per second, mean suck interval in seconds, sucking amplitude variability, suck interval variability, number of suck bursts, mean number of sucks per suck burst, mean suck burst duration, and mean interburst gap duration. For analyses, test sessions were divided into 4 * 2-min segments. In single-study tests, 36 of 60 possible comparisons of ten parameters over six pairs of 2-min time intervals showed a p value of 0.05 or less. In 15 paired tests in the same infants at different ages, 33 of 50 possible comparisons of ten parameters over five time intervals showed p values of 0.05 or less. Quantification of nutritive sucking is feasible, showing statistically valid results for ten parameters that change during a feed and with age. These findings suggest that further research, based on our approach, may show clinical value in feeding assessment, diagnosis, and clinical management. PMID- 20853120 TI - Idiopathic scoliosis: relations between the Cobb angle and the dynamical strategies when sitting on a seesaw. AB - The aim of this study was to determine the influence of the severity of the spinal curve on the postural regulation when self-imposed disturbances occur in a seated position in anteroposterior (AP) and mediolateral (ML) orientations. Twelve female adolescents with a right thoracic scoliosis (Cobb = 30.4 degrees +/- 9.7) were included in this study. The ground reaction forces (GRF) were studied while the subjects were maintaining their sitting on a seesaw (ML or AP destabilisation). Five conditions were tested: eyes open; with additional loads placed onto the subject's right or left shoulder; or onto the subject's right or left pelvis. We tested the correlation between the Cobb angle and the postural parameters (index of performance and GRF variability) for each condition. When the destabilisation was AP, the Cobb angle was significantly correlated with GRF variability and anterior and concavity index of performance. Two conditions showed higher correlations: stabilisation with the concavity pelvis load (GRF variability) and the open eyes (index of performance). In contrast, whatever the condition tested was, no link was found when the destabilisations were applied in ML direction. The destabilisation in a seated position highlights the influence of the curve severity on the postural organisation. In seated position, the postural control strategies specific to the scoliotic patients were always correlated by severity of curve, especially when the destabilisation is applied in AP directions. This study showed that the unstable seating position can be considered as a pertinent paradigm to help finding a postural clinical index for adolescent idiopathic scoliosis. PMID- 20853121 TI - Deep brain stimulation therapy for treatment-refractory Tourette's syndrome: A review. AB - Tourette's syndrome is a chronic neurobehavioral disorder that can demonstrate refractoriness to conservative treatments, or to invasive nonsurgical treatments such as botulinum toxin infiltration, or to psychobehavioral treatments. In these cases, the surgical option is often proposed, either with lesional interventions, or more recently with deep brain stimulation (DBS). This latter modality is currently preferred because of its reversibility and modularity. Some relevant issues, however, still persist in terms of appropriate indication to treatment, selection of target, and follow-up evaluation. PMID- 20853122 TI - Reoperation after selective amygdalohippocampectomy: an MRI analysis of the extent of temporomesial resection in ten cases. AB - BACKGROUND: Selective amygdalohippocampectomy (SAHE) yields 60-80% of patients with medically refractory mesial temporal lobe epilepsy seizure-free and seems to be equally effective compared to the more extended temporal lobe resections. The resection of the entire entorhinal cortex (EC) is of crucial importance to warrant complete seizure control for those patients. Thus, evidence of residual EC could be a predictor of a potentially successful reoperation in patients with recurrent seizures after SAHE. We performed an analysis of preoperative and postoperative magnetic resonance imaging (MRI) in patients who underwent a reoperation after an unsuccessful transsylvian SAHE to assess the presence of residual EC before reoperation and to determine whether certain anatomical variants may dispose patients to incomplete resection of EC. MATERIALS AND METHODS: Ten patients who underwent reoperation after SAHE for the recurrence of medically refractory seizures were studied. MRI after SAHE was assessed for the presence of residual EC using T2-weighted and inversion recovery sequences perpendicularly to the main axis of the hippocampus. The results were compared with a control group of ten patients who became seizure-free after SAHE. In the nine patients of the study group, the sulcal anatomy of the basal temporal lobe was graphically outlined and analysed on MRI scans performed before SAHE to characterise the sulcal boundaries of the EC. FINDINGS: Residual EC was found in nine of ten patients and was absent in the control group. After reoperation (median follow-up of 36.5 months), eight out of ten patients were completely seizure-free. In seven out of nine patients, a discontinuous course of the lateral sulcal boundaries of the EC was determined. CONCLUSIONS: Careful analysis of MRI verified residual mesiotemporal structures in the majority of patients who became seizure-free after reoperation. Certain temporobasal sulcal patterns might dispose for a higher risk of incomplete resection of the EC. The study confirms that reoperation is an effective treatment modality for patients with recurrent seizures after transsylvian SAHE. PMID- 20853123 TI - The binding properties of the H5N1 influenza virus neuraminidase as inferred from molecular modeling. AB - The avian influenza H5N1 virus has emerged as an important pathogen, causing severe disease in humans and posing a pandemic threat. Substrate specificity is crucial for the virus to obtain the ability to spread from avian to human. Therefore, an investigation of the binding properties of ligands at the molecular level is important for understanding the catalytic mechanism of the avian influenza virus neuraminidase and for designing novel and specific inhibitors of H5N1 neuraminidase. Based on the available crystal structure of H5N1, we have characterized the binding properties between sialic acid, methyl 3'sialyllactoside, methyl 6'sialyllactoside and the H5N1 influenza virus neuraminidase using molecular docking and molecular dynamics simulations. Obtained molecular dynamics trajectories were analyzed in terms of ligand conformations, N1-ligand interactions, and in terms of loop flexibility. It was found that in the N1-SA complex the sialic acid ring undergoes a transition from the B(2,5) to the (2)C(5) conformation. However, in the N1-3SL and N1-6SL complexes sialic acid remained in the distorted boat conformation. The obtained results indicate that 3SL has only weak interactions with the 150-loop, whereas the N1-6SL complex shows strong interactions. Most of the differences arise from the various conformations around the glycosidic linkage, between the sialic acid and galactose, which facilitate the above interactions of 6SL with the enzyme, and as a consequence the interactions between the 150- and 430- loops. This finding suggests that the altered flexibility of loops in and around the active site is one of the reasons why the avian N1 preferentially cleaves sialic acid from alpha-(2-3)-Gal glycoconjugates over alpha-(2-6)-Gal. These molecular modeling results are consistent with available experimental results on the specificity of N1. PMID- 20853124 TI - Hybridization-displaced charges for amino-acids: a new model using two point charges per atom along with bond-center charges. AB - A new charge distribution is proposed for the amino acids where each atom is associated with two point charges while each bond center is associated with one point charge. Centroids of charges arising due to atomic orbital hybridization called hybridization-displaced charges (HDC) and those located at the atomic sites and bond centers obtained by a modified form of the Mulliken scheme were combined. The density matrix calculations required for this analysis were performed at the B3LYP/6-31G** level of density functional theory. The combination of HDC centroids with the modified Mulliken charges was found to yield dipole moments and surface molecular electrostatic potentials (MEP) of the amino acids in good agreement with those obtained by rigorous DFT calculations or those obtained using the MEP-fitted CHelpG charges. This study shows that the combination of HDC centroids with the modified Mulliken charges is significantly superior to the conventional Mulliken charges. PMID- 20853125 TI - Molecular dynamics study of solvation effect on diffusivity changes of DNA fragments. AB - DNA sequence analyzing and base pair separation techniques have attracted much attention, such as denaturing gradient gel electrophoresis, temperature gradient gel electrophoresis, and capillary electrophoresis. However, details of sequence separation mechanisms in electrophoresis are not clarified enough. Understanding and controlling flow characteristics of DNA are important not only for fundamental research but also for further developments of bio-nano technologies. In the present study, we theoretically discuss the relationship between diffusivity and hydrated structures of DNA fragments in water solvent using molecular dynamics methods. In particular, influence of base pair substitutions on the diffusivity is investigated, focusing on an adenine-thymine (AT) rich B DNA decamer 5'-dCGTATATATA-3'. Consequently, it is found that water molecules that concentrate on dissociated base pairs form hydrated structures and change the diffusivity of DNA decamers. The diffusion coefficients are affected by the substitution of GC for AT because of the different manner of interactions between the base molecules and water solvent. This result predicts a possibility of base pair separation according to differences in the diffusivity. PMID- 20853126 TI - Decomposing the determinants of health care expenditure: the case of Spain. AB - The aim of this paper is to analyze the determinants of regional health-care expenditure in Spain. The coexistence of several models concerning the degree of spending power decentralization and financing systems makes Spain a singular case. It also allows us to draw conclusions relevant to other countries in decentralizing their health-care systems, and to understand cross-country differences with estimated parameters. Using data from the Spanish regions for the period 1992-2005, we show that the estimated health public expenditure income elasticity does change depending on the omission of relevant variables, econometric specifications and techniques, and institutional arrangements. Moreover, while demographic structure is a very relevant factor when explaining health-care expenditure dynamics, multicollinearity biases econometric parameter estimates. PMID- 20853127 TI - Market structure and hospital-insurer bargaining in the Netherlands. AB - In 2005, competition was introduced in part of the hospital market in the Netherlands. Using a unique dataset of transactions and list prices between hospitals and insurers in the years 2005 and 2006, we estimate the influence of buyer and seller concentration on the negotiated prices. First, we use a traditional structure-conduct-performance model (SCP-model) along the lines of Melnick et al. (J Health Econ 11(3): 217-233, 1992) to estimate the effects of buyer and seller concentration on price-cost margins. Second, we model the interaction between hospitals and insurers in the context of a generalized bargaining model similar to Brooks et al. (J Health Econ 16: 417-434, 1997). In the SCP-model, we find that the market shares of hospitals (insurers) have a significantly positive (negative) impact on the hospital price-cost margin. In the bargaining model, we find a significant negative effect of insurer concentration, but no significant effect of hospital concentration. In both models, we find a significant impact of idiosyncratic effects on the market outcomes. This is consistent with the fact that the Dutch hospital sector is not yet in a long-run equilibrium. PMID- 20853128 TI - Intron creation and DNA repair. AB - The genesis of the exon-intron patterns of eukaryotic genes persists as one of the most enigmatic questions in molecular genetics. In particular, the origin and mechanisms responsible for creation of spliceosomal introns have remained controversial. Now the issue appears to have taken a turn. The formation of novel introns in eukaryotes, including some vertebrate lineages, is not as rare as commonly assumed. Moreover, introns appear to have been gained in parallel at closely spaced sites and even repeatedly at the same position. Based on these discoveries, novel hypotheses of intron creation have been developed. The new concepts posit that DNA repair processes are a major source of intron formation. Here, after summarizing the current views of intron gain mechanisms, I review findings in support of the DNA repair hypothesis that provides a global mechanistic scenario for intron creation. Some implications on our perception of the mosaic structure of eukaryotic genes are also discussed. PMID- 20853129 TI - Transformation of amyloid beta(1-40) oligomers into fibrils is characterized by a major change in secondary structure. AB - Alzheimer's disease (AD) is a neurodegenerative disorder occurring in the elderly. It is widely accepted that the amyloid beta peptide (Abeta) aggregation and especially the oligomeric states rather than fibrils are involved in AD onset. We used infrared spectroscopy to provide structural information on the entire aggregation pathway of Abeta(1-40), starting from monomeric Abeta to the end of the process, fibrils. Our structural study suggests that conversion of oligomers into fibrils results from a transition from antiparallel to parallel beta-sheet. These structural changes are described in terms of H-bonding rupture/formation, beta-strands reorientation and beta-sheet elongation. As antiparallel beta-sheet structure is also observed for other amyloidogenic proteins forming oligomers, reorganization of the beta-sheet implicating a reorientation of beta-strands could be a generic mechanism determining the kinetics of protein misfolding. Elucidation of the process driving aggregation, including structural transitions, could be essential in a search for therapies inhibiting aggregation or disrupting aggregates. PMID- 20853130 TI - A novel strategy for development of glucocorticoids through non-genomic mechanism. AB - Glucocorticoids (GCs) are routinely believed to take effect through genomic mechanisms, which are also largely responsible for GCs' side effects. Beneficial non-genomic effects of GCs have been reported as being independent of the genomic pathway. Here, we synthesized a new type of GCs, which took effect mainly via non genomic mechanisms. Hydrocortisone was conjugated with glycine, lysine and phenylalanine to get a bigger molecular structure, which could hardly go through the cell membrane. Evaluation of the anti-inflammatory efficacy showed that hydrocortisone-conjugated glycine (HG) and lysine could inhibit neutrophil degranulation within 15 min. HG could inhibit IgE-mediated histamine release from mast cells via a non-genomic pathway, and rapidly alleviate allergic reaction. Luciferase reporter assay showed that HG would not activate the glucocorticoid response element within 30 min, which verified the rapid effects independent of the genomic pathway. The work proposes a novel insight into the development of novel GCs, and provides new tools for experimental study on non-genomic mechanisms. PMID- 20853131 TI - Identification of two functional nuclear localization signals mediating nuclear import of liver receptor homologue-1. AB - Liver receptor homologue-1 (LRH-1) is a member of the nuclear receptor superfamily. We characterized two functional nuclear localization signals (NLSs) in LRH-1. NLS1 (residues 117-168) overlaps the second zinc finger in the DNA binding domain. Mutagenesis showed that the zinc finger structure and two basic clusters on either side of the zinc finger loop are critical for nuclear import of NLS1. NLS2 (residues 169-204) is located in the Ftz-F1 box that contains a bipartite signal. In full-length LRH-1, mutation of either NLS1 or NLS2 had no effect on nuclear localization, but disruption of both NLS1 and NLS2 resulted in the cytoplasmic accumulation of LRH-1. Either NLS1 or NLS2 alone was sufficient to target LRH-1 to the nucleus. Both NLS1 and NLS2 mediate nuclear transport by a mechanism involving importin alpha/beta. Finally, we showed that three crucial basic clusters in the NLSs are involved in the DNA binding and transcriptional activities of LRH-1. PMID- 20853132 TI - Phase II study of metronomic chemotherapy with bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. AB - We evaluated the efficacy of metronomic etoposide or temozolomide administered with bevacizumab among recurrent glioblastoma (GBM) patients who progressed on prior bevacizumab therapy in a phase 2, open-label, two-arm trial. Twenty-three patients received bevacizumab (10 mg/kg) every 2 weeks with either oral etoposide (50 mg/m2) daily for 21 consecutive days each month or daily temozolomide (50 mg/m2). The primary endpoint was 6-month progression-free survival (PFS-6) and secondary endpoints included safety and overall survival. Both the etoposide and temozolomide arms of the study closed at the interim analysis due to lack of adequate anti-tumor activity. No radiographic responses were observed. Although 12 patients (52%) achieved stable disease, PFS-6 was 4.4% and the median PFS was 7.3 weeks. The only grade 4 adverse event was reversible neutropenia. Grade 3 toxicities included fatigue (n = 2) and infection (n = 1). Metronomic etoposide or temozolomide is ineffective when administered with bevacizumab among recurrent GBM patients who have progressed on prior bevacizumab therapy. Alternative treatment strategies remain critically needed for this indication. PMID- 20853133 TI - Human hedgehog interacting protein expression and promoter methylation in medulloblastoma cell lines and primary tumor samples. AB - Medulloblastoma is the most common pediatric brain tumor and its development is affected by genetic and epigenetic factors. In this study we found there is low or no expression of the hedgehog interacting protein (HHIP), a negative regulator of the sonic hedgehog pathway, in most medulloblastoma cell lines and primary samples explored. We proceeded to promoter methylation assays of this gene by MCA Meth, and found that HHIP was hypermethylated in all medulloblastoma cell lines, but only in 2 out of 14 (14%) primary tumor samples. Methylation correlated with low or unexpressed HHIP in cell lines but not in primary tumor samples. These results suggest the possibility of epigenetic regulation of HHIP in medulloblastoma, similarly to gastric, hepatic and pancreatic cancer. However, HHIP seems to be not only under regulation of promoter methylation, but under other factors involved in the control of its low levels of expression in medulloblastoma. PMID- 20853134 TI - KIT expression and methylation in medulloblastoma and PNET cell lines and tumors. AB - The stem cell factor/kit tyrosine kinase receptor pathway is related to tumor growth and progression in several cancers including Ewing sarcoma, a peripheral PNET (pPNET). Identifying additional groups of tumors that may use the pathway is important as they might be responsive to imatinib mesylate treatment. MB and central PNET (cPNET) are embryonal tumors of the CNS that share similar undifferentiated morphology with Ewing sarcomas and display aggressive clinical behavior. cPNET outcome is significantly lower than MB outcome, even for localized tumors treated with high-risk MB therapy. The elucidation of signaling pathways involved in MB and cPNET pathogenesis, and the discovery of new therapeutic targets is necessary to improve the treatment of these neoplasms. We analyzed KIT expression in 2 MB, one pPNET, one cPNET and 2 rhabdomyosarcoma (RMS) cell lines. Also, in 13 tumor samples (12 MB and one cPNET), we found KIT overexpression in the most aggressive cell lines (metastatic MB and pPNET). Hypermethylation of KIT was clear in the RMS non-expressing cell lines. Among MB tumors, we could see variable levels of KIT expression; a subset of them (25%) might be related in its growth pattern to KIT up-regulation. No methylated KIT was detected in the tumors expressing the lowest levels of KIT. Our results point to methylation as an epigenetic regulatory mechanism for KIT inhibition only in the KIT non-expressing RMS cell lines, and neither in the rest of the cell lines nor in the tumor samples. PMID- 20853136 TI - Clinical impact of simultaneous complete revascularization vs. culprit only primary angioplasty in patients with st-elevation myocardial infarction and multivessel disease: a meta-analysis. AB - Primary Percutaneous Intervention (PCI) is the treatment of choice for acute ST elevation myocardial infarction (STEMI). Nearly half of STEMI patients have multivessel (MV) disease that has been associated with worse survival. However, current guidelines recommend to treat only the culprit artery (COR) during the acute procedure. Thus, the aim of the current study was to perform a meta analysis of trials comparing MV PCI vs. COR for STEMI patients with MV disease. Medline/CENTRAL and Web were searched for comparative studies (both randomized and non randomized trials) about MV PCI vs. COR for STEMI patients reporting mortality, re-PCI and re-MI data. Primary endpoint was 30-day mortality. The meta analysis included 10 studies (2 randomized and 8 registries; N = 31224). As compared with COR, MV PCI significantly reduced long term rate of re-PCI (OR [95% CI] = 0.47 [0.28-0.78], P = 0.003) without increasing 30-day mortality (OR [95% CI] = 1.30 [0.79-2.12], P = 0.31) and long term re-MI (OR [95% CI] = 0.94 [0.43 2.06], P = 0.88). This meta-analysis showed safety and efficacy of MV PCI approach as compared with COR, with a significant reduction in rate of revascularizations, but no advantages in death and re-MI. PMID- 20853135 TI - Pathophysiology, clinics and diagnostics of non-thrombotic pulmonary embolism. AB - Non-thrombotic pulmonary embolism (NTPE) is commonly defined as the partial or total occlusion of the pulmonary circulation caused by a variety of non thrombotic embolic agents. Although its prevalence is much lower than that of pulmonary thromboembolism, this life-threatening pathology is often underestimated due to the low specificity of signs and symptoms and because it might be frequently overlooked in the differential diagnosis of the chest pain. The main sources of non-thrombotic pulmonary emboli include cancers, fat, infective agents, amniotic fluid, a variety of foreign materials and gases. The diagnosis is particularly challenging. The spectrum of imaging findings using imaging techniques such as computed tomography is unpredictable and typically heterogeneous, whereas laboratory tests can only be helpful for establishing the cause but not the presence of the disease (i.e., D-dimer testing is frequently negative). As such, the clinical history along with the identification a potential underlying disease are the often the mainstay for the differential diagnosis. The aim of this article is to provide an overview of the pathophysiology, clinics and diagnostic approach to NTPE. PMID- 20853137 TI - Identification of new members within suites of amphiphilic marine siderophores. AB - Marine bacterial isolates Vibrio sp. HC0601C5 and Halomonas meridiana str. HC4321C1 were isolated off the coast of southern California and were found to produce an expanded suite of previously identified amphiphilic siderophores. Specifically two new members of the amphibactin family, amphibactins S and T, which have a C14:1 omega-7 fatty acid and a saturated C12 fatty acid, respectively, were produced by Vibrio sp. HC0601C5. These siderophores are produced in addition to a number of previously described amphibactins and are excreted into the culture supernatant. Two new members of the aquachelin family of siderophores, aquachelins I and J, which have an hydroxylated C12 fatty acid and a saturated C10 fatty acid, respectively, were produced by Halomonas meridiana str. HC4321C1. These four new siderophores are more hydrophilic than their previously reported relatives, aquachelins A-D and the amphibactin suite of siderophores. PMID- 20853138 TI - Differential responses of oat genotypes: oxidative stress provoked by aluminum. AB - The phytotoxic effects of aluminum and the mechanisms of genetically-based Al tolerance have been widely investigated, as reported in many papers and reviews. However, investigations on many Al-sensitive and Al-resistant species demonstrate that Al phytotoxicity and Al-resistance mechanisms are extremely complex phenomena. The objective of the present study was to analyze the effects of aluminum on the activity of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and ascorbate peroxidase (APX). Also was evaluated the lipid peroxidation, H(2)O(2) content, levels of ascorbic acid (ASA), non protein thiols (NPSH) and Al content in three genotypes of oat, Avena sativa L. (UFRGS 930598, UFRGS 17, and UFRGS 280). The genotypes were grown in different concentrations of Al ranging from 90 to 555 MUM for 5 days. The antioxidant system was unable to overcome toxicity resulting in negative effects such as lipid peroxidation and H(2)O(2) content in UFRGS 930598. The results showed that UFRGS 930598 was the most sensitive genotype. UFRGS 17 and UFRGS 280 were more resistant to Al toxicity. These results suggest that UFRGS 17 has mechanisms of external detoxification and UFRGS 280 has mechanisms of internal detoxification. The different behavior of enzymatic and non-enzymatic antioxidants of the genotypes showed that aluminum resistance in UFGRS 17 and UFRGS 280 may be related to oxidative stress. PMID- 20853139 TI - Equality in obstetrical care: racial/ethnic variation in group B streptococcus screening. AB - The objective of this article is to determine whether racial/ethnic disparities exist in screening for group B streptococcus (GBS) colonization among pregnant women. A retrospective cohort study of deliveries at a single institution was conducted. The primary outcome was the availability of GBS culture data at the time of delivery; the primary predictor was maternal race/ethnicity. Analyses were stratified by the time periods before and after the CDC recommendations for universal screening for GBS. Among 16,333 deliveries, 60.4% of the population was screened for GBS but screening rates varied markedly by year of delivery. Black women had a lower odds of having available GBS data (AOR 0.81 [0.69, 0.95]) but this disparity was limited to the period of time before universal screening was recommended. Prior to the recommendation for universal screening for GBS, racial/ethnic disparities existed in rates of screening among pregnant women delivering at term. These differences were reduced after 2002, suggesting that uniform policies regarding obstetrical care may be effective in eliminating disparities in obstetrical care and outcomes. PMID- 20853140 TI - Semi-high throughput method of measuring proteasome inhibition in vitro and in cultured cells. AB - The ubiquitin proteasome-proteolytic pathway has emerged as one of the most significant pathways in modulating protein homeostasis under both normal and disease states. The use of proteasome inhibitors (PI) has played a pivotal role in understanding protein turn over. The main objective of this work was to develop a comprehensive, fast, and reliable, yet simple in vitro assay that would allow for the identification and characterization of a wide range of PIs. The assays consist of a 96-well plate high throughput (HTP) method to assess proteasome activity in Hs578T breast cancer cell extracts, purified 20S proteasome, using a fluorogenic substrate, Suc-leu-leu-val-tyr-7-AMC, specific to the chymotrypsin-like enzymatic activity of the proteasome. We showed that the chymotrypsin-like activity of the proteasome was inhibited in the two in vitro systems, albeit to different degrees. The assay system also includes two cell based assays consisting of a vector expressing a fusion protein of green fluorescent protein (gfp) and Mouse Ornithine Decarboxylase (MODC) in Zs578T (parental Hs578T carrying the vector that expresses the fusion protein). In the cell-based assay analyses (qualitatively by microscopy and quantitatively by flow cytometry), treatment of Zs578T with PIs prevented the degradation of MODC, accumulated gfp, indicative of increased proteasome inhibition. Because no single assay represents a definitive proof of proteasome inhibitory activity, combined, these assays should serve as a comprehensive benchmark for the identification and partial characterization of novel inhibitors. In summary, the four-step assay protocol can easily be adapted into a high throughput format to rapidly screen unknown inhibitors. PMID- 20853141 TI - Tissue binding patterns and in vitro effects of Campylobacter jejuni DNA-binding protein from starved cells. AB - Campylobacter jejuni (C. jejuni) is frequently associated with axonal Guillain Barre syndrome (GBS). We reported that C. jejuni DNA-binding protein from starved cells (C-Dps) binds to and damages myelinated nerves in vivo. We studied the binding patterns of C-Dps to nervous tissues and its in vitro effects on neural cells. Immunohistochemically, C-Dps labeled the nodes of Ranvier, the outermost parts of internodal myelin and the basement membrane in the peripheral nerves, and neurons and myelin in the central nervous tissues. Its binding was blocked by sulfatide. C-Dps bound to the cell surfaces of nerve growth factor (NGF)-treated PC12 cells leading to dose-dependent LDH release, which was inhibited by either heat-denaturation of C-Dps or coincubation with an anti-C-Dps mAb. However, its binding to the surfaces of cultured NSC34 cells, S16 cells, or dorsal root ganglion cells, did not induce cytotoxicity. These findings suggest a possible involvement of C-Dps in C. jejuni-related GBS. PMID- 20853142 TI - Abnormalities of serum potassium concentration in dialysis-associated hyperglycemia and their correction with insulin: a unique clinical/physiologic exercise in internal potassium balance. AB - The absence of significant losses of potassium in the urine makes dialysis associated hyperglycemia (DH) a model for the study of the internal potassium balance. Studies of DH have revealed that hyperkalemia is frequent at presentation, insulin infusion is usually the only treatment required, and the magnitude of the decrease in serum potassium concentration (K(+)) during treatment of DH with insulin depends on the starting serum K(+) level, the decreases in serum glucose concentration and tonicity, and the increase in serum total carbon dioxide level. We present an analysis of these findings based on previously studied actions of insulin. Calculations of transcellular potassium shifts based on the combined effects of insulin-the increase in the electrical potential differences (hyperpolarization) of the cell membranes and the correction of the hyperglycemic intracellular dehydration through decrease in serum glucose concentration-produced quantitative predictions of the decrease in serum K(+) similar to the reported changes in serum K(+) during treatment of DH with insulin. The lessons from analyzing serum K(+) changes during treatment of DH with insulin are applicable to other conditions where internal potassium balance is called upon to protect serum K(+), such as the postprandial state. The main questions related to internal potassium balance in DH that await clarification include the structure and function of cell membrane potassium channels, the effect of insulin on these channels, and the mechanisms of feedforward potassium regulation. PMID- 20853143 TI - Serological evidence of Paracoccidioides brasiliensis infection in chickens from Parana and Mato Grosso do Sul States, Brazil. AB - The objective of this study was to detect antibodies against Paracoccidioides brasiliensis in free-range and caged chickens Gallus domesticus. Initially, the humoral immune response of two chickens immunized with P. brasiliensis was evaluated. Both animals showed the production of antibodies to gp43, the major P. brasiliensis antigen. The seroepidemiological survey was conducted in chickens from the Pantanal region in Mato Grosso do Sul State (free-range n = 40) and from northern region of Parana State (free-range n = 100, caged n = 43). The serum samples were analyzed by indirect ELISA using gp43 as antigen. The positivity observed in free-range chickens from Mato Grosso do Sul (55%) was significantly higher (P = 0.0001) than in free-range chickens from Parana State (16%). In contrast to the free-range chickens, no positivity was observed in the caged chickens (P = 0.003). This is the first report showing serological evidence of P. brasiliensis infection in chickens. The results suggest that free-range chickens are more frequently infected by P. brasiliensis, probably due to the constant contact with soil than caged chickens and could be useful as epidemiological markers of paracoccidioidomycosis. PMID- 20853144 TI - The frequency of factor V Leiden mutation, ACE gene polymorphism, serum ACE activity and response to ACE inhibitor and angiotensin II receptor antagonist drugs in Iranians type II diabetic patients with microalbuminuria. AB - The aim of present study was to determine if factor V Leiden (FVL) mutation and angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism are associated with diabetic nephropathy (DN) among Kurdish population from Western Iran. This case-control study comprised 144 unrelated adult type 2 diabetic mellitus patients (T2DM) including 72 patients with microalbuminuria and 72 age and sex matched patients without nephropathy. The ACE I/D polymorphism and FVL mutation were detected by polymerase chain reaction (PCR) and PCR-RFLP, respectively. The frequency of FVL G1691A and ACE D allele in T2DM patients with microalbuminuria were 1.6 and 57%, respectively and in normoalbuminuric T2DM patients were 4.9 and 58.3%, respectively (P > 0.05). ACE genotypes affected on serum ACE activity and a better response to ACE inhibitor therapy (captopril) compared to angiotensin II receptor antagonist (losartan) was obtained with significant reduction of ACE activity in diabetic patients without nephropathy carrying DD genotype. However, the beneficial effect of losartan therapy was observed in microalbuminuric patients with II genotype compared to ID and DD genotypes. PMID- 20853145 TI - Cloning and characterization of the Salicornia brachiata Na(+)/H(+) antiporter gene SbNHX1 and its expression by abiotic stress. AB - Salinity causes multifarious adverse effects to plants. Plants response to salt stress involves numerous processes that function in coordination to alleviate both cellular hyperosmolarity and ion disequilibrium. A Na(+)/H(+) antiporter NHX1 gene has been isolated from a halophytic plant Salicornia brachiata in this study. Predicted amino acid sequence similarity, protein topology and the presence of functional domains conserved in SbNHX1 classify it as a plant vacuolar NHX gene. The SbNHX1 cDNA has an open reading frame of 1,683 bp, encoding a polypeptide of 560 amino acid residues with an estimated molecular mass 62.44 kDa. The SbNHX1 shows high amino acid similarity with other halophytic NHX gene and belongs to Class-I type NHXs. TMpred suggests that SbNHX1 contains 11 strong transmembrane (TM). Real time PCR analysis revealed that SbNHX1 transcript expresses maximum at 0.5 M. Transcript increases gradually by increasing the treatment duration at 0.5 M NaCl, however, maximum expression was observed at 48 h. The overexpression of SbNHX1 gene in tobacco plant showed NaCl tolerance. This study shows that SbNHX1 is a potential gene for salt tolerance, and can be used in future for developing salt tolerant crops. PMID- 20853146 TI - Molecular characterization and association analysis of porcine interferon regulatory factor 1 gene. AB - Interferon regulatory factor 1 (IRF1) is a member of IRF-family that was discovered to activate promoters in type I interferon (IFN) genes. It is shown to play functionally diverse role in the regulation of the immune system. In this report, the porcine IRF1 cDNA were cloned and a 7500 bp genomic DNA structure was identified. The putative IRF1 protein included 322 amino acids. Alignment and phylogenetic analysis of the predicted porcine IRF1 amino acids sequence with its homologies of other species show high identity (over 88%). Tissues expression of IRF1 mRNA was observed by RT-PCR, the results revealed IRF1 gene expressed widely in all analyzed tissues. Using the radiation hybrid panel, the porcine IRF1 gene was mapped to porcine chromosome 2 and closely linked to the locus IL4 (LOD = 7.09, 57cR). A SNP in exon2 of porcine IRF1 gene was demonstrated by sequencing and PCR-RFLP analysis. The further association analysis indicated that the SNP was significant associate with level of IFN-gamma (day 20) in serum (P = 0.0001) and the ratio of IFN-gamma to IL10 (day 20; day 35) in serum (P = 0.0165; P = 0.0095). The results suggested that the porcine IRF1 gene is strong candidate gene for these immune traits in pig. PMID- 20853147 TI - Molecular cloning, sequence identification and tissue expression profile of three novel genes Sfxn1, Snai2 and Cno from Black-boned sheep (Ovis aries). AB - The complete coding sequences of three of Black-boned sheep (Ovis aries) genes Sfxn1, Snai2 and Cno were amplified using the reverse transcriptase polymerase chain reaction (RT-PCR) according to the conserved sequence information of the cattle or other mammals and known highly homologous sheep ESTs. Black-boned sheep Sfxn1 gene encodes a protein of 322 amino acids which has high homology with the Sfxn1 proteins of five species--cattle 98%, pig 95%, human 95%, rat 93%, and mouse 93%. Black-boned sheep Snai2 gene encodes a protein of 268 amino acids that has high identity with the Snai2 proteins of six species--cattle 99%, pig 94%, human 93%, dog 93%, rat 91%, and mouse 90%. Black-boned sheep Cno gene encodes a protein of 214 amino acids that has high homology with the Cno proteins of four species--cattle 97%, human 75%, mouse 67%, and rat 65%. The phylogenetic tree analysis demonstrated that Black-boned sheep Sfxn1, Snai2 and Cno proteins have close relationship with cattle Sfxn1, Snai2 and Cno proteins. The tissue expression analysis indicated that Black-boned sheep Sfxn1, Snai2 and Cno genes were expressed in a range of tissues including leg muscle, kidney, skin, longissimus dorsi muscle, spleen, heart and liver. Our experiment is the first to provide the primary foundation for further insight into these three sheep genes. PMID- 20853148 TI - Recombinant expression, characterization and expressional analysis of clam Meretrix meretrix cathepsin B, an enzyme involved in nutrient digestion. AB - Cathepsin B is one of the most important proteolytic enzymes involved in the nutrient metabolism of clam Meretrix meretrix. The recombinant fusion protein GST MmeCB (rGST-MmeCB) was obtained at a high level from Escherichia coli and identified using LC-ESI-MS/MS. The GST tag was cleaved from rGST-MmeCB, and the resulting recombinant MmeCB (rMmeCB) was able to degrade the selective substrate carbobenzoxy-L-arginyl-L-arginyl-7-amino-4-trifluoromethylcoumarin (Z-Arg-Arg AFC) in vitro. The kinetic parameters of the rMmeCB were calculated as follows: K (m), V(max) and k (cat) are 6.11 MUM, 0.0174 MUM min(-1) and 277.57 s(-1), respectively. Rabbit anti-rGST-MmeCB polyclonal antibodies was prepared and used to analyze the tissue distribution of MmeCB protein in M. meretrix. The results showed that the highest level of cathepsin B was found in the digestive gland and moderate levels were found in gill and mantle. Similar expression patterns were found at the mRNA level as detected by real time PCR. Further analysis showed that starvation caused a slight increase in MmeCB protein synthesis in the digestive gland, while refeeding after starvation caused an apparent increase in MmeCB synthesis in digestive gland, gill and mantle. Real time PCR analysis showed that MmeCB mRNA in digestive gland was significantly up-regulated by starvation and returned to normal level after the starved clams were refed. Together, these results indicated that cathepsin B is probably involved in the nutrient digestion of M. meretrix. PMID- 20853149 TI - Molecular analysis of ARF1 expression profiles during development of physic nut (Jatropha curcas L.). AB - A cDNA clone designated arf1 was isolated from a physic nut (Jatropha curcas L.) endosperm cDNA library which encodes a small GTP-binding protein and has significant homology to ADP-ribosylation factors (ARF) in plants, animals and microbes. The cDNA contains an open reading frame that encodes a polypeptide of 181 amino acids with a calculated molecular mass of 20.7 kDa. The deduced amino acid sequence showed high homology to known ARFs from other organisms. The products of the arf1 obtained by overexpression in E. coli revealed the specific binding activity toward GTP. The expression of arf1 was observed in flowers, roots, stems and leaves as analyzed by RT-PCR, and its transcriptional level was highest in flowers. In particular, the accumulation of arf1 transcripts was different under various environmental stresses in seedlings. The results suggest that arf1 plays distinct physiological roles in Jatropha curcas cells. PMID- 20853150 TI - Tobacco microRNAs prediction and their expression infected with Cucumber mosaic virus and Potato virus X. AB - MicroRNAs (miRNAs) are a newly identified class of non-coding small RNAs of about 21-24 nucleotides. They play important roles in multiple biological processes by degrading targeted mRNAs or repressing mRNA translation. To date, a total of 2,043 plant miRNAs are present in the miRNA Registry database (miRBase Release 14.0), and none for tobacco (Nicotiana tabacum). In this research, we used known plant miRNAs against both genomic survey sequence (GSS) and expressed sequence tags (EST) databases to search for potential miRNAs in tobacco. A total of 25 potential miRNAs were identified following a range of strict filtering criteria, and 33 potential targets of miRNAs were predicted by searching the tobacco Unigene database. Most of these miRNA targeting genes were predicted to encode transcription factors which play important roles in tobacco development. Additionally, real-time PCR assays were performed to profile the expression levels of 10 miRNAs after the infection of Cucumber mosaic virus (CMV) and Potato virus X (PVX). The results showed that symptom severity is correlated to the miRNA accumulation, and increased miR168 expression during virus infection is a common, plant- and virus-independent response. PMID- 20853151 TI - Freeze-thaw induced genotoxicity in buffalo (Bubalus bubalis) spermatozoa in relation to total antioxidant status. AB - Use of cryopreserved semen has become an important tool in assisted reproduction but freezing and thawing cause sub-lethal damage to spermatozoa. This is detrimental to sperm because of the membrane damage including permeability and integrity. An excess generation of reactive oxygen species (ROS) creates oxidative stress due to reduced antioxidant status of the cryopreserved spermatozoa. In the present study fresh buffalo semen was collected and divided into two aliquots. One aliquot was used for fresh semen analysis and the other was cryopreserved in Tris-egg yolk-citrate extender. The semen samples were used to study different sperm quality parameters like motility, viability, membrane integrity and total antioxidant status. The DNA integrity in fresh and cryopreserved spermatozoa was also studied using comet assay. The sperm quality parameters like post-thaw sperm motility, viability, membrane integrity and total antioxidant status of cryopreserved spermatozoa were significantly lowered (P < 0.05) compared to fresh spermatozoa. The DNA fragmentation in cryopreserved spermatozoa was significantly higher (P < 0.01) as compared to fresh spermatozoa. The results show that the irreversible DNA damage occurs in spermatozoa during cryopreservation. PMID- 20853152 TI - The ethics of implementing human papillomavirus vaccination in developed countries. AB - Human papillomavirus (HPV) infection is the world's most common sexually transmitted infection. It is a prerequisite for cervical cancer, the second most common cause of death in cancer among women worldwide, and is also believed to cause other anogenital and head and neck cancers. Vaccines that protect against the most common cancer-causing HPV types have recently become available, and different countries have taken different approaches to implementing vaccination. This paper examines the ethics of alternative HPV vaccination strategies. It devotes particular attention to the major arguments for and against one strategy: voluntary, publicly funded vaccination for all adolescent boys and girls. This approach seems attractive because it would protect more people against cervical cancer and other HPV-related cancers than less inclusive alternatives, without the sacrifice of autonomy that a comparably broad compulsory programme would require. Also, the herd immunity that it would likely generate would protect those who remain unvaccinated, a major advantage from a justice perspective. However, there is a possibility that a HPV vaccination programme targeting all adolescents of both sexes is not considered sufficiently cost-effective. Also, it might pose more difficulties for achieving informed consent than comparable vaccination programmes against other diseases. Ultimately, society's choice of HPV vaccination strategy requires careful consideration not only of the values at stake but also of available and emerging scientific evidence. PMID- 20853153 TI - Shortened time interval between colorectal cancer diagnosis and risk testing for hereditary colorectal cancer is not related to higher psychological distress. AB - Current diagnostic practices have shortened the interval between colorectal cancer (CRC) diagnosis and genetic analysis for Lynch syndrome by MSI-testing. We studied the relation of time between MSI-testing since CRC diagnosis (MSI-CRC interval) and psychological distress. We performed a cross-sectional study in 89 patients who had previously been treated for CRC. Data were collected during MSI testing after genetic counseling. Psychological distress was measured with the IES, the SCL-90 and the POMS; social issues with the ISS, ISB and the ODHCF. The median time of MSI-CRC interval was 24 months (range 0-332), with 23% of the patients diagnosed less than 12 months and 42% more than 36 months prior to MSI testing. In 34% of the patients cancer specific distress was high (IES scores >26). Mean psychopathology (SCL-90) scores were low, mean mood states (POMS) scores were moderate. Interval MSI-CRC was not related to psychological distress. High cancer specific distress was reported by 24% of patients diagnosed with CRC less than 12 months ago versus 39 and 35% by those diagnosed between 12 and 36 months and more than 36 months ago respectively. Distress was positively related to female gender (P = 0.04), religiousness (P = 0.01), low social support (P = 0.02) and difficulties with family communication (P < 0.001). Shortened time interval between CRC diagnosis and MSI-testing is not associated with higher psychological distress. Females, religious persons, those having low social support and those reporting difficulties communicating hereditary colorectal cancer with relatives are at higher risk for psychological distress. PMID- 20853154 TI - Designing of sampling programmes for industrial effluent monitoring. AB - INTRODUCTION: Monitoring of effluent discharges from industrial establishments discharging directly into municipality sewers is one of the major water pollution control activities conducted by municipalities. For largely industrialised municipalities, the task can be quite expensive and not effective if sampling programmes are not properly designed. In most cases, samples are randomly collected without proper knowledge of the discharge patterns of various industries. As a result, the information obtained does not give a good reflection of the quality of effluent being discharged. METHODS: These problems can be resolved by adapting a statistical approach to the design of sampling programmes. This approach is useful in determining the frequency of sampling, the number of samples needed to estimate the average concentration of target pollution indicator parameters and the magnitude of the uncertainty involved. RESULTS: The benefits and applications of this approach are demonstrated by a case study presented in this paper. It was found that the number of samples and cost of sample analysis can be greatly reduced by the use of systematic instead of random sampling. CONCLUSION: The statistical approach greatly improves the estimate of monthly means of pollution indicator parameters and is an effective approach for pollution control when coupled with the "polluter pays principle". PMID- 20853155 TI - Conjugated linoleic acid reduces hepatic steatosis and restores liver triacylglycerol secretion and the fatty acid profile during protein repletion in rats. AB - Protein depletion is associated with hepatic steatosis and decreased circulating triacylglycerol (TAG). Since conjugated linoleic acid (CLA) increases lean body mass, protects against muscle catabolism, and modulates lipid metabolism, the aim of this work was to investigate the effects of CLA with two different amounts of dietary fat on the regulation of plasma and hepatic TAG concentration, and its possible connections with changes in fatty acid (FA) profile in plasma, liver and adipose tissue and hepatic oxidative status during protein repletion. Rats were fed a low protein diet (14 days) and then a protein repletion diet (30 days), supplemented or not with CLA, containing 7% (w/w) or 20% (w/w) of fat. Hepatic TAG secretion and removal by muscle and adipose tissue lipoprotein lipase, FA profile and liver oxidative status were evaluated. Protein depletion affected hepatic TAG secretion and peripheral removal, decreasing plasma and increasing liver TAG concentration, whereas protein repletion with CLA improved these abnormalities independently of the amount of dietary fat by increasing hepatic TAG secretion. This prevention in the absence of CLA was not observed. CLA was incorporated in plasma and tissues (adipose > liver > plasma, and c9,t11-CLA > t10,c12-CLA), accompanied by alterations in FA composition, mainly in adipose tissue. The hepatic oxidative stress was overcome by protein repletion. CLA had a beneficial impact on TAG metabolism in protein repleted animals, preventing hepatic steatosis through higher hepatic TAG secretion. PMID- 20853156 TI - Chronic kidney disease and the risk of end-stage renal disease versus death. AB - BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown. OBJECTIVE: To compare the rates of ESRD, cardiovascular and non cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants. DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older. PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003. MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol. KEY RESULTS: During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD. CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD. PMID- 20853158 TI - Using ecological theory to evaluate the effectiveness of an indigenous community intervention: A study of Sexual Assault Nurse Examiner (SANE) programs. AB - In recent years, there has been renewed interest among community psychologists in indigenous interventions, which are programs created by local practitioners (rather than researchers) already rooted in their communities. Indigenous interventions have strong ecological validity, but their effectiveness is often unknown because so few are rigorously evaluated. The goal of this project was to use Kelly and Trickett's ecological theory as a conceptual framework for evaluating an indigenous intervention and its mediating mechanisms of effectiveness. The focal intervention was a midwestern Sexual Assault Nurse Examiner (SANE) program, which provides post-assault medical care, crisis intervention, and medical forensic exams for sexual assault survivors. Prior studies of SANE programs have suggested that these interventions may help increase sexual assault prosecution rates. In this case example, we used a mixed methods design to determine if this program contributed to increased prosecution rates, and if so, why. Based on qualitative interviews with key stakeholders, we found substantial evidence for the Principle of Interdependence such that the SANE program strengthened the interconnections between the legal and medical systems, which contributed to increased prosecution. The intervention was effective in these outcomes because it promoted Cycling of Resources throughout the systems and fostered Adaptation of new roles for legal and medical personnel. Moving beyond this specific case example, this paper also examines cross-cutting advantages and struggles of using an ecological approach in the evaluation of indigenous community interventions. PMID- 20853157 TI - Derivation and characterization of replicate high- and low-alcohol preferring lines of mice and a high-drinking crossed HAP line. AB - Selectively breeding lines of mice and rats to differ in alcohol intake has proven useful for defining which traits correlate with high alcohol drinking behavior, as well as for creating animal models of alcoholism. This study reports the derivation of two novel sets of selected lines, High Alcohol Preferring (HAP) and Low Alcohol Preferring (LAP) replicate 2 and 3 lines. Mice were mass-selected using the same procedure as in the replicate 1 lines: using HS/Ibg as a progenitor, mice were selected for differences in 2-bottle choice intake of 10% alcohol during a 4-week testing period. In addition, another high-drinking line, the crossed HAP (cHAP) line was selectively bred from a progenitors that were a cross of replicate 1 (S27) * replicate 2 (S21) HAP lines. All lines were characterized for saccharin intake. Overall, the response to selection of the HAP and LAP replicate 2 and 3 lines was quite similar. As anticipated, following selection, the cHAP line drank more than either parent HAP line (consuming 26.0 g/kg per day of alcohol by S11), suggesting that this method of crossing replicate lines and selecting from that cross captures more alleles than any single selected line, as well as producing a line with exceptionally high voluntary alcohol intake. As expected, saccharin consumption was highly associated with alcohol consumption; data from 7 lines (HAP 1, 2, and 3, LAP 1, 2, and 3, and cHAP) indicated a genetic correlation between 10% alcohol and 0.32% saccharin intake of 0.91. Overall, these findings show the practicality of developing replicate lines divergent in alcohol preference, and validate a novel procedure for generating very high-drinking mouse populations. PMID- 20853159 TI - Incisional hernia prophylaxis in morbidly obese patients undergoing biliopancreatic diversion. AB - BACKGROUND: The development of incisional hernia after open bariatric surgery is a major cause of morbidity and hospital readmission. The use of prosthetic material in clean-contaminated procedures remains controversial and correlated to high rate of local complications. A prospective observational clinical study on two different surgical techniques used to close the abdominal wall has been performed to better assess the safety (primary end point) and the efficacy (secondary end point) of polypropylene mesh placement to prevent incisional hernia in morbidly obese patients undergoing biliopancreatic diversion (BPD). METHODS: Between January 2007 and February 2009, two consecutive series of 25 obese patients, each undergoing BPD, have been analyzed to compare prophylactic retrorectal muscle prosthetic mesh placement with conventional suture repair of the abdominal wall. The first 25 consecutive patients selected to BPD underwent abdominal closure without mesh (group A), and the next 25 consecutive ones have been treated with prophylactic retrorectal muscle prosthetic mesh placement (group B). RESULTS: No mesh infection occurred in patients in group B. The incidence of minor local complications (seroma or hematoma) was similar in both groups. The incidence of incisional hernia was significantly higher (p = 0.009) in no-mesh group (group A) than in the mesh group (group B) at 1-year follow-up (range, 12 to 24 months). The incidence of incisional hernia was 4% (one case reported) in the group treated with mesh versus an incidence of 32% (eight cases reported) in the group conventionally closed. CONCLUSIONS: The mesh placement in clean-contaminated bariatric surgery seems to be safe (primary end point) and effective (secondary end point) at 1-year follow-up. PMID- 20853160 TI - Characterization of biosorption process of acid orange 7 on waste brewery's yeast. AB - The use of cheap, high-efficiency, and ecofriendly adsorbent has been studied as an alternative way for the removal of dyes from wastewater. This paper investigated the use of waste brewery's yeast for the removal of acid orange 7 from aqueous solution. The optimum removal of acid orange 7 was found to be 3.561 mg/g at pH 2.0, 10 mg/L initial concentration and 303 K. The kinetic studies indicated that the biosorption process of acid orange 7 agreed well with the pseudo-second-order model. The external diffusion is the rate-controlling step of the initial fast adsorption (<20 min) and then the intraparticle diffusion dominated the mass transfer process. Langmuir, Freundlich, and Dubinin Radushkevich models were applied to describe the biosorption isotherm of acid orange 7 by waste brewery's yeast. Langmuir isotherm model fits the equilibrium data, at all the studied temperatures, better than the other isotherm models which indicates monolayer dye biosorption process. The highest monolayer biosorption capacity was found to be 2.27 x 10-3 mol/g at 303 K. The calculated thermodynamic parameters (DeltaG, DeltaS, DeltaH) showed the biosorption process to be spontaneous and exothermic in nature. Amine or amino, amide, carboxyl, phosphate groups are responsible for the dyes biosorption based on the result of Fourier transform infrared analysis. PMID- 20853161 TI - Recovery and characterization of a serine collagenolytic extract from snow crab (Chionoecetes opilio) by-products. AB - Sequential acidic precipitation followed by a single chromatographic step (gel filtration) allowed the recovery of a collagenolytic fraction containing several proteases from by-products of snow crab (Chionoecetes opilio). The partial purification was particularly efficient to recover tryptic (purification fold = 1,352.5; yield = 110%) but also chymotryptic, elastolytic, and collagenolytic activities. A temperature of 40 degrees C and pH 8.0-8.5 were optimal for enzyme activity, which was stable for 2 h under these conditions. Calcium was not required for stability and thus activity. The isoelectric points of the protein components ranged from 3.7 to 4.6. Zymography revealed 29 and 48 kDa major components and others from 22 to 56 kDa. Enzymes were inhibited by PMSF and TLCK but were insensitive to TPCK. In view of these properties, the proteases likely belong to the serine collagenase group. Inhibition by EDTA could be due to a mechanism other than Ca(2+) chelation. Using a food system (ground fish), the fraction was more proteolytic than a commercial bacterial protease, suggesting potential applications in enzymatic hydrolysis processes. PMID- 20853162 TI - Neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinases as novel stress markers in children and young adults on chronic dialysis. AB - Phenomena related to chronic kidney disease, such as atherosclerosis, aggravate with the introduction of dialysis. Matrix metalloproteinases (MMP) and factors modifying their activity, such as their tissue inhibitors (TIMP) or neutrophil gelatinase-associated lipocalin (NGAL), take part in the matrix turnover and the endothelial damage characteristic for atherogenesis. However, there are no data on the associations between these parameters and other known pro-atherogenic factors, or on the impact of various dialysis modalities on them. The aim of our study was to assess the serum concentrations of NGAL, MMP-7, MMP-9, and TIMP-1, as well as their correlations with human heat shock proteins (Hsp90alpha, anti Hsp60), endothelial dysfunction (sE-selectin), and inflammation (hsCRP) in pediatric patients chronically dialyzed. Twenty-two children on automated peritoneal dialysis (APD), 17 patients on hemodialysis (HD) and 24 controls were examined. The serum concentrations of NGAL, MMP-7, MMP-9, TIMP-1, Hsp90alpha, anti-Hsp60, and sE-selectin were assessed by enzyme-linked immunosorbent assay (ELISA). The median values of NGAL, MMP-7, MMP-9, TIMP-1, and MMP-9/NGAL ratio were significantly elevated in all dialyzed children vs. controls and were higher in HD than in APD. The values of MMP-9/TIMP-1 and MMP-7/TIMP-1 ratios in the HD subjects were lower than those in the APD children. Hsp90alpha and anti-Hsp60 predicted the values of NGAL, MMPs, and TIMP-1. Additionally, sE-selectin was a predictor of NGAL levels, whereas NGAL predicted the MMP and TIMP-1 concentrations. The increased concentrations of examined parameters indicate the dysfunction of MMP/TIMP/NGAL system in the dialyzed children, more pronounced on hemodialysis. The discrepancies between dialysis modalities and correlations with heat shock proteins (HSPs) suggest that NGAL may be considered a novel stress protein, whereas MMP-7, MMP-9, and TIMP-1 may be regarded as indicators of stress response in the pediatric population on chronic dialysis. PMID- 20853163 TI - Contralateral prophylactic mastectomy is associated with a survival advantage in high-risk women with a personal history of breast cancer. AB - BACKGROUND: The aim of this study was to investigate whether contralateral prophylactic mastectomy (CPM) in addition to therapeutic mastectomy (TM) is associated with a survival advantage in high-risk women with breast cancer. METHODS: A total of 385 women with stage I or II breast cancer and a family history of breast cancer who underwent TM and CPM between 1971 and 1993 were evaluated and compared to 385 patients matched on age at diagnosis, tumor stage, nodal status, and year of diagnosis who underwent TM-only. Contralateral breast cancer (CBC) events and survival outcomes were compared. RESULTS: At a median follow-up of 17.3 years, 2 CBCs (0.5%) developed in the CPM cohort and 31 (8.1%) in the TM-only cohort, representing a 95% decreased risk of CBC (hazard ratio [HR] = 0.05, 95% confidence interval [95% CI] 0.01-0.22, P < 0.0001). One hundred twenty-eight women in the CPM group and 162 women in the TM-only group have died, resulting in 10-year overall survival estimates of 83 and 74%, respectively (HR 0.68, 95% CI 0.54-0.86, P = 0.001). This difference in overall survival persisted in multivariate analysis (HR 0.77, P = 0.03). Disease-free survival (DFS) was better in the CPM cohort than the TM-only group (HR 0.66, 95% CI 0.53-0.82, P = 0.0002) and remained significant in multivariate analysis (HR 0.67, P = 0.0005). CONCLUSIONS: In this retrospective cohort study, CPM was associated with decreased CBC event and improved overall survival and disease free survival. PMID- 20853164 TI - Retention prediction and hydrophobicity estimation of weak acidic compounds by reversed-phase liquid chromatography using acetic and perchloric acids as ion suppressors. AB - Simple acids are usually applied to suppress the ionization of weakly ionizable acidic analytes in reversed-phase liquid chromatography. The purpose of this study is to investigate the retention behavior of various weak acidic compounds (monoprotic, diprotic, triprotic, and tetraprotic acids) using acetic or perchloric acid as ion suppressor in a binary hydroorganic mobile phase. The apparent n-octanol-water partition coefficient (K(ow)") was proposed to calibrate the n-octanol-water partition coefficient (K(ow)) of weak acidic compound. LogK(ow)" was found to have a better linear correlation with logk(w), the logarithm of the retention factor obtained by extrapolating to neat aqueous fraction of the mobile phase, for all weakly ionizable acidic compounds. This straightforward relationship offers a potential medium for direct measurement of K(ow) data of weak acidic analytes and can be used to predict retention behavior of these compounds in the ion suppression reversed-phase liquid chromatographic mode. PMID- 20853166 TI - Increased electrical output when a bacterial ABTS oxidizer is used in a microbial fuel cell. AB - Microbial fuel cells (MFCs) are a technology that provides electrical energy from the microbial oxidation of organic compounds. Most MFCs use oxygen as the oxidant in the cathode chamber. This study examined the formation in culture of an unidentified bacterial oxidant and investigated the performance of this oxidant in a two-chambered MFC with a proton exchange membrane and an uncoated carbon cathode. DNA, FAME profile and characterization studies identified the microorganism that produced the oxidant as Burkholderia cenocepacia. The oxidant was produced by log phase cells, oxidized the dye 2,2'-azino-bis(3 ethylbenzthiazoline-6-sulphonic acid) (ABTS), had a mass below 1 kD, was heat stable (121 degrees C) and was soluble in ethanol. In a MFC with a 1000 Omega load and ABTS as a mediator, the oxidizer increased cell voltage 11 times higher than atmospheric oxygen and 2.9 times higher than that observed with ferricyanide in the cathode chamber. No increase in cell voltage was observed when no mediator was present. Organisms that produce and release oxidizers into the media may prove useful as bio-cathodes by improving the electrical output of MFCs. PMID- 20853165 TI - Hyphenated techniques for the analysis of heparin and heparan sulfate. AB - The elucidation of the structure of glycosaminoglycan has proven to be challenging for analytical chemists. Molecules of glycosaminoglycan have a high negative charge and are polydisperse and microheterogeneous, thus requiring the application of multiple analytical techniques and methods. Heparin and heparan sulfate are the most structurally complex of the glycosaminoglycans and are widely distributed in nature. They play critical roles in physiological and pathophysiological processes through their interaction with heparin-binding proteins. Moreover, heparin and low-molecular weight heparin are currently used as pharmaceutical drugs to control blood coagulation. In 2008, the health crisis resulting from the contamination of pharmaceutical heparin led to considerable attention regarding their analysis and structural characterization. Modern analytical techniques, including high-performance liquid chromatography, capillary electrophoresis, mass spectrometry, and nuclear magnetic resonance spectroscopy, played critical roles in this effort. A successful combination of separation and spectral techniques will clearly provide a critical advantage in the future analysis of heparin and heparan sulfate. This review focuses on recent efforts to develop hyphenated techniques for the analysis of heparin and heparan sulfate. PMID- 20853167 TI - Identification and pathogenicity of Aeromonas sobria on tail-rot disease in juvenile tilapia Oreochromis niloticus. AB - Thirty-six strains, numbered from PY01 to PY36, were isolated from six moribund Oreochromis niloticus. The biochemical characteristics of all strains conformed to the species description of Aeromonas sobria on the basis of API 20E and Biolog GN system. Furthermore, gyrB sequence of strain PY36 was sequenced and showed high similarity (99.8%) with A. sobria in Genbank. Antibiotic-resistance of strain PY36 was assessed by the Kirby-Bauer disk diffusion method, and the results showed it was susceptible and moderately susceptible to 12 and 3 of the 19 antimicrobials tested. Virulence of strain PY36 to juvenile tilapia was also tested, and we found that LD50 was about 4.17 * 103 CFU per fish in intraperitoneal injection. This is the first article to report that A. sobria was the pathogenic agent of tail-rot disease in juvenile tilapia. A. sobria was multi resistant to the most frequently used antimicrobial drugs in China, so the antimicrobial resistance test should be carried out when these bacteria are isolated from biological samples in order to avoid therapeutic failures and spread of the pathogenic organisms in the environment. PMID- 20853168 TI - Structural characterization and expression of five novel canine kallikrein related peptidases in mammary cancer. AB - Kallikrein-related peptidases (KLKs) constitute a major family of proteolytic enzymes implicated in the pathogenesis of many diseases, including cancer. Recently, we have suggested that the dog might represent a useful animal model for in vivo KLK studies and sought to investigate the expression patterns of the largely unknown canine KLK family. Along the same lines, in the present report we experimentally characterized five previously unidentified (CANFA)KLKs and investigated their expression in normal and tumorous mammary tissues. We demonstrated that the GenBank sequences that were predicted in silico to represent the canine orthologs of human KLK5, KLK6, KLK7, and KLK8 mRNAs were correct, whereas the one corresponding to the canine KLK4 had a major inconsistency within its 5'-terminus. More specifically, two internal segments of the first intron of KLK4, 78 and 97 bp long, respectively, were wrongfully determined to constitute the initial 175-nucleotide sequence of the KLK4 coding region. (CANFA)KLK8 was further shown to undergo alternative splicing that generated an mRNA transcript missing exon 4 (variant 1). All five (CANFA)KLKs were almost ubiquitously expressed in both cancerous and noncancerous mammary tissues. Lower positivity rates were identified for (CANFA)KLK8 variant 1. A trend for upregulation in tumors was observed for (CANFA)KLK5, (CANFA)KLK7, and (CANFA)KLK8, whereas (CANFA)KLK8 variant 1 tended to be downregulated in cancer. Moreover, a parallel expression of the studied canine KLKs was observed, which suggested a possible participation of the encoded enzymes in interrelated proteolytic cascades taking place in the mammary gland. PMID- 20853170 TI - "When patients and families feel abandoned". AB - PURPOSE: Patients with serious illness derive a sense of security by forming strong, healing relationships with their providers. These bonds are particularly strong in life-threatening illnesses, such as cancer, which carry the stigma of death and suffering. These strong relationships create expectations in patients that are not necessarily shared by their clinicians. Providers often focus on treating disease and emphasize technically excellent, "evidence-based" practice while failing to fully appreciate the power of the patient-provider relationship. In contrast, vulnerable patients expect much more than technical competence, including open and clear communication, security, continuity, and access. Patients are often left feeling abandoned when their providers do not meet their expectations, even when their care is technically sound. METHODS/RESULTS: In this paper, we describe scenarios that can lead to feelings of abandonment and discuss strategies to avoid and respond to them. CONCLUSIONS: These strategies can help us maintain healing relationships with our patients by maintaining their trust, confidence, and satisfaction. Cultivating relational aspects of medical practice requires an interchange and takes time. Experienced doctors know this and continue to do so because being present and staying with the patient during difficult times is a pillar of moral and ethical training and a fundamental attribute of a good physician. PMID- 20853169 TI - Stem cell marker TRA-1-60 is expressed in foetal and adult kidney and upregulated in tubulo-interstitial disease. AB - The kidney has an intrinsic ability to repair itself when injured. Epithelial cells of distal tubules may participate in regeneration. Stem cell marker, TRA-1 60 is linked to pluripotency in human embryonic stem cells and is lost upon differentiation. TRA-1-60 expression was mapped and quantified in serial sections of human foetal, adult and diseased kidneys. In 8- to 10-week human foetal kidney, the epitope was abundantly expressed on ureteric bud and structures derived therefrom including collecting duct epithelium. In adult kidney inner medulla/papilla, comparisons with reactivity to epithelial membrane antigen, aquaporin-2 and Tamm-Horsfall protein, confirmed extensive expression of TRA-1-60 in cells lining collecting ducts and thin limb of the loop of Henle, which may be significant since the papillae were proposed to harbour slow cycling cells involved in kidney homeostasis and repair. In the outer medulla and cortex there was rare, sporadic expression in tubular cells of the collecting ducts and nephron, with positive cells confined to the thin limb and thick ascending limb and distal convoluted tubules. Remarkably, in cortex displaying tubulo interstitial injury, there was a dramatic increase in number of TRA-1-60 expressing individual cells and in small groups of cells in distal tubules. Dual staining showed that TRA-1-60 positive cells co-expressed Pax-2 and Ki-67, markers of tubular regeneration. Given the localization in foetal kidney and the distribution patterns in adults, it is tempting to speculate that TRA-1-60 may identify a population of cells contributing to repair of distal tubules in adult kidney. PMID- 20853171 TI - Identifying tumor patients' depression. AB - PURPOSE: The aim of this study was to compare the precision of two different methods in detecting clinical depression in tumor patients: the use of a screening questionnaire versus the assessment by health care providers (nurses and doctors). METHODS: During their first days of inpatient cancer treatment, tumor patients were interviewed using the Structured Clinical Interview for DSM (SCID). Their physicians and nurses were asked to assess the mental health of the patients and their need for professional psychosocial support. Additionally, every patient completed the Hospital Anxiety and Depression Scale (HADS). RESULTS: Out of 329 patients, 28 were diagnosed with either a major or a minor depression according to the SCID. Physicians assessed 15 of the depressed patients as being depressed (sensitivity, 0.54; specificity, 0.38). Nurses identified 19 (sensitivity, 0.68; specificity, 0.45) and the HADS 27 (sensitivity, 0.96; specificity, 0.50) of the depressed patients. CONCLUSION: The HADS performed well in detecting depressed cancer patients in acute oncological care, whereas physicians and nurses often were unable to recognize depressed patients. PMID- 20853172 TI - Assessment of splenic function. AB - Hyposplenic patients are at risk of overwhelming post-splenectomy infection (OPSI), which carries mortality of up to 70%. Therefore, preventive measures are warranted. However, patients with diminished splenic function are difficult to identify. In this review we discuss immunological, haematological and scintigraphic parameters that can be used to measure splenic function. IgM memory B cells are a potential parameter for assessing splenic function; however, more studies are necessary for its validation. Detection of Howell-Jolly bodies does not reflect splenic function accurately, whereas determining the percentage of pitted erythrocytes is a well-evaluated method and seems a good first-line investigation for assessing splenic function. When assessing spleen function, (99m)Tc-labelled, heat-altered, autologous erythrocyte scintigraphy with multimodality single photon emission computed tomography (SPECT)-CT technology is the best approach, as all facets of splenic function are evaluated. In conclusion, although scintigraphic methods are most reliable, they are not suitable for screening large populations. We therefore recommend using the percentage of pitted erythrocytes, albeit suboptimal, as a first-line investigation and subsequently confirming abnormal readings by means of scintigraphy. More studies evaluating the value of potentially new markers are needed. PMID- 20853173 TI - Complex protein patterns formation via salt-induced self-assembly and droplet evaporation. AB - Complex and elegant protein patterns in rosette, scallop, Chinese arrow and dendrite shapes at macroscopic length scales were prepared using salt-induced molecular self-assembly and droplet evaporation methods. The direct visual observation method using fluorescence microscopy was adopted to characterize the formation of these protein patterns in situ. Further studies from an optical interferometric profiler have shown that both rosette and scalloped protein patterns are hierarchical structures of concentric rings consisting of many prism like columnar stacks, with each of the stack having thousands of protein molecules. Systematic experimental studies were performed to investigate the influence of salt concentration, protein concentration and evaporation rate on the morphologies of protein patterns. Upon the analysis of the representative fluorescent microscope images some theoretical explanations, based on Deegan's theory on the "coffee ring" effect and the dynamic self-assembly mechanism, were proposed to illustrate the dynamics for the formation of different protein patterns. Two different evaporation modes have been found: edge-enhanced evaporation for low salt concentration solutions, i.e., the higher evaporation rate exists at the edge of the droplet; center-enhanced evaporation for high salt concentration solutions, in which faster evaporation occurs at the droplet center consisting of a lot of crystallized salts. PMID- 20853174 TI - Toll-like receptor 4 can recognize SapC-DOPS to stimulate macrophages to express several cytokines. AB - OBJECTIVE AND DESIGN: SapC-DOPS is a newly combined compound consisting of saposin C and dioleoylphosphatidylserine (DOPS). Our recent study showed that SapC-DOPS exhibits anti-tumor activity. However, SapC-DOPS has recognition elements of Toll-like receptor (TLR) 2 and TLR4; therefore, we want to know whether SapC-DOPS can induce abnormal immunoreaction via identification TLRs. METHODS: We investigated the capacity of SapC-DOPS to induce cytokines in vivo and in vitro and analyzed the involvement of TLR and NF-kB in these cytokines production. RESULTS: SapC-DOPS could activate the cytokine production by peripheral macrophages, enhance the expressions of TLR4 and stimulate the NF kappaB nuclear translocation. PDTC, an NF-kappaB inhibitor, could decrease the SapC-DOPS inducible TNF-alpha and IL-1beta production. CONCLUSIONS: SapC-DOPS was similar to LPS in the immune response and may induce the production of cytokines in macrophages via the TLR4 signaling pathway and, at least in part, the alteration of the NF-kappaB pathway. PMID- 20853176 TI - A 10-year follow-up of treatment outcomes in patients with early stage breast cancer and clinically negative axillary nodes treated with tangential breast irradiation following sentinel lymph node dissection or axillary clearance. AB - We compare long-term outcomes in patients with node negative early stage breast cancer treated with breast radiotherapy (RT) without the axillary RT field after sentinel lymph node dissection (SLND) or axillary lymph node dissection (ALND). We hypothesize that though tangential RT was delivered to the breast tissue, it at least partially sterilized occult axillary nodal metastases thus providing low nodal failure rates. Between 1995 and 2001, 265 patients with AJCC stages I-II breast cancer were treated with lumpectomy and either SLND (cohort SLND) or SLND and ALND (cohort ALND). Median follow-up was 9.9 years (range 8.3-15.3 years). RT was administered to the whole breast to the median dose of 48.2 Gy (range 46.0 50.4 Gy) plus boost without axillary RT. Chi-square tests were employed in comparing outcomes of two groups for axillary and supraclavicular failure rates, ipsilateral in-breast tumor recurrence (IBTR), distant metastases (DM), and chronic complications. Progression-free survival (PFS) was compared using log rank test. There were 136/265 (51%) and 129/265 (49%) patients in the SLND and ALND cohorts, respectively. The median number of axillary lymph nodes assessed was 2 (range 1-5) in cohort SLND and 18 (range 7-36) in cohort ALND (P < 0.0001). Incidence of AFR and SFR in both cohorts was 0%. The rates of IBTR and DM in both cohorts were not significantly different. Median PFS in the SLND cohort is 14.6 years and 10-year PFS is 88.2%. Median PFS in the ALND group is 15.0 years and 10 year PFS is 85.7%. At a 10-year follow-up chronic lymphedema occurred in 5/108 (4.6%) and 40/115 (34.8%) in cohorts SLND and ALND, respectively (P = 0.0001). This study provides mature evidence that patients with negative nodes, treated with tangential breast RT and SLND alone, experience low AFR or SFR. Our findings, while awaiting mature long-term data from NSABP B-32, support that in patients with negative axillary nodal status such treatment provides excellent long-term cure rates while avoiding morbidities associated with ALND or addition of axillary RT field. PMID- 20853175 TI - Up-regulation and redistribution of protein kinase C-delta in chronically hypoxic heart. AB - The adaptation to chronic hypoxia confers long-lasting cardiac protection against acute ischemia-reperfusion injury. Protein kinase C (PKC) appears to play a role in the cardioprotective mechanism but the involvement of individual PKC isoforms remains unclear. The aim of this study was to examine the effects of chronic intermittent hypoxia (CIH; 7,000 m, 8 h/day) and acute administration of PKC delta inhibitor (rottlerin, 0.3 mg/kg) on the expression and subcellular distribution of PKC-delta and PKC-epsilon in the left ventricular myocardium of adult male Wistar rats by Western blot and quantitative immunofluorescence microscopy. CIH decreased the total level of PKC-epsilon in homogenate without affecting the level of phosphorylated PKC-epsilon (Ser729). In contrast, CIH up regulated the total level of PKC-delta as well as the level of phosphorylated PKC delta (Ser643) in homogenate. Rottlerin partially reversed the hypoxia-induced increase in PKC-delta in the mitochondrial fraction. Immunofluorescent staining of ventricular cryo-sections revealed increased co-localization of PKC-delta with mitochondrial and sarcolemmal membranes in CIH hearts that was suppressed by rottlerin. The formation of nitrotyrosine as a marker of oxidative stress was enhanced in CIH myocardium, particularly in mitochondria. The expression of total oxidative phosphorylation complexes was slightly decreased by CIH mainly due to complex II decline. In conclusion, up-regulated PKC-delta in CIH hearts is mainly localized to mitochondrial and sarcolemmal membranes. The inhibitory effects of rottlerin on PKC-delta subcellular redistribution and cardioprotection (as shown previously) support the view that this isoform plays a role in the mechanism of CIH-induced ischemic tolerance. PMID- 20853177 TI - Perceptions of tuberculosis among immigrants and refugees at an adult education center: a community-based participatory research approach. AB - English as a Second Language programs serve large foreign-born populations in the US with elevated risks of tuberculosis (TB), yet little is known about TB perceptions in these settings. Using a community-based participatory research approach, we elicited perceptions about TB among immigrant and refugee learners and staff at a diverse adult education center. Community partners were trained in focus groups moderation. Ten focus groups were conducted with 83 learners and staff. Multi-level, team-based qualitative analysis was conducted to develop themes that informed a model of TB perceptions among participants. Multiple challenges with TB control and prevention were identified. There were a variety of misperceptions about transmission of TB, and a lack of knowledge about latent TB. Feelings and perceptions related to TB included secrecy, shame, fear, and isolation. Barriers to TB testing include low awareness, lack of knowledge about latent TB, and the practical considerations of transportation, cost, and work schedule conflicts. Barriers to medication use include suspicion of generic medications and perceived side effects. We posit adult education centers with large immigrant and refugee populations as excellent venues for TB prevention, and propose several recommendations for conducting these programs. Content should dispel the most compelling misperceptions about TB transmission while clarifying the difference between active and latent disease. Learners should be educated about TB in the US and that it is curable. Finally, TB programs that include learners and staff in their design and implementation provide greater opportunity for overcoming previously unrecognized barriers. PMID- 20853179 TI - The importance of defining 'data' in data management policies: Commentary on: "Issues in data management". AB - What comprises 'data' varies from one institution to another based on the information which is deemed important by individual institutions. To effectively and efficiently produce, collect, and retain data, an organization develops specific defining characteristics of data to meet its informational needs. Procedures to maintain and retain knowledge among laboratory members and principal investigators will allow for improved efficiency of data collection. Optimization of communication, maintenance of inventories, record keeping, and updating relevant training programs are all critical to supporting the quality and integrity of a particular organization's data. Concurrent revisions to such procedures will ensure that the definition of data as well as the means by which it is collected and maintained remain appropriate to the needs of the individual organization. PMID- 20853178 TI - Epidermal growth factor receptor and mammalian target of rapamycin as therapeutic targets in malignant glioma: current clinical status and perspectives. AB - Despite advances in the understanding of the molecular biology of glioblastomas (GB), these neoplasms still are incurable with conventional therapies. Current efforts therefore focus on the development of new molecular approaches that exploit the genetic aberrations of cancer cells. Based on their frequent activation or mutation in human GB and their paramount role for the maintenance of the neoplastic phenotype, both the epidermal growth factor receptor (EGFR) and the mammalian target of rapamycin (mTOR) are plausible targets for molecular therapies. However, clinical trials with drugs targeting EGFR or mTOR, so far, have produced largely disappointing results. In this article, we review strategies targeting EGFR and mTOR as therapies for malignant glioma. Recent advances in the understanding of the complex signaling network involved are highlighted and the results of clinical trials are summarized. Mechanisms of resistance are explored, and potential future directions as well as trends in preclinical and clinical development are discussed. PMID- 20853180 TI - Endobronchial sand casts: an unusual marker of saltwater immersion in a juvenile pygmy sperm whale (Kogia breviceps). PMID- 20853181 TI - Evaluation of data-driven network analysis approaches for functional connectivity MRI. AB - Correlated low frequency fluctuations in the blood oxygenation level dependent signal have been widely observed in highly connected brain regions and are considered to be indicative of coordinated activity within those regions. A typical functional connectivity MRI study consists of hundreds of time points acquired from thousands of image voxels, and thus exploratory data analysis is a significant challenge. This paper investigates the utilization of analytical methods based upon graph theory that can potentially provide a data-driven approach to examining the relationships between and within groups of voxels. Three algorithms, based on reachable groups, path-length analysis, and hierarchical clustering, are described and evaluated in the relatively simple context of the rodent brain. Analysis indicates that (based on the cross correlation coefficient) cortical voxels are the most strongly connected network nodes. These voxels exhibit stronger clustering than would be expected in a randomly connected graph, and the amount of clustering is dependent on the cross correlation threshold chosen. The analysis algorithms identify core groups in somatosensory areas and indicate that left and right somatosensory regions are more strongly connected to each other than to midline cortical areas. The results show that algorithms based on graph theory are well-suited for the data-driven analysis of functional connectivity studies. PMID- 20853182 TI - Arginine interactions with anatase TiO2 (100) surface and the perturbation of 49Ti NMR chemical shifts--a DFT investigation: relevance to Renu-Seeram bio solar cell. AB - Density functional theoretical calculations have been utilized to investigate the interaction of the amino acid arginine with the (100) surface of anatase and the reproduction of experimentally measured (49)Ti NMR chemical shifts of anatase. Significant binding of arginine through electrostatic interaction and hydrogen bonds of the arginine guanidinium protons to the TiO(2) surface oxygen atoms is observed, allowing attachment of proteins to titania surfaces in the construction of bio-sensitized solar cells. GIAO-B3LYP/6-31G(d) NMR calculation of a three layer model based on the experimental structure of this TiO(2) modification gives an excellent reproduction of the experimental value (-927 ppm) within +/- 7 ppm, however, the change in relative chemical shifts, EFGs and CSA suggest that the effect of the electrostatic arginine binding might be too small for experimental detection. PMID- 20853183 TI - Integrating computational and mixture-based screening of combinatorial libraries. AB - Mixture-based synthetic combinatorial library (MB-SCL) screening is a well established experimental approach for rapidly retrieving structure-activity relationships (SAR) and identifying hits. Virtual screening is also a powerful approach that is increasingly being used in drug discovery programs and has a growing number of successful applications. However, limited efforts have been made to integrate both techniques. To this end, we combined experimental data from a MB-SCL of bicyclic guanidines screened against the kappa-opioid receptor and molecular similarity methods. The activity data and similarity analyses were integrated in a biometric analysis-similarity map. Such a map allows the molecules to be categorized as actives, activity cliffs, low similarity to the reference compounds, or missed hits. A compound with IC(50) = 309 nM was found in the "missed hits" region, showing that active compounds can be retrieved from a MS-SCL via computational approaches. The strategy presented in this work is general and is envisioned as a general-purpose approach that can be applied to other MB-SCLs. PMID- 20853184 TI - Novel ATP13A2 (PARK9) homozygous mutation in a family with marked phenotype variability. AB - Mutations in the ATP13A2 (PARK9) and FBXO7 (PARK15) genes are linked to different forms of autosomal recessive juvenile-onset neurodegenerative diseases with overlapping phenotypes, including levodopa-responsive parkinsonism, pyramidal disturbances, cognitive decline, and supranuclear gaze disturbance. However, the associated genotypes and phenotypes are poorly characterized due to the small number of patients described. Here, we report clinical, instrumental, and genetic findings in an Italian family with novel PARK9 and PARK15 mutations. The proband developed a severe progressive phenotype including juvenile-onset parkinsonism, pyramidal disturbances, cognitive decline, and oculomotor abnormalities. On the contrary, his brother only shows mild abnormalities (pyramidal, cognitive, and oculomotor) on the neurological examination at the age of 31 years. These two brothers both carry a novel homozygous PARK9 missense (p.G877R) and a novel heterozygous PARK15 mutation (p.R481C). The PARK9 mutation replaces a crucial residue for the ATPase activity, and is therefore most likely a loss-of-function mutation and disease-causing in homozygous state. The pathogenic significance of the PARK15 single heterozygous mutation remains unclear. In both sibs, DaTSCAN single photon emission computed tomography showed marked nigrostriatal dopaminergic defects, and transcranial magnetic stimulation detected prolonged central motor conduction time. MRI, including T2*-weighted imaging, detected no evidence of brain iron accumulation. This family, the third reported with homozygous PARK9 mutations and the first with mutations in two genes for atypical juvenile parkinsonism, illustrates that PARK9-linked disease might display wide intra-familial clinical variability and milder phenotypes, suggesting the existence of strong, still unknown, modifiers. PMID- 20853186 TI - Differential diagnosis of pancreatobiliary carcinoma from autoimmune pancreatitis related diseases: a report of three cases. AB - BACKGROUND: "Japanese clinical guidelines for autoimmune pancreatitis" advised to carefully differentiate between two conditions: autoimmune pancreatitis (AIP) and associated sclerosing cholangitis (SC), and pancreatobiliary malignancy. METHODOLOGY: We report a series of three cases for which differential diagnosis of pancreatobiliary carcinoma from AIP and associated SC was crucial. RESULT: Three patients presented with biliary stenosis secondary to pancreatic swelling or mass lesion, followed by further examinations: Case 1 was first diagnosed as having tumor-forming pancreatitis associated with AIP but eventually proven to be pancreatic head carcinoma; case 2 was operated for suspected bile duct cancer combined with AIP and associated cholangitis, and early cancer was found in the resected specimen; case 3 was operated on for presumed cholangiocarcinoma combined with AIP-associated SC, but no malignancy was found. CONCLUSIONS: Current series of cases would raise an alert on diagnosis of AIP and associated SC, and pancreatobiliary malignancy should be carefully excluded by any means. Surgical intervention would be required in selected cases of this clinical entity. PMID- 20853187 TI - NDVI indicated characteristics of vegetation cover change in China's metropolises over the last three decades. AB - How urban vegetation was influenced by three decades of intensive urbanization in China is of great interest but rarely studied. In this paper, we used satellite derived Normalized Difference Vegetation Index (NDVI) and socioeconomic data to evaluate effects of urbanization on vegetation cover in China's 117 metropolises over the last three decades. Our results suggest that current urbanization has caused deterioration of urban vegetation across most cities in China, particularly in East China. At the national scale, average urban area NDVI (NDVI(u)) significantly decreased during the last three decades (P < 0.01), and two distinct periods with different trends can be identified, 1982-1990 and 1990 2006. NDVI(u) did not show statistically significant trend before 1990 but decrease remarkably after 1990 (P < 0.01). Different regions also showed difference in the timing of NDVI(u) turning point. The year when NDVI(u) started to decline significantly for Central China and East China was 1987 and 1990, respectively, while NDVI(u) in West China remained relatively constant until 1998. NDVI(u) changes in the Yangtze River Delta and the Pearl River Delta, two regions which has been undergoing the most rapid urbanization in China, also show different characteristics. The Pearl River Delta experienced a rapid decline in NDVI(u) from the early 1980s to the mid-1990s; while in the Yangtze River Delta, NDVI(u) did not decline significantly until the early 1990s. Such different patterns of NDVI(u) changes are closely linked with policy-oriented difference in urbanization dynamics of these regions, which highlights the importance of implementing a sustainable urban development policy. PMID- 20853188 TI - Incidence of metal and antibiotic resistance in Pseudomonas spp. from the river water, agricultural soil irrigated with wastewater and groundwater. AB - A total of 144 isolates of Pseudomonas spp. (48 each from the Yamuna River water, wastewater irrigated soil and groundwater irrigated soil) were tested for their resistance against certain heavy metals and antibiotics. Minimum inhibitory concentrations (MICs) of Hg(2+ ), Cd(2+ ), Cu(2+ ), Zn(2+ ), Ni(2+ ), Pb(2+ ), Cr(3+ ) and Cr(6+ ) for each isolate were also determined. A maximum MIC of 200 MUg/ml for mercury and 3,200 MUg/ml for other metals were observed. The incidences of metal resistance and MICs of metals for Pseudomonas isolates from the Yamuna water and wastewater irrigated soil were significantly different to those of groundwater irrigated soil. A high level of resistance against tetracycline and polymyxin B (81.2%) was observed in river water isolates. However, 87.5% of Pseudomonas isolates from soil irrigated with wastewater showed resistance to sulphadiazine, whereas 79.1% were resistant to both ampicillin and erythromycin. Isolates from soil irrigated with groundwater exhibited less resistance towards heavy metals and antibiotics as compared to those of river water and wastewater irrigated soil. Majority of the Pseudomonas isolates from water and soil exhibited resistance to multiple metals and antibiotics. Resistance was transferable to recipient Escherichia coli AB2200 strains by conjugation. Plasmids were cured with the curing agent ethidium bromide and acridine orange at sub-MIC concentration. PMID- 20853190 TI - Dynamics of medicinal plants knowledge and commerce in an urban ecosystem (Pernambuco, Northeast Brazil). AB - Given the importance of markets and fairs for the commerce of medicinal plants, an ethnobotanical study was undertaken at the Caruaru Fair (Pernambuco, northeastern Brazil) to compare the richness of species sold and their values of relative importance (RI) using two datasets collected with a 4-year interval. The seasonality of these plants' supplies was also analyzed. The Caruaru Fair is located in the 18 de Maio Park. It covers an area 40,000 m(2) and is used by merchants who sell several types of products, such as supplies, handicrafts, clay and aluminum utensils, shoes, clothes and medicinal plants. Semistructured interviews were carried out with the vendors who agreed to take part in the study in order to record which plants were sold and their respective indications. The plants were collected, and the species were determined. The information was analyzed with quantitative tools. A total of 169 plants were identified from both surveys, which were significantly different with regard to species richness (p < 0.05) but did not vary in relation to species' Relative Importance (p > 0.05). In relation to the seasonality of the plant supply, habit may explain the lack of some species during certain periods of the year, as most of the absent plants are herbaceous. In terms of the species most sold locally, it was found that spontaneous tree species are well known and extensively commercialized. PMID- 20853189 TI - Scaling the trophic index (TRIX) in oligotrophic marine environments. AB - The TRIX index used for the assessment of trophic status of coastal waters has been applied in many European seas (Adriatic, Tyrrhenian, Baltic, Black Sea, and North Sea). However, all these waters are characterized by high nutrient levels and phytoplankton biomass; index calibration based on systems that are principally eutrophic may introduce bias to the index scaling. In the present work the TRIX trophic index is evaluated using three standard sets of data characterizing oligotrophy, mesotrophy, and eutrophication in the Aegean (Eastern Mediterranean) marine environment. A natural eutrophication scale based on the TRIX index that is suitable to characterize trophic conditions in oligotrophic Mediterranean water bodies is proposed. This scale was developed into a five grade water quality classification scheme describing different levels of eutrophication. It is questionable whether this index can form a universal index of eutrophication or the scaling of TRIX should be region specific. PMID- 20853191 TI - Insights into molecular pathways for targeted therapeutics in acute leukemia. AB - Despite the development of modern chemotherapeutic regimens, acute leukaemia remains incurable in the majority of adult patients and potential cure is associated with considerable side effects. Clinical and experimental research of the last two decades has demonstrated that acute leukaemia is the consequence of multiple collaborative molecular aberrations affecting protein kinases and transcriptional regulators induced by genetic alterations and/or epigenetic mechanisms. New technologies have been developed to detect aberrations of the entire (epi)genome of a leukaemic blast that will result in a long list of potential therapeutic targets needing to be functionally validated in cellular and animal leukaemia models. Using these methods, several "druggable" protein kinases have been identified. These kinases exert their oncogenic potential not only through expansion of the leukaemic clone, but also by regulating critical interactions of leukaemic stem cells with the microenvironment. Due to the molecular complexity of acute leukaemia, new functional genome-wide screens have been established and may help to identify targets that when blocked result in synthetic lethality of the leukaemic blasts harbouring distinct (epi)genomic lesions. A close interaction between the academic and the pharmaceutical biomedical research will be essential to translate these exciting new molecular findings into improved therapies for acute leukaemia. PMID- 20853192 TI - Superparamagnetic nanoparticles - a tool for early diagnostics. AB - Nanoparticles show several interesting new physical and biological properties and therefore play an increasing role in pharmaceutics and medicine. For more than 30 years this research field has been developing slowly but steadily from physical and biological interest (bench) to applications in clinics (bedside). However, many of these particles for biomedical applications are still in the pre-clinical or clinical phase. Combined with drugs or genes these nanoparticles may change the viability of or the transcription processes in cells, which make them interesting for the pharmaceutical industry, cell biology and diagnostics. Because most of the application of superparamagnetic nanoparticles as therapeutic tool, like non-viral vector, drug delivery, are still far from clinical use, this review will concentrate on superparamagnetic nanoparticles as versatile agent for early diagnosis, including the use of such particles as contrast agent for MR imaging and as vehicle for the detection of biomarkers. PMID- 20853193 TI - Utilisation of information technologies in ambulatory care in Switzerland. AB - BACKGROUND: The importance of electronic medical records for the healthcare system is well documented. IT enables easy storage, communication and decision support and can provide important tools in the care of chronically ill patients in the form of a reminder system. METHODS: A questionnaire was developed and send out to 1200 physicians extracted from the official data base. After four weeks the non-responders received a written reminder. Data collection started in December 2007 and was completed in February 2008. RESULTS: 719 questionnaires were received back, representing a response rate of 59.9%. The data revealed a significant underuse of electronic medical records (EMRs) and IT compared to other European countries. Smaller practices, older physicians and especially primary care physicians tended to use less EMR. Only 10.2% of all physicians declared an interest in considering investment in IT in the next three years, 66.9% expressly denied wishing to do so. The most important barriers were the costs, the unclear benefit and a feared worsening of the doctor-patient communication during consultation. CONCLUSION: IT and especially EMRs are underused in daily ambulatory care in Switzerland. To increase the use of EMRs, several approaches could be helpful. First of all, the benefit of EMRs in daily routine care have to be increased as, for example, by decision support systems, tools to avoid pharmaceutical interactions and reminder systems to enable a proactive treatment of chronically ill patients. Furthermore, adequate approaches to offer appropriate reimbursement for the financial investments have to considered such as an additional payment for electronically generated, evidence based quality indicators. PMID- 20853194 TI - High prevalence of vitamin D deficiency in children and adolescents with type 1 diabetes. AB - BACKGROUND: Vitamin D is important for bone health. An inadequate supply of vitamin D to the body is associated with a higher fracture risk in the elderly. Young adults with type 1 diabetes are reported to have a lower peak bone mass than healthy individuals, which could possibly lead to an increased fracture risk in the future. The prevalence of vitamin D deficiency in healthy young people is high. Thus, optimal supply of vitamin D may be of particular importance for bone health in children with type 1 diabetes. METHODS: In this prospective cross sectional study we measured serum 25-hydroxy-vitamin D, iPTH, total and ionised calcium, phosphate, and alkaline phosphatase in 129 Swiss children and adolescents with type 1 diabetes. RESULTS: Of the 129 subjects 78 (60.5%) were vitamin D deficient, defined as a 25-hydroxy-vitamin-D level below 50 nmol/L. During the winter this number rose to 84.1%. 25-hydroxy-vitamin-D levels showed marked seasonal fluctuations, whereas there was no correlation with diabetes control. Despite the high prevalence of vitamin D deficiency, we found a low prevalence of secondary hyperparathyroidism in vitamin D deficient diabetic children and adolescents. CONCLUSIONS: Prevalence of vitamin D deficiency in diabetic children and adolescents is high. Therefore, screening for vitamin D deficiency and supplementation in children with low vitamin D levels may be considered. PMID- 20853195 TI - Domestic violence against women: Definitions, epidemiology, risk factors and consequences. AB - BACKGROUND: Domestic violence is considered one of the most common forms of gender-related violence, and various studies estimate that between 10 and 35% of women experience domestic violence at some point in their lives. Nevertheless, it is a frequently neglected problem in crisis intervention centres, emergency wards, and obstetrics and gynaecological emergency rooms. This paper contributes to clarifying the definition, epidemiology, risk factors and consequences of domestic violence against women as well as the psychopathological profile of victims with a focus on Central European countries. Although different studies on domestic violence report different risk factors, such as younger age, being unmarried, lower education, violence experienced during childhood and alcohol/drug abuse of the partner or the victim herself, the results show no overall consistency. There seems to be neither a definite risk profile nor a specific association with a psychopathological profile. Women who have been victimised find it hard to share their experiences and seek help. It is often difficult for medical personnel who encounter these women to recognise violence and discuss this problem with them, just as it is difficult to offer adequate help. Medical personnel should be alerted to this subject and prepare guidelines for the further management and treatment of abused women. Infor-mation and support for medical staff can help to identify domestic violence, and encourage communication about this problem, thereby leading to a better and more efficient use of available services and resources. PMID- 20853196 TI - Prognostic evaluation of early rheumatoid arthritis. AB - The progression of rheumatoid arthritis (RA) is quite variable, ranging from very mild or subclinical forms (approx. 10%) to rapidly progressing and debilitating forms (10-15%). The majority of patients present with an intermediate stage with episodes of exacerbation separated by periods of relative inactivity, which evolves to progressive functional losses. To optimise the therapeutic management of early RA it is necessary to perform periodic evaluations of the clinical and laboratory test responses to the treatment instituted, as well as the parameters indicating disease prognosis. Composite measures are frequently used to evaluate the disease activity score (DAS), including the response criteria of the American College of Rheumatology (ACR), the response criteria and the DAS according to the European League Against Rheumatism (EULAR) and the composite indices of disease activity (CIDsA): DAS, the index of disease activity based on 28 joints (DAS 28), the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI). The evaluation of prognosis includes investigation of the absence or occurrence of disease and joint damage remission. Due to the multifaceted nature of RA, no single clinical or laboratory parameter is able to describe satisfactorily the level of inflammatory activity or the disease prognosis at any given time. PMID- 20853197 TI - Neurocysticercosis: risk and primary prevention strategies update. AB - Neurocysticercosis results from the infestation of the central nervous system with invading tapeworm larvae. Though uncommon in the US prior to 1965, new cases are currently being diagnosed at an unprecedented rate. Drawing on environmental health, intervention and risk data retrieved from standard/alternative databases and in-country sources, we present an update and summary of modifiable risk factors and field-tested primary prevention measures. While points of intervention, subpopulations at risk and overall magnitude of the problem are addressed, particular attention is paid to defining risk reduction measures that can be adopted by individuals and high risk groups in the near-term to interrupt or eliminate pathways of exposure leading to disease transmission. Though global eradication is not attainable in the near future, effective preventative measures exist and should be taken now by international travellers and workers, US/foreign government agencies, and individuals living in endemic regions to reduce human suffering. PMID- 20853198 TI - Isolation and identification of Legionella pneumophila from material reclamation facilities. AB - Sampling points at a material reclamation facility (MRF) were monitored over three months for the presence of Legionella spp. A number of different Legionellae were isolated and typed to identify L. pneumophila serogroup 1, the serotype which is the most common human pathogen. Phenotypic methods resulted in a total of 61 presumptive isolates of Legionella spp. Using latex agglutination, 26 out of the 61 were identified as L. pneumophila serogroup 1, 23 as L. pneumophila serogroups 2-14, and the remaining 12 were Legionella spp. However, on typing using pulse field gel electrophoresis, the 26 L. pneumophila serotype 1 isolates were a diverse group of 25 PFGE types with none persisting in the environment over time. This diversity suggests that there are a number of contamination sources for this important human pathogen in the MRF environment which constitute a risk to health for operatives in these facilities. PMID- 20853199 TI - The prevalence of tinea pedis and tinea manuum in adults in rural areas in Turkey. AB - The aim of this study was to determine the frequency of tinea pedis and manuum (dermatophyte infections of the hands and feet) in adults in rural areas of Turkey, the risk factors and self-administered treatment options. A total of 2,574 people living in a rural area were enrolled in the study. Participants were asked demographic data, hygienic habits in a questionnaire. KOH preparations and culture were performed from suspicious lesions. Medical and alternative therapy methods and former dermatophytosis diagnosis history were taken from the respondents with suspicious lesions. Microbiological samples were taken from 285 (11.1%) participants. Culture was positive in 109 (4.2%) of those. The most common agent was Trichophyton rubrum. The predisposing factors were found as age older than 40, male gender and obesity. Forty-nine (44.9%) of patients had taken a medical therapy, 56 (51.4%) had performed non-medical methods (cologne, Lawsonia inermis-Henna and softener creams). Patient's education about the treatment compliance is important. PMID- 20853200 TI - The ecological complexity of the Thai-Laos Mekong River: II. Metals and polyaromatic hydrocarbons (PAHs) monitoring, modelling and environmental fate. AB - The Mekong is an essential source of water and protein for the denizens of Thai Laos countries. It is hypothesized that pollution may be adversely affecting the water and sediment quality, which threatens the short and long-term use of this major river system. This directly impacts on the health and population of the aquatic life and ultimately human health and the economy for both countries is affected. The quality of the river can be assessed from various chemical and physical parameters, such as PAHs and metals content of both the water and the sediment. The introduction of Environmental Quality Standards (EQS) allows comparison of the values obtained with the guidelines. Furthermore the modelling program EPISUITE was used to determine the environmental partitioning of pollutants within the different environmental compartments. Using the data produced for PAHs and metals the experimental model was compared to the default model. This involved experimentally measuring the log K(oc) for Mekong sediments and from this determining the log K(ow). High availability in sediment of pollutants may lead to greater biomagnification in bethnic fish, which may then be hazardous for human consumption even if it is safe for the species that is accumulating pollutants. The potential for this is shown by the calculated accumulation in biota C(bio) values exceeding both the Chronic value (ChrV) and Lethal Concentration 50 (LC(50)) for fish in the Mekong River. When compared to the EQS guidelines the amount of some PAHs, cadmium and lead in sediment were above the lowest effect level but below the severe effect level. PMID- 20853201 TI - The ecological complexity of the Thai-Laos Mekong River: III. Health status of Mekong catfish and cyprinids, evidence of bioaccumulative effects. AB - Histopathology of fish organs was used as biomarkers of toxicity from environmental pollutants. A total of 117 fishes comprising of 52 cyprinids and 65 catfishes were randomly collected from the Mekong River from 5 stations: Chiang Rai, Loei, Nongkhai, Nakhon Phanom and Ubonratchathani. The health of the fish collected in December and April, winter and summer respectively, was evaluated. All fish from the 5 stations developed pathologic lesions with the same characteristics in their livers, kidneys and spleen. In the liver, there was vacuolation of hepatocytes, accumulation of brownish-green granules in the cytoplasm of hepatocytes, necrosis of hepatocytes, granuloma formation and angiogenesis. Kidney lesions consisted of glomerular degeneration, necrosis and focal hyperplasia of renal tubules. In the spleen, there were haemorrhage, melanomacrophage centre infiltration and necrosis of the red pulp and white pulp. The pathologic severity of the catfish was found to be more severe than in the cyprinids and the catfish collected in summer were less healthy than the catfish collected in the winter. These histopathological appearances might arise from the fish feeding on the benthos and thereby accumulating toxic pollutants in their organs. The activities of the serum enzymes, Glutamic Oxalacetic Transaminase (GOT) and Glutamic Pyruvic Transaminase (GPT), were markedly increased, indicating detoxification activity. The highest activity of GOT found in the cyprinids from Chiang Rai 365.30 U/L whereas in the catfish from Nakhon Phanom the activity was 300.73 U/L. The highest GPT activity found in the cyprinids from Nakhon Phanom was 203.23 U/L where as in the catfish from the same station was GPT 389.77 U/L. According to the results from this study, catfish collected from Chiang Rai, Nakhon Phanom and Ubonratchathani showed more severe pathological changes than catfish from the other stations. Fish organs and river water were analysed for Polyaromatic Hydrocarbons (PAHs) and metals. The fish organs showed bioaccumulation of these toxic pollutants. BioConcentration Factors (BCFs) were calculated. Therefore an attempt is made to correlate these findings to the Mekong study in general. PMID- 20853202 TI - Lead distribution and its potential risk to the environment: lesson learned from environmental monitoring of abandon mine. AB - There are many abandon and existing mines (tin, lead and zinc) in the mountainous areas of Thailand. Toxic elements including heavy metals such as lead (Pb), cadmium (Cd) and arsenic (As) have been released and transported from the mining sites to the adjacent landscape. In Thong Pha Phum District, Kanchanaburi Province, Thailand Pb contamination in the vicinity of the mine has occurred which could lead to potential health problems in downstream communities. To better understand current status of Pb contamination and accumulation in the surrounding environment and potential health impact, surface sediment, soil and plant samples were collected seasonally from representative monitoring sites along the aquatic track or flow regime. Potential health risk was determined using hazard quotient (HQ) as an index for local inhabitants who consume rice. Environmental monitoring illustrated that Pb concentrations in the surface sediment was as high as 869.4 mg kg(-1) dry weight and varied differently among stations sampled. Lead content in agricultural soil ranged between 137.8 to 613.5 mg kg(-1) dry weight and was inversely proportion to the distance from the point source. Moreover Pb was transported from the point source to down hill areas. At the highly polluted monitoring stations (S1, S2, and S3), concentrations of Pb exceeded the maximum allowable concentration for Pb in agricultural soil (300 mg kg(-1)) by 1.7-2 times. The Pb in soil was primarily associated with Fe/Mn oxides bound fraction (46-56%) followed by the organic bound fraction (25-30%). Lead uptake by plant varied and was species dependent. However root and tuber crops like cassava (19.92 mg Pb kg(-1) dry weight) and curcumin (3.25 mg Pb kg(-1) dry weight) could have removed Pb from the soil which suggest growing root crops in Pb contaminated soils should be avoided. However Cd, a co-contaminant at one of monitored stations (S4) yielded rice grain with Cd exceeding the maximum allowable concentration suggesting some potential health risk (HQ = 5.34) if people consume rice grown at this station. Overall result shows a low risk associated with Pb release into the environment. PMID- 20853203 TI - Fit testing respirators for public health medical emergencies. AB - Concerns about limiting pandemic infectious disease transmission when vaccines are not yet available prompted the Food and Drug Administration (FDA) to develop guidance for marketing respirators for use in public health medical emergencies. This project describes the results of filtering facepiece fit tests using 35 untrained, inexperienced subjects meeting the face size criteria of the National Institute for Occupational Safety and Health bivariate panel, in preparation for an FDA 510(k) application. Quantitative fit factors were measured for each subject on two replicates of each of two N95 filtering facepiece respirators (A and B) using the TSI Portacount Plus with N95 Companion. Subjects received no training or assistance with donning and had no prior experience with wearing respirators. The panel consisted of 20 females and 15 males; 80% were between 18 and 34 years of age. Almost all subjects properly placed the respirator on the face and formed the nose clip. Straps were improperly placed 25% of the time. Users reviewed the donning instructions 73% of the time and performed a seal check 80% of the time. Leaks were observed during 80% of the fit tests, most frequently at the chin during the head up and down exercise. For Respirator A, all but one subject had a 95% fit factor greater than 2 (the minimum required by FDA); one subject had a 95% fit factor of 1.5. All subjects had a 95% fit factor greater than 2.5 for Respirator B. Geometric mean fit factors ranged from 19-28 for these two respirators, and a majority of subjects were able to achieve a fit factor of 10 most of the time. However, fewer than 25% of subjects received the fit factor of 100 expected in workplace settings. PMID- 20853204 TI - Motor variability in sports: a non-linear analysis of race walking. AB - This aim of this study was to analyse the nature of movement variability and to assess whether entropy measures may represent a valuable synthetic index of neuromuscular organization. The regularity of kinematic/kinetic time series during race walking, the changes in the structure of intra-individual variability over the test session, and the influence of athletic skill in (inter)national rank athletes were investigated. Motion analysis techniques were used. Sample entropy (SampEn) was adopted to examine fluctuations in lower limb angles and ground reaction forces. The regularity of both original and surrogate time series was assessed and compared, by estimating SampEn, to verify the presence of non linear features in movement variability. SampEn was statistically lower in the original data than in surrogates. In contrast, the regularity of time series did not change significantly throughout the subsequent intra-individual repetitions. Hip and ankle joint angles and vertical ground reaction force manifested increased entropy for skilled athletes. Results suggest that race walking variability was not only the product of random noise but also contained information about the inherent propriety of the neuro-musculo-skeletal system. Furthermore, they provide some indications about neuromuscular control of the lower limb joints during race walking gait, and about the differences between more and less skilled individuals. PMID- 20853205 TI - Concentrations of salivary testosterone, cortisol, and immunoglobulin A after supra-maximal exercise in female adolescents. AB - The aim of this study was to examine the effect of supra-maximal exercise on circulating concentrations of salivary testosterone, salivary cortisol, and salivary immunoglobulin A in female adolescents. Nineteen apparently healthy females aged 15-16 years participated in this study. All participants completed 668 s sprints, interspersed with 30 s recovery intervals on a cycle ergometer. Salivary testosterone, cortisol, and immunoglobulin A samples were taken before and 5 min after exercise. Experimental procedures continued over two mornings, at least 3 h after a light breakfast. Participants refrained from performing any strenuous physical activity for at least 24 h prior to the exercise test. None of the participants were engaged in a structured training programme. The group mean (+/- s) for peak power output was 562 +/- 113.0 W. Female adolescents recruited for this study showed no changes in salivary testosterone, cortisol or immunoglobulin A following repeated bouts of supra-maximal cycling (P > 0.05). To date, there has been a paucity of information concerning adolescents' hormonal and mucosal immune function responses to supra-maximal exercise. Our data provide further guidance with regard to physical activities and sports prescription for female adolescents. Further research, on a larger sample of females, is required to elucidate the physiological significance of these findings. PMID- 20853206 TI - Collecting kinematic data on a ski/snowboard track with panning, tilting, and zooming cameras: is there sufficient accuracy for a biomechanical analysis? AB - For biomechanical research in several sports (e.g. skiing and snowboarding), field experiments are essential because these activities are performed over a great distance and in conditions that could not be reproduced in a controlled laboratory environment. High technical standards in kinematic set-up are necessary to achieve the required accuracy for biomechanical analysis. The purpose of this study was to determine the accuracy of the kinematic data collected in a ski and snowboard field experiment. Eight tests generally used in laboratory settings were adapted to field conditions on a skiing slope to determine the error related to motion capture. The calculated photogrammetric errors in the x-, y-, and z-direction were 11 mm, 9 mm, and 13 mm, respectively. The maximum error caused by soft tissue artifacts was 39 mm. These results indicate that accuracy of kinematic data in the described field experiment was comparable to that found in literature for laboratory experiments. It may be concluded that accurate kinematic data collection for skiing and snowboarding can be performed in a field setting and that these results are accurate enough to serve as input data for further analyses. PMID- 20853207 TI - Kinematic analysis of netball goal shooting: a comparison of junior and senior players. AB - The aim of this study was to investigate the effect of playing experience on the kinematic characteristics of the goal shooting action in netball players. Six county-level junior and six senior goal shooters took part in the study. They were asked to perform eight shots at goal and were equipped with 33 retro reflective markers fixed to anatomical landmarks for three-dimensional motion tracking. The shot was divided into three periods: start of throw, shooting action, and release. The following variables were determined for each period: position of the ball, joint angles, timings between actions, joint angular velocities, and ranges of motion. The main results showed a significant effect of playing experience, with senior shooters showing a shorter delay between the movements involved in the shooting action, a significant difference between the right and left elbow angles at the start of forearm extension, and greater extension of the left shoulder and greater flexion of the left elbow at release compared with junior shooters. These results might help justify some of the empirical observations made by coaches and direct them in their advice to players. In particular, recommendations to junior players should focus on the simultaneity of leg and arm actions and dissociation between the right and left arms during the shooting action. PMID- 20853208 TI - Poverty and union formation among never-married single mothers in the Netherlands, 1989-2005. AB - Using panel data from Dutch tax records linked to the municipality registry, we investigate how the partner status of never-married single mothers changes in the years after the birth of their first child. To explore a possible accumulation of financial problems, we study the effects of income on the chances of entering a marital or cohabiting union. We also examine the effects of finding a partner on income for never-married single mothers. Finding a partner substantially improves income. We find that about half of the never-married single mothers marry or start cohabiting within 10 years of the first birth, but that these are usually mothers with average and higher incomes. Not only are never-married single mothers more likely to be poor at the time of first birth, the poor are also more likely to remain single. There seems to be an accumulation of disadvantage in this special group in Dutch society. PMID- 20853209 TI - Post-traumatic stress disorder and HIV: a snapshot of co-occurrence. AB - Although the medical advances in the area of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) have undoubtedly improved the length and quality of life for those who are HIV-affected and medication adherent, there are still many psychosocial obstacles to effective HIV/AIDS medication adherence. Recent research has focused on one such obstacle. The significant link between post-traumatic stress disorder (PTSD) and HIV. This article reports on the nature of this relationship with a cross-sectional study of active clients (n = 186) who were receiving HIV services from community-based settings in the New York City area. With the use of the PTSD Checklist (PCL), this study determined that more than half of the sample tested positively for PTSD. Policy and clinical implications of this and other findings are discussed. PMID- 20853210 TI - Discoveries on a data-mining expedition: single session social work in hospitals. AB - Data-mining is a method for practice-based research that draws on existing organizational data to inform practice issues and build social work knowledge. This article reports on how a study investigating social work practice questions about the nature and extent of single session work in hospitals was enhanced by accessing the extensive hospital patient data system. Useful descriptive statistics on the level, purpose, location, and activities of single session social work in nine hospitals in a region of Australia were generated from the patient data. The researchers also report on the importance of a consultative and collaborative process for effective data-mining outcomes. PMID- 20853211 TI - Nursing assistant beliefs about their roles and nursing home residents: implications for nursing home social work practice. AB - The purpose of this study is to examine beliefs and assumptions held by nursing assistants working in nursing homes using a qualitative approach. Unchallenged notions about residents and the roles held by nursing assistants influence their way of interacting with residents, which inevitably influences quality of care in nursing homes. When nursing assistants have an opportunity to be heard and mentored by social workers, they can address and resolve the dilemma of providing informal care as a formal caregiver by discussing what is acceptable and appropriate in nursing home care. PMID- 20853213 TI - Disrupted caregiving and maternal HIV disease: a proposed model for evaluating HIV-affected children's psychosocial adjustment. AB - A current concern among social science researchers is the impact of human immunodeficiency virus (HIV) disease on the family, especially on the parenting abilities of mothers with HIV. Beginning research suggests that the children of HIV-positive parents are vulnerable, pointing to the impact of HIV disease on children's social and emotional adjustment. The objective of this article is to propose a model of the HIV disease-related disruption of care on children's psychosocial adjustment. The schematic model can be used to evaluate the mechanisms by which maternal HIV disease may influence the psychosocial adjustment of elementary school-age children. PMID- 20853212 TI - Do trajectories of at-home dementia caregiving account for burden after nursing home placement? A growth curve analysis. AB - Transitioning to the nursing home setting is a complex process for family caregivers of older adults with dementia. While nursing home placement (NHP) can alleviate certain caregiving responsibilities, new stressors can also emerge. In the present study, the researchers examined how care-related factors can change leading up to NHP and how these factors influence caregiver outcomes following NHP. A sample of 634 family dementia caregivers (n = 634) were surveyed at three six-month intervals prior to NHP and once during the 12 month period following institutionalization. Growth curve modeling revealed dynamic changes in certain factors leading up to NHP (e.g., caregivers' perceived health), while other factors remained stable (e.g., caregiver burden). Several factors emerged as significant predictors of caregiver burden following NHP, including pre-placement burden and adult day service utilization. For geriatric social workers, these findings may be useful in assessing family caregivers, and in the development and utilization of appropriate interventions. PMID- 20853215 TI - Complex attentional control settings. AB - The visual system prioritizes information through a variety of mechanisms, including "attentional control settings" that specify features (e.g., colour) that are relevant to current goals. Recent work shows that these control settings may be more complex than previously thought, such that participants can monitor for independent features at different locations (Adamo, Pun, Pratt, & Ferber, 2008). However, this result leaves unclear whether these control settings affect early attentional selection or later target processing. We dissociated between these possibilities in two ways. In Experiment 1, participants were asked to determine whether a target object, which was preceded by an uninformative cue, matched one of two target templates (e.g., a blue vertical object or a green horizontal object). Participants monitored for independent features in the same location, but in different objects, which should reduce the effectiveness of the control setting if it is due to early attentional selection, but not if it is due to later target processing. In Experiment 2, we removed the ability of the cue to prime the target identity, which makes the opposite prediction. Together, the results suggest that complex attentional control settings primarily affect later target identity processing, and not early attentional selection. PMID- 20853216 TI - Relationships between menstrual and menopausal attitudes and associated demographic and health characteristics: the Hilo Women's Health Study. AB - The objective of this study was to examine the relation of menstrual attitudes to menopausal attitudes and the demographic and health characteristics associated with each. This cross-sectional study consisted of a randomly selected sample of 1,824 respondents aged 16 to 100 years in multi-ethnic Hilo, Hawai'i. Women completed questionnaires for demographic and health information, such as age, ethnicity, education, residency in Hawai'i, menopausal status, exercise, and attitudes toward menstruation and menopause. Women more often chose positive terms, such as "natural," to describe menstruation (60.8%) and menopause (59.4%). In bivariate analyses, post-menopausal women were significantly more likely to have positive menstrual and menopausal attitudes than pre-menopausal women. Factor analyses were used to cluster attitudes followed by linear regression to identify demographic characteristics associated with factor scores. Asian American ethnicity, higher education, reporting more exercise, and growing up outside of Hawai'i were associated with positive menstrual attitudes. Higher education, older age, post-menopausal status, growing up outside of Hawai'i and having hot flashes were associated with positive menopausal attitudes. Bivariate correlation analyses suggested significant associations between factor scores for menstrual and menopausal attitudes. Both negative and positive menstrual attitudes were positively correlated with the anticipation of menopause, although negative attitudes toward menstruation were negatively correlated with menopause as a positive, natural life event. Demographic variables, specifically education and where one grows up, influenced women's attitudes toward menstruation and menopause and should be considered for inclusion in subsequent multi-ethnic studies. Further research is also warranted in assessing the relationship between menstrual and menopausal attitudes. PMID- 20853217 TI - Missed opportunities to prevent perinatal human immunodeficiency virus transmission in 15 jurisdictions in the United States during 2005-2008. AB - The objective of this study was to identify factors related to failure to receive recommended interventions for the prevention of mother-to-child HIV transmission among HIV-infected pregnant women in the United States. Using Enhanced Perinatal Surveillance data from 2005 through 2008, we identified characteristics of HIV infected women (n = 5,391) that increased their odds of missing an opportunity to prevent perinatal HIV transmission. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were calculated by using backward step-wise logistic regression analyses to determine the relationship between demographic variables and missed opportunities. Of 4,220 HIV-infected pregnant women with complete data, 2,545 (60%) did not receive all of the recommended interventions. Missed opportunities for prevention occurred more often among HIV-infected women aged 25-34 years (aOR = 1.9, 95% CI = 1.4-2.5), and greater than 34 years (aOR = 2.0, 95% CI = 1.5-2.7) compared to those 13-19 years and among injection drug users (aOR = 1.3, CI = 1.0-1.5) compared to women infected with HIV through heterosexual contact. Clinicians can decrease missed opportunities by routinely providing recommended interventions, especially among HIV-infected women who are injection drug users or aged 25 years or older. PMID- 20853218 TI - Factors associated with health information-seeking in low-income pregnant women. AB - The purpose of this study was to examine the relationships of health literacy, self-efficacy, and fetal health locus of control to health information-seeking in low-income pregnant women and the contribution from each factor alone or in combination to the variance in health information-seeking. This was a cross sectional study of 143 English-speaking pregnant women who were recruited from a prenatal clinic and were 18 years of age or older in 2007-2008. Health literacy, self-efficacy, fetal health locus of control, and health information-seeking were measured using the Short Form of the Test of Functional Health Literacy in Adults, the Health Information Competence Scale, the Fetal Health Locus of Control Scale, and the Pregnancy Health Information-Seeking Scale. Health literacy was not significantly correlated with health information-seeking. Self efficacy (r = .33) and internal fetal health locus of control (r = .27) demonstrated significant correlations with health information-seeking, and together they accounted for 15% of the variance in health information-seeking. After controlling for covariates, self-efficacy (p = .0006) and internal fetal health locus of control (p = .03) remained significantly associated with health information-seeking. In conclusion, pregnant women's characteristics, such as self-efficacy and internal fetal health locus of control belief, are associated with their health information-seeking during pregnancy. PMID- 20853219 TI - Self-esteem and perception of quality of life among Israeli women with and without physical disability. AB - This study compared the relationship between self-esteem and perceived quality of life among Jewish Israeli women with and without physical disabilities, and estimated the moderating effects of marital status and age on these relationships. A quasi-experimental design was employed. A total of 134 women aged from 21 to 45 years participated in the study: 70 of them with disabilities and 64 without disabilities (case and control groups, respectively). Significant differences were found between these groups in marital status, education, and employment. The mean self-esteem and perceived quality of life scores of women with physical disabilities were significantly lower than those of the control group. These differences were much more significant among young adult women (21 30 years) than among older women. General self-esteem was the main factor that explained the variance in perceived quality of life in both groups of women: with and without disabilities. The study revealed a significant moderating effect of marital status on the association between self-esteem and perceived quality of life only among women with physical disabilities. In cases in which the general self-esteem level was the same, the perceived quality of life score was higher among married women with physical disabilities than among single women. These results can be used in planning therapeutic interventions, including the development of educational programs for women with disabilities. PMID- 20853220 TI - The relationship of chronic disease and demographic variables to physical activity in a sample of women aged 65 to 79 years. AB - This study explored the relationship between physical activity, marital status, income, education, and chronic disease in older women to determine which individuals are at risk of being inactive and to identify potential moderators of physical activity behavior. This was an analysis of cross-sectional data from a convenience sample of 271 community-dwelling women aged 65 to 79 years. Self reported physical activity was measured using the Physical Activity Scale for the Elderly. Socio-demographic characteristics (including age, gender, marital status, education, employment, and income) and self-reported health were measured using previously validated instruments. To avoid seasonal variations in physical activity, data were collected during the summer months. Physical activity was negatively associated with age and the presence of cardio-respiratory disease and positively associated with income greater than $20,000 (p < 0.05). After controlling for other co-variates, no significant differences were observed in physical activity between married and unmarried individuals. Given the strong association between cardio-respiratory disease and income with physical activity, women 65 years of age and older in lower income brackets and suffering from these health conditions should be targeted for exercise counseling and support. Intervention research is needed to determine the most effective means to decrease inactivity among these women. PMID- 20853221 TI - Factors associated with postmenopausal osteoporosis: a case-control study of Belgrade women. AB - The aim of this study was to investigate factors related to osteoporosis in postmenopausal women in Belgrade. A case-control study was conducted during 2006 2007. The study group consisted of 100 newly diagnosed osteoporosis patients and 100 age-matched controls (+/- 2 years). The inclusion criteria for the case group were newly diagnosed osteoporosis confirmed by dual-energy X-ray absorptiometry of the lumbar spine and being menopausal (at least 2 years of amenorrhea). The inclusion criteria for the control group were postmenopausal women with confirmed normal bone mineral density of the lumbar spine by dual-energy X-ray absorptiometry. All study participants were interviewed using a structured questionnaire. Univariate and multivariate logistic regression analyses were used. The following factors were significantly independently related to osteoporosis: low body weight (P < 0.001), thin constitution in childhood (P = 0.002), history of previous fracture (P = 0.033), menopause at age <47 years (P < 0.001), family history of fracture (P = 0.005), and less frequent consumption of cheese (P = 0.027) and fish (P = 0.020). The majority of factors identified may be modifiable and could be influenced to prevent postmenopausal osteoporosis. PMID- 20853224 TI - An introduction to stem cell biology. AB - The field of stem cell biology has undergone tremendous expansion over the past two decades. Scientific investigation has continued to expand our understanding of these complex cells at a rapidly increasing rate. This understanding has produced a vast array of potential clinical applications. This article will serve as an overview of the current state of stem cell research as it applies to scientific and medical applications. Included in the discussion is a review of the many different types of stem cells, including but not limited to adult, embryonic, and perinatal stem cells. Also, this article describes somatic cell nuclear transfer, an exciting technology that allows the production of totipotent stem cells from fully differentiated cells, thereby eliminating the use of embryonic sources. This discussion should serve as a review of the field of stem cell biology and provide a foundation for the reader to better understand the interface of stem cell technology and facial plastic and reconstructive surgery. PMID- 20853225 TI - Overview of current thoughts on facial volume and aging. AB - Facial aging is a dynamic process involving the aging of soft tissue and bony structures. Much is known in regards to how the face loses volume as the soft tissue structures age. Epidermal thinning and the decrease in collagen cause skin to lose its elasticity. Loss of fat, coupled with gravity and muscle pull, leads to wrinkling and the formation of dynamic lines. The aging process has also been shown to affect the facial bones. Multiple studies suggest that the bony aging of the orbit and midface is a process primarily of contraction and morphologic change. This loss of bony volume and projection may contribute to the aged appearance. In this review, we will demonstrate how specific soft tissue and bony aspects of the face change with age in both genders and what impact these structural changes may have on overall facial aesthetics. PMID- 20853226 TI - Fat harvesting techniques for facial fat transfer. AB - Fat grafting has become popular as a stand-alone technique or as part of a combined procedure for facial rejuvenation, as volume restoration has increasingly become recognized as an important component in overall facial aging. Many facial plastic surgeons who are experienced in operating only in the head and neck region are unaccustomed to working elsewhere in the body. Accordingly, this article sets out to detail the specific technique for safe and effective lipoharvesting for facial fat transfer. In addition, site-specific considerations for the lower abdomen, inner/anterior/outer thighs, triceps, inner knee, buttock, and lower back are also discussed. PMID- 20853227 TI - Lipotransfer in the upper third of the face. AB - Autologous lipotransfer provides an effective means of volume restoration for facial rejuvenation. The upper one-third of the face falls victim to age-related volume depletion and can be a target for fat transfer. This article describes the senior author's technique of fat transfer in some of the specific anatomic subunits of the upper face. PMID- 20853228 TI - Fat grafting of the midface. AB - Autogenous fat injection of the midface is a viable and lasting remedy for midface soft tissue loss and has become a mainstay in facial rejuvenation. This serves as either a stand-alone technique or as an adjunct to other restorative lifting and repositioning techniques depending on patient needs. Although the use of fat grafting carries the inherent concern for resorption and a need for additional augmentation in the future, several tenets of fat transfer have emerged over the past century. Founded in these principles, the regimen set forth here has proved reliable and reproducible with little to no evidence of resorption over time. PMID- 20853229 TI - Autologous fat grafting viability: lower third of the face. AB - The process of aging is the result of subcutaneous loss of volume, in addition to vertical tissue descent. Surgeons are therefore emphasizing soft tissue augmentation to achieve a natural, rejuvenated appearance in patients. Autologous fat grafting is now a commonly performed aesthetic procedure. Autologous fat grafting is a challenging procedure, due to the fragile characteristic of adipose tissue. Viability of transplanted fat is a main consideration when fat grafting is performed. Poor fat viability produces an inadequate result and thus can be considered as a complication of this procedure. Many studies have demonstrated that fat longevity is dependent upon handling and preparation of fat. This article outlines the history of autologous fat grafting. The technique of fat grafting is described, along with review of the evidence of fat viability according to the technique used. The specific technique for autologous fat grafting in the lower third of the face is described including augmentation of the labiomandibular fold, lips, chin, and the jaw. PMID- 20853230 TI - Clinical applications of stem cells in craniofacial surgery. AB - Few areas of translational medicine carry as much excitement and hope as stem cell therapies. Because of recent advances in material science and stem cell and developmental biology that help to target molecules and pathways to restore the body's regenerative capacity, the "engineering" of missing tissue is quickly becoming a reality. Classically, tissue engineering has been thought to require external regenerative resources including a scaffold, cells, and growth factors. The allure of providing an exact replica of a missing bone that incorporates to become indistinguishable from self, has the capacity to heal and grow, is resistant to infection, and has minimal morbidity is a "holy grail" to all surgeons who work with bone. This article attempts to shed light on the use of stem cells for craniofacial reconstruction, including important principles learned from other scientific disciplines, relevant animal models for tissue engineering, early clinical reports from our experience and that of others, and future directions. PMID- 20853231 TI - Septal cartilage tissue engineering: new horizons. AB - Cartilage tissue engineering is a dynamically changing field that has the potential to address some of the tissue repair challenges seen in nasal and craniofacial reconstructive surgeries. The scope of the problem includes limited autologous tissue availability, donor site morbidity associated with the harvesting of these tissue grafts, and the risk of an immune reaction to allogenic or synthetic implants that might be used as alternatives. Current tissue engineering strategies involve harvesting a small biopsy specimen from a patient and then isolating chondrocytes through enzymatic digestion of the extracellular matrix. These isolated chondrocytes can be expanded in monolayer and reseeded into a three-dimensional scaffold that could potentially be used as autologous surgical grafts. Using cell-expansion techniques, it would be feasible to generate abundant amounts of cartilage in defined shapes and sizes. The ideal tissue-engineered cartilage would resemble native tissue in terms of its biochemical, structural, and metabolic properties so that it could restore stability, function, and contour to the damaged or defective facial region. In this article, emerging technology and major challenges are described to highlight recent advances and overall trends within septal cartilage tissue engineering. PMID- 20853232 TI - Embryonic progenitor cells in adipose tissue engineering. AB - Adipose tissue is extensively used in facial plastic surgery as a soft tissue filler for small-to-large facial defects. Variable results with autologous fat grafting and lipoinjection has led to interest in alternative forms of adipose tissue, including tissue engineered adipose tissue. Tissue engineering combines cells, scaffolds, and bioactive signals to regenerate organs or tissue. Cell sources include preadipocytes, adult stem cells, and embryonic stem cells. Although adult cells may be easily accessible from a patient, embryonic progenitor cells have comparative advantages over adult stem cells including indefinite self-renewal (high proliferative and expansion capacity) and strong tissue-forming capacity. This article will describe the types of embryonic progenitor cells and the cell culture conditions, common biomaterials, signaling factors, and biomechanical forces used in adipose tissue engineering. We will identify optimal conditions to generate functional, long-lasting adipose-like tissue. Lastly, we will propose potential future directions for the rapidly expanding field of adipose tissue engineering. PMID- 20853233 TI - Adipose tissue engineering from adult human stem cells: a new concept in biosurgery. AB - Current autologous fat grafting technique suffers from the drawbacks of donor site morbidity and, more importantly, significant resorption of the grafted fat. Adipose tissue engineering using adult human stem cells has been found to overcome the shortcomings of autologous fat grafting in reconstructing facial defects. Mesenchymal stem cells that can self-renew and differentiate into mature adipocytes have been used to generate adipose tissue, in both in vitro and in vivo cell transplantation studies. However, long-term maintenance of the shape and dimension of the produced adipose tissue remains a challenge, even in tissue engineering with cell transplantation. The choice of appropriate scaffolds to promote stem cell adhesion, proliferation, and differentiation is essential for successful adipogenesis. Recent advances in nanotechnology allow the development of nanostructured scaffolds with a cellular environment that maximally enhances not only cell expansion but also the neovascularization that is crucial for long term maintenance of cell volume. Cell homing is a technique that actively recruits endogenous host stem cells into a predefined anatomic location for the desired tissue generation. Bypassing ex vivo cell manipulation, the cell homing technique eliminates donor site morbidity and rejection, reducing the regulation issue in clinical translation. Mao et al. introduced the concept of biosurgery, which combined nanostructured scaffolds and growth factor biocues, with or without cell transplantation, for successful de novo adipogenesis in restoring facial defects. Important questions, such as the necessity of cell transplantation in scaling up the size of engineered adipose tissue, need to be answered with further studies. However, the era of biosurgery replacing conventional treatments such as biologically inactive filler injections and alloplastic implants appears to be in the near future. PMID- 20853234 TI - Stem cell and peripheral nerve injury and repair. AB - Peripheral motor nerve injuries are a significant source of morbidity. Neural stem cells (NSCs), a group of relatively primitive cells, possess self-renewal ability and multidifferentiation potential. NSCs may be successfully separated from the human embryo and central nervous system (CNS) and differentiated into mature neurons and gliacytes by in vitro induction or transplantation into the body and may be differentiated into Schwann-like cells under specific conditions. It has been demonstrated that the ability of peripheral nerves to regenerate is mainly attributable to Schwann cells. NSC transplantation can promote peripheral nerve regeneration and provide a new means for treatment of peripheral nerve injury. In recent years, the study of NSCs has become a focus of many laboratories, but the biological characteristics and differentiation regulation mechanisms are not fully clear. In this article, we provide a brief review of NSC characteristics, cultivation, oriented differentiation, and clinical application. PMID- 20853235 TI - Brighter Smiles Africa--translation of a Canadian community-based health promoting school program to Uganda. AB - PROJECT GOAL: To adapt a successful Canadian health-promoting school initiative to a Ugandan context through international partnership. RATIONALE: Rural children face many health challenges worldwide; health professionals in training understand these better through community-based learning. Aboriginal leaders in a Canadian First-Nations community identified poor oral health as a child health issue with major long-term societal impact and intervened successfully with university partners through a school-based program called "Brighter Smiles". Makerere University, Kampala, Uganda (MUK) sought to implement this delivery model for both the benefit of communities and the dental students. KEY STEPS/HURDLES ADDRESSED: MUK identified rural communities where hospitals could provide dental students with community-based learning and recruited four local schools. A joint Ugandan and Canadian team of both trainees and faculty planned the program, obtained ethics consent and baseline data, initiated the Brighter Smiles intervention model (daily at-school tooth-brushing; in-class education), and recruited a cohort to receive additional bi-annual topical fluoride. Hurdles included: challenging international communication and planning due to inconsistent internet connections; discrepancies between Canadian and developing world concepts of research ethics and informed consent; complex dynamics for community engagement and steep learning curve for accurate data collection; an itinerant population at one school; and difficulties coordinating Canadian and Ugandan university schedules. ACCOMPLISHMENTS: Four health-promoting schools were established; teachers, children, and families were engaged in the initiative; community-based learning was adopted for the university students; quarterly team education/evaluation/service delivery visits to schools were initiated; oral health improved, and new knowledge and practices were evident; an effective international partnership was formed providing global health education, research and health care delivery. PMID- 20853236 TI - Tips for better visual elements in posters and podium presentations. AB - CONTEXT: The ability to effectively communicate through posters and podium presentations using appropriate visual content and style is essential for health care educators. OBJECTIVES: To offer suggestions for more effective visual elements of posters and podium presentations. METHODS: We present the experiences of our multidisciplinary publishing group, whose combined experiences and collaboration have provided us with an understanding of what works and how to achieve success when working on presentations and posters. Many others would offer similar advice, as these guidelines are consistent with effective presentation. FINDINGS/SUGGESTIONS: Certain visual elements should be attended to in any visual presentation: consistency, alignment, contrast and repetition. Presentations should be consistent in font size and type, line spacing, alignment of graphics and text, and size of graphics. All elements should be aligned with at least one other element. Contrasting light background with dark text (and vice versa) helps an audience read the text more easily. Standardized formatting lets viewers know when they are looking at similar things (tables, headings, etc.). Using a minimal number of colors (four at most) helps the audience more easily read text. For podium presentations, have one slide for each minute allotted for speaking. The speaker is also a visual element; one should not allow the audience's view of either the presentation or presenter to be blocked. Making eye contact with the audience also keeps them visually engaged. CONCLUSIONS: Health care educators often share information through posters and podium presentations. These tips should help the visual elements of presentations be more effective. PMID- 20853237 TI - Factors that affect implementation of web-based faculty evaluation forms: residents' perspectives from a developing country. AB - CONTEXT: A web-based evaluation system for residents to provide feedback on faculty was piloted in four training programs at the Aga Khan University prior to institution-wide implementation. Of the four programs, less than 50% of forms were submitted by residents of three programs while more than 70% of forms were submitted by the residents of one program. This study was conducted to identify reasons for the varying participation rates of the four programs with a view to improving the system. METHODS: A qualitative approach was employed using focus group discussions (FGDs). Volunteers were invited and three groups of eight to ten residents each were formed. Participants for FGDs were selected from all residency years. FGDs were used to identify residents' perceptions regarding the web-based faculty evaluation system and to identify residents' problems and concerns with completing the web-based faculty evaluating forms. RESULTS: Technical issues in completing and submitting the forms online were identified to be the main deterrents to completing the evaluation forms. Non-accessibility of a resource person for resolving technical problems with the software and the burden of taking time out to complete the forms were considered as limiting factors by many residents. Residents recommended a focused orientation session to the new system within the departments. CONCLUSION: Residents' confidence and support are key to promoting adequate participation in web-based evaluations. Focused orientation sessions, reinforcement, reminders, assurances of confidentiality, and removal of technical glitches should help to improve resident participation. PMID- 20853238 TI - What community-based preceptors want in teaching medical students: findings from a mixed methods study. AB - CONTEXT: Clinical clerkships in medical colleges are increasingly relying on teaching by community physicians in ambulatory clinics. OBJECTIVES: The aim of the study was to determine the attitudes and perceptions of community physicians towards teaching medical students at their clinics. METHODS: A focus group discussion with 14 and a survey questionnaire of 23 community-based physicians were conducted. FINDINGS: The focus group discussion session yielded insight into the expectations of community physicians about student attachments, including: the need for learning objectives; continuity; feedback; ongoing communication; and planned placement of students. The answers to the survey questions showed willingness to teach medical students (mean score=4.7 on a scale of 1 to 5) and the view that medical students added value to the clinics (mean=4.4). However, the respondents gave lower ratings to the questions about students being able to independently evaluate patients in the beginning of their clerkship (mean=3.3). CONCLUSIONS: Community physicians request clear learning objectives, assessment criteria and advance planning for teaching medical students. Clerkship coordinators should ensure ongoing communication with community preceptors in these areas as well as offer recognition of teaching contribution and opportunities for professional development. PMID- 20853239 TI - The development of competency-based education for mid-level eye care professionals: a process to foster an appropriate, widely accepted and socially accountable initiative. AB - INTRODUCTION: The Western Pacific region has a dearth of appropriately educated eye care providers, training programs and large and increasing eye health needs. METHOD: To ensure regional eye health needs would be met, an iterative process sought triangulations between the literature and consultations with local stakeholders from various fields. This information was used to develop competencies to meet quality standards for educational outcomes. A framework for social accountability was used to evaluate the proposed educational initiative, and the subsequent eye care service the graduates could provide. RESULTS: Current human resource development and deployment is inadequate to protect and restore ocular and visual health in the region. Some of these service needs could be met by task-shifting from conventional health professionals to appropriately trained mid-level personnel. A competency-based curriculum was developed to meet eye care needs and define this new cadre of mid-level professionals in relation to other professionals. This initiative met the relevance, equity, cost effectiveness and quality criteria for social accountability. DISCUSSION: The consultative process resulted in broad acceptance of the need for an appropriately educated mid-level cadre that could be recruited, educated, deployed, supported and retained in the Western Pacific region to supplement and substitute for established eye care professionals. This process also provided validation of the initiative prior to implementation, as being appropriate to the region, meeting educational standards and social accountability criteria for outcomes. It could be replicated in other regions that wish to develop such an education for new cadres of health care professionals. PMID- 20853240 TI - Determinants of effective clinical learning: a student and teacher perspective in Saudi Arabia. AB - CONTEXT: Graduating clinically competent medical students is probably the principal objective of all medical curricula. Training for clinical competence is rather a complex process and to be effective requires involving all stakeholders, including students, in the processes of planning and implanting the curriculum. This study explores the perceptions of students of the College of Medicine at King Abdul-Aziz Bin Saud University for Health Sciences (KASU-HS), Riyadh, Saudi Arabia of the features of effective clinical rotations by inviting them to answer the question: "Which experiences or activities in your opinion have contributed to the development of your clinical competence? This college was established in 2004 and adopted a problem-based learning curriculum. METHODS: This question was posed to 24 medical students divided into three focus groups. A fourth focus group interview was conducted with five teachers. Transcriptions of the tape recorded focus group interviews were qualitatively analyzed using a framework analysis approach. FINDINGS: Students identified five main themes of factors perceived to affect their clinical learning: (1) the provision of authentic clinical learning experiences, (2) good organization of the clinical sessions, (3) issues related to clinical cases, (4) good supervision and (5) students' own learning skills. These themes were further subdivided into 18 sub-themes. Teachers identified three principal themes: (1) organizational issues, (2) appropriate supervision and (3) providing authentic experiences. CONCLUSION: Consideration of these themes in the process of planning and development of medical curricula could contribute to medical students' effective clinical learning and skills competency. PMID- 20853241 TI - Postgraduates' perceptions of preparedness for work as a doctor and making future career decisions: support for rural, non-traditional medical schools. AB - INTRODUCTION: The intern year is a critical time for making career decisions and gaining confidence in clinical skills, communication and teamwork practices; this justifies an interest in junior doctors' perceptions of their level of preparedness for hospital work. This study explored Australian junior doctors' perspectives regarding the transition from student to doctor roles, their preparation as medical undergraduates within either traditional metropolitan schools or smaller, outer metropolitan-based (rural) programs such as Rural Clinical Schools (RCS), and the educational environment they experienced in their internship. METHODS: A qualitative cross-sectional design used semi-structured interviews with postgraduate year one and two junior doctors (9 females and 11 males) within teaching hospitals in Queensland Australia. Interview questions focussed on four major content areas: preparedness for hospital work, undergraduate training, building confidence and career advice. Data were analyzed using a framework method to identify and explore major themes. RESULTS: Junior doctors who spent undergraduate years training at smaller, non-traditional medical schools felt more confident and better prepared at internship. More hands on experience as students, more patient contact and a better grounding in basic sciences were felt by interns to be ideal for building confidence. Junior doctors perceived a general lack of career guidance in both undergraduate and postgraduate teaching environments to help them with the transition from the student to junior doctor roles. DISCUSSION: Findings are congruent with studies that have confirmed student opinion on the higher quality of undergraduate medical training outside a traditional metropolitan-based program, such as a RCS. The serious shortage of doctors in rural and remote Australia makes these findings particularly relevant. It will be important to gain a better understanding of how smaller non-traditional medical programs build confidence and feelings of work readiness in graduates. Career advice should become a more regular part of the medical education continuum. PMID- 20853242 TI - Academic-community partnership: an orientation for employees of a community mental health agency to its research program. AB - CONTEXT: Community agency employees' interest and involvement in academic community research partnerships are keys to successful collaborations. One main barrier to success can be employees' lack of knowledge about research. We present data on an "orientation to research" program for community agency employees in a large U.S. city designed to improve knowledge about research in general and that specific to the agency. METHODS: We developed an agency intranet website, a scavenger hunt to facilitate learning through the intranet research website, and a ten-item quantitative knowledge assessment tool. Academic and agency partners were actively involved in the design of the program and its evaluation. FINDINGS: More educated and long-term employees had higher pre-test scores but not post test scores. Significant improvement in post-test scores was observed for employees after completion of the program. Informal feedback about course content and the academic-community partnership was positive. CONCLUSIONS: This report examines the feasibility of a structured knowledge program targeted at community agency employees at all levels within an agency. We believe that this approach is generalizable to other settings to the extent that there are shared interests, resources, and investment of the academic partner and agency. PMID- 20853243 TI - Helping students become the medical teachers of the future--the Doctors as Teachers and Educators (DATE) Programme of Barts and the London School of Medicine and Dentistry, London. AB - CONTEXT: In the United Kingdom (UK), learning about teaching is an integral part of the General Medical Council's recommendations for the undergraduate medical curriculum. Yet often, implementing this aspect of learning presents a challenge to curriculum organisers in terms of content, timing and student interest. PROGRAMME OBJECTIVES AND STRUCTURE: The Doctors as Teachers and Educators (DATE) programme was set up at Barts and the London School of Medicine and Dentistry specifically to meet the requirements for development in teaching. Although largely practical, the two-day programme offers an introduction to educational theory and the teaching requirements for junior doctors in training. The methods used are lectures and group work within plenary sessions, followed by small group micro-teaching sessions. The DATE programme has now been undertaken by over 900 graduates. EVALUATION METHODS: We evaluated the Date programme by means of end-of course questionnaires completed by two cohorts of students during the 2007/8 academic year and through the use of Nominal Group Technique in 2008/9. In line with the goals of the evaluation, the data on students' views were analysed to elicit self-reported learning and develop the programme. RESULTS: Response rates of the two cohorts to the surveys were high (80% and 98%). Nearly 100% of the students reported through the survey that they had gained confidence in teaching. In the nominal groups, students indicated that they had gained insight into educational principles like student-centredness and gained an appreciation for the nature of educational evidence and scholarship. They challenged the curriculum organisers to achieve an appropriate balance between theory and practice. CONCLUSIONS: A programme about teaching at the undergraduate medical level can be well-received by students; the DATE model could be transferred to other international contexts. PMID- 20853244 TI - Rationale for using OSCEs to assess student competency in evidence-based medicine. PMID- 20853245 TI - Communication skills training in English alone can leave Arab medical students unconfident with patient communication in their native language. AB - INTRODUCTION: Communications skills curricula and pedagogy for medical students are often exported to non-English speaking settings. It is assumed that after learning communication skills in English, doctors will be able to communicate effectively with patients in their own language. METHODS: We distributed a questionnaire to third year Emirati students at a medical school within the United Arab Emirates. We assessed their confidence in interviewing patients in Arabic after communication skills training in English. Of the 49 students in the sample, 36 subjects (73.5%) completed and returned the questionnaire. RESULTS: Nearly three-quarters (72.2%) of students said they felt confident in taking a history in English, while 27.8% of students expressed confidence in taking a history in Arabic. Half of students anticipated that after their training they would be communicating with their patients primarily in Arabic, and only 8.3% anticipated they would be communicating in English. CONCLUSIONS: Communication skills training purely in English can leave Arab medical students ill equipped to communicate with patients in their own communities and tongue. PMID- 20853246 TI - How to make healthcare delivery in India more "informed". PMID- 20853247 TI - In the news! An opinion feelings about students' emotions. PMID- 20853248 TI - Education for health: what's in a name? PMID- 20853249 TI - Co-editors' notes 23:2. PMID- 20853250 TI - Back to the future: extended dialysis for treatment of acute kidney injury in the intensive care unit. AB - On September 11, 1945, Maria Schafstaat was the first patient who successfully underwent a dialysis treatment for acute kidney injury (AKI). The ingenious design of the first dialysis machine, made of cellophane tubing wrapped around a cylinder that rotated in a bath of fluid, together with the brave determination to treat patients with AKI, enabled the Dutch physician W.J. Kolff to save the life of the 67-year-old woman. By treating her for 690 minutes (i.e., 11.5 hours) with a blood flow rate of 116 ml/min, Kolff also set the coordinates of a renal replacement therapy that has enjoyed an unsurpassed renaissance over the last decade for treatment of severely ill patients with AKI in the intensive care unit (ICU). Prolonged dialysis time with low flow rates - these days, called extended dialysis (ED) - combines several advantages of both intermittent and continuous techniques, which makes it an ideal treatment method for ICU patients with AKI. This review summarizes our knowledge of this method, which is increasingly used in many centers worldwide. We reflect on prospective controlled studies in critically ill patients that have documented that small-solute clearance with ED is comparable with that of intermittent hemodialysis and continuous venovenous hemofiltration, as well as on studies showing that patients' cardiovascular stability during ED is similar to that with continuous renal replacement therapy. Furthermore, we report on logistic and economic advantages of this method. We share our view on how extended dialysis offers ample opportunity for a collaborative interaction between nephrologists and intensivists as the nephrology staff, enabling optimal treatment of complex critically ill patients by using the skill and knowledge of 2 indispensable specialties in the ICU. Lastly, we address the problem of ED intensity, which does not seem to have an impact on survival at higher doses, a finding that might be caused by the fact that we still adhere to dosing guidelines for antibiotics which are at best ineffectual but might also lead to potentially dangerous underdosing of these life-saving drugs. PMID- 20853251 TI - VenaTracTM device for over-the-wire placement of chronic dialysis catheters. AB - PURPOSE: The VenaTracTM is designed for exchange and primary placement of chronic tunneled hemodialysis catheters over a wire. It occludes both lumens of the catheter for the purpose of reducing the risk of air embolism and blood loss. The purpose of this paper is to report our experience with the use of this device. METHODS: A retrospective review of chronic hemodialysis dialysis catheters exchanges over a 30-month period was performed. Two hundred and ninety-seven over the-wire catheter exchanges and 47 primary placements using the VenaTracTM device were reviewed. In addition, 430 over-the-wire catheter exchanges without the use of the VenaTracTM were reviewed. RESULTS: No insertional complications or air embolism occurred when using the VenaTracTM. Symptomatic air embolism was documented in 5 out of 430 catheter exchanges performed without the use of VenaTracTM (1.2%). CONCLUSIONS: VenaTracTM over-the-wire insertion device demonstrated safe and reliable use with no incidence of air embolism. PMID- 20853252 TI - Endovascular treatment of dysfunctional hemodialysis catheters. AB - Hemodialysis-catheter dysfunction is a common clinical condition in nephrology. Like other central venous devices, hemodialysis-catheters show a disposition for partial or complete thrombotic obstruction and fibrin sleeve formation. Thrombolytic infusion is recommended as therapy of first choice. Alternative interventional strategies include over-the-wire catheter exchange, mechanical fibrin sleeve stripping with a snare and angioplastic sleeve disruption. Those approaches show extremely variable results with mediocre long-term patency rates. Therefore, catheter-avoiding strategies should be considered in detail and AV fistula creation preferred. PMID- 20853253 TI - Myofascial necrosis as a complication of central venous catheterization in a patient with paroxysmal nocturnal hemoglobinuria. PMID- 20853254 TI - Treatment for acetabular dysplasia using the uncemented RM acetabular component - a 20 year follow-up. AB - Our study reports a sub-group of patients with developmental dysplasia from a previously published larger series, with particular emphasis on the use of the uncemented RM acetabular component. We evaluated the long term results of 93 consecutive uncemented THAs in 80 patients using the titanium-coated RM acetabular component and the CLS femoral component in a prospective study. Eighteen hips in 16 patients had osteoarthritis secondary to developmental dysplasia of the hip. The mean follow-up was 19.6 years (18.2 to 20.9). Fourteen patients with 15 hips were clinically and radiographically examined and evaluated. Two patients with 3 hips died. No patient was lost to follow-up. No implant had to be revised, and no cases showed evidence of radiographic loosening. Nine acetabular components were not completely covered by host bone but this did not affect the outcome. At the latest follow-up the mean Harris Hip Score was 92 (81 to 100). The mean annual wear rate was 0.12 mm. The RM acetabular component performed well over 20 years in this selected group of patients. Complete acetabular containment was not needed, thus allowing reliable reconstruction of the anatomical centre of rotation. PMID- 20853255 TI - Polypoidal choroidal vasculopathy and macroaneurysm: respective roles of scanning laser ophthalmoscopy-indocyanine green angiography and optical coherence tomography. AB - PURPOSE: To report on a patient with exudative age-related macular degeneration, polypoidal choroidal vasculopathy, and macroaneurysm. METHODS: Scanning laser ophthalmoscopy (SLO)-indocyanine green angiography (ICGA) demonstrated the coexistence of several lesions in the same patient. Optical coherence tomography (OCT) combined with ICGA defined the nature of the lesions and the severity of the exudative phenomena. RESULTS: The eye tracking system ensured precise follow up of the course of the lesions on both ICGA and spectral domain (SD) OCT. Image correlation provided a precise diagnosis, defining the indications for local and systemic therapy. CONCLUSIONS: In this patient with multiple lesions, only correlation of clinical examinations and SLO-ICG and SD-OCT imaging allowed a complete assessment with the proposal of a coherent and effective treatment plan. PMID- 20853256 TI - Recent trends in medical statistics: their relevance to evidence-based medicine and to complementary alternative medicine. PMID- 20853257 TI - Validity and limits of the rebound tonometer (ICare(r)): clinical study. AB - PURPOSE: The aim of this study was to evaluate the measurement of intraocular pressure (IOP) using a new induction/impact rebound tonometer (ICare(r)) compared with Goldmann applanation tonometry (GAT). We also aimed to quantify the systematic and random errors (bias) of the 2 methods, to evaluate the sensitivity and specificity of the ICare(r) tonometer in identifying patients with 21 mmHg or more measured with the GAT, and to study the influence of corneal thickness on IOP measurement with the 2 tonometers. METHODS: We compared the IOP values obtained with the 2 instruments in 97 patients. RESULTS: Analysis based on the Bland and Altman method revealed that the IOP values recorded with the ICare(r) tonometer were slightly higher than those obtained with the GAT. The estimated bias for right eye measurements was 0.78 mmHg with 95% limits of agreement +/ 3.55 mmHg. This overestimation, which is not clinically relevant, was confirmed when we used the IOP values corrected according to central corneal thickness for data analysis. The sensitivity and specificity were 0.90 and 0.95, respectively. CONCLUSIONS: The ICare(r) tonometer proved to be comparable with other nonconventional tonometers and can be used by nonophthalmologists and paramedical personnel during screening tests of populations. In addition, the ICare(r) tonometer could be considered a valid alternative to GAT when GAT is not available. PMID- 20853258 TI - Posterior hyaloid peeling in advanced stages of aggressive posterior ROP. AB - PURPOSE: To evaluate the indications and timing of surgical intervention on eyes with aggressive posterior retinopathy of prematurity (ROP). METHODS: Retrospective review of a consecutive case series of 9 eyes of 7 children, with aggressive posterior ROP, who underwent early lens-sparing vitrectomy. Preoperative retinal and vitreal features, intraoperative and postoperative complications, postoperative anatomic status, and fixation behavior 1 year after surgery were investigated. RESULTS: Vitreous hemorrhage and recurrence of plus disease with retinal detachment were the main indications for surgery. Vitrectomy was performed from the 37th to the 44th postmenstrual week (mean 40th week). In 7 eyes, vitrectomy could stop the disease progression. In all of these cases, posterior hyaloid could be peeled together with the proliferative tissue. CONCLUSIONS: Lens-sparing vitrectomy with posterior hyaloid peeling at early postmenstrual ages (37-40 postmenstrual weeks) seems to be advantageous in infants with aggressive posterior ROP. The formation of a gliotic membrane growing ahead to the posterior surface of the lens resulted in unfavorable outcomes in our cases. PMID- 20853259 TI - The role of pars plana vitrectomy in the diagnosis and treatment of uveitis. AB - PURPOSE: To assess the diagnostic yield of vitreous fluid analysis and the therapeutic effect of pars plana vitrectomy in patients with suspected intraocular inflammation. METHODS: During 2004-2008, pars plana vitrectomy was performed in 89 patients (101 eyes) out of 1233 patients with uveitis. Vitreous specimens were analyzed by cytologic and histopathologic examination, microbiologic culture, polymerase chain reaction, antibody determination, and flow cytometry. Vitrectomy was performed in 85 eyes for both diagnostic and therapeutic purposes; the remaining 16 eyes underwent only diagnostic pars plana vitrectomy. Preoperative and postoperative best-corrected Snellen visual acuity was compared. RESULTS: Preoperative diagnoses were infection in 40 patients, malignant masquerade syndrome in 10 patients, and idiopathic uveitis in 39 patients. Vitreous analysis contributed to the determination of diagnosis in 54 patients (61%). Final diagnoses were infection in 42 patients, malignant masquerade syndrome in 6 patients, benign masquerade syndrome in 16 patients, and idiopathic uveitis in 25 patients. Vitreous fluid collected from each eye underwent approximately 2.2 (range 1-6) laboratory tests. Therapeutic reasons for vitrectomy were the treatment of complications of uveitis in 42 eyes and/or intravitreal application of anti-infectious or cytostatic drugs in 49 eyes. Overall, the visual acuity improved in 45% of eyes, remained unchanged in 45% of eyes, and decreased in 10% of eyes in 3 months after surgery. CONCLUSIONS: Pars plana vitrectomy with carefully selected testing is a valuable tool for assessment of diagnosis in a large proportion of patients with uveitis. Moreover, the therapeutic effect of vitrectomy can improve the visual outcomes in these patients. PMID- 20853260 TI - Pneumatic displacement of acute submacular hemorrhage with and without the use of tPA. PMID- 20853261 TI - The efficacy of vertical rectus transposition and its modalities in patients with abducens nerve palsy. AB - PURPOSE: Patients with VIth nerve palsy that does not resolve within 6 months should undergo surgery. The most common procedure used in such cases is transposition of a whole or a part of a vertical rectus muscle combined or not with a resection of the lateral rectus muscle. Commonly, a simultaneous recession of medial rectus muscle with or without prior injection of botulinum toxin is performed. The aim of our study was to evaluate the results of vertical rectus transposition performed in patients with abducens nerve palsy. METHODS: Nine cases of abducens nerve palsy ware retrospectively analyzed. All patients underwent full ophthalmic and orthoptic examination before and after surgery. All patients underwent vertical rectus muscle transposition to the lateral rectus insertion in the affected eye. Additional procedures included Jensen procedure, botulinum toxin injection, resection of the lateral rectus, recession of the medial rectus on the same side with or without adjustable sutures, and Foster modification of lateral rectus posterior fixation. RESULTS: In all cases, we found a varying degree of postoperative improvement. There was a significant reduction in the strabismus angle for distance and near, increase in abduction of the affected eye, and broadening of the field of binocular single vision. CONCLUSIONS: The vertical rectus muscle transposition technique is a safe and successful method of treatment in abducens nerve palsy. Its use together with additional procedures and modifications allows one to achieve orthophoria, improvement of abduction, and larger field of binocular single vision. PMID- 20853262 TI - Evaluation of corneal biomechanical properties with the Reichert Ocular Response Analyzer. AB - PURPOSE: To compare corneal hysteresis (CH) and corneal resistance factor (CRF) measured with the Ocular Response Analyzer (ORA) in patients with primary open angle glaucoma (POAG), patients with ocular hypertension (OHT), and normal subjects (NL); and to assess correlations of CH and CRF with corneal-compensated intraocular pressure (IOPcc), Goldmann applanation tonometry (GAT), glaucoma type, central corneal thickness (CCT), previous filtering procedure, and antiglaucoma medications. METHODS: A total of 108 POAG, 22 OHT, and 24 NL were enrolled in this observational study. Goldmann applanation tonometry and ORA were performed in a randomized sequence followed by pachymetry. One eye per subject was selected at random for analysis. Chi-square, Wilcoxon, and Kruskal-Wallis tests were used for comparison and Spearman coefficient for assessing correlations. RESULTS: Mean CH and CRF were significantly lower in POAG than in OHT and NL. Ocular Response Analyzer IOPcc overestimated IOP compared to GAT only in POAG. This difference increased with higher GAT. Goldmann applanation tonometry and IOPcc were correlated. Corneal hysteresis was negatively correlated with age in POAG. Corneal resistance factor and CH were positively correlated with CCT in POAG and OHT. Unlike CRF, CH was not correlated with GAT in POAG and OHT. Corneal-compensated intraocular pressure was not correlated with CCT. Difference between GAT and IOPcc was not CCT dependent. Corneal hysteresis and CRF were comparable in POAG and NTG, unchanged after filtering procedure. Corneal hysteresis was not altered by topical medications. Corneal resistance factor was significantly lower in treated eyes and those receiving prostaglandin analogues with no correlation with the treatment duration. CONCLUSIONS: Patients with glaucoma seem to have distinctive corneal biomechanical properties compared to OHT and NL. They may be influenced by many other unknown subparameters. PMID- 20853263 TI - Interface corneal stromal irregularities after flap creation using femtosecond laser. AB - PURPOSE: To report a case of interface corneal stromal irregularities after flap creation with the advanced IntraLase femtosecond (150 Hz) laser system (Abbott Medical Optics, Inc.). METHODS: Case report. RESULTS: An 18-year-old man underwent bilateral laser in situ keratomileusis (LASIK) using the IntraLase femtosecond laser to create 110-um flaps. The procedure was uneventful in the left eye. In the right eye, after flap lifting a central irregular stromal interface was noted. The created flap was thicker than expected (139 um) as measured intraoperatively with ultrasound pachymetry. The excimer laser ablation procedure was performed and the flap was repositioned. On the first postoperative day and during the 6-month follow-up period, uncorrected distance visual acuity was 20/20 in both eyes. CONCLUSIONS: Interface corneal stromal irregularities may occur after femtosecond corneal flap creation during LASIK. PMID- 20853264 TI - Postural control in subjects with visual impairment. AB - PURPOSE: To investigate the effect of long-term, not experimentally induced visual impairment on balance, and to clarify which means are used to compensate for this sensory deficit. METHODS: Posturography was examined in 50 visually impaired subjects (11 with congenital blindness and 39 with acquired visual impairment) and 50 healthy controls. Examination was performed in 4 testing conditions: while standing on firm surface or foam pads (which decreases the somatosensory input) and with open or closed eyes (manipulating visual input). RESULTS: Subjects with acquired visual impairment were significantly less stable than controls when tested with open eyes, especially when standing on foam pads, but equal to controls when eyes were closed. Congenitally blind subjects performed equally to normal controls in all test conditions when tested with eyes open, and performed significantly better than controls with eyes closed. In comparison to subjects with acquired visual impairment, the congenitally blind were significantly more stable in all test conditions. Fourier analysis revealed that the visually impaired subjects showed decreased intensity values within the lowest frequency range of 0.1 Hz and below, a range believed to be sensitive to the function of the visual system. CONCLUSIONS: We have found that vision impairment influenced postural control, especially if acquired and not congenital. The somatosensory and vestibular systems serve as compensatory mechanisms, which is utilized most effectively by the congenitally blind. PMID- 20853265 TI - Reproducibility of ocular biometry with a new noncontact optical low-coherence reflectometer in children. AB - PURPOSE: To evaluate the reproducibility of Lenstar in the pediatric population. METHODS: Three consecutive measurements per eye by 2 ophthalmologists with a total of 6 measurements per eye were performed using Lenstar. Axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness (LT), and corneal curvatures (K1 and K2) were measured for right and left eyes in 154 school-age children. Right and left eyes were analyzed separately. Each optical parameter obtained by 2 examiners was compared by paired samples t test. Intraobserver and interobserver correlation coefficients (r) were calculated for each variable. Significance was attributed when p<0.05. RESULTS: Measurements could be performed in 152 of the children included. The mean measurements were not different statistically except for left AL (23.22+/-0.81 vs 23.21+/-0.82 mm; p=0.014), left CCT (548.5+/-32.3 vs 548.0+/-32.7 um; p=0.013), and right ACD (3.19+/-0.25 vs 3.19+/-0.25 mm; p=0.033). Intraobserver r values were all above 0.957 except for left LT (r=0.786) for examiner 2. Interobserver r values were all above 0.979. CONCLUSIONS: Although statistical significance was obtained in some variables, they were clinically negligible. The intraobserver and interobserver relation coefficients were very high for all optical parameters including the r value for left LT for examiner 2 (r=0.786). Lenstar is a highly reproducible, user independent, and tolerable instrument for ocular biometry in the pediatric population, with no anesthesia or discomfort. PMID- 20853266 TI - Intrasession, intersession, and interexaminer variabilities of retinal nerve fiber layer measurements with spectral-domain OCT. AB - PURPOSE: To evaluate the intrasession, intersession, and interexaminer variabilities of retinal nerve fiber layer measurements (RNFL) with spectral domain optical coherence tomography (OCT). METHODS: A total of 32 healthy individuals and 34 patients with chronic glaucoma underwent RNFL measurements with the Cirrus HD-OCT Model 4000 (Carl Zeiss Meditec, Dublin, CA, USA) 5 times during the same sitting by one examiner to assess intrasession variability. The same examiner performed RNFL measurements in the same patients on 5 different days to assess intersession variability. A second examiner performed RNFL measurements in the same patients to assess interexaminer variability. The coefficients of variation and intraclass correlation coefficients were obtained for the following parameters: average thickness, quadrant thickness, and Clock hour thickness measurements. RESULTS: Intrasession variability: In patients with glaucoma, coefficients of variation ranged from 4.51% to 11.84%. Intraclass correlation coefficients ranged from 0.74 to 0.99. In healthy individuals, coefficients of variation ranged from 2.92% to 6.99%. Intraclass correlation coefficients ranged from 0.89 to 0.98. Intersession variability: In patients with glaucoma, coefficients of variation ranged from 3.68% to 10.50%. Intraclass correlation coefficients ranged from 0.82 to 0.99. In healthy individuals, coefficients of variation ranged from 3.13% to 6.92%. Intraclass correlation coefficients ranged from 0.87 to 0.99. Interexaminer variability: In patients with glaucoma, coefficients of variation ranged from 2.62% to 14.94%. Intraclass correlation coefficients ranged from 0.55 to 0.98. In healthy individuals, coefficients of variation ranged from 2.04% to 7.31%. Intraclass correlation coefficients ranged from 0.86 to 0.98. CONCLUSIONS: These findings indicate that RNFL measurements with spectral-domain OCT display excellent reproducibility, with low intrasession, intersession, and interexaminer variabilities. PMID- 20853267 TI - Experimental femtosecond laser-assisted nanosurgery of anterior lens capsule. AB - PURPOSE: To investigate femtosecond laser-assisted nanosurgery of the anterior lens capsule in a prospective in vitro study. METHODS: Eight anterior lens capsules obtained during conventional phaco surgery were irradiated with a nonamplified 80-MHz near-infrared 800-nm titanium:sapphire femtosecond laser. Line intratissue laser cuts were examined by femtosecond multiphoton laser scanning microscopy (MLSM) and transmission electron microscopy (TEM). RESULTS: Speed parameters of the laser beam, laser ablation time, and pulse power determined the width of the lesions, which ranged from 220+/-40 nm (SD) to 1.49+/ 0.15 um. Both MLSM and TEM revealed minimal collateral alterations in the tissue surrounding the laser cuts. CONCLUSIONS: Nonamplified near-infrared femtosecond laser pulses at low pulse energies may be a promising strategy for precise noncontact nanosurgery of the anterior lens capsule with minimal collateral damage to surrounding tissue. High-resolution MLSM offers 3-dimensional, noninvasive, nondestructive imaging at submicrometer resolution within seconds before and after ablation. PMID- 20853268 TI - Acute hyperopic shift in refraction associated with posterior choroidal detachment following phacoemulsification surgery. AB - PURPOSE: To describe a patient who presented with hyperopic shift as an initial manifestation of choroidal detachment in the posterior pole following an uneventful phacoemulsification cataract surgery. METHODS: An 82-year-old woman with preexisting diabetes mellitus and hypertension had bilateral primary angle closure glaucoma on maximal tolerated hypotensive medication. An uneventful phacoemulsification surgery using topical anesthesia was performed in her left eye. RESULTS: On the next day, refraction was markedly increased to +7.25 -1.00 * 65 and axial length was reduced from 23.24 mm to 20.13 mm. Funduscopic examination revealed choroidal detachment in the posterior pole without involvement of the peripheral fundus. Axial length increased to 22.19 mm following corticosteroid treatment 1 month later. Six months postoperatively, axial length improved to 22.87 mm with a residual hyperopia of +1.00 -1.00 * 63. CONCLUSIONS: To our knowledge, there have been no reports of choroidal detachment in the posterior pole after phacoemulsification. Acute hyperopic shift following phacoemulsification surgery should lead one to suspect a posterior choroidal detachment. Considering axial length and refractive errors along with fundus examination may contribute to a more accurate follow-up. PMID- 20853270 TI - Refractive lens exchange with Acri.LISA bifocal intraocular lens implantation. AB - PURPOSE: To assess efficacy, safety, and predictability after refractive lens exchange (RLE) in patients who had bilateral implantation of an Acri.LISA 366D diffractive bifocal intraocular lens (IOL). METHODS: Sixty-six eyes of 33 consecutive patients were examined after RLE who had bilateral implantation of an Acri.LISA bifocal 366D IOL. Eyes were divided into myopic and hyperopic groups. Monocular uncorrected distance visual acuity, best-corrected distance visual acuity (BCVA), uncorrected distance near visual acuity, and best distance corrected near visual acuity (BCNVA) were recorded preoperatively and 6 months after surgery. RESULTS: Efficacy indexes were 0.73 for myopic and 0.85 for hyperopic eyes at 6 months postoperatively. For the myopic group, 2 eyes lost 1 line, 4 eyes gained 1 line, and 6 eyes gained >=2 lines; for the hyperopic group, 11 eyes lost 1 line, 8 eyes gained 1 line, and 7 eyes gained 2 lines. Safety indexes were 1.07 and 1.03 for myopic and hyperopic eyes, respectively. Safety indexes at near were 1.03 for myopic and 1.00 for hyperopic eyes. Efficacy indexes at near were 1.00 for myopic and 0.99 for hyperopic eyes. CONCLUSIONS: Bilateral implantation of an Acri.LISA 366D bifocal IOL after RLE is an effective procedure for correcting ametropia and presbyopia. PMID- 20853269 TI - Prophylactic intravitreal bevacizumab for diabetic macular edema (thickening) after cataract surgery: prospective randomized study. AB - PURPOSE: To determine the role of intravitreal bevacizumab injected at the time of cataract surgery on postoperative increase of retinal thickness in patients with diabetic retinopathy. METHODS: Patients were randomized to a standardized procedure of phacoemulsification with intraocular lens implantation alone (control group; 30 eyes) or to receive 1.25 mg intravitreal bevacizumab at the end of surgery (IVB group; 31 eyes). Efficacy measures included best-corrected visual acuity (BCVA) testing, optical coherence tomography (OCT), and ophthalmoscopic examination at each postoperative visit during a 6-month follow up. RESULTS: There were no significant differences in central macular thickness, BCVA, or systemic condition between the control and IVB groups at baseline. One month after surgery, the control group showed a significant increase in central macular thickness, whereas the bevacizumab group did not show an increase. After 6 months, there was no significant difference in macular thickness and postoperative visual acuity between the 2 groups. CONCLUSIONS: Intravitreal administration of 1.25 mg bevacizumab at the time of cataract surgery is effective just for the short term and 6-month results are the same as the control group. PMID- 20853271 TI - Intraoperative floppy iris syndrome associated with risperidone intake. AB - PURPOSE: Intraoperative floppy iris syndrome (IFIS) has been strongly associated with intake of selective a1 adrenergic blockers, particularly tamsulosin. Intraoperative floppy iris syndrome has also been linked to the use of other drugs with some a antagonist activity. METHODS: We identified patients on long term treatment with the antipsychotic agent risperidone who showed typical features of IFIS during cataract surgery. RESULTS: We report 3 eyes in 2 patients taking risperidone in which typical features of IFIS were noted during cataract surgery. CONCLUSIONS: Risperidone is a widely prescribed drug in psychiatric practice and has a-blocking actions as well as strong affinity for serotonin 2A receptors. Ophthalmologists should be aware of the possible association with IFIS when performing cataract surgery on patients taking risperidone. PMID- 20853272 TI - Comparative study of in vitro digestibility of major allergen, tropomyosin and other proteins between Grass prawn (Penaeus monodon) and Pacific white shrimp (Litopenaeus vannamei). AB - BACKGROUND: Stability in simulated gastric fluid is supposed to be an important parameter for the estimation of food allergenicity. In the present study, the digestive stability of allergenic protein tropomyosin (TM) and other food proteins from Grass prawn and Pacific white shrimp in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) digestion assay system was investigated and comparatively studied by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting, and inhibition enzyme-linked immunosorbent assay (ELISA). RESULTS: In the SGF system, proteins such as actin and myosin heavy chain (MHC) were rapidly degraded within a short period of time, while TM was relatively resistant to pepsin digestion. In the SIF system, MHC was also easily decomposed, while TM and actin were resistant to digestion. Western blotting using a specific polyclonal antibody against TM indicated that the degradation pattern of shrimp TM by SGF and SIF was almost unaffected by the presence of other myofibrillar proteins. Further study by IgE immunoblotting and inhibition ELISA using sera from crustacean-allergic patients indicated that IgE binding of TM was decreased. CONCLUSION: Proteinase digestion is effective in reducing IgE binding of shrimp TM. It is also of interest to notice that Pacific white shrimp TM had higher digestion stability than Grass prawn TM. However, Pacific white shrimp TM revealed enhanced IgE binding over that of TM from Grass prawn and thus it is possibly more allergenic. PMID- 20853273 TI - Solanum nigrum L. polyphenolic extract inhibits hepatocarcinoma cell growth by inducing G2/M phase arrest and apoptosis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is a rapidly progressive cancer with poor prognosis. However, there have been no significant new developments in treating liver cancer. To search for an effective agent against HCC progression, we prepared a polyphenolic extract of Solanum nigrum L. (SNPE), a herbal plant indigenous to Southeast Asia and commonly used in oriental medicine, to evaluate its inhibitive effect on hepatocarcinoma cell growth. The growth inhibition of HepG2 cells in vitro and in vivo was determined in the presence of SNPE. RESULTS: We found 1 ug mL(-1) SNPE-fed mice showed decreased tumor weight and tumor volume by 90%. Notably, 2 ug mL(-1) SNPE resulted in almost complete inhibition of tumor weight as well as tumor volume. In line with this notion, SNPE reduced the viability of HepG(2) cells in a dose-dependent manner. HepG(2) cells were arrested in the G(2)/M phase of the cell cycle; meanwhile, the protein levels of cell CDC25A, CDC25B, and CDC25C were clearly reduced. Moreover, sub-G(1) phase accumulation and caspases-3, 8, and 9 cleavages were induced by SNPE. CONCLUSION: This study shows that SNPE is a potent agent for HCC treatment through targeting G(2)/M arrest and apoptosis induction, achieving cell growth inhibition. PMID- 20853274 TI - A new yeast genetic resource for analysis and breeding. AB - We made a library of Saccharomyces cerevisiae F(1) hybrids from all possible crosses of 16 wild-type strains, including two common laboratory strains and two commercial winemaking varieties. Fourteen of the starting strains have been sequenced. Thus, the sequences of both genomes are known in 182 novel hybrids, and the sequence of one genome is known in 56. All tested strains sporulated. Fertilities were in the range 0-100%. Hybrids showed no more variation than parental strains for ethanol production, ethanol tolerance or growth at temperature extremes, but some F(1) s appeared to display hybrid vigour (heterosis). We tested four tetrads from one hybrid for their ability to grow at low temperature or in the presence of an inhibitory concentration of ethanol. Only one F(2) was as tolerant as the most tolerant F(0) parent. A few showed intermediate tolerance, but most were less tolerant than either parent or the F(1) hybrid, consistent with uncoupling of genes contributing to an optimized quantitative trait. The diversity and structure of the library should make it useful for analysis of genetic interactions among diverse strains, quantitative inheritance and heterosis, and for breeding. PMID- 20853275 TI - Calcium and pH influence on orange juice cloud stability. AB - BACKGROUND: Clarification of citrus juice is a severe quality defect related to pectin methylesterase (PME) activity. PME activity and calcium chelation of pectic acid as well as other physical interactions of cloud components influence cloud stability. The cloud stability and physical properties of pulp-free, fresh juice with and without ammonium oxalate (AO) at pH 4.0 and pH 5.5 was evaluated. RESULTS: The only juice to clarify in the 3-week study was the sample without AO at pH 4.0. Particle size analysis showed that the samples at pH 4.0 were larger than those at pH 5.5, and samples at pH 5.5 had a more negative zeta potential than samples at pH 4.0. Furthermore, cloud particle size increased and then decreased prior to the onset of clarification. CONCLUSION: Ammonium oxalate prevented sedimentation via calcium pectate cross-bridges and subsequent clarification. Interaction of cloud constituents, change in particle size with pH and change in particle size with storage time suggest that, in addition to electrostatic attraction and calcium binding, cloud particles associate and dissociate via non-covalent, non-electrostatic interactions. PMID- 20853277 TI - High CO(2) storage capacity in alkali-promoted hydrotalcite-based material: in situ detection of reversible formation of magnesium carbonate. AB - Alkali-promoted hydrotalcite-based materials showed very high CO(2) storage capacity, exceeding 15 mmol g(-1) when the carbonation reaction was carried out at relatively high temperature (300-500 degrees C) and high partial pressure of steam and CO(2). In situ XRD experiments have allowed correlation of high CO(2) capacity to the transformation of magnesium oxide centres into magnesium carbonate in alkali-promoted hydrotalcite-based material. Moreover, it has been clearly shown that crystalline magnesium carbonate may be reversibly formed at temperatures above 300 degrees C in the presence of sufficient partial pressure of steam in the gas phase, conditions that are prevalent in pre-combustion CO(2) capture. The role of steam appears to be of utmost importance for the formation of the bulk carbonate phase and for its reversibility. It is proposed that a high partial pressure of steam keeps the magnesium oxide periclase phase sufficiently hydroxylated to allow magnesium carbonate formation if a relatively high partial pressure CO(2) is present in the gas phase. PMID- 20853276 TI - The effect of environmental conditions on nutritional quality of cherry tomato fruits: evaluation of two experimental Mediterranean greenhouses. AB - BACKGROUND: The aim of this study was to examine how different environmental factors (temperature, solar radiation, and vapour-pressure deficit [VPD]) influenced nutritional quality and flavour of cherry tomato fruits (Solanum lycopersicum L. cv. Naomi) grown in two types of experimental Mediterranean greenhouses: parral (low technology) and multispan (high technology). RESULTS: Fruits were sampled three times during 3 years (2004, 2005 and 2006): at the beginning, middle and end of the fruit production period. Values for temperature, solar radiation, and VPD peaked in the third sampling in both greenhouses; values were higher in the parral-type greenhouse, triggering abiotic stress. This stress reduced the accumulation of lycopene and essential elements, augmenting the phytonutrient content and the antioxidant capacity of tomatoes. During the third sampling, sugars were increased while organic acid content diminished, producing tomatoes with a sweeter-milder flavour. The parral greenhouse produced tomatoes with higher phenolic compounds and ascorbic acid contents, together with a greater antioxidant capacity, without showing differences in flavour parameters. CONCLUSION: The higher phytonutrients content and antioxidant activity during the environmental stress, more pronounced in parral than multispan greenhouse, together with the sweeter-milder flavour, conferred a notable nutritional benefit, which considerably improved the nutritional and organoleptic quality of these tomatoes. PMID- 20853278 TI - Excited-state prototropic equilibrium dynamics of 6-hydroxyquinoline encapsulated in microporous catalytic faujasite zeolites. AB - The excited-state proton transfer and geminate recombination of 6 hydroxyquinoline (6HQ) encaged in catalytic Na(+)-exchanged faujasite zeolites X (NaX) and Y (NaY) have been explored by measuring steady-state and picosecond time-resolved spectra. The pathways and rate constants of proton transfer of excited 6HQ are determined by the microscopic environment of zeolitic hosts surrounding the guest molecules. The excited-state proton transfer of a 6HQ molecule encapsulated in a zeolitic nanocavity is initiated by deprotonation of the enolic group to form an anionic intermediate and completed by subsequent protonation of the imino group to form a zwitterionic tautomer. Geminate recombination occurs to compete with proton transfer at each tautomerization step of excited-state 6HQ because of the confined environment of dehydrated zeolitic supercages. Consequently, excited-state equilibria among three prototropic species of 6HQ are established in microporous catalytic faujasite zeolites. Kinetic differences in NaX and NaY are attributed to dissimilarities in acidity/basicity. PMID- 20853280 TI - Simple preparation and application of TEMPO-coated Fe(3)O(4) superparamagnetic nanoparticles for selective oxidation of alcohols. AB - The organic oxidant TEMPO (2,2,4,4-tetramethylpiperdine-1-oxyl) was immobilized on iron oxide (Fe(3)O(4)) superparamagnetic nanoparticles by employing strong metal-oxide chelating phosphonates and azide/alkyne "click" chemistry. This simple preparation yields recyclable TEMPO-coated nanoparticles with good TEMPO loadings. They have excellent magnetic response and efficiently catalyze the oxidation of a wide range of primary and secondary alcohols to aldehydes, ketones, and lactones under either aerobic acidic Mn(II)/Cu(II) oxidizing Minisci conditions, or basic NaOCl Anelli conditions. The nanoparticles could be recycled more than 20 times under the Minisci conditions and up to eight times under the Anelli conditions with good to excellent substrate conversions and product selectivities. Immobilization of the catalyst through a phosphonate linkage allows the particles to withstand acidic oxidizing environments with minimal catalyst leaching. Clicking TEMPO to the phosphonate prior to phosphonate immobilization, rather than after, ensures the clicked catalyst is the only species on the particle surface. This facilitates quantification of the catalyst loading. The stability of the phosphonate linker and simplicity of this catalyst immobilization method make this an attractive approach for tethering catalysts to oxide supports, creating magnetically separable catalysts that can be used under neutral or acidic conditions. PMID- 20853279 TI - Fluorescent probes for Pd2+ detection by allylidene-hydrazone ligands with excellent selectivity and large fluorescence enhancement. AB - Because palladium is widely used in various catalysts and converters, which results in a high level of contamination of water systems and the soil by residual palladium, there is an urgent need for Pd(2+)-sensitive and -selective probes. Based on the special affinity of Pd(2+) to conjugated double-bond ligands, two fluorescence probes (RPd2 and RPd3) that contain conjugated allylidene-hydrazone ligands that link to colorless rhodamine-spirolactam have been developed. The results show that conjugated allylidene-hydrazones have a much better affinity toward Pd(2+), and consequently provide the probes with more acute color change and fluorescence enhancement (~170-fold), and better selectivity over other metal ions (especially platinum-group elements, or PGEs) than the unconjugated allyl-hydrazine. With richer electron density and a more suitable stereo effect in the allylidene-hydrazone group, RPd2 displays the best specificity toward Pd(2+) and affords convenient detection by the naked eye. Its potential application for Pd(2+)-contaminated water and soil-sample analysis is revealed by proof-of-concept experiments. PMID- 20853281 TI - Control of the optical properties of a star copolymer with a hyperbranched conjugated polymer core and poly(ethylene glycol) arms by self-assembly. AB - A self-assembly approach to tuning the optical properties of a star copolymer is reported herein. The star copolymer HCP-star-PEG with a hyperbranched conjugated polymer (HCP) core and many linear poly(ethylene glycol) (PEG) arms has been prepared successfully. The HCP core was synthesized by Wittig coupling of N-(n hexyl)-3,6-diformylcarbazole and 1,3,5-bis[(triphenylphosphonio)methyl]benzene tribromide. Subsequently, the linear PEG arms were grafted onto the HCP core by acylhydrazone connection. It was found that the optical properties of HCP-star PEG in chloroform solution changed on addition of acid. Both (1)H NMR and UV/Vis spectroscopic investigations confirmed that the variation of the optical properties was related to the complexation of the acid and the imine bond in the acylhydrazone group. HCP-star-PEG self-assembled into core-shell micelles in the mixed solvent of chloroform and acetonitrile, which affected the protonation of the imine bond. Therefore the optical properties of HCP-star-PEG can be readily controlled by self-assembly. PMID- 20853282 TI - An autonomous bio-barcode DNA machine for exponential DNA amplification and its application to the electrochemical determination of adenosine triphosphate. AB - A novel autonomous bio-barcode DNA machine that is driven by template-dependent DNA replication is developed to exponentially amplify special DNA sequences. Combined with a DNA aptamer recognition element, the DNA machine can be further applied in the aptamer-based, amplified analysis of small molecules. As a model analyte, adenosine triphosphate (ATP) is determined by using the DNA machine system in combination with a DNA aptamer recognition strategy and differential pulse anodic stripping voltammetry (DPASV). Under the optimum conditions, detection limits as low as 2.8*10(-17) M (3sigma) for target DNA and 4.7*10(-9) M (3sigma) for ATP are achieved. The satisfactory determination of ATP in K562 leukemia cell and Ramos Burkitt's lymphoma cell reveal that this protocol possesses good selectivity and practicality. As a promising biomolecular device, this DNA machine may have an even broader application in the rapidly developing field of nanobiotechnology. PMID- 20853283 TI - Chiral mesoporous organosilica nanospheres: effect of pore structure on the performance in asymmetric catalysis. AB - (R)-(+)-1,1'-Bi-2-naphthol ((R)-(+)-Binol)-functionalized (Binol=2,2'-dihydroxy 1,1'-binaphthyl) chiral mesoporous organosilica nanospheres with uniform particle size (100 to 300 nm) have been synthesized by co-condensation of tetraethoxysilane and (R)-2,2'-di(methoxymethyl)oxy-6,6'-di(1-propyl trimethoxysilyl)-1,1'-binaphthyl in a basic medium with cetyltrimethylammonium bromide as the template. Nanospheres with a radiative 2D hexagonal channel arrangement exhibit higher enantioselectivity and turnover frequency than those with a penetrating 2D hexagonal channel arrangement (94 versus 88 % and 43 versus 15 h(-1), respectively) in the asymmetric addition of diethylzinc to aldehydes. In addition, under similar conditions, the enantioselectivity of the nanospheres can be greatly improved as the structural order of the framework increases. These results clearly show that the structural order of nanospheres affects enantioselective reactions. The enantioselectivity of the nanospheres synthesized by the co-condensation method is higher than that of nanospheres prepared by a grafting method and even higher than that of their homogeneous counterpart. These results indicate that the bite angle of (R)-(+)-Binol bridging in a more rigid porous network is in a more favorable position for achieving higher enantioselectivity. The efficiency of a co-condensation method for the synthesis of high-performance heterogeneous asymmetric catalysts is also reported. PMID- 20853284 TI - A brush-gel/metal-nanoparticle hybrid film as an efficient supported catalyst in glass microreactors. AB - A polymer-brush-based material was applied for the formation and in situ immobilization of silver and palladium nanoparticles, as a catalytic coating on the inner wall of glass microreactors. The brush film was grown directly on the microchannel interior by means of atom-transfer radical polymerization (ATRP), which allows control over the polymer film thickness and therefore permits the tuning of the number of nanoparticles formed on the channel walls. The wide applicability of the catalytic devices is demonstrated for the reduction of 4 nitrophenol and for the Heck reaction. PMID- 20853285 TI - Ultrasensitive SERS detection of TNT by imprinting molecular recognition using a new type of stable substrate. AB - We report herein a method for the ultra-trace detection of TNT on p aminothiophenol-functionalized silver nanoparticles coated on silver molybdate nanowires based on surface-enhanced Raman scattering (SERS). The method relies on pi-donor-acceptor interactions between the pi-acceptor TNT and the pi-donor p,p' dimercaptoazobenzene (DMAB), with the latter serving to cross-link the silver nanoparticles deposited on the silver molybdate nanowires. This system presents optimal imprint molecule contours, with the DMAB forming imprint molecule sites that constitute SERS "hot spots". Anchoring of the TNT analyte at these sites leads to a pronounced intensification of its Raman emission. We demonstrate that TNT concentrations as low as 10(-12) M can be accurately detected using the described SERS assay. Most impressively, acting as a new type of SERS substrate, the silver/silver molybdate nanowires complex can yield new silver nanoparticles during the detection process, which makes the Raman signals very stable. A detailed mechanism for the observed SERS intensity change is discussed. Our experiments show that TNT can be detected quickly and accurately with ultra-high sensitivity, selectivity, reusability, and stability. The results reported herein may not only lead to many applications in SERS techniques, but might also form the basis of a new concept for a molecular imprinting strategy. PMID- 20853286 TI - Total synthesis of berkelic acid. AB - A productive total synthesis of both enantiomers of berkelic acid (1) is outlined that takes the structure revision of this bioactive fungal metabolite previously proposed by our group into account. The successful route relies on a fully optimized triple-deprotection/1,4-addition/spiroacetalization cascade reaction sequence, which delivers the tetracyclic core 32 of the target as a single isomer in excellent yield. The required cyclization precursor 31 is assembled from the polysubstituted benzaldehyde derivative 20 and methyl ketone 25 by an aldol condensation, in which the acetyl residue in 20 transforms from a passive protecting group into an active participant. Access to fragment 25 takes advantage of the Collum-Godenschwager variant of the ester enolate Claisen rearrangement, which clearly surpasses the classical Ireland-Claisen procedure in terms of diastereoselectivity. Although it is possible to elaborate 32 into the target without any additional manipulations of protecting groups, a short detour consisting in the conversion of the phenolic -OH into the corresponding TBS-ether is beneficial. It tempers the sensitivity of the compound toward oxidation and hence improves the efficiency and reliability of the final stages. Orthogonal ester groups for the benzoate and the aliphatic carboxylate terminus of the side chain secure an efficient liberation of free berkelic acid in the final step of the route. PMID- 20853287 TI - Inclusion of a nitronyl nitroxyl radical and its hydrochloride in cucurbit[8]uril. AB - The recognition properties of cucurbit[8]uril (CB8) toward nitronyl nitroxide 2 (2-benzimidazolyl)-4,4,5,5-tetramethylimidazolidinyl-3-oxide-1-oxy (1) and its hydrochloride have been investigated. 1.HCl led to 1:1 inclusion complex [1.HCl@CB8], which was characterized both in solution and by single-crystal X-ray diffraction. In this compound only the tetramethylimidazolidinyl fragment is included in the host. The magnetic behavior of the complex corresponds to a Curie law with a large separation of the spin carriers in the solid. In contrast, an insoluble species exhibiting ferromagnetic behavior is formed when pure 1 reacts with acid-free CB8. The formula [(1)(2)@(CB8)(3)], in which two radical guests are arranged in such a way that the phenyl groups of the benzimidazolyl substituents are both stacked into one CB8 and the tetramethyl fragments are each capped by a terminal macrocycle, is proposed, in agreement with microanalysis, spectrophotometric, EPR, and magnetic measurements. According to McConnell's rules, the alternating spin densities within the stacked aromatic fragments result in a ferromagnetic interaction (J=+2.3 cm(-1), H=-2JS(1)S(2)) and a triplet ground spin state for the inclusion complex. PMID- 20853288 TI - Quantification of CH...pi interactions: implications on how substituent effects influence aromatic interactions. AB - Attractive interactions between a substituted benzene ring and an alpha substituted acetate group were determined experimentally by using the triptycene model system. The attractive interaction correlates well with the Hammett constants sigma(m) (R(2)=0.90), but correlates much better with the acidity of the alpha-protons (R(2)=0.98). PMID- 20853289 TI - Selective one-pot access to symmetrical or unsymmetrical diaryl ethers by copper catalyzed double arylation of a simple oxygen source. PMID- 20853290 TI - Synthesis, characterisation and photophysical study of alkynylrhenium(I) tricarbonyl diimine complexes and their metal-ion coordination-assisted metallogelation properties. AB - A series of alkynylrhenium(I) tricarbonyl diimine complexes has been synthesized and characterized. A blue shift of the intense low-energy MLCT absorption band in the visible region was observed upon coordination of Cu(I) or Ag(I). This class of complexes has been found to show rich thermotropic gelation behaviour upon Cu(I) or Ag(I) coordination with their morphology characterized by SEM. Their variable-temperature UV/Vis absorption and emission properties have also been studied. A blue shift in the MLCT absorption band and the switching on of luminescence were observed upon sol-gel transition. PMID- 20853291 TI - Tribenzotriquinacenes based on regioselective bis-formylation: optical resolution and absolute configuration of inherently chiral derivatives and synthesis of the first cyclophane-type tribenzotriquinacene dimers. AB - Enantiomerically pure tribenzotriquinacenes (TBTQs) bearing two monofunctionalized aromatic nuclei were synthesized for the first time and their optical properties and absolute configuration determined. A remarkably regioselective bis-formylation of the fully bridgehead methylated parent TBTQ hydrocarbon with MeOCHCl(2)/TiCl(4) afforded a mixture of two C(s)-symmetrical (achiral) difunctionalized derivatives together with one C(1)-symmetrical (chiral) isomer. Reduction and subsequent column chromatography furnished the three respective benzylic TBTQ dialcohols. Optical resolution of the racemic 2,6 bis(hydroxymethyl) derivative was achieved via the diastereomeric (R)-1,1'-bi-2 naphthol ethers and the absolute configuration of the enantiomers was determined by CD exciton model analysis. The electronic circular dichroism (ECD) spectra and the specific rotation of the enantiomers were found to agree with the results of DFT calculations. Among the C(s)-symmetrical isomers, the "proximal" 2,11 dialdehyde and the corresponding benzylic dialcohol were identified by 2D NMR spectroscopy and X-ray crystallographic analysis, respectively, and used as the starting point for the synthesis of several novel dithiametacyclophanes. These include the first "dimeric" tribenzotriquinacene-based cyclophanes bearing the bowls of the two TBTQ units attached to each other in a syn (concave-concave) or anti (convex-concave) configuration. The usefulness of such thiacyclophanes as fluorescent chemosensors for different metal ions is also demonstrated. PMID- 20853292 TI - Palladium- and nickel-catalyzed direct alkylation of azoles with unactivated alkyl bromides and chlorides. PMID- 20853293 TI - Homoleptic zincate-promoted room-temperature halogen-metal exchange of bromopyridines. AB - Homoleptic lithium tri- and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine-metal exchanges were realized at room temperature with a substoichiometric amount of nBu(4)ZnLi(2).TMEDA reagent (1/3 equiv; TMEDA=N,N,N',N' tetramethylethylenediamine). This reactivity contrasted with that of tBu(4)ZnLi(2).TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N...Li stabilized polypyridyl zincates in the reaction. The one-pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C-Zn bonds in bromopyridines enabled us to perform efficient Negishi-type cross-couplings. PMID- 20853294 TI - Manipulation of ordered nanostructures of protonated polyoxometalate through covalently bonded modification. PMID- 20853295 TI - Synthesis of a GaN cage compound with a hydrazinetetraide fragment, [N-N]4-, stabilised by six gallium atoms. AB - Thermolysis of the bicyclic gallium hydrazide [(GaMe(2))(4)(NH-NMe)(NH-NHMe)(2)] (1) yielded the unique cage compound [(GaMe)(4)(GaMe(2))(4)(N(2))(NH-NMe)(4)] (2). Compound 2 contains a remarkable hydrazinetetraide moiety, [N-N](4-), as the central structural motif which is stabilised by coordination to six gallium atoms. PMID- 20853296 TI - Unprecedented solution-stable silver(I) ethynediyl clusters. PMID- 20853297 TI - Unexpected deformations induced by surface interaction and chiral self-assembly of Co(II)-tetraphenylporphyrin (Co-TPP) adsorbed on Cu(110): a combined STM and periodic DFT study. AB - In a combined scanning tunnelling microscopy (STM) and periodic density functional theory (DFT) study, we present the first comprehensive picture of the energy costs and gains that drive the adsorption and chiral self-assembly of highly distorted Co(II)-tetraphenylporphyrin (Co-TPP) conformers on the Cu(110) surface. Periodic, semi-local DFT calculations reveal a strong energetic preference for Co-TPP molecules to adsorb at the short-bridge site when organised within a domain. At this adsorption site, a substantial chemical interaction between the molecular core and the surface causes the porphyrin macrocycle to accommodate close to the surface and in a flat geometry, which induces considerable tilting distortions in the phenyl groups. Experimental STM images can be explained in terms of these conformational changes and adsorption-induced electronic effects. For the ordered structure we unambiguously show that the substantial energy gain from the molecule-surface interaction recuperates the high cost of the induced molecular and surface deformations as compared with gas phase molecules. Conversely, singly adsorbed molecules prefer a long-bridge adsorption site and adopt a non-planar, saddle-shape conformation. By using a van der Waals density functional correction scheme, we found that the intermolecular pi-pi interactions make the distorted conformer more stable than the saddle conformer within the organic assembly. These interactions drive supramolecular assembly and also generate chiral expression in the system, pinning individual molecules in a propeller-like conformation and directing their assembly along non symmetric directions that lead to the coexistence of mirror-image chiral domains. Our observations reveal that a strong macrocycle-surface interaction can trigger and stabilise highly unexpected deformations of the molecular structure and thus substantially extend the range of chemistries possible within these systems. PMID- 20853298 TI - An organocatalytic [3+2] cyclisation strategy for the highly enantioselective synthesis of spirooxindoles. PMID- 20853299 TI - A nickel(II)-sulfur-based radical-ligand complex as a functional model of hydrogenase. PMID- 20853300 TI - A pH switchable pseudorotaxane based on a metal cage and a bis-anionic thread. PMID- 20853301 TI - Metal-free transformation of phenols into substituted benzamides: a highly selective radical 1,2-O->C transposition in O-aryl-N-phenylthiocarbamates. PMID- 20853302 TI - "Organic aqua regia"--powerful liquids for dissolving noble metals. PMID- 20853303 TI - Catalytic intermolecular tail-to-tail hydroalkenylation of styrenes with alpha olefins: regioselective migratory insertion controlled by a nickel/N-heterocyclic carbene. PMID- 20853304 TI - Enhanced photovoltaic performance of low-bandgap polymers with deep LUMO levels. PMID- 20853305 TI - Morphological and qualitative characterisation of globe artichoke head from new seed-propagated cultivars. AB - BACKGROUND: Three new artichoke seed-propagated hybrids (Tempo, Opal and Madrigal) were compared with two standard cultivated varietal types [Catanese and Violet du Provence (VP)] in terms of head morphology, processing performance, nutritional or technological qualitative traits, in order to define their best use. RESULTS: Compared to the other genotypes, Opal and Madrigal had more rounded, heavier, larger heads, higher processing yield (>400 g of heart kg(-1) raw head) and lower total phenol (TP) content (2.4 g of gallic acid equivalents kg(-1) FW). VP gave a higher processing yield than Catanese and showed the highest TP content (6.5 g kg(-1) FW). Tempo hearts were more similar to those of VP in biometrical and chemical terms (P, Na, K, Ca); they had the highest dry matter content (163 g kg(-1) FW) and the waste left after peeling had the highest TP content. CONCLUSIONS: Hybrid artichokes, especially Opal and Madrigal, appear more suitable for the processing industry and also for fresh-cut production due to their highest processing yield and lowest total phenol content. Because of its high total phenol content, Tempo waste represents a possible source of natural antioxidant in the pharmaceutical field and in the food industry (as a food additive). PMID- 20853306 TI - Improved Fmoc-based solid-phase synthesis of homologous peptide fragments of human and mouse prion proteins. AB - The synthesis of difficult peptide sequences has been a challenge since the very beginning of SPPS. The self-assembly of the growing peptide chains has been proposed as one of the causes of this synthetic problem. However, there is an increasing need to obtain peptides and proteins that are prone to aggregate. These peptides and proteins are generally associated with diseases known as amyloidoses. We present an efficient SPPS of two homologous peptide fragments of HuPrP (106-126) and MoPrP105-125 based on the use of the PEGA resin combined with proper coupling approaches. These peptide fragments were also studied by CD and TEM to determine their ability to aggregate. On the basis of these results, we support PEG-based resins as an efficient synthetic tool to prepare peptide sequences prone to aggregate on-resin. PMID- 20853307 TI - Modeling and predicting interactions between the human amphiphysin SH3 domains and their peptide ligands based on amino acid information. AB - In this paper, VHESH, which was a novel set of amino acid descriptors including hydrophobic, electronic, steric, and hydrogen bond contribution properties, were proposed to characterize the structures of the decapeptides binding the human amphiphysin-1 Src homology 3 (SH3) domains, and QSAR model was constructed by partial least square (PLS) with genetic algorithm-variable selection. It was found that diversified properties of the residues between P(2) and P(-3) (including P(2) and P(-3)) of the decapeptide (P(4)P(3)P(2)P(1)P(0)P(-1)P(-2)P( 3)P(-4)P(-5)) may contribute remarkable effect to the interactions between the SH3 domain and decapeptides. Particularly, hydrogen bond and steric properties of P(2) and electronic properties, steric properties of P(-3) may provide relatively large positive contributions to the interactions. Based on the GA-PLS model, a series of decapeptides, with relatively high binding affinities were designed. These results showed that VHESH descriptors can well represent the decapeptides. Furthermore, the model obtained, which showed low computational complexity, correlated VHESH descriptors with the binding affinities as well as that VHESH may also be applied in QSAR studies of peptides. PMID- 20853308 TI - The biological role of pituitary adenylate cyclase-activating polypeptide (PACAP) in growth and feeding behavior in juvenile fish. AB - To date, many technologies have been developed to increase efficiency in aquaculture, but very few successful biotechnology molecules have arrived on the market. In this context, marine biotechnology has an opportunity to develop products to improve the output of fish in aquaculture. Published in vivo studies on the action of the pituitary adenylate cyclase-activating polypeptide (PACAP) in fish are scarce. Recently, our group, for the first time, demonstrated the biological role of this neuropeptide administrated by immersion baths in the growth and development of larval fish. In this work, we have evaluated the effects of recombinant Clarias gariepinus PACAP administration by intraperitoneal injection on growth performance and feeding behavior in juvenile fish. Our results showed the physiological role of this peptide for growth control in fish, including the juvenile stage, and confirm that its biological functions are well conserved in fish, since C. gariepinus PACAP stimulated growth in juvenile tilapia Oreochromis niloticus. In addition, we have observed that the growth promoting effect of PACAP in juvenile tilapia was correlated with higher GH concentration in serum. With regard to the neuroendocrine regulation of growth control by PACAP, it was demonstrated that PACAP stimulates food intake in juvenile tilapia. In general, PACAP appears to act in the regulation of the growth control in juvenile fish. These findings propose that PACAP is a prominent target with the potential to stimulate fish growth in aquaculture. PMID- 20853309 TI - ChemMatrix((r)) for complex peptides and combinatorial chemistry. AB - CM resin is a totally PEG-based resin, made exclusively from primary ether bonds and therefore highly chemically stable. Compared to other PEG resins, it exhibits good loading and is user friendly because of its free-flowing form upon drying. It shows improved performance over PS resins for the preparation of hydrophobic, highly structured poly-Arg peptides. In combination with psiPros, it allows the synthesis of small proteins such as the chemokine RANTES. Like other PEG-based resins, CM resin swells well in biocompatible solvents such as water, thereby allowing on-bead screening. Furthermore, the high loading of this resin permits the use of a tiny quarter of a bead as a microreactor for HPLC and MALDI-TOF analysis, thus further extending its applications in the field of combinatorial chemistry. PMID- 20853310 TI - Increase in the duration of antidepressant treatment from 1994 to 2003: a nationwide population-based study from Finland. AB - OBJECTIVE: We examined the length and continuity of antidepressant treatment and factors associated with long-term of treatment among adults. METHODS: Nationwide data from all reimbursed antidepressant prescriptions in 1994-2003 were linked with patients' data retrieved from Statistics Finland and the Finnish Hospital Discharge Register. Logistic regression models were used to analyse long term use of antidepressants. RESULTS: The annual prevalence of antidepressant use increased from 3.6% in 1994 to 7.3% in 2003. Short-term use (<3 months) decreased from 58% in 1995 to 51% in 2000 and long-term treatment (>=12 months) increased from 18 to 21%. In 2000, 31% of treatment periods lasted >=6 months and 24% >=9 months. Long-term treatment correlated to the purchase of other psychotropics, in patient psychiatric care, and prescription by a psychiatrist. CONCLUSIONS: Treatment periods with antidepressants have become longer over time. Clinical factors related to mental disorder severity predict long-term use. Only a quarter had the treatment duration recommended by clinical guidelines for depression. PMID- 20853311 TI - Conformations of peptides containing a chiral cyclic alpha, alpha-disubstituted alpha-amino acid within the sequence of Aib residues. AB - A single chiral cyclic alpha,alpha-disubstituted amino acid, (3S,4S)-1-amino-(3,4 dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)], was placed at the N terminal or C-terminal positions of achiral alpha-aminoisobutyric acid (Aib) peptide segments. The IR and (1)H NMR spectra indicated that the dominant conformations of two peptides Cbz-[(S,S)-Ac(5)c(dOM)]-(Aib)(4)-OEt (1) and Cbz (Aib)(4)-[(S,S)-Ac(5)c(dOM)]-OMe (2) in solution were helical structures. X-ray crystallographic analysis of 1 and 2 revealed that a left-handed (M) 3(10) helical structure was present in 1 and that a right-handed (P) 3(10)-helical structure was present in 2 in their crystalline states. PMID- 20853312 TI - Elastin peptides prepared from piscine and mammalian elastic tissues inhibit collagen-induced platelet aggregation and stimulate migration and proliferation of human skin fibroblasts. AB - We obtained pure elastin peptides from bovine ligamentum nuchae, porcine aorta, and bonito bulbus arteriosus. The inhibitory activity of these elastin peptides on platelet aggregation induced by collagen and the migratory and proliferative responsivenesses of human skin fibroblasts to these elastin peptides were examined. All of bonito, bovine, and porcine elastin peptides found to inhibit platelet aggregation, but bonito elastin peptides showed a higher inhibitory activity than bovine and porcine elastin peptides did. All elastin peptides enhanced the proliferation of fibroblasts 3.5- to 4.5-fold at a concentration of 10 ug/ml. Bovine and porcine elastin peptides stimulated the migration of fibroblasts, with the optimal response occurring at 10(-1) ug/ml, while maximal response was at 10(2) ug/ml for bonito elastin peptides. Furthermore, pretreatment of fibroblasts by lactose depressed their ability to migrate in response to all elastin peptides, suggesting the involvement of elastin receptor in cell response. These results suggest that both mammalian and piscine elastin peptides can be applied as useful biomaterials in which elasticity, antithrombotic property, and the enhancement of cell migration and proliferation are required. PMID- 20853313 TI - Disability culture in West Africa: qualitative research indicating barriers and progress in the greater Accra region of Ghana. AB - In 2006, Ghana passed a Disability Rights Bill which proposes that by 2016 Ghana will provide disabled persons in the country with a variety of services and equal employment opportunities. This article presents interviews conducted with community leaders from the Greater Accra region of Ghana in 2009, examining the current views of persons with disabilities in the country. Using qualitative analytic methods, these interviews were coded for themes and examined in relation to historical perceptions of disabled persons in Ghana. The results suggest that there appears to be a growing acceptance that people with disabilities have rights as human beings and that the Disability Rights Bill is a positive step in the right direction for Ghana. There was no consensus, however, on what these basic rights entail, and who is responsible for enforcing and funding new policies. A potential barrier to progress included non-biologically based beliefs about what causes disability, which were reported to resonate strongly with many Ghanaians. PMID- 20853314 TI - Peptide hormone isoforms: N-terminally branched PYY3-36 isoforms give improved lipid and fat-cell metabolism in diet-induced obese mice. AB - The prevalence of obesity is increasing with an alarming rate worldwide and there is a need for efficacious satiety drugs. PYY3-36 has been shown to play a role in hypothalamic appetite regulation and novel analogs targeting the Y2 receptor have potential as drugs for the treatment of obesity. We have designed a series of novel PYY3-36 isoforms, by first adding the dipeptide Ile-Lys N-terminal to the N(alpha) of Ser-13 in PYY13-36 and then anchoring the N-terminal segment, e.g. PYY3-12, to the new Lys N(epsilon)-amine. We hypothesized that such modifications would alter the folding of PYY, due to changes in the turn motif, which could change the binding mode to the Y receptor sub-types and possibly also alter metabolic stability. In structure-affinity/activity relationship experiments, one series of PYY isoforms displayed equipotency towards the Y receptors. However, an increased Y2 receptor potency for the second series of PYY isoforms resulted in enhanced Y receptor selectivity compared to PYY3-36. Additionally, acute as well as chronic mice studies showed body-weight-lowering effects for one of the PYY isoforms, which was also reflected in a reduction of circulating leptin levels. Interestingly, while the stability and pharmacokinetic profile of PYY3-36 and the N-terminally modified PYY3-36 analogue were identical, only mice treated with the branched analogue showed marked increases in adiponectin levels as well as reductions in non-esterified free fatty acids and triglycerides. PMID- 20853315 TI - Insight into the complex regulation of CD133 in glioma. AB - The transmembrane protein CD133 and its extracellular epitope AC133 are controversial cancer markers. In glioma, AC133 demarcates a subpopulation of stem like tumor cells, so-called cancer stem cells (CSCs), which seem to drive tumor formation and are highly resistant to conventional chemo- and radiotherapy. Lately, experimental evidence for the existence of AC133-independent CSCs has challenged the importance previously attributed to AC133-positive glioma cells. These findings either imply that (i) AC133-positive and AC133-negative glioma cells comprise different, independent CSC populations, (ii) AC133-positive glioma cells are derived from primordial AC133-negative CSCs or (iii) AC133-negative CSCs have lost AC133 expression, while retaining their stem-like features and tumor initiation capacity, and can reacquire AC133 expression in vivo. In our article, we review evidence for and against each of the possible tumor models in glioma and will discuss technical hurdles in the AC133 detection process. In addition, we will outline new insights into CD133 regulation, which suggest certain degree of plasticity between some AC133-positive and AC133-negative CSC populations. PMID- 20853316 TI - FGFR2 intronic SNPs and breast cancer risk: associations with tumor characteristics and interactions with exogenous exposures and other known breast cancer risk factors. AB - Recent genome-wide association studies have revealed several new candidate genes for breast cancer, including fibroblast growth factor receptor 2 (FGFR2) gene. The associations were also replicated in several other independent studies. The next important step is to study whether these common variants interact with known breast cancer risk factors, exogenous exposures and tumor characteristics. In a population-based case-control study of 1,170 breast cancer cases and 2,115 controls, we examined genetic associations of four intronic FGFR2 single nucleotide polymorphisms (SNPs) and breast tumor characteristics and assessed the potential interactions with smoking, alcohol consumption, adiposity and known breast cancer risk factors. FGFR2 variants were significantly associated with breast cancer risk regardless of estrogen and progesterone receptor status, metastasis, lymph node involvement and histologic and nuclear grade. The FGFR2 breast cancer association was modified by smoking status, with increased risk for former and current smokers compared to never smokers; former/current smokers carrying two copies of the rs1219648 minor allele were at highest risk with a crude OR (95% confidence interval) of 2.11 (1.52-2.92) compared to never smokers with no rs1219648 variant alleles. Our study found no evidence for either modification of FGFR2 and breast cancer by alcohol intake or adiposity, even when analyses were stratified by menopausal status. Although these results require further replication, they may provide new insight into the possible new exposures that may interact with FGFR2 susceptibility alleles. PMID- 20853317 TI - Prevalence of genotype-specific human papillomavirus infection and cervical neoplasia in Taiwan: a community-based survey of 10,602 women. AB - Human papillomavirus (HPV) causes cervical neoplasia; but limited data are available from Asia. We conducted a large-scale community-based cohort study in Taiwan to estimate prevalence of genotype-specific HPV infection and cervical neoplasia. Following written informed consent, cervical cells for cytology and HPV testing were collected from 11,923 participants (aged 30-65 years old, mean 46.3) in 1991-1992. Genotyping was performed using MY11/GP6+ PCR-based HPV Blot (EasyChip) for 39 HPV types. The overall HPV prevalence was 16.2% for 10,602 eligible participants, and 13.8% for 10,190 cytologically normal participants. The most common carcinogenic types were HPV52 (2.5%), HPV16 (2.0%), HPV56 (1.8%), HPV18 (1.6%), HPV33 (1.2%), HPV58 (1.3%) and HPV39 (1.0%). Among the 56 prevalent invasive and in situ cases, HPV16 (48.2%) was most common, followed by HPV58 (25.0%), HPV52 (19.6%), HPV31 (8.9%), HPV33 (8.9%) and HPV18 (3.6%). HPV16 and HPV58 caused cytological HSIL+ at younger ages than HPV52. Approximately half of the cervical cancer cases and high-grade precursors in Taiwan could be prevented by prophylactic vaccines against HPV16 and HPV18 infection. Up to 40% more could be prevented by targeting HPV58, HPV52, HPV33 and HPV31, arguing for the introduction of vaccines including more types. PMID- 20853318 TI - Gold(III)-dithiocarbamato anticancer agents: activity, toxicology and histopathological studies in rodents. AB - Gold(III)-dithiocarbamato complexes have recently gained increasing attention as potential anticancer agents because of their strong tumor cell growth--inhibitory effects, generally achieved by exploiting non-cisplatin-like mechanisms of action. The rationale of our research work is to combine the antitumor properties of the gold(III) metal center with the potential chemoprotective function of coordinated dithiocarbamates in order to reduce toxic side effects (in particular nephrotoxicity) induced by clinically established platinum-based drugs. In this context, [Au(III) Br(2) (ESDT)] (AUL12) was proved to exert promising and outstanding antitumor activity in vitro and to overcome both acquired and intrinsic resistance showed by some types of tumors toward cisplatin. As a subsequent extension of our previous work, we here report on detailed in vivo studies in rodents, including antitumor activity toward three transplantable murine tumor models, toxicity, nephrotoxicity and histopathological investigations. Remarkably, the gold(III) complex AUL12 stands out for higher anticancer activity than cisplatin toward all the murine tumor models examined, inducing up to 80% inhibition of tumor growth. In addition, it shows low acute toxicity levels (lethal dose, LD(50) = 30 mg kg(-1) ) and reduced nephrotoxicity. Altogether, these results confirm the reliability of our drug design strategy and support the validation of this gold(III)-dithiocarbamato derivative as a suitable candidate for clinical trials. PMID- 20853319 TI - How to kill tumor cells with inhibitors of poly(ADP-ribosyl)ation. AB - Poly(ADP-ribosyl)ation is a post-translational modification catalyzed by the enzyme family of poly(ADP-ribose) polymerases (PARPs). PARPs exhibit pleiotropic cellular functions ranging from maintenance of genomic stability and chromatin remodeling to regulation of cell death, thereby rendering PARP homologues promising targets in cancer therapy. Depending on the molecular status of a cancer cell, low-molecular weight PARP inhibitors can (i) either be used as monotherapeutic agents following the concept of synthetic lethality or (ii) to support classical chemotherapy or radiotherapy. The rationales are the following: (i) in cancers with selective defects in homologous recombination repair, inactivation of PARPs directly causes cell death. In cancer treatment, this phenomenon can be employed to specifically target tumor cells while sparing nonmalignant tissue. (ii) PARP inhibitors can also be used to sensitize cells to cytotoxic DNA-damaging treatments, as some PARPs actively participate in genomic maintenance. Apart from that, PARP inhibitors possess antiangiogenic functions, thus opening up a further option to inhibit tumor growth. In view of the above, a number of high-potency PARP inhibitors have been developed during the last decade and are currently evaluated as cancer therapeutics in clinical trials by several leading pharmaceutical companies. PMID- 20853320 TI - Differential survival of gammadeltaT cells, alphabetaT cells and NK cells upon engagement of NKG2D by NKG2DL-expressing leukemic cells. AB - Herein, we show that gammadeltaT, CD8(+) alphabetaT lymphocytes and natural killer (NK) cells display a different sensitivity to survival signals delivered via NKG2D surface receptor. All the three effector cell populations activate Akt1/PKBalpha through the engagement of this molecule. Upon binding to leukemic cells expressing NKG2D ligands (NKG2DL), including chronic lymphocytic leukemias treated with transretinoic acid, most gammadeltaT (>60%) and half CD8(+) alphabetaT cells (about 50%) received a survival signal, at variance with the majority of NK cells (>80%) that underwent apoptosis by day 5. Interestingly, oligomerization of NKG2D in gammadeltaT or CD8(+) alphabetaT cells, led to a significant rise in nuclear/cytoplasmic ratio of both NF-kBp52 and RelB, the two NF-kB subunits mainly involved in the transcription of antiapoptotic proteins of the Bcl family. Indeed, the ratio between the antiapoptotic protein Bcl-2 or Bcl x(L) and the proapoptotic protein Bax raised in gammadeltaT or CD8(+) alphabetaT cells following NKG2D engagement by specific monoclonal antibodies or by NKG2DL expressing leukemic cells. Conversely, nuclear translocation of NF-kBp52 or RelB did not increase, nor the Bcl-2/Bax or the Bcl-x(L) /Bax ratios changed significantly, in NK cells upon oligomerizaton of NKG2D. Of note, transcripts for alpha5 importin, responsible for nuclear translocation of NF-kBp52/Rel B heterodimer, are significantly higher in gammadeltaT and CD8(+) alphabetaT cells than in NK cells. These biochemical data may explain, at least in part, why gammadeltaT and CD8(+) alphabetaT cells are cytolytic effector cells more resistant to target-induced apoptosis than NK cells. PMID- 20853321 TI - Synergistic effects of CTLA-4 blockade with tremelimumab and elimination of regulatory T lymphocytes in vitro and in vivo. AB - Anti-CTLA-4 monoclonal antibodies (mAb) that block the interaction of CTLA-4 with CD80 and CD86 such as tremelimumab and ipilimumab are currently being tested in the clinic for cancer treatment exploiting their properties to de-repress tumor specific cellular immunity. Addition of the fully human anti-CTLA-4 (tremelimumab) to cultures of human T cells with allogenic dendritic cells (DCs) did not increase proliferation. Magnetic bead-mediated elimination of CD4(+) CD25(+) regulatory T cells (T(reg)) before setting up those alloreactive cultures also largely failed to increase primary proliferation. In contrast, predepletion of CD4(+) CD25(+) T(reg) and culture in the presence of tremelimumab synergistically resulted in increased proliferation and DC:T-cell aggregation. These effects were much more prominent in CD4 than in CD8 T cells. The synergy mechanism can be traced to enhanced CTLA-4 expression in effector cells as a result of T(reg) elimination, thereby offering more targets to the blocking antibody. Human T cells and allogenic DCs (derived both from healthy donors and advanced cancer patients) were coinjected in the peritoneum of Rag2(-/-) IL 2Rgamma(-/-) mice. In these conditions, tremelimumab injected intravenously did not significantly enhance alloreactive proliferation unless T(reg) cells had been predepleted. Synergistic effects in vivo were again largely restricted to the CD4 T-cell compartment. In addition, T(reg) depletion and CTLA-4 blockade synergistically enhanced specific cytotoxicity raised in culture against autologous EBV-transformed cell lines. Taken together, these experiments indicate that tremelimumab therapy may benefit from previous or concomitant T(reg) depletion. PMID- 20853322 TI - Dietary factors and in situ and invasive cervical cancer risk in the European prospective investigation into cancer and nutrition study. AB - Some dietary factors could be involved as cofactors in cervical carcinogenesis, but evidence is inconclusive. There are no data about the effect of fruits and vegetables intake (F&V) on cervical cancer from cohort studies. We examined the association between the intake of F&V and selected nutrients and the incidence of carcinoma in situ (CIS) and invasive squamous cervical cancer (ISC) in a prospective study of 299,649 women, participating in the European Prospective Investigation into Cancer and Nutrition study. Cox proportional hazard models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CI). A calibration study was used to control measurement errors in the dietary questionnaire. After a mean of 9 years of follow-up, 253 ISC and 817 CIS cases were diagnosed. In the calibrated model, we observed a statistically significant inverse association of ISC with a daily increase in intake of 100 g of total fruits (HR 0.83; 95% CI 0.72-0.98) and a statistically nonsignificant inverse association with a daily increase in intake of 100 g of total vegetables (HR 0.85: 95% CI 0.65-1.10). Statistically nonsignificant inverse associations were also observed for leafy vegetables, root vegetables, garlic and onions, citrus fruits, vitamin C, vitamin E and retinol for ISC. No association was found regarding beta-carotene, vitamin D and folic acid for ISC. None of the dietary factors examined was associated with CIS. Our study suggests a possible protective role of fruit intake and other dietary factors on ISC that need to be confirmed on a larger number of ISC cases. PMID- 20853323 TI - Non-Hodgkin lymphoma and autoimmunity: does gender matter? AB - Autoimmune disorders are more frequent in women, whereas most non-Hodgkin lymphomas (NHLs) are common in men; yet, sexspecific autoimmune-lymphoma associations are rarely reported. Detailed data on autoimmune disease were abstracted from medical records of 791 cases (including 316 diffuse large B-cell lymphomas (DLBCLs); 228 follicular lymphomas (FLs); 127 marginal zone lymphomas (MZLs); 64 T-cell lymphomas and 38 mantle cell lymphomas) and 872 controls. The combined prevalence of autoimmune disease was higher among women (15.7% controls; 19.7% cases) than men (6.6% controls; 14.5% cases), but the overall association with NHL was stronger for men (odds ratio 2.4, 95% confidence interval: 1.5-3.8) than women (1.3, 0.9-1.9), the disparity persisting when data for the year immediately preceding lymphoma diagnosis were excluded (men 2.0, 1.3-3.3; women 1.2, 0.8-1.8). For both sexes, the strongest individual associations were for DLBCL, MZL and T-cell lymphomas, with no associations evident for FL. Among women, there were strong links between MZL and both Sjogren's syndrome and idiopathic thrombocytopenia, and among men, between DLBCL and both rheumatoid arthritis and Crohn's disease. The expected association between coeliac disease and T-cell lymphoma was seen in both sexes. Our results add to the accumulating knowledge on this topic and suggest that future studies should analyze data for men and women separately. PMID- 20853324 TI - Latissimus dorsi muscle flap for lower extremity reconstruction in children. AB - Complete loss of free latissimus dorsi muscle flaps to the leg is frequently reported. The purpose of this study is to analyze the outcome of latissimus dorsi muscle flaps to the lower extremity in children. PATIENTS AND METHODS: This retrospective analysis includes 11 children treated with a free latissimus dorsi muscle flap after severe trauma to the lower leg and foot. RESULTS: Fourteen free latissimus dorsi muscle flaps were performed in 11 children with a mean age of 13 +/- 4 years. The injuries were caused by traffic accidents, lawnmower accidents, and a crush trauma. Thirteen (92.8%) flaps needed surgical revision. Three complete flap losses and 1 partial flap loss were registered. CONCLUSIONS: Free latissimus dorsi muscle flaps seem to be a useful technique for lower extremity salvage after severe injury, but there is a relevant flap failure risk in children. PMID- 20853325 TI - Salvage of SIEA flaps using the retrograde internal mammary system. AB - Superficial inferior epigastric artery (SIEA) flaps are ideal for breast reconstruction when the anatomy permits it. Due to the peripheral and superficial location of the pedicle, these flaps can be complicated by vessel kinking against the remaining ribs after insetting. Here, we describe a novel method for SIEA flap salvage after kinking or avulsion of the traditional anastomosis to the internal mammary vessels. PMID- 20853326 TI - Shaping the breast in secondary microsurgical breast reconstruction: single- vs. two-esthetic unit reconstruction. AB - The esthetic outcome is dictated essentially not only by the position, size, and shape of the reconstructed breast, but also by the extra scaring involved. In the present study, we conducted a visual analog scale survey to compare the esthetic outcome in delayed autologous breast reconstruction following two different abdominal flaps inset. Twenty-five patients had their reconstruction using the Single-esthetic Unit principle and were compared with 25 patients that their breast was reconstructed using the Two-Esthetic Unit principle. Photographic images were formulated to a PowerPoint presentation and cosmetic outcomes were assessed from 30 physicians, by means of a Questionnaire and a visual analog scale. Our data showed that the single-esthetic unit breast reconstruction presents significant advantages over the traditional two-esthetic units, due to inconspicuous flap reconstruction, better position of the inframammary fold, and more natural transition from native and reconstructed tissues. Moreover, patient self-evaluation of esthetic outcome and quality of life showed that single esthetic unit reconstruction is associated with higher patient satisfaction, therefore should be considered the method of choice. PMID- 20853327 TI - Surgical algorithm for treatment of post-traumatic trigeminal nerve pain. AB - BACKGROUND: Acute postoperative pain following craniofacial or esthetic surgery, or trauma is readily treated with medicinal regimens. Facial pain persisting for more than six months is defined as chronic and must be distinguished from nontraumatic atypical facial pain or "tic-douloureaux." Our surgical experience managing chronic facial (trigeminal) pain is reviewed to provide insight into the success of our current algorithm for managing patients with chronic facial pain. METHODS: We performed a retrospective review of nine consecutive patients operated for post-traumatic chronic trigeminal nerve pain. Most patients were women (mean age 41 years). Data evaluated included mechanism of nerve injury, physical exam, CT scans, computer-aided neurosensory testing, and diagnostic nerve blocks. Surgical management included hardware removal, neurolysis, and/or neuroma resection with nerve grafting when indicated. Primary outcome measurement included Likert pain scale score (range 0-10). Secondary outcome measurements included sensory exam, medication requirement, and return to work. Based on these outcome measures, results were defined as excellent, good, fair, or poor. RESULTS: Five of the nine patients had excellent outcomes, one was good, two were fair, and one was poor. The one patient with a poor result had temporary improvements, but later returned to baseline. No patient was made symptomatically worse or had operative complications. CONCLUSIONS: Successful treatment of chronic, post-traumatic trigeminal nerve pain can be expected using an algorithm that measures sensory function of the involved trigeminal nerve branch. Then either preserves that function through neurolysis or reconstruction with a nerve graft, or eliminates that function through neuroma resection. PMID- 20853328 TI - Classification schema for anatomic variations of the inferior epigastric vasculature evaluated by abdominal CT angiograms for breast reconstruction. AB - BACKGROUND: Many studies demonstrate direct patient benefits from use of preoperative computed tomography angiograms (CTA) for abdominal tissue-based breast reconstruction. We present a novel classification schema to translate imaging results into further clinical relevance. METHODS: Each hemiabdomen CTA was classified into a schema that addressed findings of expected anatomy, anatomy that necessitates a change in operative technique and anatomy that suggests less morbid procedures may be considered. RESULTS: Eighty-six patients (172 hemiabdomens) were available for study. Of the reconstructions performed in this time period, 40 (47%) were bilateral and 46 (53%) unilateral. Based on perforator size and location, relative perimuscular anatomy, and continuity of vessels, five categories were defined: type I "Traditional" anatomy (n = 150, 87%), type II "Highly Favorable" anatomy (n = 11, 6.4%), type III "Altered-Superiorly Translocated" anatomy (n = 9, 5.2%), type IV "Superficial Dominant" anatomy (n = 26, 15%), and type V "Hostile" anatomy (n = 4, 2.3%). The additive total is greater than 100%, because vessels may fall into more than one category. DISCUSSION: In providing the microsurgeon with a preoperative vascular map that has the potential to influence the preoperative, operative, and postoperative course, abdominal CTAs should be considered a worthy adjunct to the diagnostic armamentarium of the reconstructive surgeon. These classifications and their clinical impacts become even more important in centers performing increasing numbers of bilateral reconstructions. We believe that our simple schema can facilitate effective use of this powerful tool, aiding in overall care of the breast reconstruction patient. PMID- 20853329 TI - Lymphaticovenous shunt for the treatment of chylous reflux by subcutaneous vein grafts with valves between megalymphatics and the great saphenous vein: a case report. AB - Chylous reflux is a rare disorder in which chyle flows antidromically from its normal route to the extremities, thorax, abdominal cavity, or other parts of the body. We present a case of chylous reflux with megalymphatics in a 28-year-old boy who presented chylorrhea in the foot, leg, and external genitalia, lymphedema, and hemangioma in the affected limb. Lymphaticovenous shunts using subcutaneous vein grafts with valves were applied to the patient for treatment of repeated chylorrhea. After surgery, the patient has not complained of chylorrhea and been freed from conservative physiotherapy such as bandaging or application of compression stockings for lymphedema for two years. A subcutaneous vein graft with valves may be considered a useful method as a shunt between incompetent and dilated lymphatics and veins instead of a saphenous vein graft in the treatment of chylous reflux in lower extremities. We discuss these treatments based on the literature about chylous disorders. PMID- 20853330 TI - The effect of supporting a surgeon's wrist on their hand tremor. AB - BACKGROUND: Operative tremor can greatly influence the outcome of certain, precise, microsurgical operations. Reducing a surgeons tremor may not only improve the operative results but decrease the operative time. Previous studies have only measured uni or bi directional tremor and therefore have been unable to calculate both the overall tremor amplitude and the tremor reduction by resting the wrists. MATERIALS AND METHODS: We measured the tremor of 21 neurologically normal volunteers while performing a micromanipulation task, with and without wrist support. Measurements were acquired in three dimensions using three accelerometers attached to the hand, allowing an overall tremor amplitude to be calculated. RESULTS: Resting the wrist on a gelled surface decreases an individuals tremor by a factor of 2.67 (P = 0). CONCLUSIONS: Supporting the wrists significantly decreases the amplitude of the tremor. Surgeons should consider using wrist supports when performing parts of operations which necessitate a high degree of accuracy. PMID- 20853331 TI - A modified technique for hepatic artery reconstruction in living donor liver transplantation. AB - Reconstruction of the hepatic artery (HA) is challenging, because there are technical difficulties. Especially, it is difficult to repair the posterior wall. In 2006, we reported an experimental study of the posterior wall first continuous suturing combined with the interrupted suturing and we also confirmed the safety of this procedure. In this article, we report our clinical experiences using this procedure for the HA reconstruction in living-donor liver transplantation. First, we repaired the posterior wall of the HA with continuous suturing. Then, the anterior wall is repaired with the interrupted suturing using a nylon suture with double needle. Between 2006 and 2009, we performed 13 HA reconstructions using our procedure. In all patients, the HA reconstruction was completed easily and uneventfully without oozing from the posterior wall or postoperative HA thrombosis. Our procedure has the benefits of both continuous and interrupted suturing. We believe that it is useful for reconstruction of the HA in living donor liver transplantation. PMID- 20853332 TI - Rapid harvesting both kidneys from one donor rat for transplantation with a technique of sharp dissection after irrigation. AB - The comparisons of two different methods of donor nephrectomy were performed in this study. Fisher inbred rats were used as donors and recipients of kidneys. In method A (the conventional technique), meticulous blunt dissection of the abdominal aorta, inferior vena cava, and renal arteries/veins, was followed by ligating and cutting the superior mesenteric artery and small vessels entering the above vessels. Both donor kidneys were irrigated after the suprarenal aorta and inferior vena cava were cross-clamped (n = 10). In method B, donor rats were systematically irrigated by infrarenal aorta catheterization following laparotomy, then the vessels were sharply mobilized using a pair of microscissors to directly cut the fat and adherent connective tissues away from the edge of the vessels (n = 10). Isotransplantation was performed by end-to-side anastomosis of the blood vessels and end-to-end anastomosis of the ureters. Irrigating the donor kidney before dissection provided a clear visual field, reduced the operation time (37.50 +/- 6.84 versus 68.30 +/- 11.53 minutes, p < 0.001), facilitated the dissection of vessels, and reduced the risk of vasospasm (5 out of 19 versus 0 out of 18, p < 0.05). This study has demonstrated the proposed technique is fast and safe, and may be useful in research of renal transplantation in the rat model. PMID- 20853333 TI - Postoperative care of perforator-based distant tissue flaps--a common but erroneous practice. PMID- 20853334 TI - Morphological, hemodynamical and hemorheological changes of mature artificial saphenous arterio-venous shunts in the rat model. AB - Artificial femoral arterio-venous (AV) shunts are widely used in rodent models for studying shunt maturation and to optimize various surgical techniques. However, little is known about complex circulatory, microcirculatory, and hemorheological effects of end-to-side saphenous AV shunts. We aimed to study these parameters in mature AV shunts. Studying these questions in CD rats, end-to side anastomoses were made between the left saphenous artery and vein. On the right-side the nonoperated saphenous vessels served as own control. Furthermore healthy control animals were also investigated. On the 8th to 12th postoperative week microcirculatory and blood flow measurements were performed and blood samples were taken both from the shunt's arterial and venous limbs and from the nonoperated side vessels. Hematological parameters, erythrocyte aggregation, and deformability were determined. The entire shunt and the control vessels were removed for histological examinations. The skin microcirculation on shunt side slightly increased on thigh and decreased on paws versus the nonoperated side. Blood flow measurements made directly on the vessels showed that arterial to venous blood flow rate ratio was 1.59 +/- 0.29 on nonoperated side and 1.2 +/- 0.13 on the shunt side, and 1.49 +/- 0.05 in control animals. Erythrocyte aggregation and deformability worsened on the shunt side. Histologically increased number of smooth muscle elements and connective tissue were found in venous limb of the shunts. The artificial AV shunt between the saphenous artery and vein seems to be a suitable model for further functional-morphological and hemorheological examinations of hemodialysis in various states and diseases. PMID- 20853335 TI - Reconstruction of lateral through and through oro-mandibular defects following oncological resections. AB - BACKGROUND: Resections of oromandibular squamous cell carcinoma involving lateral mandible, oral cavity, and the skin, lead to composite oromandibular defects that can be approached in several ways depending on the extension of the bone defect, of the soft tissue and cutaneous resection, the patient's general status and the prognosis. Purpose of the study is to evaluate retrospectively functional and esthetic outcome obtained with different reconstructive technique employed. METHODS: A retrospective evaluation of 42 patients has been performed. The study population consisted of 24 males (57.1%) and 18 females (42.9%), ranging in age from 25 to 81 years (mean, 62.6 years). The primary location of the tumor was the mandibular alveolar crest (18 cases), retromolar trigon (9), floor of the mouth (8), cheek (5), and oral commissure (2). For reconstruction a single free flap technique was used eight times; a double free flap technique, seven times; free and locoregional flap association, 25 times; and a single locoregional flap and two associated locoregional flaps, one time each. Postoperative follow-up ranged from 12 to 144 months. Final results were evaluated with regards to deglutition, speech, oral competence, and esthetic outcome. RESULTS: When free bone-containing flaps or two free flaps technique were used, the functional results were better (normal diet, 67%-71%; good oral competence, 100%-71%; good or intelligible speech, 100%-86%). When free and locoregional flap association was chosen, the esthetic results were best (excellent, 76%; acceptable 24%; poor 0%). The worst results were obtained with the use of a single free soft tissue flap and with the use of single or double locoregional flap technique. CONCLUSION: Bone reconstruction of the lateral mandible is indicated whenever possible. In elderly or poor prognosis patients acceptable results can be achieved with free soft tissue flaps techniques. When the defect involves different structures of the oral cavity, the best results are provided by the association of two free flaps. Finally, the association of free and locoregional flaps is a good option for external coverage reconstruction. PMID- 20853336 TI - Clinical experience with the delay phenomenon in autologous breast reconstruction with the deep inferior epigastric artery perforator flap. AB - PURPOSE: The delay phenomenon has been used for breast reconstruction with pedicled flaps but has not been widely reported with free flaps. Our goals were to (1) describe our operative technique for vascular delay of deep inferior epigastric artery perforator (DIEP) flaps when a large percentage of the contralateral hemiabdomen would be needed for added volume of a breast reconstruction, (2) document any clinical improvement in flap vascularization after the delay period, and (3) develop a patient selection algorithm for this procedure. METHODS: From August 2008 through July 2009, six patients at The Johns Hopkins Breast Center underwent autologous breast reconstruction with vascularly delayed DIEP flaps, a technique that preserves lateral skin bridges to the flap. This technique was used based on preoperative three-dimensional computed tomography angiograms showing potential vascular compromise. We assessed length of delay, flap weight, length of stay, and outcome. RESULTS: Transfer delay averaged 15.8 +/- 4.1 days from the original surgery. Transferred flap weight averaged 620.2 +/- 156.7 g. The flaps in all six patients developed adequate arterial inflow and/or venous drainage on reassessment at final transfer. Preoperative screening with three-dimensional computed tomography angiography of the abdominal wall and modification of the flap harvest technique, including use of the clamp test to establish need for delay, were thought to be paramount for patient selection. CONCLUSION: In a very select group of patients undergoing breast reconstruction whose DIEP flaps showed vascular compromise before detachment, the delay phenomenon successfully enhanced vascularity and prevented fat necrosis. PMID- 20853337 TI - The possible role of regenerating axons in pain persistence after brachial plexus grafting. AB - We tested the hypothesis that chronic pain in patients with grafted brachial plexus injuries stems from regenerating axons. Eight patients who had undergone brachial plexus grafting still reported persistent pain 24 months after surgery, and were followed for an additional 6 months. After recording each patient's self reported pain severity using a 10-point verbal analogue scale, a tourniquet was inflated in the injured arm for 90 seconds. Then, patients were asked again to rate their pain. Finally, anesthetic blocks were administered to the nonavulsed C5 root. After tourniquet application to the injured limb, pain significantly decreased by 85% (P < 0.001) in all grafted patients. Anesthetic blocks yielded at least 90% pain reduction. Our findings suggest that pain after brachial plexus injury arises from nonavulsed rather than avulsed roots. After grafting, regenerating axons which have attained the periphery might be responsible for pain maintenance. PMID- 20853338 TI - Knee joint reconstruction after hemiarticular resection using pedicled patella and vascularized fibular graft. AB - Between 1999 and 2005, seven patients had resection of tumors around the knee joint that involved half of the articular surface of the femoral or tibial side. Average age of the patients was 28 years (range, 14-40). Tumor pathology was giant cell tumor in four patients, osteoblastoma in two, and benign fibrous histocytoma in one patient. Two patients had recurrent tumors. The tumor was located in the distal femur in five patients and in the proximal tibia in the remaining two. The ipsilateral patella pedicled on the infrapatellar fat pad was used to substitute the resected articular surface and a vascularized fibula osteoseptocutaneous flap was used to reconstruct the metaphyseal defect. Average follow-up period was 6.5 years (range, 3.5-10 years). All flaps survived. Average time to bone union was 3.5 months (range, 3-4 months), and average time to full weight-bearing was 5 months (range, 4-6 months). No radiological signs of avascular necrosis of the patella were observed in any patient. Two patients required secondary procedures for correction of instability. One patient had local recurrence. At final follow-up, the median range of knee motion was from 10 degrees to 100 degrees . The average Knee Society Score (KSS) was 76 points (range; 50-85 points), and the average KSS functional score was 76.6 points (range, 70-90 points). In conclusion, the procedure is a reliable option for after resection of tumors that involve half the articular surface of the femur or the tibia. PMID- 20853339 TI - Reconstruction of soft tissue defects of the Achilles tendon with rotation flaps, pedicled propeller flaps and free perforator flaps. AB - INTRODUCTION: Soft tissue defects exposing the Achilles tendon are challenging. Local perforator flaps represent a valuable option gaining increasing popularity. Despite preoperative planning an adequate perforator cannot always be found intraoperatively. The free peroneal artery perforator flap can serve as a back-up option limiting the donor site morbidity to the same extremity without sacrificing major vessels or nerves. METHODS: Nine patients with soft tissue defects exposing the Achilles tendon were treated with local perforator flaps, seven were scheduled for 180 degrees propeller flap coverage after Doppler ultrasound examination. However, in two patients (22%) no adequate perforators were found intraoperatively. As the perforators for the free peroneal artery perforator flap were routinely mapped out, this flap was harvested for microsurgical reconstruction. RESULTS: One patient with a 180 degrees propeller flap developed a partial flap necrosis, another patient developed superficial epidermolysis, both requiring skingrafting. no complications were seen with free tissue transfer. CONCLUSION: Pedicled perforator flaps as propeller flaps add options to the armamentarium of microsurgeons. Despite thorough preoperative planning the surgeons must be prepared to perform a different method of reconstruction if inadequate vessels are encountered. To limit additional donor site morbidity, local options are preferred. The free peroneal artery perforator flap represents a good option as it matches the original tissue properties closely. The complication rate of propeller flaps in this series is tolerable. Propeller flaps should therefore be considered an alternative but not as a replacement of local fasciocutaneous flaps. PMID- 20853340 TI - Structure of influenza virus ribonucleoprotein complexes and their packaging into virions. AB - The influenza A virus genome consists of eight segmented, single-stranded, negative-sense RNAs. Each viral RNA (vRNA) segment forms a ribonucleoprotein (RNP) complex together with NPs and a polymerase complex, which is a fundamental unit for transcription and replication of the viral genome. Although the exact structure of the intact RNP remains poorly understood, recent electron microscopic studies have revealed certain structural characteristics of the RNP. This review focuses on the findings of these various electron microscopic analyses of RNPs extracted from virions and RNPs inside virions. Based on the morphological and structural observations, we present the architecture of RNPs within a virion and discuss the genome packaging mechanism by which the vRNA segments are incorporated into virions. PMID- 20853341 TI - Imaging cells in three-dimensional collagen matrix. AB - The use of in vitro three-dimensional (3-D) collagen matrices to mimic an in vivo cellular environment has become increasingly popular and is broadening our understanding of cellular processes and cell-ECM interactions. To study cells in in vitro 3-D collagen matrices, both cellular proteins and the collagen matrix must be visualized. In this unit, the authors describe the protocol and provide troubleshooting for immunolabeling of cells in 3-D collagen gels to localize and visualize cellular proteins with high-resolution fluorescence confocal microscopy. The authors then describe confocal reflection microscopy as a technique for direct imaging of 3-D fibrillar collagen matrices by discussing the advantages and disadvantages of the technique. They also provide instrument settings required for simultaneous imaging of cellular proteins with fluorescence confocal imaging and 3-D collagen fibrils with confocal reflection microscopy. Additionally, the authors provide protocols for a "cell sandwiching" technique to prepare cell cultures in 3-D collagen matrices required for high-resolution confocal imaging. PMID- 20853342 TI - Analysis of Arf GTP-binding protein function in cells. AB - This unit describes techniques and approaches that can be used to study the functions of the ADP-ribosylation factor (Arf) GTP-binding proteins in cells. There are six mammalian Arfs and many more Arf-like proteins (Arls), and these proteins are conserved in eukaryotes from yeast to humans. Like all GTPases, Arfs cycle between GDP-bound, inactive and GTP-bound active conformations, facilitated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that catalyze GTP binding and hydrolysis, respectively. This unit describes approaches that can be taken to examine the localization and function of Arf and Arl proteins in cells. A simple protocol for measuring activation (GTP binding) of specific Arf proteins in cells using a pull-down assay is also described. Approaches that can be taken to assess function of GEFs and GAPs in cells is described. PMID- 20853343 TI - Isolation of aggresomes and other large aggregates. AB - Upon permanent stresses and in various diseases, small protein aggregates may accumulate in cells and cause toxicity. A recently discovered protective system transports these aggregates to the centrosome location via microtubules, to form a large agglomerate of aggregates called the aggresomes. Here, we describe a newly developed method for isolating aggresomes. This principle can also be used for purification of other large structures and even organelles. PMID- 20853344 TI - Isolation of chromaffin granules. AB - Adrenal medullary chromaffin granules (dense core secretory vesicles) have been a valuable model system for the study of the proteins and membrane components involved in the process of exocytosis. Because of the abundance of chromaffin granules in a readily available tissue source, bovine adrenal medullae, and their unique sedimentation properties, it is possible to obtain large quantities of highly purified granules and granule membranes in a short period of time. Two protocols are presented here for the isolation of chromaffin granules: a basic protocol based on differential centrifugation in an iso-osmotic medium that yields intact chromaffin granules, and an alternate protocol based on sedimentation through a density step gradient that provides a greater yield of more highly purified chromaffin granules. Since in the latter case the granules cannot be returned to a medium of physiological osmolarity without lysis after purification on the step gradient, the alternate protocol is more useful to obtain the granule membranes or contents for further study. PMID- 20853345 TI - Dynamic proliferation assessment in flow cytometry. AB - Dynamic proliferation assessment via flow cytometry is legitimately supposed to be the most powerful tool for recording cell cycle kinetics in-vitro. The preeminent feature is a single cell-based multi-informative analysis by temporal high-resolution. Flow cytometric approaches are based on labeling of proliferating cells via thymidine substitution by a base analog (e.g., 5-bromo-2' deoxyuridine, BrdU) that is added to cell cultures either for a short period of time (pulse labeling) or continuously until cell harvesting. This unit describes the alternative use of the thymidine analog 5-ethynyl-2'-deoxyuridine (EdU) in place of BrdU for three different applications: (1) dynamic proliferation assessment by EdU pulse cell labeling; (2) the same approach as (1) but in combination with live/dead cell discrimination; and (3) dynamic cell cycle analysis based on continuous cell labeling with EdU and Hoechst fluorochrome quenching. In contrast to the detection of BrdU incorporation, EdU-positive cells can be identified by taking advantage of click chemistry, which facilitates a simplified and fast cell preparation. Further analysis options but also limitations of the utilization of EdU are discussed. PMID- 20853346 TI - Reactivity of gaseous sodiated ions derived from benzene dicarboxylate salts toward residual water in the collision gas. AB - The sodium adduct of disodium salts of benzene dicarboxylic acids (m/z 233), when subjected to collision-induced dissociation (CID), undergoes a facile loss of CO(2) to produce an ion of m/z 189, which retains all the three sodium atoms of the precursor. The CID spectrum of this unusual m/z 189 ion shows significant peaks at m/z 167, 63 and 85. The enigmatic m/z 167 ion, which appeared to represent a loss of a 22-Da neutral fragment from the precursor ion is in fact a fragment produced by the interaction of the m/z 189 ion with traces of water present in the collision gas. The change of the m/z 167 peak to 168, when D(2)O vapor was introduced to the collision gas of a Q-ToF instrument, proved that such an intervention of water could occur even in collision cells of tandem-in-space mass spectrometers. The m/z 189 ion has such high affinity for water; it forms an ion/molecule complex even during the brief residence time of ions in collision cells of triple quadrupole instruments. The complex formed in this way then eliminates elements of NaOH to produce the ion observed at m/z 167. In an ion trap, the relative intensity of the m/z 167 peak increases with longer activation time even at the lowest possible collision energy setting. Similarly, the m/z 145 ion (which represents the sodium adduct of phenelenedisodium, formed by two consecutive losses of CO(2) from the m/z 233 ion of meta- and para-isomers) interacts with water to produce a fragment ion at m/z 123 for the sodium adduct of phenylsodium. Other uncommon ions that originate also from water/ion interactions are observed at m/z 85 and 63 for [Na(3)O](+) and [Na(2)OH](+), respectively. Tandem mass spectrometric experiments conducted with appropriately deuterium-labeled compounds confirmed that the proton required for the formation of the [Na(2)OH](+) ion originates from traces of water present in the collision gas and not from the ring protons of the aromatic moiety. PMID- 20853347 TI - Downstream antibody purification using aqueous two-phase extraction. AB - The extraction of antibodies using a polyethylene glycol (PEG)-citrate aqueous two-phase system (ATPS) was investigated. Studies using purified monoclonal antibody (mAb) identified operating ranges for successful phase formation and factors that significantly affected antibody partitioning. The separation of antibody and host cell protein (HCP) from clarified cell culture media was examined using statistical design of experiments (DOE). The partitioning of antibody was nearly complete over the entire range of the operating space examined. A model of the HCP partitioning was generated in which both NaCl and citrate concentrations were identified as significant factors. To achieve the highest purity, the partitioning of HCP from cell culture fluid into the product containing phase was minimized using a Steepest Descent algorithm. An optimal ATPS consisting of 14.0% (w/w) PEG, 8.4% (w/w) citrate, and 7.2% (w/w) NaCl at pH 7.2 resulted in a product yield of 89%, an approximate 7.6-fold reduction in HCP levels relative to the clarified cell culture fluid before extraction and an overall purity of 70%. A system consisting of 15% (w/w) PEG, 8% (w/w) citrate, and 15% (w/w) NaCl at pH 5.5 reduced product-related impurities (aggregates and low molecular product fragments) from ~40% to less than 0.5% while achieving 95% product recovery. At the experimental conditions that were optimized in the batch mode, a scale-up model for the use of counter-current extraction technology was developed to identify potential improvements in purity and recovery that could be realized in the continuous operational mode. PMID- 20853348 TI - Transapical repair of mitral valve paravalvular leakage using 3-D transesophageal guidance. AB - We report a case where transapical access with real time 3D transesophageal echocardiographic guidance is used for repair of a mitral valve paravalvular leakage. The transapical approach is a new, elegant, and relative safe alternative for repair of a paravalvular defect in high-risk patients. The use of real time 3DTEE for guiding the procedure provides the operator fast and complete information about the leakage, and allowing online monitoring of the procedure. PMID- 20853349 TI - The effect of CTO recanalization on FFR of the donor artery. AB - This case illustrates that fractional flow reserve (FFR) in addition to the severity and length of the coronary stenosis is critically dependent on the extent of viable myocardium perfused. In the presented case, the left anterior descending artery (LAD) that had modest angiographic stenosis supplied collaterals to the entire left ventricle. After recanalization of chronic total occlusions (CTO) of the right and circumflex arteries, FFR in the LAD had normalized. PMID- 20853351 TI - Extended follow-up safety and effectiveness of the Endeavor zotarolimus-eluting stent in real-world clinical practice: two-year follow-up from the E-Five Registry. AB - OBJECTIVES: To present data from the cohort of patients in the all-comers Endeavor zotarolimus-eluting stent (ZES) registry (E-Five) who underwent 2-year follow-up. BACKGROUND: The Endeavor ZES has been shown to be safe and efficacious for treatment of single, de novo lesions in patients with stable coronary artery disease. E-Five evaluated the ZES in over 8,000 real-world patients, at 188 sites followed to 1 year. A subset of sites continued follow-up through 2 years to evaluate late-term safety and effectiveness of the ZES in this population with diverse clinical and lesion characteristics. METHODS: E-Five, a prospective, multicenter, nonrandomized global registry, collected 2-year outcomes for 2,116 patients from 26 centers. Sites were selected for participation based on patient accrual rates and the ability to continue follow-up activities for an additional year. Complete data was available for 2,054 patients. To observe whether or not a sustained benefit was achieved, data for all patients from the selected sites were included in the analysis. RESULTS: The outcomes in the 2-year cohort tracked with the results of randomized controlled trials using the Endeavor ZES. One year results were MACE 7.5%, TLR 4.5%, and ARC definite/probable stent thrombosis 0.6%. Outcomes at 2 years for MACE, TLR, and ARC definite/probable stent thrombosis were 8.5, 5.1, and 0.7%, respectively. CONCLUSIONS: Long-term efficacy and safety outcomes were maintained between 1 and 2 years for the 2-year patient cohort, with only a small number of additional MACE, TLR, and very late stent thrombosis events. PMID- 20853352 TI - Safety and efficacy of dual-axis rotational coronary angiography vs. standard coronary angiography. AB - OBJECTIVE: To determine the safety and efficacy of dual-axis rotational coronary angiography (DARCA) by directly comparing it to standard coronary angiography (SA). BACKGROUND: Standard coronary angiography (SA) requires numerous fixed static images of the coronary tree and has multiple well-documented limitations. Dual-axis rotational coronary angiography (DARCA) is a new rotational acquisition technique that entails simultaneous LAO/RAO and cranial/caudal gantry movement. This technological advancement obtains numerous unique images of the left or right coronary tree with a single coronary injection. We sought to assess the safety and efficacy of DARCA as well as determine DARCA's adequacy for CAD screening and assessment. METHODS: Thirty patients underwent SA following by DARCA. Contrast volume, radiation dose (DAP) and procedural time were recorded for each method to assess safety. For DARCA acquisitions, blood pressure (BP), heart rate (HR), symptoms and any arrhythmias were recorded. All angiograms were reviewed for CAD screening adequacy by two independent invasive cardiologists. RESULTS: Compared to SA, use of DARCA was associated with a 51% reduction in contrast, 35% less radiation exposure, and 18% shorter procedural time. Both independent reviewers noted DARCA to be at least equivalent to SA with respect to the ability to screen for CAD. CONCLUSION: DARCA represents a new angiographic technique which is equivalent in terms of image quality and is associated with less contrast use, radiation exposure, and procedural time than SA. PMID- 20853353 TI - Rescue treatment by percutaneous closure of interatrial septal defect or PFO in infants with Berlin heart. AB - During the past two decades, important progress has been achieved in the treatment of end-stage congestive heart failure in newborns and infants. The use of ventricular assist devices (VAD) in these patients is now available as a bridge to heart transplantation. The use of a VAD may reveal the presence of a silent interatrial septal defect or a patent foramen ovale (PFO), inducing a right to left shunt resulting in systemic desaturation and hemodynamic instability. We present two cases of low weight infants on circulatory support with VADs and right to left shunt through interatrial septum that were successfully treated by percutaneous intervention with an occlusion device. PMID- 20853354 TI - Percutaneous device closure of congenital and iatrogenic ventricular septal defects in adult patients. AB - OBJECTIVES: We report our 10-year experience with percutaneous closure of adult congenital and acquired (non-post-infarct) ventricular septal defects (VSDs) using different types of Amplatzer occluder devices. BACKGROUND: Adult congenital and acquired VSDs may produce significant morbidity and mortality. Furthermore, such VSDs pose a significant surgical challenge. METHODS: Between February 2000 and August 2009, data were retrospectively reviewed from 28 patients who underwent 29 procedures for percutaneous device closure of hemodynamically significant VSDs. Seventeen had unrepaired congenital VSDs, 10 had post-operative VSDs (5 with residual patch-margin defects, 4 post-aortic valve replacement, 1 post-myomectomy), and one had an acquired traumatic VSD. INDICATIONS FOR CLOSURE INCLUDED: symptoms related to significant shunt (dyspnea on exertion); unexplained deterioration of LV function, and/or LV dilation; recurrent endocarditis, and pulmonary hypertension. Outcome parameters were procedural success, procedure-related complications, evidence of residual shunt by echocardiography, and improvement in the signs/symptoms for which the procedure was performed. The mean follow-up interval was 68 months. RESULTS: Of the 28 patients studied, a single VSD was present in 26 patients, while one patient had two defects, and one patient had one defect on the LV side with three openings at the RV side. The median size of the defects by echocardiography was 6 mm. A device was successfully implanted in 28 of 29 (97%) procedures and 28 of 28 (100%) patients. PROCEDURE-RELATED COMPLICATIONS OCCURRED IN TWO CASES: one involving an access site hematoma not requiring transfusion as well as nonsustained ventricular tachycardia that resolved spontaneously and the other involving acute mitral regurgitation due to inadvertent trapping of the anterior mitral valve leaflet between the left ventricular disk and the septum that was resolved by recapturing of the disk. There was immediate complete closure in 20 patients (71%). In six cases there was trivial residual shunt and in two patients the residual shunt was mild. At the latest follow-up, four of the eight with a residual shunt had no shunt and in the remaining four the residual shunt was trivial. Among symptomatic patients 18 (64%), there was marked improvement in symptoms and for those patients 17 (61%) for whom the procedure was performed to address left ventricular enlargement, there was reduction or stabilization in LV size on serial echoes. CONCLUSIONS: Percutaneous closure of VSDs in the adult patient appears to be safe and effective. PMID- 20853355 TI - Percutaneous revascularization of long femoral artery lesions for claudication: patency over 2.5 years and impact of systematic surveillance. AB - BACKGROUND: Angioplasty and stenting are preferred treatments for revascularizing femoral artery lesions up to 100 mm, but surgical bypass is recommended for longer lesions. We assessed long-term patency after percutaneous revascularization of long femoral artery lesions for claudication with intensive out-patient surveillance. METHODS: We followed a cohort of 111 consecutive patients receiving angioplasty or stenting in 142 limbs in two institutions. Patients were followed for 2.5 years, and event curves and multivariable survival analysis used to compare outcomes in three groups according to lesion length (< 100 mm, 100-200 mm, and greater than 200 mm). Failed patency was defined as recurrence of symptoms with a decline in ankle brachial index, or stenosis identified by duplex ultrasound, or reintervention. RESULTS: Compared to lesions less than 100 mm, longer lesions had higher failed primary patency (100-200 mm: HR = 2.0, P = 0.16, >200 mm: HR = 2.6, P = 0.03). Failed secondary patency was similar for short and intermediate lesions (< 5% incidence), but trended higher for lesions >200 mm (HR = 4.2, P = 0.06). An initial procedure residual stenosis greater than 20% was the only significant multivariable factor related to poorer long-term patency (HR = 15.8, P = 0.003). Compared to short lesions, the gain in long-term patency with out-patient surveillance and reintervention was higher for longer lesions and significantly so for intermediate lesions (100-200 mm = 23% versus <100 mm = 8%, P = 0.041). CONCLUSION: Percutaneous treatment of long femoral artery lesions can provide acceptable long-term patency for patients with claudication when out-patient surveillance is used to identify patients who require repeat interventions. Future long-term studies should consider overall patency encompassing more than one percutaneous reintervention. PMID- 20853356 TI - Rebuttal: Use of embolic protection devices in saphenous vein graft interventions: the ongoing challenge. PMID- 20853357 TI - Percutaneous retrieval of the locked helex septal occluder. AB - The HELEX device is approved for percutaneous closure of an atrial septal defect (ASD). It is also often used off-label to close patent foramen ovale (PFO). The device is well tolerated because it is very flexible, but this characteristic increases the likelihood of embolization of locked implants. While the company provides a mechanism to retrieve devices that do not lock correctly, retrieval of locked and released devices is much more difficult. A case of percutaneous retrieval of an embolized, locked HELEX device is reported. This device was successfully retrieved from the aorta by snaring the left atrial eyelet and unlocking the device. A variety of potential techniques for retrieval of these devices was explored on the bench top. Strategies which can be used to successfully retrieve embolized HELEX devices are described. PMID- 20853358 TI - Long-term outcomes of intraoperative pulmonary artery stent placement for congenital heart disease. AB - OBJECTIVE: Our objective was to examine long-term outcomes of intraoperative pulmonary artery stents and determine risk factors for reintervention BACKGROUND: Short-term outcomes of intraoperative pulmonary artery stents have been reported previously. However, long-term results are unknown. METHODS: We conducted a retrospective review of patients who underwent intraoperative pulmonary artery stent placement for branch pulmonary artery stenosis. RESULTS: Ninety-six stents were implanted intraoperatively in 67 patients. Twenty-seven patients received two or more stents at initial intervention. Median patient age at initial stent placement was 1.8 years. Median post-inflation diameter was 8 mm. At a mean follow-up of 7.6+/-4.5 years, 49% of stents required reintervention (balloon angioplasty at catheterization in 28 patients and surgical revision in 19 patients). Actuarial freedom from reintervention at 2, 5, and 10 years was 68%, 49%, and 40%, respectively. In univariate analysis of time to first reintervention, age at implantation<2 yrs (P<0.0009) and initial post-inflation stent diameter<10 mm (P<0.0002) were associated with risk for reintervention. Multivariable Cox regression analysis showed age<2 years (P<0.005) and diagnosis of tetralogy of Fallot (p<0.002) or truncus arteriosus (P<0.007) to be significant risk factors for reintervention. CONCLUSION: Intraoperative placement of stents in the pulmonary arteries is an alternative to surgical angioplasty, but is associated with a high incidence of reintervention. Age<2 years and the diagnosis of tetralogy of Fallot or truncus arteriosus are risk factors for reintervention. PMID- 20853359 TI - Retrograde approach to recanalization of complex tibial disease. AB - A significant proportion (~ 20%) of patients with complex tibial artery occlusions cannot be treated using a conventional antegrade approach. We report our experience using the retrograde approach for the treatment of complex tibial artery occlusive disease using retrograde pedal/tibial access in 13 limbs from 12 patients. Retrograde pedal/tibial access was achieved in all cases (facilitated by surgical cutdown in one case), and procedural success was achieved in 11 of 13 limbs (85%). Based on this experience, a discussion of clinical and technical aspects of the retrograde pedal/tibial approach is provided, and a new classification for tibial artery occlusive disease is proposed. PMID- 20853350 TI - Usage patterns and 1-year outcomes with the TAXUS Liberte stent: results of the TAXUS OLYMPIA registry. AB - OBJECTIVES: The TAXUS OLYMPIA registry is a prospective, global, post-approval program designed to collect clinical outcome data through 1 year from patients receiving the TAXUS Liberte paclitaxel-eluting stent in routine interventional cardiology practice. BACKGROUND: The thin-strut TAXUS Liberte stent has been studied in ongoing clinical trials with specific inclusion/exclusion criteria. METHODS: Between September 2005 and April 2007, a total of 21,954 patients from 365 sites in 57 countries eligible to receive a TAXUS Liberte stent were enrolled in the TAXUS OLYMPIA registry. Baseline characteristics and procedure patterns were collected and clinical follow-up is available for 1 year. The primary endpoint was the composite cardiac event (cardiac death, MI, and reintervention of the target vessel) rate related to the TAXUS Liberte stent at 1 year. All cardiac events were monitored and all endpoints were independently adjudicated. RESULTS: Complex patients and lesions were prevalent, including: 27% medically treated diabetes, 58% ACC/AHA type B2/C lesions, 32% multiple stenting, 13% long lesions (>28 mm), and 10% small vessels (<2.5 mm). At 1 year, the composite cardiac event rate was 4.4%, including 1.4% cardiac death, 1.0% MI, and 3.2% TVR. Stent thrombosis (ST, angiographically confirmed) occurred in 0.8% of patients, with 0.4% ST occurring >30 days postprocedure. The composite cardiac event rate related to the TAXUS Liberte stent was 3.8% at 1 year. CONCLUSIONS: Low 1-year cardiac event rates were reported with TAXUS Liberte in a broad spectrum of patients, thereby confirming the technical and clinical performance of this stent in a "real-world" setting. PMID- 20853361 TI - Acute myocardial infarction and the five-chambered heart. AB - The case of a patient presenting with acute inferior ST-elevation myocardial infarction is described. Emergent coronary angiography of the right coronary artery revealed what appeared to be the abrupt drainage of contrast into a large, peculiar cavity or chamber. Echocardiography and cardiac computed tomography demonstrated a giant right coronary aneurysm in the right coronary artery that gave the impression of a "fifth heart chamber." The patient underwent successful surgical resection of the aneurysm. Diagnostic and treatment approaches to giant coronary aneurysms are discussed. PMID- 20853360 TI - Low frequency of embolic protection devices in saphenous vein intervention: a matter of lack of conviction? PMID- 20853362 TI - In-stent restenotic lesions can rupture--a case against plaque sealing. AB - We present a case of plaque rupture located inside a restenotic stent. Intravascular ultrasound defined a lesion with a minimal lumen area (MLA) of 3.59 cm2, plaque burden of 72%, and reference vessel luminal diameter of 4.0 mm with an external elastic membrane lumen cross-section area of 12.6 mm2. There was a clearly identified plaque rupture, with a flap-like dissection within the stented segment. Virtual histology intravascular ultrasound confirmed that the adjacent plaque had necrotic core with a thin overlying fibrous cap. The remaining tissue next to the dissection plane was fibrotic. This case illustrates that neointimal hyperplasia may organize into an unstable plaque, with a thin fibrous cap overlying a lipid-rich necrotic core-a so-called virtual histology thin-capped fibroatheroma. As defined in the PROSPECT trial, the in-stent stenotic lesion in our case conformed to the definition of a high-risk plaque-it had an MLA < 4 mm2, plaque burden was >= 70%, and there was >10% necrotic core. It became unstable and ruptured. The demonstrated findings of this case may sway physicians against sealing hemodynamically nonsignificant unstable plaques. PMID- 20853363 TI - Amplatzer vascular plug closure of a subclavian arteriovenous fistula associated with implantable cardioverter-defibrillator implantation. AB - Subclavian arteriovenous fistula (AVF) is a rare complication of implantable cardioverter-defibrillator (ICD) implantation. This report illustrates the case of a subclavian AVF after ICD implantation in a patient with nonischemic cardiomyopathy and the successful closure of this AVF using an Amplatzer vascular occlusion plug. Given the increasing number of ICD implantations, physicians should be made aware of this uncommon complication. In addition, as more percutaneous endovascular techniques are developed to treat peripheral vascular and structural heart disease, iatrogenic AVFs may occur more frequently. The Amplatzer vascular plug should be considered as a potential treatment strategy for AVFs alongside other endovascular and surgical techniques. PMID- 20853364 TI - Expanding the base for teaching of percutaneous coronary interventions: the explicit approach. AB - OBJECTIVES: Accelerate and improve the training and learning process of operators performing percutaneous coronary interventions (PCI). BACKGROUND: Operator cognitive, in particular decision-making skills and technical skills are a major factor for the success of coronary interventions. Currently, cognitive skills are commonly developed by three methods: (1) Cognitive learning of rules for which statistical evidence is available. This is very incomprehensive and isolates cognitive learning from skill acquisition. (2) Informal tutoring received from experienced operators, and (3) personal experience by trial-and-error are both very slow. METHODS: We propose in this concept article a conceptual framework to elicit, capture, and transfer expert PCI skills to complement the current approach. This includes the development of an in-depth understanding of the nature of PCI skills, terminology, and nomenclature needed to streamline communication, propensity of reproducible performance assessment, and in particular an explication of intervention planning and intra-intervention decision-making. We illustrate the impact of improved decision-making by simulation results based on a stochastic model of intervention risk. RESULTS: We identify several key concepts that form the basis of this conceptual framework, in particular different risk types and the notions of strategy, interventional module, and tactic. CONCLUSIONS: The increasing complexity of cases have brought PCI to the point where the decision-making skills of master operators need to be made explicit to make them systematically learnable such that the skills of beginner and intermediate operators can be improved much faster than is currently possible. PMID- 20853365 TI - Neuroprotection during carotid artery stenting using the GORE flow reversal system: 30-day outcomes in the EMPiRE Clinical Study. AB - BACKGROUND: Each of the embolic protection devices used in carotid artery stenting (CAS) has advantages and disadvantages. The prospective, multicenter, single-arm EMPiRE Clinical Study investigated a proximally placed device (GORE Flow Reversal System) that provides distal neuroprotection during CAS by reversing blood flow in the internal carotid artery, thereby directing emboli away from the brain. METHODS: The study evaluated 30-day outcomes in 245 pivotal high-surgical-risk patients (mean age, 70 years; 32% symptomatic; 16% >=80-years old) with carotid stenosis who underwent CAS using the flow reversal system. The primary endpoint was a major adverse event (MAE; stroke, death, myocardial infarction, or transient ischemic attack) within 30 days of CAS. The MAE rate was compared with an objective performance criterion (OPC) derived from CAS studies that included embolic protection. RESULTS: The MAE rate was 4.5% (11 patients; P=0.002 compared with the OPC). The stroke and death rate was 2.9%. No patient had a major ischemic stroke. Six patients (2.4%) had intolerance to flow reversal. The death and stroke rates in the symptomatic, asymptomatic, and octogenarian subgroups were 2.6, 3, and 2.6%, respectively, meeting American Heart Association guidelines for carotid endarterectomy. CONCLUSION: The stroke and death rate in this study was among the lowest in CAS trials. The results indicate that the flow reversal system is safe and effective when used for neuroprotection during CAS and that it provides benefits in a broad patient population. PMID- 20853366 TI - Therapeutic ultrasound to noninvasively create intracardiac communications in an intact animal model. AB - OBJECTIVE: To determine if pulsed cavitational ultrasound therapy (histotripsy) can accurately and safely generate ventricular septal defects (VSDs) through the intact chest of a neonatal animal, with the eventual goal of developing a noninvasive technique of creating intra-cardiac communications in patients with congenital heart disease. BACKGROUND: Histotripsy is an innovative ultrasonic technique that generates demarcated, mechanical tissue fractionation utilizing high intensity ultrasound pulses. Previous work has shown that histotripsy can create atrial septal defects in a beating heart in an open-chest canine model. METHODS: Nine neonatal pigs were treated with transcutaneous histotripsy targeting the ventricular septum. Ultrasound pulses of 5-MUsec duration at a peak negative pressure of 13 MPa and a pulse repetition frequency of 1 kHz were generated by a 1 MHz focused transducer. The procedure was guided by real-time ultrasound imaging. RESULTS: VSDs were created in all pigs with diameters ranging from 2 to 6.5 mm. Six pigs were euthanized within 2 hrs of treatment, while three were recovered and maintained for 2-3 days to evaluate lesion maturation and clinical side effects. There were only transient clinical effects and pathology revealed mild collateral damage around the VSD with no significant damage to other cardiac or extra-cardiac structures. CONCLUSIONS: Histotripsy can accurately and safely generate VSDs through the intact chest in a neonatal animal model. These results suggest that with further advances, histotripsy can be a useful, noninvasive technique to create intracardiac communications, which currently require invasive catheter-based or surgical procedures, to clinically stabilize newborn infants with complex congenital heart disease. PMID- 20853367 TI - On cardiac shunt calculations made too easy. PMID- 20853368 TI - Multivessel peripheral revascularization for acute stroke intervention: successful M2 bifurcation stenting and the growing case for comprehensive endovascular interventional training. AB - A comprehensive endovascular skill set is desirable and key to successful intervention in the patient with complex cardiovascular disease. Acute stroke intervention is the next frontier for the endovascular specialist. We report a case of acute stroke intervention in a patient with severe peripheral vascular disease performed by interventional cardiologists with peripheral endovascular skills that clearly demonstrates the new paradigm of global revascularization. PMID- 20853370 TI - Comparing procedural risks to select the optimal revascularization strategy: certainty in an uncertain anatomical world. PMID- 20853369 TI - Outcomes from patients with multi-vessel disease following primary PCI: staged PCI imparts very low mortality. AB - BACKGROUND: CABG and PCI are effective means for revascularization of patients with multi-vessel coronary artery disease, but previous studies have not focused on treatment of patients that first undergo primary PCI. METHODS: Among patients enrolled in the global registry of acute coronary events (GRACE), clinical outcomes for patients presenting with STEMI treated with primary PCI were compared according to whether residual stenoses were treated medically, surgically, or with staged PCI. Clinical characteristics and data pertaining to major adverse cardiac events during hospitalization and 6 months after discharge were collected. RESULTS: Of the 1,705 patients included, 1,345 (79%) patients were treated medically, 303 (18%) underwent staged PCI, and 57 (3.3%) underwent CABG following primary PCI. Hospital mortality was lowest among patients treated with staged PCI (Medical = 5.7%; PCI = 0.7%; CABG = 3.5%; P < 0.001 [PCI vs. Medical]), a finding that persisted after risk adjustment (Odds Ratio PCI vs. Medical 5 0.16, [0.04-0.68]; P 5 0.01). Six month postdischarge mortality likewise was lowest in the staged PCI group (Medical = 3.1%; PCI = 0.8%; CABG = 4.0%; P = 0.04 [PCI vs. Medical]). Patients revascularized surgically were rehospitalized less frequently (Medical = 20%; PCI = 19%; CABG = 6.3%; P < 0.05) and underwent fewer unscheduled procedures (Medical 5 9.8%; PCI = 10.0%; CABG = 0.0%; P < 0.02). CONCLUSIONS: The results of this multinational registry demonstrate that hospital mortality in patients who undergo staged percutaneous revascularization of multivessel coronary disease following primary PCI is very low. Patients undergoing CABG following primary PCI are hospitalized less frequently and undergo fewer unplanned catheter-based procedures. PMID- 20853371 TI - Dual vascular access for critical limb ischemia: immediate and follow-up results. AB - PURPOSE: To describe a procedural technique involving a combined antegrade femoral and retrograde tibial approach for treatment of complex popliteal and infrapopliteal occlusions, and to determine the safety and efficacy of this technique. MATERIALS AND METHODS: From May 2008 to March 2010, seven patients presenting with critical limb ischemia received dual vascular access intervention in this institution. Five legs were treated via the retrograde tibial approach after failure of antegrade intervention. A dual access approach was planned and adopted in another two legs. The target vessels were located at popliteal or infrapopliteal arteries. RESULTS: We successfully gained all retrograde tibial access sites and achieved 100% procedural success and immediate hemodynamic improvement. Five legs required stent implantation to optimize the procedural results. No major complication occurred at the tibial access site. During the follow-up period (11.3 +/- 7.2, range 3-23 months), no patients required any major amputation; only one patient underwent a mid-foot amputation. The target vessel revascularization rate at 3 and 6 months was 0 and 28.6%, respectively. CONCLUSION: Dual vascular access was successfully used in a small number of selected patients and this technique may hold promise in improving the success rates in the treatment of complex popliteal and infrapopliteal occlusions. PMID- 20853372 TI - A molecular dynamics simulation of the stability-limited growth mechanism of peptide-mediated gold-nanoparticle synthesis. PMID- 20853373 TI - A temperature-responsive nanoreactor. AB - An originally designed temperature-responsive nanoreactor is reported. The nanoreactor is made of Ag nanoparticles and a functional polymer composite of poly(acrylamide) (PAAm) and poly(2-acrylamide-2-methylpropanesulfonic acid) (PAMPS). At a relatively low temperature (e.g., 20 degrees C), this nanoreactor displayed weak reactivity because of the interpolymer complexation between PAAm and PAMPS, which largely restricted the access of reactants to the encapsulated Ag nanoparticles. On the contrary, at a relatively high temperatures (e.g., 40 degrees C), the nanoreactor demonstrated significant catalytic activity resulting from the dissociation of the interpolymer complexation between PAAm and PAMPS, which allowed reactants to get access to the encapsulated Ag nanoparticles. By taking account of previously reported PNIPAm-based nanoreactors, which show inverse temperature response, i.e., reactivity decreases whilst temperature increases, this temperature-responsive nanoreactor would greatly facilitate and enrich the increasing studies on smart nanomaterials, generating numerous applications in a wide range of areas, such as catalysis and sensing. PMID- 20853374 TI - Self-assembly of hyperbranched polymers and its biomedical applications. AB - Hyperbranched polymers (HBPs) are highly branched macromolecules with a three dimensional dendritic architecture. Due to their unique topological structure and interesting physical/chemical properties, HBPs have attracted wide attention from both academia and industry. In this paper, the recent developments in HBP self assembly and their biomedical applications have been comprehensively reviewed. Many delicate supramolecular structures from zero-dimension (0D) to three dimension (3D), such as micelles, fibers, tubes, vesicles, membranes, large compound vesicles and physical gels, have been prepared through the solution or interfacial self-assembly of amphiphilic HBPs. In addition, these supramolecular structures have shown promising applications in the biomedical areas including drug delivery, protein purification/detection/delivery, gene transfection, antibacterial/antifouling materials and cytomimetic chemistry. Such developments promote the interdiscipline researches among surpramolecular chemistry, biomedical chemistry, nano-technology and functional materials. PMID- 20853375 TI - Functional organic field-effect transistors. AB - Functional organic field-effect transistors (OFETs) have attracted increasing attention in the past few years due to their wide variety of potential applications. Research on functional OFETs underpins future advances in organic electronics. In this review, different types of functional OFETs including organic phototransistors, organic memory FETs, organic light emitting FETs, sensors based on OFETs and other functional OFETs are introduced. In order to provide a comprehensive overview of this field, the history, current status of research, main challenges and prospects for functional OFETs are all discussed. PMID- 20853376 TI - Pericyclic reactions in an aqueous molecular flask. AB - A self-assembled molecular flask with a nanometer-sized restricted cavity offers a new reaction environment that is quite different from the bulk solution. The self-assembled cage accommodates a pair of hydrophobic molecules to perform unusual Diels-Alder reactions and [2+2] photoadditions of otherwise unreactive aromatic molecules. In this cage, for example, the Diels-Alder reaction of naphthalene proceeds smoothly under mild conditions, and aceanthrylene shows reactivity for both [2+2] and [2+4] cycloadditions via the identical ternary host guest complex. The observed greatly enhanced reactivity stems from the increased local concentration and pre-organization of the substrate pair within the cage, which reduces the entropic cost and switches the reaction profile from a bimolecular to a pseudo-intramolecular reaction pathway. The reinforced orientation and arrangement of substrate pairs specify regio- and stereo selectivities of the subsequent reactions in the cavity. Chiral auxiliaries outside the cage create the inner chiral environment and induce asymmetric reactions inside the cage (up to 50% ee). PMID- 20853378 TI - Structural covariance in the cortex of very preterm adolescents: a voxel-based morphometry study. AB - On the basis of findings in normative samples that different cortical brain regions covary in gray matter volume, most likely as a result of mutually trophic influences during cortical development, we aimed to study whether patterns of covariation in regional gray matter, i.e., structural covariance, differed between adolescents who were born very preterm and full-term controls. Optimized voxel-based morphometry was used to study structural magnetic resonance imaging scans from 218 very preterm adolescents (gestational age <33 weeks) and 127 controls at 14-15 years of age. Local gray matter volumes were obtained for 18 regions of interest involved in sensorimotor and higher-order cognitive functions. These were then used to predict local volumes in the remaining areas of the cortex, with total gray matter volume, age and gender used as confounding variables. Very preterm adolescents compared with controls demonstrated differential (i.e., both increased and decreased) structural covariance between medial, frontal and cingulate gyri, caudate nucleus, thalamus, primary visual cortex, cerebellum and several other cortical and subcortical regions of the cortex. These findings support previous research indicating that preterm birth is associated with altered cortical development, and suggest that developmental changes in one brain region may result in a cascade of alterations in multiple regions. PMID- 20853379 TI - A {Cu2S}2+ mixed-valent core featuring a Cu-Cu bond. PMID- 20853377 TI - Visual phonetic processing localized using speech and nonspeech face gestures in video and point-light displays. AB - The talking face affords multiple types of information. To isolate cortical sites with responsibility for integrating linguistically relevant visual speech cues, speech and nonspeech face gestures were presented in natural video and point light displays during fMRI scanning at 3.0T. Participants with normal hearing viewed the stimuli and also viewed localizers for the fusiform face area (FFA), the lateral occipital complex (LOC), and the visual motion (V5/MT) regions of interest (ROIs). The FFA, the LOC, and V5/MT were significantly less activated for speech relative to nonspeech and control stimuli. Distinct activation of the posterior superior temporal sulcus and the adjacent middle temporal gyrus to speech, independent of media, was obtained in group analyses. Individual analyses showed that speech and nonspeech stimuli were associated with adjacent but different activations, with the speech activations more anterior. We suggest that the speech activation area is the temporal visual speech area (TVSA), and that it can be localized with the combination of stimuli used in this study. PMID- 20853380 TI - Reversible pH-regulated control of photosensitized singlet oxygen production using a DNA i-motif. PMID- 20853381 TI - Programmed nanoparticle aggregation using molecular beacons. PMID- 20853382 TI - Formation of gold(I) edge oxide at flat gold nanoclusters on an ultrathin MgO film under ambient conditions. PMID- 20853383 TI - Synthesis and characterization of multimetallic Pd/Au and Pd/Au/FePt core/shell nanoparticles. PMID- 20853384 TI - Supramolecular cross-linking of [60]fullerene-tagged polyphenylacetylene by the host-guest interaction of calix[5]arene and [60]fullerene. PMID- 20853386 TI - Atmospheric lifetimes and global warming potentials of CF3CH2CH2OH and CF3(CH2)2CH2OH. AB - A comprehensive study of several atmospheric degradation routes for two hydrofluoroalcohols, CF(3)(CH(2))(x=1,2)CH(2)OH, is presented. The gas-phase kinetics of their reactions with hydroxyl radicals (OH) and chlorine (Cl) atoms are investigated by absolute and relative techniques, respectively. The room temperature rate coefficients (+/-sigma, in cm(3) molecule(-1) s(-1)) k(OH) and k(Cl), are respectively (9.7+/-1.1)*10(-13) and (1.60+/-0.45)*10(-11) for CF(3)CH(2)CH(2)OH, and (2.62+/-0.32)*10(-12) and (8.71+/-0.24)*10(-11) for CF(3)(CH(2))(2)CH(2)OH. Average lifetimes of CF(3)CH(2)CH(2)OH and CF(3)(CH(2))(2)CH(2)OH due to the OH and Cl reactions are estimated to be 12 and 4 days, and greater than 20 and 4 years, respectively. Also, the IR and UV absorption cross sections of CF(3)(CH(2))(x=1,2)CH(2)OH are determined in the spectral ranges of 500-4000 cm(-1) and 200-310 nm. Photolysis of CF(3)(CH(2))(x=1,2)CH(2)OH in the actinic region (lambda>=290 nm) is negligible compared to their homogeneous removal. Additionally, computational IR spectra are consistent with the experimental ones, thus giving high confidence in the obtained results. The lifetimes of CF(3)(CH(2))(x=1,2)CH(2)OH and IR spectra reported herein allow the calculation of the direct global warming potential of these hydrofluoroalcohols. The contribution of CF(3)(CH(2))(x)CH(2)OH to radiative forcing of climate change will be negligible. PMID- 20853387 TI - CdS-encapsulated TiO2 nanotube arrays lidded with ZnO nanorod layers and their photoelectrocatalytic applications. AB - A novel TiO(2) nanotube array/CdS nanoparticle/ZnO nanorod (TiO(2) NT/CdS/ZnO NR) photocatalyst was constructed which exhibited a wide-absorption (200-535 nm) response in the UV/Vis region and was applied for the photoelectrocatalytic (PEC) degradation of dye wastewater. This was achieved by chemically assembling CdS into the TiO(2) NTs and then constructing a ZnO NR layer on the TiO(2) NT/CdS surface. Scanning electron microscopy (SEM) results showed that a new structure had been obtained. The TiO(2) NTs looked like many "empty bottles" and the ZnO NR layer served as a big lid. Meanwhile the CdS NPs were encapsulated between them with good protection. After being sensitized by the CdS NPs, the absorption-band edge of the obtained photocatalyst was obviously red-shifted to the visible region, and the band gap was reduced from its original 3.20 eV to 2.32 eV. Photoelectric-property tests indicated that the TiO(2) NT/CdS/ZnO NR material maintained a very high PEC activity in both the ultraviolet (UV) and the visible region. The maximum photoelectric conversion efficiencies of TiO(2) NT/CdS/ZnO NR were 31.8 and 5.98% under UV light (365 nm) and visible light (420-800 nm), respectively. In the PEC oxidation, TiO(2) NT/CdS/ZnO NR exhibited a higher removal ability for methyl orange (MO) and a high stability. The kinetic constants were 1.77*10(-4) s(-1) under UV light, which was almost 5.9 and 2.6 times of those on pure TiO(2) NTs and TiO(2) NT/ZnO NR, and 2.5*10(-4) s(-1) under visible light, 2.4 times those on TiO(2) NT/CdS. PMID- 20853388 TI - Generation and reactions of an unsubstituted N-heterocyclic carbene boryl anion. PMID- 20853389 TI - Kinetic study of OH radical reactions with CF3CCl=CCl2, CF3CCl=CClCF3 and CF3CF=CFCF3. AB - The relative rate technique has been used to determine the rate constants of the reactions of OH radicals with CF(3)CCl=CCl(2) (k(1)), CF(3)CCl=CClCF(3) (k(2)) and CF(3)CF=CFCF(3) (k(3)). Experiments were carried out at (298+/-2) K and atmospheric pressure using ultrapure nitrogen as gas bath. The decay rates of the organic species were measured relative to those of ethane, methanol, acetone, chloroethane and 2-butanone. The following rate constants were derived in units of cm(3) molecule(-1) s(-1): k(1)= (10+/-1)*10(-13), k(2)=(2.1+/-0.2)*10(-13) and k(3)=(3.7+/-0.2)*10(-13). This is the first experimental determination of k(1) and k(2). The rate constants obtained are compared with previous literature data to establish reactivity trends and are used to estimate the atmospheric lifetimes of the studied perhaloalkenes. From the calculated lifetimes, using an average global concentration of hydroxyl radicals, the atmospheric loss of these compounds by the OH-initiated oxidation was determined. Also, estimations have been made of the ozone depletion potential (ODP), the radiative forcing efficiency (RE), the halocarbon global warming potential (HGWP) and the global warming potential (GWP) of the perhaloalkenes. The approximate nature of these values is stressed considering that these are short-lived compounds for which these atmospheric parameters may vary according to latitude and season. PMID- 20853390 TI - Developments in nonsteroidal antiandrogens targeting the androgen receptor. PMID- 20853391 TI - 1,4-Diiodo-1,3-dienes: versatile reagents in organic synthesis. AB - 1,4-Diiodo-1,3-dienes are unique reagents in organic synthesis and have been employed in several well-known and recently developed areas of application. Furthermore, these dienes are easily accessible, starting from the alkynes and iodine, and they have demonstrated high reactivity in cross-coupling reactions, organometallic synthesis, in the preparation of heterocyclic compounds, and several other transformations. The high reactivity of the 1,4-diiodo-1,3-dienes allows for the development of synthetic procedures that use mild conditions (room temperature). The key advantages in assembling complex organic molecules, natural products, and compounds for material science using 1,4-diiodo-1,3-dienes as building blocks include high yields, excellent selectivity, and diverse reactivity in carbon-carbon and carbon-heteroatom bond formation. This Focus Review describes the scope and application of the 1,4-diiodo-1,3-dienes in organic synthesis as well as summarizes the methods for preparation of the dienes. PMID- 20853393 TI - Controlled aqueous solution synthesis of platinum-palladium alloy nanodendrites with various compositions using amphiphilic triblock copolymers. AB - In a recent study, we demonstrated that Pluronic F127 triblock copolymer plays a critical role in the formation of dendritic Pt nanostructures (L. Wang, Y. Yamauchi, J. Am. Chem. Soc. 2009, 131, 9152-9153). Herein, we expand this concept to produce novel dendritic Pt-Pd alloy nanoparticles. In this paper, a very simple, one-step and efficient route is proposed to directly produce dendritic Pt Pd alloy nanoparticles with high surface area in high yield, which is carried out simply by stirring an aqueous solution that contains K(2)PtCl(4) and Na(2)PdCl(4) binary precursors in the presence of Pluronic F127 block copolymer and ascorbic acid at room temperature within 30 min without the need for any template, seed mediated growth, or additive. By simply changing the compositional ratios of the Pt and Pd sources in the precursor solutions, Pt-Pd nanodendrites with various compositions can be easily produced. Because of its unique simplicity, the proposed approach can be considered as a powerful strategy for producing Pt-Pd alloy nanoparticles with unique nanoarchitectures for commercial devices. PMID- 20853392 TI - Liberation of cellulose from the lignin cage: A catalytic pretreatment method for the production of cellulosic ethanol. PMID- 20853394 TI - Role of prevolitional processes in aggressive behavior: the indirect influence of goal. AB - The central aim of this article is to investigate the relationship between prevolitional processes and aggressive behavior. More specifically, the role of the goal underlying aggressive behavior was examined. A model of attitude, the Extended Model of Goal-directed Behavior, was tested with structural equation models to analyze the process that leads to the verbally aggressive behavior of calling someone names. Results showed that Goal Desire was a significant predictor but its relation to behavior is indirect, through desire toward and intention of calling someone names. Moreover, the results indicated that the positive emotions one anticipates if successful in calling someone names and the control one has over calling someone names play a significant role in the desire to call someone names. The discussion emphasizes the necessity of considering prevolitional processes when studying deliberative processes involved in the emergence of aggressive behavior. PMID- 20853395 TI - Differences between the normal vaginal bacterial community of baboons and that of humans. AB - Humans and baboons (Papio spp.) share considerable anatomical and physiological similarities in their reproductive tracts. Given the similarities, it is reasonable to expect that the normal vaginal microbial composition (microbiota) of baboons would be similar to that of humans. We have used a 16S rRNA phylogenetic approach to assess the composition of the baboon vaginal microbiota in a set of nine animals from a captive facility and six from the wild. Results show that although Gram-positive bacteria dominate in baboons as they do in humans, there are major differences between the vaginal microbiota of baboons and that of humans. In contrast to humans, the species of Gram-positive bacteria (Firmicutes) were taxa other than Lactobacillus species. In addition, some groups of Gram-negative bacteria that are not normally abundant in humans were found in the baboon samples. A further level of difference was also seen even within the same bacterial phylogenetic group, as baboon strains tended to be more phylogenetically distinct from human strains than human strains were with each other. Finally, results of our analysis suggests that co-evolution of microbes and their hosts cannot account for the major differences between the microbiota of baboons and that of humans because divergences between the major bacterial genera were too ancient to have occurred since primates evolved. Instead, the primate vaginal tracts appear to have acquired discrete subsets of bacteria from the vast diversity of bacteria available in the environment and established a community responsive to and compatible with host species physiology. PMID- 20853396 TI - The first chimpanzee sanctuary in Japan: an attempt to care for the "surplus" of biomedical research. AB - This article specifically examines several aspects of the human-captive chimpanzee bond and the effort to create the first chimpanzee sanctuary in Japan. We discuss our ethical responsibility for captive chimpanzees that have been used in biomedical research. On April 1, 2007, the Chimpanzee Sanctuary Uto (CSU) was established as the first sanctuary for retired laboratory chimpanzees in Japan. This initiative was the result of the continuous efforts by members of Support for African/Asian Great Apes (SAGA), and the Great Ape Information Network to provide a solution to the large chimpanzee colony held in biomedical facilities. However, the cessation of invasive biomedical studies using chimpanzees has created a new set of challenges because Japan lacks registration and laws banning invasive ape experiments and lacks a national policy for the life-long care of retired laboratory chimpanzees. Therefore, CSU has initiated a relocation program in which 79 retired laboratory chimpanzees will be sent to domestic zoos and receive life-long care. By the end of 2009, the number of chimpanzees living at CSU had decreased from 79 to 59 individuals. A nationwide network of care facilities and CSU to provide life-long care of retired laboratory chimpanzees is growing across Japan. This will result in humane treatment of these research animals. PMID- 20853397 TI - Patterns of gastro-intestinal parasites and commensals as an index of population and ecosystem health: the case of sympatric western chimpanzees (Pan troglodytes verus) and guinea baboons (Papio hamadryas papio) at Fongoli, Senegal. AB - The exponential decline of great apes over the past 50 years has resulted in an urgent need for data to inform population viability assessment and conservation strategies. Health monitoring of remaining ape populations is an important component of this process. In support of this effort, we examined endoparasitic and commensal prevalence and richness as proxies of population health for western chimpanzees (Pan troglodytes verus) and sympatric guinea baboons (Papio hamadryas papio) at Fongoli, Senegal, a site dominated by woodland-savanna at the northwestern extent of chimpanzees' geographic range. The small population size and extreme environmental pressures experienced by Fongoli chimpanzees make them particularly sensitive to the potential impact of pathogens. One hundred thirty two chimpanzee and seventeen baboon fecal samples were processed using sodium nitrate floatation and fecal sedimentation to isolate helminth eggs, larvae, and protozoal cysts. Six nematodes (Physaloptera sp., Ascaris sp., Stronglyloides fuelleborni, Trichuris sp., an unidentified hookworm, and an unidentified larvated nematode), one cestode (Bertiella sp.), and five protozoans (Iodamoeba buetschlii, Entamoeba coli, Troglodytella abrassarti, Troglocorys cava, and an unidentified ciliate) were detected in chimpanzee fecal samples. Four nematodes (Necator sp., S. fuelleborni, Trichuris sp., and an unidentified hookworm sp.), two trematodes (Shistosoma mansoni and an unidentified fluke), and six protozoans (Entamoeba histolytica/dispar, E. coli, Chilomastix mesnili, Balantidium coli, T. abrassarti, and T. cava) were detected in baboon fecal samples. The low prevalence of pathogenic parasite species and high prevalence of symbiotic protozoa in Fongoli chimpanzees are indicative of good overall population health. However, the high prevalence of pathogenic parasites in baboons, who may serve as transport hosts, highlight the need for ongoing pathogen surveillance of the Fongoli chimpanzee population and point to the need for further research into the epidemiology and cross-species transmission ecology of zoonotic pathogens at this site. PMID- 20853398 TI - Measuring infant attachment security in rhesus macaques (Macaca mulatta): adaptation of the attachment Q-set. AB - John Bowlby defined offspring-parent attachment as a relationship in which an infant or child uses one or a few preferred adults as a secure base from which to explore and as a haven of safety. He defined attachment security in terms of confidence in the adult's availability and responsiveness and the smooth organization of exploration and proximity seeking. Developmental psychologists have found this perspective productive in both observational and laboratory research. At the same time, they emphasize that such a construct cannot be operationalized in terms of one or a few behaviors. Instead, naturalistic observations of human infant attachment typically employ the Q-sort method to develop the Attachment q-set (AQS), 90 behaviorally descriptive items sorted in terms of how characteristic each item is of the infant's typical behavior. Meta analyses of research using the AQS attest to its reliability and validity. This article reports an adaptation of the AQS to the task of assessing infant attachment security in nonhuman primates and illustrates its use. The availability of comparable measures of attachment security will contribute to an expanded understanding of patterns of attachment behavior in nonhuman primate societies and will facilitate interaction between comparative and developmental psychologists. PMID- 20853399 TI - Associations between the drill (Mandrillus leucophaeus) and sympatric monkeys in Korup National Park, Cameroon. AB - Studies of polyspecific associations among African forest primates have primarily focused on arboreal Cercopithecus and Procolobus/Colobus species. We examined the association frequency of the terrestrial drill (Mandrillus leucophaeus) with six sympatric monkey species in Korup National Park, Cameroon, testing reports that Mandrillus associations are infrequent and transient. We conducted 3,284 km of trail walks for 12 months (February-June 2006; July 2007 to January 2008), recording species composition in 612 primate clusters. Using a Markov chain Monte Carlo test, we compared the observed frequency of dyadic associations against null models of "no association." A novel conservative statistical approach which addresses possible dependence of observations close in time was also used, further strengthening confidence in our findings. Drills associated with all monkeys throughout the study period, and were with at least one other species (range 1-5) in half of the encounters. The association frequency of drills with red-capped mangabeys (Cercocebus torquatus) was greater than expected by chance, which is interesting given the morphological adaptation of the Mandrillus Cercocebus clade for the exploitation of the same dietary niche, hard seeds. The difference we observed in the use of forest strata by drills and mangabeys may reflect a strategy to reduce food competition while in association. The nature and duration of observed drill associations varied. Although some associations seemed to be chance encounters, others lasted for hours with the involved species foraging together. PMID- 20853400 TI - Estrous asynchrony causes low birth rates in wild female chimpanzees. AB - Estrous cycle asynchrony likely functions to elevate individual females' sexual attractiveness during female mate choice. Female chimpanzees show physiological estrus as anogenital swelling. Copulations are concentrated during the period of maximal tumescence, which is called the estrous period. A group of female chimpanzees in Mahale Mountains National Park, Tanzania, was shown to display asynchrony in both maximal tumescence and periovulatory periods. We tested the hypothesis that females establish asynchronous maximal tumescence or periovulatory periods with respect to other females to increase copulation frequency and birth opportunities (Hypothesis 1). We analyzed differences in birth rates between four asynchronous years and five nonasynchronous years. Counter to Hypothesis 1, females in periovulatory periods during asynchronous years showed significantly lower birth rates than those in nonasynchronous years. In addition, periovulatory females copulated more frequently on days on which no other female in a periovulatory period was present. These results suggest that birth rates tend to decrease when females experience nonoverlapping ovulation cycles, although copulation frequency is high. Such a decrease in the birth rate may have resulted from the cost associated with multiple copulations. We tested two other hypotheses: paternity confusion (Hypothesis 2) and sperm competition (Hypothesis 3). Both of these hypotheses were partially supported. The highest ranking male most effectively monopolized access to receptive females when relatively few other males and receptive females from the party (or subgroup) were present. The viability of Hypotheses 2 and 3 requires that dominant males are able to hinder a female from mating with other males. Given that the male biased operational sex ratio created by female asynchrony is likely to reduce the efficiency of mate guarding by dominant males, an asynchronous female may gain a fitness benefit by increasing the probability of mating with at least one male who produces superior sperm. PMID- 20853402 TI - Small data set analysis in surface metrology: an investigation using a single point incremental forming case study. AB - A new method for applying statistical techniques with small data sets in surface metrology is demonstrated. This method allows for surfaces or surface-creation processes to be differentiated with as few as six measurement regions. A case study in surface roughness of single point incremental forming is used to demonstrate this method because previous work in this area has not provided quantitative statistical testing to support conclusions. The results from the case study indicate that surface roughness parameters Sz and relative length at scales less than 200 nm are greater when the roll marks on the surface are oriented perpendicular rather than parallel to the forming direction. PMID- 20853403 TI - Laser profilometry and length-scale analysis of stone tools: second series experiment results. AB - Based on the need to develop a method to reliably and objectively document and discriminate the use-wear on archaeological stone tools, Stemp et al. (2009) tested whether the surface roughness measured on experimentally worn stone tools used on different contact materials could be discriminated. Results of these initial experiments indicated that discrimination was possible and also determined the scales over which this discrimination occurred. In this article, we report the results of additional experiments using the same method on a second set of tools to test its reliability and reproducibility. In these experiments, four flint flakes were intensively used for 20 min on either conch shell or dry deer antler. The surface roughness or texture of the stone tools was measured by generating 2D profiles using a UBM laser profilometer. Relative lengths (RLs) calculated from the profiles were used directly as characterization parameters and subsequently compared statistically at each scale using the F-test to establish a level of confidence for the differentiation at each scale represented in the measured profiles. The mean square ratios of measurement data were used to determine whether the variation in roughness was statistically significant and to what level of confidence. The scales at which there was a high level of confidence were the ones at which the tools were differentiable. The results of these experiments confirm our previous findings that RLs, over certain scale ranges, can discriminate the stone tool surface wear profiles produced by the different contact materials. PMID- 20853404 TI - Tribo-electrochemical surface modification of tantalum using in situ AFM techniques. AB - A scanning-probe-based technique to observe tribo-electrochemically stimulated surface was demonstrated. The configuration consists of an electrochemical cell attached to an atomic force microscope (AFM) scanner. Under an applied electrical potential and in various chemical environments, the surface morphology, roughness, skew, bearing ratio, as well as surface adhesive forces between probes were measured, and the effects of mechano-electrochemical stimuli were evaluated. The effects of mechanical, electrochemical, and mechano-electrochemical stimuli were found to compete during AFM sliding process. Their effects do not follow a linear relationship, implying that the mechanical stimulus promotes electrochemical reactions. Similarly, electrochemically enhanced mechanical removal of surface materials is possible. PMID- 20853405 TI - Nanoscale crystallization of phase change Ge2Sb2Te5 film with AFM lithography. AB - We have made nanoindents on Ge(2)Sb(2)Te(5)(GST) films using electric field assisted atomic force microscope (AFM) lithography. GST shows increase of material density and electric conductivity as it changes from amorphous to crystalline phases. By applying electric field between AFM probe-tip and GST surface, nanoscale crystallization could be induced on tip contact area. As the crystallized GST exhibits increase of material density, that is to say depression of volume, nanoindented surface with crystallization is created on host amorphous GST (a-GST) film. For the AFM lithography, a highly conductive tip, which showed voltage-switching characteristics in current-voltage spectroscopy of GST film, was found to be very suitable for recording and sensing crystallized nanoindents on the GST film. By varying sample bias voltages, we performed nanoscale crystallization, and measured the nanostructured film in AFM conductance-image (C image) mode and topography-image (T-image) mode, simultaneously. Two types of crystallized wires were fabricated on (a-GST) film. Type-I was sensed in only C image, whereas Type-II was sensed in both C-image and T-image. These nanowires are discussed in terms of crystallization of GST and sensitivity of current (or topography) sensing. By repeated lithography, larger size of nanoindented wires were also produced, which indicates line-dimension controllability of AFM lithography. PMID- 20853406 TI - Evaluation of surface structural and mechanical changes following remineralization of dentin. AB - This study sought to gain insights into the surface structural and mechanical changes leading to remineralization of dentin. Remineralization was compared between a continuous remineralization approach and a nonbuffered static approach using solutions of the same initial composition. Artificial carious lesions were treated for 5 days and analyzed every 24 h using nanoindentation in water, SEM, and AFM. The continuous approach yielded a recovery of mechanical properties of up to 60% of normal dentin, whereas the static approach led to recovery of only 10%. Image analysis revealed that the static approach yielded the formation of areas suggestive of an apatite precipitate on the surface of the dentin matrix. In contrast, surface precipitate was absent using the continuous approach, suggesting that mineral formed within the lesion and re-associated with the collagenous matrix. This study provided evidence that mechanical recovery of dentin in near physiological conditions is attainable through the continuous delivery of calcium and phosphate ions. PMID- 20853407 TI - How access to exhibit space impacts the behavior of female tigers (Panthera tigris). AB - Little is known about how socially housed captive carnivores respond to temporary reductions in available space. We documented rates of aggression and affiliation in our group of six female tigers, under their normal housing conditions and during a period of exhibit renovations which resulted in a 50% reduction in time spent in an outdoor enclosure. During the period of reduced availability of space, significant declines in aggression and affiliation were observed indicating that these tigers responded in a manner consistent with a strategy of conflict avoidance. These reductions in rates of social behavior remained in place during the year following the return to their original housing conditions. Thus, even temporary alterations to housing practices have the potential to have lasting impacts on the social behavior of this species. PMID- 20853408 TI - Serum concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein-2 and -3 in eight hoofstock species. AB - The somatotropic axis, which includes growth hormone, insulin-like growth factor (IGF)-I, and IGF binding proteins (IGFBP), is involved in the regulation of growth and metabolism. Measures of the somatotropic axis can be predictive of nutritional status and growth rate that can be utilized to identify nutritional status of individual animals. Before the somatotropic axis can be a predictive tool, concentrations of hormones of the somatotropic axis need to be established in healthy individuals. To begin to establish these data, we quantified IGF-I, IGFBP-2, and IGFBP-3 in males and females of eight threatened hoofstock species at various ages. Opportunistic blood samples were collected from Bos javanicus (Java banteng), Tragelaphus eurycerus isaaci (bongo), Gazella dama ruficollis (addra gazelle), Taurotragus derbianus gigas (giant eland), Kobus megaceros (Nile lechwe), Hippotragus equines cottoni (roan antelope), Ceratotherium simum simum (white rhinoceros), and Elephas maximus (Asian elephant). Serum IGF-I and IGFBPs were determined by radioimmunoassay and ligand blot, respectively. Generally, IGF I and IGFBP-3 were greater in males, and IGFBP-2 was greater in females. In banteng (P = 0.08) and male Nile lechwe (P < 0.05), IGF-I increased with age, but decreased in rhinoceros (P = 0.07) and female Nile lechwe (P < 0.05). In banteng, IGFBP-3 was greater (P < 0.01) in males. In elephants (P < 0.05) and antelope (P = 0.08), IGFBP-2 were greater in females. Determination of concentrations of hormones in the somatotropic axis in healthy animals makes it possible to develop models that can identify the nutritional status of these threatened hoofstock species. PMID- 20853409 TI - Blood groups in the Species Survival Plan(r), European endangered species program, and managed in situ populations of bonobo (Pan paniscus), common chimpanzee (Pan troglodytes), gorilla (Gorilla ssp.), and orangutan (Pongo pygmaeus ssp.). AB - Blood groups of humans and great apes have long been considered similar, although they are not interchangeable between species. In this study, human monoclonal antibody technology was used to assign human ABO blood groups to whole blood samples from great apes housed in North American and European zoos and in situ managed populations, as a practical means to assist blood transfusion situations for these species. From a subset of each of the species (bonobo, common chimpanzee, gorilla, and orangutans), DNA sequence analysis was performed to determine blood group genotype. Bonobo and common chimpanzee populations were predominantly group A, which concurred with historic literature and was confirmed by genotyping. In agreement with historic literature, a smaller number of the common chimpanzees sampled were group O, although this O blood group was more often present in wild-origin animals as compared with zoo-born animals. Gorilla blood groups were inconclusive by monoclonal antibody techniques, and genetic studies were inconsistent with any known human blood group. As the genus and, specifically, the Bornean species, orangutans were identified with all human blood groups, including O, which had not been reported previously. Following this study, it was concluded that blood groups of bonobo, common chimpanzees, and some orangutans can be reliably assessed by human monoclonal antibody technology. However, this technique was not reliable for gorilla or orangutans other than those with blood group A. Even in those species with reliable blood group detection, blood transfusion preparation must include cross-matching to minimize adverse reactions for the patient. PMID- 20853410 TI - The effectiveness of indigestible markers for identifying individual animal feces and their prevalence of use in North American zoos. AB - Techniques for analyzing hormone metabolites in animal excreta have created many opportunities for noninvasive monitoring of health, reproduction, and welfare in zoo animals, but can be difficult to implement when individual samples are not readily identifiable in animal groups. A common approach to this problem is to feed animals an indigestible marker that subsequently appears in feces, but there has been little systematic research on the use of such "fecal markers." First, we used an online survey to assess the prevalence of fecal marker use in North American zoological institutions. Second, we conducted a series of experimental tests utilizing commonly employed fecal markers in a variety of typical zoo taxa to determine the: (1) effectiveness of several markers to accurately distinguish samples in a variety of species, (2) minimum quantity of marker needed for detection, and (3) length of time between ingestion and detection in the feces. The majority of the 45 institutions that completed the survey reported using fecal markers with their collections. The survey also revealed that the most frequently used markers are seeds/grains and food colorants, with the former generally used in Carnivora and the latter in Primates. Our experimental data confirmed the success of these taxa/marker combinations and also revealed that food colorants function as markers in a variety of avian, reptilian, and mammalian species. Our data describe successful fecal markers for a wide variety of zoo taxa and should, therefore, be useful for zoological managers and researchers needing to employ fecal markers in future investigations. PMID- 20853411 TI - Genetic structure analysis of a highly inbred captive population of the African antelope Addax nasomaculatus. Conservation and management implications. AB - The African antelope Addax nasomaculatus is a rare mammal at high risk of extinction, with no more than 300 individuals in the wild and 1,700 captive animals distributed in zoos around the world. In this work, we combine genetic data and genealogical information to assess the structure and genetic diversity of a captive population located at Parque Lecocq Zoo (N=27), originated from only two founders. We amplified 39 microsatellites previously described in other Artiodactyls but new to this species. Seventeen markers were polymorphic, with 2 4 alleles per locus (mean=2.71). Mean expected heterozygosity (He) per locus was between 0.050 (marker ETH3) and 0.650 (marker D5S2), with a global He of 0.43. The mean inbreeding coefficient of the population computed from pedigree records of all registered individuals (N=53) was 0.222. The mean coancestry of the population was 0.298 and F(IS) index was -0.108. These results reflect the importance of an adequate breeding management on a severely bottlenecked captive population, which would benefit by the incorporation of unrelated individuals. Thanks to the successful amplification of a large number of microsatellites commonly used in domestic bovids, this study will provide useful information for the management of this population and serve as future reference for similar studies in other captive populations of this species. PMID- 20853412 TI - Long-term transportation, by road and air, of chub mackerel (Scomber japonicus) and atlantic bonito (Sarda sarda). AB - During the second semester of 2009, three trips were made from Olhao (Southern Portugal) to Stralsund (Northern Germany) carrying 2.122 animals, which included multiple teleosts, elasmobranchs and invertebrates. This group included scombrids, such as 1.869 Scomber japonicus and 9 Sarda sarda, which are notoriously difficult to transport. However, multiple adaptations to transport regimes adopted regularly have allowed the authors to successfully move these animals by road and air over a total of up to 25 hr. Such adaptations included maintaining oxygen saturation rates at approximately 200%, and also the constant addition of AmQuel((r)) , sodium bicarbonate, and sodium carbonate. Different formulations were used during the three trips, with the best results corresponding to 20/30/30 ppm of the three aforementioned chemicals, respectively. The authors suggest, however, that a modified formula of 20/40/40 ppm will allow for an even more stable pH on future trips. PMID- 20853413 TI - Food habits of Rhinopithecus bieti as assessed by fecal analysis at Mt. Longma, Southwest China. AB - The food habits of Rhinopithecus bieti were studied at Mt. Longma in Tianchi Nature Reserve, Yunnan Province, China using microhistological analysis of feces and phytochemical component analysis of food items, from January 2007 to March 2008. This region is the southernmost location of R. bieti with the most complex and varied vegetation types. R. bieti fed on 83 plant species of 26 families, at least 3 species of lichens and bamboos, respectively. The number of food items exploited varied markedly among seasons, with dietary diversity being greatest in summer and autumn. Young leaves of broadleaf plant, monocotyledonous plant leaves (bamboos), and 3 species of lichens in the genera Bryoria (Bryoria confuse) and Usnea (Unsea longissima and Unsea florida) were frequently eaten. Bamboos (Poaceae) and lichens formed a stable dietary constituent throughout the year, contributing about 24 and 13%, respectively, of the total feeding records. There was seasonal variation in the proportion of each food type in the diet of the R. bieti. Results of the phytochemistry analysis showed that food selectivity of R. bieti was positively correlated with the ratio of crude protein to neutral detergent fibre (CP/NDF) and negatively correlated with condensed tannins (CT). Results from the study also showed that the primary food items eaten by R. bieti in summer had higher CP and lower CT than in winter. PMID- 20853414 TI - Evaluation of two milk replacers fed to hand-reared cheetah cubs (Acinonyx jubatus): nutrient composition, apparent total tract digestibility, and comparison to maternal cheetah milk. AB - Commercially prepared milk replacers are frequently used to provide the sole source of nutrition for hand-reared cheetah cubs (Acinonyx jubatus). The nutrient composition of two commonly used milk replacers was determined. Using titanium dioxide as an indigestible marker, nutrient digestibility was calculated from the analyses of fecal samples collected from each cub (n = 4 on formula 1, and n = 2 on formula 2). Mean apparent total tract digestibility for both formulas was >90% for all nutrients analyzed (crude protein, amino acids, crude fat (CF), and dry matter). However, the total CF content and the concentration of the essential fatty acids, such as alpha-linolenic, linolenic, and arachidonic acid, of both formulas was lower than reported for maternal cheetah milk. Additionally, one formula contained a comparatively high amount of carbohydrate, at the expense of protein. Although data were lacking for cheetah maternal milk, comparison with domestic cat milk revealed high concentrations of a number of minerals (K, Fe, Zn, and Cu), while vitamin D(3) was not detected in one formula. Both formulas were low in the majority of essential amino acids compared with domestic cat maternal milk. Despite their apparently high digestibility, neither formula was complete or balanced in terms of nutrient concentrations and ratios when maternal cheetah milk and/or the requirements established for growth in domestic cats were used as estimates of ideal. On this basis, although all cubs in this study were healthy and maintained good body conditions for the duration of the trial, the results of dietary analyses indicate that these milk replacers may not provide optimal nutrition for growth in cheetah cubs when used for extended periods. PMID- 20853415 TI - Development of husbandry practices for the captive breeding of Key Largo woodrats (Neotoma floridana smalli). AB - The Key Largo woodrat is an endangered rodent endemic to the island of Key Largo in the Florida Keys. After several reports documented a steep decline in the population, the US Fish and Wildlife Service developed a recovery plan, including captive breeding and reintroduction. Captive breeding efforts were to be focused on providing animals for future reintroduction to protected areas on Key Largo. However, little was known about the husbandry needs or reproductive behavior of this elusive nocturnal species. In 2005, Disney's Animal Kingdom((r)) received 11 animals and began to systematically investigate methods of breeding Key Largo woodrats. Since the program's inception, 30 pups have been born and successfully parent reared. In this report, we describe some of the husbandry techniques that have contributed to the success of the Key Largo woodrat captive breeding program at Disney's Animal Kingdom((r)) . The results obtained may be of use to other facilities maintaining woodrats and other rodent species. PMID- 20853416 TI - Infestation experience of a rodent host and offspring viability of fleas: variation among host-parasite associations. AB - We studied survival and development of preimagoes and the ability to withstand starvation of adults in two flea species, host-specific Parapulex chephrenis and host-opportunistic Xenopsylla ramesis, when parent fleas fed on a typical (Acomys cahirinus and Dipodillus dasyurus, respectively) or an atypical (D. dasyurus and A. cahirinus, respectively) rodent host that either had never been parasitized by fleas (pristine) or had previously been exposed to fleas. We asked whether a repeatedly infested host acquired resistance that would cause decreased viability of the next generation fleas. Survival of preimaginal P. chephrenis was similar, independent of host species or its infestation status. Preimaginal X. ramesis had a higher survival rate when their parents fed on preinfested than on pristine typical hosts, whereas no effect of infestation status of an atypical host was found. P. chephrenis developed faster if their parents fed on atypical than on typical hosts and on pristine than on preinfested hosts of either species. X. ramesis developed faster if parents fed on pristine than preinfested typical hosts, but no difference in duration of development was found for atypical hosts. Under starvation, P. chephrenis lived longer if their parents fed on preinfested than on pristine typical hosts, but their lifespan did not depend on infestation status of atypical hosts. The latter was also true for X. ramesis and both host species. We conclude that a host is constrained in its ability to cope with a parasite, whereas a parasite is able to cope with defence responses of a host. PMID- 20853417 TI - Fast and furious: effects of body size on strike performance in an arboreal viper Trimeresurus (Cryptelytrops) albolabris. AB - Body size has a pervasive effect on animal functioning and life history with size dependent changes in performance and physiology throughout ontogeny being common in many ectothermic vertebrates. However, as selection on juvenile life history stages is strong, juveniles often offset the disadvantages of small body size by disproportionate levels of performance. Here, we investigate size-related changes in defensive strike performance in an arboreal pit viper, Trimerusurus (Cryptelytrops) albolabris. Our data show a significant negative allometry in the scaling of head dimensions and head mass to body mass. However, strike velocity and strike distance are independent of body mass, with juveniles in our sample striking as fast and as far as adults. In contrast to model predictions suggesting that acceleration capacity should decrease with increasing body mass, acceleration capacity increases with snake body mass. Our results suggest that this is the result of a negative allometric scaling of head mass combined with an isometric scaling of the dorsal epaxial musculature. Finally, our data show a significant sexual dimorphism in body size and strike velocity with females being heavier and striking faster independent of the dimorphism in body size. PMID- 20853418 TI - The peacock's train (Pavo cristatus and Pavo cristatus mut. alba) I. structure, mechanics, and chemistry of the tail feather coverts. AB - The feathers in the train of the peacock serve not for flying but for sexual display. They are long, slender beams loaded in bending by their own weight. An outer circular conical shell, the cortex, is filled by a closed foam of 7.6% relative density, the medulla, both of feather keratin. Outer diameter and thickness of the cortex decrease linearly from the body toward the tip. This self similar geometry leads to a division of labor. The cortex (longitudinal Young's modulus 3.3 GPa, transverse modulus 1 GPa) provides 96% of the longitudinal strength and bending rigidity of the feather. The medulla (Young's modulus 10 MPa) provides 96% of the transverse compressive rigidity. Fracture stress of the cortex, both longitudinal and transverse, is 120 MPa. PMID- 20853419 TI - Potential genetic bases of morphological evolution in the triassic fish Saurichthys. AB - Originating from an ancestor covered entirely by uniform rhomboid scales with numerous, highly segmented fin rays, the Triassic basal actinopterygian fish Saurichthys radiated into species diagnosed by different degrees of loss in scales, rays, and dermal bones. Such changes are analogous to those reported in mutants of different extant species, such as sticklebacks, zebrafish, and medaka. With this background, we infer a loss of function or a regulatory change of a signaling pathway as a key mechanism behind the morphological diversity of Saurichthys. Either the fibroblast growth factor pathway was affected, assuming that gene duplication had occurred, as for example in the closely related acipenserids or in teleosts, or the ectodysplasin pathway was involved, assuming that its pleiotropic effects led to viable morphological diversification. In contrast to a gradualistic model of evolution, a change in a major developmental gene serves as a viable explanation for the essential differences among the species of Saurichthys in the paleoecological context in which they originated. PMID- 20853420 TI - Thermal constraints for range expansion of the invasive green mussel, Perna viridis, in the southeastern United States. AB - Cold temperatures are thought to be among the most important determining factors of geographic distribution for tropical and sub-tropical marine invertebrates. The Asian green mussel, Perna viridis, has been introduced into coastal waters of Florida where its current distribution is hypothesized to be limited by low temperatures during winter. Lethal and sub-lethal effects (heat shock protein/Hsp70 expression) of cold water and air temperatures were analyzed in two size classes of P. viridis from Florida in an effort to determine the effects of current and forecasted temperatures on the potential for range expansion. Mussels were exposed to water temperatures of 14, 10, 7 and 3 degrees C for up to 30 days, or to air temperatures of 14, 7, 0 and -10 degrees C for periods of 2 hr. Mortality was significantly increased at all water and air temperatures <=14 degrees C. No differences in mortality rates were observed between small (15-45 mm) and large (75-105 mm) size classes except after exposure to 7 degrees C air, in which small mussels had higher mortality. Significant increases in Hsp70 expression were observed after a 2-hour exposure to 10 degrees C water, but Hsp70 expression was not significantly increased at any temperatures in which mortality was not also significant. The temperature threshold for survival in this population appears to be between 10 and 14 degrees C, suggesting that under current conditions P. viridis may already be at the northern edge of its potential range in the United States. If water temperatures increase with global climate change, northerly flowing currents may permit range expansion as temperatures allow. PMID- 20853421 TI - Revisiting a classic example of transcription factor functional equivalence: are Eyeless and Pax6 functionally equivalent or divergent? AB - A major, and sometimes heated, debate in evolutionary and developmental biology is about the genetic basis of morphological evolution and the molecular mechanisms of gene regulatory evolution. Central to this argument is whether gene regulation most often evolves from changes in the cis-regulatory elements of genes or through changes in the transcription factors that bind to regulatory elements. Although various kinds of theoretical and experimental evidence have been used to advance the cause of both sides, none has been more influential than the finding that transcription factors from very different organisms can be functionally conserved. In this perspective, we review the now classic finding that Pax6 genes from flies and vertebrates are functionally conserved in eye development and can induce the formation of eyes when swapped between species. While a conserved role for Pax6 genes in eye development is undebatable, we show that evidence of divergent Pax6 functions has been overlooked and propose that Pax6 genes have evolved novel protein functions during the development of the Drosophila eye, coincident with the evolution of a novel eye developmental mechanism in cyclorrhaphan dipterans. Thus, we conclude that Pax6 genes are both functionally equivalent and divergent between species. PMID- 20853422 TI - Did Paul Kammerer discover epigenetic inheritance? No and why not. AB - In a recent article in this journal, Alexander Vargas presents a new, epigenetic explanation of Paul Kammerer's controversial midwife toad experiments, but he has constructed his model without first reading Kammerer's original articles. A look at the articles shows that Vargas is seriously misinformed about what Kammerer did and what the results even were. His model simply cannot explain the results as they were originally reported and it cannot easily be corrected. Similarly, Vargas' historical inferences about the Kammerer affair, Kammerer's priority for the discovery of parent-of-origin effects, and the negative reactions of geneticists to this purported discovery, are unsupported and do not stand up to scrutiny. PMID- 20853423 TI - Predicting memapsin 2 (beta-secretase) hydrolytic activity. AB - Memapsin 2 (BACE1, beta-secretase), a membrane aspartic protease, functions in the cleavage of brain beta-amyloid precursor protein (APP) leading to the production of beta-amyloid. Because the excess level of beta-amyloid in the brain is a leading factor in Alzheimer's disease (AD), memapsin 2 is a major therapeutic target for inhibitor drugs. The substrate-binding cleft of memapsin 2 accommodates 12 subsite residues, from P(8) to P(4)'. We have determined the hydrolytic preference as relative k(cat)/K(M) (preference constant) in all 12 subsites and used these data to establish a predictive algorithm for substrate hydrolytic efficiency. Using the sequences from 12 reported memapsin 2 protein substrates, the predicted and experimentally determined preference constants have an excellent correlation coefficient of 0.97. The predictive model indicates that the hydrolytic preference of memapsin 2 is determined mainly by the interaction with six subsites (from P(4) to P(2)'), a conclusion supported by the crystal structure B-factors calculated for the various residues of transition-state analogs bound to different memapsin 2 subsites. The algorithm also predicted that the replacement of the P(3), P(2), and P(1) subsites of APP from Val, Lys, and Met, respectively, to Ile, Asp, and Phe, respectively, (APP(IDF)) would result in a highest hydrolytic rate for beta-amyloid-generating APP variants. Because more beta-amyloid was produced from cells expressing APP(IDF) than those expressing APP with Swedish mutations, this designed APP variant may be useful in new memapsin 2 substrates or transgenic mice for AD studies. PMID- 20853424 TI - Effects of functionalized fullerenes on bifenthrin and tribufos toxicity to Daphnia magna: Survival, reproduction, and growth rate. AB - Incorporation of carbon nanomaterials into industrial and consumer products is increasing, yet their impact on aquatic ecosystems alone and in chemical mixtures is largely unknown. Carbon nanomaterials may be found in the aquatic environment as mixtures with pesticides because of their proposed use in agriculture as smart delivery systems and nanosensors. The interaction effects of a functionalized fullerene ([1,2-methanofullerene C60]-61-carboxylic acid) (fC60) at 52.8 ug/L and the hydrophobic pesticides bifenthrin and tribufos were examined. The test organism was Daphnia magna, and response variables included 48-h survival, reproduction (bifenthrin, 70-d; tribufos, 21-d), and 10-d growth. Both pesticides reduced D. magna survival and reproduction (p < 0.05). Fullerenes significantly increased bifenthrin acute toxicity but did not significantly affect chronic endpoints or growth (p > 0.05). Median lethal concentrations (LC50s), median inhibition concentrations (IC50s) for days surviving, and IC50s for reproduction were 0.86, 0.55, and 0.49 ug/L for bifenthrin; 0.22, 0.39, and 0.77 ug/L for fC60 bifenthrin mix; 6.63, 9.89, and 5.79 ug/L for tribufos; and 9.17, 8.17, and 6.59 ug/L for fC60-tribufos mix. Mixtures did not affect instantaneous growth rate (p > 0.05). These results suggest that fC60 had little effect on pesticide chronic toxicity but influenced acute toxicity. Given the widespread application of nanotechnology, the influence of nanomaterials on environmental contaminants is an important consideration. Thus, our results may be useful in the development and use of nanotechnology in agricultural practices. PMID- 20853425 TI - Assignment of absolute configuration using chiral reagents and NMR spectroscopy. AB - An overview of chiral reagents that are used to assign the absolute configuration of particular classes of compounds using NMR spectroscopy is presented. The use of chiral derivatizing agents, chiral solvating agents, metal complexes, and liquid crystals is described. PMID- 20853427 TI - A comparison of the different helices adopted by alpha- and beta-peptides suggests different reasons for their stability. AB - The right-handed alpha-helix is the dominant helical fold of alpha-peptides, whereas the left-handed 3(14)-helix is the dominant helical fold of beta peptides. Using molecular dynamics simulations, the properties of alpha-helical alpha-peptides and 3(14)-helical beta-peptides with different C-terminal protonation states and in the solvents water and methanol are compared. The observed energetic and entropic differences can be traced to differences in the polarity of the solvent-accessible surface area and, in particular, the solute dipole moments, suggesting different reasons for their stability. PMID- 20853426 TI - Phenotypic effects of Ehlers-Danlos syndrome-associated mutation on the FnIII domain of tenascin-X. AB - Tenascin-X (TNX) is an extracellular matrix (ECM) protein and interacts with a wide variety of molecules in the ECM as well as on the membrane. Deficiency of TNX causes a recessive form of Ehlers-Danlos syndrome (EDS) characterized by hyperelastic and fragile skin, easy bruising, and hypermobile joints. Three point mutations in TNX gene were found to be associated with hypermobility type EDS and one of such mutations is the V1195M mutation at the 7th fibronectin Type III domain (TNXfn7). To help elucidate the underlying molecular mechanism connecting this mutation to EDS, here we combined homology modeling, chemical denaturation, single molecule atomic force microscopy, and molecular dynamics (MD) simulation techniques to investigate the phenotypic effects of V1195M on TNXfn7. We found that the V1195M mutation does not alter the three-dimensional structure of TNXfn7 and had only mild destabilization effects on the thermodynamic and mechanical stability of TNXfn7. However, MD simulations revealed that the mutation V1195M significantly alters the flexibility of the C'E loop of TNXfn7. As loops play important roles in protein-protein and protein-ligand interactions, we hypothesize that the decreased loop flexibility by V1195M mutation may affect the binding of TNX to ECM molecules and thus adversely affect collagen deposition and fibrillogenesis. Our results may provide new insights in understanding the molecular basis for the pathogenesis of V1195M-resulted EDS. PMID- 20853428 TI - Ubiquitous expression of the monomeric red fluorescent protein mCherry in transgenic mice. AB - The use of the green fluorescent protein (GFP) to label specific cell types and track gene expression in animal models, such as mice, has evolved to become an essential tool in biological research. Transgenic animals expressing genes of interest linked to GFP, either as a fusion protein or transcribed from an internal ribosomal entry site (IRES) are widely used. Enhanced GFP (eGFP) is the most common form of GFP used for such applications. However, a red fluorescent protein (RFP) would be highly desirable for use in dual-labeling applications with GFP derived fluorescent proteins, and for deep in vivo imaging of tissues. Recently, a new generation of monomeric (m)RFPs, such as monomeric (m)Cherry, has been developed that are potentially useful experimentally. mCherry exhibits brighter fluorescence, matures more rapidly, has a higher tolerance for N terminal fusion proteins, and is more photostable compared with its predecessor mRFP1. mRFP1 itself was the first true monomer derived from its ancestor DsRed, an obligate tetramer in vivo. Here, we report the successful generation of a transgenic mouse line expressing mCherry as a fluorescent marker, driven by the ubiquitin-C promoter. mCherry is expressed in almost all tissues analyzed including pre- and post-implantation stage embryos, and white blood cells. No expression was detected in erythrocytes and thrombocytes. Importantly, we did not encounter any changes in normal development, general physiology, or reproduction. mCherry is spectrally and genetically distinct from eGFP and, therefore, serves as an excellent red fluorescent marker alone or in combination with eGFP for labelling transgenic animals. PMID- 20853429 TI - Postnatal male germ-cell expression of cre recombinase in Tex101-iCre transgenic mice. AB - We have generated a transgenic mouse line that expresses improved Cre recombinase (iCre) under the control of the testis-expressed gene 101 (Tex101) promoter. This transgenic mouse line was named Tex101-iCre. Using the floxed ROSA reporter mice, we found that robust Cre recombinase activity was detected in postnatal testes with weak or no activity in other tissues. Within the testis, Cre recombinase was active in spermatogenic cells as early as the prospermatogonia stage at day 1 after birth. In 30- and 60-day-old mice, positive Cre recombinase activity was detected not only in prospermatogonia but also in spermatogenic cells at later stages of spermatogenesis. There was little or no Cre activity in interstitial cells. Breeding wild-type females with homozygous floxed fibroblast growth factor receptor 2 (Fgfr2) males carrying the Tex101-iCre transgene did not produce any progeny with the floxed Fgfr2 allele. All the progeny inherited a recombined Fgfr2 allele, indicating that complete deletion of the floxed Fgfr2 allele by Tex101-iCre can be achieved in the male germline. Furthermore, FGFR2 protein was not detected in spermatocytes and spermatids of adult Fgfr2(fl/fl) ;Tex101-iCre mice. Taken together, our results suggest that the Tex101-iCre mouse line allows the inactivation of a floxed gene in spermatogenic cells in adult mice, which will facilitate the functional characterization of genes in normal spermatogenesis and male fertility. PMID- 20853430 TI - Diving and intrapulmonary shunting of venous gas microemboli. PMID- 20853432 TI - Rapid increase in the prevalence of inflammatory bowel disease in candidates for the military service born after 1988 in Korea. PMID- 20853433 TI - Degradation of the extracellular matrix components by bacterial-derived metalloproteases: implications for inflammatory bowel diseases. AB - BACKGROUND: Proteolytic degradation of the extracellular matrix, a feature of mucosal homeostasis and tissue renewal, also contributes to the complications of intestinal inflammation. Whether this proteolytic activity is entirely host derived, or, in part, produced by the gut microbiota, is unknown. METHODS: We screened the bacterial colonies for gelatinolytic activity from fecal samples of 20 healthy controls, 23 patients with ulcerative colitis, and 18 with Crohn's disease (CD). In addition, the genes encoding metalloproteases were detected by conventional or real-time polymerase chain reaction (PCR). RESULTS: Gelatinolytic activity was found in approximately one-quarter of samples regardless of the presence of inflammation and without any attempt to enhance the sensitivity of the culture-based screen. This was associated with a diversity of bacteria, particularly in CD, but was predominantly linked with Clostridium perfringens. Culture supernatants from C. perfringens degraded gelatin, azocoll, type I collagen, and basement membrane type IV collagen, but different isolates varied in the degree of proteolytic activity. Results were confirmed by detection of the C. perfringens colA gene (encoding collagenase) in fecal DNA, again regardless of the presence or absence of inflammation. However, the biologic significance and potential implications of microbial-derived proteolytic activity were confirmed by reduced transepithelial resistance (TER) after exposure of rat distal colon to culture supernatants of C. perfringens in Ussing chambers. CONCLUSIONS: The study shows that microbial-derived proteolytic activity has the capacity to contribute to mucosal homeostasis and may participate in the pathogenesis of inflammatory bowel disease. PMID- 20853435 TI - Entomotoxic action of Sambucus nigra agglutinin I in Acyrthosiphon pisum aphids and Spodoptera exigua caterpillars through caspase-3-like-dependent apoptosis. AB - In this project, the toxicity and mechanism of action of the ricin-B-related lectin SNA-I from elderberry (Sambucus nigra) in the pea aphid (Acyrthosiphon pisum) and the beet armyworm (Spodoptera exigua), two important pest insects in agriculture, were studied. SNA-I is a chimeric lectin belonging to the class of ribosome-inactivating proteins and consists of an A-chain with N-glycosidase activity and a carbohydrate-binding B-chain. Incorporation of 2 mg/ml of SNA-I in the diet of neonates and adults of A. pisum caused 40-46% mortality within 2 days, while in third instars of S. exigua, the larval biomass was significantly reduced by 12% after feeding for 3 days on a diet containing 5 mg/g of SNA-I. Interestingly, extracts of the (mid)gut of treated A. pisum and S. exigua demonstrated DNA fragmentation and this was accompanied with an increase in caspase-3-like activity. The involvement of cell death or apoptosis in the entomotoxicity of SNA-I through induction of caspase-3-like activity was also confirmed by addition of the permeable caspase-3 inhibitor III in the diet, leading to a rescue of the treated aphid neonates. Finally, similar to the chimeric lectin SNA-I, the hololectin SNA-II, consisting of two carbohydrate binding B-chains caused high mortality to neonate A. pisum aphids with an LC50 of 1.59 mg/ml, suggesting that the entomotoxic action of the lectins under study mainly relies on their carbohydrate-binding activity. PMID- 20853434 TI - Colitis-associated DNA aneuploidy and dysplasia in Crohn's disease and risk of colorectal cancer. AB - BACKGROUND: There is uncertainty about how patients with Crohn's colitis should be monitored for colorectal cancer (CRC). By analogy to ulcerative colitis, regular colonoscopy with biopsies for dysplasia has been used. We describe the occurrence of dysplasia and DNA aneuploidy in a cohort of patients with Crohn's colitis. METHODS: In all, 245 patients with extensive colitis (225 with a firm diagnosis of Crohn's disease, and 20 diagnosed as indeterminate colitis) at Stockholm Soder Hospital and Karolinska University Hospital, Huddinge were included. They were followed with regular colonoscopies with biopsies both for dysplasia and DNA aneuploidy. The cumulative occurrence of DNA aneuploidy and dysplasia was estimated using Kaplan-Meier curves. Time sequences and interactions between DNA aneuploidy, dysplasia, and CRC were studied using Cox regression analysis, adjusted for age, sex, and age at diagnosis. RESULTS: During a median follow-up time of 9.2 person-years, DNA aneuploidy was found in 53 patients (22%), with 10 patients having multifocal aneuploidy and high S-phase values. Dysplasia was found in 42 patients (17%), 10 having multifocal dysplasia. Relative risk (RR) of dysplasia given DNA aneuploidy was 5.3 (95% confidence interval [CI] 2.3-12). RR of CRC given dysplasia was 10 (95% CI 2-50), and RR of CRC given aneuploidy was 1.5 (95% CI 0.3-9.3). CONCLUSIONS: Dysplasia and DNA aneuploidy including S-phase analysis may complement stratification of patients with Crohn's PMID- 20853436 TI - One-year clinical outcome in an unselected patient population treated with the GenousTM endothelial progenitor cell capturing stent. AB - OBJECTIVE: We assessed the 1-year clinical outcome in a large cohort of unselected patients treated with an endothelial progenitor cell (EPC) capturing coronary stent. BACKGROUND: The novel EPC capturing stent is coated with CD34+ antibodies that bind circulating EPCs to the stent surface, thereby accelerating endothelialization of the stent struts; it is hypothesized that this may prevent restenosis and stent thrombosis. METHODS: A total of 405 unselected patients were treated percutaneously with the EPC capturing stent. The majority of patients had complex lesions with an estimated high risk of restenosis. RESULTS: The primary endpoint defined as the composite of cardiac death, myocardial infarction (MI), and target lesion revascularization (TLR) at 1-year was 13.3%, mainly attributable to TLR which was 10.9%. The occurrence of definite and probable ST was low, 0.5 and 0.7%, respectively. Based on the risk of restenosis, in patients with an estimated high risk of restenosis (n = 249), the composite primary endpoint was 16.1% versus 9.0% in patients with an estimated low risk (n = 155). Moreover, the 1 year clinical outcomes in diabetic patient compared well with the nondiabetic patients. CONCLUSION: In this single-center study, the 1-year clinical follow-up in a "real-world" population treated with the EPC capturing stent showed good results. Currently, large randomized studies are conducted to evaluate the long-term safety and efficacy of this stent. PMID- 20853437 TI - Oligodendrocyte PTEN is required for myelin and axonal integrity, not remyelination. AB - OBJECTIVE: Repair of myelin injury in multiple sclerosis may fail, resulting in chronic demyelination, axonal loss, and disease progression. As cellular pathways regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN; eg, phosphatidylinositol-3-kinase [PI-3K]) have been reported to enhance axon regeneration and oligodendrocyte maturation, we investigated potentially beneficial effects of Pten loss of function in the oligodendrocyte lineage on remyelination. METHODS: We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of Pten in oligodendrocytes, Olig2-cre, Pten(fl/fl) mice. Using a model of central nervous system demyelination, lysolecithin injection into the spinal cord white matter, we performed short- and long-term lesioning experiments and quantified oligodendrocyte maturation and myelin sheath thickness in remyelinating lesions. RESULTS: During development, we observed dramatic hypermyelination in the corpus callosum and spinal cord. Following white matter injury, however, there was no detectable improvement in remyelination. Moreover, we observed progressive myelin sheath abnormalities and massive axon degeneration in the fasciculus gracilis of mutant animals, as indicated by ultrastructure and expression of SMI-32, amyloid precursor protein, and caspase 6. INTERPRETATION: These studies indicate adverse effects of chronic Pten inactivation (and by extension, activation PI-3K signaling) on myelinating oligodendrocytes and their axonal targets. We conclude that PTEN function in oligodendrocytes is required to regulate myelin thickness and preserve axon integrity. In contrast, PTEN is dispensable during myelin repair, and its inactivation confers no detectable benefit. PMID- 20853438 TI - Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). AB - OBJECTIVE: Neurodegeneration with brain iron accumulation (NBIA) represents a distinctive phenotype of neurodegenerative disease for which several causative genes have been identified. The spectrum of neurologic disease associated with mutations in NBIA genes is broad, with phenotypes that range from infantile neurodegeneration and death in childhood to adult-onset parkinsonism-dystonia. Here we report the discovery of a novel gene that leads to a distinct form of NBIA. METHODS: Using autozygosity mapping and candidate gene sequencing, we identified mutations in the fatty acid hydroxylase gene FA2H, newly implicating abnormalities of ceramide metabolism in the pathogenesis of NBIA. RESULTS: Neuroimaging demonstrated T2 hypointensity in the globus pallidus, confluent T2 white matter hyperintensities, and profound pontocerebellar atrophy in affected members of two families. Phenotypically, affected family members exhibited spastic quadriparesis, ataxia, and dystonia with onset in childhood and episodic neurological decline. Analogous to what has been reported previously for PLA2G6, the phenotypic spectrum of FA2H mutations is diverse based on our findings and those of prior investigators, because FA2H mutations have been identified in both a form of hereditary spastic paraplegia (SPG35) and a progressive familial leukodystrophy. INTERPRETATION: These findings link white matter degeneration and NBIA for the first time and implicate new signaling pathways in the genesis of NBIA. PMID- 20853439 TI - Morphometrics and pattern of growth in wild sifakas (Propithecus edwardsi) at Ranomafana National Park, Madagascar. AB - We summarize morphometric data collected over a period of 22 years from a natural population of rainforest sifakas (Propithecus edwardsi) at Ranomafana National Park, Madagascar, and we use those data to document patterns of growth and development. Individually identified, known-age sifakas were successfully captured, measured, and released. We found that body segment lengths increased faster during growth than did body mass, with individuals attaining adult lengths earlier than adult mass. Females can begin reproducing before they are fully grown, but this may not be common. With the exception of hand length, we found no significant sex difference in any adult metric including body mass, chest, and limb circumferences, body segment lengths, and canine tooth height; however, body masses of individual females fluctuated more, independently of pregnancy, than did those of males. We found considerable interannual fluctuation in body mass with single individuals differing more within the same season in different years than from season to season in the same year. Such body mass fluctuation may be a consequence of eastern Madagascar's variable and unpredictable environment in which rainfall during any selected month varies from year to year. PMID- 20853440 TI - A multipoint method for meta-analysis of genetic association studies. AB - Meta-analyses of genetic association studies are usually performed using a single polymorphism at a time, even though in many cases the individual studies report results from partially overlapping sets of polymorphisms. We present here a multipoint (or multilocus) method for multivariate meta-analysis of published population-based case-control association studies. The method is derived by extending the general method for multivariate meta-analysis and allows for multivariate modelling of log(odds ratios (OR)) derived from several polymorphisms that are in linkage disequilibrium (LD). The method is presented in a genetic model-free approach, although it can also be used by assuming a genetic model of inheritance beforehand. Furthermore, the method is presented in a unified framework and is easily applied to both discrete outcomes (using the OR), as well as to meta-analyses of a continuous outcome (using the mean difference). The main innovation of the method is the analytical calculation of the within studies covariances between estimates derived from linked polymorphisms. The only requirement is that of an external estimate for the degree of pairwise LD between the polymorphisms under study, which can be obtained from the same published studies, from the literature or from HapMap. Thus, the method is quite simple and fast, it can be extended to an arbitrary set of polymorphisms and can be fitted in nearly all statistical packages (Stata, R/Splus and SAS). Applications in two already published meta-analyses provide encouraging results concerning the robustness and the usefulness of the method and we expect that it would be widely used in the future. PMID- 20853441 TI - A mindfulness-based approach to the treatment of insomnia. AB - Mindfulness meditation has emerged as a novel approach to emotion regulation and stress reduction that has several health benefits. Preliminary work has been conducted on mindfulness-based therapy for insomnia (MBT-I), a meditation-based program for individuals suffering from chronic sleep disturbance. This treatment integrates behavioral treatments for insomnia with the principles and practices of mindfulness meditation. A case illustration of a chronic insomnia sufferer demonstrates the application of mindfulness principles for developing adaptive ways of working with the nocturnal symptoms and waking consequences of chronic insomnia. PMID- 20853442 TI - Treatment of adult insomnia with cognitive-behavioral therapy. AB - Insomnia is a highly prevalent disorder that occurs frequently in its acute form and at a rate of approximately 10% in its chronic form. There is a high prevalence of insomnia in a variety of medical and psychiatric conditions. Cognitive-behavioral therapy (CBT) may be employed for chronic insomnia as well as for insomnia in the context of other conditions such as chronic pain conditions. In such cases, some simple adaptations to standard CBT for insomnia are useful. This article reviews the typical assessment and CBT for adult insomnia, which have substantial empirical support for its efficacy. A case illustrates the core treatment processes and demonstrates that improving sleep in the context of conditions like chronic pain can lead to better management of such conditions. PMID- 20853443 TI - Use of GC * GC/TOF-MS and LC/TOF-MS for metabolomic analysis of Hyalella azteca chronically exposed to atrazine and its primary metabolite, desethylatrazine. AB - Atrazine is one of the most commonly detected contaminants in the U.S. Little information is available on one of atrazine's metabolites, desethylatrazine (DEA). Two-dimensional gas chromatography and liquid chromatography coupled with time of flight- mass spectrometry were used to examine metabolite profiles of Hyalella azteca chronically exposed to 30 ug/L atrazine and DEA. The majority of identified metabolites were by-products of beta-oxidation of fatty acids suggesting possible disruption in energy metabolism. Eicosanoids increased in exposed females suggesting possible perturbations in neuropeptide hormonal systems. Overall, this research demonstrates the feasibility of utilizing metabolomic profiling of invertebrate species exposed to environmental contaminants as a way to determine mechanisms of toxicity. PMID- 20853444 TI - Impact of STZ-induced hyperglycemia and insulin-induced hypoglycemia in plasma amino acids and cortical synaptosomal neurotransmitters. AB - In this work, we evaluated the effects of streptozotocin (STZ)-induced hyperglycemia and an acute episode of insulin-induced hypoglycemia in plasma amino acids and cortical neurotransmitters. For that purpose, we used citrate (vehicle)-treated Wistar rats, STZ-treated rats [i.p., 50 mg/kg body weight], and STZ-treated rats injected with insulin [s.c., dose adjusted with blood glucose levels] 1 h prior to sacrifice to induce an acute episode of hypoglycemia. Plasma was collected for determination of amino acids levels. In addition, cortical synaptosomal preparations were obtained and the total levels of neurotransmitters, levels of aspartate, glutamate, taurine, and GABA released by the action of KCl, iodoacetic acid (IAA), ouabain, and veratridine, membrane potential and ATP levels were evaluated. Compared with control rats, plasma from hypoglycemic rats presented increased levels of aspartate, glutamate, glutamine, and taurine whereas GABA levels were decreased in STZ and hypoglycemic rats. Similarly, glutamate and taurine levels were increased in hypoglycemic synaptosomes while GABA decreased in hypoglycemic and STZ-diabetic synaptosomes. The depolarizing agent KCl promoted an increase in aspartate, glutamate, and taurine release from hypoglycemic synaptosomes. The highest release of neurotransmitters occurred in the presence of veratridine and ouabain, two other depolarizing agents, in all groups of experimental animals. However, a higher release of glutamate was observed in the diabetic and hypoglycemic synaptosomes. No alterations were observed in synaptosomal membrane potential and ATP levels. These results show that in the presence of a metabolic insult a higher release of excitatory amino acids occurs, which may underlay the neuronal injury observed in type 1 diabetic patients under insulin therapy. PMID- 20853445 TI - Role of presynaptic and postsynaptic IP3-dependent intracellular calcium release in long-term potentiation in sympathetic ganglion of the rat. AB - In the rat superior cervical ganglion, a form of long term potentiation (LTP) can be elicited by a brief high frequency stimuli applied to the preganglionic nerve. Cumulative evidence shows that a transient increase in cytoplasmic Ca2+ concentration is essential for the generation of the ganglionic LTP. Calcium influx and calcium release from intracellular calcium stores contribute to LTP. However, the differential role of presynaptic and postsynaptic calcium signaling has not been established. Herein, by using heparin, a membrane-impermeant inositol trisphosphate receptor (IP3R) blocker, we explored the contribution of presynaptic and postsynaptic IP3-sensitive calcium stores to the ganglionic LTP. The LTP was produced by a conditioning train of 40 Hz for 3 s. We analyzed the effects of heparin on the posttetanic potentiation: PTP magnitude and PTP time constant, and on two parameters that describe the LTP: LTP decay time (elapsed time required by the potentiated response to fall to 20% above the basal value) and LTP extent (the integral of the potentiated response). Heparin (100 and 200 MUg/ml) was loaded in the preganglionic, the postganglionic, or in both nerves. We found that in all tested conditions heparin significantly decreased LTP but practically did not affect PTP. The preganglionic and postganglionic inhibitory effects of heparin were not additive. De-N-sulfated heparin, an ineffective IP3R blocker, had no effect on LTP, but abolished the heparin blocking effect. Data suggest that presynaptic and postsynaptic IP3-dependent intracellular calcium release equally contribute to ganglionic LTP, supporting our proposal of a trans synaptic mechanism for LTP. PMID- 20853446 TI - Neuron-glial cell communication in the traumatic stress-induced immunomodulation. AB - We have previously reported that neuron and glia could collaboratively govern the immunomodulation in traumatic rats. Herein, we characterized the sequential involvement of cortical neuron, microglia, and astrocytes in the traumatic stress mediated neuroimmune modulation. At day 1 of trauma, transient extracellular signal related kinase 1/2 (ERK1/2) activation was initiated in neuron and microglia, which was accompanied by RSK-1 expression in the cytosol. At day 3 of trauma, persistent ERK1/2 activation occurred in astrocytes, which were destined for the nucleus leading to Elk-1 expression. Furthermore, the functional overlap of ERK1/2 and neuroligin 1 in astrocytes was strengthened at day 3 of trauma and responsible for the recovery from the immnosuppression. These effects could be disrupted by beta-neurexin blockade. Altogether, we proposed the mechanism underlying the traumatic stress-induced immunosuppression, in which local activity ensured the initial establishment of neural circuitry in the frontal cortex. ERK1/2-signaling events are required for the temporal and spatial coordination between neuron and glial cells. PMID- 20853447 TI - Surfactant-facilitated remediation of metal-contaminated soils: efficacy and toxicological consequences to earthworms. AB - The effectiveness of surfactant formulations to remove aged metals from a field soil and their influence on soil toxicity was investigated. Batch studies were conducted to evaluate the efficacy of cationic (1-dodecylpyridinium chloride; DPC), nonionic (oleyl dimethyl benzyl ammonium chloride; trade name Ammonyx KP), and anionic (rhamnolipid biosurfactant blend; trade name JBR-425) surfactants for extracting Zn, Cu, Pb, and Cd from a soil subjected to more than 80 years of metal deposition. All three surfactants enhanced removal of the target metals. The anionic biosurfactant JBR-425 was most effective, reducing Zn, Cu, Pb, and Cd in the soil by 39, 56, 68, and 43%, respectively, compared with less than 6% removal by water alone. Progressive acidification of the surfactants with citric acid buffer or addition of ethylenediaminetetra-acetic acid (EDTA) further improved extraction efficiency, with more than 95% extraction of all four metals by surfactants acidified to pH 3.6 and generally greater than 90% removal of all metals with addition of 0.1 M EDTA. In two species of earthworm, Eisenia fetida and Lumbricus terrestris, metal bioaccumulation was reduced by approximately 30 to 80%, total biomass was enhanced by approximately threefold to sixfold, and survival was increased to greater than 75% in surfactant-remediated soil compared with untreated soil. The data indicate that surfactant washing may be a feasible approach to treat surface soils contaminated with a variety of metals, even if those metals have been present for nearly a century, and that the toxicity and potential for metal accumulation in biota from the treated soils may be significantly reduced. PMID- 20853448 TI - Field measurement of nickel sediment toxicity: role of acid volatile sulfide. AB - A field experiment was performed in four freshwater systems to assess the effects of Ni on the benthic macroinvertebrate communities. Sediments were collected from the sites (in Belgium, Germany, and Italy), spiked with Ni, and returned to the respective field sites. The colonization process of the benthic communities was monitored during a nine-month period. Nickel effect on the benthos was also assessed in the context of equilibrium partitioning model based on acid volatile sulfides (AVS) and simultaneously extracted metals (SEM). Benthic communities were not affected at (SEM - AVS) <= 0.4 umol/g, (SEM - AVS)/fraction of organic carbon (f(OC)) < 21 umol/g organic carbon (OC). Sediments with (SEM - AVS) > 2 umol/g, (SEM - AVS)/f(OC) > 700 umol/g OC resulted in clear adverse effects. Uncertainty about the presence and absence of Ni toxicity occurred at (SEM - AVS) and (SEM - AVS)/f(OC) between 0.4 to 2 umol/g and 21 to 700 umol/g OC, respectively. The results of our study also indicate that when applying the SEM:AVS concept for predicting metal toxicity in the field study, stressors other than sediment characteristics (e.g., sorption capacity), such as environmental disturbances, should be considered, and the results should be carefully interpreted. PMID- 20853449 TI - Physiological effects of temperature and a herbicide mixture on the soft-shell clam Mya arenaria (Mollusca, Bivalvia). AB - The aim of the current study was to investigate effects of temperature and a mixture of herbicides on the physiological status of the bivalve Mya arenaria. Bivalves acclimated to two temperatures (7 and 18 degrees C) were exposed for 28 d to 0.01 mg/L of a pesticide formulation containing dichlorophenoxyacetic acid (2,4-D), 2-(2-methyl-4-chlorophenoxy) propionic acid (mecoprop), and 3,6-dichloro 2-methoxybenzoic acid (dicamba). At days 7, 14, and 28, mortality, immune parameters (hemocyte number, phagocytic activity, and efficiency), biomarkers of oxidative stress (catalase [CAT] and superoxide dismutase [SOD] activities and malondialdehyde [MDA] content), the metabolic enzyme cytochrome C oxidase (CCO), a biomarker of pesticide exposure (acetylcholinesterase [AChE]), and the activity of an enzyme related to gametogenesis (aspartate transcarbamylase [ATCase]) were monitored in clam tissues. Gonadosomatic index (GSI), condition factor (CF), and sex were also assessed. In clams acclimated to 7 degrees C, exposure to pesticide enhanced CCO activity and CF and decreased MDA content, hemocyte number, CAT, and SOD activities. In clams kept at 18 degrees C, pesticide effects appeared minor compared with samples kept at 7 degrees C. In bivalves acclimated to 18 degrees C, CCO, SOD, and ATCase activity and MDA content were enhanced, and hemocyte number, CAT, and AchE activities and phagocytosis were suppressed. In samples exposed to pesticides, increased temperature enhanced MDA content and CCO and SOD activity and suppressed hemocyte number and CAT and AchE activity. A gradual sexual maturation was observed in both sexes through experimental time, but females had a higher sensitivity to temperature and pesticides compared to males. Increased temperature altered the ability of the sentinel species Mya arenaria to respond to pesticide exposures. Further work is needed to understand the impacts of increasing temperature on the whole St. Lawrence estuary ecosystem. PMID- 20853451 TI - An assessment of honeybee colony matrices, Apis mellifera (Hymenoptera: Apidae) to monitor pesticide presence in continental France. AB - The frequency of occurrence and relative concentration of 44 pesticides in apicultural (Apis mellifera) matrices collected from five French locations (24 apiaries) were assessed from 2002 to 2005. The number and nature of the pesticides investigated varied with the matrices examined-living honeybees, pollen loads, honey, and beeswax. Pollen loads and beeswax had the highest frequency of pesticide occurrence among the apiary matrices examined in the present study, whereas honey samples had the lowest. The imidacloprid group and the fipronil group were detected in sufficient amounts in all matrices to allow statistical comparisons. Some seasonal variation was shown when residues were identified in pollen loads. Given the results (highest frequency of presence) and practical aspects (easy to collect; matrix with no turnover, unlike with bees that are naturally renewed), pollen loads were the best matrix for assessing the presence of pesticide residues in the environment in our given conditions. PMID- 20853450 TI - Plants growing on contaminated and brownfield sites appropriate for use in Organisation for Economic Co-operation and Development terrestrial plant growth test. AB - The Organisation for Economic Co-operation and Development (OECD) terrestrial plant test is often used for the ecological risk assessment of contaminated land. However, its origins in plant protection product testing mean that the species recommended in the OECD guidelines are unlikely to occur on contaminated land. Six alternative species were tested on contaminated soils from a former Zn smelter and a metal fragmentizer with elevated concentrations of Cd, Cu, Pb, and Zn. The response of the alternative species was compared with that of two species recommended by the OECD: Lolium perenne (perennial ryegrass) and Trifolium pratense (red clover). Urtica dioica (stinging nettle) and Poa annua (annual meadowgrass) had low emergence rates in the control soil and so may be considered unsuitable. Festuca rubra (Chewings fescue), Holcus lanatus (Yorkshire fog), Senecio vulgaris (common groundsel), and Verbascum thapsus (great mullein) offer good alternatives to the OECD species. In particular, H. lanatus and S. vulgaris were more sensitive to the soils with moderate concentrations of Cd, Cu, Pb, and Zn than the OECD species. PMID- 20853452 TI - Influence of season, location, and feeding strategy on bioaccumulation of halogenated organic contaminants in Arctic marine zooplankton. AB - The influence of season, location, feeding strategy, and trophic position on concentration, compositional pattern, and bioaccumulation factors (BAFs) of halogenated organic contaminants (HOCs; polychlorinated biphenyls, chlorinated pesticides, and brominated flame retardants) was investigated within an Arctic zooplankton food web. Water (dissolved fraction) and seven Arctic marine pelagic zooplankton species (including herbivores, omnivores, and predators) were sampled in May, July, and October 2007 at two stations in Kongsfjorden, Svalbard, Norway. The HOC concentrations in both water and zooplankton generally decreased from May to October. The HOC concentrations and patterns among zooplankton species were explained by their feeding strategies, roughly categorized as herbivores, omnivores, and predators, and not stable isotope-derived trophic position. Field derived BAFs varied greatly, with higher BAFs in May compared with July and October. Furthermore, BAFs differed among the species according to their feeding strategies. The relationship between BAFs from the different seasons and K(OW) (octanol:water partitioning coefficient) showed comparable intercepts and different slopes between May and October, with all relationships diverging from the assumed 1:1 relationship between BAF and K(OW). Differences in HOC concentrations and BAFs from herbivores to predators showed that biomagnification occurred in zooplankton. The results suggest that concentrations and patterns of HOCs in zooplankton species are influenced not only by equilibrium partitioning with water but also by feeding strategy. PMID- 20853453 TI - Bioconcentration of perfluorinated compounds in blackrock fish, Sebastes schlegeli, at different salinity levels. AB - Bioconcentration of perfluorinated compounds (PFCs) was studied in a biphasic (uptake and elimination) study with blackrock fish, Sebastes schlegeli. The blackrock fish was acclimated to varying salinities over a two-week period before the present study. Among the four selected PFCs: perfluorooctane sulfonate (PFOS), perfluoro-octanoic acid (PFOA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA), PFUnDA accumulated significantly in serum, followed by PFDA, PFOS, and PFOA, in that order, while the accumulation profile in liver was PFOS > PFUnDA > PFDA > PFOA. Total PFC levels in plasma were approximately four times greater than those found in liver. The uptake and elimination rate constants (K(u) and K(e)) of PFCs decreased as salinity decreased, suggesting delayed diffusion of PFCs between water and fish, possibly associated with the osmolality gradient. A significant correlation was found between bioconcentration factors (BCF) of PFCs and salinity, except for PFOA, possibly resulting from the effects of salinity on biological responses and chemical activity of PFCs. Even though salinity did not affect the kinetics of PFC accumulation in serum and liver, the results provide useful information on the toxicokinetics of PFCs for saltwater fish. PMID- 20853454 TI - Immunotoxicity of pyrethroid metabolites in an in vitro model. AB - Risk assessment of man-made chemicals such as pesticides are mainly focused on parent compounds, and relatively little is known about their metabolites, especially with regard to target organ damages such as immunotoxicity. In the present study, the immunotoxicity of five synthetic pyrethroids (SPs) and three common metabolites was evaluated using an in vitro model by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cytoflow, and enzyme-linked immunosorbent assay (ELISA). Cell viability and apoptosis assays showed that both SPs and their metabolites possessed cytotoxicity to the monocytic cells. The aldehyde and acid derivatives were more effective than the other compounds at cytotoxicity, with inhibition of cell viability by 56.8 and 50.6% at 10-5 mol L-1, and induction of 8.52 and 8.81% cell apoptosis, respectively. Exposure to SPs and their metabolites also led to changes in the secretion levels of tumor necrosis factor alpha (TNF alpha) and interleukins (ILs), and again the metabolites showed stronger effects than the parent compounds. The aldehyde derivative upregulated IL-12p70 level by 1.87-fold, and the alcohol and acid derivative increased the secretion of TNF alpha 5.88 and 7.96-fold, relative to the control group. In the in vitro model, the common metabolites of SPs clearly exerted greater immunotoxic effects to monocytes than the intact parent compounds. Results from the present study suggested the need for considering metabolites in achieving more comprehensive health risk assessment of man-made chemicals, including target organ toxicities such as immunotoxicity. PMID- 20853455 TI - Linking toxicity in algal and bacterial assays with chemical analysis in passive samplers deployed in 21 treated sewage effluents. AB - A diverse mix of micropollutants, including pesticides, biocides, and pharmaceuticals, reaches the aquatic environment through treated sewage effluents. We sampled 21 final effluents with polar organic chemical integrative samplers (POCIS) and investigated to what extent chemical analyses of six photosystem II (PS-II) inhibitors and 12 other chemicals explain the toxic burdens quantified with two bioassays. Baseline toxicity equivalent concentrations (TEQ) were determined with a bacterial bioluminescence inhibition assay using Vibrio fischeri (baseline-TEQ(bacteria)) and by assessing toxicity on algal growth using Pseudokirchneriella subcapitata (baseline-TEQ(algae)). Inhibition PS-II was also determined with algae and expressed using diuron equivalent concentrations (DEQ(bio)). Concentrations of chemicals and toxicities varied appreciably between effluents, typically spanning two orders of magnitude. Across 21 independent effluents, a DEQ calculated by concentration addition of PS II inhibitors (DEQ(chem)) proved a very good predictor of DEQ(bio); DEQ(chem) explained 65% of DEQ(bio). However, baseline-TEQ(bacteria,bio) correlated poorly with baseline-TEQ(algae,bio), because baseline-TEQ(algae) were strongly influenced by PS-II inhibitors. Using data on the 18 quantified compounds, and their estimated toxicities in the bacterial assay, we calculated a baseline TEQ(bacteria,chem). With one exception, a site with a high load of diclofenac, less than 1% of baseline-TEQ(bacteria,bio) was explained by the analyzed chemicals. We conclude that for the analyses of final effluents, DEQ(bio) is a robust endpoint and useful screening tool for PS-II inhibitors; in the presence of herbicides, baseline-TEQ(bacteria,bio) proves a more robust measure of baseline toxicity than baseline-TEQ(algae,bio). PMID- 20853456 TI - Novel antifouling agent zinc pyrithione: determination, acute toxicity, and bioaccumulation in marine mussels (Mytilus galloprovincialis). AB - Antifouling biocide zinc pyrithione (ZnPT) and its biological fate have received little attention because this compound was assumed not to be persistent in marine ecosystems. An analytical procedure was developed that has proved to be efficient and very sensitive in extracting ZnPT and its main secondary products, Zn and ionized pyrithione (PT(-)), from both seawater and biological samples, namely in the gills and digestive gland of the bioindicator species Mytilus galloprovincialis. Short-term experiments were carried out to investigate ZnPT toxicity and bioaccumulation. The effects on survival and tissue bioaccumulation of ZnPT and its secondary products were studied on adult mussels from a natural population, collected in the harbor area of Porto Santo Stefano (Italy) and exposed to sublethal doses of the biocide for up to 7 d. Zinc pyrithione was shown to be persistent in the experimental seawater in the short term. A basal level of ZnPT and ionized PT(-) was detected in the mussels, indicating that ZnPT availability in the sampling site is already high enough to induce a detectable accumulation in individuals of the native population. Zinc pyrithione rapidly accumulated in the tissues of the exposed mussels, proportionately to both exposure concentration and time, identifying the gills and digestive gland as important targets in the biological pathway of the contaminants. Even though the 7-d median lethal concentration (LC50) = 8.27 uM established here appears high with respect to reported ZnPT environmental concentrations, the results indicate that this biocide could represent a threat for marine organisms in coastal environments and that further investigations on its biological effects at sublethal doses are needed. PMID- 20853457 TI - Accumulation of current-use and organochlorine pesticides in crab embryos from northern California, USA. AB - Invertebrates have long been used as resident sentinels for assessing ecosystem health and productivity. The shore crabs, Hemigrapsus oregonensis and Pachygrapsus crassipes, are abundant in estuaries and beaches throughout northern California, USA and have been used as indicators of habitat conditions in several salt marshes. The overall objectives of the present study were to conduct a lab based study to test the accumulation of current-use pesticides, validate the analytical method and to analyze field-collected crabs for a suite of 74 current use and legacy pesticides. A simple laboratory uptake study was designed to determine if embryos could bioconcentrate the herbicide molinate over a 7-d period. At the end of the experiment, embryos were removed from the crabs and analyzed by gas chromatography/mass spectrometry. Although relatively hydrophilic (log K(OW) of 2.9), molinate did accumulate with an estimated bioconcentration factor (log BCF) of approximately 2.5. Following method validation, embryos were collected from two different Northern California salt marshes and analyzed. In field-collected embryos 18 current-use and eight organochlorine pesticides were detected including synthetic pyrethroids and organophosphate insecticides, as well as DDT and its degradates. Lipid-normalized concentrations of the pesticides detected in the field-collected crab embryos ranged from 0.1 to 4 ppm. Pesticide concentrations and profiles in crab embryos were site specific and could be correlated to differences in land-use practices. These preliminary results indicate that embryos are an effective sink for organic contaminants in the environment and have the potential to be good indicators of ecosystem health, especially when contaminant body burden analyses are paired with reproductive impairment assays. PMID- 20853458 TI - Altered development and reproduction in western mosquitofish (Gambusia affinis) found in the Hanxi River, southern China. AB - The current study investigated the development and reproductive health of western mosquitofish (Gambusia affinis) in the Hanxi River, which has been heavily contaminated by municipal wastewaters from towns in Dongguan of southern China. Western mosquitofish collected from four study sites, Songmu (SM), Yangwu (YW), Hengli (HL), and Zhangcun (ZC) of the Hanxi River, as well as a reference site (LX) of the Liuxi River, were dissected and analyzed for development parameters (total length, wet body mass, liver mass, gonad index, and population composition), reproductive parameters (oocyte count and weight of females, and sperm count and viability of males), and morphology (anal fin in males and females, and hemal spines in males). With the exception of the origin site (SM), mosquitofish from the Hanxi River exhibited significantly decreasing development and reproduction levels. Significant correlations were found for the collected mosquitofish between the morphological and reproductive indexes (ratio of perpendicular distance to tip to vertical distance from the tip on the 16th hemal spine) versus the sperm count of males; ratio 16P:16D versus sperm viability of males; segments of anal fin ray 3 versus oocyte count of females; and segments of anal fin ray 3 versus average oocyte mass of females. The results demonstrated that both male and female mosquitofish in the Hanxi River were affected by the discharged wastewaters, as reflected in their morphological changes in comparison with those of mosquitofish from the reference site. PMID- 20853459 TI - Development of a new toxic-unit model for the bioassessment of metals in streams. AB - Two toxic-unit models that estimate the toxicity of trace-metal mixtures to benthic communities were compared. The chronic criterion accumulation ratio (CCAR), a modification of biotic ligand model (BLM) outputs for use as a toxic unit model, accounts for the modifying and competitive influences of major cations (Ca2(+), Mg2(+), Na(+), K(+), H(+)), anions (HCO3-, CO2-3 ,SO2-4, Cl-, S2 ) and dissolved organic carbon (DOC) in determining the free metal ion available for accumulation on the biotic ligand. The cumulative criterion unit (CCU) model, an empirical statistical model of trace-metal toxicity, considers only the ameliorative properties of Ca2(+) and Mg2(+) (hardness) in determining the toxicity of total dissolved trace metals. Differences in the contribution of a metal (e.g., Cu, Cd, Zn) to toxic units as determined by CCAR or CCU were observed and attributed to how each model incorporates the influences of DOC, pH, and alkalinity. Akaike information criteria demonstrate that CCAR is an improved predictor of benthic macroinvertebrate community metrics as compared with CCU. Piecewise models depict great declines (thresholds) in benthic macroinvertebrate communities at CCAR of 1 or more, while negative changes in benthic communities were detected at a CCAR of less than 1. We observed a 7% reduction in total taxa richness and a 43% decrease in Heptageniid abundance between background (CCAR = 0.1) and the threshold of chronic toxicity on the basis of continuous chronic criteria (CCAR = 1). In this first application of the BLM as a toxic-unit model, we found it superior to CCU. PMID- 20853461 TI - Simultaneous determination of niacin and its metabolites--nicotinamide, nicotinuric acid and N-methyl-2-pyridone-5-carboxamide--in human plasma by LC MS/MS and its application to a human pharmacokinetic study. AB - An LC-MS/MS method for the simultaneous quantitation of niacin (NA) and its metabolites, i.e. nicotinamide (NAM), nicotinuric acid (NUA) and N-methyl-2 pyridone-5-carboxamide (2-Pyr), in human plasma (1 mL) was developed and validated using nevirapine as an internal standard (IS). Extraction of the NA and its metabolites along with the IS from human plasma was accomplished using a simple liquid-liquid extraction. The chromatographic separation of NA, NAM, NUA, 2-Pyr and IS was achieved on a Hypersil-BDS column (150 x 4.6 mm, 5 microm) column using a mobile phase consisting of 0.1% formic acid : acetonitrile (20:80 v/v) at a flow rate of 1 mL/min. The total run time of analysis was 2 min and elution of NA, NAM, NUA, 2-Pyr and IS occurred at 1.37, 1.46, 1.40, 1.06 and 1.27 min, respectively. A detailed validation of the method was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 100-20000 ng/mL for NA; 10-1600 ng/mL for NUA and NAM and 50-5000 ng/mL for 2-Pyr with mean correlation coefficient of >= 0.99 for each analyte. The method was sensitive, specific, precise, accurate and suitable for bioequivalence and pharmacokinetic studies. The developed assay method was successfully applied to a pharmacokinetic study in humans. PMID- 20853460 TI - An HPLC assay for the lipophilic camptothecin analog AR-67 carboxylate and lactone in human whole blood. AB - AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin, DB-67) is a camptothecin analog currently in early stage clinical trials. The lactone moiety of camptothecins hydrolyzes readily in blood to yield the pharmacologically inactive carboxylate form. However the lactone form of third-generation lipophilic congeners, such as AR-67, is more stable, possibly due to partitioning into red cell membranes. This prompted us to develop a reverse-phase HPLC method with fluorescence detection (excitation 380 nm/emission 560 nm), which could quantitate the concentration of AR-67 lactone and carboxylate in whole blood. Samples were prepared by red cell lysis, protein precipitation with methanol and centrifugation to remove denatured materials. Recovery was estimated to be >85%. Analytes were eluted isocratically with 0.15 m ammonium acetate buffer containing 10 mm TBAP (pH 6.5) and acetonitrile (65:35, v/v) on a Nova-Pak C(18) column (4 um; 3.9 * 150 mm). The assay was linear in the ranges 0.5-300 and 2.5-300 ng/mL for carboxylate and lactone, respectively. Accuracy and precision were acceptable. AR-67 forms were stable in whole blood and in methanolic supernatants. This assay has been successfully applied to measure AR-67 concentrations in whole blood of patients enrolled in a phase I study. PMID- 20853462 TI - Chromatographic studies of some cephalosporins on thin layers of silica gel G zinc ferrocyanide. AB - A simple, selective and precise thin-layer chromatographic method has been developed for the analysis of eight cephalosporin antibiotics, namely cephadroxil, cephalexin, cefixime, cefaclor, cefpodoxime proxetil, cefuroxime axetil, cefotaxime sodium and ceftriaxone sodium. The hR(F) values of these cephalosporins were investigated on silica gel G-zinc ferrocyanide layers. Mixing of zinc ferrocyanide with silica gel G resulted in a decrease in hR(F) values, removal of tailing and better resolutions. The influence of silica gel G-zinc ferrocyanide ratio and mobile phases on the chromatographic behavior of cephalosporins on thin layers was investigated. Cephalosporins were selectively separated in their binary and ternary synthetic mixtures and pharmaceutical formulations. Quantitative separations of cephalosporins from their synthetic mixtures were also achieved with good recoveries (97.8-100.3%). PMID- 20853463 TI - Determination and pharmacokinetics of periplocin in rat plasma by LC-MS. AB - A simple and sensitive LC-MS method for the determination of periplocin in rat plasma was developed and validated. The chromatographic separation was carried out using a reverse-phase Kromasil C(18) column(150 * 4.6 mm, i.d., 5 um) with a mobile phase composed of methanol-water (76:24, v/v). The flow rate of mobile phase was 0.8 mL/min. The calibration curve was linear within the concentration range 1-1000 ng/mL. The intra- and inter-day precisions across three validation days over the entire concentration range was lower than 9.2% in terms of relative standard deviation. Accuracy determined at three quality control concentrations ranged from -2.0 to 6.0% in terms of relative error. The validated method was applied to the pharmacokinetic study of periplocin in rat plasma after intravenous and intramuscular administration. PMID- 20853464 TI - Validation and clinical application of an LC-ESI-MS/MS method for simultaneous determination of tolmetin and MED5, the metabolites of amtolmetin guacil in human plasma. AB - A highly sensitive, rapid assay method has been developed and validated for the simultaneous estimation of tolmetin (TMT) and MED5 in human plasma with liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. A simple solid-phase extraction process was used to extract TMT and MED5 along with mycophenolic acid (internal standard, IS) from human plasma. Chromatographic separation was achieved with 0.2% formic acid acetonitrile (25:75, v/v) at a flow rate of 0.50 mL/min on an X-Terra RP(18) column with a total run time of 2.5 min. The MS/MS ion transitions monitored were 258.1 -> 119.0 for TMT, 315.1 -> 119.0 for MED5 and 321.2 -> 207.0 for IS. Method validation and clinical sample analysis were performed as per FDA guidelines and the results met the acceptance criteria. The lower limit of quantitation achieved was 20 ng/mL and the linearity was observed from 20 to 2000 ng/mL, for both the anlaytes. The intra-day and inter-day precisions were in the range 3.27-4.50 and 5.32-8.18%, respectively for TMT and 4.27-5.68 and 5.32-8.85%, respectively for MED5. This novel method has been applied to a clinical pharmacokinetic study. PMID- 20853465 TI - Development and validation of a highly sensitive LC-MS/MS method for simultaneous quantitation of nortriptyline and 10-hydroxynortriptyline in human plasma: application to a human pharmacokinetic study. AB - A highly sensitive and specific LC-MS/MS method has been developed for simultaneous estimation of nortriptyline (NTP) and 10-hydroxynortriptyline (OH NTP) in human plasma (250 uL) using carbamazepine as an internal standard (IS). LC-MS/MS was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. A simple liquid-liquid extraction process was used to extract NTP, OH-NTP and IS from human plasma. The total run time was 2.5 min and the elution of NTP, OH-NTP and IS occurred at 1.44, 1.28 and 1.39 min, respectively; this was achieved with a mobile phase consisting of 20 mm ammonium acetate : acetonitrile (20:80, v/v) at a flow rate of 0.50 mL/min on a HyPURITY C(18) column. The developed method was validated in human plasma with a lower limit of quantitation of 1.09 ng/mL for both NTP and OH-NTP. A linear response function was established for the range of concentrations 1.09-30.0 ng/mL (r > 0.998) for both NTP and OH-NTP. The intra- and inter-day precision values for NTP and OH-NTP met the acceptance as per FDA guidelines. NTP and OH-NTP were stable in a battery of stability studies, i.e. bench-top, auto-sampler and freeze-thaw cycles. The developed assay was applied to a pharmacokinetic study in humans. PMID- 20853466 TI - Quantitative HPLC method and pharmacokinetic studies of ergosta-4,6,8(14),22 tetraen-3-one, a natural product with diuretic activity from Polyporus umbellatus. AB - A simple and specific HPLC method with dual wavelength UV detection for the determination of ergosta-4,6,8(14),22-tetraen-3-one (ergone) in rat plasma was developed and proved to be efficient. The method used ergosterol as internal standard (IS). Following a single-step protein precipitation, the analyte and IS were separated on an Inertsil ODS-3 column with a mobile phase containing methanol-water (99:1, v/v) at a flow rate of 1 mL/min. The analytes were detected by using UV detection at wavelength of 350 (ergone) and 283 (IS) nm, respectively. The calibration curve was linear over the range of 0.1-2.0 ug/mL and the lower limit of quantification was 0.1 ug/mL. The intra-day and inter-day precision studies showed good reproducibility with RSD less than 8.5%. The intra day and inter-day accuracy ranged from 95.6 to 104%. Mean extraction recovery was above 95% at the low, medium and high concentrations. The present HPLC-UV method was simple and reliable. The method described herein had been successfully applied for the pharmacokinetic studies in male SD rats after administration of 20 mg/kg dose of solution of ergone. PMID- 20853467 TI - Chiral separation of the beta2-sympathomimetic fenoterol by HPLC and capillary zone electrophoresis for pharmacokinetic studies. AB - The development of methods for the separation of the enantiomers of fenoterol by chiral HPLC and capillary zone electrophoresis (CZE) is described. For the HPLC separation precolumn fluorescence derivatization with naphthyl isocyanate was applied. The resulting urea derivatives were resolved on a cellulose tris(3,5 dimethylphenylcarbamate)-coated silica gel column employing a column switching procedure. Detection was carried out fluorimetrically with a detection limit in the low ng/mL range. The method was adapted to the determination of fenoterol enantiomers in rat heart perfusates using liquid-liquid extraction. As an alternative a CE method was used for the direct separation of fenoterol enantiomers comparing different cyclodextrin derivatives as chiral selectors. PMID- 20853468 TI - Caffeine and paraxanthine HPLC assay for CYP1A2 phenotype assessment using saliva and plasma. AB - Caffeine has been extensively used as a probe to measure CYP1A2 activity in humans with caffeine clearance or the paraxanthine (major metabolite of caffeine) to caffeine concentration ratio being regarded as the preferred metric. A simple reverse-phased C(18) HPLC assay using ethyl acetate liquid-liquid extraction was developed to quantitate caffeine and paraxanthine concentrations in saliva and plasma. The mobile phase consisted of acetonitrile-acetic acid-H(2)O (100:1:899) and analytes were quantitated with UV detection at 280 nm. The extraction recovery for paraxanthine and caffeine was approximately 70% in both saliva and plasma. The assay was linear over the concentration ranges 0.05-2.50 and 0.05 5.00 ug/mL, for paraxanthine and caffeine, respectively, in saliva. In plasma the assay was linear over the ranges 0.025-2.50 and 0.025-5.00 ug/mL for paraxanthine and caffeine, respectively. Intra- and inter-assay precision and accuracy were less than 15%. Detection limits were 0.015 ug/mL for paraxanthine and caffeine in saliva, while it was 0.005 ug/mL for paraxanthine and caffeine in plasma. Utility was established in samples collected from two healthy volunteers who abstained from caffeine for 24 h and received a single 100 mg oral dose of caffeine. The assay developed is a robust, simple and precise technique to measure caffeine and paraxanthine in saliva and plasma of healthy volunteers after a single oral dose of caffeine. PMID- 20853469 TI - Thigh muscle strength, functional capacity, and self-reported function in patients at high risk of knee osteoarthritis compared with controls. AB - OBJECTIVE: Reduced muscle strength is suggested as a risk factor for knee osteoarthritis (OA). Meniscectomy patients have an increased risk of developing knee OA. The aim of this study was to identify reductions in different aspects of muscle strength as well as objectively measured and self-reported lower extremity function in middle-aged patients who had undergone a meniscectomy compared with controls. METHODS: Thirty-one patients who had undergone surgery in 2006 and 2007 (mean +/- SD age 46 +/- 6 years, mean +/- SD body mass index [BMI] 26 +/- 4 kg/m(2), and mean +/- SD postsurgery 21 +/- 6 months) and 31 population-based controls (mean +/- SD age 46 +/- 6 years and mean +/- SD BMI 26 +/- 4 kg/m(2)) were examined for maximal muscle strength and rapid force capacity, distance achieved during the one-leg hop test, and the maximum number of knee bends performed in 30 seconds. The Knee Injury and Osteoarthritis Outcome Score (KOOS) was used to determine self-reported outcomes. RESULTS: No differences were detected in any muscle strength variables between the operated and nonoperated leg (mean +/- SD quadriceps maximum voluntary contraction of 2.80 +/- 0.10 for the operated leg and 2.88 +/- 0.10 for the nonoperated leg), between patients and controls (mean +/- SD torque of 2.70 +/- 0.09 Nm * kg(-1) for the controls; P = 0.26 for main effect leg), or in objectively measured function (P >= 0.27). Patients reported 10-26 points worse KOOS scores in all 5 subscales (P < 0.001). CONCLUSION: Thigh muscle strength is not impaired in middle-aged adults 2 years after resection of a degenerative tear. Our findings indicate that factors other than muscle strength are responsible for the perceived functional limitations and suggest that training to improve strength alone may not be sufficient to improve self-reported function in patients at high risk of knee OA. PMID- 20853470 TI - Musculoskeletal pain and incident disability in community-dwelling older adults. AB - OBJECTIVE: To test the hypothesis that the number of areas of musculoskeletal pain reported is related to incident disability. METHODS: Subjects included 898 older persons from the Rush Memory and Aging Project without dementia, stroke, or Parkinson's disease at baseline. All participants underwent detailed baseline evaluation of self-reported pain in the neck or back, hands, hips, knees, or feet, as well as annual self-reported assessments of instrumental activities of daily living (IADLs), basic activities of daily living (ADLs), and mobility disability. Mobility disability was also assessed using a performance-based measure. RESULTS: The average followup was 5.6 years. Using a series of proportional hazards models that controlled for age, sex, and education, the risk of IADL disability increased by ~10% for each additional painful area reported (hazard ratio [HR] 1.10, 95% confidence interval [95% CI] 1.01-1.20) and the risk of ADL disability increased by ~20% for each additional painful area (HR 1.20, 95% CI 1.11-1.31). The association with self-report mobility disability did not reach significance (HR 1.09, 95% CI 0.99-1.20). However, the risk of mobility disability based on gait speed performance increased by ~13% for each additional painful area (HR 1.13, 95% CI 1.04-1.22). These associations did not vary by age, sex, or education and were unchanged after controlling for several potential confounding variables including body mass index, physical activity, cognition, depressive symptoms, vascular risk factors, and vascular diseases. CONCLUSION: Among nondisabled community-dwelling older adults, the risk of disability increases with the number of areas reported with musculoskeletal pain. PMID- 20853472 TI - Cultural consonance and body morphology: estimates with longitudinal data from an Amazonian society. AB - Researchers have hypothesized that the degree to which an individual's actual behavior approximates the culturally valued lifestyle encoded in the dominant cultural model has consequences for physical and mental health. We contribute to this line of research by analyzing data from a longitudinal study composed of five annual surveys (2002-2006 inclusive) from 791 adults in one society of foragers-farmers in the Bolivian Amazon, the Tsimane'. We estimate the association between a standard measure of individual achievement of the cultural model, cultural consonance, and three indicators of body morphology. Drawing on research suggesting that in societies in the early stages of economic development an increase in socioeconomic status is associated with an increase in mean body mass, we expect to find a positive association between cultural consonance and three anthropometric measures. We found the expected positive association between cultural consonance and anthropometric measures-especially for men-only when using ordinary least square (OLS) regression models, but not when using fixed effects regression models. The real magnitude of the association was low. The comparison of estimates from OLS and fixed-effect regression models suggests that previous findings on the effects of cultural consonance on body morphology using cross-sectional data should be read with caution because the association might be largely explained by fixed characteristics of individuals not accounted in OLS models. PMID- 20853471 TI - Prevalence of cam-type deformity on hip magnetic resonance imaging in young males: a cross-sectional study. AB - OBJECTIVE: To determine the prevalence of cam-type deformities on hip magnetic resonance imaging (MRI) in young males. METHODS: This was a population-based cross-sectional study in young asymptomatic male individuals who underwent clinical examination and completed a self-report questionnaire. A random sample of participants was invited for MRI of the hip. We graded the maximal offset at the femoral head-neck junction on radial sequences using grades from 0 to 3, where 0 = normal, 1 = possible, 2 = definite, and 3 = severe deformity. The prespecified main analyses were based on definite cam-type deformity grades 2 or 3. We estimated the prevalence of the cam-type deformity adjusted for the sampling process overall and according to the extent of internal rotation. Then we determined the location of the deformity on radial MRI sequences. RESULTS: A total of 1,080 subjects were included in the study and 244 asymptomatic males with a mean age of 19.9 years attended MRI. Sixty-seven definite cam-type deformities were detected. The adjusted overall prevalence was 24% (95% confidence interval [95% CI] 19-30%). The prevalence increased with decreasing internal rotation (P < 0.001 for trend). Among those with a clinically decreased internal rotation of < 30 degrees , the estimated prevalence was 48% (95% CI 37 59%). Sixty-one of 67 cam-type deformities were located in an anterosuperior position. CONCLUSION: Cam-type deformities can be found on MRI in every fourth young asymptomatic male individual and in every second male with decreased internal rotation. The majority of deformities are located in an anterosuperior position. PMID- 20853473 TI - Diet traditions in wild orangutans. AB - This study explores diet differences between two populations of wild Bornean orangutans (Pongo pygmaeus wurmbii) to assess whether a signal of social learning can be detected in the observed patterns. The populations live in close proximity and in similar habitats but are separated by a river barrier that is impassable to orangutans in the study region. We found a 60% between-site difference in diet at the level of plant food items (plant species-organ combinations). We also found that individuals at the same site were more likely to eat the same food items than expected by chance. These results suggest the presence of diet (food selection) traditions. Detailed tests of three predictions of three models of diet acquisition allowed us to reject a model based on exclusive social learning but could not clearly distinguish between the remaining two models: one positing individual exploration and learning of food item selection and the other one positing preferential social learning followed by individual fine tuning. We know that maturing orangutans acquire their initial diet through social learning and then supplement it by years of low-level, individual sampling. We, therefore, conclude that the preferential social learning model produces the best fit to the geographic patterns observed in this study. However, the very same taxa that socially acquire their diets as infants and show evidence for innovation-based traditions in the wild paradoxically may have diets that are not easily distinguished from those acquired exclusively through individual learning. PMID- 20853474 TI - Monkeys and apes: are their cognitive skills really so different? AB - Differences in cognitive skills across taxa, and between monkeys and apes in particular, have been explained by different hypotheses, although these often are not supported by systematic interspecific comparisons. Here, we directly compared the cognitive performance of the four great apes and three monkey species (spider monkeys, capuchin monkeys, and long-tailed macaques), differing in their phylogenetic-relatedness and socioecology. We tested subjects on their ability to remember object locations (memory task), track object displacements (transposition task), and obtain out-of-reach rewards (support task). Our results showed no support for an overall clear-cut distinction in cognitive skills between monkeys and apes as species performance varied substantially across tasks. Although we found differences in performance at tracking object displacements between monkeys and apes, interspecific differences in the other two tasks were better explained in terms of differential socioecology, especially differential levels of fission-fusion dynamics. A cluster analysis using mean scores of each condition of the three tasks for each species suggested that the only dichotomy might be between members of the genus Pan and the rest of the tested species. These findings evidence the importance of using multiple tasks across multiple species in a comparative perspective to test different explanations for the enhancement of specific cognitive skills. PMID- 20853475 TI - Articular to diaphyseal proportions of human and great ape metatarsals. AB - This study proposes a new way to use metatarsals to identify locomotor behavior of fossil hominins. Metatarsal head articular dimensions and diaphyseal strength in a sample of chimpanzees, gorillas, orangutans, and humans (n = 76) are used to explore the relationships of these parameters with different locomotor modes. Results show that ratios between metatarsal head articular proportions and diaphyseal strength of the hallucal and fifth metatarsal discriminate among extant great apes and humans based on their different locomotor modes. In particular, the hallucal and fifth metatarsal characteristics of humans are functionally related to the different ranges of motion and load patterns during stance phase in the forefoot of humans in bipedal locomotion. This method may be applicable to isolated fossil hominin metatarsals to provide new information relevant to debates regarding the evolution of human bipedal locomotion. The second to fourth metatarsals are not useful in distinguishing among hominoids. Further studies should concentrate on measuring other important qualitative and quantitative differences in the shape of the metatarsal head of hominoids that are not reflected in simple geometric reconstructions of the articulation, and gathering more forefoot kinematic data on great apes to better understand differences in range of motion and loading patterns of the metatarsals. PMID- 20853476 TI - Talar morphology, phylogenetic affinities, and locomotor adaptation of a large bodied amphipithecid primate from the late middle eocene of Myanmar. AB - A well-preserved fossil talus [National Museum of Myanmar Primates (NMMP) 82] of a large-bodied primate is described from the late middle Eocene Pondaung Formation of central Myanmar. The specimen was collected at Thandaung Kyitchaung, a well-known amphipithecid primate-bearing locality near the village of Mogaung. NMMP 82 adds to a meager but growing sample of postcranial remains documenting the large-bodied primates of the Pondaung Formation. This new talus exhibits a suite of features that resemble conditions found in living and fossil haplorhine primates, notably anthropoids. As such, the phylogenetic signal deriving from the morphology of NMMP 82 conflicts with that provided by NMMP 20, a partial skeleton (including a fragmentary calcaneus) of a second large-bodied Pondaung primate showing undoubted adapiform affinities. Analysis subtalar joint compatibility in a hypothetical NMMP 82/NMMP 20 combination (talus/calcaneus) reveals a substantial degree of functional mismatch between these two tarsal bones. The functional incongruence in subtalar joint morphology between NMMP 20 and NMMP 82 is consistent with the seemingly divergent phylogenetic affinities of these specimens, indicating that two higher level taxa of relatively large-bodied primates are documented in the Pondaung Formation. On the basis of its size and morphology, we refer the NMMP 82 talus to the large-bodied amphipithecid Pondaungia. The occurrence of anthropoid-like tali in the Pondaung Formation obviates the need to invoke homoplasy to explain the shared, derived dental characters that are common to amphipithecids and undoubted anthropoids. Functionally, the NMMP 82 talus appears to have pertained to a primate that is engaged in active quadrupedalism in an arboreal environment along broad and subhorizontal branches. The primate taxon represented by NMMP 82 was capable of climbing and leaping, although it was not particularly specialized for either of these activities. PMID- 20853477 TI - The phylogenetic affinities of the Pondaung tali. AB - The phylogenetic affinities of the primates of the late middle Eocene Pondaung Formation of Myanmar have long been disputed. The discovery of the NMMP 39 talus (Marivaux et al.: Proc Natl Acad Sci USA 100 (2003) 13173-13178) provided the first clear evidence from the postcranium that a relatively large-bodied haplorhine primate is represented in the Pondaung fauna. Another talus (NMMP 82; Marivaux et al., 2010). Talar morphology, phylogenetic affinities and locomotor adaptation of a large-bodied amphipithecid primate from the late middle Eocene of Myanmar, Am J Phys Anthropol DOI: 10.1002/ajpa.21307) has been recently recovered which also pertains to Haplorhini. The metric and nonmetric features supporting the hypothesis of anthropoid affinities for NMMP 39 have been criticized by Gunnell and Ciochon (Gunnell GF, Ciochon RL. 2008. Revisiting primate postcrania from the Pondaung Formation of Myanmar. In: Fleagle JG, Gilbert CC, editors. Elwyn Simons: a search for origins. New York: Springer. p 211-228). Their analysis, however, was based on a very limited choice of variables, taxa, and individuals. Based on an extended sample, we are able to produce both principal components and discriminant functions that yield a rather clear separation of extant haplorhine and strepsirhine tali. Both principal components and discriminant function scores of the Pondaung tali fall with those of haplorhine primates. In addition, the Pondaung tali lack all the derived nonmetric features characteristic of strepsirhine primates, but exhibit all the features characteristic of haplorhine primates. We dispute the features Gunnell and Ciochon (2008) claim are uniquely shared by the Pondaung tali and adapiforms. Their rejection of the phylogenetic significance of the features shared by these tali and haplorhines is unwarranted by the evidence. Based on both metric and nonmetric features, the Pondaung tali are structurally most similar to the tali of haplorhines, particularly anthropoids. PMID- 20853478 TI - Diet and mobility in Early Medieval Bavaria: a study of carbon and nitrogen stable isotopes. AB - This study investigates patterns of mobility in Early Medieval Bavaria through a combined study of diet and associated burial practice. Carbon and nitrogen isotope ratios were analyzed in human bone samples from the Late Roman cemetery of Klettham and from the Early Medieval cemeteries of Altenerding and Straubing Bajuwarenstrasse. For dietary comparison, samples of faunal bone from one Late Roman and three Early Medieval settlement sites were also analyzed. The results indicate that the average diet was in keeping with a landlocked environment and fairly limited availability of freshwater or marine resources. The diet appears not to have changed significantly from the Late Roman to the Early Medieval period. However, in the population of Altenerding, there were significant differences in the diet of men and women, supporting a hypothesis of greater mobility among women. Furthermore, the isotopic evidence from dietary outliers is supported by "foreign" grave goods and practices, such as artificial skull modification. These results reveal the potential of carbon and nitrogen isotope analysis for questions regarding migration and mobility. PMID- 20853479 TI - A comparative analysis of internal cranial anatomy in the hylobatidae. AB - Craniometric studies on the hylobatids using external metrics (Creel and Preuschoft, 1976, 1984) sorted hylobatid populations into primary species groupings which are in accordance with the four currently recognized generic level groupings. The goal of the current study was to assess the relative orientations of the orbits, palate, and basioccipital clivus among the hylobatid genera in an effort to further clarify whether the lesser apes differ significantly in these internal cranial features and how that variation patterns across the groups. Nine angular variables quantifying orbital, palatal, and basioccipital clivus orientations were measured on lateral view radiographs of adults representing three of the four hylobatid genera: Hylobates; Nomascus; and, Symphalangus. The interspecific adult hylobatid means for the angular variables were analyzed using t-test contrasts. The total sample was further subjected to discriminant function analysis (DFA) to test for the ability of craniofacial angular variables to distinguish the hylobatid genera from one another. The three hylobatid genera displayed significant morphological differentiation in orbital, palatal, and posterior skull base orientations. Normal, jackknifed, and cross validation DFA procedures correctly identified the hylobatids 50-100% of the time. The observed morphological patterns generally mapped onto the findings of earlier external craniometric hylobatid studies and suggest concordance between specific internal and external cranial features. This article is the first comprehensive study of variation in internal cranial anatomy of the Hylobatidae and includes the first published craniofacial angular data for Nomascus. PMID- 20853480 TI - Activity-induced dental modification in holocene siberian hunter-fisher gatherers. AB - The use of teeth as tools provides clues to past subsistence patterns and cultural practices. Five Holocene period hunter-fisher-gatherer mortuary sites from the south-western region of Lake Baikal, Siberia, Russian Federation, are observed for activity-induced dental modification (AIDM) to further characterize their adaptive regimes. Grooves on the occlusal surfaces of teeth are observed in 25 out of 123 individuals (20.3%) and were most likely produced during the processing of fibers from plants and animals, for making items such as nets and cordage. Regional variation in the frequency of individuals with occlusal grooves is found in riverine versus lakeshore sites. This variation suggests that production of material culture items differed, perhaps in relation to different fishing practices. There is also variation in the distribution of grooves by sex: grooves are found predominately in females, except at the Late Neolithic-Bronze Age river site of Ust'-Ida I where grooves are found exclusively in males. Occlusal grooves were cast using polyvinylsiloxane and maxillary canine impressions were examined by scanning electron microscopy (SEM) to determine striation patterns. Variation in striae orientation suggests that a variety of activities, and/or different manufacturing techniques, were involved in groove production. Overall, the variability in occlusal groove frequency, sex and regional distribution, and microscopic striae patterns, points to the multiplicity of activities and ways in which people used their mouths and teeth in cultural activities. PMID- 20853481 TI - Determination of sex from the hyoid bone. AB - This article explores size differences related to sex in the hyoid bones from the Robert J. Terry Anatomical Collection. A series of measurements were taken from 398 hyoids, both fused and unfused. The inclusion of unfused hyoids in the study provides the opportunity to investigate previously unknown size differences between sexes as well as to determine their utility in determining sex. Two-way ANOVA was used to explore differences in hyoid size as related to ancestry and sex. Discriminant function analysis was employed to test the ability of the hyoids to be classified by sex. Six discriminant function equations ranging in accuracy from 82% to 85% are provided, each of which is more accurate than many of the discriminant functions developed in past hyoid research, are simple to use, and can be used to estimate the sex of a hyoid regardless of its state of fusion. In addition to providing further information about the morphological form of the hyoid, these analyses provide a method that can be easily employed to assess sex of the individual from the hyoid bone. PMID- 20853483 TI - Brief communication: Identification reassessment of the isolated tooth Krapina D58 through occlusal fingerprint analysis. AB - High variability in the dentition of Homo can create uncertainties in the correct identification of isolated teeth. For instance, standard tooth identification criteria cannot determine with absolute certainty if an isolated tooth is a second or third maxillary molar. In this contribution, using occlusal fingerprint analysis, we reassess the identification of Krapina D58 (Homo neanderthalensis), which is catalogued as a third maxillary molar. We have hypothesized that the presence/absence of the distal occlusal wear facets can be used to differentiate second from third maxillary molars. The results obtained confirm our hypothesis, showing a significant difference between second and third maxillary molars. In particular we note the complete absence of Facets 7 and 10 in all third molars included in this analysis. The presence of these facets in Krapina D58 eliminates the possibility that it is a third maxillary molar. Consequently it should be reclassified as a second molar. Although this method is limited by the degree of dental wear (i.e., unworn teeth cannot be analyzed) and to individual molars in full occlusion, it can be used for tooth identification when other common criteria are not sufficient to discriminate between second and third maxillary molars. PMID- 20853484 TI - Letter to the editor: Canine displays are not aggressive signals: a comment on Plavcan and Ruff (2008). PMID- 20853482 TI - Sex differentials in frailty in medieval England. AB - In most modern populations, there are sex differentials in morbidity and mortality that favor women. This study addresses whether such female advantages existed to any appreciable degree in medieval Europe. The analyses presented here examine whether men and women with osteological stress markers faced the same risks of death in medieval London. The sample used for this study comes from the East Smithfield Black Death cemetery in London. The benefit of using this cemetery is that most, if not all, individuals interred in East Smithfield died from the same cause within a very short period of time. This allows for the analysis of the differences between men and women in the risks of mortality associated with osteological stress markers without the potential confounding effects of different causes of death. A sample of 299 adults (173 males, 126 females) from the East Smithfield cemetery was analyzed. The results indicate that the excess mortality associated with several osteological stress markers was higher for men than for women. This suggests that in this medieval population, previous physiological stress increased the risk of death for men during the Black Death to a greater extent than was true for women. Alternatively, the results might indicate that the Black Death discriminated less strongly between women with and without pre-existing health conditions than was true for men. These results are examined in light of previous analyses of East Smithfield and what is known about diet and sexually mediated access to resources in medieval England. PMID- 20853486 TI - The Ruggero Ceppellini advanced School of Immunology 2009. PMID- 20853490 TI - Some active areas of DC research and their medical potential. AB - This Viewpoint series provides authoritative and detailed outlines of exciting areas of DC research. Some of the subjects that frequently come up include development of DC; distribution of DC in lymphoid and non-lymphoid tissues such as skin, intestine and lung; different forms or subsets of DC; and the role of DC in initiating tolerance and immunity. In this Preface, I will introduce the Viewpoints and consider some future challenges as well as the medical relevance of DC research. PMID- 20853491 TI - From skin dendritic cells to a simplified classification of human and mouse dendritic cell subsets. AB - Recent studies have identified several DC subsets within the mouse skin and showed that functional specialization exists among them. This Viewpoint summarizes recent data on functional specialization of skin DC subsets and integrates this knowledge into a unifying DC classification that emphasizes the similarities between the DC subsets found in both lymphoid and nonlymphoid tissues of several mammalian species. PMID- 20853493 TI - Development and homeostasis of dendritic cells. AB - DC are specialized antigen-presenting cells that serve as essential mediators of immunity and tolerance. DC's functional versatility is enabled in part by the various DC subsets with heterogeneous cell surface markers and anatomic locations. Here, we review the development and homeostasis of DC found in lymphoid and nonlymphoid tissues. PMID- 20853492 TI - Accumulation of plasmacytoid DC: Roles in disease pathogenesis and targets for immunotherapy. AB - Plasmacytoid DC (pDC) secrete type I IFN in response to viruses and RNA/DNA/immunocomplexes. Type I IFN confer resistance to viral infections and promote innate and adaptive immune responses. pDC also produce cytokines and chemokines that influence recruitment and function of T cells and differentiation of B cells. Thus, pDC have been implicated both in protective immune responses and in induction of tolerance. In this Viewpoint, we discuss how the recruitment and accumulation of pDC may impact pathogenesis of several diseases and how pDC can be targeted for therapeutic interventions. PMID- 20853494 TI - The in situ dynamics of dendritic cell interactions. AB - DC regulate T-cell function by promoting either tolerance or activation, and in the latter case, by directing the quality of the ensuing response. New imaging tools now permit direct visualization of the relevant DC-T-cell interactions in vivo and have provided a new perspective on the dynamics of these crucial cellular contacts. In this Viewpoint, we discuss the insights generated by direct visualization of DC-T-cell interactions and the controversies/unanswered questions that need to be addressed in future work. PMID- 20853495 TI - The puzzle of intestinal lamina propria dendritic cells and macrophages. AB - A specialized network of immune cells is positioned directly in the mucosa of the intestinal tract. In this Viewpoint, we discuss the nature and function of DC and macrophages occupying the intestinal lamina propria of mice. DC and macrophages share phenotypic traits and functional plasticity, properties that preclude simple classification of the two cell types. Nevertheless, the information available appears to have reached "critical mass" to allow for a clear demarcation between intestinal macrophages and DC. PMID- 20853496 TI - Origin and functional specializations of DC subsets in the lung. AB - Lung DC bridge innate and adaptive immunity, and depending on the context, induce Th1, Th2 or Th17 response, to optimally clear infections. Conversely, lung DC can also prevent overt and harmful immune responses to harmless inhaled antigens via induction of Treg cells or via induction of neutralizing mucosal IgA antibodies. Here, we propose that these functions are not the result of a single population of DC, and instead, subsets of DC perform specialized functions. PMID- 20853497 TI - Dendritic cells in tolerance induction for the treatment of autoimmune diseases. AB - Autoimmune diseases are characterized by the loss of tolerance toward self antigens and the induction of destructive immune responses leading to tissue damage. Most patients with autoimmune diseases are treated with immunosuppressive drugs that suppress the immune response in a non-specific fashion, which is inevitably accompanied by several side effects. Antigen-specific immunomodulation and patient-tailored therapies are likely to solve these issues and to elicit long-term protection against disease flares. This Viewpoint analyzes the potential use of DC for induction of antigen-specific tolerance in autoimmune disease settings. PMID- 20853498 TI - Dendritic cells in cancer immunotherapy. AB - DC initiate and regulate T-cell immunity and are thus the key to optimization of all types of vaccines. Insights into DC biology offer many opportunities to enhance immunogenicity. In this Viewpoint, I discuss some recent developments and findings that are of immediate relevance for the clinical development of cancer vaccines. In addition, I emphasize my personal view that we should explore the potential of adoptively transferred DC (i.e. DC vaccination) as cancer vaccines by performing two-armed trials that address critical variables and by delivering antigens via mRNA-transfected DC. PMID- 20853499 TI - Characterizing follicular dendritic cells: A progress report. AB - In 1965, Mitchell and Abbot (Mitchell, J. and Abbot A, Nature 1965. 30: 500-502) discovered peculiar cells with filiform processes, which were capable of capturing and retaining antigens within secondary lymphoid organs. Yet half a century since the first description of follicular dendritic cells (FDC), their function and their histogenesis remain largely mysterious. FDC are thought to help with organization of the lymphoid follicles, to facilitate the germinal center reaction by presenting antigen to B cells, and to legislate the engulfment of apoptotic bodies, but it has proved difficult to stringently verify any of these functions. One reason for such slow progress is a dearth of markers specific to FDC and their precursors, which limits our ability to isolate, target, and follow FDC. Here we review the current state of FDC science with specific reference to a study in this issue of the European Journal of Immunology and its efforts in discovering new FDC markers. PMID- 20853500 TI - Polyfunctional T cells in human tuberculosis. AB - Studies of chronic viral infections have highlighted the phenotypic and functional heterogeneity of antigen-specific T cells and suggested that polyfunctional T cells that secrete multiple cytokines and are able to proliferate on encounter with antigen are more likely than single cytokine secretors to represent correlates of protective immunity. These findings have prompted the evaluation of such T-cell responses in chronic bacterial infections, such as tuberculosis (TB). A number of studies in humans suggested that polyfunctional T cells may indeed be involved in mediating protection in TB; however, studies that question these findings are also emerging, including a study published in this issue of the European Journal of Immunology. These differing findings highlight the difficulties of studying human immunity to TB and the need for polyfunctional T cells to be evaluated in longitudinal studies as opposed to case-control analyses. PMID- 20853506 TI - Astroglial structures in the zebrafish brain. AB - To understand components shaping the neuronal environment we studied the astroglial cells in the zebrafish brain using immunocytochemistry for structural and junctional markers, electron microscopy including freeze fracturing, and probed for the water channel protein aquaporin-4. Glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) showed largely overlapping immunoreactivity: GFAP in the main glial processes and GS in main processes and smaller branches. Claudin-3 immunoreactivity was spread in astroglial cells along their major processes. The ventricular lining was immunoreactive for the tight-junction associated protein ZO-1, in the telencephalon located on the dorsal, lateral, and medial surface due to the everting morphogenesis. In the tectum, subpial glial endfeet were also positive for ZO-1. Correspondingly, electron microscopy revealed junctional complexes between subpial glial endfeet. However, in freeze fracture analysis tight junctional strands were not found between astroglial membranes, either in the optic tectum or in the telencephalon. Occurrence of aquaporin-4, the major astrocytic water channel in mammals, was demonstrated by polymerase chain reaction (PCR) analysis and immunocytochemistry in tectum and telencephalon. Localization of aquaporin-4 was not polarized but distributed along the entire radial extent of the cell. Interestingly, their membranes were devoid of the orthogonal arrays of particles formed by aquaporin-4 in mammals. Finally, we investigated astroglial cells in proliferative areas. Brain lipid basic protein, a marker of early glial differentiation but not GS, were present in some proliferation zones, whereas cells lining the ventricle were positive for both markers. Thus, astroglial cells in the zebrafish differ in many aspects from mammalian astrocytes. PMID- 20853507 TI - Asymmetric distribution of cadherin 23 and protocadherin 15 in the kinocilial links of avian sensory hair cells. AB - Cadherin 23 and protocadherin 15 are components of tip links, fine filaments that interlink the stereocilia of hair cells and are believed to gate the hair cell's mechanotransducer channels. Tip links are aligned along the hair bundle's axis of mechanosensitivity, stretching obliquely from the top of one stereocilium to the side of an adjacent, taller stereocilium. In guinea pig auditory hair cells, tip links are polarized with cadherin 23 at the upper end and protocadherin 15 at the lower end, where the transducer channel is located. Double immunogold labeling of avian hair cells was used to study the distribution of these two proteins in kinocilial links, a link type that attaches the tallest stereocilia of the hair bundle to the kinocilium. In the kinocilial links of vestibular hair bundles, cadherin 23 localizes to the stereocilium and protocadherin 15 to the kinocilium. The two cadherins are therefore asymmetrically distributed within the kinocilial links but of a polarity that is, within those links that are aligned along the hair bundle's axis of sensitivity, reversed relative to that of tip links. Conventional transmission electron microscopy of hair bundles fixed in the presence of tannic acid reveals a distinct density in the 120-130 nm long kinocilial links that is located 35-40 nm from the kinociliary membrane. The location of this density is consistent with it being the site at which interactions occur in an in trans configuration between the opposing N-termini of homodimeric forms of cadherin 23 and protocadherin 15. PMID- 20853508 TI - Immunolocalization of the voltage-gated potassium channel Kv2.2 in GABAergic neurons in the basal forebrain of rats and mice. AB - The Kv2 voltage-gated potassium channels, Kv2.1 and Kv2.2, are important regulators of neuronal excitability in mammalian brain. It has been shown that Kv2.1 channels are expressed in virtually all neurons in the brain. However, the cellular localization of Kv2.2 has not been fully elucidated. In this article we report that Kv2.2 is highly expressed in a subset of neurons in the magnocellular preoptic nucleus (MCPO) and the horizontal limb of the diagonal band of Broca (HDB) of the basal forebrain complex, which are areas highly implicated in the regulation of cortical activity and the sleep/wake cycle. It has been shown that MCPO and HDB contain distinct populations of neurons that differ in their neurochemicals, cholinergic, glutamatergic, and gamma-aminobutyric acid (GABA)ergic neurons. Using specific immunolabeling and knockin mice in which green fluorescent protein (GFP) is expressed in GABAergic neurons, we found that Kv2.2 is abundantly expressed in a large subpopulation of the GABAergic neurons in the MCPO and HDB. These data offer Kv2.2 as a molecular target to study the role of the specific subpopulation of basal forebrain GABAergic neurons. PMID- 20853509 TI - Immunogold electron microscopic evidence of differential regulation of GluN1, GluN2A, and GluN2B, NMDA-type glutamate receptor subunits in rat hippocampal CA1 synapses during benzodiazepine withdrawal. AB - Benzodiazepine withdrawal-anxiety is associated with enhanced alpha-amino-3 hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)-mediated glutamatergic transmission in rat hippocampal CA1 synapses due to enhanced synaptic insertion and phosphorylation of GluA1 homomers. Interestingly, attenuation of withdrawal-anxiety is associated with a reduction in N-methyl-D aspartate receptor (NMDAR)-mediated currents and subunit expression, secondary to AMPA receptor potentiation. Therefore, in this study ultrastructural evidence for possible reductions in NMDAR GluN1, GluN2A, and GluN2B subunits was sought at CA1 stratum radiatum synapses in proximal dendrites using postembedding immunogold labeling of tissues from rats withdrawn for 2 days from 1-week daily oral administration of the benzodiazepine, flurazepam (FZP). GluN1-immunogold density and the percentage of immunopositive synapses were significantly decreased in tissues from FZP-withdrawn rats. Similar decreases were observed for GluN2B subunits; however, the relative lateral distribution of GluN2B-immunolabeling within the postsynaptic density did not change after BZ withdrawal. In contrast to the GluN2B subunit, the percentage of synapses labeled with the GluN2A subunit antibody and the density of immunogold labeling for this subunit was unchanged. The spatial localization of immunogold particles associated with each NMDAR subunit was consistent with a predominantly postsynaptic localization. The data therefore provide direct evidence for reduced synaptic GluN1/GluN2B receptors and preservation of GluN1/GluN2A receptors in the CA1 stratum radiatum region during BZ withdrawal. Based on collective findings in this benzodiazepine withdrawal anxiety model, we propose a functional model illustrating the changes in glutamate receptor populations at excitatory synapses during benzodiazepine withdrawal. PMID- 20853511 TI - Topographic arrangement of the rotundo-entopallial projection in the pigeon (Columba livia). AB - The tectofugal pathway (retina--optic tectum--nucleus rotundus--entopallium) is a prominent route mediating visual discrimination in diurnal birds. Several lines of evidence have shown that at the tecto-rotundal stage this pathway is composed of multiple parallel channels. Anatomical studies show that the nucleus rotundus is composed of at least four subdivisions, according to differences in cytoarchitectonic, histochemical, and hodological properties. Each of these subdivisions is in receipt of a highly convergent, nontopographic tectal projection, originating from a distinct subset of tecto-rotundal neurons. Physiological studies show that neurons of different subdivisions respond specifically to different visual dimensions, such as color, luminance, two dimensional motion, and in-depth motion. At present it is less clear whether or to what extent this channel segregation is preserved at the telencephalic stage of the tectofugal pathway. The entopallium shows no obvious subdivisions or laminations. Nevertheless, tract-tracing experiments show that separate portions of the entopallium receive efferent projections from different rotundal subdivisions, in a way that maintains the rostrocaudal order of these subdivisions. In the present study we investigate in detail the topography of the rotundo-entopallial projection by means of anterograde and retrograde neuronal tracers. Our results confirm the zonal topography proposed by previous studies and indicate that each zone in the entopallium receives a direct and topographically organized projection from its corresponding rotundal subdivision. These results suggest that the spatial arrangement of the different rotundal functional modules is preserved at the entopallial level. PMID- 20853510 TI - Olfactory ensheathing glia express aquaporin 1. AB - Olfactory ensheathing glia (OEG) are distinct from other glia in their developmental origin, presence in both the peripheral and central nervous systems, and highly restricted location. OEG are present only in the olfactory lamina propria, olfactory nerve, and the outer two layers of the olfactory bulb, where they envelop bundles of olfactory sensory neuron axons in a manner distinct from myelination. Because of their unique properties and their association with the continually generated olfactory sensory neurons, OEG have attracted interest for their potential capacity to support axonal regeneration, for example, after spinal cord injury. However, study of the properties and function of OEG has been hampered by a paucity of neurochemical markers with which to identify and distinguish them definitively from other types of glia. Here we provide evidence through anatomical colocalization studies that OEG express the water channel aquaporin 1 (AQP1), both in vivo and in vitro. We propose that AQP1 expression represents an important distinguishing characteristic of OEG, which may impart unique function to these glia. PMID- 20853512 TI - Subcellular distribution of alpha1G subunit of T-type calcium channel in the mouse dorsal lateral geniculate nucleus. AB - T-type calcium channels play a pivotal role in regulating neural membrane excitability in the nervous system. However, the precise subcellular distributions of T-type channel subunits and their implication for membrane excitability are not well understood. Here we investigated the subcellular distribution of the alpha1G subunit of the calcium channel which is expressed highly in the mouse dorsal lateral geniculate nucleus (dLGN). Light microscopic analysis demonstrated that dLGN exhibits intense immunoperoxidase reactivity for the alpha1G subunit. Electron microscopic observation showed that the labeling was present in both the relay cells and interneurons and was found in the somatodendritic, but not axonal, domains of these cells. Most of the immunogold particles for the alpha1G subunit were either associated with the plasma membrane or the intracellular membranes. Reconstruction analysis of serial electron microscopic images revealed that the intensity of the intracellular labeling exhibited a gradient such that the labeling density was higher in the proximal dendrite and progressively decreased towards the distal dendrite. In contrast, the plasma membrane-associated particles were distributed with a uniform density over the somatodendritic surface of dLGN cells. The labeling density in the relay cell plasma membrane was about 3-fold higher than that of the interneurons. These results provide ultrastructural evidence for cell-type-specific expression levels and for uniform expression density of the alpha1G subunit over the plasma membrane of dLGN cells. PMID- 20853513 TI - Tuberoinfundibular peptide of 39 residues modulates the mouse hypothalamic pituitary-adrenal axis via paraventricular glutamatergic neurons. AB - Neurons in the subparafascicular area at the caudal border of the thalamus that contain the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39) densely innervate several hypothalamic areas, including the paraventricular nucleus (PVN). These areas contain a matching distribution of TIP39's receptor, the parathyroid hormone receptor 2 (PTH2R). Frequent PTH2R coexpression with a vesicular glutamate transporter (VGlut2) suggests that TIP39 could presynaptically regulate glutamate release. By using immunohistochemistry we found CRH-ir neurons surrounded by PTH2R-ir fibers and TIP39-ir axonal projections in the PVN area of the mouse brain. Labeling hypothalamic neuroendocrine neurons by peripheral injection of fluorogold in PTH2R-lacZ knock in mice showed that most PTH2Rs are on PVN and peri-PVN interneurons and not on neuroendocrine cells. Double fluorescent in situ hybridization revealed a high level of coexpression between PTH2R and VGlut2 mRNA by cells located in the PVN and nearby brain areas. Local TIP39 infusion (100 pmol) robustly increased pCREB ir in the PVN and adjacent perinuclear zone. It also increased plasma corticosterone and decreased plasma prolactin. These effects of TIP39 on pCREB ir, corticosterone, and prolactin were abolished by coinfusion of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and DL 2-amino-5-phosphonopentanoic acid (AP-5; 30 pmol each) and were absent in PTH2R knockout mice. Basal plasma corticosterone was slightly decreased in TIP39 knockout mice just before onset of their active phase. The present data indicate that the TIP39 ligand/PTH2 receptor system provides facilitatory regulation of the hypothalamic-pituitary-adrenal axis via hypothalamic glutamatergic neurons and that it may regulate other neuroendocrine systems by a similar mechanism. PMID- 20853514 TI - Neurochemical coding of enteric neurons in adult and embryonic zebrafish (Danio rerio). AB - Although the morphology and development of the zebrafish enteric nervous system have been extensively studied, the precise neurochemical coding of enteric neurons and their proportional enteric distribution are currently not known. By using immunohistochemistry, we determined the proportional expression and coexpression of neurochemical markers in the embryonic and adult zebrafish intestine. Tyrosine hydroxylase (TH), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) were observed only in nerve fibers, whereas other markers were also detected in neuronal cell bodies. Calretinin and calbindin had similar distributions. In embryos, all markers, except for choline acetyltransferase (ChAT) and TH, were present from 72 hours postfertilization. Nitrergic neurons, evenly distributed and remaining constant in time, constituted the major neuronal subpopulation. The neuronal proportions of the other markers increased during development and were characterized by regional differences. In the adult, all markers examined were expressed in the enteric nervous system. A large percentage of enteric neurons displayed calbindin and calretinin, and serotonin was the only marker showing significant distribution differences in the three intestinal regions. Colocalization studies showed that serotonin was not coexpressed with any of the other markers. At least five neuronal subpopulations were determined: a serotonergic, a nitrergic noncholinergic, two cholinergic nonnitrergic subpopulations along with one subpopulation expressing both ChAT and neuronal nitric oxide synthase. Analysis of nerve fibers revealed that nitrergic neurons coexpress VIP and PACAP, and that nitrergic neurons innervate the tunica muscularis, whereas serotonergic and cholinergic nonnitrergic neurons innervate the lamina propria and the tunica muscularis. PMID- 20853515 TI - Immunohistochemical parcellation of the ferret (Mustela putorius) visual cortex reveals substantial homology with the cat (Felis catus). AB - Electrophysiological mapping of the adult ferret visual cortex has until now determined the existence of 12 retinotopically distinct areas; however, in the cat, another member of the Carnivora, 20 distinct visual areas have been identified by using retinotopic mapping and immunolabeling. In the present study, the immunohistochemical approach to demarcate the areal boundaries of the adult ferret visual cortex was applied in order to overcome the difficulties in accessing the sulcal surfaces of a small, gyrencephalic brain. Nonphosphorylated neurofilament (NNF) expression profiles were compared with another classical immunostain of cortical nuclei, Cat-301 chondroitin sulfate proteoglycan (CSPG). Together, these two markers reliably demarcated the borders of the 12 previously defined areas and revealed further arealization beyond those borders to a total of 19 areas: 21a and 21b; the anterolateral, posterolateral, dorsal, and ventral lateral suprasylvian areas (ALLS, PLLS, DLS, and VLS, respectively); and the splenial and cingulate visual areas (SVA and CVA). NNF expression profile and location of the newly defined areas correlate with previously defined areas in the cat. Moreover, NNF and Cat-301 together revealed discrete expression domains in the posteroparietal (PP) cortex, demarcating four subdivisions in the caudal lateral and medial domains (PPcL and PPcM) and rostral lateral and medial domains (PPrL and PPrM), where only two retinotopic maps have been previously identified (PPc and PPr). Taken together, these studies suggest that NNF and Cat-301 can illustrate the homology between cortical areas in different species and draw out the principles that have driven evolution of the visual cortex. PMID- 20853517 TI - An examination of the impact of the Maudsley Collaborative Care skills training workshops on patients with anorexia nervosa: a qualitative study. AB - PURPOSE: The objective of this study was to examine the experience of adult inpatients with Anorexia Nervosa (AN) whose carers had taken part in the Collaborative Care skills training workshops. Workshops were offered to carers of someone with an eating disorder (ED) to address carer distress and proposed interpersonal maintaining factors. METHOD: Semi-structured interviews were conducted probing the sufferer's perception of the workshops, their experience of their carers attending the workshops and any associated behaviour change. RESULTS: Qualitative data were analysed using Interpretative Phenomenological Analysis (IPA). Key findings suggest that patients hold positive attitudes towards involving carers in their care and that the skills training approach can have positive effects for AN adult inpatients. Positive effects are congruent with workshop aims supporting fidelity of the skills based training. Negative effects and ideas for improvements were examined. CONCLUSION: Involving carers in skills based Collaborative Care workshops based on an interpersonal maintenance model of EDs may be beneficial for adult inpatients with AN and future research is warranted to extend these findings. PMID- 20853516 TI - Evidence of cell-nonautonomous changes in dendrite and dendritic spine morphology in the met-signaling-deficient mouse forebrain. AB - Human genetic findings and murine neuroanatomical expression mapping have intersected to implicate Met receptor tyrosine kinase signaling in the development of forebrain circuits controlling social and emotional behaviors that are atypical in autism-spectrum disorders (ASD). To clarify roles for Met signaling during forebrain circuit development in vivo, we generated mutant mice (Emx1(Cre)/Met(fx/fx)) with an Emx1-Cre-driven deletion of signaling-competent Met in dorsal pallially derived forebrain neurons. Morphometric analyses of Lucifer yellow-injected pyramidal neurons in postnatal day 40 anterior cingulate cortex (ACC) revealed no statistically significant changes in total dendritic length but a selective reduction in apical arbor length distal to the soma in Emx1(Cre)/Met(fx/fx) neurons relative to wild type, consistent with a decrease in the total tissue volume sampled by individual arbors in the cortex. The effects on dendritic structure appear to be circuit-selective, insofar as basal arbor length was increased in Emx1(Cre)/Met(fx/fx) layer 2/3 neurons. Spine number was not altered on the Emx1(Cre)/Met(fx/fx) pyramidal cell populations studied, but spine head volume was significantly increased (~20%). Cell-nonautonomous, circuit level influences of Met signaling on dendritic development were confirmed by studies of medium spiny neurons (MSN), which do not express Met but receive Met expressing corticostriatal afferents during development. Emx1(Cre)/Met(fx/fx) MSN exhibited robust increases in total arbor length (~20%). As in the neocortex, average spine head volume was also increased (~12%). These data demonstrate that a developmental loss of presynaptic Met receptor signaling can affect postsynaptic morphogenesis and suggest a mechanism whereby attenuated Met signaling could disrupt both local and long-range connectivity within circuits relevant to ASD. PMID- 20853518 TI - Determination of subnanomolar concentrations of vanadium in environmental water samples using flow injection with luminol chemiluminescence detection. AB - A flow injection chemiluminescence method is described for the determination of subnanomolar concentrations of vanadium in environmental water samples. The procedure is based on the oxidation of luminol in the presence of dissolved oxygen catalyzed by vanadium(IV). Vanadium(V) reduction and preconcentration of vanadium(IV) was carried out using in-line silver reductor and 8-hydroxyquinoline chelating columns at pH 3.15, respectively. The calibration graph for vanadium(IV) was linear in the concentration range of 0.025-10 ug/L with relative standard deviation in the range of 0.4-5.58%. The detection limit (3s blank) was 3.8 * 10(-3) ug/L without preconcentration; when the vanadium(IV) was preconcentrated with an 8-HQ column for 1 min (2.0 mL of sample loaded), the detection limit of 5.1 * 10(-4) ug/L was achieved. One analytical cycle can be completed in 2.0 min. The analysis of certified reference materials (CASS-4, NASS 5 and SLRS-4) by the proposed method showed good agreement with the certified values. The method was successfully applied to the determination of total dissolved vanadium in environmental water samples. PMID- 20853519 TI - The photodynamic effect: the comparison of chemiexcitation by luminol and phthalhydrazide. AB - The presence of light, oxygen and photosensitizer (organic dye) is required for the photodynamic effect. Light and photosensitizer are harmless by themselves, but when combined with oxygen, reactive oxygen species (ROS) can be produced. This photodynamic effect is used in photodynamic therapy (PDT); the production of ROS as lethal cytotoxic agents can inactivate tumor cells. However, during PDT, there are many difficulties, so it is not possible to excite the photosensitizer using a laser, a source of light at the wavelengths specific to the photosensitizer (in visible region of the spectrum). Chemiluminescence is the light emission as a result of a chemical reaction. It is possible to use a chemiluminescent mixture to excite the photosensitizer even if the light emission does not conform to the absorption maximum of the photosensitizer. Luciferin and luminol have been used as chemiluminescent compounds (energizers) for the excitation of the photosensitizers. The aim of this work was to compare the chemiexcitation of some selected photosensitizers (e.g. fluorescein, eosin, methylene blue, hypericin and phthalocyanines) by chemiluminescent mixtures containing luminol (high chemiluminescent quantum yield) or phthalhydrazide (low chemiluminescent quantum yield) on some Gram-positive (Enterococcus faecalis, Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa, E. coli) bacteria and some cell lines (NIH3T3 and MCF7). The efficiency of the chemiexcitation was dependent on the kind of the photosensitizer and on the type of the bacterial strain or cell line and was independent of the energizers. PMID- 20853520 TI - The male-female gap in physician earnings: evidence from a public health insurance system. AB - Empirical evidence from US studies suggests that female physicians earn less than their male counterparts, on average. The earnings gap does not disappear when individual and market characteristics are controlled for. This paper investigates whether a gender earnings difference can also be observed in a health-care system predominantly financed by public insurance companies. Using a unique data set of physicians' earnings recorded by a public social security agency in an Austrian province between 2000 and 2004, we find a gender gap in average earnings of about 32%. A substantial share of this gap (20-47%) cannot be explained by individual and market characteristics, leaving labor market discrimination as one possible explanation for the observed gender earnings difference of physicians. PMID- 20853521 TI - Monitoring prioritisation in the public health-care sector by use of medical guidelines. The case of Norway. AB - This paper presents a new way to monitor priority settings in public health-care systems. We take departure in medical guidelines prescribing acceptable waiting times for different medical descriptions. Allocating ICD10 codes to the medical descriptions, we are able to compare actual waiting times to the recommended maximum waiting times. This way we use the medical guidelines as a tool for monitoring prioritisation in the health sector. In an application, using data from the Norwegian Patient Register, we test statistically for compliance with the guidelines. The results indicate that patients suffering from the most severe conditions are receiving too low priority in the Norwegian health-care sector relative to patients of lower priority. PMID- 20853522 TI - Carbon nanotube-coupled cell adhesion peptides are non-immunogenic: a promising step toward new biomedical devices. AB - Carbon nanotubes functionalized with cell adhesion peptides can be considered as novel, promising candidates for the development of advanced drug delivery systems or for designing new generation of self-assembling nerve 'bridges'. An important step toward the integration of these types of conjugates in living bodies is the assessment of their impact on the immune system. In this direction, an integrin derived peptide has been covalently conjugated to carbon nanotubes. Following intraperitoneal administration, peptide-carbon nanotubes do not trigger an anti peptide antibody production. Demonstration of the immune neutrality of peptide carbon nanotubes reinforces their potential use as substrates for neuronal regeneration in vivo. PMID- 20853524 TI - Why are placebos used, and why do they sometimes work? PMID- 20853523 TI - Compatibility of superparamagnetic iron oxide nanoparticle labeling for 1H MRI cell tracking with 31P MRS for bioenergetic measurements. AB - Labeling of cells with superparamagnetic iron oxide nanoparticles permits cell tracking by (1)H MRI while (31)P MRS allows non-invasive evaluation of cellular bioenergetics. We evaluated the compatibility of these two techniques by obtaining (31)P NMR spectra of iron-labeled and unlabeled immobilized C2C12 myoblast cells in vitro. Broadened but usable (31)P spectra were obtained and peak area ratios of resonances corresponding to intracellular metabolites showed no significant differences between labeled and unlabeled cell populations. We conclude that (31)P NMR spectra can be obtained from cells labeled with sufficient iron to permit visualization by (1)H imaging protocols and that these spectra have sufficient quality to be used to assess metabolic status. This result introduces the possibility of using localized (31)P MRS to evaluate the viability of iron-labeled therapeutic cells as well as surrounding host tissue in vivo. PMID- 20853525 TI - New fisheries battle looms. AB - Iceland is heading for a fight with the European Union by flouting mackerel quotas. PMID- 20853526 TI - Web effects. AB - Cyrus Martin looks at a study showing how an invasive plant can dramatically alter predator-prey relations. PMID- 20853527 TI - The effectiveness of laser acupuncture in women with menopausal symptoms. PMID- 20853528 TI - Why methylmercury remains a conundrum 50 years after Minamata. PMID- 20853529 TI - Proceedings of the Nobel Conference: The role of genetics in promoting suicide prevention and the mental health of the population. June 8-10, 2009, Stockholm, Sweden. PMID- 20853530 TI - "Being there" in the psychotherapeutic relationship: introduction. PMID- 20853531 TI - Psychotherapy with pen and ink. PMID- 20853532 TI - Tip of the iceberg. PMID- 20853533 TI - Abstracts of the 112th Annual AOA Congress and the 39th Annual AOSA Conference, Washington, DC, USA, June 2009. PMID- 20853534 TI - E-mailing doctors improves care. PMID- 20853535 TI - Arsenicosis: unusual neurological presentation from West Bengal. PMID- 20853536 TI - Consultation skills training for specialist trainees. PMID- 20853537 TI - Care closer to home--a changing role for physicians. PMID- 20853538 TI - Care closer to home is not what the NHS needs. PMID- 20853539 TI - Serum sodium disorders: safe management. PMID- 20853540 TI - How effective are acute geriatric wards at admitting geriatric patients? PMID- 20853541 TI - Heat and disasters spur climate researchers. AB - Climate researchers are bouncing back in spite of fresh criticism of the IPCC management and are looking to understand catastrophic individual events. PMID- 20853542 TI - Conservation measures continue. AB - Efforts to protect some marine environments and species are growing. PMID- 20853543 TI - E. Peter Geiduschek. AB - Peter Geiduschek was an undergraduate Chemistry major at Columbia University and received his Physical Chemistry Ph.D. at Harvard in 1952 for research under the direction of Paul Doty. After short stints teaching chemistry at Yale and the University of Michigan, and an early two-year sabbatical asa US Army draftee, he came to the University of Chicago's Committee on Biophysics, where he was first introduced to enzymology and to phage. In 1970, he joined the Department of Biology of the then relatively new University of California campus at La Jolla, and has remained at UCSD since. His research contributions have primarily dealt with mechanisms of transcription and gene regulation, pursued in the specific microbial context of phage-infected bacteria, eukaryotes (budding yeast and RNA polymerase III) and archaea. PMID- 20853544 TI - HPMA Copolymers: 30 Years of Advances. Issue Dedicated to Prof. Jindrich Kopecek on the Occasion of his 70th Birthday. PMID- 20853545 TI - New insight into the mechanism of hepatic involvement in brucellosis. PMID- 20853546 TI - The electrode-skin interface and optimal detection of bioelectric signals. PMID- 20853547 TI - Global programme to eliminate lymphatic filariasis. PMID- 20853548 TI - A novel antibacterial dental glass-ionomer cement. AB - This study reports the synthesis and evaluation of a novel non-leachable poly(quaternary ammonium salt) (PQAS)-containing antibacterial glass-ionomer cement. Fuji II LC cement was used for comparison. Compressive strength (CS) and Streptococcus mutans viability were used to evaluate strength and antibacterial activity, respectively. All specimens were conditioned in distilled water at 37 degrees C before testing. After the addition of 1-30% PQAS, both cements showed a reduction in CS, of 25-95% for Fuji II LC and 13-78% for the experimental cement, and a reduction in S. mutans viability, of 40-79% for Fuji II LC and 40-91% for the experimental cement. The experimental cement showed less CS reduction and higher antibacterial activity compared with Fuji II LC. The result also indicates that the cements are permanently antibacterial, with no leaching of PQAS. It appears that the experimental cement is a clinically attractive dental restorative that can be potentially used for longlasting restorations as a result of its high mechanical strength and permanent antibacterial function. PMID- 20853549 TI - Prophylactic use of aspirin does not induce anaemia among adults. AB - BACKGROUND: Aspirin is considered one of the most prescribed drugs worldwide, predominantly for its cardioprotective effects. However, its use may be precluded by gastrointestinal and haematological side-effects. OBJECTIVE: To investigate the association between the prophylactic use of aspirin and the prevalence of anaemia among adults. Other demographic factors and co-morbid conditions such as kidney or liver failure, diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, ulcer, ulcer medications, and the use of non-steroidal anti-inflammatory drugs, which might be associated with anaemia, were also investigated. RESULTS: No association between aspirin use and prevalence of anaemia was observed. Age and smoking were the only factors contributing significantly to the occurrence of anaemia. Moreover, gender, age and the use of peptic ulcer medication were associated with reduced haemoglobin levels. CONCLUSION: The results may help in minimizing concerns about the development of anaemia among patients on aspirin. They highlight the importance of age, gender, smoking and ulcer medication in determining the incidence of anaemia among those patients. PMID- 20853550 TI - Management of acute coronary syndrome in a tertiary care general medical unit in Sri Lanka: how closely do we follow the guidelines? AB - BACKGROUND AND OBJECTIVES: Acute coronary syndrome (ACS) is a leading cause of death. Correct implementation of evidence-based guidelines should improve outcome. We conducted this study to determine to what extent management of ACS in a tertiary care medical ward in Sri Lanka adhered to current guidelines. STUDY METHODS: This prospective observational study was carried out in the University Medical Unit of the National Hospital, Colombo, Sri Lanka, for a 5-month period commencing April 2008. All patients presenting with ACS to the unit were included. RESULTS: During the period of study, there were 101 admissions of confirmed ACS. Thirty-one (30.6%) and 40 (39.6%) patients had not received the required correct loading dose of aspirin and clopidogrel, respectively. There were 34 cases of ST-elevation myocardial infarction (STEMI); 26 patients were eligible for thrombolysis and streptokinase was given to 22 (84.6%). The rest were treated with low-molecular-weight heparin (LMWH). Of the 67 patients who did not have STEMI, 66 received the correct dose of LMWH. Fifty-two patients (51.4%) were started on a b-blocker at presentation. None of the patients received intravenous b-blockers. Seventy-four patients (73.2%) were started on either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker on presentation. None of the patients underwent primary percutaneous intervention. CONCLUSION: Adherence to guidelines is limited by lack of funds and resources in our setting; however, attention must be paid to non-costly easily correctable deficits. PMID- 20853551 TI - GSTT1 and GSTM1 gene deletions are not associated with hepatotoxicity caused by antitubercular drugs. AB - BACKGROUND AND OBJECTIVE: Susceptibility to antitubercular drug (ATD)-induced hepatotoxicity may be genetically mediated, with variant alleles of genes such as N-acetyltransferase (NAT2) and CYP2E1 reported as risk factors. Two studies of Asian populations have reported that GSTM1*0 / *0 (null) genotype was a likely predictor of hepatotoxicity, whereas another of a Caucasian population implicated GSTT1*0 / *0. We undertook a prospective case-control study to investigate whether GSTM*0 / *0 and GSTT1*0 / *0 were risk factors for ATD-induced hepatotoxicity. METHODS: Pulmonary tuberculosis patients on isoniazid, rifampicin and pyrazinamide who developed hepatotoxicity using defined criteria were prospectively identified. These cases were then matched with at least one control subject on the same drugs but without hepatotoxicity. Genotyping for GSTM1 and GSTT1 was performed by multiplex PCR on genomic DNA. The odds ratios for the frequency of specific GSTM1 and GSTT1 homozygotes in the case and control subjects were calculated to test for association between the genotypes and hepatotoxicity. RESULTS AND DISCUSSION: Hundred and fifty-one subjects (51 cases, 100 controls) were enrolled. Odds ratio for GSTM1 null genotype was 1.00 (95% CI 0.51-1.97) and GSTT1 null was 2.02 (95% CI 0.39-10.39), respectively, showing that these genotypes are not associated with hepatotoxicity. CONCLUSION: GSTM1 *0 / *0 or GSTT1 *0 / *0 or both null genotypes, do not appear to be associated with ATD-induced hepatotoxicity in our Indian population. PMID- 20853552 TI - "Will wonder drugs never cease!": a prehistory of direct-to-consumer advertising. PMID- 20853553 TI - Persephone's seeds: Abortifacients and contraceptives in Ancient Greek medicine and their recent scientific appraisal. PMID- 20853554 TI - Cardiovascular services and human resources in Puerto Rico - 2008. AB - Available information (2004-2008) concerning population statistics, the occurrence of cardiovascular disease, cardiovascular services and human resources in Puerto Rico is presented. Relevant information concerning life expectancy at birth, death by specific causes in a recent four years period, the commonest causes of death, and the related cardiovascular risk factors prevalence data available is included. The surgical and medical interventional services rendered to cardiovascular patients in different institutions and their locations in Puerto Rico in the year 2008 is presented. Some remarks concerning the productivity of physicians by our Schools of Medicine is included. Information about ACGME accredited postgraduate cardiovascular training programs conducted in Puerto Rico is presented. Data concerning the prevalence of hypertension, diabetes mellitus, overweight and obesity obtained by BRFSS in presented. PMID- 20853555 TI - Cardiac biomakers for the evaluation of acute coronary syndrome. AB - The traditional diagnosis of myocardial infarction relies primarily within the exhibited patient's clinical presentation, electrocardiographic changes, and elevation in cardiac markers. Since the clinical presentation can be highly variable and EKG changes are not readily present for all patients, the use of markers of cardiac injury to support the diagnosis of myocardial infarction has become a fundamental part of the evaluation of a patient with suspected acute coronary syndrome. In 2007 the Joint European Society of Cardiology/ American College of Cardiology Committee for the Redefinition of Myocardial Infarction concluded that the main criteria for myocardial infarction should be a rise or fall of cardiac biomarkers (namely cardiac troponins and CK-MB) along with: (1) ischemic symptoms, (2) ischemic changes in EKG, (3) Q waves in EKG, or (4) imaging evidence of loss of myocardial viability or (5) wall motion abnormalities. These changes have increased search interests for more sensitive and specific markers of acute myocardial injury; furthermore, dedicated research has commenced in order to specifically allocate markers that could even predict myocardial ischemia. Therefore this article will review traditional employment of cardiac markers, providing current insight, information and experimental data with respect to emerging markers of myocardial ischemia. PMID- 20853556 TI - Ventricular septal defects. AB - This is a review article that summarizes updated information concerning isolated ventricular septal defects (VSD). VSD are one of the most common congenital heart diseases. It includes anatomic consideration and classification of the different types of VSD, pathophysiologic categories, clinical features and diagnostic tools such as electrocardiography, chest radiography, echocardiography and cardiac catheterization. We also reviewed the most important aspects of the therapeutic management, including surgical indications for correction of ventricular septal defects. PMID- 20853557 TI - An update to the National Cholesterol Education Program: 2009 suggested changes. AB - In view of new, robust data published after the publication of the NCEP-ATP III in 2001, I am proposing a more aggressive management of cholesterol. Lower LDL-C levels must be achieved to stop and regress atherosclerosis and further reduce cardiovascular mortality. PMID- 20853558 TI - The "crush and aspiration" technique for debridement of the aortic annulus revisited. AB - An effective technique for the debridement of the aortic annulus using a needle holder to crush the calcify nodules, follow by the immediate aspiration of the pulverized material using a Yankauer suction device is reported. PMID- 20853559 TI - Giant aneurysm of the non-coronary sinus of Valsalva: a case report. AB - A 68 year old female patient with history of chronic lymphocytic leukemia, arterial hypertension and dyslipidemia came for evaluation since she is constantly aware of the beating of her heart. The echocardiogram showed an aneurysm of the non coronary Sinus of Valsalva. Chest computer tomography showed an aneurysm of the Sinus of Valsalva measuring 5.5 cm of diameter. A sternotomy was performed with resection of aneurysm and replacement of the aortic valve. The postoperative course was uneventful. PMID- 20853560 TI - Giant cardiac myxoma in an asymptomatic 57-year-old woman: a case report. AB - Primary cardiac neoplasms are rare and left atrial myxomas represent the most common form of primary cardiac masses. We present the case of a 57-year-old woman with Diabetes Mellitus and arterial hypertension who was incidentally found to have a giant myxoma in the left atrium. She was asymptomatic but given the high risk of embolization and sudden cardiac death, surgical removal of the tumor was performed. A 6.0 x 5.0 x 4.5 cm mass was recovered, confirmed to be a benign cardiac myxoma on microscopic examination. Symptoms associated with cardiac masses will depend upon tumor location and size, usually related to flow obstruction and embolization. An inflammatory response due to secretion of cytokines may also be observed. In this case, the patient had no symptoms despite the size of the tumor that occupied virtually 90% of the left atrial volume. PMID- 20853561 TI - Coexistent asymptomatic persistent left superior vena cava, partial anomalous venous connection and atrial septal defect: a case report. AB - Congenital structural abnormalities not associated with cyanosis may go undetected until late adulthood if clinical symptoms are not evident. We report the case of 17 year-old male, referred to cardiology clinics for evaluation of a murmur, which was found to have asymptomatic severe right heart chambers dilatation. Right heart catheterization and angiography revealed the diagnoses of partial anomalous pulmonary venous connection, an atrial septal defect and persistent left superior vena cava. PMID- 20853563 TI - Challenging educational electrocardiography cases. AB - Three challenging educational electrocardiography cases are presented and the electrocardiographic findings discussed. PMID- 20853562 TI - Spontaneous coronary artery dissection: a rare etiology of ST elevation myocardial infarction. AB - Spontaneous coronary artery dissection (SCAD) is an extremely rare etiology of acute myocardial infarction, most commonly seen in pre-menopausal women with no risk factors for atherosclerotic coronary artery disease (CAD). We present the case of a 41-year-old woman with no history of systemic illness who presented severe, oppressive retrosternal pain with ST-segment elevations in leads I, AVL, V1 through V6 in the absence of risk factors for CAD. Emergency percutaneous coronary intervention (PCI) revealed an aneurysmatic dilatation of the left main coronary artery with complete dissection of the left anterior descending artery and the ramus branch, causing distal occlusion of the affected vessels. The patient was submitted for emergency Coronary Artery Bypass Graft (CABG) surgery. This is thought to be caused by hormonal changes that cause weakness of the vasa vasorum and promote hemorrhage into the media. PMID- 20853564 TI - Physicians and pharmacists in Puerto Rico during the Wars of Independence, 1810 1830. AB - At the beginning of the 19th Century, there was a "chronic lack of physicians, medications, and hospital facilities, easily overwhelmed epidemics" in Puerto Rico. But, the arrival of newcomers from various parts of the world to the Island contributed to socio-economic development and the improvement of health conditions and health care. The Wars of Independence throughout Spanish American colonies (1808-1826), resulted in population movements into the Island, particularly from Tierra Firme (Venezuela), as well as from Spain (1808-1814). In 30 years the population doubled. Puerto Rico had 44 physicians, 13 pharmacists, and 45 "curanderos" or "healers"; the municipality of Ponce had 6 physicians and 2 pharmacists. The progress made by the southern society was remarkable. Those arriving from Venezuela were at the time the most benefited of the Spanish emigrants. They were educated people mastering languages, commerce, agriculture, science and medicine. This, in turn, stimulated progress, and economic and social wellbeing in Puerto Rico. PMID- 20853565 TI - Knowledge and misconceptions about immunizations among medical students, pediatric, and family medicine resident. AB - BACKGROUND: Previous research has indicated that, despite being the most trusted source of health information, medical students, residents and other health related professionals lack accurate and current knowledge regarding immunization practices. OBJECTIVE: To evaluate medical students and primary care resident knowledge about immunizations. METHODS: Self-administered survey given to students from four medical schools, Pediatrics residents (2 training programs) and Family Medicine residents (2 programs). Data was analyzed using Statistix 8.0. One-way ANOVA test was used to compare means, and a p-value less than 0.05 was considered statistically significant. RESULTS: Participants (N=376) included 3rd (64%) and 4th (18%) year medical students and a homogenous distribution of 1st, 2nd and 3rd year residents. The mean percent of correct answers about immunizations was 61%. The participants showed poor knowledge about indications (62% correct answers), contraindications (46% correct answers) and myths (71% correct answers). Knowledge about immunizations correlated with higher levels of education (p < 0.01). Most participants identified conferences (72%) as their primary source to learn about immunizations followed by books (48%) and the internet (36%). They referred poor exposure to immunizations in clinical settings. CONCLUSIONS: Most medical students do not have the expected knowledge about immunization indications and contraindications. Residents were not proficient in immunization contraindications. Both groups had an adequate understanding about vaccination myths. Efforts towards ensuring adequate exposure to immunizations education during training years are needed in order to eliminate one of the barriers to adequate immunizations in children. PMID- 20853566 TI - Exclusive breastfeeding reduces asthma in a group of children from the Caguas municipality of Puerto Rico. AB - Breast-feeding is the preferred method of infant nutrition. Its role in preventing childhood asthma is controversial. OBJECTIVE: Determine whether breastfeeding protects against the development of bronchial asthma in children. METHODS: A survey was answered by parents of children less than 18 years of age attending a Pediatric clinic at Cidra, Puerto Rico from July to December 2008. RESULTS: A group of 175 mothers were included in the study. The mean age was 28 years (range 14-50). The mean age of the children was 5 years. There was family history of asthma in 64% of the families. The prevalence of asthma in these children was 50%. Sixty-six percent of the mother's breastfed but only 27% did it exclusively. Children who were exclusively breastfed had a lower prevalence of asthma and milk protein allergy. CONCLUSIONS: This study correlates with literature reports linking exclusive breastfeeding to a reduction in asthma and other allergic diseases. PMID- 20853567 TI - Efficacy, safety and cost-efficiency of using an alternative technique for automated exchange transfusion in pediatric patients with sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) patients suffer complications requiring simple and/or exchange transfusion. In 1999 we developed an automated exchange technique using infusion pumps and vascular catheters (IV Pump Method). OBJECTIVE: To prove that IV Pump Method is cost-efficient, and as safe and effective as automated cell separators. METHODS: Retrospective chart review of SCD patients requiring exchange transfusion admitted to PICU from 2003-2009. Evaluated method used, complications, costs, and Hemoglobin S% (HgS%) change, excluding patients not requiring exchange transfusion. RESULTS: Cost-reduction with IV Pump Method is around $1000. Average HgS% reduction using IV Pump Method was 30.3 vs. 28.8 in Blood Cell Separator group (p = 0.84). We had no complications or mortalities, with the majority of patients being male (p = 0.03) and on the oldest age group (11-19 y/o) for both methods. CONCLUSION: The IV Pump Method is a safe, effective, and cost-efficient alternative to perform exchange transfusion. PMID- 20853568 TI - Respiratory illness in late preterm infants during the first six months of life. AB - Late preterm infants are physiologically immature and at risk for respiratory complications. The study's objective was to determine the incidence of respiratory illnesses in a group of preterm infants (33-35 weeks) during the first six months of life. METHODS: Parents were contacted by phone in the six months period after participating in an educational program and a short survey was performed. RESULTS: None of the infants required admission to the intensive care unit in the newborn period. According to parents, 71% of the babies had a common cold, 9% bronchiolitis, and 3% pneumonia. Fifty four percent of the babies visited the emergency room due to respiratory illnesses and (12%) required admission. CONCLUSION: Late preterm infants present respiratory illnesses during the first months of life which result in medical expenditures, emergency room visits, and hospital admissions. Educational interventions about preventive measures are needed to decrease the morbidity associated to these illnesses. PMID- 20853569 TI - Prenatal breastfeeding intentions in a group of women with high risk pregnancies. AB - The American Academy of Pediatrics recommends exclusive breastfeeding for the first 6 months of life. In spite of a limited number of contraindications, there are mothers who decide not to breastfeed their infants. OBJECTIVE: To determine intention to breastfeed in women with high-risk pregnancies. METHODS: Pregnant women who attended the Obstetrics high-risk clinics at the University District Hospital answered a survey. RESULTS: Participants included 186 women. Mean maternal age was 27 years (15-47) and mean gestational age 27 weeks (9-41). Ninety-four percent intended to breastfeed. The most common reason for not planning to was the use of medications. Breastfeeding intentions were associated to higher education (p < 0.01) and to confidence in their babies being able to be breastfed (p < 0.01). CONCLUSIONS: Women with high risk pregnancies showed high interest in breastfeeding their babies but there are misconceptions that need to be addressed so that more high risk babies can benefit from breastfeeding. PMID- 20853570 TI - Minor head injury in children younger than two years of age: description, prevalence and management in the emergency room of the pediatric university hospital. AB - BACKGROUND: In children less than two years old, minor head trauma can result in intracranial injury. No known studies exist that determine the number of children younger than two years old who visit the emergency room (ER) due to minor head injury in Puerto Rico. OBJECTIVE: To determine the prevalence of children with minor head trauma and describe related issues. METHODS: Information was gathered from the medical records of children 0 to 2 years old who visited the University Pediatric Hospital ER from 2004-2006. Several factors were analyzed. RESULTS: From our 136 subjects, there was a male prevalence of 59%. The predominant reason for head injury was a fall (86%). There was abuse in 7% of the subjects. Eighty five percent (85%) of injuries occurred at home. CONCLUSIONS: The most common etiology of head trauma was a fall at home. The prevalence of abuse in 7% of these children should alert physicians. PMID- 20853571 TI - Rooming-in improves breastfeeding initiation rates in a community hospital in Puerto Rico. AB - Several studies have shown that rooming-in can have a positive impact on lactation success. The objective of this study was to assess if the establishment of rooming-in in a community hospital has an impact on breastfeeding success. METHODS: Participants included volunteer women who delivered babies at a community hospital. The participants answered a survey. RESULTS: Sixty females were included. The mean age was 23 years (18-38) and the mean gestational age 38 weeks (34-41). Breastfeeding in the hospital was reported by 54% with 6% doing it exclusively. Rooming-in was practiced by 70%. Rooming-in was associated to breastfeeding (OR 5.0, 95% CI 1.5-16.9, p = 0.0069). Thirty-percent of the babies in rooming-in started breastfeeding during the first 6 hours after delivery as compared to none of those not roomed-in. CONCLUSION: The advantages offered by the rooming-in practice in the maternity ward of this hospital resulted in successful breastfeeding in this group of mothers. PMID- 20853572 TI - Esophageal atresia: new guidelines in management. AB - Esophageal atresia is the most common congenital anomaly of the esophagus in newborns. This review article discusses the incidence, embryological classification, diagnosis and associated anomalies of esophageal atresia. Emphasis is placed in the current guidelines of standard surgical management of this congenital condition. PMID- 20853573 TI - Clinical versus pathologic diagnosis: acrodermatitis enteropathica. AB - Malnutrition is a well-known cause of infant morbidity and mortality. In developed societies malnutrition still exists, especially in patients fed insufficient diets during chronic and critical illnesses. Malnutrition impacts all organs. Skin manifestations are common, and its diagnosis is mostly visual. We present four cases of malnutrition with associated zinc deficiency were the clinical diagnosis proved correct. Acrodermatitis Enteropathica cannot be distinguished histologically form other forms of deficiency dermatitis and psoriasis. A thorough history and physical examination plus the clinical response to therapy are sufficient to make the correct diagnosis. PMID- 20853574 TI - Candida albicans meningitis and brain abscesses in a neonate: a case report. AB - BACKGROUND: Invasive Candida infection is an increasingly important cause of morbidity and mortality in the neonatal intensive care unit. Neonatal candidemia occurs in 4-15% of extremely low birth weight infants. Meningitis occurs in 5-9% of patients with candidemia. A few infants with Candida meningitis (4%) present ventriculitis or brain abscess. OBSERVATIONS: We report a neonate born at 34 weeks gestational age, who at 12 days old presented apnea and seizures. Cerebrospinal fluid (CSF) grew Candida Albicans, and blood cultures were negative. A head sonogram and head computed tomography scan were negative. Brain magnetic resonance imaging (MRI) detected multiple brain parenchyma micro abscesses. CONCLUSIONS: This case confirms the need of obtaining adequate cultures including blood, urine, and CSF when sepsis is suspected. Neuroimaging studies should be included in diagnostic workup of patients with systemic fungal infection. Improved neuroimaging techniques such as MRI may lead to earlier diagnosis of cerebral abscesses. PMID- 20853575 TI - Dengue virus associated hemophagocytic syndrome in children: a case report. AB - Hemophagocytic Syndrome (HS) is a clinico-pathologic entity characterized by activation of T lymphocytes and macrophages. It may be diagnosed in association with malignant, genetic, or autoimmune diseases, but is most linked with Epstein Barr virus. There are few reports of association between HS and Dengue in pediatrics. Dengue fever, caused by a flavivirus, is an important mosquito transmitted disease. It can cause increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation known as dengue hemorrhagic fever (DHF). We present the case of a 10 month-old-female who developed DHF and dengue shock syndrome, requiring admission to intensive care unit. She developed hemophagocytosis diagnosed by bone marrow aspiration and atypical skin changes that have not been previously described in association with dengue fever. This is an unusual case of dengue related hemophagocytic syndrome that adds to the limited pediatric cases reported in literature. PMID- 20853576 TI - Transanal circular-stapled reanastomosis as a management alternative for anastomotic colonic strictures: a novel technique in the pediatric patient. AB - A 12-year-old male patient with a recalcitrant rectal anastomotic stricture following two failed endorectal pull-through (Soave) procedures for Hirschsprung's disease was satisfactorily managed with transanal resection using a circular stapling device. This is the first reported case of a benign colonic anastomotic stricture treated transanally with a circular stapling device in a pediatric patient. PMID- 20853578 TI - ED quality performance moves into the public reporting arena. AB - As an ED manager, you face the growing challenge of your performance data being shared with the public and with hospital administration. Be sure to share the good news with your administration, so they can use it to help market the hospital. When adverse rankings appear, you have two options: Seek additional resources to improve performance, or challenge the data. Use an automated system to access"real-time"data on your department's performance, so you will always be ready to defend your ED. PMID- 20853577 TI - Mutagenicity of stereochemical configurations of 1,3-butadiene epoxy metabolites in human cells. AB - The mutagenic and carcinogenic effects of 1,3-butadiene (BD*) are related to its bioactivation to several DNA-reactive metabolites, including 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO diol). Accumulated evidence indicates that stereochemical configurations of BD metabolites may play a role in the mutagenic and carcinogenic action of BD. The objective of this study was to evaluate the cytotoxicity and mutagenicity of each stereoisomer of major BD metabolites in human cells. For this purpose, nine stereochemical forms of BDO, BDO2, and BDO-diol were synthesized. TK6 cells, a human lymphoblastoid cell line, were exposed to each stereoisomer. Cytotoxicity was measured by comparing cloning efficiencies (CEs) in chemical-exposed cells versus those in control cells. Based on the results of cytotoxicity tests, TK6 cells were exposed to 0; 2, 4, or 6 pM of each form of BDO2, or to 0, 200, 400, or 600 pMof each form of BDO for 24 hours to determine the mutagenic efficiencies. The exposure concentrations for BDO-diol ranged from 5 to 1000 pM. The mutagenicity was measured by determining, in a lymphocyte cloning assay, the mutant frequencies (Mfs) in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) genes. HPRT mutants collected from cells exposed to the three forms of BDO2 were analyzed by polymerase chain reaction (PCR) to characterize large genetic alterations. All three stereoisomers of BDO2 [(2R,3R) BDO2, (2S,3S)-BDO2, and meso-BDO2] caused increased HPRT and TK Mfs compared with the concurrent control samples, with P values ranged from 0.05 to 0.001. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of BDO2. Molecular analysis ofHPRTmutants revealed similar distributions of deletion mutations caused by the three isomers of BDO2. There were also no statistical differences in mutagenic efficiencies between the two isomers of BDO [(2R)-BDO and (2S)-BDO] in TK6 cells. These results were consistent with the in vivo finding that there was little difference in the mutagenic efficiencies of (+)-BDO2 versus meso-BDO2 in rodents. Thus, in terms of mutagenic potency, there was no evidence that stereochemical configurations of BDO and BDO2 play a significant role in the mutagenicity and carcinogenicity of BD. The most significant results of this study were the marked differences in cytotoxicity and mutagenicity among the four stereoisomers of BDO-diol [(2R,3R)-BDO-diol, (2R,3S) BDO-diol, (2S,3R)-BDO-diol, and (2S,3S)-BDO-diol]. (2R,3S)-BDO-diol was at least 30-fold more cytotoxic and mutagenic than the other three forms of BDO-diol. This was consistent with the finding that 75% of the adduct N7-(2,3,4 trihydroxybutyl)guanine (THB-Gua) originated from (2R,3S)-BDO-diol in the lungs of mice exposed to BD. The mutagenic potency of (2R,3S)-BDO-diol was much closer to that of BDO2 than previously demonstrated in experiments in which stereochemistry was not considered. The current study demonstrated that the mutagenic potency of (2R,3S)-BDO-diol was only 5-to-l0-fold less than the average equimolar effect of BDO2 stereoisomers in the HPRT and TK genes, and was 10-to-20 fold greater than the average equimolar effect of BDO stereoisomers in the HPRT and TKgenes. Previous DNA and hemoglobin adduct data demonstrated that BDO-diol is the dominant BD metabolite available to react with macromolecules in vivo after BD exposure (Perez et al. 1997; Swenberg et al. 2001). Thus, the differences in BD carcinogenesis among rodent species may be significantly accounted for by the stereochemistry-dependent distributions of BDO-diol metabolites and BDO-diol-DNA adducts, and by the mutagenic efficiencies of BDO diol in mice and rats. PMID- 20853579 TI - EDs trying not to let the bed bugs bite. AB - As bed bugs have emerged as a growing problem for EDs, managers have developed strategies for prevention and decontamination. Here are some of the approaches they have shared with ED Management: Educate your staff on what they should look for on patients and in rooms that would indicate the presence of bed bugs. Be proactive. Have an exterminator examine your ED on a regular basis. A decontamination room on the outside of the building will prevent the spread of these bugs in your ED. PMID- 20853580 TI - 'Triage center' takes pressure off EDs. AB - Behavioral health care is a major concern for EDs. Lee Memorial Health System helped relieve the ED burden with a shelter for homeless and uninsured individuals. A former director of emergency services provided ED-specific input into the planning process. A contracted nurse with ED experience provides the initial assessment of patients referred to the shelter. System EDs now have a referral option for patients with behavioral health issues and no longer have to discharge them "onto the street". PMID- 20853581 TI - Information exchange yields better decisions. AB - A new study from the Medical College of Wisconsin shows that the Wisconsin Health Information Exchange has not only saved time for the EDs participating, but has helped them make better-informed patient care decisions. EDs in the Milwaukee area are linked to the system with a dedicated computer housed in a separate area of the department. Once registration enters the patient's name into the system, basic information appears about the previous ED visits at all facilities in the city. ED staff can also obtain additional patient information if the need arises. PMID- 20853582 TI - 'No wait' policy has broad goal. AB - A combination of staffing and process changes have enabled the EDs of the Bon Secours system to deliver on a "no-wait" promise to patients. All patients are now greeted by an RN. Floaters provide backup if several patients present at once. Protocols were streamlined to aid in the speedup of patient flow. Patients are provided an information folder that gives them contact information for their comments on the new system. PMID- 20853583 TI - Growing trend of identity theft poses safety and billing loss threats. AB - Identity theft is more than just a legal issue. Patients with improper identification are at risk for receiving potentially harmful treatment. Have registration department require photo identification from all patients. Ask additional questions, such as the patient's date of birth. Ask staff members to be the "eyes and ears" of registration and security, and ask them to report anything suspicious. PMID- 20853584 TI - 15-minute policy results in few refunds. AB - Emerus Emergency Hospitals, a licensed emergency specialty hospital company in Texas, has taken the bold step of guaranteeing patients they will be seen by a physician within 15 minutes or their visit is free. In the first six weeks of the policy, the deadline was missed only four times. Patients in distress are sent right back to a nurse. Complete registration takes only a few minutes. Nurses are cross-trained so that they often do not have to wait for others to complete labs or other tests. The radiology technician is in the ED and accountable to ED leadership. PMID- 20853585 TI - What every ED manager needs to know about RACs. PMID- 20853586 TI - ED handoffs to inpatient: patient safety at stake. PMID- 20853587 TI - Sentinel Event Alert says access control holds the key to reducing ED violence. AB - A new Joint Commission Sentinel Event Alert notes that EDs are the most vulnerable area of the hospital when it comes to violence and that access control is a key to preventing that violence. * Perform a risk assessment, so you know where your greatest threats lie. Examine physical control barriers, and consider access control products such as keypads. Position security personnel in the greeting area of the ED. PMID- 20853588 TI - Joint Commission suspends 'auto' adverse decision. AB - The Joint Commission's revision of its policy on root cause analysis puts greater attention of something that, quite frankly, some ED managers might not have been aware of. The ED manager plays an important role when events occur in the department, such as: knowing who the main Joint Commission contact is in the hospital, and making them aware of a potential adverse or sentinel event that has occurred; participating in the root cause analysis to identify what ED processes might need improvement; making sure the remedial activities recommended can be measured, so The Joint Commission can see an active attempt is being made to improve. PMID- 20853589 TI - Drug enforcement and the Drug Enforcement Administration. PMID- 20853590 TI - Weight-loss supplements: what is the evidence? AB - Obesity has reached epidemic proportions in this country. In an effort to address this major public health problem, people have adopted a variety of strategies. These include medical and surgical interventions, both rational and fad diets, exercise and assorted weight-loss dietary supplements. Recent U.S. Food & Drug Administration (FDA) action involving some of these proprietary supplements raises questions of both their safety and efficacy. This article reviews the evidence behind the components of many of these supplements and discusses the role of nutrition in weight loss. PMID- 20853591 TI - State of South Dakota's child 2009, part 2: multiple births. AB - Currently in South Dakota, multiples comprise between three and four percent of all births and are increasingly contributing to annual cohorts of newborns. In recent years, multiples contribute to between 20 and 30 percent of all low-birth weight newborns. In 2008, almost 35 percent of all very low-birth-weight infants were multiples. Over the past ten years, multiples contributed 10 percent of all infant deaths. Nationally, 15 percent of all infants who die were the outcome of a multiple gestation. PMID- 20853592 TI - Treatment of hepatitis C 2010: a focus on protease inhibitors. PMID- 20853593 TI - New patient safety and inpatient quality indicators for hospitals. PMID- 20853594 TI - Quality, safety and imaging accreditation. PMID- 20853595 TI - In vivo antioxidant and hypolipidemic effect OF Cardiospermum halicacabum leaf extract in streptozotocin-induced diabetic rats. AB - In this study we investigated the antioxidant and antihyperlipidemic of an ethanolic leaf extract of Cardiospermum halicacabum (CHE) in plasma and tissues of streptozotocin (STZ)-induced diabetic rats. The plasma and tissue concentrations of thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxide were significantly elevated in STZ diabetic rats. CHE administration decreased TBARS and lipid hydroperoxide levels. The plasma vitamin E level increased and the vitamin C level decreased. The reduced glutathione level significantly decreased in plasma and tissues, as did the activities of enzymatic antioxidants. The enzymatic and non enzymatic alterations reversed toward normalcy after treatment with CHE. STZ-induced diabetic rats showed significant increases in plasma total cholesterol, phospholipids, triglycerides, and free fatty acids, which returned to near normalcy in CHE-treated animals. Plasma LDL-C and VLDL-C increased and HDL-C decreased and both reverted to near normalcy following CHE treatment. We conclude that CHE possesses antioxidant and hypolipidemic effects in diabetic rats, which may be due to the presence of flavonoids, such as apigenin and luteolin in the extract. PMID- 20853596 TI - Increased iNOS, MMP-2, and HSP-72 in skeletal muscle following high-intensity exercise training. AB - Skeletal muscle adapts to exercise by an upregulation of cellular defenses, such as inducible nitric oxide synthase (iNOS) and matrix metalloproteinase type 2 (MMP-2) and heat shock protein type-72 (HSP-72). The aims of the study were to examine iNOS, MMP-2, and HSP-72 mRNA and protein expression after high-intensity exercise training and to examine whether the expression levels are fiber type dependent. Young Wistar rats were assigned to either 2 or 4 weeks of a high intensity (32 m/min) running exercise for 40 minutes 5 day per week. A non running group served as a control. Western blotting and reverse transcriptase polymerase chain reaction of muscle mRNA and protein levels were assessed in the medial gastrocnemius, quadriceps, soleus, crural, and sternal head of diaphragm muscles. High-intensity exercise training for 4 weeks but not for 2 weeks resulted in a significant increase in both RNA and protein levels of iNOS, MMP-2, and HSP-72 in all muscles examined except the sternal head of diaphragm. High intensity exercise training is required to promote the expression of iNOS, MMP-2, and HSP-72 in hind limb muscles regardless their muscle fiber type, whereas in the diaphragm the changes are fiber-type dependent. PMID- 20853597 TI - Spermatoxic effects of operation sweep herbal supplement in male albino rats. AB - Operation Sweep (OPS) de rheumatism powder is a registered Nigerian poly-herbal medicine. The acute and sub-chronic testicular toxicology of the OPS powder was investigated in male albino rats. The rats, divided into 10 per group, received aqueous extract of the OPS powder, orally, at 0, 0.75, 1.50, 2.25 g/kg for 30 days. Animals were sacrificed on day 30; the testes and epididymis were excised and weighed. The testes were processed for histological analysis, and the epididymis was used for sperm quality: epididymal sperm count (ESC), epididymal sperm motility (ESMot) and the epididymal sperm morphology (ESMor) determination. The results showed a non-significant increase in the body weights of the treated groups. Treatment with OPS caused a significant (p < .05) reduction of the relative weight of the epididymis in the 2.25g/kg dose group; a significant (p < .05) decrease in the ESC and active ESMot, an increase in the dead ESMot, and a nonsignificant (p > .05) effect on the ESMor. Histologic examination of the testes indicated no serous pathological changes except for some mild vascular congestion at 1.5 and 2.25 g/kg. This study suggests that the aqueous extract of the OPS powder may cause epididymal toxicity as shown in the adverse effect on sperm quality. PMID- 20853598 TI - Bauhinia tomentosa stimulates the immune system and scavenges free radical generation in vitro. AB - A methanolic extract of Bauhinia tomentosa was studied for its immunomodulatory, antioxidant, and anti-inflammatory activity in BALB/c mice. Intraperitoneal administration of the extract significantly increased the total leukocyte account (10075 +/- 542 cells/cm2) on the 18th day, bone marrow cellularity (93.1 x 10(5) +/- 3.35 cells/femur), and alpha-esterase positive cells (1332 +/- 32 cells/4000 bone marrow cells) when compared with untreated control mice. The weights of lymphoid organs, such as spleen and thymus, also increased. An evaluation of the antioxidant activity of B. tomentosa revealed that the extract inhibited non enzymic lipid peroxidation in mouse liver microsomes at all concentrations, with an IC50 value of 90 microg/ml. For nitric oxide radical scavenging activity, the IC50 of B. tomentosa was 65.0 microg/ml, indicating that B. tomentosa is a good antioxidant. The anti-inflammatory effect B. tomentosa also significantly reduced acute inflammation of the paw edema induced by carrageenan and formalin. PMID- 20853599 TI - Spermidine influence on the nitric oxide synthase and arginase activity relationship during experimentally induced seizures. AB - Nitric oxide (NO), a potential candidate for a modulator of convulsive activity, is a mediator in several pathological events in the central nervous system. The polyamines, spermidine (Spd) and spermine, are neuromodulators influencing the metabolism of L-arginine and NO production. Here we examined the effects of Spd on NO production and arginase activity during convulsions induced by pentylenetetrazol (PTZ). Male Wistar rats were allocated into four experimental groups of 8 animals each and received the following treatments: I (control)- saline, intraperitoneally (i.p.); II (PTZ)--seizures induced by pentylenetetrazol (100mg/kg bw i.p); III (Spd)--Spd (1 mg/kg bw i.p.) 50 min before PTZ application; IV (Mid)--antiepileptic Midazolam (100 mg/kg bw) 45 min before PTZ. In brain cortex, striatum, hippocampus, cerebellum, and brainstem homogenates, nitrite + nitrate levels and arginase activity were determined. Spermidine showed proepileptic effects. shortening seizure latency and inducing a more profound increase of NO production than PTZ in all brain structures. PTZ reduced arginase activity, whereas Spd pretreatment increased enzyme activity, with the most profound effects in cerebellum and brainstem. The results point out the importance of polyamine and arginine metabolism in the brain during seizures, suggesting a regulatory role for polyamines and arginase in NO production. PMID- 20853600 TI - Arginase activity in human milk during the first month of lactation. AB - Arginase (L-arginine amidinohydrolase, EC 3.5.3.1) is the key enzyme in urea synthesis, hydrolyzing L-arginine into L-ornithine and urea. Arginase modulates levels of nitric oxide, creatine, and creatinine, likely by regulating intracellular L-arginine availability. The objective of the present study was to determine the arginase activity and concentration of urea and creatinine in colostrum and mature human milk obtained from nursing mothers. Our longitudinal biochemical analyses show that arginase activities and urea concentrations were the highest at the first day of lactation (colostrum). The decreasing enzyme activity and urea start at the second day, remaining at this level until the end of the first month of lactation (30th day). The concentration of creatinine in human colostrum and mature milk did not significantly change. The alteration of arginase activity between colostrum and mature milk may be a consequence of the transfer of arginase from the blood of the breast mother mammary glands into the colostrum and mature milk. The concentration of nutrients in colostrum and mature milk undergo alterations, probably to satisfy the requirements of the nursing infant for arginine, essential amino acids for human body growth, and normal physiology. PMID- 20853601 TI - Effect of cell phone exposure on physiologic and hematologic parameters of male medical students of Bijapur (Karnataka) with reference to serum lipid profile. AB - The public awareness about cell phone safety increased greatly in the last few years as various reports of potential adverse health effects on humans exposed to radiations emitted from cellular phones were published. The aim of the study was to assess the effect of long term cell phone exposure on physiological and hematological parameters along with its impact on serum lipid profiles and a single call effect on heart rate, blood pressure and SpO2(%) of healthy male medical students. The students were divided into two groups, group I (n=22, age 20.63 +/- 1.17 yrs) comprising first year medical students who were never exposed to cell phones at the time of this study and group II (n=35, age 22.00 +/- 1.56 yrs) consists of final year (fourth year) male medical students who were using cell phone for more than four years before this study. The results showed no significant differences the groups in basal heart rate, systolic blood pressure, SpO2(%), or various hematologic parameters. Acute exposure (single call of cell phone with 900 MHz for 1 minute) in both groups showed a significant increase in peak heart rate in group II as compared with group I and a significant decrease in peak SpO2 (%) in group I as compared with group II. Serum total cholesterol, VLDL-cholesterol, and triglycerides concentration were significantly higher in group II (long term cell phone exposed) than in group I, suggesting a mild alteration of lipid profile among group II subjects. PMID- 20853602 TI - [Toxicity of different treatment protocols for acute myeloid leukemias in adults: the results of four Russian multicenter studies]. AB - AIM: To comparatively analyze the toxicity of 4 treatment protocols in patients with acute myeloid leukemia (AML), which were used in the Russian multicenter center in 1992 to 2009. MATERIALS AND METHODS: The information obtained in 4 Russian multicenter studies conducted in 33 hematology departments of 26 cities and towns of the Russian Federation in 1992 to 2009 was analyzed. Randomization was made in 243 patients with AML (median age 38 years) in 1992-1995, 396 patients (median age 39 years) in 1995-1999, 392 patients (median age 39 years) in 2001-2006, and 137 patients (median age 40 years) in 2006-2009. The analysis excluded patients with acute promyelocytic leukemias who were recruited in the AML-92 and AML-95 studies. These patients' statutory forms adequately filled in were 60-70% therefore toxicity was analyzed on the basis of the data of 631 patients. RESULTS: The baseline clinical and laboratory parameters in the patients enrolled in the studies in different years slightly differ in the count of leukocytes at the onset of the disease and in the level of lactate dehydrogenase (LDH): the recent studies revealed a larger number of high-risk group patients (leukocytes more than 30 10(9)(/l; LDH more than 500 units) possibly due to the later diagnosis of AML. During the studies, the number of complete remissions remained as before (55%) after the first course and increased from 65 to 78% after the second course using cytosine arabinoside in high doses. Despite treatment intensification, mortality in the induction period remained as before (19-21%). Remission mortality decreased from 18 to 10-13%. The long-term results of using the aggressive therapy did not differ from those obtained during the standard treatment protocols. The duration of leucopenia after standard induction courses during the all studies remained equal (17-19 days); the exclusion was a HAM course as the second induction course after which the duration of neutropenia was much more than that of the standard course (17 and 10 days, respectively). During the study years, there was an increase in platelet transfusion volumes (from 20 to 53 doses during the first course and from 7 to 28 doses during the second course) and a reduction in the percentage of severe hemorrhagic complications. The incidence of pneumonias remained at the same level (40-50%) during the induction courses and that of septic complications and necrotic enteropathy considerably decreased from 40-46 to 17-19%. The incidence of invasive aspergillosis during the current programs from AML treatment was 10% (two induction courses), that of invasive candidiasis was 4.7% (two induction courses). CONCLUSION; The long-term results of treatment for AML were virtually unchanged regardless significant therapy intensification. Mortality remained high during induction treatment and in the postremission period. Its cause is severe infectious complications developing during myelotoxic agranulocytosis. The results of the analysis provide the basis for developing a new AML treatment protocol that should take into account all the merits and demerits of the previous protocols and provide a toxicity-treatment efficiency balance. PMID- 20853603 TI - [Efficiency of the ALL-MB-2002 protocol in children with acute lymphoblastic leukemia]. AB - AIM: To evaluate the efficiency of the original ALL-MB-2002 protocol within the multicenter study of treatment of acute lymphoblastic leukemia (ALL) in children. SUBJECTS AND METHODS: A total of 1873 primary patients with ALL aged 1 to 18 years, of whom 1544 patients were enrolled in this study, were notified at 36 clinics of Russia and Belarus from April 15, 2002, to January 1, 2008. RESULTS: With the median observation of 4.12 years, 7-year event-free survival (EFS) was 73 +/- 13%; overall survival (OS) 78 +/- 2%; relapse-free survival 82 +/- 1%. The rates of EFS and OS were equal and amounted to 76 +/- 2 and 80 +/- 2% in the standard-risk group (SRG) and intermediate-risk group (ImRG), respectively. In the high-risk group (HRG) patients, EFS and OS were as high as 30 +/- 6 and 37 +/ 6%, respectively. The frequency of relapses with central nervous system lesion was as much as 4.7% in all the patients, 6-year cumulative risk for isolated neurorecurrences being 2.5% in the SRG patients. Adolescents, patients with the baseline leukocytosis (more than 100 x 10(9)/l), and those with a splenic size of over 4 cm or more from the costal arch margin had substantially worse survival rates. A poor early response to therapy (on induction days 8 and 15) was also associated with its lower efficiency. CONCLUSION: Despite a considerable rise in the number of centers and a slight increase in the intensity of therapy, the results of the new ALL-MB-2002 protocol are as minimum equivalents obtained in the use of the previous ALL-MB-91 protocol. A significant improvement in the overall results of therapy and a reduction in the cumulative risk for isolated neurorecurrences were noted in the ImRG patients. PMID- 20853604 TI - [Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation]. AB - AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO. PMID- 20853605 TI - [Determinants for iron overload in patients with acute leukemias and aplastic anemia]. AB - AIM: to reveal the determinants of the development of iron overload in patients with acute leukemias (AL) and aplastic anemia (AA). SUBJECTS AND METHODS: The investigation included 104 patients, including 64 with various types of AL, 31 with AA, and 9 with myelodysplastic syndromes (MDS). A group affiliation and an erythrocyte phenotype were determined from rhesus system antigens in all the patients and the HFE gene was studied to identify mutations. For control of siderosis, the authors determined serum iron (SI) by a colorimetric technique, by applying the kits of the AGAT firm (Russia), serum ferritin (SF) by an immunoradiometric method, by using the kits of Immunotech (Czechia). The volume of transfusion was estimated in the period of June 2007 to November 2009. RESULTS: There is evidence for a relationship between the higher level of SF and the number of transfusions. SF was 1046.1 microg/l in patients, H63D heterozygous carriers who had received less than 10 packed red blood cell transfusions and 2856 microg/l in those who had 20 transfusions (p < 0.005). HFE gene mutation carriage accelerates iron accumulation and is an additional risk factor for siderosis. In patients with transfusion chimeras and a rare phenotype in terms of rhesus antigens, packed red blood cell transfusion results in a much more increase in iron stores. CONCLUSION: The most important factor of iron overload acceleration is no specific choice of packed red blood cells for patients with rare combinations of red blood cell antigens and for those with artificially induced chimeras. PMID- 20853606 TI - [Prolonged bone marrow aplasia in patients with acute leukemia after chemotherapy]. AB - AIM: To analyze the causes of prolonged hematopoietic tissue aplasias in patients with acute leukemias (AL) after chemotherapy courses. MATERIALS AND METHODS: Data on 7 patients with acute myeloid leukemia, followed up at the Hematology Departments, Hematology Research Center, Russian Academy of Medical Sciences, over the period 2003 to 2007, who had developed deep bone marrow aplasia (BMA) inadequate to cytostatic drug exposure during chemotherapy, were analyzed. The authors compared in all the patients the values of peripheral blood and bone marrow (BM) puncture specimens and the results of blood tests using the polymerase chain reaction at different AL development stages with the results of an immunohistochemical study using the markers of viruses of hepatitis C and B, a herpes group (EBV, CMV, HSV-1, HSV-2) and parvovirus B19. RESULTS: The marker of hepatitis C was detected in 6 of the 7 patients with prolonged BMA; 3 of these 6 patients showed a simultaneous infection with hepatitis B. Six of the 7 patients were found to have concomitant BM lesion with various herpes group viruses. Two patients had a resistant form of AL. CONCLUSION: Hepatitis C virus infection in patients and the resistant form of the disease were the principal causes of the development of BMA inadequate to cytostatic drug exposure. Affliction of abundant bone marrow cells with herpes group viruses was not a direct cause, but might substantially aggravate BMA. PMID- 20853607 TI - [Results of hematopoietic cell transplantation in the first complete remission in children with acute myeloid leukemia from an intermediate risk group]. AB - AIM: To analyze the results of allogeneic and autologous hemopoietic cell transplantations (allo- and auto-HCT) in children with acute myeloid leukemia (AML) from an intermediate risk group, most of which were performed using lower intensity conditioning modes. SUBJECTS AND METHODS. The study enrolled 36 children from an intermediate risk group, who had undergone auto-HCT (n = 22) or allo-HCT (n = 14) in December 1994 to December 2008. The patients' age was 0.7 to 16.6 years (median 12.8 years). Chemotherapeutic conditioning regimens were applied to all the patients. Melphalan was a basic myeloablative agent in 83.3% of cases. RESULTS: With a median follow-up of 4.6 years (1.1-13.8 years), three year relapse-free survival (RFS) was 80.4%; overall survival (OS) was 65.6%. Recurrences were documented only in 6 (16.6%) patients from the auto-HCT. Transplantation-associated mortality (TAM) was 13.8% (five patients died). After allo-HCT versus auto-HCT, RFS, OS, and TAM were 100 and 68.7% (p = 0.03), 93.2 and 55.5% (p = 0.02), and 7.1 and 18.2%, respectively. Acute and chronic graft versus-host reactions developed in 57.1 and 23.1%, respectively. CONCLUSION: Transplantation of allogeneic hemopoietic cells from a compatible related donor in the intermediate risk group children with AML, by using melphalan-based conditioning regimen, demonstrates a high survival rate with the minimum toxicity. PMID- 20853608 TI - [Transplantation of the bone marrow from a HLA-compatible unrelated donor after immunoablative conditioning in children with acquired aplastic anemia unresponsive to combined immunosuppressive therapy: preliminary results]. AB - AIM: To analyze the efficiency of transplantation of the bone marrow from a HLA compatible unrelated donor and continued immunosuppressive therapy (IST) in children with aplastic anemia (AA) unresponsive to 2 courses of IST. SUBJECTS AND METHODS: The study enrolled 14 children aged 2-16 years (median 9 years). A control group comprised 26 patients in whom IST was continued. The median interval between the diagnosis of AA and transplantation was 26 months (9-156 months). The conditioning regimen consisted of thoracoabdominal irradiation in a dose of 2 Gy, fludarabin (Flu) 100-150 mg/m2, cyclophosphamide (Cy) 100-200 mg/kg, antithymocyte globulin (ATG) in 11 patients and Flu, Cy, and ATG in 3. A graft-versus-host reaction was prevented with mycophenolate mefetil in all the patients, tacrolimus in 11, and cyclosporin A in 3. Donors were compatible for high-resolution typing of 10/10 and 9/10 alleles in 8 and 6 patients, respectively; the source of a transplant was bone marrow in 13 patients and granulocyte colony-stimulating factor-mobilized peripheral blood precursors in one case. RESULTS: Thirteen patients achieved primary engraftment after single transplantation; one patient did after repeat transplantation. Grades I to II graft-versus-host reaction (GVHR) developed in 9 patients; postengraftment life threatening infections in 3, extensive chronic GVHR in 2, circumscribed GVHR in 7. All fourteen hemopoietic cell transplant recipients followed for a median 17.5 months (range 1-71 months) were survivors. CONCLUSION: The likelihood of good survival after unrelated transplantations in AA is much higher than that after continued IST: 100% versus 15 +/- 11%. PMID- 20853609 TI - [The use of allogeneic bone marrow transplantation and immunosuppressive therapy in the treatment of patients with acquired aplastic anemia]. AB - AIM: To evaluate the efficiency of related and unrelated allogeneic bone marrow transplantation (alloBMT) versus immunosuppressive therapy (IST) in patients with aplastic anemia (AA) having no HLA-compatible bone marrow donor. SUBJECTS AND METHODS: The study covered 61 patients (34 men and 27 women) diagnosed as having acquired AA. Of them, 51 patients were diagnosed as having severe AA, 5 had supersevere AA, and 5 had non-severe AA. Combined IST (antithymocyte globulin (ATG) + cyclosporin A (CsA)) was used in 43 patients; allo-BMT was performed in 18. The basic types of ATG (ATGAM (Pfizer), thymoglobulin (Genzim), ATG (Fresenius), and goat antilymphocyte globulin (ALG) (Research Institute of Gerontology, Ministry of Health of the Russian Federation) were administered. CsA was given in a dose of 5 mg/kg/day. The standard conditioning regimen (ATGAM + cyclophosphanum) and fludarabine-containing (fludarabine + cyclophosphanum + ATG; busulfan + fludarabine + ATG) programs were used in the allo-BMT group. A combination of CsA and metothrexate was given to prevent a graft-versus-host reaction. RESULTS: Among the IST-receiving patients, overall survival (OS) was 71%. After the first course of IST by follow-up month 6, the response rate was 74%. The second course of IST was performed in 7 patients unresponsive after the first-line IST and in 8 patients with recurrent AA. After the second course of IST, the response rate was 46.7%. Four patients who failed to achieve remission after 2 courses of IST received its third course. A complete response was obtained in 3 patients. In 18 patients following allo-BMT (related and unrelated), OS was 86%; event-free survival was 65. In 12 patients after related allo-BMT, OS was 91.7%. CONCLUSION: Related allo-BMT is the method of choice if there is a HLA-compatible sibling. If there are contraindications to it or no related donor, IST with ATG + CsA is indicated. Ineffective IST is an indication for unrelated allo-BMT that may be recommended as life-saving therapy for young patients under 40 years of age. PMID- 20853610 TI - [The basic properties of mesenchymal stromal cells from the donor bone marrow: superficial markers]. AB - AIM: To characterize a superficial phenotype and to make a cytogenetic analysis of bone marrow (BM) mesenchymal stromal cells (MSC) from donors. MATERIALS AND METHODS: The study analyzed BM samples from 11 healthy donors. The phenotype of obtained MSC was analyzed using cytofluorometry. Chromosomal analysis was carried out at the first-second passage. RESULTS: The superficial phenotype of MSC was steady-state during 8 passages and conformed to the worldwide standard for this cell population. The marker NGFR+ was detectable only during the first 2 passages and the count of CD146+ cells was decreased to 50% as consecutive passages were carried out, which confirms that MSCs have lost their neural and endothelial differentiation capacity. MSCs are stably able to differentiate only into the mesenchymal lineage. The detection of chromosomal rearrangements in MSCs at different stages of cultivation revealed no clonal rearrangements in any case. However, chromosomal aberrations were found 3-10% of metaphases at the first and second passages, which may be associated with chromosome instability in primary cultures. CONCLUSION: The pooled data suggest that the analyzed MSCs meet the conventional worldwide standards. PMID- 20853611 TI - [Effectiveness of bortezomib and bortezomib-containing programs for the treatment of recurrent and resistant multiple myeloma]. AB - AIM: To evaluate the effectiveness of bortezomib and bortezomib-containing treatment programs in the therapy of resistant and recurrent multiple myeloma (MM) within a large unicenter study in real clinical practice conditions. SUBJECTS AND METHODS: The study enrolled 101 patients (48 men and 53 women aged 34 to 77 years, mean age 54 years) with resistant and recurrent MM. According to the types of paraprotein (PIg), the authors revealed the usual distribution: G, 60.7%; A, 23.8%; BJ, 13%; M, 1.15%; D, 1.15%. The PIg kappa/lambda light chain ratio was 1.7. The complicated course of the disease was noted in 50.4% of the patients. The patients were randomized into 4 treatment groups: V1--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of a 21-day cycle; V2--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 20 mg orally on day 2 of a 28-day cycle; V3--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days of a 42-day cycle; V4--velcade 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, melphalan 9 mg/m2 orally for 4 days, prednisolone 60 mg/m2 orally for 4 days, cyclophosphanum, 250 mg/m2 intravenously dropwise on days 1 to 7 of a 60-day cycle. An average of 6.5 induction treatment cycles was performed. RESULTS: Amongst the 27 patients receiving bortezomib therapy (V1), an objective response to therapy was obtained in 70.3%, including a complete response (CR) in 18.5%, a near-complete response (NCR) in 14.8%, and a partial response (PR) in 37%. When a combination of melphalan and bortezomib (VM; V2) was used, 22 patients achieved CR, NCR, and PR, which were equal to 9, 13, and 45.4%, respectively. In the group of 20 patients on the triple combination (VMP; V3), the amount of CR and PR was 90%. The use of the quadruple combination regimen (V4; VMCP) yielded an objective response (CR + NCR + PR) in 63.2% of the 32 patients, which did not virtually differ from other programs other than V3. However, the amount of CR +NCR (43.6%) was more than that in other groups. When all these programs were implemented, clinically significant myelotoxicity and grades 3 and 4 polyneuropathy were not seen. When the bortezomib-containing programs were applied, the median overall survival from the moment of diagnosis was 103 months. CONCLUSION: Bortezomib in the monotherapy and multidrug therapy for resistant and recurrent MM shows immediate and long-term benefits and a low toxicity. PMID- 20853612 TI - [Diffuse large B-cell lymphoma with primary involvement of mediastinal lymph nodes: diagnosis and treatment]. AB - AIM: To diagnose diffuse large B-cell lymphosarcoma (DLBCLS) with primary involvement of the mediastinal lymph nodes (LN) and to evaluate the efficiency of aggressive polychemotherapy (PCT). SUBJECTS AND METHODS: The study included 15 patients (6 men and 9 women aged 18 to 70 years; median 38 years) followed up at the Hematology Research Center, Russian Academy of Medical Sciences, in 2004 to 2009. Three and 12 patients had Stages II and IE DLBCLS, respectively. B symptoms were found in 14 (93.4%) patients. Increased lactate dehydrogenase (LDH) concentrations were detectable in 14 (93.4%) patients; tumors of 10 cm or more (bulky disease) were seen in 11 (73.3%). Enlarged cervical, supraclavicular, and axillary lymph nodes were found in 9 (60%) patients; lung involvement via extension in 9 (60%), and invasion into the pericardium in 5 (33.3%) and soft tissues of the anterior thoracic wall in (13.3%). There were no signs of involvement of extranodal organs at the moment of diagnosis. All the 15 patients received PCT according to the modified NHL-BFM-90 program: 4 to 6 courses depending on the response to the therapy; 10 (66.6%) and 5 (33.3%) patients had 4 and 6 courses, respectively; for consolidating purpose, 11 (78.5%) patients were prescribed radiotherapy applied to the mediastinum in a cumulative dose of 36 Gy due to the fact that they had a residual mass. RESULTS: Thirteen (86.6%) patients achieved a complete remission (CR). Primary PCT resistance was confirmed in one case. Another patient was stated to have near-complete remission. No recurrences were notified during the follow-up. The mean CR duration was 24.5 (range 2-49) months. CONCLUSION: DLBCLS with primary LN involvement is an individual nosological entity to be differentiated from primary mediastinal large B-cell lymphosarcoma. In most cases, DLBCLS shows signs of a poor prognosis, which makes it necessary to perform aggressive PCT. PMID- 20853613 TI - [Polyclonal rabbit antithymocyte globulin (thymoglobulin): immunomodulatory effects and new aspects of its clinical application]. AB - Antithymocyte immunoglobulins remain to be one of the most effective immunosuppressants used in transplantology and in the treatment of autoimmune diseases. The unique features of the mechanisms of individual antithymocyte globulin preparations should be borne in mind. Due to its polyclonal nature, thymoglobulin provides a wide spectrum of diverse immunomodulatory effects, which is the basis for its wide use in order to reduce the risk for graft rejection and a graft-versus-host reaction and to treat aplastic anemia. PMID- 20853614 TI - [Hereditary spherocytic hemolytic anemia in an adult with the formation of ectopic foci of extramedullary hemopoiesis in the chest]. AB - The paper describes a rare case of formation of paravertebral extramedullary hemopoietic foci in microspherocytic anemia or Minkovsky-Shoffar disease in an adult. Therapeutic splenectomy has led to regression of extramedullary hemopoietic foci, which supports that there is a direct relationship of the above formations to the specific features of the etiology and pathogenesis of microspherocytic anemia. PMID- 20853615 TI - [Multiple myeloma in renal transplant recipients]. AB - Severe renal failure (RF) may be the first and only clinical manifestation of multiple myeloma (MM). Occasionally the disease remains long unrecognized and the patients receive renal function replacement therapy, including renal transplantation (RT). To treat MM in renal transplant recipients is a complex medical and ethical problem. The paper presents the authors' experience in treating 3 patients with MM diagnosed after RT and evolving transplant lesion. Various morphological types of grafted kidney lesion were detected. These included fibrillar glomerulonephritis, cast nephropathy, and the latter concurrent with light-chain deposition disease. RF most rapidly progressed in cast nephropathy. The natural history of the disease was unfavorable in all patients; VAD and PAD chemotherapy programs proved to be ineffective. It is concluded that RT should not be performed in patients with extended-stage MM due to the fact that there is a considerable risk for renal transplant lesion and severe infectious complications that may occur during chemotherapy. Blood and urine immunochemical studies should be conducted in all the patients who are to undergo RT. PMID- 20853616 TI - [Neurosurgical treatment for chronic subdural hematoma in a patient with chronic autoimmune thrombocytopenic purpura]. AB - Intracranial hemorrhage in patients with chronic autoimmune thrombocytopenic purpura (CATP) is a rare and severe complication of the disease. By taking into account a concomitance of chronic subdural hematoma (CSH) and CATP and no generally accepted approaches to managing the patients with this concomitance, the authors describe a clinical case of mini-invasive CSH drainage in a patient with CATP. PMID- 20853617 TI - [Biological reductionism and the medicine of the 21st century]. AB - They were bothered by the fact that biological science, which was focusing on individual parts of the living systems in the hope that their knowledge should help understand the organization and principles of the living systems' existence, would be at a deadlock sooner or later. The development of fundamental molecular sciences proves them to be actually in a crisis. I would like to show, in this review, that the elevated expectations of a radical revolution in the field of fundamental biological sciences and in applied spheres, particularly, in practical medicine, which are due to the progress of high-effective technologies of the cell's molecular organization, especially the technologies designed for the sequencing of entire genomes, do not prove valid. These technologies cause the accumulation of vast amounts of information with no functional interpretation done. It starts to be comprehensible now that we advance at a painfully slow step to some successive stage on the path towards the answer to the essential question of biology -- What is Life? Moreover, understanding forms that we are advancing, equally slowly and painfully, along the path of progress in the field of medicine, especially so when it concerns the widely spread diseases, which are complex diseases. On this path, we often find ourselves at impasses with no way out, and although we witness the birth of a new biology -- the system biology, a synthetic one, constituting a unique alloy of many sciences, it is far from being definite that this new biology wouldalso answer this principal fundamental question and push forward the medical applications of genomics. Nonetheless, the accumulated information is very helpful and can be used for the elaboration of fundamental vetoes of biology [1] which will allow a considerable portion of the efforts in the practical, namely medical, area to be rejected as unrealizable, in the same way as the second principle of thermodynamics puts a ban on the creation of the perpetuum mobile. I am also trying to postulate that in the area of practice one should possibly think about the approaches directed to the eradication or substitution of ill cells or a damaged system's tissues, and not about the reductionistic approaches aimed at repairing the diseased organism's individual molecular components. I tried to demonstrate this statement using the example of cancer genetic surgerys. Employment of stem cells, including those modified by gene engineering, provides another instance of a holistic approach. PMID- 20853618 TI - [Participation of D(1)-receptors in anxiety-depression-like behaviour in female rats for ovary cycle]. AB - The present work was devoted to the comparative analysis of influence of chronic administration of D(1)-receptors agonist - SKF-38393 (0,1 mg/kg, i.p.) and D1 receptors antagonist - SCH-23390 (0,1 mg/kg, i.p.) for 14 days on anxiety and depressive-like behavior in the adult female rats. Model of depression in rats was carried out in Porsolt test. Anxiety level was assessed in the elevated plus maze. It was established that SCH-23390 rendered antidepressive and anxiolytic effects in females during estrous and proestrous. SKF-38393 resulted in prodepressive effect in estrous and proestrous. Also, it was noted definite modulation of anxiety behavior in connection of ovary cycle phases in rats treated with SKF-38393: at increased level of estrogens was anxiolytic effect while at reduced level of estrogen - anxiogenic effect. It is suggested different extent of D1-receptors receptors involvement in the mechanisms of anxiety depressive-like behavior at alterations of hormonal balance during ovary cycle. PMID- 20853619 TI - [The effect of taurine derivative of change the biochemical parameters carbohidrate and lipide status by starvation]. AB - The results obtained on the model of starvation shows that nutritional dropsy led to the significant decrease of glucose, total cholesterol (TCh) and triglycerides (TC), as well as increase of non-estherified fatty acids (NEFA) in blood serum. In the rats with nutritional dropsy after treatment fed with standard diet enriched with soybean protein body weight returned to normal values as well as levels of Glucose, TCh and TC. However, concentration of NEFA remained increased. In the experimental group received additionally taurepar or taurhythman the level of NEFA decreased up to the normal one. It is necessary to mention that taurine derivatives did not change the biochemical parameters in blood of normal non starved rats. We suppose that these new substances promote reduction of intensity of hyperlipidemic processes. It is known, that during starvation incomplete oxidation of fatty acids leads to acidosis with following destruction of mitochondria membraine. Finding property of taurine derivatives to decrease the concentration of non-estherified fatty acids points at their ability for restoration of tricarboxilic acid's cycle and prevention of accumulation of suboxidized molecules of NEFA and acidosis development. PMID- 20853620 TI - [Peculiarity modification mechanical property of a pulmonary tissue in the period of physiological pregnancy]. AB - In the period of pregnancy are reduced elastic of property of a pulmonary tissue. More than in 2 times is enlarged an extensibility, as at the expense of participation of the surface active agents, and some factors of parenchyma. The conditions for augmentation of the size of alveolus's, delay in them of air and infringement of a bodily machinery of respiration are framed. Obviously, as a result of rising a hydrophilic nature the effective viscosity plasticity of system of a pulmonary tissue is reduced, that causes infringement of alveolar ventilation (close-effect) and hypercarbondioxide in respiratory ways. The combined influence of the factors of pregnancy at some women promotes formation dynamic hyperinflation mild, development of respiratory failure and hypoxia to complications on the part of a fetus. PMID- 20853621 TI - [Physiological and pathological role of adipose tissue innate immune system receptors]. AB - The data of TLR-4 and TLR-2 existance in adipose tissue cells is presented in the review, their signal pathway is described, and an idea of physiological and pathological role of innate immune system receptors is given proof. TLRs activation leads to insulin resistance of adipose, hepatic and muscle cells, which increases glucose and lipids level in blood. This reaction is defined as a condition of physiological insulin resistance, which role is in providing immune processes with energetic and plastic substances. Ligands of TLRs are components of microorganisms: bacterial lipoproteins and liopolysacharides, as well as nonsaturated fatty acids. Inadequate uptake of the latter with food activates TLR 4 and R-2, acting as a mechanism for pathological alterations. Under the conditions of innate imunity receptors excessive activation, there is an adipose tissue inflammation, overproduction of cytokines, along with insulin resistance. It promotes the progress of obesity, diabetes and atherosclerosis. PMID- 20853622 TI - [Bioelectric brain activity under exposure to vibration]. AB - Patients with vibration disease caused by local vibration and those with the disease caused by general vibration demonstrate similar changes in regulation of central nervous system, as shown by EEG--diffuse changes and locus of pathologic activity mostly in right temporal cortex. Unlike local vibration, the combined one acting long (over 10-15 years) causes more pathologic changes in brain, not only in cerebral cortex, but also in brainstem and diencephalic structures. PMID- 20853623 TI - [Life quality as an additional criterion to evaluate efficacy of treating vibration disease patients]. AB - Studies covered as an additional criterion to evaluate efficiency of treating vibration disease patients. Studies covered life quality in 40 males having vibration disease during the treatment course. Before the treatment, all the examinees demonstrated decrease in all life quality parameters especially of "role physical functioning" (16.89 points), general health (38.39 points), role emotional functioning (39.64 points). After the treatment most the parameters reliably improved, besides physical and social functioning. The authors recommend SF-36 life quality questionnaire to evaluate treatment efficiency for occupational diseases. PMID- 20853624 TI - [Chronic pain syndrome and sleep disorders in patients with occupational diseases of upper extremities]. AB - Polling method revealed prevalence of chronic nightly pain syndrome and insomnia peculiarities in 126 patients having occupational hands diseases. Prevalence of chronic nightly pain syndrome in upper limbs among actively working patients with occupational hands diseases caused by functional overstrain was 68%; that among the vibration disease patients equalled 58%. The nightly pains were absent in the reference group. Prevalence of the nighly pains among the patients in post contact period was 83.3%. Insomnia prevalence, according to polling data in the workers, equalled 76% in functional overstrain cases and 63% in vibration disease cases, in post-contact period 72%, in the reference group 60% without reliable difference. Pilot polysomnographic study before and after the treatment of insomnia in 6 patients with sleep disorders demonstrated improvement of qualitative characteristics of sleep after the treatment. PMID- 20853625 TI - [Lipid metabolism state under exposure to noise and aluminum dust]. AB - Serum levels of total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides were studied in experimental machinery workers and in reference group. The examinees exposed to occupational hazards demonstrated severe dyslipidemia. PMID- 20853626 TI - [Safe levels of exposure to femtosecond laser impulse]. AB - The authors present results of studies concerning organic retinal lesions in laboratory animals exposed to femtosecond laser impulse. Conclusions necessitate changes of present laser safety norms on impulse effects of extra-short laser rays. PMID- 20853627 TI - [Retinoprotective and reparative properties of bioregulatory peptides for laser injury to eyeground]. AB - The article desribes biologic effects of impulse nanosecond length laser in visual range. Experimental studies proved retinoprotective and reparative properties of AV-17 preparation based on synthetic bioregulatory peptides. PMID- 20853628 TI - [Evaluation of matrix metalloproteinases (pro-MMP-1, MMP-2,8) and their inhibitor (TIMP-1) contents in patients with occupational lung diseases]. AB - Studies of matrix metalloproteinases in patients with occupational bronchopulmonary diseases and in individuals exposed to asbestos dust revealed hyperactivated protease system--lower level of MMP-1 proenzyme and increased production of TIMP-1 (metalloproteinases inhibitor)--in all the examinees groups. Patients with pneumoconiosis and occupational dust bronchitis demonstrated increased neutrophilic elastase that is activator of metalloproteinases inducing sclerotic changes and pulmonary fibrosis. PMID- 20853629 TI - [New approaches to treatment of occupational bronchial asthma]. AB - Clinical and biochemical studies considering pathogenetic mechanisms of bronchial asthma supported efficiency of "Singular" preparation and its promising quality for complex therapy of bronchial asthma. PMID- 20853630 TI - [Should locomotor disorders of upper extremities under exposure to local vibration be considered as a pathogenetic sign of vibration disease?]. AB - To understand role of local vibration in development of locomotory disorders in hands of vibration disease patients, the authors studied relationship between these disorders with major syndromes in vibration disease. Findings are that the main etiologic factor leading to locomotory changes at work with local vibration is a degree of static efforts in this type of work. PMID- 20853631 TI - [Measuring regulated values of workers' infrared irradiation]. AB - Using radiometers with limited visual angle to measure intensity of workers' all round infrared irradiation, the author demonstrated that the measured value should be reestablished through separate measurements. The reverse task is generally inconsistent. In sanitary and hygienic examinations, this objective could be targeted through spherical thermometer. Heat balance ratio enables to determine biologically effective flux of infrared irradiation. PMID- 20853632 TI - AMA, TMA involvement the key to fixing health system reform, SGR. PMID- 20853633 TI - Merge or die. PMID- 20853634 TI - How do I recognize and report a doctor shopper? PMID- 20853635 TI - Tennessee's new & improved doctor shopping law...and other victories for medicine in 2010. PMID- 20853636 TI - Public reporting quality information: what grade do the report cards get? PMID- 20853637 TI - Don't be sidetracked--follow the clues. PMID- 20853638 TI - Why physicians misprescribe. PMID- 20853639 TI - Selling your practice: are you making every dollar count? PMID- 20853640 TI - Smart solutions to ease your financial pressure. PMID- 20853641 TI - Prevalence of 25-hydroxyvitamin D deficiency in an urban general internal medicine academic practice. AB - Vitamin D deficiency has received increased academic interest because of its association with many common disease processes. The goal of our study was to document the prevalence of vitamin D deficiency. A retrospective chart review of 25-hydroxyvitamin D (ng/ml) levels at the University of Tennessee Health Science Center was conducted on general internal medicine patients over an 18-month period. The 25-hydroxyvitamin D deficient patients were divided into four groups: severe (<7 ng/ml), moderate (7.0-20.9 ng/ml), mild (21-31.9 ng/ml), and sufficient (>32 ng/ml). We found that an overwhelming majority of our patients were mildly to severely deficient (87 percent) with 17 percent severely deficient, 53 percent moderately deficient, 17 percent mildly deficient, and only 13 percent sufficient. The prevalence of 25-hydroxyvitamin D deficiency among this population was higher than expected based on the prevalence of 25 hydroxyvitamin D deficiency reported in literature. Based on this data, we believe a greater percentage of the general population needs to be studied in order to discover the true prevalence of vitamin D deficiency. PMID- 20853642 TI - Two newborn infants with middle cerebral artery infarct presenting with seizures. PMID- 20853643 TI - The Patient Protection and Affordable Care Act, cost control, and the battle for health care reform. PMID- 20853644 TI - Coping with triplets: perspectives of parents during the first four years. AB - Over the last several decades, there has been a dramatic increase in the number of triplets that are successfully conceived and delivered. With these increased numbers, there is a need for social workers to better understand the experiences of higher order multiple-birth parents. With the use of a qualitative approach, this study focuses on seven interviews obtained from a sample of parents with triplets ages four years or younger. The themes that emerged from the parents included confusion over high-risk pregnancy, learning to manage three babies, gathering support and creating community, adjusting relationships and responsibilities, and opportunities to strengthen triplet families. The results of the study have implications for social workers seeking to assist with the unique needs and experiences of these families. PMID- 20853646 TI - Challenges and mental health experiences of lesbian and bisexual women who are trying to conceive. AB - To date, there is little evidence to inform social work practice with lesbian and bisexual women who are trying to conceive (TTC). The authors report a preliminary examination of the mental health experiences of lesbian and bisexual women who are TTC, through a comparison with lesbian and bisexual women in the postpartum period (PP). Thirty-three lesbian and bisexual women (TTC, n = 15; PP, n = 18) completed standardized questionnaires assessing symptoms of depression and anxiety as well as relationship satisfaction and perceived social support. Qualitative interviews were also conducted to further investigate the experience of TTC. No significant differences were found between groups on any of the dependent variables. Analysis of qualitative data highlighted the challenges for lesbian and bisexual women who are TTC, particularly in terms of difficulty conceiving, lack of support during the conception process, and heterosexism in the fertility system. Women perceived these challenges to conception as having emotional consequences. The findings from this study begin to elucidate the unique context of TTC for lesbian and bisexual women, and they highlight the importance of culturally competent social work practice with this population. PMID- 20853647 TI - Using art as a self-regulating tool in a war situation: a model for social workers. AB - War poses a challenge for social workers, adding exposure to direct risk of personal harm to the general stress of social work practice. Artworks are frequently used in health care settings with people in high distress. This study had three goals: (1) to characterize the stressors of social workers living in a war zone, (2) to teach social workers in crisis situations to identify stress and resilience factors in their artworks, and (3) to develop a general self-care model for arts intervention for professionals in these situations. Common stressors experienced by participants were anxiety and fear as a result of bombs, sirens, worry over loved ones, and overexposure to media. These were layered onto professional stressors, including constant work communication on cell phones during war and dilemmas related to work-family conflicts. Allowing social workers to name and identity the sources of their stress and then change their artwork to enhance resilience helped them to gain a sense of control over diffuse sources of anxiety. The authors propose this method as an effective intervention model with social workers in high-stress situations. PMID- 20853645 TI - Is there disparity in physician service use? A comparison of Hispanic and white Medicare beneficiaries. AB - This article investigates general physician service use by a national sample of non-Hispanic white and Hispanic Medicare beneficiaries age 65 and older. Using the health behavior model as the conceptual framework, Oaxaca decomposition multivariate analyses were conducted to examine predictors for contact with a physician and the number of physician's office visits. Racial and ethnic differences were found in the predictor variables of initial contact with the physician and volume of physician service use. Besides needs factors, poverty level and having Medicaid were also significant predictors. Oaxaca decomposition analysis indicated that Hispanic beneficiaries' being less likely to make the initial physician contact could not be explained only by racial and ethnic differences. Although findings point to the equitable and nondiscriminatory treatment of Hispanic beneficiaries already using physician services, there is variance in the entry point of contact with a general physician for this minority group. Implications for social work are discussed. PMID- 20853649 TI - Intervention following a sudden death: the social work-medical examiner model. AB - The suddenly bereaved are faced with not only a very difficult grief experience, but also a lack of access to supportive services to assist them in working through that grief. The social work-medical examiner model was developed in an effort to address the challenge of reaching this population. The model provides a connection between social work practice and families experiencing sudden death. The model is rooted in services embedded within social work practice--crisis intervention, grief support, and referral assessment. In addition, the model demonstrates a mutually beneficial relationship between the social worker and the ME--each benefiting from the intricacies of the model process. Social work has had a prominent voice in the advancement of end-of-life care as it relates to families grieving long-term illness. The intervention described in this model expands this care, showing how social work practice can reach the suddenly bereaved population. The implementation of this model provides the field of social work a rare opportunity to reach a vulnerable population in need of support. PMID- 20853648 TI - Tailoring disaster mental health services to diverse needs: an analysis of 36 crisis counseling projects. AB - The federal Crisis Counseling Program (CCP) funds states' delivery of mental health services after disasters. These services are provided by social workers, other mental health professionals, and paraprofessionals from the local community. The present study examined whether CCP grant recipients that reported more tailoring of their interventions to the needs of diverse community segments achieved greater community penetration. The study reviewed archival records from 36 crisis counseling projects ending between 1996 and 2001. Numbers of clients and client ethnicity were determined through service logs. Tailoring ofservices was determined by content coding of projects' reports. Community demographics were determined from census data. Fifty-six percent of the projects reported using three or more tailoring strategies, suggesting a "precompetence" or greater stage of cultural competence. The proportion of members of racial or ethnic minority groups among program clients closely matched the proportion in grantees' communities. Projects that reported more types of tailored activities reached more clients and served more members ofminority groups. These findings confirm that adapting crisis counseling services to diverse local needs is associated with greater community penetration of mental health services. PMID- 20853650 TI - Supporting indirectly traumatized populations: the need to assess secondary traumatic stress for helping professionals in DSM-V. PMID- 20853651 TI - Unnatural causes: is inequality making us sick? PMID- 20853652 TI - A call to action for social work: minimizing financial hardship for families of children with special health care needs. PMID- 20853653 TI - [Conquering mucoviscidosis]. PMID- 20853654 TI - [Preparation for return home and coordination with hospitalization]. PMID- 20853655 TI - [Education involving non-invasive ventilation equipment at home]. PMID- 20853656 TI - [Learning to live better with chronic bronchopneumatic obstructive disease]. PMID- 20853657 TI - [Nursing professionalism for accompanying the patient to his home]. PMID- 20853658 TI - ["Nurses need to be concerned with their sense of caring for another, which is appropriate for their particular life"]. PMID- 20853659 TI - [The nurse and the care of the mentally retarded]. PMID- 20853660 TI - [Dying alone, a veritable project]. PMID- 20853661 TI - [Anticancer agents and risks for the nursing personnel]. PMID- 20853662 TI - [Introduction and evaluation of a new agent in the matter of hospital hygiene]. PMID- 20853663 TI - [Initiation of the Erasmus program in Ifsi]. PMID- 20853664 TI - [Maintaining the welcome, a meeting of nurse and patient]. PMID- 20853665 TI - Sophie's first day at the hospital. PMID- 20853666 TI - [Mental disorders in daily nursing]. PMID- 20853667 TI - [Nelly Martyl Scott (1884-1953)]. PMID- 20853668 TI - [The deaf have their rights: they need to be respected!]. PMID- 20853669 TI - Utility of virosomal adjuvated influenza vaccines: a review of the literature. AB - In spite of the efforts of the World Health Organization (WHO), influenza continues to be a major public health problem, both because of its impact on the health of subjects at risk, such as the elderly, and because of the economic burden that it places on society. Adjuvants are agents which, when incorporated into vaccines, enhance the immunogenicity of their antigens. The need for ever more immunogenic and efficacious influenza vaccines has led to the development of innovative vaccines. One of these, the virosomal vaccine, has been on the market since 1997. The results obtained through controlled clinical studies and widespread application in the field suggest that the virosomal vaccine is not only an important tool for the prevention of seasonal influenza but also a valid means of potentiating the effect of a pandemic influenza vaccine and, perhaps, of preparing multivalent or combined vaccines. PMID- 20853670 TI - The intradermal vaccination: past experiences and current perspectives. PMID- 20853671 TI - Study of the correlation between microfauna and the macrostructure of activated sludge and the efficiency of biological wastewater treatment plants. AB - Assessment of protozoan populations is an important tool in evaluating the efficiency of activated sludge in the treatment of wastewater. In this process, protozoa play a significant role by grazing on dispersed bacteria, supporting a healthy food web in activated sludge artificial ecosystems. The objective of this study was to verify how the success of the purification process in activated sludge plants, mainly in terms of TSS, BOD, and COD, is related to ciliate protozoa communities and the presence of filamentous bacteria. Samples were collected from five water treatment plants in the Puglia region, in the period May 2007 - April 2008. Microfauna and filamentous bacteria were identified and quantified, and the sludge biotic index calculated. The data show a correlation between the biological components of activated sludge and traditional chemical parameters. Our results indicate that biological analyses represent a valid alternative to traditional chemical testing in assessing the performance of activated sludge systems. PMID- 20853672 TI - A survey on planning, expectations and factors influencing the stabilization process of migrating people in Palermo, western Sicily. AB - BACKGROUND: Europe constitutes a major pole of attraction for the migratory fluxes. The migrating population is made up of many different individuals, carrying different projects of life and expectations. The consistence of the phenomena, in few decades, will be responsible for deep changes in the demographic structure of the European population. The purpose of this investigation was to attempt to draw an identikit of migrating people and to evaluate those factors which may be considered important to positively influence the process of stabilization. Moreover, the research tried to evaluate the differences among those migrating people who have recently arrived, still considering this country as a landing shore, and those who have definitely settled in Sicily. METHODS: The research was carried out through a 42 items multiple choice answer questionnaire administered to two groups of individuals who were born in a non European Union (EU) country. Individuals, who were still trying to settle (group A), were chosen at random in the streets of the city, while individuals with a solid and integrated family were chosen at random from the municipality of Palermo, Sicily. To compare the two different groups of individuals Student's t and Chi square tests were used together with standard descriptive statistics and linear regression analysis. RESULTS: Results seem to indicate that positive factors for integration are years of residence in the same place, support from the family since the very beginning of the migratory project, stable interethnic social structure. What did not seem to constitute determining factors in the territory analysed are: age, gender, country of origin, religion. Higher education levels apparently play a negative role. Child bearing indexes are higher than European levels. Birth rate was use in the attempt of modelling a projection of population growth. DISCUSSION: The collected data brings forth the snapshot of the typical immigrant as a young strong healthy individual, longing to start a family on safe values, who accepts transitory precarious living conditions in order to improve them. The major negative factors in the migratory project are those of social nature. Governments have generally adopted a politics of control on entry and of managing the emergency. There is a need for a politics of empowerment and exploitation of the capacity of the migrants. Deep changes occurring in the demographic structure of the European population might influence the social contest. Decrease European birth rate and increasing immigration may create a melting pot, where Europeans may take a role of an endangered species. PMID- 20853673 TI - Hepatitis E virus (HEV) in sewage from treatment plants of Messina University Hospital and of Messina City Council. AB - Samples of sewage from treatment plants at the "G. Martino" University Hospital of Messina (AOU) and that of Messina City Council were analysed to detect the hepatits E virus. Samples were taken on sewage entering and exiting the treatment plants on a monthly basis over a one-year period from both the hospital plant (24 samples) and the municipal plant (22 samples). All sewage samples were pretreated by ultrafiltraton and concentration and finally processed by the PCR method to amplify gene material. A total of three samples tested positive: two (8.33%) entering the AOU treatment plant and one (4.5%) entering the municipal plant while no cases of HEV were detected in samples of treated sewage. These findings confirm the presence of the virus in the city of Messina and showed that the two treatment plants to be working efficiently when tested. PMID- 20853674 TI - Molecular detection of virulence factors and antibiotic resistance pattern in clinical Enterococcus faecalis strains in Sardinia. AB - In this study, the antibiotic resistance pattern and the presence of genes encoding several virulence factors in 91 Enterococcus faecalis strains isolated from different human clinical sources in Sardinia were investigated. Genotypic determination of virulence genes (gelE, esp, agg, ace, cylA,B,M,L(L),L(S), efaA, fsrB) was carried out by PCR. The production of gelatinase and haemolytic activity were also determined. Antimicrobial susceptibility tests were performed by an automated microdilution test (Vitek). The strains examined in this study contained at least one and up to as many as all virulence genes investigated. Examining the distribution of these factors in the different groups of clinical strains, we found that all but one virulence determinant were detected more frequently among urinary isolates. The detection of some factors by PCR did not always correlate with its phenotypic expression. Antibiotic susceptibilities among the Enterococcus faecalis strains investigated in our study were typical for the species, with expected levels of acquired resistance. Faecal isolates had the highest percentage of resistance, especially to high level-gentamicin, ciprofloxacin and norfloxacin. In summary, a wide variety of genes encoding virulence factors have been detected among our clinical Enterococcus faecalis strains, and those isolated from UTI were characterized by a higher virulence potency compared with strains from other clinical sources. Silent virulence genes (cyl or gelE) were frequently detected, therefore both the genotypic and phenotypic assays seem necessary for a better characterization of the strains. Our results may serve as a basis for additional surveillance studies of infections caused by this microorganism. PMID- 20853675 TI - Microbial and nutritional aspects on the production of live feeds in a fish farming industry. AB - Aquaculture is an enterprise in constant development, in particular relating to its effect on the environment and also the quality of its products. It represents a valid alternative to traditional fishing, facing the increasing demand for fish products. To guarantee to the consumer a product of high nutritional, organoleptic and hygienic quality, it is fundamental to monitor every phase of the fish farming industry, isolating the potential risk points. For this reason there has been a rapid evolution of productive technique, particularly in the technology, artificial reproduction and feed sectors. The aim of this research has been the monitoring of the evolution of certain microbial and nutritional quality indexes (total microbial counts and lipid analysis on suspensions of Rotifers and Artemia, used as live feed) in the larval phase of the productive cycle of the farm raised fish, in an intensive system. The study has shown an increment in the total microbial counts in the fish farming industry within the production of Rotifers and Artemia, more evident in the suspensions of Rotifers. In addition the study has demonstrated that the maintenance phase, in the enrichment protocol, can reduce the EPA and DHA content. The results confirm the importance of microbial and nutritional control of the live feeds before they get supplied to fish larvae. PMID- 20853676 TI - How a university hospital improves its prevention performance: results of two biennial studies 2004-2006. AB - INTRODUCTION: Prevention is a legal obligation for French hospitals and should be systematically assessed. AIM: To measure how a French University Hospital improved its prevention performance between two biennial prevention studies after incentives measures were applied. METHODS: 45 medical, obstetrical or surgical units were included. A doctor-nurse pair was free to select inpatients at random. 14 preventive procedures were evaluated: blood pressure check, measures of weight, height and body mass index, screenings for diabetes, cervix and breast cancers, tetanus and influenza immunizations, serologies of viruses, research for a prostatic and cognitive disorder and evaluation of alcohol and tobacco consumptions and addictions. Incentives measures for prevention were enacted during the same time. RESULTS: In 2004 and in 2006, respectively 253 inpatients and 243 inpatients were respectively included. Tetanus immunization was checked in less than one tenth of cases in both the studies. Seven acts were performed more in 2006 and only body mass index was measured less. DISCUSSION: The results were encouraging but insufficient especially for tetanus immunization. Weight was measured more than body mass index, probably meaning that's weight and more precisely its variations are a better clinical sign. Bad results for tetanus immunization meant that incentive strategies only displayed within the hospital were ineffective. Lastly, two propositions were done to improve the questionnaire and the prevention performance: to add five preventive services and a medical file first page, common to all units, summing up all preventive procedures evaluated. CONCLUSION: The ability of this University Hospital to improve its prevention performance answering to local incentive measures was weak. Another solutions need to be found. PMID- 20853677 TI - Traumatic myiasis from Sarcophaga (Bercaeal cruentata Meigen, 1826 (Diptera, Sarcophagidae) in a hospital environment: reporting of a clinical case following polytrauma. AB - We present a case of cutaneous myiasis occurring in a hospital environment (nosocomial myiasis) in an patient with serious multiple traumas sustained in a motorcycle accident. The agent responsible for the myiasis was identified as Sarcophaga cruentata (Meigen 1826). The larvae found in the necrotic wound were removed and the necessary environmental measures were taken to avoid further infestation. Although nonocomial myiasis is a form of parasitosis already cited in the in literature, it is a rare event and worthy of attention to aid in identifying parasitosis in hospitalized subjects in order to expedite proper diagnosis and treatment. PMID- 20853678 TI - [Clinical trial on standard treatment of acute organophosphorus poisoning]. AB - OBJECTIVE: To explore the norms of treatment of acute organophosphorus pesticide poisoning (AOPP), and observe the curative effect. METHODS: On basis of the pre research, the norms of treatment of AOPP were summarized, and a multi-center clinical trial was performed in 6 hospitals selected from high incidence of AOPP in Shandong Province. RESULTS: 422 patients of AOPP in 6 hospitals in observation period were treated and observed by the norms of treatment. Among them, the proportion of oral poisoning was 97.16%, middle and severe degree were 87.44%. Compared with themselves 2 years ago before standard treatment, the curative effect of the norms of treatment for AOPP was much better than before. The mortality rate of AOPP declined from 9.87% to 1.66% (Chi2 = 27.92, P < 0.01), that was much better than the average therapeutic effect level of all our province in the same period (the mortality rate: 8.92%) (Chi2 = 26.05, P < 0.01). The average amount of atropine [(37.54 +/- 17.76) mg], dropped greatly [(1280.70 +/- 69.22) mg] (U = 439.22, P < 0.01).The usage of atropine by continuous intravenous injection with venous pump was better than ordinary intravenous injection. The mean dosage of pralidoxime chloride increased twice than the previous (U = 19.48, P < 0.01). There was no drug poisoning. CONCLUSION: The standard treatment of AOPP is urgently needed in our country, especially in rural area. By this trial, the satisfactory effect of the norms of treatment for AOPP summarized is observed and it reduces the fatality rate remarkably. PMID- 20853679 TI - [Expression and significance of Clara cell secretory protein in injury lungs of Kunming mice after n-hexane long-term inhalation]. AB - OBJECTIVE: To observe the expression of Clara cell secretory protein(CCSP) in the Kunming mouse model of n-hexane long-term inhalation, and to discuss the functions of Clara cell in injury lung induced by n-hexane. METHODS: 24 healthy mice were randomly divided into 4 groups: one control group and three n-hexane groups (4 w, 8 w and 12 w), 6 each group. Primary concentration of n-hexane was 17.6 g/m3, 8 hours per day, 6 d per week. After inhalation, n-hexane concentration of blood from celiac artery was detected. The lungs were embedded with paraffin and HE staining in the routine. The ratio of Clara cells with CCSP reaction in bronchiole and the number of macrophage cells with lysozyme reaction were determined by immuno-histochemistry. RESULTS: In the poisoning groups, the average n-hexane concentration of blood was significantly higher than that of the control group (P < 0.01). There were apparent pathologic damages in lungs of the poisoning mice. In poisoning 4 w, 8 w and 12 w groups, the ratio of Clara cells was significantly decreased [(73.33 +/- 4.21)%, (60.98 +/- 4.94)%, (34.04 +/- 2.33)% in terminal bronchiole, and (75.44 +/- 7.91)%, (58.54 +/- 4.86)%, (33.35 +/- 2.67)% in respiratory bronchiole] as compared with the control mice [(80.26 +/- 6.43)% and (81.74 +/- 7.75)%, P < 0.05 or P < 0.01], meanwhile the numbers of macrophage cells were gradually increased [(21.39 +/- 7.41), (28.54 +/- 10.73), (48.97 +/- 19.55) per microscopic field at 200x] in poisoning mice than those in control mice [(7.84 +/- 3.12) per microscopic field at 200x, P < 0.05 or P < 0.01]. CONCLUSION: In injury lungs after n-hexane inhalation, Clara cells are the target cells of n-hexane toxicity effect. Clara cells play an extensive protective role in lung inflammation. PMID- 20853680 TI - [Effect of Schisandrin B on mitogen-activated protein kinases and nuclear factor kappaB in rat lungs exposed to silica]. AB - OBJECTIVE: To investigate the effect of Schisandrin B on mitogen-activated protein kinases (MAPKs) and nuclear factor-KB in rat lungs exposed to silica. METHODS: 92 Wistar rats were randomly divided into four groups: Control (20), Silica (30), Sch-B treated 1 group (Sch-B 1) (24) and Sch-B treated 2 group (Sch B 2)(18). Silicotic animal models received an intratracheal injection of silica. From the first day after model establishment, rats in Sch-B 1 were treated intragastrically with Sch-B at a dose of 80 mg/kg, once daily. From the 8th day after model establishment, rats in Sch-B 2 were treated intragastrically with Sch B at a dose of 80 mg/kg, once daily. 6 rats in Sch-B 1 were sacrificed on the 3rd, 7th, 14th and 21st days, and 6 rats in Sch-B 2 on the 14th, 21st and 28th days, 4 Control rats, 6 silica rats on the 3rd, 7th, 14th, 21st and 28th days accordingly, lungs were collected. Right lung for protein extraction, the phosphorylation level of extracellular signal-regulated protein kinase, c-Jun NH2 terminal amino kinase and p38 in lungs were detected by Western Blot. Left lung was fixed by neutral formalin. The ratio of nuclear transfer of NF-kappaB was evaluated by immunohistochemistry. RESULTS: 1. The phosphorylation level of ERK1/2 in Sch-B 1 on 3rd, 7th, 14th and 21st (0.974 +/- 0.169, 0.987 +/- 0.149, 0.920 +/- 0.092 and 0.884 +/- 0.078) and Sch-B 2 on 14th, 21st and 28th (1.012 +/ 0.050, 1.167 +/- 0.083 and 1.002 +/- 0.060) were significantly lower than in silica groups P < 0.05 or P < 0.01); The phosphorylation level of JNK1 in Sch-B 1 reached its summit on 7th day (P < 0.01 ), and that in Sch-B 2 on 14th, 21st and 28th (0.882 +/- 0.064, 0.802 +/- 0.061, 0.792 +/- 0.015) was lower than Silica groups at every time points (P < 0.01); The phosphorylation level of p-p38 in Sch B 1 was higher than silica group on 3rd day (0.309 +/- 0.045) and lower on 7th, 14th and 21st day, but that in Sch-B 2 were lower and lower. 2. The ratio of nuclear transfer of NF-KB in Sch-B 1 on 3rd, 7th, 14th and 21st [(13.54 +/- 5.36)%, (21.01 +/- 6.43)%, (30.55 +/- 6.44)%, (37.39 +/- 9.32)%] was lower than that in silica groups (P < 0.01); but in Sch-B 2, it was lower than silica group on the 21st [(44.33 +/- 22.88)%] and higher on the 28th day [(58.52 +/- 14.57)%] (P < 0.01). CONCLUSIONS: Sch-B has some depression effects on the activation of MAPKs in rat lungs exposed to silica. The nuclear transfer of NF-kappaB could be suppressed by Sch-B in the initial stage of rat lungs exposed to silica. Protection of Sch-B against silica induced lung injury in rats may be via MAPKs and NF-kappaB signal transduction pathway. PMID- 20853681 TI - [Synergistic interaction between MMP-3, VDR gene polymorphisms and occupational risk factors on lumbar disc degeneration]. AB - OBJECTIVE: To explore the synergistic interaction between MMP-3,VDR gene polymorphisms and occupational risk factors on lumbar disc degeneration. METHODS: A case-control study including 178 cases of lumbar disc degeneration and 284 controls was carried out through questionnaire and polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technology. Additive model was used to analyze the synergistic interaction between gene polymorphisms and occupational risk factors. RESULTS: The non-conditional logistic regression analysis showed that bending/twisting, whole-body vibration, heavy physical workload, alleles 5A of MMP-3 (6A5A/5A5A) and A of VDR-Apa (AA/Aa) were significantly associated with lumbar disc degeneration(OR = 4.06, 8.96, 5.46, 1.96 and 1.70, respectively, P < 0.05). There were synergistic interactions between the mutation genotype 5A of MMP-3 and whole-body vibration exposure, between the mutation genotype 5A of MMP-3 and bending/twisting, and between the mutation genotype A of VDR-Apa and whole-body vibration exposure (SI: 13.27, 2.91 and 2.35 respectively, P < 0.05). CONCLUSION: People with the mutation genotypes 5A of MMP-3 and/or A of VDR-Apa may have the increased risk of developing lumbar disc degeneration if they are exposed to whole-body vibration and/or bending/twisting. PMID- 20853682 TI - [Effects of 1-bromopropane on neurological and hematological changes of female exposed workers]. AB - OBJECTIVE: To investigate the health effects of 1-bromopropane (1-BP) on female exposed workers. METHODS: Four 1-BP manufacturing plants were investigated. Workers were interviewed with questionnaire and examined with neurobehavioral core test battery, nerve conduction velocity tests of nervus tibialis and nervus suralis, vibration sensation test, hematological and biochemical tests. Ambient 1 BP concentration was measured with detection tube, and time-weighed average levels of individual workers were estimated with passive samplers. RESULTS: 1-BP concentration in the plants ranged from 0 to 402.40 mg/m3 (Geomean 32.19 mg/m3). Time-weighted average exposure levels (TWA-8 h) ranged from 0.35 to 535.19 mg/m3 (Geomean 14.08 mg/m3). Compared with the control group, 1-BP exposed workers showed reduced motor nerve conduction velocity [(44.8 +/- 8.7) m/s] and sensory nerve conduction velocity [(45.5 +/- 4.9) m/s], prolonged distal latency [(7.5 +/ 2.1) ms], reduced toe vibration perception, and altered neurobehavior parameters(POMS vigor, tension, anxiety, confusion) significantly (P < 0.05). As to hematological and biochemical indicators, the exposed workers showed decreased white blood cell count [(5.6 +/- 2.17) x 10(3)/microl], red blood cell count [(3.9 +/- 0.4) x 10(6)/microl], hemoglobin [(121.1 +/- 14.5) g/L] and creatine kinase [(82.0 +/- 27.5) IU/L] (P < 0.05), and increased serum total protein (8.0 +/- 0.5 g/dl), lactate dehydrogenase [(335.2 +/- 356.6) IU/L], thyroid stimulating hormone [(3.6 +/- 2.3) microIU/ml] and follicle-stimulating hormone levels (18.7 +/- 24.4 mIU/ml) (P < 0.05). CONCLUSION: 1-BP exposure may affect peripheral nerves and central nervous system, and lead to abnormal hematological and biomedical indicators. PMID- 20853683 TI - [One case of isophthalonitrile mixture burning combined with peripheral nerve injury]. PMID- 20853684 TI - [Rat kidney mitochondrial damage induced by acute cadmium administration]. AB - OBJECTIVE: To evaluate effect of acute cadmium administration on mitochondria from rat kidney. METHODS: 24 male Sprague-Dawley (SD) rats were randomly divided into four groups. Four groups of rats were injected with saline, 0.6, 1.2, and 1.8 mg/kg weight subcutaneously, once daily, for 5 days, respectively. Ultrastructural change of rat kidney mitochondria was observed, and respiration function, membrane potential, mitochondria swelling, and superoxide level were determined. RESULTS: Ultrastructural changes included matrix vacuolation, swelling and condensation of mitochondria. In group of 1.8 mg/kg body weight, the oxygen consumption rate during state 3 respiration [(6.25 +/- 0.61) nmol/L O2 x min(-1) x mg(-1)] and RCR value (2.45 +/- 0.23) were significantly lower than those of control group [(9.66 +/- 1.16) nmol/L O2 x min(-1) x mg(-1)] (P < 0.05), indicating respiration inhibition. The membrane potential and superoxide level of the same group were 85.89% +/- 3.82% and 116.33% +/- 3.06% of control values (P < 0.05), respectively. CONCLUSIONS: Acute cadmium administration can cause rat kidney mitochondrial damage in a dose-effect manner, including inhibition of respiration, dissipation of membrane potential, swelling of mitochondria matrix. Such damage might be related to the increase of mitochondrial free radical. PMID- 20853685 TI - [Analysis for conditions of use of organic solvents in enterprises of five categories]. PMID- 20853686 TI - [Investigation on level of DDT accumulation in women and children of a polluted area]. PMID- 20853687 TI - [P16 and Rb protein in lung tissue of patients with coal workers' pneumoconiosis and lung cancer]. PMID- 20853688 TI - [Experimental research on Paraquat clearance rate after hemoperfusion adsorption]. PMID- 20853689 TI - [Observation on therapeutic effect of double unrelated umbilical cord blood transplantation for treatment of leukemia due to chronic benzene poisoning in adults]. PMID- 20853690 TI - [Modified silica gel for absorption of ammonia]. PMID- 20853691 TI - [High performance liquid chromatography for determination of sevin in air of working places]. PMID- 20853692 TI - [Preparation of dust quality control samples in laboratory]. PMID- 20853693 TI - [Thermal desorption gas chromatography for determination of hexafluoropropylene in air of working places]. PMID- 20853694 TI - [Occupational health sentinel surveillance in basic occupational health services]. PMID- 20853695 TI - [Effect of basic occupational health service on prevention and treatment of occupational diseases]. PMID- 20853696 TI - [Outline of revision of hygienic standards for design of industrial enterprises (GBZ 1-2010)]. PMID- 20853697 TI - [Research and determination of occupational exposure limits of nitroguanidine in air of working places]. PMID- 20853698 TI - [On occupational hygiene work]. PMID- 20853699 TI - [Bibliometrics evaluation for articles published in China between 1999 and 2008 from nine provincial level occupational diseases prevention and treatment institutions]. PMID- 20853700 TI - [Investigation and application of methods for evaluation of occupational risks of chemical hazards factors in working places]. PMID- 20853701 TI - [One case of pneumoconiosis combined with pulmonary alveolar proteinosis]. PMID- 20853702 TI - [Whole lung lavage for treatment of six patients with pulmonary alveolar proteinosis]. PMID- 20853703 TI - [Two cases of chronic benzene poisoning induced macrocytic anemia]. PMID- 20853704 TI - [Progress in research on biological monitoring indicators of occupational xylene exposure]. PMID- 20853705 TI - [Value of gastrointestinal decontamination in treatment of acute poisoning]. PMID- 20853706 TI - From descent to ascent--the human exception in the evolutionary synthesis. AB - As the 'Darwin anniversary' (2009) has amply illustrated, Charles Darwin is seen as having forced a new understanding of self on humankind as a product of blind natural forces. However, mechanisms such as orthogenesis and the inheritance of acquired characteristics were maintained post-Origin to explain purposeful evolution. Only with the modern synthesis these mechanisms lost their validity, and Darwinian selection theory became the core of evolutionary biology. Thereafter, teleology was no longer an aspect of the natural world. This is how Theodosius Dobzhansky, Julian Huxley, Ernst Mayr, and George Gaylord Simpson told the history of evolutionary biology after Darwin throughout their lives. In the aftermath of the Darwin-year, it is worth taking another look: Was it in the evolutionary theories of the synthesis that humans finally became generally regarded as just another kind of living organism, subjected to the indifferent mechanisms of evolution and the whims of chance? PMID- 20853707 TI - [Between radical change and conservation: the investigation of bioelectric phenomena in Germany in the late nineteenth century]. AB - This paper aims at illustrating the historical circumstances which led Julius Bernstein in 1902 to formulate a membrane theory on resting current in muscle and nerve fibers. It was a truly paradigm shift in research into bioelectrical phenomena, if qualified by the observation that, besides Bernstein, many other electrophysiologists between 1890 and 1902 borrowed ideas from the recent ionistic approach in the physical chemistry domain. But the Bernstein's subjective perception of that paradigm shift was that it constitued a mere re interpretation of the so-called pre-existence theory advanced by his teacher Emil du Bois-Reymond in the first half of the 19 century. PMID- 20853708 TI - Cultural objects as objects: materiality, urban space, and the interpretation of AIDS campaigns in Accra, Ghana. AB - AIDS media lead unexpected lives once distributed through urban space: billboards fade, posters go missing, bumper stickers travel to other cities. The materiality of AIDS campaign objects and of the urban settings in which they are displayed structures how the public interprets their messages. Ethnographic observation of AIDS media in situ and interview data reveal how the materiality of objects and places shapes the availability of AIDS knowledge in Accra, Ghana. Significantly for AIDS organizations, these material conditions often systematically obstruct access to AIDS knowledge for particular groups. Attending to materiality rethinks how scholars assess the cultural power of media. PMID- 20853709 TI - [In search of well-being]. PMID- 20853710 TI - [Apathy and therapeutic non-observance]. PMID- 20853711 TI - [What is the ideal blood pressure goal for the hypertensive population in 2010? Review of the evidence in the literature]. AB - The guidelines for treating high blood pressure, published in 2007, have been discussed in 2009. Currently, when hypertension is confirmed, it is proposed to treat the patients with a blood pressure goal of 130-139/80-85 mmHg whatever the diseases associated with hypertension. The authors recommended that if the patient tolerates lower blood pressures, the treatment could be continued. Many questions remained without any clear answer for the lowest protective target of blood pressure. The choice of antihypertensive agents appears to become more important in people with high cardiovascular risk. However, never forget to improve the cardiovascular risk by modifying the lifestyle and diet of the whole hypertensive population and by optimally acting on the associated risk factors identified. PMID- 20853712 TI - [Multirisk approach of the type 2 diabetic patient: controversies surrounding target values after the ACCORD trial]. AB - The ACCORD trial investigated the effects of intensifying the global management of 10,251 type 2 diabetic patients, with established cardiovascular disease or at least two other cardiovascular risk factors, on a composite endpoint (non fatal myocardial infarction, stroke and cardiovascular death). The attempt to reduce HbA1c level below 6% was associated with an increased cardiovascular mortality (despite a reduction in non fatal myocardial infarcts); lowering systolic blood pressure below 120 mmHg instead of 140 mmHg did not provide any additional benefit; finally, the control of atherogenic dyslipidaemia, with fenofibrate added to a statin, did not modify the composite endpoint (despite a positive effect in the subgroup of patients with high triglycerides and low HDL cholesterol). These rather disappointing results should be interpreted to provide practical guidelines. PMID- 20853713 TI - [New trends in treatment of hypertrophic cardiomyopathy]. AB - The management of patients with hypertrophic cardiomyopathy has largely evolved over the past two decades. One important finding is that medical treatment appears under used. Invasive procedure are reserved to patients with obstructive hypertrophic cardiomyopathy who remain symptomatic despite optimal medical treatment. Indications for implantable cardiac defibrillator are still debated. A global and multidisciplinary approach of the patient and of his family is mandatory. PMID- 20853714 TI - [Therapeutic education and continuous glucose monitoring in insulin-treated diabetic patients]. AB - The effectiveness of a specific educational programme involving the use of a real time glucose-sensor system to improve glucose control was investigated in patients with type 1 diabetes (glucose sensor combined with a portable insulin pump--Paradigm Real Time) and in patients with type 2 diabetes poorly controlled despite insulin therapy (Guardian RT one week per month for 3 months compared to blood glucose self-monitoring). Both studies showed a reduction in glycated haemoglobin (HbA1c) levels with the glucose sensor, associated with less symptomatic hypoglycaemic episodes. Despite some technical difficulties (mainly in patients with type 2 diabetes), this approach represents a useful tool for therapeutic education. These promising results justify the initiation of larger studies evaluating glucose sensor use in well selected diabetic patients. PMID- 20853715 TI - [Anti-cancer activity of metformin: new perspectives for an old drug]. AB - Type 2 diabetes is associated with a higher risk of cancer, which appears more obvious since the reduction of cardiovascular mortality. All glucose-lowering oral agents do not have the same impact on cancer: the risk is increased with sulfonylureas and decreased with metformin (and glitazones). Numerous epidemiological observational and case-control studies showed that metformin is associated with a lower incidence of cancer and a lower cancer-related death rate. A dose-response relationship and a relation between duration of prior treatment with metformin and the protective effect against cancer have been reported. Mechanisms involved are the activation of the AMPK enzyme and the inhibition of the mTOR pathway. Studies with metformin are ongoing in the field of oncology, especially as adjunct to treatment of breast cancer. PMID- 20853716 TI - [Reduction of obesity-related metabolic risk by modulating tissue exposition to cortisol]. AB - The 11-beta-hydroxysteroid dehydrogenase type 1 (11HSD1) enzyme promotes the local conversion from cortisone to cortisol, especially in the liver and the adipose tissue. It may play a role in the pathophysiology of abdominal obesity and the metabolic syndrome, both showing some similarities with the Cushing syndrome. Considering experimental results obtained in rodents, the inhibition of this enzyme could exert favourable metabolic effects, with significant reductions in plasma glucose, insulin resistance and dyslipidaemia. Synthetic inhibitors of 11HSD1 are currently in development with encouraging preliminary results, first in animals, and more recently in humans. Selective inhibitors of 11HSD1 may represent an innovative approach in the pharmacological management of obesity, metabolic syndrome and type 2 diabetes in a near future. PMID- 20853717 TI - [The mandate of maintenance of medical records by health professionals]. PMID- 20853718 TI - [Postgraduate medical education]. PMID- 20853719 TI - [Type 2 diabetes: is the treatment based on evidence?]. PMID- 20853720 TI - [Intramuscular injection techniques for prevention of complications]. PMID- 20853721 TI - ["Injection rooms:" a sad French controversy]. PMID- 20853722 TI - [Those with interest, experts, and followers of witchcraft]. PMID- 20853723 TI - [One never forgets, even when one tries hard to]. PMID- 20853724 TI - The new word of mouth. PMID- 20853725 TI - Reader takes exception to article. PMID- 20853726 TI - People with Moebius syndrome show improved adjustment to facial disorder. PMID- 20853727 TI - Step-by-step dentistry. PMID- 20853728 TI - Revisiting the design of minimal and no-preparation veneers: a step-by-step technique. AB - The concept of minimal preparation is more than 25 years old. Interest in conservative treatments is being revisited as dentistry embraces thinner ceramic veneers and adhesive bonding agents that keep preparations in enamel. Experience and professional knowledge help determine appropriate treatments based on patients' clinical situations and esthetic demands. This article reviews the veneer modality, its role as a conservative treatment, and the protocol to be implemented to ensure proper treatment planning and material selection. PMID- 20853729 TI - Implant verification cast--a predictable restorative system in implant prosthodontics. AB - An implant verification cast is designed to provide an accurate representation of dental implant positions extraorally. It can be used by the laboratory as a trusted cast to create a passively fitting framework and by the clinician to verify framework fit prior to intraoral trial. This article discusses the treatment philosophy behind this specific cast and reviews applications, fabrication techniques and benefits of the verification cast compared to the conventional technique. PMID- 20853730 TI - Challenges in achieving gingival harmony. AB - Gingival harmony is an important element in the esthetics of the smile. Clinicians need to have the essential knowledge to create an optimal soft-tissue profile around teeth and implant restorations. The goal of this article is to describe the requirements for ideal gingival architecture and techniques used to achieve them. The patient presentations in this article will demonstrate different aspects of esthetic soft-tissue surgery as well as treatment challenges and limitations. PMID- 20853731 TI - Orthodontic treatment of a complex open-bite malocclusion with temporary anchorage devices: a case report. AB - Orthodontic temporary anchorage devices provide a novel alternative to orthognathic surgery for the treatment of severe anterior open-bite malocclusions. These implantable devices provide skeletal anchorage for maxillary molar intrusion, allowing for mandibular autorotation and subsequent open-bite closure. This case demonstrates step-by-step treatment of a 41-year-old woman with a severe open-bite malocclusion. Detailed orthodontic mechanics are described at every stage of treatment. PMID- 20853732 TI - The little dental clinic that could. PMID- 20853733 TI - Stop! Evaluate website before use. PMID- 20853734 TI - Dissatisfaction inside the dental office. PMID- 20853735 TI - Nitrous oxide and oxygen sedation: an update. AB - Nitrous oxide/oxygen sedation remains a viable option for managing a patient's pain and anxiety in the dental office. There are several advantages to its use and relatively few contraindications. Knowing how to minimize the operator's exposure to the gas is also an important consideration. N2O/O2 sedation has a long-standing history of safety and success and it is likely that this type of sedation will be used far into the future. It is necessary to educate the entire office team on the biohazard issues of nitrous oxide safety in the dental office and keep abreast of sound scientific literature in this area. Many states are starting to include nitrous oxide administration and monitoring in their state practice acts for dental assistants. Refer to your state practice act for current requirements in your location. PMID- 20853736 TI - Disease dynamics of Montipora white syndrome within Kaneohe Bay, Oahu, Hawaii: distribution, seasonality, virulence, and transmissibility. AB - We report on an investigation of Montipora white syndrome (MWS), which is a coral disease reported from Hawaii, U.S.A., that results in tissue loss. Disease surveys of Montipora capitata within Kaneohe Bay (Oahu) found colonies that were affected by MWS on 9 reefs within 3 regions of Kaneohe Bay (south, central, north). Mean MWS prevalence ranged from 0.02 to 0.87% and average number of MWS cases per survey site ranged from 1 to 28 colonies. MWS prevalence and number of cases were significantly lower in the central region as compared to those in the north and south regions of Kaneohe Bay. There was a positive relationship between host abundance and MWS prevalence, and differences in host abundance between sites explained approximately 27% of the variation in MWS prevalence. Reefs in central Kaneohe Bay had lower M. capitata cover and lower MWS levels. MWS prevalence on reefs was neither significantly different between seasons (spring versus fall) nor among 57 tagged colonies that were monitored through time. MWS is a chronic and progressive disease causing M. capitata colonies to lose an average of 3.1% of live tissue mo(-1). Case fatality rate was 28% after 2 yr but recovery occurred in some colonies (32%). Manipulative experiments showed that the disease is acquired through direct contact. This is the first study to examine the dynamics of MWS within Hawaii, and our findings suggest that MWS has the potential to degrade Hawaii's reefs through time. PMID- 20853737 TI - Amphibian pathogen Batrachochytrium dendrobatidis prevalence is correlated with season and not urbanization in central Virginia. AB - The global amphibian pathogen Batrachochytrium dendrobatidis (Bd) has been documented among many species throughout the United States, though cases of chytridiomycosis, the resulting disease, have occurred mostly on the west coast. We conducted a 2 yr survey of amphibians along an urban gradient in Virginia, U.S.A., to test whether Bd prevalence among the amphibians sampled varied with urbanization and/or season. A total of 867 adult amphibians from 13 species and 49 tadpoles from 3 species were tested for Bd. The level of urbanization was based on surrounding human population density and anthropogenic disturbance. Bd was detected in 6 species. Bd prevalence was not found to vary with increases in urbanization, but did vary with season. Prevalence peaked in the spring at 45%, when temperatures were between 14 and 25 degrees C, and dropped to below 2% in the autumn. Results from this survey support the hypothesis that Bd is endemic to the studied sites in Virginia. The present study, in concurrence with previous research by other investigators, shows that Bd is affected strongly by weather patterns. Urbanization, defined by human population density, appeared to have minimal impact on the prevalence of Bd. In addition to understanding the geographic distribution of Bd, it is important to understand factors that affect its prevalence if we are to develop approaches to managing this emerging disease. PMID- 20853738 TI - Effects of Batrachochytrium dendrobatidis infection on ion concentrations in the boreal toad Anaxyrus (Bufo) boreas boreas. AB - Batrachochytrium dendrobatidis causes mortality in various amphibian species including the boreal toad Anaxyrus (Bufo) boreas boreas. The purpose of this study was to determine the physiological effects of this pathogen on experimentally infected boreal toads. Plasma osmolality, sodium, and potassium concentrations were analyzed to evaluate the differences between diseased and non exposed animals. Infected animals with clinical signs of chytridiomycosis had significantly lower plasma osmolality, sodium, and potassium levels than non infected animals (p < 0.06). On average, clinically infected animals housed in an aquatic environment had sodium and potassium levels of 60.1 (SE = 9.7) and 2.06 (SE = 0.32) mmol l(-1), respectively. These ion levels were significantly lower than the negative controls (sodium = 115.0 mmol l(-1), potassium = 3.7 mmol l( 1)) and consistent with the clinical signs observed in affected animals. We propose that infection with B. dendrobatidis results in an electrolyte disorder in boreal toads. PMID- 20853739 TI - Comparative susceptibility of representative Great Lakes fish species to the North American viral hemorrhagic septicemia virus Sublineage IVb. AB - The present study compared the susceptibility of representative Laurentian Great Lakes fish species to the emerging viral hemorrhagic septicemia virus (VHSV) Genotype IVb. The median lethal dose of infection by intraperitoneal injection (IP-LD50) was obtained from fish that were experimentally infected with the MI03 index strain of VHSV-IVb. Fish were injected at doses ranging from 7 x 10(7) to 7 x 10(-2) plaque-forming units (pfu) and maintained at 12 +/- 1 degrees C. The infection trials identified species of high, medium, and low susceptibility based on the IP-LD50 values. Pathogenicity of VHSV-IVb was highest in largemouth bass Micropterus salmoides, which resulted in an IP-LD50 of 1.5 x 10(2) pfu, while also demonstrating the clinical diathesis of VHSV-infected fish. The virus was moderately pathogenic in yellow perch Perca flavescens (IP-LD50 of 2.5 x 10(5) pfu), but also showed the classical signs of VHSV infection. Salmonids were the least susceptible to VHSV-IVb with IP-LD50 values of no less than 1.4 x 106 pfu; however, in fish that succumbed to infection, characteristic VHSV lesions were observed. Histopathologic alterations were most profound in gill, skin, muscle, gonads, and liver of largemouth bass and yellow perch, while in salmonids, hemorrhages in the swimbladder and/or degenerative changes in the liver were the most common lesions noticed. VHSV was isolated from infected fish, and its identity was confirmed by the reverse transcriptase polymerase chain reaction. These results highlight the variations among fish species susceptibility to this emerging strain of VHSV and offer insights into the potential impact of VHSV-IVb on the Laurentian Great Lakes fish community. PMID- 20853740 TI - Low genetic variation in the salmon and trout parasite Loma salmonae (Microsporidia) supports marine transmission and clarifies species boundaries. AB - Loma salmonae is a microsporidian parasite prevalent in wild and farmed salmon species of the genus Oncorhynchus. This study compared ribosomal RNA (rDNA) and elongation factor-1 alpha (EF-1alpha) gene sequences to look for variation that may provide a basis for distinguishing populations. Specimens were collected from laboratory, captive (sea netpen farm and freshwater hatchery) and wild populations of fish. The host range included rainbow trout O. mykiss, Pacific salmon Oncorhynchus spp. and brook trout Salvelinus fontinalis from British Columbia, Prince Edward Island, Canada, from California, Colorado, Idaho, U.S.A. and from Chile. Both loci suggested that a variant in S. fontinalis (named 'SV') was a separate species. This was supported by the absence of similar variants in the source material (isolated from laboratory-held O. tshawytscha) and high divergence (1.4 to 2.3% in the rDNA and EF-1alpha) from L. salmonae in the type host and locality (0. mykiss in California). L. salmonae from freshwater and anadromous Oncorhynchus spp. were distinguished, providing a basis on which to evaluate possible sources of infection and suggesting geographic boundaries are important. Higher genetic variation occurred among samples of freshwater origin and from a sea netpen farm in Chile, suggesting these environments may present greater population diversity. Invariance in rDNA sequence across 17 samples from anadromous salmon in rivers, lakes, ocean, farms and hatcheries supports the hypothesis that marine transmission occurs and effectively prevents population substructuring caused by freshwater transmission. PMID- 20853742 TI - Ulcerative disease outbreak in crayfish Orconectes propinquus linked to Saprolegnia australis in big Muskellunge Lake, Wisconsin. AB - Crayfish populations in the area of the North Temperate Lakes Long Term Ecological Research (LTER) project, Wisconsin, USA, have been monitored for >25 yr. In 2005, native crayfish Orconectes propinquus from Big Muskellunge Lake were found with ulcerated lesions in the cuticle. In 2006, lesions occurred in 9.5% of sampled crayfish from the lake (n=3146). Ulcers generally occurred on the appendages of affected individuals but varied in location and severity. The prevalence of ulcers varied widely among sites, sample depths, and sampling dates, ranging from < 2% to >20%. The prevalence of ulcers in crayfish increased from a minimum in early June to a maximum in late July and August. In aquarium trials, healthy crayfish representing either O. propinquus or O. rusticus co housed with ulcerated crayfish did not develop ulcers within 4 wk of exposure. Gross and histopathologic analyses of ulcerated crayfish revealed the presence of filamentous hyphae in the lesions while hemocytic infiltrates, melanotic reactions and silver-stained sections indicated that the ulcers had an oomycete etiology. Excised samples of ulcerated crayfish cuticle grown in culture developed an oomycete that was identified as Saprolegnia australis by PCR amplification and sequence analysis of 2 different DNA fragments. This is the first report of the occurrence of ulcers in wild crayfish associated with S. australis infection in the U.S.A. The advent of the outbreak and its underlying ecological causes are still under investigation. PMID- 20853743 TI - Histopathology of oedema in pearl oysters Pinctada maxima. AB - In October 2006, severe mortalities (80 to 100%) were reported in pearl oyster Pinctada maxima production farms from Exmouth Gulf, Western Australia. Only P. maxima were affected; other bivalves including black pearl oysters P. margaratifera remained healthy. Initial investigations indicated that the mortality was due to an infectious process, although no disease agent has yet been identified. Gross appearance of affected oysters showed mild oedema, retraction of the mantle, weakness and death. Histology revealed no inflammatory response, but we did observe a subtle lesion involving tissue oedema and oedematous separation of epithelial tissues from underlying stroma. Oedema or a watery appearance is commonly reported in published descriptions of diseased molluscs, yet in many cases the terminology has been poorly characterised. The potential causes of oedema are reviewed; however, the question remains as to what might be the cause of oedema in molluscs that are normally iso-osmotic with seawater and have no power of anisosmotic extracellular osmotic regulation. PMID- 20853741 TI - Pleistophora hyphessobryconis (Microsporidia) infecting zebrafish Danio rerio in research facilities. AB - Zebrafish Danio rerio are important models for biomedical research, and thus, there is an increased concern about diseases afflicting them. Here we describe infections by Pleistophora hyphessobryconis (Microsporidia) in zebrafish from 3 laboratories. As reported in other aquarium fishes, affected zebrafish exhibited massive infections in the skeletal muscle, with no involvement of smooth or cardiac muscle. In addition, numerous spores within macrophages were observed in the visceral organs, including the ovaries. Transmission studies and ribosomal RNA (rRNA) gene sequence comparisons confirmed that the parasite from zebrafish was P. hyphessobryconis as described from neon tetra Paracheirodon innesi. Ten 15 d old zebrafish were exposed to P. hyphessobryconis collected from 1 infected neon tetra, and 7 of 10 fish became infected. Comparison of P. hyphessobryconis small subunit rRNA gene sequence from neon tetra with that obtained from zebrafish was nearly identical, with < 1% difference. Given the severity of infections, P. hyphessobryconis should be added to the list of pathogens that should be avoided in zebrafish research facilities, and it would be prudent to avoid mixing zebrafish used in research with other aquarium fishes. PMID- 20853744 TI - Novel Chlamydiales associated with epitheliocystis in a leopard shark Triakis semifasciata. AB - The Chlamydiales is a diverse order of obligate intracellular gram-negative bacteria that are known to cause a wide range of diseases in terrestrial animals, including humans. Molecular analyses have revealed that these organisms are also associated with epitheliocystis in teleost fish species, highlighting the suspected deep evolutionary origin of members of this bacterial order. However, our knowledge of their fish host range and of the diversity of the bacteria themselves is still very limited. In this study, we provide molecular evidence for a novel member of the Order Chlamydiales in a nonteleost species, the leopard shark Triakis semifasciata. Based on phylogenetic analysis of the 16S rRNA gene, this novel organism appears to represent a unique lineage in the Order Chlamydiales despite appearing histologically similar to epitheliocystis-causing organisms in other fish species. A greater understanding of the genetic diversity of marine Chlamydiales will assist our attempts to manage and control epitheliocystis outbreaks and to understand the evolution of this unique obligate intracellular pathogen. PMID- 20853745 TI - Pseudobranchial X-cell pseudotumors in young wild and farmed atlantic cod Gadus morhua in Iceland. AB - This study investigated the prevalence of pseudobranchial X-cell pseudotumors in 2 year classes of wild juvenile cod and to a lesser extent in older cod in NW Iceland. The disease was also monitored in farmed wild-caught juvenile cod. The youngest wild cod detected that had X-cell infections were 6.5 to 13.0 cm in length, with prevalence reaching a maximum level of 7%. The highest prevalence (23%) was recorded in 18.5 to 27.0 cm fish. The mean prevalence in older cod (25.0 to 76.0 cm in length) was 7% but decreased with increasing age. The mean prevalence of X-cell pseudotumors in farmed juvenile cod was < or =1% during winter rearing in land-based tanks. Higher prevalence (2 to 15%) was noted in dead and moribund fish. Diseased farmed fish were usually emaciated, and mortality due to the disease was noticeable. PMID- 20853746 TI - Integrating fluorescent dye flow-curve testing and acoustic Doppler velocimetry profiling for in situ hydraulic evaluation and improvement of clarifier performance. AB - Enhancing the performance of clarifiers requires a thorough understanding of their hydraulics. Fluorescence spectroscopy and acoustic doppler velocimeter (ADV) profiling generally have been used separately to evaluate secondary settlers. We propose that simultaneous use of these techniques is needed to obtain a more reliable and useful evaluation. Experiments were performed on laboratory- and full-scale clarifiers. Factors affecting Fluorescein and Rhodamine 6G properties were identified. Underestimations up to 500% in fluorescence intensities may be derived from differential fluorescence quenching by oxygen. A careful control and interpretation of fluorescent dye experiments is needed to minimize artifacts in real settings. While flow-curve tests constructed under controlled conditions provided a more accurate overall quantitative estimation of the hydraulic performance, ADV velocity and turbulence profiling provided a detailed spatial understanding of flow patterns that was used to troubleshoot and fix the causes of hydraulic short-circuits. PMID- 20853747 TI - Treatment of ammonia by catalytic wet oxidation process over platinum-rhodium bimetallic catalyst in a trickle-bed reactor: effect of pH. AB - This work adopted aqueous solutions of ammonia for use in catalytic liquid-phase reduction in a trickle-bed reactor with a platinum-rhodium bimetallic catalyst, prepared by the co-precipitation of chloroplatinic acid (H2PtCl6) and rhodium nitrate [Rh(NO3)3]. The experimental results demonstrated that a minimal amount of ammonia was removed from the solution by wet oxidation in the absence of any catalyst, while approximately 97.0% of the ammonia was removed by wet oxidation over the platinum-rhodium bimetallic catalyst at 230 degrees C with an oxygen partial pressure of 2.0 MPa. The oxidation of ammonia has been studied as a function of pH, and the main reaction products were determined. A synergistic effect is manifest in the platinum-rhodium bimetallic structure, in which the material has the greatest capacity to reduce ammonia. The reaction pathway linked the oxidizing ammonia to nitric oxide, nitrogen, and water. PMID- 20853748 TI - Sonochemical decomposition of levofloxacin in aqueous solution. AB - The decomposition of levofloxacin was performed in an aqueous solution under ultrasound irradiation. The effect of operating conditions, including pH value, reaction time, initial concentration, and ultrasound power on the chemical oxygen demand (COD) removal rate was examined at room temperature (23 +/- 2 degrees C). Under a given condition (initial levofloxacin concentration = 20 mg/L, ultrasonic power = 400 W, and pH = 5.86), a 56.6% COD removal rate was obtained after 120 minutes of reaction time. It also was found that 5-day biochemical oxygen demand (BOD5) of the solution increased evidently after sonochemical treatment, and the ratio of BOD5/COD, which was a good measure for biodegradability, increased from 0 to 0.40, indicating that the biodegradability of the solution was enhanced. Based on the results, it is feasible that sonochemical oxidation can be used for the pretreatment of levofloxacin effluent before biological treatment processes. PMID- 20853749 TI - The capture and destruction of Escherichia coli from simulated urban runoff using conventional bioretention media and iron oxide-coated sand. AB - The performance, sustainability, and mechanisms of bacterial removal from stormwater runoff by bioretention systems are poorly understood. The potential for removal of microorganisms in bioretention systems was evaluated using column studies and simulated urban stormwater runoff. Conventional bioretention media (CBM) removed 82% of Escherichia coli O157:H7 strain B6914 cells; iron-oxide coated sand (IOCS) significantly enhanced capture, with 99% efficiency. This improvement possibly was because of the greater positive surface charge and roughness, of the IOCS. Trapped strain B6914 cells decayed more rapidly in CBM, however, with more than 99.98% die-off within one week compared with the IOCS in which approximately 48% of trapped cells survived. Predation and competition from native microorganisms in CBM were verified to play a dominant role in rapid destruction of trapped strain B6914. In particular, protozoan grazing appeared to play an important role, with the die-off of trapped B6914 increasing with increasing concentrations of protozoa. PMID- 20853750 TI - Effect of aluminum (Al3+) on granulation in upflow anaerobic sludge blanket reactor treating low-strength synthetic wastewater. AB - The effect of aluminum on agglomeration in the sludge bed and chemical oxygen demand (COD) removal efficiency in laboratory-scale upflow anaerobic sludge blanket (UASB) reactors treating low-strength synthetic wastewater (approximately 665 to 738 mg/L of COD) was investigated. Continuous application of aluminum chloride (200 mg/L) caused poor COD removal, less sludge density, and adversely affected agglomeration in the sludge bed. An adverse effect on granulation also was observed when 300 mg/L aluminum chloride was added only during the startup, and the effect continued even after it was discontinued. A lower concentration of aluminum chloride (50 mg/L) added for 30 days after the reactors reached steady state did not affect the COD removal efficiency, but adversely affected the growth of agglomerates and caused temporary degeneration of existing agglomerates. The adverse effect of aluminum appeared to stem from the precipitation of aluminum hydroxide on the surfaces of agglomerates. The effect of aluminum on agglomeration was shown to be a function of influent strength. PMID- 20853751 TI - Anaerobic biological treatment of alginate production wastewaters in a pilot scale expended granular sludge bed reactor under moderate to low temperatures. AB - Psychrophilic anaerobic digestion recently has been demonstrated as a cost effective option for the treatment of a range of wastewater categories. In this study, the treatment of alginate production wastewaters was carried out in a pilot-scale expended granular sludge bed (EGSB) reactor. After a 40-day startup with two inocula, a 163-day experiment was run, from moderate to low temperatures, to treat seaweed-based-production wastewater. The results showed that inoculating with the active granular sludge instead of flocculent biomass can remarkably speed up the startup, and, at applied organic loading rates of 1.5 to 3.0 kg chemical oxygen demand (COD)/m3 x d, COD removal efficiencies of 55.4 to 72.6% were achieved. The volatile suspended solids ratio decreased slowly with operation time, as a result of the extremely slow growth rates of microorganisms and the accumulation of inorganic substances. Morphological examination and particle-size distribution of the granules revealed their tendency to disintegrate. Inorganic precipitates, microorganism shift, and substrate limitations may have contributed to it. PMID- 20853752 TI - Modification of pineapple peel fiber as metal ion adsorbent through reaction with succinic anhydride in pyridine and dimethyl sulfoxide solvents. AB - Reactions between saponified pineapple peel fiber (SPPF) and succinic anhydride were performed in refluxed pyridine and dimethyl sulfoxide to obtain modified pineapple peel fiber in pyridine (MPPF-PY) and modified pineapple peel fiber in dimethyl sulfoxide at room temperature (MPPF-DMRT) and at 70 degrees C (MPPF DM70) as novel metal ionic adsorbents. The modified pineapple peel fibers were characterized by Fourier transform infrared (FTIR) and X-ray diffraction (XRD). The MPPF-PY, MPPF-DMRT, and MPPF-DM70 showed higher Cu2+, Cd2+, and Pb2+ adsorption capacity than raw pineapple peel fiber (RPPF) and SPPF. Dimethyl sulfoxide favored introduction of a carboxylic function group into pineapple peel fiber compared with pyridine. The elevated reaction temperature of dimethyl sulfoxide could increase the adsorption capacity of the modified pineapple fiber. Optimum pH values for Cu2+, Cd2+, and Pb2+ removal by MPPF-DM70 were pH 5.5, 7.5, and 5.5, respectively. The Cu2+, Cd2+, and Pb2+ adsorptions by MPPF-DM70 followed the pseudo second-order kinetics model and Langmuir model. PMID- 20853753 TI - Spatial and temporal variability of water quality of an urbanized river in Algeria: the case of Soummam Wadi. AB - Spatial and temporal variations of water quality were investigated at four sites of an urbanized river in Algeria during a period of low water level in the years 2002, 2003, and 2004. Physical-chemical parameters (temperature, pH, conductivity, dissolved oxygen, suspended matter, chemical oxygen demand [COD], and 5-day biochemical oxygen demand [BOD5]) were measured. The Soummam River showed a strong pollutant load, which was organic in origin and expressed by mean concentrations in suspended matter, COD and BOD5 exceeding 150, 100, and 50 mg/L, respectively. The spatial variation highlighted two areas--(1) the first one gathers the upstream and central sites of the river, and (2) the second one is found downstream. In the downstream area, the pollutant load is almost twice as high as in the first area and, the percent saturation of dissolved oxygen is relatively weak (< 55%). This load is the result of the significant volume of urban and industrial emissions in the river, the high temperature during low water-level periods, and flood events, which occurred just before the period of low water level. The Soummam River was classified according to the criteria of appreciation of surface water and was found to be extremely polluted. This work is one of the first studies on the quality of rivers in Algeria. This research will be useful as a first step for future works in North Africa and will add to knowledge on the water quality in the Mediterranean Basin. PMID- 20853754 TI - Spatial distribution of risk factors for Cryptosporidium spp. transport in an Irish catchment. AB - Cryptosporidium spp. has become a major public health concern in many parts of the globe, including Ireland, as a result of recent reported waterborne outbreaks of Cryptosporidiosis. Continuous monitoring of Cryptosporidium spp. in water supplies is not feasible, so a risk-forecasting approach is required. This study reports a globally applicable approach for evaluating the spatial variation in relative risk of contaminating surface water by Cryptosporidium spp. based on a risk potential index (RPI) as an indicator of the potential pollution of surface water. The RPI is predicted by readily available data on land use, rainfall, soil type, slope, soil moisture deficit, and distance from water course. A small catchment in County Meath, Ireland, was chosen to illustrate the analysis of the approach. Data for the study area were digitized and rectified using surveyed ground control points to capture each of the RPI factors, field boundaries, and land use. The six parameters were classified and assigned a relative risk score out of 5. A Geographic Information Systems overlay analysis then was used to calculate a cumulative relative risk score for each month of the year. The analysis indicated that April and June experienced a relatively low risk of Cryptosporidium spp. transport compared with other months of the year. June had the least risk, because more than 98% of the catchment was estimated to be of low or moderate risk (RPI ranges = 0 to 2). December had the highest risk of Cryptosporidium spp. transport, because approximately 20% of the catchment area had a moderately high to very high risk (RPI ranges = 2 to 5). The study also made an attempt to reduce the risk of contaminating surface water by alternative land-use practice and relocating the field boundaries. The study demonstrated a semi-quantitative and readily implemented method for using spatial risk assessment for planning land management to reduce the risk of surface water contamination by Cryptosporidium spp. from agricultural sources. The approach could be used in any catchment with similar hydrological characteristics subject to a surface water pathogen contamination risk from grazing livestock. PMID- 20853755 TI - Constructed wetlands for water pollution management of aquaculture farms conducting earthen pond culture. AB - This study established farm-scale constructed wetlands integrated to shrimp ponds, using existing earthern pond areas, with a wetland-to-pond ratio of only 0.086 for shrimp culture. The constructed wetlands were used as practice for aquaculture water and wastewater treatment, to regulate the water quality of shrimp ponds and manage pollution from pond effluents. The results of water quality monitoring for influent and effluent showed that constructed wetlands significantly reduced total suspended solids (59 to 72%), turbidity (55 to 65%), chlorophyll a (58 to 72%), 5-day biochemical oxygen demand (29 to 40%), and chemical oxygen demand (13 to 24%) from pond water. The wetland treatment sufficiently regulated water quality of the recirculating shrimp pond, which was significantly (p < 0.05) better than that in a control shrimp pond, without the connection of constructed wetlands. Furthermore, the wetland-treated effluent satisfied the national effluent standards for aquaculture farms (R.O.C. Environmental Protection Administration, 2007). Accordingly, wetland treatment applications were proposed to implement the best management practices to reduce pollution from aquaculture farms in Taiwan. PMID- 20853756 TI - What meaningful use means now. PMID- 20853757 TI - ICD: intensive cash-flow disruption? PMID- 20853758 TI - Racing for incentives. PMID- 20853759 TI - Data breach. PMID- 20853760 TI - Catch and release. PMID- 20853761 TI - Home truths. PMID- 20853762 TI - No interruptions, please. Strategies take aim at safer medication administration. PMID- 20853764 TI - IOM nurse scholar looks at past to help shape nursing's future. PMID- 20853763 TI - A recipe worth repeating. Nurse-managed health center is valuable resource for Massachusetts seniors. PMID- 20853765 TI - New clinical guide to surgical fire prevention. Patients can catch fire--here's how to keep them safer. AB - Surgical fires, though rare, can have devastating consequences for patients, staff, and the healthcare facility as a whole. it's important to know how such fires can be prevented--and how to handle them if they occur. This article includes new clinical practice recommendations for oxygen delivery that are designed to reduce the likelihood of fires. PMID- 20853766 TI - Integrating your o.r. for less. Six cost-saving tips that can save you thousands. PMID- 20853767 TI - Dartmouth-Hitchcock Medical Center wins Health Devices Achievement Award. Innovative application of pulse oximetry monitoring reduces failure-to-rescue events. PMID- 20853768 TI - Hazard report. ECRI Institute recommends providing power-cord-specific data when reporting device incidents. AB - When power cord defects or damage contributes to device-related incidents, crucial information about the cord and/or plug (e.g., manufacturer, details of damage) is often not included in incident reports. To facilitate the investigation of these events--which frequently pose a risk of shock or fire- ECRI Institute is asking hospitals to include cord and plug details when reporting the incidents to us, to device manufacturers, and to regulatory agencies. PMID- 20853769 TI - Hazard report. Flammable material introduced into draeger ventilator and anesthesia unit flow sensors could ignite, posing risks to patients. AB - In rare cases, when flammable material is introduced into the Spirolog or SpiroLife flow sensor used with Draeger Medical ventilators and anesthesia units, the material could ignite, posing the risk of patient injury or device damage. Users can reduce this risk by carefully inspecting circuit components before use, by not introducing flammable products into the circuit during use, and by strictly complying with the company's instructions to allow the sensors to dry completely following alcohol disinfection. PMID- 20853770 TI - Hazard report. Overlap of surgical lighthead beams may present burn risk. AB - The heat created when the beams from multiple surgical lightheads overlap can sometimes present the risk of patient burns during a procedure. Safe use of multiple heads requires limiting the total light intensity to acceptable levels. PMID- 20853771 TI - Asbestos and asbestos-related diseases. PMID- 20853772 TI - [Issues related to long-term asbestos use and manufacture]. AB - Extensive measures to ban mining, manufacture, use, and trade of asbestos and asbestos materials have been taken worldwide. In this century asbestos will continue to be an economic, industrial, health, social, and environmental issue. Five thousand products that are still in use have been inherited from a century of asbestos processing. In 1999, the EU member states decided to take steps that would eventually terminate the use of asbestos. At the same time, about 4000 t of asbestos had been imported to Croatia every year. EU member states started to enforce asbestos ban in 2005. This encouraged the Croatian Ministry of Health and Social Welfare to issue a list of toxicants whose manufacture, trade, and use were banned, and which included asbestos and asbestos products. In 2007, several national acts came to force regulating protection of workers occupationally exposed to asbestos. Asbestos is ubiquitous in the environment. It has been released from construction materials during renovations, demolitions, maintenance, and other building activities. It is released by drilling, blowing, demolishing, loading, transport, and improper storage of asbestos materials. Asbestos was often used for insulation. It was favoured for its resistance to heat, fire, moisture, noise, electricity, friction, and fraying. Materials used for firefighting, insulation, protection from noise, and construction frequently contain one or more types of asbestos. Landfills present a particular problem, since asbestos materials can not be recognised macroscopically. Asbestos can be identified by standardised polarising microscopy. This raises the need for education, because human exposure should be kept as low as possible to prevent the development of asbestos-related diseases. PMID- 20853773 TI - [Disposal of waste containing asbestos in Croatia]. AB - In order to ensure systematic disposal of asbestos waste in the whole of Croatia, its government has mandated the Environmental Protection and Energy Efficiency Fund to implement emergency measures to collect and dispose of asbestos containing construction waste. This requires a construction of 45 special disposal containers in the existing municipal waste landfills and contracting collection of asbestos-containing construction waste. By now, the Fund has disposed of 8000 m3 of asbestos cement waste, recovered five dumps with asbestos containing construction waste, reclaimed a location contaminated by asbestos in Vranjic, and has continued to recover the land at the premises of factory Salonit in bankruptcy, which had been producing corrugated asbestos sheets before the ban. In collaboration with several non-governmental organisations, the Fund has started an educational campaign to protect the environment. PMID- 20853774 TI - [Expectations after ban on asbestos]. AB - This article brings a brief review of asbestos exposure and asbestos-related diseases in Croatia in view of the asbestos ban. The first cases of asbestosis were diagnosed in workers from an asbestos-cement factory in 1961. Between 1990 and 2007, 403 cases of asbestosis had been registered as occupational disease: 300 with parenchymal fibrosis and the rest with parenchymal and pleural changes, or pleural plaques. As a rule, asbestos-related changes were diagnosed at an early stage thanks to regular checkups of the exposed workers. Pleural plaques, considered to be the consequence of asbestos exposure, were also occasionally found in subjects who lived in areas with asbestos processing plants, but were not occupationally exposed. Early epidemiological studies on respiratory and gastrointestinal tract tumours in areas with an asbestos processing plant (1994) and an asbestos-cement plant (1995, 1996) focused on the occurrence of malignant tumours in persons exposed to asbestos at work or in the environment. More recently, the focus has shifted to the malignant pleural mesotelioma (MPM). An epidemiological study published in 2002 showed that the MPM incidence was significantly higher in the coastal area than in the rest of the country. About two thirds of patients with the tumour were occupationally exposed to asbestos. This uneven distribution of the tumour incidence is obviously related to shipbuilding and other industrial sources of asbestos exposure located in the coastal Croatia. Sources of environmental exposure to asbestos also have to be taken into account. The second part of this article ventures into the issues ahead of us, after asbestos has been banned in the country. The long latency period of cancers, and particularly of asbestos-related mesothelioma, implies that the incidence of this tumour will not drop over the next few decades. In Croatia, the average annual rate of MPM between 1991 and 2006 was 40, and ranged between 20 in 1991 to 61 in 1999. In 2006 it was 58. Age-standardised incidence of this tumour between 1991 and 1997 was 0.74 per 100,000 (1.34 per 100,000 for men and 0.27 per 100,000 for women). Sadly, the diagnosis of mesothelioma is seldom timely, and treatment is usually unsuccessful. PMID- 20853775 TI - [Incidence and prevalence of asbestos-related diseases in Croatia]. AB - The aim of this study was to identify the incidence and prevalence of asbestos related diseases in Croatia, based on the Hospital Morbidity Database and General Mortality Database of the Croatian National Institute of Public Health. Both databases cover a period from 2002 to 2007), and include information from the Register of Occupational Diseases. Diagnoses in focus were mesothelioma (C45), asbestosis, and pleural plaque (J61 and J92). Yearly rates of inpatients treated for mesothelioma, asbestosis, or pleural plaque that were higher than the Croatian average (2.1) were recorded in the Counties of Split-Dalmatia (5.0), Dubrovnik-Neretva (3.9), Istria (3.7), and Primorje-Gorski kotar (3.1 per 100,000 people). From 2002 to 2007, 649 occupational diseases were reported, out of which 11.7% were asbestos-related. The most frequent were pleural plaque with asbestosis (38 cases, 50.0%), pleural plaque (23 cases, 30.3%), and mesothelioma (6 cases, 7.9%). Mortality attributable to asbestos was assessed using official Croatian National Statistics Bureau reports for 2002 to 2007 at the county and national level. During that period, Croatia recorded 312 deaths with the average yearly rate of 1.2 per 100.000 people. Four counties had higher rates than the national average: Primorje-Gorski kotar (3.4), Split-Dalmatia (2.8), Istria (2.8), and S1. Brod-Posavina (1.5). The number of inpatients treated for asbestos related diseases was higher than the national average in the counties of Split Dalmatia, Dubrovnik-Neretva, and Primorje-Gorski Kotar. Mesothelioma incidence was above the national average in the counties of Split-Dalmatia, Primorje-Gorski Kotar, and Istria. The rates of occupational, asbestos-related diseases were higher than the national average in the counties of Split-Dalmatia and Primorje Gorski Kotar. We were aware that the interpretation of data is somewhat limited by the relatively small absolute number of treated persons and deaths for the observed period, by the fact that crude rates have not been adjusted for total numbers and for regional differences in population distribution by age and gender. The real extent of asbestos-related burden in Croatian general population remains unknown, because only occupational exposure has been monitored. Therefore, the National Public Health Institute and county public health institutes should implement a specific monitoring programme in collaboration with government environmental bodies to assess asbestos exposure of the population living in the vicinity of asbestos plants. It is also necessary to establish the number of exposed persons who have developed an asbestos-related disease. Their health should be monitored and their environment inspected on a regular basis. PMID- 20853776 TI - [Incidence of malignant pleural mesothelioma in Split-Dalmatia County]. AB - Between 2001 and 2005, 1150 patients with respiratory symptoms were admitted to our Pneumology Clinic whose workplace or residence could involve exposure to asbestos One hundred and twenty (10.4%) patients were confirmed a disease of the lung and/or pleura which could have been asbestos-related. A follow-up of these patients showed that 52 of 120 (43.3%) developed malignant pleural mesothelioma (MPM), but it was also found in 12 of 1030 (1.1%) patients without an asbestos related disease. Of the 64 patients with MPM, 54 (84.3%) were men and 10 (15.6%) women. Fifty-two (81.2%) were professionally or residentially exposed to asbestos. The incidence ofmesothelioma for the Split-Dalmatia County between 2001 and 2005 was 13.8 per 100,000 inhabitants, while in the whole of Croatia it was 3.9. Mean annual incidence in the Split-Dalmatia County was 2.7 per 100,000 inhabitants, and in the whole of Croatia 0.8. This means that 22.7% of all patients with MPM in Croatia were from the Split-Dalmatia County (whose population is about 10.5% of Croatia's). This distribution of MPM may be related to the strong shipbuilding industry and other asbestos-related industries in this part of the country. PMID- 20853777 TI - [Malignant pleural mesothelioma in patients hospitalised at the Clinical Hospital Centre Rijeka between 1989 and 2008]. AB - Malignant pleural mesothelioma (MPM) is a relatively rare tumour, mainly associated with occupational exposure to asbestos. We retrospectively analysed the records of MPM patients treated at the Pulmonology Department of the Clinic for Internal Diseases, Clinical Hospital Centre Rijeka between 1989 and 2008. to establish the incidence of MPM in that period. Between 1989 and 2008 the hospital received 121 MPM patients, 117 of whom were men and four women. We observed a continued increase in newly diagnosed MPM patients from year to year. Occupational exposure to asbestos was established in 72 patients who worked in shipbuilding. In our region the incidence of MPM has been rising significantly. We believe that this is not related to improved diagnostics, but to the long latency of the disease. This is why we expect this trend to continue for a while. In the U.S.A. and Europe, MPM incidence is expected to peak by 2020, while in countries with poor control over asbestos use this may take longer. PMID- 20853778 TI - [Immunological aspects of asbestos-related diseases]. AB - Asbestos is a generic name for a group of silicate minerals. The most common are chrysotile, crocidolite, amosite, tremolite and anthophyllite. Exposure to asbestos may cause asbestos-related non-malignant diseases of the lung and pleura, including asbestosis, pleural plaques, diffuse pleural fibrosis, small airway disease, and malignant diseases such as lung cancer and malignant mesothelioma. Inhaled asbestos fibres deposit in the distal regions of the respiratory system where they interact with epithelial cells and alveolar macrophages, and trigger active immunological response which leads to a slowly progressing lung fibrosis. Asbestos may affect immunocompetent cells and induce malignant transformation of mesothelial cells. It is still not clear whether asbestos causes mesothelioma directly or indirectly. There is a general opinion that malignant mesothelioma is a complex tumour that results from the accumulation of multiple genetic alterations over many years. There is no specific antibody for malignant mesothelioma as yet which could act as a single diagnostic tool. Recent studies have demonstrated that asbestos acts on peripheral T cells as superantigen and that in malignant mesothelioma patients there is an overexpression of the Bcl-2 gene on peripheral CD4+ T cells. These findings contribute to better understanding of biological effects of asbestos in respect to the duration and intensity of exposure. PMID- 20853779 TI - [Lung function in children residentially exposed to asbestos]. AB - Impairment of respiratory function is one of the most sensitive indicators used in the evaluation of the effects of air pollution on human health. We compared predicted values of flow-volume curve according to Knudson and the spirometry results in 81 healthy children; 40 girls and 41 boy, aged (10.69 +/- 2.24) years. We also measured the transfer factor of the lungs for carbon monoxide (TLCO) using the single-breath method and compared the results with reference values by Cotes. Patients were selected randomly among pre-school and elementary school children from the Split area, who were residentially exposed to asbestos. Children with atopic diseases, family history of atopy, history of severe respiratory diseases, and history of smoking were excluded from study. We found a statistically significant difference in FVC (p < 0.0001) from normal values according to Knudson, but when expressed in the percentage of the Knudson values, this difference was not significant (p > 0.05). No statistically significant difference was found for FEV1, FEF75, FEF50, FEF25, and FEV1/FVC. TLCO reached (107.37 +/- 20.50)% of normal values according to Cotes, and was not significantly different. At this point, it is hard to predict the consequences of exposure to low levels of asbestos in childhood, because it takes a long time for complications such as neoplasms, pulmonary fibrosis, or respiratory insufficiency to develop. PMID- 20853780 TI - [Croatian and international regulations on the protection and rights of workers exposed to asbestos at work]. AB - New regulations on the protection and rights of workers occupationally exposed to asbestos were introduced in Croatia in 2007 and 2008. They have been harmonised with the European Union (EU) and International Labour Organization (ILO) regulations, and make a step forward in safety at work, health protection, social rights, and pension schemes for Croatian workers occupationally exposed to asbestos. The 2007 Croatian regulation on the protection of workers from the risks related to exposure to asbestos at work defines and describes activities in which workers can be occupationally exposed to asbestos, defines the threshold value of asbestos in the air at work, defines valid methods for measurement of asbestos concentrations in the air, and establishes measures to reduce asbestos exposure at work or protect the exposed workers. Croatian law regulating obligatory health surveillance of workers occupationally exposed to asbestos from year 2007 defines activities and competent authorities to implement health surveillance of workers occupationally exposed to asbestos and to diagnose occupational diseases related to asbestos. This law also defines "occupational exposure to asbestos", and "occupational asbestos-related diseases", including asbestosis (pulmonary asbestos-related fibrosis), pleural asbestos-related disorders (plaques, pleural thickening, and benign effusion), lung and bronchial cancer, and malignant mesothelioma of serous membranes. These regulations have been harmonised with ILO, Directive 2003/18/EC amending Council Directive 83/477/EEC on the protection of workers from the risks related to exposure to asbestos at work, and with the Commission Recommendation 2003/670/EC concerning the European schedule of occupational diseases. The 2008 Croatian regulation on conditions of health surveillance, diagnostic procedures and criteria for confirmation of occupational asbestos-related diseases "defines the terms and the content of medical examination of workers exposed to asbestos, and criteria for the confirmation of occupational asbestos-related diseases which are harmonised with the Helsinki criteria acknowledged by ILO and EU, particularly concerning the level and length of exposure. Croatian law on compensation of workers occupationally exposed to asbestos from 2007 regulates compensation claims for workers with occupational asbestos-related disease, authorities competent to process these claims, and funds and coefficients for compensation payments. Accordingly, Croatia is responsible for compensation claims payment for workers with occupational asbestos-related disease. The 2007 law on conditions for entitlement to full pension for workers exposed to asbestos at work defines the conditions for fulfilling criteria for retirement pension for workers exposed to asbestos at work. PMID- 20853781 TI - [A model to diagnose occupational, asbestos-related pneumoconiosis and thickening of the pleura]. AB - To correctly diagnose occupational asbestos-related disease, a specialist in occupational health has to answer a set of questions: (A) is the asbestos-related disease diagnosed by a specialist in pulmonology with the help of a radiologist and cardiologist occupational or non-occupational; (B) is the occupational asbestos-related disease caused by more than one source of asbestos dust, and, if it is, to what has of each of these sources contributed to the development of the disease; (C) how many functional disorders and symptoms (pulmonary, cardiac, chest pain, reactive fear from death, reactive psychoneurotic disorder in which fear is not the main symptom) has occupational asbestos-related disease produced and to what degree; (D) have these disorders and symptoms permanently reduced patient's work ability, and, if they have, can we speak of work disability; (E) have these disorders permanently reduced vital activity, and, if they have, can we speak of vital disability; and (F) does the patient suffer mental pain because of reduced vital activity, and if he does, what sort of pain. This approach should assume the form and content of an expert specialist opinion, that is, of a legal medical expertise and should rely on a more extensive medical and non medical documentation than the one serving for therapeutic purposes. As such methodological approach is rarely met in practice, we have proposed a model that includes evaluation of cumulative exposure to asbestos dust, determination of work and vital disability, and evaluation of mental pain. This method stems from our long-time practice and experience with patients suffering from asbestos related diseases, including the experience acquired since 2002 from cooperation with the Reference Centre for Asbestosis and Other Asbestos-Related Diseases of the Croatian Ministry of Health at the Department for Pulmonary Diseases of the Clinical Hospital Split. PMID- 20853782 TI - [An exposition on hospital "humanization"]. PMID- 20853783 TI - [Open clinics, matrices of hospital humanization]. PMID- 20853784 TI - [The issue of the poor: the State and the poor in Neuchatel (Switzerland), 1773 1830. Perceptions of the results of a study]. PMID- 20853785 TI - [The building of the asylum of Sarthe and the arrival of the first patients]. PMID- 20853786 TI - [What is the history of the reforms of the psychiatric hospital?]. PMID- 20853787 TI - [From the rescued child to the assisted child: evolution and issues of assistance in the Basses-Alpes in the 19th century]. PMID- 20853788 TI - [Giving to the hospital. Donors of civil hospices in Lyon during the first half of the 19th century]. PMID- 20853789 TI - [Saint Anthony's Fire or gangrenous ergotism and the iconography of Anthony from the origin to the present day]. PMID- 20853790 TI - [The hospital or the theater of operations, essays on hospital anthropology]. PMID- 20853791 TI - [Notre Dame a la Rose Hospital of Lessines, a successful heritage reconversion]. PMID- 20853792 TI - [Clot-Bey. Founder of modern medicine in Egypt]. PMID- 20853793 TI - [Working conditions of baker boys at the Hotel-Dieu in Paris (1701-1750)]. PMID- 20853794 TI - [Evolution of nursing care at the hospitals in Toulouse (1689-2008)]. PMID- 20853795 TI - [Male and female regents of charity facilities in the Netherlands in the 17th century: the orphanage of Amsterdam and the hospice for the aged of Haarlem]. PMID- 20853796 TI - [Hospitals, power issues. Northern France and Belgium (4th-20th century]. PMID- 20853798 TI - Assessing the readability of non-English-language consent forms: the case of Kiswahili for research conducted in Kenya. PMID- 20853797 TI - Comprehension and informed consent: assessing the effect of a short consent form. PMID- 20853799 TI - Assessing the quality of human research protection programs: the experience at the Department of Veterans Affairs. PMID- 20853800 TI - Handheld juggernaut. AB - Not only are hospital, health system, and medical group ClOs and clinical informaticists deploying handheld mobile devices across their enterprises as clinical computing tools; clinicians, especially physicians, are increasingly bringing their own BlackBerrys, iPhones, iPads, Android devices, and other handhelds, into patient care organizations for their personal clinical use. Not surprisingly, the challenges--as well as the opportunities--are multilayered and complex, and include the strategic planning, infrastructure, clinician preference, clinician workflow, and security issues involved in the emerging mobile handheld revolution. The diversity of approaches among ClOs and other healthcare IT leaders on such issues is striking, and underscores the need for flexibility and nimbleness going forward. PMID- 20853801 TI - Crunch time. CIOs balance cost and flexibility to plan for storing large volumes of diagnostic imaging data. AB - Faced with skyrocketing imaging data storage costs, CIOs at three healthcare facilities found alternatives that have enabled them to slash expenditures, monitor their storage requirements, and provide more cost-effective backup solutions. PMID- 20853802 TI - Realizing the promise of EMRs. How a group of physicians in Texas moved forward on EMR and HIE at the same time. AB - North Texas Specialty Physicians (NTSP), an independent practice association based in Forth Worth, has been working with healthcare organizations across North Texas to build an HIE known as SandlotConnect. NTSP Executive Director Karen Van Wagner, Ph.D. lays out four key strategies that appear to have been successful in winning broad and sustained acceptance by clinicians. PMID- 20853803 TI - Getting the message. Pioneering organizations are using tools like text messaging to enable patients to take better control of their health. AB - As text messaging becomes more established in everyday routines by millions of users, healthcare organizations are embracing the technology as a powerful tool to allow patients to better manage their health. Two health provider networks, Kaiser Permanente and Riverview Health System, have launched successful pilots and plan to build on those initiatives. PMID- 20853804 TI - Critical access: the need to connect. Connecting midsize hospitals to rural critical access hospitals is important to the growth of both--but there are things larger hospitals need to know. AB - Many small, rural critical access hospitals are reaching out to each other and to larger hospitals as a way of setting up affordable health information technology systems that will meet meaningful use requirements. CIOs who have followed this strategy weigh in on its benefits and potential pitfalls. PMID- 20853805 TI - Leapfrog Group releases new CPOE study. Leapfrog leaders discuss CPOE performance testing results. PMID- 20853806 TI - The entity information officer at Penn Medicine. Entity information officers are a liaison between entity-level needs and a medical center's overall information system goals. PMID- 20853807 TI - Revenue cycle management changes horizon. Report sees rise in claims management and EDI spending. PMID- 20853808 TI - Indiana data network provides one stop for inter-hospital connectivity. How an Indiana-based regional health data exchange helps CIOs save time and money. PMID- 20853809 TI - Non-performers or just a bad fit? It's time to assess your employees to make sure you are making the best use of their talents. PMID- 20853810 TI - Early school leaving among immigrants in Toronto secondary schools. AB - While education statistics confirm that there is little difference in the dropout rates of native-born and immigrant youth, analyses of Toronto District School Board (TDSB) data have revealed significant variation in school persistence within immigrant groups. Among newcomer youth, the decision to leave school early has been reported to be strongly influenced by socioeconomic status as well as such factors as country of origin, age at arrival, generational status, family structure, and academic performance. While living in low-income conditions is thought to place both foreign- and Canadian-born youth at risk of poor school performance and early school withdrawal, their substantially higher incidence of poverty suggests that today's immigrant youth are likely to face greater obstacles to academic success that may in turn have detrimental, long-term consequences. This paper uses TDSB data to investigate the extent to which living below the low-income cutoff affects the likelihood of dropping out of secondary school, while taking into account generational status as well as a variety risk factors, noted above. Policy implications are discussed. PMID- 20853811 TI - Cars before kids: automobility and the illusion of school traffic safety. AB - Traffic safety is a contested public issue and highly negotiated practice that requires sociological analysis and systematic public policy attention. In our case study, we examine elementary school traffic safety programs in Vancouver, British Columbia. We illustrate how such programs assume a politics of responsibility that largely targets children and parents for traffic safekeeping within an institutional environment that gives programs only sporadic support and funding to manage traffic risks. While this context of school traffic safety programs helps to maintain an "illusion of safety," it does not challenge the current auto-dominant mobility structure and its inherent problems. PMID- 20853812 TI - Provisioning responsibilities: how relationships shape the work that women do. AB - This study documents the work women do to provision for themselves and others. It charts the contours of this work and examines associated responsibilities. The concept of provisioning informed interviews with 100 women. The diversity and range of women's work were surfaced by selecting women from six community groups, marginalized by income, race, and age, in two Canadian provinces. Findings summarize the types of provisioning activities and strategies women use to meet their responsibilities. Because the latter flow through pathways of relationships, negotiating the boundaries of their provisioning responsibilities shapes women's daily work and possibilities for engaging in civil society. PMID- 20853813 TI - The sources of Gessner's pictures for the Historia animalium. AB - Gessner's sources for the pictures in his Historia animalium were varied in kind and in quality. This should be understood within the larger context of the Historia animalium in which Gessner sought to collect everything ever written about animals, an enterprise that could not be completed by a single individual. Just as Gessner did not distil or reduce similar texts but retained these as well as contradictory or false textual descriptions as part of a repository of knowledge, so also Gessner included several pictures of the same animal, false or badly drawn ones, and juxtaposed erroneous and 'true' images. The attribution of images to witnesses and correspondences also reflects Gessner's strategy to credit those who drew his attention to new information first. The sources of Gessner's images thus indicate how his visual world encompassed more than the strictly self-observable, and a pictorial practice that was intimately connected with textual traditions and intellectual networks. PMID- 20853814 TI - Fabricius's and Harvey's representations of animal generation. AB - Fabricius ab Aquapendente commissioned coloured paintings of the reproductive parts and foetuses of a vast spectrum of animals. His published works on generation feature corresponding engravings. In contrast, his student William Harvey questioned the accuracy and usefulness of anatomical illustrations and used alternative approaches to represent his observations. I discuss these anatomists' criteria for selecting specimens, their techniques of investigation, and how these decisions affected their observations and representations of animal generation. I consider what each medium--paintings, intaglios, written accounts- discloses or highlights and also their respective limitations. My study of Fabricius's colour plates also reveals the possibility that they served as inspiration for the first colour anatomical prints: a copy of the illustrations of foetuses is bound with drafts of Aselli's plates, and I suggest a possible link between the colour images. PMID- 20853815 TI - Searching the animal psyche with Charles Le Brun. AB - Around 1670 the French court painter and Academician Charles Le Brun produced a series of drawings featuring naturalistic animal heads, as well as imaginary heads in which he refashioned various nonhuman animal species to make humanoid physiognomies. What were the purpose and significance of these unusual works? I argue that they show Le Brun's interest in what we today would call animal psychology: focusing upon the sensory organs and their connections with the animal's brain, Le Brun studied his animals as conscious protagonists of the natural realm. One source that may have served him in this project was Marin Cureau de La Chambre's De la Connoissance des bestes of 1645, in which the physician argued that animals possess a conscious soul grounded in the senses. However, Le Brun's animal-humans have no clear place in the artist's taxonomy- nor, indeed, in any seventeenth-century understandings of species. It is rather John Locke, at his most skeptical, who offers the best parallel in the realm of natural philosophy to Le Brun's unsettling animal-humans. Probably without meaning to, Le Brun demonstrated through his eerie, boundary-crossing creatures the limits of visual classification. PMID- 20853816 TI - The king's animals and the king's books: the illustrations for the Paris Academy's Histoire des animaux. AB - This essay explores the place of natural philosophy among the patronage projects of Louis XIV, focusing on the Memoires pour servir a l'histoire naturelle des animaux (or Histoire des animaux) of the 1670s, one of a number of works of natural philosophy to issue from Louis XIV's printing house. Questions particular to the Histoire des animaux include the interaction between text and image, the credibility and authority of images of exotic animals, and the relationship between comparative anatomy and natural history, and between human and animal anatomy. At the same time that the Histoire des animaux contributed to Jean Baptiste Colbert's management of patronage and of Louis's image, it was a work of natural philosophy, representing the collaborative efforts of the new Paris Academy of Sciences. It examined natural history and comparative anatomy in new ways, and its illustrations broke new ground in their depiction of animals in a natural setting. However, the lavishly formatted books were presentation volumes and did not gain wide circulation until their republication in 1733. Sources consulted include Colbert's manuscript memoires on the royal printers and engravers. PMID- 20853817 TI - The representation of insects in the seventeenth century: a comparative approach. AB - The investigation and representation of insects in the seventeenth century posed huge problems: on the one hand, their size and texture required optical tools and fixation techniques to disentangle and identify their tiny parts; on the other, the esoteric nature of those parts required readers to make sense of images alien to their daily experiences. Naturalists and anatomists developed sophisticated techniques of investigation and representation, involving tacit and unusual conventions that even twentieth-century readers found at times baffling. This essay develops a comparative approach based on seven pairs of investigations involving Francesco Stelluti, Francesco Redi, Giovanni Battista Hodierna, Robert Hooke, Marcello Malpighi, and Jan Swammerdam. Seen together, they document an extraordinary time in the study of insects and reconstruct a number of iconographic dialogues shedding light on the conventions and styles adopted. PMID- 20853818 TI - Inscribing the perimeter of the PagP hydrocarbon ruler by site-specific chemical alkylation. AB - The Escherichia coli outer membrane phospholipid:lipid A palmitoyltransferase PagP selects palmitate chains using its beta-barrel-interior hydrocarbon ruler and interrogates phospholipid donors by gating them laterally through an aperture known as the crenel. Lipid A palmitoylation provides antimicrobial peptide resistance and modulates inflammation signaled through the host TLR4/MD2 pathway. Gly88 substitutions can raise the PagP hydrocarbon ruler floor to correspondingly shorten the selected acyl chain. To explore the limits of hydrocarbon ruler acyl chain selectivity, we have modified the single Gly88Cys sulfhydryl group with linear alkyl units and identified C10 as the shortest acyl chain to be efficiently utilized. Gly88Cys-S-ethyl, S-n-propyl, and S-n-butyl PagP were all highly specific for C12, C11, and C10 acyl chains, respectively, and longer aliphatic or aminoalkyl substitutions could not extend acyl chain selectivity any further. The donor chain length limit of C10 coincides with the phosphatidylcholine transition from displaying bilayer to micellar properties in water, but the detergent inhibitor lauryldimethylamine N-oxide also gradually became ineffective in a micellar assay as the selected acyl chains were shortened to C10. The Gly88Cys-S-ethyl and norleucine substitutions exhibited superior C12 acyl chain specificity compared to that of Gly88Met PagP, thus revealing detection by the hydrocarbon ruler of the Met side chain tolerance for terminal methyl group gauche conformers. Although norleucine substitution was benign, selenomethionine substitution at Met72 was highly destabilizing to PagP. Within the hydrophobic and van der Waals-contacted environment of the PagP hydrocarbon ruler, side chain flexibility, combined with localized thioether-aromatic dispersion attraction, likely influences the specificity of acyl chain selection. PMID- 20853819 TI - Electrochemical oxidation of hydroxylamine on gold in aqueous acidic electrolytes: an in situ SERS investigation. AB - The electrooxidation of hydroxylamine (HAM) on roughened Au electrodes has been examined in aqueous buffered electrolytes (pH 3) using in situ surface-enhanced Raman scattering (SERS). Two distinct spectral features were observed at potentials, E, within the range in which HAM oxidation was found to ensue, centered at 803 cm(-1) for 0.55 < E < 0.8 V and at 826 cm(-1) for 1.0 < E < 1.40 V versus SCE, attributed, respectively, to adsorbed nitrite and adsorbed NO(2). Similar experiments performed in solutions containing nitrite instead of HAM under otherwise identical conditions displayed only the peak ascribed to adsorbed nitrite over the range of 0.1 < E < 0.8 V versus SCE with no additional features at higher potentials. These observations strongly suggest that under the conditions selected for these studies the oxidation of HAM on Au proceeds at least in part through a pathway that does not involve nitrite as a solution-phase intermediate. PMID- 20853820 TI - Reduction of surface hydrophobicity using a stimulus-responsive polysaccharide. AB - The adsorption of carboxymethyl cellulose (CMC) onto a hydrophobic self-assembled monolayer has been characterized using the quartz crystal microbalance (with dissipation monitoring, QCM-D). Adsorption was studied as a function of initial solution conditions. CMC adsorbs to a greater extent at high ionic strength (10( 1) M KCl as opposed to 10(-2) M KCl) or low pH (3 as opposed to 9). The solution conditions that yielded the lowest initial adsorbed amount (10(-2) M KCl, pH 9) were used as a reference to investigate the response of the adsorbed layer to a switch in solution conditions after adsorption (i.e., to higher ionic strength (10(-1) M KCl) or lower pH (pH 3)). The adsorbed layer released significant amounts of hydration water after each solution switch, as determined by the QCM-D measurements. This expulsion of hydration water was fully reversible. For the two solution switches, reducing the solution pH resulted in a more pronounced change in the amount of hydration water within the adsorbed CMC, accompanied by a distinct conformational change, as determined from a QCM D-f plot. In addition to studying adsorption using QCM-D, the effect of adsorbed CMC on surface hydrophobicity has been investigated using captive bubble contact angle measurements. The effect of the polymer on the contact angle of the surface was seen to be greatest when adsorbed at low pH or at higher ionic strength. CMC was also seen to have a significantly enhanced ability to reduce the surface hydrophobicity after both the ionic strength and pH switches, lowering the advancing water contact angle by 6 and 23 degrees and the receding water contact angle by 10 and 40 degrees for the ionic strength and pH switches, respectively. As with the change in hydration water content, the change in the contact angle of the polymer-coated surface following the solution switches was reversible. PMID- 20853821 TI - A "clickable" titanium surface platform. AB - A straightforward functionalization of a titanium surface using "click" chemistry is reported. A "clickable" titanium surface platform was prepared by the immobilization of an azide-functionalized electroactive catechol anchor and was subsequently derivatized with an electroactive or fluorinated probe via the CuAAC (copper-catalyzed azide-alkyne cycloaddition) reaction. The course of the reaction was investigated by contact angle, XPS, and electrochemical measurements. PMID- 20853822 TI - Spatially resolved ballistic optoelectronic transport measured by quantized photocurrent spectroscopy. AB - GaAs-based quantum point contacts (QPCs) are exploited to spatially resolve and analyze the ballistic, nonequilibrium flow of photogenerated electrons in a nanoscale circuit. Electron-hole pairs are photogenerated in a two-dimensional electron gas (2DEG), and the resulting current through an adjacent QPC is measured as a function of the laser spot position. The transmission of photogenerated electrons through the QPC is governed by the energy dispersion and the quantized momentum values of the electron modes in the QPC. PMID- 20853823 TI - Why metrics matter: evaluating policy choices for reactive nitrogen in the Chesapeake Bay watershed. AB - Despite major efforts, the reduction of reactive nitrogen (Nr) using traditional metrics and policy tools for the Chesapeake Bay has slowed in recent years. In this article, we apply the concept of the Nitrogen Cascade to the chemically dynamic nature and multiple sources of Nr to examine the temporal and spatial movement of different forms of Nr through multiple ecosystems and media. We also demonstrate the benefit of using more than the traditional mass fluxes to set criteria for action. The use of multiple metrics provides additional information about where the most effective intervention point might be. Utilizing damage costs or mortality metrics demonstrates that even though the mass fluxes to the atmosphere are lower than direct releases to terrestrial and aquatic ecosystems, total damage costs to all ecosystems and health are higher because of the cascade of Nr and the associated damages, and because they exact a higher human health cost. Abatement costs for reducing Nr releases into the air are also lower. These findings have major implications for the use of multiple metrics and the additional benefits of expanding the scope of concern beyond the Bay itself and support improved coordination between the Clean Air and Clean Water Acts while restoring the Chesapeake Bay. PMID- 20853824 TI - Use of barcoded pyrosequencing and shared OTUs to determine sources of fecal bacteria in watersheds. AB - While many current microbial source tracking (MST) methods rely on the use of specific molecular marker genes to identify sources of fecal contamination, these methods often fail to determine all point and nonpoint contributors of fecal inputs into waterways. In this study, we developed a new library-dependent MST method that uses pyrosequencing-derived shared operational taxonomy units (OTUs) to define sources of fecal contamination in waterways. A total 56,841 pyrosequencing reads of 16S rDNA obtained from the feces of humans and animals were evaluated and used to compare fecal microbial diversity in three freshwater samples obtained from the Yeongsan river basin in Jeonnam Province, South Korea. Sites included an urbanized agricultural area (Y1) (Escherichia coli counts >= 1600 CFU/100 mL), an open area (Y2) with no major industrial activities (940 CFU/100 mL), and a typical agricultural area (Y3) (>= 1600 CFU/100 mL). Data analyses indicated that the majority of bacteria in the feces of humans and domesticated animals were comprised of members of the phyla Bacteroidetes or Firmicutes, whereas the majority of bacteria in wild goose feces and freshwater samples were classified to the phylum Proteobacteria. Analysis of OTUs shared between the fecal and environmental samples suggested that the potential sources of the fecal contamination at the sites were of human and swine origin. Quantification of fecal contamination was also examined by comparing the density of pyrosequencing reads in each fecal sample within shared OTUs. Taken together, our results indicated that analysis of shared OTUs derived from barcoded pyrosequencing reads provide the necessary resolution and discrimination to be useful as a next generation platform for microbial source tracking studies. PMID- 20853825 TI - A conserved glutamate controls the commitment to acyl-adenylate formation in asparagine synthetase. AB - Inhibitor docking studies have implicated a conserved glutamate residue (Glu-348) as a general base in the synthetase active site of the enzyme asparagine synthetase B from Escherichia coli (AS-B). We now report steady-state kinetic, isotope transfer, and positional isotope exchange experiments for a series of site-directed AS-B mutants in which Glu-348 is substituted by conservative amino acid replacements. We find that formation of the beta-aspartyl-AMP intermediate, and therefore the eventual production of asparagine, is dependent on the presence of a carboxylate side chain at this position in the synthetase active site. In addition, Glu-348 may also play a role in mediating the conformational changes needed to (i) coordinate, albeit weakly, the glutaminase and synthetase activities of the enzyme and (ii) establish the structural integrity of the intramolecular tunnel along which ammonia is translocated. The importance of Glu 348 in mediating acyl-adenylate formation contrasts with the functional role of the cognate residues in beta-lactam synthetase (BLS) and carbapenem synthetase (CPS) (Tyr-348 and Tyr-345, respectively), which both likely evolved from asparagine synthetase. Given the similarity of the chemistry catalyzed by AS-B, BLS, and CPS, our work highlights the difficulty of predicting the functional outcome of single site mutations on enzymes that catalyze almost identical chemical transformations. PMID- 20853826 TI - Glutathione transferase classes alpha, pi, and mu: GSH activation mechanism. AB - Since the early 1960s, glutathione transferases (GSTs) have been described as detoxification enzymes. In fact, GSTs are the most important enzymes involved in the metabolism of electrophilic xenobiotic/endobiotic compounds. These enzymes are able to catalyze the nucleophilic addition of glutathione (GSH) sulfur thiolate to a wide range of electrophilic substrates, building up a less toxic and more soluble compound. Cytosolic classes alpha, pi, and mu are the most extensively studied GSTs. However, many of the catalytic events are still poorly understood. In the present work, we have resorted to density functional theory (DFT) and to potential of mean force (PMF) calculations to determine the GSH activation mechanism of GSTP1-1 and GSTM1-1 isoenzymes. For the GSTP1-1 enzyme, we have demonstrated that a water molecule, after an initial conformational rearrangement of GSH, can assist a proton transfer between the GSH cysteine thiol (GSH-SH) and the GSH glutamate alpha carboxylate (GSH-COO(-)) groups. The energy barrier associated with the proton transfer is 11.36 kcal.mol(-1). The GSTM1-1 enzyme shows a completely different behavior from the previous isoenzyme. In this case, two water molecules, positioned between the GSH-SH and the xi N atom of His107, working like a bridge, are able to promote the proton transfer between these two active groups with an energy barrier of 7.98 kcal.mol(-1). All our results are consistent with all the enzymes kinetics and mutagenesis experimental studies. PMID- 20853827 TI - Natural attenuation of zinc pollution in smelter-affected soil. AB - Previous synchrotron X-ray microprobe measurements of Zn speciation in contaminated and uncontaminated soils have identified phyllosilicate as the main sequestration phase. The emphasis now is focused on comparing the nature and properties of neoformed and geogenic phyllosilicate species to understand natural attenuation processes. Refined structural characterization of the two types of Zn containing phyllosilicate in slightly basic smelter-affected agricultural soils were obtained using a so far unprecedented combination of X-ray microscopic techniques, including fluorescence (MU-XRF), absorption (MU-EXAFS), and diffraction (MU-XRD), and X-ray bulk-sensitive techniques, including powder and polarized EXAFS spectroscopy. The unpolluted and polluted species are both dioctahedral smectites, but the first which contains minor Zn (ca. 150 mg/kg) is aluminous and Fe-free, and the second, which contains several hundreds to a few thousands mg/kg Zn depending on the distance to the smelter and wind direction, is ferruginous with an average Fe/Al atomic ratio of 1.1 +/- 0.5. The Zn(2+) and Fe(3+) in the neoformed smectite are derived from the weathering of ZnS, ZnO, FeS(2), and ZnFe(2)O(4) particles from the smelter. These cations diffuse away from their particulate mineral sources and coprecipitate with Al and Si in the soil clay matrix. Zinc sequestration in the octahedral sheet of dioctahedral smectite is potentially irreversible, because this type of phyllosilicate is stable over a large pH range, and the neoformed species is analogous to the native species which formed over time during pedogenesis. PMID- 20853828 TI - Fabrication of a novel atrazine biosensor and its subpart-per-trillion levels sensitive performance. AB - The present study describes an atrazine biosensor with the detection limit of 0.1 part-per-trillion (ppt). The atrazine biosensor is fabricated on tyrosinase immobilized vertical growth TiO(2) nanotubes (Tyr/TiO(2)-NTs), based on the inhibition of tyrosinase by atrazine. The designed Tyr/TiO(2)-NTs present excellent applicability in atrazine determination, with high sensitivity and stability, and rapid response. The outstanding sensing characteristics for atrazine is attributed to the appropriate bioelectrochemical interface of Tyr/TiO(2)-NTs, resulting from the preponderant tubular structure, excellent biocompatibility, and hydrophilicity of TiO(2)-NTs. The atrazine biosensor possesses a wide detection range from 0.2 ppt to 2 part-per-billion (ppb). The practical application of the biosensor is realized for the determination of atrazine and the analysis of its transport in soil samples. A new method for determination of atrazine in soil samples is thus established, which greatly simplifies the preparation procedure of sample and is helpful to evaluate the pollution risk of atrazine to soil, groundwater, and surface water. PMID- 20853829 TI - IR spectroscopy of molecular ions by nonthermal ion ejection from helium nanodroplets. AB - Infrared spectroscopy provides a means to determine the intrinsic geometrical structures of molecules. Here we present a novel spectroscopic method that uses superfluid helium nanodroplets to record IR spectra of cold molecular ions, in this particular case aniline cations. The method is based on the detection of ions that are ejected from the helium droplets following vibrational excitation of these ions. We find that spectra can be recorded with a high sensitivity and that they exhibit only a small matrix shift. The widths of the individual transitions depend on the excited vibrational level and are thought to be related to the interaction of the ion with the surrounding helium solvent shells. PMID- 20853830 TI - Direct observation of grain rotation-induced grain coalescence in two-dimensional colloidal crystals. AB - A spatially modulated laser is used to produce multiple localized thermal gradients in a colloidal sample placed above a gold surface. We use an optical microscope to observe real time dynamics of the resulting two-dimensional colloidal crystal grains and find that grain rotation-induced grain coalescence (GRIGC) occurs with the rotation of both grains before coalescence. Control over the grain size shows that the time scale for grain boundary annealing in our system is in good agreement with theoretical expressions formulated for nanocrystal growth. PMID- 20853831 TI - Fluorescent chemosensor for detection and quantitation of carbon dioxide gas. AB - CO(2) sensing is of great societal implications, as CO(2) is a component of gas mixtures from many natural and anthropogenic processes with huge impacts on globe climate and human well-being. Herein we report a CO(2) assay scheme over a wide concentration range, utilizing a fluorogen with an aggregation-induced emission feature and a liquid with tunable polarity and viscosity. The CO(2) sensing process is specific, quantitative, and interferent tolerant. PMID- 20853832 TI - Fabrication and optoelectronic properties of novel films based on functionalized multiwalled carbon nanotubes and (phthalocyaninato)ruthenium(II) via coordination bonded layer-by-layer self-assembly. AB - 4-(2-(4-pyridinyl)Ethynyl)benzenic diazonium salt (PBD) was used to modify multiwalled carbon nanotubes (MWCNTs) by the self-assembly technique. After the decomposition of the diazonium group in PBD under UV irradiation, the PBD monolayer film covalently anchored on multiwalled carbon nanotubes is very stable. The obtained pyridine-modified MWCNTs (Py(Ar)-MWCNTs) have good solubility in common organic solvents. Furthermore, the layer-by-layer (LBL) self assembled fully conjugated films of Py(Ar)-MWCNTs and (phthalocyaninato)ruthenium(II) (RuPc) were fabricated on the PBD-modified substrates, and characterized using UV-vis absorption spectroscopy, scanning electron microscopy (SEM), and electrochemistry. The UV-vis analysis results indicate that the LBL RuPc/Py(Ar)-MWCNTs self-assembled multilayer films with axial ligands between the ruthenium atom and pyridine group were successfully fabricated, and the progressive assembly runs regularly with almost equal amounts of deposition in each cycle. A top view SEM image shows a random and homogeneous distribution of Py(Ar)-MWCNTs over the PBD-modified silicon substrate, which indicates well independence between all Py(Ar)-MWCNTs. Moreover, the opto electronic conversion was also studied by assembling RuPc/Py(Ar)-MWCNTs multilayer films on PBD-modified ITO substrate. Under illumination, the LBL self assembled films on ITO showed an effective photoinduced charge transfer because of their conjugated structure and the ITO current density changed with the number of bilayer. As the number of bilayers was increased, the photocurrent increases and reaches its maximum value (~300 nA/cm(2)) at nine bilayers. These results allow us to design novel materials for applications in optoelectronic devices by using LBL self-assembly techniques. PMID- 20853833 TI - A responsive europium(III) chelate that provides a direct readout of pH by MRI. AB - A europium(III) DO3A-tris(amide) complex is reported for imaging pH by MRI using ratiometric chemical exchange saturation transfer (CEST) principles. Deprotonation of a single phenolic proton between pH 6 and 7.6 results in an ~5 ppm shift in the water exchange CEST peak that is easily detected by MRI. Collection of two CEST images at two slightly different activation frequencies provides a direct readout of solution pH without the need of a concentration marker. PMID- 20853834 TI - Relative contribution of small and large intestine to deglycosylation and absorption of flavonoids from Chrysanthemun morifolium extract. AB - The flower of Chrysanthemum morifolium Ramat (CM) is an established part of traditional Chinese medicine (TCM). Luteolin and apigenin flavonoids are the effective components of the CM extract (CME); however, they exist in the orally consumed CME as glycosides. The present study was carried out to determine the relative contribution of the small and large intestine to the deglycosylation and absorption of flavonoids from CME using a rat model system. The distribution of luteolin and apigenin in rat gastrointestinal (GI) luminal contents, tissues, and plasmas was assessed after the oral administration of CME. The hydrolysis and absorption of CME flavonoids in different rat GI segments were further evaluated by using in situ ligated models and cell-free extracts prepared from rat GI segments. The results demonstrated that after the oral administration of CME, the magnitude of deglycosylation in rats was surprisingly high (about 30%) in the stomach and upper intestine within the first 5 min after ingestion, and early absorption in the plasma was detected. The results from site-limited administration revealed that the stomach was the initial hydrolysis site, while the duodenum was the first effective absorption site for CME flavonoids. Diminishing microbial flora in the jejunum had no significant effect on the hydrolysis of the flavonoids from CME, but the cell-free extracts prepared from rat GI segments demonstrated a strong ability to hydrolyze. Taken together, our findings suggest that enteric disposition contributes to the pharmacokinetics of luteolin and apigenin after oral administration of CME. Moreover, the upper digestive tract plays a key role in the hydrolysis and absorption of flavonoids in CME. PMID- 20853835 TI - Activation of polyphenol oxidase in dormant wild oat caryopses by a seed-decay isolate of Fusarium avenaceum. AB - Incubation of dormant wild oat (Avena fatua L., isoline M73) caryopses for 1-3 days with Fusarium avenaceum seed-decay isolate F.a.1 induced activity of the plant defense enzyme polyphenol oxidase (PPO). Both extracts and leachates obtained from F.a.1-treated caryopses had decreased abundance of an ~57 kDa antigenic PPO and increased abundance of antigenic PPOs ranging from ~52 to 14 kDa, as compared to extracts and leachates from untreated caryopsis. Leachates from caryopsis incubated for 2 days with F.a.1 also had 5.1- and 7.5-fold more total PPO activity/g fwt and specific activity, respectively. Fractionation of leachate proteins by ion-exchange chromatography associated the majority of PPO activity with an ~36 kDa protein from untreated caryopses and ~36, 25, and 24 kDa proteins from F.a.1-treated caryopses. Predicted peptide sequences obtained from high-performance liquid chromatography-tandem mass spectrometry analyses indicated that the ~57 and 36 kDa wild oat proteins had a strong similarity to wheat PPO. However, the 25 and 24 kDa proteins were most similar to a Chitinase and oxalate oxidase, respectively. Our results indicate that F.a.1-induced activation of latent PPO in wild oat caryopsis likely involves a cleavage mechanism allowing activated PPOs to be readily mobilized into their surrounding environment. PMID- 20853836 TI - Expeditious synthesis and assembly of sub-100 nm hollow spherical gold nanoparticle superstructures. AB - Sub-100 nm hollow gold nanoparticle superstructures were prepared in a direct one pot reaction. A gold-binding peptide conjugate, C(6)-AA-PEP(Au) (PEP(Au) = AYSSGAPPMPPF), was constructed and used to direct the simultaneous synthesis and assembly of gold nanoparticles. Transmission electron microscopy and electron tomography revealed that the superstructures are uniform and consist of monodisperse gold nanoparticles arranged into a spherical monolayer shell. PMID- 20853837 TI - Stereoselective synthesis of beta-hydroxy enamines, aminocyclopropanes, and 1,3 amino alcohols via asymmetric catalysis. AB - Tandem methods for the catalytic asymmetric preparation of enantioenriched beta hydroxy (E)-enamines and aminocyclopropanes are presented. The diastereoselective hydrogenation of enantioenriched (E)-trisubstituted hydroxy enamines to generate 1,2-disubstituted-1,3-amino alcohols is also outlined. These methods are initiated by highly regioselective hydroboration of N-tosyl-substituted ynamides with diethylborane to generate beta-amino alkenyl boranes. In situ boron-to-zinc transmetalation generates beta-amino alkenylzinc reagents. These functionalized vinylzinc intermediates are subsequently added to aldehydes in the presence of a catalyst derived from an enantioenriched amino alcohol (morpholino isoborneol, MIB). The catalyst promotes highly enantioselective C-C bond formation to provide beta-hydroxy enamines in good isolated yields (68-86%) with 54-98% enantioselectivity. The intermediate zinc beta-alkoxy enamines can be subjected to a tandem cyclopropanation to afford aminocyclopropyl carbinols with three continuous stereocenters in a one-pot procedure with good yields (72-82%), enantioselectivities of 76-94%, and >20:1 diastereomeric ratios. Diastereoselective hydrogenation of isolated enantioenriched beta-hydroxy enamines over Pd/C furnished syn-1,2-disubstituted-1,3-amino alcohols in high yields (82-90%) with moderate to excellent diastereoselectivities. These methods were used in an efficient preparation of the enantioenriched precursor to PRC200 SS derivatives, which are potent serotonin-norepinephrine-dopamine reuptake inhibitors. PMID- 20853839 TI - Analysis of adenosine A2a receptor stability: effects of ligands and disulfide bonds. AB - G protein-coupled receptors (GPCRs) constitute the largest family of integral membrane proteins present in all eukaryotic cells, yet relatively little information about their structure, folding, and stability has been published. In this work, we describe several approaches to characterizing the conformational stability of the human adenosine A(2)a receptor (hA(2)aR). Thermal denaturation and chemical denaturation were not reversible, yet clear differences in the unfolding behavior were observed upon ligand binding via circular dichroism and fluorescence spectrometry. We found that the stability of hA(2)aR was increased upon incubation with the agonist N(6)-cyclohexyladenosine or the antagonist theophylline. When extracellular disulfide bonds were reduced with a chemical reducing agent, the ligand binding activity decreased by ~40%, but reduction of these bonds did not compromise the unfolding transition observed via urea denaturation. Overall, these approaches offer a general strategy for characterizing the effect of surfactant and ligand effects on the stability of GPCRs. PMID- 20853840 TI - Solid-phase synthesis of azaphthalocyanine-oligonucleotide conjugates and their evaluation as new dark quenchers of fluorescence. AB - Hydrophobic nonaggregating metal-free azaphthalocyanines (AzaPc) of the tetrapyrazinoporphyrazine type were synthesized, characterized, and used for oligonucleotide labeling. Both 3'-end and 5'-end labeling methods using solid phase synthesis suitable for automatic processes in the DNA/RNA synthesizer were developed. The hydrophobic character of AzaPc enabled the anchoring of the conjugates on reverse phase of the oligonucleotide purification cartridge, thus enabling their simple purification. AzaPc did not show any fluorescence and extremely low singlet oxygen quantum yields (Phi(Delta) = 0.015-0.018 in DMF) in a monomeric state due to ultrafast intramolecular charge transfer. That is why they were investigated as a new dark quencher structural type. They profit particularly from absorption in a wide range of wavelengths (300-740 nm) that covers all fluorophores used in hybridization assays nowadays. As an example, quenching efficiency was evaluated in a simple hybridization assay using monolabeled probes. AzaPc-based probes efficiently quenched both fluorescein and Cy5 fluorescence by both resonance energy transfer and contact quenching. The results were compared with three established dark quenchers, and the AzaPc exerted better (BHQ-1 and BHQ-2) or comparable (BBQ-650) quenching efficiencies for both fluorophores. PMID- 20853838 TI - Ligand-accelerated C-H activation reactions: evidence for a switch of mechanism. AB - Initial rate studies have revealed dramatic acceleration in aerobic Pd(II) catalyzed C-H olefination reactions of phenylacetic acids when mono-N-protected amino acids are used as ligands. In light of these findings, systematic ligand tuning was undertaken, which has resulted in drastic improvements in substrate scope, reaction rate, and catalyst turnover. We present evidence from intermolecular competition studies and kinetic isotope effect experiments that implies that the observed rate increases are a result of acceleration in the C-H cleavage step. Furthermore, these studies suggest that the origin of this phenomenon is a change in the mechanism of C-H cleavage from electrophilic palladation to proton abstraction. PMID- 20853841 TI - Compound ice-binding site of an antifreeze protein revealed by mutagenesis and fluorescent tagging. AB - By binding to the surface of ice crystals, type III antifreeze protein (AFP) can depress the freezing point of fish blood to below that of freezing seawater. This 7-kDa globular protein is encoded by a multigene family that produces two major isoforms, SP and QAE, which are 55% identical. Disruptive mutations on the ice binding site of type III AFP lower antifreeze activity but can also change ice crystal morphology. By attaching green fluorescent protein to different mutants and isoforms and by examining the binding of these fusion proteins to single crystal ice hemispheres, we show that type III AFP has a compound ice-binding site. There are two adjacent, flat, ice-binding surfaces at 150 degrees to each other. One binds the primary prism plane of ice; the other, a pyramidal plane. Steric mutations on the latter surface cause elongation of the ice crystal as primary prism plane binding becomes dominant. SP isoforms naturally have a greatly reduced ability to bind the prism planes of ice. Mutations that make the SP isoforms more QAE-like slow down the rate of ice growth. On the basis of these observations we postulate that other types of AFP also have compound ice-binding sites that enable them to bind to multiple planes of ice. PMID- 20853842 TI - The ATP-dependent remodeler RSC transfers histone dimers and octamers through the rapid formation of an unstable encounter intermediate. AB - RSC, an essential chromatin remodeling complex in budding yeast, is involved in a variety of biological processes including transcription, recombination, repair, and replication. How RSC participates in such diverse processes is not fully understood. In vitro, RSC uses ATP to carry out several seemingly distinct reactions: it repositions nucleosomes, transfers H2A/H2B dimers between nucleosomes, and transfers histone octamers between pieces of DNA. This raises the intriguing mechanistic question of how this molecular machine can use a single ATPase subunit to create these varied products. Here, we use a FRET-based approach to kinetically order the products of the RSC reaction. Surprisingly, transfer of H2A/H2B dimers and histone octamers is initiated on a time scale of seconds when assayed by FRET, but formation of stable nucleosomal products occurs on a time scale of minutes when assayed by native gel. These results suggest a model in which RSC action rapidly generates an unstable encounter intermediate that contains the two exchange substrates in close proximity. This intermediate then collapses more slowly to form the stable transfer products seen on native gels. The rapid, biologically relevant time scale on which the transfer products are generated implies that such products can play key roles in vivo. PMID- 20853844 TI - Mn3O4-graphene hybrid as a high-capacity anode material for lithium ion batteries. AB - We developed two-step solution-phase reactions to form hybrid materials of Mn(3)O(4) nanoparticles on reduced graphene oxide (RGO) sheets for lithium ion battery applications. Selective growth of Mn(3)O(4) nanoparticles on RGO sheets, in contrast to free particle growth in solution, allowed for the electrically insulating Mn(3)O(4) nanoparticles to be wired up to a current collector through the underlying conducting graphene network. The Mn(3)O(4) nanoparticles formed on RGO show a high specific capacity up to ~900 mAh/g, near their theoretical capacity, with good rate capability and cycling stability, owing to the intimate interactions between the graphene substrates and the Mn(3)O(4) nanoparticles grown atop. The Mn(3)O(4)/RGO hybrid could be a promising candidate material for a high-capacity, low-cost, and environmentally friendly anode for lithium ion batteries. Our growth-on-graphene approach should offer a new technique for the design and synthesis of battery electrodes based on highly insulating materials. PMID- 20853843 TI - Gadolinium doped europium sulfide. AB - We have prepared gadolinium doped europium sulfides, Eu(1-x)Gd(x)S for a doping range of 0 <= x <= 0.1 by thermal decomposition of the precursors Eu(S(2)CNEt(2))(3)Phen/Gd(S(2)CNEt(2))(3)Phen with respective ratios. Electron doping provides indirect evidence for the magnetic coupling through carrier electrons in magnetic semiconductors. Based on the magnetic properties, we determined that the paramagnetic Curie temperature, Thetap, varies with doping level, in a similar way to Eu(1-x)Gd(x)O exhibiting a significant increase at low doping levels. All materials have been characterized by X-ray powder diffraction, magnetic measurements, ICP-MS, and TEM. PMID- 20853845 TI - Real-time investigations of Pt(111) surface transformations in sulfuric acid solutions. AB - We present the first broadband sum-frequency generation (SFG) spectra of adlayers from sulfuric acid solutions on Pt(111) surfaces and reveal surface transformations of (bi)sulfate anions in unprecedented detail. SFG amplitudes, bandwidth, and electrochemical Stark tuning of (bi)sulfate vibrational bands centered at 1250-1290 cm(-1) strongly depend on the applied potential and are correlated with prominent voltammetric features. (Bi)sulfate adlayers on Pt(111) are important model systems for weak, specific adsorption of anions on catalytically active surfaces. Although the existence of surface transformations on Pt(111) in dilute H(2)SO(4) solutions has been established by previous studies, so far they have not been observed with surface vibrational spectroscopy. Our results confirm previous reports of a surface transformation at 0.21 V and provide new information on a second transformation at 0.5 V due to surface hydroxyl formation and rearrangement of the electric double layer. PMID- 20853846 TI - Gold-catalyzed highly regioselective oxidation of C-C triple bonds without acid additives: propargyl moieties as masked alpha,beta-unsaturated carbonyls. AB - Gold-catalyzed intermolecular oxidations of internal alkynes have been achieved with high regioselectivities using 8-alkylquinoline N-oxides as oxidants and in the absence of acid additives. Synthetically versatile alpha,beta-unsaturated carbonyls are obtained in good to excellent yields and with excellent E selectivities. A range of functional groups such as THP, MOMO, N(3), OTBS, and N Boc are tolerated. This reaction allows alpha,beta-unsaturated carbonyls to be masked as propargyl moieties, thus offering a practical solution to compatibility issues with these functional groups likely encountered in syntheses of complex structures. PMID- 20853847 TI - Aldehyde oxidase: an enzyme of emerging importance in drug discovery. PMID- 20853848 TI - Concave cubic gold nanocrystals with high-index facets. AB - A new class of gold nanostructures, concave nanocubes, enclosed by 24 high-index {720} facets, have been prepared in a monodisperse fashion by a modified seed mediated synthetic method. The Cl(-) counterion in the surfactant plays an essential role in controlling the concave morphology of the final product. The concave nanocubes exhibit higher chemical activities compared with low-index {111}-faceted octahedra. PMID- 20853849 TI - Serum amyloid A activates peroxisome proliferator-activated receptor gamma through extracellularly regulated kinase 1/2 and COX-2 expression in hepatocytes. AB - Serum amyloid A (SAA) is an acute phase protein whose level of expression increases markedly during bacterial infection, tissue damage, and inflammation. The potential beneficial roles of SAA include its involvement in reverse cholesterol transport and possibly extracellular lipid deposition at sites of inflammation and tissue repair. It is an attractive therapeutic target for the treatment of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) plays a major regulatory role in adipogenesis and in the expression of genes involved in lipid metabolism. Activation of PPARgamma leads to multiple changes in gene expression, some of which are believed to be atherogenic while others are antiatherogenic. In this study, we investigated the effects of SAA on PPARgamma activation and its downstream target gene expression profiles in HepG2 cells. We demonstrated that SAA could activate PPARgamma transcriptional activity. Preincubation of HepG2 cells with SAA enhanced the efflux of cholesterol to HDL and apoA-I. In addition, SAA increased the level of intracellular 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), which is a potent natural ligand for PPARgamma. Our data suggested that SAA activated PPARgamma through extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent COX-2 expression. Furthermore, SAA-induced cholesterol efflux was suppressed when the ERK1/2 pathway or COX-2 was inhibited. Overall, our study has established, for the first time, a relationship between SAA and PPARgamma. Additionally, the data from our study have also provided new insights into the role of SAA in cholesterol efflux. PMID- 20853851 TI - Carbon nanotubes as a low background signal platform for a molecular aptamer beacon on the basis of long-range resonance energy transfer. AB - Although holding the advantages of both an aptamer and a molecular beacon (MB), a molecular aptamer beacon (MAB) needs complicated and expensive modifications at both of its ends and usually has a high background signal because of the low energy transfer efficiency between the donor and the acceptor. To overcome these shortcomings, in this study, we develop a long-range resonance energy transfer (LrRET) system by separating the donor from the acceptor, wherein only one end of the MAB is fluorescently labeled and acts as the energy donor and multiwalled carbon nanotubes (MWCNTs) are introduced as the energy acceptor. To test the feasibility of the newly designed MAB system, adenosine triphosphate (ATP) has been employed as a proof-of-concept target. It is found that the fluorescence of the designed MAB is completely quenched by MWCNTs, supplying a very low background signal. Then the quenched fluorescence is recovered significantly with the addition of ATP, so that ATP can be detected in the range of 0.8-80 MUM with a limit of detection of 0.5 MUM (3sigma). Compared with the conventional fluorescence resonance energy transfer, the efficiency of LrRET between the dye and MWCNTs is much higher. Since only one end of the MAB needs the modification, the present strategy is simple and cost-effective. Furthermore, the use of MWCNTs can greatly reduce the fluorescence background of the MAB and supply a high sensitivity, showing its generality for detection of a variety of targets. PMID- 20853850 TI - Biodistribution and excretion of monosaccharide-albumin conjugates measured with in vivo near-infrared fluorescence imaging. AB - Target specific small molecules as modulators of drug delivery may play a significant role in the future development of therapeutics. Small molecules can alter the in vivo pharmacokinetics of therapeutic macromolecules leading to more efficient drug delivery with less systemic toxicity. The potential of creating a more effective drug delivery system through glycosylation has led, for instance, to the addition of galactose to increase drug delivery to the liver. However, there are many other monosaccharides with potentially useful targeting properties that require further characterization. Here, we investigate the potential of glycosylation to guide molecular therapies using five different monosaccharides conjugated to human serum albumin (HSA). Additionally, we investigate how the amount of glycosylation may alter the pharmacokinetic profile of HSA. We introduce the use of in vivo near-infrared optical imaging to characterize the effect of differential glycosylation on the pharmacokinetics of macromolecules. PMID- 20853853 TI - Viscoelastic sensing of conformational changes in plasminogen induced upon binding of low molecular weight compounds. AB - Plasminogen is a precursor to the fibrinolytic enzyme plasmin and is known to undergo large conformational changes when subjected to low molecular lysine analogues such as tranexamic acid (TA) or epsilon-amino-n-caproic acid (EACA). Here, we demonstrate how well-controlled surface immobilization of biotinylated plasminogen allows for monitoring of the interaction between TA and EACA with plasminogen. The interaction was studied by the quartz crystal microbalance with dissipation monitoring (QCM-D) technique as well as by surface plasmon resonance (SPR) based sensing. QCM-D measures changes in acoustically coupled mass (by detection of changes in the resonance frequency of the crystal, Deltaf) and is sensitive to changes in mass adsorbed on the sensor surface including how liquid medium is associated with this material. Through the dissipation factor (i.e., changes in the energy dissipation of the crystal oscillation, DeltaD), QCM-D is also sensitive to the viscoelastic properties of material adsorbed to the sensor surface. Upon binding of TA or EACA, changes in the plasminogen structure were recorded as distinct, although small, DeltaD responses which were used to determine affinity constants. By comparing native and truncated plasminogen, we conclude that the observed dissipation shifts were caused by conformational changes in the proteins leading to changes in the viscoelastic properties of the protein layer on the surface. These results demonstrate a novel application of the QCM-D technique, paving the way for a whole new approach to screening of this target for novel lead structures. PMID- 20853852 TI - Evaluation of phenylthiocarbamoyl-derivatized peptides by electrospray ionization mass spectrometry: selective isolation and analysis of modified multiply charged peptides for liquid chromatography-tandem mass spectrometry experiments. AB - Edman degradation in the gas phase has been observed by collision activated dissociation of N-terminal phenylthiocarbamoyl (PTC) protonated peptide to yield abundant complementary b1 and y(n-1) ion pairs. Here, we demonstrated the relation between the observed losses of aniline and/or the entire PTC derivatizing group with the availability of mobile protons using electrospray ionization mass spectrometry. In order to select the peptides with more efficient fragmentation, while simplifying the mixture of peptides, we extend the phenylisotiocyanate (PITC) derivatization of amino groups to the selective isolation of multiply charged peptides (those having the number of arginines and histidines residues higher than one) using a procedure previously developed in our group. Thus, it was possible to identify in the filtered protein database the sequence of the isolated multiply charged peptides derived from a single protein and a complex mixture of proteins extracted from Escherichia coli using only the molecular mass and the N-terminal amino acid information. For this purpose, we developed a novel bioinformatic tool for automatic identification of peptides from liquid chromatography-tandem mass spectrometry (LC-MS/MS) experiments, which potentially can be used in high-throughput proteomics. PMID- 20853854 TI - Food allergens profiling with an imaging surface plasmon resonance-based biosensor. AB - Food allergy is a growing health concern, which currently affects approximately 4% of adults and 8% of infants. For consumer protection purposes, food producers are required by law to disclose on the product label whether a major allergen is used during the production process. The commonly employed monitoring methods are highly laborious, time-consuming, and often expensive when screening for multiple allergens. Here, we utilize imaging surface plasmon resonance (iSPR) in combination with antibody array for rapid, quantitative, and multianalyte food allergens detection. We demonstrate how the use of this technology provides a complete allergen profile within short measurement time and with adequate sensitivity. The successful applicability of this approach is demonstrated by analyzing cookies and dark chocolate products from different manufacturers. Hazelnut content of the tested food products is also determined by enzyme linked immunosorbent assay and is found to correlate well with the hazelnut content determined by iSPR. This newly developed method opens the door to automated and high-throughput allergen analysis, ultimately aiming at providing the consumer with safer food. PMID- 20853855 TI - Temperature difference between the cooled and the noncooled parts of an electrolyte in capillary electrophoresis. AB - Joule heating always accompanies electrophoresis and unavoidably leads to a temperature increase of the electrolyte. The elevated temperatures are known to adversely affect the quality of separation and detection. To minimize the temperature increase in capillary electrophoresis (CE), Joule heat is removed by actively cooling the capillary. However, there are always small parts of the capillary, such as its inlet, outlet, and detection window, which are not actively cooled. The noncooled capillary inlet has been recently proven to have an elevated temperature which is high enough to significantly affect CE-based quantitative affinity analyses. The temperature difference between the cooled and noncooled regions has never been determined due to the lack of a suitable method. Here, we report on the first experimental determination of temperature in the cooled part of the capillary and the noncooled inlet region of the capillary. We found that, under typical CE conditions, with a low-conductivity run buffer, the temperature in the noncooled inlet exceeded the temperature in the cooled region by more than 15 degrees C. High-conductivity buffers are anticipated to have even greater temperature differences between the noncooled and cooled capillary parts. Our results strongly suggest the potential effect of the noncooled capillary regions on the quality of CE-based analyses, which cannot be ignored. The simplest way to avoid potential errors is to move the sample to the cooled region by pressure or by applying a low electric field. PMID- 20853857 TI - High carbon dioxide solubilities in imidazolium-based ionic liquids and in poly(ethylene glycol) dimethyl ether. AB - This work is focused on the possible capture of carbon dioxide using ionic liquids (ILs). Such solvents are gaining special attention because the efficiency of many processes can be enhanced by the judicious manipulation of their properties. The absorption of greenhouse gases can be enhanced by the basic character of the IL. In this work, these characteristics are evaluated through the study of the gas-liquid equilibrium of four imidazolium-based ILs: 1-butyl-3 methylimidazolium tetrafluoroborate [BMIM][BF(4)], 1-butyl-3-methylimidazolium thiocyanate [BMIM][SCN], 1,3-dimethylimidazolium methylphosphonate [DMIM][MP], and 1,3-diethoxyimidazolium bis(trifluoromethylsulfonyl)imide [(ETO)(2)IM][Tf(2)N] with CO(2) at temperatures up to 373 K and pressures up to 300 bar. Solubility of carbon dioxide in poly(ethylene glycol) dimethyl ether, component of selexol, was also measured to evaluate the capture's efficiency of ionic liquids. Experimental data indicate that 67 to 123 g of CO(2) can be absorbed per kg of ionic liquid and 198 g per kg of poly(ethylene glycol) dimethyl ether. PMID- 20853856 TI - High-resolution crystal structures of Streptococcus pneumoniae nicotinamidase with trapped intermediates provide insights into the catalytic mechanism and inhibition by aldehydes . AB - Nicotinamidases are salvage enzymes that convert nicotinamide to nicotinic acid. These enzymes are essential for the recycling of nicotinamide into NAD(+) in most prokaryotes and most single-cell and multicellular eukaryotes, but not in mammals. The significance of these enzymes for nicotinamide salvage and for NAD(+) homeostasis has stimulated interest in nicotinamidases as possible antibiotic targets. Nicotinamidases are also regulators of intracellular nicotinamide concentrations, thereby regulating signaling of downstream NAD(+) consuming enzymes, such as the NAD(+)-dependent deacetylases (sirtuins). Here, we report several high-resolution crystal structures of the nicotinamidase from Streptococcus pneumoniae (SpNic) in unliganded and ligand-bound forms. The structure of the C136S mutant in complex with nicotinamide provides details about substrate binding, while a trapped nicotinoyl thioester in a complex with SpNic reveals the structure of the proposed thioester reaction intermediate. Examination of the active site of SpNic reveals several important features, including a metal ion that coordinates the substrate and the catalytically relevant water molecule and an oxyanion hole that both orients the substrate and offsets the negative charge that builds up during catalysis. Structures of this enzyme with bound nicotinaldehyde inhibitors elucidate the mechanism of inhibition and provide further details about the catalytic mechanism. In addition, we provide a biochemical analysis of the identity and role of the metal ion that orients the ligand in the active site and activates the water molecule responsible for hydrolysis of the substrate. These data provide structural evidence of several proposed reaction intermediates and allow for a more complete understanding of the catalytic mechanism of this enzyme. PMID- 20853858 TI - Heterogeneous consecutive electron transfer at graphite electrodes under steady state. AB - In this report, the theory based on thin-layer cyclic voltammetry (TLCV) for consecutive electron transfer (ET) across the interface between two immiscible electrolyte solutions (ITIES) is well developed and experimentally verified. The voltammetric responses to multistep electron transfer at the ITIES are predicted by numerical simulations. Moreover, the impact of empirical parameters on the shape of the multistep current-voltage curve has been examined. The results obtained not only give information regarding the effect of the concentration ratio of the reactants in two phases and the thin-layer thickness on multistep electron transfer, but also prove the excellent agreement between simulations and experiments. The model system of two-step electron transfer of ZnTPP/[Fe(CN)6]4- was studied, indicating that the Bulter-Volmer (B-V) theory is suitable for the consecutive electron transfer. Thus, TLCV is demonstrated to be a useful means for investigating the kinetics of heterogeneous consecutive ET. PMID- 20853859 TI - High yield precipitation of crystalline alpha-zirconium phosphate from oxalic acid solutions. AB - Microcrystalline zirconium phosphate (ZrP) has been synthesized by precipitating a Zr(IV) salt (i.e., zirconium propionate, chloride, or oxide chloride) with H(3)PO(4) from aqueous solutions of oxalic acid (H(2)C(2)O(4)) at 80 degrees C. Independent of the Zr(IV) salt, crystalline materials have been obtained with reaction yields >90% and reaction time of one day for the following molar ratios: H(3)PO(4)/Zr = 6 and H(2)C(2)O(4)/Zr = 10. The material prepared from Zr propionate (ZrP(prop)) has been further investigated by scanning electron microscopy, thermogravimetry, and ion exchange titrations. Structural characterization has been performed by X-ray powder diffraction and solid state (1)H-(31)P 2D correlation NMR experiments. Structural parameters obtained by Rietveld analysis of powder diffraction data agree with those reported in the literature for single crystal determinations. Moreover, NMR data show that the closest proton environment of the phosphorus atom in ZrP(prop) is the same as in ZrP samples of similar crystallinity prepared according to literature methods. PMID- 20853860 TI - The triplet state of fac-Ir(ppy)3. AB - The emitting triplet state of fac-Ir(ppy)(3) (fac-tris(2-phenylpyridine)iridium) is studied for the first time on the basis of highly resolved optical spectra in the range of the electronic 0-0 transitions. For the compound dissolved in CH(2)Cl(2) and cooled to cryogenic temperatures, three 0-0 transitions corresponding to the triplet substates I, II, and III are identified. They lie at 19,693 cm(-1) (507.79 nm, I -> 0), 19,712 cm(-1) (507.31 nm, II -> 0), and 19,863 cm(-1) (503.45 nm, III -> 0). From the large total zero-field splitting (ZFS) of 170 cm(-1), the assignment of the emitting triplet term as a (3)MLCT state (metal to-ligand charge transfer state) is substantiated, and it is seen that spin-orbit couplings to higher lying (1,3)MLCT states are very effective. Moreover, the studies provide emission decay times for the three individual substates of tau(I) = 116 MUs, tau(II) = 6.4 MUs, and tau(III) = 200 ns. Further, group-theoretical considerations and investigations under application of high magnetic fields up to B = 12 T allow us to conclude that all three substates are nondegenerate and that the symmetry of the complex in the CH(2)Cl(2) matrix cage is lower than C(3). It follows that the triplet parent term is of (3)A character. Studies of the emission decay time and photoluminescence quantum yield, Phi(PL), of Ir(ppy)(3) in poly(methylmethacrylate) (PMMA) in the temperature range of 1.5 <= T <= 370 K reveal average and individual radiative and nonradiative decay rates and quantum yields of the substates. In the range 80 <= T <= 370 K, Phi(PL) is as high as almost 100%. The quantum yield Phi(PL) drops to ~88% when cooled to T = 1.5 K. The investigations show further that the emission properties of Ir(ppy)(3) depend distinctly on the complex's environment or the matrix cage according to distinct changes of spin-orbit coupling effectiveness. These issues also have consequences for optimizations of the material's properties if applied as an organic light emitting diode (OLED) emitter. PMID- 20853861 TI - Polar or non-polar? Syntheses, crystal structures, and optical properties of three new palladium(II) iodates. AB - Three new novel palladium(II) iodates with square-planar PdO(4) units, namely, Pd(IO(3))(2), AgPd(IO(3))(3), and BaPd(IO(3))(4), have been successfully hydrothermally synthesized. They represent the first ternary and quaternary palladium(II) iodates and display three different structural types. Pd(IO(3))(2) exhibits a novel two-dimensional (2D) layered structure in which each PdO(4) square further connects with four neighboring ones by four bridging IO(3) groups. AgPd(IO(3))(3) exhibits a unique three-dimensional (3D) network based on unique one-dimensional (1D) [Pd(IO(3))(3)](-) anionic chains along the c-axis which are further interconnected by Ag(+) cations. BaPd(IO(3))(4) is isostructural with KAu(IO(3))(4), and its structure features zero-dimensional (0D) [Pd(IO(3))(4)](2 ) anionic units that are interconnected by Ba(2+) cations. These materials can be polar or non-polar depending on the different alignments of the lone pairs of the I(V) atoms. Pd(IO(3))(2) and AgPd(IO(3))(3) are non-polar and centrosymmetric, hence not second-harmonic generation (SHG) active. BaPd(IO(3))(4) is polar and displays a moderate SHG response of about 0.4* KTP. Thermal analyses, optical, luminescent, and ferroelectric properties as well as electronic structure calculations have also been performed. PMID- 20853862 TI - Signature of nonadiabatic transitions on the pump-probe infrared spectra of a hydrogen-bonded complex dissolved in a polar solvent: a computational study. AB - The mixed quantum-classical Liouville equation provides a unified and self consistent platform for modeling the spectral signatures of nonequilibrium solvation dynamics, non-Condon effects, and nonadiabatic transitions. These features are demonstrated in this paper in the context of the pump-probe infrared spectra of the hydrogen stretch in a moderately strong hydrogen-bonded complex dissolved in a polar solvent. Particular emphasis is put on incorporating nonadiabatic transitions and accounting for their unique spectral signature. PMID- 20853864 TI - Direct observation of nanoscale size effects in Ge semiconductor nanowire growth. AB - Progress in the synthesis of semiconductor nanowires (NWs) has prompted intensive inquiry into understanding the science of their growth mechanisms and ultimately the technological applications they promise. We present new results for the size dependent growth kinetics of Ge NWs and correlate the results with a direct experimental measurement of the Gibbs-Thomson effect, a measured increase in the Ge solute concentration in liquid Au-Ge droplets with decreasing diameter. This nanoscale-dependent effect emerges in vapor-liquid-solid Ge NW growth and leads to a decrease in the NW growth rate for smaller diameter NWs under a wide range of growth conditions with a cutoff in growth at sufficiently small sizes. These effects are described quantitatively by an analytical model based on the Gibbs Thomson effect. A comprehensive treatment is provided and shown to be consistent with experiment for the effect of NW growth time, temperature, pressure, and doping on the supersaturation of Ge in Au, which determines the growth rate and critical cutoff diameter for NW growth. These results support the universal applicability of the Gibbs-Thomson effect to sub-100 nm diameter semiconductor NW growth. PMID- 20853866 TI - Improving water quality assessments through a hierarchical Bayesian analysis of variability. AB - Water quality measurement error and variability, while well-documented in laboratory-scale studies, is rarely acknowledged or explicitly resolved in most model-based water body assessments, including those conducted in compliance with the United States Environmental Protection Agency (USEPA) Total Maximum Daily Load (TMDL) program. Consequently, proposed pollutant loading reductions in TMDLs and similar water quality management programs may be biased, resulting in either slower-than-expected rates of water quality restoration and designated use reinstatement or, in some cases, overly conservative management decisions. To address this problem, we present a hierarchical Bayesian approach for relating actual in situ or model-predicted pollutant concentrations to multiple sampling and analysis procedures, each with distinct sources of variability. We apply this method to recently approved TMDLs to investigate whether appropriate accounting for measurement error and variability will lead to different management decisions. We find that required pollutant loading reductions may in fact vary depending not only on how measurement variability is addressed but also on which water quality analysis procedure is used to assess standard compliance. As a general strategy, our Bayesian approach to quantifying variability may represent an alternative to the common practice of addressing all forms of uncertainty through an arbitrary margin of safety (MOS). PMID- 20853865 TI - Controllable growth of nanoscale conductive filaments in solid-electrolyte-based ReRAM by using a metal nanocrystal covered bottom electrode. AB - Resistive memory (ReRAM) based on a solid-electrolyte insulator is a promising nanoscale device and has great potentials in nonvolatile memory, analog circuits, and neuromorphic applications. The underlying resistive switching (RS) mechanism of ReRAM is suggested to be the formation and rupture of nanoscale conductive filament (CF) inside the solid-electrolyte layer. However, the random nature of the nucleation and growth of the CF makes their formation difficult to control, which is a major obstacle for ReRAM performance improvement. Here, we report a novel approach to resolve this challenge by adopting a metal nanocrystal (NC) covered bottom electrode (BE) to replace the conventional ReRAM BE. As a demonstration vehicle, a Ag/ZrO(2)/Cu NC/Pt structure is prepared and the Cu NC covered Pt BE can control CF nucleation and growth to provide superior uniformity of RS properties. The controllable growth of nanoscale CF bridges between Cu NC and Ag top electrode has been vividly observed by transmission electron microscopy (TEM). On the basis of energy-dispersive X-ray spectroscopy (EDS) and elemental mapping analyses, we further confirm that the chemical contents of the CF are mainly Ag atoms. These testing/metrology results are consistent with the simulation results of electric-field distribution, showing that the electric field will enhance and concentrate on the NC sites and control location and orientation of Ag CFs. PMID- 20853867 TI - Impact of titanium dioxide nanomaterials on nitrogen fixation rate and intracellular nitrogen storage in Anabaena variabilis. AB - This study comprehensively investigated the impact of titanium dioxide nanomaterials (nTiO(2)) exposure on cell growth, nitrogen fixation activity, and nitrogen storage dynamics in the primary producer cyanobacteria Anabaena variabilis at various dose concentrations and exposure time lengths. The results indicated that both growth rate (EC(50)-96 h of 0.62 mgTiO(2)/L) and nitrogen fixation activity (EC(50)-96 h of 0.4 mgTiO(2)/L) were inhibited by nTiO(2) exposure. The Hom's law (C(n)T(m)) was used as inactivation model to predict the concentration- and time-dependent inhibition of growth and nitrogen fixation activity. The kinetic parameters determined suggested that the time of exposure has a greater influence than the nTiO(2) concentration in toxicity. We observed, for the first time, that nTiO(2) induced a dose (concentration and time) dependent increase in both the occurrence and intracellular levels of the nitrogen-rich cyanophycin grana proteins (CGPs). The results implied that CGPs may play an important role in the stress response mechanisms of nTiO(2) exposure and can serve as a toxicity assessment endpoint indicator. This study demonstrated that nitrogen-fixing activity could be hampered by the release of nTiO(2) in aquatic environments; therefore it potentially impacts important biogeochemical processes, such as carbon and nitrogen cycling. PMID- 20853868 TI - Surface effects on the atomic and electronic structure of unpassivated GaAs nanowires. AB - On the basis of accurate ab initio calculations, we propose a model for predicting the stability of III-V nanowires (NW) having different side walls and ridge configurations. The model allows us to obtain the NW formation energies by performing calculations only on relatively "small" systems, small diameter NWs and flat surfaces, to extract the contributions to the stability of each structural motif. Despite the idea illustrated here for the case of hexagonally shaped GaAs NWs grown along the [111]/[0001] direction, the method can also be applied generally to other differently shaped and oriented III-V NWs. The model shows that NW surfaces (side walls plus ridges) mainly determine the NW stability, so the changes to the surface structure (e.g., induced by defects or different growth conditions) would modify the final NW structure in a remarkable way. We find that wurtzite and zinc blende nanowires have similar energies over a wide diameter range, thus explaining the observed polytypism. Furthermore, new more stable ridge reconstructions are proposed for zinc blende nanowires. The surface-related structural motifs also have clear fingerprints on the NW electronic structure. We find that the more stable nanowires are all semiconducting. The band gaps are ruled by surface states and do not follow the trend mandated by the quantum confinement effect. Small diameter wurtzite nanowires have an indirect band gap, but for some of them, an indirect to direct transition can be foreseen to occur at larger diameters. Surface states have a larger impact on the zinc blende NW band gaps than on the wurtzite NW ones. Zinc blende nanowire band gaps reduce significantly with increasing nanowire radius, reaching the bulk value at a diameter of about 30 A. The surface structure and the high surface related DOS below the conduction band are going to affect the nanowire dopant incorporation and efficiency when doping is carried out during the NW growth. PMID- 20853869 TI - Oxygen gas sensing by luminescence quenching in crystals of Cu(xantphos)(phen)+ complexes. AB - We have shown that crystals of the highly emissive copper(I) compounds [Cu(POP)(dmp)]tfpb, [Cu(xantphos)(dmp)]tfpb, [Cu(xantphos)(dipp)]tfpb, and [Cu(xantphos)(dipp)]pftpb, (where POP = bis[2-(diphenylphosphino)phenyl]ether; xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dmp = 2,9-dimethyl 1,10-phenanthroline; dipp = 2,9-diisopropyl-1,10-phenanthroline (dipp); tfpb(-) = tetrakis(bis-3,5-trifluoromethylphenylborate); and pftpb = tetrakis(pentfluorophenyl)borate) are oxygen gas sensors. The sensing ability correlates with the amount of void space calculated from the crystal structures. The compounds exhibit linear Stern-Volmer plots with reproducible K(SV) constants from sample to sample; these results reinforce the observations that the sensing materials are crystalline and the sensing sites are homogeneous within the crystals. The long lifetime (~30 MUs), high emission quantum yield (phi = 0.66), appreciable K(SV) value (5.65), and very rapid response time (51 ms for the 95% return constant) for [Cu(xantphos)(dmp)]tfpb are significantly better than those for the [Cu(NN)(2)]tfpb complexes studied previously and compare favorably with [Ru(4,7-Me2phen)(3)](tfpb)(2), (K(SV) = 4.76; 4,7-Me(2)phen = 4,7-dimethyl-1,10- phenanthroline). The replacement of precious metals (like Ru or Pt) with copper may be technologically significant and the new compounds can be synthesized in one or two steps from commercially available starting materials. The strictly linear Stern-Volmer behavior observed for these systems and the absence of a polymer matrix that might cause variability in sensor to sensor sensitivity may allow a simple single-reference point calibration procedure, an important consideration for an inexpensive onetime limited use sensor that could be mass produced. PMID- 20853870 TI - Reductive cleavage mechanism of Co-C bond in cobalamin-dependent methionine synthase. AB - The key step in the catalytic cycle of methionine synthase (MetH) is the transfer of a methyl group from the methylcobalamin (MeCbl) cofactor to homocysteine (Hcy). This mechanism has been traditionally viewed as an S(N)2-type reaction, but a different mechanism based on one-electron reduction of the cofactor (reductive cleavage) has been recently proposed. In this work, we analyze whether this mechanism is plausible from a theoretical point of view. By means of a combination of gas-phase as well as hybrid QM/MM calculations, we show that cleavage of the Co-C bond in a MeCbl...Hcy complex (Hcy = methylthiolate substrate (Me-S(-)), a structural mimic of deprotonated homocysteine) proceeds via a [Co(III)(corrin(*-))]-Me...*S-Me diradical configuration, involving electron transfer (ET) from a pi*(corrin)-type state to a sigma*(Co-C) one, and the methyl transfer displays an energy barrier <=8.5 kcal/mol. This value is comparable to the one previously computed for the alternative S(N)2 reaction pathway (10.5 kcal/mol). However, the ET-based reductive cleavage pathway does not impose specific geometrical and distance constraints with respect to substrate and cofactor, as does the S(N)2 pathway. This might be advantageous from the enzymatic point of view because in that case, a methyl group can be transferred efficiently at longer distances. PMID- 20853871 TI - Synthesis, excited state dynamics, and optical characteristics of oligophenyl based swivel cruciforms in solution and solid state. AB - Oligophenyl-based swivel cruciforms are an amorphous class of materials for potential use in display applications. In this work, we describe the design, synthesis, and structural and optical properties of a group of chromophores with varying degrees of pi-conjugation that produce blue emission and high photoluminescence quantum yields (PLQYs). The swivel cruciforms are branched complexes consisting of two arms, and the relative rotation of these arms is an important factor that determines the optical properties of these systems. The studies reveal that the physical size of the system, that is, the arms, and the presence and position of functional groups results in different degrees of sterical effects. This has a dramatic impact on the interplay between nonradiative and radiative decay of the excited state. For the least pi-extended system, control of the excited state decay can be achieved by modifying the properties of the medium through an increase in the viscosity, which is demonstrated accordingly. The data shows that an intramolecular excited state is responsible for the swivel cruciform emission in solution. The character of this "aggregate" and its emission is not dissimilar to an excimer, and we therefore attribute it to an intramolecular excimer. In the solid state, a combination of intra- and intermolecular excimers are the most likely source of the emission. The data also shows that intra molecular excimers can produce a surprisingly high PLQY, when either properties of the medium facilitate this or when functional groups introduce steric hindrance, which subsequently prevents the nonraditive decay through conformational change. PMID- 20853872 TI - Quantification of flavoring constituents in cinnamon: high variation of coumarin in cassia bark from the German retail market and in authentic samples from indonesia. AB - Coumarin is a flavoring which can cause hepatotoxicity in experimental animals and in a proportion of the human population. The tolerable daily intake (TDI) may be exceeded in consumers with high intake of cinnamon containing high levels of coumarin. The objective of this study was to determine these levels in cinnamon samples and to identify possible factors influencing them. A HPLC method to quantify coumarin and related constituents (cinnamaldehyde, cinnamic acid, cinnamyl alcohol, eugenol) in a single run was used. Results found in 47 cinnamon powder samples obtained from the German retail market confirmed high levels of coumarin in cassia cinnamon. A huge variation was observed in stick samples from two packages (range from below the limit of detection to about 10000 mg/kg). Cassia bark samples of five trees received directly from Indonesia were analyzed additionally. Interestingly, a high variation was observed in one of the trees, whereas no coumarin was detected in the samples of two other trees. In conclusion, coumarin levels in cassia cinnamon can vary widely even within a single tree. PMID- 20853873 TI - Quercetin prevents unloading-derived disused muscle atrophy by attenuating the induction of ubiquitin ligases in tail-suspension mice. AB - The effects of quercetin (1) were investigated on disused muscle atrophy using mice that underwent tail suspension. Periodic injection of 1 into the gastrocnemius muscle suppressed muscle weight loss and ubiquitin ligase expression. Compound 1 reduced the enhancement of lipid peroxidation in the muscle. Injection of N-acetyl-l-cysteine, but not flavone (2), also prevented muscle weight loss and enhancement of lipid peroxidation. These findings demonstrate that 1 can prevent disused muscle atrophy by attenuating the expression of ubiquitin ligases and that such prevention originates from its antioxidant activity. PMID- 20853874 TI - The tomato saponin, esculeoside A. AB - Esculeoside A (2), a spirosolane steroidal glycoside, is a major constituent isolated from Solanum lycopersicum, a commercial strain of mini tomatoes. The content variability of esculeoside A (2) was examined in mini, midi, and Momotaro tomatoes and various processed tomato products. In the green immature tomato fruit, tomatine (1) is oxidized at C-23 and C-27 to produce esculeoside A (2) in the ripe fruit. Further, esculeoside A (2) is partly converted to 3beta-hydroxy 5alpha-pregn-16-en-20-one 3-O-beta-lycotetraoside (6), a pregnane glycoside, in the overripe fruit. Esculeogenin A (3), the sapogenol of 2, is easily converted into 3beta,16beta-dihydroxy-5alpha-pregn-20-one (17). Metabolic studies showed excretion of androstane derivatives in the urine of human volunteer subjects after tomato consumption. Esculeogenin A (3) inhibited the accumulation of cholesterol esters in macrophages through its effects on acyl-CoA:cholesterol acyl transferase (ACAT). Oral administration of esculeoside A (2) to apoE deficient mice significantly reduced serum levels of cholesterol, triglycerides, and LDL-cholesterol and ameliorated the severity of atherosclerotic lesions. PMID- 20853875 TI - Lignans and Triterpenes from the Bark of Durio carinatus and Durio oxleyanus. AB - Investigation of chemical constituents from the bark of Durio carinatus has led to the isolation of three lignans, boehmenan X (1), threo-carolignan X (2), and erythro-carolignan X (3), together with the three known lignans boehmenan, threo carolignan E, and erythro-carolignan E. The bark of D. oxleyanus yielded two new lignan ethers, threo-carolignan Y (4) and erythro-carolignan Y (5), together with compounds 1, 3, and boehmenan. J-Based configurational analysis and NOE measurements were used to explore conformational issues for the lignan diastereomers, while CD measurements supported an 8'S configuration for the various lignans. The triterpenes 3beta-O-cis-caffeoylbetulinic acid and 3beta-O trans-caffeoylbetulinic acid were also characterized from D. carinatus. PMID- 20853876 TI - Revision of the Structures of 1,5-Dihydroxy-3,8-epoxyvalechlorine, Volvaltrate B, and Valeriotetrate C from Valeriana jatamansi and V. officinalis. AB - The structures of 1,5-dihydroxy-3,8-epoxyvalechlorine (1a) and volvaltrate B (6a), two new chlorinated iridoids isolated from Valeriana jatamansi and V. officinalis, respectively, were originally assigned on the basis of spectroscopic methods. Reinvestigation using X-ray analysis and chemical transformation revealed that the original assignment of H-7 in 1a and OH-8 in 6a should be inverted and that the structures should be revised to 1 and 6, respectively. Correspondingly, the structure of valeriotetrate C (7a) should be revised to 7. Volvaltrate B (6) showed cytotoxic activity against the lung adenocarcinoma (A549), metastatic prostate cancer (PC-3M), colon cancer (HCT-8), and hepatoma (Bel7402) cell lines, with IC50 values of 8.5, 2.0, 3.2, and 6.1 MUM, respectively. PMID- 20853877 TI - From infinite one-dimensional helix to discrete Cu(II)15 cluster along with in situ S(N)2 ring-cleavage of cis-epoxysuccinic acid: pH-controlled assemblies, crystal structures, and properties. AB - Two Cu(II) coordination complexes {[Cu(ces)(H(2)O)(2)](H(2)O)(0.5)}(n) (1) and [Cu(15)(dhs)(6)(OH)(6)(H(2)O)(10)](H(2)O)(20) (2) have been synthesized from cis epoxysuccinic acid (cis-H(2)ces) and Cu(II) perchlorate under different pH conditions (ces = cis-epoxysuccinate and dhs = 2,3-dihydroxysuccinate), and fully characterized by IR spectra, elemental analyses, as well as single crystal and powder X-ray diffraction techniques. Notably, when the reaction was performed at pH above about 7.4, a one-dimensional (1-D) helical chain complex 1 is formed, whereas a neutral isolated Cu(15) nanocluster 2 is generated when the pH value is decreased to the range of about 6.6-7.3, being concomitant with in situ S(N)2 ring-cleavage reaction of cis-H(2)ces to form (2S,3S)- and (2R,3R)-H(4)dhs. Further, extended supramolecular architectures are constructed via secondary interactions in both structures. The magnetic properties of 1 and 2 have also been studied in detail, showing that 1 is an antiferromagnetic helical chain of S = 1/2 spins and 2 possesses an S = 3/2 spin ground state. PMID- 20853879 TI - alpha-Chloro-beta,gamma-ethylenic esters: enantiocontrolled synthesis and substitutions. AB - Chiral nonracemic gamma-seleno-alpha,beta-ethylenic esters, when treated with sulfuryl chloride and ethyl vinyl ether in hexanes, produced alpha-chloro beta,gamma-ethylenic esters in 65-75% yields, with ee values of 95-97%, and with 1,3-syn transfer of chirality. Reaction of these allylic chloride electrophiles with methylcuprate and with sodium azide nucleophiles afforded exclusively gamma substituted-alpha,beta-ethylenic esters with faithful anti-transfer of chirality on multigram scale. PMID- 20853878 TI - Dolabellane Diterpenoids from the South Atlantic Gorgonian Convexella magelhaenica. AB - Two new dolabellane diterpenoids (1 and 2) were isolated from a small sample of the deep water gorgonian octocoral Convexella magelhaenica collected as a nontarget by-catch by dredging (-93 m) in commercial Patagonian scallop fishing grounds in the South Atlantic. The structures of the new compounds, which are major metabolites in the extract, were established by spectroscopic techniques and chemical transformations. Both compounds were cytotoxic against a human pancreatic adenocarcinoma cell line at micromolar concentrations. PMID- 20853880 TI - Ruthenium-catalyzed tandem ring-opening/ring-closing/cross-metathesis of 1,6 cyclopropene-ynes and olefins for the construction of the 3-pyrroline skeleton. AB - Catalyzed by the first-generation Grubbs' ruthenium complex, tandem intramolecular/intermolecular metathesis of 1,6-enynes bearing a cyclopropene ring took place smoothly to produce 3-pyrroline derivatives in satisfactory yields via ring-opening/ring-closing/cross-metathesis processes. PMID- 20853881 TI - Smooth and jump-like metal-dielectric transitions in single-walled carbon nanotubes under functionalization. AB - We examine at the DFT level of theory the topology of side wall functionalization of the (5,5)metallic single-wall carbon nanotube (CNT) with carbenes (>CX(2)) and its effect on electronic properties of the system. It is demonstrated that specific substructures/topology known to stabilize functionalized fullerene molecules can play the same role in CNTs, as well. Upon deepening of functionalization, "uniformity" of addition motives and related continuous changes in properties transform into regular addition patterns with isolated aromatic islands on the nanotube backbone that give rise to jump-like changes in electronic structure. PMID- 20853882 TI - Electron transfer from oligothiophenes in the higher triplet excited states. AB - In the present paper, we have investigated the inter- and intramolecular electron transfer processes from the higher triplet excited state (T(n)) of oligothiophenes (3T and 4T). In the case of the intermolecular systems, two-color two-laser flash photolysis using nanosecond lasers was applied to the solution including benzophenone, oligothiophene, and halogenated benzene as a photosensitizer, an electron donor, and an electron acceptor, respectively. The first laser light irradiation generated the lowest triplet excited state (T(1)) of oligothiophene via energy transfer from benzophenone. Upon the second laser light irradiation, the absorption band of the radical cation of oligothiophene appeared with the simultaneous bleaching of the absorption band of the T(1) state, indicating the electron transfer from the T(2) state of the oligothiophene to the electron acceptor. The observed electron transfer rate dependent on the free energy change was explained on the basis of the Marcus theory. The intramolecular electron transfer in the dyad molecule of oligothiophene and acceptor was investigated using the two-color two-laser flash photolysis employing femtosecond laser. Upon the second laser light irradiation, which generates the T(n) state, the kinetic trace of the absorption band of T(1) state showed the bleaching and recovery, the rate of which depends on the driving force for the charge separation from the T(2) state of the oligothiophene. This observation suggests the existence of charge separation process from the T(2) state, and the observation of the charge-separated state was difficult probably due to the low charge separation yield and fast charge recombination. PMID- 20853883 TI - Evaluation of nanocopper removal and toxicity in municipal wastewaters. AB - Bench scale studies were performed to evaluate removal and toxicity of copper nanoparticles (CuNPs) and copper ions in activated sludge biomass. The data indicated that, under the test conditions, copper nanoparticles were removed more effectively (~95%) than copper ions (30-70%) from the wastewater. Mechanisms of CuNP removal were further investigated by equilibrating CuNP and copper ion in activated sludge filtrate (0.45 MUm). The predominant mechanisms of copper removal appear to be aggregation and settling (CuNP) or precipitation (copper ion) rather than biosorption. Most probable number (MPN) test data indicated that addition of 10 mg/L of copper ion was toxic to both coliform and ammonia oxidizing bacteria in the wastewater while no inhibitory effects were observed with the addition of the same amount of copper nanoparticles. Respirometry data indicated a 55% decrease in respiration rate when 10 mg/L ionic copper was added. However, no significant decrease in respiration rate was observed in the presence of copper nanoparticles. The toxicity of copper to activated sludge microorganisms appears to be a function of the concentration and characteristics of copper remaining in solution/suspension. PMID- 20853884 TI - Molecular composition of monoterpene secondary organic aerosol at low mass loading. AB - The molecular composition of secondary organic aerosol (SOA) from the ozonolysis of monoterpenes (alpha-pinene and beta-pinene) was studied by liquid chromatography mass spectrometry and high-resolution Fourier transform ion cyclotron resonance mass spectrometry techniques, both employing electrospray ionization (ESI). SOA particles were generated in a flow tube reactor with a reaction time of 23 s. A microsampling assembly in combination with ESI-FTICR analysis permitted SOA with a mass loading as low as 3.5 MUg/m(3) to be characterized with high accuracy and precision mass analysis. Hundreds of product molecular formulas were identified that were common to all mass loadings; however the relative intensities changed significantly. In particular, a species with the (neutral molecule) formula C(17)H(26)O(8) increased substantially in intensity relative to other products as the mass loading decreased. Tandem mass spectrometry (MS(n)) of this species showed it to be a dimer of C(9)H(14)O(4) and C(8)H(12)O(4), most likely pinic acid and terpenylic acid, respectively. LCMS analysis showed different elution times for the dimer and monomer species, confirming that the dimer was not an artifact of ESI analysis. The particle number concentration increased linearly with ozone concentration (the limiting reactant in the experiment), arguing against gas phase dimerization as the rate limiting step in particle formation. PMID- 20853885 TI - Effect of the substituent and hydrogen bond on the geometry and electronic properties of OH and O(-) groups in para-substituted phenol and phenolate derivatives. AB - Interrelations between intra- and intermolecular interactions were analyzed by using computational modeling of the para-X-substituted derivatives of phenol and phenolate (where X = NO, NO(2), CHO, COMe, COOH, CONH(2), Cl, F, H, Me, OMe, and OH) and their equilibrium H-bonded complexes with HB and B(-) (where HB = HF and HCN and B(-) = F(-) and CN(-)). B3LYP/6-311++G** computation was applied. Both the substituent effect and H-bonding changed the electronic properties of the -O( ) and -OH groups and geometric parameters of phenol and phenolate derivatives and their H-bonded complexes. C-O bond lengths and aromaticity indices of the ring were found to depend linearly on sigma(p)(-) of the substituents. In the first case the greatest sensitivity on the substituent effect was for 4-X C(6)H(4)OH...CN(-) and 4-X-C(6)H(4)O(-)...HF complexes, whereas for 4-X C(6)H(4)O(-)...HCN systems it was comparable with that for phenol derivatives and a little smaller than that for 4-X-C(6)H(4)O(-) derivatives. This means that the strength of H-bonding may considerably change the sensitivity of the C-O bond length to the substituent effect. The greatest sensitivity of the aromaticity indices, both HOMA and NICS(1)zz, to sigma(p)(-) was found for phenolate and then for phenolate H-bonded complexes, followed by phenol complexes, and the lowest sensitivity was observed for phenol derivatives. The interatomic proton-acceptor distance, being a measure of the H-bond strength, was found to depend linearly on sigma(p)(-) of the substituents with a positive slope for O...HB (HF or HCN) interactions and a negative slope for OH...B(-) interactions. NBO charges on the oxygen and hydrogen atoms also depend on sigma(p)(-) of the substituents. In the latter case for strong H-bonded complexes (energy less than ~-20 kcal/mol) the substituent effect works oppositely for 4-X-C(6)H(4)OH...B(-) in comparison with the 4-X-C(6)H(4)O(-)...HB systems. Moreover, following the Espinoza et al. [J. Chem. Phys. 2002, 117, 5529] and Grabowski et al. [J. Phys. Chem. B 2006, 110, 6444] classifications, the above and q(H) vs proton-acceptor distance relationships suggest a partially covalent character of the hydrogen bond for these complexes and the degree of its covalent nature depending on the substituent. PMID- 20853886 TI - Hydrogen bonding in hydrates with one acetic acid molecule. AB - Hydrogen bonding (H-bond) interaction significantly influences the separation of acetic acid (HAc) from the HAc/H(2)O mixtures, especially the dilute solution, in distillation processes. It has been examined from the HAc mono-, di-, tri-, and tetrahydrates by analyzing the structures, binding energies, and infrared vibrational frequencies from quantum chemical calculations. For the first coordinate shell the 6-membered head-on ring is surely the most favorable structure because it has (1) the most favorable H-bonding parameters, (2) almost the largest binding energy per H-bond, (3) the biggest wavenumber shifts, and (4) the highest ring distribution (the AIMD simulations). Moreover, the comparison of the calculations with the experiments (the X-ray scattering data and IR frequencies) suggests that the possible structures in dilute aqueous solution are those involving two or more coordinate shells. The H-bonding in these water surrounded HAc hydrates are the origin of the low-efficiency problem of isolating HAc from the dilute HAc/H(2)O mixtures. It is apparently a tougher work to break the H-bonds among HAc and the surrounded H(2)O molecules with respect to the case of more concentrated solutions, where the dominant structures are HAc or H(2)O aggregates. PMID- 20853888 TI - Plasmonics: an emerging field fostered by Nano Letters. AB - While studies of surface plasmons on metals have been pursued for decades, the more recent appearance of nanoscience has created a revolution in this field with "Plasmonics" emerging as a major area of research. The direct optical excitation of surface plasmons on metallic nanostructures provides numerous ways to control and manipulate light at nanoscale dimensions. This has stimulated the development of novel optical materials, deeper theoretical insight, innovative new devices, and applications with potential for significant technological and societal impact. Nano Letters has been instrumental in the emergence of plasmonics, providing its readership with rapid advances in this dynamic field. PMID- 20853887 TI - Comprehensive structural and functional characterization of the human kinome by protein structure modeling and ligand virtual screening. AB - The growing interest in the identification of kinase inhibitors, promising therapeutics in the treatment of many diseases, has created a demand for the structural characterization of the entire human kinome. At the outset of the drug development process, the lead-finding stage, approaches that enrich the screening library with bioactive compounds are needed. Here, protein structure based methods can play an important role, but despite structural genomics efforts, it is unlikely that the three-dimensional structures of the entire kinome will be available soon. Therefore, at the proteome level, structure-based approaches must rely on predicted models, with a key issue being their utility in virtual ligand screening. In this study, we employ the recently developed FINDSITE/Q-Dock ligand homology modeling approach, which is well-suited for proteome-scale applications using predicted structures, to provide extensive structural and functional characterization of the human kinome. Specifically, we construct structure models for the human kinome; these are subsequently subject to virtual screening against a library of more than 2 million compounds. To rank the compounds, we employ a hierarchical approach that combines ligand- and structure-based filters. Modeling accuracy is carefully validated using available experimental data with particularly encouraging results found for the ability to identify, without prior knowledge, specific kinase inhibitors. More generally, the modeling procedure results in a large number of predicted molecular interactions between kinases and small ligands that should be of practical use in the development of novel inhibitors. The data set is freely available to the academic community via a user friendly Web interface at http://cssb.biology.gatech.edu/kinomelhm/ as well as at the ZINC Web site ( http://zinc.docking.org/applications/2010Apr/Brylinski 2010.tar.gz ). PMID- 20853889 TI - Effect of Watson-Crick and Hoogsteen base pairing on the conformational stability of C8-phenoxyl-2'-deoxyguanosine adducts. AB - Bulky DNA addition products (adducts) formed through attack at the C8 site of guanine can adopt the syn orientation about the glycosidic bond due to changes in conformational stability or hydrogen-bonding preferences directly arising from the bulky group. Indeed, the bulky substituent may improve the stability of (non native) Hoogsteen pairs. Therefore, such adducts often result in mutations upon DNA replication. This work examines the hydrogen-bonded pairs between the Watson Crick and Hoogsteen faces of the ortho or para C8-phenoxyl-2'-deoxyguanosine adduct and each natural (undamaged) nucleobase with the goal to clarify the conformational preference of this type of damage, as well as provide insight into the likelihood of subsequent mutation events. B3LYP/6-311+G(2df,p)//B3LYP/6 31G(d) hydrogen-bond strengths were determined using both nucleobase and nucleoside models for adduct pairs, as well as the corresponding complexes involving natural 2'-deoxyguanosine. In addition to the magnitude of the binding strengths, the R(C1'...C1') distances and ?(N9C1'C1') angles, as well as the degree of propeller-twist and buckle distortions, were carefully compared to the values observed in natural DNA strands. Due to structural changes in the adduct monomer upon inclusion of the sugar moiety, the monomer deformation energy significantly affects the relative hydrogen-bond strengths calculated with the nucleobase and nucleoside models. Therefore, we recommend the use of at least a nucleoside model to accurately evaluate hydrogen-bond strengths of base pairs involving flexible, bulky nucleobase adducts. Our results also emphasize the importance of considering both the magnitude of the hydrogen-bond strength and the structure of the base pair when predicting the preferential binding patterns of nucleobases. Using our best models, we conclude that the Watson-Crick face of the ortho phenoxyl adduct forms significantly more stable complexes than the Hoogsteen face, which implies that the anti orientation of the damaged base will be favored by hydrogen bonding in DNA helices. Additionally, regardless of the hydrogen-bonding face involved, cytosine forms the most stable base pair with the ortho adduct, which implies that misincorporation due to this type of damage is unlikely. Similarly, cytosine is the preferred binding partner for the Watson Crick face of the para adduct. However, Hoogsteen interactions with the para adduct are stronger than those with natural 2'-deoxyguanosine or the ortho adduct, and this form of damage binds with nearly equal stability to both cytosine and guanine in the Hoogsteen orientation. Therefore, the para adduct may adopt multiple orientations in DNA helices and potentially cause mutations by forming pairs with different natural bases. Models of oligonucleotide duplexes must be used in future work to further evaluate other factors (stacking, major groove contacts) that may influence the conformation and binding preference of these adducts in DNA helices. PMID- 20853890 TI - Isotopic composition and fractionation of mercury in Great Lakes precipitation and ambient air. AB - Atmospheric deposition is a primary pathway by which mercury (Hg) enters terrestrial and aquatic ecosystems; however, the chemical and meteorological processes that Hg undergoes from emission to deposition are not well understood. Hg stable isotope geochemistry is a growing field used to better understand Hg biogeochemical cycling. To examine the atmospheric Hg isotopic composition in the Great Lakes, precipitation and ambient vapor-phase Hg samples were collected in Chicago, IL, Holland, MI, and Dexter, MI, between April 2007 and September 2009. Precipitation samples were characterized by negative mass-dependent fractionation (MDF) (delta(202)Hg = -0.790/00 to 0.180/00), while most vapor-phase samples displayed positive MDF (delta(202)Hg = -0.590/00 to 0.430/00). Positive mass independent fractionation (MIF) (Delta(199)Hg = 0.040/00 to 0.520/00) was observed in precipitation, whereas MIF was slightly negative in vapor-phase samples (Delta(199)Hg = -0.210/00 to 0.060/00). Significant positive MIF of (200)Hg up to 0.250/00 was also measured in precipitation. Such MIF of an even mass Hg isotope has not been previously reported in natural samples. These results contrast with recent predictions of the isotopic composition of atmospheric Hg and suggest that, in addition to aqueous photoreduction, other atmospheric redox reactions and source-related processes may contribute to isotopic fractionation of atmospheric Hg. PMID- 20853891 TI - Bifunctional conjugates comprising beta-cyclodextrin, polyethylenimine, and 5 fluoro-2'- deoxyuridine for drug delivery and gene transfer. AB - Earlier reports indicated that the conjugates (PEI(600)-CD, PC) of beta cyclodextrin and low-molecular-weight polyethylenimine (PEI, M(w) 600) can be used as efficient gene carriers in glioma cancer therapy. Incorporating anticancer drugs onto PC conjugates may endow them with new and interesting properties for great applications. In this work, FU-PEI(600)-CD (FPC) conjugates comprising PC and 5-fluoro-2'-deoxyuridine (FdUrd) were prepared as new bifunctional anticancer prodrugs with improved therapeutic effects, as well as good gene transfer efficiency. In comparison with free FdUrd, FPC could inhibit proliferation and enhance cytotoxicity on glioma cells. The results of hematoxylin and eosin (HE) staining indicated that C6 cells treated with FPC shrunk more seriously. Unlike FdUrd, cell cycle analysis indicated that C6 cells were primarily arrested in the G1 phase in the presence of FPC. Cellular uptake of FPC in C6 cells was about 10 times higher than that of FdUrd. In addition, the in vitro and in vivo gene transfection indicated that FPC still exhibited good gene expression efficiency. With the ability to deliver drugs and transfer genes, such bifunctional FPC conjugates may have great potential applications in combination therapy of cancers. PMID- 20853892 TI - Induced biosynthesis of cryptic polyketide metabolites in a Burkholderia thailandensis quorum sensing mutant. AB - Genetic manipulation of the LuxR-type quorum sensing regulator system in Burkholderia thailandensis caused a significant change in the metabolic profile: it led to activation of the thailandamide biosynthesis gene cluster, dramatically increased thailandamide production, and induced strong pigmentation. A novel polyketide metabolite, thailandamide lactone (2), which cannot be detected in the wild type, was isolated from the mutant broth, and its structure was elucidated by high-resolution mass spectrometry and IR and NMR spectroscopy. In a biological assay using tumor cell lines, 2 showed moderate antiproliferative activities. This finding not only points to complex regulation but also serves as a proof of concept that engineering quorum sensing mutants may enable the discovery of novel bioactive natural products encoded by silent or only weakly expressed biosynthetic pathway genes. PMID- 20853894 TI - Finite magnetization plateau from a two-dimensional antiferromagnet: density functional analysis of the magnetic structure of Cu3(P2O6OH)2. AB - We evaluated the intrachain and interchain spin exchanges of Cu(3)(P(2)O(6)OH) consisting of (Cu2-Cu2-Cu1)(infinity) chains by density functional calculations to find that the magnetic properties of Cu(3)(P(2)O(6)OH)(2) are not governed by the J(1)-J(2)-J(2) trimer chain along the c-direction, but by a two-dimensional (2D) antiferromagnetic lattice in which J(1)-J(3)-J(3) trimer chains along the (a c/2)-direction are interconnected by J(6) monomer chains along the a-direction. Despite its 2D character, Cu(3)(P(2)O(6)OH)(2) shows a 1/3 magnetization plateau because it is a spin-1/2 trimer system with one dominant antiferromagnetic dimer exchange. PMID- 20853893 TI - Relationship between MALDI IMS intensity and measured quantity of selected phospholipids in rat brain sections. AB - MALDI IMS positive ion images of rat brain show a regional distribution of phosphocholine species that is striking in the apparent distinctiveness and reproducibility of such depictions. The interpretation of these images, specifically the relationship between MALDI IMS ion intensity and the amount of the phosphocholine (PC) species in the tissue is complicated by numerous factors, such as ion suppression, ion molecule chemistry, and effects of tissue structure. This study was designed to test the hypothesis that the intensity of PC molecular species does relate to the quantity of molecules in a tissue sample. A set of comparison studies for a limited but representative selection of cell-derived PC molecular species was carried out using LC/MS/MS to measure the amounts of these species in brain tissue extracts. There was good correlation between the MALDI IMS ion abundance of PC molecular species and the relative abundance of corresponding PC molecular species in microdissected regions analyzed by LC/MS/MS. PMID- 20853895 TI - {Mo96La8} eggshell ring and self-assembly to {Mo132} Keplerate through Mo-blue intermediate, involved in UV-photolysis of [Mo7O24](6-)/carboxylic acid system at pH 4. AB - The prolonged UV-photolysis of aqueous solutions containing [Mo(7)O(24)](6-) and C(2)H(5)CO(2)H (as electron donor) at pH 3.9-4.1 generates the carboxylate coordinated {Mo(132)} Keplerate (1a) isolated as a formamidinium/ammonium-mixed salt, [HC(NH(2))(2)](26)(NH(4))(28)[Mo(V)(60)Mo(VI)(72)O(372)(H(2)O)(48)(C(2)H(5)CO(2)) 36)((i)C(3)H(7)CO(2))(6)].16H(2)O (1), through the Mo-blue intermediate (2). The coordination of 2 to La(3+) gives rise to the formation of the chain structure of the C(2)-symmetric {Mo(96)La(8)} eggshell rings, formulated by H(22)[Mo(V)(20)Mo(VI)(76)O(301)(H(2)O)(29){La(H(2)O)(6)}(2)]{La(H(2)O)(5)}(6)].54 5H(2)O (3). The eggshell-ring geometry results from the insertion of [Mo(VI)(2)O(7)(H(2)O)](2-) (spacer) into the equator outer ring of the wheel shaped Mo-blue, and 10 {(Mo(VI))(Mo(VI)(5))} pentagonal subunits alternately above and below the equator outer ring are connected by eight La(3+) and two {Mo(VI)(2)} linkers within two inner rings. The neighboring eggshell rings are linked through two Mo-O-Mo bonds formed by dehydrative condensation between the {Mo(VI)(2)} linkers to result in the chain structure. Together with the results of the elemental analysis and IR, electronic absorption, (13)C NMR, and ESI-MS spectra for 2, the ring profile analysis of 3 let us identify 2 with a carbolylate-coordinated Mo-blue ring of high nuclearity. The Mo(VI)->Mo(V) photoreductive change of 2 to the 60-electron reduced Keplerate in the presence of C(2)H(5)CO(2)H involves both degradation of the outer ring and splitting of the binuclear linkers, which leads to the formation of [(Mo(VI))Mo(VI)(5)O(21)(H(2)O)(4)(carboxylate)](7-) pentagonal subunits and [Mo(V)(2)O(4)(carboxylate)](+)/[Mo(V)O(2)(carboxylate)(1/2)](0.5+)-mixed linkers for 1. PMID- 20853896 TI - A pyrrolyl-based triazolophane: a macrocyclic receptor with CH and NH donor groups that exhibits a preference for pyrophosphate anions. AB - A pyrrolyl-based triazolophane, incorporating CH and NH donor groups, acts as a receptor for the pyrophosphate anion in chloroform solution. It shows selectivity for this trianion, followed by HSO(4)(-) > H(2)PO(4)(-) > Cl(-) > Br(-) (all as the corresponding tetrabutylammonium salts), with NH-anion interactions being more important than CH-anion interactions. In the solid state, the receptor binds the pyrophosphate anion in a clip-like slot via NH and CH hydrogen bonds. PMID- 20853897 TI - Ferrier-Petasis rearrangement of 4-(vinyloxy)azetidin-2-ones: an entry to carbapenams and carbacephams. AB - Trimethylsilyl triflate promotes Ferrier-Petasis rearrangement of 4-(vinyloxy)-, 4-(propenyloxy)-, and 4-(isopropenyloxy)azetidin-2-ones to corresponding 4 (carbonylmethyl)azetidin-2-ones. The latter compounds may serve as attractive intermediates in the synthesis of carbapenem antibiotics. To illustrate the potential of this reaction, selected rearrangement products have been transformed into carbapenams. PMID- 20853898 TI - Observations on the low-energy limits for metal-to-ligand charge-transfer excited state energies of ruthenium(II) polypyridyl complexes. AB - The 77 K emission spectral maxima of bis(bipyridine)ruthenium(II) complexes are found to approach a limit at energies below about 14,000 cm(-1). There is also evidence for related low-energy excited-state limits in some other classes of ruthenium polypyridyl complexes. The shapes of the vibronic sidebands found in these limits differ from those of complexes that emit at higher energies. These low-energy excited states are not simple "charge-transfer" excited states and are analogous to pipi* excited states. The observations are consistent with effective ground state/excited state mixing matrix elements in the range of (5-10) * 10(3) cm(-1) for ruthenium polypyridine complexes. PMID- 20853899 TI - Metallic corner atoms in gold clusters supported on rutile are the dominant active site during water-gas shift catalysis. AB - Au/TiO(2) catalysts used in the water-gas shift (WGS) reaction at 120 degrees C, 7% CO, 22% H(2)O, 9% CO(2), and 37% H(2) had rates up to 0.1 moles of CO converted per mole of Au per second. However, the rate per mole of Au depends strongly on the Au particle size. The use of a nonporous, model support allowed for imaging of the active catalyst and a precise determination of the gold size distribution using transmission electron microscopy (TEM) because all the gold is exposed on the surface. A physical model of Au/TiO(2) is used to show that corner atoms with fewer than seven neighboring gold atoms are the dominant active sites. The number of corner sites does not vary as particle size increases above 1 nm, giving the surprising result that the rate per gold cluster is independent of size. PMID- 20853900 TI - Synthesis and evaluation of selected key methyl ether derivatives of vancomycin aglycon. AB - A select series of methyl ether derivatives of vancomcyin aglycon were prepared and examined for antimicrobial activity against vancomycin-sensitive Staphylococcus aureus and vancomycin-resistant Enterococci faecalis as well as their binding affinity for D-Ala-D-Ala and D-Ala-D-Lac. The intent of the study was to elucidate the role selected key methyl groups may play in the improvement of the in vitro antimicrobial profile of the tetra methyl ether derivative of vancomycin aglycon against vancomycin-resistant Enterococci faecalis previously reported. In these studies, methodology for selective derivatization of the A-, B , and D-ring was developed that defines the relative reactivity of the four phenols of vancomycin aglycon, providing a foundation for future efforts for site directed modification of the vancomycin aglycon core. PMID- 20853901 TI - Determination of dry matter content in potato tubers by low-field nuclear magnetic resonance (LF-NMR). AB - The objective of this study was to develop a calibration model between time domain low-field nuclear magnetic resonance (LF-NMR) measurements and dry matter (DM) content in single potatoes. An extensive sampling procedure was used to collect 210 potatoes from eight cultivars with a wide range in DM content, ranging from 16 to 28%. The exponential NMR relaxation curves were resolved into four mono-exponential components using a number of solution diagnostics. Partial least-squares (PLS) regression between NMR parameters (relaxation time constants T(2,1-4) and magnitudes M(0,1-4)) and DM content resulted in a model with low error (RMSECV, 0.71; RMSEP, 0.60) and high correlation (r(CV), 0.97; r(test), 0.98) between predicted and actual DM content. Correlation between DM content and each of the proton populations revealed that M(0,1) (T(2,1), 3.6 ms; SD, 0.3 ms; r, 0.95) and M(0,4) (T(2,4), 508 ms; SD, 53 ms; r, -0.90) were the major contributors to the PLS regression model. PMID- 20853903 TI - Enantio- and diastereoselective synthesis of piperidines by coupling of four components in a "one-pot" sequence involving diphenylprolinol silyl ether mediated Michael reaction. AB - An efficient, asymmetric, four-component, one-pot synthesis of highly substituted piperidines with excellent diastereo- and enantioselectivity was established through the diphenylprolinol silyl ether mediated Michael reaction of aldehyde and nitroalkene, followed by the domino aza-Henry reaction/hemiaminalization reaction and a Lewis acid mediated allylation or cyanation reaction. All carbons of the piperidine ring are substituted with different groups, and its five contiguous stereocenters are completely controlled in both relative and absolute senses. PMID- 20853902 TI - Ingestion of epilactose, a non-digestible disaccharide, improves postgastrectomy osteopenia and anemia in rats through the promotion of intestinal calcium and iron absorption. AB - Gastrectomy often results in osteopenia and anemia because of calcium (Ca) and iron (Fe) malabsorption. Here, we investigated the effects of feeding epilactose, a non-digestible disaccharide, on gastrectomy-induced osteopenia, anemia, and Ca and Fe malabsorption in male Sprague-Dawley rats. Totally gastrectomized or sham operated rats were fed the control or epilactose (50 g/kg) diets for 30 days. Gastrectomy severely decreased intestinal Ca and Fe absorption, femoral bone strength, Ca content, hemoglobin concentration, and hematocrit. These decreases were partly or totally restored by feeding epilactose. Feeding epilactose increased the cecal tissue weight and the soluble Ca concentration and short chain fatty acid pools of the cecal contents. Collectively, the increases in cecal mucosal area and/or soluble Ca concentration of the cecal contents, resulting from short-chain fatty acid production by intestinal microbes, are thought to be responsible for the epilactose-mediated promotion of Ca and Fe absorption in the gastrectomized rats. PMID- 20853904 TI - Palladium-catalyzed propargylic substitution with phosphorus nucleophiles: efficient, stereoselective synthesis of allenylphosphonates and related compounds. AB - A new, efficient method is developed, based on a palladium(0)-catalyzed reaction of propargylic derivatives with various phosphorus nucleophiles, to produce allenylphosphonates and their analogues with defined stereochemistry in the allenic and the phosphonate moiety. PMID- 20853906 TI - Surface chemistry for stable and smart molecular and biomolecular interfaces via photochemical grafting of alkenes. AB - Many emerging fields such as biotechnology and renewable energy require functionalized surfaces that are "smart" and highly stable. Surface modification schemes developed previously have often been limited to simple molecules or have been based on weakly bound layers that have limited stability. In this Account, we report on recent developments enabling the preparation of molecular and biomolecular interfaces that exhibit high selectivity and unprecedented stability on a range of covalent materials including diamond, vertically aligned carbon nanofibers, silicon, and metal oxides. One particularly successful pathway to ultrastable interfaces involves the photochemical grafting of organic alkenes to the surfaces. Bifunctional alkenes with a suitable functional group at the distal end can directly impart functionality and can serve as attachment points for linking complex structures such as DNA and proteins. The successful application of photochemical grafting to a surprisingly wide range of materials has motivated researchers to better understand the underlying photochemical reaction mechanisms. The resulting studies using experimental and computational methods have provided fundamental insights into the electronic structure of the molecules and the surface control photochemical reactivity. Such investigations have revealed the important role of a previously unrecognized process, photoelectron emission, in initiating photochemical grafting of alkenes to surfaces. Molecular and biomolecular interfaces formed on diamond and other covalent materials are leading to novel types of molecular electronic interfaces. For example, electrical, optical, or electromechanical structures that convert biological information directly into analytical signals allow for direct label-free detection of DNA and proteins. Because of the preferential adherence of molecules to graphitic edge-plane sites, the grafting of redox-active species to vertically aligned carbon nanofibers leads to good electrochemical activity. Therefore researchers could graft electrocatalytic materials to carbon nanofibers to develop new types of selective electrocatalytic interfaces. Extending this chemistry to include metal oxides such as TiO(2) may lead to highly specific and efficient chemical reactions and new materials with useful applications in photovoltaic and photocatalytic energy conversion. PMID- 20853907 TI - A new class of semiconducting polymers for bulk heterojunction solar cells with exceptionally high performance. AB - Solar cells based on the polymer-fullerene bulk heterojunction (BHJ) concept are an attractive class of low-cost solar energy harvesting devices. Because the power conversion efficiency (PCE) of these solar cells is still significantly lower than that of their inorganic counterparts, however, materials design and device engineering efforts are directed toward improving their output. A variety of factors limit the performance of BHJ solar cells, but the properties of the materials in the active layer are the primary determinant of their overall efficiency. The ideal polymer in a BHJ structure should exhibit the following set of physical properties: a broad absorption with high coefficient in the solar spectrum to efficiently harvest solar energy, a bicontinuous network with domain width within twice that of the exciton diffusion length, and high donor-acceptor interfacial area to favor exciton dissociation and efficient transport of separated charges to the respective electrodes. To facilitate exciton dissociation, the lowest unoccupied molecular orbital (LUMO) energy level of the donor must have a proper match with that of the acceptor to provide enough driving force for charge separation. The polymer should have a low-lying highest occupied molecular orbital (HOMO) energy level to provide a large open circuit voltage (V(oc)). All of these desired properties must be synergistically integrated to maximize solar cell performance. However, it is difficult to design a polymer to fulfill all these requirements. In this Account, we summarize our recent progress in developing a new class of semiconducting polymers, which represents the first polymeric system to generate solar PCE greater than 7%. The polymer system is composed of thieno[3,4-b]thiophene and benzodithiophene alternating units. These polymers have low bandgaps and exhibit efficient absorption throughout the region of greatest photon flux in the solar spectrum (around 700 nm). The stabilization of the quinoidal structure from thieno[3,4 b]thiophene is believed to be primarily responsible for these properties. Additionally, the rigid backbone enables the polymer to form an assembly with high hole mobility. Proper side chains on the polymer backbone ensure good solubility and miscibility with fullerene acceptors. The flexibility in structural tuning on the polymer backbone provides the polymers with relatively low-lying HOMO energy levels and enhanced V(oc), short-circuit current density (J(sc)), and fill factor (FF) and, thus, enhanced PCE. All of these features indicate that the polymer system exhibits a host of properties that are indeed synergistically combined, leading to the enhancement in solar cell output. Our preliminary results demonstrate why these polymers are excellent materials for solar energy conversion and represent prime candidates for further improvements through research and development. PMID- 20853905 TI - Biochemical and structural characterization of bisubstrate inhibitors of BasE, the self-standing nonribosomal peptide synthetase adenylate-forming enzyme of acinetobactin synthesis. AB - The human pathogen Acinetobacter baumannii produces a siderophore called acinetobactin that is derived from one molecule each of threonine, histidine, and 2,3-dihydroxybenzoic acid (DHB). The activity of several nonribosomal peptide synthetase (NRPS) enzymes is used to combine the building blocks into the final molecule. The acinetobactin synthesis pathway initiates with a self-standing adenylation enzyme, BasE, that activates the DHB molecule and covalently transfers it to the pantetheine cofactor of an aryl-carrier protein of BasF, a strategy that is shared with many siderophore-producing NRPS clusters. In this reaction, DHB reacts with ATP to form the aryl adenylate and pyrophosphate. In a second partial reaction, the DHB is transferred to the carrier protein. Inhibitors of BasE and related enzymes have been identified that prevent growth of bacteria on iron-limiting media. Recently, a new inhibitor of BasE has been identified via high-throughput screening using a fluorescence polarization displacement assay. We present here biochemical and structural studies to examine the binding mode of this inhibitor. The kinetics of the wild-type BasE enzyme is shown, and inhibition studies demonstrate that the new compound exhibits competitive inhibition against both ATP and 2,3-dihydroxybenzoate. Structural examination of BasE bound to this inhibitor illustrates a novel binding mode in which the phenyl moiety partially fills the enzyme pantetheine binding tunnel. Structures of rationally designed bisubstrate inhibitors are also presented. PMID- 20853908 TI - Highly electrophilic organometallics for carbocationic polymerizations: from anion engineering to new polymer materials. AB - Ion-ion interactions are a crucial but often overlooked aspect of many polymerization reactions. The precise nature of cation-anion binding is as yet poorly understood, and little is known of the extent of ionic interactions in the typically nonaqueous, low-polarity reaction media of most polymerizations. Nevertheless, adequate control of cation-anion interactions can greatly enhance the productivity and efficiency of chemical processes and can provide low-energy alternatives to current methods. This is illustrated here with the carbocationic polymerization of isoalkenes. Carbocationic polymerizations involve, as the name implies, carbocations as propagating species. Of the various types of substrates that can be polymerized cationically, the copolymerization of isobutene to isobutene-isoprene rubber stands out as the only large-scale, industrially important implementation of this reaction type. The products, elastomers with controlled degrees of unsaturation for subsequent cross-linking, have excellent gas barrier and mechanical dampening properties that make them indispensable components in polymer composites. For such applications, the polymer molecular weight has to be high, ~5 * 10(5) g/mol, with 1-2 mol % isoprene. Cationic polymerizations are however notoriously difficult to control. As a means of suppressing chain transfer, the process is carried out at temperatures as low as 100 degrees C, with aluminum chloride initiators in chloromethane. Current industrial production of isobutene-isoprene butyl rubber is thus highly energy intensive and produces aluminum and chloride effluent. This Account summarizes how highly electrophilic organometallics coupled with new types of very weakly coordinating counteranions can provide the basis for a more environmentally friendly, lower energy alternative. Because any copolymerization of two monomers, here primarily isobutene and isoprene, leads to two different propagating species, each of which is characterized by different chain growth and chain termination kinetics, variation of the associated counteranions can give rather unexpected results. With judicious choice of the initiator and the counteranion, new chemistry can be injected into such processes and can open avenues to new families of polymer materials. Mechanistic investigations of the initiation process with zirconocene hydrides illustrate the complexity of this first step. Replacing aluminum with zinc initiators not only provides a nontoxic alternative but also generates a system in which the polymer molecular weight is much less affected by temperature and comonomer concentration, which can lead to a range of products, from oligomeric lubricant precursors to C?C-rich high-molecular-weight elastomers. The key in all these cases is the construction of either preformed or in situ-generated complex anions that are resistant to electrophilic or redox degradation and are capable of stabilizing tightly associated carbocations. Such initiator systems allow much more benign operating temperatures, reduce the need for chlorocarbon solvents, and can operate at concentrations as low as 5 * 10(-5) M. Along the way are provided the first examples of structurally characterized sec-alkyl carbocations and carbocation salts of organometallic zincates. PMID- 20853910 TI - Metabolomics study of human urinary metabolome modifications after intake of almond (Prunus dulcis (Mill.) D.A. Webb) skin polyphenols. AB - Almond, as a part of the nut family, is an important source of biological compounds, and specifically, almond skins have been considered an important source of polyphenols, including flavan-3-ols and flavonols. Polyphenol metabolism may produce several classes of metabolites that could often be more biologically active than their dietary precursor and could also become a robust new biomarker of almond polyphenol intake. In order to study urinary metabolome modifications during the 24 h after a single dose of almond skin extract, 24 volunteers (n = 24), who followed a polyphenol-free diet for 48 h before and during the study, ingested a dietary supplement of almond skin phenolic compounds (n = 12) or a placebo (n = 12). Urine samples were collected before ((-2)-0 h) and after (0-2 h, 2-6 h, 6-10 h, and 10-24 h) the intake and were analyzed by liquid chromatography-mass spectrometry (LC-q-TOF) and multivariate statistical analysis (principal component analysis (PCA) and orthogonal projection to latent structures (OPLS)). Putative identification of relevant biomarkers revealed a total of 34 metabolites associated with the single dose of almond extract, including host and, in particular, microbiota metabolites. As far as we know, this is the first time that conjugates of hydroxyphenylvaleric, hydroxyphenylpropionic, and hydroxyphenylacetic acids have been identified in human samples after the consumption of flavan-3-ols through a metabolomic approach. The results showed that this non-targeted approach could provide new intake biomarkers, contributing to the development of the food metabolome as an important part of the human urinary metabolome. PMID- 20853909 TI - Metabolome-wide association study identifies multiple biomarkers that discriminate north and south Chinese populations at differing risks of cardiovascular disease: INTERMAP study. AB - Rates of heart disease and stroke vary markedly between north and south China. A (1)H NMR spectroscopy-based metabolome-wide association approach was used to identify urinary metabolites that discriminate between southern and northern Chinese population samples, to investigate population biomarkers that might relate to the difference in cardiovascular disease risk. NMR spectra were acquired from two 24-h urine specimens per person for 523 northern and 244 southern Chinese participants in the INTERMAP Study of macro/micronutrients and blood pressure. Discriminating metabolites were identified using orthogonal partial least squares discriminant analysis and assessed for statistical significance with conservative family wise error rate < 0.01 to minimize false positive findings. Urinary metabolites significantly (P < 1.2 * 10(-16) to 2.9 * 10(-69)) higher in northern than southern Chinese populations included dimethylglycine, alanine, lactate, branched-chain amino acids (isoleucine, leucine, valine), N-acetyls of glycoprotein fragments (including uromodulin), N acetyl neuraminic acid, pentanoic/heptanoic acid, and methylguanidine; metabolites significantly (P < 1.1 * 10(-12) to 2 * 10(-127)) higher in the south were gut microbial cometabolites (hippurate, 4-cresyl sulfate, phenylacetylglutamine, 2-hydroxyisobutyrate), succinate, creatine, scyllo inositol, prolinebetaine, and trans-aconitate. These findings indicate the importance of environmental influences (e.g., diet), endogenous metabolism, and mammalian-gut microbial cometabolism, which may help explain north-south China differences in cardiovascular disease risk. PMID- 20853911 TI - Comparative proteomics of yeast-elicited Medicago truncatula cell suspensions reveals induction of isoflavonoid biosynthesis and cell wall modifications. AB - The temporal proteome response of Medicago truncatula suspension cell cultures to yeast elicitation (which mimics fungal infection) was investigated using two dimensional polyacrylamide gel electrophoresis (2-DE) and nanoliquid chromatography coupled to tandem mass spectrometry (nano LC-MS/MS). Reproducibility of 2-DE was assessed using the number of the visualized protein spots and spot volume. Average coefficient of variation was determined to be less than 6% for the number of spots and around 50% for spot volume. About 4% of the total visualized proteins, that is, 34 out of 861, were differentially accumulated in the suspension cells 24 h after yeast elicitation, including isoflavononid biosynthetic enzymes and a putative laccase. The induction of the putative laccase was highly correlated with the polymerization of phenolics such as 4-hydroxybenzoic acid, 4-hydroxybenzaldehyde, and ferulic acid into cell walls. In contrast, lignin was only induced at the later stages of the temporal study, indicating that this specific laccase is primarily involved in cell wall modifications and/or fortifications rather than in lignification in response to yeast elicitation. PMID- 20853912 TI - Hierarchical self-assembly of superlattice hybrids consisting of periodic and alternating cores of porphyrin molecules separated by nanoscale silica walls. AB - Molecularly engineered superlattice hybrids consisting of periodic and alternating cores of porphyrin molecules separated by nanoscale silica walls were synthesized through a one-step organic-inorganic hierarchical self-assembly approach. The self-assembly process not only could lock both porphyrin and inorganic building blocks into ordered 3D nanostructure but also could allow for the molecular-level controllable organization of porphyrin molecules in the central regions of the silica pore channels, which leads to the formation of porphyrin core-silica wall superlattice hybrids with molecular-scale and mesoscale ordering. It was demonstrated that both the mesostructure and morphology of the hybrids can be finely tailored by turning the cooperative self assembly process. It is significant that the hybrids show self-assembled optical properties consistent with the orientational arrangement of the porphyrins within periodic nanoscale silica channels. The methodology introduced herein demonstrates high versatility with respect to the self-assembly of optical active macrocycles into highly ordered superlattice hybrid architectures. PMID- 20853913 TI - Age of onset, symptom threshold, and expansion of the nosology of conduct disorder for girls. AB - The study of conduct disorder (CD) in girls is characterized by several nosologic controversies that center on the most common age of onset, the most valid symptom threshold, and the possible inclusion of other manifestations of antisocial behavior and dimensions of personality as part of the definition of CD. Data from a prospective, longitudinal study of a community sample of 2,451 racially diverse girls were used to empirically inform these issues. Results revealed that adolescent-onset CD is rare in girls. There was mixed support for the threshold at which symptoms are associated with impairment: Parent-reported impairment provided the clearest evidence of maintaining the current Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) threshold of 3 symptoms. The impact of callousness and relational aggression on impairment varied by informant, with small effects for parent- and youth-reported impairment and larger effects for teacher-rated impairment relative to the effects for CD. These results support arguments for revising the typical age of onset of CD for girls but for maintaining the current symptom threshold. The results also suggest the need to consider subtyping according to the presence or absence of callousness. Given its content validity, relational aggression requires further study in the context of oppositional defiant disorder and CD. PMID- 20853914 TI - Classification of behavior disorders in adolescence: scaling methods, predictive validity, and gender differences. AB - The present study examined issues relating to the measurement and discriminant validity of Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for behavior disorders in adolescence (conduct disorder [CD], oppositional defiant disorder [ODD], attention-deficit/hyperactivity disorder [ADHD]). Data were obtained from a birth cohort of 995 New Zealand-born individuals studied to the age of 25 years and modeled associations between behavior disorder from ages 14 to 16 years and later outcomes including crime, substance use, mental health, parenthood and partnership outcomes, and education and employment outcomes to age 25 years. The associations between behavior disorders and outcomes were adjusted for both comorbid behavior disorders and a range of confounding factors. The results suggested that (a) dimensional measures of behavior disorder were more strongly correlated with outcomes than categorical (DSM) measures; (b) CD, ODD, and ADHD each had a distinctive pattern of associations with longer term consequences; and (c) there was no evidence to suggest that the developmental consequences of CD, ODD, and ADHD differed by gender. In general, the results supported the validity of DSM diagnostic domains but also highlighted the importance of including in DSM-V methods for both recognizing the severity of disorder and addressing subclinical symptom levels. PMID- 20853916 TI - Narcissistic personality disorder and the DSM-V. AB - We address 3 issues relevant to narcissistic personality disorder (NPD) and the DSM-V. First, we argue that excluding NPD while retaining other traditional personality disorder constructs (e.g., avoidant) makes little sense given the research literature on NPD and trait narcissism and their association with clinically relevant consequences such as aggression, self-enhancement, distorted self-presentation, failed relationships, cognitive biases, and internalizing and externalizing dysregulation. Second, we argue that the DSM-V must include content (in diagnostic form or within a dimensional trait model) that allows for the assessment of both grandiose and vulnerable variants of narcissism. Finally, we suggest that any dimensional classification of personality disorder should recover all of the important component traits of narcissism and be provided with official recognition in the coding system. PMID- 20853915 TI - It's the algorithm! Why differential rates of chronicity and comorbidity are not evidence for the validity of the abuse-dependence distinction. AB - The validity of the abuse-dependence distinction within alcohol use disorders (AUDs) has been increasingly questioned on psychometric and conceptual grounds. Two types of findings are often cited as support for the validity of this distinction: (a) Dependence is more persistent than abuse, and (b) dependence is more highly comorbid with other Axis I and Axis II disorders than is abuse. Using data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC), we examined the extent to which the current diagnostic algorithm (3 of 7 dependence criteria for a diagnosis of dependence; 1 of 4 abuse criteria for a diagnosis of abuse if dependence criteria are not met) produces this pattern of findings independent of item set. Analyses in which all 330 permutations of the 11 AUD criteria were partitioned into a 4-item abuse set and a 7-item dependence set were conducted to examine the relevance of the criteria sets to estimates of persistence and comorbidity independent of criteria. Regardless of the criteria used, the dependence set (i.e., 3/7 criteria) always and substantially outperformed the abuse set (1/4) with respect to both persistence and comorbidity. These data indicate that chronicity and comorbidity are flawed indicators for the abuse-dependence distinction (and likely other conditions in which hierarchical decision rules are used). In addition, our analyses show that the current set of criteria defining alcohol dependence and abuse are not optimal. PMID- 20853917 TI - Episodic memory and episodic future thinking in adults with autism. AB - The ability to remember past experiences (episodic memory) is thought to be related to the ability to imagine possible future experiences (episodic future thinking). Although previous research has established that individuals with autism spectrum disorder (ASD) have diminished episodic memory, episodic future thinking has not previously been investigated within this population. In the present study, high-functioning adults with ASD were compared to closely matched typical adults on a task requiring participants to report a series of events that happened to them in the past and a series of events that might happen to them in the future. For each event described, participants completed two modified Memory Characteristics Questionnaire items to assess self-reported phenomenal qualities associated with remembering and imagining, including self-perspective and degree of autonoetic awareness. Participants also completed letter, category, and ideational fluency tasks. Results indicated that participants with ASD recalled/imagined significantly fewer specific events than did comparison participants and that participants with ASD demonstrated impaired episodic memory and episodic future thinking. In line with this finding, participants with ASD were less likely than comparison participants to report taking a field (first person) perspective and were more likely to report taking an observer (third person) perspective during retrieval of past events (but not during simulation of future events), highlighting that they were less likely to mentally reexperience past events from their own point of view. There were no group differences in self reported levels of autonoetic awareness or fluency task performance. PMID- 20853918 TI - The latent structure of social anxiety disorder: consequences of shifting to a dimensional diagnosis. AB - Despite longstanding debate over the nature of the boundary between social anxiety disorder (SAD) and less severe social anxiety, no study has tested directly whether the defining features of the disorder correspond to a latent category or dimension. The present study examined this question using data from the National Comorbidity Survey Replication (NCS-R), a nationally representative survey of the U.S. household population. Indicators representing the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria for SAD were submitted to taxometric analyses in a subsample of adults (n = 2,166) who reported excessive social fear in their lifetime. Multiple taxometric procedures and consistency tests converged on a dimensional solution, suggesting that SAD is continuous with milder social anxiety. In follow-up analyses, a dimensional SAD diagnosis outperformed the DSM IV diagnosis in predicting the subsequent onset of a range of clinically important outcomes. Large differences in associations with comorbid mood disorders, suicidality, and treatment seeking in particular favored the prognostic value of dimensional over categorical diagnosis. These findings support the validity and potential utility of a dimensional conceptualization of SAD that may inform efforts to revise the diagnosis for DSM-V. PMID- 20853919 TI - Predictive validity of childhood oppositional defiant disorder and conduct disorder: implications for the DSM-V. AB - Data are presented from 3 studies of children and adolescents to evaluate the predictive validity of childhood oppositional defiant disorder (ODD) and conduct disorder (CD) as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV; American Psychiatric Association, 1994) and the International Classification of Diseases, Version 10 (ICD-10; World Health Organization, 1992). The present analyses strongly support the predictive validity of these diagnoses by showing that they predict both future psychopathology and enduring functional impairment. Furthermore, the present findings generally support the hierarchical developmental hypothesis in DSM-IV that some children with ODD progress to childhood-onset CD, and some youth with CD progress to antisocial personality disorder (APD). Nonetheless, they reveal that CD does not always co-occur with ODD, particularly during adolescence. Importantly, the present findings suggest that ICD-10 diagnostic criteria for ODD, which treat CD symptoms as ODD symptoms when diagnostic criteria for CD are not met, identify more functionally impaired children than the more restrictive DSM-IV definition of ODD. Filling this "hole" in the DSM-IV criteria for ODD should be a priority for the DSM-V. In addition, the present findings suggest that although the psychopathic trait of interpersonal callousness in childhood independently predicts future APD, these findings do not confirm the hypothesis that callousness distinguishes a subset of children with CD with an elevated risk for APD. PMID- 20853920 TI - Gender differences in life events prior to onset of major depressive disorder: the moderating effect of age. AB - Theoretical models attempting to explain why approximately twice as many women as men suffer from depression often involve the role of stressful life events. However, detailed empirical evidence regarding gender differences in rates of life events that precede onset of depression is lacking, due in part to the common use of checklist assessments of stress that have been shown to possess poor validity. The present study reports on a combined sample of 375 individuals drawn from 4 studies in which all participants were diagnosed with major depressive disorder and assessed with the Life Events and Difficulties Schedule (Bifulco et al., 1989), a state-of-the-art contextual interview and life stress rating system. Women reported significantly more severe and nonsevere, independent and dependent, and other-focused and subject-focused life events prior to onset of depression than did men. Further, these relations were significantly moderated by age, such that gender differences in rates of most types of events were found primarily in young adulthood. These results are discussed in term of their implications for understanding the etiological role of stressful life events in depression. PMID- 20853921 TI - Experimental effect of positive urgency on negative outcomes from risk taking and on increased alcohol consumption. AB - The current pair of experimental studies sought to further validate the role of positive urgency (acting rashly when in an extreme positive emotional state) as a risk factor for impulsive and maladaptive behavior. Previous research has supported the use of emotion-based dispositions to rash action in predicting a wide range of maladaptive acts. However, that research was conducted in the field and relied on self-reported behavior, thus lacking tight experimental controls and direct observation of risky behaviors. In the 2 experimental studies described here, we found that among college students (1) positive urgency significantly predicted negative outcomes on a risk-taking task following a positive mood manipulation (n = 94), and (2) positive urgency significantly predicted increases in beer consumption following positive mood induction (n = 33). Positive urgency's role was above and beyond previously identified risk factors; these findings, combined with prior cross-sectional and longitudinal field studies, provide support for the role of positive urgency in rash action. PMID- 20853922 TI - Self-regulation as a protective factor against risky drinking and sexual behavior. AB - Prior research suggests that high dispositional self-regulation leads to decreased levels of risky drinking and sexual behavior in adolescence and the early years of college. Self-regulation may be especially important when individuals have easy access to alcohol and freedom to pursue sexual opportunities. In the current 1-year longitudinal study, we followed a sample of N = 1,136 college students who had recently reached the legal age to purchase alcohol and enter bars and clubs to test whether self-regulation protected against heavy episodic drinking, alcohol-related problems, and unprotected sex. We tested main effects of self-regulation and interactions among self-regulation and established risk factors (e.g., sensation seeking) on risky drinking and sexual behavior. High self-regulation inversely predicted heavy episodic drinking, alcohol-related problems, and unprotected sex, even when taking into account gender and risk factors. Moreover, in predicting unprotected sex, we found three-way interactions among self-regulation, sensation seeking, and heavy episodic drinking. Self-regulation buffered against risk associated with heavy drinking but only among those low in sensation seeking. The protective effects of self-regulation for risky drinking and sexual behavior make it a promising target for intervention, with the caveat that self-regulation may be less protective among those who are more drawn to socially and emotionally rewarding stimuli. PMID- 20853924 TI - Is it beneficial to have an alcoholics anonymous sponsor? AB - Alcoholics Anonymous (AA) attendance is predictive of increased abstinence for many problem drinkers and treatment referral to AA is common. Strong encouragement to acquire an AA sponsor is likewise typical, and findings about the benefits associated with social support for abstinence in AA support this practice, at least indirectly. Despite this widespread practice, however, prospective tests of the unique contribution of having an AA sponsor are lacking. This prospective study investigated the contribution of acquiring an AA sponsor using a methodologically rigorous design that isolated the specific effects of AA sponsorship. Participants were recruited from AA and outpatient treatment. Intake and follow-up assessments included questionnaires, semi-structured interviews, and urine toxicology screens. Eligibility criteria limited prior treatment and AA histories to clarify the relationship of interest while, for generalizability purposes, broad substance abuse criteria were used. Of the 253 participants, 182 (72%) provided complete data on measures central to the aims of this study. Overall reductions in alcohol, marijuana, and cocaine use were found over 12 months and lagged analyses indicated that AA attendance significantly predicted increased abstinence. During early AA affiliation but not later logistic regressions showed that having an AA sponsor predicted increased alcohol abstinence and abstinence from marijuana and cocaine after first controlling for a host of AA-related, treatment, and motivational measures that are associated with AA exposure or are generally prognostic of outcome. PMID- 20853923 TI - Parental alcohol involvement and adolescent alcohol expectancies predict alcohol involvement in male adolescents. AB - Current models of adolescent drinking behavior hypothesize that alcohol expectancies mediate the effects of other proximal and distal risk factors. This longitudinal study tested the hypothesis that the effects of parental alcohol involvement on their children's drinking behavior in mid-adolescence are mediated by the children's alcohol expectancies in early adolescence. A sample of 148 initially 9-11 year old boys and their parents from a high-risk population and a contrast group of community families completed measures of drinking behavior and alcohol expectancies over a 6-year interval. We analyzed data from middle childhood (M age = 10.4 years), early adolescence (M age = 13.5 years), and mid adolescence (M age = 16.5 years). The sample was restricted only to adolescents who had begun to drink by mid-adolescence. Results from zero-inflated Poisson regression analyses showed that 1) maternal drinking during their children's middle childhood predicted number of drinking days in middle adolescence; 2) negative and positive alcohol expectancies in early adolescence predicted odds of any intoxication in middle adolescence; and 3) paternal alcoholism during their children's middle childhood and adolescents' alcohol expectancies in early adolescence predicted frequency of intoxication in middle adolescence. Contrary to predictions, child alcohol expectancies did not mediate the effects of parental alcohol involvement in this high-risk sample. Different aspects of parental alcohol involvement, along with early adolescent alcohol expectancies, independently predicted adolescent drinking behavior in middle adolescence. Alternative pathways for the influence of maternal and paternal alcohol involvement and implications for expectancy models of adolescent drinking behavior were discussed. PMID- 20853925 TI - Associations of marijuana use and sex-related marijuana expectancies with HIV/STD risk behavior in high-risk adolescents. AB - Multiple studies suggest an association of marijuana use with increased rates of sexual risk behavior and sexually transmitted diseases (STDs). Most studies have focused on global associations of marijuana use with sexual risk outcomes and few have examined relevant cognitive variables. Adolescents in the juvenile justice system are at elevated risk for HIV/STDs and preliminary evidence suggests that marijuana is a potentially important cofactor for sexual risk behavior in this population. This study evaluated global, situational and event-level associations of marijuana use and sex-related marijuana expectancies with sexual risk outcomes in a large, racially diverse sample of adjudicated youth (n = 656, 66% male, mean age = 16.7 years). Cross-sectional and prospective analyses identified associations of marijuana use and dependence symptoms with sexual risk outcomes, including lower frequency of condom use and higher STD incidence. Stronger sex related marijuana expectancies predicted greater intentions for and frequency of marijuana use in sexual situations. In event-level analyses that controlled for alcohol, marijuana use predicted a significantly decreased likelihood of condom use; this association was moderated by sex-related marijuana expectancies. Mediation analyses suggested that behavioral intentions partly accounted for the prospective association of expectancies with marijuana use before sex. These results provide further evidence that marijuana use is a potentially important cofactor for HIV/STD transmission in high-risk adolescents and suggest that cognitive factors could be important for characterizing this association. PMID- 20853926 TI - Prescription drug misuse among dating partners: Within-couple associations and implications for intimate relationship quality. AB - This study examined the associations between dating partners' misuse of prescription medications and the implications of misuse for intimate relationship quality. A sample of 100 young adult dating pairs completed ratings of prescription drug use and misuse, alcohol use, and relationship quality. Results indicated positive associations between male and female dating partners' prescription drug misuse, which were more consistent for past year rather than lifetime misuse. Dyadic associations obtained through actor-partner interdependence modeling further revealed that individuals' prescription drug misuse holds problematic implications for their own but not their partners' intimate relationship quality. Models accounted for individuals' alcohol-related risk and medically appropriate prescription drug use, suggesting the independent contribution of prescription drug misuse to reports of relationship quality. The findings highlight the importance of considering young adults' substance behaviors in contexts of their intimate relationships. PMID- 20853927 TI - Daily patterns of conjoint smoking and drinking in college student smokers. AB - Epidemiological data indicate a robust association between smoking and alcohol use. However, a critical question that is less resolved is the extent to which the smoking event takes place during the time of alcohol consumption. The present study used data from an 8-week prospective web-based study of college student smokers to examine daily associations between smoking and alcohol use, using measures of both likelihood and level of use. Findings indicated that consumption of alcohol and smoking covaried on a daily basis per person. In addition, consistent with the idea of smoking as a social activity for college students, light smokers were more likely than heavier smokers to smoke while drinking and to smoke more cigarettes while drinking. Smoking behavior among light smokers may be influenced by external social contextual cues, in contrast to heavier smokers who may be more affected by internal cues. Implications of findings for prevention work suggest the importance of targeting social situations in which smoking and drinking co-occur. PMID- 20853929 TI - Social cognitive mediators of adolescent smoking cessation: results from a large randomized intervention trial. AB - Only one prior study has examined why adolescent smoking cessation interventions are effective. To address this understudied and important issue, we examined whether a large adolescent smoking cessation intervention trial's outcomes were mediated by social cognitive theory processes. In a randomized trial (N = 2,151), counselors proactively delivered a telephone intervention to senior year high school smokers. Mediators and smoking status were self-reported at 12-months postintervention eligibility (88.8% retention). At least 6-months abstinence was the outcome. Among all enrolled smokers, increased self-efficacy to resist smoking in (a) social and (b) stressful situations together statistically mediated 55.6% of the intervention's effect on smoking cessation (p < .001). Among baseline daily smokers, increased self-efficacy to resist smoking in stressful situations statistically mediated 56.9% of the intervention's effect (p < .001). Self-efficacy to resist smoking is a possible mediator of the intervention's effect on smoking cessation. PMID- 20853930 TI - Practicing self-control lowers the risk of smoking lapse. AB - Recent research has suggested that practicing small acts of self-control can lead to an improvement in self-control performance. Because smoking cessation requires self-control, it was hypothesized that a treatment that builds self-control should help in quitting smoking. A total of 122 smokers either practiced small acts of self-control for 2 weeks before quitting smoking or practiced a task that increased their awareness of self-control or feelings of confidence, without exercising self-control. Their smoking status was assessed using daily telephone calls and biochemically verified. Individuals who practiced self-control remained abstinent longer than those who practiced tasks that did not require self control. Supplemental analyses suggested that the increased survival times were a product of building self-control strength and were not produced by changes in feelings that practicing should help in cessation, effort exerted on the practice task, or thinking more about self-control while practicing. PMID- 20853932 TI - Maternal mental health and integrated programs for mothers with substance abuse issues. AB - To examine the impact of integrated treatment programs (those with substance use treatment and pregnancy-, parenting-, or child-related services) on maternal mental health, we compiled a database of studies of integrated programs published between 1990 and 2007 with outcome data on maternal mental health. There were 18 cohort studies, 3 randomized trials, and 2 quasi-experimental studies. Of the five studies comparing integrated to nonintegrated programs, three studies provided enough information to allow for them to be combined in a meta-analysis. The average effect size was 0.23 (95% CI = 0.15 to 0.31, SE = 0.04), p < .001. There was no statistically significant heterogeneity among the studies, Q = 5.66, p = .059. This meta-analysis is the first systematic quantitative review of studies evaluating the impact of integrated programs on maternal mental health. Findings suggest that integrated programs may be associated with a small advantage over nonintegrated programs in improving maternal mental health. This review highlights the need for further research with improved methodology, study quality, and reporting to improve our understanding of how best to meet the mental health needs of mothers with substance abuse issues. PMID- 20853931 TI - Clinical outcomes of an integrated treatment for depression and substance use disorders. AB - The authors compared longitudinal treatment outcomes for depressed substance dependent veterans (N = 206) assigned to integrated cognitive-behavioral therapy plus standard pharmacotherapy (ICBT + P) or 12-step facilitation therapy plus standard pharmacotherapy (TSF + P). Drug and alcohol involvement and depressive symptomology were measured at intake and at 3-month intervals during treatment and up to 1 year posttreatment. Participants in both treatment conditions showed decreased depression and substance use from intake. ICBT + P participants maintained improvements in substance involvement over time, whereas TSF + P participants had more rapid increases in use in the months following treatment. Decreases in depressive symptoms were more pronounced for TSF + P than ICBT + P in the 6 months posttreatment. Within both treatment groups, higher attendance was associated with improved substance use and depression outcomes over time. Initial levels of depressive symptomology had a complex predictive relationship with long-term depression outcomes. Early treatment response predicted long-term substance use outcomes for a portion of the sample. Although both treatments were associated with improvements in substance use and depression, ICBT + P may lead to more stable substance use reductions compared with TSF + P. PMID- 20853934 TI - Sexual compulsivity, state affect, and sexual risk behavior in a daily diary study of gay and bisexual men. AB - Researchers have identified a strong link between sexual compulsivity (SC) and risky sexual behavior among men who have sex with men (MSM). Meanwhile, affect/mood has also been connected with negative sexual health outcomes (sexually transmitted infection/human immunodeficiency virus [HIV] transmission, sexual risk, sex under the influence of drugs/alcohol). Given that SC is characterized by marked distress around one's own sexual behavior, affect may play a central role in SC and HIV risk behavior. Data were taken from the Pillow Talk Project, a pilot study conducted in 2008-2009 with 50 highly sexually active MSM (9 or more male sex partners, <= 90 days), of which half displayed SC symptoms and half did not. Forty-seven men completed a daily diary online for 30 days (n = 1,060 diary days), reporting on their sexual behavior and concurrent affect: positive activation, negative activation, anxious arousal, and sexual activation. We conducted HLM analyses using daily affect (Level 1, within subjects) and SC and HIV status (Level 2, between subjects) to predict sexual behavior outcomes. Increased negative activation (characterized by fear, sadness, anger, and disgust) was associated with reduced sexual risk behavior, but less so among sexually compulsive MSM. Sexual activation was associated with increased sexual risk taking, but less so among sexually compulsive MSM. Anxious arousal was associated with increased sexual behavior, but not necessarily sexual risk taking. Findings indicate that affect plays key roles in sexual behavior and sexual risk taking; however, the association between affect and behavior may be different for sexually compulsive and non-sexually compulsive MSM. PMID- 20853933 TI - The acquired preparedness model of risk for bulimic symptom development. AB - The authors applied person-environment transaction theory to test the acquired preparedness model of eating disorder risk. The model holds that (a) middle school girls high in the trait of ineffectiveness are differentially prepared to acquire high-risk expectancies for reinforcement from dieting or thinness; (b) those expectancies predict subsequent binge eating and purging; and (c) the influence of the disposition of ineffectiveness on binge eating and purging is mediated by dieting or thinness expectancies. In a three-wave longitudinal study of 394 middle-school girls, the authors found support for the model. Seventh grade girls' scores on ineffectiveness predicted their subsequent endorsement of high-risk dieting or thinness expectancies, which in turn predicted subsequent increases in binge eating and purging. Statistical tests of mediation supported the hypothesis that the prospective relation between ineffectiveness and binge eating was mediated by dieting or thinness expectancies, as was the prospective relation between ineffectiveness and purging. This application of a basic science theory to eating disorder risk appears fruitful, and the findings suggest the importance of early interventions that address both disposition and learning. PMID- 20853935 TI - Eye movement desensitization and reprocessing in addiction continuing care: a phenomenological study of women in recovery. AB - Traditional models of addiction treatment and relapse prevention fail to consider the role that unresolved trauma plays in an addicted woman's recovery experience. Implementing Eye Movement Desensitization and Reprocessing (EMDR) into the treatment process offers a potential solution to this problem. Ten women (alumnae of an extended-care treatment facility) participated in a semistandardized interview to share their experiences with active addiction, treatment, EMDR therapy, and recovery. With the use of A. P. Giorgi's descriptive phenomenological psychological method for analysis, four major thematic areas emerged from the interview data: the existence of safety as an essential crucible of the EMDR experience, the importance of accessing the emotional core as vital to the recovery experience, the role of perspective shift in lifestyle change, and the use of a combination of factors for successful treatment. All 10 women, to some degree, credited EMDR treatment as a crucial component of their addiction continuing-care processes, especially in helping with emotional core access and perspective shift. Implications emerge from the data on how to best implement EMDR into a comprehensive addiction treatment program. PMID- 20853936 TI - Electrophysiological evidence of alcohol-related attentional bias in social drinkers low in alcohol sensitivity. AB - Low sensitivity to the acute effects of alcohol is a known risk factor for alcoholism. However, little is known concerning potential information-processing routes by which this risk factor might contribute to increased drinking. We tested the hypothesis that low-sensitivity (LS) participants would show biased attention to alcohol cues, compared with their high-sensitivity (HS) counterparts. Participants performed a task in which alcoholic and nonalcoholic beverage cues were presented bilaterally followed by a target that required categorization by color. Response times were faster for targets appearing in alcohol-cued than non-alcohol-cued locations for LS but not for HS participants. Event-related potential markers of early attention orienting (P1 amplitude) and subsequent attention reorienting (ipsilateral invalid negativity amplitude) indicated preferential selective attention to alcohol-cued locations among LS individuals. Controlling for recent drinking and family history of alcoholism did not affect these patterns, except that among HS participants, relatively heavy recent drinking was associated with difficulty reorienting attention away from alcohol-cued locations. These findings suggest a potential information-processing bias through which low sensitivity could lead to heavy alcohol involvement. PMID- 20853937 TI - The link between alcohol use and aggression toward sexual minorities: an event based analysis. AB - The current study used an event-based assessment approach to examine the day-to day relationship between heterosexual men's alcohol consumption and perpetration of aggression toward sexual minorities. Participants were 199 heterosexual drinking men between the ages of 18-30 who completed (1) separate timeline followback interviews to assess alcohol use and aggression toward sexual minorities during the past year, and (2) written self-report measures of risk factors for aggression toward sexual minorities. Results indicated that aggression toward sexual minorities was twice as likely on a day when drinking was reported than on nondrinking days, with over 80% of alcohol-related aggressive acts perpetrated within the group context. Patterns of alcohol use (i.e., number of drinking days, mean drinks per drinking day, number of heavy drinking days) were not associated with perpetration after controlling for demographic variables and pertinent risk factors. Results suggest that it is the acute effects of alcohol, and not men's patterns of alcohol consumption, that facilitate aggression toward sexual minorities. More importantly, these data are the first to support an event-based link between alcohol use and aggression toward sexual minorities (or any minority group), and provide the impetus for future research to examine risk factors and mechanisms for intoxicated aggression toward sexual minorities and other stigmatized groups. PMID- 20853938 TI - Group identification as a moderator of the relationship between perceived social norms and alcohol consumption. AB - Previous research has shown that social norms are among the strongest predictors of college student drinking. Among college students, perceiving that others drink more heavily than themselves has been strongly and consistently associated with heavier drinking. Research has also shown that the more specifically others are defined, the stronger the association is with one's own drinking. In the current research, we evaluated whether group identification as defined by feeling closer to specific groups moderates the associations between perceived drinking norms in the group and one's own drinking. Participants included 3,752 (61% female) students who completed online assessments of their perceived drinking norms for 4 groups of students on their campus and identification with each group and participants' own drinking behavior. Results indicated that greater identification with same-sex students, same-race students, and same-Greek-status students was associated with stronger relationships between perceived drinking norms in the specific groups and own drinking. PMID- 20853939 TI - Social anxiety and motives for alcohol use among adolescents. AB - Social anxiety evidences significant comorbidity with alcohol use disorders and alcohol-related problems. In an effort to better understand this co-occurrence, researchers are beginning to evaluate specific drinking-related factors, including alcohol use motives, among socially anxious individuals. Drawing on Cooper's (1994) 4-factor model of drinking motives (enhancement, social, conformity, coping), a growing body of work suggests that socially anxious individuals may consume alcohol in an effort to cope with their anxious symptoms; however, no study to date has examined these relations among youth. Accordingly, we examined alcohol use motives as a function of social anxiety in a community based sample of 50 adolescents ages 12 to 17 years (Mage = 16.35, SD = 1.10). As predicted, heightened social anxiety was associated with elevated coping-related drinking motives. More important, other alcohol-use motives did not vary as a function of social anxiety. Collectively, these findings uniquely extend research conducted with adults, and suggest socially anxious youth may be motivated to use alcohol to manage their anxious arousal. PMID- 20853940 TI - When in Rome: factors associated with changes in drinking behavior among American college students studying abroad. AB - Study abroad programs have the potential to promote cultural, experiential, and personal development for escalating numbers of American college students each year. Despite reports that study abroad students may be at particular risk for increased and problematic alcohol use, there is limited empirical documentation of this risk. Thus, the present study used a longitudinal design to examine the factors associated with changes in alcohol use among college students studying in foreign countries. A sample of 177 students completed measures of demographics, drinking behavior, and perceived peer drinking behavior 1 month before departure and 1-month postreturn from study abroad trips. Analyses revealed that participants more than doubled their drinking during study abroad trips and those who drank at heavier levels while abroad returned home drinking at significantly elevated levels. This pattern of increased use while abroad was moderated by several factors, with participants studying abroad in Europe (e.g., Italy, France) and Oceania (e.g., Australia, New Zealand), those under the age of 21, those with higher intentions of drinking while abroad, and those with higher drinking perceptions of other study abroad students in their host country increased their alcohol consumption to a greater extent than other participants. Results suggest drinking while abroad is a concern warranting further investigation, especially regarding how changes in drinking may contribute to the experience of alcohol-related consequences abroad. Continued identification of the risk factors associated with increased drinking can help inform targeted predeparture preventive interventions with these students. PMID- 20853941 TI - Suicide and gambling: psychopathology and treatment-seeking. AB - The aim of this study was to evaluate suicides with a history of problem gambling (PG) and others with no such history (NPG) and to compare the two on mental health problems and service utilization. Data on a sample of 49 PG suicides and 73 NPG suicides were obtained from informants and hospital records. Psychopathology was prevalent in both groups, but problem gamblers were twice as likely to have a personality disorder. Moreover, PG suicides were less in contact with mental health services in their last month, their last year, and their lifetime. NPG suicides consulted specialized services from 3 (last month and last year) to 13 times (lifetime) as often as their PG counterparts. Lower service utilization associated with PG suicides argues in favor of stepping up detection, engagement in care and treatment with respect to problem gambling, especially when comorbidity is present. PMID- 20853942 TI - The association between childhood maltreatment and gambling problems in a community sample of adult men and women. AB - The association between childhood maltreatment and gambling problems was examined in a community sample of men and women (N = 1,372). As hypothesized, individuals with gambling problems reported greater childhood maltreatment than individuals without gambling problems. Childhood maltreatment predicted severity of gambling problems and frequency of gambling even when other individual and social factors were controlled including symptoms of alcohol and other drug use disorders, family environment, psychological distress, and symptoms of antisocial disorder. In contrast to findings in treatment-seeking samples, women with gambling problems did not report greater maltreatment than men with gambling problems. These results underscore the need for both increased prevention of childhood maltreatment and increased sensitivity towards trauma issues in gambling treatment programs for men and women. PMID- 20853944 TI - Frame-of-reference training effectiveness: effects of goal orientation and self efficacy on affective, cognitive, skill-based, and transfer outcomes. AB - Empirical evidence supporting frame-of-reference (FOR) training as an effective intervention for calibrating raters is convincing. Yet very little is known about who does better or worse in FOR training. We conducted a field study of how motivational factors influence affective, cognitive, and behavioral learning outcomes, as well as near transfer indexed by achieving professional certification. Relying on goal orientation theory, we hypothesized effects for 3 goal orientations: learning, prove performance, and avoid performance. Results were generally supportive across learning outcomes and transfer. Findings further supported a hypothesized interaction between learning self-efficacy and avoid performance goal orientation, such that higher levels of learning self-efficacy mitigated the negative effects of higher performance avoid tendencies. PMID- 20853943 TI - Clarifying work-family intervention processes: the roles of work-family conflict and family-supportive supervisor behaviors. AB - Drawing on a conceptual model integrating research on training, work-family interventions, and social support, we conducted a quasi-experimental field study to assess the impact of a supervisor training and self-monitoring intervention designed to increase supervisors' use of family-supportive supervisor behaviors. Pre- and postintervention surveys were completed, 9 months apart, by 239 employees at 6 intervention (N = 117) and 6 control (N = 122) grocery store sites. Thirty-nine supervisors in the 6 intervention sites received the training consisting of 1 hr of self-paced computer-based training, 1 hr of face-to-face group training, followed by instructions for behavioral self-monitoring (recording the frequency of supportive behaviors) to facilitate on-the-job transfer. Results demonstrated a disordinal interaction for the effect of training and family-to-work conflict on employee job satisfaction, turnover intentions, and physical health. In particular, for these outcomes, positive training effects were observed for employees with high family-to-work conflict, whereas negative training effects were observed for employees with low family-to work conflict. These moderation effects were mediated by the interactive effect of training and family-to-work conflict on employee perceptions of family supportive supervisor behaviors. Implications of our findings for future work family intervention development and evaluation are discussed. PMID- 20853945 TI - Dynamic aspects of voluntary turnover: an integrated approach to curvilinearity in the performance-turnover relationship. AB - Previous research pertaining to job performance and voluntary turnover has been guided by 2 distinct theoretical perspectives. First, the push-pull model proposes that there is a quadratic or curvilinear relationship existing between these 2 variables. Second, the unfolding model of turnover posits that turnover is a dynamic process and that a downward performance change may increase the likelihood of organizational separation. Drawing on decision theory, we propose and test an integrative framework. This approach incorporates both of these earlier models. Specifically, we argue that individuals are most likely to voluntarily exit when they are below-average performers who are also experiencing a downward performance change. Furthermore, the interaction between this downward change and performance partially accounts for the curvilinear relationship proposed by the push-pull model. Findings from a longitudinal field study supported this integrative theory. PMID- 20853946 TI - When it comes to pay, do the thin win? The effect of weight on pay for men and women. AB - Cultivation theory suggests that society holds very different body standards for men versus women, and research indicates that the consequences of defying these social norms may not be linear. To test these notions in the employment context, we examined the relationship between weight and income and the degree to which the relationship varies by gender. For women, we theorized a negative weight income relationship that is steepest at the thin end of the distribution. For men, we predicted a positive weight-income relationship until obesity, where it becomes negative. To test these hypotheses, we utilized 2 longitudinal studies, 1 German and 1 American. In Study 1, weight was measured over 2 time periods, and earnings were averaged over the subsequent 5 years. Study 2 was a multilevel study in which weight and earnings were within-individual variables observed over time, and gender was a between-individual variable. Results from the 2 studies generally support the hypotheses, even when examining within-individual changes in weight over time. PMID- 20853947 TI - Rhesus monkeys (Macaca mulatta) rapidly learn to select dominant individuals in videos of artificial social interactions between unfamiliar conspecifics. AB - Social animals, such as primates, must behave appropriately in complex social situations such as dominance interactions. Learning dominance information through trial and error would be dangerous; therefore, cognitive mechanisms for rapid learning of dominance information by observation would be adaptive. We used a set of digitally edited artificial social interactions to examine whether rhesus monkeys (Macaca mulatta) can learn dominance relationships between unfamiliar conspecifics through observation. Our method allowed random assignment of stimulus monkeys to ranks in an artificial hierarchy, controlling for nonbehavioral cues that could indicate dominance. Subject monkeys watched videos depicting 1 stimulus monkey behaving dominantly toward another and were rewarded for selecting the dominant individual. Monkeys rapidly learned this discrimination across 5 behavior types in Experiment 1 and transferred performance to novel videos of new individuals in Experiment 2. In addition, subjects selected the dominant individual more often than expected by chance in probe videos containing no behavioral dominance information, indicating some retention of the relative dominance status of stimulus monkeys from training. Together, our results suggest that monkeys can learn dominance hierarchies through observation of third-party social interactions. PMID- 20853948 TI - Spectral preferences and the role of spatial coherence in simultaneous integration in gray treefrogs (Hyla chrysoscelis). AB - The perceptual analysis of acoustic scenes may often require the integration of simultaneous sounds arising from a single source. Few studies have investigated the cues that promote simultaneous integration in the context of acoustic communication in nonhuman animals. This study of Cope's gray treefrog (Hyla chrysoscelis) examined female preferences based on spectral features of conspecific male advertisement calls to test the hypothesis that cues related to common spatial origin promote the perceptual integration of simultaneous signal elements (harmonics). The typical advertisement call comprises two harmonically related spectral peaks near 1.1 kHz and 2.2 kHz. Females generally exhibited preferences for calls with two spatially coherent harmonics over alternatives with just one harmonic. When given a choice between a spatially coherent call (both harmonics originating from the same speaker) and a spatially incoherent call (each harmonic from different spatially separated speakers), females preferentially chose the former in the same relative proportions in which it was chosen over single-harmonic alternatives. Preferences for spatially coherent calls over spatially incoherent alternatives did not appear to result from greater difficulty localizing the spatially incoherent sources. These results are consistent with the hypothesis that spatial coherence promotes perceptual integration of simultaneous signal elements in frogs. PMID- 20853952 TI - Varying coefficient meta-analytic methods for alpha reliability. AB - The conventional fixed-effects (FE) and random-effects (RE) confidence intervals that are used to assess the average alpha reliability across multiple studies have serious limitations. The FE method, which is based on a constant coefficient model, assumes equal reliability coefficients across studies and breaks down under minor violations of this assumption. The RE method, which is based on a random coefficient model, assumes that the selected studies are a random sample from a normally distributed superpopulation. The RE method performs poorly in typical meta-analytic applications where the studies have not been randomly sampled from a normally distributed superpopulation or have been randomly sampled from a nonnormal superpopulation. A new confidence interval for the average reliability coefficient of a specific measurement scale is based on a varying coefficient statistical model and is shown to perform well under realistic conditions of reliability heterogeneity and nonrandom sampling of studies. New methods are proposed for assessing reliability moderator effects. The proposed methods are especially useful in meta-analyses that involve a small number of carefully selected studies for the purpose of obtaining a more accurate reliability estimate or to detect factors that moderate the reliability of a scale. PMID- 20853949 TI - Differences in social and vocal behavior between left- and right-handed common marmosets (Callithrix jacchus). AB - Common marmosets (Callithrix jacchus) show either a left- or right-hand preference for reaching to pick up food and they retain the same preference throughout adult life. We compared the behavior of 10 right-handed and 10 left handed marmosets, matched for age and sex. They were presented with live crickets both when alone and when in their social group. The marmosets captured more crickets and the latency to capture the first cricket was shorter when they were in a group than when they were alone. This effect of social facilitation was significantly greater for right- than left-handed individuals. The number of vocalizations (tsik, crackle, very brief whistle, cough, and phee) produced by the left- and right-handed marmosets differed significantly: right-handed marmosets produced an increased number of all of these calls when the crickets were presented, whereas left-handed marmosets did not show a change from pretesting levels. The right-handed marmosets also produced more tsik (mobbing) calls than left-handed marmosets when they were presented with a fear-inducing stimulus and performed more head cocking and parallax movements than the left handed marmosets. Hence, hand preference is associated with differences in exploratory and social behavior, the latter including vocal communication. PMID- 20853953 TI - Psychometric inferences from a meta-analysis of reliability and internal consistency coefficients. AB - A meta-analysis of the reliability of the scores from a specific test, also called reliability generalization, allows the quantitative synthesis of its properties from a set of studies. It is usually assumed that part of the variation in the reliability coefficients is due to some unknown and implicit mechanism that restricts and biases the selection of participants in the studies' samples. Sometimes this variation has been reduced by adjusting the coefficients by a formula associated with range restrictions. We propose a framework in which that variation is included (instead of adjusted) in the models intended to explain the variability and in which parallel analyses of the studies' means and variances are performed. Furthermore, the analysis of the residuals enables inferences to be made about the nature of the variability accounted for by moderator variables. The meta-analysis of the 3 studies' statistics-reliability coefficient, mean, and variance--allows psychometric inferences about the test scores. A numerical example illustrates the proposed framework. PMID- 20853954 TI - Expected versus observed information in SEM with incomplete normal and nonnormal data. AB - Maximum likelihood is the most common estimation method in structural equation modeling. Standard errors for maximum likelihood estimates are obtained from the associated information matrix, which can be estimated from the sample using either expected or observed information. It is known that, with complete data, estimates based on observed or expected information are consistent. The situation changes with incomplete data. When the data are missing at random (MAR), standard errors based on expected information are not consistent, and observed information should be used. A less known fact is that in the presence of nonnormality, the estimated information matrix also enters the robust computations (both standard errors and the test statistic). Thus, with MAR nonnormal data, the use of the expected information matrix can potentially lead to incorrect robust computations. This article summarizes the results of 2 simulation studies that investigated the effect of using observed versus expected information estimates of standard errors and test statistics with normal and nonnormal incomplete data. Observed information is preferred across all conditions. Recommendations to researchers and software developers are outlined. PMID- 20853955 TI - Fitting data to model: structural equation modeling diagnosis using two scatter plots. AB - This article introduces two simple scatter plots for model diagnosis in structural equation modeling. One plot contrasts a residual-based M-distance of the structural model with the M-distance for the factor score. It contains information on outliers, good leverage observations, bad leverage observations, and normal cases. The other plot contrasts the residual-based M-distance with the quantile of a chi distribution. It allows the researcher to visually identify clusters of potential outliers. The article further studies the effect of the potential outliers on the overall model evaluation when they are removed according to the order of the clusters exhibited in the plot. Suggestions are provided on determining the outlier status of outstanding cases in real data analysis. Recommendations are also made on the choice of robust methods and maximum likelihood following outlier removal. PMID- 20853956 TI - The independent influence of apathy and depression on cognitive functioning in Parkinson's disease. AB - OBJECTIVE: The purpose of the present study was to examine the independent influence of symptoms of depression and apathy, two of the most common neuropsychiatric symptoms in Parkinson's disease (PD), on executive functioning and memory in PD patients using measures designed to discriminate between these symptoms. METHOD: Participants included 68 nondemented, idiopathic PD patients, ages 56-82 years. The Apathy Evaluation Scale-Self-Rating and select items of the Beck Depression Inventory II were used to assess symptoms of apathy and depression, respectively. Cognitive function was assessed using the Wisconsin Card Sorting Test and Hopkins Verbal Learning Test-Revised. Correlations and hierarchical regressions were conducted to investigate the relationships between apathy, depression, and cognitive function. Hierarchical regression analyses were conducted to evaluate the degree of influence of depression and apathy on cognitive function. RESULTS: Results revealed that symptoms of apathy, but not depression, were significantly and negatively associated with executive functioning. Immediate memory was significantly and negatively associated with both apathy and depression. However, apathy accounted for additional variance in memory performance after controlling for depression at a level approaching significance. CONCLUSIONS: Apathy is not only associated with cognitive impairment, but also with impaired daily functioning, caregiver burden and distress, medication noncompliance, and increased mortality. Differentiating apathy and depression, understanding their unique effects, and appropriately identifying apathy symptoms in patients have robust implications for the development of neuropsychological models of these effects in PD as well as practical implications in guiding improvements to patient care and enhancing quality of life in patients and caregivers. PMID- 20853957 TI - Intraindividual variability in reaction time predicts cognitive outcomes 5 years later. AB - OBJECTIVE: Building on results suggesting that intraindividual variability in reaction time (inconsistency) is highly sensitive to even subtle changes in cognitive ability, this study addressed the capacity of inconsistency to predict change in cognitive status (i.e., cognitive impairment, no dementia [CIND] classification) and attrition 5 years later. METHOD: Two hundred twelve community dwelling older adults, initially aged 64-92 years, remained in the study after 5 years. Inconsistency was calculated from baseline reaction time performance. Participants were assigned to groups on the basis of their fluctuations in CIND classification over time. Logistic and Cox regressions were used. RESULTS: Baseline inconsistency significantly distinguished among those who remained or transitioned into CIND over the 5 years and those who were consistently intact (e.g., stable intact vs. stable CIND, Wald (1) = 7.91, p < .01, Exp(beta) = 1.49). Average level of inconsistency over time was also predictive of study attrition, for example, Wald (1) = 11.31, p < .01, Exp(beta) = 1.24. CONCLUSIONS: For both outcomes, greater inconsistency was associated with a greater likelihood of being in a maladaptive group 5 years later. Variability based on moderately cognitively challenging tasks appeared to be particularly sensitive to longitudinal changes in cognitive ability. Mean rate of responding was a comparable predictor of change in most instances, but individuals were at greater relative risk of being in a maladaptive outcome group if they were more inconsistent rather than if they were slower in responding. Implications for the potential utility of intraindividual variability in reaction time as an early marker of cognitive decline are discussed. PMID- 20853958 TI - Is decision making really impaired in eating disorders? AB - OBJECTIVE: Decision making has been reported to be reduced in eating disorders. However, studies are sparse and have been carried out in various selected populations. In the current study we arranged to confirm previous observations and to assess the relationship between decision making and dimensions relevant to eating disorders. METHOD: Patients suffering from anorexia nervosa (n = 49), bulimia nervosa (n = 38), and healthy controls (n = 83) were assessed using the Iowa Gambling Task (IGT). All patients were euthymic and free of psychotropic medication. Self-questionnaires (Eating Disorder Inventory-2; Gardner, 1991; and Eating Attitude Test; Garner & Garfinkel, 1979) were used to assess clinical dimensions relevant to eating disorders. RESULTS: No significant differences in IGT performance were observed between patients and healthy controls or between restrictive and purging types of anorexia nervosa. No correlations were found between IGT performance and eating disorder questionnaires. CONCLUSION: These results do not support reduced decision making in patients with eating disorders, and suggest that previously reported alterations could be related to other clinical characteristics. This should stimulate new topic-related studies designed to reach a firm conclusion. PMID- 20853959 TI - Comparing perceived injustices from supervisors and romantic partners as predictors of aggression. AB - To examine the predictive effects of perceived injustice in two different interpersonal relationships (i.e., working relationship with a supervisor, romantic relationship with a partner) on aggression enacted in those relationships, we computed a series of multilevel regressions on 62 heterosexual couples with all 124 partners employed part-time and working for different supervisors. Higher levels of perceived supervisor injustice predicted higher supervisor-directed aggression, whereas higher levels of perceived partner injustice predicted lower supervisor-directed aggression. An interaction between perceived partner injustice and anger predicted higher levels of partner-directed aggression. Implications and recommendations for future research on the relationship specificity of perceived injustice are discussed. PMID- 20853960 TI - Age differences in reading with distraction: sensory or inhibitory deficits? AB - Two experiments examined how sensory acuity affects age differences in susceptibility to interference in the reading-with-distraction task. In both experiments, older and younger adults read texts in an italic font and were required to ignore distractor words in an upright font. Experiment 1 examined whether the age-related increase in distractibility can be simulated in younger adults by reducing their visual acuity. Experiment 2 investigated whether the age differences in distractibility disappear if visual acuity is equated across all participants in both age groups. Both experiments showed that an impairment in visual acuity leads to increased interference in the reading-with-distraction task. However, older adults were much more impaired by the distractor material than younger adults with reduced visual acuity (Experiment 1). The age differences in the reading-with-distraction task persisted when visual acuity was equated between older and younger adults (Experiment 2). We conclude that the age related increase in susceptibility to interference in the reading-with distraction task is not solely due to perceptual deficits of older adults but arises from a deficit in higher cognitive processes such as inhibitory attention. Nevertheless, sensory acuity has to be taken into account as a potential confounding factor in perceptually demanding visual attention tasks. PMID- 20853961 TI - The status of rapid response learning in aging. AB - Strong evidence exists for an age-related impairment in associative processing under intentional encoding and retrieval conditions, but the status of incidental associative processing has been less clear. In 2 experiments, we examined the effects of age on rapid response learning-the incidentally learned stimulus response association that results in a reduction in priming when a learned response becomes inappropriate for a new task. Specifically, we tested whether priming was equivalently sensitive in both age groups to reversal of the task specific decision cue. Experiment 1 showed that cue inversion reduced priming in both age groups with a speeded inside/outside classification task, and in Experiment 2, cue inversion eliminated priming on an associative version of this task. Thus, the ability to encode an association between a stimulus and its initial task-specific response appears to be preserved in aging. These findings provide an important example of a form of associative processing that is unimpaired in older adults. PMID- 20853962 TI - Psychological resilience predicts decreases in pain catastrophizing through positive emotions. AB - The study used a daily process design to examine the role of psychological resilience and positive emotions in the day-to-day experience of pain catastrophizing. A sample of 95 men and women with chronic pain completed initial assessments of neuroticism, psychological resilience, and demographic data, and then completed short diaries regarding pain intensity, pain catastrophizing, and positive and negative emotions every day for 14 consecutive days. Multilevel modeling analyses indicated that independent of level of neuroticism, negative emotions, pain intensity, income, and age, high-resilient individuals reported greater positive emotions and exhibited lower day-to-day pain catastrophizing compared with low-resilient individuals. Mediation analyses revealed that psychologically resilient individuals rebound from daily pain catastrophizing through experiences of positive emotion. Implications for research on psychological resilience, pain catastrophizing, and positive emotions are discussed. PMID- 20853963 TI - Turning points and lessons learned: stressful life events and personality trait development across middle adulthood. AB - The present research examined stressful life events and personality development across middle adulthood. Participants (N = 533) related the most stressful event they had experienced within the last 10 years, indicated whether they considered the event to be a turning point and/or lesson learned, and twice completed a comprehensive measure of traits defined by the five-factor model of personality; the stressful event occurred between these two assessments. Descriptions were coded to classify events into broad content domains based on the nature of the event. Prospectively, individuals high in Neuroticism perceived the event as a turning point; extraverts learned a lesson from it. Longitudinally, perceiving the event as a negative turning point was associated with increases in Neuroticism, whereas learning a lesson from the event was associated with increases in Extraversion and Conscientiousness. Characteristics of the events themselves were primarily unrelated to trait change. Across middle adulthood, personality trait change may be more strongly related to how individuals understand the stressful events in their lives rather than simply the occurrence of such events. PMID- 20853965 TI - Intraindividual variability is related to cognitive change in older adults: evidence for within-person coupling. AB - In this study, the authors addressed the longitudinal nature of intraindividual variability over 3 years. A sample of 304 community-dwelling older adults, initially between the ages of 64 and 92 years, completed 4 waves of annual testing on a battery of accuracy- and latency-based tests covering a wide range of cognitive complexity. Increases in response-time inconsistency on moderately and highly complex tasks were associated with increasing age, but there were significant individual differences in change across the entire sample. The time varying covariation between cognition and inconsistency was significant across the 1-year intervals and remained stable across both time and age. On occasions when intraindividual variability was high, participants' cognitive performance was correspondingly low. The strength of the coupling relationship was greater for more fluid cognitive domains such as memory, reasoning, and processing speed than for more crystallized domains such as verbal ability. Variability based on moderately and highly complex tasks provided the strongest prediction. These results suggest that intraindividual variability is highly sensitive to even subtle changes in cognitive ability. PMID- 20853964 TI - The utility of Stroop task switching as a marker for early-stage Alzheimer's disease. AB - Past studies have suggested attentional control tasks such as the Stroop task and the task-switching paradigm may be sensitive for the early detection of dementia of the Alzheimer's type (DAT). The authors of the current study combined these tasks to create a Stroop switching task. Performance was compared across young adults, older adults, and individuals diagnosed with very mild dementia. Results indicated that this task strongly discriminated individuals with healthy aging from those with early-stage DAT. In a logistic regression analysis, incongruent error rates from the Stroop switching task discriminated healthy aging from DAT better than any of the other 18 cognitive tasks given in a psychometric battery. PMID- 20853966 TI - Aging does not affect gray matter asymmetry. AB - Previous research has shown that asymmetry of brain activity is decreased in older adults. This study investigates whether cortical gray matter asymmetry also shows age-related differences, and whether gray matter asymmetry differs between cognitively stable persons and persons who have shown profound age-related declines in cognitive functioning. In addition, we have examined whether prodromal dementia affects the study outcome. The gray matter volumes of seven prefrontal and temporal regions of interest were delineated on T1-weighted MRI scans in 70 adults aged between 52 and 84 years. Statistical analyses were conducted with and without participants who developed dementia within 6 years after the MRI scan session. It was found that asymmetry did not differ over the age range of 52-84 years of age. This result did not change when data from participants who were diagnosed with dementia within 6 years after MRI assessment were excluded from the analysis. In addition, no gray matter asymmetry differences were found between cognitively stable participants and participants who showed cognitive decline. We conclude that alterations in gray matter asymmetry may not be part of the healthy aging process. PMID- 20853967 TI - Age and individual differences in prospective memory during a "Virtual Week": the roles of working memory, vigilance, task regularity, and cue focality. AB - Young (ages 18-22 years) and older (ages 61-87 years) adults (N = 106) played the Virtual Week board game, which involves simulating common prospective memory (PM) tasks of everyday life (e.g., taking medication), and performed working memory (WM) and vigilance tasks. The Virtual Week game includes regular (repeated) and irregular (nonrepeated) PM tasks with cues that are either more or less focal to other ongoing activities. Age differences in PM were reduced for repeated tasks, and performance improved over the course of the week, suggesting retrieval was more spontaneous or habitual. Correlations with WM within each age group were reduced for PM tasks that had more regular or focal cues. WM (but not vigilance) ability was a strong predictor of irregular PM tasks with less focal cues. Taken together, these results support the hypothesis that habitual and focally cued PM tasks are less demanding of attentional resources (specifically, WM), whereas tasks that are more demanding of controlled attentional processes produce larger age differences, which may be attributable to individual differences in WM. PMID- 20853968 TI - Effects of aging, distraction, and response pressure on the binding of actors and actions. AB - Two experiments provide evidence for an age-related deficit in the binding of actors with actions that is distinct from binding deficits associated with distraction or response pressure. Young and older adults viewed a series of actors performing different actions. Participants returned 1 week later for a recognition test. Older adults were more likely than young adults to falsely recognize novel conjunctions of familiar actors and actions. This age-related binding deficit occurred even when older adults could discriminate old items from new items just as well as could young adults. Young adults who experienced distraction or time pressure also had difficulty discriminating old items from conjunction items, but this deficit was accompanied by a deficit at discriminating old and new items. These results suggest that distraction and response pressure lead to deficits in memory for stimulus components, with any deficits in binding ability commensurate with these deficits in component memory. Aging, in turn, may lead to binding difficulties that are independent of attention-demanding executive processes involved in maintaining individual stimulus components in working memory, likely reflecting declines in hippocampally mediated associative processes. PMID- 20853969 TI - Resilience-as-process: negative affect, stress, and coupled dynamical systems. AB - Resilience is often considered both a trait and a process. The current study proposes a new way to conceptualize resilience-as-process based on dynamical systems modeling, which allows researchers to capture the process of stress management in real time. Coupled damped linear oscillator models succinctly describe daily stress and negative affect in terms of developmental forces (e.g., velocity, acceleration). Models were fit to 56-day daily response data from 42 aging adults (M(age) = 78.8 years; SD(age) = 6.6 years) to observe and understand linkages between daily stress and affect. It was speculated that individuals with greater resilience would experience stress as less coupled to changes in negative affect (less stress reactivity), and would recover their affective equilibrium more quickly following a given exogenous stressor (greater stress recovery). To identify resilience resources related to reliable interindividual differences in coupling and damping between stress and negative affect, we examined possible protective factors. Aspects of personality and social support predicted both the strength and nature of this coupling, such that higher levels of these resources resulted in greater protection from the cost to negative affect from stress, as observed in damping of negative affect and decreased coupling between systems. PMID- 20853970 TI - Age differences in psychosocial predictors of positive and negative affect: a longitudinal investigation of young, midlife, and older adults. AB - Research has consistently shown that despite aging-related losses, older adults have high levels of emotional well-being relative to those in young and midlife adults. We aimed to contribute to knowledge around the factors that predict emotional well-being over the life course by examining age group differences in associations of positive and negative social exchanges and mastery beliefs with positive and negative affect in a sample of 7,472 young, midlife, and older adults assessed on 2 measurement occasions, 4 years apart. Results from structural equation models indicated lower levels of negative affect with advancing age. Mastery was consistently related to higher well-being, with the strongest associations evident for young adults. Older adults reported the most frequent positive and least frequent negative social exchanges; however, associations of social relations with affect tended to be stronger among young and midlife adults relative to older adults. Results are discussed in the context of life course perspectives on goal orientations and self-regulatory processes. PMID- 20853971 TI - Prospective predictors of positive emotions following spousal loss. AB - Whereas theoreticians are interested in modeling how bereavement contributes to health, the bulk of research on spousal bereavement is conducted after a loss has occurred. Using prospective longitudinal data, this study examined the extent to which positive emotion following spousal loss varies on the basis of preloss characteristics of the bereaved spouse and the marital relationship prior to loss. Analyses are based on the National Survey of Midlife Development (MIDUS), a 2-wave panel survey of adults in the contiguous United States. Results indicate that compared with continuously married controls, widowed participants experienced a significant decline in positive emotion within 3 years following loss. Conversely, no significant declines in positive emotion were evident among widowed persons with greater preloss trait resilience or greater marital strain. Results provide support for the notion that adjustment to loss may be linked to factors that precede actual loss. PMID- 20853972 TI - Aging and inhibition processes: the case of metaphor treatment. AB - The inhibitory deficit hypothesis has often been cited as a possible explanation for cognitive changes related to age. The aim of this study was to develop a new procedure for evaluating effortful inhibition on the basis of the comprehension of metaphors. Our experiment was carried out on younger and older adults, in whom we also measured inhibitory capacity, working memory, and processing speed. The results show that older participants required a longer time and made more frequent errors in rejecting metaphors versus literally false statements. The interference effect was predicted by the psychometric tests designed to evaluate inhibition. PMID- 20853973 TI - The effects of age on using prosody to convey meaning and on judging communicative effectiveness. AB - We tested the effects of aging on the use of prosody to convey meaning and the ability to monitor communicative effectiveness. Participants read aloud ambiguous sentences with the goal of clearly communicating one designated meaning. Young and older adults produced intonational boundaries consistent with the designated meaning equally often, but listener judgments indicated that older adults disambiguated the sentences more often than chance and young adults did so only marginally more often than chance. Young adults believed they communicated their message clearly, and older adults evaluated their own communication even more favorably. Participants were more confident for structurally ambiguous sentences than for lexically ambiguous sentences (which cannot be differentiated through prosody), and older adults demonstrated more overconfidence than young adults for both types of ambiguous sentences. PMID- 20853974 TI - Preview benefit during eye fixations in reading for older and younger readers. AB - Older and younger readers read sentences as their eye movements were recorded, and the boundary paradigm (Rayner, 1975) was used to present either a valid or an invalid parafoveal preview of a target word. During the saccade to the target word, the preview word changed to the target word. For early measures of processing time (first fixation duration and single fixation duration), the standard preview benefit effect (shorter fixation times on the target word with a valid preview than an invalid preview) was obtained for both older and younger readers. However, for gaze duration and go-past time, the preview benefit was somewhat attenuated in the older readers in comparison to the younger readers, suggesting that on some fixations older readers obtain less preview benefit from the word to the right of fixation. PMID- 20853975 TI - The rise and fall of word retrieval across the lifespan. AB - Picture-naming performance for 48 black-and-white drawings was investigated in 1,145 Hebrew speakers, ages 5-86. Both a linear and a curvilinear quadratic model fit the data, reflecting an increase in ability with age as well as an increase followed by a decrease beyond that linear rise. Late-life performance was more affected by access difficulty than was early-life performance, with children's responses limited by lexicon size. Immigrants performed more poorly than nonimmigrants, but an identical correlation between participant age and naming scores was found in both groups. We discuss the role of vocabulary funds and controlled access in naming pictures throughout life. PMID- 20853976 TI - Cross-cultural aging in cognitive and affective components of subjective well being. AB - The present study examined age and cultural differences in cognitive and affective components of subjective well-being. A sample of 188 American and Chinese young and older adults completed surveys measuring self-life satisfaction, perceived family's life satisfaction, positive affect, and negative affect. Across cultures, older adults reported lower negative affect than did young adults. Americans reported higher self-life satisfaction, perceived family's life satisfaction, and positive affect than did Chinese. In addition, perceived family's life satisfaction was more related to self-life satisfaction for Chinese than for Americans. Findings are discussed in light of socioemotional selectivity theory and theories on culture and self-construal. PMID- 20853977 TI - Response latencies in auditory sentence comprehension: effects of linguistic versus perceptual challenge. AB - Older adults with good hearing and with mild-to-moderate hearing loss were tested for comprehension of spoken sentences that required perceptual effort (hearing speech at lower sound levels), and two degrees of cognitive load (sentences with simpler or more complex syntax). Although comprehension accuracy was equivalent for both participant groups and for young adults with good hearing, hearing loss was associated with longer response latencies to the correct comprehension judgments, especially for complex sentences heard at relatively low amplitudes. These findings demonstrate the need to take into account both sensory and cognitive demands of speech materials in older adults' language comprehension. PMID- 20853978 TI - Comprehension of a novel accent by young and older listeners. AB - The authors investigated perceptual learning of a novel accent in young and older listeners through measuring speech reception thresholds (SRTs) using speech materials spoken in a novel-unfamiliar-accent. Younger and older listeners adapted to this accent, but older listeners showed poorer comprehension of the accent. Furthermore, perceptual learning differed across groups: The older listeners stopped learning after the first block, whereas younger listeners showed further improvement with longer exposure. Among the older participants, hearing acuity predicted the SRT as well as the effect of the novel accent on SRT. Finally, a measure of executive function predicted the impact of accent on SRT. PMID- 20853979 TI - Simulator driving performance predicts accident reports five years later. AB - L. Hoffman, J. M. McDowd, P. Atchley, and R. A. Dubinsky (2005) reported that visual and attentional impairment (measured by the Useful Field of View test and DriverScan) and performance in a low-fidelity driving simulator did not predict self-reported accidents in the previous 3 years. The present study applied these data to predict accidents occurring within a subsequent 5-year period (N = 114 older adults, 75% retention rate). Multivariate path models revealed that accidents in which the driver was at least partially at fault were significantly more likely in persons who had shown impaired simulator performance. These results suggest that even low-fidelity driving simulators may be useful in predicting real-world outcomes. PMID- 20853980 TI - Feelings change: accounting for individual differences in the temporal dynamics of affect. AB - People display a remarkable variability in the patterns and trajectories with which their feelings change over time. In this article, we present a theoretical account for the dynamics of affect (DynAffect) that identifies the major processes underlying individual differences in the temporal dynamics of affective experiences. It is hypothesized that individuals are characterized by an affective home base, a baseline attractor state around which affect fluctuates. These fluctuations vary as the result of internal or external processes to which an individual is more or less sensitive and are regulated and tied back to the home base by the attractor strength. Individual differences in these 3 processes- affective home base, variability, and attractor strength--are proposed to underlie individual differences in affect dynamics. The DynAffect account is empirically evaluated by means of a diffusion modeling approach in 2 extensive experience-sampling studies on people's core affective experiences. The findings show that the model is capable of adequately capturing the observed dynamics in core affect across both large (Study 1) and shorter time scales (Study 2) and illuminate how the key processes are related to personality and emotion dispositions. Implications for the understanding of affect dynamics and affective dysfunctioning in psychopathology are also discussed. PMID- 20853981 TI - The expression of determination: similarities between anger and approach-related positive affect. AB - In this set of studies, we examine the perceptual similarities between emotions that share either a valence or a motivational direction. Determination is a positive approach-related emotion, whereas anger is a negative approach-related emotion. Thus, determination and anger share a motivational direction but are opposite in valence. An implemental mind-set has previously been shown to produce high-approach-motivated positive affect. Thus, in Study 1, participants were asked to freely report the strongest emotion they experienced during an implemental mind-set. The most common emotion reported was determination. On the basis of this result, we compared the facial expression of determination with that of anger. In Study 2, naive judges were asked to identify photographs of facial expressions intended to express determination, along with photographs intended to express basic emotions (joy, anger, sadness, fear, disgust, neutral). Correct identifications of intended determination expressions were correlated with misidentifications of the expressions as anger but not with misidentifications as any other emotion. This suggests that determination, a high approach-motivated positive affect, is perceived as similar to anger. In Study 3, naive judges quantified the intensity of joy, anger, and determination expressed in photographs. The intensity of perceived determination was directly correlated with the intensity of perceived anger (a high-approach-motivated negative affect) and was inversely correlated with the intensity of perceived joy (a low-approach motivated positive affect). These results demonstrate perceptual similarity between emotions that share a motivational direction but differ in valence. PMID- 20853982 TI - Blocking and overshadowing in human geometry learning. AB - In a two-dimensional computer-based search task, human participants were required to learn the location of a goal by using the geometric information available on the screen. When the goal location was defined by two shapes that differed in salience, the more salient shape overshadowed learning based on the less salient shape but not the other way round. Furthermore, when one shape was pretrained as a signal for the location of the goal, learning about the geometric cues of the other shape was blocked. These results suggest that spatial learning based on geometry is ruled by associative principles and support learning models that do not invoke a special status for geometric cues (e.g., Miller & Shettleworth, 2007). PMID- 20853983 TI - Dimensions of air traffic control tower information needs: from information requests to display design. AB - In an effort to determine the information needs of tower air traffic controllers, instructors from the Federal Aviation Administration's Academy in Oklahoma City were asked to control traffic in a high-fidelity tower cab simulator. Information requests were made apparent by eliminating access to standard tower information sources. Instead, controllers were required to ask for precisely the information they needed during the scenarios. The information requests were classified using an elaboration of Zwaan and Radvansky's (1998) dimensions of situation models. The vast majority of requests were about three of the dimensions originally developed for reading comprehension: the protagonist, intentionality, and space. The information requests were also classified into 28 operational categories (e.g., aircraft identification, destination). From these results, the data were summarized, not just statistically, but by the creation of display-hypotheses. The display-hypotheses were organized according to the situation-model dimensions. Controllers preferred data blocks organized by the situation-model principle over those that violated this organization. The summary display hypotheses were quite simple and accounted for the vast majority of the information requests controllers made. The display-hypotheses accounted for the information needs of controllers during routine as well as off-nominal events. PMID- 20853984 TI - Measuring search efficiency in complex visual search tasks: global and local clutter. AB - Set size and crowding affect search efficiency by limiting attention for recognition and attention against competition; however, these factors can be difficult to quantify in complex search tasks. The current experiments use a quantitative measure of the amount and variability of visual information (i.e., clutter) in highly complex stimuli (i.e., digital aeronautical charts) to examine limits of attention in visual search. Undergraduates at a large southern university searched for a target among 4, 8, or 16 distractors in charts with high, medium, or low global clutter. The target was in a high or low local clutter region of the chart. In Experiment 1, reaction time increased as global clutter increased, particularly when the target was in a high local-clutter region. However, there was no effect of distractor set size, supporting the notion that global clutter is a better measure of attention against competition in complex visual search tasks. As a control, Experiment 2 demonstrated that increasing the number of distractors leads to a typical set size effect when there is no additional clutter (i.e., no chart). In Experiment 3, the effects of global and local clutter were minimized when the target was highly salient. When the target was nonsalient, more fixations were observed in high global clutter charts, indicating that the number of elements competing with the target for attention was also high. The results suggest design techniques that could improve pilots' search performance in aeronautical charts. PMID- 20853985 TI - Viewing another person's eye movements improves identification of pulmonary nodules in chest x-ray inspection. AB - Double reading of chest x-rays is often used to ensure that fewer abnormalities are missed, but very little is known about how the search behavior of others affects observer performance. A series of experiments investigated whether radiographers benefit from knowing where another person looked for pulmonary nodules, and whether the expertise of the model providing the search behavior was a contributing factor. Experiment 1 compared the diagnostic performance of novice and experienced radiographers examining chest x-rays and found that both groups performed better when shown the search behavior of either a novice radiographer or an expert radiologist. Experiment 2 established that benefits in performance only arose when the eye movements shown were related to the search for nodules; however, only the novices' diagnostic performance consistently improved when shown the expert's search behavior. Experiment 3 reexamined the contribution of task, image, and the expertise of the model underlying this benefit. Consistent with Experiment 1, novice radiographers were better at identifying nodules when shown either a naive's search behavior or an expert radiologist's search behavior, but they demonstrated no improvement when shown a naive model not searching for nodules. Our results suggest that although the benefits of this form of attentional guidance may be short-lived, novices can scaffold their decisions based on the search behavior of others. PMID- 20853986 TI - Embedded promotions in online services: how goal-relevance ambiguity shapes response and affect. AB - Adding promotions to online services is increasingly commonplace, yet consumers may have difficulty determining whether service-embedded promotions are goal relevant, due to the linear and transactional nature of online services. This contextual effect of goal-relevance ambiguity on promotions is explored across three studies. An exploratory study utilizing actual service websites and a broad range of consumers as participants showed promotional elements in online services generated considerable confusion, and instructions labeling promotions as optional did little to relieve goal-relevance ambiguity. A second study using student participants inserted promotions into an online airline ticket service, a shopping site, a local news blog, and a news headline aggregator, to explore how linear and transactional sites such as online services compared to more exploratory or informational online environments. Results showed that service embedded promotions enjoyed initial compliance far beyond promotions in traditional websites but also generated increased confusion, frustration, and anger. A third study utilizing student participants explored how varying levels of online service experience created differing responses to promotions in services; novices were less able to judge promotional goal-relevance and experienced more confusion, whereas experienced searchers were more likely to respond with frustration and anger. Many participants complied with promotional offers at the time of the service transaction, but stated intentions to use the promotion postservice were very low. The overall results spotlight goal-relevance ambiguity as an important driver of consumer response to online promotions, and highlight the role website context can play in the processing of online promotional elements. PMID- 20853987 TI - The effects of technical difficulties on learning and attrition during online training. AB - Although online instruction has many potential benefits, technical difficulties are one drawback to the increased use of this medium. A repeated measures design was used to examine the effect that technical difficulties have on learning and attrition from voluntary online training. Adult learners (N = 530) were recruited online and volunteered to participate in a 4-hr training program on using computer spreadsheets. Technical difficulties were inserted in some of the training modules in the form of error messages. Using multilevel modeling, the results indicated that the presence of these technical difficulties impaired learning, such that test scores were lower in modules where trainees encountered technical difficulties than in modules where they did not encounter technical difficulties. Furthermore, the effect on learning was greater among trainees who eventually withdrew from the course than among trainees who completed the course. With regards to attrition, pretraining motivation provided a buffer against dropping out, especially when trainees encountered technical difficulties. Learning also predicted attrition from the subsequent module, such that attrition was higher among trainees with low test scores in the previous module. The current study disentangles some of the implications of technical difficulties and suggests that organizations should provide trainees with the technical support required to overcome technical difficulties in training. Furthermore, the findings contribute to our theoretical understanding of the implications of interruptions on performance in online training. PMID- 20853988 TI - Identifying and profiling scholastic cheaters: their personality, cognitive ability, and motivation. AB - Despite much research, skepticism remains over the possibility of profiling scholastic cheaters. However, several relevant predictor variables and newer diagnostic tools have been overlooked. We remedy this deficit with a series of three studies. Study 1 was a large-scale survey of a broad range of personality predictors of self-reported cheating. Significant predictors included the Dark Triad (Machiavellianism, narcissism, psychopathy) as well as low agreeableness and low conscientiousness. Only psychopathy remained significant in a multiple regression. Study 2 replicated this pattern using a naturalistic, behavioral indicator of cheating, namely, plagiarism as indexed by the Internet service Turn It-In. Poor verbal ability was also an independent predictor. Study 3 examined possible motivational mediators of the association between psychopathy and cheating. Unrestrained achievement and moral inhibition were successful mediators whereas fear of punishment was not. Practical implications for researchers and educators are discussed. PMID- 20853989 TI - A comparison of study strategies for passages: rereading, answering questions, and generating questions. AB - Students are often encouraged to generate and answer their own questions on to-be remembered material, because this interactive process is thought to enhance memory. But does this strategy actually work? In three experiments, all participants read the same passage, answered questions, and took a test to get accustomed to the materials in a practice phase. They then read three passages and did one of three tasks on each passage: reread the passage, answered questions set by the experimenter, or generated and answered their own questions. Passages were 575-word (Experiments 1 and 2) or 350-word (Experiment 3) texts on topics such as Venice, the Taj Mahal, and the singer Cesaria Evora. After each task, participants predicted their performance on a later test, which followed the same format as the practice phase test (a short-answer test in Experiments 1 and 2, and a free recall test in Experiment 3). In all experiments, best performance was predicted after generating and answering questions. We show, however, that generating questions led to no improvement over answering comprehension questions, but that both of these tasks were more beneficial than rereading. This was the case on an immediate short-answer test (Experiment 1), a short-answer test taken 2 days after study (Experiment 2), and an immediate free recall test (Experiment 3). Generating questions took at least twice as long as answering questions in all three experiments, so although it is a viable alternative to answering questions in the absence of materials, it is less time efficient. PMID- 20853990 TI - English speakers attend more strongly than Spanish speakers to manner of motion when classifying novel objects and events. AB - Three experiments provide evidence that the conceptualization of moving objects and events is influenced by one's native language, consistent with linguistic relativity theory. Monolingual English speakers and bilingual Spanish/English speakers tested in an English-speaking context performed better than monolingual Spanish speakers and bilingual Spanish/English speakers tested in a Spanish speaking context at sorting novel, animated objects and events into categories on the basis of manner of motion, an attribute that is prominently marked in English but not in Spanish. In contrast, English and Spanish speakers performed similarly at classifying on the basis of path, an attribute that is prominently marked in both languages. Similar results were obtained regardless of whether categories were labeled by novel words or numbered, suggesting that an English-speaking tendency to focus on manner of motion is a general phenomenon and not limited to word learning. Effects of age of acquisition of English were also observed on the performance of bilinguals, with early bilinguals performing similarly in the 2 language contexts and later bilinguals showing greater contextual variation. PMID- 20853991 TI - Predicting behavior in economic games by looking through the eyes of the players. AB - Social scientists often rely on economic experiments such as ultimatum and dictator games to understand human cooperation. Systematic deviations from economic predictions have inspired broader conceptions of self-interest that incorporate concerns for fairness. Yet no framework can describe all of the major results. We take a different approach by asking players directly about their self interest--defined as what they want to do (pleasure-maximizing options). We also ask players directly about their sense of fairness--defined as what they think they ought to do (fairness-maximizing options). Player-defined measures of self interest and fairness predict (a) the majority of ultimatum-game and dictator game offers, (b) ultimatum-game rejections, (c) exiting behavior (i.e., escaping social expectations to cooperate) in the dictator game, and (d) who cooperates more after a positive mood induction. Adopting the players' perspectives of self interest and fairness permits better predictions about who cooperates, why they cooperate, and when they punish noncooperators. PMID- 20853992 TI - When the future feels worse than the past: a temporal inconsistency in moral judgment. AB - Logically, an unethical behavior performed yesterday should also be unethical if performed tomorrow. However, the present studies suggest that the timing of a transgression has a systematic effect on people's beliefs about its moral acceptability. Because people's emotional reactions tend to be more extreme for future events than for past events, and because such emotional reactions often guide moral intuitions, judgments of moral behavior may be more extreme in prospect than in retrospect. In 7 studies, participants judged future bad deeds more negatively, and future good deeds more positively, than equivalent behavior in the equidistant past. In addition, participants thought that future unfair actions deserved more punishment than past unfair actions, and were more willing to sacrifice their own financial gain to be treated fairly in the future compared with in the past. These patterns were explained in part by the stronger emotions that were evoked by thoughts of future events than by thoughts of past events. Taken together, the results suggest that permission for actions with ethical connotations may be harder to get than forgiveness for those same actions, and demonstrate a systematic way in which moral judgments of the same action are inconsistent across time. PMID- 20853993 TI - Decision making and the avoidance of cognitive demand. AB - Behavioral and economic theories have long maintained that actions are chosen so as to minimize demands for exertion or work, a principle sometimes referred to as the law of less work. The data supporting this idea pertain almost entirely to demands for physical effort. However, the same minimization principle has often been assumed also to apply to cognitive demand. The authors set out to evaluate the validity of this assumption. In 6 behavioral experiments, participants chose freely between courses of action associated with different levels of demand for controlled information processing. Together, the results of these experiments revealed a bias in favor of the less demanding course of action. The bias was obtained across a range of choice settings and demand manipulations and was not wholly attributable to strategic avoidance of errors, minimization of time on task, or maximization of the rate of goal achievement. It is remarkable that the effect also did not depend on awareness of the demand manipulation. Consistent with a motivational account, avoidance of demand displayed sensitivity to task incentives and covaried with individual differences in the efficacy of executive control. The findings reported, together with convergent neuroscientific evidence, lend support to the idea that anticipated cognitive demand plays a significant role in behavioral decision making. PMID- 20853995 TI - Why don't we learn to accurately forecast feelings? How misremembering our predictions blinds us to past forecasting errors. AB - Why do affective forecasting errors persist in the face of repeated disconfirming evidence? Five studies demonstrate that people misremember their forecasts as consistent with their experience and thus fail to perceive the extent of their forecasting error. As a result, people do not learn from past forecasting errors and fail to adjust subsequent forecasts. In the context of a Super Bowl loss (Study 1), a presidential election (Studies 2 and 3), an important purchase (Study 4), and the consumption of candies (Study 5), individuals mispredicted their affective reactions to these experiences and subsequently misremembered their predictions as more accurate than they actually had been. The findings indicate that this recall error results from people's tendency to anchor on their current affective state when trying to recall their affective forecasts. Further, those who showed larger recall errors were less likely to learn to adjust their subsequent forecasts and reminding people of their actual forecasts enhanced learning. These results suggest that a failure to accurately recall one's past predictions contributes to the perpetuation of forecasting errors. PMID- 20853994 TI - Situated naive physics: task constraints decide what children know about density. AB - Children's understanding of density is riddled with misconceptions-or so it seems. Yet even preschoolers at times appear to understand density. This article seeks to reconcile these conflicting outcomes by investigating the nature of constraints available in different experimental protocols. Protocols that report misconceptions about density used stimulus arrangements that make differences in mass and volume more salient than differences in density. In contrast, protocols that report successful performance used stimulus arrangements that might have increased the salience of density. To test this hypothesis, the present experiments manipulate the salience of object density. Children between 2 and 9 years of age and adults responded whether an object would sink or float when placed in water. Results indicated that children's performance on exactly the same objects differed as a function of the saliency of the dimension of density, relative to the dimensions of mass and volume. These results support the idea that constraints--rather than stable knowledge--drive performance, with implications for teaching children about nonobvious concepts such as density. PMID- 20853996 TI - Spatial context learning survives interference from working memory load. AB - The human visual system is constantly confronted with an overwhelming amount of information, only a subset of which can be processed in complete detail. Attention and implicit learning are two important mechanisms that optimize vision. This study addressed the relationship between these two mechanisms. Specifically we asked, Is implicit learning of spatial context affected by the amount of working memory load devoted to an irrelevant task? We tested observers in visual search tasks where search displays occasionally repeated. Observers became faster when searching repeated displays than unrepeated ones, showing contextual cuing. We found that the size of contextual cuing was unaffected by whether observers learned repeated displays under unitary attention or when their attention was divided using working memory manipulations. These results held when working memory was loaded by colors, dot patterns, individual dot locations, or multiple potential targets. We conclude that spatial context learning is robust to interference from manipulations that limit the availability of attention and working memory. PMID- 20853997 TI - The dissipating task-repetition benefit in cued task switching: task-set decay or temporal distinctiveness? AB - Decay of task-set activation, as commonly assumed in models of task switching, has been thought to be indexed by manipulating the response-to-cue interval (RCI) in a task-cuing paradigm. We propose an alternative account for RCI effects suggesting that episodic task retrieval is modulated by temporal distinctiveness, which we define as the ratio between previous RCI and current RCI. In Experiment 1, increasing RCI decreased the task-repetition benefit, but the slope of the RCI function depended on the range of RCIs rather than on the absolute duration of the RCI. In Experiment 2, the RCIs were blocked or random, and in Experiment 3, trial-wise predictability of RCIs was manipulated. RCI influenced the task repetition benefit only when RCI changed from the previous to the current trial. Experiment 4 used two cues for each task and dissociated cue-repetition priming from task-repetition priming, suggesting that it is episodic task-set retrieval that is influenced by temporal distinctiveness. We discuss theoretical implications for persisting-task-set-activation theories and the relation to long term decay, inhibition, and temporal preparation in task switching. PMID- 20853998 TI - Visual marking and change blindness: moving occluders and transient masks neutralize shape changes to ignored objects. AB - Visual search efficiency improves by presenting (previewing) one set of distractors before the target and remaining distractor items (D. G. Watson & G. W. Humphreys, 1997). Previous work has shown that this preview benefit is abolished if the old items change their shape when the new items are added (e.g., D. G. Watson & G. W. Humphreys, 2002). Here we present 5 experiments that examined whether such object changes are still effective in recapturing attention if the changes occur while the previewed objects are occluded or masked. Overall, the findings suggest that masking transients are effective in preventing both object changes and the presentation of new objects from capturing attention in time-based visual search conditions. The findings are discussed in relation to theories of change blindness, new object capture, and the ecological properties of time-based visual selection. PMID- 20853999 TI - Subjectively interpreted shape dimensions as privileged and orthogonal axes in mental shape space. AB - The shape of an object is fundamental in object recognition but it is still an open issue to what extent shape differences are perceived analytically (i.e., by the dimensional structure of the shapes) or holistically (i.e., by the overall similarity of the shapes). The dimensional structure of a stimulus is available in a primary stage of processing for separable dimensions, although it can also be derived cognitively from a perceived stimulus consisting of integral dimensions. Contrary to most experimental paradigms, the present study asked participants explicitly to analyze shapes according to two dimensions. The dimensions of interest were aspect ratio and medial axis curvature, and a new procedure was used to measure the participants' interpretation of both dimensions (Part I, Experiment 1). The subjectively interpreted shape dimensions showed specific characteristics supporting the conclusion that they also constitute perceptual dimensions with objective behavioral characteristics (Part II): (1) the dimensions did not correlate in overall similarity measures (Experiment 2), (2) they were more separable in a speeded categorization task (Experiment 3), and (3) they were invariant across different complex 2-D shapes (Experiment 4). The implications of these findings for shape-based object processing are discussed. PMID- 20854000 TI - Sound affects the speed of visual processing. AB - The authors examined the effects of a task-irrelevant sound on visual processing. Participants were presented with revolving clocks at or around central fixation and reported the hand position of a target clock at the time an exogenous cue (1 clock turning red) or an endogenous cue (a line pointing toward 1 of the clocks) was presented. A spatially irrelevant sound presented 100 ms before the cue speeded visual latency when compared with a sound presented 100 ms after the cue. The effect of the sound was larger the farther the target was from fixation, and it was larger for endogenous than exogenous cues. A visual temporal warning signal had different effects on perceptual latency. These results demonstrate that an asynchronous sound can shift the perceived time of occurrence of a visual cue (temporal ventriloquism) and speed the velocity of the attentional shift toward the target. Sounds thus have multiple effects on visual perception. PMID- 20854001 TI - Social postural coordination. AB - The goal of the current study was to investigate whether a visual coupling between two people can produce spontaneous interpersonal postural coordination and change their intrapersonal postural coordination involved in the control of stance. We examined the front-to-back head displacements of participants and the angular motion of their hip and ankle during a visual tracking task performed alone and paired. Our results showed that visually paired participants exhibited spontaneous coordination between the movements of their head, hip, and ankle. Moreover, the visual coupling modified the spontaneous intrapersonal ankle-hip coordination dynamics of participants and their performance during visual tracking. Generally, our findings demonstrated reciprocal relations between intrapersonal and interpersonal coordination during social interaction. PMID- 20854002 TI - Implicit versus explicit frequency comparisons: two mechanisms of auditory change detection. AB - Listeners had to compare, with respect to pitch (frequency), a pure tone (T) to a combination of pure tones presented subsequently (C). The elements of C were either synchronous, and therefore difficult to hear out individually, or asynchronous and therefore easier to hear out individually. In the "present/absent" condition, listeners had to judge if T reappeared in C or not. In the "up/down" condition, the task was to judge if the element of C most similar to T was higher or lower than T. When the elements of C were synchronous, the up/down task was found to be easier than the present/absent task; the converse result was obtained when the elements of C were asynchronous. This provides evidence for a duality of auditory comparisons between tone frequencies: (1) implicit comparisons made by automatic and direction-sensitive "frequency shift detectors"; (2) explicit comparisons more sensitive to the magnitude of a frequency change than to its direction. Another experiment suggests that although the frequency-shift detectors cannot compare effectively two tones separated by an interfering tone, they are largely insensitive to interfering noise bursts. PMID- 20854003 TI - No negative priming without cognitive control. AB - There is evidence that the efficiency of selective attention depends on the availability of cognitive control mechanisms as distractor processing has been found to increase with high load on working memory or dual task coordination (Lavie, Hirst, de Fockert, & Viding, 2004). We tested the prediction that cognitive control load would also affect the negative priming effect produced when a distractor from 1 trial appears as a target on the next trial. We measured priming on trials that involved either high or low cognitive control load, and found that under high control load, negative priming was eliminated, and could even be reversed to positive priming, suggesting that the negative priming effect depends on the availability of cognitive control resources. PMID- 20854004 TI - The frequency-predictability interaction in reading: it depends where you're coming from. AB - A word's frequency of occurrence and its predictability from a prior context are key factors determining how long the eyes remain on that word in normal reading. Past reaction-time and eye movement research can be distinguished by whether these variables, when combined, produce interactive or additive results, respectively. Our study addressed possible methodological limitations of prior experiments. Initial results showed additive effects of frequency and predictability. However, we additionally examined launch site (the distance from the pretarget fixation to the target) to index the extent of parafoveal target processing. Analyses revealed both additive and interactive effects on target fixations, with the nature of the interaction depending on the quality of the parafoveal preview. Target landing position and pretarget fixation time were also considered. Results were interpreted in terms of models of language processing and eye movement control. Our findings with respect to parafoveal preview and fixation time constraints aim to help parameterize eye movement behavior. PMID- 20854006 TI - The dynamic microstructure of speech production: semantic interference built on the fly. AB - We present 4 experiments investigating dynamic and flexible aspects of semantic activation spread during speech planning. In a semantic blocking paradigm, pictures of objects were presented in categorically homogeneous blocks consisting of semantic category members (e.g., foods), in blocks consisting of seemingly unrelated objects that could potentially be integrated into a common theme (e.g., fishing trip), or in heterogeneous blocks consisting of entirely unrelated objects. In Experiment 1 we observed a classic semantic interference effect for the categorically homogeneous condition but no effect for the thematically homogeneous condition. In Experiment 2 the blocks were preceded once by visually presented title words. When titles were presented that referred to the semantic category or theme of the block, interference was observed not only in the categorically homogeneous condition but also in the thematically homogeneous condition. The ad hoc semantic interference effects for thematic relations were replicated with a different set of materials in Experiments 3 and 4. These observations reveal the dynamic nature of the speech production system, shaped by context and formations of flexible ad hoc categories and semantic relations. PMID- 20854005 TI - Ending on a high note: adding a better end to effortful study. AB - Remembered utility is the retrospective evaluation about the pleasure and pain associated with a past experience. It has been shown to influence prospective choices about whether to repeat or to avoid similar situations in the future (D. Kahneman 2000; D. Kahneman, D. L. Fredrickson, C. A. Schreiber, & D. A. Redelmeier, 1993). Evaluations about our hedonic past often disregard the duration of the experience and are influenced more by the peak and the final levels of discomfort (B. L. Fredrickson & D. Kahneman, 1993). Two experiments explored the remembered discomfort of an effortful learning experience and the influence of this evaluation on prospective study choices. The design of the studies mimicked D. Kahneman et al.'s (1993) cold-pressor study, but used an exceptionally challenging learning experience in place of the painful experience of submerging one's hand in ice water. An extremely effortful study episode extended by a more moderate interval was preferred to a shorter, unextended interval, despite better test performance following the shorter interval. Future study choices reflected this preference. These findings suggest that the act of acquiring knowledge has value in the learning process. PMID- 20854007 TI - Avoiding the approach trap: a response bias theory of the emotional Stroop effect. AB - In the laboratory, people classify the color of emotion-laden words slower than they do that of neutral words, the emotional Stroop effect. Outside the laboratory, people react to features of emotion-laden stimuli or threatening stimuli faster than they do to those of neutral stimuli. A possible resolution to the conundrum implicates the counternatural response demands imposed in the laboratory that do not, as a rule, provide for avoidance in the face of threat. In 2 experiments we show that when such an option is provided in the laboratory, the response latencies follow those observed in real life. These results challenge the dominant attention theory offered for the emotional Stroop effect because this theory is indifferent to the vital approach-avoidance distinction. PMID- 20854008 TI - Task effects on eye movements during reading. AB - The present study examined how proofreading and reading-for-comprehension instructions influence eye movements during reading. Thirty-seven participants silently read sentences containing compound words as target words while their eye movements were being recorded. We manipulated word length and frequency to examine how task instructions influence orthographic versus lexical-semantic processing during reading. Task instructions influenced both temporal and spatial aspects of eye movements: The initial landing position in words was shifted leftward, the saccade length was shorter, first fixation and gaze duration were longer, and refixation probability was higher during proofreading than during reading for comprehension. Moreover, in comparison to instructions for reading for comprehension, proofreading instructions increased both orthographic and lexical-semantic processing. This became apparent in a greater word length and word frequency effect in gaze duration during proofreading than during reading for comprehension. The present study suggests that the allocation of attentional resources during reading is significantly modulated by task demands. PMID- 20854009 TI - Memory variability is due to the contribution of recollection and familiarity, not to encoding variability. AB - It is well established that the memory strength of studied items is more variable than the strength of new items on tests of recognition memory, but the reason why this occurs is poorly understood. One account for this old item variance effect is based on single-process theory, which proposes that this effect is due to variability in how well items are initially encoded into memory (i.e., the encoding variability account). In contrast, dual-process theory argues that old items are more variable because they are influenced by both recollection and familiarity, whereas recognition of new items relies primarily on familiarity. The present study shows that increasing encoding variability did not increase old item variance and that old item variance is directly related to the contribution of recollection. These results indicate that old item memory variability is due to the relative contribution of recollection and familiarity. PMID- 20854010 TI - The effect of incidental hints when problems are suspended before, during, or after an impasse. AB - Two studies examine how the time at which problem solving is suspended relative to an impasse affects the impact of incidental hints. An impasse is a point in problem solving at which a problem solver is not making progress and does not know how to proceed. In both studies, work on remote associates problems was suspended before an impasse was reached, at the time an impasse was reached, or after a period of continued work during an impasse. After problem solving was suspended on a set of problems, participants completed a lexical decision task before resuming work on the set of unsolved problems. For half of the problems suspended during each impasse state, solution words were presented as incidental hints in the lexical decision task. The proportion of initially unsolved problems that were solved after the intervening lexical decision task was greater when problem solving was suspended at the point an impasse was reached than when problem solving was suspended before an impasse or after a period of continued work during an impasse. These results suggest that suspending problem solving at the point of impasse may increase susceptibility to incidentally presented hints. The point of impasse may be an opportune time for hints because the problem has been explored but there has not been a large increase in fixation on failed solution attempts. PMID- 20854012 TI - Effects of shear stress and stretch on endothelial function. AB - Vascular endothelial cells (ECs) play a central role in the control of blood vessel function and circulatory system homeostasis. It is well known that that EC functions are regulated by chemical mediators, including hormones, cytokines, and neurotransmitters, but it has recently become apparent that EC functions are also controlled by hemodynamic forces such as shear stress and stretch (cyclic strain). ECs recognize shear stress and cyclic strain as mechanical stimuli, and transmit the signal into the interior of the cells, thereby triggering a variety of cellular responses that involve alterations in cell morphology, cell function, and gene expression. Impaired EC responses to shear stress and cyclic strain lead to vascular diseases, including hypertension, thrombosis, and atherosclerosis. A great deal of research has already been conducted on the mechanotransduction of shear stress and cyclic strain, and its molecular mechanisms are gradually coming to be understood. However, much remains unclear, and further studies of mechanotransduction should increase our understanding of the molecular basis of the hemodynamic-force-mediated control of vascular functions. PMID- 20854011 TI - Method matters: systematic effects of testing procedure on visual working memory sensitivity. AB - Visual working memory (WM) is traditionally considered a robust form of visual representation that survives changes in object motion, observer's position, and other visual transients. This article presents data that are inconsistent with the traditional view. We show that memory sensitivity is dramatically influenced by small variations in the testing procedure, supporting the idea that representations in visual WM are susceptible to interference from testing. In the study, participants were shown an array of colors to remember. After a short retention interval, memory for one of the items was tested with either a same different task or a 2-alternative-forced-choice (2AFC) task. Memory sensitivity was much lower in the 2AFC task than in the same-different task. This difference was found regardless of encoding similarity or of whether visual WM required a fine or coarse memory resolution. The 2AFC disadvantage was reduced when participants were informed shortly before testing which item would be probed. The 2AFC disadvantage diminished in perceptual tasks and was not found in tasks probing visual long-term memory. These results support memory models that acknowledge the labile nature of visual WM and have implications for the format of visual WM and its assessment. PMID- 20854013 TI - Evaluation of bystander exposures to asbestos in occupational settings: a review of the literature and application of a simple eddy diffusion model. AB - This article presents a review of the publicly available information as it relates to airborne asbestos concentrations at varying distances from a source in an occupational environment. Personal and area samples collected 5-75 feet from the primary worker from workplace surveys conducted in the 1970s and area samples collected 5-50 feet from the primary worker during more recent simulation studies were identified, compiled, and analyzed. As expected, airborne asbestos concentrations generally decreased with distance from the worker who performed a given task. Based on this review, however, the authors found that no systematic research to quantitatively relate fiber concentration with distance from the source (including consideration of fiber length, dilution ventilation, and initial momentum of the particle) has been conducted to date. A simple mathematical model was therefore used, and the results were considered, along with available published data comparing exposure data for both workers and persons/areas near workers. From this analysis, the authors offer guidance for estimating airborne asbestos concentrations at distance from a source. Based on the available data and our modeling results, the authors propose the following approach as a rule of thumb: for persons 1-5 feet from the source, airborne asbestos concentrations can be roughly approximated at 50% of the source concentration; 35% at >5-10 feet, 10% for >10-30 feet, and less than 1% at distances greater than 30 feet. This approach should be helpful for bracketing the range of likely exposures to bystanders being evaluated in asbestos-related dose-reconstruction analyses. PMID- 20854014 TI - Improved cytotoxicity and multidrug resistance reversal of chitosan based polymeric micelles encapsulating oxaliplatin. AB - To overcome the side effects and drug resistance in cancer chemotherapy, oxaliplatin (OXA) was encapsulated in chitosan based polymeric micelles with glycolipid-like structure, which were formed by stearic acid-grafted chitosan oligosaccharide (CSO-SA). CSO-SA with 6.89% amino substituted degree was synthesized in this paper. The critical micelle concentration was about 0.12 mg/mL. CSO-SA micelles with the concentration of 1.0 mg/mL had 34.8 nm number average diameter and +50.8 mV surface potential in the aqueous medium. Thin-film dispersed method mediated by lecithin was chosen to prepare OXA-loaded CSO-SA micelles (CSO-SA/OXA), encapsulation efficiency of which could reach up to about 47%. In vitro anti-tumor activity of CSO-SA/OXA micelles against drug sensitive tumor cells and drug resistant cells was then examined. Using SGC-7901, SKOV3, BEL-7402, K562, and MCF-7 as model drug sensitive tumor cells, the 50% inhibition of cellular growth (IC(50)) of CSO-SA/OXA micelles could be lowered about 3-6 folds compared to that of free OXA solution. Furthermore, cytotoxicity test of CSO-SA/OXA micelles against MCF-7 and multidrug resistant MCF-7 (MCF-7/Adr) cells presented the reversal activity against MCF-7/Adr cells. The present micelles are a promising carrier candidate for platinum drug to improve the anti-tumor activity. PMID- 20854015 TI - Reiterative membranous proliferation with giant-cell deposits on hydrophobic acrylic intraocular lenses after triple procedures in eyes with cataracts and uveitis. AB - PURPOSE: To report 2 cases of reiterative membranous proliferation with giant cell deposits on hydrophobic acrylic intraocular lenses (IOLs) after a triple procedure of vitrectomy, phacoemulsification, and IOL implantation in uveitic eyes with cataracts and vitreous opacity. METHODS: A 72-year-old Japanese woman and a 67-year-old Japanese man underwent AcrySof IOL (SA60AT) implantation in their eyes (both eyes in the first case and the left eye in the second case) for the treatment of cataract and vitreous opacity with uveitis. Although intraocular inflammation seemed to be successfully controlled, the number of giant-cell deposits on the posterior surface of the posterior capsule was gradually increased with the development of posterior capsular opacification in 5 and 9 months, respectively, and neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy was required. RESULTS: After the treatment, Nd:YAG laser membranotomy (4 and 5 times) was required because of repeated membranous proliferation with giant-cell deposits occurring on the posterior surface of the IOL monthly, although postoperative intraocular inflammation seemed to be controlled. CONCLUSIONS: The possibility of development of this undesirable complication, which is believed to be limited in cases with hydrophobic acrylic IOL implantation, should be kept in mind. Also, Nd:YAG laser membranotomy for the proliferative membrane is an available option for recovery of vision. PMID- 20854016 TI - West Nile virus monitoring of migratory and resident birds in Germany. AB - West Nile virus (WNV) is a mosquito-borne flavivirus naturally circulating in wild bird populations. The virus is also capable to infect a broad range of vertebrate species. Humans and equines are highly susceptible and can develop mild flu-like illnesses as well as severe encephalitis leading to fatalities. Most recently, WNV was found to circulate in countries close to Germany, such as France, Czech Republic, Italy, Austria, and Hungary. Given this epidemiological situation its spread to Germany cannot be ruled out. As no data on the WNV situation were available for Germany for the most recent past, we have conducted a serological survey to reveal WNV antibodies in wild birds. More than 2700 blood samples from migratory and resident birds representing 72 species that were collected during 2005-2009 were tested using an immunofluorescence assay and partly by micro-virus neutralization test. By immunofluorescence assay WNV reactive antibodies could be demonstrated in 11 wild bird species. Similarly, WNV neutralizing antibodies were revealed in migratory birds belonging to 10 species, but not in resident birds. According to the absence of WNV-reactive antibodies in resident birds and the absence of WNV-specific RNA in all investigated bird samples, there is currently no evidence for a WNV circulation in Germany. PMID- 20854017 TI - Transcriptional upregulation of SOCS 1 and suppressors of cytokine signaling 3 mRNA in the absence of suppressors of cytokine signaling 2 mRNA after infection with West Nile virus or tick-borne encephalitis virus. AB - Suppressors of cytokine signaling (SOCS) proteins are a family of proteins that are able to act in a classic negative feedback loop to regulate cytokine signal transduction. The regulation of the immune response by SOCS proteins may contribute to persistent infection or even a fatal outcome. In this study, we have investigated the induction of SOCS 1-3 after peripheral infection with West Nile virus (WNV) or tick-borne encephalitis virus (TBEV) in the murine model. We have shown that the cytokine response after infection of mice with WNV or TBEV induces an upregulation in the brain of mRNA transcripts for SOCS 1 and SOCS 3, but not SOCS 2. We hypothesize that SOCS proteins may play a role in limiting cytokine responses in the brain as a neuroprotective mechanism, which may actually enhance the ability of neuroinvasive viruses such as WNV and TBEV to spread and cause disease. PMID- 20854018 TI - West Nile virus lineage 2 as a cause of zoonotic neurological disease in humans and horses in southern Africa. AB - West Nile virus (WNV) is widely distributed in South Africa, but since a few cases of neurological disease have been reported from this region, endemic lineage 2 strains were postulated to be of low virulence. Several cases of nonfatal encephalitis in humans as well as fatal cases in a foal, dog, and ostrich chicks have, however, been associated with lineage 2 WNV in South Africa. The pathogenesis of lineage 2 WNV strains was investigated using mouse neuroinvasive experiments, gene expression experiments, and genome sequence comparisons which indicated that lineage 2 strains that are highly pathogenic exist. To determine whether cases of WNV were being missed in South Africa, horses with fever and neurological disease were investigated. Several cases of WNV were identified, all associated with severe neurological disease, 85% of which had to be euthanized or died. All cases positive by RT-PCR were shown to belong to lineage 2 WNV by DNA sequencing and phylogenetic analysis. Two cases of occupational infection were investigated, including a case of zoonotic transmission to a veterinarian who performed an autopsy on one of the horses as well as a laboratory infection after a needle stick injury with a neuroinvasive lineage 2 strain. Both resulted in neurological disease. Cytokine expression was investigated in the second case to assess the immunopathogenesis of WNV. Collectively, these studies suggest that lineage 2 WNV may be significantly under estimated as a cause of neurological disease in South Africa. PMID- 20854019 TI - Assessment of a novel real-time pan-flavivirus RT-polymerase chain reaction. AB - Outbreaks of West Nile virus (WNV) have occurred intermittently in regions around the Mediterranean coast, and the virus may have become established in Northern Italy and Romania, with reported intermittent outbreaks in Spain, Hungary, and France. WNV has also spread rapidly throughout the Americas since its introduction into New York in 1999. This capacity to emerge in new geographical locations and to spread rapidly together with the current increase in incidence of other flaviviruses such as tick-borne encephalitis virus, dengue virus, and Usutu virus has prompted us to design a novel pan-flavivirus RT-polymerase chain reaction for the purpose of surveillance for a range of flaviviruses. The assay utilizes degenerate primers targeting the flavivirus NS5 gene (RNA-dependent RNA polymerase) and detects a range of flaviviruses, including WNV. A small panel of WNV bird samples obtained from the United States has been shown to be detected using this assay. The amplicon generated is of sufficient size to provide sequence data to confirm the identity of the virus detected and undertake limited phylogenetic analysis. Testing using this assay has shown its ability to detect a range of tick-borne flaviviruses, particularly louping ill virus that is endemic in areas of the United Kingdom. The assay has been used to survey 160 bird samples and 1000 mosquito samples from the United Kingdom and found no evidence for WNV. PMID- 20854020 TI - Mosquito surveys and West Nile virus screening in two different areas of southern Portugal, 2004-2007. AB - Longitudinal mosquito surveys were carried out in southern Portugal from 2004 to 2007, in a wetland area (Comporta, District of Setubal) and around the perimeter of a dam irrigation plant that created the largest artificial lake in Europe, 250 km(2) (Alqueva, Districts of Evora and Beja). Our aim was to study the diversity, abundance, and seasonal dynamics of mosquitoes, comparing these two different areas, to screen mosquitoes for West Nile Virus (WNV), an arboviral agent already detected in Portugal, because these areas are populated with abundant avian fauna. Monthly collections of adult mosquitoes were carried out by Centers for Disease Control light-traps with CO(2) and by indoor resting collections. Mosquitoes were identified and screened for arboviruses by reverse transcriptase (RT)-polymerase chain reaction directed toward amplification of a 217-bp fragment of the NS5 gene. Mosquito peak densities were observed in July-August in Comporta and May-June, with a plateau in July-October, in Alqueva. However, densities were far higher in Comporta area (220,821 specimens) than in Alqueva area (9442 specimens), with a clear difference in species distribution, as in Comporta the predominant species was Culex theileri (85%), followed by Aedes caspius (6%), Anopheles atroparvus (4%), and Culex pipiens sensu latu (s.l.) (3%), whereas in Alqueva the predominant species was Cx. pipiens s.l. (56%), followed by An. atroparvus (18%), Cx. theileri (14%), and Culiseta longiareolata (9%). Female mosquitoes (8842 in 175 pools) of the species Ae. caspius, An. atroparvus, Culex mimeticus, Cx. pipiens Sensu latu (s.l.), Cx. theileri, and Culex univittatus were screened and found to be negative for WNV genomic RNA. Although there was no detection of WNV sequences in mosquitoes, vigilance should continue as the circulation of virus has been previously detected more than once in Portugal, in humans, animals, and mosquitoes, and in other surrounding Mediterranean countries. PMID- 20854021 TI - Replication of Clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, in Aedes and Culex mosquitoes. AB - Rift Valley fever virus continues to cause large outbreaks of acute and febrile illness among humans and domestic animals in Africa. The high pathogenicity of the virus is mainly due to the non-structural protein derived from the S segment NSs, which was shown to inhibit the type I interferon expression at the transcriptional level and to suppress host cell RNA synthesis. Clone 13, a naturally attenuated clone containing a deletion of 70% in NSs, is a promising vaccine candidate as it has no pathogenicity for mice and is highly immunogenic leading to long-lasting immunity. If Clone 13 succeeds in inducing a transient viremia in inoculated animals, is a mosquito vector able to replicate Clone 13 and is the vector affected by viral infection? In this work, we orally infected two mosquito species, Aedes vexans and Culex pipiens quinquefasciatus, with the avirulent Clone 13. We showed that the mosquito Ae. vexans better replicated the avirulent Clone 13 than Cx. p. quinquefasciatus. Moreover, infection with Clone 13 did not cause any important changes in mosquito's life-history traits compared to noninfected females. Nevertheless, it is likely that Clone 13 would not be efficiently transmitted by mosquito vectors. PMID- 20854022 TI - Experimental infection of young adult European breed sheep with Rift Valley fever virus field isolates. AB - The increasing interest in Rift Valley fever virus (RVFV) and its potential impact on naive animal populations deserve revisiting experimental reproduction of RVFV infection, particularly in those animal breeds for which no data about their susceptibility to RVFV infection have ever been recorded. In this study we show the susceptibility of 9-10 weeks old European sheep (Ripollesa breed) to RVFV infection, showing a mild, subacute form of disease. Four different viral isolates efficiently replicated in vivo after subcutaneous experimental inoculation, and consistent viral loads in blood and virus shedding (variable in length depending on the RVFV isolate used) were detected, showing horizontal transmission to a noninfected, sentinel lamb. RVFV infection caused transient pyrexia in adult lambs and no other clinical symptoms were observed, with the exception of corneal opacity ("blue eye") found in 3 out of 16 subcutaneously inoculated sheep. In conclusion, adult sheep from this European breed are readily infected with RVFV without apparent clinical manifestations. PMID- 20854023 TI - Comparison of enzyme-linked immunosorbent assay-based techniques for the detection of antibody to Rift Valley fever virus in thermochemically inactivated sheep sera. AB - Different enzyme-linked immunosorbent assay (ELISA)-based techniques for the detection of antibodies to Rift Valley fever virus (RVFV) have been developed in recent years, but their diagnostic sensitivity was not directly compared. In addition, their use might still be restricted to high biocontainment facilities when sera to be tested are collected from viremic individuals. In this study, we report on direct comparison of various ELISA forms for the detection of anti-RVFV antibody in preinactivated sera using a simple thermochemical treatment. Results in naive and treated sera from experimentally infected sheep demonstrate that inactivation method used had no adverse effect on ELISA readings, but the assays analyzed differ in their ability to detect the early humoral responses to infection with RVFV. The IgM-capture ELISA was slightly more sensitive than the IgG-sandwich ELISA to detect early humoral response after infection. The indirect IgG ELISA, using Protein G Horseradish Peroxidase, was less sensitive in detecting seroconversion than the IgG-sandwich ELISA, but this problem was alleviated when using anti-sheep IgG conjugated with Horseradish Peroxidase. The high concentration of viral antigen in sheep sera collected shortly after infection might contribute to false-positive results in the inhibition ELISA, but its ability to detect seroconversion was comparable to that of IgM-capture ELISA. PMID- 20854024 TI - Virus-like particles expressing the nucleocapsid gene as an efficient vaccine against Rift Valley fever virus. AB - Rift Valley fever virus (RVFV), a member of the family Bunyaviridae, regularly accounts for large and severe outbreaks among humans and livestock in Africa and Arabia. Therefore, safe and efficient vaccines are highly needed. Here, we report the production of recombinant virus-like particles (VLPs) that, in addition to their similarity to RVFV particles, are able to express the viral nucleocapsid (N) gene. A single inoculation of 1 * 10(6) of these N-VLPs was sufficient to protect 100% of mice from infection with a lethal dose of 1 * 10(5) PFU of RVFV. Our study demonstrates that N-VLPs can be considered as a safe and efficient vaccine against the emerging pathogen RVFV, and that VLPs that actively produce a viral antigen may be considered a strategy to improve the immunogenicity of VLPs in general. PMID- 20854025 TI - Geographical distribution and surveillance of Crimean-Congo hemorrhagic fever in Iran. AB - Crimean-Congo hemorrhagic fever (CCHF) is viral hemorrhagic fever caused by CCHF virus, which belongs to the family Bunyaviridae and the genus Nairovirus. The virus is transmitted to humans via contact with blood and tissue from infected livestock, a tick bite, or contact with an infected person. Since 2000, we have shown the disease to be prevalent in 23 out of 30 provinces of Iran. Among those, Sistan-va-Baluchistan, Isfahan, Fars, Tehran, Khorasan, and Khuzestan demonstrated the highest infection, respectively. Notably, Sistan-va-Baluchistan province, southeast of Iran, has the highest prevalence of CCHF, and has shown to be present since at least 2000. Phylogenetic study of the CCHF virus genome isolated from Iranian patients showed a close relationship with the CCHF Matin strain (Pakistan). Our epidemiological data in the last decade have implied that the severity and fatality rate of the disease has ranged variably in different provinces of Iran. More pathogenesis and phylogenetic studies should therefore be investigated to clarify these differences. PMID- 20854026 TI - Interventions against West Nile virus, Rift Valley fever virus, and Crimean-Congo hemorrhagic fever virus: where are we? AB - ARBO-ZOONET is an international network financed by the European Commission's seventh framework program. The major goal of this initiative is capacity building for the control of emerging viral vector-borne zoonotic diseases, with a clear focus on West Nile virus, Rift Valley fever virus, and Crimean-Congo hemorrhagic fever virus. To evaluate the status quo of control measures against these viruses, an ARBO-ZOONET meeting was held in Istanbul, Turkey, from 19 to 20 November 2009. The symposium consisted of three themes: (1) vaccines: new and existing ones; (2) antivirals: existing and new developments; and (3) antivector vaccines. In addition, a satellite workshop was held on epidemiology and diagnosis. The meeting brought together foremost international experts on the subjects from both within and without the ARBO-ZOONET consortium. This report highlights selected results from these presentations and major conclusions that emanated from the discussions held. PMID- 20854027 TI - Interview with Dr. Anthony R. Fooks. Interview by Vicki Glaser. PMID- 20854028 TI - Insights into severe asthma control as assessed by guidelines, pulmonologist, patient, and partner. AB - INTRODUCTION: The most recent guidelines on asthma management advocate a treatment strategy based on control of the disease rather than severity, a switch based on reported evidence. AIMS: This observational, questionnaire-based study set out to investigate how control of the disease is assessed by the physician as well as the patient and his/her live-in partner and to compare these assessments with an assessment made according to the guidelines. METHODS: In 169 patients with severe, persistent asthma on at least a high-dose inhaled corticosteroid plus an inhaled long-acting beta2-agonist, control of the disease was assessed by the pulmonologist, the patient, and the patient's live-in partner. These assessments were compared with an assessment based on the guidelines. Results. Both patients and partners tended to judge disease control as better than their pulmonologists who, in turn, estimated control as acceptable in 58% of their patients in whom the guidelines would advocate more aggressive treatment. The most common guidelines criteria defining inadequate control in the "uncontrolled" 87.4% of this population were "limitation of physical activity" (72.3%) and "FEV1" <= 85% of personal best" (63.3%). CONCLUSIONS: To assess control in severe asthma, the patient's opinion is of limited value, as is that of their partners. Although a guidelines-based strategy has been shown to be effective in clinical trials conducted on large-scale populations in which mild or moderate disease is predominant, more aggressive treatment to achieve definitive control may not be appropriate in the 10% of asthma sufferers with severe disease; in everyday practice, lung specialists appear to implement such a strategy. PMID- 20854029 TI - An unusual cause of dyspnea. AB - BACKGROUND: Right-sided arcus aorta (RSAA) is a rare condition and usually asymptomatic. However, it may be symptomatic if it causes tracheal or esophageal compression. METHODS: The authors evaluated clinical and radiological features of seven patients with RSAA who had the diagnosis between May 2006 and May 2009. RESULTS: The authors found that the incidence of RSAA was 0.16% in patients who had applied to their clinic. The age of patients ranged from 17 to 55 years. The male to female ratio was 6/1. Four patients were symptomatic due to RSAA. Most common symptoms were dyspnea during exercise, which is similar to exercise induced asthma and dysphagia. Two patients were misdiagnosed as asthma. The flow volume curves on spirometry of the patients showed intrathoracic upper airway obstruction. Thorax magnetic resonance imaging (MRI) revealed marked narrowing of the tracheal air column due to external compression of RSAA in three patients. CONCLUSIONS: RSAA should be included in the differential diagnosis of asthma. Spirometry may help to suspect RSAA. Thorax computed tomography (CT) and/or MRI are the best imaging methods for the diagnosis of RSAA. PMID- 20854033 TI - Perinatal depression in men. PMID- 20854030 TI - Bronchial reactivity to histamine is correlated with airway remodeling in adults with moderate to severe asthma. AB - BACKGROUND: Chronic eosinophilic inflammation may promote airway remodeling, including thickening of the reticular basement membrane (RBM), hypertrophy and hyperplasia of the airway smooth muscles (ASM), and an increase in the production of tenascin. The authors examined the correlation between airway remodeling and bronchial reactivity to histamine (Hist) and acetylcholine (ACh) in patients with moderate to severe asthma. METHODS: In 30 adult patients with asthma, the authors assessed bronchial hyperresponsiveness (BHR) to various concentrations of ACh and Hist by measuring decreases in forced expiratory volume in one second (FEV1) of >20% from the preprovocation state, and % recoveries of FEV1 after inhalation of beta-stimulant. After corticosteroid therapy, the authors evaluated the thickening of RBM and ASM and the production of tenascin in bronchial specimens. RESULTS: The % decrease in FEV1 was correlated with the % recovery in FEV1 after provocation by ACh or Hist. Hypertrophy of ASM was correlated with the % decrease in FEV1 after provocation by Hist, but not by ACh. Thickening of ASM, up regulation of tenascin in RBM, and duration of asthma were inversely correlated with the % recovery of FEV1 after provocation by Hist, but not by ACh. CONCLUSIONS: In adult patients with moderate to severe asthma, a strong bronchial contraction provoked by Hist and a subsequent small recovery indicate airway remodeling. PMID- 20854035 TI - Use of genomic assessments and interventions in psychiatric nursing practice. AB - The purpose of this study was to determine the impact of a genomic educational session by measuring participants' application of the class content to their nursing care. A sample of 65 psychiatric nurses participated in a staff development activity and completed a survey. Every respondent reported use of a genomic assessment or intervention with a patient from their clinical practice. The mean use of genomic assessment and intervention items was 5.5 out of the possible 10 which were identified and described in the educational session, providing evidence that nurses are able to include genomic assessments and interventions when caring for a patient with a psychiatric disorder. PMID- 20854036 TI - Systematic review of psychosocial benefits and harms of genetic testing. AB - Genetic testing can help individuals and families by giving them a sense of control over their futures; however, results of some types of testing cause individuals and their families great distress and anxiety. The purpose of this paper is to report findings from a systematic review of literature about perceived benefits and harms associated with genetic testing. A second purpose was to determine if perceived benefits and harms varied by age and gender. We reviewed a sample of 30 articles published between 1997 and 2009. Most of the articles were other literature reviews. We summarized the benefits and harms associated with each type of genetic testing and made recommendations for future study. As technologies increase, genetic testing will expand and psychiatric mental health nurses must be prepared to meet the challenges of psychosocial disorders that may develop in response to genetic testing. PMID- 20854037 TI - The Mental Health Nurse Incentive Program: the benefits from a client perspective. AB - It is now acknowledged that a substantial proportion of the Australian population will experience a mental health condition at some time during their lives. Only a small proportion will access care and treatment for these conditions, and those who do are more likely to access general medical practitioners than specialist mental health providers. The Mental Health Nurse Incentive Program (MHNIP) was introduced by the Commonwealth Government to enhance access to mental health care by engaging mental health nurses in collaboration with general practitioners and private psychiatrists. The aim of the current study was to explore the experiences and opinions of clients utilising these services. A qualitative exploratory approach involving in-depth semi-structured interviews was utilised to enhance understanding of the client perspective. Interviews were conducted with 14 clients. Data were analysed using NVivo to assist with the identification of major themes. The findings revealed the major themes to be: initial reactions; a comfortable setting; flexibility; holistic care; and affordable care. These findings suggest that clients perceive the MHNIP as a valuable intervention that met the mental health needs of clients to a greater extent than had previously been possible. PMID- 20854038 TI - Psychiatric hospital nursing staff's experiences of participating in group-based clinical supervision: an interview study. AB - Group-based clinical supervision is commonly offered as a stress-reducing intervention in psychiatric settings, but nurses often feel ambivalent about participating. This study aimed at exploring psychiatric nurses' experiences of participating in group-based supervision and identifying psychosocial reasons for their ambivalence. Semi-structured interviews were conducted with 22 psychiatric nurses at a Danish university hospital. The results indicated that participation in clinical supervision was difficult for the nurses because of an uncomfortable exposure to the professional community. The sense of exposure was caused by the particular interactional organisation during the sessions, which brought to light pre-existing but covert conflicts among the nurses. PMID- 20854039 TI - Mental health treatment fearfulness and help-seeking. AB - A majority of people meeting the criteria for mental disorders underutilize mental health services. Treatment fearfulness is a barrier to help-seeking. This study explores the way treatment fearfulness affects the help-seeking behaviour of individuals who sought help from the Community Mental Health Centre. A total of 290 participants completed a structured questionnaire. Information was obtained on a number of variables, including orientation toward utilization of social networks, attitudes toward seeking professional psychological help, opinions about psychiatry, and fears about therapy. Factor analysis was conducted on the scale, measuring fears about therapy. Those with fewer fears about therapy have more positive network orientation, more positive attitudes toward seeking professional psychological help, and more positive opinions about psychiatry so it is more possible for those individuals to visit a mental health service sooner than those with more fears. Reducing the delays in individuals initiating treatment requires clearer understanding of the contributing factors. PMID- 20854040 TI - Adults with ADHD: who are we missing? AB - Attention deficit hyperactivity disorder (ADHD) has long been identified as a common disorder of childhood. There is increasing recognition that adults also are affected by this disorder. Many adults, however, are often undiagnosed or misdiagnosed until their child is diagnosed with the disorder. Improved recognition and treatment for parental ADHD needs to occur given the genetic and environmental etiologies of the disorder. This paper examines three areas where there is a dearth of data in extant literature: parental ADHD culture and ethnicity; parenting and undiagnosed ADHD; and professional care and ADHD, and focuses on parents from ethnic minority cultures. PMID- 20854041 TI - Childhood experiences of incarcerated male child sexual abusers. AB - While numerous efforts have been made to understand the impact of child sexual abuse, little has been done to examine the childhood experiences of those who abuse children. Child sexual abusers have been studied from quantitative perspectives using behavioral checklists, parental-bonding surveys, and sexual history questionnaires. The purpose of this study was to explore incarcerated child sexual abusers' recollections of their childhood experiences using the descriptive existential lens of phenomenology. Eight incarcerated male child sexual abusers described their childhood from existential perspectives of lived space, lived other, lived body, and lived time via face-to-face semi-structured interviews. Analysis was accomplished through the qualitative, descriptive method of Max van Manen. Rich descriptions of the participants' insights into their daily childhood life experiences that shaped their self-concepts and contributed to their adult behaviors were gathered. Four major themes were identified: (1) failure to root, (2) what you see is what you learn, (3) stupid is as stupid does, and (4) life's moments. Data from this study suggest that the experiences of childhood significantly contribute to an adult self-concept that can be distorted by the lack of a secure home space, maladaptive relationships, internalization of inappropriate behavior, and a lack of significant family development. This study explores the psychosocial and behavioral consequences of early childhood experiences. The findings support the need for family and psychological mental health nurse practitioners to be more aware of early home environments; improve their assessment of children's developing self-concept and the potential for abusive relationships. PMID- 20854042 TI - DSM proposed changes, Part I: criticisms and influences on changes. PMID- 20854044 TI - Searching for COPD: are questionnaires the answer? PMID- 20854045 TI - Improving quality of life in depressed COPD patients: effectiveness of a minimal psychological intervention. AB - Depression and anxiety are highly prevalent in elderly COPD patients. Since symptoms of depression and anxiety reduce quality of life in these patients, treatments aimed at improving mental health may improve their quality of life. This study evaluated the effectiveness of a nurse-led Minimal Psychological Intervention (MPI) in reducing depression and anxiety, and improving disease specific quality of life in elderly COPD patients. In a randomized controlled trial an MPI was compared with usual care in COPD patients. COPD patients aged 60 years or over, and with minor or mild to moderate major depression were recruited in primary care (n = 187). The intervention was based on principles of cognitive behavioural therapy (CBT) and self-management. Outcomes were symptoms of depression, symptoms of anxiety, and disease-specific quality of life, assessed at baseline and at one week and three and nine months after the intervention. Results showed that patients receiving the MPI had significantly fewer depressive symptoms (mean BDI difference 2.92, p = 0.04) and fewer symptoms of anxiety (mean SCL difference 3.69, p = 0.003) at nine months than patients receiving usual care. Further, mean SGRQ scores were significantly more favourable in the intervention group than in the control group after nine months (mean SGRQ difference 7.94, p = 0.004). To conclude, our nurse-led MPI reduced symptoms of depression and anxiety and improved disease-specific quality of life in elderly COPD patients. The MPI appears to be a valuable addition to existing disease management programmes for COPD patients. PMID- 20854046 TI - Significant bronchodilator responsiveness and "reversibility" in a population sample. AB - Chronic Obstructive Pulmonary Disease (COPD) is defined by being "not fully reversible", most guidelines recommend measurement of lung function after the administration of a bronchodilator. The objective of this study was to compare bronchodilator responsiveness (significant improvement in the FEV(1) or FVC) to full-, partial- or "inverse'" reversibility in obstruction status in a population based sample in Southeastern Kentucky. The study population was selected using random digit dialing of an adult population in Southeastern Kentucky as part of the Burden of Lung disease (BOLD) project. Lung function was assessed using spirometry pre- and post-bronchodilation. Subjects presence and severity of COPD was classified using modified Global Obstructive Lung Disease (GOLD) criteria. We examined the relation between changes in "obstruction" status (based on the FEV(1)/ FVC of 0.7) and the presence of "significant bronchodilator responsiveness" (based on >= 12% improvement in the FEV(1) or the FVC). The final population with acceptable pre- and post-bronchodilator spirometry included 440 participants. 32/440 subjects (7.3%) changed from obstructed to unobstructed (full-reversibility), 19/440 (4.3%) changed from unobstructed to obstructed ("inverse"-reversibility), 389/440 (88.4%) had either no-change or partial reversibility, and 65/440 (14.8%) had bronchodilator responsiveness. Among those with full-reversibility, only 9/32 (28.1%) had bronchodilator responsiveness, whereas among subjects with "inverse"-reversibility, 10/19 (52.6%) had bronchodilator responsiveness. Among all subjects with bronchodilator responsiveness, only 19/65 (29.2%) changed categories. Our findings suggest that significant bronchodilator responsiveness is not the same as "reversibility" of "obstruction", even though these terms are often used interchangeably. PMID- 20854047 TI - Onset of effect of aclidinium, a novel, long-acting muscarinic antagonist, in patients with COPD. AB - ABSTRACT Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). The aim of this study was to assess the rate of onset of bronchodilation with aclidinium compared with placebo and tiotropium. This was a double-blind, double-dummy, multicenter, crossover study in COPD patients with a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) >=30% and <60% predicted. On study days, patients received single doses of aclidinium 200 MUg, tiotropium 18 MUg, or placebo. Serial spirometry was conducted from 10 minutes to 3 hours post-dose. The primary variable was the percentage of patients with an increase in FEV(1) of >=10% above baseline at 30 minutes post-dose. Other assessments included change from baseline in FEV(1) and dyspnea over 3 hours post dose. A total of 115 patients entered the study. Significantly more patients had an increase in FEV(1) of >=10% above baseline at 30 minutes with aclidinium and tiotropium versus placebo (49.5% and 51.8% versus 13.8%; p < 0.0001). At 30 minutes, the relative increase from baseline in FEV(1) was significantly higher for aclidinium and tiotropium versus placebo (12% and 11% versus 3%; p < 0.0001). Aclidinium and tiotropium also significantly increased FEV(1) (p < 0.01) and improved the perception of dyspnea compared with placebo at all measured time points from 10 minutes to 3 hours post-dose. In conclusion, aclidinium provided effective bronchodilation, similar to that seen with tiotropium, with significant improvements compared with placebo observed from 10 minutes post-dose. PMID- 20854048 TI - Antibiotic resistance in sputum isolates of Streptococcus pneumoniae in chronic obstructive pulmonary disease is related to antibiotic exposure. AB - Streptococcus pneumoniae (S. pneumoniae) is recovered from sputum of patients with chronic obstructive pulmonary disease (COPD) during stable disease and exacerbations. In patients with community acquired pneumonia, antibiotic exposure in the prior 3-6 months is associated with recovery of antibiotic resistant isolates of S. pneumoniae. Whether the same relationship is seen in COPD is not known. From April 1994 to June 2004, 127 adults with COPD were enrolled in a prospective longitudinal study. Sputum isolates of S. pneumoniae were characterized with susceptibility testing and pulsed-field gel electrophoresis (PFGE). The relationship between antibiotic use in the previous 3 and 6 months with either new acquisition of a resistant pneumococcal isolate or development of resistance (4-fold increase in MIC) in a pre-existing colonizing pneumococcal strain was determined. A total of 194 pneumococcal isolates were recovered from 38 patients. Among 71 newly acquired and 4 resistance-emergent strains analyzed further, rates of resistance to penicillin (MIC >=2), erythromycin (MIC >=1), tetracycline (MIC >=8) and trimethoprim/sulfamethoxazole (MIC >=4) were 8%, 24%, 17% and 16% respectively. Flouroquinolone resistance was not seen. Among strains isolated from patients exposed to a macrolide within 6 months, 53.6% displayed erythromycin resistance vs. 14% of strains without such exposure (p = 0.00085). Similar associations were not seen for other antibiotics. Macrolide use in the previous 6 months is associated with macrolide resistance in sputum isolates of S. pneumoniae. Recent antibiotic exposure may help in determining appropriate antibiotic treatment in these patients. PMID- 20854049 TI - Modification of COPD presentation during the last 25 years. AB - During the last decades progress has been made in the treatment of Chronic Obstructive Pulmonary Disease (COPD). We compared a random sample of patients admitted for an exacerbation in the period 2001-2005 (n = 101), with a random sample of patients hospitalized for the same reason in the period 1980-1984 (n = 51). Patients of the 2001-2005 cohort had a lower FEV1 (48 +/- 3 vs. 41 +/- 2% predicted, p = 0.01) for similar mean age, gender and body- mass index when compared to the historical sample. Co-morbidities, according to the Charlson's index, were more prevalent in the 2001-2005 cohort compared to the 1980-1984 cohort, with a reduction of hemoglobin (13.9 +/- 0.2 gr/dl vs. 14.9 +/- 0.2, p < 0.01) and higher prevalence of anemia in the most recent cohort. We found an increase in the use of cardiovascular drugs and respiratory medications over time with exception for the long-term use of oxygen. Despite lower FEV1 and more prevalent co-morbidities, no difference in length of hospitalization (13.6 +/- 1.4 days vs. 12.7 +/- 0.7 days, p = 0.52) and 30 months survival post exacerbation was noted (66.6% vs. 69.3%, p = 0.85). Over the course of 20 years, the presentation of COPD patients admitted for an exacerbation seems to be changed towards a more severe phenotype with lower FEV1 and more co-morbidities. As the length of hospitalization and the overall survival were not different between the two samples, a currently improved management of COPD can be hypothesized. PMID- 20854050 TI - COPD screening in general practice using a telephone questionnaire. AB - Chronic obstructive pulmonary disease (COPD) is a growing health problem, and an underestimated and underdiagnosed disease in primary care. The aim of this survey was to study the feasibility of detecting undiagnosed COPD patients in the general practice population with the aid of a telephone questionnaire. The study was held in 2 general practices in the Netherlands. During 2 weeks, all patients registered with these 2 practices and aged between 40 and 75 years were contacted through a call center. Persons known with a previous history or diagnosis of COPD or asthma or comorbidity were excluded from the telephone list. The telephone interview used the Respiratory Health Screening Questionnaire (DB Price, 2006). Based on the score on this instrument, respondents were classified as having a low, moderate or high risk of having COPD. Smoking behaviour and BMI were also recorded. Patients with medium and high risk for COPD were invited for spirometry, performed by 2 experienced registered nurses. The results of the telephone interview and spirometric findings were assessed by the attending GP, who established the final diagnosis. The call center reached 1032 persons, 813 of whom answered the questions. The percentage of smokers was 49.2%, with an average number of pack-years of 17.9 (SD = 17); mean BMI was 26.1. Spirometry and analysis by the GP showed that 15.7% of the medium-risk group had previously undiagnosed COPD, versus 39.6% of the high-risk group. The number of undiagnosed COPD patients in the general practice population is considerable. Case finding can focus on moderate- and high-risk groups after telephone risk assessment. PMID- 20854051 TI - UK National COPD Resources and Outcomes Project (NCROP): 2008 National audit data presents an opportunity to highlight the areas for improvement in COPD care in the ageing population. PMID- 20854052 TI - Asthma and COPD in alpha-1 antitrypsin deficiency. Evidence for the Dutch hypothesis. AB - This review summarizes the current information on the relationship between severe alpha-1 antitrypsin deficiency (AATD), asthma and COPD. AATD is a genetic predisposition to the development of early COPD in susceptible individuals and reduction in known factors that enhance lung function loss is the paramount aim of management. Asthma is one controllable condition that leads to the accelerated decline in lung function. Current literature indicates that asthma signs and symptoms are common in those AATD with or without COPD and that bronchodilator response is a risk factor for FEV(1) decline. Furthermore AATD itself predisposes to airway hyper responsiveness, an essential ingredient for reversible airflow obstruction. In the absence of well-characterized markers to distinguish COPD from asthma, clinical diagnosis leads to a delay in the recognition that asthma symptoms such as wheezing can be an early manifestation of COPD in AATD. In addition failure to appreciate asthma overlap in AATD may lead to inadequate suppression of airway inflammation leading to the development of airflow obstruction. The implications of this are discussed as are potential approaches and recommendations for treatment. PMID- 20854053 TI - Mortality in COPD: causes, risk factors, and prevention. AB - Chronic obstructive pulmonary disease (COPD) is a leading and increasing cause of death, the extent of which is underestimated as a consequence of underdiagnosis and underreporting on death certificates. Data from large trials, such as the Lung Health Study, Towards a Revolution in COPD Health (TORCH), Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT), European Respiratory Society Study on Chronic Obstructive Pulmonary Disease (EUROSCOP), and Inhaled Steroids in Obstructive Lung Disease (ISOLDE), have shown that the causes of death in patients with mild COPD are predominantly cancer and cardiovascular disease, but as COPD severity increases, deaths due to non malignant respiratory disease are increasingly common. In practice, mortality of patients with COPD can be predicted by a variety of measures including: forced expiratory volume in one second (FEV(1)), the ratio of inspiratory and total lung capacities, exercise capacity, dyspnea scores, and composite indices such as the body-mass index (B), degree of airflow obstruction (O), degree of functional dyspnea (D), and exercise capacity (E) (BODE) index. Smoking cessation improves survival in COPD patients, and in select patients with advanced disease, oxygen therapy, lung volume reduction surgery, or lung transplantation may also improve survival. PMID- 20854054 TI - The COPD pipeline VI. PMID- 20854056 TI - Metabolic syndrome and physical fitness in a sample of Azorean adolescents. AB - BACKGROUND: Metabolic syndrome, a predecessor of cardiovascular disease and type 2 diabetes, has become prevalent in adolescents. This study aimed to estimate the prevalence of metabolic syndrome and its components and to analyze the relationship between metabolic syndrome and overall physical fitness levels in a sample of Azorean adolescents. METHODS: A cross-sectional school-based study, the Azorean Physical Activity and Health Study II, was conducted on 517 adolescents (297 girls, 220 boys) aged 15-18 years old from the Azorean Islands. Body height, weight, waist circumference, and arterial blood pressure were measured according to standards. Fasting intravenous blood samples were analyzed (high-density lipoprotein cholesterol, triglycerides, and glucose). Physical fitness was assessed using five tests from Fitnessgram Test Battery 8.0: Curl-up, push-up, trunk lift, pacer, and sit-and-reach. Adolescents were then classified as being in the healthy zone or above or under the healthy zone. Metabolic syndrome was defined according to the 2007 International Diabetes Federation's guidelines for adolescents. RESULTS: The prevalence of metabolic syndrome was 5% (4.7% in girls and 5.5% in boys, P > 0.05). Waist circumference was the most prevalent component (32.9%), and hypertriglyceridemia the least (4.4%). Logistic regression analysis showed that after adjusting for pubertal stage and socioeconomic status, unfit adolescents (healthy zone criteria in 80 and presence of Bcl-6 expression showed independent significant association with favourable patient outcome. CONCLUSIONS: PCNSL represents a histologically and immunophenotypically very homogeneous lymphoma type, probably derived from germinal centre exit B cells. The frequent overexpression of FOXP1 appears not to be related to FOXP1 gene rearrangement. Survival analyses disclosed Bcl-6 expression and high Karnofsky performance score as independent prognostic parameters associated with favourable outcome. PMID- 20854074 TI - Opposite expression patterns of Sonic hedgehog and Indian hedgehog are associated with aberrant methylation status of their promoters in colorectal cancers. AB - AIMS: Activation of the Hedgehog (Hh) signalling pathway in colorectal cancers (CRCs) is controversial, and its regulation mechanism remains to be elucidated. In the present study we attempted to clarify the regulatory mechanism of the expression of Hh ligands during colorectal carcinogenesis. METHODS: Reverse transcriptase polymerase chain reaction and immunohistochemistry were used to characterise expressions of the SHH, IHH and GLI1 genes in 36 CRCs, and the findings compared to 21 hyperplastic polyps and 32 colorectal adenomas. In addition, the methylation status of the SHH and IHH promoters in these samples were investigated. RESULTS: Expressions of SHH and GLI1 proteins were increased significantly in CRCs compared with those in hyperplastic polyps and colorectal adenomas (p<0.01 for both). In contrast, IHH was almost lost in both colorectal adenomas and CRCs. Furthermore, DNA methylation analysis revealed that the frequency of SHH methylation in CRCs (20.6%) was significantly lower than that in colorectal adenomas (72.4%, p<0.001) and hyperplastic polyps (64.7%, p = 0.002). IHH promoter methylation was frequently observed in colorectal adenomas (55.2%, p = 0.004) and CRCs (70.6%, p<0.001) compared with that in hyperplastic polyps (11.8%). CONCLUSION: SHH hypomethylation could lead to the SHH dependent activation of Hh pathway in CRCs. On the other hand, down-regulation of IHH expression as a result of hypermethylation, may be an early event in colorectal carcinogenesis. PMID- 20854075 TI - The presence of a micropapillary component predicts aggressive behaviour in early and advanced gastric adenocarcinomas. AB - AIMS: A micropapillary component (MC) consists of small tight clusters of tumour cells surrounded by clear spaces resembling lymphatic tumour emboli. Carcinoma with a MC has recently been described as a highly aggressive variant. However, little is known about the clinicopathological significance of the MC in gastric adenocarcinoma. METHODS: We investigated the clinicopathological characteristics of gastric adenocarcinoma with a MC and compared them with those of conventional gastric adenocarcinoma. RESULTS: Among 172 cases, 23 (13.4%) cases had a MC. The amount of micropapillary growth pattern in entire tumour areas ranged from 10% to 80%. The presence of a MC in gastric adenocarcinoma was significantly associated with the depth of invasion, lymph node metastasis, lymphovascular invasion, perineural invasion, higher clinical stages, and poor overall survival rates, but not with age, gender, tumour size, location, and Lauren histological types. The MC was present in four (4.7%) of 86 early gastric cancers and all but one of the early gastric cancers with a MC showed lymph node metastasis (p = 0.02). CONCLUSIONS: Recognition of a MC in early and advanced gastric adenocarcinomas is very important as it can predict cancer invasion and metastasis leading to a poor clinical outcome. PMID- 20854076 TI - Tranilast modulates fibrosis, epithelial-mesenchymal transition and peritubular capillary injury in unilateral ureteral obstruction rats. AB - AIM: Tranilast is an anti-allergic compound suppressing transforming growth factor-beta 1 (TGF-beta1) induced fibrosis. This study evaluated the efficacy of tranilast to attenuate renal fibrosis induced by unilateral ureteral obstruction (UUO) in rats in relation to epithelial-mesenchymal transition (EMT) and peritubular capillary injury. METHODS: Rats were divided into four groups: UUO with vehicle or tranilast and sham operation with vehicle or tranilast. Tranilast (400 mg/kg/day) was administrated to rats for 7 and 14 days after UUO. RESULTS: Fibrosis and tubular injuries were attenuated in UUO kidneys with tranilast (Tr UUO kidneys) compared with UUO kidneys with vehicle (V-UUO kidneys). Decreased E cadherin and increased vimentin expression in the tubular epithelium and Snail expression in V-UUO kidneys were also attenuated in Tr-UUO kidneys in which heparan sulfate proteoglycan in the tubular basement membrane was preserved and matrix metalloproteinase-2 expression was attenuated. Increased TGF-beta1 and phospho-Smad2 expression and increased numbers of myofibroblasts and macrophages in V-UUO kidneys were attenuated by tranilast. Decreased VE-cadherin expression and cytoplasmic swelling of the endothelium of peritubular capillaries that occurred in V-UUO kidneys was prevented by tranilast. CONCLUSIONS: Tranilast modulates fibrogenesis by reducing EMT, preventing disintegration of the tubular basement membrane, and reducing peritubular capillary injury in UUO kidneys. PMID- 20854077 TI - False-positive intercellular cement substance antibodies due to group A/B red cell antibodies: frequency and approach. AB - AIM: Antibodies to the intercellular cement substance of skin (ICSA) are characteristic of pemphigus vulgaris, and are commonly detected by indirect immunofluorescence (IIF). However, false-positive staining may arise when blood group antibodies, directed against A and B red cell antigens, bind to epitopes of similar distribution in the substrate. We sought to determine the frequency of such false-positive ICSA staining and to establish optimal conditions for its elimination. METHODS: IIF was performed on 100 de-identified routine serum samples of known blood group (A, B or O), along with serum from four pemphigus patients. Blocking was performed on samples which displayed typical ICSA staining using either a mixture of soluble A and B antigens in solution ('soluble A/B antigens'), or red blood cells from a group AB donor ('AB-RBCs'). RESULTS: ICSA staining was detected in 12 of 100 (12%) routine samples at a titre of between 1:10 and 1:160, and was most frequent in (but not restricted to) samples of blood group O (10/54, 19%). Blocking with soluble A/B antigens eliminated staining in 10 of 12 (83%) samples, whilst blocking with AB-RBCs eliminated staining in 11 of 12 (92%); one sample failed to block using either method, suggesting true ICSA reactivity. Blocking had no effect on the positive pemphigus samples, the titres of which were significantly higher (1:160 to 1:640). CONCLUSIONS: Staining of the intercellular cement substance arising from group A/B red cell antibodies is common, particularly but not exclusively in patients of blood group O, making blocking mandatory in the routine evaluation of samples with such staining, particularly in a hospital-based population. Blocking using either soluble A/B antigens or AB-RBCs appears to be of comparable efficacy, although the former method is more convenient for a diagnostic laboratory. PMID- 20854078 TI - Detection of human cytomegalovirus IgG antibody using automated immunoassay with recombinant antigens gives uniform results to established assays using whole virus antigens. AB - AIM: Serological testing for human cytomegalovirus (CMV) immunoglobulin G (IgG) continues to play a major role in the evaluation of tissue and organ transplant donors and recipients, screening blood donors and in estimating the risk of infection in pregnant women. In this study we evaluated the performance and technical characteristics of two semi-automated commercial CMV IgG immunoassays. METHODS: One hundred consecutive sera submitted to a referral serology laboratory for CMV IgG antibody testing were assayed using two automated CMV IgG immunoassays: the Architect (Abbott Diagnostics) and Elecsys (Roche Diagnostics) immunoassays. Because this patient population has a high rate (~87%) of seropostivity, we took a further 50 sera that were CMV IgG negative on Architect and tested on the Elecsys assay, in order to assess the specificity of the assays. RESULTS: The assays showed an excellent qualitative agreement with two (2%) discrepant results in the 100 patients tested initially, with all of the 50 additional sera negative on Architect also negative on the Elecsys. However, there was no correlation between the optical density of results generated by the instruments for the set of samples. CONCLUSION: Both Elecsys and Architect immunoassays are convenient for detection of CMV IgG antibody, with near identical qualitative results. PMID- 20854079 TI - Plexiform angiomyxoid myofibroblastic tumour of the stomach: a case report. PMID- 20854080 TI - Frameshift mutations of ATBF1, WNT9A, CYLD and PARK2 in gastric and colorectal carcinomas with high microsatellite instability. PMID- 20854081 TI - Chondroid metaplasia of the peritoneum. PMID- 20854082 TI - Oncocytic meningioma: study of eight new cases and analysis of 13 reported cases. PMID- 20854083 TI - Mixed corticomedullary tumour with myelolipoma: a rare coexistence. PMID- 20854084 TI - Epithelioid angiomyolipoma with skeletal and pulmonary metastasis on 8 year follow-up. PMID- 20854085 TI - Malignant glomus tumour of the lung. PMID- 20854086 TI - Cellular non-specific interstitial pneumonia as a pulmonary manifestation of primary biliary cirrhosis. PMID- 20854087 TI - Biclonal follicular lymphoma: histological, clinical and molecular characteristics. PMID- 20854088 TI - Balloon cell neurofibroma. PMID- 20854089 TI - Inflammatory melanoma: a potential diagnostic pitfall. PMID- 20854090 TI - Tissue reaction to cosmetic fillers. PMID- 20854091 TI - Robust variables in texture analysis. PMID- 20854093 TI - One-hour postload plasma glucose levels, a predictor of additional risk for diabetes: prevalence, mechanisms, and associated cardiovascular and metabolic risk factors in Hispanics. AB - OBJECTIVE: The aim of this study was to determine the prevalence of and the mechanisms by which elevated glucose concentrations at 1-h after a glucose load, conferred increased risk for type 2 diabetes mellitus (T2DM). The study was conducted in subjects with glucose abnormalities (impaired fasting glucose [IFG], and impaired glucose tolerance [IGT]), as well as in normal fasting-normal tolerant subjects (NFG-NGT). METHOD: One-hour plasma glucose concentrations were measured as part of 0- to 180-min oral glucose tolerance test (OGTT) performed in an unselected sample of 490 Latino-Hispanics. A cutoff of 154 mg/dL at 1-h during the OGTT was employed, because higher glucose levels define subjects at increased risk for T2DM. Surrogate markers of insulin sensitivity and release, and glucose and insulin time courses were measured. Obesity, cardiovascular risk factors, and presence of metabolic syndrome were also assessed. RESULTS: One-hour plasma glucose concentrations above the cutoff (>= 155 mg/dL) were found in 8.3% of NFG NGT, 43% of IFG, 65% of IGT, and in 90% of IFG + IGT, and were associated with greater postload hyperglycemia (AUCG) and hyperinsulinemia (AUCI), and with reductions in indices of beta-cell function (Delta I 0-30/Delta G 0-30 and Delta I 0-180/Delta G 0-180), insulin sensitivity [Matsuda index, homeostasis model assessment of insulin resistance (HOMA-IR)], and disposition index (Delta 0 30/Delta 0-30 G / HOMA-I), markers of increased risk of T2DM. In addition, those with >= 155 mg/dL were older, more obese, had higher blood pressure, and higher prevalence of metabolic syndrome. These clinical and metabolic changes were characteristic of subjects with 1-h plasma glucose concentrations >= 155 mg/dL, irrespectively of whether they were classified as NFG-NGT, IFG, or IGT. CONCLUSIONS: One-hour postload plasma glucose levels >= 155 mg/dL identified a subgroup of subjects, which by current guidelines are classified as NFG-NGT, IFG, or IGT, but that are at a higher risk that their average group risk. Recognition and management of these subjects may reduce incidence of diabetes and cardiovascular events. PMID- 20854094 TI - Depressive symptoms and metabolic syndrome in preventive healthcare: the Cooper Center longitudinal study. AB - BACKGROUND: Depression, metabolic syndrome, and reduced cardiorespiratory fitness (CRF) are known to increase the risk of developing diabetes and cardiovascular disease. The association among these factors in a generally healthy, active population with access to health care is not well defined. METHODS: This was a cross-sectional analysis of data collected on 5,125 women and men during preventive care examinations at the Cooper Clinic from 2000 to 2008. The main outcome measures were depressive symptoms as assessed by the Centers for Epidemiologic Studies Depression Scale short form (CES-D-10) questionnaire, presence or absence of metabolic syndrome, and CRF as measured by a maximal exercise treadmill test. RESULTS: Women and men who exhibited depressive symptoms had a statistically higher prevalence of metabolic syndrome compared to those who did not (for women, 15.4% versus 7.2%, P < 0.0001; for men, 31.6% versus 22.8%, P < 0.0001). Individuals with depressive symptoms had an increased frequency of higher waist circumference, higher triglycerides, and lower high-density lipoprotein. Women with depressive symptoms also had marginally higher fasting blood glucose levels. After adjusting for age and smoking status, the odds of metabolic syndrome in women with depressive symptoms was 2.81 [95% confidence interval (CI), 2.01-3.93] times the odds of metabolic syndrome in those without depressive symptoms, and in men with depressive symptoms, the odds were 1.69 (95% CI, 1.42-2.00) times the odds of metabolic syndrome in men without. When controlled for CRF level, the presence or absence of depressive symptoms on the presence of metabolic syndrome is attenuated but remains statistically significant in women. CONCLUSION: Even in a generally healthy population with access to health care, the presence of depressive symptoms was associated with increased metabolic syndrome. PMID- 20854095 TI - PORCN mutations and variants identified in patients with focal dermal hypoplasia through diagnostic gene sequencing. AB - Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by mutations in the gene PORCN, which encodes a protein required for the secretion and signaling of Wnt proteins. While deletions are responsible for a small percentage of FDH-causing mutations, the vast majority of mutations are single nucleotide substitutions or small deletions or insertions that can be identified by sequence analysis. In 2007, we implemented a PORCN gene sequencing test for individuals with a clinical diagnosis of FDH. To date, we have detected 12 novel PORCN mutations and 6 previously reported mutations in 53 such unrelated patients. The pathogenic PORCN mutations included nine nonsense mutations, three missense mutations, one small deletion, two small duplications, and three splice site mutations. Of these mutations, two were found in affected men and were mosaic; one of these was found in three other affected women. The remaining 16 mutations were found only in women. All the mutations detected in women were presumed heterozygous. In addition to the disease-causing mutations, eight nucleotide variants of unknown significance were identified. Further characterization of these variants suggests that four of them are pathogenic mutations. These findings add to the heterogeneity of mutations in the PORCN gene that cause FDH. PMID- 20854096 TI - Trust it or trash it? a tool for evaluating the quality of genetic information. PMID- 20854097 TI - Polymorphisms of glutathione-S-transferase genes and the risk of aerodigestive tract cancers in the Northeast Indian population. AB - BACKGROUND: Widespread use of tobacco and betel quid consumption and a high incidence of tobacco-associated aerodigestive tract cancers have been reported in different ethnic groups from several regions of Northeast (NE) India. This study was done to explore the possibility of phase II metabolic enzymes being responsible for the high prevalence of cancers in this region of India. METHODS: Samples from 370 cases with oral, gastric, and lung cancers and 270 controls were analyzed for polymorphism of glutathione-S-transferase (GST) genes using polymerase chain reaction-restriction fragment length polymorphism-based methods. RESULTS AND CONCLUSIONS: Tobacco smoking and betel quid chewing were found to be high risk factors for oral and lung cancers but not for gastric cancer, whereas tobacco chewing was found to be a risk factor for oral cancer but not for gastric or lung cancer. The variant genotypes of GSTP1 were not associated with any of the aerodigestive tract cancers. GSTT1 and GSTM1 null genotypes appeared to play a protective role for lung cancer (odds ratio [OR] = 0.47, 95% confidence interval [95% CI]: 0.24-0.93, p = 0.03) and (OR = 0.52, 95% CI: 0.28-0.96, p = 0.04), but they were not associated with oral and gastric cancers. However, when data was analyzed in different geographic regions the GSTT1 null genotype was found to be a significant risk factor for oral (OR = 2.58, 95% CI 1.01-6.61, p = 0.05) as well as gastric cancer (OR = 3.08, 95% CI 1.32-7.19, p = 0.009) in samples obtained from the Assam region of NE India. This is the first study on the association of GST polymorphisms and aerodigestive tract cancers in the high risk region of NE India. PMID- 20854098 TI - Infant temperament is associated with potentially obesogenic diet at 18 months. AB - OBJECTIVE: This study investigated whether infants' temperament at 18 months is associated with the feeding of foods and drinks that may increase the risk for later obesity. METHODS: This was a cross-sectional study of mothers and infants (N = 40 266) participating in the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Data were collected by questionnaire. Predictor variables were: infants' temperament at 18 months (internalizing, externalizing, and surgency/extraversion), and mothers' negative affectivity. Outcome variables were feeding of sweet foods, sweet drinks, and night-time caloric drinks at 18 months (all dichotomized). Confounders were child's gender, weight-for-height at 1 year, breastfeeding, and mother's level of education. RESULTS: After controlling for confounders, infant temperament dimensions at 18 months were significantly associated with mothers' feeding of potentially obesogenic foods and drinks independent of mothers' negative affectivity. Infants who were more internalizing were more likely to be given sweet foods (OR 1.47, CI 1.32-1.65), sweet drinks (OR 1.76, CI 1.56-1.98), and drinks at night (OR 2.91, CI 2.54-3.33); infants who were more externalizing were more likely to be given sweet food (OR 1.53, CI 1.40-1.67) and sweet drinks (OR 1.22, CI 1.11-1.34); and infants who were more surgent were more likely to be given drinks at night (OR 1.66, CI 1.42-1.92). CONCLUSIONS: The association between infant temperament and maternal feeding patterns suggests early mechanisms for later obesity that should be investigated in future studies. PMID- 20854099 TI - Familial subtelomeric rearrangement of chromosomes 19 and 20: a new contribution to partial distal 19q trisomy. AB - The role of cryptic translocations in human syndromes is a matter of fact, though this phenomenon is apparently rare. Apart from episodic case reports due to the increasing application of new molecular cytogenetic techniques, no data on its frequency in the general population are currently available. Rearrangements due to the unbalanced segregation of cryptic translocations are found in many anomalies responsible for different clinical pictures. In nearly 50% of cases, subtelomeric abnormalities are inherited from a parent carrying a balanced cryptic chromosome rearrangement. To date, very few cases of partial trisomies of 19q have been reported, with different breakpoints. Involvement of the distal region 19q is even more rare, and the delineation of its main clinical characteristics is still vague and awaiting better definition. We report two new cases of partial 19q13.42-qter trisomy associated with a partial 20p13-pter monosomy in a family found to have the cryptic translocation t(19;20)(q13.42;p13). We investigated a 5-year-old boy and his 49-year-old paternal uncle, and both had a similar, previously unrecognized mental retardation pattern, associated with the same subtelomeric rearrangement. PMID- 20854100 TI - Evaluation of the contribution of renin angiotensin system polymorphisms to the risk of coronary artery disease among Tunisians. AB - Recent studies have identified genetic markers that may directly influence the risk of the coronary artery disease (CAD), in particular the renin angiotensin system genes. Since there are no existing data for the Tunisian population, we investigated the association between these polymorphisms (angiotensin-converting enzyme [ACE] insertion/deletion [Ins/Del]; the angiotensinogen T174M and M235T; and the angiotensin II type 1 receptor A1166C polymorphisms) and CAD in Tunisians. Study subjects comprised 341 cases and 316 age- and sex-matched healthy individuals. Clinical characteristics and other biochemical and environmental risk factors were collected for both. The distribution of the Ins/Del genotypes was significantly different between cases and controls (p = 0.049) with the genotype Ins/Ins identified as a risk, p = 0.02. Similarly, the distributions of the T174M and M235T genotypes were significantly different between cases and controls (p = 0.037 and 0.047, respectively) with 174 M/M and 235 T/T as the risky genotypes (p = 0.001 and 0.026, respectively). However, A1166C genotype frequencies were not significantly different between patients and controls. In conclusion, our results suggest that a significantly higher risk of CAD was associated with the Ins/Del, the M235T, and T174M polymorphisms; other environmental variables such as body mass index; and biochemical variables such as cholesterol. PMID- 20854101 TI - Alpha- and beta-synucleins mRNA expression in lymphocytes of schizophrenia patients. AB - Alpha-synuclein is largely, but not entirely, expressed in the central nervous system. A high concentration of alpha-synuclein in presynaptic terminals can mimic the normal function of endogenous alpha-synuclein in regulating synaptic vesicle mobilization at nerve terminals. Beta-synuclein protein is seen primarily in brain tissue and it is suggested that beta-synuclein acts as an inhibitor of alpha-synuclein aggregation, which occurs in neurodegenerative diseases. With respect to the role of synucleins in neurologic diseases such as Parkinson's disease, we decided to study the changes of alpha- and beta-synucleins in schizophrenia patients in relation to a control group. For this purpose, total RNA was extracted from the lymphocytes of patients and controls and then cDNA was synthesized and used for real-time polymerase chain reaction. Calculation of the relative expression of alpha- and beta-synucleins showed downregulation in patients in comparison to the control group. Independent two-tailed t-test showed that beta-synuclein mRNA expression in the control group was significantly higher than that in the patient group (p < 0.01), but downregulation of alpha-synuclein gene was not significant. Therefore, a significant downregulation of beta synuclein mRNA expression appears to be a suitable biomarker for the diagnosis of schizophrenia. PMID- 20854102 TI - Upregulation of fecal cytokeratin 19 is associated with prognosis in older colorectal cancer patients. AB - The upregulation of fecal cytokeratin 19 (CK19) correlates with age and metastatic status in human colorectal cancer (CRC). To further explore its clinical significance in older patients (>60 years), their fecal CK19 was measured by quantitative reverse transcription-polymerase chain reaction. Differences in CK19 transcripts were compared using the nonparametric Mann Whitney U test. Clinical significance was assessed with the chi-squared test and a binary logistic regression model. The association between overall survival and expressions of fecal CK19 in combination with other serum markers, carcinoembryonic antigen and carbohydrate antigen 19-9 (CA19-9), was evaluated using the Kaplan-Meier method. In these older groups, CRC patients had significantly higher median fecal CK19 expression (p = 0.006) than controls. The highest risk of CRC (odds ratio, 5.8; 95% confidence interval, 2.3-14.7; p < 0.001) was detected when the cutoff value for fecal CK19 expression was set at the median value of the 28 healthy controls. The lowest overall survival (29.2% +/- 21.4%) occurred in patients in whom serum CA19-9 levels were high and fecal CK19 was overexpressed. Our results suggest that fecal CK19 expression is associated with CRC, and together with serum carcinoembryonic antigen or CA19-9, it can predict overall survival in older patients. PMID- 20854103 TI - Frequencies of four ATP-binding cassette transporter G8 polymorphisms in patients with ischemic vascular diseases. AB - ATP-binding cassette transporter G8 (ABCG8) was found to participate in plant sterol and cholesterol (CHOL) transport; however, the potential associations of ABCG8 genetic variants and ischemic vascular diseases are largely unknown. Determinations of allele frequencies of four common ABCG8 polymorphisms (D19H, Y54C, T400K, and A632V) were carried out in 241 unrelated patients with ischemic stroke, 148 patients with coronary heart disease, and 191 blood donors (controls). Allele frequencies of the investigated polymorphisms in patient groups showed no significant differences compared with controls. There was a tendency toward reduced 54YY-genotype frequency among male patients with stroke. On stratification by age at disease onset, male patients with stroke under the age of 50 (n = 62) showed significantly reduced 54YY-frequency compared with male controls (n = 92; 24.2% vs. 41.3%; odds ratio: 0.45 [95% confidence intervals: 0.22-0.93]; p = 0.038). No such associations were found among women. In healthy controls, CHOL levels of individuals with the 54YY genotype (n = 71; median: 4.51 mM, 25th-75th percentiles: 4.19-5.43) were significantly reduced compared with 54YC and 54CC individuals combined (n = 120; median: 4.95 mM, 25th-75th percentiles: 4.42-5.88, p = 0.009). Further, we identified a new ABCG8-variant, T401S, in a control subject. In conclusion, ABCG8 54YY-genotype may be a potential protecting factor against ischemic stroke in young men and may influence plasma CHOL levels. PMID- 20854104 TI - Altered mitochondrial function and genome frequency post exposure to γ radiation and bystander factors. AB - PURPOSE: To further evaluate irregular mitochondrial function and mitochondrial genome damage induced by direct gamma-irradiation and bystander factors in human keratinocyte (HPV-G) epithelial cells and hamster ovarian fibroblast (CHO-K1) cells. This is as a follow-up to our recent reports of gamma-irradiation-induced loss of mitochondrial function and mitochondrial DNA (mtDNA) damage. MATERIALS AND METHODS: Mitochondrial function was evaluated post direct radiation and irradiated cell conditioned medium (ICCM) by determining: Activity of the individual complexes of oxidative phosphorylation (OxPhos); mtDNA-encoded protein synthesis; and mitochondrial genome frequency and mtDNA damage. RESULTS: Mitochondria show a loss of OxPhos enzyme function as early as 4 h post treatment with recovery observed 12-96 h in some but not all complexes demonstrating a non uniform sensitivity to gamma-radiation. We also identified irregular mtDNA directed protein synthesis. Long range Polymerase Chain Reaction (PCR) analysis identified mitochondrial genome damage and real-time PCR identified increases in mitochondrial genome frequency. CONCLUSIONS: The study reaffirms the sensitive nature of mitochondria to both low-level direct radiation exposure and radiation induced bystander factor mediated damage. Furthermore, we report for the first time, the loss of function in the enzymes of OxPhos post exposure to bystander factors and identify altered mtDNA-directed protein synthesis post both direct radiation and bystander factors. PMID- 20854105 TI - Impact of EXO1 polymorphism in susceptibility to colorectal cancer. AB - BACKGROUND AND AIM: One candidate gene for colorectal cancer (CRC) susceptibility is exonuclease 1 (EXO1). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of CRC in Iranian patients. METHODS: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with CRC risk and also clinicopathological characteristics. RESULTS: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of CRC (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with CRC at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284). CONCLUSIONS: Our results provide evidence diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with CRC. In addition, despite other investigations, we could define a significant association between the Leu allele and CRC (p = 0.001). PMID- 20854106 TI - School-level correlates of physical activity intensity in 10-year-old children. AB - PURPOSE: Little is known about school environmental factors that promote or inhibit activity, especially from studies using objective measures in large representative samples. We therefore aimed to study associations between activity intensities and physical and social school environmental factors. METHODS: A population-based sample of 1 908 British children (SPEEDY study), mean age 10.3 years (Standard deviation [SD]: 0.3), recruited from 92 schools across Norfolk, UK, with valid activity data (assessed with Actigraph accelerometers). Outcome measures were school-based (8 am-4 pm on weekdays) time (in minutes) spent in sedentary (<100 counts/min), moderate (2 000-3 999 counts/min) and vigorous (>=4 000 counts/min) activity. A total of 40 school physical and social environmental factors were assessed. Multivariable multilevel linear regression analyses adjusted for children's sex and body mass index were conducted; interactions with sex were investigated. RESULTS: Availability of a 'Park and Stride' scheme was negatively associated with sedentary minutes (-7.74; 95% CI: -14.8; -0.70). Minutes of moderate activity were associated with the availability of a lollypop person (1.33, 95% CI: 0.35; 2.62) and objectively-assessed walking provision (1.70, 95% CI: 0.85; 2.56). The number of sports facilities of at least medium quality (0.47, 95% CI: 0.16; 0.79), not having a policy on physical activity ( 2.28, 95% CI: -3.62; -0.95), and, in boys only, provision of pedestrian training (1.89; 95% CI: 0.77; 3.01) were associated with minutes of vigorous activity. CONCLUSIONS: Only a small number of school-level factors were associated with children's objectively-measured physical activity intensity, giving few pointers for potential future intervention efforts. Further research should focus on using objective measures to elucidate what factors may explain the school-level variance in activity levels. PMID- 20854107 TI - Lipid and lipoprotein profile in HIV-infected patients treated with lopinavir/ritonavir as a component of the first combination antiretroviral therapy. AB - We characterized lipid and lipoprotein changes associated with a lopinavir/ritonavir-containing regimen. We enrolled previously antiretroviral naive patients participating in the Swiss HIV Cohort Study. Fasting blood samples (baseline) were retrieved retrospectively from stored frozen plasma and posttreatment (follow-up) samples were collected prospectively at two separate visits. Lipids and lipoproteins were analyzed at a single reference laboratory. Sixty-five patients had two posttreatment lipid profile measurements and nine had only one. Most of the measured lipids and lipoprotein plasma concentrations increased on lopinavir/ritonavir-based treatment. The percentage of patients with hypertriglyceridemia (TG >150 mg/dl) increased from 28/74 (38%) at baseline to 37/65 (57%) at the second follow-up. We did not find any correlation between lopinavir plasma levels and the concentration of triglycerides. There was weak evidence of an increase in small dense LDL-apoB during the first year of treatment but not beyond 1 year (odds ratio 4.5, 90% CI 0.7 to 29 and 0.9, 90% CI 0.5 to 1.5, respectively). However, 69% of our patients still had undetectable small dense LDL-apoB levels while on treatment. LDL-cholesterol increased by a mean of 17 mg/dl (90% CI -3 to 37) during the first year of treatment, but mean values remained below the cut-off for therapeutic intervention. Despite an increase in the majority of measured lipids and lipoproteins particularly in the first year after initiation, we could not detect an obvious increase of cardiovascular risk resulting from the observed lipid changes. PMID- 20854109 TI - Meta-analysis to determine the effects of plant disease management measures: review and case studies on soybean and apple. AB - The continuing exponential increase in scientific knowledge, the growing availability of large databases containing raw or partially annotated information, and the increased need to document impacts of large-scale research and funding programs provide a great incentive for integrating and adding value to previously published (or unpublished) research through quantitative synthesis. Meta-analysis has become the standard for quantitative evidence synthesis in many disciplines, offering a broadly accepted and statistically powerful framework for estimating the magnitude, consistency, and homogeneity of the effect of interest across studies. Here, we review previous and current uses of meta-analysis in plant pathology with a focus on applications in epidemiology and disease management. About a dozen formal meta-analyses have been published in the plant pathological literature in the past decade, and several more are currently in progress. Three broad research questions have been addressed, the most common being the comparative efficacy of chemical treatments for managing disease and reducing yield loss across environments. The second most common application has been the quantification of relationships between disease intensity and yield, or between different measures of disease, across studies. Lastly, meta-analysis has been applied to assess factors affecting pathogen-biocontrol agent interactions or the effectiveness of biological control of plant disease or weeds. In recent years, fixed-effects meta-analysis has been largely replaced by random- (or mixed ) effects analysis owing to the statistical benefits associated with the latter and the wider availability of computer software to conduct these analyses. Another recent trend has been the more common use of multivariate meta-analysis or meta-regression to analyze the impacts of study-level independent variables (moderator variables) on the response of interest. The application of meta analysis to practical problems in epidemiology and disease management is illustrated with case studies from our work on Phakopsora pachyrhizi on soybean and Erwinia amylovora on apple. We show that although meta-analyses are often used to corroborate and validate general conclusions drawn from more traditional, qualitative reviews, they can also reveal new patterns and interpretations not obvious from individual studies. PMID- 20854108 TI - Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults. AB - Abstract The safety and immunogenicity of the MRK adenovirus type 5 (Ad5) HIV-1 clade B gag vaccine was assessed in an international Phase I trial. Three-hundred and sixty healthy HIV-uninfected adults were enrolled on five continents. Subjects received placebo or 1 * 10(9) or 1 * 10(10) viral particles (vp) per dose of the MRKAd5 HIV-1 gag vaccine at day 1, week 4, and week 26. Immunogenicity was evaluated using an IFN-gamma ELISPOT gag 15-mer assay with positive responses defined as >=55 SFC/10(6) PBMCs and >=4-fold over mock control. The vaccine was well tolerated. The most common adverse events were injection site reactions, headache, pyrexia, diarrhea, fatigue, and myalgia. At week 30, geometric mean ELISPOT responses were 24, 114, and 226 SFC/10(6) PBMCs in the placebo, 1 * 10(9) vp/dose, and 1 * 10(10) vp/dose groups, respectively. Overall, responses to 1 * 10(10) vp were 85% and 68% in subjects with low (<=200) and high (>200) baseline Ad5 titers, respectively. The MRKAd5 HIV-1 gag vaccine was immunogenic in diverse geographic regions. Gag ELISPOT responses were greater in the 1 * 10(10) vp/dose groups than in the 1 * 10(9) vp/dose groups. Data from this first international study indicate that adenovirus-vectored vaccines are well tolerated and may be immunogenic in subjects from regions with high prevalence of preexisting Ad5 immunity. PMID- 20854110 TI - Characterizing monoclonal antibodies to antigenic domains of TCblR/CD320, the receptor for cellular uptake of transcobalamin-bound cobalamin. AB - Monoclonal antibodies (mAbs) were generated to the extracellular domain of transcobalamin receptor (TCblR) and used to identify the regions of the receptor protein involved in antibody binding. Based on the effect of transcobalamin bound cobalamin (TC-Cbl) on antibody binding, this study identified both blocking and binding antibodies. Both types of antibodies bind apo as well as holo receptors, whereas the blocking antibody when bound to the apo receptor prevents the binding and cellular uptake of TC-Cbl. Binding of these antibodies to truncated receptor constructs has identified the peptide domains of the receptor involved in antibody binding. These antibodies have potential utility in blocking cellular uptake of Cbl and delivery of drugs via TCblR, which is over-expressed in many cancers. PMID- 20854111 TI - Identification of genes involved in the response of banana to crown rot disease. AB - Variations in banana susceptibility to crown rot disease have been observed but the molecular mechanisms underlying these quantitative host-pathogen relationships are still unknown. This study was designed to compare gene expression between crowns of banana fruit showing a high susceptibility (S(+)) and crowns showing a low susceptibility (S(-)) to the disease. Comparisons were performed at two situation times: i) between crowns (S(+) and S(-)) collected 1 h before inoculation and ii) between crowns (S+ and S-) collected 13 days after inoculation. Gene expression comparisons were performed with cDNA-amplified fragment length polymorphism (AFLP) and results were confirmed by real-time reverse-transcription polymerase chain reaction. Among genes identified as differentially expressed between S(+) and S(-) crowns, two were involved in signal transduction, three in proteolytic machinery, two had similarity to pathogenesis-related protein 14, one to a CCR4-associated factor protein, and one to a cellulose synthase. Paradoxically, the overexpression of the cellulose synthase gene was associated with banana showing a high susceptibility in both pre- and post-inoculation situations. Finally, the cDNA-AFLP identified a gene that seems to be associated with the quantitative banana responses to crown rot disease; this gene encodes a dopamine-beta-monooxygenase, which is involved in the catecholamine pathway. To our knowledge, this work is the first to address both pre- and post-infection gene expression with the same host-pathogen combination and distinct susceptibility levels. PMID- 20854112 TI - Functional characterization of fst1 in Fusarium verticillioides during colonization of maize kernels. AB - The putative hexose transporter gene fst1 in Fusarium verticillioides was identified previously by microarray analysis as a gene that was more highly expressed during colonization of autoclaved maize endosperm than germ. In contrast to a previous study, in which disruption of fst1 did not affect growth of the pathogen on autoclaved maize kernels, in the current study, we demonstrated that disruption of fst1 delayed growth and symptom development on wounded maize ears. Characterization of the fst1 promoter revealed that regulation of fst1 expression was similar to that of fumonisin biosynthetic (fum) genes; expression was highest during growth on endosperm tissue and repressed by elevated concentrations of ammonium in the growth medium. With a fluorescent tag attached to FST1, the protein localized transiently to the periphery of the cells near the plasma membrane and in vacuole-like structures, suggesting that membrane localized FST1 was internalized and degraded in vacuoles. Expression of fst1 in a yeast strain lacking hexose transporter genes did not complement the yeast mutation, suggesting that FST1 does not transport glucose, fructose, or mannose. The results indicate a functional role for FST1 in pathogenesis during the colonization of living kernels. PMID- 20854113 TI - Costs of inpatient and emergency department care for chronic obstructive pulmonary disease in an elderly Medicare population. AB - OBJECTIVE: Treatment in the hospital setting accounts for the largest portion of healthcare costs for COPD, but there is little information about components of hospital care that contribute most to these costs. The authors determined the costs and characteristics of COPD-related hospital-based healthcare in a Medicare population. METHODS: Using administrative data from 602 hospitals, 2008 costs of COPD-related care among Medicare beneficiaries age >= 65 years were calculated for emergency department (ED) visits, simple inpatient admissions and complex admissions (categorized as intubation/no intensive care, intensive care/no intubation, and intensive care/intubation) in a cross-sectional study. Rates of death at discharge and trends in costs, length of stay and readmission rates from 2005 to 2008 also were examined. MAIN RESULTS: There were 45,421 eligible healthcare encounters in 2008. Mean costs were $679 (SD, $399) for ED visits (n = 10,322), $7,544 ($8,049) for simple inpatient admissions (n = 25,560), and $21,098 ($46,160) for complex admissions (n = 2,441). Intensive care/intubation admissions (n = 460) had the highest costs ($45,607, SD $94,794) and greatest length of stay (16.3 days, SD 13.7); intubation/no ICU admissions had the highest inpatient mortality (42.1%). In 2008, 15.4% of patients with a COPD-related ED visit had a repeat ED visit and 15.5-16.5% of those with a COPD-related admission had a readmission within 60 days. From 2005 to 2008, costs of admissions involving intubation increased 10.4-23.5%. Study limitations include the absence of objective clinical data, including spirometry and smoking history, to validate administrative data and permit identification of disease severity. CONCLUSIONS: In this Medicare population, COPD exacerbations and related inpatient and emergency department care represented a substantial cost burden. Admissions involving intubation were associated with the highest costs, lengths of stay and inpatient mortality. This population needs to be managed and treated adequately in order to prevent these severe events. PMID- 20854114 TI - Genotype-phenotype relationship of the delta-thalassemia and Hb A(2) variants: observation of 52 genotypes. AB - The increase of Hb A(2) (alpha2delta2) beyond the upper limit [2.0-2.2/3.3-3.4% of the total hemoglobin (Hb)] is an invaluable tool in the hematological screening of beta-thalassemia (beta-thal) carriers. Factors decreasing Hb A(2) percentages can hinder correct diagnosis. In order to analyze the genotype phenotype relationship, we characterized delta-, beta- and alpha-globin genotypes in 190 families where the probands had Hb A(2) values of <=2.0% or were beta-thal heterozygotes with normal Hb A(2) levels. Hb A(2) was measured with cation exchange high performance liquid chromatography (HPLC). Mutations were detected with allele-specific methods or DNA sequencing; two multiplex-ARMS (amplification refractory mutation system) assays were set up. The molecular basis underlying the decrease in Hb A(2) was extremely heterogeneous. Nineteen delta-globin alleles (Hb A(2)-S.N. Garganico was new) were detected; their interaction with alpha- or beta-globin alleles (10 and eight, respectively) led us to observe 52 genotypes in 261 carriers. The type of delta-globin mutations, the relative genotypes, the interaction with alpha(0)-thal traits, are the most important factors in decreasing the Hb A(2) percentage. These results are extremely useful in addressing the molecular diagnosis of hemoglobinopathies and thalassemias. PMID- 20854115 TI - Early detection of response to hydroxyurea therapy in patients with sickle cell anemia. AB - Red blood cells (RBC) and reticulocyte parameters were determined on peripheral blood from a subset of patients enrolled in the multicenter study of hydroxyuea (HU) in sickle cell anemia. Multiple blood samples were obtained every 2 weeks. Cellular indices were measured by flow cytometry. Generalized linear models were used to determine the relationship between the longitudinal trajectories of RBC and reticulocyte indices and HU usage. There was a significant relationship between HU usage and most of the RBC and reticulocyte indices. Hydroxyurea produced higher value trajectories than those generated by placebo usage for the hemoglobin (Hb) content of both the RBCs and reticulocytes and for the mean corpuscular volume (MCV) of reticulocytes. These changes were first detected 10 weeks after starting HU and before the increase in Hb F levels. The data suggest that subtle and early markers of response to HU reside in the hemogram. PMID- 20854116 TI - Variable and often severe phenotypic expression in patients with the alpha thalassemic variant Hb Agrinio [alpha29(B10)Leu->Pro (alpha2)]. AB - Hb Agrinio [alpha29(B10)Leu->Pro] is a highly unstable variant, classified as a nondeletional alpha-thalassemia (alpha-thal) mutation. To date it has only been described in individuals of Greek and Cypriot origin. Evaluation of the phenotypic presentation of 12 Hb Agrinio homozygotes or compound heterozygotes, diagnosed in a single center in Greece during a 15-year period, found a wide clinical expression, ranging from thalassemia intermedia (with or without transfusion requirement) to Hb H hydrops fetalis, with some phenotype-to-genotype correlation. The often severe clinical presentation of Hb Agrinio homozygotes or Hb Agrinio compound heterozygotes, coinheriting severe alpha-thal determinants, indicates that molecular identification of carriers of the Hb Agrinio mutation should be considered within the context of screening programs involving individuals of Greek and Cypriot origin. Selective molecular investigation of candidate carriers is facilitated by the observation that all heterozygotes for the Hb Agrinio mutation present with at least one hematological parameter implicating an alpha-thal carrier state. PMID- 20854117 TI - Hb St. Truiden [alpha68(E17)Asn->His] and Hb Westeinde [alpha125(H8)Leu->Gln]: two new abnormalities of the alpha2-globin gene. AB - We report two new abnormal hemoglobins (Hbs) caused by mutations on the alpha2 gene. One resulted into an Asn->His substitution at position 68, the other in a Leu->Gln substitution at position 125. The first mutation was observed in a 61 year-old North European Belgian male during Hb A(1c) analysis and subsequently in other members of his family. The variant was expressed at a normal level and caused no hematological abnormalities in the carriers. The second was found in a 27-year-old Turkish male living in The Hague, The Netherlands, who presented with microcytic hypochromic parameters without iron deficiency and was also carrier of the common alpha2 IVS-I (-5 nt) deletion. PMID- 20854118 TI - New and known beta-thalassemia determinants masked by known and new delta gene defects [Hb A(2)-Ramallah or delta6(A3)Glu->Gln, GAG>>CAG]. AB - We report a novel thalassemia determinant found in a Nigerian woman living in the Netherlands, resulting from a 2 bp insertion at codons 9/10 of the beta-globin gene (HBBc.28_29insTA p.Ser10LeufsX11). The novel defect causes a frameshift with a consequent premature TGA stop codon, located at 11 positions downstream from the mutated codon. The phenotype was typical of a beta-thalassemia (beta-thal), trait with high RBC counts and compensated mild microcytic anemia. However, the Hb A(2) level was reported to be normal due to the presence of the common Hb A(2)' or Hb B2 [delta16(A13)Gly->Arg, GGC>CGC] variant that was not taken into account. We also present the opposite but comparable situation found in an a Palestinian man living in the USA. He was a carrier of a common beta-globin gene defect [codon 6 (-A), HBB:c.20delA] in combination with a novel delta-globin gene defect at codon 6 [HBD. c.19G>C, Glu6Gln] that we have named Hb A(2)-Ramallah. In both cases, the provisional diagnosis could have been compromised when based on the measurement of the normal Hb A(2) fraction only. PMID- 20854119 TI - Spectrum of alpha-globin gene mutations in the Kerman Province of Iran. AB - Mutation of the alpha-globin gene may result in alpha-thalassemia (alpha-thal) which is characterized by a reduction or complete absence of the gene expression. In this study, 607 individuals with low levels of blood cell indices and normal Hb A(2) were referred to our laboratory for investigation of any alpha-thal mutations. We used the gap-polymerase chain reaction (gap-PCR) method and an alpha-globin strip assay kit to detect the mutation. Our results showed that alpha(3.7) was the most common mutation (83.8%) in the overall mutated alleles of the alpha-globin gene. The second and third most frequent alpha-globin gene defects were codon 19 (alpha2) and IVS-I, -5 nt/alphaalpha (alpha2), 5.7 and 4.2%, respectively. We found that the spectrum of alpha-globin gene mutation in Kerman Province was in accordance with what was previously reported in other Iranian provinces where malaria has selected these protective traits. PMID- 20854120 TI - Comprehensive spectrum of the beta-Thalassemia mutations in Khuzestan, southwest Iran. AB - beta-Thalassemia (beta-thal) is characterized by reduction or absence of beta globin gene expression. We describe the spectrum of mutations observed in a large cohort of beta-thal carriers in Khuzestan, Southwest Iran. All together 1,241 blood samples from individuals with decreased mean corpuscular volume (MCV) and elevated Hb A(2) levels, were analyzed either by reverse dot-blot or by direct sequencing of the HBB gene. We found 42 different mutations associated with beta thal and identified eight common beta-globin variants, namely, Hb S [beta6(A3)Glu >Val], Hb C [beta6(A3)Glu->Lys], Hb D-Punjab [beta121(GH4)Glu->Gln] and Hb O-Arab [beta121(GH4)Glu->Lys]. No mutations were found in two individuals. The distribution is characteristic of a heterogenous population with three preferential mutations being present [codons 36/37 (-T), IVS-II-1 (G>A) and IVS-I 110 (G>A)] at a frequency of 20.5, 20.0 and 14.2%, respectively, followed by 39 mutations in decreasing frequencies from 5.2 down to 0.1%. These data are of importance when planning prevention strategies in the country. PMID- 20854121 TI - beta-Thalassemia mutations in the Kurdish population of northeastern Iraq. AB - A random 123 carriers of beta-thalassemia (beta-thal), identified by the Sulaimaniyah Provincial Premarital Screening Program in northeastern Iraq, were screened for beta-thal mutations using multiplex polymerase chain reaction followed by reverse hybridization StripAssay and direct sequencing. A total of 11 different beta-thal mutations was identified in the studied samples, of which eight represented 96% of the mutated beta-globin genes. These were IVS-II-1 (G>A), IVS-I-110 (G>A), codon 8 (-AA), codons 8/9 (+G), IVS-I-5 (G>C), codon 5 ( CT), IVS-I-6 (T>C) and IVS-I-1 (G>A). Other mutations were less common or sporadic. There were some notable differences in frequencies of various mutations in comparison to other eastern Mediterranean populations, as well as with previous studies of Iraqi Kurds. The latter illustrate the relative heterogeneity of the mutations distributed in Iraq, and the need to screen other areas of the country, to ensure the establishment of an effective prenatal diagnosis program. PMID- 20854122 TI - Thalassemia syndromes in Serbia: an update. AB - Thalassemia syndromes constitute a group of genetic disorders, widespread throughout the world. The present study contains data on thalassemia syndromes and their chromosomal environment obtained in Serbia over a period of 10 years. Ten different beta-thalassemia (beta-thal) mutations and two hemoglobin (Hb) variants were detected in 127 members of 68 families. Hb Lepore-Boston-Washington (Lepore-BW) (delta87Gln-beta-IVS-II-8), a thalassemic Hb variant, was shown to be the most common cause of thalassemia in Serbia. Haplotype analyses of the beta globin gene clusters of healthy individuals as well as of individuals affected with beta-thal showed that haplotype I was the most frequent haplotype in the Serbian population, followed by haplotypes II and IX. Two novel haplotypes were detected. Haplotype analyses showed the association between certain haplotypes and the most common thalassemic mutations. Results presented in this paper will update the Serbian national mutation database and contribute to a better understanding of genographic history of South European and Balkan populations. PMID- 20854123 TI - Diagnosis of thalassemia on dried blood spot samples by high performance liquid chromatography. AB - High performance liquid chromatography (HPLC) on fresh lysates is the standard test for identification of thalassemia. Samples in the form of dried blood spot(s) (DBS) mailed to reference laboratories where HPLC is available could be an alternative. Hemoglobin (Hb) on DBS at day 1, 7, 15 and 30 were analyzed by HPLC and compared to those analyzed from fresh liquid whole blood at day 0. A 100% consistent interpretation of beta-thalassemia (beta-thal) trait and beta thal/Hb E disease between liquid whole blood and DBS was observed when analyzing Hb A(2) on DBS at a level of 2.7-9.9% in conjunction with a lower MCV (<80 fL) and MCH (<27 pg) and analyzing beta-thal/Hb E by using Hb E and Hb F at a level of 30-48% and >10%, respectively. Therefore, our results show that detection of thalassemia carriers using DBS is possible and is the alternative of choice in a low resource setting. PMID- 20854124 TI - Further studies on Hb Canebiere [beta12(G4)Asn->His], a low affinity hemoglobin variant. AB - A case of Hb Canebiere [beta102(G4)Asn->His] was diagnosed in an otherwise healthy 21-year-old Danish woman. The clinical consequences were minor, since her only symptom consisted of transient cyanosis in lips and fingers when exposed to cold environments. Whole blood p50 was 59.9 mmHg. The Hb Canebiere variant could not be separated from Hb A by high performance liquid chromatography (HPLC) and isoelectric focusing (IEF), and it was thus missed by routine hemoglobin (Hb) fractionation techniques. PMID- 20854125 TI - Hb S-San Martin: a new sickling hemoglobin with two amino acid substitutions [beta6(A3)Glu->Val;beta105(G7)Leu->Pro] in an Argentinean family. AB - A new sickling hemoglobin (Hb) detected in an Argentinean family from San Martin, Buenos Aires, Argentina, is hereby described. Two mutations were identified on the same beta-globin gene resulting in a new variant named Hb San Martin. One mutation was found on exon 1, corresponding to Hb S [beta6Glu->Val, GAG>GTG] and the second one on exon 3 at beta105(G7)Leu->Pro, CTC>CCC. The replacement of leucine by proline will likely impair the structure breaking helix G and causing instability of the molecule and the clinical manifestations typical of unstable Hbs. The mutation at beta105 seemed to be a de novo one in our patients, arising on a previously mutated gene, due to the fact that Hb S is the most frequent structural variant. PMID- 20854126 TI - Severe beta-thalassemia intermedia in a compound heterozygous patient for the -30 (T>A) beta(+)-thalassemia mutation and the delta(0)beta(+)-Senegalese deletion. AB - We report the clinical and biochemical studies of a patient initially diagnosed with beta-thalassemia intermedia (beta-TI), which, with age, has progressed to a severe transfusion-dependent form. The patient is a compound heterozygote for the -30 (T>A) beta(+)-thalassemia (beta(+)-thal) mutation and the rare delta(0)beta(+)-Senegalese deletion. Many complications are reported as well as the specific treatments initiated. PMID- 20854127 TI - Mechanical integrity of hemodialysis catheters after exposure to a novel catheter lock solution. AB - OBJECTIVE: To examine the mechanical integrity of hemodialysis catheters after exposure to the combination of N-acetylcysteine, tigecycline, and heparin, compared with that of catheters exposed to heparin alone. METHODS: We used 3 types of hemodialysis catheters: polyurethane, silicone, and carbothane catheters. Catheter segments were incubated in vitro for various time intervals of up to 2 weeks either in a novel catheter lock solution (novel CLS), which consisted of N-acetylcysteine, tigecycline, and heparin, or in heparin alone (as a control). At the time of testing, each segment was rinsed and cut longitudinally into 2 sections. All catheter sections were scanned using an optical dissecting microscope to check for surface abnormalities and to measure wall thickness. We also carried out tensile strength testing of another set of catheters using a universal testing machine. Tested parameters included stress at yield, strain at yield, stress at break, strain at break, modulus of elasticity, and force at break. RESULTS: The surfaces of catheters in both groups appeared similar by microscopy. The mean thickness of the catheter wall was not significantly different for the catheters exposed to the novel CLS and the catheters exposed to heparin (P > .05). Results for most of the tensile strength parameters tested were similar in the 2 groups of catheters at the end of 2 weeks of incubation. In particular, the force-at-break value of all tested catheters remained much greater than that recommended by industry standards. CONCLUSIONS: The use of the novel catheter lock solution did not impair the mechanical integrity or increase the propensity for fracture of hemodialysis catheters. PMID- 20854128 TI - Composting of municipal solid waste. AB - This paper reviews the literature on the composting process, which is one of the technological options for the processing of municipal solid wastes (MSWs). The process assumes a great significance, particularly from the point of its economic viability, capability for recycling of nutrients and waste minimization with minimum environmental problems. A number of studies on various aspects of the composting process, including process control and monitoring parameters such as temperature, pH, moisture content, aeration, and porosity are reviewed. Salient observations on microbial properties of composting are described and details of vermicomposting, as well as a detailed analysis of patents on composting of MSW, are presented. PMID- 20854129 TI - Fetoprotective activity of breast cancer resistance protein (BCRP, ABCG2): expression and function throughout pregnancy. AB - The medical treatment of pregnant women, as well as their fetuses, has become a common clinical practice in developed countries. Therefore, detailed knowledge of maternofetal pharmacokinetics, including the role of drug-efflux transporters in the fetoplacental unit, is crucial to optimize drug choice and dosage schemes and to avoid or exploit possible drug-drug interactions on placental transporters in order to assure appropriate drug levels in the mother and/or fetus. Breast cancer resistance protein (BCRP, ABCG2) is the most recent member of ATP-binding cassette drug-efflux transporters that has been associated with resistance in cancer chemotherapy. Importantly, ABCG2 has also been localized in various normal tissues, affecting the pharmacokinetics of several xenobiotics as well as a number of physiological substances. Extensive expression of ABCG2 in tissue barriers, such as the blood-brain barrier, intestine, testis, or placenta, suggests that ABCG2 plays an important role in the protection of sensitive tissues against toxins. In the placenta, ABCG2 has been experimentally evidenced to actively pump its substrates in the fetal-to-maternal direction and to play an important role in transplacental pharmacokinetics, fetal protection, and detoxication. Further, ABCG2 expression in embryonic and fetal membranes over the course of pregnancy helps ensure proper function of the fetoplacental unit. In this review, we summarize the current knowledge regarding expression and function of ABCG2 in the fetoplacental unit during the development of the fetus and overview the aspects of transplacental pharmacokinetics, ABCG2 regulation, and clinical significance of the transporter for pharmacotherapy in pregnancy. PMID- 20854130 TI - Reduction in burst release after coating poly(D,L-lactide-co-glycolide) (PLGA) microparticles with a drug-free PLGA layer. AB - The high initial burst release of a highly water-soluble drug from poly (D,L lactide-co-glycolide) (PLGA) microparticles prepared by the multiple emulsion (w/o/w) solvent extraction/evaporation method was reduced by coating with an additional polymeric PLGA layer. Coating with high encapsulation efficiency was performed by dispersing the core microparticles in peanut oil and subsequently in an organic polymer solution, followed by emulsification in the aqueous solution. Hardening of an additional polymeric layer occurred by oil/solvent extraction. Peanut oil was used to cover the surface of core microparticles and, therefore, reduced or prevented the rapid erosion of core microparticles surface. A low initial burst was obtained, accompanied by high encapsulation efficiency and continuous sustained release over several weeks. Reduction in burst release after coating was independent of the amount of oil. Either freshly prepared (wet) or dried (dry) core microparticles were used. A significant initial burst was reduced when ethyl acetate was used as a solvent instead of methylene chloride for polymer coating. Multiparticle encapsulation within the polymeric layer increased as the size of the core microparticles decreased (< 50 um), resulting in lowest the initial burst. The initial burst could be controlled well by the coating level, which could be varied by varying the amount of polymer solution, used for coating. PMID- 20854131 TI - No relationship between TNF-alpha genetic variants and combination antiretroviral therapy-related lipodystrophy syndrome in HIV type 1-infected patients: a case control study and a meta-analysis. AB - Tumor necrosis factor alpha (TNF-alpha) is thought to be involved in the pathogenic and metabolic events associated with HIV-1 infection. We assessed whether carriage of the TNF-alpha gene promoter single nucleotide polymorphism (SNP) is associated with lipodystrophy and metabolic derangements in HIV-1 infected patients treated with cART. We also assessed variations in TNF-alpha receptor plasma levels. The study group comprised 286 HIV-1-infected patients (133 with and 153 without lipodystrophy) and 203 uninfected controls (UC). TNF alpha -238G > A, -308G > A, and -863 C > A SNP were assessed using PCR-RFLPs on white cell DNA. Plasma sTNF-alpha R1 and R2 levels were measured by ELISA. Student's t test, the chi(2) test, Pearson correlations, and the logistic regression test were performed for statistical analysis. The TNF-alpha -308G > A SNP was significantly associated with lipodystrophy in the univariate analysis (p = 0.04). This association, however, was no longer significant in the multivariate analysis. A meta-analysis of the published literature and our own data, which included 284 patients with lipodystrophy and 338 without lipodystrophy, showed that there was no relationship between the TNF-alpha -238G > A and -308G > A SNP and lipodystrophy (p > 0.05 for all comparisons). HIV-1-infected patients had greater sTNF-alpha R2 plasma levels than UC (p = 0.001) whereas sTNF-alpha R1 and R2 levels were not significantly different in both the HIV-1-infected cohorts, lipodystrophy vs. nonlipodystrophy (p = NS). In our cohort of white Spaniards the TNF-alpha -238G > A, -308G > A, and -863C > A SNP were not associated with lipodystrophy in HIV-1-infected patients treated with cART. This finding was replicated in a meta-analysis of the published data, which showed no associations between the TNF-alpha -238G > A and -308G > A SNP and lipodystrophy. In HIV-1 infected patients under cART there is a systemic overproduction of sTNF-alpha R2, which is unrelated to the presence of lipodystrophy. PMID- 20854132 TI - Multiple PAR and E4BP4 bZIP transcription factors in zebrafish: diverse spatial and temporal expression patterns. AB - Circadian rhythms of physiology and behavior are generated by an autonomous circadian oscillator that is synchronized daily with the environment, mainly by light input. The PAR subfamily of transcriptional activators and the related E4BP4 repressor belonging to the basic leucine zipper (bZIP) family are clock controlled genes that are suggested to mediate downstream circadian clock processes and to feedback onto the core oscillator. Here, the authors report the characterization of these genes in the zebrafish, an increasingly important model in the field of chronobiology. Five novel PAR and six novel e4bp4 zebrafish homolog genes were identified using bioinformatic tools and their coding sequences were cloned. Based on their evolutionary relationships, these genes were annotated as ztef2, zhlf1 and zhlf2, zdbp1 and zdbp2, and ze4bp4-1 to -6. The spatial and temporal mRNA expression pattern of each of these factors was characterized in zebrafish embryos in the context of a functional circadian clock and regulation by light. Nine of the factors exhibited augmented and rhythmic expression in the pineal gland, a central clock organ in zebrafish. Moreover, these genes were found to be regulated, to variable extents, by the circadian clock and/or by light. Differential expression patterns of multiple paralogs in zebrafish suggest multiple roles for these factors within the vertebrate circadian clock. This study, in the genetically accessible zebrafish model, lays the foundation for further research regarding the involvement and specific roles of PAR and E4BP4 transcription factors in the vertebrate circadian clock mechanism. PMID- 20854133 TI - Photic induction of Fos in the suprachiasmatic nucleus of African mole-rats: responses to increasing irradiance. AB - African mole-rats (family Bathyergidae) are strictly subterranean rodent species that are rarely exposed to environmental light. Morphological and physiological adaptations to the underground environment include a severely reduced eye size and regressed visual system. Responses of the circadian system to light, however, appear to be intact, since mole-rats are able to entrain their circadian activity rhythms to the light-dark cycle and light induces Fos expression in the suprachiasmatic nucleus (SCN). Social organization varies from solitary species to highly elaborated eusocial structures, characterized by a distinct division of labor and in which one reproductive female regulates the behavior and reproductive physiology of other individuals in the colony. The authors studied light-induced Fos expression in the SCN to increasing light intensities in four mole-rat species, ranging from strictly solitary to highly social. In the solitary Cape mole-rat, light induces significant Fos expression in the SCN, and the number of Fos-immunopositive cells increases with increasing light intensity. In contrast, Fos induction in the SCN of social species was slightly greater than, but not statistically different from, the dark-control animals as is typical of most rodents. One species showed a trend for an increase in expression with increased light, whereas a second species showed no trend in expression. In the naked mole-rat, Fos expression appeared higher in the dark-controls than in the animals exposed to light, although the differences in Fos expression were not significant. These results suggest a gradient in the sensitivity of the circadian system to light in mole-rats, with a higher percentage of individuals that are unresponsive to light in correlation with the degree of sociality. In highly social species, such as the naked mole-rat that live in a relatively stable subterranean milieu in terms of food availability, temperature, constant darkness, and devoid of 24-h cyclic environmental cues, the temporal coordination of rest-wake activities may be dependent on social interactions and social status rather than on photic regulation of the circadian timing system. PMID- 20854134 TI - Diurnal, age, and immune regulation of interleukin-1beta and interleukin-1 type 1 receptor in the mouse suprachiasmatic nucleus. AB - Circadian clocks serve to impose a near-24-h temporal architecture on an organism's physiology, metabolism, and behavior. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master circadian pacemaker. There is growing evidence that immunomodulators, such as cytokines, may impinge on circadian timekeeping. We examined whether there is endogenous expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) and its signaling receptor IL-1R1 in the SCN of young and older mice across the diurnal cycle. We found expression of both IL-1beta and IL-1R1 in the young SCN, although only IL 1R1 displayed temporal regulation. In the older SCN, levels of IL-1beta were expressed at lower levels than in the young SCN, and IL-1R1 did not vary across the 24 h. We also report age-related day-night variation of IL-1beta and IL-1R1 in the paraventricular nucleus (PVN) of the hypothalamus. Further, we examined the effect of peripheral immune challenge on IL-1beta and IL-1R1 in the SCN. We found that IL-1beta immunoreactivity was not altered 6 or 24 h after a septic dose of lipopolysaccharide (LPS; 5 mg/kg), whereas IL-1R1 was significantly up regulated in the SCN both 6 and 24 h after LPS. We also demonstrate cellular activation in the SCN 24 h following LPS treatment, as evidenced by increased c Fos and p65-NF-kappaB (nuclear factor kappa B) expression. Our results indicate that IL-1beta and its associated signaling system may play a role in mediating the response of the circadian timing system to immune challenge as well as potentially contributing to the basal functioning of the SCN clock. PMID- 20854135 TI - Internal temporal order in the circadian system of a dual-phasing rodent, the Octodon degus. AB - Daily rhythms in different biochemical and hematological variables have been widely described in either diurnal or nocturnal species, but so far no studies in the rhythms of these variables have been conducted in a dual-phasing species such as the degus. The Octodon degus is a rodent that has the ability to switch from diurnal to nocturnal activity under laboratory conditions in response to wheel running availability. This species may help us discover whether a complete temporal order inversion occurs parallel to the inversion that has been observed in this rodent's activity pattern. The aim of the present study is to determine the phase relationships among 26 variables, including behavioral, physiological, biochemical, and hematological variables, during the day and at night, in diurnal and nocturnal degus chronotypes induced under controlled laboratory conditions through the availability of wheel running. A total of 39 male degus were individually housed under a 12:12 light-dark (LD) cycle, with free wheel-running access. Wheel-running activity (WRA) and body temperature (Tb) rhythms were recorded throughout the experiment. Melatonin, hematological, and biochemical variables were determined by means of blood samples obtained every 6 h (ZT1, ZT7, ZT13, and ZT19). In spite of great differences in WRA and Tb rhythms between nocturnal and diurnal degus, no such differences were observed in the temporal patterns of most of the biological variables analyzed for the two chronotypes. Variation was only found in plasma urea level and lymphocyte number. A slight delay in the phase of the melatonin rhythm was also observed. This study shows the internal temporal order of a dual-phasing mammal does not show a complete inversion in accordance with its activity and body temperature pattern; it would appear that the switching mechanism involved in the degu's nocturnalism is located downstream from the pacemaker. PMID- 20854136 TI - Dissociation of the circadian system of Octodon degus by T28 and T21 light-dark cycles. AB - Octodon degus is a primarily diurnal rodent that presents great variation in its circadian chronotypes due to the interaction between two phase angles of entrainment, diurnal and nocturnal, and the graded masking effects of environmental light and temperature. The aim of this study was to test whether the circadian system of this diurnal rodent can be internally dissociated by imposing cycles shorter and longer than 24 h, and to determine the influence of degus chronotypes and wheel-running availability on such dissociation. To this end, wheel-running activity and body temperature rhythms were studied in degus subjected to symmetrical light-dark (LD) cycles of T28h and T21h. The results show that both T-cycles dissociate the degus circadian system in two different components: one light-dependent component (LDC) that is influenced by the presence of light, and a second non-light-dependent component (NLDC) that free runs with a period different from the external lighting cycle. The LDC was more evident in the nocturnal than diurnal chronotype, and also when wheel running was available. Our results show that, in addition to rats and mice, degus must be added to the list of species that show an internal dissociation in their circadian rhythms when exposed to forced desynchronization protocols. The existence of a multioscillatory circadian system having two groups of oscillators with low coupling strength may explain the flexibility of degus chronotypes. PMID- 20854137 TI - Hypocretin deficiency in narcolepsy with cataplexy is associated with a normal body core temperature modulation. AB - Narcolepsy with cataplexy (NC) is a sleep disorder caused by the loss of the hypothalamic neurons producing hypocretin. The clinical hallmarks of the disease are excessive daytime sleepiness, cataplexy, other rapid eye movement (REM) sleep phenomena, and a fragmented wake-sleep cycle. Experimental data suggest that the hypocretin system is involved primarily in the circadian timing of sleep and wakefulness but also in the control of other biological functions such as thermoregulation. The object of this study was to determine the effects of the hypocretin deficit and of the wake-sleep cycle fragmentation on body core temperature (BcT) modulation in a sample of drug-free NC patients under controlled conditions. Ten adult NC patients with low cerebrospinal fluid (CSF) hypocretin levels (9 men; age: 38 +/- 12 yrs) were compared with 10 healthy control subjects (7 men; age: 44.9 +/- 12 yrs). BcT and sleep-wake cycle were continuously monitored for 44 h from 12:00 h. During the study, subjects were allowed to sleep ad libitum, living in a temperature- and humidity-controlled room, lying in bed except when eating, in a light-dark schedule (dark [D] period: 23:00-07:00 h). Sleep structure was analyzed over the 24-h period, the light (L) and the D periods. The wake-sleep cycle fragmentation was determined by calculating the frame-shift index (number of 30-s sleep stage shifts occurring every 15 min) throughout the 44-h study. The analysis of BcT circadian rhythmicity was performed according to the single cosinor method. The time-course changes in BcT and in frame-shift index were compared between narcoleptics and controls by testing the time * group (controls versus NC subjects) interaction effect. The state-dependent analysis of BcT during D was performed by fitting a mixed model where the factors were wake-sleep phases (wake, NREM stages 1 and 2, slow-wave sleep, and REM sleep) and group. The results showed that NC patients slept significantly more than controls during the 24 h due to a higher representation of any sleep stage (p < .001) during L, whereas the total amount of night sleep and its architecture were comparable in the two groups. Wake-sleep fragmentation was higher (p < .001) in NC subjects especially during L. Despite these differences, mesor (24-h mean), amplitude, and acrophase (peak time) of BcT circadian rhythm were comparable in narcoleptics and controls, and no between group differences were detected in the time-course changes and in the state dependent modulation at night of BcT. These data indicate that the hypocretin deficit in drug-free NC patients and their altered wake-sleep cycle couple with an intact modulation of BcT. PMID- 20854138 TI - Heart-rate variability in women during 40-hour prolonged wakefulness. AB - Heart-rate variability patterns of 18 women during a 40-h constant routine of prolonged wakefulness under controlled laboratory conditions were analyzed. The authors tested the circadian timing of the autonomic nervous system and the relationship between the sympathetic and vagal branches in women with both a functional disorder of vascular regulation (main symptom: cold hands and feet) and prolonged sleep onset and controls without these symptoms. Spectral analysis of R-R intervals during paced breathing episodes revealed significantly lower power values in the high-frequency band (HF; 0.15-0.4 Hz) but not in the low frequency band (LF; 0.04-0.15 Hz), leading to a significantly elevated LF/HF ratio in the former group. A significant circadian rhythm in LF power and heart rate occurred in both groups, and a significant correlation was found between sleepiness and sympathovagal balance (r = .53, p < .05). These findings indicate not only an autonomic imbalance in the first group compared with controls, but also two strategies of the autonomic nervous system to fight against fatigue in women. One implies circadian control and the other homeostatic control, and both are reflected by the LF/HF ratio. PMID- 20854139 TI - Influence of circadian time of hypertension treatment on cardiovascular risk: results of the MAPEC study. AB - Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP) lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with >=1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6 +/- 13.6 (mean +/- SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or >=1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p < .001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p < .001). After a median follow-up of 5.6 yrs, subjects ingesting >=1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29-0.51]; number of events 187 versus 68; p < .001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19-0.55]; number of events: 55 versus 18; p < .001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with >=1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non dipping, and, most importantly, significantly reduced CVD morbidity and mortality. PMID- 20854140 TI - Perspectives on the chronotherapy of hypertension based on the results of the MAPEC study. AB - Appreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional beta blocker and diuretic medications versus a special drug-delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of >=1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a "more normal" day-night variation, simply by enhancing natriuresis during the night-the time-of-day when it can be most effective. A modification as simple and inexpensive as switching >=1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as "normotensive non dipper" (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high "smoothness index" medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration. PMID- 20854144 TI - Characterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET 2 clinical studies. AB - The randomized, placebo-controlled Phase III DUET studies enrolled treatment experienced, HIV-1-infected patients. We examined the genotypic and phenotypic changes at endpoint relative to baseline, including the emergence of individual reverse transcriptase (RT) mutations, in patients who received the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine and experienced virologic failure by rebound by the time of the Week 96 analysis. Patients received etravirine 200 mg twice-daily in combination with a background regimen containing darunavir/ritonavir, investigator-selected nucleoside reverse transcriptase inhibitors, and optional enfuvirtide. Virologic failure by rebound occurred in 93 (15.5%) etravirine-treated patients (compared with 170 [28.1%] placebo-treated patients). Patients experiencing virologic failure had more baseline antiretroviral resistance and lower activity of the background regimen relative to those not experiencing failure. Emergence of NNRTI resistance-associated mutations was observed in 55 of 93 patients. The most frequently emerging RT mutations were V179F, V179I, and Y181C, with positions K101 and E138 also showing frequent changes. Mutations usually emerged in a background of multiple other NNRTI mutations and were, in most cases, associated with a decrease in phenotypic sensitivity to etravirine at endpoint. Further analysis is needed to clarify the role of mutations at position 138 as determinants of etravirine resistance. PMID- 20854145 TI - Assessment of instructors' readiness for implementing e-learning in continuing medical education in Iran. AB - BACKGROUND: E-learning provides new levels of flexibility in learning and teaching. This contribution of e-learning is dependent on the levels of readiness in several critical factors particularly in an educational organization. AIM: The purpose of this study was to assess instructors' readiness and to identify the most important factors that affect their readiness in e-learning in CME programs in order to use the effective opportunities that facilitate e-learning in CME programs. METHODS: A 5-point Likert scale instrument consisting of two domains (technical and pedagogical) was constructed according to four subdomains (knowledge, attitude, skills, and habits) and distributed to 70 faculty members. A factor analysis was employed to extract significant factors. RESULTS: The results revealed that the mean of readiness on e-learning for faculty members was 3.25 +/- 0.58 in technical and 3.37 +/- 0.49 in pedagogical domains on a 5-point Likert scale (1-5). The factors such as "familiarity with learning management system," "willingness to teach by adopting a new technology," "willingness to use e-learning as a viable alternative," "ability to deliver e-material and to provide e-content for teaching," and "being accustomed to the virtual environment and utilization of the computer and the internet" were extracted on technical readiness domain. In addition, the pedagogical readiness factors were: "familiarity with online teaching principle and method," "willingness to use technology in instruction and material development," "ability to design content for e-material and online course evaluation," and "being accustomed to providing information back up regularly and employing eclectic methods and multiple approaches in teaching." CONCLUSION: The findings of this study suggest that training should be offered to instructors on a continuous, rather than a one-off basis so that their IT knowledge and skills are upgraded over time. In addition, results indicate that pedagogical innovations are required to develop and implement an effectiveness e-learning program. PMID- 20854146 TI - The role of the assessor in the assessment of practice: An alternative view. AB - BACKGROUND: Traditionally, the assessment of the competent practical performance of student health professionals places a high level of confidence upon the ability of a second party to judge whether students are able to apply theory in practical contexts. More often than not, the specific assessment tool has a clear focus on the conduct of skills to explicit performance criteria. However, what has proven particularly problematic is the ability to devise a tool to assess the less overtly procedural qualities, such as professionalism, interpersonal skills, clinical reasoning and so forth. When such assessment tools are designed there is also particular challenge to counter the potential for conscious or unconscious bias on the part of the assessor. AIM: With direct reference to enactivist theory, and using illustrations from undergraduate medical, nursing and physiotherapy education, it is argued that in the conduct of any assessment the assessor is as much an integral part of the assessment as is the student. CONCLUSION: The enactivist perspective has clear implications for the role of the assessor in the preparation, conduct and outcome of the assessment of practice related activities. PMID- 20854147 TI - Empathy and its correlates in Iranian physicians: A preliminary psychometric study of the Jefferson Scale of Physician Empathy. AB - BACKGROUND: Empathy is one of the fundamental factors in patient care that is beneficial to both patient and physician. AIMS: To assess the psychometric properties of the Persian version of the Jefferson Scale of Physician Empathy (JSPE) in a sample of Iranian physicians and examine its correlates. METHOD: Two hundred and seven general physicians completed the JSPE. The associations of empathy scores with demographic characteristics and practice-related variables were examined. RESULTS: The scale showed an acceptable internal consistency (alpha = 0.78). Three of six extracted factors were considered as prominent based on the scree test, which were similar to those obtained in the US samples. Women scored higher than men. Empathy improved with increasing practice experiences. Other practice-related variables did not show a significant association with empathy. CONCLUSIONS: Results support the construct and criterion-related validities and reliability of the Persian version of the JSPE. Score difference between Iranian and American samples may not reflect a genuine difference in empathy trait and can be explained by cultural factors. PMID- 20854148 TI - Study-related health and behavior patterns of medical students: A longitudinal study. AB - BACKGROUND: Little is known about specific health risks and resources and their development influencing medical students' stress. AIM: To evaluate the development of quality of life and study-related behavior and experience patterns among medical students. METHODS: Data were collected in the first (n = 112 of 182 in 2006) and the fourth semesters (n = 164 of 176 in 2008). The instruments "Work Related Behavior and Experience Patterns" (AVEM, including four main patterns: "Health", "Unambitious," "Overexertion," "Burnout") and "Short Form-12 Health Survey (SF-12)" were used at both points in time. RESULTS: The medical students scored significantly lower on mental health compared with reference samples of young adults. The proportion of students with a healthy pattern decreased from 47.3% (95% CI 38.1-56.5%) in the first semester to 36.9% (29.4-44.4%) in the fourth semester. This corresponded to an increase in the proportion of students at risk for burnout from 7.1% (2.3-11.9%) to 20% (13.8-26.2%). At both time points, female students had a higher risk for overexertion and a lower prevalence of a healthy pattern than male students. CONCLUSION: Our data provide evidence for a decrease in the healthy pattern and an increase in the burnout pattern. Intervention is needed, especially for students at risk for burnout. PMID- 20854149 TI - Improvements in medical school wellness and career counseling: A comparison of one-on-one advising to an Advisory College Program. AB - BACKGROUND: Medical students have unmet needs in the areas of career and wellness advising. AIMS: The goal of this study is to describe the development of an Advisory College Program (ACP) and assess its effectiveness compared to a traditional one-on-one faculty advisor system. METHODS: The ACP, consisting of four colleges co-led by Advisory College Directors and supported by key Faculty, was developed to provide structured career and wellness advising. The authors compared the ACP to the former Faculty Advisory Program (FAP) using two parallel questionnaires. RESULTS: Surveys were completed by 74% of first-year students, 60% of second-year students, and 88% of third-year students. Survey data demonstrated a significant increase in the number of students who could identify their advisor, the frequency of student-advisor contacts, and the perceived accessibility of advisors in the ACP compared to the FAP. While an ordinal logistic regression model did not demonstrate a significant effect of the new advising system on overall satisfaction, univariate analysis demonstrated a significant increase in student satisfaction with wellness and career counseling. CONCLUSIONS: The ACP was more effective in promoting student wellness and career counseling than the traditional one-on-one faculty advisor system. Similar college-based programs may be beneficial to students at other medical school programs. PMID- 20854150 TI - Teaching for clinical reasoning - helping students make the conceptual links. AB - BACKGROUND: Dental educators complain that students struggle to apply what they have learnt theoretically in the clinical context. This paper is premised on the assumption that there is a relationship between conceptual thinking and clinical reasoning. AIMS: The paper provides a theoretical framework for understanding the relationship between conceptual learning and clinical reasoning. METHOD: A review of current literature is used to explain the way in which conceptual understanding influences clinical reasoning and the transfer of theoretical understandings to the clinical context. RESULTS: The paper argues that the connections made between concepts are what is significant about conceptual understanding. From this point of departure the paper describes teaching strategies that facilitate the kinds of learning opportunities that students need in order to develop conceptual understanding and to be able to transfer knowledge from theoretical to clinical contexts. Along with a variety of teaching strategies, the value of concept maps is discussed. The paper provides a framework for understanding the difficulties that students have in developing conceptual networks appropriate for later clinical reasoning. CONCLUSION: In explaining how students learn for clinical application, the paper provides a theoretical framework that can inform how dental educators facilitate the conceptual learning, and later clinical reasoning, of their students. PMID- 20854151 TI - Competency-based integrated practical examinations: Bringing relevance to basic science laboratory examinations. AB - BACKGROUND: The practical examinations in subject-based curriculum have been criticized for lack of relevance and clinical application. We developed competency-based integrated practical examinations (IPEs) for first two years incorporating basic science principles with clinical relevance in our integrated curriculum. AIM: To bring relevance to basic science laboratory practical examinations by conducting competency-based IPEs. METHODS: IPEs were developed according to competency-based blueprinting for each integrated module. Clinical scenarios were used as triggers followed by tasks pertaining to laboratory tests, relevant physical diagnosis and ethics/professional aspects utilizing standardized patients. Checklists were developed for standardized marking. A feedback questionnaire and two focus group discussions were administered to a random group of students from both first and second year students. Faculty members' feedback was also recorded on a questionnaire. RESULTS: Almost all the students agreed that IPE was a useful experience. Eighty-nine percent agreed that it was a fair examination and elicited a lesser degree of psychological stress. Eighty-two percent agreed that IPE encouraged critical thinking and application of knowledge. However, students suggested better organization and longer duration of stations. Faculty members also liked the experience. CONCLUSION: In conclusion, IPEs were well-received and valued both by students and faculty members. PMID- 20854152 TI - The role of general practice in postgraduate basic training. AB - BACKGROUND: In recent years, there has been growing interest in the role of primary care in postgraduate training. Relatively little has been published about benefits of early and sustained postgraduate basic training in general practice, especially for doctors with other ambitions than family medicine. AIM: To explore young Danish doctors' views on basic medical training including views on the participation of general practice. METHODS: We conducted a cross-sectional survey of all Danish doctors, who took part in the postgraduate basic training programmes in 2009. The survey consisted of rating scale and qualitative questions. We used a phenomenological approach. RESULTS: Almost all of the young Danish doctors responding felt that training in general practice is a necessary part of a postgraduate basic training programme. Early training in primary care not only gives doctors a broad understanding of the health care system but also strengthens the ability to collaborate with general practitioners upon entering another specialty. It also develops important medical and communicative competences. The training in general practice is considered beneficial for the development of professional identity. The educational environment in general practice is rated highly. CONCLUSION: The inclusion of family medicine in postgraduate basic training should be considered for all doctors. PMID- 20854153 TI - Building a competency-based workplace curriculum around entrustable professional activities: The case of physician assistant training. AB - BACKGROUND AND AIM: Competency-based medical education (CBME) is increasingly dominating clinical training, but also poses questions as to its practical implementation. There is a need for practical guidelines to translate CBME to the clinical work floor. This article aims to provide a practical model, based on the concept of entrustable professional activities (EPAs) to make this translation, derived from curriculum building for physician assistants (PAs). METHOD: For the training of PAs at the Utrecht University of Applied Sciences, a three-step model was developed to guide competency-based curriculum development, teaching and assessment. It includes specific guidelines for the identification, systematic description and planning of EPAs. RESULTS: The EPA concept appeared to be a useful tool to build competency-based clinical workplace curricula. Implementation of the curriculum requires use of trainee portfolios and progress interviews, statements of rewarded responsibility and training of supervisors. The individualised approach and flexibility that true CBME implies is brought into practice with this model. DISCUSSION: The model may also be transferred to other domains of clinical training, among which postgraduate training for medical specialties. PMID- 20854154 TI - Patient-centredness in a context of increasing diversity: Location, location, location. PMID- 20854155 TI - How to measure the quality of the OSCE: A review of metrics - AMEE guide no. 49. AB - With an increasing use of criterion-based assessment techniques in both undergraduate and postgraduate healthcare programmes, there is a consequent need to ensure the quality and rigour of these assessments. The obvious question for those responsible for delivering assessment is how is this 'quality' measured, and what mechanisms might there be that allow improvements in assessment quality over time to be demonstrated? Whilst a small base of literature exists, few papers give more than one or two metrics as measures of quality in Objective Structured Clinical Examinations (OSCEs). In this guide, aimed at assessment practitioners, the authors aim to review the metrics that are available for measuring quality and indicate how a rounded picture of OSCE assessment quality may be constructed by using a variety of such measures, and also to consider which characteristics of the OSCE are appropriately judged by which measure(s). The authors will discuss the quality issues both at the individual station level and across the complete clinical assessment as a whole, using a series of 'worked examples' drawn from OSCE data sets from the authors' institution. PMID- 20854156 TI - University medical education in Kenya: The challenges. AB - There are two medical schools training doctors in Kenya: the Moi University established in 1984 and the University of Nairobi established in 1967. The University of Nairobi has so far produced the majority of Kenyan doctors. Both are public universities with the Government being the main financier. The increased demand for university education and the inability to meet these demands has led to the introduction of a system of training self-sponsored medical students alongside Government-subsidised students. One other public university has started a medical school. The pressure to increase the number of schools and students in the absence of increased resources poses a particular challenge to the country. PMID- 20854157 TI - How are we 'doing' cultural diversity? A look across English Canadian undergraduate medical school programmes. AB - BACKGROUND: Cultural diversity education is a required curriculum component at all accredited North American medical schools. Each medical school determines its own content and pedagogical approaches. AIM: This preliminary study maps the approaches to cultural diversity education in English Canadian medical schools. METHODS: A review of 14 English Canadian medical school websites was undertaken to identify the theoretical approaches to cultural diversity education. A PubMed search was also completed to identify the recent literature on cultural diversity medical education in Canada. Data were analysed using 10 criteria that distinguish pedagogical approaches, curricular structure, course content and theoretical understandings of cultural diversity. RESULTS: Based on the information posted on English Canadian medical school websites, all schools offer cultural diversity education although how each 'does' cultural diversity differs widely. Two medical schools have adopted the cultural competency model; five have adopted a critical cultural approach to diversity; and the remaining seven have incorporated some aspects of both approaches. CONCLUSIONS: More comprehensive research is needed to map the theoretical approaches to cultural diversity at Canadian medical schools and to evaluate the long-term effectiveness of these approaches on improving physician-patient relationships, reducing health disparities, improving health outcomes and producing positive learning outcomes in physicians. PMID- 20854158 TI - Developing professionalism through the use of wikis: A study with first-year undergraduate medical students. AB - AIM: Learning about professionalism occurs through collaboration, with peer groups being important sources of support for students [Sandars J, Homer M, Pell G, Croker T. 2008. Web 2.0 and social software: The medical student way of e learning. Med Teach 14:1-5. Accessed 2008 February 14]. This study aimed to discover whether the use of wikis (collaborative websites) could enhance medical students' development of professionalism. METHODS: An online wiki was made available to four problem-based learning (PBL) groups, involving 32 students. Data collection comprised a small-scale student survey and four focus groups eliciting their views about wiki use, triangulated with facilitator interviews and wiki usage statistics. RESULTS: Several factors affected individual student and group engagement with wikis, such as positive group dynamics. Students shared web links, helping clarify PBL discussions and increase their confidence. CONCLUSIONS: Two main benefits of using wikis for the development of professionalism with medical students were revealed. First, wikis acted as a shared knowledge base for hard-to-find resources on professionalism. Second, it was precisely when students reflected on the difference between interacting in wikis and their online social spaces, or when they considered whether or not to post a resource that their sense of professionalism emerged. PMID- 20854159 TI - Developing expertise in surgery. AB - The concept of expertise is widely embraced but poorly defined in surgery. Dictionary definitions differentiate between authority and experience, while a third view sees expertise as a mind-set rather than a status. Both absolute and relative models of expertise have been developed, and each allows a richer understanding of the application of these concepts to emerge. Trainees must develop both independent and interdependent expertise, and an appreciation of the essentially constructivist and uncertain nature of medical knowledge. Approach may be more important than innate talent; the concepts of 'flow', sustained 'deliberate practice' and 'adaptive expertise' are examples of expert approaches to learning. Non-analytical reasoning plays a key role in decision making at expert levels of practice. A technically gifted surgeon may be seen as a safety hazard rather than an expert if inter-dependent expertise has not been developed. Key roles of a surgical educator are to facilitate the development of an expert approach to education and to enable entry into and movement towards the centre of an expert community of practice. PMID- 20854160 TI - Putting theory into practice - a case study in one UK medical school of the nature and extent of unprofessional behaviour over a 6-year period. AB - BACKGROUND: Producing a medical profession which is fit for the demands and expectations of society involves ensuring that practitioners learn what it means to behave in a 'professional' way. Codes of professional conduct have been developed for medical students in the UK, but the literature on how medical schools actually apply these is small. More detail is needed to evaluate approaches to assessing professionalism, or to analyse the extent to which students 'fail' this aspect. AIM: To describe one UK medical school's approach to monitoring and assessing aspects of professional behaviour; quantify the prevalence and severity of behaviours recognised as cause of concern in the first 6 years of the programme; evaluate whether there is evidence of any association between professional and academic underperformance and draw conclusions for further development of fitness to practice procedures. METHODS: Mixed methods utilising exam board and administrative data for statistical and descriptive analysis. RESULTS: Even under detailed scrutiny, only 3% of students received formal warnings for behavioural problems over the course of a 5-year programme, and notifications decreased as students entered the senior years. There was a trend towards association between academic and professional underperformance. CONCLUSION: Creating clear expectations, providing positive role models and monitoring student behaviour makes explicit what is expected of students as 'professionals in the making', and contributes to overall low rates of misdemeanour. The predictive value of recurrent and serious behavioural problems is not yet known as it is too soon for these graduates to have established careers. Students who are struggling academically may also present with unprofessional behaviours but the cause of this is unclear. Further research is needed to benchmark systems across the UK, and to know whether formalising expectations of undergraduates result in less problems in subsequent practice. PMID- 20854161 TI - Virtual patient simulation for learning and assessment: Superior results in comparison with regular course exams. AB - BACKGROUND: Our study aimed to observe the differences in assessment results between virtual patient simulation (VPS) and regular course exams in an Internal Medicine course for undergraduate medical students. METHODS: Four cohorts of students (n = 216) used: a VPS or lectures for learning (terms 1 and 2); VPS and lectures or only lectures (term 3); and a paired set-up with both VPS and lectures (term 4). The assessment results, measured with both a VPS-based exam and a paper-based exam, were compared. A scoring rubric (0-6), developed and validated for the purpose of the trial, was applied to both types of assessment. Mean score differences of the results were compared for the four cohorts. RESULTS: Both VPS and regular examination results were significantly higher in the VPS group compared to regular exam group (p < 0.001) in terms 1, 2 and 3. The paired mean difference in term 4 was 0.66 (95% confidence interval (CI) 0.50, 0.83; p < 0.001) for haematology and 0.57 (95% CI 0.45, 0.69; p < 0.001) for cardiology. CONCLUSION: Our findings suggest that using VPS both for learning and for assessment supports learning. VPS are better than traditional assessment methods when the virtual application is used for both learning and evaluation. PMID- 20854162 TI - Quality of courses evaluated by 'predictions' rather than opinions: Fewer respondents needed for similar results. AB - BACKGROUND: A well-known problem with student surveys is a too low response rate. Experiences with predicting electoral outcomes, which required much smaller sample sizes, inspired us to adopt a similar approach to course evaluation. We expected that having respondents estimate the average opinions of their peers required fewer respondents for comparable outcomes than giving own opinions. METHODS: Two course evaluation studies were performed among successive first-year medical students (N = 380 and 450, respectively). Study 1: Half the cohort gave opinions on nine questions, while the other half predicted the average outcomes. A prize was offered for the three best predictions (motivational remedy). Study 2: Half the cohort gave opinions, a quarter made predictions without a prize and a quarter made predictions with previous year's results as prior knowledge (cognitive remedy). The numbers of respondents required for stable outcomes were determined following an iterative process. Differences between numbers of respondents required and between average scores were analysed with ANOVA. RESULTS: In both studies, the prediction conditions required significantly fewer respondents (p < 0.001) for comparable outcomes. The informed prediction condition required the fewest respondents (N < 20). CONCLUSION: Problems with response rates can be reduced by asking respondents to predict evaluation outcomes rather than giving opinions. PMID- 20854163 TI - Does medical student knowledge of anticoagulation differ by future intended practice? AB - BACKGROUND: The scope of medical student knowledge may differ by the student's future intended specialty. AIM: To determine whether medical student knowledge of and confidence with anticoagulation differed by perceived likelihood of managing anticoagulation in future practice. METHODS: One hundred and twenty-three third- and fourth-year medical students (41% response rate) participated in a cross sectional web-based survey. We assessed whether perceived likelihood of managing anticoagulation in future intended practice was associated with anticoagulation knowledge and confidence with managing anticoagulation. RESULTS: Out of 24 questions assessing anticoagulation knowledge, the mean percentage correct was 58% (SD 29%). Anticoagulation knowledge did not differ by perceived likelihood of managing anticoagulation as part of their future practice. However, students predicting higher likelihood of managing anticoagulation in their future practice were significantly more confident about their abilities to manage anticoagulation (p = 0.005). CONCLUSION: Using anticoagulation as a model, we did not find evidence that medical student knowledge differed by perceived scope of future practice. Future study will need to confirm whether range and depth of medical knowledge differs by medical students' intended future practice and specialties. PMID- 20854164 TI - Can nonverbal communication skills be taught? AB - BACKGROUND: While nonverbal communication (NVC) is an essential part of a physician's interpersonal skills, it has attracted relatively little attention in medical education. AIM: To develop a program for teaching NVC skills, and to examine whether it would improve student's awareness and performance of NVC. METHODS: A total of 106 preclerkship medical students were randomly assigned to 14 groups for a communication skills training session before an objective structured clinical examination (OSCE). Five faculty members served as session facilitators, of whom three provided the original program (n = 67) and two provided the NVC intervention program (n = 39). After the training session, students wrote their goals for the OSCE medical interview, which were analyzed for content. The student's performance of NVC was evaluated based on the video recording of the OSCE. RESULTS: Students in NVC group were significantly more likely to write goals related to NVC, but no significant differences were found in the NVC evaluations at the OSCE. CONCLUSION: The intervention was effective in increasing student's awareness of NVC, but it was not sufficient to change the actual performance. Further research is needed to explore whether additional training would actually improve their NVC performance. PMID- 20854165 TI - An introduction to the status of radiology education in a leading Chinese medical school: Comparison to a leading US medical school. PMID- 20854167 TI - Weight misperception and psychosocial health in normal weight Chinese adolescents. AB - OBJECTIVE: To investigate the association between weight misperception and psychosocial health problems among normal weight Chinese adolescent boys and girls. METHODS: In the Youth Smoking Survey 2003-04, 20 677 normal weight students aged 11-18 years from 85 randomly selected schools throughout Hong Kong were analysed. Students who perceived themselves as very thin, thin, fat or very fat were classified as having weight misperception in contrast to the reference group who correctly perceived themselves as normal weight. Psychosocial health outcomes included headache, feeling stressful, feeling depressed, poorer appetite, sleepless at night, having nightmares and less confidence in getting along with friends. Logistic regression yielded adjusted odds ratios (ORs) for each outcome by weight misperception in boys and girls separately. RESULTS: In girls, misperceived fatness was associated with all outcomes, while misperceived thinness was associated with poorer appetite and less confidence. Boys who misperceived themselves as very thin or fat had greater odds of all outcomes except having nightmares. In general, greater ORs were observed for misperceived fatness than thinness in girls, but similar ORs were observed in boys. Misperceived thinness and fatness accounted for 0.6% to 45.1% of the psychosocial health problems in adolescents. CONCLUSIONS: Normal weight adolescents with weight misperception were more likely to have psychosocial health problems, and the associations were stronger for extreme misperceptions (i.e., very fat or very thin) in both boys and girls. PMID- 20854168 TI - SDF-1alpha secreted by human CD133-derived multipotent stromal cells promotes neural progenitor cell survival through CXCR7. AB - We recently reported that concentrated conditioned medium (CdM) from human CD133 derived bone marrow progenitor cells (CD133 CdM) was neuroprotective after stroke. Here we identify stromal-derived factor 1 alpha (SDF-1) as a potential neuroprotective candidate in CD133 CdM by interrogating the transcriptional responses of CD133-derived multipotent stromal cells (CD133dMSCs) after cell injection into the ischemic brain. Human SDF-1 mRNA was upregulated 79-fold by CD133dMSCs when injected into the stroke peri-infarct area compared with cells injected into the uninjured parenchyma of sham-operated animals. In cell protection assays, we replaced the typical growth medium in mouse neural progenitor cell (mNPC) cultures with serum-free CD133 CdM immediately before exposure to hypoxia (1% oxygen) for 48 h. CD133 CdM significantly increased the survival of mNPCs during hypoxia exposure and growth factor withdrawal. To determine whether MSC-secreted SDF-1 influenced mNPC survival, we used lentiviral short hairpin RNA against SDF1 (shSDF-1) to knockdown SDF-1 expression in CD133dMSCs. The CdM generated from shSDF-1-treated cells had a 94% decrease in secreted SDF-1 and was significantly less protective for mNPCs when compared with control CdM from CD133dMSCs transduced with scrambled short hairpin RNA. Pharmacological inhibition of the 2 known SDF-1 receptors, CXCR4 and CXCR7, revealed that only CXCR7 activity was functionally linked to survival signaling in mNPCs during hypoxia exposure. Treatment of mNPCs with CD133 CdM and CXCR7 inhibitor decreased mNPC viability by 36.5% +/- 12.8% and decreased cell number by 21% +/- 6.7% compared with dimethyl sulfoxide treated controls. These data indicate that SDF-1 is a key neuroprotective cytokine secreted by CD133dMSCs that protects mNPCs through CXCR7. PMID- 20854169 TI - Genotypic impact of prolonged detectable HIV type 1 RNA viral load after HAART failure in a CRF01_AE-infected cohort. AB - HIV subtype-specific data on mutation type, rate, and accumulation following HAART treatment failure are limited. We studied patterns and accrual of drug resistance mutations in a Cambodian CRF01_AE-infected cohort continuing a virologically failing first-line, nonnucleoside reverse transcriptase inhibitor- (NNRTI-) based, HAART. Between 2005 and 2007, 837 adult HIV-infected patients had regular plasma HIV-1 RNA viral load measurements at Sihanouk Hospital Centre of Hope (SHCH), Cambodia. Drug resistance testing was performed in all patients with HIV-1 RNA >1000 copies/ml after at least 6 months of HAART. Seventy-one patients with a mean age of 34 years, of whom 68% were male, were retrospectively assessed at virological failure. The median duration of antiretroviral therapy was 12.3 (IQR 7.1-18.23) months, the median CD4 cell count was 173 (IQR 118-256) cells/mm(3), and the mean plasma HIV-1 RNA viral load was 3.9 log (SD 0.72) at failure. NNRTI mutations, M184I/V mutation, thymidine analogue mutations, and K65R were observed in 78.9%, 69%, 20%, and 12.7% of patients, respectively. For 33 patients, genotypic testing was carried out on at least two occasions before the switch to second-line HAART after a median duration of 5.8 (IQR 4.3-6.1) months of virological failure: 54.5% of patients accumulated new mutations with a rate of 1.6 mutations per person-year. Accumulation was seen both for nucleoside and nonnucleoside reverse transcriptase inhibitors, and also in patients with low level viremia. Subtype-specific data on mutation type, rate, and accumulation after HAART failure are urgently needed to optimize treatment strategies in resource-limited settings. PMID- 20854171 TI - Physiologically-based pharmacokinetics in drug development and regulatory science. AB - The application of physiologically-based pharmacokinetic (PBPK) modeling is coming of age in drug development and regulation, reflecting significant advances over the past 10 years in the predictability of key pharmacokinetic (PK) parameters from human in vitro data and in the availability of dedicated software platforms and associated databases. Specific advances and contemporary challenges with respect to predicting the processes of drug clearance, distribution, and absorption are reviewed, together with the ability to anticipate the quantitative extent of PK-based drug-drug interactions and the impact of age, genetics, disease, and formulation. The value of this capability in selecting and designing appropriate clinical studies, its implications for resource-sparing techniques, and a more holistic view of the application of PK across the preclinical/clinical divide are considered. Finally, some attention is given to the positioning of PBPK within the drug development and approval paradigm and its future application in truly personalized medicine. PMID- 20854170 TI - Isolation of potent neutralizing monoclonal antibodies from an SIV-Infected rhesus macaque by phage display. AB - The humoral immune response is a mechanism that potently suppresses or prevents viral infections. However, genetic diversity and resistance to antibody-mediated neutralization are serious obstacles in controlling HIV-1 infection. In this study, we isolated monoclonal antibodies from an SIV-infected macaque by using the phage display method to characterize antibodies in SIV infection. Variable regions of immunoglobulin genes were amplified by rhesus macaque-specific primers and inserted into the phagemid pComb3X, which produced the Fab fragment. Antibodies against SIV proteins were selected by biopanning using an SIV protein coated 96-well plate. A total of 20 Fab clones obtained included 14 clones directed to gp41, four clones to gp120, and two clones to p27. The anti-gp120 Fab clones completely neutralized the homologous neutralization-sensitive SIVsmH635FC and the genetically divergent SIVmac316, and showed at least 50% inhibition against the neutralization-resistant strain, SIVsmE543-3. Competition ELISA revealed that these anti-gp120 Fab clones recognize the same epitope on gp120 including the V3 loop. Identification of antibodies with potent neutralizing activity will help to elucidate the mechanisms for inducing broadly neutralizing antibodies. PMID- 20854172 TI - HTLV-2b among HIV type 1-coinfected injecting drug users in Spain. AB - Human T cell lymphotropic virus type 2 (HTLV-2) infection is endemic in the American Indian population and Pygmy tribes in Africa. Nevertheless, HTLV-2 infection has been predominantly detected in U.S. and European injecting drug users (IDU). Noteworthy is that the HTLV-2a subtype is the main circulating variant in North America and Eastern Europe whereas the HTLV-2b subtype is mainly found in Western Europe, particularly in Italy and Spain where coinfection with HIV-1 is frequent. Twelve Spanish subjects infected with HTLV-2 were recruited for the study. All of them were IDUs coinfected with HIV-1. Molecular epidemiology was done by sequencing the LTR, env, and tax regions and by generating phylogenetic trees. The present study showed that all the sequences belonged to the HTLV-2b subtype and were closely related to other Spanish and Portuguese reported sequences, clearly differentiated from those belonging to the HTLV-2a subtype from Eastern Europe. Therefore, infection with HTLV-2b remains prevalent in Spain based on previous studies. PMID- 20854173 TI - Directly observed antiretroviral therapy in substance abusers receiving methadone maintenance therapy does not cause increased drug resistance. AB - Direct observation of antiretroviral therapy (DOT) can increase adherence rates in HIV-infected substance users, but whether this affects the development of antiretroviral drug resistance has not been fully explored. We conducted a 24 week randomized controlled trial of methadone clinic-based antiretroviral DOT compared with treatment as usual (TAU) among antiretroviral-experienced substance users. To examine the development of new resistance mutations, we identified all participants with an amplifiable resistance test at both baseline and either week 8 or week 24. We compared the development of new drug resistance mutations between participants in the two arms of the trial. Among the 77 participants enrolled in the parent trial, antiretroviral DOT was efficacious for improving adherence and decreasing HIV viral load. Twenty-one participants had a detectable HIV viral load at both baseline and a second time point. Of these, nine developed new drug resistance mutations not seen at baseline (three in the DOT arm and six in the TAU arm; p = 0.27). Overall, five subjects in the TAU arm developed major mutations correlating with their current antiretroviral regimen, while no subjects in the DOT arm developed such mutations. Direct observation of antiretroviral therapy was associated with improved adherence and viral suppression among methadone maintained HIV-infected substance users, but was not associated with an increase in the development of antiretroviral drug resistance. DOT should be considered for substance users attending methadone maintenance clinics who are at high risk of nonadherence. PMID- 20854175 TI - Development of the Illness Perception Questionnaire Mental Health. AB - BACKGROUND: It has been suggested that illness perceptions in mental health are related to treatment outcomes. AIMS: We aimed to develop a short generic questionnaire to assess clients' problem perceptions in mental health, congruent with the Illness Perception Questionnaire (IPQ) for somatic health. METHODS: We adapted the IPQ-R (Moss-Morris, R., Weinman, J., Petrie, K.J., Horne, R., Cameron, L.D., & Buick, D. ( 2002 ). Psychology and Health, 17, 1-16) to psychological complaints, in particular the IPQ-R's scales that assess clients' perceptions of what their problem actually is and what its causes are. We administered our adapted instrument, the IPQ-MH, to large groups of mental health clients, and subsequently performed psychometric analyses over the scores. RESULTS: The identity scale of the IPQ-MH differentiates different clients; the structure scale of the IPQ-MH replicates that of the original IPQ-R; the cause scale reliably measures clients' attributions of causes to their mental problems. CONCLUSIONS: We conclude that our IPQ-MH can reliably assess clients' mental health problem perceptions. PMID- 20854174 TI - State of the art in therapeutic hypothermia. AB - Historically, hypothermia was induced prior to surgery to enable procedures with prolonged ischemia, such as open heart surgery and organ transplant. Within the past decade, the efficacy of hypothermia to treat emergency cases of ongoing ischemia such as stroke, myocardial infarction, and cardiac arrest has been studied. Although the exact role of ischemia/reperfusion is unclear clinically, hypothermia holds significant promise for improving outcomes for patients suffering from reperfusion after ischemia. Research has elucidated two distinct windows of opportunity for clinical use of hypothermia. In the early intra ischemia window, hypothermia modulates abnormal cellular free radical production, poor calcium management, and poor pH management. In the more delayed post reperfusion window, hypothermia modulates the downstream necrotic, apoptotic, and inflammatory pathways that cause delayed cell death. Improved cooling and monitoring technologies are required to realize the full potential of this therapy. Herein we discuss the current state of clinical practice, clinical trials, recommendations for cooling, and ongoing research on therapeutic hypothermia. PMID- 20854176 TI - Effect on virulence and pathogenicity of H5N1 influenza A virus through truncations of NS1 eIF4GI binding domain. AB - To study the effect of NS1 eIF4GI binding domain on virulence and pathogenicity of H5N1 influenza A virus, 5 recombinant H5N1 viruses encoding eIF4GI binding domain-truncated NS1 proteins and parental NS1 (NS1-wt) were generated by an 8 plasmid-based reverse genetics system. The results indicated that the recombinants with the addition of 5-amino acid and the deletion position of 85-89 in NS1-wt were attenuated in replication in vitro and in vivo, compared with the recombinant wild-type virus rNS1-wt, whereas the deletion position 85-94 or the entire eIF4GI binding domain in NS1-wt displayed a significantly attenuated phenotype in chicken and mice. We also showed that the eIF4GI binding domain truncated mutants were impaired in their ability to inhibit interferon production in vitro, and they did not replicate as efficiently as the parental recombinant strain in embryonated hen eggs, in Madin -Darby Canine Kidney cells, or in vivo in chickens and in a mouse model. Therefore, these attenuated NS1-truncated viruses may have a great potential as live attenuated vaccine candidates against H5N1 influenza A virus. PMID- 20854177 TI - MicroRNAs as therapeutic targets for lung cancer. AB - Lung cancer is one of the leading causes of mortality in the world, indicating the need for innovative therapies for the disease. In recent years, microRNAs have emerged as one of the key players in regulating gene expression. Numerous studies have documented the implications of microRNAs in nearly every carcinogenesis process of lung cancer, including tumor development, apoptosis, invasion and metastasis, as well as anti-cancer drug resistance. Forced expression or suppression of microRNA can regulate the biological alteration during carcinogenesis, underscoring the therapeutic potential of microRNAs in lung cancer. This editorial summarizes recent reports of some key microRNAs that can modulate the lung cancer carcinogenesis process, expound the mechanisms by which they exert their functions, introduce some approaches for manipulating the action of microRNAs, and discuss the perspectives of microRNAs as therapeutic targets for lung cancer. PMID- 20854178 TI - PPARs as therapeutic targets in cardiovascular disease. AB - IMPORTANCE OF THE FIELD: The role of peroxisome proliferator-activated receptors PPARalpha, PPARdelta and PPARgamma in cardiovascular disease is receiving widespread attention. As ligand-activated nuclear receptors, they play a role in regulation of lipid and glucose metabolism. This feature of the PPARs has been successfully exploited to treat systemic metabolic diseases, like hyperlipidemia and type-2 diabetes. Indirectly, their lipid lowering effect also leads to a reduction of the risk for cardiovascular diseases, primarily atherosclerosis. AREAS COVERED IN THIS REVIEW: The pleiotropic effects of each of the PPAR isotypes on vascular and cardiac disease are discussed, with special emphasis on the molecular mechanism of action and on preclinical observations. The mechanism underlying the beneficial effect of PPARs is not confined to whole body metabolism, but also includes modulation of other vital processes, such as inflammation and cell fate (proliferation, differentiation, apoptosis). WHAT THE READER WILL GAIN: A large body of preclinical studies indicates that, in addition to their effect on atherogenesis, PPAR ligands also impact on ischemic heart disease and the development of cardiac failure. It remains to be established to what extent these intriguing observations can be translated into clinical practice. TAKE HOME MESSAGE: The versatile mechanism of action extends the potential therapeutic profile of the PPARs enormously. Conversely, this versatility makes it harder to attain a specific therapeutic effect, without increasing the risk of undesirable side effects. The future challenge will be to design PPAR-based therapeutic strategies that minimize the detrimental side effects. PMID- 20854179 TI - HIF, hypoxia and the role of angiogenesis in non-small cell lung cancer. AB - IMPORTANCE OF THE FIELD: The role of angiogenesis in the initiation and progression of NSCLC and the molecular alterations leading to the growth of tumor vasculature are areas of great interest and recent therapeutic success. AREAS COVERED IN THIS REVIEW: VEGF and its receptors play critical roles in the development of tumor vasculature and can be targeted by agents such as bevacizumab in the treatment of NSCLC. Furthermore, tumor hypoxia and the expression of the hypoxia-inducible factor (HIF) family of proteins are also linked to poorer survival in these patients. Recent studies using genetically engineered mouse models expressing stabilized HIF validate the importance of HIF in the evolution of NSCLC and demonstrate genetically that HIF is involved in NSCLC. WHAT THE READER WILL GAIN: An overview of the key pathways and mediators of tumor angiogenesis, their relevance to the pathogenesis of NSCLC, and an update on the current status of angiogenesis inhibitors in NSCLC. TAKE HOME MESSAGE: Angiogenesis is a key mediator of NSCLC progression. Several antiangiogenic strategies are in clinical use and under development. While candidate predictive biomarkers of response to antiangiogenic therapy exist, they await independent and prospective validation. PMID- 20854181 TI - H-coil repetitive transcranial magnetic stimulation for the treatment of bipolar depression: an add-on, safety and feasibility study. AB - OBJECTIVES: The H1-Coil is a novel transcranial magnetic stimulation (TMS) device capable of inducing a magnetic field with a deeper and wider distribution than standard coils. This pilot study evaluated the safety and feasibility of the H1 Coil as adjuvant treatment for bipolar depression (BPD). METHODS: Nineteen patients diagnosed as having BPD and under treatment with psychotropic medication were enrolled in the study. They received daily prefrontal repetitive TMS (rTMS: 20 Hz, 2 s on, 20 s off, totaling 1680 stimuli) every weekday for four consecutive weeks. The primary outcome measure was the change from baseline in the Hamilton Depression Rating Scale (HDRS-24) score a week after the last treatment session. RESULTS: A significant mean decrease of 12.9 points in the HDRS-24 scale (P< 0.001) was found. Response rate was 63.2% and remission rate was 52.6%. Treatment was well tolerated in terms of headache and overall discomfort, and there were no significant change in cognitive functioning or mood switches. One patient had a short induced generalized seizure without complications. CONCLUSIONS: An add-on H-coil rTMS treatment protocol in BPD subjects indicated improvement in bipolar depression symptoms. Sham-control studies to further determine the efficacy and safety of the H-Coil for BPD are warranted. PMID- 20854182 TI - Assessment of systemic matrix metalloproteinase and their regulator response in children with Helicobacter pylori gastritis. AB - BACKGROUND: Helicobacter pylori causes gastritis and is the most important risk factor of peptic ulcer disease and gastric cancer. In chronic adulthood H. pylori infection some matrix metalloproteinases (MMPs), which are proteolytic metalloendopeptidases regulated by tissue inhibitors of metalloproteinases (TIMPs), are upregulated. Our aim was to determine circulating levels of MMPs and their regulators TIMP-1, human neutrophil elastase (HNE) and myeloperoxidase (MPO) in childhood H. pylori infection. DESIGN AND METHODS: Twenty-six H. pylori positive and 34 H. pylori negative children whose H. pylori status was verified by histological examination of gastric biopsies were included. Serum samples were analysed by enzyme-linked immunosorbent assay. RESULTS: Significantly decreased serum levels of TIMP-1 were detected in H. pylori-infected children (median, 97.50 ng/mL) as compared to H. pylori-negative children (median, 118.5 ng/mL, p = 0.003). However, there were no significant differences in serum levels of MMP-2, 7, -8, -9, and their regulators HNE and MPO between H. pylori-positive and negative children. CONCLUSIONS: Differing from the recent findings in adulthood H. pylori infection, only circulating TIMP-1 levels were significantly different between H. pylori-positive and -negative children. Whether this reflects the first sign of a proteolytic cascade later leading to increased levels of MMPs remains to be shown. PMID- 20854183 TI - Pharmacotherapy of ovarian hyperstimulation syndrome. AB - IMPORTANCE OF THE FIELD: One of the main objectives in assisted reproduction techiques (ART) is the maturation of multiple follicles and the recovery of multiple good quality oocytes. To realize this, it is necessary to interfere with the mechanisms of selection and follicular dominance, characteristic of spontaneous mono-ovulatory cycles, by administering gonadotrophins. In 12 - 20% of the stimulation cycles, the response to ovarian stimulation in terms of follicular development is higher than expected, with the onset of the so-called ovarian hyperstimulation syndrome (OHSS). This is considered to be an exaggerated response: an iatrogenic - possibly life-threatening - complication of ovarian stimulation. AREAS COVERED IN THIS REVIEW: This review deals about reproductive, obstetric and gynecological aspects of OHSS. WHAT THE READER WILL GAIN: Understanding the pathophysiology of OHSS is the key to establishing a correct pharmacotherapy. However, the mechanisms underlying OHSS have not yet been completely clarified. Treatment of OHSS is empirical, so prevention is the most important aspect in its management. Several studies support the role of vascular endothelial growth factor in the development of OHSS in humans, so future studies about anti-angiogenetic molecules seem to be an important goal in ART. TAKE HOME MESSAGE: Methods to prevent OHSS. PMID- 20854180 TI - Targeting Fas in osteoresorptive disorders. AB - IMPORTANCE OF THE FIELD: Fas receptor is a mediator of the external apoptotic pathway in many cells and tissues. It is proposed that Fas receptor mediates osteoresorptive effects of estrogen deficiency and local/systemic inflammation. AREAS COVERED IN THIS REVIEW: This review covers the past two decades of research on the expression and function of the Fas-Fas ligand system on bone cells, involvement in the pathogenesis of osteoresorption and potential therapeutic modulation. WHAT THE READER WILL GAIN: We review the structure, biological function and intracellular signaling pathways of the Fas-Fas ligand system emphasizing the role of the non-apoptotic signaling pathways in bone cells, particularly osteoblast differentiation. We also present data on the in vitro expression and function of the Fas-Fas ligand system on osteoblast/osteoclast lineage cells, animal and human studies confirming its involvement in osteoresorptive disorders and potential therapeutic approaches to modulate its function. TAKE HOME MESSAGE: Tissue specific therapeutic approaches need to be established to modify the Fas-Fas ligand system in osteoresorptive disorders as systemic targeting has many side effects. The most promising approach would be to target Fas signaling molecules coupled with osteoblast/osteoclast differentiation pathways, but a precise definition of these targets is still needed. PMID- 20854184 TI - Combined medical treatment using dutasteride and tamsulosin for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. AB - IMPORTANCE OF THE FIELD: Benign prostatic hyperplasia (BPH) is the fourth most commonly diagnosed medical condition in the elderly. Selective alpha-blockers (tamsulosin) and dual 5alpha-reductase inhibitors (dutasteride) have an important role in the medical treatment of symptomatic BPH. Safety and efficacy of combination therapy with dutasteride and tamsulosin as well as long-term benefit on prevention of disease progression have been widely studied in recent trials. AREAS COVERED IN THIS REVIEW: The present article summarizes the pharmacologic properties of both dutasteride and tamsulosin. Clinical efficacy of combination therapy in different trials has also been reported. Major randomized trials on this concept published between 2000 and 2010 have been covered in this article. WHAT THE READER WILL GAIN: Long-term efficacy and safety of combination therapy and its beneficial effect on quality of life and risk reduction of need for BPH related surgeries have been discussed. TAKE HOME MESSAGE: Combination therapy with dutasteride and tamsulosin is a highly efficacious medical treatment in patients with moderate-to-severe lower urinary tract symptoms due to benign prostatic enlargement, which could be safely tolerated and administrated for >= 4 years. PMID- 20854185 TI - Paliperidone extended-release: a review of efficacy and tolerability in schizophrenia, schizoaffective disorder and bipolar mania. AB - IMPORTANCE OF THE FIELD: Paliperidone extended-release (ER), a once-daily, oral, atypical antipsychotic, has been available in the USA and the EU for the treatment of schizophrenia for more than 2 years and was recently (July 2009) approved in the USA for treatment of schizoaffective disorder. Additional data on its efficacy and safety, including that for additional indications, is emerging. AREAS COVERED IN THIS REVIEW: This review provides a background on the compound and summarizes recent data available on treatment of schizophrenia, including comparative data with other antipsychotics, and efficacy and safety data from clinical trials in schizoaffective and bipolar disorders. WHAT THE READER WILL GAIN: The reader will gain knowledge of the compound and the existing clinical data so far for paliperidone ER. TAKE HOME MESSAGE: Paliperidone ER is effective for the treatment of schizophrenia and is at present the only antipsychotic approved in the USA for treatment of schizoaffective disorder. Its efficacy and tolerability profile in treating patients with schizophrenia or schizoaffective disorder indicates that paliperidone ER offers an important treatment option among atypical antipsychotic therapy for these patients. PMID- 20854186 TI - Neovascularization by bFGF releasing hyaluronic acid-gelatin microspheres: in vitro and in vivo studies. AB - Therapeutic angiogenesis with angiogenic growth factors has been described as a promising approach for tissue engineering, wound healing, and for treating ischemic tissues. Here, we assessed the merit of heparin-entrapped hyaluronic acid-gelatin (HA-G) microspheres for the sustained release of recombinant basic fibroblast growth factor (rbFGF) to promote localized neovascularization. HA-G microspheres were prepared by a water-in-oil emulsion method, and the in vitro release kinetics were first examined using three model proteins. Then, bFGF was incorporated into microspheres, and the bioactivity of the in vitro-released rbFGF was tested on human umbilical vein endothelial cell cultures. The ability to promote microvessel growth was assessed in vivo, at the subcutaneous groin fascia of Wistar rats after 3, 7, 14, and 21 days. Histological and morphometrical analysis indicated that heparin-entrapped HA-G microspheres have the capacity to release bioactive rbFGF, leading to localized neovascularization in the rat subcutaneous tissue. PMID- 20854187 TI - Soluble receptors for vascular endothelial growth factor (sVEGFR1/sVEGFR2) in infantile hemangioma. AB - Vascular endothelial growth factor (VEGF) and its receptors were postulated to be involved in pathogenesis of infantile hemangioma. The aim of this study was to determine the serum levels of VEGF and soluble VEGF receptors (sVEGFR1/sVEGFR2) in children with hemangiomas. MATERIALS AND METHODS: Thirty-eight children with infantile hemangiomas (25 proliferating, 13 involuting) and 34 healthy children were included in the study. sVEGFR1 and sVEGFR2 serum levels in peripheral blood and in vascular tumors were determined with ELISA test. RESULTS: sVEGFR1 serum levels were slightly lower in hemangioma patients (p = 0.049). No significant differences in sVEGFR2 levels were observed in any study group. VEGF levels did differ significantly, with median level being 364.05 pg/ml in hemangioma patients and 107.40 pg/ml in the control group (p < 0.0001). CONCLUSIONS: The obtained results suggest that VEGF is involved in hemangioma angiogenesis but that soluble VEGFRs marginally influence this process. Lower serum levels of sVEGFR1 in hemangioma patients indicate the possible dysregulation between VEGFR1 and VEGFR2 receptors. PMID- 20854188 TI - Platelet growth factors suppress ex vivo expansion and enhance differentiation of umbilical cord blood CD133+ stem cells to megakaryocyte progenitor cells. AB - BACKGROUND AND OBJECTIVES: Umbilical cord blood (UCB) is a rich source of hematopoietic cells. Here, for the first time, we surveyed the effects of different concentrations of platelet growth factors and cytokine cocktail (CC) on the expansion and differentiation of UCB CD133(+) stem cells into megakaryocyte progenitors. MATERIALS AND METHODS: UCB CD133(+) cells were separated by magnetic cell sorting and cultured in different concentrations of platelet growth factors in combination with a CC containing interleukins 3 and 6, stem cell factor, and thrombopoietin. Cell expansion and differentiation were assessed using mononuclear cell count and flow cytometry. RESULTS: The results show that either activated platelet-rich plasma or the platelet supernatant, when added in the first day of culture, significantly suppress the expansion of CD133(+) cells after 7 days in culture (p < 0.05). By contrast, the expression of CD41, CD61, and CD42b markers in the presence of all platelet growth factors increased compared with that of the control (p < 0.05). CONCLUSION: Taken together, platelet growth factors in the presence of CC suppress ex vivo expansion of UCB CD133(+) cells and enhance their differentiation into megakaryocytic progenitor cells in a dose- and time-dependent manner. PMID- 20854189 TI - Effects of LNG-IUS on nerve growth factor and its receptors expression in patients with adenomyosis. AB - The levonorgestrel-releasing intrauterine system (LNG-IUS) is effective in the treatment of dysmenorrhea associated with adenomyosis. However, the mechanism of pain relief of LNG-IUS in patients with adenomyosis is unclear. We aimed to investigate the effects of LNG-IUS on the expression of nerve growth factor (NGF) and its receptors, NGFR p75 and TrkA in patients with adenomyosis. Endometrial and myometrial tissues were prepared from 17 LNG-IUS-treated patients and 15 hormonally untreated patients who had undergone hysterectomies for adenomyosis. Immunohistochemistry with antibodies against NGF, NGFR p75, and TrkA, was performed. The expression of NGF, NGFR p75, and TrkA in endometrium and myometrium of LNG-IUS-treated patients was significantly decreased compared to those of hormonally untreated patients. Our findings may indicate that the suppression of NGF and its receptors by LNG-IUS is another possible mechanism of relieving pain in patients with adenomyosis. PMID- 20854190 TI - Biodistribution and acute toxicity of naked gold nanoparticles in a rabbit hepatic tumor model. AB - There is a paucity of data regarding the safety of administering solid gold nanoparticles (AuNPs) in large animal tumor models. We assessed the acute toxicity and biodistribution of 5 nm and 25 nm solid AuNPs in New Zealand White rabbits (n = 6 in each) with implanted liver Vx2 tumors 24 h after intravenous injection. Gold concentration was determined by inductively coupled plasma atomic emission spectrometry (ICP) and imaged with transmission electron microscopy (TEM). There was no clinico-pathologic evidence of renal, hepatic, pulmonary, or other organ dysfunction. After 25 nm AuNP administration, the concentration of white blood cells increased after treatment (p = 0.001). Most other blood studies were unchanged. AuNPs were distributed to the spleen, liver, and Vx2 tumors, but not to other tissues. The urinary excretion of AuNPs was bimodal as measured by ICP. 25 nm AuNPs were more evenly distributed throughout tissues and may be better tools for medical therapy. PMID- 20854192 TI - Human and environmental health challenges for the next decade (2010–2020). AB - The public health and environmental communities will face many challenges during the next decade. To identify significant issues that might be addressed as part of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) scientific portfolio, an expert group of key government, academic, and industry scientists from around the world were assembled in 2009 to map the current and future landscape of scientific and regulatory challenges. The value of the scientific mapping exercise was the development of a tool which HESI, individual companies, research institutions, government agencies, and regulatory authorities can use to anticipate key challenges, place them into context, and thus strategically refine and expand scientific project portfolios into the future. PMID- 20854193 TI - Pneumocystis jirovecii infection: Cell wall (1→3)-β-D-glucan biology and diagnostic utility. AB - Pneumocystis jirovecii has emerged as an important pulmonary pathogen. Historically associated with the immunocompromised, it is being increasingly observed in immunocompetent populations. (1->3)-beta-D-glucan (BG) is a major component of the cyst cell wall and plays an important role in the inflammatory response to the organism. Inflammatory synergy by co-stimulation with BG and Toll like receptor ligands has been demonstrated in vitro and may be a factor in the pathophysiology of Pneumocystis pneumonia. Detection of highly elevated serum concentrations of BG in the serum of patients has been shown to be highly sensitive for the presence of pulmonary P. jirovecii. PMID- 20854191 TI - Drug-metabolizing enzyme, transporter, and nuclear receptor genetically modified mouse models. AB - Determining the in vivo significance of a specific enzyme, transporter, or xenobiotic receptor in drug metabolism and pharmacokinetics may be hampered by gene multiplicity and complexity, levels of expression, and interaction between various components involved. The development of knockout (loss-of-function) and transgenic (gain-of-function) mouse models opens the door to the improved understanding of gene function in a whole-body system. There is also growing interest in the development of humanized mice to overcome species differences in drug metabolism and disposition. This review, therefore, aims to summarize and discuss some successful examples of drug-metabolizing enzyme, transporter, and nuclear-receptor genetically modified mouse models. These genetically modified mouse models have been proven as invaluable models for understanding in vivo function of drug-metabolizing enzymes, transporters, and xenobiotic receptors in drug metabolism and transport, as well as predicting potential drug-drug interaction and toxicity in humans. Nevertheless, concerns remain about interpretation of data obtained from such genetically modified mouse models, in which the expression of related genes is altered significantly. PMID- 20854194 TI - Hair highlights and severe acute irritant dermatitis ("burn") of the scalp. AB - CONTEXT: These days, most celebrities--young and old--have their hair highlighted. That is why it is not surprising that even the youth have their hair highlighted as they emulate their favorite actors, unaware of the harmful consequences of this unsafe procedure. Hair highlighting involves decolorizing melanin pigments of select hair strands through an oxidation reaction under alkaline conditions by the active ingredients of the highlighting mixture- hydrogen peroxide, persulfates, and metasilicate. Hydrogen peroxide and the persulfates are flammable, necessitating that regulatory bodies (namely, the U.S. Food and Drug Administration [FDA] and the Cosmetic Ingredient Review [CIR] Expert Panel, the European Union's (EU), European Economic Community [EEC] directives, the Australian government's National Industrial Chemicals Notification and Assessment Scheme [NICNAS], and the Association of Southeast Asian Nations [ASEAN]) to regulate the permissible amounts of these chemicals in hair highlighting products. OBJECTIVES: To review published case reports of resulting in severe acute irritant dermatitis ("burns") of the scalp caused by hair highlighting, to explain why these scalp burns happen, to identify preventive measures to avoid such occurrences, and to discuss the implications for society. MATERIALS AND METHODS: We searched medical and scientific search engines and used keywords such as hair highlights, scalp burn, and other related terms.. RESULTS: Six articles were obtained, yielding 8 reported cases (2 of the 6 articles had 2 cases each) of hair highlighting resulting in scalp burns; these 8 cases were reviewed and analyzed. Five of the 8 patients belonged to the pediatric age group. DISCUSSION: The causes of scalp burn were classified into 2 categories: chemical (caustic nature of the highlighting mixture, spillage of the hot mixture, toxic reaction to the dyes) and thermal (by contact of the scalp with overheated aluminum foil and by the blow dryer). The 5 pediatric patients in the group unnecessarily suffered pain and embarrassment caused by this procedure, as well as the risk of developing malignancy in the future. CONCLUSIONS: Hairstylists play a large role in the occurrence of scalp burns. Thus, they need to be careful and knowledgeable of the caustic nature of the highlighting mixture and the potential harm these chemicals may cause. The authors strongly propose that the relevant regulatory bodies review the permissible levels of the caustic chemicals, and that this unsafe procedure should be performed only on adults. PMID- 20854195 TI - Short communication: evidence of HIV type 1 clade C env clones containing low V3 loop charge obtained from an AIDS patient in India that uses CXCR6 and CCR8 for entry in addition to CCR5. AB - Abstract HIV-1 clade C is the major subtype circulating in India and preferentially uses CCR5 during the entire disease course. We have recently shown that env clones from an Indian patient; NARI-VB105 uses multiple coreceptors for entry and was presented with an unusual V3 loop sequence giving rise to high net V3 loop positive charges. Here we show that env clones belonging to subtype C obtained from an AIDS patient, NARI-VB52, use CXCR6 and CCR8 in addition to CCR5 for entry. However, unlike the NARI-105 patient, the env clones contained a low V3 loop net charge of +3 with a conserved GPGQ motif typical of CCR5 using subtype C strains, indicating that residues outside the V3 loop contributed to extended coreceptor use in this particular patient. PMID- 20854196 TI - Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial. AB - Low levels of vitamin D are reported in HIV-infected individuals. In HIV-negative people, low vitamin D levels have been associated with an increased risk of cardiovascular disease and cancer and with worse survival. The MONET trial recruited 256 European patients with HIV RNA <50 copies/ml at screening, while taking either NNRTI- or PI-based HAART. Patients were switched to DRV/r 800/100 mg once daily, either as monotherapy or with two NRTIs. In all, 221 patients were measured for 25-hydroxyvitamin D at a central laboratory before randomized treatment started and at week 96. Multiple regression was used to correlate vitamin D levels with gender, season, ethnic group, treatment group, and use of antiretrovirals. Overall, 80% of patients were male and 91% were white, with a mean age of 44 years. At screening, 170/221 (77%) patients had vitamin D deficiency (<50 nmol/liter). At the screening visit, lower vitamin D levels were significantly associated with calendar month (p = 0.0067), black ethnicity (p = 0.013), use of efavirenz (p = 0.0062), and use of zidovudine (p = 0.015). Mean vitamin D levels were lowest from January to April (mean = 35.8 nmol/liter) and highest in September (mean = 45.4 nmol/liter). Increases in vitamin D between screening and week 96 were significantly greater for patients who discontinued efavirenz or zidovudine before the MONET trial versus those who stopped other antiretrovirals. At screening, lower vitamin D levels were associated with season, race, and use of efavirenz and/or zidovudine. Switching from efavirenz and/or zidovudine to darunavir/ritonavir during the trial led to increases in vitamin D levels. Routine screening of HIV-positive patients for vitamin D should be considered and the optimal management further defined. PMID- 20854197 TI - Beyond 2010: Gaps, Challenges, and Priorities for the Future of Preclinical HIV Preexposure Prophylaxis (PrEP): Summary of the October 20-21, 2009 Workshop. AB - Abstract A workshop entitled Beyond 2010: Gaps, Challenges, and Priorities for the Future of Preclinical HIV Pre-Exposure Prophylaxis (PrEP) was sponsored by the Division of AIDS (DAIDS) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), on October 20-21, 2009, in Bethesda, Maryland. The objective of the workshop was to identify the main gaps in current knowledge, challenges, and priorities for the establishment of a PrEP preclinical pipeline and to also provide guidance for future directions of the field and DAIDS activities in this area. This 2-day workshop, through various presentations and breakout group discussions, specifically addressed four main topics that will be critical in identifying and advancing the next generation of PrEP candidates for clinical testing. The topics were (1) drug discovery, (2) pharmacokinetics (PK) and pharmacodynamics (PD), (3) animal models, and (4) delivery systems for prolonged activity. We report here a summary of the presentations and highlights of salient discussion topics from this workshop. PMID- 20854198 TI - Prolonged control of an HIV type 1 escape variant following treatment interruption in an HLA-B*27-positive patient. AB - The HLA-B*27 allele is overrepresented in patients who control HIV-1 replication without antiretroviral therapy. CD8(+) T cell responses that target the immunodominant KK10 epitope in Gag are thought to play a major role in this control, and escape at R264 of KK10 is often associated with dramatic virologic breakthrough. We present a case in which an HLA-B*27-positive chronic progressor transmitted HIV-1 to an HLA-B*27-positive viremic controller who was temporarily on HAART, but who has since controlled viremia for over 4 years. We hypothesized that differences in the KK10 epitope of these patients would affect pathogenesis and viral fitness, but found no correlation between autologous KK10 mutations and disease progression or between the predicted fitness impact of autologous HLA B*27-associated mutations and the actual fitness of autologous virus. This case of viral transmission between two HLA-B*27-positive individuals provides further evidence that prolonged control of fully pathogenic HIV-1 is possible. PMID- 20854200 TI - Short communication: epidemiological evidence that simian T-lymphotropic virus type 1 in Macaca fuscata has an alternative transmission route to maternal infection. AB - Serological inspection of Simian T-lymphotropic Virus Type 1 was conducted for a wild colony of Macaca fuscata, which was captured in the middle Honshu, Japan. The increase of positive rate after the juvenile stage with the positive rate reaching 100% (or 35/35) in youngster and adult stages, was observed. This finding suggests that, in contrast with human T-lymphotropic Virus Type 1, horizontal transmission play an important role in increasing prevalence of STLV-1 with age among M. fuscata. PMID- 20854199 TI - Genetic analysis of a UNAIDS HIV type 1 from Brazil revealed an unexpected recombination pattern. PMID- 20854201 TI - Asthma electronic medical records in primary care: an integrative review. AB - BACKGROUND: Quality management, evaluation, and surveillance of asthma may be enhanced by access to and utilization of an asthma electronic medical record (EMR) in primary care. PURPOSE: To describe the current status, support tools, and utility of asthma EMRs in primary care. METHODS: An integrative review of the literature published between 1996 and 2008 was completed using Ovid MEDLINE, EMBASE, and CINAHL databases. Key search terms included asthma, medical records, computerized, primary health care, primary care, family physician, family practice, chronic disease, COPD, neoplasm, diabetes mellitus, and cardiovascular disease. Articles related to concepts, systems in development, and sources such as acute care and pharmacy EMRs were excluded. Each article was reviewed by two reviewers. RESULTS: Of 309 articles identified, 76 met the inclusion criteria. Twenty-two percent were specific to asthma, 78% pertained to other chronic diseases and/or the overall status of an EMR in primary care. The literature varied in methodology, topics of discussion and value of data. Articles describing an asthma EMR most often reported on decision support tools (n = 3) and/or utility (n = 14), specifically the ability to predict mortality and assess severity and timeliness of diagnosis. A primary care EMR containing a validated asthma minimum data set was not found. Three themes emerged from the review: status (description of users, functionalities and adoption issues), tools (decision support tools to enhance knowledge uptake), and utility (data quality, extraction and outcomes). CONCLUSIONS: There is a paucity of asthma elements in EMRs in primary care, with the exception of discussion of decision support tools and utility. Integration of a more robust asthma EMR in primary care, including a minimum data set, standardized terminology, and validated indicators, may further enhance care and enable outcomes monitoring. PMID- 20854202 TI - Changes in the renal function after tenofovir-containing antiretroviral therapy initiation in a Senegalese cohort (ANRS 1215). AB - To describe and compare the changes in renal function between HIV-1 infected adult patients receiving antiretroviral therapy (ART) with and without tenofovir (TDF). The population consisted of 40 patients starting a TDF-containing regimen and 388 patients starting regimen not containing TDF, and followed during 42 months. The estimated glomerular filtration rate (eGFR) was calculated using the Cockroft-Gault and MDRD equations and modeled separately for the first 12 months and the subsequent period. Between baseline and 12 months, the eGFR decreased significantly in patients receiving TDF (-10.40 ml/min), whereas it increased in the other +4.33 ml/min). A significant variability in the eGFR trajectories of patients receiving TDF was observed; 12 (30%) of them experienced a persistent decrease, 5 (12%) had an initial transient increase, and 23 (58%) a steady slow increase in eGFR. The characteristics at baseline of the patients with persistent decrease were not different from the other patients but their immune reconstitution was impaired. After 12 months, patients receiving TDF experienced a higher rate of transition from mild renal impairment (60-90 ml/min/1.73 m(2)) to moderate renal impairment (30-60 ml/min/1.73 m(2)) when compared with patients not receiving TDF. A significant though moderate decline in the renal function was observed in one-third of the patients receiving TDF compared to patients not receiving TDF. Moreover, this impairment was persistent after the first year of treatment. PMID- 20854204 TI - Suppression of CCR5-tropic HIV type 1 infection by OX40 stimulation via enhanced production of beta-chemokines. AB - To elucidate the immunological role for the costimulatory molecule OX40 against the early stage of HIV-1 infection, fresh peripheral blood mononuclear cells (PBMCs) from normal donors were stimulated with immobilized anti-CD3 monoclonal antibody (mAb) together with soluble anti-CD28 mAb for 24 h, infected with CCR5 tropic (R5) HIV-1, and then cocultured in the presence or absence of OX40 ligand (OX40L). Results of these studied showed that OX40 stimulation led to a marked reduction in levels of p24, the frequency of intracellular p24(+) cells, as well as HIV-1-mediated syncytium formation. The suppression was reversed by anti-OX40L mAb. The mechanism underlying the R5 HIV-1 suppression was shown to be mediated in part by the CCR5-binding beta-chemokines RANTES, MIP-1alpha, and MIP-1beta, since the effect of the OX40 stimulation was reversed by a neutralizing antibody mixture against these three beta-chemokines. Thus, OX40 stimulation enhanced the production of these CCR5-binding beta-chemokines by the activated PBMCs and subsequently down-modulated CCR5 expression on the activated CD4(+) T cells. Taken together, the present data revealed a new role for OX40 in HIV-1 infection and documents the fact that OX40 stimulation suppresses the infection of primary activated PBMCs with R5 HIV-1 via enhanced production of R5 HIV-1 suppressing beta-chemokines. PMID- 20854203 TI - HIV-1 diversity after a class switch failure. AB - The purpose of this study is to evaluate whether the choice of a PI- or an efavirenz (EFV)-based HAART initial regimen impacts on the viral diversity after failure from a second, class-switch salvage regimen. Sequential HAART failures after a class switch were identified for which the genotypes showed evidence of signature mutations at each failure. Each second failure was required to be from a viral burden <400 RNA c/ml. Thirteen cases of sequential failure from an initial EFV-containing to a PI-containing regimen (EP), and 19 sequential failures from an initial PI-containing to an EFV-containing regimen (PE) were identified. The persistence of signature mutations from the first failure were evaluated at second failure and compared between the EP and PE groups. Phylogenetic trees were constructed for a subgroup of cases from existing genetic sequence information and branch length analysis was used to determine evidence of viral diversity between groups. For EP sequential therapy, 10 of 12 cases carried forward a key non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation in the second failure compared to 5 of 13 cases for PE sequential therapy (p = 0.041). Phylogenetic analysis demonstrated that there was more viral diversity in the PE group as compared to the EP group, consistent with the interpretation that mutations at the second failure added to an ancestral virus closer to baseline rather than to the dominant virus at first failure. The development of HIV viral diversity after multiple HAART failures is determined by the sequence in which the regimens are ordered. PMID- 20854206 TI - Stable and low prevalence of transmitted HIV type 1 drug resistance despite two decades of antiretroviral therapy in Hong Kong. AB - Transmitted HIV resistance is of both clinical and public health importance. Baseline genotypic resistance testing was performed for HIV-1-infected treatment naive patients who were newly diagnosed between 2003 and 2007 and attended the government HIV clinic in Hong Kong. International AIDS Society-USA mutation figures and the Stanford resistance interpretation algorithm were used to identify resistance mutations and drug susceptibility, respectively. The pattern and factors associated with resistance were examined. The presence of one or more IAS-USA resistance mutations was found in 26 (3.6%) of 731 patients over the 5 year study period. Overall, protease inhibitor (PI) resistance mutations were most common (16), followed by nucleoside reverse transcriptase inhibitors (NRTIs) (8) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) (3). Resistance to drugs in one, two, and three classes was present in 25 (3.4%), 1 (0.1%), and 0, respectively. Seventy-eight (10.7%) had strains of reduced susceptibility, as predicted by the Stanford algorithm to display at least low-level resistance to one or more drugs of the three classes. Intermediate or high-level resistance was found in 1.6% overall, and in descending order for NRTIs, PIs, and NNRTIs. There was no temporal trend of increase in resistance. Sex between men, Chinese ethnicity, and lower baseline CD4 were associated with harboring resistant strains as elucidated by either method. We conclude that transmitted HIV-1 drug resistance is uncommon in up to two decades of antiretroviral therapy in Hong Kong. The situation has to be continually monitored for any change in significance. PMID- 20854207 TI - Pharmacokinetic assessment of dapivirine vaginal microbicide gel in healthy, HIV negative women. AB - To assess the pharmacokinetics of dapivirine in plasma and dapivirine concentrations in cervicovaginal fluids (CVF) and cervicovaginal tissues following vaginal administration of dapivirine microbicide gel in healthy, HIV negative women for 10 days. A randomized, double-blind, phase I study was conducted at a single research center in South Africa. A total of 18 women used dapivirine gel (0.001%, 0.005%, or 0.02%) once daily on Days 1 and 10 and twice daily on Days 2-9. Pharmacokinetics of dapivirine were assessed in plasma on Days 1 and 10. Dapivirine concentrations were measured in CVF on Days 1 and 10 and in cervicovaginal tissues on Day 10. Safety was evaluated through laboratory tests (hematology, clinical chemistry, and urinalysis), physical examinations, and assessment of adverse events. Plasma concentrations of dapivirine increased over time with gel dose and were greater on Day 10 (C(max) 31 to 471 pg/ml) than Day 1 (C(max) 23 to 80 pg/ml). T(max) was 10-12 h on Day 1, and 9 h on Day 10. Concentrations in CVF generally increased with dose but were highly variable among participants. Mean peak values ranged from 4.6-8.3 * 10(6) pg/ml on Day 1 and from 2.3-20.7 * 10(6) pg/ml on Day 10 across dose groups. Dapivirine was detectable in all tissue biopsies on Day 10 at concentrations of 1.0-356 * 10(3) pg/mg. CONCLUSIONS: Dapivirine was widely distributed throughout the lower genital tract with low systemic absorption when administered in a vaginal gel formulation for 10 consecutive days. The gel was safe and well tolerated. PMID- 20854205 TI - Hematological safety of perinatal exposure to zidovudine in uninfected infants born to HIV type 1-infected women in Thailand. AB - The evolution of hematological parameters in HIV-1-exposed uninfected infants according to various durations of perinatal zidovudine exposure was studied. We used data prospectively collected among 1122 HIV-uninfected formula-fed infants born to HIV-infected mothers who participated in a clinical trial to prevent perinatal transmission in Thailand (PHPT-1). Infants were exposed to different durations of zidovudine both in utero and after birth. Hemoglobin level and leukocyte, absolute neutrophil, and lymphocyte counts were measured at birth and at 6 weeks of age. The association between hematological parameters at birth and the duration of zidovudine exposure in utero was studied using a linear regression model, and changes between birth and 6 weeks of age and the duration of postnatal zidovudine exposure using mixed effects models. At birth, the hemoglobin level was lower in newborns exposed to zidovudine for more than 7.5 weeks in utero (adjusted regression coefficient: -0.6 g/dl; 95% confidence interval: -1.1 to -0.1). Six weeks after birth, the hemoglobin level had decreased faster in infants administered zidovudine for more than 4 weeks (adjusted regression coefficient: -0.1 g/dl; 95% confidence interval: -0.2 to 0.1). The duration of perinatal zidovudine exposure was not associated with the evolution of leukocyte, neutrophil, and lymphocyte counts. Despite the differences in hemoglobin levels, grade 3 or 4 anemia did not significantly differ by maternal or infant zidovudine duration. The clinical impact appeared modest, but longer exposure may warrant close monitoring. PMID- 20854208 TI - Lower prevalence of human immunodeficiency virus type 1 Brazilian subtype B found in northeastern Brazil with slower progression to AIDS. AB - Besides being extremely useful in measuring the level of HIV-1 diversity and prevalence in populations, the molecular analysis of genomic sequences provides crucial surveillance support and aids in the development of new therapies and effective vaccines. The present study focused on gag and env DNA and amino acid sequences that were generated from samples taken from 61 infected patients in the City of Salvador, Bahia, located in northeastern Brazil. In order to determine selective pressure and predict coreceptor usage, Bioinformatics tools were employed in phylogeny reconstruction. Fifty-six (91.8%) viruses were classified as belonging to subtype B, three (4.9%) from F1, and two (3.3%) from BF1 recombinants. Based on the characterization of the V3 region, the subtype B strains were represented by eight (18.2%) Brazilian variants (B'-GWGR), 20 (46.5%) European/EUA B variants (GPGR), and 15 (34.9%) GXGX variants. The mean time elapsed since diagnosis was 13 years among subtype B' and 9 years in subtype B. The mean dN/dS ratios from the GWGR, GPGR, and GXGX groups, when compared to an HXB2 reference, were 0.72, 0.77, and 0.67, respectively. Seventy-six percent of the viruses studied were predicted to use the CCR5 coreceptor for cell entry (R5 viruses), while 24% were predicted to use the CXCR4 or were classified as dual tropic viruses. The prevalence of subtypes B' and recombinant B/F1 was shown to be lower than findings from previous studies performed both in Brazil (B') and in Bahia (B/F1). The association between subtype B' and a lengthy period of time since diagnosis can be correlated with a slower disease progression in infected patients, when compared with those infected with subtype B. PMID- 20854209 TI - Dosimetry is alive and well. PMID- 20854210 TI - Membrane type 1 matrix metalloproteinase detection in tumors, using the iodinated endogenous [123I]-tissue inhibitor 2 of metalloproteinases as imaging agent. AB - Matrix metalloproteinases (MMPs) are principal participants in tumor development. In addition to serve as a useful biochemical marker, MMP expression may also provide a target for the diagnostic in vivo imaging of tumors, using a radiolabeled inhibitor. This study investigates the use of membrane type 1 (MT1) MMP as target for in vivo tumor diagnosis. Specific binding of the endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2) to MT1-MMP has been previously described. In this study, biodistribution and imaging experiments were performed on MT1-MMP-overexpressing (S.1.5) and control (C.IV.3) tumor-inoculated mice using [(123)I]-recombinant human TIMP-2 (rhTIMP-2) as radioligand and [(123)I] rhTIMP-1 as control. The expression profile was controlled in vitro and on tumor extracts. rhTIMP-2 as well as rhTIMP-1 were labeled using the Iodogen method and characterized. Biodistribution of [(123)I]-rhTIMP-2 showed a tumor uptake of 2.87% +/- 1.58% ID/g at 3 hours postinjection in S.1.5. Tumor values of [(123)I] rhTIMP-1 and [(123)I]-rhTIMP-2 evaluated in S.1.5 and C.IV.3, respectively, were significantly lower. Planar imaging revealed significant uptake of [(123)I] rhTIMP-2 in S.1.5 compared with contralateral background areas. This could not be observed in C.IV.3 and with [(123)I]-rhTIMP-1 in S.1.5. All tumors were well established (200-800 mg). These results suggest that rhTIMP-2 holds potential for development of radiotracers for in vivo imaging in overexpressing MT1-MMP but not in similar tumors that do not express this protease. PMID- 20854211 TI - Glucose transporter protein 1-targeted RNA interference inhibits growth and invasion of the osteosarcoma cell line MG63 in vitro. AB - Malignant cells show increased glucose uptake, which is thought to be mediated by glucose transporters. Glucose transporter protein 1 (Glut-1) is critical for growth, proliferation, and migration of tumor cells and Glut-1 overexpression is associated with poor overall survival in osteosarcoma patients. The present study was designed to determine the role of Glut-1 in the growth and invasion of the osteosarcoma cell line MG63, using RNA interference technology in vitro. shRNA expressing lentiviral vectors targeting the Glut-1 gene were constructed, which were stably expressed in MG63 cells. The level of Glut-1 mRNA was investigated using real-time reverse transcription-polymerase chain reaction, and the protein expression of Glut-1 mRNA was observed using western blotting. MG63 cellular glucose uptake, proliferation, and migration were detected by methyl thiazole tetrazolium assay and flow cytometry. A Glut-1-specific shRNA-expressing lentiviral vector was obtained, which could efficiently inhibit the mRNA and protein expression of Glut-1 to ~82%-85% in MG63 cells. Downregulation of Glut-1 inhibited the cellular glucose uptake, growth, and invasion of MG63 cells in vitro. These results indicate that RNA interference targeting of Glut-1 could be an effective strategy for the treatment of osteoscarcoma patients. PMID- 20854212 TI - Prognostic implications of quantitative ST-segment characteristics and T-wave amplitude for cardiovascular mortality in a general population from the Health 2000 Survey. AB - AIMS: We determined the gender-specific prognostic importance of quantitative measures of the ST segment and T wave in a community cohort. METHODS: Data were collected from 5613 Finnish individuals. Four electrocardiogram (ECG) lead groups were used: anterior, lateral, inferior, and lead V5. ST-segment depression, determined at four points along the ST segment, and T-wave amplitude were treated as continuous variables in Cox regression analyses. RESULTS: During a median follow-up period of 72.4 months, 120 cardiovascular deaths were registered. Among women, lateral lead group as well as lead V5 showed highly significant adjusted hazard ratios at all four ST-depression assessment points. This significance was lost in women >= 55 years when those with ECG-based criteria of left ventricular hypertrophy (LVH) were excluded. Results for ST-segment depression were not significant among men. As those with LVH were excluded, men >= 55 years showed borderline significance. T-wave amplitude did not reach significance among men, while lateral leads and lead V5 bore prognostic information among women. CONCLUSION: Quantitative ST-segment depression, regardless of the measurement point, allows prediction of cardiovascular death in women within a general population. However, the effect disappears as those with LVH are excluded. This observation highlights the need for consideration of LVH when depressed ST segments are clinically observed. PMID- 20854213 TI - New Finnish growth references for children and adolescents aged 0 to 20 years: Length/height-for-age, weight-for-length/height, and body mass index-for-age. AB - BACKGROUND AND OBJECTIVES: Growth curves require regular updates due to secular trends in linear growth. We constructed contemporary growth curves, assessed secular trends in height, and defined body mass index (BMI) cut-off points for thinness, overweight, and obesity in Finnish children. MATERIAL AND METHODS: Mixed cross-sectional/longitudinal data of 73,659 healthy subjects aged 0-20 years (born 1983-2008) were collected from providers in the primary health care setting. Growth references for length/height-for-age, weight-for-length/height, and BMI-for-age were fitted using generalized additive models for location, scale, and shape (GAMLSS). BMI percentile curves passing through BMIs 30, 25, 18.5, 17, and 16 kg/m(2) at the age of 18 years were calculated to define limits for obesity, overweight, and various grades of thinness. RESULTS: Increased length/height-for-age was seen in virtually all age-groups when compared to previous Finnish growth data from 1959 to 1971. Adult height was increased by 1.9 cm in girls and 1.8 cm in boys. The largest increases were seen during the peripubertal years: up to 2.8 cm in girls and 5.6 cm in boys. Median weight-for length/height had not increased. CONCLUSIONS: New Finnish references for length/height-for-age, weight-for-length/height, and BMI-for-age were constructed and should be implemented to monitor growth of children in Finland. PMID- 20854214 TI - Correlation between the extent of catalytic activity and charge density of montmorillonites. AB - The clay mineral montmorillonite is a member of the phyllosilicate group of minerals, which has been detected on martian soil. Montmorillonite catalyzes the condensation of activated monomers to form RNA-like oligomers. Extent of catalysis, that is, the yield of oligomers, and the length of the longest oligomer formed in these reactions widely varies with the source of montmorillonite (i.e., the locality where the mineral is mined). This study was undertaken to establish whether there exists a correlation between the extent of catalytic property and the charge density of montmorillonites. Charge density was determined by saturating the montmorillonites with alkyl ammonium cations that contained increasing lengths of alkyl chains, [CH3-(CH2)(n)-NH3](+), where n = 3 16 and 18, and then measuring d(001), interlayer spacing of the resulting montmorillonite-alkyl ammonium-montmorillonite complex by X-ray diffractometry (XRD). Results demonstrate that catalytic activity of montmorillonites with lower charge density is superior to that of higher charge density montmorillonite. They produce longer oligomers that contain 9 to 10 monomer units, while montmorillonite with high charge density catalyzes the formation of oligomers that contain only 4 monomer units. The charge density of montmorillonites can also be calculated from the chemical composition if elemental analysis data of the pure mineral are available. In the next mission to Mars, CheMin (Chemistry and Mineralogy), a combined X-ray diffraction/X-ray fluorescence instrument, will provide information on the mineralogical and elemental analysis of the samples. Possible significance of these results for planning the future missions to Mars for the search of organic compounds and extinct or extant life is discussed. PMID- 20854215 TI - Gene expression signatures of mouse bone marrow-derived mesenchymal stem cells in the cutaneous environment and therapeutic implications for blistering skin disorder. AB - BACKGROUND AIMS: Multiple studies have demonstrated that mesenchymal stromal cells (MSC) can be utilized therapeutically for various congenital and acquired disorders. The involvement of MSC in the maintenance of skin homeostasis and their curative application for the treatment of skin wounds have also been documented. However, it is not known whether MSC can commit to cutaneous lineages, produce structural proteins essential for the skin integrity or be used for hereditary skin disorders. METHODS: To address these questions, we conducted a comparative expression analysis between MSC and potentially adjacent cutaneous cells, fibroblasts and keratinocytes, with specific emphasis on extracellular matrix encoding and related genes. RESULTS: Our data demonstrated that MSC share many features with cutaneous fibroblasts. We also observed that under direct influence of cutaneous fibroblasts in vitro and fibroblast-derived matrix in vivo, MSC acquired a fibroblastic phenotype, suggesting that specific cell-cell interactions play a key regulatory role in the differentiation of MSC. Additionally, the observed fibroblastic transition of MSC was underlined by a significant up-regulation of several cutaneous-specific genes encoding lumican, decorin, type VII collagen, laminin and other structural proteins. As many of the identified genes have considerable therapeutic value for dermatologic afflictions, particularly type VII collagen, we evaluated further the therapeutic potential of congenic MSC in the skin of Col7a1-null mice recapitulating human recessive dystrophic epidermolysis bullosa (RDEB). Remarkably, MSC-derived type VII collagen was sufficient for restoration of the damaged dermal-epidermal junction and partial reversal of the RDEB phenotype. CONCLUSIONS: Collectively, our results suggest that MSC may offer promising therapeutics for the treatment of RDEB and potentially other genodermatoses. PMID- 20854216 TI - Successful salvage therapy with inhaled zanamivir in a patient with peramivir resistant pandemic influenza A (H1N1) 2009 virus. AB - We describe a patient with multiple myeloma who developed a pandemic influenza A (H1N1) 2009 virus infection during chemotherapy. The clinical condition of the patient worsened and viral shedding persisted despite 10 days of peramivir treatment; however viral shedding ceased and the patient recovered completely with inhaled zanamivir. PMID- 20854217 TI - Granulomatous hepatitis after intravesical bacillus Calmette-Guerin treatment. AB - A 79-y-old man presented with systemic inflammatory response syndrome (SIRS) and jaundice, 6 h after the first intravesical instillation of bacillus Calmette Guerin (BCG) for bladder cancer; he had a subsequent reaction 4 weeks later. Liver biopsy findings were compatible with BCG hepatitis. Anti-mycobacterial treatment induced complete recovery. The first episode probably represents a hypersensitivity reaction, whereas the latter course suggests BCG dissemination. PMID- 20854218 TI - Chickenpox in a Swiss prison: susceptibility, post-exposure vaccination and control measures. AB - After the occurrence of a case of chickenpox in Switzerland's largest pre-trial prison, protective measures including post-exposure vaccination were implemented, as chickenpox can cause severe complications in adults. Serology for chickenpox was carried out for all contacts of the index case and rapid post-exposure vaccination proposed to all prisoners with a negative history for chickenpox. Susceptibility was found in 14 out of 110 prisoners (12.7%; 95% confidence interval 6.5-18.9). The positive predictive value of a history of chickenpox was 90%. In this predominantly migrant population, susceptibility to chickenpox was approximately 6 times higher than in the general Swiss adult population. Since the attack rate among susceptible household contacts is usually high, preventive measures such as vaccination and quarantine probably allowed containment of the spread of infection. PMID- 20854219 TI - Clinical characteristics and computed tomography findings in children with 2009 pandemic influenza A (H1N1) viral pneumonia. AB - In this article we review the clinical characteristics and computed tomography (CT) findings in children with 2009 pandemic H1N1 influenza viral pneumonia. The medical charts of 88 children with pandemic H1N1 influenza virus infection, admitted to our hospital in Japan from 10 August to 28 December 2009, were reviewed; we compared the clinical features of these children with those of 61 children admitted with seasonal influenza A during the previous 3 seasons. Of 88 patients, 53 (60%) had radiographic findings consistent with pneumonia and 34 patients underwent a chest computed tomography (CT) scan. Pneumonia was a more frequent complication in children with pandemic H1N1 influenza compared with those with seasonal influenza (60% vs 11%; p < 0.001). The predominant CT findings were unilateral or bilateral multifocal consolidation (15/34; 44%) associated with ground-glass opacities in the peribronchovascular region. The second most common CT finding was unilateral diffuse consolidation or atelectasis in 1 or more lung zones (12/34; 35%). The chest CT findings of unilateral or bilateral multifocal consolidation often associated with ground-glass opacities were commonly seen in children with pandemic H1N1 influenza viral pneumonia. Atelectasis was seen in patients who required oxygen administration. PMID- 20854221 TI - No-shows, drop-outs and completers in psychotherapeutic treatment: demographic and clinical predictors in a large sample of non-psychotic patients. AB - BACKGROUND: A primary challenge in mental health services is a high rate of non attendance (i.e. no-show and drop-out) for patients referred to treatment for psychiatric disorders. AIM: The aim of the present study was to assess the influence of demographic and clinical variables on mental health treatment attendance and to investigate differences in predictors for no-shows and drop outs. METHODS: A naturalistic study of 2473 non-psychotic consecutive patients offered psychotherapeutic treatment at a community mental health centre in Denmark. Fifteen demographic and clinical variables were recorded at assessment. Bivariate and multiple logistic regression analyses were conducted to investigate the associations between these variables and no-show and drop-out. RESULTS: Of the 2473 participants, 668 (27.0%) did not show up for treatment, whereas 290 (11.7%) dropped out of treatment. Regression analysis showed that the significant predictors of treatment no-show were: age below 25, no more than the compulsory 9 years of school education, no sick leave, a diagnosis of personality disorder, a Global Assessment of Functioning score (GAF) below 40 or above 70, no previous psychiatric/psychological treatment, no use of antidepressants and substance abuse. The significant predictors of treatment drop-out were: age below 45, no more than the compulsory 9 years of school education or up to 11 years of school education, no vocational/university education, unemployment and substance abuse. CONCLUSION: No-show was predicted by both demographic and clinical factors, whereas drop-out was predicted by demographic factors and substance abuse as the only clinical factor. Results and strategies to reduce non-attendance are discussed. PMID- 20854220 TI - Healthcare personnel infected with novel influenza A H1N1 virus in university hospitals in Buenos Aires, Argentina. AB - Data on the clinical presentation, risk factors, and outcomes for healthcare personnel (HCP) infected with influenza A H1N1 virus (H1N1) are limited. From June to July 2009, a prospective study was conducted among HCP with influenza like illness (ILI) at university hospitals in Buenos Aires. A reverse transcription polymerase chain reaction (RT-PCR) was used to diagnose H1N1. A logistic regression model was developed to identify factors associated with H1N1. Among 1519 HCP, 96 (6.3%) were diagnosed with an ILI. Of these, 85 (88.5%) were swabbed for H1N1 detection, with 43 positive cases (2.8%). Seasonal influenza immunization was recorded in 76%. Comparison of H1N1-positive vs. H1N1-negative cases showed that H1N1-positive cases more frequently had asthenia (72% vs. 48%, p = 0.03) and cough (79% vs. 43%, p = 0.008) and less frequently had diarrhoea (9% vs. 29%, p = 0.03) and prior prophylaxis with oseltamivir (5% vs. 31%, p = 0.002). The logistic regression model showed that presence of cough (odds ratio (OR) 6.93, 95% confidence interval (CI) 2.24, 21.4) was associated with an increased risk of H1N1. Prior prophylaxis with oseltamivir (OR 0.08, 95% CI 0.01, 0.43) was associated with a lower probability of H1N1 infection. A high proportion of HCP with an ILI were infected with H1N1. Complication rates were relatively low. Prior prophylaxis with oseltamivir was associated with a lower risk of developing H1N1. PMID- 20854222 TI - Mental health among torture survivors: cultural background, refugee status and gender. AB - BACKGROUND: The experience of torture places the survivors at a heightened risk for somatic and mental health problems. AIMS: This study examined the role of culture, refugee status and gender in the mental and somatic health among help seekers in a centre for torture survivors in Finland. METHOD: The 78 participants (29 women and 49 men) were interviewed and assessed with the Impact of Event Scale-Revised (IES-R) and the Hopkins Symptom Checklist-25 (HSCL-25) scales and their somatic complaints were registered. Groups with Middle Eastern, Central African, Southern Asian and South Eastern European cultural backgrounds were compared. RESULTS: Group differences were found in post-traumatic stress disorder (PTSD) and depressive symptoms and somatic complaints. As hypothesized, Southern European torture survivors showed a higher level of PTSD than cultural groups from more traditional collective societies in Middle East, Asia and Africa, and more depressive symptoms than survivors from a Southern Asian background. Against the hypothesis, South Eastern European subjects reported also more somatic complaints than Central African survivors. Women suffered more from PTSD and depressive symptoms than men in all cultural groups. Asylum-seeking status was marginally associated with anxiety symptoms only in the South Eastern European group. CONCLUSION: Health services should consider the influence of culture in the expression of psychological and somatic symptoms and avoid a simplistic distinction between somatic and psychological expressions of pain. PMID- 20854223 TI - Ultrasound-facilitated formalin fixation of biological specimens. AB - In a previous study, we showed that ultrasound can dramatically reduce the time required for tissue fixation in formalin. It generally is believed that ultrasound increases the speed of tissue fixation in two possible ways: 1) increasing the speed of penetration of fixative molecules into tissue samples and 2) increasing the speed of cross-linking reactions. We addressed here the second possible way by using protein solutions and cultured cells, which minimized the effects of the penetration factor. Proteins or cultured cells in solution were fixed with formalin with or without ultrasound irradiation. Fixed proteins and cell lysates then were separated by SDS-poly acrylamide gel electrophoresis and subjected to Western blotting to examine cross-linking formation in certain proteins. Unexpectedly, irradiation with ultrasound did not produce an observable difference in the rate of cross-linking in protein solutions. In similar experiments using cultured cells, however, we observed a significant reduction in recovery of certain proteins from cells fixed by formalin under the influence of ultrasound, which indicated that the ultrasound fixation procedure accelerated cross-linking formation within cells. Studies on protein and cell fixation without ultrasound showed that cross-linking formation was closely related to incubation temperature, which indicates that the heating function, which is inherently associated with ultrasound is another major factor in the ability of ultrasound to accelerate cross-linking. PMID- 20854224 TI - Whole fruit staining with aniline blue at harvest is associated with superficial pathogenesis of "Fuji" apples after storage. AB - Whole "Fuji" apples (Malus domestica Borkh cv. Fuji) were treated with 0.2% aniline blue before storage in 2006, 2007 and 2008 to determine whether cuticular microcracking was associated with post-storage disorders. After storage for 7 months at 0 degrees C and 90% relative humidity followed by 3 days at 20 degrees C, a higher aniline blue staining scale value was associated with a higher peel browning and decay index. These results indicate that superficial disorders or diseases of apples may be related to cuticular microcracking that can be seen by aniline blue staining. Scanning electron microscopy was used to analyze the ultrastructure of stained portions of the cuticular complex. Disorders or diseases of the cuticle of epidermal tissue was associated with cracked lenticels, unhealed microcracks around the edge of the lenticel, and collapsed epicuticular wax; these areas stained more intensely. Our results indicated the potential of using an aniline blue staining prior to storing the fruit to predict the ultimate quality. PMID- 20854225 TI - The application of heated detergent dewaxing and rehydration to immunohistochemistry. AB - Hot commercial dishwashing detergent has been used to deparaffinize and hydrate formalin fixed, paraffin embedded sections for immunohistochemistry. Fifty-five antibodies, used routinely for diagnosis, were used to compare hot detergent dewaxing with the proprietary hydrocarbon-based dewaxing reagent supplied with the Bond Max immunohistochemistry system(r). A 2% concentration of commercial dishwashing detergent in distilled water was heated to 90 degrees C and paraffin sections were treated twice for 1 min each. Nearly all antibodies gave equivalent results except CD10 and CD57 (hydrocarbon-based dewaxing better) and CD45 and alpha fetoprotein (detergent dewaxing better); the differences, however, were minimal. There also was a significant cost saving using detergent dewaxing. PMID- 20854227 TI - Trafficking of Candida albicans through oral epithelial endocytic compartments. AB - Oral epithelial cells are the first cells that interact with C. albicans during the establishment of oropharyngeal candidiasis. Following initial adhesion, C. albicans invades oral epithelial cells by inducing its own endocytosis and gains access to epithelial vacuolar compartments. Epithelial endocytic pathways are key innate immune mechanisms in host defense. We examined the trafficking of C. albicans through oral epithelial endocytic compartments. We present evidence that C. albicans is internalized by oral epithelial cells through actin-dependent clathrin-mediated endocytosis and is taken into vacuolar compartments immediately following its internalization. C. albicans-containing endosomes transiently acquired early endosomal marker EEA1, but showed marked defects in acquisition of late endosomal marker LAMP1 and lysosomal marker cathepsin D. Defective endolysosomal maturation may partially explain the inability of oral epithelial cells to kill C. albicans. PMID- 20854226 TI - Histomorphometric comparison after fixation with formaldehyde or glyoxal. AB - Formaldehyde has long been the fixative of choice for histological examination of tissue. The use of alternatives to formaldehyde has grown, however, owing to the serious hazards associated with its use. Companies have striven to maintain the morphological characteristics of formaldehyde-fixed tissue when developing alternatives. Glyoxal-based fixatives now are among the most popular formaldehyde alternatives. Although there are many studies that compare staining quality and immunoreactivity, there have been no studies that quantify possible structural differences. Histomorphometric analysis commonly is used to evaluate diseased tissue. We compared fixation with formaldehyde and glyoxal with regard to the histomorphological properties of plantar foot tissue using a combination of stereological methods and quantitative morphology. We measured skin thickness, interdigitation index, elastic septa thickness, and adipocyte area and diameter. No significant differences were observed between formaldehyde and glyoxal fixation for any feature measured. The glyoxal-based fixative used therefore is a suitable fixative for structural evaluation of plantar soft tissue. Measurements obtained from the glyoxal-fixed tissue can be combined with data obtained from formalin-fixed for analysis. PMID- 20854228 TI - Focal pulmonary granuloma caused by Cladophialophora bantiana in a domestic short haired cat. AB - Following a 4-week history of coughing, a 12-year-old cat with a history of insulin-dependent diabetes mellitus was diagnosed with a pulmonary granuloma caused by Cladophialophora bantiana. Thoracic radiographs revealed consolidation of the right caudal lung lobe and cytology confirmed the presence of mycotic pneumonia. Results of clinical investigations showed no evidence of extra pulmonary infection. A thoracotomy and lung lobe resection was performed. Histological examination of the mass revealed black pigmented fungal hyphae and pyogranulomatous inflammation. Cultures inoculated with portions of these tissues yielded a dark walled fungus consistent with an etiologic agent of phaeohyphomycosis and DNA sequencing confirmed the presence of Cladophialophora bantiana. The cat was treated with itraconazole for 4 weeks post-operatively and then with posaconazole for 7 months but was euthanized 13 months after initial diagnosis due to a hepatocellular carcinoma. On post-mortem examination there was no evidence of recurrent fungal infection. This is the first report of localized pulmonary C. bantiana infection in a cat. PMID- 20854229 TI - Seasonal variations in the prevalence of Cryptococcus neoformans var. grubii and Cryptococcus gattii in decayed wood inside trunk hollows of diverse tree species in north-western India: a retrospective study. AB - This study presents a 7-year retrospective analysis of seasonal variations in the prevalence of Cryptococcus neoformans var. grubii and Cryptococcus gattii in decayed wood inside trunk hollows of 518 trees belonging to 20 species in north western India during 2000-2007. Of the 1,439 wood samples investigated, 406 (28.2%) were found to be positive for the Cryptococcus neoformans species complex which included 247 samples from which C. neoformans var. grubii was recovered and 171 which yielded C. gattii. While both of the pathogens were isolated through all the seasons, the overall prevalence of C. neoformans var. grubii was significantly higher (17.2%) than that of C. gattii serotype B (11.9%, P < 0.0001), indicating that decayed wood was as good, if not better, a natural habitat of C. neoformans var. grubii as that of C. gattii. The highest recovery of both yeasts was in the autumn, followed by that in the summer. For C. gattii, the lowest prevalence occurred during the winter and for C. neoformans var. grubii during the rainy season. The low prevalence of C. gattii during winter is similar to that reported from Bogota, Colombia, where C. gattii had a low population density in bark samples but it was not found in decayed wood of trunk hollows investigated during the period of January and February. The prevalence of C. neoformans var. grubii was significantly lower in the rainy season than in the other portions of the year. This finding is similar to the reported low isolation frequency (4%) of C. neoformans var. grubii from chicken feces in the rainy season in northern Thailand. Further investigations are warranted to determine the clinical significance of seasonal variations in the prevalence of C. neoformans var. grubii and C. gattii in decayed trunk wood of various trees in climatically divergent regions of India. PMID- 20854230 TI - A rare complication of ear piercing: a case of subcutaneous phaeohyphomycosis caused by Veronaea botryosa in China. AB - We present the third case of phaeohyphomycosis caused by Veronaea botryosa in China and the tenth case worldwide. A 16-year-old Chinese girl developed crusted, verrucous lesions, initially on the left ear and later on the left buttock, within 2-5 months of receiving an ear piercing. Histopathological examination of biopsy specimens confirmed diagnosis of subcutaneous phaeohyphomycosis. Microscopic examination of the colonies recovered in culture from a portion of the biopsy specimen resulted in the identification of Veronaea botryosa based primarily on the presence of two-celled, brownish pigmented, cylindrical conidia produced sympodially from erect conidiogenous cells. The lesions significantly improved with daily oral treatment with itraconazole 400 mg and adjuvant thermotherapy for 6 months. A maintenance therapy with low dose itraconazole was prescribed in order to achieve clinical and mycological cure. A two-year follow up didn't reveal any recurrence of infection. Our case is the first report of V. botryosa infection associated with a cosmetic procedure, which suggests that skin piercing could precipitate V. botryosa or other dematiaceous, as well as opportunistic fungal infections. PMID- 20854231 TI - Genetic differences among North African Berber and Arab-speaking populations revealed by Y-STR diversity. AB - Y-chromosome STR polymorphisms are inherited in a haploid state which makes them a powerful tool for easy tracing of paternal lineage and for use in human population evolutionary studies. North-African Y chromosomal diversity has traditionally been studied in order to find genetic and geographic associations as well as to test how natural and cultural barriers have affected the degree of genetic flow not only within North Africa but also in a wider Mediterranean context. The degree of Berber/Arab genetic differentiation in the Moroccan population has been tested for a complete set of forensic markers as sixteen Y chromosomal short tandem repeats (STRs) (DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1). The results suggest considerable population heterogeneity in North Africa. PMID- 20854232 TI - At last, a national health measurement survey program for Australia! AB - Objective assessment of the health of the population is the key to policy and planning. PMID- 20854233 TI - Aboriginal and Torres Strait Islander communities forgotten in new Australian National Action Plan for Human Influenza Pandemic: "Ask us, listen to us, share with us". AB - The epidemiology of influenza pandemics demands that Aboriginal and Torres Strait Islander people occupy centrestage in future planning. PMID- 20854234 TI - The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV. AB - Circumcision now to prevent heterosexual HIV transmission in 2030 makes sense. PMID- 20854235 TI - Cost-effectiveness of lowering blood pressure with a fixed combination of perindopril and indapamide in type 2 diabetes mellitus: an ADVANCE trial-based analysis. AB - OBJECTIVE: To determine the cost-effectiveness of routine administration, irrespective of blood pressure (BP), of a fixed-dose combination of perindopril and indapamide to patients with type 2 diabetes mellitus. DESIGN, SETTING AND PARTICIPANTS: Prospective cost-effectiveness analysis within the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial, an international, multicentre, randomised controlled trial of 11,140 participants with type 2 diabetes randomly allocated to receive perindopril plus indapamide (4 mg-1.25 mg/day) or placebo. MAIN OUTCOME MEASURES: Health-related quality-of-life measured by the EuroQol-5D, resource utilisation, and cost-effectiveness (cost per death averted at 4.3 years' average follow-up, and estimated cost per life-year gained, by extrapolation). RESULTS: The mean health-related quality-of-life score of survivors was 0.80 (on a 0-1 scale [death to full health]), with no difference between treatment groups. Active treatment reduced hospital admissions for coronary heart disease and coronary revascularisation by 5%. For the Australian participants, perindopril-indapamide cost A$1368 per patient during the trial period, but reduced total hospitalisation costs by A$410 and other medication costs (mainly other BP lowering drugs) by A$332. The absolute reduction in all-cause mortality for the active treatment group was 1.1%, giving a cost per life saved of A$49,200. Lifetime extrapolation gave an estimated cost per life-year saved of A$10,040 (discounted at 5% per year). CONCLUSION: The combination of perindopril and indapamide in patients with type 2 diabetes appears to be cost-effective. TRIAL REGISTRATION: United States National Library of Medicine NCT00145925. PMID- 20854236 TI - Pathways to the diagnosis of epithelial ovarian cancer in Australia. AB - OBJECTIVE: To describe the diagnostic pathways experienced by a large, representative group of Australian women with ovarian cancer, and to document the time between first presentation to a medical professional and clinical diagnosis. DESIGN, SETTING AND PARTICIPANTS: 1463 women with epithelial ovarian cancer from an Australia-wide population-based study (2002-2005) completed a telephone interview in which they described the events that led to the diagnosis of their cancer. MAIN OUTCOME MEASURES: Number and type of doctors consulted, investigations performed, referral patterns and the time from first presentation to diagnosis. RESULTS: Of the 1463 women, 145 had their cancer diagnosed incidentally and were excluded from analysis. Most of the remaining 1318 women (1222, 93%) presented first to their general practitioner. As a result of their first medical consultation, 75 women (6%) were given a diagnosis, and 484 (37%) were referred to a gynaecologist, gynaecological oncologist or oncologist for further assessment. Overall, 85% of women visited three or fewer doctors before their cancer was diagnosed; 66% of cancers were diagnosed within 1 month of the initial presentation, and 80% were diagnosed within 3 months. For 12% of women, the diagnostic process took longer than 6 months; this was more likely for women residing in remote Australia, those with lower incomes, and those presenting with abdominal pain or bowel symptoms, or with more than one symptom. CONCLUSIONS: Despite anecdotal suggestions to the contrary, most women with ovarian cancer in Australia are investigated and diagnosed promptly. The diagnostic process is more protracted for a minority of women, and the factors we found to be associated with diagnostic delay warrant further investigation. PMID- 20854237 TI - Systematic care for asthma in Australian general practice: a randomised controlled trial. AB - OBJECTIVE: To evaluate whether systematic asthma care involving a register-recall system, postcard prompts for review, and education for general practitioners and staff in Australian general practice improves the quality of care and health outcomes for adult patients with moderate to severe asthma. DESIGN AND SETTING: Cluster randomised controlled trial in 40 general practices in urban and rural South Australia and New South Wales over the 2 years 2004 and 2005; practices were randomly allocated to the intervention or control group. PARTICIPANTS: 565 adult patients of these randomly allocated practices who had doctor-diagnosed moderate to severe asthma and were taking inhaled corticosteroids. MAIN OUTCOME MEASURES: Clinical asthma indicators, quality of care, acceptability of the intervention to patients, quality of life, and asthma self-management skills at baseline, 6 months and 12 months. RESULTS: Although 46% of patients in the intervention group practices responded to the postcard prompts, only 32% actually attended for their asthma review. At 12 months, there was a statistically significant difference in provision of written asthma action plans (rate ratio, 1.9; 95% CI, 1.0-3.5; P = 0.04) for intervention group patients compared with control group patients; there was no significant difference in other indicators. CONCLUSION: We found little objective evidence of improvement in patient management and outcomes resulting from a systematic model of asthma care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12605000091606. PMID- 20854238 TI - Predictors of sexual intercourse and rapid-repeat pregnancy among teenage mothers: an Australian prospective longitudinal study. AB - OBJECTIVES: To examine the determinants of pregnancy within 2 years of a teenager giving birth for the first time (rapid-repeat pregnancy [RRP]) and resumption of sexual intercourse after the birth. DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study between June 2004 and September 2006 at the sole tertiary obstetric hospital in Western Australia involving teenagers who gave birth for the first time. Data were collected using questionnaires at recruitment, 6 weeks and 3 monthly intervals for up to 2 years postpartum. MAIN OUTCOME MEASURES: RRP and time to a return to sexual intercourse after giving birth. RESULTS: Of the 147 participants, 49 (33%) experienced an RRP. Sexual intercourse was independently significantly associated with using an oral contraceptive (odds ratio [OR], 2.83; 95% CI, 1.38-5.82); living with the birth father (OR, 8.43; 95% CI, 5.12-13.86); intending to become pregnant (OR, 3.20; 95% CI, 1.53-6.65); smoking marijuana (OR, 2.60; 95% CI, 1.38-4.79); and using alcohol (OR, 1.93; 95% CI, 1.17-3.20). Use of long-acting contraceptives was associated with reduced odds of RRP (OR, 0.27; 95% CI, 0.12-0.62), while teenagers who used an oral contraceptive had a similar risk of RRP compared with those using barrier methods or no contraception. Other factors predicting RRP were: being sexually active for more than 3 months (OR, 8.96; 95% CI, 1.97-40.74); intending to become pregnant (OR, 2.39; 95% CI, 1.62-4.93); and being an Indigenous Australian (OR, 2.38; 95% CI, 1.38-4.11). CONCLUSION: There are two options available to health care providers for reducing the rate of RRP: to facilitate teenage mothers' access to long acting contraceptives; and to gain clear understanding of their intention with regard to repeat pregnancy and to provide appropriate support. PMID- 20854239 TI - Interviewer bias in medical student selection. AB - OBJECTIVE: To investigate whether interviewer personality, sex or being of the same sex as the interviewee, and training account for variance between interviewers' ratings in a medical student selection interview. DESIGN, SETTING AND PARTICIPANTS: In 2006 and 2007, data were collected from cohorts of each year's interviewers (by survey) and interviewees (by interview) participating in a multiple mini-interview (MMI) process to select students for an undergraduate medical degree in Australia. MMI scores were analysed and, to account for the nested nature of the data, multilevel modelling was used. MAIN OUTCOME MEASURES: Interviewer ratings; variance in interviewee scores. RESULTS: In 2006, 153 interviewers (94% response rate) and 268 interviewees (78%) participated in the study. In 2007, 139 interviewers (86%) and 238 interviewees (74%) participated. Interviewers with high levels of agreeableness gave higher interview ratings (correlation coefficient [r] = 0.26 in 2006; r = 0.24 in 2007) and, in 2007, those with high levels of neuroticism gave lower ratings (r = -0.25). In 2006 but not 2007, female interviewers gave higher overall ratings to male and female interviewees (t = 2.99, P = 0.003 in 2006; t = 2.16, P = 0.03 in 2007) but interviewer and interviewee being of the same sex did not affect ratings in either year. The amount of variance in interviewee scores attributable to differences between interviewers ranged from 3.1% to 24.8%, with the mean variance reducing after skills-based training (20.2% to 7.0%; t = 4.42, P = 0.004). CONCLUSION: This study indicates that rating leniency is associated with personality and sex of interviewers, but the effect is small. Random allocation of interviewers, similar proportions of male and female interviewers across applicant interview groups, use of the MMI format, and skills-based interviewer training are all likely to reduce the effect of variance between interviewers. PMID- 20854240 TI - Selecting medical students for academic and attitudinal outcomes in a Catholic medical school. AB - OBJECTIVES: To evaluate whether the four criteria used by the University of Notre Dame Australia (UNDA) to select medical students are successful in selecting for graduates with the desired outcomes of academic excellence and Catholic "mission fit". DESIGN, SETTING AND PARTICIPANTS: Prospective cohort study of medical students selected for 2008 and 2009 entry to UNDA in Sydney, New South Wales. MAIN OUTCOME MEASURES: The statistical association between the two academic selection criteria of the Graduate Australian Medical School Admissions Test (GAMSAT) and grade point average (GPA) compared with the outcome of medical school examination performance, and the two mission selection criteria of a portfolio score and interview score compared with the outcome of a positive attitude towards serving underserved communities as measured using the Medical Student Attitudes Toward the Underserved (MSATU) test. RESULTS: A total of 223 students were enrolled. GAMSAT section 3, GPA and the interview scores were significantly positively associated with academic performance (P < 0.05). However, none of the selection variables were significantly associated with a positive attitude towards serving underserved communities, as measured by the MSATU score. CONCLUSION: None of the four selection tools used were significantly associated with medical students who had a positive attitude towards serving underserved communities. PMID- 20854241 TI - Legal aspects of open disclosure II: attitudes of health professionals - findings from a national survey. AB - OBJECTIVE: To assess the attitudes of health care professionals engaged in open disclosure (OD) to the legal risks and protections that surround this activity. DESIGN AND PARTICIPANTS: National cross-sectional survey of 51 experienced OD practitioners conducted in mid 2009. MAIN OUTCOME MEASURES: Perceived barriers to OD; awareness of and attitudes towards medicolegal protections; recommendations for reform. RESULTS: The vast majority of participants rated fears about the medicolegal risks (45/51) and inadequate education and training in OD skills (43/51) as major or moderate barriers to OD. A majority (30/51) of participants viewed qualified privilege laws as having limited or no effect on health professionals' willingness to conduct OD, whereas opinion was divided about the effect of apology laws (state laws protecting expressions of regret from subsequent use in legal proceedings). In four states and territories (Western Australia, South Australia, Tasmania and the Northern Territory), a majority of participants were unaware that their own jurisdiction had apology laws that applied to OD. The most frequent recommendations for legal reform to improve OD were strengthening existing protections (23), improving education and awareness of applicable laws (11), fundamental reform of the medical negligence system (8), and better alignment of the activities of certain legal actors (eg, coroners) with OD practice (6). CONCLUSIONS: Concerns about both the medicolegal implications of OD and the skills needed to conduct it effectively are prevalent among health professionals at the leading edge of the OD movement in Australia. The ability of current laws to protect against use of this information in legal proceedings is perceived as inadequate. PMID- 20854242 TI - Chronic suppurative lung disease and bronchiectasis in children and adults in Australia and New Zealand. AB - Consensus recommendations for managing chronic suppurative lung disease (CSLD) and bronchiectasis, based on systematic reviews, were developed for Australian and New Zealand children and adults during a multidisciplinary workshop. The diagnosis of bronchiectasis requires a high-resolution computed tomography scan of the chest. People with symptoms of bronchiectasis, but non-diagnostic scans, have CSLD, which may progress to radiological bronchiectasis. CSLD/bronchiectasis is suspected when chronic wet cough persists beyond 8 weeks. Initial assessment requires specialist expertise. Specialist referral is also required for children who have either two or more episodes of chronic (> 4 weeks) wet cough per year that respond to antibiotics, or chest radiographic abnormalities persisting for at least 6 weeks after appropriate therapy. Intensive treatment seeks to improve symptom control, reduce frequency of acute pulmonary exacerbations, preserve lung function, and maintain a good quality of life. Antibiotic selection for acute infective episodes is based on results of lower airway culture, local antibiotic susceptibility patterns, clinical severity and patient tolerance. Patients whose condition does not respond promptly or adequately to oral antibiotics are hospitalised for more intensive treatments, including intravenous antibiotics. Ongoing treatment requires regular and coordinated primary health care and specialist review, including monitoring for complications and comorbidities. Chest physiotherapy and regular exercise should be encouraged, nutrition optimised, environmental pollutants (including tobacco smoke) avoided, and vaccines administered according to national immunisation schedules. Individualised long-term use of oral or nebulised antibiotics, corticosteroids, bronchodilators and mucoactive agents may provide a benefit, but are not recommended routinely. PMID- 20854243 TI - Iatrogenic Creutzfeldt-Jakob disease in Australia: time to amend infection control measures for pituitary hormone recipients? AB - From 1967, the Australian Human Pituitary Hormone Program offered treatment for short stature and infertility using human cadaver-acquired pituitary hormones (human growth hormone [hGH] and human pituitary gonadotrophin [hPG]). The program was suspended in 1985 when a growth-hormone recipient in the United States developed Creutzfeldt-Jakob disease (CJD), an incurable and rapidly progressive neurodegenerative disorder. Since this time, recipients have lived with the significant anxiety that they have an elevated risk of developing CJD. Furthermore, additional CJD infection control measures are required when recipients undergo some types of surgery. As it is 20 years since the last Australian pituitary hormone recipient developed CJD, we evaluated the risk for Australian recipients of developing iatrogenic CJD, and compared Australian data with data from New Zealand and selected other countries who had pituitary hormone programs. Our evaluation indicates that pituitary hormone recipients in Australia have the lowest risk of developing iatrogenic CJD, and that Australia is the only country not to have experienced ongoing CJD-related deaths. Thus, we believe that: in the Australian hGH recipient cohort, the risk of developing CJD is sufficiently low for this cohort to no longer require additional infection control measures in the health care setting; and in the Australian hPG recipient cohort, if another 5 years elapses with no further occurrence of CJD in this group, the hPG recipient cohort could also be considered as not requiring additional infection control measures in the health care setting. These recommendations should not be misunderstood as implying that there is no ongoing risk, but that the risk is acceptably low and generally in keeping with guidelines that stratify the risk. PMID- 20854244 TI - Cancer patients at risk from inaccurate clinical reporting in a high-profile alternative treatment story: comments and corrections. PMID- 20854245 TI - Using the CEC paediatric calling criteria in emergency department triage. PMID- 20854246 TI - Evaluating AUSDRISK for predicting incident diabetes in an independent sample of women. PMID- 20854247 TI - Managing residual risk in patients receiving statin therapy. PMID- 20854248 TI - Free radical scavenger edaravone administration protects against tissue plasminogen activator induced oxidative stress and blood brain barrier damage. AB - One of the therapeutics for acute cerebral ischemia is tissue plasminogen activator (t-PA). Using t-PA after 3 hour time window increases the chances of hemorrhage, involving multiple mechanisms. In order to show possible mechanisms of t-PA toxicity and the effect of the free radical scavenger edaravone, we administered vehicle, plasmin, and t-PA into intact rat cortex, and edaravone intravenously. Plasmin and t-PA damaged rat brain with the most prominent injury in t-PA group on 4-HNE, HEL, and 8-OHdG immunostainings. Such brain damage was strongly decreased in t-PA plus edaravone group. For the neurovascular unit immunostainings, occludin and collagen IV expression was decreased in single plasmin or t-PA group, which was recovered in t-PA plus edaravone group. In contrast, matrix metalloproteinase-9 intensity was the strongest in t-PA group, less in plasmin, and was the least prominent in t-PA plus edaravone group. In vitro data showed a strong damage to tight junctions for occludin and claudin 5 in both administration groups, while there were no changes for endothelial (NAGO) and perivascular (GFAP) stainings. Such damage to tight junctions was recovered in t-PA plus edaravone group with similar recovery in Sodium-Fluorescein permeability assay. Administration of t-PA caused oxidative stress damage to lipids, proteins and DNA, and led to disruption of outer parts of neurovascular unit, greater than the effect in plasmin administration. Additive edaravone ameliorated such an oxidative damage by t-PA with protecting outer layers of blood-brain barrier (in vivo) and tight junctions (in vitro). PMID- 20854249 TI - Interleukin-1 drives cerebrovascular inflammation via MAP kinase-independent pathways. AB - Cerebrovascular inflammation is triggered by diverse central nervous system (CNS) insults and contributes to disease pathogenesis. The pro-inflammatory cytokine interleukin (IL)-1 is central to this cerebrovascular inflammatory response and understanding the underlying signalling mechanisms of IL-1 actions in brain endothelium may provide therapeutic targets for disease intervention. For the first time, we compare the contributions of p38, JNK and ERK mitogen-activated protein (MAP) kinase and NF-kB pathways to IL-1-induced brain endothelial activation. In cultures of primary mouse brain endothelium and the rat brain endothelial GPNT cell line, interleukin-1beta (IL-1beta induced a rapid (within 5 minutes) and transient activation of p38 and JNK (but not ERK) MAP kinases. IL 1beta also induced nuclear recruitment of nuclear factor (NF)-kB p65. IL-1beta induced brain endothelial expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was insensitive to MAP kinase inhibitors. IL-1beta-induced brain endothelial expression of ICAM-1 and VCAM-1 was inhibited (80-88 %) by the proteasome inhibitor MG132 or the antioxidant caffeic acid phenethyl ester (CAPE), effects suggested to be NF-kB-dependent. IL 1beta-induced brain endothelial CXCL1 expression was partially inhibited by JNK MAP kinase or MG132 (62 or 56 %, respectively). However, CXCL1 secretion from brain endothelium was reduced (65 %) only by MG132, and not MAP kinase inhibitors. Similarly, IL-1beta-induced neutrophil transendothelial migration was reduced (77-89 %) by MG132, but not MAP kinase inhibitors. In summary, we show that several key components of IL-1beta-induced brain endothelial activation (CAM, CXCL1 expression or release and neutrophil transmigration) are largely independent of MAP kinase activity but are reduced by proteasome inhibition, possibly reflecting a requirement for NF-kB activity. Similar mechanisms may contribute to cerebrovascular inflammation in response to CNS injury. PMID- 20854250 TI - Chronic hypoxia potentiates age-related oxidative imbalance in brain vessels and synaptosomes. AB - This study was aimed to evaluate and compare the effect of chronic hypoxia and aging in the oxidative status of brain vessels and synaptosomes. For this purpose we isolated brain vessels and synaptosomes from 3- and 12-month-old rats subjected to chronic hypoxia (10% O2 for 7 days) or normoxia (21% O2). Several parameters were evaluated: mitochondrial aconitase activity, hydrogen peroxide (H2O2) and malondialdehyde (MDA) levels and enzymatic [superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx) and glutathione reductase (GR)] and non-enzymatic [glutathione (GSH), glutathione disulfide (GSSG) and vitamin E] antioxidant defences. Concerning brain vessels, we observed an age-dependent increase in MDA levels and SOD, catalase, GR and GPx activities. In vessels isolated from young animals, chronic hypoxia induced an increase in H2O2, GSSG and vitamin E levels and CuZnSOD and catalase activities and a decrease in GSH levels. In mature animals, hypoxia induced a decrease in GSH/GSSG ratio, vitamin E levels and mitochondrial aconitase, MnSOD and GR activities and an increase in H2O2 levels and CuZnSOD and catalase activities. Concerning synaptosomes we observed an age-dependent increase in MDA levels, CuZnSOD and GPx activities and a decrease in MnSOD activity. In synaptosomes from young animals, chronic hypoxia induced a decrease in mitochondrial aconitase activity and GSH levels and an increase in CuZnSOD activity and GSSG levels. In synaptosomes from mature animals, hypoxia induced a decrease in mitochondrial aconitase activity, GSH/GSSG ratio, GSH and vitamin E levels and an increase in GSSG levels. Our results show that chronic hypoxia promotes and potentiates age-dependent oxidative imbalance predisposing to neurodegeneration. Further, synaptosomes and brain vessels are differently affected by aging and chronic hypoxia supporting the idea of the existence of tissue-specific susceptibilities. PMID- 20854251 TI - Human platelets express authentic CB1 and CB2 receptors. AB - In the last decade, the neurovascular effects exerted by endocannabinoids (eCBs) have attracted growing interest, because they hold the promise to open new avenues of therapeutic intervention against major causes of death in Western society. Several actions of eCBs are mediated by type-1 (CB1) or type-2 (CB2) cannabinoid receptors, yet there is no clear evidence of the presence of these proteins in platelets. To demonstrate that CB1 and CB2 are expressed in human platelets, we analyzed their protein level by Western blotting and ELISA, visualized their cellular localization by confocal microscopy, and ascertained their functionality by binding assays. We found that CB1, and to a lesser extent CB2, are expressed in highly purified human platelets. Both receptor subtypes were predominantly localized inside the cell, thus explaining why they might remain undetected in preparations of plasma membranes. The identification of authentic CB1 and CB2 in human platelets supports the potential exploitation of selective agonists or antagonists of these receptors as novel therapeutics to combat neurovascular disorders. It seems remarkable that some of these substances have been already used in humans to treat disease states. PMID- 20854252 TI - Environmental enrichment influences BDNF and NR1 levels in the hippocampus and restores cognitive impairment in chronic cerebral hypoperfused rats. AB - An enriched environment (EE) is beneficial in modifying behaviors, particularly in tasks involving complex cognitive functions. However, the impact of EE on cognitive impairment induced by chronic cerebral hypoperfusion (CCH) has not been studied. We investigated the effects of EE on cognitive impairment caused by CCH and examined whether CCH altered the protein levels of brain-derived neurotrophic factor (BDNF) and N-methyl-D-aspartate (NMDA) receptor subunit 1 (NR1) and subunit 2B (NR2B) in the hippocampus of rats and whether EE exposure attenuated the effects. Rats were divided into four groups that received either permanent bilateral ligation of the common carotid arteries (2-vessel occlusion) surgery or sham surgery followed by either EE housing or standard environment housing for 4 weeks. We examined non-spatial recognition memory in the novel object recognition task, spatial learning, and memory ability in the Morris water maze as well as the protein levels of BDNF, NR1, and NR2B in the hippocampus. CCH impaired both spatial and non-spatial cognitive functions, and EE exposure reversed the spatial cognitive performance and improved non-spatial memory performance. CCH resulted in decreased levels of BDNF and NR1 protein in the hippocampus, and EE exposure restored the decreased expression. Our results demonstrate for the first time that EE exposure restores cognitive impairment induced by CCH and up-regulates the decreased protein levels of BDNF and NR1. Inversely, BDNF and NR1 may contribute to the beneficial effects of EE on CCH in rats. PMID- 20854254 TI - An overview on synthetic methodologies and biological activities of pyrazoloquinolines. AB - The chemistry of pyrazoloquinolines is well established. This system has proved to be a very attractive scaffold for medicinal chemist in the recent past. Pyrazoloquinolines were extensively studied as bioactive compounds and are known to possess remarkable biological activities such as anti cancer, anti-anxiety, anti-inflammatory, anti-asthmatic, cerebroprotective and antiviral among others. For many of the activities the molecular mode of action is known. Recent research efforts have also highlighted the ability of agents based on pyrazoloquinoline skeleton to modulate adenosine A3 receptors and the phosphodiesterase receptors. In this review the developments in the medicinal chemistry of pyrazoloquinolines is discussed. PMID- 20854253 TI - Hsp20 protects neuroblastoma cells from ischemia/reperfusion injury by inhibition of apoptosis via a mechanism that involves the mitochondrial pathways. AB - Hsp20 is chaperone protein that is highly and constitutively expressed in the brain, cardiac tissue and many other organs. Recently, it is well established that Hsp20 can enhance cardiac function and render cardioprotection. However, the potential benefits of Hsp20 and its phosphorylation form action on ischemic stroke and its underlying mechanism(s) are largely unknown.To investigate whether Hsp20 exerts protective effects in vitro ischemia/reperfusion (I/R) injury, mouse neuroblastoma cells were subjected to oxygen-glucose deprivation (OGD) and reoxygenation. Expression mRNA and protein levels of Hsp20 were strongly downregulated in mouse N2A cells at the 0-hour and 6-hour recovery time points following 4 hours of OGD, and returned to basal level 12 and 24 hours after OGD treatment. The ratio of phosphorylated to total Hsp20 protein was not significantly affected by OGD treatment at the 0-hour and 6-hour recovery time points following 4 hours of OGD. However, markedly higher serine phosphorylation of Hsp20 was observed 12 and 24 hours after OGD treatment. Furthermore, overexpression of Hsp20 reduced OGD-induced apoptosis by reducing the release of cytochrome c from mitochondria to cytosol. However, blockade of Hsp20 phosphorylation at Ser16 abrogated this anti-apoptotic effect.Our data demonstrate that increased Hsp20 expression in mouse N2A neuroblastoma cells protects against I/R injury, resulting in reduced apoptosis, which is by reducing the release of cytochrome c from mitochondria to cytosol. Phosphorylation of Ser16 plays an important role in its protective effect. Thus, Hsp20 may constitute a new therapeutic target for cerebral ischemic diseases. PMID- 20854255 TI - Diquaternized curarelike myorelaxants: structure and biological activity. AB - This review discusses the most active natural and synthetic curarelike compounds demonstrating myorelaxants activity. The data are grouped according to chemical structures, namely, quinoline and isoquinoline myorelaxants, myorelaxants with saturated heterocyclic or alkylamine fragments, myorelaxants with a steroid framework, natural and synthetic alkaloid myorelaxants. PMID- 20854256 TI - Recent advances in the development of small-molecule CCR5 inhibitors for HIV. AB - CCR5 (C-C chemokine receptor type 5) is a chemokine receptor that has been identified as a major HIV co-receptor in viral entry and therefore is a highly validated target for the development of new anti-HIV drugs. Here, we discuss the insights gained so far relevant to the development of small-molecule CCR5 inhibitors for the treatment of HIV, and highlight small-molecule CCR5 inhibitors that are currently under preclinical and clinical trials. PMID- 20854257 TI - Antifolate inhibitors of thymidylate synthase as anticancer drugs. AB - Inhibitors of thymidylate synthase (TS) play an essential role in the pharmacological management of several tumors. Two antifolates, Raltitrexed and Pemetrexed, are licensed anticancer drugs, with Pemetrexed, unlike Raltitrexed, undergoing further intense clinical development. Other antifolate TS inhibitors, recently/currently tested in clinical studies, that show encouraging anticancer activities are Plevitrexed, GW7904L and Nolatrexed. A new prospect among antifolates, demonstrating a very desirable pattern of pharmacological properties, is BGC 945 that showed promising antitumor activities and has been nominated for clinical development. In this paper, apart from reviewing their biochemical and pharmacological properties, up-to-date characteristics of clinical development of all the mentioned agents are presented. In addition, trends and perspectives for developing improved antifolate inhibitors of TS and future drugs are discussed. Drug resistance is the main barrier to more effective treatment of cancers with antifolates; therefore, mechanisms of antifolate resistance and currently applied approaches to overcome it are also pointed out in the review. PMID- 20854258 TI - Medium optimization based on the metabolic-flux spectrum of recombinant Escherichia coli for high expression of human-like collagen II. AB - Recombinant Escherichia coli BL21 was used to produce human-like collagen II in fed-batch cultivation. By performing MFA (metabolic-flux analysis), the carbon/nitrogen molar ratios in both the batch and feeding media were optimized for high-level production of human-like collagen II. Three carbon/nitrogen molar ratios in both the batch and feeding media were used in the present study, and the MFA results showed that the optimal carbon/nitrogen molar ratios for the batch and feeding media were 2.36:1 and 5.12:1 respectively, yielding the highest dry-cell density (67.2 g/l dry cell weight) and human-like collagen production (10.8 g/l). PMID- 20854259 TI - High-content screening of feeder-free human embryonic stem cells to identify pro survival small molecules. AB - The propensity of human embryonic stem cells to die upon enzymatic disaggregation or low-density plating is an obstacle to their isolation and routine use in drug discovery and basic research. Equally, the very low rate of establishment of implanted cells hinders cell therapy. In the present study we have developed a high-content assay for human embryonic stem cell survival and used this to screen a range of libraries of 'lead-like' small molecules and known bioactives. From this we identified 18 confirmed hits with four structural classes being represented by multiple compounds: a series of 5-(acyl/alkyl-amino)indazoles, compounds with a 4-(acylamino)pyridine core, simple N6,N6-dialkyladenines and compounds with a 5-(acylamino)indolinone core. In vitro kinase profiling indicated that the ROCK (Rho-associated kinase)/PRK2 (protein kinase C-related kinase 2) protein kinases are of pivotal importance for cell survival and identified previously unreported compound classes that inhibited this important biological activity. An evaluation using an extensive panel of protein kinases showed that six of our hit compounds exhibited better selectivity for ROCK inhibition than the routinely used commercially available ROCK inhibitor Y-27632. In this screen we also identified the K(+)-ATP channel opener pinacidil and show that it probably promotes cell survival, by 'off-target' inhibition of ROCK/PRK2. We have therefore identified novel pro-survival compounds of greater specificity, equivalent potency and reduced toxicity relative to the routinely employed ROCK inhibitor Y-27632. PMID- 20854260 TI - Dynamic analysis of cytosolic glucose and ATP levels in yeast using optical sensors. AB - Precise and dynamic measurement of intracellular metabolite levels has been hampered by difficulties in differentiating between adsorbed and imported fractions and the subcellular distribution between cytosol, endomembrane compartments and mitochondria. In the present study, genetically encoded FRET (Forster resonance energy transfer)-based sensors were deployed for dynamic measurements of free cytosolic glucose and ATP with varying external supply and in glucose-transport mutants. Moreover, by using the FRET sensors in a microfluidic platform, we were able to monitor in vivo changes of intracellular free glucose in individual yeast cells. We demonstrate the suitability of the FRET sensors for gaining physiological insight by demonstrating that free intracellular glucose and ATP levels are reduced in a hxt5Delta hexose transporter mutant compared with wild-type and other hxtDelta strains. PMID- 20854261 TI - Natural occurrence and physiological role of a truncated eIF4E in the porcine endometrium during implantation. AB - The present study is the first report providing evidence for a physiological role of a truncated form of the mRNA cap-binding protein eIF4E1 (eukaryotic initiation factor 4E1). Our initial observation was that eIF4E, which mediates the mRNA cap function by recruiting the eIF4F complex (composed of eIF4E, 4G and 4A), occurs in two forms in porcine endometrial tissue in a strictly temporally restricted fashion. The ubiquitous prototypical 25 kDa form of eIF4E was found in ovariectomized and cyclic animals. A new stable 23 kDa variant, however, is predominant during early pregnancy at the time of implantation. Northern blotting, cDNA sequence analysis, in vitro protease assays and MS showed that the 23 kDa form does not belong to a new class of eIF4E proteins. It represents a proteolytically processed variant of eIF4E1, lacking not more than 21 amino acids at the N-terminus. Steroid replacements indicated that progesterone in combination with 17beta-oestradiol induced the formation of the 23 kDa eIF4E. Modified cell-free translation systems mimicking the situation in the endometrium revealed that, besides eIF4E, eIF4G was also truncated, but not eIF4A or PABP [poly(A)-binding protein]. The 23 kDa form of eIF4E reduced the repressive function of 4E-BP1 (eIF4E-binding protein 1) and the truncated eIF4G lacked the PABP-binding site. Thus we suggest that the truncated eIF4E provides an alternative regulation mechanism by an altered dynamic of eIF4E/4E-BP1 binding under conditions where 4E-BP1 is hypophosphorylated. Together with the impaired eIF4G-PABP interaction, the modified translational initiation might particularly regulate protein synthesis during conceptus attachment at the time of implantation. PMID- 20854262 TI - Carbohydrate-response-element-binding protein (ChREBP) and not the liver X receptor alpha (LXRalpha) mediates elevated hepatic lipogenic gene expression in a mouse model of glycogen storage disease type 1. AB - GSD-1 (glycogen storage disease type 1) is caused by an inherited defect in glucose-6-phosphatase activity, resulting in a massive accumulation of hepatic glycogen content and an induction of de novo lipogenesis. The chlorogenic acid derivative S4048 is a pharmacological inhibitor of the glucose 6-phosphate transporter, which is part of glucose-6-phosphatase, and allows for mechanistic studies concerning metabolic defects in GSD-1. Treatment of mice with S4048 resulted in an ~60% reduction in blood glucose, increased hepatic glycogen and triacylglycerol (triglyceride) content, and a markedly enhanced hepatic lipogenic gene expression. In mammals, hepatic expression of lipogenic genes is regulated by the co-ordinated action of the transcription factors SREBP (sterol-regulatory element-binding protein)-1c, LXRalpha (liver X receptor alpha) and ChREBP (carbohydrate-response-element-binding protein). Treatment of Lxra-/- mice and Chrebp-/- mice with S4048 demonstrated that ChREBP, but not LXRalpha, mediates the induction of hepatic lipogenic gene expression in this murine model of GSD-1. Thus ChREBP is an attractive target to alleviate derangements in lipid metabolism observed in patients with GSD-1. PMID- 20854263 TI - Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first phase insulin secretion through TrpV2 recruitment in pancreatic beta-cells. AB - Functional insulin receptor and its downstream effector PI3K (phosphoinositide 3 kinase) have been identified in pancreatic beta-cells, but their involvement in the regulation of insulin secretion from beta-cells remains unclear. In the present study, we investigated the physiological role of insulin and PI3K in glucose-induced biphasic insulin exocytosis in primary cultured beta-cells and insulinoma Min6 cells using total internal reflection fluorescent microscopy. The pretreatment of beta-cells with insulin induced the rapid increase in intracellular Ca2+ levels and accelerated the exocytotic response without affecting the second-phase insulin secretion. The inhibition of PI3K not only abolished the insulin-induced rapid development of the exocytotic response, but also potentiated the second-phase insulin secretion. The rapid development of Ca2+ and accelerated exocytotic response induced by insulin were accompanied by the translocation of the Ca2+-permeable channel TrpV2 (transient receptor potential V2) in a PI3K-dependent manner. Inhibition of TrpV2 by the selective blocker tranilast, or the expression of shRNA (short-hairpin RNA) against TrpV2 suppressed the effect of insulin in the first phase, but the second phase was not affected. Thus our results demonstrate that insulin treatment induced the acceleration of the exocytotic response during the glucose-induced first-phase response by the insertion of TrpV2 into the plasma membrane in a PI3K-dependent manner. PMID- 20854264 TI - Extraction of high molecular weight DNA from microbial mats. AB - Due to the presence of inhibitors such as extracellular polymeric substances (EPSs) and salts, most microbial mat studies have relied on harsh methods of direct DNA extraction that result in DNA fragments too small for large-insert vector cloning. High molecular weight (HMW) DNA is crucial in functional metagenomic studies, because large fragments present greater access to genes of interest. Here we report improved methodologies for extracting HMW DNA from EPS rich hypersaline microbial mats. The protocol uses a combination of microbial cell separation with mechanical and chemical methods for DNA extraction and purification followed by precipitation with polyethylene glycol (PEG). The protocol yields >2 ug HMW DNA (>48 kb) per gram of mat sample, with A260:280 ratios >1.7. In addition, 16S rRNA gene analysis using denaturing gradient gel electrophoresis and pyrosequencing showed that this protocol extracts representative DNA from microbial mat communities and results in higher overall calculated diversity indices compared with three other standard methods of DNA extraction. Our results show the importance of validating the DNA extraction methods used in metagenomic studies to ensure optimal recovery of microbial richness. PMID- 20854265 TI - Novel mouse model of colitis characterized by hapten-protein visualization. AB - Trinitrobenzene sulfonic acid (TNBS) and oxazolone are used to induce colitis for the investigation of inflammatory reactions in the colon. Although these chemicals are presumed to bind proteins in the colonic mucosa and then induce colitis as haptens, hapten-protein formation has not yet been confirmed in the colonic mucosa. We developed a mouse model of colitis characterized by hapten protein visualization, using 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl), which emits fluorescence after binding to proteins. The enema of 1 mg/mL NBD-Cl induced severe diarrhea, rectal bleeding, and body weight reductions in BALB/c mice. Mucosal signs indicative of colitis, such as redness and swelling observed under stereomicroscopy or inflammatory cell infiltration and crypt-epithelium destruction under microscopy, were manifested around NBD-proteins visualized with fluorescence. Fluorescence microscopy showed the infiltration of F4/80+ cells around areas of NBD-proteins, and flow cytometry indicated the uptake of NBD proteins by CD11b+ cells. We also found critical roles for T cells and interleukin-6 in colitis induction with NBD-proteins. NBD-Cl-induced colitis presents a unique model to study the relevance between hapten-protein formation and inflammatory reactions and offers a method to assess experimental interventions on colitis induction in the mucosa, where hapten-protein formation is confirmed. PMID- 20854266 TI - The case for trypsin release of affinity-selected phages. AB - Libraries of phages displaying diverse peptides are typically surveyed by affinity selection, using immobilized biomolecules as selectors. After exposing the library to the selector and washing away unbound phages, the bound phages are enriched for clones displaying selector binding peptides. Those phages are recovered by release from the selector and propagation in fresh host cells. Release is generally achieved by weakening the peptide-selector interaction without impairing phage infectivity. A perennial concern with this mode of release is recovery bias--that is, underrepresentation of the highest-affinity peptides because they are not effectively released. Here we argue for trypsin digestion as a superior release mode. It requires that the displayed peptide be connected to the phage body through a trypsin-sensitive tether, and exploits the resistance of the phage itself to that protease. We show that trypsin release is nearly complete even when phages are captured by multiple irreversible bonds, which implies little or no recovery bias. PMID- 20854267 TI - Extraction of nucleic acids from yeast cells and plant tissues using ethanol as medium for sample preservation and cell disruption. AB - Here we report that dehydrated ethanol is an excellent medium for both in situ preservation of nucleic acids and cell disruption of plant and yeast cells. Cell disruption was strongly facilitated by prior dehydration of the ethanol using dehydrated zeolite. Following removal of ethanol, nucleic acids were extracted from the homogenate pellet using denaturing buffers. The method provided DNA and RNA of high yield and integrity. Whereas cell wall disruption was essential for extraction of DNA and large RNA molecules, smaller molecules such as tRNAs could be selectively extracted from undisrupted, ethanol-treated yeast cells. Our results demonstrate the utility of absolute ethanol for sample fixation, cell membrane and cell wall disruption, as well as preservation of nucleic acids during sample storage. PMID- 20854269 TI - Reducing the multidimensionality of high-content screening into versatile powerful descriptors. AB - High-content image analysis captures many cellular parameters, but current methods of interpretation of acquired multiple dimensions assume a normal distribution, which is rarely seen in biological data sets. We describe a novel statistically based approach that collapses a set of cellular measurements into a single value, permitting a simplified and unbiased comparison of heterogeneous cellular populations. Differences in multiple cellular responses across two populations are measured using nonparametric Kolmogorov-Smirnov (KS) statistics. This method can be used to study cellular functions, to identify novel target genes and pharmacodynamic biomarkers, and to characterize drug mechanisms of action. PMID- 20854268 TI - Auto-induction medium containing glyphosate for high-level incorporation of unusual aromatic amino acids into proteins. AB - We describe the use of an auto-induction medium containing N-(phosphono methyl)glycine (glyphosate) as a means for high-level introduction of nonstandard aromatic amino acids into a protein. We illustrate this approach by preparing maltose binding protein (MBP) wherein all eight tryptophan residues have been replaced with 6-fluorotryptophan at an incorporation level of 99.3%. Such a high level of incorporation is important for spectroscopic investigations, in particular 19F NMR, because each species' differing amino acid sequence potentially yields a different peak pattern that complicates spectral analysis. PMID- 20854270 TI - A novel mixing device for the reproducible generation of nonviral gene therapy formulations. AB - Nonviral gene therapy utilizing plasmid DNA (pDNA) complexed with cationic lipids (lipoplexes) or cationic polymers (polyplexes) has demonstrated considerable potential for the treatment of a variety of diseases. However, progress toward clinical application is often delayed by the lack of reliable and scalable mixing of components sufficient to guarantee consistent performance in vivo. Attempts to improve and standardize mixing have been limited by the sensitivity of pDNA to shear-related degradation. Here we describe a simple pneumatic mixing device that enables the rapid and reproducible production of large volumes of nonviral gene therapy formulations and demonstrate its suitability for use with shear-sensitive pDNA. PMID- 20854271 TI - Fine-scale genetic structure and inferences on population biology in the threatened Mediterranean red coral, Corallium rubrum. AB - Identifying microevolutionary processes acting in populations of marine species with larval dispersal is a challenging but crucial task because of its conservation implications. In this context, recent improvements in the study of spatial genetic structure (SGS) are particularly promising because they allow accurate insights into the demographic and evolutionary processes at stake. Using an exhaustive sampling and a combination of image processing and population genetics, we highlighted significant SGS between colonies of Corallium rubrum over an area of half a square metre, which sheds light on a number of aspects of its population biology. Based on this SGS, we found the mean dispersal range within sites to be between 22.6 and 32.1 cm, suggesting that the surveyed area approximately corresponded to a breeding unit. We then conducted a kinship analysis, which revealed a complex half-sib family structure and allowed us to quantify the level of self-recruitment and to characterize aspects of the mating system of this species. Furthermore, significant temporal variations in allele frequencies were observed, suggesting low genetic drift. These results have important conservation implications for the red coral and further our understanding of the microevolutionary processes acting within populations of sessile marine species with a larval phase. PMID- 20854272 TI - Pushing north one bottleneck at a time: site frequency spectra tell the history of Sitka spruce. AB - Reconstructing the history of populations is a longstanding goal of molecular ecologists. In addition to a better understanding of the past, it is hoped that this knowledge would also facilitate predictions regarding species' responses to future events such as climate change. The traditional way of doing this is through the fossil record, but these historical records are often incomplete. Inferring historical demography from patterns of nucleotide variability can help to fill these gaps. In this issue of Molecular Ecology, Holliday et al. (2010) glimpse into the demographic past of Sitka spruce, Picea sitchensis, an economically and ecologically important species native to northwestern United States and Canada, by examining the site frequency spectrum (SFS) of 153 loci in six populations covering the species entire range. PMID- 20854273 TI - Three sisters in the same dress: cryptic speciation in African odonates. AB - The discovery of cryptic species (i.e. two or more distinct but morphologically undistinguishable species) has grown exponentially in the last two decades, due mainly to the increasing availability of DNA sequences. This suggests that hidden in the known species, many of which have been described based solely on morphological information, there might be a high number of species waiting to be discovered. In this issue Damm et al. (2010) use a combination of genetic, morphological and ecological evidence to identify the first cryptic species complex found within dragonflies (insect order Odonata). Their findings add more evidence for the importance of combining information from different disciplines to new species' discovery (DeSalle et al. 2005). PMID- 20854274 TI - On the relative roles of selection and genetic drift in shaping MHC variation. AB - Genes of the major histocompatibility complex (MHC) have provided some of the clearest examples of how natural selection generates discordances between adaptive and neutral variation in natural populations. The type and intensity of selection as well as the strength of genetic drift are believed to be important in shaping the resulting pattern of MHC diversity. However, evaluating the relative contribution of multiple microevolutionary forces is challenging, and empirical studies have reported contrasting results. For instance, balancing selection has been invoked to explain high levels of MHC diversity and low population differentiation in comparison with other nuclear markers. Other studies have shown that genetic drift can sometimes overcome selection and then patterns of genetic variation at adaptive loci cannot be discerned from those occurring at neutral markers. Both empirical and simulated data also indicate that loss of genetic diversity at adaptive loci can occur faster than at neutral loci when selection and population bottlenecks act simultaneously. Diversifying selection, on the other hand, explains accelerated MHC divergence as the result of spatial variation in pathogen-mediated selective regimes. Because of all these possible scenarios and outcomes, collecting information from as many study systems as possible, is crucial to enhance our understanding about the evolutionary forces driving MHC polymorphism. In this issue, Miller and co workers present an illuminating contribution by combining neutral markers (microsatellites) and adaptive MHC class I loci during the investigation of genetic differentiation across island populations of tuatara Sphenodon punctatus. Their study of geographical variation reveals a major role of genetic drift in shaping MHC variation, yet they also discuss some support for diversifying selection. PMID- 20854275 TI - The making of a rapid plant invader: genetic diversity and differentiation in the native and invaded range of Senecio inaequidens. AB - To become invasive, exotic species have to succeed in the consecutive phases of introduction, naturalization, and invasion. Each of these phases leaves traces in genetic structure, which may affect the species' success in subsequent phases. We examined this interplay of genetic structure and invasion dynamics in the South African Ragwort (Senecio inaequidens), one of Europe's fastest plant invaders. We used AFLP and microsatellite markers to analyze 19 native African and 32 invasive European populations. In combination with historic data, we distinguished invasion routes and traced them back to the native source areas. This revealed that different introduction sites had markedly different success in the three invasion phases. Notably, an observed lag-phase in Northern Germany was evidently not terminated by factors increasing the invasiveness of the resident population but by invasive spread from another introduction centre. The lineage invading Central Europe was introduced to sites in which winters are more benign than in the native source region. Subsequently, this lineage spread into areas in which winter temperatures match the native climate more closely. Genetic diversity clearly increases with population age in Europe and less clearly decreases with spread rate up to population establishment. This indicates that gene flow along well-connected invasion routes counteracted losses of genetic diversity during rapid spread. In summary, this study suggests that multiple introductions, environmental preadaptation and high gene flow along invasion routes contributed to the success of this rapid invader. More generally, it demonstrates the benefit of combining genetic, historical, and climatic data for understanding biological invasions. PMID- 20854276 TI - Phylogeography of ninespine sticklebacks (Pungitius pungitius) in North America: glacial refugia and the origins of adaptive traits. AB - The current geographical distribution of the ninespine stickleback (Pungitius pungitius) was shaped in large part by the glaciation events of the Pleistocene epoch (2.6 Mya-1 Kya). Previous efforts to elucidate the phylogeographical history of the ninespine stickleback in North America have focused on a limited set of morphological traits, some of which are likely subject to widespread convergent evolution, thereby potentially obscuring relationships among populations. In this study, we used genetic information from both mitochondrial DNA (mtDNA) sequences and nuclear microsatellite markers to determine the phylogenetic relationships among ninespine stickleback populations. We found that ninespine sticklebacks in North America probably dispersed from at least three glacial refugia-the Mississippi, Bering, and Atlantic refugia-not two as previously thought. However, by applying a molecular clock to our mtDNA data, we found that these three groups diverged long before the most recent glacial period. Our new phylogeny serves as a critical framework for examining the evolution of derived traits in this species, including adaptive phenotypes that evolved multiple times in different lineages. In particular, we inferred that loss of the pelvic (hind fin) skeleton probably evolved independently in populations descended from each of the three putative North American refugia. PMID- 20854277 TI - Sympatric wolf and coyote populations of the western Great Lakes region are reproductively isolated. AB - Interpretation of the genetic composition and taxonomic history of wolves in the western Great Lakes region (WGLR) of the United States has long been debated and has become more important to their conservation given the recent changes in their status under the Endangered Species Act. Currently, the two competing hypotheses on WGLR wolves are that they resulted from hybridization between (i) grey wolves (Canis lupus) and western coyotes (C. latrans) or (ii) between grey wolves and eastern wolves (C. lycaon). We performed a genetic analysis of sympatric wolves and coyotes from the region to assess the degree of reproductive isolation between them and to clarify the taxonomic status of WGLR wolves. Based on data from maternal, paternal and bi-parental genetic markers, we demonstrate a clear genetic distinction between sympatric wolves and coyotes and conclude that they are reproductively isolated and that wolf-coyote hybridization in the WGLR is uncommon. The data reject the hypothesis that wolves in the WGLR derive from hybridization between grey wolves and western coyotes, and we conclude that the extant WGLR wolf population is derived from hybridization between grey wolves and eastern wolves. Grey-eastern wolf hybrids (C. lupus * lycaon) comprise a substantial population that extends across Michigan, Wisconsin, Minnesota and western Ontario. These findings have important implications for the conservation and management of wolves in North America, specifically concerning the overestimation of grey wolf numbers in the United States and the need to address policies for hybrids. PMID- 20854280 TI - Intravenous clusterin administration reduces myocardial infarct size in rats. AB - BACKGROUND: Clusterin (Apolipoprotein J), a plasma protein with cytoprotective and complement-inhibiting activities, localizes in the infarcted heart during myocardial infarction (MI). Recently, we have shown a protective effect of exogenous clusterin in vitro on ischaemically challenged cardiomyocytes independent of complement. We therefore hypothesized that intravenous clusterin administration would reduce myocardial infarction damage. METHODS: Wistar rats undergoing experimental MI, induced by 40 min ligation of a coronary vessel, were treated with either clusterin (n=15) or vehicle (n=13) intravenously, for 3 days post-MI. After 4 weeks, hearts were analysed. The putative role of megalin, a clusterin receptor, was also studied. RESULTS: Administration of human clusterin significantly reduced both infarct size (with 75 +/- 5%) and death of animals (23% vehicle group vs. 0% clusterin group). Importantly, histochemical analysis showed no signs of impaired wound healing in the clusterin group. In addition, significantly increased numbers of macrophages were found in the clusterin group. We also found that the clusterin receptor megalin was present on cardiomyocytes in vitro which, however, was not influenced by ischaemia. Human clusterin co localized with this receptor in vitro, but not in the human heart. In addition, using a megalin inhibitor, we found that clusterin did not exert its protective effect on cardiomyocytes through megalin. CONCLUSIONS: Our results thus show that clusterin has a protective effect on cardiomyocytes after acute myocardial infarction in vivo, independent of its receptor megalin. This indicates that clusterin, or a clusterin derivate, is a potential therapeutic agent in the treatment of MI. PMID- 20854281 TI - Case of Paracoccus yeei infection documented in a transplanted heart. AB - After a successful cardiac transplantation, routine endomyocardial biopsies showed severe infiltrates comparable with myocarditis. Polymerase chain reaction analysis of native myocardial samples revealed infection with Paracoccus yeei, and the clinical condition of the patient deteriorated. After administration of ciprofloxacin, his clinical condition improved, and further biopsies showed no infiltrates in the cardiac specimens. To our knowledge this is the first documented case of P. yeei infection in a heart transplant patient. PMID- 20854282 TI - Donor-transmitted adenovirus infection causing kidney allograft nephritis and graft loss. AB - Adenovirus (AdV) infection can occur early after transplantation, especially with potent immunosuppression for induction or acute rejection treatment. We present the largest case series of adult renal recipients from a single institution with AdV infection, and the first apparent case of transferred AdV infection from 1 deceased donor to 2 kidney recipients. Three patients received kidneys from 2 deceased donors: 2 from a 23-year-old donor, and the third from a 4-year-old donor. The recipients with the same donor both displayed early rejection. One who eventually lost his graft to AdV nephritis required treatment with plasmapheresis, intravenous immunoglobulin, rituximab, and anti-thymocyte globulin for severe antibody-mediated rejection. The second required only steroids for acute cellular rejection and has good renal function at 7 years. The third recipient was discovered to have AdV and microabscesess on renal biopsy and required nephrectomy. In the 2 cases of graft loss, we observed sudden deterioration of graft function with rising creatinine and subsequent necrosis resulting in nephrectomy within 40 days after transplantation. AdV was detected by polymerase chain reaction in urine or serum and/or renal tissue. AdV activation after potent immunosuppression can lead to systemic infection and may trigger rejection and/or early graft loss. PMID- 20854283 TI - Absence of lymphatic vessels in the dog dental pulp: an immunohistochemical study. AB - In spite of numerous investigations it has not been precisely determined whether lymphatic vessels are present in the dental pulp of dogs. Therefore, this study attempted a specific immunohistochemical detection of lymphatic endothelium. The canine teeth of 19 healthy beagle dogs were dissected into three segments (apical, intermediate and occlusal). After decalcification, specimens were embedded in paraffin wax and histologic cross-sections were stained immunohistochemically using a reliable antibody (anti-Prox-1) against the homeobox transcription factor Prox-1, which is located within the nucleus of lymphatic endothelium. Anti-Prox-1 reacted positively with canine control tissues (lymph nodes, gingiva, nasal mucosa), but showed no staining in tissue sections of the dental pulp. The dog dental pulp contained no vascular structures lined with lymphatic endothelium. This suggests that drainage of interstitial fluid makes use of other routes, i.e. extravascular pathways. PMID- 20854285 TI - Histopathological aspects of cardiac biopsy in pediatric patients with dilated cardiomyopathy. AB - BACKGROUND: Dilated cardiomyopathy (DCM) is a heart muscle disease with cardiac dysfunction and a heterogeneous disorder. This disease may show various histopathological aspects of the myocardium, but little is known about these in children. METHODS: Histopathological findings of endomyocardial biopsy from 20 pediatric patients with DCM were analyzed and compared with those in adult patients. RESULTS: Advanced histopathology, including myocytolysis and/or fragmentation of muscle bundles, was frequently observed in patients with poor prognosis. Patchy fibrosis was predominantly demonstrated in the pediatric patients, whereas perivascular fibrosis was mostly observed in the older adults. The myocarditic index, assessed in terms of the findings of fibrosis, size variation of myocytes, disarrangement of muscle bundles and mononuclear cell infiltration was higher in the pediatric patients than in the older adults (P < 0.05). Bizarre myocardial hypertrophy with disorganization, which tends to be frequently demonstrated in hypertrophic cardiomyopathy, was revealed in 30% of the pediatric patients, whereas it was disclosed in none of the older adult patients (P < 0.05). CONCLUSION: These results suggest that the major pathogenetic factors of DCM in children may be different from those in adults. PMID- 20854284 TI - Survey of pediatric ward hospitalization due to respiratory syncytial virus infection after the introduction of palivizumab to high-risk infants in Japan. AB - BACKGROUND: Respiratory syncytial virus (RSV) infection is a major cause of hospitalization during the winter among infants and young children. In 2002 palivizumab was introduced to high-risk infants for RSV hospitalization in Japan. It is important to characterize the hospitalized children due to RSV infection after the introduction of palivizumab. METHODS: A survey was conducted to collect the data from the hospitalized children at 12 participating hospitals during the winter of 2007. RESULTS: From October 2007 through April 2008, 8163 children were admitted to participating hospitals, with RSV infection accounting for 811 of those hospitalizations. Mean age in children with RSV infection at hospitalization was 12.4 +/- 12.7 months, and children under 24 months of age accounted for 86.4%. The mean gestational age of those at birth was 38.0 +/- 2.6 weeks, with 82.4% of the children born at term. Palivizumab was administered in 24 cases of RSV infection, while there were 28 patients who were not treated with palivizumab, even though they met the indication for palivizumab. Death, in a total of five cases, occurred in children who were not treated with palivizumab. CONCLUSIONS: Palivizumab has been widely used in high-risk infants who were covered by health insurance, and most of the hospitalized children with RSV infection in the study hospitals were not treated with palivizumab. PMID- 20854286 TI - Clinical aspects of very-low-birthweight infants showing reopening of ductus arteriosus. AB - BACKGROUND: Indomethacin is used to treat the hemodynamically significant patent ductus arteriosus in premature infants. Some infants show ductus arteriosus reopening after effective constriction by the drug. The purpose of this study was to examine the clinical characteristics of such infants. METHODS: We studied 57 very-low-birthweight infants with effective constriction of patent ductus arteriosus by the initial course of indomethacin. They were classified into the reopened group if they developed hemodynamically significant patent ductus arteriosus again or into the closed group if they showed complete closure. Clinical characteristics were compared between the two groups. RESULTS: Ductus arteriosus reopening was shown in 15 (26%) of the 57 infants. These 15 infants had successful clinical ductal closure after a subsequent course of indomethacin or oral mefenamic acid treatment or surgical ligation without any severe complications. Infants in the reopened group showed significantly higher rates of developing chronic lung disease at 36 weeks of gestation than those in the closed group (53% vs 18%; P= 0.009). Furthermore, multivariate logistic regression analysis revealed ductus arteriosus reopening was the only independent risk factor for developing chronic lung disease at 36 postconceptional weeks in this population (adjusted odds ratio, 6.1; 95% confidence interval, 1.4-31.2; P= 0.02). CONCLUSIONS: Incomplete closure of the ductus arteriosus is associated with recurrence of a clinically significant patent ductus arteriosus and reopening of the ductus after initial closure with indomethacin is associated with chronic lung disease. PMID- 20854287 TI - Motor performance of children with mild intellectual disability and borderline intellectual functioning. AB - BACKGROUND: There is a relatively small body of research on the motor performance of children with mild intellectual disabilities (MID) and borderline intellectual functioning (BIF). Adequate levels of motor skills may contribute to lifelong enjoyment of physical activity, participation in sports and healthy lifestyles. The present study compares the motor skills of children with intellectual disability (ID) to the abilities observed in typically developing children. It also aimed to determine whether there is an association between degree of ID and motor performance. METHODS: A total of 170 children between 7 and 12 years old with MID or BIF, who attended schools for special education, were examined on the test component of the Movement Assessment Battery for Children (MABC) test. Both groups were compared with the norm scores of the total score, sub-scale scores and individual items of the MABC test. RESULTS: Of the children, 81.8% with MID and 60.0% with BIF performed below the 16th percentile on the total score of the MABC. Both groups demonstrated a relative weakness in the area of manual dexterity. Comparisons between both groups showed small to moderate effect sizes on the total score of the MABC, as well as for all three sub-scales, favouring the children with BIF. CONCLUSIONS: Children with ID had significantly more borderline and definite motor problems than the normative sample and there was an association between degree of ID and performance of manual dexterity, ball skills and balance skills. This study highlights the importance of improving motor skill performance in both children with borderline and mild ID, and the results support the notion that the level of motor and cognitive functioning are related in children with ID. PMID- 20854291 TI - Equine colic surgery. PMID- 20854288 TI - Adaptive behaviour in Angelman syndrome: its profile and relationship to age. AB - BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder usually caused by an anomaly in the maternally inherited chromosome 15. The main features are severe intellectual disability, speech impairment, ataxia, epilepsy, sleep disorder and a behavioural phenotype that reportedly includes happy disposition, attraction to/fascination with water and hypermotoric behaviour. METHOD: We studied the level of adaptive behaviour and the adaptive behavioural profile in the areas of 'motor skills', 'language and communication', 'personal life skills' and 'community life skills' in a group of 25 individuals with genetically confirmed AS, to determine whether there is a specific adaptive behaviour profile. RESULTS AND CONCLUSIONS: None of the individuals, whatever their chronological age, had reached a developmental age of 3 years. A specific adaptive behaviour profile was found, with 'personal life skills' emerging as relative strengths and 'social and communication skills' as weaknesses. PMID- 20854292 TI - Computed tomography diagnosis of eight dogs with brain infarction. AB - OBJECTIVE: Medical records of eight dogs presenting with acute onset of neurological signs and a diagnosis of brain infarction as determined by computed tomography (CT) imaging were reviewed. DESIGN: Retrospective single-centre case review. RESULTS: Ischaemic infarction in the territory of the rostral cerebellar artery was identified in three spaniel-breed dogs. All cerebellar infarcts were non-haemorrhagic. Telencephalic infarcts were identified in five dogs, in the territories of the middle cerebral artery (2/5) and rostral cerebral artery (3/5). One of these dogs had an ischaemic infarction, but all other infarctions appeared haemorrhagic. All dogs were geriatric (>= 8 years old), with concurrent medical conditions identified in six dogs. One dog was euthanased after diagnosis because of the severity of its neurological signs and one dog was euthanased as a result of associated renal disease 2 months after diagnosis. Six dogs were alive at least 1 year after diagnosis. CONCLUSIONS: CT is useful in the diagnosis of cerebrovascular accident in dogs, which can present as a spectrum of images with early changes in attenuation and subtle mass effects detected after infarction. CT is particularly sensitive for detecting haemorrhagic infarction, but under represent ischaemic and lacunar infarctions when compared with MRI. PMID- 20854293 TI - Tibial tuberosity advancement in 92 canine stifles: initial results, clinical outcome and owner evaluation. AB - OBJECTIVE: To investigate the clinical outcomes, complications and owners' evaluation of the tibial tuberosity advancement (TTA) procedure in canine stifles. METHODS: A retrospective study of hospital records was performed to identify dogs diagnosed with partial or complete cranial cruciate ligament (CCL) rupture that had undergone TTA repair. Information obtained included signalment, period of lameness, surgical report, evidence of meniscal injury, postoperative recovery and peri-operative complications. Owners were asked to assess the long term outcome. RESULTS: In a total of 72 dogs (median age, 6 years; median body weight, 34.8 kg), TTA was performed in 92 stifles. Twenty breeds were represented, with Labrador Retrievers and Rottweilers the most common. The period of lameness ranged from 3 days to 24 months. The median pre-operative lameness score was 3/4 and meniscal injury was present in 51 stifles. Minor complications occurred in 29% of cases. Major complications occurred in 6.5% of cases and consisted of meniscal injury and two tibial tuberosity fractures. All were successfully managed, with good limb function when subsequently assessed. In the owner evaluation, 96% reported moderate to great improvement postoperatively, with no lameness at rest and mild to no lameness after vigorous exercise. CONCLUSION: Clinical outcome and owner evaluations in this case series indicate favourable results can be expected when CCL-deficient stifles are treated with TTA. PMID- 20854294 TI - Holter monitoring in 36 dogs with myxomatous mitral valve disease. AB - OBJECTIVE: Describe the presence of arrhythmias in dogs with myxomatous mitral valve disease (MMVD) and the potential association with class of heart failure and left atrial enlargement. Compare the standard electrocardiogram (ECG) with Holter monitoring for assessing heart rate (HR). EXPERIMENTAL PROCEDURE: The study group of 36 dogs weighing less than 20 kg was divided into MMVD and no clinical signs (preclinical) or MMVD and clinical signs (clinical). A standard echocardiogram, ECG and 24-h Holter recording were obtained in all dogs. RESULTS: Minimum and mean Holter HRs were higher in the clinical group than in the preclinical group. Clinical dogs had more ventricular arrhythmias than preclinical dogs. An enlarged left atrium was associated with the presence of more supraventricular arrhythmias. CONCLUSIONS: Arrhythmias are a common finding in dogs with MMVD and Holter monitoring is a reliable tool for both HR monitoring and diagnosis. PMID- 20854295 TI - Staggers in horses grazing paspalum infected with Claviceps paspali. AB - Invasion of the flowering heads of grasses by Claviceps spp. can produce sclerotia (ergots) containing several toxins. Ingestion of these toxins, through the consumption of paspalum (Paspalum dilatatum), can induce a range of clinical symptoms, including staggers. Cattle are the most commonly affected species, but although sheep and horses have been reported affected there are no published descriptions of paspalum staggers in horses. We describe two occurrences of paspalum staggers, the first in three Australian Stockhorse foals and the second in mature Standardbred horses. All three foals presented with ataxia in all limbs after consuming infected paspalum. One foal died from misadventure and the other two recovered within 1 week of removal from the infected paddock. In the second case, two of eight mares and geldings grazing in an irrigation channel developed hindquarter paresis. After removal of all horses from the area, one of the affected horses continued to deteriorate. Both horses were treated with antibiotics. The more severely affected horse was also treated with fluids and electrolytes, but had to be euthanased. The second affected horse recovered after 2 days. Paspalum pastures should inspected for Claviceps paspali infection before the introduction of horses. PMID- 20854296 TI - Distal luxation of the patella in a horse. AB - A 19-year-old Thoroughbred gelding presented with sudden onset, non-weight bearing lameness in the right hindlimb. Radiography confirmed distal luxation of the patella, which was replaced into its normal anatomical location under general anaesthesia. There were no pathological sequelae noted on follow-up examination 9 months after the initial injury. To our knowledge, this is a rare manifestation of patellar luxation, only reported once previously in the equine literature. PMID- 20854297 TI - Concentration and prevalence of Escherichia coli O157 and Salmonella serotypes in sheep during slaughter at two Australian abattoirs. AB - OBJECTIVE: This study aimed to determine the presence and concentration of Escherichia coli O157 and Salmonella spp. on fleece, faeces and carcases of sheep during slaughter. PROCEDURE: Faeces, fleece and pre-chill carcase samples were collected from 164 sheep slaughtered at two Australian abattoirs. The presence of E. coli O157 and Salmonella spp. were determined by use of automated immunomagnetic separation (AIMS) with enumeration by use of the 'most probable number' (MPN) method. RESULTS: Escherichia coli O157 was isolated from 5% of faeces, 3% of fleeces and 0.6% of pre-chill carcases. The mean log(10) count of E. coli O157 positive faecal samples was 2.32 MPN/g, but counts on fleeces and carcases were below the countable limit (-1 log(10) MPN/cm(2) ). Salmonella spp. were isolated from 20% of faeces, 13% of fleeces and 1.3% of pre-chill carcases. The mean log(10) count of Salmonella spp. in faeces was 1.43 MPN/g and on fleece was -0.24 MPN/cm(2) , but counts on carcases were below the countable limit (-1 log(10) MPN/cm(2) ). CONCLUSION: The prevalence and concentration of pathogens were low in the sheep tested in this study, indicating a low risk of human infection from products derived from these animals. PMID- 20854298 TI - Alzheimer type II astrocytes in the brains of pigs with salt poisoning (water deprivation/intoxication). AB - The finding of Alzheimer type II astrocytes, in addition to the pathognomonic combination of laminar cerebrocortical necrosis and eosinophil infiltration, in the brains of pigs is reported for the first time in cases of indirect salt poisoning following water deprivation. PMID- 20854300 TI - Two mortality events in sea-caged yellowtail kingfish Seriola lalandi Valenciennes, 1833 (Nannopercidae) from Western Australia. AB - In November 2008 a commercial sea-cage operator farming yellowtail kingfish, Seriola lalandi, in Western Australia reported more than 70% mortality of the sea caged fish. Several parasites and potentially pathogenic bacteria were isolated from the fish, but despite a detailed laboratory investigation the cause of the mortality event was never ascertained. That episode of deaths was followed in January 2009 by a smaller mortality event in fish in a sea cage that had been stocked several weeks earlier. Pathogens similar to those seen in the first mortality event were isolated, but again a single causative agent could not be identified. Multiple stress factors resulting in immunosuppression may have precipitated the mortality events. PMID- 20854299 TI - Application of high-resolution melt curve analysis for classification of infectious bronchitis viruses in field specimens. AB - OBJECTIVE: A real-time polymerase chain reaction (PCR)/high-resolution melt (HRM) curve analysis protocol was developed in our laboratory to differentiate infectious bronchitis (IB) virus reference strains. In the current study, this method was used to detect and classify IB viruses in field submissions. PROCEDURE: Over an 11-month period samples from 40 cases of suspected IB virus were received and 17 submissions were positive for IB virus by polymerase chain reaction. HRM curve analysis classified each strain as subgroup 1, 2 or 3 strain (12 submissions) or a strain that was unable to be classified (5 submissions). The 3' untranslated region (UTR) and partial S1 gene nucleotide sequences for the 17 IB virus strains were determined and their identity with those of the relative reference strains compared to confirm the classifications generated using the HRM curve analysis. RESULTS: Of the 12 IB field viruses classified as subgroup 1, 2, or 3 using HRM curve analysis, the 3'UTR and S1 gene nucleotide sequences had identities >=99% with the respective subgroup reference strain. Analysis of the 3' UTR and S1 gene nucleotide sequences for the five IB virus strains that could not be classified indicated that four belonged to one of the subgroups, and one was a potential recombinant strain (between strains from subgroups 2 and 3). A novel recombinant strain was also detected. CONCLUSION: HRM curve analysis can rapidly assign the majority of IB viruses present in field submissions to known subgroups. Importantly, HRM curve analysis also identified variant genotypes that require further investigation. PMID- 20854303 TI - Sudden cardiac death--the challenge to cardiology. PMID- 20854304 TI - Optimizing ICD programming for shock reduction. AB - With the increasing numbers of patients with implantable cardioverter/defibrillators for primary prevention (PP), the topic of inappropriate therapy becomes more and more important. If a shock intervention, e.g. for rapidly conducted atrial fibrillation or fast VT (FVT), represents the first reminder of the implantable cardioverter/defibrillator (ICD), the adherence to the therapy will decrease. Moreover, anxiety to receive the next inappropriate ICD Rx is able to initiate a bad quality of life or depression. Starting with the PainFREE Rx II Trial results, the programming of antitachycardia pacing was able to terminate even fast ventricular arrhythmia, i.e. >= 188 bpm, in three of four episodes. Thereafter, several studies evaluated whether a prolongation in ventricular tachyarrhythmia (VT) detection is able to reduce unnecessary ICD Rx owing to nonsustained VT. The PREPARE trial evaluated this concept in a cohort of PP patients. This nonrandomized study compared a historical control group to patients with a prolonged detection interval. The results underline the idea that an extension in detection time leads to a significant decrease in ICD Rx for supra- as well as VT. The RELEVANT study investigated in a randomized fashion the outcome of an increase in detection time in nonischemic patients under CRT including an ICD. The findings clearly demonstrated a reduction in ICD Rx as well as hospital admissions, significantly. Currently, the ADVANCE III trial investigates a 30/40 interval detection compared to 18/24 for FVT in prospective randomized fashion in patients for primary or secondary prevention including all ICD devices. PMID- 20854306 TI - Contact allergy to corticosteroids and Malassezia furfur in seborrhoeic dermatitis patients. AB - BACKGROUND: Seborrhoeic dermatitis (SD) is a chronic skin disease, requiring long term treatment, which might promote sensitization. Malassezia furfur (Mf) plays an important role in seborrhoeic dermatitis. Objectives The aim of this study was to determine the frequency of contact sensitivity in SD patients. PATIENTS AND METHODS: A total of 100 patients and 20 healthy controls (HC) were investigated: 50 suffering from SD with no previous local corticosteroid treatment (SDN), 50 SD patients treated with local corticosteroids (SDC). Mycological examination for Mf was performed. All patients were patch tested with the baseline standard, corticosteroid series, with 12 commercial corticosteroid preparations frequently used in Croatia; and also with Mf. RESULTS: Malassezia furfur was found in 44 (88%) SDN, 37 (74%) SDC, and in 4 (20%) HC; patch test reaction to Mf was positive in one SDN and in three SDC. Positive patch tests to standard allergens were observed in 17 (34%) SDN, 33 (66%) SDC and 2 (10%) HC. Patch tests to the corticosteroid series revealed positive reactions in 4 SDC and to commercial corticosteroids in seven patients, i.e. 2 SD and 5 SDC. CONCLUSIONS: Patch tests to the baseline series and to both individual corticosteroid and commercial corticosteroid preparations should be performed in SD patients with persistent dermatitis, as contact-allergic reactions may complicate their dermatitis. Sensitization to Mf was found to be infrequent. PMID- 20854305 TI - A comparative subjective assessment study of PENNSAID(r) and Voltaren Gel(r), two topical formulations of diclofenac sodium. AB - Osteoarthritis (OA) is a chronic degenerative joint disease that is debilitating for many individuals. While oral nonsteroidal anti-inflammatory drugs (NSAIDs) remain a common and effective treatment approach to managing OA, concerns over cardiovascular and gastrointestinal adverse events can potentially limit their use. Various formulations of topical NSAIDs have been shown to provide effective localized treatment with minimal adverse events. A patient perception study was conducted to evaluate patient preference between topical diclofenac sodium gel and that of diclofenac sodium topical solution with the penetration enhancer dimethyl sulfoxide (DMSO). Twenty-four healthy volunteers were randomized and asked to administer one dose of the topical products. Surveys were provided and assessed immediately after application, 5 minutes after application, and after the application had dried to gauge subjects' overall experience with the topical preparation. Overall, each drug's application was well tolerated and no adverse events were reported. Results of the patient preference survey demonstrated that topical diclofenac solution with DMSO had a number of characteristics that were rated significantly better than for diclofenac sodium gel. Mean subjective responses to topical diclofenac solution with DMSO were also more favorable for most items in the questionnaire, and more subjects preferred or highly preferred topical diclofenac solution with DMSO over diclofenac sodium gel. PMID- 20854307 TI - Treatment of chronic pain by long-acting opioids and the effects on sleep. AB - Chronic pain affects a substantial part of the population, and conveys a huge economic cost to society. Owing to its prevalence and adverse impact, it is of particular interest to clinicians, patients, and the pharmaceutical industry. Conversely, the effects of pain on sleep, sleep on pain, and opioid analgesics on sleep represent a large gap in our understanding, even though pain and sleep are closely linked, inter-related conditions. Chronic pain is often treated by opioid analgesics, which are often thought to promote restful sleep. Indeed it may be assumed that by relieving pain, sleep quality will improve concomitantly. In fact, the reality is much more complicated. The effects of opioids vary according to their formulation and duration of action, and have diverse effects on sleep processes. Despite the prevalence of this problem, there is a surprising paucity of data on the effects of opioids on sleep. This review attempts to summarize the links between pain and sleep, and to look at the studies with opioid analgesics, particularly those with extended-release formulations, that have investigated the effects of opioid analgesics on sleep. PMID- 20854308 TI - The relation between the duty cycle and anesthetic effect in lidocaine iontophoresis using alternating current. AB - We assessed the effect of the duty cycle on the anesthetic effect during lidocaine alternating current (AC) iontophoresis. A solution of 2% lidocaine was delivered to the medial antecubital skin for 20 minutes using AC iontophoresis with a duty cycle of 60%, 70%, or 80%. The von Frey test was then performed to evaluate the anesthetic effect. In the groups treated with a duty cycle of 80% or 70% the touch thresholds (TT) were significantly elevated from 0 minutes to 30 minutes and from 0 minutes to 20 minutes. TT were significantly elevated at 0 minutes in the group treated with a 60% duty cycle. The anesthetic effect was significantly enhanced in a duty cycle-dependent manner. PMID- 20854309 TI - Radiofrequency treatment of the sacroiliac joint: quo vadis? PMID- 20854310 TI - Indigenous child health issue editorial introduction. PMID- 20854311 TI - Editorial overview on Maori health. PMID- 20854312 TI - Lower respiratory infections in Australian Indigenous children. AB - Despite Australia being one of the wealthiest countries of the world, Australian Indigenous children have a health status and social circumstance comparable to developing countries. Indigenous infants have 10 times the mortality rate for respiratory conditions. The lower respiratory infection (LRI) rate in Australian Indigenous children is at least as high as that of children in developing countries; the frequency of hospitalisations of Indigenous infants is triple that of non-Indigenous Australian infants (201.7 vs. 62.6/1000, respectively). While Indigenous Australian children have many risk factors for LRIs described in developing countries, there is little specific data, and hence, evidence-based intervention points are yet to be identified. Efficacy of conjugate vaccines for common bacterial causes of pneumonia has been less marked in Indigenous children than that documented overseas. Gaps in the management and prevention of disease are glaring. Given the burden of LRI in Indigenous children and the association with long-term respiratory dysfunction, LRIs should be addressed as a matter of priority. PMID- 20854314 TI - The challenge of providing child health care in the indigenous population of New Zealand. AB - This paper defines who is Maori, and traditional Maori attitudes to health and children. It notes the differing levels of engagement of Maori with their culture and the reliance of most Maori on Non Maori practitioners for their medical services. Three relatively common paediatric problems are then used to illustrate the challenges of neither underplaying nor overplaying environmental factors in working with Maori families. The key role of the word respect in working towards positive encounters with Maori is emphasized. PMID- 20854313 TI - Indigenous child health in New Zealand: some surgical issues. AB - New Zealand Maori make up nearly 15% of the population of New Zealand, and their population has increased significantly in the last 20 years. Because of this, the average age of Maori is only 22.7 years with 35% of Maori aged 15 years or less. In spite of this youthful profile, the Maori population has high health needs with trauma, ear disease, respiratory disease and infectious diseases as significant causes of hospitalisation and death. The role of surgery in the management of three potentially preventable but significant health issues affecting Maori children - trauma, cutaneous sepsis (cellulitis and superficial abscess) and obesity - is reviewed. PMID- 20854315 TI - Indigenous perinatal and neonatal outcomes: a time for preventive strategies. AB - Pregnancy outcomes for Indigenous mothers and babies have improved, but marked disparities remain between Indigenous and non-Indigenous women. Many contributors to these disparities such as smoking, alcohol use, poor nutrition, infection, teenage pregnancy and stress are preventable or modifiable particularly if addressed prior to pregnancy. It is suggested that we expand our reproductive health research, education and care to a life course approach beginning in early adolescence. PMID- 20854316 TI - Nutrition and indigenous health in New Zealand. AB - Within New Zealand, Maori experience a greater burden than non-Maori from childhood communicable diseases and from adult non-communicable diseases, for which malnutrition is recognised to have an important role in causality. The nutritional status of Maori is poorer than non-Maori. A larger proportion of Maori newborns are small for gestational age. Weight gain during the first 2 years of life is then more rapid than for non-Maori, and the proportion of Maori that are obese is higher than non-Maori through childhood and into adulthood. Across the age range from infancy to women of childbearing age, iron deficiency is more prevalent, and vitamin D status is poorer in Maori than non-Maori. Over the past two decades, the nutritional status of Maori has improved at birth and during childhood. The proportion of Maori infants small for gestational age and the mean body mass of Maori children aged 2-14 years have decreased. These improvements have been larger than in non-Maori. Further reduction in disparities in nutritional status between Maori and non-Maori must be a priority if the health status of New Zealand's population is to improve. The interventions must address the role that poverty plays in malnutrition, need to be rooted in local food systems and be community driven. If population health status is to improve, New Zealand must secure access to nutritious food for pregnant women, infants and children living in low-income families. PMID- 20854317 TI - The oral health of Indigenous children: a review of four nations. AB - This review of the oral health of children in Australia, New Zealand, Canada and the USA demonstrates that significant oral health inequalities exist in each nation. Despite traditionally low levels of disease in Indigenous communities, dental caries is now highly prevalent and of increased severity among Indigenous children in comparison to their non-Indigenous counterparts. Early childhood caries is particularly prevalent. The high level of dental disease experience at an early age is associated with increased rates of general anaesthesia and greater risk of dental caries in later life. The rates and severity of dental caries experienced by young Indigenous children are even more alarming when we consider that dental caries is essentially a preventable disease. The success of specific preventive programmes is encouraging; these approaches should be further evaluated and implemented as part of broader health promotion programmes for Indigenous children and families in order to decrease current oral health disparities. PMID- 20854318 TI - Type 2 diabetes in indigenous Australian children and adolescents. AB - Rates of type 2 diabetes are higher among Indigenous than non-Indigenous Australian children and adolescents. Presentation may be incidental, part of obesity investigation, symptomatic (polyuria and polydipsia) or in ketoacidosis. Investigation should include assessment of fasting insulin, c-peptide and autoantibodies, as well as assessment of diabetes complications and co morbidities. Management is a challenge, particularly in a resource-limited setting. Management should involve the whole family and, in some cases, extended family, and community, local health-care providers are key, and a multidisciplinary team approach is essential. The primary initial intervention involves life-style change, but medications (oral and insulin) are frequently necessary. Screening of high-risk individuals is recommended. Waist circumference is a key component of risk assessment. Prevention strategies targeting children and adolescents from this high-risk population are urgently required. PMID- 20854319 TI - Hygiene improvement: essential to improving child health in remote Aboriginal communities. AB - It is generally recognised that poor living conditions and poor hygiene underlie the high burden of infection experienced by Indigenous (Aboriginal and Torres Strait Islander) children living in remote communities. There has been little research on this topic. Taking an ecological approach, our study aimed to identify the key factors contributing to poor hygiene in one remote Aboriginal community and to determine appropriate approaches for improving hygiene and reducing the burden of infection among children. Key findings include that multifaceted interventions are required to ensure that household water and sanitation technology are functional, hygiene behaviour change is achieved and environments that enable good hygiene behaviour are created. Many of the factors contributing to the problem of poor living conditions and poor hygiene in these communities are outside the control of the health system. Intersectoral collaboration and action is required to identify acceptable, effective and sustainable solutions. PMID- 20854320 TI - Undernutrition among children in South and South-East Asia. AB - Undernutrition remains a major public health problem among children living in Asia. Although the burden is maximal among poorer, rural and Indigenous communities, the problem affects the majority in many Asian countries, especially in South Asia. In order to prevent the pervasive consequences of undernutrition, strategies that address this burden are required. Successful implementation of strategies may be limited by the complex aetiology of undernutrition, including the political setting. Rising food insecurity because of climate change, land use for biofuel production and the recent global financial crisis threaten to exacerbate childhood malnutrition. In this review, we describe the burden of undernutrition among Asian children and discuss contributing factors and potential solutions. PMID- 20854321 TI - The burden of kidney disease in indigenous children of Australia and New Zealand, epidemiology, antecedent factors and progression to chronic kidney disease. AB - AIMS: To review and present the most important issues related to kidney disease in Aboriginal, Torres Strait Islander, Maori and Pacific Islander children from Australia and New Zealand. METHODS: A review of medical literature about: 1. incidence of kidney disease in Indigenous children in Australia and New Zealand, especially where rates are different from the general populations, 2. factors in early life which increase risk for chronic kidney disease in adult life, and 3. early identification and primary and secondary interventions in childhood which may prevent chronic kidney disease in adults. RESULTS: Kidney diseases, both acute and chronic are more common in Maori, Pacific Islander, Australian Aboriginal and Torres Strait Islander people. The reasons are multiple and include genetic, environmental and socio-economic factors. In childhood post streptococcal glomerulonephritis, haemolytic uraemic syndrome, renal stones and acute kidney injury all occur at higher frequency in at least some of the Indigenous populations. Chronic kidney disease CKD occurs more commonly, and at a younger age in Indigenous than non Indigenous people. Factors involved may include reduced nephron endowment at birth, and subsequent insults including nephritis, obesity, and early onset type 2 diabetes, as well as underlying socioeconomic and environmental determinants. CONCLUSION: A lifecourse understanding allows one to conceptualise multiple risk factors and target interventions. PMID- 20854322 TI - The mysterious practice of petrol sniffing in isolated indigenous groups. AB - The practice of petrol sniffing is a unique and poorly understood phenomenon that is associated with substantial morbidity, mortality and social devastation in affected remote Indigenous communities. For these groups and for the wider community, much mystery has surrounded the practice and its effects. Here we introduce the epidemiology of petrol sniffing among Indigenous groups internationally, review its impact on the brain, behaviour and social functions and summarise related interventions. PMID- 20854323 TI - Smoking and Aboriginal and Torres Strait Islander and Maori children. AB - Smoking and the deaths and suffering it causes are more common among Aboriginal and Torres Strait Islander peoples and Maori than other Australians and New Zealanders. While, many tobacco control activities that are not specifically targeted at children will have a positive impact on child health, this review concentrates on recent tobacco control research on pregnant women and children. The important tasks are to reduce smoking by pregnant Maori and Aboriginal and Torres Strait Islander women to reduce infant and child exposure to second-hand smoke and to reduce smoking initiation of children and adolescents. Health professionals who want to reduce the suffering caused by smoking among Maori and Aboriginal and Torres Strait Islander children can be guided by much new relevant research evidence and clear frameworks about how to approach tobacco control in these communities. PMID- 20854324 TI - Respiratory infections in Tamariki (children) and Taitamariki (young people) Maori, New Zealand. AB - The Maori population is young, with 53% aged less than 25 years and with a higher prevalence of both acute (bronchiolitis, pneumonia, pertussis, tuberculosis) and chronic (bronchiectasis) respiratory tract infections than non-Maori. Environmental, economic and poorer access to health promotion programmes and health care rather than specific or genetic underlying disorders appear to contribute to this burden. While new initiatives are needed, we can do better with current public health programmes and building on regional initiatives that have already proven successful. PMID- 20854325 TI - Rheumatic fever in indigenous Australian children. AB - Rheumatic heart disease (RHD) caused by acute rheumatic fever (ARF) is a disease of poverty, poor hygiene and poor living standards. RHD remains one of the major causes of childhood cardiac disease in developing nations. Within developed nations, there has been a dramatic drop in the prevalence of RHD because of the improvement of living standards, access to health care and the widespread availability of penicillin-based drugs. Despite a dramatic reduction of RHD in Australia overall, it continues to be a major contributor to childhood and adult cardiac disease in Indigenous communities throughout northern and central Australia. Currently, Australia has among the highest recorded rates of ARF and RHD in the world. The most accurate epidemiological data in Australia come from the Northern Territory's RHD control programme. In the Northern Territory, 92% of people with RHD are Indigenous, of whom 85% live in remote communities and towns. The incidence of ARF is highest in 5-14-year-olds, ranging from 150 to 380 per 100,000. Prevalence rates of RHD since 2000 have steadily increased to almost 2% of the Indigenous population in the Northern Territory, 3.2% in those aged 35-44 years. Living in remote communities is a contributing factor to ARF/RHD as well as a major barrier for adequate follow-up and care. Impediments to ARF/RHD control include the paucity of specialist services, rapid turnover of health staff, lack of knowledge of ARF/RHD by health staff, patients and communities, and the high mobility of the Indigenous population. Fortunately, the recently announced National Rheumatic Fever Strategy, comprising recurrent funding to the Northern Territory, Queensland and Western Australia for control programmes, as well as the creation of a National Coordination Unit suggest that RHD control in Australia is now a tangible prospect. For the disease to be eradicated, Australia will have to address the underpinning determinants of poverty, social and living conditions. PMID- 20854326 TI - The primary prevention of rheumatic fever. AB - Rheumatic fever (RF), caused by untreated group A streptococcal (GAS) pharyngitis, is a major cause of morbidity and mortality throughout much of the less developed world and disadvantaged populations (Indigenous and other) in the developed world. Through systematic literature searches, our group has identified potential risk factors for RF and possible interventions for its prevention. The causes can be divided into biological factors, socio-economic, and lifestyle factors and health-care systems and services. Currently, the most promising medical areas look to be improving access to health care and introducing community and school-based sore throat interventions (which aim to diagnose and treat GAS pharyngitis). We could find no convincing support for skin sepsis causing RF. Overall evidence suggests that measures that aim to alleviate poverty and crowding may also reduce the incidence of RF. In comparatively rich countries such as New Zealand and Australia, urgent measures based on available evidence should be undertaken to reduce the very striking health disparity seen with RF and its sequela, rheumatic heart disease in our at-risk populations. PMID- 20854327 TI - Prevalence of obesity in Dakar. AB - The present study is to our knowledge the first to evaluate the prevalence of obesity among both men and women in Dakar. It was carried out on a sample of 600 dwellers of the Senegalese capital. The prevalence of general obesity is 8.3%, and that of overweight is 22.3%. The underweight rate remains high, given that 12.3% of the adults in this sample show a body mass index (BMI) of <18.5 kg/m(2) . The prevalence of central obesity is 41.2% according to waist to hip ratio (WHR), and 21.2% according to waist circumference (WC). These figures mask considerable differences between men and women and between generations. For instance, women are often more obese than men, whether it is a question of general obesity (13% and 3.9% respectively) or central obesity (37.5% and 5.5% by WC respectively). Moreover, prevalence of general and central obesity rise drastically with age, irrespective of gender. Thus, in addition to combating infectious disease and undernutrition, Senegal must now face problems associated with overweight and obesity. PMID- 20854328 TI - Reference values for B cell subpopulations from infancy to adulthood. AB - The composition of the peripheral blood lymphocyte compartment underlies developmental changes during ontogeny. Recently, several new B cell populations have been characterized which were suggested to develop in an age-dependent manner. However, age-dependent reference values for distinct B cell populations have rarely been reported. Therefore, we have characterized developmental changes in peripheral B cell populations from infancy to adulthood in order to define age dependent reference values. Using a flow cytometric approach we analysed the frequencies as well as the absolute counts of naive, switched and non-switched memory B cells, CD27-negative memory B cells, transitional B cells as well as CD21(low) CD38(low) B cells from neonates up to the age of 50 years. Most of the B cell subsets showed age-dependent developmental changes: while the peripheral B cell pool during infancy is characterized predominantly by transitional and naive B cells, the fraction of switched and non-switched memory B cells increases gradually with age. CD21(low) CD38(low) B cells as well as plasmablasts do not exhibit developmental changes. In summary, we could demonstrate particular changes in the peripheral blood B cell compartment during ontogeny. This study provides reference values of different B cell subpopulations offering comparability for studies addressing disturbed peripheral B cell development in immunodeficiency, autoimmunity or B cell reconstitution following cell-depleting therapies. PMID- 20854330 TI - Survival with short-daily hemodialysis: association of time, site, and dose of dialysis. AB - In thrice-weekly hemodialysis, survival correlates with the length of time (t) of each dialysis and the dose (Kt/V), and deaths occur most frequently on Mondays and Tuesdays. We studied the influence of t and Kt/V on survival in 262 patients on short-daily hemodialysis (SDHD) and also noted death rate by weekday. Contingency tables, Kaplan-Meier analysis, regression analysis, and stepwise Cox proportional hazard analysis were used to study the associations of clinical variables with survival. Patients had been on SDHD for a mean of 2.1 (range 0.1 11) years. Mean dialysis time was 12.9 +/- 2.3 h/wk and mean weekly stdKt/V was 2.7 +/- 0.5. Fifty-two of the patients died (20%) and 8-year survival was 54 +/- 5%. In an analysis of 4 groups by weekly dialysis time, 5-year survival continuously increased from 45 +/- 8% in those dialyzing <12 hours to 100% in those dialyzing >15 hours without any apparent threshold. There was no association between Kt/V and survival. In Cox proportional hazard analysis, 4 factors were independently associated with survival: age in years Hazard Ratio (HR)=1.05, weekly dialysis hours HR=0.84, home dialysis HR=0.50, and secondary renal disease HR=2.30. Unlike conventional HD, no pattern of excessive death occurred early in the week during SDHD. With SDHD, longer time and dialysis at home were independently associated with improved survival, while Kt/V was not. Homedialysis and dialysis 15+ h/wk appear to maximize survival in SDHD. PMID- 20854329 TI - The methane cycle in ferruginous Lake Matano. AB - In Lake Matano, Indonesia, the world's largest known ferruginous basin, more than 50% of authigenic organic matter is degraded through methanogenesis, despite high abundances of Fe (hydr)oxides in the lake sediments. Biogenic CH4 accumulates to high concentrations (up to 1.4 mmol L-1) in the anoxic bottom waters, which contain a total of 7.4 * 105 tons of CH4. Profiles of dissolved inorganic carbon (SigmaCO2) and carbon isotopes (delta13C) show that CH4 is oxidized in the vicinity of the persistent pycnocline and that some of this CH4 is likely oxidized anaerobically. The dearth of NO3- and SO42- in Lake Matano waters suggests that anaerobic methane oxidation may be coupled to the reduction of Fe (and/or Mn) (hydr)oxides. Thermodynamic considerations reveal that CH4 oxidation coupled to Fe(III) or Mn(III/IV) reduction would yield sufficient free energy to support microbial growth at the substrate levels present in Lake Matano. Flux calculations imply that Fe and Mn must be recycled several times directly within the water column to balance the upward flux of CH4. 16S gene cloning identified methanogens in the anoxic water column, and these methanogens belong to groups capable of both acetoclastic and hydrogenotrophic methanogenesis. We find that methane is important in C cycling, even in this very Fe-rich environment. Such Fe rich environments are rare on Earth today, but they are analogous to conditions in the ferruginous oceans thought to prevail during much of the Archean Eon. By analogy, methanogens and methanotrophs could have formed an important part of the Archean Ocean ecosystem. PMID- 20854331 TI - The long-term effects of arteriovenous fistula creation on the development of pulmonary hypertension in hemodialysis patients. AB - The aim of this prospective study was to evaluate long-term effects of arteriovenous fistula (AVF) on the development of pulmonary arterial hypertension (PAH) and the relationship between blood flow rate of AVF and pulmonary artery pressure (PAP) in the patients with end-stage renal disease (ESRD). This prospective study was performed in 20 patients with ESRD. Before an AVF was surgically created for hemodialysis, the patients were evaluated by echocardiography. Then, an AVF was surgically created in all patients. After mean 23.50 +/- 2.25 months, the second evaluation was performed by echocardiography. Also, the blood flow rate of AVF was measured at the second echocardiographic evaluation. Pulmonary arterial hypertension was defined as a systolic PAP above 35 mmHg at rest. Mean age of 20 patients with ESRD was 55.05 +/- 13.64 years; 11 of 20 patients were males. Pulmonary arterial hypertension was detected in 6 (30%) patients before AVF creation and in 4 (20%) patients after AVF creation. Systolic PAP value was meaningfully lower after AVF creation than before AVF creation (29.95 +/- 10.26 mmHg vs. 35.35 +/- 7.86 mmHg, respectively, P: 0.047). However, there was no significant difference between 2 time periods in terms of presence of PAH (P>0.05). Pulmonary artery pressure did not correlate with blood flow rate of AVF and duration after AVF creation (P>0.05). In hemodialysis patients, a surgically created AVF has no significant effect on the development of PAH within a long-term period. Similarly, blood flow rate of AVF also did not affect remarkably systolic PAP within the long-term period. PMID- 20854332 TI - The multiple facets of HIV attachment to dendritic cell lectins. AB - Entry of enveloped viruses into host cells depends on the interactions of viral surface proteins with cell surface receptors. Many enveloped viruses maximize the efficiency of receptor engagement by first binding to attachment-promoting factors, which concentrate virions on target cells and thus increase the likelihood of subsequent receptor engagement. Cellular lectins can recognize glycans on viral surface proteins and mediate viral uptake into immune cells for subsequent antigen presentation. Paradoxically, many viral and non-viral pathogens target lectins to attach to immune cells and to subvert cellular functions to promote their spread. Thus, it has been proposed that attachment of HIV to the dendritic cell lectin DC-SIGN enables the virus to hijack cellular transport processes to ensure its transmission to adjacent T cells. However, recent studies show that the consequences of viral capture by immune cell lectins can be diverse, and can entail negative and positive regulation of viral spread. Here, we will describe key concepts proposed for the role of lectins in HIV attachment to host cells, and we will discuss recent findings in this rapidly evolving area of research. PMID- 20854333 TI - Which came first: the readiness or the change? Longitudinal relationships between readiness to change and drinking among college drinkers. AB - AIMS: Although readiness to change (RTC) is cited as a key mechanism underlying drinking behavior change, empirical evidence supporting RTC as a predictor of college drinking has been mixed. Considering methodological limitations of previous studies, the current aim was to conduct a more comprehensive test of longitudinal relationships between readiness to change and college drinking. DESIGN: In this correlational, longitudinal study, we used a series of cross lagged path analyses to test associations between RTC and college drinking outcomes over a 2-year period. SETTING: Data collection was conducted via online surveys on a university campus in the US Pacific Northwest. PARTICIPANTS: Participants (n = 818; 58% women) were college students who reported at least one heavy-drinking episode in the past month and participated in a randomized controlled trial of personalized normative feedback interventions. MEASUREMENTS: Drinking quantity-frequency items and the Rutgers Alcohol Problem Index assessed drinking outcomes. The Readiness to Change Questionnaire assessed RTC. FINDINGS: For drinking-related problems, the best-fitting model included cross-lagged paths between RTC and subsequent drinking-related problems. For drinking quantity frequency, best-fitting models also included the cross-lagged paths between drinking quantity-frequency and subsequent RTC. Higher RTC almost uniformly predicted higher subsequent levels of drinking and greater experience of drinking related problems, and drinking quantity-frequency variables were primarily positive predictors of subsequent RTC. CONCLUSIONS: Contrary to previous assumptions, 'the Readiness to Change Questionnaire' does not appear to be predictive of lower levels of subsequent drinking. PMID- 20854334 TI - Quality versus quantity: acquisition of coping skills following computerized cognitive-behavioral therapy for substance use disorders. AB - AIMS: To evaluate the changes over time in quality and quantity of coping skills acquired following cognitive behavioral therapy (CBT), and examine potential mediating effects on substance use outcomes. DESIGN: A randomized controlled trial (RCT) evaluating the effectiveness of a computerized version of CBT (CBT4CBT) as an adjunct to standard out-patient treatment over an 8-week period. SETTING: Data were collected from individuals seeking treatment for substance dependence in an out-patient community setting. PARTICIPANTS: Fifty-two substance abusing individuals (50% African American), with an average age of 42 years, and a majority reporting cocaine as their primary drug of choice. MEASUREMENTS: Participants' responses to behavioral role-plays of situations associated with high risk for drug and alcohol use were audio-taped and rated independently to assess their coping responses. FINDINGS: There were statistically significant increases in mean ratings of the quality of participants' coping responses for those assigned to CBT4CBT compared to treatment as usual, and these differences remained significant 3 months after treatment completion. Moreover, quality of coping responses mediated the effect of treatment on participants' duration of abstinence during the follow-up period. CONCLUSIONS: These findings suggest that assignment to the computerized CBT program improved participants' coping skills, as measured by independent ratings of a role-playing task. It is also the first study to test and support quality of coping skills acquired as a mediator of the effect of CBT for substance use. PMID- 20854335 TI - Harsh physical punishment as a specific childhood adversity linked to adult drinking consequences: evidence from China. AB - AIMS: The aim of the current study is to estimate the association between childhood physical punishment (CPP) and level of alcohol use disorder (AUD), using two different approaches to take other childhood adversities into account. DESIGN AND SETTING: Population survey using face-to-face interviews to a representative sample of non-institutionalized adult residents of Beijing and Shanghai, China. PARTICIPANTS: A total of 5201 participants aged 18-70 years. MEASUREMENTS: A version of the World Mental Health Composite International Diagnostic Interview was used. Standardized assessments covered early life experiences of childhood physical punishment, other childhood adversities, parental drinking problems, childhood conduct problems and clinical features of AUD. FINDINGS: A robust association linking CPP and level of AUD was found, holding other childhood adversities constant (probit coefficient = 0.70, 95% CI = 0.40, 1.00) via covariate terms in structural equations modeling. Furthermore, there was evidence that CPP might exert an additional influence on level of AUD over and above a generally noxious family environment (probit coefficient = 0.20, 95% CI = 0.02, 0.38). CONCLUSIONS: There appears to be a robust association between reports of harsh punishment in childhood and alcohol dependence in adulthood adjusting for a range of possible confounding factors. Whether the association is causal or whether both are related to a common underlying factor or recall bias needs to be investigated further. PMID- 20854336 TI - Pathological gambling recovery in the absence of abstinence. AB - AIMS: To examine the role of abstinence from gambling versus controlled gambling in recovery from pathological gambling (PG) in a community-based survey. DESIGN: Individuals with a life-time history of PG identified in a community-based survey were divided into three groups based on their current levels of PG symptoms. These three groups were compared to each other on their past-year gambling involvement. SETTING: National general population twin survey conducted in Australia. PARTICIPANTS: Overall, there were 4764 participants in the community based survey (mean age 37.7 years, 57.2% women). Among these were 104 participants with a life-time history of PG; of the 104 with a life-time diagnosis of PG, 28 had a past-year diagnosis of PG, 32 had past-year problem gambling and 44 had no symptoms of PG in the past year ('recovery'). MEASUREMENTS: The measure of PG was based on the NODS (NORC DSM-IV Screen for Gambling Problems). Past-year participation in 11 different gambling activities was assessed, as well as the following composite indicators: any gambling, gambling versatility, the number of days and hours spent gambling and the proportion of household income spent on gambling. FINDINGS: Ninety per cent of those in the recovery group participated in some form of gambling in the past year. CONCLUSIONS: In this general population survey, nearly all the PG recoveries were achieved in the absence of abstinence. Controlled gambling appears to be a popular road to recovery in the community. PMID- 20854337 TI - The self-reported personal wellbeing of a sample of Australian injecting drug users. AB - AIMS: To examine the self-reported personal wellbeing of a sample of Australian injecting drug users (IDU) using a standardized instrument and determine the key correlates of variations in self-reported personal wellbeing. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional survey of 881 Australian IDU. MEASUREMENTS: Self reported personal wellbeing collected using the Personal Wellbeing Index (PWI). FINDINGS: IDU scored significantly lower than the general Australian population on the PWI and all subscales. Lower PWI scores were associated with a range of socio-demographic, drug use and other health and social characteristics. Across all PWI subscales, lower personal wellbeing scores were associated with unemployment, past 6-month mental health problems and more frequent injecting (all P < 0.05). CONCLUSIONS: The PWI is sufficiently sensitive to distinguish between IDU and the general population, and to identify key correlates of PWI among IDU. Some domains canvassed within the scale, such as health, standard of living and life achievements, are well within the scope of current intervention strategies, such as pharmacotherapy maintenance treatment and housing and employment support services. This suggests that the PWI could be useful in clinical settings by allowing structured identification of the areas of a person's life to be addressed as a part of a treatment regimen. In order to inform targeted prevention and intervention efforts, longitudinal studies of PWI and its correlates among IDU are required. PMID- 20854339 TI - Enhancing our clinical links and credibility: nurse lecturers in clinical practice. PMID- 20854340 TI - Symptom burden in inflammatory bowel disease: rethinking conceptual and theoretical underpinnings. AB - Symptom control is fundamental to the nursing management of inflammatory bowel disease (IBD). However, symptom control can be problematic for individuals with IBD, which could result in symptom burden. Symptom burden is an evolving concept in the discipline of nursing and to date little is known about how the defining characteristics of this concept have been applied to symptom research in IBD. In this discussion paper, the concept of symptom burden and the theory of unpleasant symptoms are explored as a basis for understanding symptom research in IBD. This is followed by a critical examination of previous symptom research in IBD. Our conclusion is that there is a need to rethink conceptual and theoretical underpinnings of symptom burden when researching IBD to take account of its defining characteristics, namely symptom severity, frequency and duration, quality and distress. Research knowledge on these defining characteristics will be important to inform nursing assessment of symptom burden in clinical practice. PMID- 20854341 TI - Demands of immigration among Chinese immigrant nurses. AB - The purpose of this study was to identify the demands of immigration among Chinese nurses that have immigrated to the USA. The relationship between the demands of immigration and length of stay in the USA was investigated also. A descriptive correlational study design was used. A convenience sample of 128 nurses was recruited. A self-administered survey was conducted using the demands of immigration scale developed by Aroian, along with a demographic questionnaire. The results showed Chinese immigrant nurses have high demands of immigration. There were significant negative relationships between the demands of immigration and length of stay in the USA. Immigration demands decreased as length of stay increased but remained high even for those who had been in the USA for > 5 years. This information is vital to health-care agencies designing and implementing adaptation programmes targeting these demands to facilitate Chinese nurses' adaptation process. PMID- 20854338 TI - Prenatal methadone exposure, meconium biomarker concentrations and neonatal abstinence syndrome. AB - AIMS: Methadone is standard pharmacotherapy for opioid-dependent pregnant women, yet the relationship between maternal methadone dose and neonatal abstinence syndrome (NAS) severity is still unclear. This research evaluated whether quantification of fetal methadone and drug exposure via meconium would reflect maternal dose and predict neonatal outcomes. DESIGN: Prospective clinical study. SETTING: An urban drug treatment facility treating pregnant and post-partum women and their children. PARTICIPANTS: Forty-nine opioid-dependent pregnant women received 30-110 mg methadone daily. MEASUREMENTS: Maternal methadone dose, infant birth parameters and NAS assessments were extracted from medical records. Thrice weekly urine specimens were screened for opioids and cocaine. Newborn meconium specimens were quantified for methadone, opioid, cocaine and tobacco biomarkers. FINDINGS: There was no relationship between meconium methadone concentrations, presence of opioids, cocaine and/or tobacco in meconium, maternal methadone dose or NAS severity. Opioid and cocaine were also found in 36.7 and 38.8 of meconium specimens, respectively, and were associated with positive urine specimens in the third trimester. The presence of opioids other than methadone in meconium correlated with increased rates of preterm birth, longer infant hospital stays and decreased maternal time in drug treatment. CONCLUSIONS: Methadone and its metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentrations in meconium did not predict infant birth parameters or NAS severity. Prospective urine testing defined meconium drug detection windows for opiates and cocaine as 3 months, rather than the currently accepted 6 months. The presence of opioids in meconium could be used as a biomarker for infants at elevated risk in the newborn period. PMID- 20854342 TI - Effect of foot massage to decrease physiological lower leg oedema in late pregnancy: a randomized controlled trial in Turkey. AB - This study aims to evaluate the effect of foot massage for decreasing physiological lower leg oedema in late pregnancy. Eighty pregnant women were randomly divided into two groups; study group had a 20 min foot massage daily for 5 days whereas the control group did not receive any intervention beyond standard prenatal care. The research was conducted between March and August 2007 in Manisa Province Health Ministry Central Primary Health Care Clinic 1, in Manisa, Western Turkey. Compared with the control group, women in the experimental group had a significantly smaller lower leg circumference (right and left, ankle, instep and metatarsal-phalanges joint) after 5 days of massage. The results obtained from our research show that foot massage was found to have a positive effect on decreasing normal physiological lower leg oedema in late pregnancy. PMID- 20854343 TI - A randomized controlled trial to assess the impact of an Admission Service on patient and staff satisfaction. AB - This study aims to assess the benefits of an Admission Service (AS) wherein the nurse, when fluent in the language spoken by the patient (Arabic), improves the accuracy and efficiency of acquiring key assessment data needed to guide nursing care. Patients' satisfaction with their hospital experience begins formulating from their time of admission. Dissatisfaction is frequently reported in areas requiring careful, skilled communication such as obtaining emotional support and family participation and education. Over a 3-month study recruitment, 314 patients were randomly assigned to be admitted either through the AS (n=150) or to the unit via the standard admission process (n=164). The AS improved the efficiency of admission time by >150%. The nurse's assessment of their quality of admission was also improved: 76 vs. 26 nurses rated their quality of admission as 'very good' when assisted by the AS compared with standard admission to the unit. PMID- 20854344 TI - How nurses address the burden of disease in remote or isolated areas in Queensland. AB - Nurses have a role in addressing the burden of disease in remote or isolated areas of Queensland. Activities to prevent chronic and acute disease and injury, while promoting a health lifestyle, are a part of nurses' work that help to meet the goal of keeping a population healthy. The findings presented in this paper, as part of a broader study into the role of nurses working in remote or isolated areas of Queensland, describe how registered nurse in these locations address local burden of disease. Participants discussed the increased workload that engaging in health promotion and disease prevention activities creates for them when providing health-care services for their communities. Establishing stronger working relationships with visiting members of the primary health-care team, while addressing organizational barriers, might have a significant impact on the nurses' ability to help reduce the burden of disease in these areas. PMID- 20854345 TI - A quantitative study of Iranian nursing students' knowledge and attitudes towards pain: implication for education. AB - It is well documented that pain management and pain assessment is an indispensible part of the nursing care of patients. This study sought to quantify the current knowledge and attitudes of nursing students in Iran about pain management. We conducted a cross-sectional study using a well-validated questionnaire entitled the 'Knowledge and Attitudes Regarding Pain Tool', previously used to evaluate undergraduate nursing students. Results from the survey questionnaire showed that there was a severe deficit in knowledge relating to pain and its management. It is argued that there is a real need for improving the content of pain and its management in the undergraduate nursing education curriculum, which might improve the delivery of optimal nursing care of patients. The limitations of the study are discussed and some recommendations are made for reforming pain management education for future practice. PMID- 20854346 TI - Evaluation of the implementation of Assistant in Nursing workforce in haemodialysis units. AB - The aim of this project was to evaluate the introduction of Assistant in Nursing (AINs) in the haemodialysis units at a major tertiary Area Health Service in Sydney, Australia. All nursing staff were asked to complete a baseline and follow up survey to determine changes to their attitudes to the new skill mix model and their satisfaction with the new organization of care delivery in their dialysis units. Comparison of the baseline and follow-up surveys in the paired data was favourable with nurses acknowledging that they would cope well with the introduction of AINs, and they were more likely to disagree with the statement that their workload would increase after the introduction of AINs in the follow up survey. There was little difference in (i) the workload of the dialysis units before and during the intervention; and (ii) the incidence of patient and nursed related adverse outcome events. PMID- 20854347 TI - Knowledge of heart attack symptoms and risk factors among native Thais: a street intercept survey method. AB - This study aimed to determine Thais' knowledge of heart attack symptoms and risk factors and whether that knowledge was related to age, gender or education. Via a street-intercept survey method, a convenience sample of people aged >= 35 years (n = 192) was recruited. Mean age was 47 +/- 9.6 years (range 35-81), and 55.2% were female. Participants identified on average 5.6 of 9 heart attack symptoms (SD 1.8) and 5.3 of 8 heart attack risk factors (SD 2.1). However, 66.7% mistakenly thought the chest discomfort would be severe, sharp and stabbing, and many subjects erroneously selected symptoms that are actually stroke symptoms. There were no gender or educational differences in knowledge of heart attack symptoms and risk factors. Older adults recognized fewer total symptoms than did younger adults. These findings could direct health-care providers to help the Thai population differentiate symptoms of heart attack from stroke. PMID- 20854348 TI - Physically restraining elder residents of long-term care facilities from a nurses' perspective. AB - The purpose of the current study was to identify and analyse major variables affecting intended decisions of nursing staff to physically restrain elder residents of long-term care facilities. The study explored whether a research model constructed of staff characteristics and resident characteristics would prove useful for predicting behavioural intentions. A total of 120 reliable and validated questionnaires, based on the research model, were administered to nurses working in a large long-term care facility for older adults in central Israel; 104 questionnaires were returned for a response rate of 86%. The research findings indicate that most of the nurses who responded (67.2%) reported that they had physically restrained elder residents more than 10 times over the past year; however, the nurses had a low intention of restraining residents during the coming year. The research results indicate that the intended decision of nursing staff to restrain elderly residents is a derivative of their behavioural beliefs and attitudes, normative beliefs and subjective norms, as well as of residents' dementia, physical state and stress. PMID- 20854349 TI - Comparison between ambulatory infusion mode and inpatient infusion mode from the perspective of quality of life among colorectal cancer patients receiving chemotherapy. AB - Folfox and Folfiri are active chemotherapy treatments used in advanced colorectal cancer. The total admission for these treatments has been significantly increasing in the study hospital. An ambulatory infusion programme was launched to address the problems of long waiting list and bed shortage. The study objective was to compare the quality of life between patients receiving the chemotherapy treatments in the ambulatory infusion group and the inpatient infusion group. The results showed that some demographic variables of education level, family role and employment status were determinants of the treatment mode. Patients in the ambulatory infusion group of social and global domains performed better than the inpatient group. However, the inpatient group had better quality of life of nauseated symptom at different stages. Some nursing educations should be reinforced to address the symptom management for patients receiving ambulatory infusion at home. The ambulatory infusion programme offered considerable quality of life benefits to colorectal cancer patients receiving chemotherapy. PMID- 20854350 TI - The first Australian nurse practitioner census: A protocol to guide standardized collection of information about an emergent professional group. AB - Internationally, collection of reliable data on new and evolving health-care roles is crucial. We describe a protocol for design and administration of a national census of an emergent health-care role, namely nurse practitioners in Australia using databases held by regulatory authorities. A questionnaire was developed to obtain data on the role and scope of practice of Australian nurse practitioners. Our tool comprised five sections and included a total of 56 questions, using 28 existing items from the National Nursing and Midwifery Labour Force Census and nine items recommended in the Nurse Practitioner Workforce Planning Minimum Data Set. Australian Nurse Registering Authorities (n = 6) distributed the survey on our behalf. This paper outlines our instrument and methods. The survey was administered to 238 authorized Australian nurse practitioners (85% response rate). Rigorous collection of standardized items will ensure health policy is informed by reliable and valid data. We will re administer the survey 2 years following the first survey to measure change over time. PMID- 20854351 TI - A new SEMA7A variant found in Native Americans with alloantibody. AB - BACKGROUND AND OBJECTIVES: John Milton Hagen (JMH) antigens are carried by Semaphorin 7A that plays important roles in the nervous system and the immune responses. Its role on the erythrocytes is unclear. Over the years, few samples were referred to our Immunohaematology Reference Laboratory to elucidate their JMH status. MATERIALS AND METHODS: Seven blood samples with antibodies compatible with JMH1-negative red cells were studied at the molecular level to identify polymorphisms and explain the JMH diversity observed. Four samples were of Native American background and three were Caucasians. Molecular analyses of the SEMA7A were undertaken, and soluble form of recombinant Sema7A proteins was produced to characterize the antibodies. RESULTS: Sequencing of the cDNA showed a polymorphism in SEMA7A exon 9 at position 1040 (G>T) in the four Native American samples. Caucasians had a normal sequence. This polymorphism precludes a change at position 347 where an Arg is replaced by a Leu. Plasma was assayed in ELISA on wild-type Sema7AArg347 and variant Sema7ALeu347 proteins. Results clearly indicated a specific recognition of the antibody produced by the Native Americans for the wild-type Sema7AArg347 protein and not the variant one. CONCLUSION: A new SEMA7A variant was identified in this study. The antibody present in the Native American plasma samples should be considered as an alloantibody because it recognizes the wild-type protein. PMID- 20854352 TI - Liver involvement in post-smolt Atlantic salmon, Salmo salar L., infected with infectious pancreatic necrosis virus (IPNV): a retrospective histopathological study. AB - Histological changes associated with infectious pancreatic necrosis virus (IPNV) infection have historically been described for the pancreas and gut, but any involvement of the liver was poorly acknowledged or described. The aims of this study were to find robust evidence that the reported increase in liver pathology in Atlantic salmon post-smolts in natural outbreaks was effectively related to IPNV infection and retrospectively to report when such a shift in the involvement of the liver had taken place, supported by a histopathological description for a differential diagnosis. The study reports new findings concerning the dynamics of liver pathology development, with apoptosis, demonstrated by histological and immunological techniques, described as the most relevant and particular feature. Immunohistochemical examination of affected liver suggests apoptosis is not only the result of the virus infection itself but triggered through the action of the host's innate immune response. Liver involvement contributes to the nature of infection and becomes an important factor in the disease process. Additionally, it was established that the increase in infectious pancreatic necrosis prevalence is correlated with a new distinct pattern of outbreak distribution throughout the year. The role of smolt category (i.e. S1, S1/2 or S0), hence timing of seawater transfer as a strong correlating factor, is discussed. PMID- 20854353 TI - Association of red-mark syndrome with a Rickettsia-like organism and its connection with strawberry disease in the USA. AB - Red-mark syndrome (RMS), a disease seen mostly in rainbow trout, Oncorhynchus mykiss, is of unknown aetiology. The research presented here indicates the presence of an intracellular bacterium in RMS-affected fish. A positive reaction was observed using immunohistochemistry (IHC) with skin lesions, liver, kidney and spleen of affected fish sampled from several locations within the United Kingdom using two different polyclonal antisera raised against Piscirickettsia salmonis. The same reaction was also seen with a number of different anti-P. salmonis monoclonal antibodies (MAbs). A disease with similar clinical signs to RMS, referred to as strawberry disease (SD), has been reported in the USA. A Rickettsia-like organism (RLO) has recently been associated with SD based on analysis of 16S rDNA sequences. Using the same panel of anti-P. salmonis antibodies used to screen the RMS samples, similar staining was obtained in tissue of SD-affected fish by IHC. A polymerase chain reaction (PCR) using RLO specific primers was also performed on RMS-affected fish from the United Kingdom, and the samples were positive for the RLO 16S rRNA sequence. These findings suggest that the same aetiological agent may be responsible for RMS in the United Kingdom and SD in the USA. PMID- 20854354 TI - Finite resources, limitless possibilities. PMID- 20854355 TI - Beliefs of ambulatory care physicians about accuracy of patient medication records and technology-enhanced solutions to improve accuracy. AB - The continuing problem of inaccurate medication records and resultant harm from medication errors has prompted the Institute of Medicine and others to encourage information technology (IT) solutions to improve medication list accuracy. There are few studies on how ambulatory care documentation contributes to medication list inaccuracies and medication reconciliation failures. To address medication reconciliation issues in ambulatory care, office-based physicians in a region with a high adoption rate for electronic medical records (EMRs) were surveyed about current reconciliation practices, the need for redesigning reconciliation processes, and acceptable IT solutions for improving availability of medication information. Physicians selected from a list of potential IT platforms that would create a single reconciled record of prescription medications, nonprescription medications, and supplements accessible wherever patients go. The two most popular platforms were either an aggregated list within existing EMRs accessible by inpatient and outpatient providers regardless of their EMR system, or a web based repository that was not integrated into an EMR. Respondents felt that implementation of such platforms would not require major changes to clinical workflow, perhaps due to the region's existing familiarity with health IT. Leveraging community acceptance of health IT could result in rapid implementation of universally accessible medication list platforms. PMID- 20854356 TI - Using technology to enhance the quality of home health care: three case studies of health information technology initiatives at the visiting nurse service of New York. AB - There is a growing recognition among health services researchers and policy makers that Health Information Technology (HIT) has the potential to address challenging issues that face patients and providers of healthcare. The Visiting Nurse Service of New York (VNSNY), a large not-for-profit home healthcare agency, has integrated technology applications into the service delivery model of several programs. Case studies, including the development and implementation, of three informatics initiatives at VNSNY are presented on: (1) Quality Scorecards that utilize process, outcomes, cost, and satisfaction measures to assess performance among clinical staff and programs; (2) a tool to identify patients at risk of being hospitalized, and (3) a predictive model that identifies patients who are eligible for physical rehabilitation services. Following a description of these initiatives, we discuss their impact on quality and process indicators, as well as the opportunities and challenges to implementation. PMID- 20854357 TI - Leveraging information technology to drive improvement in patient satisfaction. AB - A healthcare organization's commitment to quality and the patient experience requires senior leader involvement in improvement strategies, and accountability for goals. Further, improvement strategies are most effective when driven by data, and in the world of patient satisfaction, evidence is growing that nurse leader rounding and discharge calls are strategic tactics that can improve patient satisfaction. This article describes how The Ohio State University Medical Center (OSUMC) leveraged health information technology (IT) to apply a data-driven strategy execution to improve the patient experience. Specifically, two IT-driven approaches were used: (1) business intelligence reporting tools were used to create a meaningful reporting system including dashboards, scorecards, and tracking reports and (2) an improvement plan was implemented that focused on two high-impact tactics and data to hardwire accountability. Targeted information from the IT systems enabled clinicians and administrators to execute these strategic tactics, and senior leaders to monitor achievement of strategic goals. As a result, OSUMC's inpatient satisfaction scores on the Hospital Consumer Assessment of Healthcare Providers and Systems survey improved from 56% nines and tens in 2006 to 71% in 2009. PMID- 20854358 TI - Moving from good to great in ambulatory electronic health record implementation. AB - Despite a good general understanding of the need to ensure provider adoption and use of electronic health record (EHR) systems, many implementations fall short of expectations, and little is known about effective approaches in the ambulatory care area. We aimed to comprehensively study and synthesize best practices for ambulatory EHR system implementation in healthcare organizations, emphasizing strategies that maximize physician adoption and use. Following an extensive literature review, we held 47 key informant interviews with representatives of six U.S. healthcare organizations purposively selected based on reported success with ambulatory EHR system implementation. We interviewed both administrative and clinical informants in order to improve our understanding of ambulatory EHR implementation from both perspectives. We found that while all 6 sites studied were reported to have strong EHR implementation practices, we were able to characterize "good" versus "great" approaches across the sites. Specifically, "great" implementations included a key element focused on optimization and improvement over time that helped healthcare organizations support physician adoption and use of the EHR system. The "great" implementation approaches we saw also included explicit considerations of improved data capture and quality of care in their focus on optimization in order to maximize the value of the EHR. PMID- 20854359 TI - Improving transitions of care at hospital discharge--implications for pediatric hospitalists and primary care providers. AB - Delays, omissions, and inaccuracy of discharge information are common at hospital discharge and put patients at risk for adverse outcomes. We assembled an interdisciplinary team of stakeholders to evaluate our current discharge process between hospitalists and primary care providers (PCPs). We used a fishbone diagram to identify potential causes of suboptimal discharge communication to PCPs. Opportunities for improvement (leverage points) to achieve optimal transfer of discharge information were identified using tally sheets and Pareto charts. Quality improvement strategies consisted of training and implementation of a new discharge process including: (1) enhanced PCP identification at discharge, (2) use of an electronic discharge order and instruction system, and (3) autofaxing discharge information to PCPs. The new discharge process's impact was evaluated on 2,530 hospitalist patient discharges over a 34-week period by measuring: (1) successful transfer of discharge information (proportion of discharge information sheets successfully faxed to PCPs), (2) timeliness (proportion of sheets faxed within 2 days of discharge), and (3) content (presence of key clinical elements in discharge sheets). Postintervention, success, and timeliness of discharge information transfer between pediatric hospitalists and PCPs significantly improved while content remained high. PMID- 20854360 TI - Association of ignitable liquid residues to neat ignitable liquids in the presence of matrix interferences using chemometric procedures. AB - In fire debris analysis, weathering of ignitable liquids and matrix interferences can make the identification of ignitable liquid residues (ILRs) difficult. An objective method was developed to associate ILRs with the corresponding neat liquid with discrimination from matrix interferences using principal components analysis (PCA) and Pearson product moment correlation (PPMC) coefficients. Six ignitable liquids (gasoline, diesel, ultra pure paraffin lamp oil, adhesive remover, torch fuel, paint thinner) were spiked onto carpet, which was burned, then extracted using passive headspace extraction, and analyzed by gas chromatography-mass spectrometry. Both light and heavy burn conditions were investigated. In the PCA scores plot, ignitable liquids were discriminated based on alkane and aromatic content. All ILRs were successfully associated with the corresponding neat liquid using both PCA and PPMC coefficients, regardless of the extent of burning. The method developed in this research may make the association of ILRs with corresponding neat liquids more objective. PMID- 20854361 TI - Age estimation in Indians using Demirjian's 8-teeth method. AB - Demirjian's grading of tooth calcification is widely used to assess age of individuals with developing dentitions. However, its application on numerous populations has resulted in wide variations in age estimates and consequent suggestions for the method's adaptation to the local sample. Conventionally, Demirjian's method utilized seven mandibular teeth on the left side. A recent modification incorporated the third molar with a view to apply the method on a wider age-group. Moreover, the revised method developed regression formulas for assessing age. This paper tested the 8-teeth method using 547 Indians (348 females, 199 males) aged 7-25 years. Demirjian's formulas resulted in inferior age prediction in Indians (9.2% misclassification at 99% confidence interval vs. 0% misclassification in the original study); therefore, India-specific regression formulas were developed, which gave better age estimates (mean absolute error, MAE=0.87 years) than the original formulas (MAE=1.29 years). This suggests that Demirjian's 8-teeth method also needs adaptation prior to use in diverse populations. PMID- 20854362 TI - Forensic discrimination of dyed hair color: II. Multivariate statistical analysis. AB - This research is intended to assess the ability of UV-visible microspectrophotometry to successfully discriminate the color of dyed hair. Fifty five red hair dyes were analyzed and evaluated using multivariate statistical techniques including agglomerative hierarchical clustering (AHC), principal component analysis (PCA), and discriminant analysis (DA). The spectra were grouped into three classes, which were visually consistent with different shades of red. A two-dimensional PCA observations plot was constructed, describing 78.6% of the overall variance. The wavelength regions associated with the absorbance of hair and dye were highly correlated. Principal components were selected to represent 95% of the overall variance for analysis with DA. A classification accuracy of 89% was observed for the comprehensive dye set, while external validation using 20 of the dyes resulted in a prediction accuracy of 75%. Significant color loss from successive washing of hair samples was estimated to occur within 3 weeks of dye application. PMID- 20854363 TI - The Child Behavior Checklist-Dysregulation Profile predicts substance use, suicidality, and functional impairment: a longitudinal analysis. AB - BACKGROUND: Recent studies have identified a Child Behavior Checklist profile that characterizes children with severe affective and behavioral dysregulation (CBCL-dysregulation profile, CBCL-DP). In two recent longitudinal studies the CBCL-DP in childhood was associated with heightened rates of comorbid psychiatric disorders, among them bipolar disorder, an increased risk for suicidality, and marked psychosocial impairment at young-adult follow-up. This is the first study outside the US that examines the longitudinal course of the CBCL-DP. METHODS: We studied the diagnostic and functional trajectories and the predictive utility of the CBCL-DP in the Mannheim Study of Children at Risk, an epidemiological cohort study on the outcome of early risk factors from birth into adulthood. A total of 325 young adults (151 males, 174 females) participated in the 19-year assessment. RESULTS: Young adults with a higher CBCL-DP score in childhood were at increased risk for substance use disorders, suicidality and poorer overall functioning at age 19, even after adjustment for parental education, family income, impairment and psychiatric disorders at baseline. Childhood dysregulation was not related to bipolar disorder in young adulthood. The CBCL-DP was neither a precursor of a specific pattern of comorbidity nor of comorbidity in general. CONCLUSIONS: Children with high CBCL-DP values are at risk for later severe, psychiatric symptomatology. The different developmental trajectories suggest that the CBCL-DP is not simply an early manifestation of a single disease process but might rather be an early developmental risk marker of a persisting deficit of self-regulation of affect and behavior. PMID- 20854364 TI - Developmental trajectories of reading development and impairment from ages 3 to 8 years in Chinese children. AB - BACKGROUND: Early prediction of reading disabilities in Chinese is important for early remediation efforts. In this 6-year longitudinal study, we investigated the early cognitive predictors of reading skill in a statistically representative sample of Chinese children from Beijing. METHOD: Two hundred sixty-one (261) native Chinese children were administered seven language-related skills over three years between the ages of 3 and 6 years. Performances on these skills were then examined in relation to subsequent word reading accuracy and fluency. Individual differences in developmental profiles across tasks were then estimated using growth mixture modeling. RESULTS: Four developmental trajectories were classified - the typical (control), catch-up (with low initial cognitive performances but adequate subsequent reading), literacy-related-cognitive-delay (with difficulties in morphological awareness, phonological awareness, and speeded naming and subsequent word recognition), and language-delay (relatively low across all tasks) groups. CONCLUSION: Findings suggest that the combination of phonological awareness, rapid naming and morphological awareness are essential in the early prediction of later reading difficulties in Chinese children. PMID- 20854365 TI - Longitudinal links between impulsivity, gambling problems and depressive symptoms: a transactional model from adolescence to early adulthood. AB - BACKGROUND: Research shows high co-morbidity between gambling problems and depressive symptoms, but the directionality of this link is unclear. Moreover, the co-occurrence of gambling problems and depressive symptoms could be spurious and explained by common underlying risk factors such as impulsivity and socio family risk. The goals of the present study were to examine 1) whether common antecedent factors explain the concurrent links between depressive symptoms and gambling problems, and 2) whether possible transactional links between depressive symptoms and gambling problems exist from late adolescence to early adulthood. METHODS: A total of 1004 males from low SES areas participated in the study. RESULTS: Analyses revealed a positive predictive link between impulsivity at age 14 and depressive symptoms and gambling problems at age 17. In turn, gambling problems at age 17 predicted an increase in depressive symptoms from age 17 to age 23, and depressive symptoms at age 17 predicted an increase in gambling problems from age 17 to age 23. CONCLUSIONS: Common antecedent factors may explain the initial emergence of an association between depressive symptoms and gambling problems in adolescence. However, once emerged, their escalation seems to be better explained by a mutual direct influence between the two sets of disorders. PMID- 20854366 TI - Prenatal maternal stress programs infant stress regulation. AB - OBJECTIVE: Prenatal exposure to inappropriate levels of glucocorticoids (GCs) and maternal stress are putative mechanisms for the fetal programming of later health outcomes. The current investigation examined the influence of prenatal maternal cortisol and maternal psychosocial stress on infant physiological and behavioral responses to stress. METHODS: The study sample comprised 116 women and their full term infants. Maternal plasma cortisol and report of stress, anxiety and depression were assessed at 15, 19, 25, 31 and 36 + weeks' gestational age. Infant cortisol and behavioral responses to the painful stress of a heel-stick blood draw were evaluated at 24 hours after birth. The association between prenatal maternal measures and infant cortisol and behavioral stress responses was examined using hierarchical linear growth curve modeling. RESULTS: A larger infant cortisol response to the heel-stick procedure was associated with exposure to elevated concentrations of maternal cortisol during the late second and third trimesters. Additionally, a slower rate of behavioral recovery from the painful stress of a heel-stick blood draw was predicted by elevated levels of maternal cortisol early in pregnancy as well as prenatal maternal psychosocial stress throughout gestation. These associations could not be explained by mode of delivery, prenatal medical history, socioeconomic status or child race, sex or birth order. CONCLUSIONS: These data suggest that exposure to maternal cortisol and psychosocial stress exerts programming influences on the developing fetus with consequences for infant stress regulation. PMID- 20854367 TI - Non-linear relationship between 5-HT transporter gene expression and frequency sensitivity of 5-HT signals. AB - Much evidence suggests that variation in expression of the 5-hydroxytryptamine (5 HT) transporter (5-HTT) is linked to risk of psychiatric illness, but the neurobiological basis of this association is uncertain. In this study, we investigated the impact of variation in 5-HTT expression on subsecond fluctuations in extracellular 5-HT concentrations ([5-HT](o) ). Stimulus-evoked [5-HT](o) was detected using fast-scan cyclic voltammetry at carbon-fibre microelectrodes in the substantia nigra in brain slices from 5-HTT knockout (KO) and 5-HTT over-expressing (OE) mice. Compared with wild-type (WT) controls, evoked [5-HT](o) was greater in KO and less in OE mice. In WT controls, evoked [5 HT](o) was frequency-sensitive; however, in both KO and OE mice, evoked [5-HT](o) showed a striking loss of frequency sensitivity. The latter was observed in WT mice after application of a 5-HTT blocker. These data show that while variation in 5-HTT expression modified the peak magnitude of [5-HT](o) evoked by any given stimulus in a gene dose dependent manner, there was a non-linear relationship between 5-HTT expression and frequency sensitivity. Overall, the findings suggest that variation in 5-HTT expression has a marked effect on frequency sensitivity which is a fundamental property of normal 5-HT transmission. PMID- 20854369 TI - Endosomal signaling and a novel pathway defined by the natural killer receptor KIR2DL4 (CD158d). AB - In addition to ligand-induced activation of receptors at the cell surface, certain internalized receptor-ligand complexes are activated in endosomes which are, now recognized as important intracellular platforms of signal transduction. The major receptor families that signal from endosomes and illustrate the diversity and complexity of endosomal signaling include receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs) and toll-like receptors (TLRs). Natural killer (NK) cells, an important component of the innate immune system, not only provide a rapid defense against foreign invaders, such as bacteria and viruses, but also positively shape local responses by cytokine and chemokine secretion. The NK cell receptor KIR2DL4 (CD158d) utilizes a new mode of endosomal signaling after binding its ligand, soluble HLA-G, in the extracellular milieu. Internalization of the receptor and its ligand into endosomes and initiation of signaling at this site result in a proinflammatory and proangiogenic response with important functions at sites of ligand expression, such as at the maternal fetal interface during early pregnancy. After a brief overview of the modes of endosomal signaling and its value in generating distinct physiological responses, this review will highlight the mechanism and physiological significance of a novel intracellular signaling pathway used by the endosome-resident immune receptor KIR2DL4. PMID- 20854368 TI - Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid beta-peptide elimination from the brain. AB - Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the low density lipoprotein receptor family, has major roles in the cellular transport of cholesterol, endocytosis of 40 structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid beta-peptide (Abeta). According to the two-hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Abeta accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a three-level serial LRP1-dependent homeostatic control of Abeta clearance including (i) cell surface LRP1 at the blood-brain barrier and cerebrovascular cells mediating brain to-blood Abeta clearance (ii) circulating LRP1 providing a key endogenous peripheral 'sink' activity for plasma Abeta which prevents free Abeta access to the brain, and (iii) LRP1 in the liver mediating systemic Abeta clearance. Pitfalls in experimental Abeta brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD. PMID- 20854371 TI - Monitoring new oral antithrombotics: what we should know before we can decide. PMID- 20854370 TI - Insulin-regulated trafficking of GLUT4 requires ubiquitination. AB - A major consequence of insulin binding its receptor on fat and muscle cells is translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the cell surface where it serves to clear glucose from the bloodstream. Sorting of GLUT4 into its insulin-sensitive store requires the GGA [Golgi localized, gamma-ear-containing, ADP ribosylation factor (ARF)-binding] adaptor proteins, but the signal on GLUT4 to direct this sorting step is unknown. Here, we have identified a role for ubiquitination of GLUT4 in this process. We demonstrate that GLUT4 is ubiquitinated in 3T3-L1 adipocytes, and that a ubiquitin-resistant version fails to translocate to the cell surface of these cells in response to insulin. Our data support a model in which ubiquitination acts as a signal for the trafficking of GLUT4 from the endosomal/trans-Golgi network (TGN) system into its intracellular storage compartment, from where it is mobilized to the cell surface in response to insulin. PMID- 20854372 TI - The HIT Expert Probability (HEP) Score: a novel pre-test probability model for heparin-induced thrombocytopenia based on broad expert opinion. AB - BACKGROUND: The diagnosis of heparin-induced thrombocytopenia (HIT) is challenging. Over-diagnosis and over-treatment are common. OBJECTIVES: To develop a pre-test clinical scoring model for HIT based on broad expert opinion that may be useful in guiding clinical decisions regarding therapy. PATIENTS/METHODS: A pre-test model, the HIT Expert Probability (HEP) Score, was constructed based on the opinions of 26 HIT experts. Fifty patients referred to a reference laboratory for HIT testing comprised the validation cohort. Two hematology trainees scored each patient using the HEP Score and a previously published clinical scoring system (4 T's). A panel of three independent experts adjudicated the 50 patients and rendered a diagnosis of HIT likely or unlikely. All subjects underwent HIT laboratory testing with a polyspecific HIT ELISA and serotonin release assay (SRA). RESULTS: The HEP Score exhibited significantly greater interobserver agreement [intraclass correlation coefficient: 0.88 (95% CI 0.80-0.93) vs. 0.71 (0.54-0.83)], correlation with the results of HIT laboratory testing and concordance with the diagnosis of the expert panel (area under receiver-operating curve: 0.91 vs. 0.74, P = 0.017) than the 4 T's. The model was 100% sensitive and 60% specific for determining the presence of HIT as defined by the expert panel and would have allowed for a 41% reduction in the number of patients receiving a direct thrombin inhibitor (DTI). CONCLUSION: The HEP Score is the first pre-test clinical scoring model for HIT based on broad expert opinion, exhibited favorable operating characteristics and may permit clinicians to confidently reduce use of alternative anticoagulants. Prospective multicenter validation is warranted. PMID- 20854373 TI - A monopartite sequence is essential for p45 NF-E2 nuclear translocation, transcriptional activity and platelet production. AB - BACKGROUND: p45 NF-E2 is a bZIP transcription factor crucial for thrombopoiesis, as indicated by the fact that loss of p45 NF-E2 function results in dramatic embryonic lethal thrombopoietic defects and its overexpression boosts platelet release. OBJECTIVES: In the present study, we set out to identify the sequences responsible for p45 NF-E2 nuclear import, evaluate its transport mechanism and ascertain its functional significance. METHODS: A series of p45 NF-E2 deletion constructs fused to green fluorescent protein (GFP) was created and their cellular localization examined in mammalian cells, with the factor responsible for nuclear import identified using an in vitro transport assay. A p45 NF-E2 derivative mutated in the nuclear targeting sequence (NLS) was generated and its biological activity compared with wild type (wt) in luciferase assays, and proplatelet and platelet production measured in murine megakaryocytes transduced with a retroviral vector. RESULTS: Here we show that residues 271-273 are essential for nuclear import of p45 NF-E2 in COS-7 and in primary bone marrow cells. The p45 NF-E2 NLS facilitates nuclear import specifically via importin (IMP) 7. Although within the DNA-binding domain of p45 NF-E2, the NLS is not essential for DNA-binding, but is crucial for transcriptional activation and biological activity; where, in contrast to wt, a mutant derivative with a mutated NLS failed to promote proplatelet and platelet production in murine megakaryocytes. CONCLUSIONS: The NLS is critical for p45 NF-E2 function, with the present study being the first to demonstrate the importance of NLS-dependent nuclear import of p45 NF-E2 for platelet development. PMID- 20854374 TI - Alterations of mRNA processing and stability as a pathogenic mechanism in von Willebrand factor quantitative deficiencies. AB - INTRODUCTION: von Willebrand disease (VWD) is an inherited bleeding disorder due to a deficiency or abnormality of von Willebrand factor (VWF), associated with heterogeneous phenotypes. While VWD mutations acting at the protein level have been deeply investigated, fewer data are available on genetic defects affecting VWF mRNA. AIM: The aim of this study was to characterize the molecular mechanism underlying VWD in three patients. METHODS: Mutational screening of the patients (P1-3) was accomplished by DNA sequencing of all VWF exons and splicing junctions. Platelet mRNA was analyzed by reverse-transcription (RT)-PCR and real time RT-PCR. RESULTS: P1 is a compound heterozygote for a c.1534-3C>A transversion in intron 13 and for a nonsense mutation (p.Q77X) in exon 4. P2 is heterozygous for a splicing mutation in intron 9 (c.1109+2T>C). RT-PCR assays on the patient's platelet RNA revealed three mRNA populations: (i) wild type; (ii) lacking exon 9; and (iii) lacking exons 8 and 9. P3 showed a novel homozygous splicing mutation in intron 46 (c.7770+1G>T), producing three different mRNA species: (i) retaining the first 25 bp of intron 46; (ii) skipping exon 46; and (iii) skipping exon 46 while retaining 5 bp of intron 45. Whenever possible, the effect of mutations on the levels of VWF transcripts was analyzed, showing that mRNA variants containing a premature termination codon are downregulated, probably by the nonsense-mediated mRNA decay pathway. CONCLUSIONS: The identification of the genetic basis of VWD in three patients confirmed that mutations leading to null alleles in the VWF gene are associated with allele specific mRNA degradation. PMID- 20854375 TI - Incidental pulmonary emboli in lymphoma patients are associated with aggressive disease and poor prognosis. PMID- 20854376 TI - Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target. AB - Clinical studies in Type 2 diabetes mellitus have shown that the effects of metformin go beyond improving HbA(1c) and include reductions in cardiovascular endpoints. Metformin therapy has been widely used in the treatment of Type 2 diabetes for many years, yet the precise mode of action remains uncertain. It has recently been proposed that metformin-mediated stimulation of hepatic AMP activated protein kinase (AMPK) underlies the hypoglycaemic effects of metformin. AMPK is a heterotrimeric enzyme that is expressed in many tissues and plays a central role in the regulation of energy homoeostasis. Furthermore, there is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. The generation of more specific and potent activators of AMPK, however, could have additional metabolic and vascular benefits for patients with Type 2 diabetes. PMID- 20854377 TI - Baseline serum 25-hydroxyvitamin D concentrations in the Tromso Study 1994-95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up. AB - AIMS: We wanted to test the hypothesis that low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased risk of developing Type 2 diabetes mellitus (DM) in a population-based cohort during 11 years of follow-up. METHODS: The analyses included 4157 non-smokers and 1962 smokers from the Tromso Study 1994-95 without diabetes at baseline. Subsequent Type 2 DM was defined using a hospital journal-based end-point registry, completed through the year 2005. Participants were allocated into quartiles of serum 25(OH)D within each month to account for seasonal variation, and serum 25(OH)D values both as a continuous variable and in quartiles were used in Cox regression models. The analyses were stratified by smoking. Adjustments were made for age, sex, body mass index (BMI), physical activity and, in non-smokers, former smoking. RESULTS: Type 2 DM was registered in 183 non-smoking and 64 smoking participants. Using the fourth (highest) quartile of serum 25(OH)D as the reference, non-smoking participants in the third, second and first quartiles had age- and sex-adjusted hazard ratios (95% confidence intervals) of incident Type 2 DM of 1.00 (0.62 1.61), 1.50 (0.97-2.31) and 1.89 (1.25-2.88), respectively, whereas the corresponding values for smokers were 1.79 (0.77-4.19), 2.33 (1.02-5.35) and 2.68 (1.18-6.08). Adjustment for BMI attenuated the hazard ratios, and they were no longer significant. CONCLUSIONS: Baseline serum 25(OH)D was inversely associated with subsequent Type 2 DM in a population-based 11 year follow-up study, but not after adjustment for BMI. Randomized trials are needed to define the possible role of serum 25(OH)D status, and thereby the role of supplementation, in the prevention of Type 2 DM. PMID- 20854378 TI - Prediction models for incident type 2 diabetes mellitus?in the older population: KORA S4/F4 cohort study. AB - BACKGROUND: The aim was to derive Type 2 diabetes prediction models for the older population and to check to what degree addition of 2-h glucose measurements (oral glucose tolerance test) and biomarkers improves the predictive power of risk scores which are based on non-biochemical as well as conventional clinical parameters. METHODS: Oral glucose tolerance tests were carried out in a population-based sample of 1353 subjects, aged 55-74 years (62% response) in Augsburg (Southern Germany) from 1999 to 2001. The cohort was reinvestigated in 2006-2008. Of those individuals without diabetes at baseline, 887 (74%) participated in the follow-up. Ninety-three (10.5%) validated diabetes cases occurred during the follow-up. In logistic regression analyses for model 1, variables were selected from personal characteristics and additional variables were selected from routinely measurable blood parameters (model 2) and from 2-h glucose, adiponectin, insulin and homeostasis model assessment of insulin resistance (HOMA-IR) (model 3). RESULTS: Age, sex, BMI, parental diabetes, smoking and hypertension were selected for model 1. Model 2 additionally included fasting glucose, HbA(1c) and uric acid. The same variables plus 2-h glucose were selected for model 3. The area under the receiver operating characteristic curve significantly increased from 0.763 (model 1) to 0.844 (model 2) and 0.886 (model 3) (P<0.01). Biomarkers such as adiponectin and insulin did not improve the predictive abilities of models 2 and 3. Cross-validation and bootstrap-corrected model performance indicated high internal validity. CONCLUSIONS: This longitudinal study in an older population provides models to predict the future risk of Type 2 diabetes. The OGTT, but not biomarkers, improved discrimination of incident diabetes. PMID- 20854379 TI - A 12-year follow-up study of all-cause and cardiovascular mortality among 10,532 people newly diagnosed with Type 2 diabetes in Tayside, Scotland. AB - AIMS: To determine absolute and relative risks of all-cause and cardiovascular mortality among patients newly diagnosed with Type 2 diabetes. METHODS: In an observational cohort study using record-linkage databases, based in Tayside, Scotland, UK, we identified newly diagnosed patients with Type 2 diabetes in 1993 2004. We also identified a set of non-diabetic comparators from lists of patients registered with a general practice, individually matched to the diabetic patients by sex, age and deprivation. We followed up patients for mortality and cardiovascular mortality over a 12-year period and calculated hazard ratios using Cox regression. RESULTS: There were 10,532 patients with Type 2 diabetes and 21,056 non-diabetic comparators. Diabetic patients in every age/sex group had higher absolute mortality rates. Even taking deprivation into account, the hazard ratio for mortality was 1.32 (95% CI 1.25-1.40), decreasing to 1.15 (1.09-1.22) after adjusting for pre-existing cardiovascular disease. The hazard ratios for cardiovascular mortality were higher, decreasing from 1.51 (1.37-1.67) to 1.23 (1.11-1.36) after adjusting for pre-existing cardiovascular disease. The hazard ratios decreased with increasing age at diagnosis, although the difference in absolute rate of mortality increased slightly with age. Increased mortality risks were only evident 2 years after diagnosis and increased thereafter. CONCLUSIONS: Patients with Type 2 diabetes have an increased risk of all-cause and cardiovascular mortality compared with non-diabetic comparators, although this is not observable immediately after diagnosis. Age at diagnosis and duration of the disease independently affect absolute and relative mortality risk. PMID- 20854380 TI - Association between alcohol consumption and diabetic retinopathy and visual acuity-the AdRem Study. AB - AIMS: We investigated the association between alcohol consumption and diabetic retinopathy and deterioration of visual acuity in individuals with Type 2 diabetes. METHODS: We conducted a cohort analysis of 1239 participants with Type 2 diabetes aged 55-81 years enrolled in the AdRem study, a sub-study of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Current and past consumption of wine, spirits and beer was measured by self-report. Moderate and heavy alcohol consumption was defined as 1-14 and >14 drinks/week, respectively. Diabetic retinopathy, measured by mydriatic stereoscopic seven-field retinal photography, was defined by a 2 step progression in the Early Treatment of Diabetic Retinopathy Study (ETDRS) score or the presence of any retinal vascular lesions. Deterioration of visual acuity was defined by a decrease of two lines in best vision in either eye, measured corrected, or through a pinhole using a Snellen chart. RESULTS: In a mean follow-up of 5.5 years, we identified 182 participants with a 2-step progression in the ETDRS score, 640 participants with the presence of any retinal vascular lesions and 693 participants with a deterioration of visual acuity. Current moderate consumption of alcohol, compared with no current consumption, was not associated with presence or progression of diabetic retinopathy; however, it was associated with higher risk of deterioration of visual acuity (multivariable-adjusted OR 1.83; 95% CI 1.34-2.48; P<0.001). CONCLUSIONS: Alcohol consumption is associated with increased risk of deterioration of visual acuity, but not with retinopathy in individuals with Type 2 diabetes. PMID- 20854381 TI - Reduced incidence of blindness in relation to diabetes mellitus in southern Germany? AB - AIMS: We estimated the incidence of blindness in the diabetic and non-diabetic population in 2008 and compared it with results from 1990-1998 in a neighbouring region. METHODS: All newly registered blindness allowance recipients in 2008 were drawn up in a German region (population 4.5 million). We estimated sex-specific, age-specific and standardized incidence rates of blindness in the diabetic and the non-diabetic population and relative and attributable risks as a result of diabetes. A comparison to the data from 1990-1998 was performed using log-linear Poisson regression. RESULTS: Four-hundred and sixty-eight cases were drawn up (63% female). One-hundred and twenty-two (26.1%) had diabetes. Blindness incidence rates (per 100, 000 person-years) standardized to the 2008 German population were: men 9.1 (95% confidence interval 7.8-10.5), women 9.9 (8.8 11.1); diabetic population: men 21.8 (11.6-31.9), women 19.7 (9.2-30.1); non diabetic population: men 8.0 (6.6-9.5), women 9.1 (7.9-10.3). Relative risk of blindness, diabetic vs. non-diabetic population: men 2.7 (1.6-4.5), women 2.2 (1.3-3.8). Attributable risk among exposed: 63% in men, 54% in women. Population attributable risk: 12% in men, 8% in women. Incidences of blindness were significantly lower than in all years of the period 1990-1998 in both the diabetic and the non-diabetic population. CONCLUSIONS: We found the incidence of blindness to be approximately 2.5-fold higher in the diabetic compared with the non-diabetic population. Fifty-eight per cent of the risk to become blind in diabetic individuals and 9% of the risk to become blind in the entire population were attributable to diabetes. The decrease of the blindness incidence observed during the 1990s may have continued. PMID- 20854382 TI - Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM1) in patients with diabetic nephropathy: a cross-sectional study and the effects of lisinopril. AB - AIMS: Our aim was to evaluate the markers of tubulointerstitial damage, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule1 (KIM1) in Type 1 diabetic patients with different levels of albuminuria and in control subjects. In addition, the effect of renoprotective treatment on urinary NGAL was evaluated in diabetic nephropathy. METHODS: This was a cross-sectional study in 58 normoalbuminuric (u-albumin <30 mg/24 h), 45 microalbuminuric (30-300 mg/24 h) and 45 macroalbuminuric (>300 mg/24 h) Type 1 diabetic patients and 55 non-diabetic control subjects. Furthermore, in a second study, urine-NGAL was measured in a randomized cross-over study of 56 Type 1 diabetic patients with diabetic nephropathy treated with lisinopril 20, 40 and 60 mg daily. RESULTS: Urine-NGAL levels were [geometric mean (95% CI)]: control subjects 74 (52-104) (pg/mmol creatinine), normoalbuminuric 146 (97-221), microalbuminuric 222 (158 312) and macroalbuminuric group 261 (175-390). Urine-NGAL increased significantly from the normo- to the micro- and further to the macroalbuminuric group (P<0.05). Urine-NGAL was higher in normoalbuminuric vs. control subjects (P<0.01). Plasma NGAL was significantly higher in the normoalbuminuric and macroalbuminuric groups than in the control group. Urine-KIM1 was higher in all diabetic groups than in the control group (P<0.001), with no difference between diabetic groups. During lisinopril treatment, urine-NGAL was reduced (95% CI) 17% (11-50) (not significant). CONCLUSIONS: Urine-NGAL and urine-KIM1 (u-KIM1) are elevated in Type1 diabetic patients, with or without albuminuria, indicating tubular damage at an early stage. Urine-NGAL increases significantly with increasing albuminuria. The ACE inhibitor lisinopril reduced urine-NGAL, but this was not statistically significant. PMID- 20854383 TI - Fear of hypoglycaemia in adults with Type 1 diabetes. AB - AIMS: The aim of this study was to examine the fear of hypoglycaemia and its association with demographic and disease-specific variables in a large and unselective population of adult patients with Type 1 diabetes. METHODS: Questionnaires were sent by post to all patients with Type 1 diabetes who were identified in the local diabetes registries of two hospitals in Stockholm, Sweden (n=1387). Fear of hypoglycaemia was measured using the Swedish Hypoglycaemia Fear Survey, the Worry subscale and the Aloneness subscale. Demographic variables and disease-specific factors were collected from patients' self reports and medical records. Univariate analysis and multiple stepwise linear regression analysis were used in the statistical analyses of the data. RESULTS: Seven hundred and sixty-four (55%) patients participated in the study (mean age 43.3 years and mean HbA(1c) 7.0%, normal <5.0%). The Hypoglycaemia Fear Survey - Worry subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, hypoglycaemic symptoms during hyperglycaemia and hypoglycaemic unawareness. The Hypoglycaemia Fear Survey - Aloneness subscale was significantly associated with frequency of severe hypoglycaemia, number of symptoms during mild hypoglycaemia, gender, frequency of mild hypoglycaemia, HbA(1c) , hypoglycaemic unawareness and visits to the emergency room because of severe hypoglycaemia. Fear of hypoglycaemia proved to be more prevalent in females and indicated a different pattern between genders in relation to factors associated with fear of hypoglycaemia. CONCLUSIONS: This study identifies the frequency of severe hypoglycaemia as the most important factor associated with fear of hypoglycaemia. Moreover, for the first time, we document gender differences in fear of hypoglycaemia, suggesting that females are more affected by fear of hypoglycaemia than men. PMID- 20854384 TI - Glycated haemoglobin and blood pressure-lowering effect of cinnamon in multi ethnic Type 2 diabetic patients in the UK: a randomized, placebo-controlled, double-blind clinical trial. AB - AIMS: To determine the blood glucose lowering effect of cinnamon on HbA1c, blood pressure and lipid profiles in people with type 2 diabetes. METHODS: 58 type 2 diabetic patients (25 males and 33 females), aged 54.9 +/- 9.8, treated only with hypoglycemic agents and with an HbA1c more than 7% were randomly assigned to receive either 2g of cinnamon or placebo daily for 12 weeks. RESULTS: After intervention, the mean HbA1c was significantly decreased (P<0.005) in the cinnamon group (8.22% to 7.86%) compared with placebo group (8.55% to 8.68%). Mean systolic and diastolic blood pressures (SBP and DBP) were also significantly reduced (P<0.001) after 12 weeks in the cinnamon group (SBP: 132.6 to 129.2 mmHg and DBP: 85.2 to 80.2 mmHg) compared with the placebo group (SBP: 134.5 to 134.9 mmHg and DBP: 86.8 to 86.1 mmHg). A significant reduction in fasting plasma glucose (FPG), waist circumference and body mass index (BMI) was observed at week 12 compared to baseline in the cinnamon group, however, the changes were not significant when compared to placebo group. There were no significant differences in serum lipid profiles of total cholesterol, triglycerides, HDL and LDL cholesterols neither between nor within the groups. CONCLUSIONS: Intake of 2g of cinnamon for 12 weeks significantly reduces the HbA1c, SBP and DBP among poorly controlled type 2 diabetes patients. Cinnamon supplementation could be considered as an additional dietary supplement option to regulate blood glucose and blood pressure levels along with conventional medications to treat type 2 diabetes mellitus. PMID- 20854386 TI - Factors affecting improved glycaemic control in youth using insulin pumps. AB - AIMS: The purpose of this study was to evaluate factors associated with insulin pump therapy resulting in lower HbA(1c) levels in young people with Type 1 diabetes mellitus. METHODS: Insulin pumps were downloaded from 150 youth (81 male), ages 5-20 years. Consecutive insulin pump downloads, 3 months apart, were available for 85 (43 male) of the 150 youth and changes in pump use were correlated with changes (>=0.5%, >= 6 mmol/mol) in HbA(1c) levels. RESULTS: Using cross-sectional data, lower HbA(1c) values correlated with use of more frequent daily insulin boluses (r=-0.46, P<0.0001) and more frequent blood glucose checks/day (r=-0.35, P<0.0001). Young people with HbA(1c) levels <7.5% (58 mmol/mol) vs. values of 7.5-9.0% (58-75 mmol/mol) or >= 9.0% (75 mmol/mol) tested blood glucose more frequently/day (P<0.0001), bolused more frequently/day (P<0.0001), reported more grams of carbohydrates eaten/day (P<0.05) and had a higher per cent bolus insulin/day (P<0.05) compared with the >=9.0% of youth. Using longitudinal data, 48 of 85 patients had a change in HbA(1c) level of >=0.5% (6 mmol/mol) between downloads (24 improved). Increased bolus insulin (OR=1.15, P=0.03) and time of temporary basal rate use (OR=1.017, P=0.01) predicted >=0.5% (6 mmol/mol) decrease in HbA(1c) in logistic regression. CONCLUSIONS: This study emphasizes the importance of blood glucose testing, of bolus insulin administration and of an increase in the time of temporary basal rate use in relation to improving glycaemic control. PMID- 20854385 TI - Prophylactic use of anti-emetic medications reduced nausea and vomiting associated with exenatide treatment: a retrospective analysis of an open-label, parallel-group, single-dose study in healthy subjects. AB - AIMS: Transient nausea and, to a lesser extent, vomiting are common adverse effects of exenatide that can be mitigated by dose titration and usually do not result in treatment discontinuation. This retrospective analysis of data from a phase 1, open-label, parallel-group, single-dose study in healthy subjects evaluated the effect of oral anti-emetics on exenatide-associated nausea and vomiting and on the pharmacokinetics of exenatide. METHODS: A single subcutaneous dose (10 MUg) of exenatide was administered to 120 healthy subjects (19-65 years, BMI 23-35 kg/m(2) ). Incidences of nausea and vomiting were compared between 60 subjects premedicated with two oral anti-emetics 30 min before the exenatide dose and 60 non-premedicated subjects. Similarly, the area under the concentration time curve (AUC) and the maximum observed concentration (C(max) ) of plasma exenatide concentrations over 8 h post-dose were compared. RESULTS: Among all subjects [61% male, 32 +/- 12 years, body mass index (BMI) 29.1 +/- 3.4 kg/m(2) (mean +/- sd)], mild to moderate nausea was the most frequent adverse event after exenatide dosing. Vomiting was also observed. Subjects premedicated with anti emetics experienced significantly less nausea and vomiting (16.7 and 6.7%, respectively) vs. non-premedicated subjects (61.7 and 38.3%, respectively; P value <0.0001 for both nausea and vomiting). The mean area under the concentration-time curve and the maximum observed concentration AUC and C(max) of plasma exenatide concentrations during 8 h post-dose were not significantly different between groups. CONCLUSION: Administration of oral anti-emetics before a single 10-MUg exenatide dose was associated with significant reductions in treatment-emergent nausea and vomiting, with no discernible effect on the pharmacokinetics of exenatide. Use of anti-emetic therapy may provide a short term strategy to minimize the nausea and vomiting associated with exenatide treatment. PMID- 20854387 TI - Reduced adipogenic gene expression in fibroblasts from a patient with type 2 congenital generalized lipodystrophy. AB - AIMS: Beradinelli-Seip congenital generalized lipodystrophy is a rare autosomal recessive disorder characterized by near-complete absence of adipose tissue, Herculean appearance, insulin resistance, hypoleptinaemia and diabetes mellitus. The aim of this study was to investigate the in vitro effects of pioglitazone on the expression of genes involved in adipogenesis in fibroblasts from a patient with this condition due to a seipin mutation. METHODS: Primary cultures of fibroblasts from the skin of the patient were obtained. Fibroblasts were treated with classic adipose differentiation medium, with and without pioglitazone. Several adipogenes were evaluated by real-time reverse transcriptase-polymerase chain reaction and western blotting. Intracellular localization of prelamin A was studied by immunofluorescence microscopy. RESULTS: The expression of the adipogenic genes PPARG, LPL, LEP and SLC2A4 was reduced in lipodystrophic fibroblasts, while treatment with pioglitazone increased the expression of these genes. Moreover, and unexpectedly, we found an accumulation of farnesylated prelamin A in lipodystrophic fibroblasts. CONCLUSIONS: The process of adipocyte differentiation is compromised in patients with Beradinelli-Seip congenital lipodystrophy owing to diminished expression of the regulatory genes involved, which pioglitazone treatment partially rescues. Prelamin A accumulation establishes a link with other types of familial lipodystrophies, as familial partial lipodystrophy. PMID- 20854388 TI - Investigation of ACE, ACE2 and AGTR1 genes for association with nephropathy in Type 1 diabetes mellitus. AB - BACKGROUND: Polymorphisms in ACE and AGTR1 genes have been assessed in multiple studies for association with diabetic nephropathy; however, results are conflicting. The ACE2 gene has not been studied extensively for association with diabetic nephropathy. METHODS: We investigated variants in ACE, ACE2 and AGTR1 for association with nephropathy in a case-control group (1467 participants with Type1 diabetes, case subjects n=718; control subjects n=749) of white descent with grandparents born in the British Isles. All recruited individuals were carefully phenotyped and genotyping was performed using Sequenom, Taqman and gel electrophoresis methods. The chi(2) -test for contingency tables was used to compare genotype and allele frequencies in case and control groups. RESULTS: No departure from Hardy-Weinberg equilibrium was observed in cases or controls. Two variants within the ACE gene (rs4293, P(allelic) =0.02, P(genotypic) =0.008; rs4309, P(allelic) =0.02, P(genotypic) =0.01) were significantly associated with nephropathy at the 5% level. No variant remained statistically significant following adjustment for multiple comparisons. No single nucleotide polymorphisms in the ACE2 or AGTR1 genes were significantly associated with nephropathy when analysed either by genotype or allele frequencies. CONCLUSIONS: Our independent case-control study provides no evidence that common variants in ACE, ACE2 and AGTR1 play a major role in genetic susceptibility to diabetic nephropathy in a white population with Type1 diabetes. PMID- 20854389 TI - Genetic investigation in an Italian child with an unusual association of atrial septal defect, attributable to a new familial GATA4 gene mutation, and neonatal diabetes due to pancreatic agenesis. AB - AIMS: Permanent neonatal diabetes is a rare condition affecting 1 in 300,000 400,000 live births; only in 60% of cases it is possible to identify the genetic defect. The condition of pancreatic agenesis is rarer still. Only two genes are known to determine this phenotype: PDX-1 and PTF1A. Congenital heart defects are among the most common developmental anomalies, affecting 1% of newborns, and the GATA4 gene is less frequently involved in these disorders. An Italian child with pancreatic agenesis and an atrial septal defect was genetically investigated to elucidate whether the association of the two pathologies was casual, or represented a new pancreatic/cardiac syndrome. METHODS: A panel of pancreas development genes, including GCK, Kir6.2, PTF1A, PDX-1, HNF-1A, NgN3, SOX17, SOX7, SOX9, INS, HNF1-B and SUR1 plus the GATA4 gene, were screened for characterization of pancreatic agenesis and cardiac defect. RESULTS: Screening for genes causing permanent neonatal diabetes was negative. A novel mutation in GATA4 (c1512C>T) was detected and functional characterization confirmed a reduced activity of the protein. In the family members, the GATA4 mutation co-segregates with a cardiac phenotype, but not with pancreatic agenesis. CONCLUSIONS: We describe the first report of pancretic agenesis with an associated cardiac defect and a mutation in the GATA4 gene. We could not establish that the GATA4 mutation was causative for pancreatic agenesis and further genetic investigation to detect the genetic cause of the pancreas agenesis was unsuccessful. We conclude that, the two pathologies are attributable to two independent events. PMID- 20854390 TI - Are there differences in cardiovascular and metabolic risk profiles among men and women with Type2 diabetes? A cross-sectional analysis. PMID- 20854391 TI - Glycated haemoglobin A(1c) (HbA(1c) ) in the diagnosis of diabetes mellitus: don't forget the performance of the HbA(1c) assay. PMID- 20854392 TI - Using a PCT-wide electronic system called the Deadly Trio database to provide safety alerts about prescribing of metformin in renal disease. PMID- 20854393 TI - Longitudinal findings from a Norwegian case-cohort study on internalizing problems in children with congenital heart defects. AB - AIM: To examine the association of the severity of congenital heart defects (CHDs) with internalizing problems in 18-month-olds and to explore the extent to which the internalizing problems are influenced by maternal distress and emotional reactivity in the child at age 6 months. METHODS: We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health, with a nationwide CHD registry and identified 198 18 month-olds with CHDs in a cohort of 47 692 toddlers. Maternal reports on the children's emotional reactivity at age 6 months, the children's internalizing problems (anxiety, sleep problems, emotional reactivity) at age 18 months and maternal distress were assessed by questionnaires. RESULTS: We found an association at age 18 months between the severity of the CHD and anxiety but not sleep problems or emotional reactivity. Children with severe but not with mild or moderate CHDs were twice as likely to experience the symptoms of anxiety compared with controls. These symptoms are not merely sequelae of earlier psychological reactions or concurrent maternal distress. CONCLUSION: Should these findings be replicated, future studies ought to investigate the mechanisms leading to elevated anxiety in toddlers with CHDs. In addition, clinical interventions should address the child's anxiety as well as the interaction between the parents and the child. PMID- 20854394 TI - SGT1 contributes to coronatine signaling and Pseudomonas syringae pv. tomato disease symptom development in tomato and Arabidopsis. AB - * Pseudomonas syringae pv. tomato DC3000 (Pst DC3000) causes an economically important bacterial speck disease on tomato and produces symptoms with necrotic lesions surrounded by chlorosis. The chlorosis is mainly attributed to a jasmonic acid (JA)-isoleucine analogue, coronatine (COR), produced by Pst DC3000. However, the molecular processes underlying lesion development and COR-induced chlorosis are poorly understood. * In this study, we took advantage of a chlorotic phenotype elicited by COR on Nicotiana benthamiana leaves and virus-induced gene silencing (VIGS) as a rapid reverse genetic screening tool and identified a role for SGT1 (suppressor of G2 allele of skp1) in COR-induced chlorosis. * Silencing of SGT1 in tomato resulted in reduction of disease-associated symptoms (cell death and chlorosis), suggesting a molecular connection between COR-induced chlorosis and cell death. In Arabidopsis, AtSGT1b but not AtSGT1a was required for COR responses, including root growth inhibition and Pst DC3000 symptom (water soaked lesion) development. Notably, overexpression of AtSGT1b did not alter Pst DC3000 symptoms or sensitivity to COR. * Taken together, our results demonstrate that SGT1/SGT1b is required for COR-induced chlorosis and subsequent necrotic disease development in tomato and Arabidopsis. SGT1 is therefore a component of the COR/JA-mediated signal transduction pathway. PMID- 20854395 TI - Insidious effects of sequencing errors on perceived diversity in molecular surveys. PMID- 20854396 TI - What is stress? Concepts, definitions and applications in seed science. AB - 'Stresses' that impact upon seeds can affect plant reproduction and productivity, and, hence, agriculture and biodiversity. In the absence of a clear definition of plant stress, we relate concepts from physics, medicine and psychology to stresses that are specific to seeds. Potential 'eustresses' that enhance function and 'distresses' that have harmful effects are considered in relation to the seed life cycle. Taking a triphasic biomedical stress concept published in 1936, the 'General Adaptation Syndrome', to the molecular level, the 'alarm' response is defined by post-translational modifications and stress signalling through cross talk between reactive oxygen and nitrogen species, and seed hormones, that result in modifications to the transcriptome. Protection, repair, acclimation and adaptation are viewed as the 'building blocks' of the 'resistance' response, which, in seeds, are the basis for their longevity over centuries. When protection and repair mechanisms eventually fail, depending on dose and time of exposure to stress, cell death and, ultimately, seed death are the result, corresponding to 'exhaustion'. This proposed seed stress concept may have wider applicability to plants in general. PMID- 20854397 TI - Growth-mediated stress escape: convergence of signal transduction pathways activated upon exposure to two different environmental stresses. AB - * Plants can escape from specific environmental stresses through active growth strategies. Here, we compared two such stress-escape syndromes to investigate whether plants use conserved signal transduction pathways to escape from different stresses. * Full submergence is a threat to terrestrial plants as it cuts off their access to oxygen and CO(2). Proximate neighbors, in contrast, take away resources such as light. Both submergence and shade can be escaped through rapid shoot elongation. We analysed the precise kinetics and physiological control of petiole elongation responses to shade and submergence in the flood tolerant species Rumex palustris. * We found that petiole elongation induced by submergence and that induced by shade occurred with similar kinetics, both involving cell expansion. These responses were induced by two different signals, elevated ethylene and a reduced red : far-red light ratio (R : FR), respectively. A downstream target for ethylene was abscisic acid, but low R : FR appeared to act independently of this hormone. Gibberellin, however, appeared to be essential to both ethylene- and low R : FR-induced petiole elongation. * We propose that gibberellin and expansins, a family of cell wall-loosening proteins, represent elements of a conserved growth machinery that is activated by stress-specific signaling events to regulate escape from stress. PMID- 20854398 TI - Monoclonal antibodies against Stx1B subunit of Escherichia coli O157:H7 distinguish the bacterium from other bacteria. AB - AIMS: The Shiga-like toxins (Stx) are critical virulence factors of enterohaemorrhagic Escherichia coli (EHEC). Stx1B subunit plays important roles in EHEC infection. This work aims to generate and characterize monoclonal antibodies (mAbs) against the Stx1B and to investigate their utility in discrimination ELISA. METHODS AND RESULTS: Two newly identified mAbs (designated 2H8 and 1B10, respectively) against the Stx1B protein were prepared via hybridoma techniques. The immunoreactivity of both mAbs to the Stx1B protein was confirmed in ELISA and Western blot. Moreover, they differentiate EHEC from Salmonella enteritis, non-Stx1-producing E. coli, Mycobacterium tuberculosis, Listeria monocytogenes, Streptococcus agalactiae and Staphylococcus aureus. CONCLUSIONS: The anti-STx1B mAbs are valuable diagnostic reagents for distinguishing EHEC from other bacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report regarding the usage of anti-STx1B mAbs in discrimination ELISA. The established ELISA may have potential in clinical surveillance of EHEC infection. PMID- 20854399 TI - Switching biologics for psoriasis. PMID- 20854400 TI - British Association of Dermatologists' guidelines for the management of lichen sclerosus 2010. PMID- 20854401 TI - Molecular mechanisms of nonablative fractionated laser resurfacing. AB - BACKGROUND: Nonablative fractionated laser resurfacing improves the texture of treated skin, but little is known about the molecular mechanisms that underlie clinical improvements. OBJECTIVES: We sought to examine and quantify the time course and magnitude of dermal matrix changes that occur in response to nonablative fractionated laser resurfacing, with the dual goals of better understanding the molecular mechanisms that underlie clinical improvements and of gaining knowledge that will enable evidence-based treatment parameter optimization. METHODS: Twenty patients (mean age 58 years) with photodamaged skin were focally treated on dorsal forearms with a nonablative fractionated laser. Serial skin samples were obtained at baseline and at various times after treatment. Biopsies were examined with real-time polymerase chain reaction technology and immunohistochemical techniques. RESULTS: Laser treatment resulted in an initial inflammatory response as indicated by statistically significant induction of proinflammatory cytokines (interleukin-1beta and tumour necrosis factor-alpha). This was followed by substantial increases in levels of several matrix metalloproteinases and later by significant induction of type I collagen. Dermal remodelling was noted with both low and high microbeam energy treatment parameters. CONCLUSIONS: Nonablative fractionated laser resurfacing induces a well-organized wound-healing response that leads to substantial dermal remodelling and collagen induction. Surprisingly, only minimal differences were observed between lower and higher microbeam energy settings. These data suggest that lower microbeam energy/higher microbeam density treatment parameters, which are generally better tolerated by patients, may yield dermal changes similar to those that result from higher microbeam energy/lower microbeam density treatment parameters. PMID- 20854402 TI - Nonclinical influences, beyond diagnosis and severity, on clinical decision making in dermatology: understanding the gap between guidelines and practice. AB - BACKGROUND: Clinical decision making in dermatology is a complex process and might be influenced by a wide range of nonclinical factors. OBJECTIVES: The aim of this study was to explore the role of nonclinical influences, beyond diagnosis and severity, on clinical decision making in dermatology. METHODS: Semi structured qualitative interviews were conducted with 46 clinicians working in departments of dermatology of nine different hospitals in Wales. Interviews were audio-recorded and later transcribed and their contents analysed. RESULTS: Nonclinical factors influencing patient management decisions in dermatology that were identified related to patients, clinicians and practice characteristics. Patient-related factors included place of residence, socioeconomic circumstances, education and intelligence, ethnicity, age, treatment adherence, expectations from treatment, quality of life, concerns and worries, difficult patients, and family members or friends. Clinician-related factors included time constraints in clinic, clinicians' personal circumstances, relationship with colleagues, and relationship with pharmaceutical companies. Practice-related factors included working in private practice, cost of treatment to the National Health Service (NHS), prescribing bureaucracy, and availability of treatment service in the work place. There was a difference between the consultants' views and those of the other clinicians over the impact of pharmaceutical companies on clinicians' prescribing and the awareness of treatment costs to the NHS. Most of the factors identified could potentially influence the clinicians' decision-making process subconsciously. Some clinicians highlighted that these factors are untaught in the medical curriculum, and are usually ignored in clinical guidelines, and therefore represent a challenge to the practice of evidence-based medicine. CONCLUSIONS: This study has described one aspect of the reality of medical decision making beyond the conventional evidence-based guidelines approach. Proper understanding of nonclinical influences on decision making is of paramount importance for the best patient-centred treatment outcomes. PMID- 20854403 TI - Systemic sclerosis and the risk of cancer: a nationwide population-based cohort study. AB - BACKGROUND: Earlier studies reported an increased cancer risk among patients with systemic sclerosis. Study size limitations and paucity of population-based study designs may have resulted in imprecise risk estimates. OBJECTIVES: To assess cancer risk among patients with systemic sclerosis in a nationwide follow-up study. METHODS: Patients with a first diagnosis of systemic sclerosis from 1977 to 2006 were identified from the nationwide Danish National Registry of Patients (DNRP), whose records encompass all hospitalizations and outpatient visits. Patients' DNRP records were linked to the Danish Cancer Registry. We compared their cancer incidence with that expected from cancer incidence in the general population, calculating standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: Two thousand and forty patients with systemic sclerosis were identified and followed for 16,003 person-years, with a median follow-up time of 6.4 years (interquartile range 2.2-11.5). Among these patients, 222 cases of cancer were identified. The overall SIR for cancer was 1.5 (95% CI 1.3-1.7), with a gender-specific SIR of 2.2 (95% CI 1.7-2.8) for men and 1.3 (95% CI 1.1 1.6) for women. The most frequent cancers were smoking- and alcohol-related cancers including lung cancer (SIR = 1.6, 95% CI 1.2-2.0), haematological cancers (SIR = 2.5, 95% CI 1.5-4.0) and immune-related cancers (SIR = 1.4, 95% CI 1.0 1.9). CONCLUSIONS: Systemic sclerosis is a risk factor for cancer, particularly smoking- and alcohol-related cancers. Men with systemic sclerosis generally are at higher cancer risk than women. Both primary and secondary cancer preventive measures are needed in the care of patients with systemic sclerosis. PMID- 20854404 TI - Melanoma survivors are dissatisfied with perceived information about their diagnosis, treatment and follow-up care. PMID- 20854405 TI - Topical methyl aminolaevulinate-photodynamic therapy in erosive facial mycosis fungoides. PMID- 20854406 TI - Systemic therapies containing ethanol and gelatine excipients. PMID- 20854407 TI - A novel mutation in MBTPS2 causes ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome in a Chinese family. PMID- 20854408 TI - Switching to adalimumab in patients with moderate to severe psoriasis who have failed on etanercept: a retrospective case cohort study. PMID- 20854410 TI - The impact of Pleistocene glaciation across the range of a widespread European coastal species. AB - There is a growing consensus that much of the contemporary phylogeography of northern hemisphere coastal taxa reflects the impact of Pleistocene glaciation, when glaciers covered much of the coastline at higher latitudes and sea levels dropped by as much as 150 m. The genetic signature of postglacial recolonization has been detected in many marine species, but the effects of coastal glaciation are not ubiquitous, leading to suggestions that species may intrinsically differ in their ability to respond to the environmental change associated with glacial cycles. Such variation may indeed have a biological basis, but apparent differences in population structure among taxa may also stem from our heavy reliance on individual mitochondrial loci, which are strongly influenced by stochasticity during coalescence. We investigated the contemporary population genetics of Syngnathus typhle, one of the most widespread European coastal fish species, using a multilocus data set to investigate the influence of Pleistocene glaciation and reduced sea levels on its phylogeography. A strong signal of postglacial recolonization was detected at both the northern and eastern ends of the species' distribution, while southern populations appear to have been relatively unaffected by the last glacial cycle. Patterns of population variation and differentiation at nuclear and mitochondrial loci differ significantly, but simulations indicate that these differences can be explained by the stochastic nature of the coalescent process. These results demonstrate the strength of a multilocus approach to phylogeography and suggest that an overdependence on mitochondrial loci may provide a misleading picture of population-level processes. PMID- 20854411 TI - Inbreeding coefficient and heterozygosity-fitness correlations in unhatched and hatched song sparrow nestmates. AB - Heterozygosity-fitness correlations use molecular measures of heterozygosity as proxy estimates of individual inbreeding coefficients (f) to examine relationships between inbreeding and fitness traits. Heterozygosity-fitness correlations partly depend on the assumption that individual heterozygosity and f are strongly and negatively correlated. Although theory predicts that this relationship will be strongest when mean f and variance in f are high, few studies of heterozygosity-fitness correlations include estimates of f based on pedigrees, which allow for more thorough examinations of the relationship between f, heterozygosity and fitness in nature. We examined relationships between pedigree-based estimates of f, multilocus heterozygosity (MLH) and the probability of survival to hatch in song sparrow nestmates. f and MLH were weakly, but significantly negatively correlated. Inbreeding coefficient predicted the probability of survival to hatch. In contrast, MLH did not predict the probability of survival to hatch nor did it account for residual variation in survival to hatch after statistically controlling for the effects of f. These results are consistent with the expectation that heterozygosity-f correlations will be weak when mean and variance in f are low. Our results also provide empirical support for recent simulation studies, which show that variation in MLH among siblings with equal f can be large and may obscure MLH-fitness relationships. PMID- 20854412 TI - Lineage divergence and speciation in the Web-toed Salamanders (Plethodontidae: Hydromantes) of the Sierra Nevada, California. AB - Peripatric speciation and the importance of founder effects have long been controversial, and multilocus sequence data and coalescent methods now allow hypotheses of peripatric speciation to be tested in a rigorous manner. Using a multilocus phylogeographical data set for two species of salamanders (genus Hydromantes) from the Sierra Nevada of California, hypotheses of recent divergence by peripatric speciation and older, allopatric divergence were tested. Phylogeographical analysis revealed two divergent lineages within Hydromantes platycephalus, which were estimated to have diverged in the Pliocene. By contrast, a low-elevation species, Hydromantes brunus, diverged from within the northern lineage of H. platycephalus much more recently (mid-Pleistocene), during a time of major climatic change in the Sierra Nevada. Multilocus species tree estimation and coalescent estimates of divergence time, migration rate, and growth rate reject a scenario of ancient speciation of H. brunus with subsequent gene flow and introgression from H. platycephalus, instead supporting a more recent divergence with population expansion. Although the small, peripheral distribution of H. brunus suggests the possibility of peripatric speciation, the estimated founding population size of the species was too large to have allowed founder effects to be important in its divergence. These results provide evidence for both recent speciation, most likely tied to the climatic changes of the Pleistocene, and older lineage divergence, possibly due to geological events, and add to evidence that Pleistocene glacial cycles were an important driver of diversification in the Sierra Nevada. PMID- 20854413 TI - Multidonor bone marrow transplantation improves donor engraftment and increases the graft versus tumor effect while decreasing graft-versus-host disease. AB - In partially matched donor transplantation, mandatory T-cell depletion (TCD) increases the risks of rejection/graft failure, relapse, and post-transplant infections. A multi-donor approach was offered to resolve some of these drawbacks. This hypothesis was previously tested in a TCD fully mismatched murine model. However, the effect of multi-donor transplantation (MDT) on graft-versus host disease (GVHD) and graft versus tumor (GVT) effect were never tested. To assess the safety and efficacy of MDT, we used it in non-TCD transplantation and murine breast carcinoma model. We found that when transplanting non-TCD MDT composed by C57Bl/6 and C3H cells into BALB/c, a consistent trichimerism is established, dominated by C57Bl/6 cells. Following MDT the study animals experienced reduced GVHD compare with those transplanted from C57Bl/6 alone, while the GVT effect was superior. We conclude that MDT may serve as a technique that suppresses GVHD while maintaining the GVT effect. PMID- 20854414 TI - 5-Aminolevulinic acid-induced protoporphyrin IX levels in tissue of human malignant brain tumors. AB - Protoporphyrin IX (PpIX) produced from exogenous, orally administered 5 aminolevulinic acid (ALA) displays high tumor-selective uptake and is being successfully employed for fluorescence-guided resection (FGR) of human malignant gliomas. Furthermore, the phototoxicity of PpIX can be utilized for photodynamic therapy (PDT) of brain tumors, which has been shown previously. Here, the absolute PpIX concentration in human brain tissue was investigated following oral ALA administration (20 mg kg(-1) b.w.). An extraction procedure was used to quantify PpIX in macroscopic tissue samples, weighing 0.013-0.214 g, obtained during FGR. The PpIX concentration was significantly higher in vital grade IV tumors (5.8 +/- 4.8 MUm, mean +/- SD, range 0-28.2 MUm, n = 8) as compared with grade III tumors (0.2 +/- 0.4 MUm, mean +/- SD, range 0-0.9 MUm, n = 4). There was also a large heterogeneity within grade IV tumors with PpIX displaying significantly lower levels in infiltration zones and necrotic regions as compared with vital tumor parts. The average PpIX concentration in vital grade IV tumor parts was in the range previously shown sufficient for PDT-induced tissue damage following irradiation. However, the feasibility of PDT for grade III brain tumors and for grade IV brain tumors displaying mainly necrotic tissue areas without solid tumor parts needs to be further investigated. PMID- 20854415 TI - Rapid functional definition of extended spectrum beta-lactamase activity in bacterial cultures via competitive inhibition of fluorescent substrate cleavage. AB - The functional definition of extended-spectrum beta-lactamase (ESBL) activity is a clinical challenge. Here we report a rapid and convenient assay of beta lactamase activity through the competitive inhibition of fluorescent substrate hydrolysis that provides a read-out nearly 40* more rapidly than conventional techniques for functional definition. A panel of beta-lactam antibiotics was used for competition against beta-lactamase enzyme-activated photosensitizer (beta LEAP) yielding a competitive index (C(i)) in 30 min. Significant differences in the relative C(i) values of the panel of beta-lactams were determined in vitro for Bacillus cereus penicillinase. Additionally, the relative C(i) values for whole bacterial cell suspensions of B. cereus 5/beta were compared with the relative minimal inhibitory concentration (MIC) values and a correlation coefficient of 0.899 was determined. We further demonstrated the ability of beta LEAP to probe the capacity of ceftazidime to inhibit the enzyme activity of a panel of ESBL-producing Escherichia coli. The bacteria were assayed for susceptibility to ceftazidime and the relative MIC values were compared with the relative C(i) values for ceftazidime yielding a correlation coefficient of 0.984. This work demonstrates for the first time the whole cell assay of the competitive inhibition of beta-lactamase enzyme activity and derivation of associated constants. PMID- 20854416 TI - Role of ubiquitination in endocytic trafficking of G-protein-coupled receptors. AB - Lysyl ubiquitination has long been known to target cytoplasmic proteins for proteasomal degradation, and there is now extensive evidence that ubiquitination functions in vacuolar/lysosomal targeting of membrane proteins from both the biosynthetic and endocytic pathways. G-protein-coupled receptors (GPCRs) represent the largest and most diverse family of membrane proteins, whose function is of fundamental importance both physiologically and therapeutically. In this review, we discuss the role of ubiquitination in the vacuolar/lysosomal downregulation of GPCRs through the endocytic pathway, with a primary focus on lysosomal trafficking in mammalian cells. We will summarize evidence indicating that mammalian GPCRs are regulated by ubiquitin-dependent mechanisms conserved in budding yeast, and then consider evidence for additional ubiquitin-dependent and independent regulation that may be specific to animal cells. PMID- 20854417 TI - LG186: An inhibitor of GBF1 function that causes Golgi disassembly in human and canine cells. AB - Brefeldin A-mediated inhibition of ADP ribosylation factor (Arf) GTPases and their guanine nucleotide exchange factors, Arf-GEFs, has been a cornerstone of membrane trafficking research for many years. Brefeldin A (BFA) is relatively non selective inhibiting at least three targets in human cells, Golgi brefeldin A resistance factor 1 (GBF1), brefeldin A inhibited guanine nucleotide exchange factor 1 (BIG1) and brefeldin A inhibited guanine nucleotide exchange factor 2 (BIG2). Here, we show that the previously described compound Exo2 acts through inhibition of Arf-GEF function, but causes other phenotypic changes that are not GBF1 related. We describe the engineering of Exo2 to produce LG186, a more selective, reversible inhibitor of Arf-GEF function. Using multiple-cell-based assays and GBF1 mutants, our data are most consistent with LG186 acting by selective inhibition of GBF1. Unlike other Arf-GEF and reported GBF1 inhibitors including BFA, Exo2 and Golgicide A, LG186 induces disassembly of the Golgi stack in both human and canine cells. PMID- 20854418 TI - CHRNB2 promoter region: association with subjective effects to nicotine and gene expression differences. AB - Smoking behavior is a complex, which includes multiple stages in the progression from experimentation to continued use and dependence. The experience of subjective effects, such as dizziness, euphoria, heart pounding, nausea and high, have been associated with varying degrees of persistence and subsequent abuse/dependence of marijuana, cocaine, tobacco and alcohol (Grant et al. 2005, Wagner & Anthony 2002). Previous studies have reported associations between neuronal nicotinic receptor (CHRN) genes and subjective effects to nicotine. We sought to replicate and expand this work by examining eight single nucleotide polymorphisms (SNPs) in a sample of adult smokers (n = 316) who reported subjective effects following cigarette smoking in a controlled laboratory environment. Two SNPs each in the CHRNB2, CHRNB3, CHRNA6 and CHRNA4 genes were examined. A significant association was found between two SNPs and physical effects reported after smoking the first experimental cigarette. SNP rs2072658 is upstream of CHRNB2 (P-value = 0.0046) and rs2229959 is a synonymous change in exon 5 of CHRNA4 (P value = 0.0051). We also examined possible functional relevance of SNP rs2072658 using an in vitro gene expression assay. These studies provided evidence that the minor allele of rs2072658 may lead to decreased gene expression, using two separate cell lines, P19 and SH-SY5Y (18% P < 0.001 and 26% P < 0.001 respectively). The human genetic study and functional assays suggest that variation in the promoter region of CHRNB2 gene may be important in mediating levels of expression of the beta2 nicotinic receptor subunit, which may be associated with variation in subjective response to nicotine. PMID- 20854419 TI - SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function. AB - BACE1 (beta-secretase) plays a central role in the beta-amyloidogenesis of Alzheimer's disease (AD). The ubiquitin-proteasome system, a major intracellular protein quality control system, has been implicated recently in BACE1 metabolism. We report that the SCF(Fbx2) -E3 ligase is involved in the binding and ubiquitination of BACE1 via its Trp 280 residue of F-box-associated domain. Physiologically, we found that Fbx2 was expressed in various intracellular organelles in brain neurons and that BACE1 is colocalized with Fbx2 and the amyloid precursor protein (APP), mainly at the early endosome and endoplasmic reticulum. The former are believed to be the major intracellular compartments where the APP is cleaved by BACE1 and beta-amyloid is produced. Importantly, we found that overexpression of Fbx2 in the primary cortical and hippocampal neurons derived from Tg2576 transgenic mice significantly promoted BACE1 degradation and reduced beta-amyloid production. In the search for specific endogenous modulators of Fbx2 expression, we found that PPARgamma coactivator-1alpha (PGC-1alpha) was capable of promoting the degradation of BACE1 through a mechanism involving Fbx2 gene expression. Interestingly, we found that the expression of both Fbx2 and PGC 1alpha was significantly decreased in the brains of aging Tg2576 mice. Our in vivo studies using a mouse model of AD revealed that exogenous adenoviral Fbx2 expression in the brain significantly decreased BACE1 protein levels and activity, coincidentally reducing beta-amyloid levels and rescuing synaptic deficits. Our study is the first to suggest that promoting Fbx2 in the brain may represent a novel strategy for the treatment of AD. PMID- 20854420 TI - PAPP-A: a new anti-aging target? AB - This article focuses on the role of PAPP-A in mammalian aging. It introduces PAPP A and a little of its history, briefly discusses the function of PAPP-A in the insulin-like growth factor (IGF) system and the regulators of PAPP-A expression, and then reviews data concerning PAPP-A in aging and age-related diseases especially in regard to the PAPP-A knockout (KO) mouse. The PAPP-A KO mouse is a valuable new model to test hypotheses concerning the control of the tissue availability of IGF, independent from systemic levels, on healthspan as well as lifespan. PMID- 20854423 TI - The polymorphism -2548G/A in leptin and severity of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease characterized by airway obstruction that is not fully reversible, and there is evidence of a hereditary component in COPD. We aimed to determine whether the polymorphisms -2548G/A of leptin (LEP) gene were associated with COPD and its severity in Chinese. A total of 456 subjects with COPD and 422 healthy controls from West China Hospital were enrolled in this study. COPD patients had been undergone a spirometry and a physical examination to refer the GOLD I-IV stages. The polymorphisms in the leptin promoter region at position -2548G/A were detected by Polymerase chain reaction-restriction fragment length polymorphism analysis. The genotypes and alleles were scored, and the frequencies of the alleles and genotypes in patients and controls were compared. A significantly higher risk for COPD was observed for carriers of the LEP -2548AA genotype [odds ratio (OR)=7.87, 95% confidence interval (CI) 4.19-14.77, P<0.001] and carriers of the LEP -2548GA genotype (OR=2.98, 95% CI 1.57-5.66, P=0.001). The LEP -2548A allele: frequency was significantly higher in the patient group compared with the control group (OR=2.75, 95% CI: 2.20-3.44, P<0.001). We also found a significant relationship between leptin gene polymorphism and the severity of COPD. In the present case-control study, we found an association between the -2548G/A variant of the leptin gene and pathogenesis, severity of COPD in the Chinese population. It suggests that leptin -2548G/A should be used as a genetic marker of COPD severity. PMID- 20854421 TI - The telomeric protein SNM1B/Apollo is required for normal cell proliferation and embryonic development. AB - Conserved metallo beta-Lactamase and beta-CASP (CPSF-Artemis-Snm1-Pso2) domain nuclease family member SNM1B/Apollo is a shelterin-associated protein that localizes to telomeres through its interaction with TRF2. To study its in vivo role, we generated a knockout of SNM1B/Apollo in a mouse model. Snm1B/Apollo homozygous null mice die at birth with developmental delay and defects in multiple organ systems. Cell proliferation defects were observed in Snm1B/Apollo mutant mouse embryonic fibroblasts (MEFs) owing to high levels of telomeric end to-end fusions. Deficiency of the nonhomologous end-joining (NHEJ) factor Ku70, but not p53, rescued the developmental defects and lethality observed in Snm1B/Apollo mutant mice as well as the impaired proliferation of Snm1B/Apollo deficient MEFs. These findings demonstrate that SNM1B/Apollo is required to protect telomeres against NHEJ-mediated repair, which results in genomic instability and the consequent multi-organ developmental failure. Although Snm1B/Apollo-deficient MEFs exhibited high levels of apoptosis, abrogation of p53 dependent programmed cell death did not rescue the multi-organ developmental failure in the mice. PMID- 20854422 TI - Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. AB - Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality. PMID- 20854424 TI - Actinobaculum schaalii: clinical observation of 20 cases. AB - Actinobaculum schaalii is a new species that has so far been isolated from human blood, urine and pus. Its importance has probably been underestimated and other Actinobaculum spp. may also have been underdiagnosed. This retrospective study comprises all known cases of A. schaalii infections identified since 2004 in the canton of Neuchatel (170,000 inhabitants), Switzerland. Strains were cultivated and isolated in the bacteriology laboratory using its routine procedure. Identification included a Rapid ID 32 A strip (bioMerieux) and 16S rRNA gene sequencing. Twenty-one positive samples were found in 19 patients (11 male, 8 female) of all ages (range 16-91 years): 10 from urine (50%), six from blood (30%), one from both blood and urine (5%), and three from pus (15%). Thirteen out of 17 (76%) cases with either blood or urine specimens had underlying genitourinary tract pathologies. When urine cultures were positive for A. schaalii, leucocytes were found in all samples (10/10, 100%) but all nitrite tests were negative (10/10, 100%). The onset of appropriate treatment was delayed due to the diminished sensitivity of A. schaalii to the antibiotics commonly used for UTIs (i.e. ciprofloxacin and trimethoprim/sulfamethoxazole) and to the delay in microbiological diagnosis. A. schaalii should specifically be searched in all cases of leukocyturia with a negative nitrite test but with Gram-positive rods in the Gram stain, in patients with underlying genitourinary tract pathology, instead of dismissing these findings as clinically irrelevant colonization by coryneform bacteria. This infection may be much more common than previously thought. PMID- 20854425 TI - Comparing clinical and microbiological methods for the diagnosis of true bacteraemia among patients with multiple blood cultures positive for coagulase negative staphylococci. AB - We assessed the accuracy of the Centers for Disease Control and Prevention (CDC) clinical criteria as well as other microbiological methods for the diagnosis of coagulase-negative staphylococci bacteraemia. The CDC clinical criteria had low accuracy, which can be improved by speciation, particularly if the patient had more than two positive blood cultures. PMID- 20854426 TI - The dominant methicillin-resistant Staphylococcus aureus clone from hospitals in Cape Town has an unusual genotype: ST612. AB - There is currently limited information available on the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in South Africa. A molecular characterization of 100 MRSA from five hospitals in Cape Town was carried out in this study. The strains were separated into six clusters by pulsed-field gel electrophoresis, indicating transmission of MRSA between local hospitals. None of the strains carried the Panton-Valentine Leukocidin gene. SCCmec typing, multilocus sequence typing and spa typing were used to further characterize the MRSA. Three clones corresponded to frequently described pandemic clones: ST239 MRSA-III, ST36-MRSA-II and ST5-MRSA-I. ST239-MRSA-III and ST36-MRSA-II were minor clones and collectively accounted for 16% of the isolates. ST5-MRSA-I was the second-most prevalent clone and accounted for 37% of the isolates. The dominant local clone was the infrequently described ST612-MRSA-IV (44% of isolates), which has only been described in South Africa and Australia. PMID- 20854427 TI - Evolution patterns of raltegravir-resistant mutations after integrase inhibitor interruption. AB - The objective of this study was to address the evolution of human immunodeficiency virus type 1 (HIV-1) mutations resistant to the integrase inhibitor raltegravir after drug interruption. Thirteen HIV-1 infected patients undergoing virological failure due to the selection of raltegravir-resistant variants, who had interrupted raltegravir treatment, were enrolled. For all patients, the virological failure was associated with the selection of variants, with mutations conferring resistance to all of the drugs present in their regimens. Patients were prospectively monitored at baseline (raltegravir interruption) and every 4-24 weeks for clinical, virological and immunological parameters, including HIV-1 viraemia, CD4(+) T-cell counts, and sequence analysis of the HIV-1 integrase sequence. Reversion to the wild-type HIV-1 integrase sequence genotype was observed between 4 and 36 weeks after raltegravir withdrawal in eight out of the 13 patients. Reversion was not observed in three patients. In two patients, reversion was partial at week 24 from raltegravir interruption. These results highlight that in eight out of 13 patients under treatment with raltegravir and experiencing a virological failure, HIV-1 variants harbouring mutations associated with raltegravir resistance become undetectable after drug interruption within a few weeks (in some cases, very rapidly). This occurs under different therapy regimens and in patients receiving 3TC mono therapy. In the other patients, complete reversion of the integrase sequence is not observed, and either primary or secondary resistance mutations are fixed in the replication competent viral population in vivo also for long time, suggesting that other factors may influence this dynamic process. PMID- 20854428 TI - Gastroenteritis in a Taipei emergency department: aetiology and risk factors. AB - A matched case-control study was used to determine pathogens and risk factors associated with gastroenteritis in a Taipei Emergency Department. Viruses (40.0%) were the leading cause of gastroenteritis, with noroviruses the most prevalent (33.2%). Bacteria were found in 26.0% of all cases, mostly suspected diarrheagenic E. coli (22.2%), followed by Salmonella spp. (5.4%) and Vibrio parahaemolyticus (4.2%). Giardia lamblia was identified in 16.4% of all cases. Statistical significance was noted for seven risk factors: taking antacids before gastroenteritis (OR = 3.91; 95% CI, 2.13, 7.15), other household members with gastroenteritis (OR = 5.18; 95% CI, 2.09, 12.85), attending a banquet (OR = 1.93; 95% CI, 1.25, 2.98), eating out (OR = 2.35; 95% CI, 1.30, 4.23), drinking bottled water (OR = 1.72; 95% CI, 1.07, 2.75), eating honey peaches (OR = 3.26; 95% CI, 1.24, 8.58), and eating raw oysters (OR = 3.24; 95% CI, 1.02, 10.28). Eating out was identified as the highest risk behavior, as measured by population attributable risk fraction (PAR) (50.9%). Respective PAR values for drinking bottled water, attending a banquet and taking antacids before illness were 19.7%, 19.6% and 17.6%. Of these, additional research on bottled water appears to be the highest priority, because this is the first time it has been identified as a risk factor for gastroenteritis. PMID- 20854429 TI - Stimulation of natriuretic peptide receptor C attenuates accumulation of reactive oxygen species and nitric oxide synthesis in ammonia-treated astrocytes. AB - Oxidative and nitrosative stress contribute to ammonia-induced astrocytic dysfunction in hepatic encephalopathy. Treatment of cultured astrocytes with 5 mmol/L ammonium chloride ('ammonia') increased the production of reactive oxygen species (ROS), including the toxic NADPH oxidase reaction product, *O(2)(-). Atrial natriuretic peptide (ANP), natriuretic peptide C and a selective natriuretic peptide receptor (NPR)-C ligand, cANP((4-23),) each decreased the total ROS content both in control cells and cells treated with ammonia. However, attenuation of *O(2)(-) accumulation by ANP and cANP((4-23),) was observed in ammonia-treated cells only and the effect of cANP((4-23)) was decreased when the NADPH oxidase-regulatory protein G(ialpha-2) was blocked with a specific anti G(ialpha-2) antibody. Although in contrast to ANP, cANP((4-23)) did not elevate the cGMP content in control astrocytes, it decreased cAMP content and reduced the expression of G(ialpha-2), the NADPH oxidase-regulatory protein. The results show the presence of functional NPR-C in astrocytes, activation of which (i) attenuates basal ROS production, and (ii) prevents excessive accumulation of the toxic ROS species, *O(2)(-) by ammonia. Ammonia, ANP and cANP((4-23)) added separately, each stimulated formation of NO(x) (nitrates + nitrites) which was associated with up-regulation of the activity [cANP((4-23))] or/and expression (ammonia) of the endothelial isoform of nitric oxide synthase. However, the ammonia-induced increase of NO(x) was not augmented by co-addition of ANP, and was reduced to the control level by co-addition of cANP((4-23)) , indicating that activation of NPR-C may also reduce nitrosative stress. Future hepatic encephalopathy therapy might include the use of cANP((4-23)) or other NPR-C agonists to control oxidative/nitrosative stress induced by ammonia. PMID- 20854430 TI - Ammonium influx pathways into astrocytes and neurones of hippocampal slices. AB - Ammonium (NH(4) (+) ) is required to maintain pathways involved in shuttling metabolic precursors between astrocytes and neurones. Under hyperammonaemic conditions, increases in the cellular influx of NH(4) (+) , and accompanying changes in ion concentrations, may contribute to disruptions in metabolism and neurotransmission. We investigated mechanisms of cellular NH(4) (+) influx in hippocampal slices by measuring acute NH(4) (+) /NH(3) -evoked changes in intracellular pH (pH(i) ) and sodium ([Na(+) ](i) ). In both astrocytes and neurones, application of 5 mM NH(4) Cl for 30-45 min decreased pH(i) by 0.2-0.3 units, consistent with NH(4) (+) influx. In astrocytes, but not neurones, acidifications were accompanied by [Na(+) ](i) increases of 25-30 mM. Glial [Na(+) ](i) increases were blocked by bumetanide, suggesting that NH(4) (+) /NH(3) activated Na(+) -dependent, K(+) , Cl(-) cotransport. Bumetanide also reduced NH(4) (+) /NH(3) -evoked acidifications in astrocytes. Neuronal acidifications were insensitive to bumetanide and inhibition of Cl(-) -dependent transport and K(+) channels, but were prevented by inhibition of Na(+) ,K(+) ATPase with ouabain. Furthermore, ouabain reduced astrocyte acidifications. Our results suggest that following rapid elevation of NH(4) (+) , Na(+) ,K(+) -ATPase is the major influx pathway for NH(4) (+) in neurones, whereas Na(+) ,K(+) ATPase and Na(+) -dependent, K(+) , Cl(-) cotransport mediate NH(4) (+) transport into astrocytes. The different mechanisms of NH(4) (+) influx in astrocytes and neurones may contribute to the different susceptibility of both cell types to acute hyperammonaemic conditions. PMID- 20854431 TI - Regulation of ryanodine receptors by dopamine D1 receptors during methamphetamine induced place conditioning. AB - Little is known about ryanodine receptors (RyRs) related to the methamphetamine (METH)-induced place preference. The present study was designed to ascertain whether RyRs could play a role in the development of METH-induced place preference in the mouse. The METH-induced place preference was dose-dependently suppressed by dantrolene, a RyRs receptor antagonist. The levels of RyRs 1 and 2 in the frontal cortex and RyRs 1 in the limbic forebrain were significantly increased in METH-conditioned mice. This up-regulation of RyRs were not inhibited by nifedipine. Both the dopamine D(1) receptor antagonist SCH23390 and the dopamine D(2) receptor antagonist sulpiride inhibited the development of METH induced place conditioning. In contrast, the increases of RyRs 1 and 2 in the frontal cortex and of RyRs 1 in the limbic forebrain were completely abolished by SCH23390, whereas sulpiride had no effect. These findings indicate that up regulation of RyRs is regulated through the activation of dopamine D(1) receptors in the METH-conditioning. PMID- 20854432 TI - Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction. AB - J. Neurochem. (2010) 115, 1215-1221. ABSTRACT: Synaptic dysfunction is widely thought to be a pathogenic precursor to neurodegeneration in Alzheimer's disease (AD), and the extent of synaptic loss provides the best correlate for the severity of dementia in AD patients. Presenilins 1 and 2 are the major causative genes of early-onset familial AD. Conditional inactivation of presenilins in the adult cerebral cortex results in synaptic dysfunction and memory impairment, followed by age-dependent neurodegeneration. To characterize further the consequence of presenilin inactivation in the synapse, we evaluated the temporal development of pre-synaptic and post-synaptic deficits in the Schaeffer collateral pathway of presenilin conditional double knockout (PS cDKO) mice prior to onset of neurodegeneration. Following presenilin inactivation at 4 weeks, synaptic facilitation and probability of neurotransmitter release are impaired in PS cDKO mice at 5 weeks of age, whereas post-synaptic NMDA receptor (NMDAR) mediated responses are normal at 5 weeks but impaired at 6 weeks of age. Long term potentiation induced by theta burst stimulation is also reduced in PS cDKO mice at 6 weeks of age. These results show that loss of presenilins results in pre-synaptic deficits in short-term plasticity and probability of neurotransmitter release prior to post-synaptic NMDAR dysfunction, raising the possibility that presenilins may regulate post-synaptic NMDAR function in part via a trans-synaptic mechanism. PMID- 20854433 TI - Midwifery. PMID- 20854434 TI - Analysis of cytokine secretion from lymphocytes of patients with hypersensitivity reactions to contaminated heparins. AB - BACKGROUND: Beginning in 2007, anaphylactoid reactions associated with unfractionated heparin (UFH) occurred and resulted in some fatalities. These reactions were reported to be linked to the complement and contact system activation induced by certain batches of UFH containing the adulterant oversulphated chondroitin sulphate (OSCS). OBJECTIVES: Drug-specific secretion of selected cytokines from peripheral blood mononuclear cells (PBMC) of patients with hypersensitivity reactions to contaminated heparin was compared with the respective in vitro cytokine pattern of individuals with or without hypersensitivity to heparin, different glycosaminoglycans or other drugs. METHODS: Study individuals (n = 13) were classified as follows: patients with hypersensitivity reactions to contaminated (OSCS) heparin (n = 3), noncontaminated heparin (n = 1) or other compounds (n = 3) and patients with ongoing heparin therapy without symptoms of intolerance (n = 2). Four healthy individuals served as controls. PBMC were incubated with six different glycosaminoglycan structures. Drug-specific intracellular interleukin (IL)-5, interferon (IFN)-gamma and IL-10 production was investigated by flow cytometry, while secretion of IL-5, IL-2 and IFN-gamma was analysed by enzyme-linked immunosorbent assay. RESULTS: PBMC from individuals with hypersensitivity reactions to contaminated heparin secreted considerable amounts of IL-2 in vitro. There was a suggestion that ongoing heparin therapy and the Li-heparin in the vials may have an impact on the lymphocyte reactivity of PBMC. CONCLUSIONS: The in vitro lymphocyte reactivity pattern of PBMC from individuals with hypersensitivity reactions to contaminated heparins was neither typical for an immune-mediated nor for a nonimmune-mediated reaction. Possible effects of heparins in the test system itself may require consideration. PMID- 20854435 TI - Development of a simple enzyme-linked immunosorbent assay for the detection of autoantibodies in anti-p200 pemphigoid. AB - BACKGROUND: Anti-p200 pemphigoid is a subepidermal blistering skin disease characterized by autoantibodies against a 200-kDa protein (p200) of the dermal epidermal junction. The laminin gamma1 chain has recently been identified as target antigen in this disease and the C-terminus was described as an immunodominant region of laminin gamma1. Diagnosis of anti-p200 pemphigoid requires detection of serum IgG at the dermal side of 1 mol L(-1) salt-split skin by indirect immunofluorescence microscopy and labelling of a 200-kDa protein by Western blotting of dermal extract. However, preparation of dermal extract is not widely available, limiting the possibility of diagnosing this disease to a few laboratories. OBJECTIVES: To develop a simple, sensitive and specific diagnostic tool for anti-p200 pemphigoid. METHODS: Sera from patients with anti-p200 pemphigoid (n = 35), bullous pemphigoid (BP, n = 101), epidermolysis bullosa acquisita (EBA, n = 10), antilaminin 332 mucous membrane pemphigoid (MMP, n = 14), pemphigus vulgaris (PV, n = 51) and healthy volunteers (HV, n = 131) were tested by a novel enzyme-linked immunosorbent assay (ELISA) that employed a recombinant monomeric C-terminal fragment of human laminin gamma1 (hLAMC1-cterm) expressed in Escherichia coli. RESULTS: Serum reactivity with hLAMC1-cterm was detected in sera from 24 of 35 (69%) patients with anti-p200 pemphigoid, two of 101 (2%) with BP, 0 of 10 with EBA, two of 14 (14%) with anti-laminin 332 MMP, 0 of 51 with PV, and 0 of 131 HV. CONCLUSIONS: This novel ELISA will facilitate the diagnosis of anti-p200 pemphigoid. PMID- 20854436 TI - Tomato paste rich in lycopene protects against cutaneous photodamage in humans in vivo: a randomized controlled trial. AB - BACKGROUND: Previous epidemiological, animal and human data report that lycopene has a protective effect against ultraviolet radiation (UVR)-induced erythema. OBJECTIVES: We examined whether tomato paste--rich in lycopene, a powerful antioxidant--can protect human skin against UVR-induced effects partially mediated by oxidative stress, i.e. erythema, matrix changes and mitochondrial DNA (mtDNA) damage. METHODS: In a randomized controlled study, 20 healthy women (median age 33 years, range 21-47; phototype I/II) ingested 55 g tomato paste (16 mg lycopene) in olive oil, or olive oil alone, daily for 12 weeks. Pre- and postsupplementation, UVR erythemal sensitivity was assessed visually as the minimal erythema dose (MED) and quantified with a reflectance instrument. Biopsies were taken from unexposed and UVR-exposed (3 * MED 24 h earlier) buttock skin pre- and postsupplementation, and analysed immunohistochemically for procollagen (pC) I, fibrillin-1 and matrix metalloproteinase (MMP)-1, and by quantitative polymerase chain reaction for mtDNA 3895-bp deletion. RESULTS: Mean +/- SD erythemal D(30) was significantly higher following tomato paste vs. control (baseline, 26.5 +/- 7.5 mJ cm(-2); control, 23 +/- 6.6 mJ cm(-2); tomato paste, 36.6 +/- 14.7 mJ cm(-2); P = 0.03), while the MED was not significantly different between groups (baseline, 35.1 +/- 9.9 mJ cm(-2); control, 32.6 +/- 9.6 mJ cm(-2); tomato paste, 42.2 +/- 11.3 mJ cm(-2)). Presupplementation, UVR induced an increase in MMP-1 (P = 0.01) and a reduction in fibrillin-1 (P = 0.03). Postsupplementation, UVR-induced MMP-1 was reduced in the tomato paste vs. control group (P = 0.04), while the UVR-induced reduction in fibrillin-1 was similarly abrogated in both groups, and an increase in pCI deposition was seen following tomato paste (P = 0.05). mtDNA 3895-bp deletion following 3 * MED UVR was significantly reduced postsupplementation with tomato paste (P = 0.01). CONCLUSIONS: Tomato paste containing lycopene provides protection against acute and potentially longer-term aspects of photodamage. PMID- 20854437 TI - A novel missense mutation in GJB2, p.Tyr65His, causes severe Vohwinkel syndrome. AB - Gap junctions are intercellular channels which are permeable to ions and small molecules up to about 1 kDa in size. They are prominent in the skin, but their precise function there is largely unknown. Mutations in skin-expressed gap junction genes disrupt epidermal growth and differentiation. A relatively minor epidermal connexin, connexin 26 (Cx26), is associated with a wide variety of phenotypes, each specifically associated with a particular amino acid residue. How the different mutations in GJB2 lead to such distinctive phenotypes is poorly understood. Analysis of new GJB2 mutations can shed new light on pathogenesis and the apparently vital role of Cx26 in maintaining epidermal integrity. PMID- 20854438 TI - SLURP1 mutation-impaired T-cell activation in a family with mal de Meleda. AB - BACKGROUND: Mal de Meleda (MDM) is palmoplantar erythrokeratoderma with an autosomal recessive inheritance and is caused by a mutation in the gene encoding SLURP-1 (lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein-1). SLURP-1 is an allosteric agonist to the nicotinic acetylcholine receptor (nAchR) and it regulates epidermal homeostasis. In addition, murine studies have shown that nAchR signalling is important for the regulation of T-cell function. Among the family members, patients with the homozygous SLURP1 (previously known as ARS component B) mutation are prone to melanoma and viral infection, which might link to defective T-cell function as well as a derangement of epidermal homeostasis. OBJECTIVES: To investigate the association of the SLURP1 gene mutation with T-cell activation in a Taiwanese family with MDM. To test that SLURP-1 is essential for T-cell activation. METHODS: Human peripheral blood mononuclear cells (PBMCs) were isolated from a Taiwanese MDM family bearing the G to A substitution in nucleotide 256 in the SLURP1 gene, corresponding to a glycine to arginine substitution at amino acid 86 (G86R) in the SLURP-1 protein. PBMCs from homozygotes and wild-type controls were stimulated with anti-CD3/anti-CD28 antibodies and the level of T-cell activation was determined by the stimulation index. RESULTS: PBMCs with the heterozygous and homozygous SLURP-1 G86R mutation had defective T-cell activation. This was restored by the addition of 0.5 MUg mL(-1) recombinant human SLURP-1 protein. CONCLUSIONS: Patients with MDM with the homozygous SLURP-1 G86R mutation may have an impaired T-cell activation. The presence of wild-type SLURP-1 is essential for normal T-cell activation. PMID- 20854439 TI - Watch and wait policy remains experimental for the management of rectal cancer. PMID- 20854440 TI - Histological grading of tumour regression and radiation colitis in locally advanced rectal cancer following neoadjuvant therapy: a critical appraisal. AB - AIM: Locally advanced rectal cancer is commonly treated by neoadjuvant therapy and the resultant tumour response can be quantified histologically. This therapy may also induce radiation colitis, which also can be graded. The aim of this study was to assess the grading of tumour regression and of radiation colitis and their relationship to other prognostic parameters. METHOD: Between 2000 and 2006, 75 patients (23 women; median duration of follow up, 58 months) with rectal cancer were evaluated. Sixty-three had short-course radiotherapy and 12 had long course radiotherapy. Tumour regression was graded histologically using the three point Ryan system: patients with grades 1 and 2 were considered as responders and patients with grade 3 were considered as nonresponders. Radiation colitis was graded histologically as mild, moderate or severe, as described previously (J Pathol 2006; 210: P25). RESULTS: Twenty-nine patients were classified as responders and 46 as nonresponders. The former were less likely to be lymph node positive compared with the latter (P=0.001). Tumour response did not correlate with local recurrence. Responders showed a disease-free survival (not overall survival) advantage at 2 and 5 years over nonresponders. Responders showed a higher rate of postoperative abdominal complications. Histological evidence of regression was demonstrated in patients treated with short-course radiotherapy. There was no relationship between radiation colitis grade and abdominal complications. CONCLUSION: Radiation colitis grade does not correlate with postoperative complications. More abdominal complications occurred in patients receiving long-course radiotherapy. PMID- 20854441 TI - Laparoscopic versus transverse Incision right colectomy for colon carcinoma. AB - AIM: We investigated whether laparoscopic right colectomy has short-term and / or oncological advantages compared with transverse incision right colectomy. METHOD: Patients who underwent an elective laparoscopic right colectomy or an open right colectomy through a transverse incision at the VU University Medical Center or Zaans Medical Center from 2005 to 2009 were prospectively followed. RESULTS: Patient groups were comparable in terms of gender, body mass index and American Society of Anesthesiology classification. Patients in the transverse incision group were older (68 years vs 75 years, P = 0.07) and blood loss was greater during this procedure (60 ml vs 130 ml, P = 0.001), which cost less than the laparoscopic procedure (?6.033 vs ?7.221, P = 0.03). Hospital stay for the laparoscopic group was shorter (8 days vs 9 days, P = 0.04), but laparoscopic procedures took longer (155 min vs 77 min, P < 0.001) and 8% of patients in the laparoscopic group were converted to a median laparotomy. Postoperative complications were comparable for both groups (28% vs 32%, P = 0.74), and in both groups a radical resection rate of 96% (P = 0.94) was achieved. At a median follow up of 20 months the incidence of incisional hernia was similar in both groups and no patient required additional surgery as a result. Overall survival at 60 months was 70% for the laparoscopic group and 67% for the transverse incision group (P = 0.84). CONCLUSION: There a re few clinically relevant differences between a laparoscopic right colectomy and a transverse incision right colectomy. Transverse incision right colectomy is cheaper. The study may be the first to compare these two techniques, but it is a nonrandomized trial and therefore has its limitations. PMID- 20854442 TI - Synchronous diagnosis of colorectal malignancy and lymphoma. AB - AIM: To perform case series from one centre over 9 years, and review of the literature. The synchronous diagnosis of colorectal malignancy and lymphoma is rare. METHOD: Case note review of patients identified from clinical databases. RESULTS: Five patients were identified and findings discussed. In two patients colorectal malignancy staging CT scans identified pathological lymphadenopathy consistent with lymphoma. A further two patients had an incidental lymphoma on histological examination of the colorectal malignancy specimen. The fifth patient was found to have suspicious superior mesenteric lymph nodes at laparotomy. Histology confirmed two nodular lymphocyte-predominant Hodgkin's lymphomas, a lymphocytic-rich classical Hodgkin's lymphoma, a diffuse large B-cell lymphoma and a B-cell follicular lymphoma. CONCLUSION: There is a need for vigilance for the possibility of dual pathologies in all specialties. PMID- 20854443 TI - Anatomical and functional results after stapled transanal rectal resection (STARR) for obstructed defaecation syndrome. AB - AIM: The STARR procedure is a surgical option for the treatment of rectocoele associated with obstructed defaecation syndrome (ODS). The aim of the study was to assess the efficacy of this technique in restoring anatomy and the long-term sustainability of symptom control and quality of life. METHODS: Of 48 patients operated on from 2003 to 2007, 30 were enrolled for this prospective assessment of anatomical correction and functional improvement of ODS. Results from a standardised questionnaire concerning functional results (ODS score), faecal incontinence (Cleveland Clinic score) and Patient Assessment of Constipation Quality of Life (PAC-QoL) were prospectively collected. Systematic dynamic defaecography, together with anorectal physiology testing, were performed before surgery and 6 months after. 25 patients were available for long-term assessment of functional outcome (more than 4 years). RESULTS: The mean age of the population was 57 +/- 7 years. STARR produced significant improvements in the PAC QoL (p < 0.05) and ODS score (p < .0001), but not in the incontinence score. At defaecography, correction was significant with respect to the depth (p = 0.007), perimeter (p < 0.0001) and neck (p = 0.001) of rectocoele. Anorectal physiology revealed a lower maximal tolerated rectal volume (p<.0001). After 58 months, the 25 patients showed sustained functional results and QoL. Four patients (16%) underwent further surgical procedure for pelvic floor disorders and 8 patients (32%) still required laxatives. CONCLUSION: Our study confirms the efficacy of the STARR procedure, with sustained improvement in function and QoL. However, a substantial number of patients remain symptomatic. PMID- 20854444 TI - Topical negative pressure as a safe and helpful treatment in patients with large abdominal wounds with multiple fistulae. PMID- 20854445 TI - Development of the Children's Attributions about Psychological Problems in their Peers Scale. AB - BACKGROUND: Research has shown that children's beliefs about the causes of psychological problems are related to their attitudes and reactions towards affected peers. This study describes the development of the Children's Attributions about Psychological Problems in their Peers (CAPPP) Scale, which assesses children's beliefs about the causes of an internalizing and an externalizing condition. METHODS: The 16 items comprising the CAPPP are derived from previous qualitative research findings. Five hundred and ninety-five young people, drawn from five different age groups spanning early childhood to late adolescence, completed a CAPPP Scale for each of two vignettes describing the behaviour of hypothetical peers with attention deficit hyperactivity disorder (ADHD) and depression. RESULTS: Modifications following consideration of psychometric properties and conceptual fit resulted in a 12-item scale. For both the ADHD and depression conditions, the components that emerged were 'Volition', 'Recent Life Stress', 'Family Factors' and 'School Factors'. CONCLUSIONS: The present study represents the first field trial of the CAPPP. Results suggest that children's and adolescents' beliefs about the causes of psychological problems are multidimensional and incorporate both individual and environmental factors. PMID- 20854446 TI - An evaluation of social skills in children with and without prenatal alcohol exposure. AB - BACKGROUND: The goal of this study was to examine social skills deficits among children with and without prenatal alcohol exposure (PAE) who were both referred to a respite programme. METHODS: Thirty-seven children with PAE and 23 non exposed children (aged 3 to 8 years) were evaluated on the Social Skills Rating System (SSRS) by their caregivers and respite workers. RESULTS: As compared with the non-exposed children, those with PAE showed more deficits on caregiver ratings of responsibility, hyperactivity, internalizing problems and overall social skills, as well as respite worker ratings of hyperactivity. The social skills among the PAE group were not related to home placement variables. Among both groups, caregivers rated social skills lower than respite workers, and among the PAE group, girls tended to display more social skills deficits than boys. CONCLUSIONS: The SSRS is useful in identifying unique social skills deficits among children with PAE. PMID- 20854447 TI - Including children in medical decisions and treatments: perceptions and practices of healthcare providers. AB - BACKGROUND: With growing awareness of the need to involve children in their own health-related decisions, attention has primarily focused on the concept of assent, or a minor's participation in a research trial or experimental treatment. This study attempts to broaden that focus by examining the perceptions and practices of healthcare providers with respect to the role of children in more routine healthcare decisions and treatments. METHODS: In total, 103 nurses and 40 physicians who work in a hospital in Israel completed self-administered perceptions and practices questionnaires. RESULTS: Many participants agreed that children should be included in decision making. Factors that respondents felt would influence their approach to a particular child included child behaviour (80%), child communication (66%), experience of child, parent and healthcare provider (90%) and type of medical intervention (60%). Responses differed between physicians and nurses. In response to the question 'How often do you suggest the following methods to achieve child participation in treatment?' most respondents reported that they provide an explanation (98%) and recruit the parents (90%). The use of play was reported by only 63% of the professionals. CONCLUSION: This study demonstrated that many healthcare providers recognize the need to include children in routine health-related practices and outlined factors healthcare providers use in deciding when to include children in medical decisions. Involving children in even the minute aspects of everyday decisions and treatments can allow children to feel part of the process, improve their co operation, increase their sense of control and affect future healthcare encounters. PMID- 20854448 TI - Prevalence of overweight, obesity and underweight among 5-year-old children in Saint Lucia by three methods of classification and a comparison with historical rates. AB - BACKGROUND: The study aimed to determine if child obesity rates have risen in the Caribbean nation of Saint Lucia, as found globally, and whether under-nutrition coexists, as in other developing nations. The average adult in Saint Lucia is overweight, thus considerable child obesity might be expected, but there are no current data. METHODS: Heights and weights were obtained from a sample (n= 425) of the 2001 birth cohort of Saint Lucian children measured during the nation-wide 2006/2007 Prior to School Entry Five-Year Assessment. Prevalence of overweight, obesity and underweight were estimated by Centers for Disease Control (CDC), Cole et al. and new World Health Organization (WHO) methods. Previously reported 1976 estimates, including children <=60 months of age only, based on National Centre for Health Statistics curves, were adjusted to new WHO equivalents using an algorithm developed by Yang and de Onis, and compared with rates in our subsample of children <=60 months of age (n= 99). RESULTS: Regardless of classification method, overweight and obesity rates were high: 14.4% and 9.2% (WHO); 11.3% and 12.0% (CDC); and 9.9% and 7.1% (Cole et al.), respectively. Underweight estimates also varied: 4.7% (WHO); 11.3% (CDC) and 6.6% (Cole et al.). Obesity in our young subsample (15.2%; WHO) was more than 3 times the adjusted 1976 rate (4.3%). CONCLUSIONS: Obesity among Saint Lucian pre-schoolers has tripled in 30 years. Our findings also suggest that this country, like many undergoing a 'nutrition transition', faces the dual challenge of over-nutrition and under-nutrition. Routine monitoring of overweight and underweight is needed in Saint Lucia, as is the implementation and evaluation of programmes to address these problems. PMID- 20854449 TI - Incredible Years parent training support for foster carers in Wales: a multi centre feasibility study. AB - BACKGROUND: the incidence of conduct disorder in young children is 10% in the general population and 37% among fostered children. Up to 40% of untreated children diagnosed with conduct disorder develop problems later in life including drug misuse, criminal and violent behaviour. There are more than 80,000 looked after children in the UK, with 5000 in Wales. Challenging child behaviour is the main reason for placement breakdown and has huge cost implications as challenging children cost up to 10 times more in service use than children without conduct disorder. The Incredible Years (IY) evidence-based parenting programme is an effective, low cost solution in improving child behaviour and social competence in 'conventional' families and thus has the potential to support foster carers in managing difficult behaviours. Our main aims were to establish: * The feasibility of delivery and the effectiveness of the IY parenting programme in supporting carers in managing difficult behaviour in looked after children. * Service use costs for foster carers and looked after child. METHODS: This was a 12-month trial platform study with 46 foster carers in three authorities in Wales. Carers were allocated 2:1 intervention to waiting-list control. Validated measures were used to assess 'parenting' competency, carers' depression levels, child behaviour and service use. Measures were administered at baseline and 6-month follow-up. Intervention carers received the programme between baseline and follow-up. RESULTS: Analyses showed a significant reduction in child problem behaviour and improvement in carers' depression levels for intervention families at follow-up, compared with control. Unexpectedly, there was a significant improvement in control carers' self-reported 'parenting' strategies. Special education was the greatest service cost for looked after children. CONCLUSIONS: Initial foster carer training could incorporate the IY programme to support carers in establishing positive relationships and managing difficult child behaviour. Programme participation may lead to reduced service use and improved placement stability. PMID- 20854450 TI - Time-use diaries are acceptable to parents with a disabled preschool child and are helpful in understanding families' daily lives. AB - BACKGROUND: In order to provide services for children with disabilities which are family focused, strengthening and enabling families in addition to meeting the child's identified needs, it is important to understand families' lives. This study investigates whether time-use diaries can provide an acceptable tool to explore the daily lives of parents with a disabled child. METHODS: A precoded time-use diary divided into 15 min time slots was designed. Father-mother pairs with a preschool child with either autism (ASD) or technology dependence (TD) were asked to complete a 7-day diary independently, over the same time period. Each parent was then interviewed separately to ascertain their experiences of using the diary. Participants were identified through their involvement with a Child Development Centre. RESULTS: Twenty-six parents (13 father-mother pairs) were invited to participate. Eighteen parents agreed to be involved; 16 completed the diaries and interviews. Three father-mother pairs in the ASD group and one father-mother pair in the TD group declined to be involved. One father-mother pair from the TD group withdrew from the study. Of the 18 parents who agreed to participate, 15 found the diaries acceptable and either easy or straightforward to complete. One parent with dyslexia and one who described himself as a non reader completed the diaries successfully, finding the colour coding helpful. Parents spent between 10 and 60 min a day completing the diaries, with the median 20-30 min. The diaries provided information on the total amount of time spent on different activities and how much time parents spent together, with their other children, at home or elsewhere. CONCLUSION: The time-use diaries designed for this study were acceptable to the majority of parents and provided detailed information about their daily lives. PMID- 20854451 TI - Pachyonychia congenita type 2. PMID- 20854452 TI - Local anesthesia in dermatology. AB - Local and regional anesthetic procedures are an integral part of daily dermatological practice. Safe and effective analgesia in skin and soft tissues is crucial for otherwise painful diagnostic or therapeutic interventions. Tumescent local anesthesia allows for pain-free interventions that previously had to be done by using general anesthesia. Older patients with multiple co-morbidities are especially suited for local anesthetic procedures, because they may significantly reduce surgical risks. For dermatologists, the knowledge of mode of action and toxicity of local anesthetics, as well as the emergency management of their potential complications, is essential. PMID- 20854453 TI - Usefulness of resistant gene markers for predicting treatment outcome on second line anti-tuberculosis drugs. AB - AIM: Mutations in rrs [nucleotide (nt) 1401], gyrA gene (codons 90, 91 or 94), tlyA, ethA and thyA genes of Mycobacterium tuberculosis (MTB) were evaluated for their usefulness in predicting treatment outcome of kanamycin (KM), capreomycin (CPM), ofloxacin (OFX), ethionamide (ETH) and para-aminosalicylic acid (PAS). METHODS AND RESULTS: DNA sequence analyses of these genes were performed against 188 MTB isolates obtained from patients put on second-line anti-TB drugs (SLDs) with well-documented clinical history and treatment outcome. Mutations in rrs and gyrA have 100% positive predictive value (PPV) in predicting treatment failure for KM and OFX, while 88.9 and 80% were obtained, respectively, when tlyA and rrs mutations were considered in CPM. For ETH and PAS, the PPV of using ethA and thyA mutations to predict treatment failure was 82.5 and 89.3%, respectively. CONCLUSIONS: Our study demonstrated high specificities of gene mutations in predicting poor treatment outcome; however, further technical advancement is required to make the molecular detection of resistances to other SLDs feasible in clinical laboratories. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study to correlate different polymorphisms of major SLD resistance gene markers with predicted treatment outcome, using an international set of well-documented clinical MTB strains. PMID- 20854454 TI - Increased synthesis of alpha-tocopherol, paramylon and tyrosine by Euglena gracilis under conditions of high biomass production. AB - AIMS: To analyse the production of different metabolites by dark-grown Euglena gracilis under conditions found to render high cell growth. METHODS AND RESULTS: The combination of glutamate (5 g l(-1) ), malate (2 g l(-1) ) and ethanol (10 ml l(-1) ) (GM + EtOH); glutamate (7.15 g l(-1) ) and ethanol (10 ml l(-1) ); or malate (8.16 g l(-1) ), glucose (10.6 g l(-1) ) and NH(4) Cl (1.8 g l(-1) ) as carbon and nitrogen sources, promoted an increase of 5.6, 3.7 and 2.6-fold, respectively, in biomass concentration in comparison with glutamate and malate (GM). In turn, the production of alpha-tocopherol after 120 h identified by LC-MS was 3.7 +/- 0.2, 2.4 +/- 0.1 and 2 +/- 0.1 mg [g dry weight (DW)](-1) , respectively, while in the control medium (GM) it was 0.72 +/- 0.1 mg (g DW)(-1) . For paramylon synthesis, the addition of EtOH or glucose induced a higher production. Amino acids were assayed by RP-HPLC; Tyr a tocopherol precursor and Ala an amino acid with antioxidant activity were the amino acids synthesized at higher concentration. CONCLUSIONS: Dark-grown E. gracilis Z is a suitable source for the generation of the biotechnologically relevant metabolites tyrosine, alpha tocopherol and paramylon. SIGNIFICANCE AND IMPACT OF THE STUDY: By combining different carbon and nitrogen sources and inducing a tolerable stress to the cell by adding ethanol, it was possible to increase the production of biomass, paramylon, alpha-tocopherol and some amino acids. The concentrations of alpha tocopherol achieved in this study are higher than others reported previously for Euglena, plant and algal systems. This work helps to understand the effect of different carbon sources on the synthesis of bio-molecules by E. gracilis and can be used as a basis for future works to improve the production of different metabolites of biotechnological importance by this organism. PMID- 20854455 TI - Hexavalent chromium reduction by bacterial consortia and pure strains from an alkaline industrial effluent. AB - AIMS: To characterize the bacterial consortia and isolates selected for their role in hexavalent chromium removal by adsorption and reduction. METHODS AND RESULTS: Bacterial consortia from industrial wastes revealed significant Cr(VI) removal after 15 days when incubated in medium M9 at pH 6.5 and 8.0. The results suggested chromium reduction. The bacterial consortia diversity (T-RFLP based on 16S rRNA gene) indicated a highest number of operational taxonomic units in an alkaline carbonate medium mimicking in situ conditions. However, incubations under such conditions revealed low Cr(VI) removal. Genomic libraries were obtained for the consortia exhibiting optimal Cr(VI) removal (M9 medium at pH 6.5 and 8.0). They revealed the dominance of 16S rRNA gene sequences related to the genera Pseudomonas/Stenotrophomonas or Enterobacter/Halomonas, respectively. Isolates related to Pseudomonas fluorescens and Enterobacter aerogenes were efficient in Cr(VI) reduction and adsorption to the biomass. CONCLUSIONS: Cr(VI) reduction was better at neutral pH rather than under in situ conditions (alkaline pH with carbonate). Isolated strains exhibited significant capacity for Cr(VI) reduction and adsorption. SIGNIFICANCE AND IMPACT OF STUDY: Bacterial communities from chromium-contaminated industrial wastes as well as isolates were able to remove Cr(VI). The results suggest a good potential for bioremediation of industrial wastes when optimal conditions are applied. PMID- 20854456 TI - Enhanced germicidal effects of pulsed UV-LED irradiation on biofilms. AB - AIMS: The major objective of the study was to evaluate the enhanced germicidal effects of low-frequency pulsed ultraviolet A (UVA)-light-emitting diode (LED) on biofilms. METHODS AND RESULTS: The germicidal effects of UVA-LED irradiation (365 nm, 0.28 mW cm(-2) , in pulsed or continuous mode) on Candida albicans or Escherichia coli biofilms were evaluated by determining colony-forming units. The morphological change of microbial cells in biofilms was observed using scanning electron microscopy. After 5-min irradiation, over 90% of viable micro-organisms in biofilms had been killed, and pulsed irradiation (1-1000 Hz) had significantly greater germicidal ability than continuous irradiation. Pulsed irradiation (100 Hz, 60 min) almost completely killed micro-organisms in biofilm (>99.9%), and 20 min irradiation greatly damaged both microbial species. Interestingly, few hyphae were found in irradiated Candida biofilms. Moreover, mannitol treatment, a scavenger of hydroxyl radicals (OH(*) ), significantly protected viable micro organisms in biofilms from UVA-LED irradiation. CONCLUSIONS: The study demonstrated that pulsed UVA-LED irradiation has a strong germicidal effect (maximum at 100 Hz, over 5-min irradiation) and causes the disappearance of hyphal forms of Candida. SIGNIFICANCE AND IMPACT OF THE STUDY: This study can assist in developing a low-frequency pulsed UVA-LED system to be applied to pathogenic biofilms for disinfection. PMID- 20854457 TI - Salmonella rarely detected in Mississippi coastal waters and sediment. AB - AIMS: Standards for the rapid detection of individual pathogens from environmental samples have not been developed, but in their absence, the use of molecular-based detection methods coupled with traditional microbiology techniques allows for rapid and accurate pathogen detection from environmental waters and sediment. The aim of this research was to combine the use of enrichment with PCR for detection of Salmonella in Mississippi coastal waters and sediment and observe if that presence correlated with levels of enterococci and climatological variables. METHODS AND RESULTS: Salmonella were primarily found in samples that underwent nutrient enrichment and were present more frequently in freshwater than marine waters. Salmonella were detected infrequently in marine and freshwater sediments. There was a significant positive correlation between the presence of detectable Salmonella and the average enterococcal count. An inverse relationship, however, was observed between the frequency of detection and the levels of salinity, turbidity and sunlight exposure. CONCLUSIONS: Results from this study indicated the presence of Salmonella in Mississippi coastal waters, and sediments are very low with significant differences between freshwater and marine environments. SIGNIFICANCE AND IMPACT OF THE STUDY: Using pathogenic and novel nonpathogenic molecular markers, Salmonella do not appear to be a significant pathogenic genus along the Mississippi Coast. PMID- 20854458 TI - Detection of mycoplasma contamination in cell substrates using reverse transcription-PCR assays. AB - AIMS: To assess the limit of detection (LOD) and the feasibility of 16S rRNA based reverse transcription-PCR (RT-PCR) assays for advanced detection of mycoplasma contamination in cell substrates. MATERIALS AND METHODS: The RT-PCR approach is based on detecting the 16S rRNA molecules that, in contrast to genomic bacterial DNA, are represented by multiple copies in mycoplasma cell. The number of 16S rRNA molecules in mycoplasma cells of five species i.e. Mycoplasma arginini, Myc. fermentans, Myc. hyorhinis, Myc. orale and Acholeplasma laidlawii, all known to be frequent cell line contaminants in industrial and research laboratories, was measured using molecular methods. The results of two independently prepared mycoplasma cultures harvested at the stationary phase of their growth showed that the 16S rRNA copy number per cell varied in the range from about 400 to 2000 copies, depending on species, but stayed close between different preparations of one species. The assessment of the LOD of the in-house 16S rRNA-based RT-PCR was performed using samples of MDCK cell culture spiked with different amounts of five aforementioned mycoplasma species. To minimize the bias in methods comparison, the LOD of the RT-PCR assay was expressed in terms of genome equivalents (GEs) and compared with that determined for highly optimized 16S rDNA-based mycoplasma testing methods previously described in scientific literature. CONCLUSIONS: The results of the study showed that the in-house 16S rRNA-based RT-PCR assay was able to reliably detect the presence of less than one mycoplasma GE that is at least 10-fold higher of the LOD previously determined for well-optimized 16S rDNA-based assays developed and described by other researchers. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of the study showed that rapid RT-PCR methods based on the detection of bacterial 16S rRNA are able to expedite mycoplasma testing of cell cultures (1-2 days vs 28 days) and to ensure the limits of detection comparable to that of currently used culture-based mycoplasma testing methods. PMID- 20854459 TI - Muco-cutaneous manifestations in 178 renal transplant recipients. AB - INTRODUCTION: Mucosal membrane and skin can be affected by immunosuppressive drug(s) and immunosuppression itself. The spectrum of muco-cutaneous lesions can range from malignancy at one end to infection, iatrogenic lesions, and esthetic effects on the other end. METHOD: In Razi Hospital of Guilan University of Medical Sciences, a cross-sectional study for the detection of muco-cutaneous lesions in 178 renal transplant recipients (RTRs) was conducted from the years 2001 to 2006. Biopsy and skin scraping according to the type of skin lesions were performed. RESULTS: A total of 31 RTRs (25%) had normal skin. Iatrogenic lesions were the most common (70%) followed by infectious lesions (57%), and miscellaneous skin lesions were exhibited by 26% of the patients. Among the iatrogenic skin lesions, gingival hyperplasia was the most common lesion (48%), followed by hypertrichosis and acne. Malignant lesions (biopsy proven) were recorded in seven patients (5%). Four patients were found to have Kaposi's sarcoma, and three patients were identified with basal cell carcinoma. CONCLUSION: Our results showed that muco-cutaneous lesions are crucial problems with RTRs. Attending physicians must pay close attention to skin care regularly and consider reduction of immunosuppression to a safe level, and patient must have self-checkups. PMID- 20854460 TI - Screening of platelets for bacterial contamination at the Welsh Blood Service. AB - BACKGROUND AND OBJECTIVE: This report details the results of the implementation of a bacterial screening system at the Welsh Blood Service and provides an estimate of the levels of bacterial contamination at the time of sampling. MATERIALS AND METHODS: Apheresis (Caridian BCT) and buffy coat-derived pooled platelet components were sampled on day 1 for bacterial contamination and the sample was monitored throughout the lifespan of the platelet component. Unused platelet components were re-tested to determine the effectiveness of the screening. Results from the BacT/ALERT are uploaded to the in-house Blood Establishment Computer System (BECS) every 12 min. Positive alerts are automatically sent to staff, facilitating a timely intervention. RESULTS: Between February 2003 and March 2010 the screening system tested 54 828 platelets and detected 257 (1 in 213) initial positives of which 35 (1 in 1567, 0.06%) were confirmed [95% confidence interval (CI), 0.04-0.08%]. Additionally, screening of 6438 unused platelet components detected another 6 (1 in 1073, 0.09%) confirmed positives not detected during initial testing (95% CI, 0.02-0.16%). Analysis of the data suggests that on day 1 the number of bacteria in such platelet component packs was between 5 and 62 cfus total. Day 1 culture has a sensitivity of 40%. CONCLUSIONS: The bacterial screening system has removed a significant number, but not all bacterially contaminated platelet components from the supply. The sample volume is an important factor in sensitivity due to the low number of bacteria in a platelet component pack on day 1. An effective notification and recall system is a critical part of the bacterial screening system. PMID- 20854461 TI - HIV in 2010: potent antiretroviral drugs treat and sensitive assays monitor the infection; but there remain outstanding issues. PMID- 20854462 TI - Fibrosis with emphysema. AB - The concept of fibrosis with emphysema is confused by the existence of two very different clinical/pathological scenarios: first, cases in which a diffuse fibrosing interstitial pneumonia, most commonly usual interstitial pneumonia (UIP), occurs in a patient with emphysema. This combination is largely of clinical interest because of its effects on pulmonary function and pulmonary hypertension, but can produce unusual appearances in surgical lung biopsies when the fibrotic areas are wrapped around emphysematous spaces. However, the underlying morphology of emphysema and UIP or other interstitial lung disease remains unchanged. Radiological consultation is often helpful to show that the patient has both lesions; secondly, cases in which there is localized fibrosis that is part of emphysema, or related to respiratory bronchiolitis, or both. These lesions have been called 'respiratory bronchiolitis' (RB), 'respiratory bronchiolitis-interstitial lung disease' (RB-ILD), 'airspace enlargement with fibrosis', 'RB-ILD with fibrosis' and 'clinically occult interstitial fibrosis in smokers', but are probably all the same entity. Such changes are associated only rarely with the physiological or radiological features of an interstitial lung disease. Care should be taken when describing these lesions in biopsies so as not to give the impression that a diffuse interstitial lung disease is present. PMID- 20854463 TI - Desquamative interstitial pneumonia. AB - Desquamative interstitial pneumonia (DIP) is one of the rarest of the idiopathic interstitial pneumonias. It is characterized by the accumulation of macrophages in large numbers in the alveolar spaces associated with interstitial inflammation and/or fibrosis. The macrophages frequently contain light brown pigment, and because of their association with smoking have been called 'smoker's macrophages'. Lymphoid nodules are common, as is a sparse but distinct eosinophil infiltrate. Most cases of DIP are caused by cigarette smoking, but drugs and other inhaled agents, including marijuana smoke, can also produce the same disease. Although respiratory bronchiolitis-interstitial lung disease (RB-ILD) is a closely related process, there are prognostic reasons for continuing to separate it from DIP when possible. The proposed relationship of DIP to fibrotic non-specific interstitial pneumonia (NSIP) remains uncertain. The prognosis of DIP appears to be significantly better than that of fibrotic NSIP, so while there can be morphological overlap between the two, merging them into one disease may hide important prognostic information. Although the majority of DIP patients improve on treatment, some patients develop progressive irreversible fibrosis. PMID- 20854464 TI - Acute exacerbations of fibrotic interstitial lung disease. AB - An acute exacerbation is the development of acute lung injury, usually resulting in acute respiratory distress syndrome, in a patient with a pre-existing fibrosing interstitial pneumonia. By definition, acute exacerbations are not caused by infection, heart failure, aspiration or drug reaction. Most patients with acute exacerbations have underlying usual interstitial pneumonia, either idiopathic or in association with a connective tissue disease, but the same process has been reported in patients with fibrotic non-specific interstitial pneumonia, fibrotic hypersensitivity pneumonitis, desquamative interstitial pneumonia and asbestosis. Occasionally an acute exacerbation is the initial manifestation of underlying interstitial lung disease. On biopsy, acute exacerbations appear as diffuse alveolar damage or bronchiolitis obliterans organizing pneumonia (BOOP) superimposed upon the fibrosing interstitial pneumonia. Biopsies may be extremely confusing, because the acute injury pattern can completely obscure the underlying disease; a useful clue is that diffuse alveolar damage and organizing pneumonia should not be associated with old dense fibrosis and peripheral honeycomb change. Consultation with radiology can also be extremely helpful, because the fibrosing disease may be evident on old or concurrent computed tomography scans. The aetiology of acute exacerbations is unknown, and the prognosis is poor; however, some patients survive with high-dose steroid therapy. PMID- 20854466 TI - Generation of self-renewing immature dendritic cells from mouse spleen that can take up mycobacteria and present antigens to T cells. AB - Dendritic cells (DC) play a key role in driving the adaptive immune response to Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB). However, studying these important yet very sparse immune cells in the context of MTB pathogenesis is severely restricted by the lack of suitable cell lines and the complexity of culturing of DC progenitors, usually obtained from the bone marrow. However, significant advances have been made towards generating long-term DC cultures from various lymphoid tissues. Here, we report the evidence for generating a long-term, self-renewing DC culture from the Balb/c mouse spleen. We demonstrate that these cells, termed IDC-3, have a myeloid DC origin, i.e. they are CD11c(+) CD11b(++) CD8-alpha(-) F4/80(+/-) and that they also display a phenotype MHC-II(+) CD16/32(++) CD80(+/-) CD86(+) , indicating that they are immature DC. Following incubation with Mycobacterium bovis BCG (Bacillus Calmette Guerin), the IDC-3 efficiently took up bacteria and acquired the morphology of mature DC. Importantly though, when IDC-3 were pre-stimulated with a mycobacterial antigen in vitro, they were able to induce proliferation of T lymphocytes from mice immunized with the same antigen. The T-cell stimulatory potential of IDC-3 was further enhanced when the cells were co-stimulated with an anti-CD40 mAb. We therefore suggest that the IDC-3 culture system could be a useful tool for studying the interaction of DC with mycobacteria. PMID- 20854467 TI - A simple and economical method for the manual construction of frozen tissue arrays. AB - Tissue microarray has been developed to enable multiple cores of tissue in one or more new paraffin blocks. Currently, almost all tissue microarrays are made by coring cylindrical tissues from formalin-fixed and paraffin-embedded tissues. The disadvantages of formalin-fixed and paraffin-embedded tissues include the poor preservation of antigenicity of certain proteins and mRNA degradation induced by the fixation and embedding process. However, frozen tissue array construction presents technical difficulties, and tissue array devices are expensive, particularly for small- and medium-sized laboratories. We describe a simple manual method for producing well-aligned tissue arrays by a capsule freeze method that allows us to successfully perform hematoxylin-eosin and immunohistochemical stain. All 120 tissue samples were collected and constructed into blocks by this capsule freeze method. The capsules were not affected during the sectioning process, and the capsule material always disappeared during the aqueous steps of the stain processing. The frozen tissue arrays were smoothly sectioned without the use of a tape transfer system and immunohistochemical study was performed with satisfactory results. This alternative method can be applied in any laboratory, and is both simple and economical. PMID- 20854465 TI - Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis. AB - The programmed cell death-10 (PDCD10; also known as cerebral cavernous malformation-3 or CCM3) gene encodes an evolutionarily conserved protein associated with cell apoptosis. Mutations in PDCD10 result in cerebral cavernous malformations, an important cause of cerebral hemorrhage. PDCD10 is associated with serine/threonine kinases and phosphatases and modulates the extracellular signal-regulated kinase pathway suggesting a role in the regulation of cellular growth. Here we provide evidence of a constitutive expression of PDCD10 in malignant T cells and cell lines from peripheral blood of cutaneous T-cell lymphoma (Sezary syndrome) patients. PDCD10 is associated with protein phosphatase-2A, a regulator of mitogenesis and apoptosis in malignant T cells. Inhibition of oncogenic signal pathways [Jak3, Notch1, and nuclear factor-kappaB (NF-kappaB)] partly inhibits the constitutive PDCD10 expression, whereas an activator of Jak3 and NF-kappaB, interleukin-2 (IL-2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10 and cancer. PMID- 20854468 TI - Immunohistochemical characteristics of diffuse sclerosing variant of papillary carcinoma: comparison with conventional papillary carcinoma. AB - Diffuse sclerosing variant of papillary carcinoma (DSVPC) is a rare variant of papillary thyroid carcinoma (PTC). It shows different clinicopathologic features to the conventional PTC, but the immunohistochemical characteristics of DSVPC are yet to be more clearly defined. The purpose of this study was to investigate the immunohistochemical features of DSVPC, which are different from those of PTC. Tissue microarray was constructed from the paraffin-embedded tissue of 49 DSVPC and 50 conventional PTC samples. Immunohistochemical stains for p63, p53, galectin-3, cytokeratin 19, beta-catenin, Bcl-2, EMA, E-cadherin, CD15, and CD56 were performed on each tissue microarray. Immunohistochemical stain for p63 was negative in all conventional PTCs, but 14 (28.6%) cases of DSVPC showed p63 expression (p = 0.000). p53 was expressed in 38 (76.0%) cases of conventional PTC and 21 (42.9%) cases of DSVPC (p = 0.001). Galectin-3 was expressed in all 50 cases of conventional PTC, but eight (16.3%) cases of DSVPC did not express galectin-3 (p = 0.003). EMA was expressed more in DSVPC (40.8%) than in conventional PTC (20.0%, p = 0.024). In univariate analyses, Bcl-2 positivity (p = 0.016) and EMA negativity (p = 0.036) in DSVPC were associated with shorter time interval to tumor recurrence, but there was no significance for the two in multivariate analyses. DSVPC, a rare variant of PTC, has different immunohistochemical features from the conventional PTC, showing higher expression rate of p63 and lower expression rate of p53. It also shows galectin-3 negativity and EMA positivity. PMID- 20854470 TI - A new cleavage site for elastase within the complement component 3. AB - The lysosomal enzyme elastase was earlier shown to cleave the complement molecule C3. During some preliminary experiments on the interactions of certain pathogenic bacteria with the innate defence mechanisms, we observed C3 cleavage, in the presence of elastase, to fragments not previously described. To elucidate this proteolytic reaction, the present study was conducted. Degradation of C3 in mixtures with elastase or cathepsin G was detected by an immunoblot procedure using anti-C3c and anti-C3d antibodies after separating the proteins by SDS-PAGE. Certain C3 fragments were analysed for amino acid sequence. The results revealed the existence of a cleavage site for elastase at the position alanine1350/lysine1351 of the C3 molecule, which has not been previously described. The fragment resulted from this cleavage has a size of about 39 kDa and it contains a part or the whole of C3d. This cleavage was distinct from the one previously described at position 987/988, which gives a 34 kDa C3d-containing fragment. PMID- 20854469 TI - Skin wound healing in diabetic beta6 integrin-deficient mice. AB - Integrin alphavbeta6 is a heterodimeric cell surface receptor, which is absent from the normal epithelium, but is expressed in wound-edge keratinocytes during re-epithelialization. However, the function of the alphavbeta6 integrin in wound repair remains unclear. Impaired wound healing in patients with diabetes constitutes a major clinical problem worldwide and has been associated with the accumulation of advanced glycated endproducts (AGEs) in the tissues. AGEs may account for aberrant interactions between integrin receptors and their extracellular matrix ligands such as fibronectin (FN). In this study, we compared healing of experimental excisional skin wounds in wild-type (WT) and beta6 knockout (beta6(-/-) ) mice with streptozotocin-induced diabetes. Results showed that diabetic beta6(-/-) mice had a significant delay in early wound closure rate compared with diabetic WT mice, suggesting that alphavbeta6 integrin may serve as a protective role in re-epithelialization of diabetic wounds. To mimic the glycosylated wound matrix, we generated a methylglyoxal (MG)-glycated variant of FN. Keratinocytes utilized alphavbeta6 and beta1 integrins for spreading on both non-glycated and FN-MG, but their spreading was reduced on FN-MG. These findings indicated that glycation of FN and possibly other integrin ligands could hamper keratinocyte interactions with the provisional matrix proteins during re epithelialization of diabetic wounds. PMID- 20854471 TI - Expression of ezrin, Bcl-2, and Ki-67 in chondrosarcomas. AB - The aim of the present study was to investigate whether the expression of ezrin, a membrane-cytoskeleton linker and regulator of cellular signaling, is associated with clinical features of chondrosarcoma. For this purpose, we studied the expression of ezrin in 54 chondrosarcomas by immunohistochemistry and correlated the expression with other tumor characteristics, markers of proliferation, apoptosis and with clinical parameters. The intensity of ezrin staining increased with the histologic grade, and a significant positive association existed between the tumor grade and ezrin expression (p = 0.0475). In addition, there was a positive correlation between the expression of ezrin and Bcl-2, an anti-apoptotic protein (r = 0.83, p < 0.0001), as well as between ezrin expression and increased proliferation as measured by Ki-67 index (r = 0.70, p < 0.0001). The positive correlation of ezrin expression with Bcl-2 and Ki-67 as well as with tumor grade suggests that an aggressive behavior of chondrosarcoma may be related to activation of ezrin and that ezrin inhibitors could provide a much needed adjuvant therapy in chondrosarcomas. In conclusion, our results indicate that high ezrin expression correlates with aggressive features of chondrosarcomas. Further analyses on the pathways downstream of ezrin are warranted. PMID- 20854472 TI - Extramammary Paget's diseases in men from the Shanghai area: its association with PSA level increase. AB - The aim of this study was to determine the incidence of prostate cancer in patients with extramammary Paget's disease (EMPD). All cases of EMPD diagnosed between 1992 and 2007 in Shanghai Cancer Hospital were collected and analyzed for the incidence of prostate cancer. The median follow-up was 78 months. In total, 38 cases of invasive and 10 cases of in situ EMPD had been registered. A second malignancy was found in 28.9% (11/38) of patients with invasive EMPD and in 30% (3/10) of patients with in situ EMPD. Patients had an increased risk of developing a second cancer compared with the general population (standardized incidence ratio: 1.7; 95% confidence interval 1.2-2.4). Sixteen patients had serum prostate-specific antigen (PSA) level above 4 ng/mL; five developed prostate cancer, three of them with PSA levels beyond 100 ng/mL. The incidence of prostate cancer is 10.4% in this patient group. Patients with EMPD were more likely to have prostate cancer than the general population. Although the prognosis of EMPD is fairly good, a thorough search for a second tumor is recommended. PMID- 20854473 TI - Glycogen synthase kinase-3beta does not correlate with the expression and activity of beta-catenin in gastric cancer. AB - The regulation of beta-catenin activation by glycogen synthase kinase-3beta (GSK 3beta) in cancer has been shown to be cell type-specific. This study was performed to investigate the relationship between activated GSK-3beta (phosphorylated at Tyr216) and beta-catenin in gastric cancer. Immunohistochemical tissue array analysis of 278 human gastric carcinoma specimens showed positive immunoreactivity for activated GSK-3beta in 44% of the samples, whereas membranous beta-catenin and nuclear beta-catenin were observed in 19% and 20% of the samples, respectively. However, GSK-3beta activation was not correlated with the expression of either membranous beta-catenin or nuclear beta-catenin. Moreover, SNU gastric cancer cell lines over-expressing kinase dead GSK-3beta and the same cells treated with a GSK-3beta inhibitor showed that GSK 3beta inhibition did not alter either the protein expression or transcriptional activity of beta-catenin. In addition, GSK-3beta activation was positively correlated with the expressions of anti-adenomatous polyposis coli (p = 0.002), p16 (p < 0.001), p21 (p < 0.001), p27 (p = 0.001), and p53 (p = 0.013). On the other hand, the nuclear expression of beta-catenin was positively correlated with those of Bcl-2 (p = 0.025) and cyclin D1 (p = 0.043), but these expressions were not correlated with GSK-3beta activation. Thus, the GSK-3beta pathway seems to function in gastric cancer cells without involving the beta-catenin pathway. PMID- 20854474 TI - Increased expression of epidermal fatty acid-binding protein by alveolar macrophages during acute rejection of rat lungs. AB - In the lung, epidermal fatty acid-binding protein (E-FABP) is expressed by alveolar macrophages (AM) and alveolar epithelial cells type II (AEII). E-FABP may regulate macrophage activation and is involved in the metabolism of surfactant phospholipids. As macrophage activation and surfactant dysfunction are associated with rejection, we hypothesize that E-FABP expression is changed during acute rejection of pulmonary grafts. Orthotopic left lung transplantations were performed in the Dark Agouti to Lewis and in the isogeneic Lewis to Lewis rat strain combinations. E-FABP expression was analyzed in the lung by immunohistochemistry, immunoblotting and quantitative reverse transcription polymerase chain reaction (RT-PCR). Alveolar leukocytes obtained by bronchoalveolar lavage were analyzed by RT-PCR. Immunohistochemistry of isografts revealed strong E-FABP immunoreactivity in AEII and a moderate immunoreactivity in AM. In allografts undergoing acute rejection, AM exhibiting increased E-FABP immunoreactivity accumulated. Immunoblots revealed a single band at 15 kDa, which corresponds to the expected molecular mass of E-FABP. The levels of E-FABP mRNA were higher in allografts than in isografts and control lungs. Furthermore, alveolar leukocytes isolated by bronchoalveolar lavage from allografts displayed higher E-FABP mRNA expression levels than leukocytes from isografts and controls. In conclusion, we demonstrate for the first time upregulation of E-FABP expression in AM during severe inflammation. PMID- 20854475 TI - Prevalence and resistance patterns of extended-spectrum and AmpC beta-lactamase in Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Salmonella serovar Stanley in a Korean tertiary hospital. AB - A total of 100 clinical isolates of Escherichia coli (n = 35), Klebsiella pneumoniae (n = 63), Proteus mirabilis (n = 1), and Salmonella serovar Stanley (n = 1), showing resistance to cefoxitin, or returning positive in extended-spectrum beta-lactamase (ESBL) by Clinical and Laboratory Standards Institute (CLSI) ESBL confirmatory method, were studied. The isolates were examined by the boronic acid (BA) disk test, polymerase chain reaction, and pulsed-field gel electrophoresis (PFGE) to investigate genetic similarities. The concurrence rates for ESBLs by the CLSI and the BA disk test were 97% for E. coli and 96.7% for K. pneumoniae. A total of 41 isolates showing cefoxitin resistance yielded all positive by the BA disk test. All the 33 K. pneumoniae isolates, which showed positive by the BA disk test, were carrying AmpC genes. The TEM and CTX-M types were predominant in E. coli and the SHV and the CIT and/or DHA types were predominant in K. pneumoniae. PFGE analysis showed almost 75% of genetic similarities among K. pneumoniae isolates producing ESBLs and/or AmpC beta-lactamases (AmpCs) as each K. pneumoniae carried variable genes and showed variable antibiotic patterns. Clearly, the BA disk test was a useful method for the detection of ESBLs and AmpCs. In particular, cefoxitin resistance and BA-positive trait of K. pneumoniae do reflect the presence of AmpC genes in the organism. PMID- 20854476 TI - Bilateral intravesical ureterocele associated with unilateral partial duplication of the ureter and other anomalies: proposal of a new variant to the classification of ureterocles based on a perinatal autopsy, review of the literature and embryology. AB - The aims of this study were to demonstrate a case of bilateral intravesical ureterocele associated with megacystis and mega-ureters, unilateral partial duplication of the ureter and unilateral segmental renal dysplasia of the upper pole and an accessory spleen and to propose an addition of the new variant to the classification of ureteroceles. A perinatal necropsy was conducted on the 21-week fetus by employing the Rokitansky procedure with evisceration performed in blocks. The autopsy revealed the aforementioned abnormalities without cardiac or neural anomalies. The amniocentesis report was normal. Ureterocele is a saccular expansion of the distal ureter. It is most commonly observed in females and children and usually affects the upper moiety of a complete pyeloureteral duplication. Four types of ureteroceles are described: (A) ureterocele with single ureter (10%); (B) ureterocele with total duplication and intravesical development (10%); (C) ureterocele with total duplication and extravesical development (62%); and (D) ureterocele with ectopic ureter (3%). One case in a new born with bilateral intravesical ureterocele associated with hydrouretero nephrosis and hyperechogenic spots in kidneys has been reported, but bilateral intravesical ureterocele with unilateral incomplete pyeloureteral duplication has never been described in the literature. PMID- 20854477 TI - Glandular lesions of the urinary bladder:clinical significance and differential diagnosis. AB - A variety of glandular or pseudoglandular lesions may be seen in the urinary bladder, ranging from those that are entirely benign to aggressive-behaving malignant primary and secondary tumours. Lesions with minimal to no evident premalignant potential include several proliferative and reactive processes, such as cystitis cystica and cystitis glandularis, although the possibility exists for confusion of such lesions with an infiltrative neoplasm, particularly in limited biopsy specimens. Similarly, ectopic tissues of Mullerian origin may be seen occasionally in the urinary bladder and their differentiation from a true glandular neoplasm is important to avoid improper treatment. As urothelial carcinoma has a propensity for divergent differentiation, a wide spectrum of morphological variants exists with varying degrees of glandular differentiation. Some such variants have demonstrated clinical behaviour that is more aggressive than their histology would suggest, thus deserving recognition and potentially different treatment. In this paper, we review the glandular lesions of the urinary bladder ranging from benign proliferative processes to malignant primary and secondary neoplasms, with emphasis on clinical significance and features useful in resolving their differential diagnoses. PMID- 20854478 TI - Forest refugia revisited: nSSRs and cpDNA sequences support historical isolation in a wide-spread African tree with high colonization capacity, Milicia excelsa (Moraceae). AB - The impact of the Pleistocene climate oscillations on the structure of biodiversity in tropical regions remains poorly understood. In this study, the forest refuge theory is examined at the molecular level in Milicia excelsa, a dioecious tree with a continuous range throughout tropical Africa. Eight nuclear microsatellites (nSSRs) and two sequences and one microsatellite from chloroplast DNA (cpDNA) showed a deep divide between samples from Benin and those from Lower Guinea. This suggests that these populations were isolated in separate geographical regions, probably for several glacial cycles of the Pleistocene, and that the nuclear gene pools were not homogenized despite M. excelsa's wind pollination syndrome. The divide could also be related to seed dispersal patterns, which should be largely determined by the migration behaviour of M. excelsa's main seed disperser, the frugivorous bat Eidolon helvum. Within Lower Guinea, a north-south divide, observed with both marker types despite weak genetic structure (nSSRs: F(ST) = 0.035, cpDNA: G(ST) = 0.506), suggested the existence of separate Pleistocene refugia in Cameroon and the Gabon/Congo region. We inferred a pollen-to-seed dispersal distance ratio of c.1.8, consistent with wide-ranging gene dispersal by both wind and bats. Simulations in an Approximate Bayesian Computation framework suggested low nSSR and cpDNA mutation rates, but imprecise estimates of other demographic parameters, probably due to a substantial gene flow between the Lower Guinean gene pools. The decline of genetic diversity detected in some Gabonese populations could be a consequence of the relatively recent establishment of a closed canopy forest, which could negatively affect M. excelsa's reproductive system. PMID- 20854479 TI - PsOr1, a potential target for RNA interference-based pest management. AB - Insect pests cause billions of dollars in agricultural losses, and attempts to kill them have resulted in growing threats from insecticide resistance, dietary pesticide pollution and environmental destruction. New approaches to control refractory insect pests are therefore needed. The host-plant preferences of insect pests rely on olfaction and are mediated via a seven transmembrane-domain odorant receptor (Or) family. The present study reports the cloning and characterization of PsOr1, the first candidate member of the Or gene family from Phyllotreta striolata, a devastating beetle pest that causes damage worldwide. PsOr1 is remarkably well conserved with respect to other insect orthologues, including DmOr83b from Drosophila melanogaster. These insect orthologues form an essential non-conventional Or sub-family and may play an important and generalized role in insect olfaction. We designed double-stranded (ds) RNA directly against the PsOr1 gene and exploited RNA interference (RNAi) to control P. striolata. The chemotactic behavioural measurements showed that adult beetles were unable to sense the attractant or repellent odour stimulus after microinjection of dsRNA against PsOr1. Reverse Transcription (RT)-PCR analysis showed specific down-regulation of mRNA transcript levels for this gene. Furthermore, host-plant preference experiments confirmed that silencing PsOr1 by RNAi treatment impaired the host-plant preferences of P. striolata for cruciferous vegetables. These results demonstrate that this insect control approach of using RNAi to target PsOr1 and its orthologues might be effective in blocking host-plant-seeking behaviours in diverse insect pests. The results also support the theory that this unique receptor type plays an essential general role in insect olfaction. PMID- 20854480 TI - Expression of diverse midgut serine proteinases in the sericigenous Lepidoptera Antheraea assamensis (Helfer) is influenced by choice of host plant species. AB - Antheraea assamensis is reared on various species of the Lauraceae family from north-east India for its distinctive cocoon silk. We demonstrate differential expression of digestive trypsin and chymotrypsins in larvae feeding on a primary host, Persea bombycina Kosterm., in comparison to larvae feeding on Litsea monopetala Roxb. using in vitro proteolytic assays, zymogram analyses with proteinase inhibitors, restriction digestion of RNA-PCR amplicons and quantitative real-time PCR (RT-PCR). Eight novel members of the serine proteinase gene family were identified, including an intron-spliced trypsin (AaPb4) and seven putative chymotrypsins (AaPb2, AaPb4, AaPb12, AaLm4, AaLm6, AaLm19 and AaLm29). Midgut transcript levels of the putative trypsin were higher in larvae fed P. bombycina whereas levels of transcripts encoding putative chymotrypsins were higher in larvae reared on L. monopetala. Complex, differential expression of sequence divergent midgut serine proteinases may reflect the ability of lepidopteran larvae to feed on different species of host plants. Possible implications of host plant choice on the digestive physiology of A. assamensis are discussed. PMID- 20854481 TI - Functional test of the influence of Wolbachia genes on cytoplasmic incompatibility expression in Drosophila melanogaster. AB - Wolbachia are inherited intracellular bacteria that infect a broad range of invertebrate hosts. They commonly manipulate host reproduction in a variety of ways and thereby favour their invasion into host populations. While the biology of Wolbachia has been extensively studied at the ecological and phenotypic level, little is known about the molecular mechanisms underlying the interaction between Wolbachia and their hosts. Recent comparative genomics studies of Wolbachia strains have revealed putative candidate genes involved in the expression of cytoplasmic incompatibility (CI) in insects. However the functional testing of these genes is hindered by the lack of available genetic tools in Wolbachia. To circumvent this problem we generated transgenic Drosophila lines expressing various Wolbachia CI candidate genes under the control of the GAL4/UAS system in order to evaluate their possible role in Wolbachia-related phenotypes in Drosophila. The expression of a number of these genes in Drosophila melanogaster failed to mimic or alter CI phenotypes across a range of Wolbachia backgrounds or in the absence of Wolbachia. PMID- 20854483 TI - Working with children and families: occupational therapists contributing to national disability priorities. PMID- 20854482 TI - Differential transcription of two highly divergent gut-expressed Bm86 antigen gene homologues in the tick Rhipicephalus appendiculatus (Acari: Ixodida). AB - The transcriptional control of gene expression is not well documented in the Arthropoda. We describe transcriptional analysis of two exceptionally divergent homologues (Ra86) of the Bm86 gut antigen from Rhipicephalus appendiculatus. Bm86 forms the basis of a commercial vaccine for the control of Rhipicephalus (Boophilus) microplus. The R. appendiculatus Ra86 proteins contain 654 and 693 amino acids, with only 80% amino acid sequence identity. Reverse-transcription PCR of gut cDNA showed transcription of only one genotype in individual female ticks. PCR amplification of 3' untranslated sequences from genomic DNA indicated that both variants could be encoded within a single genome. When both variants were present, one of the two Ra86 genotypes was transcriptionally dominant. PMID- 20854484 TI - Conceptualising a modified system for classification of in-hand manipulation. AB - Occupational therapists consider in-hand manipulation (IHM) to be an important component of fine motor skills and to be related to handwriting and self-care proficiency. These relationships have not been well explored nor has the impact of intervention including IHM skill enhancement on proficiency in motor tasks. We propose that the existing conceptualisation of IHM may contribute to a dearth of evidence in this area. This paper closely examines the existing classification systems of IHM. We propose an adaptation of Exner's classification system which contains more discrete categories of IHM movements and includes: finger-to-palm translation to achieve stabilisation, palm-to-finger translation, simple shift, complex shift, simple rotation and complex rotation. Further research to test this modified classified system and to explore evidence for IHM intervention is warranted. PMID- 20854485 TI - Coaching parents to enable children's participation: an approach for working with parents and their children. AB - In this paper, Occupational Performance Coaching (OPC) is presented as a means whereby occupational therapists can support parents in achieving goals for themselves and their children. OPC is a coaching intervention that assists parents to recognise and implement social and physical environment changes that support more successful occupational performance for themselves and their children. OPC utilises collaborative problem-solving within a coaching relationship in which parents are guided towards identifying and implementing effective, autonomous solutions to occupational performance dilemmas. OPC is described in relation to the principles of contemporary practice; in particular that intervention is both family- and occupation-centred, and leads, as directly as possible, to the enablement of children's participation at home and in the community. Tentative empirical support for coaching parents draws on the supporting evidence for similar interventions in cognate disciplines. The unique features of OPC, namely, overt collaborative analysis of performance with parents and parent-initiated solution finding, are highlighted and their potential contributions to interventions currently employed by therapists are outlined. Recommendations are advanced as to how further research can support the adoption of this intervention strategy. PMID- 20854486 TI - The relationship between physical performance and self-perception in children with and without cerebral palsy. AB - AIM: This study examined the relationship between physical performance and perceived self-competence and global self-worth in children with and without spastic diplegia. METHOD: A matched-pairs design, including eight children with spastic diplegia and eight typically developing children, was used to compare the children's performance and to examine relationships. Children aged 7 to 11 years were assessed to determine their gross and fine motor abilities and they completed a modified version of the Harter Self-Perception Profile for Children. RESULTS: Children with diplegia performed at lower levels in all gross and fine motor assessments compared with children without diplegia. Self-perception was lower in children with diplegia in fine motor competence (P = 0.03) and global self-worth (P = 0.05). Clinically important differences (> 10%) in gross motor and athletic competence were also found. Positive correlations between physical performance assessments and some self-perception domains were present, although strength and direction of relationships differed for each group in some instances. CONCLUSION: This small study found that in addition to having reduced physical skills, children with spastic diplegia may experience a less positive global self-worth than typically developing children. These findings are in contrast to some previous research. Future research should examine the hypothesised relationship more definitively to determine whether improvement in physical skills results in a higher level of self-competence and consequently a higher global self-worth. This might further justify interventions aimed at improving fine and gross motor skills of children with cerebral palsy. Clinicians should be mindful of addressing both physical issues and self-worth with clients. PMID- 20854487 TI - Pretend play, social competence and involvement in children aged 5-7 years: the concurrent validity of the Child-Initiated Pretend Play Assessment. AB - BACKGROUND AND AIMS: The aims of this study were to investigate the relationship between pretend play, social competence and involvement in school-based activities in children aged 5-7 years and to determine whether children's social competence and level of involvement could be inferred from their scores on the Child-Initiated Pretend Play Assessment. PROCEDURE: The pretend play skills of 41 primary school-aged children aged 5-7 years were assessed on a one-on-one basis. Classroom teachers of the children assessed the children's social competence using the Penn Interactive Peer Play Scale and their involvement in school based activities using the Leuven Involvement Scale for Young Children. MAIN FINDINGS: Significant positive relationships were found between elaborate pretend play and object substitution scores, involvement scores and peer play interaction scores (P < 0.05, P < 0.01). A significant negative relationship was found between elaborate pretend play scores, and social disconnection and social disruption scores (P < 0.05). Play deficit indicators were significantly negatively related to involvement scores (P < 0.01). This suggests that children with proficient pretend play skills are socially competent with peers and are able to engage in classroom activity. Children who scored poorly on the play assessment were more likely to have difficulty interacting with their peers and engaging in school activities. CONCLUSION: Social competence and involvement skills are related to a child's ability to engage in pretend play. A child's social skills and ability to engage in school activities as assessed by teachers can be inferred from their scores on the Child-Initiated Pretend Play Assessment. PMID- 20854488 TI - Cognitive Orientation to (daily) Occupational Performance (CO-OP) with children with Asperger's syndrome who have motor-based occupational performance goals. AB - BACKGROUND/AIM: Motor difficulties associated with Asperger's syndrome (AS) are commonly reported, despite these not being diagnostically significant. Cognitive Orientation to daily Occupational Performance (CO-OP) is a verbal problem-solving intervention developed for use with children with developmental coordination disorder to address their motor-based difficulties. This paper reports on two case studies of children with AS illustrating the outcomes of CO-OP to address motor-based occupational performance goals. METHODS: A case study approach was used to document how two children with AS engaged in 10 weekly sessions of CO-OP addressing child-chosen motor-based occupational performance goals and the outcomes of this intervention. RESULTS: Pre and post-intervention assessment using the Canadian Occupational Performance Measure, Vineland Adaptive Behaviour Scales and the Performance Quality Rating Scale indicated that both children were able to engage in CO-OP intervention to successfully improve their occupational performance. CONCLUSIONS: Further research into the application of CO-OP with children with AS is warranted based on preliminary positive findings regarding the efficacy of this intervention to address motor-based performance difficulties in two children with AS. PMID- 20854489 TI - Occupational therapists prefer combining multiple intervention approaches for children with learning difficulties. AB - BACKGROUND/AIM: Research to date has not fully explored how occupational therapists provide intervention for children with learning difficulties in their day-to-day practice. The purpose of this study was to provide an in-depth description of the approaches and techniques used and how they are applied and combined to meet the complex and multifaceted needs of these children. METHODS: In-depth interviews and short questionnaires were completed by seven occupational therapists who had provided intervention to children with learning difficulties. Observations of therapy sessions were also conducted. Thematic analysis gained insight into the approaches and techniques therapists used and how these were applied in practice. RESULTS: Therapists use a wide range of approaches in various combinations because they feel that these best meet the needs of individual children. Sensory-based and cognitive approaches were most frequently drawn from and combined with other approaches such as visual information analysis, biomechanical and psychosocial approaches added for particular purposes. Approaches were usually combined simultaneously within an activity or session. CONCLUSIONS: Therapists create their own 'multimodel' approach in order to best meet the needs of their clients. They are able to articulate the theoretical basis behind these choices, although lack of clarity exists about the frames of reference being used. PMID- 20854490 TI - Paediatricots: Utilisation of an Australian list serve to support occupational therapists working with children. AB - BACKGROUND/AIM: The development of list serves has enabled occupational therapists working in a range of practice settings and geographical locations to share information and provide each other with professional support. The aim of this study was to gain insight into the nature of communications occurring on the Paediatricots list serve, and determine whether topics and issues raised were congruent with current practice trends for therapists working with children. METHODS: A content analysis was undertaken of all archived Paediatricots emails sent between 1 June 2003 and 31 May 2004, using the previous Yahoo paediatricots group. The group is now maintained by the NSW Department of Health. RESULTS: A total of 2104 postings were made to Paediatricots during the 12-month period. These postings addressed a wide range of issues; however, the majority were of a clinical nature related to day-to-day practice. The focus of these communications was mainly on the performance components of children's skills, with less emphasis on task demands, environmental factors and practice approaches. CONCLUSIONS: The variety of issues raised, coupled with high membership levels and reciprocity rates, suggests that Paediatricots is providing a valuable professional resource for occupational therapists. Members appear to predominantly utilise the list serve to address day-to-day practice issues, particularly concerning performance components impacting on children's occupations. The facility also served to support organisational and professional development needs. PMID- 20854491 TI - Editor's note - reporting of trials of non-pharmacological interventions. PMID- 20854492 TI - There was insufficient evidence to conclude that upper extremity casting was effective for individuals with central nervous system disorders. PMID- 20854493 TI - Preliminary evidence suggests that hand-arm bimanual intensive therapy (HABIT) improves bimanual upper limb performance in children with mild to moderate hemiplegic cerebral palsy. PMID- 20854494 TI - Occupational therapists should be more involved in the Cochrane Collaboration. PMID- 20854495 TI - Mental health needs post-disaster: Supporting recovery of children and families. PMID- 20854496 TI - The challenge of interdisciplinary collaboration in acute psychiatry: Impacts on the occupational milieu. AB - This paper, based on a larger ethnographic exploration of the acute inpatient environment for older people with mental illness, describes and provides interpretations of staff perceptions and actions in order to highlight tensions between professional groups which adversely affect opportunities for patients to engage in meaningful occupations. Fieldwork conducted in 1999-2000, supplemented by 20 in-depth interviews with a range of mental health professionals, provides the foundation for suggesting that the extent and nature of occupational engagement is significantly impacted by interdisciplinary relations. The skill of occupational therapists to collaborate with their nursing colleagues in a socially complex environment, and the importance of personal leadership skills among our new graduates are discussed. PMID- 20854497 TI - Using the assessment of motor and process skills to measure functional change in adults with severe traumatic brain injury: A pilot study. AB - AIM: To measure functional change in 10 adults following severe traumatic brain injury using the Assessment of Motor and Process Skills (AMPS). METHODS: This clinical pilot study used a standardised occupational therapy tool, the AMPS, to measure motor and process scores during activities of daily living, for over 3 weeks of inpatient rehabilitation. RESULTS: Wilcoxon signed ranks tests indicate significant improvement in motor and process scores from initial assessment to repeat evaluation (z = -2.70, p = 0.01; z = -2.81, P = 0.01, respectively). CONCLUSIONS: The AMPS measured statistically and clinically significant change in motor and process abilities over 3 weeks of neurosurgical rehabilitation. Findings suggest that the AMPS is a sensitive measure of functional change for the study sample and timeframe. PMID- 20854498 TI - Learning from the past, looking to the future: Exploring our place with Indigenous Australians. AB - This paper aims to explore ways in which we as occupational therapists in Australia can participate in enabling a different and better future for all Australians. In doing so, it is necessary to explore our history and our cultures, both individually and collectively as a profession, and to understand the ways in which these shape who we are and what we do. As occupational therapists, we have valuable knowledge and skills that have the potential to contribute in a positive way to the health and educational outcomes of Indigenous Australians. As a profession operating in Australia, we also have a responsibility to reach this potential. This paper aims to present some of these contributions and to provide examples of practical and culturally safe ways in which we can take action. PMID- 20854499 TI - Cognitive strategy use by children with Asperger's syndrome during intervention for motor-based goals. AB - BACKGROUND: Cognitive Orientation for (daily) Occupational Performance (CO-OP) is a cognitive approach utilised by occupational therapists to help guide children in the discovery of appropriate strategies for effective task performance through a structured problem-solving process. There has been limited research into its utility for children with Asperger's syndrome (AS). These children often present with motor difficulties, although these are not required for diagnosis of the syndrome. A recent study found that children with AS were able to use the CO-OP framework to enhance their performance of motor-based goals. METHODS: This paper presents two case studies demonstrating the use of CO-OP with children with AS, and explores the global and domain-specific strategies and types of guidance utilised to improve their task performance. Two children with AS, aged 9 and 11, with above average intellectual ability, engaged in 10 sessions of CO-OP. All sessions were videotaped. One hundred minutes of randomly selected footage were coded per child using the Observer Software Package version 5.0. RESULTS: The mean interrater agreement for the two children was 94.06% and 89.30%. Both children (i) utilised the global strategies 'do', followed by 'plan' and 'check', (ii) used at least three domain-specific strategies in each session with 'task specification/modification' and 'body position' utilised most, and (iii) used limited verbal self-guidance. CONCLUSION: These two children with AS were able to utilise cognitive strategies to effectively solve their motor performance problems. Children with AS and those with DCD used similar strategies to achieve motor goals. CO-OP appears to have potential as an effective intervention for children with AS. Study limitations, clinical implications and directions for future research are discussed. PMID- 20854500 TI - Occupational therapists' perception of their practice: A phenomenological study. AB - BACKGROUND: International literature seems consistent in reporting that occupational therapists value their methods. However, little empirical evidence has been generated supporting the basic system of belief for occupational therapy. Few studies have explored the nature of the occupational therapists' experiences and thoughts about their use of occupation as means and ends, and which strategies they use to implement their tools in their current practice. Accordingly, the aim of this study was to explore how occupational therapists understood and presented their practice and interventions. METHODS: A sample of six occupational therapists graduated in different decades, from diverse client populations and health-care settings was selected to participate in a semistructured interview. RESULTS: Three main themes were developed: 'To make the client's potentials visible', 'reaching a position one values' and 'looking with other eyes'. Whatever their specialities, the participants were unanimous in the way they described their role. Their common focus was 'activities of daily living'. However, they had problems describing their therapeutic tools, and were not able to clearly articulate the 'common sense aspects' of their own methods. The participants were engaged in constructing their professional identities, and stressed the need to construct professional boundaries relevant to their particular work. CONCLUSION: The occupational therapists perceived their practice and interventions as distinctly different from other team members, thus, they provided a 'counterpoint'. The participants used various ways of marketing their perspectives. While the novices tended to go along with the team, the experienced therapists tended to assert their own special contribution. PMID- 20854501 TI - A case study of occupational therapy managers in NSW: Roles, responsibilities and work satisfaction. AB - BACKGROUND: Job satisfaction has been shown to affect levels of staff retention and productivity, but few studies have been conducted on the work of occupational therapy managers and their job satisfaction. This study explores the roles and responsibilities of occupational therapy managers who are clinician-managers or manager-administrators, and sources of their work satisfaction. METHODS: A collective case study involved telephone interviews with 16 occupational therapy managers. Semistructured interview questions were based on an earlier discussion with a separate group of occupational therapy managers. Interview transcripts were analysed for emerging themes. RESULTS: There were no clear differences in the roles and responsibilities of the two types of managers (manager administrators and clinician-managers); however, manager-administrators tended to be responsible for larger numbers of staff. Managers reported that taking a clinical caseload is often at their own discretion. A common challenge for managers is the balancing of priorities as a clinician and a manager. Managing people was a common source of joy and sometimes a source of frustration. Mediating between staff and senior management and the need for budget control and efficiencies was an important aspect of managers' work, as was their autonomy to make decisions. CONCLUSIONS: Occupational therapy managers assume responsibilities consistent with clinician managers across disciplines. The main sources of work satisfaction related to people management particularly when staff were working effectively as a team and there was respect from senior management. Further research will confirm whether there are no obvious differences between clinician-manager and manager-administrators, and whether there are clear differences in work-related frustration across sectors. PMID- 20854502 TI - Interrater reliability of the Personal Care Participation Assessment and Resource Tool (PC-PART) in a rehabilitation setting. AB - BACKGROUND: The Personal Care Participation Assessment and Resource Tool (PC PART), formerly the Handicap Assessment and Resource Tool (HART), assesses the domains of clothing, hygiene, nutrition, mobility, safety, residence and supports. AIM: To examine the interrater reliability of the PC-PART in a rehabilitation setting. METHODS: Assessments made by the researcher were compared to the interdisciplinary rehabilitation team. The research and standard assessments occurred within three working days. Raters were blind to each other's scores. Sample participants were a consecutive case-series of rehabilitation clients with varied diagnoses, activity limitations and participation restrictions. Of 66 consecutive patients seen during the a priori determined enrolment period, 25 were included in the study (nine males and 16 females, aged 44-85 years). The remaining 41 patients did not meet the inclusion criteria. CONCLUSION: The PC-PART has good interrater reliability. Clinicians, administrators and researchers can be reassured about this aspect of the validity of the tool. PMID- 20854503 TI - Why occupational therapy needs evidence of participation in continuing professional development. PMID- 20854504 TI - Focussed, comprehensive home visits prevent falling when targeted to specific groups of older people at high risk of falls. PMID- 20854505 TI - A nurse-led program of functional activities did not reduce falls, improve quality of life nor improve function for people living in residential care. PMID- 20854507 TI - Interpreting research evidence to support clinical practice. PMID- 20854506 TI - Scholarly communication and concerns for our conferences. PMID- 20854508 TI - Reliability reconsidered: Cronbach's alpha and paediatric assessment in occupational therapy. AB - BACKGROUND/AIM: Using reliable outcome measures is a necessity for the occupational therapy profession in enabling valid assessments of clients. Although Cronbach's alpha is the most widely applied index of internal consistency reliability, there are misconceptions about its use and interpretation. This paper aims to guide assessment developers in paediatric occupational therapy, as well as practitioners who are evaluating outcome measures in using and interpreting the Cronbach's alpha estimates appropriately. This will enable them to decide on the tools' clinical value and incorporate them into their practice with children. METHOD: Previously published papers reporting on internal consistency issues of outcome measures in paediatric occupational therapy were searched through the Allied and Complementary Medicine database. These papers were used as a basis to discuss possible reasons for reporting of low internal consistency. RESULTS: The analysis demonstrates that Cronbach's alpha reports are not always interpreted in a sound way. The paper emphasises that one should be cautious about judging estimates of internal consistency. Low size of the coefficient alpha might not always indicate problems with the construction of the tool; whereas large sizes do not always suggest adequate reliability. Instead, these reports might be related to the data characteristics of the construct. CONCLUSION: In judging an outcome measure's internal consistency, researchers and practitioners in occupational therapy should report and consider the nature of data, the scale's length and width, the linearity and the normality of response distribution, the central response tendency, the sample response variability and the sample size. PMID- 20854509 TI - Identification of occupational therapy clinical expertise: decision-making characteristics. AB - BACKGROUND: Experts are usually determined on the basis of length of experience, reputation, peer acknowledgement, and certification. While these characteristics are important they may, however, not be sufficient for this purpose. Another method for determining clinical expertise is to look at how individuals make decisions in their area of expertise. This study aims to identify clinician expertise on the basis of participants' decision performance and examines this in relation to their length of experience and type of decision-making. METHODS: The Cochran-Weiss-Shanteau (CWS) is a statistical method that can be used to examine individuals' expertise on the basis of how they discriminate between hypothetical cases and consistency in their decision-making. Participants comprised 18 occupational therapists, each with more than 5 years of experience working with children with cerebral palsy. They were required to make treatment judgements for 110 cases (20 of which were repeated) of children with cerebral palsy. The CWS was calculated for each participant. RESULTS AND CONCLUSIONS: Two groups of participants were identified on the basis of their CWS index--one with both high consistency in decision-making and the ability to discriminate between cases, the other with low consistency and poor discrimination. These two groups did not differ significantly on the basis of length of experience or work setting but did differ on the basis of intervention chosen and their type of decision-making. The CWS method seems to offer promise as a means of determining clinical expertise on the basis of clinical decision-making. Its application to the investigation of clinical reasoning and education is discussed. PMID- 20854510 TI - The Tree Theme Method as an intervention in psychosocial occupational therapy: client acceptability and outcomes. AB - BACKGROUND/AIM: The Tree Theme Method (TTM) is an intervention in which the client paints trees representing certain periods in his/her life. The intervention comprises five sessions, using trees as a starting point to tell one's life story. This study, which is part of an implementation project, aimed to examine the therapeutic alliance and client satisfaction, in relation to perceptions of everyday occupations and health-related factors, with clients going through a TTM intervention. METHODS: Nine occupational therapists recruited 35 clients, at general outpatient mental health care units, for the TTM intervention. Self-rating instruments, targeting therapeutic alliance (HAq-II), different aspects of daily occupations (Canadian Occupational Performance Measure, Satisfaction with Daily Occupations), health-related factors (Sense of Coherence measure, Mastery Scale, Symptom Checklist-90-R) and client satisfaction (Client Satisfaction Questionnaire), were administrated before and after the intervention. RESULTS: A good initial therapeutic alliance, experienced by both therapists and clients, was correlated to increased changes regarding occupational performance and self-mastery. According to the therapists' ratings, a good initial therapeutic alliance was correlated to increased sense of coherence and a decreased level of psychiatric symptoms. The results showed positive significant changes in occupational performance and health-related factors. High ratings of the therapeutic alliance by the therapists were also related to high client satisfaction. CONCLUSIONS: The TTM seemed to function well in psychosocial occupational therapy, but there is a need for further implementation studies to deepen our understanding of the treatment process, comprising both technique and formation of the therapeutic alliance. PMID- 20854511 TI - Comparison of time use, role participation and life satisfaction of older people after stroke with a sample without stroke. AB - BACKGROUND/AIMS: This study investigated the time use, role participation and life satisfaction of older Australians (aged 65 years and older) who were 1-3 years post-stroke and living in the community. The results of this study were compared with a published study on the time use, role participation and life satisfaction of older Australians who had not experienced stroke. METHODS: Twenty-three participants with stroke (mean age 74.2 years, 69.6% men) were interviewed using measures of time use, role participation and life satisfaction. RESULTS: Participants with stroke spent most of their time in sleep (7.2 h/day), solitary leisure (7.0 h/day), social leisure (3.0 h/day), and basic activities of daily living (2.9 h/day). Compared to the sample without stroke, participants with stroke spent significantly less time in sleep, instrumental activities of daily living, and volunteer work, and significantly more time at home, with others, and engaged in solitary leisure. Similar to the sample without stroke, the most common roles for participants with stroke were family member, friend, and home maintainer. Participants with stroke engaged in fewer roles than participants without stroke. Unlike the sample without stroke, role loss was not correlated with life satisfaction for participants with stroke; however, having more roles was correlated with greater life satisfaction. CONCLUSION: Experiencing a stroke can affect the configuration of older people's time use and reduce their role participation. Facilitation of older people's role participation after stroke may enhance their life satisfaction. PMID- 20854512 TI - Use of the Perceive, Recall, Plan and Perform System of Task Analysis for persons with schizophrenia: a preliminary study. AB - BACKGROUND/AIM: Task analysis that targets information processing skills is an essential tool to understanding difficulties encountered by people with schizophrenia in their daily activities. The purpose of this preliminary study was to explore the use of the Perceive, Recall, Plan and Perform (PRPP) System of Task Analysis for this clientele. The specific objectives were to describe information processing difficulties as measured by the PRPP and to examine preliminary evidence of construct validity and interrater reliability. METHODS: In the first part of this study, 10 participants with schizophrenia living in the community were assessed using the PRPP during both a simple and a complex meal preparation task. Community functioning was measured using the Independent Living Skills Survey. In the second part, interrater reliability was appraised using three trained raters, who scored 15 participants preparing the complex meal preparation task. RESULTS: Analysis of performance demonstrates that people with schizophrenia have difficulties especially in the Perceive and Plan quadrants of the PRPP and are more challenged in the complex task. The PRPP total score for the complex task is strongly related to the community functioning score. Results indicate good interrater reliability for the PRPP total score and moderate interrater reliability for the quadrant scores. CONCLUSION: Despite the small sample size, results from this preliminary study support the use of the PRPP System of Task Analysis to further explore the impact cognitive deficits have on daily task performance and thus on community functioning in people with schizophrenia. PMID- 20854513 TI - The DriveABLE Competence Screen as a predictor of on-road driving in a clinical sample. AB - BACKGROUND/AIM: There is growing concern regarding the need for screening of older drivers. The objective of this study was to determine whether the DriveABLE Competence Screen, a computerised test, predicts on-road driving outcome in clients referred for a driving assessment. METHODS: This retrospective study evaluated the predictive validity of pre-road testing using the DriveABLE Screen. Fifty-two clients with varying health conditions were consecutively referred to a private practice that conducts comprehensive driving evaluations. Screen results are classified as recommend cessation of driving, indeterminate (requires on-road evaluation), or no evidence of reduced competence. The DriveABLE Road Test classifies subjects as pass, borderline pass, or fail. RESULTS: Sensitivity, specificity, positive and negative predictive values were generated using the Road Test as the criterion outcome. The positive predictive validity of the Screen in identifying those who would fail the Road Test was 97% (n= 32 of 33). The negative predictive validity was 47%. The sensitivity was 76% with a corresponding specificity of 90%. CONCLUSION: The DriveABLE Screen, when used as a case finding tool, is highly predictive of clients who will fail an on-road driving evaluation. PMID- 20854514 TI - Questioning: a critical skill in postmodern health-care service delivery. AB - Occupational therapists can no longer rely exclusively on biomedical frameworks to guide their practice and facilitate clinical problem-solving. A postmodernist perspective of health and well-being underlines that the illness experience is not a linear, cause-and-effect equation. Rather, life experiences are constructed through a myriad of social, cultural, physical and economic contexts that are highly unique to each individual. In other words, the assumption that 'one-size fits-all' is as flawed in health care as it is in clothing design. This paper contributes to the growing discussion of health care within the postmodern context of the twenty-first century through first presenting a brief discussion of emerging postmodern thinking and application within the profession, followed by a rationale for the need to scrutinise prevalent modernist assumptions that guide decision-making. Finally, the paper introduces the method of Socratic questioning as a critical tool in successfully carrying out this scrutiny in an empowering and respectful manner for all stakeholders. PMID- 20854515 TI - Use of a night-time hand positioning splint reduced pain, improved grip and pinch strength, upper limb function and functional status in patients with rheumatoid arthritis. PMID- 20854516 TI - Static resting splints in early rheumatoid arthritis were not effective in improving grip strength, ulnar deviation, dexterity, hand function or pain. PMID- 20854517 TI - Response to 'Scholarly communication and concerns for our conferences'. PMID- 20854518 TI - Further concerns for occupational therapy conferences. PMID- 20854522 TI - Profile of cognitive problems in schizophrenia and implications for vocational functioning. AB - AIM: This literature review attempts to profile specific areas of cognition that have shown unique and consistent evidence of dysfunction among people with schizophrenia. In addition, their impact on vocational functioning is illustrated, so as to highlight the importance of managing these cognitive difficulties in vocational rehabilitation. METHODS: Literature search was carried out on seven key cognitive domains identified by the National Institute of Mental Health in the USA. Their impact on vocational function was also reviewed. RESULTS: It is found that attention, declarative and working memory, reasoning, problem-solving and social cognition are areas of impairment that have great impact on vocational functioning. Attention and memory problems affect learning of new work tasks. Executive function is particularly crucial in determining supported and open employment outcomes, as executive dysfunction cannot be easily compensated. Lastly, social cognition plays a major role in determining the success of workplace social exchanges. CONCLUSION: Occupational therapists need to have a good understanding of the profile of cognitive problems among people with schizophrenia, in order to tailor our intervention according to their cognitive strengths and difficulties. Several cognitive remediation strategies and programs have been designed specifically for people with mental illness. Equipping ourselves with skills in conducting such programs will augment our expertise in vocational rehabilitation. PMID- 20854523 TI - Employer-sponsored occupational therapy professional development in a multicampus facility: a quality project. AB - AIM: To critically assess and develop recommendations for professional development (PD) for occupational therapists in a multisite specialist cerebral palsy occupational therapy service. METHOD: Quality improvement project based on principles of participatory action research: audit of PD resources/activity; stakeholder consultations and literature review. RESULTS: The PD program goal, resources, strategies, activities and evaluations conducted at the centre were identified and described. Areas for improvement were identified by critically considering the PD program in the context of reviewed literature. There was an assumption that personal change through PD would help attain the organisational goal of clinically competent practitioners who use evidence-based practice in a family-centred context. RECOMMENDATIONS: Future PD plans and evaluations need to explicitly address this assumption. The use of structured reflection and the 'clinical reasoning' conceptual framework was recommended as one way to help personal change from PD to have workplace impact. This project provides a precedent and guide to occupational therapy PD planners regarding a whole-of organisation approach to developing and maintaining competence through PD. PMID- 20854524 TI - Governing the Majority World? Critical reflections on the role of occupation technology in international contexts. AB - BACKGROUND: Within occupational therapy, increasing attention has been focussed on international development work. However, many have critiqued the focus of knowledge development within occupational therapy and occupational science, arguing that it is focussed on Western values. Questions arise about how occupational therapy and occupational science, and the knowledge and therapeutic technologies that are associated with these communities, will affect the 'developing' world, which, recently, some have described as the Majority World. AIM AND METHOD: Using Foucauldian analytical tools, this paper reflects on specific discourses that are foundational for development work. Specifically, this paper attempts to better understand how concepts like 'occupational justice' and the 'occupational being' are presented in the literature and relate to practices in international contexts. Within this analysis, attention is focussed on how practices associated with occupational development work might also be enmeshed in power dynamics. RESULTS: This paper outlines how occupational discourses may shape and order life in particular ways and challenges researchers and practitioners to develop a better understanding of how power can operate through occupational discourses and occupational therapy practices. This paper also adds to the literature through the interpretation and explication of various theories that may underpin work in international contexts. CONCLUSIONS/FUTURE DIRECTIONS: Suggestions for future directions that will enable the development of more politically and culturally sensitive knowledge and practices are also explored. It is crucial that as a community we become more aware of how our theoretical frameworks may impact and shape practice. PMID- 20854525 TI - Knowledge generation and utilisation in occupational therapy: towards epistemic reflexivity. AB - AIM: The purpose of this article is to consider the ways in which theory generation, and hence knowledge generation, in occupational therapy is a complex social process, and therefore carries (often hidden) responsibilities for those who are part of our epistemic community. An epistemic community is a knowledge producing community, who apply their standards of credibility, and epistemic values, to theory choice. In occupational therapy this community is comprised of a worldwide group of scholars and practitioners. METHODS: We propose that epistemic reflexivity can be used to critique and contribute to our disciplinary knowledge and to critically consider 'who' makes epistemological choices in our profession, and the consequent implications for the theories we adopt. The purpose of this article is to make these relations explicit so that scholars and therapists can become increasingly conscious and empowered with respect to their contributions to occupational therapy's epistemic community. To demonstrate an application of epistemic reflexivity, we critically consider a theoretical construction that has been widely adopted by the international occupational therapy community: evidence-based practice. RESULTS: As authors, we engage in epistemic reflexivity to critically consider the challenge posed by evidence based practice. We propose a conception of practice knowledge that is informed by evidence yet based on a conception of wise practice. CONCLUSION: Our intention is to stimulate discussion and debate in occupational therapy's epistemic community, a number of approaches for fostering epistemic reflexivity in occupational therapy are suggested. PMID- 20854526 TI - Movement skills proficiency and physical activity: a case for Engaging and Coaching for Health (EACH)-Child. AB - BACKGROUND/AIM: Supporting children's participation in health-enhancing physical activities is an important occupational goal for therapists. Fundamental movement skills (FMS) are thought to underpin and enable many activity options. This study had two goals: first, to examine the relationship between fundamental movement skills (FMS) and physical activity, and second, to use this and existing evidence to inform strategies whereby children's motivation for and engagement in physical activity can be supported. METHODS: A cross-sectional investigation of 124 children, aged 6-12 years, was undertaken. FMS were assessed using the Movement Assessment Battery for Children (M-ABC) and physical activity by pedometer step counts. RESULTS: A weak but significant association was found between weekend physical activity and balance skills for girls. Correlations between physical activity and ball skills or manual dexterity were not significant for either gender, however, having age appropriate ball skills did result in greater but not significant levels of physical activity for all children when grouped together. CONCLUSIONS: Findings from this study question the magnitude of the relationship between children's FMS and physical activity as measured by pedometers. If the goal of health enhancement through physical activity engagement is to be realised, it is proposed that community, occupation-based approaches may offer more potential than skills-based interventions at increasing activity participation. The concept of Engaging and Coaching for Health (EACH)-Child is introduced to this end. Occupational therapists are encouraged to work collaboratively with school and community organisations to assist children to find the physical activities that best accommodate their interests, abilities and offer opportunities for lifelong engagement. PMID- 20854527 TI - Belonging to a community-based football team: an ethnographic study. AB - PURPOSE: This study considered the benefits derived from participation in a community-based Australian Rules Football league in Melbourne, Australia. The RecLink league deliberately tackles the social and occupational disadvantages associated with mental illness, addictions, unemployment and homelessness. METHODS: An ethnographic methodology was used to study one team from the RecLink football league throughout an entire season. Fieldnotes were written following participant observation at training, games and events, and five in-depth interviews were conducted and transcribed. A constant comparative approach to data analysis was adopted. RESULTS: Three major themes were identified: a spirit of inclusion, team-building and meaning of team involvement. The first describes how members were accepted, welcomed and given the opportunity for team involvement, with the expectation that they 'had a go', and 'tried their best'. The second illustrates how the team collectively fostered a culture of friendship, cooperation and support. The third examines the significance of being part of the team, incorporating personal contributions and gains, and meanings attributed to team involvement. CONCLUSIONS: These findings demonstrated how football can be used as non-clinical, community-based occupational therapy: enabling participation in a personally meaningful and culturally valued occupation. Occupational therapists are challenged to explore further how such community-based sports programs may complement existing clinical and welfare based approaches to social disadvantage. PMID- 20854528 TI - Clinical reasoning in neurology: use of the repertory grid technique to investigate the reasoning of an experienced occupational therapist. AB - BACKGROUND/AIM: The aim of this paper is to describe the use of a structured interview methodology, the repertory grid technique, for investigating the clinical reasoning of an experienced occupational therapist in the domain of upper limb hypertonia as a result of brain injury. METHOD: Repertory grid interviews were completed before and after exposure to a protocol designed to guide clinical reasoning and decision-making in relation to upper limb neurological rehabilitation. Data were subjected to both qualitative and quantitative analyses. RESULTS: Qualitative analysis focussed on clinical reasoning content. Common themes across the pre- and post-exposure interviews were the use of theoretical frameworks and practice models, the significance of clinical expertise, and discrimination of 'broad' and 'specific' aspects, as well as differentiation between 'therapist and client-related' aspects of the clinical situation. Quantitative analysis indicated that for both pre- and post-exposure repertory grids, clinical reasoning was structured in terms of two main concepts. In the pre-exposure grid, these were related to the therapist's role, and to the 'scope' of practice tasks (either broad or specific). In the post-exposure grid the two main concepts were upper limb performance, and client-centred aspects of the therapy process. CONCLUSIONS: The repertory grid technique is proposed as an effective tool for exploring occupational therapy clinical reasoning, based on its capacity for accessing personal frames of reference, and elucidating both the meaning and the structure supporting clinical reasoning. PMID- 20854529 TI - Introducing attachment theory to occupational therapy. PMID- 20854530 TI - Students with mild disabilities demonstrate lower quality of schoolwork performance as measured by the School AMPS compared to typically developing students. PMID- 20854531 TI - The Assisting Hand Assessment is a reliable and valid measure of assessing hand function for children with hemiplegic cerebral palsy and obstetric brachial plexus palsy. PMID- 20854532 TI - Coaching parents; enabling participation. PMID- 20854535 TI - Evaluation of an employment program for people with mental illness using the Supported Employment Fidelity Scale. AB - BACKGROUND: The Individual Placement and Support (IPS) model aims to achieve open employment for people with mental illness. The Supported Employment Fidelity Scale (SEFS) is a 15-item instrument that evaluates the extent to which a service follows the IPS principles of best practice. This paper describes the IPS model and an evaluation of a specialist employment program for people with mental illness using the SEFS. METHODS: The SEFS enabled a quantitative assessment of service provision against the criteria of evidence-based practice principles. Data were collected from multiple sources. In addition, a literature review was conducted, and personnel engaged in implementation of the IPS model at other Australian employment programs were consulted. RESULTS: The program achieved a score of 59 of a possible 75 on the SEFS, which is described as fair supported employment. DISCUSSION: Analysis of the 15-scale items resulted in the identification of strengths, areas for further development, and a set of recommendations. CONCLUSIONS: The program was operating substantially in line with evidence-based practice principles and had considerable scope for further development. Issues arising from the evaluation, areas of applicability of the SEFS and the underlying literature, and implications for occupational therapy are highlighted. PMID- 20854536 TI - Reliability of the Perceive, Recall, Plan and Perform System of Task Analysis: a criterion-referenced assessment. AB - OBJECTIVE: To conduct preliminary examination of the rater and test-reliability of the Perceive, Recall, Plan and Perform (PRPP) System of Task Analysis, an ecological measure designed to assess task-embedded information processing capacity during occupational therapy assessment of confused and agitated adults following traumatic brain injury. METHODS: Occupational therapists observed and scored client performance using the PRPP System of Task Analysis. Correlational analysis and measures of agreement were performed to determine interrater and intrarater reliability. Test procedures were examined for reliability and internal consistency. RESULTS: Interrater and test reliability considered three factors: therapists, clients and tasks. A moderate level of interrater reliability was achieved between trained therapists (intraclass correlation coefficient (ICC) = 0.60). Test procedures were highly reliable (ICC = 0.88). Across two measurement occasions, therapists showed a tendency towards harder rating on the second test occasion (-4.5%; 95% confidence interval for: -10.67% > 3.17%). CONCLUSION: The findings of this study support the use of criterion referenced tests in the area of occupational performance measurement. Occupational therapists achieved moderate interrater reliability when measuring the performance of adults with brain injury on various activities of daily living. Test procedures were found to be highly reliable in measuring the occupational performance of adults demonstrating confusion and agitation typical to the stage of post-traumatic amnesia following head injury. PMID- 20854537 TI - Assessment of need and capacity to benefit for people with a disability requiring aids, appliances and equipment. AB - AIM: To develop an equitable system for allocating equipment, aids and appliances to adults with disabilities based on assessment of need and capacity to benefit for use by occupational therapists, who are the main professional group involved in assessing and prioritising applications. METHODS: An assessment tool was developed, pilot tested and field tested at four sites in New South Wales. Assessments were undertaken in parallel with existing systems. Feedback on use of the tool was obtained from those conducting the assessments and those making decisions to fund applications for equipment based on the assessments. RESULTS: One hundred and six assessments were undertaken. Applications for bed, sleeping and seating equipment and equipment to assist with mobility, toileting, showering and transfers accounted for 94.2% of equipment requested. Provision of equipment was expected to have greatest impact on the physical effort and safety of carers and the safety and quality of life of applicants. Regression analysis identified assessment items that explain variation between applicants and that can avoid unnecessary data collection. CONCLUSIONS: The assessment tool provides a standardised method for assessing requests for equipment based on the twin concepts of need and capacity to benefit. The results support the use of both concepts as the foundation of the assessment process. Further development is required, particularly to move to the next stage of using the assessment tool as the basis for prioritising applications for equipment. PMID- 20854538 TI - Management of patients with cognitive impairment after stroke: a survey of Australian occupational therapists. AB - BACKGROUND/AIM: Cognitive impairment is a common and often debilitating consequence of stroke. The current practice patterns of Australian occupational therapists who work in this area are not clearly known. The aim of this study was to investigate the theoretical approaches, assessments, interventions and research evidence used by Australian occupational therapists who work with patients who have cognitive impairment poststroke. METHODS: A self-administered, purpose-designed online survey was used. RESULTS: Survey responses were received from 102 occupational therapists. The client-centred approach was the most commonly used theoretical approach, with 81.3% and 72% using it often or all of the time with inpatients and outpatients, respectively. Assessments that were most frequently used were the Mini Mental State Examination (63.7% of participants), the Lowenstein Occupational Therapy Cognitive Assessment (45.1%), the Functional Independence Measure (57.8%, and the Assessment of Living Skills and Resources (10.0%). Interventions involving functional activities were used more frequently than compensatory techniques, such as diaries, alarms, or other electronic devices, and paper and pencil remedial exercises. Few (16%) participants used computer programs specifically designed for cognitive rehabilitation. Although 60.8% of the participants reported using research literature when making decisions about interventions, a higher percentage reported relying on their past experience (88.3%) and colleagues' opinions (77.4%). CONCLUSION: This study provides an insight into the current practices of Australian occupational therapists who work with people who have cognitive impairment after stroke. Client-centredness is emphasised in current practice; however, the use of research evidence to inform practice appears to be limited. PMID- 20854539 TI - A model for play-based intervention for children with ADHD. AB - BACKGROUND/AIM: The importance of play in the social development of children is undisputed. Even though children with attention-deficit hyperactivity disorder (ADHD) experience serious social problems, there is limited research on their play. By integrating literature on ADHD with literature on play, we can postulate how play is influenced by the characteristics of ADHD. These postulations enabled us to propose a theoretical model (proposed model) to depict the interactive process between the characteristics of ADHD and factors that promote play. This paper presents the revised model and principles for intervention based on the results of a study investigating the play of children with ADHD (reported elsewhere). METHODS: We tested the proposed model in a study comparing two groups of children (n = 350) between the ages of 5 and 11 years. One group consisted of children diagnosed with ADHD (n = 112) paired with playmates (n = 112) who were typically developing; the control group consisted of typically developing children paired with typically developing playmates (n = 126). The Test of Playfulness was administered, and the model was revised in line with the findings. RESULTS AND CONCLUSIONS: The findings suggest difficulties in the social play and lack of interpersonal empathy in the play of children with ADHD. We draw on the revised model to propose preliminary principles for play-based interventions for children with ADHD. The principles emphasise the importance of capturing the motivation of children with ADHD, counteracting the effects of lack of interpersonal empathy, and considerations for including playmates in the intervention process. PMID- 20854540 TI - From student to therapist: follow up of a first cohort of Bachelor of Occupational Therapy students. AB - AIM: This study aimed to investigate the perception of graduate students on their preparation for practice, at 7 months post graduation. METHOD: Using an anonymous postal questionnaire, 18 respondents (58% response rate) provided data on the nature of current employment, the experience as a graduate therapist, and perceptions of their undergraduate experience in preparing them for practice. RESULTS: Fifty percent of the respondents were practising in a rural environment. There was a significant positive relationship between respondents perception of their curriculum and fieldwork experiences and their preparation for practice (rho = 0.52, p < 0.05, and rho = 0.55, p < 0.05, respectively). Of the fieldwork experiences, respondents rated block placements as more beneficial to practice than non-traditional placements. However, a correlational analysis showed the non traditional placement was significantly related to preparation for practice (rho = 0.54, p < 0.05). On a seven-point Likert scale, respondents rated themselves from 5.2 to 5.7 for perceived self-competence as a newly graduated practitioner with community-based graduates having the higher rating. Confidence in clinical decision-making was rated 5.0 to 5.6 with community-based graduates having higher rating. Respondents reported a positive perception that the undergraduate program prepared them to enter the workforce and practise as an occupational therapist (mean ratings 5.5 to 6.2). CONCLUSION: Respondents felt adequately prepared to enter the occupational therapy profession and workforce. Strengths and weaknesses in their preparation are discussed as well as the need for further research. PMID- 20854541 TI - Factors affecting the number and type of impairments of visual perception and praxis following stroke. AB - AIM: This study aimed to examine the effect of clinical factors including side of stroke, region of affected cerebral circulation, type of stroke and time since stroke, as well as age on the number and type of impairments of visual perception and praxis in patients following stroke. METHODS: Two hundred and eight participants with stroke were conveniently sampled from 12 hospitals in Brisbane and the Gold Coast. Background information was collected and each participant was assessed for impairments of visual perception and praxis using the Occupational Therapy Adult Perceptual Screening Test. RESULTS: Participants with left hemisphere stroke were more likely to have impaired body scheme than participants with right-hemisphere stroke. Additionally, participants with right-hemisphere stroke were more likely to have unilateral neglect and impaired constructional skills than those with left-hemisphere stroke. There was a significant relationship between region of affected cerebral circulation and the occurrence of agnosia, unilateral neglect and constructional skill impairment. Moreover, the number of visual perceptual impairments experienced by participants was associated with the region of affected cerebral circulation. Increasing age was significantly related to the occurrence of constructional skill impairment and acalculia. CONCLUSIONS: Side of stroke, region of affected cerebral circulation and age affected the type of impairments of visual perception and praxis experienced by patients following stroke. Furthermore, region of affected cerebral circulation also influenced the number of impairments of visual perception and praxis in patients after stroke. The results have implications for more specific targeting of assessment and treatment practices following stroke. PMID- 20854542 TI - No implementation strategy can yet be recommended to improve clinical guideline implementation by allied health professionals. PMID- 20854543 TI - Organisational changes leading to use of Assertive Community Treatment and supported employment improve outcomes for people with severe mental illness. PMID- 20854544 TI - The climate change debate: ageing and the impacts on participating in meaningful occupations. PMID- 20854545 TI - Measuring the fidelity of supported employment for people with severe mental illness. PMID- 20854546 TI - Response to 'Measuring the fidelity of supported employment for people with severe mental illness'. PMID- 20854547 TI - When to seek ethical review for a study. PMID- 20854548 TI - A comparison of international occupational therapy competencies: implications for Australian standards in the new millennium. AB - BACKGROUND/AIM: A timely evaluation of the Australian Competency Standards for Entry-Level Occupational Therapists (1994) was conducted. This thorough investigation comprised a literature review exploring the concept of competence and the applications of competency standards; systematic benchmarking of the Australian Occupational Therapy Competency Standards (OT AUSTRALIA, 1994) against other national and international competency standards and other affiliated documents, from occupational therapy and other cognate disciplines; and extensive nationwide consultation with the professional community. This paper explores and examines the similarities and disparities between occupational therapy competency standards documents available in English from Australia and other countries. METHODS: An online search for national occupational therapy competency standards located 10 documents, including the Australian competencies. RESULTS: Four 'frameworks' were created to categorise the documents according to their conceptual underpinnings: Technical-Prescriptive, Enabling, Educational and Meta Cognitive. Other characteristics that appeared to impact the design, content and implementation of competency standards, including definitions of key concepts, authorship, national and cultural priorities, scope of services, intended use and review mechanisms, were revealed. CONCLUSION: The proposed 'frameworks' and identification of influential characteristics provided a 'lens' through which to understand and evaluate competency standards. While consistent application of and attention to some of these characteristics appear to consolidate and affirm the authority of competency standards, it is suggested that the national context should be a critical determinant of the design and content of the final document. The Australian Occupational Therapy Competency Standards (OT AUSTRALIA, 1994) are critiqued accordingly, and preliminary recommendations for revision are proposed. PMID- 20854549 TI - A national evaluation of the Australian Occupational Therapy Competency Standards (1994): a multistakeholder perspective. AB - This paper summarises results from an evaluation of the adequacy and utility of the Australian Competency Standards for Entry-Level Occupational Therapists (OT AUSTRALIA, 1994a). It comprised a two-part study, incorporating an online survey of key national stakeholders (n = 26), and 13 focus groups (n = 152) conducted throughout Australia with occupational therapy clinicians, academics, OT AUSTRALIA association and Occupational Therapy Registration Board representatives, as well as university program accreditors. The key recommendations were that: (i) urgent revision to reflect contemporary practice, paradigms, approaches and frameworks is required; (ii) the standards should exemplify basic competence at graduation (not within two years following); (iii) a revision cycle of five years is required; (iv) the Australian Qualifications Framework should be retained, preceded by an introduction describing the scope and nature of occupational therapy practice in the national context; (v) access to the standards should be free and unrestricted to occupational therapists, students and the public via the OT AUSTRALIA (national) website; (vi) the standards should incorporate a succinct executive summary and additional tools or templates formatted to enable occupational therapists to develop professional portfolios and create working documents specific to their workplace; and (vii) language must accommodate contextual variation while striking an appropriate balance between providing instruction and encouraging innovation in practice. PMID- 20854550 TI - An evaluation of the construct validity of the Developmental Test of Visual-Motor Integration using the Rasch Measurement Model. AB - BACKGROUND: One method of evaluating the construct validity of instruments is the Rasch Measurement Model (RMM), an increasingly popular method used for test construction and validation. AIM: The aim was to examine the construct validity of the Developmental Test of Visual-Motor Integration 5th Edition (VMI) by applying the RMM to evaluate its scalability, dimensionality, differential item functioning and hierarchical ordering. METHOD: The participants were 400 children aged 5 to 12 years, recruited from six schools in Melbourne, Victoria, who completed the VMI under the supervision of an occupational therapist. VMI items 1, 2 and 3 were excluded from the Rasch analysis since all of the children achieved a perfect score on these items. RESULTS: None of the items exhibited RMM misfit due to goodness-of-fit mean square (MnSq) infit statistics and standardised z (ZStd) scores being outside the specified acceptable range. VMI item 9 (copied circle) exhibited differential item functioning based on gender. In relation to hierarchical ordering of items, several were found to have similar logit difficulty values. For example, VMI items 26, 27 and 29; items 18, 22 and 24; and items 4, 5 and 11 were found to have the same level of challenge. As well, the VMI scale item logit measure order did not match that presented in the VMI test manual. CONCLUSION: Theoretically, the VMI items are developmentally ordered; however, this ordering was not mirrored by the item logit difficulty scores obtained. This has scoring implications, where scoring a respondent's VMI test booklet is terminated after three consecutive items are not passed. Clinicians should also be aware that item 9 may exhibit bias related to gender. PMID- 20854551 TI - Rater reliability of the adapted scoring criteria of the Minnesota Handwriting Assessment for children with cerebral palsy. AB - BACKGROUND/AIM: Current handwriting assessment tools are standardised mostly on typically developing students. This study estimated the intrarater and interrater reliabilities of the adapted scoring criteria, titled the Minnesota Handwriting Assessment-Cerebral Palsy (MHA-CP), for evaluating the effectiveness of handwriting interventions for children with cerebral palsy. METHODS: We scored two batches of 20 random samples each from 80 handwriting samples produced by 30 children with cerebral palsy using the MHA-CP to estimate the intrarater and interrater reliabilities, respectively. RESULTS: Intraclass correlation coefficients exceeded 0.95 for both intrarater and interrater reliabilities for all quality subscales of the MHA-CP. CONCLUSIONS: The MHA-CP is shown to be a reliable measure of the manuscript handwriting performance of children with cerebral palsy who are in Grades 1 and 2. Further empirical testing is recommended to confirm its validity as an outcome measure for this population. PMID- 20854552 TI - Increasing the occupational therapy mental health workforce through innovative practice education: a pilot project. AB - AIM: This paper describes the evaluation of a pilot trial of two innovative placement models in the area of mental health, namely role emerging and collaborative supervision. The Queensland Occupational Therapy Fieldwork Collaborative conducted this trial in response to workforce shortages in mental health. METHOD: Six occupational therapy students and eight practice educators were surveyed pre- and post-placements regarding implementation of these innovative models. RESULTS: Students participating in these placements reported that they were highly likely to work in mental health upon graduation, and practice educators were positive about undertaking innovative placements in future. An overview of the placement sites, trials, outcomes and limitations of this pilot trial is provided. CONCLUSION: Though limited by its small sample size, this pilot trial has demonstrated the potential of innovative placement models to provide valuable student learning experiences in mental health. The profession needs to develop expertise in the use of innovative placement models if students are to be adequately prepared to work with the mental health issues of the Australian community now and in the future. PMID- 20854553 TI - The structure of novice and expert occupational therapists' clinical reasoning before and after exposure to a domain-specific protocol. AB - BACKGROUND/AIM: The research aimed to determine the influence of a protocol designed for use in the domain of upper limb hypertonia due to brain injury on novice and expert occupational therapy clinical reasoning. METHOD: Individual, structured repertory grid interviews were completed with 13 novice and eight expert occupational therapists prior to, and following, exposure to a domain specific clinical reasoning protocol. Data were subjected to quantitative analyses (Principal Components Analysis, Generalised Procrustes Analysis). RESULTS: Novice participants demonstrated statistically significant change in the structure of their clinical reasoning following exposure to the protocol (P < 0.004). Prior to exposure, novices relied on therapy tasks, the problem-solving process, environmental factors and standard practice to structure their reasoning. Following exposure, novices' clinical reasoning changed to more closely reflect experts' reasoning. Thus, a 'structured approach' and (theoretical) practice perspectives became evident. Prior to exposure to the protocol, experts structured reasoning in terms of (personal and theoretical) practice perspectives, therapy tasks and the scope of such tasks (either 'general' or 'specific'). Following exposure, therapist/client collaboration and upper-limb-related constructs emerged as being used to structure experts' reasoning, although these changes were not statistically significant. CONCLUSION: A protocol designed for guiding clinical reasoning in the context of upper limb hypertonia was perceived to be conceptually useful by novice and expert occupational therapists. PMID- 20854554 TI - Are we applying interventions with research evidence when targeting secondary complications of the stroke-affected upper limb. AB - BACKGROUND/AIM: This study aimed to survey occupational therapy practice with reference to the current evidence for management of secondary complications of the stroke-affected upper limb. METHODS: A questionnaire was developed to identify the clinical practice of occupational therapists in managing the client's stroke-affected upper limb. Participants were recruited via an email to the national occupational therapy neurology listserve. Occupational therapists working in stroke rehabilitation were invited to complete the questionnaire online or to print off and return. RESULTS: Fifty-five occupational therapists completed the questionnaire. Results revealed that treatment techniques with little to no evidence were used frequently, including pillow cushion supports (98%), positional stretch (94%) and slings (61%). Alternatively, treatment techniques with significant supporting evidence were used at a lower frequency, such as electrical stimulation (39%). CONCLUSIONS: The results of the questionnaire highlight an inconsistent application of evidence within clinical practice and the consistent application of treatment techniques with poor supporting evidence. This result does not represent poor clinical practice. Rather, it highlights the need for the research literature to articulate the clinical reasoning underpinning clinicians' selection of treatment techniques and to determine the effectiveness of frequently used, but poorly supported treatment techniques. PMID- 20854555 TI - Occupational therapists and the use of constraint-induced movement therapy in neurological practice. PMID- 20854556 TI - Early physical and occupational therapy in mechanically ventilated, critically ill patients resulted in better functional outcomes at hospital discharge. PMID- 20854557 TI - Newborn Individualised Developmental Care and Assessment Programme for infants born less than 32 weeks' gestation did not improve neurodevelopmental outcomes at one and two years more than standard developmental care. PMID- 20854558 TI - Occupational therapy, a central role in the future health and wellbeing of an ageing Australia. PMID- 20854559 TI - Navigating ethical discharge planning: A case study in older adult rehabilitation. AB - BACKGROUND: Ethical issues are becoming more complex as individuals live longer with increased disability and medical needs. This article elucidates common ethical issues encountered in discharge planning with older adults. METHODS: We conducted normative ethical analysis of a clinical case using methods of philosophical inquiry, including thick description, reflexivity, conceptual clarification and examination of competing arguments for internal consistency. RESULTS: The analysis demonstrates how health-care teams struggle to balance protection from harm while honouring informed choices. We argue that ethical discharge planning requires judicious identification of client values, even if these conflict with team determinations of best interests. CONCLUSION: Dialogue is needed to identify risks, help clients determine their personal level of acceptable risk and determine provisions to minimise risks. PMID- 20854560 TI - Retirement: What will you do? A narrative inquiry of occupation-based planning for retirement: Implications for practice. AB - AIM: To examine, using a retrospective narrative study, the factors influencing four older people's decision to plan for the activities they would undertake once retired, the planning process undertaken and their subsequent experience of retirement. METHOD: Semi-structured interviews were conducted to examine the factors influencing older people's decision to commence pre-retirement planning, the planning process undertaken and their experience of retirement. In keeping with narrative inquiry, paradigmatic-type narrative analysis led to the development of categories and subsequent themes to reveal the participants' experiences of these issues. RESULTS: Three themes: environmental influences, the planning process and retirement experiences: the outcome of planning, were derived from the participants' narratives. Overall, retirement activities that were continued or initiated led to a positive experience even when these planned activities were temporarily interrupted or altered. Planning for future years in retirement and older age also continued. CONCLUSION: Occupational therapists have a unique understanding of the centrality of occupation to health and wellbeing. Thus occupational therapists are well-positioned to assist people identify, plan and engage in meaningful occupations outside work in retirement. PMID- 20854561 TI - Happy and healthy only if occupied? Perceptions of health sciences students on occupation in later life. AB - BACKGROUND/AIM: In this study, we bring attention to the university education of health science students with respect to occupation in later life. Our goal was to provide descriptive data from narratives of a group of undergraduate students and initiate discussion about the place of occupation in the context of ageing to answer the following questions: (i) How young people perceive successful ageing in relation to occupation? and (ii) can spirituality-related activities be considered occupations in later life? METHODS: Based on a thematic selection, the quality of photographs and reflective narratives, 60 Photovoice assignments created by health sciences students were analysed using content analysis. RESULTS: The findings of this study indicate that students seem to neglect the benefits of 'being' through spiritual engagement, and instead emphasise the importance of 'doing', and perpetuate pervasive successful ageing discourses in Western societies. CONCLUSIONS: Occupational therapists have potential to take an active role in undergraduate health science education and to inform the development of holistic models that would include spirituality as an avenue to live late life to its fullest potential. Photovoice emerged as a powerful teaching method to increase awareness, empathy and compassion of young adults towards ageing. PMID- 20854562 TI - Investigation into the occupational lives of healthy older people through their use of time. AB - BACKGROUND/AIM: Older people are one of the largest groups using health-care services; therefore, it is important for occupational therapists to have an understanding of their occupational lives. Temporality is a key element of occupation, yet little research exists regarding older people and time use, despite the considerable temporal adjustments taking place at this lifestage. The aim of this study was to identify the occupational lives of healthy older people through the activities they undertake in a 24-hour period. METHOD: Data analysis of time-use diaries from 90 older UK residents (aged 60-85 years) who considered themselves to be healthy was undertaken, using 15 activity codes and three pre coded terms: necessary, enjoyable and personal. RESULTS: The participants spent most of their time sleeping and resting (34%), followed by performing domestic activities (13%), watching television, listening to the radio or music, or using computers (11%), eating and drinking (9%) and socialising (6%). Enjoyable activities occupied most of their time (42% of the day), followed by necessary (34%) and personal activities (16%). CONCLUSION: These data contribute to the growing evidence base regarding older people as occupational beings, indicating that they are a diverse group of individuals who are meeting their needs with dynamic, positive activities. This highlights the importance of a client-centred approach to occupational therapy, as it enables the clients to have choice, control and diversity in their activities when meeting their needs. PMID- 20854563 TI - Impact of fatigue on everyday life among older people with chronic heart failure. AB - AIM: To explore the relationship between fatigue and performance of activities of daily living (ADL), use of assistive devices, home-help service and community mobility services in older clients with chronic heart failure. METHODS: A cross sectional descriptive study of 40 patients was performed using the Multidimensional Fatigue Inventory, the Staircase of ADL, Assessment of Motor and Process Skills and a demographic checklist. RESULTS: We found high levels of general fatigue, physical fatigue and reduced activity. Greater fatigue was associated significantly with increased dependence and decreased quality of ADL, but not for shopping. Use of community mobility services and assistive devices was frequent and home help less frequent. Use of assistive devices and home help were associated significantly with greater fatigue, but not the use of community mobility services. CONCLUSIONS: Fatigue had a negative impact on ADL mainly from physical rather than from mental causes. Improved energy conservation strategies to reduce the consequences of fatigue are needed. PMID- 20854564 TI - LiFE Pilot Study: A randomised trial of balance and strength training embedded in daily life activity to reduce falls in older adults. AB - BACKGROUND: Exercise as a falls prevention strategy is more complex with people at risk than with the general population. The Lifestyle approach to reducing Falls through Exercise (LiFE) involves embedding balance and lower limb strength training in habitual daily routines. METHODS: A total of 34 community-residing people aged >=70 years were randomised either into the LiFE programme or into a no-intervention control group and followed up for six months. Inclusion criteria were two or more falls or an injurious fall in the past year. RESULTS: There were 12 falls in the intervention group and 35 in the control group. Therelative risk (RR) analysis demonstrated a significant reduction in falls (RR = 0.23; 0.07 0.83). There were indications that dynamic balance (P = 0.04 at three months) and efficacy beliefs (P = 0.04 at six months) improved for the LiFE programme participants. In general, secondary physical and health status outcomes, which were hypothesised as potential mediators of fall risk, improved minimally and inconsistently. CONCLUSIONS: LiFE was effective in reducing recurrent falls in this at-risk sample. However, there were minimal changes in secondary measures. The study was feasible in terms of recruitment, randomisation, blinding and data collection. A larger randomised trial is needed to investigate long-term efficacy, mechanisms of benefit and clinical significance of this new intervention. PMID- 20854565 TI - The physical environment as a fall risk factor in older adults: Systematic review and meta-analysis of cross-sectional and cohort studies. AB - BACKGROUND/AIM: Evidence that the physical environment is a fall risk factor in older adults is inconsistent. The study evaluated and summarised evidence of the physical environment as a fall risk factor. METHODS: Eight databases (1985-2006) were searched. Investigators evaluated quality of two categories (cross-sectional and cohort) of studies, extracted and analysed data. RESULTS: Cross-sectional: falls occur in a variety of environments; gait aids were present in approximately 30% of falls. COHORT: Home hazards increased fall risk (odds ratio (OR) = 1.15; 95% confidence interval (CI): 0.97-1.36) although not significantly. When only the high quality studies were included, the OR = 1.38 (95% CI: 1.03-1.87), which was statistically significant. Use of mobility aids significantly increased fall risk in community (OR = 2.07; 95% CI: 1.59-2.71) and institutional (OR = 1.77; 95% CI: 1.66-1.89) settings. CONCLUSIONS: Home hazards appear to be a significant risk factor in older community-dwelling adults, although they may present the greatest risk for persons who fall repeatedly. Future research should examine relationships between mobility impairments, use of mobility aids and falls. PMID- 20854566 TI - Can this patient go home? Assessment of decision-making capacity. PMID- 20854567 TI - Hand exercise leads to modest improvement in grip and pinch strength, but no difference in hand function, pain, stiffness or dexterity in older people with hand osteoarthritis. PMID- 20854568 TI - Patient perspectives of hand osteoarthritis in relation to current measures of function. PMID- 20854569 TI - Response to Critically Appraised Paper, 'Patient perspectives of hand osteoarthritis in relation to current measures of function'. PMID- 20854570 TI - The climate change debate: Another perspective. PMID- 20854572 TI - Implementing Clinical Practice Guidelines in occupational therapy practice: recommendations from the research evidence. AB - BACKGROUND: Clinical Practice Guidelines (CPGs) are prominent tools in evidence based practice which integrate research evidence, clinical expertise and client input to develop recommendations for specific clinical circumstance. With the push to use research evidence in health care, it is anticipated that occupational therapists will become increasingly involved in implementing CPGs in practice. The research evidence has revealed several factors that can affect guideline uptake, and a variety of strategies that can facilitate implementation. METHODS: This narrative review examines the health-related literature in CPGs to answer the following questions. Based on the research evidence, (i) what are the factors that may influence guideline implementation? (ii) What implementation strategies may enhance guideline implementation? RESULTS: Factors within the guideline itself (e.g. quality, complexity and clarity), within the practitioner (e.g. experience, perceptions and beliefs), the patient (e.g. expectations and preferences) and the practice context (e.g. resource availability, organisational culture and opinion leaders) can all affect implementation success. Currently, there is no conclusive evidence to support the use of one implementation strategy over another, in all situations. The choice of implementation strategy must take into account the guideline to be implemented, the practice context and the anticipated challenges to implementation. CONCLUSIONS: By understanding the factors that can influence implementation and the strategies for successful implementation, occupational therapists will be better prepared to implement guidelines. Recommendations to assist with guideline uptake and implementation are provided. PMID- 20854573 TI - Occupational therapists as expert witnesses on work capacity. AB - AIM: The aim of this study was to explore the particular challenges for occupational therapists during their cross-examination as an expert witness on work capacity. METHODS: Grounded theory methodology was used to collect and analyse data. Interviews were conducted with 31 participants with direct experience of occupational therapy work capacity assessments. Of these, 19 were occupational therapists, six were medical specialists and six were lawyers. RESULTS: All participant groups perceived that maintaining one's credibility in the witness box was of paramount importance. The occupational therapists identified 11 strategies that barristers may use to challenge their credibility as an expert witness. CONCLUSIONS: The three professional groups proposed practices that maintain occupational therapists' credibility as expert witnesses on the work capacity of personal injury claimants. PMID- 20854574 TI - Scope of practice of occupational therapists working in Victorian community health settings. AB - BACKGROUND/AIM: Current health policy places emphasis on community-based health care and it is expected that there will be an increase in the number of people receiving care in community settings. This study aimed to examine the profile and scope of practice of occupational therapists working in Victorian community health settings and the amount and type of health promotion activity incorporated into their role. METHOD: An anonymous postal questionnaire was sent to 205 community-based Victorian occupational therapists. One hundred and one (49.3% response rate) questionnaires were returned, with 72 respondents (35.1%) meeting study inclusion criteria. A descriptive research design was used to address study aims. RESULTS: Results indicate that the majority of community health occupational therapists are experienced practitioners, have a varied scope of practice and report a high level of job satisfaction. Compared with previous studies, there is an increase in new graduate occupational therapists starting their career in community health settings, a greater number of part-time workers and a diversification of clinical and non-clinical roles. Barriers to practice that exist include high demand for service, limited funding and time spent on administrative tasks. Although health promotion was regarded as an important role of community health workers, a large number of therapists were not involved in this activity because of limited knowledge and clinical work taking priority. CONCLUSION: Study findings have implications for occupational therapy training, and there is a clear need for input at policy level to address the significant resource allocation issues raised. PMID- 20854575 TI - Recruitment and retention issues for occupational therapists in mental health: balancing the pull and the push. AB - BACKGROUND/AIM: Recruitment and retention issues for mental health occupational therapists have been the subject of significant concern for many years. This paper describes recruitment and retention issues as reported by mental health occupational therapists employed by a large Area Health Service in metropolitan Sydney. METHOD: Thirty-eight mental health occupational therapists (response rate 84%) completed a survey in the first half of 2008. Key themes investigated were: overall satisfaction; attractive elements of positions; positive aspects of positions; constraints of positions; factors associated with leaving positions; supervision; professional development; career pathways; and interest in and access to management positions. RESULTS: Key elements that kept respondents in positions included the nature of the work, being in a supportive team and the opportunity to use occupational therapy skills. Elements that prompted people to consider leaving positions were the desire for new and different types of work, a desire to work closer to home, insufficient time or high workloads, feeling 'bored' or 'stale', organisational change or juggling multiple demands, working in unsupportive or dysfunctional teams and family or other personal factors. CONCLUSIONS: The results supported the development of a 'push and pull' conceptualization of recruitment and retention issues, including job-related (intrinsic) and non-job-related (extrinsic) issues. This conceptualization allows organisations to closely examine factors that attract practitioners to positions and those that support or damage staff tenure. PMID- 20854576 TI - Routine administration of the Canadian Occupational Performance Measure: effect on functional outcome. AB - BACKGROUND/AIM: Routinely using outcome measures as an integral component of practice has been encouraged for decades yet has not been widely adopted. There are many reasons to measure outcomes yet any positive effect of measurement on our programs or clients has not been substantiated. If the time-consuming nature of outcome measurement is to be encouraged, we need to begin addressing larger questions of the value of outcome measurement on care and outcomes. This cohort study evaluated the impact of routinely administering the Canadian Occupational Performance Measure on client outcomes on a geriatric rehabilitation unit. METHODS: Changes in Functional Independence MeasureTM scores between an experimental group (n = 45) that received the routine use of the Canadian Occupational Performance Measure for evaluation/planning versus a historical comparison group (n = 58) that received 'usual' care were analysed using generalised linear modeling. RESULTS: Both groups had significant changes in Functional Independence MeasureTM scores over time. Results for differences between groups were inconclusive with a significantly underpowered analysis; however, results suggest that a medium to large effect of this intervention cannot be expected. CONCLUSIONS: Results are significant for the field of routine outcome measurement, suggesting that when adding the Canadian Occupational Performance Measure to routine assessment within an inpatient rehabilitation setting, substantially improved Functional Independence MeasureTM score outcomes should not be expected. The value of routine outcome measurement on client outcomes remains largely unexplored. Routinely, using outcome measures requires additional research to determine the specific benefits to our programs and client outcomes. PMID- 20854577 TI - Children's participation in home, school and community life after acquired brain injury. AB - AIMS: This study aimed to describe participation at home, school and in the community of Australian children who had sustained an acquired brain injury (ABI). Parent ratings regarding the impact of cognitive, motor and behavioural impairments on participation were obtained. In addition, the influence of environmental factors on participation was investigated. METHODOLOGY: This study used a cross-sectional design with convenience sampling to recruit 20 children who attended a rehabilitation review clinic between September 2006 and September 2007. Participants completed the Child and Family Follow-up Survey (Bedell, 2004) to describe the participation of their children in home, school and community settings. The CFFS was developed based on the International Classification of Function, and uses parent report to measure the impact of impairments and environmental factors on children's participation in home, school and community life. RESULTS: The children were reported to have the greatest participation restrictions for structured events in the community, and social, play or leisure activities with peers either at school or in the community. Children were least restricted moving about in and around their own homes. CONCLUSIONS: This research describes difficulties encountered by Australian children with ABI in participating in community-based activities with their same aged peers. This study adds to the current literature describing patterns of participation of United States children who have sustained brain injuries, and provides useful information for Australian therapists to consider when addressing children's return to school and engagement with their peers following brain injury. PMID- 20854578 TI - Impact of caring for a school-aged child with a disability: understanding mothers' perspectives. AB - AIM: Children with a disability are reliant on a capable, healthy and well resourced carer. Most often the child's mother provides the care that ensures the child's health, service access and community integration are attended to successfully. Through in-depth interviews with mothers and professionals, this study explores issues that challenge the mother's performance in her very important role as a caregiver. METHOD: Qualitative methodology(n=8)resulted in verbatim transcriptions that were analysed and categorised, and common themes were derived. RESULTS: Participants identified a multitude of challenges related to issues surrounding the child, maternal characteristics, the family, services and the community. Emotional distress and mental health issues were reported. CONCLUSION: Many aspects of caregiving can be relentless and challenging. Occupational therapy clinical implications aimed at supporting mothers and their children are discussed. PMID- 20854579 TI - Comparison of the play of children with attention deficit hyperactivity disorder by subtypes. AB - BACKGROUND: Studies have found differences in the nature and severity of social problems experienced by children with different subtypes of attention deficit hyperactivity disorder (ADHD). Given that play is often the context for acquiring social skills, there is surprisingly limited research examining whether these differences distinguish the play of children within the groups. METHODS: Using the Test of Playfulness (ToP), we examined the similarities and differences in play between children (aged 5-11 years) diagnosed with the three DSM-IV ADHD subtypes: inattentive (I-subtype; n=46), hyperactive-impulsive (HI-subtype; n=28) and combined subtypes (C-subtype; n=31). RESULTS AND CONCLUSIONS: Bias interaction, an item-by-item analysis, revealed that the hierarchy of ToP items was similar for children with the HI- and C-subtypes, but differed for children with the I-subtype. Specifically, children with the I-subtype found it more difficult to become intensely engaged in play and to take on playful mischief and clowning; however, they found social play items to be easier. Conversely, whereas mischief and clowning were relatively easier for children with the HI- and C subtypes, many items reflecting social interaction were more difficult. These findings suggest that interventions can be tailored to these differing presentations. However, further research is needed to confirm the findings. PMID- 20854580 TI - Patient-based educational interventions for cancer pain management reduce pain intensity and improve attitudes and knowledge towards cancer pain. PMID- 20854581 TI - Some limited evidence exists for the benefits of psychosocial interventions in the management of cancer-related fatigue. PMID- 20854582 TI - The not-so-impossible dream. PMID- 20854583 TI - Family-centred outcome measurement following paediatric stroke. AB - BACKGROUND/AIM: Therapy programmes aim to provide services that are family centred and address the specific needs of children. The Canadian Occupational Performance Measure (COPM) and the Perceived Efficacy and Goal Setting system (PEGS) are two measures that are available to assist in determining therapy priorities for children and their parents; however, the use of these measures has not been documented for children who have sustained a stroke. This project aimed to describe the functional concerns identified by children and their parents following paediatric stroke. METHODOLOGY: A cross-sectional design was used. A total of 26 children were recruited from a paediatric stroke outpatient clinic, and functional concerns were identified using either the COPM or the PEGS. RESULTS: Children and their parents identified similar issues. Of the 26 participants, 23 (88.5%) reported ongoing functional concerns at three months or more following stroke, whereas three participants did not identify any ongoing functional concerns. Functional concerns were grouped into categories of self care, productivity and leisure as outlined in the Canadian Model of Occupational Performance. Concerns were identified across all functional domains by both children and their parents. CONCLUSIONS: The COPM and PEGS provided useful information about functional issues that are important to children and their parents following paediatric stroke. Use of these client-centred measures provides an opportunity to better understand the impact of paediatric stroke on children's functional abilities, and allows greater scope for service provision and planning for this group of children. PMID- 20854584 TI - An exploration of participation in leisure activities post-stroke. AB - AIM: The purpose of this study was to illuminate the experiences of older adults' return to leisure activities, following rehabilitation, post-stroke. METHOD: A phenomenological approach was used to explore the experiences of re-engaging in leisure occupations post-stroke. In-depth interviews were conducted with five community-dwelling individuals (three men, two women) aged 68-74 years who had experienced a stroke in the past year. Data were analysed using thematic analysis. FINDINGS: Four themes emerged: (i) Re-engaging in leisure activities, (ii) acceptance of physical limitations post-stroke, (iii) gratitude for help and support and (iv) looking forward to the future. CONCLUSION: Implications revealed that post-stroke interventions need a more occupation-focussed approach, including return to leisure at an earlier stage of stroke rehabilitation. PMID- 20854585 TI - Family caregivers' perceptions of hospital-based allied health services post stroke: use of the Measure of Processes of Care to investigate processes of care. AB - AIM: To investigate family caregiver perceptions of allied health professional processes of care and support in hospital following stroke, and to test an adapted version of the Measure of Processes of Care (MPOC) for its suitability of use in the stroke care setting. METHODS: The first stage involved the adaptation and refinement of the MPOC, designed to measure caregiver perceptions of processes of professional care and support across five care dimensions. The second stage involved mailing out of questionnaires to primary caregivers of stroke survivors. A total of 107 completed questionnaires were included in the analysis. The reliability of the adapted questionnaire was assessed and summary statistics were computed. RESULTS: The reliability of the adapted MPOC was found to be high, with good internal consistency of items within each subscale. Mean scores indicated that caregivers were most likely to report negative perceptions of the way allied health professionals engaged with and supported them, particularly in the area of information provision. CONCLUSION: The number of families being affected by stroke is predicted to rise substantially in the near future. Allied health professionals have a significant role to play in supporting family caregivers. Results highlight caregiver-identified areas of weakness in current clinical practice. PMID- 20854586 TI - Assessment of the upper limb in acute stroke: the validity of hierarchal scoring for the Motor Assessment Scale. AB - BACKGROUND/AIM: Stroke is the greatest contributor to disability in Australian adults and much of this disability results from a stroke-affected upper limb. This study aimed to determine the validity of hierarchal scoring for the upper limb subscale of the Motor Assessment Scale (UL-MAS) in acute stroke using Rasch analysis. METHOD: This study applied Rasch analysis to 40 UL-MAS assessment results across 25 subjects to determine the validity of the hierarchy of the three upper limb subsets: upper arm function (six), hand movements (seven) and advanced hand activities (eight). Rasch analysis examines the relationship between 'item difficulty' and 'person ability' and produces an output which represents the difficulty of each item in relation to each other. RESULTS: As hypothesised, the hierarchy was upheld within subset 6. In subset 7, the hierarchy was not upheld. Results indicated that item 3 was the least difficult, followed by items 1, 4, 2, 5 and 6 in order of increasing difficulty. In subset 8 the hierarchy was not upheld. Results indicated that item 1 was the least difficult, followed by item 6, then 2 and 5 of equal value and then 3 and 4 of equal value. CONCLUSIONS: The hierarchal scoring is not supported for subsets 7 and 8 and future research is required to explore the validity of alternate scoring methods. At present, the authors recommend that the UL-MAS should be scored non-hierarchally, meaning that every item within the subsets should be scored regardless of its place within the hierarchy (UL-MAS-NH). PMID- 20854587 TI - Clock drawing from the occupational therapy adult perceptual screening test: its correlation with demographic and clinical factors in the stroke population. AB - BACKGROUND/AIM: The aim of this study was to explore the relationships between clock drawing ability following stroke, and key clinical variables including cognition, functional independence, side and type of stroke, educational level and age. METHODS: One hundred and ninety-seven people with stroke were recruited from 12 hospital and rehabilitation facilities. The participants' scores from the Clock Drawing Test in the Occupational Therapy Adult Perceptual Screening Test were the dependent variables and were entered into logistic regression with Functional Independence Measure motor scores, side of stroke, Oxfordshire Classification System of Stroke, educational level and age as independent variables. Correlation with the Mini-Mental State Examination was analysed independently, due to its strong correlation with other variables. RESULTS: The Mini-Mental State Examination correlated significantly with the Clock Drawing Test ( Exp (B) = 0.826, P < 0.001). In the multivariate analysis, a significant relationship was found with age (Exp ( B) = 1.052, P < 0.001), Functional Independence Measure - motor (Exp (B) = 0.984, P = 0.030) and side of stroke (Exp (B) = 0.384, P = 0.003). Age demonstrated the strongest correlation with the Clock Drawing Test ability and the greatest decline was from approximately 70 years of age. CONCLUSIONS: The Clock Drawing Test may be a useful and quick screen of cognitive impairments following stroke. Age-related decline must be considered and it is essential that clinicians use this only as a strategy to determine whether a more comprehensive assessment is required. PMID- 20854588 TI - Information provision to clients with stroke and their carers: self-reported practices of occupational therapists. AB - BACKGROUND: The literature promotes the use of a wide range of educational materials for teaching and training clients with chronic conditions such as stroke. Client education is a valuable tool used by occupational therapists to facilitate client and carer ability to manage the stroke-affected upper limb. The aim of this study was to identify what information was provided to clients and carers, how this information was delivered, when the information was delivered and the client factors that influenced the method of information provision. METHODS: Convenience and snowball sampling was used to recruit occupational therapists working in stroke. Twenty-eight participants completed the study questionnaire anonymously and their responses were summarised descriptively. RESULTS: There was a clinically important trend for carers to receive less information than clients. Written and/or verbal information was the favoured method for delivering information related to handling (57%), soft-tissue injury minimisation (46.4%) and oedema management (50%). Information was delivered with decreasing frequency from admission (86%) to discharge (64%). More than 90% of participants indicated that the client's cognitive ability, visual ability, level of communication, primary language and perceptual ability were considered prior to the delivery of information. DISCUSSION: Participants regularly conveyed information to clients and carers with respect to management of the stroke affected upper limb. However, an increased emphasis on the development of practical self-management skills, awareness of the impact of personal factors and a timeline for information provision may prove useful. PMID- 20854589 TI - Neuroscience makes sense for occupational therapy. PMID- 20854590 TI - Evidence for the retraining of sensation after stroke remains limited. PMID- 20854591 TI - An ankle foot orthosis improves walking in the short-term but there is no evidence that an upper limb splint improves function, range of movement or reduces pain after a stroke or non-progressive brain lesion. PMID- 20854592 TI - Response to commentary of 'evidence for the retraining of sensation after stroke: a systematic review'. PMID- 20854593 TI - Response to commentary, 'evidence for the retraining of sensation after stroke remains limited'. PMID- 20854596 TI - Has undergraduate education prepared occupational therapy students for possible practice in palliative care? AB - BACKGROUND: It has been argued that the unique nature of the occupational therapy role in palliative care (PC) warrants dedicated attention in undergraduate programmes to improve the confidence of occupational therapy graduates to work in this setting. Nevertheless, little is known about either the present PC education or the preparedness of graduates to work in this field. In addressing each of these issues, this study also sought information to guide the development of occupational therapy-specific undergraduate teaching resources. METHODS: Survey information was gathered from two participant groups: (i) six occupational therapy schools from Australia and New Zealand and (ii) 24 occupational therapists employed in PC in Australia and New Zealand. Two different surveys were used, targeting issues specific to each of these two groups. Where possible, data were analysed quantitatively, whereas open-ended questions were interpreted thematically. RESULTS: Occupational therapy schools reported 2-10 hours of PC specific content and requested teaching resources specific to the occupational therapy role. Less than half of the clinicians (45.8%) recalled receiving undergraduate content in PC, and 75% reported having felt unprepared to work in this field. Clinicians who had received PC-specific content at university felt more prepared to work in this field than those who had not. Several recommendations for teaching PC were made. CONCLUSIONS: The link between the extent of PC education received and perceived readiness to work in this field, together with the relatively small amount of dedicated undergraduate PC-specific content, supports the need to optimise teaching in this unique field. PMID- 20854595 TI - Systematic review of early intervention programmes for children from birth to nine years who have a physical disability. AB - AIM: To systematically review the literature on the effectiveness of early intervention programmes for children with physical disabilities. METHODS: Twelve electronic databases were searched for articles published between 1990 and April 2008. The quality of articles was appraised using an adapted version of the Checklist for the Evaluation of Research Articles and the Physiotherapy Evidence Database (PEDro) scale. RESULTS: Ten studies were included in the review. Cross sectional and interrupted time-series studies were of moderate methodological quality, whereas the non-randomised control trial was of moderate-to-high methodological quality. Studies differed considerably with respect to participants, types of intervention and outcomes measured. CONCLUSIONS: Positive outcomes for both children and families have resulted from early intervention. However, methodological limitations hamper a more rigorous analysis of findings across studies. PMID- 20854597 TI - Occupational therapy entry-level education in Australia: which path(s) to take? AB - BACKGROUND/AIM: There has been an increase in the number of occupational therapy educational programmes offered in Australia over recent years. Although universities offer bachelor, masters and graduate-entry masters programmes, there is a push to consider phasing out occupational therapy bachelor degrees. The aim of this study was to identify advantages and disadvantages associated with current and future credentials needed for entry into the profession. METHODS: This article reviews current literature and other issues concerning entry-level occupational therapy education. RESULTS: The underlying issues are complex and require great consideration as a profession. CONCLUSION: As a profession we need to take charge of our destiny before governments, universities and other stakeholders/professions determine the basic level of entry for our profession. PMID- 20854598 TI - Randomised controlled trial comparing two school furniture configurations in the printing performance of young children with cerebral palsy. AB - AIM: This randomised controlled trial compared the same-session effects of two different school furniture configurations on printing legibility. METHODS: A total of 30 school-age children with ambulatory cerebral palsy participated in this study. Each child provided one near-point printing sample of up to 34 letters while positioned on Mandal-type specialty school furniture and on standard school furniture. An assessor who was unaware of the intervention assignment scored printing errors. RESULTS: No significant difference in legibility score mean values between the interventions was detected and the effect size was small. CONCLUSIONS: Compared with standard school furniture, the use of specialty school furniture did not lead to immediate gains in printing legibility and other printing performance areas for children with cerebral palsy. Further study of the influence of functional abilities, other contextual factors and the longer-term use of school furniture on handwriting performance is recommended. PMID- 20854599 TI - Examination of the change in Assessment of Motor and Process Skills performance in patients with acquired brain injury between the hospital and home environment. AB - AIM: The Assessment of Motor and Process Skills (AMPS) is a standardised, valid, reliable, observational assessment that is sensitive to change over time. This research aimed to examine the change in AMPS performance in patients discharged from a neurosurgical rehabilitation ward to a home-based therapy programme over a four-week time frame. METHODS: A total of 15 individuals with acquired brain injury who were participating in rehabilitation were recruited to the study. The AMPS was conducted with each individual during the participant's inpatient rehabilitation and again approximately four weeks later, while participating in home-based rehabilitation. Assessment results were collated using the AMPS computer programme and entered into a statistics package from which data were analysed. RESULTS: As a group, no statistically significant change in function was identified between the home and hospital environments; however, individual results did indicate a change in occupational performance for many of the participants. CONCLUSIONS: The AMPS was shown to reflect a change in occupational performance for many of the research participants. This research supports previous studies which indicate that some individuals' motor and process skill abilities appear to be affected by the environment in which they perform. This suggests that occupational therapists wishing to know how an individual will perform activities of daily living should evaluate the individual's performance in the environment in which they will be functioning. PMID- 20854600 TI - Interrater, intra-rater and internal consistency reliability of the Theory Application Assessment Instrument. AB - AIM: To investigate the interrater, intra-rater and internal consistency reliability of the Theory Application Assessment Instrument, a tool for testing competency in combining multiple theoretical conceptual practice models in client evaluation and treatment planning. METHODS: The assessment was administered to 27 graduate students in two phases. The principal investigator rated the participants on the assessment scale on two separate occasions. RESULTS: Interrater and intra-rater reliability were good for Phase 2 data. Internal consistency reliability for Phase 2 data was in the 'questionable' range. CONCLUSION: The instrument shows promise of being an efficient tool. However, this was an exploratory study with a small sample. Its replication with a larger more representative sample is needed to increase external validity. PMID- 20854601 TI - A working reality: evaluating enhanced intersectoral links in supported employment for people with psychiatric disabilities. AB - BACKGROUND/AIM: Supported employment (SE) programmes have been found to improve the rates of competitive employment for people with severe mental illness. Evidence has suggested that the most effective SE model is one in which the employment specialist is co-located with mental health services. However, this may not always be achievable. The aim of this study was to investigate the effectiveness of the enhanced intersectoral links approach to SE. METHODS: A total of 43 people with a mental illness participated in the programme in which formal links were created between a community mental health team and three employment services. The outcomes of the programme were evaluated over 24 months. RESULTS: Of all participants, 77% achieved a competitive employment outcome, with 60.6% remaining in employment at the end of the evaluation period. The average duration of employment was 44.8 weeks. For those who were unable to maintain a job, the average period of employment was 14.2 weeks. The study found that participants with less severe symptoms at baseline were more likely to obtain employment and those who had worked in the year preceding entry into the programme were employed for a higher proportion of time. The factors related to job loss were the short-term nature of the position, cognitive difficulties and social skills. CONCLUSIONS: The study found that the enhanced intersectoral links approach was effective in achieving outcomes consistent with international studies of SE programmes and may offer a viable alternative to the co-location of employment specialists with community mental health teams. PMID- 20854602 TI - Evaluation of the Australian adaptation of the Keeping It Together (KIT Australia) information package with carers of children with special needs. AB - BACKGROUND: Australian carers of children with special needs have expressed concerns about the limited availability and accessibility of suitable information resources. The 'Keeping It Together' (KIT) information package was developed and trialled in Canada and found to be effective in meeting the information needs of this population. AIM: The study aimed to evaluate the KIT-Australian Adaptation (KIT-Australia) to determine if it met its purpose of providing carers of children with special needs with strategies to access resources, organise information and communicate with others about their child. The study also aimed to determine whether additional changes were required to increase the KIT Australia's utility. METHODS: Eighteen carers of children with special needs participated in the study. All participants had accessed services from the Royal Children's Hospital, Melbourne, Victoria. Demographic information was collected and carers were orientated to the KIT-Australia prior to using it. After eight weeks, a telephone survey interview was completed with each participant. A content analysis of qualitative and quantitative data provided the results. RESULTS: Most participants stated that they would continue to use the KIT Australia, and would recommend it to other carers. Six key themes were identified: getting started, accessing resources, organising and storing information, communicating information about my child to others, recommendations and non-use of the KIT-Australia. CONCLUSIONS: Preliminary data from this study suggests that the KIT-Australia met its purpose of assisting carers of children with special needs, to access resources, organise information and communicate with others about their child. Participant recommendations to improve the usability of the KIT-Australia should be implemented for future editions of the resource. Further research may be required to adapt and facilitate use of the KIT Australia in other Australian states and territories. PMID- 20854603 TI - Helping children with autism spectrum disorders and their families: are we losing our occupation-centred focus? PMID- 20854604 TI - Timely comprehensive occupational therapy significantly improves functional and work-related outcomes in employed patients with rheumatoid arthritis who are at risk of work loss. PMID- 20854606 TI - The march of the generics. PMID- 20854609 TI - Current textbooks and anatomy of the prostate--a case for an update. PMID- 20854610 TI - Video-games station or minimally invasive skills training station? PMID- 20854611 TI - Female robotic radical cystectomy. PMID- 20854615 TI - From the World Stroke Day to the World Stroke Campaign: one in six: act now! PMID- 20854616 TI - Feasibility of a pilot programme to increase awareness of blood pressure as an important risk factor for stroke in Australia. AB - BACKGROUND: Reduction of blood pressure represents one of the most effective means of reducing stroke risk. However, lack of community awareness and uncontrolled blood pressure remain a significant problem. In 2007, the National Stroke Foundation (Australia) conducted the 'Know Your Numbers' pilot programme to improve community knowledge, based on a similar UK programme developed by the Blood Pressure Association. We aimed to determine the success of the pilot in improving knowledge and in identifying factors to improve the programme. METHODS: Pharmacy Guild of Australia and Rotary International recruited volunteers to provide a 'free' blood pressure check and educational resources between 25 and 27 October 2007 via 'pressure stations'. evaluation methods: registration log and a survey of a 'one in 10 sample' at baseline and 3 months. Data were analysed using descriptive statistics. RESULTS: 77 out of 104 pressure stations returned data. The median tested per pressure station: 29 (interquartile range 19, 50), 66% tested by pharmacy and 32% by Rotary. Of the 2834 registrants (58% female, 55% aged >55 years), 46% had 'high' readings (>140/90 mmHg). Of those with high readings, 45% reported no history of high blood pressure and one-third of the registrants were unaware of their blood pressure level. There was evidence of improved knowledge at the 3-month follow-up, with most participants with high blood pressure (85%, n=22) being reviewed by their doctor. CONCLUSION: The 'Know Your Numbers' pilot programme was a successful model for improving knowledge of blood pressure as an important stroke risk factor and encouraging individuals with high blood pressure to be reviewed by their doctor. Further programmes with evaluation are being planned. PMID- 20854617 TI - Age and gender variations in the management of ischaemic stroke in China. AB - BACKGROUND: Stroke is a major health issue in China. AIMS: We aimed to describe the management of patients admitted to hospitals in China with acute ischaemic stroke, and to determine whether there were any differences by age and gender. METHODS: Using a multicentre prospective hospital register across all eight major economic (geographic) regions in China, data on the socioeconomic characteristics, medical history, clinical features, and in-hospital investigations, management, and outcomes were collected on consecutive patients with acute stroke due to cerebral ischaemia during a 5-month period in 2006. RESULTS: Overall, traditional Chinese medicine and neuroprotectant use were remarkably high, with nearly 80% of patients receiving the former and >70% receiving the latter in hospital. Length of hospital stay was also long (median duration 16-days). Multivariate analyses revealed no clinically important differences in management between the genders. For the age-specific analyses, there were significant trends of decreasing use of thrombolysis (P=0.04), warfarin (P=0.01), corticosteroids (P=0.03), and lipid-lowering therapy (P=0.001); however, more assisted feeding (P=0.004) and rising rates of disability and in-hospital complications occurred with increasing age. CONCLUSIONS: New information is provided regarding the current state of ischaemic stroke management in China. Notably, there is high use of traditional Chinese medicine and neuroprotectants and long lengths of hospital stay. Similar to many other countries, differences in stroke care and management by age and gender also exist to a small extent in China. PMID- 20854618 TI - Vascular retinal, neuroimaging and ultrasonographic markers of lacunar infarcts. AB - BACKGROUND: Lacunar infarcts may be caused by macro- or microvascular disease due to several mechanisms. AIM: This study aims to demonstrate that retinal vascular disturbances in patients with lacunar infarcts associated with neuroimaging and ultrasound markers can help to identify small-vessel disease. METHODS: Prospective ambulatory study of patients with ischaemic stroke and a control group. A retinographic study was performed by 20 degrees bilateral optic disc stereophotography and 50 degrees bilateral optic fundus retinography. Microangiopathy was evaluated as the presence of nonparenchymal vascular affectation and retinopathy as at least one retinal disturbance. Ultrasonographic study evaluated carotid disorder parameters and the mean pulsatility index. The MRI protocol included T1-weighted, T2-weighted, DP-weighted and FLAIR. RESULTS: We included 156 nonlacunar infarcts, 39 lacunar infarcts and 50 controls. Microangiopathy was more frequent in hypertensive (62.6% vs. 35.7%, P<0.0001) and vascular retinopathy in diabetic patients (11.7% vs. 3.8%, P=0.039). Microangiopathy (97.4% vs. 41.1%, P<0.0001) and leukoaraiosis (94.4% vs. 50.3%, P<0.0001) were more frequent and the mean pulsatility index was higher (1.9 +/- 0.2 vs. 1.4 +/- 0.5, P<0.0001) in patients with lacunar infarcts. Lacunar infarcts were independently associated with microangiopathy (odds ratio 12.81, 95% CI 1.52-107.86), the mean pulsatility index (odds ratio 8.13, 95% CI 1.17 56.20) and leukoaraiosis (odds ratio 3.45, 95% CI 1.09-10.93). The presence of leukoaraiosis plus microangiopathy was associated with lacunar infarcts with odds ratio 21.31 (95% CI 8.74-51.93). CONCLUSIONS: The association of retinal microangiopathy (but not vascular retinopathy) and leukoaraiosis is linked to small-vessel disease and may be a useful marker of lacunar infarcts not secondary to a macrovascular lesion. PMID- 20854619 TI - Correlation between focal brain metabolism and higher brain function in patients with Moyamoya disease. AB - BACKGROUND: Moyamoya disease is one of the causes of higher brain dysfunction in younger patients. Fortunately, it may be possible to protect younger Moyamoya disease patients from brain dysfunction via surgical manoeuvres. AIM: Our group retrospectively analysed the correlation between preoperative positron emission tomography data and the intelligence quotient scores of 60 Japanese Moyamoya disease patients (age range 9-64). METHOD: All patients underwent a quantitative measurement of the cerebral metabolic rate of oxygen by inhalation of C(15)O(2) and (15)O(2) gas with positron emission tomography. The data was analysed using spm99 software to determine the cerebral regions in which regional cerebral metabolic rate of oxygen was significantly correlated with full-scale intelligence quotient, verbal intelligence quotient, or performance intelligence quotient measured using the Wechsler intelligence scale. RESULTS: All scores (full-scale intelligence quotient, verbal intelligence quotient, and performance intelligence quotient) showed significant positive correlations with the cerebral metabolic rate of oxygen in the lower part of the bilateral frontal lobe, the right anterior temporal lobe, and the medial occipital lobe. The verbal intelligence quotient was significantly and positively correlated with the cerebral metabolic rate of oxygen in the left inferior frontal lobe, including Broca's area. Infarcted lesions in the left posterior temporal lobe and the right upper frontal lobe influenced the decline of all of the intelligence quotient scores measured. CONCLUSION: The present analysis indicates that the higher brain function of Moyamoya disease patients tends to be affected by the cerebral metabolism of specific regions. This information may be useful in seeking optimal clinical management to preserve higher brain function in patients with Moyamoya disease. PMID- 20854620 TI - Lenticulostriate arteries in chronic stroke patients visualised by 7 T magnetic resonance angiography. AB - BACKGROUND: Noninvasive magnetic resonance angiography using ultra-high-field magnetic resonance imaging has recently provided us with the potential to image cerebral microvascular structures such as the lenticulostriate arteries. However, most studies using ultra-high-field magnetic resonance angiography have been limited to the visualisation of microvessels in healthy subjects, and the direct comparison of patients with microvascular disease has not been reported. AIM: The aim of this study was to investigate the lenticulostriate arteries of patients with lacunar strokes of the basal ganglia and surrounding areas using 7 T magnetic resonance angiography. METHODS: Ten stroke patients who had infarctions in the basal ganglia and adjacent areas detected using T2(*)-weighted images obtained from a conventional 1.5 T magnetic resonance imaging and 10 age-matched healthy subjects were recruited for this study. The large main vessels in the patient group were inspected to identify abnormalities such as stenosis. The characteristics of the lenticulostriate arteries visualised by 7 T magnetic resonance angiography, such as the number of branches and stems, curvature and tortuosity were analysed and compared between the patient and the control groups. RESULTS: All patients had infarctions in the basal ganglia and adjacent regions, which were clearly determined by T2(*)-weighted images. However, there was no evidence of large-vessel abnormalities in the patient group. Analysis of 7 T magnetic resonance angiography data revealed that the overall number of lenticulostriate arteries branches in the patient group was significantly less than the control group (P=0.003). However, no statistical difference in the number of stems, curvature and tortuosity between the two groups was found (P=0.396, 0.258 and 0.888, respectively). CONCLUSIONS: This study demonstrates that noninvasive magnetic resonance angiography using 7 T magnetic resonance imaging can visualise abnormalities in the cerebral microvasculature of stroke patients, and that the number of lenticulostriate arteries supplying the region of the basal ganglia is less in these patients compared with age-matched controls. PMID- 20854621 TI - 'Where are we now with intravenous thrombolysis for acute ischaemic stroke'? AB - The publication of the updated individual patient data meta-analysis of the larger randomised trials of intravenous rt-PA for acute ischaemic stroke has re opened the debate about how the treatment should be used in routine practice, and what information can be expected to emerge in the next 2-3 years from the ongoing trials [the largest of which is the Third International Stroke Trial (IST-3)]. PMID- 20854622 TI - Is there a role for echocardiography in intracerebral haemorrhage? AB - Hypertension (HTN) is the most common cause of non-traumatic ICH, yet echocardiography, which can stage hypertensive heart disease (HHD), is not part of the routine evaluation of patients with ICH. Previous studies have shown that angiotensin converting enzyme inhibitors and angiotensin receptor blockers are associated with regression of left ventricular hypertrophy (LVH) and reversal of myocardial fibrosis. Improvement in these architectural changes in the heart has been shown to improve outcomes and prevent major adverse cardiac events, including stroke. Obtaining echocardiography on ICH patients routinely could help to access the prevalence of HHD and to tailor antihypertensive regimens in this high risk group of patients. Further study is required to determine whether angiotensin directed therapies provide optimal secondary prevention in ICH patients with HHD. PMID- 20854623 TI - A review of hereditary and acquired coagulation disorders in the aetiology of ischaemic stroke. AB - The diagnostic workup in patients with ischaemic stroke often includes testing for prothrombotic conditions. However, the clinical relevance of coagulation abnormalities in ischaemic stroke is uncertain. Therefore, we reviewed what is presently known about the association between inherited and acquired coagulation disorders and ischaemic stroke, with a special emphasis on the methodological aspects. Good-quality data in this field are scarce, and most studies fall short on epidemiological criteria for causal inference. While inherited coagulation disorders are recognised risk factors for venous thrombosis, there is no substantial evidence for an association with arterial ischaemic stroke. Possible exceptions are the prothrombin G20210A mutation in adults and protein C deficiency in children. There is proof of an association between the antiphospholipid syndrome and ischaemic stroke, but the clinical significance of isolated mildly elevated antiphospholipid antibody titres is unclear. Evidence also suggests significant associations of increased homocysteine and fibrinogen concentrations with ischaemic stroke, but whether these associations are causal is still debated. Data on other acquired coagulation abnormalities are insufficient to allow conclusions regarding causality. For most coagulation disorders, a causal relation with ischaemic stroke has not been definitely established. Hence, at present, there is no valid indication for testing all patients with ischaemic stroke for these conditions. Large prospective population based studies allowing the evaluation of interactive and subgroup effects are required to appreciate the role of coagulation disorders in the pathophysiology of arterial ischaemic stroke and to guide the management of individual patients. PMID- 20854624 TI - Loss of skeletal muscle mass after stroke: a systematic review. AB - Loss of muscle mass after stroke has implications for strength and functional ability and may also contribute to impaired glucose metabolism. Therefore, prevention of muscle loss is desirable. Before interventions to prevent loss of muscle can be designed and evaluated, the expected rate, magnitude and timing of muscle loss need to be understood. A systematic search was undertaken to identify all studies that investigated changes in skeletal muscle mass, volume or cross sectional area in people after stroke. Studies that used either direct measures of muscle size (computer tomography, magnetic resonance imaging or ultrasound) or measures of lean tissue mass (dual X-ray absorptiometry) were included. Fourteen trials were found and the results were pooled for differences in lean tissue mass between the paretic and the nonparetic leg and arm as well as differences in the midthigh cross-sectional area. In individuals at least 6-month poststroke, there was significantly less lean tissue mass in the paretic compared with the nonparetic lower limb (MD 342.3 g, 95% confidence interval 247.0-437.6 g) and upper limb (MD 239.9 g, 95% confidence interval 181.7-298.2 g), and significantly less midthigh muscle cross-sectional area (MD 15.4 cm(2), 95% confidence interval 13.8-16.9 cm(2)). There were insufficient data to pool with regard to change in muscle mass over time. There is a significant difference in the regional muscle mass in the paretic vs. the nonparetic limb in individuals greater than 6-months poststroke but little is known about how early and how quickly changes in muscle mass occur. PMID- 20854625 TI - Cerebral amyloid angiopathy in East and West. AB - Cerebral amyloid angiopathy, a vasculopathy characterised by the deposition of amyloid fibrils in the arteries and arterioles in the cerebral cortex and meninges, has been reported to be associated with intracerebral haemorrhage and cognitive impairment in the elderly. Advances in neuroimaging and validation of the clinical diagnostic criteria aid in making a correct clinical diagnosis. Associations with Alzheimer's disease, asymptomatic microbleeds and white matter changes on neuroimaging have an influence on the clinical treatment for patients with probable cerebral amyloid angiopathy. Reviewing the reports from Asian countries, we found that patients with cerebral amyloid angiopathy have a strong age-related prevalence and a consistent association with dementia, but a weaker correlation with intracerebral haemorrhage, most likely due to a higher incidence of hypertensive intracerebral haemorrhage. Involvement of the occipital lobe arteries by CAA is common in all races and ethnicities, while frontal lobe arteries may be more frequently involved in the East compared to the West. The clinical impact of cerebral amyloid angiopathy on intracerebral haemorrhage and cognitive impairment could be increasingly obvious in Asian countries with ageing populations, especially with improving control of hypertension, the leading cause of intracerebral haemorrhage. PMID- 20854626 TI - Stroke training and education for health and social care staff: a partnership between the NHS and the voluntary sector. AB - Following the Scottish Stroke Services Audit published in 1999, Chest Heart and Stroke Scotland (CHSS) commissioned the Scottish Association of Health Councils to undertake a survey of patient and carers' views of Scottish stroke services. Survey results suggested stroke carers perceived that staff caring for stroke survivors often showed a lack of awareness of the specific challenges that stroke presented. The report recommended that Chest Heart and Stroke Scotland should work with professional bodies to develop awareness training for staff working in stroke care. PMID- 20854627 TI - Ten years of stroke programmes in Poland: where did we start? Where did we get to? AB - Risk factors and a high stroke mortality rate are a heavy stroke burden on Central and Eastern European countries. The 1995 Helsingborg Declaration outlined the aim of the coming decade was to improve patient care. In Poland it led to the foundation of the National Stroke Prevention and Treatment Programme, (1998-2008) which later became part of the National Cardiovascular Disease Prevention and Treatment Programme. THE AIM: * Improve acute and postacute management * Implement innovative therapies * Develop poststroke rehabilitation, and * Monitor epidemiology. Establishing and equipping stroke units has raised their number from three to 111. Thrombolysis for stroke and carotid angioplasty and stenting procedures were supported and supervised. The needs in poststroke rehabilitation were assessed and services have improved due to the support of the programme. Continuous monitoring of patient care proved that the mortality and disability rates have decreased and the quality of treatment has improved. PMID- 20854628 TI - Endovascular treatments of atherosclerotic carotid diseases in China. AB - Stroke induces heavy socioeconomic burdens particularly in developing countries. Considering the multisectional discrepancies, strategies of stroke prevention and management adapted for western populations are not always applicable for patients in developing countries. Currently, carotid endarterectomy is the recommended treatment for severe carotid stenosis in the west. Carotid angioplasty and stenting is an alternative treatment only for patients with a high surgery risk. However, in developing countries such as China, where carotid endarterectomy is widely unavailable, Carotid angioplasty and stenting has developed rapidly in recent years and is becoming a choice of treatment for occlusive carotid diseases. PMID- 20854629 TI - Reduce, reuse and recycle. PMID- 20854631 TI - Risk factors and aetiology of cerebral infarction in young adults: a comparative study between Malaysia and Australia. PMID- 20854632 TI - Community reintegration in Nigerian stroke survivors. PMID- 20854630 TI - Angiotensin receptor blockade in acute stroke. The Scandinavian Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and placebo-controlled clinical trial (NCT00120003). AB - BACKGROUND: Elevated blood pressure following acute stroke is common, and yet early antihypertensive treatment is controversial. ACCESS suggested a beneficial effect of the angiotensin receptor blocker candesartan in the acute phase of stroke, but these findings need to be confirmed in new, large trials. AIMS AND DESIGN: The Scandinavian Candesartan Acute Stroke Trial is an international randomised, placebo-controlled, double-blind trial of candesartan in acute stroke. We plan to recruit 2500 patients presenting within 30 h of stroke (ischaemic or haemorrhagic) and with systolic blood pressure >=140 mmHg. The recruited patients are randomly assigned to candesartan or placebo for 7-days (doses increasing from 4 to 16 mg once daily). Randomisation is performed centrally via a secure web interface. The follow-up period is 6-months. Patients are included from the following nine North-European countries: Norway, Sweden, Denmark, Belgium, Germany, Poland, Lithuania, Estonia and Finland. STUDY OUTCOMES: There are two co-primary effect variables: * Functional status at 6 months, measured by the modified Rankin Scale, and * vascular death, myocardial infarction or stroke during the first 6-months. Secondary outcome variables: Secondary effect variables include * the Barthel index (functional status) * EuroQol (quality of life) and * Mini-mental state examination (cognition) at 6 months * Health economic costs during the first 6-months FUNDING: The Scandinavian Candesartan Acute Stroke Trial receives basic funding from Norwegian health authorities. AstraZeneca supplies the trial drugs, and AstraZeneca and Takeda support the trial with limited, unrestricted grants. SUMMARY: The Scandinavian Candesartan Acute Stroke Trial is the first large trial of angiotensin receptor blockers in patients with elevated blood pressure and acute stroke, and aims to answer whether treatment with angiotensin receptor blockers is beneficial for this indication. PMID- 20854633 TI - How many patients might receive thrombolytic therapy in the light of the ECASS-3 and IST-3 data? PMID- 20854635 TI - Singapore: at the hub of advanced practice nursing development in Asia. PMID- 20854636 TI - Recognizing and treating upper extremity lymphedema in postmastectomy/lumpectomy patients: a guide for primary care providers. AB - PURPOSE: To provide an overview of the lymphatics, physiology of lymphedema (LE), incidence, risks, and costs as well as a guide for the primary care provider on how to recognize the symptoms of LE, a review of current published treatment recommendations, and advice about making a referral to appropriate LE specialists. DATA SOURCES: Selected studies on diagnosing and treating LE in breast cancer patients following mastectomy/lumpectomy and evidence-based treatment guidelines. CONCLUSIONS: LE is the most common complication related to breast cancer treatment with an occurrence estimated between 10% and 60% depending on the parameters used for measurement. Most commonly, LE occurs within the first 3 years after breast cancer treatment, but the remaining cases happen beyond this period of time and can occur after many years. This means that significant numbers of patients with LE can present to primary care clinicians. IMPLICATIONS FOR PRACTICE: A patient who is treated for breast cancer will be followed for a time by the oncology team, but eventually, that patient will be discharged from the oncology practice and will be seen in primary care. Risk factors for developing LE include treatment-related (number of nodes removed and radiation to axilla), disease-related (stage and location of tumor), and patient related (younger age, obesity, and comorbid conditions) factors. A systematic evaluation of any patient presenting with LE will assure accurate diagnosis and prompt treatment. PMID- 20854637 TI - The environment and pediatric overweight: a review for nurse practitioners. AB - PURPOSE: The primary aim of this article is to review environmental determinates on eating and physical activity behaviors that lead to overweight status in the pediatric population. DATA SOURCES: Selected articles on pediatric obesity and overweight and federal government publications addressing pediatric overweight, physical activity, and dietary habits. CONCLUSIONS: Obesity is one of the leading preventable causes of disease and death in the United States and is considered a major public health threat to Americans of all ages. An energy-dense diet coupled with low physical activity creates an environment conducive to obesity. Obesity warrants immediate attention and nurse practitioners (NPs) must implement proactive strategies to prevent the development of chronic disease in American children and adolescents. An initial key to successful prevention is identification of environmental supports and barriers that influence pediatric overweight. IMPLICATIONS FOR PRACTICE: NPs must identify at-risk and overweight youth and translate current research findings into their practices. Designing and implementing age and family appropriate strategies that address positive and negative environmental influences is crucial to prevent or reduce the overweight epidemic. PMID- 20854638 TI - Diagnostic challenge: Myasthenia gravis in the emergency department. AB - PURPOSE: To describe an instructive case of neurological disease encountered by a nurse practitioner (NP) student in the emergency department (ED). Characteristics, epidemiology, pathophysiology, diagnostic considerations, and appropriate testing options for myasthenia gravis (MG) are included. DATA SOURCES: Findings from the history, physical examination, and diagnostic testing of a 41-year-old male with neck weakness and pain. Review of published literature about MG. CONCLUSIONS: MG is a pure motor syndrome characterized by fluctuating muscle weakness and fatigue and is exacerbated by sustained muscle use. It is usually caused by an autoimmune process that is chronic and progressive. Multiple patient encounters with the healthcare system often occur prior to diagnosis. Many viable treatment options now exist that can enhance quality of life and improve function. IMPLICATIONS FOR PRACTICE: The NP must include MG in the differential diagnosis with any report of fluctuating muscle weakness or other neurological, upper gastrointestinal, respiratory, or ophthalmic complaint. The key diagnostic finding is a specific muscle weakness that can be reproduced and exacerbated with sustained muscle use. These considerations will lead to earlier diagnosis and treatment. PMID- 20854639 TI - Characteristics of risk in patients of nurse practitioner safety net practices. AB - PURPOSE: The purpose of this article is to describe the characteristics of vulnerability in patients at safety net practices where nurse practitioners (NPs) provide the majority of the health care and to discuss the implications regarding patient data collection for all NPs who provide safety net care. DATA SOURCES: Data were collected from patients at four safety net practices: a rural health clinic, a rural nurse-managed health clinic, an urban nurse-managed health clinic, and an urban Indian health clinic. CONCLUSIONS: The users of these practices reflected a significant degree of risk for poor health outcomes based on characteristics of risk identified in the literature. Patients seen in nurse managed health clinics without federal subsidies had more risk that those in federally supported clinics. IMPLICATIONS FOR PRACTICE: Given the increasing evidence of the impact of social and environment factors on poor health outcomes, the importance of assessing and describing the characteristics of risk is discussed. These data are essential for supporting the value of these NP-provided safety net services to healthcare insurers and federal health policy makers. PMID- 20854640 TI - Self-care and quality of life among patients with heart failure. AB - PURPOSE: The purpose of this cross-sectional, descriptive study was to determine if there were specific self-care deficits among patients with heart failure at the time of discharge in an acute care setting, which may be related to a decreased quality of life. DATA SOURCES: Patients admitted with acute, chronic congestive heart failure were recruited to complete both the Self-care of Heart Failure Index and the Minnesota Living with Heart Failure questionnaires. Data analyses were conducted to determine if there were any significant relationships between self-care abilities and quality of life. CONCLUSIONS: Results from this study were promising as "self-care confidence" and perceived better health were found to be significantly related to improved quality of life. Heart failure is a chronic disease that requires patients to develop confidence in their self-care abilities to maintain and improve quality of life. IMPLICATIONS FOR PRACTICE: Findings from this research study suggest that nurse practitioners need to first identify patients with heart failure who lack the self-care confidence required to manage their condition at home, and then focus on specific educational interventions to build confidence in self-care prior to discharge. PMID- 20854641 TI - Antibiotic identification, use, and self-medication for respiratory illnesses among urban Latinos. AB - PURPOSE: The purpose of this study was to describe the extent to which antibiotic and nonantibiotic medications commonly used for upper respiratory infections (URIs) were correctly identified by a sample of urban dwelling Latinas and the association of medication identification with antibiotic use and self-medication. DATA SOURCES: One hundred women completed an interview and were asked to identify whether a list of 39 medications (17 antibiotics, 22 nonantibiotics) were antibiotics or not, whether anyone in the household had used the medication, their ages, and the source of the medication. RESULTS: Overall, participants correctly identified 62% of nonantibiotics and 34% of antibiotics. Seventy three (73%) women in the study reported antibiotic use by at least one member of the household in the past year. Among users, self-medication was reported in 67.2% of antibiotics for adults, but in only 2.4% of children. There was no difference in antibiotic recognition between those who self-medicated and those who did not, but antibiotic self-medication was associated with a significantly lower recognition of nonantibiotics (p= .01). IMPLICATIONS FOR PRACTICE: Measures to improve antibiotic utilization should address self-medication and consider the cultural and social context in which antibiotic use occurs. PMID- 20854642 TI - Diagnostic accuracy for coronary artery disease of multislice CT scanners in comparison to conventional coronary angiography: an integrative literature review. AB - PURPOSE: To examine the quality of cardiac imaging done by multislice computed tomography (MSCT) and its ability to correctly identify significantly occluded segments of coronary arteries compared with quantitative coronary angiography. DATA SOURCES: Databases searched were CINAHL, MEDLINE, EBSCO, Academic Search Premier, and Web of Science and Health Source: Nursing/Academic edition. Keywords used were "Computed Tomography,""Coronar* Angiogra*," and "Coronary Artery Disease." Studies from peer-reviewed journals published from 2002 to 2008 that compared quantitative coronary angiography to MSCT were evaluated. Additional sources were identified from review of reference lists from articles found in the electronic search. CONCLUSIONS: MSCT was best employed to screen for the absence of disease in patients who were in sinus rhythm, who had no previous bypass grafts or stents placed, had a low risk of calcifications, and who were not obese. Both 40- and 64-slice technology demonstrated the highest accuracy in screening for the absence of disease on a vessel-based analysis. IMPLICATIONS FOR PRACTICE: Those who have multiple risk factors and are asymptomatic should still be screened via catheterization. More studies are needed to determine the effectiveness of newer 64-slice technology as a tool to positively identify CAD. PMID- 20854644 TI - Abstracts of the Danish Society for Emergency Medicine Research Symposium 2010. Roskilde, Denmark. May 20-21, 2010. PMID- 20854643 TI - A review of the International Brain Research Foundation novel approach to mild traumatic brain injury presented at the International Conference on Behavioral Health and Traumatic Brain Injury. AB - "The International Conference on Behavioral Health and Traumatic Brain Injury" held at St. Joseph's Regional Medical Center in Paterson, NJ., from October 12 to 15, 2008, included a presentation on the novel assessment and treatment approach to mild traumatic brain injury (mTBI) by Philip A. DeFina, PhD, of the International Brain Research Foundation (IBRF). Because of the urgent need to treat a large number of our troops who are diagnosed with mTBI and post-traumatic stress disorder (PTSD), the conference was held to create a report for Congress titled "Recommendations to Improve the Care of Wounded Warriors NOW. March 12, 2009." This article summarizes and adds greater detail to Dr. DeFina's presentation on the current standard and novel ways to approach assessment and treatment of mTBI and PTSD. Pilot data derived from collaborative studies through the IBRF have led to the development of clinical and research protocols utilizing currently accepted, valid, and reliable neuroimaging technologies combined in novel ways to develop "neuromarkers." These neuromarkers are being evaluated in the context of an "Integrity-Deficit Matrix" model to demonstrate their ability to improve diagnostic accuracy, guide treatment programs, and possibly predict outcomes for patients suffering from traumatic brain injury. PMID- 20854645 TI - Computational ecosystems for data-driven medical genomics. AB - In the path towards personalized medicine, the integrative bioinformatics infrastructure is a critical enabling resource. Until large-scale reference data became available, the attributes of the computational infrastructure were postulated by many, but have mostly remained unverified. Now that large-scale initiatives such as The Cancer Genome Atlas (TCGA) are in full swing, the opportunity is at hand to find out what analytical approaches and computational architectures are really effective. A recent report did just that: first a software development environment was assembled as part of an informatics research program, and only then was the analysis of TCGA's glioblastoma multiforme multi omic data pursued at the multi-omic scale. The results of this complex analysis are the focus of the report highlighted here. However, what is reported in the analysis is also the validating corollary for an infrastructure development effort guided by the iterative identification of sound design criteria for the architecture of the integrative computational infrastructure. The work is at least as valuable as the data analysis results themselves: computational ecosystems with their own high-level abstractions rather than rigid pipelines with prescriptive recipes appear to be the critical feature of an effective infrastructure. Only then can analytical workflows benefit from experimentation just like any other component of the biomedical research program. PMID- 20854646 TI - Pharmacogenomic considerations in the opioid management of pain. AB - Physicians continue to struggle with the clinical management of pain, in part because of the large interindividual variability in the efficacy, occurrence of side effects and undesired severe adverse drug reactions from the prescribed analgesics. Pharmacogenomics, the study of how an individual's genetic inheritance affects the body's response to medications, has an important role and can explain some of this interindividual variability. Genetic identification of known variant alleles that affect the pharmacokinetics or pharmacodynamics of medications used for pain management can enable physicians to select the appropriate analgesic drug and dosing regimen for an individual patient, instead of empirical selection and dosing escalation. In this article, clinically relevant pharmacogenomic targets for the management of opioid pain, including efflux transporters, proteins that metabolize drugs, enzymes that regulate the neurotransmitters that modulate pain, and opioid receptors, will be reviewed. PMID- 20854647 TI - Using pump for bypass surgery--on-off-on again? PMID- 20854648 TI - Clostridium difficile: moving beyond antimicrobial therapy. PMID- 20854649 TI - Direct antimicrobial activity of antithrombin? PMID- 20854650 TI - Sizing up stability: combination therapy with Apo-AI peptide mimetics and statins in systemic lupus erythematosus-mediated atherosclerosis. AB - In a study published recently in Arthritis Research & Therapy, Woo and colleagues investigated the effects of pravastatin in combination with an apolipoprotein-AI (Apo-AI) mimetic peptide in a mouse model of lupus-accelerated atherosclerosis. Combination treatment resulted in a significant decrease in systemic inflammation but increased aortic root lesion size. However, this treatment changed the phenotype of the lesion to a more stable plaque. Because plaque stability is also important for protection against the deadly manifestations of atherosclerosis, combination therapies using Apo-AI mimetics and statin might offer a good additional therapy to treat autoimmunity and cardiovascular disease in patients with lupus. PMID- 20854651 TI - From model system to clinical medicine: pathophysiologic links of common proteinopathies. AB - Recent clinical evidence suggests that Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB), though distinct neurological disorders, have some common pathological features that may have an impact on the clinical characteristics of these diseases. However, the question of whether these disorders have a common pathophysiology remains. Clinton and colleagues recently reported a mouse model that exhibits the combined pathologies of AD, PD, and DLB, a finding that may shed some light on this issue. Using this mouse model, the authors demonstrate that the pathogenic proteins amyloid beta, tau, and alpha-synuclein interact synergistically to enhance the accumulation of one another and accelerate cognitive decline. These data indicate shared pathogenic mechanisms and suggest the possibility that therapeutic interventions successfully targeting one of these pathogenic proteins have implications for a number of related neurodegenerative disorders. PMID- 20854652 TI - Fungal colonization in patients with chronic respiratory diseases from Himalayan region of India. AB - BACKGROUND: We screened patients with chronic respiratory diseases for microbiological and serological evidences of fungal colonisation; in order to determine its prevalence in this group of patients, examine potential clinical and radiological predictors of fungal colonisation and characterise fungal agents associated with individual diseases. METHODS: BAL samples from 60 consecutive patients were subjected to microscopy and culture for fungal agents. Serum samples were analysed for precipitin antibodies to Aspergillus antigen and Candida cytoplasmic antigen. Statistical significance in the difference of fungal recovery between patient groups was determined using the Chi-square test. RESULTS: The major diagnostic groups included patients with bronchogenic carcinoma (n = 31) and tubercular sequelae (n = 16). In all, 28 patients (46.7%) were culture-positive, with Candida and Aspergillus being recovered from 14 and 13 patients respectively. Twenty-one patients (35%) showed presence of precipitin antibodies. Patients with bronchogenic carcinoma showed increased predilection for colonisation with Aspergillus, while Candida was recovered more commonly in tubercular sequelae (p = 0.02). There was no statistically significant association between culture-positivity and specific risk factors/radiological findings. CONCLUSION: The point-prevalence of fungal colonization was almost 50%. The combination of fungal culture and serology helped improve diagnostic sensitivity. An interesting predilection was observed for Aspergillus and Candida, to preferentially infect patients with Bronchogenic carcinoma and Tubercular sequelae respectively. In absence of specific predictors, the possibility of fungal colonization needs to be explored actively in these patients. PMID- 20854653 TI - A method for addressing research gaps in HTA, developed whilst evaluating robotic assisted surgery: a proposal. AB - BACKGROUND: When evaluating health technologies with insufficient scientific evidence, only innovative potentials can be assessed. A Regional policy initiative linking the governance of health innovations to the development of clinical research has been launched by the Region of Emilia Romagna Healthcare Authority. This program, aimed at enhancing the research capacity of health organizations, encourages the development of adoption plans that combine use in clinical practice along with experimental use producing better knowledge. Following the launch of this program we developed and propose a method that, by evaluating and ranking scientific uncertainty, identifies the moment (during the stages of the technology's development) where it would be sensible to invest in research resources and capacity to further its evaluation. The method was developed and tested during a research project evaluating robotic surgery. METHODS: A multidisciplinary panel carried out a 5-step evaluation process: 1) definition of the technology's evidence profile and of all relevant clinical outcomes; 2) systematic review of scientific literature and outline of the uncertainty profile differentiating research results into steady, plausible, uncertain and unknown results; 3) definition of the acceptable level of uncertainty for investing research resources; 4) analysis of local context; 5) identification of clinical indications with promising clinical return. RESULTS: Outputs for each step of the evaluation process are: 1) evidence profile of the technology and systematic review; 2) uncertainty profile for each clinical indication; 3) exclusion of clinical indications not fulfilling the criteria of maximum acceptable risk; 4) mapping of local context; 5) recommendations for research.Outputs of the evaluation process for robotic surgery are described in the paper. CONCLUSIONS: This method attempts to rank levels of uncertainty in order to distinguish promising from hazardous clinical use and to outline a research course of action. Decision makers wishing to tie coverage policies to the development of scientific evidence could find this method a useful aid to the governance of innovations. PMID- 20854655 TI - Cerebral amyloidoma mimicking intracranial tumor: a case report. AB - INTRODUCTION: Cerebral amyloidoma is an infrequently recognized condition that can be confused with a more malignant etiology. Few cases have been reported. We present a case report and a review of the literature. CASE PRESENTATION: Our patient was a 64-year-old Caucasian man who was incidentally discovered to have a brain mass. He was found to have a cerebral amyloidoma. CONCLUSION: After discovery of the true etiology of his brain abnormality, it was determined that our patient had a more benign disease than was initially feared. Cases such as this demonstrate why consideration of this disorder is important. PMID- 20854654 TI - Putting prevention into practice: qualitative study of factors that inhibit and promote preventive care by general practitioners, with a focus on elderly patients. AB - BACKGROUND: General practitioners (GPs) have a key role in providing preventive care, particularly for elderly patients. However, various factors can inhibit or promote the implementation of preventive care. In the present study, we identified and examined factors that inhibit and promote preventive care by German GPs, particularly for elderly patients, and assessed changes in physicians' attitudes toward preventive care throughout their careers. METHODS: A qualitative, explorative design was used to identify inhibitors and promoters of preventive care in German general medical practice. A total of 32 GPs in Berlin and Hannover were surveyed. Questions about factors that promote or inhibit implementation of preventive care and changes in physicians' perceptions of promoting and inhibiting factors throughout their careers were identified. Episodic interviews, which encouraged the reporting of anecdotes regarding daily knowledge and experiences, were analyzed using ATLAS/ti. Socio-demographic data of GPs and structural information about their offices were collected using short questionnaires. The factors identified as inhibitory or promoting were classified as being related to patients, physicians, or the healthcare system. The changes in GP attitudes toward preventive care throughout their careers were classified as personal transitions or as social and health policy transitions. RESULTS: Most of the identified barriers to preventive care were related to patients, such as a lack of motivation for making lifestyle changes and a lack of willingness to pay for preventive interventions. In addition, the healthcare system seemed to inadequately promote preventive care, mainly due to poor reimbursement for preventive care and fragmentation of care. GPs own attitudes and health habits seemed to influence the implementation of preventive care. GPs recognized their own lack of awareness of effective preventive interventions, particularly for elderly patients. GPs were motivated by positive preventive experiences, but often lacked the necessary training to counsel and support their patients. CONCLUSIONS: German GPs had positive attitudes towards prevention, but the implementation of preventive care was neither systematic nor continuous. Identification and elimination of barriers to preventive care is crucial. Further research is needed to identify effective practice-based approaches to overcome these barriers. PMID- 20854656 TI - Molecular characterization of tlyA gene product, Rv1694 of Mycobacterium tuberculosis: a non-conventional hemolysin and a ribosomal RNA methyl transferase. AB - BACKGROUND: Mycobacterium tuberculosis is a virulent bacillus causing tuberculosis, a disease responsible for million deaths each year worldwide. In order to understand its mechanism of pathogenesis in humans and to help control tuberculosis, functions of numerous Mycobacterium tuberculosis genes are being characterized. In this study we report the dual functionality of tlyA gene product of Mycobacterium tuberculosis annotated as Rv1694, a 268 amino acid long basic protein. RESULTS: The recombinant purified Rv1694 protein was found to exhibit hemolytic activity in vitro. It showed concentration and time-dependent hemolysis of rabbit and human erythrocytes. Multiple oligomeric forms (dimers to heptamers) of this protein were seen on the membranes of the lysed erythrocytes. Like the oligomers of conventional, well-known, pore-forming toxins, the oligomers of Rv1694 were found to be resistant to heat and SDS, but were susceptible to reducing agents like beta-mercaptoethanol as it had abolished the hemolytic activity of Rv1694 indicating the role of disulfide bond(s). The Rv1694 generated de novo by in vitro transcription and translation also exhibited unambiguous hemolysis confirming the self assembly and oligomerization properties of this protein. Limited proteolytic digestion of this protein has revealed that the amino terminus is susceptible while in solution but is protected in presence of membrane. Striking feature of Rv1694 is its presence on the cell wall of E. coli as visualized by confocal microscopy. The surface expression is consistent with the contact dependent haemolytic ability of E. coli expressing this protein. Also, immune serum specific to this protein inhibits the contact dependent hemolysis. Moreover, Rv1694 protein binds to and forms stable oligomers on the macrophage phagosomal membranes. In addition to all these properties, E. coli expressing Rv1694 was found to be susceptible to the antibiotic capreomycin as its growth was significantly slower than mock vector transformed E. coli. The S30 extract of E. coli expressing the Rv1694 had poor translational activity in presence of capreomycin, further confirming its methylation activity. Finally, incorporation of methyl group of [3H]-S-adenosylmethionine in isolated ribosomes also confirmed its methylation activity. CONCLUSIONS: The Rv1694 has an unusual dual activity. It appears to contain two diverse functions such as haemolytic activity and ribosomal RNA methylation activity. It is possible that the haemolytic activity might be relevant to intra-cellular compartments such as phagosomes rather than cell lysis of erythrocytes and the self-assembly trait may have a potential role after successful entry into macrophages by Mycobacterium tuberculosis. PMID- 20854657 TI - The blue lizard spandrel and the island syndrome. AB - BACKGROUND: Many small vertebrates on islands grow larger, mature later, lay smaller clutches/litters, and are less sexually dimorphic and aggressive than their mainland relatives. This set of observations is referred to as the 'Island Syndrome'. The syndrome is linked to high population density on islands. We predicted that when population density is low and/or fluctuating insular vertebrates may evolve correlated trait shifts running opposite to the Island Syndrome, which we collectively refer to as the 'reversed island syndrome' (RIS) hypothesis. On the proximate level, we hypothesized that RIS is caused by increased activity levels in melanocortin receptors. Melanocortins are postranslational products of the proopiomelanocortin gene, which controls pleiotropically pigmentation, aggressiveness, sexual activity, and food intake in vertebrates. RESULTS: We tested the RIS hypothesis performing a number of behavioral, genetic, and ontogenetic tests on a blue colored insular variant of the Italian Wall lizard Podarcis sicula, living on a small island off the Southern Italian coast. The population density of this blue-colored variant was generally low and highly fluctuating from one year to the next.In keeping with our predictions, insular lizards were more aggressive and sexually dimorphic than their mainland relatives. Insular males had wide, peramorphic heads. The growth rate of insular females was slower than growth rates of mainland individuals of both sexes, and of insular males. Consequently, size and shape dimorphism are higher on the Island. As predicted, melanocortin receptors were much more active in individuals of the insular population. Insular lizards have a higher food intake rate than mainland individuals, which is consistent with the increased activity of melanocortin receptors. This may be adaptive in an unpredictable environment such as Licosa Island. Insular lizards of both sexes spent less time basking than their mainland relatives. We suspect this is a by-product (spandrel) of the positive selection for increased activity of melanocortins receptors. CONCLUSIONS: We contend that when population density is either low or fluctuating annually as a result of environmental unpredictability, it may be advantageous to individuals to behave more aggressively, to raise their rate of food intake, and allocate more energy into reproduction. PMID- 20854658 TI - Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. AB - INTRODUCTION: Genome wide association studies, replicated by numerous well powered validation studies, have revealed a large number of loci likely to play a role in susceptibility to many multifactorial diseases. It is now well established that some of these loci are shared between diseases with similar aetiology. For example, a number of autoimmune diseases have been associated with variants in the PTPN22, TNFAIP3 and CTLA4 genes. Here we have attempted to define overlapping genetic variants between rheumatoid arthritis (RA), type 1 diabetes (T1D) and coeliac disease (CeD). METHODS: We selected eight SNPs previously identified as being associated with CeD and six T1D-associated SNPs for validation in a sample of 3,962 RA patients and 3,531 controls. Genotyping was performed using the Sequenom MassArray platform and comparison of genotype and allele frequencies between cases and controls was undertaken. A trend test P value < 0.004 was regarded as significant. RESULTS: We found statistically significant evidence for association of the TAGAP locus with RA (P = 5.0 * 10-4). A marker at one other locus, C1QTNF6, previously associated with T1D, showed nominal association with RA in the current study but did not remain statistically significant at the corrected threshold. CONCLUSIONS: In exploring the overlap between T1D, CeD and RA, there is strong evidence that variation within the TAGAP gene is associated with all three autoimmune diseases. Interestingly a number of loci appear to be specific to one of the three diseases currently studied suggesting that they may play a role in determining the particular autoimmune phenotype at presentation. PMID- 20854659 TI - Overestimation of physical activity level is associated with lower BMI: a cross sectional analysis. AB - BACKGROUND: Poor recognition of physical inactivity may be an important barrier to healthy behaviour change, but little is known about this phenomenon. We aimed to characterize a high-risk population according to the discrepancies between objective and self-rated physical activity (PA), defined as awareness. METHODS: An exploratory cross-sectional analysis of PA awareness using baseline data collected from 365 ProActive participants between 2001 and 2003 in East Anglia, England. Self-rated PA was defined as 'active' or 'inactive' (assessed via questionnaire). Objective PA was defined according to achievement of guideline activity levels (>=30 minutes or <30 minutes spent at least moderate intensity PA, assessed by heart rate monitoring). Four awareness groups were created: 'Realistic Actives', 'Realistic Inactives', 'Overestimators' and 'Underestimators'. Logistic regression was used to assess associations between awareness group and 17 personal, social and biological correlates. RESULTS: 63.3% of participants (N = 231) were inactive according to objective measurement. Of these, 45.9% rated themselves as active ('Overestimators'). In a multiple logistic regression model adjusted for age and smoking, males (OR = 2.11, 95% CI = 1.12, 3.98), those with lower BMI (OR = 0.89, 95% CI = 0.84, 0.95), younger age at completion of full-time education (OR = 0.83, 95% CI = 0.74, 0.93) and higher general health perception (OR = 1.02 CI = 1.00, 1.04) were more likely to overestimate their PA. CONCLUSIONS: Overestimation of PA is associated with favourable indicators of relative slimness and general health. Feedback about PA levels could help reverse misperceptions. PMID- 20854660 TI - Trees on networks: resolving statistical patterns of phylogenetic similarities among interacting proteins. AB - BACKGROUND: Phylogenies capture the evolutionary ancestry linking extant species. Correlations and similarities among a set of species are mediated by and need to be understood in terms of the phylogenic tree. In a similar way it has been argued that biological networks also induce correlations among sets of interacting genes or their protein products. RESULTS: We develop suitable statistical resampling schemes that can incorporate these two potential sources of correlation into a single inferential framework. To illustrate our approach we apply it to protein interaction data in yeast and investigate whether the phylogenetic trees of interacting proteins in a panel of yeast species are more similar than would be expected by chance. CONCLUSIONS: While we find only negligible evidence for such increased levels of similarities, our statistical approach allows us to resolve the previously reported contradictory results on the levels of co-evolution induced by protein-protein interactions. We conclude with a discussion as to how we may employ the statistical framework developed here in further functional and evolutionary analyses of biological networks and systems. PMID- 20854661 TI - Feasibility study of volumetric modulated arc therapy for the treatment of retroperitoneal sarcomas. AB - BACKGROUND: Radiotherapy for retroperitoneal sarcomas remains controversial and a technical challenge considering the threshold of contiguous critical organs tolerance. We performed consecutive RapidArc dosimetric plans in preoperative or postoperative setting. METHODS: A dosimetric study was carried out from six preoperative (group A) and four postoperative (group B) CT-scans, performed in 7 patients.Prescribed dose was 45 and 50 Gy for groups A and B, respectively. The planning target volume (PTV) was defined as the clinical target volume (CTV) plus 5 mm. The CTV encompassed the gross tumor volume (GTV) plus 10 mm or the tumoral bed. The dosimetric plans were optimized on a RapidArc Eclipse console using the progressive resolution algorithm, PRO version 8.8. Normalization method allowed the coverage of 99% of the PTV by 95% of the dose. RESULTS: Mean PTV were 2318.5 +/- 2223.9 cc [range 348-6198 cc] and 698.3 +/- 216.6 cc [range 463 -933 cc] for groups A and B, respectively. Plans were optimized for single arcs in group B and for single or two arcs in group A. The contralateral kidney volume receiving 5 Gy (V5Gy) was 21.5 +/- 23.3% [range 0-55%] and 3.1 +/- 2.6% [range 0-7.3%] for groups A and B, respectively. The mean dose received by 1% of the kidney (D1%) was 5.6 +/- 2.4 Gy [range 3.6 -7.6 Gy] for group A and 5.4 +/- 0.7 Gy [range 4.3 6 Gy] for group B. The volume of small bowel excluding the PTV (small bowel-PTV) that received 40 Gy and 30 Gy (V40Gy and V30Gy) in group A were 7.5 +/- 4.4% [range 5.4-14.1%] and 18.5 +/- 7.1% [range 10-30.4%], respectively.In group B, small bowel-PTV V40Gy and V30Gy were 4.7 +/- 3.3% [range 3.3-8%] and 21.6 +/- 7.5% [range 9.4-30%] respectively. In a second step, we treated two patients in the postoperative group. Treatment time delivery with one arc was 74 seconds. No severe acute toxicity was observed. CONCLUSION: RapidArc technology for retroperitoneal sarcomas showed acceptable dosimetric results in preoperative or postoperative clinical situation. From the first treated patients, acute tolerability was good to excellent. PMID- 20854662 TI - Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. AB - INTRODUCTION: To elucidate in polymyalgia rheumatica (PMR) the role of tumor necrosis factor (TNF) alpha and the therapeutic potential of blockade with soluble TNF-alpha receptor, we carried out the first randomized controlled trial with etanercept in PMR. METHODS: Twenty newly diagnosed, glucocorticoid (GC) naive patients with PMR and 20 matched non-PMR control subjects completed the trial. Subjects were randomized in a 1:1 ratio to monotherapy with etanercept (25 mg s.c. biweekly) or placebo (saline) for 14 days. Study outcomes were assessed at baseline and after 14 days. The primary outcome was the change in PMR activity score (PMR-AS). Secondary outcomes were: changes in erythrocyte sedimentation rate (ESR) and plasma levels of TNF-alpha and interleukin (IL) 6; patients' functional status (health assessment questionnaire) and cumulative tramadol intake during the trial. RESULTS: At baseline, plasma TNF-alpha was higher in patients than in controls (P < 0.05). The concentration always increased with etanercept treatment (P < 0.05). In patients, etanercept decreased PMR-AS by 24% (P = 0.011), reflecting significant improvements in shoulder mobility, physician's global assessment and C-reactive protein, and insignificant (P > 0.05) improvements in duration of morning stiffness and patient's assessment of pain. In parallel, ESR and IL-6 were reduced (P < 0.05). Placebo treatment did not change PMR-AS, ESR and IL-6 (P > 0.05). Functional status did not change and tramadol intake did not differ between patient groups. In controls, no changes occurred in both groups. CONCLUSIONS: Etanercept monotherapy ameliorates disease activity in GC naive patients with PMR. However, the effect is modest, indicating a minor role of TNF-alpha in PMR. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00524381). PMID- 20854663 TI - Image resizing using saliency strength map and seam carving for white blood cell analysis. AB - BACKGROUND: A new image-resizing method using seam carving and a Saliency Strength Map (SSM) is proposed to preserve important contents, such as white blood cells included in blood cell images. METHODS: To apply seam carving to cell images, a SSM is initially generated using a visual attention model and the structural properties of white blood cells are then used to create an energy map for seam carving. As a result, the energy map maximizes the energies of the white blood cells, while minimizing the energies of the red blood cells and background. Thus, the use of a SSM allows the proposed method to reduce the image size efficiently, while preserving the important white blood cells. RESULTS: Experimental results using the PSNR (Peak Signal-to-Noise Ratio) and ROD (Ratio of Distortion) of blood cell images confirm that the proposed method is able to produce better resizing results than conventional methods, as the seam carving is performed based on an SSM and energy map. CONCLUSIONS: For further improvement, a faster medical image resizing method is currently being investigated to reduce the computation time, while maintaining the same image quality. PMID- 20854664 TI - Designing and implementing a longitudinal study of children with neurological, genetic or metabolic conditions: charting the territory. AB - BACKGROUND: Children with progressive metabolic, neurological, or chromosomal conditions and their families anticipate an unknown lifespan, endure unstable and often painful symptoms, and cope with erratic emotional and spiritual crises as the condition progresses along an uncertain trajectory towards death. Much is known about the genetics and pathophysiology of these diseases, but very little has been documented about the trajectory of symptoms for children with these conditions or the associated experience of their families. A longitudinal study design will help to close this gap in knowledge. METHODS/DESIGN: Charting the Territory is a longitudinal descriptive, correlational study currently underway with children 0-19 years who are diagnosed with progressive neurological, metabolic, or chromosomal conditions and their families. The purpose of the study is to determine and document the clinical progression of the condition and the associated bio-psychosocial-spiritual experiences of the parents and siblings age 7-18 years. Approximately 300 families, both newly diagnosed children and those with established conditions, are being recruited in six Canadian cities. Children and their families are being followed for a minimum of 18 months, depending on when they enroll in the study. Family data collection will continue after the child's death if the child dies during the study period. Data collection includes monthly parental assessment of the child's symptoms; an annual functional assessment of the child; and completion of established instruments every 6 months by parents to assess family functioning, marital satisfaction, health status, anxiety, depression, stress, burden, grief, spirituality, and growth, and by siblings to assess coping and health. Impact of participation on parents is assessed after 1 year and at the end of the study. Chart reviews are conducted at enrollment and at the conclusion of the study or at the time of the child's death. DISCUSSION: Knowledge developed from this study will provide some of the first-ever detailed descriptions of the clinical symptom trajectory of these non curable progressive conditions and the bio-psychosocial-spiritual aspects for families, from diagnosis through bereavement. Information about developing and implementing this study may be useful to other researchers who are interested in designing a longitudinal study. PMID- 20854665 TI - Palliative care for the elderly--developing a curriculum for nursing and medical students. AB - BACKGROUND: Delivering palliative care to elderly, dying patients is a present and future challenge. In Germany, this has been underlined by a 2009 legislation implementing palliative care as compulsory in the medical curriculum. While the number of elderly patients is increasing in many western countries multimorbidity, dementia and frailty complicate care. Teaching palliative care of the elderly to an interprofessional group of medical and nursing students can help to provide better care as acknowledged by the ministry of health and its expert panels. In this study we researched and created an interdisciplinary curriculum focussing on the palliative care needs of the elderly which will be presented in this paper. METHODS: In order to identify relevant learning goals and objectives for the curriculum, we proceeded in four subsequent stages. We searched international literature for existing undergraduate palliative care curricula focussing on the palliative care situation of elderly patients; we searched international literature for palliative care needs of the elderly. The searches were sensitive and limited in nature. Mesh terms were used where applicable. We then presented the results to a group of geriatrics and palliative care experts for critical appraisal. Finally, the findings were transformed into a curriculum, focussing on learning goals, using the literature found. RESULTS: The literature searches and expert feedback produced a primary body of results. The following deduction domains emerged: Geriatrics, Palliative Care, Communication & Patient Autonomy and Organisation & Social Networks. Based on these domains we developed our curriculum. CONCLUSIONS: The curriculum was successfully implemented following the Kern approach for medical curricula. The process is documented in this paper. The information given may support curriculum developers in their search for learning goals and objectives. PMID- 20854666 TI - Field experiments of Anopheles gambiae attraction to local fruits/seedpods and flowering plants in Mali to optimize strategies for malaria vector control in Africa using attractive toxic sugar bait methods. AB - BACKGROUND: Based on recent studies in Israel demonstrating that attractive toxic sugar bait (ATSB) methods can be used to decimate local anopheline and culicine mosquito populations, an important consideration is whether the same methods can be adapted and improved to attract and kill malaria vectors in Africa. The ATSB approach uses fruit or flower scent as an attractant, sugar solution as a feeding stimulant, and an oral toxin. The ATSB solutions are either sprayed on vegetation or suspended in simple bait stations, and the mosquitoes ingesting the toxic solutions are killed. As such, this approach targets sugar-feeding female and male mosquitoes. This study examines the attractiveness of African malaria vectors to local fruits/seedpods and flowering plants, key biological elements of the ATSB approach for mosquito control. METHODS: Three field experiments were conducted at sites in Mali. The attraction of Anopheles gambiae s.l. to 26 different local fruits and seedpods was determined at a site in the semi-arid Bandiagara District of Mali. Wire mesh glue traps with fruits/seedpods suspended on skewers inside were set along a seasonal lagoon. Seven replicates of each fruit/seedpod species were tested, with a water-soaked sponge and a sugar-soaked sponge as controls. The attraction of An. gambiae s.l. to 26 different types of flowering plants was determined at a site near Mopti in Mali. The flowering plants held in a water-filled buried container were tested using the same glue traps, with controls including water only and sugar solution. Six replicates of each selected plant type were tested on transects between rice paddies. Additional studies using CDC light traps were done to determine the relative densities and periodicity of An. gambiae s.l. attraction to branches of the most highly attractive flowering plant, branches without flowers, human odor, and candescent light. RESULTS: Of the 26 fruits and seedpods tested, 6 were attractive to An. gambiae s.l. females and males, respectively. Guava (Psidium guajava) and honey melon (Cucumis melo) were the two most attractive fruits for both females and males. Of the 26 flowering plants tested, 9 were significantly attractive for females, and 8 were attractive for males. Acacia macrostachya was the most attractive flowering plant. Periodicity studies using this plant showed peaks of An. gambiae s.l. attraction between 1930 and 2200 h and 0400-0500 h, which differed considerably from the response to human odors, which expectedly peaked at around midnight. CONCLUSION: These field experiments in Mali highlight that female and male An. gambiae s.l. have pronounced differences in attraction for diverse types of indigenous fruits/seedpods and flowering plants. The identification of attractive fruits and seedpods shows that a variety of indigenous and locally abundant natural products could potentially be used as juices to make ATSB solution for mosquito control. As well, the simple methods used to identify the most attractive flowering plants provide valuable insights into the natural history of sugar feeding for An. gambiae s.l. These observations can be used to guide future strategies for employing ATSB methods for malaria vector control in Africa. They also provide a basis for subsequent chemical analysis and development of attractive baits for mosquito control. PMID- 20854667 TI - Allergic bronchopulmonary aspergillosis with coexistant aspergilloma: a case report. AB - INTRODUCTION: The coexistence of allergic bronchopulmonary aspergillosis and aspergilloma is rare. CASE PRESENTATION: We present the case of a 56-year-old Caucasian man who worked as a farmer, with infiltrates in the right lower and middle lung lobes, partial consolidation of the middle lobe and with previous diagnosis of chronic obstructive bronchitis. Evaluation of our patient led to the diagnosis of allergic bronchopulmonary aspergillosis with coexistent aspergilloma in the right lower lobe. He was treated with oral methylprednisolone and itraconazole. At the five-year follow-up he is without any sign of recurrence. CONCLUSION: Aspergillus infection after the inhalation of spores in the form of a hypersensitivity reaction and saprophytic colonization can be coexistent. PMID- 20854668 TI - Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study. AB - AIMS: To investigate the impact of iron intake on the development of type 1 diabetes (T1DM). METHODS: Case-control study with self-administered questionnaire among families of children with T1DM who were less than 10 years old at the time of the survey and developed diabetes between age 1 and 6 years. Data on the types of infant feeding in the first 4 months of life was collected from parents of children with T1DM (n = 128) and controls (n = 67) <10 years old. Because some cases had sibling controls, we used conditional logistic regression models to analyze the data in two ways. First we performed a case-control analysis of all 128 cases and 67 controls. Next, we performed a case-control analysis restricted to cases (n = 59) that had a sibling without diabetes (n = 59). Total iron intake was modeled as one standard deviation (SD) increase in iron intake. The SD for iron intake was 540 mg in the total sample and 539 mg in the restricted sample as defined above. RESULTS: The median (min, max) total iron intake in the first 4 months of life was 1159 (50, 2399) mg in T1DM cases and 466 (50, 1224) mg among controls (P < 0.001). For each one standard deviation increase in iron intake, the odds ratio (95% confidence interval) for type 1 diabetes was 2.01 (1.183, 3.41) among all participants (128 cases and 67 controls) while it was 2.26 (1.27, 4.03) in a restricted sample of T1 D cases with a control sibling (59 cases and 59 controls) in models adjusted for birth weight, age at the time of the survey, and birth order. CONCLUSION: In this pilot study, high iron intake in the first 4 months of infancy is associated with T1DM. Whether iron intake is causal or a marker of another risk factor warrants further investigation. PMID- 20854669 TI - Colonization of Morus alba L. by the plant-growth-promoting and antagonistic bacterium Burkholderia cepacia strain Lu10-1. AB - BACKGROUND: Anthracnose, caused by Colletotrichum dematium, is a serious threat to the production and quality of mulberry leaves in susceptible varieties. Control of the disease has been a major problem in mulberry cultivation. Some strains of Burkholderia cepacia were reported to be useful antagonists of plant pests and could increase the yields of several crop plants. Although B. cepacia Lu10-1 is an endophytic bacterium obtained from mulberry leaves, it has not been deployed to control C. dematium infection in mulberry nor its colonization patterns in mulberry have been studied using GFP reporter or other reporters. The present study sought to evaluate the antifungal and plant-growth-promoting properties of strain Lu10-1, to clarify its specific localization within a mulberry plant, and to better understand its potential as a biocontrol and growth promoting agent. RESULTS: Lu10-1 inhibited conidial germination and mycelial growth of C. dematium in vitro; when applied on leaves or to the soil, Lu10-1 also inhibited the development of anthracnose in a greenhouse, but the effectiveness varied with the length of the interval between the strain treatment and inoculation with the pathogen. Strain Lu10-1 could survive in both sterile and non-sterile soils for more than 60 days. The strain produced auxins, contributed to P solubilization and nitrogenase activity, and significantly promoted the growth of mulberry seedlings. The bacteria infected mulberry seedlings through cracks formed at junctions of lateral roots with the main root and in the zone of differentiation and elongation, and the cells were able to multiply and spread, mainly to the intercellular spaces of different tissues. The growth in all the tissues was around 1-5 * 105 CFU per gram of fresh plant tissue. CONCLUSIONS: Burkholderia cepacia strain Lu10-1 is an endophyte that can multiply and spread in mulberry seedlings rapidly and efficiently. The strain is antagonistic to C. dematium and acts as an efficient plant-growth-promoting agent on mulberry seedlings and is therefore a promising candidate as a biocontrol and growth-promoting agent. PMID- 20854670 TI - Development of the interRAI Pressure Ulcer Risk Scale (PURS) for use in long-term care and home care settings. AB - BACKGROUND: In long-term care (LTC) homes in the province of Ontario, implementation of the Minimum Data Set (MDS) assessment and The Braden Scale for predicting pressure ulcer risk were occurring simultaneously. The purpose of this study was, using available data sources, to develop a bedside MDS-based scale to identify individuals under care at various levels of risk for developing pressure ulcers in order to facilitate targeting risk factors for prevention. METHODS: Data for developing the interRAI Pressure Ulcer Risk Scale (interRAI PURS) were available from 2 Ontario sources: three LTC homes with 257 residents assessed during the same time frame with the MDS and Braden Scale for Predicting Pressure Sore Risk, and eighty-nine Ontario LTC homes with 12,896 residents with baseline/reassessment MDS data (median time 91 days), between 2005-2007. All assessments were done by trained clinical staff, and baseline assessments were restricted to those with no recorded pressure ulcer. MDS baseline/reassessment samples used in further testing included 13,062 patients of Ontario Complex Continuing Care Hospitals (CCC) and 73,183 Ontario long-stay home care (HC) clients. RESULTS: A data-informed Braden Scale cross-walk scale using MDS items was devised from the 3-facility dataset, and tested in the larger longitudinal LTC homes data for its association with a future new pressure ulcer, giving a c statistic of 0.676. Informed by this, LTC homes data along with evidence from the clinical literature was used to create an alternate-form 7-item additive scale, the interRAI PURS, with good distributional characteristics and c-statistic of 0.708. Testing of the scale in CCC and HC longitudinal data showed strong association with development of a new pressure ulcer. CONCLUSIONS: interRAI PURS differentiates risk of developing pressure ulcers among facility-based residents and home care recipients. As an output from an MDS assessment, it eliminates duplicated effort required for separate pressure ulcer risk scoring. Moreover, it can be done manually at the bedside during critical early days in an admission when the full MDS has yet to be completed. It can be calculated with established MDS instruments as well as with the newer interRAI suite instruments designed to follow persons across various care settings (interRAI Long-Term Care Facilities, interRAI Home Care, interRAI Palliative Care). PMID- 20854671 TI - Dual task interference during gait in patients with unilateral vestibular disorders. AB - BACKGROUND: Vestibular patients show slower and unsteady gait; they have also been shown to need greater cognitive resources when carrying out balance and cognitive dual tasks (DT). This study investigated DT interference during gait in a middle-aged group of subjects with dizziness and unsteadiness after unilateral vestibular neuronitis and in a healthy control group. METHODS: Fourteen individuals with subacute unilateral vestibular impairment after neuronitis and seventeen healthy subjects performed gait and cognitive tasks in single and DT conditions. A statistical gait analysis system was used and spatio-temporal parameters were considered. The cognitive task, consisting of backward counting by three, was tape recorded and the number of right figures was then calculated. RESULTS: Both patients and controls showed a more conservative gait during DT and between groups significant differences were not found. A significant decrease in cognitive performance during DT was found only in the vestibular group. CONCLUSIONS: Results suggest that less attentional resources are available during gait in vestibular patients compared to controls, and that a priority is given in keeping up the motor task to the detriment of a decrease of the cognitive performance during DT. PMID- 20854672 TI - Bystander T cells in human immune responses to dengue antigens. AB - BACKGROUND: Previous studies of T cell activation in dengue infection have focused on restriction of specific T cell receptors (TCRs) and classical MHC molecules. However, bystander T cell activation, which is TCR independent, occurs via cytokines in other viral infections, both in vitro and in vivo, and enables T cells to bypass certain control checkpoints. Moreover, clinical and pathological evidence has pointed to cytokines as the mediators of dengue disease severity. Therefore, we investigated bystander T cell induction by dengue viral antigen. RESULTS: Whole blood samples from 55 Thai schoolchildren aged 13-14 years were assayed for in vitro interferon-gamma (IFN-gamma) induction in response to inactivated dengue serotype 2 antigen (Den2). The contribution of TCR-dependent and independent pathways was tested by treatment with cyclosporin A (CsA), which inhibits TCR-dependent activation of T cells. ELISA results revealed that approximately 72% of IFN-gamma production occurred via the TCR-dependent pathway. The major IFN-gamma sources were natural killer (NK) (mean +/- SE = 55.2 +/- 3.3), CD4+T (24.5 +/- 3.3) and CD8+T cells (17.9 +/- 1.5), respectively, as demonstrated by four-color flow cytometry. Interestingly, in addition to these cells, we found CsA-resistant IFN-gamma producing T cells (CD4+T = 26.9 +/- 3.6% and CD8+T = 20.3 +/- 2.1%) implying the existence of activated bystander T cells in response to dengue antigen in vitro. These bystander CD4+ and CD8+T cells had similar kinetics to NK cells, appeared after 12 h and were inhibited by anti-IL 12 neutralization indicating cytokine involvement. CONCLUSIONS: This study described immune cell profiles and highlighted bystander T cell activation in response to dengue viral antigens of healthy people in an endemic area. Further studies on bystander T cell activation in dengue viral infection may reveal the immune mechanisms that protect or enhance pathogenesis of secondary dengue infection. PMID- 20854673 TI - SeqAnt: a web service to rapidly identify and annotate DNA sequence variations. AB - BACKGROUND: The enormous throughput and low cost of second-generation sequencing platforms now allow research and clinical geneticists to routinely perform single experiments that identify tens of thousands to millions of variant sites. Existing methods to annotate variant sites using information from publicly available databases via web browsers are too slow to be useful for the large sequencing datasets being routinely generated by geneticists. Because sequence annotation of variant sites is required before functional characterization can proceed, the lack of a high-throughput pipeline to efficiently annotate variant sites can act as a significant bottleneck in genetics research. RESULTS: SeqAnt (Sequence Annotator) is an open source web service and software package that rapidly annotates DNA sequence variants and identifies recessive or compound heterozygous loci in human, mouse, fly, and worm genome sequencing experiments. Variants are characterized with respect to their functional type, frequency, and evolutionary conservation. Annotated variants can be viewed on a web browser, downloaded in a tab-delimited text file, or directly uploaded in a BED format to the UCSC genome browser. To demonstrate the speed of SeqAnt, we annotated a series of publicly available datasets that ranged in size from 37 to 3,439,107 variant sites. The total time to completely annotate these data completely ranged from 0.17 seconds to 28 minutes 49.8 seconds. CONCLUSION: SeqAnt is an open source web service and software package that overcomes a critical bottleneck facing research and clinical geneticists using second-generation sequencing platforms. SeqAnt will prove especially useful for those investigators who lack dedicated bioinformatics personnel or infrastructure in their laboratories. PMID- 20854674 TI - Use of anchorchip-time-of-flight spectrometry technology to screen tumor biomarker proteins in serum for small cell lung cancer. AB - BACKGROUND: The purpose of this study is to discover potential biomarkers in serum for the detection of small cell lung cancer (SCLC). METHODS: 74 serum samples including 30 from SCLC patients and 44 from healthy controls were analyzed using ClinProt system combined with matrix-assisted laser desorption/ionization time-of-flight masss spectrometry (MALDI-TOF-MS). ClinProt software and genetic algorithm analysis selected a panel of serum markers that most efficiently predicted which patients had SCLC. RESULTS: The diagnostic pattern combined with 5 potential biomarkers could differentiate SCLC patients from healthy persons, with a sensitivity of 90%, specificity of 97.73%. Remarkably, 88.89% of stage I/II patients were accurately assigned to SCLC. CONCLUSIONS: Anchorchip-time-of-flight spectrometry technology will provide a highly accurate approach for discovering new biomarkers for the detection of SCLC. PMID- 20854675 TI - Adder bite: an uncommon cause of compartment syndrome in northern hemisphere. AB - Snakebite envenomation is an uncommon condition in the northern hemisphere, but requires high vigilance with regard to both the systemic effects of the venom and the locoregional impact on the soft tissues. Bites from the adder, Vipera Berus, may have serious clinical consequences due to systemic effects. A case of a 44 year-old man is reported. The patient was bitten in the right hand. He developed fasciotomy-requiring compartment syndrome of the upper limb. Recognition of this most seldom complication of an adder bite is vital to save the limb. We recommend that the classical signs and symptoms of compartment syndrome serve as indication for surgical decompression. PMID- 20854676 TI - Evaluating gene by sex and age interactions on cardiovascular risk factors in Brazilian families. AB - BACKGROUND: In family studies, it is important to evaluate the impact of genes and environmental factors on traits of interest. In particular, the relative influences of both genes and the environment may vary in different strata of the population of interest, such as young and old individuals, or males and females. METHODS: In this paper, extensions of the variance components model are used to evaluate heterogeneity in the genetic and environmental variance components due to the effects of sex and age (the cutoff between young and old was 43 yrs). The data analyzed were from 81 Brazilian families (1,675 individuals) of the Baependi Family Heart Study. RESULTS: The models allowing for heterogeneity of variance components by sex suggest that genetic and environmental variances are not different in males and females for diastolic blood pressure, LDL-cholesterol, and HDL-cholesterol, independent of the covariates included in the models. However, for systolic blood pressure, fasting glucose and triglycerides, the evidence for heterogeneity was dependent on the covariates in the model. For instance, in the presence of sex and age covariates, heterogeneity in the genetic variance component was suggested for fasting glucose. But, for systolic blood pressure, there was no evidence of heterogeneity in any of the two variance components. Except for the LDL-cholesterol, models allowing for heterogeneity by age provide evidence of heterogeneity in genetic variance for triglycerides and systolic and diastolic blood pressure. There was evidence of heterogeneity in environmental variance in fasting glucose and HDL-cholesterol. CONCLUSIONS: Our results suggest that heterogeneity in trait variances should not be ignored in the design and analyses of gene-finding studies involving these traits, as it may generate additional information about gene effects, and allow the investigation of more sophisticated models such as the model including sex-specific oligogenic variance components. PMID- 20854677 TI - Scoping studies: advancing the methodology. AB - BACKGROUND: Scoping studies are an increasingly popular approach to reviewing health research evidence. In 2005, Arksey and O'Malley published the first methodological framework for conducting scoping studies. While this framework provides an excellent foundation for scoping study methodology, further clarifying and enhancing this framework will help support the consistency with which authors undertake and report scoping studies and may encourage researchers and clinicians to engage in this process. DISCUSSION: We build upon our experiences conducting three scoping studies using the Arksey and O'Malley methodology to propose recommendations that clarify and enhance each stage of the framework. Recommendations include: clarifying and linking the purpose and research question (stage one); balancing feasibility with breadth and comprehensiveness of the scoping process (stage two); using an iterative team approach to selecting studies (stage three) and extracting data (stage four); incorporating a numerical summary and qualitative thematic analysis, reporting results, and considering the implications of study findings to policy, practice, or research (stage five); and incorporating consultation with stakeholders as a required knowledge translation component of scoping study methodology (stage six). Lastly, we propose additional considerations for scoping study methodology in order to support the advancement, application and relevance of scoping studies in health research. SUMMARY: Specific recommendations to clarify and enhance this methodology are outlined for each stage of the Arksey and O'Malley framework. Continued debate and development about scoping study methodology will help to maximize the usefulness and rigor of scoping study findings within healthcare research and practice. PMID- 20854678 TI - Validity of self-assessment of hallux valgus using the Manchester scale. AB - BACKGROUND: Hallux valgus (HV) is a common condition involving the progressive subluxation of the first metatarsophalangeal joint due to lateral deviation of the hallux and medial deviation of the first metatarsal. The objective of this study was to evaluate the re-test reliability and validity of self-assessment of HV using a simple clinical screening tool involving four standardised photographs (the Manchester scale), in order to determine whether this tool could be used for postal surveys of the condition. METHODS: HV was assessed with the Manchester scale in 138 people aged 65 to 93 years of age (102 women and 36 men) as part of a larger randomised controlled trial. At the six month follow-up assessment, HV was reassessed to determine re-test reliability, and participants were asked to self-assess their degree of HV independent of the examiners. Associations between (i) baseline and follow-up assessments of the examiners and (ii) participant and examiner assessments were performed using weighted kappa statistics. Analyses were then repeated after HV was dichotomised as present or absent using unweighted kappa, and sensitivity and specificity of self-assessment of HV was determined. RESULTS: Re-test reliability of the examiners was substantial to almost perfect (weighted kappa = 0.78 to 0.90), and there was a substantial level of agreement between observations of the participants and the examiners (weighted kappa = 0.71 to 0.80). Overall, there was a slight tendency for participants to rate their HV as less severe than the examiners. When the Manchester scale scores were dichotomised, agreement was substantial to almost perfect for both re-test comparisons (kappa = 0.80 to 0.89) and substantial for comparisons between participants and examiners (kappa = 0.64 to 0.76). The sensitivity and specificity of self-assessment of HV using the dichotomous scale were 85 and 88%, respectively. CONCLUSIONS: The Manchester scale demonstrates high re-test reliability, and self-assessment scores obtained by participants are strongly associated with scores obtained by examiners. These findings indicate that the tool can be used with confidence in postal surveys to document the presence and severity of HV. TRIAL REGISTRATION: ACTRN12608000065392. PMID- 20854679 TI - Knowledge and attitudes of primary health care physicians and nurses with regard to population screening for colorectal cancer in Balearic Islands and Barcelona. AB - BACKGROUND: Primary health care (PHC) professionals play a key role in population screening of colorectal cancer. The purposes of the study are: to assess knowledge and attitudes among PHC professionals with regard to colorectal cancer screening, as well as the factors that determine their support for such screening. METHODS: Questionnaire-based survey of PHC physicians and nurses in the Balearic Islands and in a part of the metropolitan area of Barcelona. RESULTS: We collected 1,219 questionnaires. About 84% of all professionals believe that screening for colorectal cancer by fecal occult blood test (FOBT) is effective. Around 68% would recommend to their clients a colorectal cancer screening program based on FOBT and colonoscopy. About 31% are reluctant or do not know. Professionals perceive the fear of undergoing a colonoscopy as the main obstacle in getting patients to participate, and the invasive nature of this test is the main reason behind their resistance to this program. The main barriers to support the screening program among PHC professionals are lack of knowledge (nurses) and lack of time (physicians). On multivariate analysis, the factors associated with reluctance to recommend colorectal cancer screening were: believing that FOBT has poor sensitivity and is complicated; that colonoscopy is an invasive procedure; that a lack of perceived benefit could discourage client participation; that only a minority of clients would participate; thinking that clients are fed up with screening tests and being unaware if they should be offered something to ensure their participation in the programme. CONCLUSIONS: Two in every three PHC professionals would support a population screening program for colorectal cancer screening. Factors associated with reluctance to recommend it were related with screening tests characteristics as sensitivity and complexity of FOBT, and also invasive feature of colonoscopy. Other factors were related with patients' believes. PMID- 20854680 TI - Fatigue in fibromyalgia: a conceptual model informed by patient interviews. AB - BACKGROUND: Fatigue is increasingly recognized as an important symptom in fibromyalgia (FM). Unknown however is how fatigue is experienced by individuals in the context of FM. We conducted qualitative research in order to better understand aspects of fatigue that might be unique to FM as well as the impact it has on patients' lives. The data obtained informed the development of a conceptual model of fatigue in FM. METHODS: Open-ended interviews were conducted with 40 individuals with FM (US [n = 20], Germany [n = 10] and France [n = 10]). Transcripts were analyzed using qualitative methods based upon grounded theory to identify key themes and concepts. RESULTS: Participants were mostly female (70%) with a mean age of 48.7 years (range: 25-79). Thirty-one individuals (i.e., 77.5%) spontaneously described experiencing tiredness/lack of energy/fatigue due to FM. Participants discussed FM fatigue as being more severe, constant/persistent and unpredictable than normal tiredness. The conceptual model depicts the key elements of fatigue in FM from a patient perspective. This includes: an overwhelming feeling of tiredness (n = 17, 42.5%), not relieved by resting/sleeping (n = 15, 37.5%), not proportional to effort exerted (n = 25, 62.5%), associated with a feeling of weakness/heaviness (n = 20, 50%), interferes with motivation (n = 22, 55%), interferes with desired activities (n = 27, 67.5%), prolongs tasks (n = 15, 37.5%), and makes it difficult to concentrate (n = 21, 52.5%), think clearly (n = 12, 30%) or remember things (n = 9, 22.5%). CONCLUSION: The majority of individuals with FM who participated in this study experience fatigue and describe it as more severe than normal tiredness. PMID- 20854681 TI - Dioecious Silene latifolia plants show sexual dimorphism in the vegetative stage. AB - BACKGROUND: Prior to this study, no differences in gene expression between male and female dioecious plants in the vegetative state had been detected. Among dioecious plants displaying sexual dimorphism, Silene latifolia is one of the most studied species. Although many sexually dimorphic traits have been described in S. latifolia, all of them are quantitative, and they usually become apparent only after the initiation of flowering. RESULTS: We present RT-PCR-based evidence that in S. latifolia, sexual dimorphism in gene expression is present long before the initiation of flowering. We describe three ESTs that show sex-specific (two male specific and one female specific) transcription at the rosette stage before the first flowering season. CONCLUSIONS: To our knowledge, this study provides the first molecular evidence of early pre-flowering sexual dimorphism in angiosperms. PMID- 20854682 TI - Reference gene selection for quantitative reverse transcription-polymerase chain reaction normalization during in vitro adventitious rooting in Eucalyptus globulus Labill. AB - BACKGROUND: Eucalyptus globulus and its hybrids are very important for the cellulose and paper industry mainly due to their low lignin content and frost resistance. However, rooting of cuttings of this species is recalcitrant and exogenous auxin application is often necessary for good root development. To date one of the most accurate methods available for gene expression analysis is quantitative reverse transcription-polymerase chain reaction (qPCR); however, reliable use of this technique requires reference genes for normalization. There is no single reference gene that can be regarded as universal for all experiments and biological materials. Thus, the identification of reliable reference genes must be done for every species and experimental approach. The present study aimed at identifying suitable control genes for normalization of gene expression associated with adventitious rooting in E. globulus microcuttings. RESULTS: By the use of two distinct algorithms, geNorm and NormFinder, we have assessed gene expression stability of eleven candidate reference genes in E. globulus: 18S, ACT2, EF2, EUC12, H2B, IDH, SAND, TIP41, TUA, UBI and 33380. The candidate reference genes were evaluated in microccuttings rooted in vitro, in presence or absence of auxin, along six time-points spanning the process of adventitious rooting. Overall, the stability profiles of these genes determined with each one of the algorithms were very similar. Slight differences were observed in the most stable pair of genes indicated by each program: IDH and SAND for geNorm, and H2B and TUA for NormFinder. Both programs identified UBI and 18S as the most variable genes. To validate these results and select the most suitable reference genes, the expression profile of the ARGONAUTE1 gene was evaluated in relation to the most stable candidate genes indicated by each algorithm. CONCLUSION: Our study showed that expression stability varied between putative reference genes tested in E. globulus. Based on the AGO1 relative expression profile obtained using the genes suggested by the algorithms, H2B and TUA were considered as the most suitable reference genes for expression studies in E. globulus adventitious rooting. UBI and 18S were unsuitable for use as controls in qPCR related to this process. These findings will enable more accurate and reliable normalization of qPCR results for gene expression studies in this economically important woody plant, particularly related to rooting and clonal propagation. PMID- 20854683 TI - Gravitation field algorithm and its application in gene cluster. AB - BACKGROUND: Searching optima is one of the most challenging tasks in clustering genes from available experimental data or given functions. SA, GA, PSO and other similar efficient global optimization methods are used by biotechnologists. All these algorithms are based on the imitation of natural phenomena. RESULTS: This paper proposes a novel searching optimization algorithm called Gravitation Field Algorithm (GFA) which is derived from the famous astronomy theory Solar Nebular Disk Model (SNDM) of planetary formation. GFA simulates the Gravitation field and outperforms GA and SA in some multimodal functions optimization problem. And GFA also can be used in the forms of unimodal functions. GFA clusters the dataset well from the Gene Expression Omnibus. CONCLUSIONS: The mathematical proof demonstrates that GFA could be convergent in the global optimum by probability 1 in three conditions for one independent variable mass functions. In addition to these results, the fundamental optimization concept in this paper is used to analyze how SA and GA affect the global search and the inherent defects in SA and GA. Some results and source code (in Matlab) are publicly available at http://ccst.jlu.edu.cn/CSBG/GFA. PMID- 20854685 TI - Association of the eNOS E298D polymorphism and the risk of myocardial infarction in the Greek population. AB - BACKGROUND: Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays a key role in the regulation of vascular tone. Endothelium-derived NO exerts vasoprotective effects by suppressing platelet aggregation, leukocyte adhesion and smooth muscle cell proliferation. The E298D polymorphic variant of eNOS has been associated with myocardial infarction (MI), but data relating to this variant are divergent in Greece. Accordingly, we examined a possible association between the E298D polymorphism of the eNOS gene and MI in a subgroup of the Greek population. METHODS: The study population consisted of 204 patients with a history of MI and 218 control subjects. All subjects were of Greek origin and were selected from the general population of the greater Athens area. Genotyping was performed with melting curve analysis (Lightcycler system) of polymerase chain reaction amplified products using hybridization probes. RESULTS: According to the univariate findings, the risk for MI in E298D TT was 2.06 (95%CI: 1.06-4.00, p = 0.032) versus GG+GT and 2.34 (95%CI: 1.17-4.68, p = 0.016) versus GG. The risk for the T allele was estimated at 1.42 (95%CI, 1.06-1.89, p = 0.022) as compared to G allele. Regarding the additive model, one allele increase was associated with 43% higher risk of MI (OR = 1.43, 95%CI: 1.07-1.93, p = 0.018) as compared to the baseline category of homozygous GG. The positive association of TT versus GG+GT with MI risk remained even after adjusting for the main study covariates. Moreover, strong evidence was found for an increased risk for MI among carriers of the TT genotype who were smokers, hypertensive and had a family history of CAD. CONCLUSIONS: This study indicates that E298D polymorphism of the eNOS gene seems to be associated with MI occurrence in the Greek population. It is possible that TT genotype is closely linked to the etiology of MI even after adjusting for known MI risk factors. PMID- 20854686 TI - Immunologgical self-tolerance in allophenic and embryo-aggregated mice. AB - Allophenic mice, supposedly containing almost equal numbers of cells derived from embryos of mouse strains C57Bl and FVB, were shown in a recent paper to grow the B16 melanoma, a long transplanted tumor of C57Bl origin, much better than did mice of either the parental C57Bl strain or the C57Bl x FVB F1 hybrid. Mice containing smaller proportions of C57Bl cells rejected the tumor. A reconsideration of these suprising data, in light of the current literature, suggests that the better growth of the tumor in the 50-50% allophenics than in the C57Bl parental strain was almost certainly caused by the tumor stimulation engendered by a weak anti-C57Bl immune reaction in the overtly healthy allophenic mice. PMID- 20854684 TI - Use of an innovative model to evaluate mobility in seniors with lower-limb amputations of vascular origin: a pilot study. AB - BACKGROUND: The mobility of older individuals has often been only partially assessed, without considering all important aspects such as potential (available) versus effective (used) mobilities and the physical and psychosocial factors that modulate them. This study proposes a new model for evaluating mobility that considers all important aspects, applied here to lower-limb amputees with vascular origin. This model integrates the concepts of potential mobility (e.g. balance, speed of movement), effective mobility (e.g. life habits, movements in living areas) and factors that modulate these two types of mobility (e.g. strength, sensitivity, social support, depression). The main objective was to characterize potential and effective mobility as well as mobility modulators in a small sample of people with lower-limb amputations of vascular origin with different characteristics. The second objective of this pilot study was to assess the feasibility of measuring all variables in the model in a residential context. METHODS: An observational and transversal design was used with a heterogeneous sample of 10 participants with a lower-limb amputation of vascular origin, aged 51 to 83, assessed between eight and 18 months after discharge from an acute care hospital. A questionnaire of participant characteristics and 16 reliable and valid measurements were used. RESULTS: The results show that the potential mobility indicators do not accurately predict effective mobility, i.e., participants who perform well on traditional measures done in the laboratory or clinic are not always those who perform well in the real world. The model generated 4 different profiles (categories) of participants ranging from reduced to excellent potential mobility and low to excellent effective mobility, and characterized the modulating factors. The evaluations were acceptable in terms of the time taken (three hours) and the overall measurements, with a few exceptions, which were modified to optimize the data collected and the classification of the participants. For the population assessed, the results showed that some of the negative modulators (particularly living alone, no rehabilitation, pain, limited social support, poor muscle strength) played an important role in reducing effective mobility. CONCLUSION: The first use of the model revealed interesting data that add to our understanding of important aspects linked to potential and effective mobility as well as modulators. The feasibility of measuring all variables in the model in a residential context was demonstrated. A study with a large number of participants is now warranted to rigorously characterize mobility levels of lower-limb amputees with vascular origin. PMID- 20854687 TI - Coxiella burnetii Nine Mile II proteins modulate gene expression of monocytic host cells during infection. AB - BACKGROUND: Coxiella burnetii is an intracellular bacterial pathogen that causes acute and chronic disease in humans. Bacterial replication occurs within enlarged parasitophorous vacuoles (PV) of eukaryotic cells, the biogenesis and maintenance of which is dependent on C. burnetii protein synthesis. These observations suggest that C. burnetii actively subverts host cell processes, however little is known about the cellular biology mechanisms manipulated by the pathogen during infection. Here, we examined host cell gene expression changes specifically induced by C. burnetii proteins during infection. RESULTS: We have identified 36 host cell genes that are specifically regulated when de novo C. burnetii protein synthesis occurs during infection using comparative microarray analysis. Two parallel sets of infected and uninfected THP-1 cells were grown for 48 h followed by the addition of chloramphenicol (CAM) to 10 MUg/ml in one set. Total RNA was harvested at 72 hpi from all conditions, and microarrays performed using Phalanx Human OneArray slides. A total of 784 (mock treated) and 901 (CAM treated) THP-1 genes were up or down regulated >=2 fold in the C. burnetii infected vs. uninfected cell sets, respectively. Comparisons between the complementary data sets (using >0 fold), eliminated the common gene expression changes. A stringent comparison (>=2 fold) between the separate microarrays revealed 36 host cell genes modulated by C. burnetii protein synthesis. Ontological analysis of these genes identified the innate immune response, cell death and proliferation, vesicle trafficking and development, lipid homeostasis, and cytoskeletal organization as predominant cellular functions modulated by C. burnetii protein synthesis. CONCLUSIONS: Collectively, these data indicate that C. burnetii proteins actively regulate the expression of specific host cell genes and pathways. This is in addition to host cell genes that respond to the presence of the pathogen whether or not it is actively synthesizing proteins. These findings indicate that C. burnetii modulates the host cell gene expression to avoid the immune response, preserve the host cell from death, and direct the development and maintenance of a replicative PV by controlling vesicle formation and trafficking within the host cell during infection. PMID- 20854689 TI - Diabetes: cost of illness in Norway. AB - BACKGROUND: Diabetes mellitus places a considerable burden on patients in terms of morbidity and mortality and on society in terms of costs. Costs related to diabetes are expected to increase due to increasing prevalence of type 2 diabetes. The aim of this study was to estimate the health care costs attributable to type 1 and type 2 diabetes in Norway in 2005. METHODS: Data on inpatient hospital services, outpatient clinic visits, physician services, drugs, medical equipment, nutrition guidance, physiotherapy, acupuncture, foot therapy and indirect costs were collected from national registers and responses to a survey of 584 patients with diabetes. The study was performed with a prevalence approach. Uncertainty was explored by means of bootstrapping. RESULTS: When hospital stays with diabetes as a secondary diagnosis were excluded, the total costs were ?293 million, which represents about 1.4% of the total health care expenditure. Pharmaceuticals accounted for ?95 million (32%), disability pensions ?48 million (16%), medical devices ?40 million (14%) and hospital admissions ?21 million (7%). Patient expenditures for acupuncture, physiotherapy and foot therapy were many times higher than expenditure for nutritional guidance. Indirect costs (lost production from job absenteeism) accounted for ?70.1 million (24% of the ?293 million) and included sick leave (?16.7 million), disability support and disability pensions (?48.2 million) and other indirect costs (?5.3 million). If all diabetes related hospital stays are included (primary- and secondary diagnosis) total costs amounts to ?535 million, about 2.6% of the total health care expenditure in Norway. CONCLUSIONS: Diabetes represents a considerable burden to society in terms of health care costs and productivity losses. PMID- 20854688 TI - Biophysical analysis of HTLV-1 particles reveals novel insights into particle morphology and Gag stochiometry. AB - BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1) is an important human retrovirus that is a cause of adult T-cell leukemia/lymphoma. While an important human pathogen, the details regarding virus replication cycle, including the nature of HTLV-1 particles, remain largely unknown due to the difficulties in propagating the virus in tissue culture. In this study, we created a codon optimized HTLV-1 Gag fused to an EYFP reporter as a model system to quantitatively analyze HTLV-1 particles released from producer cells. RESULTS: The codon-optimized Gag led to a dramatic and highly robust level of Gag expression as well as virus-like particle (VLP) production. The robust level of particle production overcomes previous technical difficulties with authentic particles and allowed for detailed analysis of particle architecture using two novel methodologies. We quantitatively measured the diameter and morphology of HTLV-1 VLPs in their native, hydrated state using cryo-transmission electron microscopy (cryo-TEM). Furthermore, we were able to determine HTLV-1 Gag stoichiometry as well as particle size with the novel biophysical technique of fluorescence fluctuation spectroscopy (FFS). The average HTLV-1 particle diameter determined by cryo-TEM and FFS was 71 +/- 20 nm and 75 +/- 4 nm, respectively. These values are significantly smaller than previous estimates made of HTLV-1 particles by negative staining TEM. Furthermore, cryo-TEM reveals that the majority of HTLV-1 VLPs lacks an ordered structure of the Gag lattice, suggesting that the HTLV-1 Gag shell is very likely to be organized differently compared to that observed with HIV-1 Gag in immature particles. This conclusion is supported by our observation that the average copy number of HTLV-1 Gag per particle is estimated to be 510 based on FFS, which is significantly lower than that found for HIV-1 immature virions. CONCLUSIONS: In summary, our studies represent the first quantitative biophysical analysis of HTLV-1-like particles and reveal novel insights into particle morphology and Gag stochiometry. PMID- 20854690 TI - Surfing the web during pandemic flu: availability of World Health Organization recommendations on prevention. AB - BACKGROUND: People often search for information on influenza A(H1N1)v prevention on the web. The extent to which information found on the Internet is consistent with recommendations issued by the World Health Organization is unknown. METHODS: We conducted a search for "swine flu" accessing 3 of the most popular search engines through different proxy servers located in 4 English-speaking countries (Australia, Canada, UK, USA). We explored each site resulting from the searches, up to 4 clicks starting from the search engine page, analyzing availability of World Health Organization recommendations for swine flu prevention. RESULTS: Information on hand cleaning was reported on 79% of the 147 websites analyzed; staying home when sick was reported on 77.5% of the websites; disposing tissues after sneezing on 75.5% of the websites. Availability of other recommendations was lower. The probability of finding preventative recommendations consistent with World Health Organization varied by country, type of website, and search engine. CONCLUSIONS: Despite media coverage on H1N1 influenza, relevant information for prevention is not easily found on the web. Strategies to improve information delivery to the general public through this channel should be improved. PMID- 20854691 TI - Evaluation of the bacterial diversity of pressure ulcers using bTEFAP pyrosequencing. AB - BACKGROUND: Decubitus ulcers, also known as bedsores or pressure ulcers, affect millions of hospitalized patients each year. The microflora of chronic wounds such as ulcers most commonly exist in the biofilm phenotype and have been known to significantly impair normal healing trajectories. METHODS: Bacterial tag encoded FLX amplicon pyrosequencing (bTEFAP), a universal bacterial identification method, was used to identify bacterial populations in 49 decubitus ulcers. Diversity estimators were utilized and wound community compositions analyzed in relation to metadata such as Age, race, gender, and comorbidities. RESULTS: Decubitus ulcers are shown to be polymicrobial in nature with no single bacterium exclusively colonizing the wounds. The microbial community among such ulcers is highly variable. While there are between 3 and 10 primary populations in each wound there can be hundreds of different species present many of which are in trace amounts. There is no clearly significant differences in the microbial ecology of decubitus ulcer in relation to metadata except when considering diabetes. The microbial populations and composition in the decubitus ulcers of diabetics may be significantly different from the communities in non diabetics. CONCLUSIONS: Based upon the continued elucidation of chronic wound bioburdens as polymicrobial infections, it is recommended that, in addition to traditional biofilm-based wound care strategies, an antimicrobial/antibiofilm treatment program can be tailored to each patient's respective wound microflora. PMID- 20854692 TI - Home healthcare services in Taiwan: a nationwide study among the older population. AB - BACKGROUND: Home healthcare services are important in aging societies worldwide. The present nationwide study of health insurance data examined the utilization and delivery patterns, including diagnostic indications, for home healthcare services used by seniors in Taiwan. METHODS: Patients >=65 years of age who received home healthcare services during 2004 under the Taiwanese National Health Insurance Program were identified and reimbursement claims were analyzed. Age, gender, disease diagnoses, distribution of facilities providing home healthcare services, and patterns of professional visits, including physician and skilled nursing visits, were also explored. RESULTS: Among 2,104,978 beneficiaries >=65 years of age, 19,483 (0.9%) patients received 127,753 home healthcare visits during 2004 with a mean number of 6.0 +/- 4.8 visits per person. The highest prevalence of home healthcare services was in the 75-84 year age group in both sexes. Females received more home healthcare services than males in all age groups. Cerebrovascular disease was the most frequent diagnosis in these patients (50.7%). More than half of home healthcare visits and around half of the professional home visits were provided by community home nursing care institutions. The majority of the home skilled nursing services were tube replacements, including nasogastric tubes, Foley catheter, tracheostomy, nephrostomy or cystostomy tubes (95%). CONCLUSIONS: Nine out of 1,000 older patients in Taiwan received home healthcare services during 2004, which was much lower than the rate of disabled older people in Taiwan. Females used home healthcare services more frequently than males and the majority of skilled nursing services were tube replacements. The rate of tube replacement of home healthcare patients in Taiwan deserves to be paid more attention. PMID- 20854693 TI - Serodiagnosis of sheeppox and goatpox using an indirect ELISA based on synthetic peptide targeting for the major antigen P32. AB - BACKGROUND: Sheeppoxvirus (SPPV), goatpoxvirus (GTPV) and lumpy skin disease virus (LSDV) of cattle belong to the Capripoxvirus genus of the Poxviridae family and can cause significant economic losses in countries where they are endemic. Despite the considerable threat that these viruses pose to livestock production and global trade in sheep, goats, cattle and their products, convenient and effective serodiagnostic tools are not readily available. Toward this goal, two synthetic peptides corresponding to the major antigen P32 were synthesized. These synthetic peptides were then used as antigen to develop an ELISA method to detect anti-SPPV and GTPV antibodies. RESULTS: The results indicated that the optimal concentration of coated recombinant antigen was 0.2 MUg per well for a serum dilution of 1:10. The ELISA performed favorably when sera from sheep immunized experimentally were tested. CONCLUSION: This assay offers the prospect of synthetic peptide as antigens for indirect ELISA to detect SPPV and GTPV antibody in sheep and goat sera. PMID- 20854694 TI - Development of a serum-free medium for in vitro expansion of human cytotoxic T lymphocytes using a statistical design. AB - BACKGROUND: Serum-containing medium (SCM), which has a number of poorly defined components with varying concentrations, hampers standardization of lymphocyte cultures. In order to develop a serum-free medium (SFM) for the expansion of human lymphocytes from peripheral blood mononuclear cells (PBMCs), a statistical optimization approach based on a fractional factorial method and a response surface method was adopted. A basal medium was prepared by supplementing RPMI1640 medium with insulin, albumin, ferric citrate, ethanolamine, fatty acids, glutamine, sodium pyruvate, 2-mercaptoethanol, 1-thioglycerol, nonessential amino acids, and vitamins. We identified additional positive determinants and their optimal concentrations for cell growth through a statistical analysis. RESULTS: From a statistical analysis using the fractional factorial method, cholesterol and polyamine supplement were identified as positive determinants for cell growth. Their optimal concentrations were determined by the response surface method. The maximum viable cell concentration in the developed SFM was enhanced by more than 1.5-fold when compared to that in RPMI1640 supplemented with 10% fetal bovine serum (FBS). Furthermore, a cytotoxicity assay and an enzyme-linked immunospot assay revealed that the effector function of cytotoxic T lymphocytes generated from PBMCs grown in SFM, by stimulation of peptide-presenting dendritic cells, was retained or even better than that in SCM. CONCLUSIONS: The use of a developed SFM with cholesterol and polyamine supplement for human lymphocyte culture resulted in better growth without loss of cellular function when compared to SCM. PMID- 20854695 TI - Comparison of 454-ESTs from Huperzia serrata and Phlegmariurus carinatus reveals putative genes involved in lycopodium alkaloid biosynthesis and developmental regulation. AB - BACKGROUND: Plants of the Huperziaceae family, which comprise the two genera Huperzia and Phlegmariurus, produce various types of lycopodium alkaloids that are used to treat a number of human ailments, such as contusions, swellings and strains. Huperzine A, which belongs to the lycodine type of lycopodium alkaloids, has been used as an anti-Alzheimer's disease drug candidate. Despite their medical importance, little genomic or transcriptomic data are available for the members of this family. We used massive parallel pyrosequencing on the Roche 454 GS FLX Titanium platform to generate a substantial EST dataset for Huperzia serrata (H. serrata) and Phlegmariurus carinatus (P. carinatus) as representative members of the Huperzia and Phlegmariurus genera, respectively. H. serrata and P. carinatus are important plants for research on the biosynthesis of lycopodium alkaloids. We focused on gene discovery in the areas of bioactive compound biosynthesis and transcriptional regulation as well as genetic marker detection in these species. RESULTS: For H. serrata, 36,763 unique putative transcripts were generated from 140,930 reads totaling over 57,028,559 base pairs; for P. carinatus, 31,812 unique putative transcripts were generated from 79,920 reads totaling over 30,498,684 base pairs. Using BLASTX searches of public databases, 16,274 (44.3%) unique putative transcripts from H. serrata and 14,070 (44.2%) from P. carinatus were assigned to at least one protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology annotations revealed that the functions of the unique putative transcripts from these two species cover a similarly broad set of molecular functions, biological processes and biochemical pathways.In particular, a total of 20 H. serrata candidate cytochrome P450 genes, which are more abundant in leaves than in roots and might be involved in lycopodium alkaloid biosynthesis, were found based on the comparison of H. serrata and P. carinatus 454-ESTs and real-time PCR analysis. Four unique putative CYP450 transcripts (Hs01891, Hs04010, Hs13557 and Hs00093) which are the most likely to be involved in the biosynthesis of lycopodium alkaloids were selected based on a phylogenetic analysis. Approximately 115 H. serrata and 98 P. carinatus unique putative transcripts associated with the biosynthesis of triterpenoids, alkaloids and flavones/flavonoids were located in the 454-EST datasets. Transcripts related to phytohormone biosynthesis and signal transduction as well as transcription factors were also obtained. In addition, we discovered 2,729 and 1,573 potential SSR-motif microsatellite loci in the H. serrata and P. carinatus 454-ESTs, respectively. CONCLUSIONS: The 454-EST resource allowed for the first large-scale acquisition of ESTs from H. serrata and P. carinatus, which are representative members of the Huperziaceae family. We discovered many genes likely to be involved in the biosynthesis of bioactive compounds and transcriptional regulation as well as a large number of potential microsatellite markers. These results constitute an essential resource for understanding the molecular basis of developmental regulation and secondary metabolite biosynthesis (especially that of lycopodium alkaloids) in the Huperziaceae, and they provide an overview of the genetic diversity of this family. PMID- 20854696 TI - Does suprascapular nerve block reduce shoulder pain following stroke: a double blind randomised controlled trial with masked outcome assessment. AB - BACKGROUND: Shoulder pain is a common complication of a stroke which can impede participation in rehabilitation programs and has been associated with poorer outcomes. The evidence base for current medical and therapeutic management options of hemiplegic shoulder pain is limited. This study will evaluate the use of suprascapular nerve block injection as part of an interdisciplinary approach to the treatment of shoulder pain following stroke. The technique has previously been proven safe and effective in the treatment of shoulder pain associated with rheumatoid arthritis and degenerative shoulder conditions but its usefulness in a stroke population is unclear. METHODS/DESIGN: A double blind randomised placebo controlled trial will assess the effect of a suprascapular nerve block compared with placebo in a population of 66 stroke patients. The trial will measure effect of injection on the primary outcome of pain, and secondary outcomes of function and quality of life. Measurements will take place at baseline, and 1, 4 and 12 weeks post intervention. Both groups will continue to receive routine physiotherapy and standard ward care. DISCUSSION: The results of this study could reduce pain symptoms in persons with mechanical shoulder pain post stroke and provide improvement in upper limb function. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) - ACTRN12609000621213. PMID- 20854697 TI - Integration of bovine herpesvirus 4 genome into cultured persistently infected host cell genome. AB - Persistent infection of macrophages with bovine herpesvirus 4 (BoHV-4) has been proposed to play a secondary causal role, along with bacterial infection, in bovine post-partum metritis. Mechanisms of maintenance of BoHV-4 persistent infection are not understood. We previously generated in vitro models of BoHV-4 persistent infection in human rhadomyosarcoma and bovine macrophage cell lines by drug selection of cells infected with BoHV-4 carrying a drug-resistance marker, and demonstrated circular episomal BoHV-4 genomes. In the present study, we used fluorescent in situ hybridization (FISH) to demonstrate BoHV-4 genomes also integrated into the genomes of these persistently infected cells. PMID- 20854698 TI - Effects of pepsin and trypsin on the anti-adipogenic action of lactoferrin against pre-adipocytes derived from rat mesenteric fat. AB - Lactoferrin (LF) is a multifunctional glycoprotein in mammalian milk. In a previous report, we showed that enteric-coated bovine LF tablets can decrease visceral fat accumulation, hypothesising that the enteric coating is critical to the functional peptides reaching the visceral fat tissue and exerting their anti adipogenic activity. The aim of the present study was to assess whether ingested LF can retain its anti-adipogenic activity. We therefore investigated the effects of LF and LF treated with digestive enzymes (the stomach enzyme pepsin and the small intestine enzyme trypsin) on lipid accumulation in pre-adipocytes derived from the mesenteric fat tissue of male Sprague-Dawley rats. Lipid accumulation in pre-adipocytes was significantly reduced by LF in a dose-dependent manner and was associated with reduction in gene expression of CCAAT/enhancer binding protein delta, CCAAT/enhancer binding protein alpha and PPARgamma as revealed by DNA microarray analysis. Trypsin-treated LF continued to show anti-adipogenic action, whereas pepsin-treated LF abrogated the activity. When an LF solution (1000 mg bovine LF) was administered by gastric intubation to Sprague-Dawley rats, immunoreactive LF determined by ELISA could be detected in mesenteric fat tissue at a concentration of 14.4 MUg/g fat after 15 min. The overall results point to the importance of enteric coating for action of LF as a visceral fat-reducing agent when administered in oral form. PMID- 20854699 TI - Fermentation of calcium-fortified soya milk does not appear to enhance acute calcium absorption in osteopenic post-menopausal women. AB - Ageing women may choose to drink soya milk to reduce menopausal symptoms. As fermentation enriches soya milk with isoflavone aglycones, its beneficial qualities may improve. To reduce osteoporotic risk, however, soya milk must be Ca enriched, and it is not known how fermentation affects Ca bioavailability. A randomised crossover pilot study was undertaken to compare the Ca absorption of fortified soya milk with that of fermented and fortified soya milk in twelve Australian osteopenic post-menopausal women. The fortified soya milk was inoculated with Lactobacillus acidophilus American Type Culture Collection (ATCC) 4962 and fermented for 24 h at 37 degrees C. Ca absorption from soya milk samples was measured using a single isotope radiocalcium method. Participants had a mean age of 54.8 (sd 12.3) years, with mean BMI of 26.5 (sd 5.5) kg/m2 and subnormal to normal serum 25-hydroxyvitamin D (mean 62.5 (sd 19.1) nmol/l). Participants consumed 185 kBq of 45Ca in 44 mg of Ca carrier. The mean fractional Ca absorption (alpha) from soya milk and fermented soya milk was 0.64 (sd 0.23) and 0.71 (sd 0.29), respectively, a difference not of statistical significance (P = 0.122). Although fermentation of soya milk may provide other health benefits, fermentation had little effect on acute Ca absorption. PMID- 20854700 TI - Feeding a thermally oxidised fat inhibits atherosclerotic plaque formation in the aortic root of LDL receptor-deficient mice. AB - Activators of PPARalpha have been demonstrated to inhibit atherosclerosis development due to lipid lowering in plasma and direct protective effects on the vasculature. Because dietary oxidised fats (OF) have strong PPARalpha-activating and lipid-lowering properties, we hypothesised that dietary OF has also an inhibitory influence on atherosclerosis development. To verify our hypothesis, we investigated the effect of feeding diets containing an OF (a 92 : 8 mixture of heated (170 degrees C, 48 h) hydrogenated palm fat and fresh sunflower oil) compared with a fresh fat (fresh hydrogenated palm fat) on the development of atherosclerotic lesions in LDL receptor-deficient (LDLR- / - ) mice. We observed that a dietary OF caused a strong up-regulation of PPARalpha-regulated genes in the liver and a marked reduction in plasma concentrations of cholesterol and TAG (P < 0.05). Cross-sectional lesion area and the lipids and collagen levels in the aortic root were approximately 40-50 % lower in mice fed diets containing OF than in those fed diets containing fresh fat (P < 0.05). Immunohistochemical analysis of aortic root sections revealed an about 8-fold increased expression of PPARalpha and a markedly reduced expression of the proinflammatory vascular cell adhesion molecule-1 and smooth muscle cell (SMC)-specific marker alpha-actin in LDLR- / - mice fed OF (P < 0.05). We postulate that OF exert anti-atherogenic effects by activation of PPARalpha both in the liver, which contributes to lipid lowering in plasma, and in the vasculature, which inhibits pro-atherogenic events such as monocyte recruitment and SMC proliferation and migration. PMID- 20854701 TI - Comparison of the effects of dietary protein, androstenediol and forearm muscle area on radial bone variables in healthy prepubertal children. AB - Adequate dietary habits are supposed to be one of the most important modifiable factors in osteoporosis prevention. However, the importance of specific nutrients is controversial. We examined relevant nutrients which are supposed to have an impact on bone parameters and compared their effect sizes with those of two known predictors of bone development: bone-related muscle mass and androgen levels. We analysed nutritional, hormonal and anthropometric data from 107 prepubertal children participating in the Dortmund Nutritional and Anthropometric Longitudinally Designed Study. Diaphyseal bone mineral content (BMC), cortical area (CA), periosteal circumference, strength strain index and muscle area of the non-dominant forearm were measured by peripheral quantitative computed tomography. Data on long-term nutrient intakes (e.g. protein, Ca and vitamin D) were derived from 3 d weighed dietary records. Twenty-four hour urinary excretion rates of androgen metabolites including the sex steroid androstenediol were measured using GC-MS. Of all considered nutrients, only protein showed a trend for an association with BMC (beta = +0.11; P = 0.073) and CA (beta = +0.11; P = 0.056) in stepwise linear regression models. None of the other considered dietary variables was associated with bone parameters. The size of the bone anabolic effect of protein was partly comparable with that of androstenediol. Even though boys gained more bone mass in comparison with girls, the protein effect did not differ between sexes. Bone-related muscle area and sex steroids have the strongest effects on prepubertal diaphyseal bone. However, dietary protein may have a similar bone anabolic influence compared with androstenediol. In children without explicit nutrient deficits, protein seems to be the most important dietary component for diaphyseal bone status. PMID- 20854703 TI - Higher risk of zinc deficiency in New Zealand Pacific school children compared with their Maori and European counterparts: a New Zealand national survey. AB - Few multi-ethnic national surveys have examined Zn nutriture, despite its importance for optimal growth and development during childhood. We assessed the Zn status of urban and semi-urban children aged 5-15 years from three ethnic groups in New Zealand (NZ) in the 2002 Children's National Nutrition Survey and investigated the factors predisposing them to Zn deficiency. In a 10-month cross sectional survey, Pacific and Maori children were over-sampled permitting ethnic specific analyses. Anthropometry, serum Zn and Zn intakes via 24 h recalls were measured. Anthropometric z scores were highest in Pacific children. Overall, mean adjusted serum Zn at 11 years was for males and females, respectively: 11.9 (95% CI 11.5, 12.3) and 12.5 (95% CI 12.0, 12.9) MUmol/l in NZ European and Other (NZEO) children (n 395); 11.9 (95% CI 11.4, 12.4) and 12.0 (95% CI 11.4, 12.5) MUmol/l in Maori children (n 379); and 11.5 (95% CI 11.1, 11.9) and 11.4 (95% CI 11.1, 11.8) MUmol/l in Pacific children (n 589). The predictors of serum Zn were age, serum Se and sex for NZEO children; serum Se and age for Pacific children; and none for Maori children. Pacific children had the highest prevalence of low serum Zn (21 (95% CI 11, 30) %), followed by Maori children (16 (95% CI 12, 20) %) and NZEO children (15 (95% CI 9, 21) %). Prevalence of inadequate Zn intakes, although low, reached 8% for Pacific children who had the lowest Zn intake/kg body weight. Pacific boys but not girls with low serum Zn had a lower mean height for-age z-score (P < 0.007) than those with normal serum Zn. We conclude that the biochemical risk of Zn deficiency in Pacific children indicates a public health problem. However, a lack of concordance with the risk of dietary Zn inadequacy suggests the need for better defined cut-offs in children. PMID- 20854704 TI - Juvenile didymozoids of the types, Torticaecum and Neotorticaecum (Didymozoidae: Digenea), from new marine fish hosts (Pisces: Teleostei) in the neotropical region of Brazil. AB - From December 2006 to March 2008, 60 specimens of Paralichthys isosceles and 25 specimens of P. patagonicus were investigated for helminths. One hundred and sixty-nine digeneans were recovered and parasites were identified as juvenile didymozoids of two types. Torticaecum and Neotorticaecum were found in 48 of the 60 P. isosceles (80%) and 10 of the 25 P. patagonicus (40%). Torticaecum and Neotorticaecum are reported for the first time in fish in South America (Brazil), found in the Atlantic Ocean. Morphometrics and illustrations are presented. PMID- 20854705 TI - Morphological and molecular characterization of Paractinolaimus sahandi n. sp. (Nematoda: Actinolaimidae) from the Sahand Mountains in Iran. AB - Paractinolaimus sahandi n. sp., found in wet soil samples collected from the rhizosphere of grasses of Sahand Mountains, Iran, is described. This new species is characterized by its long body (3.5-4.7 mm), high a value (74.5-88.5), anterior location of posterior subventral nuclei, occupying 62.5-68.0% of glandularium distance, the presence of 1-4 pre- and 1-3 post-vulval papillae and numerous tiny, not innervated papillae in front and behind the vulva in the outer layer of cuticle; common functional males in the population, with 62.5-81.3 MUm long spicules and 15-17 ventromedian supplements. The new species, which is the only one in the genus showing the advulval cuticular tiny papillae and is unusually slender, is compared to four species of Paractinolaimus, namely P. macrolaimus, P. longidrilus, P. spanithelus and P. rafiqi. The ribosomal 18S rDNA (1246 bp sequenced) and 28S rDNA D2/D3 region (844 bp sequenced) of P. sahandi n. sp. were sequenced for molecular characterization. Sequences of the 18S and 28S D2/D3 of P. sahandi n. sp. have distinct differences from those of the only sequenced P. macrolaimus, with 6 bp differences in 18S and 38 bp differences and five gaps in 28S. This is the first report of the occurrence of members of Actinolaimidae in Iran. PMID- 20854706 TI - Molecular approaches to the identification of Bulinus species in south-west Nigeria and observations on natural snail infections with schistosomes. AB - The current study considers the distribution of a small sample of 138 Bulinus snails, across 28 localities within eight Nigerian states. Snails were identified using a combination of molecular methods involving both DNA sequencing of a partial cytochrome oxidase subunit 1 (cox1) fragment and restriction profiles obtained from ribosomal internal transcribed spacer (its) amplicons. The results showed that the majority of Bulinus samples tested belonged to the species Bulinus truncatus while only two were Bulinus globosus. The use of RsaI restriction endonuclease to cleave the ribosomal its of Bulinus, as a method of species identification, was adopted for the majority of samples, this being a quicker and cheaper method better suited to small laboratory environments. Polymerase chain reaction (PCR) amplification of the schistosome Dra1 repeat within each of the collected Bulinus samples was employed to determine the extent and distribution of infected snails within the sample areas. Successful amplification of the Dra1 repeat demonstrated that 29.7% of snails were infected with schistosomes. Sequencing of the partial schistosome its from a small subset of snail samples suggested that some snails were either penetrated by both Schistosoma haematobium and Schistosoma bovis miracidia or hybrid miracidia formed from the two species. PMID- 20854707 TI - Supraglottitis and abscess formation. AB - OBJECTIVE: This case series report aims to raise awareness of the association between supraglottic infection and abscess formation, which has been rarely documented. METHOD: We report a series of four patients who developed cervical abscesses following supraglottic infection. The diagnosis was confirmed by imaging in three patients, and by incision and drainage of pus at direct laryngoscopy in one. RESULTS: All four patients were treated with intravenous antibiotics, steroids and humidification; two also underwent surgical drainage of pus. All made an uneventful recovery. CONCLUSION: The factors that lead to neck abscess formation are poorly understood. Physicians should always be aware of this potential complication. If it is suspected, appropriate neck imaging should be undertaken, after excluding airway copromise; this will aid early diagnosis and treatment. PMID- 20854708 TI - Diagnostic otoscopy skills of community ear assistants in Western Nepal. AB - INTRODUCTION: Deafness is a major problem in developing countries. Rural communities tend to be affected more than urban ones, and chronic otitis media is common. The World Health Organization has proposed primary ear care as a method of providing otological services in developing countries. This study aimed to assess the diagnostic otoscopy skills of community ear assistants in rural Western Nepal. MATERIALS AND METHODS: Community ear assistants undertook the pre operative evaluation of 92 patients selected for middle-ear surgery in an 'ear camp' setting. The otoscopy skills of community ear assistants were also assessed by means of an otoscopy quiz. Consultant otologists and trainee otolaryngologists underwent an identical assessment. RESULTS: The community ear assistants' selection of patients for middle-ear surgery concurred with the consultant otologists' opinion in 87 of 92 patients (94.5 per cent). The level of community ear assistants' otoscopy skills was between that of junior and senior otolaryngology trainees. CONCLUSIONS: With intensive training, medically unqualified community ear assistants can develop otoscopy skills comparable to those of medically qualified otolaryngology trainees. These results support the development of primary ear care in poorer countries where access to specialist otological services is difficult or impossible. PMID- 20854709 TI - Hammondia triffittae n. comb. of foxes ( Vulpes spp.): biological and molecular characteristics and differentiation from Hammondia heydorni of dogs. AB - Genomic DNAs from 3 oocyst isolates of Hammondia sp. from foxes (Vulpes vulpes and V. lagopus) and 1 oocyst isolate of Hammondia heydorni from a dog, were examined by PCR and sequence analysis of 6 loci in order to determine whether the isolates were conspecific. Consistent genetic differences were found between the fox and dog isolates, respectively, at the ITS-2 region, the lsu rRNA gene, the alpha tubulin gene and the HSP70 gene, but not at the ssu rRNA gene or ITS-1 locus. Infection experiments established that dogs were unsuitable as definitive hosts for Hammondia sp. of foxes; hence this species is regarded as separate from H. heydorni of wolf-like canids, but probably identical with Isospora triffittae (syn. Isospora triffitti) previously reported from foxes. This species has therefore been named Hammondia triffittae n. comb. Reindeer, moose, sheep, goats, foxes and rabbits may act as intermediate hosts for H. triffittae. Muscle tissues of inoculated intermediate hosts were infectious for foxes from 16 days post infection. Oocysts of H. triffittae were subspherical, averaging 12.5 * 10.9 MUm in size. The lsu rRNA gene and the alpha tubulin gene seem to be suitable genetic markers for differentiating between H. triffittae and H. heydorni. PMID- 20854710 TI - Nucleases: diversity of structure, function and mechanism. AB - Nucleases cleave the phosphodiester bonds of nucleic acids and may be endo or exo, DNase or RNase, topoisomerases, recombinases, ribozymes, or RNA splicing enzymes. In this review, I survey nuclease activities with known structures and catalytic machinery and classify them by reaction mechanism and metal-ion dependence and by their biological function ranging from DNA replication, recombination, repair, RNA maturation, processing, interference, to defense, nutrient regeneration or cell death. Several general principles emerge from this analysis. There is little correlation between catalytic mechanism and biological function. A single catalytic mechanism can be adapted in a variety of reactions and biological pathways. Conversely, a single biological process can often be accomplished by multiple tertiary and quaternary folds and by more than one catalytic mechanism. Two-metal-ion-dependent nucleases comprise the largest number of different tertiary folds and mediate the most diverse set of biological functions. Metal-ion-dependent cleavage is exclusively associated with exonucleases producing mononucleotides and endonucleases that cleave double- or single-stranded substrates in helical and base-stacked conformations. All metal ion-independent RNases generate 2',3'-cyclic phosphate products, and all metal ion-independent DNases form phospho-protein intermediates. I also find several previously unnoted relationships between different nucleases and shared catalytic configurations. PMID- 20854711 TI - Changing epidemiology of methicillin-resistant Staphylococcus aureus in Alberta, Canada: population-based surveillance, 2005-2008. AB - SUMMARYIncreasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has been reported in Canada. We report the results of a prospective surveillance of MRSA infections in Alberta over a consecutive 3-year period. A total of 8910 unique clinical MRSA isolates was analysed from July 2005 to June 2008. The incidence of MRSA infection increased over the study period and was highest in males, age group ?85 years, and the Calgary Area. CMRSA10 (USA300) and CMRSA2 (USA100/800) were the most common PFGE strain types, representing 53.0% and 27.9% of all isolates, respectively. Significant differences were noted between MRSA strains in the source of infection and antimicrobial susceptibility. The incidence of MRSA infection in Alberta has nearly doubled in the last 3 years; this is attributed to the emergence of CMRSA10 as the predominant strain. PMID- 20854712 TI - The incidence of hepatitis E virus infection in the general population of the USA. AB - Hepatitis E virus (HEV) infection is as an emerging disease of global importance because it is one of the major causes of acute hepatitis worldwide. There are few reports on the incidence of HEV in the USA. For better assessing the burden of primary HEV infection as well as understanding the epidemiology of HEV in the US population this analysis was conducted to estimate the force of infection of HEV in the USA. HEV force of infection in the general US population was calculated using catalytic models as cumulative markers of past infection from HEV seroprevalence data from the NHANES Survey. In the US population the force of infection was seven infections per 1000 susceptible persons per year. This study shows that in the USA HEV can be acquired locally and from developing countries. HEV is circulating more frequently in the non-Hispanic White racial/ethnic group and those who consume fish more frequently. PMID- 20854713 TI - Serological survey of 2009 H1N1 influenza in residents of Beijing, China. AB - In order to determine the prevalence of antibody against 2009 H1N1 influenza in Beijing, we conducted a serological survey in 710 subjects, 1 month after the epidemic peak. We found that 13.8% of our cohort was seropositive. Subjects aged >=60 years recorded the lowest seroprevalence (4.5%). The age-weighted seroprevalence of 14.0% was far lower than the supposed infection rate at the epidemic peak, derived from the basic reproduction number for 2009 H1N1 virus. For subjects who had received the pandemic vaccine seroprevalence was 51.4%. In subjects aged >=60 years the seasonal influenza vaccination was not significantly associated with being seropositive. Our study suggests that many factors, and not just the immunological level against 2009 H1N1 influenza in the community, affected the spread of the virus within the population of Beijing. PMID- 20854714 TI - Onychomadesis after a hand, foot, and mouth disease outbreak in Spain, 2009. AB - Few reports exist regarding the association between onychomadesis and an enterovirus infection presenting clinically as hand, foot, and mouth disease (HFMD). In February 2009, an outbreak of HFMD occurred in a Spanish nursery school, followed by onychomadesis 36-69 days later. Twelve of 17 children with HFMD developed nail shedding; enterovirus was detected in stool samples from eight (47%) of the 17. However, in only three of the children could an enterovirus serotype coxsackievirus B1 be identified. The epidemiological results of this study confirm onychomadesis as a complication in HFMD. In future outbreaks, molecular characterization of enterovirus from appropriate clinical samples should be studied. PMID- 20854715 TI - Dendritic morphology and tracer-coupling pattern of physiologically identified transient uniformity detector ganglion cells in rabbit retina. AB - Transient uniformity detectors (UDs) are a unique type of retinal ganglion cell (RGC) whose maintained firing is transiently suppressed by all types of visual stimuli. In this study, we have characterized the dendritic morphology and tracer coupling pattern of UDs that were labeled by loose-seal electroporation of Neurobiotin following functional identification in the isolated rabbit retina. The UDs have a bistratified dendritic tree, branching near the margins of the inner plexiform layer in stratum 1 (part of the OFF sublamina) and stratum 4/5 (part of the ON sublamina). Characteristically, many of the distal dendrites in the OFF arbor do not terminate there but dive recurrently back to the ON arbor. As a consequence, the ON dendritic arbor is usually twice as large as the OFF dendritic arbor in area. The UDs sometimes show homologous tracer coupling to neighboring RGCs with the same morphology, and from this material, we estimate that the UDs have a threefold dendritic field overlap and a maximum density of ~100 cells/mm2 on the peak visual streak, accounting for ~2% of RGCs in rabbit retina. The UDs also show strong heterologous tracer coupling to a novel type of amacrine cell that costratifies with the ON arbor of the UD. Consistent with their unistratified medium-field morphology, these St4/5 amacrine cells appear to be GABAergic: their somata are immunopositive for GABA but immunonegative for glycine and glycine transporter 1. We compare the dendritic morphology of the UDs to that of other types of bistratified RGCs described in rabbit retina and note that the stratification levels and distinctive recurrent dendrites closely resemble those of the "ON bistratified diving" RGCs. This raises the possibility that there are two types of RGCs with distinctive physiological properties that have almost identical bistratified dendritic morphologies. PMID- 20854716 TI - Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. AB - OBJECTIVE: Vegetarians and vegans exclude certain food sources of vitamin D from their diet, but it is not clear to what extent this affects plasma concentrations of 25-hydroxyvitamin D (25(OH)D). The objective was to investigate differences in vitamin D intake and plasma concentrations of 25(OH)D among meat eaters, fish eaters, vegetarians and vegans. DESIGN: A cross-sectional analysis. SETTING: United Kingdom. SUBJECTS: Plasma 25(OH)D concentrations were measured in 2107 white men and women (1388 meat eaters, 210 fish eaters, 420 vegetarians and eighty-nine vegans) aged 20-76 years from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford cohort. RESULTS: Plasma 25(OH)D concentrations reflected the degree of animal product exclusion and, hence, dietary intake of vitamin D; meat eaters had the highest mean intake of vitamin D (3.1 (95 % CI 3.0, 3.2) MUg/d) and mean plasma 25(OH)D concentrations (77.0 (95 % CI 75.4, 78.8) nmol/l) and vegans the lowest (0.7 (95 % CI 0.6, 0.8) MUg/d and 55.8 (95 % CI 51.0, 61.0) nmol/l, respectively). The magnitude of difference in 25(OH)D concentrations between meat eaters and vegans was smaller (20 %) among those participants who had a blood sample collected during the summer months (July-September) compared with the winter months (38 %; January-March). The prevalence of low plasma concentrations of 25(OH)D (<25 nmol/l) during the winter and spring ranged from <1 % to 8 % across the diet groups. CONCLUSIONS: Plasma 25(OH)D concentrations were lower in vegetarians and vegans than in meat and fish eaters; diet is an important determinant of plasma 25(OH)D in this British population. PMID- 20854717 TI - Eating and weight concerns among Sikkimese adolescent girls and their biocultural correlates: an exploratory study. AB - OBJECTIVES: Growing concern about ideal body image among adolescent girls in developing countries has led them to follow dietary modifications. In general, the ideal body image is perceived as a 'thin body' and now tagged with the concept of being physically fit. The present study evaluates the prevalence of weight concerns, and subsequent eating behaviour modifications among a group of adolescent girls in Sikkim. DESIGN: Pre-tested FFQ and dietary behaviour questionnaire were canvassed through direct interviews. Anthropometric measurements were taken following standard techniques. In the present study, dieting stands for skipping meals or avoiding certain food items. SETTING: Sikkim, India. SUBJECTS: A total of 577 girls were selected from several blocks of all four districts of Sikkim. RESULTS: The results of the study show that concern with weight reduction is growing among adolescent girls, particularly among urban girls of affluent families. Girls from families with a higher economic status are about two times more likely to report dissatisfaction with their body weight (OR = 1.96; P <= 0.05) and these girls are five times more likely to report the need for dieting. CONCLUSIONS: It is evident that weight concern and dissatisfaction over body weight are growing among adolescents. It can be safely argued that eating disorder, once a problem of the Western world, is now slowly creeping in among adolescents of the developing world as a consequence of rapid lifestyle changes over the past few decades. PMID- 20854718 TI - A qualitative evaluation of an Australian public health nutrition workforce development intervention involving mentoring circles. AB - OBJECTIVE: To evaluate a mentoring circle workforce development intervention among a group of public health nutrition novices. DESIGN: The mentoring circle intervention focused on facilitating practice-based public health nutrition competence development and supporting reorientation of practice from clinical services to preventive services. A retrospective post-intervention qualitative semi-structured interview was used to explore the experiences of those participating in the mentoring circle and to make evaluative judgements about intervention attributes and effectiveness. SETTING: Victoria, Australia. SUBJECTS: Thirty-two novice public health nutrition practitioners employed in the state public health system. RESULTS: Key evaluative theme categories relating to the mentoring circle intervention were identified, including the structure and function of the group, the utility of using advanced-level competency items to guide planning, having a safe and supportive environment for learning and the utility of learning via mentoring and on-the-job experiences. These qualitative evaluation data identify the attributes of the mentoring circle intervention contributing to intervention effectiveness. CONCLUSIONS: This qualitative evaluation indicates that mentoring circles can be an effective workforce capacity-building intervention, particularly in novice workforces characterised by professional isolation and split function roles. PMID- 20854719 TI - Grocery purchasing among older adults by chewing ability, dietary knowledge and socio-economic status. AB - OBJECTIVES: Nutrition plays a central role in health, with poor dietary habits and nutritional intake being associated with a range of chronic diseases. The aim was to examine grocery purchasing behaviour in relation to chewing ability, dietary knowledge and socio-economic status (SES) among older adults. DESIGN: Data were collected by mailed survey in 2008. Grocery purchasing was measured using a sixteen-item index of compliance of food purchasing with dietary guidelines. Self-reported number of teeth was classified as an inadequate dentition if less than twenty-one teeth were present. Chewing ability was based on a five-item chewing index. Dietary knowledge was collected using twenty true/false items. SES was assessed using a subjective social status rating representing where people stand in society. SETTING: Population survey in Adelaide, South Australia. SUBJECTS: Adults aged 60-71 years. RESULTS: Responses were collected from 444 persons (response rate = 68.8 %). Among dentate persons, 24.4 % had an inadequate dentition with 10.3 % defined as 'chewing deficient'. Multivariate regression coefficients adjusted for age, sex and income showed chewing deficiency (-5.8) and low SES (-3.6) was associated (P < 0.05) with lower grocery purchasing scores, but dietary knowledge was not statistically significant. CONCLUSIONS: For older adults, chewing deficiency and lower social status were associated with lower compliance with dietary guidelines, independent of dietary knowledge. PMID- 20854720 TI - Nutritional adequacy of three dietary patterns defined by cluster analysis in 997 pregnant Japanese women: the Osaka Maternal and Child Health Study. AB - OBJECTIVE: To examine the adequacy and inadequacy of dietary patterns in pregnant women for which information is absolutely lacking. DESIGN: Diet was assessed by a validated, self-administered diet history questionnaire (DHQ). Dietary patterns were extracted from the intake of thirty-three food groups (g/4184 kJ (1000 kcal)), which were summarized from 147 foods assessed with the DHQ, by cluster analysis. Nutritional inadequacy for selected twenty nutrients in each dietary pattern was examined using the reference values given in the Dietary Reference Intakes (DRI) for Japanese as the temporal gold standard. SETTING: Japan. SUBJECTS: Nine hundred and ninety-seven pregnant Japanese women aged 18-43 years. RESULTS: The three dietary patterns identified were labelled as 'meat and eggs' (n 423), 'wheat products' (n 371) and 'rice, fish and vegetables' (n 203). The 'rice, fish and vegetables' pattern characterized by high intake of rice, vegetables, potatoes, pulses, fruits, seaweed, fish and miso soup showed significantly the lowest prevalence of inadequate intake for fifteen nutrients and significantly the highest prevalence of inadequate sodium intake. In contrast, the 'wheat products' pattern characterized by high intake of bread, noodles, confectioneries and soft drinks showed the highest prevalence of inadequate intake for fourteen nutrients. The median number of nutrients not meeting the DRI as a marker of overall nutritional inadequacy was eight in the 'rice, fish and vegetables' pattern. It was significantly lower at ten in the 'meat and eggs' and eleven in the 'wheat products' patterns (P<0.001). CONCLUSIONS: In pregnant Japanese women, the dietary pattern high in rice, fish, vegetables, fruit and some others showed a better profile of nutritional adequacy except for sodium. PMID- 20854722 TI - Adherence to the Nordic Nutrition Recommendations as a measure of a healthy diet and upper respiratory tract infection. AB - OBJECTIVE: The Nordic countries have published joint dietary recommendations, the Nordic Nutrition Recommendations (NNR), since 1980. We evaluated adherence to the NNR as a measure of a healthy diet and its potential association with self reported upper respiratory tract infection (URTI). DESIGN: A prospective, population-based study with a follow-up period of 4 months. Dietary intake was assessed using a semi-quantitative FFQ with ninety-six items, along with other lifestyle factors, at baseline. URTI was assessed every three weeks. A Poisson regression model was used to control for age, sex and other confounding factors. SETTING: A middle-sized county in northern Sweden. SUBJECTS: Swedish men and women (n 1509) aged 20-60 years. RESULTS: The NNR include recommendations on macronutrient proportions, physical activity and intake of micronutrients, sodium, fibre and alcohol. We found that overall adherence to the NNR was moderately good. In addition, we found that high adherence to the NNR (>5.5 adherence points) was not associated with a lower risk of URTI (incidence rate ratio (IRR) 0.89, 95% CI 0.73, 1.08) compared with low adherence (<4.5 adherence points). When investigating individual components of the NNR, only high physical activity was associated with lower URTI risk (IRR = 0.82, 95% CI 0.69, 0.97) whereas none of the dietary components were associated with risk of URTI. CONCLUSIONS: Overall adherence to the NNR was moderately good. Overall adherence to the NNR was not associated with URTI risk in our study. However, when investigating individual components of the NNR, we found that high physical activity was associated with lower URTI risk. PMID- 20854721 TI - Receiver-operating characteristics of adiposity for metabolic syndrome: the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. AB - OBJECTIVE: To assess the predictive values of various adiposity indices for metabolic syndrome (MetS) among adults using baseline data from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) cohort. DESIGN: In a cross-sectional study, BMI, waist circumference (WC), body composition by dual energy X-ray absorptiometry (DEXA) and metabolic risk factors such as TAG, HDL cholesterol, blood pressure, fasting glucose and insulin, uric acid and C reactive protein were measured. Receiver-operating characteristic (ROC) curves and logistic regression analyses were conducted. SETTING: Baltimore, Maryland. SUBJECTS: White and African-American US adults (n 1981), aged 30-64 years. RESULTS: In predicting risk of MetS using obesity-independent National Cholesterol Education Program Adult Treatment Panel III criteria, percentage total body fat mass (TtFM) assessed using DEXA measuring overall adiposity had no added value over WC. This was true among both men (area under the ROC curve (AUC) = 0.680 v. 0.733 for TtFM and WC, respectively; P < 0.05) and women (AUC = 0.581 v. 0.686). Percentage rib fat mass (RbFM) was superior to TtFM only in women for MetS (AUC = 0.701 and 0.581 for RbFM and TtFM, respectively; P < 0.05), particularly among African-American women. Elevated percentage leg fat mass (LgFM) was protective against MetS among African-American men. Among white men, BMI was inferior to WC in predicting MetS. Optimal WC cut-off points varied across ethnic-sex groups and differed from those recommended by the National Institutes of Health/North American Association for the Study of Obesity. CONCLUSIONS: The study provides evidence that WC is among the most powerful tools to predict MetS, and that optimal cut-off points for various indices including WC may differ by sex and race. PMID- 20854723 TI - Incentives, health promotion and equality. AB - The use of incentives to encourage individuals to adopt 'healthier' behaviours is an increasingly popular instrument in health policy. Much of the literature has been critical of 'negative' incentives, often due to concerns about equality; 'positive' incentives, however, have largely been welcomed as an instrument for the improvement of population health and possibly the reduction of health inequalities. The aim of this paper is to provide a more systematic assessment of the use of incentives from the perspective of equality. The paper begins with an overview of existing and proposed incentive schemes. I then suggest that the distinction between 'positive' and 'negative' incentives - or 'carrots' and 'sticks' - is of limited use in distinguishing those incentive schemes that raise concerns of equality from those that do not. The paper assesses incentive schemes with respect to two important considerations of equality: equality of access and equality of outcomes. While our assessment of incentive schemes will, ultimately, depend on various empirical facts, the paper aims to advance the debate by identifying some of the empirical questions we need to ask. The paper concludes by considering a number of trade-offs and caveats relevant to the assessment of incentive schemes. PMID- 20854726 TI - [Pay emphasis on the significance and potential role of endoplasmic reticulum stress in sepsis]. PMID- 20854727 TI - [Pay more attention to the anticoagulation for sepsis]. PMID- 20854728 TI - [Expression of secretory type II phospholipase A2 in acute lung injury following acute pancreatitis and interventional effect of Qingyi decoction on it]. AB - OBJECTIVE: To investigate the expression of secretory type II phospholipase A(2) (sPLA(2)-II) in lung of rats with acute lung injury (ALI) complicating severe acute pancreatitis (SAP), and the effect of Qingyi decoction (QYT) on ALI. METHODS: Thirty Sprague Dawley (SD) rats were randomly divided into three groups: sham operation (SO) group, model group and QYT group, with 10 rats in each group. SAP model was reproduced by reverse injection of sodium deoxycholate into the common bile- pancreatic duct of rats. The pancreas of rats was just exposed in SO group. QYT (10 ml/kg) was gavaged 30 minutes and 12 hours after SAP was induced in QYT group. The blood gas analysis was performed 24 hours after operation. Serum amylase (AMY) levels, sPLA(2) and lung wet/dry ratio (W/D) were determined. The sPLA(2)-II mRNA and sPLA(2)-II protein expression in lung were detected by reverse transcription- polymerase chain reaction (RT-PCR) and Western blotting. The pathological changes in lung and pancreas were observed. RESULTS: Compared with SO group, the levels of arterial partial pressure of oxygen (PaO(2)) and pH value in model group were significantly decreased [PaO(2) (mm Hg, 1 mm Hg=0.133 kPa): 79.24+/-5.84 vs. 96.78+/-3.81, pH value: 7.269+/-0.054 vs. 7.391+/-0.054], arterial partial pressure of carbon dioxide (PaCO(2)), the serum levels of AMY, W/D ratio and the serum levels of sPLA(2) were significantly increased [PaCO(2) (mm Hg): 47.57+/-2.55 vs. 27.69+/-1.02, AMY (U/L): 7 144.19+/-727.91 vs. 1 193.41+/-192.54, W/D ratio: 8.57+/-2.45 vs. 3.70+/-0.90, sPLA(2) (nmol*min(-1) *ml(-1)): 45.13+/-6.05 vs. 29.94+/-6.39], the expression of sPLA(2)-II mRNA (1.28+/-0.21 vs. 0.80+/-0.08) and protein were significantly increased (all P <0.05). Compared with model group, blood PaO(2) and pH value were significantly increased [PaO(2): (88.16+/-5.07) mm Hg, pH value: 7.322+/-0.039], the PaCO(2), the serum levels of AMY, W/D ratio and the serum levels of sPLA(2) in QYT group were significantly decreased [PaCO(2): (33.13+/-2.14) mm Hg, AMY: (4 283.51+/ 527.52) U/L, W/D ratio: 4.05+/-0.52, sPLA(2): (28.00+/-4.78) nmol*min(-1) *ml( 1)], and the expression of sPLA(2)-II mRNA (0.89+/-0.08) and protein were significantly decreased (all P <0.05). The pathological changes in lung and pancreas in QYT group were milder than those in SAP group. CONCLUSION: The higher expression of sPLA(2)-IIin lung may be one of pathogenetic factors in ALI induced by SAP. Administration of QYT can reduce the injury of lung by decreasing the expression of sPLA(2)-II in transcriptional level and thus protecting pulmonary function. PMID- 20854729 TI - [Effect of liquid resuscitation on homeostasis of patients with severe acute pancreatitis]. AB - OBJECTIVE: To evaluate the effect of liquid resuscitation on acid-base balance and electrolytes of patients with severe acute pancreatitis (SAP). METHODS: According to the target of liquid resuscitation, 22 patients with SAP involved in this self-controlled prospective study received sufficient liquid resuscitation in acute stage of acute pancreatitis. The results of blood gas analysis, acid base balance and electrolytes were compared before and after liquid resuscitation. The correlation between the volume of liquid used in resuscitation and the level of blood chlorine was analyzed. RESULTS: The mean resuscitation duration was (15.0+/-2.4) hours, and the volume of liquid resuscitation was 3 4594 203 ml, with mean volume (3 910+/- 102) ml in 22 patients; blood sodium (mmol/L) and chlorine (mmol/L) levels were both significantly higher after resuscitation compared with those before resuscitation (Na(+): 145.83+/-1.85 vs. 139.67+/-2.25, Cl(-): 117.33+/-1.64 vs. 101.83+/-1.77, both P<0.05). Blood pH value, hematocrit (Hct), anion gap (AG, mmol/L), blood lactic acid (mmol/L) were slightly lowered after resuscitation (pH value: 7.39+/-0.02 vs. 7.42+/-0.02, Hct: 35.63+/-1.58 vs. 46.85+/-2.38, AG: 8.02+/-1.21 vs. 14.47+/-0.89, blood lactic acid: 1.10+/-0.18 vs. 1.97+/-0.15, P<0.05 or P <0.01). In addition, the level of blood chlorine was significantly correlated with the volume of liquid used in resuscitation (r=0.720 8,P<0.01). CONCLUSION: The target of liquid resuscitation in patients with SAP should be cautiously determined, including control of the volume of liquid for resuscitation, in order to avoid acid-base imbalance or hyperchloraemia. At the same time, the change in internal environment should be monitored. PMID- 20854730 TI - [Effects of hyperbaric oxygen on T lymphocyte subpopulation and its electron microscopic changes in rats with acute pancreatitis]. AB - OBJECTIVE: To investigate the effect of hyperbaric oxygen (HBO) therapy on T lymphocyte subpopulations in rats with acute pancreatitis (AP). METHODS: According to random number table, 56 Sprague Dawley (SD) rats were divided into three groups: the sham group, model group, and HBO therapy group. The rats of model and HBO groups underwent pancreatic duct ligation to induce pancreatitis, then they were divided into three subgroups of 8 rats each. The HBO group was treated with a daily exposure to HBO [2.5 atm (1 atm=101.325 kPa)]. The rats in each subgroup were euthanased on days 1, 3, 7, and the subpopulations of T lymphocytes in peripheral blood were detected respectively using flow cytometry. The nuclei, mitochondrion, rough and smooth endoplasmic reticulum of the pancreatic cells were examined using electron microscopy. RESULTS: The serum level of amylase on day 1 in model and HBO groups was significantly lower than that in sham group. In the model group the CD4(+)CD8(+) cells and the CD4(+)/CD8(+) ratio in AP rats was significantly decreased, indicating the presence of immune suppression. After 7 days of HBO therapy, compared with the model group, the CD4(+) lymphocytes in the HBO group were markedly increased on day 3 and day 7 [(27.92+/-2.10)% vs. (20.79+/-2.80)%, (26.58+/-4.50)% vs. (17.76+/-4.40)%]. The number of CD8(+) lymphocytes were also increased to a certain extent on day 7 [(25.32+/-3.70)% vs. (22.46+/-3.10)%]. The CD4(+)/CD8(+) ratio was obviously increased on day 3 and day 7 (1.07+/-0.14 vs. 0.86+/-0.15, 1.04+/-0.11 vs. 0.79+/-0.12, P<0.05 or P <0.01). Also beneficial effects as evaluated on the nuclei, mitochondrion, rough and smooth endoplasmic reticulum were found in the HBO group (10.8+/-1.6 vs. 17.9+/-1.7, 22.1+/-1.6 vs. 27.5+/ 1.3, 16.8+/-1.0 vs. 29.3+/-0.8, 21.2+/-1.4 vs. 28.7+/-1.2, all P <0.01). CONCLUSION: This study shows that 7-day HBO therapy can promote a more balanced profile of T lymphocyte subpopulations, resulting in improvement of cellular immune function, and it can ameliorate pathological changes as shown by electron microscopic examination. PMID- 20854731 TI - [The role of p38 mitogen-activated protein kinase/nuclear factor-KappaB transduction pathway on coagulation disorders due to endothelial injury induced by sepsis]. AB - OBJECTIVE: To determine the activation status of p38 mitogen-activated protein kinase (p38MAPK)/nuclear factor-KappaB (NF-KappaB) in coagulation disorders due to endothelial injury induced by sepsis. METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to plasma obtained from 22 patients suffering from sepsis. Plasma was also obtained from 8 healthy individuals to serve as negative control, and tumor necrosis factor-alpha (TNF-alpha) was used as positive control. Phosphorylation and activity of p38MAPK and NF-KappaB were determined with enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunofluorescence assay. RESULTS: The level of TNF-alpha (ng/L) in sepsis plasma was significantly higher than that in healthy plasma (155.68+/-89.74 vs. 5.00+/ 0.47, P <0.01). Compared with healthy plasma in 20% concentration it was found when HUVECs were treated with sepsis plasma in 20% concentration, tissue factor (TF, MUg/L) reached the peak at 180 minutes (5.87+/-0.14 vs. 1.25+/-0.11, P <0.01), von Willebrand factor (vWF, MUg/L) reached the peak at 120 minutes (9.59+/-0.07 vs. 3.59+/-0.06, P <0.01), then they began to decline. When HUVECs were treated with sepsis plasma in 20% concentration increased phosphorylation and activity of p38MAPK and NF-KappaB, phosphorylation of p38MAPK occurred before phosphorylation of NF-KappaB (2 minutes vs. 5 minutes). When the inhibitor of p38MAPK (SB239063) was added, NF-KappaB phosphorylation (activation) and NF KappaB nuclear translocation were inhibited. CONCLUSION: This study demonstrates that p38MAPK/NF-KappaB transduction pathway plays an important role in septic coagulopathy. PMID- 20854732 TI - [Correlation between in vitro bacterial growth velocity of blood of patients with clinical parameters and prognosis in patients with Escherichia coli bacteremia]. AB - OBJECTIVE: To identify the clinical and laboratory parameters correlating with speed of bacterial growth in culture and independent risk factors of in-hospital mortality in patients with Escherichia coli bacteremia. METHODS: This retrospective study was conducted at Beijing University Third Hospital. The medical records and microbiological database of the patients diagnosed as Escherichia coli bacteremia between January 2007 and December 2009 were collected. The parameter of time to positivity (TTP) was used to be a surrogate marker of bacterial growth. Univariate analysis was used to identify relationship between clinical parameters and the speed of bacterial growth. Logistic multivariate analysis was used to identify risk factors of in-hospital mortality. RESULTS: The medical records of 112 patients during the study period were collected, 25 patients died during hospital stay, the overall in-hospital mortality rate was 22.3%. Univariate analysis indicated the rapid-growth (TTP<=7 hours) group (n=20) had higher incidence of neutropenia (40.0% vs. 15.2%), higher incidence of primary bacteremia (40.0% vs. 18.5%) and higher in-hospital mortality rate (45.0% vs. 17.4%) than those with slow bacterial growth (TTP>7 hours) group (n =92, all P<0.05). The death group (n=25) was found to have a higher incidence of TTP<=7 hours (36.0% vs. 12.6%), higher incidence of active malignancies (44.0% vs. 24.1%), higher incidence of neutropenia (36.0% vs. 14.9%), higher rate of isolation of extended spectrum beta lactamases (ESBL) producing strains (48.0% vs. 24.1%) than the survival group (n=87, all P<0.05). Logistic multivariate analysis suggested the significant predictors of in hospital mortality included TTP<=7 hours [odds ratio (OR)=3.412, 95% confidence interval (95% CI)=1.1819.856, P=0.023], ESBL-producing strains (OR=2.545, 95% CI=0.9776.625, P=0.056). CONCLUSION: In vitro Escherichia coli growth speed in the blood culture correlates with the incidence of neutropenia and primary bacteremia, and TTP<=7 hours and ESBL-producing strains may be the strong, independent risk factors of a worse prognosis in patients with Escherichia coli bacteremia. PMID- 20854733 TI - [The cost-efficiency and safety of bedside forceps dilatational tracheostomy in the intensive care unit]. AB - OBJECTIVE: To study the cost-efficiency and safety of bedside forceps dilatational tracheostomy (FDT) in the intensive care unit (ICU). METHODS: FDT was performed in 83 patients who needed prolonged artificial airway. The time interval between the decision and actual time of operation, time for completing the procedure, operation cost, perioperative and postoperative complications were recorded and analyzed. The operation cost was compared between 83 FDT cases and other 102 surgical tracheostomy (ST) cases which were performed in the operation room during the same period. RESULTS: FDT was successfully performed for 83 patients. The average time interval between the decision and undertaking FDT was (11.5+/-8.5) hours, the average operating time was (14.5+/-5.5) minutes, the operation cost of FDT [(1 560+/-340) yuan] was lower than that of ST [(2 600+/ 450) yuan, P <0.05]. The incidence of the perioperative and postoperative complication of the 83 patients was 15.66% and 2.41% respectively. Nine patients died within 28 days after FDT. CONCLUSION: FDT performed by intensivists for critically ill patients in ICU is safe and cost-effective. PMID- 20854734 TI - [Expression of microRNA-146a in lipopolysaccharide challenged alveolar macrophages in vitro]. AB - OBJECTIVE: To investigate the expression of microRNA-146a (miRNA-146a) in NR8383 alveolar macrophages treated with lipopolysaccharides (LPS). METHODS: NR8383 alveolar macrophages were divided into two groups: LPS treated group and phosphate buffer saline (PBS) control group, and they cultured for 6 hours. The production of tumor necrosis factor-alpha (TNF-alpha) in the supernatant of cells was determined with enzyme-linked immunosorbent assay (ELISA), and the expression of miRNA-146a of cells was detected by real-time polymerase chain reaction (PCR). RESULTS: Compared with PBS control group, the TNF-alpha content (ng/L) in LPS treated group was significantly increased (650.26+/-40.53 vs. 6.23+/-1.76, P<0.01), and miRNA-146a in LPS treated group increased by about (5.33+/-0.81) folds (P<0.01). CONCLUSION: The expression of miRNA-146a was increased in LPS treated NR8383 cells, and miRNA-146a may be involved in the modulation inflammatory response of the NR8383 alveolar macrophage. PMID- 20854735 TI - [The DNA binding activity of nuclear factor-KappaB in patients with severe pneumonia and the intervention effects of Xuebijing injection]. AB - OBJECTIVE: To investigate the role of nuclear factor-KappaB (NF-KappaB) in severe pneumonia and observe the effects of Xuebijing injection in its treatment. METHODS: Thirty hospitalized patients with severe pneumonia were divided into the routine therapy group (n=14) and Xuebijing therapy group (n=16) in whom with Xuebijing injection 100 ml was given once daily for 7 days besides routine therapies, according to the random numeral. The DNA binding activity of NF-KappaB in human monocytes was detected before and 3 days and 7 days after administration, the contents of tumor necrosis factor-alpha (TNF-alpha), procalcitonin (PCT) and C-reactive protein (CRP) were determined, and the changes in coagulatory and fibrinolytic parameters were assayed at the same time. Acute physiology and chronic health evaluationII (APACHEII) score was also recorded. Ten healthy volunteers served as the healthy control group. RESULTS: The DNA binding activities of NF-KappaB, the contents of TNF-alpha, PCT, CRP, fibrinogen (Fib), D-dimer in hospitalized subjects with severe pneumonia were higher before treatment than those in healthy control group, while the prothrombin time (PT), thrombin time (TT) were significantly lower (P<0.05 or P<0.01). Compared with the routine therapy group, the DNA binding activity of NF-KappaB (grey level) at the 7 days (66.60+/-36.23 vs. 79.90+/-39.11) was notably decreased in Xuebijing therapy group; the levels of TNF-alpha (ng/L, 25.81+/-11.67 vs. 33.78+/-13.36), PCT (MUg/L, 1.91+/-1.09 vs. 2.96+/-1.80), CRP (mg/L, 20.01+/-7.21 vs. 26.59+/ 10.66), Fib (g/L, 4.02+/-1.26 vs. 5.09+/-1.43), D-dimer (mg/L, 0.24+/-0.06 vs. 0.31+/-0.11) were significantly lower in Xuebijing therapy group, and APACHEII score (15.81+/-3.47 vs. 17.93+/-3.05) was obviously lowered (all P<0.05). There was statistical difference of the TT (s) between two groups at 3 days (15.68+/ 1.89 vs. 14.65+/-1.33,P<0.05). There was a significant positive correlation between NF-KappaB DNA binding activity and the levels of TNF-alpha (r(1)=0.373, r(2)=0.362, r(3)=0.419), PCT (r (1)=0.800, r(2)=0.716, r(3)=0.920) or CRP (r(1)=0.368, r(2)=0.441, r(3)=0.366, all P<0.05) before and 3 days and 7 days after the treatment. CONCLUSION: NF-KappaB activation and coagulopathy were observed in patients with severe pneumonia, and NF-KappaB was involved in the process of inflammatory response. Inflammatory response was partly alleviated by Xuebijing injection. These effects of Xuebijing injection may be mediated by inhibition of the activation of NF-KappaB and its anticoagulation property. PMID- 20854736 TI - [Effect of ulinastatin preconditioning on gene expression profile of kidney tissue in a rat sepsis model]. AB - OBJECTIVE: To investigate the modulation effect of ulinastatin (UTI) preconditioning on gene expression of kidney tissue in septic rats by DNA microarrays. METHODS: Forty-five male Wistar rats were divided into control group, sepsis group and UTI group, with 15 rats in each group by means of random number table. Cecal ligation and puncture (CLP) was used to reproduce rat sepsis model. The control group only experienced a simulated operation without CLP. In UTI group the rats were treated with intramuscular injection of UTI (100 kU/kg). In sepsis group and control group intramuscular balanced solution (5 ml/kg) was given. Gene expression spectrum was studied with oligonucleotide gene expression profile microarray that contained 22 523 rat cDNA clones to detect the changes in gene expression pattern of rat kidney tissue 24 hours after CLP. Genes with fluorescent signal of Cy3/Cy5 of ratio average (RA)>2.0 or RA<0.5 were identified as differential genes, then those highly correlated to sepsis and UTI were screened by means of related computer software, and their relationship was analyzed. RESULTS: Three hundred and twenty-seven differential genes were found in sepsis group/control group, accounting for 1.45%, and among them 181 genes showed up-regulation,with 78 known functional genes, and 146 genes showed down regulation, with 51 known functional genes. One hundred and twenty-seven differential genes were found in UTI group/sepsis group, accounting for 0.56%, and among them 41 genes showed up-regulation, with 14 known functional genes, and 86 genes showed down-regulation, with 37 known functional genes. Twenty-two genes were down-regulated in sepsis group/control group but up-regulated in UTI group/sepsis group, with 11 known functional genes, 51 genes were up-regulated in sepsis group/control group but down-regulated in UTI group/sepsis group, with 24 known functional genes. CONCLUSION: UTI preconditioning can alleviate the damage of kidney tissue in rat sepsis model, thus showing a protective effect on kidney, and the mechanism may be attributable to effect of UTI on modulation of immune reaction, energy metabolism, inflammatory reaction, signal transduction, defense reaction, oxidation-reduction reaction, DNA replication, and transcription related genes. PMID- 20854737 TI - [Clinical research on the incidence of ventilator associated pneumonia with daily arousal therapy in patients with severe head-injury]. PMID- 20854738 TI - [Effect of heparin on the levels of interleukin-6, tumor necrosis factor-alpha and angiotensin II in rat with sepsis]. PMID- 20854739 TI - [An analysis of the risk factors in prognosis of severe acute pancreatitis]. PMID- 20854745 TI - Educating teenagers about sex in the United States. AB - KEY FINDINGS: Most teenagers received formal sex education before they were 18 (96% of female and 97% of male teenagers). Female teenagers were more likely than male teenagers to report first receiving instruction on birth control methods in high school (47% compared with 38%). Younger female teenagers were more likely than younger male teenagers to have talked to their parents about sex and birth control. Nearly two out of three female teenagers talked to their parents about "how to say no to sex" compared with about two out of five male teenagers. Most teenagers received formal sex education before they were 18 (96% of female and 97% of male teenagers). Female teenagers were more likely than male teenagers to report first receiving instruction on birth control methods in high school (47% compared with 38%). Younger female teenagers were more likely than younger male teenagers to have talked to their parents about sex and birth control. Nearly two out of three female teenagers talked to their parents about "how to say no to sex" compared with about two out of five male teenagers. PMID- 20854746 TI - Emergency department visits for chest pain and abdominal pain: United States, 1999-2008. AB - KEY FINDINGS: The number of noninjury emergency department (ED) visits in which abdominal pain was the primary reason for the visit increased 31.8%. The percentage of ED visits for which chest pain was the primary reason decreased 10.0%. Use of advanced medical imaging increased strongly for ED visits related to abdominal pain (122.6%) and chest pain (367.6%). The percentage of ED visits for chest pain that resulted in a diagnosis of acute coronary syndrome decreased 44.9%. Chest and abdominal pain are the most common reasons that persons aged 15 years and over visit the emergency department (ED). Because EDs provide both emergency and nonemergency care, visits for these symptoms may vary in their acuity. Advanced medical imaging is often ordered to assist in both diagnosing and ruling out serious illness associated with these symptoms. This report describes trends in visits for chest and abdominal pain in adults and the seriousness of illness and use of imaging in these visits. All data shown are for persons aged 18 and over whose visit was not injury related. PMID- 20854747 TI - Prescription drug use continues to increase: U.S. prescription drug data for 2007 2008. AB - KEY FINDINGS: Over the last 10 years, the percentage of Americans who took at least one prescription drug in the past month increased from 44% to 48%. The use of two or more drugs increased from 25% to 31%. The use of five or more drugs increased from 6% to 11%. In 2007-2008, 1 out of every 5 children and 9 out of 10 older Americans reported using at least one prescription drug in the past month. Those who were without a regular place for health care, health insurance, or prescription drug benefit had less prescription drug use compared with those who had these benefits. The most commonly used types of drugs included: asthma medicines for children, central nervous system stimulants for adolescents, antidepressants for middle-aged adults, and cholesterol lowering drugs for older Americans. PMID- 20854749 TI - Biomarkers for the early stages of clinical development in Alzheimer's disease. AB - As the failure of several recent Phase III drug development programmes bears witness, the clinical development of "disease-modifying" drugs in Alzheimer's disease has been confronted with challenging methodological difficulties. Taking into account the financial stakes involved taking drug candidates to the Phase III stage of development, and the risk of investing time and resources fruitlessly in the evaluation of poor candidate drugs, the crucial decision remains whether to proceed from Phase II to Phase III (Go/Nogo). The aim of Phase II studies is to select a molecule likely to be effective in Phase III, but also to eliminate candidate-drugs with an inadequate effect. No consensus currently exists on the best possible design of Phase II studies to inform the Go/Nogo decision optimally. The challenges in choosing the best study design relate to the target population, the end-point criteria used, in particular the use of biomarkers, the experimental protocol, and the study duration. The objective of the Round Table (RT) was to gather the opinions of French experts from the academic, industrial, and regulatory world in order to arrive at a consensus recommendation for the best possible design to be used in Phase II studies in Alzheimer's disease. PMID- 20854751 TI - Clinical Trials Legislation - preparing for the revision of the European Directive Scheduled for 2011. AB - The aim of the Round Table was to make recommendations with regard to the imminent revision of the European Directive on clinical drug trials (2001/20/CE). While recognising the importance of compliance with this Directive, which is not optimal in some member states of the European Union, it would be constructive to simplify further and harmonise its application in every country. Without necessarily resorting to a revision, some of the Directive's dispositions could be improved, such as the definition of "investigational medicinal products" (IMP) and what should be considered as "substantial amendements", as well as harmonising and improving the way in which Ethics Committees are run, either on a European Commission level, or by relying more on the European Network of Research Ethics Committees (EUREC) which already exists in several European member states. Other points in the Directive do require revision, especially those relating to: the definition of the respective roles of Ethics Committees and Competent Authorities, the simplification of safety information to Ethics Committees (giving them access to the Eudravigilance database for adverse reactions occurring during clinical trials and providing them with only new safety issues or with a summary of the Annual Safety Report), the possibility of one single European authorisation for the trial, centralised and/or decentralised, when the trial is multinational. The recommended changes could be made within the scope of a European Regulation, avoiding the need to transpose it at a later date into each country's regulations, which is a source of possible lack of harmonisation. More specifically, for trials with institutional sponsors and/or investigator driven trials such as "drug therapy strategy trials", modulating restrictions according to the "risk added by the research" would enable the trial's organisation to be simplified regarding monitoring, adverse reactions reporting and study drugs labelling. PMID- 20854753 TI - Clinical trials and E-health: impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research. AB - Within the last few years, new technology has come to play an important part in our professional and private daily environment. Healthcare has not escaped this progressive mutation with computers reaching the bedside. Clinical research has also shown growing interest in these new tools available to the clinical investigator, the patient, as well as to specialist departments for diagnosis and follow-up of patients, and to the different professions in clinical research. If the use of new technology seems to make life easier, by centralizing data or by simplifying data-sharing between different teams, it is still a matter of private data which must remain reliable, confidential and secure, whether it is being used in ordinary healthcare or in academic or industrial research. The aim of the round table was to estimate the impact of new information technology applied to clinical trials (including source data-medical records) and to human and drug research. First, an inventory was made of the development of these new technologies in the healthcare system. The second point developed was identification of expected benefits in order to issue guidelines for their good use and hazard warnings in clinical trials. Finally, the impact of these new technologies on the investigator as well as the project manager was analysed. PMID- 20854755 TI - Comparators (medicinal and non medicinal) for marketing authorization, for public health, for payers and at the European level. AB - Drug evaluation is based on comparison. Thus, the choice of the comparator for any new treatment becomes a key issue, especially when there are great differences in medical practice and of use conditions of the comparators depending on the geographical zones and their evolution with time. The choice of the comparators must satisfy sometimes different expectations from the registration authorities and for insurance coverage. The universal comparator that allows answering all the clinical assessment questions does not exist. Placebo, when it can be used, remains a reference for the MA (marketing authorisation) application, but does not exclude the use of the reference drug available on the market and prescribed under optimal efficacy conditions. The reference treatment is sometimes a difficult choice due to the absence of validated therapeutic recommendations or if the recommendations vary depending on the countries. The expansion and international harmonization of prescription guidelines (clinical practice guidelines) would reinforce the robustness and efficiency of clinical research efforts with respect to the relevance of the comparison to reference treatments. This principle also applies to the use of a non-drug comparator when it has been recognized as the reference comparator in the treatment of the pathology in question. In as much as possible, the search for a consensus must also aim at defining in the clinical development recommendations significant thresholds for the size of evaluated effects. Optimization of the information made available after clinical trials could also be helped by the development of use of methodologies that allow assessing superiority on secondary criteria during a non-inferiority study on the main criterion. Finally, the development of early scientific consultations by the Haute Autorite de Sante (HAS, French Health Authority) would contribute to adapt phase III clinical trials better to questions concerning the assessment of the clinical added value of the medicinal products evaluated. PMID- 20854757 TI - How to best define target populations of medicines in view of their coverage by the national health insurance scheme? AB - The target population of a medicine may include different populations that may partially overlap including the population that has been evaluated in the clinical trials, the population for which the medicine provides an actual benefit (SMR), that for which the drug provides an improvement of the actual benefit (ASMR), etc. The definition of the target population in both qualitative and quantitative terms has key public health and economic implications. Recommendations are made to shed light on the definitions, to clarify the requests of the public decision makers and to improve the methods and the sources allowing the quantification of target populations. PMID- 20854759 TI - Vaccines: specific features, simulation of impact and medico-economic modelling. AB - In a context where a number of vaccinations have recently been recommended in France, and where a large number of vaccines are under development, the Round Table has reviewed the specific features of vaccines in France, namely clinical development, medico-economic modelling, evaluation and communication. In each of these domains, the key stages and processes to be improved have been identified, and proposals made. The main strategic challenges are to promote the development of vaccines in France by access to the large-scale monitoring of populations, to look ahead and coordinate the evaluation of vaccines by the various parties involved, to widen communication about vaccination strategies, in order to improve the perception of vaccines and the acceptability of vaccinations, and to increase vaccination coverage. The Round Table has also proposed the creation of a working group to be responsible for pursuing, monitoring and implementing the proposals formulated. PMID- 20854761 TI - Assessing cancer drugs for reimbursement: methodology, relationship between effect size and medical need. AB - Reimbursement is assessed by the Transparency Commission from the Health Authority (HAS) using a medical benefit (SMR) score that gives access to reimbursement, an "improvement of medical service rendered" (ASMR) that determines the added therapeutic value, and the target population. Assessing cancer drugs for reimbursement raises the same issues as other therapeutic classes, with some key differences. Overall survival (OS) is considered by the Transparency Commission as the endpoint for assessing clinical benefit, and yet it is not an applicable primary endpoint in all types of cancer. Later lines of treatment, particularly during the development process, may make it difficult to interpret OS as the primary endpoint. Therefore, progression-free survival (PFS) for metastatic situations and disease-free survival (DFS) in adjuvant situations are wholly relevant endpoints for decisions on the reimbursement of a new cancer drug. Effect size is assessed using actuarial survival curves of the product versus the comparator, and it is difficult to summarise them into one single parameter. Results are generally interpreted based on median survival, which is fragmented because it only measures one point of the curve. The hazard ratio measures the effect of treatment throughout the duration of survival and is therefore more comprehensive in quantifying clinical benefit. Determining an effect size threshold for granting reimbursement is difficult given the diversity of cancer settings and the level of medical need, which influences assessment of the clinical relevance of the observed difference. Rapid progress in comparators (700 molecules in development) and the identification of predictive factors of efficacy (biomarkers, histology, etc.) during development may lead to different ASMR scores per population, or to the restriction of the target population to a subgroup of the marketing authorisation (MA) population in which the expected effect size is greater. To address these issues, the roundtable recommends the possibility of early scientific opinions by the office of the Transparency Commission in order to discuss comparators and the relevance of responder subgroups. It also recommends the possibility of granting a temporary ASMR, on condition of subsequent confirmation by production of data, when reimbursement appears justified in a subpopulation of the MA for which only subgroup analysis is available. PMID- 20854762 TI - [Terminology used in publications of pharmacoepidemiological research in france using health insurance reimbursement databases: need for harmonisation]. AB - The reimbursement databases of the French health insurance systems are greatly used for pharmaceoepidemiological research. However, the terminology used to describe them in subsequent articles and abstracts vary greatly and thus lead to a problem of identification during bibliograhic research or during the process of indexation in medline. In this article we have fixed the terminology used and proposed both a terminology and appropriate MeSH terms for indexation for the futur. Fifty-six published studies were included. At least six different root terms were found to define the French health insurance system, 64.3% of the publications mentioned the term "database", and 30.4% mentioned the term "reimbursement". We propose that abstracts of future articles contain the three terms: database, reimbursement, and health insurance. We also propose to include in the keywords of an article the MeSH terms that are most appropriate to define these three concepts: Insurance, Health, Reimbursement and Databases, Factual. PMID- 20854763 TI - [Appropriateness of medical prescriptions, French experience]. AB - Appropriateness of care, applied to medical prescription, is a fast-growing professional practice evaluation method, within a context of control spending and quality improvement. A literature review related to the last ten years found 38 publications, including 19 original studies. Results showed that only few studies were published, and that methodologies were not standardized. Development of pedagogical data tools is essential to increase doctor's awareness. Analysis of causes of inappropriateness has to be conducted, in order to plan improvement actions. A second evaluation is necessary to assess the impact of appropriateness review on professional practices. PMID- 20854766 TI - Nessun Dorma ("None Shall Sleep")... At least not before we digest Treatment of Adolescent Suicide Attempters (TASA). PMID- 20854767 TI - Location, location, and thickness: volumetric neuroimaging of attention deficit/hyperactivity disorder comes of age. PMID- 20854768 TI - Socioeconomic risk for psychopathology: the search for causal mechanisms. PMID- 20854769 TI - Changing paradigms in child institutionalization: the case of bulgaria. PMID- 20854772 TI - Distinguishing suicide attempts from nonsuicidal self-harming behaviors. PMID- 20854770 TI - Depressive symptoms and clinical status during the Treatment of Adolescent Suicide Attempters (TASA) Study. AB - OBJECTIVE: To examine the course of depression during the treatment of adolescents with depression who had recently attempted suicide. METHOD: Adolescents (N = 124), ages 12 to 18 years, with a 90-day history of suicide attempt, a current diagnosis of depressive disorder (96.0% had major depressive disorder), and a Children's Depression Rating Scale-Revised (CDRS-R) score of 36 or higher, entered a 6-month treatment with antidepressant medication, cognitive behavioral therapy focused on suicide prevention, or their combination (Comb), at five academic sites. Treatment assignment could be either random or chosen by study participants. Intent-to-treat, mixed effects regression models of depression and other relevant ratings were estimated. Improvement and remission rates were computed with the last observation carried forward. RESULTS: Most patients (n = 104 or 84%) chose treatment assignment, and overall, three fourths (n = 93) received Comb. In Comb, CDRS-R declined from a baseline adjusted mean of 49.6 (SD 12.3) to 38.3 (8.0) at week 12 and to 27.0 (10.1) at week 24 (p < .0001), with a Clinical Global Impression -defined improvement rate of 58.0% at week 12 and 72.2% at week 24 and a remission (CDRS-R <= 28) rate of 32.5% at week 12 and 50.0% at week 24. The CDRS-R and the Scale for Suicidal Ideation scores were correlated at baseline (r = 0.43, p < .0001) and declined in parallel. CONCLUSIONS: When vigorously treated with a combination of medication and psychotherapy, adolescents with depression who have recently attempted suicide show rates of improvement and remission of depression that seem comparable to those observed in nonsuicidal adolescents with depression. PMID- 20854780 TI - Personalized medicine and pharmacogenomics in child psychiatry. PMID- 20854781 TI - Little emperors and the 4:2:1 generation: China's singletons. PMID- 20854782 TI - Pharmacogenomics of methylphenidate response: making progress. PMID- 20854784 TI - Settling in: editor's report--Volume 48, 2009. PMID- 20854788 TI - Active intermediates in heme monooxygenase reactions as revealed by cryoreduction/annealing, EPR/ENDOR studies. AB - This review describes the use of cryoreduction/annealing EPR/ENDOR techniques for determining the active oxidizing species in reactions catalyzed by heme monooxygenases. The three candidate heme states are: ferric peroxo, ferric hydroperoxo and compound I intermediates. The enzymes discussed include cytochromes P450, nitric oxide synthase and heme oxygenase. PMID- 20854789 TI - Structure and mechanism of enzymes involved in biosynthesis and breakdown of the phosphonates fosfomycin, dehydrophos, and phosphinothricin. AB - Recent years have seen a rapid increase in the mechanistic and structural information on enzymes that are involved in the biosynthesis and breakdown of naturally occurring phosphonates. This review focuses on these recent developments with an emphasis on those enzymes that have been characterized crystallographically in the past five years, including proteins involved in the biosynthesis of phosphinothricin, fosfomycin, and dehydrophos and proteins involved in resistance mechanisms. PMID- 20854790 TI - Requirement of SIRPalpha for protective immunity against Leishmania major. AB - Signal regulatory protein alpha (SIRPalpha) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is abundantly expressed on dendritic cells and macrophages. Wild-type (WT) C57BL/6 mice are known to be resistant to Leishmania major infection. We here found that C57BL/6 mice that express a mutant version of SIRPalpha lacking most of the cytoplasmic region manifested increased susceptibility to L. major infection, characterized by the marked infiltration of inflammatory cells in the infected lesions. The numbers of the parasites in footpads, draining lymph nodes and spleens were also markedly increased in the infected SIRPalpha mutant mice, compared with those for the infected WT mice. In addition, soluble leishmanial antigen-induced production of IFN-gamma by splenocytes of the infected SIRPalpha mutant mice was markedly reduced. By contrast, the ability of macrophages of SIRPalpha mutant mice to produce nitric oxide in response to IFN-gamma was almost equivalent to that of macrophages from WT mice. These results suggest that SIRPalpha is indispensable for protective immunity against L. major by the induction of Th1 response. PMID- 20854791 TI - Prediction of midbody, centrosome and kinetochore proteins based on gene ontology information. AB - In the process of cell division, a great deal of proteins is assembled into three distinct organelles, namely midbody, centrosome and kinetochore. Knowing the localization of microkit (midbody, centrosome and kinetochore) proteins will facilitate drug target discovery and provide novel insights into understanding their functions. In this study, a support vector machine (SVM) model, MicekiPred, was presented to predict the localization of microkit proteins based on gene ontology (GO) information. A total accuracy of 77.51% was achieved using the jackknife cross-validation. This result shows that the model will be an effective complementary tool for future experimental study. The prediction model and dataset used in this article can be freely downloaded from http://cobi.uestc.edu.cn/people/hlin/tools/MicekiPred/. PMID- 20854792 TI - PPARalpha deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPARgamma activation in the liver. AB - An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor alpha (PPARalpha) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPARalpha-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPARalpha-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPARalpha target genes such as Cyp4A10 and FGF21 was damped in PPARalpha-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPARalpha-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPARalpha activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPARgamma and its coactivator PCG-1alpha were more effectively induced in PPARalpha-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPARgamma antagonist, in both WT and PPARalpha-null mice. PPARgamma activation seems to be involved in KD-induced hypofibrinolysis by augmenting PAI-1 gene expression in the fatty liver. PMID- 20854793 TI - TGFbeta and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. AB - The epithelial-mesenchymal transition (EMT) is associated with progression and metastasis of epithelial ovarian cancer (EOC). Snail and Slug (two members of the Snail family of transcription factors) down-regulate the expression of the adhesion molecule E-cadherin and thus function as positive regulators of EMT. Their expression is associated with a more invasive phenotype of EOC. However, how their expression in EOC cells is regulated needs to be further defined. Here, we show that transforming growth factor beta (TGFbeta) and epidermal growth factor (EGF) synergistically induce the expression of Slug and Snail at both mRNA and protein levels in an EOC cell line OVCA429 cells. Using specific chemical inhibitors, we demonstrate that Slug and Snail expression induced by TGFbeta is mediated by TGFbeta/ALK5 pathway, and EGF-induced expression of Slug and Snail is MEK1/2-dependent. Interestingly, TGFbeta-induced Slug expression is also MEK1/2 dependent. Further, we demonstrate that combined TGFbeta and EGF stimulation is more potent than either alone in repressing the expression of E-cadherin. Functionally, combined stimulation of TGFbeta and EGF enhances the mobility of OVCA429 cells and induces the production of MMP2 by OVCA429 cells more potently than either alone. Taken together, our data demonstrate that TGFbeta and EGF signaling pathways synergistically induce EMT and render EOC cells a more invasive phenotype. PMID- 20854794 TI - Interaction of fused-pyrimidine nucleoside analogs with human concentrative nucleoside transporters: High-affinity inhibitors of human concentrative nucleoside transporter 1. AB - Human concentrative nucleoside transporters (hCNTs) mediate electrogenic secondary active transport of physiological nucleosides and nucleoside drugs into cells. Six fused-pyrimidine ribonucleosides and one 2'-deoxynucleoside were assessed for their abilities to inhibit [(3)H]uridine transport in the yeast Saccharomyces cerevisiae producing recombinant hCNT1, hCNT2 or hCNT3. Six of the analogs inhibited hCNT1 with K(i) values<1MUM whereas only two analogs inhibited hCNT3 with K(i) values<1MUM and none inhibited hCNT2. To assess if the inhibitory analogs were also permeants, currents evoked were measured in oocytes of Xenopus laevis producing recombinant hCNT1, hCNT2 or hCNT3. Significant inward currents, indicating permeant activity, were generated with (i) three of the analogs in hCNT1-producing oocytes, (ii) none of the analogs in hCNT2-producing oocytes and (iii) all of the analogs in hCNT3-producing oocytes. Four were not, or were only very weakly, transported by hCNT1. The thienopyrimidine 2'-deoxynucleoside (dMeThPmR, 3) and ribonucleoside (MeThPmR, 4) were the most active inhibitors of uridine transport in hCNT1-producing oocytes and were an order of magnitude more effective than adenosine, a known low-capacity transport inhibitor of hCNT1. Neither was toxic to cultured human leukemic CEM cells, and both protected CEM cell lines with hCNT1 but not with hENT1 against gemcitabine cytotoxicity. In summary, dMeThPmR (3) and MeThPmR (4) were potent inhibitors of hCNT1 with negligible transportability and little apparent cytotoxicity, suggesting that pending further evaluation for toxicity against normal cells, they may have utility in protecting normal hCNT1-producing tissues from toxicities resulting from anti-cancer nucleoside drugs that enter via hCNT1. PMID- 20854796 TI - UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate. AB - Methotrexate is a chemotherapeutic agent used in breast cancer treatment, but the occurrence of resistance limits its therapeutic use. A microarrays analysis between sensitive and methotrexate resistant MCF7 and MDA-MB-468 breast cancer cells pointed out the UDP-glucuronosyltransferase 1A (UGT1A) family as a common deregulated node in both cell lines. This family of genes is involved in Phase II metabolism. UGT1A6 was the main isoform responsible for UGT1A family overexpression in these cells. Its overexpression was not due to gene amplification. Transfection of a vector encoding for UGT1A6 in sensitive cells counteracted the cytotoxicity caused by methotrexate. Methotrexate increased the transcriptional activity from a luciferase reporter driven by the UGT1A6 promoter and induced UGT1A6 mRNA and enzymatic activity. Promoter analysis suggested that UGT1A6 induction by methotrexate could be driven by the transcription factors ARNT (HIF-1) and AhR/ARNT. Cells incubated with anticancer drugs susceptible to glucuronidation, such as tamoxifen or irinotecan, together with methotrexate, showed a lesser degree of cytotoxicity, due to UGT1A6 induction. The pharmacological effect of this induction should be taken into account when combining methotrexate with other drugs that are glucuronidated. PMID- 20854795 TI - Opioidergic mechanisms underlying the actions of Vitex agnus-castus L. AB - Vitex agnus-castus (VAC) has been used since ancient Greek times and has been shown clinically to be effective for the treatment of pre-menstrual syndrome. However, its mechanism of action has only been partially determined. Compounds, fractions, and extracts isolated from VAC were used in this study to thoroughly investigate possible opioidergic activity. First, an extract of VAC was found to bind and activate MU- and delta-, but not kappa-opioid receptor subtypes (MOR, DOR, and KOR respectively). The extract was then resuspended in 10% methanol and partitioned sequentially with petroleum ether, CHCl(3), and EtOAc to form four fractions including a water fraction. The highest affinity for MOR was concentrated in the CHCl(3) fraction, whereas the highest affinity for DOR was found in the CHCl(3) and EtOAc fractions. The petroleum ether fraction had the highest agonist activity at MOR and DOR. Several flavonoids from VAC were found to bind to both MOR and DOR in a dose-dependent manner; however only casticin, a marker compound for genus Vitex, was found to have agonist activity selective for DOR at high concentrations. These results suggest VAC may exert its therapeutic effects through the activation of MOR, DOR, but not KOR. PMID- 20854797 TI - The platinum (II) complex [Pt(O,O'-acac)(gamma-acac)(DMS)] alters the intracellular calcium homeostasis in MCF-7 breast cancer cells. AB - It was previously demonstrated that [Pt(O,O'-acac)(gamma-acac)(DMS)] exerted toxic effects at high doses, whilst sub-cytotoxic concentrations induced anoikis and decreased cell migration. Aim of this study was to investigate the hypothesis that [Pt(O,O'-acac)(gamma-acac)(DMS)] alters the [Ca(2+)](i) and that this is linked to its ability to trigger rapid apoptosis in MCF-7 cells. Thus, cells were treated with [Pt(O,O'-acac)(gamma-acac)(DMS)] and its effects on some of the systems regulating Ca(2+) homeostasis were studied, also in cells dealing with the complex changes occurring during the Ca(2+) signalling evoked by extracellular stimuli. [Pt(O,O'-acac)(gamma-acac)(DMS)] caused the decrease of PMCA activity (but not SERCA or SPCA) and Ca(2+) membrane permeability. These two opposite effects on [Ca(2+)](i) resulted in its overall increase from 102+/-12nM to 250+/-24nM after 15min incubation. The effects of [Pt(O,O'-acac)(gamma acac)(DMS)] were also evident when cells were stimulated with ATP: the changes in Ca(2+) levels caused by purinergic stimulation resulted altered due to decreased PMCA activity and to the closure of Ca(2+) channels opened by purinergic receptor. Conversely, [Pt(O,O'-acac)(gamma-acac)(DMS)] did not affect the store operated Ca(2+) channels opened by thapsigargin or by ATP. [Pt(O,O'-acac)(gamma acac)(DMS)] provoked the activation of PKC-alpha and the production of ROS that were responsible for the Ca(2+) permeability and PMCA activity decrease, respectively. The overall effect of [Pt(O,O'-acac)(gamma-acac)(DMS)] is to increase the [Ca(2+)](i), an effect that is likely to be linked to its ability to trigger rapid apoptosis in MCF-7 cells. These data reinforce the notion that [Pt(O,O'-acac)(gamma-acac)(DMS)] would be a promising drug in cancer treatment. PMID- 20854798 TI - Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease antiprotease system by the mTOR inhibitor rapamycin. AB - The mTOR-inhibitor rapamycin is a potent drug used in many immunosuppressive and antiinflammatory therapeutic regimes. In renal transplantation despite its beneficial roles rapamycin in some cases can promote renal fibrosis in the kidney but the underlying mechanisms are unknown. In this study, we tested for possible modulatory effects of rapamycin on the cytokine-triggered matrix metalloproteinase 9 (MMP-9)/tissue inhibitor of metalloproteinase (TIMP)-1 protease-antiprotease system which is critically involved in renal inflammation and fibrosis. Treatment of rat mesangial cells (MC) with rapamycin dose dependently reduced the interleukin 1beta (IL-1beta)-triggered increase in gelatinolytic levels as demonstrated by zymography. The reduction in the extracellular MMP-9 content by rapamycin coincided with an attenuation in cytokine-induced steady-state MMP-9 mRNA levels. Conversely, rapamycin caused a dose-dependent increase in cytokine-evoked TIMP-1 expression in a Smad binding element (SBE)-dependent manner. Surprisingly, the attenuation of MMP-9 mRNA levels by rapamycin is accompanied by a potentiation of IL-1beta-induced MMP-9 promoter activity in which the stimulatory effects by rapamycin are mainly attributed to a proximal AP-1 binding site. Furthermore, the rapamycin-dependent potentiation of MMP-9 expression is accompanied by an amplification of cytokine triggered activities of nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1) transcription factors. Importantly, rapamycin-triggered increase in MMP-9 promoter activity is fully impaired when we used a MMP-9 reporter construct which is under the additional control of the 3' untranslated region (3'-UTR) of MMP-9. Collectively, these data imply that rapamycin inhibits the cytokine-induced MMP-9 mainly through posttranscriptional events and thereby exerts profibrotic activities. PMID- 20854799 TI - Human dental pulp stem cells protect mouse dopaminergic neurons against MPP+ or rotenone. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive death of substantia nigra dopaminergic neurons that results in a regional loss of striatal dopamine (DA) levels. Dental pulp contains ex vivo expandable cells called dental pulp stem cells (DPSCs), with the capacity to differentiate into multiple cell lineages. More interestingly, due to their embryonic origin, DPSCs express neurotrophic factors such as brain-derived neurotrophic factor, nerve growth factor and glial cell-derived neurotrophic factor. The aim of the present study was to investigate the neuroprotective effects of DPSCs against MPP+ (2.5, 5, and 10 MUM) and rotenone (0.25, 0.5 and 1 MUM) in an in vitro model of PD, using an indirect co-culture system with mesencephalic cell cultures. When mesencephalic cultures were challenged with MPP+ or rotenone, in the presence of DPSCs a statistically significant protective effect was observed at all the tested doses in terms of DA uptake. DPSCs protective effect on DA neurons was also confirmed by immunocytochemistry: an increased number of spared tyrosine hydroxylase (TH)+ cells was observed in co culture conditions compared to controls, and neurons showed longer processes in comparison with mesencephalic cells grown without DPSCs. In conclusion, the co culture with DPSCs significantly attenuated MPP+ or rotenone-induced toxicity in primary cultures of mesencephalic neurons. Considering that the direct contact between the two cell types was prevented, it can be speculated that neuroprotection could be due to soluble factors such as BDNF and NGF, released by DPSCs. Blocking BDNF and NGF with neutralizing antibodies, the neuroprotecting effect of DPSCs was completely abolished. Therefore DPSCs can be viewed as possible candidates for studies on cell-based therapy in neurodegenerative disorders. PMID- 20854800 TI - Genotyping three SNPs affecting warfarin drug response by isothermal real-time HDA assays. AB - BACKGROUND: The response to the anticoagulant drug warfarin is greatly affected by genetic polymorphisms in the VKORC1 and CYP2C9 genes. Genotyping these polymorphisms has been shown to be important in reducing the time of the trial and error process for finding the maintenance dose of warfarin thus reducing the risk of adverse effects of the drug. METHOD: We developed a real-time isothermal DNA amplification system for genotyping three single nucleotide polymorphisms (SNPs) that influence warfarin response. For each SNP, real-time isothermal Helicase Dependent Amplification (HDA) reactions were performed to amplify a DNA fragment containing the SNP. Amplicons were detected by fluorescently labeled allele specific probes during real-time HDA amplification. RESULTS: Fifty clinical samples were analyzed by the HDA-based method, generating a total of 150 results. Of these, 148 were consistent between the HDA-based assays and a reference method. The two samples with unresolved HDA-based test results were repeated and found to be consistent with the reference method. CONCLUSION: The HDA-based assays demonstrated a clinically acceptable performance for genotyping the VKORC1 -1639G>A SNP and two SNPs (430C>T and 1075A>C) for the CYP2C9 enzyme (CYP2C9*2 and CYP2C9*3), all of which are relevant in warfarin pharmacogenentics. PMID- 20854801 TI - Differential activity of EWG transcription factor isoforms identifies a subset of differentially regulated genes important for synaptic growth regulation. AB - The vast majority of genes in the human genome is alternatively spliced. The functional consequences of this type of post-transcriptional gene regulation that is particularly prominent in the brain, however, remains largely elusive. Here we analyzed the role of alternative splicing in the transcription factor erect wing (ewg) in Drosophila and dissect its function through differential rescue with transgenes encoding different isoforms. Transgenes expressing the SC3 ORF isoform fully rescue viability and synaptic growth defects. In contrast, transgenes expressing the ?DJ isoform, that lack exons D and J, have a lower activity as inferred from their expression levels and exert reduced rescue of viability and synaptic growth defects. By comparison of the gene expression profile of ewg(l1) mutants rescued either by the SC3 ORF or the ?DJ transgene, we identified a set of genes whose expression is exclusively restored by the SC3 isoform. These genes are mostly involved in regulating gene expression while a core function of EWG is indicated by the regulation of metabolic genes by both isoforms. In conclusion, we demonstrated that differential rescue with different isoform encoding transgenes of the transcription factor EWG identifies a unique set of genes associated with synaptic growth regulation. PMID- 20854802 TI - Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: a possible role of IP3 receptors. AB - ROCK, a serine/threonine protein kinase that has been identified as a Rho GTP binding protein, is a promising target for neuropsychiatric disorders. The selective ROCK inhibitor Y-27632 has been shown to induce neurite outgrowth in PC12 cells. However, the precise cellular and molecular mechanisms underlying ROCK inhibition-induced neurite outgrowth are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of nerve growth factor (NGF)-induced neurite outgrowth by Y-27632. Y-27632 significantly potentiated NGF (2.5 ng/ml)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. Furthermore, another ROCK inhibitor, H-1152, and the Rho inhibitor botulinum exoenzyme C3 also potentiated NGF (2.5 ng/ml)-induced neurite outgrowth. The effects by Y-27632 were antagonized by co administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C or 2-aminoethoxydiphenylborate (2-APB)). Moreover, the potentiation by Y-27632 was blocked by co-administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or an Akt inhibitor. In contrast, the specific inhibitors of phospholipase C (PLC-gamma), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways did not affect the potentiation of NGF-induced neurite outgrowth by Y-27632. The results of double-staining immunocytochemistry suggested that both ROCK1 and type-1 IP3 receptors may be co-localized in the cell body of PC12 cells. In conclusion, these findings suggest that IP3 receptors and PI3K-Akt signaling pathways might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by ROCK inhibitors. PMID- 20854803 TI - [125I]YP20: a novel radioligand specific for the extracellular domain of the CRF1 receptor. AB - The peptide corticotropin-releasing factor (CRF) binds to the CRF1 receptor via a two-domain mechanism such that the extracellular domain (ECD) of the receptor captures the CRF's C-terminus to facilitate the binding of CRF's N-terminus to the juxta-membrane or "J"-site. Known small molecule antagonists bind to the J site while known CRF1 receptor peptide radioligands bind to both sites. We report here the in vitro binding properties of the first radioligand that binds exclusively to the ECD of the CRF1 receptor. This ligand, which we named [125I]Yamada peptide 20 ([125I]YP20), is a radiolabeled analog of a synthetic peptide first reported by Yamada et al. (2004). We confirmed its high affinity for the [125I]CRF binding site on the hCRF1 receptor and also found it to potently antagonize CRF-stimulated cAMP production in hCRF1-CHO cells. Under optimized conditions, 20 pM [125I]YP20 reproducibly bound to hCRF1-CHO membranes with a pharmacology consistent with binding specific to the ECD of the CRF1 receptor. Saturation binding studies revealed the presence of a high affinity site with an estimated K(d) of ~0.9 nM. The kinetic association of 20 pM [125I]YP20 binding best fit to a rapid component (t(1/2)=0.69 min) and a sluggish component (t(1/2)=42 min). [125I]YP20's specific binding was rapidly reversible with dissociation kinetics also best described by two phases (t(1/2)=0.92 min and t(1/2)=11.7 min). While [125I]YP20's binding kinetics are complex, its high affinity and pharmacological specificity indicate that it is an excellent radioligand for probing the ECD site of the CRF1 receptor. PMID- 20854804 TI - Antagonism of ?9-THC induced behavioral effects by rimonabant: time course studies in rats. AB - The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ?9-tetrahydrocannabinol (?9-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ?9-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ?9-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ?9-THC and the time course for rimonabant in its ability to block the discriminative stimulus effects of ?9-THC. For antagonism testing, the training doses of ?9-THC were used and the rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post rimonabant administration; ?9-THC was always administered 20 min prior to testing. For EXP 2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ?9-THC, rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (+/-0.28-0.51) and 0.50 (+/ 0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ?9-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (+/ 95.7-172.2) and 98.4 (+/-64.2-150.7) min by rimonabant for the two groups in EXP 1, respectively. Similarly, the functional half-life of rimonabant was 118.9 (+/ 66.1-213.9) min in EXP-2. Thus, antagonism of ?9-THC by rimonabant is relatively short lasting. PMID- 20854805 TI - Antagonistic effect of flavonoids on NSC-741909-mediated antitumor activity via scavenging of reactive oxygen species. AB - NSC-741909 (1-[(4-chlorophenyl)methyl]-1H-Indole-3-methanol) is a novel anticancer agent that is highly active against several NCI-60 cancer cell lines. This agent induces sustained activation of mitogen-activated protein kinases (MAPK), including JNK and p38 MAP kinases. However, the mechanisms of its selective antitumor activity in some cancer cell lines remain unknown. We tested the combined effects of NSC-741909 and several kinase inhibitors that target the Raf/MEK/ERK1/2 or PI3K/AKT pathways in two sensitive lung cancer cells. We found that PD98059 (2'-amino-3'-methoxyflavone), a flavone derivative and a selective MEK inhibitor, can dramatically block the cell killing effect of NSC-741909. To determine whether this inhibitory effect is associated with MEK inhibition or other mechanisms, we evaluated the effects of other MEK inhibitors with different chemical structures and flavone derivatives that do not have an effect on MEK. We found that several flavonoids can markedly block NSC-741909-induced apoptosis and JNK activation in a time-dependent manner, regardless of whether they inhibit MEK or not. In contrast, NSC-741909-induced JNK activation and apoptosis were not blocked by other MEK-specific inhibitors U0126 and CI1040. Our results also showed that NSC-741909 induced a dramatic increase of reactive oxygen species in sensitive cells and that flavonoids effectively blocked the NSC-741909-induced reactive oxygen species production which are associated with flavonoids' antagonistic effects on NSC-741909-induced JNK activation and apoptosis. Those results demonstrated that flavonoids-mediated antagonist effect is through scavenging of reactive oxygen species. Our results may have implication on the design of clinical evaluation of antitumor activity of NSC-741909 or its analogues. PMID- 20854806 TI - Neuroprotective effects of chlorogenic acid on scopolamine-induced amnesia via anti-acetylcholinesterase and anti-oxidative activities in mice. AB - Chlorogenic acid is a major polyphenolic component of many plants and beverages, and is particularly abundant in coffee. We evaluated the neuroprotective effects of chlorogenic acid on learning and memory impairment induced by scopolamine (0.5 mg/kg, i.p.), a muscarinic antagonist, using the Y-maze, passive avoidance, and Morris water maze tests. The chlorogenic acid significantly improved the impairment of short-term or working memory induced by scopolamine in the Y-maze test, and significantly reversed cognitive impairments in mice as measured by the passive avoidance test. In addition, chlorogenic acid decreased escape latencies in the Morris water maze test. In a probe trial session, chlorogenic acid increased the latency time in the target quadrant in a dose-dependent manner. Ex vivo, chlorogenic acid inhibited acetylcholinesterase activity in the hippocampus and frontal cortex. Chlorogenic acid also decreased malondialdehyde levels in the hippocampus and frontal cortex. In vitro, chlorogenic acid was found to inhibit acetylcholinesterase activity (IC50=98.17 MUg/ml) and free radical scavenging activity (IC50=3.09 MUg/ml) in a dose-dependent manner. These results indicate that chlorogenic acid may exert anti-amnesic activity via inhibition of acetylcholinesterase and malondialdehyde in the hippocampus and frontal cortex. PMID- 20854807 TI - Genistein attenuates low temperature induced pulmonary hypertension in broiler chicks by modulating endothelial function. AB - Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension. PMID- 20854808 TI - Leonurine (SCM-198) improves cardiac recovery in rat during chronic infarction. AB - Leonurine, an alkaloid typically found in Herba leonuri, is known to have both antioxidant and cardioprotective properties. In the present study, we investigated the cardioprotective mechanism of leonurine the in vivo rat model of chronic myocardial ischemia and in vitro H9c2 cardiac myocyte model of oxidative stress. Myocardial ischemia was induced by ligating the left anterior descending coronary artery. Rats were divided into sham, myocardial ischemia+saline, and myocardial ischemia+leonurine (15 mg/kg/day). Cardiac function was recorded by catheterization. Apoptosis-related factor vascular endothelial growth factor (VEGF), survivin, Bcl-2 and Bax and pro-survival signaling pathways Akt, hypoxia inducible factor (HIF)-1alpha were measured by Western blotting or RT-PCR. Our results showed leonurine significantly improved myocardial function as evidenced by the decreased left ventricle end-diastolic pressure and the increased +dP/dt. Interestingly, leonurine increased the phosphorylation of Akt, the protein and gene expression of Bcl-2, but it reduced the protein and gene expression of Bax in vivo. Meanwhile leonurine significantly increased Akt phosphorylation in a concentration-dependent manner in H9c2 cardiac myocyte induced by oxidative stress in vitro, which was abolished by a phosphoinositide 3-kinase (PI3K) inhibitor, LY294002. Furthermore, leonurine not only increased the expression of HIF-1alpha but also the expression of survivin and VEGF. The results of present study demonstrated, for the first time that leonurine has potent anti-apoptotic effects after chronic myocardial ischemia mediated by activating the PI3K/Akt signaling pathway. Angiogenic mechanisms may be partially responsible for such an effect, which needs to be studied further. PMID- 20854809 TI - Tanshinone IIA attenuates atherosclerosis in ApoE(-/-) mice through down regulation of scavenger receptor expression. AB - This study is designed to investigate the protection of tanshinone IIA (TSIIA) against atherosclerosis in apolipoprotein E deficient (ApoE(-/-)) mice and to explore the mechanisms by focusing on the expressions of scavenger receptors, scavenger receptor-A (SR-A) and CD36. The in vivo study demonstrated that TSIIA (10-90mg/kg) inhibited the atherosclerotic lesions, down-regulated the CD68 protein expression in lesion and decreased the contents of cholesterol in aortas of ApoE(-/-) mice. In addition, TSIIA reduced the serum levels of oxidized LDL (oxLDL) and down-regulated the mRNA expression of CD36, SR-A and peroxisome proliferator-activated receptor gamma (PPARgamma) in aortas. The in vitro study showed that TSIIA (0.1-10MUM) decreased cholesterol level and DiI-oxLDL uptake in mouse peritoneal macrophages treated with oxLDL (50MUg/ml). In addition, TSIIA down-regulated the mRNA and protein expression of CD36 but not that of SR-A in oxLDL treated macrophages. TSIIA also down-regulated the mRNA expression of PPARgamma in oxLDL treated macrophages. Furthermore, TSIIA reduced the mRNA expression of CD36 in macrophages treated with PPARgamma agonist 15d-PGJ(2) (2MUM) or troglitazone (50MUM), whereas both 15d-PGJ(2) (0.5-1.5MUM) and troglitazone (5-20MUM) dose-dependently abolished the down-regulation of CD36 expression by TSIIA in oxLDL treated macrophages. These results suggest that TSIIA attenuates the atherosclerotic lesion in ApoE(-/-) mice, which might be attributed to the properties of both anti-oxidation and down-regulation of scavenger receptors. Furthermore, antagonism of PPARgamma might be involved in the down-regulation of CD36 by TSIIA. PMID- 20854810 TI - Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders. AB - Acid sensing ion channels (ASICs) are implicated in various brain functions including learning and memory and are involved in a number of neurological disorders such as pain, ischemic stroke, depression, and multiple sclerosis. We have recently defined ASICs as one of receptor targets of aromatic diamidines in neurons. Aromatic diamidines are DNA-binding agents and have long been used in the treatment of leishmaniasis, trypanosomiasis, pneumocystis pneumonia and babesiosis. Moreover, some aromatic diamidines are used as skin-care and baby products and others have potential to suppress tumor growth or to combat malaria. A large number of aromatic diamidines or analogs have been synthesized. Many efforts are being made to optimize the therapeutic spectrum of aromatic diamidines, i.e. to reduce toxicity, increase oral bioavailability and enhance their penetration of the blood-brain barrier. Aromatic diamidines therefore provide a shortcut of screening for selective ASIC inhibitors with therapeutic potential. Intriguingly nafamostat, a protease inhibitor for treating acute pancreatitis, also inhibits ASIC activities. Aromatic diamidines and nafamostat have many similarities although they belong to distinct classes of medicinal agents for curing different diseases. Here we delineate background, clinical application and drug development of aromatic diamidines that could facilitate the screening for selective ASIC inhibitors for research purposes. Further studies may lead to a drug with therapeutic value and extend the therapeutic scope of aromatic diamidines to combat neurological diseases. PMID- 20854811 TI - Anti-inflammatory effects of crocin and crocetin in rat brain microglial cells. AB - Microglial cells play critical roles in the immune and inflammatory responses of the central nervous system (CNS). Under pathological conditions, the activation of microglia helps in restoring CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that observed in Alzheimer's and Parkinson's diseases. Crocin and crocetin, found in the fruits of gardenia and in the stigmas of saffron, have been considered for the treatment of various disorders in traditional oriental medicine. Crocin and crocetin have been reported to have diverse pharmacological functions, such as anti-hyperlipidemic, anti atherosclerotic, and anti-cancer effects. Specifically, the neuroprotective potential of crocetin derivatives has previously been demonstrated. The specific aim of this study was to examine whether crocin or crocetin represses microglial activation. Crocin and crocetin were shown to be effective in the inhibition of LPS-induced nitric oxide (NO) release from cultured rat brain microglial cells. These compounds reduced the LPS-stimulated productions of tumor necrosis factor alpha, interleukin-1beta, and intracellular reactive oxygen species. The compounds also effectively reduced LPS-elicited NF-kappaB activation. In addition, crocin reduced NO release from microglia stimulated with interferon gamma and amyloid-beta. In organotypic hippocampal slice cultures, both crocin and crocetin blocked the effect of LPS on hippocampal cell death. These results suggest that crocin and crocetin provide neuroprotection by reducing the production of various neurotoxic molecules from activated microglia. PMID- 20854812 TI - Tetrahydroxystilbene glucoside ameliorates diabetic nephropathy in rats: involvement of SIRT1 and TGF-beta1 pathway. AB - Oxidative stress caused by hyperglycaemia is believed to be a major molecular mechanism underlying diabetic nephropathy. 2,3,5,4'-tetrahydroxystilbene-2-O-beta d-glucoside (TSG), an active component extract from Polygonum multiflorum Thunb, exhibits antioxidative and anti-inflammatory effects. Possible protective mechanisms of TSG on diabetic nephropathy were investigated in rats and cultured rat mesangial cells. Total cholesterol and triglyceride levels of diabetic rats were clearly increased and these increases were diminished by treatment with TSG. Treatment of diabetic rats with TSG also significantly reduced blood urea nitrogen, creatinine, 24 h urinary protein levels, and kidney weight/body weight. The activities of superoxide dismutase and glutathione peroxidase in renal homogenate were increased markedly, whereas malonaldehyde levels were decreased significantly in TSG-treated diabetic rats. TSG dramatically inhibited diabetes induced overexpression of TGF-beta1 and COX-2, and restored the decrease of SIRT1 expression in diabetic rats. High glucose-induced overexpression of TGF-beta1 in cultured mesangial cells was significantly inhibited, whereas the decease of SIRT1 expression was restored by pretreatment of TSG. Nicotinamide, the inhibitor of SIRT1, partially relieved the inhibitory effect of TSG on TGF-beta1 expression under high glucose condition. These findings indicate that the protective mechanisms of TSG on diabetic nephropathy are involved in the alleviation of oxidative stress injury and overexpression of COX-2 and TGF-beta1, partially via activation of SIRT1. PMID- 20854813 TI - Mast cell death induced by 24(S),25-epoxycholesterol. AB - Mast cell is one of the central effectors in inflammatory responses. Recent studies suggest that a promising therapeutic approach for various inflammatory immune diseases, including rheumatoid arthritis, multiple sclerosis, and type I allergies, is to inhibit mast cell growth and/or survival. Studies also indicate that a balanced lipid metabolism is crucial for regulating the life span of cells. Oxysterol is a well-known regulator of lipid metabolism and has diverse functions, such as inhibition of the mevalonate isoprenoid pathway, efflux of free cholesterols, and synthesis of cholesterol esters. Here, we show that 24(S),25-epoxycholesterol, a representative endogenous oxysterol, induces apoptosis in bone marrow-derived murine mast cells. Furthermore, we have revealed, for the first time, that the accumulation of neutral lipids catalyzed by acyl-CoA:cholesterol acyltransferase in the cells was involved in induction of mast cell apoptosis. Our present findings confer new insights into the roles of lipid metabolism during oxysterol-mediated mast cell apoptosis. PMID- 20854814 TI - Ascending multisynaptic pathways from the trigeminal ganglion to the anterior cingulate cortex. AB - By means of retrograde transneuronal transport of rabies virus, ascending multisynaptic pathways from the trigeminal ganglion (TG) to the anterior cingulate cortex (ACC) were identified in the rat. After rabies injection into an electrophysiologically defined trigeminal projection region of the ACC, transsynaptic labeling of second-order neurons via the medial thalamus (including the parafascicular nucleus) was located in the spinal trigeminal nucleus pars caudalis. Third-order neuron labeling occurred in the TG. Most of these TG neurons were medium- or large-sized cells giving rise to myelinated Adelta or Abeta afferent fibers, respectively. By contrast, TG neurons labeled transsynaptically from the orofacial region of the primary somatosensory cortex contained many small cells associated with unmyelinated C afferent fibers. Furthermore, the TG neurons retrogradely labeled with fluorogold injected into the mental nerve were smaller in their sizes compared to those labeled with rabies. Our extracellular unit recordings revealed that a majority of ACC neurons responded to trigeminal nerve stimulation with latencies of shorter than 20ms. Thus, somatosensory information conveyed to the ACC by multisynaptic ascending pathways derived predominantly from myelinated primary afferents (i.e., the medial nociceptive system) and may be used to subserve affective-motivational aspects of pain. Lack of overlap with the lateral nociceptive system is notable and suggests that the medial and lateral nociceptive systems perform separate and non-overlapping functions. PMID- 20854815 TI - Albumin activates the canonical TGF receptor-smad signaling pathway but this is not required for activation of astrocytes. AB - The use of albumin as a resuscitation fluid is considered safe for most critically ill patients. However, clinical data suggest albumin may increase mortality in neurotrauma, but improve outcome after stroke. Albumin has been shown to activate glia, and to play a role in the mechanisms of epileptogenesis via the TGFbeta-receptor (TGFbetaR). We have previously shown that albumin induces the production of inflammatory mediators including IL-1beta via activation of MAPK pathways in primary astrocytes and microglia. The extracellular signaling mechanisms leading to the activation of glial cells in response to albumin are not well understood. Here, we investigated the role of the TGFbetaR and the canonical TGFbeta receptor-smad signaling pathway in astrocyte activation by albumin. In primary astrocyte cultures, albumin activated the smad pathway downstream of the TGFbetaR by increasing the phosphorylation of smad2, and in the level of smad3 and smad4 translocated to the nucleus. Albumin produced an increase in IL-1beta which was not dependent on smad activation, but was prevented by blockade of the TGFbetaR. Increase in the chemokine CX3CL1, and the decrease in S100B produced by albumin were independent of the TGFbetaR and smad activation. Albumin induced an increase in LDH release that was inhibited by blockade of the TGFbetaR and by inhibition of smad activation. These findings show that albumin activates the canonical TGF receptor-smad signaling pathway. The albumin-induced increase in the pro-epileptogenic cytokine IL-1beta involves the TGFbetaR, but is independent of smad activation. Taken together, the effects of albumin on both IL-1beta and activation of the TGFbetaR pathway are further evidence for a role for albumin in neurotrauma-related epileptogenesis. PMID- 20854816 TI - mTOR inhibitor rapamycin suppresses striatal post-ischemic LTP. AB - The two complexes of the mammalian target of rapamycin (mTOR), mTORC1 and mTORC2, have central functions in the integration of both extracellular and intracellular signals that are also critical players in the induction of post-ischemic long term potentiation (i-LTP), a pathological form of plasticity inducible in striatal medium spiny neurons (MSNs) after a brief episode of in vitro ischemia. To evaluate the involvement of mTOR complexes during ischemia we analyzed the time course of i-LTP by intracellular recordings of MSNs from corticostriatal slices incubated with 1MUM mTOR inhibitor rapamycin. Although rapamycin did not affect the amplitude and duration of ischemia-induced membrane depolarization it fully prevented i-LTP, leaving unaffected the capability to undergo activity dependent LTP following high-frequency stimulation of corticostriatal fibers. The present results argue for a role of mTOR complex in i-LTP and suggest that rapamycin, by selectively blocking i-LTP, represents a promising therapeutic tool to limit cellular damage after ischemic brain insult. PMID- 20854817 TI - SsrA (tmRNA) acts as an antisense RNA to regulate Staphylococcus aureus pigment synthesis by base pairing with crtMN mRNA. AB - SsrA RNA (small stable RNA A), also known as tmRNA and 10Sa RNA, functions both as tRNA and mRNA through its unique structure. The carotenoid pigment is the eponymous feature of human pathogen Staphylococcus aureus. Here, we found that the pigment of the mutant strain with ssrA deletion was increased. Furthermore, it was demonstrated that ssrA could act as an antisense RNA aside from its well known biological function, and crtMN, encoding two essential enzymes for the pigment synthesis, was identified as target of ssrA. Further investigation showed ssrA could specifically base pair with the RBS (ribosomal binding site) region of the crtMN mRNA. Our results revealed a new mechanism by which ssrA regulated the biosynthesis of pigment in S. aureus. PMID- 20854818 TI - Analysis of administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal cancer. AB - BACKGROUND & AIMS: Most quality indicators for colonoscopy measure processes; little is known about their relationship to patient outcomes. We investigated whether characteristics of endoscopists, determined from administrative data, are associated with development of postcolonoscopy colorectal cancer (PCCRC). METHODS: We identified individuals diagnosed with colorectal cancer in Ontario from 2000 to 2005 using the Ontario Cancer Registry. We determined performance of colonoscopy using Ontario Health Insurance Plan data. Patients who had complete colonoscopies 7 to 36 months before diagnosis were defined as having a PCCRC. Patients who had complete colonoscopies within 6 months of diagnosis had detected cancers. We determined if endoscopist factors (volume, polypectomy and completion rate, specialization, and setting) were associated with PCCRC using logistic regression, controlling for potential covariates. RESULTS: In the study, 14,064 patients had a colonoscopy examination within 36 months of diagnosis; 584 (6.8%) with distal and 676 (12.4%) with proximal tumors had PCCRC. The endoscopist's specialty (nongastroenterologist/nongeneral surgeon) and setting (non-hospital based colonoscopy) were associated with PCCRC. Those who underwent colonoscopy by an endoscopist with a high completion rate were less likely to have a PCCRC (distal: odds ratio [OR], 0.73; 95% confidence interval [CI], 0.54-0.97; P = .03; proximal: OR, 0.72; 95% CI, 0.53-0.97; P = .002). Patients with proximal cancers undergoing colonoscopy by endoscopists who performed polypectomies at high rates had a lower risk of PCCRC (OR, 0.61; 95% CI, 0.42-0.89; P < .0001). Endoscopist volume was not associated with PCCRC. CONCLUSIONS: Endoscopist characteristics derived from administrative data are associated with development of PCCRC and have potential use as quality indicators. PMID- 20854819 TI - Histomorphometric analysis reveals reduced bone mass and bone formation in patients with quiescent Crohn's disease. AB - BACKGROUND & AIMS: Crohn's disease (CD) is associated with an increased prevalence of osteoporosis, but the pathogenesis of this bone loss is only partly understood. We assessed bone structure and remodeling at the tissue level in patients with quiescent CD. We also investigated the roles of osteocyte density and apoptosis in CD-associated bone loss. METHODS: The study included 23 patients with quiescent CD; this was a subgroup of patients from a large randomized, double-blind, placebo-controlled, multicenter trial. We obtained transiliac bone biopsy samples and performed histomorphometric analysis. Results were compared with data from age- and sex-matched healthy individuals (controls). RESULTS: Trabecular bone volume was decreased among patients with CD compared with controls (18.90% vs 25.49%; P < .001). The low bone volume was characterized by decreased trabecular thickness (120.61 vs 151.42 MUm; P < .01). Bone formation and resorption were reduced, as indicated by a decreased mineral apposition rate (0.671 vs 0.746 MUm/day; P < .01) and a low osteoclast number and surface area compared with controls and published values, respectively. In trabecular bone of patients with CD, osteocyte density and apoptosis were normal. The percentage of empty lacunae among patients was higher than that of published values in controls. CONCLUSIONS: In adult patients with quiescent CD, bone histomorphometric analysis revealed a reduction in bone mass that was characterized by trabecular thinning. The CD-associated bone loss was caused by reduced bone formation, possibly as a consequence of decreased osteocyte viability in the patients' past. PMID- 20854820 TI - Detection of dysplasia in Barrett's esophagus with in vivo depth-resolved nuclear morphology measurements. AB - BACKGROUND & AIMS: Patients with Barrett's esophagus (BE) show increased risk of developing esophageal adenocarcinoma and are routinely examined using upper endoscopy with biopsy to detect neoplastic changes. Angle-resolved low coherence interferometry (a/LCI) uses in vivo depth-resolved nuclear morphology measurements to detect dysplasia. We assessed the clinical utility of a/LCI in the endoscopic surveillance of patients with BE. METHODS: Consecutive patients undergoing routine surveillance upper endoscopy for BE were recruited at 2 endoscopy centers. A novel, endoscope-compatible a/LCI system measured the mean diameter and refractive index of cell nuclei in esophageal epithelium at 172 biopsy sites in 46 patients. At each site, an a/LCI measurement was correlated with a concurrent endoscopic biopsy specimen. Each biopsy specimen was assessed histologically and classified as normal, nondysplastic BE, indeterminate for dysplasia, low-grade dysplasia (LGD), or high-grade dysplasia (HGD). The a/LCI data from multiple depths were analyzed to evaluate its ability to differentiate dysplastic from nondysplastic tissue. RESULTS: Pathology characterized 5 of the scanned sites as HGD, 8 as LGD, 75 as nondysplastic BE, 70 as normal tissue types, and 14 as indeterminate for dysplasia. The a/LCI nuclear size measurements separated dysplastic from nondysplastic tissue at a statistically significant (P < .001) level for the tissue segment 200 to 300 MUm beneath the surface with an accuracy of 86% (147/172). A receiver operator characteristic analysis indicated an area under the curve of 0.91, and an optimized decision point gave 100% (13/13) sensitivity and 84% (134/159) specificity. CONCLUSIONS: These preliminary data suggest a/LCI is accurate in detecting dysplasia in vivo in patients with BE. PMID- 20854821 TI - S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. AB - BACKGROUND & AIMS: Less than half of patients infected with hepatitis C virus (HCV) achieve sustained viral clearance after pegylated interferon (peginterferon) and ribavirin therapy. S-adenosyl methionine (SAMe) improves interferon signaling in cell culture. We assessed the effect of SAMe on the kinetics of the early antiviral response and interferon signaling in nonresponders to previous antiviral therapy and investigated the mechanisms involved. METHODS: Nonresponders with HCV genotype 1 were given peginterferon alfa-2a and ribavirin for 2 weeks (course A, baseline/control). After 1 month, patients received SAMe (1600 mg daily) for 2 weeks and then peginterferon and ribavirin for 48 weeks (course B; completed by 21 of 24 patients). Viral kinetics and interferon-stimulated gene (ISG) expression in peripheral blood mononuclear cells (PBMCs) were compared between courses. RESULTS: The decrease in HCV RNA from 0 to 48 hours (phase 1) was similar with and without SAMe. However, the second phase slope of viral decline was improved with SAMe (course A, 0.11 +/- 0.04 log(10) IU/mL/wk; course B, 0.27 +/- 0.06; P = .009); 11 patients (53%) achieved an early virological response, and 10 (48%) had undetectable HCV RNA by week 24. Induction of ISGs in PBMCs was significantly greater during course B. In cultured cells, SAMe increased induction of ISGs and the antiviral effects of interferon by increasing STAT1 methylation, possibly affecting STAT1-DNA binding. CONCLUSIONS: The addition of SAMe to peginterferon and ribavirin improves the early viral kinetics and increases ISG induction in nonresponders to previous therapy. SAMe might be a useful adjunct to peginterferon-based therapies in chronic HCV infection. PMID- 20854823 TI - Secretory mediators regulate Nod2-induced tolerance in human macrophages. AB - BACKGROUND & AIMS: Nucleotide oligomerization domain 2 (Nod2) polymorphisms increase the risk of developing Crohn's disease, which is characterized by chronic intestinal inflammation. Bacterial peptidoglycan products chronically stimulate Nod2 in the intestine. Recent studies found that chronic Nod2 stimulation in human macrophages down-regulates proinflammatory cytokines on Nod2 or Toll-like receptor (TLR) restimulation. Therefore, an emerging hypothesis is that Nod2-mediated cytokine down-regulation is required for intestinal homeostasis, but the mechanisms mediating this down-regulation are incompletely understood. METHODS: Utilizing primary human macrophages, we examined secretory mediators as a mechanism of Nod2-mediated tolerance by inhibiting their function and assessing tolerance reversal through cytokine secretion. Signaling pathways contributing to secretory mediator induction and Nod2-mediated tolerance were identified through pathway inhibition. RESULTS: We found that chronic Nod2 stimulation cross-tolerizes not only to TLRs but also to the interleukin (IL)-1 receptor. Moreover, chronic IL-1beta stimulation down-regulates Nod2 responses. Accordingly, IL-1beta blockade partially reverses Nod2-mediated tolerance. We found that an additional essential mechanism for Nod2-mediated tolerance is the early secretion of the anti-inflammatory mediators IL-10, transforming growth factor beta, and IL-1Ra. Importantly, the mammalian target of rapamycin (mTOR) pathway, involved in cell growth, differentiation, and activation, significantly contributes to Nod2-induced anti-inflammatory as opposed to proinflammatory cytokines and to Nod2-mediated tolerance. CONCLUSIONS: Inflammatory responses through the IL-1R are down-regulated upon chronic Nod2 stimulation, secretory mediators are a critical mechanism for Nod2-mediated cytokine down-regulation, and the mTOR pathway is crucial for Nod2-mediated tolerance. These results further contribute to our understanding of the mechanisms through which Nod2, a protein critical to intestinal homeostasis, down-regulates cytokine responses. PMID- 20854824 TI - Effects of parental and progeny rearing densities on locomotor activity of 1st stadium nymphs in the migratory locust, Locusta migratoria: an analysis by long term monitoring using an actograph. AB - The effects of parental and progeny rearing densities on locomotor activity in 1st-stadium nymphs of the migratory locust, Locusta migratoria, were observed over a 24- or 36-h period using an actograph. Newly hatched nymphs showed a small activity peak shortly after hatching and the peak level was significantly higher in offspring (gregarious nymphs) of crowd-reared adults than in those (solitarious nymphs) of isolated-reared adults. However, no significant difference was found between the two groups in maximum activity levels exhibited after the initial peak. Post-hatching crowding enhanced locomotor activity during 2-5h of measurements in 2-day-old nymphs. In this case, the parental density resulted in no significant influence on locomotor activity. However, the maximum activity level shown later in the observation period was higher in gregarious nymphs than in solitarious nymphs. Interestingly, this parental effect was more pronounced in nymphs reared in group than in those reared in isolation. The parental density appeared to affect the degree of response to crowding in the progeny. No evidence was found for the phase accumulation in terms of locomotor activity. The variation observed in locomotor activity among geographical populations did not correspond to their phylogenetic relationships. PMID- 20854822 TI - Mature chief cells are cryptic progenitors for metaplasia in the stomach. AB - BACKGROUND & AIMS: Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells. METHODS: Taking advantage of the chief cell-restricted expression of Mist1-Cre ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection. RESULTS: Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells. CONCLUSIONS: These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation. PMID- 20854825 TI - Quantitative trait loci for electrocardiographic parameters and arrhythmia in the mouse. AB - Cardiac arrhythmias associated with sudden death are influenced by multiple biological pathways and are modulated by numerous genetic and environmental factors. Elevated heart rate and prolonged ECG indices of conduction and repolarization have been associated with risk of sudden death. Insight into the genetic underpinnings of these parameters thus provides an important means to the dissection of the genetic components modulating risk of sudden cardiac death. In this study we mapped quantitative trait loci (QTL) modulating heart rate, ECG indices of conduction and repolarization, and susceptibility to arrhythmia, in a conduction disease-sensitized F(2) mouse population. Heart rate, P-duration, PR-, QRS- and QT-interval were measured at baseline (n=502) and after flecainide administration (n=370) in mutant F(2) progeny (F(2)-MUT) resulting from the FVB/NJ-Scn5a1798(insD/+) X 129P2-Scn5a1798(insD/+) mouse cross. Episodes of sinus arrhythmia and ventricular tachyarrhythmia occurring post-flecainide were treated as binary traits. F(2)-MUT mice were genotyped using a genome-wide 768 single nucleotide polymorphism (SNP) panel. Interval mapping uncovered multiple QTL for ECG parameters and arrhythmia. A sex-interacting scan identified QTL displaying sex-dependency, and a two-dimensional QTL scan unmasked locus-locus (epistasis) interactions influencing ECG traits. A number of QTL coincided at specific chromosomal locations, suggesting pleiotropic effects at these loci. Through transcript profiling in myocardium from the parental mouse strains we identified genes co-localizing at the identified QTL that constitute highly relevant candidates for the observed effects. The detection of QTL influencing ECG indices and arrhythmia is an essential step towards identifying genetic networks for sudden, arrhythmic, cardiac death. PMID- 20854826 TI - Human embryonic stem cell-derived cardiomyocytes engraft but do not alter cardiac remodeling after chronic infarction in rats. AB - Previous studies indicated that, in an acute myocardial infarction model, human embryonic stem cell-derived cardiomyocytes (hESC-CM) injected with a pro-survival cocktail (PSC) can preserve contractile function. Because patients with established heart failure may also benefit from cell transplantation, we evaluated the physiological effects of hESC-CM transplanted into a chronic model of myocardial infarction. Intramyocardial injection of hESC-CM with PSC was performed in nude rats at 1 month following ischemia-reperfusion. The left ventricular function of hESC-CM injected rats was evaluated at 1, 2 and 3 months after the cell injection procedure and was compared to 3 control groups (rats injected with serum-free media, PSC only, or non-cardiac human cells in PSC). Histology at 3 months revealed that human cardiomyocytes survive, develop increased sarcomere organization and are still proliferating. Despite successful engraftment, both echocardiography and MRI analyses showed no significant difference in left ventricular structure or function between these 4 groups at any time point of the study, suggesting that human cardiomyocytes do not affect cardiac remodeling in a rat model of chronic myocardial infarction. When injected into a chronic infarct model, hESC-CM can engraft, survive and form grafts with striated cardiomyocytes at least as well as was previously observed in an acute myocardial infarction model. However, although hESC-CM transplantation can attenuate the progression of heart failure in an acute model, the same hESC-CM injection protocol is insufficient to restore heart function or to alter adverse remodeling of a chronic myocardial infarction model. PMID- 20854828 TI - A model for the evolutionary diversification of religions. AB - We address the problem of cultural diversification by studying selection on cultural ideas that colonize human hosts and using diversification of religions as a conceptual example. In analogy to studying the evolution of pathogens or symbionts colonizing animal hosts, we use models for host-pathogen dynamics known from theoretical epidemiology. In these models, religious content colonizes individual humans. Rates of transmission of ideas between humans, i.e., transmission of cultural content, and rates of loss of ideas (loss of belief) are determined by the phenotype of the cultural content, and by interactions between hosts carrying different ideas. In particular, based on the notion that cultural non-conformism can be negative frequency-dependent (for example, religion can lead to oppression of lower classes and emergence of non-conformism and dissent once a religious belief has reached dominance), we assume that the rate of loss of belief increases as the number of humans colonized by a particular religious phenotype increases. This generates frequency-dependent selection on cultural content, and we use evolutionary theory to show that this frequency dependence can lead to the emergence of coexisting clusters of different cultural types. The different clusters correspond to different cultural traditions, and hence our model describes the emergence of distinct descendant cultures from a single ancestral culture in the absence of any geographical isolation. PMID- 20854827 TI - Neonatal gene transfer of Serca2a delays onset of hypertrophic remodeling and improves function in familial hypertrophic cardiomyopathy. AB - Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant genetic disorder linked to numerous mutations in the sarcomeric proteins. The clinical presentation of FHC is highly variable, but it is a major cause of sudden cardiac death in young adults with no specific treatments. We tested the hypothesis that early intervention in Ca(2+) regulation may prevent pathological hypertrophy and improve cardiac function in a FHC displaying increased myofilament sensitivity to Ca(2+) and diastolic dysfunction. A transgenic (TG) mouse model of FHC with a mutation in tropomyosin at position 180 was employed. Adenoviral-Serca2a (Ad.Ser) was injected into the left ventricle of 1-day-old non-transgenic (NTG) and TG mice. Ad.LacZ was injected as a control. Serca2a protein expression was significantly increased in NTG and TG hearts injected with Ad.Ser for up to 6 weeks. Compared to TG-Ad.LacZ hearts, the TG-Ad.Ser hearts showed improved whole heart morphology. Moreover, there was a significant decline in ANF and beta-MHC expression. Developed force in isolated papillary muscle from 2- to 3-week-old TG Ad.Ser hearts was higher and the response to isoproterenol (ISO) improved compared to TG-Ad.LacZ muscles. In situ hemodynamic measurements showed that by 3 months the TG-Ad.Ser hearts also had a significantly improved response to ISO compared to TG-Ad.LacZ hearts. The present study strongly suggests that Serca2a expression should be considered as a potential target for gene therapy in FHC. Moreover, our data imply that development of FHC can be successfully delayed if therapies are started shortly after birth. PMID- 20854829 TI - Endothelin-1 as a potential marker of melatonin's therapeutic effects in smoking induced vasculopathy. AB - AIMS: Smoking is a significant independent risk factor for cardiovascular disease. Among the chemicals present in the cigarette smoke, nicotine is responsible for much of the damage; it induces marked vessel morphological dysfunction and vasoconstriction. Unfortunately, pharmacological or behavioural treatment is not useful against cigarette smoking. The purpose of this study is to test, in experimental conditions, the therapeutic ability of exogenous melatonin administered after smoking-induced vasculopathy and to evaluate the targets of its effects. MAIN METHODS: Nicotine was orally administered for 28 days. Thereafter, the rats were orally treated with melatonin for another 28 days. Vessel damage, an important vasoconstrictor peptide (endothelin-1) and the oxidative stress markers were analysed. KEY FINDINGS: Nicotine treatment induced marked endothelial damage and an obvious vasoconstriction in the aorta as evaluated by an increased endothelin-1 (ET-1) expression. These alterations were correlated with a reduction of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD) and with increases of heat shock protein (Hsp70) and inducible nitric oxide synthase (iNOS) activities. Melatonin not only improved the impairment of endothelial-dependent relaxation, but also induced the increase of eNOS and SOD and the reduction of iNOS and Hsp70. SIGNIFICANCE: The findings indicate that nicotine is associated with an elevated synthesis of the vasoconstrictor peptide (ET-1); it also induces a reduction of nitric oxide mediated vasodilatation (eNOS) and promotes oxidative stress in the vessel wall. We propose that melatonin should be considered as a therapeutic intervention for smokers since it reduces vasoconstriction and oxidative stress and improves endothelial physiology. PMID- 20854832 TI - More and more toxins around-analysis of cyanobacterial strains isolated from Lake Chao (Anhui Province, China). AB - Lake Chao, China, is highly eutrophicated and experiences recurrent dense cyanobacterial blooms. Its surface water is used as drinking water resource for Hefei city, hence the potential toxicity of those cyanobacteria was of interest. Sixteen isolated strains of Microcystis aeruginosa evidenced that non-toxic, toxic and highly toxic strains coexist in the lake. Microcystin variants within one strain ranged up to 11, the concentration up to 4.799 mg g DW(-1). Mass spectrometry analysis confirmed desmethylated microcystin variants. PMID- 20854830 TI - Stimulation of alpha2-adrenergic receptors in the central nucleus of the amygdala attenuates stress-induced reinstatement of nicotine seeking in rats. AB - Tobacco addiction is a chronic disorder that is characterized by craving for tobacco products, withdrawal upon smoking cessation, and relapse after periods of abstinence. Previous studies demonstrated that systemic administration of alpha2 adrenergic receptor agonists attenuates stress-induced reinstatement of drug seeking in rats. The aim of the present experiments was to investigate the role of noradrenergic transmission in the central nucleus of amygdala (CeA) in stress induced reinstatement of nicotine seeking. Rats self-administered nicotine for 14 16 days and then nicotine seeking was extinguished by substituting saline for nicotine. The effect of the intra-CeA infusion of the alpha2-adrenergic receptor agonists clonidine and dexmedetomidine, the nonselective beta1/beta2-adrenergic receptor antagonist propranolol, and the alpha1-adrenergic receptor antagonist prazosin on stress-induced reinstatement of nicotine seeking was investigated. In all the experiments, exposure to footshocks reinstated extinguished nicotine seeking. The administration of clonidine or dexmedetomidine into the CeA attenuated stress-induced reinstatement of nicotine seeking. The administration of propranolol or prazosin into the CeA did not affect stress-induced reinstatement of nicotine seeking. Furthermore, intra-CeA administration of clonidine or dexmedetomidine did not affect operant responding for food pellets. This suggests that the effects of clonidine and dexmedetomidine on stress-induced reinstatement of nicotine seeking were not mediated by motor impairments or sedation. Taken together, these findings indicate that stimulation of alpha2 adrenergic receptors, but not blockade of alpha1 or beta-adrenergic receptors, in the CeA attenuates stress-induced reinstatement of nicotine seeking. These findings suggest that alpha2-adrenergic receptor agonists may at least partly attenuate stress-induced reinstatement of nicotine seeking by stimulating alpha2 adrenergic receptors in the CeA. PMID- 20854831 TI - Prenatal L-DOPA exposure produces lasting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference. AB - Dopamine, its receptors and transporter are present in the brain beginning from early in the embryonic period. Dopamine receptor activation can influence developmental events including neurogenesis, neuronal migration and differentiation raising the possibility that dopamine imbalance in the fetal brain can alter development of the brain and behavior. We examined whether elevated dopamine levels during gestation can produce persisting changes in brain dopamine content and dopamine-mediated behaviors. We administered L-3,4 dihydroxyphenylalanine (L-DOPA) in drinking water to timed-pregnant CD1 mice from the 11th day of gestation until the day of parturition. The prenatal L-DOPA exposure led to significantly lower cocaine conditioned place preference, a behavioral test of reward, at postnatal day 60 (P60). However, in vivo microdialysis measurements showed significant increases in cocaine-induced dopamine release in the caudate putamen of P26 and P60 mice exposed to L-DOPA prenatally, ruling out attenuated dopamine release in the caudate putamen as a contributor to decreased conditioned place preference. Although dopamine release was induced in the nucleus accumbens of prenatally L-DOPA exposed mice at P60 by cocaine, the dopamine release in the nucleus accumbens was not significantly different between the L-DOPA and control groups. However, basal dopamine release was significantly higher in the prenatally L-DOPA exposed mice at P60 suggesting that the L-DOPA exposed mice may require a higher dose of cocaine for induction of cocaine place preference than the controls. The prenatal L-DOPA exposure did not alter cocaine-induced locomotor response, suggesting dissociation between the effects of prenatal L-DOPA exposure on conditioned place preference and locomotor activity. Tissue concentration of dopamine and its metabolites in the striatum and ventral midbrain were significantly affected by the L-DOPA exposure as well as by developmental changes over the P14-P60 period. Thus, elevation of dopamine levels during gestation can produce persisting changes in brain dopamine content, cocaine-induced dopamine release and cocaine conditioned place preference. PMID- 20854833 TI - Context-specific saccadic adaptation in monkeys. AB - When environmental or sensory conditions change suddenly, the brain must be capable of learning different behavioral modes to produce accurate movements under multiple circumstances. A form of this dual-state adaptation known as "context-specific adaptation" has been widely investigated using the saccade gain adaptation paradigm in humans. In this study, we asked whether or not context specific adaptation of saccade gain exists in monkeys and if so to explore its properties. Here, vertical eye position was used as a context cue for adaptation of horizontal saccade gain. We asked for a gain-increase in one context and gain decrease in another context, and then determined if a change in the context would invoke switching between the adapted states. After training, our monkeys developed context-specific adaptation: in most cases gain-decrease adaptation could be induced, but there was little or no gain-increase adaptation. This context-specific adaptation developed gradually and switching of gains was evident on the first saccades with each change in context. Along with these results, the retention of an adaptation aftereffect overnight indicates that contextual-specific adaptation in monkeys is not a strategy, but involves a true adaptive process of reorganization in the brain. We suggest that context-specific adaptation in monkeys could be an important tool to provide insights into the mechanisms of saccade adaptation that occurs during the more natural circumstances of daily life. PMID- 20854835 TI - Age-associated modifications of Base Excision Repair activities in human skin fibroblast extracts. AB - Base Excision Repair (BER) is the predominant repair pathway responsible for removal of so-called small DNA lesions such as abasic sites (AP site), uracil (U), 8-oxo-7,8-dihydroguanine (8oxoG), thymine glycol (Tg). In this study, we investigated effect of aging on excision efficacy of several endogenous base lesions and AP sites using an in vitro multiplexed fluorescent approach on support (parallelized oligonucleotide cleavage assay). Human fibroblasts nuclear extracts from 29 donors of different ages were characterized in their ability to simultaneously excise the different lesions. Clearly, three different groups of lesions emerged according to the efficiency of their cleavage: one exhibited very high cleavage efficiency (AP sites and U paired with G), one showed intermediate cleavage efficiency (U paired with A and Tg). The third group included 8oxoG, A paired with 8oxoG, T at CpG site and hypoxanthine (Hx) and displayed poor repair. Aging was significantly associated with modification of excision efficiency for AP sites, uracil, Tg and 8oxoG. Repair rate decreased for the first three lesions and the most drastic effects were observed for repair of U:A. Surprisingly, excision of 8oxoG increased with aging suggesting a completely different regulation or adaptation for the initiation step of this related specific repair pathway. PMID- 20854834 TI - Color-deficient cone mosaics associated with Xq28 opsin mutations: a stop codon versus gene deletions. AB - Our understanding of the etiology of red-green color vision defects is evolving. While missense mutations within the long- (L-) and middle-wavelength sensitive (M ) photopigments and gross rearrangements within the L/M-opsin gene array are commonly associated with red-green defects, recent work using adaptive optics retinal imaging has shown that different genotypes can have distinct consequences for the cone mosaic. Here we examined the cone mosaic in red-green color deficient individuals with multiple X-chromosome opsin genes that encode L opsin, as well as individuals with a single X-chromosome opsin gene that encodes L opsin and a single patient with a novel premature termination codon in his M-opsin gene and a normal L-opsin gene. We observed no difference in cone density between normal trichomats and multiple or single-gene deutans. In addition, we demonstrate different phenotypic effects of a nonsense mutation versus the previously described deleterious polymorphism, (LIAVA), both of which differ from multiple and single-gene deutans. Our results help refine the relationship between opsin genotype and cone photoreceptor mosaic phenotype. PMID- 20854836 TI - Oxygen-induced changes in mitochondrial DNA and DNA repair enzymes in aging rat lens. AB - The treatment of patients with hyperbaric oxygen (HBO), vitrectomy and loss of vitreous gel during aging is associated with a high risk of subsequent development of nuclear cataract. Many studies proved that oxidation is the key reason of nuclear cataract. Reactive oxygen species (ROS) are formed in mitochondria as a by-product of normal metabolism and as a consequence of exposure to environmental compounds. Therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases and aging. However, the effect of mtDNA damage to the lens has not been studied. The goals of the study were to identify if there was increased mtDNA damage in lens when the eye were exposed to hyperoxic or hypoxic conditions and also to evaluate the changes in gene expression of mtDNA base excision repair (mtBER) enzymes. Our data have shown that the damage of mtDNA, the expression of mtBER enzymes and the level of 8-OHdG in lens increased after inspired hyperoxia, which is likely associated with oxidative stress. However, there was no effect to mtDNA and mtBER enzymes in lens after inspired hypoxia. Nuclear cataract appeared rapidly at 14 month old rats in hyperoxia group, and lens kept transparency in other groups. PMID- 20854837 TI - Leisure-time physical activity and metabolic syndrome plus depressive symptoms in the FIN-D2D survey. AB - OBJECTIVE: To examine the association between leisure-time physical activity (LTPA) and simultaneous presence of metabolic syndrome (MetS) and depressive symptoms (DS) based on a population-based FIN-D2D cross-sectional survey conducted in 2007. METHODS: 4500 randomly selected Finnish men and women aged 45 74 years were initially enrolled; 2868 (64%) attended a health examination. Participants with complete information (n=2778) were grouped into three LTPA categories: low, moderate and high. MetS was based on the National Cholesterol Education Program criteria and DS on the Beck Depression Inventory (>=10 points). RESULTS: The prevalence of MetS and DS were 53% and 15%, respectively; the prevalence of simultaneous MetS and DS was 10%. The proportion of subjects with MetS, DS and simultaneous presence of MetS and DS increased with decreasing LTPA (p<0.001). On multivariate ordered analysis, LTPA was related to education years, household income, smoking, and the presence of MetS only, DS only and simultaneous MetS and DS. CONCLUSION: The prevalence of simultaneous MetS and DS was higher in participants with low LTPA compared with participants with high LTPA. Furthermore, LTPA level was associated with socioeconomic status and other health related outcomes, outlining the importance of LTPA as part of the general health promotion. PMID- 20854838 TI - Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. AB - Data on the potential health benefits of dietary flavanols and procyanidins, especially in the context of cardiovascular health, are considerable and continue to accumulate. Significant progress has been made in flavanol analytics and the creation of phytonutrient-content food databases, and novel data emanated from epidemiological investigations as well as dietary intervention studies. However, a comprehensive understanding of the pharmacological properties of flavanols and procyanidins, including their precise mechanisms of action in vivo, and a conclusive, consensus-based accreditation of a causal relationship between intake and health benefits in the context of primary and secondary cardiovascular disease prevention is still outstanding. Thus, the objective of this review is to identify and discuss key questions and gaps that will need to be addressed in order to conclusively demonstrate whether or not dietary flavanols and procyanidins have a role in preventing, delaying the onset of, or treating cardiovascular diseases, and thus improving human life expectancy and quality of life. PMID- 20854839 TI - Bioavailability of dietary flavonoids and phenolic compounds. AB - This paper reviews recent human studies on the bioavailability of dietary flavonoids and related compounds, including chlorogenic acids and ellagitannins, in which the identification of metabolites, catabolites and parent compounds in plasma, urine and ileal fluid was based on mass spectrometric methodology. Compounds absorbed in the small intestine appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites which seemingly are treated by the body as xenobiotics as they are rapidly removed from the bloodstream. As a consequence, while analysis of plasma provides valuable information on the identity and pharmacokinetic profiles of circulating metabolites after acute supplementation, it does not provide accurate quantitative assessments of uptake from the gastrointestinal tract. Urinary excretion, of which there are great variations with different classes of flavonoids, provides a more realistic figure but, as this does not include the possibility of metabolites being sequestered in body tissues, this too is an under estimate of absorption, but to what degree remains to be determined. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amounts of the parent compounds and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compounds will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites is absorbed into the bloodstream and passes through the body prior to excretion in urine. There is growing evidence that these compounds, which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of dietary flavonoids and related phenolic compounds. PMID- 20854840 TI - Basic biochemical mechanisms behind the health benefits of polyphenols. AB - Polyphenols and consequently many flavonoids have several beneficial actions on human health. However, the actual molecular interactions of polyphenols with biological systems remain mostly speculative. This review addresses the potential mechanisms of action that have been so far identified, as well as the feasibility that they could occur in vivo. Those mechanisms include: i) non specific actions, based on chemical features common to most polyphenols, e.g. the presence of a phenol group to scavenge free radicals; and ii) specific mechanisms; based on particular structural and conformational characteristics of select polyphenols and the biological target, e.g. proteins, or defined membrane domains. A better knowledge about the nature and biological consequences of polyphenol interactions with cell components will certainly contribute to develop nutritional and pharmacological strategies oriented to prevent the onset and/or the consequences of human disease. PMID- 20854841 TI - Identification of cis- and trans-acting elements in pHW126, a representative of a novel group of rolling circle plasmids. AB - pHW126, pIGRK, pIGMS31 and pRAO1 are the only known members of a novel and as yet uncharacterised family of rolling circle plasmids. pHW126 contains only two open reading frames, of which one shows homology to pMV158-family mobilisation proteins. Here we provide evidence that the second open reading frame encodes a replication protein (Rep). Mutation or deletion of this gene resulted in replication deficient constructs, but providing functional Rep from a compatible vector rescued these constructs, indicating that Rep acts in trans. An approximately 300 bp cis-acting region representing the origin of replication was identified upstream of the rep gene. The origin was identified to be composed of three parts: an accessory region, a conserved stretch and four perfect tandem repeats. The two latter elements were essential for replication. Constructs with a deletion of the accessory region could still replicate, but their loss rate was high, indicating that the accessory region is necessary for plasmid maintenance under non-selective conditions. Interestingly, pHW126 could replicate in all Enterobacteriaceae tested while Agrobacterium tumefaciens and Pseudomonas syringae were inappropriate hosts. Thus, pHW126 seems to have a rather limited host range. PMID- 20854842 TI - Adaptive modulation of behavioural profiles by social stress during early phases of life and adolescence. AB - The development of individual behavioural profiles can be powerfully influenced by stressful social experiences. Using a comparative approach, we focus on the role of social stressors for the modulation of behavioural profile during early phases of life and adolescence. For gregarious species, the stability of the social environment in which the pregnant and lactating female lives is of major importance for foetal brain development and the behavioural profile of the offspring in later life. Social instability during these critical periods of development generally brings about a behavioural and neuroendocrine masculinisation in daughters and a less pronounced expression of male-typical traits in sons. Moreover, when mothers live in a socially threatening world during this time, anxiety-like behaviour of their offspring often is elevated in adulthood. These effects of the social environment are likely to be mediated by maternal hormones and/or maternal behaviour. In addition, they can be modulated significantly by offspring genotype. We favour the hypothesis that the behavioural effects of social stress during this phase of life are not necessarily "pathological" (nonadaptive) consequences or constraints of adverse social conditions. Rather, mothers could be adjusting the offspring to their environment in an adaptive way. Adolescence is another period in which behavioural development is particularly susceptible to social influences. There is some evidence that stressful social events experienced at this time alter and canalize behaviour in an adaptive fashion, so that earlier influences on behavioural profile development can be complemented and readjusted, if necessary, to meet current environmental conditions. In terms of underlying neuroendocrine mechanism, a central role for the interaction of testosterone and stress hormones is suggested. In summary, the modulation of behavioural profiles by social stress from the prenatal phase through adolescence appears to represent an effective mechanism for repeated and rapid adaptation. PMID- 20854844 TI - Antiseptic properties of two calix[4]arenes derivatives on the human coronavirus 229E. AB - Facing the lack in specific antiviral treatment, it is necessary to develop new means of prevention. In the case of the Coronaviridae this family is now recognized as including potent human pathogens causing upper and lower respiratory tract infections as well as nosocomial ones. Within the purpose of developing new antiseptics molecules, the antiseptic virucidal activity of two calix[4]arene derivatives, the tetra-para-sulfonato-calix[4]arene (C[4]S) and the 1,3-bis(bithiazolyl)-tetra-para-sulfonato-calix[4]arene (C[4]S-BTZ) were evaluated toward the human coronavirus 229E (HCoV 229E). Comparing these results with some obtained previously with chlorhexidine and hexamidine, (i) these two calixarenes did not show any cytotoxicity contrary to chlorhexidine and hexamidine, (ii) C[4]S showed as did hexamidine, a very weak activity against HCoV 229E, and (iii) the C[4]S-BTZ showed a stronger activity than chlorhexidine, i.e. 2.7 and 1.4log10 reduction in viral titer after 5min of contact with 10-3mol L-1 solutions of C[4]S-BTZ and chlorhexidine, respectively. Thus, the C[4]S-BTZ appeared as a promising virucidal (antiseptic) molecule. PMID- 20854845 TI - Nucleus accumbens carbachol disrupts olfactory and contextual fear-potentiated startle and attenuates baseline startle reactivity. AB - Although the nucleus accumbens (NAc) typically is not considered a primary component of the circuitry underlying either the acquisition or retrieval of conditioned fear, evidence suggests that this region may play some role in modulating fear-related behaviors. The goal of the present study was to explore a potential role for NAc cholinergic receptors in the expression of fear potentiated startle (FPS) and baseline startle reactivity. Intra-NAc infusion of the broad-acting cholinergic receptor agonist, carbachol, suppressed FPS elicited by re-exposure to both a discrete odor previously paired with footshock and the conditioning context. Although carbachol elevated spontaneous motor activity, activity bouts did not account for startle suppression in carbachol-treated Ss. In addition, intra-NAc carbachol suppressed baseline startle over a range of acoustic pulse intensities in the absence of explicit fear conditioning. Collectively, these findings suggest that NAc cholinergic receptors play a role in the modulation of baseline startle reactivity, rather than in the retrieval of learned fear, and that this role is independent of overt motor activity. PMID- 20854847 TI - A non-invasive fluorescent staining procedure allows Confocal Laser Scanning Microscopy based imaging of Mycobacterium in multispecies biofilms colonizing and degrading polycyclic aromatic hydrocarbons. AB - To study the micro scale interactions of Mycobacterium with bacteria belonging to other genera by means of Confocal Laser Scanning Microscopy (CLSM), a procedure was developed to non-invasively and fluorescently stain Mycobacterium without compromising the signal produced by commonly used fluorescent reporter genes. The procedure makes use of the commercial non-specific nucleic acid stain Syto62 and was optimized to efficiently stain Mycobacterium cells in suspensions and biofilms. The staining procedure was found non-invasive towards overall cell viability, biofilm architecture and fluorescence signals emitted by other organisms expressing the fluorescent reporter genes gfp and dsRed. The procedure was successfully applied to visualize the comportment of the PAH-degrading Mycobacterium sp. VM552 in triple species biofilms containing, in addition to strain VM552, the GFP labeled PAH-degrading Sphingomonas sp. LH128-GFP and DsRed labeled Pseudomonas putida OUS82(RF), and colonizing a glass substrate coated with phenanthrene crystals in flow chambers. CLSM imaging and subsequent appropriate image processing of the biofilms show that the comportment of strain Mycobacterium sp. VM552 was largely affected by the presence of the other organisms. The data support the value of the staining procedure to study ecological questions about micro scale behavior and niche occupation of Mycobacterium in multi-species systems. PMID- 20854846 TI - Telmisartan attenuates aortic hypertrophy in hypertensive rats by the modulation of ACE2 and profilin-1 expression. AB - Profilin-1 has recently been linked to vascular hypertrophy and remodeling. Here, we assessed the hypothesis that angiotensin (Ang) II type I receptor antagonist telmisartan improves vascular hypertrophy by modulation of expression of profilin 1 and angiotensin-converting enzyme 2 (ACE2). Ten-week-old male spontaneously hypertensive rats (SHR) were received oral administration of telmisartan (5 or 10mg/kg; daily) or saline for 10 weeks. Compared with Wistar-Kyoto (WKY) rats, there were marked increases in systolic blood pressure and profilin-1 expression and reduced ACE2 and peroxisome proliferator activated receptor-gamma (PPARgamma) levels in aorta of SHR, associated with elevated extracellular-signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) phosphorylation signaling and aortic hypertrophy characterized with increased media thickness, which were strikingly reversed by telmisartan. In cultured human umbilical artery smooth muscle cells (HUASMCs), Ang II induced a dose-dependent increase in profilin-1 expression, along with decreased ACE2 protein expression and elevated ERK1/2 and JNK phosphorylation. In addition, blockade of ERK1/2 or JNK by either specific inhibitor was able to abolish Ang II-induced ACE2 downregulation and profilin-1 upregulation in HUASMCs. Importantly, treatment with telmisartan (1 or 10 MUM) or recombinant human ACE2 (2mg/ml) largely ameliorated Ang II-induced profilin-1 expression and ERK1/2 and JNK phosphorylation and augmented PPARgamma ?expression in the cultured HUASMCs. In conclusion, telmisartan treatment attenuates vascular hypertrophy in SHR by the modulation of ACE2 and profilin-1 expression with a marked reversal of ERK1/2 and JNK phosphorylation signaling pathways. PMID- 20854843 TI - Apolipoprotein E: from lipid transport to neurobiology. AB - Apolipoprotein (apo) E has a storied history as a lipid transport protein. The integral association between cholesterol homeostasis and lipoprotein clearance from circulation are intimately related to apoE's function as a ligand for cell surface receptors of the low-density lipoprotein receptor family. The receptor binding properties of apoE are strongly influenced by isoform specific amino acid differences as well as the lipidation state of the protein. As understanding of apoE as a structural component of circulating plasma lipoproteins has evolved, exciting developments in neurobiology have revitalized interest in apoE. The strong and enduring correlation between the apoE4 isoform and age of onset and increased risk of Alzheimer's disease has catapulted apoE to the forefront of neurobiology. Using genetic tools generated for study of apoE lipoprotein metabolism, transgenic "knock-in" and gene-disrupted mice are now favored models for study of its role in a variety of neurodegenerative diseases. Key structural knowledge of apoE and isoform-specific differences is driving research activity designed to elucidate how a single amino acid change can manifest such profoundly significant pathological consequences. This review describes apoE through a lens of structure-based knowledge that leads to hypotheses that attempt to explain the functions of apoE and isoform-specific effects relating to disease mechanism. PMID- 20854848 TI - Reading emotional words within sentences: the impact of arousal and valence on event-related potentials. AB - Effects of emotional word meaning have been studied exclusively for words in isolation but not in the context of sentences. We addressed this question within the framework of two-dimensional models of affect, conceiving emotion as a function of valence and arousal. Negative and neutral target verbs, embedded within sentences, were presented while event-related brain potentials (ERPs) and the activity of the Corrugator muscle were recorded. Twenty-one participants performed a semantic decision task on the target verbs. In contrast to single word studies no early posterior negativity was present. However, emotion effects in ERPs were evident in a late positive complex (LPC) for negative, high-arousal words in comparison to neutral words. Interestingly, the LPC was unaffected by pure arousal variation when valence was controlled for, indicating the importance of valence for this emotion-related ERP effect. PMID- 20854849 TI - Athletic training in badminton players modulates the early C1 component of visual evoked potentials: a preliminary investigation. AB - One basic question in brain plasticity research is whether individual life experience in the normal population can affect very early sensory-perceptual processing. Athletes provide a possible model to explore plasticity of the visual cortex as athletic training in confrontational ball games is quite often accompanied by training of the visual system. We asked professional badminton players to watch video clips related to their training experience and predict where the ball would land and examined whether they differed from non-player controls in the elicited C1, a visual evoked potential indexing V1 activity. Compared with controls, the players made judgments significantly more accurately, albeit not faster. An early ERP component peaking around 65 ms post-stimulus with a scalp topography centering at the occipital pole (electrode Oz) was observed in both groups and interpreted as the C1 component. With comparable latency, amplitudes of this component were significantly enhanced for the players than for the non-players, suggesting that it can be modulated by long-term physical training. The results present a clear case of experience-induced brain plasticity in primary visual cortex for very early sensory processing. PMID- 20854850 TI - EspA is a novel fusion partner for expression of foreign proteins in Escherichia coli. AB - Escherichia coli secreted protein A (EspA) is a component of the type 3 secretion system (T3SS). The high level of expression when self-stimulated suggests that EspA may be used as a fusion partner. In the present study, EspA was used as a "fusion partner" to construct a fusion expression system, pEspA, in order to improve the expression and solubility of proteins from prokaryotes and eukaryotes. Target proteins were linked to the C-terminus of EspA by a linker containing a YAPQDP sequence, multiple cloning sites and an enterkinase cleavage site. Six proteins, IL-24, Stx2A1, Stx2B, S1, IntiminC300 and GFP, were expressed as EspA-fusion proteins using this vector. The expression level of each protein was enhanced by EspA and the majority of them (Stx2B, IntiminC300, GFP, Stx2A1, IL-24) were expressed in soluble form. EspA-fusion proteins can be purified by affinity chromatography (Sepharose chelated with EspA-specific monoclonal antibody) and by Ni(2+) affinity chromatography for they contain a 6* His tag at their C-terminus. In addition, IL-24 remains soluble and demonstrates certain anti-tumor activity after the removal of EspA by enterkinase. The EspA fusion expression system was efficient in enhancing expression levels and the solubility of target proteins. PMID- 20854852 TI - Reduction of glycerol production to improve ethanol yield in an engineered Saccharomyces cerevisiae using glycerol as a substrate. AB - Ethanol plays an important role in substituting the increasingly limited oil as the high-value, renewable fuel. In our previous studies, we successfully established the conversion of glycerol to ethanol by overexpression of pGcyaDak with pGup1Cas in Saccharomyces cerevisiae. In addition to increasing ethanol production using glycerol as substrate, we minimized the synthesis of glycerol, which is the main by-product in ethanol fermentation processing. The glycerol production pathway was impaired by deletion of the genes FPS1 and GPD2. Strains deleted for both FPS1 and GPD2 reduce glycerol production and become highly sensitive to osmotic stress. We provide osmotic protection in YPH499fps1Deltagpd2Delta by overexpression of Gup1. In this study, S. cerevisiae using glycerol as substrate was modified through one-step gene disruption for redirection of glycerol carbon flux into ethanol by the deletion of two glycerol production genes, FPS1 and GPD2. The overall ethanol production in the modified strain YPH499fps1Deltagpd2Delta (pGcyaDak, pGupCas) was about 4.4 gl-1. These results demonstrate the possibility of providing protection against osmotic stress while simultaneously increasing ethanol and reducing glycerol production in S. cerevisiae strains using glycerol as a carbon source. PMID- 20854851 TI - Over-expression of PR-10a leads to increased salt and osmotic tolerance in potato cell cultures. AB - The PR-10a protein (formerly STH-2) is known to be induced by biotic stress in potato. The present study demonstrates that transgenic suspension cells of the potato cultivar Desiree over-expressing the PR-10a protein exhibit significantly increased salt and osmotic tolerance compared to the respective wild type cells. A comparison of the proteome pattern of Solanum tuberosum suspension cultures cv. Desiree before and after the treatment with NaCl or sorbitol under equiosmolar conditions (740mOs/kg) revealed the pathogenesis related protein PR-10a to be one of the predominant differentially expressed proteins in potato cell cultures. The pr-10a mRNA was confirmed to be present by RT-PCR from salt challenged suspension cells and was transcribed into cDNA. For PR-10a over-expression Agrobacterium tumefaciens mediated transformation of the potato cells and a dicistronic vector harboring the cDNA of the pr-10a gene linked to a luciferase gene by an IRES (Internal Ribosome Binding Site) was used. The IRES mediated translation leads to co-expression of PR-10a and luciferase in a fixed ratio. By non-invasive luciferase assay homologous PR-10a over-expressing callus was identified after selection on phosphinothricin supplemented medium. This callus was used for the setup of a transgenic suspension culture. Along with increased salt and osmotic tolerance the transformed culture showed changed proline and glutathione levels under abiotic stress conditions in comparison to the wild type. PMID- 20854853 TI - Adaptation of AmtR-controlled gene expression by modulation of AmtR binding activity in Corynebacterium glutamicum. AB - In corynebacteria, nitrogen regulation is controlled by the TetR family protein AmtR, which was extensively studied in the last years. In frame of these studies a number of AmtR binding sites were identified and characterized and it became obvious that for distinct genes the number and sequences of these sites varied significantly. In this study, the influence of numbers and alterations of AmtR binding sites were addressed by in vivo and in vitro studies. It can be concluded that in general a single highly conserved AmtR site is sufficient for stringent regulation and that non-conserved binding sites have a very limited influence, despite the fact that binding of AmtR was shown for several of these sites, e.g. upstream of amtA, amtB and gdh. Furthermore, the reason for and consequences of the lack of AmtR autoregulation were addressed in vivo. The introduction of a spacing nucleotide between the two conserved half sites of the AmtR binding box alone is sufficient to restore AmtR autoregulation. The main differences observed between wild type and an AmtR autoregulation strain were a slightly enhanced background of transcription of AmtR-controlled genes and a slightly slower response to nitrogen limitation. PMID- 20854854 TI - Production of heterologous glycoproteins by a glycosylation-defective alg3och1 mutant of Schizosaccharomyces pombe. AB - The early stages of N-linked glycosylation are highly conserved between fungal and mammalian cells. Such N-linked oligosaccharides are synthesized through the ordered assembly of a dolichyl pyrophosphate (Dol-PP)-linked Glc(3)Man(9)GlcNAc(2) structure by the sequential actions of several glycosyltransferases located in the endoplasmic reticulum (ER). Of the glycosyltransferase genes, Saccharomyces cerevisiae ALG3 has been identified to encode the Dol-P-Man:Man(5)GlcNAc(2)-PP-Dol alpha1,3-mannosyltransferase, and an alg3 mutant has been shown to accumulate an Endo H-resistant M5B (Manalpha1,2 Manalpha1,2-Manalpha1,3(Manalpha1,6-)-Manbeta1,4-GlcNAcbeta1,4-GlcNAc) structure. Although Schizosaccharomyces pombe contains a homolog of the ALG3 gene (SPAC7D4.06c), the role of this gene in oligosaccharide biosynthesis is not at all clear. In this study, we deleted the alg3(+) gene in the och1Delta mutant and analyzed the detailed oligosaccharide structures in alg3Deltaoch1Delta double mutant. The oligosaccharides were prepared from cell-surface glycoproteins by hydrazinolysis and fluorescent labeling with 2-aminopyridine. The labeled oligosaccharides were analyzed by high performance liquid chromatography, in combination with sequential glycosidase digestion and methylation analysis. These analyses revealed that the N-linked oligosaccharides of S. pombe alg3Deltaoch1Delta cells mainly consisted of two or three alpha-galactose-capped M5B structures. Finally, western blot analysis of recombinant human transferrin suggested that heterologously expressed glycoproteins in alg3Deltaoch1Delta cells have Endo H-resistant N-linked oligosaccharide structures similar to those of alg3Deltaoch1Delta cell-surface glycoproteins. PMID- 20854855 TI - pH-responsive polymeric micelle based on PEG-poly(beta-amino ester)/(amido amine) as intelligent vehicle for magnetic resonance imaging in detection of cerebral ischemic area. AB - A series of pH-responsive polymeric micelles is developed to act as intelligent carriers to deliver iron oxide (Fe(3)O(4)) nanoparticles and respond rapidly to an acidic stimuli environment for magnetic resonance imaging (MRI). The polymeric micelle can be self-assembled at physiological pH by a block copolymer, consisting of a hydrophilic methoxy poly(ethylene glycol) (PEG) and a pH responsive poly(beta-amino ester)/(amido amine) block. Consequently, the Fe(3)O(4) nanoparticles can be well encapsulated into polymeric micelles due to the hydrophobic interaction, shielded by a PEG coronal shell. In an acidic environment, however, the pH-responsive component, which has ionizable tert-amino groups on its backbone, can become protonated to be soluble and release the hydrophobic Fe(3)O(4) nanoparticles. The Fe(3)O(4)-loaded polymeric micelle was measured by dynamic light scattering (DLS), superconducting quantum interference device (SQUID) and a 3.0T MRI scanner. To assess the ability of this MRI probe as a pH-triggered agent, we utilize a disease rat model of cerebral ischemia that produces acidic tissue due to its pathologic condition. We found gradual accumulation of Fe(3)O(4) nanoparticles in the brain ischemic area, indicating that the pH-triggered MRI probe may be effective for targeting the acidic environment and diagnostic imaging of pathologic tissue. PMID- 20854856 TI - Delivery of messenger RNA using poly(ethylene imine)-poly(ethylene glycol) copolymer blends for polyplex formation: biophysical characterization and in vitro transfection properties. AB - Nucleic acid based therapies have so far mainly been focused on plasmid DNA (pDNA), small interfering RNA (siRNA), antisense and immunostimulatory oligonucleotides. Messenger RNA (mRNA) was the subject of only a few studies. The objective of this investigation was the preparation of new composite polyplexes with mRNA consisting of poly(ethylene imine) (PEI) and poly(ethylene imine) poly(ethylene glycol)-copolymers (PEI-PEG) as blends. These complexes were designed to increase the stability of mRNA, to improve transfection efficiency and to reduce cytotoxicity. Hydrodynamic diameters of the polyplexes were measured by dynamic light scattering, polyplex stability was analyzed by gel retardation assay and transfection efficiency of luciferase (Luc) encoding mRNA was evaluated under in vitro conditions. Most of the polyplexes generated showed small particle sizes <200 nm and positive zeta-potentials of +20 mV to +30 mV. Stable complexes were formed even at low nitrogen to phosphate ratios. Polyplexes with mRNA Luc and blends of low molecular weight PEI(5 kDa) and PEI(25k Da) PEG(20 kDa)1-block-copolymer showed protein expression as high as polyplexes with PEI(25 kDa). Moreover, luciferase expression was significantly higher than that obtained with one of the components alone. These results suggest that delivery systems for pulmonary application of mRNA merit further investigation under in vitro and in vivo conditions. PMID- 20854857 TI - A novel peptide specifically targeting the vasculature of orthotopic colorectal cancer for imaging detection and drug delivery. AB - Colorectal cancer (CRC) is the third most common malignancy and the fourth most frequent cause of cancer deaths worldwide. Ligand-mediated diagnosis and targeted therapy would have vital clinical applications in cancer treatment. In this study, an orthotopic model of colorectal cancer was established in mice. In vivo phage library selection was then utilized to isolate peptides specifically recognizing the vasculature of colorectal cancer tissues. A phage (termed TCP-1 phage) was isolated by this manner and it homed to the colorectal cancer tissues by 11- to 94-fold more than other organs. Chemical synthetic peptide (CTPSPFSHC, termed TCP-1) displayed by TCP-1 phage inhibited the homing ability of the phage to the tumor mass when co-injected intravenously with the TCP-1 phage into mice with colon cancer. Meanwhile, immunostaining analysis indicated that TCP-1 phage and peptide localized in the vasculature of the colorectal cancer tissue, but not of normal tissues. Moreover, TCP-1 peptide bound to blood vessels of surgical tissue samples of human colorectal cancer. After intravenous injection of FITC labeled TCP-1 into the tumor-bearing mice for 20h, there was a strong fluorescent signal in the tumors but not other tissues when observed under blue light. In addition, TCP-1 conjugated with a pro-apoptotic peptide specifically induced apoptosis of tumor-associated blood vessels in vivo. The data define a novel peptide TCP-1 as an effective agent for imaging detection and drug delivery for colorectal cancer. PMID- 20854858 TI - A duplex oligodeoxynucleotide-dendrimer bioconjugate as a novel delivery vehicle for doxorubicin in in vivo cancer therapy. AB - We designed a bioconjugate between duplex oligodeoxynucleotides (dODNs) and a dendrimer (DEN) and demonstrate its feasibility as a novel delivery system for doxorubicin (Dox) in animal tumor models and against cancer cells in vitro. The dODNs-DEN conjugates formed stable complexes with Dox (~184 Dox molecules per conjugate) and the resulting Dox-loaded conjugate exhibited a sustained drug release pattern both in vitro and in vivo. Pharmacokinetic studies showed that Dox-loaded dODNs-DEN conjugates were cleared from plasma much more slowly (up to 5.3h) than was free Dox (0.65h). Furthermore, tumors retained a higher amount of Dox in mice treated with the conjugate group compared to that of free Dox-treated group at the same dosage. In mice bearing 4T1 murine breast tumor allografts, the dendrimer conjugate, at a Dox concentration of 1mg/kg, was more effective than the equivalent concentration of free Dox and tumor size reduction was equivalent to that seen using 4mg/kg free Dox. We observed no severe systemic toxicity or cardiotoxicity in mice treated with the conjugate, as indicated by body weight change and heart tissue histology. These findings indicate that dODNs-DEN conjugates can be used to administer Dox with improved pharmacokinetics, lower toxicity, and an increased ability to concentrate drugs in tumors, compared with free drug, and that such conjugates are effective against tumors in vivo. PMID- 20854859 TI - Mannosylated solid lipid nanoparticles as vectors for site-specific delivery of an anti-cancer drug. AB - The purpose of the present study was to investigate the tumor targeting potential of surface tailored solid lipid nanoparticles (SLNs) loaded with an anti-cancer drug doxorubicin HCl (DOX). DOX encapsulating SLNs were prepared, characterized and further mannosylated. The developed formulations were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), particle size/polydispersity index and zeta-potential analysis. The formulations were evaluated for in vitro drug release and hemolytic toxicity. The ex vivo cytotoxicity and cellular uptake studies were performed on A549 cell lines. In vivo studies were conducted to determine pharmacokinetics, tissue distribution pattern and nephrotoxic/hepatotoxic effect of mannosylated SLNs. In vitro, the formulations exhibited a biphasic pattern characterized by initial rapid release of the drug followed by rather slow and prolonged release. Further, the in vitro studies depicted mannose-conjugated SLNs to be least hemolytic and suitable for sustained drug delivery. Mannosylated SLNs were most cytotoxic and were preferably taken up A549 tumor cells as evaluated against uncoated SLNs and plain DOX. Pharmacokinetic studies revealed improved bioavailability, half life and mean residence time of DOX upon mannose conjugation. The biodistribution pattern exhibited that mannosylated SLNs were able to deliver a higher concentration of DOX in the tumor mass. They were also proficient to circumvent damage to renal as well as hepatic tissues. It may therefore be interpreted that mannosylated SLNs are capable to ferry bioactives selectively and specifically to the tumor sites with the interception of minimal side effects, thereby suggesting their potential application in cancer chemotherapy. PMID- 20854860 TI - Radiopharmaceutical chemistry for positron emission tomography. AB - Molecular imaging is an emerging technology that allows the visualization of interactions between molecular probes and biological targets. Molecules that either direct or are subject to homeostatic controls in biological systems could be labeled with the appropriate radioisotopes for the quantitative measurement of selected molecular interactions during normal tissue homeostasis and again after perturbations of the normal state. In particular, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short-lived positron emitting radionuclide. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the gamma rays formed as a result of the annihilation of the positrons emitted. Despite the great wealth of information that such probes can provide, the potential of PET strongly depends on the availability of suitable PET radiotracers. However, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor for the field of PET. In this review, we provided an overview of the most common chemical approaches for the synthesis of PET-labeled molecules and highlighted the most recent developments and trends. The discussed PET radionuclides include 11C (t1(/)2=20.4min), 13N (t1(/)2=9.9min), 15O (t1(/)2=2min), 68Ga (t1(/)2=68min), 18F (t1(/)2=109.8min), 64Cu (t1(/)2=12.7h), and 124I (t1(/)2=4.12d). PMID- 20854861 TI - Radionuclide probes for molecular imaging of pancreatic beta-cells. AB - Islet transplantation is a promising treatment option for patients with type 1 diabetes (T1D); however, the fate of the graft over time remains difficult to follow, due to the lack of available tools capable of monitoring graft rejection and inflammation prior to islet graft loss. Due to the challenges imposed by the location of the pancreas and the sparsely dispersed beta-cell population within the pancreas, currently, the clinical verification of beta-cell abnormalities can only be obtained indirectly via metabolic studies, which typically is not possible until after a significant deterioration in islet function has already occurred. The development of non-invasive imaging methods for the assessment of the pancreatic beta-cells, however, offers the potential for the early detection of beta-cell dysfunction prior to the clinical onset of T1D and type 2 diabetes (T2D). Ideal islet imaging agents would have an acceptable residence time in the human body, be capable of providing high-resolution images with minimal uptake in surrounding tissues (e.g., the liver), would not be toxic to islets, and would not require pre-treatment of islets prior to transplantation. A variety of currently available imaging techniques, including magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and nuclear imaging have been tested for the study of beta-cell diseases. In this article, we summarize the recent advances made in nuclear imaging techniques for non-invasive imaging of pancreatic beta-cells. The use of radioactive probes for islet imaging is also discussed. PMID- 20854862 TI - Food consumption patterns and economic growth. Increasing affluence and the use of natural resources. AB - This study analyzes relationships between food supply, consumption and income, taking supply, meat and dairy, and consumption composition (in macronutrients) as indicators, with annual per capita GDP as indicator for income. It compares food consumption patterns for 57 countries (2001) and gives time trends for western and southern Europe. Cross-sectional and time series relationships show similar patterns of change. For low income countries, GDP increase is accompanied by changes towards food consumption patterns with large gaps between supply and actual consumption. Total supply differs by a factor of two between low and high income countries. People in low income countries derive nutritional energy mainly from carbohydrates; the contribution of fats is small, that of protein the same as for high income countries and that of meat and dairy negligible. People in high income countries derive nutritional energy mainly from carbohydrates and fat, with substantial contribution of meat and dairy. Whenever and wherever economic growth occurs, food consumption shows similar change in direction. The European nutrition transition happened gradually, enabling agriculture and trade to keep pace with demand growth. Continuation of present economic trends might cause significant pressure on natural resources, because changes in food demand occur much faster than in the past, especially in Asia. PMID- 20854863 TI - Characterization of tumor necrosis factor-alpha block haplotypes associated with susceptibility to chronic venous leg ulcers in Caucasian patients. AB - Polymorphisms in the central major histocompatibility complex (MHC) are associated with several immunopathologic and inflammatory diseases, including chronic venous leg ulcers (CVLU). Because of strong linkage disequilibrium, identification of loci affecting disease susceptibility must be based on comparisons between haplotypes. Here we examine the association of conserved tumor necrosis factor (TNF) block haplotypes with CVLU susceptibility. A total of 171 Caucasian patients with CVLU were compared with 173 age-/gender-matched controls, excluding individuals with type 1 diabetes or rheumatoid arthritis. A total of 194 healthy subjects formed a separate population-based control group. Samples were typed for 38 tumor necrosis factor (TNF) block single nucleotide polymorphisms (SNP), human leukocyte antigen (HLA)-B and HLA-DRB1 alleles. TNF haplotypes were derived using the PHASE algorithm and assigned numbers (FVx) defined previously. The patients and matched controls shared 16 TNF block haplotypes. The patients had increased carriage of FV16 and alleles of the 8.1 and 60.3 MHC ancestral haplotypes (AH). CVLU risk is modulated by alleles within FV16 (e.g., TNF-308A and BAT1intron10 C insertion) or near FV16 in the 8.1AH. CVLU risk may also be mediated by unidentified alleles (not in FV22) marked by HLA-B40 and HLA-DR13. FV16 appears to be the best MHC and TNF block marker of susceptibility. After disease onset, an individual's TNF block haplotype does not modulate CVLU severity. PMID- 20854864 TI - Chemokines and chemokine receptors coordinate the inflammatory immune response in human cutaneous leishmaniasis. AB - Cutaneous leishmaniasis (CL) includes different clinical manifestations displaying diverse intensities of dermal inflammatory infiltrate. Diffuse CL (DCL) cases are hyporesponsive, and lesions show very few lymphocytes and a predominance of macrophages. In contrast, localized CL (LCL) cases are responsive to leishmanial antigen, and lesions exhibit granulocytes and mononuclear cell infiltration in the early phases, changing to a pattern with numerous lymphocytes and macrophages later in the lesion. Therefore, different chemokines may affect the predominance of cell infiltration in distinct clinical manifestations. In lesions from LCL patients, we examined by flow cytometry the presence of different chemokines and their receptors in T cells, and we verified a higher expression of CXCR3 in the early stages of LCL (less than 30 days of infection) and a higher expression of CCR4 in the late stages of disease (more than 60 days of infection). We also observed a higher frequency of T cells producing IL-10 in the late stage of LCL. Using immunohistochemistry, we observed a higher expression of CCL7, CCL17 in lesions from late LCL, as well as CCR4 suggesting a preferential recruitment of regulatory T cells in the late LCL. Comparing lesions from LCL and DCL patients, we observed a higher frequency of CCL7 in DCL lesions. These results point out the importance of the chemokines, defining the different types of cells recruited to the site of the infection, which could be related to the outcome of infection as well as the clinical form observed. PMID- 20854865 TI - Regulatory causality evaluation methods applied in kava hepatotoxicity: are they appropriate? AB - Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava. PMID- 20854866 TI - Probable psychosis associated with levetiracetam: a case report. PMID- 20854867 TI - High dose quetiapine in the treatment of psychosis due to traumatic brain injury: a case report. PMID- 20854868 TI - Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder. AB - Transcranial direct current stimulation (tDCS) is a non-invasive method for brain stimulation. Although pilot trials have shown that tDCS yields promising results for major depressive disorder (MDD), its efficacy for bipolar depressive disorder (BDD), a condition with high prevalence and poor treatment outcomes, is unknown. In a previous study we explored the effectiveness of tDCS for MDD. Here, we expanded our research, recruiting patients with MDD and BDD. We enrolled 31 hospitalized patients (24 women) aged 30-70 years 17 with MDD and 14 with BDD (n = 14). All patients received stable drug regimens for at least two weeks before enrollment and drug dosages remained unchanged throughout the study. We applied tDCS over the dorsolateral prefrontal cortex (anodal electrode on the left and cathodal on the right) using a 2 mA-current for 20 min, twice-daily, for 5 consecutive days. Depression was measured at baseline, after 5 tDCS sessions, one week later, and one month after treatment onset. We used the scales of Beck (BDI) and Hamilton-21 items (HDRS). All patients tolerated treatment well without adverse effects. After the fifth tDCS session, depressive symptoms in both study groups diminished, and the beneficial effect persisted at one week and one month. In conclusion, our preliminary study suggests that tDCS is a promising treatment for patients with MDD and BDD.2. PMID- 20854869 TI - Aripiprazole can treat psychotic features but not motor symptoms of Parkinson's disease: evidence from a SPECT study. PMID- 20854870 TI - Recurrence of konzo in southern Tanzania: rehabilitation and prevention using the wetting method. AB - There have been four konzo outbreaks in Tanzania from 1985 to 2002/2003 with a total of 363 cases of konzo. Every outbreak of konzo resulted from large cyanogen intakes from bitter cassava during drought, which caused food shortages and led to people using short-cut methods of cassava processing. Rehabilitation of the 214 konzo subjects from the two most recent outbreaks of konzo in southern Tanzania was carried out by screening konzo subjects and included provision of crutches and wheel chairs. The wetting method was taught to 216 women activists from the konzo-prone villages, in the first large scale community based intervention to reduce cyanogen intake. Using cassava cyanide kits, the average total cyanide content was reduced by the wetting method about 4-fold, in agreement with previous studies. This model to help prevent konzo requires the widespread education of women activists to use the wetting method. PMID- 20854871 TI - Antimycin A-induced mitochondrial apoptotic cascade is mitigated by phenolic constituents of Phyllanthus amarus aqueous extract in Hep3B cells. AB - Antimycin A (AMA) treatment of cells blocks mitochondrial electron transport chain, and leads to elevated ROS generation, thereby causing damage to mtDNA, proteins and lipids, along with mitochondrial membrane depolarization, release of pro-apoptotic proteins into the cytoplasm, and induction of apoptosis. Prevention of such oxidative cellular damage by the aqueous extract of Phyllanthus amarus has been investigated in this study. The extract demonstrated significant potential in mitigating H(2)O(2)-induced membrane damage along with considerable recession in AMA-governed mitochondrial protein and lipid degradation in Hep3B cells. 8-OHdG analysis of mtDNA damage revealed substantial protective potential of the extract against mtDNA damage. SQ-PCR of selected mtDNA sequences confirmed the potential of the extract to alleviate levels of mtDNA damage. FACS analysis with JC-1 fluorescent dye established significant escalation of mitochondrial membrane potential by the extract in AMA-treated cells. Extract treatment resulted in a distinct decline in the degrees of AMA-induced release of cytochrome c and AIF into the cytoplasm along with consequent pacification of apoptosis. All protective efficiencies of the extract reported in this study were found to hold strong and significant (P<0.05) positive correlation to its total phenolic contents, thereby proving that polyphenolic constituents of P. amarus aqueous extract mitigate oxidative stress-induced cellular degeneration and aging. PMID- 20854872 TI - Brain oxidative stress after dermal and subcutaneous exposure of T-2 toxin in mice. AB - T-2 toxin belongs to group of mycotoxins and is found as a natural contaminant in cereals, feed and vegetables. In the present study we evaluated acute toxicity of dermal and subcutaneous exposure of T-2 toxin on brain oxidative stress in mice. Mice were exposed to 1 LD50 of T-2 toxin either by dermal (5.94 mg/kg) or subcutaneous (1.54 mg/kg body weight) route and sacrificed at 1, 3 and 7 days post-exposure. T-2 toxin treated animals showed time dependent increase in reactive oxygen species generation, glutathione depletion, lipid peroxidation and protein carbonyl content in brain in both the routes of exposure. Gene expression profile of antioxidant enzymes showed significant increase in superoxide dismutase and catalase in percutaneous route and glutathione reductase and glutathione peroxidase in subcutaneous route. Immunoblot analysis of antioxidant enzymes correlated with gene expression profile. T-2 toxin exposure resulted in down regulation of transcription factor Nrf2 and its downstream target genes of phase II detoxifying enzymes NQO1, Gclc, Gclm and hemeoxygenase-1. Results of our study show that percutaneously and subcutaneously applied T-2 toxin can cause brain oxidative damage possibly after crossing blood-brain barrier by altering its permeability. PMID- 20854873 TI - Antioxidant, cytoprotective and antibacterial effects of Sea buckthorn (Hippophae rhamnoides L.) leaves. AB - The present study was carried out to investigate the antioxidant, cytoprotective and antibacterial effects of aqueous and hydroalcoholic extracts of Hippophae rhamnoides L. (Sea buckthorn) (SBT) leaves by using various in vitro systems and analysis of marker compounds by reverse phase-high performance liquid chromatography (RP-HPLC). The chemical composition of the leaf extracts was quantified by colorimetric reaction in terms of total phenol and flavonoids contents. Further, some of its bioactive phenolic constituents, such as quercetin 3-O-galactoside, quercetin-3-O-glucoside, kaempferol and isorhamnetin were also quantified in both SBT leaf extracts by RP-HPLC. The SBT leaf extracts exhibited potent antioxidant activity determined by 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) diammonium salt (ABTS), 2,2-diphenyl-1-picryl-hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. Further, both extracts were observed to have cytoprotective activity against hydrogen peroxide and hypoxanthine-xanthine oxidase induced damage to BHK-21 cell line. The SBT leaf extracts showed growth inhibiting effect against Bacillus cereus, Pseudomonas aeruginosa, Staphylococcus aureus and Enterococcus faecalis. These observations suggest that aqueous and hydroalcoholic extracts of Sea buckthorn leaves have marked antioxidant, cytoprotective and antibacterial activities. PMID- 20854874 TI - MYEOV is a prognostic factor in multiple myeloma. AB - OBJECTIVE: Multiple myeloma is a plasma cell neoplasm characterized by the accumulation of malignant plasma cells within the bone marrow. This disease remains incurable despite major treatment improvements. However, gene expression profiling of multiple myeloma cells (MMC) may lead to identification of new therapeutic targets. MATERIALS AND METHODS: Using Affymetrix microarrays, we identified the overexpression of the MYEOV gene in MMC of 171 patients with newly diagnosed multiple myeloma compared to normal plasma cells. RESULTS: The MYEOV gene was present (Affymetrix call) in 79% of MMC and in 15% of normal plasma cells. MYEOV gene is not expressed in cells of the patients' bone marrow environment. The downregulation of MYEOV gene reduced the growth of a MYEOV(present) myeloma cell line, unlike a MYEOV(absent) one. Patients with MYEOV(absent) MMC have an increased event-free survival compared to patients with MYEOV(present) MMC, after high-dose therapy and stem cell transplantation and a trend for increased overall survival. In a Cox proportional hazard model, MYEOV expression in MMC is predictive for event-free survival for patients independently of International Staging System stage, t(4;14) translocation, albumin, or B2M serum levels. A knockout of MYEOV significantly reduced the growth of MMC. CONCLUSIONS: Thus, MYEOV expression is a prognostic factor for patients with multiple myeloma, in part through a role of MYEOV in the control of MMC proliferation. PMID- 20854875 TI - Naturally occurring CD4+ CD25+ FOXP3+ T-regulatory cells are increased in chronic myeloid leukemia patients not in complete cytogenetic remission and can be immunosuppressive. AB - OBJECTIVE: Clinical presentation of chronic myeloid leukemia (CML) requires not only the deregulated tyrosine kinase BCR-ABL, but also the failure of an immune response against BCR-ABL-expressing cells. T-cell responses against BCR-ABL and other antigens are well-described, but their relevance to the in vivo control of CML is unclear. The suppressive role of naturally occurring T regulatory (T-reg) cells in antitumor immunity is well-established, although little is known about their role in modulating the T-cell response to BCR-ABL. MATERIALS AND METHODS: Naturally occurring T-reg cells were characterized and quantified by flow cytometry in 39 CML patients and 10 healthy donors. Their function was studied by observing their effect on responses to purified protein derivative, a recall antigen, and on the response of an autologous T-cell line recognizing BCR-ABL. RESULTS: T-reg cells were CD4(+), CD25(+), FOXP3(+), CD127(low), and CD62L(high). T-reg numbers in patients in complete cytogenetic remission were significantly lower than in patients not in complete cytogenetic remission (p < 0.01). T-reg cell depletion using anti-CD25 selection enhanced proliferative responses to purified protein derivative. Furthermore, the interferon-gamma and/or granzyme-B production of effector cells specific for viral peptides or a BCR-ABL HLA-A3 restricted peptide was inhibited when autologous T-reg cells were present. CONCLUSIONS: Taken together, these data suggest a role for T-reg cells in limiting immune responses in CML patients and this may include immune responses to BCR-ABL. The increased frequency of T-reg cells in patients with high levels of BCR-ABL transcripts indicates that an immune mechanism may be important in the control of CML. PMID- 20854876 TI - MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia. AB - OBJECTIVE: The aim of this study was to better understand how mixed lineage leukemia (MLL) fusion proteins deregulate the expression of genes critical for leukemia. MATERIALS AND METHODS: The transforming domain of one of the most common MLL fusion partners, AF9, was immunopurified after expression in myeloblastic M1 cells, and associating proteins were identified by mass spectrometric analysis. Chromatin immunoprecipitation followed by quantitative polymerase chain reaction was used to determine how binding of associating proteins compare across Hoxa9 and Meis1 in cell lines with and without MLL fusion proteins and how binding is altered during gene down-regulation and differentiation. RESULTS: Consistent with earlier purifications of ENL and AF4 from 293 cells, the 90 amino acid C-terminal domain of AF9 associates with many other MLL translocation partners including Enl, Af4, Laf4, Af5q31, Ell, and Af10. This complex, termed elongation assisting proteins (EAPs), also contains the RNA polymerase II C-terminal domain kinase Cdk9/Cyclin T1/T2 (pTEFb) and the histone H3 lysine 79 methyltransferase Dot1L. Myeloid cells transformed by MLL fusions show higher levels and a broader distribution of EAP components at genes critical for leukemia. Inhibition of EAP components pTEFb and Dot1l show that both contribute significantly to activation of Hoxa9 and Meis1 expression. EAP is dynamically associated with the Hoxa9 and Meis1 loci in hematopoietic cells and rapidly dissociates during induction of differentiation. In the presence of MLL fusion proteins, its dissociation is prevented. CONCLUSIONS: The findings suggest that MLL fusion proteins deregulate genes critical for leukemia by excessive recruitment and impaired dissociation of EAP from target loci. PMID- 20854877 TI - Chronic treatment of exendin-4 affects cell proliferation and neuroblast differentiation in the adult mouse hippocampal dentate gyrus. AB - Exendin-4 isolated from Heloderma suspectum venom acts via glucagon-like peptide 1 (GLP-1) receptor and has clinically been used in the type 2 diabetes. In this study, we investigated the effects of exendin-4 on cell proliferation and neuroblast differentiation in the subgranular zone (SGZ) of the dentate gyrus in mice. Exendin-4 was treated intraperitoneally to male ICR mice twice a day for 21 days. The exendin-4-treated group showed a significantly higher number of Ki67- (1.51-fold), doublecortin (DCX)- (2.5-fold) and 5-bromo-2'-deoxyuridine (BrdU)+DCX- (2.46-fold) immunoreactive cells in the SGZ of the dentate gyrus compared to the control group. The results of this study showed that treatment with exendin-4 increased cell proliferation neuroblast differentiation in the SGZ of the dentate gyrus, suggesting that exendin-4 promotes structural plasticity in the dentate gyrus. PMID- 20854879 TI - Does a period of detraining cause a decrease in serum brain-derived neurotrophic factor? AB - Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins promoting cognitive function and contributing to neurogenesis and neuroprotection. Available evidence suggests that exercise influences serum BDNF concentrations, but that the effect is transient. The purpose of this study is to determine whether a period of aerobic training, followed by a period of detraining, can influence basal serum BDNF levels in humans. Sixteen young, sedentary subjects were assigned to an experimental group (n=9) and a control group (n=7). The experimental group performed an aerobic training program during 8 weeks, followed by 8 weeks of detraining, during which subjects returned to their previous, sedentary activity level. The control group remained physically inactive during 16 weeks. In both groups, performance on short-term (Digit Span test) and mid term memory (Recall of Images) was assessed. Aerobic training significantly increased the VO(2) peak in the experimental group, and these values returned to baseline after 8 weeks of detraining. Basal serum BDNF was not influenced by 8 weeks of aerobic training and detraining did not seem to have an effect on basal peripheral BDNF concentrations. Both training and detraining did not clearly influence short-term memory performance on the Digit Span test and no differences were present between the experimental and control group on the mid-term memory test. Future studies should focus on patient groups and elderly to further investigate the effect of training and detraining on neurotrophic factors and cognitive function, and on the effects of training and detraining on the BDNF response to acute exercise. PMID- 20854878 TI - Protective effect of metabotropic glutamate mGluR5 receptor elimination in a 6 hydroxydopamine model of Parkinson's disease. AB - Pharmacologic or genetic blockade of metabotropic glutamate mGlu5 receptors (mGluR5) has been shown to attenuate parkinsonian motor deficits and protect nigrostriatal neurons from damage in the acute MPTP model of Parkinson's disease (PD), suggesting that therapeutically targeting the mGluR5 receptor may offer a novel approach to improving motor symptoms and/or slowing neurodegeneration in PD. This study further explored the neuroprotective potential of targeting mGluR5 receptors. We examined the behavioral and neurochemical effects of receptor elimination on toxicity induced by intra-striatal application of 6 hydroxydopamine (6-OHDA), thought to represent a comparatively progressive model of PD. mGluR5 knockout (KO) mice and wild-type (WT) littermates received unilateral 6-OHDA infusions. Reflecting the imbalance expected following unilateral infusion, WT but not KO mice demonstrated predominantly ipsilateral forepaw use and robust ipsilateral amphetamine-induced rotation. Further, performance on the vertical pole descent task was profoundly impaired in WT mice, while KO mice completed the task significantly faster. Consistent with the behavioral observations, neurochemical analyses of striatal dopamine depletion showed significantly diminished severity in KO mice with only 64% of striatal dopamine lost, compared to 92% in WT mice. The absence of brain mGluR5 receptors in living KO mice was verified using positron emission tomography (PET). Our findings substantiate the key role of mGluR5 receptors in animal models of PD, strengthening the rationale for the development of mGluR5 antagonists for their neuroprotective, as well as symptomatic, benefit. PMID- 20854880 TI - Granulocyte-colony stimulating factor ameliorates irradiation-induced suppression of hippocampal neurogenesis in adult mice. AB - Granulocyte-colony stimulating factor (G-csf) is a member of the hematopoietic growth factor family and demonstrates neuroprotective functions in neurodegenerative diseases. This study evaluated the radioprotective effects of G csf in the suppression of hippocampal neurogenesis in adult mice undergoing irradiation. The radioprotective effects were assessed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay and immunohistochemical markers of neurogenesis, including the proliferating cell marker Ki-67 and the immature progenitor neuron marker doublecortin (DCX). Acute exposure to cranial irradiation (5Gy gamma-rays) induced neural apoptosis and inhibited neurogenesis in the dentate gyrus (DG) of the adult mouse hippocampus. Pretreatment with G-csf (100MUg/kg every 12h subcutaneously on three consecutive days) attenuated neural apoptosis and decreased the number of Ki-67- and DCX positive cells in the DG of the irradiated mouse hippocampus. Therefore, G-csf inhibited the detrimental effects of irradiation on hippocampal neurogenesis, suggesting that G-csf administration has potential therapeutic utility in brain irradiation. PMID- 20854881 TI - Lack of adrenomedullin, but not complement factor H, results in larger infarct size and more extensive brain damage in a focal ischemia model. AB - Adrenomedullin (AM) and its binding protein, complement factor H (FH), are expressed throughout the brain. In this study we used a brain-specific conditional knockout for AM and a complete knockout for FH to investigate the effect of these molecules on the pathophysiology of stroke. Following 48 h of middle cerebral artery permanent occlusion, there was a statistically significant infarct size increase in animals lacking AM when compared to their wild type littermates. In contrast, lack of FH did not affect infarct volume. To investigate some of the mechanisms by which lack of AM may augment brain damage, markers of nitrosative stress, apoptosis, and autophagy were studied at the mRNA and protein levels. There was a significant increase of inducible nitric oxide synthase (iNOS), matrix metalloproteinase-9 (MMP9), fractin, and Beclin-1 in the peri-infarct area of AM-deficient mice when compared to their wild type counterparts and to contralateral and sham-operated controls. These data suggest that AM exerts a neuroprotective action in the brain and that this protection may be mediated by regulation of iNOS, matrix metalloproteases, and inflammatory mediators. In the future, substances that increase AM actions in the central nervous system may be used as potential neuroprotective agents in stroke. PMID- 20854883 TI - Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting. AB - The present study discusses polyethylene sebacate (PES)-doxorubicin (DOX) nanoparticles (PES-DOX NP) using pullulan as asialoglycoprotein receptor (ASGPR) ligand for hepatic targeting. Pullulan, a hydrophilic polymer served as ligand and as stealth agent. PES-DOX NP were prepared by modified nanoprecipitation using PES and Gantrez AN 119 (Gantrez), as complexing agent in the organic phase, while DOX was dissolved in the aqueous phase. Pullulan was adsorbed on the formed nanoparticles (PES-DOX-PUL). Intimate association of PES and Gantrez, and ionic complexation of DOX with Gantrez (confirmed by FTIR), coupled with rapidity of nanoprecipitation resulted in nanoparticles with high entrapment efficiency and high drug loading. Nanoparticles were successfully freeze dried. Drug release from PES NP followed zero order kinetics. PES-DOX NP and PES-DOX-PUL exhibited low hemolytic potential and good serum stability. Comparative biodistribution study in rats using (99m)Tc labeled formulations revealed higher blood concentration and lower liver concentration of PES-DOX-PUL, confirming the long circulating nature of PES-DOX-PUL, and thereby the possibility of improved targeting to hepatocytes. Nanoparticles revealed lower DOX concentration in the heart suggestive of low cardiotoxicity. Our study presents a radically different yet simple approach for the design of PES-DOX nanoparticles with high drug loading for improved therapy in hepatic cancer. PMID- 20854882 TI - Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction. AB - Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR. In the present study, we examined possible age-related changes in the functional microcircuitry of the synapses in the stratum lacunosum molecular (SL-M) of the CA3 region of the hippocampus, and whether lifelong CR might prevent these age-related alterations. We used serial electron microscopy to reconstruct and classify SL-M synapses and their postsynaptic spines. We analyzed synapse number and size as well as spine surface area and volume in young (10 months) and old (29 months) ad libitum fed rats and in old rats that were calorically restricted from 4 months of age. We limited our analysis to SL-M because previous work demonstrated age-related decreases in synaptophysin confined to this specific layer and region of the hippocampus. The results revealed an age-related decrease in macular axo-spinous synapses that was not reversed by CR that occurred in the absence of changes in the size of synapses or spines. Thus, the benefits of CR for CA3 function and synaptic plasticity may involve other biological effects including the stabilization of synaptic proteins levels in the face of age-related synapse loss. PMID- 20854884 TI - PEGylation and preliminary biocompatibility evaluation of magnetite-silica nanocomposites obtained by high energy ball milling. AB - High energy ball milling (HEBM) has been used for the first time to prepare PEGylated magnetite-silica (Fe(3)O(4)-SiO(2)) nanocomposites intended to be used for biological purposes. Surface amine groups were introduced by a silanization reaction involving 3-aminopropyl triethoxysilane (APTS) followed by PEGylation to yield long-term stable and stealth nanocomposites of 200nm in diameter. The efficient coverage by PEG chains was shown by isothermal titration calorimetry (ITC) where PEGylated nanocomposites did not interact with BSA compared to non PEGylated counterparts which led to a significant change in enthalpy. By cell viability (MTT) assays and cell morphology investigations, it was evidenced that PEGylated Fe(3)O(4)-SiO(2) nanocomposites did not provide any appreciable cytotoxicity on J774 macrophage and MCF-7 breast cancer cell lines. Furthermore, noticeable internalization was evidenced by J774 cells with PEGylated Fe(3)O(4) SiO(2) nanocomposites in contrast to MCF-7 cells, in good agreement with the respective tendency of each cell line for endocytosis. PMID- 20854885 TI - Investigating the potential of non-thermal microwave as a novel skin penetration enhancement method. AB - Microwaves (MW), a part of the electromagnetic spectrum at 0.3-300GHz, affect human body in different ways through its thermal and athermal effects, including fluidization of cell membranes and liquid crystalline systems. Due to presence of such structures in skin barrier, it was decided here to investigate the potential of athermal MW as skin penetration enhancer. In this investigation, nitrofurazone was chosen as the model penetrant and its permeation through rat skin was studied in vitro at 45 and 90min exposure intervals using MW intensities of 3, 15, 30, 60, 120W at 2450MHz. Results revealed that at 30 degrees C and 45min exposure, 3W MW does not affect permeation of nitrofurazone (P=0.148), while higher intensities increased its flux significantly (P<0.05) in a intensity-dependent manner up to 2.7 times. When the duration of exposure increased to 90min, the enhancement ratio also increased to reach a maximum of 3.3. Applying 60W MW at 25, 30, 37 and 42 degrees C resulted in a parabolic relationship between temperature and enhancement ratio. The present results reveal that microwave can act as a skin penetration enhancement method and that its effect depends on applied intensities, exposure time and temperature. PMID- 20854886 TI - Study of the factors influencing the encapsulation of zidovudine in rat erythrocytes. AB - Antiretroviral-loaded erythrocytes offer a promising therapy against HIV owing to their potential to deliver this kind of drugs to macrophages and reticulo endothelial (RES) tissues. The aim of the present work was to develop and optimize a hypotonic dialysis method for the encapsulation of the antiretroviral Zidovudine (AZT) in rat erythrocytes. The influence of several factors in the encapsulation was also evaluated. Variables such as the initial AZT concentration, the dialysis time, and the dialysis bag/buffer volume ratio exhibited statistically significant differences in the encapsulation of the drug in erythrocytes. The amount of drug encapsulated was related to the different values of the variables by multiple linear regression. Osmotic fragility and haematological parameters were estimated as indicators of erythrocyte viability. No statistically significant differences in the osmotic fragility profiles of the control and carrier erythrocytes were observed, and this parameter was also independent of the dialysis concentration of AZT, the hypo-osmotic dialysis time, and the dialysis bag/buffer volume ratio. The in vitro release of AZT from carrier erythrocytes pointed to a fast leakage of the drug; however, around 30% of the drug remained encapsulated for a prolonged period of time. Pre-dialysis diamide treatment did not have a significant effect on the encapsulation and release of AZT in erythrocytes. PMID- 20854887 TI - Age-associated alterations of the neuromuscular junction. AB - Age-related loss of muscle mass and function greatly affects quality of life in the elderly population. Several hypotheses have been proposed but accumulating evidence point to alterations in neuromuscular system during aging as a key event that leads to functional denervation, muscle wasting, and weakness. Over the past few decades, age-associated degeneration of the neuromuscular junction (NMJ) and its components have been well documented. With advancing age, pre-terminal portions of motor axons exhibit regions of abnormal thinning, distension, and sprouting whereas postsynaptic endplates decrease in size and reduce in number, length, and density of postsynaptic folds. Although the exact underlying mechanisms are still lacking, recent studies provided direct evidence that age associated increase in oxidative stress plays a crucial role in NMJ degeneration and progression of sarcopenia. Homozygous deletion of an important antioxidant enzyme, Cu,Zn superoxide dismutase (CuZnSOD, SOD1) leads to acceleration of age dependent muscle atrophy, with a significant NMJ degeneration similar to that seen in old wild-type sarcopenic animals. In this short review, we briefly summarize the current understanding of some of the cellular and molecular changes in the NMJ during aging and suggest a role for oxidative stress and mitochondrial dysfunction in age-related changes in the maintenance of neuromuscular innervation. PMID- 20854888 TI - Steroid hormone regulation of C. elegans and Drosophila aging and life history. AB - In the last two decades it has become clear that hormones and gene mutations in endocrine signaling pathways can exert major effects on lifespan and related life history traits in worms, flies, mice, and other organisms. While most of this research has focused on insulin/insulin-like growth factor-1 signaling, a peptide hormone pathway, recent work has shown that also lipophilic hormones play an important role in modulating lifespan and other life history traits. Here we review how steroid hormones, a particular group of lipophilic hormones, affect life history traits in the nematode worm (Caenorhabditis elegans) and the fruit fly (Drosophila melanogaster), with a particular focus on longevity. Interestingly, a comparison suggests that parallel endocrine principles might be at work in worms and flies in these species and that steroid hormones interact with the gonad to affect lifespan. PMID- 20854889 TI - Cytotoxic activity of guaiazulene on gingival fibroblasts and the influence of light exposure on guaiazulene-induced cell death. AB - Guaiazulene (GA) is widely used as a natural ingredient in many health care products and solutions. Although it has been reported to have interesting biological effects, GA and azulene derivatives have been proven to be cytotoxic against normal human cells and human tumor cells; moreover, guaiazulene has shown photomutagenic properties on bacterial strains. Therefore, we evaluated and compared the cytotoxicity of GA at different concentrations on human gingival fibroblast (HGF) cell cultures under normal conditions and under UV irradiation (UV-A dose: 6.4 J/cm(2)). The compound tested was found to significantly reduce cell viability (dose-dependent trend, IC(50) 72.1 MUM), decrease protein procollagen alpha1 type I synthesis, a marker for HGF protein, and COL1A1 mRNA expression. The cytotoxic effects were accompanied by activation of an intrinsic apoptotic pathway, studied using transmission electron microscopy (TEM) and caspase-3 activation. The light exposure of the cell culture treated decreased GA induced cell death (IC(50) 128.9 MUM), suggesting a photoprotective effect due to the photodegradation of the toxic agent, guaiazulene. Furthermore, the products of the photodegradation reaction of GA proved not to be toxic against HGFs. PMID- 20854890 TI - Assessment of toxic interactions of heavy metals in multi-component mixtures using sea urchin embryo-larval bioassay. AB - The toxicities of copper, lead, zinc and cadmium ions and various concentrations of mixtures of them were studied using sea urchin (Strongylocentyotus intermedius) embryo-larval bioassay. Toxic unit analysis was used to determine type of joint action for each mixture combination (binary, ternary and quaternary). For the majority of the binary combinations, the interactions were of synergistic nature, but in ternary or quaternary mixtures, the joint action was mainly concentration additive, while antagonism was only observed for two mixtures (Cu+Pb and Zn+Cd) among all the 11 combinations. Two prevailing theoretical models: the concentration addition (CA) model and the independent action (IA) model were used to predict the mixture toxicities. The weak correlation obtained (R?0.55) indicated that the hypotheses of mode of action involved in the two models to some extent failed to describe the behavior of the mixture system. Then a novel bio-concentration factor-based model was developed and was successful to predict the toxicities of mixtures, with an obtained R of 0.92. This model indicated that in a mixture system of heavy metals, the joint toxicity was mainly determined by the combined action of bio-concentrations of metals other than the simply similar (CA) or dissimilar (IA) modes of action of the mixture components. PMID- 20854891 TI - Endothelial IL-1R1 is a critical mediator of EAE pathogenesis. AB - Interleukin-1 (IL-1) has been implicated in the disease progression of multiple sclerosis (MS). In the animal model of MS, experimental autoimmune encephalomyelitis (EAE), the induction of disease is significantly attenuated in mice lacking the type I IL-1 receptor (IL-1R1). In this study, we created a transgenic mouse (eIL-1R1 kd) in which IL-1R1 expression is knocked down specifically in endothelial cells. Induction of EAE in eIL-1R1 kd mice results in a decrease in incidence, severity and delayed onset of EAE. In addition, eIL-1R1 kd mice show significant decrease in VCAM-1 expression and diminished CD45(+) and CD3(+) infiltrating leukocytes in the spinal cord in animals challenged with EAE. Further, IL-1 and IL-23 stimulate IL-17 production by splenocytes from both wild type and the eIL-1R1 kd animals. Similarly, IL-1 and IL-23 synergistically stimulate splenocytes proliferation in these two strains of animals. After immunization with MOG(79-96), although eIL-1R1 kd mice displayed greatly reduced clinical scores, their splenocytes produced IL-17 and proliferated in response to a second MOG challenge, similar to wild type animals. These findings indicate a critical role for endothelial IL-1R1 in mediating the pathogenesis of EAE, and describe a new model that can be used to study endothelial IL-1R1. PMID- 20854892 TI - Maternal immune stimulation during pregnancy affects adaptive immunity in offspring to promote development of TH17 cells. AB - Behavioral abnormalities in offspring of murine dams that receive immune stimulation with (poly)I:C during pregnancy are well-documented. In this prenatal model, (poly)I:C-induced maternal cytokines, particularly IL-6, appear involved in the etiology of the behavioral abnormalities. While much has been published on the abnormal behaviors of offspring in this model, much less is known about how maternal immune stimulation affects the adaptive immune system of the offspring, and its possible role in the observed pathophysiology. In the present study, pregnant dams were stimulated with (poly)I:C at E12, and 24h later cytokine levels were measured in maternal sera and amniotic fluids. Lymphocytes from offspring were also analyzed for T Helper (TH) cell subsets. The results demonstrate that lymphocytes from offspring of pregnant dams stimulated with (poly)I:C develop into TH17 cells upon in vitro activation. This preferential TH17 cell differentiation occurs in offspring of pregnant dams with an immunological "memory" phenotype, but not in offspring of immunologically "naive" dams. Comparable levels of IL-6 were found in the sera of immune and naive pregnant dams, however, there was a disparity between levels of IL-6 in maternal sera and amniotic fluids of (poly)I:C-injected dams. In matings between IL-6 KO dams (IL-6-/-) and wild-type males (IL-6+/+) there was no IL-6 in sera from (poly)I:C-injected dams, but there were high levels of IL-6 in their amniotic fluids. Analysis of supernatants of cultured placental cell preparations from these IL-6 KO dams confirmed that the IL-6 was produced from the fetal (IL-6+/-) component, and heterozygous IL-6+/- offspring could also produce IL-6. PMID- 20854894 TI - A circadian clock in murine bone marrow-derived mast cells modulates IgE dependent activation in vitro. AB - Circadian rhythm is expressed in most organisms, and many functions and parameters in the immune system are associated with time-of-day. However, it is largely unknown if local circadian clocks in immune cells directly control physiological outcomes. We hypothesized that a circadian clock in murine bone marrow derived mast cells (BMMCs) modulates IgE-dependent activation in vitro. Mature BMMCs, grown from bone marrow of C57BL/6 mice, were synchronized with serum rich media (50% horse serum). Total RNA was harvested from BMMCs at 4 h intervals for up to 72 h following synchronization and expression of circadian genes (mPer1, mPer2, Bmal1, Rev-erbalpha, and Dbp) was measured by quantitative PCR. Serum shock synchronized expression of circadian genes (mPer2, Bmal1, Rev erbalpha, and Dbp) in BMMCs. Synchronized BMMCs stimulated via the high affinity IgE receptor (FcepsilonRI) at different time intervals display circadian rhythms in IL-13 and IL-6 mRNA expression. The expression of fcer1a gene and FcepsilonRIalpha protein displayed a circadian pattern following serum shock, with mean periods of 18.9 and 28.6 h, respectively. These results demonstrate that synchronized BMMCs provide an in vitro model to study circadian mechanism(s) associated with allergic disease and that circadian oscillation of cytokine production following IgE-dependent activation is at least in part due to circadian oscillation of FcepsilonRIalpha. PMID- 20854893 TI - Fatigue and gene expression in human leukocytes: increased NF-kappaB and decreased glucocorticoid signaling in breast cancer survivors with persistent fatigue. AB - Fatigue is highly prevalent in the general population and is one of the most common side effects of cancer treatment. There is growing evidence that pro inflammatory cytokines play a role in cancer-related fatigue, although the molecular mechanisms for chronic inflammation and fatigue have not been determined. The current study utilized genome-wide expression microarrays to identify differences in gene expression and associated alterations in transcriptional activity in leukocytes from breast cancer survivors with persistent fatigue (n=11) and non-fatigued controls (n=10). We focused on transcription of inflammation-related genes, particularly those responsive to the pro-inflammatory NF-kappaB transcription control pathway. Further, given the role of glucocorticoids as key regulators of inflammatory processes, we examined transcription of glucocorticoid-responsive genes indicative of potential glucocorticoid receptor (GR) desensitization. Plasma levels of cortisol were also assessed. Consistent with hypotheses, results showed increased expression of transcripts with response elements for NF-kappaB, and reduced expression of transcripts with response elements for glucocorticoids (p<.05) in fatigued breast cancer survivors. No differences in plasma levels of cortisol were observed. These data indicate that increased activity of pro-inflammatory transcription factors may contribute to persistent cancer-related fatigue and provide insight into potential mechanisms for tonic increases in NF-kappaB activity, specifically decreased expression of GR anti-inflammatory transcription factors. PMID- 20854896 TI - Role of developmental immunotoxicity and immune dysfunction in chronic disease and cancer. AB - The developing immune system is among the most sensitive targets for environmental insult and risk of chronic disease including cancer. Developmental immunotoxicity (DIT)-associated health risks include not only pediatric diseases like childhood asthma and type 1 diabetes, but also multi-disease "patterns" of conditions linked to the initial immune dysfunction. DIT contributes to ever increasing health care costs, increasing reliance on drugs and reduced quality of life. Drug discovery efforts using cutting-edge immunology produce effective tools for management of allergic, autoimmune and inflammatory diseases; in stark contrast, required immunotoxicity testing clings to an outdated understanding of the immune system and its relationship to disease. As currently required, immune safety evaluation of drugs and chemicals lacks the capability of protecting against the most prevalent pediatric immune dysfunction-based diseases. For this reason, mandatory and relevant DIT testing is needed for all drugs and chemicals where pregnant women and children are at risk. PMID- 20854895 TI - Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. AB - Docosahexaenoic acid (DHA), the most abundant essential n-3 polyunsaturated fatty acid in the CNS, emerged recently together with eicosapentaenoic acid (EPA) and DHA/EPA metabolic derivatives as a major player in the resolution of inflammation. Protective anti-inflammatory effects of DHA were reported in clinical studies and animal models of colitis, sepsis, and stroke. Here we report for the first time a beneficial effect of dietary n-3 fatty acids in experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis. In the present study we investigated the effects of DHA on the function of bone marrow derived dendritic cells (DC) in CD4(+) T cell stimulation and differentiation. Pretreatment of DC with DHA prevented LPS-induced DC maturation, maintaining an immature phenotype characterized by low expression of costimulatory molecules and lack of proinflammatory cytokine production (IL-12p70, IL-6, and IL-23). DHA treated DC were poor stimulators of antigen-specific T cells in terms of proliferation and Th1/Th17 differentiation. This was associated with an increase in p27(kip1), a cell cycle arresting agent, and with decreases in Tbet, GATA-3, and RORgammat, master transcription factors for Th1, Th2, and Th17. In contrast, T cells co-cultured with DC-DHA express higher levels of TGFbeta and Foxp3, without exhibiting a functional Treg phenotype. Similar to the in vitro results, the beneficial effect of DHA in EAE was associated with reduced numbers of IFNgamma- and IL-17-producing CD4(+) T cells in both spleen and CNS. PMID- 20854897 TI - Distinct immune responses of recombinant plasmid DNA replicon vaccines expressing two types of antigens with or without signal sequences. AB - Here, DNA replicon vaccines encoding the Hc domain of botulinum neurotoxin serotype A (AHc) or the receptor binding domain of anthrax protective antigen (PA4) with or without signal sequences were evaluated in mice. Strong antibody and protective responses were elicited only from AHc DNA vaccines with an Ig kappa signal sequence or tissue plasminogen activator signal sequence. Meanwhile, there were no differences in total antibody responses or isotypes, lymphocyte proliferative responses, cytokine profiles and protective immune responses with the PA4 DNA vaccines with or without a signal sequence. Therefore, use of targeting sequences in designing DNA replicon vaccines depends on the specific antigen. PMID- 20854898 TI - HPV related surveillance activities in Australia. PMID- 20854899 TI - Tick-borne encephalitis after vaccination: vaccine failure or misdiagnosis. AB - The aim of the paper is to present the results of the investigation of a series of four cases of tick-borne encephalitis (TBE) reported from Gorenjska region in Slovenia in 2008 despite vaccination against TBE, propose surveillance case definition for TBE and classification criteria for TBE vaccine failure cases, to discuss challenges in the interpretation of TBE serology results in previously vaccinated patients and propose ascertainment procedures for vaccine failure cases. Establishing surveillance of vaccine failure cases on national and European level is essential for monitoring and evaluating the impact of immunization, evaluation of vaccine effectiveness and early warning for the need to change the vaccination schedule recommendations. PMID- 20854900 TI - Hepatotoxicity of di-(2-ethylhexyl)phthalate is attributed to calcium aggravation, ROS-mediated mitochondrial depolarization, and ERK/NF-kappaB pathway activation. AB - Di-(2-ethylhexyl)phthalate (DEHP) is a widely used plasticizer found in a variety of polyvinyl chloride medical products. Although DEHP-induced cytotoxicity and apoptosis are well studied in various cell types, the precise mechanisms are not well understood so far. This study, aimed at going beyond the toxicology approach, focuses on the molecular mechanisms through which DEHP causes hepatotoxicity. We show that DEHP induces apoptotic cell death in a dose dependent manner, as proven by an increase in annexin V-positively stained cells, DAPI/PI staining, and immunofluorescence studies. The DEHP-induced decrease in cell viability was significantly inhibited by adding catalase (CAT), but CAT treatment did not suppress the DEHP-stimulated calcium flux in the hepatocytes, whereas BAPTA-AM significantly reduced the DEHP-stimulated DCF intensity. These results demonstrate that DEHP increases the intracellular calcium level, which mediates the generation of H(2)O(2) in hepatocytes. Investigating cell-signaling mechanisms, we found that DEHP induced apoptotic cell death by mitochondrial dependent caspase-3 activation and PARP cleavage. These changes due to DEHP exposure were associated with increased IKK and NF-kappaB phosphorylation. Preexposure of hepatocytes to an IKK inhibitor (PS-1145) prevented DEHP-induced caspase-3 and PARP cleavage. DEHP also markedly increased the activity of ERK1/2 MAPK. Pretreatment with the ERK inhibitor PD98059 attenuated NF-kappaB and IKK phosphorylation, indicating that ERK MAPK is mainly involved in DEHP-induced NF kappaB activation. These results, for the first time, reveal that DEHP induces apoptosis in hepatocytes via the activation of the ERK/NF-kappaB signaling pathway, in which calcium ions and hydrogen peroxide act as the pivotal mediators of the apoptotic signaling. PMID- 20854901 TI - Development of a DNA-binding TEMPO derivative for evaluation of nuclear oxidative stress and its application in living cells. AB - Oxidative stress in nuclei is known to induce either oxidative modification of DNA bases or single/double-strand breaks, which may lead to carcinogenesis. To evaluate the redox status in nuclei in living cells, we designed a novel nucleus localizing redox spin probe, F-DisT, which contains a fluorescein fluorophore linked to a DNA minor-groove-binding moiety. Nuclear distribution of the probe was easily confirmed by colocalization with a nuclear stain, Hoechst 33342, in confocal microscopy. Measurement of oxidative stress with F-DisT in a murine macrophage cell line exposed to endotoxin (lipopolysaccharide) showed a remarkable increase in the ESR signal decay rate. This increase was significantly inhibited by N(omega)-nitro-l-arginine (nitric oxide synthase inhibitor) and diphenyleneiodonium chloride (NADPH oxidase inhibitor). These results indicate that nitric oxide and superoxide contribute to oxidative stress in nuclei. Similar studies in membrane or mitochondria using respective organelle-specific spin probes indicated that the redox microenvironments in these organelles are markedly different from that in nuclei. Thus, subcellular redox microenvironments show marked variability in endotoxin-stimulated living cells. PMID- 20854902 TI - Iron species-mediated dopamine oxidation, proteasome inhibition, and dopaminergic cell demise: implications for iron-related dopaminergic neuron degeneration. AB - Iron species have been suggested to be highly involved in the pathogenesis of Parkinson disease. However, the detailed mechanism of iron-induced dopaminergic degeneration is still unclear. In this study, we demonstrate that free iron ions (trivalent or bivalent) and iron ions in stable complex with cyanide ions (K(4)Fe(CN)(6) and K(3)Fe(CN)(6)) can induce dopamine (DA) oxidation with different profiles and subsequently lead to proteasome inhibition and even dopaminergic MN9D cell demise via different mechanisms. The free iron ions could mediate extensive DA oxidation in an iron-DA complex-dependent manner. However, iron ions in stable complex with cyanide ions could not induce, or could induce only brief, DA oxidation. Deferoxamine, a specific iron ion chelator, could disrupt iron-DA complex formation and thus abrogate free iron ion-catalyzed DA oxidation and subsequent cell toxicity. Glutathione could neither disrupt iron-DA complex formation nor influence free iron ion-catalyzed DA oxidation but could protect against iron-mediated toxicity via detoxification of toxic by-products of iron-mediated DA oxidation. The resulting DA oxidation could inhibit chymotrypsin like, trypsin-like, and caspase-like proteasome activities. However, we demonstrated that oxidative damage was not the major toxic mechanism of MN9D cell degeneration, but it was the DA quinones derived from iron-induced DA oxidation that contributed significantly to proteasome inhibition and even dopaminergic cell demise. PMID- 20854904 TI - Ion pair stabilization effects on a series of procaine structural analogs. AB - In this work, a series of 10 structural procaine analogs have been synthesized in order to investigate the structural features affecting the stability of ion pair formation and its influence on the lipophilicity of ionizable compounds. The structural variation within this series was focused on the terminal nitrogen substituents and on the intermediate chain linkage nature. The hydrophobic parameters logP(n) and logP(i) (partition coefficient of the neutral and ionic species, respectively), as well as the ionization constants pK(a) and pK(a)(oct), were obtained from logD-pH profiles measured at pH values ranging from 2 to 12. The difference between logP(i) and logP(n) values (i.e. difflogP) of each prepared compound was considered a measure of the stability of ion pair formation. In this set, the difflogP values varied nearly over one log unit, ranging from -2.40 to -3.37. It has been observed that the presence of hydrogen bonding groups (especially donor) and low steric hindrance around the terminal amine ionizable group increases the relative lipophilicity of the ionic species as compared to the corresponding neutral species. These results were interpreted as due to the increased stability of ion pairs of the compounds bearing these structural features. PMID- 20854903 TI - Phosphorylation-dependent control of ZIPK nuclear import is species specific. AB - ZIPK (zipper-interacting protein kinase) is a Ca(2+)-independent protein kinase that promotes myosin phosphorylation in both smooth muscle and non-muscle cells. A recent report attempted to clarify a debate over the subcellular localization of ZIPK in non-muscle cells (Shoval et. al. (2007) Plos Genetics. 3: 1884-1883). A species-specific loss of a key phosphorylation site (T299) in murine (mouse and rat) ZIPK seems to direct it to the nucleus, while the presence of the T299 site in human ZIPK correlates with cytoplasmic localization. T299 is immediately adjacent to a putative nuclear localization sequence (NLS) and may mask its function when phosphorylated, therefore explaining the species-specific dichotomy of intracellular localization. However, despite the murine ZIPK (mZIPK) lacking the T299 residue that is critical for controlling human ZIPK (hZIPK) subcellular localization, mutational analysis showed that this NLS control locus is nonfunctional in the murine context. A constitutively active Rho promoted the cytoplasmic retention of a human ZIPK mutant that would otherwise localize to the nucleus. Endogenous hZIPK showed sensitivity to the nuclear export inhibitor leptomycin B, suggesting a continuous shuttling between cytoplasm and nucleus that is dependent upon T299 dephosphorylation. Thus, the C-terminal domain of human and murine ZIPK demonstrated quite divergent nuclear import and export functionality. We conclude that in the case of ZIPK, studies between the species may not be directly comparable to each other given the gross differences in intracellular localization and movement. PMID- 20854905 TI - A controlled release system of titanocene dichloride by electrospun fiber and its antitumor activity in vitro. AB - In order to improve both safety and efficacy of cancer chemotherapy of titanocene dichloride and overcome the shortcomings such as instability and short half-life in the human body, we report a controlled release system of titanocene dichloride by electrospun fiber and its in vitro antitumor activity against human lung tumor spca-1 cells. The system was developed by electrospinning. The release profiles of titanocene dichloride in PBS were researched by UV-Vis spectrophotometer. In vitro antitumor activities of the fibers were examined by MTT method. Titanocene dichloride was well incorporated in biodegradable poly(L-lactic acid) fibers. XRD results suggest that titanocene dichloride exists in the amorphous form in the fibers. The controlled release of titanocene dichloride can be gained for long time. MTT showed actual titanocene dichloride content 40, 80, 160 and 240 mg/L from the fibers mat, cell growth inhibition rates of 11.2%, 22.1%, 44.2% and 68.2% were achieved, respectively. The titanocene dichloride released has obvious inhibition effect against lung tumor cells. The system has an effect of controlled release of titanocene dichloride and may be used as an implantable anticancer drug in clinical applications in the future. PMID- 20854906 TI - Air permeability of powder: a potential tool for Dry Powder Inhaler formulation development. AB - Dry Powder Inhalers have drawn great attention from pharmaceutical scientists in recent years in particular those consisting of low-dose micronized drug particles associated with larger carrier particles and called interactive mixtures. However, there is little understanding of the relation between bulk powder properties such as powder structure and its aerodynamic dispersion performance. The aim of this work was to develop a simple method to measure the air permeability of interactive mixtures used in Dry Powder Inhalers by using Blaine's apparatus--a compendial permeameter and to relate it to the aerodynamic behaviour. The study was done with fluticasone propionate and terbutaline sulphate as drug models that were blended with several lactoses having different particle size distribution thus containing different percentages of fine particle lactose. The quality of the blends was examined by analysing the drug content uniformity. Aerodynamic evaluation of fine particle fraction was obtained using a Twin Stage Impinger. A linear correlation between a bulk property--air permeability of packed powder bed--and the fine particle fraction of drug was observed for the tested drugs. The air permeability reflects the quantity of the free particle fraction in the interparticulate spaces of powder bed that leads to fine particle fraction during fluidization in air flow. A theoretical approach was developed in order to link the air permeability of powder bed and drag force acting on powders during aerosolization process. The permeability technique developed in this study provides a potential tool for screening Dry Powder Inhaler formulations at the development stage. PMID- 20854907 TI - Effect of ethanol on the water permeability of controlled release films composed of ethyl cellulose and hydroxypropyl cellulose. AB - The robustness of controlled release formulations when co-ingested with alcohol is a current concern expressed by regulatory authorities, especially with regard to dose dumping. One such controlled release formulation commonly used is film coating composed of ethyl cellulose (EC) and hydroxypropyl cellulose (HPC). The aim of this study was to investigate how the presence of ethanol in the dissolution medium affects the water permeability of such films. Film samples were prepared in various EC-HPC compositions, and the effect of different ethanol concentrations in the dissolution medium on the permeability was studied using a modified Ussing chamber and tritiated water. It was found that the effect of ethanol on the film permeability varied depending on the composition of the films. The results were interpreted in terms of swelling of the EC in the films, where the swelling increased with increasing ethanol concentration. Thus, for films with low HPC content (non-interconnected pores), the water permeability of the films increased with increasing ethanol concentration as the diffusion through the ethyl cellulose increased due to swelling. However, for films with higher HPC content (having interconnected pores through the films), the permeability decreased, likely due to the swelling of the ethyl cellulose blocking the pores. The interpretation of the results was supported by dynamic mechanic analysis and SEM analysis. PMID- 20854908 TI - Differences between reversible (self-association) and irreversible aggregation of rHuG-CSF in carbohydrate and polyol formulations. AB - Severe immunogenic and other debilitating human disorders potentially induced by protein aggregates have brought this phenomenon into the focus of biopharmaceutical science over the past decade. Depending on its driving forces, the process induced in the model protein rHuG-CSF may be either reversible or irreversible, resulting in the assembly of self-associated protein species or irreversible aggregates of various final morphologies. The aim of our work was to investigate the correlation between irreversible and reversible aggregation and the protective effect of non-specific formulation stabilisers, selected from the group of carbohydrates and polyols including trehalose, xylitol, cellobiitol, turanose, cellobiose, leucrose, lactitol, lyxose, and sorbitol, against both irreversible protein aggregation and reversible self-association processes of the rHuG-CSF. The formation of irreversible aggregates was thermally induced and evaluated using differential scanning calorimetry and size-exclusion chromatography. As opposed to the irreversible aggregation process, the process of self-association was induced by the agitation experiment by directly augmenting the protein solution contact surfaces. Absence of statistical connectivity between different stabilisers' ability to inhibit self-association or aggregation reactions indicates that these are two distinct physicochemical processes with different formulation stabilizing outcomes. Reaction mechanism of thermally induced aggregation observed in the study was in line with published literature data, while the reaction mechanism for self-association process was postulated. The postulate has been verified experimentally by isothermal calorimetry and agitation set of experiments conducted after size-exclusion chromatography and asymmetrical flow field-flow fractionation separation of monomeric, dimeric, trimeric, oligomeric, and large self-associated forms detected on multi-angle light scattering, fluorescence, UV, and refractive index detectors. Besides defining the mechanism and kinetic of self-association in stabilized rHuG-CSF formulations, special attention was also paid to the shifts and ranks of the free energy of the aggregation or self-association transition states. PMID- 20854909 TI - Functional characterization of cis-acting elements mediating flavone-inducible expression of CYP321A1. AB - How plant allelochemicals elicit herbivore counterdefense genes remains largely unknown. To define the cis-acting elements for flavone inducibility of the allelochemical-metabolizing CYP321A1 from Helicoverpa zea, functions of varying length of CYP321A1 promoter are examined in H. zea fatbody cells. Progressive 3' deletions reveal presence of positive elements in the 5' untranslated region (UTR). Progressive 5' deletions map out regions of one essential element, four enhancers, and two silencers. Further progressive 5'deletions localize the essential element to a 36-bp region from -109 to -74. This essential element, designated as xenobiotic response element to flavone (XRE-Fla), contains a 5' AT only TAAT inverted repeat, a GCT mirror repeat and a 3' antioxidant response element-like element. Internal deletions and substitution mutations show that the TAAT repeat is only necessary for the maximal flavone inducibility, whereas the other two components are necessary for the basal and flavone-induced expression of CYP321A1. Electrophoresis mobility shift assays demonstrate that XRE-Fla specifically binds to H. zea fatbody cell nuclear extracts and flavone treatment increases the nuclear concentrations of the yet-to-be characterized transcription factors binding to XRE-Fla. Taken together, CYP321A1 expression is regulated primarily by XRE-Fla and secondarily by other cis elements scattered in its promoter and 5' UTR. PMID- 20854910 TI - Highly efficient production of phosphorylated hepatitis B core particles in yeast Pichia pastoris. AB - Virus-like particles (VLPs) of the recombinant hepatitis B virus (HBV) core protein (HBc) are routinely used in HBV diagnostics worldwide and are of potential interest as carriers of foreign peptides (e.g., immunological epitopes and targeting addresses, and/or as vessels for packaged diagnostic and therapeutic nanomaterials). Despite numerous reports exploiting different expression systems, a rapid and comprehensive large-scale methodology for purification of HBc VLPs from yeast is still lacking. Here, we present a convenient protocol for highly efficient production and rapid purification of endotoxin-free ayw subtype HBc VLPs from the methylotrophic yeast Pichia pastoris. The HBc gene expression cassette along with the geneticin resistance gene was transferred to the P. pastoris genome via homologous recombination. A producer clone was selected among 2000 transformants for the optimal synthesis of the target protein. Fermentation conditions were established ensuring biomass accumulation of 163g/L. A simple combination of pH/heat and salt treatment followed by a single anion-exchange chromatography step resulted in a more than 90% pure preparation of HBc VLPs, with a yield of about 3.0mg per 1g of wet cells. Purification is performed within a day and may be easily scaled up if necessary. The quality of HBc VLPs was verified by electron microscopy. Mass spectrometry analysis and direct polyacrylamide gel staining revealed phosphorylation of HBc at at least two sites. To our knowledge, this is the first report of HBc phosphorylation in yeast. PMID- 20854911 TI - Matching structural densities from different biophysical origins with gain and bias. AB - The registration of volumetric structures in real space involves geometric and density transformations that align a target map and a probe map in the best way possible. Many computational docking strategies exist for finding the geometric transformations that superimpose maps, but the problem of finding an optimal density transformation, for the purposes of difference calculations or segmentation, has received little attention in the literature. We report results based on simulated and experimental electron microscopy maps, showing that a single scale factor (gain) may be insufficient when it comes to minimizing the density discrepancy between an aligned target and probe. We propose an affine transformation, with gain and bias, that is parameterized by known surface isovalues and by an interactive centering of the "cancellation peak" in the surface thresholded difference map histogram. The proposed approach minimizes discrepancies across a wide range of interior densities. Owing to having only two parameters, it avoids overfitting and requires only minimal knowledge of the probe and target maps. The linear transformation also preserves phases and relative amplitudes in Fourier space. The histogram matching strategy was implemented in the newly revised volhist tool of the Situs package, version 2.6. PMID- 20854912 TI - Conformational dynamics of supramolecular protein assemblies. AB - Supramolecular protein assemblies including molecular motors, cytoskeletal filaments, chaperones, and ribosomes play a central role in a broad array of cellular functions ranging from cell division and motility to RNA and protein synthesis and folding. Single-particle reconstructions of such assemblies have been growing rapidly in recent years, providing increasingly high resolution structural information under native conditions. While the static structure of these assemblies provides essential insight into their mechanism of biological function, their dynamical motions provide additional important information that cannot be inferred from structure alone. Here we present an unsupervised computational framework for the analysis of high molecular weight protein assemblies and use it to analyze the conformational dynamics of structures deposited in the Electron Microscopy Data Bank. Protein assemblies are modeled using a recently introduced coarse-grained modeling framework based on the finite element method, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the ribosome-bound termination factor RF2 from Escherichia coli, the nuclear pore complex from Dictyostelium discoideum, and the chaperonin GroEL from E. coli. Elastic strain energy distributions reveal hinge regions associated with specific conformational change pathways, and correlations in collective molecular motions reveal dynamical coupling between distant molecular domains that suggest new, as well as confirm existing, allosteric mechanisms. Results are publically available for use in further investigation and interpretation of biological function including cooperative transitions, allosteric communication, and molecular mechanics, as well as in further classification and refinement of electron microscopy based structures. PMID- 20854913 TI - Global fiber reconstruction becomes practical. AB - Global fiber reconstruction aims at providing a consistent view of the fiber architecture in the whole volume of cerebral white matter on the basis of diffusion-sensitized magnetic resonance imaging. A new realization of this principle is presented. The method utilizes data acquired with high angular resolution diffusion imaging (HARDI), a measurement method that fulfills clinical requirements. For the first time among global reconstruction methods, the computation time is acceptable for a broad class of practical applications. The method does not involve any boundary conditions that prescribe the location of the ends of reconstructed fibers. This helps to minimize necessary user interaction and operator dependence. Results obtained in a physical phantom demonstrate a high reconstruction quality. In vivo results have been obtained in several volunteers. The algorithm found a number of prominent fascicles including those in the limbic system, which had been problematic for a previously published version of global tracking. PMID- 20854914 TI - Neuroimaging reveals dual routes to reading in simultaneous proficient readers of two orthographies. AB - Orthographic differences across languages impose differential weighting on distinct component processes, and consequently on different pathways during word reading tasks. Readers of transparent orthographies such as Italian and Hindi are thought to rely on spelling-to-sound assembly and show increased activation in phonologically tuned areas along the dorsal pathway, whereas reading an opaque orthography such as English is thought to rely more on lexically mediated processing associated with increased activation of semantically tuned regions along the ventral pathway. To test if biliterate Hindi/English readers exhibit orthography-specific reading pathways, we used behavioural measures and functional neuroimaging. Reaction times and activation patterns of monolingual English and Hindi readers were compared to two groups of adult biliterates; 14 simultaneous readers who learnt to read both languages at age 5 and 10 sequential readers who learnt Hindi at 5 and English at 10. Simultaneous, but not sequential readers demonstrated relative activation differences of dorsal and ventral areas in the two languages. Similar to native counterparts, simultaneous readers preferentially activated the left inferior temporal gyrus for English and left inferior parietal lobule (L-IPL) for Hindi, whereas, sequential readers showed higher activation along the L-IPL for reading both languages. We suggest that early simultaneous exposure to reading distinct orthographies results in orthography-specific plasticity that persists through adulthood. PMID- 20854915 TI - Perception of the touch-induced visual double-flash illusion correlates with changes of rhythmic neuronal activity in human visual and somatosensory areas. AB - A single brief visual stimulus accompanied by two brief tactile stimuli is frequently perceived incorrectly as two flashes, a phenomenon called double-flash illusion (DFI). We investigated whether the DFI is accompanied by changes in rhythmic neuronal activity, using magnetoencephalography in human subjects. Twenty-two subjects received visuo-tactile stimulation and reported the number of perceived visual stimuli. We sorted trials with identical physical stimulation according to the reported subjective percept and assessed differences in spectral power in somatosensory and occipital sensors. In DFI trials, occipital sensors displayed a contralateral enhancement of gamma-band (80-140 Hz) activity in response to stimulation. In somatosensory sensors, the DFI was associated with an increase of spectral power for low frequencies (5-17.5 Hz) around stimulation and a decrease of spectral power in the 22.5-30 Hz range between 450 and 750 ms post stimulation. In summary, several components of rhythmic activity predicted variable subjective experience for constant physical stimulation. Notably, the enhanced occipital gamma-band activity during DFI was similar in time and frequency extent to the somatosensory gamma-band response to tactile stimulation. We speculate that the DFI might therefore occur when the somatosensory gamma response is transmitted to visual cortex. This transmission might be supported by the observed modulations in low-frequency activity. PMID- 20854916 TI - Estimating divergence times of lizardfishes and their allies (Euteleostei: Aulopiformes) and the timing of deep-sea adaptations. AB - The divergence times of lizardfishes (Euteleostei: Aulopiformes) are estimated utilizing a Bayesian approach in combination with knowledge of the fossil record of teleosts and a taxonomic review of fossil aulopiform taxa. These results are integrated with a study of character evolution regarding deep-sea evolutionary adaptations in the clade, including simultaneous hermaphroditism and tubular eyes. Divergence time estimations recover that the stem species of the lizardfishes arose during the Early Cretaceous/Late Jurassic in a marine environment with separate sexes, and laterally directed, round eyes. Tubular eyes have arisen independently at different times in three deep-sea pelagic predatory aulopiform lineages. Simultaneous hermaphroditism evolved a single time in the stem species of the suborder Alepisauroidei, the clade of deep-sea aulopiforms during the Early Cretaceous. This result indicates the oldest known evolutionary event of simultaneous hermaphroditism in vertebrates, with the Alepisauroidei being the largest vertebrate clade with this reproductive strategy. PMID- 20854917 TI - Molecular phylogenetics and phylogeography of the white-fronted capuchin (Cebus albifrons; Cebidae, Primates) by means of mtCOII gene sequences. AB - A total of 696 base pairs (bp) of the mitochondrial COII gene were sequenced from 118 individuals of Cebus albifrons (plus an individual of Cebus olivaceus) sampled from diverse geographical areas of Colombia, Peru, Ecuador and Brazil. These animals represented all of the C. albifrons's taxa described by Hershkovitz (1949) in Colombia and Peru (10 out of 13 subspecies are described by this author). The sequences analyzed demonstrate the existence of three well defined groups in northern Colombia (trans-Andean): malitosus, versicolor-pleei-cesarae and leucocephalus. They arose from at least, three distinct migrations from different Amazonian groups. Five different Amazonian and Eastern Llanos C. albifrons's groups (I, II, III, IV, and V) were also found. In many Amazonian localities, some of these groups live in sympatry probably by secondary expansion after their respective formations. Amazonian group I is closely related to the versicolor-pleei-cesarae group, malitosus is closely related to Amazonian group V, while leucocephalus is closely related to Amazonian group IV. Nevertheless, our genetic analysis could not resolve the genetic relationships among the main C. albifrons groups. The rho-statistic applied to the median-joining network yielded that the major part of the temporal splits estimated occurred in the Pleistocene, reinforcing the importance of the Pleistocene refugia during the evolution of C. albifrons. PMID- 20854918 TI - Memory for reward location is enhanced even though acetylcholine efflux within the amygdala is impaired in rats with damage to the diencephalon produced by thiamine deficiency. AB - A rodent model of diencephalic amnesia produced by thiamine deficiency (pyrithiamine-induced thiamine deficiency [PTD]) was implemented to assess both changes in behavior and acetylcholine (ACh) efflux in the amygdala across four training sessions of a delayed alternation task. Two versions of the delayed alternation task were used. In one version, when a correct alternation was made a unique reward was paired with each spatial location ([left arm-chocolate milk] or [right arm-rat chow]). This paradigm is called the differential outcomes procedure (DOP). In the second version of the task, correct delayed alternation resulted in the same rewards but randomized across location (Nondifferential Outcomes Procedure [NOP]). The PTD rats were impaired on the first session of delayed alternation testing. However, both control and PTD rats using the DOP performed significantly better on delayed alternation than rats trained with the NOP.This effect was driven primarily by the PTD rats in the DOP condition outperforming all other groups on sessions 2-4. Although ACh efflux in the amygdala increased during delayed alternation testing in all groups, the NOP trained rats had a greater rise in training-related ACh release in the post training period. This suggests that increased amygdalar cholinergic activation is more critical for processing spatial information than episodic reward information. These data correspond with the idea that cholinergic activation of the amygdala promotes processing in other neural systems. PMID- 20854919 TI - Prolonged thrombocytopenia following allogeneic hematopoietic stem cell transplantation and its association with a reduction in ploidy and an immaturation of megakaryocytes. AB - Prolonged thrombocytopenia is a frequent complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, its pathogenesis has remained obscure. In the present study, we used flow cytometry to determine the frequency of bone marrow megakaryocytes (MKs) and MK ploidy distributions in allo-HSCT recipients with or without prolonged thrombocytopenia (n = 32 and 27, respectively) and healthy volunteers (n = 13). In addition, the expression of c Mpl in MKs was measured. The results indicate that the proportions of MKs in marrow mononuclear cells or the percentages of CD110(+) MKs in total MKs did not significantly differ between the 3 groups; however, in a comparison of nonthrombocytopenic allo-HSCT recipients to healthy volunteers, the allo-HSCT patients who had prolonged thrombocytopenia exhibited significant shifts toward low ploidy cells (left shift), which were accompanied by a marked increase in <= 8N cells (P = .036 and P < .001, respectively) and significant decreases in 16N cells (P < .001 and P < .001, respectively) and >= 32N cells (P = .01 and P <.001, respectively). These results indicate that there were more immature MKs in allo-HSCT recipients who had prolonged thrombocytopenia, in comparison to nonthrombocytopenic allo-HSCT recipients and healthy volunteers. We conclude that prolonged thrombocytopenia and slow platelet engraftment after allo-HSCT may be related to a reduction in ploidy and an immaturation of MKs. PMID- 20854921 TI - Genomic evidence of repeat-induced point mutation (RIP) in filamentous ascomycetes. AB - The genomes of 49 filamentous ascomycetes (subphylum Pezizomycotina) were examined by two independent methods for evidence of multiple C->T transitions typical of RIP. At least one transposable element or other repeat family was identified in each genome, and members were assessed for transition and transversion mutations relative to a model of their intact progenitor. Occurrence of RIP was indicated where family members differed by excess of directional transitions over transversions. Transition mutations were quantified by an algorithm taking double mutations in CpG and CpC dinucleotides into account. A second method assessed dinucleotide frequency distribution anomalies in whole genomes, a procedure that allowed quantification of fractions of the non-coding genome that had been subject to extensive directional mutation. The results of both methods revealed that RIP-like activity varied greatly, both in extent of mutation and in dinucleotide context for C->T transitions. In the most extreme case, 75% of a Blastomyces dermatitidis genome had suffered conspicuous GC depletion, all of it in the non-coding fraction. Many genomes carried both intact repeats as well as others that had suffered heavily from transitions. Only one species, Chaetomium globosum, showed no evidence of directional mutation. PMID- 20854920 TI - Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation. AB - Patients with hematologic malignancies undergoing allogeneic stem cell transplantation (HSCT) commonly have an elevated serum ferritin prior to HSCT, which has been associated with increased mortality after transplantation. This has led to the suggestion that iron overload is common and deleterious in this patient population. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. We report a prospective study of 48 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) undergoing myeloablative HSCT, using magnetic resonance imaging (MRI) to estimate liver iron content (LIC) and cardiac iron. The median (and range) pre-HSCT value of serum ferritin was 1549 ng/mL (20-6989); serum hepcidin, 59 ng/mL (10-468); labile plasma iron, 0 LPI units (0.0-0.9). Eighty-five percent of patients had hepatic iron overload (HIO), and 42% had significant HIO (LIC >=5.0 mg/gdw). Only 1 patient had cardiac iron overload. There was a strong correlation between pre HSCT serum ferritin and estimated LIC (r = .75), which was mostly dependent on prior transfusion history. Serum hepcidin was appropriately elevated in patients with HIO. Labile plasma iron elevation was rare. A regression calibration analysis supported the hypothesis that elevated pre-HSCT LIC is significantly associated with inferior post-HSCT survival. These results contribute to our understanding of the prevalence, mechanism, and consequences of iron overload in HSCT. PMID- 20854922 TI - Application of carbon fiber composite minielectrodes for measurement of kinetic constants of nitric oxide decay in solution. AB - Carbon fiber microelectrodes and carbon fiber composite minielectrodes (CFM/CFCM) have been generally used for measurements of nitric oxide (NO) concentration in chemical and biological systems. The response time of a CFM/CFCM is usually from milliseconds to seconds depending on the electrode size, the thickness of coating layers on the electrode, and NO diffusion coefficients of the coating layers. As a result, the time course of recoded current changes (I-t curves) by the CFM/CFCM may be different from the actual time course of NO concentration changes (c-t curves) if the half-life of NO decay is close to or shorter than the response time of the electrode used. This adds complexity to the process for determining rate constants of NO decay kinetics from the recorded current curves (I-t curves). By computer simulations based on a mathematical model, an approximation method was developed for determining rate constants of NO decay from the recorded current curves. This method was first tested and valuated using a commercial CFCM in several simple reaction systems with known rate constants. The response time of the CFCM was measured as 4.7+/-0.7 s (n=5). The determined rate constants of NO volatilization and NO autoxidation in our measurement system at 37 degrees C are (1.9+/-0.1)*10(-3) s(-1) (n=4) and (2.0+/-0.3)*10(3) M(-1) s(-1) (n=7), which are close to the reported rate constants. The method was then applied to determine the rate of NO decay in blood samples from control and smoking exposed mice. It was observed that the NO decay rate in the smoking group is >20% higher than that in control group, and the increased NO decay rate in the smoking group was reversed by 10 MUM diphenyleneiodonium chloride (DPI), an inhibitor of flavin enzymes such as leukocyte NADPH oxidase. PMID- 20854923 TI - Prediction of nitric oxide concentrations in melanomas. AB - The presence of iNOS and nitrotyrosine in cutaneous melanomas has been correlated with poor survival rates of patients, suggesting that NO plays a role in the tumor pathophysiology. However, the concentrations of NO that melanoma cells are exposed to in vivo have been unknown. To provide cell kinetic data for use in predicting those concentrations, synthesis and consumption of NO was examined in A375 melanoma cells. Nitric oxide synthesis was undetectable. The rate of intracellular NO consumption was determined by continuous monitoring of NO concentrations following injection of NO solutions in a closed chamber. After correcting for autoxidation and consumption from media-generated O(2)(-), the rate constant obtained for cellular consumption was 7.1+/-1.1 s(-1). This information was combined with previous data on macrophage NO kinetics to develop a mathematical model to predict NO levels in cutaneous melanomas. Synthesis of NO by macrophages in the stroma was found to give a maximum concentration at the tumor periphery of 0.2 MUM. Because of the high rates of cellular consumption, the elevation in NO concentration is predicted to be very localized, approximately 90% of the concentration decay occurring within 30 MUm of the tumor edge. High NO concentrations at the periphery of a melanoma may contribute to metastasis by stimulating cell proliferation, inhibiting apoptosis, or acting as a lymphangiogenic factor. PMID- 20854924 TI - Metabolic engineering of Saccharomyces cerevisiae for the biotechnological production of succinic acid. AB - The production of bio-based succinic acid is receiving great attention, and several predominantly prokaryotic organisms have been evaluated for this purpose. In this study we report on the suitability of the highly acid- and osmotolerant yeast Saccharomyces cerevisiae as a succinic acid production host. We implemented a metabolic engineering strategy for the oxidative production of succinic acid in yeast by deletion of the genes SDH1, SDH2, IDH1 and IDP1. The engineered strains harbor a TCA cycle that is completely interrupted after the intermediates isocitrate and succinate. The strains show no serious growth constraints on glucose. In glucose-grown shake flask cultures, the quadruple deletion strain Deltasdh1Deltasdh2Deltaidh1Deltaidp1 produces succinic acid at a titer of 3.62 g L(-1) (factor 4.8 compared to wild-type) at a yield of 0.11 mol (mol glucose)( 1). Succinic acid is not accumulated intracellularly. This makes the yeast S. cerevisiae a suitable and promising candidate for the biotechnological production of succinic acid on an industrial scale. PMID- 20854925 TI - N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. AB - Transcription factor Stat5a/b is critical for prostate cancer cell survival and for prostate xenograft tumor growth. In addition, the Stat5a/b signaling pathway may contribute to progression of organ-confined prostate cancer to castration resistant and/or metastatic disease. Expression of nuclear Stat5a/b is clustered to high grade human prostate cancers, and nuclear Stat5a/b in primary prostate cancer predicts early disease recurrence after initial treatment. Here, we show by Western blotting and electromobility shift assay that Stat5a/b protein in human prostate cancer is N-terminally truncated. This short form of Stat5a/b is generated post-translationally in vivo in prostate cancer cells and is the predominant form of Stat5a/b that binds to DNA. We further demonstrate by mutagenesis and co-immunoprecipitations that the N-domain of Stat5a/b is required for binding to PIAS3, and that PIAS3 inhibits transcriptional activity of Stat5a/b in breast cancer cells but not in prostate cancer cells. Thus, the proteolytic cleavage of the N-terminus of Stat5a/b may be a mechanism by which Stat5 evades the transcriptional repression by PIAS3 in prostate cancer cells, and results in increased Stat5-driven gene expression and prostate cancer progression. PMID- 20854926 TI - Non-steroidal anti-inflammatory drugs inhibit calpain activity and membrane localization of calpain 2 protease. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are used frequently worldwide for the alleviation of pain despite their capacity to cause adverse gastrointestinal (GI) side effects. GI toxicity, once thought to be the result of non-specific inhibition of cyclooxegenase (COX) enzymes, is now hypothesized to have multiple other causes that are COX independent. In particular, NSAIDs inhibit intestinal epithelial restitution, the process by which barrier function in intestinal mucosa is restored at sites of epithelial wounds within hours through cell spreading and migration. Accordingly, recent evidence indicates that the expression of calpain proteases, which play a key role in cell migration, is decreased by NSAIDs that inhibit cell migration in intestinal epithelial cells (IEC). Here, we examine the effect of NSAIDs on calpain activity and membrane expression in IEC-6 cells. Indomethacin, NS-398, and SC-560 inhibited calpain activity and decreased expression of calpain 2 in total membrane fractions and in plasma membranes involved in cell attachment to the substrate. Additionally, we demonstrated that inhibition of calpain activity by NSAIDs or ALLM, a calpain inhibitor, limits cell migration and in vitro wound healing of IEC-6 cells. Our results indicate that NSAIDs may inhibit cell migration by decreasing calpain activity and membrane-associated expression of calpain 2. Our results provide valuable insight into the mechanisms behind NSAID-induced GI toxicity and provide a potential pathway through which these negative side effects can be avoided in future members of the NSAID class. PMID- 20854927 TI - Strategies in case of positive in vivo results in genotoxicity testing. AB - At the 2009 International Workshop on Genotoxicity Testing in Basel, an expert group gathered to provide guidance on suitable follow-up tests to describe risk when basic in vivo genotoxicity tests have yielded positive results. The working group agreed that non-linear dose-response curves occur in vivo with at least some DNA-reactive agents. Quantitative risk assessment in such cases requires the use of (1) adequate data, i.e., the use of all available data for the selection of reliable in vivo models to be used for quantitative risk assessment, (2) appropriate mathematical models and statistical analysis for characterizing the dose-response relationships and allowing the use of quantitative and dose response information in the interpretation of results, (3) mode of action (MOA) information for the evaluation and analysis of risk, and (4) reliable assessments of the internal dose across species for deriving acceptable margins of exposure and risk levels. Hence, the elucidation of MOA and understanding of the mechanism underlying the dose-response curve are important components of risk assessment. The group agreed on the need for (i) the development of in vivo assays, especially multi-endpoint, multi-species assays, with emphasis on those applicable to humans, and (ii) consensus about the most appropriate mathematical models and statistical analyses for defining non-linear dose-responses and exposure levels associated with acceptable risk. PMID- 20854928 TI - The end is near....of tinkering that is. PMID- 20854929 TI - Medical device reuse: the return of Robin Hood? PMID- 20854930 TI - Sertraline vs. ELectrical Current Therapy for Treating Depression Clinical Trial- SELECT TDCS: design, rationale and objectives. AB - BACKGROUND: Despite significant advancements in psychopharmacology, treating major depressive disorder (MDD) is still a challenge considering the efficacy, tolerability, safety, and economical costs of most antidepressant drugs. One approach that has been increasingly investigated is modulation of cortical activity with tools of non-invasive brain stimulation - such as transcranial magnetic stimulation and transcranial direct current stimulation (tDCS). Due to its profile, tDCS seems to be a safe and affordable approach. METHODS AND DESIGN: The SELECT TDCS trial aims to compare sertraline vs. tDCS in a double-blinded, randomized, factorial trial enrolling 120 participants to be allocated to four groups to receive sertraline+tDCS, sertraline, tDCS or placebo. Eligibility criteria are moderate-to-severe unipolar depression (Hamilton Depression Rating Scale >17) not currently on sertraline treatment. Treatment will last 6weeks and the primary outcome is depression change in the Montgomery-Asberg Depression Rating Score (MADRS). Potential biological markers that mediate response, such as BDNF serum levels, Val66Met BDNF polymorphism, and heart rate variability will also be examined. A neuropsychological battery with a focus on executive functioning will be administered. DISCUSSION: With this design we will be able to investigate whether tDCS is more effective than placebo in a sample of patients free of antidepressants and in addition, we will be able to secondarily compare the effect sizes of sertraline vs. tDCS and also the comparison between tDCS and combination of tDCS and sertraline. PMID- 20854931 TI - Brain magnetic resonance imaging in adults with asthma. AB - BACKGROUND: In individuals with asthma, potential central nervous system changes can occur as a consequence of their asthma or therapy. Clinical trials of anti asthmatic therapies might benefit from using magnetic resonance imaging (MRI) to assess potential brain abnormalities. PURPOSE: As part of the clinical safety evaluation of a monoclonal antibody directed against interleukin-9 for the treatment of asthma, we assessed whether brain MRI is an appropriate screening tool to evaluate potential neurotoxicity. METHODS: Brain MRIs were conducted as part of a prespecified safety evaluation in adults aged 19 to 47 years with mild to moderate asthma treated with either the investigational monoclonal antibody or placebo. An independent neuroradiologist performed a blinded review of brain MRI scans obtained at baseline before dosing and day 28 after dosing from two separate clinical studies. RESULTS: Fifteen brain MRI abnormalities were noted in 13 of 21 subjects with asthma (62%). Nonspecific deep white matter hyperintensities (24%), perivascular space (24%), and abnormal anatomic findings (14%) were noted either at baseline or follow-up. Only 8 of 21 subjects (38%) with asthma had normal brain MRI results. CONCLUSIONS: The high rate of incidental brain MRI findings suggests that these abnormalities are relatively common in patients with asthma. Thus, brain MRI may not be an appropriate screening tool to evaluate potential neurotoxicity in subjects during routine clinical studies without a baseline examination. Due to artifacts simulating lesions, an experienced radiologist should interpret all brain MRI results. PMID- 20854932 TI - Safety and effectiveness of antiretroviral drugs during pregnancy, delivery and breastfeeding for prevention of mother-to-child transmission of HIV-1: the Kesho Bora Multicentre Collaborative Study rationale, design, and implementation challenges. AB - To evaluate strategies to reduce HIV-1 transmission through breastfeeding, a multicentre study including a nested randomized controlled trial was implemented in five research sites in West, East and South Africa (The Kesho Bora Study). The aim was to optimize the use of antiretroviral (ARV) drugs during pregnancy, delivery and breastfeeding to prevent mother-to-child transmission of HIV-1 (PMTCT) and to preserve the health of the HIV-1-infected mother. The study included long-term ARV treatment for women with advanced disease, and short course ARV prophylaxis stopped at delivery for women with early disease. Women with intermediate disease participated in a randomized controlled trial to compare safety and efficacy of triple-ARV prophylaxis prolonged during breastfeeding with short-course ARV prophylaxis stopped at delivery. Between January 2005 and August 2008 a total of 1140 women were enrolled. This paper describes the study design, interventions and protocol amendments introduced to adapt to evolving scientific knowledge, international guidelines and availability of ARV treatment. The paper highlights the successes and challenges during the conduct of the trial. The Kesho Bora Study included one of the few randomized controlled trials to assess safety and efficacy of ARV prophylaxis continued during breastfeeding and the only randomized trial to assess maternal prophylaxis started during pregnancy. The findings have been important for informing international and national guidelines on MTCT prevention in developing countries where, due to poverty, lack of reliable and affordable supply of replacement feed and stigma associated with HIV/AIDS, HIV-infected women have little or no option other than to breastfeed their infants. (ISRCTN71468401). PMID- 20854933 TI - Diversity of Orientia tsutsugamushi clinical isolates in Cambodia reveals active selection and recombination process. AB - Orientia tsutsugamushi, the causative agent of scrub typhus in South East Asia and Pacific, is an obligate intracellular bacterium closely related to the Rickettsia. The pathogen is transmitted to humans through the bites of infected larvae of trombiculid mites of the genus Leptotrombidium in which is maintained trough vertical transmission mechanism. The infection in rodents has been described in over 20 species. Scrub typhus is commonly confused with other tropical fevers and late diagnosis and treatment can lead to severe organ failures and a strain-dependent mortality rate of up to 50%. A MLST scheme associating seven core function genes: adk, lepB, lipA, lipB, secY, sodB and sucA was developed and validated on seven Cambodian strains detected in patients and two complete reference genomes from Korea and Japan. Sequence data were analyzed both with respect to sequence type (ST) diversity and DNA polymorphism. Differing trends were revealed. DNA polymorphism and phylogeny of individual gene loci indicated a significant level of recombination and genetic diversity. However, the ST distribution is clearly clonal and the clinical situation can be summarized by the formula: one patient, one strain, one ST. This contradiction is only apparent and is most likely the consequence of the unique life cycle of O. tsutsugamushi. The quasi exclusive vertical transmission mode in mites generates repeated bottlenecks and small-size populations and strongly limits genetic diversity. O. tsutsugamushi has developed specific mechanisms for generating genetic diversity which include recombination, duplication and conjugation. Recombination and other mechanisms for increasing genetic diversity are likely to occur in rodents which can act as maintenance hosts, although occurrence in mites cannot be excluded. Consequences for the epidemiology of scrub typhus are discussed. PMID- 20854934 TI - What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes. AB - Allotopic expression is potentially a gene therapy for mtDNA-related diseases. Some OXPHOS proteins like ATP6 (subunit a of complex V) and COX3 (subunit III of complex IV) that are typically mtDNA-encoded, are naturally nucleus-encoded in the alga Chlamydomonas reinhardtii. The mitochondrial proteins whose genes have been relocated to the nucleus exhibit long mitochondrial targeting sequences ranging from 100 to 140 residues and a diminished overall mean hydrophobicity when compared with their mtDNA-encoded counterparts. We explored the allotopic expression of the human gene products COX3 and ATP6 that were re-designed for mitochondrial import by emulating the structural properties of the corresponding algal proteins. In vivo and in vitro data in homoplasmic human mutant cells carrying either a T8993G mutation in the mitochondrial atp6 gene or a 15bp deletion in the mtDNA-encoded cox3 gene suggest that these human mitochondrial proteins re-designed for nuclear expression are targeted to the mitochondria, but fail to functionally integrate into their corresponding OXPHOS complexes. PMID- 20854935 TI - Clinical and laboratory aspects of Ro/SSA-52 autoantibodies. AB - Anti-Ro/SSA antibodies, which were described for the first time in systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS), are the most prevalent extractable nuclear antigen (ENA) specificity identified in laboratories. Two types of anti-Ro/SSA antibodies have been described, anti-SSA-52 kDa (aSSA52) and anti-SSA-60 kDa (aSSA60), each specific to different antigens. Anti-Ro/SSA52 autoantibodies are more frequent than other autoantibodies possibly because of the antigen's accessible and ubiquitous nature. The sites involved and the symptoms associated with these autoantibodies depend on the antigen's structural variability. Isolated congenital complete atrioventricular block (CAVB) shows a close association with maternal anti-Ro/SSA and anti-La/SSB antibodies; the highest relative risks of CAVB are seen in offspring of mothers with antibodies against 52-kDa Ro and 48-kDa La proteins. Anti-Ro/SSA52 antibodies have little impact on adult rheumatic autoimmune diseases or adult cardiac arrhythmias, but the course of autoimmune liver diseases is greatly worsened by their presence, and solid tumours tend to relapse. Their diagnostic role in rheumatic diseases is controversial, although a significant association between isolated anti-Ro/SSA52 kDa positivity and myositis and to a lesser extent with systemic sclerosis (SSc) has been described. However, the majority of the specific diagnosis is mostly based on the simultaneous presence of other autoantibodies that seems diagnostically more relevant. PMID- 20854936 TI - Evaluation and comparison of nasal airway flow patterns among three subjects from Caucasian, Chinese and Indian ethnic groups using computational fluid dynamics simulation. AB - Nasal airflow is one of the most important determinants for nasal physiology. During the long evolution of human beings, different races have developed their own attributes of nasal morphologies which result in variations of nasal airflow patterns and nasal functions. This study evaluated and compared the effects of differences of nasal morphology among three healthy male subjects from Caucasian, Chinese and Indian ethnic groups on nasal airflow patterns using computational fluid dynamics simulation. By examining the anterior nasal airway, the nasal indices and the nostril shapes of the three subjects were found to be similar to nasal cavities of respective ethnic groups. Computed tomography images of these three subjects were obtained to reconstruct 3-dimensional models of nasal cavities. To retain the flow characteristics around the nasal vestibules, a 40 mm radius semi sphere was assembled around the human face for the prescription of zero ambient gauge pressure. The results show that more airflow tends to pass through the middle passage of the nasal airway in the Caucasian model, and through the inferior portion in the Indian model. The Indian model was found with extremely low flow flux flowing through the olfactory region. The sizes of vortexes near the anterior cavity were found to be correlated with the angles between the upper nasal valve wall and the anterior head of the nasal cavity. PMID- 20854937 TI - Low temperature degradation of a Y-TZP dental ceramic. AB - Bars of Y-TZP ceramic for dental restorations were subjected to hydrothermal degradation via in vitro exposure to water steam at 140 degrees C for 7 days. X ray diffraction, atomic force microscopy and scanning electron microscopy techniques were applied to observe and quantify the tetragonal-monoclinic (t-m) phase transformation associated with the process. Nanoindentation was used to assess the ceramic's mechanical properties before and after hydrothermal degradation. Texture associated with martensitic t-m transformation was observed at the grain surface. The t-m transformation followed nucleation-and-growth kinetics, with predominance of the nucleation process. The transformation occurred within a layer of 6 MUm below the surface. Mechanical properties deteriorated with hydrothermal degradation, resulting in a 30% reduction of Young's modulus and hardness. A strong correlation was found between the increasing monoclinic fraction and the decline in mechanical response. It was thus concluded that the emergence of the monoclinic phase and the associated microcracking were the most likely causes for the degradation of mechanical properties. PMID- 20854938 TI - Study of a novel ultrasonically triggered drug vehicle with magnetic resonance properties. AB - We developed a novel ultrasonically triggered drug vehicle with magnetic resonance (MR) properties by encapsulating superparamagnetic iron oxide (SPIO) nanoparticles in hydroxyapatite (HA)-coated liposomes. The effects of HA coating on the background leakage, ultrasound response and MR signal were investigated. HA coating of liposomes significantly reduced the background leakage of liposome. It also enhanced their sensitivity to ultrasound regardless of HA thickness or ultrasound frequency, even under sonication conditions of high frequency (1 and 3 MHz) and low power density (0.2-0.4 Wcm(-2)) used for diagnosis. However, it was found that the ultrasonically triggered vehicle could exhibit T(2) contrast in MR images by encapsulating SPIO. However, HA coating reduced the r(2) value of SPIO encapsulated in liposomes, but had no significant effect on the r(2)(*) value, implying that MR images of HA-coated liposomes encapsulating SPIO could be probed by the T(2)(*) signal. Most importantly, the r(2)(*)-r(2) value of HA-coated liposomes encapsulating SPIO decreased after sonication, suggesting that the proposed vehicle could be used not only as a MR-guided drug vehicle capable of ultrasonically triggered release but also as a MR reporter to probe ultrasonic triggering. PMID- 20854939 TI - Compositionally graded hydroxyapatite/tricalcium phosphate coating on Ti by laser and induction plasma. AB - In this study we report the fabrication of compositionally graded hydroxyapatite (HA) coatings on Ti by combining laser engineering net shaping (LENS) and radio frequency induction plasma spraying processes. Initially, HA powder was embedded in the Ti substrates using LENS, forming a Ti-HA composite layer. Later, RF induction plasma spraying was used to deposit HA on these Ti substrates with a Ti HA composite layer on top. Phase analysis by X-ray diffraction indicated phase transformation of HA to beta-tricalcium phosphate in the laser processed coating. Laser processed coatings showed the formation of a metallurgically sound and diffused substrate-coating interface, which significantly increased the coating hardness to 922 +/- 183 Hv from that of the base metal hardness of 189 +/- 22 Hv. In the laser processed multilayer coating a compositionally graded nature was successfully achieved, however, with severe cracking and a consequent decrease in the flexural strength of the coating. To obtain a structurally stable coating with a composition gradient across the coating thickness a phase pure HA layer was sprayed on top of the laser processed single layer coatings using induction plasma spray. The plasma sprayed HA coatings were strongly adherent to the LENS TCP coatings, with adhesive bond strength of 21 MPa. In vitro biocompatibility of these coatings, using human fetal osteoblast cells, showed a clear improvement in cellular activity from uncoated Ti compared with LENS-TCP-coated Ti and reached a maximum in the plasma sprayed HA coating. PMID- 20854940 TI - Investigation of alendronate-doped apatitic cements as a potential technology for the prevention of osteoporotic hip fractures: critical influence of the drug introduction mode on the in vitro cement properties. AB - Combination of a bisphosphonate (BP) anti-osteoporotic drug, alendronate, with an apatitic calcium phosphate cement does not significantly affect the main properties of the biomaterial, in terms of injectability and setting time, provided that the BP is introduced chemisorbed onto calcium-deficient apatite, one of the components of the cement. In contrast to other modes of introducing the BP into the cement formulation, this mode allows to minimize alendronate release in the cement paste, thus limiting the setting retardant effect of the BP. An original approach based on high frequency impedance measurements is found to be a convenient method for in situ monitoring of the cement setting reaction. The release profile of the drug from a cement block under continuous flow conditions can be well described using a coupled chemistry/transport model, under simulated in vivo conditions. The results show that the released alendronate concentration is expected to be much lower than the cytotoxic concentration. PMID- 20854941 TI - Assessment of using laponite cross-linked poly(ethylene oxide) for controlled cell adhesion and mineralization. AB - The in vitro cytocompatibility of silicate (Laponite clay) cross-linked poly(ethylene oxide) (PEO) nanocomposite films using MC3T3-E1 mouse preosteoblast cells was investigated while cell adhesion, spreading, proliferation and mineralization were assessed as a function of film composition. By combining the advantageous characteristics of PEO polymer (hydrophilic, prevents protein and cell adhesion) with those of a synthetic and layered silicate (charged, degradable and potentially bioactive) some of the physical and chemical properties of the resulting polymer nanocomposites could be controlled. Hydration, dissolution and mechanical properties were examined and related to cell adhesion. Overall, this feasibility study demonstrates the ability of using model Laponite cross-linked PEO nanocomposites to create bioactive scaffolds. PMID- 20854942 TI - Skeletal complications and survival in renal cancer patients with bone metastases. AB - Skeletal metastases occur in around one third of patients with advanced or metastatic renal cell carcinoma (RCC). Skeletal involvement is commonly an aggressive, lytic process which causes substantial morbidity through skeletal complications and occurrence of skeletal related events (SREs). However, compared with bone metastases in breast and prostate cancer, there is a paucity of data relating to the demographics of bone metastases in RCC and their sequelae in terms of SREs and survival. The study population included all patients (N=803) with advanced or metastatic RCC treated in a tertiary centre serving a regional population of 2.6 million between 1998 and 2007. Demographic and survival data and information relating to metastatic disease were extracted from electronic records. Thirty-two percent (N=254) of the study population presented with (N=131) or later developed (N=123) bone metastases and 83% of these (N=210) also developed metastases elsewhere. The mean number of SREs experienced by the bone metastatic patients over the course of their disease was 2.4 and only 37 patients experienced no SRE. A high proportion of patients (80%) received radiotherapy for bone pain and there was a surprising and strikingly high incidence of spinal cord/nerve root compression, which was experienced by 28% patients. Although bisphosphonate use increased following the availability of zoledronic acid in 2004, approximately 50% patients with bone metastases did not receive bisphosphonate treatment. The skeletal morbidity rate (number of SREs per patient years at risk) was 1.0 and 1.4 for patients who received or did not receive bisphosphonates, respectively. The median survival following diagnosis of RCC was similar in patients who developed bone metastases (20.4 months) and those who did not (20.9 months). Median survival from diagnosis of metastases was 13.3 months for those who never developed bone metastases, 10.6 months for those who presented with them, 19.6 months for those who developed them later and 22.6 months for patients who had bone only metastases. This is the largest study to date focusing specifically on skeletal complications in RCC. A striking finding was the high incidence of spinal cord/nerve root compression and more research into this area is needed. Clearer, internationally accepted guidelines are recommended for the management of this patient group. PMID- 20854943 TI - Ameloblastin expression and putative autoregulation in mesenchymal cells suggest a role in early bone formation and repair. AB - Ameloblastin is mainly known as a dental enamel protein, synthesized and secreted into developing enamel matrix by the enamel-forming ameloblasts. The function of ameloblastin in tooth development remains unclear, but it has been suggested to be involved in processes varying from regulating crystal growth to activity as a growth factor or partaking in cell signaling. Recent studies suggest that some enamel matrix proteins also might have important functions outside enamel formation. In this context ameloblastin has recently been reported to induce dentin and bone repair, as well as being present in the early bone and cartilage extracellular matrices during embryogenesis. However, what cells express ameloblastin in these tissues still remains unclear. Thus, the expression of ameloblastin was examined in cultured primary mesenchymal cells and in vivo during healing of bone defects in a "proof of concept" animal study. Real time RT PCR analysis revealed human ameloblastin (AMBN) mRNA expression in human mesenchymal stem cells and primary osteoblasts and chondrocytes. Expression of AMBN mRNA was also confirmed in human CD34 positive cells and osteoclasts. Western and dot blot analysis of cell lysates and medium confirmed the expression and secretion of ameloblastin from mesenchymal stem cells, primary human osteoblasts and chondrocytes. Expression of ameloblastin was also detected in newly formed bone in experimental bone defects in adult rats. Together these findings suggest a role for this protein in early bone formation and repair. PMID- 20854945 TI - Kashin-Beck disease and Sayiwak disease in China: prevalence and a comparison of the clinical manifestations, familial aggregation, and heritability. AB - OBJECTIVE: To compare the prevalence, the clinical manifestations, familial aggregation and heritability of Kashin-Beck disease (KBD) and Sayiwak disease (SD) in China. METHODS: 10,823 people from 1361 families in 14 villages in Linyou County, Shaanxi Province, were examined for KBD, and 2264 people from 552 families in Sayiwak village, Kashi city, Xinjiang, were examined for SD. The investigation included documentation of individual information and clinical manifestations. Patients were subject to radiographic imaging of the right hand. t-Tests and chi-square tests were used to examine correlations of the diseases with age and gender in each of the two groups. Analysis of familial aggregation was conducted with the chi-square distribution analysis of goodness of fit using the SAS8.0 program. The Li-Mantel-Gart method was employed for the segregation analysis. The Falconer regression method11 was employed to estimate heritability (h2). RESULTS: The prevalence of KBD in Linyou County was 10.90%, and of SD in Sayiwak village was 0.57%. Of the 21 clinical signs examined, KBD cases exhibited 19 signs (90.48%) and SD cases exhibited 18 signs (85.71%), which indicate similarities between the two diseases. However, different clinical signs were evident between the KBD and SD cases, with different impairment rates among joints of limbs in KBD and similar rates in SD. A comparison of radiological features of limb arthropathy between the two diseases showed differences in several characteristics between the two diseases. In addition, measurements of stature and sitting height showed significant differences in bone development between the two diseases. For KBD cases, the values of h2 in the first-degree and the second-degree relatives were 41.76% and 37.20% (P<0.05). The CI of h2 was 31.17-52.38 and 19.86-54.55, with a segregation ratio of P=0.12, SE(P)=0.014, 95%CI 0.09-0.15, less than 0.25(chi2=42.36, df=1, P<0.001). For SD cases, the values of h2 were 155.61%, 273.63% and 236.83%. The 95% CIs of h2 were 133.20 178.12, 229.83-317.42 and 145.83-327.81, respectively, with a segregation ratio of P=0.34, SE(P)=0.059, and CIs between 0.22 and 0.45(chi2=4.9817, df=1, P>0.05). CONCLUSION: The results indicate both similarities and differences in the clinical manifestations of KBD and SD. However, environmental factors appear to play a major role in KBD, while hereditability is a major factor in SD. PMID- 20854944 TI - Sustained blockade of neurotrophin receptors TrkA, TrkB and TrkC reduces non malignant skeletal pain but not the maintenance of sensory and sympathetic nerve fibers. AB - Current therapies for treating skeletal pain have significant limitations as available drugs (non-steroidal anti-inflammatory drugs and opiates) have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomysin receptor kinase A (TrkA) has recently become an attractive target for inhibition of adult skeletal pain. Here we explore whether sustained administration of a selective small molecule Trk inhibitor that blocks TrkA, TrkB and TrkC kinase activity with nanomolar affinity reduces skeletal pain while allowing the maintenance of sensory and sympathetic neurons in the adult mouse. Twice-daily administration of a Trk inhibitor was begun 1 day post fracture and within 8 h of acute administration fracture pain-related behaviors were reduced by 50% without significant sedation, weight gain or inhibition of fracture healing. Following administration of the Trk inhibitor for 7 weeks, there was no significant decline in the density of unmyelinated or myelinated sensory nerve fibers, sympathetic nerve fibers, measures of acute thermal pain, acute mechanical pain, or general neuromuscular function. The present results suggest that sustained administration of a peripherally selective TrkA, B and C inhibitor significantly reduces skeletal pain without having any obvious detrimental effects on adult sensory and sympathetic nerve fibers or early fracture healing. As with any potential therapeutic advance, understanding whether the benefits of Trk blockade are associated with any risks or unexpected effects will be required to fully appreciate the patient populations that may benefit from this therapeutic approach. PMID- 20854946 TI - RANKL and OPG activity is regulated by injury size in networks of osteocyte-like cells. AB - Bone remodelling is an intricate process encompassing numerous paracrine and autocrine biochemical pathways and mechanical mechanisms. It is responsible for maintaining bone homeostasis, structural integrity and function. The RANKL-RANK OPG cytokine system is one of the principal mediators in the maintenance of bone cell function and activation of bone remodelling by the Basic Multicellular Unit (BMU) which carries out remodelling. Theories surrounding the initiation of bone remodelling include mechanical loading, fluid flow and microdamage as potential stimuli. This study focused on microdamage. In an in vitro simulated bone environment, gel embedded MLO-Y4 cell networks were subjected to damage in the form of planar, crack-like defects of constant area and varying thickness. The biochemical response was determined by ELISA and luciferase assay. The results showed that RANKL release increased and OPG decreased in a manner which depended on injury size (i.e. thickness) and time following application of injury. The effect of microdamage on cell viability and apoptosis was also evaluated. This work demonstrates that injury alone, in the absence of imposed strain or fluid flow, is sufficient to initiate changes in cytokine concentrations of the type which are known to stimulate bone remodeling. PMID- 20854947 TI - Constitutively expressed COX-2 in osteoblasts positively regulates Akt signal transduction via suppression of PTEN activity. AB - Cyclooxygenase-2 (COX-2) is thought to be an inducible enzyme, but increasing reports indicate that COX-2 is constitutively expressed in several organs. The status of COX-2 expression in bone and its physiological role remains undefined. Non-selective non-steroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, which commonly suppress COX-2 activity, were reported to suppress osteoblast proliferation via Akt/FOXO3a/p27(Kip1) signaling, suggesting that COX 2 may be the key factor of the suppressive effects of NSAIDs on proliferation. Although Akt activation correlates with PTEN deficiency and cell viability, the role of COX-2 on PTEN/Akt regulation remains unclear. In this study, we hypothesized that COX-2 may be constitutively expressed in osteoblasts and regulate PTEN/Akt-related proliferation. We examined the localization and co expression of COX-2 and p-Akt in normal mouse femurs and in cultured mouse (mOBs) and human osteoblasts (hOBs). Our results showed that osteoblasts adjacent to the trabeculae, periosteum and endosteum in mouse femurs constitutively expressed COX 2, while COX-2 co-expressed with p-Akt in osteoblasts sitting adjacent to trabeculae in vivo, and in mOBs and hOBs in vitro. We further used COX-2 siRNA to test the role of COX-2 in Akt signaling in hOBs; COX-2 silencing significantly inhibited PTEN phosphorylation, enhanced PTEN activity, and suppressed p-Akt level and proliferation. However, replenishment of the COX-2 enzymatic product, PGE2, failed to reverse COX-2-dependent Akt phosphorylation. Furthermore, transfection with recombinant human COX-2 (rhCOX-2) significantly reversed COX-2 siRNA-suppressed PTEN phosphorylation, but this effect was reduced when the enzymatic activity of rhCOX-2 was blocked. This finding indicated that the effect of COX-2 on PTEN/Akt signaling is not related to PGE2 but still dependent on COX 2 enzymatic activity. Conversely, COX-1 silencing did not affect PTEN/Akt signaling. Our findings provide new insight into bone physiology; namely, that COX-2 is constitutively expressed in osteoblasts in the dynamic bone growth area, which facilitates osteoblast proliferation via PTEN/Akt/p27(Kip1) signaling. PMID- 20854948 TI - [Gender patterns in Spanish otolaryngologic doctoral theses]. AB - INTRODUCTION AND OBJECTIVE: In last decades women in Spain have a greater access to postgraduate education. The objective of this study was to perform a gender analysis on the Otolaryngology doctoral theses presented in a 25 year-period. METHODS: The TESEO data base on doctoral theses was searched for theses on Otorhinolaryngology written between 1981 and 2005. As strategy for the research we employed the terms: 1) Otorrinolaringologia (Otorhinolaryngology); 2) Cirugia de garganta, nariz y oidos (Ear, nose and throat surgery); 3) Fisiologia de la audicion (Physiology of hearing); 4) Fisiologia del equilibrio (Physiology of balance); 5) Fisica de la audicion (Physics of hearing); and 6) Bioacustica (Bioacoustics). RESULTS: A total of 450 theses (18.0+/-8.3 theses/year) were found, of which 129 were written by females (28.6%). There was a gender imbalance among authors, with 5.2+/-3.4 theses/year for women vs. 12.9+/-6.6 theses/year for men (p=0.0002). Nevertheless, there was a tendency toward equality in the last 10 years (p=0.001). On the other hand, the PhD student's gender was clearly related to the supervisor's gender (p=0.0001). With respect to the main topics in our area (otology, audiology/vestibular diseases, rhinology and pathology of paranasal sinuses and neck diseases), there were no significant differences between males and females (p=0.231). CONCLUSIONS: These results indicate a tendency towards equality in the number of men and women successfully completing doctoral studies in Otolaryngology. However, the PhD student's gender is clearly related to the supervisor's gender. PMID- 20854949 TI - Risk of all-cause mortality, recurrent myocardial infarction, and heart failure hospitalization associated with smoking status following myocardial infarction with left ventricular dysfunction. AB - Patients with left ventricular (LV) systolic dysfunction after myocardial infarction (MI) are at particularly high risk for recurrent adverse outcomes. The magnitude of the decrease in risk associated with smoking cessation after MI has not been well described in patients with LV dysfunction after MI. We aimed to quantify the risk decrease associated with smoking cessation in subjects with LV dysfunction after MI. The Survival and Ventricular Enlargement (SAVE) trial randomized 2,231 subjects with LV dysfunction 3 to 16 days after MI. Smoking status was assessed at randomization and at regular intervals during a median follow-up of 42 months. Propensity score-adjusted Cox proportional hazard models were used to quantify the decrease in risk of all-cause mortality, death or recurrent MI, and death or heart failure (HF) hospitalization associated with smoking cessation. In baseline smokers who survived to 6 months without interval events, smoking cessation at 6-month follow-up was associated with a significantly lower adjusted risk of all-cause mortality (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.31 to 0.91), death or recurrent MI (HR 0.68, 95% CI 0.47 to 0.99), and death or HF hospitalization (HR 0.65, 95% CI 0.46 to 0.92). In conclusion, in patients with LV dysfunction after MI, smoking cessation is associated with a 40% lower hazard of all-cause mortality and a 30% lower hazard of death or recurrent MI or death or HF hospitalization. These findings indicate that smoking cessation is beneficial after high-risk MI and highlight the importance of smoking cessation as a therapeutic target in patients with LV dysfunction after MI. PMID- 20854950 TI - Serial assessment of left ventricular remodeling by measurement of left ventricular torsion using speckle tracking echocardiography in patients with acute myocardial infarction. AB - The relation between remodeling and left ventricular (LV) torsion has not yet been fully investigated. The aim of this study was to determine whether LV torsion assessed by speckle tracking imaging can predict progressive LV dilation after acute myocardial infarction (AMI). From January 2006 through June 2008, 91 patients with AMI who were successfully treated with primary coronary intervention underwent conventional and speckle tracking echocardiographies at initial presentation and 3 days and 6 months after first AMI. Patients were divided into 2 groups based on presence of LV remodeling (increase of LV end diastolic volume >20%) at 6-month follow-up. LV remodeling developed in 23 patients. At initial presentation, LV end-diastolic volume was not significantly different between the no-remodeling and remodeling groups (91.27 +/- 35.68 vs 85.74 +/- 28.89 ml, p = 0.51), but LV torsion (2.23 +/- 0.67 vs 1.70 +/- 0.58 degrees /cm, p <0.05) was significantly decreased in the remodeling group. At 6 month follow-up speckle tracking echocardiography, apical rotation and global torsion in patients with remodeling were 6.7 +/- 2.6 (p <0.05) and 1.7 +/- 0.7 degrees /cm (p = 0.76 from baseline), respectively, and in patients without remodeling, 8.8 +/- 3.4 (p <0.01) and 2.5 +/- 0.7 degrees /cm (p <0.01 from baseline), respectively. According to receiver operating characteristic analysis, LV torsion of 1.9 degrees /cm (area under curve 0.79, sensitivity 75%, specificity 78%) at initial presentation was selected as a significant predictor of remodeling. In conclusion, decreased LV torsion assessed by speckle tracking echocardiography may predict late LV remodeling after reperfusion therapy after AMI. PMID- 20854951 TI - Angiographic and magnetic resonance imaging evaluation of in-hospital delay in primary percutaneous intervention delivery on myocardial salvage. AB - Shortening symptom-to-reperfusion time improves prognosis in patients with ST segment elevation myocardial infarction. Accordingly, current guidelines target a door-to-balloon time <90 minutes, irrespective of symptom-to-door time; nevertheless, the relation between door-to-balloon and symptom-to-door time and its potential impact on myocardial salvage remains largely unknown. We investigated the influence of door-to-balloon guideline fulfillment on myocardial salvage in patients presenting with different symptom-to-door times. Contrast enhanced magnetic resonance study was performed acutely to measure infarct size in 172 patients admitted for primary percutaneous coronary intervention of their first ST-segment elevation myocardial infarction to 2 tertiary hospitals. The Bari score was adapted to quantify the angiographic area at risk, and the myocardial salvage index (MSI) was computed as percent area at risk that spared necrosis. Increased symptom-to-balloon time was associated with a significant decrease in MSI only within the first 5 hours (p <0.001). Accomplishment of a target door-to-balloon <90 minutes was associated with a significant increase in MSI only in patients presenting within the first hour of symptom onset (48.5 +/- 30.9 vs 29.6 +/- 22.3%, p <0.05). Achieving a door-to-balloon time <60 minutes further increased MSI in patients presenting within the second hour of symptoms (43.5 +/- 8.6 vs 26.3 +/- 20.5%, p <0.01). In conclusion, myocardial salvage progressively decreases up to 5 hours after symptom onset. However, the benefit of the recommended door-to-balloon time appears to be confined to patients presenting within 1 hour of symptom onset. PMID- 20854952 TI - Implementation of a prehospital triage system for patients with chest pain and logistics for primary percutaneous coronary intervention in the region of Amsterdam, the Netherlands. AB - We aimed to describe the logistics of a prehospital triage system for patients with acute chest pain in the region of Amsterdam, The Netherlands. Ambulance electrocardiograms (ECGs) were evaluated immediately in 1 of the percutaneous coronary intervention (PCI)-capable centers. Patients accepted for primary PCI (PPCI) were directly transferred to the catheterization laboratory. Two thousand three hundred fifty ECGs of 2,192 patients were transmitted to the region's intervention centers. Median duration of chest complaints before ambulance dispatch was 67 minutes; ambulance crews recorded the first ECG within 7 minutes after arrival. Actual transmission of the ECG took an additional (median) 10 minutes. Seven hundred eleven patients (32.4%) were transported to the catheter laboratory and were treated with PPCI. Time between first prehospital ECG and start of PPCI procedure was 66 minutes. The PPCI procedure started 36 minutes after ambulance arrival at the hospital. In conclusion, the results of this study compare favorably to other reported performances of prehospital triage systems of PPCI for ST-segment elevated myocardial infarction and demonstrate that the European Society of Cardiology and American Heart Association guidelines for treatment of patients with ST-segment elevated myocardial infarction can be met. PMID- 20854953 TI - Comparison of radiation dose and the effect of operator experience in femoral and radial arterial access for coronary procedures. AB - Radial access coronary procedures are associated with fewer access site complications compared to femoral access. There is controversy regarding greater radiation exposure to patient and operator using radial access. We aimed to compare radiation dose during coronary procedures for the 2 access routes and assess the effect of operator experience with radial access on radiation dose. Fluoroscopy time (FT) and dose-area product (DAP) were recorded for all radial access and femoral access procedures during default femoral access, transition phase (femoral access and early radial access), and default radial access. Femoral access cases (n = 848, 412 diagnostic, 436 percutaneous coronary interventions [PCIs]) and radial access cases (n = 965, 459 diagnostic, 506 PCIs) were assessed. For diagnostics, median FT for radial access was longer than for femoral access (4.43 minutes, interquartile range [IQR] 2.55 to 8.18, vs 2.34 minutes, IQR 1.49 to 4.18, p <0.001) and associated with larger DAP (radial access 1,837 MUGy.m(2), IQR 1,172 to 2,783, vs femoral access 1,657 MUGy.m(2), IQR 1,064 to 2,376, p <0.001). For PCI, FT was longer for radial access (median 12.02 minutes, IQR 7.57 to 17.54, vs femoral access 9.36 minutes, IQR 6.13 to 14.27, p <0.001)-this did not translate into an increased DAP (femoral access median 3,392 MUGy.m(2), IQR 2,139 to 5,193, vs radial access 3,682 MUGy.m(2), IQR 2,388 to 5,314, p = NS). For diagnostic radial access, FT decreased from the transition phase (n = 134) to the default radial access phase (n = 323, 5.12 minutes, IQR 3.07 to 9.40, vs 4.21 minutes, IQR 2.49 to 7.52, p = 0.03). This was not observed for PCI. In conclusion, transition from femoral access to radial access for diagnostics and PCI increased FT. DAP increased for diagnostic radial access but not PCI compared with femoral access. FTs for radial access diagnostic cases decreased with experience. PMID- 20854954 TI - Comparison of Bivalirudin versus Bivalirudin plus glycoprotein IIb/IIIa inhibitor versus heparin plus glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes having percutaneous intervention for narrowed saphenous vein aorto-coronary grafts (the ACUITY trial investigators). AB - Clinical outcomes in patients with acute coronary syndromes randomized in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial who underwent percutaneous coronary intervention (PCI) of saphenous vein grafts (SVGs) were examined. The ACUITY trial assessed the safety and efficacy of bivalirudin alone versus bivalirudin plus a glycoprotein (GP) IIb/IIIa inhibitor versus heparin plus a GP IIb/IIIa inhibitor in 13,819 patients with moderate- and high-risk acute coronary syndromes, 7,789 of whom underwent PCI. A total of 329 patients (4.2%) underwent PCI of SVGs in ACUITY. The primary end points at 30 days were composite ischemia or major adverse cardiac events (death, myocardial infarction, or unplanned target vessel revascularization), major bleeding (unrelated to coronary artery bypass grafting), and net adverse clinical events (composite ischemia or major bleeding). The rates of ischemic, bleeding, and net clinical end points were similar with bivalirudin monotherapy, bivalirudin plus a GP IIb/IIIa inhibitor, and heparin plus a GP IIb/IIIa inhibitor. Net adverse clinical outcome rates at 30 days were 22%, 26%, and 22% (p = 0.67), respectively, for the 3 groups. Major adverse cardiac event rates at 1 year were 37%, 37%, and 43% (p = 0.95), respectively. Minor bleeding unrelated to coronary artery bypass grafting at 30 days was significantly lower with bivalirudin alone compared with heparin plus a GP IIb/IIIa inhibitor (26% vs 38%, p = 0.05). In conclusion, bivalirudin is an effective anticoagulant in PCI of SVGs in acute coronary syndromes, with similar rates of major adverse cardiac events and net adverse cardiac events and lower minor bleeding complications in comparison with heparin plus a GP IIb/IIIa inhibitor or bivalirudin plus a GP IIb/IIIa inhibitor. PMID- 20854956 TI - Intravascular ultrasound findings of stent fractures in patients with Sirolimus- and Paclitaxel-eluting stents. AB - We compared intravascular ultrasound (IVUS) findings of fractures of sirolimus eluting stents (SESs) versus paclitaxel-eluting stents (PESs). IVUS findings in 6 PES fractures (all in the right coronary artery) in 6 patients from a clinical trial cohort were compared to 14 SES fractures (8 in the right coronary artery, 2 in the left anterior descending coronary artery, and 4 in the left circumflex coronary artery) in 13 patients from our institutional cohort. Comparing PES fractures to SES fractures, IVUS analysis showed (1) similar frequency of complete stent fracture (1 of 6, 17%, vs 3 of 14, 21%, p >0.99), (2) similar frequency of fracture adjacent to calcified plaque or stent metal overlap (5 of 6, 86%, vs 14 of 14, 100%, p = 0.99), (3) more frequent complete malalignment of proximal and distal fragments in PES strut fractures compared to SES fractures (5 of 6, 83%, vs 1 of 14, 7%, p = 0.002), (4) similar stent lengths (45.2 mm, 23.8 to 50.7, vs 39.3 mm, 22.6 to 73.4, p >0.99), (5) similar fracture lengths (0.5 mm, 0.4 to 0.7, vs 0.7 mm, 0.6 to 1.0, p = 0.14), and (6) larger reference external elastic membrane area (15.0 mm(2), 13.5 to 18.0, vs 10.4 mm(2), 6.8 to 13.6, p = 0.01). In conclusion, malalignment of proximal and distal stent fragments more often occurred in PES fractures compared to SES fractures; otherwise the IVUS features of PES and SES fractures were similar. PMID- 20854955 TI - Comparison of drug-eluting and bare metal stents for saphenous vein graft lesions (from the National Heart, Lung, and Blood Institute Dynamic Registry). AB - The effectiveness and safety of drug-eluting stents (DES) compared with bare metal stents (BMS) in saphenous vein graft (SVG) disease remains unclear. In particular, there is a paucity of data on long-term outcomes. In this study, 395 patients enrolled in the National Heart, Lung, and Blood Institute Dynamic Registry who underwent stenting of SVG lesions with BMS (n = 192) from 1999 to 2006 or DES (n = 203) from 2004 to 2006 were analyzed. Patients were followed prospectively for the occurrence of cardiovascular events and death at 3 years. Patients treated with DES were more likely to have diabetes mellitus and other co morbidities and previous percutaneous coronary intervention. Treated lesions in DES patients were more complex than those in BMS patients. At 3 years of follow up, the adjusted risk for target vessel revascularization (hazard ratio 1.03, 95% confidence interval 0.65 to 1.62, p = 0.91) and death or myocardial infarction (hazard ratio 0.72, 95% confidence interval 0.49 to 1.04, p = 0.08) was similar in patients treated with DES and those treated with BMS. The combined outcome of death, myocardial infarction, or target vessel revascularization excluding periprocedural myocardial infarction was also similar (adjusted hazard ratio 0.82, 95% confidence interval 0.62 to 1.09, p = 0.16). In conclusion, this multicenter nonrandomized study of unselected patients showed no benefit of DES in SVG lesions, including no reduction in target vessel revascularization, compared with BMS at 3 years. An adequately powered randomized controlled trial is needed to determine the optimal stent type for SVG percutaneous coronary intervention. PMID- 20854957 TI - Usefulness of postoperative heart rate as an independent predictor of mortality after coronary bypass grafting. AB - Heart rate (HR) predicts mortality and cardiovascular events in the general population and in patients with coronary artery disease. However, little evidence is available for patients after coronary revascularization. The aim of this study was to assess the prognostic value of ambulatory postoperative HR after coronary artery bypass grafting. Data from a prospective cohort study enrolling patients who underwent nonurgent coronary artery bypass grafting from 1998 to 2002 were analyzed. Baseline postoperative HR was measured 2 months after surgery, and patients were followed annually thereafter. The primary outcome was all-cause mortality. The secondary outcome combined any of the following events: death, nonfatal acute coronary syndromes, stroke or transient ischemic attack, secondary coronary revascularization, or vascular surgery. Seven hundred ninety-four patients (mean age 65.8 +/- 9.3 years) were eligible for follow-up, predominantly men (84.1%). The mean follow-up duration was 3.2 +/- 1.3 years, during which 40 patients (5.0%) died. In the univariate analysis, HR >90 beats/min was significantly associated with all outcomes. After adjustments for major confounding factors and the use of beta blockers, postoperative HR >90 beats/min remained significantly associated with the secondary outcome (hazard ratio 2.26, 95% confidence interval 1.04 to 4.91, p = 0.04). Association of postoperative HR >90 beats/min with all-cause mortality was only borderline in the multivariate analysis (hazard ratio 3.57, 95% confidence interval 0.90 to 14.17, p = 0.07), because of the limited sample population size. In conclusion, postoperative HR >90 beats/min may be associated with poor prognoses in patients with coronary artery disease, even after surgical revascularization. PMID- 20854958 TI - Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. AB - Vitamin D recently has been proposed to play an important role in a broad range of organ functions, including cardiovascular (CV) health; however, the CV evidence-base is limited. We prospectively analyzed a large electronic medical records database to determine the prevalence of vitamin D deficiency and the relation of vitamin D levels to prevalent and incident CV risk factors and diseases, including mortality. The database contained 41,504 patient records with at least one measured vitamin D level. The prevalence of vitamin D deficiency (<=30 ng/ml) was 63.6%, with only minor differences by gender or age. Vitamin D deficiency was associated with highly significant (p <0.0001) increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Also, those without risk factors but with severe deficiency had an increased likelihood of developing diabetes, hypertension, and hyperlipidemia. The vitamin D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, and stroke (all p <0.0001), as well as with incident death, heart failure, coronary artery disease/myocardial infarction (all p <0.0001), stroke (p = 0.003), and their composite (p <0.0001). In conclusion, we have confirmed a high prevalence of vitamin D deficiency in the general healthcare population and an association between vitamin D levels and prevalent and incident CV risk factors and outcomes. These observations lend strong support to the hypothesis that vitamin D might play a primary role in CV risk factors and disease. Given the ease of vitamin D measurement and replacement, prospective studies of vitamin D supplementation to prevent and treat CV disease are urgently needed. PMID- 20854959 TI - 30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. AB - Data from National Health and Nutrition Examination Survey (NHANES) II (1976 to 1980), NHANES III (1988 to 1994), and NHANES 1999 to 2006 were examined to assess trends in total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high density lipoprotein cholesterol, triglycerides (TGs), lipid-lowering medication use, and obesity. Age-adjusted decreases in TC (210 to 200 mg/dl) and LDL cholesterol (134 to 119 mg/dl) were observed. Those with high TC showed a decrease of 9% from NHANES II to NHANES 1999 to 2006, whereas those with LDL cholesterol >=160 mg/dl showed a decrease of 8%. A significant increase in mean high-density lipoprotein cholesterol was observed (50 to 53 mg/dl, p <0.001), most likely due to changes in methods. Those with TG levels >=150 mg/dl showed a decrease from NHANES II to NHANES III from 30% to 27% but then an increase from NHANES III to NHANES 1999 to 2006 from 27% to 33%. Since NHANES III, mean TG levels have increased 12% from 130 to 146 mg/dl. In the 2 most recent surveys, self-reported "high cholesterol" increased from 17% to 27%, and self-reported lipid medication use by those with high cholesterol increased from 16% to 38%. Mean body mass index increased from 26 to 29 kg/m(2), and prevalence of obesity doubled and was significantly associated with increased TG. In conclusion, recent favorable trends in TC and LDL cholesterol are likely due to increased awareness of high cholesterol and the greater use of lipid-lowering drugs. However, countertrends in obesity and TG levels, if continued, will likely have a negative impact on cardiovascular disease in the future. PMID- 20854960 TI - Usefulness of microalbuminuria in patients with the metabolic syndrome to predict subclinical atherosclerosis and cardiovascular disease outcomes. AB - The clinical implications of microalbuminuria (MA) in nondiabetic persons with the metabolic syndrome (MS) are largely unknown. The present post hoc analysis of the Multiethnic Study of Atherosclerosis (MESA) included 5,809 nondiabetic persons with no history of cardiovascular disease aged 45 to 84 years. The study population was divided according to the presence or absence of MS and MA into 4 study groups: no MS and no MA, MA only, MS only, and MS plus MA. The measurements included markers of systemic inflammation, subclinical atherosclerosis, left ventricular mass index, composite and individual cardiovascular end points, and all-cause mortality. Prospective and cross-sectional analyses were performed to ascertain the association of study groups with these covariates. The MS plus MA group showed a consistently stronger association with the markers of systemic inflammation, subclinical atherosclerosis, and most clinical end points compared to the other study groups. In conclusion, stratification by MA can help identify a high-risk subset of nondiabetic patients with the MS. PMID- 20854961 TI - Relation between common allergic symptoms and coronary heart disease among NHANES III participants. AB - We investigated whether there is an increased risk of coronary heart diseases (CHD) in those with common allergic symptoms using the NHANES III, which is a representative sample of the United States population in 1988 to 1994. CHD was defined by Rose questionnaire and history of heart attack. Allergic symptoms were categorized into no symptoms (NO), rhinoconjunctivitis without wheezing (RC), and wheezing (WZ) based on symptoms. Multivariate logistic regression was used to obtain odds ratios (ORs) of CHD. Eight thousand six hundred fifty-three nonpregnant subjects >=20 years old with overnight fasting >=8 hours were included. CHD was present in 5.9% of the population; 36.5% did not have allergic symptoms (NO), 45.9% had RC, and 17.6% had WZ. The prevalence of CHD was 3.9% in NO, 4.8% in RC, and 12.8% in WZ (p <0.001). Compared to NO, unadjusted ORs of CHD were 1.24 (95% confidence interval 0.94 to 1.62) in RC and 3.58 (2.68 to 4.78) in WZ and ORs adjusted for sociodemographic factors and co-morbidities were 1.40 (1.02 to 1.92) in RC and 2.64 (1.79 to 3.90) in WZ. Only the group of women <50 years of age had significantly increased ORs in RC and WZ. In conclusion, common allergic symptoms were significantly associated with an increased risk of CHD. PMID- 20854962 TI - Red cell distribution width and risk of coronary heart disease events. AB - Red cell distribution width (RDW) has emerged as a powerful predictor of all cause mortality in variety of cardiovascular settings. However, no data are available associating RDW with coronary heart disease (CHD) risk in a healthy and nationally representative multiethnic population. A total of 7,556 participants of the National Health and Nutrition Examination Surveys 1999 to 2006 (age 41.5 +/- 15.8 years, 60% women) were divided into 3 categories according to their 10 year Framingham risk of hard CHD events: <10% (n = 6,173, reference category), 10% to 20% (n = 1,093, intermediate-risk category), and >20% (n = 290, high-risk category). Unadjusted and adjusted multivariate logistic regression analyses were performed evaluating RDW as a predictor of CHD risk. Each unit increase (0.1) in RDW posed a statistically significant greater odds of being in the intermediate risk category (odds ratio -1.35, 95% confidence interval 1.27 to 1.45, p <0.001) and high-risk category (odds ratio -1.38, 95% confidence interval 1.25 to 1.53, p <0.001) compared to the reference category, after adjusting for race, body mass index, estimated glomerular filtration rate, hemoglobin A1c, C-reactive protein, hemoglobin, and mean corpuscular volume. Additional adjustments with serum iron, vitamin B(12), and folic acid levels did not affect the association. Subsequently, we divided participants into 2 categories according to their anemia status (as defined by the World Health Organization) to evaluate its effect. An RDW level greater than the seventy-fifth percentile in both anemic and nonanemic participants was a significant predictor of greater CHD risk while RDW of the seventy-fifth percentile or less in anemic participants failed to predict CHD (compared to nonanemic participants with similar RDW as the reference category). In conclusion, a higher RDW appears to be a powerful independent predictor of future CHD risk. PMID- 20854963 TI - KIF6 polymorphism as a predictor of risk of coronary events and of clinical event reduction by statin therapy. AB - Evidence from multiple large prospective studies suggests that a common polymorphism that encodes an arginine (Arg)-to-tryptophan substitution at position 719 in the KIF6 gene is associated with coronary heart disease (CHD) and reduction in coronary events from statin therapy. Carriers of the 719Arg allele were at greater risk for primary and secondary CHD events, and statin therapy significantly reduced coronary events in 719Arg carriers but not in noncarriers. The number needed to treat to prevent a single CHD event ranged from 10 to 20 for 719Arg carriers, compared to >80 for noncarriers in the Cholesterol and Recurrent Events (CARE) study, the West of Scotland Coronary Prevention Study (WOSCOPS), the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) study. In conclusion, assessment of 719Arg carrier status holds promise for stratification of coronary event risk and for selection of optimal therapy in primary and secondary CHD prevention. PMID- 20854964 TI - Prognostic significance of left ventricular diastolic dysfunction in patients with left ventricular hypertrophy and systemic hypertension (the LIFE Study). AB - Patients with hypertension and left ventricular (LV) hypertrophy commonly have impaired diastolic filling. However, it remains unknown whether changes in LV diastolic filling variables are associated with cardiovascular morbidity and mortality. In this study, 778 patients with hypertension with electrocardiographic LV hypertrophy who underwent echocardiography at baseline and annually thereafter during randomized losartan- or atenolol-based antihypertensive treatment were followed for a mean of 4.6 years. The composite cardiovascular end point was the first occurrence of fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, and cardiovascular mortality. Antihypertensive therapy resulted in an increase in the prevalence of normal transmitral flow pattern from 28% to 46% of patients. Although antihypertensive treatment often resulted in a marked increase in the prevalence of normal mitral valve flow pattern, this was not associated with reduced cardiovascular morbidity and mortality when adjusting for blood pressure, left atrial diameter, LV mass index, and treatment in time-varying Cox analyses. In contrast, lower in treatment E/A ratios and shorter mitral valve deceleration times were associated with less risk for heart failure. Similarly, normal in-treatment transmitral flow pattern was strongly associated with less risk for heart failure (hazard ratio 0.22, 95% confidence interval 0.05 to 0.98, p = 0.048), even when taking in treatment left atrial diameter and blood pressure into account. In conclusion, antihypertensive treatment in patients with hypertension with electrocardiographic LV hypertrophy resulted in significant improvement in transmitral flow patterns; this was not associated with reduced cardiovascular morbidity and mortality. However, normal in-treatment LV filling was strongly associated with a reduced risk for hospitalization for heart failure. PMID- 20854965 TI - Effect of Metformin on mortality in patients with heart failure and type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre-dispensed prescribing database for the population of Tayside, Scotland (population ~400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean +/- SD 75.4 +/- 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 +/- 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 +/- 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 +/- 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial. PMID- 20854967 TI - Usefulness of magnetic resonance imaging to distinguish hypertensive and hypertrophic cardiomyopathy. AB - Different pathophysiologic pathways in the development of left ventricular (LV) hypertrophy can be reflected in phenotypical differences. A total of 119 subjects (39 with hypertension [HTN]; 43 with nonobstructive hypertrophic cardiomyopathy [HC], and 37 control subjects) underwent a standardized cardiac magnetic resonance imaging protocol for assessment of global and regional morphology and function using balanced steady-state free precession sequences and late gadolinium enhancement studies. Compared to controls, both hypertrophic groups had significantly greater maximal wall thickness and LV mass index (p <0.01). The patients with HTN had reduced ejection fraction, increased heart cavities, and increased LV wall stress (p <0.01). The HC group had supernormal ejection fraction and reduced LV wall stress (p <0.01). The HTN group had reduced anteroseptal systolic strains (p <0.02), and the HC group displayed a marked decrease in longitudinal systolic strain (p <0.01). In the HC group, an inverse relation was seen between a globally increased late gadolinium enhancement score and the ejection fraction (r = -0.5, p = 0.01), and between regional late gadolinium enhancement scores and regional systolic strain in the inferoseptal segments. Increased LV wall stress was identified as the hallmark of HTN (odds ratio 1.2, p = 0.002), while HC was best characterized by reduced total longitudinal strain (odds ratio 1.3, p = 0.002). In conclusion, our findings indicate the presence of distinctive hypertrophic phenotypes detectable by means of multiparametric magnetic resonance imaging. In HTN, impaired deformation follows the distribution of LV wall stress. On the contrary, HC is characterized by reduced global and regional deformation, in association with fibrosis. PMID- 20854966 TI - Relation of level of B-type natriuretic peptide with outcomes in patients with infective endocarditis. AB - Elevated B-type natriuretic peptide (BNP) is a marker of poor outcomes in heart failure, acute coronary syndromes, and sepsis. Elevated cardiac troponin I (cTnI) is associated with adverse outcomes in infective endocarditis. It was hypothesized that elevated BNP would be associated with increased rates of morbidity and mortality in patients with infective endocarditis, particularly when combined with elevated cTnI. Consecutively enrolled patients in the International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS) were evaluated at a single center. The association between elevated BNP and a composite outcome of death, intracardiac abscess, and central nervous system event and the individual components of the composite was determined. Similar analyses were performed in patients who had BNP and cTnI measured. Of 103 patients, 45 had BNP measured for clinical indications. The median BNP level was higher in patients with the composite outcome (1,498 vs 433 pg/ml, p = 0.03) and in those who died (2,150 vs 628 pg/ml, p = 0.04). Elevated BNP was significantly associated with the composite outcome (p <0.01) and intracardiac abscess (p = 0.02). Patients with elevation of BNP and cTnI had a significantly higher probability of the composite outcome (69%) than patients with either BNP or cTnI elevated (29%) or neither BNP nor troponin elevated (0%) (p for trend <0.01). In conclusion, these data demonstrate a significant association between elevated BNP alone and in combination with cTnI for serious outcomes in infective endocarditis and warrant prospective evaluation. PMID- 20854968 TI - Effect of abnormal pulmonary flow distribution on ventilatory efficiency and exercise capacity after arterial switch operation for transposition of great arteries. AB - Patients with anatomic repair of transposition of the great arteries (TGA) can present with branch pulmonary artery (PA) stenosis; however, its relation to an abnormal cardiopulmonary response to exercise is unknown. We investigated the relation between the PA anatomy and pulmonary blood flow (PBF) distribution and the cardiopulmonary response to exercise in patients with anatomic repair of TGA. We used cardiopulmonary exercise testing and magnetic resonance imaging to study 55 consecutive patients (62% male; age 14.4 +/- 2.3 years) who had undergone neonatal anatomic repair of TGA. The peak oxygen uptake and slope of carbon dioxide elimination/minute ventilation was 79 +/- 15% of predicted and 29.8 +/- 3.8, respectively. Abnormal peak oxygen uptake (R = 0.363, p = 0.0082) and slope of carbon dioxide elimination/minute ventilation (R = 0.612, p <0.0001) values were associated with an abnormal right/left PBF distribution. However, although an increased ventilatory response to exercise appeared to be primarily related to an abnormal right/left PBF distribution, exercise capacity appeared to be related to the extent of the proximal PA branches and main PA stenosis (R = 0.476, p = 0.0004), suggesting that mechanical obstruction to PBF during exercise could be the main mechanism causing an abnormal exercise capacity. In conclusion, an abnormal PBF distribution related to branch PA stenosis or hypoplasia was associated with a reduced exercise capacity and increased ventilatory drive during exercise in patients with anatomic repair of TGA. Cardiopulmonary exercise test data can complement the anatomic and magnetic resonance imaging data in selecting those lesions that are functionally important. PMID- 20854969 TI - Abnormalities of cardiac repolarization in Williams syndrome. AB - Williams syndrome (WS) affects 1 in 8,000 live births and has a high risk of sudden death. No previous studies have evaluated corrected QT (QTc) prolongation in WS. Retrospective review of all patients with WS evaluated at our institution from January 1, 1980 to December 31, 2007 was performed. WS was diagnosed by a medical geneticist and/or by fluorescence in situ hybridization. Patients with >=1 electrocardiogram (ECG) with sinus rhythm and measurable intervals were included. Normal control ECGs were identified from a large clinical database. Corrected JT (JTc) interval was calculated when QRS and QTc intervals were prolonged. QTc interval >=460 ms and JTc interval >340 ms were defined as prolonged. Prevalence comparisons were made using Fisher's exact test. Statistical probability of <0.05 was considered significant. Of 270 patients identified, 188 had ECGs for review. Complete data were present in 499 of 517 ECGs (patients' mean age 10.3 +/- 9.9 years); 1,522 normal ECGs of age-similar patients composed the control group. QTc prolongation prevalences were 2.0% in controls and 13.6% in WS (p <0.0001); in those, JTc prolongation prevalences were 1.8% in controls and 11.7% in WS (p <0.0001). Four patients died during follow up; 2 had QTc prolongation and 1 died during noncardiac surgery. Another patient with QTc prolongation sustained cardiac arrest during a procedure. In conclusion, cardiac repolarization is prolonged in WS. Presence of prolonged cardiac repolarization may contribute to the high incidence of periprocedural mortality in these patients. All patients with WS should be screened for cardiac repolarization abnormalities, especially before surgery. PMID- 20854970 TI - Results of transcatheter closure of perimembranous ventricular septal defect. AB - This study reports the midterm results and experience of a single center of transcatheter closure of perimembranous ventricular septal defect (VSD) with Amplatzer membranous VSD occluders. Data of 301 patients who underwent attempted transcatheter closure were collected prospectively from May 2002 to December 2008. Patients' mean age was 9.8 years, and their mean weight was 32 kg. The procedure was successful in 294 patients (97.6%). No death occurred. Complications included aortic regurgitation in 11 patients (3.7%, 2 requiring occluder retrieving), tricuspid regurgitation in 16 patients (5.4%), hemolysis in 2 patients (0.7%), and complete atrioventricular block (cAVB) in 17 patients (15 early cAVBs, 3 late cAVBs, 1 patient had early and late cAVBs). Among the 15 early cAVBs, 12 were transient and 3 were considered prolonged cAVBs (persisted >2 weeks). The 3 patients underwent surgery (1.0%) and obtained stable sinus rhythm. Pacemaker implantation was needed in all 3 patients with late cAVB (1.0%). Univariate analysis showed that risk factors were age (p = 0.01) and weight (p = 0.021). No risk factors were found in multivariate analysis. In conclusion, midterm results of transcatheter closure of perimembranous VSD showed high closure rate and limited complications. The major concern is the occurrence of cAVB. Long-term investigation is needed to assess the efficacy and safety compared to surgery. PMID- 20854971 TI - The variant associations of aortic isthmic coarctation. AB - The term "coarctation" necessarily calls attention to a specific morphologic abnormality of the aortic isthmus. However, in this report, the author seeks to dispel the simplistic notion that coarctation is best characterized by isthmic obstruction, which is only 1 of an assemblage of abnormalities that include the proximal paracoarctation aorta, the distal paracoarctation aorta, the ascending aorta, the transverse aorta, the coronary arteries, the conduit arteries (radial, brachial, and carotid), the retinal vascular bed, dissecting aneurysms, cerebral aneurysms, vascular rings, systemic hypertension, and a decrease in left ventricular interpapillary muscle distance. Some of these abnormalities are secondary to the coarctation, such as collateral arteries and dissecting aneurysms. Others frequently or invariably coexist but are not secondary, such as bicuspid aortic valve and aneurysm of the circle of Willis. Still other abnormalities are seemingly contradictory, such as aneurysmal dilatation of the low-pressure distal paracoarctation aorta, while the high-pressure proximal segment does not dilate significantly. In conclusion, coarctation should be regarded as an assemblage of cardiovascular abnormalities rather than as isolated obstruction of the aortic isthmus. PMID- 20854972 TI - Left ventricular mechanical dyssynchrony by phase analysis of gated single photon emission computed tomography in end-stage renal disease. AB - The presence and degree of left ventricular (LV) dyssynchrony in patients with end-stage renal disease (ESRD) has not been well studied. We hypothesized that these patients would be more likely to have mechanical dyssynchrony than a control cohort. The indexes of LV mechanical dyssynchrony were measured by automated analysis of gated single photon emission computed tomography myocardial perfusion imaging in 290 patients with ESRD and 109 control patients. Only patients with normal myocardial perfusion imaging findings and a narrow QRS duration were included. The following variables were derived: LV ejection fraction (EF), volume, mass, and 2 indexes of dyssynchrony, the standard deviation and bandwidth. The standard deviation and bandwidth were significantly greater in those with ESRD (23 degrees +/- 13 degrees vs 15 degrees +/- 6 degrees and 65 degrees +/- 40 degrees vs 42 degrees +/- 14 degrees , respectively, p <0.001 for each). The LV volumes and LV mass were significantly lower and LVEF significantly greater in the control group than in the patients with ESRD (p <0.001 for each). The subgroup of 217 patients with ESRD and normal LVEF also had a significantly greater standard deviation and bandwidth than did the control group (21 degrees +/- 12 degrees and 57 degrees +/- 35 degrees , p <0.001 for each). However, their values were lower than those of the 73 patients with ESRD and a LVEF <50% (30 degrees +/- 13 degrees and 90 degrees +/- 45 degrees , p <0.001 for each). Finally, 25 patients (9%) with ESRD and none of the control group had a standard deviation >43 degrees (p = 0.01). In conclusion, patients with ESRD had significantly more mechanical dyssynchrony than did the control group, even in absence of electrical dyssynchrony and abnormal LV perfusion or function. PMID- 20854973 TI - Frequency and age-related course of mitral valve dysfunction in the Marfan syndrome. AB - Mitral valve (MV) prolapse (MVP) has a high prevalence of 2% to 3% in the general population and thus constitutes the most common cause of severe nonischemic MV regurgitation (MVR). MVP is also common in persons with the Marfan syndrome. However, to date, a large-scale population-based cohort study using modern echocardiographic techniques has not been performed, and the frequency of MVP and the relation of MV dysfunction and age have not been investigated. Therefore, we conducted a population-based cohort study of 204 patients (108 males and 96 females, aged 31.2 +/- 16.4 years) with classic Marfan syndrome. We performed echocardiographic follow-up of 174 patients for a mean of 4.4 +/- 4.3 years. On the initial or subsequent echocardiographic scan, MVP was present in 82 patients (40%), severe MVR in 25 (12%), and MV endocarditis in 5 patients (2.5%). At 30 years of age, the Weibull cumulative distribution was 42.6% (95% confidence interval [CI] 36% to 50%) for MVP, 56.5% (95% CI 49.3% to 64%) for MVR of any degree, 6.7% (95% CI 3.9% to 11.3%) for severe MVR, and 0.92% (95% CI 0.21% to 3.91%) for MV endocarditis. The cumulative hazard for severe MVR and MV endocarditis was estimated to increase with age. MVP was associated with dural ectasia (p = 0.01), ectopia lentis (p = 0.02), and skeletal involvement (p <0.001). Severe MVR was related to tricuspid valve prolapse (p = 0.002) and to the sporadic form of the Marfan syndrome (p = 0.006). In conclusion, MVP was comparatively frequent in patients with the Marfan syndrome and carries an increased risk of progression to severe MVR and endocarditis, especially in older adults. PMID- 20854974 TI - Usefulness of intravenously administered fluid replenishment for detection of patent foramen ovale by transesophageal echocardiography. AB - Patent foramen ovale (PFO) is associated with cryptogenic stroke, migraine headache, decompression sickness, and platypnea-orthodeoxia syndrome. Patients undergoing transesophageal echocardiography are often hypovolemic from preprocedural fasting and might not demonstrate right to left shunting owing to insufficient right atrial pressure generation, despite provocative maneuvers. We hypothesized that volume replenishment with saline loading could potentially unmask a PFO by favorably modulating the interatrial pressure gradient. Our study sought to examine the role of pre- or intraprocedural intravenous fluid replenishment on PFO detection during transesophageal echocardiography. A total of 103 patients were enrolled. An initial series of bubble injections was performed unprovoked and then with provocative maneuvers such as the Valsalva maneuver and coughing. The patients were then given a rapid 500 ml saline bolus, and the same sequence of bubble injections was repeated. The presence, type, and magnitude of the right to left shunts were noted before and after the saline bolus. The detection rate of PFO increased from 10.6% to 26.2% after saline loading without any provocative maneuvers. When combined with provocative maneuvers (Valsalva or cough), saline loading improved the detection rate from 17.4% to 32.0%. Overall, from amongst the 103 enrolled patients, saline bolusing resulted in a de novo diagnosis of PFO in 15 patients, atrial septal aneurysm in 15, PFO coexisting with an atrial septal aneurysm in 10, and pulmonary arteriovenous fistula in 5 patients. In conclusion, saline infusion in appropriately selected patients during transesophageal echocardiography significantly enhances the detection of PFOs and pulmonary arteriovenous fistulas. PMID- 20854975 TI - Percutaneous stenting versus bypass surgery for unprotected left main coronary artery disease. PMID- 20854976 TI - Lack of correlation between Doppler and catheter in pulmonary pressure: flawed noninvasive technique or straw man. PMID- 20854978 TI - Invited review: Lactobacillus helveticus--a thermophilic dairy starter related to gut bacteria. AB - The strain Lactobacillus helveticus DPC4571 has emerged as a promising flavor adjunct culture for Cheddar cheese given that it is consistently associated with improved flavor. The availability of the complete genome sequence of Lb. helveticus DPC4571 has enabled the search for the presence or absence of specific genes on the genome, in particular those of technological interest. Indeed, this analysis has facilitated a greater understanding into the functioning of lactic acid bacteria as a whole. The biochemical pathways of Lb. helveticus responsible for producing flavor compounds during cheese ripening are poorly understood but now with the availability of a complete genomic sequence are ripe for exploitation. Bioinformatic analysis of the genome of Lb. helveticus DPC4571 has revealed a plethora of genes with industrial potential including those responsible for key metabolic functions that contribute to cheese flavor development such as proteolysis, lipolysis, and cell lysis. In addition, it has been demonstrated that Lb. helveticus has the potential to produce bioactive peptides such as angiotensin converting enzyme inhibitory activity in fermented dairy products, demonstrating the therapeutic value of this species. A most intriguing feature of the genome of Lb. helveticus DPC4571 is the remarkable similarity in gene content with many intestinal lactobacilli, although originating from considerably different environments. Bioinformatic analysis demonstrated that 65 to 75% of genes were conserved between the commensal and dairy lactobacilli, which allowed key niche-specific gene sets to be described. This review focuses on the isolation, characterization, and exploitation of the Lb. helveticus species with particular emphesis on taking into consideration recent genome sequence data for Lb. helveticus and other Lactobacillus species. PMID- 20854979 TI - Invited review: modeling within-herd transmission of Mycobacterium avium subspecies paratuberculosis in dairy cattle: a review. AB - Epidemiological models have been developed to test hypotheses on Mycobacterium avium ssp. paratuberculosis (Map) transmission in a herd, and to compare different paratuberculosis control strategies and alternatives for certification and-surveillance schemes. The models are simplified representations of existing biological processes tailored to the questions they are intended to answer. Such models depend on available knowledge about the underlying processes, notably in relation to pathogen transmission. All decisions relating to integration of specific aspects of the herd structure and transmission mechanisms as well as modeling objective will influence model behavior and simulation results. This paper examines assumptions on pathogen transmission and risk mitigation represented in 8 epidemiological models of within-herd Map transmission in dairy cattle. We describe available models' structure and examine them in the context of current knowledge about host infection and pathogen transmission pathways. We investigate how population structure and herd management are modeled with regard to their influence on contact structure and pathogen transmission. We show that assumptions about routes of transmission and their contribution within a herd vary greatly among models. Gaps of knowledge that are pivotal to defining transmission equations and parameters, such as variation of susceptibility with age and variability of pattern of shedding, are identified. Quantitative estimates of this incomplete information should be targeted by future research. Existing models could be improved by considering indirect transmission via the environment taking account of Map survival and contact structure between animals in a herd, and by including calf-to-calf transmission, which has recently been proven as being important. PMID- 20854980 TI - Sensory and microbiological quality of yogurt drinks with prebiotics and probiotics. AB - The popularity of dairy products fortified with prebiotics and probiotics continues to increase as consumers desire flavorful foods that will fulfill their health needs. Our objectives were to assess the sensory profile of drinkable yogurts made with prebiotics and probiotics and to determine the viability of the probiotics in the yogurt drink over the duration of storage. Thirteen trained descriptive panelists evaluated 10 yogurt drinks on a 16-point category scale. Three selected prebiotics, soluble corn fiber, polydextrose, and chicory inulin, were each present individually at an amount to claim an excellent source of fiber (5 g of fiber/serving) or a good source of fiber (2.5 g of fiber/serving) in 6 different yogurt drinks. Three additional yogurt drinks contained 5 g of each of the separate prebiotics along with a mixture of the selected probiotics (Bifidobacterium lactis Bb-12 and Lactobacillus acidophilus LA-5). A control sample with no prebiotics or probiotics was also included in the experimental design. Data were analyzed by ANOVA, Fisher's least significant difference, and principal component analysis. Survival of the probiotics in the yogurt drinks during a 30-d refrigerated storage period was also analyzed. Results showed that clover honey aroma, buttermilk aroma, butter aroma, sweetness, sourness, chalky mouthfeel, and viscosity were identified as significant attributes in the yogurt drinks. Total variance explained by the principal component analysis biplot of factors 1 and 2 was 65%, which showed yogurt drinks with soluble corn fiber and inulin varying by the sweet versus sour attributes and yogurt drinks with polydextrose varying by the mouthfeel attributes. The viability study determined a 2- to 3-log decrease in the survival of probiotics in all of the yogurt treatments during a 30-d refrigerated storage period. Based on the results of the current study, only the polydextrose treatment would be an acceptable vehicle to deliver the probiotic health effects at the end of the 30-d storage period. PMID- 20854981 TI - Effect of bovine lactoferrin addition to milk in yogurt manufacturing. AB - The aim of this work was to study the effect of milk supplementation with lactoferrin of different iron saturation on the manufacturing and characteristics of yogurt. Bovine lactoferrin was added at concentrations of 0.5, 1, and 2 mg/mL in the holo (iron saturated) and apo (without iron) forms. Some physicochemical properties, such as pH, concentration of lactic acid, and texture of supplemented yogurts, were determined throughout the shelf-life period storage (28 d) at 4 degrees C. We also evaluated the stability of lactoferrin in supplemented yogurt throughout the storage time. The supplementation of milk with bovine lactoferrin did not greatly affect the physical properties of the yogurt, though apo lactoferrin slightly delayed the decrease of pH. This could be attributed to the partial inhibition observed on the growth of Streptococcus thermophilus. The integrity and immunoreactive concentration of lactoferrin, determined by Western blotting and noncompetitive ELISA, respectively, remained constant throughout the shelf life of yogurt. PMID- 20854982 TI - Classification of Pecorino cheeses produced in Italy according to their ripening time and manufacturing technique using Fourier transform infrared spectroscopy. AB - Fourier-transform infrared spectroscopy, followed by linear discriminant analysis of the spectral data, was used to classify Italian Pecorino cheeses according to their ripening time and manufacturing technique. The Fourier transform infrared spectra of the cheeses were divided into 18 regions and the normalized absorbance peak areas within these regions were used as predictors. Linear discriminant analysis models were constructed to classify Pecorino cheeses according to different ripening stages (hard and semi-hard) or according to their manufacturing technique (fossa and nonfossa cheeses). An excellent resolution was achieved according to both ripening time and manufacturing technique. Also, a final linear discriminant analysis model considering the 3 categories (hard nonfossa, hard fossa, and semi-hard nonfossa) was constructed. A good resolution among the 3 categories was obtained. PMID- 20854983 TI - Potent antilisterial cell-free supernatants produced by complex red-smear cheese microbial consortia. AB - The microbial surface ripening consortia of 49 soft cheeses were investigated with respect to their inhibition of Listeria monocytogenes. When L. monocytogenes EGDe (serovar 1/2a) was cultivated in cell-free supernatants obtained from consortia grown for 8 h in liquid medium, a strong bactericidal activity was observed in several cases. The cell-free supernatants of 2 of these consortia (I and II) reduced an initial L. monocytogenes inoculum of 5 * 10(7) cfu/mL to zero after 24 h of incubation. No inhibitory substances could be washed off the complex consortia when incubated for a 10-min period. A taxonomical analysis of the antilisterial consortia I and II using Fourier transform infrared spectroscopy yielded a considerable species diversity, with lactic acid bacteria increasing strongly during the 8-h cultivation. Therefore, 23 lactic acid bacteria bacteriocin genes were assayed using specific PCR primers, identifying 3 bacteriocin genes in both microbial communities. However, no transcription of these genes was found on cheese surfaces or in consortia propagated in liquid culture. Individual lactic acid bacteria isolates of consortia I and II displayed no or only weak inhibition of L. monocytogenes on solid medium. The complex cell free supernatants I and II, in contrast, exhibited an unusually broad inhibitory spectrum, killing L. monocytogenes ssp., Bacillus spp., Staphylococcus aureus, as well as gram-negative bacteria such as Escherichia coli DH5alpha and Salmonella enterica serovar Typhimurium. Inhibition could not be abolished by heating to 100 degrees C or by proteinase K treatment. Initial purification of an inhibitory substance from consortium I by solid-phase extraction and HPLC indicates the presence of rather small, extremely stable compounds, which, most probably, are not bacteriocins. PMID- 20854984 TI - Production efficiency of micellar casein concentrate using polymeric spiral-wound microfiltration membranes. AB - Most current research has focused on using ceramic microfiltration (MF) membranes for micellar casein concentrate production, but little research has focused on the use of polymeric spiral-wound (SW) MF membranes. A method for the production of a serum protein (SP)-reduced micellar casein concentrate using SW MF was compared with a ceramic MF membrane. Pasteurized (79 degrees C, 18s) skim milk (1,100 kg) was microfiltered at 50 degrees C [about 3 * concentration] using a 0.3-MUm polyvinylidene fluoride spiral-wound membrane, bleed-and-feed, 3-stage process, using 2 diafiltration stages, where the retentate was diluted 1:2 with reverse osmosis water. Skim milk, permeate, and retentate were analyzed for SP content, and the reduction of SP from skim milk was determined. Theoretically, 68% of the SP content of skim milk can be removed using a single-stage 3* MF. If 2 subsequent water diafiltration stages are used, an additional 22% and 7% of the SP can be removed, respectively, giving a total SP removal of 97%. Removal of SP greater than 95% has been achieved using a 0.1-MUm pore size ceramic uniform transmembrane pressure (UTP) MF membrane after a 3-stage MF with diafiltration process. One stage of MF plus 2 stages of diafiltration of 50 degrees C skim milk using a polyvinylidene fluoride polymeric SW 0.3-MUm membrane yielded a total SP reduction of only 70.3% (stages 1, 2, and 3: 38.6, 20.8, and 10.9%, respectively). The SP removal rate for the polymeric SW MF membrane was lower in all 3 stages of processing (stages 1, 2, and 3: 0.05, 0.04, and 0.03 kg/m(2) per hour, respectively) than that of the comparable ceramic UTP MF membrane (stages 1, 2, and 3: 0.30, 0.11, and 0.06 kg/m(2) per hour, respectively), indicating that SW MF is less efficient at removing SP from 50 degrees C skim milk than the ceramic UTP system. To estimate the number of steps required for the SW system to reach 95% SP removal, the third-stage SP removal rate (27.4% of the starting material SP content) was used to extrapolate that an additional 5 water diafiltration stages would be necessary, for a total of 8 stages, to remove 95% of the SP from skim milk. The 8-plus stages necessary to remove >95% SP for the SW MF membrane would create more permeate and a lengthier process than required with ceramic membranes. PMID- 20854985 TI - Bactericidal activity of lauric arginate in milk and Queso Fresco cheese against Listeria monocytogenes cold growth. AB - Lauric arginate (LAE) at concentrations of 200 ppm and 800 ppm was evaluated for its effectiveness in reducing cold growth of Listeria monocytogenes in whole milk, skim milk, and Queso Fresco cheese (QFC) at 4 degrees C for 15 to 28 d. Use of 200 ppm of LAE reduced 4 log cfu/mL of L. monocytogenes to a nondetectable level within 30 min at 4 degrees C in tryptic soy broth. In contrast, when 4 log cfu/mL of L. monocytogenes was inoculated in whole milk or skim milk, the reduction of L. monocytogenes was approximately 1 log cfu/mL after 24 h with 200 ppm of LAE. When 800 ppm of LAE was added to whole or skim milk, the initial 4 log cfu/mL of L. monocytogenes was nondetectable following 24 h, and no growth of L. monocytogenes was observed for 15 d at 4 degrees C. With surface treatment of 200 or 800 ppm of LAE on vacuum-packaged QFC, the reductions of L. monocytogenes within 24 h at 4 degrees C were 1.2 and 3.0 log cfu/g, respectively. In addition, the overall growth of L. monocytogenes in QFC was decreased by 0.3 to 2.6 and by 2.3 to 5.0 log cfu/g with 200 and 800 ppm of LAE, respectively, compared with untreated controls over 28 d at 4 degrees C. Sensory tests revealed that consumers could not determine a difference between QFC samples that were treated with 0 and 200 ppm of LAE, the FDA-approved level of LAE use in foods. In addition, no differences existed between treatments with respect to flavor, texture, and overall acceptability of the QFC. Lauric arginate shows promise for potential use in QFC because it exerts initial bactericidal activity against L. monocytogenes at 4 degrees C without affecting sensory quality. PMID- 20854986 TI - Bifidobacterium bifidum BF-1 suppresses Helicobacter pylori-induced genes in human epithelial cells. AB - Helicobacter pylori infection alters gene expression in host cells. Specifically, inflammatory chemokines such as IL-8 are upregulated in the gastric mucosa during H. pylori infection. Although the mechanism by which H. pylori causes inflammation of the gastric mucosa is not yet understood, many studies have suggested that nuclear factor kappa B (NF-kappaB) plays a key regulatory role in host cells. We have shown that preincubation with Bifidobacterium bifidum strain BF-1, a probiotic strain known to improve H. pylori-associated gastritis, suppresses induction of IL-8 by the pathogen. To investigate how how BF-1 affects gene expression in H. pylori-infected cells, we performed microarray analysis to assess gene expression in epithelial cells, which had been preincubated with BF-1 and infected with H. pylori. We found that preincubation with BF-1 suppresses the expression of H. pylori-induced genes in human cells and that most of the affected genes are related to the NF-kappaB signaling pathways. These results suggest that BF-1 can affect the regulatory mechanism of the NF-kappaB signaling pathways. PMID- 20854987 TI - A synbiotic containing Lactobacillus gasseri [corrected] CHO-220 and inulin improves irregularity of red blood cells. AB - This randomized, double-blind, placebo-controlled, and parallel-design study was conducted to investigate the effect of a synbiotic product containing Lactobacillus gasseri [corrected] CHO-220 and inulin on the irregularity in shape of red blood cells (RBC) in hypercholesterolemic subjects. The subjects (n=32) were randomly allocated to 2 groups, a treatment group (synbiotic product) and a control group (placebo), and received 4 capsules of either synbiotic or placebo daily for 12 wk. Morphological representation via scanning electron microscopy showed that the occurrence of spur RBC was improved upon supplementation of the synbiotic. In addition, the supplementation of synbiotic reduced the cholesterol:phospholipids ratio of the RBC membrane by 47.02% over 12 wk, whereas the control showed insignificant changes. Our present study also showed that supplementation of the synbiotic reduced the concentration of saturated fatty acids (SFA), increased unsaturated fatty acids (UFA), and increased the ratio of UFA:SFA over 12 wk, whereas the control showed inconspicuous changes. The alteration of RBC membrane was assessed using fluorescence anisotropy (FAn) and fluorescence probes with different affinities for varying sections of the membrane phospholipid bilayer. A noticeable decrease in FAn of three fluorescent probes was observed in the synbiotic group compared with the control over 12 wk, indicative of increased membrane fluidity and reduced cholesterol enrichment in the RBC membrane. PMID- 20854988 TI - Influence of milk pretreatment on production of free fatty acids and volatile compounds in hard cheeses: heat treatment and mechanical agitation. AB - This work aimed to identify technological steps that can increase fat hydrolysis and volatile compounds production in hard cheeses; these biochemical events have been related with improved piquant taste and development of genuine flavor during cheese ripening. For that purpose, 2 different pretreatments of cheese milk were tested: heat treatment and mechanical agitation. Both factors were assayed at 2 levels: milk was either batch pasteurized or nonthermally treated, and mechanical agitation was either applied or not applied. For all combinations, hard cheeses (Reggianito type) were produced in a pilot plant and ripened for 90 d. In all cheeses the degree of lipolysis, assessed by gas chromatography, increased similarly during ripening. However, the proportion of short-chain fatty acids was higher in the cheeses made with unpasteurized milk, suggesting a higher activity of lipases with positional specificity toward the sn-3 position of the triglyceride, among which milk lipoprotein lipase is found. Similar results were found for most of the volatile compounds, determined by solid-phase microextraction-gas chromatography flame-ionization detector/mass spectrometry, which constitute the groups of ketones, alcohols, esters, and the group of acids. On the contrary, no effect of mechanical agitation was observed, although some interactions between factors were found. In the conditions of the study, results suggest that heat treatment had a higher effect on cheese lipolysis and volatile compounds production than partial destabilization of the fat emulsion produced by the agitation method applied. PMID- 20854989 TI - Production of functional probiotic, prebiotic, and synbiotic ice creams. AB - In this work, 3 types of ice cream were produced: a probiotic ice cream produced by adding potentially probiotic microorganisms such as Lactobacillus casei and Lactobacillus rhamnosus; a prebiotic ice cream produced by adding inulin, a prebiotic substrate; and a synbiotic ice cream produced by adding probiotic microorganisms and inulin in combination. In addition to microbial counts, pH, acidity, and physical and functional properties of the ice creams were evaluated. The experimental ice creams preserved the probiotic bacteria and had counts of viable lactic acid bacteria after frozen storage that met the minimum required to achieve probiotic effects. Moreover, most of the ice creams showed good nutritional and sensory properties, with the best results obtained with Lb. casei and 2.5% inulin. PMID- 20854990 TI - Rheological properties and microstructure of Cheddar cheese made with different fat contents. AB - Reduced- and low-fat cheeses are desired based on composition but often fall short on overall quality. One of the major problems with fat reduction in cheese is the development of a firm texture that does not break down during mastication, unlike that observed in full-fat cheeses. The objective of this investigation was to determine how the amount of fat affects the structure of Cheddar cheese from initial formation (2 wk) through 24 wk of aging. Cheeses were made with target fat contents of 3 to 33% (wt/wt) and moisture to protein ratios of 1.5:1. This allowed for comparisons based on relative amounts of fat and protein gel phases. Cheese microstructure was determined by confocal scanning laser microscopy combined with quantitative image analysis. Rheological analysis was used to determine changes in mechanical properties. Increasing fat content caused an increase in size of fat globules and a higher percentage of nonspherical globules. However, no changes in fat globules were observed with aging. Cheese rigidity (storage modulus) increased with fat content at 10 degrees C, but differences attributable to fat were not apparent at 25 degrees C. This was attributable to the storage modulus of fat approaching that of the protein gel; therefore, the amount of fat or gel phase did not have an effect on the cheese storage modulus. The rigidity of cheese decreased with storage and, because changes in the fat phase were not detected, it appeared to be attributable to changes in the gel network. It appeared that the diminished textural quality in low-fat Cheddar cheese is attributed to changes in the breakdown pattern during chewing, as altered by fat disrupting the cheese network. PMID- 20854991 TI - Short communication: relationships between alpha-lactalbumin and quality traits in bulk milk. AB - The main objective of this study was to investigate whether the alpha-lactalbumin (alpha-LA) content of bulk milk is related with some known inflammatory markers and milk quality traits. An additional objective was to study whether combining alpha-LA, haptoglobin (Hp), and serum amyloid A (SAA) in an acute phase index (API) could be useful as an alternative marker for bulk milk quality. For the dairy industry, it is of great importance to receive high quality bulk milk for manufacture of liquid milk and dairy products. The somatic cell count (SCC) is currently used as an indirect marker for bulk milk quality, but because it is somewhat insensitive and unspecific, interest exists in alternative markers. Bulk milk samples were analyzed for alpha-LA, SCC, polymorphonuclear leukocyte count, Hp, SAA, fat, lactose, total protein and casein contents, casein number, protein composition, proteolysis, and coagulating properties. No significant differences were found in SCC, polymorphonuclear leukocyte count, Hp, or SAA between milk samples containing low, medium, or high concentrations of alpha-LA. Differences between alpha-LA groups were, however, found in some milk quality traits because high alpha-LA concentration was related to low concentrations of alpha(S1)-, alpha(S2)-, and beta-caseins and high concentrations of lactose and beta lactoglobulin. A high API was related to low lactose content and casein number. Samples with high SCC contained less casein and had a lower casein number than milk with a low SCC, and proteolysis was significantly higher in high SCC milk than in low SCC milk. Neither alpha-LA nor API proved to be a better marker than SCC for the quality traits investigated, and alpha-LA was not considered to be a useful inflammatory marker in bulk milk. PMID- 20854992 TI - The use of an internal teat sealant in combination with cloxacillin dry cow therapy for the prevention of clinical and subclinical mastitis in seasonal calving dairy cows. AB - Cows (n=2,053) from 6 seasonally calving dairy herds were enrolled in a trial to compare the efficacy of 2 dry cow treatments. Cows received either a combination dry cow therapy of 600 mg of cloxacillin (CL) followed by an internal teat sealant (ITS) containing 2.6 g of bismuth subnitrate in all 4 quarters immediately following their final milking for the season, or only an intramammary infusion of 600 mg of CL. All cases of clinical mastitis were recorded and cultured during the first 150 d of lactation in each herd, and cow somatic cell count (SCC) was measured between 7 and 50 d postcalving. A large difference was found between treatment groups in the rate at which cows were diagnosed with clinical mastitis over the first 21 d of lactation, after which time the rate at which cows were diagnosed with clinical mastitis was similar between treatment groups. Analysis of the relative proportions of cows with clinical mastitis was performed at both the gland and cow levels. The relative risk (RR) of clinical mastitis diagnosed within 21, 30, and 100 d of calving in a gland treated with the ITS-CL combination was, respectively, 0.30 [95% confidence interval (CI)=0.21 0.44], 0.39 (0.28-0.53), and 0.58 (0.46-0.75) that of the CL group. An interaction between treatment and previous SCC was found when clinical mastitis was analyzed at the cow level. In a subset of cows that had low SCC in their previous lactation, the RR of mastitis in cows with the ITS-CL combination within 21, 30, and 100 d of calving was, respectively, 0.54 (95% CI=0.33-0.87), 0.57 (0.37-0.88), and 0.69 (0.50-0.99) that of cows that received only CL at drying off. In the subset of cows that had at least 1 high SCC in the previous lactation, the RR of mastitis in the ITS-CL combination group within 21, 30, and 100 d of calving was, respectively, 0.26 (95% CI=0.16-0.44), 0.37 (0.24-0.57), and 0.72 (0.55-0.96) that of the CL-only group. The ITS-CL combination of dry cow treatments was associated with a reduction in subclinical mastitis [SCC >=250,000 cells/mL; RR=0.80 (95% CI=0.65-0.98)] when compared with treatment with CL alone. The use of an ITS in combination with CL dry cow treatment was associated with significantly lower clinical and subclinical mastitis in the following lactation, with a greater difference found in cows that had a history of subclinical mastitis in the previous lactation. PMID- 20854994 TI - The effect of selenium supplementation before calving on early-lactation udder health in pastured dairy heifers. AB - Selenium (Se) deficiency has been associated with lowered resistance to mastitis in dairy cattle. However, little published data exists on the effect of Se supplementation before calving on udder health of pastured dairy heifers. Further, the relative efficacy of injectable barium selenate and oral organic Se for improving udder health in cows has not previously been tested. The objectives of this study were to determine the effects of precalving Se supplementation and type of supplementation on the blood activity of glutathione peroxidase and measures of udder health immediately after calving and during the first month of lactation in pastured dairy heifers. One hundred forty pregnant Chilean Holstein Friesian heifers were fed a basal diet containing, on average, 0.15 mg of Se/kg of dry matter. One month before predicted calving, heifers were allocated to 1 of 3 groups. Group 1 (n=49) received no supplementary Se, group 2 (n=46) received a single subcutaneous injection of Se (1 mg/kg of live weight, as barium selenate), and group 3 (n=45) was fed Se yeast (3 mg/heifer/d until calving). Heifers supplemented with barium selenate had a higher glutathione peroxidase activity from 14 d in milk onwards. Selenium supplementation, irrespective of source, tended to reduce the prevalence of intramammary infection (IMI) and decrease the prevalence of quarters with high somatic cell count (SCC) at calving. Overall, Se supplementation did not result in a reduction of the incidence of new IMI or clinical mastitis or in decreased SCC during the balance of the first month of lactation. However, in pasture-based heifers injected with barium selenate before calving, and fed diets with 1.3 and 2.5 mg of Se/d precalving and during lactation, respectively, no cases of clinical mastitis were observed in the first month of lactation. PMID- 20854993 TI - Activin-related proteins in bovine mammary gland: localization and differential expression during gestational development and differentiation. AB - Bovine mammary gland morphogenesis and differentiation are regulated by actions of growth factors including members of the transforming growth factor beta superfamily. Activins A and B, which are members of the transforming growth factor beta superfamily, bind selectively to ActRIB and ActRIIA receptors and their biological effects are antagonized by inhibins and follistatins. In the present paper we evaluated gene and protein expression of the activin and inhibin subunits betaA, betaB, and alpha-inhibin and follistatin and ActRIB and ActRIIA receptors in the mammary gland of nonpregnant and pregnant heifers. Mammary glands were obtained from nonpregnant Nelore (Bos indicus) heifers (n=9) and from primigravid Nelore heifers during early (n=9), mid (n=6), and late (n=5) pregnancy. Specimens of mammary tissue were analyzed by real-time PCR and immunohistochemistry. The betaA and alpha-inhibin subunits and ActRIB and ActRIIA mRNA expression was higher in the early-pregnancy group compared with the nonpregnant group. In the mid-pregnancy group, the subunits betaA, betaB, and alpha-inhibin as much as follistatin mRNA expression was higher compared with the nonpregnant group, whereas ActRIB transcripts were absent in the late-pregnancy group. Immunostaining of these proteins, with the exception of ActRIB, was observed in the mammary tissue sections at all time points analyzed; these findings are in agreement with the observed pattern of mRNA expression. Staining and mRNA expression for ActRIB were undetected in the late-pregnancy group. In summary, the present study demonstrated that the activin-related proteins, betaA, betaB, and alpha-inhibin subunits, as much as follistatin and ActRIB and ActRIIA receptors display different patterns of expression regarding time of gestation in the bovine mammary gland. The modulation of the expression pattern during gestation suggests that activin-related proteins may play a key role in regulating bovine mammary branching morphogenesis and epithelial differentiation. PMID- 20854995 TI - Effect of cytochrome P450 and aldo-keto reductase inhibitors on progesterone inactivation in primary bovine hepatic cell cultures. AB - Progesterone is required for maintenance of pregnancy, and peripheral concentrations of progesterone are affected by both production and inactivation. Hepatic cytochrome P450 (EC 1.14.14.1) and aldo-keto reductase (EC 1.1.1.145-151) enzymes play a pivotal role in the first step of steroid inactivation, which involves the addition of hydroxyl groups to various sites of the cyclopentanoperhydrophenanthrene nucleus. The current objective was to discern the proportional involvement of hepatic progesterone inactivating enzymes on progesterone decay using specific enzyme inhibitors. Ticlopidine, diltiazem, curcumin, dicumarol, and naproxen were used because of their selective inhibition of cytochrome P450s, aldo-keto reductases, and glucuronosyltransferases. Liver biopsies were collected from 6 lactating Holstein dairy cows, and cells were dissociated using a nonperfusion technique. Confluent wells were preincubated for 4 h with enzyme inhibitor and then challenged with progesterone for 1 h. Cell viability was unaffected by inhibitor treatment and averaged 84+/-1%. In control wells, 50% of the progesterone had been inactivated after a 1-h challenge with 5 ng/mL of progesterone. Preincubation with curcumin, ticlopidine, or naproxen caused the greatest reduction in progesterone inactivation compared with controls and averaged 77, 39, or 37%, respectively. Hydroxylation of 4-nitrophenol to 4 nitrocatechol in intact cells was inhibited by approximately 65% after treatment with curcumin or ticlopidine. Glucuronidation of phenol red or 4-nitrocatechol in intact cells was inhibited by treatment with curcumin, dicumarol, or naproxen. In cytoplasmic preparations, aldo-keto reductase 1C activity was inhibited by curcumin, dicumarol, or naproxen treatment. Microsomal cytochrome P450 2C activity was inhibited by treatment with curcumin or ticlopidine, whereas cytochrome P450 3A activity was inhibited by treatment with curcumin or diltiazem. The contribution of cytochrome P450 2C and cytochrome P450 3A enzymes to progesterone inactivation in bovine hepatic cell cultures was 40 and 15%, respectively. Depending on the inhibitor used, it would appear that the aldo-keto reductase enzymes contribute approximately 40% to the observed progesterone inactivation, although a portion of this inactivation may be attributed to the loss of glucuronosyltransferase activity. Future work focusing on decreasing the activity of these enzymes in vivo could lead to an increase in the bioavailability of progesterone. PMID- 20854996 TI - Molecular characterization of Prototheca strains isolated from Italian dairy herds. AB - One hundred sixty-one Prototheca spp. strains isolated from composite milk and barn-surrounding environmental samples (bedding, feces, drinking, or washing water, surface swabs) of 24 Italian dairy herds were characterized by genotype specific PCR analysis. Overall, 97.2% of strains isolated from composite milk samples were characterized as Prototheca zopfii genotype 2, confirming its role as the main mastitis pathogen, whereas Prototheca blaschkeae was only sporadically isolated (2.8%). Regarding environmental sampling, 84.9% of isolates belonged to P. zopfii genotype 2, 13.2% to P. blaschkeae, and 1.9% to P. zopfii genotype 1. The data herein contradict previous hypotheses about the supposed exclusive role of P. zopfii genotype 2 as the causative agent of protothecal mastitis and, on the contrary, confirm the hypothesis that such pathology could be caused by P. blaschkeae in a few instances. PMID- 20854997 TI - Effect of inseminating cows in estrus following a presynchronization protocol on reproductive and lactation performances. AB - Objectives were to evaluate the effects of inseminating cows observed in estrus following a PGF(2alpha)-based presynchronization protocol on reproductive and lactation performance. Weekly, Holstein cows (260 primiparous and 379 multiparous) were balanced by parity, body condition score at 3 d in milk (DIM), and previous lactation milk yield (multiparous cows) and assigned randomly to either of 2 reproductive programs. All cows received 2 injections of PGF(2alpha) at 35 and 49 DIM and a controlled internal drug release insert containing progesterone from 42 to 49 DIM. Cows assigned to the short voluntary waiting period (SVWP) treatment were inseminated if observed in estrus after the second injection of PGF(2alpha) of the presynchronization protocol, and those not inseminated were submitted to a timed artificial insemination (TAI) protocol (GnRH 62 DIM, PGF(2alpha) 69 DIM, GnRH 71 DIM, and TAI 72 DIM), whereas cows assigned to the long voluntary waiting period (LVWP) were all submitted to the TAI protocol and were TAI at 72 DIM. Plasma progesterone was determined at 35, 49, and 62 DIM for evaluation of interval from parturition to resumption of cyclicity. Pregnancy was diagnosed weekly at 32 and 60 d after first AI and at 42 d after subsequent inseminations. Percentage of SVWP cows inseminated in estrus was 58.9% and the interval from parturition to first AI was shorter for SVWP cows (64.7+/-0.4 vs. 74.2+/-0.5 DIM). Cows cyclic by 49 and 62 DIM were more likely to be inseminated in estrus than those anovular by 62 DIM (67.9, 61.0, and 32.8%, respectively) and cyclic cows by 49 and 62 DIM had shorter interval from parturition to first AI than anovular cows (62.6+/-0.7, 63.1+/-1.2, and 70.1+/ 1.1 DIM). Treatment did not affect pregnancy per AI after first postpartum AI or the rate at which cows became pregnant. Cows that resumed cyclicity by 49 DIM had greater pregnancy per AI than cows still anovular by 62 DIM and became pregnant at a faster rate than cows that resumed cyclicity by 62 DIM and those still anovular by 62 DIM. Inseminating cows that displayed estrus after the presynchronization protocol did not affect reproductive performance compared with submission of 100% of cows to a TAI protocol. PMID- 20854998 TI - Output of selenium in milk, urine, and feces is proportional to selenium intake in dairy cows fed a total mixed ration supplemented with selenium yeast. AB - Fifteen rumen fistulated Holstein cows in late lactation and fed a total mixed ration offered ad libitum were supplemented with Se yeast to provide 0, 11, 20, 30, or 42 mg of supplemental Se/day to test the hypothesis that amounts of Se secreted in milk, excreted in urine and feces, and apparently retained in tissues would increase in direct proportion to Se intake. One-half of the yeast supplement was placed directly into the rumen through the fistula of each cow just before milking in the morning and again in the evening, and estimates of average daily excretion of Se were made using total collections of urine and feces from 25 to 31 d after treatments commenced. Amounts of Se secreted daily in milk and apparently retained in tissues increased linearly with average daily intake of Se. The amount of Se excreted in feces and total excretion of Se in urine plus feces increased curvilinearly with Se intake, such that proportionately less Se was excreted as the amount of Se fed increased. On average, total Se excretion accounted for 66%, Se secretion in milk accounted for 17%, and Se apparently retained in tissues accounted for 17% of total Se intake by cows. Thus, in herds fed large amounts of Se yeast, most of the Se will be excreted and retained on-farm. High concentrations of Se will be found where urine and feces accumulate (e.g., yards and effluent ponds), and effluent management practices must be tailored to avoid environmental issues. PMID- 20854999 TI - Activation of liver X receptor (LXR) enhances de novo fatty acid synthesis in bovine mammary epithelial cells. AB - Liver X receptor (LXR) is a nuclear receptor and a known regulator of lipid synthesis in rodents; however, the role of LXR in the regulation of fatty acid synthesis in bovine mammary epithelial cells has not yet been defined. The objective of the study was to evaluate the effect of LXR activation on the de novo synthesis of fatty acids in bovine mammary epithelial cells (BME-UV). Bovine mammary epithelial cells were treated with T0901317 (T09), an LXR agonist. Treatment of BME-UV with T09 increased the transcription of ATP-binding cassette transporter-G1, an LXR target gene, without modifying LXRalpha mRNA abundance. Acute and chronic treatment of BME-UV with T09 dramatically increased de novo fatty acid synthesis. Activation of LXR resulted in the upregulation of transcription, translation, and proteolytic cleavage of sterol regulatory element binding protein-1 (SREBP1), a lipogenic transcription factor expressed in the bovine mammary gland. Additionally, the mRNA abundance of fatty acid synthase, an LXR and SREBP1 target gene, increased in response to LXR activation. Our data indicate that SREBP1 is regulated by LXR activation in BME-UV. Controlling LXR activation may prove useful in regulating milk fat production in lactating dairy cows. PMID- 20855000 TI - The Garfagnina goat: a zootechnical overview of a local dairy population. AB - Domestic livestock with a limited distribution are increasingly recognized in the action plans of the European Union as a reason for protecting rural land. The preservation and enhancement of the native germplasm and traits selected through the ages in different areas of farming is the first step in increasing typical products at a time when high quality products are increasingly in demand. This is the first time that a zootechnical overview has been performed on the Italian native goat population named "Garfagnina," which is registered on the Tuscan regional repertory of genetic resources at risk of extinction. The aim of the study was to give added value to this population by focusing on particular traits that could be used for promoting typical products. Data on the size of the local goats, zoometric measures, breeding system, milk quality, and genetic polymorphisms were collected to get insight into the current state of the population of this type of goat. The native goat population is reared in Tuscany in central Italy, mostly for its milk. The local goat farms considered in our study are located in the hills and mountains of the northwestern Tuscan Apennine area. For every farm we measured at least 10% of the reproductive females (273), randomly chosen, and all reproductive males (47) for a total of 320 subjects. Regarding the management of the animals and the feeding system, semi-extensive farming is practiced in all the flocks. From a morphological point of view the animals are relatively homogeneous, especially in terms of zoometric data, whereas they show a wider variability regarding coat. Milk gross and fatty acid composition were similar to that reported in the literature for bulk goat milk. Moreover, the average of somatic cell count and standard plate count found in Garfagnina goat milk indicated good hygienic farm management and correct milking practices, although milking is mainly manual. The average number of globules per milliliter found in Garfagnina goat milk was almost double compared with the literature, whereas the average diameter was lower. Milk coagulation properties were scarce, thus indicating poor cheesemaking aptitude of Garfagnina milk. Selecting haplotypes carrying alleles associated with a higher expression of the specific casein could help improve milk cheesemaking aptitude. Moreover, the rather high frequency of the faint CSN1S1*F allele and the occurrence of CSN2*0 might suggest that Garfagnina goat milk could be used, after an appropriate selection, for direct consumption of milk at low casein content for intolerant human subjects. PMID- 20855001 TI - Associations between cow hygiene, hock injuries, and free stall usage on US dairy farms. AB - This cross-sectional study evaluated cow comfort measures in free stall dairies across the United States as part of the National Animal Health Monitoring System's Dairy 2007 study. The study was conducted in 17 states and evaluations were completed between March 5 and September 5, 2007. Assessors recorded hygiene and hock scores, number of cows housed in the pen, the number of cows standing with only the front feet in a stall, standing fully in a stall, and lying in a stall. Facility design measures included bedding type, bedding quantity, stall length and width, presence of a neck rail or brisket locator, and relevant distances from the rear and bed of the stall. Of the 491 operations that completed the cow comfort assessment, 297 had Holstein cows housed in free stalls and were included in this analysis. Negative binomial models were constructed to evaluate the following outcomes: the number of cows that were very dirty, had severe hock injuries, stood with front feet in the stall, stood with all feet in the stall, and were lying in the stall. Hygiene was better on farms that did not tail dock cows compared with those that did (5.7 vs. 8.8% were dirty) and on farms located in the study's west region compared with those located in the east region (5.2 vs. 9.7% were dirty). Severe hock injuries were less common on farms in the west than those in the east (0.5 vs. 4.1%). In addition, severe hock injuries were less common on farms that used dirt as a stall base or sand as bedding compared with farms that did not. A higher percentage of cows was standing with front feet in the stall at higher ambient temperatures (incidence rate ratio=1.016) and as time since feeding increased (incidence rate ratio=1.030). A lower percentage of cows were standing with front feet in the stall when the stalls were shorter and when there were fewer cows per stall. Standing fully in a stall was performed by a higher percentage of cows during the summer than during the spring (13.6 vs. 8.1%), when cows were provided free stalls with rubber mats or mattresses, and as the distance from the rear curb to neck rail increased. A higher percentage of cows were lying in a stall when sand bedding was used, when bedding was added more frequently, and during the spring months. Results of this national survey indicate that tail docking provides no benefit to cow hygiene and that stall base and bedding are key factors influencing hock injuries and stall usage on US free stall dairy farms. PMID- 20855002 TI - Use of individual cow milk recording data at the start of lactation to predict the calving to conception interval. AB - Milk recording data collected in 2,128 dairy herds in England and Wales between 2004 and 2006 were used to predict the calving to conception intervals. The average cumulative milk production was 8,200 kg. Conception (or not) within 5 intervals measured in days (20 to 60 d, 61 to 81 d, 82 to 102 d, 103 to 123 d, 124 to 144 d) was modeled as a function of milk yields and milk constituents at the start of lactation using multilevel discrete-time survival models. Milk yield, weight and percentage of fat, protein, and lactose, and somatic cell counts on the first 2 test-days of lactation were corrected for either stage of lactation alone or stage of lactation and time of year. Five hundred and 1,628 herds, respectively, were used for parameter estimation and cross-validation. Covariates were retained in the final model if their coefficient was at least twice its standard error and their inclusion resulted in a decrease in the deviance. Overall, 73% of cows recalved. The percentage of cows that had conceived by d 20, 61, 82, 103, 124, and 145 were 0.5, 7.3, 17.9, 29.3, 38.7, and 46, respectively. The probability of conception before 145 d in milk increased with lower milk production on the second test-day, higher percentage of protein on the second test-day, and higher percentage of lactose on the first test-day. Positive associations were of a limited magnitude but nonetheless significant with the percentage of protein on the first test-day, the percentage of butterfat on the first test-day, and somatic cell count on both test-days. The model predicted the probability of conception in the cross validation data set very well. Despite the common use of fat to protein ratio as a measure of energy balance, this parameter exhibited wide variation with stage of lactation and time of the year and had a much-reduced ability to predict an early conception compared with other combinations of milk quantity and constituents. PMID- 20855003 TI - Blood profiles in dairy cows with displaced abomasum. AB - An observational study was carried out in Swedish dairy herds to investigate differences between cows with and without displaced abomasum (DA), in concentrations of glucose, insulin, fructosamine, nonesterified fatty acids (NEFA), beta-hydroxybutyrate, cholesterol, haptoglobin, increased enzyme activity of aspartate aminotransferase and glutamate dehydrogenase, and the revised Quantitative Insulin Sensitivity Check Index (RQUICKI). A secondary aim was to study how blood profiles for DA cows vary with time in relation to calving. Sixty nine DA cows within 2 to 56 d postpartum, in 60 herds, were clinically examined and blood samples were drawn at the time DA was diagnosed. At the same time, 104 healthy control cows matched by herd and stage of lactation were also sampled. The blood parameters were studied using mixed linear models, including herd as a random effect, and DA (case or control), parity, breed, sampling time in relation to calving, other diseases, and the interaction between DA and time as fixed effects. Concentrations were higher in DA cows than in control cows for NEFA (least squares means 1.36 vs. 0.34 mmol/L), beta-hydroxybutyrate (1.56 vs. 0.90 mmol/L), aspartate aminotransferase (1.96 vs. 0.97 MUkat/L), glutamate dehydrogenase (197 vs. 78 MUkat/L), and haptoglobin (0.76 vs. 0.17 g/L), whereas concentrations were lower in DA cows than in control cows for insulin (3.61 vs. 8.48 mU/L) and cholesterol (3.04 vs. 3.75 mmol/L). Glucose (2.83 vs. 2.79 mmol/L) and fructosamine (266 vs. 252 MUmol/L) concentrations were similar in both groups; however, a tendency toward lower RQUICKI values (0.42 vs. 0.46) in the DA cows was found, indicating reduced insulin sensitivity. For most blood parameters, differences between DA cows and controls remained constant over time. Seventy-two percent of the DA cows had at least one other disease in the period from 1 wk antepartum to 1 wk after the DA was diagnosed. Haptoglobin could potentially be used to detect treatable infectious or inflammatory conditions in the early postpartum period, possibly reducing the incidence of DA. Consequently, there were major changes in blood profiles in cows with DA compared with healthy control cows, indicating a negative energy balance, liver cell damage, and an inflammatory response. The results contribute to an understanding of the metabolic changes in DA cows. PMID- 20855004 TI - Milk selenium concentration and its association with udder health in Atlantic Canadian dairy herds. AB - Soils and plants in Atlantic Canadian provinces are known to contain low concentrations of selenium (Se). Earlier studies have indicated that dairy producers in Atlantic Canada are providing insufficient supplementary Se in the ration to meet the Se requirements of dairy cattle, as measured by herd-level milk Se concentration. The objective of this study was to evaluate the association between milk Se concentration and somatic cell count (SCC) and the risk of new intramammary infection (IMI) in the dry period, in Atlantic Canadian dairy cows. Eighteen dairy farms participating in the Canadian Bovine Mastitis Research Network cohort study were selected as a convenience sample. On each farm 15 cows to be dried off were selected. Quarter milk samples were collected at 4 and 2 wk before drying-off, within 24 h after calving, and at 7 d after calving to evaluate IMI status. Composite milk samples were analyzed for SCC and Se concentration. Mean milk Se concentration was marginal in 14% of the cows that were on pasture during the grazing season. Milk Se concentration was not associated with the overall odds of new IMI in the dry period; however, the odds of having a new Streptococcus spp. and other gram-positive pathogen IMI in the dry period increased with increasing milk Se concentration. Somatic cell count increased with milk Se concentration, even after adjusting for IMI status. The dairy population in our study had higher ranges for milk Se concentration, whereas ranges for prevalence of IMI, and SCC were lower, compared with those in studies where a negative relationship between Se status and udder health was first noted. Therefore, under the current management conditions, milk Se concentration did not appear to be a principal determinant of udder health. PMID- 20855005 TI - Diagnosis and treatment of subclinical mastitis in early lactation in dairy goats. AB - The objectives of the study were to define the sensitivity and specificity of the California Mastitis Test (CMT) in determining the presence of intramammary infection in postpartum dairy goats and to determine whether antibiotic therapy increased bacteriological cure rate and lowered somatic cell count (SCC) compared with untreated controls. A CMT was performed and milk samples were collected for bacteriology from 211 glands of 106 does between 0 and 10 d after kidding. From a population of 3,239 glands from goats in 4 commercial herds, goats with one or both glands with a CMT score of >1 and from which bacteria were isolated were either assigned to be treated with 3 intramammary infusions at 12-h intervals of 75 mg of sodium ampicillin and 250 mg of sodium cloxacillin (n=57 glands) or left as untreated controls (n=49 glands). Milk samples were collected again 14 +/- 3 and 21 +/- 3 d later for bacteriology and SCC determination. Composite milk yield, goat SCC, length of lactation, and survival data were collected. A partial budget was constructed to assess the cost effectiveness of treatment. At a cut point of greater than trace, the sensitivity, specificity, and positive and negative predictive values of the CMT were 0.74, 0.74, 0.42, and 0.92, respectively. Treatment increased the bacteriological cure rate compared with no treatment [30/57 (53%) vs. 6/49 (12%)], but there was a pathogen by treatment interaction whereby treatment increased cure proportion in glands infected with minor, but not major, pathogens. Treatment reduced the foremilk gland-level SCC [1,595 (95% CI=1,106-2,300) vs. 3,028 (95% CI=2,091-4,385) geometric mean (* 1,000) cells/mL] but not the SCC at goat level [1,596 (95% CI=1,219-2,090) vs. 1,488 (95% CI=1,132-1,955) geometric mean (* 1,000) cells/mL] compared with no treatment. Milk yield, risk of removal from the herd, and length of lactation were not altered by treatment. Treatment resulted in a loss of NZ$20.39/doe. It was concluded that use of the CMT as a screening test resulted in a higher likelihood of finding a gland that would be infected than selecting a gland at random. Treatment increased bacteriological cure rate and reduced SCC at gland level compared with no treatment. However, at goat level, milk yield, SCC, and survival were not altered, resulting in no economic benefit of treatment. PMID- 20855006 TI - Localization of Mycobacterium avium subspecies paratuberculosis in artificially inoculated milk and colostrum by fractionation. AB - The purpose of the study was to determine the distribution of Mycobacterium avium ssp. paratuberculosis (MAP) across the main milk and colostrum fractions (cream, curd, and whey). Raw milk and colostrum were inoculated with 1 of 2 MAP strains, ATCC 19698 or S-23, yielding initial concentrations of 10(6) to 10(7) cfu/mL. After fractionation, for milk as well as for colostrum, 80 to 90% of the recovered MAP cells were found in the curd fraction and 10 to 20% in the cream fraction. Total MAP colony counts in milk whey were 4 to 5 log(10) units lower than colony counts of inoculated milk. In colostrum, colony counts were 2 to 3 log(10) units lower in whey than in inoculated colostrum. Because of the slow growth of MAP and to proceed more smoothly with set-up and optimization of the method, luminescent MAP strains were used. The high correlation coefficient (r=0.960) between colony counts and luminescence measurements showed that the use of luminescent MAP strains during method development was plausible. PMID- 20855007 TI - Short communication: analysis of milk yield and composition for dairy heifers limit-fed lower forage diets during the rearing period. AB - Methods to improve feed efficiency in dairy heifers have been studied that employ limit feeding and high concentrate or highly digestible diet ingredients. To date, the published studies have used differing daily gains, diet components, and management systems. All of these studies have had limited numbers of animals, which limits the power of each study by itself. The objective of this analysis was to evaluate, using all available studies, the overall effect of limit feeding dairy heifers during the rearing phase on milk production and composition during the first lactation. To accomplish this objective, responses from published experiments were analyzed using random effects meta-analytic procedures. The results of this analysis confirmed the results of the individual experiments in that no significant differences were found in lactation performance between the limit-fed, lower forage diets and the higher forage control diets. Heterogeneity of results between experiments was low to moderate for the response variables evaluated, indicating that the results were reasonably consistent among the trials. Limit feeding of higher concentrate diets represents a viable alternative to traditional high forage heifer feeding systems when environmental or economic conditions favor these systems. PMID- 20855008 TI - Evaluation of in vitro gas production and rumen bacterial populations fermenting corn milling (co)products. AB - The objective of this study was to evaluate the fermentation dynamics of 2 commonly fed corn (co)products in their intact and defatted forms, using the in vitro gas production (IVGP) technique, and to investigate the shifts of the predominant rumen bacterial populations using the 16S rDNA bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP) technique. The bTEFAP technique was used to determine the bacterial profile of each fermentation time at 24 and 48 h. Bacterial populations were identified at the species level. Species were grouped by substrate affinities (guilds) for cellulose, hemicellulose, pectin, starch, sugars, protein, lipids, and lactate. The 2 (co)products were a dried distillers grain (DDG) plus solubles produced from a low-heat drying process (BPX) and a high-protein DDG without solubles (HP). Chemical analysis revealed that BPX contained about 11.4% ether extract, whereas HP contained only 3.88%. Previous studies have indicated that processing methods, as well as fat content, of corn (co)products directly affect fermentation rate and substrate availability, but little information is available regarding changes in rumen bacterial populations. Fermentation profiles of intact and defatted BPX and HP were compared with alfalfa hay as a standard profile. Defatting before incubation had no effect on total gas production in BPX or HP, but reduced lag time and the fractional rate of fermentation of BPX by at least half, whereas there was no effect for HP. The HP feed supported a greater percentage of fibrolytic and proteolytic bacteria than did BPX. Defatting both DDG increased the fibrolytic (26.8 to 38.7%) and proteolytic (26.1 to 37.2%) bacterial guild populations and decreased the lactate utilizing bacterial guild (3.06 to 1.44%). Information regarding the fermentation kinetics and bacterial population shifts when feeding corn (co)products may lead to more innovative processing methods that improve feed quality (e.g., deoiling) and consequently allow greater inclusion rates in dairy cow rations. PMID- 20855009 TI - Inclusion of psyllium in milk replacer for neonatal calves. 2. Effects on volatile fatty acid concentrations, microbial populations, and gastrointestinal tract size. AB - Fermentable fibers such as psyllium increase volatile fatty acid (VFA) concentrations in the lower digestive tract and increase the gastrointestinal tract (GIT) mass of many mammals. We reasoned that psyllium inclusion in milk replacer might produce similar effects in neonatal dairy calves, which could lead to improved growth and health. Male Holstein calves were fed a milk replacer (22% crude protein, 20% fat) either without or with psyllium (1.1% of dry matter, DM) from 2 d through 28 d of age. Milk replacer was reconstituted to 12.5% DM and fed at 12% of calf body weight, adjusted weekly. Water was offered ad libitum but no starter was fed. Three calves per treatment were harvested weekly to sample digesta from the reticulo-rumen, abomasum, jejunum, proximal colon, and distal colon, and to determine length and mass of GIT components. Psyllium in milk replacer increased the proportion of butyrate in reticulo-rumen contents from 2.4 to 3.2% of total but did not affect total VFA concentrations. Total VFA concentrations were very low in the jejunum but psyllium tended to increase total VFA, acetate, and valerate concentrations; valerate accounted for 15.9 and 16.7% of total VFA (molar basis) for control and psyllium calves, respectively. Psyllium increased total VFA concentrations in the proximal and distal colon by 104.4 and 45.6%, respectively, but had little effect on the profile of VFA. Psyllium in milk replacer increased populations of bifidobacteria (from 9.7 to 10.3 log(10) cfu/g of DM) and lactobacilli (from 8.2 to 9.4 log(10) cfu/g of DM) in the reticulo-rumen, but did not affect populations in jejunum or colon. Calves fed psyllium had 12.0% greater total GIT mass and 9.4% greater GIT as a percentage of body weight. Psyllium tended to increase mass of the reticulo-rumen and significantly increased mass of duodenum (34.2%), jejunum (14.5%), and colon (14.6%). Density of intestinal tissues from calves fed psyllium-supplemented milk replacer was 25.9% greater in the jejunum and 25.3% greater in the ileum, and tended to be greater in duodenum and colon than tissue from control calves. Supplementation of psyllium to milk replacer increased fermentation in the colon, mass of the total GIT, and populations of bifidobacteria and lactobacilli in the reticulo-rumen. PMID- 20855010 TI - Effect of induction of subacute ruminal acidosis on milk fat profile and rumen parameters. AB - High-concentrate diets can lead to subacute ruminal acidosis and are known to result in changes of the ruminal fermentation pattern and mammary secretion of fatty acids. The objective of this paper is to describe modifications in milk fatty acid proportions, particularly odd- and branched-chain fatty acids and rumen biohydrogenation intermediates, associated with rumen parameters during a 6 wk subacute ruminal acidosis induction protocol with 12 ruminally fistulated multiparous cows. The protocol involved a weekly gradual replacement of a standard dairy concentrate with a wheat-based concentrate (610 g of wheat/kg of concentrate) during the first 5 wk and an increase in the total amount of concentrate in wk 6. Before the end of induction wk 6, cows were switched to a control diet because 7 cows showed signs of sickness. The pH was measured continuously by an indwelling pH probe. Milk and rumen samples were taken on d 2 and 7 of each week. Data were analyzed using a linear mixed model and by principal component analysis. A pH decrease occurred after the first concentrate switch but rumen parameters returned to the original values and remained stable until wk 5. In wk 5 and 6, rumen pH values were indicative of increasing acidotic conditions. After switching to the control diet in wk 6, rumen pH values rapidly achieved normal values. Odd- and branched-chain fatty acids and C18:1 trans-10 increased with increasing amount of concentrate in the diet, whereas C18:1 trans 11 decreased. Four fatty acids [C18:1 trans-10, C15:0 and C17:0+C17:1 cis-9 (negative loadings), and iso C14:0 (positive loading)] largely correlated with the first principal component (PC1), with cows spread along the PC1 axis. The first 4 wk of the induction experiment showed variation across the second principal component (PC2) only, with high loadings of anteiso C13:0 (negative loading) and C18:2 cis-9,trans-11 and C18:1 trans-11 (positive loadings). Weeks 5 and 6 deviated from PC2 and tended toward the negative PC1 axis. A discriminant analysis using a stepwise approach indicated the main fatty acids discriminating between the control and acidotic samples as iso C13:0, iso C16:0, and C18:2 cis 9,trans-11 rather than milk fat content or C18:1 trans-10, which have been used before as indicators of acidosis. This shows that specific milk fatty acids have potential in discriminating acidotic cases. PMID- 20855011 TI - Effects of supplementing dairy cows with chromium propionate on milk and tissue chromium concentrations. AB - Eight primiparous and 8 multiparous Holstein cows were used to determine the effects of Cr supplementation, in the form of Cr propionate (Cr Prop), on milk and tissue Cr concentrations. Cows were randomly assigned by parity to one of 2 diets: 1) control diet or 2) 2 mg of supplemental Cr/kg of DM. The level of Cr Prop supplemented exceeded by 4-fold the concentration of 0.5 mg of Cr/kg permitted by the FDA. Experimental diets were fed from approximately 30 d prepartum until at least 91 d postpartum, resulting in a minimum of 121 d of exposure to supplemental Cr. The control prepartum and postpartum diets analyzed 0.48 and 0.38 mg of Cr/kg of DM, respectively. Milk samples were obtained from the a.m. milking on d 0 (colostrum), 7, 14, 21, 28, 42, 56, 77, and 90 and on the final day of the study for Cr analysis. Cows were harvested after lactating for a minimum of 91 d and samples of liver, kidney, semitendinosus muscle, and fat were obtained for Cr analysis. Chromium was measured using electrothermal atomic absorption spectrophotometry. Milk Cr concentration averaged 1.7 ng/mL and was affected by day of lactation but not by Cr or a Cr * day interaction. Supplementation of 2 mg of Cr/kg of DM increased kidney Cr by approximately 3 fold and liver Cr concentrations by approximately 2-fold. Chromium concentrations in muscle and fat were not affected by Cr supplementation. In summary, supplementation of Cr Prop at a level of 2 mg of Cr/kg of DM did not affect Cr concentration in milk, muscle, or fat, the major bovine products consumed by humans. PMID- 20855012 TI - Abomasal or ruminal administration of flax oil and hulls on milk production, digestibility, and milk fatty acid profile of dairy cows. AB - Four ruminally fistulated primiparous lactating Holstein cows were assigned to a 4 * 4 Latin square design to determine the effects of the site of administration (rumen or abomasum) of flax oil and flax hulls on diet digestibility and milk fatty acid profile of dairy cows. The treatments were 1) oil and hulls administered in the rumen and abomasal infusion of water (RUM/RUM), 2) oil and hulls infused in the abomasum (ABO/ABO), 3) oil administered in the rumen and hulls infused in the abomasum (RUM/ABO), and 4) oil infused in the abomasum and hulls placed in the rumen (ABO/RUM). Cows on the ABO/ABO and RUM/RUM treatments had the highest and lowest amounts of basal dry matter eaten, respectively. Higher dry matter digestibility was obtained when flax oil bypassed the rumen (ABO/ABO and ABO/RUM) compared with when flax oil was administered directly in the rumen (RUM/ABO and RUM/RUM). Apparent digestibility of ether extract was higher when flax hulls were administered in the rumen (RUM/RUM and ABO/RUM) compared with when flax hulls were infused in the abomasum (ABO/ABO and RUM/ABO). The lowest digestibility of acid detergent fiber and neutral detergent fiber was obtained when both flax products were added in the rumen, which may be attributed to the high amount of oil present in the rumen (7.8% of total dry matter input). The lowest yield of 4% fat-corrected milk was obtained for cows on the RUM/RUM treatment, probably as a result of lower dry matter intake and digestibility of fiber. Milk concentrations of protein, fat, total solids, and lactose were similar among treatments. Administration of oil and hulls in the rumen resulted in the highest concentrations of intermediate products of biohydrogenation and total trans fatty acids in milk fat compared with the other treatments. All ratios of n-6 to n-3 fatty acids in milk fat were lower than the 4 to 1 ratio recommended to improve human health. These results suggest that the presence of both flax oil and flax hulls in the rumen decreases 4% fat-corrected milk yield and digestibility but provides a desirable fatty acid profile of milk to enhance consumers' health. PMID- 20855013 TI - Effect of feed sorting on chewing behavior, production, and rumen fermentation in lactating dairy cows. AB - Ration sorting is thought to allow cows to eat different rations throughout the day, causing fluctuations in rumen fermentation patterns that can be detrimental to production and possibly animal health. The objective of this experiment was to study the effects of varying total mixed ration (TMR) particle size on sorting behavior of lactating dairy cows and to evaluate effects on chewing behavior, milk yield, milk components, and rumen fermentation. Eight multiparous, Holstein cows (90+/-32 d in milk; 4 rumen cannulated) were randomly assigned to replicated 4*4 Latin squares. Cows were fed diets that varied in the chop length of dry grass hay. The diet consisted of 29.4% corn silage, 22.9% ground corn, 17.6% alfalfa haylage, and 11.8% dry grass hay on a dry matter basis. The percentage of hay particles >26.9 mm was 4.2, 34.1, 60.4, and 77.6% for the short (S), medium (M), long (L), and extra long (XL) hays, respectively. This resulted in the TMR of each diet having 1.5 (S), 6.5 (M), 8.6 (L), and 11.7% (XL) of particles >26.9 mm. Daily ruminating time [19.3, 19.2, 22.4, and 21.3 min/kg of dry matter intake (DMI) for S, M, L, and XL] and eating time (13.9, 14.6, 17.2, and 16.1 min/kg of DMI for S, M, L, and XL) increased linearly as TMR particle size increased. Daily DMI decreased linearly as TMR particle size increased and was 26.9 (S), 27.0 (M), 24.1 (L), and 25.1 (XL) kg/d. No differences were found in rumen volatile fatty acids and NH(3), and only slight changes were found in rumen pH. Milk production and milk components were also similar among diets. Despite large differences in particle size among these diets and certain chewing and ruminating differences, no changes in rumen fermentation, milk production, or milk components were found in this study. PMID- 20855014 TI - Effect of fish oil and sunflower oil on rumen fermentation characteristics and fatty acid composition of digesta in ewes fed a high concentrate diet. AB - Studies in ruminants have shown that supplementing the diet with a mixture of fish oil (FO) and sunflower oil (SO) enhances the concentration of cis-9, trans 11 conjugated linoleic acid (CLA), 20:5 n-3, and 22:6 n-3 in milk because of alterations in ruminal biohydrogenation, but the intermediates formed under these conditions are not well characterized. Five ewes fitted with rumen cannula and fed a high concentrate diet were used to examine the effect of a mixture (30 g/kg of DM) of FO and SO (1:2, wt/wt) on temporal changes in rumen fermentation characteristics and the relative abundance of biohydrogenation intermediates in ruminal digesta collected after 0, 3, and 10 d on diet. Appearance and identification of biohydrogenation intermediates was determined based on complementary gas-liquid chromatography and Ag+-HPLC analysis of fatty acid methyl esters and gas chromatography-mass spectrometry analysis of corresponding 4,4-dimethyloxazoline derivatives. Inclusion of FO and SO in the diet had no effect on rumen pH, volatile fatty acid concentrations, or nutrient digestion, but altered the fatty acid composition of ruminal digesta, changes that were characterized by time-dependent decreases in 18:0 and 18:2 n-6 and the accumulation of trans 16:1, trans 18:1, 10-O-18:0, and trans 18:2. Lipid supplements enhanced the proportion of 20:5 n-3 and 22:6 n-3 in digesta and resulted in numerical increases in cis-9, trans-11 conjugated linoleic acid concentrations, but decreased the relative abundance of trans-10, cis-12 conjugated linoleic acid. Furthermore, detailed analysis revealed the appearance of several unique 20:1, 20:2, 22:1, 22:3, and 22:4 products in ruminal digesta that accumulated over time, providing the first indications of 20 and 22 carbon fatty acid intermediates formed during the biohydrogenation of long-chain unsaturated fatty acids in sheep. In conclusion, FO and SO in a high concentrate diet caused a time-dependent inhibition of the complete biohydrogenation of 16 and 18 carbon unsaturated fatty acids, and resulted in the accumulation of trans 16:1, trans 18:1, and trans 18:2, 20, and 22 carbon metabolites in ruminal digesta of sheep, with no evidence of a shift in ruminal biohydrogenation pathways toward trans-10 18:1 formation. PMID- 20855015 TI - Effects of stage of lactation and dietary concentrate level on energy utilization by Alpine dairy goats. AB - Twenty-four lactating and 13 nonlactating Alpine goats were used to determine effects of stage of lactation and dietary concentrate level on energy utilization. Diets comprising 60 or 20% concentrate (60%C and 20%C, respectively) were consumed ad libitum by lactating animals and at a level of intake near maintenance by nonlactating animals. Measurement periods were d 25 to 31 (early), 87 to 94 (mid), and 176 to 183 (late) of lactation. Eleven observations were made in early and mid lactation for each diet, and 8 and 7 were made in late lactation for the 60%C and 20%C diets, respectively. Efficiency of metabolizable energy (ME) use for maintenance (66.9, 71.4, and 61.1% for early, mid, and late lactation, respectively) and the maintenance ME requirement (479, 449, and 521 kJ/kg of BW(0.75) for early, mid, and late lactation, respectively) determined with nonlactating animals differed among stages of lactation. The efficiency of ME use for maintenance was similar between diets, but the maintenance requirement tended to be greater for the 60%C than for the 20%C diet (504 vs. 463 kJ/kg of BW(0.75)). The latter difference may have involved greater ME intake for the 60%C diet, resulting in a slightly greater difference between ME intake and total heat energy for the 60%C compared with the 20%C diet (11 vs. -8 kJ/kg of BW(0.75)). Intake of ME by lactating goats was greater for the 60%C than for the 20%C diet (18.6 vs. 16.3 MJ/d). Recovered energy in lactation from mobilized tissue tended to be greater for the 60%C than for the 20%C diet (8.44 vs. 6.55 MJ/d) and differed among stages of lactation (2.60, 1.59, and 1.13 MJ/d in early, mid, and late lactation, respectively). Recovered energy in tissue gain was similar among stages of lactation and between diets and was not different from 0. Efficiency of use of dietary ME for lactation differed among stages of lactation (59.5, 51.9, and 65.4% for early, mid, and late lactation, respectively) and tended to be greater for the 60%C than for the 20%C diet (64.2 vs. 54.9%). The efficiency of use of dietary ME for maintenance and lactation was similar among stages of lactation and was greater for the 60%C compared with the 20%C diet (64.3 vs. 60.9%). Predicted milk yield from National Research Council requirements was reasonably accurate. In conclusion, using data of nonlactating goats to study energy utilization for maintenance in lactation has limitations. Efficiency of energy use by lactating dairy goats consuming diets high in concentrate appears greater than that by goats consuming diets low in concentrate. Despite differences in nutrient requirement expressions, observations of this study support National Research Council recommendations of energy requirements of lactating dairy goats. PMID- 20855016 TI - Effects of stage of lactation and level of feed intake on energy utilization by Alpine dairy goats. AB - Thirty-six lactating Alpine does were used to determine effects of stage of lactation and level of feed intake on energy utilization. Twelve does were assigned to measurement periods in early, mid, and late lactation (wk 5, 13, and 27, respectively). For 6 does of each group, after ad libitum consumption of a 60% concentrate diet, feed intake was restricted to near the metabolizable energy (ME) requirement for maintenance (ME(m)) for 8 d followed by fasting for 4 d. For other does, fasting immediately followed ad libitum consumption. Intake of ME was similar among stages of lactation with ad libitum intake (22.1, 22.1, and 19.8 kJ/d in early, mid, and late lactation, respectively). The efficiency of ME use for maintenance determined with does fed near ME(m) averaged 81%. Fasting heat energy was greater for ad libitum consumption than for near ME(m) consumption [368 vs. 326 kJ/kg of body weight (BW)(0.75)] and was numerically lowest among stages in late lactation with near ME(m) intake (334, 350, and 295 kJ/kg of BW(0.75) in early, mid, and late lactation, respectively) and ad libitum consumption (386, 384, and 333 kJ/kg of BW(0.75) in early, mid, and late lactation, respectively). The efficiency of use of dietary ME for lactation was greater for consumption near ME(m) than for consumption ad libitum (67.9 vs. 58.6%) and with ad libitum consumption tended to decrease with advancing stage of lactation (63.9, 57.3, and 54.5% for early, mid, and late lactation, respectively). Estimated ME(m) was greater for ad libitum intake than for near ME(m) intake and was lowest during late lactation (429, 432, and 358 kJ/kg of BW(0.75) for near ME(m) intake and 494, 471, and 399 kJ/kg of BW(0.75) for ad libitum intake in early, mid, and late lactation, respectively). However, because of increasing BW as the experiment progressed, ME(m) (MJ/d) was similar among stages of lactation with both levels of intake. The efficiency of ME use for maintenance and lactation was similar among stages of lactation and greater with near ME(m) intake than ad libitum intake (77.1 vs. 67.7%). In conclusion, the ME(m) requirement (kJ/kg of BW(0.75)) of does in late lactation was less than in early and mid lactation. A marked effect of restricted feed intake subsequent to ad libitum consumption on estimates of efficiency of energy use for maintenance and lactation was observed compared with use of nonlactating animals. Level of feed intake can have substantial effect on estimates of energy utilization by lactating dairy goats. PMID- 20855017 TI - A single mild episode of subacute ruminal acidosis does not affect ruminal barrier function in the short term. AB - Twenty-four German Merino sheep (72.3+/-10.1 kg of body weight) were fed an all hay diet and assigned to either the subacute ruminal acidosis (SARA) treatment (n=17) or sham treatment (n=7). The SARA sheep were orally dosed with a 2.2 M glucose solution to supply 5 g of glucose/kg of body weight, whereas sham sheep received an equal volume of water. Ruminal pH was measured for 48 h before and 3 h after the oral dose. Sheep were then killed and ruminal epithelia from the ventral sac were mounted in Ussing chambers. The serosal-to-mucosal flux rate of partially (3)H-labeled mannitol (J(mannitol-SM)), an indicator of barrier function, was measured while epithelia were exposed to 3 sequential in vitro measurement periods lasting 1 h each. The measurement periods consisted of baseline, challenge, and recovery periods and were interspersed by 30-min periods for treatment equilibration. Baseline conditions were pH 6.1 (mucosal solution) and pH 7.4 (serosal solution) with a bilateral osmolarity of 293 mOsm/L. During the challenge period, the mucosal side of the epithelia was exposed to either an acidotic challenge (pH 5.2, osmolarity 293 mOsm/L) or an osmotic challenge (pH 6.1, osmolarity 450 mOsm/L); a third group served as control (pH 6.1, osmolarity 293 mOsm/L). The mucosal buffer solution was replaced for the recovery period. In vivo, sheep on the SARA treatment had lower mean (5.77 vs. 6.67) and nadir (5.48 vs. 6.47) ruminal pH for the 3h following the oral drench compared with sham sheep, indicating the successful induction of SARA with the oral glucose dose. Despite the marked reduction in pH in vivo, induction of SARA had no detectable effects on the baseline measurements of J(mannitol-SM), tissue conductance (G(t)), and short-circuit current (I(sc)) in vitro. However, reducing mucosal pH to 5.2 in vitro had negative effects on epithelial barrier function in the recovery period, including increased J(mannitol-SM), increased G(t), and decreased I(sc). The osmotic challenge increased J(mannitol-SM) and G(t) and decreased I(sc) during the challenge period, which was reversible in the recovery period except for slight reduction in I(sc). Interactions between the in vitro treatment and measurement period were detected for J(mannitol-SM), G(t), and I(sc). These data indicate that a mild episode of SARA (nadir pH, 5.48; duration ruminal pH <5.8, 111 min relative to the 180-min measurement period) does not affect ruminal epithelial barrier function immediately after the episode but that a rapid and more severe acidification (pH 5.2) in vitro increases epithelial permeability following the insult. PMID- 20855018 TI - Short communication: in vitro ruminal fermentability of a modified corn cultivar expressing a thermotolerant alpha-amylase. AB - The fermentability of a corn cultivar that expresses a thermostable alpha-amylase (CA3272) was evaluated under various in vitro conditions. The CA3272 corn was developed as a replacement to microbial enzyme additions during the high temperature processing of corn to produce ethanol. The alpha-amylase activity in the corn might have the potential for positive effects on ruminant performance if incorporated into the ration. Four corn cultivars were evaluated in an in vitro ruminal fermentation where the digestion of starch was measured after 6 h. The cultivars included a flint corn, an opaque corn, CA3272, and its near-isogenic counterpart (IC). The flint corn produced less total volatile fatty acids (18.4 mM) than the other 3 corns (average of 25.3 mM), supporting the fact that it had the highest concentration of prolamins, which are negatively associated with starch availability. A second 6-h in vitro ruminal fermentation evaluated mixtures of the CA3272 and IC corns (0, 25, 50, 75, and 100% concentrations of CA3272). Total volatile fatty acid production was not different among treatments for any proportions of CA3272. In a third in vitro experiment, there was a small but significant difference in starch degradation of CA3272 compared with IC (90.6 vs. 89.7%) but this difference is most likely not biologically relevant. In a fourth in vitro experiment, CA3272 and IC were incubated in water at 40 and 65 degrees C for 24 h. Degradation of starch from native amylase activity at 40 degrees C was 1.99 and 1.60% for CA3272 and IC, respectively, but when they were incubated at 65 degrees C, starch degradation was 10.56 and 0.85% for CA3272 and IC, respectively. These data demonstrate that amylase activity in CA3272 is expressed at a high temperature (65 degrees C) but at the physiological temperature expected in a rumen of a cow (39-40 degrees C), expression of amylase activity does not appear to be sufficient to have any positive (or negative) effects on ruminal metabolism. PMID- 20855019 TI - Short communication: effect of grazing on the concentrations of total sialic acid and hexose in bovine milk. AB - Sialic acid, which is located at the terminal end of glycoconjugates, is believed to have important biological functions. Its concentration in bovine milk varies depending on lactation stage and season. However, it remains unclear whether dietary factors, especially fresh forage, affect the total sialic acid concentration in milk. The purpose of the present study was to investigate the effect of grazing on the concentrations of total sialic acid and hexose in bovine milk. Six healthy dairy cows were used in a crossover design (3 cows fed fresh forage and 3 cows fed grass silage) for 2 wk. Individual milk samples were collected at 2 consecutive milkings (morning and evening) at 0, 1, 3, 5, 8, 11, and 14 d of the experimental period, and 2 consecutive samples in each cow were combined on each sampling day in proportion of the morning and evening milk yields. No differences in body weight, milk yield, or milk composition were observed between the 2 groups during the experimental period. The hexose concentration in milk did not differ between these groups during the experimental period. Conversely, the total sialic acid concentration in the milk of each grazing cow significantly increased at 11 and 14 d of the experimental period compared with that at 0 d. In the grass silage group, the total sialic acid concentration at the end of the experimental period tended to be lower than that at 0 d, but the decrease was not significant. These results indicate that grazing management could have increased the concentration of sialoglycoconjugates in milk. This suggests that grazing may increase the biological function of milk because it is thought that sialic acid is significant in many ways. PMID- 20855020 TI - Technical note: precision and accuracy of in vitro digestion of neutral detergent fiber and predicted net energy of lactation content of fibrous feeds. AB - The objective of this study was to test the precision and agreement with in situ data (accuracy) of neutral detergent fiber degradability (NDFD) obtained with the rotating jar in vitro system (Daisy(II) incubator, Ankom Technology, Fairport, NY). Moreover, the precision of the chemical assays requested by the National Research Council (2001) for feed energy calculations and the estimated net energy of lactation contents were evaluated. Precision was measured as standard deviation (SD) of reproducibility (S(R)) and repeatability (S(r)) (between- and within-laboratory variability, respectively), which were expressed as coefficients of variation (SD/mean * 100, S(R) and S(r), respectively). Ten fibrous feed samples (alfalfa dehydrated, alfalfa hay, corn cob, corn silage, distillers grains, meadow hay, ryegrass hay, soy hulls, wheat bran, and wheat straw) were analyzed by 5 laboratories. Analyses of dry matter (DM), ash, crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) had satisfactory S(r), from 0.4 to 2.9%, and S(R), from 0.7 to 6.2%, with the exception of ether extract (EE) and CP bound to NDF or ADF. Extending the fermentation time from 30 to 48 h increased the NDFD values (from 42 to 54% on average across all tested feeds) and improved the NDFD precision, in terms of both S(r) (12 and 7% for 30 and 48 h, respectively) and S(R) (17 and 10% for 30 and 48 h, respectively). The net energy for lactation (NE(L)) predicted from 48-h incubation NDFD data approximated well the tabulated National Research Council (2001) values for several feeds, and the improvement in NDFD precision given by longer incubations (48 vs. 30 h) also improved precision of the NE(L) estimates from 11 to 8%. Data obtained from the rotating jar in vitro technique compared well with in situ data. In conclusion, the adoption of a 48-h period of incubation improves repeatability and reproducibility of NDFD and accuracy and reproducibility of the associated calculated NE(L). Because the in vitro rotating jar technique is a simple apparatus, further improvement would probably be obtained by reducing the laboratory differences in rumen collection procedures and type of animal donors, which, however, reflect practical conditions. PMID- 20855021 TI - Identification of single nucleotide polymorphisms in the bovine interleukin-12 and interleukin-23 receptor genes and their associations with health and production traits in Holstein cows. AB - Interleukin-12 (IL-12) and interleukin-23 (IL-23) are proinflammatory cytokines produced by macrophages and dendritic cells in response to infection with intracellular pathogens. The IL-12 receptor (IL-12R) is a heterodimer composed of 2 subunits, beta1 and beta2. The IL-23 receptor (IL-23R) is a heterodimer composed of the IL-12Rbeta1 subunit and a unique IL-23R subunit. Given the importance of IL-12 and IL-23 for modulating inflammation and the host immune response, the IL-12 and IL-23 receptor genes may be suitable candidate genes for studying disease resistance in dairy cattle. We hypothesize that single nucleotide polymorphisms (SNP) exist within these genes and that they contribute to variation in health and production traits in dairy cattle. To investigate this, a selective DNA pool was constructed using bull semen based on the estimated breeding values for somatic cell score (SCS), an indicator trait used to achieve genetic improvement for resistance to mastitis. Gene segments were amplified from this pool by PCR and the amplicons were sequenced to reveal SNP. A total of 10 SNP, including 2 in IL-12Rbeta1, 5 in IL-12Rbeta2, and 3 in IL-23R were identified. The SNP (n=5) were found in the 5' untranslated region (UTR) putative promoter regions of the genes, and SNP IL-23R c.1714A>C was a nonsynonymous SNP. Canadian Holstein bulls (n=492) were genotyped using Sequenom MassARRAY (Sequenom Inc., San Diego, CA). No association was found with SCS based on bull deregressed estimated breeding values for SCS; however, associations of SNP in the IL-12Rbeta2 gene (c.-511A>G, c.87A>G, c.2957A>C) were found with milk and protein yield. Further investigation will be required to elucidate the biological and practical relevance of these SNP. PMID- 20855022 TI - The effect of the number of observations used for Fourier transform infrared model calibration for bovine milk fat composition on the estimated genetic parameters of the predicted data. AB - Fourier transform infrared spectroscopy is a suitable method to determine bovine milk fat composition. However, the determination of fat composition by gas chromatography, required for calibration of the infrared prediction model, is expensive and labor intensive. It has recently been shown that the number of calibration samples is strongly related to the model's validation r(2) (i.e., accuracy of prediction). However, the effect of the number of calibration samples used, and therefore validation r(2), on the estimated genetic parameters of data predicted using the model needs to be established. To this end, 235 calibration data subsets of different sizes were sampled: n=100, n=250, n=500, and n=1,000 calibration samples. Subsequently, these data subsets were used to calibrate fat composition prediction models for 2 specific fatty acids: C16:0 and C18u (where u=unsaturated). Next, genetic parameters were estimated on predicted fat composition data for these fatty acids. Strong relationships between the number of calibration samples and validation r(2), as well as strong genetic correlations were found. However, the use of n=100 calibration samples resulted in a broad range of validation r(2) values and genetic correlations. Subsequent increases of the number of calibration samples resulted in narrowing patterns for validation r(2) as well as genetic correlations. The use of n=1,000 calibration samples resulted in estimated genetic correlations varying within a range of 0.10 around the average, which seems acceptable. Genetic analyses for the human health related fatty acids C14:0, C16:0, and C18u, and the ratio of saturated fatty acids to unsaturated fatty acids showed that replacing observations on fat composition determined by gas chromatography by predictions based on infrared spectra reduced the potential genetic gain to 98, 86, 96, and 99% for the 4 fatty acid traits, respectively, in dairy breeding schemes where progeny testing is practiced. We conclude that a relatively large number of calibration samples is required to be able to obtain genetic correlations that lie within a limited range. Considering that the routine recording of infrared spectra is relatively cheap and straightforward, we concluded that this methodology provides an excellent means for the dairy industry to genetically alter milk fat composition. PMID- 20855023 TI - Claw health index for Dutch dairy cattle based on claw trimming and conformation data. AB - The purpose of this study was to develop a model for a routine genetic evaluation of claw health traits and to develop an index including data on claw health and conformation traits. Claw health data comprised observations on 40,536 dairy cows of claw traits recorded by claw trimmers. Claw health traits scored were sole hemorrhage (SH), digital dermatitis (DD), interdigital dermatitis (ID), wall ulcer (WU), sole ulcer (SU), interdigital hyperplasia (IH), and white line disease (WL). A combined claw health trait was added as a trait to the data, combining all claw disorders. Observations on 5 feet and leg conformation traits on 41,048 animals were evaluated as predictive traits for claw health. These conformation traits were rear leg side view, rear leg rear view, foot angle, locomotion, and feet and legs. Prevalence of claw disorders ranged from 3% (WU) to 38% (SH). Overall, 69% of the animals had at least one claw disorder. Estimated heritabilities for claw health traits ranged from 0.01 (WU) to 0.13 (IH), and repeatabilities (within and across lactation) ranged from 0.15 (WU) to 0.57 (IH). Genetic correlations of claw health traits in parity 1 and parities >=2 ranged from 0.72 to 1.00. Estimated genetic correlations among claw health traits ranged from -0.35 to 0.88 and between claw health and conformation traits ranged from -0.58 to 0.41. The breeding goal for claw health was to reduce costs due to claw disorders. The economic index for claw health, which included claw health and feet and leg conformation traits, had a reliability of 59% for an average progeny-tested bull in the Netherlands. The prevalence of claw disorders can be reduced up to 0.7% per year with selection on claw health only. PMID- 20855024 TI - Genetic parameters of feed intake, production, body weight, body condition score, and selected type traits of Holstein cows in commercial tie-stall barns. AB - The objectives of this study were to determine the feasibility of measuring feed intake in commercial tie-stall dairies and infer genetic parameters of feed intake, yield, somatic cell score, milk urea nitrogen, body weight (BW), body condition score (BCS), and linear type traits of Holstein cows. Feed intake, BW, and BCS were measured on 970 cows in 11 Pennsylvania tie-stall herds. Historical test-day data from these cows and 739 herdmates who were contemporaries during earlier lactations were also included. Feed intake was measured by researchers once per month over a 24-h period within 7 d of 6 consecutive Dairy Herd Information test days. Feed samples from each farm were collected monthly on the same day that feed intake was measured and were used to calculate intakes of dry matter, crude protein, and net energy of lactation. Test-day records were analyzed with multiple-trait animal models, and 305-d fat-corrected milk yield, dry matter intake, crude protein intake, net energy of lactation intake, average BW, and average BCS were derived from the test-day models. The 305-d traits were also analyzed with multiple-trait animal models that included a prediction of 40 wk dry matter intake derived from National Research Council equations. Heritability estimates for 305-d intake of dry matter, crude protein, and net energy of lactation ranged from 0.15 to 0.18. Genetic correlations of predicted dry matter intake with 305-d dry matter, crude protein, and net energy of lactation intake were 0.84, 0.90, and 0.94, respectively. Genetic correlations among the 3 intake traits and fat-corrected milk yield, BW, and stature were moderate to high (0.52 to 0.63). Results indicate that feed intake measured in commercial tie-stalls once per month has sufficient accuracy to enable genetic research. High-producing and larger cows were genetically inclined to have higher feed intake. The genetic correlation between observed and predicted intakes was less than unity, indicating potential variation in feed efficiency. PMID- 20855025 TI - Assessment of inbreeding depression in a Guzerat dairy herd: effects of individual increase in inbreeding coefficients on production and reproduction. AB - Influences of inbreeding on daily milk yield (DMY), age at first calving (AFC), and calving intervals (CI) were determined on a highly inbred zebu dairy subpopulation of the Guzerat breed. Variance components were estimated using animal models in single-trait analyses. Two approaches were employed to estimate inbreeding depression: using individual increase in inbreeding coefficients or using inbreeding coefficients as possible covariates included in the statistical models. The pedigree file included 9,915 animals, of which 9,055 were inbred, with an average inbreeding coefficient of 15.2%. The maximum inbreeding coefficient observed was 49.45%, and the average inbreeding for the females still in the herd during the analysis was 26.42%. Heritability estimates were 0.27 for DMY and 0.38 for AFC. The genetic variance ratio estimated with the random regression model for CI ranged around 0.10. Increased inbreeding caused poorer performance in DMY, AFC, and CI. However, some of the cows with the highest milk yield were among the highly inbred animals in this subpopulation. Individual increase in inbreeding used as a covariate in the statistical models accounted for inbreeding depression while avoiding overestimation that may result when fitting inbreeding coefficients. PMID- 20855026 TI - A genome scan for quantitative trait loci affecting milk somatic cell score in Israeli and Italian Holstein cows by means of selective DNA pooling with single- and multiple-marker mapping. AB - Mastitis is an important and common dairy cattle disease affecting milk yield, quality, and consumer safety as well as cheese yields and quality. Animal welfare and residues of the antibiotics used to treat mastitis cause public concern. Considerable genetic variation may allow selection for increased resistance to mastitis. Because of high genetic correlation to milk somatic cell score (SCS), SCS can serve as a surrogate trait for mastitis resistance. The present study intended to identify quantitative trait loci (QTL) affecting SCS in Israeli and Italian Holstein dairy cattle (IsH and ItH, respectively), using selective DNA pooling with single and multiple marker mapping. Milk samples of 4,788 daughters of 6 IsH and 7 ItH sires were used to construct sire-family high- and low-tail pools, which were genotyped at 123 (IsH) and 133 (ItH) microsatellite markers. Shadow correction was used to obtain pool allele frequency estimates. Frequency difference between the tails and empirical standard error of D, SE(D), were used to obtain P-values. All markers significant by single marker mapping were also significant by multiple marker mapping, but not vice versa. Combining both populations, 22 QTL on 21 chromosomes were identified; all corresponded to previous reports in the literature. Confidence intervals were set by chi-squared drop method. Heterozygosity of QTL was estimated at 44.2%. Allele substitution effects ranged from 1,782 to 4,930 cells/mL in estimated breeding value somatic cell count units. Most (80%) of the observed variation in estimated breeding value somatic cell score could be explained by the QTL identified under the stringent criteria. The results found here can be used as a basis for further genome-wide association studies for the same trait. PMID- 20855027 TI - Processing factors that influence casein and serum protein separation by microfiltration. AB - Our objective was to demonstrate the effect of various processing factors on the performance of a microfiltration system designed to process skim milk and separate casein (CN) from serum proteins (SP). A mathematical model of a skim milk microfiltration process was developed with 3 stages plus an additional fourth finishing stage to standardize the retentate to 9% true protein (TP) and allow calculation of yield of a liquid 9% TP micellar CN concentrate (MCC) and milk SP isolate (MSPI; 90% SP on a dry basis). The model was used to predict the effect of 5 factors: 1) skim milk composition, 2) heat treatment of skim milk, 3) concentration factor (CF) and diafiltration factor (DF), 4) control of CF and DF, and 5) SP rejection by the membrane on retentate and permeate composition, SP removal, and MCC and MSPI yield. When skim milk TP concentration increased from 3.2 to 3.8%, the TP concentration in the third stage retentate increased from 7.92 to 9.40%, the yield of MCC from 1,000 kg of skim milk increased from 293 to 348 kg, and the yield of MSPI increased from 6.24 to 7.38 kg. Increased heat treatment (72.9 to 85.2 degrees C) of skim milk caused the apparent CN as a percentage of TP content of skim milk as measured by Kjeldahl analysis to increase from 81.97 to 85.94% and the yield of MSPI decreased from 6.24 to 4.86 kg, whereas the third stage cumulative percentage SP removal decreased from 96.96 to 70.08%. A CF and DF of 2* gave a third stage retentate TP concentration of 5.38% compared with 13.13% for a CF and DF of 5*, with the third stage cumulative SP removal increasing from 88.66 to 99.47%. Variation in control of the balance between CF and DF (instead of an equal CF and DF) caused either a progressive increase or decrease in TP concentration in the retentate across stages depending on whether CF was greater than DF (increasing TP in retentate) or CF was less than DF (decreasing TP in retentate). An increased rejection of SP by the membrane from an SP removal factor of 1 to 0.6 caused a reduction in MSPI yield from 6.24 to 5.19 kg/1,000 kg of skim milk, and third stage cumulative SP removal decreased from 96.96 to 79.74%. Within the ranges of the 5 factors studied, the TP content of the third stage retentate was most strongly affected by the target CF and DF and variation in skim milk composition. Cumulative percentage SP removal was most strongly affected by the heat treatment of skim milk, the SP removal factor, and the target CF and DF. The MCC yield was most strongly affected by initial skim milk composition. Yield of MSPI was strongly affected by skim milk composition, whereas the heat treatment of milk and SP removal factor also had a large effect. PMID- 20855028 TI - Understanding the milk-to-feed price ratio as a proxy for dairy farm profitability. AB - This research examines the definition, historical pattern, and utility of the milk-to-feed price ratio (MF) as a measure of dairy farm profitability. The MF was generally an acceptable proxy of profitability in an annual sense from 1985 to 2006. The MF was steady at an average of 2.8 from 1985 to 2006 even as average annual milk price in nominal terms increased from $12 to $14/hundredweight. An alternative proxy for profitability is income over feed costs, which is measured in dollars per hundredweight. Comparison with an actual profit measure, rate of return on assets, is used to examine the appropriateness of the proxies. The volatility from 2007 to 2009 resulted in MF being a poor measure of profitability over that period. The implication is that MF is not the preferred measure of profitability when a significant change in the pattern of one or both price series occurs. Income over feed cost is a better measure of profitability in periods of volatility. PMID- 20855029 TI - Effects of running time of a cattle-cooling system on core body temperature of cows on dairy farms in an arid environment. AB - Two experiments were conducted on a commercial dairy farm to describe the effects of a reduction in Korral Kool (KK; Korral Kool Inc., Mesa, AZ) system operating time on core body temperature (CBT) of primiparous and multiparous cows. In the first experiment, KK systems were operated for 18, 21, or 24 h/d while CBT of 63 multiparous Holstein dairy cows was monitored. All treatments started at 0600 h, and KK systems were turned off at 0000 h and 0300 h for the 18-h and 21-h treatments, respectively. Animals were housed in 9 pens and assigned randomly to treatment sequences in a 3 * 3 Latin square design. In the second experiment, 21 multiparous and 21 primiparous cows were housed in 6 pens and assigned randomly to treatment sequences (KK operated for 21 or 24 h/d) in a switchback design. All treatments started at 0600 h, and KK systems were turned off at 0300 h for the 21 h treatments. In experiment 1, cows in the 24-h treatment had a lower mean CBT than cows in the 18- and 21-h treatments (38.97, 39.08, and 39.03+/-0.04 degrees C, respectively). The significant treatment by time interaction showed that the greatest treatment effects occurred at 0600 h; treatment means at this time were 39.43, 39.37, and 38.88+/-0.18 degrees C for 18-, 21-, and 24-h treatments, respectively. These results demonstrate that a reduction in KK system running time of >=3 h/d will increase CBT. In experiment 2, a significant parity by treatment interaction was found. Multiparous cows on the 24-h treatment had lower mean CBT than cows on the 21-h treatment (39.23 and 39.45+/-0.17 degrees C, respectively), but treatment had no effect on mean CBT of primiparous cows (39.50 and 39.63+/-0.20 degrees C for 21- and 24-h treatments, respectively). A significant treatment by time interaction was observed, with the greatest treatment effects occurring at 0500 h; treatment means at this time were 39.57, 39.23, 39.89, and 39.04+/-0.24 degrees C for 21-h primiparous, 24-h primiparous, 21-h multiparous, and 24-h multiparous cows, respectively. These results demonstrate that multiparous and primiparous cows respond differently when KK system running time decreases from 24 to 21 h. We conclude that in desert climates, the KK system should be operated continuously to decrease heat stress of multiparous dairy cows, but that operating time could be reduced from 24 to 21 h for primiparous cows. Reducing system operation time should be done carefully, however, because CBT was elevated in all treatments. PMID- 20855030 TI - A comparison of the effects of 2 cattle-cooling systems on dairy cows in a desert environment. AB - An experiment was conducted to investigate the effects of operation time and size of Korral Kool (KK; Korral Kool Inc., Mesa, AZ) systems on core body temperature (CBT) of dairy cows. Two KK systems were compared: a system with 1.29-m-diameter, 3-hp fans spaced 6 m apart (referred to as small) and a system with 1.52-m diameter, 5-hp fans spaced 8 m apart (referred to as big). Forty-eight multiparous Holstein cows were assigned randomly to 8 pens (4 big, 4 small), and pens were assigned randomly to a sequence of treatments (KK operated for 21 or 24 h/d) in a switchback design. A complementary calorimetric analysis was developed to investigate the cooling area under the KK units of the big and small systems. Twenty-five sensors distributed equally under the KK units measured ambient temperature at 5-min intervals for 2 h. Average ambient temperature was 35.0+/ 0.6 degrees C and relative humidity was 45+/-8%. There were significant treatment effects on mean CBT: cows on the small 24-h treatment had a lower mean CBT than cows on the small 21-h treatment (39.22 vs. 39.36+/-0.14 degrees C), and cows on the big 24-h treatment had a lower mean CBT than cows on the big 21-h treatment (38.95 vs. 39.09+/-0.13 degrees C). A significant treatment by time interaction was observed. The greatest difference between systems occurred at 0100 h; treatment means at this time were 39.05, 39.01, 39.72, and 39.89+/-0.16 degrees C for the big 24-h, big 21-h, small 24-h, and small 21-h treatments, respectively. At certain times of day, the big system reduced CBT more than the small system. These results show that CBT of multiparous cows decreased when KK system operational time was increased from 21 to 24 h regardless of the size of the KK cooling system used. The calorimetric analysis showed that even though the big system resulted in lower mean ambient temperatures than the small system, the distance between units in the big system should be decreased to reduce the variation in temperature under the big units. PMID- 20855031 TI - "Global" and "local" predictions of dairy diet nutritional quality using near infrared reflectance spectroscopy. AB - The objective of the study was to evaluate performance of classic (global) and innovative (local) calibration techniques to monitor cattle diet, based on fecal near infrared reflectance spectroscopy (NIRS). A 3-yr on-farm survey (2005-2008) was carried out in Vietnam and La Reunion Island to collect animal, feed intake, and feces excretion data. Feed and feces were scanned by a Foss NIRsystem 5000 monochromator (Foss, Hillerod, Denmark) to estimate diet characteristics and nutrient digestibility. A data set including 1,322 diet-fecal pairs was built and used to perform global and local calibrations. Global equations gave satisfactory accuracy [coefficient of determination (R(2)) >0.8, 10% <= relative standard error of prediction (RSEP) <=20%], whereas local equations gave good accuracy (R(2) >0.8, RSEP <10%) or excellent accuracy (R(2) >0.9, RSEP <10%) for the prediction of diet intake, quality, and digestibility. When validating the equations using the external individual data, both techniques were robust, with similar RSEP (8%) and R(2) (0.82) values. The predictive performance of global and local equations was improved (RSEP = 5% and R(2)=0.90) when averaged animal data from farm, visit, and similar milk production were used. In particular, local equations reduced RSEP by 43% and increased R(2) by 15%, on average, compared with those obtained from individual data. The low RSEP (4%), high R(2) (0.96), and good ratio performance deviation (RPD=5) illustrated the excellent accuracy and robustness of the local equations. Findings suggest the ability of fecal NIRS to successfully and more accurately predict diet properties (intake, quality, and digestibility) with local calibration techniques compared with classic global techniques, especially on an averaged data set. Local calibration techniques represent an alternative promising method and potentially a decision support tool to decide whether diets meet dairy cattle requirements or need to be modified. PMID- 20855032 TI - Effect of pregrazing herbage mass on methane production, dry matter intake, and milk production of grazing dairy cows during the mid-season period. AB - Increasing milk production from pasture while increasing grass dry matter intake (GDMI) and lowering methane (CH(4)) emissions are key objectives of low-cost dairy production systems. It was hypothesized that offering swards of low herbage mass with increased digestibility leads to increased milk output. A grazing experiment was undertaken to investigate the effects of varying levels of HM on CH(4) emissions, GDMI and milk production of grazing dairy cows during the mid season grazing period (June to July). Prior to the experiment, 46 Holstein Friesian dairy cows (46 d in milk) were randomly assigned to 1 of 2 treatments (n=23) in a randomized block design. The 2 treatments consisted of 2 target pregrazing HM: 1,000 kg of dry matter (DM)/ha (low herbage mass, LHM) or 2,200 kg of DM/ha (high herbage mass, HHM). The experimental period lasted 2 mo from June 1 until July 31. Within the experimental period, there were 2 measurement periods, measurement 1 (M1) and measurement 2 (M2), where CH(4) emissions, GDMI, and milk production were measured. Mean herbage mass throughout the measurement periods was 1,075 kg of DM/ha and 1,993 kg of DM/ha for the LHM and HHM treatments, respectively. Grass quality in terms of organic matter digestibility was significantly higher for the LHM treatment in M2 (+12 g/kg of DM). In M1, the effect of herbage mass on grass quality was approaching significance in favor of the LHM treatment. Herbage mass did not significantly affect milk production during the measurement periods. Cows grazing the LHM swards had increased GDMI in M1 (+1.5 kg of DM) compared with cows grazing the HHM swards; no difference in GDMI was observed in M2. Grazing HHM swards increased CH(4) production per cow per day (+42 g), per kilogram of milk yield (+3.5 g/kg of milk), per kilogram of milk solids (+47 g/kg of milk solids), and per kilogram of GDMI (+3.1 g/kg of GDMI) in M2. Cows grazing the HHM swards lost a greater proportion of their gross energy intake as CH(4) during both measurement periods (+0.9% and +1% for M1 and M2, respectively). It was concluded that grazing LHM swards would increase grass quality with a concurrent reduction in CH(4) emissions. PMID- 20855033 TI - Associations of breed and feeding management with milk production curves at herd level using a random regression test-day model. AB - Earlier studies identified large between-herd variation in estimated lactation curve parameters from test-day milk yield and milk composition records collected in Ragusa province, Italy. The objective of this study was to identify sources of variation able to explain these between-herd differences in milk production curves, by estimating associations of animal breed (Holstein Friesian vs. Brown Swiss), feeding system [separate feeding (SF) vs. total mixed ration (TMR)], and TMR chemical composition on milk and milk components herd curves. Data recorded from 1992 through 2007 for test-day (TD) milk, fat, and protein yields from 1,287,019 records of 148,951 lactations of 51,489 cows in 427 herds were processed using a random regression TD model. Random herd curves (HCUR) for milk, fat, and protein yields were estimated from the model per herd, year, and parity (1, 2, and 3+) using 4-order Legendre polynomials. From March 2006 through December 2007, samples of TMR were collected every 3 mo from 37 farms in Ragusa province. Samples were analyzed for dry matter, ash, crude protein, soluble nitrogen, acid detergent lignin, neutral detergent fiber, acid detergent fiber, and starch. Traits used to describe milk production curves were peak, days in milk at peak, persistency, and mean. Association of feeding system and animal breed with HCUR traits was investigated using a general mixed model procedure. Association of TMR chemical composition with HCUR traits was investigated using multivariate analysis with regression and stepwise model selection. Results were consistent for all traits and parities. Feeding system was significantly associated with HCUR peak and mean, with higher values for TMR. Animal breed was significantly associated with HCUR persistency, with higher values for Brown Swiss herds. Furthermore, animal breed influenced HCUR peak and mean, with higher values for Holstein Friesian herds. Crude protein had the largest effect on HCUR peak and mean, whereas the interaction between crude protein and dry matter mainly affected persistency. When provided by a national evaluation system, HCUR can be used as an indicator of herd feeding management. PMID- 20855034 TI - Passing the torch. PMID- 20855035 TI - Accepting the torch. PMID- 20855036 TI - Medicinial chemistry. Preface. PMID- 20855037 TI - The Journey to the Discovery of Boceprevir: an NS3-NS4 HCV protease inhibitor for the treatment of chronic hepatitis C. PMID- 20855038 TI - A decade of progress in the discovery and development of 'atypical' antipsychotics. PMID- 20855039 TI - Structural trends among second-generation voltage-gated sodium channel blockers. PMID- 20855040 TI - Computational analysis of structure-activity relationships. PMID- 20855041 TI - Prevalence of mental health disorders in children and adolescents around the globe. PMID- 20855042 TI - Catecholamine modulators: lessons from nonhuman primates. PMID- 20855043 TI - Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A). AB - OBJECTIVE: To present estimates of the lifetime prevalence of DSM-IV mental disorders with and without severe impairment, their comorbidity across broad classes of disorder, and their sociodemographic correlates. METHOD: The National Comorbidity Survey-Adolescent Supplement NCS-A is a nationally representative face-to-face survey of 10,123 adolescents aged 13 to 18 years in the continental United States. DSM-IV mental disorders were assessed using a modified version of the fully structured World Health Organization Composite International Diagnostic Interview. RESULTS: Anxiety disorders were the most common condition (31.9%), followed by behavior disorders (19.1%), mood disorders (14.3%), and substance use disorders (11.4%), with approximately 40% of participants with one class of disorder also meeting criteria for another class of lifetime disorder. The overall prevalence of disorders with severe impairment and/or distress was 22.2% (11.2% with mood disorders, 8.3% with anxiety disorders, and 9.6% behavior disorders). The median age of onset for disorder classes was earliest for anxiety (6 years), followed by 11 years for behavior, 13 years for mood, and 15 years for substance use disorders. CONCLUSIONS: These findings provide the first prevalence data on a broad range of mental disorders in a nationally representative sample of U.S. adolescents. Approximately one in every four to five youth in the U.S. meets criteria for a mental disorder with severe impairment across their lifetime. The likelihood that common mental disorders in adults first emerge in childhood and adolescence highlights the need for a transition from the common focus on treatment of U.S. youth to that of prevention and early intervention. PMID- 20855044 TI - Trends in serious emotional disturbance among youths exposed to Hurricane Katrina. AB - OBJECTIVE: To examine patterns and predictors of trends in DSM-IV serious emotional disturbance (SED) among youths exposed to Hurricane Katrina. METHOD: A probability sample of adult pre-hurricane residents of the areas affected by Katrina completed baseline and follow-up telephone surveys 18 to 27 months post hurricane and 12 to 18 months later. Baseline adult respondents residing with children and adolescents (4-17 years of age) provided informant reports about the emotional functioning of these youths (n = 576) with the Strengths and Difficulties Questionnaire (SDQ). The surveys also assessed hurricane-related stressors and ongoing stressors experienced by respondent families. RESULTS: SED prevalence decreased significantly across survey waves from 15.1% to 11.5%, although even the latter prevalence was considerably higher than the pre hurricane prevalence of 4.2% estimated in the US National Health Interview Survey. Trends in hurricane-related SED were predicted by both stressors experienced in the hurricane and ongoing stressors, with SED prevalence decreasing significantly only among youths with moderate stress exposure (16.8% versus 6.5%). SED prevalence did not change significantly between waves among youths with either high stress exposure (30.0% versus 41.9%) or low stress exposure (3.5% versus 3.4%). Pre-hurricane functioning did not predict SED persistence among youths with high stress exposure, but did predict SED persistence among youth with low-moderate stress exposure. CONCLUSIONS: The prevalence of SED among youths exposed to Hurricane Katrina remains significantly elevated several years after the storm despite meaningful decrease since baseline. Youths with high stress exposure have the highest risk of long-term hurricane-related SED and consequently represent an important target for mental health intervention. PMID- 20855045 TI - National trends in child and adolescent psychotropic polypharmacy in office-based practice, 1996-2007. AB - OBJECTIVE: To examine patterns and recent trends in multiclass psychotropic treatment among youth visits to office-based physicians in the United States. METHOD: Annual data from the 1996-2007 National Ambulatory Medical Care Surveys were analyzed to examine patterns and trends in multiclass psychotropic treatment within a nationally representative sample of 3,466 child and adolescent visits to office-based physicians in which a psychotropic medication was prescribed. RESULTS: There was an increase in the percentage of child visits in which psychotropic medications were prescribed that included at least two psychotropic classes. Across the 12 year period, multiclass psychotropic treatment rose from 14.3% of child psychotropic visits (1996-1999) to 20.2% (2004-2007) (adjusted odds ratio [AOR] = 1.89, 95% confidence interval [CI] = 1.22-2.94, p < .01). Among medical visits in which a current mental disorder was diagnosed, the percentage with multiclass psychotropic treatment increased from 22.2% (1996 1999) to 32.2% (2004-2007) (AOR = 2.23, 95% CI = 1.42-3.52, p < .001). Over time, there were significant increases in multiclass psychotropic visits in which ADHD medications, antidepressants, or antipsychotics were prescribed, and a decrease in those visits in which mood stabilizers were prescribed. There were also specific increases in co-prescription of ADHD medications and antipsychotic medications (AOR = 6.22, 95% CI = 2.82-13.70, p < .001) and co-prescription of antidepressant and antipsychotic medications (AOR = 5.77, 95% CI = 2.88-11.60, p < .001). CONCLUSIONS: Although little is known about the safety and efficacy of regimens that involve concomitant use of two or more psychotropic agents for children and adolescents, multiclass psychotropic pharmacy is becoming increasingly common in outpatient practice. PMID- 20855046 TI - Methylphenidate and atomoxetine enhance prefrontal function through alpha2 adrenergic and dopamine D1 receptors. AB - OBJECTIVE: This study examined the effects of the attention-deficit/hyperactivity disorder treatments, methylphenidate (MPH) and atomoxetine (ATM), on prefrontal cortex (PFC) function in monkeys and explored the receptor mechanisms underlying enhancement of PFC function at the behavioral and cellular levels. METHOD: Monkeys performed a working memory task after administration of a wide range of MPH or ATM doses. The optimal doses were challenged with the alpha(2) adrenoceptor antagonist, idazoxan, or the D(1) dopamine receptor antagonist, SCH23390 (SCH). In a parallel physiology study, neurons were recorded from the dorsolateral PFC of a monkey performing a working memory task. ATM, SCH, or the alpha(2) antagonist, yohimbine, were applied to the neurons by iontophoresis. RESULTS: MPH and ATM generally produced inverted-U dose-response curves, with improvement occurring at moderate doses, but not at higher doses. The beneficial effects of these drugs were blocked by idazoxan or SCH. At the cellular level, ATM produced an inverted-U dose-response effect on memory-related firing, enhancing firing for preferred directions (increasing "signals") and decreasing firing for the nonpreferred directions (decreasing "noise"). The increase in persistent firing for the preferred direction was blocked by yohimbine, whereas the suppression of firing for the nonpreferred directions was blocked by SCH. CONCLUSIONS: Optimal doses of MPH or ATM improved PFC cognitive function in monkeys. These enhancing effects appeared to involve indirect stimulation of alpha(2) adrenoceptors and D(1) dopamine receptors in the PFC. These receptor actions likely contribute to their therapeutic effects in the treatment of attention-deficit/hyperactivity disorder. PMID- 20855047 TI - Predictors and moderators of treatment outcome in the Pediatric Obsessive Compulsive Treatment Study (POTS I). AB - OBJECTIVE: To identify predictors and moderators of outcome in the first Pediatric OCD Treatment Study (POTS I) among youth (N = 112) randomly assigned to sertraline, cognitive behavioral therapy (CBT), both sertraline and CBT (COMB), or a pill placebo. METHOD: Potential baseline predictors and moderators were identified by literature review. The outcome measure was an adjusted week 12 predicted score for the Children's Yale Brown Obsessive Compulsive Scale (CY BOCS). Main and interactive effects of treatment condition and each candidate predictor or moderator variable were examined using a general linear model on the adjusted predicted week 12 CY-BOCS scores. RESULTS: Youth with lower obsessive compulsive disorder (OCD) severity, less OCD-related functional impairment, greater insight, fewer comorbid externalizing symptoms, and lower levels of family accommodation showed greater improvement across treatment conditions than their counterparts after acute POTS treatment. Those with a family history of OCD had more than a sixfold decrease in effect size in CBT monotherapy relative to their counterparts in CBT without a family history of OCD. CONCLUSIONS: Greater attention is needed to build optimized intervention strategies for more complex youth with OCD. Youth with a family history of OCD are not likely to benefit from CBT unless offered in combination with an SSRI. CLINICAL TRIALS REGISTRATION INFORMATION: Treatment of Obsessive Compulsive Disorder (OCD) in Children, http://www.clinicaltrials.gov, NCT00000384. PMID- 20855048 TI - Prolonged exposure versus dynamic therapy for adolescent PTSD: a pilot randomized controlled trial. AB - OBJECTIVE: To examine the efficacy and maintenance of developmentally adapted prolonged exposure therapy for adolescents (PE-A) compared with active control time-limited dynamic therapy (TLDP-A) for decreasing posttraumatic and depressive symptoms in adolescent victims of single-event traumas. METHOD: Thirty-eight adolescents (12 to 18 years old) were randomly assigned to receive PE-A or TLDP A. RESULTS: Both treatments resulted in decreased posttraumatic stress disorder and depression and increased functioning. PE-A exhibited a greater decrease of posttraumatic stress disorder and depression symptom severity and a greater increase in global functioning than did TDLP-A. After treatment, 68.4% of adolescents beginning treatment with PE-A and 36.8% of those beginning treatment with TLDP-A no longer met diagnostic criteria for posttraumatic stress disorder. Treatment gains were maintained at 6- and 17-month follow-ups. CONCLUSIONS: Brief individual therapy is effective in decreasing posttraumatic distress and behavioral trauma-focused components enhance efficacy. CLINICAL TRIAL REGISTRY INFORMATION: Prolonged Exposure Therapy Versus Active Psychotherapy in Treating Post-Traumatic Stress Disorder in Adolescents, URL: http://clinicaltrials.gov, unique identifier: NCT00183690. PMID- 20855049 TI - Does cognitive behavioral therapy for youth anxiety outperform usual care in community clinics? An initial effectiveness test. AB - OBJECTIVE: Most tests of cognitive behavioral therapy (CBT) for youth anxiety disorders have shown beneficial effects, but these have been efficacy trials with recruited youths treated by researcher-employed therapists. One previous (nonrandomized) trial in community clinics found that CBT did not outperform usual care (UC). The present study used a more stringent effectiveness design to test CBT versus UC in youths referred to community clinics, with all treatment provided by therapists employed in the clinics. METHOD: A randomized controlled trial methodology was used. Therapists were randomized to training and supervision in the Coping Cat CBT program or UC. Forty-eight youths (56% girls, 8 to 15 years of age, 38% Caucasian, 33% Latino, 15% African-American) diagnosed with DSM-IV anxiety disorders were randomized to CBT or UC. RESULTS: At the end of treatment more than half the youths no longer met criteria for their primary anxiety disorder, but the groups did not differ significantly on symptom (e.g., parent report, eta-square = 0.0001; child report, eta-square = 0.09; both differences favoring UC) or diagnostic (CBT, 66.7% without primary diagnosis; UC, 73.7%; odds ratio 0.71) outcomes. No differences were found with regard to outcomes of comorbid conditions, treatment duration, or costs. However, youths receiving CBT used fewer additional services than UC youths (chi(2)(1) = 8.82, p = .006). CONCLUSIONS: CBT did not produce better clinical outcomes than usual community clinic care. This initial test involved a relatively modest sample size; more research is needed to clarify whether there are conditions under which CBT can produce better clinical outcomes than usual clinical care. CLINICAL TRIAL REGISTRY INFORMATION: Community Clinic Test of Youth Anxiety and Depression Study, URL: http://clinicaltrials.gov, unique identifier: NCT01005836. PMID- 20855050 TI - Infant brain development and vulnerability to later internalizing difficulties: the Generation R study. AB - OBJECTIVE: Although clinical studies have demonstrated smaller subcortical volumes in structures such as the amygdala, hippocampus, caudate nucleus, and thalamus in adults and adolescents with depressive disorders and anxiety, no study has assessed such structures in babies, long before the development of the disorders. This study examined whether the size of the "gangliothalamic ovoid" (encompassing the basal ganglia and thalamus) assessed during infancy is associated with increased internalizing problems in early childhood. METHOD: Cranial ultrasounds were used to assess gangliothalamic ovoid diameter and ventricular volume at 6 weeks of postnatal age; moreover, head circumference was measured. Outcome data included ratings of internalizing and externalizing problems using the Child Behavior Checklist (reported by mothers and fathers) at 18 and/or 36 months. Analyses were based on a total of 651 children. RESULTS: Smaller gangliothalamic diameter was associated with higher Child Behavior Checklist Internalizing scores at ages 18 and 36 months. Results remained significant after correcting for head circumference and were evident for the DSM oriented subscales of anxiety problems and affective problems. Total ventricular volume was not consistently associated with Internalizing scores. CONCLUSIONS: Findings associating infant brain measurements with Child Behavior Checklist mother and father reports at two time points are consistent with previous cross sectional reports of smaller subcortical volumes in depression. Results were not simply reflective of overall brain development, because the pattern held after adjustment for head circumference. This is the first study to point toward a biological vulnerability evident in infancy, involved in the development of internalizing problems in childhood. PMID- 20855053 TI - Tailoring patient reported outcome measurement. PMID- 20855051 TI - Emotion processing influences working memory circuits in pediatric bipolar disorder and attention-deficit/hyperactivity disorder. AB - OBJECTIVE: This functional magnetic resonance imaging (fMRI) study examined how working memory circuits are affected by face emotion processing in pediatric bipolar disorder (PBD) and attention-deficit/hyperactivity disorder (ADHD). METHODS: A total of 23 patients with PBD, 14 patients with ADHD, and 19 healthy control (HC) subjects (mean age, 13.36 +/- 2.55 years) underwent an affective, two-back fMRI task with blocks of happy, angry, and neutral faces. RESULTS: For angry versus neutral faces PBD patients, relative to ADHD patients, exhibited increased activation in the subgenual anterior cingulate cortex (ACC) and orbitofrontal cortex, and reduced activation in the dorsolateral prefrontal cortex (DLPFC) and premotor cortex. Relative to the HC group, the PBD group showed no increased activation and reduced activation at the junction of DLPFC and ventrolateral prefrontal cortex (VLPFC). Relative to HC, the ADHD patients exhibited greater activation in the DLPFC and reduced activation in the ventral and medial PFC, pregenual ACC, striatum, and temporo-parietal regions. For happy versus neutral faces, relative to the ADHD group, the PBD group exhibited greater activation in the bilateral caudate, and relative to the HC group the ADHD group showed increased activation in the DLPFC, striatal, and parietal regions, and no reduced activation. The ADHD group, compared with the HC group, showed no reduced activation and increased activation in regions that were underactive for the angry face condition. CONCLUSIONS: Relative to the ADHD group, the PBD group exhibited greater deployment of the emotion-processing circuitry and reduced deployment of working memory circuitry. Commonalities across PBD and ADHD patients, relative to the HC individuals, entailed cortico-subcortical activity that was reduced under negative emotional challenge and increased under positive emotional challenge. PMID- 20855054 TI - Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy. AB - PURPOSE: To characterize microaneurysms in diabetic retinopathy (DR) depicted by spectral-domain optical coherence tomography (SD-OCT). DESIGN: Retrospective, observational case series. METHODS: We surveyed a consecutive series of 76 eyes from 60 patients with DR (22 mild nonproliferative diabetic retinopathy [NPDR]; 43 moderate NPDR; 9 severe NPDR; 2 proliferative diabetic retinopathy [PDR]) who underwent Spectralis OCT, fluorescein angiography (FA), and color fundus photography on the same day. The microaneurysms on OCT were oval and well demarcated at the points where those on color fundus photographs and FA were delineated. The characteristics of microaneurysms were evaluated. RESULTS: Based on the status of the capsular structure shown in the sectional images of OCT (called ring sign), we classified 147 microaneurysms depicted by all of SD-OCT, FA, and color fundus photographs in 76 eyes: 28 with complete ring sign, 54 with incomplete one, and 65 with no structure. Microaneurysms with no ring sign had hyperreflective spots in the lumen and were accompanied by nearby cystoid spaces more frequently than other types (P = .033 and P = .007). Thirteen of 75 microaneurysms with nearby cystoid spaces protruded into the cystoid spaces, and 11 of those 13 microaneurysms presented with no ring sign. Microaneurysms resided mainly in the inner nuclear layer (INL) (80.3%), and 65 of such microaneurysms (55.1%) were accompanied by nearby cystoid spaces. CONCLUSIONS: SD-OCT delineated the capsular structure, hyperreflective spots, and location of microaneurysms, and microaneurysms with the ring sign were positively correlated with nearby cystoid spaces and protrusion into the cystoid spaces. PMID- 20855055 TI - [B-type natriuretic peptide levels and renal function in the diagnosis of heart failure in the elderly]. AB - AIM OF THE STUDY: BNP levels are accurate in the diagnosis of heart failure and useful in clinical practice. Relationship between BNP, heart failure (HF) and renal function are little known in the elderly. Renal function influence the optimal cut point of BNP in patients with a Glomerular Filtration Rate (eGFR) lesser than 60 ml/min/1.73 m(2). METHODOLOGY: A total of 71 patients (mean age = 85 years) were admitted in a Cardiogeriatric Unit. We noted several parameters, age, gender, the presence or the absence of Systolic Heart Failure (clinical history and physical examination), the echographic measure of the left ventricular ejection fraction, the eGFR value calculated by simplified MDRD formula and the BNP value. We divided these patients into six groups according the presence of HF and eGFR value higher than 60ml/min/1.73m(2),or between 30 and 60 or between 15 and 30. RESULTS: Our results show that the BNP value is higher in all the three groups of patients with Heart Failure with or without diminution of the eGFR: for example, 1220 pg/ml in the presence of HF versus 788 pg/ml in the absence of HF in the two groups with the eGFR is calculated between 15 and 30 ml/min/1.73m(2). CONCLUSION: BNP is a helpful tool in clinical practice for the diagnosis of Systolic Heart Failure in the presence of renal impairment in the elderly with a higher biomarker cut point. PMID- 20855056 TI - [Value of cardiac MRI for intraventricular thrombi's diagnosis]. AB - BACKGROUND: Intraventricular thrombosis is a serious event, generally complicating a wide myocardial infarction. It requires an adapted therapy, based on the oral anticoagulants. The diagnosis is generally carried out by trans thoracic echocardiography but with an insufficient sensitivity and a specificity. In this context, the place of cardiac MRI remains to be explored. PATIENTS AND METHOD: We carried out a retrospective registry of all cardiac MRI done in our hospital since 2003, for assessment of an intracardiac mass or an cerebral stroke. The aim was to compare the results of cardiac MRI with those of echocardiography and contrast ventriculography. RESULTS: Our registry includes 26 cases of intraventricular thrombi, confirmed by cardiac MRI. Our results confirm the lack of sensitivity of echocardiography and the ventriculography. The Kappa correlation coefficient of echocardiography and ventriculography, with respect to the MRI, are very weak, respectively of -0.08 and 0.16. CONCLUSIONS: The values of echocardiography and contrast ventriculography seem limited. The realization of a complementary cardiac MRI must be recommended as often as possible in case of doubt or high risk disease. PMID- 20855057 TI - [Influence of leukocytes on coronary flow reserve, left ventricular systolic function, and in-hospital events, in patients with acute anterior myocardial infarction treated by primary angioplasty]. AB - OBJECTIVE: To assess the relationship between leukocyte count, non invasive coronary flow reserve (CFR), left ventricular systolic function, and in-hospital adverse events in acute anterior myocardial infarction (AMI) treated by primary angioplasty. METHODS: Leukocyte count at admission and within 24h after angioplasty, and differential count at admission were obtained in 72 consecutive patients with a first AMI (mean age 56+/-12 years) successfully treated by primary angioplasty. Transthoracic Doppler echocardiography was performed within 24h after angioplasty and 3 months later to assess the CFR (using intravenous adenosine), in the left anterior descending artery (LAD), left ventricular ejection fraction (LVEF) and the wall motion score index using the nine segments assigned to the LAD territory (WMSi-lad). In hospital events were defined as death, heart failure (Killip>=2) and reinfarction. RESULTS: Leukocyte count was higher before and after angioplasty in patients with impaired acute CFR (<1.7), when compared to patients without such impairment (P<=0.01), and a significant correlation was found between CFR and leukocyte, neutrophil and monocyte count (P<0.05). Leukocyte (before and after angioplasty), and neutrophil count, were lower in patients with recovery of global and regional LV function (P<0.05). A significant correlation was found between leukocyte count before and after angioplasty, and, initial and follow-up LVEF, and WMSi-lad (all, P<=0.01). Leukocyte (before and after angioplasty) and monocyte count were higher in patients with in-hospital events (n=14), by comparison to patients without events (all, P<0.01). In multivariate analysis, leukocyte count after angioplasty was an independent predictor of CFR, and in-hospital events, and neutrophil count of WMSi-lad at follow-up (all, P<0.05). CONCLUSION: In the first AMI treated successfully by primary angioplasty, leukocyte count is inversely correlated to CFR, and global and regional LV systolic function at follow-up. These links are higher after than before reperfusion. And, leukocyte count after angioplasty is an independent predictor of in-hospital adverse events. PMID- 20855058 TI - [Are very old patients good candidates for percutaneous coronary intervention? A monocentric retrospective study]. AB - AIM: To determine the feasibility of percutaneous coronary intervention (PCI) in very old patients. BACKGROUND: The elderly are a growing population with a high prevalence of ischemic heart disease and then subsequent possibility to benefit from coronary interventions. METHOD: We have conducted a retrospective study using our PCI database since January 2000. Population characteristics, clinical presentation, type of lesions, technical procedure, immediate results and in hospital outcome are compare between patients older than 85 and the other. RESULTS: Between January 2008 and March 2009, 3130 patients benefit from coronary angioplasty. Among them, 85 patients were older than 85. There were more female in this group (24.7 vs. 14.3%, P=0.007), but no difference in cardiovascular risk profile. The older was more symptomatic (acute coronary syndrome: 59.52 vs. 44%, P=0.004; silent ischemia: 3.6 vs. 25.7%, P=0.000003). The ejection fraction was worse (EF<55%: 29.4 vs. 14.5%, P=0.0001). The lesion was more complex (B2 and C: 67.2 vs. 57.1% P=0.027) and concern more often the left descending artery (85.9 vs. 57.1%, P=0.000001). The technical success was similar in the two groups (93.28 vs. 94.32%, P=0.34) with similar rate of per procedure complications (2.35 vs. 1.5%, P=0.37). Nevertheless, the in-hospital rate mortality was higher in the older patients (7 vs 1.38%, P=0.0014). CONCLUSION: PCI is safe and safety in very old patients despite significant but acceptable increasing in-hospital mortality due to more severe disease and co morbidities. Further evaluations are necessary in order to edict specific recommendations. PMID- 20855059 TI - The impact of occlusal function on structural adaptation in alveolar bone of the growing pig, Sus Scrofa. AB - OBJECTIVES: this study investigated the effects of growth and tooth loading on the structural adaptation of the developing alveolar bone adjacent to the tooth root as the tooth erupted into function. Growth and occlusal function were expected to lead to increased alveolar bone density. Meanwhile, the supporting alveolar bone was expected to develop a dominant trabecular orientation (anisotropy) only after occlusal loading. DESIGN: minipigs with erupting and occluding mandibular first molars (M(1)'s) were used to study the effects of growth and occlusal function on developing alveolar bone structure through comparison of alveolar bone surrounding M(1)'s. A second minipig model with one side upper opponent teeth extracted prior to occlusal contact with the M(1) was raised until the non-extraction side M(1)'s developed full occlusal contact. The comparisons between extraction and non-extraction side M(1) alveolar bone were used to emphasize the impact of occlusal loading on alveolar bone structure. Specimens were scanned on a Scanco Medical MUCT 20 at a 22MUm voxel resolution for structural analysis. RESULTS: with growth and occlusal function a distinct alveolar bone proper tended to develop immediately adjacent to the tooth root. The cancellous bone had thicker but fewer and more separated trabeculae after growth or occlusal loading. On the other hand, occlusal function did not lead to increased alveolar structural anisotropy. CONCLUSION: during tooth eruption, growth and masticatory loads effect structural change in alveolar bone. The impact of occlusal function on cancellous bone anisotropy may need a more extensive period of time to demonstrate. PMID- 20855060 TI - The neural correlates of emotional memory in posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is marked by intrusive, chronic, and distressing memories of highly emotional events. Previous research has highlighted the role of the amygdala and its interactions with the hippocampus in mediating the effect of enhanced memory for emotional information in healthy individuals. As the functional integrity of these regions may be compromised in PTSD, the current study examined the neural correlates of emotional memory in PTSD. METHODS: We used functional magnetic resonance imaging and an event-related subsequent memory recognition paradigm to study amygdala and hippocampus activation in 18 individuals with PTSD and 18 trauma-exposed non-PTSD control participants. RESULTS: Memory enhancement for negative, relative to neutral, pictures was found across all subjects, without significant differences between groups. Relative to the trauma-exposed non-PTSD group, the PTSD group showed exaggerated amygdala activation during the encoding of negative versus neutral pictures. This effect was even more pronounced when the analysis included data from only pictures that were subsequently remembered 1 week later. In the PTSD group, degree of amygdala activation during the encoding of negative versus neutral pictures was positively correlated with hippocampal activation and current PTSD symptom severity. The PTSD group also showed exaggerated hippocampal activation in response to negative pictures that were remembered versus forgotten. Finally, hippocampal activation associated with the successful encoding of negative relative to neutral pictures was significantly greater in the PTSD group. CONCLUSIONS: Exaggerated amygdala activation during the encoding of emotionally negative stimuli in PTSD is related to symptom severity and to hippocampal activation. PMID- 20855061 TI - [Prognostic importance of pulmonary hypertension in heart failure with preserved ejection fraction]. AB - OBJECTIVES: Pulmonary hypertension (PH) is a frequent complication in heart failure (HF). However, its impact factor in heart failure with preserved ejection fraction (HFPEF) is not well-known. This study has aimed to identify the prognostic value of PH in hospitalized patients with HFPEF. MATERIAL AND METHODS: An observational and prospective trial of patients admitted due to HFPEF (LVEF >45%). Pulmonary hypertension was defined by Pulmonary artery systolic pressure (PASP) >35mm Hg measured by the tricuspid regurgitation velocity plus atrial pressure. The primary endpoint was all-cause mortality and/or readmissions during 1-year follow-up. Kaplan-Meier survival curves and Cox regression were performed to identify adjusted hazard ratios (HR). RESULTS: A total of 218 patients completed the follow-up period, 56 patients (32.2%) had PASP >35mm Hg. Primary endpoint was observed in 126 patients (57.8%) and 70 patients (32.2%) died. Kaplan-Meier survival curves showed increased significantly all-cause mortality and/or readmission in patients with PH (Log Rank <0.001) and mortality (Log Rank 0.019). Patients with PH were an increased adjusted risk for primary endpoint, HR 2.03 (CI 95%: 1.39-2.96; p<0.001) and all-cause mortality, HR 1.84 (CI 95%: 1.11 3.03; p=0.017). CONCLUSIONS: Pulmonary hypertension (PASP >35mm Hg) measured by non-invasive methods is a strong and independent predictor of an unfavorable outcome in patients hospitalized due to heart failure and normal or only mildly reduced ejection fraction. PMID- 20855062 TI - Differential diagnosis of pancreatic cancer from normal tissue with digital imaging processing and pattern recognition based on a support vector machine of EUS images. AB - BACKGROUND: EUS can detect morphologic abnormalities of pancreatic cancer with high sensitivity but with limited specificity. OBJECTIVE: To develop a classification model for differential diagnosis of pancreatic cancer by using a digital imaging processing (DIP) technique to analyze EUS images of the pancreas. DESIGN: A retrospective, controlled, single-center design was used. SETTING: The study took place at the Second Military Medical University, Shanghai, China. PATIENTS: There were 153 pancreatic cancer and 63 noncancer patients in this study. INTERVENTION: All patients underwent EUS-guided FNA and pathologic analysis. MAIN OUTCOME MEASUREMENTS: EUS images were obtained and correlated with cytologic findings after FNA. Texture features were extracted from the region of interest, and multifractal dimension vectors were introduced in the feature selection to the frame of the M-band wavelet transform. The sequential forward selection process was used for a better combination of features. By using the area under the receiver operating characteristic curve and other texture features based on separability criteria, a predictive model was built, trained, and validated according to the support vector machine theory. RESULTS: From 67 frequently used texture features, 20 better features were selected, resulting in a classification accuracy of 99.07% after being added to 9 other features. A predictive model was then built and trained. After 50 random tests, the average accuracy, sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of pancreatic cancer were 97.98 +/- 1.23%, 94.32 +/- 0.03%, 99.45 +/- 0.01%, 98.65 +/- 0.02%, and 97.77 +/- 0.01%, respectively. LIMITATIONS: The limitations of this study include the small sample size and that the support vector machine was not performed in real time. CONCLUSION: The classification of EUS images for differentiating pancreatic cancer from normal tissue by DIP is quite useful. Further refinements of such a model could increase the accuracy of EUS diagnosis of tumors. PMID- 20855063 TI - Esophageal squamous cell carcinoma with intramural metastasis presenting as a pendiculated polyp. PMID- 20855064 TI - Remote magnetic control of a wireless capsule endoscope in the esophagus is safe and feasible: results of a randomized, clinical trial in healthy volunteers. AB - BACKGROUND: Remote control of esophageal capsule endoscopes could enhance diagnostic accuracy. OBJECTIVE: To assess the safety and efficacy of remote magnetic manipulation of a modified capsule endoscope (magnetic maneuverable capsule [MMC]; Given Imaging Ltd, Yoqneam, Israel) in the esophagus of healthy humans. DESIGN: Randomized, controlled trial. SETTING: Academic hospital. PATIENTS: This study involved 10 healthy volunteers. INTERVENTION: All participants swallowed a conventional capsule (ESO2; Given Imaging) and a capsule endoscope with magnetic material, the MMC, which is activated by a thermal switch, in random order (1 week apart). An external magnetic paddle (EMP; Given Imaging) was used to manipulate the MMC within the esophageal lumen. MMC responsiveness was evaluated on a screen showing the MMC film in real time. MAIN OUTCOME MEASUREMENTS: Safety and tolerability of the procedure (questionnaire), responsiveness of the MMC to the EMP, esophageal transit time, and visualization of the Z-line. RESULTS: No adverse events occurred apart from mild retrosternal pressure (n = 5). The ability to rotate the MMC around its longitudinal axis and to tilt it by defined movements of the EMP was clearly demonstrated in 9 volunteers. Esophageal transit time was highly variable for both capsules (MMC, 111-1514 seconds; ESO2, 47-1474 seconds), but the MMC stayed longer in the esophagus in 8 participants (P < .01). Visualization of the Z-line was more efficient with the ESO2 (inspection of 73% +/- 18% of the circumference vs 33% +/ 27%, P = .01). LIMITATIONS: Magnetic forces were not strong enough to hold the MMC against peristalsis when the capsule approached the gastroesophageal junction. CONCLUSION: Remote control of the MMC in the esophagus of healthy volunteers is safe and feasible, but higher magnetic forces may be needed. PMID- 20855065 TI - Caught on camera: an unusual type of bug in the gut. PMID- 20855066 TI - Feasibility of a novel system for intraductal balloon-anchored direct peroral cholangioscopy and endotherapy with an ultraslim endoscope (with videos). AB - BACKGROUND: Advantages of direct peroral cholangioscopy (DPOCS) by using an ultraslim endoscope include a single-operator platform, image quality equal to that of standard endoscopy, and separate water and air channels. However, DPOCS has significant limitations, including cumbersome biliary access, en-face position with the ampulla, and gastric looping of the endoscope. A newly designed anchoring balloon may overcome these challenges. OBJECTIVE: To report the feasibility of DPOCS with the anchoring balloon. DESIGN: Pilot study, porcine model. SETTING: Animal resources center. INTERVENTION: The anchoring balloon system developed by Cook Medical (Winston-Salem, NC) was used for DPOCS. MAIN OUTCOME MEASUREMENTS: Primary: Feasibility of biliary access maintenance and intraductal mobility. Secondary: Feasibility of intraductal therapeutic procedures. RESULTS: Four animal subjects underwent DPOCS with the anchoring balloon. Ductal access was achieved with sphincterotomy in 2 subjects and with a balloon sphincteroplasty in 2 subjects. Intraductal placement of the ultraslim endoscope was achieved in all biliary access attempts without balloon migration or deflation. Common bile duct, cystic duct, bifurcation, and main right and left duct direct visualization was achieved in all cases. Therapeutic interventions by DPOCS, including intraductal biopsy, balloon dilatation, and intraductal bilateral metal stent placement, were all completed successfully. Biliary perforation occurred in one case because of balloon overinflation and in a second case because of sphincterotomy. LIMITATIONS: Prototype study in an animal model and small study size. CONCLUSION: Our results show that the novel anchoring balloon system successfully and safely enables DPOCS for both diagnostic and therapeutic interventions. If corroborated in human trials, it could offer a new platform for biliary interventions. PMID- 20855067 TI - Mortality after percutaneous endoscopic gastrostomy in patients with cirrhosis: a case series. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tube placement can improve the nutritional status and the ability of a patient with cirrhosis to recover from surgery such as orthotopic liver transplantation. However, cirrhosis has been considered a significant contraindication to PEG tube placement. OBJECTIVE: Our aim in this study was to describe the mortality and complications in a series of cirrhotic patients who underwent PEG at our institution. DESIGN: Retrospective, single-institution case series. PATIENTS: This study involved 26 consecutive patients with cirrhosis who underwent PEG between 1995 and 2005. INTERVENTION: PEG tube placement. MAIN OUTCOME MEASUREMENTS AND RESULTS: The 30 day mortality of the series of patients was 10 of 26 (38.5%), whereas the 90-day mortality was 11 of 26 (42.3%). Nine of the 10 patients who died in the first 30 days had ascites at the time of PEG tube placement. Two patients died as a direct consequence of complications from the PEG procedure, whereas the other deaths were related to progression of liver disease or factors not directly related to the PEG. LIMITATIONS: The patients in this case series had varying levels of illness and reasons for PEG tube placement such that a generalization of outcomes may not be possible. CONCLUSIONS: The overall mortality of patients with cirrhosis who underwent PEG is high. Although there is an increased risk, PEG tube placement in cirrhotic patients without ascites may be less risky. The benefits of PEG tube placement in patients with cirrhosis should be weighed heavily against the risks. PMID- 20855068 TI - Predictive factors for acute renal failure in crush injuries in the Sichuan earthquake. AB - INTRODUCTION: The Sichuan earthquake caused a large number of crush injuries and many of them developed acute renal failure (ARF). A retrospective study was performed on victims with crush injuries of West China Hospital to investigate the predictive factors for acute renal failure (ARF) in crush injuries. PATIENTS AND METHODS: Medical records of injured victims treated in West China Hospital within the first week after the Sichuan earthquake were retrospectively reviewed and 101 patients with crush injury were enrolled in the study. We divided them into an ARF group and a non-ARF group. The clinical data of included patients were extracted and analysed. RESULTS: Patients with ARF accounted for 42% of the included population. Patients younger than 20 made up the biggest age category (45%), and the entrapped time under the debris (22 [IQR 3.5-38]h) was longer than previous reports. In univariate analysis, male gender, multiple crush injuries, medical comorbidities, surgical interventions and infections were more frequent in patients with ARF than in those without ARF. Mean arterial pressure was higher in the ARF group. Besides, the risk of ARF was increased by creatine kinase >14,494.5IU/L most significantly, followed by time under the rubble >4h, aspartate transaminase >453.5IU/L, albumin <27.15g/L and white blood cell >11.8*10(9)/L. In multivariate analysis, male gender, time under the rubble, multiple crush injuries, surgical interventions, infections and creatine kinase level were independently associated with ARF in crush injuries. CONCLUSIONS: The entrapped time under the debris, multiple crush injuries, male gender, infections, and creatine kinase level are predictive factors for ARF in crush injuries. PMID- 20855069 TI - Biomechanical analysis of the sliding hip screw, cannulated screws and Targon1 FN in intracapsular hip fractures in cadaver femora. PMID- 20855071 TI - The appropriateness of healthcare provider requests for obstetric and gynecologic ultrasound in a low-resource setting. PMID- 20855070 TI - The effect of time intervals on neonatal outcome in elective cesarean delivery at term under regional anesthesia. AB - OBJECTIVES: To measure 3 intervals of time-induction of regional anesthesia to delivery (I-D), initial skin incision to delivery (S-D), and uterine incision to delivery (U-D)-in elective cesareans and to evaluate the impact of the duration of these 3 components on short-term neonatal outcome. METHODS: We reviewed retrospective data on the duration of the components from the computerized database of the obstetrics operation room at the Sheba Medical Center, Tel Aviv, Israel, and from the medical records of term neonates. RESULTS: Sufficient data were available in 933 cases. The parameters associated with longer time to delivery at any stage were epidural rather than spinal anesthesia, maternal diabetes, previous cesarean delivery, antihypertensive treatment, higher birth weight (3456 g and 3285 g for U-D interval longer than 2 minutes and U-D interval up to 2 minutes, respectively; P=0.02), and male fetus. The duration of the I-D, S-D, and U-D intervals had no significant impact on any of the measured neonatal parameters. CONCLUSION: With regard to neonatal wellbeing, obstetricians have a relatively large safety margin in the time taken for inducing regional anesthesia and making the first and uterine incisions. PMID- 20855072 TI - Optimal pharmacologic approach to patients with hypertriglyceridemia and low high density lipoprotein-cholesterol: randomized comparison of fenofibrate 160 mg and niacin 1500 mg. AB - OBJECTIVES: Atherogenic dyslipidemia is emerging as a target of lipid-modifying therapy. However, an optimal pharmacologic approach has not yet been established. The aim of this study is to compare the efficacy and tolerability of the typical doses of fenofibrate and niacin. METHODS: After an eight-week dietary run-in, 201 patients who had triglyceride (TG) levels of 150-499 mg/dL, high-density lipoprotein-cholesterol (HDL-C) levels of <45 mg/dL and low-density lipoprotein cholesterol (LDL-C) levels of <130 mg/dL were randomly assigned to one of two treatment groups for 16 weeks: fenofibrate 160 mg or niacin extended release 1500 mg (starting at 500 mg and up-titrated at the fifth and ninth weeks). RESULTS: One hundred forty patients completed the study. The percent reductions in apoB/A1 were not different between the two groups (-20% and -22% in the fenofibrate and niacin groups, respectively, p=0.47). The effects of the two regimens on HDL-C were similar (24% and 20%, respectively, p=0.22), while fenofibrate reduced TG more than did niacin (-53% and -48%, respectively, p=0.045). Niacin was more effective at lowering LDL-C, Lp (a), and hs-CRP. However, niacin worsened the parameters of glycemic control, whereas fenofibrate improved them. Niacin showed more frequent adverse events including pruritus and skin flushing. CONCLUSIONS: These two regimens have largely comparable lipid-modifying effects. However, their effects on glucose metabolism and inflammation, and their adverse events need to be considered additionally. Our results underscore more individualized pharmacologic approaches to patients with atherogenic dyslipidemia. PMID- 20855073 TI - Novel application of parameters in waveform contour analysis for assessing arterial stiffness in aged and atherosclerotic subjects. AB - OBJECTIVE: Although contour analysis of pulse waves has been proposed as a non invasive means in assessing arterial stiffness in atherosclerosis, accurate determination of the conventional parameters is usually precluded by distorted waveforms in the aged and atherosclerotic objects. We aimed at testing reliable indices in these patient populations. METHODS: Digital volume pulse (DVP) curve was obtained from 428 subjects recruited from a health screening program at a single medical center from January 2007 to July 2008. Demographic data, blood pressure, and conventional parameters for contour analysis including pulse wave velocity (PWV), crest time (CT), stiffness index (SI), and reflection index (RI) were recorded. Two indices including normalized crest time (NCT) and crest time ratio (CTR) were also analysed and compared with the known parameters. RESULTS: Though ambiguity of dicrotic notch precluded an accurate determination of the two key conventional parameters for assessing arterial stiffness (i.e. SI and RI), NCT and CTR were unaffected because the sum of CT and T(DVP) (i.e. the duration between the systolic and diastolic peak) tended to remain constant. NCT and CTR also correlated significantly with age, systolic and diastolic blood pressure, PWV, SI and RI (all P<0.01). CONCLUSION: NCT and CTR not only showed significant positive correlations with the conventional parameters for assessment of atherosclerosis (i.e. SI, RI, and PWV), but they also are of particular value in assessing degree of arterial stiffness in subjects with indiscernible peak of diastolic wave that precludes the use of conventional parameters in waveform contour analysis. PMID- 20855074 TI - The influence of body weight support on ankle mechanics during treadmill walking. AB - The use of body weight support (BWS) systems during locomotor retraining has become routine in clinical settings. BWS alters load receptor feedback, however, and may alter the biomechanical role of the ankle plantarflexors, influencing gait. The purpose of this study was to characterize the biomechanical adaptations that occur as a result of a change in limb load (controlled indirectly through BWS) and gait speed during treadmill locomotion. Fifteen unimpaired participants underwent gait analysis with surface electromyography while walking on an instrumented dual-belt treadmill at seven different speeds (ranging from 0.4 to 1.6m/s) and three BWS conditions (ranging from 0% to 40% BWS). While walking, spatiotemporal measures, anterior/posterior ground reaction forces, and ankle kinetics and muscle activity were measured and compared between conditions. At slower gait speeds, propulsive forces and ankle kinetics were unaffected by changing BWS; however, at gait speeds >= approximately 0.8m/s, an increase in BWS yielded reduced propulsive forces and diminished ankle plantarflexor moments and powers. Muscle activity remained unaltered by changing BWS across all gait speeds. The use of BWS could provide the advantage of faster walking speeds with the same push-off forces as required of a slower speed. While the use of BWS at slower speeds does not appear to detrimentally affect gait, it may be important to reduce BWS as participants progress with training, to encourage maximal push off forces. The reduction in plantarflexor kinetics at higher speeds suggests that the use of BWS in higher functioning individuals may impair the ability to relearn walking. PMID- 20855075 TI - A stability-indicating reversed-phase high performance liquid chromatography method for simultaneous assay of two corticosteroids and estimation of their related compounds in a pharmaceutical injectable formulation. AB - Betamethasone Sodium Phosphate and Betamethasone Acetate are the two corticosteroids active pharmaceutical ingredients (APIs) that are present in the injectable formulation, Celestone Chronodose((r)) Injection. It is extremely challenging to develop a Quality Control friendly HPLC method to separate all the potential impurities and degradation products of the two APIs from each other using a single HPLC method. A novel stability-indicating reversed-phase HPLC (RP HPLC) method using two oxo-cyclic organic modifiers in the mobile phase was developed and validated. This method can separate a total of 32 potential impurities and degradation products from the two APIs and also from each other. Peak symmetry and separation efficiency were enhanced by using two chaotropic agents (trifluoroacetic acid and potassium hexafluorophosphate) in the mobile phases of this method. The stability-indicating capability of this method has been demonstrated by analyzing aged and stressed degraded stability samples of the drug product. This method uses an ACE 3 C18 (15 cm * 4.6 mm) HPLC column. The method was validated per ICH guidelines and proved to be suitable for routine QC use. PMID- 20855076 TI - Factors affecting peak shape in comprehensive two-dimensional gas chromatography with non-focusing modulation. AB - In the case of a non-focusing modulator for comprehensive two-dimensional gas chromatography (GC*GC), the systematic distortions introduced when the modulator loads the second-dimension column give rise to a characteristic peak shape. Depending on the operating conditions this systematic distortion can be the dominant component of the second-dimension elution profiles in the GC*GC peak. The present investigation involved a systematic investigation of peak shape in pulsed-flow modulation (PFM)-GC*GC. It is shown that low flow ratio can lead to significant peak skewing and increasing the flow ratio reduces the magnitude of peak skewing. Validation of the peak shape model is made by comparison with experimental data. The residuals from the fitting process (normalised to the maximum detector response) vary between -1.5% and +2.6% for an isothermal model and between -1.0% and +3.0% for a temperature-programmed model. PMID- 20855077 TI - A hybrid liquid chromatography-mass spectrometry strategy in a forensic laboratory for opioid, cocaine and amphetamine classes in human urine using a hybrid linear ion trap-triple quadrupole mass spectrometer. AB - A rapid method has been developed to analyse morphine, codeine, morphine-3 glucuronide, 6-monoacetylmorphine, cocaine, benzoylegonine, buprenorphine, dihydrocodeine, cocaethylene, 3,4-methylenedioxyamphetamine, ketamine, 3,4 methylenedioxymethamphetamine, pseudoephedrine, lignocaine, benzylpiperazine, methamphetamine, amphetamine, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine and methadone in human urine. Urine samples were diluted with methanol:water (1:1, v/v) and sample aliquots were analysed by hybrid linear ion trap-triple quadrupole mass spectrometry with a runtime of 12.5 min. Multiple reaction monitoring (MRM) as survey scan and an enhanced product ion (EPI) scan as dependent scan were performed in an information-dependent acquisition (IDA) experiment. Finally, drug identification and confirmation was carried out by library search with a developed in-house MS/MS library based on EPI spectra at a collision energy spread of 35+/-15 in positive mode and MRM ratios. The method was validated in urine, according to the criteria defined in Commission Decision 2002/657/EC. At least two MRM transitions for each substance were monitored in addition to EPI spectra and deuterated analytes were used as internal standards for quantitation. The reporting level was 0.05 MUg mL(-1) for the range of analytes tested. The regression coefficients (r(2)) for the calibration curves (0 4 MUg mL(-1)) in the study were >=0.98. The method proved to be simple and time efficient and was implemented as an analytical strategy for the illicit drug monitoring of opioids, cocaines and amphetamines in criminal samples from crime offenders, abusers or victims in the Republic of Ireland. To the best of our knowledge there are no hybrid LC-MS applications using MRM mode and product ion spectra in the linear ion trap mode for opioids, cocaines or amphetamines with validation data in urine. PMID- 20855078 TI - Validation of a gas chromatography-mass spectrometry isotope dilution method for the determination of 2-butoxyethanol and other common glycol ethers in consumer products. AB - A gas chromatography-mass spectrometry isotope dilution (GC-MS ID) method was developed and tested for the determination of 14 common glycol ethers in consumer products. Stable isotope labelled standards, 2-methoxyethanol-D(7) and 2 butoxyethanol-(13)C(2) (CDN isotopes) were employed to enhance the accuracy and precision of the glycol ethers determination. A 1000-fold sample dilution with methanol was applied to avoid column overload and contamination. At this dilution matrix effects were in most cases negligible and did not interfere with the analysis. The instrument detection limit (IDL) for analysed compounds varied from 0.01 to 1 MUg/mL; while the estimated limit of quantification (LoQ) varied between different glycol ethers from 0.02 to 3.4 MUg/mL. Calibration was tested in the range of 0.1-200 MUg/mL and showed that the linear fit is upheld from 0.1 to 10 MUg/mL, and extends beyond this range for some of the analytes. Recoveries of glycol ethers from products with different matrices were similar. The recoveries varied from 87% to 116% between the analysed compounds, while measurements precision varied between 2% and 14%. The method is applicable to products with glycol ether concentrations above 0.002-0.2% (w/w). The concentration range can be extended below the specified limits by decreasing the dilution factor; however, with lower dilution the sample matrix effect is expected to be stronger. Products with very high concentrations of glycol ether (>20%) may need to be further diluted prior to injection to avoid column overload. The method can be used for testing liquid and aerosol products designed for household use, such as cleaners, paints, solvents and paint stripers, for compliance and enforcement of regulations which limit glycol ethers content. PMID- 20855079 TI - Leukocyte telomere length in healthy Caucasian and African-American adolescents: relationships with race, sex, adiposity, adipokines, and physical activity. AB - OBJECTIVE: To examine the relationships of race, sex, adiposity, adipokines, and physical activity to telomere length in adolescents. STUDY DESIGN: Leukocyte telomere length (T/S ratio) was assessed cross-sectionally in 667 adolescents (aged 14-18 years; 48% African-Americans; 51% girls) using a quantitative polymerase chain reaction method. Generalized estimating equations analyses were performed. RESULTS: Telomere length was greater in the African-American adolescents than in the Caucasian adolescents (age- and sex-adjusted T/S ratio +/ SE, 1.32 +/- 0.01 vs 1.27 +/- 0.01: P = .014) and greater in girls than in boys (age- and race-adjusted T/S ratio +/- SE, 1.31 +/- 0.01 vs 1.27 +/- 0.01; P = .007). None of the adiposity or adipokine measures explained a significant proportion of the variance in telomere length. Vigorous physical activity was positively associated with telomere length (adjusted R(2) = 0.019; P = .009) and accounted for 1.9% of the total variance only in girls. CONCLUSIONS: This study, conducted in a biracial adolescent cohort, demonstrated that (1) race and sex differences in telomere length have already emerged during adolescence; (2) adiposity and adipokines are not associated with telomere length at this age; and (3) the antiaging effect of vigorous physical activity may begin in youth, especially in girls. PMID- 20855080 TI - Gestational glucose tolerance and cord blood leptin levels predict slower weight gain in early infancy. AB - OBJECTIVE: To determine the extent to which known prenatal and perinatal predictors of childhood obesity also predict weight gain in early infancy. STUDY DESIGN: We studied 690 infants participating in the prospective cohort Project Viva. We measured length and weight at birth and at 6 months. Using multivariable linear regression, we examined relationships of selected maternal and infant factors with change in weight-for-length z-score (WFL-z) from 0 to 6 months. RESULTS: Mean (standard deviation) change in WFL-z from 0 to 6 months was 0.23 (1.11), which translates to 4500 grams gained from birth to 6 months of life in an infant with average birth weight and length. After adjustment for confounding variables and birth weight-for-gestational age z-score (-0.28 [95% confidence interval, -0.37, -0.19] per unit), cord blood leptin (-0.40 [95%confidence interval, -0.61, -0.19] per 10 ng/mL), and gestational diabetes -0.50 [95%confidence interval, -0.88, -0.11] versus normal glucose tolerance)were each associated with slower gain in WFL-z from 0 to 6 months. CONCLUSIONS: Higher neonatal leptin and gestational diabetes predicted slower weight gain in the first 6 months of life. The hormonal milieu of the intrauterine environment may determine growth patterns in early infancy and thus later obesity. PMID- 20855081 TI - Liver metabolomic changes identify biochemical pathways in hemorrhagic shock. AB - BACKGROUND: Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock (n = 6) would reflect resultant metabolic changes. MATERIALS AND METHODS: The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs (n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ((1)H) and phosphorous ((31)P) nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. CONCLUSIONS: These results indicate that (1)H and (31)P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process. PMID- 20855082 TI - Abdominal wall endometrioma; a 10-year experience and brief review of the literature. AB - BACKGROUND: Abdominal wall endometrioma is a rare condition, which usually develops in a surgical scar of Cesarean section or hysterectomy. Certain factors relating to knowledge of the clinical pattern of this disease make correct diagnosis and treatment difficult. The aim was to identify the different forms of presentation of this disease entity through publishing the results from our experience of surgical management of such lesions. METHODS: Patients diagnosed with abdominal wall endometrioma over a period of 10 y were identified from the comprehensive surgical database of our institution. The age, parity, symptoms, previous surgeries, initial diagnosis, diagnostic modalities, current operation, and recurrences were surveyed and analyzed. RESULTS: There were 40 patients with a mean age of 32.3 +/- 5.2 y. All of the patients (100%, n = 40) had an abdominal mass in or adjacent to surgical scars. The main symptom was pain, noncyclic (45%, n =18), or cyclic (40%, n = 16) in nature. The mean duration of symptoms was 18.2 +/- 23.4 mo. The preoperative diagnosis was correct in 47.5% (n = 19) of the cases. Surgical treatment failed in 3 cases (3/33, 9.1%), and the operations were performed once again. CONCLUSIONS: Abdominal wall endometriosis may be difficult to diagnose as it is comparatively an unfamiliar entity that has not received its due attention among general surgeons, so far. Therefore, in patients with a palpable subcutaneous mass in or around surgical scars with a history of violation of uterus, a thorough history and physical examination is necessary, and usually sufficient to make correct diagnosis of endometrioma. PMID- 20855083 TI - Vitamin D binding protein-macrophage activating factor inhibits HCC in SCID mice. AB - BACKGROUND: A high incidence of recurrence after treatment is the most serious problem in hepatocellular carcinoma (HCC). Therefore, a new strategy for the treatment of the disease is needed. The aim of the present study was to investigate whether vitamin D binding protein-macrophage activating factor (DBP maf) is able to inhibit the growth of HCC. METHODS: The effects of DBP-maf on endothelial cells and macrophage were evaluated by WST-1 assay and phagocytosis assay, respectively. Human HCC cells (HepG2) were implanted into the dorsum of severe combined immunodeficiency (SCID) mice. These mice were divided into control and DBP-maf treatment groups (n = 10/group). The mice in the treatment group received 40 ng/kg/d of DBP-maf for 21 d. RESULTS: DBP-maf showed anti proliferative activity against endothelial cells and also activated phagocytosis by macrophages. DBP-maf inhibited the growth of HCC cells (treatment group: 126 +/- 18mm(3), untreated group: 1691.5 +/- 546.9mm(3), P = 0.0077). Histologic examinations of the tumors revealed the microvessel density was reduced and more macrophage infiltration was demonstrated in the tumor of mice in the treatment group. CONCLUSION: DBP-maf has at least two novel functions, namely, an anti angiogenic activity and tumor killing activity through the activation of macrophages. DBP-maf may therefore represent a new strategy for the treatment of HCC. PMID- 20855084 TI - Propofol prevents lung injury following intestinal ischemia-reperfusion. AB - BACKGROUND: The antioxidant properties of propofol have been shown to improve ischemia/reperfusion injury. We investigated whether anesthesia with propofol can ameliorate remote lung injury induced by intestinal ischemia-reperfusion (IIR). MATERIALS AND METHODS: Thirty male Wistar rats were randomly allocated in three groups (n = 10 each): animals in group Sham were anesthetized with ketamine and xylazine and then laparotomy and sham IIR followed. Animals in group IIR received ketamine and xylazine and were then subjected to clamping of the superior mesenteric artery for 45 min and reperfusion for 4 h. Group IIR+P received anesthesia with propofol and then IIR was induced, as in group IIR. Blood samples for blood gases and malondialdehyde measurements were drawn at the end of reperfusion. Bronchoalveolar lavage fluid (BALF) was obtained to measure cell counts, total protein, and phospholipids levels. RESULTS: Induction of IIR resulted in deteriorated oxygenation, acidemia, and inflammatory cells sequestration, along with increased BALF protein content and increased proportions of small surfactant aggregates. Anesthesia with propofol alleviated intestinal injury and efficiently prevented lipid oxidation. In group IIR+P inflammatory cell infiltration and pulmonary histologic changes were significantly limited. The increase in BALF total protein and the changes in surfactant aggregates were prevented, leading to normal systemic oxygenation. CONCLUSION: Using propofol to induce and maintain anesthesia efficiently prevented IIR-induced lung injury. Systemic antioxidant protection, improvement of intestinal injury, inhibition of the inflammatory response, and preservation of the alveolar-capillary permeability seem to be crucial mediating mechanisms for this simple and clinically relevant intervention. PMID- 20855085 TI - Enhancing melanoma treatment with resveratrol. AB - BACKGROUND: Resveratrol (RESV) is a naturally occurring compound that possesses anti-cancer capabilities. The goal of this study was to evaluate the potential of RESV as an adjunct to chemotherapy in melanoma treatment. METHODS: The in vitro and in vivo cytotoxic activity of RESV with or without chemotherapy was tested using cellular assays and a xenograft model. Two Duke melanoma cell lines (DM738, DM443) were used for both in vivo and in vitro experiments, and two nonmalignant human fibroblast lines (NHDF, HS68) were used for in vitro cellular assays. Xenografts were randomized to treatment arms and tumors measured to evaluate response. Results were analyzed using a Student's t-test and ANOVA. Western blots were performed on in vivo tissue. RESULTS: In vitro RESV significantly decreased melanoma cell viability in all lines tested (all P < 0.0001). Treatment of fibroblast cell lines revealed that RESV selectively spared NHDF and HS68 cells compared with its cytotoxic effects on melanoma cells (P < 0.0001). Treatment of malignant cells with 50 MUM RESV and temozolomide (TMZ) for 72 h significantly enhanced cytotoxicity compared with treatment with TMZ alone (P < 0.0001). In vivo, however, there was no significant difference between any treatment arms (P = 0.65). CONCLUSION: RESV shows promise as a novel therapeutic in the management of melanoma for its selective anti-tumor activity in vitro. Translating in vitro results to in vivo models has proven difficult. Barriers thought to prevent such translation are identified, and a rationale for overcoming them is discussed. PMID- 20855086 TI - Pretransplant free fatty acids (FFA) and allograft survival in renal transplantation. AB - BACKGROUND: Fatty acids and their eicosanoid metabolites have been shown to be important mediators of the immune response in transplantation. We hypothesize that elevated pretransplant free fatty acids (FFA) levels may be associated with prolonged survival of kidney transplants. METHODS: Archived pretransplant sera of 130 patients who received a kidney transplant from 1991 to 1997 were analyzed by gas liquid chromatography for a comprehensive FFA profile. FFA levels were categorized by quartiles, and the association between quartiles of the levels for each free-fatty acid and graft survival was initially screened by serial univariate analyses (Kaplan-Meier). All significant variables (FFAs and transplant-specific risk factors) were entered into a multivariable (Cox regression) model. RESULTS: With > 10 y of follow-up, 68 kidney allografts were lost. Factors associated with decreased graft survival by univariate analysis included delayed graft function (DGF), acute rejection (AR), and cold ischemic time (CIT) > 24 h. High levels of arachidonic and gamma-linolenic FFA were associated with higher graft survival rates. By multivariate analysis, only DGF, AR, CIT, and arachidonic acid levels were significant. The odds ratios for graft failure for the highest, third, and second quartiles of the pretransplant level of arachidonic acid, compared with the lowest quartile, were 0.18, 0.32, and 0.64, respectively (P = 0.050, log-rank test). For arachidonic acid the survival benefit appeared to be graded with the highest quartile associated with a greater than 80% reduction of risk of kidney graft failure. CONCLUSION: Pretransplant level of arachidonic acid was independently associated with higher kidney graft survival rates. Further studies are necessary to identify the underlying mechanisms and to determine whether interventions aimed at increasing pretransplant arachidonic acid levels might prove beneficial for renal transplant outcomes. PMID- 20855087 TI - Pancreatic neuroendocrine tumors: selection, selection, selection.... PMID- 20855088 TI - Susac's Syndrome--update. AB - Susac's Syndrome (SS) consists of the clinical triad of encephalopathy, branch retinal artery occlusion (BRAO), and hearing loss (HL). It is an autoimmune endotheliopathy affecting the precapillary arterioles of the brain, retina, and inner ear (cochlea and semicircular canals). The age range extends from 7 to 72 years, but young women (20-40) are most vulnerable. Headache routinely accompanies the encephalopathy and may be constant (best explained by leptomeningeal involvement), migrainous, or both. Multifocal neurological manifestations--particularly bilateral long-tract signs--commonly accompany the encephalopathy, which is laden with psychiatric features, confusion, memory loss and other cognitive changes. Left untreated, dementia can ensue. SS has an unexplained proclivity for attacking the central corpus callosum. In its encephalopathic form, pathognomonic callosal lesions permit an immediate diagnosis. We believe that the diagnosis of SS can be made when only the encephalopathy and pathognomonic MRI lesions are present; the BRAO and HL need not be present. We have also found the "string of pearls" MRI finding--the studding of the internal capsules with microinfarcts--to be most helpful--if not pathognomonic. This sign is always associated with the clusters of corpus callosum lesions, is especially striking on diffusion weighted imaging, and is associated with long-tract findings. We discuss the newly appreciated BRAO subset of SS and offer preliminary treatment suggestions for this subset. We also call attention to our development of an International Collaborative Study of SS and an educational website (http://www.ucalgary.ca/susac). PMID- 20855089 TI - Relationship between orthostatic hypotension and cognitive impairment in the elderly. AB - BACKGROUND AND PURPOSE: To determine the relationship between orthostatic hypotension (OH) and cognitive function in elderly subjects with memory complaints. METHODS: We studied the association between cognitive function and OH in 495 consecutive elderly outpatients attending a memory centre. Blood pressure (BP) was measured in a sitting and standing position. We examined cognitive function using a validated comprehensive battery of neuropsychological tests, the cognitive efficiency profile (CEP) assessing the main cognitive areas. Subjects were classified into 4 categories according to their cognitive status: normal cognitive function, mild cognitive impairment (MCI), Alzheimer's disease (AD) or vascular dementia (VaD). RESULTS: In this population, 76+/-8 years of age (women 72%), 18% had normal cognitive function, 28% had MCI, 47% AD, and 7% VaD. Hypertension was observed in 74% of patients. OH was present in 14% of subjects (n=69). After adjustment for age, education level, systolic BP, diastolic BP, weight, and antihypertensive drugs, subjects with OH had worse cognitive function than those without OH (CEP score 50+/-24 vs 56+/-22, p<0.05). Moreover, a significant relationship was observed between OH and cognitive status (normal cognitive function, MCI, AD, or VaD). OH was present in 22% in VaD subjects, 15% in AD subjects, 12% in MCI subjects and 4% in normal control subjects (p<0.01 for overall test). CONCLUSION: Our results showed an association between OH and cognitive impairment and emphasize the need for longitudinal studies designed to evaluate the nature of the relationship between OH and cognitive decline. PMID- 20855090 TI - Clinical trials for preventing post stroke cognitive impairment. AB - Post stroke dementia (PSD) develops in up to 40% of patients and often co-exists with Alzheimer's disease in the elderly. Unsurprisingly, the combination of stroke and dementia is associated with considerable morbidity and mortality, and is devastating to patients and carers. Limited trial evidence suggests that lowering high blood pressure reduces the development of cognitive decline, vascular dementia and PSD, although whether this relates to the magnitude of BP reduction or specific drug classes remains unclear. Biological plausibility and/or existing studies suggest that other types of drug treatments might also be effective, including choline esterase inhibitors, lipid lowering agents, antiplatelet agents, and selective serotonin reuptake inhibitors. Preventing cognitive decline and dementia post stroke is critical and large definitive trials are now needed. PMID- 20855091 TI - Timing for successful surgical management of heart block after placement of an Amplatzer occlusion device for secundum atrial septal defect repair. PMID- 20855092 TI - Reducing operative mortality in valvular reoperations: the "valve in ring" procedure. PMID- 20855093 TI - Effect of storage time of transfused plasma on early and late mortality after coronary artery bypass grafting. AB - OBJECTIVES: Because some concern has been raised about the storage time of red blood cells and outcomes after cardiac surgery, we investigated whether longer storage time of transfused plasma increases the risk for early or late mortality among patients who have undergone coronary artery bypass grafting. METHODS: We retrospectively analyzed the data of all 10,626 patients who underwent isolated coronary artery bypass grafting in Catharina Hospital, Eindhoven, The Netherlands, between January 1998 and December 2007. All patients who received at least 1 unit of plasma intraoperatively or during the first 5 postoperative days were studied. They were divided into 3 groups (only younger plasma, only older plasma, and any older plasma groups) according to the storage time of the plasma (cutoff point, 323 days). RESULTS: After we had excluded 122 patients who were unavailable for follow-up, we found that 375 of the remaining patients (n = 745) received only younger plasma 370 patients received any older plasma, and 200 patients received only older plasma (mean follow-up, 1565 +/- 1137 days; median follow-up, 1629 days). The storage time of plasma, when entered as either a continuous variable or a dichotomous variable, was a risk factor for early but not late mortality. Log-rank testing revealed no statistical difference in long term survival among the groups. CONCLUSIONS: Longer storage time of plasma is a risk factor for early but not late mortality among patients who have undergone coronary artery bypass grafting. PMID- 20855094 TI - Autoantibodies to recombinant canine proinsulin in canine diabetic patients. AB - OBJECTIVE: To determine whether dogs with spontaneously-occurring diabetes mellitus demonstrate serological reactivity to proinsulin. SAMPLE POPULATION: Serum samples were collected from 15 newly-diagnosed diabetic, 15 insulin-treated diabetic and 15 non-diabetic control dogs. PROCEDURES: Canine proinsulin was cloned into a prokaryotic expression vector to generate recombinant poly histidine-tagged protein in Escherichia coli. A Western blotting assay was developed for detection of proinsulin autoantibodies in canine sera. RESULTS: Reactivity to canine proinsulin was detected in 3 of 15 control dogs, 8 of 15 newly-diagnosed diabetic dogs and 6 of 15 insulin-treated diabetic patients. Of these reactors, only 1 control dog, 1 newly-diagnosed diabetic dog and 3 insulin treated diabetic dogs recognised porcine insulin by ELISA, suggesting that the remaining proinsulin reactors might have been recognising proinsulin-specific epitopes. CONCLUSIONS AND CLINICAL RELEVANCE: This study suggests that proinsulin autoantibodies are present in a proportion of diabetic dogs. Further work is required to refine the assay and clarify the significance of these autoantibodies. PMID- 20855095 TI - Correlation between helical surface waves and guided modes of an infinite immersed elastic cylinder. AB - Scattering of obliquely incident plane acoustic waves from immersed infinite solid elastic cylinders is a complex phenomenon that involves generation of various types of surface waves on the body of the cylinder. Mitri [F.G. Mitri, Acoustic backscattering enhancement resulting from the interaction of an obliquely incident plane wave with an infinite cylinder, Ultrasonics 50 (2010) 675-682] recently showed that for a solid aluminum cylinder, there exist acoustic backscattering enhancements at a normalized frequency of ka?0.1. The incidence angle alpha(c) at which these enhancements are observed lies between the first (longitudinal) and second (shear) coupling angles of the cylinder. He also confirmed the observations previously reported by the authors that there exist backscattering enhancements of the dipole mode at large angles of incidence where no wave penetration into the cylinder is expected. In this paper, physical explanations are provided for the aforementioned observations by establishing a correlation between helical surface waves generated by oblique insonification of an immersed infinite solid elastic cylinder and the longitudinal and flexural guided modes that can propagate along the cylinder. In particular, it is shown that the backscattering enhancement observed at ka?0.1 is due to the excitation of the first longitudinal guided mode travelling at the bar velocity along the cylinder. It is also demonstrated that the dipole resonance mode observed at incidence angles larger than the Rayleigh coupling angle is associated with the first flexural guided mode of the cylinder. The correlation established between the scattering and propagation problems can be used in both numerical and experimental studies of interaction of mechanical waves with cylinders. PMID- 20855096 TI - Modelling nonlinearity in piezoceramic transducers: From equations to nonlinear equivalent circuits. AB - Quadratic nonlinear equations of a piezoelectric element under the assumptions of 1D vibration and weak nonlinearity are derived by the perturbation theory. It is shown that the nonlinear response can be represented by controlled sources that are added to the classical hexapole used to model piezoelectric ultrasonic transducers. As a consequence, equivalent electrical circuits can be used to predict the nonlinear response of a transducer taking into account the acoustic loads on the rear and front faces. A generalisation of nonlinear equivalent electrical circuits to cases including passive layers and propagation media is then proposed. Experimental results, in terms of second harmonic generation, on a coupled resonator are compared to theoretical calculations from the proposed model. PMID- 20855097 TI - IFN-gamma production downstream of NKT cell activation in mice infected with influenza virus enhances the cytolytic activities of both NK cells and viral antigen-specific CD8+ T cells. AB - Natural killer T (NKT) cell activation is responsible for eliminating pathogens. However, the biological functions of NKT cells against influenza virus are not fully understood. We therefore investigated the effects of NKT cells in viral infection using CD1d knockout (KO) mice. When CD1d KO or wild-type (WT) mice were infected with a sub-lethal dosage of the influenza virus, the survival rate of CD1d KO mice was significantly lower than for WT mice in association with delayed viral clearance in the lungs. Consistently, IFN-gamma production in bronchoalveolar lavage fluid of CD1d KO mice was largely reduced compared to WT mice during infection. Moreover, the cytotoxic activities of NK cells and viral antigen-specific CD8(+) T cells were impaired in CD1d KO mice. It was concluded that activated NKT cell-induced IFN-gamma release enhances both NK-cell activity and antigen-specific CD8(+) T cells to eliminate the influenza virus, thus leading to an enhanced survival. PMID- 20855098 TI - UL84-independent replication of human cytomegalovirus strain TB40/E. AB - The UL84 gene of human cytomegalovirus is implicated in the initiation of viral DNA replication during lytic infection. UL84 is essential for replication of a cloned viral origin of lytic replication (oriLyt) in vitro and mutants of strains AD169 or Towne with deletions or insertions in UL84 fail to grow in cells permissive for wild type virus. Here we show that UL84 is dispensable for replication of a strain TB40/E clone derived from a bacterial artificial chromosome. The genomes of the fibroblast-adapted strains AD169 and Towne are altered substantially from the consensus for strains that have not been propagated extensively in cell culture. The parental TB40/E genome conforms to the consensus genomic organization. Accordingly, natural HCMV strains may possess replication capability that extends beyond the known oriLyt-dependent replication system of laboratory strains. PMID- 20855099 TI - Intrinsic disorder and oligomerization of the hepatitis delta virus antigen. AB - The 195 amino acid basic protein (deltaAg) of hepatitis delta virus (HDV) is essential for replication of the HDV RNA genome. Numerous properties have been mapped to full-length deltaAg and attempts made to link these to secondary, tertiary and quaternary structures. Here, for the full-size deltaAg, extensive intrinsic disorder was predicted using PONDR-FIT, a meta-predictor of intrinsic disorder, and evidenced by circular dichroism measurements. Most deltaAg amino acids are in disordered configurations with no more than 30% adopting an alpha helical structure. In addition, dynamic light scattering studies indicated that purified deltaAg assembled into structures of as large as dodecamers. Cross linking followed by denaturing polyacrylamide gel electrophoresis revealed hexamers to octamers for this purified deltaAg and at least this size for deltaAg found in virus-like particles. Oligomers of purified deltaAg were resistant to elevated NaCl and urea concentrations, and bound without specificity to RNA and single- and double-stranded DNAs. PMID- 20855100 TI - Reactivity of mucohalic acids in water. AB - One group of disinfection byproducts of increasing interest are the halogenated furanones, which are formed in the chlorination of drinking water. Among these halofuranones is mucochloric acid (MCA, 3,4-dichloro-5-hydroxyfuran-2(5H)-one), and mucobromic acid (MBA, 3,4-dibromo-5-hydroxyfuran-2(5H)-one). Both mucohalic acids (MXA) are direct genotoxins and potential carcinogens, with the capacity to alkylate the DNA bases guanosine, adenosine and cytosine, and they have been measured in concentrations ranging up to 700 ng/l in tap water. MCA and MBA react in basic aqueous medium to form mucoxyhalic acids (4-halo-3,5-hydroxyfuran-2(5H) one). Since: i) this reaction may represent the first step in the abiotic decomposition of mucohalic acids, ii) mucoxyhalic acids have been proposed as possible intermediates in the reaction of MXA with DNA, a kinetic study of the reaction mechanism is of interest. Here, the following conclusions were drawn: a) At moderately basic pH, the reaction of mucohalic acids with OH(-) to form mucoxyhalic acids is kinetically significant. b) The nucleophilic attack of hydroxide ions on MXA occurs through a combination of two paths: one of them is first-order in hydroxide whereas the other is second-order and are proposed to occur through the deprotonation of the hydrate of MXA. c) The hydration constants of mucohalic acids -0.23 and 0.17 for MCA and MBA respectively - corresponds to the very significant hydrate concentrations. Since hydrates are not electrophilic, these values imply a decrease in the alkylating capacity of mucohalic acids. PMID- 20855101 TI - Efficient synthesis of 16 aromatic Morita-Baylis-Hillman adducts: Biological evaluation on Leishmania amazonensis and Leishmania chagasi. AB - Sixteen aromatic Morita-Baylis-Hillman adducts (MBHA) 1-16 were efficiently synthesized in a one step Morita-Baylis-Hillman reaction (MBHR) involving commercial aldehydes with methyl acrylate or acrylonitrile (81-100% yields) without the formation of side products on DABCO catalysis and at low temperature (0 degrees C). The toxicities of these compounds were assessed against promastigote form of Leishmania amazonensis and Leishmania chagasi. The low synthetic cost of these MBHA, green synthetic protocols, easy one-step synthesis from commercially available and cheap reagents as well as the very good antileishmanial activity obtained for 14 and 16 (IC50 values of 6.88MUgmL-1 and 11.06MUgmL-1 respectively on L. amazonensis; 9.58MUgmL-1 and 14.34MUgmL-1 respectively on L. chagasi) indicates that these MBHA can be a novel and promising class of anti-parasitic compounds. PMID- 20855102 TI - Nickel(II) removal by mixtures of Acorga M5640 and DP8R in pseudo-emulsion based hollow fiber with strip dispersion technology. AB - This work presents the investigation of Ni(II) extraction from aqueous solution through pseudo-emulsion based hollow fiber strip dispersion (PSEHFSD) containing the mixture 2-hydroxy-5-nonylbenzaldehyde oxime+di(2-ethylhexyl) phosphoric acid/Exxsol D100 as extractant in the form of a pseudo-emulsion with H2SO4. The organic and aqueous strip phases are separated when the stirring device is stopped. The permeation of Ni(II) is investigated as a function of various experimental variables: hydrodynamic conditions, feed pH, extractants mixture concentration in the pseudo-emulsion, initial Ni(II) concentration in feed phase, H2SO4 concentration in the pseudo-emulsion as strippant. In PEHFSD, pseudo emulsion is an emulsion that is formed temporarily between organic and stripping solutions. In this investigation, feed was circulated through the lumen side in counter-current mode. The selectivity of 2-hydroxy-5-nonylbenzaldehyde oxime+di(2 ethylhexyl) phosphoric acid/Exxsol D100 based PEHFSD toward different metals was also examined. PMID- 20855103 TI - Biological transformation pathways of 2,4-dinitro anisole and N-methyl paranitro aniline in anaerobic fluidized-bed bioreactors. AB - The US Army is evaluating new, insensitive explosives to produce safer munitions. Two potential new components are 2,4-dinitro anisole (DNAN) and N-methyl paranitro aniline (MNA), which would eventually make their way to waste streams generated in the production and handling of new munitions. The effectiveness of anaerobic fluidized-bed bioreactors (AFBB) was studied for treatment and transformation of these two new chemical components in munitions. Each compound was fed into a separate reactor and monitored for removal and transformation, using ethanol as the electron donor. The results show that both were degradable using the AFBB system. DNAN was found to transform into diaminoanisole and MNA was found to transform into N-methyl-p-phenylenediamine. Both of these by products appeared to form azobond polymers after exposure to air. To test the resilience of the reactors, the compounds were removed from the feed streams for 3 weeks and then reintroduced. DNAN showed that a re-acclimation period was necessary for it to be degraded again, while MNA was removed immediately upon reintroduction. The AFBB technology was shown here to be an effective means of removing the new munitions, but produce secondary compounds that could potentially be just as harmful and require further study. PMID- 20855104 TI - Ozonation performance of WWTP secondary effluent of antibiotic manufacturing wastewater. AB - The ozonation performance of wastewater treatment plant secondary effluent of oxytetracycline (OTC) manufacturing wastewater was investigated in terms of ozone dosage and initial pH levels when OTC contributed to a negligible fraction in the chemical oxygen demand (COD) ingredients of the medium-organic-strength wastewater with low biodegradability. A particular emphasis was placed on ammonia, OTC, and residual antibacterial activity (RAA) (evaluated using the objective pathogenic bacterium Staphylococcus aureus). It appears that an ozone dosage of 657 mg L-1 (120 min of reaction) was enough to achieve an OTC abatement of 96%, and COD and biochemical oxygen demand removals of 29% and 33%, respectively, at initial levels of 10.4, 1360, and 300 mg L-1 , respectively. There is a clear correlation between complete OTC depletion and complete RAA disappearance with an increase of ozone dosage. The presence of plentiful non antibiotic refractory substances influenced the determination of the optimum ozone dosage for biodegradability enhancement and OTC/RAA reduction as well as the ozonation transformation of NH(3). The initial pH adjustment from the original level (pH 9) to pH 11 significantly reduced COD removal while RAA and NH(3) levels were not significantly influenced. PMID- 20855105 TI - Face mask application as a tool to diminish the particulate matter mediated heavy metal exposure among citizens of Lucknow, India. AB - Traffic related fine particulate emissions, enriched in metal contents, are directly linked to respiratory disorders in human subjects. In view of the growing traffic related emissions in India, the present study was undertaken to estimate the heavy metal exposure among non-occupationally exposed two vehicle riders of Lucknow City and related health effects via application of face masks (FMs) fitted with cellulose nitrate filters and measuring the peak respiratory flow rate (PEFR). Carefully selected 200 volunteers (asymptomatic n=154 and symptomatic n=46) were advised to use FMs during their deriving time for 30 days and PEFR test was conducted on each subject at the beginning, i.e. 0 day, and at end of the study period, i.e. 30 days. On completion of the prescribed study period, filters from the used FMs were collected, acid leached and analyzed for Fe, Mn, Cu, Zn, Pb, Ni, Cr and Cd. Asymptomatic and symptomatic subject groups were further divided into two age groups of 15-40 years and 41-68. Pb, Cu and Cd were significantly higher in lower age group (15-40) of symptomatic group and Cr was in asymptomatic group. Negative associations were observed between metals viz. Pb (r=-0.39, p<0.001), Cd (r=-0.26, p<0.001), Fe (r=-0.37, p<0.001), Mn (r= 0.15, p<0.05) and the lung functioning. 30 days PEFR of all subjects were higher by nearly 10% than 0 day in all 200 samples irrespective of age and symptomatic nature of the subject. The improvement could also be due to metals and other organic species, not analyzed herein. Nevertheless the results indicate that FM usage has a role to play for immediate, if not ultimate, improvement in public health and need further studies. PMID- 20855106 TI - Identification of nanominerals and nanoparticles in burning coal waste piles from Portugal. AB - A range of carbon nanoparticles, agglomerates and mineral phases have been identified in burning coal waste pile materials from the Douro Coalfield of Portugal, as a basis for identifying their potential environmental and human health impacts. The fragile nature and fine particle size of these materials required novel characterization methods, including energy-dispersive X-ray spectrometry (EDS), field-emission scanning electron microscope (FE-SEM), and high-resolution transmission electron microscopy (HR-TEM) techniques. The chemical composition and possible correlations with morphology of the nanominerals and associated ultra-fine particles have been evaluated in the context of human health exposure, as well as in relation to management of such components in coal-fire environments. PMID- 20855107 TI - Role of Saharan dust in the relationship between particulate matter and short term daily mortality among the elderly in Madrid (Spain). AB - BACKGROUND: Saharan dust outbreaks are a common phenomenon in the Madrid atmosphere. The current Directive 2008/50 CE governing air quality in European cities, draws no distinction between which particulate matter (PM(10), PM(2.5) or PM(10-2.5)) would be the best indicator on days with/without Saharan dust intrusions. This study sought to identify the role played by Saharan dust in the relationship between particulate matter (PM(10), PM(2.5) and PM(10-2.5)) concentrations and daily mortality among the elderly in the city of Madrid. METHODS: We conducted an ecological longitudinal time-series study on daily mortality among the over-75 age group, from 2003 to 2005. Poisson regression models were constructed for days with and without Saharan dust intrusions. The following causes of daily mortality were analysed: total organic causes except accidents (International Classification of Diseases-10th revision (ICD-10): A00 R99); circulatory causes (ICD-10: I00-I99); and respiratory causes (ICD-10: J00 J99). Daily mean PM(10), PM(2.5) and PM(10-2.5) levels were used as independent variables. Control variables were: other ambient pollutants (chemical, biotic and acoustic); trend; seasonalities; influenza epidemics; and autocorrelations between mortality series. RESULTS: While daily mean PM(2.5) concentrations in Madrid displayed a significant statistical association with daily mortality for all the above causes on days without Saharan dust intrusions, this association was not in evidence for PM(10) or PM(10-2.5) in the multivariate models. The relative risks (RRs) obtained for an increase of 10 MUg/m(3) in PM(2.5) concentrations were: 1.023 (1.010-1.036) for total organic causes; 1.033 (1.031 1.035) for circulatory causes; and 1.032 (1.004-1.059) for respiratory causes. On Saharan dust days, a significant statistical association was detected between PM(10) (though not PM(2.5) or PM(10-2.5)) and mortality for all 3 causes analysed, with RRs statistically similar to those reported for PM(2.5). CONCLUSIONS: The best air quality indicators for evaluating the short-term health effects of particulate matter in Madrid are therefore PM(10) concentrations on days with, and PM(2.5) concentrations on days without Saharan dust outbreaks. This fact should be taken into account in a European Directive regulating ambient air quality in almost all countries in the Mediterranean area. PMID- 20855108 TI - An evaluation of mercury levels in Louisiana fish: trends and public health issues. AB - To characterize statewide fish tissue mercury levels in edible finfish the first comprehensive analysis of Louisiana's fish tissue mercury database was conducted. Analyses were based on fifteen years of fish tissue mercury data collected from 368 waterbodies between 1994 and 2008 (n=14,344). The overall objectives of this study were to establish baseline fish tissue mercury levels; and evaluate species specific temporal and spatial trends in fish tissue mercury levels. Fish tissue mercury levels ranged from 0.001 ppm (the detection limit) to 5.904 ppm for king mackerel; with an overall geometric mean of 0.218 ppm. Ninety-five percent of samples had mercury levels below the FDA's action level of 1.0 ppm for methylmercury in commercial food. Forty-four percent of all samples had mercury levels above the U.S. EPA's methylmercury fish tissue criterion of 0.3 ppm for sportfish. Species of potential concern include cobia, king mackerel, blackfin tuna, greater amberjack, spotted bass, bowfin, largemouth bass and freshwater drum. There was a significant but small decline in statewide length-adjusted largemouth bass mercury levels between 1994-1999 to 2003-2008 (p<0.05). The highest fish mercury levels were observed in Pearl, Calcasieu, Mermentau, Ouachita, Pontchartrain and Sabine basins. Length-adjusted largemouth bass mercury levels were significantly higher in wetlands and rivers/streams vs. lakes; and in wetlands vs. estuaries (p<0.05). Data were analyzed from a public health perspective to make recommendations for optimizing monitoring and outreach. PMID- 20855109 TI - Physicochemical characterisation of depleted uranium (DU) particles at a UK firing test range. AB - Depleted uranium (DU) particles were isolated from soils at Eskmeals, UK, where DU munitions have been tested against hard targets and unfired DU buried in soils for corrosion studies. Using electron microscopy and X-ray analyses, three classes of particles were identified: (1) DU aerosols and fragments, typically 1 20 MUm diameter, composed mainly of uranium as UO(2) and U(3)O(8), (2) solidified molten particles, typically 200-500 MUm diameter, composed of U, mixed with Fe from target materials and (3) deposits and coatings, often of metaschoepite on sand grains up to 500 MUm diameter. The first two particle types are derived from firing impacts, the last from corrosion of buried uranium metal. Alpha and mass spectrometry allowed quantitative elemental and isotopic characterisation of DU containing particulate environmental samples. PMID- 20855111 TI - A call for action: Comparative effectiveness research in asthma. AB - Comparative effectiveness research (CER) has received considerable research attention in recent months, and efforts to promote CER are part of the newly enacted Patient Protection and Affordable Care Act. In this article we define CER and how it complements traditional efficacy research in asthma and discuss how CER can help provide the basis for rational decision making about the care of individual patients with asthma and how best to deliver this care in real-world settings. We present information about the challenges and opportunities to conduct CER, including enhanced patient registries for observational CER and effectiveness trials (also called pragmatic trials). We discuss the urgent need to define the appropriate methodologies for CER and to develop and prioritize a research agenda for CER studies in asthmatic subjects with the help of a diverse group of stakeholders. PMID- 20855112 TI - Acute apenditis in patient with acute promyelocytic leukemia. PMID- 20855113 TI - Role of Rho-ROCK signaling in MOLT4 cells metastasis induced by CCL25. AB - Our previous research has revealed that binding of the chemokine CCL25 to the CCR9 provides chemotactic cues guiding leukemic cells to specific tissues and organs. The RhoA-ROCK pathway might be involved in cancer migration. The purpose of this study was to explore the role of the RhoA-ROCK-MLC axis in leukemic cell migration following exposure to CCL25. The results showed that CCL25 could increase the amount of the GTPase RhoA and activate MLC in MOLT4 cells in a time dependent manner. C3 exoenzyme and Y-27632 could block MOLT4 cell migration and chemotaxis. Thus, the RhoA-ROCK-MLC axis might play an important role in MOLT4 cell metastasis induced by CCL25. PMID- 20855114 TI - Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. AB - OBJECTIVES: To determine the long-term effects of ranibizumab (RBZ) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: One hundred twenty-six patients with DME. METHODS: Subjects were randomized 1:1:1 to receive 0.5 mg RBZ at baseline and months 1, 3, and 5 (group 1), focal or grid laser photocoagulation at baseline and month 3 if needed (group 2), or a combination of 0.5 mg RBZ and focal or grid laser at baseline and month 3 (group 3). Starting at month 6, if retreatment criteria were met, all subjects could be treated with RBZ. MAIN OUTCOME MEASURES: The mean change from baseline in best-corrected visual acuity (BCVA) at month 24. RESULTS: After the primary end point at month 6, most patients in all groups were treated only with RBZ, and the mean number of injections was 5.3, 4.4, and 2.9 during the 18-month follow-up period in groups 1, 2, and 3, respectively. For the 33 patients in group 1, 34 patients in group 2, and 34 patients in group 3 who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5, and 3.8 letters at the 6-month primary end point, compared with 7.7, 5.1, and 6.8 letters at month 24, and the percentage of patients who gained 3 lines or more of BCVA was 21, 0, and 6 at month 6, compared with 24, 18, and 26 at month 24. The percentage of patients with 20/40 or better Snellen equivalent at month 24 was 45% in group 1, 44% in group 2, and 35% in group 3. Mean foveal thickness (FTH), defined as center subfield thickness, at month 24 was 340 MUm, 286 MUm, and 258 MUm for groups 1, 2, and 3, respectively, and the percentage of patients with center subfield thickness of 250 MUm or less was 36%, 47%, and 68%, respectively. CONCLUSIONS: Intraocular injections of RBZ provided benefit for patients with DME for at least 2 years, and when combined with focal or grid laser treatments, the amount of residual edema was reduced, as were the frequency of injections needed to control edema. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 20855115 TI - In the company of my sisters: sister circles as an anxiety intervention for professional African American women. AB - BACKGROUND: Sister circles have been used within African American communities to raise awareness about physical health. The possibility exists that sister circles could be used to educate and teach women strategies about managing anxiety and panic. In this paper we examine professional Black women's conceptualization of panic attacks and other related anxiety issues. Then, we explore the feasibility of sister circles as a psycho-educational anxiety intervention for African American professional women. METHODS: Four focus groups (n=37) were conducted. Focus group interviews were transcribed and were coded into three categories: (a) a major theme; (b) a minor theme; or (c) an off-topic comment. Specifically, we generate information regarding the key content and research components of a sister circle for African American female professionals. RESULTS: Focus group members saw a distinct difference between anxiety and panic. The number of African American women who experienced was seen as low. Women felt sister circles were a nice vehicle for helping African American women manage their anxiety and panic. Confidentially was a key component. Sister circles for anxiety and panic were seen as a natural outgrowth of African American women's professional networks. LIMITATIONS: Limited data were collected on participant's anxiety levels. CONCLUSIONS: Overall, sister circles were seen as feasible interventions for African American professional women. The data from the focus groups were used to enhance the development of a sister circle intervention for anxious professional African American women. PMID- 20855116 TI - Correlates of first-episode polarity in a French cohort of 1089 bipolar I disorder patients: role of temperaments and triggering events. AB - OBJECTIVES: As only a few studies so far systematically reported on bipolar patients subtyped according to first-episode polarity, we took the opportunity of having at disposal a large sample of bipolar I patients to specify the characteristics of patients included in these subtypes, with a special focus on temperament and triggering events. METHODS: A total of 1089 consecutive DSM-IV bipolar I manic inpatients were subtyped in manic onset (MO), depressive onset (DO) and mixed onset (MXO), and assessed for demographic, illness course, clinical, psychometric, comorbidity and temperament characteristics. RESULTS: The main characteristics of MO patients were a hyperthymic temperamental predisposition, a first episode triggered by substance abuse and an illness course with pure, severe and psychotic mania. In comparison, DO patients had more depressive temperaments, a first episode triggered by stress and alcohol, an illness course with more episodes, cyclicity, suicide attempts, anxious comorbidity and residual symptoms. Although sharing characteristics with either MO or DO, MXO patients had more mixed episodes and cyclothymic temperament. LIMITATIONS: The following are the limitations of this study: retrospective design, bias toward preferential enrolment of MO patients, and lack of information on the number and polarity of lifetime episodes. CONCLUSIONS: Findings from this study tend to confirm most of the differences previously evidenced among patients subtyped according to first-episode polarity. Differences found in temperamental predisposition and illness onset triggering events are worth noting and may help target early preventive interventions as well as orientate the search for specific genetic risk factors. PMID- 20855117 TI - Triclosan persistence through wastewater treatment plants and its potential toxic effects on river biofilms. AB - Triclosan is a commonly used bactericide that survives several degradation steps in WWTP (wastewater treatment plants) and potentially reaches fluvial ecosystems. In Mediterranean areas, where water scarcity results in low dilution capacity, the potential environmental risk of triclosan is high. A set of experimental channels was used to examine the short-term effects of triclosan (from 0.05 to 500MUgL-1) on biofilm algae and bacteria. Environmentally relevant concentrations of triclosan caused an increase of bacterial mortality with a no effect concentration (NEC) of 0.21MUgL-1. Dead bacteria accounted for up to 85% of the total bacterial population at the highest concentration tested. The toxicity of triclosan was higher for bacteria than algae. Photosynthetic efficiency was inhibited with increasing triclosan concentrations (NEC=0.42MUgL-1), and non photochemical quenching mechanisms decreased. Diatom cell viability was also affected with increasing concentrations of triclosan. Algal toxicity may be a result of indirect effects on the biofilm toxicity, but the clear and progressive reduction observed in all the algal-related endpoints suggest the existence of direct effects of the bactericide. The toxicity detected on the co-occurring non target components of the biofilm community, the capacity of triclosan to survive through WWTP processes and the low dilution capacity that characterizes Mediterranean systems extend the relevance of triclosan toxicity beyond bacteria in aquatic habitats. PMID- 20855118 TI - Planning study for available dose of hypoxic tumor volume using fluorine-18 labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer. AB - PURPOSE: To investigate the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ((18)F-FMISO PET/CT)-guided intensity-modulated radiotherapy (IMRT) in dose escalation to attack the hypoxic volume of a tumor mass without increasing the normal tissue dose in head and neck cancer patients. MATERIALS AND METHODS: Eight consecutive head and neck cancer patients underwent (18)F-FMISO PET/CT simulation. Hypoxic tumor volume (HTV) was defined using a tumor-to-cerebellum ratio (T/C) of 1.3 as the threshold for (18)F FMISO PET/CT. Dose-escalation plans for treating HTVs using (18)F-FMISO PET/CT guided IMRT were performed for these patients. The standard plan was 72Gy to the gross tumor volume (GTV) administered as 30 daily fractions of 2.4Gy. In biologically optimized IMRT plans, the daily dose to the HTV ranged from 2.6 to 3.6Gy. Dose-volume histograms (DVHs) were generated as part of each plan, and the results of planning were analyzed. RESULTS: Dose-escalation IMRT plans, delivering 30 daily doses of 2.6Gy (total of 78Gy) to the HTVs without increases in normal tissue doses, were feasible for six patients. Further acceptable dose escalation on HTV depended primarily on the primary tumor site and the extent of disease. CONCLUSIONS: It was possible to dose escalate the HTV radiation to 78Gy in six of eight head and neck cancer patients using (18)F-FMISO PET/CT-guided IMRT. PMID- 20855119 TI - Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. AB - PURPOSE: To analyze the recurrence patterns in patients with newly diagnosed glioblastoma (GBM) treated with conformal radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ), and to compare the patterns of failure according to different target volume delineations. METHODS AND MATERIALS: One hundred and five patients with GBM which recurred after three-dimensional (3D) conformal RT plus TMZ were evaluated. The clinical target volume (CTV) used for our treatment planning (S'Andrea plans) consisted of residual tumor and resection cavity plus 2 cm margins according to recent randomized trials of the European Organisation for Research and Treatment of Cancer (EORTC). MRI scans showing tumor recurrences were fused with the planning computed tomography (CT), and the patterns of failure were analyzed dosimetrically using dose-volume histograms. For each patient a theoretical plan based on the addition of postoperative edema plus 2-cm margins according to current guidelines of Radiation Therapy Oncology Group (RTOG) was created and patterns of failure were evaluated. RESULTS: The median overall survival and progression-free survival were 14.2 months and 7.5 months, respectively. Recurrences were central in 79 patients, in-field in 6 patients, marginal in 6 patients, and distant in 14 patients. Analysis of O(6) methylguanine-DNA-methyltransferase (MGMT) promoter methylation status showed different recurrence patterns of GBMs in patients with MGMT methylated compared with patients with MGMT unmethylated status. Recurrences occurred central/in field and outside in 64% and 31% of methylated patients, and in 91% and 5.4% of unmethylated patients, respectively (P=0.01). Patterns of failure were similar between the different treatment plans, however the median volume percent of brain irradiated to high doses was significantly smaller for our plans than for RTOG plans (P=0.0001). CONCLUSION: Most of patients treated with RT plus concomitant and adjuvant RT have central recurrences, however distant new lesions may occur in more than 10% of patients. The use of target delineation using postoperative residual tumor and cavity plus 2-cm margins is associated with smaller volumes of normal brain irradiated to high doses as compared with plans including expanded edema, without a significant increase of the risk of marginal recurrences. Future clinical randomized studies need to compare the different planning methods in terms of efficacy and risk of late radiation-induced toxicity. PMID- 20855120 TI - A novel strategy to obtain quantitative data for modelling: combined enrichment and real-time PCR for enumeration of salmonellae from pig carcasses. AB - Salmonella is a major zoonotic pathogen which causes outbreaks and sporadic cases of gastroenteritis in humans worldwide. The primary sources for Salmonella are food-producing animals such as pigs and poultry. For risk assessment and hazard analysis and critical control point (HACCP) concepts, it is essential to produce large amounts of quantitative data, which is currently not achievable with the standard cultural based methods for enumeration of Salmonella. This study presents the development of a novel strategy to enumerate low numbers of Salmonella in cork borer samples taken from pig carcasses as a first concept and proof of principle for a new sensitive and rapid quantification method based on combined enrichment and real-time PCR. The novelty of the approach is in the short pre-enrichment step, where for most bacteria, growth is in the log phase. The method consists of an 8h pre-enrichment of the cork borer sample diluted 1:10 in non-selective buffered peptone water, followed by DNA extraction, and Salmonella detection and quantification by real-time PCR. The limit of quantification was 1.4 colony forming units (CFU)/20 cm(2) (approximately 10 g) of artificially contaminated sample with 95% confidence interval of +/- 0.7 log CFU/sample. The precision was similar to the standard reference most probable number (MPN) method. A screening of 200 potentially naturally contaminated cork borer samples obtained over seven weeks in a slaughterhouse resulted in 25 Salmonella-positive samples. The analysis of salmonellae within these samples showed that the PCR method had a higher sensitivity for samples with a low contamination level (<6.7 CFU/sample), where 15 of the samples negative with the MPN method was detected with the PCR method and 5 were found to be negative by both methods. For the samples with a higher contamination level (6.7-310 CFU/sample) a good agreement between the results obtained with the PCR and MPN methods was obtained. The quantitative real-time PCR method can easily be applied to other food and environmental matrices by adaptation of the pre-enrichment time and media. PMID- 20855121 TI - Shift from farm to dairy tank milk microbiota revealed by a polyphasic approach is independent from geographical origin. AB - Detailed information on the natural microbial community present in raw milk, especially on the non-cultivable part of the milk microbiota, is rather limited as research in the past mainly focused on the detection of bacterial pathogens or microorganisms responsible for the deterioration of raw milk. In frame of the EU project BIOtracer raw milk samples from three different European countries were analyzed to gain a deeper insight into the diversity of the natural bacterial flora of raw milk by combining culture-dependent and -independent methods. Fourier-transform infrared (FTIR) spectroscopy was used as rapid and cost efficient metabolic fingerprinting technique to monitor the cultivable microbiota of raw milk. In addition, direct sequencing was applied to acquire additional information on the non-cultivable part of the bacterial raw milk flora. Subsequent performed biostatistical analysis revealed a high correlation between the data gathered by culture-dependent and independent methods. Both methods revealed significant differences between the microbiota of farm and dairy tank milk, which appeared to be rather independent from geographical regions. Based on the results from FTIR and direct sequencing, the predominant bacterial raw milk flora was determined, representative isolates were selected and two model floras, representative for farm tank milk and dairy bulk tank milk, were compiled. These bacterial model floras for raw milk are now available for the Biotracer partners and can be used for validation purposes or contamination scenarios. The knowledge gained on the variation range of the normal raw milk microbiota will help to identify raw milk with divergent microbiota, pointing towards potential pathogen contaminations. PMID- 20855122 TI - Taurine prevents free fatty acid-induced hepatic insulin resistance in association with inhibiting JNK1 activation and improving insulin signaling in vivo. AB - We infused the 48 h intralipid plus heparin (IH) to normal rats to elevate plasma free fatty acids (FFAs). Co-infusion of taurine was designed for the purpose of studying the effects of taurine on insulin sensitivity, oxidative stress, c-Jun NH-terminal kinase (JNK)1 activity and insulin signaling in livers of prolonged IH-infused rats. Cannulated rats were infused for 48 h intravenously with either saline or IH, with or without taurine. Hyperinsulinemic-euglycemic clamps with [6 3H] glucose infusion were performed to assess hepatic insulin sensitivity. IH infusion increased plasma 8-isoprostaglandin and hepatic malondialdehyde (MDA). IH also increased JNK1 activity and insulin receptor substrate 1/2 (IRS-1/2) serine phosphorylation, reduced insulin-stimulated IRS-1/2 tyrosine phosphorylation and Akt serine 473 phosphorylation, and induced hepatic insulin resistance. Taurine co-infusion with IH prevented the rise in 8-isoprostaglandin and MDA, inhibited the activation of JNK1, and improved insulin signaling and insulin resistance in liver. The present study has demonstrated that taurine, as an antioxidant, prevented hepatic oxidative stress and ameliorated hepatic insulin resistance. And this effect may be associated with the inhibition of JNK1 activation and the improvement of insulin signaling. This study suggests the therapeutic value of taurine in protecting from hepatic insulin resistance caused by elevated FFAs. PMID- 20855123 TI - Assessing glycaemic variability with continuous glucose monitoring system before and after continuous subcutaneous insulin infusion in people with Type 1 diabetes. AB - We evaluated glycaemic variability with continuous glucose monitoring system in 31 people with Type 1 diabetes mellitus using multiple daily injections initially and after switching to continuous subcutaneous insulin infusion. There was a significant improvement in HbA1c, mean glucose, standard deviation of mean glucose and in hyperglycaemic excursions with CSII. PMID- 20855124 TI - An alternative approach to evaluating, measuring, and comparing domestic and international health institutions: insights from social science theories. AB - OBJECTIVES: This article introduces the benefits of applying social science theories discussing institutional stasis and change to better measure, explain, and compare elite behavior within health administration and decentralization processes. A new comparative method based on these theories is introduced, as well as methods for collecting and analyzing data. METHODS: A literature review of health governance, health system governance, and path dependency and institutional change theory was conducted to reveal the limitations of health governance approaches explaining elite behavior. Next, path dependency and institutional change theory was applied to case studies in order to demonstrate their utility in explaining institutional stasis and change. RESULTS: Current approaches to analyzing and comparing elite behavior in the health governance frameworks are limited in their ability to accurately explain the willingness of elites to pursue more efficient institutional and policy designs. Current indicators measuring elite behavior are also too static, failing to account for periodic resistance to change and the conditions for it. CONCLUSIONS: By applying path dependency and institutional change theory, the policy community can obtain greater insight into the willingness and thus capacity of institutions to pursue innovations while developing alternative analytic frameworks and databases that better measure and predict this process. PMID- 20855125 TI - Capacity building in and for health promoting schools: results from a qualitative study. AB - OBJECTIVES: Research has shown that schools have problems reaching the aim of becoming health promoting for many different reasons and that capacity building in and for schools is needed to develop necessary resources. We use the concept of capacity building as an analytical tool to answer the question of how the implementation of health promotion (HP) in schools can be supported. METHODS: As part of a wider qualitative study concerning capacity building in the Austrian school system 11 school heads were interviewed about their needs regarding the success of HP in schools. The interviews were analysed with qualitative content analysis. RESULTS: Schools can build several capacities themselves and are well informed about the requirements for implementing HP. The most important resource is institutionalisation of HP, which is not easy to reach. Concerning their environment, schools display a need for financial and human resources for HP, as well as knowledge management and quality control of HP service providers. CONCLUSION: Schools need support from their environment not only in building resources but also in taking the important step of institutionalising HP into their core and management processes. A concept of implementation, drawing attention to necessary but unforeseen capacities and resources, is needed. PMID- 20855126 TI - 'Balancing acts': the politics and processes of smokefree area policymaking in a small state. AB - OBJECTIVE: To examine the influences on contemporary smokefree area policy development in New Zealand. METHOD: Semi-structured interviews were conducted with 62 New Zealand politicians and senior officials. They were asked about their views of possible interventions to reduce smoking around children, and how to achieve progress on smokefree homes, cars and public places. Transcribed data were analysed for themes, some of which were determined by the questions asked, and some emerged from the dynamic nature of the interviews. RESULTS: Policymaking for smokefree areas was seen by participants as a complex, highly politicised activity, concerned with balancing a number of factors including evidence, personal experience, concern for smokers, and the desire for public support for policy. The majority of participants were cautious about making substantive policy moves on smokefree places because of their perception of the issue as highly controversial, their wish to avoid public resistance and their desire for community engagement. Preference was shown for a policy approach based on persuasion rather than legislation, as a means to make progress on smokefree cars and outdoor spaces. CONCLUSIONS: The results indicate the need for good communication of the acceptability and benefits of legislative smokefree changes to both the political and public arena. PMID- 20855127 TI - Risk of vascular events in emergency department patients discharged home with diagnosis of dizziness or vertigo. AB - STUDY OBJECTIVE: Dizziness and vertigo are common reasons for visiting the emergency department (ED), but many patients are discharged home without a specific diagnosis. Given the concern that important diagnoses could be missed, we measure the incidence of subsequent major vascular events in patients after discharge home. METHODS: We identified all adults discharged home from California EDs with a primary diagnosis of dizziness or vertigo from January to June 2005, using comprehensive encounter records. Events were captured with linked statewide hospital discharge and national mortality data. We used Nelson-Aalen survival analysis for the primary outcome, hospitalization or death for cerebrovascular (acute ischemic or hemorrhagic stroke) or cardiovascular events (acute myocardial infarction, unstable angina, and ventricular arrhythmia), and the secondary outcomes, repeat ED visit for dizziness or vertigo, cerebrovascular events, and cardiovascular events. RESULTS: Among 31,159 patients identified, median age was 56 years and 63.5% were women. During the follow-up period, there were 274 deaths, 231 cerebrovascular events, and 115 cardiovascular events. The 180-day cumulative incidence of vascular event, cerebrovascular event, or cardiovascular event was 0.93% (95% confidence interval [CI] 0.83% to 1.04%), 0.63% (95% CI 0.55% to 0.72%), and 0.32% (0.26% to 0.38%), respectively. The risk of cerebrovascular events was higher in the first month (95% CI 30.2 [24.4 to 37.0] versus 6.5 [5.3 to 7.9] events/10,000 person-months thereafter). CONCLUSION: Few patients experience a major vascular event after discharge home with a diagnosis of dizziness or vertigo, with a stroke occurring in less than 1 in 500 patients within the first month. Future studies will be required to accurately stratify the risk for individual patients. PMID- 20855128 TI - Key requirements for a new era of emergency department operations research. PMID- 20855129 TI - The Six-Item Screener and AD8 for the detection of cognitive impairment in geriatric emergency department patients. AB - STUDY OBJECTIVE: We evaluate the diagnostic test characteristics of the Six-Item Screener and the AD8 to detect cognitive dysfunction in adults older than 65 years and using the emergency department (ED) for any reason. METHODS: We conducted an observational cross-sectional cohort study at a single academic urban university-affiliated hospital. Subjects were consenting, non--critically ill, English-speaking adults older than 65 years and receiving care in the ED. We quantitatively assessed the diagnostic test characteristics of the Six-Item Screener and AD8 by using the Mini-Mental State Examination score less than 24 as the criterion standard for cognitive dysfunction. RESULTS: The prevalence of cognitive dysfunction was 35%, but only 6% of charts noted a pre-existing deficit. The Six-Item Screener was superior to either the caregiver-administered AD8 or the patient-administered AD8 for the detection of cognitive dysfunction. CONCLUSION: The Six-Item Screener was superior to the caregiver- or patient administered AD8 to identify older adults at increased risk for occult cognitive dysfunction. PMID- 20855130 TI - An assessment of the incremental value of the ABCD2 score in the emergency department evaluation of transient ischemic attack. AB - STUDY OBJECTIVE: We study the incremental value of the ABCD2 score in predicting short-term risk of ischemic stroke after thorough emergency department (ED) evaluation of transient ischemic attack. METHODS: This was a prospective observational study of consecutive patients presenting to the ED with a transient ischemic attack. Patients underwent a full ED evaluation, including central nervous system and carotid artery imaging, after which ABCD2 scores and risk category were assigned. We evaluated correlations between risk categories and occurrence of subsequent ischemic stroke at 7 and 90 days. RESULTS: The cohort consisted of 637 patients (47% women; mean age 73 years; SD 13 years). There were 15 strokes within 90 days after the index transient ischemic attack. At 7 days, the rate of stroke according to ABCD2 category in our cohort was 1.1% in the low risk group, 0.3% in the intermediate-risk group, and 2.7% in the high-risk group. At 90 days, the rate of stroke in our ED cohort was 2.1% in the low-risk group, 2.1% in the intermediate-risk group, and 3.6% in the high-risk group. There was no relationship between ABCD2 score at presentation and subsequent stroke after transient ischemic attack at 7 or 90 days. CONCLUSION: The ABCD2 score did not add incremental value beyond an ED evaluation that includes central nervous system and carotid artery imaging in the ability to risk-stratify patients with transient ischemic attack in our cohort. Practice approaches that include brain and carotid artery imaging do not benefit by the incremental addition of the ABCD2 score. In this population of transient ischemic attack patients, selected by emergency physicians for a rapid ED-based outpatient protocol that included early carotid imaging and treatment when appropriate, the rate of stroke was independent of ABCD2 stratification. PMID- 20855132 TI - [Contribution of endoscopic ultrasonography to the diagnosis of neuroendocrine pancreatic tumors]. AB - Neuroendocrine pancreatic tumors (NEPT) are relatively infrequent tumors, with an incidence of approximately 1 case per 100.000 inhabitants, representing only 1-2% of pancreatic neoplasms. Localization and staging of NEPT prior to surgery is essential to allow treatment optimization. However, localizing these tumors is often difficult, mainly because of their small size. On ultrasound, NEPT usually appear as rounded, hypoechoic and homogeneous lesions, with precise limits and peripheral enhancement due to their significant vascularization. The most precise technique for the diagnosis and localization of NEPT is endoscopic ultrasound (EUS), with a sensitivity and specificity as high as 95%, clearly superior to those of other imaging procedures. Overall diagnostic accuracy may even be increased by associating EUS-guided fine-needle aspiration. PMID- 20855131 TI - Nonlinear time course of brain volume loss in cognitively normal and impaired elders. AB - The goal was to elucidate the time course of regional brain atrophy rates relative to age in cognitively normal (CN) aging, mild cognitively impairment (MCI), and Alzheimer's disease (AD), without a priori models for atrophy progression. Regional brain volumes from 147 cognitively normal subjects, 164 stable MCI, 93 MCI-to-AD converters and 111 ad patients, between 51 and 91 years old and who had repeated 1.5 T magnetic resonance imaging (MRI) scans over 30 months, were analyzed. Relations between regional brain volume change and age were determined using generalized additive models, an established nonparametric concept for approximating nonlinear relations. Brain atrophy rates varied nonlinearly with age, predominantly in regions of the temporal lobe. Moreover, the atrophy rates of some regions leveled off with increasing age in control and stable MCI subjects whereas those rates progressed further in MCI-to-AD converters and AD patients. The approach has potential uses for early detection of AD and differentiation between stable and progressing MCI. PMID- 20855133 TI - Synthesis and identification of a new class of antileukemic agents containing 2 (arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole. AB - Recently we have reported the effect of (S)-6-aryl urea/thiourea substituted-2 amino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent anti-leukemic agents. To elucidate further the Structure Activity Relationship (SAR) studies on the anti-leukemic activity of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole moiety, a series of 2-arlycarboxamide substituted-(S)-6-amino-4,5,6,7 tetrahydrobenzo[d]thiazole were designed, synthesized and evaluated for their anti-leukemic activity by trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays and cell cycle analysis. Results suggest that the position, number and bulkiness of the substituent on the phenyl ring of aryl carboxamide moiety at 2nd position of 6 amino-4,5,6,7-tetrhydrobenzo[d]thiazole play a key role in inhibiting the proliferation of leukemia cells. Compounds with ortho substitution showed poor activity and with meta and para substitution showed good activity. PMID- 20855134 TI - Proposed continuing professional education programme for midwives in China: new mothers' and midwives' views. AB - BACKGROUND: Chinese midwifery is under threat and has been denigrated, with virtually all midwives practising in the labour wards. AIMS: The present study aims to inform the development of a proposed continuing professional education programme. METHOD: Questionnaire surveys and semi-structured interviews were used to investigate the views of new mothers after vaginal births and midwives. The questions focussed on midwives' education, practice and mothers' experience and knowledge of maternity care. Data were analysed using descriptive statistical techniques. PARTICIPANTS: Five researchers, 253 midwives and 214 women. SETTINGS: Ten maternity units/hospitals in seven Chinese cities. FINDINGS: Both mothers and midwives valued continuity of midwifery care. The majority of midwives were obstetric nursing educated; one-fifth had a midwifery background. A smaller minority had a maternity/childcare or obstetric education. Midwifery education is medico/nursing orientated, with only 11.6% of the curriculum midwifery-oriented. DISCUSSION: The perceived different needs reflect the different orientations of the respondents. The programme should be structured to meet mothers' and midwives' needs, cultivate midwives' lifelong learning capacity, and encourage evidence-based practice. CONCLUSION: The study has shown a fundamental problem in Chinese midwifery education, in that midwives do not have access to evidence based material. Self-directed learning with portfolio assessment is likely to prove useful for the proposed programme; this may facilitate midwives' personal/professional development to update their knowledge, understanding and competence towards their full role as midwives. PMID- 20855135 TI - Students' perspectives on the outcomes of the joint international programme for nurse practitioners. AB - Nurse practitioners (NPs) play a vital role in the primary healthcare systems in several countries. However, the NP system has either only recently been established or has yet to be set up in many Asian countries. The Joint International Programme for Nurse Practitioners (JIPNP), developed by a university in South Korea and one in the United States, has been running since 1998. The purpose of this study was to evaluate this programme by assessing student satisfaction through an e-mail-based questionnaire survey. The results of the survey indicated that the students found that this programme helped refine their professional skills. The students were most satisfied with the practicum. Their responses to the open-ended question regarding their individual experiences during the course indicated that they were most satisfied with their improvement in the following areas: understanding of the role of the NP, the responsibility and limitations of NPs with regard to diagnosing and prescribing, familiarity with culture and language, and understanding of healthcare systems. They were also pleased with the teaching methods deployed. It is anticipated that the graduates who completed this programme will help develop the NP system in Korea by assuming leading positions in many NP fields in South Korea. PMID- 20855136 TI - Energy dense oleic acid rich formula to newly admitted geriatric patients- feasibility and effects on energy intake. AB - BACKGROUND & AIMS: Old patients seldom reach their energy requirements. The effects of an oleic acid rich formula on energy intake and appetite were studied. METHODS: Recently admitted geriatric patients (n = 71), likely to stay >1 week were randomised to receive 30 ml of a fat emulsion (Calogen((r))) 3 times daily, i.e., 420 kcal, at the regular medication rounds (intervention group (IG)) or to standard care (control group (CG)). Food intake and self-rated appetite were registered at baseline, i.e., 2-3 days after admission and on day 8 or the day prior to discharge. Nutritional risk screening (NRS) 2002, serum lipids and fatty acid profiles were analysed. RESULTS: Fifty-one subjects fulfilled the study, i.e., 24 in the IG (83 +/- 7 y) and 27 controls (85 +/- 7 y). NRS showed that two thirds were at risk of malnutrition. Per-protocol analyses indicated that the daily energy intake was around 50% higher in IG compared to CG at the two measurements, respectively (p < 0.0001). The IG displayed a significantly improved appetite compared with the CG (P = 0.021). Serum lipids and fatty acid profile changed favourably by the intervention. CONCLUSIONS: An energy dense oleic acid rich liquid supplement given three times daily at medication rounds to geriatric patients may result in increased energy intake and better appetite with positive effects on serum lipids. ClinicalTrials.gov Identifier: NCT01042340. PMID- 20855137 TI - Effects of mercury on behavior and performance of northern two-lined salamanders (Eurycea bislineata). AB - Mercury (Hg) causes a range of deleterious effects in wildlife, but little is known about its effects on amphibians. Our objective was to determine whether Hg affects performance and behavior in two-lined salamanders (Eurycea bislineata). We collected salamanders from Hg-contaminated and reference sites and assessed speed, responsiveness, and prey capture ability. Mercury concentrations were >17* higher in salamanders from the contaminated sites and were among the highest documented in amphibians. In the first, but not in the second, locomotion trial, we found a significant effect of Hg on speed and responsiveness. In the prey capture experiment, reference salamanders ate approximately twice as many prey items as the contaminated salamanders. Together, our results suggest that sublethal Hg concentrations may negatively affect salamanders by reducing their ability to successfully execute tasks critical to survival. Future work is warranted to determine whether Hg has other sublethal effects on salamanders and whether other amphibians are similarly affected. PMID- 20855138 TI - Sorption of atrazine and phenanthrene by organic matter fractions in soil and sediment. AB - Atrazine and phenanthrene (Phen) sorption by nonhydrolyzable carbon (NHC), black carbon (BC), humic acid (HA) and whole sediment and soil samples was examined. Atrazine sorption isotherms were nearly linear. The single-point organic carbon (OC)-normalized distribution coefficients (K(OC)) of atrazine for the isolated HA1, NHC1 and BC1 from sediment 1 (ST1) were 36, 550, and 1470 times greater than that of ST1, respectively, indicating the importance of sediment organic matter, particularly the condensed fractions (NHC and BC). Similar sorption capacity of atrazine and Phen by NHC but different isotherm nonlinearity indicated different sorption domains due to their different structure and hydrophobicity. The positive relationship between (O+N)/C ratios of NHC and atrazine logK(OC) at low concentration suggests H-bonding interactions. This study shows that sediment is probably a less effective sorbent for atrazine than Phen, implying that atrazine applied in sediments or soils may be likely to leach into groundwater. PMID- 20855139 TI - Ecological risk of anthropogenic pollutants to reptiles: Evaluating assumptions of sensitivity and exposure. AB - A large data gap for reptile ecotoxicology still persists; therefore, ecological risk assessments of reptiles usually incorporate the use of surrogate species. This necessitates that (1) the surrogate is at least as sensitive as the target taxon and/or (2) exposures to the surrogate are greater than that of the target taxon. We evaluated these assumptions for the use of birds as surrogates for reptiles. Based on a survey of the literature, birds were more sensitive than reptiles in less than 1/4 of the chemicals investigated. Dietary and dermal exposure modeling indicated that exposure to reptiles was relatively high, particularly when the dermal route was considered. We conclude that caution is warranted in the use of avian receptors as surrogates for reptiles in ecological risk assessment and emphasize the need to better understand the magnitude and mechanism of contaminant exposure in reptiles to improve exposure and risk estimation. PMID- 20855140 TI - Contrasting ozone sensitivity in related evergreen and deciduous shrubs. AB - Plant responses to enhanced ozone levels have been studied in two pairs of evergreen-deciduous species (Pistacia terebinthus vs. P. lentiscus; Viburnum lantana vs. V. tinus) in Open Top Chambers. Ozone induced widespread visible injury, significantly reduced CO(2) assimilation and stomatal conductance (g(s)), impaired Rubisco efficiency and regeneration capacity (V(c,max,)J(max)) and altered fluorescence parameters only in the deciduous species. Differences in stomatal conductance could not explain the observed differences in sensitivity. In control plants, deciduous species showed higher superoxide dismutase (SOD) activity than their evergreen counterparts, suggesting metabolic differences that could make them more prone to redox imbalances. Ozone induced increases in SOD and/or peroxidase activities in all the species, but only evergreens were able to cope with the oxidative stress. The relevancy of these results for the effective ozone flux approach and for the current ozone Critical Levels is also discussed. PMID- 20855141 TI - Apoplastic ascorbate contributes to the differential ozone sensitivity in two varieties of winter wheat under fully open-air field conditions. AB - We studied leaf apoplastic ascorbates in relation to ozone (O(3)) sensitivity in two winter wheat (Triticum aestivum L.) varieties: Yangfumai 2 (Y2) and Yangmai 16 (Y16). The plants were exposed to elevated O(3) concentration 27% higher than the ambient O(3) concentration in a fully open-air field from tillering stage until final maturity. The less sensitive variety Y16 had higher concentration of reduced ascorbate in the apoplast and leaf tissue by 33.5% and 12.0%, respectively, than those in the more sensitive variety Y2, whereas no varietal difference was detected in the decline of reduced ascorbate concentration in response to elevated O(3). No effects of O(3) or variety were detected in either oxidized ascorbate or the redox state of ascorbate in the apoplast and leaf tissue. The lower ascorbate concentrations in both apoplast and leaf tissue should have contributed to the higher O(3) sensitivity in variety Y2. PMID- 20855142 TI - Assessing and understanding quality of care in a labour ward: a pilot study combining clinical and social science perspectives in Gondar, Ethiopia. AB - Ensuring high quality intrapartum care in developing countries is a crucial component of efforts to reduce maternal and neonatal mortality and morbidity. Conceptual frameworks for understanding quality of care have broadened to reflect the complexity of factors affecting quality of health care provision. Yet, the role of social sciences within the assessment and understanding of quality of care in this field has focused primarily on seeking to understand the views and experiences of service users and providers. In this pilot study we aimed to combine clinical and social science perspectives and methods to best assess and understand issues affecting quality of clinical care and to identify priorities for change. Based in one referral hospital in Ethiopia, data collection took place in three phases using a combination of structured and unstructured observations, interviews and a modified nominal group process. This resulted in a thorough and pragmatic methodology. Our results showed high levels of knowledge and compliance with most aspects of good clinical practice, and non-compliance was affected by different, inter-linked, resource constraints. Considering possible changes in terms of resource implications, local stakeholders prioritised five areas for change. Some of these changes would have considerable resources implications whilst others could be made within existing resources. The discussion focuses on implications for informing quality improvement interventions. Improvements will need to address health systems issues, such as supply of key drugs, as well as changes in professional practice to promote the rational use of drugs. Furthermore, the study considers the need to understand broader organizational factors and inter-professional relationships. The potential for greater integration of social science perspectives as part of currently increasing monitoring and evaluation activity around intrapartum care is highlighted. PMID- 20855143 TI - Knowledge, legitimacy and economic practice in informal markets for medicine: a critical review of research. AB - Current debates and market based interventions in international public health seek to bring about explicit improvements in the quality of care offered by informal providers. In this paper we examine how informal providers are framed as problematic and question assumptions about what constitutes appropriate knowledge and expectations of how economic actors in the medical marketplace will behave. We argue that existing portraits of informal providers tend to establish clear cut distinctions between different kinds of practitioner; 'dis-embed' biomedical transactions from the broader relationships within which they take place; freeze or anatomise what are dynamic economic relationships between stakeholders, and obscure or ignore the position of informal providers in a global pharmaceutical supply chain. PMID- 20855144 TI - [The surgical innovation: From the legal framework through the veritable ethics innovation - Technical aspects and practical applications]. AB - Grace to the creativity of surgeons and the introduction of new technologies, second half of the XXth century opened the era of innovations and decisive progress. At the same time, however, is born the feeling of distrust and claiming which has come with the graving and threatening juridiciarisation. The evolution of complex structures of our society joined the ingenuity researchers unlimited makes formal law and the legal framework constantly to adapt oneself to circumstances. In the field of surgery, it's necessary to make work in integrity the innovation and protection at the patient's and their dignity. The legal framework that governs today innovation in surgery must still to go further and will precise. Dignity, compelling paradigm for all those who seek to better understand and better protect human starred as impassable limit any search and any experimentation. To make this chapter more alive, we have supplemented it and illustrated by the testimony some of the most fruitful French last years innovative in order to enrich our thinking of the fruit of their large and brilliant experience. PMID- 20855145 TI - Assessment of cardiomyopathy in fetuses of women with false positive oral glucose loading test. AB - OBJECTIVE: To evaluate fetal asymmetric septal hypertrophy in women with a false positive oral glucose loading test (OGL). STUDY DESIGN: OGL was applied to 79 pregnant women at gestational age between 24 and 28 weeks. The first study group consisted of patients with a normal OGL. Cases having glucose levels above 130 mg/dL after 50 g OGL but a normal 100g oral glucose tolerance test (OGTT) formed a second group. M-mode echocardiography was then performed. Fetal septal and left ventricular posterior wall (LVPW) thicknesses in Group 1 and Group 2 were compared. RESULTS: Mean septal and LVPW thickness was slightly higher in the second group but there was no statistically significant difference between the two groups. CONCLUSIONS: Although statistically not significant, there is some increase in septal and ventricular wall thickness in cases with high OGL but normal OGTT. The study also provides evidence of the absence of prominent septal and ventricular thickening in these cases with minimal glucose intolerance. PMID- 20855146 TI - Comparing the impacts of mitigation and non-mitigation on mountain pine beetle populations. AB - Mountain pine beetles, Dendroctonus ponderosae (Hopkins) attack and can ultimately kill individuals and groups of pine trees, specifically lodgepole pine (Pinus contorta Dougl. ex. Loud var. latifolia Engl.). In British Columbia, beetle attack has increased from 164 000 ha in 1999 to over 13 million ha in 2008. Mitigation efforts can play a key role in addressing the impact beetle infestations can have on the forested landscape. In this research, the impact of mitigation on a mountain pine beetle infestation is examined within a network of 28 research plots where sanitation harvesting was completed (10 mitigated plots) and not completed (18 unmitigated plots). Three forest stand level modelling scenarios which predict the number of attacked trees, based on current infestation within the plots, were utilized to compare the differences between mitigated and non-mitigated plots. In the first scenario in the non-mitigated plots, 125 trees were infested after 10 years, while in the mitigated plots no trees were infested in the same time period. The second scenario indicates the level of mitigation required to suppress beetle infestations where the proportion of mitigated trees was calculated for each plot by counting the residual attack and the number of mitigated trees. The average mitigation rate over all plots of 43% (range 0-100%) is not sufficient to provide control. In the non-mitigated plots, the average population expansion rate was 5 (range of 0-18) which requires a detection accuracy of 74% to reliably detect infestation. The third scenario estimated the length of time required for ongoing detection, monitoring, and mitigation to bring an infestation under control. If mitigation efforts were maintained at the current rate of 43%, the beetle population would not be adequately controlled. However, when aided by continued detection and monitoring of attacked trees, mitigation rates greater than 50% are sufficient to control infestations, especially with persistent implementation, aided by continued detection and monitoring of infested trees. PMID- 20855147 TI - Chemical properties and biological activity in soils of Mallorca following twenty years of treated wastewater irrigation. AB - On the Mediterranean island of Mallorca, the use of secondary-treated municipal wastewater in irrigation was introduced with the construction of the first wastewater treatment plants in the 1970s. In this study, the chemical properties and biological activity of 21 arable soils, irrigated for more than 20 years with secondary-treated wastewater, were tested in order to assess their quality. Soil quality was evaluated by measuring cation exchange capacity, pH, calcium carbonate equivalent, soil organic matter, total nitrogen, available phosphorus, water-soluble organic carbon, soil microbial biomass, soil basal respiration, and the activities of the enzymes dehydrogenase, beta-glucosidase and alkaline phosphatase. No negative effects of the irrigation treatment were observed on the measured soil parameters. Indeed, soil water-soluble organic carbon, soil microbial biomass and beta-glucosidase and alkaline phosphatase activities increased under treated wastewater irrigation. Biological activity of soils irrigated with treated wastewater was affected mainly by soil organic matter content. Although the typical crop management of alfalfa, and other forage crops associated with treated wastewater irrigation, may have contributed to the increase of these parameters, the results suggest that irrigation with treated wastewater is a strategy with many benefits to agricultural land management. PMID- 20855148 TI - Does the housing market respond to information disclosure?: effects of toxicity indices in Japan. AB - The policy instruments that provide information on a firm's or facility's environmental performance, such as the U.S. Toxic Release Inventory (TRI) and the Pollutant Release and Transfer Register system (PRTRs) used in some European countries and Japan, play an important role in encouraging firms or facilities to improve their environmental performance, if investors, consumers and residents recognize their environmental performance. This study uses a hedonic approach to explore how the Japanese rental housing market responds to carcinogenic risk arising from releases and transfers of chemical substances produced and used at close facilities. We found that residents do not perceive carcinogenic risk generated more than 1.0 km away from their residence and that they seem to recognize the increased carcinogenic risk at distances from 0.5 km to 1.0 km away; a 1% increase in carcinogenic risk reduces the average rent by 0.0007%. The distance at which residents perceive the risk arising from such facilities is less than in previous studies. This suggests that the risk perception recognized in previous studies may capture the other externalities in addition to the chemical risk because the risk is measured by the distance. PMID- 20855149 TI - Combating desertification in Iran over the last 50 years: an overview of changing approaches. AB - Desertification in Iran was recognized between the 1930s and 1960s. This paper traces Iran's attempts to reclaim desertified areas, evaluates the anti desertification approaches adopted, and identifies continuing challenges. Iran has areas vulnerable to desertification due to extensive areas of drylands and increasing population pressure on land and water resources. Over-grazing of rangelands is a particular problem. Initially desertification was combated mainly at the local level and involved dune stabilization measures, especially the use of oil mulch, re-vegetation and windbreaks. Insufficient technical planning in the early years has led to changed approaches to plant densities and species diversity in plantations, and increased on-going management of existing plantations. Since the late 1980s forage and crop production has increased in areas where runoff control techniques are practiced. The social and economic aspects of anti-desertification programs have assisted in poverty reduction by providing off-season employment in rural areas. In 2004 a national plan to combat desertification was ratified and this placed an emphasis on community participation. Continuing challenges include managing existing desertified areas as well as taking into account potential future problems associated with rapidly depleting groundwater supplies and a predicted reduction in the plant growth period accompanying climate change. PMID- 20855150 TI - Small interfering RNA-directed knockdown of S100A4 decreases proliferation and invasiveness of osteosarcoma cells. AB - Osteosarcoma is the most common osteogenic malignant tumor characterized by a high level of malignancy, relapse, metastasis and poor prognosis. S100A4 has been implicated in the proliferation, cell cycle progression, and metastasis of many malignant tumors, although the roles of S100A4 in osteosarcoma have not been documented. This study showed that the expression of S100A4 was found in two osteosarcoma cell lines MG-63 and U-2OS, and in 70.7% of osteosarcoma clinical tissues, and the expression was correlated with the expression of CD44V6. In addition, transfection with S100A4 siRNA significantly reduced the proliferation and the invasiveness of MG-63 cells. Furthermore, S100A4 siRNA down-regulated the expression of CD44 and MMP2, suggesting that S100A4 may promote the proliferation, invasion and metastasis of osteosarcoma cells by regulating the expression of other proteins that are crucial in modulating cell-ECM adhesion and facilitating ECM degradation. Therefore, siRNA-directed knockdown of S100A4 may represent a viable clinical therapy for osteosarcoma. PMID- 20855152 TI - Degradation of malachite green on Pd/WO3 photocatalysts under simulated solar light. AB - The photocatalytic degradation of malachite green (MG) dye molecules in aqueous solution was investigated by using palladium (Pd) modified tungsten trioxide (WO(3)) under simulated solar light. The optimum values for Pd content vs. WO(3) and catalyst concentration in solution for MG (5.0 MUmol L(-1)) degradation were 0.5 wt.% and 150 mg L(-1), respectively. The MG concentration change followed the pseudo first order kinetics of the Langmuir-Hinshelwood model. Since MG was also degraded under visible light (lambda>470 nm), which was not absorbed by WO(3), the mechanism involved both the photocatalytic degradation and self-sensitized degradation of MG. Pd modified WO(3) would be useful as an efficient tool for the decolorization of wastewater under solar light. PMID- 20855153 TI - Photocatalytic degradation of malathion in aqueous solution using an Au-Pd-TiO2 nanotube film. AB - The extensive use of pesticides has promoted the agricultural production, but a series of subsequent environmental issues have drawn the concern of governments and people worldwide, such as groundwater and surface water pollutions. In order to remove these pollutants, photocatalysis has emerged as a powerful method. In this paper, the photocatalytic degradation of an organophosphorus pesticide malathion was investigated using an Au-Pd co-modified TiO(2) nanotube film (Au-Pd TiO(2)). This film was fabricated by simultaneously photo-depositing Au and Pd precursors on a self-organized TiO(2) nanotube film. Its morphology and structures were well characterized by a scanning electron microscope (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). The photocatalytic experiments revealed that the malathion elimination rate increased by 172% when the photocatalyst of the naked TiO(2) nanotube film was replaced by Au-Pd-TiO(2). Additionally, the amount of H(2)O(2) yielded on the Au-Pd-TiO(2) film in 60 min was 2.89 times that on the naked TiO(2). The enhanced photocatalytic performance could be attributed to both the effective separation of photo-generated charge carriers and the higher synthesis rate of H(2)O(2). The possible photocatalytic mechanism was discussed. PMID- 20855151 TI - Raf kinase inhibitor protein suppresses nuclear factor-kappaB-dependent cancer cell invasion through negative regulation of matrix metalloproteinase expression. AB - Accumulating evidence suggests that Raf kinase inhibitor protein (RKIP), which negatively regulates multiple signaling cascades including the Raf and nuclear factor-kappaB (NF-kappaB) pathways, functions as a metastasis suppressor. However, the basis for this activity is not clear. We investigated this question in a panel of breast cancer, colon cancer and melanoma cell lines. We found that RKIP negatively regulated the invasion of the different cancer cells through three-dimensional extracellular matrix barriers by controlling the expression of matrix metalloproteinases (MMPs), particularly, MMP-1 and MMP-2. Silencing of RKIP expression resulted in a highly invasive phenotype and dramatically increased levels of MMP-1 and MMP-2 expression, while overexpression of RKIP decreased cancer cell invasion in vitro and metastasis in vivo of murine tumor allografts. Knockdown of MMP-1 or MMP-2 in RKIP-knockdown cells reverted their invasiveness to normal. In contrast, when examining migration of the different cancer cells in a two-dimensional, barrier-less environment, we found that RKIP had either a positive regulatory activity or no activity, but in no case a negative one (as would be expected if RKIP suppressed metastasis at the level of cell migration itself). Therefore, RKIP's function as a metastasis suppressor appears to arise from its ability to negatively regulate expression of specific MMPs, and thus invasion through barriers, and not from a direct effect on the raw capacity of cells to move. The NF-kappaB pathway, but not the Raf pathway, appeared to positively control the invasion of breast cancer cells. A regulatory loop involving an opposing relationship between RKIP and the NF-kappaB pathway may control the level of MMP expression and cell invasion. PMID- 20855154 TI - External mass transfer analysis for simultaneous removal of carbohydrate and protein by immobilized activated sludge culture in a packed bed batch bioreactor. AB - External mass transfer effects were analyzed for removal of carbohydrate and protein by immobilized activated sludge culture in a packed bed bioreactor. The bioreactor was made from 52 cm glass tubing with 5.0 cm inner diameter (with a total volume of 1020 cm(3)). The microbial culture was immobilized on microporus polyurethane cut into cubic pieces of approximately 1.5 cm in length. The effect of flow rate on mass transfer and removal of carbohydrate and protein were analyzed theoretically and compared with experimental data. The rate constants were estimated using external film diffusion models at different flow rates (900, 1200, 1800 cm(3)h(-1)). Based on the experimental data, correlations between the Colburn factor (J(D)) and Reynolds number (Re) as J(D)=5.7 * Re(-0.90) and J(D)=5.7 * Re(-0.18) were found to be adequate to predict the removal of carbohydrate and protein, respectively. PMID- 20855155 TI - Utilization of concentrate of membrane filtration of bleach plant effluent in brick production. AB - Utilization potential of membrane filtration retentate (concentrate) of bleach plant effluent from paper industry, in bricks production, was investigated in the present study. Bricks were prepared by using retentate of membrane filtration in place of water. The physical properties measured for bricks were dimensions, density, moisture content, compressive strength, water absorption and porosity. Chemical analysis of the bricks was performed for water leachability and acid leachability, using ASTM Standard methods D 3987-06 and D 5233-92 respectively. The leachate samples were analyzed for Al, Cu, Fe, Co, Cr, Pb, Ni and Zn using AAS (atomic absorption spectrophotometer). Adsorbable organic halides (AOX) of leachate were analyzed by using AOX analyzer model ECS 1200 using column method. It was observed that the physical and chemical properties of bricks especially fire clay bricks were not adversely affected by the use of wastewater. Therefore, the organic matter of the retentate of membrane filtration creates no problems for this application. PMID- 20855156 TI - Flammable gas cloud build up in a ventilated enclosure. AB - Ventilation is frequently used as a means for preventing the build up of flammable or toxic gases in enclosed spaces. The effectiveness of the ventilation often has to be considered as part of a safety case or risk assessment. In this paper methods for assessing ventilation effectiveness for hazardous area classification are examined. The analysis uses data produced from Computational Fluid Dynamics (CFD) simulations of low-pressure jet releases of flammable gas in a ventilated enclosure. The CFD model is validated against experimental measurements of gas releases in a ventilation-controlled test chamber. Good agreement is found between the model predictions and the experimental data. Analysis of the CFD results shows that the flammable gas cloud volume resulting from a leak is largely dependent on the mass release rate of flammable gas and the ventilation rate of the enclosure. The effectiveness of the ventilation for preventing the build up of flammable gas can therefore be assessed by considering the average gas concentration at the enclosure outlet(s). It is found that the ventilation rate of the enclosure provides a more useful measure of ventilation effectiveness than considering the enclosure air change rate. PMID- 20855157 TI - Sorption of quaternary ammonium compounds in soils: implications to the soil microbial activities. AB - Despite their widespread use in household activities and various industries, information on the toxicity of quaternary ammonium compounds (QACs) to microbial activities in soil is scant. This study investigated the effect of three commonly used QACs namely hexadecyltrimethyl ammonium bromide (HDTMA), octadecyltrimethyl ammonium bromide (ODTMA) and Arquad on dehydrogenase and potential nitrification activities in three different soils. The toxicity of QACs on the dehydrogenase activity and potential nitrification in these soils followed the order: HDTMA>ODTMA>Arquad and Arquad>HDTMA>ODTMA, respectively. HDTMA, ODTMA and Arquad exhibited toxicity to dehydrogenase activity at concentration of 50, 100 and 750 mg kg(-1) soil, respectively, whereas potential nitrification was inhibited by HDTMA and ODTMA even at 50 mg kg(-1) soil. Arquad exhibited toxicity to potential nitrification at comparatively higher concentration of 250 mg kg(-1) soil, with the severity of toxicity very intense at higher concentrations. The nature of QACs and soil properties influenced the toxicity. The toxic effect of QACs on soil microbial activities was more influenced by the relative release of sorbed QACs in soils. This study provides valuable information on the toxicological properties of some widely used QACs on important soil microbial activity parameters. To our knowledge, this is the first report. PMID- 20855158 TI - Enhancement of tributyltin degradation under natural light by N-doped TiO2 photocatalyst. AB - Photo-degradation of tributyltin (TBT) has been enhanced by TiO(2) nanoparticles doped with nitrogen (N-doped TiO(2)). The N-doped catalyst was prepared by a sol gel reaction of titanium (IV) tetraisopropoxide with 25% ammonia solution and calcined at various temperatures from 300 to 600 degrees C. X-ray diffraction results showed that N-doped TiO(2) remained amorphous at 300 degrees C. At 400 degrees C the anatase phase occurred then transformed to the rutile phase at 600 degrees C. The crystallite size calculated from Scherrer's equation was in the range of 16-51 nm which depended on the calcination temperature. N-doped TiO(2) calcined at 400 degrees C which contained 0.054% nitrogen, demonstrated the highest photocatalytic degradation of TBT at 28% in 3h under natural light when compared with undoped TiO(2) and commercial photocatalyst, P25-TiO(2) which gave 14.8 and 18% conversion, respectively. PMID- 20855159 TI - Composition, diagenetic transformation and alkalinity potential of oil shale ash sediments. AB - Oil shale is a primary fuel in the Estonian energy sector. After combustion 45 48% of the oil shale is left over as ash, producing about 5-7 Mt of ash, which is deposited on ash plateaus annually almost without any reuse. This study focuses on oil shale ash plateau sediment mineralogy, its hydration and diagenetic transformations, a study that has not been addressed. Oil shale ash wastes are considered as the biggest pollution sources in Estonia and thus determining the composition and properties of oil shale ash sediment are important to assess its environmental implications and also its possible reusability. A study of fresh ash and drillcore samples from ash plateau sediment was conducted by X-ray diffractometry and scanning electron microscopy. The oil shale is highly calcareous, and the ash that remains after combustion is derived from the decomposition of carbonate minerals. It is rich in lime and anhydrite that are unstable phases under hydrous conditions. These processes and the diagenetic alteration of other phases determine the composition of the plateau sediment. Dominant phases in the ash are hydration and associated transformation products: calcite, ettringite, portlandite and hydrocalumite. The prevailing mineral phases (portlandite, ettringite) cause highly alkaline leachates, pH 12-13. Neutralization of these leachates under natural conditions, by rainwater leaching/neutralization and slow transformation (e.g. carbonation) of the aforementioned unstable phases into more stable forms, takes, at best, hundreds or even hundreds of thousands of years. PMID- 20855160 TI - Preparation of capsules containing rejuvenators for their use in asphalt concrete. AB - Every year, there is a demand of more than 110 million metric tons of asphalt all around the world. This represents a huge amount of money and energy, from which a good part is for the preservation and renovation of the existing pavements. The problem of asphalt is that it oxidizes with time and therefore its beneficial properties disappear. Traditionally, rejuvenators spread in the road surface, are used to restore the original properties of the pavement. The problem is that, for a rejuvenator to be successful, it must penetrate the pavement surface. Furthermore, application of a rejuvenator will reduce the skid resistance of the pavement and, besides, rejuvenators have many aromatic compounds that can be harmful for the environment. To solve these problems this paper introduces a new concept in road construction: encapsulated rejuvenators. The basic principle is that when the stress in capsules embedded in the asphalt reaches a certain threshold value, the capsules break and some rejuvenator is released, restoring the original properties of the pavement. This paper will show how to prepare such capsules and how to determine their characteristics. This is one of the first steps towards intelligent pavements. PMID- 20855161 TI - Entrapment of nanoscale zero-valent iron in chitosan beads for hexavalent chromium removal from wastewater. AB - Nanoscale zero-valent iron (NZVI) was successfully entrapped in chitosan (CS) beads for reduction of Cr (VI) from wastewater. The removal mechanism may include both physical adsorption of Cr (VI) on the surface or inside of CS-NZVI beads and subsequent reduction of Cr (VI) to Cr (III). The free amino groups and hydroxyl groups on CS may contribute little to hinder the formation of Fe(III)-Cr(III) precipitate. Entrapment of NZVI in CS beads prevents the particles from aggregation and oxidation. The results indicate that there is no significant difference between the reaction rates of bare NZVI and entrapped NZVI. Cr (VI) reduction kinetics follows a pseudo-first-order rate expression. The reduction capacity for Cr (VI) increases with increasing temperature and NZVI dosage but decreases with the increase in initial concentration of Cr (VI) and pH values. This study demonstrates that entrapment of NZVI in CS beads has the potential to become a promising technique for in situ groundwater remediation. PMID- 20855162 TI - Processing of spent platinum-based catalysts via fusion with potassium hydrogenosulfate. AB - This work describes a route for processing spent platinum-based commercial catalysts (Pt and PtSnIn/Al(2)O(3)) via fusion with potassium hydrogenosulfate (KHSO(4)). Samples were previously ground. The optimized experimental parameters were: temperature, 450 degrees C; time, 3h; sample/flux mass ratio, 1/10. The fused mass was dissolved in water and the elements present were isolated by a multi-step separation procedure. Platinum was recovered as the only water insoluble residue. About 45 wt% of aluminium was recovered as KAl(SO(4))(2).12H(2)O (alum), whereas the remaining element was recovered as Al(OH)(3). Tin and indium were recovered together as sulfides at pH 1. About 72 wt% of potassium was recovered as K(2)SO(4) when the final effluent was treated with sulfuric acid (pH 1) and slowly evaporated. Generation of final wastes was greatly reduced. More than 98 wt% of the elements present in the catalysts examined was recovered. PMID- 20855163 TI - The EU Seveso regime in practice: from uncertainty blindness to uncertainty tolerance. AB - The chemical sector is confronted with risks pertaining to accidents involving dangerous substances. At the European level, a set of regulations - the Seveso regime - aims at controlling such risks. This article explores how this regime is put into practice, by analyzing the local practices of enforcement by Dutch inspectors and compliance by Dutch chemical companies. These empirical insights demonstrate that the classical 'positivistic risk paradigm' - which treats all risks as calculable, controllable and reducible - seems to dominate in the Seveso regime. The analysis in this article shows that this can lead to 'uncertainty blindness'; a regulatory regime where only yesterday's accidents are managed and salient future risks are potentially overlooked. We suggest that both regulators and regulated should start accepting the possibility of uncertain risks, which implies a cultural change in the current regulatory regime to 'uncertainty tolerance'. PMID- 20855165 TI - The investigation of phenol removal from aqueous solutions by zeolites as solid adsorbents. AB - This work reports results on phenol adsorption from aqueous solutions on synthetic BEA (beta) and MFI (ZSM-5) zeolites, studied by heat-flow microcalorimetry. For the sake of comparison, the adsorption was performed on activated carbon, a solid customarily used for removal of phenol from water. The obtained values of heats evolved during phenol adsorption indicate the heterogeneity of active sites present on the investigated systems for the adsorption of phenol. In addition, the amounts of adsorbed pollutant were determined and presented in the form of adsorption isotherms, which were interpreted using Langmuir, Freundlich, Dubinin-Astakov and Sips' equations. The latter was found to express high level of agreement with experimental data. The results obtained in this work reveal that the adsorption of phenol on zeolites depends on both Si/Al ratio and on the pore size. Hydrophobic zeolites that possess higher contents of Si show higher affinities for phenol adsorption. Among investigated zeolites, zeolite beta possesses the highest capacity for adsorption of phenol. The possibility of regeneration of used adsorbents was investigated by thermal desorption technique. It has been shown that in the case of beta zeolite the majority of adsorbed phenol is easily released in the low temperature region. PMID- 20855164 TI - Hydrothermal synthesis of TiO2 hollow microspheres for the photocatalytic degradation of 4-chloronitrobenzene. AB - TiO(2) hollow microspheres were synthesized by a simple hydrothermal method followed by calcination at different temperatures ranging from 400 to 800 degrees C. The prepared samples were characterized by XRD, SEM, TEM, SAED, HRTEM, N(2) adsorption, and UV-vis spectroscopy. The photocatalytic activities of the hollow microspheres were evaluated by photocatalytic decomposition of 4 chloronitrobenzene (4-CNB). Results showed that the TiO(2) hollow microspheres, which had an average external diameter of 1.75 MUm, were composed of numerous TiO(2) nanoparticles. Photocatalysis experiments indicated that the TiO(2) hollow microspheres calcined at 500 degrees C exhibited the highest photocatalytic activity, which was nearly 2 and 1.5 times higher than that of the uncalcined sample and Degussa P25, respectively. The catalyst crystallinity, catalyst dosage and 4-CNB concentration were found to have a significant impact on the degradation efficiency whereas solution pH has relatively less effect. The removal of total organic carbon (TOC) and formation of chloride, nitrate (V) anions were monitored to follow the mineralization process of 4-CNB. In addition, it was demonstrated that these TiO(2) hollow microspheres could be recycled easily without decreasing their photocatalytic activities. PMID- 20855166 TI - Carbon composite-PVC based membrane coated platinum electrode for chromium determination. AB - A new synthesized 1-(2-(1H-imidazole-1-yl)-1-(4-methoxyphenyl)ethylidene)-2 phenyl hydrazine has been used as an ionophore in carbon composite-PVC coated platinum electrode for fabrication of chromium(III)-selective sensor. The homogenization procedure of membrane mixture was performed by applying of the ultrasound in this respect. The sensor shows a good Nernstian slope of 19.62 +/- 0.45 mV decade(-1) in a wide linear range concentration of 8.4 * 10(-8)-1.0 * 10( 2)M and a detection limit of 6.8 * 10(-8)M for Cr(NO(3))(3). The proposed electrode has a short response time of about 10s and is reproducible and stable for a period of at least 2 months. The performance of the sensor is pH independent in the pH range of 3.3-5.9 and it also works well in partially non aqueous medium. The electrode has good selectivity relative to variety of metal ions. The practical analytical utility of the electrode is demonstrated by measurement of Cr(III) quantitatively in multivitamin, mineral water and also as an indicator electrode in the potentiometric titration of chromium (III) against EDTA. PMID- 20855167 TI - A new alternative paraffinic-palmbiodiesel fuel for reducing polychlorinated dibenzo-p-dioxin/dibenzofuran emissions from heavy-duty diesel engines. AB - Polychlorinated dibenzo-p-dioxin/dibenzofuran (PCDD/F) emissions from heavy-duty diesel engines (HDDEs) fuelled with paraffinic-palmbiodiesel blends have been rarely addressed in the literature. A high-resolution gas chromatograph/high resolution mass spectrometer (HRGC/HRMS) was used to analyze 17 PCDD/F species. Experimental results indicate that the main species of PCDD/Fs were OCDD (octachlorinated debenzo-p-dioxin) and OCDF (octachlorodibenzofuran), and they accounted for 40-50% of the total PCDD/Fs for all test fuels. Paraffinic palmbiodiesel blends decreased PCDD/Fs by 86.1-88.9%, toxic PCDD/Fs by 91.9 93.0%, THC (total hydrocarbons) by 13.6-23.3%, CO (carbon monoxide) by 27.2 28.3%, and PM (particulate matter) by 21.3-34.2%. Using biodiesel blends, particularly BP9505 or BP8020, instead of premium diesel fuel (PDF) significantly reduced emissions of both PCDD/Fs and traditional pollutants. Using BP9505 (95vol% paraffinic fuel+5vol% palmbiodiesel) and BP8020 instead of PDF can decrease PCDD/F emissions by 5.93 and 5.99gI-TEQyear(-1) in Taiwan, respectively. PMID- 20855168 TI - Internet-enhanced management of fibromyalgia: a randomized controlled trial. AB - Both pharmacological and non-pharmacological interventions have demonstrated efficacy in the management of fibromyalgia (FM). Non-pharmacological interventions however are far less likely to be used in clinical settings, in part due to limited access. This manuscript presents the findings of a randomized controlled trail of an Internet-based exercise and behavioral self-management program for FM designed for use in the context of a routine clinical care. 118 individuals with FM were randomly assigned to either (a) standard care or (b) standard care plus access to a Web-Enhanced Behavioral Self-Management program (WEB-SM) grounded in cognitive and behavioral pain management principles. Individuals were assessed at baseline and again at 6 months for primary endpoints: reduction of pain and an improvement in physical functioning. Secondary outcomes included fatigue, sleep, anxiety and depressive symptoms, and a patient global impression of improvement. Individuals assigned to the WEB-SM condition reported significantly greater improvement in pain, physical functioning, and overall global improvement. Exercise and relaxation techniques were the most commonly used skills throughout the 6 month period. A no-contact, Internet-based, self-management intervention demonstrated efficacy on key outcomes for FM. While not everyone is expected to benefit from this approach, this study demonstrated that non-pharmacological interventions can be efficiently integrated into routine clinical practice with positive outcomes. PMID- 20855169 TI - Effects of urea on the cattle tick Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - This study aimed at evaluating the effects of urea on Rhipicephalus (Boophilus) microplus. The experiment was divided into two stages. In Stage I, Brachiaria brizantha was placed into 30 pots, each with an area of 18 cm(2).These were divided into three groups of ten pots each: G1 non-treated control group, G2 treated with 15 g of urea per pot and G3 treated with 15 g of urea+10% of ammonium sulphate. Three engorged female ticks were placed in each pot and then 1.8l of water were added. In the second stage, a control group was maintained without the addition of urea and another group was treated with urea, each group comprising ten Mombaca grass (Panicum maximum cv. Mombaca) beds. On day zero, 12 engorged females were placed in each grass bed where were then fertilized with 60 g of urea per bed, only in the grass beds of the treated group. On the 27th day, the grass was cut in beds 1-5 in both groups and beds 1-5 in the treated group were fertilized a second time. On the 40th day, pieces of white flannel measuring 1.60 m * 1.00 m were spread over the grass to check for larvae presence. In stage I, observations conducted 24h after contact with urea showed a 100% death rate among the engorged females in G2; in group 3, only one engorged female still remained alive. In stage II, the counting of larvae reported 85.97% (P<0.0001) fewer parasites in the treated group compared to the control group. PMID- 20855170 TI - Peer, parent and media influences on adolescent smoking by developmental stage. AB - Previous studies of social influences on adolescent smoking have focused on peers and parents, using data collected prior the 1998 Master Settlement Agreement. This study used the 2004 wave of the National Youth Tobacco Survey to examine associations between peer smoking, smoking at home, tobacco-related media exposure, and smoking behavior during early and middle adolescence. Findings indicate that peer smoking and smoking at home remain strongly associated with current smoking among early and middle adolescents, controlling for gender, race/ethnicity and exposure to tobacco industry and anti-tobacco media. The magnitude of the association between peer smoking and current smoking decreases from early adolescence to middle adolescence while the association between smoking at home and current smoking is static across developmental stage. Exposure to tobacco-related media is associated with increased current and former smoking in both early and middle adolescence. PMID- 20855171 TI - History of reported sexual or physical abuse among long-term heroin users and their response to substitution treatment. AB - Opioid-dependent individuals with a history of abuse have exhibited worse mental and physical health compared to those without such a history; however, the evidence regarding the influence of abuse histories on addiction treatment outcomes are conflicting. In the present study, we identified history of physical or sexual abuse at treatment initiation in relation to drug use and health among long-term opioid-dependent individuals and we determined the relationship of abuse histories with treatment outcomes following substitution treatment. We analyzed data from a randomized controlled trial that compared the effectiveness of opioid-agonists in the treatment of chronic opioid dependence. The North American Opiate Medication Initiative (NAOMI) was conducted in Vancouver and Montreal (Canada) and provided oral methadone, injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A total of 112 (44.6%) participants reported a history of physical or sexual abuse at baseline. Participants with an abuse history reported a significantly higher number of chronic medical problems, suicide attempts, and previous drug treatments and had poorer psychiatric, family and social relations, and quality of life status compared to those without abuse histories. No differences in current and past substance use were found between those with and without abuse histories. Following 12 months of treatment, the participants with abuse histories improved to a similar degree as those without a history of abuse in all of the European Addiction Severity Index sub-scales, with the exception of medical status. The findings suggest that individuals with abuse histories were able to achieve similar outcomes as those without abuse histories following treatment despite having poorer scores in physical and mental health, social status and quality of life at treatment initiation. These findings suggest that the substitution treatments as provided in this study can benefit the most vulnerable and access needs to be expanded to reach this population. PMID- 20855172 TI - Moisture and fat content, marbling level and color of boneless rib cut from Nellore steers varying in maturity and fatness. AB - This study analyzed rib steaks (M. longissimus thoracis) of Nellore steers (n=60) for intramuscular moisture and fat content, marbling level, and visual and instrumental color. Carcass sides were classified on the kill floor according to teeth maturity (2, 4 and 6 permanent incisors), and fatness (2 - slight and 3 - average). The cranial end of the boneless cut was aged for 14 days, and frozen. Steaks of 2.5 cm thick were cut and thawed for analysis. Moisture and fat content were determined in minced lean. CIE color was measured with a MiniScan XETM, and visually evaluated by an eight-member panel, which also assessed marbling. In this type of cattle and ranges of maturity and fatness considered, increasing either maturity or fatness causes a slight reduction in moisture and an increment in lipid content. But neither maturity nor fatness seems to affect the visual perception of meat color on display. PMID- 20855173 TI - The use of natural herbal extracts for improving the lipid stability and sensory characteristics of irradiated ground beef. AB - Ground Longissimus dorsi of beef were treated with herbal extracts of marjoram, rosemary and sage at concentration of 0.04% (v/w), radiation (2 or 4.5 kGy) or their combination. Treated samples were stored at 5 degrees C and analyzed periodically for thiobarbituric acid reactive substances (TBARS), sensory characteristics and psychrotrophic bacterial counts during storage for 41 and 48 days for samples treated at 2 and 4.5 kGy respectively. Results demonstrated a significant benefit of the addition of herbal extracts to the ground beef prior to irradiation. All three extracts significantly (P<0.05) lowered the TBARS values and off-odor scores and significantly (P<0.05) increased color and acceptability scores in all samples with marjoram being the most effective. The combination treatment with herbal extracts plus irradiation resulted in extension of the shelf life of samples treated with 2 kGy by one week and samples treated with 4.5 kGy by two weeks, over that treated with irradiation alone. In conclusion, the addition of herbal extracts can minimize lipid oxidation, improve color and decrease off-odor production in irradiated ground beef. PMID- 20855174 TI - Genetic analysis of two Taiwanese bluetongue viruses. AB - BTV2/KM/2003 and BTV12/PT/2003 are the first identified bluetongue viruses in Taiwan. The prototype virus BTV2/KM/2003 was previously characterized in various respects as low virulent. In the present study, nucleotide sequences of the ten genome segments and their coding regions of the Taiwan strains were determined and analyzed. The two strains had >96.8% nucleotide and >97.9% deduced amino acid identities to each other, except for the VP2 genes. Their genome sequences, except for NS1 and VP2 genes, clustered overall in the Asian lineage, and were closely related to strains from China, India, Indonesia, and Japan. The phylogenetic trees and nucleotide identities of six BTV genes were suggestive of the geographical origin of the bluetongue virus strains analyzed, with a few exceptions. To examine which genes better distinguished strains from different origins (topography), the distribution of and the levels of differences in nucleotide identities were analyzed, revealing that VP3, NS2, and NS3 genes were more suitable for topotyping of BTVs. Analysis of ratios of non synonymous/synonymous substitutions (dN/dS values) between putative ancestry and their descendant strains suggested that most BTV genes evolved under a negative selection, whereas the VP7 gene evolved under positive selection, and its non synonymous substitutions accumulated more rapidly in strains from the Mediterranean region. PMID- 20855175 TI - Detection of small hypervascular hepatocellular carcinomas by EASL criteria: comparison with double-phase CT during hepatic arteriography. AB - BACKGROUND AND AIMS: To compare the detectability of small hypervascular hepatocellular carcinoma (HCC) between double-phase CT during hepatic arteriography (CTHA) criteria (hypervascular on the early-phase of CTHA and corona enhancement on the late-phase of CTHA) widely introduced in Japan and EASL criteria (hypervascular on the arterial dominant phase and wash out on the equilibrium phase of dynamic CT and/or MRI). METHODS: 116 hypervascular HCC lesions (<=2 cm) of 38 patients were evaluated. CTHA was performed in every patient, both dynamic CT and dynamic MRI in 22 patients, only dynamic CT in 8, and only dynamic MRI in 8. Among them, the detectability of HCC lesions was statistically analyzed with chi2 test. RESULTS: Double-phase CTHA detected all HCCs. Dynamic CT revealed 38 (40%) of 95 small HCCs; during dynamic MRI 38 (40%) of 95 small HCCs were detected. The difference between dynamic CT or dynamic MRI and CTHA was statistically significant (p<0.05). CONCLUSION: The detectability of small hypervascular HCC on dynamic CT and dynamic MRI was almost the same and significantly lower as compared to that of CTHA. When comparing differences in the results of HCC treatment, differences in the diagnostic criteria applied should always be kept in mind. PMID- 20855176 TI - Rapid resolution liquid chromatography (RRLC) analysis and studies on the stability of Shuang-Huang-Lian preparations. AB - Shuang-Huang-Lian (SHL) is a traditional Chinese formula which comprises of three medicinal herbs: Flos Lonicerae, Radix Scutellariae and Fructus Forsythiae, and is commonly used to treat acute upper respiratory tract infection, acute bronchitis and light pneumonia. A simple, reliable and reproducible rapid resolution liquid chromatography (RRLC) method was developed for the quality control of SHL preparations, which baseline separates the major bioactive compounds within 6min. The method uses a C18-HST column (2.5MUm, 100mm*3.0mm) kept at 40 degrees C. The mobile phases consist of 0.1% phosphoric acid aqueous solution and acetonitrile. Flow rate is 1.0ml/min and UV detection is performed at 327nm from 0 to 4min and 229nm from 4 to 7min. This method was further validated according to the ICH guidelines. Eight batches of commercial SHL preparations obtained from different pharmaceutical manufacturers as well as individual herbs were examined and their chromatographic profiles were compared. The stability test revealed that chlorogenic acid is stable only at acidic pH, and hence it is necessary to further evaluate and optimize the preparatory procedures and storage conditions for commercial SHL preparations. PMID- 20855177 TI - Risk factor analysis of thoracic endovascular repair using the Matsui-Kitamura stent graft for acute aortic emergencies in the descending thoracic aorta. AB - OBJECTIVE: In recent years, thoracic endovascular aneurysm repair (TEVAR) has been attempted for acute aortic emergencies (AAEs). However, the risk factors for achieving good results have not been identified. Besides focusing on Acute Physiology and Chronic Health Evaluation (APACHE) II score as a general indicator of patient condition, we analyzed both preoperative factors and intraoperative/postoperative factors. The purpose of this study was to identify those factors affecting the results of TEVAR using our Matsui-Kitamura stent graft (MKSG) for AAEs involving descending thoracic aortic aneurysm. METHODS: Between July 2000 and June 2008, a total of 32 patients (23 men, 9 women) with AAEs underwent endovascular repair. AAE was a result of aortic aneurysm rupture in 16 cases, rupture of penetrating atherosclerotic ulcer in 2 cases, traumatic aortic injury in 9 cases, complicated type B dissection in 4 cases, and aortic infiltration of sarcoma in 1 case. Low blood pressure in 6 patients, acute renal failure in 7 patients, anemia due to bleeding in 12 patients were found at the time of operation. Urgent TEVAR using the MKSG was performed. Perioperative and long-term results for these patients were investigated. RESULTS: The delivery and technical success rate for TEVAR using the MKSG, was 100%. Perioperative mortality was 12.5%, and 5-year survival rate was 71%. In both univariate and multivariate analysis, the APACHE II score clarified a risk factor. Among the various elements of an APACHE II score, age, hematocrit, and total score were identified as significant factors. The mean of an APACHE II score was 9.5. Patients with an APACHE II score >= 10 showed significantly lower 5-year survival rates than patients with an APACHE II score <= 9. CONCLUSIONS: Good results were obtained using TEVAR to treat AAEs with MKSGs, both perioperatively and during medium-term follow-up. Evaluation of risk factors for TEVAR of AAEs showed the utility of APACHE II score (particularly age, hematocrit, and total score) with a score >= 10 indicating high risk. PMID- 20855178 TI - Hull early walking aid for rehabilitation of transtibial amputees--randomized controlled trial (HEART). AB - PURPOSE: To compare articulated and nonarticulated early walking aids (EWAs) for clinical and quality-of-life outcomes in transtibial amputees. METHODS: Patients undergoing lower limb amputation in a tertiary-care vascular surgical unit were screened over a 4-year period. Recruited patients were randomized to receive articulated amputee mobility aid (AMA) or nonarticulated pneumatic postamputation mobility aid (PPAMA) during early rehabilitation. Primary (10-meter walking velocity) and secondary clinical (number and duration of physiotherapy treatments during EWA/prosthesis use) and quality-of-life (SF-36) outcome measures were recorded at five standardized assessment visits. Inter-group and intra-group analyses were performed. RESULTS: Two hundred seventy-two patients were screened and 29 transtibial amputees (median age, 56 years) were recruited (14/treatment arm). No significant difference was seen in demographics and comorbidities at baseline. Inter-group analysis: Median 10-meter walking velocity was significantly (Mann-Whitney, P = .020) faster in the PPAMA group (0.245 m/s, interquartile range [IQR] 0.218-0.402 m/s) compared with the AMA group (0.165 m/s; IQR, 0.118-0.265 m/s) at visit 1. However, there was no difference between the groups at any other visit. Similarly, the number of treatments using EWA was significantly (P = .045) lower in the PPAMA group (5.0; IQR, 3.5-8.0) compared with the AMA group (6.0; IQR, 6.0-10.5). No difference was observed between the groups in duration of physiotherapy or SF-36 domain and summary scores. Intra group analysis: Both treatment groups showed significant improvement in 10-meter walking velocity (Friedman test; AMA P = .001; PPAMA P = .007); however, other clinical outcomes did not show any statistically significant improvement. Only physical function domain of SF-36 demonstrated significant improvement (Friedman test; AMA P = .037; PPAMA P = .029). CONCLUSIONS: There is no difference in clinical and QOL outcomes between articulated and nonarticulated EWAs in rehabilitation of transtibial amputees. PMID- 20855179 TI - Inference from clinical and fluid dynamic studies about underlying cause of spontaneous isolated superior mesenteric artery dissection. AB - PURPOSE: Due to increased use and improvements in diagnostic imaging studies, spontaneous isolated superior mesenteric artery dissection (SISMAD), which is a rare vascular event, has been reported to occur on a more frequent basis. Although there have been some anecdotal case reports describing the underlying pathology of SISMAD, the etiology of the majority of SISMAD is still poorly understood. The purpose of this study was to determine the underlying cause of SISMAD. METHOD: From July 2001 to March 2010, 51 consecutive patients with SISMAD (symptomatic 39, asymptomatic 12) and 38 patients with combined aortic and superior mesenteric artery dissection (CASMAD) were identified in a single institution by retrospective investigations. Diagnosis was dependent on multi detector helical computed tomography (CT) scan. To find clinical characteristics of SISMAD, we compared demographic, clinical, and lesion (site of entry tear, type, length) characteristics between the two groups. To find any flow dynamic abnormalities at the proximal segment of the superior mesenteric artery (SMA), we conducted flow dynamic studies using computational fluid dynamic models (V.12; ANSYS, Inc., Canonsburg, Pa). Streamline patterns and wall shear stress distributions were tested with computer simulation models using three different branching angles of SMA from the abdominal aorta. RESULTS: Compared to CASMAD, SISMAD was more common in men (90.2% vs 71.1%; P = .02), less frequently associated with hypertension (31.4% vs 65.8%; P = .001), and more frequently associated with intra-abdominal cancers (11.8% vs 0%; P = .036). In a fluid dynamic study using computational fluid dynamic models, we found abnormal mechanical stresses at the anterior wall around the convex portion of the SMA. CONCLUSION: Development of SISMAD seems to be less likely the result of hypertension or connective tissue disease but more likely due to hemodynamic force caused by convex curvature. PMID- 20855180 TI - Use of the 70 degrees arthroscope for improved visualization with common arthroscopic procedures. AB - The vast majority of common arthroscopic procedures are performed with a 30 degrees arthroscope for visualization. Although the 70 degrees arthroscope has been described for a myriad of applications, its utility has recently been forgotten. We have explored the use of the 70 degrees arthroscope for a myriad of arthroscopic procedures and identified a number of circumstances in which it offers superior visualization to a 30 degrees arthroscope. These procedures include arthroscopic shoulder stabilization, distal clavicle resection, acromioclavicular joint reconstruction, rotator cuff repair, elbow arthroscopy, anterior cruciate ligament reconstruction, posterior cruciate ligament reconstruction, arthroscopy of the posterior knee compartments, hip arthroscopy, and subdeltoid shoulder arthroscopy. PMID- 20855181 TI - Evaluation of a porous polyurethane scaffold in a partial meniscal defect ovine model. AB - PURPOSE: The objective of this study was to assess the performance of a degradable porous polyurethane scaffold in a partial meniscectomy ovine model. METHODS: We subjected 42 skeletally mature ewes to unilateral partial excision of the lateral meniscus. In 19 animals the defect was left unfilled; in 23 animals a scaffold was inserted. Knees were examined by magnetic resonance imaging, gross inspection, and histologic inspection of the cartilage of the tibial plateau. RESULTS: In contrast to what has been previously reported in a complete meniscal replacement model, cartilage damage did not occur under the site of scaffold implantation; this was likely influenced by the rapid infiltration of cells and the dense tissue that formed within the scaffold. Cartilage damage in both groups was located close to the midline of the joint. No significant difference in the condition of the articular cartilage of the tibial plateau was seen between groups up to 12 months postoperatively. This result was influenced by the fact that the partly meniscectomized knees also showed unexpected tissue regeneration within the defect site, which raises concern about the suitability of using a partial meniscectomy as a control in the ovine model. CONCLUSIONS: Our study has shown that implantation of a polyurethane scaffold in a partial meniscectomy ovine model promotes tissue ingrowth without damaging the cartilage with which it articulates. CLINICAL RELEVANCE: Meniscal deficiency is a common occurrence, the effective clinical management of which is limited by the absence of an off-the shelf implantable construct. PMID- 20855182 TI - [Triple nerve block for ambulatory knee arthroscopy]. AB - BACKGROUND: The purpose of this study was to evaluate intra- and postoperative conditions of the triple nerve block technique (femoral, obturator, sciatic block) for outpatient knee arthroscopic procedures. METHODS: After written informed consent, ASA I-III patients received a combined triple nerve block with 30-40 ml lidocaine or mepivacaine (1,5%). Blocks were performed using a nerve stimulation technique. Onset time, block failure, supplemental general anesthesia (GA) or analgesia and pain score were recorded intraoperatively. After surgery, side effects (at days 0, 1, 3, 7 and after 4 weeks), patient and surgeon satisfactions were noted. RESULTS: Three hundred and twelve patients were screened and 115 triple blocks were performed (157 chose GA, 19 spinal anaesthesia, 21 exclusion for regional anaesthesia). Failed blocks occurred for 12 (10%) patients. These 12 patients received GA before surgery incision. Time to complete block was 40 (10-60) min. Supplemental GA was required for 12 patients (12%) due to surgical (n=7, 7%) or tourniquet (n=5, 5%) pain. Intraoperative surgeon satisfaction was 90 (60-100). After surgery, time to discharge the postoperative care unit was 15 (5-60) min. Pain score at rest (Visual Analog Scale) until six hours was less than 30 /100, without any additional morphine. Two patients (< 2%) failed for ambulatory discharge criteria (no relation with triple block). At day 0, 3, 5% patients suffered PONV (8% at D1), paresthesia was noted in 1.7% at D0 (0,8% D3). No other secondary effects were observed after seven days and 91% patients "would like same anaesthesia" for next surgery. CONCLUSION: We conclude that triple nerve block provided reliable intraoperative patient and surgical conditions for outpatient knee arthroscopy. Failed block (10%) was the major reason of supplemental anaesthesia. To increase surgical turn over under triple nerve block, a preoperative room may be required (block onset time). PMID- 20855183 TI - [Fast-tracking and regional anaesthesia: preliminary feasibility study]. AB - OBJECTIVE: The monitoring in the post-anaesthesia care unit (PACU) improves the safety, the comfort and the analgesia of patients. At present, studies suggest the possibility to bypass the PACU according to the principle of fast-tracking (FT). The aim of this study was to evaluate the feasibility and the safety of a simulated protocol of FT after a regional anaesthesia. PATIENTS AND METHODS: Seven hundred patients were prospectively included in this study over a period of 6 months. METHODS: The Withes' scoring system was used for determining when patients could be safely discharged from PACU. We added a variable concerning the monitoring of surgical site. A minimum score of 14 was required on arrival to the PACU to consider a FT. The success rate of blocks, the use of sedation or general anaesthesia were noted. Adverse events were recorded. RESULTS: The success rate of blocks was 93 %. The score was higher than 14 in 98 % of case on arrival to the PACU. Thirteen adverse events were reported before surgery and/or operating room. No adverse events were reported during the stay in the PACU. CONCLUSION: Regional anaesthesia seems to be an appropriate principle to fast-track the PACU. It could be a way to reduce health care costs, and can offer solution for the PACU congestion problem. In France, the fast-tracking is a marginal concept without any support regulatory. An evolution to such a practice could be considered. PMID- 20855184 TI - Ethnic identity, perceptions of disadvantage, and psychosis: findings from the AESOP study. AB - Many studies have shown that rates of psychosis are elevated in the Black and minority ethnic (BME) population in the UK. One important, but relatively less researched explanation of these high rates may be social adversity associated with acculturation processes. Strong identification with an ethnic minority group subjected to social disadvantage may exert adverse effects on individuals from BME groups. Using data from a large epidemiological case-control study of first episode psychosis, we aimed to investigate whether strong ethnic identification is a factor contributing to the excess of psychosis in BME groups compared with the White British, after adjustment for perceptions of disadvantage. All cases with a first episode of psychosis presenting to specialist mental health services within tightly defined catchment areas in London and Nottingham, UK, and geographically matched community controls were included in the study. Data were collected on socio-demographic and clinical characteristics, perceptions of disadvantage, and identification with one's own ethnic group. Analysis was performed on data from 139 cases and 234 controls. There was evidence that, as levels of ethnic identification increased, the odds of psychosis increased in the BME but not in the White British group, independent of potential confounders. However, the association between strong ethnic identity and psychosis in BME individuals was attenuated and non-significant when controlled for perceived disadvantage. Strong identification with an ethnic minority group may be a potential contributory factor of the high rates of psychosis in the BME population, the effects of which may be explained by perceptions of disadvantage. PMID- 20855185 TI - Clinical significance of neurological soft signs in schizophrenia: factor analysis of the Neurological Evaluation Scale. AB - BACKGROUND: Nonlocalizing neurologic deficits detectable by clinical evaluation "soft signs"-are a robust finding in patients diagnosed with schizophrenia, but their conceptual and neuroanatomical correlates remain unclear. The purpose of this study was to evaluate the organization of these deficits and their clinical correlates using the Neurological Evaluation Scale (NES). METHODS: Ninety-three male veterans with schizophrenia and schizoaffective disorder were evaluated using a detailed clinical assessment that included the NES, the Extrapyramidal Symptom Rating Scale, the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Scale, the Positive and Negative Syndrome Scale, the Wisconsin Card Sorting Test (WCST), the Schedule for the Deficit Syndrome (SDS), and the Digit Symbol Substitution Task (DSST). RESULTS: Four factors explained 73% of the variance and had distinct clinical and neuropsychological correlates. Factor 1 reflected deficits involved with memory and sensory integration, and was associated with lower PANSS positive and higher AIMS scores. Factor 2 reflected impairments in motor control, and was associated with lower intelligence, more cognitive deficits, and deficit-syndrome schizophrenia. Factor 3 was related to lower intelligence and more perseverative errors on the WCST. Factor 4 was related to increasing age, more extrapyramidal symptoms, more perseverative errors, and worse scores on the DSST. CONCLUSIONS: Neurologic deficits in schizophrenia have an intrinsic organization that appears to have clinical significance, highlighting the continued utility of the NES in studies of neurological deficits in schizophrenia patients. The theoretical underpinning of this organization remains unclear. PMID- 20855186 TI - Decline in the incidence of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) correlates with deceased antimicrobial consumption at a tertiary care hospital in Taiwan, 2001-2009. AB - The present study investigated the long-term impact of antibiotic use policy on the rates of consumption (expressed as daily-defined doses/1000 patient-days) of various parenteral antibiotics and on the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and the incidence of healthcare-associated MRSA (HA MRSA) infection at a tertiary care hospital from 2001 to 2009. During this time, consumption of all antimicrobials for systemic use decreased by 33%. This change was driven by a 44% decrease in the consumption of unrestricted antibacterials, which was offset by a 42% increase in the consumption of restricted agents. The trends in MRSA prevalence (number of isolates/1000 patient-days) and HA-MRSA incidence (number of HA-MRSA-infected persons/1000 patient-days) correlated with the trend in overall consumption of antimicrobials. Significant positive correlations were observed between MRSA prevalence and the consumption of extended-spectrum and beta-lactamase-resistant penicillins, first-generation cephalosporins, macrolides, lincosamides and streptogramins, aminoglycosides, and glycopeptides. Significant positive correlations were found between the incidence of HA-MRSA infection and the consumption of tetracyclines, extended-spectrum and beta-lactamase-resistant penicillins, sulfonamides and trimethoprim, macrolides, lincosamides and streptogramins, and aminoglycosides. In conclusion, we have documented the ongoing successful reduction in total consumption of antimicrobials associated with a decrease in the incidence of HA-MRSA and the prevalence of MRSA over a 9-year period. PMID- 20855187 TI - Quick self-healing and thermo-reversible liposome gel. AB - Self-assembled liposome gel from liposome and cholesterol-end capped polyethylene glycol, was systematically investigated by rheological method, especially in the aspect of its recovery ability upon either mechanical deformation or temperature change. The liposome gel was found to have rheological behavior similar to that of Maxwell model. The dynamic shear modulus of the liposome gel was dependent on both the liposome concentration and the polymer concentration. At low liposome concentration range (5-20 mM), dynamic shear modulus decreased considerably with the liposome concentration, implying the decrease of effective cross-linking density inside gel network due to the addition of liposome. The liposome gel network had a fast, self-healing ability even after high deformation, and the injectability of the gel was confirmed by injection experiment in vitro. The liposome gel also exhibited temperature stimuli responsive behavior and thermo reversibility. Dynamic light scattering studies proved that the particle size of liposome remained almost unchanged before and after the addition of the polymer. PMID- 20855188 TI - Long term performance characteristics of an electrochemical nitric oxide analyser. AB - BACKGROUND: The NIOX MINO((r)) is a nitric oxide (FE(NO)) analyser based on electrochemical technology. It includes a replaceable sensor. Quality control procedures are recommended, but regular calibration is not possible. We aimed to evaluate the performance characteristics of the NIOX MINO((r)) to identify if reproducibility changed over time, or with different sensors. Also, there are reports that reproducibility of FE(NO) may be reduced in patients with high FE(NO): our secondary aim was to address this issue. METHODS: Reproducibility in 24 separate sensor-analyser units was calculated on three occasions over two months in 17 patients. These included 9 patients whose FE(NO) was high (mean 80 ppb) and 8 in whom FE(NO) was low (mean 16 ppb). RESULTS: One device failed quality control testing. For the remaining 23 sensor-analyser combinations, the mean coefficient of variation was 4.0% (range 1.2-7.2%) at baseline, 3.6% (range 2.0-7.0) at one month, and 3.6% (range 1.6-7.6%) at two months. The 95% C.I. for the mean limits of agreement for FE(NO) was +/- 4.2 ppb (range 0.9-9.6 ppb), +/- 3.8 ppb (range 1.6-6.9 ppb) and +/- 3.2 ppb (range 1.2-6.8 ppb) respectively (NS). The limits of agreement exceeded the manufacturer's specifications (+/- 5 ppb) in 0 devices at baseline, 3 (13%) at one month, and 5 (22%) at two months. CONCLUSIONS: Reproducibility of FE(NO) using the NIOX MINO((r)) was within clinically acceptable limits (+/- 10 ppb) and was generally stable. However, with time, a proportion of individual sensor-analyser combinations yielded variability outside the manufacturer's specifications. PMID- 20855189 TI - 5*5 CMOS capacitive sensor array for detection of the neurotransmitter dopamine. AB - This work presents miniaturized CMOS (complementary metal oxide semiconductor) capacitive sensors for detection of the neurotransmitter dopamine (DA) down to the sub-fM range. Sensing resolution is significantly enhanced by monolithic sensor integration to reduce the parasitic effect and the use of sub-MUm interdigitated microelectrodes as the sensing interface. The 5 * 5 sensor array contains five designs of different electrode sizes and each design has five sensors. The positive charges produced from protonation of boronate and amino group after immobilization of 4-carboxyphenylboronic acid (CPBA) result in an increase of the electrode-analyte capacitance. Then the negative charges produced after binding of CPBA and DA molecules decrease the electrode-analyte capacitance. Signal transduction is achieved through a CMOS readout circuit whose output frequency is inversely proportional to the capacitance. Experimental results showed the ratios of average percentage capacitance changes of the experiment groups over those of the control groups were all larger than one for the five designs at DA concentration of 0.1 fM. Selectivity against the non analyte species, such as tyramine, has also been demonstrated. PMID- 20855190 TI - Electrochemical DNA hybridization sensors applied to real and complex biological samples. AB - DNA hybridization biosensors, also known as genosensors, are analytical devices for the detection of specific DNA "target" sequences in solution, upon hybridization of the targets with complementary "probes" immobilized on a solid substrate. Electrochemical genosensors hold great promise to serve as devices suitable for point-of-care diagnostics and multiplexed platforms for fast, simple and inexpensive nucleic acids analysis. Although a lot of progress has been made in the past few years, the performance of genosensors in complex biological samples has been assayed in only a small fraction of published research articles. This review covers such a group of reports, from the year 2000 onwards. Special attention is played in the nature and complexity of the samples and in the way matrix effects were treated and specificity controls were performed. PMID- 20855191 TI - Detection of swine-origin influenza A (H1N1) viruses using a localized surface plasmon coupled fluorescence fiber-optic biosensor. AB - Swine-origin influenza A (H1N1) virus (S-OIV) was identified as a new reassortant strain of influenza A virus in April 2009 and led to an influenza pandemic. Accurate and timely diagnoses are crucial for the control of influenza disease. We developed a localized surface plasmon coupled fluorescence fiber-optic biosensor (LSPCF-FOB) which combines a sandwich immunoassay with the LSP technique using antibodies against the hemagglutinin (HA) proteins of S-OIVs. The detection limit of the LSPCF-FOB for recombinant S-OIV H1 protein detection was estimated at 13.9 pg/mL, which is 10(3)-fold better than that of conventional capture ELISA when using the same capture antibodies. For clinical S-OIV isolates measurement, meanwhile, the detection limit of the LSPCF-FOB platform was calculated to be 8.25 * 10(4)copies/mL, compared with 2.06 * 10(6)copies/mL using conventional capture ELISA. Furthermore, in comparison with the influenza A/B rapid test, the detection limit of the LSPCF-FOB for S-OIV was almost 50-fold in PBS solution and 25-fold lower in mimic solution, which used nasal mucosa from healthy donors as the diluent. The findings of this study therefore indicate that the high detection sensitivity and specificity of the LSPCF-FOB make it a potentially effective diagnostic tool for clinical S-OIV infection and this technique has the potential to be applied to the development of other clinical microbe detection platforms. PMID- 20855192 TI - Esterification of oleic acid in a three-phase, fixed-bed reactor packed with a cation exchange resin catalyst. AB - Esterification of oleic acid was performed in a three-phase fixed-bed reactor with a cation exchange resin catalyst (Amberlyst-15) at high temperature, which was varied from 80 to 120 degrees C. The fatty acid methyl ester (FAME) yields in the fixed-bed reactor were increased with increases in the reaction temperature, methanol flow rate and bed height. Moreover, the FAME yields were higher than those obtained using a batch reactor due to an equilibrium shift toward the product that resulted from continuous evaporation of the produced water. In addition, there was no catalyst deactivation during the esterification of oleic acid. However, addition of sunflower oil to the oleic acid reduced the FAME yield obtained from simultaneous esterification and transesterification. The FAME yield was 97.5% at a reaction temperature of 100 degrees C in the fixed-bed with a height of 5 cm when the methanol and oleic acid feed rates were 8.6 and 9.0 mL/h, respectively. PMID- 20855193 TI - Influence of bulking agents on organic matter evolution during sewage sludge composting; consequences on compost organic matter stability and N availability. AB - The influence of bulking agents on organic matter (OM) stability and nitrogen (N) availability in sludge composts was investigated. Seven mixtures were composted over a 12-week period in 170 L-reactors using the same sludge with different bulking agent mixtures. The OM evolution was characterised by carbon (C) and N mass balances in biochemical fractions. The evolution of OM stability and N potential availability were measured during soil incubations. The type of bulking agent had little influence on the intensity of OM stabilisation and the N availability in final composts. However, they influenced the time to reach similar OM stability and the biochemical evolution of OM. Depending on their ligno-cellulosic characteristics and a careful control of aeration, initial mixtures with high C:N ratio and rather biodegradable carbonaceous materials could favour the organisation of initially present mineral N or easily mineralisable sludge N and therefore limit NH3 volatilisation responsible for the low compost N availability measured. PMID- 20855194 TI - Biochemical characteristics of a textile dye degrading extracellular laccase from a Bacillus sp. ADR. AB - Bacillus sp. ADR secretes an extracellular laccase in nutrient broth, and this enzyme was purified up to 56-fold using acetone precipitation and DEAE-cellulose anion exchange chromatography. The molecular weight of purified laccase was estimated to be 66 kDa using sodium dodecyl sulfate polyacrylamide gel electrophoresis. The purified laccase oxidized 2,6-dimethoxy phenol, o-tolidine, hydroquinone, L-DOPA and guaiacol. The optimum pH for oxidation of o-tolidine, 2,6-dimethoxy phenol and guaiacol were 3.0, 4.0 and 5.0, respectively. The purified laccase contained 2.7 mol/mol of copper. The laccase was stable up to 40 degrees C and within the pH range of 7.0-9.0. Well-known inhibitors of multicopper oxidases such as, sodium azide, L-cysteine and dithiothreitol showed significant inhibition of laccase activity. The purified enzyme decolorized structurally different azo dyes with variable decolorization rates and efficiencies of 68-90%. This study is useful for understanding the precise use of Bacillus sp. ADR in the decolorization of textile dyes containing industrial wastewater. PMID- 20855195 TI - Utilization of deoiled Jatropha curcas seed cake for production of xylanase from thermophilic Scytalidium thermophilum. AB - Jatropha curcas is a major biodiesel crop. Large amount of deoiled cake is generated as by-product during biodiesel production from its seeds. Deoiled J. curcas seed cake was assessed as substrate for the production of xylanase from thermophilic fungus Scytalidium thermophilum by solid-state fermentation. The seed cake was efficiently utilized by S. thermophilum for its growth during which it produced good amount of heat stable extracellular xylanase. The solid-state fermentation conditions were optimized for maximum xylanase production. Under the optimized conditions viz. deoiled seed cake supplemented with 1% oat-spelt xylan, adjusted to pH 9.0, moisture content 1:3 w/v, inoculated with 1*10(6) spores per 5 g cake and incubated at 45 degrees C, 1455 U xylanase/g deoiled seed cake was obtained. The xylanase was useful in biobleaching of paper pulp. Solid-state fermentation of deoiled cake appears a potentially viable approach for its effective utilization. PMID- 20855196 TI - Particle properties of sugar maple hemicellulose hydrolysate and its influence on growth and metabolic behavior of Pichia stipitis. AB - In this study the influence of the insoluble solids in nano-filtrated sugar maple hemicellulosic hydrolysate on the metabolic behavior of Pichia stiptis was investigated. The particle properties of hemicellulosic hydrolysate were analyzed. Phosphoric acid and ammonium (PA) were applied to remove the particles. The metabolic behavior and growth property of P. stipitis in particle--removed hydrolysate was measured. Results demonstrated that the average particle size and zeta potential of the untreated hydrolysate were 2266.9+/-78.2 nm and -6.09+/ 0.49 mV. Xylose consumption and ethanol production rate were significantly decreased when particle content is greater than 1.63 g/L. Because the majority of particles (34 g/L) were removed from hydrolysates by phosphoric acid and ammonium treatment, the fermentability of the hydrolysate was significantly improved. These results indicated particles play an important role in hydrolysate inhibition effect. PMID- 20855198 TI - Integrated reactive absorption process for synthesis of fatty esters. AB - Reactive separations using green catalysts offer great opportunities for manufacturing fatty esters, involved in specialty chemicals and biodiesel production. Integrating reaction and separation into one unit provides key benefits such as: simplified operation, no waste, reduced capital investment and low operating costs. This work presents a novel heat-integrated reactive absorption process that eliminates all conventional catalyst related operations, efficiently uses the raw materials and equipment, and considerably reduces the energy requirements for biodiesel production--85% lower as compared to the base case. Rigorous simulations based on experimental results were carried out using Aspen Plus and Dynamics. Despite the high degree of integration, the process is well controllable using an efficient control structure proposed in this work. The main results are provided for a plant producing 10 ktpy fatty acid methyl esters from methanol and waste vegetable oil with high free fatty acids content, using sulfated zirconia as solid acid catalyst. PMID- 20855197 TI - Mosquito biolarvicide production by sequential fermentation with dual strains of Bacillus thuringiensis subsp. israelensis and Bacillus sphaericus using sewage sludge. AB - This study demonstrated the bioconversion of sewage sludge into a composite biolarvicide for mosquito control based on sequential fermentation with dual strains of Bacillus thuringiensis subsp. israelensis (Bti) and Bacillus sphaericus (Bs). Results showed that sewage sludge was a suitable fermentation substrate for supporting growth, sporulation and mosquitocidal proteins synthesis by Bti and Bs. Through sequential fermentation with dual strains, a 10-L bench scale fermentor was capable of producing Bti and Bs at a cell concentration of 2.1*10(9) and 6.8*10(8) CFU/mL, respectively. Such sequential fermentation can save half of raw materials and energy consumption comparing with the sludge fermentation with single strain. The toxic activity and persistence of the composite biolarvicide against mosquito larvae in the polluted waters were enhanced by the increased toxin complexity and synergistic interactions. This study, for the first time, validates the technical feasibility of using sewage sludge to produce a cost-effective composite biolarvicide based on Bti and Bs. PMID- 20855199 TI - Rapid evaluation of the antibiotic susceptibility of fuel ethanol contaminant biofilms. AB - Bacterial contaminants from commercial fuel ethanol production facilities were previously shown to form biofilms as mixed cultures under laboratory conditions. In this study, a rapid assay was developed to simultaneously compare isolates for their ability to form biofilms as pure cultures. A total of 10 strains were isolated from a dry-grind fuel ethanol plant that routinely doses with virginiamycin. These were identified by sequence analysis as six strains of Lactobacillus fermentum, two strains of L. johnsonii, and one strain each of L. mucosae and L. amylovorus. Isolates exhibited a range of susceptibility to virginiamycin in a planktonic assay, with MIC's (minimum inhibitory concentration) of <=0.5-16 MUg/ml. Even though all strains were isolated from a mixed culture biofilm, they varied greatly in their ability to form biofilms as pure cultures. Surprisingly, growth as biofilms did not appear to provide resistance to virginiamycin, even if biofilms were grown for 144 h prior to antibiotic challenge. PMID- 20855200 TI - Nonlinear modelisation of heavy metal removal from aqueous solution using Ulva lactuca algae. AB - After extensive analysis, Ulva lactuca dried algae, collected from the Monastir coastal zone, was proven to be successful as an adsorbent for the removal of certain inorganic pollutants. The main objective of this study was the nonlinear modeling of heavy metal removal from an aqueous solution, using a freely available and well analyzed biomaterial, as well as the evaluation of its efficacy on various metal ion sorptions. Although relatively low specific surface area, compared to more conventional adsorbents, the selected biomaterial displays very interesting retention capacities when used with aqueous inorganic pollutants. The pseudo, first and second-order kinetic models were used to investigate the kinetic retention mechanism. Assuming the nonlinear form, the results indicate that the retention mechanism is diffusion controlled. Concerning the heavy metal uptake capacity, it was found that the selected biomaterial has a retention capacity of 67 mg g(-1) of Ni(II), 112 mg g(-1) of Cu(II), 127 mg g(-1) of Cd(II) and 230 mg g(-1) of Pb(II). PMID- 20855201 TI - Effects of Cr(VI) on the performance and kinetics of the activated sludge process. AB - The substrates removal performance, removal kinetics and the electron transport system (ETS) of sludge were investigated by sequencing batch reactors (SBR) and batch assays, respectively. Compared to the control system, significant decreases were observed in substrate removal efficiency with the Cr(VI)-feeding concentration up to 5 mg L(-1) in SBR system. And the recovery for NH4+-N removal were more difficult than that of COD after the termination of Cr(VI)-feeding. Significant inhibitory effects of Cr(VI) on the ETS activity and substrate removal kinetics were observed in the batch assays. The inhibitory effects of Cr(VI) would be overestimated on COD removal and underestimated on NH4+-N removal by the short-term batch assay as compared to the long-term operations. Additionally, significant correlations between the ETS activity and the inhibitory rates of Cr(VI) on substrate removal indicated the ETS activity can provide effective predictions on the potential performance of substrate removal in activated sludge. PMID- 20855202 TI - Enhanced production of total flavones and exopolysaccharides viaVitreoscilla hemoglobin biosynthesis in Phellinus igniarius. AB - The Vitreoscilla hemoglobin gene (vgb) was expressed by chromosomal integration in Phellinus igniarius to alleviate oxygen limitation and improve metabolites yields during submerged fermentation. Firstly, an expression vector containing vgb was constructed, and transformed into protoplast from P. igniarius. Carbon monoxide difference spectrum absorbance assay showed that vgb was successfully expressed and had biological activity. In shake flasks, the vgb expression enhanced dry mycelial weight 1.32-fold and increased total flavones and exopolysaccharides production 1.78- and 1.33-fold, respectively. When P. igniarius (vgb+) and P. igniarius (vgb-) strains were cultured in bioreactor, Vitreoscilla hemoglobin in P. igniarius promoted the mycelia growth from 5.40 to 10.90 g/L and stimulated total flavones and exopolysaccharides synthesis; their maximum productions reached to 11.43 and 1.33 g/L. Furthermore, compared to P. igniarius (vgb-), the acetic acid accumulation in P. igniarius (vgb+) cultures decreased from 1.54 and 1.78 to 1.19 and 1.27 g/L in flask and bioreactor, respectively. PMID- 20855203 TI - Kinetics modeling of dynamic pyrolysis of bagasse fibers. AB - The thermal decomposition mechanism of raw and treated bagasse fibers was modeled with three parallel independent first-order reactions. The kinetic parameters and pseudo components which best fit the experimental dynamic pyrolysis rate of bagasse was determined by means of the Matlab program using the least-square method. The calculated rate of thermal decomposition for each bagasse sample was consistent with experimental pyrolysis rate very well. A method was adopted to calculate the contents of cellulose, hemicelluloses, and lignin for bagasse fiber based on the dynamic pyrolysis model. The calculated contents of the untreated bagasse fiber agreed very well with some reported values from the literature. The effect of treatment conditions on the bagasse fiber compositions was also studied. From the three-dimensional plot for each of the three components, it could be observed that bagasse fibers treated under the intermediate alkaline condition could achieve the higher content of cellulose. PMID- 20855204 TI - Kinetically controlled synthesis of monoglyceryl esters from chiral and prochiral acids methyl esters catalyzed by immobilized Rhizomucor miehei lipase. AB - Partial acylation of only one primary hydroxyl group of glycerol generates a chiral center at position 2. Rhizomucor miehei lipase (RML) catalyzes the kinetically controlled transesterification of different aromatic carboxylic acids methyl esters with glycerol. High synthetic yields of glyceryl esters (around 70 80%) were obtained even in the presence of significant concentrations of water (from 5% to 20%). After a long incubation of the reaction mixture in the presence of the biocatalyst only pure free acid was obtained. Other lipases (from Geobacillus thermocatenulatus and from Thermomyces lanuginose) also catalyzed similar kinetically controlled transesterifications although less efficiently. RML immobilized on Sepharose-Q showed a high activity and specificity, compared to the immobilization by other techniques, only producing monoglyceryl esters with all substrates. In particular, monoglyceryl-phenylmalonate product was synthesized in 82% overall yield and >99% diastereomeric excess at pH 7.0 and 37 degrees C and 90% glycerol. PMID- 20855205 TI - Enhancement of the thermostability of the maltogenic amylase MAUS149 by Gly312Ala and Lys436Arg substitutions. AB - Based on sequence alignments and homology modeling, Gly 312 and Lys 436 of the maltogenic amylase from Bacillus sp. US149 (MAUS149) were selected as targets for site-directed mutagenesis to improve the thermostability of the enzyme. Variants of MAUS149 with amino acid substitutions G312A, K436R and G312A-K436R had substrate specificities, kinetic parameters and pH optima similar to those of the wild-type enzyme; however, the enzymes with substitutions K436R and G312A-K436R, had an optimal temperature of 45 degrees C instead of the 40 degrees C for the wild-type enzyme. The half-life time at 55 degrees C increased from 15 to 25 min for the double mutant. Molecular modeling suggests that the increase in thermostability was due to new hydrophobic interactions and the formation of a salt bridge and hydrogen bond in the G312A and K436R variants, respectively. The double mutant could be a potential candidate for application in the bread industry. PMID- 20855206 TI - Synthesis and antiproliferative evaluation of N,N-disubstituted-N'-[1-aryl-1H pyrazol-5-yl]-methnimidamides. AB - A series of N,N-disubstituted-N'-[1-aryl-1H-pyrazol-5-yl]-methnimidamides was synthesized by a newly developed microwave reaction and their antiproliferative activities were evaluated. Microwave irradiation of 5-amino-1,3-disubstituted pyrazoles with various amide solvents in the presence of POCl(3) provided the corresponding 2a-2k, 3a-3c, and 4a-4f in good to excellent yields. The obtained methnimidamides were tested against NCI-H661, NPC-TW01, and Jurkat cancer cell lines and the results indicated that compounds 2d and 2e were the most potent with IC(50) values in low micromolar range. PMID- 20855207 TI - Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. AB - We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model. PMID- 20855209 TI - Concise synthesis and antiangiogenic activity of artemisinin-glycolipid hybrids on chorioallantoic membranes. AB - Novel hybrids of non acetal and acetal-type derivatives at C-12 of artemisinin and glycolipids were synthesized via efficient coupling reactions. Some of these hybrids showed potent in vivo antiangiogenic activity on the chorioallantoic membrane (CAM) that was higher than or comparable to those of fumagillin and thalidomide at a concentration of 2.5 nmol. PMID- 20855208 TI - Selenium-containing analogs of SAHA induce cytotoxicity in lung cancer cells. AB - Cancer therapy has moved beyond conventional chemotherapeutics to more mechanism based targeted approaches. Studies demonstrate that histone deacetylase (HDAC) is a promising target for anticancer agents. Numerous, structurally diverse, hydroxamic acid derivative, HDAC inhibitors have been reported and have been shown to induce growth arrest, differentiation, autophagy, and/or apoptotic cell death by inhibiting multiple signaling pathways in cancer cells. Suberoylanilide hydroxamic acid (SAHA) has emerged as an effective anticancer therapeutic agent and was recently approved by the FDA for the treatment of advanced cutaneous T cell lymphoma. In our previous study, we reported the development of the novel, potent, selenium-containing HDAC inhibitors (SelSA-1 and SelSA-2). In this study, the effects of SelSA-1 and SelSA-2 on signaling pathways and cytotoxicity were compared with the known HDAC inhibitor, SAHA, in lung cancer cell lines. After 24 h of treatment, SelSA-1 and SelSA-2 inhibited lung cancer cell growth to a greater extent than SAHA in a dose-dependent manner with IC(50) values at low micromolar concentrations. SelSA-1 and SelSA-2 inhibited ERK and PI3K-AKT signaling pathways while simultaneously increasing in autophagy in A549 cells in a time dependent manner. This preliminary study demonstrates the effectiveness of the selenium-containing analogs of SAHA, SelSA-1, and SelSA-2, as HDAC inhibitors and provides insight into the improvement and/or development of these analogs as a therapeutic approach for the treatment of lung cancer. PMID- 20855210 TI - A conformationally constrained inhibitor with an enhanced potency for beta tryptase and stability against semicarbazide-sensitive amine oxidase (SSAO). AB - A novel beta-tryptase inhibitor with a basic benzylamine P1 group, a piperidine amide linker, and a substituted indole P4 group was discovered. A substitution at 4-indole position was introduced to constrain the conformational flexibility of the inhibitor to the bioactive conformation exhibited by X-ray structures so that entropic penalty was decreased. More importantly, this constrained conformation limited the accessibility of this molecule to anti-targets, especially SSAO, so that an enhanced metabolic profile was achieved. PMID- 20855212 TI - Evaluation of amide replacements in CCR5 antagonists as a means to increase intrinsic permeability. Part 2: SAR optimization and pharmacokinetic profile of a homologous azacyle series. AB - Replacement of a secondary amide with a piperidine or azetidine moiety in a series of CCR5 antagonists led to the discovery of compounds with increased intrinsic permeability. This effort led to the identification of a potent CCR5 antagonist which exhibited an improved in vivo pharmacokinetic profile. PMID- 20855211 TI - Subtype-selective Na(v)1.8 sodium channel blockers: identification of potent, orally active nicotinamide derivatives. AB - A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain. PMID- 20855213 TI - Classic chordoma coexisting with benign notochordal cell rest demonstrating different immunohistological expression patterns of brachyury and galectin-3. AB - Increasing numbers of studies support the hypothesis that chordoma arises from notochordal cell rests, although the mechanism awaits further research. Brachyury is the first specific molecule linking chordoma with the notochord, and galectin 3 has been widely used as a marker of notochordal cells. We conducted a histological study of the expression of these two molecules in 46 classic chordoma specimens and unexpectedly found that classic chordoma tumor cells coexisted with benign notochordal cell rests in six specimens. Brachyury and galectin-3 expression were investigated by immunohistochemistry. All specimens contained atypical chordoma tumor cells set within an abundant myxoid matrix, which strongly expressed brachyury and galectin-3. However, brachyury and galectin-3 were not expressed in the notochordal cells. Benign notochordal cells, present as notochord rests, could undergo malignant transformation to form chordoma; however, the cause and role of brachyury and galectin-3 expression in chordoma tumorigenesis requires further careful study. PMID- 20855215 TI - Analysis of neutron flux distribution for the validation of computational methods for the optimization of research reactor utilization. AB - In order to verify and validate the computational methods for neutron flux calculation in TRIGA research reactor calculations, a series of experiments has been performed. The neutron activation method was used to verify the calculated neutron flux distribution in the TRIGA reactor. Aluminium (99.9 wt%)-Gold (0.1 wt%) foils (disks of 5mm diameter and 0.2mm thick) were irradiated in 33 locations; 6 in the core and 27 in the carrousel facility in the reflector. The experimental results were compared to the calculations performed with Monte Carlo code MCNP using detailed geometrical model of the reactor. The calculated and experimental normalized reaction rates in the core are in very good agreement for both isotopes indicating that the material and geometrical properties of the reactor core are modelled well. In conclusion one can state that our computational model describes very well the neutron flux and reaction rate distribution in the reactor core. In the reflector however, the accuracy of the epithermal and thermal neutron flux distribution and attenuation is lower, mainly due to lack of information about the material properties of the graphite reflector surrounding the core, but the differences between measurements and calculations are within 10%. Since our computational model properly describes the reactor core it can be used for calculations of reactor core parameters and for optimization of research reactor utilization. PMID- 20855214 TI - 2-Hexadecynoic acid inhibits plasmodial FAS-II enzymes and arrests erythrocytic and liver stage Plasmodium infections. AB - Acetylenic fatty acids are known to display several biological activities, but their antimalarial activity has remained unexplored. In this study, we synthesized the 2-, 5-, 6-, and 9-hexadecynoic acids (HDAs) and evaluated their in vitro activity against erythrocytic (blood) stages of Plasmodium falciparum and liver stages of Plasmodium yoelii infections. Since the type II fatty acid biosynthesis pathway (PfFAS-II) has recently been shown to be indispensable for liver stage malaria parasites, the inhibitory potential of the HDAs against multiple P. falciparum FAS-II (PfFAS-II) elongation enzymes was also evaluated. The highest antiplasmodial activity against blood stages of P. falciparum was displayed by 5-HDA (IC(50) value 6.6 MUg/ml), whereas the 2-HDA was the only acid arresting the growth of liver stage P. yoelii infection, in both flow cytometric assay (IC(50) value 2-HDA 15.3 MUg/ml, control drug atovaquone 2.5 ng/ml) and immunofluorescence analysis (IC(50) 2-HDA 4.88 MUg/ml, control drug atovaquone 0.37 ng/ml). 2-HDA showed the best inhibitory activity against the PfFAS-II enzymes PfFabI and PfFabZ with IC(50) values of 0.38 and 0.58 MUg/ml (IC(50) control drugs 14 and 30 ng/ml), respectively. Enzyme kinetics and molecular modeling studies revealed valuable insights into the binding mechanism of 2-HDA on the target enzymes. All HDAs showed in vitro activity against Trypanosoma brucei rhodesiense (IC(50) values 3.7-31.7 MUg/ml), Trypanosoma cruzi (only 2 HDA, IC(50) 20.2 MUg/ml), and Leishmania donovani (IC(50) values 4.1-13.4 MUg/ml) with generally low or no significant toxicity on mammalian cells. This is the first study to indicate therapeutic potential of HDAs against various parasitic protozoa. It also points out that the malarial liver stage growth inhibitory effect of the 2-HDA may be promoted via PfFAS-II enzymes. The lack of cytotoxicity, lipophilic nature, and calculated pharmacokinetic properties suggests that 2-HDA could be a useful compound to study the interaction of fatty acids with these key P. falciparum enzymes. PMID- 20855216 TI - Electrodeposition of carrier-free 57Co on rhodium as an approach to the preparation of Mossbauer sources. AB - Electrodeposition of carrier-free (57)Co on a rhodium matrix as the first step of preparing Mossbauer sources was studied. To optimize the plating parameters, the influences of current density, volume and pH of the electrolyte solution, shape, thickness, and surface area of the rhodium cathode, mode of cathode pretreatment, concentration of (57)Co and duration of electrolysis were investigated. PMID- 20855217 TI - Molecular cloning and expression of Chimonanthus praecox farnesyl pyrophosphate synthase gene and its possible involvement in the biosynthesis of floral volatile sesquiterpenoids. AB - Farnesyl pyrophosphate (FPP) synthase catalyzes the biosynthesis of FPP, which is the precursors of sesquiterpenoids such as floral scent volatiles, from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). cDNA encoding wintersweet (Chimonanthus praecox L.) FPP synthase was isolated by the RT-PCR and RACE methods. The deduced amino acid sequence showed a high identity to plant FPP synthases. Expression of the gene in Escherichia coli yielded FPPS activity that catalyzed the synthesis of FPP as a main product. Tissue-specific and developmental analyses of the mRNA levels of CpFPPS and volatile sesquiterpenoids levels in C. praecox flowers revealed that the FPPS may play a regulatory role in floral volatile sesquiterpenoids of wintersweet. PMID- 20855218 TI - Phenotyping BOS could improve understanding of mechanisms involved. PMID- 20855219 TI - Re: Amelioration of rat cardiac cold ischemia/reperfusion injury with inhaled hydrogen or carbon monoxide, or both. PMID- 20855220 TI - Subcutaneous treprostinil in pulmonary arterial hypertension: Practical considerations. AB - Treprostinil, which is available for subcutaneous (SC) and intravenous (IV) administration, has demonstrated efficacy in increasing exercise capacity, reducing signs and symptoms of pulmonary arterial hypertension (PAH), and improving cardiopulmonary hemodynamics in patients with PAH; however, the infusion site pain commonly experienced with SC treprostinil has limited its use. Prospective and observational clinical studies have shown that the dose of SC treprostinil can be escalated at a higher rate than described in early clinical trials to achieve symptom relief, in part because of favorable tolerability of treatment and the apparent dose independence of site pain. In addition, pain management protocols that include non-pharmacologic and pharmacologic (i.e., topical and systemic) approaches provide analgesic relief from infusion site pain. With experience, physicians and patients have recognized that some infusion sites are better than others, and the frequency of site rotation can be reduced to improve tolerability. Dosing to achieve rapid onset of efficacy and proactively managing infusion site pain enhance the likelihood for a patient with PAH to maintain and derive benefit from SC treprostinil therapy. PMID- 20855221 TI - Antibody testing for cardiac antibody-mediated rejection: which panel correlates best with cardiovascular death? AB - BACKGROUND: Recent efforts are being undertaken to update and refine current diagnostic criteria for antibody-mediated rejection (AMR) in heart transplantation. We believe that the appropriate reactants are those that best predict the adverse consequences of AMR and therefore tested various models using different reactants to find the best predictors of cardiovascular mortality in pathologically defined AMR. METHODS: The study group included only patients in whom all immunofluorescence antibodies of interest had been tested on biopsy specimens obtained after 2002 when C4d was routinely added. We analyzed our data using 3 Cox proportional hazard models with time-varying covariates using an end point of cardiovascular mortality, as previously defined. RESULTS: In 3,712 biopsy specimens from 422 patients, the 2-antibody model achieved a value of R(2) = 0.930 using C3d and C4d antibodies alone. A model that used 4 antibodies--C3d, C4d, human leukocyte antigen-D related (HLA-DR) and fibrin--was superior (R(2) = 0.988). The model that best predicted cardiovascular mortality included all 6 antibodies: HLA-DR, immunoglobulin (Ig) G, IgM, C3d, C4d, and fibrin (R(2) = 0.989). The models using 4 or 6 antibodies were significantly superior to the model using only C3d and C4d (for each interaction, p < 0.0001). CONCLUSIONS: The combination of complement components, HLA-DR and fibrin, is valuable in defining AMR in patients at risk for allograft loss from cardiovascular causes. Fibrin is particularly important for detecting the presence of severe AMR, with a high likelihood of poor long-term patient outcome. PMID- 20855222 TI - Development of accurate binding affinity predictions of novel renin inhibitors through molecular docking studies. AB - In this study, an attempt was made to explore a possible correlation between different docking scoring functions (Glide InducedFit docking score and GOLD's GoldScore and ChemScore) and binding energy values of a set of renin inhibitors, using linear regression model. The renin inhibitors under study are characterized by known bound to the receptor crystal structures possessing a great variety of pharmacophore groups and a wide range of IC50 values. Linear regression models were derived to relate the docking scoring function and pIC50 values of renin inhibitors under study. The developed derived models are seeking to be helpful for the rational design of new, more potent renin inhibitors. PMID- 20855223 TI - Molecular characterization of CPS1 deletions by array CGH. AB - CPSI deficiency usually results in severe hyperammonemia presenting in the first days of life warranting prompt diagnosis. Most CPS1 defects are non-recurrent, private mutations, including point mutation, small insertions and deletions. In this study, we report the detection of large deletions varying from 1.4 kb to >130 kb in the CPS1 gene of 4 unrelated patients by targeted array CGH. These results underscore the importance of analysis of large deletions when only one mutation or no mutations are identified in cases where CPSI deficiency is strongly indicated. PMID- 20855224 TI - Functional analysis of genetic variations in the 5'-flanking region of the human MDR1 gene. AB - P-glycoprotein (P-gp), the product of the MDR1 gene, shows large interindividual variations in expression, which leads to differences in the pharmacokinetics of the substrate drugs. The functions of single nucleotide polymorphisms located in the nuclear receptor-responsive element of the 5'-flanking region in the human MDR1 gene were analyzed in order to clarify the mechanism underlying the interindividual variation in P-gp expression. Electrophoretic mobility shift assays revealed that the -7833C>T substitution in the nuclear receptor-responsive region of MDR1 decreases the binding affinities of four nuclear receptors to their responsive elements: vitamin D receptor (VDR), thyroid hormone receptor (TR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR). A reporter gene assay revealed that the C-to-T substitution at -7833 also reduces the transcriptional activation of MDR1 by VDR, TRbeta, CAR, and PXR. However, another SNP (-1211T>C substitution), which results in the formation of a xenobiotic responsive element-like sequence and a hypoxia responsive element-like sequence, failed to affect the aryl hydrocarbon receptor-dependent and hypoxia induced transcriptional activation of MDR1. Although the frequency of the 7833C>T substitution in MDR1 is relatively low, the SNP is crucial because it may alter the pharmacokinetics of P-gp substrates in a small subset of the population. PMID- 20855225 TI - Genetics of bone diseases: Paget's disease, fibrous dysplasia, osteopetrosis, and osteogenesis imperfecta. AB - Over the last few years, research into the genetics of bone diseases has produced new insights into the pathophysiology of bone remodeling. The identification of SQSTM1 mutations in Paget's disease of bone established that osteoclast activation involved both binding to ubiquitin and the proteasome pathway. However, murine models fail to replicate the full phenotype, and somatic SQSTM1 mutations have been identified, suggesting a role for complex mechanisms. In patients with fibrous dysplasia of bone, postzygotic somatic mutations in the GNAS gene are now well documented. Technological advances have improved the detection of somatic mutations in peripheral blood cells. Osteopetrosis is characterized by increased bone density due to deficient osteoclastic bone resorption. Most of the genes involved in the various clinical patterns of osteopetrosis have been identified. The identification of LRP5 gain-of-function mutations in autosomal dominant osteopetrosis type I prompted a revision of the classification scheme, and this form is now being included among the high-bone mass diseases. Osteogenesis imperfecta is characterized by an inherited abnormality in bone formation that manifests as osteopenia with increased bone fragility. Mutations in the COL1A1 and COL1A2 genes are found in over 90% of patients. The recent identification of mutations in the CRTAP, LEPRE1, and PPIB genes in recessive forms has radically changed the classification of osteogenesis imperfecta and generated new pathophysiological hypotheses. PMID- 20855226 TI - Micron particle deposition in a tracheobronchial airway model under different breathing conditions. AB - Effective management of asthma is dependent on achieving adequate delivery of the drugs into the lung. Inhalers come in the form of dry powder inhalers (DPIs) and metered dose inhalers (pMDIs) with the former requiring a deep fast breath for activation while there are no restrictions on inhalation rates for the latter. This study investigates two aerosol medication delivery methods (i) an idealised case for drug particle delivery under a normal breathing cycle (inhalation exhalation) and (ii) for an increased effort during the inhalation with a breath hold. A computational model of a human tracheobronchial airway was reconstructed from computerised tomography (CT) scans. The model's geometry and lobar flow distribution were compared with experimental and empirical models to verify the current model. Velocity contours and secondary flow vectors showed vortex formation downstream of the bifurcations which enhanced particle deposition. The velocity contour profiles served as a predictive tool for the final deposition patterns. Different spherical aerosol particle sizes (3-10MUm, 1.55g/cm(3)) were introduced into the airway for comparison over a range of Stokes number. It was found that a deep inhalation with a breath hold of 2s did not necessarily increase later deposition up to the sixth branch generation, but rather there was an increase in the deposition in the first few airway generations was found. In addition the breath hold allows deposition by sedimentation which assists in locally targeted deposition. Visualisation of particle deposition showed local "hot-spots" where particle deposition was concentrated in the lung airway. PMID- 20855227 TI - Automated anatomical demarcation using an active shape model for videofluoroscopic analysis in swallowing. AB - The current gold standard method in the clinical assessment of swallowing is the visual inspection of videofluoroscopic frames. Specific clinical measurements are estimated based on various anatomical and bolus positional information with respect to time (or frame number). However, due to the subjective nature of visual inspection clinicians face intra- and inter-observer repeatability issues and bias when making these estimations. The correct demarcations of reference lines highlighting the positions of important anatomical landmarks would serve as a visual aid and could also be used in conjunction with bolus detection methods to objectively determine these desirable measurements. In this paper, we introduce and test the reliability of applying a 16-point Active Shape Model as a deformable template to demarcate the boundaries of salient anatomical boundaries with minimal user input. A robust end and corner point detection algorithm is also used to provide image information for the suggested movement of the template during the fitting stage. Results show the model deformation constraints calculated from a training set of images are clinically coherent. The Euclidean distances between the fitted model points against their corresponding target points were measured. Test images were taken from two different data sets from frames acquired using two different videofluoroscopy units. Overall, fitting was found to be more reliable on the vertebrae and inferior points of the larynx compared to the superior laryngeal points and hyoid bone, with the model always fitting the C7 vertebra with discrepancies no higher than a distance of 23 pixels (3.2% of the image width, approximately 7.6mm). PMID- 20855228 TI - Fluctuation in plasma entacapone concentrations in accordance with variable plasma levodopa concentrations. PMID- 20855229 TI - Vibrational and ab initio studies of 3-acetyl-6-bromocoumarin and 3-acetyl-6 methylcoumarin. AB - Infrared absorption and Raman spectra (3500-50 cm(-1)) of 3-acetyl-6 bromocoumarin and 3-acetyl-6-methylcoumarin have been measured and interpreted, aided by electronic structure calculations at RHF and B3LYP using 6-31(d, p) basis set. It has been determined that the rotation of the acetyl group with respect to the coumarin ring results in three conformers--two trans and one cis- for each molecule, with one trans conformer being the most stable in both cases. There are significant changes in the vibrational structure as characterized by positions and intensities of certain modes in going from 3-acetyl-6-bromocoumarin to 3-acetyl-6-methylcoumarin. The carbonyl stretching mode of the pyrone ring is stable in both molecules whereas the same mode in acetyl groups is not. Ring stretching vibrations are coupled to C-H in-plane bending vibrations. Down shifting of frequencies of methyl vibrations in acetyl group occurs vis-a-vis methyl vibrations in 3-acetyl-6-methylcoumarin. A strong Raman band at 126 cm(-1) in both molecules is structure-independent non-genuine mode, correlated to lattice vibrations in the solid phase. PMID- 20855230 TI - Molecular monitoring of causative viruses in child acute respiratory infection in endemo-epidemic situations in Shanghai. AB - BACKGROUND: Numerous viruses are responsible for respiratory infections; however, both their distribution and genetic diversity, in a limited area and a population subgroup, have been studied only rarely during a sustained period of time. METHODS: A 2-year surveillance program of children presenting with acute respiratory infections (ARIs) was carried out to characterize the viral etiology and to assess whether using gene amplification and sequencing could be a reliable approach to monitor virus introduction and spread in a population subgroup. RESULTS: Using multiplex RT-PCR, 15 different respiratory viruses were detected within the 486 nasopharyngeal positive samples collected among 817 children aged <9-year old who presented with ARI during October 2006 to September 2008. A single virus was detected in 373 patients (45.7%), and two to four viruses in 113 patients (13.8%). The most frequent causative viruses were respiratory syncytial virus (RSV) (24.7%), human bocavirus (24.5%), and human rhinovirus (HRV) (15%). RSV was more prevalent in winter and among young infants. Cases of seasonal influenza A and B viruses were reported mainly in January and August. An increase in adenovirus infection was observed during the spring of the second year of the study. Sequence analyses showed multiple introductions of different virus subtypes and identified a high prevalence of the newly defined HRV-C species. A higher viral incidence was observed during the winter of 2008, which was unusually cold. CONCLUSIONS: This study supports the usefulness of multiplex RT PCR for virus detection and co-infection, and for implementation of a molecular monitoring system for endemic and epidemic viral respiratory infections. PMID- 20855231 TI - Using a simplified human immunodeficiency virus type 1 p24 antigen assay to diagnose pediatric HIV-infection in Malawi. AB - BACKGROUND: There is a worldwide need for a pediatric HIV-1 diagnostic test that has a high diagnostic accuracy, is technically simple and cost efficient. The Up24 HIV-1 assay, which requires both the HIV-1 p24 ELISA and the ELAST signal amplification kit, has previously been shown to be a robust tool to diagnose pediatric HIV-1 from dried whole blood spots (DBS) (Cachafeiro et al., JCM 2009;47:459-62(13)). In order to make the assay more accessible to a resource limited clinical setting, we eliminated the ELAST system, which simplified the Up24 assay, reduced its cost, and tested the accuracy of the modified assay in a rural Malawian hospital. OBJECTIVES: In this proof of concept study, we tested the ability of a simplified Up24 antigen assay, without ELAST, to detect HIV-1 on DBS obtained via heel prick from 6-week-old Malawian infants. STUDY DESIGN: A case-control study of DBS collected from 113 HIV-infected and 109 HIV-negative infants, using the HIV-1 DNA PCR assay as the reference standard. RESULTS: The simplified HIV-1 Up24 assay had a sensitivity and specificity of 84% and 98%, respectively. When HIV-1 prevalence is 15%, the positive- and negative-predictive values are 89% and 97%, respectively. CONCLUSION: The simplified Up24 assay has a good positive- and a robust negative-predictive values, is easier to perform and has a reduced cost compared to both HIV DNA PCR and Up24 assays. With additional testing, the simplified Up24 assay has the potential to increase global access to pediatric HIV-1 diagnostics. PMID- 20855232 TI - Production of peritrichate bacterionanofibers and their proteinaceous components by Acinetobacter sp. Tol 5 cells affected by growth substrates. AB - The toluene-degrading bacterium Acinetobacter sp. Tol 5 is highly adhesive through cell-surface nanofibers. Previously, we identified two morphologically distinct nanofibers on Tol 5 cells, namely, nonperitrichate anchor-like and peritrichate pilus-like nanofibers. In the present study, the application of improved electron microscopy techniques enabled discrimination of three distinct types of peritrichate nanofibers on Tol 5 cells. Interestingly, production of these nanofibers was affected by the available growth substrate. Thick, long, straight nanofibers a, which were present on cells grown on toluene, lactate, and ethanol, were not observed on cells grown on triacylglycerol (TAG). In contrast, cells grown on TAG were covered with long, curved nanofibers c, which only existed sparsely on cells grown on toluene, lactate, and ethanol. Thin, short, straight nanofibers b were found densely covering the margin of cells grown on all four growth substrates. SDS-PAGE of Tol 5 cell-surface proteins detected a protein of 17.5 kDa that was expressed at a high level on ethanol, but was undetectable on TAG. Conversely, a 26kDa protein was identified that was exclusively expressed on TAG, but was only faintly expressed by cells grown on the other substrates. Based on N-terminal amino acid sequences, the 17.5 and 26 kDa proteins were identified as the major subunits of type 1 and Fil pili, respectively, which are typical bacterionanofibers. From these results, we deduced that nanofibers a and c are type 1 and Fil pili, respectively. The adhesiveness of Tol 5 cells was low only when they were grown on TAG. PMID- 20855233 TI - Synergistic effects of detergents and organic solvents on protein refolding: control of aggregation and folding rates. AB - This paper presents the synergistic enhancement of the refolding yield of denatured and reduced lysozyme by using detergents as aggregation inhibitors and water-miscible organic cosolvents as modulators for the detergents. Adding only cetyltrimethylammonium bromide (CTAB) led to a slight increase in the refolding yield (up to 13%). Further addition of dimethylsulfoxide (DMSO) with CTAB drastically increased the refolding yield up to 35%, a value which was higher than the simple sum of the refolding yields in the presence of only CTAB or DMSO. The synergistic enhancement was also observed in the coexistence of other detergents, such as polyethylene glycol monooleyl ether (n = 50) and N-tetradecyl N,N-dimethyl-3-ammonio-1-propanesulfonate, and cosolvents, such as N,N dimethylformamide and N,N-dimethylacetamide. Experimental data and a kinetic analysis revealed the guideline for selecting a couple of additives; detergents which can adequately inhibit the aggregation of proteins by binding to hydrophobic surfaces of refolding intermediates should be employed as an aggregation inhibitor, and cosolvents which can properly prevent both protein protein and protein-detergent interactions act as effective modulators for the aggregation inhibitor, resulting in a desirable balance between folding and aggregation rates. PMID- 20855234 TI - Perceptions of breast health awareness in Black British women. AB - PURPOSE: Breast cancer is a global concern. Published studies indicate that 43% of Black and ethnic minority women interviewed have reported that they did not practice breast awareness because they did not know the relevant breast changes that occur in breast cancer. Black women are also more likely to receive a diagnosis of breast cancer when it is in an advanced stage. This pilot study aimed to address the views of Black British women on breast health awareness and breast health screening practices. METHODS AND SAMPLE: In this qualitative study I used semi-structured interviews were used to investigate breast health perceptions, practices and education in a pilot sample of ten women. KEY RESULTS: Women held numerous perceptions of breast cancer which ranged from no knowledge to well informed through receiving extensive education. Two out of ten women were relatively uneducated with regard to breast self examination (BSE). The remaining eight women participated in a variety of screening routines which varied from undertaking BSE everyday to once every few months. Women's experience of breast health education was also variable. One woman, younger woman, had not received any health education advice in relation to breast health awareness or BSE. The remaining nine women had received some health advice following visit to their General Practitioners, Medical consultant, media information or as a result of participating in mammographic screening. CONCLUSIONS: Black British women require health education that focuses on breast cancer and its associated risk factors, technique of BSE, and national breast cancer screening recommendations. PMID- 20855235 TI - Changes in seizure severity and quality of life in patients with refractory partial epilepsy. AB - This 6-month observational, prospective, multicenter study assessed the influence of changes in seizure severity on quality of life in patients with refractory partial epilepsy. Patients (N = 262) diagnosed with partial epilepsy and receiving two antiepileptic drugs as determined by usual clinical practice were enrolled in this study. The primary endpoint was the mean seizure severity score obtained from the Seizure Severity Questionnaire. Reductions in seizure severity were detected from baseline to months 3 and 6 (P<0.0001). Improvements compared with baseline were found for several secondary measures: Hamilton Anxiety and Depression scales (P<0.0001), most Medical Outcomes Study-Sleep subscales (P<0.05), and seven subscales of the Quality of Life in Epilepsy Inventory-31 (QOLIE-31; P<0.0005). Seizure severity correlated directly with anxiety (P<0.0001) and inversely with QOLIE-31 measures (P<0.0001). In conclusion, reducing seizure severity with appropriate medication may lead to improvement in the overall quality of life of patients with refractory partial epilepsy. PMID- 20855236 TI - Determination of nicotine, anabasine, and cotinine in urine and saliva samples using single-drop microextraction. AB - A simple, sensitive, and inexpensive singe-drop microextraction (SDME) followed by gas chromatography and flame-ionization detection (GC-FID) was developed for determination of nicotine, anabasine, and cotinine in human urine and saliva samples. The target compounds were extracted from alkaline aqueous sample solution into an organic acceptor drop suspended on the tip of a 25-MUL GC microsyringe in the aqueous sample solution. This microsyringe was also used for direct injection after extraction. Under optimized experimental conditions, calibration plots were found to be linear in the range of 0.5-25.0, 0.5-65.0, and 0.5-45.0mgL(-1) for nicotine, anabasines and cotinine, respectively. The method detection limit values were in the range of 0.33-0.45mgL(-1). Intra-day and inter day precisions for peak area ratios were in the range of 1.3-9.2% and 2.0-7.0%, respectively. The proposed procedure was successfully applied to the determination of analytes in spiked urine and saliva samples with satisfactory results. The mean relative recoveries of spiked water samples ranged over 71.2 111.0%, with relative standard deviations varying from 2.3% to 10.0%. PMID- 20855237 TI - Microarray analysis reveals strategies of Tribolium castaneum larvae to compensate for cysteine and serine protease inhibitors. AB - The transcriptome response of Tribolium castaneum larvae to dietary protease inhibitors was evaluated by whole-genome microarray analysis. RNA was isolated from guts of larvae fed control diet (no inhibitor), or diets containing 0.1% E 64 (cysteine protease inhibitor), 5.0% soybean trypsin inhibitor (STI, serine protease inhibitor), or a combination of 0.1% E-64 and 5.0% STI. Data were analyzed by pairwise analysis, in which each inhibitor treatment group was compared to control, or ANOVA of all treatment groups. In pairwise analysis, the expression of only 253 genes was significantly altered (p<0.05) in response to STI treatment, whereas E-64 and combination treatments resulted in 1574 and 1584 differentially regulated genes. The data indicate that treatments containing E 64, whether alone or in combination, significantly impacts gene expression in T. castaneum larvae. ANOVA analysis revealed 2175 genes differentially expressed in inhibitor-treated larvae compared to control (p<0.05), including genes related to proteases that were mostly up-regulated, namely cathepsins B and L, chymotrypsins, and nonproteolytic cysteine cathepsin or serine protease homologs. Inhibitor treatments induced the differential expression of other gut-related genes, as well as genes encoding proteins of unknown function. These data suggest that T. castaneum larvae compensate for dietary cysteine protease inhibitors by altering large-scale gene expression patterns. PMID- 20855238 TI - Specific complications of monochorionic twin pregnancies: twin-twin transfusion syndrome and twin reversed arterial perfusion sequence. AB - Monochorionic twins are subjected to specific complications which originate in either imbalance or abnormality of the single placenta serving two twins. This unequal placental sharing can cause complications including twin-twin transfusion syndrome (TTTS), twin anemia-polycythemia sequence (TAPS), selective intrauterine growth restriction or twin reversed arterial perfusion sequence (TRAP). Monochorionicity also makes the management of these specific complications as well as that of a severe malformation in one twin hazardous since the spontaneous death of one twin exposes the co-twin to a risk of exsanguination into the dead twin and its placenta. The latter is responsible for the death of the co-twin in up to 20% of the cases and in ischemic sequelae in about the same proportions in the survivors. Although the symptoms of all these complications are very different, the keystone of their management comes down to either surgical destruction of the inter-twin anastomoses on the chorionic plate when aiming at dual survival or selective and permanent occlusion of the cord of a severely affected twin aiming at protecting the normal co-twin. This can be best achieved by fetoscopic selective laser coagulation and bipolar forceps cord coagulation respectively. PMID- 20855239 TI - Intellectual impairment in school-age children exposed to manganese from drinking water. AB - BACKGROUND: Manganese is an essential nutrient, but in excess it can be a potent neurotoxicant. Despite the common occurrence of manganese in groundwater, the risks associated with this source of exposure are largely unknown. OBJECTIVES: Our first aim was to assess the relations between exposure to manganese from drinking water and children's intelligence quotient (IQ). Second, we examined the relations between manganese exposures from water consumption and from the diet with children's hair manganese concentration. METHODS: This cross-sectional study included 362 children 6-13 years of age living in communities supplied by groundwater. Manganese concentration was measured in home tap water (MnW) and children's hair (MnH). We estimated manganese intake from water ingestion and the diet using a food frequency questionnaire and assessed IQ with the Wechsler Abbreviated Scale of Intelligence. RESULTS: The median MnW in children's home tap water was 34 ug/L (range, 1-2,700 ug/L). MnH increased with manganese intake from water consumption, but not with dietary manganese intake. Higher MnW and MnH were significantly associated with lower IQ scores. A 10-fold increase in MnW was associated with a decrease of 2.4 IQ points (95% confidence interval: -3.9 to 0.9; p < 0.01), adjusting for maternal intelligence, family income, and other potential confounders. There was a 6.2-point difference in IQ between children in the lowest and highest MnW quintiles. MnW was more strongly associated with Performance IQ than Verbal IQ. CONCLUSIONS: The findings of this cross-sectional study suggest that exposure to manganese at levels common in groundwater is associated with intellectual impairment in children. PMID- 20855240 TI - Similarity of bisphenol A pharmacokinetics in rhesus monkeys and mice: relevance for human exposure. AB - OBJECTIVE: Daily adult human exposure to bisphenol A (BPA) has been estimated at <1 ug/kg, with virtually complete first-pass conjugation in the liver in primates but not in mice. We measured unconjugated and conjugated BPA levels in serum from adult female rhesus monkeys and adult female mice after oral administration of BPA and compared findings in mice and monkeys with prior published data in women. METHODS: Eleven adult female rhesus macaques were fed 400 ug/kg deuterated BPA (dBPA) daily for 7 days. Levels of serum dBPA were analyzed by isotope-dilution liquid chromatography-mass spectrometry (0.2 ng/mL limit of quantitation) over 24 hr on day 1 and on day 7. The same dose of BPA was fed to adult female CD-1 mice; other female mice were administered 3H-BPA at doses ranging from 2 to 100,000 ug/kg. RESULTS: In monkeys, the maximum unconjugated serum dBPA concentration of 4 ng/mL was reached 1 hr after feeding and declined to low levels by 24 hr, with no significant bioaccumulation after seven daily doses. Mice and monkeys cleared unconjugated serum BPA at virtually identical rates. We observed a linear (proportional) relationship between administered dose and serum BPA in mice. CONCLUSIONS: BPA pharmacokinetics in women, female monkeys, and mice is very similar. By comparison with approximately 2 ng/mL unconjugated serum BPA reported in multiple human studies, the average 24-hr unconjugated serum BPA concentration of 0.5 ng/mL in both monkeys and mice after a 400 ug/kg oral dose suggests that total daily human exposure is via multiple routes and is much higher than previously assumed. PMID- 20855241 TI - [Phyllodes tumors and breast sarcomas: a review]. AB - Phyllodes tumors and sarcomas of the breast are non-epithelial tumors of the breast. Phyllodes tumors are benign tumors, tumors of intermediate malignancy or malignant tumors. The differential diagnosis with a very proliferant fibroadenoma may be difficult. Histological sub-type, type of surgery (definitive or not) and stromal proliferation determine the prognosis. There is a risk of local relapse and distant metastases, in particular to the lung. Surgery (often radical) is the standard treatment. Radiotherapy is recommended in case of high-grade tumor and after conservativetreatment. Breast sarcomas are even rarer. All histological types exist with a predominance of histiofibrocytome type tumors. Grade, involved margins and sometimes tumor necrosis are major prognostics factors. Among the various sub-types, angiosarcoma is characterized by a high risk of occurrence in irradiated fields and by a poor prognosis with a high risk of lung metastases. The treatment is mostly based on mastectomy without lymph node dissection given the exceptional flooding axillary. In some situations, a conservative treatment can be discussed, based on tumor size, grade and volume of the breast. Locoregional radiotherapy is often proposed for tumors over 5 cm and/or of high grade. Systemic chemotherapy is not a standard but should be discussed in the forms at high risk of relapse (like angiosarcoma). PMID- 20855242 TI - [Cloning of human LUNX gene enhancers and analysis of transcriptional regulation]. AB - OBJECTIVE: To identify the enhancers of human lung specific X protein (LUNX) and their regulation at the transcription level in vitro. METHODS: Three enhancer fragments (E1:+3770~+3959bp; E2: +6454~+6555bp; E3: +14553~+14652 bp) predicted by bioinformatics software were isolated from the human genomic DNA by PCR amplification. Luciferase assay was performed to detect the activities of the enhancers in transcriptional regulation. RESULTS: PCR products were confirmed by DNA sequencing. The amplified enhancers digested by Kpn I/Xho I and BamH I/Sal I, to generate the sticky-end fragments were inserted into PGL3-promoter in a reporter vector, and 6 luciferase expression vectors were obtained. All the reporter plasmids and pGL3-promoter were transiently transfected into HEK293 cells with an internal control of pSV-beta-Galactosidase reporter vector. The enhancer activity of each construct was evaluated by luciferase assay of the cell extracts after transfection for 48 h. The results showed that the 3 fragments, when located upstream, did not increase transcription of reporter gene, but when at the downstream, E1 and E3 increased the transcription by 2.83 and 1.59 folds of that of pGL3-promoter, respectively. CONCLUSION: LUNX gene sequences from +3770 to +3959 bp and +14553 to +14652 bp possess the capacity to enhance gene transcription. PMID- 20855243 TI - [Repair of subacute spinal cord crush injury by bone marrow stromal cell transplantation and chondroitinase ABC microinjection in adult rats]. AB - OBJECTIVE: To investigate the possibility of repairing spinal cord injury by bone marrow stromal cell (MSC) transplantation and microinjection of chondroitinase ABC (ChABC) in adult rats. METHODS: MSCs isolated from the femoral and tibial bones of new-born Wistar rats were cultured and the cell density was adjusted to 1*10(5)ul before transplantation. SD rats with T8 spinal cord crush injury were divided into 4 groups, namely group A (control) and groups B, C and D with injections of the MSCs, ChABC and MSCs+ChABC at the injury site, respectively. At 0 h, 1 day, 2 days, 3 days, 1 week, and 2 weeks after the injury, the BBB score system was used to evaluate the motion function. At 14 days after the injury, the maximal transverse diameter and actual area of necrosis were evaluated on HE stained sections. GFAP-CS56, GFAP-GAP43 and GFAP-NF160 immunofluorescence double labeling staining were carried out to evaluate the regeneration of the nerve fibers. RESULTS: At the 14th day after the injury, BBB scores showed significant differences between group A and groups B, C and D (P<0.05), between the groups B and D and between groups C and D, butnot between groups B and C. HE staining showed cavity formation at the injury site in each group, with significant differences between group A and groups B, C and D and also between the latter 3 groups. Immunofluorescence staining revealed more intense expression of GFAP in group A than in the other groups with apparent cavity formation at the lesion site, which was only moderate in groups B and C. The expression of GAP-43 was more intense in group D than in groups B and C. The expression of NF-160 was more intense in group D than in the other 3 groups. CONCLUSION: The strategy of MSC transplantation combined with ChABC can be effective for repairing spinal cord injury in adult rats. PMID- 20855244 TI - [Synthetic evaluation of the clinical effect of the Shengmai capsule for treatment of chronic congestive heart failure using analytic hierarchy process]. AB - OBJECTIVE: To explore the approaches and techniques for synthetic evaluation of the clinical therapeutic effect of new Chinese herbal medicine in clinical trials. METHODS: In a double-blind, randomized, and placebo-controlled clinical trail, analytic hierarchy process (AHP) was applied to evaluate the clinical therapeutic effect of Shengmai capsule in the treatment of chronic congestive heart failure. RESULTS: Shengmai capsule produced positive therapeutic effect on chronic congestive heart failure. CONCLUSION: A feasible method is established for evaluating and grading the clinical therapeutic effect of Chinese herbal medicine. PMID- 20855245 TI - [Dedifferentiation of epidermal cells into transit amplifying cells induced by bFGF]. AB - OBJECTIVE: TTo explore the method for inducing the dedifferentiation of epidermal cells into their progenitor stem cells in vitro without external gene intervention. METHODS: HEK cells obtained from Casacade were induced to reverse their differentiated process and produce immature stem-like cells, namely the dedifferentiation derived epidermal stem cells (dESCs), by induction with basic fibroblasts growth factors (bFGF) in vitro. Immunochemical staining, flow FACS analysis, RT-PCR and immunofluorescent staining were used to detect the phenotypic and functional changes of the differentiated epidermal cells, using human epidermal stem cells (ESCs) as the positive control. RESULTS: Immunohistochemical staining revealed that the expressions of beta1-integrin, CK19 and CK14 were up-regulated, while CK10 expression was down-regulated significantly after bFGF treatment. Two-color flow cytometric analysis of alpha6 integrin and CD71 showed that the percentages of alpha6(+)CD71(-), alpha6(+)CD71(+) and CD71(+) expressing populations reached 13.24%, 58.26% and 23.12% of the total isolated cells, as compared with those of the control (0.12%, 3.06%, 51.50%) and positive control cells (37.49%, 45.13%, 5.86%). RT-PCR analysis indicated that the relative gene expressions of beta1-integrin, CK19 and CK14 increased in bFGF treatment group, whereas the expression of CK10 was significantly suppressed. Although there was no significant difference in the expression levels of beta1 integrin, CK19 and CK10 between the bFGF-treated and the positive controls, the expression of CK14 in bFGF-treated cells showed a 1.4 fold increase as compared with that in ESCs (P < 0.05). Immunofluorescent staining showed that a regional difference in the subcellular localization of telomerase between dESCs and ESCs. CONCLUSION: bFGF can induce the epidermal cells to convert into epidermal precursor cells. Although they are more likely to be transient amplifying cells, the method for reprogramming somatic epidermal cells into their progenitors by bFGF induction other than genetic manipulation offers a new approach to generate residual healthy stem cells for wound repair and regeneration. PMID- 20855246 TI - [Prokaryotic expression and purification of SPAG4L, a novel human testis gene]. AB - OBJECTIVE: To express SPAG4L, a novel human testis gene in E. coli and purify it's fusion protein. METHODS: The fragment encoding SPAG4L126-379 was amplified by RT-PCR and the PCR products were cloned into PUCm-T vectors. After digestion by EcoR I and Hind III, the fragment was subcloned into PQE-30, a prokaryotic expression vector with 6*His tag. The recombinant plasmid PQE-30-SPAG4L was sequenced and transformed into E.coli M15. The expression of his-tagged fusion protein was induced by IPTG. The fusion protein was identified by Western blotting and purified using Ni-NTA magnetic agarose beads. RESULTS: The recombinant plasmid PQE-30-SPAG4L was constructed successfully and expressed in E.coli M15. The fusion protein SPAG4Lwith 6*his-tag was confirmed by Western blotting. The micro-scale purification system of 6*His-tagged SPAG4Lprotein was established and purified fusion protein was obtained. CONCLUSION: The recombinant plasmid PQE-30-SPAG4L can be expressed in vitro and used for studying the biological function of SPAG4L in spermatogenesis. PMID- 20855247 TI - [Expression of high mobility group box-1 in the lung tissue and BALF of asthmatic mice and the influence of dexamethasone]. AB - OBJECTIVE: To investigate the expression of high mobility group box-1 (HMGB1) in the lung tissue and bronchoalveolar lavage fluid (BALF) of asthmatic mouse models and the influence of dexamethasone (DM). METHODS: Eighteen female Balb/C mice were randomly divided PBS control group, OVA group and OVA/DM group, and asthmatic mouse models were established in the latter two groups. The airway responsiveness of the mice was assessed by whole-body plethysmography, and the cells in the BALF were counted and classified, with the supernatants of the BALF collected for detection of the level of HMGB1 by ELISA. The left lung of the mice was collected for HE staining, and the expression of HMGB1 in the right lung tissue was detected by Western blotting. RESULTS: Asthmatic mouse models were successfully established. The level of HMGB1 in the BALF was significantly higher in OVA group than in the control group (6.31 +/- 4.05 ng/ml vs 2.59 +/- 0.73 ng/ml, P = 0.017), but no significant difference was found between OVA/DM group (3.39 +/- 0.50 ng/ml) and OVA group (PP = 0.052). The expression of HMGB1 relative to tubulin was significantly higher in OVA group than in the control group (2.08 +/- 0.87 vs 0.85 +/- 0.30, P = 0.032), but similar between OVA/DM group (1.15 +/- 0.48) and OVA group (PP = 0.133). CONCLUSION: The expression of HMGB1 is obviously increased in the lung and BALF of asthmatic mice and DM produces no significant effect on HMGB1 expression, suggesting that HMGB1 may serve as a new therapeutic target for asthma treatment. PMID- 20855248 TI - [Optimization of lyophilization procedures for freeze-drying of human red blood cells]. AB - OBJECTIVE: To investigate the different parameters of the lyophilization procedures that affect the recovery of the rehydrated red blood cells (RBCs). METHODS: Human RBCs loaded in tubes were cooled with 4 different modes and subjected to water bath at 25 degrees celsius;. The morphological changes of the RBCs were observed to assess the degree of vitrification, and the specimens were placed in the freeze-dryer with the temperature set up at 40, -50, -60, -70 and 80 degrees celsius;. The rates of temperature rise of the main and secondary drying in the lyophilization procedures were compared, and the water residue in the specimens was determined. RESULTS: The protectant did not show ice crystal in the course of freezing and thawing. No significant difference was found in the recovery rate of the rehydrated RBCs freeze-dried at the minimum temperature of 70 degrees celsius; and -80 degrees celsius; (P > 0.05). The E procedure resulted in the maximum recovery of the RBCs (83.14% +/- 9.55%) and Hb (85.33% +/- 11.42%), showing significant differences from the other groups(P < 0.01 or 0.05). The recovery of the RBCs showed a positive correlation to the water residue in the samples. CONCLUSION: Fast cooling in liquid nitrogen and shelf precooling at 70 degrees celsius; with a moderate rate of temperature rise in lyophylization and a start dry temperature close to the shelf equilibrium temperature produce optimal freeze-drying result of human RBCs. PMID- 20855249 TI - [Role of Na(+)-K(+)-ATPase in lipopolysaccharide-induced cardiomyocyte hypertrophy in rats]. AB - OBJECTIVE: To explore the possible mechanism of lipopolysaccharide (LPS)-induced cardiomyocyte hypertrophy in rats. METHODS: Neonatal rat cardiomyocytes cultured in vitro were stimulated with 100 ug/L LPS for 1, 4 or 8 h and scanned by atomic force microscopy (AFM) for measurement of the two-dimensional area, three dimensional surface area and volume of each cell. The total proteins and Na(+) K(+)-ATPase activity in the cardiomyocytes were determined. The same measurements were also carried out in neonatal rat cardiomyocyte cultures stimulated by 0.5 umol/L ouabain for 8 h and the total protein levels were measured. RESULTS: Following a 8-hour stimulation with LPS, the two-dimensional area, three dimensional surface area and volume of the single cardiomyocyte became enlarged and the total cellular proteins increased significantly as compared with those in the normal control cells (P < 0.05). LPS treatment for 4 and 8 h resulted in significantly decreased activity of Na(+)-K(+)-ATPase in the cardiomyocytes (P < 0.05). In the cells treated with ouabain for 8 h, the two-dimensional area, three dimensional surface area, volume of the single cardiomyocyte and the total cellular proteins increased significantly in comparison with the normal control group (P < 0.05). CONCLUSION: LPS can result in cardiomyocyte hypertrophy in rats possibly in relation to lowered Na(+)-K(+)-ATPase activity in the cardiomyocytes after LPS exposure. PMID- 20855250 TI - [A new method for infering vessel structure based on circle detection and Gabor filter]. AB - To automatically infer the patterns of vessel structure such as the distal ends, segments, bifurvessel structures, and crossing of two vessels in X-ray angiographic images, a novel method is presented based on Gabor filter and circle detector. The method can cope with varying vessel curvature and intensity feature occur along the longitudinal vessel direction. The present study can facilitate 2 D quantitative description of vessel tree and 3-D vessel reconstruction, and provide an elementary clue for the diagnostics. The proposed method has been successively applied to both synthetic images for validation purposes and the actual angiographic images, which yielded encouraging results. PMID- 20855251 TI - [Detection and its clinical value of CCR5 and CCR7 in dendritic cells from patients with active rheumatoid arthritis]. AB - OBJECTIVE: To detect the expressions of CCR5 and CCR7 on dendritic cells (DCs) in patients with rheumatoid arthritis (RA) in different phases of disease activity, and explore the relationship between the disease activity and the expression of chemokine receptors. METHODS: Twenty-eight patients with low, moderate and high disease activity and 10 normal control subjects were enrolled in this study. Peripheral blood was obtained from the subjects and the DCs were isolated. The expression of CCR5 and CCR7 on DCs were detected by flow cytometry, and the serum levels of rheumatoid factor (RF), C-reactive protein (CRP) and anti-CCP antibody (ACPA) were assessed. The correlation of the expressions of CCR5 and CCR7 to serum RF, CRP, and ACPA levels of the RA patients were analyzed. RESULTS: Compared to the normal control group, RA patients showed enhanced expressions of CCR5 and CCR7 on the DCs. A linear correlation was noted between CCR5 and CCR7 expressions on the DCs and the serum levels of RF and CRP, but not ACPA, in the RA patients. CONCLUSION: The expressions of CCR5 and CCR7 on the DCs may correlate to the disease activity of RA, and may serve as valuable indices in monitoring the disease activity and the efficacy of the treatment. PMID- 20855252 TI - [Construction of pGEX-KG/mTSARG3 recombinant vector and preparation of anti mTSARG3 polyclonal antibody]. AB - OBJECTIVE: To construct pGEX-KG/mTSARG3 recombinant vector and prepare the fusion protein to obtain rabbit polyclonal antibody against mTSARG3. METHODS: The open reading frame (ORF) of mTSARG3 gene was amplified from mouse testis cDNA library by PCR. The products were cloned into pGEM-T Easy vectors and sequenced. The recombinant plasmids were digested by EcoRI and SalI and subcloned into PGEX-KG vector. After identification by DNA sequence analysis, the recombinant plasmids were transformed into component E.coli BL21 cells, and the GST/mTSARG3 fusion protein was expressed with IPTG induction. The anti-mTSARG3 polyclonal antibody was produced by immunization of rabbits with the fusion protein. The resultant antibody was purified by antigen column and used for Western blotting for detecting mTSARG3 expression. RESULTS: The recombinant vector pGEX-KG/mTSARG3 was successfully constructed. GST/mTSARG3 fusion protein was expressed abundantly at 4 h after IPTG induction and polyclonal antibodies were obtained. Western blot analysis demonstrated that the antibodies specifically detected mTSARG3 expression in E.coli BL21. CONCLUSION: We have successfully constructed pGEX KG/mTSARG3 recombinant vector and obtained rabbit polyclonal antibody, which may facilitate further investigation of the role of mTSARG3 in spermatogenesis. PMID- 20855253 TI - [Gibbs artifact reduction in magnetic resonance images based on inverse diffusion]. AB - In magnetic resonance imaging (MRI), Gibbs artifact is often introduced by the reconstruction involving only part of the k-space data. The current methods of Gibbs artifact reduction are generally based on the k-space data. In this paper, an image processing method based on inverse diffusion is proposed. This method is directly applied to the MR images, which can achieve the reduction of artifacts while enhancing the edge by the diffusion of pixel gray value. Experiments showed that the Gibbs artifact was effectively reduced and the valuable details of the images were maintained. PMID- 20855254 TI - [Construction of a eukaryotic expression vector harboring the small interfering RNA targeting HCMV-IE1 gene and its gene silencing efficiency]. AB - OBJECTIVE: To investigate the effect of RNA interference targeting human cytomegalovirus immediate early gene 1 (HCMV- IE1) on the gene expression in vitro. METHODS: According to the sequence of HCMV-IE1 gene, the small interfering RNA (siRNA) sequences were designed and introduced into the eukaryotic expression vector containing the U6 promoter. After verification by sequence analysis, the recombinant eukaryotic plasmid (pHCMV-IE1i) was transfected into HEL HCMVAD169 cells. The effectiveness of HCMV-IE1 gene silencing was investigated by fluorescence microscopy, flow cytometry and RT-PCR. RESULTS: Sequence analysis confirmed successful construction of the recombinant eukaryotic expression plasmid pHCMV-IE1i. The expression of HCMV-IE1 was effectively suppressed by pHCMV-IE1i transfection in HEL cells as shown by fluorescence microscopy, flow cytometry (P < 0.05) and RT-PCR (P < 0.05). CONCLUSION: The expression of HCMV IE1 can be effectively suppressed by RNA interference technique in vitro, which provides experimental data for prevention and treatment of HCMV infection. PMID- 20855255 TI - [Primary culture of rat hippocampal neurons and detection of the neuronal excitability]. AB - OBJECTIVE: To improve the efficiency of primary culture of hippocampal neurons and obtain highly purified neurons with good in vitro growth and minimal risk of contamination. METHODS: The hippocampal neurons of neonatal Wistar rats were isolated and the single cell suspension was prepared by mechanical trituration and sedimentation in stead of trypsin digestion and filteration. Twenty-four hours after the cell plating, the culture medium was removed and replaced by serum-free DMEM/F12 with B27 supplementation. Half of the culture medium was changed 2-3 times every week. The morphological changes of the neurons were observed under inverted phase-contrast microscope. Immunofluorescence staining for NSE was performed to identify the neurons, and the purity of neurons was calculated. The hippocampal neurons were stained with calcium-sensitive fluorescent dye to monitor the effect of KCl on neuronal excitability by a calcium imaging system. RESULTS AND CONCLUSION: This simplified method is time saving and cost-effective for primary culture of hippocampal neurons with reduced risk of contamination, and the neurons obtained showed high uniformity, purity and long-term viability. PMID- 20855256 TI - [Analysis of the clinical indications of asthma control test]. AB - OBJECTIVE: To investigate the clinical indications of asthma control test (ACT). METHODS: A total of 120 asthmatic patients with a diagnosis in line with the American Thoracic Society criteria and treated for over a month were enrolled in this study. The patients were asked to complete a survey to assess their symptoms and asthma attacks, and ACT evaluation was conducted by physicians familiar with ACT evaluation. The patients were classified into two groups based on the pulmonary function test (positive for bronchodilator test and provocation test) or based on disease severity (mild and moderate-to-severe asthma groups). The effect of ACT evaluation was graded as good (no less than 4 item available for evaluation), fair (2-3 items available) and poor (no more than 1 item). To further analyze the ACT sensitivity in relation to different disease severity, 29 asthmatic patients with an initial diagnosis and BDT positivity were included, and the ACT score of the patients with mild, moderate and severe asthma based on FEV1% were compared. RESULTS: In patients positive for bronchodilator test, good, fair and poor evaluation effects were found in 48, 15, and 5 cases, as compared to 10, 15, and 27 in those positive for provocation test, respectively, showing significant differences between the two groups (P < 0.001). In mild asthma group, good, fair and poor evaluation effects were found in 12, 15, and 18 cases, respectively, significantly different from those in moderate-to- severe asthma group (50, 21, and 4 cases, P < 0.001). ACT scores showed a positive correlation to FEV1% in 29 patients with positive BDT (r = 0.55, P = 0.003). ACT scores had no significant difference between mild and moderate asthma groups (P > 0.05), but showed significant differences between mild and severe groups (P = 0.009) and between moderate and severe groups (P = 0.008). CONCLUSION: ACT is more suitable for evaluating patients positive for bronchodilator test or with moderate to severe asthma. PMID- 20855257 TI - [Potential distribution of electrocardiac field around chick embryonic heart]. AB - OBJECTIVE: To explore the essential features of the potential distribution of electrocardiac field. METHODS: The ECGs of 60 hearts of 5-day chick embryos were immersed in normal saline solution or distilled water and their different conductivities were recorded at 5 points at different distances in 4 directions perpendicular to each other. Comparison of the form and amplitude of ECGs was made between every two points with the same distance to the heart in 2 opposite directions to determine the potential distribution of the electrocardiac field of the one-chambered heart. RESULTS: The ECGs recorded at every 2 points in 2 opposite directions with the same distance to the heart immersed in the same liquid medium were both upper standing, with no significant different between their amplitude of R(r) wave (P > 0.05). CONCLUSION: The uniform outward potential distribution of the electrocardiac field might not represent the form of depolarization but that of sphere-like and single-source when the influence of different reference points and thickness of different chamber walls upon mapping of body surface is excluded. PMID- 20855258 TI - [Evaluation of quality of life after simultaneous pancreas-kidney transplantation]. AB - OBJECTIVE: To evaluate the influence of simultaneous pancreas-kidney (SPK) transplantation on the quality of life of diabetic recipients with end-stage renal disease. METHODS: We performed a retrospective analysis of the data of diabetic patients with end-stage renal disease and evaluated the quality of life of the recipients using SF-36 health survey. RESULTS: One patient died of cerebrovascular accident, and 7 patients recovered smoothly. During the follow-up lasting for a mean of 23.3 months, the blood glucose, C-peptide and creatine levels of the patients remained stable. The score of 8 domains of SF-36 of the diabetic recipient at 2 years after SPK transplantation showed a significant improvement compared with that before the operation, similar to that of Chinese normal population(P > 0.05). CONCLUSIONS: SPK transplantation can achieve a significant improvement of the quality of life of diabetic patients with end stage renal disease. PMID- 20855259 TI - [Construction and identification of siRNA recombinant expression vector targeting parathyroid hormone 1 receptor gene and its effect on the cell cycle of INS-1 cells]. AB - OBJECTIVE: To construct the expression vector of siRNA targeting parathyroid hormone 1 receptor (PTH1R) gene and evaluate its effect on the cell cycle of INS 1 cells. METHODS: The sequences of PTH1R gene was retrieved from Genbank, and 4 pairs of oligonucleotides were synthesized and inserted into pSUPERretro RNAi, which was identified by RT-PCR and sequence analysis. The vectors were then transfected into INS-1 cells, in which the expression of PTH1R was observed by Western blotting to evaluate the transfection efficiency. The cell cycle of INS-1 cells in high glucose medium was detected by flow cytometry. RESULTS: RT-PCR and sequence analysis confirmed the correct construction of the siRNA recombinant expression vector targeting PTH1R gene. The vectors were successfully transfected into INS-1 cells, and the most effective vector was selected by Western blotting. Transfection with the siRNA for PTH1R gene silencing resulted in the inhibition of INS-1 form entering the S phase. CONCLUSION: The successful construction of the recombinant PTH1R-siRNA vectors establishes a basis for further study of protective role of the PTH1R gene in INS-1 cells in high glucose medium. PMID- 20855260 TI - [Flow cytometric analysis for detecting mitochondrial permeability transition pore opening]. AB - OBJECTIVE: To introduce a new method for detecting mitochondrial permeability transition pore (PTP) opening with flow cytometry using the resveratrol-inducing PTP opening model. METHODS: Mitochondria were isolated from rat livers and selectively labeled with nonyl acridine orange. The mitochondrial membrane potential was detected using flow cytometry with TMRE (tetramethylrhodamine, ethyl ester) labeling. PTP opening induced by resveratrol was represented by the changes of mitochondrial side-scattering (SSC) detected by flow cytometry. RESULTS: Flow cytometry was capable of defining the purity of the mitochondria isolated. The fluorescence intensities and SSC of the mitochondria were decreased after resveratrol treatment, indicating that resveratrol could induce PTP opening. Ciclosporin A inhibited resveratrol-induced PTP opening. CONCLUSION: Flow cytometric analysis allows accurate and convenient detection of mitochondrial membrane potential, mitochondrial swelling and PTP opening. PMID- 20855261 TI - [Hemocompatibility evaluation in vitro of small-caliber expanded polytetrafluoroethylene vessel with silk fibroin coating sulfonated by low temperature plasma]. AB - OBJECTIVE: To evaluate the hemocompatibility of a small-caliber expanded polytetrafluoroethylene vessel with silk fibroin coating sulfonated by low temperature plasma treatment. METHODS: The composite blood vessel was prepared by first coating the small-caliber expanded polytetrafluoroethylene vessel with silk fibroin followed by sulfonation by low temperature plasma treatment. After hemolysis test in vitro, dynamic coagulation time test, blood platelet adhesion test, and recalcification time test were performed to evaluate the hemocompatibility of the composite blood vessel. RESULTS: Scanning electronic microscopy revealed obvious platelets adhesion on the conventional artificial (control) vessel, which seldom occurred on the composite vessel. The curve of absorbance-clotting time of the composite vessel declined more slowly than that of the control vessel. The recalcification time of the composite blood vessel averaged 603 s, significantly longer than that of the control vessel (480 s, P = 0.000). CONCLUSION: The composite blood vessel has good antithrombotic activity and hemocompatibility as a promising vascular prosthesis. PMID- 20855263 TI - [Correlation of ornidazole concentration in saliva and serum of healthy volunteers]. AB - OBJECTIVE: To investigate the distribution of ornidazole in the salivary and serum of healthy adults and explore the feasibility of monitoring serum drug concentration with salivary. METHODS: Six volunteers received a single dose of 0.6 g ornidazole via intravenous infusion. The concentrations of ornidazole in the saliva and serum were assayed by high-performance liquid chomatography, and the correlation of the drug concentrations in saliva to that in serum was analyzed. RESULTS: The concentration of ornidazole in the saliva was strongly associated with that in the serum (r = 0.825-0.969), and the ratio of saliva-to serum concentration (S/P) of ornidazole was 0.99 +/- 0.13. CONCLUSION: Detection of saliva ornidazole concentration is feasible for monitoring the therapeutic concentration of ornidazole. PMID- 20855262 TI - [Butylphthalide improves learning and memory abilities of rats with Alzheimer's disease possibly by enhancing protein disulfide isomerase and inhibiting P53 expressions]. AB - OBJECTIVE: To determine the effect of butylphthalide on the expressions of protein disulfide isomerase (PDI) and P53 in the brain tissue of rats with Alzheimer's disease (AD). METHODS: Sixty male adult rats were randomly divided into AD model group, butylphthalide group and control group (n = 20). AD models were established by injecting beta-amyloid protein 1-42 into the hippocampus of rats. Sixty days later, the learning and memory abilities of the rats were evaluated using Y-maze test, and the expressions of PDI and P53 in the brain tissue of the rats were measured by immunohistochemistry. RESULTS: Compared with the control group, the rats in AD model group exhibited significantly reduced learning and memory abilities, lowered expressions of PDI in the hippocampus and increased expression of P53 in the cortex (P > 0.01). In comparison with the model group, the rats in the butylphthalide group showed significantly increased PDI-positive cells in the hippocampus and decreased expression of P53 in the cortex (P < 0.01). CONCLUSION: Butylphthalide improves the learning and memory abilities of rats with experimental AD, the mechanism of which may involve inhibition of P53 expression and enhancement of PDI expression in the brain tissues. PMID- 20855264 TI - [Role of renal sympathetic nerves in renal sodium transport in ouabain hypertensive rats]. AB - OBJECTIVE: To investigate the role of renal sympathetic nerves in renal sodium transport in ouabain-hypertensive rats (OHR). METHODS: Sixteen male SD rats with sham renal denervation (Sham-RDNX) and 16 with renal denervation (RDNX) were randomly into normal control group and ouabain group to receive intraperitoneal injection of normal saline (1 ml/kg) and ouabain (27.8 ug/kg) once a day, respectively. Systolic blood pressure (SBP), heart rate and body weight were recorded weekly. Food consumption of the rats was determined twice a week. After a 4-week treatment, blood and 24 h urine samples were collected to measure the serum and urinary concentration of sodium, trace lithium and creatinine. Endogenous creatinine clearance rate (Ccr), fractional excretions of sodium (FENa), fractional excretions of lithium (FELi) and fractional reabsorption of sodium in the postproximal tubules (FDRNa) were calculated. Plasma renin activity was determined by radioimmunoassay. Norepinephrine was extracted from the renal tissue and assayed for norepinephrine content by HPLC. RESULTS: The body weight, food intake and heart rate showed no significant difference among the 4 groups (P > 0.05). After 4 weeks, the SBP of control RDNX group (CDNX) was significantly lower than that of the control Sham-DNX group (Csham)(P < 0.05); the SBP of ouabain RDNX group (ODNX) was also significantly lower than that of ouabain Sham DNX group (Osham) (P < 0.05); RNDX lowered SBP by about 10 mmHg in both ouabain groups and control groups. The SBP was significantly higher in Osham and ODNX groups than in the corresponding control groups (P < 0.01), also significantly higher in ODNX group than in Csham group (P < 0.01). Ccr showed no significant difference among the 4 groups(P > 0.05). FENa, FELi and FDRNa were significantly lower in ouabain groups than in the corresponding control groups (P < 0.05, P < 0.01, P < 0.05), but FENa, FELi and FDRNa of ODNX group were similar with those of Osham group (P > 0.05); FENa , FELi and FDRNa were similar between CDNX and Csham groups (P > 0.05). The plasma renin activity was comparable between the 4 groups (P > 0.05). Renal norepinephrine level was markedly reduced in RDNX group compared with that in Sham-RDNX group in both ouabain and control groups (P < 0.01). CONCLUSION: The increase of proximal tubule sodium reabsorption in OHR is not dependent on the renal sympathetic nerve. PMID- 20855265 TI - [Effect of tanshinone IIA pretreatment on IL-1beta and RelA mRNA expression in rats with focal cerebral ischemia]. AB - OBJECTIVE: To observe the effect of tanshinone IIA (TS IIA) pretreatment on the expression of the inflammatory factor IL-1beta and RelA mRNA in rats with focal cerebral ischemia. METHODS: A total of 100 adult male SD rats were randomly divided into 6 groups, namely the model, ischemic preconditioning (IPC), TSIIA preconditioning, TSIIA treatment, sham-operated, and blank control groups. In the former 4 groups, rat models of focal cerebral ischemia were established with corresponding treatments. The expressions of IL-1beta and RelA mRNA in each group were detected using RT-PCR. RESULTS: All the groups showed expressions of IL 1beta and RelA mRNA with the exception of the blank control group. Compared to the model group, TSIIA preconditioning group, TSIIA treatment group, and IPC group all had significantly reduced expression of IL-1beta and RelA mRNA (P < 0.05). The expressions were lower in IPC group than in TSIIA preconditioning group and TSIIA treatment group(P < 0.05), and no significant difference was found in the expressions between the latter two groups. CONCLUSION: The protective effect of pretreatment with TS IIA against cerebral ischemia is related to the reduction of IL-1beta and RelA mRNA expressions. PMID- 20855266 TI - [Glucagon-like peptide-1 protects INS-1 cells from interleukin-1beta-induced damage by inhibiting the nuclear factor-kappaB pathway.]. AB - OBJECTIVE: To observe the effect of glucagon-like peptide-1 (GLP-1) on interleukin-1beta (IL-1beta)-induced damage in INS-1 cells and explore its possible mechanisms. METHODS: INS-1 cells were divided into normal control group, IL-1beta group, and GLP-1+IL-1beta group with corresponding treatments. The cell viability was determined by MTT assay, the expression of IKKbeta mRNA was detected by real-time PCR, and that of the protein p65 was detected by Western blotting. RESULTS: In comparison with the normal control group, the cells in the IL-1beta group showed a significantly decreased viability by 29% (P < 0.01); compared with those in IL-1beta group, the cells in GLP-1+IL-1beta group exhibited an significant increase in the cell viability by 30% (P < 0.01). In comparison with the normal control group, the cells in IL-1beta group showed an significantly increased expression of IKKbeta mRNA (1.967 +/- 0.091 vs 1 +/- 0, P < 0.05); GLP-1 significantly reduced IL-1beta-induced increment of IKKbeta mRNA expression to 1.287 +/- 0.084 (P < 0.05). IL-1beta treatment significantly increased NF-kappaB protein expression as compared to the control level (0.814 +/ 0.111 vs 0.396 +/- 0.026, P < 0.01), and GLP-1 significantly inhibited such effect (0.622 +/- 0.059, P < 0.05). CONCLUSIONS: GLP-1 inhibits IL-1beta-induced beta-cell damage probably by inhibiting the NF-kappaB pathway. PMID- 20855267 TI - [Epidemiological investigation of diabetes and prediabetes in community residents in the suburbs of Guangzhou]. AB - OBJECTIVE: To identify the prevalence and risk factors of diabetes and prediabetes in the community residents above 18 years old in the suburbs of Guangzhou. METHODS: Between April and May in 2008, the residents above 18 years living in 6 communities of Guangzhou for 5 or more years were sampled with multistage clustering sampling. The sampled residents were surveyed by questionnaires, and physical examination and glucose determination were carried out. RESULTS: A total of 1532 residents were sampled. The incidence of diabetes mellitus in these community residents was 8.46%, and that of impaired glucose regulation was 6.59%. Age, body mass index, family history of diabetes mellitus, case history of hypertension, hyperlipidemia, hypertension and smoking were all the independent risk factors for impaired glucose regulation and diabetes mellitus. CONCLUSION: Diabetes and prediabetes are prevalent in the community residents in Guangzhou. Controlling the risk factors such as obesity, hypertension, lipid metabolism disorder among the residents above 40 years with a family history of diabetes mellitus and hypertension is key to prevention of impaired glucose regulation and diabetes mellitus. PMID- 20855268 TI - [Clinical value of dual-source CT in evaluating coronary artery disease]. AB - OBJECTIVE: To analyze the clinical value of dual-source CT (DSCT) in the diagnosis of coronary artery disease. METHODS: Fifty-five patients with suspected coronary heart disease underwent both DSCT coronary angiography (DSCTCA) and selective coronary angiography (CAG) examination, and the diagnostic sensitivity, specificity and accuracy of the DSCTCA was evaluated. RESULTS: The sensitivity, specificity, positive and negative predictive value, and accuracy of DSCT in the diagnosis of coronary heart disease were 97.7%, 72.6%, 93.5%, 88.9% and 92.7% by the number of patients, respectively; by calculating the coronary arteries, the sensitivity, specificity, positive and negative predictive value, accuracy were 94.9%, 95.8%, 92.5%, 97.1%, 95.5%, respectively. According to the lesion segment, these values were 88.2%, 96.9%, 90.5%, 96.1%, 94.7%, respectively. DSCTCA showed no significant difference from CAG for a diagnostic purpose, nor did their vessel sensitivity, specificity, positive and negative predictive value, and accuracy in different coronaries differ significantly. CONCLUSION: DSCT has a diagnostic accuracy of coronary heart disease close to that CAG and can on some occasion serve as an alternative to CAG in the screening of coronary artery disease. PMID- 20855269 TI - [Comparison of the clinicopathological characteristics of colorectal cancer between elderly and young patients]. AB - OBJECTIVE: To compare the clinicopathological characteristics between elderly and young patients with colorectal cancer (CRC). METHODS: A total of 727 patients with CRC treated between Jan 2003 and Dec 2005 were divided into elderly group (>= 60 years old), middle-aged group (36-59 years old), and young group (<= 35 years old). The clinicopathological characteristics of the 3 groups were analyzed retrospectively. RESULTS: The tumor occurred mainly in the rectum, sigmoid colon and ascending colon of the patients. The major initial symptoms included hemafecia and changes in bowel habits in the elderly and middle-aged cases, as compared to abdominal pain and hemafecia in the young group. The elderly patients had greater ratio of well differentiated neoplasm than the middle-aged and young patients. The ratio of radical operation was markedly higher in the elderly and middle-aged group than in the young group. The elderly patients were more likely to have stage II and III tumors than the middle-aged and young patients, having also significantly higher incidences of such complications as heart and lung diseases upon diagnosis. CONCLUSIONS: Compared with the middle-aged and young patients, elderly patients with CRC are more likely to have well differentiated tumor, multiple complications upon diagnosis, and higher radical operation rate. PMID- 20855271 TI - [Computer-assisted screening system for individualized treatment of type 2 diabetes mellitus]. AB - OBJECTIVE: To establish a computer-assisted screening system for individualized treatment of type 2 diabetes mellitus. METHODS: The clinical data of the diabetic patients were retrospectively analyzed, and the regression equation for the affecting factors and therapeutic effect was established. With computer-aided programming, a computer-assisted screening system was established. RESULTS: A computer-assisted screening system for individualized treatment type 2 diabetes was established, which showed a concordance rate was 98% in clinical verification. CONCLUSION: Using epidemiological methods and assistance by computer technique, a computer-assisted screening system for individualized prescription can be established for selecting therapeutic regimen for type 2 diabetes. PMID- 20855270 TI - [ERCC1 expression and outcomes of neo-adjuvant chemotherapy in elderly patients with non-small cell lung cancer]. AB - OBJECTIVE: To study the association of positive expression of nucleotide excision repair cross complementary group 1 (ERCC1) in the tumor tissues with platinum resistance of the tumor cells and the clinical outcomes of neo-adjuvant chemotherapy in elderly patients with non-small cell lung cancer (NSCLC). METHODS: ERCC1 expression was detected immunohistochemically in the tumor tissues from 113 elderly patients with NSCLC, of which 58 patients received platinum containing neo-adjuvant chemotherapy, and the impact of ERCC1 expression on the outcomes of neo-adjuvant chemotherapy was analyzed. RESULTS: The total positivity rate of ERCC1 expression was 35% in these patients. The positivity rates was significantly higher in the patients receiving neo-adjuvant chemotherapy than in the control group (46.7% vs 21.05%, chi2 = 3.770, P = 0.048). In the 39 patients positive for ERCC1, the response rate to treatment was 53.85%, as compared to the rate of 51.35% in the 74 ERCC1-negative patients. After neoadjuvant chemotherapy, the median survival time (MST) was 53 months in ERCC1-negative patients, as compared to 37 months in the positive patients. The ERCC1-negative and ERCC1 postivie patients showed similar 3- and 5-year survival rates (48.3% vs 44.4%, chi2 = 0.033, P = 0.856; 22.5% vs 18.5%, chi2 = 0.096, P = 0.757). Multivariate COX regression analysis showed that ERCC1 expression level in the tumor tissue and TNM stages were independent factors that affected the prognosis of the patients (P < 0.05). CONCLUSION: Neoadjuvant chemotherapy can induce ERCC1 expression in the tumor, and the objective response rate of neoadjuant chemotherapy can be low in NSCLC patients with high ERCC1 expression. ERCC1 expression is an independent factor affecting the prognosis of elderly patients with NSCLC receiving neoadjuant chemotherapy. PMID- 20855272 TI - [Relationship between apnea and hyperbilirubinemia in premature infants]. AB - OBJECTIVE: To explore the association between hyperbilirubinemia and apnea in premature infants. METHODS: Premature infants with apnea and birth weight >1500 g were tested for the heart rate, serum level of bilirubin, saturation of blood oxygen (SO2) and partial pressure of oxygen (PO2) before and after treatment, with term infants serving as the control. A comparative analyses of the serum level of bilirubin, SO2 and PO2 were carried out in the premature infants with birth weight <1500 g suffering apneic syndrome or not on the first and third days after birth. RESULTS: Of the premature and term infants with apnea and birth weight <1500 g, 92.5% and 70.00% showed increased serum level of indirect bilirubin (IBIL), respectively. The infants with birth weight <1500 g who presented the syndrome of apnea on the first day after birth had significantly higher levels of IBIL than those without an apparent syndrome of apnea. A three day conventional therapy resulted in an obvious improvement of apneic syndrome and lowered bilirubin level. CONCLUSION: Increased bilirubin level can be one of the reasons for the development of apnea in premature infants, and therapies for reducing bilirubin level can ameliorate the syndrome of apnea. PMID- 20855273 TI - [Correlation of D-amino acid-oxidase gene polymorphism to schizophrenia]. AB - OBJECTIVE: To investigate the genetic association between schizophrenia and polymorphism of D-amino acid-oxidase (DAAO) gene. METHODS: A total of 112 parent/offspring trios in which the proband met the Amerecan Classification and Diagnostic Criteria for Mental Disorders (Fourth Revised Edition) were included in this study. Correlation analysis between schizophrenia and DAAO gene polymorphism and haplotype relative risk analysis were conducetd by using PCR and SNP typing in all the nuclear families. RESULTS: The rs3918347 allele was correlated to schizophrenia (P = 0.014). Allele A was a protective factor (Z = 2.37) and allele G the hazard factor (Z = 2.37). The frequency of rs3918347 allele A was 0.41 and that of the allele G was 0.59. The rs3741775, rs3825251 and rs4964770 alleles were not associated with schizophrenia. Three haplotypes of C/G in the rs3825251-rs3918347, G/T in the rs3918347-rs4964770, C/G/T in the rs3825251-rs3918347-rs4964770 were associated with schizophrenia (P = 0.021, 0.036, and 0.028, with genotype frequencies of 0.33, 0.28, and 0.15, respectively). CONCLUSION: The nucleotide polymorphism of DAAO gene is associated with schizophrenia in Chinese population. PMID- 20855274 TI - [Construction of the digital models of masseter and temporal muscles with three dimensional laser scanning]. AB - OBJECTIVE: To explore a new method for establishing digital models of the masseter and temporal muscles and superficial soft tissue using three-dimensional laser scanning technique. METHODS: One adult male cadaveric head without malformation was dissected to expose the superficial portion of the masseter and temporalis. Multiple aspects of the sample were scanned with three-dimensional laser scanning system, and the point clouds of the masseter and temporal muscles were generated. The specimen was scanned again after the masseter and temporal muscles had been removed. The digital model of the muscles was reconstructed with the point clouds using Geomagic software, and the morphology of the muscle model was observed and measured. RESULTS: The 3-D digital models of the masseter and temporal muscles with the anatomical characteristics were reconstructed based on the point clouds using Geomagic 8.0 software. CONCLUSION: The digital model of the muscles can vividly demonstrate the muscle contours, which provides a basis for morphological study and biomechanical analysis of the muscles. PMID- 20855275 TI - [Value of detecting p16 gene methylation in the diagnosis of malignant pleural effusion]. AB - OBJECTIVE: To investigate aberrant methylation in the promoter of p16 gene in the sediment cells of pleural effusion and evaluate its clinical significance in the differentiating benign and malignant pleural effusion. METHODS: Using methylation specific PCR (MSP), aberrant promoter methylation of p16 gene was detected in the sedimental cells of pleural effusion samples from 66 patients with pleural effusion. RESULTS: Of the 66 patients with pleural effusion, 36 had a definite diagnosis of malignant pleural effusion, and the rest were confirmed to have benign pleural effusion. The positivity rate of p16 gene promoter methylation was 69.4% (25/36) in malignant pleural effusion and 13.3% (4/30) in benign pleural effusion specimens, showing a significant difference between them (chi2 = 20.915, P < 0.01). The diagnostic sensitivity, specificity and accuracy of aberrant promoter methylation of p16 gene in the 36 malignant cases were 69.4%, 86.7% and 77.3%, respectively. The positive expression of p16 gene promoter methylation in malignant pleural effusion was not correlated to the histological type or the pathological grade of the tumor (P > 0.05). CONCLUSION: Detection of aberrant methylation in p16 gene promoter in the sediment cells of pleural effusion specimens by MSP method allows differentiation between benign and malignant pleural effusion. PMID- 20855276 TI - [Effect of different approaches to transplanting bone marrow stromal stem cells into the allogenic rat liver]. AB - OBJECTIVE: To compare the effect of different approaches of bone marrow stromal stem cell (BMSCs) transplantation into the allogenic rat liver. METHODS: Thirty male SD rats were randomized equally into local liver group, portal vein group, and femoral vein group, and received injection of 1*106/ml BMSCs directly into the rat liver, through the portal vein and through the femoral vein, respectively. The rat livers were scanned by magnetic resonance imaging (MRI) at 12 h and 1, 3, 5, 7, 14 days after the cell transplantation. Prussian blue staining of the rat liver sections was also performed 14 days after the transplantation. RESULTS: MRI showed decreased signal intensity in all the rat livers of the local liver group; the ovoid area of the signal intensity gradually shrunk and the signal intensity increased with the passage of time. Lowered signal intensity was also seen in the rat livers of the portal vein group, appearing constantly branch-shaped, indistinct and increased gradually. Decreased signal intensity did not occur in the livers of femoral vein group. Prussian blue staining of all the rat livers at day 14 showed the presence of cells containing blue particles in all the groups, most numerous in the local liver group followed by the portal vein group and then the femoral vein group. CONCLUSION: Direct intrahepatic injection of the BMSCs results in better effect than cell transplantation via the portal vein or the femoral vein. PMID- 20855277 TI - [Toxicity of matrine in Kunming mice]. AB - OBJECTIVE: To investigate the acute toxicity and assess the median lethal dose (LD50) of matrine in Kunming mice. METHODS: Matrine at different doses were administered in Kunming mice via intraperitoneal injection, and the toxic reactions and LD50 of matrine was observed and determined. RESULTS: The acute toxicity test of matrine indicated that the tolerable dose of matrine was above 80 mg/kg in Kunming mice, and the LD50 was 157.13 mg/kg (95%CI, 88.08-280.31 mg/kg). Morphological observation revealed degenerative changes of the nerve cells in the brain tissue of the mice. CONCLUSION: The nervous system is the main target organ by the toxicity of matrine. PMID- 20855278 TI - [Real-time volume rendering based on gradient adaptive shading]. AB - For medical image volume rendering, it is very difficult to simultaneously visualize interior and exterior structures while preserving clear shape cues. Highly transparent transfer functions produce cluttered images with many overlapping structures, while clipping techniques completely remove possibly important contextual information. To address this issue, A gradient adaptive shading based illumination model is proposed and implemented in CUDA architecture. The coefficients of ambient, diffuse and specular lighting are tuned adaptively according to gradient. The experiments show that our method is capable of preserving 3-D contextual information in medical image dataset while still show clear boundaries with real-time interactive speed. PMID- 20855279 TI - [Analgesic effect of Corydalis yanhusuo in a rat model of trigeminal neuropathic pain]. AB - OBJECTIVE: To evaluate the analgesic effect of Corydalis yanhusuo on trigeminal neuropathic pain.in a rat model. METHOD: Rat model of trigeminal neuralgia pain were established by inducing chronic constriction injury (CCI) of the infraorbital branch of the trigeminal nerve (ION). The effect of Corydalis yanhusuo, a traditional Chinese medicine, in ameliorating the pain was tested. Western blotting was performed to investigate the change of cannabinoid CB1 receptors in the Vc the injury of the infraorbital branch of the trigeminal nerve (ION-CCI). CB1 receptor antagonist AM 251 was applied to observe its effect on the analgesic effect of Yanhusuo. RESULT: Administration of dl-THP (2 mg/kg) intraperitoneally increased the response threshold and the cut-off threshold to the mechanical stimulation in ION-CCI rat models. ION-CCI induced an upregulation of cannabinoid CB1 receptors within the ipsilateral of Vc. The effect of Yanhusuo was antagonized by the application of AM 251. CONCLUSION: The analgesic effect of Yanhusuo involves the participation of CB1 receptors, suggesting that Yanhusuo may offer a useful therapeutic approach for trigeminal neuropathic pain. PMID- 20855280 TI - [Effects of neurotrophin 3 on interdigestive migrating motor complex in rats with acute liver injury.]. AB - OBJECTIVE: To observe the effects of neurotrophin 3(NT-3)on interdigestive migrating motor complex (MMC) in rats with D-galactosamine induced acute liver injury. METHODS: Twenty-four specific pathogen-free purebred rats were equally randomized into control and acute liver injury groups. The control group was injected with equal volume of normal saline via tail vein. Acute liver injury model of the rats was induced by D-galactosamine injection via the tail vein in the acute liver injury group. And the indexes of interdigestive MMC before and after NT-3 injection were recorded by a polygraph and analyzed in model group. The serum NT-3 concentration was assayed in the two groups. RESULTS: There were no significant changes of gastrointestinal MMC cycle and jejunal phase I MMC after NT-3 injection. Compared with the acute liver injury rats before NT-3 injection , the antral phases I, III and IV MMC were significantly prolonged [(577.44 +/- 248.60)s vs (343.58 +/- 227.30) s, (80.94 +/- 21.15) s vs (24.76 +/- 7.41) s, (405.69 +/- 131.34) s vs (191.67 +/- 128.15) s, P < 0.05] and the phase II MMC was shortened [ (883.94 +/- 488.50) s vs (1519.00 +/- 831.14) s, P < 0.05] in the acute liver injury group. The duodenal phases I, III and IV MMC were significantly prolonged [ (557.63 +/- 335.14) s vs (309.46 +/- 220.22) s,(75.91 +/- 15.75) s vs (31.15 +/- 13.67) s, (423.38 +/- 135.22) s vs (209.77 +/- 123.83) s, P < 0.05] and MMC II phase was shortened [ (748.81 +/- 579.69) s vs (1535.86 +/- 930.50) s, P < 0.05] in the acute liver injury rats. In addition, the jejunal MMC III and MMC IV phase was significantly prolonged [ (86.58 +/- 23.40) s vs (31.41 +/- 16.09) s,(385.18 +/- 110.02) s vs (220.59 +/- 159.30) s, P < 0.05] and phase II MMC was shortened [ (876.89 +/- 652.01) s vs (1870.89 +/- 1010.35) s, P < 0.05 ] in the acute liver injury rats. The serum NT-3 level was significantly higher in model group than in control group. CONCLUSION: NT-3 could enhance the gastrointestinal motility in acute liver injury rats. PMID- 20855281 TI - [Clinical assessment of Tpeak-end interval for prediction of myocardial infarction]. AB - OBJECTIVE: To assess the value of Tpeak-end interval (Tpe) in predicting myocardial infarction (MI). METHODS: Tpe and Tpeak-end internal after correcting the heart rate (TpeRR) were measured and analyzed in 234 MI patients, who were followed-up for an average of 32 +/- 10 months. RESULTS: Clinical events occurred in 45 (19.2%) patients at the end TpeRR of the follow-up. Tpe and of the patients with clinical events were significantly higher than those in patients without the clinical events (P < 0.001). The incidence of clinical events in patients with Tpe > 140 ms were significantly higher than that in patients with Tpe <= 140 ms by Kaplan-Meier analysis (P < 0.001). With clinical event as the end point, the proportional hazards rate was 2.48 in univariate COX analysis (P < 0.01). After controlling for risk factors, the hazards rate was 2.66 by multvariate COX regression (P < 0.01). CONCLUSION: Tpe is positively correlated to the prognosis of MI and serves as an new index for predicting the clinical events in MI patients. PMID- 20855282 TI - [Response to metoprolol succinate sustained-release tablets in correlation to pulse pressure, serum vascular endothelial growth factor and C-reactive protein in elderly hypertensive patients with chronic heart failure]. AB - OBJECTIVE: To investigate the effect of metoprolol succinate sustained-release tablets on cardiac function, serum vascular endothelial growth factor (VEGF) and C-reactive protein (CRP) in elderly hypertensive patients and its relation with pulse pressure (PP). METHODS: A total of 330 elderly hypertensive patients with chronic heart failure receiving basic therapy were included. Before initiation and 3 months after the maximal tolerated dose of metoprolol succinate sustained release tablets, the parameters of blood pressure, clinical features, radionuclide ventriculographic and laboratory findings of the patients were analyzed. RESULTS: As the PP was elevated, the serum levels of VEGF, hs-CRP and BNP increased and the cardiac systolic and diastolic functions decreased. In patients with PP of 59-68 mmHg and > 68 mmHg, 3 months of treatment with the tablets caused significantly increased LVEF by (3.32 +/- 2.35)% and (4.12 +/- 3.05)% and LVPER by 0.37 +/- 0.26 and 0.53 +/- 0.37, respectively; PP were decreased by 8.2 +/- 3.1 mmHg and 9.4 +/- 4.3 mmHg and VEGF by 18.39 +/- 8.43 pg/ml and 26.79 +/- 14.32 pg/ml, respectively. The treatment also resulted in lowered hs-CRP and BNP in these patients by 0.26 +/- 0.13 mg/L and 0.33 +/- 0.16 mg/L and by 140.36 +/- 68.62 ng/L and 155.39 +/- 73.58 ng/L, respectively. CONCLUSION: Obvious elevation of PP is associated with a better response to metoprolol succinate sustained-release tablets in elderly hypertensive patients with chronic heart failure, and 3 months of treatment with the tablets can significantly improve the cardiac function and lower the levels of VEGF, hs-CRP and BNP in these patients. PMID- 20855283 TI - [Comparative study of primordial germ cells in male and female mouse embryos]. AB - OBJECTIVE: To investigate the differences in the development of primordial germ cells (PGCs) between male and female mouse embryos. METHODS: The morphological changes of genital ridge development were detected in C57BL/6J mouse embryos of 11-13.5 days, and the changes of PGCs quantity and proliferation were compared between the male and female embryos using immunofluorescence histochemistry. RESULTS: The PGCs was the most numerous at 13.5 days in male and female embryos, and the quantity of proliferating PGCs reached the maximum at 13 days. The quantity of PGCs and proliferating PGCs in male embryos at 13 days was significantly larger than that in female embryos. CONCLUSION: The development of PGCs is characterized by a gender differences in early development of mouse embryos (11-13.5 days). PMID- 20855284 TI - [Effect of Bufeishenqingre decoction on bronchial hyperresponsiveness-induced cough]. AB - OBJECTIVE: To evaluate the effect of traditional Chinese medicine preparations on bronchial hyperesponsiness (BHR)-induced cough. METHOD: Sixty patients with cough due to BHR (shown by positive bronchial provocation test) were randomly divided into Chinese medicine group (n = 30) and control group (n = 30) to receive Bufeishenqingre decoction twice a day and 100 mg theophylline sustained-release capsules twice a day for one month, respectively. The changes of the clinical symptoms were observed during the treatment and bronchial infrared imaging was performed before and after the treatment. RESULTS: The symptoms of patients in the Chinese medicine group were more effectively alleviated than those of the control group (P < 0.05). The difference in the temperature between the bronchial lesions and the surrounding normal mucosa changed more obviously in the Chinese medicine group (P < 0.01). CONCLUSION: Bufeishenqingre decoction can relieve the symptoms and improve the abnormalities in infrared imaging of patients with BHR induced cough. PMID- 20855285 TI - [Therapeutic effect of ossicular reconstruction with bioceramic or porous macromolecular polyethylene partial ossicular replacement prosthesis in patients with tympanosclerosis]. AB - OBJECTIVE: To evaluate the effect of ossicular reconstruction with partial ossicular replacement prosthesis (PORP) in patients with tympanosclerosis. METHODS: The data of 31 cases of tympanosclerosis treated between 1992 and 2009 were reviewed. Of the 31 patients, 17 (17 ears) underwent ossicular reconstruction with porous macromolecular polyethylene PORP, and 14 (14 ears) with bioceramic PORP. All the patients were followed up for 3-24 months. RESULTS: Significant improvement was found in postoperative speech frequency (500, 1000, 2000 Hz) pure tone average (PTA) and air-bone gap (ABG) (P < 0.05) after the treatments without statistically significant differences between the two groups (P > 0.05). CONCLUSION: Porous macromolecular polyethylene and bioceramic are valuable ossicular prosthesis for tympanosclerosis. PMID- 20855286 TI - Allergic reaction to Croscarmellose sodium used as excipient of a generic drug. PMID- 20855287 TI - Thyroid hormone resistance in identical twins. PMID- 20855288 TI - Adolescent predictors of emerging adulthood milestones in youth with spina bifida. AB - OBJECTIVE: To examine the predictive utility of demographic (illness status and SES), individual (neurocognitive functioning and intrinsic motivation), and family-based (parental intrusiveness) factors during adolescence on the achievement of emerging adulthood milestones in youth with and without spina bifida (SB). METHODS: Questionnaire and observational data were collected from 14/15-year-old adolescents with SB, typically developing peers, mothers, and teachers. Emerging adulthood milestones (i.e., leaving home, attending college, employment, romantic relationship experience, and number of friendships) were assessed at ages 18/19 years in the full sample and subset of youth who graduated from high school. RESULTS: Typically, developing youth were more likely to achieve milestones compared to youth with SB in the full sample but not when only high school graduates were compared. Executive function, SES, intrinsic motivation, and parental intrusiveness emerged as significant predictors for particular milestones. CONCLUSIONS: Interventions targeting executive function, intrinsic motivation, and parenting behavior may facilitate achievement of emerging adulthood milestones. PMID- 20855289 TI - Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation. AB - The steroid receptor RNA activator (SRA) has the unusual property to function as both a non-coding RNA (ncRNA) and a protein SRAP. SRA ncRNA is known to increase the activity of a range of nuclear receptors as well as the master regulator of muscle differentiation MyoD. The contribution of SRA to either a ncRNA or a protein is influenced by alternative splicing of the first intron, the retention of which disrupts the SRAP open reading frame. We reported here that the ratio between non-coding and coding SRA isoforms increased during myogenic differentiation of human satellite cells but not myotonic dystrophy patient satellite cells, in which differentiation capacity is affected. Using constructs that exclusively produce SRA ncRNA or SRAP, we demonstrated that whereas SRA ncRNA was indeed an enhancer of myogenic differentiation and myogenic conversion of non-muscle cells through the co-activation of MyoD activity, SRAP prevented this SRA RNA-dependant co-activation. Interestingly, the SRAP inhibitory effect is mediated through the interaction of SRAP with its RNA counterpart via its RRM like domain interacting with the functional sub-structure of SRA RNA, STR7. This study thus provides a new model for SRA-mediated regulation of MyoD transcriptional activity in the promotion of normal muscle differentiation, which takes into account the nature of SRA molecules present. PMID- 20855290 TI - Cyclical regulation of the insulin-like growth factor binding protein 3 gene in response to 1alpha,25-dihydroxyvitamin D3. AB - The nuclear receptor vitamin D receptor (VDR) is known to associate with two vitamin D response element (VDRE) containing chromatin regions of the insulin like growth factor binding protein 3 (IGFBP3) gene. In non-malignant MCF-10A human mammary cells, we show that the natural VDR ligand 1alpha,25 dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) causes cyclical IGFBP3 mRNA accumulation with a periodicity of 60 min, while in the presence of the potent VDR agonist Gemini the mRNA is continuously accumulated. Accordingly, VDR also showed cyclical ligand-dependent association with the chromatin regions of both VDREs. Histone deacetylases (HDACs) play an important role both in VDR signalling and in transcriptional cycling. From the 11 HDAC gene family members, only HDAC4 and HDAC6 are up-regulated in a cyclical fashion in response to 1alpha,25(OH)(2)D(3), while even these two genes do not respond to Gemini. Interestingly, HDAC4 and HDAC6 proteins show cyclical VDR ligand-induced association with both VDRE regions of the IGFBP3 gene, which coincides with histone H4 deacetylation on these regions. Moreover, combined silencing of HDAC4 and HDAC6 abolishes the cycling of the IGFBP3 gene. We assume that due to more efficient VDR interaction, Gemini induces longer lasting chromatin activation and therefore no transcriptional cycling but monotonically increasing IGFBP3 mRNA. In conclusion, 1alpha,25(OH)(2)D(3) regulates IGFBP3 transcription through short term cyclical association of VDR, HDAC4 and HDAC6 to both VDRE-containing chromatin regions. PMID- 20855291 TI - The geometry of DNA supercoils modulates the DNA cleavage activity of human topoisomerase I. AB - Human topoisomerase I plays an important role in removing positive DNA supercoils that accumulate ahead of replication forks. It also is the target for camptothecin-based anticancer drugs that act by increasing levels of topoisomerase I-mediated DNA scission. Evidence suggests that cleavage events most likely to generate permanent genomic damage are those that occur ahead of DNA tracking systems. Therefore, it is important to characterize the ability of topoisomerase I to cleave positively supercoiled DNA. Results confirm that the human enzyme maintains higher levels of cleavage with positively as opposed to negatively supercoiled substrates in the absence or presence of anticancer drugs. Enhanced drug efficacy on positively supercoiled DNA is due primarily to an increase in baseline levels of cleavage. Sites of topoisomerase I-mediated DNA cleavage do not appear to be affected by supercoil geometry. However, rates of ligation are slower with positively supercoiled substrates. Finally, intercalators enhance topoisomerase I-mediated cleavage of negatively supercoiled substrates but not positively supercoiled or linear DNA. We suggest that these compounds act by altering the perceived topological state of the double helix, making underwound DNA appear to be overwound to the enzyme, and propose that these compounds be referred to as 'topological poisons of topoisomerase I'. PMID- 20855292 TI - Dual-specificity phosphatase 23 mediates GCM1 dephosphorylation and activation. AB - Glial cells missing homolog 1 (GCM1) is a transcription factor essential for placental development. GCM1 promotes syncytiotrophoblast formation and placental vasculogenesis by activating fusogenic and proangiogenic gene expression in placenta. GCM1 activity is regulated by multiple post-translational modifications. The cAMP/PKA-signaling pathway promotes CBP-mediated GCM1 acetylation and stabilizes GCM1, whereas hypoxia-induced GSK-3beta-mediated phosphorylation of Ser322 causes GCM1 ubiquitination and degradation. How and whether complex modifications of GCM1 are coordinated is not known. Here we show that the interaction of GCM1 and dual-specificity phosphatase 23 (DUSP23) is enhanced by PKA-dependent phosphorylation of GCM1 on Ser269 and Ser275. The recruitment of DUSP23 reverses GSK-3beta-mediated Ser322 phosphorylation, which in turn promotes GCM1 acetylation, stabilization and activation. Supporting a central role in coordinating GCM1 modifications, knockdown of DUSP23 suppressed GCM1 target gene expression and placental cell fusion. Our study identifies DUSP23 as a novel factor that promotes placental cell fusion and reveals a complex regulation of GCM1 activity by coordinated phosphorylation, dephosphorylation and acetylation. PMID- 20855293 TI - Determinants of eukaryal cell killing by the bacterial ribotoxin PrrC. AB - tRNA damage inflicted by the Escherichia coli anticodon nuclease PrrC (EcoPrrC) underlies an antiviral response to phage T4 infection. PrrC homologs are present in many bacterial proteomes, though their biological activities are uncharted. PrrCs consist of two domains: an N-terminal NTPase module related to the ABC family and a distinctive C-terminal ribonuclease module. In this article, we report that the expression of EcoPrrC in budding yeast is fungicidal, signifying that PrrC is toxic in a eukaryon in the absence of other bacterial or viral proteins. Whereas Streptococcus PrrC is also toxic in yeast, Neisseria and Xanthomonas PrrCs are not. Via analysis of the effects of 118 mutations on EcoPrrC toxicity in yeast, we identified 22 essential residues in the NTPase domain and 11 in the nuclease domain. Overexpressing PrrCs with mutations in the NTPase active site ameliorated the toxicity of wild-type EcoPrrC. Our findings support a model in which EcoPrrC toxicity is contingent on head-to-tail dimerization of the NTPase domains to form two composite NTP phosphohydrolase sites. Comparisons of EcoPrrC activity in a variety of yeast genetic backgrounds, and the rescuing effects of tRNA overexpression, implicate tRNA(Lys(UUU)) as a target of EcoPrrC toxicity in yeast. PMID- 20855294 TI - 'Willpower' over the life span: decomposing self-regulation. AB - In the 1960s, Mischel and colleagues developed a simple 'marshmallow test' to measure preschoolers' ability to delay gratification. In numerous follow-up studies over 40 years, this 'test' proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on 'cognitive control' mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of 'willpower' and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued. PMID- 20855295 TI - Self-reference modulates the processing of emotional stimuli in the absence of explicit self-referential appraisal instructions. AB - Self-referential evaluation of emotional stimuli has been shown to modify the way emotional stimuli are processed. This study aimed at a new approach by investigating whether self-reference alters emotion processing in the absence of explicit self-referential appraisal instructions. Event-related potentials were measured while subjects spontaneously viewed a series of emotional and neutral nouns. Nouns were preceded either by personal pronouns ('my') indicating self reference or a definite article ('the') without self-reference. The early posterior negativity, a brain potential reflecting rapid attention capture by emotional stimuli was enhanced for unpleasant and pleasant nouns relative to neutral nouns irrespective of whether nouns were preceded by personal pronouns or articles. Later brain potentials such as the late positive potential were enhanced for unpleasant nouns only when preceded by personal pronouns. Unpleasant nouns were better remembered than pleasant or neutral nouns when paired with a personal pronoun. Correlation analysis showed that this bias in favor of self related unpleasant concepts can be explained by participants' depression scores. Our results demonstrate that self-reference acts as a first processing filter for emotional material to receive higher order processing after an initial rapid attention capture by emotional content has been completed. Mood-congruent processing may contribute to this effect. PMID- 20855296 TI - Depression, rumination and the default network. AB - Major depressive disorder (MDD) has been characterized by excessive default network activation and connectivity with the subgenual cingulate. These hyper connectivities are often interpreted as reflecting rumination, where MDDs perseverate on negative, self-referential thoughts. However, the relationship between connectivity and rumination has not been established. Furthermore, previous research has not examined how connectivity with the subgenual cingulate differs when individuals are engaged in a task or not. The purpose of the present study was to examine connectivity of the default network specifically in the subgenual cingulate both on- and off-task, and to examine the relationship between connectivity and rumination. Analyses using a seed-based connectivity approach revealed that MDDs show more neural functional connectivity between the posterior-cingulate cortex and the subgenual-cingulate cortex than healthy individuals during rest periods, but not during task engagement. Importantly, these rest-period connectivities correlated with behavioral measures of rumination and brooding, but not reflection. PMID- 20855297 TI - Individual differences in reward-prediction-error: extraversion and feedback related negativity. AB - Medial frontal scalp-recorded negativity occurring ~200-300 ms post-stimulus [known as feedback-related negativity (FRN)] is attenuated following unpredicted reward and potentiated following unpredicted non-reward. This encourages the view that FRN may partly reflect dopaminergic 'reward-prediction-error' signalling. We examined the influence of a putatively dopamine-based personality trait, extraversion (N = 30), and a dopamine-related gene polymorphism, DRD2/ANKK1 (N = 24), on FRN during an associative reward-learning paradigm. FRN was most negative following unpredicted non-reward and least-negative following unpredicted reward. A difference wave contrasting these conditions was significantly more pronounced for extraverted participants than for introverts, with a similar but non significant trend for participants carrying at least one copy of the A1 allele of the DRD2/ANKK1 gene compared with those without the allele. Extraversion was also significantly higher in A1 allele carriers. Results have broad relevance to neuroscience and personality research concerning reward processing and dopamine function. PMID- 20855298 TI - A recombinant catalytic domain of matriptase induces detachment and apoptosis of small-intestinal epithelial IEC-6 cells cultured on laminin-coated surface. AB - Matriptase is a type-II transmembrane serine protease that is expressed strongly in the epithelial elements of various organs. In the small intestine, it is expressed prominently at the villus tip where aged epithelial cells undergo shedding and/or apoptosis. This observation, together with the ability of matriptase to cleave laminin (a basement membrane component critical for epithelial cell attachment), prompted us to hypothesize that it plays an important part in the removal of aged epithelial cells in the small intestine. We tested this hypothesis by determining whether a recombinant catalytic domain of rat matriptase (His(6)t-S-CD) causes detachment and/or apoptosis of small intestinal epithelial IEC-6 cells. His(6)t-S-CD caused detachment of cells attached to laminin-coated plates but did not detach cells attached to fibronectin- or type-IV collagen-coated plates. Pre-treatment of laminin-coated plates with His(6)t-S-CD decreased the attachment of cells, suggesting that the recombinant matriptase caused detachment through a mechanism involving a direct effect on laminin. His(6)t-S-CD was also found to induce apoptosis in the cells cultured on laminin-coated plates, as assessed by annexin-V staining, DNA fragmentation and caspase-3 activity assays. These findings support our hypothesis regarding the role of matriptase in the small intestine. PMID- 20855299 TI - Mortality in Vermont granite workers and its association with silica exposure. AB - OBJECTIVES: To assess mortality in Vermont granite workers and examine relationships between silica exposure and mortality from lung cancer, kidney cancer, non-malignant kidney disease, silicosis and other non-malignant respiratory disease. Methods Workers employed between 1947 and 1998 were identified. Exposures were estimated using a job-exposure matrix. Mortality was assessed through 2004 and standardised mortality ratios (SMRs) were computed. Associations between mortality and exposure to silica were assessed by nested case-control analyses using conditional logistic regression. Results 7052 workers had sufficient data for statistical analysis. SMRs were significantly elevated for lung cancer (SMR 1.37, 95% CI 1.23 to 1.52), silicosis (SMR 59.13, 95% CI 44.55 to 76.97), tuberculosis (SMR 21.74, 95% CI 18.37 to 25.56) and other non malignant respiratory disease (SMR 1.74, 95% CI 1.50 to 2.02) but not for kidney cancer or non-malignant kidney disease. In nested case-control analyses, significant associations with cumulative exposure to respirable free silica were observed for silicosis (OR 1.13, 95% CI 1.05 to 1.21 for each 1 mg/m(3)-year increase in cumulative exposure) and other non-malignant respiratory disease (OR 1.10, 95% CI 1.03 to 1.16) but not for lung cancer (OR 0.99, 95% CI 0.94 to 1.03), kidney cancer (OR 0.96, 95% CI 0.84 to 1.09) or non-malignant kidney disease (OR 0.95, 95% CI 0.84 to 1.08). Conclusions Exposure to crystalline silica in Vermont granite workers was associated with increased mortality from silicosis and other non-malignant respiratory disease, but there was no evidence that increased lung cancer mortality in the cohort was due to exposure. Mortality from malignant and non-malignant kidney disease was not significantly increased or associated with exposure. PMID- 20855300 TI - The first four million years of human evolution. PMID- 20855301 TI - In search of the last common ancestor: new findings on wild chimpanzees. AB - Modelling the behaviour of extinct hominins is essential in order to devise useful hypotheses of our species' evolutionary origins for testing in the palaeontological and archaeological records. One approach is to model the last common ancestor (LCA) of living apes and humans, based on current ethological and ecological knowledge of our closest living relations. Such referential modelling is based on rigorous, ongoing field studies of the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). This paper reviews recent findings from nature, focusing on those with direct implications for hominin evolution, e.g. apes, using elementary technology to access basic resources such as food and water, or sheltering in caves or bathing as thermoregulatory adaptations. I give preference to studies that directly address key issues, such as whether stone artefacts are detectible before the Oldowan, based on the percussive technology of hammer and anvil use by living apes. Detailed comparative studies of chimpanzees living in varied habitats, from rainforest to savannah, reveal that some behavioural patterns are universal (e.g. shelter construction), while others show marked (e.g. extractive foraging) or nuanced (e.g. courtship) cross-populational variation. These findings allow us to distinguish between retained, primitive traits of the LCA versus derived ones in the human lineage. PMID- 20855302 TI - More reliable estimates of divergence times in Pan using complete mtDNA sequences and accounting for population structure. AB - Here, we report the sequencing and analysis of eight complete mitochondrial genomes of chimpanzees (Pan troglodytes) from each of the three established subspecies (P. t. troglodytes, P. t. schweinfurthii and P. t. verus) and the proposed fourth subspecies (P. t. ellioti). Our population genetic analyses are consistent with neutral patterns of evolution that have been shaped by demography. The high levels of mtDNA diversity in western chimpanzees are unlike those seen at nuclear loci, which may reflect a demographic history of greater female to male effective population sizes possibly owing to the characteristics of the founding population. By using relaxed-clock methods, we have inferred a timetree of chimpanzee species and subspecies. The absolute divergence times vary based on the methods and calibration used, but relative divergence times show extensive uniformity. Overall, mtDNA produces consistently older times than those known from nuclear markers, a discrepancy that is reduced significantly by explicitly accounting for chimpanzee population structures in time estimation. Assuming the human-chimpanzee split to be between 7 and 5 Ma, chimpanzee time estimates are 2.1-1.5, 1.1-0.76 and 0.25-0.18 Ma for the chimpanzee/bonobo, western/(eastern + central) and eastern/central chimpanzee divergences, respectively. PMID- 20855303 TI - Spinopelvic pathways to bipedality: why no hominids ever relied on a bent-hip bent-knee gait. AB - Until recently, the last common ancestor of African apes and humans was presumed to resemble living chimpanzees and bonobos. This was frequently extended to their locomotor pattern leading to the presumption that knuckle-walking was a likely ancestral pattern, requiring bipedality to have emerged as a modification of their bent-hip-bent-knee gait used during erect walking. Research on the development and anatomy of the vertebral column, coupled with new revelations from the fossil record (in particular, Ardipithecus ramidus), now demonstrate that these presumptions have been in error. Reassessment of the potential pathway to early hominid bipedality now reveals an entirely novel sequence of likely morphological events leading to the emergence of upright walking. PMID- 20855304 TI - Arboreality, terrestriality and bipedalism. AB - The full publication of Ardipithecus ramidus has particular importance for the origins of hominin bipedality, and strengthens the growing case for an arboreal origin. Palaeontological techniques however inevitably concentrate on details of fragmentary postcranial bones and can benefit from a whole-animal perspective. This can be provided by field studies of locomotor behaviour, which provide a real-world perspective of adaptive context, against which conclusions drawn from palaeontology and comparative osteology may be assessed and honed. Increasingly sophisticated dynamic modelling techniques, validated against experimental data for living animals, offer a different perspective where evolutionary and virtual ablation experiments, impossible for living mammals, may be run in silico, and these can analyse not only the interactions and behaviour of rigid segments but increasingly the effects of compliance, which are of crucial importance in guiding the evolution of an arboreally derived lineage. PMID- 20855305 TI - Two new Mio-Pliocene Chadian hominids enlighten Charles Darwin's 1871 prediction. AB - The idea of an evolutionary sequence for humans is quite recent. Over the last 150 years, we have discovered unexpected ancestors, numerous close relatives and our deep evolutionary roots in Africa. In the last decade, three Late Miocene hominids have been described, two about 6 Ma (Ardipithecus and Orrorin) in East Africa and the third dated to about 7 Ma (Sahelanthropus) in Central Africa. The specimens are too few to propose definite relationship to other species, but clearly these belong to a new evolutive grade distinct from Australopithecus and Homo. Moreover, all of them were probably habitual bipeds and lived in woodlands, thus falsifying the savannah hypothesis of human origins. In light of all this recent knowledge, Charles Darwin predicted correctly in 1871 that Africa is the birthplace of humans, chimpanzees and our close relatives. PMID- 20855306 TI - Phylogeny of early Australopithecus: new fossil evidence from the Woranso-Mille (central Afar, Ethiopia). AB - The earliest evidence of Australopithecus goes back to ca 4.2 Ma with the first recorded appearance of Australopithecus 'anamensis' at Kanapoi, Kenya. Australopithecus afarensis is well documented between 3.6 and 3.0 Ma mainly from deposits at Laetoli (Tanzania) and Hadar (Ethiopia). The phylogenetic relationship of these two 'species' is hypothesized as ancestor-descendant. However, the lack of fossil evidence from the time between 3.6 and 3.9 Ma has been one of its weakest points. Recent fieldwork in the Woranso-Mille study area in the Afar region of Ethiopia has yielded fossil hominids dated between 3.6 and 3.8 Ma. These new fossils play a significant role in testing the proposed relationship between Au. anamensis and Au. afarensis. The Woranso-Mille hominids (3.6-3.8 Ma) show a mosaic of primitive, predominantly Au. anamensis-like, and some derived (Au. afarensis-like) dentognathic features. Furthermore, they show that, as currently known, there are no discrete and functionally significant anatomical differences between Au. anamensis and Au. afarensis. Based on the currently available evidence, it appears that there is no compelling evidence to falsify the hypothesis of 'chronospecies pair' or ancestor-descendant relationship between Au. anamensis and Au. afarensis. Most importantly, however, the temporally and morphologically intermediate Woranso-Mille hominids indicate that the species names Au. afarensis and Au. anamensis do not refer to two real species, but rather to earlier and later representatives of a single phyletically evolving lineage. However, if retaining these two names is necessary for communication purposes, the Woranso-Mille hominids are best referred to as Au. anamensis based on new dentognathic evidence. PMID- 20855307 TI - Anterior dental evolution in the Australopithecus anamensis-afarensis lineage. AB - Australopithecus anamensis is the earliest known species of the Australopithecus human clade and is the likely ancestor of Australopithecus afarensis. Investigating possible selective pressures underlying these changes is key to understanding the patterns of selection shaping the origins and early evolution of the Australopithecus-human clade. During the course of the Au. anamensis afarensis lineage, significant changes appear to occur particularly in the anterior dentition, but also in jaw structure and molar form, suggesting selection for altered diet and/or food processing. Specifically, canine tooth crown height does not change, but maxillary canines and P(3)s become shorter mesiodistally, canine tooth crowns become more symmetrical in profile and P(3)s less unicuspid. Canine roots diminish in size and dimorphism, especially relative to the size of the postcanine teeth. Molar crowns become higher. Tooth rows become more divergent and symphyseal form changes. Dietary change involving anterior dental use is also suggested by less intense anterior tooth wear in Au. afarensis. These dental changes signal selection for altered dietary behaviour and explain some differences in craniofacial form between these taxa. These data identify Au. anamensis not just as a more primitive version of Au. afarensis, but as a dynamic member of an evolving lineage leading to Au. afarensis, and raise intriguing questions about what other evolutionary changes occurred during the early evolution of the Australopithecus-human clade, and what characterized the origins of the group. PMID- 20855308 TI - Molar microwear textures and the diets of Australopithecus anamensis and Australopithecus afarensis. AB - Many researchers have suggested that Australopithecus anamensis and Australopithecus afarensis were among the earliest hominins to have diets that included hard, brittle items. Here we examine dental microwear textures of these hominins for evidence of this. The molars of three Au. anamensis and 19 Au. afarensis specimens examined preserve unobscured antemortem microwear. Microwear textures of these individuals closely resemble those of Paranthropus boisei, having lower complexity values than Australopithecus africanus and especially Paranthropus robustus. The microwear texture complexity values for Au. anamensis and Au. afarensis are similar to those of the grass-eating Theropithecus gelada and folivorous Alouatta palliata and Trachypithecus cristatus. This implies that these Au. anamensis and Au. afarensis individuals did not have diets dominated by hard, brittle foods shortly before their deaths. On the other hand, microwear texture anisotropy values for these taxa are lower on average than those of Theropithecus, Alouatta or Trachypithecus. This suggests that the fossil taxa did not have diets dominated by tough foods either, or if they did that directions of tooth-tooth movement were less constrained than in higher cusped and sharper crested extant primate grass eaters and folivores. PMID- 20855309 TI - An enlarged postcranial sample confirms Australopithecus afarensis dimorphism was similar to modern humans. AB - In a previous study, we introduced the template method as a means of enlarging the Australopithecus afarensis postcranial sample to more accurately estimate its skeletal dimorphism. Results indicated dimorphism to be largely comparable to that of Homo sapiens. Some have since argued that our results were biased by artificial homogeneity in our Au. afarensis sample. Here we report the results from inclusion of 12 additional, newly reported, specimens. The results are consistent with those of our original study and with the hypothesis that early hominid demographic success derived from a reproductive strategy involving male provisioning of pair-bonded females. PMID- 20855310 TI - The cranial base of Australopithecus afarensis: new insights from the female skull. AB - Cranial base morphology differs among hominoids in ways that are usually attributed to some combination of an enlarged brain, retracted face and upright locomotion in humans. The human foramen magnum is anteriorly inclined and, with the occipital condyles, is forwardly located on a broad, short and flexed basicranium; the petrous elements are coronally rotated; the glenoid region is topographically complex; the nuchal lines are low; and the nuchal plane is horizontal. Australopithecus afarensis (3.7-3.0 Ma) is the earliest known species of the australopith grade in which the adult cranial base can be assessed comprehensively. This region of the adult skull was known from fragments in the 1970s, but renewed fieldwork beginning in the 1990s at the Hadar site, Ethiopia (3.4-3.0 Ma), recovered two nearly complete crania and major portions of a third, each associated with a mandible. These new specimens confirm that in small brained, bipedal Australopithecus the foramen magnum and occipital condyles were anteriorly sited, as in humans, but without the foramen's forward inclination. In the large male A.L. 444-2 this is associated with a short basal axis, a bilateral expansion of the base, and an inferiorly rotated, flexed occipital squama--all derived characters shared by later australopiths and humans. However, in A.L. 822 1 (a female) a more primitive morphology is present: although the foramen and condyles reside anteriorly on a short base, the nuchal lines are very high, the nuchal plane is very steep, and the base is as relatively narrow centrally. A.L. 822-1 illuminates fragmentary specimens in the 1970s Hadar collection that hint at aspects of this primitive suite, suggesting that it is a common pattern in the A. afarensis hypodigm. We explore the implications of these specimens for sexual dimorphism and evolutionary scenarios of functional integration in the hominin cranial base. PMID- 20855311 TI - Hominin diversity in the Middle Pliocene of eastern Africa: the maxilla of KNM-WT 40000. AB - The 3.5-Myr-old hominin cranium KNM-WT 40000 from Lomekwi, west of Lake Turkana, has been assigned to a new hominin genus and species, Kenyanthropus platyops, on the basis of a unique combination of derived facial and primitive neurocranial features. Central to the diagnosis of K. platyops is the morphology of the maxilla, characterized by a flat and relatively orthognathic subnasal region, anteriorly placed zygomatic processes and small molars. To study this morphology in more detail, we compare the maxillae of African Plio-Pleistocene hominin fossils and samples of modern humans, chimpanzees and gorillas, using conventional and geometric morphometric methods. Computed tomography scans and detailed preparation of the KNM-WT 40000 maxilla enable comprehensive assessment of post-mortem changes, so that landmark data characterizing the morphology can be corrected for distortion. Based on a substantially larger comparative sample than previously available, the results of statistical analyses show that KNM-WT 40000 is indeed significantly different from and falls outside the known range of variation of species of Australopithecus and Paranthropus, contemporary Australopithecus afarensis in particular. These results support the attribution of KNM-WT 40000 to a separate species and the notion that hominin taxonomic diversity in Africa extends back well into the Middle Pliocene. PMID- 20855312 TI - Stable isotopes in fossil hominin tooth enamel suggest a fundamental dietary shift in the Pliocene. AB - Accumulating isotopic evidence from fossil hominin tooth enamel has provided unexpected insights into early hominin dietary ecology. Among the South African australopiths, these data demonstrate significant contributions to the diet of carbon originally fixed by C(4) photosynthesis, consisting of C(4) tropical/savannah grasses and certain sedges, and/or animals eating C(4) foods. Moreover, high-resolution analysis of tooth enamel reveals strong intra-tooth variability in many cases, suggesting seasonal-scale dietary shifts. This pattern is quite unlike that seen in any great apes, even 'savannah' chimpanzees. The overall proportions of C(4) input persisted for well over a million years, even while environments shifted from relatively closed (ca 3 Ma) to open conditions after ca 1.8 Ma. Data from East Africa suggest a more extreme scenario, where results for Paranthropus boisei indicate a diet dominated (approx. 80%) by C(4) plants, in spite of indications from their powerful 'nutcracker' morphology for diets of hard objects. We argue that such evidence for engagement with C(4) food resources may mark a fundamental transition in the evolution of hominin lineages, and that the pattern had antecedents prior to the emergence of Australopithecus africanus. Since new isotopic evidence from Aramis suggests that it was not present in Ardipithecus ramidus at 4.4 Ma, we suggest that the origins lie in the period between 3 and 4 Myr ago. PMID- 20855314 TI - Green tribology. PMID- 20855315 TI - Green tribology: principles, research areas and challenges. AB - In this introductory paper for the Theme Issue on green tribology, we discuss the concept of green tribology and its relation to other areas of tribology as well as other 'green' disciplines, namely, green engineering and green chemistry. We formulate the 12 principles of green tribology: the minimization of (i) friction and (ii) wear, (iii) the reduction or complete elimination of lubrication, including self-lubrication, (iv) natural and (v) biodegradable lubrication, (vi) using sustainable chemistry and engineering principles, (vii) biomimetic approaches, (viii) surface texturing, (ix) environmental implications of coatings, (x) real-time monitoring, (xi) design for degradation, and (xii) sustainable energy applications. We further define three areas of green tribology: (i) biomimetics for tribological applications, (ii) environment friendly lubrication, and (iii) the tribology of renewable-energy application. The integration of these areas remains a primary challenge for this novel area of research. We also discuss the challenges of green tribology and future directions of research. PMID- 20855313 TI - Retrieving chronological age from dental remains of early fossil hominins to reconstruct human growth in the past. AB - A chronology of dental development in Pan troglodytes is arguably the best available model with which to compare and contrast reconstructed dental chronologies of the earliest fossil hominins. Establishing a time scale for growth is a requirement for being able to make further comparative observations about timing and rate during both dento-skeletal growth and brain growth. The absolute timing of anterior tooth crown and root formation appears not to reflect the period of somatic growth. In contrast, the molar dentition best reflects changes to the total growth period. Earlier initiation of molar mineralization, shorter crown formation times, less root length formed at gingival emergence into functional occlusion are cumulatively expressed as earlier ages at molar eruption. Things that are similar in modern humans and Pan, such as the total length of time taken to form individual teeth, raise expectations that these would also have been the same in fossil hominins. The best evidence there is from the youngest fossil hominin specimens suggests a close resemblance to the model for Pan but also hints that Gorilla may be a better developmental model for some. A mosaic of great ape-like features currently best describes the timing of early hominin dental development. PMID- 20855317 TI - The rose petal effect and the modes of superhydrophobicity. AB - The wetting of rough surfaces remains a subject of active investigation by scientists. The contact angle (CA) is a traditional parameter used to characterize the hydrophobicity/philicity of a solid surface. However, it was found recently that high CAs can coexist with strong adhesion between water and a solid surface in the case of the so-called 'rose petal effect'. Several additional parameters have been proposed to characterize the interaction of water with a rough solid surface, including the CA hysteresis, the ability of water droplets to bounce off a solid surface, the tilt angle needed to initiate the flow of a droplet, and the normal and shear adhesion. It is clear now that wetting is not characterized by a single parameter, since several modes or regimes of wetting of a rough surface can exist, including the Wenzel, Cassie, lotus and petal. Understanding the wetting of rough surfaces is important in order to design non-adhesive surfaces for various applications. PMID- 20855316 TI - Wetting transitions on biomimetic surfaces. AB - Biomimetic hierarchical surfaces demonstrate a potential for a variety of green technologies, including energy conversion and conservation, owing to their remarkable water repellence. The design of such surfaces allowing emerging green applications remains a challenging scientific and technological task. Understanding the physical mechanism of wetting transitions (WTs) is crucial for the design of highly stable superhydrophobic materials. The main experimental and theoretical approaches to WTs are reviewed. Reducing the micro-structural scales is the most efficient measure needed to enlarge the threshold pressure of WTs. The trends of future investigations are envisaged. PMID- 20855318 TI - Designing biomimetic antifouling surfaces. AB - Marine biofouling is the accumulation of biological material on underwater surfaces, which has plagued both commercial and naval fleets. Biomimetic approaches may well provide new insights into designing and developing alternative, non-toxic, surface-active antifouling (AF) technologies. In the marine environment, all submerged surfaces are affected by the attachment of fouling organisms, such as bacteria, diatoms, algae and invertebrates, causing increased hydrodynamic drag, resulting in increased fuel consumption, and decreased speed and operational range. There are also additional expenses of dry docking, together with increased fuel costs and corrosion, which are all important economic factors that demand the prevention of biofouling. Past solutions to AF have generally used toxic paints or coatings that have had a detrimental effect on marine life worldwide. The prohibited use of these antifoulants has led to the search for biologically inspired AF strategies. This review will explore the natural and biomimetic AF surface strategies for marine systems. PMID- 20855319 TI - Self-organization at the frictional interface for green tribology. AB - Despite the fact that self-organization during friction has received relatively little attention from tribologists so far, it has the potential for the creation of self-healing and self-lubricating materials, which are important for green or environment-friendly tribology. The principles of the thermodynamics of irreversible processes and of the nonlinear theory of dynamical systems are used to investigate the formation of spatial and temporal structures during friction. The transition to the self-organized state with low friction and wear occurs through destabilization of steady-state (stationary) sliding. The criterion for destabilization is formulated and several examples are discussed: the formation of a protective film, microtopography evolution and slip waves. The pattern formation may involve self-organized criticality and reaction-diffusion systems. A special self-healing mechanism may be embedded into the material by coupling the corresponding required forces. The analysis provides the structure-property relationship, which can be applied for the design optimization of composite self lubricating and self-healing materials for various ecologically friendly applications and green tribology. PMID- 20855320 TI - Shark-skin surfaces for fluid-drag reduction in turbulent flow: a review. AB - The skin of fast-swimming sharks exhibits riblet structures aligned in the direction of flow that are known to reduce skin friction drag in the turbulent flow regime. Structures have been fabricated for study and application that replicate and improve upon the natural shape of the shark-skin riblets, providing a maximum drag reduction of nearly 10 per cent. Mechanisms of fluid drag in turbulent flow and riblet-drag reduction theories from experiment and simulation are discussed. A review of riblet-performance studies is given, and optimal riblet geometries are defined. A survey of studies experimenting with riblet topped shark-scale replicas is also given. A method for selecting optimal riblet dimensions based on fluid-flow characteristics is detailed, and current manufacturing techniques are outlined. Due to the presence of small amounts of mucus on the skin of a shark, it is expected that the localized application of hydrophobic materials will alter the flow field around the riblets in some way beneficial to the goals of increased drag reduction. PMID- 20855321 TI - Tribological design constraints of marine renewable energy systems. AB - Against the backdrop of increasing energy demands, the threat of climate change and dwindling fuel reserves, finding reliable, diverse, sustainable/renewable, affordable energy resources has become a priority for many countries. Marine energy conversion systems are at the forefront of providing such a resource. Most marine renewable energy conversion systems require tribological components to convert wind or tidal streams to rotational motion for generating electricity while wave machines typically use oscillating hinge or piston within cylinder geometries to promote reciprocating linear motion. This paper looks at the tribology of three green marine energy systems, offshore wind, tidal and wave machines. Areas covered include lubrication and contamination, bearing and gearbox issues, biofouling, cavitation erosion, tribocorrosion, condition monitoring as well as design trends and loading conditions associated with tribological components. Current research thrusts are highlighted along with areas needing research as well as addressing present-day issues related to the tribology of offshore energy conversion technologies. PMID- 20855322 TI - Tribological advancements for reliable wind turbine performance. AB - Wind turbines have had various limitations to their mechanical system reliability owing to tribological problems over the past few decades. While several studies show that turbines are becoming more reliable, it is still not at an overall acceptable level to the operators based on their current business models. Data show that the electrical components are the most problematic; however, the parts are small, thus easy and inexpensive to replace in the nacelle, on top of the tower. It is the tribological issues that receive the most attention as they have higher costs associated with repair or replacement. These include the blade pitch systems, nacelle yaw systems, main shaft bearings, gearboxes and generator bearings, which are the focus of this review paper. The major tribological issues in wind turbines and the technological developments to understand and solve them are discussed within. The study starts with an overview of fretting corrosion, rolling contact fatigue, and frictional torque of the blade pitch and nacelle yaw bearings, and references to some of the recent design approaches applied to solve them. Also included is a brief overview into lubricant contamination issues in the gearbox and electric current discharge or arcing damage of the generator bearings. The primary focus of this review is the detailed examination of main shaft spherical roller bearing micropitting and gearbox bearing scuffing, micropitting and the newer phenomenon of white-etch area flaking. The main shaft and gearbox are integrally related and are the most commonly referred to items involving expensive repair costs and downtime. As such, the latest research and developments related to the cause of the wear and damage modes and the technologies used or proposed to solve them are presented. PMID- 20855323 TI - Influence of boric acid additive size on green lubricant performance. AB - As the industrial community moves towards green manufacturing processes, there is an increased demand for multi-functional, environmentally friendly lubricants with enhanced tribological performance. In the present investigation, green (environmentally benign) lubricant combinations were prepared by homogeneously mixing nano- (20 nm), sub-micrometre- (600 nm average size) and micrometre-scale (4 MUm average size) boric acid powder additives with canola oil in a vortex generator. As a basis for comparison, lubricants of base canola oil and canola oil mixed with MoS(2) powder (ranging from 0.5 to 10 MUm) were also prepared. Friction and wear experiments were carried out on the prepared lubricants using a pin-on-disc apparatus under ambient conditions. Based on the experiments, the nanoscale (20 nm) particle boric acid additive lubricants significantly outperformed all of the other lubricants with respect to frictional and wear performance. In fact, the nanoscale boric acid powder-based lubricants exhibited a wear rate more than an order of magnitude lower than the MoS(2) and larger sized boric acid additive-based lubricants. It was also discovered that the oil mixed with a combination of sub-micrometre- and micrometre-scale boric acid powder additives exhibited better friction and wear performance than the canola oil mixed with sub-micrometre- or micrometre-scale boric acid additives alone. PMID- 20855324 TI - Green waxes, adhesives and lubricants. AB - General characteristics of waxes, adhesives and lubricants as well as the recent fundamental investigations on their physical and mechanical behaviour are introduced. The current R&D status for new type/generation of waxes, adhesives and lubricants from natural products is reviewed, with an emphasis on their tribological applications. In particular, some crucial issues and challenges relating to technological improvement and materials development are discussed. Based on the current predicted shortage of energy resources and environmental concerns, prospective research on the development of green waxes, adhesives and lubricants is suggested. PMID- 20855325 TI - Use of oral contraceptives is not associated with increased risk of death in the UK; a net benefit in all-cause mortality was seen in ever users versus never users - RR 0.88, 95% CI 0.82 to 0.93. PMID- 20855326 TI - Increasing nurse staffing levels in cardiac surgery centres appears to be a cost effective patient safety intervention. PMID- 20855327 TI - Nineteen per cent of paediatric inpatient medication orders were associated with administration errors and 13.2% had prescribing errors in five London hospitals. PMID- 20855328 TI - National survey shows the majority of nurses use very little research in the first 2 years after their graduation, highlighting a gap between research and clinical practice. PMID- 20855329 TI - US survey finds higher availability of palliative care programs, palliative physicians and consultation teams and palliative outpatient services in National Cancer Institute centres compared to non-NCI centres. PMID- 20855331 TI - Severe adverse reactions are rare with infusions of infliximab in a community setting. PMID- 20855330 TI - In surveyed Australian medical-surgical units about a third of nurses on perceive emotional abuse in recent shifts and a fifth report actual violence; perception of violence in the workplace is associated with unstable or negative working conditions and adverse patient outcomes. PMID- 20855332 TI - Survey finds only 15% of emergency departments have formal alcohol screening and intervention policies for trauma patients. PMID- 20855333 TI - Activity levels inversely associated with weight gain in women only when BMI is less than 25. PMID- 20855334 TI - Nurses rate readiness for discharge higher than patients do, and nurses scores predict readmission or ED utilisation after discharge better than patient self assessment. PMID- 20855335 TI - Survey of people with type 2 diabetes shows the majority prefer diabetes education to be given during regular diabetes check-ups; other education preferences and opinions on self-care vary depending on patient characteristics. PMID- 20855336 TI - Limited literature available regarding the role of nurses, midwives and health visitors in development and implementation of protocol-based care. PMID- 20855337 TI - Different attitudes towards mental health revealed in a survey of nurses across five European countries; more positive attitudes found in Portugal, in women and in those in senior roles. PMID- 20855338 TI - Small survey finds that new mothers use self-care approaches to manage fatigue more often than other strategies such as seeking help from others. PMID- 20855339 TI - Computer-assisted module for nursing students provides similar improvements in handwashing knowledge and may improve handwashing practice compared with face-to face teaching. PMID- 20855340 TI - Antimicrobial silver dressings beneath compression for venous ulceration are not cost-effective compared with standard dressings. PMID- 20855341 TI - A web-based tailored educational intervention increases positive perceptions of mammography and intention to obtain mammography compared to standardised mammography brochures among Taiwanese women. PMID- 20855342 TI - A nurse-led disease management programme for chronic kidney disease improves outcomes such as adherence to diet and continuous ambulatory peritoneal dialysis. PMID- 20855343 TI - Administration of annual oral high-dose vitamin D to community dwelling older women in autumn and winter months increases risk of falls and fractures. PMID- 20855344 TI - Use of a project nurse to encourage evidence-based falls injury prevention strategies did not reduce falls or fall injuries over 17 months in residential aged care facilities in Australia. PMID- 20855345 TI - Nurse-delivered, home-based pragmatic rehabilitation has a short-term effect on improving fatigue in people with chronic fatigue syndrome compared with usual GP care, but effects were not sustained at 1 year. PMID- 20855346 TI - 57% of RCTs of cardiovascular nursing interventions show that they improve at least one outcome for secondary prevention patients; optimum intervention strategy unclear. PMID- 20855347 TI - Care management increases the use of primary and medical care services by people with severe mental illness in community mental health settings. PMID- 20855348 TI - Update on treatments for head lice. AB - Head lice infestation is common, and mainly affects children of primary school age.1 Treatments include conventional chemical insecticides; fine tooth louse combs; and fluid preparations that work by a physical rather than chemical mode of action.1 However, each of these fails to eradicate head lice in some patients.1 Other disadvantages include the long contact time required for certain preparations (e.g. 8 hours) and the time commitment for combing regimens. Isopropyl myristate 50% in cyclomethicone solution (Full Marks Solution - SSL International) is a new fluid treatment with a physical mode of action that uses a 10-minute contact time.2 Here, we consider this product in the context of updating advice we gave in 2007 on treatments for head lice. PMID- 20855349 TI - Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. AB - Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and long-term subjective effects of psilocybin in healthy humans by pooling raw data from eight double blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1-4 oral doses of psilocybin (45-315 ug/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk. PMID- 20855350 TI - Acute and subchronic effects of bilastine (20 and 40 mg) and hydroxyzine (50 mg) on actual driving performance in healthy volunteers. AB - Bilastine is a new second-generation H1 antagonist. Although bilastine has been demonstrated to produce little or no performance impairment in laboratory tests, it cannot be excluded that it produces impairments in real-life performance such as driving. This study aims to assess the effects of two doses of bilastine (20 and 40 mg) on actual driving after single and repeated administration. Hydroxyzine 50 mg was included as an active control. Twenty-two participants (11 females, 11 males) were tested in a placebo-controlled, randomized, double-blind, four-way cross-over design. Participants were treated with once-daily doses for eight consecutive days. On day 1 and 8 of each treatment period participants performed an actual highway driving test. The primary variable was standard deviation of lateral position (SDLP), a measure of weaving. Results demonstrated that hydroxyzine significantly increased SDLP on days 1 and 8 of treatment. Bilastine did not affect SDLP. It is concluded that hydroxyzine produces severe driving impairment after single doses and that this impairment only partly mitigates over time due to a lack of complete tolerance. Bilastine did not produce any driving impairment after single and repeated doses and can be safely used in traffic in doses up to 40 mg. PMID- 20855351 TI - Improving waste management through a process of learning: the South African waste information system. AB - Piloting of the South African Waste Information System (SAWIS) provided an opportunity to research whether the collection of data for a national waste information system could, through a process of learning, change the way that waste is managed in the country, such that there is a noticeable improvement. The interviews with officials from municipalities and private waste companies, conducted as part of the piloting of the SAWIS, highlighted that certain organizations, typically private waste companies have been successful in collecting waste data. Through a process of learning, these organizations have utilized this waste data to inform and manage their operations. The drivers of such data collection efforts were seen to be financial (business) sustainability and environmental reporting obligations, particularly where the company had an international parent company. However, participants highlighted a number of constraints, particularly within public (municipal) waste facilities which hindered both the collection of waste data and the utilization of this data to effect change in the way waste is managed. These constraints included a lack of equipment and institutional capacity in the collection of data. The utilization of this data in effecting change was further hindered by governance challenges such as politics, bureaucracy and procurement, evident in a developing country context such as South Africa. The results show that while knowledge is a necessary condition for resultant action, a theoretical framework of learning does not account for all observed factors, particularly external influences. PMID- 20855352 TI - An investigation of carbon release rate via leachate from an industrial solid waste landfill. AB - Long-term behaviour of leachate pollutants is a key factor to estimate time and cost required for the leachate treatment in landfills. Estimating carbon release via leachate can be a good way by which to understand the long-term behaviour, however, most studies have had a timeline of only several months or years. In this study, a release rate of carbon via leachate for 20 years was estimated at an industrial solid waste landfill. The total carbon content in dumped waste was estimated based on combustible contents determined by collecting samples from other industrial landfills and pretreatment facilities, and carbon contents in literature values. Leachate quantity data, which were not recorded for the first ten years, were estimated using a macro-moisture balance model including the effect of snow melt. Because leachate quantity and quality at each site were only measured after leachates were mixed, the quantity at each site was calculated by assuming infiltration rates with and without final cover. Results indicated that less than 2% of total input carbon was released from each site via leachate regardless of landfill age. PMID- 20855353 TI - Sustainable landfilling in tropical conditions: comparison between open and closed cell approach. AB - Two landfill test cells were constructed in a tropical climate using locally available low-cost materials. One cell was operated without a cover on the municipal solid waste to simulate 'open landfill' conditions and the other cell was covered to create 'closed landfill' conditions. Both test cells were monitored over a period of 290 days under rainy, dry and artificial wetting conditions. Due to the relatively high compaction density of waste in the closed test cell, the substrate settlement was gradual and comparatively lower than in the open test cell. Multiple top covers in the closed test cell resulted in significant run-off of incident precipitation during the rainy season, which delayed the waste stabilization and subsequently produced a lesser volume of leachate. On the other hand, operation of the open test cell was found to be advantageous in terms of leachate management and substrate settlement along with waste stabilization pattern. Infiltration of rain-water into the waste mass leached out the maximum organic pollutants and oxidized the nitrogen content, which is deemed to be a benefit of operating an open cell landfill under tropical conditions. Artificial wetting during dry periods by recirculation of stored leachate notably accelerated the waste stabilization and secondary substrate settlement in the open test cell. The continuous monitoring of ground-water quality from the site showed only seasonal variations. PMID- 20855354 TI - A methodology for developing strategic municipal solid waste management plans with an application in Greece. AB - A rational approach for developing optimal municipal solid waste (MSW) management plans comprises the strategic and the detailed planning phases. The present paper focuses on the former, the objective of which is to screen management alternatives so as to select the ones that are able to fulfil all legal and other management requirements with reasonable cost. The analysis considers the transportation, treatment and final disposal of the commingled wastes that remain after the application of material recovery at the source programmes and comprises 10 elements, four of which are region-dependent and the remaining ones application-dependent. These elements and their inter-dependencies are described and the entire methodology is applied to Greece. The application considers the existing regional plans and shows that they are incompatible with the existing EU Directives, as well as overly expensive. To address this problem, a new plan is developed in accordance with the rational planning principles of the present methodology. The comparative evaluation of the above alternatives shows that the existing regional plans, in addition to being incompatible with the applicable EU Directives, require 4.3 to 4.8 times (3.7 to 4.4 billion ?) higher capital investment and their annual cost is at least 2.1 to 2.3 times (590 to 735 million ? year(-1)) higher in comparison with the new national plan. PMID- 20855355 TI - Characterization of immune cell subsets during the active phase of multiple sclerosis reveals disease and c-Jun N-terminal kinase pathway biomarkers. AB - BACKGROUND: Autoimmune activation and deregulated apoptosis of T lymphocytes are involved in multiple sclerosis (MS). c-Jun N-terminal kinase (JNK) plays a role in T-cell survival and apoptosis. OBJECTIVES: The aim of this work was to investigate the role of the JNK-dependent apoptosis pathway in relapsing remitting MS (RRMS). METHODS: The immunomodulatory effect of AS602801, a JNK inhibitor, was firstly evaluated on activated peripheral blood mononuclear cells (PBMCs) from healthy volunteers (HVs) and secondly in unstimulated purified CD4+, CD8+ and CD11b+ cells from RRMS patients and HVs. Moreover JNK/inflammation/apoptosis related genes were investigated in RRMS and HV samples. RESULTS: In activated PBMCs from HVs, we showed that AS602801 blocked T lymphocyte proliferation and induced apoptosis. In RRMS CD4+ and CD8+ cells, AS602801 induced apoptosis genes and expression of surface markers, while in RRMS CD11b+ cells it induced expression of innate immunity receptors and co stimulatory molecules. Untreated cells from RRMS active-phase patients significantly released interleukin-23 (IL-23) and interferon-gamma (IFN-gamma) and expressed less apoptosis markers compared to the cells of HVs. Moreover, gene expression was significantly different in cells from RRMS active-phase patients vs. HVs. By comparing RRMS PBMCs in the active and stable phases, a specific genomic signature for RRMS was indentified. Additionally, CASP8AP2, CD36, ITGAL, NUMB, OLR1, PIAS-1, RNASEL, RTN4RL2 and THBS1 were identified for the first time as being associated to the active phase of RRMS. CONCLUSIONS: The analysis of the JNK-dependent apoptosis pathway can provide biomarkers for activated lymphocytes in the active phase of RRMS and a gene expression signature for disease status. The reported results might be useful to stratify patients, thereby supporting the development of novel therapies. PMID- 20855356 TI - Active commuting to school in children and adolescents: an opportunity to increase physical activity and fitness. AB - AIMS: The purpose was to describe the patterns of commuting to school in young people and to examine its associations with physical activity (PA) and cardiorespiratory fitness. METHODS: The sample comprised 2271 Estonian and Swedish children and adolescents (1218 females) aged 9-10 years and 15-16 years. Data were collected in 1998/99. Mode of commuting to and from school was assessed by questionnaire. Time spent (min/day) in PA and average PA (counts/min) was measured by accelerometry. Cardiorespiratory fitness was assessed by means of a maximal cycle ergometer test. RESULTS: Sixty-one percent of the participants reported active commuting to school (ACS). Estonian youth showed lower levels of ACS than Swedish (odds ratio, 0.64; 95% confidence interval, 0.53-0.76) and girls reported lower levels than boys (0.74; 0.62-0.88). ACS boys showed higher PA levels than non-ACS boys for moderate, vigorous, MVPA, and average PA levels (all p <= 0.01). Participants who cycled to school had higher cardiorespiratory fitness than walkers or passive travellers (p < 0.001). CONCLUSIONS: Nearly two thirds of the participants actively commuted to school. ACS may provide an opportunity to increase levels of daily PA, especially in boys, and cardiorespiratory fitness, especially if cycling. Public health strategies should develop and test ACS patterns to get more evidence and promote bike-friendly environments. PMID- 20855357 TI - Return to work among employees with common mental disorders: study design and baseline findings from a mixed-method follow-up study. AB - AIMS: Most research on return-to-work (RTW) has focused on musculoskeletal disorders. To study RTW in employees sick-listed with common mental disorders (CMD), e.g., stress, depression, and anxiety, the National Research Centre for the Working Environment initiated a study on ''Common Mental Disorders, Return-to work, and Long-term Sickness Absence'' (CORSA). The aim of the study is (1) to identify predictors of RTW from the environmental, the individual, and the health related domain and (2) to explore the RTW process based on study participants' experiences. The purpose of this paper is to present the study design and the characteristics of the participants, including analyses on non-response and the prevalence of major depression. METHODS: CORSA is a mixed-method follow-up study encompassing quantitative and qualitative analyses in a cohort of employees sick listed with CMD. Participants were all employees who suffered from CMD and whose applications for sickness absence benefits were processed by the Job Centre Copenhagen (a subunit of the municipality) between July and December 2007 (n = 721). Data on predictors for RTW were collected from (1) administrative application forms filled out by all participants when applying for benefits (n = 721), and (2) baseline questionnaires sent to all participants (responders: n = 298). Data on RTW was retrieved from a national sickness absence registry and from 6-month follow-up questionnaires (n = 226). To explore the RTW process we will primarily use data from in-depth interviews with selected participants (n = 16) supplemented with data from the two questionnaires. CONCLUSIONS: The mixed method design allows for a more comprehensive understanding of RTW by triangulating qualitative and quantitative methods. PMID- 20855358 TI - Aura attacks from acute convexity subarachnoid haemorrhage not due to cerebral amyloid angiopathy. AB - BACKGROUND AND PURPOSE: Convexity subarachnoid haemorrhage (cSAH) has recently been recognised as a cause of recurrent aura-like symptoms, mimicking transient ischaemic attacks (TIAs). Subarachnoid haemorrhage and recurrent aura-like episodes can occur in patients with cerebral amyloid angiopathy (CAA), which has been the presumed cause in the majority of reported cases. However, this syndrome can occur following cSAH secondary to other conditions, and it is important for clinicians to investigate and manage such patients appropriately. METHOD: Case series. RESULTS: We describe two patients who presented with recurrent stereotyped transient neurological symptoms in the setting of acute cSAH identified on MRI. In one patient, SAH occurred secondary to cerebral venous sinus thrombosis. In the other, SAH was due to extension of a traumatic subdural haematoma. CONCLUSIONS: Conditions other than CAA can cause the clinicoradiological syndrome of cSAH with recurrent TIA-like events. Gradient echo or susceptibility-weighted imaging should be included in the diagnostic work up of patients presenting with such events. When cSAH is detected, the full differential diagnosis for this should be considered. Aetiologies other than CAA can cause this syndrome and management can vary greatly depending on the underlying cause. PMID- 20855359 TI - Calcitonin gene related peptide (CGRP)-provoked migraine-like attacks. PMID- 20855360 TI - 5-Hydroxyptryptamine 1F (5-HT1F) receptor agonism. A possible new treatment principle for acute migraine attacks. PMID- 20855361 TI - Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. AB - INTRODUCTION: Lasmiditan (also known as COL-144 and LY573144; 2,4,6-trifluoro-N [6-[(1-methylpiperidin-4-yl)carbonyl]pyridin-2yl]benzamide) is a high-affinity, highly selective serotonin (5-HT) 5-HT(1F) receptor agonist. RESULTS: In vitro binding studies show a K(i) value of 2.21 nM at the 5-HT(1F) receptor, compared with K(i) values of 1043 nM and 1357 nM at the 5-HT(1B) and 5-HT(1D) receptors, respectively, a selectivity ratio greater than 470-fold. Lasmiditan showed higher selectivity for the 5-HT(1F) receptor relative to other 5-HT(1) receptor subtypes than the first generation 5-HT(1F) receptor agonist LY334370. Unlike the 5 HT(1B/1D) receptor agonist sumatriptan, lasmiditan did not contract rabbit saphenous vein rings, a surrogate assay for human coronary artery constriction, at concentrations up to 100 uM. In two rodent models of migraine, oral administration of lasmiditan potently inhibited markers associated with electrical stimulation of the trigeminal ganglion (dural plasma protein extravasation, and induction of the immediate early gene c-Fos in the trigeminal nucleus caudalis). CONCLUSIONS: Lasmiditan presents a unique pyridinoyl piperidine scaffold not found in any other antimigraine class. Its chemical structure and pharmacological profile clearly distinguish it from the triptans. The potency and selectivity of lasmiditan make it ideally suited to definitively test the involvement of 5-HT(1F) receptors in migraine headache therapy. PMID- 20855362 TI - Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan -a randomised proof-of-concept trial. AB - INTRODUCTION: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT(1F) receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. SUBJECTS AND METHODS: In a randomised, multicentre, placebo-controlled, double blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2 h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. RESULTS: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5-45 mg. Subjects were observed in the clinic for 4 h after treatment and used a diary card to record symptoms and adverse events for up to 24 h. The study was terminated when the 20 mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54-75% showed a 2 h headache response, compared to 45% in the placebo group (P = 0.0126 for the linear association between response rates and dose levels). Patient global impression at 2 h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. CONCLUSIONS: At intravenous doses of 20 mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774. PMID- 20855363 TI - Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. AB - INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a key molecule in migraine pathogenesis. Intravenous CGRP infusion triggers delayed migraine-like attacks in patients with migraine without aura (MO). In contrast to patients with MO, in prior studies patients with familial hemiplegic migraine (FHM) did not report more migraine-like attacks compared to controls. Whether CGRP triggers migraine in patients with typical (non-hemiplegic) migraine with aura is (MA) unknown. In the present study we examined the migraine inducing effect of CGRP infusion in patients suffering from MA and healthy controls. METHODS: Fourteen patients suffering exclusively from migraine with typical aura (MA) and 11 healthy volunteers received a continuous intravenous infusion of 1.5 ug/min CGRP over 20 minutes. Headache and other migraine symptoms were scored every 10 minutes for one hour and self recorded hourly thereafter and until 13 hours post infusion. RESULTS: CGRP infusion induced significantly more delayed headaches in MA patients (12 out of 14) than in controls (2 out of 11) (p = 0.001). Furthermore, significantly more MA patients (57%; 8 out of 14) fulfilled criteria for an experimentally induced migraine attack after CGRP than controls (0%; 0 out of 11) (P = 0.003). Four patients (28%) reported aura symptoms after CGRP infusion. CONCLUSION: CGRP triggered migraine-like attacks without aura in patients suffering exclusively from MA. It also triggered a typical aura in 28% of the patients. These data indicate similar neurobiological pathways responsible for triggering migraine headache in MA and MO patients, and suggest differences between MA/MO and FHM. PMID- 20855364 TI - Menstrual and nonmenstrual migraines differ in women with menstrually-related migraine. AB - INTRODUCTION: We compared migraine features and acute therapy response in menstrually-related migraines (MRMs) and non-menstrually-related migraines (NMRMs). METHODS: Women with frequent, disabling migraines were prospectively diagnosed with MRM according to the International Classification of Headache Disorders (ICHD-II; N = 107) criteria using a daily electronic headache dairy. Participants received individualized acute therapy while free of prophylactic migraine medications. RESULTS: Repeated measures logistic regression revealed MRMs were longer (23.4 vs. 16.1 hours, odds ratio [OR] = 1.01, confidence interval [CI] 1.01, 1.02) and more likely associated with disability (85.6% vs. 75.6%, OR = 1.82, CI 1.27, 2.58) than NMRMs. MRMs were also less responsive to acute therapy (two-hour pain-free response = 6.7% vs. 13.4%, OR = .45, CI .26, .80) and reoccurred more frequently within 24 hours after a four-hour pain-free response (36.0% vs. 19.6%, OR = 2.12, CI 1.27, 3.53) than NMRMs. DISCUSSION: These results support the proposed ICHD-II classification of MRMs and suggest that MRMs may require a treatment approach different from that for NMRMs. PMID- 20855365 TI - Does single cortical spreading depression elicit pain behaviour in freely moving rats? AB - INTRODUCTION: Behavioural animal studies are critical, particularly to translate results to human beings. Cortical spreading depression (CSD) has been implicated in migraine pathogenesis. We aimed to investigate the effects of CSD on the behaviour of freely moving rats, since available CSD models do not include awake animals. MATERIALS AND METHODS: We developed a new model to induce single CSD by applying topical N-methyl-D-aspartate (NMDA) and employed a combination of an automated behavioural analysis system, video camera and ultrasonic vocalisation (USV) calls for the first time. Electrocorticograms were also studied during CSD in freely moving rats. Behaviour associated with cephalic pain was assessed in a group of rats that received sumatriptan. Cortical c-fos immunoreactivity was performed in order to confirm CSD. RESULTS: NMDA induced single CSD in ipsilateral cortex, evoked freezing behaviour (P < 0.01) and increased the number of wet dog shakes (WDS; P < 0.01). Grooming, locomotion, eating, drinking, and circling were not significantly altered among groups. Ultrasonic vocalisations compatible with pain calls (22-27 kHz) were only detected in 3 out of 25 rats. Sumatriptan did not significantly reduce the freezing behaviour. CSD induced significant c-fos expression in ipsilateral cerebral cortex and amygdala (P < 0.01). CONCLUSIONS: CSD induces freezing behaviour by invoking anxiety/fear via amygdala activation in freely-moving rats. Single CSD is unlikely to lead to severe pain in freely-moving rats, though the development of mild or vague pain cannot be excluded. The relevance of rat behavioural responses triggered by CSD to migraine symptoms in humans needs further evaluation. PMID- 20855366 TI - Clinical determinants of migraine preventive treatment: contribution of SMILE, an observational survey of primary care migraine management in France. AB - METHODS: SMILE was an observational study carried out in France among office based general practitioners (GPs) and neurologists from November 2005 to July 2006 to assess the determinants of prescription of migraine preventive therapy in primary care medicine. A total of 1467 GPs and 83 neurologists were included, treating 5417 and 248 migraine sufferers, respectively. RESULTS: The main factors leading physicians to deem a patient eligible for preventive treatment were perceived medication overuse and frequency of headaches, and secondarily, severity of headaches and functional impact. On the other hand, patient satisfaction with the acute treatment of attacks and triptan use, and secondarily, a long migraine history were found to influence patient eligibility negatively. DISCUSSION/CONCLUSION: Noticeably, psychiatric disorders (anxiety, stress) did not appear, aside from somatic factors, among the determinants that significantly influence physicians' judgment about the option of establishing a preventive treatment. However, they are important features of migraine condition and should be listed among the factors guiding choices about migraine preventive therapy. PMID- 20855367 TI - Predictors of outcome of the treatment programme in a multidisciplinary headache centre. AB - INTRODUCTION: Despite the high prevalence of headaches, multidisciplinary headache clinics are few and their efficacy still needs validation. The objective was to characterise patients and treatment results in a tertiary headache centre. SUBJECTS AND METHODS: A systematic review of all referred patients in the Danish Headache Centre in a 2-year period. Outcome results were analysed with respect to diagnoses and sociodemographics. RESULTS: A total of 1326 patients with a mean age of 43.7 years and male : female ratio of 3 : 7 were included. In total, frequency and absence rate from work were reduced from 20 to 11 days (P < 0.001) and 5 to 2 days/month (P < 0.001), respectively. Predictors for good outcome were female gender, migraine, triptan overuse and a frequency of 10 days/month, whereas tension-type headache and overuse of simple analgesics predicted a poor outcome. CONCLUSIONS: The present analysis provided support for a multidisciplinary approach in a tertiary headache centre. Further evaluation of specific treatment strategies and outcome predictors are important for future planning. PMID- 20855368 TI - Inhibition of nitric oxide synthases prevents and reverses alpha,beta-meATP induced neck muscle nociception in mice. AB - INTRODUCTION: Tension-type headache (TTH) is associated with noxious input from neck muscles. Intravenous administration of the unspecific nitric oxide synthase inhibitor L-NMMA in chronic TTH patients caused analgesia and reduction of neck muscle tenderness. METHODS: The unspecific nitric oxide synthase inhibitor L-NMMA was applied in an experimental model for neck muscle nociception in anesthetized mice (N = 25). RESULTS: Local injection of alpha,beta-meATP into semispinal neck muscles induced sustained facilitation of brainstem nociception as monitored by the jaw-opening reflex. Preceding intraperitoneal administration of L-NMMA (0.05, 0.1, 1 mg/kg) prevented reflex facilitation evoked by alpha,beta-meATP in a dose dependent manner. Intraperitoneal injection of L-NMMA subsequent to intramuscular alpha,beta-meATP application reversed established brainstem reflex facilitation back to baseline values. DISCUSSION: Both experiments with preceding and subsequent L-NMMA indicate the involvement of nitric oxide synthases in the induction and maintenance of facilitation. However, future experiments will have to address the involvement of various isoenzymes in order to provide for new therapeutic concepts in TTH. PMID- 20855369 TI - Effect of the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant in human cranial arteries. AB - INTRODUCTION: Calcitonin gene-related peptide (CGRP) is a neuronal messenger in intracranial sensory nerves and is considered to play a significant role in migraine pathophysiology. MATERIALS AND METHODS: We investigated the effect of the CGRP receptor antagonist, telcagepant, on CGRP-induced cranial vasodilatation in human isolated cerebral and middle meningeal arteries. We also studied the expression of the CGRP receptor components in cranial arteries with immunocytochemistry. Concentration response curves to alphaCGRP were performed in human isolated cerebral and middle meningeal arteries in the absence or presence of telcagepant. Arterial slices were stained for RAMP1, CLR and actin in a double immunofluorescence staining. RESULTS: In both arteries, we found that: (i) telcagepant was devoid of any contractile or relaxant effects per se; (ii) pretreatment with telcagepant antagonised the alphaCGRP-induced relaxation in a competitive manner; and (iii) immunohistochemistry revealed expression and co localisation of CLR and RAMP1 in the smooth muscle cells in the media layer of both arteries. CONCLUSIONS: Our findings provide morphological and functional data on the presence of CGRP receptors in cerebral and meningeal arteries, which illustrates a possible site of action of telcagepant in the treatment of migraine. PMID- 20855371 TI - The classification of chronic headache: room for further improvement? AB - In this commentary, the authors briefly discuss their views on some of the limitations in the current terminology and classification of chronic headache. Suggestions for consideration and further debate include the acceptance of chronic daily headache as the umbrella term for this group of headache disorders, a more consistent definition of 'chronic' and the use of a multi-axial classification approach. PMID- 20855370 TI - Neurophysiological markers of central sensitisation in the trigeminal pathway and their modulation by the cyclo-oxygenase inhibitor ketorolac. AB - Central sensitisation is a key mechanism of migraine; understanding its modulation by anti-migraine drugs is essential for rationalising treatment. We used an animal model of central trigeminal sensitisation to investigate neuronal responses to dural electrical stimulation as a putative electrophysiological marker of sensitisation and its modulation by ketorolac. In anaesthetised rats, responses of single convergent wide-dynamic range neurons of the spinal trigeminal nucleus to dural electrical simulation were recorded in parallel to their ongoing activity and responses to facial mechanical stimulation before and after a short-term dural application of an IS. Both ongoing activity and responses to dural electrical stimuli were enhanced by the inflammatory challenge, whereas neuronal thresholds to mechanical skin stimulation were reduced (p < .05, N = 12). Intravenous ketorolac (2 mg/kg, N = 6) reduced ongoing activity and responses to dural electrical stimulation, and increased mechanical thresholds versus vehicle controls (p < .05, N = 6). We conclude that neuronal responses to dural electrical stimulation can serve as a suitable marker which together with admitted electrophysiological signs can objectively detect central trigeminal sensitisation and its modulation by anti-migraine treatments in this preclinical model of migraine. PMID- 20855372 TI - Reversible cerebral vasoconstriction syndrome in two patients with a carotid glomus tumour. AB - We report two patients with reversible cerebral vasoconstriction syndrome (RCVS) and carotid glomus tumour. The first patient presented with multiple thunderclap headaches. Cervical and cerebral magnetic resonance imaging showed diffuse cerebral vasoconstriction on magnetic resonance angiogram (MRA) and a carotid glomus tumour. The second patient presented with a cervical mass and was diagnosed with a non-secreting paraganglioma of the carotid body. Surgery with pre-operative angiography was followed by thunderclap headaches and MRA showed segmental cerebral vasoconstriction. Both patients were treated with nimodipine and headaches stopped. Both had normal cerebral arteries on the control MRA at 3 months. These two cases suggest that a paraganglioma may increase the susceptibility to develop RCVS. As a consequence, patients with RCVS should be investigated for a carotid glomus tumour, and patients with paraganglioma reporting severe headaches should have a cerebral MRA in order to rule out cerebral vasoconstriction. PMID- 20855373 TI - Consistency of response to sumatriptan/naproxen sodium in a placebo-controlled cross-over study. PMID- 20855374 TI - Idiopathic ventricular arrhythmias originating from the left ventricular summit: anatomic concepts relevant to ablation. AB - BACKGROUND: The summit of the left ventricle (LV) is the most superior portion of the epicardial LV bounded by an arc from the left anterior descending coronary artery, superior to the first septal perforating branch to the left circumflex coronary artery. Ventricular arrhythmias (VAs) originating from this region may present challenges for catheter ablation. METHODS AND RESULTS: We studied 27 consecutive patients with VAs originating from the LV summit. The great cardiac vein (GCV) divides this region between an inferior area accessible to ablation and a superior, inaccessible area. Successful ablation was achieved within the GCV in 14 patients and on the epicardial surface in 4. Ventricular prepotentials were recorded at the successful ablation site in 80% of these patients. In 5 patients, ablation was abandoned because of inaccessibility of the catheter to the myocardium or high impedance with radiofrequency application within the GCV. In the remaining 4 patients, epicardial mapping suggested VA origins in a region of low voltage that was located superior to the GCV (inaccessible area), and ablation was abandoned because of close proximity to the coronary arteries or high impedance. A right bundle-branch block, transition zone, R-wave amplitude ratio in leads III to II, Q-wave amplitude ratio in leads aVL to aVR, and S waves in lead V(6) accurately predicted the site of origin. CONCLUSIONS: LV summit VAs may be ablated within the GCV or inferior to the GCV on the epicardial surface, though sites superior to the GCV are usually inaccessible to ablation. PMID- 20855375 TI - Iron deficiency and anaemia in heart failure: understanding the FAIR-HF trial. AB - Treatment of anaemia in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction has traditionally focused on erythropoietin stimulating agents. However, recent studies have shown that treatment with intravenous (IV) iron can improve the symptoms and quality of life in patients with CHF and iron deficiency (ID), with or without anaemia. The management of ID is becoming an important therapeutic target in patients with CHF, and in this article, we will review iron metabolism in the context of anaemia and heart failure. We will also focus on the importance of diagnosing and treating ID, preferably with IV iron preparations, in patients with CHF. PMID- 20855381 TI - Impact of children with medically complex conditions. PMID- 20855382 TI - Fetal growth retardation and risk of febrile seizures. AB - OBJECTIVE: The goal was to examine the associations between fetal growth characteristics in different trimesters of pregnancy and the occurrence of febrile seizures in early childhood. METHODS: This study was embedded in a population-based, prospective, cohort study from early fetal life onward. Fetal growth characteristics (femur length, abdominal circumference, estimated fetal weight, head circumference, biparietal diameter, and transverse cerebellar diameter [TCD]) were measured with ultrasonography in the second and third trimesters of pregnancy. Information on the occurrence of febrile seizures was collected with questionnaires at the ages of 12 and 24 months. Analyses were based on data for 3372 subjects. RESULTS: In the second trimester, children in the lowest tertile of TCDs were at increased risk of developing febrile seizures, compared with children in the highest tertile (odds ratio 2.87 [95% confidence interval: 1.31-6.28]). In the third trimester, children in the lowest tertile of all general growth characteristics (femur length, abdominal circumference, and estimated fetal weight) were at increased risk of developing febrile seizures. This association was strongest for children in the lowest tertile of estimated fetal weight (odds ratio: 2.57 [95% confidence interval: 1.34-4.96]). Children in the lowest tertile of biparietal diameter in the third trimester also were at increased risk of febrile seizures. Similar but not statistically significant tendencies were observed for head circumference and TCD. CONCLUSIONS: Fetal growth retardation is associated with increased risk of febrile seizures in the first 2 years of life. Adverse environmental and genetic factors during pregnancy may be important in the development of febrile seizures. PMID- 20855383 TI - Increasing prevalence of medically complex children in US hospitals. AB - OBJECTIVE: In this study we used national data to determine changes in the prevalence of hospital admissions for medically complex children over a 15-year period. PATIENTS AND METHODS: Data from the Nationwide Inpatient Sample, a component of the Healthcare Cost and Utilization Project, was analyzed in 3-year increments from 1991 to 2005 to determine national trends in rates of hospitalization of children aged 8 days to 4 years with chronic conditions. Discharge diagnoses from the Nationwide Inpatient Sample were grouped into 9 categories of complex chronic conditions (CCCs). Hospitalization rates for each of the 9 CCC categories were studied both individually and in combination. Trends of children hospitalized with 2 specific disorders, cerebral palsy (CP) and bronchopulmonary dysplasia, with additional diagnoses in more than 1 CCC category were also examined. RESULTS: Hospitalization rates of children with diagnoses in more than 1 CCC category increased from 83.7 per 100,000 (1991-1993) to 166 per 100 000 (2003-2005) (P[r]<.001). The hospitalization rate of children with CP plus more than 1 CCC diagnosis increased from 7.1 to 10.4 per 100 000 (P=.002), whereas the hospitalization rates of children with bronchopulmonary dysplasia plus more than 1 CCC diagnosis increased from 9.8 to 23.9 per 100,000 (P<.001). CONCLUSIONS: Consistent increases in hospitalization rates were noted among children with diagnoses in multiple CCC categories, whereas hospitalization rates of children with CP alone have remained stable. The relative medical complexity of hospitalized pediatric patients has increased over the past 15 years. PMID- 20855385 TI - Adenovirus 36 and obesity in children and adolescents. AB - OBJECTIVE: The primary aim of this study was to assess the relationship between adenovirus 36 (AD36)-specific antibodies and obesity in children. METHODS: A cross-sectional study of children 8 to 18 years of age was performed. Children were classified according to BMI percentile as nonobese (<95th percentile) or obese (>=95th percentile). The presence of AD36-specific neutralizing antibodies was assessed by using the serum neutralization assay. RESULTS: A total of 124 children (median age: 13.6 years) were studied. Of those children, 46% were nonobese and 54% were obese. AD36 positivity was present in 19 children (15%). The majority of children found to be AD36-positive were obese (15 [78%] of 19 children). AD36 positivity was significantly (P<.05) more frequent in obese children (15 [22%] of 67 children) than nonobese children (4 [7%] of 57 children). Among the subset of children who were obese, those who were AD36 positive had significantly larger anthropometric measures, including weight, BMI, waist circumference, and waist/height ratio. CONCLUSION: These data support an association of obesity and higher body weight with the presence of neutralizing antibodies to AD36 in children. If a cause-and-effect relationship is established, it would have considerable implications for the prevention and treatment of childhood obesity. PMID- 20855384 TI - Home intervention improves cognitive and social-emotional scores in iron deficient anemic infants. AB - BACKGROUND: Iron-deficiency anemia (IDA) is associated with alterations in infant behavior and development that may not be corrected with iron therapy. OBJECTIVE: To determine if a home-based intervention to foster child development improves behavior and development of infants with IDA. METHODS: Infants with IDA and nonanemic infants aged 6 and 12 months were treated with oral iron and randomly assigned to a year of surveillance or intervention. Infants in the surveillance group were visited weekly, and information on iron intake, feeding, and health were recorded. Infants in the intervention were visited weekly, and the home visits included an hour-long program to foster child development by providing support to the mother-infant relationship. The number of infants enrolled was 128 (66 who received intervention) and 149 (70 intervention) at 6 and 12 months, respectively. Psychologists who were unaware of iron status and intervention assignment assessed infants' cognitive, motor, and social-emotional development (Bayley Scales) at the beginning, midpoint, and end of the year; 116 6-month-olds and 134 12-month-olds had at least 2 assessments. Hierarchical linear modeling was used to analyze change over time. RESULTS: Infants with IDA, regardless of enrollment age, were rated as less positive in social-emotional behavior at baseline. There were significant interactions between iron status and intervention associated with change in cognitive performance and positive social emotional behavior. Infants with IDA who received intervention had developmental trajectories comparable to those of nonanemic infants in the intervention and surveillance groups, but these infants did not catch up in social-emotional behavior. Infants with IDA who received surveillance showed less increase in cognitive scores and had declines in positive social-emotional ratings. CONCLUSIONS: Home-based intervention to foster child development improved cognitive and social-emotional scores in infants with IDA, but social-emotional differences remained between infants with IDA and those without IDA. PMID- 20855386 TI - Corticosteroids may improve clinical outcomes during hospitalization for Henoch Schonlein purpura. AB - OBJECTIVE: To characterize the effect of corticosteroid exposure on clinical outcomes in children hospitalized with new-onset Henoch-Schonlein purpura (HSP). PATIENTS AND METHODS: We conducted a retrospective cohort study of children discharged with an International Classification of Diseases, Clinical Modification code of HSP between 2000 and 2007 by using inpatient administrative data from 36 tertiary care children's hospitals. We used stratified Cox proportional hazards regression models to estimate the relative effect of time varying corticosteroid exposure on the risks of clinical outcomes that occur during hospitalization for acute HSP. RESULTS: During the 8-year study period, there were 1895 hospitalizations for new-onset HSP. After multivariable regression modeling adjustment, early corticosteroid exposure significantly reduced the hazard ratios for abdominal surgery (0.39 [95% confidence interval (CI): 0.17-0.91]), endoscopy (0.27 [95% CI: 0.13-0.55]), and abdominal imaging (0.50 [95% CI: 0.29-0.88]) during hospitalization. CONCLUSIONS: In the hospital setting, early corticosteroid exposure was associated with benefits for several clinically relevant HSP outcomes, specifically those related to the gastrointestinal manifestations of the disease. PMID- 20855387 TI - Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. AB - OBJECTIVE: Mild hypothermia after perinatal hypoxic-ischemic encephalopathy (HIE) reduces neurologic sequelae without significant adverse effects, but studies are needed to determine the most-efficacious methods. METHODS: In the neo.nEURO.network trial, term neonates with clinical and electrophysiological evidence of HIE were assigned randomly to either a control group, with a rectal temperature of 37 degrees C (range: 36.5-37.5 degrees C), or a hypothermia group, cooled and maintained at a rectal temperature of 33.5 degrees C (range: 33-34 degrees C) with a cooling blanket for 72 hours, followed by slow rewarming. All infants received morphine (0.1 mg/kg) every 4 hours or an equivalent dose of fentanyl. Neurodevelopmental outcomes were assessed at the age of 18 to 21 months. The primary outcome was death or severe disability. RESULTS: A total of 129 newborn infants were enrolled, and 111 infants were evaluated at 18 to 21 months (53 in the hypothermia group and 58 in the normothermia group). The rates of death or severe disability were 51% in the hypothermia group and 83% in the normothermia group (P=.001; odds ratio: 0.21 [95% confidence interval [CI]: 0.09 0.54]; number needed to treat: 4 [95% CI: 3-9]). Hypothermia also had a statistically significant protective effect in the group with severe HIE (n=77; P=.005; odds ratio: 0.17 [95% CI: 0.05-0.57]). Rates of adverse events during the intervention were similar in the 2 groups except for fewer clinical seizures in the hypothermia group. CONCLUSION: Systemic hypothermia in the neo.nEURO.network trial showed a strong neuroprotective effect and was effective in the severe HIE group. PMID- 20855388 TI - Trends and outcomes of adolescent bariatric surgery in California, 2005-2007. AB - OBJECTIVE: The goal of this study was to evaluate trends, and outcomes of adolescents who undergo bariatric surgery. PATIENTS AND METHODS: Patients younger than 21 years who underwent elective bariatric surgery between 2005 and 2007 were identified from the California Office of Statewide Health Planning and Development database. Multivariate logistic regression was used to identify factors associated with the type of surgery. RESULTS: Overall, 590 adolescents (aged 13-20 years) underwent bariatric surgery in 86 hospitals. White adolescents represented 28% of those who were overweight but accounted for 65% of the procedures. Rates of laparoscopic adjustable gastric banding (LAGB) increased 6.9 fold from 0.3 to 1.5 per 100,000 population (P<.01), whereas laparoscopic Roux-en Y gastric bypass (LRYGB) rates decreased from 3.8 to 2.7 per 100 000 population (P<.01). Self-payers were more likely to undergo LAGB (relative risk [RR]: 3.51 [95% confidence interval: 2.11-5.32]) and less likely to undergo LRYGB (RR: 0.45 [95% confidence interval: 0.33-0.58]) compared with privately insured adolescents. The rate of major in-hospital complication was 1%, and no deaths were reported. Of the patients who received LAGB, 4.7% had band revision/removal. In contrast, 2.9% of those who received LRYGB required reoperations. CONCLUSIONS: White adolescent girls disproportionately underwent bariatric surgery. Although LAGB has not been approved by the US Food and Drug Administration for use in children, its use has increased dramatically. There was a complication rate and no deaths. Long-term studies are needed to fully assess the efficacy, safety, and health care costs of these procedures in adolescents. PMID- 20855389 TI - Vitamin B12 optic neuropathy in autism. AB - Dietary vitamin B12 deficiency was identified as a cause of partially reversible optic neuropathy in 3 autistic children. All of the affected children presented with gradual visual loss. Examination revealed optic atrophy, and further questioning regarding diet revealed that all 3 children had severe food selectivity and highly stereotyped diets that resulted in an almost total lack of animal products in their diets. Vitamin B12 levels were low in all 3 children. Treatment with intramuscular vitamin B12 and normalization of vitamin B12 levels resulted in improvement of visual functioning in all 3 children. These cases illustrate that food selectivity, a known complication of autism, can result in vitamin deficiency that can cause visual loss and optic atrophy. Physicians must have a high index of suspicion when evaluating children with autism and visual loss to detect this rare cause of optic atrophy. PMID- 20855390 TI - Clinical disease caused by Klebsiella in 2 unrelated patients with interleukin 12 receptor beta1 deficiency. AB - Patients with interleukin 12 (IL-12)p40 or IL-12 receptor beta1 (IL12Rbeta1) deficiencies are prone to develop infections caused by mycobacteria and salmonella; other infections have only been rarely observed. In this report we describe 2 unrelated patients with complete autosomal recessive IL12Rbeta1 deficiency who suffered from sepsis attributable to Klebsiella pneumoniae. A Mexican boy suffered from disseminated bacille Calmette-Guerin disease and infections caused by K pneumoniae and Candida albicans and had a fatal outcome. A Turkish girl living in France suffered from disseminated Nocardia nova infection and K pneumoniae sepsis. Therefore, Klebsiella infections should be considered in patients with IL12Rbeta1 deficiency. Conversely, IL12Rbeta1 deficiency should be considered in patients with unexplained klebsiellosis. PMID- 20855391 TI - Head-circumference distribution in a large primary care network differs from CDC and WHO curves. AB - OBJECTIVE: To compare currently available head-circumference growth curves to curves constructed from clinical measurements from patients in a large US primary care network (PCN). PATIENTS AND METHODS: We performed a retrospective cohort study of 75 412 patients in an urban-suburban PCN. Patients with a birth weight of <1500 g or gestational age of <33 weeks at birth were excluded. We compared percentile values and the proportion of head-circumference observations above the 95th percentile and below the 5th percentile for the existing and PCN curves. RESULTS: The PCN curves were most similar to the National Center for Health Statistics (NCHS) curves and were substantially different from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) curves. The overall proportion of observations above the 95th percentile was 4.9% (PCN), 6.2% (NCHS), 8.6% (CDC), and 14.0% (WHO). The proportion below the 5th percentile was 4.4% (PCN), 5.1% (NCHS), 2.9% (CDC), and 2.3% (WHO). When using the CDC curves, the proportion above the 95th percentile increased from 0.2% for children younger than 2 weeks to 11.8% for children 12 months old. When using the WHO curves, the proportion above the 95th percentile was >5% at all ages, with a maximum of 18.0% for children older than 24 months. CONCLUSIONS: The CDC and WHO head-circumference curves describe different distributions than the clinical measurements in our PCN population, especially for children with larger heads. The resulting percentile misclassification may delay diagnosis in children with intracranial pathology in very young infants and spur unnecessary evaluation of healthy children older than 6 months. PMID- 20855392 TI - The neo.nEURO.network Hypothermia Randomized Controlled Trial. PMID- 20855394 TI - Children with complex chronic conditions in inpatient hospital settings in the United States. AB - OBJECTIVES: Hospitalized children are perceived to be increasingly medically complex, but no such trend has been documented. The objective of this study was to determine whether the proportion of pediatric inpatient use that is attributable to patients with a diagnosis of one or more complex chronic condition (CCC) has increased over time and to assess the degree to which CCC hospitalizations are associated with attributes that are consistent with heightened medical complexity. METHODS: A retrospective observational study that used the 1997, 2000, 2003, and 2006 Kids Inpatient Databases examined US hospitalizations for children. Attributes of medical complexity included hospital admissions, length of stay, total charges, technology-assistance procedures, and mortality risk. RESULTS: The proportion of inpatient pediatric admissions, days, and charges increased from 1997 to 2006 for any CCC and for every CCC group except hematology. CCCs accounted for 8.9% of US pediatric admissions in 1997 and 10.1% of admissions in 2006. These admissions used 22.7% to 26.1% of pediatric hospital days, used 37.1% to 40.6% of pediatric hospital charges, accounted for 41.9% to 43.2% of deaths, and (for 2006) used 73% to 92% of different forms of technology-assistance procedures. As the number of CCCs for a given admission increased, all markers of use increased. CONCLUSIONS: CCC-associated hospitalizations compose an increasing proportion of inpatient care and resource use. Future research should seek to improve methods to identify the population of medically complex children, monitor their increasing inpatient use, and assess whether current systems of care are meeting their needs. PMID- 20855393 TI - Motor outcomes after neonatal arterial ischemic stroke related to early MRI data in a prospective study. AB - OBJECTIVE: We aimed to correlate early imaging data with motor outcomes in a large, homogeneous, cohort of infants with neonatal (diagnosed before 29 days of life) arterial ischemic stroke (AIS). METHODS: From a prospective cohort of 100 children with neonatal AIS, we analyzed the MRI studies performed within the 28 first days of life for 80 infants evaluated at 2 years of age. The relationships between infarction location and corticospinal tract (CST) involvement and motor outcomes were studied RESULTS: Seventy-three infarctions involved the middle cerebral artery (MCA) territory. Of those, 50 were superficial infarctions, 5 deep infarctions, and 18 mixed infarctions. The CST was involved in 24 cases. Nineteen patients with MCA infarctions (26% [95% confidence interval: 16%-34%]) developed hemiplegia. Mixed infarctions (P<.0001) and CST involvement (P<.0001) were highly predictive of hemiplegia. In contrast, 88% of children with isolated superficial MCA infarctions did not exhibit impairment. CONCLUSIONS: Accurate prediction of motor outcomes can be obtained from early MRI scans after neonatal AIS. The absence of involvement of the CST resulted in normal motor development in 94% of cases. CST involvement resulted in congenital hemiplegia in 66% of cases. PMID- 20855396 TI - Racial differences in the effects of postnatal environmental tobacco smoke on neurodevelopment. AB - OBJECTIVES: We used the 2001-2004 National Health and Nutrition Examination Survey to examine the association between postnatal environmental tobacco smoke exposure, measured as serum cotinine levels, and attention-deficit/hyperactivity disorder (ADHD) among children 4 to 15 years of age. We further investigated the interactions of race and serum cotinine levels with ADHD. METHODS: Logistic regression models were used to evaluate associations. RESULTS: This study found that the prevalence of ADHD increased as blood cotinine levels increased. The effects of blood cotinine levels on ADHD differed according to race. Compared with children of the same racial group with the lowest blood cotinine levels, the odds ratios were 2.72 (95% confidence interval: 1.25-5.93) for Mexican American children and 5.32 (95% confidence interval: 1.55-18.3) for children in other racial groups with the highest blood cotinine levels, with controlling for the effect of maternal smoking during pregnancy. However, no significant associations between blood cotinine levels and ADHD were observed among non-Hispanic white or non-Hispanic black children. CONCLUSIONS: The findings of this study underscore the possibility of racial disparities in the effects of environmental tobacco smoke on behavioral problems in children. These findings warrant further investigation. PMID- 20855397 TI - Randomized controlled trial of day care versus hospital care of severe pneumonia in Bangladesh. AB - OBJECTIVE: A randomized controlled trial compared day care versus hospital care management of pneumonia. METHODS: Children 2 to 59 months of age with severe pneumonia received either day care, with antibiotic treatment, feeding, and supportive care from 8:00 am to 5:00 pm, or hospital care, with similar 24-hour treatment. RESULTS: In 2006-2008, 360 children were assigned randomly to receive either day care or hospital care; 189 (53%) had hypoxemia, with a mean+/-SD oxygen saturation of 93+/-4%, which increased to 99+/-1% after oxygen therapy. The mean+/-SD durations of day care and hospital care were 7.1+/-2.3 and 6.5+/ 2.8 days, respectively. Successful management was possible for 156 (87.7% [95% confidence interval [CI]: 80.9%-90.9%]) of 180 children in the day care group and 173 (96.1% [95% CI: 92.2%-98.1%]) of 180 children in the hospital care group (P=.001). Twenty-three children in the day care group (12.8% [95% CI: 8.7%-18.4%] and 4 children in the hospital care group (2.2% [95% CI: 0.9%-5.6%] required referral to hospitals (P<.001). During the follow-up period, 22 children in the day care group (14.1% [95% CI: 9.5%-20.4%]) and 11 children in the hospital care group (6.4% [95% CI: 3.6%-11%]) required readmission to hospitals (P=.01). The estimated costs per child treated successfully at the clinic and the hospital were US$114 and US$178, respectively. CONCLUSION: Severe childhood pneumonia without severe malnutrition can be successfully managed at day care clinics, except for children with hypoxemia who require prolonged oxygen therapy. PMID- 20855395 TI - Improving detection of blindness in childhood: the British Childhood Vision Impairment study. AB - OBJECTIVES: In industrialized countries, there are established programs of childhood vision screening and surveillance, but little is known about their performance. We investigated the patterns of presentation/detection and early treatment of a nationally representative cohort of children with severe visual impairment or blindness (SVI/BL) in 1 year (2000) in the United Kingdom. METHODS: All children who were younger than 16 years and had a new diagnosis of SVI/BL were identified by active surveillance through the British Ophthalmological and Pediatric Surveillance Units. Data that were collected up to 1 year after diagnosis included sociodemographic characteristics, detection of SVI/BL, nonophthalmic disorders/impairments, ophthalmic findings, and early management. RESULTS: Of 439 identified children, 65% were younger than 1 year at diagnosis, 28% were of nonwhite ethnicity, and 40% in the worst quintile of deprivation score. A total of 77% had associated nonophthalmic disorders/impairments. Although 70% had established symptoms or signs at diagnosis by a health professional, parents had suspected blindness in only 47%. A quarter of isolated SVI/BL was detected through routine vision screening; however, 46% of children's SVI/BL and associated nonophthalmic disorders/impairments were diagnosed through a clinical surveillance examination undertaken because of high risk for a specific eye disease. CONCLUSIONS: The "patient journey" of children with visual impairment is markedly influenced by the presence of additional impairments/chronic diseases. Parents' understanding of normal visual development needs to be improved. Increasingly, new evidence-based formal programs of clinical (ophthalmic) surveillance are needed in response to the changing population of children who are at risk for blinding eye disease. PMID- 20855402 TI - WHO officials press Russia to consider needle exchanges to reduce spread of HIV. PMID- 20855399 TI - Cutting the research budget. PMID- 20855403 TI - People with severe mental health conditions in poor nations need better treatment, says WHO. PMID- 20855404 TI - Future of Australia's supervised injecting centre is now more certain. PMID- 20855405 TI - Head and neck cancer--Part 1: Epidemiology, presentation, and prevention. PMID- 20855407 TI - Cancer services in England and Scotland are improving faster than in rest of UK. PMID- 20855408 TI - Paediatrician in Baby P case will appear before GMC in October. PMID- 20855409 TI - Case against interventional cardiologist resumes with new evidence. PMID- 20855410 TI - Predictive factors for relapse after an integrated inpatient treatment programme for unipolar depressed and bipolar alcoholics. AB - AIM: The aim of this study was to examine prospectively examined predictors of relapse in alcohol dependence with comorbid affective disorder. METHODS: One hundred and eighty-three unipolar depressed or bipolar alcoholics who completed an integrated inpatient treatment programme for dual diagnosis were assessed at baseline, post-treatment discharge and at 3 and 6 months post treatment. Backwards stepwise likelihood ratio multiple logistic regression was used to investigate the impact of multiple covariates on relapse to alcohol in the 0-3- and 3-6-month period post discharge. RESULTS: The retention rate at 3 months post discharge was 95.3% (177 patients) and at 6 months it was 87.4% (162 patients). Higher level of anxiety at baseline and discharge was significantly associated with relapse at 3, but not at 6 months, in all subjects. Higher baseline alcohol use disorder identification test scores were associated with relapse at 3 and at 6 months. Intention and planning to attend aftercare after discharge from the hospital were associated with non-relapse at 3 and 6 months, respectively. Levels of depression, of elation and of craving at baseline were not significantly predictive of relapse. Those who had relapsed at 3 months were significantly more likely to remain drinking at 6 months. Rehospitalization within the first 3 months post discharge appeared to be protective against further relapse. CONCLUSIONS: Baseline patient factors, including levels of anxiety, appear to play a significant role in relapse to alcohol in this difficult to treat population. PMID- 20855411 TI - Comparison of alcohol-dependent patients at a gastroenterological and a psychiatric ward according to the Lesch alcoholism typology: implications for treatment. AB - AIMS: To assess the clinical and biological status of alcohol-dependent patients admitted to a psychiatric or a gastroenterological ward, assessing and comparing dimensions important for prescribing treatment for withdrawal and relapse prevention. METHODS: Eighty patients, alcohol-dependent according to international classification of diseases tenth revision and diagnostic and statistical manual, text revised, version IV, admitted to the Vienna General Hospital between January 2005 and November 2006, were examined, of whom 44 were admitted to the psychiatric ward and 36 to the gastroenterological ward. Dimensions of alcohol dependence were assessed using a computerized structured interview, the Lesch alcoholism typology (LAT). Biological markers and the model for end-stage liver disease (MELD) score defined the severity of alcohol-related physical disturbances. RESULTS: As might be expected, gastroenterological patients had more advanced physical diseases than psychiatric patients, and affective disorders and suicidal tendencies were significantly commoner among the psychiatric patients. Thus, LAT Type II patients were overrepresented at the gastroenterological ward and LAT Type III patients at the psychiatric ward. CONCLUSION: The severity of somatic diseases and psychiatric disorders as well as the distribution of the four types according to Lesch differ between alcohol dependent patients admitted to a psychiatric ward or a gastroenterological ward. Regarding the positive long-term outcome, different evidence-based medical treatment approaches for withdrawal and relapse prevention are needed for these patients. PMID- 20855412 TI - CYP1A1 modifies the effect of maternal exposure to environmental tobacco smoke on child behavior. AB - INTRODUCTION: Maternal environmental tobacco smoke (ETS) has been identified as a key risk factor for problem behavior in children, but the role of genetic susceptibility is not clear. The purpose of this study was to examine the metabolic genetic modification effect of exposure to ETS in nonsmoking mothers on child behavior at 2 years of age. METHODS: A prospective cohort study was conducted among 191 mothers who gave births between 2004 and 2005 and their infants in Taiwan. The mothers completed a questionnaire before delivery in which they provided information on exposure to ETS during pregnancy. Four metabolic genes, CYP1A1 MspI, CYP1A1 Ile462Val, GSTT1, and GSTM1 were isolated from both maternal and infant DNA samples. Children's behavior problems at 2 years of age were reported by their mothers using the Child Behavior Checklist/1.5-5. Multiple linear models were used to estimate the effects of ETS and genotype on child behavior. RESULTS: Maternal ETS exposure was associated with the anxious score. The ETS-exposed group with both the CYP1A1 MspI and the CYP1A1 Ile462Val variants had higher scores, as reflected in total CBCL score as well as scores on the internalizing scale and its emotional subdomain, the anxious scale, and the externalizing scale and its aggressive subdomain. CONCLUSIONS: Child behavioral problems may be associated with prenatal ETS exposure, and this effect may be modified by infant CYP1A1 MspI and CYP1A1 Ile462Val genes. PMID- 20855413 TI - A population-based examination of cigarette smoking and mental illness in Black Americans. AB - INTRODUCTION: This study examines the relation between tobacco use and cessation with lifetime and past year mental illness in a nationally representative sample of Blacks. METHODS: This cross-sectional study analyzed nationally representative data from 3,411 adult Blacks participating in the 2001-2003 National Survey of American Life. Smoking prevalence and quit rates according to lifetime and past year Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition mental disorders were assessed by a modified version of the Composite International Diagnostic Interview. RESULTS: Compared with those without mental illness, respondents with a lifetime, past year, or past month mental illness had a higher smoking prevalence (20.6%, 35.6%, 36.0%, and 45.4%, respectively) and lower quit rate (40.5%, 31.2%, and 26.2%, respectively). The odds of being a current smoker among Blacks with mental illness in their lifetime, past year, and past month, after adjusting for age, gender, education, poverty, and marital status were 1.76 (95% CI = 1.39-2.22), 1.57 (95% CI = 1.22-2.03), and 2.20 (95% CI = 1.56-3.12), respectively. Mental illness also was associated with heavier smoking. Blacks with past year mental illness represented 18.1% of the sample, yet consumed 23.9% of cigarettes smoked by Black smokers. Past year (odds ratio [OR] = 0.72, 95% CI = 0.53-0.97) and past month (OR = 0.54, 95% CI = 0.29-0.98) mental illness were associated with a lower odds of quitting for at least 1 year. CONCLUSIONS: Findings indicate that mental illness is significantly associated with tobacco use in Blacks. Tobacco cessation interventions that address mental illness as a barrier to cessation are needed. PMID- 20855414 TI - Brief smoking cessation intervention in relation to breast cancer surgery: a randomized controlled trial. AB - BACKGROUND: Smokers are more prone to develop postoperative complications. Smoking cessation intervention beginning 4-8 weeks prior to surgery improves the postoperative outcome. Cancer patients, however, often undergo surgery less than 4 weeks after diagnosis. The primary objective of this study was therefore to examine if a brief smoking cessation intervention shortly before breast cancer surgery would influence postoperative complications and smoking cessation. METHODS: A randomized controlled multicentre trial with blinded outcome assessment conducted at 3 hospitals in Denmark. One hundred and thirty patients were randomly assigned to brief smoking intervention (n = 65) or standard care (n = 65). The intervention followed the principles of motivational interviewing and included personalized nicotine replacement therapy aimed at supporting smoking cessation from 2 days before to 10 days after surgery. RESULTS: The overall postoperative complication rate (including seroma requiring aspiration) was 61% in both groups risk ratio (RR) 1.00 (95% CI 0.75-1.33). The wound complication rate was 44% versus 45%. The effect on perioperative smoking cessation was modest, 28% intervention versus 11% control group patients, RR 2.49 (95% CI 1.10 5.60). There was no effect on smoking cessation at 12 months, 13% versus 9%. CONCLUSIONS: Brief smoking intervention administered shortly before breast cancer surgery modestly increased self-reported perioperative smoking cessation without having any clinical impact on postoperative complications. The study adds to the body of evidence indicating that brief intervention has no clinical importance for surgical patients in regard to postoperative morbidity. Future studies should be designed to determine the optimal time of smoking cessation before surgery. PMID- 20855416 TI - Demyelination versus remyelination in progressive multiple sclerosis. AB - The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ~18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number (P<0.05). Conversely, the proportion of remyelinated shadow plaques (P<0.05) and the overall remyelination capacity (P<0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis. By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding demyelination. Spinal cord lesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new demyelination, including active demyelination in secondary progressive multiple sclerosis. 'Recurrent' slowly expanding demyelination, affecting remyelinated areas, and the load of slowly expanding demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r = -0.53; P<0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain. We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing remitting/secondary progressive multiple sclerosis. Our data also indicate that slowly expanding demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding demyelination as an important pathological correlate of clinical progression. PMID- 20855415 TI - Schizophrenia, myelination, and delayed corollary discharges: a hypothesis. AB - Any etiological theory of schizophrenia must account for at least 3 distinctive features of the disorder, namely its excessive dopamine neurotransmission, its frequent periadolescent onset, and its bizarre, pathognomonic symptoms. In this article, we theorize that each of these features could arise from a single underlying cause--namely abnormal myelination of late-developing frontal white matter fasciculi. Specifically, we suggest that abnormalities in frontal myelination result in conduction delays in the efference copies initiated by willed actions. These conduction delays cause the resulting corollary discharges to be generated too late to suppress the sensory consequences of the willed actions. The resulting ambiguity as to the origins of these actions represents a phenomenologically and neurophysiologically significant prediction error. On a phenomenological level, the perception of salience in a self-generated action leads to confusion as to its origins and, consequently, passivity experiences and auditory hallucinations. On a neurophysiological level, this prediction error leads to the increased activity of dopaminergic neurons in the midbrain. This dopaminergic activity causes previously insignificant events to be perceived as salient, which exacerbates the budding hallucinations and passivity experiences and triggers additional first-rank symptoms such as delusions of reference. The article concludes with a discussion of the implications of the theory and some testable predictions which may form a worthwhile basis for future research. PMID- 20855417 TI - Expanding the concept of inflammatory neuropathies. PMID- 20855418 TI - Prospective 10-year surveillance of human prion diseases in Japan. AB - We analysed the epidemiological data and clinical features of patients with prion diseases that had been registered by the Creutzfeldt-Jakob Disease Surveillance Committee, Japan, over the past 10 years, since 1999. We obtained information on 1685 Japanese patients suspected as having prion diseases and judged that 1222 patients had prion diseases, consisting of definite (n=180, 14.7%) and probable (n=1029, 84.2%) cases, except for dura mater graft-associated Creutzfeldt-Jakob disease which also included possible cases (n=13, 1.1%). They were classified into 922 (75.5%) with sporadic Creutzfeldt-Jakob disease, 216 (17.7%) with genetic prion diseases, 81 (6.6%) with acquired prion diseases, including 80 cases of dura mater graft-associated Creutzfeldt-Jakob disease and one case of variant Creutzfeldt-Jakob disease, and three cases of unclassified Creutzfeldt Jakob disease (0.2%). The annual incidence rate of prion disease ranged from 0.65 in 1999 to 1.10 in 2006, with an average of 0.85, similar to European countries. Although methionine homozygosity at codon 129 polymorphism of the prion protein gene was reported to be very common (93%) in the general Japanese population, sporadic Creutzfeldt-Jakob disease in Japan was significantly associated with codon 129 homozygosity (97.5%), as reported in western countries. In sporadic Creutzfeldt-Jakob disease, MM1 type (Parchi's classification) is the most common, as in western countries. Among atypical sporadic Creutzfeldt-Jakob disease cases, the MM2 type appeared most common, probably related to the very high proportion of methionine allele in the Japanese population. As for iatrogenic Creutzfeldt Jakob disease, only dura mater graft-associated Creutzfeldt-Jakob disease cases were reported in Japan and, combined with the data from previous surveillance systems, the total number of dura mater graft-associated Creutzfeldt-Jakob disease was 138, comprising the majority of worldwide dura mater graft-associated Creutzfeldt-Jakob disease patients. Regarding genetic prion diseases, the most common mutation of prion protein gene was V180I (41.2%), followed by P102L (18.1%), E200K (17.1%) and M232R (15.3%), and this distribution was quite different from that in Europe. In particular, V180I and M232R were quite rare mutations worldwide. Patients with V180I or M232R mutations rarely had a family history of prion diseases, indicating that a genetic test for sporadic cases is necessary to distinguish these from sporadic Creutzfeldt-Jakob disease. In conclusion, our prospective 10-year surveillance revealed a frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease, and unique phenotypes of sporadic Creutzfeldt-Jakob disease and genetic prion diseases related to the characteristic distribution of prion protein gene mutations and polymorphisms in Japan, compared with those in western countries. PMID- 20855419 TI - Conduction block in acute motor axonal neuropathy. AB - Guillain-Barre syndrome is divided into two major subtypes, acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. The characteristic electrophysiological features of acute motor axonal neuropathy are reduced amplitude or absence of distal compound muscle action potentials indicating axonal degeneration. In contrast, autopsy study results show early nodal changes in acute motor axonal neuropathy that may produce motor nerve conduction block. Because the presence of conduction block in acute motor axonal neuropathy has yet to be fully recognized, we reviewed how often conduction block occurred and how frequently it either reversed or was followed by axonal degeneration. Based on Ho's criteria, acute motor axonal neuropathy was electrodiagnosed in 18 patients, and repeated motor nerve conduction studies were carried out on their median and ulnar nerves. Forearm segments of these nerves and the across-elbow segments of the ulnar nerve were examined to evaluate conduction block based on the consensus criteria of the American Association of Electrodiagnostic Medicine. Twelve (67%) of the 18 patients with acute motor axonal neuropathy had definite (n=7) or probable (n=5) conduction blocks. Definite conduction block was detected for one patient (6%) in the forearm segments of both nerves and probable conduction block was detected for five patients (28%). Definite conduction block was present across the elbow segment of the ulnar nerve in seven patients (39%) and probable conduction block in two patients (11%). Conduction block was reversible in seven of 12 patients and was followed by axonal degeneration in six. All conduction blocks had disappeared or begun to resolve within three weeks with no electrophysiological evidence of remyelination. One patient showed both reversible conduction block and conduction block followed by axonal degeneration. Clinical features and anti-ganglioside antibody profiles were similar in the patients with (n=12) and without (n=6) conduction block as well as in those with (n=7) and without (n=5) reversible conduction block, indicating that both conditions form a continuum; a pathophysiological spectrum ranging from reversible conduction failure to axonal degeneration, possibly mediated by antibody attack on gangliosides at the axolemma of the nodes of Ranvier, indicating that reversible conduction block and conduction block followed by axonal degeneration and axonal degeneration without conduction block constitute continuous electrophysiological conditions in acute motor axonal neuropathy. PMID- 20855420 TI - The greater black krait (Bungarus niger), a newly recognized cause of neuro myotoxic snake bite envenoming in Bangladesh. AB - Prospective studies of snake bite patients in Chittagong, Bangladesh, included five cases of bites by greater black kraits (Bungarus niger), proven by examination of the snakes that had been responsible. This species was previously known only from India, Nepal, Bhutan and Burma. The index case presented with descending flaccid paralysis typical of neurotoxic envenoming by all Bungarus species, but later developed generalized rhabdomyolysis (peak serum creatine kinase concentration 29,960 units/l) with myoglobinuria and acute renal failure from which he succumbed. Among the other four patients, one died of respiratory paralysis in a peripheral hospital and three recovered after developing paralysis, requiring mechanical ventilation in one patient. One patient suffered severe generalized myalgia and odynophagia associated with a modest increase in serum creatine kinase concentration. These are the first cases of Bungarus niger envenoming to be reported from any country. Generalized rhabdomyolysis has not been previously recognized as a feature of envenoming by any terrestrial Asian elapid snake, but a review of the literature suggests that venoms of some populations of Bungarus candidus and Bungarus multicinctus in Thailand and Vietnam may also have this effect in human victims. To investigate this unexpected property of Bungarus niger venom, venom from the snake responsible for one of the human cases of neuro-myotoxic envenoming was injected into one hind limb of rats and saline into the other under buprenorphine analgesia. All animals developed paralysis of the venom-injected limb within two hours. Twenty-four hours later, the soleus muscles were compared histopathologically and cytochemically. Results indicated a predominantly pre-synaptic action (beta bungarotoxins) of Bungarus niger venom at neuromuscular junctions, causing loss of synaptophysin and the degeneration of the terminal components of the motor innervation of rat skeletal muscle. There was oedema and necrosis of extrafusal muscle fibres in envenomed rat soleus muscles confirming the myotoxic effect of Bungarus niger venom, attributable to phospholipases A2. This study has demonstrated that Bungarus niger is widely distributed in Bangladesh and confirms the risk of fatal neuro-myotoxic envenoming, especially as no specific antivenom is currently manufactured. The unexpected finding of rhabdomyolysis should prompt further investigation of the venom components responsible. The practical implications of having to treat patients with rhabdomyolysis and consequent acute renal failure, in addition to the more familiar respiratory failure associated with krait bite envenoming, should not be underestimated in a country that is poorly equipped to deal with such emergencies. PMID- 20855422 TI - Effect of size fractionation on the toxicity of amosite and Libby amphibole asbestos. AB - Abnormally high incidences of asbestos-related pulmonary disease have been reported in residents of Libby, Montana, because of occupational and environmental exposure to asbestos-contaminated vermiculite. The mechanism by which Libby amphibole (LA) causes pulmonary injury is not known. The purpose of this study is to compare the cellular stress responses induced in primary human airway epithelial cells (HAECs) exposed to a respirable size fraction (<= 2.5 MUm) of Libby amphibole (LA(2.5)) to a similar size fraction of a reference amphibole sample amosite (AM(2.5)). HAEC were exposed to 0, 2.64, 13.2, or 26.4 MUg/cm(2) AM(2.5) or LA(2.5) or to equivalent doses of unfractionated amosite (AM) or LA for 2 or 24 h. Comparable messenger RNA transcript levels were observed for interleukin-8, cyclooxygenase-2, and heme oxygenase-1 in HAEC following a 24-h exposure to AM or LA. Conversely, exposure to AM(2.5) resulted in a 4- to 10-fold greater induction in these proinflammatory mediators compared with LA(2.5) after 24 h. Evaluation of the expression of 84 additional genes involved in cellular stress and toxicity responses confirmed a more robust response for AM(2.5) compared with LA(2.5) on an equal mass basis. Differences in total surface area (TSA) by gas adsorption, total particle number, or oxidant generation by the size-fractionated particles did not account for the observed difference in response. In summary, AM(2.5) and LA(2.5) are at least as potent in stimulating production of proinflammatory cytokines as unfractionated AM and LA. Interestingly, AM(2.5) was more potent at inducing a proinflammatory response than LA(2.5). This difference could not be explained by differences in mineral contamination between the two samples, TSA, or oxidant generation by the samples. PMID- 20855421 TI - Mapping Go-No-Go performance within the subthalamic nucleus region. AB - The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions. PMID- 20855424 TI - Emodin triggers DNA double-strand breaks by stabilizing topoisomerase II-DNA cleavage complexes and by inhibiting ATP hydrolysis of topoisomerase II. AB - Emodin, an anthraquinone derived from a plant and fungi, has been reported to possess potential genotoxicity, but the mechanism is not entirely clear. Here, we report that emodin causes DNA double-strand breaks (DSBs) through stabilization of topoisomerase (Topo) II-DNA cleavage complexes and inhibition of ATP hydrolysis. In our study, emodin did not induce mutagenecity in the salmonella mutation assay but caused genotoxicity in the thymidine kinase gene mutation assay and in the micronucleus test. Moreover, emodin induced DNA DSBs demonstrated by induction of comet tails, the expression of phosphorylated histone H2AX, and phosphorylation of ataxia telangiectasia mutated. Our studies also revealed that emodin exerted strong inhibitory activity against Topo II in the supercoiled pBR322 relaxation assay and in Topo II-mediated kinetoplast DNA decatenation, similar to the previous report. We also showed that the inhibitory effect of emodin on Topo II was because of its ability to stabilize Topo II-DNA complexes and to inhibit the ATP hydrolysis of Topo II. Furthermore, emodin was found to trigger DNA DSBs in a Topo II-dependent manner using the Topo II catalytic inhibitor aclarubicin and in Topo II-deficient mitoxantrone-resistant variant HL-60/MX2 cells. Together, these results suggest that in emodin-induced DNA DSBs and genotoxicity, stabilization of Topo II-DNA cleavage complexes and inhibition of ATP hydrolysis play an important role. PMID- 20855423 TI - SKN-1/Nrf2 inhibits dopamine neuron degeneration in a Caenorhabditis elegans model of methylmercury toxicity. AB - Methylmercury (MeHg) exposure from occupational, environmental, and food sources is a significant threat to public health. MeHg poisonings in adults may result in severe psychological and neurological deficits, and in utero exposures can confer embryonic defects and developmental delays. Recent epidemiological and vertebrate studies suggest that MeHg exposure may also contribute to dopamine (DA) neuron vulnerability and the propensity to develop Parkinson's disease (PD). In this study, we describe a Caenorhabditis elegans model of MeHg toxicity that shows that low, chronic exposure confers embryonic defects, developmental delays, decreases in brood size and animal viability, and DA neuron degeneration. Toxicant exposure results in the robust induction of the glutathione-S transferases (GSTs) gst-4 and gst-38 that are largely dependent on the PD associated phase II antioxidant transcription factor SKN-1/Nrf2. We also demonstrate that the expression of SKN-1, a protein previously localized to a small subset of chemosensory neurons and intestinal cells in the nematode, is also expressed in the DA neurons, and a reduction in SKN-1 gene expression increases MeHg-induced animal vulnerability and DA neuron degeneration. These studies recapitulate fundamental hallmarks of MeHg-induced mammalian toxicity, identify a key molecular regulator of toxicant-associated whole-animal and DA neuron vulnerability, and suggest that the nematode will be a useful in vivo tool to identify and characterize mediators of MeHg-induced developmental and DA neuron pathologies. PMID- 20855425 TI - The wrong of rights: the moral authority of the family. AB - I argue that the notion of human rights is a flawed notion of relatively recent historical origin, growing primarily out of Enlightenment concerns to separate human beings from their metaphysical and communal heritage. I critique liberal, secular individualism as an abstract perspective that fails to comprehend those fundamental family relations out of which genuine human life emerges and within which it must remain if it is to be perceptive, grounded, and concrete. Finally, I argue that the most important relations humans sustain to each other are internal, not external to them and that the bonding found through empathy is more insightful in decision making than the analytic connections engendered through human reason. PMID- 20855426 TI - The family and harmonious medical decision making: cherishing an appropriate Confucian moral balance. AB - This essay illustrates what the Chinese family-based and harmony-oriented model of medical decision making is like as well as how it differs from the modern Western individual-based and autonomy-oriented model in health care practice. The essay discloses the roots of the Chinese model in the Confucian account of the family and the Confucian view of harmony. By responding to a series of questions posed to the Chinese model by modern Western scholars in terms of the basic individualist concerns and values embedded in the modern Western model, we conclude that the Chinese people have justifiable reasons to continue to apply the Chinese model to their contemporary health care and medical practice. PMID- 20855427 TI - Functional conservation of DNA methylation in the pea aphid and the honeybee. AB - DNA methylation is a fundamental epigenetic mark known to have wide-ranging effects on gene regulation in a variety of animal taxa. Comparative genomic analyses can help elucidate the function of DNA methylation by identifying conserved features of methylated genes and other genomic regions. In this study, we used computational approaches to distinguish genes marked by heavy methylation from those marked by little or no methylation in the pea aphid, Acyrthosiphon pisum. We investigated if these two classes had distinct evolutionary histories and functional roles by conducting comparative analysis with the honeybee, Apis (Ap.) mellifera. We found that highly methylated orthologs in A. pisum and Ap. mellifera exhibited greater conservation of methylation status, suggesting that highly methylated genes in ancestral species may remain highly methylated over time. We also found that methylated genes tended to show different rates of evolution than unmethylated genes. In addition, genes targeted by methylation were enriched for particular biological processes that differed from those in relatively unmethylated genes. Finally, methylated genes were preferentially ubiquitously expressed among alternate phenotypes in both species, whereas genes lacking signatures of methylation were preferentially associated with condition specific gene regulation expression. Overall, our analyses support a conserved role for DNA methylation in insects with comparable methylation systems. PMID- 20855428 TI - Aging is accompanied by a progressive decrease of expression of the WRN gene in human blood mononuclear cells. AB - The WRN gene encodes DNA helicase participating in genome maintenance. We looked for associations of natural aging with expression and methylation of this gene in blood mononuclear cells and with its common polymorphisms. Analyses were performed in ethnically homogenous Polish Caucasians. The mean level of the WRN messenger RNA was significantly lower in long-living individuals than in young and middle-aged controls (p < .001 and p = .025, respectively). Analysis of the 361 bp WRN promoter CpG island showed that aging might be accompanied by a slight increase of its methylation status; however, it seems to be biologically insignificant. Finally, analysis of the WRN R834C, L1074F, and C1367R polymorphisms showed that the frequencies of the L1074F and C1367R polymorphisms were similar in all age groups tested, whereas the R834C polymorphism was absent from Polish Caucasians. We suggest that age-related decrease of the WRN expression but not its common genetic variants might contribute to human immunosenescence. PMID- 20855429 TI - Generation-biased gene expression in a bryophyte model system. AB - The evolution of land plants is tightly linked to the evolution of the alternation of generations. Because alternating ploidal generations share their genomes, investigating generation-biased gene expression can give insight into the evolution of life cycles in land plants. Toward this end, we describe gene expression differences associated with the alternation of isogenic sporophyte and gametophyte generations in bryophytes, extant representatives of early diverging land plants, using a moss model system (Funaria hygrometrica). We found that differentiation in gene expression between the sporophyte and gametophyte generations is weaker in the bryophyte model system than in Arabidopsis thaliana. This is in line with the basal phylogenetic position of bryophytes and with the origin of alternating generations from a purely haplontic life cycle. Comparative analysis of F. hygrometrica and A. thaliana gene expression data shows that there is limited conservation of generation-biased gene expression across land plants. However, genes showing shared sporophyte-biased expression in both F. hygrometrica and A. thaliana appear to be enriched for biological pathways representing critical molecular adaptations to terrestrial life. Comparative analyses of the expression of F. hygrometrica and A. thaliana regulatory genes suggest that conserved regulatory networks may be involved in growth and reproductive tissue development of the angiosperm and bryophyte sporophyte generations despite their morphological divergence. This study represents the first attempt to describe generation-biased gene expression in a plant with a well-developed sporophyte and gametophyte generations, and as such it lays the foundation for future targeted research on the developmental mechanisms underlying evolutionary diversification of plant sporophytes. PMID- 20855430 TI - Out of America to Africa or Asia: inference of dispersal histories using nuclear and plastid DNA and the S-RNase self-incompatibility locus. AB - The plant genus Lycium (Solanaceae) originated in the Americas and includes approximately 85 species that are distributed worldwide. The vast majority of Old World species occur in southern Africa and eastern Asia. In this study, we examine biogeographic relationships among Old World species using a phylogenetic approach coupled with molecular evolutionary analyses of the S-RNase self incompatibility gene. The phylogeny inferred from nuclear granule-bound starch synthase I (GBSSI), nuclear conserved ortholog set II (COSII) marker C2_At1g24360, and plastid spacer data (trnH-pbsA, trnD(GUC)-trnT(GGU), rpl32 trnL(UAG), and ndhF-rpl32) includes a clade of eastern Asian Lycium nested within the African species, suggesting initial dispersal from the Americas to Africa, with subsequent dispersal to eastern Asia. Molecular dating estimates suggest that these dispersal events occurred relatively recently, with dispersal from the Americas to Africa approximately 3.64 Ma (95% highest posterior density [HPD]: 1.58-6.27), followed by subsequent dispersal to eastern Asia approximately 1.21 Ma (95% HPD: 0.32-2.42). In accordance, the S-RNase genealogy shows that S-RNases isolated from Old World species are restricted to four lineages, a subset of the 14 lineages including S-RNases isolated from New World Lycium species, supporting a bottleneck of S-RNase alleles concomitant with a single dispersal event from the Americas to the Old World. Furthermore, the S-RNase genealogy is also consistent with dispersal of Lycium from Africa to Asia, as eastern Asian alleles are restricted to a subset of the lineages that also include African alleles. Such a multilocus approach, including complementary data from GBSSI, COSII, plastid spacer regions, and S-RNase, is powerful for understanding dispersal histories of closely related species. PMID- 20855431 TI - Patterns of codon usage bias in Silene latifolia. AB - Patterns of codon usage bias (CUB) convey useful information about the selection on synonymous codons induced by gene expression and contribute to an understanding of substitution patterns observed at synonymous sites. They can also be informative about the distinctive evolutionary properties of sex chromosomes such as genetic degeneration of the Y chromosome, dosage compensation, and hemizygosity of the X chromosome in males, which can affect the selection on codon usage. Here, we study CUB in Silene latifolia, a species of interest for studying the early stages of sex chromosome evolution. We have obtained a large expressed sequence tag data set containing more than 1,608 sequence fragments by 454 sequencing. Using three different methods, we conservatively define 21 preferred codons. Interestingly, the preferred codons in S. latifolia are almost identical to those in Arabidopsis thaliana, despite their long divergence time (we estimate average nonsynonymous site divergence to be 0.216, and synonymous sites are saturated). The agreement suggests that the nature of selection on codon usage has not changed significantly during the long evolutionary time separating the two species. As in many other organisms, the frequency of preferred codons is negatively correlated with protein length. For the 43 genes with both exon and intron sequences, we find a positive correlation between gene expression levels and GC content at third codon positions, but a strong negative correlation between expression and intron GC content, suggesting that the CUB we detect in S. latifolia is more likely to be due to natural selection than to mutational bias. Using polymorphism data, we detect evidence of ongoing natural selection on CUB, but we find little support for effects of biased gene conversion. An analysis of ten sex-linked genes reveals that the X chromosome has experienced significantly more unpreferred to preferred than preferred to unpreferred substitutions, suggesting that it may be evolving higher CUB. In contrast, numbers of substitutions between preferred and unpreferred codons are similar in both directions in the Y-linked genes, contrary to the expectation of genetic degeneration. PMID- 20855432 TI - Bullying and cyberbullying among deaf students and their hearing peers: an exploratory study. AB - A questionnaire on bullying and cyberbullying was administered to 30 secondary students (Grades 7-12) in a charter school for the Deaf and hard of hearing and a matched group of 22 hearing students in a charter secondary school on the same campus. Because the sample size was small and distributions non-normal, results are primarily descriptive and correlational. No significant differences by hearing status were detected in rates of conventional or cyberbullying or both forms of victimization. Cyberbullying and cybervictimization were strongly correlated, as were conventional bullying and victimization. Moral disengagement was positively correlated only with conventional bullying. Implications for practice and future research are discussed. PMID- 20855433 TI - Maturation of synaptic partners: functional phenotype and synaptic organization tuned in synchrony. AB - Maturation of principal neurons of the medial nucleus of the trapezoid body (MNTB) was assessed in the context of the developmental organization and activity of their presynaptic afferents, which grow rapidly to form calyces of Held and to establish mono-innervation between postnatal days (P)2 and 4. MNTB neurons and their inputs were studied from embryonic day (E)17, when the nucleus was first discernable, until P14 after the onset of hearing. Using a novel slice preparation containing portions of the cochlea, cochlear nucleus and MNTB, we determined that synaptic inputs form onto MNTB neurons at E17 and stimulation of the cochlear nucleus can evoke action potentials (APs) and Ca(2+) signals. We analysed converging inputs onto individual MNTB neurons and found that competition among inputs was resolved quickly, as a single large input, typically larger than 4 nA, emerged from P3-P4. During calyx growth but before hearing onset, MNTB cells acquired their mature, phasic firing property and quantitative real-time PCR confirmed a coincident increase in low threshold K(+) channel mRNA. These events occurred in concert with an increase in somatic surface area and a 7 fold increase in the current threshold (30 to >200 pA) required to evoke action potentials, as input resistance (R(in)) settled from embryonic values greater than 1 GOmega to approximately 200 MOmega. We postulate that the postsynaptic transition from hyperexcitability to decreased excitability during calyx growth could provide a mechanism to establish the mature 1:1 innervation by selecting the winning calyceal input based on synaptic strength. By comparing biophysical maturation of the postsynaptic cell to alterations in presynaptic organization, we propose that maturation of synaptic partners is coordinated by synaptic activity in a process that is likely to generalize to other neural systems. PMID- 20855434 TI - Protein kinase G-dependent mechanisms modulate hypoglossal motoneuronal excitability and long-term facilitation. AB - Since protein kinase-dependent modulation of motoneuronal excitability contributes to adaptive changes in breathing, we hypothesized that cGMP-dependent pathways activating protein kinase G (PKG) modulate motoneuronal inspiratory drive currents and long-term plasticity. In a medullary slice preparation from neonatal rat (postnatal days 0-4) generating spontaneous respiratory-related rhythm, hypoglossal (XII) motoneuronal inspiratory drive currents and respiratory related XII nerve activity were recorded. Focal application of a PKG activator, 8 bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP), to voltage-clamped XII motoneurones decreased inspiratory drive currents. In the presence of tetrodotoxin (TTX), 8-Br-cGMP decreased the exogenous postsynaptic inward currents induced by focal application of AMPA. Intracellular dialysis of XII motoneurones with an inhibitory peptide to PKG (PKGI) increased endogenous inspiratory-drive currents and exogenous AMPA-induced currents. Application of 8 Br-cGMP with PKGI had no further effect on spontaneous or evoked currents, confirming that the observed effects were induced by PKG. However, PKG differentially increased longer-term plasticity. Three 3 min applications (separated by 5 min) of the alpha(1)-adrenergic agonist phenylephrine (PE) in combination with 8-Br-cGMP yielded greater in vitro long-term facilitation than PE alone. These data indicate the presence of a cGMP/PKG-dependent signalling pathway in XII motoneurones that modulates inspiratory drive currents and plasticity of XII motoneurones, possibly contributing to their adaptation during physiological challenges, such as sleep and exercise. PMID- 20855435 TI - Comparison of synaptic transmission and plasticity between sensory and cortical synapses on relay neurons in the ventrobasal nucleus of the rat thalamus. AB - Relay neurons in the ventrobasal nucleus of the thalamus transmit somatosensory information to the cerebral cortex and receive sensory and cortical (feedback) synaptic inputs via, respectively, medial lemniscal (ML) and corticothalamic (CT) fibres. Here, we report that calcium-permeable AMPA receptors are expressed at CT synapses, but not ML synapses, and that the NMDA receptor (NMDAR)-mediated/non NMDAR-mediated synaptic current ratio is significantly larger at CT synapses than at ML synapses. Moreover, NMDAR-dependent LTP and L-type voltage-gated calcium channel-dependent LTD are readily induced at CT synapses, but not ML synapses. In particular, LTD of CT synaptic transmission is induced by spiking of postsynaptic relay neurons in continuous mode, but not burst mode, in current-clamp recordings. These results show that the strength of the cortical input to thalamic relay neurons is selectively subjected to use-dependent modification, which could be a mechanism for regulation of thalamocortical-corticothalamic interactions and the underlying sensory processing. PMID- 20855436 TI - Head direction cell firing properties and behavioural performance in 3-D space. AB - Previous studies have identified a population of neurons in the rat brain that discharge as a function of the animal's directional heading in the horizontal plane, independent of their location and on-going behaviour. Most studies on head direction (HD) cells have explored how they respond in two-dimensional environments within the horizontal plane. Many animals, however, live and locomote in a three-dimensional world. This paper reviews how HD cells respond when the animal locomotes on a vertical surface or inverted on a ceiling. We found that HD cells fire in a normal, direction-dependent manner when the rat is in the vertical plane, but not when the animal is inverted. Recent behavioural studies reported that rats are capable of accurately performing a navigational task when inverted, but only when the task was simple and started from not more than one or two entry points. Probe trials found that they did not have a flexible, map-like representation of space when inverted. The loss of the directional signal when the animal is in an inverted orientation may account for the absence of the map-like representation. Taken together, these findings indicate that a normal otolith signal contributes an important role to HD cell discharge. PMID- 20855437 TI - Lack of otolith involvement in balance responses evoked by mastoid electrical stimulation. AB - Passing current through mastoid electrodes (conventionally termed galvanic vestibular stimulation; GVS) evokes a balance response containing a short- and a medium-latency response. The origins of these two responses are debated. Here we test the hypotheses that they originate from net signals evoked by stimulation of otolith and semi-circular canal afferents, respectively. Based on anatomy and function, we predicted the directions of the stimulus-evoked net head rotation vector from the canals and the linear acceleration net vector from the otoliths. We tested these predictions in healthy adults by obtaining responses with the head in strategic postures to alter the relevance of the signals to the balance system. Cross-covariance between a stochastic waveform of stimulating current and motor output was used to assess the balance responses. Consistent with the canal hypothesis, with the head pitched down the medium-latency EMG response was abolished while the short-latency EMG response was maintained. The results, however, did not support the otolith hypothesis. The direction of the linear acceleration signal from the otoliths was predicted to change substantially when using monaural stimuli compared to binaural stimuli. In contrast, short-latency response direction measured from ground-reaction forces was not altered. It was always directed along the inter-aural axis irrespective of whether the stimulus was applied binaurally or monaurally, whether the head was turned in yaw through 90 deg, whether the head was pitched down through 90 deg, or combinations of these manipulations. We conclude that a net canal signal evoked by GVS contributes to the medium-latency response whilst a net otolith signal does not make a significant contribution to either the short- or medium-latency responses. PMID- 20855438 TI - Fatigue preconditioning increases fatigue resistance in mouse flexor digitorum brevis muscles with non-functioning K(ATP) channels. AB - The objective of this study was to determine how an initial fatigue bout (FAT1 at 37 degrees C) affects free myoplasmic Ca(2+) concentration and force ([Ca(2+)](i)/force) during a subsequent fatigue bout (FAT2) in mouse flexor digitorum brevis (FDB). During FAT1, both tetanic [Ca(2+)](i)/force decreased; however, they decreased to significantly lower levels when FAT1 was carried out in the presence of glibenclamide, a sarcolemmal K(ATP) (sK(ATP)) channel blocker. Glibenclamide also elicited greater increases in unstimulated [Ca(2+)](i)/force, which occurred when fibres failed to fully relax between contractions during FAT1. Finally, glibenclamide impaired force recovery after FAT1. The decreases in tetanic [Ca(2+)](i)/force and increases in unstimulated [Ca(2+)](i)/force were slower during FAT2 elicited 60 min after FAT1. Under control conditions, the effects were small with very few significant differences. In the presence of glibenclamide, on the other hand, the differences between FAT1 and FAT2 were very large. Unexpectedly, the differences in unstimulated and tetanic [Ca(2+)](i)/force between control and glibenclamide conditions observed during FAT1 were no longer observed during FAT2. The lack of differences was not related to a failure of glibenclamide to block K(ATP) channels during FAT2 because the effects of FAT1 on FAT2 were also observed using Kir6.2(-/-) mouse FDB, which lack sK(ATP) channel activity. The differences in [Ca(2+)](i)/force between FAT1 and FAT2 could be observed with FAT1 duration of just 30 s and a FAT1-FAT2 interval of at least 30 min. A modulation of factors involved in ischaemic pre conditioning, i.e. A1-adenosine receptors, sK(ATP) and mitochondrial K(ATP) (mK(ATP)) channels, PKC and reactive oxygen species, during FAT1 had no effect on FAT2 fatigue kinetics. It is concluded that a preceding fatigue bout triggers an acute physiological process that prevents the contractile dysfunction induced by non-functioning K(ATP) channels. PMID- 20855439 TI - Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis. AB - Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterised by the accumulation of lung surfactant in the alveoli. In most cases it is an autoimmune disease with antibodies directed against the growth factor granulocyte-macrophage colony stimulating factor (GM-CSF). Standard of care consists of whole lung lavages in symptomatic patients. An alternative treatment is GM-CSF injections. The case history is reported of a patient with PAP and severe dyspnoea and hypoxaemia. Whole lung lavages and GM-CSF initially resulted in partial remission. However, the patient's condition deteriorated and her saturation during rest with high-flow oxygen treatment was 85%. The patient was treated with an anti-CD20 antibody rituximab which resulted in dramatic improvement. Room air saturation increased to 98% with exercise and she no longer required supplemental oxygen. The diffusion capacity for carbon monoxide increased from 27% to 48% of predicted and the chest x-rays improved. Rituximab may be useful in the treatment of patients with unresponsive PAP. PMID- 20855441 TI - The lottery of mitral valve repair surgery. AB - Valve repair, where feasible, rather than valve replacement is the guideline recommended treatment for severe mitral regurgitation. To characterise 'real world' clinical practice data were reviewed on 12,255 mitral valve operations performed in the UK between 2004 and 2008, as reported in the 2009 UK Adult Cardiac Surgical Database Report. The data demonstrate a large variation in the use of mitral valve repair; while the national repair rate was 51%, this varied from 20% to 90% among different hospitals. Outcomes were worse in patients who had valve replacement as opposed to repair, including a higher risk of operative mortality and stroke, in all subgroups examined. Some patients were, by virtue of the hospitals they attend, therefore, less likely to survive and more likely to have complications, because of a low use of valve repair in those centres. Concentration of mitral valve surgery in designated regional reference centres should allow more equitable access to mitral valve repair. PMID- 20855440 TI - International prevalence of recurrent wheezing during the first year of life: variability, treatment patterns and use of health resources. AB - BACKGROUND: Recurrent wheezing (RW) during the first year of life is a major cause of respiratory morbidity worldwide, yet there are no studies on its prevalence at an international level. A study was undertaken to determine the prevalence of RW in infants during their first year of life in affluent and non affluent localities. METHODS: This international population-based study was performed in random samples of infants aged 12-15 months from 17 centres in Latin America and Europe. It uses a validated questionnaire answered by parents at the primary care health clinics where infants attend for growth/development monitoring and/or vaccine administration. RESULTS: Among the 30,093 infants surveyed, 45.2% (95% CI 44.7% to 45.8%) had at least one episode of wheezing and 20.3% (95% CI 19.8% to 20.7%) had RW. The mean prevalence of RW in Latin American and European centres was 21.4% (95% CI 20.9% to 21.9%) and 15.0% (95% CI 14.0% to 15.9%), respectively (p<0.001). There was significant morbidity associated with RW in terms of severe episodes (59.4%), visits to the emergency department (71.1%) and hospital admissions (26.8%); 46.1% used inhaled corticosteroids. CONCLUSIONS: The prevalence of RW in infants during the first year of life is high and varies between localities. A significant proportion of infants progress to a more severe condition which results in high use of health resources (visits to emergency department and hospitalisations). The prevalence of RW is lower and less severe in European than in Latin American centres, suggesting there is a higher risk for the disease in developing areas. PMID- 20855442 TI - Cardiac hybrid imaging with high-speed single-photon emission computed tomography/CT camera to detect ischaemia and coronary artery obstruction. PMID- 20855443 TI - Down-regulation of Rad51 expression overcomes drug resistance to gemcitabine in human non-small-cell lung cancer cells. AB - Gemcitabine (2',2'-difluorodeoxycytidine), a deoxycytidine analog, and erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor, are used clinically to treat patients with non-small-cell lung cancer (NSCLC). However, the molecular mechanisms for the drug resistance of gemcitabine in NSCLC cells are poorly understood. In this study, we used constructs containing human Rad51 cDNA or specific Rad51 small interfering RNA (siRNA) to examine the role of Rad51 in chemoresistance of gemcitabine in three different human NSCLC cell lines. Exposure of human NSCLC cell lines to gemcitabine increased the phosphorylation levels of mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal regulated kinase (ERK) 1/2 and AKT in a time- and dose-dependent manner, which was accompanied by an induction of Rad51 mRNA and protein expression. Gemcitabine increased the expression of Rad51 by increasing its mRNA and protein stability. Blockage of ERK1/2 or AKT activation by 1,4-diamino-2,3-dicyano-1,4 bis(methylthio)butadiene (U0126; MKK1/2 inhibitor) or 2-(4-morpholinyl)-8-phenyl 4H-1-benzopyran-4-one (LY294002; phosphatidyl inositol 3-kinase inhibitor), respectively, decreased the gemcitabine-induced Rad51 expression. Gemcitabine induced cytotoxicity was significantly increased using siRNA depletion of Rad51 or blockage of ERK1/2 and AKT activation. Erlotinib enhanced the gemcitabine induced cytotoxicity via the inactivation of ERK1/2 and AKT and the down regulation of Rad51. Enforced expression of constitutively active MKK1/2 or AKT recovered cell viability and Rad51 protein levels that were decreased by the combination of erlotinib and gemcitabine. Suppression of Rad51 expression or the inactivation of ERK1/2 or AKT signaling may be considered potential therapeutic modalities for gemcitabine-resistant lung cancer. PMID- 20855444 TI - Dopamine transporter-dependent and -independent striatal binding of the benztropine analog JHW 007, a cocaine antagonist with low abuse liability. AB - The benztropine analog N-(n-butyl)-3alpha-[bis(4'-fluorophenyl)methoxy]-tropane (JHW 007) displays high affinity for the dopamine transporter (DAT), but unlike typical DAT ligands, has relatively low abuse liability and blocks the effects of cocaine, including its self-administration. To determine sites responsible for the cocaine antagonist effects of JHW 007, its in vitro binding was compared with that of methyl (1R,2S,3S,5S)-3-(4-fluorophenyl)-8-methyl-8 azabicyclo[3.2.1]octane-2-carboxylate (WIN 35428) in rats, mice, and human DAT (hDAT)-transfected cells. A one-site model, with K(d) values of 4.21 (rat) and 8.99 nM (mouse) best fit the [(3)H]WIN 35428 data. [(3)H]JHW 007 binding best fit a two-site model (rat, 7.40/4400 nM; mouse, 8.18/2750 nM), although a one-site fit was observed with hDAT membranes (43.7 nM). Drugs selective for the norepinephrine and serotonin transporters had relatively low affinity in competition with [(3)H]JHW 007 binding, as did drugs selective for other sites identified previously as potential JHW 007 binding sites. The association of [(3)H]WIN 35428 best fit a one-phase model, whereas the association of [(3)H]JHW 007 best fit a two-phase model in all tissues. Because cocaine antagonist effects of JHW 007 have been observed previously soon after injection, its rapid association observed here may contribute to those effects. Multiple [(3)H]JHW 007 binding sites were obtained in tissue from mice lacking the DAT, suggesting these as yet unidentified sites as potential contributors to the cocaine antagonist effects of JHW 007. Unlike WIN 35428, the binding of JHW 007 was Na(+) independent. This feature of JHW 007 has been linked to the conformational status of the DAT, which in turn may contribute to the antagonism of cocaine. PMID- 20855445 TI - Adenosine receptor regulation of coronary blood flow in Ossabaw miniature swine. AB - Adenosine clearly regulates coronary blood flow (CBF); however, contributions of specific adenosine receptor (AR) subtypes (A(1), A(2A), A(2B), A(3)) to CBF in swine have not been determined. ARs generally decrease (A(1), A(3)) or increase (A(2A), A(2B)) cyclic adenosine monophosphate, a major mediator of vasodilation. We hypothesized that A(1) antagonism potentiates coronary vasodilation and coronary stent deployment in dyslipidemic Ossabaw swine elicits impaired vasodilation to adenosine that is associated with increased A(1)/A(2A) expression. The left main coronary artery was accessed with a guiding catheter allowing intracoronary infusions. After placement of a flow wire into the left circumflex coronary artery the responses to bolus infusions of adenosine were obtained. Steady-state infusion of AR-specific agents was achieved by using a small catheter fed over the flow wire in control pigs. CBF was increased by the A(2)-nonselective agonist 2-phenylaminoadenosine (CV1808) in a dose-dependent manner. Baseline CBF was increased by the highly A(1)-selective antagonist 8 cyclopentyl-1,3-dipropylxanthine (DPCPX), but not changed by other AR-specific agents. The nonselective A(2) antagonist 3,7-dimethyl-1-propargylxanthine and A(2A)-selective antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3 a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385) abolished adenosine-induced CBF, whereas A(2B) and A(3) antagonism had no effect. Dyslipidemia and stenting decreased adenosine-induced CBF ~70%, whereas A(1), A(2A), and A(2B) mRNA were up regulated in dyslipidemic versus control >5-fold and there was no change in the ratio of A(1)/A(2A) protein in microvessels distal to the stent. In control Ossabaw swine A(1) antagonism by DPCPX positively regulated basal CBF. Impaired adenosine-induced CBF after stenting in dyslipidemia is most likely caused by the altered balance between A(1) and A(2A) signaling, not receptor expression. PMID- 20855446 TI - Induction of insulin-producing cells derived from endometrial mesenchymal stem like cells. AB - Studies have demonstrated that mesenchymal stem-like cells can be isolated from endometrium. However, the potential of endometrial-derived stem cells to differentiate into insulin-positive cells and functionally secrete insulin remains undetermined. We isolated endometrial mesenchymal stem-like cells (EMSCs) from human endometrial tissue from six donors. The insulin-secreting function of EMSCs was further analyzed in vitro and in transplanted grafts in vivo. We successfully isolated EMSCs from human endometrium, and our results showed that EMSCs expressed high levels of stemness genes (Nanog, Oct-4, Nestin). Under specific induction conditions for 2 weeks, EMSCs formed three-dimensional spheroid bodies (SBs) and secreted C-peptide. The high insulin content of SB EMSCs was confirmed by enzyme-linked immunosorbent assay, and glucose responsiveness was demonstrated by measuring glucose-dependent insulin secretion. Using cDNA microarrays, we found that the expression profiles of SB-EMSCs are related to those of islet tissues. Insulin and C-peptide production in response to glucose was significantly higher in SB-EMSCs than in undifferentiated EMSC controls. Furthermore, upon differentiation, SB-EMSCs displayed increased mRNA expression levels of NKx2.2, Glut2, insulin, glucagon, and somatostatin. Our results also showed that SB-EMSCs were more resistant to oxidative damage and oxidative damage-induced apoptosis than fibroblasts from the same patient. It is noteworthy that SB-EMSCs xenotransplanted into immunocompromised mice with streptozotocin-induced diabetes restored blood insulin levels to control values and greatly prolonged the survival of graft cells. These data suggest that EMSCs not only play a novel role in the differentiation of pancreatic progenitors, but also can functionally enhance insulin production to restore the regulation of blood glucose levels in an in vivo transplantation model. PMID- 20855451 TI - Oxaliplatin in combination with liver-specific expression of interleukin 12 reduces the immunosuppressive microenvironment of tumours and eradicates metastatic colorectal cancer in mice. AB - BACKGROUND AND AIMS: New options are needed for the management and prevention of colorectal cancer liver metastases. Interleukin 12 (IL-12) is an immunostimulatory cytokine with proven antitumour effect in animal models. Despite evidence indicating its biological effect in humans, neither the recombinant protein nor gene therapy vectors expressing IL-12 have shown a relevant benefit in patients with cancer. OBJECTIVE: To develop a new approach to overcome the difficulties in obtaining a suitable expression pattern and the immunosuppressive milieu in the tumours which contribute to this poor performance. METHODS: A high-capacity ('gutless') adenoviral vector carrying a liver-specific, mifepristone (Mif)-inducible system for the expression of IL-12 (HC-Ad/RUmIL-12) was used in combination with chemotherapy. Tumours were established in the liver of C57BL/6 mice by inoculation of MC38 colon cancer cells. RESULTS: Intrahepatic injection of HC-Ad/RUmIL-12 and tailored induction regimens allowed the maintenance of safe and efficient levels of IL-12 in vivo. An individualised, stepwise increase in the dose of Mif (125-4000 MUg/kg) was needed to compensate for the progressive but transient downregulation of the inducible system. Repeated cycles of Mif induction (every 24 h for 10 days) were needed for optimal tumour eradication. However, complete protection against tumour rechallenge was seen in < 25% of the animals. The administration of oxaliplatin (5 mg/kg intraperitoneally) 3 days before starting the induction regimen achieved efficient elimination of liver metastases with a single cycle of IL-12 induction, and improved protection against tumour rechallenge. This was associated with a shift in the tumour microenvironment towards a more pro immunogenic phenotype, with an increase in the CD8+/T regulatory cell ratio and a reduction in myeloid-derived suppressor cells. These effects were not seen with 5 fluorouracil, irinotecan or gemcitabine. CONCLUSIONS: Long-term controlled expression of IL-12 using an HC-Ad vector in combination with oxaliplatin is effective and clinically applicable against hepatic colon cancer metastases. PMID- 20855452 TI - The London Classification of gastrointestinal neuromuscular pathology: a little more flexibility would be wise... PMID- 20855453 TI - Analysis of microarray data from the macaque corpus luteum; the search for common themes in primate luteal regression. AB - The factors and processes involved in regression of the primate corpus luteum (CL) are complex and not fully understood. Systemic identification of those genes that are differentially expressed utilizing macaque model systems of luteal regression could help clarify some of the important molecular events involved in loss of primate luteal structure and function during luteolysis. In addition, examining gene pathways involved in luteal regression may help elucidate novel approaches for overcoming infertility or designing ovary-based contraceptives. This review provides an overview of the current published microarray experiments evaluating the transcriptome of the macaque CL, and compares and contrasts the data from spontaneous, GnRH antagonist and prostaglandin F2alpha-induced luteal regression. In addition, further uses of these databases are discussed, as well as limitations of both array technology and the rhesus macaque genome array. PMID- 20855454 TI - RNA synthesis precision is regulated by preinitiation complex turnover. AB - TATA-binding protein (TBP) nucleates the assembly of the transcription preinitiation complex (PIC), and although TBP can bind promoters with high stability in vitro, recent results establish that virtually the entire TBP population is highly dynamic in yeast nuclei in vivo. This dynamic behavior is surprising in light of models that posit that a stable TBP-containing scaffold facilitates transcription reinitiation at active promoters. The dynamic behavior of TBP is a consequence of the enzymatic activity of the essential Snf2/Swi2 ATPase Mot1, suggesting that ensuring a highly mobile TBP population is critical for transcriptional regulation on a global scale. Here high-resolution tiling arrays were used to define how perturbed TBP dynamics impact the precision of RNA synthesis in Saccharomyces cerevisiae. We find that Mot1 plays a broad role in establishing the precision and efficiency of RNA synthesis: In mot1-42 cells, RNA length changes were observed for 713 genes, about twice the number observed in set2Delta cells, which display a previously reported propensity for spurious initiation within open reading frames. Loss of Mot1 led to both aberrant transcription initiation and termination, with prematurely terminated transcripts representing the largest class of events. Genetic and genomic analyses support the conclusion that these effects on RNA length are mechanistically tied to dynamic TBP occupancies at certain types of promoters. These results suggest a new model whereby dynamic disassembly of the PIC can influence productive RNA synthesis. PMID- 20855455 TI - Root responses to cadmium in the rhizosphere: a review. AB - This article reviews the responses of plant roots to elevated rhizosphere cadmium (Cd) concentrations. Cadmium enters plants from the soil solution. It traverses the root through symplasmic or apoplasmic pathways before entering the xylem and being translocated to the shoot. Leaf Cd concentrations in excess of 5-10 MUg g( 1) dry matter are toxic to most plants, and plants have evolved mechanisms to limit Cd translocation to the shoot. Cadmium movement through the root symplasm is thought to be restricted by the production of phytochelatins and the sequestration of Cd-chelates in vacuoles. Apoplasmic movement of Cd to the xylem can be restricted by the development of the exodermis, endodermis, and other extracellular barriers. Increasing rhizosphere Cd concentrations increase Cd accumulation in the plant, especially in the root. The presence of Cd in the rhizosphere inhibits root elongation and influences root anatomy. Cadmium concentrations are greater in the root apoplasm than in the root symplasm, and tissue Cd concentrations decrease from peripheral to inner root tissues. This article reviews current knowledge of the proteins involved in the transport of Cd across root cell membranes and its detoxification through sequestration in root vacuoles. It describes the development of apoplastic barriers to Cd movement to the xylem and highlights recent experiments indicating that their maturation is accelerated by high Cd concentrations in their immediate locality. It concludes that accelerated maturation of the endodermis in response to local Cd availability is of functional significance in protecting the shoot from excessive Cd loads. PMID- 20855456 TI - Potato tuber pectin structure is influenced by pectin methyl esterase activity and impacts on cooked potato texture. AB - Although cooked potato tuber texture is an important trait that influences consumer preference, a detailed understanding of tuber textural properties at the molecular level is lacking. Previous work has identified tuber pectin methyl esterase activity (PME) as a potential factor impacting on textural properties. In this study, tuber PME isoform and gene expression profiles have been determined in potato germplasm with differing textural properties as assessed using an amended wedge fracture method and a sloughing assay, revealing major differences between the potato types. Differences in pectin structure between potato types with different textural properties were revealed using monoclonal antibodies specific for different pectic epitopes. Chemical analysis of tuber pectin clearly demonstrated that, in tubers containing a higher level of total PME activity, there was a reduced degree of methylation of cell wall pectin and consistently higher peak force and work done values during the fracture of cooked tuber samples, demonstrating the link between PME activity, the degree of methylation of cell wall pectin, and cooked tuber textural properties. PMID- 20855457 TI - Testing the IMEter on rice introns and other aspects of intron-mediated enhancement of gene expression. AB - In many eukaryotes, spliceosomal introns are able to influence the level and site of gene expression. The mechanism of this Intron Mediated Enhancement (IME) has not yet been elucidated, but regulation of gene expression is likely to occur at several steps during and after transcription. Different introns have different intrinsic enhancing properties, but the determinants of these differences remain unknown. Recently, an algorithm called IMEter, which is able to predict the IME potential of introns without direct testing, has been proposed. A computer program was developed for Arabidopsis thaliana and rice (Oryza sativa L.), but was only tested experimentally in Arabidopsis by measuring the enhancement effect on GUS expression of different introns inserted within otherwise identical plasmids. To test the IMEter potential in rice, a vector bearing the upstream regulatory sequence of a rice beta-tubulin gene (OsTub6) fused to the GUS reporter gene was used. The enhancing intron interrupting the OsTub6 5'-UTR was precisely replaced by seven other introns carrying different features. GUS expression level in transiently transformed rice calli does not significantly correlate with the calculated IMEter score. It was also found that enhanced GUS expression was mainly due to a strong increase in the mRNA steady-state level and that mutations at the splice recognition sites almost completely abolished the enhancing effect. Splicing also appeared to be required for IME in Arabidopsis cell cultures, where failure of the OsTub6 5' region to drive high level gene expression could be rescued by replacing the poorly spliced rice intron with one from Arabidopsis. PMID- 20855459 TI - Superior plasma retention of a cross-linked human serum albumin dimer in nephrotic rats as a new type of plasma expander. AB - Human serum albumin (HSA) is used clinically as a plasma expander in patients with hypoalbuminemia and can also function as a drug carrier. However, the administered HSA is readily eliminated from the blood circulation under pathological conditions, especially the nephrotic syndrome. In this study, we present data on the pharmacokinetics of a structurally defined HSA dimer [two HSA molecules that are cross-linked by reaction with 1,6-bis(maleimido)hexane via Cys34] in nephrotic rats and its superior circulation persistence, owing to the molecular size effect. The half-time (t(1/2)) of the HSA dimer persisted in the circulation 1.3 times longer than that of monomeric HSA in normal rats, primarily because of the suppression of the accumulation of the HSA dimer in the skin and muscle. In nephrotic rats, the t(1/2) of the HSA monomer decreased considerably, whereas the HSA dimer remained unaltered in the blood stream, similar to that for normal rats. As a result, the t(1/2) of the HSA dimer was 2-fold longer than that of the HSA monomer. This longer t(1/2) can be attributed to the fact that accumulation in the kidney and urinary excretion of the HSA dimer were significantly suppressed. The cross-linked HSA dimer shows a longer blood circulation than native HSA monomer in nephrotic rats, which can be attributed to the suppression of renal filtration and leakage into the extravascular space. This HSA dimer has the potential for use as a drug carrier, new plasma expander, and an artificial albumin-based oxygen carrier under a high glomerular permeability condition such as nephrosis. PMID- 20855458 TI - Ecto-5'-nucleotidase and thiopurine cellular circulation: association with cytotoxicity. AB - Thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat acute lymphoblastic leukemia of childhood. To test the hypothesis that variation in the expression of genes within the "thiopurine pathway" might influence 6-MP and 6-TG sensitivity, we generated basal gene expression profiles and IC(50) values for both of these thiopurine drugs using a model system consisting of 194 Human Variation Panel lymphoblastoid cell lines. Association analysis showed that thiopurine S-methyltransferase, ecto-5'-nucleotidase (NT5E), and multidrug resistance protein 4 (ABCC4) expression were correlated with thiopurine cytotoxicity. Those observations suggested the possible existence of a "thiopurine cellular circulation" involving nucleotide efflux by ABCC4, hydrolysis of thiopurine nucleotide monophosphates outside of the cell by NT5E, and subsequent transport of thiopurine nucleosides back into the cell by nucleoside transporters. The existence of this cellular circulation was confirmed by a series of functional experiments performed with cultured cells stably or transiently transfected with ABCC4 and/or NT5E. Because of the central role of NT5E in this cellular circulation, the NT5E gene was resequenced using 287 DNA samples from three ethnic groups, with the identification of 68 single nucleotide polymorphisms (SNPs), 46 of which were novel. Several SNPs in the 5'-flanking region of NT5E were highly correlated with expression, rs9450278 having the lowest p value (p = 2.4 * 10(-10), R = -0.376). The thiopurine cellular circulation and genetic polymorphisms for genes encoding the proteins involved should be incorporated into future studies of thiopurine drug therapy and effect. PMID- 20855460 TI - Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer: a phase I study. AB - PURPOSE: Folate receptor alpha expression is highly restricted in normal adult tissues but upregulated in a wide range of human cancer types, including epithelial ovarian cancer. Farletuzumab, a humanized monoclonal antibody against folate receptor alpha, has shown antitumor activity and favorable toxicity in preclinical evaluation. This phase I, dose-escalation study was conducted to determine the safety of weekly i.v. farletuzumab and establish the maximum tolerated dose (MTD). EXPERIMENTAL DESIGN: Patients with platinum-refractory or platinum-resistant epithelial ovarian cancer received farletuzumab (12.5-400 mg/m(2)) on days 1, 8, 15, and 22 of a 5-week cycle. Intrapatient dose escalation was not permitted. Dose-limiting toxicity (DLT) was defined by treatment-related adverse event of grade 3 or higher, and the MTD was the highest dose at which one or none of six patients experienced a DLT. Disease progression was recorded using Response Evaluation Criteria in Solid Tumors criteria and serum CA-125. RESULTS: Twenty-five heavily pretreated patients were included in the safety, efficacy, and pharmacokinetic analyses. No DLTs or MTDs were encountered, and dose escalation was continued to farletuzumab 400 mg/m(2). C(max) and AUC(0-24) (area under the serum concentration-time curve) increased in an approximately dose proportional manner, and a nuclear imaging substudy confirmed tumor targeting. There were no objective responses. Stable disease by Response Evaluation Criteria in Solid Tumors was observed in nine (36%) patients and CA-125 reduction in four. Three patients received continued therapy and completed a total of up to three cycles. CONCLUSIONS: In this phase I study, farletuzumab administered as an i.v. infusion at doses of 12.5 to 400 mg/m(2) was generally safe and well tolerated in the management of heavily pretreated patients with epithelial ovarian cancer. PMID- 20855461 TI - Orally administered particulate beta-glucan modulates tumor-capturing dendritic cells and improves antitumor T-cell responses in cancer. AB - PURPOSE: The beneficial properties of beta-glucans have been recognized for centuries. Their proposed mechanisms of action in cancer therapy occur via stimulation of macrophages and priming of innate neutrophil complement receptor 3 for eliciting complement receptor 3-dependent cellular cytotoxicity of iC3b opsonized tumor cells. The current study is to investigate whether beta-glucan therapy has any effect on antitumor adaptive T-cell responses. EXPERIMENTAL DESIGN: We first examined the trafficking of orally administered particulate yeast-derived beta-glucan and its interaction with dendritic cells (DC) that captured tumor materials. Antigen-specific T cells were adoptively transferred into recipient mice to determine whether oral beta-glucan therapy induces augmented T-cell responses. Lewis lung carcinoma and RAM-S lymphoma models were used to test oral beta-glucan therapeutic effect. Further mechanistic studies including tumor-infiltrating T cells and cytokine profiles within the tumor milieu were determined. RESULTS: Orally administered particulate beta-glucan trafficked into spleen and lymph nodes and activated DCs that captured dying tumor cells in vivo, leading to the expansion and activation of antigen-specific CD4 and CD8 T cells. In addition, IFN-gamma production of tumor-infiltrating T cells and CTL responses were significantly enhanced on beta-glucan treatment, which ultimately resulted in significantly reduced tumor burden. Moreover, beta glucan-treated tumors had significantly more DC infiltration with the activated phenotype and significant levels of Th1-biased cytokines within the tumor microenvironment. CONCLUSIONS: These data highlight the ability of yeast-derived beta-glucan to bridge innate and adaptive antitumor immunity and suggest that it can be used as an adjuvant for tumor immunotherapy. PMID- 20855462 TI - Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population. AB - PURPOSE: The tumor suppressor p53 plays a crucial role in maintaining genomic stability and tumor prevention. Mdm2, Mdm4, and Hausp are all critical regulators of the p53 protein. Despite the importance of the p53 pathway in prostate cancer development and progression, little is known about the association of functional single-nucleotide polymorphisms (SNP) in the p53 pathway genes and prostate cancer aggressiveness. EXPERIMENTAL DESIGN: In this study, we analyze the association of SNPs in p53, Mdm2, Mdm4, and Hausp genes with prostate cancer clinicopathologic variables in a large hospital-based Caucasian prostate cancer cohort (N = 4,073). RESULTS: We found that the Mdm2 SNP309 T allele was associated with earlier onset prostate cancer (P = 0.004), higher Gleason scores (P = 0.004), and higher stages in men undergoing a radical prostatectomy (P = 0.011). Both the Mdm4 and Hausp SNPs (rs1380576 and rs1529916) were found to be associated with higher D'Amico risk prostate cancer category at the time of diagnosis (P = 0.023 and P = 0.046, respectively). Mdm4 SNP was also found to be associated with higher Gleason score at radical prostatectomy (P = 0.047). We did not observe any statistically significant association between the p53 Arg72Pro polymorphism and prostate cancer aggressiveness or pathologic variables. CONCLUSIONS: These results suggested the importance of these p53 regulators in prostate cancer development and progression. PMID- 20855463 TI - The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. AB - The voltage-gated sodium channel Na(v)1.7 plays a crucial role in pain, and drugs that inhibit hNa(v)1.7 may have tremendous therapeutic potential. ProTx-II and huwentoxin-IV (HWTX-IV), cystine knot peptides from tarantula venoms, preferentially block hNa(v)1.7. Understanding the interactions of these toxins with sodium channels could aid the development of novel pain therapeutics. Whereas both ProTx-II and HWTX-IV have been proposed to preferentially block hNa(v)1.7 activation by trapping the domain II voltage-sensor in the resting configuration, we show that specific residues in the voltage-sensor paddle of domain II play substantially different roles in determining the affinities of these toxins to hNa(v)1.7. The mutation E818C increases ProTx-II's and HWTX-IV's IC(50) for block of hNa(v)1.7 currents by 4- and 400-fold, respectively. In contrast, the mutation F813G decreases ProTx-II affinity by 9-fold but has no effect on HWTX-IV affinity. It is noteworthy that we also show that ProTx-II, but not HWTX-IV, preferentially interacts with hNa(v)1.7 to impede fast inactivation by trapping the domain IV voltage-sensor in the resting configuration. Mutations E1589Q and T1590K in domain IV each decreased ProTx-II's IC(50) for impairment of fast inactivation by ~6-fold. In contrast mutations D1586A and F1592A in domain IV increased ProTx-II's IC(50) for impairment of fast inactivation by ~4-fold. Our results show that whereas ProTx-II and HWTX-IV binding determinants on domain II may overlap, domain II plays a much more crucial role for HWTX-IV, and contrary to what has been proposed to be a guiding principle of sodium channel pharmacology, molecules do not have to exclusively target the domain IV voltage sensor to influence sodium channel inactivation. PMID- 20855464 TI - Functional selectivity in adrenergic and angiotensin signaling systems. AB - beta-Adrenergic and angiotensin II type 1A receptors are therapeutic targets for the treatment of a number of common human diseases. Pharmacological agents designed as antagonists for these receptors have positively affected the morbidity and mortality of patients with hypertension, heart failure, and renal disease. Antagonism of these receptors, however, may only partially explain the therapeutic benefits of beta-blockers and angiotensin receptor blockers given the emerging concept of functional selectivity or biased agonism. This new pharmacological paradigm suggests that multiple signaling pathways can be differentially modified by a single ligand-receptor interaction. This review examines the functional selectivity of beta-adrenergic and angiotensin II type 1A receptors with respect to their ability to signal via both G protein-dependent and G protein-independent mechanisms, with a focus on the multifunctional protein beta-arrestin. Also highlighted are the concept of "biased signaling" through beta-arrestin mediated pathways, the affect of ligand/receptor modification on such biased agonism, and the implications of functional selectivity for the development of the next generation of beta-blockers and angiotensin receptor blockers. PMID- 20855466 TI - The need to promote independent research on drugs. PMID- 20855465 TI - Monoacylglycerol lipase activity is a critical modulator of the tone and integrity of the endocannabinoid system. AB - Endocannabinoids are lipid molecules that serve as natural ligands for the cannabinoid receptors CB1 and CB2. They modulate a diverse set of physiological processes such as pain, cognition, appetite, and emotional states, and their levels and functions are tightly regulated by enzymatic biosynthesis and degradation. 2-Arachidonoylglycerol (2-AG) is the most abundant endocannabinoid in the brain and is believed to be hydrolyzed primarily by the serine hydrolase monoacylglycerol lipase (MAGL). Although 2-AG binds and activates cannabinoid receptors in vitro, when administered in vivo, it induces only transient cannabimimetic effects as a result of its rapid catabolism. Here we show using a mouse model with a targeted disruption of the MAGL gene that MAGL is the major modulator of 2-AG hydrolysis in vivo. Mice lacking MAGL exhibit dramatically reduced 2-AG hydrolase activity and highly elevated 2-AG levels in the nervous system. A lack of MAGL activity and subsequent long-term elevation of 2-AG levels lead to desensitization of brain CB1 receptors with a significant reduction of cannabimimetic effects of CB1 agonists. Also consistent with CB1 desensitization, MAGL-deficient mice do not show alterations in neuropathic and inflammatory pain sensitivity. These findings provide the first genetic in vivo evidence that MAGL is the major regulator of 2-AG levels and signaling and reveal a pivotal role for 2-AG in modulating CB1 receptor sensitization and endocannabinoid tone. PMID- 20855467 TI - Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. AB - BACKGROUND: Docosahexaenoic acid-paclitaxel (DHA-paclitaxel, Taxoprexin((r))) is made by covalently conjugating the essential fatty acid DHA to the paclitaxel molecule. Preclinical studies of DHA-paclitaxel have demonstrated increased activity relative to paclitaxel and the potential for an improved therapeutic ratio. In the present study, the efficacy and toxicity profiles of DHA-paclitaxel were compared with those of dacarbazine. METHODS: In this study, 393 chemonaive patients with metastatic melanoma were randomly assigned to receive either DHA paclitaxel at a starting dose of 900 mg/m(2) IV on day 1 every 3 weeks or dacarbazine at a starting dose of 1000 mg/m(2) IV on day 1 every 3 weeks. The primary end point of the study was the comparison of overall survival (OS). RESULTS: No significant difference in OS was noted between patients in the DHA paclitaxel and dacarbazine arms. Similarly, there were no significant differences in response rate, duration of response, time to progression, and time to treatment failure between the two drugs. Safety results of the two drugs were as predicted from prior studies. Myelosuppression was more common with DHA paclitaxel. CONCLUSIONS: DHA-paclitaxel was not superior to dacarbazine. We conclude that further studies with the drug on an every 3-week schedule in melanoma are not warranted. PMID- 20855468 TI - Two doses of NGR-hTNF in combination with capecitabine plus oxaliplatin in colorectal cancer patients failing standard therapies. AB - BACKGROUND: asparagine-glycine-arginine-human tumour necrosis factor (NGR-hTNF), an agent selectively damaging the tumour vasculature, showed a biphasic dose response curve in preclinical models. Previous phase I trials of NGR-hTNF indicated 0.8 and 45 MUg/m(2) as optimal biological and maximum-tolerated dose, respectively. PATIENTS AND METHODS: Two sequential cohorts of 12 colorectal cancer (CRC) patients who had failed standard therapies received NGR-hTNF 0.8 or 45 MUg/m(2) in combination with capecitabine-oxaliplatin (XELOX). RESULTS: Median number of prior treatment lines was 3 in the low-dose and 2 in the high-dose cohort. Overall, 21 patients had been pretreated with oxaliplatin-based regimens. No grade 3-4 NGR-hTNF-related toxicities were observed. Grade 1-2 chills were reported in 43% and 40% of cycles in the low-dose and high-dose cohorts, respectively. In the low-dose cohort, one patient achieved a partial response and five had stable disease for a median of 4.6 months. In the high-dose cohort, six patients had stable disease for a median of 3.6 months. Three-month progression free survival (PFS) rates were 50% and 33% in the low-dose and high-dose cohort, respectively. Three patients in low-dose cohort experienced PFS longer than PFS on last prior therapy. CONCLUSIONS: Both NGR-hTNF doses were safely combined with XELOX in pretreated CRC patients. Hint of activity was apparent only with low dose NGR-hTNF. PMID- 20855469 TI - Advances in population surveillance for physical activity and sedentary behavior: reliability and validity of time use surveys. AB - Many countries conduct regular national time use surveys, some of which date back as far as the 1960s. Time use surveys potentially provide more detailed and accurate national estimates of the prevalence of sedentary and physical activity behavior than more traditional self-report surveillance systems. In this study, the authors determined the reliability and validity of time use surveys for assessing sedentary and physical activity behavior. In 2006 and 2007, participants (n = 134) were recruited from work sites in the Australian state of New South Wales. Participants completed a 2-day time use diary twice, 7 days apart, and wore an accelerometer. The 2 diaries were compared for test-retest reliability, and comparison with the accelerometer determined concurrent validity. Participants with similar activity patterns during the 2 diary periods showed reliability intraclass correlations of 0.74 and 0.73 for nonoccupational sedentary behavior and moderate/vigorous physical activity, respectively. Comparison of the diary with the accelerometer showed Spearman correlations of 0.57-0.59 and 0.45-0.69 for nonoccupational sedentary behavior and moderate/vigorous physical activity, respectively. Time use surveys appear to be more valid for population surveillance of nonoccupational sedentary behavior and health-enhancing physical activity than more traditional surveillance systems. National time use surveys could be used to retrospectively study nonoccupational sedentary and physical activity behavior over the past 5 decades. PMID- 20855470 TI - Expression regulation and function of heparan sulfate 6-O-endosulfatases in the spermatogonial stem cell niche. AB - Glial cell line-derived neurotrophic factor (GDNF) is a heparan sulfate (HS) binding factor. GDNF is produced by somatic Sertoli cells, where it signals to maintain spermatogonial stem cells (SSCs) and reproduction. Here, we investigate the roles of extracellular HS 6-O-endosulfatases (Sulfs), Sulf1 and Sulf2, in the matrix transmission of GDNF from Sertoli cells to SSCs. Although Sulfs are not required for testis formation, Sulf deficiency leads to the accelerated depletion of SSCs, a testis phenotype similar to that of GDNF+/- mice. Mechanistically, we show that Sulfs are expressed in GDNF-producing Sertoli cells. In addition, reduced Sulf activity profoundly worsens haplo-deficient GDNF phenotypes in our genetic studies. These findings establish a critical role of Sulfs in promoting GDNF signaling and support a model in which Sulfs regulate the bioavailability of GDNF by enzymatically remodeling HS 6-O-desulfation to release GDNF from matrix sequestration. Further, Sertoli cell-specific transcriptional factor Wilm's tumor 1 (WT1) directly activates the transcription of both Sulf1 and Sulf2 genes. Together, our studies not only identify Sulfs as essential regulators of GDNF signaling in the SSC niche, but also as direct downstream targets of WT1, thus establishing a physiological role of WT1 in Sertoli cells. PMID- 20855471 TI - High-sensitivity O-glycomic analysis of mice deficient in core 2 {beta}1,6-N acetylglucosaminyltransferases. AB - Core 2 beta1,6-N-acetylglucosaminyltransferase (C2GnT), which exists in three isoforms, C2GnT1, C2GnT2 and C2GnT3, is one of the key enzymes in the O-glycan biosynthetic pathway. These isoenzymes produce core 2 O-glycans and have been correlated with the biosynthesis of core 4 O-glycans and I-branches. Previously, we have reported mice with single and multiple deficiencies of C2GnT isoenzyme(s) and have evaluated the biological and structural consequences of the loss of core 2 function. We now present more comprehensive O-glycomic analyses of neutral and sialylated glycans expressed in the colon, small intestine, stomach, kidney, thyroid/trachea and thymus of wild-type, C2GnT2 and C2GnT3 single knockouts and the C2GnT1-3 triple knockout mice. Very high-quality data have emerged from our mass spectrometry techniques with the capability of detecting O-glycans up to at least 3500 Da. We were able to unambiguously elucidate the types of O-glycan core, branching location and residue linkages, which allowed us to exhaustively characterize structural changes in the knockout tissues. The C2GnT2 knockout mice suffered a major loss of core 2 O-glycans as well as glycans with I-branches on core 1 antennae especially in the stomach and the colon. In contrast, core 2 O glycans still dominated the O-glycomic profile of most tissues in the C2GnT3 knockout mice. Analysis of the C2GnT triple knockout mice revealed a complete loss of both core 2 O-glycans and branched core 1 antennae, confirming that the three known isoenzymes are entirely responsible for producing these structures. Unexpectedly, O-linked mannosyl glycans are upregulated in the triple deficient stomach. In addition, our studies have revealed an interesting terminal structure detected on O-glycans of the colon tissues that is similar to the RM2 antigen from glycolipids. PMID- 20855473 TI - Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies. AB - The dominant tibial muscular dystrophy (TMD) and recessive limb-girdle muscular dystrophy 2J are allelic disorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentations were initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To further understand the physiopathology of these two diseases, we generated a mouse model carrying the FINmaj mutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distal muscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend to most muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutation leads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner of titin. By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected, demonstrating a participation of calpain 3 in the pathogenesis of this disease. PMID- 20855472 TI - Allele-specific DNA methylation: beyond imprinting. AB - Allele-specific DNA methylation (ASM) and allele-specific gene expression (ASE) have long been studied in genomic imprinting and X chromosome inactivation. But these types of allelic asymmetries, along with allele-specific transcription factor binding (ASTF), have turned out to be far more pervasive-affecting many non-imprinted autosomal genes in normal human tissues. ASM, ASE and ASTF have now been mapped genome-wide by microarray-based methods and NextGen sequencing. Multiple studies agree that all three types of allelic asymmetries, as well as the related phenomena of expression and methylation quantitative trait loci, are mostly accounted for by cis-acting regulatory polymorphisms. The precise mechanisms by which this occurs are not yet understood, but there are some testable hypotheses and already a few direct clues. Future challenges include achieving higher resolution maps to locate the epicenters of cis-regulated ASM, using this information to test mechanistic models, and applying genome-wide maps of ASE/ASM/ASTF to pinpoint functional regulatory polymorphisms influencing disease susceptibility. PMID- 20855474 TI - Association of SRD5A2 variants and serum androstane-3alpha,17beta-diol glucuronide concentration in Chinese elderly men. AB - BACKGROUND: Results of recent studies have demonstrated that genetic variants of the enzyme steroid 5alpha reductase type II (SRD5A2) are associated with serum concentrations of major androgen metabolites such as conjugates of androstane 3alpha,17beta-diol-glucuronide (3alpha-diol-G). However, this association was not consistently found among different ethnic groups. Thus, we aimed to determine whether the association with SRD5A2 genetic variations exists in a cohort of healthy Chinese elderly men, by examining 2 metabolite conjugates: androstane 3alpha,l7beta-diol-3-glucuronide (3alpha-diol-3G) and androstane-3alpha,17beta diol-17-glucuronide (3alpha-diol-17G). METHODS: We used GC-MS and LC-MS to measure serum sex steroid concentrations, including testosterone and dihydrotestosterone, and 3alpha-diol-3G and 3alpha-diol-17G in 1182 Chinese elderly men age 65 and older. Genotyping of the 3 SRD5A2 tagSNPs [rs3731586, rs12470143, and rs523349 (V89L)] was performed by using melting-temperature-shift allele-specific PCR. RESULTS: The well-described SRD5A2 missense variant rs523349 (V89L) was modestly associated with the 3alpha-diol-17G concentration (P = 0.040). On the other hand, SNP rs12470143 was found to be significantly correlated with 3alpha-diol-3G concentration (P = 0.021). Results of haplotype analysis suggested that the presence of an A-C-G haplotype leads to an increased 3alpha-diol-3G concentration, a finding consistent with results of single SNP analysis. CONCLUSIONS: The genetic variation of SRD5A2 is associated with circulating 3alpha-diol-3G and 3alpha-diol-17G concentrations in Chinese elderly men. In addition, we showed that SRD5A2 haplotypic association, rather than a single SNP alone, might be a better predictor of the 3alpha-diol-G concentration. Thus, the effect of either the haplotype itself or of other ungenotyped SNPs in linkage disequilibrium with the haplotype is responsible for the interindividual variation of 3alpha-diol-G. PMID- 20855477 TI - Management of patients with acute hyperkalemia. PMID- 20855478 TI - The "hypertriglyceridemic waist" phenotype and glucose intolerance in pregnancy. AB - BACKGROUND: Abdominal visceral adiposity in early pregnancy has been associated with impaired glucose tolerance in later pregnancy. The "hypertriglyceridemic waist" phenotype (i.e., abdominal obesity in combination with hyper triglyceridemia) is a clinical marker of visceral obesity. Our study aimed to assess the association between the hyper-triglyceridemic-waist phenotype in early pregnancy and glucose intolerance in later pregnancy. METHODS: Plasma triglycerides and waist girth were measured at 11-14 weeks of gestation among 144 white pregnant women. Glycemia was measured following a 75-g oral glucose tolerance test performed at 24-28 weeks of gestation. RESULTS: A waist girth greater than 85 cm in combination with a triglyceride level >= 1.7 mmol/L in the first trimester was associated with an increased risk of two-hour glucose >= 7.8 mmol/L following the 75-g oral glucose tolerance test (odds ratio [OR] 6.1, p = 0.002). This risk remained significant even after we controlled for maternal age, fasting glucose at first trimester and previous history of gestational diabetes (OR 4.7, p = 0.02). INTERPRETATION: Measurement of waist girth in combination with measurement of triglyceride concentrations in the first trimester of pregnancy could improve early screening for gestational glucose intolerance. PMID- 20855480 TI - Managing anticoagulation and antiplatelet therapy before interventional radiology procedures. PMID- 20855479 TI - Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study. AB - BACKGROUND: Previous studies have shown an association between acute myocardial infarction and preceding respiratory infection. Contradictory evidence exists on the influence of influenza vaccination and pneumococcal vaccination in preventing cardiovascular disease. We aimed to investigate the possible association of influenza vaccination and pneumococcal vaccination with acute myocardial infarction. METHODS: We used a matched case-control design with data from the United Kingdom General Practice Research Database. Cases were patients who were at least 40 years of age at diagnosis of first acute myocardial infarction recorded from Nov.1, 2001, to May 31, 2007, and were matched for sex, general practice, age and calendar time (i.e., month corresponding to index date of acute myocardial infarction), with up to four controls each. Data were analyzed using conditional logistic regression, adjusted for vaccination target groups, cardiovascular risk factors, treatment medications and attendances at a general practice. RESULTS: We included 78 706 patients, of whom 16 012 were cases and 62 694 were matched controls. Influenza vaccination had been received in the previous year by 8472 cases (52.9%) and 32 081 controls (51.2%) and was associated with a 19% reduction in the rate of acute myocardial infarction (adjusted odds ratio [OR] 0.81, 95% confidence interval [CI] 0.77-0.85). Early seasonal influenza vaccination was associated with a lower rate of acute myocardial infarction (adjusted OR 0.79, 95% CI 0.75-0.83) than vaccination after mid-November (adjusted OR 0.88, 95% CI 0.79-0.97). Pneumococcal vaccination was not associated with a reduction in the rate of acute myocardial infarction (adjusted OR 0.96, 95% CI 0.91-1.02). INTERPRETATION: Influenza vaccination but not pneumococcal vaccination is associated with a reduced rate of first acute myocardial infarction. This association and the potential benefit of early seasonal vaccination need to be considered in future experimental studies. PMID- 20855481 TI - Bedbug bites becoming bigger battle. PMID- 20855483 TI - Alberta doctors vote on province-wide medical staff bylaws. PMID- 20855482 TI - Global action urged in response to new breed of drug-resistant bacteria. PMID- 20855484 TI - Caring for HIV/AIDs orphans in Uganda. PMID- 20855485 TI - Standardization of genetic tests needed. PMID- 20855486 TI - A functional-structural kiwifruit vine model integrating architecture, carbon dynamics and effects of the environment. AB - BACKGROUND AND AIMS: Functional-structural modelling can be used to increase our understanding of how different aspects of plant structure and function interact, identify knowledge gaps and guide priorities for future experimentation. By integrating existing knowledge of the different aspects of the kiwifruit (Actinidia deliciosa) vine's architecture and physiology, our aim is to develop conceptual and mathematical hypotheses on several of the vine's features: (a) plasticity of the vine's architecture; (b) effects of organ position within the canopy on its size; (c) effects of environment and horticultural management on shoot growth, light distribution and organ size; and (d) role of carbon reserves in early shoot growth. METHODS: Using the L-system modelling platform, a functional-structural plant model of a kiwifruit vine was created that integrates architectural development, mechanistic modelling of carbon transport and allocation, and environmental and management effects on vine and fruit growth. The branching pattern was captured at the individual shoot level by modelling axillary shoot development using a discrete-time Markov chain. An existing carbon transport resistance model was extended to account for several source/sink components of individual plant elements. A quasi-Monte Carlo path-tracing algorithm was used to estimate the absorbed irradiance of each leaf. KEY RESULTS: Several simulations were performed to illustrate the model's potential to reproduce the major features of the vine's behaviour. The model simulated vine growth responses that were qualitatively similar to those observed in experiments, including the plastic response of shoot growth to local carbon supply, the branching patterns of two Actinidia species, the effect of carbon limitation and topological distance on fruit size and the complex behaviour of sink competition for carbon. CONCLUSIONS: The model is able to reproduce differences in vine and fruit growth arising from various experimental treatments. This implies it will be a valuable tool for refining our understanding of kiwifruit growth and for identifying strategies to improve production. PMID- 20855487 TI - Septic arthritis and Clostridium septicum: a clue to colon cancer. PMID- 20855488 TI - Quality evidence important for quality guidelines. PMID- 20855490 TI - Multiple sclerosis: liberation procedure. PMID- 20855491 TI - Preoperative marking of limbs. PMID- 20855492 TI - IDRC public scandal: phase 2. PMID- 20855493 TI - The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review. AB - BACKGROUND: It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3 3 was included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. METHODS: CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997-2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. RESULTS AND DISCUSSION: CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3 3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD. PMID- 20855494 TI - Reorganization of inhibitory synaptic circuits in rodent chronically injured epileptogenic neocortex. AB - Reduced synaptic inhibition is an important factor contributing to posttraumatic epileptogenesis. Axonal sprouting and enhanced excitatory synaptic connectivity onto rodent layer V pyramidal (Pyr) neurons occur in epileptogenic partially isolated (undercut) neocortex. To determine if enhanced excitation also affects inhibitory circuits, we used laser scanning photostimulation of caged glutamate and whole-cell recordings from GAD67-GFP-expressing mouse fast spiking (FS) interneurons and Pyr cells in control and undercut in vitro slices to map excitatory and inhibitory synaptic inputs. Results are 1) the region-normalized excitatory postsynaptic current (EPSC) amplitudes and proportion of uncaging sites from which EPSCs could be evoked (hotspot ratio) "increased" significantly in FS cells of undercut slices; 2) in contrast, these parameters were significantly "decreased" for inhibitory postsynaptic currents (IPSCs) in undercut FS cells; and 3) in rat layer V Pyr neurons, we found significant decreases in IPSCs in undercut versus control Pyr neurons. The decreases were mainly located in layers II and IV, suggesting a reduction in the efficacy of interlaminar synaptic inhibition. Results suggest that there is significant synaptic reorganization in this model of posttraumatic epilepsy, resulting in increased excitatory drive and reduced inhibitory input to FS interneurons that should enhance their inhibitory output and, in part, offset similar alterations in innervation of Pyr cells. PMID- 20855495 TI - NKX3.1 is a direct TAL1 target gene that mediates proliferation of TAL1 expressing human T cell acute lymphoblastic leukemia. AB - TAL1 (also known as SCL) is expressed in >40% of human T cell acute lymphoblastic leukemias (T-ALLs). TAL1 encodes a basic helix-loop-helix transcription factor that can interfere with the transcriptional activity of E2A and HEB during T cell leukemogenesis; however, the oncogenic pathways directly activated by TAL1 are not characterized. In this study, we show that, in human TAL1-expressing T-ALL cell lines, TAL1 directly activates NKX3.1, a tumor suppressor gene required for prostate stem cell maintenance. In human T-ALL cell lines, NKX3.1 gene activation is mediated by a TAL1-LMO-Ldb1 complex that is recruited by GATA-3 bound to an NKX3.1 gene promoter regulatory sequence. TAL1-induced NKX3.1 activation is associated with suppression of HP1-alpha (heterochromatin protein 1 alpha) binding and opening of chromatin on the NKX3.1 gene promoter. NKX3.1 is necessary for T-ALL proliferation, can partially restore proliferation in TAL1 knockdown cells, and directly regulates miR-17-92. In primary human TAL1-expressing leukemic cells, the NKX3.1 gene is expressed independently of the Notch pathway, and its inactivation impairs proliferation. Finally, TAL1 or NKX3.1 knockdown abrogates the ability of human T-ALL cells to efficiently induce leukemia development in mice. These results suggest that tumor suppressor or oncogenic activity of NKX3.1 depends on tissue expression. PMID- 20855496 TI - gammadelta T cells protect against lung fibrosis via IL-22. AB - Inflammation-induced pulmonary fibrosis (PF) leads to irreversible loss of lung function and is a predictor of mortality in numerous lung diseases. Why some subjects with lung inflammation but not others develop PF is unclear. In a mouse model of hypersensitivity pneumonitis that progresses to lung fibrosis upon repeated exposure to the ubiquitous microorganism Bacillus subtilis, gammadelta T cells expand in the lung and inhibit collagen deposition. We show that a subset of these gammadelta cells represents the predominant source of the Th17 cytokine IL-22 in this model. Preventing expression of IL-22, either by mutating the aryl hydrocarbon receptor (AhR) or inhibiting AhR signaling, accelerated lung fibrosis. Direct blockade of IL-22 also enhanced collagen deposition in the lung, whereas administration of recombinant IL-22 inhibited lung fibrosis. Moreover, the presence of protective gammadelta T cells and IL-22 diminished recruitment of CD4(+) T cells to lung. These data reveal a protective pathway that involves the inhibition of alphabeta T cells by regulatory IL-22-secreting gammadelta T cells. PMID- 20855497 TI - Conversion of Helicobacter pylori CagA from senescence inducer to oncogenic driver through polarity-dependent regulation of p21. AB - The Helicobacter pylori CagA bacterial oncoprotein plays a critical role in gastric carcinogenesis. Upon delivery into epithelial cells, CagA causes loss of polarity and activates aberrant Erk signaling. We show that CagA-induced Erk activation results in senescence and mitogenesis in nonpolarized and polarized epithelial cells, respectively. In nonpolarized epithelial cells, Erk activation results in oncogenic stress, up-regulation of the p21(Waf1/Cip1) cyclin-dependent kinase inhibitor, and induction of senescence. In polarized epithelial cells, CagA-driven Erk signals prevent p21(Waf1/Cip1) expression by activating a guanine nucleotide exchange factor-H1-RhoA-RhoA-associated kinase-c-Myc pathway. The microRNAs miR-17 and miR-20a, induced by c-Myc, are needed to suppress p21(Waf1/Cip1) expression. CagA also drives an epithelial-mesenchymal transition in polarized epithelial cells. These findings suggest that CagA exploits a polarity-signaling pathway to induce oncogenesis. PMID- 20855498 TI - Lnk-dependent axis of SCF-cKit signal for osteogenesis in bone fracture healing. AB - The therapeutic potential of hematopoietic stem cells/endothelial progenitor cells (HSCs/EPCs) for fracture healing has been demonstrated with evidence for enhanced vasculogenesis/angiogenesis and osteogenesis at the site of fracture. The adaptor protein Lnk has recently been identified as an essential inhibitor of stem cell factor (SCF)-cKit signaling during stem cell self-renewal, and Lnk deficient mice demonstrate enhanced hematopoietic reconstitution. In this study, we investigated whether the loss of Lnk signaling enhances the regenerative response during fracture healing. Radiological and histological examination showed accelerated fracture healing and remodeling in Lnk-deficient mice compared with wild-type mice. Molecular, physiological, and morphological approaches showed that vasculogenesis/angiogenesis and osteogenesis were promoted in Lnk deficient mice by the mobilization and recruitment of HSCs/EPCs via activation of the SCF-cKit signaling pathway in the perifracture zone, which established a favorable environment for bone healing and remodeling. In addition, osteoblasts (OBs) from Lnk-deficient mice had a greater potential for terminal differentiation in response to SCF-cKit signaling in vitro. These findings suggest that inhibition of Lnk may have therapeutic potential by promoting an environment conducive to vasculogenesis/angiogenesis and osteogenesis and by facilitating OB terminal differentiation, leading to enhanced fracture healing. PMID- 20855500 TI - Bone matrix to growth factors: location, location, location. AB - The demonstration that fibrillin-1 mutations perturb transforming growth factor (TGF)-beta bioavailability/signaling in Marfan syndrome (MFS) changed the view of the extracellular matrix as a passive structural support to a dynamic modulator of cell behavior. In this issue, Nistala et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201003089) advance this concept by demonstrating how fibrillin-1 and 2 regulate TGF-beta and bone morphogenetic protein (BMP) action during osteoblast maturation. PMID- 20855499 TI - The Ets-1 transcription factor controls the development and function of natural regulatory T cells. AB - Regulatory T cells (T reg cells) constitute a population of CD4(+) T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1(-/-)) developed T cell-mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1(-/-) mice contained mostly activated T cells, including Th2 polarized CD4(+) cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1(-/-) T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1(-/-) T reg cells appeared intrinsically altered as Foxp3 expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1(-/-) T reg cells showed decreased in vitro suppression activity and did not protect Rag2(-/-) hosts from naive T cell induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression. PMID- 20855502 TI - Cdc48/p97 and Shp1/p47 regulate autophagosome biogenesis in concert with ubiquitin-like Atg8. AB - The molecular details of the biogenesis of double-membraned autophagosomes are poorly understood. We identify the Saccharomyces cerevisiae AAA-adenosine triphosphatase Cdc48 and its substrate-recruiting cofactor Shp1/Ubx1 as novel components needed for autophagosome biogenesis. In mammals, the Cdc48 homologue p97/VCP and the Shp1 homologue p47 mediate Golgi reassembly by extracting an unknown monoubiquitinated fusion regulator from a complex. We find no requirement of ubiquitination or the proteasome system for autophagosome biogenesis but detect interaction of Shp1 with the ubiquitin-fold autophagy protein Atg8. Atg8 coupled to phosphatidylethanolamine (PE) is crucial for autophagosome elongation and, in vitro, mediates tethering and hemifusion. Interaction with Shp1 requires an FK motif within the N-terminal non-ubiquitin-like Atg8 domain. Based on our data, we speculate that autophagosome formation, in contrast to Golgi reassembly, requires a complex in which Atg8 functionally substitutes ubiquitin. This, for the first time, would give a rationale for use of the ubiquitin-like Atg8 during macroautophagy and would explain why Atg8-PE delipidation is necessary for efficient macroautophagy. PMID- 20855501 TI - The cell biology of vision. AB - Humans possess the remarkable ability to perceive color, shape, and motion, and to differentiate between light intensities varied by over nine orders of magnitude. Phototransduction--the process in which absorbed photons are converted into electrical responses--is the first stage of visual processing, and occurs in the outer segment, the light-sensing organelle of the photoreceptor cell. Studies of genes linked to human inherited blindness have been crucial to understanding the biogenesis of the outer segment and membrane-trafficking of photoreceptors. PMID- 20855503 TI - Elm1 kinase activates the spindle position checkpoint kinase Kin4. AB - Budding yeast asymmetric cell division relies upon the precise coordination of spindle orientation and cell cycle progression. The spindle position checkpoint (SPOC) is a surveillance mechanism that prevents cells with misoriented spindles from exiting mitosis. The cortical kinase Kin4 acts near the top of this network. How Kin4 kinase activity is regulated and maintained in respect to spindle positional cues remains to be established. Here, we show that the bud neck associated kinase Elm1 participates in Kin4 activation and SPOC signaling by phosphorylating a conserved residue within the activation loop of Kin4. Blocking Elm1 function abolishes Kin4 kinase activity in vivo and eliminates the SPOC response to spindle misalignment. These findings establish a novel function for Elm1 in the coordination of spindle positioning with cell cycle progression via its control of Kin4. PMID- 20855504 TI - Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability. AB - Von Hippel-Lindau (VHL) tumor suppressor gene mutations predispose carriers to kidney cancer. The protein pVHL has been shown to interact with microtubules (MTs), which is critical to cilia maintenance and mitotic spindle orientation. However, the function for pVHL in the regulation of MT dynamics is unknown. We tracked MT growth via the plus end marker EB3 (end-binding protein 3)-GFP and inferred additional parameters of MT dynamics indirectly by spatiotemporal grouping of growth tracks from live cell imaging. Our data establish pVHL as a near-optimal MT-stabilizing protein: it attenuates tubulin turnover, both during MT growth and shrinkage, inhibits catastrophe, and enhances rescue frequencies. These functions are mediated, in part, by inhibition of tubulin guanosine triphosphatase activity in vitro and at MT plus ends and along the MT lattice in vivo. Mutants connected to the VHL cancer syndrome are differentially compromised in these activities. Thus, single cell-level analysis of pVHL MT regulatory function allows new predictions for genotype to phenotype associations that deviate from the coarser clinically defined mutant classifications. PMID- 20855505 TI - An Atg9-containing compartment that functions in the early steps of autophagosome biogenesis. AB - Eukaryotes use the process of autophagy, in which structures targeted for lysosomal/vacuolar degradation are sequestered into double-membrane autophagosomes, in numerous physiological and pathological situations. The key questions in the field relate to the origin of the membranes as well as the precise nature of the rearrangements that lead to the formation of autophagosomes. We found that yeast Atg9 concentrates in a novel compartment comprising clusters of vesicles and tubules, which are derived from the secretory pathway and are often adjacent to mitochondria. We show that these clusters translocate en bloc next to the vacuole to form the phagophore assembly site (PAS), where they become the autophagosome precursor, the phagophore. In addition, genetic analyses indicate that Atg1, Atg13, and phosphatidylinositol-3 phosphate are involved in the further rearrangement of these initial membranes. Thus, our data reveal that the Atg9-positive compartments are important for the de novo formation of the PAS and the sequestering vesicle that are the hallmarks of autophagy. PMID- 20855506 TI - alpha-Synuclein impairs macroautophagy: implications for Parkinson's disease. AB - Parkinson's disease (PD) is characterized pathologically by intraneuronal inclusions called Lewy bodies, largely comprised of alpha-synuclein. Multiplication of the alpha-synuclein gene locus increases alpha-synuclein expression and causes PD. Thus, overexpression of wild-type alpha-synuclein is toxic. In this study, we demonstrate that alpha-synuclein overexpression impairs macroautophagy in mammalian cells and in transgenic mice. Our data show that alpha-synuclein compromises autophagy via Rab1a inhibition and Rab1a overexpression rescues the autophagy defect caused by alpha-synuclein. Inhibition of autophagy by alpha-synuclein overexpression or Rab1a knockdown causes mislocalization of the autophagy protein, Atg9, and decreases omegasome formation. Rab1a, alpha-synuclein, and Atg9 all regulate formation of the omegasome, which marks autophagosome precursors. PMID- 20855507 TI - Two distinct secretory vesicle-priming steps in adrenal chromaffin cells. AB - Priming of large dense-core vesicles (LDCVs) is a Ca(2+)-dependent step by which LDCVs enter a release-ready pool, involving the formation of the soluble N-ethyl maleimide sensitive fusion protein attachment protein (SNAP) receptor complex consisting of syntaxin, SNAP-25, and synaptobrevin. Using mice lacking both isoforms of the calcium-dependent activator protein for secretion (CAPS), we show that LDCV priming in adrenal chromaffin cells entails two distinct steps. CAPS is required for priming of the readily releasable LDCV pool and sustained secretion in the continued presence of high Ca(2+) concentrations. Either CAPS1 or CAPS2 can rescue secretion in cells lacking both CAPS isoforms. Furthermore, the deficit in the readily releasable LDCV pool resulting from CAPS deletion is reversed by a constitutively open form of syntaxin but not by Munc13-1, a priming protein that facilitates the conversion of syntaxin to the open conformation. Our data indicate that CAPS functions downstream of Munc13s but also interacts functionally with Munc13s in the LDCV-priming process. PMID- 20855508 TI - Fibrillin-1 and -2 differentially modulate endogenous TGF-beta and BMP bioavailability during bone formation. AB - Extracellular regulation of signaling by transforming growth factor (TGF)-beta family members is emerging as a key aspect of organ formation and tissue remodeling. In this study, we demonstrate that fibrillin-1 and -2, the structural components of extracellular microfibrils, differentially regulate TGF-beta and bone morphogenetic protein (BMP) bioavailability in bone. Fibrillin-2-null (Fbn2( /-)) mice display a low bone mass phenotype that is associated with reduced bone formation in vivo and impaired osteoblast maturation in vitro. This Fbn2(-/-) phenotype is accounted for by improper activation of latent TGF-beta that selectively blunts expression of osterix, the transcriptional regulator of osteoblast maturation, and collagen I, the structural template for bone mineralization. Cultured osteoblasts from Fbn1(-/-) mice exhibit improper latent TGF-beta activation as well, but mature faster because of increased availability of otherwise matrix-bound BMPs. Additional in vitro evidence excludes a direct role of microfibrils in supporting mineral deposition. Together, these findings identify the extracellular microfibrils as critical regulators of bone formation through the modulation of endogenous TGF-beta and BMP signaling. PMID- 20855509 TI - Inhibition of T cells provides protection against early invasive pneumococcal disease. AB - Infections caused by Streptococcus pneumoniae are major causes of morbidity and mortality, which are in part mediated by immune cell-dependent mechanisms. Yet, the specific contributions of individual cell types to immunopathology are only partially understood. T cells are well characterized with respect to their function in protective humoral immune responses; however, their roles during early stages of infection and invasive pneumococcal disease (IPD) are less well defined. Using a mouse model of pneumococcal sepsis, we found that CD4(+) T cells were recruited to the lung as early as 12 h after intranasal infection. Recruitment was accompanied by upregulation of CD69 and B7-H1, reflecting T-cell activation. Unexpectedly, major histocompatibility complex (MHC) class II deficient mice, which lack CD4(+) T cells, displayed an increased survival despite comparable bacterial titers in the blood, spleen, and lung. The higher survival correlated with a lower cytokine and chemokine response upon S. pneumoniae challenge in MHC class II-deficient mice, suggesting that inflammation may contribute to the mortality of IPD. Comparable to the case for MHC class II deficient mice, antibody-mediated depletion of CD4(+) T cells and drug-induced inhibition of T-cell function with cyclosporine, or interference with T-cell activation using CTLA4-immunoglobulin (Abatacept), led to significant increases in survival during IPD. Our results reveal an important and adverse role of CD4(+) T cells in the pathogenesis of IPD and suggest that modulation of T-cell activation during early phases of S. pneumoniae invasive infection may provide a therapeutic option. PMID- 20855510 TI - Znu is the predominant zinc importer in Yersinia pestis during in vitro growth but is not essential for virulence. AB - Little is known about Zn homeostasis in Yersinia pestis, the plague bacillus. The Znu ABC transporter is essential for zinc (Zn) uptake and virulence in a number of bacterial pathogens. Bioinformatics analysis identified ZnuABC as the only apparent high-affinity Zn uptake system in Y. pestis. Mutation of znuACB caused a growth defect in Chelex-100-treated PMH2 growth medium, which was alleviated by supplementation with submicromolar concentrations of Zn. Use of transcriptional reporters confirmed that Zur mediated Zn-dependent repression and that it can repress gene expression in response to Zn even in the absence of Znu. Virulence testing in mouse models of bubonic and pneumonic plague found only a modest increase in survival in low-dose infections by the znuACB mutant. Previous studies of cluster 9 (C9) transporters suggested that Yfe, a well-characterized C9 importer for manganese (Mn) and iron in Y. pestis, might function as a second, high-affinity Zn uptake system. Isothermal titration calorimetry revealed that YfeA, the solute-binding protein component of Yfe, binds Mn and Zn with comparably high affinities (dissociation constants of 17.8 +/- 4.4 nM and 6.6 +/- 1.2 nM, respectively), although the complete Yfe transporter could not compensate for the loss of Znu in in vitro growth studies. Unexpectedly, overexpression of Yfe interfered with the znu mutant's ability to grow in low concentrations of Zn, while excess Zn interfered with the ability of Yfe to import iron at low concentrations; these results suggest that YfeA can bind Zn in the bacterial cell but that Yfe is incompetent for transport of the metal. In addition to Yfe, we have now eliminated MntH, FetMP, Efe, Feo, a substrate-binding protein, and a putative nickel transporter as the unidentified, secondary Zn transporter in Y. pestis. Unlike other bacterial pathogens, Y. pestis does not require Znu for high level infectivity and virulence; instead, it appears to possess a novel class of transporter, which can satisfy the bacterium's Zn requirements under in vivo metal-limiting conditions. Our studies also underscore the need for bacterial cells to balance binding and transporter specificities within the periplasm in order to maintain transition metal homeostasis. PMID- 20855511 TI - Constitutive MEK1 activation rescues anthrax lethal toxin-induced vascular effects in vivo. AB - Anthrax lethal toxin (LT) increases vascular leakage in a number of mammalian models and in human anthrax disease. Using a zebrafish model, we determined that vascular delivery of LT increased permeability, which was phenocopied by treatment with a selective chemical inhibitor of MEK1 and MEK2 (also known as mitogen-activated protein kinase [MAPK] kinase, MEK, or MKK). Here we investigate further the role of MEK1/phospho-ERK (pERK) in the action of LT. Overexpression of wild-type zebrafish MEK1 at high levels did not induce detrimental effects. However, a constitutively activated version, MEK1(S219D,S223D) (MEK1DD), induced early defects in embryonic development that correlated with increased ERK/MAPK phosphorylation. To bypass these early developmental defects and to provide a genetic tool for examining the action of lethal factor (LF), we generated inducible transgenic zebrafish lines expressing either wild-type or activated MEK1 under the control of a heat shock promoter. Remarkably, induction of MEK1DD transgene expression prior to LT delivery prevented vascular damage, while the wild-type MEK1 line did not. In the presence of both LT and MEK1DD transgene expression, cardiovascular development and function proceeded normally in most embryos. The resistance to microsphere leakage in transgenic animals demonstrated a protective role against LT-induced vascular permeability. A consistent increase in ERK phosphorylation among LT-resistant MEK1DD transgenic animals provided additional confirmation of transgene activation. These findings provide a novel genetic approach to examine mechanism of action of LT in vivo through one of its known targets. This approach may be generally applied to investigate additional pathogen-host interactions and to provide mechanistic insights into host signaling pathways affected by pathogen entry. PMID- 20855512 TI - Interleukin-17-mediated control of parasitemia in experimental Trypanosoma congolense infection in mice. AB - BALB/c mice are highly susceptible to experimental Trypanosoma congolense infections, whereas C57BL/6 mice are relatively resistant. Infected highly susceptible BALB/c mice die of systemic inflammatory response syndrome. Because interleukin-17 (IL-17) and Th17 cells regulate inflammatory responses, we investigated their role in the pathogenesis of experimental African trypanosomiasis in mice. We show that the production of IL-17 by spleen and liver cells and the serum IL-17 level increased after T. congolense infection in mice. Interestingly, infected highly susceptible BALB/c mice produced more IL-17 and had more Th17 cells than infected relatively resistant C57BL/6 mice. Paradoxically, neutralization of IL-17 with anti-IL-17 monoclonal antibody in vivo induced higher parasitemia in both the susceptible and the relatively resistant mice. Interestingly, anti-IL-17 antibody-treated mice had higher serum levels of alanine aminotransferase and aspartate aminotransferase, and the production of IL-10 and nitric oxide by liver cells was markedly decreased. Moreover, recombinant IL-17-treated mice exhibited significantly faster parasite control and lower peak parasitemia compared to control mice. Collectively, these results suggest that the IL-17/Th17 axis plays a protective role in murine experimental African trypanosomiasis. PMID- 20855513 TI - The capsular serotype of Streptococcus pneumoniae is more important than the genetic background for resistance to complement. AB - The polysaccharide capsule of Streptococcus pneumoniae inhibits phagocytic killing by innate immune mechanisms. Certain serotypes are associated with invasive disease while others with a nasopharyngeal carriage. The invasiveness of serotypes may partly be explained by ability to resist deposition of complement (C3) on the bacterial surface and consequent opsonophagocytic killing. In our previous studies, we observed that clinical isolates of serotypes 1 and 5, which are rarely detected in asymptomatic carriage, were resistant to complement deposition and opsonophagocytosis, whereas serotypes 6B and 23F, both common in carriage, were more sensitive to deposition of C3 and opsonophagocytic killing. However, presence of significant variation in C3 deposition between isolates of the same serotype indicated that factors other than the capsule also affect complement resistance. To distinguish the relative effect of the capsular serotype and other virulence factors on C3 deposition, we compared capsule switched mutants prepared in genetic backgrounds of pneumococcal strains TIGR4, 603, and 618. Clinical isolates which had the same multilocus sequence type but expressed different serotypes were also compared. We found that the serotype had a significant impact on complement resistance and that the more resistant the strain was to complement, the higher was the concentration of polysaccharide specific antibodies required for opsonophagocytic killing. Comparison of strains expressing the same capsular polysaccharides in the different genetic backgrounds and various capsular mutants of the same strain suggests that while the genotype affects complement resistance, the serotype is the most important determinant. Differences between serotypes were more significant than the differences between strains. PMID- 20855514 TI - Entamoeba histolytica infection and secreted proteins proteolytically damage enteric neurons. AB - The enteric protozoan parasite Entamoeba histolytica causes amebic colitis through disruption of the mucus layer, followed by binding to and destruction of epithelial cells. However, it is not known whether ameba infections or ameba components can directly affect the enteric nervous system. Analysis of mucosal innervations in the mouse model of cecal amebiasis showed that axon density was diminished to less than 25% of control. To determine whether amebas directly contributed to axon loss, we tested the effect of either E. histolytica secreted products (Eh-SEC) or soluble components (Eh-SOL) to an established coculture model of myenteric neurons, glia, and smooth muscle cells. Neuronal survival and axonal degeneration were measured after 48 h of exposure to graded doses of Eh SEC or Eh-SOL (10 to 80 MUg/ml). The addition of 80 MUg of either component/ml decreased the neuron number by 30%, whereas the axon number was decreased by 50%. Cytotoxicity was specific to the neuronal population, since the glial and smooth muscle cell number remained similar to that of the control, and was completely abrogated by prior heat denaturation. Neuronal damage was partially prevented by the cysteine protease inhibitor E-64, showing that a heat-labile protease was involved. E. histolytica lysates derived from amebas deficient in the major secreted protease EhCP5 caused a neurotoxicity similar to that of wild-type amebas. We conclude that E. histolytica infection and ameba protease activity can cause selective damage to enteric neurons. PMID- 20855515 TI - EseG, an effector of the type III secretion system of Edwardsiella tarda, triggers microtubule destabilization. AB - Edwardsiella tarda is a Gram-negative enteric pathogen that causes hemorrhagic septicemia in fish and both gastrointestinal and extraintestinal infections in humans. A type III secretion system (T3SS) was recently shown to contribute to pathogenesis, since deletions of various T3SS genes increased the 50% lethal dose (LD(50)) by about 1 log unit in the blue gourami infection model. In this study, we report EseG as the first identified effector protein of T3SS. EseG shares partial homology with two Salmonella T3SS effectors (SseG and SseF) over a conserved domain (amino acid residues 142 to 192). The secretion of EseG is dependent on a functional T3SS and, in particular, requires the chaperone EscB. Experiments using TEM-1 beta-lactamase as a fluorescence-based reporter showed that EseG was translocated into HeLa cells at 35 degrees C. Fractionation of infected HeLa cells demonstrated that EseG was localized to the host membrane fraction after translocation. EseG is able to disassemble microtubule structures when overexpressed in mammalian cells. This phenotype may require a conserved motif of EseG (EseG(142-192)), since truncated versions of EseG devoid of this motif lose their ability to cause microtubule destabilization. By demonstrating the function of EseG, our study contributes to the understanding of E. tarda pathogenesis. Moreover, the approach established in this study to identify type III effectors can be used to identify and characterize more type III and possible type VI effectors in Edwardsiella. PMID- 20855517 TI - Serotype-related variation in susceptibility to complement deposition and opsonophagocytosis among clinical isolates of Streptococcus pneumoniae. AB - The polysaccharide capsule is a major virulence factor of Streptococcus pneumoniae; it affects complement resistance and shields the bacterium from phagocytes. Certain capsular serotypes appear to be better able to cause invasive disease than others. Serotypes 1 and 5 are common causes of invasive disease but are rarely isolated from healthy carriers, whereas serotypes 6B and 23F are more frequently isolated from carriage than invasive disease. We have recently shown that serotypes 6B and 19F differ in resistance to complement C3 deposition and opsonophagocytic killing. In this study we assessed the complement resistance and susceptibility to opsonophagocytosis of several other serotypes targeted by the pneumococcal conjugate vaccines. Clinical isolates of serotypes 1, 4, 5, 14, 18C, and 23F were tested along reference strains of corresponding capsular types. The concentration of anticapsular antibodies required for opsonophagocytic killing correlated inversely with C3 deposition on the serotype. Serotype 1 was the most resistant of the clinical isolates to C3 deposition and, along with serotypes 5 and 19F, required the highest concentration of capsule antibodies for opsonophagocytic killing, whereas serotype 23F was the most sensitive to opsonophagocytosis. Sensitivity to C3 deposition and opsonophagocytosis was associated with serotype-specific mortality of invasive pneumococcal disease, suggesting that the primary pathogens, such as serotypes 1 and 5, are more resistant to complement and require a higher concentration of capsule antibodies for opsonophagocytic killing than the opportunistic serotypes such as 6B and 23F, which are associated with a more severe disease outcome. PMID- 20855516 TI - The type VI secretion system plays a role in type 1 fimbria expression and pathogenesis of an avian pathogenic Escherichia coli strain. AB - Avian pathogenic Escherichia coli (APEC) strains frequently cause extraintestinal infections and are responsible for significant economic losses in the poultry industry worldwide. APEC isolates are closely related to human extraintestinal pathogenic E. coli (ExPEC) strains and may also act as pathogens for humans. Known APEC virulence factors include adhesins such as type 1 fimbriae and curli, iron acquisition systems, and cytotoxins. Here we show that APEC strain SEPT362, isolated from a septicemic hen, expresses a type VI secretion system (T6SS); causes cytoskeleton rearrangements; and invades epithelial cells, replicates within macrophages, and causes lethal disease in chicks. To assess the contribution of the T6SS to SEPT362 pathogenesis, we generated two mutants, hcp (which encodes a protein suggested to be both secreted and a structural component of the T6SS) and clpV (encoding the T6SS ATPase). Both mutants showed decreased adherence and actin rearrangement on epithelial cells. However, only the hcp mutant presented a mild decrease in its ability to invade epithelial cells, and none of these mutants were defective for intramacrophage replication. Transcriptome studies showed that the level of expression of type 1 fimbriae was decreased in these mutants, which may account for the diminished adhesion and invasion of epithelial cells. The T6SS seems to be important for the disease process, given that both mutants were attenuated for infection in chicks. These results suggest that the T6SS influences the expression of type 1 fimbriae and contributes to APEC pathogenesis. PMID- 20855518 TI - Seed cell wall storage polysaccharides: models to understand cell wall biosynthesis and degradation. PMID- 20855519 TI - Nitric oxide is associated with long-term zinc tolerance in Solanum nigrum. AB - Nitric oxide (NO) has been identified as a signal molecule that interplays with reactive oxygen species in response to heavy metal stresses. Roles of NO in regulating cadmium toxicity and iron deficiency have been proposed; however, the function of NO in zinc (Zn) tolerance in plants remains unclear. Here, we investigated NO accumulation and its role in plant Zn tolerance. Zn-induced NO production promoted an increase in reactive oxygen species accumulation in Solanum nigrum roots by modulating the expression and activity of antioxidative enzymes. Subsequently, programmed cell death (PCD) was observed in primary root tips. Inhibiting NO accumulation by 2-phenyl-4,4,5,5-tetramethyl-imidazoline-1 oxyl-3-oxide (a specific NO scavenger) or N(G)-nitro-l-arginine-methyl ester (a NO synthase inhibitor) prevented the increase of superoxide radical and hydrogen peroxide as well as the subsequent cell death in the root tips, supporting the role of NO in Zn-induced PCD in the root tips. Zn-induced NO production affected the length of primary roots, the number of lateral roots, and root hair growth and thereby modulated root system architecture and activity. Investigation of metal contents in Zn-treated roots suggests that NO is required for metal (especially iron) uptake and homeostasis in plants exposed to excess Zn. Taken together, our results indicate that NO production and the subsequent PCD in root tips exposed to excess Zn are favorable for the S. nigrum seedling response to long-term Zn toxicity by modulating root system architecture and subsequent adaptation to Zn stress. PMID- 20855520 TI - The purple cauliflower arises from activation of a MYB transcription factor. AB - Anthocyanins are responsible for the color of many flowers, fruits, and vegetables. An interesting and unique Purple (Pr) gene mutation in cauliflower (Brassica oleracea var botrytis) confers an abnormal pattern of anthocyanin accumulation, giving the striking mutant phenotype of intense purple color in curds and a few other tissues. To unravel the nature of the Pr mutation in cauliflower, we isolated the Pr gene via a combination of candidate gene analysis and fine mapping. Pr encoded a R2R3 MYB transcription factor that exhibited tissue-specific expression, consistent with an abnormal anthocyanin accumulation pattern in the mutant. Transgenic Arabidopsis (Arabidopsis thaliana) and cauliflower plants expressing the Pr-D allele recapitulated the mutant phenotype, confirming the isolation of the Pr gene. Up-regulation of Pr specifically activated a basic helix-loop-helix transcription factor and a subset of anthocyanin structural genes encoding flavonoid 3'-hydroxylase, dihydroflavonol 4 reductase, and leucoanthocyanidin dioxygenase to confer ectopic accumulation of pigments in the purple cauliflower. Our results indicate that the genetic variation including a Harbinger DNA transposon insertion in the upstream regulatory region of the Pr-D allele is responsible for the up-regulation of the Pr gene in inducing phenotypic change in the plant. The successful isolation of Pr provides important information on the regulatory control of anthocyanin biosynthesis in Brassica vegetables, and offers a genetic resource for development of new varieties with enhanced health-promoting properties and visual appeal. PMID- 20855521 TI - Do metabolite transport processes limit photosynthesis? PMID- 20855522 TI - Ginsenoside-Rg1 induces angiogenesis via non-genomic crosstalk of glucocorticoid receptor and fibroblast growth factor receptor-1. AB - AIMS: Ginsenoside-Rg1, the most prevalent active constituent of Panax ginseng, has been shown to possess potent pro-angiogenic properties and therefore poses special interest for the development as a novel modality for angiotherapy. Rg1 can activate the glucocorticoid receptor (GR). However, the mechanism that transmits these pro-angiogenic effects is still unclear. METHODS AND RESULTS: By using human umbilical vein endothelial cells (HUVECs), we show for the first time that in the presence of Rg1, GR and fibroblast growth factor receptor-1 (FGFR-1) cooperate to activate a non-genomic signalling cascade that results in angiogenic activity. The activation of FGFR-1 by Rg1 was blocked by the GR antagonist RU486. Depletion of FGFR-1 expression or inhibition of its activity using small interfering RNA and small molecule inhibitor, respectively, significantly inhibited Rg1-induced phosphatidylinositol 3-kinase/Akt phosphorylation and subsequent endothelial nitric oxide synthase activation and angiogenic tube formation, confirming that the effect was FGFR-1 specific. On exploring how GR might regulate the activation of FGFR-1, we found that GR-mediated FGFR-1 activation was ligand-independent. In addition, we have shown that FGFR-1 regulation by GR was associated with GR/FGFR-1 complex formation. CONCLUSION: This study provides important new insights into the mechanism regarding the beneficial effects of Rg1 on angiogenesis. We propose that Rg1 could be a novel prototype of nutraceutical that can induce therapeutic angiogenesis. PMID- 20855523 TI - Looking down the atrioventricular canal. PMID- 20855524 TI - Chromatin loading of E2F-MLL complex by cancer-associated coregulator ANCCA via reading a specific histone mark. AB - Histone modifications are regarded as the carrier of epigenetic memory through cell divisions. How the marks facilitate cell cycle-dependent gene expression is poorly understood. The evolutionarily conserved AAA ATPase ANCCA (AAA nuclear coregulator cancer-associated protein)/ATAD2 was identified as a direct target of oncogene AIB1/ACTR/SRC-3 and a transcriptional coregulator for estrogen and androgen receptors and is strongly implicated in tumorigenesis. We report here that ANCCA directly interacts with E2F1 to E2F3 and that its N terminus interacts with both the N and C termini of E2F1. ANCCA preferentially associates via its bromodomain with H3 acetylated at lysine 14 (H3K14ac) and is required for key cell cycle gene expression and cancer cell proliferation. ANCCA associates with chromosomes at late mitosis, and its occupancy at E2F targets peaks at the G(1) to-S transition. Strikingly, ANCCA is required for recruitment of specific E2Fs to their targets and chromatin assembly of the host cell factor 1 (HCF-1)-MLL histone methyltransferase complex. ANCCA depletion results in a marked decrease of the gene activation-linked H3K4me3 mark. Bromodomain mutations disable ANCCA function as an E2F coactivator and its ability to promote cancer cell proliferation, while ANCCA overexpression in tumors correlates with tumor growth. Together, these results suggest that ANCCA acts as a pioneer factor in E2F dependent gene activation and that a novel mechanism involving ANCCA bromodomain may contribute to cancer cell proliferation. PMID- 20855525 TI - SHP2 mediates the localized activation of Fyn downstream of the alpha6beta4 integrin to promote carcinoma invasion. AB - Src family kinase (SFK) activity is elevated in many cancers, and this activity correlates with aggressive tumor behavior. The alpha6beta4 integrin, which is also associated with a poor prognosis in many tumor types, can stimulate SFK activation; however, the mechanism by which it does so is not known. In the current study, we provide novel mechanistic insight into how the alpha6beta4 integrin selectively activates the Src family member Fyn in response to receptor engagement. Both catalytic and noncatalytic functions of SHP2 are required for Fyn activation by alpha6beta4. Specifically, the tyrosine phosphatase SHP2 is recruited to alpha6beta4 and its catalytic activity is stimulated through a specific interaction of its N-terminal SH2 domain with pY1494 in the beta4 subunit. Fyn is recruited to the alpha6beta4/SHP2 complex through an interaction with phospho-Y580 in the C terminus of SHP2. In addition to activating Fyn, this interaction with Y580-SHP2 localizes Fyn to sites of receptor engagement, which is required for alpha6beta4-dependent invasion. Of significance for tumor progression, phosphorylation of Y580-SHP2 and SFK activation are increased in orthotopic human breast tumors that express alpha6beta4 and activation of this pathway is dependent upon Y1494. PMID- 20855526 TI - mRNA degradation plays a significant role in the program of gene expression regulated by phosphatidylinositol 3-kinase signaling. AB - Control of gene expression by the phosphatidylinositol (PI) 3-kinase/Akt pathway plays an important role in mammalian cell proliferation and survival, and numerous transcription factors and genes regulated by PI 3-kinase signaling have been identified. Because steady-state levels of mRNA are regulated by degradation as well as transcription, we have investigated the importance of mRNA degradation in controlling gene expression downstream of PI 3-kinase. We previously performed global expression analyses that identified a set of approximately 50 genes that were downregulated following inhibition of PI 3-kinase in proliferating T98G cells. By blocking transcription with actinomycin D, we found that almost 40% of these genes were regulated via effects of PI 3-kinase on mRNA stability. Analyses of beta-globin-3' untranslated region (UTR) fusion transcripts indicated that sequences within 3' UTRs were the primary determinants of rapid mRNA decay. Small interfering RNA (siRNA) experiments further showed that knockdown of BRF1 or KSRP, both ARE binding proteins (ARE-BPs) regulated by Akt, stabilized the mRNAs of a majority of the downregulated genes but that knockdown of ARE-BPs that are not regulated by PI 3-kinase did not affect degradation of these mRNAs. These results show that PI 3-kinase regulation of mRNA stability, predominantly mediated by BRF1, plays a major role in regulating gene expression. PMID- 20855527 TI - Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins. AB - Epac1 is a guanine nucleotide exchange factor for the small G protein Rap and is involved in membrane-localized processes such as integrin-mediated cell adhesion and cell-cell junction formation. Cyclic AMP (cAMP) directly activates Epac1 by release of autoinhibition and in addition induces its translocation to the plasma membrane. Here, we show an additional mechanism of Epac1 recruitment, mediated by activated ezrin-radixin-moesin (ERM) proteins. Epac1 directly binds with its N terminal 49 amino acids to ERM proteins in their open conformation. Receptor induced activation of ERM proteins results in increased binding of Epac1 and consequently the clustered localization of Epac1 at the plasma membrane. Deletion of the N terminus of Epac1, as well as disruption of the Epac1-ERM interaction by an interfering radixin mutant or small interfering RNA (siRNA)-mediated depletion of the ERM proteins, impairs Epac1-mediated cell adhesion. We conclude that ERM proteins are involved in the spatial regulation of Epac1 and cooperate with cAMP- and Rap-mediated signaling to regulate adhesion to the extracellular matrix. PMID- 20855528 TI - Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. AB - Mdm2 and Mdm4 are critical negative regulators of p53. A large body of evidence indicates that elevated expression of either Mdm2 or Mdm4 may favor tumor formation by inhibiting p53 tumor suppression function. To explore this possibility in vivo, we generated conditional Mdm2 and Mdm4 transgenic mice. We show that although both transgenes are designed to be expressed ubiquitously and at comparable levels, only the Mdm4 transgenic protein is produced at high levels in vivo. In contrast, exogenous Mdm2 is constitutively degraded in a proteasome dependent manner, indicating that cells are equipped with efficient mechanisms that prevent Mdm2 accumulation in vivo. Mice that are homozygous for the Mdm4 transgene die during embryogenesis owing to severe vascular maturation defects. Importantly, this lethality is not rescued on a p53-null background, indicating that high levels of Mdm4 impact on a pathway(s) other than p53 that controls vascular and embryonic development. Mice expressing a single copy of the Mdm4 transgene are viable and, surprisingly, are not prone to spontaneous, radiation induced or EMU-myc-induced tumor formation. The findings have clear implications for cancer etiology as well as for cancer therapy. PMID- 20855529 TI - Cks1, Cdk1, and the 19S proteasome collaborate to regulate gene induction dependent nucleosome eviction in yeast. AB - Cks1, Cdk1 (Cdc28), and the proteasome are required for efficient transcriptional induction of GAL1 and other genes in Saccharomyces cerevisiae. We show here that one function of these proteins is to reduce nucleosome density on chromatin in a gene induction-specific manner. The transcriptional requirement for Cks1 can be bypassed if nucleosome density is reduced by an alternative pathway, indicating that this is the primary function of Cks1 in the context of gene induction. We further show that Cks1, Cdk1, and the 19S subunit of the proteasome are recruited to chromatin by binding directly to the histone H4 amino-terminal tail. However, this activity of the proteasome does not require the protease activity associated with the 20S subunit. These data suggest a model where binding of a complex consisting of Cks1, Cdk1, and the 19S proteasome to histone H4 leads to removal of nucleosomes via a nonproteolytic activity of the proteasome. PMID- 20855533 TI - Directions for refining a school nursing intervention for Mexican immigrant families. AB - Mexican immigrant mothers and their children encounter many stressors as they adapt to life in the United States. This article reports a secondary data analysis from a school-based home visiting program focused on assisting Mexican immigrant mothers and their children develop problem-solving strategies in dealing with stressors. Data were abstracted from home visiting records to determine the types of problems Mexican immigrant mothers chose to discuss with nurses. Nine categories of problems were developed from the data. Problems most frequently identified by mothers were family health concerns and access to health care, parenting and financial concerns. Findings and implications for school nursing practice are discussed. PMID- 20855530 TI - Cooperative action of multiple cis-acting elements is required for N-myc expression in branchial arches: specific contribution of GATA3. AB - The precise expression of the N-myc proto-oncogene is essential for normal mammalian development, whereas altered N-myc gene regulation is known to be a determinant factor in tumor formation. Using transgenic mouse embryos, we show that N-myc sequences from kb -8.7 to kb +7.2 are sufficient to reproduce the N myc embryonic expression profile in developing branchial arches and limb buds. These sequences encompass several regulatory elements dispersed throughout the N myc locus, including an upstream limb bud enhancer, a downstream somite enhancer, a branchial arch enhancer in the second intron, and a negative regulatory element in the first intron. N-myc expression in the limb buds is under the dominant control of the limb bud enhancer. The expression in the branchial arches necessitates the interplay of three regulatory domains. The branchial arch enhancer cooperates with the somite enhancer region to prevent an inhibitory activity contained in the first intron. The characterization of the branchial arch enhancer has revealed a specific role of the transcription factor GATA3 in the regulation of N-myc expression. Together, these data demonstrate that correct N-myc developmental expression is achieved via cooperation of multiple positive and negative regulatory elements. PMID- 20855531 TI - 14-3-3 (Bmh) proteins inhibit transcription activation by Adr1 through direct binding to its regulatory domain. AB - 14-3-3 proteins, known as Bmh in yeast, are ubiquitous, highly conserved proteins that function as adaptors in signal transduction pathways by binding to phosphorylated proteins to activate, inactivate, or sequester their substrates. Bmh proteins have an important role in glucose repression by binding to Reg1, the regulatory subunit of Glc7, a protein phosphatase that inactivates the AMP activated protein kinase Snf1. We describe here another role for Bmh in glucose repression. We show that Bmh binds to the Snf1-dependent transcription factor Adr1 and inhibits its transcriptional activity. Bmh binds within the regulatory domain of Adr1 between amino acids 215 and 260, the location of mutant ADR1(c) alleles that deregulate Adr1 activity. This provides the first explanation for the phenotype resulting from these mutations. Bmh inhibits Gal4-Adr1 fusion protein activity by binding to the Ser230 region and blocking the function of a nearby cryptic activating region. ADR1(c) alleles, or the inactivation of Bmh, relieve the inhibition and Snf1 dependence of this activating region, indicating that the phosphorylation of Ser230 and Bmh are important for the inactivation of Gal4-Adr1. The Bmh binding domain is conserved in orthologs of Adr1, suggesting that it acquired an important biological function before the whole-genome duplication of the ancestor of S. cerevisiae. PMID- 20855534 TI - Age differences and social stratification in the long-term trajectories of leisure-time physical activity. AB - OBJECTIVES: This study assessed how and why the social stratification of leisure time physical activity changes as adults at different points in the life course, and from different birth cohorts, grow older. METHODS: A series of multilevel models were estimated using longitudinal data from a national sample of more than 3,000 adults from the Americans' Changing Lives study. RESULTS: On average, rates of leisure-time physical activity increased within younger adults and decreased within middle-aged and older adults, throughout the study period. Initial Black White differences in activity converged over time, whereas initial men advantages over women widened, particularly among older adults. Gender-based differences did not remain after accounting for differences in health; however, significant age and race differences in the trajectories of physical activity persisted, even after accounting for the effects of health and social relationships on leisure time physical activity. DISCUSSION: American adults appear to be reducing their levels of physical activity relatively early in the life course and at increasingly steep rates among older age groups. The changing patterns of stratification in physical activity, as well as the associations between several time-varying predictors and physical activity, provide insight into the forces that may be responsible for these declines. PMID- 20855537 TI - Association of albuminuria and cancer mortality. AB - BACKGROUND: The objective was to evaluate the association of albuminuria with cancer mortalities in adults ages 50 and older. METHODS: A total of 6,112 adults ages 50 years and above without a history of cancer at baseline in the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) were included in the analysis. Albuminuria was measured with urinary albumin-to creatinine ratio (UACR) in mg/mmol. Cancer mortality was obtained from the NHANES III-linked follow-up database (up to December 31, 2006). Cox-regression models were used to examine the associations of interest. RESULTS: Albuminuria was present in 705 men (17.5%) and 592 women (14.3%). During an average follow-up of 149 months, 613 subjects died of cancers including 184 lung cancers, 65 colorectal cancers, 55 prostate cancers, and 309 other cancers. There was an increased mortality risk associated with logarithmically transformed UACR for all cancer [relative risk (RR), 1.20; 95% confidence interval (CI), 1.06-1.36], lung cancer (RR, 1.22; 95% CI, 1.05-1.43), and prostate cancer mortality (RR, 1.40; 95% CI, 1.01-1.95) in men. No associations between UACR and cancer were apparent in women. CONCLUSIONS: The analysis shows that albuminuria is associated with an increased risk of cancer death, specifically for all-cause, lung, and prostate cancers in men ages 50 and above. IMPACT: Further studies are needed to explore the relationship between albuminuria and specific cancers. Understanding the biological link between albuminuria and cancer will be critical for determining whether albuminuria represents an early marker or a potential therapeutic target. PMID- 20855536 TI - Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma. AB - BACKGROUND: The t(14;18)(q32;q21) translocation is the most commonly observed chromosomal translocation in non-Hodgkin's lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, has recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL. METHODS: We genotyped 226 single nucleotide polymorphisms (SNP) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency-matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9. RESULTS: In gene-level analyses, BCL2L11 (P = 0.0019), BCLAF1 (P = 0.0097), BAG5 (P = 0.026), and CASP9 (P = 0.0022) were associated with NHL risk after accounting for multiple testing (tail strength, 0.38; 95% confidence interval, 0.05-0.70). Two of the five BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and three of the seven genotyped CASP9 tagSNPs (rs6685648, rs2020902, and rs2042370) were significant at P < 0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all four BCL2L11 and two of three CASP9 SNPs. CONCLUSION: We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP level, and identified novel associations with BCLAF1 and BAG5. IMPACT: Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted. PMID- 20855538 TI - MicroRNA sponges: progress and possibilities. AB - The microRNA (miRNA) "sponge" method was introduced three years ago as a means to create continuous miRNA loss of function in cell lines and transgenic organisms. Sponge RNAs contain complementary binding sites to a miRNA of interest, and are produced from transgenes within cells. As with most miRNA target genes, a sponge's binding sites are specific to the miRNA seed region, which allows them to block a whole family of related miRNAs. This transgenic approach has proven to be a useful tool to probe miRNA functions in a variety of experimental systems. Here we will discuss the ways sponge and related constructs can be optimized and review recent applications of this method with particular emphasis on stable expression in cancer studies and in transgenic animals. PMID- 20855539 TI - TbRGG2 facilitates kinetoplastid RNA editing initiation and progression past intrinsic pause sites. AB - TbRGG2 is an essential kinetoplastid RNA editing accessory factor that acts specifically on pan-edited RNAs. To understand the mechanism of TbRGG2 action, we undertook an in-depth analysis of edited RNA populations in TbRGG2 knockdown cells and an in vitro examination of the biochemical activities of the protein. We demonstrate that TbRGG2 down-regulation more severely impacts editing at the 5' ends of pan-edited RNAs than at their 3' ends. The initiation of editing is reduced to some extent in TbRGG2 knockdown cells. In addition, TbRGG2 plays a post-initiation role as editing becomes stalled in TbRGG2-depleted cells, resulting in an overall decrease in the 3' to 5' progression of editing. Detailed analyses of edited RNAs from wild-type and TbRGG2-depleted cells reveal that TbRGG2 facilitates progression of editing past intrinsic pause sites that often correspond to the 3' ends of cognate guide RNAs (gRNAs). In addition, noncanonically edited junction regions are either absent or significantly shortened in TbRGG2-depleted cells, consistent with impaired gRNA transitions. Sequence analysis further suggests that TbRGG2 facilitates complete utilization of certain gRNAs. In vitro RNA annealing and in vivo RNA unwinding assays demonstrate that TbRGG2 can modulate RNA-RNA interactions. Collectively, these data are consistent with a model in which TbRGG2 facilitates initiation and 3' to 5' progression of editing through its ability to affect gRNA utilization, both during the transition between specific gRNAs and during usage of certain gRNAs. PMID- 20855540 TI - YibK is the 2'-O-methyltransferase TrmL that modifies the wobble nucleotide in Escherichia coli tRNA(Leu) isoacceptors. AB - Transfer RNAs are the most densely modified nucleic acid molecules in living cells. In Escherichia coli, more than 30 nucleoside modifications have been characterized, ranging from methylations and pseudouridylations to more complex additions that require multiple enzymatic steps. Most of the modifying enzymes have been identified, although a few notable exceptions include the 2'-O methyltransferase(s) that methylate the ribose at the nucleotide 34 wobble position in the two leucyl isoacceptors tRNA(Leu)(CmAA) and tRNA(Leu)(cmnm5UmAA). Here, we have used a comparative genomics approach to uncover candidate E. coli genes for the missing enzyme(s). Transfer RNAs from null mutants for candidate genes were analyzed by mass spectrometry and revealed that inactivation of yibK leads to loss of 2'-O-methylation at position 34 in both tRNA(Leu)(CmAA) and tRNA(Leu)(cmnm5UmAA). Loss of YibK methylation reduces the efficiency of codon wobble base interaction, as demonstrated in an amber suppressor supP system. Inactivation of yibK had no detectable effect on steady-state growth rate, although a distinct disadvantage was noted in multiple-round, mixed-population growth experiments, suggesting that the ability to recover from the stationary phase was impaired. Methylation is restored in vivo by complementing with a recombinant copy of yibK. Despite being one of the smallest characterized alpha/beta knot proteins, YibK independently catalyzes the methyl transfer from S adenosyl-L-methionine to the 2'-OH of the wobble nucleotide; YibK recognition of this target requires a pyridine at position 34 and N6-(isopentenyl)-2 methylthioadenosine at position 37. YibK is one of the last remaining E. coli tRNA modification enzymes to be identified and is now renamed TrmL. PMID- 20855541 TI - Functional characterization of the Drosophila MRP (mitochondrial RNA processing) RNA gene. AB - MRP RNA is a noncoding RNA component of RNase mitochondrial RNA processing (MRP), a multi-protein eukaryotic endoribonuclease reported to function in multiple cellular processes, including ribosomal RNA processing, mitochondrial DNA replication, and cell cycle regulation. A recent study predicted a potential Drosophila ortholog of MRP RNA (CR33682) by computer-based genome analysis. We have confirmed the expression of this gene and characterized the phenotype associated with this locus. Flies with mutations that specifically affect MRP RNA show defects in growth and development that begin in the early larval period and end in larval death during the second instar stage. We present several lines of evidence demonstrating a role for Drosophila MRP RNA in rRNA processing. The nuclear fraction of Drosophila MRP RNA localizes to the nucleolus. Further, a mutant strain shows defects in rRNA processing that include a defect in 5.8S rRNA processing, typical of MRP RNA mutants in other species, as well as defects in early stages of rRNA processing. PMID- 20855542 TI - Laserspray ionization, a new method for protein analysis directly from tissue at atmospheric pressure with ultrahigh mass resolution and electron transfer dissociation. AB - Laserspray ionization (LSI) mass spectrometry (MS) allows, for the first time, the analysis of proteins directly from tissue using high performance atmospheric pressure ionization mass spectrometers. Several abundant and numerous lower abundant protein ions with molecular masses up to ~20,000 Da were detected as highly charged ions from delipified mouse brain tissue mounted on a common microscope slide and coated with 2,5-dihydroxyacetophenone as matrix. The ability of LSI to produce multiply charged ions by laser ablation at atmospheric pressure allowed protein analysis at 100,000 mass resolution on an Orbitrap Exactive Fourier transform mass spectrometer. A single acquisition was sufficient to identify the myelin basic protein N-terminal fragment directly from tissue using electron transfer dissociation on a linear trap quadrupole (LTQ) Velos. The high mass resolution and mass accuracy, also obtained with a single acquisition, are useful in determining protein molecular weights and from the electron transfer dissociation data in confirming database-generated sequences. Furthermore, microscopy images of the ablated areas show matrix ablation of ~15 MUm-diameter spots in this study. The results suggest that LSI-MS at atmospheric pressure potentially combines speed of analysis and imaging capability common to matrix assisted laser desorption/ionization and soft ionization, multiple charging, improved fragmentation, and cross-section analysis common to electrospray ionization. PMID- 20855543 TI - Deconvolution and database search of complex tandem mass spectra of intact proteins: a combinatorial approach. AB - Top-down proteomics studies intact proteins, enabling new opportunities for analyzing post-translational modifications. Because tandem mass spectra of intact proteins are very complex, spectral deconvolution (grouping peaks into isotopomer envelopes) is a key initial stage for their interpretation. In such spectra, isotopomer envelopes of different protein fragments span overlapping regions on the m/z axis and even share spectral peaks. This raises both pattern recognition and combinatorial challenges for spectral deconvolution. We present MS-Deconv, a combinatorial algorithm for spectral deconvolution. The algorithm first generates a large set of candidate isotopomer envelopes for a spectrum, then represents the spectrum as a graph, and finally selects its highest scoring subset of envelopes as a heaviest path in the graph. In contrast with other approaches, the algorithm scores sets of envelopes rather than individual envelopes. We demonstrate that MS Deconv improves on Thrash and Xtract in the number of correctly recovered monoisotopic masses and speed. We applied MS-Deconv to a large set of top-down spectra from Yersinia rohdei (with a still unsequenced genome) and further matched them against the protein database of related and sequenced bacterium Yersinia enterocolitica. MS-Deconv is available at http://proteomics.ucsd.edu/Software.html. PMID- 20855544 TI - The protein interaction network of the human transcription machinery reveals a role for the conserved GTPase RPAP4/GPN1 and microtubule assembly in nuclear import and biogenesis of RNA polymerase II. AB - RNA polymerase II (RNAPII), the 12-subunit enzyme that synthesizes all mRNAs and several non-coding RNAs in eukaryotes, plays a central role in cell function. Although multiple proteins are known to regulate the activity of RNAPII during transcription, little is known about the machinery that controls the fate of the enzyme before or after transcription. We used systematic protein affinity purification coupled to mass spectrometry (AP-MS) to characterize the high resolution network of protein interactions of RNAPII in the soluble fraction of human cell extracts. Our analysis revealed that many components of this network participate in RNAPII biogenesis. We show here that RNAPII-associated protein 4 (RPAP4/GPN1) shuttles between the nucleus and the cytoplasm and regulates nuclear import of POLR2A/RPB1 and POLR2B/RPB2, the two largest subunits of RNAPII. RPAP4/GPN1 is a member of a newly discovered GTPase family that contains a unique and highly conserved GPN loop motif that we show is essential, in conjunction with its GTP-binding motifs, for nuclear localization of POLR2A/RPB1 in a process that also requires microtubule assembly. A model for RNAPII biogenesis is presented. PMID- 20855545 TI - Regulation of fasting fuel metabolism by toll-like receptor 4. AB - OBJECTIVE: Toll-like receptor 4 (TLR4) has been reported to induce insulin resistance through inflammation in high-fat-fed mice. However, the physiological role of TLR4 in metabolism is unknown. Here, we investigated the involvement of TLR4 in fasting metabolism. RESEARCH DESIGN AND METHODS: Wild-type and TLR4 deficient (TLR4(-/-)) mice were either fed or fasted for 24 h. Glucose and lipid levels in circulation and tissues were measured. Glucose and lipid metabolism in tissues, as well as the expression of related enzymes, was examined. RESULTS: Mice lacking TLR4 displayed aggravated fasting hypoglycemia, along with normal hepatic gluconeogenesis, but reversed activity of pyruvate dehydrogenase complex (PDC) in skeletal muscle, which might account for the fasting hypoglycemia. TLR4( /-) mice also exhibited higher lipid levels in circulation and skeletal muscle after fasting and reversed expression of lipogenic enzymes in skeletal muscle but not liver and adipose tissue. Adipose tissue lipolysis is normal and muscle fatty acid oxidation is increased in TLR4(-/-) mice after fasting. Inhibition of fatty acid synthesis in TLR4(-/-) mice abolished hyperlipidemia, hypoglycemia, and PDC activity increase, suggesting that TLR4-dependent inhibition of muscle lipogenesis may contribute to glucose and lipid homeostasis during fasting. Further studies showed that TLR4 deficiency had no effect on insulin signaling and muscle proinflammatory cytokine production in response to fasting. CONCLUSIONS: These data suggest that TLR4 plays a critical role in glucose and lipid metabolism independent of insulin during fasting and identify a novel physiological role for TLR4 in fuel homeostasis. PMID- 20855546 TI - Cancer survivors' and employers' perceptions of working following cancer treatment. AB - BACKGROUND: Earlier diagnosis and improvements in treatment survival rates have led to an increase in the number of cancer survivors for whom returning to work is a realistic outcome. However, cancer survivors face a number of challenges when returning to the workplace. Little is known about how patients' illness and treatment beliefs affect return to work or of employers' beliefs about the impact of cancer on work. AIMS: To determine patient and employers' beliefs about the impact of cancer on returning to work and to identify differences in the beliefs held by patients and employers. METHODS: Patients absent from work due to breast, urological, gynaecological or head and neck cancers completed a questionnaire within 4 weeks of completing treatment. Unlinked employer respondents from medium to large organizations completed the same questionnaire. The questionnaire focused on the perceived impact of cancer and its treatment on work and an adapted version of the Brief Illness Perceptions Questionnaire. RESULTS: One hundred and ninety four patients (response rate of 82%) and 252 employers (response rate 31%) completed the questionnaire. Organizational respondents consistently reported more negative beliefs about the impact of cancer and treatment on work and in general held more negative illness perceptions about cancer in relation to work. CONCLUSIONS: A discrepancy between beliefs of organizational respondents and cancer survivors could impact on an employees' management of their work and on employers' responsiveness to the needs of survivors. Therefore, it is important that return to work plans include the elicitation of employee beliefs. PMID- 20855547 TI - A descriptive study of a specialized worker's psychological trauma program. AB - BACKGROUND: Psychological trauma in the workplace is gaining recognition as an important cause of workplace disability but little is known about the workers who are affected. The Psychological Trauma Program (PTP) in Toronto (Canada) is a specialized provincial worker's compensation board assessment program for workers with psychological sequelae of workplace trauma. AIMS: To characterize workers presenting to the PTP in terms of demographic, occupational, traumatic exposure and diagnostic variables. METHODS: A retrospective secondary analysis of all workers referred to the PTP for assessment within 1 year of traumatic event between 1999 and 2006. RESULTS: Five hundred and thiry-one referred workers were included in the study. Most workers were working-age male (76%), married (65%) and labourers (43%). Nearly half were born outside Canada. Post-traumatic stress disorder was the primary diagnosis in 44%. Fifty-eight percent had one or more secondary diagnoses. For just over half of the workers, the traumatic event resulted in a permanent physical impairment. CONCLUSIONS: Specialist referral may be indicated for workers experiencing prolonged recovery following workplace trauma. Male workers and those with co-morbidities or permanent injuries may be more likely to require referral. Individualized treatment approaches are likely important; however, more research is needed to guide future interventions. PMID- 20855548 TI - Fetal exposure to altered amniotic fluid glucose, insulin, and insulin-like growth factor-binding protein 1 occurs before screening for gestational diabetes mellitus. AB - OBJECTIVE: We explored the possibility that perturbations in amniotic fluid glucose, insulin, and insulin-like growth factor-binding protein 1(IGFBP1) and/or metabolic acids exist before routine screening for GDM. RESEARCH DESIGN AND METHODS: We selected consenting mother-infant pairs (n = 408) who met our inclusion criteria (singleton pregnancy, no genetic abnormalities, and no preexisting diabetes) and for whom sufficient amniotic fluid and appropriate medical information were available. We compared birth outcomes and second trimester amniotic fluid glucose, insulin, IGFBP1 concentrations, and amniotic fluid lactic, beta-hydroxybutyric, and uric acids of mothers with gestational diabetes mellitus (GDM) (n = 52) with those of mothers with no diagnosis of GDM at >24 weeks (n = 356). RESULTS: Higher amniotic fluid glucose, lactic acid, uric acid, and insulin and lower IGFBP1 concentrations were present by 15.1 +/- 0.1 weeks in mothers in whom GDM was subsequently diagnosed. However, logistic regression showed that second trimester amniotic fluid glucose, but not insulin, IGFBP1, or metabolic acids was associated with an increased odds ratio (1.2 [95% CI 1.052-1.338]) for diagnosis of GDM at 24-28 weeks. In addition, probability contour maps that accounted for nonlinear relationships among the dynamically changing amniotic fluid constituents showed an increased risk for GDM with elevated second trimester amniotic fluid glucose in combination with either elevated amniotic fluid insulin or low amniotic fluid IGFBP1 CONCLUSIONS: Fetuses are exposed to increased amniotic fluid glucose before 15 weeks of gestation, suggesting that metabolic perturbations are underway before diagnosis and that earlier screening and intervention may be warranted. PMID- 20855549 TI - Performance of A1C for the classification and prediction of diabetes. AB - OBJECTIVE: Although A1C is now recommended to diagnose diabetes, its test performance for diagnosis and prognosis is uncertain. Our objective was to assess the test performance of A1C against single and repeat glucose measurements for diagnosis of prevalent diabetes and for prediction of incident diabetes. RESEARCH DESIGN AND METHODS: We conducted population-based analyses of 12,485 participants in the Atherosclerosis Risk in Communities (ARIC) study and a subpopulation of 691 participants in the Third National Health and Nutrition Examination Survey (NHANES III) with repeat test results. RESULTS: Against a single fasting glucose >=126 mg/dl, the sensitivity and specificity of A1C >=6.5% for detection of prevalent diabetes were 47 and 98%, respectively (area under the curve 0.892). Against repeated fasting glucose (3 years apart) >=126 mg/dl, sensitivity improved to 67% and specificity remained high (97%) (AUC 0.936). Similar results were obtained in NHANES III against repeated fasting glucose 2 weeks apart. The accuracy of A1C was consistent across age, BMI, and race groups. For individuals with fasting glucose >=126 mg/dl and A1C >=6.5% at baseline, the 10-year risk of diagnosed diabetes was 88% compared with 55% among those individuals with fasting glucose >=126 mg/dl and A1C 5.7-<6.5%. CONCLUSIONS: A1C performs well as a diagnostic tool when diabetes definitions that most closely resemble those used in clinical practice are used as the "gold standard." The high risk of diabetes among individuals with both elevated fasting glucose and A1C suggests a dual role for fasting glucose and A1C for prediction of diabetes. PMID- 20855550 TI - Secular trends in treatment and control of type 2 diabetes in an American Indian population: a 30-year longitudinal study. AB - OBJECTIVE: Treatment guidelines for diabetes have become increasingly stringent as most research shows that more aggressive intervention reduces the risks for complications. Community data on the effect of these interventions are lacking. RESEARCH DESIGN AND METHODS: Changes in the pharmacologic treatment of diabetes, blood pressure, and cholesterol in adults with diabetes were analyzed in a longitudinal population-based study of American Indians from 10 independent 3 year time intervals between 1975 and 2004. Trends in drug use were assessed by logistic regression models and trends in glycemia, blood pressure, and cholesterol were assessed by linear models. RESULTS: Among the study participants, the use of any medicine for the treatment of diabetes increased from 53% in 1975-1978 to 67% in 2002-2004, Ptrend<0.0001. The use of insulin as a single agent declined, and the use of combinations of insulin and oral agents increased. In 1990-1992, 23% of subjects had an A1C<7% and by 2002-2004, the proportion had increased to 33%, Ptrend<0.0001. The use of anti-hypertensive medicine increased from 21% in 1975-1977 to 58% in 2002-2004, Ptrend<0.0001, coincident with a decline in mean systolic blood pressure from 137 mmHg in 1975 1977 to 123 mmHg in 2002-2004, Ptrend<0.0001. The use of lipid-lowering medicine also increased with an accompanying increase in HDL and a decrease in non-HDL cholesterol concentration. CONCLUSIONS: Major changes in community treatment patterns for diabetes and related conditions coincided with improvements in glycemia, blood pressure, and cholesterol. PMID- 20855551 TI - Identification of autoantibody-negative autoimmune type 2 diabetic patients. AB - OBJECTIVE: Islet autoimmunity has long been recognized in the pathogenesis of type 1 diabetes and is becoming increasingly acknowledged as a component in the pathogenesis of type 2 diabetes. Islet reactive T cells and autoantibodies have been demonstrated in type 1 diabetes, whereas islet autoimmunity in type 2 diabetes has been limited to islet autoantibodies. In this study, we investigated whether islet reactive T cells might also be present in type 2 diabetic patients and how islet reactive T cells correlate with beta-cell function. RESEARCH DESIGN AND METHODS: Adult phenotypic type 2 diabetic patients (n = 36) were screened for islet reactive T-cell responses using cellular immunoblotting and five islet autoantibodies (islet cell antibody, GADA, insulin autoantibody, insulinoma associated protein-2 autoantibody, and zinc transporter autoantibody). RESULTS: We identified four subgroups of adult phenotypic type 2 diabetic patients based on their immunological status (Ab(-)T(-), Ab(+)T(-), Ab(-)T(+), and Ab(+)T(+)). The Ab(-)T(+) type 2 diabetic patients demonstrated T-cell responses similar to those of the Ab(+)T(+) type 2 diabetic patients. Data were adjusted for BMI, insulin resistance, and duration of diabetes. Significant differences (P < 0.02) were observed among groups for fasting and glucagon-stimulated C-peptide responses. T-cell responses to islet proteins were also demonstrated to fluctuate less than autoantibody responses. CONCLUSIONS: We have identified a group of adult autoimmune phenotypic type 2 diabetic patients who are Ab(-)T(+) and thus would not be detected using autoantibody testing alone. We conclude that islet autoimmunity may be more prevalent in adult phenotypic type 2 diabetic patients than previously estimated. PMID- 20855552 TI - Metabolic risk and health behaviors in minority youth at risk for type 2 diabetes. AB - OBJECTIVE: The purpose of this study was to determine the impact of sex and race/ethnicity on metabolic risk and health behaviors in minority youth. RESEARCH DESIGN AND METHODS: A total of 173 seventh graders (46% male and 54% female; 49% Hispanic and 51% African American) with BMI >=85th percentile and a family history of diabetes were assessed with weight, height, BMI, percent body fat, and waist circumference measures. Laboratory indexes included 2-h oral glucose tolerance tests with insulin levels at 0 and 2 h, fasting A1C, and lipids. Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). Youth also completed questionnaires evaluating health behaviors. RESULTS: Average BMI (31.6 +/- 6.4 kg/m2) and percent body fat (39.5 +/- 10.6%) were high. All participants demonstrated insulin resistance with elevated HOMA-IR values (8.5 +/ 5.2). Compared with African American youth, Hispanic youth had higher triglycerides and lower HDL cholesterol despite similar BMI. Hispanic youth reported lower self-efficacy for diet, less physical activity, and higher total fat intake. Male youth had higher glucose (0 and 2 h) and reported more physical activity, more healthy food choices, and higher calcium intake than female youth. CONCLUSIONS: Screening high-risk youth for insulin resistance and lipid abnormalities is recommended. Promoting acceptable physical activities and healthy food choices may be especially important for Hispanic and female youth. PMID- 20855553 TI - Fibrillins in adult human ovary and polycystic ovary syndrome: is fibrillin-3 affected in PCOS? AB - Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age. Although genetic linkage analyses have demonstrated a susceptibility locus for PCOS mapping to the fibrillin-3 gene, the presence of fibrillin proteins in normal and polycystic ovaries has not been characterized. This study compared and contrasted fibrillin-1, -2, and -3 localization in normal and polycystic ovaries. Immunohistochemical stainings of ovaries from 21 controls and 9 patients with PCOS were performed. Fibrillin-1 was ubiquitous in ovarian connective tissue. Fibrillin-2 localized around antral follicles and in areas of folliculolysis. Fibrillin-3 was present in a restricted distribution within the specialized perifollicular stroma of follicles in morphological transition from primordial to primary type [transitional follicles (TFs)]. Fibrillin-1 and -2 stainings of PCOS ovaries were similar to those of the controls. However, in eight of the nine PCOS ovaries, there was a decrease in the number of TFs associated with fibrillin-3, including no staining in five PCOS samples; decreased number of fibrillin-3-associated TFs/mm(2) was confirmed by quantitative analysis. Our findings support a role for fibrillin-3 in the pathogenesis of PCOS and suggest fibrillin-3 may function in primordial to primary follicle transition. We propose that loss of fibrillin-3 during folliculogenesis may be an important factor in PCOS pathogenesis. PMID- 20855554 TI - Shockwave therapy for the treatment of chronic proximal hamstring tendinopathy in professional athletes. AB - BACKGROUND: Chronic proximal hamstring tendinopathy is an overuse syndrome that is usually managed by nonoperative methods. Shockwave therapy has proved to be effective in many tendinopathies. HYPOTHESIS: Shockwave therapy may be more effective than other nonoperative treatments for chronic proximal hamstring tendinopathy. STUDY DESIGN: Randomized controlled clinical study; Level of evidence, 1. METHODS: Forty professional athletes with chronic proximal hamstring tendinopathy were enrolled between February 1, 2004, and September 30, 2006. Patients were randomly assigned to receive either shockwave therapy, consisting of 2500 impulses per session at a 0.18 mJ/mm2 energy flux density without anesthesia, for 4 weeks (SWT group, n = 20), or traditional conservative treatment consisting of nonsteroidal anti-inflammatory drugs, physiotherapy, and an exercise program for hamstring muscles (TCT group, n = 20). Patients were evaluated before treatment, and 1 week and 3, 6, and 12 months after the end of treatment. The visual analog scale (VAS) score for pain and Nirschl phase rating scale (NPRS) were used as primary outcome measures. RESULTS: The patients were observed for a mean of 10.7 months (range, 1-12 months). Six patients were lost to follow-up because they underwent a surgical intervention: 3 (all in TCT group) were lost at 3 months; 2 (1 in each group), at 6 months; and 1 (in the TCT group), at 12 months. Primary follow-up was at 3 months after the beginning of treatment. The VAS scores in the SWT and TCT groups were 7 points before treatment (P = .84), and 2 points and 5 points, respectively, 3 months after treatment (P < .001). The NPRS scores in the SWT and TCT groups were 5 points in either group before treatment (P = .48), and 2 points and 6 points, respectively, 3 months after treatment (P < .001). At 3 months after treatment, 17 of the 20 patients (85%) in the SWT group and 2 of the 20 patients (10%) in the TCT group achieved a reduction of at least 50% in pain (P < .001). There were no serious complications in the SWT group. CONCLUSION: Shockwave therapy is a safe and effective treatment for patients with chronic proximal hamstring tendinopathy. PMID- 20855555 TI - Subjective and objective outcome after revision arthroscopic stabilization for recurrent anterior instability versus initial shoulder stabilization. AB - BACKGROUND: The value of arthroscopic revision shoulder stabilization after failed instability repair is still a matter of debate. HYPOTHESIS: Arthroscopic revision shoulder stabilization using suture anchors provides equivalent subjective and objective results compared with initial arthroscopic instability repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Twenty consecutive patients who underwent arthroscopic revision shoulder stabilization using suture anchors (group 2) were matched for age, gender, and handedness (dominant or nondominant) with 20 patients who had initial arthroscopic instability repair using the same technique (group 1). At the time of follow-up, a complete physical examination of both shoulders and evaluation with the Rowe score, Walch-Duplay score, Melbourne Instability Shoulder Score, Western Ontario Shoulder Instability Index, and the Subjective Shoulder Value were performed. In addition, standard radiographs (true AP and axillary views) were taken to evaluate signs of osteoarthritis. RESULTS: After a minimum follow-up of 24 months, no recurrent dislocations were observed in either group. The apprehension sign was positive in 2 cases of revision surgery (0 vs 2; P > .05). No significant differences in the Rowe score (89 vs 81.8 points) were found between groups 1 and 2 (P > .05). However, group 2 revealed significantly lower scores in the Walch-Duplay score (85.3 vs 75.5 points), Melbourne Instability Shoulder Score (90.2 vs 73.7 points), Western Ontario Shoulder Instability Index (89.8% vs 68.9%), and Subjective Shoulder Value (91.8% vs 69.2%) (P < .05). Signs of instability arthropathy were found more often in patients with arthroscopic revision surgery (2 vs 5; P > .05). CONCLUSION: Arthroscopic revision shoulder stabilization is associated with a lower subjective outcome compared with initial arthroscopic stabilization. The objective results found in this study may overestimate the clinical outcome in this patient population. PMID- 20855556 TI - Delay of 2 or 6 weeks adversely affects the functional outcome of augmented primary repair of the porcine anterior cruciate ligament. AB - BACKGROUND: Enhanced primary anterior cruciate ligament repair, in which suture repair is performed in conjunction with a collagen-platelet composite to stimulate healing, is a potential new treatment option for anterior cruciate ligament injuries. Previous studies have evaluated this approach at the time of anterior cruciate ligament disruption. HYPOTHESIS: Delaying surgery by 2 or 6 weeks would have a significant effect on the functional outcome of the repair. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen female Yorkshire pigs underwent staged, bilateral surgical anterior cruciate ligament transections. Anterior cruciate ligament transection was initially performed on 1 knee and the knee closed. Two or 6 weeks later, enhanced primary repair was performed in that knee while the contralateral knee had an anterior cruciate ligament transection and immediate repair. Biomechanical parameters were measured after 15 weeks in vivo to determine the effect of delay time relative to immediate repair on the healing response. RESULTS: Yield load of the repairs at 15 weeks was decreased by 40% and 60% in the groups where repair was delayed for 2 and 6 weeks, respectively (P = .01). Maximum load showed similar results (55% and 60% decrease in the 2- and 6-week delay groups, respectively; P = .011). Linear stiffness also was adversely affected by delay (50% decrease compared with immediate repair after either a 2- or 6-week delay, P = .011). Anterior-posterior laxity after 15 weeks of healing was 40% higher in knees repaired after a 2-week delay and 10% higher in those repaired after a 6-week delay (P = .012) when tested at 30 degrees of flexion, but was not significantly affected by delay when tested at 60 degrees or 90 degrees (P = .21). CONCLUSION: A delay between anterior cruciate ligament injury and enhanced primary repair has a significant negative effect on the functional performance of the repair. CLINICAL RELEVANCE: As future investigations assess new techniques of anterior cruciate ligament repair, the timing of the repair should be considered in the design and the interpretation of experimental studies. PMID- 20855558 TI - Identification of selective enzyme inhibitors by fragment library screening. AB - The microbial threat to human health is growing due to the dramatic increase in the number of multidrug-resistant organisms. The decline in effective antibiotics available to treat these growing threats has provided greater urgency to the search for new antibiotics. Clearly, new approaches must be developed against novel targets to control these resistant infectious organisms. The screening of low molecular weight compounds against new protein targets provides an opportunity to identify novel inhibitors as starting points for the development of new antibiotics. Custom fragment libraries have been assembled and screened against 3 representative forms of a key enzyme in an essential microbial biosynthetic pathway. Although each of these aspartate semialdehyde dehydrogenases (ASADHs) catalyzes the same reaction and each shares identical active site functional groups, subtle differences in enzyme structures have led to different binding selectivity among the initial hits from these fragment libraries. Amino acid analogues have been identified that show selectivity for either the gram-negative or gram-positive bacterial enzyme forms. A series of benzophenone analogues selectively inhibit the gram-negative ASADH, whereas some haloacids and substituted aromatic acids have been found to inhibit only the fungal form of ASADH. Each of these low molecular weight compounds possesses high ligand binding efficiency for their target enzyme forms. These results support the goal of designing lead compounds that will selectively target ASADHs from different microbial species. PMID- 20855557 TI - Effects of supplemental intra-articular lubricin and hyaluronic acid on the progression of posttraumatic arthritis in the anterior cruciate ligament deficient rat knee. AB - BACKGROUND: Lubricin and hyaluronic acid lubricate articular cartilage and prevent wear. Because lubricin loss occurs after anterior cruciate ligament injury, intra-articular lubricin injections may reduce cartilage damage in the anterior cruciate ligament-deficient knee. PURPOSE: This study was conducted to determine if lubricin and/or hyaluronic acid supplementation will reduce cartilage damage in the anterior cruciate ligament-deficient knee. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-six male rats, 3 months old, underwent unilateral anterior cruciate ligament transection. They were randomized to 4 treatments: (1) saline (phosphate-buffered saline [PBS]), (2) hyaluronic acid (HA), (3) purified human lubricin (LUB), and (4) LUB and HA (LUB+HA). Intra articular injections were given twice weekly for 4 weeks starting 1 week after surgery. Knees were harvested 1 week after the final injection. Radiographs of each limb and synovial fluid lavages were obtained at harvest. Histologic analysis was performed to assess cartilage damage using safranin O/fast green staining. Radiographs were scored for the severity of joint degeneration using the modified Kellgren-Lawrence scale. Synovial fluid levels of sulfated glycosaminoglycan, collagen II breakdown, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), and lubricin were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment with LUB or LUB+HA significantly decreased radiographic and histologic scores of cartilage damage (P = .039 and P = .015, respectively) when compared with the PBS and HA conditions. There was no evidence of an effect of HA nor was the LUB effect HA-dependent, suggesting that the addition of HA did not further reduce damage. The synovial fluid of knees treated with LUB had significantly more lubricin in the synovial fluid at euthanasia, although there were no differences in the other cartilage metabolism biomarkers. CONCLUSION: Supplemental intra-articular LUB reduced cartilage damage in the anterior cruciate ligament-transected rat knee 6 weeks after injury, while treatment with HA did not. CLINICAL RELEVANCE: Although longer term studies are needed, intra-articular supplementation (tribosupplementation) with lubricin after anterior cruciate ligament injury may protect the articular cartilage in the anterior cruciate ligament-injured knee. PMID- 20855559 TI - Fragment-based screening by biochemical assays: Systematic feasibility studies with trypsin and MMP12. AB - Fragment-based screening (FBS) has gained acceptance in the pharmaceutical industry as an attractive approach for the identification of new chemical starting points for drug discovery programs in addition to classical strategies such as high-throughput screening. There is the concern that screening of fragments at high uM concentrations in biochemical assays results in increased false-positive and false-negative rates. Here the authors systematically compare the data quality of FBS obtained by enzyme activity-based fluorescence intensity, fluorescence lifetime, and mobility shift assays with the data quality from surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) methods. The serine protease trypsin and the matrix metalloprotease MMP12 were selected as model systems. For both studies, 352 fragments were selected each. From the data generated, all 3 biochemical protease assay methods can be used for screening of fragments with low false-negative and low false-positive rates, comparable to those achieved with the SPR-based assays. It can also be concluded that only fragments with a solubility higher than the screening concentration determined by means of NMR should be used for FBS purposes. Extrapolated to 10,000 fragments, the biochemical assays speed up the primary FBS process by approximately a factor of 10 and reduce the protease consumption by approximately 10,000-fold compared to NMR protein observation experiments. PMID- 20855560 TI - High-throughput molecular imaging for the identification of FADD kinase inhibitors. AB - Fas-associated protein with death domain (FADD) was originally reported as a proapoptotic adaptor molecule that mediates receptor-induced apoptosis. Recent studies have revealed a potential role of FADD in NF-kappaB activation, embryogenesis, and cell cycle regulation and proliferation. Overexpression of FADD and its phosphorylation have been associated with the transformed phenotype in many cancers and is therefore a potential target for therapeutic intervention. In an effort to delineate signaling events that lead to FADD phosphorylation and to identify novel compounds that impinge on this pathway, the authors developed a cell-based reporter for FADD kinase activity. The reporter assay, optimized for a high-throughput screen (HTS), measures bioluminescence in response to modulation of FADD kinase activity in live cells. In addition, the potential use of the reporter cell line in the rapid evaluation of pharmacologic properties of HTS hits in mouse models has been demonstrated. PMID- 20855561 TI - An effective method for controlling false discovery and false nondiscovery rates in genome-scale RNAi screens. AB - In most genome-scale RNA interference (RNAi) screens, the ultimate goal is to select siRNAs with a large inhibition or activation effect. The selection of hits typically requires statistical control of 2 errors: false positives and false negatives. Traditional methods of controlling false positives and false negatives do not take into account the important feature in RNAi screens: many small interfering RNAs (siRNAs) may have very small but real nonzero average effects on the measured response and thus cannot allow us to effectively control false positives and false negatives. To address for deficiencies in the application of traditional approaches in RNAi screening, the author proposes a new method for controlling false positives and false negatives in RNAi high-throughput screens. The false negatives are statistically controlled through a false-negative rate (FNR) or false nondiscovery rate (FNDR). FNR is the proportion of false negatives among all siRNAs examined, whereas FNDR is the proportion of false negatives among declared nonhits. The author also proposes new concepts, q*-value and p* value, to control FNR and FNDR, respectively. The proposed method should have broad utility for hit selection in which one needs to control both false discovery and false nondiscovery rates in genome-scale RNAi screens in a robust manner. PMID- 20855562 TI - HCA-vision: Automated neurite outgrowth analysis. AB - Automating the analysis of neurons in culture represents a key aspect of the search for neuroactive compounds. A number of commercial neurite analysis software packages tend to measure some basic features such as total neurite length and number of branching points. However, with only these measurements, some differences between neurite morphologies that are clear to a human observer cannot be identified. The authors have developed a suite of image analysis tools that will allow researchers to produce quality analyses at primary screening rates. The suite provides sensitive and information-rich measurements of neurons and neurites. It can discriminate subtle changes in complex neurite arborization even when neurons and neurites are dense. This allows users to selectively screen for compounds triggering different types of neurite outgrowth behavior. In mixed cell populations, neurons can be filtered and separated from other brain cell types so that neurite analysis can be performed only on neurons. It supports batch processing with a built-in database to store the batch-processing results, a batch result viewer, and an ad hoc query builder for users to retrieve features of interest. The suite of tools has been deployed into a software package called HCA-Vision. The free version of the software package is available at http://www.hca-vision.com. PMID- 20855563 TI - Development of a novel nonradiometric assay for nucleic acid binding to TDP-43 suitable for high-throughput screening using AlphaScreen technology. AB - TAR DNA binding protein 43 (TDP-43) is a nucleic acid binding protein that is associated with the pathology of cystic fibrosis and neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar dementia. We have developed a robust, quantitative, nonradiometric high-throughput assay measuring oligonucleotide binding to TDP-43 using AlphaScreen technology. Biotinylated single-stranded TAR DNA (bt-TAR-32) and 6 TG repeats (bt-TG6) bound with high affinity to TDP-43, with K(D) values of 0.75 nM and 0.63 nM, respectively. Both oligonucleotides exhibited slow dissociation rates, with half-lives of 750 min for bt-TAR-32 and 150 min for bt-TG6. The affinities of unlabeled oligonucleotides, as determined by displacement of either bt-TAR-32 or bt-TG6, were consistent with previous reports of nucleic acid interactions with TDP-43, where increasing TG or UG repeats yield greater affinity. A diversity library of 7360 compounds was screened for inhibition of TDP-43 binding to bt-TAR-32, and a series of compounds was discovered with nascent SAR and IC(50) values ranging from 100 nM to 10 uM. These compounds may prove to be useful biochemical tools to elucidate the function of TDP-43 and may lead to novel therapeutics for indications where the TDP-43 nucleic acid interaction is causal to the associated pathology. PMID- 20855564 TI - Discovery of novel cyclophilin A ligands using an H/D exchange- and mass spectrometry-based strategy. AB - Cyclophilin A (CypA) is an overexpressed protein in lung cancer tumors and as a result is a potential therapeutic and diagnostic target. Described here is use of an H/D exchange- and a matrix assisted laser desorption/ionization (MALDI) mass spectrometry-based assay, termed single-point SUPREX (Stability of Unpurified Proteins from Rates of H/D Exchange), to screen 2 chemical libraries, including the 1280-compound LOPAC library and the 9600-compound DIVERSet library, for binding to CypA. This work represents the first application of single-point SUPREX using a pooled ligand approach, which is demonstrated here to yield screening rates as fast as 6 s/ligand. The false-positive and false-negative rates determined in the current work using a set of control samples were 0% and 9%, respectively. A false-positive rate of 20% was found in screening the actual libraries. Eight novel ligands to CypA were discovered, including 2-(alpha naphthoyl)ethyltrimethyl-ammonium iodide, (E)-3-(4-t-Butylphenylsulfonyl)-2 propenenitrile, 3-(N-benzyl-N-isopropyl)amino-1-(naphthalen-2-yl)propan-1-one, cis-diammineplatinum (II) chloride, 1-(3,5-dichlorophenyl)-1H-pyrrole-2,5-dione, N-(3-chloro-1, 4-dioxo-1,4-dihydro-2-naphthalenyl)-N-cyclohexylacetamide, 1-[2 (3,4-dimethoxyphenyl)ethyl]-1H-pyrrole-2,5-dione, and 4-(2-methoxy-4-nitrophenyl) 1-methyl-10-oxa-4-azatricyclo[5.2.1.0~2,6~]dec-8-ene-3,5-dione. These compounds, which had moderate binding affinities to CypA (i.e., K(d) values in the low micromolar range), provide new molecular scaffolds that might be useful in the development of CypA-targeted diagnostic imaging or therapeutic agents for lung cancer. PMID- 20855565 TI - Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease. AB - A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (<=40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL. PMID- 20855566 TI - ACC2 gene polymorphisms, metabolic syndrome, and gene-nutrient interactions with dietary fat. AB - Acetyl-CoA carboxylase beta (ACC2) plays a key role in fatty acid synthesis and oxidation pathways. Disturbance of these pathways is associated with impaired insulin responsiveness and metabolic syndrome (MetS). Gene-nutrient interactions may affect MetS risk. This study determined the relationship between ACC2 polymorphisms (rs2075263, rs2268387, rs2284685, rs2284689, rs2300453, rs3742023, rs3742026, rs4766587, and rs6606697) and MetS risk, and whether dietary fatty acids modulate this in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). Minor A allele carriers of rs4766587 had increased MetS risk (OR 1.29 [CI 1.08, 1.58], P = 0.0064) compared with the GG homozygotes, which may in part be explained by their increased body mass index (BMI), abdominal obesity, and impaired insulin sensitivity (P < 0.05). MetS risk was modulated by dietary fat intake (P = 0.04 for gene-nutrient interaction), where risk conferred by the A allele was exacerbated among individuals with a high-fat intake (>35% energy) (OR 1.62 [CI 1.05, 2.50], P = 0.027), particularly a high intake (>5.5% energy) of n-6 polyunsaturated fat (PUFA) (OR 1.82 [CI 1.14, 2.94], P = 0.01; P = 0.05 for gene-nutrient interaction). Saturated and monounsaturated fat intake did not modulate MetS risk. Importantly, we replicated some of these findings in an independent cohort. In conclusion, the ACC2 rs4766587 polymorphism influences MetS risk, which was modulated by dietary fat, suggesting novel gene-nutrient interactions. PMID- 20855567 TI - Jejunal wall triglyceride concentration of morbidly obese persons is lower in those with type 2 diabetes mellitus. AB - The overproduction of intestinal lipoproteins may contribute to the dyslipidemia found in diabetes. We studied the influence of diabetes on the fasting jejunal lipid content and its association with plasma lipids and the expression of genes involved in the synthesis and secretion of these lipoproteins. The study was undertaken in 27 morbidly obese persons, 12 of whom had type 2 diabetes mellitus (T2DM). The morbidly obese persons with diabetes had higher levels of chylomicron (CM) triglycerides (P < 0.001) and apolipoprotein (apo)B48 (P = 0.012). The jejunum samples obtained from the subjects with diabetes had a lower jejunal triglyceride content (P = 0.012) and angiopoietin-like protein 4 (ANGPTL4) mRNA expression (P = 0.043). However, the apoA-IV mRNA expression was significantly greater (P = 0.036). The jejunal triglyceride content correlated negatively with apoA-IV mRNA expression (r = -0.587, P = 0.027). The variables that explained the jejunal triglyceride content in a multiple linear regression model were the insulin resistance state and the apoA-IV mRNA expression. Our results show that the morbidly obese subjects with diabetes had lower jejunal lipid content and that this correlated negatively with apoA-IV mRNA expression. These findings show that the jejunum appears to play an active role in lipid homeostasis in the fasting state. PMID- 20855568 TI - Exploiting natural variation in Saccharomyces cerevisiae to identify genes for increased ethanol resistance. AB - Ethanol production from lignocellulosic biomass holds promise as an alternative fuel. However, industrial stresses, including ethanol stress, limit microbial fermentation and thus prevent cost competitiveness with fossil fuels. To identify novel engineering targets for increased ethanol tolerance, we took advantage of natural diversity in wild Saccharomyces cerevisiae strains. We previously showed that an S288c-derived lab strain cannot acquire higher ethanol tolerance after a mild ethanol pretreatment, which is distinct from other stresses. Here, we measured acquired ethanol tolerance in a large panel of wild strains and show that most strains can acquire higher tolerance after pretreatment. We exploited this major phenotypic difference to address the mechanism of acquired ethanol tolerance, by comparing the global gene expression response to 5% ethanol in S288c and two wild strains. Hundreds of genes showed variation in ethanol dependent gene expression across strains. Computational analysis identified several transcription factor modules and known coregulated genes as differentially expressed, implicating genetic variation in the ethanol signaling pathway. We used this information to identify genes required for acquisition of ethanol tolerance in wild strains, including new genes and processes not previously linked to ethanol tolerance, and four genes that increase ethanol tolerance when overexpressed. Our approach shows that comparative genomics across natural isolates can quickly identify genes for industrial engineering while expanding our understanding of natural diversity. PMID- 20855569 TI - The role of eIF1 in translation initiation codon selection in Caenorhabditis elegans. AB - The selection of a proper AUG start codon requires the base-pairing interactions between the codon on the mRNA and the anticodon of the initiator tRNA. This selection process occurs in a pre-initiation complex that includes multiple translation initiation factors and the small ribosomal subunit. To study how these initiation factors are involved in start codon recognition in multicellular organisms, we isolated mutants that allow the expression of a GFP reporter containing a non-AUG start codon. Here we describe the characterization of mutations in eif-1, which encodes the Caenorhabditis elegans translation initiation factor 1 (eIF1). Two mutations were identified, both of which are substitutions of amino acid residues that are identical in all eukaryotic eIF1 proteins. These residues are located in a structural region where the amino acid residues affected by the Saccharomyces cerevisiae eIF1 mutations are also localized. Both C. elegans mutations are dominant in conferring a non-AUG translation initiation phenotype and lead to growth arrest defects in homozygous animals. By assaying reporter constructs that have base changes at the AUG start codon, these mutants are found to allow expression from most reporters that carry single base changes within the AUG codon. This trend of non-AUG mediated initiation was also observed previously for C. elegans eIF2beta mutants, indicating that these two factors play a similar role. These results support that eIF1 functions in ensuring the fidelity of AUG start codon recognition in a multicellular organism. PMID- 20855570 TI - General epistatic models of the risk of complex diseases. AB - The range of possible gene interactions in a multilocus model of a complex inherited disease is studied by exploring genotype-specific risks subject to the constraint that the allele frequencies and marginal risks are known. We quantify the effect of gene interactions by defining the interaction ratio, CR=KR/KRI, where KR is the recurrence risk to relatives with relationship R for the true model and KRI is the recurrence risk to relatives for a multiplicative model with the same marginal risks. We use a Markov chain Monte Carlo (MCMC) procedure to sample from the space of possible models. We find that the average of CR increases with the number of loci for both low frequency (p=0.03) and higher frequency (p=0.25) causative alleles. Furthermore, the probability that CR>1 is nearly 1. Similar results are obtained when more weight is given to risk models that are closer to the comparable multiplicative model. These results imply that, in general, gene interactions will result in greater heritability of a complex inherited disease than is expected on the basis of a multiplicative model of interactions and hence may provide a partial explanation for the problem of missing heritability of complex diseases. PMID- 20855573 TI - Ninety years of Drosophila melanogaster hybrids. AB - Within 10 years of the beginning of experimental genetic research on Drosophila melanogaster, in 1919, A. H. Sturtevant discovered its sibling species, D. simulans. He hybridized the two species and made fundamental discoveries about the genetic basis of hybrid incompatibility. The complete sterility of surviving F(1) hybrids frustrated Sturtevant and his vision of comprehensively exploring the genetics of interspecific differences. But over the next 90 years, a combination of clever genetic tricks and close observation of natural variation has led to a wealth of discovery using these and other hybrids of D. melanogaster and D. simulans, resulting in an advanced understanding of speciation and the evolution of morphology, gene regulation, and behavior. PMID- 20855575 TI - To pool, or not to pool? PMID- 20855576 TI - Detecting selection in population trees: the Lewontin and Krakauer test extended. AB - Detecting genetic signatures of selection is of great interest for many research issues. Common approaches to separate selective from neutral processes focus on the variance of F(ST) across loci, as does the original Lewontin and Krakauer (LK) test. Modern developments aim to minimize the false positive rate and to increase the power, by accounting for complex demographic structures. Another stimulating goal is to develop straightforward parametric and computationally tractable tests to deal with massive SNP data sets. Here, we propose an extension of the original LK statistic (T(LK)), named T(F-LK), that uses a phylogenetic estimation of the population's kinship (F) matrix, thus accounting for historical branching and heterogeneity of genetic drift. Using forward simulations of single nucleotide polymorphisms (SNPs) data under neutrality and selection, we confirm the relative robustness of the LK statistic (T(LK)) to complex demographic history but we show that T(F-LK) is more powerful in most cases. This new statistic outperforms also a multinomial-Dirichlet-based model [estimation with Markov chain Monte Carlo (MCMC)], when historical branching occurs. Overall, T(F LK) detects 15-35% more selected SNPs than T(LK) for low type I errors (P < 0.001). Also, simulations show that T(LK) and T(F-LK) follow a chi-square distribution provided the ancestral allele frequencies are not too extreme, suggesting the possible use of the chi-square distribution for evaluating significance. The empirical distribution of T(F-LK) can be derived using simulations conditioned on the estimated F matrix. We apply this new test to pig breeds SNP data and pinpoint outliers using T(F-LK), otherwise undetected using the less powerful T(LK) statistic. This new test represents one solution for compromise between advanced SNP genetic data acquisition and outlier analyses. PMID- 20855574 TI - The birds and the bees and the flowers and the trees: lessons from genetic mapping of sex determination in plants and animals. AB - The ability to identify genetic markers in nonmodel systems has allowed geneticists to construct linkage maps for a diversity of species, and the sex determining locus is often among the first to be mapped. Sex determination is an important area of study in developmental and evolutionary biology, as well as ecology. Its importance for organisms might suggest that sex determination is highly conserved. However, genetic studies have shown that sex determination mechanisms, and the genes involved, are surprisingly labile. We review studies using genetic mapping and phylogenetic inferences, which can help reveal evolutionary pattern within this lability and potentially identify the changes that have occurred among different sex determination systems. We define some of the terminology, particularly where confusion arises in writing about such a diverse range of organisms, and highlight some major differences between plants and animals, and some important similarities. We stress the importance of studying taxa suitable for testing hypotheses, and the need for phylogenetic studies directed to taxa where the patterns of changes can be most reliably inferred, if the ultimate goal of testing hypotheses regarding the selective forces that have led to changes in such an essential trait is to become feasible. PMID- 20855577 TI - Defining the mechanism of polymerization in the serpinopathies. AB - The serpinopathies result from the ordered polymerization of mutants of members of the serine proteinase inhibitor (serpin) superfamily. These polymers are retained within the cell of synthesis where they cause a toxic gain of function. The serpinopathies are exemplified by inclusions that form with the common severe Z mutant of alpha(1)-antitrypsin that are associated with liver cirrhosis. There is considerable controversy as to the pathway of serpin polymerization and the structure of pathogenic polymers that cause disease. We have used synthetic peptides, limited proteolysis, monoclonal antibodies, and ion mobility-mass spectrometry to characterize the polymerogenic intermediate and pathological polymers formed by Z alpha(1)-antitrypsin. Our data are best explained by a model in which polymers form through a single intermediate and with a reactive center loop-beta-sheet A linkage. Our data are not compatible with the recent model in which polymers are linked by a beta-hairpin of the reactive center loop and strand 5A. Understanding the structure of the serpin polymer is essential for rational drug design strategies that aim to block polymerization and so treat alpha(1)-antitrypsin deficiency and the serpinopathies. PMID- 20855579 TI - Direct search for a ferromagnetic phase in a heavily overdoped nonsuperconducting copper oxide. AB - The doping of charge carriers into the CuO(2) planes of copper oxide Mott insulators causes a gradual destruction of antiferromagnetism and the emergence of high-temperature superconductivity. Optimal superconductivity is achieved at a doping concentration p beyond which further increases in doping cause a weakening and eventual disappearance of superconductivity. A potential explanation for this demise is that ferromagnetic fluctuations compete with superconductivity in the overdoped regime. In this case, a ferromagnetic phase at very low temperatures is predicted to exist beyond the doping concentration at which superconductivity disappears. Here we report on a direct examination of this scenario in overdoped La(2-x)Sr(x)CuO(4) using the technique of muon spin relaxation. We detect the onset of static magnetic moments of electronic origin at low temperature in the heavily overdoped nonsuperconducting region. However, the magnetism does not exist in a commensurate long-range ordered state. Instead it appears as a dilute concentration of static magnetic moments. This finding places severe restrictions on the form of ferromagnetism that may exist in the overdoped regime. Although an extrinsic impurity cannot be absolutely ruled out as the source of the magnetism that does occur, the results presented here lend support to electronic band calculations that predict the occurrence of weak localized ferromagnetism at high doping. PMID- 20855580 TI - Reconstructing a solid-solid phase transformation pathway in CdSe nanosheets with associated soft ligands. AB - Integrated single-crystal-like small and wide-angle X-ray diffraction images of a CdSe nanosheet under pressure provide direct experimental evidence for the detailed pathway of transformation of the CdSe from a wurtzite to a rock-salt structure. Two consecutive planar atomic slips [(001) {110} in parallel and (102) {101}with a distortion angle of ~40 degrees ] convert the wurtzite-based nanosheet into a saw-like rock-salt nanolayer. The transformation pressure is three times that in the bulk CdSe crystal. Theoretical calculations are in accord with the mechanism and the change in transformation pressure, and point to the critical role of the coordinated amines. Soft ligands not only increase the stability of the wurtzite structure, but also improve its elastic strength and fracture toughness. A ligand extension of 2.3 nm appears to be the critical dimension for a turning point in stress distribution, leading to the formation of wurtzite (001)/zinc-blende (111) stacking faults before rock-salt nucleation. PMID- 20855581 TI - Response of Colorado River runoff to dust radiative forcing in snow. AB - The waters of the Colorado River serve 27 million people in seven states and two countries but are overallocated by more than 10% of the river's historical mean. Climate models project runoff losses of 7-20% from the basin in this century due to human-induced climate change. Recent work has shown however that by the late 1800s, decades prior to allocation of the river's runoff in the 1920s, a fivefold increase in dust loading from anthropogenically disturbed soils in the southwest United States was already decreasing snow albedo and shortening the duration of snow cover by several weeks. The degree to which this increase in radiative forcing by dust in snow has affected timing and magnitude of runoff from the Upper Colorado River Basin (UCRB) is unknown. Here we use the Variable Infiltration Capacity model with postdisturbance and predisturbance impacts of dust on albedo to estimate the impact on runoff from the UCRB across 1916-2003. We find that peak runoff at Lees Ferry, Arizona has occurred on average 3 wk earlier under heavier dust loading and that increases in evapotranspiration from earlier exposure of vegetation and soils decreases annual runoff by more than 1.0 billion cubic meters or ~5% of the annual average. The potential to reduce dust loading through surface stabilization in the deserts and restore more persistent snow cover, slow runoff, and increase water resources in the UCRB may represent an important mitigation opportunity to reduce system management tensions and regional impacts of climate change. PMID- 20855582 TI - A dynamic-signaling-team model for chemotaxis receptors in Escherichia coli. AB - The chemotaxis system of Escherichia coli is sensitive to small relative changes in ambient chemoattractant concentrations over a broad range. Interactions among receptors are crucial to this sensitivity, as is precise adaptation, the return of chemoreceptor activity to prestimulus levels in a constant chemoeffector environment through methylation and demethylation of receptors. Signal integration and cooperativity have been attributed to strongly coupled, mixed teams of receptors, but receptors become individually methylated according to their ligand occupancy states. Here, we present a model of dynamic signaling teams that reconciles strong coupling among receptors with receptor-specific methylation. Receptor trimers of dimers couple to form a honeycomb lattice, consistent with cryo-electron microscopy (cryoEM) tomography, within which the boundaries of signaling teams change rapidly. Our model helps explain the inferred increase in signaling team size with receptor modification, and indicates that active trimers couple more strongly than inactive trimers. PMID- 20855583 TI - Hydration dynamics at fluorinated protein surfaces. AB - Water-protein interactions dictate many processes crucial to protein function including folding, dynamics, interactions with other biomolecules, and enzymatic catalysis. Here we examine the effect of surface fluorination on water-protein interactions. Modification of designed coiled-coil proteins by incorporation of 5,5,5-trifluoroleucine or (4S)-2-amino-4-methylhexanoic acid enables systematic examination of the effects of side-chain volume and fluorination on solvation dynamics. Using ultrafast fluorescence spectroscopy, we find that fluorinated side chains exert electrostatic drag on neighboring water molecules, slowing water motion at the protein surface. PMID- 20855584 TI - Storage of nuclear magnetization as long-lived singlet order in low magnetic field. AB - Hyperpolarized nuclear states provide NMR signals enhanced by many orders of magnitude, with numerous potential applications to analytical NMR, in vivo NMR, and NMR imaging. However, the lifetime of hyperpolarized magnetization is normally limited by the relaxation time constant T(1), which lies in the range of milliseconds to minutes, apart from in exceptional cases. In many cases, the lifetime of the hyperpolarized state may be enhanced by converting the magnetization into nuclear singlet order, where it is protected against many common relaxation mechanisms. However, all current methods for converting magnetization into singlet order require the use of a high-field, high homogeneity NMR magnet, which is incompatible with most hyperpolarization procedures. We demonstrate a new method for converting magnetization into singlet order and back again. The new technique is suitable for magnetically inequivalent spin-pair systems in weak and inhomogeneous magnetic fields, and is compatible with known hyperpolarization technology. The method involves audio-frequency pulsed irradiation at the low-field nuclear Larmor frequency, employing coupling synchronized trains of 180 degrees pulses to induce singlet-triplet transitions. The echo trains are used as building blocks for a pulse sequence called M2S that transforms longitudinal magnetization into long-lived singlet order. The time reverse of the pulse sequence, called S2M, converts singlet order back into longitudinal magnetization. The method is demonstrated on a solution of (15)N labeled nitrous oxide. The magnetization is stored in low magnetic field for over 30 min, even though the T(1) is less than 3 min under the same conditions. PMID- 20855585 TI - Structural context shapes the aquaporin selectivity filter. AB - Aquaporins are transmembrane channels that facilitate the permeation of water and small, uncharged amphipathic molecules across cellular membranes. One distinct aquaporin subfamily contains pure water channels, whereas a second subfamily contains channels that conduct small alditols such as glycerol, in addition to water. Distinction between these substrates is central to aquaporin function, though the contributions of protein structural motifs required for selectivity are not yet fully characterized. To address this question, we sequentially engineered three signature amino acids of the glycerol-conducting subfamily into the Escherichia coli water channel aquaporin Z (AqpZ). Functional analysis of these mutant channels showed a decrease in water permeability but not the expected increase in glycerol conduction. Using X-ray crystallography, we determined the atomic resolution structures of the mutant channels. The structures revealed a channel surprisingly similar in size to the wild-type AqpZ pore. Comparison with measured rates of transport showed that, as the size of the selectivity filter region of the channel approaches that of water, channel hydrophilicity dominated water conduction energetics. In contrast, the major determinant of selectivity for larger amphipathic molecules such as glycerol was channel cross-section size. Finally, we find that, although the selectivity filter region is indeed central to substrate transport, other structural elements that do not directly interact with the substrates, such as the loop connecting helices M6 and M7, and the C loop between helices C4 and C5, play an essential role in facilitating selectivity. PMID- 20855586 TI - Kudzu invasion leads to NOx increase and ozone pollution: unraveling possible mechanisms. PMID- 20855587 TI - Bihemispheric foundations for human speech comprehension. AB - Emerging evidence from neuroimaging and neuropsychology suggests that human speech comprehension engages two types of neurocognitive processes: a distributed bilateral system underpinning general perceptual and cognitive processing, viewed as neurobiologically primary, and a more specialized left hemisphere system supporting key grammatical language functions, likely to be specific to humans. To test these hypotheses directly we covaried increases in the nonlinguistic complexity of spoken words [presence or absence of an embedded stem, e.g., claim (clay)] with variations in their linguistic complexity (presence of inflectional affixes, e.g., play+ed). Nonlinguistic complexity, generated by the on-line competition between the full word and its onset-embedded stem, was found to activate both right and left fronto-temporal brain regions, including bilateral BA45 and -47. Linguistic complexity activated left-lateralized inferior frontal areas only, primarily in BA45. This contrast reflects a differentiation between the functional roles of a bilateral system, which supports the basic mapping from sound to lexical meaning, and a language-specific left-lateralized system that supports core decompositional and combinatorial processes invoked by linguistically complex inputs. These differences can be related to the neurobiological foundations of human language and underline the importance of bihemispheric systems in supporting the dynamic processing and interpretation of spoken inputs. PMID- 20855588 TI - MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. AB - Sterol regulatory element-binding protein 2 (SREBP-2) transcription factor has been identified as a key protein in cholesterol metabolism through the transactivation of the LDL receptor and cholesterol biosynthesis genes. Here, we generated mice lacking microRNA (miR)-33, encoded by an intron of the Srebp2, and showed that miR-33 repressed the expression of ATP-binding cassette transporter A1 (ABCA1) protein, a key regulator of HDL synthesis by mediating cholesterol efflux from cells to apolipoprotein A (apoA)-I. In fact, peritoneal macrophages derived from miR-33-deficient mice showed a marked increase in ABCA1 levels and higher apoA-I-dependent cholesterol efflux than those from WT mice. ABCA1 protein levels in liver were also higher in miR-33-deficient mice than in WT mice. Moreover, miR-33-deficient mice had significantly higher serum HDL cholesterol levels than WT mice. These data establish a critical role for miR-33 in the regulation of ABCA1 expression and HDL biogenesis in vivo. PMID- 20855589 TI - Cardiomyopathy-linked myosin regulatory light chain mutations disrupt myosin strain-dependent biochemistry. AB - Familial hypertrophic cardiomyopathy (FHC) is caused by mutations in sarcomeric proteins including the myosin regulatory light chain (RLC). Two such FHC mutations, R58Q and N47K, located near the cationic binding site of the RLC, have been identified from population studies. To examine the molecular basis for the observed phenotypes, we exchanged endogenous RLC from native porcine cardiac myosin with recombinant human ventricular wild type (WT) or FHC mutant RLC and examined the ability of the reconstituted myosin to propel actin filament sliding using the in vitro motility assay. We find that, whereas the mutant myosins are indistinguishable from the controls (WT or native myosin) under unloaded conditions, both R58Q- and N47K-exchanged myosins show reductions in force and power output compared with WT or native myosin. We also show that the changes in loaded kinetics are a result of mutation-induced loss of myosin strain sensitivity of ADP affinity. We propose that the R58Q and N47K mutations alter the mechanical properties of the myosin neck region, leading to altered load dependent kinetics that may explain the observed mutant-induced FHC phenotypes. PMID- 20855590 TI - Effects of past, present, and future ocean carbon dioxide concentrations on the growth and survival of larval shellfish. AB - The combustion of fossil fuels has enriched levels of CO(2) in the world's oceans and decreased ocean pH. Although the continuation of these processes may alter the growth, survival, and diversity of marine organisms that synthesize CaCO(3) shells, the effects of ocean acidification since the dawn of the industrial revolution are not clear. Here we present experiments that examined the effects of the ocean's past, present, and future (21st and 22nd centuries) CO(2) concentrations on the growth, survival, and condition of larvae of two species of commercially and ecologically valuable bivalve shellfish (Mercenaria mercenaria and Argopecten irradians). Larvae grown under near preindustrial CO(2) concentrations (250 ppm) displayed significantly faster growth and metamorphosis as well as higher survival and lipid accumulation rates compared with individuals reared under modern day CO(2) levels. Bivalves grown under near preindustrial CO(2) levels displayed thicker, more robust shells than individuals grown at present CO(2) concentrations, whereas bivalves exposed to CO(2) levels expected later this century had shells that were malformed and eroded. These results suggest that the ocean acidification that has occurred during the past two centuries may be inhibiting the development and survival of larval shellfish and contributing to global declines of some bivalve populations. PMID- 20855591 TI - PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. AB - Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage. PMID- 20855592 TI - The Dutch Hunger Winter and the developmental origins of health and disease. PMID- 20855593 TI - Autotrophic ammonia oxidation by soil thaumarchaea. AB - Nitrification plays a central role in the global nitrogen cycle and is responsible for significant losses of nitrogen fertilizer, atmospheric pollution by the greenhouse gas nitrous oxide, and nitrate pollution of groundwaters. Ammonia oxidation, the first step in nitrification, was thought to be performed by autotrophic bacteria until the recent discovery of archaeal ammonia oxidizers. Autotrophic archaeal ammonia oxidizers have been cultivated from marine and thermal spring environments, but the relative importance of bacteria and archaea in soil nitrification is unclear and it is believed that soil archaeal ammonia oxidizers may use organic carbon, rather than growing autotrophically. In this soil microcosm study, stable isotope probing was used to demonstrate incorporation of (13)C-enriched carbon dioxide into the genomes of thaumarchaea possessing two functional genes: amoA, encoding a subunit of ammonia monooxygenase that catalyses the first step in ammonia oxidation; and hcd, a key gene in the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle, which has been found so far only in archaea. Nitrification was accompanied by increases in archaeal amoA gene abundance and changes in amoA gene diversity, but no change was observed in bacterial amoA genes. Archaeal, but not bacterial, amoA genes were also detected in (13)C-labeled DNA, demonstrating inorganic CO(2) fixation by archaeal, but not bacterial, ammonia oxidizers. Autotrophic archaeal ammonia oxidation was further supported by coordinate increases in amoA and hcd gene abundance in (13)C-labeled DNA. The results therefore provide direct evidence for a role for archaea in soil ammonia oxidation and demonstrate autotrophic growth of ammonia oxidizing archaea in soil. PMID- 20855595 TI - Next-generation protein-rich potato expressing the seed protein gene AmA1 is a result of proteome rebalancing in transgenic tuber. AB - Protein deficiency is the most crucial factor that affects physical growth and development and that increases morbidity and mortality especially in developing countries. Efforts have been made to improve protein quality and quantity in crop plants but with limited success. Here, we report the development of transgenic potatoes with enhanced nutritive value by tuber-specific expression of a seed protein, AmA1 (Amaranth Albumin 1), in seven genotypic backgrounds suitable for cultivation in different agro-climatic regions. Analyses of the transgenic tubers revealed up to 60% increase in total protein content. In addition, the concentrations of several essential amino acids were increased significantly in transgenic tubers, which are otherwise limited in potato. Moreover, the transgenics also exhibited enhanced photosynthetic activity with a concomitant increase in total biomass. These results are striking because this genetic manipulation also resulted in a moderate increase in tuber yield. The comparative protein profiling suggests that the proteome rebalancing might cause increased protein content in transgenic tubers. Furthermore, the data on field performance and safety evaluation indicate that the transgenic potatoes are suitable for commercial cultivation. In vitro and in vivo studies on experimental animals demonstrate that the transgenic tubers are also safe for human consumption. Altogether, these results emphasize that the expression of AmA1 is a potential strategy for the nutritional improvement of food crops. PMID- 20855594 TI - Complement receptor 1 is the host erythrocyte receptor for Plasmodium falciparum PfRh4 invasion ligand. AB - Plasmodium falciparum is responsible for the most severe form of malaria disease in humans, causing more than 1 million deaths each year. As an obligate intracellular parasite, P. falciparum's ability to invade erythrocytes is essential for its survival within the human host. P. falciparum invades erythrocytes using multiple host receptor-parasite ligand interactions known as invasion pathways. Here we show that CR1 is the host erythrocyte receptor for PfRh4, a major P. falciparum ligand essential for sialic acid-independent invasion. PfRh4 and CR1 interact directly, with a K(d) of 2.9 MUM. PfRh4 binding is strongly correlated with the CR1 level on the erythrocyte surface. Parasite invasion via sialic acid-independent pathways is reduced in low-CR1 erythrocytes due to limited availability of this receptor on the surface. Furthermore, soluble CR1 can competitively block binding of PfRh4 to the erythrocyte surface and specifically inhibit sialic acid-independent parasite invasion. These results demonstrate that CR1 is an erythrocyte receptor used by the parasite ligand PfRh4 for P. falciparum invasion. PMID- 20855597 TI - QnAs with Thomas C. Sudhof. Interview by Prashant Nair. PMID- 20855596 TI - GLD-2/RNP-8 cytoplasmic poly(A) polymerase is a broad-spectrum regulator of the oogenesis program. AB - Regulated polyadenylation is a broadly conserved mechanism that controls key events during oogenesis. Pivotal to that mechanism is GLD-2, a catalytic subunit of cytoplasmic poly(A) polymerase (PAP). Caenorhabditis elegans GLD-2 forms an active PAP with multiple RNA-binding partners to regulate diverse aspects of germline and early embryonic development. One GLD-2 partner, RNP-8, was previously shown to influence oocyte fate specification. Here we use a genomic approach to identify transcripts selectively associated with both GLD-2 and RNP 8. Among the 335 GLD-2/RNP-8 potential targets, most were annotated as germline mRNAs and many as maternal mRNAs. These targets include gld-2 and rnp-8 themselves, suggesting autoregulation. Removal of either GLD-2 or RNP-8 resulted in shortened poly(A) tails and lowered abundance of four target mRNAs (oma-2, egg 1, pup-2, and tra-2); GLD-2 depletion also lowered the abundance of most GLD 2/RNP-8 putative target mRNAs when assayed on microarrays. Therefore, GLD-2/RNP-8 appears to polyadenylate and stabilize its target mRNAs. We also provide evidence that rnp-8 influences oocyte development; rnp-8 null mutants have more germ cell corpses and fewer oocytes than normal. Furthermore, RNP-8 appears to work synergistically with another GLD-2-binding partner, GLD-3, to ensure normal oogenesis. We propose that the GLD-2/RNP-8 enzyme is a broad-spectrum regulator of the oogenesis program that acts within an RNA regulatory network to specify and produce fully functional oocytes. PMID- 20855598 TI - Animal cells connected by nanotubes can be electrically coupled through interposed gap-junction channels. AB - Tunneling nanotubes (TNTs) are recently discovered conduits for a previously unrecognized form of cell-to-cell communication. These nanoscale, F-actin containing membrane tubes connect cells over long distances and facilitate the intercellular exchange of small molecules and organelles. Using optical membrane potential measurements combined with mechanical stimulation and whole-cell patch clamp recording, we demonstrate that TNTs mediate the bidirectional spread of electrical signals between TNT-connected normal rat kidney cells over distances of 10 to 70 MUm. Similar results were obtained for other cell types, suggesting that electrical coupling via TNTs may be a widespread characteristic of animal cells. Strength of electrical coupling depended on the length and number of TNT connections. Several lines of evidence implicate a role for gap junctions in this long-distance electrical coupling: punctate connexin 43 immunoreactivity was frequently detected at one end of TNTs, and electrical coupling was voltage sensitive and inhibited by meclofenamic acid, a gap-junction blocker. Cell types lacking gap junctions did not show TNT-dependent electrical coupling, which suggests that TNT-mediated electrical signals are transmitted through gap junctions at a membrane interface between the TNT and one cell of the connected pair. Measurements of the fluorescent calcium indicator X-rhod-1 revealed that TNT-mediated depolarization elicited threshold-dependent, transient calcium signals in HEK293 cells. These signals were inhibited by the voltage-gated Ca(2+) channel blocker mibefradil, suggesting they were generated via influx of calcium through low voltage-gated Ca(2+) channels. Taken together, our data suggest a unique role for TNTs, whereby electrical synchronization between distant cells leads to activation of downstream target signaling. PMID- 20855599 TI - Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. AB - Dengue virus (DENV) modifies cellular membranes to establish its sites of replication. Although the 3D architecture of these structures has recently been described, little is known about the cellular pathways required for their formation and expansion. In this report, we examine the host requirements for DENV replication using a focused RNAi analysis combined with validation studies using pharmacological inhibitors. This approach identified three cellular pathways required for DENV replication: autophagy, actin polymerization, and fatty acid biosynthesis. Further characterization of the viral modulation of fatty acid biosynthesis revealed that a key enzyme in this pathway, fatty acid synthase (FASN), is relocalized to sites of DENV replication. DENV nonstructural protein 3 (NS3) is responsible for FASN recruitment, inasmuch as (i) NS3 expressed in the absence of other viral proteins colocalizes with FASN and (ii) NS3 interacts with FASN in a two-hybrid assay. There is an associated increase in the rate of fatty acid biosynthesis in DENV-infected cells, and de novo synthesized lipids preferentially cofractionate with DENV RNA. Finally, purified recombinant NS3 stimulates the activity of FASN in vitro. Taken together, these experiments suggest that DENV co-opts the fatty acid biosynthetic pathway to establish its replication complexes. This study provides mechanistic insight into DENV membrane remodeling and highlights the potential for the development of therapeutics that inhibit DENV replication by targeting the fatty acid biosynthetic pathway. PMID- 20855600 TI - Phosphorylation of eukaryotic initiation factor-2{alpha} promotes the extracellular survival of obligate intracellular parasite Toxoplasma gondii. AB - While seeking a new host cell, obligate intracellular parasites, such as the protozoan Toxoplasma gondii, must be able to endure the stress of an extracellular environment. The mechanisms Toxoplasma use to remain viable while deprived of a host cell are not understood. We have previously shown that phosphorylation of Toxoplasma eukaryotic initiation factor-2alpha (TgIF2alpha) is a conserved response to stress. Here we report the characterization of Toxoplasma harboring a point mutation (S71A) in TgIF2alpha that prevents phosphorylation. Results show that TgIF2alpha phosphorylation is critical for parasite viability because the TgIF2alpha-S71A mutants are ill-equipped to cope with life outside the host cell. The TgIF2alpha-S71A mutants also showed a significant delay in producing acute toxoplasmosis in vivo. We conclude that the phosphorylation of TgIF2alpha plays a crucial role during the lytic cycle by ameliorating the stress of the extracellular environment while the parasite searches for a new host cell. PMID- 20855601 TI - INO80 chromatin remodeling complex promotes the removal of UV lesions by the nucleotide excision repair pathway. AB - The creation of accessible DNA in the context of chromatin is a key step in many DNA functions. To reveal how ATP-dependent chromatin remodeling activities impact DNA repair, we constructed mammalian genetic models for the INO80 chromatin remodeling complex and investigated the impact of loss of INO80 function on the repair of UV-induced photo lesions. We showed that deletion of two core components of the INO80 complex, INO80 and ARP5, significantly hampered cellular removal of UV-induced photo lesions but had no significant impact on the transcription of nucleotide excision repair (NER) factors. Loss of INO80 abolished the assembly of NER factors, suggesting that prior chromatin relaxation is important for the NER incision process. Ino80 and Arp5 are enriched to UV damaged DNA in an NER-incision-independent fashion, suggesting that recruitment of the remodeling activity likely takes place during the initial stage of damage recognition. These results demonstrate a critical role of INO80 in creating DNA accessibility for the NER pathway and provide direct evidence that repair of UV lesions and perhaps most bulky adduct lesions requires chromatin reconfiguration. PMID- 20855602 TI - Mutations of cellulose synthase (CESA1) phosphorylation sites modulate anisotropic cell expansion and bidirectional mobility of cellulose synthase. AB - The CESA1 component of cellulose synthase is phosphorylated at sites clustered in two hypervariable regions of the protein. Mutations of the phosphorylated residues to Ala (A) or Glu (E) alter anisotropic cell expansion and cellulose synthesis in rapidly expanding roots and hypocotyls. Expression of T166E, S686E, or S688E mutants of CESA1 fully rescued the temperature sensitive cesA1-1 allele (rsw1) at a restrictive temperature whereas mutations to A at these positions caused defects in anisotropic cell expansion. However, mutations to E at residues surrounding T166 (i.e., S162, T165, and S167) caused opposite effects. Live-cell imaging of fluorescently labeled CESA showed close correlations between tissue or cell morphology and patterns of bidirectional motility of CESA complexes in the plasma membrane. In the WT, CESA complexes moved at similar velocities in both directions along microtubule tracks. By contrast, the rate of movement of CESA particles was directionally asymmetric in mutant lines that exhibited abnormal tissue or cell expansion, and the asymmetry was removed upon depolymerizing microtubules with oryzalin. This suggests that phosphorylation of CESA differentially affects a polar interaction with microtubules that may regulate the length or quantity of a subset of cellulose microfibrils and that this, in turn, alters microfibril structure in the primary cell wall resulting in or contributing to the observed defect in anisotropic cell expansion. PMID- 20855603 TI - Early understandings of the link between agents and order. AB - The world around us presents two fundamentally different forms of patterns: those that appear random and those that appear ordered. As adults we appreciate that these two types of patterns tend to arise from very different sorts of causal processes. Typically, we expect that, whereas agents can increase the orderliness of a system, inanimate objects can cause only increased disorder. Thus, one major division in the world of causal entities is between those that are capable of "reversing local entropy" and those that are not. In the present studies we find that sensitivity to the unique link between agents and order emerges quite early in development. Results from three experiments suggest that by 12 mo of age infants associate agents with the creation of order and inanimate objects with the creation of disorder. Such expectations appear to be robust into children's preschool years and are hypothesized to result from a more general understanding that agents causally intervene on the world in fundamentally different ways from inanimate objects. PMID- 20855605 TI - Competition-defense tradeoffs and the maintenance of plant diversity. AB - Ecologists have long observed that consumers can maintain species diversity in communities of their prey. Many theories of how consumers mediate diversity invoke a tradeoff between species' competitive ability and their ability to withstand predation. Under this constraint, the best competitors are also most susceptible to consumers, preventing them from excluding other species. However, empirical evidence for competition-defense tradeoffs is limited and, as such, the mechanisms by which consumers regulate diversity remain uncertain. We performed a meta-analysis of 36 studies to evaluate the prevalence of the competition-defense tradeoff and its role in maintaining diversity in plant communities. We quantified species' responses to experimental resource addition and consumer removal as estimates of competitive ability and resistance to consumers, respectively. With this analysis, we found mixed empirical evidence for a competition-defense tradeoff; in fact, competitive ability tended to be weakly positively correlated with defense overall. However, when present, negative relationships between competitive ability and defense influenced species diversity in the manner predicted by theory. In the minority of communities for which a tradeoff was detected, species evenness was higher, and resource addition and consumer removal reduced diversity. Our analysis reframes the commonly held notion that consumers structure plant communities through a competition-defense tradeoff. Such a tradeoff can maintain diversity when present, but negative correlations between competitive ability and defense were less common than is often assumed. In this respect, this study supports an emerging theoretical paradigm in which predation interacts with competition to both enhance and reduce species diversity. PMID- 20855604 TI - Lateral opening of a translocon upon entry of protein suggests the mechanism of insertion into membranes. AB - The structure of the protein-translocating channel SecYEbeta from Pyrococcus furiosus at 3.1-A resolution suggests a mechanism for chaperoning transmembrane regions of a protein substrate during its lateral delivery into the lipid bilayer. Cytoplasmic segments of SecY orient the C-terminal alpha-helical region of another molecule, suggesting a general binding mode and a promiscuous guiding surface capable of accommodating diverse nascent chains at the exit of the ribosomal tunnel. To accommodate this putative nascent chain mimic, the cytoplasmic vestibule widens, and a lateral exit portal is opened throughout its entire length for partition of transmembrane helical segments to the lipid bilayer. In this primed channel, the central plug still occludes the pore while the lateral gate is opened, enabling topological arbitration during early protein insertion. In vivo, a 15 amino acid truncation of the cytoplasmic C-terminal helix of SecY fails to rescue a secY-deficient strain, supporting the essential role of this helix as suggested from the structure. PMID- 20855606 TI - Melanopsin-dependent light avoidance in neonatal mice. AB - Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) form a light-sensitive system separate from rods and cones. Direct light stimulation of ipRGCs can regulate many nonimage-forming visual functions such as photoentrainment of circadian rhythms and pupil responses, and can intensify migraine headache in adults. In mice, ipRGCs are light responsive as early as the day of birth. In contrast, their eyelids do not open until 12-13 d after birth (P12-13), and light signaling from rods and cones does not begin until approximately P10. No physiological or behavioral function is established for ipRGCs in neonates before the onset of rod and cone signaling. Here we report that mouse pups as young as P6 will completely turn away from a light. Light induced responses of ipRGCs could be readily recorded in retinas of pups younger than P9, and we found no evidence for rod- and cone-mediated visual signaling to the RGCs of these younger mice. These results confirm that negative phototaxis is evident before the onset of rod- and cone-mediated visual signaling, and well before the onset of image-forming vision. Negative phototaxis was absent in mice lacking melanopsin. We conclude that light activation of melanopsin ipRGCs is necessary and sufficient for negative phototaxis. These results strongly suggest that light activation of ipRGCs may regulate physiological functions such as sleep/wake cycles in preterm and neonatal infants. PMID- 20855607 TI - Proteome-wide screens for small ubiquitin-like modifier (SUMO) substrates identify Arabidopsis proteins implicated in diverse biological processes. AB - Covalent modification of proteins by small ubiquitin-like modifier (SUMO) regulates various cellular activities in yeast and mammalian cells. In Arabidopsis, inactivation of genes encoding SUMO or SUMO-conjugation enzymes is lethal, emphasizing the importance of SUMOylation in plant development. Despite this, little is known about SUMO targets in plants. Here we identified 238 Arabidopsis proteins as potential SUMO substrates because they interacted with SUMO-conjugating enzyme and/or SUMO protease (ESD4) in the yeast two-hybrid system. Compared with the whole Arabidopsis proteome, the identified proteins were strongly enriched for those containing high-probability consensus SUMO attachment sites, further supporting that they are true SUMO substrates. A high throughput assay was developed in Escherichia coli and used to test the SUMOylation of 56% of these proteins. More than 92% of the proteins tested were SUMOylated in this assay by at least one SUMO isoform. Furthermore, ADA2b, an ESD4 interactor that was SUMOylated in the E. coli system, also was shown to be SUMOylated in Arabidopsis. The identified SUMO substrates are involved in a wide range of plant processes, many of which were not previously known to involve SUMOylation. These proteins provide a basis for exploring the function of SUMOylation in the regulation of diverse processes in Arabidopsis. PMID- 20855608 TI - The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. AB - Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumor containing lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth. PMID- 20855609 TI - Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice. AB - Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic beta-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D. PMID- 20855610 TI - Tumors induce complex DNA damage in distant proliferative tissues in vivo. AB - That tumors cause changes in surrounding tissues is well documented, but whether they also affect distant tissues is uncertain. Such knowledge may be important in understanding the relationship between cancer and overall patient health. To address this question, we examined tissues distant to sites of implanted tumors for genomic damage using cohorts of C57BL/6 and BALB/c mice with early-stage subcutaneous syngeneic grafts, specifically, B16 melanoma, MO5076 sarcoma, and COLON26 carcinoma. Here we report that levels of two serious types of DNA damage, double-strand breaks (DSBs) measured by gamma-H2AX focus formation and oxidatively induced non-DSB clustered DNA lesions (OCDLs), were elevated in tissues distant from the tumor site in tumor-bearing mice compared with their age and sex-matched controls. Most affected were crypts in the gastrointestinal tract organs and skin, both highly proliferative tissues. Further investigation revealed that, compared with controls, tumor-bearing mice contained elevated amounts of activated macrophages in the distant gastrointestinal tissues, as well as elevated serum levels of several cytokines. One of these cytokines, CCL2/MCP 1, has been linked to several inflammation-related conditions and macrophage recruitment, and strikingly, CCL2-deficient mice lacked increased levels of DSBs and OCDLs in tissues distant from implanted tumors. Thus, this study is unique in being a direct demonstration that the presence of a tumor may induce a chronic inflammatory response in vivo, leading to increased systemic levels of DNA damage. Importantly, these findings suggest that tumors may have more profound effects on their hosts than heretofore expected. PMID- 20855611 TI - Membrane sphingolipids as essential molecular signals for Bacteroides survival in the intestine. AB - As predominant intestinal symbiotic bacteria, Bacteroides are essential in maintaining the health of the normal mammalian host; in return, the host provides a niche with plentiful nutrients for the symbionts. However, the intestinal environment is replete with chemical, physical, and biological challenges that require mechanisms for prompt and adept sensing of and responses to stress if the bacteria are to survive. Herein we propose that to persist in the intestine Bacteroides take advantage of their unusual bacterial sphingolipids to mediate signaling pathways previously known to be available only to higher organisms. Sphingolipids convey diverse signal transduction and stress response pathways and have profound physiological impacts demonstrated in a variety of eukaryotic cell types. We propose a mechanism by which the formation of specific sphingolipid membrane microdomains initiates signaling cascades that facilitate survival strategies within the bacteria. Our preliminary data suggest that sphingolipid signaling plays an important role in Bacteroides physiology, enabling these bacteria to persist in the intestine and to perform other functions related to symbiosis. PMID- 20855612 TI - Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium. AB - Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cell-autonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration. PMID- 20855613 TI - Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP. AB - Amyloidogenic processing of the amyloid precursor protein (APP) generates a large secreted ectodomain fragment (APPsbeta), beta-amyloid (Abeta) peptides, and an APP intracellular domain (AICD). Whereas Abeta is viewed as critical for Alzheimer's disease pathogenesis, the role of other APP processing products remains enigmatic. Of interest, the AICD has been implicated in transcriptional regulation, and N-terminal cleavage of APPsbeta has been suggested to produce an active fragment that may mediate axonal pruning and neuronal cell death. We previously reported that mice deficient in APP and APP-like protein 2 (APLP2) exhibit early postnatal lethality and neuromuscular synapse defects, whereas mice with neuronal conditional deletion of APP and APLP2 are viable. Using transcriptional profiling, we now identify transthyretin (TTR) and Klotho as APP/APLP2-dependent genes whose expression is decreased in loss-of-function states but increased in gain-of-function states. Significantly, by creating an APP knockin allele that expresses only APPsbeta protein, we demonstrate that APPsbeta is not normally cleaved in vivo and is fully capable of mediating the APP-dependent regulation of TTR and Klotho gene expression. Despite being an active regulator of gene expression, APPsbeta did not rescue the lethality and neuromuscular synapse defects of APP and APLP2 double-KO animals. Our studies identify TTR and Klotho as physiological targets of APP that are regulated by soluble APPsbeta independent of developmental APP functions. This unexpected APP mediated signaling pathway may play an important role in maintaining TTR and Klotho levels and their respective functions in Abeta sequestration and aging. PMID- 20855614 TI - Synergy of multiple partners, including freeloaders, increases host fitness in a multispecies mutualism. AB - Understanding cooperation is a central challenge in biology, because natural selection should favor "free-loaders" that reap benefits without reciprocating. For interspecific cooperation (mutualism), most approaches to this paradox focus on costs and benefits of individual partners and the strategies mutualists use to associate with beneficial partners. However, natural selection acts on lifetime fitness, and most mutualists, particularly longer-lived species interacting with shorter-lived partners (e.g., corals and zooxanthellae, tropical trees and mycorrhizae) interact with multiple partner species throughout ontogeny. Determining how multiple partnerships might interactively affect lifetime fitness is a crucial unexplored link in understanding the evolution and maintenance of cooperation. The tropical tree Acacia drepanolobium associates with four symbiotic ant species whose short-term individual effects range from mutualistic to parasitic. Using a long-term dataset, we show that tree fitness is enhanced by partnering sequentially with sets of different ant symbionts over the ontogeny of a tree. These sets include a "sterilization parasite" that prevents reproduction and another that reduces tree survivorship. Trees associating with partner sets that include these "parasites" enhance lifetime fitness by trading off survivorship and fecundity at different life stages. Our results demonstrate the importance of evaluating mutualism within a community context and suggest that lifespan inequalities among mutualists may help cooperation persist in the face of exploitation. PMID- 20855615 TI - Periplasmic domain of the sensor-kinase BvgS reveals a new paradigm for the Venus flytrap mechanism. AB - Two-component sensory transduction systems control important bacterial programs. In Bordetella pertussis, expression of the virulence regulon is controlled by the unorthodox BvgAS two-component system. BvgS is the prototype of a family of sensor-kinases that harbor periplasmic domains homologous to bacterial solute binding proteins. Although BvgAS is active under laboratory conditions, no activating signal has been identified, only negative modulators. Here we show that the second periplasmic domain of BvgS interacts with modulators and adopts a Venus flytrap (VFT) fold. X-ray crystallography reveals that the two lobes of VFT2 delimitate a ligand-binding cavity enclosing fortuitous ligands. Most substitutions of putative ligand-binding residues in the VFT2 cavity keep BvgS active, and alteration of the cavity's electrostatic potential affects responsiveness to modulation. The crystal structure of this VFT2 variant conferring constitutive kinase activity to BvgS shows a closed cavity with another nonspecific ligand. Thus, VFT2 is closed and active without a specific agonist ligand, in contrast to typical VFTs. Modulators are antagonists of VFT2 that interrupt signaling. BvgAS is active for most of the B. pertussis infectious cycle, consistent with the proposed mechanism. PMID- 20855616 TI - Induction of type I interferon by adenovirus-encoded small RNAs. AB - Transduction with replication-incompetent recombinant adenovirus (Ad) vectors results in a rapid activation of innate immune responses, such as inflammatory cytokine production and subsequent tissue damage. The precise mechanisms of the innate immune responses induced by Ad vectors remain to be clarified. Possible components of Ad vectors that activate innate immune responses are the capsid protein, the viral genome (DNA), and viral transcripts. In the present study, we demonstrate that virus-associated RNAs (VA-RNAs), which are small RNAs transcribed by RNA polymerase III, induce the production of type I IFN (IFN-alpha and IFN-beta), but they do not induce the production of inflammatory cytokines (IL-6 and IL-12), in mouse embryonic fibroblasts (MEFs) and granulocyte macrophage colony-stimulating factor-generated bone marrow-derived dendritic cells (GM-DCs). We also show that IFN-beta promoter stimulator-1 is involved in VA-RNA-dependent IFN-beta production in MEFs and is partially involved in type I IFN production in GM-DCs. This study provides important insight into the mechanisms of Ad vector-triggered innate immune responses, which may lead to more advanced and rational Ad vector designs for gene therapies and vaccine applications. PMID- 20855617 TI - Sexual dimorphism of gonadal structure and gene expression in germ cell-deficient loach, a teleost fish. AB - Germ cell-deficient fish usually develop as phenotypic males. Thus, the presence of germ cells is generally considered to be essential for female gonadal differentiation or the maintenance of ovarian structure. However, little is known of the role of germ cells in the determination of the sexual fate of gonadal somatic cells. We have established an inducible germ cell deficiency system in the loach (Misgurnus anguillicaudatus, Cypriniformes: Cobitidae), a small freshwater fish, using knockdown of the dead end gene with a morpholino antisense oligonucleotide. Interestingly, loach lacking germ cells could develop as either phenotypic males or females, as characterized morphologically by the presence or absence of bony plates in the pectoral fins, respectively. The phenotypic males and females had testicular and ovarian structures, respectively, but lacked germ cells. Gene expression patterns in these male and female germ cell-deficient gonads were essentially the same as those in gonads of normal fish. Our observations indicate that sexually dimorphic gonads can develop in germ cell deficient loach. In contrast to the situation in other model fish species, the gonadal somatic cells in phenotypic females autonomously differentiated into ovarian tissues and also played a role in the maintenance of gonadal structure. On the basis of our observations, we propose two possible models to explain the role of germ cells in sex determination in fish. PMID- 20855619 TI - Stealth predation and the predatory success of the invasive ctenophore Mnemiopsis leidyi. AB - In contrast to higher metazoans such as copepods and fish, ctenophores are a basal metazoan lineage possessing a relatively narrow set of sensory-motor capabilities. Yet lobate ctenophores can capture prey at rates comparable to sophisticated predatory copepods and fish, and they are capable of altering the composition of coastal planktonic communities. Here, we demonstrate that the predatory success of the lobate ctenophore Mnemiopsis leidyi lies in its use of cilia to generate a feeding current that continuously entrains large volumes of fluid, yet is virtually undetectable to its prey. This form of stealth predation enables M. leidyi to feed as a generalist predator capturing prey, including microplankton (approximately 50 MUm), copepods (approximately 1 mm), and fish larvae (>3 mm). The efficacy and versatility of this stealth feeding mechanism has enabled M. leidyi to be notoriously destructive as a predator and successful as an invasive species. PMID- 20855618 TI - Controlled enzymatic production of astrocytic hydrogen peroxide protects neurons from oxidative stress via an Nrf2-independent pathway. AB - Neurons rely on their metabolic coupling with astrocytes to combat oxidative stress. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) appears important for astrocyte-dependent neuroprotection from oxidative insults. Indeed, Nrf2 activators are effective in stroke, Parkinson disease, and Huntington disease models. However, key endogenous signals that initiate adaptive neuroprotective cascades in astrocytes, including activation of Nrf2-mediated gene expression, remain unclear. Hydrogen peroxide (H(2)O(2)) plays an important role in cell signaling and is an attractive candidate mediator of adaptive responses in astrocytes. Here we determine (i) the significance of H(2)O(2) in promoting astrocyte-dependent neuroprotection from oxidative stress, and (ii) the relevance of H(2)O(2) in inducing astrocytic Nrf2 activation. To control the duration and level of cytoplasmic H(2)O(2) production in astrocytes cocultured with neurons, we heterologously expressed the H(2)O(2)-producing enzyme Rhodotorula gracilis D-amino acid oxidase (rgDAAO) selectively in astrocytes. Exposure of rgDAAO-astrocytes to D-alanine lead to the concentration-dependent generation of H(2)O(2). Seven hours of low-level H(2)O(2) production (~3.7 nmol.min.mg protein) in astrocytes protected neurons from oxidative stress, but higher levels (~130 nmol.min.mg protein) were neurotoxic. Neuroprotection occurred without direct neuronal exposure to astrocyte-derived H(2)O(2), suggesting a mechanism specific to astrocytic intracellular signaling. Nrf2 activation mimicked the effect of astrocytic H(2)O(2) yet H(2)O(2)-induced protection was independent of Nrf2. Astrocytic protein tyrosine phosphatase inhibition also protected neurons from oxidative death, representing a plausible mechanism for H(2)O(2)-induced neuroprotection. These findings demonstrate the utility of rgDAAO for spatially and temporally controlling intracellular H(2)O(2) concentrations to uncover unique astrocyte-dependent neuroprotective mechanisms. PMID- 20855620 TI - Oscillatory phase coupling coordinates anatomically dispersed functional cell assemblies. AB - Hebb proposed that neuronal cell assemblies are critical for effective perception, cognition, and action. However, evidence for brain mechanisms that coordinate multiple coactive assemblies remains lacking. Neuronal oscillations have been suggested as one possible mechanism for cell assembly coordination. Prior studies have shown that spike timing depends upon local field potential (LFP) phase proximal to the cell body, but few studies have examined the dependence of spiking on distal LFP phases in other brain areas far from the neuron or the influence of LFP-LFP phase coupling between distal areas on spiking. We investigated these interactions by recording LFPs and single-unit activity using multiple microelectrode arrays in several brain areas and then used a unique probabilistic multivariate phase distribution to model the dependence of spike timing on the full pattern of proximal LFP phases, distal LFP phases, and LFP-LFP phase coupling between electrodes. Here we show that spiking activity in single neurons and neuronal ensembles depends on dynamic patterns of oscillatory phase coupling between multiple brain areas, in addition to the effects of proximal LFP phase. Neurons that prefer similar patterns of phase coupling exhibit similar changes in spike rates, whereas neurons with different preferences show divergent responses, providing a basic mechanism to bind different neurons together into coordinated cell assemblies. Surprisingly, phase coupling-based rate correlations are independent of interneuron distance. Phase coupling preferences correlate with behavior and neural function and remain stable over multiple days. These findings suggest that neuronal oscillations enable selective and dynamic control of distributed functional cell assemblies. PMID- 20855621 TI - Polyunsaturated liposomes are antiviral against hepatitis B and C viruses and HIV by decreasing cholesterol levels in infected cells. AB - The pressing need for broad-spectrum antivirals could be met by targeting host rather than viral processes. Cholesterol biosynthesis within the infected cell is one promising target for a large number of viral systems, including hepatitis C virus (HCV), hepatitis B virus (HBV) and HIV. Liposomes developed for intracellular, endoplasmic reticulum (ER)-targeted in vivo drug delivery have been modified to include polyunsaturated fatty acids that exert an independent antiviral activity through the reduction of cellular cholesterol. These polyunsaturated ER liposomes (PERLs) have greater activity than lovastatin (Mevacor, Altoprev), which is clinically approved for lowering cholesterol and preventing cardiovascular disease. Treatment of HCV, HBV, and HIV infections with PERLs significantly decreased viral secretion and infectivity, and pretreatment of naive cells reduced the ability of both HCV and HIV to establish infections because of the decreased levels of plasma membrane cholesterol. Direct competition for cellular receptors was an added effect of PERLs against HCV infections. The greatest antiviral activity in all three systems was the inhibition of viral infectivity through the reduction of virus-associated cholesterol. Our study demonstrates that PERLs are a broadly effective antiviral therapy and should be developed further in combination with encapsulated drug mixtures for enhanced in vivo efficacy. PMID- 20855622 TI - The Listeria monocytogenes InlC protein interferes with innate immune responses by targeting the I{kappa}B kinase subunit IKK{alpha}. AB - Listeria monocytogenes is an intracellular pathogen responsible for severe foodborne infections. It can replicate in both phagocytic and nonphagocytic mammalian cells. The infectious process at the cellular level has been studied extensively, but how the bacterium overcomes early host innate immune responses remains largely unknown. Here we show that InlC, a member of the internalin family, is secreted intracellularly and directly interacts with IKKalpha, a subunit of the IkappaB kinase complex critical for the phosphorylation of IkappaB and activation of NF-kappaB, the major regulator of innate immune responses. Infection experiments with WT Listeria or the inlC-deletion mutant and transfection of cells with InlC reveal that InlC expression impairs phosphorylation and consequently delays IkappaB degradation normally induced by TNF-alpha, a classical NF-kappaB stimulator. Moreover, infection of RAW 264.7 macrophages by the inlC mutant leads to increased production of proinflammatory cytokines compared with that obtained with the WT. Finally, in a peritonitis mouse model, we show that infection with the inlC mutant induces increased production of chemokines and increased recruitment of neutrophils in the peritoneal cavity compared with infection with WT. Together, these results demonstrate that InlC, by interacting with IKKalpha, dampens the host innate response induced by Listeria during the infection process. PMID- 20855623 TI - Conservation, development, and function of a cement gland-like structure in the fish Astyanax mexicanus. AB - The larvae of the fish Astyanax mexicanus transiently develop a flat and adhesive structure on the top of their heads that we have called "the casquette" (cas, meaning "hat"). We hypothesized that the cas may be a teleostean homolog of the well-studied Xenopus cement gland, despite their different positions and structures. Here we show that the cas has an ectodermal origin, secretes mucus, expresses bone morphogenic protein 4 (Bmp4) and pituitary homeobox 1/2 (Pitx1/2), is innervated by the trigeminal ganglion and serotonergic raphe neurons, and has a role in the control and the development of the larval swimming behavior. These developmental, connectivity, and behavioral functional data support a level of deep homology between the frog cement gland and the Astyanax cas and suggest that attachment organs can develop in varied positions on the head ectoderm by recruitment of a Bmp4-dependent developmental module. We also show that the attachment organs of the cichlid Tilapia mariae larvae display some of these features. We discuss the possibility that these highly diversified attachment glands may be ancestral to chordates and have been lost repetitively in many vertebrate classes. PMID- 20855624 TI - Regulation of extrafloral nectar secretion by jasmonates in lima bean is light dependent. AB - To maximize fitness, plants need to perceive changes in their light environment and adjust their physiological responses accordingly. Whether and how such changes also affect the regulation of their defense responses against herbivores remains largely unclear. We addressed this issue by studying the secretion of extrafloral nectar (EFN) in lima bean (Phaseolus lunatus), which is known to be activated by the phytohormone jasmonic acid (JA) and functions as an indirect defense mechanism against herbivores. We found that the plant's EFN secretion in response to JA was light dependent: In the dark, JA reduced EFN secretion, whereas under light conditions, JA induced EFN secretion relative to controls. This modulation was affected by the light's spectral composition [i.e., ratio of red to far-red (R:FR) radiation], but not light intensity. These findings demonstrate a unique differential effect of JA on EFN secretion depending on the ambient light conditions. Interestingly, treatment with the isoleucine-JA conjugate (JA-Ile) enhanced EFN secretion under light conditions yet did not reduce EFN secretion in the dark. Moreover, inhibition of Ile biosynthesis in light-exposed plants significantly decreased the EFN secretion rate. This reduction could be recovered by additional application of JA-Ile, suggesting that JA-Ile is the active compound required to up-regulate EFN secretion. Finally, experiments with mechanically damaged plants revealed that light was required for the formation of JA-Ile, but not of JA. These results demonstrate that in lima bean, the light environment modulates the plant's response to jasmonates as well as JA-Ile biosynthesis, which controls the subsequent EFN secretion. PMID- 20855625 TI - Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis. AB - Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth. PMID- 20855626 TI - Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells. AB - In T cell-mediated autoimmune diseases, self-reactive T cells with known antigen specificity appear to be particularly promising targets for antigen-specific induction of tolerance without compromising desired protective host immune responses. Several lines of evidence suggest that delivery of antigens to antigen presenting dendritic cells (DCs) in the steady state (i.e., to immature DCs) may represent a suitable approach to induce antigen-specific T-cell tolerance peripherally. Here, we report that anti-DEC205-mediated delivery of the self peptide proteolipid protein (PLP)139-151 to DCs ameliorated clinical symptoms in the PLP-induced SJL model of experimental autoimmune encephalomyelitis. Splenocytes from treated mice were anergized to PLP139-151, and IL-17 secretion was markedly reduced. Moreover, we show directly, using transgenic CD4(+) Vbeta6(+) TCR T cells specific for PLP139-151, that, under the conditions of the present experiments, these cells also became anergic. In addition, evidence for a CD4(+) T cell-mediated suppressor mechanism was obtained. PMID- 20855628 TI - Behavioral dimensions of food security. AB - The empirical regularities of behavioral economics, especially loss aversion, time inconsistency, other-regarding preferences, herd behavior, and framing of decisions, present significant challenges to traditional approaches to food security. The formation of price expectations, hoarding behavior, and welfare losses from highly unstable food prices all depends on these behavioral regularities. At least when they are driven by speculative bubbles, market prices for food staples (and especially for rice, the staple food of over 2 billion people) often lose their efficiency properties and the normative implications assigned by trade theory. Theoretical objections to government efforts to stabilize food prices, thus, have reduced saliency, although operational, financing, and implementation problems remain important, even critical. The experience of many Asian governments in stabilizing their rice prices over the past half century is drawn on in this paper to illuminate both the political mandates stemming from behavioral responses of citizens and operational problems facing efforts to stabilize food prices. Despite the theoretical problems with free markets, the institutional role of markets in economic development remains. All policy instruments must operate compatibly with prices in markets. During policy design, especially for policies designed to alter market prices, incentive structures need to be compatible with respect to both government capacity (bureaucratic and budgetary) and empirical behavior on the part of market participants who will respond to planned policy changes. A new theoretical underpinning to political economy analysis is needed that incorporates this behavioral perspective, with psychology, sociology, and anthropology all likely to make significant contributions. PMID- 20855627 TI - Retina is structured to process an excess of darkness in natural scenes. AB - Retinal ganglion cells that respond selectively to a dark spot on a brighter background (OFF cells) have smaller dendritic fields than their ON counterparts and are more numerous. OFF cells also branch more densely, and thus collect more synapses per visual angle. That the retina devotes more resources to processing dark contrasts predicts that natural images contain more dark information. We confirm this across a range of spatial scales and trace the origin of this phenomenon to the statistical structure of natural scenes. We show that the optimal mosaics for encoding natural images are also asymmetric, with OFF elements smaller and more numerous, matching retinal structure. Finally, the concentration of synapses within a dendritic field matches the information content, suggesting a simple principle to connect a concrete fact of neuroanatomy with the abstract concept of information: equal synapses for equal bits. PMID- 20855629 TI - IFN-{gamma} produced by CD8 T cells induces T-bet-dependent and -independent class switching in B cells in responses to alum-precipitated protein vaccine. AB - Alum-precipitated protein (alum protein) vaccines elicit long-lasting neutralizing antibody responses that prevent bacterial exotoxins and viruses from entering cells. Typically, these vaccines induce CD4 T cells to become T helper 2 (Th2) cells that induce Ig class switching to IgG1. We now report that CD8 T cells also respond to alum proteins, proliferating extensively and producing IFN gamma, a key Th1 cytokine. These findings led us to question whether adoptive transfer of antigen-specific CD8 T cells alters the characteristic CD4 Th2 response to alum proteins and the switching pattern in responding B cells. To this end, WT mice given transgenic ovalbumin (OVA)-specific CD4 (OTII) or CD8 (OTI) T cells, or both, were immunized with alum-precipitated OVA. Cotransfer of antigen-specific CD8 T cells skewed switching patterns in responding B cells from IgG1 to IgG2a and IgG2b. Blocking with anti-IFN-gamma antibody largely inhibited this altered B-cell switching pattern. The transcription factor T-bet is required in B cells for IFN-gamma-dependent switching to IgG2a. By contrast, we show that this transcription factor is dispensable in B cells both for IFN-gamma-induced switching to IgG2b and for inhibition of switching to IgG1. Thus, T-bet dependence identifies distinct transcriptional pathways in B cells that regulate IFN-gamma-induced switching to different IgG isotypes. PMID- 20855631 TI - Screening for risk with albuminuria: should we start from here? PMID- 20855630 TI - Evidence for the prepattern/cooption model of vertebrate jaw evolution. AB - The appearance of jaws was a turning point in vertebrate evolution because it allowed primitive vertebrates to capture and process large, motile prey. The vertebrate jaw consists of separate dorsal and ventral skeletal elements connected by a joint. How this structure evolved from the unjointed gill bar of a jawless ancestor is an unresolved question in vertebrate evolution. To understand the developmental bases of this evolutionary transition, we examined the expression of 12 genes involved in vertebrate pharyngeal patterning in the modern jawless fish lamprey. We find nested expression of Dlx genes, as well as combinatorial expression of Msx, Hand and Gsc genes along the dorso-ventral (DV) axis of the lamprey pharynx, indicating gnathostome-type pharyngeal patterning evolved before the appearance of the jaw. In addition, we find that Bapx and Gdf5/6/7, key regulators of joint formation in gnathostomes, are not expressed in the lamprey first arch, whereas Barx, which is absent from the intermediate first arch in gnathostomes, marks this domain in lamprey. Taken together, these data support a new scenario for jaw evolution in which incorporation of Bapx and Gdf5/6/7 into a preexisting DV patterning program drove the evolution of the jaw by altering the identity of intermediate first-arch chondrocytes. We present this "Pre-pattern/Cooption" model as an alternative to current models linking the evolution of the jaw to the de novo appearance of sophisticated pharyngeal DV patterning. PMID- 20855632 TI - Where are all the aptamers? PMID- 20855633 TI - Laboratory accreditation in Thailand: a systemic approach. AB - Improvement of quality standards for health care service delivery has been a commitment of the Ministry of Public Health in Thailand for more than 2 decades; however, laboratory quality systems in Thailand did not become a focus until 10 years ago. International accreditation can increase recognition of laboratory quality, but it is difficult to reach for many laboratories, especially those in remote areas. This article describes Thailand's experience in developing a national laboratory standard and establishing a national laboratory accreditation program to guarantee the quality of laboratory services. The Thai laboratory standard derived from multiple international standards, retaining the most important elements yet making the standard applicable to Thailand. The national accreditation program was established as a local alternative for improvement of laboratory quality. The program is affordable, feasible, scalable, sustainable, and effective. PMID- 20855634 TI - Experiences in establishing a PEPFAR-supported laboratory quality system in Nigeria. AB - The need to accurately diagnose HIV-infected persons and monitor their immune status and sequelae from increased access to antiretroviral therapy dictated the establishment of a quality assurance (QA) system supported by dedicated personnel, financial resources, and a close monitoring system. Assessment of laboratories and personnel in Nigeria revealed the need for improved laboratory infrastructure and training, including on-site didactic and wet workshops and the institution of a tiered QA unit of laboratory regional officers, focal persons, and site monitors who provided guidance and continuous monitoring. Quarterly assessments and generated reports guided corrective actions. A sustainable quality laboratory system was developed for the first time in Nigeria with funding from the US President's Emergency Plan for AIDS Relief. With expansion from 7 to 34 comprehensive treatment sites, a tiered laboratory organizational structure with regional and site-based Nigerian quality control officers was developed. Measured improvements included reduction in deficiencies from 13% to 2%. PMID- 20855635 TI - Impact of laboratory accreditation on patient care and the health system. AB - Accreditation is emerging as a preferred framework for building quality medical laboratory systems in resource-limited settings. Despite the low numbers of laboratories accredited to date, accreditation has the potential to improve the quality of health care for patients through the reduction of testing errors and attendant decreases in inappropriate treatment. Accredited laboratories can become more accountable and less dependent on external support. Efforts made to achieve accreditation may also lead to improvements in the management of laboratory networks by focusing attention on areas of greatest need and accelerating improvement in areas such as supply chain, training, and instrument maintenance. Laboratory accreditation may also have a positive influence on performance in other areas of health care systems by allowing laboratories to demonstrate high standards of service delivery. Accreditation may, thus, provide an effective mechanism for health system improvement yielding long-term benefits in the quality, cost-effectiveness, and sustainability of public health programs. Further studies are needed to strengthen the evidence on the benefits of accreditation and to justify the resources needed to implement accreditation programs aimed at improving the performance of laboratory systems. PMID- 20855636 TI - A quality management systems approach for CD4 testing in resource-poor settings. AB - Quality assurance (QA) is a systematic process to monitor and improve clinical laboratory practices. The fundamental components of a laboratory QA program include providing a functional and safe laboratory environment, trained and competent personnel, maintained equipment, adequate supplies and reagents, testing of appropriate specimens, internal monitoring of quality, accurate reporting, and external quality assessments. These components are necessary to provide accurate and precise CD4 T-cell counts, an essential test to evaluate start of and monitor effectiveness of antiretroviral therapy for HIV-infected patients. In recent years, CD4 testing has expanded dramatically in resource limited settings. Information on a CD4 QA program as described in this article will provide guidelines not only for clinical laboratory staff but also for managers of programs responsible for supporting CD4 testing. All agencies involved in implementing CD4 testing must understand the needs of the laboratory and provide advocacy, guidance, and financial support to established CD4 testing sites and programs. This article describes and explains the procedures that must be put in place to provide reliable CD4 determinations in a variety of settings. PMID- 20855637 TI - Ensuring the quality of HIV rapid testing in resource-poor countries using a systematic approach to training. AB - HIV rapid testing is a key tool in the fight against the HIV/AIDS epidemic; it enables the rapid expansion of prevention and treatment programs in resource limited countries. Meeting the goals of these programs means that millions of people will need testing annually. Accuracy and reliability of these tests are critical to the success of these programs. Given the enormous number of rapid tests that are performed each year, even a low error rate of 0.5% applied to 100 million people will result in 500,000 erroneous results. Ensuring the quality of HIV rapid testing presents unique challenges in that testing is often performed in various settings by personnel without formal laboratory training. This article describes the development and implementation of a generic HIV rapid test training package using a systems approach in an effort to standardize training and ensure the quality of rapid tests. It also highlights achievements from Uganda, Haiti, and Botswana. PMID- 20855638 TI - Scaling up HIV rapid testing in developing countries: comprehensive approach for implementing quality assurance. AB - In the last few years, the use of HIV rapid testing has expanded worldwide in response to the call for universal access to prevention, care, and treatment by UNAIDS and the World Health Organization. HIV rapid testing is performed by people with varied skills in laboratory and nonlaboratory settings. Accurate HIV diagnostic testing is the first step to identifying infected persons for follow up referral and care. However, there are several challenges related to test kit quality, test selection, testing algorithms, training, quality assurance (QA), quality of new lots, and postmarket performance. We highlight various issues that impact the quality of HIV rapid testing and provide solutions to monitor and improve test accuracy, especially in resource-limited settings. These include the use of validated kits, training with emphasis on QA, use of a standardized log book, dried-tube specimen-based proficiency testing, new kit lot verification, and postmarket surveillance. Systematic implementation of these tools should greatly enhance the quality of HIV rapid testing. PMID- 20855639 TI - Combination of an aptamer probe to CD4 and antibodies for multicolored cell phenotyping. AB - Aptamers have emerged as a new class of small molecule ligands. These short, single-stranded oligonucleotides can be produced through simple chemical synthesis, making them easier and less costly to produce than antibodies. We synthesized an RNA aptamer probe specific for human CD4 using a reported sequence and investigated the potential use of this probe in cell phenotyping. Studies in cultured cells demonstrated that the synthetic CD4 aptamer had a nearly identical cell-binding specificity as the standard CD4 antibody. Fluorescent microscopy confirmed that the aptamer and antibody generated the same CD4 staining pattern in cells without competing with one another. Multicolored flow cytometry analysis revealed that the CD4 aptamer could be combined with antibodies to phenotype cells from bone marrow, lymph nodes, and pleural fluid, suggesting that the aptamer probe has value for clinical use. PMID- 20855640 TI - Fixation time does not affect expression of HER2/neu: a pilot study. AB - It is said that HER2/neu expression by immunohistochemical analysis varies with the time of fixation. The purpose of this pilot study was to determine the impact of the length of fixation in 10% buffered formalin on the expression of HER2/neu by immunohistochemical analysis. We studied tissue samples from 10 invasive breast cancer cases after fixation for 3, 48, 72, 96, and 120 hours. The tissue was processed immediately after fixation, resembling routine practice. The 50 resulting blocks were then batch stained with PATHWAY HER2/neu clone 4B5 rabbit monoclonal antibody using the Ventana Ultraview DAB detection kit in a Ventana BenchMark XT processor (Ventana, Tucson, AZ). The stained slides were reviewed and scored. We found no significant difference in the intensity of the stain or the percentage of cells stained regardless of the time in fixation. Fixation times between 3 and 120 hours in 10% buffered formalin do not appear to have an impact on the expression of HER2/neu by immunohistochemical analysis. PMID- 20855641 TI - Multicolor FISH (UroVysion) facilitates follow-up of patients with high-grade urothelial carcinoma of the bladder. AB - The aim of the present prospective study was to assess the diagnostic benefit of UroVysion (Vysis-Abbott Laboratories, Downers Grove, IL) in the follow-up of patients with a history of high-grade non-muscle-invasive urothelial carcinoma of the bladder (NMIBC). An unselected cohort of 25 patients with a history of high grade NMIBC was prospectively followed up by office-based cystoscopy, cytology, and UroVysion in 210 events. The sensitivity and specificity for standard combined cystoscopy and cytology were 78% and 83%, respectively. UroVysion yielded a considerably higher detection rate with 94% and 93%, respectively. In 89% of the follow-up events of patients with a history of previous carcinoma in situ (CIS) and negative cystoscopy but a positive UroVysion finding, CIS recurrence was noticed within 5 months. UroVysion is a worthwhile approach in patients with previous CIS, a high risk for the development of CIS, or previous unequivocal cytology suggestive of CIS, especially during or shortly after instillation therapy. PMID- 20855642 TI - Expression of UTF1 in primary and metastatic testicular germ cell tumors. AB - We immunohistochemically evaluated UTF1 in 104 primary and 68 metastatic testicular germ cell tumors and 339 non-germ cell tumors. The percentage of tumor cells stained was semiquantitatively scored (0, no tumor cell staining; 1+, <=30% of cells; 2+, 31%-60% of cells; 3+, 61%-90% of cells; 4+, >90% of cells). Staining intensity (nuclear) was scored as weak, moderate, or strong. UTF1 staining was seen in all 56 intratubular germ cell neoplasias, unclassified type (2+, 1; 3+, 2; 4+, 53; weak, 4; moderate, 49; strong, 3), all 72 seminomas (1+, 2; 2+, 4; 3+, 8; 4+, 58; weak, 10; moderate, 33; strong, 29), and 59 embryonal carcinomas (3+, 2; 4+, 57; moderate, 1; strong, 58). Weak UTF1 staining was seen in 15 of 37 yolk sac tumors (1+, 10; 2+, 2; 3+, 2; 4+, 1). All 34 teratomas, 9 choriocarcinomas, and 6 spermatocytic seminomas were negative for UTF1 staining. Among the 339 non-germ cell tumors, only 18 showed weak UTF1 staining (1+ to 4+). Normal prepubertal and postpubertal spermatogonia showed weak to strong UTF1 staining. UTF1 was differentially expressed in testicular germ cell tumors. Strong UTF1 staining can be used for diagnosing embryonal carcinoma and seminoma. UTF1 expression in spermatogonia suggests its possible role in spermatogenesis and renewal of spermatogonia. PMID- 20855643 TI - The pathogenesis of chronic hypersensitivity pneumonitis in common with idiopathic pulmonary fibrosis: expression of apoptotic markers. AB - Previous studies showed that apoptotic epithelial cells were involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP); however, little is known about apoptosis in chronic hypersensitivity pneumonitis (HP). This study was performed to examine whether apoptosis has a role in chronic HP. We performed immunohistochemical studies for p53, p21, Fas, Fas ligand, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling methods on surgical lung specimens. The expression of Fas and Fas ligand was up-regulated in UIP-like lesions compared with nonspecific interstitial pneumonia (NSIP)-like lesions. The expression of p53 and p21 on epithelial cells increased significantly in UIP-like lesions compared with fibrotic NSIP-like lesions and in fibrotic NSIP-like lesions compared with normal lung tissues. These results confirm that apoptotic epithelial cells are present in chronic HP as seen in IPF. Augmented epithelial apoptosis may contribute much more to UIP-like lesions than to NSIP-like lesions in chronic HP. PMID- 20855644 TI - The reliability of rabbit monoclonal antibodies in the immunohistochemical assessment of estrogen receptors, progesterone receptors, and HER2 in human breast carcinomas. AB - The reliability of the rabbit monoclonal antibodies SP1, SP2, SP3, and 4B5 was immunohistochemically assessed on a range of 96 invasive breast carcinomas and the results compared with those achieved with established antibody markers for estrogen receptors (6F11), progesterone receptors (PgR636), and HER2 (polyclonal A0485 and clone CB11), with HER2 status validated by fluorescence in situ hybridization (FISH) and silver in situ hybridization. Optimal results depended on the duration of microwave antigen-retrieval time and the use of a high pH buffer for rabbit and mouse estrogen receptor antibodies (SP1 and 6F11), although only on antigen-retrieval duration for the progesterone receptors SP2 and PgR636. The highest rate of concordance between HER2 overexpression and HER2 gene amplification was with the rabbit monoclonal antibodies (SP3 and 4B5) and FISH. Rabbit monoclonal antibodies are reliable alternatives to established antibody markers for the immunohistochemical testing of estrogen receptors, progesterone receptors, and HER2 in breast cancer. PMID- 20855645 TI - Accuracy of platelet counting by automated hematologic analyzers in acute leukemia and disseminated intravascular coagulation: potential effects of platelet activation. AB - Platelet counting in patients with acute leukemia or disseminated intravascular coagulation (DIC) may have a risk for erroneous counts owing to the presence of nonplatelet particles or platelet activation. We evaluated automated platelet counting methods using the Abbott Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA), Sysmex XE-2100 (Sysmex, Kobe, Japan), ADVIA 2120 (Siemens Diagnostics, Tarrytown, NY), and Beckman Coulter LH 750 (Beckman Coulter, Miami, FL) compared with the international reference method (IRM). Automated platelet counting methods were inaccurate compared with the IRM, without evidence of interfering nonplatelet particles. It is interesting that platelet activation markers were associated with DIC severity and erroneous platelet counting, suggesting that platelet activation is a potential source of inaccuracy. Furthermore, the artifactual in vitro platelet activation induced a high degree of intermethod variation in platelet counts. The inaccuracy of automated platelet counts increased the risk for misdiagnosis of DIC. More attention needs to be given to the accuracy of platelet counts, especially in clinical conditions with florid platelet activation. PMID- 20855646 TI - Is the association of "cup-like" nuclei with mutation of the NPM1 gene in acute myeloid leukemia clinically useful? AB - Cup-like nuclear invaginations (NIs) in acute myeloid leukemia (AML) blasts have been associated with NPM1 mutations. Precision for enumeration of NI blasts has not been previously studied. Furthermore, the sensitivity and specificity for the morphologic prediction of NPM1 mutations have been variously reported. By using 66 AML specimens (17 with NPM1 mutations and 49 without), we found that interobserver reproducibility for enumeration of NI blasts was high (r = 0.98) and that identification of this feature was teachable (r = 0.96). No NPM1 mutation-negative case had greater than 7% NI blasts. The fraction of NI blasts was highly variable among 17 NPM1 mutation-positive cases, ranging from 0% to greater than 40%. These data indicate that an NI blast fraction of more than 10% is highly specific for NPM1 mutation-positive cases but with a sensitivity of about 30%. Therefore, although NI blasts can be reliably identified in routine smears and although they are a specific marker of NPM1 mutation-positive cases, the majority of NPM1 mutation-positive cases lack this distinctive finding. PMID- 20855647 TI - Evaluation of the Ves-Matic Cube 200 erythrocyte sedimentation method: comparison with Westergren-based methods. AB - The erythrocyte sedimentation rate (ESR) is still a widely used parameter for acute phase inflammation. Recently, new methods based on direct undiluted measurement of ESR in a standard EDTA tube have been developed. We evaluated the analytic performance of one of these new methods, the Ves-Matic Cube 200 (Diesse Diagnostica Senese, Siena, Italy), and compared it with several established Westergren-based diluted methods. The Ves-Matic Cube 200 showed a poor correlation (r = 0.83) with the International Council for Standardization in Haematology Westergren reference method, mainly caused by a considerable negative bias at low ESR levels. Moreover, a random bias was found at higher ESR levels that correlated with hematocrit levels, suggesting a differential influence of packed cell volume on the Ves-Matic Cube 200 results compared with Westergren results. We conclude that the Ves-Matic Cube 200 method is not interchangeable with Westergren-based diluted methods and generates ESR results that are too deviant to be clinically acceptable. PMID- 20855648 TI - Postexposure administration of a {beta}2-agonist decreases chlorine-induced airway hyperreactivity in mice. AB - Exposure to chlorine (Cl(2)) damages airway and alveolar epithelia, resulting in acute lung injury and reactive airway dysfunction syndrome. We evaluated the efficacy and mechanisms by which arformoterol, a long-term beta(2)-agonist, administered after exposure, mitigated the extent of this injury. Exposure of C57BL/6 mice to 400 ppm Cl(2) for 30 minutes increased respiratory system resistance and airway responsiveness to aerosolized methacholine (assessed by FlexiVent) up to 6 days after exposure, and decreased Na(+)-dependent alveolar fluid clearance (AFC). Inducible Nitric Oxide Synthase (iNOS) knockout mice developed similar degrees of airway hyperreactivity as wild-type controls after Cl(2) exposure, indicating that reactive intermediates from iNOS do not contribute to Cl(2)-induced airway dysfunction in our model. Intranasal administration of arformoterol mitigated the Cl(2) effects on airway reactivity and AFC, presumably by increasing lung cyclic AMP level. Arformoterol did not modify the inflammatory responses, as evidenced by the number of inflammatory cells and concentrations of IL-6 and TNF-alpha in the bronchoalveolar lavage. NF kappaB activity (assessed by p65 Western blots and electrophoretic mobility shift assay) remained at control levels up to 24 hours after Cl(2) exposure. Our results provide mechanistic insight into the effectiveness of long-term beta(2) agonists in reversing Cl(2)-induced reactive airway dysfunction syndrome and injury to distal lung epithelial cells. PMID- 20855649 TI - Mastic alleviates allergic inflammation in asthmatic model mice by inhibiting recruitment of eosinophils. AB - The pathogenesis of allergic asthma is characterized by airway inflammation, eosinophilia, and airway hyperresponsiveness. In the present study, we investigated the anti-inflammatory effects of mastic, obtained from the stem and the leaves of Pistacia lentiscus trees, on allergic asthma. In an ovalbumin induced mouse asthma model, mastic significantly inhibited eosinophilia, while reducing airway hyperresponsiveness and suppressing the production of inflammatory cytokines (IL-5 and IL-13) as well as chemokines (eotaxin, eotaxin2, and regulated upon activation, normal T-cell expressed and secreted) in bronchoalveolar lavage fluid. Moreover, mastic potently inhibited eotaxin-induced eosinophil chemotaxis in vitro without influencing eotaxin receptor, chemokine receptor 3, expression. These results suggest that mastic may contribute to the treatment of inflammatory diseases. PMID- 20855650 TI - Sox2 activates cell proliferation and differentiation in the respiratory epithelium. AB - Sox2, a transcription factor critical for the maintenance of embryonic stem cells and induction of pluripotent stem cells, is expressed exclusively in the conducting airway epithelium of the lung, where it is required for differentiation of nonciliated, goblet, and ciliated cells. To determine the role of Sox2 in respiratory epithelial cells, Sox2 was selectively and conditionally expressed in nonciliated airway epithelial cells and in alveolar type II cells in the adult mouse. Sox2 induced epithelial cell proliferation within 3 days of expression. Epithelial cell proliferation was associated with increased Ki-67 and cyclin D1 staining. Expression of cell cycle genes, including FoxM1, Ccna2 (Cyclin A2), Ccnb2 (Cyclin B2), and Ccnd1 (Cyclin D1), was increased. Consistent with a role in cell proliferation, Sox2 activated the transcription of FoxM1 in vitro. In alveoli, Sox2 caused hyperplasia and ectopic differentiation of epithelial cells to those with morphologic and molecular characteristics of conducting airway epithelium. Sox2 induced the expression of conducting airway epithelial specific genes, including Scgb1a1, Foxj1, Tubb3, and Cyp2f2. Although prolonged expression of Sox2 caused cell proliferation and epithelial hyperplasia, Sox2 did not induce pulmonary tumors. Sox2 induces proliferation of respiratory epithelial cells and, subsequently, partially reprograms alveolar epithelial cells into cells with characteristics of the conducting airways. PMID- 20855652 TI - Genetic and pharmacological evaluation of cathepsin s in a mouse model of asthma. AB - Cathepsin S (Cat S) is predominantly expressed in antigen-presenting cells and is up-regulated in several preclinical models of antigen-induced inflammation, suggesting a role in the allergic response. Prophylactic dosing of an irreversible Cat S inhibitor has been shown to attenuate pulmonary eosinophilia in mice, supporting the hypothesis that Cat S inhibition before the initiation of airway inflammation is beneficial in airway disease. In addition, Cat S has been shown to play a role in more distal events in the allergic response. To determine where Cat S inhibition may affect the allergic response, we used complementary genetic and pharmacological approaches to investigate the role of Cat S in the early and downstream allergic events in a murine model of antigen-induced lung inflammation. Cat S knockout mice did not develop ovalbumin-induced pulmonary inflammation, consistent with a role for Cat S in the development of the allergic response. Alternatively, wild-type mice were treated with a reversible, highly selective Cat S inhibitor in prophylactic and therapeutic dosing paradigms and assessed for changes in airway inflammation. Although both treatment paradigms resulted in potent Cat S inhibition, only prophylactic Cat S inhibitor dosing blocked lung inflammation, consistent with our findings in Cat S knockout mice. The findings indicate that although Cat S is up-regulated in allergic models, it does not appear to play a significant role in the downstream effector inflammatory phase in this model; however, our results demonstrate that Cat S inhibition in a prophylactic paradigm would ameliorate airway inflammation. PMID- 20855653 TI - Plasma from preeclamptic women increases blood-brain barrier permeability: role of vascular endothelial growth factor signaling. AB - Circulating factors in preeclamptic women are thought to cause endothelial dysfunction and thereby contribute to the progression of this hypertensive condition. Despite the involvement of neurological complications in preeclampsia, there is a paucity of data regarding the effect of circulating factors on cerebrovascular function. Using a rat model of pregnancy, we investigated blood brain barrier permeability, myogenic activity, and the influence of endothelial vasodilator mechanisms in cerebral vessels exposed intraluminally to plasma from normal pregnant or preeclamptic women. In addition, the role of vascular endothelial growth factor signaling in mediating changes in permeability in response to plasma was investigated. A 3-hour exposure to 20% normal pregnant or preeclamptic plasma increased blood-brain barrier permeability by ~6.5- and 18.0 fold, respectively, compared with no plasma exposure (P<0.01). Inhibition of vascular endothelial growth factor receptor kinase activity prevented the increase in permeability in response to preeclamptic plasma but had no effect on changes in permeability of vessels exposed to normal pregnant plasma. Circulating factors in preeclamptic plasma did not affect myogenic activity or the influence of endothelium on vascular tone. These findings demonstrate that acute exposure to preeclamptic plasma has little effect on reactivity of cerebral arteries but significantly increases blood-brain barrier permeability. Prevention of increased permeability by inhibition of vascular endothelial growth factor signaling suggests that activation of this pathway may be responsible for increased blood brain barrier permeability after exposure to preeclamptic plasma. PMID- 20855654 TI - The functional c.-2G>C variant of the mineralocorticoid receptor modulates blood pressure, renin, and aldosterone levels. AB - The mineralocorticoid receptor (MR) is essential in the regulation of volemia and blood pressure. Rare mutations in the MR gene cause type 1 pseudohypoaldosteronism and hypertension. In this study we characterized the common MR polymorphism c.-2G>C (rs2070951) in vitro and tested its influence on parameters related to blood pressure regulation and the renin-angiotensin system. In vitro studies showed that the G allele was associated with decreased MR protein levels and reduced transcriptional activation compared with the C allele. Association studies were performed with several outcome variables in 3 independent cohorts: a mild hypertensive group subjected to a salt-sensitivity test, a healthy normotensive group included in a crossover study to receive both a high and low Na/K diet, and a large cohort (The Netherlands Study of Depression and Anxiety), in which blood pressure was measured. Subjects with the GG genotype had significantly higher plasma renin levels both in the mild hypertensive group and in normal volunteers compared with homozygous C carriers. The GG genotype was also correlated with higher plasma aldosterone levels in healthy subjects. In both the mild hypertensive group and The Netherlands Study of Depression and Anxiety cohort the genotype GG was associated with higher systolic blood pressure in males. In conclusion, the G allele of the common functional genetic polymorphism c.-2G>C in the MR gene associates with increased activation of the renin-angiotensin-aldosterone axis and with increased blood pressure, probably related to decreased MR expression. PMID- 20855655 TI - Pregnancy downregulates actin polymerization and pressure-dependent myogenic tone in ovine uterine arteries. AB - Pregnancy is associated with significantly decreased uterine vascular tone and increased uterine blood flow. The present study tested the hypothesis that the downregulation of actin polymerization plays a key role in reduced vascular tone of uterine arteries in the pregnant state. Uterine arteries were isolated from nonpregnant and near-term pregnant sheep. Activation of protein kinase C significantly increased the filamentous:globular actin ratio and contractions in the uterine arteries, which were inhibited by an actin polymerization inhibitor cytochalasin B. The basal levels of filamentous:globular actin were significantly higher in nonpregnant uterine arteries than those in near-term pregnant sheep. Prolonged treatment (48 hours) of nonpregnant sheep with 17beta-estradiol (0.3 nmol/L) and progesterone (100.0 nmol/L) caused a significant decrease in the filamentous:globular actin. In accordance, the treatment of near-term pregnant sheep for 48 hours with an estrogen antagonist ICI 182 780 (10.0 MUmol/L) and progesterone antagonist RU 486 (1.0 MUmol/L) significantly increased the levels of filamentous:globular actin. Increased intraluminal pressure from 20 to 100 mm Hg resulted in an initial increase in uterine arterial diameter and vascular wall Ca(2+) concentrations, followed by a decrease in the diameter at a constant steady-state level of Ca(2+). Cytochalasin B blocked pressure-induced myogenic constrictions without effect on vascular wall Ca(2+) levels and eliminated the differences in pressure-dependent myogenic tone between nonpregnant sheep and near-term pregnant sheep. The results indicate a key role of actin polymerization in protein kinase C-induced myogenic contractions and suggest a novel mechanism of sex steroid hormone-mediated downregulation of actin polymerization underlying the decreased myogenic tone of uterine arteries in pregnancy. PMID- 20855657 TI - Is long QT syndrome a disease of abnormal mechanical contraction? PMID- 20855656 TI - Hemodynamic correlates of blood pressure across the adult age spectrum: noninvasive evaluation in the Framingham Heart Study. AB - BACKGROUND: Systolic blood pressure and pulse pressure are substantially higher in older adults. The relative contributions of increased forward versus reflected pressure wave amplitude or earlier arrival of the reflected wave to elevated pulse pressure remain controversial. METHODS AND RESULTS: We measured proximal aortic pressure and flow, forward pressure wave amplitude, global wave reflection, reflected wave timing, and pulse wave velocity noninvasively in 6417 (age range, 19 to 90 years; 53 women) Framingham Heart Study Third Generation and Offspring participants. Variation in forward wave amplitude paralleled pulse pressure throughout adulthood. In contrast, wave reflection and pulse pressure were divergent across adulthood: In younger participants, pulse pressure was lower and wave reflection was higher with advancing age, whereas in older participants, pulse pressure was higher and wave reflection was lower with age. Reflected wave timing differed modestly across age groups despite considerable differences in pulse wave velocity. Forward wave amplitude explained 80 (central) and 66 (peripheral) of the variance in pulse pressure in younger participants (<50 years) and 90 and 84 in the older participants (>= 50 years; all P<0.0001). In a stepwise model that evaluated age-pulse pressure relations in the full sample, the late accelerated increases in central and peripheral pulse pressure were markedly attenuated when variation in forward wave amplitude was considered. CONCLUSIONS: Higher pulse pressure at any age and higher pulse pressure with advancing age is associated predominantly with a larger forward pressure wave. The influence of wave reflection on age-related differences in pulse pressure was minor. PMID- 20855658 TI - Transmural differences in myocardial contraction in long-QT syndrome: mechanical consequences of ion channel dysfunction. AB - BACKGROUND: Long-QT syndrome (LQTS) is characterized by prolonged myocardial action potential duration. The longest action potential duration is reported in the endomyocardium and midmyocardium. Prolonged action potential duration in LQTS may cause prolonged cardiac contraction, which can be assessed by strain echocardiography. We hypothesized that myocardial contraction is most prolonged in subendocardial myofibers in LQTS patients and that inhomogeneous transmural contraction is related to the risk of spontaneous arrhythmia. METHODS AND RESULTS: We included 101 genotyped LQTS mutation carriers and 35 healthy individuals. A history of cardiac arrhythmias was present in 48 mutations carriers, and 53 were asymptomatic. Myocardial contraction duration was assessed by strain echocardiography as time from the ECG Q wave to peak strain in 16 LV segments. Strain was assessed along the longitudinal axis, predominantly representing subendocardial fibers, and along the circumferential axis, representing midmyocardial fibers. Mean contraction duration was longer in LQTS mutation carriers compared with healthy individuals (445 +/- 45 versus 390 +/- 40 milliseconds; P<0.001) and longer in symptomatic compared with asymptomatic LQTS mutation carriers (460 +/- 40 versus 425 +/- 45 milliseconds; P<0.001). Contraction duration by longitudinal strain was longer than by circumferential strain in symptomatic LQTS patients (460 +/- 45 versus 445+/-45 milliseconds; P=0.008) but not in asymptomatic patients and healthy individuals, indicating transmural mechanical dispersion. This time difference was present in a majority of LV segments and was most evident in patients with LQT2 and the Jervell and Lange-Nielsen syndrome. CONCLUSION: Contraction duration in symptomatic LQTS mutation carriers was longer in the subendocardium than in the midmyocardium, indicating transmural mechanical dispersion, which was not present in asymptomatic and healthy individuals. PMID- 20855659 TI - CD69 limits the severity of cardiomyopathy after autoimmune myocarditis. AB - BACKGROUND: Experimental autoimmune myocarditis (EAM), a mouse model of post infectious cardiomyopathy, reflects mechanisms of inflammatory cardiomyopathy in humans. EAM is characterized by an infiltration of inflammatory cells into the myocardium that can be followed by myocyte fibrosis, edema, and necrosis, leading to ventricular wall dysfunction and heart failure. Different data indicate that CD69 exerts an important immunoregulatory effect in vivo. However, the possible role of CD69 in autoimmune myocarditis has not been studied. METHODS AND RESULTS: We have explored the role of the leukocyte regulatory molecule CD69 in the inflammation that leads to cardiac dysfunction after myocardial injury in EAM. We have found that after induction of EAM, the draining lymph nodes from CD69 deficient mice developed an exacerbated Th17 inflammatory response, resulting in increases in the numbers of infiltrating leukocytes in the myocardium. In the chronic phase of EAM, transthoracic echocardiography revealed a significantly reduced left ventricular fractional shortening and a decreased ejection fraction in CD69-deficient mice, indicative of an impaired cardiac contractility. This condition was accompanied by a greater extent of myocardial fibrosis, an elevated number of sinus pauses on ECG, and an enhanced ratio of heart weight to body weight in CD69-/- mice. Moreover, both bone marrow transplantation and adoptive transfer of Th17 cells isolated from immunized CD69-/- mice with EAM into naive wild-type recipients reproduced the severity of the disease, demonstrating that CD69 exerts its function within the lymphocyte compartment. CONCLUSION: Our findings indicate that CD69 negatively regulates heart-specific Th17 responses, cardiac inflammation, and heart failure progression in EAM. PMID- 20855660 TI - Extensive primary repair of the thoracic aorta in acute type a aortic dissection by means of ascending aorta replacement combined with open placement of triple branched stent graft: early results. AB - BACKGROUND: To simplify extensive primary repair of the thoracic aorta in acute type A aortic dissection, we developed the open triple-branched stent graft placement technique. The early results of this new technique are reported. METHODS AND RESULTS: Between June 2008 and November 2009, 30 patients with acute Stanford type A aortic dissection underwent extensive primary repair of the thoracic aorta by means of ascending aorta replacement combined with open placement of triple-branched stent graft. Placement of the triple-branched stent graft into the true lumen of the descending aorta, arch, and 3 arch vessels was technically successful in all patients. The mean cardiopulmonary bypass time, aortic cross-clamp time, and lower body arrest time were 151.8 +/- 16.69, 84.1 +/ 6.97, and 31.17 +/- 5.34 minutes, respectively. The postoperative mechanical ventilation support period and duration of intensive care unit stay were 17.93 +/ 2.35 and 62.10 +/- 9.24 hours, respectively. All implanted stent grafts were fully opened and not kinked; there was no space or blood flow surrounding the triple-branched stent graft and no sidearm graft stenosis or occlusion. The false lumen of the descending aorta distal to the stent graft closed with thrombus in 25 of 30 patients at their first postoperative scans and in 26 of 30 at the 3 month postoperative scan. CONCLUSIONS: Open triple-branched stent graft placement is an effective technique with satisfactory early results. With this technique, extensive primary repair of the thoracic aorta may become easier and safer for acute type A aortic dissection. PMID- 20855661 TI - Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns. AB - BACKGROUND: Various mechanisms of atrial fibrillation (AF) have been demonstrated experimentally. Invasive methods to study these mechanisms in humans have limitations, precluding continuous mapping of both atria with sufficient resolution. In this article, we present continuous biatrial epicardial activation sequences of AF in humans using noninvasive electrocardiographic imaging (ECGI). METHODS AND RESULTS: In the testing phase, ECGI accuracy was evaluated by comparing ECGI with co-registered CARTO images during atrial pacing in 6 patients. Additionally, correlative observations from catheter mapping and ablation were compared with ECGI in 3 patients. In the study phase, ECGI maps during AF in 26 patients were analyzed for mechanisms and complexity. ECGI noninvasively imaged the low-amplitude signals of AF in a wide range of patients (97 procedural success). Spatial accuracy for determining initiation sites from pacing was 6 mm. Locations critical to maintenance of AF identified during catheter ablation were identified by ECGI; ablation near these sites restored sinus rhythm. In the study phase, the most common patterns of AF were multiple wavelets (92), with pulmonary vein (69) and non-pulmonary vein (62) focal sites. Rotor activity was seen rarely (15). AF complexity increased with longer clinical history of AF, although the degree of complexity of nonparoxysmal AF varied widely. CONCLUSIONS: ECGI offers a noninvasive way to map epicardial activation patterns of AF in a patient-specific manner. The results highlight the coexistence of a variety of mechanisms and variable complexity among patients. Overall, complexity generally increased with duration of AF. PMID- 20855662 TI - Podoplanin-expressing cells derived from bone marrow play a crucial role in postnatal lymphatic neovascularization. AB - BACKGROUND: Emerging evidence has suggested a contribution of bone marrow (BM) cells to lymphatic vessel formation; however, the exact phenotype of the cells with lymphatic endothelial progenitor cell function has yet to be identified. Here, we investigate the identity of BM-derived lymphatic endothelial progenitor cells and their role in lymphatic neovascularization. METHODS AND RESULTS: Culture of BM-mononuclear cells in the presence of vascular endothelial growth factors A and C and endothelial growth factor resulted in expression of lymphatic endothelial cell markers. Among these cells, podoplanin(+) cells were isolated by magnetic-activated cell sorting and characterized by fluorescence-activated cell sorter analysis and immunocytochemistry. These podoplanin(+) cells highly express markers for lymphatic endothelial cells, hematopoietic lineages, and stem/progenitor cells; on further cultivation, they generate lymphatic endothelial cells. We further confirmed that podoplanin(+) cells exist in small numbers in BM and peripheral blood of normal mice but are significantly (15-fold) augmented on lymphangiogenic stimuli such as tumor implantation. Next, to evaluate the potential of podoplanin(+) cells for the formation of new lymphatic vessels in vivo, we injected culture-isolated or freshly isolated BM-derived podoplanin(+) cells into wound and tumor models. Immunohistochemistry demonstrated that the injected cells were incorporated into the lymphatic vasculature, displayed lymphatic endothelial cell phenotypes, and increased lymphatic vascular density in tissues, suggesting lymphvasculogenesis. Podoplanin(+) cells also expressed high levels of lymphangiogenic cytokines and increased proliferation of lymphatic endothelial cells during coculture, suggesting a lymphangiogenic or paracrine role. CONCLUSIONS: Our results provide compelling evidence that BM-derived podoplanin(+) cells, a previously unrecognized cell type, function as lymphatic endothelial progenitor cells and participate in postnatal lymphatic neovascularization through both lymphvasculogenesis and lymphangiogenesis. PMID- 20855663 TI - Right ventricular ischemic injury in patients with acute ST-segment elevation myocardial infarction: characterization with cardiovascular magnetic resonance. AB - BACKGROUND: Experimental data show that the right ventricle (RV) is more resistant to ischemia than the left ventricle. To date, limited data are available in humans because of the difficulty of discriminating reversible from irreversible ischemic damage. We sought to characterize RV ischemic injury in patients with reperfused myocardial infarction using cardiovascular magnetic resonance. METHODS AND RESULTS: In 3 tertiary centers, 242 consecutive patients with reperfused acute ST-segment elevation myocardial infarction were studied with cardiovascular magnetic resonance at 1 week and 4 months after myocardial infarction. T2-weighted and postcontrast cardiovascular magnetic resonance scans were used to depict myocardial edema and late gadolinium enhancement, respectively. Early after infarction, RV edema was common (51% of patients), often associated with late gadolinium enhancement (31% of patients). Remarkably, RV edema and late gadolinium enhancement were found in 33% and 12% of anterior left ventricular infarcts, respectively. Baseline regional and global RV functions were inversely related to the presence and extent of RV edema and RV late gadolinium enhancement. At follow-up, a significant decrease in frequency (25/242 patients; 10%) and extent of RV late gadolinium enhancement was observed (P<0.001). With the use of multivariable analysis, the presence of RV edema was an independent predictor of RV global function improvement during follow-up (beta coefficient=0.221, P=0.003). CONCLUSIONS: Early postinfarction RV ischemic injury is common and is characterized by the presence of myocardial edema, late gadolinium enhancement, and functional abnormalities. RV injury is not limited to inferior infarcts but is commonly found in anterior infarcts as well. Cardiovascular magnetic resonance findings suggest reversibility of acute RV dysfunction with limited permanent myocardial damage at 4-month follow-up. PMID- 20855664 TI - Serial measurement of growth-differentiation factor-15 in heart failure: relation to disease severity and prognosis in the Valsartan Heart Failure Trial. AB - BACKGROUND: Growth-differentiation factor-15 (GDF-15) is emerging as a prognostic biomarker in patients with coronary artery disease. Little is known about GDF-15 as a biomarker in patients with heart failure. METHODS AND RESULTS: The circulating concentration of GDF-15 was measured at baseline (n=1734) and at 12 months (n=1517) in patients randomized in the Valsartan Heart Failure Trial (Val HeFT). GDF-15 levels at baseline ranged from 259 to 25 637 ng/L and were abnormally high (>1200 ng/L) in 85% of patients. Higher levels were associated with features of worse heart failure and biomarkers of neurohormonal activation, inflammation, myocyte injury, and renal dysfunction. Baseline GDF-15 levels (per 100 ng/L) were associated with the risks of mortality (hazard ratio, 1.017; 95% confidence interval, 1.014 to 1.019; P<0.001) and first morbid event (hazard ratio, 1.020; 95% confidence interval, 1.017 to 1.023; P<0.001). In a comprehensive multiple-variable Cox regression model that included clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T, GDF-15 remained independently associated with mortality (hazard ratio, 1.007; 95% confidence interval, 1.001 to 1.014; P=0.02) but not first morbid event. At 12 months, the GDF-15 levels had increased by a similar amount in the placebo and valsartan groups (P=0.94). Increases in GDF-15 over 12 months were independently associated with the risks of future mortality and first morbid event also after adjustment for clinical prognostic variables, B-type natriuretic peptide, high-sensitivity C-reactive protein, and high-sensitivity troponin T and their changes. CONCLUSIONS: GDF-15 reflects information from several pathological pathways and provides independent prognostic information in heart failure. GDF-15 levels increase over time, suggesting that GDF-15 reflects a pathophysiological axis that is not completely addressed by the therapies prescribed in Val-HeFT. PMID- 20855665 TI - Unusual case of nonbacterial thrombotic endocarditis attributable to primary antiphospholipid syndrome. PMID- 20855666 TI - Letter by De Servi and Navarese regarding article, "Prognostic modeling of individual patient risk and mortality impact of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention Triage Strategy trial". PMID- 20855668 TI - Assessment of the human coronary collateral circulation. PMID- 20855669 TI - Cardiovascular effects of exercise training: molecular mechanisms. PMID- 20855670 TI - Takotsubo cardiomyopathy complicated by cardiac tamponade: classic hemodynamic findings with a new disease. PMID- 20855671 TI - Treatment of clinically diagnosed laryngopharyngeal reflux disease. AB - OBJECTIVES: To determine the incidence of Helicobacter pylori (HP) stool antigen (HPSA) in patients with laryngopharyngeal reflux disease (LPRD), and to make a comparison of 2 treatment regimens that have been used based on the presence or absence of HPSA positivity in patients with LPRD. DESIGN: Randomized controlled study. SETTING: Suez Canal University Hospital, Ismalia, Egypt. PATIENTS: A total of 212 patients with symptoms of LPRD. INTERVENTION: Patients were evaluated by laryngoscopy, ambulatory pH monitoring for 24 hours, and HPSA testing. Esomeprazole magnesium as a monotherapy was evaluated vs triple therapy in patients with HP infection. MAIN OUTCOME MEASURES: To determine the incidence of HPSA in patients with LPRD, and to make a comparison of 2 treatment regimens that have been used based on the presence or absence of HPSA positivity in patients with LPRD. RESULTS: Persistent dry cough and a feeling of a lump in the throat (globus sensation) were the most frequent symptoms of LPRD, while posterior laryngeal inflammation was the main laryngoscopic finding. Results from the HPSA test were positive in 57% of the studied group. Patients with negative HPSA were treated with esomeprazole as single modality with a reported improvement score of 96.6%. Patients with positive HPSA test results were divided into 2 groups: 1 received only esomeprazole, with reported improvement in 40%, whereas the second group was treated with esomeprazole, plus amoxicillin sodium and clarithromycin (triple therapy) and reported a 90% incidence of symptom improvement. CONCLUSION: The incidence of HP infection in patients with LPRD in our study was 57%. Triple therapy showed a higher cure rate in patients with HPSA-positive test results. PMID- 20855672 TI - Histopathologic study of hidradenitis suppurativa following long-pulsed 1064-nm Nd:YAG laser treatment. AB - OBJECTIVE: To assess clinical and histopathologic changes occurring after long pulsed 1064-nm Nd:YAG laser treatment of hidradenitis suppurativa (HS). DESIGN: Prospective, controlled clinical and histologic study of patients with Hurley stage II HS disease. SETTING: Outpatient dermatology department at Henry Ford Hospital, Detroit, Michigan. PARTICIPANTS: Nineteen patients with Fitzpatrick skin types II to VI with Hurley stage II HS lesions of the axilla and groin. Interventions Two monthly laser sessions were performed using the long-pulsed 1064-nm Nd:YAG laser. Main Outcome Measure Clinical response was scored using the modified Sartorius scale for HS reflecting Lesion Area and Severity Index (LASI). Histologic changes were examined before treatment and 1 week, 1 month, and 2 months after treatment. RESULTS: The percentage change in HS severity after 2 sessions of laser treatment was -31.6 over all anatomic sites (P < .005), -24.4 for the axillary site (P = .008), and -36.8 for the inguinal site (P = .001). Histologic changes corresponded to clinical response. Findings from serial biopsy specimens showed increased inflammation at 1 week after treatment and decreased inflammation with resulting fibrosis and scarring at 1 month and 2 months after treatment. CONCLUSIONS: The long-pulsed 1064-nm Nd:YAG laser is a novel effective treatment option for HS. Our histopathologic data suggest that HS is primarily a follicular disorder. The Nd:YAG laser penetrates for selective photothermolysis of the follicular unit and destruction of organized inflammatory lesions in the superficial to mid dermis. Our study offers insight into the pathogenesis of HS and the mechanism of the Nd:YAG laser in treatment of patients with this chronic, debilitating disease. PMID- 20855673 TI - The lattice stitch technique. PMID- 20855674 TI - Validation of psoriasis clinical severity and outcome measures: searching for a gold standard. PMID- 20855675 TI - Evolution of nevi during treatment with natalizumab: A prospective follow-up of patients treated with natalizumab for multiple sclerosis. AB - BACKGROUND: Natalizumab is a monoclonal antibody directed against alpha4 integrin used in the treatment of multiple sclerosis (MS). Four cases of melanomas occurring in patients prescribed natalizumab to treat MS were recently reported. Although some fundamental data suggested that alpha4beta1 integrin could be linked to the invasiveness of melanoma, none showed any relation with the transformation of melanocytes. OBSERVATIONS: We performed a prospective follow-up of a cohort of patients with MS treated with natalizumab to assess the evolution of nevi under treatment. Clinical dermatologic examination and videodermoscopy were performed every 6 months. Nevi were compared side-by-side with baseline photographs, and histologic analysis was proposed based on clinical and dermoscopic criteria. Forty-four patients were included, and 248 nevi were examined and followed up. The mean duration of follow-up was 14 months (range, 6 20 months). Seventeen lesions (6.8%) showed modifications over time. Only 12 (4.8%) presented substantial dermoscopic changes. Five lesions were removed. All of them were classified as benign after histologic examination. CONCLUSIONS: Our results showed the same rate of clinical and dermoscopic changes of nevi during treatment with natalizumab compared with the spontaneous evolution of nevi reported in literature. In accordance with fundamental data, those results suggest that the inhibition of the alpha4 integrin does not promote the transformation of melanocytic lesions. PMID- 20855676 TI - Skin conditions that bring patients to emergency departments. PMID- 20855677 TI - Effect of a novel DNA vaccine on angiogenesis and tumor growth in vivo. AB - OBJECTIVE: To develop a DNA cancer vaccine that targets the vascular endothelial growth factor receptor. DESIGN: Mice were vaccinated intramuscularly with listeriolysin O-fetal liver kinase 1 (LLO-Flk1) or controls. Mice were also challenged subcutaneously with the tumor cell line TC-1. Tumor sizes were measured after vaccination. At the conclusion of the experiments, the tumors were harvested for immunohistochemical analysis and determination of hemoglobin content. SETTING: Research laboratory. SUBJECTS: Six- to 8-week-old C57BL/6 mice. INTERVENTION: Fifty micrograms of each vector was administered 3 times at weekly intervals. MAIN OUTCOME MEASURES: Tumor size, mean vessel density of tumors, hemoglobin content of tumor. RESULTS: Mice treated with the LLO-Flk1 vaccine experienced slower tumor growth relative to the other treatment groups. Complete tumor regression was observed in several cases. Immunohistochemical staining of tumors revealed fewer blood vessels in the mice vaccinated with the LLO-Flk1 vaccine relative to the other treatment groups. Finally, colorimetric assessment for hemoglobin suggested decreased vasculature in the tumor bed of these mice relative to the control groups. CONCLUSION: The novel DNA cancer vaccine LLO-Flk1 can slow tumor growth in vivo. PMID- 20855678 TI - A review of esophageal disc battery ingestions and a protocol for management. AB - OBJECTIVE: To review our experience with esophageal disc battery requiring endoscopic retrieval and describe a protocol for management. DESIGN: Retrospective medical chart review. PATIENTS: Pediatric patients who underwent endoscopic retrieval of an esophageal disc battery over a 10-year period. RESULTS: Ten pediatric patients had ingested an esophageal disc battery that required endoscopic removal. Three patients had minimal esophageal damage; the other 7 sustained severe and extensive esophageal damage involving the muscularis (n = 5) or developed a perforation (n = 2). One of these patients had an extensive injury that extended into the trachea resulting in a tracheoesophageal fistula. Two case reports are presented, outlining the management approach to esophageal perforations from esophageal battery ingestion. CONCLUSIONS: Severe injury can occur rapidly following disc battery ingestion. A high index of suspicion for an esophageal disc battery is necessary to expeditiously diagnose this condition. Emergency endoscopic removal is necessary. We outline a protocol for the management of this hazardous problem. PMID- 20855679 TI - Efficacy and duration of botulinum toxin treatment for drooling in 131 children. AB - OBJECTIVE: To address the efficacy of botulinum toxin and the duration of its effect when used on a large scale for the treatment of drooling in children with neurological disorders. DESIGN: Prospective cohort study. SETTING: Academic multidisciplinary drooling clinic. PATIENTS: A total of 131 children diagnosed as having cerebral palsy or another nonprogressive neurological disorder and who also have moderate to severe drooling. INTERVENTION: Injection of botulinum toxin to the submandibular glands. MAIN OUTCOME MEASURES: Direct observational drooling quotient (DQ) (0-100) and caretaker visual analog scale (VAS) scores (0-100). RESULTS: A clinically notable response was found in 46.6% of children, reflected in a significant mean reduction in DQ from a baseline of 29 to 15 after 2 months and 19 after 8 months (P < .001). The mean VAS score decreased from 80 at baseline to 53 after 2 months and increased to 66 after 8 months (P < .001). Kaplan-Meier analysis showed that patients who initially responded to treatment experienced relapse after a median of 22 weeks (interquartile range, 20-33 weeks). CONCLUSIONS: Our study provides further support for botulinum toxin's efficacy for treatment of drooling in approximately half of patients for a median of 22 weeks. Further optimization of patient selection should be an area of attention in future studies. PMID- 20855680 TI - Fusion of MRIs and CT scans for surgical treatment of cholesteatoma of the middle ear in children. AB - OBJECTIVE: To evaluate the efficiency of diffusion-weighted magnetic resonance imaging (MRI) and high-resolution computed tomographic (CT) scan coregistration in predicting and adequately locating primary or recurrent cholesteatoma in children. DESIGN: Prospective study. SETTING: Tertiary care university hospital. PATIENTS: Ten patients aged 2 to 17 years (mean age, 8.5 years) with cholesteatoma of the middle ear, some of which were previously treated, were included for follow-up with systematic CT scanning and MRI between 2007 and 2008. INTERVENTIONS: Computed tomographic scanning was performed on a Siemens Somaton 128 (0.5/0.2-mm slices reformatted in 0.5/0.3-mm images). Fine cuts were obtained parallel and perpendicular to the lateral semicircular canal in each ear (100 * 100-mm field of view). Magnetic resonance imaging was undertaken on a Siemens Avanto 1.5T unit, with a protocol adapted for young children. Diffusion-weighted imaging was acquired using a single-shot turbo spin-echo mode. To allow for diagnosis and localization of the cholesteatoma, CT and diffusion-weighted MRIs were fused for each case. RESULTS: In 10 children, fusion technique allowed for correct diagnosis and precise localization (hypotympanum, epitympanum, mastoid recess, and attical space) as confirmed by subsequent standard surgery (positive predictive value, 100%). In 3 cases, the surgical approach was adequately determined from the fusion results. Lesion sizes on the CT-MRI fusion corresponded with perioperative findings. CONCLUSIONS: Recent developments in imaging techniques have made diffusion-weighted MRI more effective for detecting recurrent cholesteatoma. The major drawback of this technique, however, has been its poor anatomical and spatial discrimination. Fusion imaging using high resolution CT and diffusion-weighted MRI appears to be a promising technique for both the diagnosis and precise localization of cholesteatomas. It provides useful information for surgical planning and, furthermore, is easy to use in pediatric cases. PMID- 20855681 TI - Neonatal vs delayed-onset fourth branchial pouch anomalies: therapeutic implications. AB - OBJECTIVES: To determine the presentation of third or fourth branchial pouch anomalies in various age groups of children and evaluate endoscopic cauterization as a treatment technique. DESIGN: Retrospective study of patients treated from 2000 to 2009. SETTING: Tertiary care children's hospital. PATIENTS: Pediatric patients aged 0 to 18 years (mean age, 5.5 years), including 5 neonates. INTERVENTIONS: Endoscopic and/or open surgical management of third and fourth branchial pouch anomalies; clinical and endoscopic follow-up. MAIN OUTCOME MEASURES: Absence of clinical recurrence; closure of the sinus tract. RESULTS: Two forms of presentation were identified: a neonatal form, characterized by a voluminous and compressive cervical mass (5 of 20 [25%]) and a childhood form, presenting as a cervical abscess (15 of 20 [75%]). The vast majority of our patients regardless of presentation were treated endoscopically (n = 19), with a success rate of 68% (13 of 19) after 1 procedure, 79% (15 of 19) after 2 procedures, and 89% (17 of 19) after 3 procedures. Neonatal and adult presentations require slightly different therapeutic approaches. CONCLUSIONS: Third and fourth branchial pouch anomalies can present in 2 distinct forms: a neonatal form and a childhood form. The endoscopic technique should be the favored approach for both forms: whenever possible, in view of its simplicity, rapidity, and the lack of serious postoperative complications. Recurrences can be treated by repeated cauterization using the same technique, with good long-term outcomes. An age-based management algorithm has been developed. PMID- 20855682 TI - Plasma levels of MCP-1 and adiponectin in obstructive sleep apnea syndrome. AB - OBJECTIVES: To evaluate the correlation between concentrations of the proinflammatory cytokines monocyte chemotactic protein 1 (MCP-1), adiponectin, interleukin 6 (IL-6), interleukin 8 (IL-8), and tumor necrosis factor (TNF) and patients with obstructive sleep apnea syndrome (OSAS). Repeated apnea attacks in patients with OSAS constitute a hypoxic condition, which induces tissue inflammation by mediation of these proinflammatory cytokines. DESIGN: Radioimmunoassay analyses of nonrandomized controlled trial. SETTING: University affiliated tertiary care hospital. PATIENTS: The study population comprised 59 patients who underwent the polysomnography. MAIN OUTCOME MEASURES: Serum concentrations of MCP-1, adiponectin, IL-6, IL-8, and TNF, as well as body mass index and polysomnographic data, including apnea-hypopnea index (AHI) and lowest oxygen saturation. RESULTS: The mean (SD) plasma level of MCP-1 in serum was increased in all patients with OSAS (P < .001), while adiponectin level was decreased in the patients with severe OSAS (6.88 [1.78] MUg/mL) compared with normal controls (8.90 [2.63] MUg/mL) (P = .006). Serum concentrations of IL-6, IL 8, and TNF did not exhibit any differences between patients with OSAS and normal controls. The correlation coefficient between plasma MCP-1 level and AHI was 0.62 and between adiponectin level and AHI was 0.66. CONCLUSIONS: Our results suggest that plasma MCP-1 and adiponectin levels were different between patients with OSAS and normal controls. Adiponectin and MCP-1 may be prognostic factors for comparing patients with OSAS before and after treatment. PMID- 20855683 TI - Brief evaluation of pleasantness of olfactory and trigeminal stimulants. AB - OBJECTIVE: To evaluate a brief olfactory test based on pleasantness rating of olfactory and trigeminal stimulants. DESIGN: Criterion standard. SETTING: University hospital. PARTICIPANTS: A total of 60 participants (48 healthy and 12 with olfactory loss) aged 16 to 81 years. INTERVENTIONS: The new test of odor pleasantness (TOP) based on classification of odorants and trigeminal stimulants into 4 categories was compared with 2 standard tests of subjective olfactometry. MAIN OUTCOME MEASURE: We evaluated the possible use of the TOP in assessment of olfactory and the trigeminal system in healthy individuals and those with olfactory loss. RESULTS: All 3 tests demonstrated significant mutual correlation (P < .01), and persons with olfactory loss scored lower than healthy participants (P < .01). Using exploratory factor analysis and cluster analysis, we found that healthy individuals classified odorants accurately according to the degree of their hedonic character. CONCLUSION: The TOP offers outcomes similar to those of standard tests of olfaction that are based on psychophysical testing. PMID- 20855684 TI - Gastroesophageal reflux-related chronic laryngitis: con. PMID- 20855685 TI - GERD-related chronic laryngitis: pro. PMID- 20855686 TI - Gastroesophageal reflux-related chronic laryngitis. Commentary. PMID- 20855687 TI - A case series and review of histoplasmosis infection in the neck. PMID- 20855688 TI - Bilateral cavernous sinus involvement by perineural spread of inverted papilloma. PMID- 20855689 TI - Radiology quiz case 1. Diagnosis: Parathyroid cyst (PC). PMID- 20855690 TI - Radiology quiz case 2. Diagnosis: Osteochondroma arising from the lateral process of C4 and hereditary multiple exostoses (HME). PMID- 20855691 TI - Pathology quiz case 1. Diagnosis: Sinonasal malignant Triton tumor (MTT) with intracranial extension. PMID- 20855692 TI - Pathology quiz case 2. Diagnosis: Nasal lobular capillary hemangioma (pyogenic granuloma). PMID- 20855693 TI - Successful treatment of necrobiotic xanthogranuloma with intravenous immunoglobulin. PMID- 20855694 TI - Martorell hypertensive ischemic leg ulcer: a model of ischemic subcutaneous arteriolosclerosis. AB - OBJECTIVES: To better define the diagnosis and treatment of Martorell hypertensive ischemic leg ulcer (HYTILU) and to compare Martorell HYTILU with calciphylaxis (calcific uremic arteriolopathy) and nonuremic forms of calciphylaxis. DESIGN: Retrospective study from 1999 through 2007. SETTING: Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland. PARTICIPANTS: Of 330 patients with leg ulcers, 31 had a clinical diagnosis of Martorell HYTILU confirmed by dermatopathologic examination. MAIN OUTCOME MEASURES: Clinical features, suspected diagnosis at initial presentation, cardiovascular risk factors, findings from vascular examination and histologic analysis, specific medical and surgical management, and outcome. RESULTS: Of the 31 patients, all presented with 1 or multiple painful necrotic skin ulcers on the laterodorsal part of the leg, with bilateral involvement in 16 of 31 cases (52%), and 16 were referred with suspected pyoderma gangrenosum. All patients had arterial hypertension, and 18 (58%) had diabetes. All patients had subcutaneous stenotic arteriolosclerosis on histologic analysis, with medial calcification in 22 of 31 of cases (71%). Martorell HYTILU, calciphylaxis, and nonuremic forms of calciphylaxis shared identical histologic features. Of the 31 patients, 29 (94%) were successfully treated with surgical debridement and split-thickness skin grafting. Three patients (9%) died of sepsis, 2 of whom were undergoing immunosuppressive treatment for wrongly diagnosed pyoderma gangrenosum. CONCLUSIONS: Ischemic subcutaneous arteriolosclerosis is the hallmark of Martorell HYTILU, calciphylaxis, and the nonuremic forms of calciphylaxis. All patients are hypertensive and approximately 60% are diabetic. Martorell HYTILU can easily be confused with pyoderma gangrenosum, which can be detrimental, since the 2 diseases require a completely different treatment strategy. PMID- 20855695 TI - Infantile hemangiomas with minimal or arrested growth: a retrospective case series. AB - OBJECTIVE: To describe clinical characteristics of infantile hemangiomas with minimal or arrested growth (IH-MAGs). DESIGN: Retrospective case series. SETTING: Ambulatory referral center at the University of California, San Francisco. Patients Infantile hemangiomas with minimal or arrested growth were defined as infantile hemangiomas with a proliferative component equaling less than 25% of their total surface area. The patients must have been at least age 2 months at the initial visit or on follow-up. Forty-two eligible patients with 47 IH-MAGs were included in the study. MAIN OUTCOME MEASURES: Medical record review was performed for demographic and gestational information, lesion size, and clinical appearance, presence of proliferation, complications, coexisting classic infantile hemangiomas, and morphologic subtype classified as localized, segmental, or indeterminate. RESULTS: Infantile hemangiomas with minimal or arrested growth manifested most commonly as fine or coarse telangiectatic patches. Proliferation was present in 30% (14 of 47 IH-MAGs), usually as small papules at the periphery of these hemangiomas. Sixty-eight percent (32 of 47 IH MAGs) of them were present on the lower body. Seventeen patients had classic infantile hemangiomas at another body site. Comparison of distribution of sites of IH-MAGs showed a 26-fold (95% confidence interval, 1.9-351.5; P = .01) likelihood of having IH-MAGs on the lower body compared with classic infantile hemangiomas. CONCLUSIONS: Infantile hemangiomas with minimal or arrested growth have a distinct clinical appearance and a unique predilection for the lower body. Recognition of IH-MAGs will help in more accurate diagnosis of vascular birthmarks of infancy, and the presence of IH-MAGs in an individual patient does not exclude the proliferative potential of other infantile hemangiomas that may be present. PMID- 20855696 TI - The sunless study: a beach randomized trial of a skin cancer prevention intervention promoting sunless tanning. AB - OBJECTIVE: To examine the impact of a skin cancer prevention intervention that promoted sunless tanning as a substitute for sunbathing. DESIGN: Randomized controlled trial. SETTING: Public beaches in Massachusetts. PARTICIPANTS: Women (N = 250) were recruited to participate in the study during their visit to a public beach. Intervention The intervention included motivational messages to use sunless tanning as an alternative to UV tanning, instructions for proper use of sunless tanning products, attractive images of women with sunless tans, a free trial of a sunless tanning product, skin cancer education, and UV imaging. The control participants completed surveys. MAIN OUTCOME MEASURES: The primary outcome was sunbathing 2 months and 1 year after the intervention. Secondary outcomes included sunburns, sun protection use, and sunless tanning. RESULTS: At 2 months, intervention participants reduced their sunbathing significantly more than did controls and reported significantly fewer sunburns and greater use of protective clothing. At 1 year, intervention participants reported significant decreases in sunbathing and increases in sunless tanning relative to control participants but no differences in the other outcomes. CONCLUSION: This intervention, which promoted sunless tanning as an alternative to UV tanning, had a short-term effect on sunbathing, sunburns, and use of protective clothing and a longer-term effect on sunbathing and sunless tanning. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00403377. PMID- 20855697 TI - Use of sunless tanning products among US adolescents aged 11 to 18 years. AB - OBJECTIVE: To describe the prevalence and correlates of the use of sunless tanning products among US adolescents and their association with UV radiation exposure behaviors, including indoor tanning, sunburn experiences, and use of sunscreen while outdoors. DESIGN: Telephone-based, random-digit-dialed, cross sectional survey conducted from July 1 through October 30, 2004. SETTING: Telephone-accessible households with resident adolescents living with parents or caregivers in the mainland United States. PARTICIPANTS: Nationally representative, population-based sample of 1600 adolescents aged 11 to 18 years and their caregivers. MAIN OUTCOME MEASURE: Prevalence of recent (past-year) use of sunless tanning products and UV radiation exposure behaviors. RESULTS: The prevalence of self-reported use of sunless tanning products in the past year among US adolescents was 10.8%. Adolescent users of these products were more likely to be older and female, to perceive a tanned appearance as desirable, to have a parent or caregiver who used sunless tanning products, and to hold positive beliefs or attitudes about these products. Use of sunless tanning products was independently associated with indoor tanning and higher frequency of sunburn but not with use of sunscreen. CONCLUSIONS: Among US adolescents, 10.8% used sunless tanning products in the past year; this practice was associated with risky UV radiation exposure-related behaviors. Adolescents, therefore, must be educated about these products and the importance of avoiding indoor tanning and practicing sun-protective behaviors. PMID- 20855699 TI - Allergic contact dermatitis to synthetic rubber gloves: changing trends in patch test reactions to accelerators. AB - BACKGROUND: Rubber gloves are one of the most frequent causes of occupational allergic contact dermatitis, especially in health care workers. OBSERVATIONS: We describe 23 patients with allergic contact dermatitis due to rubber accelerators in rubber gloves, some with disseminated dermatitis, treated during a 2-year period. Three had IgE-mediated latex allergies. Sixteen were health care workers from a single institution whose dermatitis was temporally related to the switch to latex-safe gloves. Each had positive patch test reactions to 1 or more rubber accelerators, including carbamates, thiurams, 2-mercaptobenzothiazole, and 1,3 diphenylguanidine. Chemical analysis of 6 glove samples identified 2 mercaptobenzothiazole in 4 and zinc diethyldithiocarbamate in 1. There were discordances between patch test results for glove chemicals and glove swatches and between available information on chemicals used during glove production and chemicals detected during glove analysis. Although these factors may complicate the search for culprit and alternative gloves, dermatitis cleared in each of 9 patients with follow-up data and for whom alternative gloves were provided based on published information of glove composition. CONCLUSIONS: Allergic contact dermatitis due to synthetic rubber gloves occurs even with the use of latex-safe products. More knowledge about chemicals present in these gloves, to which the skin is exposed during use, is necessary to prevent and treat allergic contact dermatitis. PMID- 20855700 TI - Cutaneous sclerosis: a previously undescribed manifestation of sclerosing mesenteritis. AB - BACKGROUND: Sclerosing mesenteritis is a rare disease of unknown etiology that is characterized by self-limited, nonspecific inflammation and fibrosis of the mesenteric adipose tissue. Histologic classification characterizes 3 main stages in the evolution of the fibroinflammatory process: mesenteric lipodystrophy (ML), mesenteric panniculitis (MP), and sclerosing (retractile) mesenteritis (SM). OBSERVATIONS: A 68-year-old woman with biopsy-proven MP presented with multiple asymptomatic, indurated subcutaneous nodules on both arms, as well as 2 indurated plaques on her abdomen. The cutaneous changes preceded the diagnosis of SM by roughly 3 years. The arm lesions were centrally depressed with a prominent groove and a peau d'orange appearance. Biopsy findings revealed a subcutaneous process with almost total replacement of adipocytes by zones of woody sclerosis and fat necrosis identical to that observed in the mesentery. To our knowledge, this manifestation of sclerosing mesenteritis has not been reported previously. CONCLUSIONS: Sclerosing mesenteritis has rarely been associated with extra abdominal idiopathic fibrosclerotic disorders, but a cutaneous component of SM has never been characterized. The fact that the cutaneous lesions were histopathologically identical to the mesenteric changes and their presence prior to the recognition of intra-abdominal disease suggests that future patients with such lesions might be evaluated for this disorder leading to earlier recognition. PMID- 20855702 TI - Effect of a single application of pulsed dye laser treatment of port-wine birthmarks on intraocular pressure. AB - BACKGROUND: A new pathophysiologic mechanism has been proposed that indicates that periorbital port-wine birthmarks (PWBs) serve as alternate collateral blood passageways when orbital venous drainage is impaired. The occlusion of such collateral venous channels could, therefore, potentially exacerbate impaired ocular venous flow and trigger the development or worsening of glaucoma in patients with Sturge-Weber syndrome. We investigated to what extent a single application of laser therapy, which occludes only the most superficial portions of a facial PWB, might affect intraocular pressure. Pressures before and after laser treatment were measured to determine pressure difference in 15 patients receiving laser treatment. OBSERVATIONS: The greatest pressure differences were observed in patients with a PWB closest to the eye (P = .02). Posttreatment pressures were significantly decreased, relative to pretreatment pressures, only in patients with a PWB on the eyelid compared with patients with a facial PWB not near the eyes (2.33 vs 0.75 mm Hg; P = .004). No correlation was found between change in pressure and patient age, PWB size, or number of previous treatments. CONCLUSIONS: A single laser application to a PWB does not appear to show a clinically relevant change in intraocular pressure. Further study is needed longitudinally in a broad range of patients. PMID- 20855704 TI - Dermoscopic and reflectance confocal microscopic features of exogenous ochronosis. AB - BACKGROUND: Exogenous ochronosis presents as an acquired asymptomatic hyperpigmentation on photoexposed areas, predominantly over bony prominences, and is caused by the topical application of several skin-lightening agents. OBSERVATIONS: We describe a 63-year-old Hispanic woman who developed exogenous ochronosis lesions on her face after using topical bleaching creams containing hydroquinone, 2% to 3%, and oxybenzone, 2%, for several years. Dermoscopy revealed irregular brown-gray globular, annular, and arciform structures that corresponded to focal deposition of ochronotic pigment on the dermis. These deposits correlated with multiple banana-shaped nonrefractile structures seen using reflectance confocal microscopy. Histopathologic sections revealed the deposition of a banana-shaped, yellow to brown material in the papillary and middle dermis. Ultrastructural examination revealed an amorphous electron-dense material mostly located in the core of elastic fibers and also in smaller amounts in the interstitium with prominent degenerative changes in the elastic fibers. A good correlation was observed between the results of both noninvasive techniques and the diagnostic histologic features of this condition. CONCLUSIONS: We characterized by means of dermoscopy, reflectance confocal microscopy, and electronic microscopy a case of exogenous ochronosis. To our knowledge, this is the first description of reflectance confocal microscopic findings in this condition. Dermoscopy and reflectance confocal microscopy are proved to be useful noninvasive techniques for the diagnosis of this pigmentary disorder. PMID- 20855705 TI - Clinical approach to atypical wounds with a new model for understanding hypertensive ulcers. PMID- 20855706 TI - Intentional tanning: more than one hammer needed to change behavior. PMID- 20855707 TI - The electronic medical record in dermatology. AB - Governmental incentives to stimulate the "meaningful use" of electronic medical records and future disincentives for Medicaid and Medicare provide an impetus for dermatologists to consider adding this technology to their clinical practice. Dermatologists should carefully weigh the pros and cons of establishing an electronic medical record system before incorporating this expensive technology. This article reviews available scientific and economic data required for dermatologists to help make an informed choice. PMID- 20855708 TI - Erythematous patch overlying a swollen knee--quiz case. Intralymphatic histiocytosis. PMID- 20855709 TI - Acral petechiae and purpuric plaques in a 3-year-old girl--quiz case. Acute hemorrhagic edema of infancy (AHEI), or Finkelstein disease. PMID- 20855711 TI - Dome-shaped papule on the posterior shoulder--quiz case. Myxoid cutaneous pleomorphic fibroma. PMID- 20855710 TI - Skin nodules in a patient with acute myeloid leukemia and neurological deterioration--quiz case. Disseminated fusariosis. PMID- 20855712 TI - An evaluation of long-term outcomes in adults with pediatric-onset morphea. PMID- 20855713 TI - Atypical fibroxanthoma in an African American woman. PMID- 20855714 TI - Failed treatment of amelanotic lentigo maligna with imiquimod followed by pigment production. PMID- 20855715 TI - Caregiver hypersensitivity. PMID- 20855716 TI - Mondor disease in a patient with psoriasis treated with an anti-interleukin 12/interleukin 23 investigational drug. PMID- 20855717 TI - A case of generalized dermatitis neglecta mimicking psoriasis vulgaris. PMID- 20855718 TI - The band-aid sign of trichotillomania: a helpful diagnostic technique in the setting of hair loss. PMID- 20855719 TI - Thermographic Follow-up of a Mild Case of Herpes Zoster. PMID- 20855720 TI - Psoriatic skin lesions induced by certolizumab pegol. PMID- 20855721 TI - Papillary thyroid cancer: an indication for thyroid palpation by the dermatologist. PMID- 20855722 TI - "Biopsy bleb": a clue to a prior biopsy site. PMID- 20855724 TI - Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. AB - Infections caused by multidrug-resistant (MDR) Gram-negative bacteria represent a major global health problem. Polymyxin antibiotics such as colistin have resurfaced as effective last-resort antimicrobials for use against MDR Gram negative pathogens, including Acinetobacter baumannii. Here we show that A. baumannii can rapidly develop resistance to polymyxin antibiotics by complete loss of the initial binding target, the lipid A component of lipopolysaccharide (LPS), which has long been considered to be essential for the viability of Gram negative bacteria. We characterized 13 independent colistin-resistant derivatives of A. baumannii type strain ATCC 19606 and showed that all contained mutations within one of the first three genes of the lipid A biosynthesis pathway: lpxA, lpxC, and lpxD. All of these mutations resulted in the complete loss of LPS production. Furthermore, we showed that loss of LPS occurs in a colistin resistant clinical isolate of A. baumannii. This is the first report of a spontaneously occurring, lipopolysaccharide-deficient, Gram-negative bacterium. PMID- 20855726 TI - Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. AB - In order to assess the natural variation in susceptibility to hepatitis C virus (HCV) NS3 protease inhibitors (PIs) among untreated HCV patient samples, the susceptibilities of 39 baseline clinical isolates were determined using a transient-replication assay on a panel of HCV PIs, including two alpha-ketoamides (VX-950 and SCH-503034) and three macrocyclic inhibitors (MK-7009, ITMN-191, and TMC-435350). Some natural variation in susceptibility to all HCV PIs tested was observed among the baseline clinical isolates. The susceptibility to VX-950 correlated strongly with the susceptibility to SCH-503034. A moderate correlation was observed between the susceptibilities to ITMN-191 and MK-7009. In contrast, the phenotypic correlations between the alpha-ketoamides and macrocyclic inhibitors were significantly lower. This difference is partly attributable to reduced susceptibility of the HCV variants containing the NS3 polymorphism Q80K (existing in 47% of genotype 1a isolates) to the macrocyclic compounds but no change in the sensitivity of the same variants to the alpha-ketoamides tested. Our results suggest that the natural variation in baseline susceptibility may contribute to different degrees of antiviral response among patients in vivo, particularly at lower doses. PMID- 20855725 TI - Binding and action of CEM-101, a new fluoroketolide antibiotic that inhibits protein synthesis. AB - We characterized the mechanism of action and the drug-binding site of a novel ketolide, CEM-101, which belongs to the latest class of macrolide antibiotics. CEM-101 shows high affinity for the ribosomes of Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. The ketolide shows high selectivity in its inhibitory action and readily interferes with synthesis of a reporter protein in the bacterial but not eukaryotic cell-free translation system. Binding of CEM-101 to its ribosomal target site was characterized biochemically and by X-ray crystallography. The X-ray structure of CEM-101 in complex with the E. coli ribosome shows that the drug binds in the major macrolide site in the upper part of the ribosomal exit tunnel. The lactone ring of the drug forms hydrophobic interactions with the walls of the tunnel, the desosamine sugar projects toward the peptidyl transferase center and interacts with the A2058/A2509 cleft, and the extended alkyl-aryl arm of the drug is oriented down the tunnel and makes contact with a base pair formed by A752 and U2609 of the 23S rRNA. The position of the CEM-101 alkyl-aryl extended arm differs from that reported for the side chain of the ketolide telithromycin complexed with either bacterial (Deinococcus radiodurans) or archaeal (Haloarcula marismortui) large ribosomal subunits but closely matches the position of the side chain of telithromycin complexed to the E. coli ribosome. A difference in the chemical structure of the side chain of CEM-101 in comparison with the side chain of telithromycin and the presence of the fluorine atom at position 2 of the lactone ring likely account for the superior activity of CEM-101. The results of chemical probing suggest that the orientation of the CEM-101 extended side chain observed in the E. coli ribosome closely resembles its placement in Staphylococcus aureus ribosomes and thus likely accurately reflects interaction of CEM-101 with the ribosomes of the pathogenic bacterial targets of the drug. Chemical probing further demonstrated weak binding of CEM-101, but not of erythromycin, to the ribosome dimethylated at A2058 by the action of Erm methyltransferase. PMID- 20855727 TI - Safety and efficacy of moxifloxacin monotherapy for treatment of orthopedic implant-related staphylococcal infections. AB - The rifampin-ciprofloxacin combination is recommended for treatment of orthopedic implant-related staphylococcal infections to avoid the emergence of ciprofloxacin resistance; however, the efficacy of this combination is limited by the tolerability problems associated with the use of rifampin. Moxifloxacin is a quinolone up to 10 times more active against staphylococci than ciprofloxacin and the risk of resistance development during monotherapy against staphylococci is theoretically lower for moxifloxacin, but information regarding its use in bone infections is lacking. The aim of the present study was to evaluate the safety and clinical efficacy of moxifloxacin monotherapy in patients with orthopedic implant-related staphylococcal infections. From June 2006 to April 2009, all patients with culture-proven infection by quinolone-sensitive staphylococcal strains associated with orthopedic implants at our institution were included in a management protocol that mostly included specific surgery, 1 to 2 weeks of an intravenous course of cloxacillin-cefazolin or vancomycin, and long-term therapy with moxifloxacin (400 mg/day for 3 months). Cure was defined as (i) a lack of clinical signs and symptoms of infection, (ii) a C-reactive protein level less than 5 mg/liter, and (iii) absence of radiological signs of loosening or infection at the latest follow-up visit. Failure was defined as (i) persisting clinical and/or laboratory signs of infection or (ii) persisting or new isolation of the initial microorganism. A total of 48 patients with a median follow-up of 716 days (range, 102 to 1,613 days) were included in the study. Complete drug compliance was achieved in all but two patients (4.2%), who required drug discontinuation because of side effects (diarrhea and dizziness). No moxifloxacin induced arrhythmia was reported. Twenty patients had joint prosthesis infections (5 acute-onset infections and 15 chronic infections), and 28 patients had osteosynthesis material infections (4 acute-onset infections and 24 chronic infections). The etiologies were methicillin-sensitive Staphylococcus aureus in 33 patients and a coagulase-negative staphylococcus (CoNS) in 15. Surgical management was performed for the majority of patients (37/48; 77%), and the implant was retained in 21 patients (43.8%). The global cure rate was 38/46 (82.6%), and the cure rate for patients with implant retention was 15/21 (71.4%). The global cure rate for the 32 patients with a minimum follow-up of 2 years was 80%. Of the eight cases of relapse, we obtained microbiological confirmation in six cases, and all bacteria recovered were quinolone susceptible. Monotherapy with moxifloxacin seems to be an effective, safe, and easy alternative for the long-term treatment of orthopedic implant-related staphylococcal infections by quinolone-sensitive strains. Comparative studies with rifampin-containing regimens are warranted. PMID- 20855728 TI - Aziridine-2,3-dicarboxylate-based cysteine cathepsin inhibitors induce cell death in Leishmania major associated with accumulation of debris in autophagy-related lysosome-like vacuoles. AB - The papain-like cysteine cathepsins expressed by Leishmania play a key role in the life cycle of these parasites, turning them into attractive targets for the development of new drugs. We previously demonstrated that two compounds of a series of peptidomimetic aziridine-2,3-dicarboxylate [Azi(OBn)(2)]-based inhibitors, Boc-(S)-Leu-(R)-Pro-(S,S)-Azi(OBn)(2) (compound 13b) and Boc-(R)-Leu (S)-Pro-(S,S)-Azi(OBn)(2) (compound 13e), reduced the growth and viability of Leishmania major and the infection rate of macrophages while not showing cytotoxicity against host cells. In the present study, we characterized the mode of action of inhibitors 13b and 13e in L. major. Both compounds targeted leishmanial cathepsin B-like cysteine cathepsin cysteine proteinase C, as shown by fluorescence proteinase activity assays and active-site labeling with biotin tagged inhibitors. Furthermore, compounds 13b and 13e were potent inducers of cell death in promastigotes, characterized by cell shrinkage, reduction of mitochondrial transmembrane potential, and increased DNA fragmentation. Transmission electron microscopic studies revealed the enrichment of undigested debris in lysosome-like organelles participating in micro- and macroautophagy like processes. The release of digestive enzymes into the cytoplasm after rupture of membranes of lysosome-like vacuoles resulted in the significant digestion of intracellular compartments. However, the plasma membrane integrity of compound treated promastigotes was maintained for several hours. Taken together, our results suggest that the induction of cell death in Leishmania by cysteine cathepsin inhibitors 13b and 13e is different from mammalian apoptosis and is caused by incomplete digestion in autophagy-related lysosome-like vacuoles. PMID- 20855729 TI - In vitro antifungal susceptibilities and amplified fragment length polymorphism genotyping of a worldwide collection of 350 clinical, veterinary, and environmental Cryptococcus gattii isolates. AB - The in vitro susceptibilities of a worldwide collection of 350 Cryptococcus gattii isolates to seven antifungal drugs, including the new triazole isavuconazole, were tested. With amplified fragment length polymorphism (AFLP) fingerprinting, human, veterinary, and environmental C. gattii isolates were subdivided into seven AFLP genotypes, including the interspecies hybrids AFLP8 and AFLP9. The majority of clinical isolates (n = 215) comprised genotypes AFLP4 (n = 76) and AFLP6 (n = 103). The clinical AFLP6 isolates had significantly higher geometric mean MICs for flucytosine and fluconazole than the clinical AFLP4 isolates. Of the seven antifungal compounds examined in this study, isavuconazole had the lowest MIC(90) (0.125 MUg/ml) for all C. gattii isolates, followed by a 1 log(2) dilution step increase (MIC(90), 0.25 MUg/ml) for itraconazole, voriconazole, and posaconazole. Amphotericin B had an acceptable MIC(90) of 0.5 MUg/ml, but fluconazole and flucytosine had relatively high MIC(90)s of 8 MUg/ml. PMID- 20855730 TI - In vitro and in vivo activities of LCB01-0371, a new oxazolidinone. AB - LCB01-0371 is a new oxazolidinone with cyclic amidrazone. In vitro activity of LCB01-0371 against 624 clinical isolates was evaluated and compared with those of linezolid, vancomycin, and other antibiotics. LCB01-0371 showed good activity against Gram-positive pathogens. In vivo activity of LCB01-0371 against systemic infections in mice was also evaluated. LCB01-0371 was more active than linezolid against these systemic infections. LCB01-0371 showed bacteriostatic activity against Staphylococcus aureus. PMID- 20855731 TI - Strong in vitro activities of two new rifabutin analogs against multidrug resistant Mycobacterium tuberculosis. AB - Two new rifabutin analogs, RFA-1 and RFA-2, show high in vitro antimycobacterial activities against Mycobacterium tuberculosis. MIC values of RFA-1 and RFA-2 were <=0.02 MUg/ml against rifamycin-susceptible strains and 0.5 MUg/ml against a wide selection of multidrug-resistant strains, compared to >=50 MUg/ml for rifampin and 10 MUg/ml for rifabutin. Molecular dynamic studies indicate that the compounds may exert tighter binding to mutants of RNA polymerase that have adapted to the rifamycins. PMID- 20855733 TI - Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors. AB - Adverse effects have limited the clinical use of telithromycin. Preferential inhibition of the nicotinic acetylcholine receptors (nAChR) at the neuromuscular junction (alpha3beta2 and NMJ), the ciliary ganglion of the eye (alpha3beta4 and alpha7), and the vagus nerve innervating the liver (alpha7) could account for the exacerbation of myasthenia gravis, the visual disturbance, and the liver failure seen with telithromycin use. The studies presented here enable the prediction of expected side effects of macrolides in development, such as solithromycin (CEM 101). PMID- 20855732 TI - Therapeutic potential of a combination of two gene-specific small interfering RNAs against clinical strains of Acanthamoeba. AB - Pathogenic strains of the genus Acanthamoeba are causative agents of severe infections, such as fatal encephalitis and a sight-threatening amoebic keratitis. Antimicrobial therapy for these infections is generally empirical, and patient recovery is often problematic, due to the existence of a highly resistant cyst stage in these amoebae. In previous studies, small interfering RNAs (siRNAs) against the catalytic domains of extracellular serine proteases and glycogen phosphorylase from Acanthamoeba were designed and evaluated for future therapeutic use. The silencing of proteases resulted in Acanthamoeba failing to degrade human corneal cells, and silencing of glycogen phosphorylase caused amoebae to be unable to form mature cysts. After the siRNA design and concentration were optimized in order to avoid toxicity problems, cultures of Acanthamoeba were treated with a combination of both siRNAs, and cells were evaluated under an inverted microscope. This siRNA-based treatment dramatically affected the growth rate and cellular survival of the amoebae. These results were observed less than 48 h after the initiation of the treatment. In order to check possible toxic effects of the siRNA combination, three eukaryotic cell lines (HeLa, murine macrophages, and osteosarcoma cells) were treated with the same molecules, and cytotoxicity was examined by measuring lactate dehydrogenase release. The future use of the combination of these siRNAs is proposed as a potential therapeutic approach against pathogenic strains of Acanthamoeba. PMID- 20855734 TI - Gene therapeutic approach for inhibiting hepatitis C virus replication using a recombinant protein that controls interferon expression. AB - The hepatitis C virus (HCV) is a continuing threat to public health. The systemic administration of interferon alpha with ribavirin is the only currently approved treatment. However, this treatment is associated with a wide spectrum of systemic side effects that limits its effectiveness; thus, there is an urgent need for new treatment modalities. In this study, we describe a novel anti-HCV strategy employing a recombinant transcription factor that we have engineered in such a way that NS3/4a viral protease controls its intracellular localization, thereby restoring interferon secretion specifically in cells infected with HCV. Proof-of concept experiments validated the strategy, showing that the recombinant transcription factor was triggered to stimulate interferon promoter by NS3/4A and remained inactive in cells without NS3/4a. Using an adenovirus-associated viral vector delivery system, we found that the recombinant transcription factor inhibited HCV replication effectively in vitro in cultured cells. PMID- 20855736 TI - In vivo pharmacodynamics of new lipopeptide MX-2401. AB - MX-2401 is a novel lipopeptide (amphomycin analog) with a broad-spectrum bactericidal activity against Gram-positive organisms. We used murine thigh and lung infection models in neutropenic and normal mice to characterize the in vivo pharmacokinetic/pharmacodynamic (PK/PD) activities of MX-2401. The compound (2.5 to 40 mg/kg of body weight) demonstrated linear PK characterized by an area under the concentration-time curve (AUC) of 228 to 3,265 MUg.h/ml and half-lives of 5.7 to 8.8 h. MICs ranged from 0.25 to 2 MUg/ml. The in vivo postantibiotic effect was prolonged (8.5 h with Staphylococcus aureus and 10.3 to 12.3 with Streptococcus pneumoniae). MX-2401 exhibited dose-dependent in vivo activity against various strains of S. pneumoniae and S. aureus; penicillin and macrolide resistance in the pneumococci and methicillin resistance in the staphylococci had no impact on the antimicrobial activity of the drug. To determine which PK/PD index correlated best with MX-2401 activity, dose fractionation studies over a 72 hour period were performed. The maximum concentration of drug in serum divided by the MIC (C(max)/MIC) correlated best with the efficacy for both S. aureus and S. pneumoniae. Static doses required free-drug C(max)/MIC values of 0.683 to 1.06. Free-drug 72-h AUC/MIC values for the static dose were in the range of 7.49 to 32.3 and were less than expected. The drug showed modest enhancement in activity in the presence of white blood cells (1.7- to 3.4-fold). The potency of the drug in the lung was only marginally lower than in the thigh (1.3- to 1.9-fold). Based on its PK/PD profile, MX-2401 appears to be a promising new lipopeptide agent for treatment of infections by Gram-positive bacteria, including those induced by antibiotic-resistant pathogens. PMID- 20855735 TI - Cadaverine suppresses persistence to carboxypenicillins in Pseudomonas aeruginosa PAO1. AB - The refractory nature of Pseudomonas aeruginosa infections is due in part to the presence of specialized cells, termed persisters, within the population. To identify genes involved in P. aeruginosa persister formation, a PAO1 transposon (Tn) library was challenged en masse with 1,000 MUg/ml of carbenicillin and was enriched for mutants that were able to survive in the presence of this antibiotic. For one mutant that was further characterized, the carbenicillin MIC was equal to that of PAO1, but persister formation exhibited a 20-fold increase after exposure to the antibiotic. Sequence analysis revealed that the Tn had inserted into PA4115, a gene encoding a putative lysine decarboxylase. A PA4115 mutant that produced 48-fold and 20-fold more survivors than PAO1 after 10-h exposures to carbenicillin and ticarcillin, respectively, was generated by allelic exchange. Furthermore, the rate of carboxypenicillin-induced lysis was reduced in the PA4115 mutant. Under certain pH conditions, lysine decarboxylase converts lysine to cadaverine. By measuring cadaverine production, we discovered that the PA4115 mutant had significantly reduced lysine decarboxylase activity. To determine if reduced cadaverine levels are responsible for the increase in carbenicillin and ticarcillin persistence, viability and lysis assays were performed in the presence of exogenous cadaverine. Cadaverine increased the rate of killing and lysis of the PA4115 mutant in the presence of both antibiotics. These findings suggest that cadaverine may be able to enhance the effectiveness of carboxypenicillins against P. aeruginosa by reducing persister formation. PMID- 20855737 TI - Impact of silver-containing wound dressings on bacterial biofilm viability and susceptibility to antibiotics during prolonged treatment. AB - The long-term antimicrobial efficacy of silver dressings against bacterial biofilms was investigated in a 7-day treatment in vitro model where the protein rich medium was refreshed daily in order to mimic the conditions found in a wound bed. The use of plate-to-plate transfer assays demonstrated measurable differences in the effectiveness of several silver dressings on the viability of biofilm bacteria and their susceptibility to antibiotics. Whereas after the first day of treatment, all dressings used resulted in a significant reduction in the number of viable cells in the biofilms and disruption of the biofilm colonies, during prolonged treatment, the efficacy of dressings with hydrophilic base materials diminished with daily transfers, and bacterial populations recovered. For dressings with hydrophobic base materials, the level of efficacy correlated with the silver species loaded. Biofilm bacteria, which survived the initial silver treatment, were susceptible to tobramycin, ciprofloxacin, and trimethoprim sulfamethoxazole, in contrast to untreated biofilms, which were highly tolerant to the same antibiotics. This acquired susceptibility was unaffected by the longevity of pretreatment with the silver dressings but depended on the dressing used. The antimicrobial efficacy of the dressings correlated with the type of the dressing base material and silver species loaded. PMID- 20855738 TI - Effect of N-1/c-8 ring fusion and C-7 ring structure on fluoroquinolone lethality. AB - Quinolones rapidly kill bacteria by two mechanisms, one that requires protein synthesis and one that does not. The latter, which is measured as lethal action in the presence of the protein synthesis inhibitor chloramphenicol, is enhanced by N-1 cyclopropyl and C-8 methoxy substituents, as seen with the highly lethal compound PD161144. In some compounds, such as levofloxacin, the N-1 and C-8 substituents are fused. To assess the effect of ring fusion on killing, structural derivatives of levofloxacin and PD161144 differing at C-7 were synthesized and examined with Escherichia coli. A fused-ring derivative of PD161144 exhibited a striking absence of lethal activity in the presence of chloramphenicol. In general, ring fusion had little effect on lethal activity when protein synthesis was allowed, but fusion reduced lethal activity in the absence of protein synthesis to extents that depended on the C-7 ring structure. Additional fused-ring fluoroquinolones, pazufloxacin, marbofloxacin, and rufloxacin, also exhibited reduced activity in the presence of chloramphenicol. Energy minimization modeling revealed that steric interactions of the trans oriented N-1 cyclopropyl and C-8 methoxy moieties skew the quinolone core, rigidly orient these groups perpendicular to core rings, and restrict the rotational freedom of C-7 rings. These features were not observed with fused-ring derivatives. Remarkably, structural effects on quinolone lethality were not explained by the recently described X-ray crystal structures of fluoroquinolone topoisomerase IV-DNA complexes, suggesting the existence of an additional drug binding state. PMID- 20855740 TI - Residual attributable mortality, a new concept for understanding the value of antibiotics in treating life-threatening acute infections. PMID- 20855739 TI - Multiplex ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification in human plasma of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, anidulafungin, and caspofungin. AB - Therapeutic drug monitoring (TDM) may contribute to optimizing the efficacy and safety of antifungal therapy because of the large variability in drug pharmacokinetics. Rapid, sensitive, and selective laboratory methods are needed for efficient TDM. Quantification of several antifungals in a single analytical run may best fulfill these requirements. We therefore developed a multiplex ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method requiring 100 MUl of plasma for simultaneous quantification within 7 min of fluconazole, itraconazole, hydroxyitraconazole, posaconazole, voriconazole, voriconazole-N-oxide, caspofungin, and anidulafungin. Protein precipitation with acetonitrile was used in a single extraction procedure for eight analytes. After reverse-phase chromatographic separation, antifungals were quantified by electrospray ionization-triple-quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. Deuterated isotopic compounds of azole antifungals were used as internal standards. The method was validated based on FDA recommendations, including assessment of extraction yields, matrix effect variability (<9.2%), and analytical recovery (80.1 to 107%). The method is sensitive (lower limits of azole quantification, 0.01 to 0.1 MUg/ml; those of echinocandin quantification, 0.06 to 0.1 MUg/ml), accurate (intra- and interassay biases of -9.9 to +5% and -4.0 to +8.8%, respectively), and precise (intra- and interassay coefficients of variation of 1.2 to 11.1% and 1.2 to 8.9%, respectively) over clinical concentration ranges (upper limits of quantification, 5 to 50 MUg/ml). Thus, we developed a simple, rapid, and robust multiplex UPLC MS/MS assay for simultaneous quantification of plasma concentrations of six antifungals and two metabolites. This offers, by optimized and cost-effective lab resource utilization, an efficient tool for daily routine TDM aimed at maximizing the real-time efficacy and safety of different recommended single-drug antifungal regimens and combination salvage therapies, as well as a tool for clinical research. PMID- 20855741 TI - In vitro sensitivity and resistance of 46 Leptospira strains isolated from rats in the Philippines to 14 antimicrobial agents. AB - The in vitro susceptibilities of 46 Leptospira isolates from rats to 14 antimicrobial agents were tested. All of the strains were found to be sensitive to ampicillin, cefotaxime, ciprofloxacin, norfloxacin, doxycycline, erythromycin, and streptomycin. In contrast, the tested isolates showed resistance to amphotericin B, 5-fluorouracil, fosfomycin, trimethoprim, sulfamethoxazole, neomycin, and vancomycin. These findings will help in selecting effective and ineffective antimicrobials for treatment of leptospirosis and for the development of new selective media, respectively. PMID- 20855743 TI - Ethidium bromide MIC screening for enhanced efflux pump gene expression or efflux activity in Staphylococcus aureus. AB - Multidrug resistance efflux pumps contribute to antimicrobial and biocide resistance in Staphylococcus aureus. The detection of strains capable of efflux is time-consuming and labor-intensive using currently available techniques. A simple and inexpensive method to identify such strains is needed. Ethidium bromide is a substrate for all but one of the characterized S. aureus multidrug resistant (MDR) efflux pumps (NorC), leading us to examine the utility of simple broth microtiter MIC determinations using this compound in identifying efflux proficient strains. Quantitative reverse transcription-PCR identified the increased expression of one or more MDR efflux pump genes in 151/309 clinical strains (49%). Ethidium bromide MIC testing was insensitive (48%) but specific (92%) in identifying strains with gene overexpression, but it was highly sensitive (95%) and specific (99%) in identifying strains capable of ethidium efflux. The increased expression of norA with or without other genes was most commonly associated with efflux, and in the majority of cases that efflux was inhibited by reserpine. Ethidium bromide MIC testing is a simple and straightforward method to identify effluxing strains and can provide accurate predictions of efflux prevalence in large strain sets in a short period of time. PMID- 20855742 TI - Microbiologic and clinical implications of bacteremia due to extended-spectrum beta-lactamase-producing Klebsiella pneumoniae with or without plasmid-mediated AmpC beta-lactamase DHA-1. AB - Bacteremias caused by Klebsiella pneumoniae producing extended-spectrum beta lactamase (ESBL-KP; n = 52) and producing both ESBL and AmpC-type DHA-1 beta lactamase (ESBL-PMABL-KP; n = 20) were analyzed. Higher MIC(50)s and MIC(90)s for carbapenems, ciprofloxacin, and piperacillin-tazobactam were observed with ESBL PMABL-KP than with ESBL-KP. Patients with oxyimino-beta-lactam exposure and high modified Pitt bacteremia scores (HMPBSs) were at higher risk, while those with piperacillin-tazobactam and aminoglycoside exposure were at lower risk for ESBL KP bacteremia. Patients with fluoroquinolone exposure, diabetes mellitus, and HMPBS were at higher risk, while those with aminoglycoside exposure were at lower risk, for ESBL-PMABL-KP bacteremia. PMID- 20855744 TI - In vitro activities of several antimicrobial agents against recently isolated and genotyped Chlamydia trachomatis urogenital serovars D through K. AB - A systematic evaluation of the susceptibility of all Chlamydia trachomatis urogenital serovars (D through K) to levofloxacin, erythromycin, doxycycline, clarithromycin, and azithromycin was performed. All C. trachomatis serovars had comparable susceptibilities with respect to the various antimicrobials tested, thus confirming the homogeneous data so far obtained regarding the susceptibility of C. trachomatis to antimicrobial agents. PMID- 20855745 TI - LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. AB - A multidrug efflux pump designated LmrS (lincomycin resistance protein of Staphylococcus aureus), belonging to the major facilitator superfamily (MFS) of transporters, was cloned, and the role of LmrS in antimicrobial efflux was evaluated. The highest relative increase in MIC, 16-fold, was observed for linezolid and tetraphenylphosphonium chloride (TPCL), followed by an 8-fold increase for sodium dodecyl sulfate (SDS), trimethoprim, and chloramphenicol. LmrS has 14 predicted membrane-spanning domains and is homologous to putative lincomycin resistance proteins of Bacillus spp., Lactobacillus spp., and Listeria spp. PMID- 20855746 TI - Fusidic acid resistance determinants in Staphylococcus aureus clinical isolates. AB - A total of 71 fusidic acid-resistant Staphylococcus aureus (45 methicillin resistant and 26 methicillin-susceptible) isolates were examined for the presence of resistance determinants. Among 45 fusidic acid-resistant methicillin-resistant S. aureus (MRSA), isolates, 38 (84%) had fusA mutations conferring high-level resistance to fusidic acid (the MIC was >=128 MUg/ml for 22/38), none had fusB, and 7 (16%) had fusC. For 26 fusidic acid-resistant methicillin-susceptible S. aureus (MSSA), only 3 possessed fusA mutations, but 15 (58%) had fusB and 8 (31%) had fusC. Low-level resistance to fusidic acid (MICs <= 32 MUg/ml) was found in most fusB- or fusC-positive isolates. For 41 isolates (38 MRSA and 3 MSSA), with fusA mutations, a total of 21 amino acid substitutions in EF-G (fusA gene) were detected, of which R76C, E444K, E444V, C473S, P478S, and M651I were identified for the first time. The nucleotide sequencing of fusB and flanking regions in an MSSA isolate revealed the structure of partial IS257-aj1-LP-fusB-aj2-aj3-IS257 partial blaZ, which is identical to the corresponding region in pUB101, and the rest of fusB-carrying MSSA isolates also show similar structures. On the basis of spa and staphylococcal cassette chromosome mec element (SCCmec) typing, two major genotypes, spa type t037-SCCmec type III (t037-III; 28/45; 62%) and t002-II (13/45; 29%), were predominant among 45 MRSA isolates. By pulsed-field gel electrophoresis analysis, 45 MRSA isolates were divided into 12 clusters, while 26 MSSA isolates were divided into 15 clusters. Taken together, the distribution of fusidic acid resistance determinants (fusA mutations, fusB, and fusC) was quite different between MRSA and MSSA groups. PMID- 20855747 TI - Differential Aspergillus lentulus echinocandin susceptibilities are Fksp independent. AB - The recently described species Aspergillus lentulus exhibits differential and reduced susceptibilities to echinocandins and other antifungal drugs in vitro. A. lentulus isolates overall are less susceptible to caspofungin, although they maintain susceptibility to anidulafungin and micafungin. Mutations or polymorphisms in fks, the gene encoding the catalytic subunit of beta-1,3-glucan synthase, are known to confer decreased susceptibility to echinocandins in Candida spp. and Aspergillus fumigatus. The analysis of the A. lentulus fks sequence did not reveal a polymorphism at any of the known hot-spot regions of the gene. Caspofungin and micafungin kinetic inhibition profiles of the A. lentulus glucan synthase were comparable to those from susceptible A. fumigatus enzymes. Although the basal cell wall chitin levels in A. lentulus averaged 60% of those in A. fumigatus, echinocandin treatment promoted the increase of cell wall chitin in both organisms, indicating that A. lentulus displays a compensatory chitin response similar to that of A. fumigatus. The data suggest that differential echinocandin susceptibilities in A. lentulus are independent of the echinocandin target, Fksp, and they emphasize the potential that the drugs' capacity to inhibit the target enzyme is unequal at the cellular level. PMID- 20855749 TI - Extralevator abdominoperineal resection for low rectal cancer: new direction or miles behind? PMID- 20855748 TI - Mitochondrial electron transport inhibition and viability of intraerythrocytic Plasmodium falciparum. AB - Although mitochondrial electron transport is a validated target of the antimalarial drug atovaquone, the molecular details underlying parasite demise are unclear. We have shown that a critical function of mitochondrial electron transport in blood-stage Plasmodium falciparum is to support pyrimidine biosynthesis. Here, we explore the effects of atovaquone, alone and in combination with proguanil, on P. falciparum viability. Our results suggest that the effects of inhibition depend upon the erythrocytic stage of the parasites and the duration of exposure. Ring- and schizont-stage parasites are most resilient to drug treatment and can survive for 48 h, with a fraction remaining viable even after 96 h. Survival of parasites does not appear to require nutrient uptake. Thus, intraerythrocytic parasites with inhibited mitochondrial electron transport and collapsed mitochondrial membrane potential do not undergo apoptosis but enter an apparent static state. These results have significant implications for desirable properties of antimalarials under development that target mitochondrial functions. PMID- 20855750 TI - Safety and efficacy of video-assisted retroperitoneal debridement for infected pancreatic collections: a multicenter, prospective, single-arm phase 2 study. AB - BACKGROUND: The feasibility of video-assisted retroperitoneal debridement (VARD) for infected pancreatic walled-off necrosis is established. We provide prospective data on the safety and efficacy of VARD. DESIGN: Multicenter, prospective, single-arm phase 2 study. SETTING: Six academic medical centers. PATIENTS: We evaluated 40 patients with pancreatic necrosis who had infection determined using Gram stain or culture. INTERVENTIONS: Percutaneous drains were placed at enrollment, and computed tomographic scans were repeated at 10 days. Patients who had more than a 75% reduction in collection size were treated with drains. Other patients were treated with VARD. Crossover to open surgery was performed for technical reasons and/or according to surgeon judgment. MAIN OUTCOME MEASURES: Efficacy (ie, successful VARD treatment without crossover to open surgery or death) and safety (based on mortality and complication rates). Patients received follow-up care for 6 months. RESULTS: We enrolled 40 patients (24 men and 16 women) during a 51-month period. Median age was 53 years (range, 32-82 years). Mean (SD) Acute Physiology and Chronic Health Evaluation II score at enrollment was 8.0 (5.1), and median computed tomography severity index score was 8. Of the 40 patients, 24 (60%) were treated with minimally invasive intervention (drains with or without VARD). Nine patients (23%) did not require surgery (drains only). For 31 surgical patients, VARD was possible in 60% of patients. Most patients (81%) required 1 operation. In-hospital 30-day mortality was 2.5% (intent-to-treat). Bleeding complications occurred in 7.5% of patients; enteric fistulas occurred in 17.5%. CONCLUSIONS: This prospective cohort study supports the safety and efficacy of VARD for infected pancreatic walled-off necrosis. Of the patients, 85% were eligible for a minimally invasive approach. We were able to use VARD in 60% of surgical patients. The low mortality and complication rates compare favorably with open debridement. An unexpected finding was that a reduction in collection size of 75% according to the results of computed tomographic scans at 10 to 14 days predicted the success of percutaneous drainage alone. PMID- 20855751 TI - Preoperative tattooing and improved lymph node retrieval rates from colectomy specimens in patients with colorectal cancers. AB - HYPOTHESIS: India ink tattooing at the time of colonoscopy increases the yield of lymph nodes found in pathological analysis of colectomy specimens. DESIGN: Retrospective study. SETTING: Virginia Mason Medical Center, Seattle, Washington. PATIENTS: Two hundred nine patients with colorectal cancers underwent surgical resections between April 5, 2006, and June 25, 2009, at one institution. MAIN OUTCOME MEASURES: A retrospective review of a prospectively collected database was performed, with review of pathology reports for all cases. Adequate lymph node analysis was defined as evaluation of at least 12 lymph nodes. RESULTS: Of 209 patients undergoing resections, 174 had colonic neoplasms, and 35 had rectal neoplasms. Sixty-two of 174 patients with colon cancer had India ink tattooing at the time of colonoscopy. The mean (range) numbers of lymph nodes examined in tattooed and nontattooed specimens were 23 (7-77) and 19 (2-74), respectively (P = .03). At least 12 lymph nodes were analyzed for 87.1% of the tattooed specimens compared with 72.3% of the nontattooed specimens (P = .02). Eight of 35 patients with rectal cancer had India ink tattooing at the time of colonoscopy. Fifty-four percent of patients with rectal cancer had undergone neoadjuvant chemoradiotherapy. The median numbers of lymph nodes examined in tattooed and nontattooed specimens were 19 and 16, respectively. CONCLUSIONS: Tattooing of colonic lesions at the time of preoperative colonoscopy seems to increase the quality of lymph node analysis. We advocate routine tattooing of all suspicious neoplasms at the time of colonoscopy. PMID- 20855752 TI - Late outcomes of endovascular and open revascularization for nonatherosclerotic renal artery disease. AB - OBJECTIVE: To evaluate the long-term outcome of endovascular and open treatment for nonatherosclerotic renal artery disease (NARAD). DESIGN: Retrospective review. SETTING: Academic institution. PATIENTS: Fifty-five patients (47 women; mean age, 40 years) with NARAD. Underlying disease included Takayasu arteritis in 31 and fibromuscular dysplasia in 24. INTERVENTIONS: Open revascularization and renal artery percutaneous transluminal angioplasty with or without stenting. MAIN OUTCOME MEASURES: Primary, primary assisted, and secondary patency rates; blood pressure; antihypertensive medication requirements; renal function; and mortality. RESULTS: Seventy-nine renal interventions were performed, including 59 aortorenal bypass (16 ex vivo), 3 visceral-renal bypass, 12 endovascular (8 percutaneous transluminal angioplasty and 4 stent placements) procedures, and 5 nephrectomies. There were no in-hospital deaths. During a mean follow-up of 75 months, 1-, 3-, and 5-year primary patency rates for any intervention were 87%, 75%, and 75%, respectively; primary assisted/secondary patency rates were 92%, 86%, and 86%, respectively. Endovascular interventions at 1, 3, and 5 years had primary patency rates of 73%, 49%, and 49%, respectively, and primary assisted/secondary patency rates of 83%, 83%, and 83%, respectively. For open revascularization, 1-, 3-, and 5-year primary patency rates were 91%, 80%, and 80%, respectively; primary assisted/secondary patency rates were 94%, 87%, and 87%, respectively. For both interventions, blood pressure and the number of antihypertensives used were reduced compared with preintervention values (all P < .05). Serum creatinine level and estimated glomerular filtration rate were also improved after revascularization (both P < .05). There were 6 deaths. Five- and 10-year actuarial survival rates were 94% and 78%, respectively. CONCLUSIONS: Endovascular and open management of NARAD confers long-term benefit for blood pressure, renal function, renal artery/graft patency, and survival. Open revascularization results in superior 1- and 5-year outcomes compared with endovascular management and provides the most durable outcome for NARAD. PMID- 20855753 TI - Prediction of the adequacy of lymph node retrieval in colon cancer by hospital type. AB - BACKGROUND: Examination of 12 or more regional lymph nodes (LNs) is the accepted minimum for nodal staging in colon cancer and serves as a surrogate for adequate resection. OBJECTIVE: To determine the contributing role of the hospital in the number of LNs retrieved. Design/ SETTING: We retrospectively reviewed colon resections in 83 patients by 2 surgical oncologists at a National Comprehensive Cancer Network (NCCN) hospital or at community-based hospitals from January 1, 2002, through December 31, 2007. PATIENTS: We included all patients undergoing colectomy for primary colon cancer and excluded patients with recurrence, rectal cancer, or preoperative chemotherapy. MAIN OUTCOME MEASURES: Total number of LNs retrieved. We also analyzed clinical factors accounting for differences. RESULTS: The median number of LNs examined at the NCCN hospital (42 patients) vs the community hospitals (41 patients) were 17.8 vs 7.0 (P < .001), and the frequency of an inadequate number of LNs examined (<12) was 11 of 42 cases (26%) vs 35 of 41 cases (85%) (P < .001). Potential predictive factors for LNs retrieved were grouped into modifiable (hospital type, surgeon, and surgical approach [laparoscopic vs open]) and nonmodifiable (age, sex, and tumor location). On multivariate analysis of the factors, hospital type was the only modifiable factor predictive of LNs reported (P < .001). CONCLUSIONS: Our study is the first, to our knowledge, to demonstrate that the number of LNs removed in colectomies performed by the same 2 surgeons depends on the hospital type (NCCN vs community) in which the resection occurred. We postulate that the number of LNs retrieved may be related to the institution's pathological review in addition to the extent of surgical resection. PMID- 20855754 TI - A new and simplified technique for laparoscopic gastric bypass in a residency training program: decreased resource utilization and enhanced training. AB - BACKGROUND: Laparoscopic gastric bypass (LGB) is an advanced complex procedure. Teaching programs must balance resident training and participation with resource utilization, patient safety, and outcomes. We prospectively studied a new simplified LGB technique (S-LGB) in a residency training program. DESIGN: Prospective observational study. SETTING: Academic bariatric program. PATIENTS: All patients undergoing S-LGB during 17 months. INTERVENTIONS: Clinical data collection and surgeon survey. MAIN OUTCOME MEASURES: Resource utilization, patient outcomes, and resident/staff satisfaction. RESULTS: There were 140 S-LGB operations performed by 4 staff members, all with postgraduate year 2 through 5 residents. There were no major intraoperative complications and no anastomotic leaks or deaths. Mean operative time for cases with no concurrent procedures was 91 minutes, with no intraoperative transfusions and 1 conversion to an open procedure. Compared with our standard technique, operative times with simple S LGB decreased by an average of 56% for all staff (range, 45%-60%; P < .01). Lower postgraduate year level increased operative times with the standard technique but not with S-LGB. The anastomotic stricture rate decreased from 10.0% to 3.6% (P = .02). The mean excess body weight lost at 3, 6, and 12 months was 42%, 55%, and 87%, respectively. All staff surgeons preferred the S-LGB technique for technical difficulty, speed, safety, and ability to teach residents. Residents scored the S LGB significantly better than our standard technique for difficulty, learning curve, and overall satisfaction (all P < .05). CONCLUSION: Introduction of S-LGB has resulted in excellent outcomes and significant reductions in resource utilization while enhancing opportunities for resident teaching and full participation. PMID- 20855755 TI - Predicting performance on the American Board of Surgery qualifying and certifying examinations: a multi-institutional study. AB - BACKGROUND: We sought to determine whether US Medical Licensing Examination (USMLE) Step 1 score, American Board of Surgery (ABS) In-Training Examination (ABSITE) score, and other variables are associated with failing the ABS qualifying and certifying examinations. Identifying such factors may assist in the early implementation of an academic intervention for at-risk residents. DESIGN: Retrospective review. SETTING: Seventeen general surgery training programs in the western United States. PARTICIPANTS: Six hundred seven residents who graduated in 2000-2007. MAIN OUTCOME MEASURES: First-time pass rates on the qualifying and certifying examinations, US vs non-US medical school graduation, USMLE Steps 1 and 2 scores, ABSITE scores, operative case volume, fellowship training, residency program type, and mandatory research. RESULTS: The first-time qualifying and certifying examination pass rates for the 607 graduating residents were 78% and 74%, respectively. On multivariable analysis, scoring below the 35th percentile on the ABSITE at any time during residency was associated with an increased risk of failing both examinations (odds ratio, 0.23 [95% confidence interval, 0.08-0.68] for the qualifying examination and 0.35 [0.20-0.61] for the certifying examination), as was scoring less than 200 on the USMLE Step 1 (0.36 [0.21-0.62] for the qualifying examination and 0.62 [0.42-0.93] for the certifying examination). A mandatory research year was associated with an increased likelihood of passing the certifying examination (odds ratio, 3.3 [95% confidence interval, 1.6-6.8]). CONCLUSIONS: Residents who are more likely to fail the ABS qualifying and certifying examinations can be identified by a low USMLE Step 1 score and by poor performance on the ABSITE at any time during residency. These findings support the use of the USMLE Step 1 score in the surgical residency selection process and a formal academic intervention for residents who perform poorly on the ABSITE. PMID- 20855756 TI - Postoperative hyperglycemia and surgical site infection in general surgery patients. AB - HYPOTHESIS: Postoperative hyperglycemia is an independent risk factor for postoperative surgical site infection (SSI). DESIGN: Retrospective medical record review. SETTING: Academic tertiary referral center. PATIENTS: A total of 2090 general and vascular surgery patients in an institutional quality improvement database between November 1, 2006, and April 30, 2009. MAIN OUTCOME MEASURE: Postoperative SSI. RESULTS: Postoperative glucose levels were available for 1561 patients (74.7.0%), of which 803 (51.4%) were obtained within 12 hours of surgery. The significant univariate predictors of SSI in general surgery patients were increasing age, emergency status, American Society of Anesthesiologists physical status classes P3 to P5, operative time, more than 2 U of red blood cells transfused, preoperative glucose level higher than 180 mg/dL (to convert to millimoles per liter, multiply by 0.0555), diabetes mellitus, and postoperative hyperglycemia. On multivariate adjustment, increasing age, emergency status, American Society of Anesthesiologists classes P3 to P5, operative time, and diabetes remained significant predictors of SSI for general surgery patients. After adjustment for postoperative glucose level, all these variables ceased to be significant predictors of SSI; only incremental postoperative glucose level remained significant. Subanalysis revealed that a serum glucose level higher than 140 mg/dL was the only significant predictor of SSI (odds ratio, 3.2; 95% confidence interval [CI], 1.4-7.2) for colorectal surgery patients. Vascular surgery patients were 1.8 times (95% CI, 1.3-2.5 times) more likely to develop SSI than were general surgery patients. Operative time and diabetes mellitus were the only significant univariate predictors of SSI among vascular surgery patients, and postoperative hyperglycemia was not associated with SSI. CONCLUSIONS: Postoperative hyperglycemia may be the most important risk factor for SSI. Aggressive early postoperative glycemic control should reduce the incidence of SSI. PMID- 20855757 TI - Operative reports: form and function. AB - HYPOTHESIS: Little is known about how closely operative reports reflect what was actually performed during an operation, nor has the construction of operative reports been adequately studied with the aims of clarifying the objectives of those reports and improving their efficacy. We hypothesized that if more attention is paid to the objectives of operative reports, their content will more predictably contain the most relevant information, which might channel thinking in beneficial directions during performance of the operation. DESIGN: Multivariate analysis of 250 laparoscopic cholecystectomy operative reports (125 uncomplicated and 125 with bile duct injury). SETTING: Academic research. PARTICIPANTS: University (105 cases) and community (145 cases) hospitals. MAIN OUTCOME MEASURES: Variations in content and design of operative reports. Cognitive task analysis of laparoscopic cholecystectomy was conducted, and a model operative report was generated and compared with the actual operative reports. RESULTS: Descriptions of key elements in adequate dissection of the Calot triangle were present in 24.8% and 0.0% of operative reports from uncomplicated and bile duct injury cases, respectively. Thorough dissection of the Calot triangle, identification of the cystic duct-infundibulum junction, and lateral retraction of the infundibulum correlated with uncomplicated cases, while irregular cues (eg, perceived anatomic or other deviations) correlated with bile duct injury cases. CONCLUSIONS: Current practice generates operative reports that vary widely in content and too often omit important elements. This research suggests that the construction of operative reports should be constrained such that the reports routinely include the fundamental goals of the operation and what was performed to meet them. Cognitive task analysis is based on the ways the mind controls the performance of tasks; it is an excellent method for determining the extra content needed in operative reports. The resulting designs should also serve as mental guidelines to facilitate learning and to enhance the safety of the operation. PMID- 20855758 TI - Using complications associated with postmastectomy radiation and immediate breast reconstruction to improve surgical decision making. AB - OBJECTIVES: To identify factors independently associated with surgical complications in oncologic and reconstructive surgery and to examine sentinel lymph node (SLN) biopsy data, along with variables that are typically known prior to definitive resection, for their ability to impact the prediction of need for postmastectomy irradiation (PMRT). DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Mastectomy patients with stage I to III breast cancer treated in 2000 to 2008. MAIN OUTCOME MEASURES: Complication rates of oncologic and reconstructive surgery requiring reoperation and clinicopathologic variables that independently predict complications and/or PMRT administration by multivariate analysis. RESULTS: Among 100 of 302 mastectomy patients who underwent PMRT, complications occurred in 44% who underwent immediate breast reconstruction (IBR) and 7% who did not (P < .001). Postmastectomy irradiation independently predicted the occurrence of a complication (odds ratio, 3.3; P < .001). Implants were removed in 31% of patients who underwent PMRT and 6% of patients who did not (P = .005). Three percent of patients with T2 or smaller tumors and zero positive SLN required PMRT. Among those with T2 tumors, 49% with a positive axilla lymph node underwent PMRT. Independent predictors of PMRT need were T2 vs T1 tumors, positive axillary lymph node status, and the number of positive SLNs, with odds ratios of 5.8 (P < .001), 14.5 (P < .001), and 2.1 (P = .001), respectively. CONCLUSIONS: Postmastectomy irradiation was associated with a high rate of surgical complications and implant loss among patients who underwent IBR. Determining the number of positive SLNs prior to definitive resection and reconstructive operations may reduce complications and implant loss by guiding surgical decision making. Patients with a negative SLN are unlikely to require PMRT. Those with positive SLN(s) are high-risk IBR candidates with a quantifiable PMRT risk. PMID- 20855759 TI - Impact of chemotherapy on postoperative complications after mastectomy and immediate breast reconstruction. AB - OBJECTIVES: To determine the impact of chemotherapy and the timing of chemotherapy on postoperative outcomes after mastectomy and immediate breast reconstruction. DESIGN: Retrospective review. SETTING: University tertiary care institution. PATIENTS: One hundred sixty-three consecutive patients undergoing mastectomy and immediate breast reconstruction. INTERVENTION: Systemic chemotherapy for breast cancer. MAIN OUTCOME MEASURES: Postoperative complications following mastectomy and immediate breast reconstruction. RESULTS: One hundred sixty-three patients underwent mastectomy and immediate breast reconstruction during the study period, with a mean postoperative follow-up of 19.2 months. Sixty-six percent of the patients had expander/implant reconstruction, while 33% underwent autologous reconstruction. Fifty-seven patients received neoadjuvant chemotherapy and 41 received postoperative chemotherapy. Eighteen patients (44%) in the adjuvant chemotherapy cohort developed postoperative infections, compared with 13 patients (23%) in the neoadjuvant chemotherapy group and 16 patients (25%) who did not receive any chemotherapy (P = .05). Overall, 31% of patients had a complication requiring an unplanned return to the operating room; this rate did not differ between groups (P = .79). Of patients who underwent expander/implant reconstruction, 8 women (26%) in the neoadjuvant chemotherapy cohort, 7 women (22%) in the adjuvant chemotherapy cohort, and 8 women (18%) without chemotherapy required expander or implant removal (P = .70). CONCLUSIONS: Although the highest rate of surgical site infections was in the adjuvant chemotherapy group, there were no differences between groups with respect to unplanned return to the operating room, expander loss, and donor-site complications. Neither the inclusion of chemotherapy nor the timing of its administration significantly affected the complication rates after mastectomy and immediate breast reconstruction in this population. PMID- 20855760 TI - Effect of delay to operation on outcomes in adults with acute appendicitis. AB - OBJECTIVE: To examine the effect of delay from surgical admission to induction of anesthesia on outcomes after appendectomy for acute appendicitis in adults. DESIGN: Retrospective cohort study with the principal exposure being time to operation. Regression models yielded probabilities of outcomes adjusted for patient and operative risk factors. SETTING: Data were submitted to the American College of Surgeons National Surgical Quality Improvement Program database from January 1, 2005, through December 31, 2008. PATIENTS: Patients with acute appendicitis who underwent an appendectomy. MAIN OUTCOME MEASURES: Thirty-day overall morbidity and serious morbidity/mortality. RESULTS: Of 32,782 patients, 24,647 (75.2%) underwent operations within 6 hours of surgical admission, 4934 (15.1%) underwent operations more than 6 through 12 hours, and 3201 (9.8%) underwent operations more than 12 hours after surgical admission. Differences in operative duration (51, 50, and 55 minutes, respectively; P < .001) were statistically significant but not clinically meaningful. The length of postoperative stay (2.2 days for the >12-hour group vs 1.8 days for the remaining groups; P < .001) was statistically significant but not clinically meaningful. No significant differences were found in adjusted overall morbidity (5.5%, 5.4%, and 6.1%, respectively; P = .33) or serious morbidity/mortality (3.0%, 3.6%, and 3.0%, respectively; P = .17). Duration from surgical admission to induction of anesthesia was not predictive in regression models for overall morbidity or serious morbidity/mortality. CONCLUSIONS: In this retrospective study, delay of appendectomy for acute appendicitis in adults does not appear to adversely affect 30-day outcomes. This information can guide the use of potentially limited operative and professional resources allocated for emergency care. PMID- 20855761 TI - One hundred two patients with pheochromocytoma treated at a single institution since the introduction of laparoscopic adrenalectomy. AB - HYPOTHESIS: Pheochromocytoma can be safely treated laparoscopically; "subclinical" pheochromocytoma is increasingly common. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Patients undergoing adrenalectomy for pheochromocytoma at our institution in 1994 to 2009. INTERVENTIONS: Laparoscopic, hand-assisted, and open adrenalectomy. MAIN OUTCOME MEASURES: Preoperative and postoperative clinical and biochemical data. RESULTS: One hundred two patients (52 women, 50 men) with pheochromocytoma underwent 108 operations. Ninety-seven operations were laparoscopic; 7, open; and 4, converted from laparoscopic to hand assisted or open. Six operations were bilateral; 3 were subtotal cortex-sparing resections. Thirty-four patients (33%) presented with adrenal incidentaloma and minimal symptoms, 28 within the past decade. Ten patients had paragangliomas, 7 of whom underwent laparoscopic resection. The mean (SD) tumor size was 5.3 (2.8) cm. Seven patients had recurrence requiring reoperation; the mean length of time between initial operation and recurrence was 6 years (range, 6 months to 17 years). There were no perioperative deaths. CONCLUSIONS: Laparoscopic adrenalectomy can be safely performed for pheochromocytoma in more than 90% of cases. More than one-third of patients presented with subclinical pheochromocytoma. Patients should be followed up closely because recurrence may develop several years after adrenalectomy. PMID- 20855762 TI - Impact of ABO-identical vs ABO-compatible nonidentical plasma transfusion in trauma patients. AB - HYPOTHESIS: Exposure to ABO-compatible nonidentical plasma will result in worse outcomes than transfusion with ABO-identical plasma only. DESIGN: Retrospective study. SETTING: Level I trauma center. PATIENTS: All patients requiring plasma (from 2000-2008) were identified. Propensity scores were used to match patients exposed to ABO-compatible plasma with those receiving exclusively ABO-identical plasma. MAIN OUTCOME MEASURES: Mortality and complications (acute respiratory distress syndrome [ARDS]), sepsis, renal failure, and liver failure). RESULTS: A total of 284 patients who received ABO-compatible nonidentical plasma were matched 1:1 with patients who received ABO-identical plasma only (230 group O, 39 A, and 15 B). ABO-compatible plasma did not affect mortality (35.2% vs 33.5%, P = .66). However, the overall complication rate was significantly higher for patients receiving ABO-compatible plasma (53.5% vs 40.5%, P = .002). The ARDS and sepsis rates were also significantly increased (19.4% vs 9.2%, P = .001, and 38.0% vs 28.9%, P = .02, respectively). As the volume of ABO-compatible plasma infused increased, a stepwise increase in complications was seen, reaching 70.0% for patients receiving more than 6 U. Patients receiving more than 6 U also had a 4-fold increase in ARDS. All recipient blood groups had an increase in overall complications, ARDS, and sepsis with exposure. This was significant for group O recipients with a higher risk of overall complications and ARDS (50.9% vs 40.0%, P = .03, and 17.4% vs 7.8%, P < .001, respectively). CONCLUSIONS: Exposure to ABO compatible plasma results in an increase in overall complications, in particular ARDS and sepsis. There is a stepwise increase in the complication rate as exposure increases. Further prospective evaluation of the impact of limiting factor replacement to ABO-identical plasma only is warranted. PMID- 20855763 TI - Transoral robotic surgery: disruptive or sustaining innovation? PMID- 20855764 TI - The power and peril of administrative databases. PMID- 20855765 TI - Image of the month. Internal iliac artery aneurysm. PMID- 20855766 TI - Image of the month. Pancreatic schwannoma. PMID- 20855767 TI - Introducing "archives classics: a contemporary perspective". PMID- 20855768 TI - The role of clinical consensus statements in facial plastic surgery literature. PMID- 20855769 TI - Functional and aesthetic concerns of patients seeking revision rhinoplasty. AB - OBJECTIVES: To assess the subjective aesthetic and functional concerns of patients seeking revision rhinoplasty and to compare them with objective deformities found on evaluation by the surgeon. METHODS: This prospective study used a questionnaire to systematically target the aesthetic and functional concerns of 104 consecutive patients seeking revision rhinoplasty. Analysis of the subjective data revealed the frequency of each concern, which was then compared with objective deformities found on evaluation by the surgeon. RESULTS: The most common patient and surgeon aesthetic concerns were (1) tip asymmetry, (2) crooked middle third of the nose, and (3) upper third irregularity. A mean of 79% of patient concerns were also reported by the surgeon. Of the 64 patients describing subjective nasal obstruction, 60 (94%) had objective physical findings related to obstruction. The 3 most troublesome patient concerns were (1) tip asymmetry, (2) difficulty breathing or nasal blockage, and (3) crooked middle third of the nose. CONCLUSIONS: Tip asymmetry was the most common deformity noted. Symptomatic nasal obstruction was the second most frequent reason for seeking revision rhinoplasty. Differences in patient and surgeon findings were largely due to differences in assessment skills and should be addressed by thorough explanation of nasal aesthetics. PMID- 20855770 TI - Functional outcomes of structured nasal tip refinement. AB - OBJECTIVE: To describe a technique to refine the nasal tip and supratip while preserving structure; traditional attempts to reduce nasal tip bulbosity involve maneuvers that may result in loss of support, leading to poor functional and cosmetic outcomes. METHODS: A prospective study of patients undergoing open structure nasal tip refinement using scroll joint excision with a septal-lateral crural suture to flatten the lateral crus. Outcomes assessed were nasal peak inspiratory flow (NPIF), nasal obstruction scores, 22-item Sinonasal Outcome Test (SNOT-22), 36-item Short-Form questionnaires (SF-36), and anchor scores for breathing and cosmesis. RESULTS: The mean NPIF improved from 100 L/min to 139 L/min, nasal obstruction improved, and the mean (SD) SNOT-22 scores improved from 1.45 (0.86) to 0.63 (0.65) (P< .01 for all comparisons). All patients had improved cosmesis, and 2.2% had both subjectively and objectively impaired nasal breathing. CONCLUSIONS: A technique is described allowing refinement of the nasal tip while maintaining or improving the nasal airway and providing a high level of patient satisfaction with the aesthetic outcome. Even in patients seen for cosmetic rhinoplasty, there may be a degree of preoperative nasal obstruction that should be recognized and addressed. PMID- 20855771 TI - Bone and cartilage wedge technique in posttraumatic enophthalmos treatment. AB - OBJECTIVE: To evaluate a new surgical method, using calvarial bone graft combined with a wedge of irradiated homologous costal cartilage, for the revision repair of posttraumatic enophthalmos. METHODS: This retrospective study was performed from January 1, 2003, through December 31, 2007. Eight patients were diagnosed as having unilateral posttraumatic enophthalmos. All the patients had previously undergone insufficient primary repair of their orbital fractures. In the revision surgery a calvarial bone graft was placed in the area of the defect using a transconjunctival approach. In combination with this technique, a wedge of irradiated rib cartilage was placed on the bone graft behind the globe. Patients were assessed preoperatively and postoperatively by ophthalmologists and maxillofacial surgeons. Standard follow-up examinations were performed at 2 and 4 weeks and at 3 and 6 months after surgery. Computed tomographic scans were obtained preoperatively and postoperatively from all patients. RESULTS: For all 8 corrected orbits, favorable cosmetic results were obtained regarding the position of the globe. The mean preoperative Hertel exophthalmometer showed a difference of 3.1 mm and 0.7 mm postoperatively. Improvement of ocular motility and reduction of diplopia were achieved in only 1 patient; in the others, motility and diplopia remained unchanged. No postoperative complications were observed. CONCLUSION: The bone and cartilage wedge technique seems to be a useful surgical technique for the cosmetic correction of posttraumatic enophthalmos. PMID- 20855772 TI - An alternative method for reconstruction of large intranasal lining defects: the Farina method revisited. AB - OBJECTIVE: To examine use of the paramedian forehead flap for intranasal lining. METHODS: The medical records and photographs were reviewed for patients who underwent a nasal reconstruction involving a paramedian forehead flap used for internal lining. RESULTS: Three patients underwent this procedure. In all patients, the flap provided excellent intranasal lining. External incisions were acceptable in all the patients. CONCLUSIONS: The paramedian forehead flap may be used for internal lining of large intranasal defects. An external rhinoplasty approach facilitates reconstruction. PMID- 20855773 TI - A new model for facial nerve research: the novel transgenic Thy1-GFP rat. AB - OBJECTIVE: To introduce a Thy1-GFP transgenic rat model, whose axons constitutively express green fluorescent protein (GFP), in order to study facial nerve regeneration. Facial nerve injury can cause devastating physical and social sequelae. The functional recovery of the facial nerve can result in synkinesis and permanent axonal misrouting. Facial nerve research has been hindered by the lack of available animal models and reliable outcome measures. METHODS: Transgenic Thy1-GFP rats underwent a proximal facial nerve crush injury and were imaged at 0, 1, 2, 4, and 8 weeks after injury. Nerve regeneration was assessed via confocal imaging and fluorescence microscopy. RESULTS: Uninjured animals reliably demonstrated facial nerve fluorescence and had predictable anatomical landmarks. Fluorescence microscopy demonstrated the loss and reappearance of fluorescence with regeneration of axons following injury. This was confirmed with the visualization of denervation and reinnervation of zygomaticus muscle motor end plates using confocal microscopy. CONCLUSIONS: The Thy1-GFP rat is a novel transgenic tool that enables direct visualization of facial nerve regeneration after injury. The utility of this model extends to a variety of clinical facial nerve injury paradigms. PMID- 20855774 TI - Molecular effects of fractional carbon dioxide laser resurfacing on photodamaged human skin. AB - Objective To elucidate the sequential changes in protein expression that play a role in the clinically beneficial results seen with fractional carbon dioxide (CO(2)) laser resurfacing of the face and neck. Methods Nine healthy volunteers were recruited for participation from the senior author's facial plastic surgery practice. After informed consent was obtained, each volunteer underwent a 2-mm punch biopsy from a discrete area of infra-auricular neck skin prior to laser treatment. Patients then immediately underwent laser resurfacing of photodamaged face and neck skin at a minimal dose (30 W for 0.1 second) with the Pixel Perfect fractional CO(2) laser. On completion of the treatment, another biopsy specimen was taken adjacent to the first site. Additional biopsy specimens were subsequently taken from adjacent skin at 2 of 3 time points (day 7, day 14, or day 21). RNA was extracted from the specimens, and reverse transcriptase polymerase chain reaction and protein microarray analysis were performed. Comparisons were then made between time points using pairwise comparison testing. Results We found statistically significant changes in the gene expression of several matrix metalloproteinases (MMPs). The data demonstrate a consistent up regulation of MMPs 1, 3, 9, and 13, all of which have been previously reported for fully ablative CO(2) laser resurfacing. There was also a statistically significant increase in MMP-10 and MMP-11 levels in this data set. Conclusion This study suggests that the molecular mechanisms of action are similar for both fractional and fully ablative CO(2) laser resurfacing. PMID- 20855775 TI - Interstitial delivery of vascular endothelial growth factor to skin flaps. AB - OBJECTIVES: To demonstrate the feasibility of using microporous catheters to deliver a growth factor in a skin flap model, and to determine whether removal of excess fluid by ultrafiltration catheters reduces edema. METHODS: In a controlled study at a research laboratory associated with major teaching hospital, vascular endothelial growth factor was delivered to porcine skin flaps by direct infusion using hollow fiber catheters. Treated flaps received either infusion alone or infusion and ultrafiltration via hollow fibers inserted into the distal portion of the flap. Controls had neither type of catheter placed. The main outcome measure was flap survival and edema. RESULTS: Treated anterior flaps were found to have increased survival (mean [SD] increase, 49.9% [9.4%]) compared with control flaps (44.1% [4.5%]) for group (P = .005) and side (P = .01) but not by interaction (P = .14). Water content was significant by analysis of variance for group, position, and interaction (all P < .001, df = 31) for treated (55.3% [9.7%]) and control (61.9% [8.2%]) groups. CONCLUSIONS: This study demonstrated feasibility of using hollow fiber technology to deliver a growth factor to skin flaps. Further study may yield clinical applications for human patients undergoing reconstructive procedures. PMID- 20855776 TI - A graded approach to repairing the stenotic nasal vestibule. AB - OBJECTIVE: To describe a graded approach to repairing vestibular stenosis that involves restoring structural support to the ala. METHODS: Retrospective review of 5 nostrils in 4 patients who presented to the senior author with vestibular stenosis. The cause was burn injury in 3 patients and congenital in 1 patient. The cornerstone is a batten graft to restore strength to the ala. A short-term thermoplastic stent helps the nostril assume its natural shape. When an obstructing cicatrix is present, it is excised in a second stage followed by full thickness skin grafting. The patients were evaluated up to 16 months postoperatively. Vestibular patency was documented using high-resolution photographs, and medical records were reviewed for complications. RESULTS: Two patients had their nostrils repaired in a single stage and the others required 2 stages. In all patients, significant improvement in nostril diameter was maintained. The patients were satisfied with the functional and aesthetic results. Stenting averaged 13 days after surgery and was well tolerated. No wound complications occurred. CONCLUSIONS: In patients with vestibular stenosis, we use a graded approach that addresses the inherent weakness of the nasal ala to achieve long-term vestibular patency. This technique restores form and function to the stenotic vestibule while avoiding long-term stenting. PMID- 20855777 TI - Anatomic comparison of the deep-plane face-lift and the transtemporal midface lift. AB - OBJECTIVE: To identify whether the deep-plane face-lift or the extended transtemporal subperiosteal midface-lift is more effective in correcting midfacial ptosis. METHODS: Five cadaveric dissections were performed with a unilateral transtemporal subperiosteal midface-lift followed by a deep-plane face lift on the same hemihead. Three suspension sutures were evaluated-transtemporal midface-lift, zygomaticofacial and melolabial sutures, and a deep-plane face-lift suture-to determine the degree of elevation on the nasolabial fold. Statistical analysis was performed to compare their effectiveness. RESULTS: The melolabial suture elevates the nasolabial fold 43.2% more than the deep-plane suture (P = .03) and 29.2% more than the zygomaticofacial suture (P = .10). At no point did the deep-plane suture offer more elevation than either the zygomaticofacial or melolabial suture. CONCLUSIONS: Midface-lifting surgery is challenging owing to the difficulty of adequately releasing the soft tissues overlying the zygomaticomaxillary region and resuspending them effectively. A comparison of the extended transtemporal midface-lift and deep-plane face-lift demonstrates the statistically significant advantage of the transtemporal midface-lift on elevating the nasolabial fold, particularly the melolabial suspension suture. PMID- 20855778 TI - Comparison of lip enhancement using autologous superficial musculoaponeurotic system tissue and postauricular fascia in conjunction with lip advancement. AB - OBJECTIVE: To evaluate and compare the short- and long-term aesthetic results of surgical lip enhancement using the superficial musculoaponeurotic system (SMAS) and postauricular fascia graft implantation with and without vermilion border advancement. METHODS: A single-blinded cohort study was performed using 39 patients who underwent surgical lip enhancement at a private facial plastic surgery practice between 2005 and 2007. The cohort was grouped as follows: 14 patients underwent lip augmentation using SMAS grafting; 10 patients underwent lip augmentation using postauricular fascia grafting; and 15 patients underwent combined lip augmentation and lip advancement (SMAS grafting was used in 8 of the procedures, and postauricular fascial tissue was used in 7). All procedures were performed in a controlled setting by a single surgeon (E.G.M.). Patients who had undergone previous lip augmentation of any kind were excluded from the study. Preoperative and postoperative photographs were analyzed by 3 blinded physician observers using the Lip Fullness Grading Scale. Postoperative photographs were evaluated at approximately 6 months and 1 year after the procedure. RESULTS: Reviewers noted a significant improvement in aesthetic scoring for each of the methods of lip augmentation examined at 6 months after surgery. This result was sustained at 12 months after surgery. Postauricular fascia graft lip augmentation and combined lip advancement and postauricular fascia augmentation recorded the highest scores after surgery. The largest mean scoring increases of 1.459 (t = 9.5049; P < .001) at 6 months and 1.584 (t = -9.0308; P < .001) at 1 year were found in the lip advancement and SMAS lip augmentation study group. CONCLUSIONS: Youthful, natural-appearing lips tend to enhance an individual's appearance. Surgical lip augmentation using SMAS or postauricular fascia, with or without vermilion border advancement, is a straightforward, safe, potentially long lasting treatment for hypoplastic lips, with little to no morbidity. PMID- 20855779 TI - Retrospective review of transconjunctival sub-orbicularis oculi pad lift blepharoplasty. PMID- 20855780 TI - Assessing outcomes in facial reanimation: evaluation and validation of the SMILE system for measuring lip excursion during smiling. PMID- 20855781 TI - The bow-tie mattress suture for the correction of nasal cartilage convexities and concavities. PMID- 20855782 TI - Effect of perioperative hyperbaric oxygen on bruising in face-lifts. PMID- 20855783 TI - Portrait of General Giles by Joseph Wright. PMID- 20855785 TI - Should patients with stroke wear compression stockings to prevent venous thromboembolism? PMID- 20855784 TI - Thigh-length versus below-knee stockings for deep venous thrombosis prophylaxis after stroke: a randomized trial. AB - BACKGROUND: Graduated compression stockings are widely used for deep venous thrombosis (DVT) prophylaxis. Although below-knee stockings are used more often than thigh-length stockings, no reliable evidence indicates that they are as effective as thigh-length stockings. OBJECTIVE: To compare the effectiveness of thigh-length stockings with that of below-knee stockings for preventing proximal DVT in immobile, hospitalized patients with stroke. DESIGN: Parallel-group trial with centralized randomization (minimization within centers) to ensure allocation concealment. The ultrasonographers who looked for DVT were blinded, but the patients and caregivers were not. (Controlled-trials.com registration number: ISRCTN28163533) SETTING: 112 hospitals in 9 countries. PATIENTS: 3114 immobile patients hospitalized with acute stroke between January 2002 and May 2009. INTERVENTION: 1552 patients received thigh-length stockings and 1562 patients received below-knee stockings to wear while they were in the hospital. MEASUREMENTS: Ultrasonographers performed compression duplex ultrasonography in 1406 patients (96% of survivors) in each treatment group between 7 and 10 days after enrollment. They performed a second scan in 643 patients in the thigh length stockings group and 639 in the below-knee stockings group at about 25 to 30 days. The primary outcome was symptomatic or asymptomatic DVT in the popliteal or femoral veins, detected on either scan. RESULTS: Patients were retained in their assigned group for all analyses. The primary outcome occurred in 98 patients (6.3%) who received thigh-length stockings and 138 (8.8%) who received below-knee stockings (absolute difference, 2.5 percentage points [95% CI, 0.7 to 4.4 percentage points]; P = 0.008), an odds reduction of 31% (CI, 9% to 47%). Seventy-five percent of patients in both groups wore the stockings for 30 days or until they were discharged, died, or regained mobility. Skin breaks occurred in 61 patients who received thigh-length stockings (3.9%) and 45 (2.9%) who received below-knee stockings. LIMITATION: Blinding was incomplete, 2 scans were not obtained for all enrolled patients, and the trial was stopped before the target accrual was reached. CONCLUSION: Proximal DVT occurs more often in patients with stroke who wear below-knee stockings than in those who wear thigh-length stockings. PRIMARY FUNDING SOURCE: Medical Research Council of the United Kingdom, Chief Scientist Office of the Scottish Government, and Chest Heart and Stroke Scotland. PMID- 20855786 TI - Summaries for patients. Palifermin can prevent severe oral mucositis during chemotherapy. PMID- 20855787 TI - ACP Journal Club: laparoscopic fundoplication is better than medical management for some quality-of-life measures in GERD. PMID- 20855788 TI - ACP Journal Club: high-dose and non-high-dose proton pump inhibitors after endoscopic treatment do not differ for bleeding peptic ulcers. PMID- 20855789 TI - ACP Journal Club: vitamin E, but not pioglitazone, improved nonalcoholic steatohepatitis in nondiabetic patients. PMID- 20855790 TI - ACP Journal Club: concomitant use of warfarin and cotrimoxazole or ciprofloxacin increased risk for admission for upper GI hemorrhage. PMID- 20855791 TI - ACP Journal Club: meta-analysis: alteplase improves functional outcomes when given within 4.5 hours of stroke onset. PMID- 20855792 TI - ACP Journal Club: a single, annual, high dose of oral vitamin D increased falls and fractures in older women. PMID- 20855793 TI - ACP Journal Club: statins do not reduce mortality in patients with no history of cardiovascular disease. PMID- 20855794 TI - ACP Journal Club: beta-agonists increase asthma-related intubations and deaths in patients with asthma. PMID- 20855795 TI - ACP Journal Club: treatment for gestational diabetes reduces risk for shoulder dystocia. PMID- 20855796 TI - ACP Journal Club: probiotics improve symptoms in adults with the irritable bowel syndrome. PMID- 20855797 TI - Review: direct thrombin inhibitors are similar to LMWH and vitamin K antagonists for preventing VTE after hip or knee replacement. PMID- 20855798 TI - ACP Journal Club: target-oriented drug treatment improves clinical outcomes more than routine care in rheumatoid arthritis. PMID- 20855800 TI - Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. AB - BACKGROUND: Mucositis can be a serious complication of cancer treatment. Palifermin reduces mucositis when given in multiple doses to patients undergoing hematopoietic stem-cell transplantation. OBJECTIVE: To evaluate the efficacy of palifermin given as a single dose before each cycle in patients receiving multicycle chemotherapy. DESIGN: Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov registration number: NCT00267046) SETTING: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS: 48 patients with sarcoma were randomly assigned in a 2:1 ratio to receive palifermin or placebo. All patients received doxorubicin-based chemotherapy (90 mg per m(2) of body surface area over 3 days, by infusion). INTERVENTION: Palifermin (180 ug per kg of body weight) or placebo was administered intravenously as a single dose 3 days before each chemotherapy cycle (maximum, 6 cycles). Patients who had severe mucositis received open-label palifermin in subsequent cycles. MEASUREMENTS: Oral assessment of mucositis by using World Health Organization (WHO) oral toxicity scale (grades 0 to 4), with moderate to severe mucositis (grades 2 to 4) as the main outcomes; patient-reported outcome questionnaire; and daily symptom record diary. RESULTS: A median of 6 blinded cycles (range, 1 to 6) were completed by the palifermin group and 2 (range, 1 to 6) by the placebo group. Compared with placebo, palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, -44 percentage points [95% CI, -71 to -16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, -38 percentage points [CI, -67 to -9 percentage points]). The main adverse effects were thickening of oral mucosa (72% in the palifermin group vs. 31% in the placebo group; P = 0.007) and altered taste. Seven of the 8 patients who had severe mucositis in the placebo group received open-label palifermin. None of these patients had severe mucositis in the subsequent cycles (a total of 17) with open-label palifermin. LIMITATIONS: Study limitations include smaller sample size for the control group, inclusion of only patients with sarcoma, and perceived unblinding of the treatment because of notable differences between the biologic effects of palifermin and placebo. CONCLUSION: A single dose of palifermin before each cycle reduced the incidence and severity of mucositis. The drug was generally well tolerated, but most patients experienced thickening of oral mucosa. Further investigation is needed to determine whether palifermin use will facilitate greater adherence to chemotherapy regimens by reducing mucositis. PMID- 20855799 TI - Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. AB - BACKGROUND: Women account for an increasing proportion of patients with HIV-1 but remain underrepresented in antiretroviral clinical trials. OBJECTIVE: To evaluate sex-based differences in efficacy and adverse events in treatment-experienced, HIV-positive women and men receiving darunavir-ritonavir therapy over 48 weeks. DESIGN: Multicenter, open-label, phase 3b study designed to enroll a high proportion of women, with sample size determined on the basis of a noninferiority design with a maximum allowable difference of 15% in virologic response favoring men. (ClinicalTrials.gov registration number: NCT00381303) SETTING: 65 sites in the United States, Puerto Rico, and Canada. PATIENTS: 287 women and 142 men. INTERVENTION: Patients received darunavir-ritonavir, 600/100 mg twice daily, plus an investigator-selected optimized background regimen. MEASUREMENTS: Virologic response (HIV RNA <50 copies/mL using a time-to-loss of virologic response [TLOVR] algorithm) and adverse events were assessed over 48 weeks. RESULTS: 67% of patients were women; 84% of patients were black or Hispanic. A higher proportion of women discontinued treatment than men (32.8% vs. 23.2%; P = 0.042); more women than men discontinued treatment for reasons other than virologic failure. Response rates in women and men at week 48 were 50.9% and 58.5%, respectively (intention-to-treat TLOVR), and 73.0% and 73.5%, respectively (TLOVR censored for patients who withdrew for reasons other than virologic failure). The absolute difference in response, based on logistic regression and adjusted for baseline log(10) viral load and CD4(+) cell count, was -9.6 percentage points (95% CI, -19.9 to 0.7 percentage points; P = 0.067) for intention-to-treat TLOVR and -3.9 percentage points (CI, -13.9 to 6.0 percentage points; P = 0.438) for TLOVR population that censored patients who withdrew for reasons other than virologic failure. Adverse events were similar between the sexes. The most common grade 2 to 4 adverse events that were considered at least possibly treatment related in women and men were nausea (5.2% and 2.8%, respectively), diarrhea (4.5% and 4.9%, respectively), and rash (2.1% and 2.8%, respectively). LIMITATION: Baseline characteristics differed between sexes. CONCLUSION: Nonsignificant, sex-based differences in response were found during the 48-week study; however, these differences were probably due to higher discontinuation rates in women, suggesting that additional efforts are needed to retain women in clinical trials. PMID- 20855801 TI - Stool DNA testing to screen for colorectal cancer in the Medicare population: a cost-effectiveness analysis. AB - BACKGROUND: The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees. OBJECTIVE: To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services. DESIGN: Comparative microsimulation modeling study using 2 independently developed models. DATA SOURCES: Derived from literature. TARGET POPULATION: A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied. TIME HORIZON: Lifetime. PERSPECTIVE: Third-party payer. INTERVENTION: Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies. OUTCOME MEASURES: Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs. RESULTS OF BASE-CASE ANALYSIS: Assuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be cost-effective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests. RESULTS OF SENSITIVITY ANALYSIS: None of the results changed substantially when a cohort of persons aged 50 years was considered. LIMITATION: No pathways other than the traditional adenoma-carcinoma sequence were modeled. CONCLUSION: Stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening. PMID- 20855802 TI - Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. AB - BACKGROUND: Controversy remains on whether the dual use of clopidogrel and proton pump inhibitors (PPIs) affects clinical efficacy of clopidogrel. OBJECTIVE: To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction. DESIGN: A nationwide cohort study based on linked administrative registry data. SETTING: All hospitals in Denmark. PATIENTS: All patients discharged after first-time myocardial infarction from 2000 to 2006. MEASUREMENTS: The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year. RESULTS: Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72). LIMITATIONS: Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible. CONCLUSION: Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone. PMID- 20855803 TI - Screening for testicular cancer: an evidence review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Testicular cancer is the most common type of cancer in men aged 15 to 34 years. Because treatment produces favorable outcomes even in advanced stages, the U.S. Preventive Services Task Force (USPSTF) concluded in 2004 that screening asymptomatic men for testicular cancer is unlikely to produce additional benefits over clinical detection. PURPOSE: To search for new evidence on the benefits and harms of screening for testicular cancer to assist the USPSTF in updating its 2004 recommendation. DATA SOURCES: English-language articles indexed in PubMed and the Cochrane Library and published between 1 January 2001 and 11 November 2009. STUDY SELECTION: Randomized, controlled trials; meta-analyses; systematic reviews; cohort studies; and case-control studies were selected to determine the benefits of screening for testicular cancer. Randomized, controlled trials; meta analyses; systematic reviews; cohort studies; case-control studies; and case series of large, multisite databases were selected to determine the harms of screening. Each author independently reviewed titles, abstracts, and full-text articles for possible inclusion. DATA EXTRACTION: One author abstracted information on the benefits and harms of screening for testicular cancer. DATA SYNTHESIS: No studies met the inclusion criteria. Three studies were considered for inclusion at the full-text stage of review. These inconclusive studies addressed testicular microlithiasis, XIST gene testing, and testis-sparing surgery. LIMITATION: The focused search strategy may have missed some smaller studies or studies published in languages other than English on the benefits or harms of testicular cancer screening. CONCLUSION: No new evidence was found on the benefits or harms of screening for testicular cancer that would affect the USPSTF's previous recommendation against screening. PMID- 20855804 TI - Clinical trials: discerning hype from substance. AB - The interest in being able to interpret and report results in clinical trials as being favorable is pervasive throughout health care research. This important source of bias needs to be recognized, and approaches need to be implemented to effectively address it. The prespecified primary analyses of the primary and secondary end points of a clinical trial should be clearly specified when disseminating results in press releases and journal publications. There should be a focus on these analyses when interpreting the results. A substantial risk for biased conclusions is produced by conducting exploratory analyses with an intention to establish that the benefit-to-risk profile of the experimental intervention is favorable, rather than to determine whether it is. In exploratory analyses, P values will be misleading when the actual sampling context is not presented to allow for proper interpretation, and the effect sizes of outcomes having particularly favorable estimates are probably overestimated because of "random high" bias. Performing exploratory analyses should be viewed as generating hypotheses that usually require reassessment in prospectively conducted confirmatory trials. Awareness of these issues will meaningfully improve our ability to be guided by substance, not hype, in making evidence-based decisions about medical care. PMID- 20855805 TI - Supportive treatments for oncology patients: not just icing on the cake. PMID- 20855806 TI - Conflicting evidence: what's a clinician to do? PMID- 20855807 TI - Survivor. PMID- 20855809 TI - Barriers to herpes zoster vaccination. PMID- 20855811 TI - Important differences in measurement of fetuin-A. PMID- 20855813 TI - Urine drug testing is still an invaluable resource for primary care. PMID- 20855814 TI - Guidelines and conflicts of interest. PMID- 20855815 TI - Guidelines and conflicts of interest. PMID- 20855816 TI - A rare cause of cardiac ischemia: systemic lupus erythematosus presenting as the hyperviscosity syndrome. PMID- 20855818 TI - Beyond grand rounds: a comprehensive and sequential intervention to improve identification of delirium. AB - PURPOSE OF THE STUDY: Delirium is a widespread concern for hospitalized seniors, yet is often unrecognized. A comprehensive and sequential intervention (CSI) aiming to effect change in clinician behavior by improving knowledge about delirium was tested. DESIGN AND METHODS: A 2-day CSI program that consisted of progressive 4-part didactic series, including evidence-based reviews of delirium recognition, prevention, and management, interspersed with interactive small group sessions and practical case conferences was conceptualized in consultation with a leading expert on delirium. Pretest and posttest instruments were designed to test the attendees on their knowledge and confidence around delirium identification. RESULTS: An average of 71 people attended each didactic session. Among all responses, 50 pretests and posttests were matched based on numeric coding (6 MD/DOs, 34 RNs, and 10 others). Mean pretest and posttest scores were 7.9 and 10.8 points, respectively (maximum: 17), showing a positive change in knowledge scores after the intervention (2.9 points, p < .001). Improvement in knowledge scores was higher in the cohort attending 2 or more lectures (3.8 points, p < .001) compared with those attending only 1 lecture (1.3 points, p < .12). Confidence in identifying patients with delirium increased by 28% (p < .001), and self-assessed capacity to correctly administer the Confusion Assessment Method increased by 36% (p < .001). IMPLICATIONS: A novel CSI increased clinician knowledge about delirium identification and management and improved confidence and self-assessed capacity to identify delirium in the hospitalized elderly patients. This strategy, which incorporates multiple reinforcing modes of education, may ultimately be more effective in influencing clinician behavior when compared with traditional grand rounds. PMID- 20855821 TI - Quality cancer care for adolescents and young adults: a position statement. AB - PURPOSE: This consensus-based position statement on behalf of the LIVESTRONG Young Adult Alliance (Alliance) offers recommendations to enhance oncologic care of adolescent and young adult (AYA) patients with cancer. BACKGROUND: In 2005 to 2006, the National Cancer Institute and the Lance Armstrong Foundation jointly sponsored the Adolescent and Young Adult Oncology Progress Review Group (PRG). The PRG report included the directive to develop standards of care for AYA patients with cancer and to disseminate these guidelines to the community. To this end, the Alliance convened a meeting of experts (clinicians, researchers, and advocates) in June 2009 and derived this position statement. RESULTS: Quality care for AYAs depends on four critical elements: timely detection; efficient processes for diagnosis, initiation of treatment, and promotion of adherence; access to health care professionals who possess knowledge specific to the biomedical and psychosocial needs of this population; and research that will ultimately derive objective criteria for the development of AYA oncology care guidelines. Achieving quality care for AYAs will require assistance with management of disease and treatment effects; cognizance of the unique psychosocial context for AYA growth and development; assessment of and attention to cognitive, psychiatric, and psychosocial issues; facilitated transition to treatment care; and referral to age-appropriate information and support services. CONCLUSION: Dissemination of recommendations stated here will raise awareness of the need for AYA-specific care guidelines and assist providers in the delivery of care that is responsive to the distinct needs of AYAs with cancer. PMID- 20855822 TI - Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. AB - PURPOSE: We have analyzed the outcome of mycosis fungoides (MF) and Sezary syndrome (SS) patients using the recent International Society for Cutaneous Lymphomas (ISCL)/European Organisation for Research and Treatment of Cancer (EORTC) revised staging proposal. PATIENTS AND METHODS: Overall survival (OS), disease-specific survival (DSS), and risk of disease progression (RDP) were calculated for a cohort of 1,502 patients using univariate and multivariate models. RESULTS: The mean age at diagnosis was 54 years, and 71% of patients presented with early-stage disease. Disease progression occurred in 34%, and 26% of patients died due to MF/SS. A significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Univariate analysis established that (1) advanced skin and overall clinical stage, increased age, male sex, increased lactate dehydrogenase (LDH), and large-cell transformation were associated with reduced survival and increased RDP; (2) hypopigmented MF, MF with lymphomatoid papulosis, and poikilodermatous MF were associated with improved survival and reduced RDP; and (3) folliculotropic MF was associated with an increased RDP. Multivariate analysis established that (1) advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sezary cells (B0b), increased LDH, and folliculotropic MF were independent predictors of poor survival and increased RDP; (2) large-cell transformation and tumor distribution were independent predictors of increased RDP only; and (3) N, M, and B stages; age; male sex; and poikilodermatous MF were only significant for survival. CONCLUSION: This study has validated the recently proposed ISCL/EORTC staging system and identified new prognostic factors. PMID- 20855820 TI - Phase II study of dasatinib in patients with advanced non-small-cell lung cancer. AB - PURPOSE: Src family kinases (SFKs) promote cancer progression and are commonly expressed in non-small-cell lung cancer (NSCLC), but the clinical effects of SFK inhibition in NSCLC are unknown. We conducted a phase II trial of the SFK inhibitor dasatinib for advanced NSCLC. We tested the hypotheses that the activation of epidermal growth factor receptor (EGFR) or SFK or modulation of serum cytokines may predict a response to dasatinib. PATIENTS AND METHODS: Patients received dasatinib as first-line therapy. Response was measured by tumor size on computed tomography scans and by metabolic activity on positron emission tomography scans. Tissue samples taken before patients received dasatinib were tested for EGFR and Kras mutation and phosphorylated SFK expression. RESULTS: Thirty-four patients were enrolled. The overall disease control rate (partial responses plus stable disease) for dasatinib was 43%. One patient had a partial response to therapy. Eleven patients (32%) had a metabolic response to dasatinib. SFK activation and EGFR and Kras mutations in tumor tissue did not predict response to dasatinib. Significant toxicities included fatigue and dyspnea. The presence of a pleural effusion before dasatanib therapy predicted the development of a clinically significant effusion during therapy. CONCLUSION: Dasatinib as a single agent had modest clinical activity that was lower than that generally observed in patients with NSCLC who receive chemotherapy. Pleural effusion was an expected and problematic toxicity that was successfully treated with steroids, diuretics, and dose interruptions. Marked activity in one patient and prolonged stable disease in four others suggested a potential subpopulation of patients with dasatinib-sensitive NSCLC. PMID- 20855823 TI - Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. AB - PURPOSE: We designed this study to evaluate efficacy of modified gemcitabine and oxaliplatin (mGEMOX) over best supportive care (BSC) or fluorouracil (FU) and folinic acid (FA) in unresectable gall bladder cancer (GBC). PATIENTS AND METHODS: Patients with unresectable GBC were enrolled for single center randomized study. Arm A, BSC; arm B, FU 425 mg/m(2) and FA 20 mg/m(2) intravenous (IV) bolus weekly for 30 weeks (FUFA); arm C, gemcitabine 900 mg/m(2) and oxaliplatin 80 mg/m(2) IV infusion on days 1 and 8 every 3 weeks for maximum of six cycles. Eighty-one patients were randomly assigned, arms A (n = 27), B (n = 28), and C (n = 26). RESULTS: Complete response plus partial response in the three groups was 0 (0%), four (14.3%), and eight (30.8%) respectively (P < .001). Two patients in the mGEMOX arm and one patient in the FUFA arm underwent curative resection after chemotherapy. One patient in the mGEMOX arm had complete pathologic response. Median overall survival (OS) was 4.5, 4.6, and 9.5 months for the BSC, FUFA, and mGEMOX arms (P = .039), respectively. Progression-free survival (PFS) was 2.8, 3.5, and 8.5 months for the three groups (P < .001). There was no difference in grade 3/4 toxicities in the chemotherapy arms except transaminitis, which was more prevalent in mGEMOX arm (P = .04). Two patients in the FUFA arm and 10 patients in the mGEMOX arm had grade 3 or 4 myelosuppression. Two patients in the mGEMOX group had neutropenic fever that resolved with antibiotics. CONCLUSION: This randomized controlled trial confirmed the efficacy of chemotherapy (mGEMOX) compared with BSC and FUFA in improving OS and PFS in unresectable GBC. PMID- 20855824 TI - Cytomegalovirus retinitis during chemotherapy with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone. PMID- 20855826 TI - Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. AB - PURPOSE: Hepatitis C virus (HCV) contributes to one third of hepatocellular carcinoma cases worldwide. Long-term predictors for HCV-related hepatocellular carcinoma are essential for early intervention. Serum HCV RNA and ALT levels and HCV genotype were assessed for their predictability of hepatocellular carcinoma risk. METHODS: A prospective cohort of 925 participants positive for antibodies against HCV and age 30 to 65 years was recruited and followed from 1991 to 2006. Serum HCV RNA and ALT levels and HCV genotypes at enrollment and during follow-up were examined. Newly developed hepatocellular carcinoma was identified by health examination and computerized linkage with national cancer registration and death certification profiles. Multivariate adjusted hazard ratios with 95% CIs were estimated using Cox regression models. RESULTS: Fifty-five participants newly developed hepatocellular carcinoma during 8,476 person-years of follow-up, giving an incidence rate of 648.9 per 100,000 person-years. The cumulative hepatocellular carcinoma risk increased from 1.1% for HCV RNA seronegative status to 6.4% for low HCV RNA levels and to 14.7% for high HCV RNA levels (P < .001). The cumulative risk also increased with elevated serum ALT levels from 1.7% for persistently <= 15 U/L to 4.2% for ever more than 15 U/L but never more than 45 U/L and to 13.8% for ALT ever >= 45 U/L (P < .001). Having HCV genotype 1 was associated with a higher cumulative hepatocellular carcinoma risk (12.6%) than not having HCV genotype 1 (4.5%; P < .001). CONCLUSION: Elevated serum levels of HCV RNA and ALT and HCV genotype 1 infection are independent risk predictors of hepatocellular carcinoma. These findings have strong implications for the management of chronic HCV. PMID- 20855825 TI - Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. AB - PURPOSE: We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor-positive advanced breast cancer who experienced progression after prior endocrine therapy. PATIENTS AND METHODS: Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). RESULTS: PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. CONCLUSION: Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg. PMID- 20855827 TI - Primary carcinoid tumor presenting as a nonpalpable testicular mass. PMID- 20855828 TI - Factors for hematopoietic toxicity of carboplatin: refining the targeting of carboplatin systemic exposure. AB - PURPOSE: Area under the curve (AUC) dosing is routinely carried out for carboplatin, but the chosen target AUC values remain largely empirical. This multicenter pharmacokinetic-pharmacodynamic (PK-PD) study was performed to determine the covariates involved in the interindividual variability of carboplatin hematotoxicity that should be considered when choosing individual target AUCs. PATIENTS AND METHODS: Three hundred eighty-three patients received carboplatin as part of established regimens. A semi-physiologic population PK-PD model was applied to describe separately the time course of absolute neutrophil and platelet counts using NONMEM software. The plasma ultrafiltrable carboplatin concentration (C(Carbo)) was assumed to inhibit the proliferation of blood cell precursors through a linear model: drug effect = slope * C(Carbo). The slope corresponds to the patients' sensitivity to carboplatin hematotoxicity. The relationships between the patients' sensitivity to the neutropenic or thrombopenic effects of carboplatin and various covariates, including associated chemotherapies, demographic, biologic, and pharmacogenetic data, were studied. RESULTS: The sensitivity of carboplatin-induced thrombocytopenia decreased in the case of concomitant paclitaxel chemotherapy (slope decreased by 24%), whereas it increased with coadministration of etoposide and gemcitabine (slope increased by 45% and 133%, respectively). For neutropenia, the sensitivity increased when carboplatin was combined with other cytotoxics (slope increased by 76%). CONCLUSION: This study provides useful information to clinicians to better estimate the hematopoietic toxicity of carboplatin and thus choose more rationally carboplatin target AUCs as a function of pretreatment or concomitantly administered chemotherapies. For example, an AUC of 5 mg/mL . min is associated with a risk of grade 3 or 4 thrombocytopenia of 2% in combination with paclitaxel versus 38% with gemcitabine in a non-pretreated patient. PMID- 20855829 TI - Randomized phase II trials: misleading and unreliable. PMID- 20855830 TI - Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. AB - PURPOSE: To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC). METHODS: Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points. RESULTS: Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs. CONCLUSION: Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC. PMID- 20855831 TI - Phase I studies of drug combinations. PMID- 20855832 TI - Unusual case of extrapulmonary metastatic recurrence in a patient with osteosarcoma. PMID- 20855833 TI - Progressive multifocal leukoencephalopathy with occult Waldenstrom macroglobulinemia. PMID- 20855834 TI - Patient with colorectal cancer with heterogeneous KRAS molecular status responding to cetuximab-based chemotherapy. PMID- 20855835 TI - Screening in women at elevated risk for breast cancer. PMID- 20855836 TI - Sarcoidois and radiation-induced astrogliosis causes pitfalls in neuro-oncologic positron emission tomography imaging by O-(2-[18F]fluoroethyl)-L-tyrosine. PMID- 20855837 TI - Lung adenocarcinoma from East Asian never-smokers is a disease largely defined by targetable oncogenic mutant kinases. AB - PURPOSE: To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations. PATIENTS AND METHODS: In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1. RESULTS: Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations. CONCLUSION: To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases. PMID- 20855838 TI - Castration-dependent pharmacokinetics of docetaxel in patients with prostate cancer. AB - PURPOSE: To assess whether the low incidence of severe neutropenia in castrated men with prostate cancer treated with docetaxel is the result of changes in systemic clearance. PATIENTS AND METHODS: A total of 10 noncastrated and 20 castrated men with prostate cancer were studied to achieve 80% power (alpha = .05) to detect at least a 25% change in the clearance of docetaxel. The erythromycin breath test was evaluated to determine hepatic activity of cytochrome P450 3A4 (CYP3A4), the main docetaxel-metabolizing enzyme. Additional studies were performed in rats and transfected cells overexpressing human or rodent transporters. RESULTS: Docetaxel clearance was increased by approximately 100% in castrated men and was associated with a two-fold reduction in area under the curve (P = .0001), although hepatic activity of CYP3A4 was unchanged (P = .26). In rats, castration was associated with higher uptake of docetaxel in the liver and a concurrent increase in the expression of rOat2 (Slc22a7), an organic anion transporter that regulates, in part, the transfer of docetaxel from the circulation into hepatocytes. CONCLUSION: It is recommended that castration- and/or hormone-related changes in the clearance of oncology drugs should be considered as a possible risk factor for treatment failure. PMID- 20855839 TI - Spiny follicular hyperkeratosis eruption: a new cutaneous adverse effect of sorafenib. PMID- 20855841 TI - Acute lymphoblastic leukemia of male-recipient origin demonstrating female karyotype after cord blood transplantation. PMID- 20855840 TI - Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. AB - PURPOSE: Synergistic/additive cytotoxicity in tumor models and widespread applicability of fluoropyrimidines in solid tumors prompted the study of the combination of the mammalian target of rapamycin (mTOR) inhibitor, non-prodrug rapamycin analog ridaforolimus, with capecitabine. PATIENTS AND METHODS: Thirty two adult patients were treated. Intravenous ridaforolimus was given once weekly for 3 weeks and capecitabine was given from days 1 to 14 every 4 weeks. Ridaforolimus was given at 25, 37.5, 50, or 75 mg with capecitabine at 1,650 mg/m(2) or 1,800 mg/m(2) divided into two daily doses. Pharmacokinetics of both drugs were determined during cycles 1 and 2. Pharmacodynamic studies in peripheral blood mononuclear cells (PBMCs) and wound tissue of the skin characterized pathways associated with the metabolism or disposition of fluoropyrimidines and mTOR and ERK signaling. RESULTS: Two recommended doses (RDs) were defined: 75 mg ridaforolimus/1,650 mg/m(2) capecitabine and 50 mg ridaforolimus/1,800 mg/m(2) capecitabine. Dose-limiting toxicities were stomatitis and skin rash. One patient achieved a partial response lasting 10 months and 10 of 29 evaluable patients had stable disease for >= 6 months. The only pharmacokinetic interaction was a ridaforolimus-induced increase in plasma exposure to fluorouracil. PBMC data suggested that prolonged exposure to capecitabine reduced the ridaforolimus inhibition of mTOR. Ridaforolimus influenced the metabolism of fluoropyrimidines and inhibited dihydropyrimidine dehydrogenase, behavior similar to that of rapamycin. Inhibition of the target thymidylate synthase by capecitabine was unaffected. mTOR and ERK signaling was inhibited in proliferating endothelial cells and was more pronounced at the RD with the larger amount of ridaforolimus. CONCLUSION: Good tolerability, feasibility of prolonged treatment, antitumor activity, and favorable pharmacologic profile support further investigation of this combination. PMID- 20855842 TI - Insights into the place of fulvestrant for the treatment of advanced endocrine responsive breast cancer. PMID- 20855844 TI - Teaching NeuroImages: occlusion of all 4 major extracranial vessels. PMID- 20855843 TI - Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high grade glioma. AB - PURPOSE: Temozolomide (TMZ) is an alkylating agent licensed for treatment of high grade glioma (HGG). No prospective comparison with nitrosourea-based chemotherapy exists. We report, to our knowledge, the first randomized trial of procarbazine, lomustine, and vincristine (PCV) versus TMZ in chemotherapy-naive patients with recurrent HGG. PATIENTS AND METHODS: Four hundred forty-seven patients were randomly assigned to PCV (224 patients) or TMZ (sub-random assignment: TMZ-5 [200 mg/m(2) for 5 days, 112 patients] or TMZ-21 [100 mg/m(2) for 21 days, 111 patients]) for up to 9 months or until progression. The primary outcomes were survival (PCV v TMZ) and 12-week progression-free survival (PFS; TMZ-5 v TMZ-21). This study is registered as ISRCTN83176944. RESULTS: Percentages of patients completing 9 months of treatment in the PCV, TMZ-5, and TMZ-21 arms were 17%, 26%, and 13%, respectively. Major toxicity was similar across all three groups. With a median follow-up time of 12 months and 382 deaths, there was no clear survival benefit when comparing PCV with TMZ (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .350). For TMZ-5 versus TMZ-21, 12-week PFS rates were similar (63.6% and 65.7%, respectively; P = .745), but TMZ-5 improved overall PFS (HR, 1.38; 95% CI, 1.05 to 1.82; P = .023), survival (HR, 1.32; 95% CI, 0.99 to 1.75; P = .056), and global quality of life (49% v 19% improved > 10 points at 6 months, respectively; P = .005). CONCLUSION: Although TMZ (both arms combined) did not show a clear benefit compared with PCV, comparison of the TMZ schedules demonstrated that the 21-day schedule was inferior to the 5-day schedule in this setting. This challenges the current understanding of increasing TMZ dose intensity by prolonged scheduling. PMID- 20855845 TI - Teaching NeuroImages: Sturge-Weber syndrome presenting in a 58-year-old woman with seizures. PMID- 20855847 TI - Mild cognitive deficits in Parkinson disease: where there is bradykinesia, there is bradyphrenia. PMID- 20855848 TI - Diffusion tensor imaging, permanent pyramidal tract damage, and outcome in subcortical stroke. AB - BACKGROUND: Studies in chronic stroke patients suggest that diffusion tensor imaging (DTI) parameters of the pyramidal tract (PT) relate to residual motor function. We performed a prospective controlled study to evaluate if the DTI parameters tract volume (TV) and fractional anisotropy (FA) in patients with acute subcortical infarcts are correlated with permanent PT damage and clinical outcome after 6 months. METHODS: We acquired DTI in 18 stroke patients with subcortical ischemic infarcts either affecting the PT (PT group, n = 12) or not (non-PT group, n = 6) and in 7 age- and risk factor-matched controls at median times of 12 and 180 days. The PT was isolated using tractography and tract volume ratios (R(TV)) and FA ratios (R(FA)) were calculated (affected tract/unaffected tract). Ratios were compared within and between groups at initial and follow-up time points, as well as in tract portions above and below the infarcts, and were correlated to Rivermead Motor Function Test (RMFT) scores. RESULTS: Mean R(FA) and R(TV) of the PT group were smaller than those of both non-PT and control groups initially and at follow-up (p < 0.01). Tract portions above the infarct had lower R(TV) than below (p < 0.05). There was no significant change in R(FA) and R(TV) over time for the whole tract or tract portions. R(FA) and R(TV) both were highly correlated with initial and follow-up RMFT scores. CONCLUSIONS: DTI parameters of PT integrity acquired within the first weeks after acute subcortical stroke measure permanent ischemic PT damage and are highly correlated with residual motor function in the acute and chronic stage. PMID- 20855849 TI - Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. AB - BACKGROUND: In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies. OBJECTIVE: The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI. METHODS: A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data. RESULTS: A total of 25.8% of subjects (95% confidence interval [CI] 23.5-28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6-15.3), followed by visuospatial (11.0%; 9.4-13.0) and attention/executive ability impairment (10.1%; 8.6-11.9). Regarding cognitive profiles, 11.3% (9.7-13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0-9.9) as amnestic single domain, 4.8% (3.8-6.1) as amnestic multiple-domain, and 1.3% (0.9-2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage. CONCLUSIONS: MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage. PMID- 20855850 TI - 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy. AB - OBJECTIVE: 3-Methylglutaconic aciduria type I is a rare inborn error of leucine catabolism. It is thought to present in childhood with nonspecific symptoms; it was even speculated to be a nondisease. The natural course of disease is unknown. METHODS: This is a study on 10 patients with 3-methylglutaconic aciduria type I. We present the clinical, neuroradiologic, biochemical, and genetic details on 2 new adult-onset patients and follow-up data on 2 patients from the literature. RESULTS: Two unrelated patients with the characteristic biochemical findings of 3 methylglutaconic aciduria type I presented in adulthood with progressive ataxia. One patient additionally had optic atrophy, the other spasticity and dementia. Three novel mutations were found in conserved regions of the AUH gene. In both patients, MRI revealed extensive white matter disease. Follow-up MRI in a 10-year old boy, who presented earlier with isolated febrile seizures, showed mild abnormalities in deep white matter. CONCLUSION: We define 3-methylglutaconic aciduria type I as an inborn error of metabolism with slowly progressive leukoencephalopathy clinically presenting in adulthood. In contrast to the nonspecific findings in pediatric cases, the clinical and neuroradiologic pattern in adult patients is highly characteristic. White matter abnormalities may already develop in the first decades of life. The variable features found in affected children may be coincidental. Long-term follow-up in children is essential to learn more about the natural course of this presumably slowly progressive disease. Dietary treatment with leucine restriction may be considered. PMID- 20855851 TI - Long-term follow-up of neuromyelitis optica with a pediatric onset. AB - BACKGROUND: Neuromyelitis optica (NMO) is a rare inflammatory disease. Average age at onset is 35 years. Few data exist on patients with pediatric-onset NMO (p NMO), with disease onset before age 18 years. We report the clinical and paraclinical features and long-term outcome of patients with p-NMO and compare them with a large adult-onset NMO (a-NMO) cohort. METHODS: We performed a retrospective, multicenter study of patients with p-NMO in pediatric and adult medical centers. We identified 125 patients with NMO (12 p-NMO; 113 a-NMO) fulfilling the 2006 criteria. Data were collected using hospital files and standardized assessment forms for NMO. RESULTS: Patients with p-NMO were followed up during a mean 19.3 years. Median age at onset was 14.5 years (4.1-17.9) with a female:male ratio of 3:1. Three patients (25%) fulfilled Paty criteria for multiple sclerosis on first brain MRI, including one patient with acute disseminated encephalomyelitis. Median interval between onset and residual Expanded Disability Status Scale (EDSS) score 4 was 20.7 years, score 6 was 26 years, and score 7 was 28.7 years. Median interval between onset and residual visual loss <=1/10 was 1.3 years. Compared with a-NMO, p-NMO showed a longer time to EDSS scores 4 and 6, largely explained by the severity of the first myelitis in the a-NMO group. Time to first treatment was longer in the p-NMO group (13.1 vs 3.4 years). CONCLUSION: Patients with p-NMO can present a diffuse inflammatory process on first brain MRI and have a longer time to disability than patients with a-NMO. PMID- 20855852 TI - Quantification of pilomotor nerves: a new tool to evaluate autonomic involvement in diabetes. AB - OBJECTIVES: Quantification of the complex, autonomic networks in the skin is difficult. Although sporadic attempts focusing mainly on sudomotor plexus have been reported, an easy and reliable method of quantification has not yet been made available. We developed a method to quantify pilomotor nerve fibers (PNFs), which, compared to sudomotor nerves, have a less complex pattern. We used this procedure on a population of normal and diabetic subjects, and propose it as a new tool to study cutaneous autonomic nerves. METHODS: Skin biopsies were performed from thigh and distal leg in 20 diabetic patients and 20 age- and sex matched controls. Samples were processed applying indirect immunofluorescence and using pan-neuronal and selective markers for cholinergic and noradrenergic fibers. Pilomotor nerve fiber density was blindly calculated on single 2-MUm optical sections selected from confocal z-stacks. Interobserver and intraobserver reliability was evaluated. Results were compared with values obtained by 2 other methods that explored PNFs more extensively. Pilomotor nerve fibers density was compared to epidermal nerve fiber (ENF) density, to pilocarpine-activated sweat gland density, and to the severity of neuropathy as assessed by the modified total neuropathy score. RESULTS: A significant loss of PNFs was found in diabetic subjects' thigh and leg. PNFs density did not correlate with ENF density, disease duration, or total neuropathy score. Noradrenergic PNFs correlated instead with sweating impairment. CONCLUSIONS: A reliable assessment of PNF density is possible. When studying cutaneous innervation, PNF quantification should be done to gain information on autonomic nerves in addition to somatic nerves. PMID- 20855853 TI - Intravenous aspirin (lysine acetylsalicylate) in the inpatient management of headache. AB - BACKGROUND: IV lysine acetylsalicylate (aspirin) has been shown to be effective in the treatment of acute migraine attacks, but little is known about its effectiveness and safety in patients hospitalized for management of severe headache, typically arising from abrupt withdrawal of other acute attack medications. METHODS: We present an audit of our use of IV aspirin in 168 patients in a tertiary referral setting. RESULTS: The findings demonstrate subjective approval of this medication by the patients and objective improvements in pain scores, a decrease of >=3 points on a 10-point visual analog pain scale being seen on >25% occasions on which the medication was administered. Further, side effect rates were low (5.9%), with no serious adverse events. CONCLUSION: IV aspirin is safe, effective, and useful in the inpatient management of headache. PMID- 20855854 TI - Olfactory system: functional organization and involvement in neurodegenerative disease. PMID- 20855855 TI - Trends in American Board of Psychiatry and Neurology specialties and neurologic subspecialties. AB - OBJECTIVE: To review the current status and recent trends in the American Board of Psychiatry and Neurology (ABPN) specialties and neurologic subspecialties and discuss the implications of those trends for subspecialty viability. METHODS: Data on numbers of residency and fellowship programs and graduates and ABPN certification candidates and diplomates were drawn from several sources, including ABPN records, Web sites of the Accreditation Council for Graduate Medical Education and the American Medical Association, and the annual medical education issues of the Journal of the American Medical Association. RESULTS: About four-fifths of neurology graduates pursue fellowship training. While most recent neurology and child neurology graduates attempt to become certified by the ABPN, many clinical neurophysiologists elect not to do so. There appears to have been little interest in establishing fellowships in neurodevelopmental disabilities. The pass rate for fellowship graduates is equivalent to that for the "grandfathers" in clinical neurophysiology. Lower percentages of clinical neurophysiologists than specialists participate in maintenance of certification, and maintenance of certification pass rates are high. CONCLUSION: The initial enthusiastic interest in training and certification in some of the ABPN neurologic subspecialties appears to have slowed, and the long-term viability of those subspecialties will depend upon the answers to a number of complicated social, economic, and political questions in the new health care era. PMID- 20855857 TI - Isolated and prolonged loss of time orientation. PMID- 20855856 TI - Low disease risk in relatives of north african lrrk2 Parkinson disease patients. PMID- 20855858 TI - Six-minute walk test demonstrates motor fatigue in spinal muscular atrophy. PMID- 20855859 TI - Undiminished regulatory T cells in the thymus of patients with myasthenia gravis. PMID- 20855860 TI - Quantification of diffuse myocardial fibrosis and its association with myocardial dysfunction in congenital heart disease. AB - BACKGROUND: the etiology of ventricular dysfunction in adult congenital heart disease (ACHD) is not well understood. Diffuse fibrosis is a likely common final pathway and is quantifiable using MRI. METHODS AND RESULTS: patients with ACHD (n=50) were studied with cardiac MRI to quantify systemic ventricular volume and function and diffuse fibrosis. The fibrosis index for a single midventricular plane of the systemic ventricle was quantified by measuring T1 values for blood pool and myocardium before and after administration of gadolinium (0.15 mmol/kg) and then adjusted for hematocrit. Results were compared to healthy volunteers (normal controls, n=14) and patients with acquired heart failure (positive controls, n=4). Patients studied (age, 37+/-12 years; female sex, 40%) included 11 with a systemic right ventricle (RV), 17 with tetralogy of Fallot, 10 with cyanosis, and 12 with other lesions. The fibrosis index was significantly elevated in patients with ACHD compared to normal controls (31.9+/-4.9% versus 24.8+/-2.0%; P=0.001). Values were highest in patients with a systemic RV (35.0+/ 5.8%; P<0.001) and those who were cyanotic (33.7+/-5.6%; P<0.001). The fibrosis index correlated with end-diastolic volume index (r=0.60; P<0.001) and ventricular ejection fraction (r=-0.53; P<0.001) but not with age or oxygen saturation in patients who were cyanotic. Late gadolinium enhancement did not account for the differences seen. CONCLUSIONS: patients with ACHD have evidence of diffuse, extracellular matrix remodeling similar to patients with acquired heart failure. The fibrosis index may facilitate studies on the mechanisms and treatment of myocardial fibrosis and heart failure in these patients. PMID- 20855861 TI - Validation of 3D echocardiographic assessment of left ventricular volumes, mass, and ejection fraction in neonates and infants with congenital heart disease: a comparison study with cardiac MRI. AB - BACKGROUND: quantitative assessment and validation of left ventricular (LV) volumes and mass in neonates and infants with complex congenital heart disease (CHD) is important for clinical management but has not been undertaken. We compared matrix-array 3D echocardiography (3D echo) measurements of volumes, mass, and ejection fraction (EF) with those measured by cardiac MRI in young patients with CHD and small LVs because of either young age or LV hypoplasia. METHODS AND RESULTS: thirty-five patients aged <4 years (median, 0.8 years) undergoing MRI were prospectively enrolled. Three-dimensional echo was acquired immediately after MRI, and volume, mass, and EF measurements, using summation of discs methodology, were compared with MRI. Three-dimensional echo end-diastolic volume (24.4+/-15.7 versus 24.8+/-46.4 mL; P=0.01; intraclass correlation coefficient [ICC], 0.96) and end-systolic volume (12.3+/-8.6 versus 9.6+/-6.8 mL; P<0.001; ICC, 0.90) correlated with MRI with small mean differences (-0.49 mL [P=0.6] and 2.7 mL [P=0.001], respectively). Three-dimensional echo EF was smaller than MRI by 9.3% (P<0.001), and 3D echo LV mass measurements were comparable to MRI (17.3+/-10.3 versus 17.6+/-12 g; P<0.77; ICC, 0.93), with a small mean difference (1.1 g; P=0.28). There was good intra- and interobserver reliability for all measurements. CONCLUSIONS: in neonates and infants with CHD and small LVs (age appropriate or hypoplastic), matrix-array 3D echo measurements of mass and volumes compare well with MRI, providing an important modality for ventricular size and performance analysis in these patients, particularly in those with left-side heart obstructive lesions. PMID- 20855862 TI - Reduced-intensity conditioning significantly improves survival of patients with hemophagocytic lymphohistiocytosis undergoing allogeneic hematopoietic cell transplantation. AB - Recent experience suggests that reduced-intensity conditioning (RIC) regimens can improve the outcomes of patients with hemophagocytic lymphohistiocytosis (HLH) undergoing allogeneic hematopoietic cell transplantation (HCT). However, studies directly comparing RIC to myeloablative conditioning (MAC) regimens are lacking. Forty patients with HLH underwent allogeneic HCT between 2003-2009 at Cincinnati Children's Hospital. Fourteen patients received MAC consisting of busulfan, cyclophosphamide, and antithymocyte globulin plus or minus etoposide. Twenty-six patients received RIC consisting of fludarabine, melphalan, and alemtuzumab. All patients engrafted. Acute graft-versus-host disease grades II to III occurred in 14% of MAC patients and 8% of RIC patients (P = .3171). Posttransplantation mixed donor/recipient chimerism developed in 18% of MAC patients and 65% of RIC patients (P = .0110). The majority of patients with mixed chimerism received intervention with reduction of immune suppression plus or minus donor lymphocyte infusion or stem cell boost, which stabilized or increased donor contribution to hematopoiesis and prevented relapse of HLH in all but 1 patient. Grade II to III graft-versus-host disease occurred in 5 of 14 RIC patients after donor lymphocyte infusion. The overall estimated 3-year survival after HCT was 43% (confidence interval = +/- 26%) for MAC patients and 92% (confidence interval = +/- 11%) for RIC patients (P = .0001). We conclude that RIC significantly improves the outcome of patients with HLH undergoing allogeneic HCT. PMID- 20855863 TI - EVI-1 oncogene expression predicts survival in chronic-phase CML patients resistant to imatinib treated with second-generation tyrosine kinase inhibitors. AB - Activation of the EVI-1 oncogene has been reported in acute myeloid leukemia, chronic myeloid leukemia (CML) in blast crisis, and less commonly, in chronic phase CML patients. We screened an unselected cohort of 75 chronic-phase CML patients who had failed imatinib for expression of EVI-1 and sought a correlation with subsequent outcome on the second-generation tyrosine kinase inhibitors dasatinib (n = 61) or nilotinib (n = 14). The 8 patients (10.7%) who expressed EVI-1 transcripts detectable by real-time polymerase chain reaction had significantly lower event-free survival, progression-free survival, and overall survival than patients with undetectable transcript. The predictive value of EVI 1 expression was validated in an independent cohort. In a multivariate analysis, EVI-1 expression status and the best cytogenetic response obtained on imatinib were the only independent predictors for overall survival, progression-free survival, and event-free survival. Our data suggest that screening for EVI-1 expression at the time of imatinib failure may predict for response to second line TKI therapy and consequently aid clinical management. PMID- 20855864 TI - How I treat patients with advanced systemic mastocytosis. AB - Advanced systemic mastocytosis (SM) is a rare myeloid neoplasm characterized by uncontrolled accumulation of neoplastic mast cells (MCs) in various organs with consecutive impairment of organ function, drug resistance, and a poor prognosis. Advanced SM may present as smoldering or slowly progressing neoplasm but may also present as rapidly progressing aggressive SM or even as MC leukemia. Approximately half of the patients have an associated hematologic non-MC-lineage disease (SM-AHNMD) or develop an AHNMD over time. Drug resistance may not only result from the KIT mutant D816V that is found in most patients, but also from KIT-independent pro-oncogenic signaling pathways that play a role in disease evolution. In patients with slow progression, advanced SM can often be kept under control for months with interferon-alpha or 2CdA. By contrast, in rapidly progressing aggressive SM and MC leukemia, even polychemotherapy and hematopoietic stem cell transplantation may fail, which points to the need to develop new drugs and treatment concepts for these patients. In SM-AHNMD, separate treatment plans should be established for the SM component and the AHNMD component of the disease, with recognition that the AHNMD often has to be managed and treated as a secondary and thus a high-risk neoplasm. PMID- 20855865 TI - Diminished contact-dependent reinforcement of Syk activation underlies impaired thrombus growth in mice lacking Semaphorin 4D. AB - We recently reported that Semaphorin 4D (Sema4D) and its receptors are expressed on the platelet surface and showed that Sema4D((-/-)) mice have a selective defect in collagen-induced platelet aggregation and an impaired vascular injury response. Here we investigated the mechanisms involved, tested the role of platelet-platelet contacts in Sema4D-mediated events, and examined the relationship between Sema4D-dependent signaling and integrin alpha(IIb)beta(3) outside-in signaling. The results show that spleen tyrosine kinase (Syk) activation, an early step in collagen signaling via the glycoprotein VI (GPVI)/FcRgamma complex, is greatly reduced in Sema4D((-/-)) platelets and can be restored by adding soluble Sema4D. Earlier events, including FcRgamma phosphorylation, occur normally; later events are impaired. In contrast, when engagement of alpha(IIb)beta(3) was blocked, Sema4D((-/-)) and control platelets were indistinguishable in assays of Syk activation, adhesion, spreading on collagen, and activation of alpha(IIb)beta(3). Finally, we found that, unlike the Sema4D knockout, alpha(IIb)beta(3) blockade inhibited FcRgamma phosphorylation and that stimulating aggregation with Mn(2+) failed to normalize Syk activation in the absence of Sema4D. Collectively, these results show that alpha(IIb)beta(3) and Sema4D jointly promote collagen responses by amplifying Syk activation, partly by forming integrin-mediated contacts that enable the binding of Sema4D to its receptors and partly through integrin outside-in signaling. These 2 processes are interdependent, but distinguishable. PMID- 20855867 TI - Inherited genetic susceptibility to monoclonal B-cell lymphocytosis. AB - Monoclonal B-cell lymphocytosis (MBL) is detectable in > 3% of the general population. Recent data are compatible, at least in a proportion of cases, with MBL being a progenitor lesion for chronic lymphocytic leukemia (CLL) and a surrogate for inherited predisposition. Common single nucleotide polymorphisms (SNPs) at 2q13 (rs17483466), 2q37.1 (rs13397985), 2q37.3 (rs757978), 6p25.3 (rs872071), 8q24.21 (rs2456449), 11q24.1 (rs735665), 15q21.3 (rs7169431), 15q23 (rs7176508), 16q24.1 (rs305061), and 19q13.32 (rs11083846) have been shown to confer a modest but significant increase in CLL risk. To examine the impact of these 10 SNPs on MBL, we analyzed 3 case-control series totaling 419 cases and 1753 controls. An association between genotype and MBL risk was seen for 9 SNPs, 6 of which were statistically significant: rs17483466 (odds ratio [OR] =1.27; P = .02), rs13397985 (OR = 1.40; P = 1.72 * 10(-3)), rs757978 (OR = 1.38; P = .02), rs872071 (OR = 1.27; P = 7.75 * 10(-3)), rs2456449 (OR = 1.31; P = 3.14 * 10( 3)), and rs735665 (OR = 1.63; P = 6.86 * 10(-6)). Collectively, these data provide support for genetic variation influencing CLL risk through predisposition to MBL. PMID- 20855866 TI - Aberrant DNA hypermethylation signature in acute myeloid leukemia directed by EVI1. AB - DNA methylation patterns are frequently dysregulated in cancer, although little is known of the mechanisms through which specific gene sets become aberrantly methylated. The ecotropic viral integration site 1 (EVI1) locus encodes a DNA binding zinc-finger transcription factor that is aberrantly expressed in a subset of acute myeloid leukemia (AML) patients with poor outcome. We find that the promoter DNA methylation signature of EVI1 AML blast cells differs from those of normal CD34(+) bone marrow cells and other AMLs. This signature contained 294 differentially methylated genes, of which 238 (81%) were coordinately hypermethylated. An unbiased motif analysis revealed an overrepresentation of EVI1 binding sites among these aberrantly hypermethylated loci. EVI1 was capable of binding to these promoters in 2 different EVI1-expressing cell lines, whereas no binding was observed in an EVI1-negative cell line. Furthermore, EVI1 was observed to interact with DNA methyl transferases 3A and 3B. Among the EVI1 AML cases, 2 subgroups were recognized, of which 1 contained AMLs with many more methylated genes, which was associated with significantly higher levels of EVI1 than in the cases of the other subgroup. Our data point to a role for EVI1 in directing aberrant promoter DNA methylation patterning in EVI1 AMLs. PMID- 20855868 TI - Beyond the enhanceosome: cluster of novel kappaB sites downstream of the human IFN-beta gene is essential for lipopolysaccharide-induced gene activation. AB - The expression of interferon-beta (IFN-beta) in virus-infected HeLa cells established a paradigm of multifactorial gene regulation, in which cooperative assembly of transcription factors (TFs) at the composite DNA element (enhanceosome), is central for amplification of weak activating signals provided by individual TFs. However, whether the same TFs and the same DNA element are essential for IFN-beta induction in response to bacterial stimuli are less well understood. Here we report that rapid and transient transcription of IFN-beta in response to TLR4 stimulation with bacterial lipopolysaccharide (LPS) follows nuclear factor-kappaB (NF-kappaB) RelA activation and recruitment to the IFN-beta genomic locus at multiple spatially separated regulatory regions. We demonstrate that the IFN-beta enhanceosome region is not sufficient for maximal gene induction in response to LPS and identify an essential cluster of homotypic kappaB sites in the 3' downstream of the gene. The cluster is characterized by elevated levels of histone 3 lysine 4 mono-methylation, a chromatin signature of enhancers, and efficiently binds RelA-containing NF-kappaB complexes in vitro and in vivo. These findings demonstrate that IFN-beta gene activation via multifactorial enhanceosome assembly is potentiated in LPS-stimulated cells by NF kappaB interactions with all functional kappaB sites in the locus. PMID- 20855869 TI - PIPKI gamma 90 negatively regulates LFA-1-mediated adhesion and activation in antigen-induced CD4+ T cells. AB - T cell activation requires the formation and maintenance of stable interactions between T cells and APCs. The formation of stable T cell-APC contacts depends on the activation of the integrin LFA-1 (CD11aCD18). Several positive regulators of LFA-1 activation downstream of proximal TCR signaling have been identified, including talin; however, negative regulators of LFA-1 activity remain largely unexplored. Extended isoform of phosphatidylinositol phosphate kinase type I gamma (PIPKIgamma90) is a member of the type I phosphatidylinositol phosphate kinase family that has been shown previously to modulate talin activation of integrins through production of phosphatidylinositol 4,5-bisphosphate and direct binding to talin. In this study, we show that PIPKIgamma90 negatively regulates LFA-1-mediated adhesion and activation of T cells. Using CD4(+) T cells from PIPKIgamma90-deficient mice, we show that CD4(+) T cells exhibit increased LFA-1 dependent adhesion to ICAM-1 and increased rates of T cell-APC conjugate formation with enhanced LFA-1 polarization at the synapse. In addition to increased adhesiveness, PIPKIgamma90-deficient T cells exhibit increased proliferation both in vitro and in vivo and increased production of IFN-gamma and IL-2. Together, these results demonstrate that PIPKIgamma90 is a negative regulator of Ag-induced T cell adhesion and activation. PMID- 20855870 TI - Acute ablation of Langerhans cells enhances skin immune responses. AB - Understanding the function of Langerhans cells (LCs) in vivo has been complicated by conflicting results from LC-deficient mice. Human Langerin-DTA mice constitutively lack LCs and develop exaggerated contact hypersensitivity (CHS) responses. Murine Langerin-diphtheria toxin receptor (DTR) mice allow for the inducible elimination of LCs and Langerin(+) dermal dendritic cells (dDCs) after administration of diphtheria toxin, which results in reduced CHS. When Langerin(+) dDCs have partially repopulated the skin but LCs are still absent, CHS returns to normal. Thus, LCs appear to be suppressive in human Langerin-DTA mice and redundant in murine Langerin-DTR mice. To determine whether inducible versus constitutive LC ablation explains these results, we engineered human Langerin-DTR mice in which diphtheria toxin ablates LCs without affecting Langerin(+) dDCs. The inducible ablation of LCs in human Langerin-DTR mice resulted in increased CHS. Thus, LC-mediated suppression does not require their absence during ontogeny or during the steady-state and is consistent with a model in which LCs actively suppress Ag-specific CHS responses. PMID- 20855871 TI - Cellular requirements for diabetes induction in DO11.10xRIPmOVA mice. AB - Type 1 diabetes (T1D) results from the immune-mediated destruction of the insulin producing beta-islet cells in the pancreas. The genetic and environmental mechanisms promoting the development of this disease remain poorly understood. We have explored the cellular requirements for T1D development in DO11.10xRIPmOVA (DORmO) mice, which carry a TCR transgene specific for an MHC class II-restricted epitope from OVA and express membrane-bound OVA in the pancreas under the control of the rat insulin promoter. We found that DORmO.RAG2(-/-) mice do not develop insulitis and are completely protected from diabetes, demonstrating that endogenous lymphocyte receptor rearrangement is required for disease development. Diabetes in DORmO mice is preceded by the development of OVA-specific autoantibodies and is delayed in B cell-deficient DORmO.JhD(-/-) mice, demonstrating that B cells contribute to disease progression. In addition, transfer of CD8(+) T cells from diabetic animals into DORmO.RAG2(-/-) mice promoted insulitis by OVA-specific CD4(+) T cells. Finally, although diabetes develops in DORmO mice in the presence of a significant population of Foxp3(+) OVA-specific regulatory T cells, boosting regulatory T cell numbers by injecting IL-2 immune complexes dampens autoantibody production and prevents development of insulitis and overt diabetes. These results help define the events leading to diabetes in DORmO mice and provide new insights into the cellular interactions required for disease development in an Ag-specific model of T1D. PMID- 20855872 TI - Plasmacytoid dendritic cells alter the antitumor activity of CpG oligodeoxynucleotides in a mouse model of lung carcinoma. AB - The effect of CpG-oligodeoxynucleotides (CpG) has been studied on a number of tumors. Although CpG may facilitate tumor regression in mouse models of melanoma, its activity in lung cancer is unclear. The aim of our study was to elucidate the effect of CpG (0.5-50 MUg/mouse) in a mouse model of Lewis lung carcinoma cell induced lung cancer. Lung tumor growth increased at 3 and 7 d after a single administration of CpG. This was associated with a greater influx of plasmacytoid dendritic cells (pDCs), immature myeloid dendritic cells, and greater recruitment of regulatory T cells. Depletion of pDCs using a specific Ab (m927) reversed the immune-suppressive environment and resulted in a decreased lung tumor burden, accompanied by a greater influx of active myeloid dendritic cells and CD8(+) T cells, and a higher production of Th1- and Th17-like cytokines. Furthermore, the rate of apoptosis in the lungs of mice treated with CpG increased following the depletion of pDCs. CpG treatment alone does not lead to tumor regression in the lung. However, ablation of pDCs renders CpG a good adjuvant for lung cancer chemotherapy in this experimental model. PMID- 20855873 TI - Functional analysis of recombinant calreticulin fragment 39-272: implications for immunobiological activities of calreticulin in health and disease. AB - Although calreticulin (CRT) is a major Ca(2+)-binding luminal resident protein, it can also appear on the surface of various types of cells and it functions as an immunopotentiating molecule. However, molecular mechanisms underlying the potent immunobiological activity of cell surface CRT are still unclear. In the present study, a recombinant fragment (rCRT/39-272) covering the lectin-like N domain and partial P domain of murine CRT has been expressed in Escherichia coli. The affinity-purified rCRT/39-272 assembles into homodimers and oligomers in solution and exhibits high binding affinity to various glycans, including carrageenan, alginic acids, and hyaluronic acids. Functionally, rCRT/39-272 is capable of driving the activation and maturation of B cells and cytokine production by macrophages in a TLR-4-dependent manner in vitro. It specifically binds recombinant mouse CD14, but not BAFFR and CD40. It is also able to trigger Ig class switching by B cells in the absence of T cell help both in vitro and in vivo. Furthermore, this fragment of CRT exhibits strong adjuvanticity when conjugated to polysaccharides or expressed as part of a fusion protein. Soluble CRT can be detected in the sera of patients with rheumatoid arthritis or systemic lupus erythematosus, but not in healthy subjects. We argue that CRT, either on the membrane surface of cells or in soluble form, is a potent stimulatory molecule to B cells and macrophages via the TLR-4/CD14 pathway and plays important roles in the pathogenesis of autoimmune diseases. PMID- 20855874 TI - IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. AB - Colorectal cancer is a leading cause of cancer-related deaths worldwide. Chronic inflammation is recognized as a predisposing factor for the development of colon cancer, but the molecular mechanisms linking inflammation and tumorigenesis have remained elusive. Recent studies revealed a crucial role for the NOD-like receptor protein Nlrp3 in regulating inflammation through the assembly of proinflammatory protein complexes termed inflammasomes. However, its role in colorectal tumor formation remains unclear. In this study, we showed that mice deficient for Nlrp3 or the inflammasome effector caspase-1 were highly susceptible to azoxymethane/dextran sodium sulfate-induced inflammation and suffered from dramatically increased tumor burdens in the colon. This was a consequence of markedly reduced IL-18 levels in mice lacking components of the Nlrp3 inflammasome, which led to impaired production and activation of the tumor suppressors IFN-gamma and STAT1, respectively. Thus, IL-18 production downstream of the Nlrp3 inflammasome is critically involved in protection against colorectal tumorigenesis. PMID- 20855875 TI - Effect of Ly49 haplotype variance on NK cell function and education. AB - The class I MHC-specific receptors expressed by murine NK cells exhibit remarkable variation. Specific activating killer Ig-related receptor/Ly49 have major effects on autoimmune and infectious disease induction and outcome in humans and mice. However, these studies are greatly affected by individual background genetics. Furthermore, the educational impact of variable inhibitory KIR/Ly49 gene numbers on NK cell development and the subsequent ability to survey for MHC class I (MHC-I) expression remain unknown. To address these questions, Ly49 congenic mice were generated that maintain a 129-derived Ly49 gene cluster on a C57BL/6 genetic background (B6.Ly49(129) mice), and the in vitro and in vivo NK cell function of these mice was compared with their inbred parental 129S1 and C57BL/6 counterparts. Notably, target cell recognition directed by activating Ly49 receptors was profoundly affected by allelic variation in B6.Ly49(129) congenic cells versus C57BL/6 NK cells. Furthermore, when assessing NK cell function based on education and subsequent recognition of the C57BL/6 MHC-I haplotype by inhibitory Ly49 receptors, B6.Ly49(129) congenic mice exhibited robust NK cell activity, demonstrating efficient NK cell education by the 129S1 Ly49 cluster during development. The responsiveness of NK cells expressing 129S1 Ly49 was shown to be mediated by subsets expressing one or more self-MHC receptors, including Ly49I, Ly49O, Ly49V, and NKG2A. These findings demonstrate that the genetically segregating and diverse MHC-I and Ly49 loci in mice exhibit independent and epistatic effects on NK cell education that can be uncoupled during the intercrossing of inbred strains. PMID- 20855876 TI - Hallmark features of immunosenescence are absent in familial longevity. AB - Seropositivity for CMV is one of the parameters of the "immune risk profile" associated with mortality in longitudinal studies of the very elderly and may accelerate immunosenescence. Thus, any genetic factors influencing human longevity may be associated with susceptibility to CMV and CMV-accelerated immunosenescence. To test this, we analyzed long-lived families in the Leiden Longevity Study (LLS) in which offspring enjoy a 30% reduced standardized mortality rate, possibly owing to genetic enrichment. Serum C-reactive protein levels and the frequency of different T cell subsets were compared between 97 LLS offspring and 97 controls (their partners, representing the normal population). We also determined the capacity of T cells to respond against immunodominant Ags from CMV in a smaller group of LLS subjects and controls. CMV infection was strongly associated with an age-related reduction in the frequency of naive T cells and an accumulation of CD45RA-re-expressing and late-differentiated effector memory T cells in the general population, but not in members of long lived families. The latter also had significantly lower C-reactive protein levels, indicating a lower proinflammatory status compared with CMV-infected controls. Finally, T cells from a higher proportion of offspring mounted a proliferative response against CMV Ags, which was also of greater magnitude and broader specificity than controls. Our data suggest that these rare individuals genetically enriched for longevity are less susceptible to the characteristic CMV associated age-driven immune alterations commonly considered to be hallmarks of immunosenescence, which might reflect better immunological control of the virus and contribute to their decreased mortality rate. PMID- 20855877 TI - Peptide length extension skews the minor HA-1 antigen presentation toward activated dendritic cells but reduces its presentation efficiency. AB - Minor histocompatibility Ags (mHags) are important targets of the graft-versus leukemia effect after HLA-matched allogeneic stem cell transplantation. mHags are HLA-restricted polymorphic peptides expressed on normal and leukemia cells. Vaccination with hematopoiesis-restricted mHag peptides, such as HA-1, may boost the graft-versus-leukemia effect. However, some animal studies indicate that peptides exactly reflecting immunogenic T cell epitopes (short peptides [SPs]) induce tolerance that is potentially due to systemic Ag spreading. Peptide length extension (long peptides [LPs]) may optimize immune responses by restricting and prolonging Ag presentation on dendritic cells (DCs). In this study, we compared the in vitro characteristics and T cell-stimulatory capacities of a human 30-mer HA-1 LP with the 9-mer HA-1 SP. DCs presented the HA-1 LP and SP and expanded HA 1-specific cytotoxic T cell lines. As hypothesized, HA-1 LP presentation, but not SP presentation, was largely restricted to activated DCs and was nearly absent on other hematopoietic cells. However, DCs presented the HA-1 LP 2-3 log levels less efficiently than the SP. Finally, the decay of HA-1 LP and SP presentation on DCs was comparable. We conclude that HA-1 LP and SP differ in their in vitro characteristics and that only comparative clinical studies after allogeneic stem cell transplantation may reveal the optimal HA-1 vaccine. PMID- 20855878 TI - Activation of p38 MAPK is required in monocytic and neuronal cells for HIV glycoprotein 120-induced neurotoxicity. AB - HIV-1 envelope protein gp120 has been implicated in neurotoxin production by monocytic cells (i.e., macrophages and microglia), as well as in the pathogenesis of HIV-1-associated neurocognitive disorders. We previously showed in cerebrocortical cell cultures from rodents containing microglia, astrocytes, and neurons that overall inhibition of p38 MAPK signaling abrogated the neurotoxic effect of HIV-1 gp120. However, the time course of p38 MAPK activation and the contribution of this kinase in the various cell types remained unknown. In this study, we found that active p38 MAPK is required in monocytic lineage cells (i.e., macrophages and microglia) and neuronal cells for HIV gp120-induced neurotoxicity to occur. In cerebrocortical cell cultures, HIV-1 gp120 stimulated a time-dependent overall increase in active p38 MAPK, and the activated kinase was primarily detected in microglia and neurons. Interestingly, increased activation of p38 MAPK and neuronal death in response to gp120 were prevented by prior depletion of microglia or the presence of CCR5 ligand CCL4 or p38 MAPK inhibitors. In human monocytic THP-1 cells and primary monocyte-derived macrophages, HIV gp120-stimulated production of neurotoxins was abrogated by prior introduction into the cells of a dominant-negative p38 MAPK mutant or p38 MAPK small interfering RNA. In addition, the neurotoxic effects of cell-free supernatants from gp120-stimulated monocytic THP-1 cells were prevented in microglia-depleted cerebrocortical cells pretreated with a pharmacological inhibitor of p38 MAPK. Thus, p38 MAPK signaling was critical, upon exposure to HIV gp120, for the neurotoxic phenotype of monocytic cells and subsequent toxin initiated neuronal apoptosis. PMID- 20855879 TI - TGF-beta-activated kinase 1 signaling maintains intestinal integrity by preventing accumulation of reactive oxygen species in the intestinal epithelium. AB - The intestinal epithelium is constantly exposed to inducers of reactive oxygen species (ROS), such as commensal microorganisms. Levels of ROS are normally maintained at nontoxic levels, but dysregulation of ROS is involved in intestinal inflammatory diseases. In this article, we report that TGF-beta-activated kinase 1 (TAK1) is a key regulator of ROS in the intestinal epithelium. tak1 gene deletion in the mouse intestinal epithelium caused tissue damage involving enterocyte apoptosis, disruption of tight junctions, and inflammation. Disruption of TNF signaling, which is a major intestinal damage inducer, rescued the inflammatory conditions but not apoptosis or disruption of tight junctions in the TAK1-deficient intestinal epithelium, suggesting that TNF is not a primary inducer of the damage noted in TAK1-deficient intestinal epithelium. We found that TAK1 deficiency resulted in reduced expression of several antioxidant responsive genes and reduced the protein level of a key antioxidant transcription factor NF-E2-related factor 2, which resulted in accumulation of ROS. Exogenous antioxidant treatment reduced apoptosis and disruption of tight junctions in the TAK1-deficient intestinal epithelium. Thus, TAK1 signaling regulates ROS through transcription factor NF-E2-related factor 2, which is important for intestinal epithelial integrity. PMID- 20855880 TI - Cutting edge: TCR ligation triggers digital activation of NF-kappaB. AB - TCR-mediated activation of the transcription factor NF-kappaB is required for T cell proliferation, survival, and effector differentiation. Although this pathway is the subject of intense study, it is not known whether TCR signaling to NF kappaB is digital (switch-like) or analog in nature. Through analysis of the phosphorylation and degradation of IkappaBalpha and the nuclear translocation and phosphorylation of the NF-kappaB subunit RelA, we show that TCR-directed NF kappaB activation is digital. Furthermore, digitization occurs well upstream of the IkappaB kinase complex, as protein kinase C translocation to the immunologic synapse and activation-associated aggregation of Bcl10 and Malt1 also demonstrate both digital behavior and high correlation with RelA nuclear translocation. Thus, similar to the TCR-to-MAPK signaling cascade, analog Ag inputs are converted to digital activation outputs to NF-kappaB at an early step downstream of TCR ligation. PMID- 20855881 TI - NK cell deficiency predisposes to viral-induced Th2-type allergic inflammation via epithelial-derived IL-25. AB - Severe respiratory syncytial virus (RSV) infection has long been associated with an increased risk for the development of childhood asthma and exacerbations of this disorder. Despite much research into the induction of Th2 responses by allergens and helminths, the factors associated with viral infection that predispose to Th2-regulated asthma remain unknown. Recently, clinical studies have shown reduced numbers of NK cells in infants suffering from a severe RSV infection. Here we demonstrate that NK cell deficiency during primary RSV infection of BALB/c mice results in the suppression of IFN-gamma production and the development of an RSV-specific Th2 response and subsequent allergic lung disease. The outgrowth of the Th2 responses was dependent on airway epithelial cell-derived IL-25, which induced the upregulation of the notch ligand Jagged1 on dendritic cells. This study identifies a novel pathway underlying viral-driven Th2 responses that may have functional relevance to viral-associated asthma. PMID- 20855882 TI - Gender differences in 1,25 dihydroxyvitamin D3 immunomodulatory effects in multiple sclerosis patients and healthy subjects. AB - Vitamin D(3) is best known as a calcium homeostasis modulator; however, it also has immune-modulating potential. In this study, we demonstrated that immunomodulatory effects of vitamin D(3) are significantly stronger in females than in males in multiple sclerosis patients, as well as in healthy subjects. Inhibition of self-reactive T cell proliferation and reduction in IFN-gamma- and IL-17-secreting cell numbers were considerably greater in females. Furthermore, the increase in IL-10-secreting and CD4(+)CD25(+)FoxP3(+) regulatory T cell numbers were also greater in females. In parallel with these findings, female subjects had fewer CYP24A1 transcripts encoding the 1,25-dihydroxyvitamin D(3) inactivating enzyme, as well as greater binding and internalization of vitamin D(3)-binding protein, a transporter for vitamin D(3) and its metabolites. These gender-based disparities lead to the accumulation of vitamin D(3) and its metabolites in target cells from female subjects and result in a more potent anti inflammatory effect. Interestingly, 17-beta estradiol reproduced these effects on self-reactive T cells and macrophages from male subjects, suggesting a functional synergy between 1,25-dihydroxyvitamin D(3) and 17-beta estradiol, mediated through estrogen receptor alpha. Collectively, these results demonstrate estrogen promoted differences in vitamin D(3) metabolism, suggesting a greater protective effect of vitamin D(3)-based therapeutic strategies in women. PMID- 20855883 TI - Glioma cells display complex cell surface topographies that resist the actions of cytolytic effector lymphocytes. AB - Gliomas are invasive cancers that resist all forms of attempted therapy. Immunotherapy using Ag-pulsed dendritic cells has improved survival in some patients. We present evidence that another level of complexity may also contribute to lack of responses by the lymphocytes toward gliomas. Atomic force microscopy of four different glioma types-human U251 and rat T9 and F98 glioma cells, including freshly isolated human glioblastoma multiforme neurosphere cultures (containing "stem cell-like cells")-revealed a complex surface topography with numerous microvilli and filopodia. These structures were not found on other cell types. Electron microscopy and immunofluorescence microscopy of glioma cells confirmed that microvilli are present. U251 cells with microvilli resisted the cytolytic actions of different human effector cells, (lymphokine activated killer cells, gammadelta T cells, conventional CTLs, and chimeric Ag receptor-redirected T cells) better than their nonmicrovilli-expressing counterparts. Killer lymphocytes released perforin, which was detected within the glioma's microvilli/filopodia, indicating these structures can receive the cytolytic effector molecules, but cytotoxicity is suboptimal. Air-dried gliomas revealed nodes within the microvilli/filopodia. The microvilli that penetrated 0.4-MUm transwell chamber's pores resisted the actions of CTLs and physical damage. Those nodelike structures may represent a compartmentalization that resists physical damage. These microvilli may play multiple roles in glioma biology, such as invasion and resistance to lymphocyte-mediated killing. PMID- 20855884 TI - Estrogen receptors bind to and activate the HOXC4/HoxC4 promoter to potentiate HoxC4-mediated activation-induced cytosine deaminase induction, immunoglobulin class switch DNA recombination, and somatic hypermutation. AB - Estrogen enhances antibody and autoantibody responses through yet to be defined mechanisms. It has been suggested that estrogen up-regulates the expression of activation-induced cytosine deaminase (AID), which is critical for antibody class switch DNA recombination (CSR) and somatic hypermutation (SHM), through direct activation of this gene. AID, as we have shown, is induced by the HoxC4 homeodomain transcription factor, which binds to a conserved HoxC4/Oct site in the AICDA/Aicda promoter. Here we show that estrogen-estrogen receptor (ER) complexes do not directly activate the AID gene promoter in B cells undergoing CSR. Rather, they bind to three evolutionarily conserved and cooperative estrogen response elements (EREs) we identified in the HOXC4/HoxC4 promoter. By binding to these EREs, ERs synergized with CD154 or LPS and IL-4 signaling to up-regulate HoxC4 expression, thereby inducing AID and CSR without affecting B cell proliferation or plasmacytoid differentiation. Estrogen administration in vivo significantly potentiated CSR and SHM in the specific antibody response to the 4 hydroxy-3-nitrophenylacetyl hapten conjugated with chicken gamma-globulin. Ablation of HoxC4 (HoxC4(-/-)) abrogated the estrogen-mediated enhancement of AID gene expression and decreased CSR and SHM. Thus, estrogen enhances AID expression by activating the HOXC4/HoxC4 promoter and inducing the critical AID gene activator, HoxC4. PMID- 20855885 TI - Secretion of the human Toll-like receptor 3 ectodomain is affected by single nucleotide polymorphisms and regulated by Unc93b1. AB - The innate immune receptor Toll-like receptor 3 (TLR3) can be present on the surface of the plasma membranes of cells and in endolysosomes. The Unc93b1 protein has been reported to facilitate localization of TLR7 and 9 and is required for TLR3, -7, and -9 signaling. We demonstrate that siRNA knockdown of Unc93b1 reduced the abundance of TLR3 on the cell surface without altering total TLR3 accumulation. In addition, siRNA to Unc93b1 reduced the secretion of the TLR3 ectodomain (T3ECD) into the cell medium. Furthermore, two human single nucleotide polymorphisms that affected herpesvirus and influenza virus encephalopathy as well as a natural isoform generated by alternative splicing were found to be impaired for T3ECD secretion and decreased the abundance of TLR3 on the cell surface. The locations of the SNP P554S and the deletion in the isoform led to the identification of a loop in the TLR3 ectodomain that is required for secretion and a second whose presence decreased secretion. Finally, a truncated protein containing the N-terminal 10 leucine-rich repeats of T3ECD was sufficient for secretion in an Unc93b1-dependent manner. PMID- 20855887 TI - TRIF mediates Toll-like receptor 5-induced signaling in intestinal epithelial cells. AB - Toll-like receptors (TLRs) associate with adaptor molecules (MyD88, Mal/TIRAP, TRAM, and TRIF) to mediate signaling of host-microbial interaction. For instance, TLR4 utilizes the combination of both Mal/TIRAP-MyD88 (MyD88-dependent pathway) and TRAM-TRIF (MyD88-independent pathway). However, TLR5, the specific receptor for flagellin, is known to utilize only MyD88 to elicit inflammatory responses, and an involvement of other adaptor molecules has not been suggested in TLR5 dependent signaling. Here, we found that TRIF is involved in mediating TLR5 induced nuclear factor kappaB (NFkappaB) and mitogen-activated protein kinases (MAPKs), specifically JNK1/2 and ERK1/2, activation in intestinal epithelial cells. TLR5 activation by flagellin permits the physical interaction between TLR5 and TRIF in human colonic epithelial cells (NCM460), whereas TLR5 does not interact with TRAM upon flagellin stimulation. Both primary intestinal epithelial cells from TRIF-KO mice and TRIF-silenced NCM460 cells significantly reduced flagellin-induced NFkappaB (p105 and p65), JNK1/2, and ERK1/2 activation compared with control cells. However, p38 activation by flagellin was preserved in these TRIF-deficient cells. TRIF-KO intestinal epithelial cells exhibited substantially reduced inflammatory cytokine (keratinocyte-derived cytokine, macrophage inflammatory protein 3alpha, and IL-6) expression upon flagellin, whereas control cells from TRIF-WT mice showed robust cytokine expression by flagellin. Compare with TRIF-WT mice, TRIF-KO mice were resistant to in vivo intestinal inflammatory responses: flagellin-mediated exacerbation of colonic inflammation and dextran sulfate sodium-induced experimental colitis. We conclude that in addition to MyD88, TRIF mediates TLR5-dependent responses and, thereby regulates inflammatory responses elicited by flagellin/TLR5 engagement. Our findings suggest an important role of TRIF in regulating host-microbial communication via TLR5 in the gut epithelium. PMID- 20855886 TI - Binding of the human complement regulators CFHR1 and factor H by streptococcal collagen-like protein 1 (Scl1) via their conserved C termini allows control of the complement cascade at multiple levels. AB - Group A streptococci (GAS) utilize soluble human complement regulators to evade host complement attack. Here, we characterized the binding of the terminal complement complex inhibitor complement Factor H-related protein 1 (CFHR1) and of the C3 convertase regulator Factor H to the streptococcal collagen-like proteins (Scl). CFHR1 and Factor H, but no other member of the Factor H protein family (CFHR2, CFHR3, or CFHR4A), bound to the two streptococcal proteins Scl1.6 and Scl1.55, which are expressed by GAS serotypes M6 and M55. The two human regulators bound to the Scl1 proteins via their conserved C-terminal attachment region, i.e. CFHR1 short consensus repeats 3-5 (SCR3-5) and Factor H SCR18-20. Binding was affected by ionic strength and by heparin. CFHR1 and the C-terminal attachment region of Factor H did not bind to Scl1.1 and Scl2.28 proteins but did bind to intact M1-type and M28-type GAS, which express Scl1.1 and Scl2.28, respectively, thus arguing for the presence of an additional binding mechanism to CFHR1 and Factor H. Furthermore mutations within the C-terminal heparin-binding region and Factor H mutations that are associated with the acute renal disease atypical hemolytic uremic syndrome blocked the interaction with the two streptococcal proteins. Binding of CFHR1 affected the complement regulatory functions of Factor H on the level of the C3 convertase. Apparently, streptococci utilize two types of complement regulator-acquiring surface proteins; type A proteins, as represented by Scl1.6 and Scl1.55, bind to CFHR1 and Factor H via their conserved C-terminal region and do not bind the Factor H-like protein 1 (FHL-1). On the contrary, type B proteins, represented by M-, M-like, and the fibronectin-binding protein Fba proteins, bind Factor H and FHL-1 via domain SCR7 and do not bind CFHR1. In conclusion, binding of CFHR1 is at the expense of Factor H-mediated regulatory function at the level of C3 convertase and at the gain of a regulator that controls complement at the level of the C5 convertase and formation of the terminal complement complex. PMID- 20855888 TI - CXCR3-B can mediate growth-inhibitory signals in human renal cancer cells by down regulating the expression of heme oxygenase-1. AB - The chemokine receptor CXCR3 may play a critical role in the growth and metastasis of tumor cells, including renal tumors. It has been shown that CXCR3 has two splice variants with completely opposite functions; CXCR3-A promotes cell proliferation, whereas CXCR3-B inhibits cell growth. We recently demonstrated that the expression of growth-promoting CXCR3-A is up-regulated, and the growth inhibitory CXCR3-B is markedly down-regulated in human renal cancer tissues; and the overexpression of CXCR3-B in renal cancer cells can significantly inhibit cell proliferation. However, the growth-inhibitory signal(s) through CXCR3-B are not well characterized. Here, we investigated the effector molecule(s) involved in CXCR3-B-mediated signaling events. We found that the overexpression of CXCR3-B in human renal cancer cells (Caki-1) promoted cellular apoptosis as observed by FACS analysis through Annexin-V staining. To examine whether the overexpression of CXCR3-B could alter the expression of any apoptosis-related genes in renal cancer cells, we performed a protein array. We found that CXCR3-B overexpression significantly down-regulated the expression of antiapoptotic heme oxygenase-1 (HO 1). By utilizing a HO-1 promoter-luciferase plasmid, we showed that CXCR3-B mediated down-regulation of HO-1 was controlled at the transcriptional level as observed by luciferase assay. We also demonstrated that the inhibition of HO-1 expression using siRNA promoted apoptosis of renal cancer cells. Finally, we observed that human renal cancer tissues expressing low amounts of CXCR3-B significantly overexpress HO-1 at both mRNA and protein level. Together, we suggest that the overexpression of CXCR3-B may prevent the growth of renal tumors through the inhibition of antiapoptotic HO-1. PMID- 20855890 TI - HNK-1 epitope-carrying tenascin-C spliced variant regulates the proliferation of mouse embryonic neural stem cells. AB - Neural stem cells (NSCs) possess high proliferative potential and the capacity for self-renewal with retention of multipotency to differentiate into neuronal and glial cells. NSCs are the source for neurogenesis during central nervous system development from fetal and adult stages. Although the human natural killer 1 (HNK-1) carbohydrate epitope is expressed predominantly in the nervous system and involved in intercellular adhesion, cell migration, and synaptic plasticity, the expression patterns and functional roles of HNK-1-containing glycoconjugates in NSCs have not been fully recognized. We found that HNK-1 was expressed in embryonic mouse NSCs and that this expression was lost during the process of differentiation. Based on proteomics analysis, it was revealed that the HNK-1 epitopes were almost exclusively displayed on an extracellular matrix protein, tenascin-C (TNC), in the mouse embryonic NSCs. Furthermore, the HNK-1 epitope was found to be present only on the largest isoform of the TNC molecules. In addition, the expression of HNK-1 was dependent on expression of the largest TNC variant but not by enzymes involved in the biosynthesis of HNK-1. By knocking down HNK-1 sulfotransferase or TNC by small interfering RNA, we further demonstrated that HNK-1 on TNC was involved in the proliferation of NSCs via modulation of the expression level of the epidermal growth factor receptor. Our finding provides insights into the function of HNK-1 carbohydrate epitopes in NSCs to maintain stemness during neural development. PMID- 20855889 TI - Molecular phylogeny and functional genomics of beta-galactoside alpha2,6 sialyltransferases that explain ubiquitous expression of st6gal1 gene in amniotes. AB - Sialyltransferases are key enzymes in the biosynthesis of sialoglycoconjugates that catalyze the transfer of sialic residue from its activated form to an oligosaccharidic acceptor. beta-Galactoside alpha2,6-sialyltransferases ST6Gal I and ST6Gal II are the two unique members of the ST6Gal family described in higher vertebrates. The availability of genome sequences enabled the identification of more distantly related invertebrates' st6gal gene sequences and allowed us to propose a scenario of their evolution. Using a phylogenomic approach, we present further evidence of an accelerated evolution of the st6gal1 genes both in their genomic regulatory sequences and in their coding sequence in reptiles, birds, and mammals known as amniotes, whereas st6gal2 genes conserve an ancestral profile of expression throughout vertebrate evolution. PMID- 20855891 TI - Identification of Ypk1 as a novel selective substrate for nitrogen starvation triggered proteolysis requiring autophagy system and endosomal sorting complex required for transport (ESCRT) machinery components. AB - Nitrogen starvation-mediated reduction of Ypk1 is suggested to suppress translational initiation, possibly in parallel with the target of rapamycin complex 1 (TORC1) signaling. However, the molecular mechanism that regulates Ypk1 in nitrogen-starved cells is poorly understood. Here we report that Ypk1 is a novel selective substrate for nitrogen starvation-triggered proteolysis requiring autophagy system. Among various nutrient starvation methods used to elicit autophagy, rapid Ypk1 degradation was specific to nitrogen starvation. In screening genes required for such nitrogen starvation-specific vacuolar proteolysis, we found that autophagy-related degradation of Ypk1 depended on the endosomal sorting complex required for transport (ESCRT) machinery, which is conventionally thought to function in endosomal trafficking. In microscopic analyses, the disruption of ESCRT subunits resulted in the accumulation of both Ypk1 and autophagosomal Atg8 at a perivacuolar site that was distinct from conventional endosomes. ESCRT machinery was not involved in autophagic flux induced by the TORC1 inhibitor rapamycin, thus suggesting that ESCRT represents an exclusive mechanism of nitrogen starvation-specific proteolysis of Ypk1. Overall, we propose a novel regulation of Ypk1 that is specific to nitrogen limitation. PMID- 20855892 TI - Whole body deletion of AMP-activated protein kinase {beta}2 reduces muscle AMPK activity and exercise capacity. AB - AMP-activated protein kinase (AMPK) beta subunits (beta1 and beta2) provide scaffolds for binding alpha and gamma subunits and contain a carbohydrate-binding module important for regulating enzyme activity. We generated C57Bl/6 mice with germline deletion of AMPK beta2 (beta2 KO) and examined AMPK expression and activity, exercise capacity, metabolic control during muscle contractions, aminoimidazole carboxamide ribonucleotide (AICAR) sensitivity, and susceptibility to obesity-induced insulin resistance. We find that beta2 KO mice are viable and breed normally. beta2 KO mice had a reduction in skeletal muscle AMPK alpha1 and alpha2 expression despite up-regulation of the beta1 isoform. Heart AMPK alpha2 expression was also reduced but this did not affect resting AMPK alpha1 or alpha2 activities. AMPK alpha1 and alpha2 activities were not changed in liver, fat, or hypothalamus. AICAR-stimulated glucose uptake but not fatty acid oxidation was impaired in beta2 KO mice. During treadmill running beta2 KO mice had reduced maximal and endurance exercise capacity, which was associated with lower muscle and heart AMPK activity and reduced levels of muscle and liver glycogen. Reductions in exercise capacity of beta2 KO mice were not due to lower muscle mitochondrial content or defects in contraction-stimulated glucose uptake or fatty acid oxidation. When challenged with a high-fat diet beta2 KO mice gained more weight and were more susceptible to the development of hyperinsulinemia and glucose intolerance. In summary these data show that deletion of AMPK beta2 reduces AMPK activity in skeletal muscle resulting in impaired exercise capacity and the worsening of diet-induced obesity and glucose intolerance. PMID- 20855893 TI - Chronic ethanol consumption-induced pancreatic {beta}-cell dysfunction and apoptosis through glucokinase nitration and its down-regulation. AB - Chronic ethanol consumption is known as an independent risk factor for type 2 diabetes, which is characterized by impaired glucose homeostasis and insulin resistance; however, there is a great deal of controversy concerning the relationships between alcohol consumption and the development of type 2 diabetes. We investigated the effects of chronic ethanol consumption on pancreatic beta cell dysfunction and whether generated peroxynitrite participates in the impaired glucose homeostasis. Here we show that chronic ethanol feeding decreases the ability of pancreatic beta-cells to mediate insulin secretion and ATP production in coordination with the decrease of glucokinase, Glut2, and insulin expression. Specific blockade of ATF3 using siRNA or C-terminally deleted ATF3(DeltaC) attenuated ethanol-induced pancreatic beta-cell apoptosis or dysfunction and restored the down-regulation of glucokinase (GCK), insulin, and pancreatic duodenal homeobox-1 induced by ethanol. GCK inactivation and down-regulation were predominantly mediated by ethanol metabolism-generated peroxynitrite, which were suppressed by the peroxynitrite scavengers N(gamma)-monomethyl-L-arginine, uric acid, and deferoxamine but not by the S-nitrosylation inhibitor DTT, indicating that tyrosine nitration is the predominant modification associated with GCK down regulation and inactivation rather than S-nitrosylation of cysteine. Tyrosine nitration of GCK prevented its association with pBad, and GCK translocation into the mitochondria results in subsequent proteasomal degradation of GCK following ubiquitination. This study identified a novel and efficient pathway by which chronic ethanol consumption may induce GCK down-regulation and inactivation by inducing tyrosine nitration of GCK, resulting in pancreatic beta-cell apoptosis and dysfunction. Peroxynitrite-induced ATF3 may also serve as a potent upstream regulator of GCK down-regulation and beta-cell apoptosis. PMID- 20855894 TI - Potentiation of ligand binding through cooperative effects in monoamine oxidase B. AB - Crystallographic and biochemical studies have been employed to identify the binding site and mechanism for potentiation of imidazoline binding in human monoamine oxidase B (MAO B). 2-(2-Benzofuranyl)-2-imidazoline (2-BFI) inhibits recombinant human MAO B with a K(i) of 8.3 +/- 0.6 MUM, whereas tranylcypromine inhibited MAO B binds 2-BFI with a K(d) of 9 +/- 2 nM, representing an increase in binding energy Delta(DeltaG) of -3.9 kcal/mol. Crystal structures show the imidazoline ligand bound in a site that is distinct from the substrate-binding cavity. Contributions to account for the increase in binding affinity upon tranylcypromine inhibition include a conformational change in the side chain of Gln(206) and a "closed conformation" of the side chain of Ile(199), forming a hydrophobic "sandwich" with the side chain of Ile(316) on each face of the benzofuran ring of 2-BFI. Data with the I199A mutant of human MAO B and failure to observe a similar binding potentiation with rat MAO B, where Ile(316) is replaced with a Val residue, support an allosteric mechanism where the increased binding affinity of 2-BFI results from a cooperative increase in H-bond strength through formation of a more hydrophobic milieu. These insights should prove valuable in the design of high affinity and specific reversible MAO B inhibitors. PMID- 20855895 TI - Substrate specificity of human carboxypeptidase A6. AB - Carboxypeptidase A6 (CPA6) is an extracellular matrix-bound metallocarboxypeptidase (CP) that has been implicated in Duane syndrome, a neurodevelopmental disorder in which the lateral rectus extraocular muscle is not properly innervated. Consistent with a role in Duane syndrome, CPA6 is expressed in a number of chondrocytic and nervous tissues during embryogenesis. To better characterize the enzymatic function and specificity of CPA6 and to compare this with other CPs, CPA6 was expressed in HEK293 cells and purified. Kinetic parameters were determined using a panel of synthetic carboxypeptidase substrates, indicating a preference of CPA6 for large hydrophobic C-terminal amino acids and only very weak activity toward small amino acids and histidine. A quantitative peptidomics approach using a mixture of peptides representative of the neuropeptidome allowed the characterization of CPA6 preferences at the P1 substrate position and suggested that small and acidic P1 residues significantly inhibit CPA6 cleavage. Finally, a comparison of available kinetic data for CPA enzymes shows a gradient of specificity across the subfamily, from the very restricted specificity of CPA2 to the very broad activity of CPA4. Structural data and modeling for all CPA/B subfamily members suggests the structural basis for the unique specificities observed for each member of the CPA/B subfamily of metallocarboxypeptidases. PMID- 20855897 TI - Psychopaths are impaired in social exchange and precautionary reasoning. AB - Psychopaths show a profound lack of morality and behavioral controls in the presence of intact general intellectual functioning. Two hallmarks of psychopathy are the persistent violation of social contracts (i.e., cheating) and chronic, impulsive risky behavior. These behaviors present a puzzle: Can psychopaths understand and reason about what counts as cheating or risky behavior in a particular situation? We tested incarcerated psychopaths' and incarcerated nonpsychopaths' reasoning about social contract rules, precautionary rules, and descriptive rules using the Wason selection task. Results were consistent with our hypotheses: Psychopaths (compared with matched nonpsychopaths) showed significant impairment on social contract rules and precautionary rules, but not on descriptive rules. These results cannot be accounted for by differences in intelligence, motivation, or general antisocial tendency. These findings suggest that examination of evolutionarily identified reasoning processes can be a fruitful research approach for identifying which specific mechanisms are impaired in psychopathy. PMID- 20855896 TI - Nedd4-1 and beta-arrestin-1 are key regulators of Na+/H+ exchanger 1 ubiquitylation, endocytosis, and function. AB - The ubiquitously expressed mammalian Na(+)/H(+) exchanger 1 (NHE1) controls cell volume and pH but is also critically involved in complex biological processes like cell adhesion, cell migration, cell proliferation, and mechanosensation. Pathways controlling NHE1 turnover at the plasma membrane, however, are currently unclear. Here, we demonstrate that NHE1 undergoes ubiquitylation at the plasma membrane by a process that is unprecedented for a mammalian ion transport protein. This process requires the adapter protein beta-arrestin-1 that interacts with both the E3 ubiquitin ligase Nedd4-1 and the NHE1 C terminus. Truncation of NHE1 C terminus to amino acid 550 abolishes binding to beta-arrestin-1 and NHE1 ubiquitylation. Overexpression of beta-arrestin-1 or of wild type but not ligase dead Nedd4-1 increases NHE1 ubiquitylation. siRNA-mediated knock-down of Nedd4-1 or beta-arrestin-1 reduces NHE1 ubiquitylation and endocytosis leading to increased NHE1 surface levels. Fibroblasts derived from beta-arrestin-1 and Nedd4 1 knock-out mice show loss of NHE1 ubiquitylation, increased plasmalemmal NHE1 levels and greatly enhanced NHE1 transport compared with wild-type fibroblasts. These findings reveal Nedd4-1 and beta-arrestin-1 as key regulators of NHE1 ubiquitylation, endocytosis, and function. Our data suggest a broader role for beta-arrestins in the regulation of membrane ion transport proteins than currently known. PMID- 20855898 TI - The art of anger: reward context turns avoidance responses to anger-related objects into approach. AB - Anger has a special status among the emotions in that it can elicit avoidance as well as approach motivation. This study tested the ignored role of reward context in potentiating approach rather than avoidance responses toward objects associated with anger. In Experiment 1, angry and neutral facial expressions were parafoveally paired with common objects, and responses to the objects were assessed by subjective reports of motivation to obtain them. In Experiment 2, objects were again paired with angry or neutral faces outside of participants' awareness, and responses toward the objects were indexed by physical effort expended in attempting to win them. Results showed that approach motivation toward anger-related objects can be observed when responding is framed in terms of rewards that one can obtain, whereas avoidance motivation occurs in the absence of such a reward context. These findings point to the importance of a reward context in modulating people's responses to anger. PMID- 20855899 TI - Stereotype threat affects financial decision making. AB - The research presented in this article provides the first evidence that one's decision making can be influenced by concerns about stereotypes and the devaluation of one's identity. Many studies document gender differences in decision making, and often attribute these differences to innate and stable factors, such as biological and hormonal differences. In three studies, we found that stereotype threat affected decision making and led to gender differences in loss-aversion and risk-aversion behaviors. In Study 1, women subjected to stereotype threat in academic and business settings were more loss averse than both men and women who were not facing the threat of being viewed in light of negative stereotypes. We found no gender differences in loss-aversion behavior in the absence of stereotype threat. In Studies 2a and 2b, we found the same pattern of effects for risk-aversion behavior that we had observed for loss-aversion behavior. In addition, in Study 2b, ego depletion mediated the effects of stereotype threat on women's decision making. These results suggest that individuals' decision making can be influenced by stereotype concerns. PMID- 20855900 TI - Why women apologize more than men: gender differences in thresholds for perceiving offensive behavior. AB - Despite wide acceptance of the stereotype that women apologize more readily than men, there is little systematic evidence to support this stereotype or its supposed bases (e.g., men's fragile egos). We designed two studies to examine whether gender differences in apology behavior exist and, if so, why. In Study 1, participants reported in daily diaries all offenses they committed or experienced and whether an apology had been offered. Women reported offering more apologies than men, but they also reported committing more offenses. There was no gender difference in the proportion of offenses that prompted apologies. This finding suggests that men apologize less frequently than women because they have a higher threshold for what constitutes offensive behavior. In Study 2, we tested this threshold hypothesis by asking participants to evaluate both imaginary and recalled offenses. As predicted, men rated the offenses as less severe than women did. These different ratings of severity predicted both judgments of whether an apology was deserved and actual apology behavior. PMID- 20855901 TI - Do babies learn from baby media? AB - In recent years, parents in the United States and worldwide have purchased enormous numbers of videos and DVDs designed and marketed for infants, many assuming that their children would benefit from watching them. We examined how many new words 12- to 18-month-old children learned from viewing a popular DVD several times a week for 4 weeks at home. The most important result was that children who viewed the DVD did not learn any more words from their monthlong exposure to it than did a control group. The highest level of learning occurred in a no-video condition in which parents tried to teach their children the same target words during everyday activities. Another important result was that parents who liked the DVD tended to overestimate how much their children had learned from it. We conclude that infants learn relatively little from infant media and that their parents sometimes overestimate what they do learn. PMID- 20855902 TI - Power posing: brief nonverbal displays affect neuroendocrine levels and risk tolerance. AB - Humans and other animals express power through open, expansive postures, and they express powerlessness through closed, contractive postures. But can these postures actually cause power? The results of this study confirmed our prediction that posing in high-power nonverbal displays (as opposed to low-power nonverbal displays) would cause neuroendocrine and behavioral changes for both male and female participants: High-power posers experienced elevations in testosterone, decreases in cortisol, and increased feelings of power and tolerance for risk; low-power posers exhibited the opposite pattern. In short, posing in displays of power caused advantaged and adaptive psychological, physiological, and behavioral changes, and these findings suggest that embodiment extends beyond mere thinking and feeling, to physiology and subsequent behavioral choices. That a person can, by assuming two simple 1-min poses, embody power and instantly become more powerful has real-world, actionable implications. PMID- 20855903 TI - A spontaneous self-reference effect in memory: why some birthdays are harder to remember than others. AB - The self-reference effect in memory is defined as the memory advantage for materials that have been processed in relation to the self. Existing demonstrations of the self-reference effect rely on laboratory stimuli and use explicit cues to prompt self-relevant encoding. In three studies, we used participants' memories for birthdays to document a naturalistic case of the self reference effect that did not depend on explicit self-cues. In Study 1, the birthdays that participants free-recalled were closer on average to their own birthday than would be expected by chance. In Study 2, participants were more likely to remember the birthday of a friend if the friend's birthday was close to their own, and they were more likely to forget the friend's birthday if it was distant. In Study 3, we demonstrated experimentally that the self-reference effect occurs for newly introduced individuals. Our findings suggest that the self-reference effect can occur spontaneously in the absence of explicit self cues if the material to be learned automatically activates self-relevant information. PMID- 20855904 TI - How magic changes our expectations about autism. AB - In the vanishing-ball illusion, the magician's social cues misdirect the audience's expectations and attention so that the audience "sees" a ball vanish in the air. Because individuals with autism spectrum disorder (ASD) are less sensitive to social cues and have superior perception for nonsocial details compared with typically developing individuals, we predicted that they would be less susceptible to the illusion. Surprisingly, the opposite result was found, as individuals with ASD were more susceptible to the illusion than a comparison group. Eye-tracking data indicated that subtle temporal delays in allocating attention might explain their heightened susceptibility. Additionally, although individuals with ASD showed typical patterns of looking to the magician's face and eyes, they were slower to launch their first saccade to the face and had difficulty in fixating the fast-moving observable ball. Considered together, the results indicate that individuals with ASD have difficulties in rapidly allocating attention toward both people and moving objects. PMID- 20855905 TI - Young children have a specific, highly robust bias to trust testimony. AB - Why are young children so willing to believe what they are told? In two studies, we investigated whether it is because of a general, undifferentiated trust in other people or a more specific bias to trust testimony. In Study 1, 3-year-olds either heard an experimenter claim that a sticker was in one location when it was actually in another or saw her place an arrow on the empty location. All children searched in the wrong location initially, but those who heard the deceptive testimony continued to be misled, whereas those who saw her mark the incorrect location with an arrow quickly learned to search in the opposite location. In Study 2, children who could both see and hear a deceptive speaker were more likely to be misled than those who could only hear her. Three-year-olds have a specific, highly robust bias to trust what people--particularly visible speakers- say. PMID- 20855907 TI - Oxytocin selectively improves empathic accuracy. PMID- 20855906 TI - Abstract structural representations of goal-directed behavior. AB - Linguistic theory holds that the structure of a sentence can be described in abstract syntactic terms, independent of the specific words the sentence contains. Nonlinguistic behavior, including goal-directed action, is also theorized to have an underlying structural, or "syntactic," organization. We propose that purposive action sequences are represented cognitively in terms of a means-ends parse, which is a formal specification of how actions fit together to accomplish desired outcomes. To test this theory, we leveraged the phenomenon of structural priming in two experiments. As predicted, participants read sentences describing action sequences faster when these sentences were presented amid other sentences sharing the same parse. Results from a second experiment indicate that the underlying representations relevant to observed action sequences are not strictly tied to language processing. Our results suggest that the structure of goal-directed behavior may be represented abstractly, independently of specific actions and goals, just as linguistic syntax is thought to stand independent of other levels of representation. PMID- 20855908 TI - Chronic obstructive pulmonary disease as disability: dilemma stories. AB - The purpose of this work was to develop an understanding of the meaning of disability for individuals living with chronic obstructive pulmonary disease (COPD) in a Canadian midwestern community from an emic perspective. A focused ethnographic design was used. Fifteen individuals participated in interviews. Narrative analysis was used to examine the interview data. Data analysis revealed 65 dilemma stories consisting of two structural components: the impairment, and the justification/explanation of the impairment. Participants' impairment might or might not have been known to others. In both situations, individuals were faced with choices of whether to explain/justify or attempt to conceal the impairment. Participants told these dilemma stories to convey the meaning of COPD as a disability invisible to others, and at times, to themselves. The information gained from this research will serve as an essential complement to the existing knowledge about this important yet often invisible chronic illness. PMID- 20855909 TI - Reliability generalization: an examination of the Positive Affect and Negative Affect Schedule. AB - The assessment of positive affect (PA) and negative affect (NA) by means of the Positive Affect and Negative Affect Schedule has received a remarkable popularity in the social sciences. Using a meta-analytic tool-namely, reliability generalization (RG)-population reliability scores of both scales have been investigated on the basis of a random effects model in 147 studies. Correcting for measurement errors, the results demonstrate moderate to high internal consistency coefficients and variations of the PA and NA reliability scores with regard to time frame instructions, language of items, and sample characteristics. The percentage of PA and NA true score variance differs in subpopulations up to 11%. RG analysis of test-retest coefficients illustrates state-like fluctuations and trait-like stability of both scales. Calculations of the fail-safe number point at the robustness of the results. Applications of RG coefficients compared to single-study coefficients highlight the relevance of population coefficients for research and assessment situations. PMID- 20855910 TI - Community leg ulcer bandaging study: lessons learned in a pilot, randomized controlled trial . AB - Compression is the cornerstone of venous leg ulcer (VLU) care but comparative effectiveness evidence is limited, especially regarding home care. In preparation for a large, community-based randomized controlled clinical trial (RCT), the "Canadian Bandaging Trial" (CBT), a pilot study was conducted to assess the practicality of the CBT study protocol. Nurses who provided home care also performed the research intervention and outcome measurements. All trial procedures were implemented to examine the following aspects of the study protocol: 1) eligibility screening, recruitment, enrollment, and randomization procedures; 2) integration of intervention protocol with usual clinical routines; 3) data collection and management and outcome measures; and 4) database creation and testing. Guided by a Pilot Research Process Framework (PReP), this 6-month pilot RCT was conducted at two community-based sites in Ontario, Canada. Participants included 12 persons with VLUs, 40 nurses providing leg ulcer care, and two site investigators. Individuals with a VLU were randomized to a four layer or short-stretch compression bandage. Eligibility screening and randomization procedures were found to be efficient but the ratio of screened (49) versus enrolled (12) patients was low and suggested the need for nine additional clinical sites, a change in ulcer size eligibility, and research to evaluate how to incorporate persons with diabetes in leg ulcer trials. Screening practices, data collection form concerns, and wound photo assessment outcomes issues were addressed. The results of this study improved and streamlined the large RCT quality and processes and confirm the value of pilot studies. Research to test the usefulness of the PReP framework for other pilot studies is needed. PMID- 20855911 TI - A retrospective comparison of clinical outcomes and Medicare expenditures in skilled nursing facility residents with chronic wounds. AB - Medicare skilled nursing facility (SNF) residents with chronic wounds require more resources and have relatively high healthcare expenditures compared to Medicare patients without wounds. A retrospective cohort study was conducted using 2006 Medicare Chronic Condition Warehouse claims data for SNF, inpatient, outpatient hospital, and physician supplier settings along with 2006 Long-Term Care Minimum Data Set (MDS) information to compare Medicare expenditures between two groups of SNF residents with a diagnosis of pressure, venous, ischemic, or diabetic ulcers whose wounds healed during the 10-month study period. The study group (n = 372) was managed using a structured, comprehensive wound management protocol provided by an external wound management team. The matched comparison group consisted of 311 SNF residents who did not receive care from the wound management team. Regression analyses indicate that after controlling for resident comorbidities and wound severity, study group residents experienced lower rates of wound-related hospitalization per day (0.08% versus 0.21%, P < 0.01) and shorter wound episodes (94 days versus 115 days, P < 0.01) than comparison group patients. Total Medicare costs were $21,449.64 for the study group and $40,678.83 for the comparison group (P < 0.01) or $229.07 versus $354.26 (P < 0.01) per resident episode day. Additional studies including wounds that do not heal are warranted. Increasing the number of SNF residents receiving the care described in this study could lead to significant Medicare cost savings. Incorporating wound clinical outcomes into a pay-for-performance measures for SNFs could increase broader SNF adoption of comprehensive wound care programs to treat chronic wounds. PMID- 20855912 TI - Topical tacrolimus for parastomal pyoderma gangrenosum: a report of two cases. AB - Pyoderma gangrenosum (PG) is an idiopathic, ulcerative, inflammatory dermatologic condition that occurs in patients with systemic diseases such as inflammatory bowel disease (IBD). This inflammatory skin disorder is presumably caused by an autoimmune mechanism and the diagnosis is one of exclusion. PG is not a common condition but it is thought to account for approximately 50% of chronic parastomal ulcers. Refractory parastomal PG (PPG) occurs in patients with inactive disease or after bowel resection. Multiple medical treatments, ranging from topical agents for mild disease to systemic immunosuppressive therapy for severe disease, have been used with varying rates of success. Using topical tacrolimus, an immunosuppressant that inhibits T-lymphocyte proliferation, and meticulous stoma care can result in successful treatment. Two women (ages 59 and 62 years) with a history of ulcerative colitis and colon resection presented with parastomal ulcers consistent with PPG. The 59-year patient presented with a painful 2 cm x 2 cm parastomal ulcer that improved following daily application of topical tacrolimus 0.1%. The 62-year old woman first was prescribed daily appliance changes and application of topical triamcinolone 0.5% to her 3-cm ulcer. The ulcer increased in size and treatment was changed to daily application of tacrolimus 0.1%. After 2 months and a reduction in ulcer size and severity, the dosage was changed to daily application of tacrolimus 0.03%. Both patients reported resolution of pain and itching, the most common symptoms of PPG, and no adverse effects were observed. The encouraging results observed in these two cases confirm that tacrolimus helps resolve PPG lesions even at concentrations previously thought to be ineffective. Additional studies to help clinicians optimize care of these painful lesions are needed. PMID- 20855913 TI - Heterogeneous Subsurface Scattering Using the Finite Element Method. AB - Materials with visually important heterogeneous subsurface scattering, including marble, skin, leaves, and minerals are common in the real world. However, general, accurate, and efficient rendering of these materials is an open problem. In this paper, we describe a finite element (FE) solution of the heterogeneous diffusion equation (DE) that solves this problem. Our algorithm is the first to use the FE method to solve the difficult problem of heterogeneous subsurface rendering. To create our algorithm, we make two contributions. First, we correct previous work and derive an accurate and complete heterogeneous diffusion formulation with two key elements: the diffusive source boundary condition (DSBC) an accurate model of the reduced intensity (RI) source-and its associated render query function. Second, we solve this formulation accurately and efficiently using the FE method. With these contributions, we can render subsurface scattering with a simple four step algorithm. To demonstrate that our algorithm is simultaneously general, accurate, and efficient, we test its performance on a series of difficult scenes. For a wide range of materials and geometry, it produces, in minutes, images that match path traced references, that required hours. PMID- 20855914 TI - Real-Time Shape Illustration Using Laplacian Lines. AB - This paper presents a novel object-space line drawing algorithm that can depict shapes with view-dependent feature lines in real time. Strongly inspired by the Laplacian-of-Gaussian (LoG) edge detector in image processing, we define Laplacian lines as the zero-crossing points of the Laplacian of the surface illumination. Compared to other view-dependent feature lines, Laplacian lines are computationally efficient because most expensive computations can be preprocessed. We further extend Laplacian lines to volumetric data and develop the algorithm to compute volumetric Laplacian lines without isosurface extraction. We apply the proposed Laplacian lines to a wide range of real-world models and demonstrate that Laplacian lines are more efficient than the existing computer generated feature lines, and can be used in interactive graphics applications. PMID- 20855915 TI - Sort-first parallel volume rendering. AB - Sort-first distributions have been studied and used far less than sort-last distributions for parallel volume rendering, especially when the data are too large to be replicated fully. We demonstrate that sort-first distributions are not only a viable method of performing data-scalable parallel volume rendering, but more importantly they allow for a range of rendering algorithms and techniques that are not efficient with sort-last distributions. Several of these algorithms are discussed and two of them are implemented in a parallel environment: a new improved variant of early ray termination to speed up rendering when volumetric occlusion occurs and a volumetric shadowing technique that produces more realistic and informative images based on half angle slicing. Improved methods of distributing the computation of the load balancing and loading portions of a subdivided data set are also presented. Our detailed test results for a typical GPU cluster with distributed memory show that our sort first rendering algorithm outperforms sort-last rendering in many scenarios. PMID- 20855916 TI - Drawing Euler Diagrams with Circles: The Theory of Piercings. AB - Euler diagrams are effective tools for visualizing set intersections. They have a large number of application areas ranging from statistical data analysis to software engineering. However, the automated generation of Euler diagrams has never been easy: given an abstract description of a required Euler diagram, it is computationally expensive to generate the diagram. Moreover, the generated diagrams represent sets by polygons, sometimes with quite irregular shapes that make the diagrams less comprehensible. In this paper, we address these two issues by developing the theory of piercings, where we define single piercing curves and double piercing curves. We prove that if a diagram can be built inductively by successively adding piercing curves under certain constraints, then it can be drawn with circles, which are more esthetically pleasing than arbitrary polygons. The theory of piercings is developed at the abstract level. In addition, we present a Java implementation that, given an inductively pierced abstract description, generates an Euler diagram consisting only of circles within polynomial time. PMID- 20855917 TI - Supervised Manifold Distance Segmentation. AB - We present a simple and robust method for image and volume data segmentation based on manifold distance metrics. This is done by treating the image as a function that maps the 2D (image) or 3D (volume) to a 2D or 3D manifold in a higher dimensional feature space. We explore a range of possible feature spaces, including value, gradient, and probabilistic measures, and examine the consequences of including these measures in the feature space. The time and space computational complexity of our segmentation algorithm is O(N), which allows interactive, user-centric segmentation even for large data sets. We show that this method, given appropriate choice of feature vector, produces results both qualitatively and quantitatively similar to Level Sets, Random Walkers, and others. We validate the robustness of this segmentation scheme with comparisons to standard ground-truth models and sensitivity analysis of the algorithm. PMID- 20855918 TI - Interactive Visualization of Rotational Symmetry Fields on Surfaces. AB - Rotational symmetries (RoSys) have found uses in several computer graphics applications, such as global surface parameterization, geometry remeshing, texture and geometry synthesis, and nonphotorealistic visualization of surfaces. The visualization of N-way rotational symmetry (N-RoSy) fields is a challenging problem due to the ambiguities in the N directions represented by an N-way symmetry. We provide an algorithm that allows faithful and interactive representation of N-RoSy fields in the plane and on surfaces, by adapting the well-known line integral convolution (LIC) technique from vector and second-order tensor fields. Our algorithm captures N directions associated with each point in a given field by decomposing the field into multiple different vector fields, generating LIC images of these fields, and then blending the results. To address the loss of contrast caused by the blending of images, we observe that the pixel values in LIC images closely approximate normally distributed random variables. This allows us to use concepts from probability theory to correct the loss of contrast without the need to perform any image analysis at each frame. PMID- 20855919 TI - A cDNA microarray gene expression data classifier for clinical diagnostics based on graph theory. AB - Despite great advances in discovering cancer molecular profiles, the proper application of microarray technology to routine clinical diagnostics is still a challenge. Current practices in the classification of microarrays' data show two main limitations: the reliability of the training data sets used to build the classifiers, and the classifiers' performances, especially when the sample to be classified does not belong to any of the available classes. In this case, state of-the-art algorithms usually produce a high rate of false positives that, in real diagnostic applications, are unacceptable. To address this problem, this paper presents a new cDNA microarray data classification algorithm based on graph theory and is able to overcome most of the limitations of known classification methodologies. The classifier works by analyzing gene expression data organized in an innovative data structure based on graphs, where vertices correspond to genes and edges to gene expression relationships. To demonstrate the novelty of the proposed approach, the authors present an experimental performance comparison between the proposed classifier and several state-of-the-art classification algorithms. PMID- 20855920 TI - Continuous cotemporal probabilistic modeling of systems biology networks from sparse data. AB - Modeling of biological networks is a difficult endeavor, but exploration of this problem is essential for understanding the systems behavior of biological processes. In this contribution, developed for sparse data, we present a new continuous Bayesian graphical learning algorithm to cotemporally model proteins in signaling networks and genes in transcriptional regulatory networks. In this continuous Bayesian algorithm, the correlation matrix is singular because the number of time points is less than the number of biological entities (genes or proteins). A suitable restriction on the degree of the graph's vertices is applied and a Metropolis-Hastings algorithm is guided by a BIC-based posterior probability score. Ten independent and diverse runs of the algorithm are conducted, so that the probability space is properly well-explored. Diagnostics to test the applicability of the algorithm to the specific data sets are developed; this is a major benefit of the methodology. This novel algorithm is applied to two time course experimental data sets: 1) protein modification data identifying a potential signaling network in chondrocytes, and 2) gene expression data identifying the transcriptional regulatory network underlying dendritic cell maturation. This method gives high estimated posterior probabilities to many of the proteins' directed edges that are predicted by the literature; for the gene study, the method gives high posterior probabilities to many of the literature predicted sibling edges. In simulations, the method gives substantially higher estimated posterior probabilities for true edges and true subnetworks than for their false counterparts. PMID- 20855921 TI - An improved heuristic algorithm for finding motif signals in DNA sequences. AB - The planted (l, d)-motif search problem is a mathematical abstraction of the DNA functional site discovery task. In this paper, we propose a heuristic algorithm that can find planted (l, d)-signals in a given set of DNA sequences. Evaluations on simulated data sets demonstrate that the proposed algorithm outperforms current widely used motif finding algorithms. We also report the results of experiments on real biological data sets. PMID- 20855922 TI - Is there an optimal substitution matrix for contact prediction with correlated mutations? AB - Correlated mutations in proteins are believed to occur in order to preserve the protein functional folding through evolution. Their values can be deduced from sequence and/or structural alignments and are indicative of residue contacts in the protein three-dimensional structure. A correlation among pairs of residues is routinely evaluated with the Pearson correlation coefficient and the MCLACHLAN similarity matrix. In literature, there is no justification for the adoption of the MCLACHLAN instead of other substitution matrices. In this paper, we approach the problem of computing the optimal similarity matrix for contact prediction with correlated mutations, i.e., the similarity matrix that maximizes the accuracy of contact prediction with correlated mutations. We describe an optimization procedure, based on the gradient descent method, for computing the optimal similarity matrix and perform an extensive number of experimental tests. Our tests show that there is a large number of optimal matrices that perform similarly to MCLACHLAN. We also obtain that the upper limit to the accuracy achievable in protein contact prediction is independent of the optimized similarity matrix. This suggests that the poor scoring of the correlated mutations approach may be due to the choice of the linear correlation function in evaluating correlated mutations. PMID- 20855924 TI - A comprehensive statistical model for cell signaling. AB - Protein signaling networks play a central role in transcriptional regulation and the etiology of many diseases. Statistical methods, particularly Bayesian networks, have been widely used to model cell signaling, mostly for model organisms and with focus on uncovering connectivity rather than inferring aberrations. Extensions to mammalian systems have not yielded compelling results, due likely to greatly increased complexity and limited proteomic measurements in vivo. In this study, we propose a comprehensive statistical model that is anchored to a predefined core topology, has a limited complexity due to parameter sharing and uses microarray data of mRNA transcripts as the only observable components of signaling. Specifically, we account for cell heterogeneity and a multilevel process, representing signaling as a Bayesian network at the cell level, modeling measurements as ensemble averages at the tissue level, and incorporating patient-to-patient differences at the population level. Motivated by the goal of identifying individual protein abnormalities as potential therapeutical targets, we applied our method to the RAS-RAF network using a breast cancer study with 118 patients. We demonstrated rigorous statistical inference, established reproducibility through simulations and the ability to recover receptor status from available microarray data. PMID- 20855923 TI - Predicting MHC-II binding affinity using multiple instance regression. AB - Reliably predicting the ability of antigen peptides to bind to major histocompatibility complex class II (MHC-II) molecules is an essential step in developing new vaccines. Uncovering the amino acid sequence correlates of the binding affinity of MHC-II binding peptides is important for understanding pathogenesis and immune response. The task of predicting MHC-II binding peptides is complicated by the significant variability in their length. Most existing computational methods for predicting MHC-II binding peptides focus on identifying a nine amino acids core region in each binding peptide. We formulate the problems of qualitatively and quantitatively predicting flexible length MHC-II peptides as multiple instance learning and multiple instance regression problems, respectively. Based on this formulation, we introduce MHCMIR, a novel method for predicting MHC-II binding affinity using multiple instance regression. We present results of experiments using several benchmark data sets that show that MHCMIR is competitive with the state-of-the-art methods for predicting MHC-II binding peptides. An online web server that implements the MHCMIR method for MHC-II binding affinity prediction is freely accessible at http://ailab.cs.iastate.edu/mhcmir. PMID- 20855925 TI - Accurate reconstruction for DNA sequencing by hybridization based on a constructive heuristic. AB - Sequencing by hybridization is a promising cost-effective technology for high throughput DNA sequencing via microarray chips. However, due to the effects of spectrum errors rooted in experimental conditions, an accurate and fast reconstruction of original sequences has become a challenging problem. In the last decade, a variety of analyses and designs have been tried to overcome this problem, where different strategies have different trade-offs in speed and accuracy. Motivated by the idea that the errors could be identified by analyzing the interrelation of spectrum elements, this paper presents a constructive heuristic algorithm, featuring an accurate reconstruction guided by a set of well defined criteria and rules. Instead of directly reconstructing the original sequence, the new algorithm first builds several accurate short fragments, which are then carefully assembled into a whole sequence. The experiments on benchmark instance sets demonstrate that the proposed method can reconstruct long DNA sequences with higher accuracy than current approaches in the literature. PMID- 20855926 TI - On position-specific scoring matrix for protein function prediction. AB - While genome sequencing projects have generated tremendous amounts of protein sequence data for a vast number of genomes, substantial portions of most genomes are still unannotated. Despite the success of experimental methods for identifying protein functions, they are often lab intensive and time consuming. Thus, it is only practical to use in silico methods for the genome-wide functional annotations. In this paper, we propose new features extracted from protein sequence only and machine learning-based methods for computational function prediction. These features are derived from a position-specific scoring matrix, which has shown great potential in other bininformatics problems. We evaluate these features using four different classifiers and yeast protein data. Our experimental results show that features derived from the position-specific scoring matrix are appropriate for automatic function annotation. PMID- 20855927 TI - Characterization of a double probe for local pulse wave velocity assessment. AB - Local pulse-wave velocity (PWV) is an accurate indicator of the degree of arteriosclerosis (stiffness) in an artery, providing a direct characterization of the properties of its wall. Devices currently available for local PWV measurement are mainly based on ultrasound systems and have not yet been generalized to clinical practice since they require high technical expertise and most of them are limited in precision, due to the lack of reliable signal processing methods. The present work describes a new type of probe, based on a double-headed piezoelectric (PZ) sensor. The principle of PWV measurement involves determination of the pulse transit time between the signals acquired simultaneously by both PZs, placed 23 mm apart. The double probe (DP) characterization is accomplished in three main studies, carried out in a dedicated test bench system, capable of reproducing a range of clinically relevant properties of the cardiovascular system. The first study refers to determination of the impulse response (IR) for each PZ sensor, whereas the second one explores the existence of crosstalk between both transducers. In the last one, DP time resolution is inferred from a set of three different algorithms based on (a) the maximum of cross-correlation function, (b) the maximum amplitude detection and (c) the zero-crossing point identification. These values were compared with those obtained by the reference method, which consists of the simultaneous acquisition of pressure waves by means of two pressure sensors. The new probe demonstrates good performance on the test bench system and results show that the signals do not exhibit crosstalk. A good agreement was also verified between the PWV obtained from the DP signals (19.55 +/- 2.02 ms(-1)) and the PWV determined using the reference method (19.26 +/- 0.04 ms(-1)). Although additional studies are still required, this probe seems to be a valid alternative to local PWV stand-alone devices. PMID- 20855928 TI - Synchronization of the small-world neuronal network with unreliable synapses. AB - As is well known, synchronization phenomena are ubiquitous in neuronal systems. Recently a lot of work concerning the synchronization of the neuronal network has been accomplished. In these works, the synapses are usually considered reliable, but experimental results show that, in biological neuronal networks, synapses are usually unreliable. In our previous work, we have studied the synchronization of the neuronal network with unreliable synapses; however, we have not paid attention to the effect of topology on the synchronization of the neuronal network. Several recent studies have found that biological neuronal networks have typical properties of small-world networks, characterized by a short path length and high clustering coefficient. In this work, mainly based on the small-world neuronal network (SWNN) with inhibitory neurons, we study the effect of network topology on the synchronization of the neuronal network with unreliable synapses. Together with the network topology, the effects of the GABAergic reversal potential, time delay and noise are also considered. Interestingly, we found a counter-intuitive phenomenon for the SWNN with specific shortcut adding probability, that is, the less reliable the synapses, the better the synchronization performance of the SWNN. We also consider the effects of both local noise and global noise in this work. It is shown that these two different types of noise have distinct effects on the synchronization: one is negative and the other is positive. PMID- 20855930 TI - Abstracts of the 34th National Congress Italian Association for the Study of the Pancreas (AISP). Peschiera del Garda, Italy. October 7-9, 2010. PMID- 20855929 TI - More than a wire. PMID- 20855932 TI - Hypertension is the metabolic syndrome component most strongly associated with microvascular complications and coronary artery calcification in Type 1 diabetes. AB - AIM: To evaluate the association of metabolic syndrome (MetS) and its individual components with microvascular complications and coronary artery calcification (CAC) in patients with Type 1 diabetes. MATERIAL/SUBJECTS AND METHODS: Cross sectional study included 261 patients with Type 1 diabetes. Patients were assessed regarding the presence of MetS according to National Cholesterol Education Program (NCEP) criteria. CAC score was measured in a subset of 100 patients without known cardiovascular disease. RESULTS: The prevalence of MetS was 13.4% according to the NCEP criteria. Microvascular complications and CAC were more frequent in patients with MetS. In a multiple logistic regression analysis, MetS remained associated with nephropathy [OR: 6.33 (95% CI 2.54 15.77), p<0.001], but not with retinopathy and CAC. Among the MetS components, hypertension was associated with presence of retinopathy [OR: 4.04 (95% CI 1.65- 9.90), p=0.002], nephropathy [OR: 5.92 (95% CI 2.42-14.4), p<0.001] and CAC [OR: 2.97 (95% CI 1.06-8.30), p=0.03]. CONCLUSIONS: Hypertension was the only MetS component associated with retinopathy, nephropathy and the presence of CAC. Hypertension was better associated with CAC than MetS itself. PMID- 20855933 TI - Gender differences in bone mineral density in obese children during pubertal development. AB - OBJECTIVE: To investigate whether body mass index (BMI) and body composition can affect peak bone mass in a population of obese (OB) (BMI SDS>2.0) and normal weight (NORM) (BMI-SD score <2.0) pubertal subjects (Tanner stage T3 to T5). PATIENTS AND METHODS: 151 subjects (81 OB, age 14.5+/-2.4 yr) were analyzed using dual-X-ray absorbiometry technique to study Lumbar and whole body bone mineral density (BMD) (areal, normalized for height) and Z-score, lean mass (LM) and lean/fat ratio. RESULTS: As a whole group, OB males did not show any significant difference in bone parameters vs NORM, while OB females showed higher bone density parameters (p<0.05). When grouped according to T, while OB males showed higher bone density at T3-4 stage (p<0.01), and lower at T5 (p<0.01) compared to NORM, OB females showed a tendency through increased BMD at T3-4 and T5 although statistically different only at T5. BMD was independently correlated to LM, lean/fat ratio, and testosterone in NORM males and, at lower level, in OB males, while to LM in NORM females and only to age in OB females. CONCLUSION: Our data seem to confirm the possible negative influence of obesity on bone density in boys, a possible explanation could be an unfavorable body composition during sexual maturation that seems not to affect bone development in adolescents girls. PMID- 20855934 TI - Phenotypic changes of the thyrocyte membrane in papillary thyroid carcinoma. A three-dimensional study. AB - Aim of the study was to assess the presence of structural changes in the complex carbohydrate chains of thyroid epithelia undergoing neoplastic transformation. We investigated thyroid cells from neoplastic lesions using a panel of lectins with specific affinity for distinct carbohydrate residues. Sixty samples of thyroid tissue, including normal, hyperplastic and neoplastic lesions were obtained from surgical specimens and blindly evaluated with lectin stains. Confocal microscopy was used to obtain three-dimensional (3-D) images of the samples with a positive reaction. Wheat germ agglutinin (WGA) was consistently positive on the apical membrane of papillary thyroid carcinomas (PTC), was weakly expressed in follicular carcinomas (FC) and resulted negative in normal thyrocytes and in benign conditions. The 3-D microscopy model showed that the WGA staining pattern in light microscopy corresponds to a continuous layer on the luminal surface of both papillary and tubular structures of PTC cells. The other lectins under evaluation did not provide any significant result. In conclusion, in PTC the apical border of thyrocytes showed a strong, specific and consistent staining with WGA. These findings may be related to a modified interaction of thyroglobulin molecule with thyroid cell membrane and with the expression of molecules that are involved in the process of tumorigenesis and tumor progression. PMID- 20855935 TI - Correlation of fl/d3 polymorphism of growth hormone receptor with the first- and second-year response to recombinant human growth hormone therapy in pre-pubertal Greek children with idiopathic isolated growth hormone deficiency. AB - BACKGROUND: fl/d3 polymorphism in human GH receptor was correlated with the response to GH therapy in different groups of children with short stature. AIM: This is a 2-yr retrospective study which evaluates the influence of fl/d3 polymorphism to the 1st-and 2nd-year response to GH replacement therapy in Greek children with isolated GH deficiency (GHD). SUBJECTS AND METHODS: A total number of 195 pre-pubertal Greek children were studied (121 controls and 74 patients with GH peak <10 ng/ml). Patients with deficiency were treated with exogenous GH at a mean dose of 28.8 MUg/kg.d. Multiplex PCR was used to genotype all children for fl/d3 polymorphism, followed by statistical analysis. The main parameters which were used to assess the association of genotype with the response to GH replacement were height SD score (SDS), height gain SDS, and growth velocity (GV) expressed as cm/yr and SDS. RESULTS: Our results revealed that the frequency of d3-homozygosity in the Greek population was 8.26%. No association was detected between the presence or abcense of GHD and genotype. Moreover, no connection between genotype and sex was observed. First-year height SDS, height gain SDS, and GV SDS were significantly higher in d3-carriers (p<0.05). However, this difference did not appear in the 2nd year of treatment. CONCLUSIONS: In our study, the d3-polymorphism seems to be associated with a higher efficacy to GH replacement, at least at the beginning of the treatment. PMID- 20855936 TI - Relationship between thyroid stimulating hormone and thyroid stimulating immunoglobulin in Graves' hyperthyroidism. AB - BACKGROUND AND AIM: In Graves' hyperthyroidism, suppression of serum TSH after restoration of normal serum T4 and T3 with treatment has been attributed to binding of TSH-receptor antibodies to TSH receptors in the pituitary. Accordingly, the relationship between TSH and serum thyroid stimulating immunoglobulin (TSI) was examined during follow-up of patients with Graves' hyperthyroidism. SUBJECTS AND METHODS: 23 patients with Graves' hyperthyroidism were identified who met the inclusion criteria of at least 24 months follow-up after initiation of methimazole and availability of concurrent measurements of serum TSH and TSI. RESULTS: TSI disappeared in 12 patients (Group A) and persisted in 11 patients (Group B). Initial T4 was not significantly different between the 2 groups. However, TSI was significantly lower in Group A than Group B [median (interquartile range) 179 (152-212)% vs 255 (208-369)%, p=0.0009]. In Group A, TSH normalized during treatment, and this anteceded disappearance of TSI by a significant time interval [median (interquartile range) 6 (3-8) months vs 15 (11-20) months, p=0.005]. In Group B, TSI persisted in all patients during follow up ranging from 24 to 73 months. No correlation was found to exist between serum TSH and TSI, and for Group B TSI at final follow-up was not significantly different from the initial value [median (interquartile range) 255 (208-369)% vs 236 (160-310)%, p=0.4]. CONCLUSIONS: These findings do not support the suggestion that TSI has a direct suppressive effect on TSH secretion. PMID- 20855937 TI - Chromatin landscape: methylation beyond transcription. AB - The nucleus is organized and compartmentalized into a highly ordered structure that contains DNA, RNA, chromosomal and histone proteins. The dynamics associated with these various components are responsible for making sure that the DNA is properly duplicated, genes are properly transcribed, and the genome is stabilized. It is no surprise that alterations in these various components are directly associated with pathologies like cancer. This Point of View focuses on the role the chromatin modification landscape, especially histone 3 lysine 9 methylation (H3K9me), and heterochromatin proteins (HP1) play in regulating DNA templated processes, with a particular focus on their role at non-genic regions and effects on chromatin structure. These observations will be further extended to the role that alterations in chromatin landscape will contribute to diseases. This Point of View emphasizes that alterations in histone modification landscapes are not only relevant to transcription but have broad range implications in chromatin structure, nuclear architecture, cell cycle, genome stability and disease progression. PMID- 20855939 TI - Immunogenicity and safety of a NeuGcGM3 based cancer vaccine: Results from a controlled study in metastatic breast cancer patients. AB - Increased levels of NeuGc-containing gangliosides have been described in human breast cancer. A controlled Phase II clinical trial was conducted in patients with metastatic breast cancer to evaluate immunogenicity, safety and to identify evidences of biological activity of a cancer vaccine composed by NeuGcGM3 in a proteoliposome of Neisseria meningitidis together with Montanide ISA 51 as adjuvant. After first line chemotherapy, 79 women were randomized 1:1 to receive the vaccine candidate or best supportive care. All patients achieved at least stable disease to the first line therapy for the metastatic condition. Treatment consisted on 5 vaccine doses every 2 weeks and then, monthly re-immunization to complete 15 doses. Vaccination with the NeuGcGM3 based vaccine was safe and the most frequent adverse events consisted on injection site reactions, fever, arthralgia and chills. The vaccine was immunogenic and a sustained increase of both IgG and IgM antibody titters against NGcGM3 was observed after the second vaccination month. Antibodies were able to recognize the NeuGcGM3(+) murine tumor cell line L1210 and the myeloma cell line P3X63. Humoral response was specific since vaccination did not result in Neu-Acetyl GM3 or GM2-antibody response. Hyperimmune sera from vaccinated patients were able to prevent the NeuGcGM3 mediated CD4 down-modulation on T lymphocytes. In the intent to treat analysis, there was a trend toward a survival advantage for the vaccine group and this effect was significant for women bearing non-visceral metastasis. Two phase III clinical studies with this vaccine candidate are ongoing. PMID- 20855938 TI - Intracellular linkers are involved in Mg2+-dependent modulation of the Eag potassium channel. AB - Modulation of activation kinetics by divalent ions is one of the characteristic features of Eag channels. Here, we report that Mg(2+)-dependent deceleration of Eag channel activation is significantly attenuated by a G297E mutation, which exhibits a gain-of-function phenotype in Drosophila by suppressing the effect of shaker mutation on behavior and neuronal excitability. The G297 residue is located in the intracellular linker of transmembrane segments S2 and S3, and is thus not involved in direct binding of Mg(2+) ions. Moreover, mutation of the only positively charged residue in the other intracellular linker between S4 and S5 also results in a dramatic reduction of Mg(2+)-dependent modulation of Eag activation kinetics. Collectively, the two mutations in eag eliminate or even paradoxically reverse the effect of Mg(2+) on channel activation and inactivation kinetics. Together, these results suggest an important role of the intracellular linker regions in gating processes of Eag channels. PMID- 20855940 TI - Vaccine effectiveness against laboratory-confirmed influenza in infants: A matched case control study. AB - Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient's positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group. PMID- 20855942 TI - Successful hepatitis B immunization in non- and low responding health care workers. AB - Health care workers (HCW) are at increased risk for acquisition of hepatitis B virus (HBV) infection from occupational exposure. This can be prevented by active immunization. We performed a retrospective chart review of HCW who were persistent low (anti-HBs antibody values <100 U/L) or non responders (<10 U/L) after 6 active immunizations and demonstrate successful immunization (anti-HBs >=100 U/l) after a total of 8-14 vaccine doses in 13 such HCW by use of various vaccination schedules. This "proof of principle" should encourage occupational health care providers to convince HCW to accept further vaccine doses until the targeted threshold considered to be the correlate of immunity has been reached. Prospective studies should be performed to determine the optimal schedule of further booster doses for HCW who are persistent non or low responders. PMID- 20855941 TI - HPV vaccine acceptance, utilization and expected impacts in the U.S.: Where are we now? AB - Human papillomavirus (HPV) vaccines represent a remarkable opportunity for the primary prevention of cervical cancer and other HPV-related diseases. With almost four years of vaccine availability now accrued in the United States (U.S.), data are beginning to accumulate about vaccine utilization patterns and how these may be affected by public opinions about the vaccines. This article describes the burden of HPV infection and related disease in the U.S., and reviews what is currently known about HPV vaccine utilization among adolescent and young adult females in this country. In addition, we report on emerging data on the personal and attitudinal factors that appear to influence HPV vaccine utilization and discuss how these data may be useful for designing future interventions to improve uptake of these vaccines. Finally, we re-examine cost-effectiveness studies of HPV vaccines, taking into account updated information on utilization of, and public attitudes about, these vaccines. PMID- 20855944 TI - Recognition of p63 by the E3 ligase ITCH: Effect of an ectodermal dysplasia mutant. AB - The E3 ubiquitin ligase Itch mediates the degradation of the p63 protein. Itch contains four WW domains which are pivotal for the substrate recognition process. Indeed, this domain is implicated in several signalling complexes crucially involved in human diseases including Muscular Dystrophy, Alzheimer's Disease and Huntington Disease. WW domains are highly compact protein-protein binding modules that interact with short proline-rich sequences. The four WW domains present in Itch belong to the Group I type, which binds polypeptides with a PY motif characterized by a PP xY consensus sequence, where x can be any residue. Accordingly, the Itch-p63 interaction results from a direct binding of Itch-WW2 domain with the PY motif of p63. Here, we report a structural analysis of the Itch-p63 interaction by fluorescence, CD and NMR spectroscopy. Indeed, we studied the in vitro interaction between Itch-WW2 domain and p63(534-551), an 18-mer peptide encompassing a fragment of the p63 protein including the PY motif. In addition, we evaluated the conformation and the interaction with Itch-WW2 of a site specific mutant of p63, I549T, that has been reported in both Hay-Wells syndrome and Rapp-Hodgkin syndrome. Based on our results, we propose an extended PP xY motif for the Itch recognition motif (P-P-P-Y-x(4)-[ST]-[ILV]), which includes these C-terminal residues to the PP xY motif. PMID- 20855945 TI - Effects of dietary folic acid level and symbiotic folate production on fitness and development in the fruit fly Drosophila melanogaster. AB - Folic acid is a vitamin for probably all animals. When converted to folate forms, it is used in DNA synthesis and amino acid metabolism. Literature suggests insects must consume folates, folates do not affect others, is a toxin for some, and that a few insects synthesize it. It has been reported that Drosophila melanogaster does not consistently need dietary folate because it can synthesize it. This seems unlikely since animals generally lack this ability. More likely, folates thought to have been made by the fly came from microbial symbionts. We aimed to clarify how dietary folic acid affects fitness and development in fruit flies and whether flies may receive folates from microbial symbionts. We found larvae were more viable and developed faster with increasing dietary folic acid, with the surprising exception that larvae fed nearly-zero folic acid developed faster. Their body folate levels did not significantly differ from those that consumed up to 600 times more folic acid. However, these flies fed little folate only achieved normal body folate levels and development times when antibiotics were excluded from the diet. When flies consumed near-zero folates with antibiotics, their body folate levels decreased and development was prolonged. An assay for the endosymbiont Wolbachia in flies used to generate the experimental flies did not show presence of these bacteria. Our data suggest D. melanogaster can harbor unknown bacterial symbiont(s) that provide essential folates to their host when it is scarce in the diet, allowing the fruit fly to maintain growth and development. PMID- 20855943 TI - Epimorphic regeneration in mice is p53-independent. AB - The process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G2/M "arrest," showed that p21(Cip1/Waf1) was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53(-/-) mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21(-/-) mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cycle-related mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgfbeta/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgfbeta/Smad pathway. PMID- 20855946 TI - Arabidopsis L10 ribosomal proteins in UV-B responses. AB - Ribosomal protein L10 (RPL10) is an ubiquitous protein that participates in joining the 40S and 60S ribosomal subunits into a functional 80S ribosome; however, increasing evidences indicate that RPL10 from various organisms has multiple extra ribosomal functions, besides being a constituent of ribosome and its role in translation. Arabidopsis thaliana contains in its genome three genes encoding RPL10, named RPL10A, RPL10B and RPL10C. Previously, we found that in maize and in A. thaliana, UV-B induces a reduction in protein biosynthesis, probably as a consequence of ribosomal damage; however, cellular recovery occurs in the absence of UV-B. Here, we show that RPL10s are differentially regulated by UV-B in a dosage and time dependent manner: RPL10C is induced, RPL10B is down regulated at high UV-B intensity, and RPL10A is not UV-B regulated. In addition, by coimmunoprecipitation studies using RPL10 antibodies and proteins from control and UV-B irradiated Arabidopsis plants, we demonstrate that RPL10 associates with different proteins under the two different conditions, including nuclear proteins, suggesting that at least one isoform may have extra-ribosomal roles. PMID- 20855947 TI - RNAi knockdown of HdmX or Hdm2 leads to new insights into p53 signaling. PMID- 20855948 TI - The role of microenvironment in testicular germ cell tumors. AB - Testicular germ cell tumors (TGCTs) are the most frequent malignancies in adolescents and young adults. The incidence of TGCTs has doubled over the last few decades and the mechanisms underlying their pervasive growth are still poorly understood. Among them, seminomatous and non-seminomatous tumors have carcinoma in situ of the testis (CIS) as a common precursor lesion. It is currently accepted that the acquisition of genetic alterations and/or exposure to environmental factors are involved in the transition from CIS to invasive tumors. Nevertheless, although several TGCT-associated genetic aberrations have been identified, the mechanisms mediating their effects on TGCT development are still largely unknown. The aim of this review is to analyze the potential role of testicular microenvironmental factors, such as hypoxia and stroma cell-derived factors, in the acquisition by TGCT cells of an aggressive phenotype and the importance of these factors as potential therapeutic targets. PMID- 20855949 TI - Involvement of DAD1-like lipases in response to salt and osmotic stress in Arabidopsis thaliana. AB - Acyl hydrolases remodel biological membranes and release signaling molecules in response to a variety of biotic and abiotic stresses. After wounding or pathogen treatment lipases are necessary to release fatty acids as substrate for jasmonate biosynthesis. In osmotic stressed tissue they maintain integrity and functionality of membranes and during senescence lipases destroy and recycle membranes. Recently the role of several acyl hydrolases including DEFECTIVE IN ANTHER DEHISCENCE (DAD1) and DAD1-like lipase, e.g. DONGLE (DGL) and the phospholipase A (PLA) PLA-Igamma1 in jasmonate biosynthesis after wounding were investigated and functional redundancy within this family has been stated. Here we report necessity of diverse DAD1-like lipases in response to salt and sorbitol treatment. The lipase PLA-Igamma1 and PLA-Ibeta2, which were both impaired in wound response, were also affected in response to osmotic stress in seed germination assays. Based on our observations and interpretations of transcription analyses generated by AtGenExpress project we speculate about more general roles of the DAD1-like lipase in diverse biological processes. PMID- 20855950 TI - Lipid binding activities of flax rust AvrM and AvrL567 effectors. AB - Effectors are pathogen-encoded proteins that are thought to facilitate infection by manipulation of host cells. Evidence showing that the effectors of some eukaryotic plant pathogens are able to interact directly with cytoplasmic host proteins indicates that translocation of these proteins into host cells is an important part of infection. Recently, we showed that the flax rust effectors AvrM and AvrL567 are able to internalize into plant cells in the absence of the pathogen. Further, N-terminal sequences that were sufficient for uptake were identified for both these proteins. In light of the possibility that the internalization of fungal and oomycete effectors may require binding to specific phospholipids, the lipid binding activities of AvrM and AvrL567 mutants with different abilities to enter cells were tested. While AvrL567 was not found to bind to phospholipids, AvrM bound strongly to phosphatidyl inositol, phosphatidyl inositol monophosphates and phosphatidyl serine. However, a fragment of AvrM sufficient to direct uptake of a fusion protein into plant cells did not bind to these phospholipids. Thus, our results do not support the role of specific binding of AvrM and AvrL567 to phospholipids for uptake into the plant cytoplasm. PMID- 20855951 TI - Vesicular neurotransmitter transporter trafficking in vivo: moving from cells to flies. AB - During exocytosis, classical and amino acid neurotransmitters are released from the lumen of synaptic vesicles to allow signaling at the synapse. The storage of neurotransmitters in synaptic vesicles and other types of secretory vesicles requires the activity of specific vesicular transporters. Glutamate and monoamines such as dopamine are packaged by VGLUTs and VMATs respectively. Changes in the localization of either protein have the potential to up- or down regulate neurotransmitter release, and some of the mechanisms for sorting these proteins to secretory vesicles have been investigated in cultured cells in vitro. We have used Drosophila molecular genetic techniques to study vesicular transporter trafficking in an intact organism and have identified a motif required for localizing Drosophila VMAT (DVMAT) to synaptic vesicles in vivo. In contrast to DVMAT, large deletions of Drosophila VGLUT (DVGLUT) show relatively modest deficits in localizing to synaptic vesicles, suggesting that DVMAT and DVGLUT may undergo different modes of trafficking at the synapse. Further in vivo studies of DVMAT trafficking mutants will allow us to determine how changes in the localization of vesicular transporters affect the nervous system as a whole and complex behaviors mediated by aminergic circuits. PMID- 20855952 TI - A microRNA regulating adult hematopoietic stem cells. PMID- 20855954 TI - The DNA-dependent protein kinase (DNA-PK): More than just a case of making ends meet? AB - The DNA-dependent protein kinase (DNA-PK) has a vital role in DNA double strand break repair and in mediating V(D) J recombination events. Over the years a body of data has implicated DNA-PK playing a significant role in mediating a p53 dependent apoptotic response under a range of cellular conditions including exposure to ionizing radiation (IR), environmental carcinogens and chemotherapeutic agents or in cells that have critically shortened telomeres. These findings raise the hypothesis that DNA-PK acts as both a sensor and transmitter of DNA damage signals that directly impact cell fate. These many overlapping roles are discussed and considered in this review article. PMID- 20855955 TI - Subtypes of cervical adenosquamous carcinomas classified by EpCAM expression related to radiosensitivity. AB - Adenosquamous carcinoma (ASC) is a relatively uncommon histological subtype of cervical cancer (CC). A point of controversy is the relative prognosis of ASC compared to squamous cell carcinoma (SCC). We hypothesized that ASC could be classified into two intrinsic molecular subtypes with different outcomes. We examined 143 biopsy samples of CC patients to identify a molecule for classification using microarray expression analysis and immunohistochemical analysis (IHA). We found specific expression profiles of candidate genes that distinguished two clusters. All adenocarcinoma (AC) patients were classified into one cluster, and most SCC patients fell into the other cluster. ASC patients were classified across the two clusters, which showed significantly different prognoses. The SCC-like expression signature comprised ANXA8, CK5, IFI16, and nectin-1; and the AC-like signature comprised EpCAM, and TMEM98. These signature specific genes hypothetically indicated specific pathways by ontological analysis. The AC-like signature suggested an epithelial-mesenchymal transition and activated beta-catenin pathway, while the SCC-like signature suggested keratinocyte differentiation, HPV infection, and p53-mediated apoptosis. IHA revealed that positive expression of the most promising protein, EpCAM, was significantly associated with poor prognosis. In addition, the inhibition of EpCAM expression using siRNA significantly increased radiation-induced cell death in the cervical cell line, ME-180. In conclusion, we identified two possible ASC subtypes associated with different expression profiles and different prognoses. This work provides a novel set of genes that could be used as independent prognostic markers and therapy targets. PMID- 20855953 TI - In search of decoy/guardee to R genes: deciphering the role of sugars in defense against Fusarium wilt in chickpea. AB - Plant responses are coordinately controlled by both external and internal signals. Apt perception of pathogen attack and its appropriate conversion to internal signals ultimately determine the outcome of innate immunity. The present review predicts the involvement of unconventional 'Guard/Decoy Model' in chickpea Fusarium encounter. Rapid alkalinization factor is predicted to act as initial 'Gatekeeper decoy' counteracting fungal entry. Phospholipases and cystatins probably function as 'Guardees' being shielded by R gene(s). Serine Threonine Kinases decodes external pathogenic signals to in planta defense alarms. 14.3.3 provides clues to the wilt mechanism. The versatile sugars serve as signal generators and transmitters maintaining intra and inter cellular connectivity during stress. PMID- 20855956 TI - Evolution of FW2.2-like (FWL) and PLAC8 genes in eukaryotes. AB - The tomato FW2.2 quantitative trait locus, which regulates tomato fruit size, was genetically and physically mapped around 15 years ago. Subsequently, the FW2.2 gene was cloned and shown to contain a PLAC8 domain, originally identified in mammalian placental proteins. Data suggest that FW2.2 likely controls tomato cell size, perhaps by direct interaction with casein kinase II. Several FW2.2-like (FWL) genes have now been identified from a variety of plant species, but until recently only the tomato FW2.2 gene had been the subject of detailed investigation. Recently, soybean and maize FWL genes were identified and shown to have a role in plant organogenesis. It is now apparent that the FWL genes in plants are a large gene family, which is even larger given inclusion of genes for the various eukaryotic PLAC8-domain proteins. Although overall the protein sequence identity/similarity among the family members is relatively low, there is strong conservation of key domains, suggesting a conservation of the core biochemical function of these proteins. In this Addendum Article, we highlight the similarities and differences exiting between plant FWL genes and enlarge this comparison to the mammalian PLAC8 genes. These comparisons suggest the possible conservation of biological function for FWL proteins. PMID- 20855957 TI - Eradication of EGFR-positive circulating tumor cells and objective tumor response with lapatinib and capecitabine. AB - For breast cancer patients, treatment decisions based on the molecular profile of the primary tumor have been used for many years. In Her2-overexpressing tumors, trastuzumab is a key component of therapy. However, despite persistent expression of Her2, most tumors eventually become resistant to trastuzumab. When this happens, the patients benefit from a regime containing lapatinib, a dual EGFR and Her2 tyrosine kinase inhibitor. We report on a patient affected by chemo refractory metastatic Her2-positive breast cancer enrolled in a translational research program for the detection and characterization of circulating tumor cells (CTCs). Depletion of the EGFR-positive CTC pool in the blood was associated with tumor response, whereas disease progression was related to a recurrence in CTCs, which were both EGFR and Her2 negative. Although a proof for the clinical significance of EGFR-positive circulating tumor cells is currently lacking, expression of EGFR may predict response to lapatinib-based treatments as in the case presented. PMID- 20855958 TI - Stomatal development and movement: the roles of MAPK signaling. AB - Stomata are epidermal pores on plant surface used for gas exchange with the atmosphere. Stomatal development and movement are regulated by environmental and internal signals. Mitogen-activated protein kinase (MAPK) cascades are universal transducers of extracellular signals among all eukaryotes. In plant, MAPK cascades regulate diverse cellular processes occurring during the whole ontogenetic plant life and ranging from normal cell proliferation to stress inducing plant-to-environment interactions. Recent reports reveal that MAPK signaling is involved in both stomatal development and movement. This mini-review summarizes the roles of MAPK signaling in stomatal development and movement. How MAPK specificity is maintained in stomatal development and movement is also discussed. PMID- 20855959 TI - Is membrane occupation and recognition nexus domain functional in plant phosphatidylinositol phosphate kinases? AB - Phosphatidylinositol phosphate kinase (PIPK) catalyzes a key step controlling cellular contents of phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2], a critical intracellular messenger involved in vesicle trafficking and modulation of actin cytoskeleton and also a substrate of phospholipase C to produce the two intracellular messengers, diacylglycerol and inositol-1,4,5-trisphosphate. In addition to the conserved C-terminal PIPK catalytic domain, plant PIPKs contain a unique structural feature consisting of a repeat of membrane occupation and recognition nexus (MORN) motifs, called the MORN domain, in the N-terminal half. The MORN domain has previously been proposed to regulate plasma membrane localization and phosphatidic acid (PA)-inducible activation. Recently, the importance of the catalytic domain, but not the MORN domain, in these aspects was demonstrated. These conflicting data raise the question about the function of the MORN domain in plant PIPKs. We therefore performed analyses of PpPIPK1 from the moss Physcomitrella patens to elucidate the importance of the MORN domain in the control of enzymatic activity; however, we found no effect on either enzymatic activity or activation by PA. Taken together with our previous findings of lack of function in plasma membrane localization, there is no positive evidence indicating roles of the MORN domain in enzymatic and functional regulations of PpPIPK1. Therefore, further biochemical and reverse genetic analyses are necessary to understand the biological significance of the MORN domain in plant PIPKs. PMID- 20855960 TI - Inhibition of MCL-1 in breast cancer cells promotes cell death in vitro and in vivo. AB - The present studies have examined approaches to suppress MCL-1 function in breast cancer cells, as a means to promote tumor cell death. Treatment of breast cancer cells with CDK inhibitors (flavopiridol; roscovitine) enhanced the lethality of the ERBB1 inhibitor lapatinib in a synergistic fashion. CDK inhibitors interacted with lapatinib to reduce MCL-1 expression and over-expression of MCL-1 or knock down of BAX and BAK suppressed drug combination lethality. Lapatinib-mediated inhibition of ERK1/2 and to a lesser extent AKT facilitated CDK inhibitor induced suppression of MCL-1 levels. Treatment of cells with the BH3 domain / MCL 1 inhibitor obatoclax enhanced the lethality of lapatinib in a synergistic fashion. Knock out of MCL-1 and BCL-XL enhanced lapatinib toxicity to a similar extent as obatoclax and suppressed the ability of obatoclax to promote lapatinib lethality. Pre-treatment of cells with lapatinib or with obatoclax enhanced basal levels of BAX and BAK activity and further enhanced drug combination toxicity. In vivo tumor growth data in xenograft and syngeneic model systems confirmed our in vitro findings. Treatment of cells with CDK inhibitors enhanced the lethality of obatoclax in a synergistic fashion. Over-expression of MCL-1 or knock down of BAX and BAK suppressed the toxic interaction between CDK inhibitors and obatoclax. Obatoclax and lapatinib treatment or obatoclax and CDK inhibitor treatment or lapatinib and CDK inhibitor treatment radiosensitized breast cancer cells. Lapatinib and obatoclax interacted to suppress mammary tumor growth in vivo. Collectively our data demonstrate that manipulation of MCL-1 protein expression by CDK inhibition or inhibition of sequestering function MCL-1 by Obatoclax renders breast cancer cells more susceptible to BAX/BAK-dependent mitochondrial dysfunction and tumor cell death. PMID- 20855961 TI - Spo5 phosphorylation is essential for its own timely degradation and for successful meiosis in Schizosaccharomyces pombe. AB - Protein phosphorylation is pivotal for meiotic progression, but little is known about its regulatory mechanisms. We show that before meiosis I, the meiosis specific Schizosaccharomyces pombe protein Spo5 is phosphorylated in vivo on T29, T55, S59 and/or T63. In a mutant strain expressing Spo5 fused to green fluorescent protein with alanine substitutions of these amino acid sites (GFP; Spo5-4A-GFP), the timely degradation of Spo5 at meiosis II was not observed. Additionally, Spo5-4A-GFP signals were retained after metaphase II and were localized to the nucleus. This was accompanied by the nuclear mislocalization of Psy1, a marker of the forespore membrane (FSM), and the generation of empty cells, in which cytoplasm had leaked from the ruptured membrane, as well as by the appearance of asci harboring deformed spores. Indeed, thin-section electron microscopy (TEM) revealed fragile-looking spo5-4A-GFP ascospores with ruffled spore walls. In contrast, a mutant strain expressing a constitutively phosphorylated form of Spo5 (Spo5-4D-GFP) was phenotypically indistinguishable from a strain expressing wild-type (WT) protein (Spo5-WT-GFP). Taken together, these results indicate that Spo5 phosphorylation ensures the timely degradation of Spo5 during meiosis and the proper localization of Psy1, leading to the production of viable spores with robust FSMs and strong walls. PMID- 20855963 TI - Tumor-initiating cells are not enriched in cisplatin-surviving BRCA1;p53 deficient mammary tumor cells in vivo. AB - Although many breast cancers respond to chemotherapy or hormonal therapy, lack of tumor eradication is a central clinical problem preceding the development of drug resistant tumors. Using the K14cre;Brca1(F5-13/F5-13);p53(F2-10/F2-10) mouse model for hereditary breast cancer, we have previously studied responses of mammary tumors to clinically relevant anti-cancer drugs, including cisplatin. The BRCA1- and p53-deficient tumors generated in this model are hypersensitive to cisplatin and never become resistant to this agent due to the large, irreversible deletion in Brca1. We show here that even dose-dense treatment with a maximum tolerated dose of cisplatin does not result in complete tumor eradication. To explain this result we have addressed the hypothesis that the lack of eradication of drug-sensitive tumors is due to increased in vivo chemotherapy resistance of tumor-initiating cells (TICs). Using the CD24 and CD49f cell surface markers which detect normal mouse mammary stem cells, we have identified tumor-initiating cells in BRCA1- and p53-deficient tumors. In addition to the Lin /CD24(+)/CD49f(+) subpopulation, we show that a larger population of Lin /CD24(+)/CD49f-cells also has tumor-initiating capability in at least two serial orthotopic transplantations, suggesting that these are not more differentiated transit-amplifying cells. However, we did not find an enrichment of TICs in cisplatin-treated tumor remnants. We conclude that in this model the tolerance of the cisplatin-surviving cells cannot be attributed to special biochemical defense mechanisms of TICs. PMID- 20855964 TI - A GFP-tagged muscleblind C protein isoform reporter construct. AB - Drosophila muscleblind (mbl), the ortholog of human Muscleblind-like 1 (MBNL1) gene involved in Myotonic Dystrophy (DM), gives raise to protein isoforms MblA to G. The specific functions and subcellular distribution of isoforms are still largely unknown. To overcome the lack of isoform-specific antibodies we generated transgenic flies that express a GFP:MblC fusion protein under the control of the Gal4/UAS system. The reporter fusion protein was able to functionally complement mbl loss of function mutations, demonstrating activity, and accumulated predominantly in adult muscle nuclei. The fluorescent nature of the reporter makes it appropriate for live imaging detection of MblC protein isoform. PMID- 20855962 TI - Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. AB - Recently, using a co-culture system, we demonstrated that MCF7 epithelial cancer cells induce oxidative stress in adjacent cancer-associated fibroblasts, resulting in the autophagic/lysosomal degradation of stromal caveolin-1 (Cav-1). However, the detailed signaling mechanism(s) underlying this process remain largely unknown. Here, we show that hypoxia is sufficient to induce the autophagic degradation of Cav-1 in stromal fibroblasts, which is blocked by the lysosomal inhibitor chloroquine. Concomitant with the hypoxia-induced degradation of Cav-1, we see the upregulation of a number of well-established autophagy/mitophagy markers, namely LC3, ATG16L, BNIP3, BNIP3L, HIF-1alpha and NFkappaB. In addition, pharmacological activation of HIF-1alpha drives Cav-1 degradation, while pharmacological inactivation of HIF-1 prevents the downregulation of Cav-1. Similarly, pharmacological inactivation of NFkappaB- another inducer of autophagy-prevents Cav-1 degradation. Moreover, treatment with an inhibitor of glutathione synthase, namely BSO, which induces oxidative stress via depletion of the reduced glutathione pool, is sufficient to induce the autophagic degradation of Cav-1. Thus, it appears that oxidative stress mediated induction of HIF1- and NFkappaB-activation in fibroblasts drives the autophagic degradation of Cav-1. In direct support of this hypothesis, we show that MCF7 cancer cells activate HIF-1alpha- and NFkappaB-driven luciferase reporters in adjacent cancer-associated fibroblasts, via a paracrine mechanism. Consistent with these findings, acute knock-down of Cav-1 in stromal fibroblasts, using an siRNA approach, is indeed sufficient to induce autophagy, with the upregulation of both lysosomal and mitophagy markers. How does the loss of stromal Cav-1 and the induction of stromal autophagy affect cancer cell survival? Interestingly, we show that a loss of Cav-1 in stromal fibroblasts protects adjacent cancer cells against apoptotic cell death. Thus, autophagic cancer-associated fibroblasts, in addition to providing recycled nutrients for cancer cell metabolism, also play a protective role in preventing the death of adjacent epithelial cancer cells. We demonstrate that cancer-associated fibroblasts upregulate the expression of TIGAR in adjacent epithelial cancer cells, thereby conferring resistance to apoptosis and autophagy. Finally, the mammary fat pads derived from Cav-1 (-/-) null mice show a hypoxia-like response in vivo, with the upregulation of autophagy markers, such as LC3 and BNIP3L. Taken together, our results provide direct support for the "Autophagic Tumor Stroma Model of Cancer Metabolism", and explain the exceptional prognostic value of a loss of stromal Cav-1 in cancer patients. Thus, a loss of stromal fibroblast Cav-1 is a biomarker for chronic hypoxia, oxidative stress and autophagy in the tumor microenvironment, consistent with its ability to predict early tumor recurrence, lymph node metastasis and tamoxifen-resistance in human breast cancers. Our results imply that cancer patients lacking stromal Cav-1 should benefit from HIF-inhibitors, NFkappaB-inhibitors, anti-oxidant therapies, as well as autophagy/lysosomal inhibitors. These complementary targeted therapies could be administered either individually or in combination, to prevent the onset of autophagy in the tumor stromal compartment, which results in a "lethal" tumor microenvironment. PMID- 20855965 TI - Positive regulation of euchromatic gene expression by HP1. AB - HP1 is a conserved prototype protein that plays an essential role in heterochromatin formation and epigenetic gene silencing through its interaction with histone methyltransferase enzymes (HMTases) and the histone H3 at lysine 9 (H3-MeK9). HP1 is also involved in telomere capping and, more surprisingly, in positive regulation of gene expression. Recently, a wide expression analysis, using a RIP-chip assays (RNA-immunoprecipitation on microarrays), has shown that HP1 associates with the transcripts of more than one hundred euchromatic genes and interacts with the heterogeneous nuclear ribonucleoproteins (hnRNPs) that are known to be involved in RNA processing. By these results, HP1 seems to be part of a complex that stabilizes RNA transcripts. Though previously unsuspected, it was also found that HP1-interacting hnRNPs have a functional role in heterochromatin formation. These proteins bind heterochromatin and are dominant suppressors of position effect variegation. Taken together, the results in the paper by Piacentini et al. open a window on a possible new conceptual landscape in which similar epigenetic mechanisms could have a significant role, both in the metabolism of RNA transcripts and in heterochromatin formation, producing opposite functional effects. These data seem to establish a functional link between euchromatin and heterochromatin. PMID- 20855966 TI - GEMC1 is a novel TopBP1-interacting protein involved in chromosomal DNA replication. AB - Chromosomal DNA must be precisely replicated in each cell cycle in order to ensure maintenance of genome stability. Most of the factors controlling this process have been identified in lower eukaryotes. Several factors involved in DNA replication are also important for the cellular response to stress conditions. However, the regulation of DNA replication in multi-cellular organisms is still poorly understood. Using the Xenopus laevis egg cell-free system, we have recently identified a novel vertebrate protein named GEMC1 required for DNA replication. xGEMC1 is a Cyclin dependent kinase (CDK) target required forCdc45 loading onto chromatin and it interacts with the checkpoint and replication factor TopBP1, which promotes its binding to chromatin during prereplication complex formation. Here we discuss our recent findings and propose possible roles for GEMC1. Interestingly, recent studies have identified other proteins with analogous functions, showing a higher level of complexity in metazoan replication control compared to lower eukaryotes. PMID- 20855967 TI - Starved cells use mitochondria for autophagosome biogenesis. PMID- 20855968 TI - Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors. AB - BACKGROUND: Single-dose infusion of the agonistic anti-CD40 monoclonal antibody (mAb) CP-870,893 accomplishes immune activation and clinical responses in patients with advanced cancers, but repeat dosing of this agent has not been reported. RESULTS: Twenty-seven patients were enrolled. The most common adverse event was transient, infusion-related cytokine release syndrome (CRS). Dose limiting toxicities included grade 3 CRS and grade 3 urticaria; the maximum tolerated dose (MTD) was estimated to be 0.2 mg/kg. Seven patients (26%) had stable disease as the best clinical response; no partial or complete responses were observed. At the MTD, patient B lymphocytes exhibited persistently increased expression of costimulatory and adhesion molecules without resetting to baseline between doses. In 4 of 8 patients (50%) evaluated at the MTD, there were marked declines in total CD3(+) T lymphocytes, as well as CD4(+) and CD8(+) subsets. PATIENTS AND METHODS: Patients with advanced solid tumor malignancies received weekly intravenous infusions of CP-870,893 in four dose level cohorts. Safety and immune pharmacodynamics were assessed. CONCLUSIONS: Weekly infusions of the agonist CD40 antibody CP-870,893 were well-tolerated, but there was little clinical activity in advanced cancer patients. Correlative studies demonstrate chronic B cell activation and in some patients, T cell depletion. Longer dosing intervals may be desirable for optimal immune pharmacodynamics. PMID- 20855969 TI - Neighborly DISCourse: DNA double strand breaks silence transcription. PMID- 20855970 TI - The FLIGHT Drosophila RNAi database: 2010 update. AB - FLIGHT (http://flight.icr.ac.uk/) is an online resource compiling data from high throughput Drosophila in vivo and in vitro RNAi screens. FLIGHT includes details of RNAi reagents and their predicted off-target effects, alongside RNAi screen hits, scores and phenotypes, including images from high-content screens. The latest release of FLIGHT is designed to enable users to upload, analyze, integrate and share their own RNAi screens. Users can perform multiple normalizations, view quality control plots, detect and assign screen hits and compare hits from multiple screens using a variety of methods including hierarchical clustering. FLIGHT integrates RNAi screen data with microarray gene expression as well as genomic annotations and genetic/physical interaction datasets to provide a single interface for RNAi screen analysis and data-mining in Drosophila. PMID- 20855971 TI - Large standard deviations and logarithmic-normality: the truth about hemocyte counts in Drosophila. AB - While many quantifiable biological phenomena can be described by making use of an assumption of normality in the distribution of individual values, many biological phenomena are not accurately described by the normal distribution. An unquestioned assumption of normality of distribution of possible outcomes can lead to misinterpretation of data, which could have serious consequences. Thus it is extremely important to test the validity of an assumption of normality of possible outcomes. As it turns out, the logarithmic-normal (log-normal) distribution pattern is often far more accurate in describing statistical biological phenomena. Herein I examine large samples of values for circulating blood cell (hemocyte) concentration (CHC) among both wild-type and mutant Drosophila larvae, and demonstrate in both cases that the distribution of individual values does not conform to normality, but does conform to log normality. PMID- 20855972 TI - Caspase 3 activity in whole cell extracts of Ba/F3 cells is unrelated to apoptosis. PMID- 20855973 TI - Why have chloroplasts developed a unique motility system? AB - Organelle movement in plants is dependent on actin filaments with most of the organelles being transported along the actin cables by class XI myosins. Although chloroplast movement is also actin filament-dependent, a potential role of myosin motors in this process is poorly understood. Interestingly, chloroplasts can move in any direction, and change the direction within short time periods, suggesting that chloroplasts use the newly formed actin filaments rather than preexisting actin cables. Furthermore, the data on myosin gene knockouts and knockdowns in Arabidopsis and tobacco do not support myosins' XI role in chloroplast movement. Our recent studies revealed that chloroplast movement and positioning are mediated by the short actin filaments localized at chloroplast periphery (cp actin filaments) rather than cytoplasmic actin cables. The accumulation of cp actin filaments depends on kinesin-like proteins, KAC1 and KAC2, as well as on a chloroplast outer membrane protein CHUP1. We propose that plants evolved a myosin XI-independent mechanism of the actin-based chloroplast movement that is distinct from the mechanism used by other organelles. PMID- 20855974 TI - Alternative efficacy-predicting markers for paclitaxel instead of CHFR in non small-cell lung cancer. AB - Experiments using cancer cell lines have revealed that CHFR methylation correlates with sensitivity to microtubule inhibitors. However, this marker may not benefit actual clinical cases because it is difficult to detect CHFR methylation without surgically resected samples. Thus, a more easily accessible marker that correlates with sensitivity to microtubule inhibitors might be useful in NSCLC, especially in advanced cases. In this study, we show that EGFR gene status and smoking are predict the efficacy of treatment with microtubule inhibitors in NSCLC. Chemosensitivity to paclitaxel and six other chemotherapeutic agents was evaluated using the succinate dehydrogenase inhibition (SDI) method in 69 NSCLC cases, consisting of 48 adenocarcinomas, 20 squamous cell carcinomas and 1 large cell carcinoma. Next, we evaluated the relationships between CHFR or EGFR status and clinicopathologic data. Methylation specific PCR (MSP) and direct DNA sequencing were performed to detect aberrant methylation of CHFR and EGFR mutations, respectively. CHFR gene promoter methylation and EGFR gene mutation were observed in 11 cases (15.9%) and 7 cases (10.1%), respectively. The SDI method revealed that CHFR gene methylation was significantly related to high sensitivity to paclitaxel (p. PMID- 20855975 TI - Mechanical and electrical anisotropy in Mimosa pudica pulvini. AB - Thigmonastic or seismonastic movements in Mimosa pudica, such as the response to touch, appear to be regulated by electrical, hydrodynamical, and chemical signal transduction. The pulvinus of Mimosa pudica shows elastic properties, and we found that electrically or mechanically induced movements of the petiole were accompanied by a change of the pulvinus shape. As the petiole falls, the volume of the lower part of the pulvinus decreases and the volume of the upper part increases due to the redistribution of water between the upper and lower parts of the pulvinus. This hydroelastic process is reversible. During the relaxation of the petiole, the volume of the lower part of the pulvinus increases and the volume of the upper part decreases. Redistribution of ions between the upper and lower parts of a pulvinus causes fast transport of water through aquaporins and causes a fast change in the volume of the motor cells. Here, the biologically closed electrochemical circuits in electrically and mechanically anisotropic pulvini of Mimosa pudica are analyzed using the charged capacitor method for electrostimulation at different voltages. Changing the polarity of electrodes leads to a strong rectification effect in a pulvinus and to different kinetics of a capacitor discharge if the applied initial voltage is 0.5 V or higher. The electrical properties of Mimosa pudica's pulvini were investigated and the equivalent electrical circuit within the pulvinus was proposed to explain the experimental data. The detailed mechanism of seismonastic movements in Mimosa pudica is discussed. PMID- 20855976 TI - Quantitative phosphoproteomics: New technologies and applications in the DNA damage response. AB - Cells are highly responsive to their environment. One of the main strategies used by cells in signal transduction is protein phosphorylation, a reversible modification that regulates numerous biological processes. Misregulation of phosphorylation-mediated processes is often implicated in many human diseases and cancers. A global and quantitative analysis of protein phosphorylation provides a powerful new approach and has the potential to reveal new insights in signaling pathways. Recent technological advances in high resolution mass spectrometers and multidimensional liquid chromatography, combined with the use of stable isotope labeling of proteins, have led to the application of quantitative phosphoproteomics to study in vivo signal transduction events on a proteome-wide scale. Here we review recent advancements in quantitative phosphoproteomic technologies, discuss their potentials and identify areas for future development. A key objective of proteomic technology is its application to addressing biological questions. We will therefore describe how current quantitative phosphoproteomic technology can be used to study the molecular basis of phosphorylation events in the DNA damage response. PMID- 20855977 TI - 4-Hydroxynonenal and fat storage: A paradoxical pro-obesity mechanism? PMID- 20855978 TI - The role of G proteins in assembly and function of Kir3 inwardly rectifying potassium channels. AB - Kir3 channels (also known as GIRK channels) are important regulators of electrical excitability in both cardiomyocytes and neurons. Much is known regarding the assembly and function of these channels and the roles that their interacting proteins play in controlling these events. Further, they are one of the best studied effectors of heterotrimeric G proteins in general and Gbetagamma subunits in particular. However, our understanding of the roles of multiple Gbetagamma binding sites on Kir3 channels is still rudimentary. We discuss potential roles for Gbetagamma in channel assembly and trafficking in addition to their known role in cellular signaling. PMID- 20855980 TI - Development and evaluation of a new taxonomy of mobility-related assistive technology devices. AB - OBJECTIVE: This article reports on the development of a new taxonomy for mobility related assistive technology devices. DESIGN: A prototype taxonomy was created based on the extant literature. Five mobility device experts were engaged in a modified Delphi process to evaluate and refine the taxonomy. RESULTS: Multiple iterations of expert feedback and revision yielded consensual agreement on the structure and terminology of a new mobility device taxonomy. The taxonomy uses a hierarchical framework to classify ambulation aids and wheeled mobility devices, including their key features that impact mobility. Five attributes of the new taxonomy differentiate it from previous mobility-related device classifications: (1) hierarchical structure, (2) primary device categories are grouped based on their intended mobility impact, (3) comprehensive inclusion of technical features, (4) a capacity to assimilate reimbursement codes, and (5) availability of a detailed glossary. CONCLUSIONS: The taxonomy is intended to support assistive technology outcomes research. The taxonomy will enable researchers to capture mobility-related assistive technology device interventions with precision and provide a common terminology that will allow comparisons among studies. The prominence of technical features within the new taxonomy will hopefully promote research that helps clinicians predict how devices will perform, thus aiding clinical decision making and supporting funding recommendations. PMID- 20855979 TI - The uniform data system for medical rehabilitation: report of patients with lower limb joint replacement discharged from rehabilitation programs in 2000-2007. AB - OBJECTIVE: To provide benchmarking information from a large national sample of patients receiving inpatient rehabilitation after lower limb joint replacement. DESIGN: Secondary data analysis from 893 medical rehabilitation facilities located in the United States that contributed information to the Uniform Data System for Medical Rehabilitation from January 2000 through December 2007. Variables analyzed included demographic information (age, sex, marital status, race/ethnicity, prehospital living setting, discharge setting), hospitalization information (length of stay, program interruptions, payer, onset date, rehabilitation impairment group, International Classification of Diseases, 9th revision codes for admitting diagnosis, comorbidities), and functional status information (FIM instrument ["FIM"] ratings at admission and discharge, FIM efficiency, FIM gain). RESULTS: Descriptive statistics from 705,345 patients showed an overall mean length of stay of 8.9 (+/-4.7) days. FIM total admission and discharge ratings declined during the 8-yr study period. Mean admission ratings decreased from 83.5 (+/-11.3) to 73.2 (+/-12.9). Mean discharge ratings decreased from 108.4 (+/-11.0) to 101.7 (+/-12.9). Conversely, mean FIM change increased from 24.9 (+/-9.2) to 28.6 (+/-12.2). The percent of persons discharged to the community decreased from 94.5% to 91.9%. All results are likely to be influenced by various policy changes affecting classification or documentation processes or both. CONCLUSIONS: National rehabilitation data from persons with lower limb joint replacement in 2000-2007 indicate that inpatient rehabilitation lengths of stay have remained relatively stable and that patients are experiencing improvements in functional independence during their stay. In addition, more than 9 of 10 patients are discharged to community settings after inpatient rehabilitation. PMID- 20855981 TI - Relationship between oscillations about the vertical axis and center of pressure displacements in single and double leg upright stance. AB - OBJECTIVES: The purposes of this study are to assess the relationship of the center of pressure (CoP) displacement parameters along the mediolateral and anteroposterior axes to whole-body oscillations about the vertical axis during single or double leg upright stance and to determine whether sensory deprivation and stance modify balance stability about the vertical axis and in the horizontal plane. DESIGN: Eleven male adults stood on a force plate during conditions in which stance (single/double) and/or vision (normal/reduced) were modified independently. The dependent variables were CoP range, CoP velocity, and free moment (TZ) range. R-squared coefficients (R) were applied to assess the relationship between CoP and TZ range, whereas multifactor analysis of variances were used to assess the differences among conditions. RESULTS: R between CoP and TZ parameters varied from 0.16 to 0.69 for three of the four conditions, suggesting that different postural mechanisms controlled CoP displacements and body axial rotations. Single leg stance with reduced vision condition revealed a higher R between CoP velocity and TZ range. TZ range was approximately seven times greater when stance was modified to single limb stance, whereas reduced vision had no effect. CONCLUSIONS: Postural control mechanisms seem to be different for the free moment (TZ) than for the CoP displacements. PMID- 20855982 TI - Effects of paraplegia on cardiac autonomic regulation during static exercise. AB - OBJECTIVES: The aim of this study was to examine whether autonomic modulation of heart rate as measured by heart rate variability and heart rate complexity at rest and during static handgrip exercise differs between individuals with and without paraplegia. This study also examined the relationships between heart rate complexity and heart rate variability parameters. DESIGN: Heart rate variability and complexity were evaluated in 20 individuals with paraplegia and in 20 individuals without paraplegia during 3 mins of rest and 2 mins of static handgrip exercise at 30% of maximum isometric strength. Spectral decomposition of heart rate variability was used to obtain total power, power in low-frequency and high-frequency ranges, and the ratio of low- to high-frequency power. Heart rate complexity was quantified with sample entropy, a measure of irregularity of the beat-to-beat time series. RESULTS: Sample entropy was lower (P < 0.05) at rest and during exercise in participants with paraplegia. Total, high-, and low frequency powers as well as the ratio of low- to high-frequency power did not differ between groups. Sample entropy did not significantly correlate with low- and high-frequency powers or their ratio. CONCLUSIONS: Individuals with paraplegia show lower heart rate complexity at rest and during static exercise. This finding may have implications for cardiovascular morbidity in persons with paraplegia. Heart rate complexity may provide unique information regarding cardiac autonomic modulation, different from that provided by traditional heart rate variability measures. PMID- 20855983 TI - Effect of autonomic dysfunction on p-wave dispersion in patients with chronic spinal cord injury. AB - OBJECTIVE: To provide information about the effect of autonomic dysfunction on P wave dispersion, as a predictor of atrial fibrillation, in patients with spinal cord injury. DESIGN: Thirty patients with chronic traumatic spinal cord injury and 27 healthy controls were included in this study. The initial assessment of the patients included routine physical examination and evaluation of 12-lead electrocardiography. In the patient group, blood pressure and electrocardiography recordings were obtained during urodynamic assessment. The measurements of the P wave duration were performed manually by two blinded investigators. P-wave dispersion was calculated as the difference between maximum P-wave duration and minimum P-wave duration. P-wave dispersion values of resting electrocardiography recordings in control and study groups were compared. In the patient group, subgroup analyses were also performed according to the injury level and severity and existence of autonomic dysfunction in examinations. RESULTS: P-wave dispersion values were greater in patients with spinal cord injury than in healthy controls. There was statistically significant difference between P-wave dispersion values of the patients with and without autonomic dysfunction. P-wave dispersion values at initial sensation of vesical filling were greater than those of the resting state in the patients without autonomic dysfunction. CONCLUSIONS: Our findings indicate that P-wave dispersion increases significantly in chronic spinal cord injured patients with autonomic dysfunction. This finding suggests a tendency for atrial fibrillation occurrence in patients with spinal cord injury, which may cause further cerebrovascular complications in this special subset of patients by creating a thromboembolic milieu. PMID- 20855984 TI - Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. AB - OBJECTIVE: To test the efficacy and safety of a cannabinoid, dronabinol, compared with an active control, diphenhydramine, in relieving neuropathic pain in persons with spinal cord injury. DESIGN: A randomized, controlled, double-blind, crossover pilot study. RESULTS: Seven adults with spinal cord injury and neuropathic pain below the level of injury participated. Two participants withdrew while receiving dronabinol, their first medication. For the remaining five participants, change in pain on a scale of 0-10 from baseline to the end of the maintenance phase did not differ significantly between the two medications (mean change, dronabinol: 0.20 +/- 0.837, range = -1.00 to 1.00; diphenhydramine: -1.80 +/- 2.490, range = -6.00 to 0; Wilcoxon Z = 1.63, P = 0.102). Similar results were found when the average of the two ratings during the maintenance phase was used (dronabinol: -0.20 +/- 0.671, range = -0.50 to 1.00; diphenhydramine: -1.40 +/- 1.245, range = -3.50 to -0.50; Wilcoxon Z = 1.60, P = 0.109). The most common side effects were dry mouth, constipation, fatigue, and drowsiness for both medications. CONCLUSIONS: On average, dronabinol was no more effective than diphenhydramine for relieving chronic neuropathic pain below the level of injury. PMID- 20855985 TI - Platelet-rich plasma in muscle healing. AB - The muscle healing process is defined as a complex and dynamic process resulting in the restoration of anatomic continuity and function. This process is characterized by a cascade of events triggered by the tissue injury itself. It is widely accepted that growth factors play a central role in the healing processes by modulating the recruitment, duplication, activation, and differentiation of different cell types. This observation is the basis on which the use of platelet rich plasma in several circumstances is founded; all of them requiring the activation or the modulation of the tissue repair process. There is an extensive documentation of in vitro and in vivo studies demonstrating the safety and efficacy of growth factors in the muscle healing process. Unfortunately, the precise biological efficacy and the lack of long-term side effects have not been clearly demonstrated. With regard to sports medicine, doping-related issues are still a matter of debate, especially regarding the treatment of muscle injuries. The purpose of this review is to examine the role of growth factors during muscle healing processes and to discuss the implications of platelet-rich plasma in its therapeutic applications. Sports medicine issues are also discussed particularly with regard to antidoping regulations. PMID- 20855986 TI - Editorial: critical need for pediatric hematologists to specialize in hemostasis and thrombosis. PMID- 20855987 TI - Thrombosis and thrombophilia: principles for pediatric patients. AB - Thrombotic complications in pediatric patients are increasingly recognized due to increased use of invasive procedures, heightened awareness, improved imaging and prothrombotic lifestyle choices. Multiple risk factors are often present in pediatric patients with thrombosis. The most common risk factor is an indwelling catheter, followed by inflammatory conditions, malignancy, immobilization, thrombophilia and congenital heart disease. Rare severe thrombophilias, whether acquired or congenital, often present in children. Neonates have distinct patterns of thrombosis promoted by sepsis, inflammation, hypotension, hypoxia and the use of intravascular catheters in small caliber and umbilical vessels. Treatment of pediatric thromboembolic disease requires an understanding of developmental hemostasis, application of nonpediatric drug formulations and consolidation of expert guidelines and relevant adult literature. The acute and chronic consequences of thrombosis can be devastating in pediatrics and correlate with the length of time of vessel occlusion, underscoring the importance of rapid diagnosis and initiation of therapy. As trials begin to define recurrence risks, outcome predictors and optimal therapy for children with thrombosis and thrombophilia, consultation with an experienced pediatric hematologist provides the best available therapy today. PMID- 20855988 TI - Interpreting coagulation assays. AB - The interpretation of coagulation assays requires knowledge of the principal clotting pathways. The activated partial thromboplastin time is sensitive to all hemostatic factors except FVII, whereas the prothrombin time reflects levels of prothrombin and FV, FVII, and FX. Using the two tests in concert is helpful in identifying hemophilia, the coagulopathy of liver disease, and disseminated intravascular coagulation. In addition, the activated partial thromboplastin time and prothrombin time are used for monitoring anticoagulant therapy with heparin and warfarin, respectively. Measurement of D-dimer is informative in patients suspected of having thrombotic disorders and determining the risk of thrombosis recurrence. Mixing tests distinguish clotting factor deficiencies from circulating anticoagulants such as heparin, the lupus anticoagulant, and antibodies directed against specific clotting factors. The modified Bethesda assay detects and provides an indication of the strength of FVIII inhibitors. However, interpreting the results of coagulation assays is not always straightforward, and expert consultation is occasionally required to resolve difficult clinical situations. PMID- 20855989 TI - Transitioning issues in adolescent to young adult hemophilia patients with inhibitors: an approach for a growing population. AB - The major adverse effect of factor replacement therapy in patients with hemophilia is the development of neutralizing antibodies termed inhibitors. This complication renders standard factor replacement therapy ineffective resulting in increased morbidity and mortality. Until recently, the population of adults with inhibitors was relatively small due to the death of many of the patients from HIV that they contracted from contaminated factor in the early 1980s. With the advent of factor products with reduced risks for deadly infections in the mid-1980s to early 1990s, a cohort of inhibitor patients is now beginning to enter adulthood thus raising the issues regarding the transition of these patients into adulthood. It is, therefore, expected that adult hematologists will be seeing more inhibitor patients and that pediatric hematologists will be faced with managing this transition process, which may not necessarily include transition to an adult facility or adult hematologist. This review will discuss the various issues ranging from choice of medical provider to a discussion of psychosocial and financial issues facing this specific patient population. PMID- 20855990 TI - Toll-like receptor 2 signaling triggers fatal arrhythmias upon myocardial ischemia-reperfusion. AB - OBJECTIVE: Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors. Toll-like receptor 2 deficiency is associated with a reduced infarct size after myocardial ischemia and reperfusion. Because a marked mortality was observed in C3HeN wild-type mice, which was absent in TLR2 mice, we tested whether cardiac arrhythmias are the underlying pathology and aimed to elucidate how toll-like receptor 2 ligation might prevent lethal arrhythmias. DESIGN: Experimental animal model. SETTING: University hospital research laboratory. SUBJECTS: Male C3HeN mice. INTERVENTIONS: Myocardial ischemia and reperfusion was surgically induced by ligation of the left anterior descending coronary artery for 20 mins followed by 24 hrs of reperfusion. Electrocardiography was continuously recorded during the observation period through an implantable telemetry transmitter to detect cardiac arrhythmias during reperfusion. MEASUREMENTS AND MAIN RESULTS: Toll-like receptor 2 expression was associated with a 51% mortality rate (23 of 45 mice died) after myocardial ischemia and reperfusion. Absence of toll-like receptor 2 improved survival toward 100% (17 of 17 mice survived). Electrocardiography diagnostics in conscious animals and histologic analysis revealed that absence of toll-like receptor 2 signaling prevented the formation of pathologic heart rate turbulence after myocardial ischemia and reperfusion and modulated the density of connexin 43-positive gap junctions in the ischemic area compared with wild-type hearts, indicating arrhythmia as the cause underlying the observed mortality. CONCLUSIONS: The results presented here indicate toll-like receptor 2 as a novel target for the prevention of lethal arrhythmic complications after myocardial ischemia and reperfusion. PMID- 20855992 TI - Toll-like receptor-2 and disturbances of the cardiac rhythm: life changes in a heartbeat. PMID- 20855993 TI - Ubi poop, ibi evacua? PMID- 20855994 TI - Prolongation of prothrombin time in the critically ill: is it time for decisive action? PMID- 20855995 TI - Taking a closer look at mechanical ventilation in the United States. PMID- 20855996 TI - Disorder of osmoregulation as a new pathogenetic mechanism of septic shock? PMID- 20855997 TI - Clinical repercussions of high-frequency percussive ventilation: a burning issue. PMID- 20855998 TI - Vasopressin, levosimendan, and cardiovascular function in septic shock. PMID- 20855999 TI - Hands-only cardiopulmonary resuscitation: Bench-to-bedside or bedside-to-bench? PMID- 20856000 TI - Caspase: the unfriendly "meat tenderizer" of sepsis. PMID- 20856001 TI - Does urinary L-type fatty acid-binding protein predict the severity of sepsis complicated by acute kidney injury? PMID- 20856002 TI - Sex, drugs, false dawns, and magic bullets. PMID- 20856003 TI - Arginine vasopressin plasma levels could indicate children undergoing cardiopulmonary bypass that might benefit from exogenous arginine vasopressin. PMID- 20856004 TI - pH1N1 influenza A: timing is everything. PMID- 20856005 TI - Diagnosis of cerebral vasospasm and transcranial Doppler: isolated velocities are not enough. PMID- 20856006 TI - Magnesium activation of the calcium-sensing receptor, a mechanism to reduce infarction and vasospasm in subarachnoid hemorrhage. PMID- 20856008 TI - Number of intervention of the bundle accomplished does not reflect degree of compliance with the sepsis bundles. PMID- 20856010 TI - Question about septic shock study. PMID- 20856012 TI - A fluorinated dendrimer-based nanotechnology platform: new contrast agents for high field imaging. AB - OBJECTIVES: We aimed to develop a directly detected magnetic resonance imaging (MRI) contrast agent for use with high fields based on a nanoscale fluorinated dendrimer-based platform for F MRI and overcome some of the problems with F MRI. MATERIALS AND METHODS: The dendrimers were prepared in a convergent manner by making the appropriate dendron, followed by coupling to a central core. The dendrons were prepared by attaching 3 equivalents of the fluorinated amino acid to the 3 carboxylic acids of the repeat branch unit followed by deprotection of the amine branch point, and either coupling to another repeat branch unit (increasing the generation G) or used directly allowing the precise growth of the dendrimer. The size of the dendrimers was determined by diffusion nuclear magnetic resonance (NMR) spectroscopy. The toxicity of the dendrimers was measured using the MTT assay. Fluorine longitudinal relaxation time measurements were performed on a Bruker ACP-500 NMR using a saturation recovery experiment at 470.59 MHz frequency. Healthy 150 g Sprague-Dawley female rats were imaged using a dendrimer solution. RESULTS: The size of the dendrimers is generally less than 3 nm, 2 orders of magnitude smaller than the size of the perfluorocarbon nanoparticles (about 200 nm). The longitudinal relaxation time, T1, decreases with increasing dendrimer generation. A significant improvement in relaxation rate and signal-to-noise ratio can be achieved by either the chemical modification of the dendrimer with a gadolinium-chelate or by the physical addition of exogenous contrast agent. Although the dendrimers with fluorine in the surface layer are toxic, this toxicity is easily reduced by burying the fluorine further into the dendrimer interior. (19)F MR images of the rat using the dendrimer solution were rapidly obtained at 7 Tesla, the strong contrast in the heart generated by the dendrimer can be seen. CONCLUSIONS: A novel fluorinated dendrimer-based nanotechnology platform in (19)F MRI and a new bifunctional DOTA chelate were prepared and characterized. We introduce 2 methods for reducing the (19)F longitudinal relaxation time: (a) Increasing the generation; (b) covalent and noncovalent introduction of Gd(III)-chelates. A new bifunctional Gd(III)-chelate is presented. The investigations of imaging on rats suggest potential importance of the dendrimers in (19)F MRI application. PMID- 20856013 TI - Genetics and dysmorphology in clinical practice--the upscale frontier. PMID- 20856014 TI - Reading genetic-speak. PMID- 20856015 TI - Evolution of a sustainable surgical delivery model. AB - For the past 28 years, Operation Smile has mobilized thousands of volunteers to provide life-changing cleft lip, cleft palate, and other facial deformity surgery to more than 150,000 children in countries all over the world. Our mission is to provide surgical care for children with the goal of developing sustainable health care delivery models for surgical services worldwide. For more than a quarter century, we have learned that good judgment comes from experience and that experience comes from bad judgment. However, it has been woven throughout this sometimes painful, always exhilarating growth process in which we have realized that our mission had so much more power than we initially anticipated that it would. Originally, we focused on the face of a child and our ability to provide a surgery that would change that child's life forever. Today, we still stand in awe of the transformative power of this experience, but we have also realized the great power that lies in educating medical professionals and providing state-of the-art equipment. For us, action took shape in the form of us establishing a business model at home and in each of our partner countries. This included setting up financial reporting systems and creating program models that organized volunteers to provide care for children outside the reach of where surgery was currently available. Through our journey, we have realized that there is power in the healed face of a child. That moment gives us the opportunity to feel the passion for the service we have the privilege to provide. It is that emotion that leads us to action. PMID- 20856016 TI - Six cyclopic ships with the death of one of them. AB - Given the knowledge of cyclopic humans and animals and their lethal nature, and given the negative way in which the cyclops is portrayed in mythology and in art, it is unusual that six naval ships--four English and two American--were named "Cyclops." However, there are also important positive attributes of the Cyclopes in Greek mythology, which explain the reasons the ships were given this name. One ship, the USS "Cyclops," with 306 men aboard, was lost at sea in the "Bermuda Triangle" in 1918 without a trace and no wreckage has ever been found. PMID- 20856017 TI - Anticipating benefits and decreasing burdens: the responsibility inherent in pediatric plastic surgery. AB - Working with child patients and their families in the practice of plastic and reconstructive surgery is rewarding and risky. Technical training is understandably intensive. However, the importance of the work that is needed before an operation does not always attract the same attention. Surgery that is done to change a child's body results in a change in that person's identity and cannot be taken lightly. A review of the overall benefit and burden of both the untreated condition and the proposed changes must be considered to support a change so that it does not damage an individual's identity development. By taking the time to understand what the patient's perspective is, surgical change can become a process that a person is part of, instead of it being something that is done to them. This helps to set up a situation where the change will be directly beneficial to the patient, and that change will be sustained over a long period. When evaluating surgical options with children, the influences and pressures that exist within families and throughout society must also be considered. A young child and his/her future must not get lost in the difficult negotiations between parents/guardians, surgeons, and society. By taking more time to consider the tremendous meaning that your work has outside the operating room and in the context of who the patient is becoming, you will have a greater chance of not just enhancing someone's appearance, but also improving his/her quality of life. PMID- 20856018 TI - Medicine's questions. PMID- 20856019 TI - Fibroblast growth factor receptor 2 and its role in caudal appendage and craniosynostosis. AB - Caudal appendage is a rare but reported finding seen in association with craniosynostosis. We report a newborn with caudal appendage secondary to sacrococcygeal eversion, a cloverleaf skull, choanal atresia, and a heterozygous mutation of Y375C in the juxtamembrane domain (exon 11) of fibroblast growth factor receptor 2 (FGFR2). Further support of this association are 22 other cases of craniosynostosis with caudal appendage or sacrococcygeal eversion in the literature. Of these, 19 had detectable mutations in FGFR2; 5, the same mutation; and 5, a similar substitution of cysteine for serine. We hypothesize that the association of craniosynostosis and caudal appendage is due to abnormal expression of FGFR2 in the tail bud of a developing embryo based on animal models. Our case and those reported in the literature suggest that in patients with caudal appendage and craniosynostosis, FGRF2 analysis should include regions outside the commonly tested exons 8 and 10, particularly the juxtamembrane domain. PMID- 20856021 TI - Ocular manifestations of Apert and Crouzon syndromes: qualitative and quantitative findings. AB - There are significant differences in the ocular manifestations of Apert and Crouzon syndromes. Here, we present qualitative and quantitative data about the oculo-orbital region to demonstrate these differences. Although ocular protosis and hypertelorism characterize both disorders, the nature of the orbital dystopia differs. In Crouzon syndrome, ocular proptosis is primarily caused by retrusion of the lateral and inferior orbital margins with a very short orbital floor. In Apert syndrome, the eyeglobe actually protrudes in relation to the cranial base and to the orbit, probably resulting from marked protrusion of the lateral orbital wall. The implications account for some of the differences encountered. Asymmetry is associated with Apert syndrome frequently. Exotropia is found in Crouzon syndrome, whereas the V pattern is more characteristic in Apert syndrome with divergent upgaze and esotropic downgaze. Subluxation of the eyeglobe is found in some cases of Crouzon syndrome but is not found in Apert syndrome. Optic atrophy found in approximately 20% of Crouzon syndrome patients is not characteristic of Apert syndrome. Structural alterations of the extraocular muscles have been associated with some cases of Apert syndrome, suggesting that ocular motility disturbances in Apert syndrome may not be caused solely by mechanical factors. Absence of the superior rectus and other extraocular muscles has been recorded. Furthermore, albinoid alterations of the fundus have also been associated with Apert syndrome. PMID- 20856020 TI - Wound complications after cleft repair in children with Van der Woude syndrome. AB - Van der Woude syndrome (VWS; OMIM 119300) is an autosomal-dominant condition associated with clefts of the lip and/or palate and lower lip pits and is caused by mutations in interferon regulatory factor 6 (IRF6). The standard of practice for children born with cleft lip/palate is surgical repair, which requires proper wound healing. We tested the hypothesis that children with VWS are more likely to have wound complications after cleft repair than children with nonsyndromic cleft lip/palate (NSCLP). Furthermore, we hypothesized that children with VWS have more surgical procedures. A retrospective, case-controlled study was performed. Seventeen children with VWS and 68 matched controls with NSCLP were scored for the presence of wound complications after cleft repair, for the severity of complications, and for number of surgeries from age 0 to 10. Of the 17 children with VWS, 8 had wound complications. Of 68 controls, 13 had wound complications (P = 0.02). Of 8 wound complications in the VWS group, 6 were major, whereas of 13 complications in the control group, 9 were major (P = 0.04). Most wound complications were fistulae and occurred in isolated cleft palate and bilateral cleft lip. The mean number of surgeries in the VWS group was 3.0 compared with 2.8 in the control group (P = 0.67). Our studies suggest that children with VWS have an increased risk for wound complications after cleft repair compared with children with NSCLP. Furthermore, these data support a role for IRF6 in wound healing. PMID- 20856022 TI - Use of ambulatory polysomnography in children with syndromic craniosynostosis. AB - Children with syndromic or complex craniosynostosis are at risk of developing obstructive sleep apnea (OSA) because of midface hypoplasia and collapse of the pharynx. The criterion standard in diagnosing OSA is polysomnography. The aims of this study were to analyze the feasibility of a home cardiorespiratory monitor in children with syndromic or complex craniosynostosis and to analyze whether oximetry alone or the sum of the amplitudes of the thoracic and abdominal movements (X flow) are valuable alternative assessments to diagnose OSA at home, when complete recording was not achieved. We performed a prospective study of 129 children and analyzed 200 different ambulatory polysomnographies. In 41% of the measurements, a complete analysis of the obstructive apnea-hypopnea index was possible based on the adequate recording of all sensors. Oximetry in comparison with polysomnography had a positive predictive value of 82% and a negative predictive value of 79% for diagnosing OSA. Moderate OSA could be excluded with a negative oximetry. Comparing the X flow and the nasal flow signals that the hypopneas were adequately recorded in 86% and the obstructive apneas in 55%, resulting in an underestimation of the severity of OSA in 10%. In conclusion, in children with syndromic or complex craniosynostosis, diagnosing OSA using home cardiorespiratory monitoring is feasible. Oximetry alone can be used as a rough estimate screening, and with a negative test result, moderate OSA can be excluded. X flow can be helpful in diagnosing OSA in the absence of nasal flow. PMID- 20856023 TI - Male with mosaicism for supernumerary ring X chromosome: analysis of phenotype and characterization of genotype using array comparative genome hybridization. AB - Supernumerary, derivative, and ring X chromosomes are relatively common in Turner syndrome females but have been reported rarely in males. To date, less than 10 cases have been published, of which only 2 have been partially characterized in defining the breakpoints and genetic content of the derivative X chromosome. We describe a male with mosaicism for a supernumerary X chromosome (46,XY/47,XY, r(X)) who has multiple congenital anomalies, including features of craniofrontonasal dysplasia (Mendelian Inheritance in Man 304110) and the presence of ectopic female reproductive organs. Using comparative genomic hybridization array mapping, we determined that the derivative X is composed of a 24-Mb fragment that contains the regions Xp11.3 through Xq13.1 and lacks the XIST gene. This is the first report to describe a detailed molecular characterization of a ring X chromosome in a male by comparative genomic hybridization array analysis. We compare the clinical and molecular findings in this patient to other 46,XY, r(X) patients reported in the literature and discuss the potential role of disomy for known genes contained on the ring X chromosome. PMID- 20856024 TI - Clefting in trisomy 9p patients: genotype-phenotype correlation using microarray comparative genomic hybridization. AB - Duplication 9p syndrome (partial trisomy 9p) is characterized by craniofacial anomalies, mental retardation, and distal phalangeal hypoplasia. Here, we present a female patient with microcephaly and incomplete bilateral cleft lip and palate, whose initial cytogenetic analysis revealed a de novo trisomy 9p. The patient, now 21 years old, has persistent microcephaly, craniofacial and hand anomalies, history of a seizure disorder, and global mental retardation. Oligonucleotide based array comparative genomic hybridization was performed and revealed partial trisomy 9p21.1->9pter and a deletion of 9p12.1 to 9p11.2. Our case supports the utility of array comparative genomic hybridization for the precise characterization of chromosomal anomalies and for the ascertainment of genotype phenotype correlation in patients with partial trisomy 9p. PMID- 20856025 TI - A second family with dominantly inherited isolated cleft palate. AB - Although a number of families have been reported with apparently dominantly inherited cleft lip with or without cleft palate, there is only 1 previous report of dominantly inherited isolated cleft palate. We report a 4-generation family with dominantly inherited clefts of the soft and hard palates, affecting both sexes and showing male-to-male transmission. We believe this is only the second such family and discuss possible reasons for the rarity of such pedigrees. PMID- 20856026 TI - Ectrodactyly-ectodermal dysplasia-clefting syndrome-plastic surgeon's considerations. AB - BACKGROUND: Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomally dominant disorder phenotypically characterized by specific abnormalities of the hand, feet, and orofacial region coexisting with ectodermal dysplasia features. The purpose of this study was to describe the plastic surgeon's approach to EEC treatment by retrospective analysis of the course of surgical treatment. METHODS: Medical documentation of 10 patients with EEC syndrome treated in the Department of Plastic Surgery in Polanica Zdroj in the years 1976-2008 was given retrospective analysis. RESULTS: In the analyzed group of patients, various levels of intensity of ectodermal dysplasia symptoms were confirmed, and in every case, severe forms of clefts were observed. Intensity of cleft malformation, but foremost belated and exacerbated healing, and coexistence of ectodermal dysplasia were the evident cause of more frequent complications and occurrence of greater postcleft deformations. Treatment of this hand and feet malformation is by its nature hampered, and procedures between subsequent stages of cleft surgery are performed. In patients with nasolacrimal duct atresia, dilatation or dacryocystorhinostomy was performed, which effectively improved patients' quality of life. CONCLUSIONS: In reference to plastic surgery point of view, treatment of coexistence with ectodermal dysplasia malformations in EEC syndrome demands more individual therapeutic approach. The presence of ectodermal dysplasia symptoms increases the risk of complications in cleft surgery and treatment of hand and foot deformities or orbital area malformations. Severity of cleft malformation requires surgery supported by experience and embracing the necessity of performing a greater number of more complex corrective procedures. PMID- 20856027 TI - Comparison of facial soft tissue measurements on three-dimensional images and models obtained with different methods. AB - AIM: The aim of this study was to compare the clinical facial soft tissue measurements with the measurements of facial plaster cast, three-dimensional scanned facial plaster cast, 3-dimensional digital photogrammetrical images, and three-dimensional laser scanner images. MATERIALS AND METHODS: Three-dimensional facial images of 15 adults were obtained with stereophotogrammetry and a three dimensional laser scanner. Facial models of subjects were obtained using silicone impression and were scanned. Landmarks were marked on the subjects and plaster casts, digitized on three-dimensional models, and measured in Mimics 12.0 software (Materialise's Interactive Medical Image Control System, Leuven, Belgium). RESULTS: No statistically significant differences were found between all three-dimensional measurement methods in mouth width, philtrum median height, and nasal width. Comparison of clinical measurements with facial plaster cast measurements revealed that philtral width, nasal tip protrusion, and right lip and nostril heights were wider and longer in clinical measurements than in facial plaster cast measurements. Comparison of clinical measurements to the laser scanned and stereophotogrammetric model measurements revealed that philtrum lateral and lip heights and philtral width were significantly different between methods. When laser scanned and stereophotogrammetric measurements were compared, significant differences were observed in lip and nostril heights. CONCLUSIONS: Facial impression may be problematic owing to the depression caused by the impression material especially on the tip of the nose. Laser scanning is not sensitive enough to visualize the deeper indentations such as nostrils. Stereophotogrammetry is promising for three-dimensional facial measurements and even will be better when color identification between mucocutaneous junctions of the lip region is achieved. PMID- 20856028 TI - Preoperative craniofacial dysmorphology in isolated sagittal synostosis: a comprehensive anthropometric evaluation. AB - Although clinical descriptions of altered calvarial shape in isolated sagittal synostosis abound in the literature, systematic quantitative assessment of the total morphologic pattern of preoperative craniofacial dysmorphology remains limited in this population. To address this deficit, a retrospective study was undertaken of 256 preoperative patients younger than 6 years with isolated sagittal synostosis who were seen at the Dallas Craniofacial Center. Patients were examined using a battery of 23 anthropometric measurements of the head and face, from which 10 proportion indices were calculated. The measurements and proportions for each patient were compared with sex- and age-matched norms and converted to standard (Z) scores. The pooled data for each variable were analyzed using 1-sample t-tests. The patients were then separated into 2 age groups- younger than 6 months (n = 162) and 6 months or older (n = 94)--and compared via 2-sample t-tests to examine age-related differences. To further elucidate craniofacial growth patterns, standardized anthropometric measures were then correlated against age. Results indicated that the head was enlarged and elongated with compensatory transverse growth of the anterior cranial vault and reduction in the height of vertex. The face was enlarged, especially along the sagittal axis. The head and face were significantly larger relative to age in children younger than 6 months and show a general decrease in size relative to age in all dimensions except cranial length. The data indicate a complex pattern of dysmorphology, which involves the entire craniofacial complex, not just the cranial vault. PMID- 20856029 TI - Audiologic findings in Pfeiffer syndrome. AB - Hearing loss has been described in patients with certain craniosynostotic syndromes but is poorly defined in Pfeiffer syndrome (PS). Our objective was to characterize the otologic and audiologic findings in PS. The records of PS patients evaluated at our craniofacial center over a 30-year period were culled. Only patients with a confirmed diagnosis and formal audiologic examination were included. Diagnostic criteria were characteristic mutations in fibroblast growth factor receptor 1 or 2 (FGFR1, FGFR2) or, in the absence of genetic testing, typical clinical findings of PS as determined by a clinical geneticist or the most senior author. Twenty patients met the inclusion criteria, and all had hearing loss. Twenty patients had traditional audiologic testing: 14 (70%) had pure conductive loss (minor to severe), and 3 (15%) had a mixed conductive/sensorineural loss (minor to severe). Two additional patients had hearing loss by Behavioral Observational Audiometry (sound fields method). One patient with early conductive hearing loss was subsequently determined to have a pure sensorineural deficit. Nine patients (45%) had permanent hearing loss significant enough to require audiologic amplification. All patients with PS demonstrated hearing loss, although the severity and the anatomic basis (ie., neural vs conductive) were variable. Conductive hearing loss, possibly caused by structural abnormalities, was most common. Sensorineural hearing loss was less common and may be related to the effect of FGFR mutations on cranial nerve and/or inner-ear development. PMID- 20856030 TI - Measuring cranial vault volume with three-dimensional photography: a method of measurement comparable to the gold standard. AB - The gold standard for measuring cranial vault volume is a computed tomography (CT) scan. Computed tomography scans in the pediatric population carry the significant risk of inducing a malignancy later in life. In a novel study, we show that a three-dimensional (3D) photograph can be used to measure and track cranial vault volume changes in craniosynostosis patients. In a study of adequate power as determined by pre hoc analysis, we demonstrate a greater than 0.91 correlation coefficient between volume as measured by CT and 3D photograph in more than 70 patients presenting to a tertiary craniofacial center (P < 0.001). Volume above a plane running through the lateral canthus (ex) and tragus (t) sag ex-t on the digital 3D photograph differs from CT by a mean percentage difference of 31.9% (SD, 14.0%; 95% confidence interval, P < 0.0001). A linear regression model was used to determine the equation describing the relationship between volume as measured by 3D photograph and CT; with this equation, the absolute volume of the cranial vault is easily determined using only the 3D image. Interrater reliability is high (>0.99, ICC). The ability to measure cranial vault volume from the 3D photograph adds an important dimension to the complete and objective analysis of skull growth and postoperative change. PMID- 20856031 TI - Effectiveness of the trapezius vein in the reconstruction of intraoral defects with bare neck. AB - In head and neck cancer reconstruction, the transverse cervical artery is a good alternative vessel when the appropriate recipient vessels cannot be identified because of preoperative radiation and radical neck dissection. Selecting the appropriate recipient vein is essential for a successful intraoral reconstruction. We attempted to determine which veins are candidate partners of the transverse cervical artery by anatomically examining 10 necks (2 sides of the neck in 5 cadavers) in a cadaver study. Three types of veins (suprascapular vein, transverse cervical vein, and descending vein from the trapezius muscle) were selected as recipient vein candidates, and the characteristics of each vein were analyzed. Clinically, we also examined which vessels were chosen as recipient veins in 13 patients in whom intraoral reconstruction with bare neck was performed using the transverse cervical artery as recipient. The descending vein from the trapezius muscles (trapezius vein) was used most frequently, followed by the transverse cervical vein. The transverse cervical vein could be considered an appropriate recipient vein, but it is prone to damage from neck dissection in some cases. Therefore, the use of the trapezius vein can aid in the successful reconstruction in such patients. PMID- 20856032 TI - Le Fort I distraction using internal devices for maxillary hypoplasia in patients with cleft lip, palate, and alveolus: complications and their prevention and management. AB - In recent years, advancement has been made in distraction osteogenesis in the facial area. It has been applied actively to treat maxillary hypoplasia in patients with cleft lip, palate, and alveolus. Le Fort I distraction using internal devices does not lead to disability in daily living, including during the retention period, and has low surgical invasiveness, facile management, and superior aesthetics. Thus, there have been occasional reports on this procedure in recent years. Because an internal device is unidirectional, the greatest disadvantage is the inability to adjust the direction of distraction after its placement. However, past reports have emphasized its advantages, and its complications have rarely been discussed. We performed Le Fort I distraction using internal devices on 15 young patients. Our results showed notable complications in a few cases. When serial cephalometric analysis was performed after maxillary distraction, it demonstrated that the maxilla assumes various three-dimensional distraction morphologies. In particular, cases with insufficient bone grafting of alveolar clefts developed collapse mainly in the alveolar cleft region during postoperative distraction. Mobility and deviation of the maxillary bone fragment occurred. We implemented preventative measures against complications such as using modifications to place the devices parallel on the left and right sides and using a bite splint for distraction. These measures produced improved outcomes, and we describe here the details. PMID- 20856033 TI - Combined aplasia of sphenoid, frontal, and maxillary sinuses accompanied by ethmoid sinus hypoplasia. AB - OBJECTIVE: To report the case of a woman who had combined aplasia of sphenoid, frontal, and maxillary sinuses accompanied by ethmoid sinus hypoplasia. METHODS AND RESULTS: A 47-year-old woman presented with complaints of headache, nasal obstruction, and postnasal drainage. She had no previous history of either facial trauma or systemic diseases affecting the skeletal system. She had a history of functional endoscopic sinus surgery twice in an other institution. However, the surgeries did not significantly alter her symptoms. Coronal and axial computed tomographic scans of the nose and the paranasal sinuses showed poorly developed frontal, sphenoid sinuses, ethmoid cells, and very severe and profound hypoplasia (aplasia) of bilateral maxillary sinuses. CONCLUSIONS: To our knowledge, this patient seems to be the first case having combined aplasias of the sphenoid, frontal, and maxillary sinuses with hypoplastic ethmoid cells without any systemic or skeletal disease. PMID- 20856034 TI - Cephalic index of Japanese children with normal brain development. AB - The cephalic index is a method of assessing skull morphology in craniosynostosis. There are known racial differences; however, there are few reports on this index in Japan. In this study, we investigated the cephalic indices of Japanese children with normal brain development using axial slice computed tomography. Children presented to our institution because of head injuries but received no particular diagnosis. One hundred four children with normal brain development (62 males and 42 females) were divided into 7 age categories, namely, 4 categories for those younger than 1 year and 3 categories for those between 1 and 3 years. The cephalic index was calculated according to the following equation: (cephalic width/cephalic length) * 100. The cephalic indices by age groups were as follows: 86.7, 0 to 3 months (n = 21); 87.5, 4 to 6 months (n = 9); 89.2, 7 to 9 months (n = 16); 86.3, 10 to 12 months (n = 9); 85.9, 1 year (n = 25); 86.3, 2 years (n = 15); and 83.7, 3 years (n = 9). In this study, the cephalic indices of Japanese children with normal brain development tended to be more brachycephalic than those of white children, as reported by Haas and Waitzman. Thus, we formulated the classification of current cephalic indices of children with normal brain development in Japan. PMID- 20856035 TI - Development of a technique for recording and transferring natural head position in 3 dimensions. AB - The purpose of this study was to develop and test a new technique for recording natural head position (NHP) in 3 dimensions and transferring it into a three dimensional computed tomography (CT) model. In this technique, a digital gyroscope was first attached to a human head using a bite-jig and a face-bow with a set of built-in fiducial markers. The relationship between the gyroscope and fiducial markers was predetermined and kept constant. The orientation (pitch, roll, and yaw) of the head was then recorded by this gyroscope. In next step, the head was CT scanned with the bite-jig and the face-bow in place, and three dimensional CT models of the head and fiducial markers were generated. The head model was coupled with a predetermined three-dimensional model of the gyroscope assembly via fiducial markers. The three-dimensional head model was reoriented to the recorded orientation by applying the recorded pitch, roll, and yaw to the gyroscope model. Finally, the accuracy of the technique was tested on a human dry skull. The results showed that the NHP was successfully recorded and transferred to the three-dimensional CT model. The orientations between the dry skull and its three-dimensional computer model were absolutely correlated. The difference (the lack of agreement) was within a range of -1.1 to 1.1 degrees, indicating no clinical significance. The authors concluded that our technique could accurately and repeatedly record NHP three-dimensionally and transfer it to a three dimensional CT head model. PMID- 20856036 TI - Associated balancing surgical treatments of hemifacial microsomia. AB - OBJECTIVE: To explore a novel approach, associated balancing surgical treatments of the first and second branchial arch syndrome and to supply an array of practical, efficacious, and relatively shorter course of treatments for clinics. METHODS: For microtia with severe ipsilateral facial dysplasia with the first and second branchial arch syndrome, auricular reconstruction using traditional methods by autologous cartilage framework and filling of the malar region and the mandible with an autologous rib for the ipsilateral zygomatic arch and the mandibular bone were begun to correct ear and jaw deformities. The second stage is turning over the auricular flap and skin graft with autologous fat transplantation to reshape facial contours. RESULTS: Six patients were followed up for 3 to 9 months postoperatively. All of them showed satisfactory surgical results with no adverse effects. The shape of the reconstructed auricle and the affected hemifacial region improved greatly. Good stereopsis with symmetry was observed on the whole. The implanted rib and the cartilage frameworks were not deformed, absorbed, or exposed. Transplanted fat particles were observed with no infection, scleroma, subcutaneous mass, cyst, or other complications. CONCLUSIONS: This method is well designed and easy to perform. The satisfactory effects and few known complications make it one of the most effective treatments of the first and second branchial arch syndrome. PMID- 20856037 TI - Management of nasal deformity in osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is a rare hereditary disorder of collagen synthesis that results in weak bones that are easily fractured resulting in deformities. Osteogenesis imperfecta refers to a wide array of genetic disorders with variable phenotypic presentation. In general, type I is the mildest form of disease; types IV, III, and II, respectively, increase in severity. There is lack of knowledge about the feasibility of nasal surgery in patients with bony disorders in the literature. Although rhinoplasty is one of the most frequent procedures all over the world, there are only very few case reports about OI patients undergoing rhinoplasty. The authors could find 2 old case reports, published in 1965 and 1977. The only recent publication that could be found was published in 2000, but it was about a follow-up case that had been operated 15 years ago. A 24-year-old woman with OI who has been operated on because of severe airway obstruction and cosmetic reasons is presented. Open rhinoplasty was performed, keeping in mind that bones and cartilages are more fragile, and they heal late in OI. Therefore, greenstick fractures were preferred instead of median osteotomies, and cartilages were fixed to each other at multiple points with nonabsorbable sutures. There were no complications in the postoperative period, and the patient was very satisfied with her breathing and appearance. Current literature is reviewed in accordance with our experience with this unique case. In conclusion, good cosmetic and functional rhinoplasty results may be obtained in OI cases with careful case selection, limited mobilization of the nasal bones, and careful fixation of the nasal cartilages with nonabsorbable sutures. PMID- 20856039 TI - Classification and craniofacial features of gummy smile in adolescents. AB - Classification of gummy smile was tried first according to gingival exposure site during posed smile, then several items were measured on cephalometric radiograph to analyze the morphologic features in both sexes and further divided into subgroups. Two hundred twenty-eight adolescents with gingival display of more than 2 mm during smile were clustered according to gingival exposure site. Measurements of 18 pertinent items with great clinical concern or controversy in previous study in each groups were compared with corresponding references. Four distinctive types of gummy smile could be distinguished, and they exposed a continuous band, posterior parts, and one side or anterior part of upper gingiva, respectively. The type exposing a continuous band of upper gingiva took up the majority (200 cases, 88%) of all subjects and were chosen for further cephalometric analysis. Among the characteristic features of gummy smile, adolescents have skeletal class II relationship, vertical growth pattern, retrusive mandible, excessive anterior maxillary height, labially inclined upper incisors and upper lip, great overjet and overbite, and relatively short lip compared with anterior maxillary height. Skeletal class III relationship and horizontal growth pattern were absolutely absent. As a result, treatment planning should be adjusted according to the exposure site and craniofacial feature of each individual patient to obtain the best result. PMID- 20856038 TI - Craniofacial morphology in complete unilateral cleft lip and palate patients consecutively treated with 1-stage repair of the cleft. AB - OBJECTIVE: To retrospectively evaluate the craniofacial morphology of children with a complete unilateral cleft lip and palate treated with a 1-stage simultaneous cleft repair performed in the first year of life. METHODS: Cephalograms and extraoral profile photographs of 61 consecutively treated patients (42 boys, 19 girls) who had been operated on at 9.2 (SD, 2.0) months by a single experienced surgeon were analyzed at 11.4 (SD, 1.5) years. The noncleft control group comprised 81 children (43 boys and 38 girls) of the same ethnicity at the age of 10.4 (SD, 0.5) years. RESULTS: In children with cleft, the maxilla and mandible were retrusive; the palatal and mandibular planes were more open, and sagittal maxillomandibular relationship was less favorable in comparison to noncleft control subjects. Soft tissues in patients with cleft reflected retrusive morphology of hard tissues--subnasal and supramental regions were less convex, profile was flatter, and nasolabial angle was more acute relative to those of the control subjects. CONCLUSIONS: Craniofacial morphology after 1-stage repair was deviated in comparison with noncleft control subjects. However, the degree of deviation was comparable with that found after treatment with alternative surgical protocols. PMID- 20856040 TI - Limited fatty infiltration due to apoptosis in human degenerated temporomandibular joint disks: an immunohistochemical study. AB - In this study, we hypothesized that caspase 3, which plays a central role in the execution phase of cell apoptosis, could be involved in limiting fatty degeneration of the temporomandibular joint (TMJ) disks and therefore inhibit the TMJ disk tissue from completely degenerating into fatty tissue. Therefore, caspase 3 immunohistochemical expression in human TMJ degenerated disks was studied. Fifty-nine degenerated TMJ disks were stained with Harry's hematoxylin, and they were then examined with light microscopy to detect any pathologic changes typical of fatty degeneration. Sections from the same TMJ disk were immunostained also by a polyclonal anti-caspase 3 antibody. On morphologic observations, 11 disks of 59 degenerated ones also presented a fatty infiltration. Immunostaining with caspase 3 antibody was detected on adipocytes in the cytoplasm as well as the nuclei. Our results sustain the hypothesis that fatty degeneration is limited by apoptosis, being adipocytes immunolabeled by caspase 3 antibody. Hence, apart from the several factors that can trigger degeneration changes in TMJ disk, their appearance, spread, and permanence, at least for fatty degeneration, seem to be influenced by apoptosis. PMID- 20856041 TI - Surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts. AB - OBJECTIVE: The objective of this study was to review the outcome of surgical rehabilitation of nasoalveolar complex in patients with alveolar clefts. STUDY DESIGN: Twenty-seven patients (13 female, 14 male) with 4 bilateral and 23 unilateral alveolar clefts who were treated in our clinic during the period between 2002 and 2009 were included in the study. RESULTS: All the patients had oronasal fistulas, and all of them were closed successfully except one. Recurrence of the oronasal fistula was seen in 1 patient. Alar base was supported by onlay cortical bone in most of the patients. Eleven of the canines at the cleft site erupted after the operation in to the grafted area. Seventy-six percent (n = 16) of the 21 patients could be assigned to the successful groups 1 and 2, whereas 24% (n = 5) were assigned to the unfavorable group. There was not any insufficient result. CONCLUSIONS: Bone graft placed along the piriform margin and alar wings during alveolar bone grafting improves the results of nasal correction. Late grafting should be performed at least to support the alar base for nasal symmetry. PMID- 20856042 TI - Evaluation of primary cleft nose repair: severity of the cleft versus final position of the nose. AB - BACKGROUND: Since 1957, when the concept of rotation-advancement repair was introduced by Millard, this technique has become the procedure of choice for unilateral cleft lip worldwide. More recently, modifications described by Noordhoof, Mohler, Skoog, and McComb started being jointly performed so that better results could be obtained. In this study, the nasal position was evaluated and related to the size of the cleft. The primary unilateral cleft lip repair was performed through a modified technique. METHODS: Forty-five patients with unilateral cleft lip underwent primary surgical repair through this technique. To analyze aesthetic results, a severity classification of deformities and a scoring system for evaluation of the results were established based on nasal alar lateralization, dome position, alignment of bone segments, and deviation of the columella. RESULTS: By means of the established system, 26.6% of mild forms, 13.4% of moderate forms, and 60% of severe forms were observed. Among aesthetic results, 17.8% were found to be good, and 82.2% were considered excellent. Among aspects considered negative, late deformity of the lower lateral cartilage prevailed. CONCLUSIONS: Through the presented evaluation, the authors observed that there was no relation between severity of the cleft and final position of the nose. Among the 27 patients considered to have had severe forms of cleft deformity, 22 were classified as excellent results (81.5%). To obtain better results along time, technical refinements and the critical analysis of results must be performed on a routinely basis. PMID- 20856043 TI - Pediatric frontal mucocele secondary to a bifid frontal sinus septum. AB - A mucocele is a mucus-containing sac lined with epithelium that arises within a sinus when its drainage is compromised. The frontal sinus is the most common location, with frontal mucocele development occurring when the nasofrontal duct becomes obstructed because of polyps, bone tumors, prior surgery, sinusitis, trauma, or anatomic variation. We report an unusual case of a sterile pediatric frontal mucocele presenting as a slowly enlarging forehead mass due to a bifid frontal sinus septum. A 9-year-old girl presented to the craniofacial clinic for evaluation of a right frontal mass that had been slowly growing over the past year. She was otherwise healthy and had no history of previous trauma or sinus infections. Computed tomography (CT) scan results revealed a localized frontal fluid collection with protrusion and thinning of the anterior frontal bone between 2 midline bony septii. Surgical cranialization of the frontal sinus was performed. The anatomy of her lesion seen both on CT scan and intraoperatively likely explains this unusual case presentation. Instead of the usual inciting event of an intact frontal sinus drainage system becoming blocked, this patient seemed to have a primary developmental lack of any drainage system that led to her mucocele. During formation of her frontal sinus, she developed a bifid septum within the midline that excluded a portion of her frontal sinus from the lateral nasofrontal ducts. With mucus-producing epithelium trapped within these bony confines, pressure began to mount with expansion and thinning of the bone both anteriorly and posteriorly. The lack of any infectious symptoms and sterile culture results may support that this space developed primarily and was never in continuity with the external drainage system. Only 4 other patients have been reported with asymptomatic forehead swelling as the only presenting symptom, with the age ranging from 33 to 79 years. This patient represents the first clinical report of a congenital developmental mucocele. PMID- 20856044 TI - Surgical and prosthetic rehabilitation of edentulous adult cleft palate patients by dental implants. AB - Adult patients who did not receive proper treatment for cleft palate are challenging for clinicians in terms of prosthetic rehabilitation. Moreover, during the late stages of adulthood when patients become edentulous, prosthetic reconstruction becomes even more challenging. This clinical report describes the prosthetic rehabilitation of 2 edentulous geriatric patients with unrepaired cleft palate by placement of dental implants after closure of the oronasal communications. PMID- 20856045 TI - Unilateral coronal craniosynostosis in Abraham Lincoln and his family. AB - Premature closure of one coronal skull suture produces a characteristic arching or relative elevation of the superior orbital rim on the involved side. This sign is associated with facial asymmetry, and both signs are usually the most conspicuous features in patients with mild unilateral coronal craniosynostosis. Photographs suggest that at least 9 individuals over 5 generations of the Abraham Lincoln family had premature closure of 1 coronal suture. In 8 males, there was involvement of the left side; in 1 female, there was involvement of the right side. PMID- 20856047 TI - Saldino-Mainzer syndrome: nephronophthisis, retinitis pigmentosa, and cone-shaped epiphyses. AB - Saldino-Mainzer syndrome is part of a group disorders, the conorenal syndromes, that are characterized by cone-shaped epiphyses with chronic renal disease in childhood and are variously associated with retinitis pigmentosa, cerebral ataxia, and/or abnormalities of the proximal epiphyses and femur metaphyses. Saldino-Mainzer syndrome usually has sporadic presentation. The present report shows the unusual findings of a 23-year-old woman, affected by the Saldino Mainzer syndrome and has undergone kidney transplantation, highlights the possible association with maxillofacial and cephalometric abnormalities. PMID- 20856046 TI - Craniosynostosis involving the squamous temporal sutures: a rare and possibly underreported etiology for cranial vault asymmetry. AB - Craniosynostosis is a condition in which 1 or more cranial sutures fuse prematurely, often secondary to a fibroblast growth factor receptor (FGFR) mutation, typically involving FGFR2 or FGFR3. This mutation may occur sporadically or in the setting of a genetic syndrome and typically presents within the first few days of life or in early infancy. Most commonly, the sagittal and coronal sutures are involved, although involvement of the lambdoidal and/or metopic sutures is not uncommon. Surgical correction is undertaken both for cosmetic purposes and to relieve raised intracranial pressure, both of which can be severe, depending on the sutures involved. We report on 2 children who presented in their first year of life with synostosis involving: in one instance, a single squamous temporal suture, and in the other, both squamous temporal sutures. The initial presentation and clinical courses of these 2 patients are highly distinct from one another, although both ultimately did quite well after extensive cranial remodeling. To the best of our knowledge, only a handful of patients with squamous synostosis have been reported in the medical literature. PMID- 20856048 TI - Intracranial fixation pin migration: a complication of external Le Fort III distraction osteogenesis in Apert syndrome. AB - External distraction osteogenesis has long been used in treatment of congenital midface hypoplasia. Distraction osteogenesis is associated with lower relapse rate and less complications compared with standard Le Fort III osteotomy. General complications in using rigid external distraction include localized infection, loosening of pins, and pin displacement. A 24-year-old female patient with Apert syndrome who underwent Le Fort III distraction osteogenesis is reported. Standard Le Fort III osteotomy was performed, and external distractor was placed. After 7 day latency period, the distractor was activated at the rate of 1 mm/d and finished after 20 days. A mild localized infection was recognized at the eighth week of consolidation period, and debridement was carried out at the left side of pin fixation. Obvious displacement of distractor occurred 1 week later while the patient was sleeping, and emergency operation was performed to remove the distractor and depress the left temporal skull bone fracture after clinical evaluation. The patient was asymptomatic clinically, and the advancement of the midface was stable. Le Fort I osteotomy was performed 3 years later to obtain a normal occlusion, and the patient was satisfied with the final outcome. We concluded that an unwanted trauma might cause severe complications such as skull bone fracture secondary to related local infection, and close follow-up and management are necessary for those cases. PMID- 20856049 TI - Complications of mandibular distraction osteogenesis. AB - BACKGROUND: Mandibular hypoplasia, retrognathia, and micrognathia are commonly encountered problems in pediatric plastic surgery. Mandibular distraction osteogenesis (MDO) is a relatively simple technique that allows for correction of the deformity with minimal morbidity. However, MDO can lead to a wide variety of complications. METHODS: The PubMed database was queried for all articles describing complications of MDO. Each article was then reviewed, and relevant data were extracted and compiled. Finally, several case reports are presented to illustrate poignant examples of complications. RESULTS: Complications of MDO include relapse (64.8% incidence), tooth injury (22.5%), hypertrophic scarring (15.6%), nerve injury (11.4%), infection (9.5%), inappropriate distraction vector (8.8%), device failure (7.9%), fusion error (2.4%), and temporomandibular joint injury (0.7%). CONCLUSIONS: Mandibular distraction osteogenesis can be associated with a wide variety of minor and major complications, but all complications can be avoided with careful planning and technique. PMID- 20856050 TI - Surgical and prosthodontic rehabilitation in a patient with Freeman-Sheldon syndrome. AB - Dental and prosthetic rehabilitation possess significant challenges in patients who have Freeman-Sheldon syndrome. Microsomia is one of the main diagnostic criteria for Freeman-Sheldon syndrome, and it creates difficulty in working in the intraoral cavity. Most patients with small orifice often have difficulties in oral hygiene maintenance, and it gives rise to loss of some of the teeth. It incurs the need for dental and oral treatment. In the presented study, the patient with limited mouth opening that disabled the dentists to perform dental treatment was given prosthodontic therapy after having commissuroplasty and implant placement simultaneously. PMID- 20856051 TI - Postpubertal nonfamilial cherubism and teeth transposition. AB - Cherubism is a rare, nonneoplastic, fibro-osseous disease. It is an autosomal dominant disorder in which the normal bone is replaced by cellular fibrous tissue and immature bone. It is genetically inherited, although many nonfamilial cases have been reported. Cherubism is a bone disease clinically characterized by bilateral, painless enlargements of the jaws. The mandible is the most severely affected craniofacial component, in which uncontrolled growth of the malady deteriorates the aesthetic balance of the face. A malocclusive and abnormal dentition, worse in the mandible, can be seen. Histopathologically, numerous randomly distributed multinucleated giant cells and vascular spaces within a fibrous connective tissue stroma with or without eosinophilic collagen perivascular cuffing were apparent. The appearance of the affected children is normal at birth. Between the ages of 2 and 7 years, swellings within the mandibular body or tuberosities of maxilla appear. This article relates to a postpubertal nonfamilial cherubism case that was noticed with multiple radiolucencies in radiographic examination and its effects on teeth. PMID- 20856052 TI - Experience of correction of prominent ears. AB - OBJECTIVE: To introduce our experience of correction of prominent ears by ear cartilage-folding method, which amalgamates some well-known techniques. METHODS: Preoperative design was in a routine way. The anterior area of antihelix was dissected subcutaneously, and the surface of the cartilage was scored thoroughly. Satisfactory antihelix was established by folding with mattress suturing. One strip of skin was removed from the back of the concha with suture of the remaining cartilage to the mastoid periost to decrease the auricle-mastoid angle. RESULTS: Fifty-nine cases of prominent ears were followed up postoperatively from 1 to 24 months, and almost all of the ears achieved satisfactory effects. Both the antihelix and auricle-mastoid angle were improved markedly. CONCLUSIONS: Not only is this technique reliable, but it also has low recurrence. PMID- 20856053 TI - Three-dimensional analysis of midfacial soft tissue changes according to maxillary superior movement after horizontal osteotomy of the maxilla. AB - Three-dimensional diagnostic and treatment planning is a promising means of improving orthognathic surgical results from the standpoint of facial aesthetics. In such planning, cone-beam computed tomography is a useful tool. The purpose of the present study was to evaluate three-dimensional soft tissue changes in the midfacial region, with specific reference to post-Le Fort I osteotomy maxillary superior movement. Twenty-two patients underwent both Le Fort I osteotomy superior impaction and bilateral sagittal split ramus osteotomy of the mandible (ie, double-jaw surgery). Reference planes and 27 * 10 grids were used in evaluating the midfacial soft tissue areas. The extent of soft tissue change before and after surgery was calculated and analyzed. The results showed no statistical difference between the male and female subjects (P > 0.05). For both the male and the female patients after double-jaw surgery, the soft tissue in the triangular area, which includes both the nasolabial grooves and the upper lip, moved in the anterior direction and maxillary superiorly. It is essential that clinicians concerned about the management of soft tissue and the quality of treatment outcomes understand the pattern of soft tissue change after double-jaw surgery. PMID- 20856054 TI - Use of array comparative genome hybridization in orofacial clefting. AB - Orofacial clefting is a common condition found in 1 per 700 to 1 per 1000 births. Although most cases are isolated, a subset is caused by a specific genetic mutation. Specific gene tests have been used for recognizable syndromes such as velocardiofacial syndrome or van der Woude syndrome, where the cleft is associated with other anomalies. However, many cleft lip and palate patients have other anomalies but do not fit in to a recognizable syndrome. For these patients, chromosome analysis has been a first-line genetic test; however, in the past few years, a new form of genetic testing has become available for these patients: array comparative genome hybridization (aCGH). We present a 7-month-old male infant with cleft palate, developmental delay, and a family history of velopharyngeal insufficiency in whom aCGH array was used to identify a small deletion on the short (p) arm of chromosome 7. This defect, which was also found in the mother, was undetected by chromosome analysis. In summary, this case demonstrates that aCGH is a new diagnostic tool that is useful in the evaluation of select cases of orofacial clefting. Array comparative genome hybridization should be considered when the suspicion for a genetic etiology of the clefting remains strong despite a normal cytogenetic analysis. PMID- 20856055 TI - New clinical-based evidence for the existence of 2 growth regulators in mandibular condyles: hemimandibular elongation in hemifacial microsomia mandible. AB - This is the first description of a secondary mandibular overgrowth due to condylar misregulation in a congenitally undergrown mandible. This case of unilateral hemifacial microsomia proves the postulated existence (Mandibular Growth Anomalies: Terminology, Aetiology, Diagnosis, Treatment, 2001) of 2 different growth regulators in the condyle of each side of the mandible. It shows clear and typical symptoms of hemimandibular hyperplasia on its right side and of hemimandibular elongation on its left mandible despite the existence of a well developed hemifacial microsomia on the same side. Correction was carried out on the basis of our routine planning and planning principles, including condylectomy on the side of the hemifacial microsomia, because of still active hemimandibular elongation. PMID- 20856056 TI - Upper lip augmentation with double-row subcutaneous pedicled V-Y flaps in Mobius syndrome. AB - Treatment of open-mouth deformity and augmentation of the upper lip were performed using a combination of double-row V-Y mucosal advancement flaps and a V Y skin advancement flap in 2 cases with Mobius syndrome. The mucosal V-Y advancement flaps were consisted for 2 rows of flaps. The first row was placed near the labial sulcus, including 3 V-Y advancement flaps. These flaps equally provided 3 directional augmentation for each segment of the upper lip. Second row V-Y mucosal advancement flap was used for the augmentation of the vermilion tubercle. In our cases, V-Y advancement flaps were used as subcutaneous based flaps unlike other distally based V-Y flap techniques for the upper lip. Postoperative complications such as scar formation, sensation problems, severe pain, and edema were decreased because of subcutaneous pedicled V-Y flaps. In addition, the relationship between mucosa and orbicularis oris muscle, which is responsible for the fine balance of the vermilion, was maintained with subcutaneous-based flaps. The skin V-Y advancement flap was used both to lengthen the upper lip and to create philtral columns on the upper lip. PMID- 20856057 TI - Bilateral orbitozygomatic reconstruction with tissue-engineered bone. AB - Critical defects of the craniomaxillofacial region and long bones are often treated with bone grafts and vascularized osteocutaneous free flaps. These lengthy operations may be associated with considerable donor site morbidity and often have suboptimal functional and aesthetic results. The allure of providing an exact replica of a missing bone that incorporates to become indistinguishable from self, has the capacity to heal and grow, is resistant to infection, and with minimal morbidity is a "holy grail" to all surgeons who work with bone. This is a report of a 14-year-old adolescent boy with Treacher Collins syndrome whose bilateral orbitozygomatic defects were treated with engineered bone made from a combination of human bone allograft, adipose-derived mesenchymal stem cells, bone morphogenic protein-2, and periosteal grafts. This single-stage reconstruction was followed by an exuberant amount of postoperative swelling that persisted for 3 weeks. He had slight lid malposition postoperatively as well but has had no long-term negative effects from the surgery. His reconstruction has remained stable during a 6-month follow-up, and a recent biopsy of the engineered bone demonstrated healthy, lamellar bone. These data are the first to demonstrate revitalization of large volume allograft bone in humans and have positive implications for craniofacial bone tissue engineering. The combination of adipose derived stem cells, bone morphogenic protein-2, bone allograft, and periosteum may provide an alternative method to both osteocutaneous free flaps and large structural allografts with less morbidity and improved long-term results. PMID- 20856058 TI - Influence of the primary cleft palate closure on the future need for orthognathic surgery in unilateral cleft lip and palate patients. AB - The aim of the study was to determine the influence of the dissection of the palate during primary surgery and the type of orthognathic surgery needed in cases of unilateral total cleft. The review concerns 58 children born with a complete unilateral cleft lip and palate and treated between 1994 and 2008 at the appropriate age for orthognathic surgery. This is a retrospective mixed longitudinal study. Patients with syndromes or associated anomalies were excluded. All children were treated by the same orthodontist and by the same surgical team. Children are divided into 2 groups: the first group includes children who had conventional primary cleft palate repair during their first year of life, with extensive mucoperiosteal undermining. The second group includes children operated on according to the Malek surgical protocol. The soft palate is closed at the age of 3 months, and the hard palate at 6 months with minimal mucoperiosteal undermining. Lateral cephalograms at ages 9 and 16 years and surgical records were compared. The need for orthognathic surgery was more frequent in the first than in the second group (60% vs 47.8%). Concerning the type of orthognathic surgery performed, 2- or 3-piece Le Fort I or bimaxillary osteotomies were also less required in the first group. Palate surgery following the Malek procedure results in an improved and simplified craniofacial outcome. With a minimal undermining of palatal mucosa, we managed to reduce the amount of patients who required an orthognathic procedure. When this procedure was indicated, the surgical intervention was also greatly simplified. PMID- 20856059 TI - Correction of Stahl ear deformity using a suture technique. AB - Correction of partial ear deformities can be a challenging task for the plastic surgeon. There are no standard techniques for correcting many of these deformities, and several different techniques are described in literature. Stahl ear is one such anomaly, characterized by an accessory third crus in the ear cartilage, giving rise to an irregular helical rim. The conventional techniques of correcting this deformity include either excision of the cartilage, repositioning of the cartilage, or scoring techniques. We recently encountered a case of Stahl ear deformity and undertook correction using internal sutures with very good results. The technical details of the surgery are described along with a review of literature on correcting similar anomalies. PMID- 20856060 TI - Prevention and treatment of rupture and infection in expanded flaps during auricular reconstruction. AB - OBJECTIVE: To analyze the risk factors of infection and necrosis of expanded postauricular flaps during auricular reconstruction and to provide effective management strategies for complications in expanding postauricular flaps. METHODS: Data were gathered retrospectively for cases of partial rupture and infection of expanding postauricular flaps from the 58 cases of patients undergoing auricular reconstruction after preliminary tissue expansion. Treatment included the following: (1) auricular reconstruction with autologous costal cartilage framework immediately (28 cases); (2) stretching the expanded postauricular flap and fixing in place after expander removal (15 cases); (3) removal of the expander and reinsertion of a similar expander more than 6 months after the wound had healed (12 cases); and (4) continuing expansion after antibiotic treatment (3 cases). RESULTS: Each method was applied to different types of cases. Most cases obtained a satisfactory contour and profile of the reconstructed auricle. CONCLUSIONS: Some individual and risks factors are involved in infection and rupture of expanded postauricular flaps, which can be prevented and minimized. An optimal method can be chosen to treat every case of infection and partial rupture of the expanded postauricular flap. PMID- 20856061 TI - Size of the superior palpebral involuntary muscle (Muller muscle). AB - The aim of this study was to elucidate the width and length of the superior palpebral muscle by using anti-alpha-smooth muscle actin antibody. Ten orbits of 5 adult Korean cadavers were used. Eyelids were cut in vertical planes through midpupilliary, medial limbus, and lateral limbus and in horizontal planes at the anterior border of the superior transverse ligament and 2 mm proximal to the upper tarsal border. Superior palpebral muscle was localized using mouse monoclonal anti-alpha-smooth muscle actin and counterstained with light green for collagen. In enlarged pictures of sections, widths, lengths, and thicknesses of the superior palpebral involuntary muscle were measured with a curved scale and were analyzed. The levator palpebrae superioris muscle was divided into superficial and deep parts below the superior transverse ligament. The levator aponeurosis originated from the superficial part and the superior palpebral muscle originated from the deep part of the levator palpebrae superioris muscle. The aponeurosis was inserted into the upper border of tarsus. The superior palpebral muscle fibers arose 2.71 +/- 0.64 mm posterior to the anterior border of the superior transverse ligament. The superior palpebral muscle was trapezoidal. The lengths of its sides were 15.58 +/- 1.82 and 22.30 +/- 5.25 mm, and its height was 13.70 +/- 2.74 mm. The levator aponeurosis covered the superior palpebral muscle anteriorly. The width of the levator aponeurosis was approximately 4 mm wider than the superior palpebral muscle. The thicknesses of the superior palpebral muscle were 0.14 +/- 0.13 mm at the anterior border of the superior transverse ligament, 0.45 +/- 0.11 mm at the superior fornix level, and 0.10 +/- 0.03 mm at the upper border of the tarsal plate. One vascular layer was between the levator aponeurosis and the superior palpebral muscle (upper vascular layer), and the other was between the superior palpebral muscle and the conjunctiva (lower vascular layer). At the superior fornix level, thickness of the upper and lower vascular layers was 0.28 +/- 0.06 and 0.38 +/- 0.21 mm, respectively. The result of our study might contribute to corrective blepharoptosis surgery. PMID- 20856062 TI - Ocular manifestations of oblique facial clefts. AB - INTRODUCTION: In the Tessier classification, craniofacial clefts are numbered from 0 to 14 and extend along constant axes through the eyebrows, eyelids, maxilla, nostrils, and the lips. We studied a patient with bilateral cleft 10 associated with ocular abnormalities. METHOD: Clinical report with orbital and cranial computed tomography. RESULTS: After pregnancy complicated by oligohydramnios, digoxin, and lisinopril exposure, a boy was born with facial and ocular dysmorphism. Examination at age 26 months showed bilateral epibulbar dermoids, covering half the corneal surface, and unilateral morning glory anomaly of the optic nerve. Ductions of the right eye were normal, but the left eye had severely impaired ductions in all directions, left hypotropia, and esotropia. Under anesthesia, the left eye could not be rotated freely in any direction. Bilateral Tessier cleft number 10 was implicated by the presence of colobomata of the middle third of the upper eyelids and eyebrows. As the cleft continued into the hairline, there was marked anterior scalp alopecia. Computed x-ray tomography showed a left middle cranial fossa arachnoid cyst and calcification of the reflected tendon of the superior oblique muscle, trochlea, and underlying sclera, with downward and lateral globe displacement. DISCUSSION: Tessier 10 clefts are very rare and usually associated with encephalocele. Bilateral 10 clefts have not been reported previously. In this case, there was coexisting unilateral morning glory anomaly and arachnoid cyst of the left middle cranial fossa but no encephalocele. CONCLUSIONS: Bilateral Tessier facial cleft 10 may be associated with alopecia, morning glory anomaly, epibulbar dermoids, arachnoid cyst, and restrictive strabismus. PMID- 20856063 TI - Burn and mandible fracture due to pressure cooker explosion. AB - A burn case of 42-year-old female patient due to pressure cooker explosion associated with mandibular fracture is presented. After early tangential excision of the deep second- and third-degree-burn areas, a split-thickness skin grafting was applied. Open reduction and internal fixation therapy with miniplate system were done for linear symphysis fracture. As much as we know, there was no report in the literature about pressure-cooking burn accompanying mandibular fracture. PMID- 20856064 TI - Angiomyoma in the buccal space. AB - Angiomyoma is a rare benign tumor originated from vascular smooth muscle cells, in other words, the tunica media, and the characteristic is the detection of numerous blood vessels together with spindle-shape smooth muscle cells. In most cases, it occurs in the subcutaneous tissue of the limbs, especially in the lower limbs, but it is very rare that it occurs in the head and neck area. In the head and neck area, it is developed most frequently in the larynx and the turbinates, and in addition, the development in the oral cavity (lip, hard palate, tonsil), nose, ear, cheek, parotid gland, and submandibular region has been reported. To the best of our knowledge, this is the first case report of angiomyoma that developed in the buccal space and some reviews of the literature. PMID- 20856065 TI - Inverted frontal bone and pericraniogaleal flap for frontal sinus hypertrophy. AB - A 31-year-old man with frontal sinus hypertrophy was treated with an inverted frontal bone and pericraniogaleal flap. Through a coronal incision and anterior supragaleal dissection, a pericraniogaleal flap was raised down to the supraorbital rim, and the frontal bone was exposed. The protruded anterior wall of the frontal sinus was removed with a drill. The excised piece of bone was inverted and replaced and fixed with microplates. The depressed surface of the inverted bone was made full with a folded pericraniogaleal flap. We think that an inversion of the anterior wall of the hypertrophied frontal sinus and topping with a folded pericraniogaleal flap are an alternative measure to treat frontal sinus hypertrophy. PMID- 20856066 TI - Anomaly of the internal carotid artery detected during tonsillectomy. AB - The blood vessel anomalies of the head-neck area may result in death with massive hemorrhage during head and neck surgery. Although anomalies of internal carotid artery (ICA) are observed particularly on the posterior pharyngeal wall, we may confront them in various localizations. Because of these anomalies, the surgeon must always be aware of this risk during tonsillectomy, adenoidectomy, and uvulopalatopharyngoplasty operations. In our case, an S curling-type anomaly of the ICA has been discovered in the distance of 1 cm to the left tonsil during tonsillectomy. Protecting the ICA, a careful tonsillectomy has been performed by using thermal welding and cold dissection method. Then, anomaly has been confirmed radiologically by angiography. This document emphasizes the fact that the surgeon must provide against vascular anomalies that may be confronted during head-neck surgery and that the preoperative examinations should be assessed within this frame. PMID- 20856067 TI - Cutaneous focal mucinosis arising from the chin. AB - Cutaneous focal mucinosis is a type of degenerative-inflammatory dermal mucinoses characterized with asymptomatic, single, dermal mucin deposition. Because of its rarity, it is often mistaken clinically for other disorders such as sebaceous cyst, fibroma, myxoma, and xanthoma. In this study, we will discuss a case of cutaneous focal mucinosis arising from the chin of a 27-year-old man. PMID- 20856068 TI - Silent period-dentate, edentulous, and patients with craniomandibular dysfunction. AB - BACKGROUND: The record of electrical activity of elevator muscles in mandible is important for the evaluation of muscular potency and diagnosis of neuromuscular pathologies, which allows prevention and treatment. The aim of this study was to define silent periods (SPs) and the importance in dentistry and compare the SPs in masticatory muscles of dentate and edentulous patients wearing prosthesis considering the presence or absence of craniomandibular dysfunction (CMD). MATERIALS AND METHODS: Literature review in PubMed database. DISCUSSION: Silent periods are isolated pulses of transcranial magnetic stimulation in the primary motor cortex during voluntary muscular activity that generates an interruption of muscular activity for hundredths of milliseconds. The SP duration depends on the patient (dentate or edentulous), type of stimulus, and presence of CMD. CONCLUSIONS: The SP is higher in complete edentulous patients and in individuals with occlusal disharmonies than in dentate patients without CMDs. The treatment of CMDs through occlusal therapy decreases SP duration. PMID- 20856069 TI - Congenital bony syngnathia with unilateral palatal shelf and soft palate agenesis. AB - Congenital fusion of upper and lower jaw is rare. Only 35 bony syngnathia have been reported up to date, and 9 of them revealed posterior topography. A 10-day old female infant with facial asymmetry, limited mouth opening, and cardiac murmurs is presented. The radiological findings revealed congenital bony fusion of right coronoid process of the mandible to posterior maxillary region and right palatal shelf agenesis of palatal bone, which seems to be the first case in the literature. Classification systems of bony syngnathia and applied treatment procedures for palatal closure and release of the bony fusion are discussed. PMID- 20856070 TI - Mandibular ramus epidermal inclusion cyst. AB - Epidermal inclusion cyst in the mandibular ramus is a very rare condition. Intraosseous epidermal cysts are benign cysts appearing clinically as radiolucent lytic bone lesions. Definitive diagnosis is made with histopathologic examination. Treatment is simple curettage and grafting if the defect is large. We present a case of a 78-year-old man who was admitted to our clinic with the complaints of swelling in the cheek and preauricular area of 8 years' duration. In computed tomography scan, a cystic mass measuring 6.5 * 4.5 cm with necrotic center causing expansion in the left ramus mandibula and thinning and rupture of the cortex was found. The mass was reported to extend to the zygomatic arch superiorly and masticator space minimally. Simple curettage was performed. Histopathologic examination revealed epidermal inclusion cyst. A case of mandibular ramus epidermal inclusion cyst is presented. PMID- 20856071 TI - Sinonasal myxoma in an infant. AB - Myxomas of the maxillofacial region are neoplastic entities of mesenchymal origin most often associated with odontogenic origin; sinonasal myxoma is rare, located in the nasolabial region and originating from the sinonasal tract. The aim of the current study was to report a well-documented case of sinonasal myxoma in a 12 month-old boy, initially presenting with obliteration of his left nasolacrimal duct. A soft-tissue mass of the nasobuccal groove, firmly attached to the underlying bone, was revealed. After biopsy where benign fibroblastic elements were found, the tumor was removed surgically in wide margins, whereas great care was taken to reconstruct the involved adjacent anatomic structures and preserve facial aesthetics. Histopathologic findings were compatible with an extragnathic, nonodontogenic sinonasal myxoma originating from the nasolacrimal duct. The clinical significance of the case presented was its rather rare location and origin. Three and a half years postoperatively, functional and aesthetic results were satisfactory with no sign of recurrence. To the authors' knowledge, this is the second youngest reported case in the literature. PMID- 20856072 TI - A unique presentation of epignathus. AB - Palatal clefts in conjunction with space-occupying lesions of the oral or nasal cavities are of interest because they may represent a developmental etiology of palatal clefts. Epignathus is a rare space-occupying tumor of the nasopharynx that can arise from the upper jaw, palate, and sphenoid. It can protrude through the mouth, causing respiratory embarrassment and death. The pathogenesis of epignathus is unknown, but several theories have been proposed. Management depends on the size of the tumor and requires a multidisciplinary approach. PMID- 20856073 TI - Two novel mutations affecting splicing in the IRF6 gene associated with van der Woude syndrome. AB - van der Woude syndrome (VWS) is a rare autosomal dominant oral facial disorder characterized by high penetrance and variable expression, manifesting with lower lip pits, cleft lips with or without cleft palate, and isolated cleft palate. The phenotypic expression of clefts ranges from incomplete to complete. Different studies have demonstrated an association between VWS and mutations of the IRF6 (interferon regulatory factor) gene. In this study, we describe 2 novel Italian families with VWS harboring 2 distinct splice site mutations in the IRF6 gene. These results add to the previous 9 splicing mutations identified in patients with VWS and strengthen the importance of this type of alterations in the pathogenesis of the disease. PMID- 20856076 TI - Spontaneous intracranial hypotension syndrome with hearing loss and pachymeningeal enhancement in the internal acoustic canal: neuroimaging correlations. PMID- 20856077 TI - Use of gelfix (lyophilized type 1 bovine collagen) pad dressing for split thickness skin graft donor area management. PMID- 20856078 TI - Two cases of periocular cutaneous angiosarcoma. AB - Angiosarcoma is a rare malignancy with only 8 previous reports of eyelid involvement. The authors report 2 further cases, one as a primary lesion and the other as a recurrence from a contiguous area. In both cases, the lesions appeared relatively inconspicuous, and their extent during micrographic excision was considerably larger than anticipated. Although wide surgical margins were obtained and adjuvant radiotherapy and chemotherapy was undertaken, one patient had died from distant metastasis, while the second had distant cutaneous recurrences within 1 year. PMID- 20856080 TI - Nursing practice. PMID- 20856079 TI - Neoadjuvant chemotherapy in recurrent sebaceous carcinoma of eyelid with orbital invasion and regional lymphadenopathy. AB - A 35-year-old man presented with a recurrent temporal conjunctival mass (25 * 12 mm) involving about six-clock hours of the limbus in the left eye. The mass encroached onto the temporal half of cornea and showed surface keratin, large intrinsic and feeder vessels. It infiltrated the deep corneal stroma. There were no cells in the anterior chamber. Ultrasound biomicroscopy confirmed infiltration of deep corneal stroma without intraocular invasion. Surgery involved excision of the conjunctival component with 4-mm margin, lamellar sclerectomy and a penetrating sclerokeratoplasty with 3 mm of healthy corneal margin. Cryotherapy (double-freeze-thaw) was done to the conjunctival margins. Histopathology showed it to be invasive sebaceous cell carcinoma. A thin layer of deep corneal stroma and all conjunctival margins were uninvolved. At thirty-six weeks after treatment the left eye recorded a visual acuity of finger counting at 1 meter distance and no recurrence. PMID- 20856081 TI - Roots, change, and growth at ONCB. PMID- 20856082 TI - Clinical practice guidelines for early mobilization hours after surgery. AB - This clinical practice guideline (CPG) is the product of cohesive interdisciplinary collaboration. The impact of this project merits more than routine attention given the lack of published nursing literature. The Department of Nursing acted as the catalyst to improve the quality of patient care. This initiative resulted in a pivotal change in the standard of care, updating outmoded orthopaedic nursing practices. The most significant change improved the time patients began their first postoperative activity. Dangling the patient on the day of surgery enhanced the benefits of early activity and reduced the time from 16.8 to 6 hr with no adverse patient consequences. The CPG also demonstrated excellent postoperative pain management, realizing pain scores below 4 (0-10 scale) at multiple time points. In addition, the length of stay improved from 4.3 to 2.8 days. The results support the value of implementing a CPG. PMID- 20856084 TI - Rotator cuff tears: an overview. AB - Rotator cuff tears are a common contributing factor of shoulder pain and occupational disability. Tears of the rotator cuff are becoming increasingly prevalent in today's musculoskeletal population. Accurate recognition and successful treatment of patients with rotator cuff tears require thorough comprehension of the normal and pathologic anatomy of the rotator cuff. This article will provide an overview of the rotator cuff that consists of normal anatomy, pathology, physical assessment, diagnostic imaging, and recommended treatment. This article also discusses the importance of providing adequate and straightforward patient education and the role it plays in positive outcomes of rotator cuff tear rehabilitation. PMID- 20856086 TI - Establishing a Safe Patient Handling/Minimal Lift Program. AB - To improve the safety of healthcare workers, a movement is gaining support in this country to limit the manual performance of high-risk patient care tasks. Many states have passed legislation-mandating policies aimed at protecting employees from injuries related to patient handling. Federal legislation has been proposed 3 times, each time moving farther along the process toward passage into law. This article describes the steps taken in the planning and implementation of a Safe Patient Handling/Minimal Lift Program in a 380-bed, licensed, not-for profit, east coast acute care hospital. PMID- 20856088 TI - Outcomes of knee replacement patients using autotransfusion. AB - BACKGROUND: More than 500,000 total knee replacements are performed annually in the United States, of which approximately 30% to 50% utilized autotransfusion. PURPOSE: The purpose of the study was to describe the difference in patient outcomes between autotransfusion and allogenic blood recipients who have a total knee replacement. DESIGN: A descriptive study using retrospective chart review (N = 115) was conducted. RESULTS: Those receiving autotransfusion had a significant shorter length of stay. No difference in hemoglobin or discharge site was found between those receiving autotransfusion and those receiving allogenic blood. Lower weight and increased age were associated with discharge to an inpatient rehabilitation unit. PMID- 20856089 TI - Violation of a moral rule. AB - A number of moral rules guide human actions. In addition, the acts of healthcare providers are guided by professional codes of biomedical ethics. This article describes the rules and ethical principles at play when treatment is considered following hip fracture in an older adult with dementia. PMID- 20856090 TI - A retrospective quality improvement study of ketorolac use following spinal fusion in pediatric patients. AB - BACKGROUND: There are studies and literature that support the claim that ketorolac use after spinal fusion in the adult population can increase the risk of pseudarthrosis, instrumentation failure, and/or nonunion. There is limited research when using ketorolac in the pediatric population, especially short-term use. METHODS: Chart review of 46 pediatric patients who had prior spinal fusions for scoliosis between July 2003 and August 2005. Twenty-five of the patients received ketorolac and 21 did not. The lengths of stay, incidence of curve progression, and/or incidence of nonunion or instrumentation failure were compared in the 2 groups. RESULTS: At the 1-year follow-up, 95% of the patients returned and at the 3-year follow-up, 52% of the patients returned and there was no clinical or radiographic evidence of curve progression, nonunion, or instrumentation failure. LEVEL OF EVIDENCE: This is a retrospective study looking at results of 2 patient groups. This is a level III study. PMID- 20856091 TI - What's new? Medication changes 2008-2010. AB - Every year there are new medications approved by the Federal Food & Drug Administration. Some medications are removed from the market, and new information or warnings about existing medications become available. Some of the information about these changes makes its way into public media and can cause concern among patients and some can be misleading for those without a full understanding of the facts. Nurses who talk to patients about their medications may be faced with questions about medications that patients have heard about from friends or the media. Informed nurses will be prepared to provide accurate information, allay fears or misperceptions, and reduce the potential for harm. In the following discussion, selected examples of information about recent changes will be identified. PMID- 20856093 TI - Acute slipped capital femoral epiphysis. PMID- 20856095 TI - Failure of the merger of the Mount Sinai and New York University hospitals and medical schools: part 2. AB - This is the second of two articles in this issue of Academic Medicine that, together, report the author's findings from his study of the attempt by the leaders of Mount Sinai and New York University (NYU) medical centers in New York City to merge their medical schools and hospitals, and the failure of those attempts. After the unsuccessful effort of the trustees to merge the medical schools and hospitals--see the first article--the two institutions successfully created Mount Sinai NYU Health, a new company of the Mount Sinai and NYU hospitals in New York City. Members of the NYU faculty, worried that the new attempt would also include the medical schools, sued their university to prevent the merger. Although they lost the suit, the NYU medical school remained within the university as they had wanted. The hospital merger, like the more comprehensive hospital/medical school merger that failed, was favored by most of the trustees and executives at Mount Sinai. Although supported by many of the NYU trustees, both mergers were strongly opposed by some of the leadership and many of the faculty at the NYU medical center.The hospital merger came into effect in July 1998, but three years later, administration of the hospitals had returned to the separate campuses. In 2008, the merger was officially terminated. Although several of the back-office functions combined, no clinical programs did, as was also the case in other mergers of teaching hospitals. The author concludes with an analysis of why this merger failed while a few others succeeded. PMID- 20856096 TI - Failure of the merger of the Mount Sinai and New York University hospitals and medical schools: part 1. AB - This is the first of two articles in this issue of Academic Medicine that, together, report the author's findings from his study of the attempts by the leaders of Mount Sinai and New York University (NYU) academic health centers in New York City to merge their medical schools and hospitals, and the failure of those attempts. The contemporary and predicted effects of managed care, capitation, and the Balanced Budget Act of 1997 were major factors stimulating this and other mergers at academic health centers. The hospital executives and board members also anticipated saving significant amounts of money by consolidating back-office functions and clinical services. The leadership at Mount Sinai were the most enthusiastic proponents of the merger. At NYU, many trustees feared that their hospital, which was generating a surplus when the merger was being planned, and its medical school, which operated at a deficit and was dependent on hospital earnings, would, in time, drain the university's endowment if the merger took place. Accordingly, some of the leading trustees favored separating its hospital and medical school from the university and consigning them to a new company with Mount Sinai. Influential members of the NYU faculty strongly opposed this. The attempt to create a merged entity of the hospitals and medical schools failed after several frustrating months of interinstitutional negotiations. The trustees and executives then attempted to develop a merger of only the hospitals; that process is described in the companion article in this issue of Academic Medicine. PMID- 20856097 TI - Commentary: Less is better: lessons from the New York University-Mount Sinai merger. AB - Elsewhere in this issue, Kastor details the merger and demerger of New York University (NYU) and Mount Sinai hospitals and medical schools. Academic medical center mergers are difficult endeavors to execute under optimal circumstances. The failure of the NYU-Mount Sinai merger was inevitable on the basis of preexisting cultural distinctions, lack of substantial faculty and staff support, and the inability to generate significant early accomplishments that were meaningful to the respective constituencies. Economies of scale and improved academic performance are challenging for merged medical centers to achieve in the short term--caveat emptor. The authors of this commentary discuss, from the NYU perspective, key lessons learned and offer insights about how certain difficulties could have been addressed. PMID- 20856098 TI - Commentary: What happens when a combined entity is lesser than the sum of its parts? AB - Elsewhere in this issue, Kastor examines the failed merger of the Mount Sinai and New York University (NYU) medical schools and hospitals. The failure of the merger is even more remarkable today than it was when the hospitals began disassociating in 2001. Today, both Mount Sinai and NYU hospitals and medical schools are stronger than they were when merger discussions began, and they are certainly far stronger than when the merger began to unwind. This fact calls into question the validity of the assumptions that initiated the desire to merge, as well as the execution of the merger. The author of this commentary offers his perspective as a leader with more than 40 years of experience at Mount Sinai. He examines the reasons behind dissolving the merger and the factors that have led to Mount Sinai's success since then. PMID- 20856099 TI - Factors associated with African American and White elders' participation in a brain donation program. AB - This study examined factors associated with brain donation program participation among African American and White elders. By postal mail, participants were recruited from an Alzheimer's research registry (all of whom had been invited to participate in the Center's brain donation program) and asked to complete surveys assessing brain donation knowledge, trust in healthcare systems, and religiousness. African American respondents completed a cultural mistrust inventory. Demographic, brain donation status, and literacy data (as assessed by the Wide Range Achievement Test-3 Reading subtest) were compiled from the respondents' most recent registry visit. The survey response rate was 60% (n=184 White and n=49 Black respondents). Logistic regression, comparing religiousness, trust in healthcare institutions, and educational attainment, identified a single predictor (ie, religiousness) in the prediction of donation status among White respondents (P=0.008), whereas no predictors were observed for donation status among the Black respondents. Using all African American donors and nondonors from the registry (n=68), comparisons revealed Wide Range Achievement Test-3 Reading score differences for African American donors (46.8+/-5.9) and nondonors (42.8+/ 8.4, P=0.02). Results suggest that increased religiousness is related to White elders' decisions not to donate, whereas lower reading ability might be related to African American participants' decisions not to donate. PMID- 20856101 TI - Toxic hepatitis induced by Gymnema sylvestre, a natural remedy for type 2 diabetes mellitus. AB - Toxic hepatitis or drug-induced liver injury (DILI) encompasses a spectrum of conditions ranging from mild biochemical abnormalities to acute liver failure. Recent studies report that 35% to 48% of patients with diabetes use some form of complementary and alternative medical therapy. Moreover, >800 plants have been traditionally used for the treatment of diabetes. Despite this widespread use, only few were supported by rigorous clinical evidence. Gymnema sylvestre, also known as gurmar (sugar destroyer in Hindi), is a plant considered to be with potent antidiabetic effects and, hence, widely used in folk, ayurvedic and homeopathic systems in medicine. The authors were unable to find previous reports associating G sylvestre to liver injury. Herein, the authors report a case of DILI in a patient who was treated with G sylvestre for diabetes mellitus and review the literature to suggest possible mechanisms that led to this acute condition. PMID- 20856100 TI - Reliability and validity of food frequency questionnaire and nutrient biomarkers in elders with and without mild cognitive impairment. AB - INTRODUCTION: There is great interest in the nutritional strategies for the prevention of age-related cognitive decline, yet the best methods for nutritional assessment in the populations at risk for dementia are still evolving. Our study objective was to examine the reliability and validity of the 2 common nutritional assessments (plasma nutrient biomarkers and Food Frequency Questionnaire) in the people at risk for dementia. METHODS: Thirty-eight elders, half with amnestic mild cognitive impairment were recruited. Nutritional assessments were collected together at the baseline and again at 1 month. Intraclass and Pearson correlation coefficients quantified reliability and validity. RESULTS: Twenty-six nutrients were examined. The reliability was very good or better for 77% (20/26, intraclass correlation coefficients or ICC >=0.75) of the plasma nutrient biomarkers and for 88% of the food frequency questionnaires (FFQ) estimates. Twelve of the nutrient biomarkers were as reliable as the commonly measured plasma cholesterol (ICC>=0.92). FFQ and plasma long-chain fatty acids (docosahexaenoic acid, r=0.39, eicosapentaenoic acid, r=0.39) and carotenoids (alpha-carotene, r=0.49; lutein + zeaxanthin, r=0.48; beta-carotene, r=0.43; beta-cryptoxanthin, r=0.41) were correlated, but these significant correlations were present only in non-impaired elders. CONCLUSION: The reliability and validity of the FFQ and nutrient biomarkers vary according to the nutrient of interest. Memory deficit attenuates validity and inflates reliability of FFQ reports. Many plasma nutrient biomarkers have very good reliability over 1-month, regardless of memory state. This objective method can circumvent sources of error seen in other less direct and subjective methods of nutritional assessment. PMID- 20856102 TI - Native aortic valve infective endocarditis caused by Streptococcus agalactiae in a renal transplant recipient. AB - Infections with Streptococcus agalactiae or group B Streptococcus (GBS) are usually seen during pregnancy or in the neonatal period. The authors report a case of GBS aortic valve endocarditis in a renal transplant patient. GBS endocarditis is often aggressive despite appropriate therapy. The reported patient required prolonged antibiotics and valve replacement. To the authors' knowledge, this is the only reported case of GBS endocarditis in a renal transplant patient. PMID- 20856103 TI - Quantification of aortic stiffness to predict the degree of left ventricular diastolic function. AB - INTRODUCTION: The association between the arterial stiffness and the severity of left ventricular (LV) diastolic function in hypertension has not been fully evaluated. This study was conducted to evaluate the relationship of aortic stiffness by brachial-ankle pulse wave velocity (baPWV) to parameters reflecting the atherosclerosis and the severity of LV diastolic function in patients with hypertension. METHODS: LV ejection fraction, the ratio of peak velocity of early rapid filling and peak velocity of atrial filling (E/A ratio) and LV mass index were determined with echocardiography in 800 patients with hypertension. LV diastolic function was estimated by pulsed-tissue Doppler imaging (TDI) echocardiography, averaging diastolic mitral annular velocity measurements (Emav, Amav and Emav/Amav ratio) from 2 separate sites (basal septal and lateral). The baPWV was measured by the volume rendering method. RESULTS: Stepwise multiple logistic regression analysis demonstrated that the independent factors of LV diastolic function were deceleration time, baPWV, age and Emav/Amav ratio. The receiver- operator characteristic curve demonstrated a baPWV of 1566 cm/sec was useful to discriminate mild LV diastolic dysfunction (sensitivity, 78%; specificity, 78%), and that a baPWV of 1730 cm/sec was useful to discriminate moderate LV diastolic dysfunction (sensitivity, 73%; specificity, 57%). CONCLUSIONS: Increased baPWV relates not only to the parameters reflecting atherosclerosis but also to those reflecting LV diastolic dysfunction. TDI detected LV diastolic dysfunction is accompanied by increased aortic stiffness in essential hypertension. Therefore, quantification of aortic stiffness can predict the degree of LV diastolic function. PMID- 20856104 TI - Ventricular noncompaction and associated cardiac anomalies. AB - An 80-year-old woman was referred for transcatheter aortic valve implantation for correction of aortic stenosis. An echocardiogram at the author's institution revealed severe hypertrophy of the left ventricle with deep recesses into the myocardium and hypokinesis involving the left ventricular apex. In addition, there was subaortic stenosis secondary to a muscular ridge. The aortic valve was only mildly stenotic. In this Cardiology Grand Rounds, the authors present a rare case of ventricular noncompaction and review the literature on this subject and its association with other cardiac abnormalities. PMID- 20856105 TI - Duration: escalation study of oral etoposide with carboplatin in patients with varied solid tumors. AB - Prolonged fractionated oral administration of etoposide may present a theoretical advantage over intravenous administration of the bolus. This phase I trial was carried out to determine the recommended duration of oral etoposide in combination with a fixed dose of carboplatin. Nineteen patients with varied solid tumors, who were not candidates for standard chemotherapy, were administered an escalating duration (6, 9 or 12 consecutive days) of oral etoposide (a 25 mg capsule three times daily) combined with carboplatin AUC5 administered on day 1, by a 30 min intravenous infusion, to define the maximum tolerated dose on the basis of the acute toxicities that were reported. Etoposide was started on day 2; the cycles repeated every 28 days until disease progression or toxicity. Pharmacokinetics was carried out during the two first cycles. The maximum tolerated dose was determined to be the 12-day treatment level, with two cases of grade 4 neutropenia, grade 3 anemia and thrombocytopenia. As no severe toxicity occurred with the 9-day treatment level and in an attempt to explore an optimal combination, a new 10-day treatment plan was studied in three patients. As one patient presented dose-limiting toxicity at that level, five additional patients were included to establish the recommended regimen. Nonhematological toxicities among all patients were moderate, consisting of grade 2 nausea and asthenia. No treatment-related death occurred. Objective responses were observed in four patients and stabilization in three patients. Pharmacokinetics highlighted no interaction between etoposide and carboplatin. Fractionated oral etoposide (3*25 mg/day) for 10 days in combination with carboplatin AUC 5 presents acceptable toxicity and efficacy. The main toxicity remains hematological. PMID- 20856106 TI - Deep anterior lamellar keratoplasty for Maroteaux-Lamy syndrome. AB - PURPOSE: To present a case of Maroteaux-Lamy syndrome (MLS), which underwent deep anterior lamellar keratoplasty (DALK) for visual rehabilitation. METHODS: A 15 year-old girl with MLS was admitted with severe corneal opacity. We performed DALK on her left eye for visual rehabilitation. Big-bubble technique was used to perform lamellar separation. RESULTS: Corneal graft was clear 24 months after surgery. Best spectacle-corrected visual acuity of left eye was 20/25 with the correction of +0.75/-0.50 diopters * 170. At the last follow-up, in vivo confocal microscopy revealed mild haze in the posterior stroma at the graft interface level. Endothelial cell count was 2473.4 cells per square millimeter using a noncontact specular microscope. CONCLUSIONS: Given systemic problems in patients with MLS and less postoperative complications of DALK in comparison with penetrating keratoplasty, it seems DALK is the better choice for these patients. PMID- 20856107 TI - The effect of subconjunctival ranibizumab on primary pterygium: a pilot study. AB - PURPOSE: A prospective interventional pilot study was performed to estimate the effect of ranibizumab injection on the clinical and histological picture of primary pterygium. METHODS: Five patients with primary pterygia received a single subconjunctival injection of ranibizumab (0.3 mg), whereas 5 nontreated pterygia served as controls. The treated pterygia were surgically removed 3 days, 1 week, 2 weeks, 1 month, and 2 months after the injection, respectively. Digital photographs of the pterygia were taken immediately before injection, 1 week after, and on the day of operation. RESULTS: Ranibizumab was well tolerated by all patients, and no side effects were reported. However, it had no effect on the extent of vascularization of pterygium, regardless of the interval between injection and operation. No regression of pterygium vessels was noted in any of the patients. Immunohistochemical analysis also showed no particular differences in the number of vessels stained positive for vascular endothelial growth factor A, in the intensity of vessel staining among the treated pterygia, and between the treated and the nontreated pterygia. CONCLUSIONS: Subconjunctival ranibizumab at a single dose of 0.3 mg was not associated with any side effects but had no effect on the extent of vascularization of primary pterygium in our study. PMID- 20856108 TI - Giant corneal keloid: case report and review of the literature. AB - PURPOSE: To report a patient with a tumor-like corneal keloid. METHODS: Retrospective review of clinical features and histopathologic findings. RESULTS: A 68-year-old woman with a remote history of an orbital tumor treated with radiation developed a corneal tumor. A biopsy of the tumor showed fibrocellular tissue, and her blind painful eye was enucleated. Pathologic findings in the enucleated eye showed that the corneal mass was consistent with a large keloid. CONCLUSIONS: A corneal keloid may clinically appear as a large corneal tumor. PMID- 20856109 TI - The molecular pathogenicity of Fusarium keratitis: a fungal transcriptional regulator promotes hyphal penetration of the cornea. AB - PURPOSE: The pathogenic mechanisms of fungal infection during human keratomycosis were investigated in an ex vivo corneal model that used strains of Fusarium oxysporum differing in the production of a fungal transcription factor. METHODS: A pacC loss-of-function mutant and a pacC dominant-activating mutant were constructed from a wild-type isolate of F. oxysporum, and the 3 strains were characterized by in vitro growth kinetics. Twenty-seven human donor corneas maintained in tissue culture were superficially scarified and topically inoculated with the wild-type, the pacC loss-of-function mutant, or the pacC dominant-activating strains. Relative hyphal invasion into the stroma was compared histopathologically in corneal sections. RESULTS: F. oxysporum strains demonstrated comparable exponential growth rates in vitro. Wild-type F. oxysporum invaded into the corneal tissue within 1 day and penetrated through the anterior stroma during the next 4 days. The pacC loss-of-function mutant invaded explanted corneas significantly less than the wild-type strain on day 1 (P < 0.0001) and on day 3 (P = 0.0003). The pacC dominant-activating strain adhered and penetrated explanted corneas similar to the wild-type strain. CONCLUSIONS: The PacC pathway regulating the transcription of fungal genes allows fungal adaptation to the ocular surface and enables invasion of the injured cornea by F. oxysporum. PMID- 20856111 TI - Prophylactic mRNA vaccination against allergy. AB - PURPOSE OF REVIEW: mRNA vaccines have recently been re-discovered as an attractive alternative to the more prominent DNA vaccines, as they harbor many advantages with respect to safety and regulatory issues. Whereas most mRNA vaccines are focused on tumor therapy, this type of vaccine has now also been successfully employed for prophylactic immunization against type I allergy in a mouse model. This concept differs from conventional immunotherapy in that it relies on immune deviation toward a TH1 phenotype, rather than induction of regulatory T cells or tolerance. RECENT FINDINGS: Conventional as well as self replicating mRNA vaccines have demonstrated their potential to prevent the induction of an allergic phenotype in terms of allergen-specific IgE, allergy associated cytokine profiles, eosinophilic lung infiltration, and airway hyperreactivity. Preliminary data raise the question whether TH1 immune deviation induced by mRNA vaccination resembles the natural phenotype of a certain proportion of nonatopic individuals.Reservations regarding Good Manufacturing Practices manufacture costs, shelf life stability, and lack of immunogenicity due to rapid in-vivo degradation have been overcome by novel findings. SUMMARY: mRNA vaccines open the field for a safety-optimized prophylactic vaccination against allergic diseases. Future studies concerning long-term effects and vaccine induced versus natural immune responses will be needed to transfer this knowledge to the clinics. PMID- 20856110 TI - An update on immunotherapy for food allergy. AB - PURPOSE OF REVIEW: Recent investigation has resulted in significant advances toward definitive therapeutic options for food allergy. In this review, we will explore novel immunotherapeutic interventions for the active treatment of food allergy. RECENT FINDINGS: Because the injection route for allergen immunotherapy to foods has been associated with an unacceptable risk of severe anaphylactic reactions, use of mucosally targeted therapeutic strategies is of significant interest for food allergy. Allergen-specific immunotherapeutic approaches such as oral, sublingual, epicutaneous, and peptide immunotherapy have demonstrated efficacy in increasing threshold dose and inducing immunologic changes associated with both desensitization and oral tolerance in animal and human trials. More global immunomodulatory strategies, such as Traditional Chinese Medicine and anti IgE therapy have been shown to effectively target the allergic response, and clinical trials are ongoing to determine the efficacy and safety in human food allergy. SUMMARY: The advent of therapies that target the mucosal immune response to promote oral tolerance have shown great promise in the treatment of food hypersensitivity. However, there is still significant risk of adverse reactions associated with these therapeutic strategies and further study is needed to carefully advance these therapeutic modalities toward general clinical implementation. PMID- 20856112 TI - The anesthetic management of cardiovascular trauma. AB - PURPOSE OF REVIEW: Although little new has been specifically written in recent years regarding the anesthesia management of cardiovascular trauma, two specific areas have seen recent interest and progress, namely the endovascular management of blunt thoracic aortic trauma and commotio cordis, or sudden death following blunt precordial injury. RECENT FINDINGS: Endovascular repair of thoracic aortic injury has been shown in multiple studies to have short to medium-term mortality and morbidity advantages over repair via thoracotomy. However, long-term (many years) outcome and the expenses required for long-term follow-up of endovascular repairs remain unknown. The risk of commotio cordis during sports activities has become more known to the general population. Recent studies have indicated a very specific limited time during the upstroke of the T-wave to be the critical time for injury, but specific channel involvement is unclear. SUMMARY: Although transesophageal echocardiography diagnosis of aortic trauma is very sensitive and specific, in general, the lack of immediate availability at all times of skilled echocardiographers and the immediate availability of spiral computed tomography scanners in trauma centers limits the use of transesophageal echocardiography as a first-line diagnostic tool. Endovascular repair of traumatic aortic injury is becoming routine. Commotio cordis is being increasingly recognized as a cause of acute post-traumatic sudden death. PMID- 20856113 TI - Ambulatory anaesthesia: there is room for further improvements of safety and quality of care--is the way forward further simple but evidence-based risk scores? PMID- 20856114 TI - Infectious colitis. AB - PURPOSE OF REVIEW: The incidence of gastrointestinal infections continues to increase and infectious colitis contributes to significant morbidity and mortality worldwide. The purpose of this review is to highlight the recent advances in knowledge of pathogens causing infectious colitis. We describe the various pathogens and specifically focus on enterohemorrhagic Escherichia coli (EHEC) O157:H7, Salmonella, Shigella, Campylobacter, and Entamoeba histolytica infections, and their impact on long-term effects, including postinfectious irritable bowel syndrome and inflammatory bowel disease. RECENT FINDINGS: Salmonella, Campylobacter, and EHEC outbreaks continue to occur with disturbing regularity. Peanut butter and peppers were recently responsible for outbreaks of nontyphoid Salmonella. Recent research has identified Salmonella genes required for colonization of various hosts and transposon-mediated differential hybridization was recently used to identify genes required during infection in different animal models. A number of other strains of EHEC in addition to O157:H7 are emerging as serious threats to food safety in the USA. Campylobacter jejuni isolates are of interest because of absence of genes encoding for classical enterotoxins, and lack of plasmids encoding genes promoting bacterial invasion. Recent research has identified that the organism is able to invade and replicate in infected epithelia via Toll-like receptor (TLR)-2 and TLR-4. Also patients with infectious colitis, in particular Salmonella and Campylobacter, are at increased risk of postinfectious irritable bowel syndrome and inflammatory bowel disease on long-term follow-up. The paradigm of Entamoeba histolytica infection is changing with recent reports of detection of E. dispar deoxyribonucleic acid sequences, previously considered nonpathogenic. SUMMARY: There has been an explosion in the understanding of the epidemiology, pathobiology, and mechanisms underlying infectious colitis. Additional studies to address prevention strategies and strict screening modalities for these infections are necessary. PMID- 20856115 TI - Proton pump inhibitors and severe hypomagnesaemia. AB - PURPOSE OF REVIEW: Hypomagnesaemia has recently been recognized as a rare, but severe, complication of proton pump inhibitor (PPI) use. We reviewed all the cases published to date in peer-reviewed journals to summarize what is known of the epidemiology, risk factors, cause and treatment. RECENT FINDINGS: Hypomagnesaemia has been described with all substituted pyridylmethylsulphonyl benzimidazadole derivatives and is a class effect, recurring with substitution of one PPI for another. A long duration of use and high rates of adherence are probably risk factors, but the prevalence is unknown. The diagnosis is often missed, despite the severe symptomatology. Renal magnesium handling is normal, so implicating impairment of net intestinal absorption as the proximate cause. It is not known whether this is the consequence of defective absorption of magnesium through the active or passive transport processes, or increased losses. SUMMARY: PPI-associated hypomagnesaemia is a rare, but potentially life-threatening, side effect that has emerged only in the era of mass use of these agents. The cause of hypomagnesaemia remains poorly understood, but it responds rapidly to withdrawal of the PPI. PMID- 20856116 TI - Mechanisms of action of zinc in acute diarrhea. AB - PURPOSE OF REVIEW: For over a decade, the importance of zinc in the treatment of acute diarrhea has been recognized. More recently, the mechanisms of action of zinc are becoming clearer. This review is focused on the new evidence on the mechanisms of action of zinc in acute diarrhea. RECENT FINDINGS: The vast majority of data derive from in-vitro studies using intestinal cell lines or from animal model. The positive action by zinc in acute diarrhea derives from a regulation of intestinal fluid transport, mucosal integrity, immunity, gene expression, and oxidative stress. A complex homeostatic network is also able to regulate zinc status at cellular and extracellular level. SUMMARY: All these data support the use of zinc in the treatment of acute diarrhea, but further clinical studies are needed to explore the selective effects of zinc against specific pathogens responsible for diarrhea. PMID- 20856117 TI - An update on auricular reconstruction: three major auricular malformations of microtia, prominent ear and cryptotia. AB - PURPOSE OF REVIEW: Microtia, prominent ear, and cryptotia are the most common types of auricular malformations. This review provides updated information on these types of reconstructions, in addition to recalling previously accepted surgical methods. RECENT FINDINGS: Autogenous costal cartilage is still considered as an ideal material for framework fabrication in microtia reconstruction. Many surgeons have adopted the Nagata approach, the Brent approach, or variations of the two, in their work. With these employed techniques, auricles reconstructed by experienced surgeons have proven to be aesthetically promising. However, with regards to the harvesting of the costal cartilage, the underdevelopment of the chest wall donor site, alopecia of the scalp, and scarring of the postauricular-mastoid region are still considered problematic aspects of these approaches. Some articles have described attempts to solve these problems, whereas some experiments in cartilage production using tissue engineering techniques have shown promise in their initial stages of development.It is generally accepted that prominent ears should be corrected through a combination of sculpting and suture techniques, according to the individual shape and the quality of the ear prominence.Most of the cryptotia malformations show not only embedded upper auricles, but also associated adhesions of the upper auricular cartilage. Their correction should therefore resolve both deformities. SUMMARY: A number of articles highlighting clinical experiences with auricular reconstructions for microtia, prominent ear, and cryptotia have been included in this review. We believe that the information synthesized here will become a basis for further development of auricular reconstruction techniques. PMID- 20856119 TI - Hyaluronic acid for the treatment of vocal fold scars. AB - PURPOSE OF REVIEW: In vocal fold scars the lamina propria layer is lost or deficient. Lamina propria replacement therapy remains a clinical challenge because this layer has a highly specialized three-dimensional organization of extracellular matrix molecules and unique viscoelastic properties. Use of a polymer such as hyaluronic acid appears most promising for replacement therapy because it has the optimal viscoelasticity and also plays a role in the maturation and maintenance of vocal fold lamina propria. RECENT FINDINGS: A variety of cross-linked hyaluronic acid formulations and growth factor therapies targeted to increase hyaluronic acid production have been used in the treatment of both acute and established vocal fold scars. Therapeutic strategies have focused on prevention of scar at the time of initial injury, and rejuvenation of lamina propria layer in established scars. Both strategies show improved histologic, viscoelastic, acoustic, and aerodynamic measures. SUMMARY: Cross linked hyaluronic acid formulations appear useful in the treatment of vocal fold scarring. Their use at the time of acute injury especially appears to lessen the degree of long-term scar formation and appears promising. While animal studies have demonstrated the safety profile of many hyaluronic acid formulations, further improvement in these materials and well designed and controlled human trials are needed to further establish the safety and efficacy of these materials and therapeutic approaches. PMID- 20856118 TI - Implantation of atelocollagen sheet for vocal fold scar. AB - PURPOSE OF REVIEW: This article reviews recent advances in scaffold-based interventions for the treatment of vocal fold scarring, with a particular emphasis on atelocollagen sheet implantation in the vocal fold lamina propria. RECENT FINDINGS: Scaffold-based therapies have demonstrated therapeutic promise in both preclinical and early clinical studies. Recent research has begun to shed light on the interactions between scaffold material properties, encapsulated and infiltrating cells, stimulatory molecules such as growth factors, and external regulatory variables such as stress, strain, and vibration. The atelocollagen sheet, a cross-linked collagen material with abundant micropores, has an established clinical track record as a scaffold for dermal and epidermal repair and exhibited potential therapeutic benefit in a recent study of patients with vocal fold scarring and sulcus vocalis. SUMMARY: Scaffolding is one of the useful tools in tissue engineering and atelocollagen sheet implantation has been shown to be effective in vocal fold regeneration. However, many of the scaffold materials under investigation still await clinical translation and those that have been investigated in human patients (such as the atelocollagen sheet) require additional research in appropriately powered placebo-controlled studies. PMID- 20856120 TI - Ultrasonographic finding of lung sliding in patients on mechanical ventilation with alveolar-interstitial syndrome. AB - BACKGROUND AND OBJECTIVES: To determine the visibility of pleural lung sliding in alveolar-interstitial syndrome (AIS) in patients on mechanical ventilation at two different time points, as a confirmatory ultrasonographic method for excluding pneumothorax. METHODS: Fifty-two mechanically ventilated patients in the semirecumbent position in a surgical/neurosurgical intensive care unit with ultrasonographic lung 'comet tails' in three upper anterolateral intercostal spaces, indicating the presence of AIS, were scanned for lung sliding in the same three intercostal spaces with a linear 5-10 MHz transducer after starting mechanical ventilation and on weaning trials. Pneumothorax and atelectasis were excluded by chest radiograph. RESULTS: Absent lung sliding was found in 22.7% of intercostal spaces scanned after starting mechanical ventilation and in 21.2% of scans taken on weaning trials. The lowest invisible rate was in patients with acute heart failure and the highest in patients with acute respiratory distress syndrome. CONCLUSION: Lung sliding specificity in AIS during mechanical ventilation was 78%. Our opinion is that different levels of airway pressure between starting mechanical ventilation and weaning trials have no influence on lung sliding visibility. PMID- 20856121 TI - Acute bleeding after spinal anaesthesia due to puncture of unsuspected lumbar myxopependimoma. PMID- 20856122 TI - Paraoxonase 1 polymorphisms and ischemic stroke risk: A systematic review and meta-analysis. AB - PURPOSE: Paraoxonase 1 (PON1) polymorphisms have been implicated as risk factors for coronary artery disease, but the results of genetic association studies on the related phenotype of ischemic stroke are inconclusive. We performed a meta analysis of published studies investigating the association between ischemic stroke and two nonsynonymous PON1 polymorphisms, rs662 (p.Q192R) and rs854560 (p.L55M) in humans. METHODS: We searched multiple electronic databases through June 30, 2009 for eligible studies. In main analyses, we calculated allele-based odds ratios with random effects models. In secondary analyses, we examined dominant and recessive genetic models as well, and performed subgroup and sensitivity analyses. RESULTS: Regarding rs662, we identified 22 eligible studies (total of 7384 cases/11,074 controls), yielding a summary odds ratio of 1.10 per G allele (95% confidence interval, 1.04-1.17) with no evidence of between-study heterogeneity. For rs854560, 16 eligible studies (total of 5518 cases/8951 controls) yielded a summary odds ratio of 0.97 per T allele (95% confidence interval, 0.90-1.04), again with no evidence of between-study heterogeneity. For both polymorphisms, analyses with dominant and recessive genetic models yielded the same inferences as allele-based comparisons. Subgroup and sensitivity analyses showed similar results. CONCLUSION: In agreement with observations in coronary artery disease, PON1 rs662 appears to be associated with a small increase in the risk of ischemic stroke. PMID- 20856123 TI - Superior antidepressant efficacy results of agomelatine versus fluoxetine in severe MDD patients: a randomized, double-blind study. AB - The objective of this international, 8-week, randomized, double-blind study was to show the superiority of the antidepressant efficacy of agomelatine, the first MT1/MT2 receptor agonist and 5-HT2C receptor antagonist antidepressant, versus fluoxetine in outpatients fulfilling Diagnostic and Statistical Manual of Mental Disorders-volume IV-TR criteria for major depressive disorder of severe intensity, defined by a baseline Hamilton Depression Rating Scale (HAM-D17) total score of at least 25 and CGI severity of illness score of at least 4. Patients received agomelatine 25-50 mg/day (n=252) or fluoxetine 20-40 mg/day (n=263) for 8 weeks. The main efficacy outcome measure was HAM-D17 total score (change from baseline to last post-baseline assessment). Secondary outcome measures were Clinical Global Impressions-improvement (CGI), severity (CGI-S), anxiety (HAM-A), and sleep (HAM-D sleep items) scores. The mean decrease in HAM-D17 total score over 8 weeks was significantly greater with agomelatine than fluoxetine with a between-group difference of 1.49 (95% confidence interval, 0.20-2.77; P=0.024). The percentage of responders at last post-baseline assessment was higher with agomelatine on both HAM-D17 (decrease in total score from baseline >=50%; 71.7% agomelatine vs. 63.8% fluoxetine; P=0.060) and CGI-improvement (score 1 or 2; 77.7 vs. 68.8%; P=0.023). There was a significant between-group difference of 0.37 (95% confidence interval, 0.06-0.68) in HAM-D sleep subscore in favor of agomelatine (P=0.018). Similar improvements were observed on HAM-A with agomelatine and fluoxetine. Both treatments were safe and well tolerated. In conclusion, in this study, agomelatine showed superior antidepressant efficacy over fluoxetine in treating patients with a severe episode of major depressive disorder after 8 weeks of treatment with a good tolerability profile. PMID- 20856124 TI - High-pitch spiral computed tomography: effect on image quality and radiation dose in pediatric chest computed tomography. AB - OBJECTIVES: computed tomography (CT) is considered the method of choice in thoracic imaging for a variety of indications. Sedation is usually necessary to enable CT and to avoid deterioration of image quality because of patient movement in small children. We evaluated a new, subsecond high-pitch scan mode (HPM), which obviates the need of sedation and to hold the breath. MATERIAL AND METHODS: a total of 60 patients were included in this study. 30 patients (mean age, 14 +/- 17 month; range, 0-55 month) were examined with a dual source CT system in an HPM. Scan parameters were as follows: pitch = 3.0, 128 * 0.6 mm slice acquisition, 0.28 seconds gantry rotation time, ref. mAs adapted to the body weight (50-100 mAs) at 80 kV. Images were reconstructed with a slice thickness of 0.75 mm. None of the children was sedated for the CT examination and no breathing instructions were given. Image quality was assessed focusing on motion artifacts and delineation of the vascular structures and lung parenchyma. Thirty patients (mean age, 15 +/- 17 month; range, 0-55 month) were examined under sedation on 2 different CT systems (10-slice CT, n = 18; 64-slice CT, n = 13 patients) in conventional pitch mode (CPM). Dose values were calculated from the dose length product provided in the patient protocol/dose reports, Monte Carlo simulations were performed to assess dose distribution for CPM and HPM. RESULTS: all scans were performed without complications. Image quality was superior with HPM, because of a significant reduction in motion artifacts, as compared to CPM with 10- and 64-slice CT. In the control group, artifacts were encountered at the level of the diaphragm (n = 30; 100%), the borders of the heart (n = 30; 100%), and the ribs (n = 20; 67%) and spine (n = 6; 20%), whereas motion artifacts were detected in the HPM-group only in 6 patients in the lung parenchyma next to the diaphragm or the heart (P < 0,001). Dose values were within the same range in the patient examinations (CPM, 1.9 +/- 0.6 mSv; HPM, 1.9 +/- 0.5 mSv; P = 0.95), although z-overscanning increased with the increase of detector width and pitch value. CONCLUSION: high-pitch chest CT is a robust method to provide highest image quality making sedation or controlled ventilation for the examination of infants, small or uncooperative children unnecessary, whereas maintaining low radiation dose values. PMID- 20856125 TI - Dual-energy computed tomography to assess tumor response to hepatic radiofrequency ablation: potential diagnostic value of virtual noncontrast images and iodine maps. AB - PURPOSE: to determine the value of dual-energy (DE) scanning with virtual noncontrast (VNC) images and iodine maps in the evaluation of therapeutic response to radiofrequency ablation (RFA) for hepatic tumors. MATERIALS AND METHODS: a total of 75 patients with hepatic tumors and who underwent DE computed tomography (CT) after RFA, were enrolled in this study. Our DE CT protocol included precontrast, arterial, and portal phase scans. VNC images and iodine maps were created from 80 to 140 kVp images during the arterial and portal phases. VNC images were then compared with true, noncontrast (TNC) images, and iodine maps were compared with linearly blended images, both qualitatively and quantitatively. For the former comparison, image quality and acceptability of the VNC images as a replacement for TNC images were both rated. The CT numbers of the hepatic parenchyma, ablation zone, and image noise were measured. For the latter comparison, lesion conspicuity of the ablation zone and the additional benefit of integrating the iodine map into the routine protocol, were assessed. Contrast-to noise ratios (CNR) of the ablation zone-to-liver and aorta-to-liver as well as the CT number differences between the center and the periphery of the ablation zone were calculated. RESULTS: The image quality of the VNC images was rated as good (mean grading score, 1.88) and the level of acceptance was 90% (68/75). The mean CT numbers of the hepatic parenchyma and ablation zone did not differ significantly between the TNC and the VNC images (P > 0.05). The lesion conspicuity of the ablation zone was rated as excellent or good in 97% of the iodine map (73/75), and the additional benefits of the iodine maps were positively rated as better to the same (mean 1.5). The CNR of the aorta-to-liver parenchyma was significantly higher on the iodine map (P = 0.002), and the CT number differences between the center and the periphery of the ablation zone were significantly lower on the iodine map (P < 0.001). CONCLUSION: with DE CT scanning, VNC images can be an alternative to TNC images for evaluating the ablation zone after RFA in patients who had no a previous transcatheter arterial chemoembolization history. The iodine map improves the conspicuity of the ablation zone more than linearly blended images because of its excellent internal homogeneity and sharp ablative margin. Higher lesion-to-liver CNR on an iodine map than on standard images can be helpful for detecting residual tumors. PMID- 20856126 TI - An endovascular canine middle cerebral artery occlusion model for the study of leptomeningeal collateral recruitment. AB - OBJECTIVES: This work aimed to refine a large animal in minimally invasive reversible middle cerebral artery (MCA) occlusion (MCAO) model to account for leptomeningeal collateral formation. MATERIALS AND METHODS: An angiographically based methodology allowed for transient MCA and carotid terminus occlusion in 12 mongrel dogs and assessment of pial collateral recruitment. Outcome measures included 1- and 24-hour magnetic resonance imaging-based infarct volume calculation, a behavioral scale and histopathologic sections. RESULTS: MCAO succeeded in 8 of 12 dogs (67% efficiency). One-hour postreperfusion infarct volume predicted 24-hour postreperfusion infarct volume (r = 0.997, P < 0.0001). Pial collateral recruitment varied with time and reproducibly assessed predicted infarct volume on 1-hour postreperfusion mean diffusivity maps (P < 0.0001; r = 0.946) and 24-hour fluid-attenuated inversion recovery FLAIR magnetic resonance imaging (P = 0.0033; r = 0.961). The canine stroke scale score correlated with infarct volumes and pial collateral score. CONCLUSION: This canine MCAO model produces defined cerebral infarct lesions whose volumes correlate with leptomeningeal collateral formation and canine behavior. PMID- 20856127 TI - Evaluation of gadodiamide versus gadobutrol for contrast-enhanced MR imaging in a rat brain glioma model at 1.5 and 3 T. AB - PURPOSE: To compare equivalently-dosed (0.1 mmol/kg) gadobutrol (Gadovist) and gadodiamide (Omniscan) in a rat brain glioma model with respect to lesion signal to-noise (SNR), contrast-to-noise (CNR), and contrast enhancement (CE) at 1.5 and 3 T. Lesion enhancement with standard-dose gadobutrol in scans performed at 1.5 T was also compared with that of half-dose gadobutrol in scans performed at 3 T. MATERIALS AND METHODS: Fifty-four rats were injected with glioma cells via a plastic brain cannula and divided into 3 groups. In the first group, each animal was studied using gadodiamide and gadobutrol, with 24 hours separating injections. The 2 agents were administered in random order at a dose of 0.1 mmol/kg. Each animal was scanned using a 3 T MR system. The procedure for the second group was similar, but scanning was performed at 1.5 T. For the third group, rats were given standard or half-dose gadobutrol and scanned at 1.5 and 3 T, respectively. For all MR examinations, T1-weighted images were obtained precontrast and at 1, 3, 5, 7, and 9 minutes postcontrast administration. RESULTS: At 3 T improvements in SNR, CNR, and CE with gadobutrol ranged from 11.8% to 16.0%, 30.5% to 35.4%, and 27.1% to 31.5%, respectively, and at 1.5 T from 7.0% to 11.1%, 27.1% to 35.8%, and 23.8% to 29.5%, respectively. Differences between these parameters with gadobutrol and gadodiamide were statistically significant (P < 0.0001-0.05) at all time points following contrast administration. In group 3, no significant differences in CNR or CE were found between full dose gadobutrol at 1.5 T and half-dose at 3 T, although SNR was significantly greater (28.5%-35.1%; P < 0.0008) at 3 T. CONCLUSION: Gadobutrol (Gadovist) demonstrates superior lesion enhancement to equivalently-dosed gadodiamide (Omniscan) in the rat brain glioma model. These results are complemented by the improved observed and theoretical safety profile of the first agent, in particular with regard to nephrogenic systemic fibrosis. The ability to image with half-dose gadobutrol at 3 T without a statistically significant decrease in lesion enhancement, compared with 1.5 T, offers an additional theoretical safety margin and potential cost-savings. PMID- 20856129 TI - Antiretroviral therapy use among HIV-infected men who have sex with men attending a sexually transmitted diseases clinic. AB - We examined antiretroviral therapy (ART) use among 501 previously diagnosed HIV infected men who have sex with men who sought care at a sexually transmitted disease clinic in King County, WA, during 2004-2008. Overall, 42% of men were not taking ART, 71% of whom had CD4 counts >350 cells per microliter. Of those who reported unprotected anal intercourse with a partner of nonconcordant HIV status in the prior year, 48% were not taking ART (78% with CD4 counts >350 cells/MUL). Sexually transmitted disease clinics may be an important venue in which to identify persons who are not taking ART. Treating these persons could help diminish HIV transmission. PMID- 20856128 TI - Determinations of renal cortical and medullary oxygenation using blood oxygen level-dependent magnetic resonance imaging and selective diuretics. AB - OBJECTIVE: This study was undertaken to test the hypothesis that blood O2 level dependent magnetic resonance imaging (BOLD MRI) can detect changes in cortical proximal tubule (PT) and medullary thick ascending limb of Henle (TAL) oxygenation consequent to successive administration of furosemide and acetazolamide (Az). Assessment of PT and TAL function could be useful to monitor renal disease states in vivo. Therefore, the adjunct use of diuretics that inhibit Na reabsorption selectively in PT and TAL, Az and furosemide, respectively, may help discern tubular function by using BOLD MRI to detect changes in tissue oxygenation. MATERIAL AND METHODS: BOLD MRI signal R2* (inversely related to oxygenation) and tissue oxygenation with intrarenal O2 probes were measured in pigs that received either furosemide (0.05 mg/kg) or Az (15 mg/kg) alone, Az sequentially after furosemide (n = 6 each, 15-minute intervals), or only saline vehicle (n = 3). RESULTS: R2* decreased in the cortex of Az-treated and medulla of furosemide-treated kidneys, corresponding to an increase in their tissue O2 assessed with probes. However, BOLD MRI also showed decreased cortical R2* following furosemide that was additive to the Az-induced decrease. Az administration, both alone and after furosemide, also decreased renal blood flow (-26% +/- 3.5% and -29.2% +/- 3%, respectively, P < 0.01). CONCLUSION: These results suggest that an increase in medullary and cortical tissue O2 elicited by selective diuretics is detectable by BOLD MRI, but may be complicated by hemodynamic effects of the drugs. Therefore, the BOLD MRI signal may reflect functional changes additional to oxygenation, and needs to be interpreted cautiously. PMID- 20856130 TI - Evolution of CCR5 antagonist resistance in an HIV-1 subtype C clinical isolate. AB - OBJECTIVES: We previously reported vicriviroc (VCV) resistance in an HIV-infected subject and used deep sequencing and clonal analyses to track the evolution of V3 sequence forms over 28 weeks of therapy. Here, we test the contribution of gp120 mutations to CCR5 antagonist resistance and investigate why certain minority V3 variants emerged as the dominant species under drug pressure. METHODS: Nineteen site-directed HIV-1 mutants were generated that contained gp120 VCV resistance mutations. Viral sensitivities to VCV, maraviroc, TAK-779, and HGS004 were determined. RESULTS: Three patterns of susceptibilities were observed as follows: sigmoid inhibition curves with 50% inhibitory concentration similar to pretreatment virus [07J-week 0 (W0)], single mutants with decreased 50% inhibitory concentrations compared with 07J-W0, and mutants that contained >=5 of 7 VCV resistance mutations with flattened inhibition curves and decreased or negative percent maximal inhibition. Substitutions such as S306P, which sensitized virus to CCR5 antagonists when present as single mutations, were not detected in the baseline virus population but were necessary for maximal resistance when incorporated into V3 backbones that included preexisting VCV resistance mutations. CONCLUSIONS: CCR5 antagonist resistance was reproduced only when a majority of V3 mutations were present. Minority V3 loop variants may serve as a scaffold upon which additional mutations lead to complete VCV resistance. PMID- 20856131 TI - Predictors of physical activity at 1 year in a randomized controlled trial of family members of patients with cardiovascular disease. AB - BACKGROUND AND OBJECTIVE: Recommendations for physical activity to lower risk of cardiovascular disease (CVD) are widely known but not often followed. The purpose of this study was to determine the demographic, lifestyle, and psychosocial variables that predict improved physical activity among participants in a CVD prevention lifestyle intervention trial. SUBJECTS AND METHODS: Adult family members (N = 501; 66% female; 36% nonwhite; mean age, 48 years) of cardiac patients were randomized to a 1-year special intervention that received education on physical activity or to a control intervention. Demographics, physical activity, stage of change, and CVD risk factors were measured systematically at baseline and 1 year (94% follow-up). Lipids were analyzed in a core laboratory. Linear regression models were adjusted for confounders. RESULTS: At baseline, 21% of participants reported exercising more than 3 d/wk, which did not differ by group assignment. The special intervention and control intervention experienced significant increases in physical activity at 1 year with mean physical activity days per week in the special intervention significantly greater than the control intervention (2.5 vs 2.0 d/wk, P = .03). Significant predictors of increased physical activity at 1 year were group assignment (P = .03), female sex (P = .04), nonminority status (P <.01), greater readiness to change (P <.01), and baseline measurements of lower body mass index (P <.01) and waist size (P <.01), greater diet adherence (P <.01), higher high-density lipoprotein cholesterol (P <.01), lower high-sensitivity C-reactive protein (P = .02), less depression (P <.01), and higher social support (P = .03). In multiple regression models, group assignment, female, and nonminority status remained independent predictors of higher physical activity levels at 1 year. CONCLUSION: Several predictors of improved physical activity levels at 1 year were documented among clinical trial participants. Racial/ethnic minorities and men were significantly less likely to make positive changes and may need more targeted efforts to improve physical activity levels. PMID- 20856132 TI - Randomized pilot study of a behavioral feedback intervention to improve medication adherence in older adults with hypertension. AB - BACKGROUND AND OBJECTIVES: Older adults' adherence to antihypertensive medications is far lower than what is considered necessary for clinical effectiveness, despite the risks for adverse cardiovascular events from uncontrolled blood pressure (BP) in the elderly. This pilot study tested a novel 8-week behavioral feedback intervention to improve antihypertensive medication adherence (MA) and BP control among older adults on existing treatment for hypertension. METHODS: Adults 60 years old, or older taking at least 1 antihypertensive medication were randomized to receive the nurse-delivered adherence intervention or usual care. Medication adherence was monitored continuously using electronic monitoring for 20 weeks. Intervention-group participants received biweekly MA and BP feedback, habit counseling, medication and disease education, a medication instruction card, and were given an electronic medication bottle cap with a digital display that provided daily adherence feedback during the 8-week intervention. Blood pressure was measured by a nurse at 12 and 20 weeks after randomization. Adherence and BP outcomes were described using descriptive statistics and analyzed for between- and within-group differences using Mann-Whitney U tests. RESULTS: Fifteen participants (median age, 71 years; 73% female) were eligible for randomization. Participants took an average of 5.8 prescription medications and 2.93 over-the-counter medications per day. A nonsignificant difference was noted in baseline MA between groups. At the end of the intervention, the treatment group had better antihypertensive MA than did the control group (median MA: 100% vs 27.3%, U = 5.00, P = .013). Systolic BP improved slightly in the intervention group during the study and was significantly different at week 12 (median systolic BP: 130 vs 152 mm Hg; U = 4.50, P = .008). Diastolic BP was largely unchanged over the course of the study. CONCLUSION: The results indicate that the intervention had a positive effect on MA. Additional testing is needed to further evaluate the intervention and its effect on adherence behavior and BP control. PMID- 20856134 TI - Noncompacted ventricular myocardium: characterization by intracardiac echo. AB - We report a patient with clinical manifestation of arrhythmias and evidence of noncompacted myocardium in both left and right ventricular apex. The diagnosis was made with intracardiac echo performed during the electrophysiologic study. This method has allowed the diagnosis of noncompaction of the ventricular myocardium due to its high resolution. Color Doppler showed trabecular recesses in communication with the ventricular cavity that could not be identified with transthoracic echocardiography. PMID- 20856133 TI - Sleep and cognition in older adults with cardiovascular disease. AB - BACKGROUND: Sleep problems are common in the normal population and likely to be especially prevalent in persons with cardiovascular disease. PURPOSE: We examined the prevalence of sleep difficulties and their impact on cognitive function in 77 persons (mean age, 62.8 [SD, 12.5] years; 24% female) presenting for perfusion stress scan at an outpatient cardiology center. METHODS: Participants completed the Pittsburgh Sleep Quality Index and Modified Mini-Mental State Examination as part of a larger project. RESULTS: Analyses showed that approximately 94% of participants met the criteria for "poor" sleep (ie, Pittsburgh Sleep Quality Index global score >=5). Poorer reported sleep was associated with reduced cognitive function as measured by the Modified Mini-Mental State Examination after adjusting for age, depression, and cardiovascular fitness (ie, estimated metabolic equivalents; R2 change = 0.08, F = 7.17; P <.001). CONCLUSION: These findings indicate that sleep problems are common in cardiovascular disease and extend previous research by demonstrating they negatively impact cognitive function. Further work is needed to identify other consequences of poor sleep in this population and optimal treatment. PMID- 20856135 TI - Posterior mitral leaflet: new anatomical insight and review of nomenclature (mitral valve anatomy). AB - OBJECTIVES: Previous studies described single components of the mitral valve, but somewhat lacked the spatial analysis of their relationship. Moreover, further information is necessary regarding reconstructive surgery. The current work aimed at in-depth analysis of the anatomy of the posterior mitral leaflet (PML) and its changes due to degenerative disease, completing the already existing anatomical information about PML and proposing a reorganization of the actual terminology. METHODS: Nine normal PMLs harvested from cadavers have been compared with 12 pathological specimens from partial resection of PML in the course of valve repair in adult patients. Dimensions of smooth and rough surfaces of the PML have been measured and compared and their dimensional relationships have been assessed; the chance of finding chordae tendineae inserting into the smooth, periannular portion of PML as well as their type have been checked. MEDLINE has been searched for the most relevant publications about PML anatomy. RESULTS: Observation of normal specimens has confirmed the presence of three types of chordae tendineae: marginal, intermediate and basal, but between the last two, there is some of alternative nature. In degenerative mitral valve disease, the rough part is only 13% greater than the smooth one. In collagen degeneration, both parts contribute in more or less equal proportion to the dimensional increase of the middle scallop, so that the ratio between rough and smooth surface is maintained as in normal specimens. CONCLUSION: This study reorganizes the previously proposed terminology of PML chordae tendineae. The research identifies the complemental and alternative presence of 'strut' and 'basal' chordae of PML, and it specifies the dimensions of the different anatomical components of the leaflet, in particular of the intermediate scallop. The observations give an accurate anatomical reference for the space of mitral reconstruction with minimal functional impact. PMID- 20856136 TI - A proposed, evidence-based approach to the treatment of chronic Hepatitis B. AB - Patients with chronic hepatitis B virus infection are at increased risk for the development of cirrhosis and hepatocellular carcinoma. Viral suppression with antiviral therapy has been shown to decrease the risk of these complications. Criteria for initiation of antiviral therapy have evolved over time to include serum alanine aminotransferase elevation, serum hepatitis B virus DNA elevations, and histologic assessment. Current societal guidelines and a treatment algorithm have been developed to guide decision-making as regards to antiviral therapy. More recent data has shown the importance of basal core/core promoter mutations, serum albumin, and platelet count in predicting complications of chronic hepatitis B. We present a new treatment strategy for determining the need for antiviral therapy in patients with chronic hepatitis B. PMID- 20856137 TI - Varices in early histological stage primary biliary cirrhosis. AB - BACKGROUND/GOALS: Esophageal varices (EV) in early histological stages of primary biliary cirrhosis (PBC) have been recognized but not well defined. We sought to determine the prevalence, clinical characteristics, and predictors of EV in early stage PBC, as well as to evaluate the effectiveness of recent guidelines regarding EV screening in PBC patients. STUDY: We retrospectively reviewed the charts of 325 PBC patients who had undergone complete evaluation before enrollment into 2 large clinical trials at the Mayo Clinic. RESULTS: Nineteen percent (62/325) of our patient population had EV on esophagogastroduodenoscopy; 6% (8/127) of early-stage PBC patients had EV. Ninety five percent of our PBC patients with varices met at least one of the following conditions: male sex, low albumin (<3.5 g/dL), elevated bilirubin level (>=1.2 mg/dL), and/or prolonged prothrombin time (>=12.9 s). The sensitivity and specificity of these variables in combination to predict the presence of varices were 95% and 55%, respectively. Serum bilirubin >=1.2 mg/dL and albumin <3.5 were independent predictors of varices with hazard values of 5.4 and 3.5 respectively. CONCLUSIONS: EV can occur in a minority of early-stage PBC patients. Various models may be used to identify PBC patients who are candidates for screening esophagogastroduodenoscopy for EV. Based on adequate performance and its simplicity, we propose that male sex, low albumin, elevated bilirubin, and/or prolonged prothrombin time be used as a model to noninvasively predict EV. Further validation is required. PMID- 20856138 TI - Stool DNA screening for colorectal cancer: opportunities to improve value with next generation tests. AB - General adoption of the screening tests for colorectal cancer (CRC) by patients, health care professionals, medical centers, and third party payers rests on a favorable assessment of value. Reported cost-effectiveness estimates of stool DNA testing for CRC screening incorporated performance assumptions based on data from the first generation tests. Given the substantial technical advances in stool DNA testing that have occurred subsequently, estimates of value will need to be revisited. This review briefly examines the early cost-effectiveness estimates for stool DNA screening and looks ahead at how the next generation tests might improve such value estimates for CRC screening. PMID- 20856139 TI - Antibiotic prophylaxis is recommended for endoscopic ultrasound-guided fiducial placements. PMID- 20856140 TI - Osteoid osteoma: fluoroscopic guided percutaneous excision technique - our experience. AB - Osteoid osteoma is a small benign bone lesion. It generally affects children and young adults. Traditional treatment of osteoid osteoma includes excision either by wide resection, or by the removal of the nidus using curettes and burrs after opening the overlying cortex. Newly developed techniques involve percutaneous ablation of the tumor by computed tomography-guided core-drill excision and destruction of the nidus by thermocoagulation. Fluoroscopic guided percutaneous extirpation and drilling resection procedures have been performed at the Institute for Health Care of Children and Youth, Pediatric Surgery Clinic in Novi Sad, Serbia. Some modifications in the methods were made and implemented, which resulted in an excellent cost-benefit ratio, shorter period of hospitalization, and faster recovery. The aim of this paper is to present the experience gained in the treatment of osteoid osteomas in the last 5 years at the Pediatric Surgery Clinic in Novi Sad and to describe the modifications to the percutaneous biopsy technique of osteoid osteoma that have been implemented. PMID- 20856141 TI - Impact of the 2004 Food and Drug Administration pediatric suicidality warning on antidepressant and psychotherapy treatment for new-onset depression. AB - OBJECTIVE: To assess the national impact of the March 2004 Food and Drug Administration (FDA) antidepressant suicidality warning on the outpatient treatment of new-onset depression in youth. METHOD: A repeated measures, longitudinal design in a cohort of youth diagnosed with new-onset depression was used to assess pre- and post-FDA warning effects. US commercial insurance enrollees in the i3 INNOVUS database from January 2003 through December 2006 were examined. The study population included youth 2- to 17-years old with a new-onset depression diagnosis from July 2003 through June 2006 (N = 40,309). The main independent variables were the warning period (post- vs. pre-FDA warning) and age group (children vs. adolescents). The main outcome measures were youth with antidepressant dispensings and psychotherapy visits measured in 30-day intervals across 36 months following a new-onset diagnosis of any depressive disorder (N = 40,309) and specifically major depressive disorder (MDD) (N = 11,532). RESULTS: Compared to youth with a new-onset diagnosis of depression in the pre-FDA warning period, youth with new-onset diagnosis of depression during the postwarning period had (1) A significantly lower likelihood of antidepressant use: (odds ratio [OR] = 0.85 [0.81-0.89]); When youth with the diagnosis of depression were separated into those with MDD and those with less severe depression diagnoses, only the latter had a significant postwarning antidepressant decline. (2) A significant increase in the odds of a psychotherapy visit (children, OR = 1.31 [1.23-1.40]; adolescents OR = 1.19 [1.15-1.24]). CONCLUSIONS: The FDA suicidality warning was associated with an overall decrease in antidepressant treatment for youth with a clinician-reported diagnosis of depression, but not for those with MDD. Also, following the warning, psychotherapy without medication increased. PMID- 20856142 TI - A comparison of health care in Canada and the United States: the case of Pap smears. AB - RATIONALE: Compliance with preventive care recommendations differs between countries. Directly comparable data are often not available. The recent release of the Joint Canada/United States Survey of Health makes available data for both Canadians and Americans. OBJECTIVES: The health care systems in the United States and Canada differ quite dramatically. Canadians are covered by a universal health care system while residents of the United States, if they are insured, obtain their insurance from various private or public sources. This paper examines how the use of the Papanicolaou test (Pap smear) by women differs in the United States and Canada. METHODOLOGY: American women are more likely than Canadians to receive a pap smear. A Blinder/Oaxaca type decomposition is used to determine influence of observed population characteristics and unobserved differences between the 2 countries on this gap. RESULTS: The decomposition shows that the gap in Pap smears between Canada and the United States is not influenced by observed demographic differences. Most of the difference is attributable to unobserved heterogeneity or how women are treated in the 2 systems. CONCLUSIONS: Although Canada has universal health coverage, the use of Pap smears is lower than that of all US women and equal to that of uninsured US women. Most of the differences in use of Pap smears is the result of differences in unobserved heterogeneity or the way that the systems treat women which may be a function of differences between the 2 health care systems in marketing, delivering, and reimbursing care. PMID- 20856143 TI - Emergency department visits and primary care among adults with chronic conditions. AB - BACKGROUND: An emergency department (ED) visit may be a marker for limited access to primary medical care, particularly among those with ambulatory care sensitive chronic conditions (ACSCC). OBJECTIVES: In a population with universal health insurance, to examine the relationships between primary care characteristics and location of last general physician (GP) contact (in an ED vs. elsewhere) among those with and without an ACSCC. RESEARCH DESIGN: A cross-sectional survey using data from 2 cycles of the Canadian Community Health Survey carried out in 2003 and 2005. SUBJECTS: The study sample comprised Quebec residents aged >=18 who reported at least one GP contact during the previous 12 months, and were not hospitalized (n = 33,491). MEASURES: The primary outcome was place of last GP contact: in an ED versus elsewhere. Independent variables included the following: lack of a regular physician, perceived unmet healthcare needs, perceived availability of health care, number of contacts with doctors and nurses, and diagnosis of an ACSCC (hypertension, heart disease, chronic respiratory disease, diabetes). RESULTS: Using multiple logistic regression, with adjustment for sociodemographic, health status, and health services variables, lack of a regular GP and perceptions of unmet needs were associated with last GP contact in an ED; there was no interaction with ACSCC or other chronic conditions. CONCLUSIONS: Primary care characteristics associated with GP contact in an ED rather than another site reflect individual characteristics (affiliation with a primary GP and perceived needs) rather than the geographic availability of healthcare, both among those with and without chronic conditions. PMID- 20856144 TI - Comparative responsiveness of pain outcome measures among primary care patients with musculoskeletal pain. AB - BACKGROUND: Comparative responsiveness data are needed to inform choices about pain outcome measures. OBJECTIVES: To compare responsiveness of pain intensity, pain-related function, and composite measures, using data from a randomized trial and observational study. RESEARCH DESIGN: Analysis of responsiveness. SUBJECTS: A total of 427 adults with persistent back, hip, or knee pain were recruited from primary care. METHODS: Participants completed Brief Pain Inventory, Chronic Pain Grade (CPG), Roland disability, SF-36 bodily pain, and pain global rating of change measures. We used the global rating as the anchor for standardized response mean and receiver operating characteristic curve analyses. We used the distribution-based standard error of measurement to estimate minimally important change. To assess responsiveness to the trial intervention, we evaluated standardized effect size statistics stratified by trial arm. RESULTS: All measures were responsive to global improvement and all had fair-to-good accuracy in discriminating between participants with and without improvement. SF bodily pain was less responsive than other measures in several analyses. The 3-item PEG was similarly responsive to full Brief Pain Inventory scales. CPG and SF bodily pain were less responsive to the trial intervention and did not perform well among participants with hip/knee pain. Agreement between anchor and distribution based methods was modest. CONCLUSIONS: If a brief measure is desired, the 3-item PEG is more responsive than the SF bodily pain scale. CPG and SF bodily pain scales may be relatively poor choices for trial outcome assessment. Both anchor and distribution-based methods should be considered when determining clinically important change. PMID- 20856145 TI - Primary care practice transformation is hard work: insights from a 15-year developmental program of research. AB - BACKGROUND: Serious shortcomings remain in clinical care in the United States despite widespread use of improvement strategies for enhancing clinical performance based on knowledge transfer approaches. Recent calls to transform primary care practice to a patient-centered medical home present even greater challenges and require more effective approaches. METHODS: Our research team conducted a series of National Institutes of Health funded descriptive and intervention projects to understand organizational change in primary care practice settings, emphasizing a complexity science perspective. The result was a developmental research effort that enabled the identification of critical lessons relevant to enabling practice change. RESULTS: A summary of findings from a 15 year program of research highlights the limitations of viewing primary care practices in the mechanistic terms that underlie current or traditional approaches to quality improvement. A theoretical perspective that views primary care practices as dynamic complex adaptive systems with "agents" who have the capacity to learn, and the freedom to act in unpredictable ways provides a better framework for grounding quality improvement strategies. This framework strongly emphasizes that quality improvement interventions should not only use a complexity systems perspective, but also there is a need for continual reflection, careful tailoring of interventions, and ongoing attention to the quality of interactions among agents in the practice. CONCLUSIONS: It is unlikely that current strategies for quality improvement will be successful in transforming current primary care practice to a patient-centered medical home without a stronger guiding theoretical foundation. Our work suggests that a theoretical framework guided by complexity science can help in the development of quality improvement strategies that will more effectively facilitate practice change. PMID- 20856147 TI - Advances and short comings in the early diagnosis of melanoma. AB - Malignant melanoma kills more people each year than any other skin cancer, with approximately 8000 lives lost and a cost of over 3 billion dollars annually in the US alone. Tumor depth is the most important prognostic factor in melanoma. Thus, early detection has the potential to diagnose melanoma when lesions are thinner, and to improve survival in primary melanomas. In this review, we discuss the implications, barriers, and advantages of melanoma screening, and describe the currently employed methods of detection, newly available modalities, and current areas of research. We also discuss the efficacy, advantages and disadvantages, and clinical practicality of each, and suggest various means of combining different methodologies as well as tailoring various strategies to individual patient needs. PMID- 20856146 TI - Evaluation of molecular markers of mesenchymal phenotype in melanoma. AB - The epithelial to mesenchymal transition is a developmental process allowing epithelial cells to dedifferentiate into cells displaying mesenchymal phenotypes. The pathological role of epithelial to mesenchymal transition has been implicated in invasion and metastasis for numerous carcinomas, yet limited data exist addressing whether mesenchymal transition (MT) occurs in malignant melanoma cells. Our group developed an in-vitro three-dimensional culture system to address MT in melanoma cells upon transforming growth factor-beta/ tumor necrosis factor-alpha treatment. Loss of E-cadherin is one of the best indicators of MT in epithelial cells. Not surprisingly, E-cadherin was expressed in only three of 12 (25%) melanoma cell lines and all three mesenchymal proteins, N-cadherin, vimentin, and fibronectin, were expressed by seven (58%) melanoma cell lines. However, after cytokine treatment, two or more mesenchymal proteins were elevated in nine (75%) melanoma cell lines. Data support the transforming growth factor beta production by melanoma cells which may induce/support MT. Evaluation of E cadherin, N-cadherin, and Snail expression in melanoma tissue samples are consistent with an inverse coupling of E-cadherin and N-cadherin expression, however, there are also examples suggesting a more complex control of their expression. These results indicate that malignant melanoma cell lines are susceptible to MT after cytokine treatment and highlight the importance of understanding the effects of cytokines on melanoma to undergo MT. PMID- 20856148 TI - Enhanced tactile resolution of the contralateral side after surgery and regional anesthesia of the hand. AB - The purpose of this study was to investigate whether enhancement of tactile resolution (measured with Grating Orientation Task) can be demonstrated for patients undergoing regional anesthesia during hand surgery compared with surgery in general anesthesia and nonoperative controls. Regional anesthesia (nine patients) induced a significant improvement in contralateral tactile resolution at 10 and 24 h after the operation (P<0.01 and <0.05) compared with baseline. In the general anesthesia group (10 patients), tactile resolution improved significantly over time, but to a lesser extent than in the regional anesthesia group. When comparing with the control group (10 individuals), only the regional anesthesia group showed significantly increased tactile resolution at both the time points (P<0.01 and P<0.05), postoperatively. PMID- 20856149 TI - Zn2+ chelation improves recovery by delaying spreading depression-like events. AB - We earlier reported that Zn2+ chelation improved recovery of synaptic potentials after transient oxygen and glucose deprivation in brain slices. Such an effect could be because of reduced accumulation of Zn2+ in postsynaptic neurons, or could also be due to prevention of the onset of spreading depression-like events. A combination of optical and electrical recording was used here to show that Zn2+ chelation is effective because it delays spreading depression-like events. If the duration of oxygen/glucose deprivation was sufficient to generate a spreading depression-like event, irrecoverable Ca2+-dependent loss of synaptic potentials occurred, regardless of Zn2+ availability. These results identify a key mechanism underlying protective effects of Zn2+ chelation, and emphasize the importance of evaluating spreading depression-like events in studies of neuroprotection. PMID- 20856150 TI - Effect of hydrogen peroxide on potassium currents in inner hair cells isolated from guinea pig cochlea. AB - Hydrogen peroxide (H2O2) is a ubiquitous reactive oxygen species that can induce several inner ear disorders. In this study, we recorded the potassium (K) currents in acutely isolated inner hair cells of guinea pig cochlea, and investigated the effects of H2O2. We also observed the morphological changes in inner hair cells induced by H2O2. In the H2O2 solutions, the amplitude of outward K currents (I(K,f) and I(K,s)) clearly decreased after perfusion for approximately 15 min. Despite the decrease in outward currents, small inward currents (I(K,n)) did not show any reduction. H2O2 induced morphological changes in the inner hair cells. All the inner hair cells in the H2O2 solutions showed shrinkage and granularity of the cell body and led to loss of viability. These results showed the vulnerability of inner hair cells to reactive oxygen species induced inner ear disorders. PMID- 20856151 TI - Awareness and understanding of nuclear medicine among junior doctors in a district general hospital setting: an audit and personal experiences. AB - AIM: To discover the level of knowledge and understanding about nuclear medicine techniques among current junior doctors in a hospital setting. METHODS: A questionnaire was sent out to all Foundation Year 1 and Foundation Year 2 doctors at my institution, asking them to list as many nuclear medicine investigations (with relevant indications) as they knew. All known nuclear medicine therapies were also listed. The data from these questionnaires were analysed. The doctors were then given a lecture entitled 'Introduction to Nuclear Medicine'. The questionnaires were then sent out again 1 month later, and the data from them were re-analysed. RESULTS: Each junior doctor, before the lectures, knew a mean of 3.1 investigations and 0.8 therapies. After the lectures, they were able to list a mean of 7.5 investigations and 3.4 therapies. This difference/improvement in knowledge is statistically significant (P<0.001). DISCUSSION: Level of knowledge regarding nuclear medicine is poor among junior doctors. After appropriate education, the audit showed a highly statistically significant improvement in the level of knowledge. A lack of exposure to nuclear medicine, and its low profile in many hospitals, are the likely causes of the initial lack of awareness. It is important to rectify this, not only for improving patient management, but also for the future of the specialty itself. PMID- 20856152 TI - Added value of positron emission tomography imaging in the surgical treatment of colorectal liver metastases. AB - OBJECTIVE: [F-18]-Fluorodeoxyglucose-positron emission tomography (FDG-PET) is used increasingly in the work-up to surgery for patients with potentially resectable colorectal liver metastases. This study evaluates the clinical effectiveness, impact on health care resources and cost-effectiveness of adding FDG-PET to the diagnostic algorithm alongside a randomized clinical trial from a health care perspective. METHODS: In a randomized clinical trial, the net monetary benefit (NMB) of FDG-PET added to conventional diagnostic work-up (CWU) was determined in patients with colorectal liver metastases. Seventy-five patients were included in each arm. Change in clinical management, futile laparotomies, preoperative findings and all relevant health care consumption were prospectively documented during 3 years. To assess health-related quality of life European Quality of Life-5 Dimensions was administered at the time of randomization, 3 and 6 weeks postoperatively, and every 3 months postoperatively for 3 years. Quality-adjusted life years (QALYs) were calculated based on European Quality of Life-5 Dimensions outcomes. RESULTS: In adding FDG-PET, diagnostic performance increased and futile laparotomies were reduced by 38%. Both health-related quality of life and QALYs showed no significant difference between the CWU and PET groups. For CWU and PET groups costs were euro 92,836 and euro 81,776, respectively, accumulated in 3 years after randomization. NMB ranged from euro 1004 to euro 11,060 depending on the monetary value given to a QALY. When costs for chemotherapy were disregarded, costs amounted to euro 15,874 for CWU and euro 18,664 for PET group. CONCLUSION: Additional costs of FDG-PET in the diagnostic work-up of patients with potentially resectable colorectal liver metastases were compensated by a reduction in futile laparotomies. The NMB analysis showed savings over a relevant range of willingness to pay for a QALY. PMID- 20856153 TI - Impact of [F-18] FDG-PET/CT in the restaging and management of patients with malignant melanoma. AB - PURPOSE: To assess the impact of [F-18] FDG-PET/CT on the restaging and changing management of patients with malignant melanoma. METHODS: Seventy-eight patients (32 female, 27-83 years) were reviewed. Treatment planning before and after [F 18] FDG-PET/CT scan was evaluated for changes in the management of the disease. Restaging was classified according to the disease extent as follows: local recurrence, locoregional recurrence or distant recurrence. Initial restaging of patients was as follows: local recurrence in 11 patients, locoregional recurrence in 23 patients and distant recurrence in 44 of 78 patients. All the patients were injected with 370 MBq of [F-18] FDG and imaged from the head to feet after 60 min. All the patients fasted for 4-6 h before imaging and blood glucose levels were below 140 mg/dl. Images were taken using a PET/CT scanner (Siemens Biograph). Two nuclear medicine physicians and a radiologist (all experienced in oncology) interpreted the images. RESULTS: In 27% of the patients the management was changed after the [F-18] FDG-PET/CT studies. Upstaging from locoregional recurrence to distant recurrence occurred in a striking 5 of 23 (22%) patients. The sensitivity, specificity and positive and negative predictive values for lesion detection were 95%, and accuracy was 94.9%. There were two false-positive and two false-negative studies. CONCLUSION: [F-18] FDG-PET/CT seems to be a valuable diagnostic tool in restaging and management of patients with malignant melanoma suspected of recurrence especially in patients with locoregional recurrence and distant recurrence. PMID- 20856154 TI - Isolated recurrent vertigo from stenotic posterior inferior cerebellar artery. PMID- 20856155 TI - Correlation of early auditory potentials and intracochlear electrode insertion properties: an animal model featuring near real-time monitoring. AB - OBJECTIVE: The goal of this work was to assess electrophysiologic response changes to acoustic stimuli as an intracochlear electrode impacted cochlear structures in an animal model of hearing preservation cochlear implantation. The ultimate goal is to develop efficient procedures for assessing the status of cochlear physiology for intraoperative use. METHODS: Sixteen gerbils and 18 ears were tested. A rigid electrode was inserted through a basal turn cochleostomy and directed toward the basilar membrane/osseous spiral lamina complex. We recorded acoustically evoked early auditory potentials including cochlear microphonics (CMs) and compound action potentials (CAPs) to a short stimulation sequence consisting of one stimulus frequency and intensity as the electrode was advanced. A microendoscope was used to visualize the electrode insertion progress and to identify the site of electrode impact. After each experiment, the site of intracochlear trauma was confirmed using whole mount preparations. RESULTS: Electrophysiologic changes correlated well with the degree and location of trauma. We observed four distinct patterns. In addition, the endoscope in conjunction with the short recording sequence allowed for the detection of response changes that were reversible when the electrode was retracted. These cases were associated with less than full-thickness damage on histology. CONCLUSION: The short recording sequence to obtain acoustically evoked intracochlear potentials and the microendoscope allowed us to detect various levels of cochlear trauma including minor and reversible damage. Recordings of this type are potentially available using current implant technology. Future improvements in the measurements can be expected to improve the efficiency of the recording paradigm to produce a clinically useful tool. PMID- 20856156 TI - Marrow-middle ear connections: a potential cause of otogenic meningitis. AB - HYPOTHESIS: We hypothesize that the connections between the hematopoietic bone marrow and middle ear is a potential cause of childhood otogenic meningitis. BACKGROUND: Although it is known that there is a causal relationship between otitis media and bacterial meningitis, the relationship has never been satisfactorily established. Human fetal and infant temporal bones prepared for light microscopic evaluation revealed direct connections between the hematopoietic bone marrow and middle ear. We noted this difference in anatomy between the infant middle ear and the adult middle ear. METHODS: We studied 10 temporal bones from 5 infants in each group: meningitis group with otitis media who died of meningitis, control Group 1 without otitis media, and control Group 2 with otitis media who died of diseases other than meningitis. A quantitative analysis of the frequency of connections between the hematopoietic bone marrow and middle ear was performed. The correlation between unabsorbed mesenchyme and otitis media also was investigated. RESULTS: The frequency of connections was significantly higher in order of the meningitis group, control Group 2, and control Group 1. The degree of unabsorbed mesenchyme tended to be more severe in order of the meningitis group, control Group 2, and control Group 1. CONCLUSION: The prevalence of connections between the hematopoietic bone marrow and middle ear in patients with meningitis and otitis media is high. A higher prevalence of connections in infants with otitis media could increase the risk for otogenic meningitis in them. PMID- 20856157 TI - Diabetes, vestibular dysfunction, and falls: analyses from the National Health and Nutrition Examination Survey. AB - OBJECTIVE: Patients with diabetes are at increased risk both for falls and for vestibular dysfunction, a known risk factor for falls. Our aims were 1) to further characterize the vestibular dysfunction present in patients with diabetes and 2) to evaluate for an independent effect of vestibular dysfunction on fall risk among patients with diabetes. STUDY DESIGN: National cross-sectional survey. SETTING: Ambulatory examination centers. PATIENTS: Adults from the United States aged 40 years and older who participated in the 2001-2004 National Health and Nutrition Examination Survey (n = 5,86). INTERVENTIONS: Diagnosis of diabetes, peripheral neuropathy, and retinopathy. MAIN OUTCOME MEASURES: Vestibular function measured by the modified Romberg Test of Standing Balance on Firm and Compliant Support Surfaces and history of falling in the previous 12 months. RESULTS: We observed a higher prevalence of vestibular dysfunction in patients with diabetes with longer duration of disease, greater serum hemoglobin A1c levels and other diabetes-related complications, suggestive of a dose-response relationship between diabetes mellitus severity and vestibular dysfunction. We also noted that vestibular dysfunction independently increased the odds of falling more than 2-fold among patients with diabetes (odds ratio, 2.3; 95% confidence interval, 1.1-5.1), even after adjusting for peripheral neuropathy and retinopathy. Moreover, we found that including vestibular dysfunction, peripheral neuropathy, and retinopathy in multivariate models eliminated the significant association between diabetes and fall risk. CONCLUSION: Vestibular dysfunction may represent a newly recognized diabetes-related complication, which acts as a mediator of the effect of diabetes mellitus on fall risk. PMID- 20856159 TI - Vestibular schwannoma presenting as a white middle ear mass behind an intact tympanic membrane. PMID- 20856158 TI - MicroRNA-21 overexpression contributes to vestibular schwannoma cell proliferation and survival. AB - HYPOTHESIS: Elevated levels of hsa-microRNA-21 (miR-21) in vestibular schwannomas (VSs) may contribute to tumor growth by downregulating the tumor suppressor phosphatase and tensin homolog (PTEN) and consequent hyperactivation of protein kinase B (AKT), a key signaling protein in the cellular pathways that lead to tumor growth. BACKGROUND: Vestibular schwannomas are benign tumors that arise from the vestibular nerve. Left untreated, VSs can result in hearing loss, tinnitus, vestibular dysfunction, trigeminal nerve dysfunction, and can even become life threatening. Despite efforts to characterize the VS transcriptome, the molecular pathways that lead to tumorigenesis are not completely understood. MicroRNAs are small RNA molecules that regulate gene expression posttranscriptionally by blocking the production of specific target proteins. METHODS: We examined miR-21 expression in VSs. To determine the functional significance of miR-21 expression in VS cells, we transfected primary human VS cultures with anti-miR-21 or control, scrambled oligonucleotides. RESULTS: We found consistent overexpression of miR-21 when compared with normal vestibular nerve tissue. Furthermore, elevated levels of miR-21 correlated with decreased levels of PTEN, a known molecular target of miR-21. Anti-miR-21 decreased VS cell proliferation in response to platelet-derived growth factor stimulation and increased apoptosis, suggesting that increased miR-21 levels contributes to VS growth. CONCLUSION: Because PTEN regulates signaling through the growth-promoting phosphoinositide 3-kinase/AKT pathway, our findings suggest that miR-21 may be a suitable molecular target for therapies aimed specifically at reducing VS growth. PMID- 20856160 TI - Results of a pilot study with a signal enhancement algorithm for HiRes 120 cochlear implant users. AB - OBJECTIVE: Cochlear implant users still experience severe limitations regarding sound quality, music appreciation, and speech perception in adverse listening situation. To improve hearing in noisy environments, the incorporation of signal enhancement algorithms was initiated. METHOD: The study group consisted of 13 postlingually deafened adults using HiRes 120. Participants were fitted with 2 versions of the noise reduction algorithm: a moderate and a strong setting. In an immediate session, the HSM sentence test in speech-shaped noise was administered using the clinical program as well as both noise reduction programs. Participants were asked to try all 3 programs in everyday listening situations at home and provide a rating of sound quality and speech perception via a questionnaire (Abbreviated Profile of Hearing Aid Benefit). RESULTS: During the fitting, no difficulties were encountered, and all participants accepted the noise reduction programs without any acclimatization. All participants achieved better results with both noise reduction programs in the HSM sentence test in noise compared with the clinical program. Group mean speech perception scores were highly significantly better for the ClearVoice settings compared with the clinical program score. The majority preferred one of the ClearVoice conditions, with 4 participants for the strong and 3 for the moderate setting. CONCLUSION: Our results demonstrate a real potential benefit for noise reduction algorithms in cochlear implant processors. Although algorithm parameters were not optimized individually, a significant improvement could still be achieved. Further investigation is required to develop fitting guidelines and achieve parameter optimization. PMID- 20856161 TI - Facial and vestibulocochlear nerve avulsion at the fundus of the internal auditory canal in a child without a temporal bone fracture. AB - OBJECTIVE: To describe a case of facial, vestibular, and cochlear nerve avulsion secondary to blunt trauma without an associated temporal bone fracture. STUDY DESIGN: Clinical capsule report. SETTING: University hospital. PATIENT: A 3.5 year-old girl presented with immediate facial nerve paralysis and complete deafness after being struck by an automobile. High-resolution computed tomography demonstrated a depressed occipital bone fracture with no visible fracture of the temporal bone. Magnetic resonance imaging sequence raised the question of VIIth nerve bundle discontinuity at the distal end of the internal auditory canal. INTERVENTION: The patient underwent a posterior fossa craniotomy via a translabyrinthine approach 9 months after the initial injury, and facial and auditory nerve avulsion at the fundus was confirmed at the time of surgery. The proximal segment of the facial nerve had formed a traumatic neuroma, which was resected, and primarily anastomosed to the rerouted distal segment. MAIN OUTCOME MEASURES: Facial nerve function. RESULTS: Patient has regained facial function to Grade III/VI House-Brackmann with no asymmetry at rest. CONCLUSION: An unusual pattern of injury is described. We suggest that in patients presenting with facial nerve paralysis secondary to blunt trauma, without an associated temporal bone fracture, high-resolution magnetic resonance imaging is recommended to evaluate internal auditory canal discontinuity of the VIIth and VIIIth nerve complexes. A potential mechanism of avulsion is explained. PMID- 20856162 TI - Incidence of influenza virus infection in early infancy: a prospective study in South Asia. AB - We evaluated infant sera from an immunization trial in Bangladesh to assess influenza hemagglutination inhibition antibody titer increases in 131 unimmunized infants from birth to 6 months. We detected 31 serologically defined infections. Combined with 10 additional rapid test-proven influenza cases, the minimal estimated incidence was 31 of 100 infants (95% CI: 24-41). These data suggest a high burden of influenza in young infants in tropical South Asia. PMID- 20856163 TI - Antibody responses to hepatitis A virus vaccination in thai hiv-infected children with immune recovery after antiretroviral therapy. AB - The prevalence of hepatitis A virus (HAV) protective antibody in 98 Thai HIV infected children who achieved immune recovery after antiretroviral therapy was 12.2%. After a 2-dose HAV vaccination, 98.8% (85 of 86 children) seroconverted. The geometric mean titer was 520.95 mIU/mL. In a multivariate analysis, female gender, age < 12 years and higher CD4 lymphocyte count at enrollment were predicting factors for high (>= 250 mIU/mL) HAV antibody response. PMID- 20856164 TI - Safety and immunogenicity of a single administration of live-attenuated Japanese encephalitis vaccine in previously primed 2- to 5-year-olds and naive 12- to 24 month-olds: multicenter randomized controlled trial. AB - BACKGROUND: Safe and effective Japanese encephalitis (JE) vaccines are needed to protect populations living in or visiting endemic areas. A live-attenuated JE chimeric virus vaccine (JE-CV) has been developed with a single-dose regimen. METHODS: In an open-label, crossover study, 100 children aged 2 to 5 years with a history of 2-dose primary vaccination with mouse-brain derived inactivated JE vaccine according to the Thai Expanded Program for Immunization schedule, and 200 JE vaccination-naive 12- to 24-month-old toddlers were randomized 1:1 to receive JE-CV, containing >=4 log10 plaque forming units, 1 month before or after hepatitis A control vaccine. Neutralizing antibody titers were assessed using PRNT50 (titers expressed in inverse of dilution) before and 28 days after JE-CV, and at months 7 and 12. RESULTS: All 2- to 5-year-olds and 96% of 12- to 24-month olds were seroprotected (titer >=10) 28 days after JE-CV administration, and geometric mean titers (GMT) (95% confidence interval) in these age groups were 2634 (1928-3600) and 281 (219-362), respectively. One year later, seroprotection rates in the 2 age groups were 97% and 84% and GMTs were 454 and 62.3, respectively. Vaccine-induced antibodies neutralized a panel of wild-type JE isolates. There were no vaccine-related serious adverse events. Reactogenicity of JE-CV was comparable with that of the inactivated hepatitis A vaccine. CONCLUSIONS: A single administration of JE-CV has a good safety profile and elicits a protective immune response in both JE-naive toddlers and JE-primed young children. PMID- 20856165 TI - Beneficial effect of erythropoietin on sensorimotor function and white matter after hypoxia-ischemia in neonatal mice. AB - There are mixed reports on the neuroprotective properties of erythropoietin (EPO) in animal models of birth asphyxia. We investigated the effect of EPO on short- and long-term outcome after neonatal hypoxic-ischemic (HI) brain injury in mice and compared the effect of two different dose regimens of EPO. Nine-day-old mice were subjected to HI, and EPO was injected i.p. at 0, 24, and 48 h after HI in a dose of either 5 or 20 kU/kg. Paw preference in the cylinder rearing test (CRT) was used as a measure of sensorimotor function. Only in female mice, administration of EPO at 5 kU/kg but not 20 kU/kg improved sensorimotor function, reduced striatum atrophy and hippocampal lesion volume, and enhanced myelin basic protein (MBP) staining as determined at 4 and 9 wk after HI. In addition, at 72 h after HI, more Ki 67 cells were found in the subventricular zone and dentate gyrus after EPO 5 kU/kg treatment, indicating an increase in progenitor cell proliferation. In conclusion, EPO improves sensorimotor function after neonatal HI and protects against striatum atrophy, hippocampus injury, and white matter loss. The protective effect of EPO is dose-dependent and only present in females. PMID- 20856166 TI - Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke. AB - Melatonin demonstrates neuroprotective properties in adult models of cerebral ischemia, acting as a potent antioxidant and anti-inflammatory agent. We investigated the effect of melatonin in a 7-d-old rat model of ischemia reperfusion, leading to both cortical infarct and injury in the underlying white matter observed using MRI and immunohistochemistry. Melatonin was given i.p. as either a single dose before ischemia or a double-dose regimen, combining one before ischemia and one 24 h after reperfusion. At 48 h after injury, neither a significant reduction in cortical infarct volume nor a variation in the number of TUNEL- and nitrotyrosine-positive cells within the ipsilateral lesion was observed in melatonin-treated animals compared with controls. However, a decrease in the density of tomato lectin-positive cells after melatonin treatment was found in the white matter underlying cortical lesion. Furthermore, we showed a marked increase in the myelin basic protein-immunoreactivity in the cingulum and in the density of mature oligodendrocytes (APC-immunoreactive) in both the ipsilateral cingulum and external capsule. These results suggest that melatonin is not able to reduce cortical infarct volume in a neonatal stroke model but strongly reduces inflammation and promotes subsequent myelination in the white matter. PMID- 20856167 TI - Focal white matter abnormalities related to neurocognitive dysfunction: an objective diffusion tensor imaging study of children with Sturge-Weber syndrome. AB - White matter (WM) loss is associated with cognitive impairment in Sturge-Weber syndrome (SWS). In this study, we evaluated if cognitive and fine motor abnormalities are associated with impaired microstructural integrity in specific WM regions in SWS. Fifteen children with unilateral SWS (age: 3-12.4 y) and 11 controls (age: 6-12.8 y) underwent diffusion tensor imaging. Tract-based spatial statistics was used for objective comparisons of WM fractional anisotropy (FA) and mean diffusivity (MD) between the two groups. In the SWS group, WM FA and MD values were correlated with intelligence quotient (IQ) and fine motor scores, with age as a co-variate. Bilateral, multilobar WM areas showed decreased FA, whereas significant MD increases were confined to small ipsilateral posterior regions in SWS children. IQ in the SWS group (range: 47-128) was positively correlated with FA in the ipsilateral prefrontal WM and inversely associated with MD in the ipsilateral posterior parietal WM. A negative correlation between fine motor function and MD was found in ipsilateral frontal WM encompassing motor pathways. Microstructural WM abnormalities occur not only ipsilateral but also contralateral to the angioma in unilateral SWS. Nevertheless, cognitive and fine motor functions are related to diffusion abnormalities in specific ipsilateral, mostly frontal, WM regions. PMID- 20856168 TI - Effect of milk formula protein content on intestinal barrier function in a porcine model of LBW neonates. AB - Our study aimed at investigating the impact of the level of protein in milk formula on intestinal structure, barrier function, and its nervous regulation in normal and LBW neonates using a porcine model. Normal birth weight (NBW) or LBW piglets were fed from d7 to d28 of age either with a high protein (HP) or with an adequate protein (AP) formula or stayed with their mother [mother fed (MF)]. The proximal jejunum and distal ileum were sampled at d28 for morphometry analysis and ex vivo permeability measurement in Ussing chambers. Formula feeding induced a trophic effect on the jejunum and ileum of both NBW and LBW piglets, which exhibited longer villi than MF animals, irrespective of the type of formula. In NBW piglets, intestinal permeability was not altered by formula feeding. On the contrary, LBW piglets fed with HP formula, but not AP, exhibited a greater ileal permeability than MF piglets. Feeding the HP formula also disturbed jejunal and ileal regulation of permeability by acetylcholine and vasoactive intestinal peptide (VIP) in LBW compared with MF LBW piglets. In conclusion, the level of protein in formulas did not modify intestinal structure and function in NBW individuals but dramatically modified intestinal barrier function physiology in LBW individuals. PMID- 20856169 TI - Arginine is synthesized from proline, not glutamate, in enterally fed human preterm neonates. AB - In neonatal mammals, arginine is synthesized in the enterocyte, with either proline or glutamate as the dietary precursor. We have shown several times in piglets that proline is the only precursor to arginine, although in vitro evidence supports glutamate in this role. Because of this uncertainty, we performed a multitracer stable isotope study to determine whether proline, glutamate, or both are dietary precursors for arginine in enterally fed human neonates. Labeled arginine (M + 2), proline (M + 1), and glutamate (M + 3) were given enterally to 15 stable, growing preterm infants (GA at birth 30-35 wk) at 1 3 wk postnatal age. Enrichment in urine of the tracer amino acids and the M + 1 and M + 3 isotopomers of arginine were measured by LC-tandem mass spectrometry to determine the contribution of proline and glutamate to arginine synthesis. Plateau enrichments of arginine and proline tracers were measurable in urine. Urinary glutamate enrichment was not detected. Conversion of proline to arginine was detected. However, the M + 3 isotopomer of arginine, which would have been synthesized from glutamate, was not detected. We conclude that, in contrast to the current consensus in the literature based on in vitro studies, proline is the major contributor to arginine synthesis in human preterm infants. PMID- 20856170 TI - Efficacy and safety of intravitreal bevacizumab compared with intravitreal and posterior sub-tenon triamcinolone acetonide for treatment of uveitic cystoid macular edema. AB - PURPOSE: To demonstrate the effect of bevacizumab compared with triamcinolone acetonide for the treatment of persistent cystoid macular edema in noninfectious uveitis. METHODS: The medical records of 31 eyes of 31 patients with uveitic cystoid macular edema that had persisted despite conventional treatment were reviewed. Ten eyes received 1.25 mg of intravitreal bevacizumab (IVB), 11 eyes received 4 mg of intravitreal triamcinolone acetonide (IVTA), and 10 eyes received 40 mg of posterior sub-Tenon triamcinolone acetonide (PSTA). Changes in visual acuity with a logarithmic minimal angle of resolution and central foveal thickness measured with optical coherence tomography were analyzed. RESULTS: The mean follow-up was 22.3 weeks. The best improvement in visual acuity and reduction in central foveal thickness was achieved at 4 weeks in all groups but worsened with time until 12 weeks (visual acuity improved from baseline by 0.19, 0.27, and 0.16 and central foveal thickness decreased from baseline by 167.4 mm, 327.6 mm, and 166.4 mm with IVB,IVTA, and PSTA, respectively; P , 0.001). The results with IVTA were better than those with IVB or PSTA, although the difference did not reach statistical significance. Intravitreal bevacizumab provided a significantly better effect in visual acuity gain in Behcet uveitis than in non-Behcet uveitis (P = 0.045). Kaplan-Meier survival analysis showed that the median period of effect were 16 weeks with IVB, 30 weeks with IVTA, and 12 weeks with PSTA.An increase in intraocular pressure (.5 mmHg greater than baseline) was observed in 1 eye(10%) with IVB, 5 eyes (45.5%) with IVTA, and 4 eyes (40%) with PSTA. CONCLUSION: Intravitreal bevacizumab was a well-tolerated and effective supplementary therapy for persistent uveitic cystoid macular edema, especially in Behcet uveitis and for patients with the risk of an increase in intraocular pressure. However, reinjection may be required because of the limited potency and duration of the positive effects of IVB. PMID- 20856171 TI - Twelve-month outcome after one intravitreal injection of bevacizumab to treat myopic choroidal neovascularization. AB - PURPOSE: To report the changes during a 1-year follow-up in visual acuity and macular thickness in a series of highly myopic eyes with choroidal neovascularization treated with bevacizumab. METHODS: Retrospective and multicenter study including 107 highly myopic eyes from 107 patients (mean age, 55 years) with subfoveal or juxtafoveal choroidal neovascularization. All cases were treated by one intravitreous injection of 1.25 mg bevacizumab. Best corrected visual acuity and macular thickness with the optical coherence tomography were evaluated at baseline and then monthly during 1 year. RESULTS: Logarithm of the minimum angle of resolution best-corrected visual acuity at baseline averaged 0.72 (standard deviation [SD], 0.43) versus 0.53 (SD, 0.41) at 1 year after treatment (P < 0.001). Logarithm of the minimum angle of resolution best-corrected visual acuity was 0.30 or better in 49 of 107 eyes (45%) at 1 year. Thirty-three eyes (30%) gained at least 3 Early Treatment Diabetic Retinopathy Study lines (15 letters) during the follow-up. In 43 eyes (40%), reinjections were necessary because signs of choroidal neovascularization activity were still evident. The mean number of reinjections was 0.8 (SD, 1.3). Best-corrected visual acuity improvement was better in the younger group (younger than 50 years). No adverse reactions were reported. CONCLUSION: One intravitreal bevacizumab injection seems to be an effective therapeutic approach to treat choroidal neovascularization in highly myopic eyes. Careful monitoring is necessary to assess the need for reinjections. PMID- 20856172 TI - Surgical outcomes after massive subretinal hemorrhage secondary to age-related macular degeneration. AB - PURPOSE: Massive subretinal hemorrhage (SRH), defined as a thick submacular bleed that extends past the equator in at least two quadrants, is a rare sequela of age related macular degeneration. This report describes outcomes after surgical intervention for massive SRH. METHODS: The study design is a retrospective interventional case series. Records of consecutive patients who underwent surgical intervention for massive SRH were reviewed. Outcomes included change from baseline in postoperative acuity at Months 1, 3, 6, 9, and 12 and postoperative complications. RESULTS: Fifteen consecutive eyes of 13 patients who underwent surgery for massive SRH were included. Procedures performed on initial surgery included subretinal instillation of 25 MUg/0.1 mL tissue plasminogen activator (15 of 15), gas tamponade (12 of 15), oil tamponade (3 of 15), 180 degrees or greater retinotomy (4 of 15), and/or cataract extraction (2 of 15). Patients were followed for a median of 20 months (range, 3-66 months). The median visual acuity at baseline and postoperative Month 1 was hand motions but improved to counting fingers at postoperative Months 3 (P = 0.04), 6 (P = 0.04), 9 (P = 0.04), and 12 (P = 0.10). Of the 15 eyes, 9 required at least 1 additional procedure for an indication of hyphema and/or vitreous hemorrhage (n = 6), retinal detachment (n = 2), glaucoma (n = 1), cataract (n = 1), and aphakia (n = 1). At the time of the onset of SRH, 5 of 13 patients were anticoagulated with warfarin (4 patients) or clopidogrel (1 patient), and 1 was diagnosed with a coagulopathy, factor XI deficiency. CONCLUSION: Massive SRH related to age related macular degeneration has a grave prognosis. Risk factors may include anticoagulation and coagulopathy. Limitations of the study include its retrospective nature, small sample size, imprecision in acuity measurements below 20/400, and lack of a control group. In this series, surgical intervention was associated with a modest improvement in median visual acuity up to 1 year postoperatively. PMID- 20856173 TI - The mucus layer is critical in protecting against ischemia-reperfusion-mediated gut injury and in the restitution of gut barrier function. AB - It is well documented that the gut injury plays a critical role in the development of systemic inflammation and distant organ injury in conditions associated with splanchnic ischemia. Consequently, understanding the mechanisms leading to gut injury is important. In this context, recent work suggests a protective role for the intestinal mucus layer and an injury-inducing role for luminal pancreatic proteases. Thus, we explored the role of the mucus layer in gut barrier function by observing how the removal of the mucus layer affects ischemia-reperfusion-mediated gut injury in rats as well as the potential role of luminal pancreatic proteases in the pathogenesis of gut injury. Ischemia was induced by the ligation of blood vessels to segments of the ileum for 45 min, followed by up to 3 h of reperfusion. The ileal segments were divided into five groups. These included a nonischemic control, ischemic segments exposed to saline, the mucolytic N-acetylcysteine (NAC), pancreatic proteases, or NAC + pancreatic proteases. Changes in gut barrier function were assessed by the permeation of fluorescein isothiocyanate dextran (molecular weight, 4,000 d) in ileal everted sacs. Gut injury was measured morphologically and by the luminal content of protein, DNA, and hemoglobin. The mucus layer was assessed functionally by measuring its hydrophobicity and morphologically. Gut barrier function was promptly and effectively reestablished during reperfusion, which was accompanied by the restoration of the mucus layer. In contrast, treatment of the gut with the mucolytic NAC for 10 min during ischemia resulted in a failure of mucus restitution and further increases in gut permeability and injury. The presence of digestive proteases by themselves did not exacerbate gut injury, but in combination with NAC, they caused an even greater increase in gut injury and permeability. These results suggest that the mucus layer not only serves as a barrier between the luminal contents and gut surface epithelia, but also plays a critical role in the maintenance and restitution of gut barrier function. PMID- 20856174 TI - Interferon regulatory factor 1 mediates acetylation and release of high mobility group box 1 from hepatocytes during murine liver ischemia-reperfusion injury. AB - Damage-associated molecular patterns (DAMPs) initiate inflammatory pathways that are common to both sterile and infectious processes. The DAMP, high-mobility group box 1 (HMGB1), and the transcription factor, interferon regulatory factor 1 (IRF-1), have been independently associated as key players in ischemia reperfusion (I/R) injury. Our study demonstrates that IRF-1 contributes to hepatocellular release of HMGB1 and further that IRF-1 is a necessary component of HMGB1 release in response to hypoxia or after liver I/R. We also link the nuclear upregulation of IRF-1 to the presence of functional Toll-like receptor 4 (TLR4), a pattern recognition receptor also important in sterile and infectious processes. Using IRF-1 chimeric mice, we show that IRF-1 upregulation in hepatic parenchymal cells, and not in the bone marrow-derived immune cells, is responsible for HMGB1 release during ischemic liver injury. Finally, our study also demonstrates a role for IRF-1 in modulating the acetylation status and subsequent release of HMGB1 through histone acetyltransferases. We found that serum HMGB1 is acetylated after liver I/R and that this process was dependent on IRF-1. Additionally, liver I/R induced a direct association of IRF-1 and the nuclear histone acetyltransferase enzyme p300. Together, these findings suggest that I/R-induced release of acetylated HMGB1 is a process that is dependent on TLR4-mediated upregulation of IRF-1. PMID- 20856175 TI - Low hemoglobin levels during normovolemia are associated with electrocardiographic changes in pigs. AB - We studied whether low hemoglobin concentrations during normovolemia change the myocardial electrical current (electrocardiogram) in a pig model. Normovolemic anemia was achieved by stepwise replacing blood with colloids (hydroxyethyl starch 6%). We measured the length of the PQ-, QT-, QTc, and the ST interval as well as the amplitude of the Q wave and T wave at hemoglobin concentrations of 9.5, 8.0, 5.5, 3.8, and 3.3 g.dL. Normovolemic anemia is accompanied by a gradual prolongation of the QT and QTc interval and a reduction in the amplitude of the T wave. The QRS complex is partly diminished in amplitude. Results were verified performing a time-frequency analysis on single heartbeats. During severe anemia and normovolemia, electrocardiographic changes can be detected. Further investigations are warranted to elucidate whether these changes indicate myocardial hypoxia. PMID- 20856176 TI - Silica exposure and silicosis: action is needed now. PMID- 20856177 TI - Ventricular tachycardia and cardiac arrest during nasogastric tube insertion. PMID- 20856178 TI - Intrahepatic expansion of amebic liver abscess can also generate life-threatening complications. PMID- 20856179 TI - Relationship of the intensity of Helicobacter pylori and severity of inflammation with beta-2 microglobulin levels in serum according to the updated Sydney System. AB - OBJECTIVE: Helicobacter pylori (HP) is a cause of chronic gastritis. Beta-2 microglobulin has been used as a simple inflammatory indicator in some diseases. We investigate the usability of beta-2 microglobulin as a simple marker that may reflect the severity of inflammation and intensity of HP in gastric mucosa. MATERIALS AND METHODS: A total of 114 patients was included in the study, who applied to an outpatient gastroenterology clinic with complaint of dyspepsia. Serum beta-2 microglobulin levels were evaluated in 109 patients. Esophagogastroduodenoscopy was performed on patients included in the study, and histological analysis was performed by obtaining two specimens from each of antrum, corpus, and incisura angularis. All specimens were evaluated according to the updated Sydney System. RESULTS: No statistically significant result was found between serum beta-2 microglobulin levels and the intensity of HP and the severity of inflammation of gastric mucosa. However, it was observed that the serum beta-2 microglobulin level in specimens taken from corpus was found to be higher in patients with moderate-severe HP intensities compared to those with lower HP intensities. CONCLUSIONS: Although HP is the cause of the chronic active gastritis characterized with the infiltration of lymphocytes, plasma cells, and neutrophils, it is accompanied by local involvement apart from diseases with a course of systemic involvement. We suggest that the serum beta-2 microglobulin level cannot be used as a simple marker of HP intensity and severity of inflammation in gastric endoscopic biopsies. PMID- 20856180 TI - Efficacy and safety of sodium phosphate for colon cleansing in type 2 diabetes mellitus. AB - OBJECTIVES: The need for colonoscopy is common among diabetic patients. However, there are no standards per se for bowel preparation in patients with type 2 diabetes. In this study, we evaluated the efficacy, safety, and tolerability of sodium phosphate (NaP), and the quality of bowel cleansing in relation to glycemic control and late complications. METHODS: A total of 50 consecutive type 2 diabetic patients and 50 non-diabetic patients underwent bowel preparation by NaP. Fasting blood glucose, sodium (Na), potassium (K), calcium (Ca), phosphorus (P), magnesium, and creatinine levels were measured on the procedure day. Patients were given a tolerability questionnaire regarding symptoms. RESULTS: With regard to bowel preparation quality, optimal bowel cleansing was achieved in 35 (70%) diabetic and 47 (94%) non-diabetic patients (P = 0.002). Abdominal pain or discomfort during and an hour after the procedure was similar in both groups (P >0.05). The changes in Na, K, Ca, P and creatinine levels after NaP use did not reach statistical significance between the groups (P >0.05). In the diabetic patients, there was a significant correlation between the quality of bowel cleansing and mean age, duration of diabetes mellitus, level of hemoglobin A1c (HbA1c), fasting blood glucose level, and diabetic late complications (P <0.05). CONCLUSION: These data suggest that NaP is safe and tolerable in diabetic patients, but the quality of bowel cleansing is worse than in non-diabetic patients. These observations support the concept that the quality of bowel cleansing in those with type 2 diabetes is closely related to the duration and regulation of the disease and the presence of late complications. PMID- 20856181 TI - Curbing readmission rates: an uphill task. PMID- 20856182 TI - Malignant Narcissism: from fairy tales to harsh reality. AB - INTRODUCTION: Malignant Narcissism has been recognized as a serious condition but it has been largely ignored in psychiatric literature and research. In order to bring this subject to the attention of mental health professionals, this paper presents a contemporary synthesis of the biopsychosocial dynamics and recommendations for treatment of Malignant Narcissism. METHODS: We reviewed the literature on Malignant Narcissism which was sparse. It was first described in psychiatry by Otto Kernberg in 1984. There have been few contributions to the literature since that time. We discovered that the syndrome of Malignant Narcissism was expressed in fairy tales as a part of the collective unconscious long before it was recognized by psychiatry. We searched for prominent malignant narcissists in recent history. We reviewed the literature on treatment and developed categories for family assessment. RESULTS: Malignant Narcissism is described as a core Narcissistic personality disorder, antisocial behavior, ego syntonic sadism, and a paranoid orientation. There is no structured interview or self-report measure that identifies Malignant Narcissism and this interferes with research, clinical diagnosis and treatment. This paper presents a synthesis of current knowledge about Malignant Narcissism and proposes a foundation for treatment. CONCLUSIONS: Malignant Narcissism is a severe personality disorder that has devastating consequences for the family and society. It requires attention within the discipline of psychiatry and the social science community. We recommend treatment in a therapeutic community and a program of prevention that is focused on psychoeducation, not only in mental health professionals, but in the wider social community. PMID- 20856183 TI - Deinstitutionalization in Europe: two recent examples from Germany and Hungary. AB - Deinstitutionalization has made possible the development of modern community psychiatric services, however radical decrease in the number of hospital beds may result in a reduction in the overall standard of psychiatric care and disruptions in service delivery. The authors present an example of deinstitutionalisation in Hungary, which led to serious difficulties in the provision of healthcare in the field of psychiatry, contrasted with a case from Germany serving as an example of an alternative solution. PMID- 20856184 TI - Efficacy and tolerability of venlafaxine extended release in patients with major depressive disorder. AB - BACKGROUND: In this study we wanted to determine the efficacy and tolerability of venlafaxine extended release in patients with major depressive disorder. SUBJECTS AND METHODS: 161 patients with major depressive disorder were included in an open label, multicentre clinical study. All patients were treated with venlafaxine extended release in flexible doses ranging from 75 to 325 mg daily over an 8-week period. Efficacy measurements included the 17-item Hamilton Depression Scale, the Clinical Global Impression-Improvement scale (CGI-I), the Severity of Illness scale (CGI-S), and the Depression and Somatic Symptom Scale (DSSS). All scales were administered at baseline and at weeks 2, 4 and 8. RESULTS: A total of 148 (91.2%) patients completed the study. After 8 weeks of treatment with venlafaxine extended release, response and remission rates were 93% and 45% respectively. At the end of the study, 52.7% of patients were rated on CGI-S with 2 or 1 (not ill/mildly ill) and on CGI-I 81.1% of patients were rated by the physician as much/very much improved. The severity of somatic symptoms such as headache, back pain, chest pain, tenderness of more than a half of body muscles, and fatigue or loss of energy decreased towards the end of the study (p<.0001). Adverse events caused discontinuation in 4.7% of patients. No significant changes of body mass (p=.237), Body Mass Index (p=.281), and heart rate (p=.840) were present, but systolic and diastolic blood pressure significantly decreased (p<.0001) towards the end of the study. CONCLUSION: The data from this study indicate that venlafaxine XR is an efficient and safe therapeutic option for patients with major depressive disorder, with the additional effect of reducing associated painful physical symptoms. PMID- 20856185 TI - Irritable bowel syndrome, anxiety, depression and personality characteristics. AB - BACKGROUND: Numerous studies have suggested that 54%-100% of patients with IBS may have associated psychiatric illness and personality pathology. This transversal controlled study was realized in order to evaluate anxiety and depression levels, as well as the personality characteristics of patients with IBS and to compare the results obtained with patients with episodes of depression and healthy individuals. SUBJECTS AND METHODS: The experimental group consisted of 30 IBS patients, while two control groups consisted of the same number of inpatients with episodes of depression and healthy individuals from the general population. There were equal number of men and women in the study sample and all subjects were aged between 25 to 65 years. Standard psychometric instruments employed included Hamilton anxiety scale, Zung depression scale, Hamilton depression scale, Minnesota Multiphasic Personality Inventory (MMPI), Eysenck Perosonality Inventory (EPI). RESULTS: The average Hamilton and Zung depression scores were significantly higher in patients with depressive episodes compared with the IBS patients, while the mentioned scores among them were also significantly higher compared with the healthy controls. There were no significant differences between IBS and the group with depressive episodes in the average Hamilton anxiety levels, EPI neuroticism and extraversion levels and MMPI neurotic scales levels (Hs, D, and Hy). The significant differences were observed comparing the IBS patients to healthy individuals. CONCLUSION: The patients suffering from irritable bowel syndrome who asked for medical help (consulters) because of their intestinal symptoms, presented emotional problems such as depression and anxiety and expressed neurotic personality characteristics. PMID- 20856186 TI - Differences in predictors of sexual satisfaction and in sexual satisfaction between female and male university students in Slovenia. AB - BACKGROUND: This paper reports on some factors correlated with sexual satisfaction and on differences between female and male university students. SUBJECTS AND METHODS: A convenience sample of 174 female and 74 male Slovene undergraduate university students was studied. RESULTS: It has been found that an increased frequency of sexual interaction and agreeableness in sexual interactions increase sexual satisfaction, while a desired frequency of sexual interactions and estimation of a partner's agreeableness in sexual interactions decrease sexual satisfaction. Sex was not found to be an important predictor of sexual satisfaction. Male students' agreeableness in sexual interaction is significantly higher than that of female students. Male students are significantly more conservative in their attitudes towards abortion and concerning sexual myths. Female students are less satisfied with their sexual life than their male colleagues. CONCLUSION: In conclusion, the findings of the study demonstrate that there are some differences in problems with sexuality between both sexes. Female students are in general more dissatisfied. On the basis of the findings of the present research it should be possible to plan interventions for increasing satisfaction with sexuality, specifically for each gender. PMID- 20856187 TI - Impact of chronic Posttraumatic Stress Disorder on the Quality of life of war survivors. AB - BACKGROUND: Research data from studies of functional neuroanatomy and neurochemistry indicate various dysfunctions in certain areas of the brain in individuals who suffer from chronic Posttraumatic Stress Disorder. These abnormalities are involved in the evolution of symptoms of PTSD, deterioration of cognitive functions and decreased quality of life of the survivors. The intensity of these symptoms is in direct correlation with the degree of dysfunction in the central nervous system. The aim of our study, was to evaluate the subjective perception of the Quality of life in subjects suffering from chronic PTSD and to compare prior to treatment results to results three and six months after receiving therapy, as well as to analyze whether perception of the Quality of life change related to treatment. The study was conducted at the Psychiatric Clinic of the Sarajevo University Clinical Center. SUBJECTS AND METHODS: The sample consisted of 100 male persons, with war trauma experiences, whose age range was between 35 and 60 years, who were seeking treatment at the Psychiatric Clinic, University of Sarajevo Clinical Center and met the criteria for the diagnosis of chronic PTSD (Posttraumatic Stress Disorder) according to ICD-10. (International Statistical Classification of Diseases and Related Health Problems, 10th Revision). The exclusion criterion was prior psychiatric illness (traumatization before the war) and less than 8 years of education. All subjects received out-patient treatment. Their treatment involved psychopharmacological and psychotherapeutic therapy. The subjects were assessed using the following instruments: Sociodemographic Questionnaire designed by the authors for registering the social and demographic characteristics of the subjects (age, years of education, current employment, and socioeconomic status) and Manchester Quality of Life Scale (MANSA) as a self-report scale. The subjects were assessed prior to treatment, and three and six months after beginning the treatment (follow-up). RESULTS: There was an increase in the mean values of subjective perception of Quality of Life between the first (3.2352), second (3.4447), and third test (3.6090). Differences between these mean values were not statistically significant between the first and second test, but significant between the second and third test. Also differences between sociodemographic characteristics prior to treatment and during six month follow-up were not statistically significant. A significant increase has been noted in the number of contacts with close friends between the first, second and third test. Also, we recorded a decrease in pertaining aggressive and criminal behavior between the three tests. CONCLUSION: The results of our study indicate that subjects who are suffering from chronic PTSD have a lower subjective perception of their quality of life. Combined psychopharmacological and psychotherapeutic treatment over a period of six months lead to improvement in the perception of quality of life. This may indicate the need for longer treatment of individuals suffering from chronic PTSD. A significant increase has been noted in the number of contacts with close friends between the first, second and third test, reflecting positive treatment effects on everyday life functioning and coping skills. PMID- 20856188 TI - Parental type of personality, negative affectivity and family stressful events in children with cancer. AB - OBJECTIVE: Psychological interactions between parents,children and social environment are very important for childhood health. The type of personality and stressful events are probably also cancer risk factors. We investigated personality types A/B and D (negative affectivity and social inhibition) in parents of children with cancer (PCC), as well as social environmental factors, and family / children's stressful events before the appearance of cancer. SUBJECTS AND METHODS: Bortner Type A Scale for evaluating parental type A/B personality, and 14 question personality test (DS14) for parental type D personality (negative affectivity and social inhibition score) were performed. Questionnaire eligible information about stressful events and social environmental factors in children with cancer (CC) were analyzed. RESULTS: Analyzing 127 PCC and 136 parents of healthy children (PHC) we found no significant differences in A/B type personality and social inhibition. There was significant difference in negative affectivity. PCC had more negative affectivity than PHC. We found more stressful events before cancer appearance in the families of children with cancer (FCC) than in healthy families (FHC), and more children's stressful events in CC then in healthy ones (HC). There were more quarrels in FCC, while CC were more "easy good-mannered children" than HC. CONCLUSIONS: Our results support the hypothesis that stress is a cancer risk factor and the idea that impaired parental functioning may be a mechanism linking family stress with the aetiology of cancer. PMID- 20856189 TI - Adverse drug reactions of psycopharmacs. AB - BACKGROUND: The objective of analysis of ADRs caused by drugs that pertain to the ATC group N (nervous system), as reported to the Croatian Agency for Medicinal Products and Medical Devices for the period from March 2005 to December 2008, was to examine the types of ADRs collected in said period, the profile of reporters and the possible impacts this could have on prescribing this group of medicinal products in the future. SUBJECTS AND METHODS: A retrospective observational study of ADRs was performed. Drugs causing ADRs were grouped according to the ATC drug classification, and subsequently entered into a database. Data were analyzed in respect of total number, gender, age, type, seriousness, expectedness, outcome, system organ class, suspected drug and reporter. RESULTS: The findings showed that 15% of all reported ADRs were caused by drugs from the ATC group N. 60% of these were caused by drugs belonging to the ATC subgroups N05 (psycholeptics) and N06A (antidepressants). A significant increase in the percentage of serious ADRs in the examined groups of medicinal products was observed. Analysis of expectedness showed that the share of unexpected ADRs is very high. CONCLUSION: The distribution of reporters is not satisfactory. The Agency, as regulatory authority, cannot undertake certain measures to improve the safe use of medicinal products without having reports. Only reporting of ADRs can result in changes to benefit all patient populations. Our joint aim should be avoiding a great number of ADRs and maintaining overall safe use of medicinal products. PMID- 20856190 TI - Parkinson's disease dementia: clinical correlates of brain spect perfusion and treatment. AB - BACKGROUND: The main clinical feature of dementia in Parkinson's disease is a dysexecutive syndrome. The neuropathology of PD dementia (PDD) is likely multifactorial and affects several neuronal populations. There is evidence that Parkinson's disease dementia is associated with a cholinergic deficit, supporting the therapeutic role of cholinesterase inhibitors, which are already first-line agents in the treatment of Alzheimer's disease. The paper includes short report on a pilot study with description of cognitive and imaging profiles in patients with mild to moderate stage of Parkinson disease dementia (PDD). SUBJECTS AND METHODS: A random sample of 16 patients with clinical diagnostic criteria for probable PDD was included in the study. Patients were characterized with mild to moderate cognitive decline slightly depressive mood and moderate motor performance. Brain perfusion [(99m)Tc]ECD / SPECT and structural MRI with emphasis on evaluation of the degree of cortical atrophy and the medial temporal atrophy index was performed. All patients had detailed neuropsychological evaluation using a "cognitive process approach". Neuropsychological data were correlated voxel-wise with normalized brain perfusion images, creating whole brain correlation maps. CONCLUSIONS: Previously reported generalized cognitive impairment in PDD with predominant executive, visouspatial and attentional deficits was confirmed. Performance on specific cognitive measures was correlated with perfusion brain SPECT findings. It could be speculated that different pathological mechanisms underlie widespread significant brain perfusion decrements in temporal, parietal and frontal regions. PMID- 20856191 TI - The bipolar spectrum: do we need a single algorithm for affective disorders? PMID- 20856192 TI - [Somatoform pain disorder - overview]. AB - Patients with severe and disabling pain and bodily distress which cannot be explained by underlying organic pathology are common in all levels of health care and are typically difficult to treat for physicians as well as for mental health specialists. Beside pain in different locations, not fully explained by specific somatic pathology, specific functional complaints such as dizziness, fatigue or vegetative disorders are common. A great proportion of patients with somatoform pain complain of comorbid depressive or anxiety disorder. Psychodynamic interpersonal psychotherapy particularly emphasises interpersonal processes as well as disturbance of body awareness and self regulation already in childhood. Cognitive-behavioral models focus on the phenomenon of somatosensory amplification. The patients do have a strong believe in an underlying somatic illness, therefore seeking for further diagnostic and somatic therapy. This frequently leads to multiple but ineffective therapeutic attempts in the field of somatic medicine resulting in frustration of the patients and a difficult doctor patient-relationship. General therapeutic recommendations include an active therapeutic approach with paying tribute for the patients' suffering and giving support to cope with the pain. A specific psychodynamic approach furthermore focuses on improvement of affect differentiation and the interaction of somatoform pain and interpersonal relationships. PMID- 20856193 TI - [A chronic pain patient: modern diagnosis and concept of therapy]. AB - Approximately 80 per cent of primary care patients seek their physician's attention due to pain. A fifth of the population suffers from chronic pain with medium to high intensity, and longer than 3 months. Especially those patients are treated insufficiently when only non-opioids and opioids are applied. Therefore it is necessary to tailor pain therapy by using an interdisciplinary, multimodal treatment regimen. This article presents a holistic concept to chronic pain treatment by using the five columns of pain therapy. Based on the bio-psycho social approach, pharmaceutical, complimentary (first column), physio- and psychotherapeutic (2(nd) and 3(rd) column), social and invasive interventions (4(th) and 5(th) column) have to be considered. The 1(st) column includes the WHO ladder, in chronic pain patients with a large focus on co-analgesics like antidepressants or antiepileptics. Based on the individual history and factors achieved from the bio-psycho-social diagnosis, components of these 5 therapeutic are selected, always in agreement with the patient, and put together to one interdisciplinary therapeutic concept. PMID- 20856194 TI - Pain and emotional processing in psychological trauma. AB - Extreme psychological and physical traumas cause dramatic symptom patterns which are insufficiently described by the psychiatric diagnostic criteria of post traumatic stress disorders (PTSD). Additionally, due to the neurobiological proximity and similarity of processing mechanisms of physical and psychological pain stimulation and extremely negative emotions, the patients often suffer from persistent pains even after the somatic healing process is completed. Epidemiological studies confirm the joint occurrence of pain and PTSD. The close relationship and the etiological and behavioral similarities of both disorders have led to the development of joined vulnerability and mutual maintenance models. The particular suffering of patients with PTSD due to chronic pain necessitates pain-therapeutic interventions. On the other hand, in chronic pain patients, the etiological role of severe traumas should be considered. PMID- 20856195 TI - [Sport and movement in chronic pain disorders]. AB - Humans were evolved to move. We need physical movement to remain healthy and to maintain performance. Pain limits our inborn ability to move and express ourselves. As we move less, the pain grows, immobilizing us further in a vicious cycle. Pain-including psychological pain-is experienced through the body, manifesting in physical postures, tensions, breathing patterns, etc. A holistic movement programme incorporates both physiological and psychological dimensions of the experience of pain. Our understanding of pain must take into account both the physical regulation of the body as well as the regulation of consciousness. Sport and regular movement at appropriate levels of intensity create a positive body sense and deepened body awareness. This is the basis for analyzing, managing, and transforming pain. In the treatment of chronic pain by means of therapeutic sport, functional exercise goals are complemented by awareness practices and an active attitude towards pain. PMID- 20856197 TI - PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis. AB - We recently identified activation of phosphatidylinositol 3'-kinase (PI3K)/Akt as a novel predictor of poor outcome in neuroblastoma. Here, we investigated the effect of small-molecule PI3K inhibitors on chemosensitivity. We provide first evidence that PI3K inhibitors, for example PI103, synergize with various chemotherapeutics (Doxorubicin, Etoposide, Topotecan, Cisplatin, Vincristine and Taxol) to trigger apoptosis in neuroblastoma cells (combination index: high synergy). Mechanistic studies reveal that PI103 cooperates with Doxorubicin to reduce Mcl-1 expression and Bim(EL) phosphorylation and to upregulate Noxa and Bim(EL) levels. This shifted ratio of pro- and antiapoptotic Bcl-2 proteins results in increased Bax/Bak conformational change, loss of mitochondrial membrane potential, cytochrome c release, caspase activation and caspase dependent apoptosis. Although Mcl-1 knockdown enhances Doxorubicin- and PI103 induced apoptosis, silencing of Noxa, Bax/Bak or p53 reduces apoptosis, underscoring the functional relevance of the Doxorubicin- and PI103-mediated modulation of these proteins for chemosensitization. Bcl-2 overexpression inhibits Bax activation, mitochondrial perturbations, cleavage of caspases and Bid, and apoptosis, confirming the central role of the mitochondrial pathway for chemosensitization. Interestingly, the broad-range caspase inhibitor zVAD.fmk does not interfere with Bax activation or mitochondrial outer membrane permeabilization, whereas it blocks caspase activation and apoptosis, thus placing mitochondrial events upstream of caspase activation. Importantly, PI103 and Doxorubicin cooperate to induce apoptosis and to suppress tumor growth in patients' derived primary neuroblastoma cells and in an in vivo neuroblastoma model, underlining the clinical relevance of the results. Thus, targeting PI3K presents a novel and promising strategy to sensitize neuroblastoma cells for chemotherapy-induced apoptosis, which has important implications for the development of targeted therapies for neuroblastoma. PMID- 20856198 TI - Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis. AB - Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out of 18 melanoma cell lines remained resistant against treatment with the death ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due to incomplete processing of caspase-3 into catalytically inactive p21 by binding of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP). Co-irradiation with sub-lethal ultraviolet (UV) B caused depletion of XIAP resulting in synergistic sensitization of all but two melanoma cell lines to TRAIL. We show here the XIAP depletion to essentially require initial caspase-mediated cleavage, which promotes proteasomal degradation of XIAP. Utilizing specific caspase inhibitors and small interfering RNA-mediated knockdown, we further identified caspase-3 to be responsible for performing the initial cleavage of XIAP after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization in response to co treatment with TRAIL and UVB, which directs the release of XIAP antagonizing factors including Smac. Distraction of XIAP consequently liberates caspase-3 to autocatalytically process into active p17. Activated caspase-3 cleaves XIAP and further enhances its activation in a positive regulatory feedback loop. The molecular mechanism discovered here appears to have broader implications, because cleavage of XIAP was also shown to accompany cisplatin-induced sensitization of melanoma cells to TRAIL. PMID- 20856196 TI - Human AP endonuclease (APE1/Ref-1) and its acetylation regulate YB-1-p300 recruitment and RNA polymerase II loading in the drug-induced activation of multidrug resistance gene MDR1. AB - The overexpression of human apurinic/apyrimidinic (AP) endonuclease 1 (APE1/Ref 1), a key enzyme in the DNA base excision repair (BER) pathway, is often associated with tumor cell resistance to various anticancer drugs. In this study, we examined the molecular basis of transcriptional regulatory (nonrepair) function of APE1 in promoting resistance to certain types of drugs. We have recently shown that APE1 stably interacts with Y-box-binding protein 1 (YB-1), and acts as its coactivator for the expression of multidrug resistance gene MDR1, thereby causing drug resistance. In this study, we show, to the best of our knowledge, for the first time that APE1 is stably associated with the basic transcription factor RNA polymerase II (RNA pol II) and the coactivator p300 on the endogenous MDR1 promoter. The depletion of APE1 significantly reduces YB-1 p300 recruitment to the promoter, resulting in reduced RNA pol II loading. Drug induced APE1 acetylation, which is mediated by p300, enhances formation of acetylated APE1 (AcAPE1)-YB-1-p300 complex on the MDR1 promoter. Enhanced recruitment of this complex increases MDR1 promoter-dependent luciferase activity and its endogenous expression. Using APE1-downregulated cells and cells overexpressing wild-type APE1 or its nonacetylable mutant, we have demonstrated that the loss of APE1's acetylation impaired MDR1 activation and sensitizes the cells to cisplatin or etoposide. We have thus established the basis for APE1's acetylation-dependent regulatory function in inducing MDR1-mediated drug resistance. PMID- 20856199 TI - Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis. AB - Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxia-inducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-alpha protein stability regulating prolyl-4 hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF 2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer. PMID- 20856201 TI - Knockdown of splicing factor SRp20 causes apoptosis in ovarian cancer cells and its expression is associated with malignancy of epithelial ovarian cancer. AB - Our previous study revealed that two splicing factors, polypyrimidine tract binding protein (PTB) and SRp20, were upregulated in epithelial ovarian cancer (EOC) and knockdown of PTB expression inhibited ovarian tumor cell growth and transformation properties. In this report, we show that knockdown of SRp20 expression in ovarian cancer cells also causes substantial inhibition of tumor cell growth and colony formation in soft agar and the extent of such inhibition appeared to correlate with the extent of suppression of SRp20. Massive knockdown of SRp20 expression triggered remarkable apoptosis in these cells. These results suggest that overexpression of SRp20 is required for ovarian tumor cell growth and survival. Immunohistochemical staining for PTB and SRp20 of two specialized tissue microarrays, one containing benign ovarian tumors, borderline/low malignant potential (LMP) ovarian tumors as well as invasive EOC and the other containing invasive EOC ranging from stage I to stage IV disease, reveals that PTB and SRp20 are both expressed differentially between benign tumors and invasive EOC, and between borderline/LMP tumors and invasive EOC. There were more all-negative or mixed staining cases (at least two evaluable section cores per case) in benign tumors than in invasive EOC, whereas there were more all-positive staining cases in invasive EOC than in the other two disease classifications. Among invasive EOC, the majority of cases were stained all positive for both PTB and SRp20, and there were no significant differences in average staining or frequency of positive cancer cells between any of the tumor stages. Therefore, the expression of PTB and SRp20 is associated with malignancy of ovarian tumors but not with stage of invasive EOC. PMID- 20856200 TI - Vimentin is a novel AKT1 target mediating motility and invasion. AB - The PI3K/AKT signaling pathway is aberrant in a wide variety of cancers. Downstream effectors of AKT are involved in survival, growth and metabolic related pathways. In contrast, contradictory data relating to AKT effects on cell motility and invasion, crucial prometastatic processes, have been reported pointing to a potential cell type and isoform type-specific AKT-driven function. By implication, study of AKT signaling should optimally be conducted in an appropriate intracellular environment. Prognosis in soft-tissue sarcoma (STS), the aggressive malignancies of mesenchymal origin, is poor, reflecting our modest ability to control metastasis, an effort hampered by lack of insight into molecular mechanisms driving STS progression and dissemination. We examined the impact of the cancer progression-relevant AKT pathway on the mesenchymal tumor cell internal milieu. We demonstrate that AKT1 activation induces STS cell motility and invasiveness at least partially through a novel interaction with the intermediate filament vimentin (Vim). The binding of AKT (tail region) to Vim (head region) results in Vim Ser39 phosphorylation enhancing the ability of Vim to induce motility and invasion while protecting Vim from caspase-induced proteolysis. Moreover, vimentin phosphorylation was shown to enhance tumor and metastasis growth in vivo. Insights into this mesenchymal-related molecular mechanism may facilitate the development of critically lacking therapeutic options for these devastating malignancies. PMID- 20856202 TI - Sustained inhibition of PKCalpha reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. AB - Metastasis is the major reason for breast cancer-related deaths. Although there is a host of indirect evidence for a role of protein kinase C (PKC) alpha in primary breast cancer growth, its role in the molecular pathways leading to metastasis has not been studied comprehensively. By treating mice with alphaV5-3, a novel peptide inhibitor selective for PKCalpha, we were able to determine how PKCalpha regulates metastasis of mammary cancer cells using a syngeneic and orthotopic model. The primary tumor growth was not affected by alphaV5-3 treatment. However, the mortality rate was reduced and metastasis in the lung decreased by more than 90% in the alphaV5-3-treated mice relative to the control treated mice. alphaV5-3 treatment reduced intravasation by reducing matrix metalloproteinase-9 activities. alphaV5-3 treatment also reduced lung seeding of tumor cells and decreased cell migration, effects that were accompanied by a reduction in nuclear factor kappa B activity and cell surface levels of the CXCL12 receptor, CXCR4. alphaV5-3 treatment caused no apparent toxicity in non tumor-bearing naive mice. Rather, inhibiting PKCalpha protected against liver damage and increased the number of immune cells in tumor-bearing mice. Importantly, alphaV5-3 showed superior efficacy relative to anti-CXCR4 antibody in reducing metastasis in vivo. Together, these data show that pharmacological inhibition of PKCalpha effectively reduces mammary cancer metastasis by targeting intravasation and lung seeding steps in the metastatic process and suggest that PKCalpha-specific inhibitors, such as alphaV5-3, can be used to study the mechanistic roles of PKCalpha specifically and may provide a safe and effective treatment for the prevention of lung metastasis of breast cancer patients. PMID- 20856203 TI - Critical role of endoglin in tumor cell plasticity of Ewing sarcoma and melanoma. AB - Tumor cell plasticity enables certain types of highly malignant tumor cells to dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which enables them to 'adapt' during tumor progression and escape conventional therapeutic strategies. This plastic phenotype of aggressive cancer cells enables them to express endothelial cell-specific markers and form tube-like structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-beta co-receptor endoglin, an endothelial cell marker, is expressed by tumor cells and its expression correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma and melanoma. Moreover, endoglin expression was significantly associated with worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells interferes with tumor cell plasticity and reduces invasiveness and anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we provide evidence that endoglin, while interfering with TGF-beta signaling, is required for efficient bone morphogenetic protein, integrin, focal adhesion kinase and phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The present study delineates an important role of endoglin in tumor cell plasticity and progression of aggressive tumors. PMID- 20856204 TI - Harnessing the immune response to treat cancer. AB - It is well established that the immune system has the capacity to attack malignant cells. During malignant transformation cells acquire numerous molecular and biochemical changes that render them potentially vulnerable to immune cells. Yet it is self-evident that a growing tumour has managed to evade these host defence mechanisms. The exact ways in which the immune system interacts with tumour cells and how cancers are able to escape immunological eradication have only recently started to be fully elucidated. Understanding the relationship between the tumour and the anti-tumour immune response and how this can be altered with conventional treatments and immune-targeted therapies is crucial to developing new treatments for patients with cancer. In this review, focusing on the anti-tumour T-cell response, we summarize our understanding of how tumours, cancer treatments and the immune system interact, how tumours evade the immune response and how this process could be manipulated for the benefit of patients with cancer. PMID- 20856205 TI - RBP-Jkappa-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice. AB - The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jkappa-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/ degrees transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP Jkappa, as it is rescued in mice lacking RBP-Jkappa in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jkappa. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells. PMID- 20856207 TI - The RNA-binding protein La contributes to cell proliferation and CCND1 expression. AB - The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA) mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors. PMID- 20856206 TI - Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active beta-catenin. AB - Constitutive activation of Wnt/beta-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the beta-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the DeltaS45 activating mutation in one of the alleles of beta-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced beta-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased [(3)H]-thymidine (in vitro) or BrdU (in vivo) incorporation, clonogenesis assays, cell cycle analysis and magnetic resonance imaging in living mice. Additionally, V3Nter switches off the beta-catenin target gene expression signature in vivo. Moreover, experiments with beta-catenin allele targeted cells showed that the DeltaS45 beta-catenin allele hampers, but does not abrogate, inhibition of Wnt signaling by SFRP-1 or by the SFRP-like frizzled domain. Finally, neither SFRP-1 nor V3Nter affect beta-catenin signaling in SW480 cells carrying nonfunctional Adenomatous polyposis coli. Thus, SFRP-1 and the SFRP-like molecule V3Nter can inhibit tumor growth of beta-catenin-activated tumor cells in vivo. PMID- 20856208 TI - Successful second haploidentical SCT in osteopetrosis. PMID- 20856209 TI - Focal segmental glomerulosclerosis: a very unusual complication of allogeneic hematopoietic cell transplantation (HCT). PMID- 20856210 TI - Allogeneic hematopoietic cell transplantation outcomes for children with B precursor acute lymphoblastic leukemia and early or late BM relapse. AB - Large registry studies have shown superior disease-free survival (DFS) with matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo HCT) over chemotherapy alone for patients with B-precursor acute lymphoblastic leukemia (ALL) and a late BM relapse. As most of these patients will not have an MSD, the decision to pursue an unrelated allo-HCT in second remission (CR2) or await a future relapse and perform HCT in third remission (CR3) continues to be debated. Between 1990 and 2006, 41 children with relapsed B-precursor ALL received a myeloablative allo-HCT at the University of Minnesota. Graft sources consisted of matched related donor (n=11), matched unrelated donor (n=9), and unrelated umbilical cord blood (n=21). Before allo-HCT, 15 patients had an early relapse (<36 months from diagnosis) and 26 had an initial late relapse (?36 months from diagnosis). In all, 30 patients (73%) were in CR2 and 11 were in CR3 (27%) at time of allo-HCT. Five year OS/DFS were similar for patients with an early or late marrow relapse, but there was inferior DFS among late-relapse patients transplanted in CR3 compared with CR2 (30% vs 75%, P=0.04). These results suggest that allo-HCT should be pursued in children after a first marrow relapse, rather than waiting for subsequent recurrence. PMID- 20856211 TI - A suggested total size for the cord blood banks of Japan. PMID- 20856213 TI - Ball and chain. AB - The classic impact factor is outmoded. Is there an alternative for assessing both a researcher's productivity and a journal's quality? PMID- 20856212 TI - Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma. AB - Positron emission tomography (PET) in conjunction with computed tomography is a frequently used modality for staging patients with lymphoma. Utility of PET computed tomography before or early following auto-SCT has not been as rigorously evaluated. We retrospectively analyzed patients who received auto-SCT for treatment of relapsed or refractory non-Hodgkins lymphoma or Hodgkins disease between the years of 1996 and 2007. Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (pre-PET), and/or a PET scan 6-14 weeks following transplantation (post-PET) were included. A total of 90 patients were identified for analysis. The median follow-up time is 3.3 years, with a range of 0.13-12.0 years. The median PFS was 4.6 years, and median OS was 5.1 years. At the time of this analysis, 34 patients (37%) experienced disease relapse, and 25 (27%) of the patients died from disease progression. In multivariate Cox proportional hazards analysis, post-PET did not predict for outcome, pre-PET positivity predicted for decrease in PFS. In conclusion, post PET scan did not predict for PFS or OS in multivariate analysis. Positive pre-PET scan did predict for PFS as seen in previous studies, and may help identify patients who would benefit from innovative post transplant therapies. PMID- 20856214 TI - The glittering prizes. AB - The Nobel Prizes will be announced at the beginning of October. Is there a possibility that immunology might make the list? PMID- 20856215 TI - Regulation of alternative macrophage activation by chromatin remodeling. PMID- 20856216 TI - IAPP boosts islet macrophage IL-1 in type 2 diabetes. PMID- 20856217 TI - Accessory to inflammation. PMID- 20856218 TI - The innate side of TOX. PMID- 20856225 TI - Effects of calcium oxalate monohydrate crystals on expression and function of tight junction of renal tubular epithelial cells. AB - Tight junction has a crucial role in regulating paracellular transports (as a barrier) and in separating apical from basolateral compartments to maintain cell polarity (as a fence). Tight junction can be disrupted by various stimuli, including oxidative stress, pathogens and proinflammatory cytokines. However, association of defective tight junction with kidney stone pathogenesis remains unknown. We therefore examined whether calcium oxalate monohydrate (COM) crystals, which are the major crystalline composition in kidney stones, have any effects on expression and function of tight junction of polarized renal tubular epithelial cells. Western blot analysis revealed marked decrease in levels of occludin and zonula occludens-1 (ZO-1) in COM-treated polarized Madin-Darby canine kidney (MDCK) cells. Immunofluorescence staining revealed not only the decline of these tight junction proteins but also their redistribution and dissociation in COM-treated cells. Additionally, transepithelial resistance was significantly decreased, indicating impaired tight junction barrier and increased paracellular permeability in COM-treated cells. Subcellular fractionation followed by western blot analysis of Na(+)/K(+)-ATPase-alpha1 revealed that this basolateral membrane marker was also detectable in apical membrane fraction of COM-treated cells, but not in apical membrane fraction of control cells. Immunofluorescence study confirmed the translocation of Na(+)/K(+)-ATPase-alpha1 (from basolateral to apical membranes) in COM-treated cells, indicating impaired fence function of the tight junction. Moreover, dihydrorhodamine assay using flow cytometry revealed the significantly higher level of hydrogen peroxide in the COM treated cells. These data provide the first evidence to demonstrate decreased expression and defective barrier and fence functions of the tight junction of renal tubular epithelial cells exposed to COM crystals that may be fundamental for subsequent renal tubulointerstitial injury, which in turn enhances the stone pathogenesis. PMID- 20856220 TI - Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. AB - Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention. PMID- 20856226 TI - Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma. AB - Cytokeratin (CK) 19-positive hepatocellular carcinoma (HCC) has been reported to have a poor prognosis. The mechanism of the development of CK19-positive HCC remains to be studied. To clarify this, in vitro experiments were performed using human HCC cell lines (PLC-5, HepG2), and the phenotypic changes after stimulation with several growth factors were examined using quantitative reverse transcriptase PCR, western blotting, and immunofluorescence staining. In vivo experiments using human HCC specimens obtained from a total of 78 patients and clinicopathological analysis were also performed. Among the growth factors tested, epidermal growth factor (EGF) had prominent effects on inducing CK19 expression in PLC-5 and HepG2, which was accompanied by the reduced expression of alpha-fetoprotein in PLC-5. The induction of CK19 expression after EGF stimulation was accompanied by the phosphorylation of c-Jun-N-terminal kinase (JNK)/stress-activated protein kinase, which was blocked by the addition of JNK inhibitors. EGF also increased proliferative abilities and invasive properties of the HCC cell lines. In vivo, 9 (12%) of 78 HCC cases showed positive immunohistochemical staining of CK19. The extent of positive immunohistochemical signals of EGF, EGF receptor (EGFR), and JNK expression was significantly intense in CK-19-positive HCC than those of CK19-negative HCC. Clinicopathological analysis showed that CK19-positive HCC had a high incidence of portal vein invasion, extrahepatic metastasis and an early relapse, which was associated with the worsened 2-year disease free survival. These results indicate that the activation of the EGF-EGFR signaling pathway is associated with the development of CK19-positive HCC, and the EGF-induced increase in growth abilities of HCC may account for the poor prognosis of the patients. PMID- 20856228 TI - RETRACTED: Blockade of TNF-alpha signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies. AB - The aim of this study was to analyze the Furin-TNF-alpha-converting enzyme (TACE) amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-alpha-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-alpha blockade on AREG expression and TNF-alpha-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-alpha produced after anti-Ro/SSA Abs uptake via Fcgamma receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-alpha blocking and TNF-alpha gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-alpha-induced IL-6 and IL-8 secretion in SGEC treated with anti Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-alpha and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-alpha as stimulant, clarified that TNF-alpha induces IL-6 and IL 8 secretion through AREG.Laboratory Investigation advance online publication, 20 September 2010; doi:10.1038/labinvest.2010.168. PMID- 20856227 TI - Overexpression of Bcl-2 in hepatocytes protects against injury but does not attenuate fibrosis in a mouse model of chronic cholestatic liver disease. AB - The role of hepatocyte apoptosis in the physiopathology of obstructive cholestasis is still controversial. Although some data have strongly suggested that hepatocellular cholestatic injury is due to Fas-mediated hepatocyte apoptosis, some others concluded that necrosis, rather than apoptosis, represents the main type of hepatocyte death in chronic cholestasis. Moreover, it has also been suggested that the reduced liver injury observed in the absence of Fas receptor after bile duct ligation was not due to lower hepatocyte apoptosis but to the indirect role of this receptor in non-hepatocytic cells such as cholangiocytes and inflammatory cells. The aim of this work was therefore to determine whether a protection against cell death limited to hepatocytes could be sufficient to reduce liver injury and delay cholestatic fibrosis. With this purpose, we performed bile duct ligation in transgenic mice overexpressing Bcl-2 in hepatocytes and in wild-type littermates. We found that, compared with necrosis, apoptosis was negligible in this model. Our results also showed that hepatocyte Bcl-2 expression protected hepatocytes against liver injury only in the early steps of the disease. This protection was correlated with reduced mitochondrial dysfunction and lipid peroxidation. However, in contrast to Fas receptor-deficient lpr mice, fibrosis progression was not hampered and liver inflammatory response was not reduced by Bcl-2 overexpression. These results therefore comfort the hypothesis that Fas-mediated apoptotic hepatocyte pathway is not a significant contributing factor to the clinical features observed in cholestasis. Moreover, in the absence of a blunted inflammatory response in transgenic mice, Bcl-2 protection against hepatocyte mitochondrial dysfunction and lipid peroxidation was not sufficient to block fibrosis progression. PMID- 20856229 TI - De novo expression of CD44 variants in sporadic and hereditary gastric cancer. AB - CD44 is the major ubiquitously expressed cell surface receptor for hyaluronate. The CD44 gene encodes several protein isoforms due to extensive alternative splicing and post-translational modifications. Some of these CD44 variable isoforms have been foreseen as key players in malignant transformation and their expression is highly restricted and highly specific, unlike the canonical CD44 standard isoform. In this study, we aimed at dissecting the mRNA splicing pattern of CD44 in normal stomach and gastric cancer (GC) cell lines (n=9) using cloning and quantitative mRNA amplification assays. Moreover, we assessed the RNA levels and protein expression pattern of relevant splicing forms in distinct premalignant and malignant gastric lesions (sporadic (n=43) and hereditary (n=3) forms) using real-time RT-PCR and immunohistochemistry. We also explored the association of CD44 and E-cadherin expression by immunohistochemistry, as E cadherin has a pivotal functional role in GC. We established the pattern of CD44 variant forms in normal stomach and gastric malignancy. We observed that although exon v6-containing isoforms were rarely expressed in normal gastric mucosa, they became increasingly expressed both in gastric premalignant (hyperplastic polyps, complete and incomplete intestinal metaplasia, low- and high-grade dysplasia) and malignant lesions (cell lines derived from GCs, primary sporadic GCs and hereditary diffuse GCs (HDGCs)). Moreover, we verified that whenever E-cadherin expression was absent, exon v6-containing CD44 isoforms were overexpressed. The lack of expression of CD44 isoforms containing exon v6 in the surface and foveolar epithelia of normal stomach and, its de novo expression in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach, pinpoint CD44 v6-containing isoforms as potential biomarkers for early transformation of the gastric mucosa. Further, our results raise the hypothesis of using CD44v6 as a marker of early invasive intramucosal carcinoma in HDGC CDH1 mutation carriers that lack CDH1 expression in their tumors. PMID- 20856233 TI - Neurodegenerative diseases: a growing challenge. PMID- 20856230 TI - IL17: potential therapeutic target in Sjogren's syndrome using adenovirus mediated gene transfer. AB - Sjogren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears that eventually result in dry mouth and dry eye diseases. T(H)17 cell populations secreting IL17A have been shown to have an important function in an increasing number of autoimmune diseases, including SS. In this study, we investigated the function of IL17A on SS development and onset. Adenovirus-5 vectors expressing either IL17R:fragment of crystallization (Fc) fusion protein or LacZ were injected through retrograde cannulation into the salivary glands of SS susceptible (SS(S)) C57BL/6.NOD-Aec1Aec2 mice between 6 and 8 weeks of age (a pre disease stage) or 15 and 17 weeks of age (a diseased stage). The mice were subsequently characterized for their SS phenotypes. Mice cannulated with the Ad5 IL17R:Fc viral vector at either 7 or 16 weeks of age exhibited a rapid temporal, yet persistent, decrease in the levels of serum IL17 as well as the overall numbers of CD4+IL17+T cells present in their spleens. Disease profiling indicated that these mice showed decreased lymphocytic infiltrations of their salivary glands, normalization of their antinuclear antibodies repertoire, and increased saliva secretion. In contrast, mice cannulated with the control Ad5-LacZ viral vector did not exhibit similar changes and progressed to the overt disease stage. The capacity of the Ad5-IL17R:Fc-blocking factor to reduce SS pathology in SS(S) mice strongly suggests that IL17 is an important inflammatory cytokine in salivary gland dysfunction. Thus, therapeutic approach targeting IL17 may be effective in preventing glandular dysfunction. PMID- 20856231 TI - Pkd1-inactivation in vascular smooth muscle cells and adaptation to hypertension. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder characterized by renal, hepatic and pancreatic cyst formation and cardiovascular complications. The condition is caused by mutations in the PKD1 or PKD2 gene. In mice with reduced expression of Pkd1, dissecting aneurysms with prominent media thickening have been seen. To study the effect of selective disruption of Pkd1 in vascular smooth muscle cells (SMCs), we have generated mice in which a floxed part of the Pkd1 gene was deleted by Cre under the control of the SM22 promotor (SM22-Pkd1(del/del) mice). Cre activity was confirmed by X-gal staining using lacZ expressing Cre reporter mice (R26R), and quantitative PCR indicated that in the aorta Pkd1 gene expression was strongly reduced, whereas Pkd2 levels remained unaltered. Histopathological analysis revealed cyst formation in pancreas, liver and kidneys as the result of extravascular Cre activity in pancreatic ducts, bile ducts and in the glomerular Bowman's capsule. Remarkably, we did not find any spontaneous gross structural blood vessel abnormalities in mice with somatic Pkd1 gene disruption in SMCs or simultaneous disruption of Pkd1 in SMCs and endothelial cells (ECs). Extensive isometric myographic analysis of the aorta did not reveal differences in response to KCl, acetylcholine, phenylephrin or serotonin, except for a significant increase in contractility induced by phenylephrin on arteries from 40 weeks old Pkd1(del/+) germ-line mice. However, SM22-Pkd1(del/del) mice showed significantly reduced decrease in heart rate on angiotensin II-induced hypertension. The present findings further demonstrate in vivo, that adaptation to hypertension is altered in SM22-Pkd1(del/del) mice. PMID- 20856237 TI - Tweaking energy metabolism to prevent and treat neurological disorders. PMID- 20856238 TI - MDR1-P-glycoprotein (ABCB1)-mediated disposition of amyloid-beta peptides: implications for the pathogenesis and therapy of Alzheimer's disease. AB - The accumulation of neurotoxic amyloid-beta (Abeta) peptides within the brain represents a hallmark of Alzheimer's disease (AD). It is proposed to be partly due to reduced elimination of Abeta from the brain into the blood. Diverse mechanisms of Abeta clearance out of the brain have been suggested. As discussed here, several lines of evidence suggest a significant role of the MDR1-P glycoprotein (ABCB1), which is a major component of the blood-brain barrier (BBB). PMID- 20856239 TI - Is P-glycoprotein involved in amyloid-beta elimination across the blood-brain barrier in Alzheimer's disease? PMID- 20856240 TI - An individualized approach to tracking and treating Alzheimer's disease. AB - There can be substantial variation in the expression of Alzheimer's disease. Patients vary in who is affected (e.g., education, age at onset), in how they are affected (e.g., neuropathological profile, comorbidities), and in when they present (i.e., stage of illness). Even people with similar starting profiles can have dramatically different courses. For these reasons, tracking disease progression in individuals and the effects of treatment on them can be challenging. This variability further complicates the difficulty of dementia's high dimensionality--Alzheimer's disease affects many aspects of cognition, function, and behavior. PMID- 20856241 TI - The impact of the Orphan Drug Act on the development and advancement of neurological products for rare diseases: a descriptive review. AB - Many neurological diseases or conditions are rare disorders. The Orphan Drug Act (ODA) of 1983 was promulgated to promote the development of products for such conditions. In this Opinion piece, we discuss how the ODA has affected neurological diseases, note how current and future sponsors (any person(s) or entity (i.e., academic, corporate body, individual, manufacturer) that applies for an official regulatory action) of products for rare neurological diseases can take advantage of ODA incentives, identify areas of success and continuing needs, and review data that can help drive the future development of products for rare neurological conditions. PMID- 20856242 TI - PMDA's challenge to accelerate clinical development and review of new drugs in Japan. AB - In recent years, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) has conducted several projects to shorten drug development and review times in Japan to resolve the "drug lag." Key to achieving this goal is greater involvement by the PMDA in drug development through enhancement of scientific consultation and improvement of the review process by reinforcing the operational system, including hiring more reviewers. We discuss here the current projects of the PMDA as well as future challenges. PMID- 20856243 TI - Understanding forgiveness: minding and mining the gaps between pharmacokinetics and therapeutics. AB - The usual objective during long-term pharmacotherapy is, in large part, to maintain continuity of action of the prescribed drug(s). Continuity of action arises from the continuity of execution of a prescribed dosing regimen that is pharmacologically sound in dose quantity and interval between successive doses. Interruptions in dosing can interrupt drug action, but the consequences vary according to length of interruption, drug, drug formulation, length of the patient's prior exposure to the drug, and the disease being treated. PMID- 20856244 TI - Neuroenhancement: wisdom of the masses or "false phronesis"? AB - Neuroenhancement (NE) refers to the use of prescription medications by healthy persons to boost their cognitive skills. This growing phenomenon represents a potential market not only for pharmaceutical manufacturers but also for physicians who might enter the potentially lucrative specialty of so-called cosmetic neurology. But before the medical establishment gears up to supply drugs to produce wisdom for the masses, we should ask whether the wisdom of the masses in regard to NE is wisdom at all. PMID- 20856245 TI - Efficacy, safety, and ethics of cosmetic neurology far from settled. AB - In this issue, Larriviere and colleagues discuss the emerging use of drugs to enhance cognitive function. Several cautions they raise warrant amplification. People have tried to pharmacologically improve cognitive function for millennia, but Larriviere and colleagues postulate that new, more effective drugs will lead to the emergence of "cosmetic neurology." The ethics of using drugs to improve performance, as opposed to treating disease or restoring normal function, are far from settled. PMID- 20856247 TI - Modulation of orbitofrontal response to amphetamine by a functional variant of DAT1 and in vitro confirmation. PMID- 20856248 TI - A functional alternative splicing mutation in human tryptophan hydroxylase-2. AB - The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences. PMID- 20856249 TI - Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment. AB - Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression, whether BDNF levels are related to the clinical features of depression and whether distinct antidepressants affect BDNF levels equally. We addressed these questions and investigated serum BDNF levels in 962 depressed patients, 700 fully remitted persons (>=6 months) and 382 healthy controls. We found serum BDNF levels to be low in antidepressant-free depressed patients relative to controls (P=0.007) and to depressed patients who were treated with an antidepressant (P=0.001). BDNF levels of fully remitted persons (whether unmedicated or treated with an antidepressant) were comparable to those of controls. Analyzing the sample of antidepressant-free depressed patients showed that BDNF levels were unrelated to the core clinical features of depression such as its severity or first versus a recurrent episode. The antidepressant associated upregulation of serum BDNF in depressed patients was confined to selective serotonin reuptake inhibitors (SSRIs) (P=0.003) and St John's wort (P=0.03). Our results suggest that low serum levels of BDNF are a state abnormality that is evident during depression and normalizes during remission. Increases in serum levels of BDNF during antidepressant treatment appear to be confined to some antidepressants and do not parallel clinical characteristics, such as the severity of depressive symptoms. PMID- 20856251 TI - Studies on the anti-obesity activity of zinc-alpha2-glycoprotein in the rat. AB - OBJECTIVE: To investigate the anti-obesity effect of the adipokine zinc-alpha(2) glycoprotein (ZAG) in rats and the mechanism of this effect. SUBJECTS: Mature male Wistar rats (540 +/- 83 g) were administered human recombinant ZAG (50 MUg per 100 g body weight given intravenously daily) for 10 days, while control animals received an equal volume of phosphate-buffered saline (PBS). RESULTS: Animals treated with ZAG showed a progressive decrease in body weight, without a decrease in food and water intake, but with a 0.4 degrees C rise in body temperature. Body composition analysis showed loss of adipose tissue, but an increase in lean body mass. The loss of fat was due to an increase in lipolysis as shown by a 50% elevation of plasma glycerol, accompanied by increased utilization of non-esterified fatty acids, as evidenced by the 55% decrease in plasma levels. Plasma levels of glucose and triglycerides were also reduced by 36 37% and there was increased expression of the glucose transporter 4 in both skeletal muscle and adipose tissue. Expression of the lipolytic enzymes adipose triglyceride lipase and hormone-sensitive lipase in the white adipose tissue (WAT) were increased twofold after ZAG administration. There was almost a twofold increased expression of uncoupling proteins 1 and 3 in brown adipose tissue and WAT, which would contribute to increased substrate utilization. Administration of ZAG increased ZAG expression twofold in the gastrocnemius muscle, BAT and WAT, which was probably necessary for its biological effect. CONCLUSION: These results show that ZAG produces increased lipid mobilization and utilization in the rat. PMID- 20856252 TI - Gender-assortative weight gain: reply to Leary, Smith and Ness. PMID- 20856250 TI - Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. AB - Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11+/-5 vs 14+/-3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD. PMID- 20856253 TI - Combined effect of C-reactive protein gene SNP +2147 A/G and interleukin-6 receptor gene SNP rs2229238 C/T on anthropometric characteristics among school children in Taiwan. AB - OBJECTIVE: The purpose of this study was to explore the combined effect of the C reactive protein (CRP) +2147 A/G (rs1205) and interleukin (IL)-6R rs2229238 C/T single-nucleotide polymorphisms (SNPs) on the anthropometric variables of school children in Taiwan. SUBJECTS AND DESIGN: Cross-sectional analyses were performed using the data from the Taipei Children Heart Study-II. After multi-stage sampling, we selected 430 boys and 463 girls with an average age of 13.1 years. We genotyped these individuals for the CRP +2147 A/G and IL-6R rs2229238 C/T SNPs using a TaqMan 5' nuclease assay. Anthropometric characteristics, which included body height, body weight (BW), body mass index (BMI), waist circumference (WC), hip circumference (HC), body fat percentage (BF), and waist circumference to height ratio (WHtR), were measured/calculated. RESULTS: When considering the CRP +2147 A/G polymorphism, GG genotype boys were heavier and had larger BMI, WC, HC, BF and WHtR than A allele carriers. The odds ratio (OR) of larger WHtR in GG genotype boys was 2.14 (95% CI: 1.09-4.21). For the IL-6R rs2229238 C/T polymorphism, T allele carrier girls had larger WC and WHtR than those carrying the CC genotype. The OR of a larger HC for T allele carrier boys was 2.33 (95% CI: 1.16-4.68). Boys with the GG genotype of CRP +2147 A/G and the CC genotype of IL-6R rs2229238 C/T had higher OR for BW, BMI, WC, HC, BF and WHtR than boys who were carriers of the A allele of CRP +2147 A/G and had the CC genotype of IL-6R rs2229238 C/T (OR range=3.86-8.04, all P<0.05). CONCLUSION: Boys who carry the GG genotype of CRP +2147 A/G and the CC genotype of IL-6R rs2229238 C/T have a greater risk of having abnormal BW, BMI, WC, HC, BF and WHtR and of developing obesity than individuals who do not have these genotypes. PMID- 20856254 TI - Changes in C-reactive protein during weight loss and the association with changes in anthropometric variables in men and women: LIFE Study. AB - OBJECTIVE: To investigate whether sex differences exist in the pattern of change in C-reactive protein (CRP) levels during weight loss, and whether the associations between weight change and CRP change differ by the types of anthropometric variables. DESIGN: Longitudinal, prospective analysis of subjects participating in an intentional weight loss trial (the Lose It For Ever: LIFE Study) followed-up for 30 months. SUBJECTS: A total of 212 healthy, obese men and women (age: 23-77 years, body mass index (BMI): 30-39 kg m(-2)) took part in this study. MEASUREMENTS: BMI, waist and hip circumferences, and waist-to-hip ratio, CRP and lifestyle variables repeatedly measured at baseline, 6, 12, 18 and 30 month follow-up. RESULTS: Weight change was J shaped with a nadir at 12 months in both men and women (P for month(2) <0.0001). CRP level was consistently higher in women than in men, but the differences were less prominent and were not statistically significant at 12- and 18-month follow-up. CRP changes between any two consecutive visits were significantly associated with changes in BMI during the same period in women. However, the associations between CRP changes and changes in waist or hip circumference were not as consistent, especially between 18- and 30-month follow-up when CRP significantly increased. The associations in men were generally similar among the different anthropometric measures. The association between changes in BMI and CRP was stronger in men than in women. CONCLUSION: BMI change generally correlated well with CRP changes in both men and women in the course of follow-up. Significant sex difference in CRP level at baseline diminished at 12- and 18-month follow-up, when both sexes had maintained the lost weight. PMID- 20856256 TI - Caloric restriction, aerobic exercise training and soluble lectin-like oxidized LDL receptor-1 levels in overweight and obese post-menopausal women. AB - BACKGROUND: Elevated circulating levels of soluble lectin-like oxidized low density lipoprotein receptor-1 (sLOX-1) have been observed in obese persons and are reduced by weight loss. However, it is not known whether combining caloric restriction (CR) with exercise training is better in reducing sLOX-1 levels than CR alone. OBJECTIVE: We examined whether the addition of aerobic exercise to a weight loss intervention differentially affects sLOX-1 levels in 61 abdominally obese post-menopausal women randomly assigned to a CR only (n = 22), CR+moderate intensity exercise (n = 22) or CR+vigorous-intensity exercise (n = 17) intervention for 20 weeks. The caloric deficit was ~2800 kcal per week for all groups. RESULTS: The intervention groups were similar at baseline with respect to body weight, body composition, lipids and blood pressure. However, plasma sLOX-1 levels were higher in the CR-only group (99.90 +/- 8.23 pg ml(-1)) compared with both the CR+moderate-intensity exercise (69.39 +/- 8.23 pg ml(-1), P = 0.01) and the CR+vigorous-intensity exercise (72.83 +/- 9.36 pg ml(-1), P = 0.03) groups. All three interventions significantly reduced body weight (~14%), body fat and waist and hip circumferences to a similar degree. These changes were accompanied by a 23% reduction in sLOX-1 levels overall (-19.00 +/- 30.08 pg ml(-1), P < 0.0001), which did not differ among intervention groups (P = 0.13). Changes in body weight, body fat and maximal oxygen consumption (VO(2) max) were not correlated with changes in sLOX-1 levels. In multiple regression analyses in all women combined, baseline sLOX-1 levels (beta = -0.70 +/- 0.06, P < 0.0001), age (beta = 0.92 +/- 0.43, P = 0.03) and baseline body mass index (BMI) (beta = 1.88 +/- 0.66, P = 0.006) were independent predictors of the change in sLOX-1 with weight loss. CONCLUSIONS: Weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese post-menopausal women, with the addition of aerobic exercise having no added benefit when performed in conjunction with CR. PMID- 20856257 TI - Vaspin is related to gender, puberty and deteriorating insulin sensitivity in children. AB - BACKGROUND: Visceral adipose tissue-derived serine protease inhibitor (vaspin) has been suggested as a novel adipocytokine related to obesity and insulin sensitivity in adults. DESIGN: We quantified vaspin serum concentrations in 65 lean and 67 obese children and aimed to evaluate the relationship of vaspin with physical development, obesity, and metabolic and cardiovascular phenotypes in children. We further assessed the acute vaspin response to glucose provocation in 20 obese adolescents and evaluated tissue expression patterns of vaspin in humans. RESULTS: Vaspin levels were significantly higher in girls than in boys. In girls, vaspin increased with age and pubertal stage, whereas there was no change with development in boys. Obese girls had lower vaspin serum levels than those of lean controls, but there was no significant correlation with body mass index (BMI). Independent of sex, age and BMI, lower vaspin was associated with better insulin sensitivity, with higher systolic blood pressure and impaired endothelial function. In response to glucose provocation during an oral glucose tolerance test, vaspin serum levels declined by approximately 25% in adolescents with hyperinsulinemia, whereas there was no significant decline in normoinsulinemic patients. In support of our clinical data, we not only confirmed vaspin mRNA expression in adipose tissue but also found consistent expression of vaspin in the liver and indications for expression in the pancreas and the skin. CONCLUSION: We showed that gender differences in circulating vaspin levels develop during pubertal progression in girls. Although vaspin's association with obesity remains controversial, vaspin was increased with worsening insulin resistance already in children and was acutely down-regulated following glucose provocation in insulin-resistant adolescents independent of obesity. Besides adipose tissue, vaspin expression in the liver and the pancreas may potentially contribute to circulating vaspin levels and their regulation. PMID- 20856258 TI - Associations between severity of obesity in childhood and adolescence, obesity onset and parental BMI: a longitudinal cohort study. AB - OBJECTIVE: To explore the relationship between severity of obesity at age 7 and age 15, age at onset of obesity, and parental body mass index (BMI) in obese children and adolescents. DESIGN: Longitudinal cohort study. SUBJECTS: Obese children (n = 231) and their parents (n = 462) from the Swedish National Childhood Obesity Centre. METHODS: Multivariate regression analyses were applied with severity of obesity (BMI standard deviation score (BMI SDS)) and onset of obesity as dependent variables. The effect of parental BMI was evaluated and in the final models adjusted for gender, parental education, age at onset of obesity, severity of obesity at age 7 and obesity treatment. RESULTS: For severity of obesity at age 7, a positive correlation with maternal BMI was indicated (P = 0.05). Severity of obesity at this age also showed a strong negative correlation with the age at onset of obesity. Severity of obesity at age 15 was significantly correlated with both maternal and paternal BMI (P < 0.01). In addition, BMI SDS at age 15 differed by gender (higher for boys) and was positively correlated with severity of obesity at age 7 and negatively correlated with treatment. Also, a negative correlation was indicated at this age for parental education. No correlation with age at onset was found at age 15. For age at onset of obesity there was no relevant correlation with parental BMI. Children within the highest tertile of the BMI SDS range were more likely to have two obese parents. CONCLUSION: The impact of parental BMI on the severity of obesity in children is strengthened as the child grows into adolescence, whereas the age at onset is probably of less importance than previously thought. The influence of parental relative weight primarily affects the severity of childhood obesity and not the timing. PMID- 20856260 TI - Sympathetic influence on biomechanical skin properties after spinal cord injury. AB - STUDY DESIGN: Case-control study. OBJECTIVES: To investigate changes of biomechanical skin properties and their relationship with paralysis following spinal cord injury (SCI). SETTING: South Korea. METHODS: A total of 48 male subjects with chronic SCI and 48 age-matched healthy controls were enrolled into this study. The C4 shoulder group and L2 thigh group were prescribed by two measured anatomical regions that represented the C4 and L2 American Spinal Injury Association sensory dermatomes. Each anatomical group was comprised of one control subgroup and three SCI subgroups determined by sympathetic paralysis at the measured region and somatic completeness. The following biomechanical skin properties were compared between the subgroups in each anatomical group by using Cutometer, a non-invasive suction device: distensibility (Uf), elasticity (Ua/Uf and Ur/Uf) and viscoelasticity (Uv/Ue and H). The impact of sympathetic and somatic sensory paralysis, somatic completeness, age, smoking, body mass index and duration of injury on the indices of skin properties were analyzed. RESULTS: In each anatomical group, sympathetic paralyzed subgroups regardless of somatic sensory completeness showed lower value of skin distensibility (Uf), and higher values of elasticity (Ua/Uf and Ur/Uf) and viscoelasticity (Uv/Ue and H), compared with other subgroups. Age and duration of injury had significant impact on biomechanical skin properties. CONCLUSION: The non-invasive suction method is useful for quantitative evaluation of skin affected by SCI. In chronic SCI patients, biomechanical skin properties are significantly altered in the skin with sympathetic paralysis rather than somatic sensory paralysis. PMID- 20856261 TI - Development and validation of a physical activity monitor for use on a wheelchair. AB - STUDY DESIGN: Keeping physically active is important for people who mobilize using a wheelchair. However, current tools to measure physical activity in the wheelchair are either not validated or limited in their application. The purpose of this study was to develop and validate a monitoring system to measure wheelchair movement. METHODS: The system developed consisted of a tri-axial accelerometer placed on the wheel of a wheelchair and an analysis algorithm to interpret the acceleration signals. The two accelerometer outputs in the plane of the wheel were used to calculate the angle of the wheel. From this, outcome measures of wheel revolutions, absolute angle and duration of movement were derived and the direction of movement (forwards or backwards) could be distinguished. Concurrent validity was assessed in comparison with video analysis in 14 people with spinal cord injury using their wheelchair on an indoor track and outdoor wheelchair skills course. Validity was assessed using intraclass correlation coefficients (ICC(2,1)) and Bland-Altman plots. RESULTS: The monitoring system demonstrated excellent validity for wheel revolutions, absolute angle and duration of movement (ICC(2,1)>0.999, 0.999, 0.981, respectively) in both manual and powered wheelchairs, when the wheelchair was propelled forwards and backwards, and for movements of various durations. CONCLUSION: This study has found this monitoring system to be an accurate and objective tool for measuring detailed information on wheelchair movement and maneuvering regardless of the propulsion technique, direction and speed. PMID- 20856262 TI - TGF-beta-regulated tyrosine phosphatases induce lymphocyte apoptosis in Leishmania donovani-infected hamsters. AB - Visceral leishmaniasis, which is caused by Leishmania donovani, is one of the major health problems of the Indian subcontinent. Infected hosts have been reported to have impaired lymphoproliferation. However, the fate of anergic cells is still elusive. In the present investigation, L. donovani-infected hamsters were used to study the mechanism of lymphocyte cell death. Lymph node-derived lymphocytes were analysed for apoptotic death through mitochondrial abnormality, caspase activity and DNA degradation. The data demonstrate that the disease progression leads to a gradual impairment of lymphocyte proliferation in the presence of Concanavalin A. The fate of the anergic lymphocytes is intrinsic apoptosis, which is evident by the depolarization of the mitochondrial membrane potential, cytosolic release of cytochrome c, caspase activation and DNA fragmentation. Tumour growth factor (TGF)-beta, which is secreted by macrophages, was significantly upregulated in the lymph node compartment of infected hamsters. Adding a neutralizing TGF-beta antibody and a recombinant TGF-beta resulted in the downregulation and induction of lymphocyte apoptosis, respectively. Furthermore, it has been observed that TGF-beta triggers the apoptotic death of lymphocytes through the upregulation of tyrosine phosphatase activity and that the use of sodium orthovanadate (Na(3)VO(4), a tyrosine phosphatase inhibitor) reduces the apoptotic frequency. Thus, this study clearly reports the novel involvement of tyrosine phosphatases in TGF-beta-induced lymphocyte apoptosis in Leishmania-infected hamsters. PMID- 20856264 TI - Chemical probing reveals insights into the signaling mechanism of inflammasome activation. AB - Caspase-1-mediated IL-1beta production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF kappaB-dependent pro-IL-1beta transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro IL-1beta expression by targeting components upstream of IKK in the TLR-NF-kappaB pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-kappaB inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-kappaB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs. PMID- 20856265 TI - miR-223 and miR-142 attenuate hematopoietic cell proliferation, and miR-223 positively regulates miR-142 through LMO2 isoforms and CEBP-beta. AB - miR-142 and miR-223 have been identified as hematopoietic specific microRNAs. miR 223 has crucial functions in myeloid lineage development. However, the function of miR-142 remains unclear. In this study, we found that both miR-142 and miR-223 attenuated the proliferation of hematopoietic cells, and that miR-223 up regulated miR-142 expression through the LMO2-L/-S isoforms and CEBP-beta. miR 223 negatively regulated both LMO2-L/-S isoforms and CEBP-beta post transcriptionally, while CEBP-beta positively regulated the LMO2-L/-S isoforms and both of the LMO2-L/-S isoforms negatively regulated miR-142. These results reveal a novel miR-223--CEBP-beta--LMO2--miR-142 regulatory pathway, which has pivotal functions in hematopoiesis. PMID- 20856263 TI - CMR for characterization of the myocardium in acute coronary syndromes. AB - The utility of cardiac magnetic resonance imaging (CMR) as a diagnostic technique is well established. CMR enables tissue characterization, distinction between myocardial scar tissue and viable tissue, and evaluation of myocardial perfusion and contractile function. To date, CMR has been mostly applied in the assessment of stable disease; however, a role for CMR in the acute setting is also emerging. An accurate appraisal of the myocardium with CMR in the first hours after the onset of chest pain could provide supporting information to standard diagnostic tools, such as electrocardiography and measurement of blood biomarkers, which could help guide the selection of appropriate treatment. The aims of this integrated approach include positive identification of an ischemic syndrome, estimation of downstream areas at risk of damage, evaluation of epicardial artery patency and small vessel integrity, quantification of infarct size, and determination of myocardial function. This Review critically evaluates both established and emerging CMR techniques, and relates the imaging findings to the underlying pathophysiological processes in acute coronary syndromes. A more thorough understanding of CMR techniques will clarify their potential clinical applications and limitations, and assess the practicality of CMR in the setting of acute coronary syndromes, where early intervention is crucial to save myocardium at risk of irreversible injury. PMID- 20856266 TI - Aspirin for primary prevention of cardiovascular disease in diabetes mellitus. AB - Aspirin is effective for the prevention of cardiovascular events in patients with a history of vascular disease, as so-called secondary prevention. In general populations with no history of previous myocardial infarction or stroke, aspirin also seems useful for primary prevention of cardiovascular events, although the absolute benefits are smaller than those seen in patients with previous cardiovascular disease. Patients with diabetes mellitus are at an increased risk of cardiovascular events, but new trials have raised questions about the benefit of aspirin for primary prevention in patients with this disorder. This Review comprehensively examines the basic pharmacology of aspirin and provides an overview of the randomized, controlled trials of aspirin therapy that have included patients with diabetes mellitus. On the basis of currently available evidence from primary prevention trials, aspirin is estimated to reduce the relative risk of myocardial infarction and stroke by about 10% in patients with diabetes mellitus; however, aspirin also increases the risk of gastrointestinal bleeding. As such, low-dose aspirin therapy (75-162 mg) is reasonable for patients with diabetes mellitus and a 10-year risk of cardiovascular events >10%. Results from upcoming large trials will help clarify the effects of aspirin with greater precision, including whether the benefits differ between men and women. PMID- 20856269 TI - Nuclear fragment drop without posterior capsular tear in a patient with congenital choroidal coloboma. PMID- 20856268 TI - Regulatory B cells in autoimmunity: developments and controversies. AB - Over a decade has now passed since the concept of B cells with a regulatory function was resurrected--B cells that produce antibodies with a suppressive effect were first reported in the 1960s and suppressor B cells in the 2000s. In the meantime, some aspects of regulatory B (B(REG))-cell biology have been elucidated. Not only have scientists begun to unravel the mechanism of how B(REG) cells suppress immune responses and which cells they target, but their ontogeny and development has also begun to be determined. To date, key roles for B(REG) cells have been identified in the regulation of several immune-mediated processes, including autoimmunity and responses to infectious disease and cancer. This Review highlights these advances in the study of B(REG) cells, and outlines what is known about their phenotype as well as their suppressive role in autoimmunity from studies in both mice and humans. A particular emphasis is placed on B(REG)-cell function in rheumatic diseases. PMID- 20856270 TI - Nanotechnology: what is it and why is small so big? AB - SIZE matters... the size of the scalpel determines the precision of the surgery. Nanotechnology affords us the chance to construct nanotools that are on the size scale of molecules, allowing us to treat each cell of the human body as a patient. Nanomedicine will allow for eradication of disease at the single-cell level. Since nanotools are self-assembling, nanomedicine has the potential to perform parallel processing medicine on a massive scale. These nanotools can be made of biocompatible and biodegradable nanomaterials. They can be "smart" in that they can use sophisticated targeting strategies, which can perform error checking to prevent harm if even a very small fraction of them are mistargeted. Built-in molecular biosensors can provide controlled drug delivery with feedback control for individual cell dosing. If designed to repair existing cells rather than to just destroy diseased cells, these nanomedical devices can perform in situ regenerative medicine, programming cells along less dangerous cell pathways to prevent tissues and organs from being destroyed by the treatments and thus providing an attractive alternative to allogeneic organ transplants. Nanomedical tools, while tiny in size, can have a huge impact on medicine and health care. Earlier and more sensitive diagnosis will lead to presymptomatic diagnosis and treatment of disease before permanent damage occurs to tissues and organs. This should result in the delivery of better medicine at lower costs with better outcomes. Lastly, and importantly, some of the first uses of nanotechnology and nanomedicine are occurring in the field of ophthalmology. Some of the potential benefits of nanotechnology for future treatment of retinopathies and optic nerve damage are discussed at the end of this paper. PMID- 20856267 TI - Life issues in multiple sclerosis. AB - A diagnosis of multiple sclerosis (MS), an incurable condition, introduces great uncertainty into virtually all aspects of a person's life. From early in the disease course, people with MS are vulnerable to disempowerment, poor psychological health, and social exclusion including high unemployment. Current health-care research for people with MS is reviewed here within the context of three philosophies of disability and health-care service provision: the biomedical, biopsychosocial and sociopolitical models. Some of the uncertainties concerning the patient's life that result from MS have been reduced by improved diagnostic tools, advances in immunotherapy, multidisciplinary rehabilitation, community programs, and provision of information specifically designed to facilitate shared decision-making and empowerment. Such progress is modest, however, and substantial improvements to the psychological health, empowerment, and quality of life of people with MS requires more sociopolitically oriented research. PMID- 20856271 TI - Socioeconomic factors and vision health in Canada. PMID- 20856272 TI - [Papillary melanocytoma, a case report]. PMID- 20856273 TI - System optimization of a long-range Brillouin-loss-based distributed fiber sensor. AB - We report a high-performance 25 km Brillouin-loss-based distributed fiber sensor through optimizing system parameters. First, the Brillouin spectrum distortion and measurement error induced by the excess amplification on probe pulse are investigated, and the results indicate that a low continuous-wave pump power is essential to decrease the measurement error. Then an optimal pulse pair is determined through the differential Brillouin gain evolution along the entire sensing fiber in a differential pulse-width pair Brillouin optical time domain analysis. Using dispersion-shifted fiber to allow a high-power probe pulse, we realize a 25 km sensing range with a spatial resolution of 30 cm and a strain accuracy of +/-20 MUepsilon, which we believe is the best performance in such a length, to the best of our knowledge. PMID- 20856274 TI - Simple two-layer reflectance model for biological tissue applications: lower absorbing layer. AB - A simple two-layer tissue reflectance model is described. This work is a continuation of our investigations on modeling reflectance from two-layered tissues that we recently initiated. In the present article, we describe a variation of a two-layer model that assumes a lower absorbing and scattering layer and an upper scattering-only layer. This two-layer configuration is a realistic model for biological tissues in the visible and near-IR spectral ranges, where the upper layer may be an epithelial layer and the lower layer is a vascularized stroma layer. Application of the model yields estimates for tissue parameters, such as the thickness of the upper layer or the absorption properties of the lower layer. These parameters are of great interest for the noninvasive study of a wide range of epithelial biological tissues. The validity range and accuracy of the model are tested on tissue phantoms in both the forward and inverse modes of application. PMID- 20856275 TI - Multiple light scattering and absorption in reef-building corals. AB - We present an experimental and numerical study of the effects of multiple scattering on the optical properties of reef-building corals. For this, we propose a simplified optical model of the coral and describe in some detail methods for characterizing the coral skeleton and the layer containing the symbiotic algae. The model is used to study the absorption of light by the layer of tissue containing the microalgae by means of Monte Carlo simulations. The results show that, through scattering, the skeleton homogenizes and enhances the light environment in which the symbionts live. We also present results that illustrate the modification of the internal light environment when the corals loose symbionts or pigmentation. PMID- 20856276 TI - Orientation-free pressure sensor based on pi-shifted single-mode-fiber Sagnac interferometer. AB - We propose and analyze a novel orientation-free pressure sensor based on a pi shifted all-single-mode-fiber (SMF) Sagnac interferometer. Compared with a conventional pressure sensor based on high-birefringence polarization-maintaining fiber, this all-SMF structure is more simple, stable, and economical. Because an initial pi shift is introduced into the Sagnac loop by adjusting actively the polarization controller, the intensity response of the sensor is independent of the birefringence orientation associated with the device under test (DUT). This configuration not only eliminates the effect of an uncertain birefringence orientation in the fiber loop, it also exhibits excellent repeatability and high sensitivity, which will ease the following demodulation of the measurand. The Jones matrix method is used to analyze the orientation-free characteristic of this sensor, and some theoretical and experimental results are also given. PMID- 20856277 TI - Imaging quality evaluation of aerodynamically heated optical dome using ray tracing. AB - An irregular grid model was employed to describe the refractive index distribution of an aerodynamically heated optical dome according to the theories of thermo-optical and elasto-optical effects. Optical transmission through the dome was simulated using the ray-tracing program based on a fourth-order Runge Kutta algorithm. Two kinds of imaging quality evaluation parameters were presented, wave aberration of the exit pupil and a modulation transfer function. To validate the ray-tracing program, a ray trace through a regular gradient medium was performed. Results were compared with those obtained from the analytic solution. The program was shown to possess great accuracy by using the appropriate parameters. PMID- 20856278 TI - Light pulse propagation along the path atmosphere-rough-surface-sea water. AB - The influence of surface waves and multiple scattering in water on the parameters of light pulses from an airborne source is studied. The contributions of various mechanisms to variations in delay of pulse and its variance are estimated. It is shown that waves make the main contribution to these values at small depths. With strong wind, the allowance for waves is important for small receiving apertures in the whole practically important depth range. For large receiving apertures or/and large widths of light beams incident on the surface, the determining factor is multiple scattering of light in water. PMID- 20856279 TI - Electronic speckle pattern interferometry and digital holographic interferometry with microbolometer arrays at 10.6 MUm. AB - Electronic speckle pattern interferometry and digital holographic interferometry are investigated at long infrared wavelengths. Using such wavelengths allows one to extend the measurement range and decrease the sensitivity of the techniques to external perturbations. We discuss the behavior of reflection by the object surfaces due to the long wavelength. We have developed different experimental configurations associating a CO(2) laser emitting at 10.6 MUm and microbolometer arrays. Phase-shifting in-plane and out-of-plane electronic speckle pattern interferometry and lensless digital holographic interferometry are demonstrated on rotation measurements of a solid object. PMID- 20856280 TI - Mode coupling in strained and unstrained step-index glass optical fibers. AB - By using the power flow equation, we have examined the state of mode coupling in strained and unstrained step-index glass optical fibers. Strained fibers show stronger mode coupling than their unstrained counterparts of the same type. As a result, the coupling length where equilibrium mode distribution is achieved and the length of fiber required for achieving the steady-state mode distribution are shorter for strained than for unstrained fibers. PMID- 20856281 TI - Definition and measurement of statistical gloss parameters from curved objects. AB - Gloss standards are commonly defined for gloss measurement from flat surfaces, and, accordingly, glossmeters are typically developed for flat objects. However, gloss inspection of convex, concave, and small products is also important. In this paper, we define statistical gloss parameters for curved objects and measure gloss data on convex and concave surfaces using two different diffractive-optical element-based glossmeters. Examples of measurements with the two diffractive optical-element-based glossmeters are given for convex and concave aluminum pipe samples with and without paint. The defined gloss parameters for curved objects are useful in the characterization of the surface quality of metal pipes and other objects. PMID- 20856282 TI - Quantization analysis of speckle intensity measurements for phase retrieval. AB - Speckle intensity measurements utilized for phase retrieval (PR) are sequentially taken with a digital camera, which introduces quantization error that diminishes the signal quality. Influences of quantization on the speckle intensity distribution and PR are investigated numerically and experimentally in the static wavefront sensing setup. Results show that 3 to 4 bits are adequate to represent the speckle intensities and yield acceptable reconstructions at relatively fast convergence rates. Computer memory requirements may be eased down by 2.4 times if a 4 bit instead of an 8 bit camera is used. This may facilitate rapid speckle data acquisition for dynamic wavefront sensing. PMID- 20856283 TI - Continuous-wave terahertz interferometry with multiwavelength phase unwrapping. AB - Continuous-wave (cw) terahertz (THz) phase imaging can accurately and noninvasively present the depth information of an object's surface and interior. However, a 2pi ambiguity limits the measurement of a sample with a thickness larger than the detection wavelength of THz waves. A multiwavelength phase unwrapping method is introduced to the cw THz phase imaging to reconstruct the exact phase map of the object. By using this method, three different types of high-density polyethylene samples were measured, and their phase profiles were well extracted. The result shows that this method is effective in cw THz phase imaging and has the potential to improve the applications of cw THz imaging. PMID- 20856284 TI - Determination of linear displacement by envelope detection with maximum likelihood estimation. AB - We demonstrate in this report an envelope detection technique with maximum likelihood estimation in a least square sense for determining displacement. This technique is achieved by sampling the amplitudes of quadrature signals resulted from a heterodyne interferometer so that the resolution of displacement measurement of the order of lambda/10(4) is experimentally verified. A phase unwrapping procedure is also described and experimentally demonstrated and indicates that the unambiguity range of displacement can be measured beyond a single wavelength. PMID- 20856285 TI - Optical section imaging of the tilted planes by illumination-angle-scanning digital interference holography. AB - A new method of optical imaging that can generate the section images of arbitrarily tilted planes has been developed from illumination-angle-scanning digital interference holography. A set of complex object fields are reconstructed from the holograms captured as the illumination angle is varied with uniform intervals. After the complex fields are modified with phase ramps that match the tilt (relative to the hologram plane) of a desired observation plane, the image of the object sliced along the tilted plane is obtained from their superposition. The axial resolution of a system employing this method is measured with a step height standard, and it is applied to the tomographic inspection of a microelectromechanical system. PMID- 20856286 TI - Modal wavefront sensor based on binary phase-only multiplexed computer-generated hologram. AB - We propose an approach for implementing a modal wavefront sensor using a binary phase-only multiplexed computer-generated hologram (BPMCGH). To simplify the coding and fabricating processes, a model based on tilt plane reference waves and an effective coding scheme for BPMCGH have been developed. The necessary number of subholograms to be recorded or coded is significantly reduced, from two or even more to just one per aberration mode, accordingly. The numerical and experimental demonstration results are presented and discussed and show that this approach is convenient for producing a BPMCGH and efficient for sensing the aberration modes. PMID- 20856287 TI - Deflectometric method for the measurement of user power for ophthalmic lenses. AB - This paper presents a deflectometric technique to measure the power of an ophthalmic lens as perceived by the user. It is based on a calibrated camera acting as a pinhole in order to measure ray deflection along the same path as the visual axis when the lens is held in front of the eye. We have analyzed numerically the accuracy of our technique, and it has been compared experimentally with a commercial "lens mapper" and with the real user power calculated from the measured topography of the lens surfaces to state the reliability and accuracy of the presented technique. PMID- 20856288 TI - Insect monitoring with fluorescence lidar techniques: field experiments. AB - Results from field experiments using a fluorescence lidar system to monitor movements of insects are reported. Measurements over a river surface were made at distances between 100 and 300 m, detecting, in particular, damselflies entering the 355 nm pulsed laser beam. The lidar system recorded the depolarized elastic backscattering and two broad bands of laser-induced fluorescence, with the separation wavelength at 500 nm. Captured species, dusted with characteristic fluorescent dye powders, could be followed spatially and temporally after release. Implications for ecological research are discussed. PMID- 20856289 TI - Fuzzy logic based feedback control system for laser beam pointing stabilization. AB - This paper reports a fuzzy logic based feedback control system for beam pointing stabilization of a high-power nanosecond Nd:YAG laser operating at 30 Hz. This is achieved by generating the correcting signal for each consequent pulse from the error in the pointing position of the previous laser pulse. We have successfully achieved a reduction of beam position fluctuation from +/-60 to +/-5.0 MUrad without the focusing optics and +/-0.9 MUrad with focusing optics. PMID- 20856290 TI - Group velocity dispersion measurement method using sinusoidally phase-modulated continuous wave light based on cyclic nature of optical waveform change by group velocity dispersion. AB - We show that any optical pulse train recovers its original waveform after passing through a group velocity dispersion (GVD) device when the total GVD value of the device is equal to an integral multiple of 1/(2pif(rep)(2)), where f(rep) is the repetition rate of the optical pulse train. In addition, we detail our proposed GVD measurement method, or optical phase-modulation (PM) method, which utilizes a sinusoidally PM continuous wave (CW) light as a probe light. The total GVD B(2) of a device under test (DUT) is derived by using a very simple equation, |B(2)|=1/(2pif(null)(2)), where f(null) is the smallest modulation frequency at which the sinusoidally PM light becomes CW light again after passing through the DUT. PMID- 20856291 TI - Efficient pump beam shaping for high-power thin-disk laser systems. AB - We report a beam-shaping technique whereby the output power from a high-power laser-diode stack is efficiently coupled, reconfigured, and transmitted to a thin disk laser by means of a compact optical fiber bundle. By using this technique, the power density is increased by a factor of 2 when compared to direct coupling with a octagonal fused silica rod while the numerical aperture is kept constant. Transmission efficiency of 80% was measured for the beam shaper without antireflection coating. The top-hat distribution is numerically calculated at the thin-disk laser crystal. PMID- 20856292 TI - Toward a photoconducting semiconductor RF optical fiber antenna array. AB - Recently, optical fibers comprising a crystalline semiconductor core in a silica cladding have been successfully drawn by a conventional drawing process. These fibers are expected to exhibit a photoconductive response when illuminated by photons more energetic than the band gap of the core. In the photoconducting state, such a fiber can be expected to support driven RF currents so as to function as an antenna element, much as a plasma antenna. In this paper, we report the first device-related results on a crystalline semiconductor core optical fiber potentially useful in a photoconducting optical fiber antenna array; namely, optically induced changes to the electrical conductivity of a glass-clad germanium-core optical fiber. Since DC photoconduction measurements were masked by a photovoltaic effect, RF measurements at 5 MHz were used to determine the magnitude of the induced photoconductive effect. The observed photoconductivity, though not large in the present experiment, was comparable to that measured for the bulk crystals from which the fibers were drawn. The absorbed pumping light generated photo-carriers, thereby transforming the core from a dielectric material to a conductor. This technology could thus enable a class of transient antenna elements useful in low observable and reconfigurable antenna array applications. PMID- 20856293 TI - Semianalytic pulsed coherent laser radar equation for coaxial and apertured systems using nearest Gaussian approximation. AB - We present a semianalytic pulsed coherent laser radar (CLR) equation for coaxial and apertured systems. It combines the conventional CLR equation, numerical Fresnel integration (NFI), and nearest Gaussian approximation, using correction factors that correspond to beam truncation. The range dependence of the signal-to noise ratio obtained by this semianalytic equation was found to agree well with the precise NFI solution for not only the focal range, but also the near-field range. Furthermore, the optimum beam truncation condition depending on the atmospheric refractive index structure constant is shown. The derived equation is useful for precisely predicting the CLR performance simply by its semianalytic expression. PMID- 20856294 TI - General method of sensitivity control for manufacturing errors. AB - In this paper, the sensitivity control for manufacturing errors is treated from three aspects. A wavefront-based sensitivity function is proposed, the effect of which is verified with the modulation transfer function (MTF)-based Monte Carlo simulation. Then, the direct optimization of the MTF-based Monte Carlo simulation result is proposed. Finally, the effect of the sensitivity control function to get better lens types is shown. PMID- 20856295 TI - Stationary nonimaging lenses for solar concentration. AB - A novel approach for the design of refractive lenses is presented, where the lens is mounted on a stationary aperture and the Sun is tracked by a moving solar cell. The purpose of this work is to design a quasi-stationary concentrator by replacing the two-axis tracking of the Sun with internal motion of the miniaturized solar cell inside the module. Families of lenses are designed with a variation of the simultaneous multiple surface technique in which the sawtooth genetic algorithm is implemented to optimize the geometric variables of the optic in order to produce high fluxes for a range of incidence angles. Finally, we show examples of the technique for lenses with 60 degrees and 30 degrees acceptance half-angles, with low to medium attainable concentrations. PMID- 20856296 TI - Patents. AB - 5,126,542; 5,152,597; 5,160,838; 5,170,269; 5,191,219; 5,191,392. PMID- 20856297 TI - Recording complex holograms on photoresist by using an ion-implantation method. AB - Photoresists have traditionally been used as a holographic recording medium for phase holograms. We demonstrate the recording of a binary amplitude hologram on photoresist by using an ion-implantation method. This amplitude recording property is based on the fact that the optical transmittance of photoresist can be changed by a high-dose ion implantation. A novel complex-hologram recording method is proposed in which the phase is represented by photoresist thickness and the amplitude is encoded on its optical transmittance. PMID- 20856298 TI - Low-frequency electromagnetic (eddy-current) holography for imaging in conductors. AB - Typical eddy-current system test data consist of the values of the system's probe impedance. The wave theory that links the phase response of the eddy-current probe impedance to the defect location relative to the probe is presented. The technique of phase multiplying the diffraction-limited hologram generated from the probe impedance is discussed. The effects and limitations of this technique are illustrated with a mathematical model of the eddy-current probe. Experimental data are presented that confirm the theoretical analysis and illustrate the ability to focus eddy-current holographic data by using backward wave propagation. PMID- 20856299 TI - Implementation of general point transforms with diffractive optics. AB - All linear finite-dimensional transformations can be implemented with diffractive optics. Such transformations include general point transforms. A technique for the implementation of general point transforms is considered. This is used to implement two point transforms. The implementation of a 90 degrees -rotation and a Hough transform is discussed. Fresnel diffraction patterns of these implementations are presented. PMID- 20856300 TI - Wave-front correction from point spread function data. AB - A distorted wave front is estimated from the intensity distribution on a focal plane. The information of the estimated wave front is used to control an adaptive mirror that corrects an atmospherically distorted wave front. A new approach to correct a distorted wave front is proposed. Several computer simulations confirm that a distorted wave front can be corrected from the information of the intensity distribution on a focal plane. PMID- 20856301 TI - Light propagation through microlenses: a new simulation method. AB - A new numrical method is described for analysis of the imaging properties of microlenses. This wave-propagation method is compared with the classical beam propagation method from which it is derived. The applicability of the two methods is given and demonstrated by examples. The beampropagation method is fast but is applicable only for small apertures; the new wave-propagation method requires no paraxial approximation but requires more computational effort. PMID- 20856302 TI - Optical programmable shifting for data processing. AB - A programmable shifter that uses birefringent crystal plates and programmable half-wave plates is described. It can accomplish right, left, right-cyclic, and left-cyclic shifting on the fly. PMID- 20856303 TI - Basic building blocks for the switch-preserving transformation of shuffle interconnections. AB - The transformations of a two-dimensional shuffle on a 4 * 4 array into a one dimensional shuffle on a vector of length 16 (and vice versa) are recognized as basic building blocks for the switch-preserving transformation of shuffle patterns of any size. [The switch-preserving transformation means the transformation of one-dimensional shuffles into two-dimensional and d-dimensional shuffles (d >= 3) and vice versa without the subdivision of switches.] The switch preserving transformation of shuffle patterns on large arrays is defined recursively by means of the presented basic building blocks. Thi concept of the transformation is restricted to the two-dimensional symmetric generalized perfect shuffle on arrays with equal sides (squares) being an even multiple of four. (Generalized means arbitrary decomposition of each coordinate, and thus an arbitrary shuffle may be defined; perfect is the counterpart to imperfect and refers to the regularity or absence of failures; symmetric means the same decomposition of the data length for both coordinates.) The relationship of the results to multistage interconnection networks is clarified. PMID- 20856304 TI - Compact interconnection networks for photonics. AB - The length of multistage interconnection networks is a crucial design parameter. The presented compact architecture overcomes this problem but raises several others, which are the additional interconnects between the separated inputs and outputs of a switch and the backreflection of light inside he architecture. Additional interconnects can be avoided by the interleaved organization of the switching arrays, or a mix of inputs and outputs. Different interconnect organization schemes are analyzed and evaluated. The avoidance of backreflection of light is discussed. PMID- 20856305 TI - Distributed optical data bus for board-level interconnects. AB - A design for a distributed free-space optical system is presented that provides interconnection of electronic processing elements at the board level of packaging. The system can be expanded to more than two boards and transfers an array of data in parallel between connection planes. The design uses binary optic microlens arrays to collimate and collect light from surface-emitting lasers, and it uses substratemode holographic window elements for directing light to and from the bus region. The use of a collection lens array for extending the alignment tolerance of the imaging system is also discussed. The paper concludes with experimental demonstrations of critical system components and performance with 64 bit data arrays. PMID- 20856306 TI - Optical perfect-shuffle interconnection using a computer-generated hologram. AB - We propose the use of a computer-generated hologram that combines a fanout and focusing element that can be used to perform an optical perfect-shuffle interconnection. The hologram is designed by calculation of the interference fringes between diverging waves from four point sources and a reference plane wave. With this element we show experimentally the resulting perfect-shuffle pattern. The use of the computer-generated hologram makes it easy to implement a planar optical perfect-shuffle interconnect, which is compact, has low aberration, and is easy to align. The planar optics configuration for a perfect shuffle interconnection network is also discussed. PMID- 20856307 TI - Optical network for real-time face recognition. AB - An optical network is described that is capable of recognizing at standard video rates the identity of faces for which it has been trained. The faces are presented under a wide variety of conditions to the system and the classification performance is measured. The system is trained by gradually adaptingphotorefrac tive holograms. PMID- 20856308 TI - Improvements in Bi(12)SiO(20) thin-film spatial light modulators. AB - Improvements introduced in Bi(12)SiO(20) thin-film spatial light modulators and consequent increased performance are described. By improving the optical and electrical uniformity of phosphorus-doped Bi(12)SiO(20) substrates and by improving the insulating properties of the insulator, we attained a resolution of higher than 50 line pairs/mm at a 50% modulation transfer function and a contrast ratio of 1000:1. The sensitivity and optical gain, defined as the ratio of output to input power, were also improved. In addition to these improvements, devices with wedge-shaped substrates for coherent readout light were fabricated, and it was shown that their write-in sensitivity and resolution were not affected by the substrate thickness. PMID- 20856309 TI - Time-resolved Fourier spectrum and imaging in highly scattering media. AB - Time and spatial-gated Fourier spectra and imaging were measured and analyzed. A picosecond Kerr-Fourier gate was used to image objects by selecting the spatial frequencies of objects illuminated by a laser pulse passing through a thick turbid medium. The earlier arriving ballistic/snake light and most of the later scattered light were spatially filtered and temporally separated to form an image. The image contrast and the signal-to-noise ratio of hidden objects in turbid media were greatly improved with the addition of Fourier spatial filtering. PMID- 20856310 TI - Optical processing for semiautonomous terminal navigation and docking. AB - An optical cross correlator that recognizes a single object is suitable for performing a single-vision function, such as pattern recognition for semiautonomous navigation, landing, and docking of vehicles to a predesignated landing mark. The optical cross correlator, with a video input from a simple imaging system and the output of the optical correlation plane processed with standard star tracker software, produces sufficient information for a spacecraft's terminal homing navigation system to complete a docking maneuver. We describe the application of the optical cross correlator to a landing on a simulated space station. PMID- 20856311 TI - Diagnostic and quality-assurance tools for low-contrast images obtained from array detectors. AB - We investigate methods of estimating a background image frame for subtraction from a data frame for use when a more suitable measured background frame is not available. We define background as any signal component that is not attributable to the phenomenon currently under investigation. We describe a technique that is based on pixel-by-pixel least-squares regression of images for computing a background frame from available data. We argue that the same technique can be a useful quality-assurance tool for evaluating instrument performance. For example, it can help to separate image structure resulting from the reading process from structure resulting from the characteristics of the detector itself. We demonstrate that background estimation can be nontrivial by comparing the results of different background estimation procedures by using data obtained from a CCD array detector. We investigate the temperature-dependent contributions of the detector and readout electronics to the total signal as a demonstration of the diagnostic capabilities of least-squares image regression. PMID- 20856312 TI - Performance analysis of the self-referenced speckle-holography image reconstruction technique. AB - Self-referenced speckle holography (SRSH) is a postdetection turbulence compensation technique for obtaining diffraction-limited imagery from ground based telescopes degraded by atmospheric turbulence. In SRSH, image-plane information is used together with wave-front distortion information to reconstruct an estimate of the object spectrum. The wave-front distortion information is obtained from a wave-front sensor in the pupil plane of the telescope. This information is used in a postprocessing environment to estimate the point spread function of the combined telescope and atmosphere. The point spread function is then used to obtain an estimate of the object intensity distribution by deconvolution. We present the results of a detailed performance analysis of SRSH. Performance is quantified in terms of a system transfer function and a system point spread function. The results show how the performance of SRSH is dependent on the sampling intervals and shot noise in the wave-front sensor. The results also indicate how the technique, for a given set of design parameters, responds to changing seeing conditions. For wave-front sensor sampling intervals of the order of a Fried coherence cell size r(0) and adequate light levels, SRSH boosts the high spatial frequencies (those near the diffraction limit of the telescope) to nearly 0.6. PMID- 20856313 TI - Multiple-object detection with a chirp-encoded joint transform correlator. AB - We investigate the performance of a chirp-encoded joint transform correlator in the presence of multiple input objects. We show that, for an input scene containing multiple targets, the chirp-encoding technique focuses the desired cross correlations between the reference signal and the input targets and the undesired self-correlations between the targets in the input scene in separate output planes. The output of the chirp-encoded joint transform correlator is mathematically analyzed for an input scene containing multiple targets. Both the linear joint transform correlator and the nonlinear joint transform correlator in the presence of multiple input targets are considered. For the nonlinear joint transform correlator, the chirp-encoding focuses the higher-order correlation terms, including the higher-order terms of the self-correlations between the targets in the input scene onto separate output planes. The separation requirements of the conventional and the chirp-encoded joint-transform correlator in the presence of multiple input targets are discussed. Computer simulations and experimental results of the chirp-encoded joint transform correlator for a scene containing multiple input targets are presented. The results are compared with a conventional joint transform correlator for an input scene containing multiple targets. PMID- 20856314 TI - Particle image velocimetry: high-speed transparency scanning and correlation-peak location in optical processing systems. AB - In order to exploit the full potential offered by optical correlation processing in the analysis of transparencies obtained by particle image velocimetry one needs to advance the transparency and to track the position of correlation peaks at great speed. In the following, this procedure is discussed with reference to an optical analysis system based on a high-speed ferroelectric optically addressed spatial light modulator. We present a system that uses scanning optics both to scan through the input transparency and to locate the correlation peaks in the resulting optical output distributions as a practical solution to the problem. The feasibility of this approach is demonstrated at a processing speed of ~500 autocorrelations/s when a one-dimensional acousto-optic output scanning device is used. PMID- 20856315 TI - Photo-compact-disk-based optical correlator. AB - A joint-transform correlator employing a recently available inexpensive photo compact-disk player is described. This is a realistic optical-disk-based correlator based on currently available technology. PMID- 20856316 TI - Horner efficiency of phase-only and binary phase-only filters. AB - The Horner efficiency for the phase-only filter and binary phase-only filter used for optical pattern recognition is discussed relative to both the filter formulation algorithm and the geometry of the object. Using computer simulations, we find that up to 80% of the incident energy can result in the peak of the correlation signal under proper conditions with the phase-only filter. Experimental results are obtained by using the binary phase-only filter written onto magneto-optic spatial light modulator. PMID- 20856317 TI - Optimal realizable filters and the minimum Euclidean distance principle. AB - Minimizing a Euclidean distance in the complex plane optimizes a wide class of correlation metrics for filters implemented on realistic devices. The algorithm searches over no more than two real scalars (gain and phase). It unifies a variety of previous solutions for special cases (e.g., a maximum signal-to-noise ratio with colored noise and a real filter and a maximum correlation intensity with no noise and a coupled filter). It extends optimal partial information filter theory to arbitrary spatial light modulators (fully complex, coupled, discrete, finite contrast ratio, and so forth), additive input noise (white or colored), spatially nonuniform filter modulators, and additive correlation detection noise (including signaldependent noise). An appendix summarizes the algorithm as it is implemented in available computer code. PMID- 20856318 TI - Wave-theory analysis of acousto-optic Bragg diffraction image formation. AB - We analyze anastigmatic Bragg diffraction imaging by use of an efficient numerical method that makes use of a plane-wave spectrum formalism applicable to weak acousto-optic diffraction involving threedimensional light and sound fields. Results from this wave-theory analysis are compared with previous results derived on the basis of ray theory, and are shown to be in good agreement, thus corroborating the validity of both techniques. PMID- 20856319 TI - Optical-coordinate transformation methods and optical-interconnection architectures. AB - The analogy between optical one-to-one point transformations and optical one-to one interconnections is discussed. Methods for performing both operations are reviewed and compared. The multifacet and multistage architectures have the flexibility to implement any arbitrary one-to-one transformation or interconnection pattern. The former would be preferred for low-cost and low resolution applications, whereas the latter would be preferred for high-cost and high-performance applications. PMID- 20856320 TI - Computer-generated holography for optical memory using sparse data words: capacity and error tolerance. AB - We discuss the capacity of parallel-access optical memories based on Fourier transform computergenerated holography. Emphasis is placed on the fundamental capacity cost associated with Fouriertransform computer-generated holography encoding. Capacity cost is discussed in terms of encoder complexity, memory overhead, and media defect tolerance. Results indicate that a sparse encoding of binary data words that supports minimal hologram area usage is an effective scheme for memories based on Fourier-transform computer-generated holography. These results are independent of computergenerated- holography algorithm and media type. PMID- 20856321 TI - Iterative procedure for improved computer-generated-hologram reconstruction. AB - A detour phase hologram is used as the initial binary pattern from which to apply an iterative Fourier method for modifying the hologram and thereby improving the signal-to-noise ratio of the reconstructed wave front. Improvements are shown to be significant with this approach, especially when a binary phase hologram is optimized with this iterative method. PMID- 20856322 TI - Optically programmed neural network capable of stand-alone operation. AB - A twa-dimensional amorphous silicon photoconductor array and a liquid-crystal display form the core components of a hardware system for the implementation of a multilayer perceptron neural network. All connections between layers, as well as the nonlinear transfer characteristics associated with the hiddenand output-layer neurons, are implemented in analog circuitry so that the network, once trained, behaves as a stand-alone processor. Subject to a standard backpropagation training algorithm, the network is shown to train very successfully. Training of the network is studied under different levels of weight quantization, neuron output resolution, and random weight-defect probability. A computer simulation of the hardware network is also performed, and excellent agreement is shown between the results of the hardware network and those of the computer simulation. It is concluded that the training capability of the present hardware network is very little degraded by its nonidealities, including the level of weight quantization and limit in neuron output resolution. PMID- 20856323 TI - Six-stage digital free-space optical switching network using symmetric self electro-optic-effect devices. AB - We describe the design and demonstration of an extended generalized shuffle interconnection network, centrally controlled by a personal computer. A banyan interconnection pattern is implemented by use of computer-generated Fourier holograms and custom metallization at each 32 * 32 switching node array. Each array of electrically controlled tristate symmetric self-electro-optic-effect devices has 10,240 optical pinouts and 32 electrical pinouts, and the six-stage system occupies a 9 in. * 12.5 in. (22.9 cm * 31.7 cm) area. Details of the architecture, optical and mechanical design, and system alignment and tolerancing are presented. PMID- 20856324 TI - Patents. AB - 5,048,937; 5,050,967; 5,054,924; 5,056,920; 5,069,545; 5,090,801; 5,111,055; 5,130,533; 5,150,170; 5,170,063; 5,170,268; 5,171,981; 5,173,748; 5,175,737; 5,175,757; 5,185,749; 5,187,756; 5,192,863; 5,194,980. PMID- 20856325 TI - Nasa patter. PMID- 20856326 TI - Mechanisms for laser-induced functional damage to silicon charge-coupled imaging sensors. AB - We measured the functional degradation of silicon CCD photodetector arrays when subjected to Nd:YAG laser irradiation at 1.06 um by 10-ns pulses. Operational tests such as dark leakage, point-spread function, and modulation transfer function were developed for testing individual pixels and applied to the testing of locally laser-damaged CCD arrays. Testing revealed that the primary failure mechanism was the spreading of the point-spread function in the direction of clocked charge motion that resulted from a decreased depth of potential wells within the laser-damaged spot. Lesser degradation was observed at pixels near the damaged spot that were served by clock lines that traversed the damage spot. This damage behavior was correlated with decreased breakdown voltage and increased leakage current between adjacent clock lines. Subsequent morphological and TEM examination of similarly constructed chips indicated that laser heating of the polysilicon clock lines led to degradation of the adjacent isolation oxide between clock lines. Functional damage occurred at locations where two clock lines were very close to each other, and the thin oxide layer separating them was subjected to high temperatures that resulted from melting of the neighboring polysilicon. PMID- 20856327 TI - Diode laser spectroscopy of methane overtone transitions. AB - With the aid of commercial room-temperature AlGaAs diode lasers, frequency modulation absorption spectroscopy was performed on the 7900 A and 8600 A rovibrational combination overtone bands of methane. Three weak transitions are reported in the range around 8610 A that, to our knowledge, have not yet been observed and measured. Self-broadening and pressure-broadening coefficients of one ofthese new absorption features (at 8608.93 A) were derived from CH(4) and for CH(4) immersed in N(2) and He buffer gases. An evaluation of the methane detection sensitivity is given for favorable laboratory conditions as well as for an open-path situation. PMID- 20856328 TI - Intrinsic limit of magneto-optical isolators because of magnetic circular dichroism. AB - The behavior of an optical isolator based on the Faraday effect of an absorbing magneto-optical material is analyzed, taking into account the effect of magnetic circular dichroism (MCD). MCD is indissolubly connected with Faraday rotation and limits the maximum obtainable isolation ratio through elliptization of the polarization of the incident beam. A formula is derived to calculate this effect and applied to a practical example. PMID- 20856330 TI - Pressure dependence of copper laser output characteristics. AB - Output characteristics of a large-bore (8-cm-diameter) copper laser were analyzed at different neon pressures. Radial delay decreased from ~40 ns at 30 Torr to ~10 ns at 110 Torr because of increased plasma impedance. When the laser was running as an amplifier, the best power was achieved at approximately 80 Torr (small-bore copper lasers normally optimize at 30-40 Torr). This occurs because a more pronounced reduction of radial delay at higher pressures can be achieved in large bore devices. As a result, a more uniform beam profile was obtained at higher pressures because of more efficient axial pumping. The improved coupling between the laser head and the pulse modulator at higher pressures also translates to a substantial improvement in laser efficiency (>50%) as the pressure rises from 30 to 100 Torr. The same laser optimizes at a much lower pressure (30-40 Torr) when its energy is extracted with a flat-flat resonator, because resonator loss increases with increasing gas pressure because of faster gain rise time at higher pressures. PMID- 20856331 TI - Dye lasers using tapered optical fibers. AB - A new type of dye laser operating in a single-mode optical fiber has been studied. The gain is produced by surrounding a tapered section of the fiber with laser dye. Interaction of the light in the fiber with the laser dye is achieved through the exposed evanescent field at the taper waist. Low lasing thresholds (25-65 mW) are obtained as a result of the high intensities at the taper waist. These tapered fiber dye lasers combine the advantages of a laser in fiber form with the wide spectral tuning ranges provided by laser dyes. Three experiments, demonstrating low-threshold operation of a grating tuned laser, an all-fiber ring laser, and cw lasing in tapered fiber dye devices, are presented. PMID- 20856329 TI - Efficient radially polarized laser beam generation with a double interferometer. AB - Conversion of a linearly polarized CO(2) laser beam into a radially polarized beam is demonstrated with a novel double-interferometer system. The first Mach Zehnder interferometer converts the linearly polarized input beam into two beams with sin(2) theta and cos(2) theta intensity profiles, where theta is the azimuthal angle. This is accomplished by using two spiral-phase-delay plates with opposite handedness in the two legs of the interferometer to impart a one-wave phase delay azimuthally across the face of the beams. After these beams are interfered with, the resulting beams are sent directly into the second Mach Zehnder interferometer, where the polarization direction of one beam is rotated by 90 degrees . The beams are then recombined at the output of the second interferometer with a polarization-sensitive beam splitter to generate a radially polarized beam. The output beam is ~92% radially polarized and contains ~85% of the input power. This system will be used in upcoming laser particle acceleration experiments. PMID- 20856332 TI - Numerical investigation of thermally induced birefringence in optical elements of solid-state lasers. AB - We have developed a method of computational simulation and estimation of thermo optical distortions in solid-state laser rods, electro-optic shutters, and modulators, considering real heat-transfer conditions, anisotropic material properties, and an arbitrary cross-section shape of the element. Numerical investigations for Nd:YAG laser rods and potassium dihydrogen phosphate electro optic shutters have been carried out, new results have been obtained, and known analytical solutions have been corrected. PMID- 20856333 TI - Optical distortion in end-pumped solid-state rod lasers. AB - We explore the thermo-optical issues of mode-matched end-pumped lasers. A combination of analytical and numerical methods is used to extract practically useful scaling relations that characterize the thermally induced optical distortions and the thermal-stress operating limits in rod lasers pumped with super-Gaussian sources. The thermally induced spherical aberration is found to be overcorrected (focal length increases with radial position), weakly dependent on the axial profile, and strongly dependent on the super-Gaussian order. For high order radial profiles it is shown that a significant portion of the extraction beam will operate aberration free. The effect of aberrations on cavity stability is addressed for the simple case of a cavity with a length that is equal to the rod length. PMID- 20856334 TI - Tunable dual-wavelength continuous-wave diode laser operated at 830 nm. AB - An external grating cavity semiconductor diode laser is made to operate simultaneously at two separately adjustable wavelengths. Lasing is restricted to the vicinity of the solitary laser 6talon resonances. PMID- 20856335 TI - High-intensity rectangular fiber-coupled diode laser array for solid-state laser pumping. AB - A high-power diode laser bar coupling scheme with rectangular optical fibers is proposed, and the concept is tested on a scale version: an individual diode laser array and a single rectangular fiber. 60% of the power from a 1-W cw, 213-um-wide 20-stripe diode array is coupled into a 216 um * 28 um 0.66 numerical aperture optical fiber, which produces intensities at the fiber output face of 9.9 kW cm( 2). The elliptical, dual-lobed far-field intensity pattern of the diode laser output, with divergence of 39 degrees * 13 degrees FWHM is converted on passing through the fiber into a single-lobed, nearly circular pattern with a FWHM divergence of 21 degrees * 22 degrees . The beam quality is reduced by only a factor of 30 when this coupling method is used. Alignment tolerances in the three planes of movement are measured and found to be in excess of 10 um. PMID- 20856336 TI - Enhanced efficiency of a continuous-wave mode-locked Nd:YAG laser by compensation of the thermally induced, polarization-dependent bifocal lens. AB - Measurements of the bifocal, thermally induced lenses of a cw Nd:YAG laser were obtained. We observed four different focal lengths that are polarization and direction dependent. The focal lengths were used to design stable resonators with large fundamental mode filling in the laser gain medium. The beam is totally polarized in the desired direction even without an intracavity Brewster window. We developed a general approach for the optimization of single-lamp, cw-pumped Nd:YAG lasers. Up to 22 W of cw output power in the vertically polarized TEM(00) mode and 15 W in the horizontal polarization are obtained for moderate lamp currents. Also, we demonstrate mode locking with 56-ps pulse duration at 33 A of lamp current and up to 13 W of average output power. PMID- 20856337 TI - Photorefractive two-wave mixing in the presence of high-speed optical phase modulation. AB - Equations that describe the steady-state dependence of the coherent-coupling properties of photorefractively induced refractive-index gratings on high-speed periodic biphase, sinusoidal, and triangular phase modulation impressed on one of the input optical beams are found and solved for both depleted and undepleted pump conditions. The period of the phase modulation wave form was kept short compared with the grating-formation time but did not cause significant spectral broadening. The results obtained were verified with data obtained from measurements of two-wave mixing in the photorefractive material, InP:Fe. PMID- 20856338 TI - Waveguide mutually pumped phase conjugators. AB - The operation of the bridge mutually pumped phase conjugator is reported in a planar waveguide structure in photorefractive BaTiO(3). The waveguide was fabricated by the technique of ion implantation, using 1.5-MeVH(+) ions at a dose of 10(16) ions/cm(2). An order of magnitude decrease in response time is observed in the waveguide as compared with typical values obtained in bulk crystals, probably as a result of a combination of the optical confinement within the waveguide and possible modification of the charge-transport properties induced by the implantation process. PMID- 20856339 TI - Attenuation, modal, and polarization properties of n < 1, hollow dielectric waveguides. AB - The attenuation coefficients for hollow sapphire and lead-based, oxide glass waveguides are calculated using an approximate formalism from Marcatili and Schmeltzer [Bell Syst. Tech. J. 43, 1783-1809 (1964)]. These results are compared with an exact calculation, and the agreement is found to be excellent for bore diameters greater than 100 um. Although the hollow lead glass waveguides have measured losses in agreement with theory, the hollow sapphire waveguides have losses greater than those calculated for the lowest-order mode. This excess loss is due to roughness of the inner surface of the sapphire. The hollow dielectric waveguides are also shown to preserve polarization and the single mode as do some of the hollow metallic waveguides. PMID- 20856340 TI - Kerr bistability in a 3 * 3 coupler optical fiber ring resonator. AB - We present a theoretical study of bistability in an optical fiber ring resonator connected to a 3 * 3 fiber coupler. The bistability is caused by the Kerr effect when the ring resonator is working in the nonlinear regime. The dependence of the bistability on various parameters of the fiber and the coupler is investigated. PMID- 20856341 TI - Nonlinear optical effects in Raman calibrations of a Thomson scattering system. AB - We present an investigation of the occurrence of stimulated Raman scattering and other nonlinear optical effects during Raman calibrations of Thomson scattering diagnostic systems for magnetic fusion plasmas. When these effects take place, the intensity of the Raman lines is unpredictable, and the calibrations are impossible. In this research Raman scattering from H(2) and D(2) at filling pressures up to 1 atm has been experimentally investigated using the Thomson scattering system of the ETA-BETA II reversed field pinch device. Stimulated Raman Stokes light has been observed at filling pressures above 230 and 500 mbars for H(2) and D(2), respectively, for input laser pulses of 8 J and 30 ns (FWHM) duration. Evidence has been found that the stimulated Raman light does not originate from the observed scattering volume but is detected as light diffused into the vacuum chamber. To explain these results, the Raman gain and the intensity of the stimulated Raman light are calculated, taking into account the multimode structure of the laser beam. We find that significant power conversion from the input laser beam to the Stokes wave takes place near the output window of the vacuum chamber. Part of this radiation is diffused back into the machine, and this part is detected as superimposed on the spontaneous Raman signal. Finally we discuss the Raman calibrations in RFX, a larger plasma device in which the Raman medium will be N(2) at a temperature up to 350 degrees C, and show that a filling pressure of 100 mbar gives a sufficient calibration signal, avoiding any nonlinear effect. PMID- 20856342 TI - Airborne tunable diode laser spectrometer for trace-gas measurement in the lower stratosphere. AB - This paper describes the airborne tunable laser absorption spectrometer, a tunable diode laser instrument designed for in situ trace-gas measurement in the lower stratosphere from an ER-2 high-altitude research aircraft. Laser-wavelength modulation and second-harmonic detection are employed to achieve the required constituent detection sensitivity. The airborne tunable laser absorption spectrometer was used in two polar ozone campaigns, the Airborne Antarctic Ozone Experiment and the Airborne Arctic Stratospheric Expedition, and measured nitrous oxide with a response time of Is and an accuracy <= 10%. PMID- 20856343 TI - Profiling of hot surfaces by pulsed time-of-flight laser range finder techniques. AB - The possibilities for using the pulsed time-of-flight (TOF) laser radar technique for hot refractory lining measurements are examined, and formulas are presented for calculating the background radiation collected, the achievable signal-to noise ratio (SNR), and the measurement resolution. An experimental laser radar device is presented based on the use of a laser diode as a transmitter. Results obtained under real industrial conditions show that a SNR of 10 can be achieved at measurement distances of up to 15-20 m if the temperature of the converter is 1400 degrees C and the peak power of the laser diode used is 10 W. The single shot resolution is about 60 mm (sigma value), but it can be improved to millimeter range by averaging techniques over a measurement time of 0.5 s. A commercial laser radar profiler based on the experimental laser radar device is also presented, and results obtained with it in real measurement situations are shown. These measurements indicate that it is possible to use the pulsed TOF laser radar technique in demanding measurement applications of this kind to obtain reliable data on the lining wear rate of a hot converter in a steel works. PMID- 20856344 TI - Near-infrared forest fire detection concept. AB - A system concept is described for a pushbroom airborne optical fire detection instrument operating in the visible and near-infrared spectral regions. In the design concept, several detection modules are used simultaneously, each having a camera lens, beam splitter, spectral filters, silicon linear array, InGaAs linear array, and signal processing. Calculations indicate that dual-wavelength signal processing should allow cool (600 K) incipient fires as small as 0.1 m in extent to be identified against the expected background of diffuse and specular sunlight. PMID- 20856345 TI - Self-consistent solutions to the equation of transfer with elastic and inelastic scattering in oceanic optics: I. Model. AB - A new self-consistent two-stream method has been developed that allows for both elastic and inelastic processes including fluorescence. What makes this method very useful is that it contains adjustable parameters that can be selected to fit experimental data. It also has the robustness to cover a complete range of inherent oceanic parameters ranging from the very clear to the most turbid. The method also uses real solar spectral input so that one can also perform chromaticity coordinate calculations for ocean color. Apparent optical properties such as irradiance and scalar irradiance can be computed at any depth in the ocean. PMID- 20856346 TI - Effect of atmospheric turbulence on heterodyne lidar performance. AB - The effect of atmospheric turbulence on heterodyne lidar performance is studied by use of scattering theory. A theoretical analysis is carried out for both bistatic and monostatic lidar systems with independently variable transmitter and receiver parameters in regimes of weak and strong intensity fluctuations. The conditions of validity of a diffuse target model for description of the optical wave scattering by aerosols in a turbulent atmosphere are presented. The equations for signal power degradation and the conditions under which the time averaged output of a heterodyne lidar does not depend on either turbulent conditions of propagation along the path or the transmitter parameters, including transmitter coherence length, are obtained. A physical interpretation of these results is given, and a comparison with the data of previous theories is made. PMID- 20856347 TI - Photolysis-laser-induced fluorescence diagnostic for GaCI. AB - A spatially resolved optical diagnostic for GaCl is described. The technique uses 248-nm excimer laser radiation to photolyze GaCl and also to excite fluorescence in the resulting gallium atoms. This yields gallium fluorescence at 245, 266, 287, 294, 403, and 417 nm. The method is specific to GaCl(3) and is not affected by the presence of a GaCl3 precursor. Gallium fluorescence is linear in both the GaCl partial pressure and the laser energy under specified conditions. The photophysics of this process are contrasted to related GACl studies of dissociative excitation at 193 nm. PMID- 20856348 TI - Temperature measurements in gases by use of planar laser-induced fluorescence imaging of NO. AB - Two techniques based on planar laser-induced fluorescence of NO are applied to the measurement of two-dimensional temperature fields in gaseous flows. In the single-line technique, the NO fluorescence signal, which is in general a function of temperature, pressure, and mole fraction, can be reduced to a function of temperature alone. In this limit, a single measurement of fluorescence can be directly related to temperature. In contrast, in the two-line thermometry technique the ratio of fluorescence signals resulting from excitation of two different rovibronic states is related to the fractional populations in the initial states, which are solely a function of temperature. The one-line method is applied to the study of a laminar heated jet, and the two-line technique is used to measure temperature in a supersonic underexpanded jet. In addition, energy transfer in NO laser-induced fluorescence is analyzed with multilevel rate equation models. Finally, an accurate model is developed for prediction of the temperature dependence of the NO fluorescence signal. PMID- 20856349 TI - Remark about the notation used for calculating the electromagnetic field scattered by a spherical particle. AB - In the theory of light scattering by small particles we use two different kinds of notation for the incident plane wave. In both cases we often use the same notation for the scattered spherical wave (compare H. C. van de Hulst, Light Scattering by Small Particles (Wiley, New York, 1957), Chap. 3, p. 18 and Chap. 1, p. 8, with C. Bohren and D. Huffman, Absorption and Scattering of Light by Small Particles (Wiley, New York, 1957), Chap. 3, p. 18 and Chap. 9, p. 124). If one is careless, this will lead to confusion. We must be aware of this and, correspondingly, change the calculated electromagnetic fields. PMID- 20856350 TI - Feature issue on optical interference coatings. AB - The feature issue on Optical Interference Coatings, stimulated by the June 1992 Topical Meeting, covers the wider field of optical surface treatments after polishing. It is the latest in a series that has been running every four years since 1976. PMID- 20856351 TI - Some theoretical aspects of thin-film optics and their applications. AB - The principal focus of my report is on the theoretical study of the properties of spectral coefficients in a complex wave-number plane. The basic results of the study are described, and their application to the synthesis of a rugate filter and to inhomogeneous layer recognition problems are considered. General results concerning the existence of solutions to synthesis problems are also presented. The close analogy between synthesis problems in thin-film optics and optimal control problems is outlined, and some applications of Pontryagin's maximum principle are considered. PMID- 20856352 TI - Rugate filter theory: an overview. AB - The principal aspects of rugate filter theory are reviewed and expanded to show how the Fouriertransform technique can be used to design rugate filters that fulfill many optical coating functions. PMID- 20856353 TI - Simulation of thin-film growth. AB - A two-dimensional simulation model of thin-film deposition, which involves the effect of the incident kinetic energy of atoms and the mobility of the substrate temperature, is developed. Lennard-Jones potential and nuclear scattering are used to characterize the atom-atom interaction. The effect of substrate temperature on the relaxation of depositing particles is also considered. Some simulation results are presented and discussed in detail. PMID- 20856354 TI - Predicting achievable design performance of broadband antireflection coatings. AB - An empirically derived formula, which can be used to predict the average residual reflection that can be expected from an antireflection (AR) coating design as a function of bandwidth, overall thickness, available indices of the coating materials, number of layers, etc., is presented. This formula can be a useful tool not only for the thin-film designer but also for the nondesigner or system engineer to estimate the performance limits of an AR coating for a given application before the design is accomplished. The general predictions are also found to be consistent with the results of two recent AR design competitions involving many independent investigators. Some insight with respect to the basic underlying principles of AR coatings can also be gleaned from the results and the process by which they are found. PMID- 20856355 TI - Accelerated exhaustive search procedure for filter design by merit function minimization. AB - A scheme that permits a considerable reduction of the computation time needed by exhaustive search procedures for merit function minimization in optical filter design is presented. PMID- 20856356 TI - Laser mirrors with variable reflected intensity and uniform phase shift: design process. AB - Optical coatings with circularly symmetric graded reflectance are used as laser mirrors in unstable resonators. A proper design of such coatings permits any maximum central reflectance to be obtained along with a null external reflectance. Different design approaches are discussed, and an optimized design that gives negligible distortion of the reflected and transmitted wave front is proposed. Coatings with super-Gaussian and step reflectance profiles are examined as two different solutions for improving laser beam quality. PMID- 20856357 TI - Multiwavelength (0.45-10.6 um) angle-resolved scatterometer or how to extend the optical window. AB - An apparatus to record scattered light in whole space over a large range of visible and infrared wavelengths (0.45-10.6 um) is described. Parasitic light, calibration, and dynamic range are discussed to point out performances and limits of the experimental setup. Angular measurements at several wavelengths give access to bidimensional roughness spectra of polished samples in different frequency bandwidths. The results show overlap of the spectra at the intersection of the bandwidths, which provides an extended view of surface microroughness. In the midinfrared, measurements are more difficult, and specific problems such as thermal emission are analyzed. PMID- 20856358 TI - Relation between light scattering and the microstructure of optical thin films. AB - Special substrate-film designs are used to measure roughness-induced scattering and scattering from the volume of optical thin films separately. So theoretical models of surface roughness and volume scattering become applicable to the experimental data, and quantitative information on thin-film microstructure can be derived. Measuring total integrated and angle-resolved scattering on oxide, fluoride, and chalcogenide films of different film thicknesses yields the evolution law of microstructural growth, which for the majority of investigated films roughly follows a square-root dependence on film thickness. Packing densities of fluoride films calculated from volume-scattering data are found to agree with results from quartz-crystal monitoring. PMID- 20856359 TI - From light scattering to the microstructure of thin-film multilayers. AB - It is shown how light scattering provides a powerful tool for thin-film characterization. The introduction of a roughness isotropy degree permits the extraction of structural parameters of the stacks. Replication functions and residual roughnesses are given for TiO(2), SiO(2), and Ta(2)O(5) materials produced by ion-assisted deposition and ion plating. Additional confirmation is given by measurements of scattering versus wavelength. The sensitivity of design to material and substrate effects is studied. At low-loss levels, surface and bulk phenomena are discussed together. Microstructure is characterized in the frequency bandwidth given by experiment. PMID- 20856360 TI - Comparison of surface and bulk scattering in optical multilayers. AB - Electromagnetic theories provide a tool to detect the origin of scattering in optical multilayers. Illumination and observation conditions that cause surface and bulk scatterings to have different behaviors are pointed out. Angular, wavelength, and polarization dependences are investigated for the location of structural irregularities at interfaces or in the bulk of a multilayer. Specific experiments can be designed. PMID- 20856361 TI - Direct observation of waveguided scattered light in multilayer dielectric thin films. AB - When a focused laser beam falls on a multilayer thin-film coating, light is scattered from the volume over which the beam intersects the coating. Some of the light may be scattered into directions that correspond to guided modes of the thin-film structure. We report the observation of scattered light at locations removed from the region of incidence of the light on the coating, resulting from the secondary scatter of the guided scattered light. The shape of the pattern observed by secondary scatter clearly resembles the pattern expected for Rayleigh scatter from a point source. This observation has important implications for the design of scatter-measuring instruments as well as for the theoretical treatment of scatter from multilayer coatings. PMID- 20856362 TI - Optical scatter characteristics of high-reflectance dielectric coatings and fused silica substrates. AB - Optical scatter characteristics for high-reflectance dielectric coatings and polished fused-silica substrates are measured. The coating materials are tantala/silica, titania/silica, and zirconia/silica. The coatings are deposited on substrates that are conventionally polished, superpolished, and irradiated with a CO(2) laser before deposition. The measurements are made at the design wavelengths of the coatings, i.e., 633 and 1320 nm, and consist of bidirectional reflectance distribution-function angle scans and spatial mappings. The substrate scatter is lower for superpolished surfaces, and the coating scatter is reduced by the use of superpolished substrates. Scatter levels are strongly influenced by coating design and materials. PMID- 20856363 TI - Recent progress of optical thin films in the automobile industry. AB - There are increasing demands for the application of optical thin films to transparent substrates such as glass and plastics for windows in automobiles with the view of adding fascinating optical properties to them. These properties include surface hardening of plastics, infrared reflection, ultraviolet absorption, polarization and birefringence, and hydrophobicity. Recent examples of applications of sophisticated thin-film processes of plasma treatment and physical vapor deposition are reviewed. The novelty of the functions provided by physical vapor deposition films together with their durability for practical usage are emphasized as areas in which the thin-film process has a significant impact. Characterization of the modified surface and interface is also included to demonstrate recent advances in surface chemistry. Finally, future challenges for optical modification of transparent substrates in the automobile industry are also discussed. PMID- 20856364 TI - Reststrahlen material bilayers: an option for tailoring in the infrared. AB - Double-layer interference calculations are used to show that the frost-preventing properties of insulating beryllium oxide can be improved. An underlying substrate of cubic boron nitride, which has a short-wavelength reststrahlen band, will reduce the thermal radiation leak of beryllium oxide in the 8-9.5 interval. The interference calculations for these highly dispersive and partly absorbing materials demonstrate that the configuration with beryllium oxide as an outer layer is essential for the performance. Less than 20% average emittance and 11 W/m(2) irradiance in the 8-13-um window is predicted when an optimum thickness of 2.5-um beryllium oxide upon cubic boron nitride is used. PMID- 20856365 TI - Making aspherical mirrors by thin-film deposition. AB - An aspherical mirror is made by a thin-film coating technique. A special mask is placed between the evaporation source and the substrate that is to be coated as an aspheric. The design principle of the mask is fully described. An ion-assisted deposition technique is used to relieve aluminum film stress and to increase surface reflectance. The final wave front is tested by conventional interferometric methods for aspherics. Less than one-fifth of a wave (632.8 nm) of spherical aberration is achieved without much trial and error. PMID- 20856366 TI - Single-mode couplers through end coatings on optical fibers. AB - For designing coatings on fiber ends, one should take into consideration the particular illumination conditions that are due to the propagation of light in the fibers. In a single-mode fiber, the guided wave is strongly polarized and the state of polarization greatly depends on the constraints applied to the fiber. In this research, we use Thelen's formalism to search for a law of index alternation of a layer stack to reduce the polarization rate for a given incidence. We present some examples of calculated results for low-polarizing beam splitters and, after a short description of the manufacturing techniques used, we compare the theoretical results with the effective performances of the single-mode couplers realied. PMID- 20856367 TI - Mirror quality and efficiency improvements of reflective spatial light modulators by the use of dielectric coatings and chemical-mechanical polishing. AB - To date, silicon backplane spatial light modulators have been characterized by poor-quality mirrors. Hillock formation during metal sintering has been identified as the source of this problem. Here hillock elimination is achieved by constraining the metal with a low-temperature plasma-enhanced chemicalvapor deposition silicon dioxide coating. A double-layer metallization procedure increases the silicon area available for circuitry and improves the mirror fill factor. Second-layer metal mirrors require a flat, intermediate dielectric substrate. Chemical-mechanical polishing is demonstrated to provide the flatness necessary to achieve high optical quality. PMID- 20856368 TI - Optimized design of an antireflection coating for textured silicon solar cells. AB - The short-circuit current density of a solar cell is used as a merit function to optimize solar cell antireflection coating designs. J(sc)/J(max) ratios reach 99%, even with a 10-nm-thick passivation layer. PMID- 20856369 TI - Amorphous silicon and amorphous silicon nitride films prepared by a plasma enhanced chemical vapor deposition process as optical coating materials. AB - Durable, uniform, and reproducible amorphous silicon and amorphous silicon nitride thin films deposited by plasma-enhanced chemical vapor deposition that are appropriate for the design and fabrication of optical interference filters in the near-infrared region are found. Optical and physicalk properties of single layer films are discussed. The durability and performance of Fabry-Perot interference filters and a 15-layer long-pass edge filter in the near-infrared region designed and fabricated with these two thin-film materials are also reported. PMID- 20856370 TI - Reactive evaporation of low-defect density hafnia. AB - Motivation for this work includes observations at Lawrence Livermore National Laboratory of a correlation between laser damage thresholds and both the absorption and the nodular-defect density of coatings. Activated oxygen is used to increase the metal-oxidation kinetics at the coated surface during electron beam deposition. A series of hafnia layers are made with various conditions: two u-wave configuations, two sources (hafnium and hafnia), and two reactive oxygen pressures. Laser damage thresholds (1064-nm, 10-ns pulses), absorption (at 511 nm), and nodular-defect densities from these coatings are reported. The damage thresholds are observed to increase as the absorption of the coatings decreases. However, no significant increase in damage thresholds are observed with the coatings made from a low nodular-defect density source material (hafnium). Hafnia coatings can be made from hafnium sources that have lower nodular-defect densities, lower absorption, and damage thresholds thatare comparable with coatings made from a conventional hafnia source. PMID- 20856371 TI - Effect of an electric field on the growth of aluminum film. AB - An electric field is applied to the substrate during the growth of aluminum films, with the results that the reflectance is increased, scattering is reduced, and the surface is smoothed. PMID- 20856372 TI - Problems of controlling the optical thickness of infrared coatings during deposition. AB - Special problems that influence the accuracy of controlling the optical thickness of infrared coatings during deposition are discussed. PMID- 20856373 TI - Optical coatings deposited by reactive ion plating. AB - The effect of different reactive ion-plating process parameters on the transmittance and the reflectance of single layers of HfO(2), Ta(2)O(5), and SiO(2) are investigated. The optical constants obtained for these three as deposited materials are presented. Laser-damage threshold trends are examined on single- and double-layer coatings at 1064 nm and on high-reflectance coatings for 248 nm. Single- and double-cavity filters are constructed for the UV (< 1-nm bandwidth) and near-infrared (50-nm bandwidth) regions, respectively. After the filters are postannealed in air at 375 degrees C for several hours, a shift in the peak wavelengths is observed along with a substantial increase in the peak transmittance. As expected, no significant wavelength shifts result from changes in the humidity of the ambient atmosphere. PMID- 20856374 TI - Comparative study of titanium dioxide thin films produced by electron-beam evaporation and by reactive low-voltage ion plating. AB - Titanium dioxide (TiO(2)) is often used as a high refractive-index material for multilayer optical coatings. However, the optical properties of TiO(2) films depend strongly on the deposition process and its parameters. A comparative study of TiO(2) films fabricated by conventional electron-beam evaporation and by reactive low-voltage ion plating that uses different phases of Ti-O as starting materials is reported. Results on the variability of TiO(2) thin films are analyzed in relation to process parameters. The potential of fabricating high and low refractive-index multilayer stacks with TiO(2) only, by employing two different deposition processes, is presented with a practical example. PMID- 20856375 TI - Optical properties and environmental stability of oxide coatings deposited by reactive sputtering. AB - Refractory metal-oxide coatings are deposited by reactive dc magnetron sputtering in an oxygen environment. The optical constants and the environmental stability of silicon oxide, aluminium oxide, hafnium oxide, zirconium oxide, tantalum oxide, titanium oxide, and a blend of hafnium oxide with silicon oxide are investigated. Properties of both single-layer and multilayer interference filters are examined. PMID- 20856376 TI - Emission spectroscopy of reactive low-voltage ion plating for metal-oxide thin films. AB - Excited species in the plasma present during reactive low-voltage ion plating (RLVIP) of refractory oxide films are studied by using emission spectroscopy. We believe we have found a higher ratio of atomic to molecular oxygen then reported for earlier analyses that employed a quadrupole mass spectrometer. The application of emission spectroscopy to the RLVIP process and self-actinometry are discussed with examples of stable and unstable processes. PMID- 20856377 TI - Synthesis and research of the optimum conditions for the optical monitoring of non-quarter-wave multilayers. AB - Many optical filtering problems require the use of assemblies of layers with thicknesses that bear no obvious relationship to each other. Here we present the results obtained for a number of examples in which optical monitoring is performed with a change of control wavelengths for each layer of the stack. For this, it is necessary to determine for each layer the different wavelengths that provide an extremum of transmittance when the required thickness is achieved. We show that this leads, in some cases, to making the benefit of error compensation analogous to the well-known method used in the production of quarter-wave stacks. Because ion-assisted deposition and ion-plating techniques are suitable from the point of view of refractive-index reproducibility, optical monitoring can be used at a good level of performance. However, the production of high-quality optical thin films needs more than just the choice of a monitoring process. In particular, problems of uniformity are critical for high-performance coatings. Here we show how uniformity can be determined for each material involved. PMID- 20856378 TI - Improved method for determining the optical constants of thin films and its application to molecular-beam-deposited polycrystalline layers. AB - Polycrystalline, dielectric thin films are grown by the ultrahigh vacuum technique of molecular-beam deposition. A method of calculating the optical constants of such weakly absorbing, homogeneous layers from spectral transmission information alone, with no prior knowledge of their characteristics, is presented. Initially, the procedure uses transmission turning-point data to estimate refractive index and thickness by an analytical approach. These data are then fitted to a function that undergoes an iterative refinement routine by means of a weighted figure of merit to determine with good accuracy the film parameters as functions of wavelength. In this way the optimum conditions for the deposition of materials such as ZnS, ZnSe, LiF, CaF(2), and BaF(2) are found. PMID- 20856379 TI - Characterization by guided wave of instabilities of optical coatings submitted to high-power flux: thermal and third-order nonlinear properties of dielectric thin films. AB - We study the reversible refractive index variations of optical thin films submitted to a high-power light flux. As a preliminary step, we study the thermorefractive coefficient ?n/?T and the laser damage threshold of our materials. From the hypothesis of a localized optical Kerr-type effect, we use the m-line technique to estimate the nonlinear refractive-index coefficients n(2) of TiO(2), Ta(2)O(5), and ZnS films with continuous illumination. Very large values of n(2) are found for the films obtained by conventional evaporation condensation. On the other hand, the study of the change in the decoupling direction of a low-power light guided in a layer disturbed by a pulsed YAG laser gives a first analysis of the phenomena versus time. PMID- 20856380 TI - Optical waveguide characterization of dielectric films deposited by reactive low voltage ion plating. AB - We determine the quality of single films of various oxides, which are deposited on thermally oxidized silicon wafers by reactive low-voltage ion plating (RLVIP), by measuring their optical waveguide losses. We use a prism coupler for inserting the radiation of a wavelength-selectable He-Ne laser into the waveguide and a CCD camera for imaging the light scattered from the surface of the films. The waveguide losses of the RLVIP films are typically of the order of 1 to 10 dB/cm. Some data obtained for TiO(2) layers on thermally grown SiO(2) and RLVIP SiO(2) seem to confirm the presence of an absorbing boundary layer between RLVIP SiO(2) and TiO(2) that has been found in SiO(2)-TiO(2) multilayers. The waveguide measurements also reveal unusual index gradients in thick (~ 10 um) single layers of Al(2)O(3) derived from multimode effective index calculations. PMID- 20856381 TI - Infrared optical absorption loss of antireflection coatings on germanium and potassium chloride substrates at the 10-um wavelength by the photothermal deflection technique. AB - The photothermal deflection technique is used to study the infrared absorption of antireflection coatings on Ge and KCl substrates. The thin films deposited by the thermal resistance evaporation technique, both with and without ion-assisted deposition, are investigated. The experimental results show that Ar-ion bombardment with low energy can evidently reduce the absorption of the coatings. PMID- 20856382 TI - Anisotropy in thin films: modeling and measurement of guided and nonguided optical properties: application to TiO(2) films. AB - The main purpose of this research is to study the anisotropic behavior of dielectric material in thin-film form. First we present a theory based on a 4 * 4 transfer matrix linking tangential components of the electromagnetic field on one interface to the tangential components of the electromagnetic field on the other interface of an anisotropic thin film. A biaxial model is associated with the columnar structure of the layer. The comparison between measurements of the transmission in normal incidence in cross-polarized light and of guided-mode propagation constants with the calculations allows us to study the biaxial behavior of TiO(2) films. The excellent consistency between measurements and computations demonstrates the validity of the model based on the columnar structure. PMID- 20856383 TI - Absorption and thermal conductivity of oxide thin films measured by photothermal displacement and reflectance methods. AB - Photothermal reflectance and photothermal displacement measurements of optical absorption and thermal conductivity are reported for electron-beam-(EB) deposited and ion-plated (IP) thin films of TiO(2), Ta(2)O(5), and ZrO(2). Of the particular set of samples investigated, the EB films have higher absorption than the IP films. The absorption of the EB samples decreases over a period of ~ 90 min on irradiations with an Ar-ion laser of 488-nm wavelength. By contrast, the absorption of the IP samples changes insignificantly or not at all. Photothermal displacement area scans of coating surfaces yield lower defect densities for the IP samples compared with the EB samples for all three oxide materials. The feasibility and limitations of photothermal measurements for thin-film optical and thermal characterizations are discussed. PMID- 20856384 TI - Effects of vacuum exposure on stress and spectral shift of high reflective coatings. AB - Coating stress and spectral shift are affected by changing from ambient to vacuum environments. This change can affect optical systems that are aligned in air and used in a vacuum or in a dry environment. Spectral shifts up to 3% and reflected wave-front changes up to 0.35 waves peak to valley are reported for conventional electron-beam deposition and ion-assisted deposition. Alternatively, ion-beam sputtered coatings have virtually no changes between different pressure environments. PMID- 20856385 TI - Thin-film optical coating filter stability under different environmental conditions. AB - Experiments are conducted to determine the degree of moisture effects in optical thin-film coatings, to determine how to specify moisture stability of these films, and to ensure that performance levels are met after these films are exposed to all anticipated environmental conditions. Three testing techniques, an air oven, a vacuum oven, and water immersion, are evaluated to determine which techniques best characterize the moisture stability of these films. The filters tested fall into three categories, based on their degree of stability: type I, which are inherently stable, type II, which are basically stable except under extreme conditions, and type III, which are unstable. PMID- 20856386 TI - Method for calculating optical coating stabilities. AB - The reflectivity R of a multilayer stack and its first and second derivatives with respect to the phase change are derived here by a recursive method. These equations improve the determination of stability conditions for coatings and widen the applications to treatments other than antireflection coatings, as reported by Mouchart [Appl. Opt. 16, 2486 (1977)]. Some calculations are performed on grazing incidence antireflection coatings, all-dielectric mirrors, and bandpass filters with non-quarter-wave layers. PMID- 20856387 TI - Least-squares estimators for the center and radius of circular patterns. AB - Applying the least-squares methods to data points of a pattern border, we have estimated the center and radius of a circular pattern. PMID- 20856388 TI - White-light directional false color coding in discrete imagery. AB - A white-light optical signal-processing technique is presented to color encode directional edges present in discrete-tone black and white imagery in real time with colors that are available in the white-light source. PMID- 20856389 TI - Measurement of the numerical aperture and f-number of a lens system by using a phase grating. AB - A simple method for measuring both the numerical aperture and the f number of a lens system by means of a phase grating is described. PMID- 20856390 TI - Noise limitations in solid state photodetectors: comment. PMID- 20856391 TI - Optical switching in cadmium telluride using a light-induced electrode nonlinearity. AB - An optically controlled buildup and erasure of an electric field under the negative electrode in CdTe:In is reviewed both experimentally and theoretically. Below-band-gap impurity-absorbed light (850-920 nm) results in the buildup of a region of very high electric field (E ~ 20 kV/cm) under the negative electrode. Illumination at wavelengths above or near the band gap (800-840 nm) can erase the high electric fields. The writing and erasure of the field follow the illumination pattern and can therefore be used, when combined with the electro optic or electroabsorption effects, for one- and two-dimensional infrared spatial modulators with signal beams in the 900-1500-nm range. Switching times are a few hundred nanoseconds at moderate intensity levels (milliwatts per square centimeter). We demonstrate a one-dimensional latching array with 170 line pairs/cm resolution, submicrosecond response, and 12-pJ/pixel switching energy. We also demonstrate a two-dimensional infrared spatial light modulator, similar to the PRZ, which uses this effect. The optically controlled electric fields are large enough for sizable Franz-Keldysh effects, and we demonstrate these effects in both one- and two-dimensional devices. PMID- 20856392 TI - Quasi-equal-path electronic speckle pattern interferometric system. AB - Limitations of a quasi-equal-path electronic speckle pattern interferometric system are discussed. We show that by replacement of the reference glass plate with a plano-concave lens the quasi-equal-path electronic speckle pattern interferometric system can be made more versatile. An arrangement to reduce the aberration in the reference beam is also presented. PMID- 20856393 TI - Reflective optical ring-array interconnects: an optical system design study. AB - We present a reflective optical ring-array interconnect architecture for handling data routings under various single-instruction-multiple-data array processing environments. The proposed architecture can perform clock-skew-free optical data communications for either a fixed-degree model, such as a nearest-neighbor network, or a variable-degree model, such as a plus-minus-2(i) network. It is found that space-variant routings, which are difficult to perform in a rectangular-array opto-electronic integrated circuit, can easily be mapped into rotation-invariant routines for optical implementation by a ring opto-electronic integrated-circuit array. Our system study also shows that the design of the optical imaging system for interconnecting a ring array of nodes is much easier than that for interconnecting a conventional rectangular-array topology. Design principles for both the individual optical components and the entire optical system are described. The optical network performance parameters, such as the diffraction- and aberration-related processing capabilities, the optical transmitter coupling efficiency, the optical free-space power distribution loss, and the power-dependent element bit rate, are analyzed. PMID- 20856394 TI - Optimization of alignability in integrated planar-optical interconnect packages. AB - The efficiency of power transfer and the alignability of an integrated planar optics holographic optical backplane for board-to-board interconnections are analyzed. Both the efficiency and the alignability are functions of lateral and angular offsets in the input, the error in the spatial frequency of the hologram, errors in the source wavelength, the distance between two boards, the thickness of the substrate, the sizes of the hologram and the beam spot, and the angle of propagation of the beam. From the analyses, design guidelines on integrated planar-optic interconnects are developed, and it is shown that the interconnect design can be optimized for maximum alignability. A design with optimum alignability may not have the highest possible peak efficiency, but it can tolerate greater offsets without a substantial efficiency decrease. PMID- 20856395 TI - Optical neural network using vector-feature extraction. AB - An optical neural network model and a key device for its optical implementation are proposed. The model, named the vector-feature-extracting optical neural network, can correctly recognize hand-written letters and can easily be implemented in optics. The key device, named a feature-extracting optical neuron device, can selectively extract specific line segments included in an optical input pattern. In this paper the structure and recognition process of the vector feature-extracting optical neural network are shown in detail. The function of the feature-extracting optical neuron device is experimentally shown. In addition, the optical system based on the vector-feature-extracting optical neural network is described. PMID- 20856396 TI - Ferroelectric liquid-crystal-based binary optical memory employing feedback. AB - A two-dimensional bit-oriented refreshing optical memory that is loosely based on the design of an electronic flip-flop is presented. The test system consisted of two amorphous-silicon liquid-crystal optically addressed spatial light modulators placed into an inverting configuration to provide a stable refreshable memory element. A description of the optically addressed spatial light modulator device and its operation is presented. The optical design of the memory with the optically addressed spatial light modulator is described, and timing and component requirements are delineated. The results and analysis of testing for a one-pixel memory system are reported. The expected requirements and limitations of a multipixel system are discussed. PMID- 20856397 TI - Maximum entropy restoration of blurred and oversaturated Hubble Space Telescope imagery. AB - A brief introduction to image reconstruction is made and the basic concepts of the maximum entropy method are outlined. A statistical inference algorithm based on this method is presented. The algorithm is tested on simulated data and applied to real data. The latter is from a 1024 * 1024 Hubble Space Telescope image of the binary stellar system R Aquarii, which suffers from both spherical aberration and detector saturation. Under these constraints the maximum entropy method produces an image that agrees closely with observed results. The calculations were performed on the MasPar MP-1 single-instruction/multiple-data computer. PMID- 20856398 TI - Extracting properties of multiple-scene objects from autocorrelation features. AB - Information about objects in a scene can sometimes be extracted directly from a spatial autocorrelation function (or equivalently, a power spectrum). Such information may be the quantity of ultimate interest, or it may constrain or provide trial solutions for an iterative image reconstruction. Previous research has described extraction of the most basic of such information, consisting of the number ofobjects present and their relative positions. From there it is possible to unfold certain properties of individual extended objects (that is, two dimensional image-plane brightness distributions). I show that when several objects are present, their defining parameter values can be extracted from the corresponding properties of subsidiary features in a set of spatial autocorrelation data by use of a least-squares approach. Furthermore, many potential ambiguities in the single-object case do not arise with multiple objects. PMID- 20856399 TI - Optical on-axis imperfect phase-only correlator using liquid-crystal television. AB - We present a VanderLugt-type optical phase-only correlator that uses the currently available liquidcrystal television. Theoretical and experimental results show that phase mismatching and phase and amplitude cross coupling of the liquid-crystal television can reduce the peak intensity to approximately 60%-70%. The imperfect phase-only filter yields on-axis correlation with high light efficiency and utilizes all the available space-bandwidth product of the liquid crystal television. PMID- 20856400 TI - Method for multilevel threshold of binarization in a hybrid joint Fourier transform correlator. AB - A hybrid system is proposed that performs joint transform correlation with a multireference by use of a self-generated threshold function. PMID- 20856401 TI - Characterization of a novel focusing/tracking technique with increased feedthrough immunity for optical-disk applications: the double-astigmatic method. AB - The astigmatic-focusing/push-pull tracking-error detection method is an elegant and sensitive optical servo technique. Unfortunately the formation of error signals far from either line focus of the astigmat (for relaxing alignment tolerances and broadening the servo's acquisition range) gives rise to undesired diffraction effects in the focus servo channel owing to track crossings of the pregrooved disk by the optical stylus, especially if certain aberrations are present. These undesired effects are given several names: pattern noise, optical servo cross talk, and feedthrough. By combining two astigmatic lenses and their associated detectors, one can configure a differential variant of the astigmatic technique. This double-astigmatic method greatly reduces pattern noise caused by the presence of spurious astigmatism oriented with its line foci at +/-45 degrees to the disk tracks. In this paper we present numerical modeling and experimental data that demonstrate the effectiveness of this focusing/tracking technique in feedthrough suppression. PMID- 20856402 TI - Acousto-optic tapped delay-line filter. AB - An acousto-optic tapped delay-line finite-impulse-response filter that operates at a system intermediate frequency without requiring a reference optical beam is introduced. Principles of operation are theoretically derived and used to model the system frequency response and multiple-tap cross-talk performance. As an element of this derivation, a focused optical illumination of a diverging acoustic wave is analyzed. Experimental results are also provided for a multichannel acousto-optic tapped delay line operational over a 10-MHz bandwidth at an 80-MHz intermediate frequency. PMID- 20856404 TI - Nasa patter. PMID- 20856403 TI - Time-domain optical memory for image storage and high-speed image processing. AB - We present an experimental study on the use of the time-domain optical memory for image storage and high-speed image processing. We focus on examining the fidelity of the recalled images and their spatial resolution as well as various image processing operations offered by the memory. The recalled images were found to be of good quality because of their phase-conjugate nature. This unique feature further motivated us to examine the feasibility of fiber optics being used for image transmission, an issue important to the development of such a memory device. Two primary processing operations, two-image convolution and correlation, were demonstrated, and implications of the results for high-speed pattern recognition and optical interconnections are discussed. PMID- 20856405 TI - Measurement of polarization mode dispersion and modal birefringence in highly birefringent fibers by means of electronically scanned shearing-type interferometry. AB - A method for measuring modal birefringence and polarization mode dispersion in highly birefringent fibers is presented. It employs a white-light interference phenomenon arising between polarization modes as a result of mode coupling induced by a pointlike lateral force applied in approximately one half the length of the tested fiber. This permits the use of a Wollaston prism without a delay line as an analyzing interferometer. Results of measurements of modal birefringence and polarization mode dispersion at lambda(0)= 826 nm are reported for four commercially available fibers: the York Bow-Tie, the Fujikura Panda, the Andrew E-type, and the Andrew D-type. PMID- 20856406 TI - Long-atmospheric-path measurements of near-visible absorption lines of O(2) isotopes and H(2)O with a prototype AlGaAs laser transceiver system. AB - Near-visible absorption lines of ambient H(2)O vapor and normal and heavy isotopes of O(2) have been measured over atmospheric paths of up to 0.46 km by using two wavelength-modulated, line-locked AlGaAs laser sources with a retroreflector-telescope system. The absolute signal levels agree with theoretical calculations for the O(2) isotopes to within 2%, which is similar to the accuracy with which the column densities were known. Measurements of (16)O(2) linewidths and line strengths were made, and they agree with literature values to within experimental error. The detection sensitivity for (16)O(18)O was found to be 0.1 part in 10(6) atm. km, correspondingto an absorbance sensitivity of 1 * 10(-5). It is concluded that atmospheric trace-gas sensing will be feasible with this apparatus over distances of several kilometers and at levels under 1 part in 10(6). PMID- 20856407 TI - Laser Stark spectrometer for the measurement of ammonia in flue gas. AB - The physical background of a laser Stark spectrometer dedicated to the measurement of ammonia slip through DeNo(x) reactors in power stations is treated. The dependence of the ammonia measurement on temperature and pressure variations is derived and verified experimentally. Selection of spectral lines with both a good absorption coefficient and a high sensitivity to the Stark effect, within the range of the CO(2) laser, has been carried out. If a (12)CO(2) laser is used at a temperature of 573 K and at atmospheric pressure, the 10R8 laser line is recommended for best results. The 10R18 line of the (13)CO(2) laser yields a still higher sensitivity (detection limit 0.4 ppm) for a moderate electric field. Theoretical predictions for the sensitivity of ammonia detection are compared with experimental data. Results of measurements in an industrial environment are presented. PMID- 20856408 TI - Evanescent-wave infrared spectroscopy of solid materials using deformable silver halide optical fibers. AB - Silver-halide crystalline infrared optical fibers are used for infrared evanescent-wave spectroscopy of solid materials. The fiber is pressed onto the material to be studied and good contact is achieved either by elastic or plastic deformation of the ductile fiber. The absorption-signal level is determined by the length and pressure of contact. This method allows convenient measurement of the absorption signals in large samples that cannot be introduced into an IR spectrometer and in materials that are practically opaque so that their spectra cannot be obtained by conventional transmission measurements. Examples of measurements of hard polymers are given, and the evanescent-wave spectra of polyethylene are compared with conventional transmission measurements. PMID- 20856409 TI - Unstable resonator modes for lasers with circular mirrors and high Fresnel numbers. AB - The design of unstable resonators for large lasers with high Fresnel numbers and circular mirrors requires an ability to calculate their mode structures. Four methods for obtaining mode structure by solving the complex integral equation are analyzed. Included are a numerical method, two hybrid methods, and a virtual source method. The hybrid methods are basically analytical methods with special numerical integration of analytical solutions (over the feedback mirror) to obtain improved solutions in the output annulus. The hybrid methods are designed for use with high-Fresnel-number resonators. However, their applicability extends into the low-Fresnel-number regime, where a comparison shows one of the hybrid methods agreeing exceptionally well with the numerical method. For analysis at high Fresnel numbers, the hybrid and virtual-source methods are compared with each other. The two hybrid methods are expected to differ from each other in the central core region when the Fresnel number is low, but they are expected to agree with each other when the Fresnel number is high. For the hybrid comparison at a high Fresnel number, the next to lowest loss modes show a similar structure. However, lack of agreement for the lowest loss mode shows that approximations in the development of the second hybrid method cause the selection of the wrong geometrical mode. PMID- 20856410 TI - Nonlinear propagation and transformation of arbitrary laser beams by means of the generalized ABCD formalism. AB - The evolution of non-Gaussian and nonspherical high-power laser beams in cubic nonlinear media is described by means of their mean or gross parameters: width, mean curvature radius, and quality factor. The influence of the beam over its own propagation is contained in a new mean parameter that measures the ability of a beam to build its own waveguide. Beam quality and threshold power for self focusing are connected. The ABCD and invariance laws for modified complex beam parameter and quality factor allow one to transform in one step the mean beam parameters through a sequence of nonlinear propagations, lenses, mirrors, and nonlinear quadratic graded index. PMID- 20856411 TI - Analysis of laser beam quality degradation caused by quartic phase aberrations. AB - Simple formulas are derived for the degradation in the beam-quality factor, M(2), of an arbitrary laser beam caused by quartic phase distortions such as those that might occur in a spherically aberrated optical component, a thermally aberrated laser output window, or a divergent beam emerging from a high-index dielectric medium as in a wide-stripe, unstable-resonator diode laser. A new formula for the defocus correction that is needed to collimate optimally a beam with quartic phase aberration is also derived. Analytical results and numerical examples are given for both radially aberrated and one-dimensionaltransversely aberrated cases, and a simple experimental measurement of the beam-quality degradation produced by a thin plano-convex lens is shown to be in good agreement with the theory. PMID- 20856412 TI - Multirod unstable resonators for high-power solid-state lasers. AB - The properties of positive-branch and negative-branch unstable resonators with variable reflectivity mirrors and several variable internal lenses were investigated both theoretically and experimentally. Design rules for optimized unstable resonators for one or more active elements are derived on the basis of the ABCD matrix formalism. Experiments were performed with a pulsed Nd:YAG system consisting of three 6 in. * 3/8 in. (15.24 cm * 0.95 cm) rods. This system provided a maximum output power of 550 W per rod when a symmetric flat-flat resonator was used. Unstable resonators achieved up to 75% of this maximum value with beam-parameter products between 2 and 10 mm mrad. The beam quality becomes worse as more active elements are used inside the resonator. This deterioration of focusability is caused by spherical aberration in combination with differences of refractive power for r and Phi polarizations. PMID- 20856413 TI - Geometrical representation of Gaussian beams propagating through complex paraxial optical systems. AB - Geometric relations are used to study the propagation environment of a Gaussian beam wave propagating through a complex paraxial optical system characterized by an ABCD ray matrix in two naturally linked complex planes. In the plane defined by beam transmitter parameters Omega(o) and Omega, the propagation path is described by a ray line similar to the ray line in the y? diagram method, whereas the path in the plane of beam receiver parameters theta and Lambda is described by a circular arc. In either plane the amplitude, phase, spot size, and radius of curvature of the Gaussian beam are directly related to the modulus and argument of the complex number designating a particular transverse plane along the propagation path. These beam parameters also lead to simple geometric relations for locating the beam waist, Rayleigh range, focal plane, and sister planes, which share the same radius of curvature but have opposite signs. Combined with the paraxial wave propagation technique based on a Huygens-Fresnel integral and complex ABCD ay matrices, this geometric approach provides a new and powerful method for the analysis and design of laser systems. PMID- 20856414 TI - Observation of Kastler ring emission from a short-cavity laser. AB - Conical ring emission from a short-cavity dye laser has been observed and modeled as Kastler rings, that is, the high-angle emission modes of a plano-plano (Fabry Perot) laser cavity in agreement with the predictions made 31 years ago by Kastler [Appl. Opt. 1, 17 (1962)]. The excitation of the discrete rings is due to a transfer of energy from the axial modes rather than to spontaneous emission. The mechanism for energy transfer is argued to be scattering of light from imperfections on the mirror surfaces. PMID- 20856415 TI - Characteristics of a downstream-mixing CO(2) gasdynamic laser caused by behavior of two supersonic flows in a laser cavity. AB - A combustion-driven downstream-mixing CO(2) gasdynamic laser (GDL) is developed. When the total mass flow rate is ~ 2 kg/s and the combustion gas temperature is 1750 K, a small-signal gain coefficient of up to 0.6% cm(-1) and a laser output power as high as 11 kW are measured. To explain the experimental values, a mixing loss factor was previously introduced into an analytical model incorporating the three-temperature kinetics model. In the present study, a numerial analysis and further experiments are carried out to clarify the mixing behavior of two supersonic flows in the laser cavity. A measuring method for the average static temperature in the laser resonator is adapted, and it is made clear that, with the current state of supersonic nozzle manufacturing technology, two supersonic flows will not mix well. PMID- 20856416 TI - Design of a stabilized He-Ne laser by using a thin-film heater. AB - Details concerning the design of the stabilization system for a He-Ne laser based on a two-mode method that uses a thin-film heater are discussed. The stability is evaluated by measuring the beat signal between two stabilized lasers; it is 1.1 * 10(-12), expressed in terms of the root Allan variance (tau = 35 s). PMID- 20856418 TI - 1079.5- and 1341.4-nm: larger energy from a dual-wavelength Nd:YAIO(3) pulsed laser. AB - On the basis of oscillation conditions of simultaneous multiple-wavelength lasing that we have established, a larger-energy (1079.5 and 1341.4 nm) dual-wavelength Nd:YAlO(3) pulsed laser has been developed. Output energies of 3.71 and 1.39 J with efficiencies of 1.29% and 0.48% for the 1341.4-and 1079.5-nm wavelengths, respectively, have been achieved. To our knowledge, this is the best result among simultaneous dual-wavelength solid-state lasers to date. The temporal and spatial distributions of these beams obtained from a free-running dual-wavelength Nd:YAlO3 pulsed laser have also been measured. Experimental results show that the temporal and spatial overlap of the two beams is quite good for this type of laser. PMID- 20856417 TI - KrF laser-pumped dye-laser studies. AB - Dye-laser efficiency measurements were performed on four Coumarin dyes: C-485, C 498, C-500, and C-503, all operating near 500 nm. They were pumped with a 16-ns pulse-length KrF laser. The most efficient of the Coumarin dyes tested was C-498. The intrinsic efficiency of this dye was found to increase with pump rate. At a pump rate of 2 MW/cm(2), an intrinsic efficiency of > 20% was measured. Longer KrF laser pulses (> 1.2 us) were also used to pump C-498 and resulted in comparable laser efficiencies at similar pump rates. The temporal relationship between the input KrF laser pump pulse and the output dye-laser pulse was studied and was found to differ significantly for long and short pulses. Significant improvement in long-pulse laser performance was observed when the laser-cavity configuration incorporated a skip mode. PMID- 20856419 TI - FM mode-locked, laser-diode-pumped La(1-x)Nd(x)MgAl(11)O(19) laser. AB - We report the operation of a laser diode pumped La(1-x)Nd(x)MgAl(11)O(19) laser mode locked by an electro-optic phase modulator. The repetition rate of the laser was 230 MHz, and the average output power was 50 mW, when pumped by a 500-mW broad-stripe laser diode. Transform-limited pulses of 14 ps duration were obtained. We have also demonstrated the FM operation of this laser, with bandwidths of up to 440 GHz being obtained. PMID- 20856420 TI - Influences of noise on the occurrence of period doubling in distributed-feedback laser diodes under direct-current modulation. AB - The influences of Langevin noise on period doubling (PD) of a strongly modulated distributed-feedback laser have been investigated. The onset of PD was confirmed to be reduced through the use of the rate equations as a model. The threshold values of PD were examined in terms of driving frequency and rf power and have been compared with the measurements of PD. PMID- 20856421 TI - Optical frequency shifter technique based on stimulated Brillouin scattering in birefringent optical fiber. AB - An optical technique for producing a heterodyne carrier frequency suitable for electronic signalprocessing schemes in sensing applications is described. The technique exploits stimulated Brillouin scattering (SBS) generated in birefringent optical fiber. Systems based on single-fiber and dual-fiber topologies are reported that yield 10.6 +/- 8.0- and 665 +/- 10.0-MHz carrier frequencies, respectively. Frequency instabilities arose from nonlinear dynamical effects inherent to the SBS process. The implications of the results for future signal-processing and sensing schemes based on SBS are then discussed. PMID- 20856422 TI - Hot images from obscurations. AB - Certain damage observed on the optics in NOVA is consistent with a phenomenon akin to holographic imaging. (NOVA is the Lawrence Livermore National Laboratory's 10-beam Nd:glass laser used for inertial confinement fusion research.) The minimization of similar damage in next-generation laser systems is sought by first identifying the sources for these holographic images, specifying glass parameters appropriately, and staging the amplifier chain to circumvent the problem. The insight gained has lead to an explanation for a 20-year-old puzzle. PMID- 20856423 TI - Approximate effective nonlinear coefficient of second-harmonic generation in KTiOPO(4). AB - A simplified approximate expression for the effective nonlinear coefficient of type-II second-harmonicgeneration in KTiOPO(4) was obtained by observing that the difference between the refractive indices n(x) and n(y) is 1 order of magnitude smaller than the difference between n(z) and n(y) (or n(x)). The agreement of this approximate equation with the true definition is good, with a maximum discrepancy of 4%. PMID- 20856424 TI - Spectral modulation of two coherently separated femtosecond laser pulses: comment. AB - In this comment the modulation is explained by the pulse lengthening that is caused by the path-length difference that accompanies the grating spectrometer. It is proposed that such a path-length difference is a direct function of the resolution of any type of spectrometer or monochromator. PMID- 20856425 TI - Diameter measurement of single-mode fiber by using interferometric and imaging techniques. AB - Two methods to measure the cladding diameter of single-mode fibers are presented. The first method is based on an interference fringe measurement technique. Interference fringe spacing at two different planes is measured to determine the cladding diameter of the fiber. The theory of the fringe formation in the interferometeric arrangement using single-mode fibers is discussed. It is theoretically shown that the far-field overlapping Gaussian field distribution from the fibers shifts the position of the fringe maxima and minima. As a special case of unit fringe visibility the minima positions do not shift, whereasthe maxima positions are shifted. In the case of a Lloyd mirror arrangement it is shown that fringes can be obtained from a rough surface as well. A lens is used in the second method to image the two identical point sources that cause the interference. Through the use of the magnification and spacing of the images, the cladding diameter is estimated. It is shown that the accuracy of the fiber cladding-diameter measurement can be enhanced by generating multiple point sources. Consistent results of the fiber cladding diameter have been obtained with the proposed methods. Fiber cladding-diameter measurements with a standard error of less than 0.15 um can be achieved. PMID- 20856428 TI - High-contrast channel waveguide switch with two sections of a nematic liquid crystal covering. AB - Theoretical and experimental results for waveguide modes with a distinctive channel waveguide switching geometry are presented from the viewpoint of improving the switching contrast for hybrid-mode propagation. The channel waveguide structure consists of two types of active material covering regions of a nematic liquid crystal; one has a pair of strip electrodes, and the other is without electrodes. An experimental switch is demonstrated to have the contrast ratio of 1430 for the hybrid modes with E(1n)(y) primary components. PMID- 20856426 TI - Interlaboratory comparisonof mode transition matrices. AB - An interlaboratory measurement round-robin was conducted by the University of Colorado and three industrial members of the Electronic Industries Association. A computational definition of mode transition matrices (MTM's) is presented, and its relationship to the basic theory of power propagation in multimode fibers is detailed. Measured data from the round-robin were used to calculate MTM's for the test components, which included four connectors, two sections of fiber cable, two power splitters, and two short fiber segments. The diagonal elements of the (2 * 2) MTM's determined from the near-field data were found to have a laboratory-to laboratory standard deviation of approximately 10% of the average value. The off diagonal elements were found to have a standard deviation approaching their mean value. The inherent launch dependence of MTM's is investigated as a source of the observed variation. Other sources of uncertainty such as errors in determining the core radius are alsoconsidered. Finally the implications of these results for the problem of characterizing components' intensive multimode fiber systems are discussed. PMID- 20856427 TI - Grating coupler acceptance design utilizing a tapered waveguide structure. AB - A tapered waveguide film was deposited on a substrate with a grating structure resulting in a hybridthin-film waveguide coupler that could be designed for a broader or narrower acceptance for wavelength or incidence angle. The optimized couplers were designed and fabricated. The couplers were found to be as efficient as traditional grating couplers but with much broader acceptance. The maximum broadening was calculated to be a coupling FWHM of 2 degrees (or 12 nm) and was confirmed experimentally. This is 4.3 times the acceptance of an identical untapered structure. PMID- 20856429 TI - Intracavity transmission ellipsometry for optically anisotropic components. AB - The relative retardation Delta, the orientation of the main axis phi, the polarization-dependent loss angle Psi, and the reciprocal and the nonreciprocal rotation angle rho of optical components can be determined, in principle, by intracavity ellipsometry. The component under test is placed inside a phase modulated cw laser, which causes a change in the beat frequency, beam polarization, and intensity. Using the diode-pumped Nd:YAG-laser ellipsometer, we demonstrate with our preliminary measurements of Delta and phi the feasibility and precision of intracavity ellipsometry for measuring optically anisotropic components. PMID- 20856430 TI - Measurement of optical properties of biological tissues by low-coherence reflectometry. AB - We show that optical properties of dense biological tissues can be determined from backscattered power curves measured by a low-coherence reflectometer. Our measurement approach is based on a first-order scattering theory that relates the backscattered power to the total and backscattering cross sections of scatterers in a turbid medium. As a validation of the technique, measurements were made with a commercially available reflectometer on suspensions of polystyrene microspheres having known optical properties. With this reflectometer, which employs a 1300-nm LED source that emits less than 20 uW, we found that skin tissues could be probed to a depth of nearly 1 mm. Estimates of optical coefficients of human dermis and of a variety of excised animal tissues are given. PMID- 20856431 TI - Mid-infrared laser reflectance of moist soils. AB - The effect of varying moisture content on the mid-infrared (9-11-um) laser backscatter reflectance of different soils was investigated experimentally. Total reflectance was separated into a diffuse and a coherent component. Consistent with observations in the visible and near-infrared spectral regimes, the diffuse mid-infrared reflectance values decrease with increasing gravimetric moisture content. At low moisture contents, this phenomenon is attributed to increased forward scattering, while total internal reflection at the water-air interface results in lower reflectance values at higher moisture contents. The coherent component, however, increases initially for low moisture content as a result of the reduction in surface roughness on moistening, decreases subsequently, and then tends to increase again as the moisture content nears the field capacity of the soil. An empirical model based on the above physical mechanisms is developed for the diffuse component and tested by using the measured data. It is conjectured that the laser reflectance is sensitive to moisture in the surface layer (? 0.25-mm depth) and thus may have the potential to monitor near-surface soil moisture. PMID- 20856432 TI - Lidar measurement of the vertical aerosol extinction profiles with range dependent backscatter-to-extinction ratios. AB - An iterative lidar-signal inversion method is presented that is valid for two component (molecular andaerosol) scattering atmospheres. The iterative procedure transforms the original lidar signal, thereby making it possible to use the lidar equation solution for a single-component atmosphere. In a manner analogous to Fernald's approach, the molecular extinction profile is used as a foundation for the boundary-condition determination, but the inversion procedure can be performed with either constant or variable (range-dependent) phase functions. A specific region in the measured range is located at which the ratio of the aerosol to molecular extinction coefficients is a minimum as determined by an examinationof the lidar-signal profile; for this region boundary conditions are specified. PMID- 20856433 TI - Dimensionality in optical fields and signals. AB - The spatial chaos in optical fields that result from diffraction of plane waves by random-phase objects with a larger-than-unity phase dispersion is studied. An analog method for evaluating the dimension of chaos in the field is described, and a real-time measuring device that uses this method is proposed. A new method for evaluating the signal-to-noise ratios in optical signals is also proposed. PMID- 20856434 TI - Long-range radiometer measurements with a close-range reference. AB - A correction procedure is described for the use of a radiometer for transmission measurements. In this application a blackbody is presented to the radiometer at close range as a field calibration. The radiometer is then used to measure atmospheric attenuation by looking at a blackbody source at a much longer range. Three factors that limit the accuracy of this approach to transmission measurements are identified, and a correction factor is derived. The theoretical correction factor is verified by measurements. Excellent agreement between the measurements and the theory suggests that the major factors limiting this technique have been identified and properly accounted for. PMID- 20856435 TI - Carbon and the optical properties of atmospheric dust. AB - Atmospheric particulate matter was examined to estimate the significance of free carbon as an absorber of near-ultraviolet, visible, and near-infrared radiation. Bulk and size-fractionated samples have been disassembled into acetone-soluble, water-soluble, and insoluble fractions. The absorption coefficients for these fractions, and for the insoluble material after removal of the free carbon by burning, have been measured. The results show that in the visible and near infrared, free carbon, although not a major component by mass, is by far the dominant absorbing material. These measurements in relation to otherresearch suggest that geographic variations in and anthropogenic contributions to the free carbon content cause much of the variation in the absorption coefficient of atmospheric particulate samples. PMID- 20856436 TI - Tunable diode-laser measurement of carbon monoxide concentration and temperature in a laminar methane-air diffusion flame. AB - The application of tunable diode lasers for in situ diagnostics in laminar hydrocarbon diffusion flames is demonstrated. By the use of both direct absorption and wavelength-modulation (second-derivative) techniques, carbon monoxide concentrations and the local flame temperature are determined for a laminar methane-air diffusion flame supported on a Wolfhard-Parker slot burner. In both cases the results are found to be in excellent agreement with prior measurements of these quantities using bothrobe and optical techniques. PMID- 20856437 TI - Laser diode wavelength-modulation spectroscopy for simultaneous measurement of temperature, pressure, and velocity in shock-heated oxygen flows. AB - Wavelength modulation at 10 MHz of an AlGaAs laser diode, superposed on repetitive linear scans of wavelength, is applied to measure second-harmonic absorption line shapes of oxygen in the A band. Theoretical expressions of the harmonic line shapes, including the effect of laser amplitude modulation and varying modulation depth, are presented. A least-squares fit of the experimental line shapes to theoretical second-harmonic line shapes permits simultaneous determination of the temperature and the pressure. The use of high-repetition rate (10-kHz) linear scans of the studied wavelength region permits application of the technique to high-speed unidimensional transient flows generated in a shock tube; velocity is derived from the Doppler shift of the absorption profiles. PMID- 20856438 TI - Absorption measurements of water-vapor concentration, temperature, and line-shape parameters using a tunable InGaAsP diode laser. AB - A tunable diode laser diagnostic based on spectrally resolved laser absorption has been developed to detect water vapor. The system uses a distributed feedback InGaAsP diode laser, emitting at ~ 1.38 um. The diode laser is tuned in wavelength by modulation of the current, resulting in 1-cm(-1) tuning at 80-Hz repetition rate. The directly measured absorption spectra yield values for water vapor concentration and temperature, as well as a collision-broadening line shape. To our knowledge, we accurately determined required data for H(2)O line strengths and self-broadening coefficients for several spectral lines in a static cell filled with pure water vapor. The temperature and concentration of the water vapor present in laboratory room air and in the postflame gases above a methane air flat flame burner have also been measured. These results agree well with calculated values and independent measurements. PMID- 20856439 TI - Laser-induced fluorescence diagnostic for temperature and velocity measurements in a hydrogen arcjet plume. AB - A diagnostic has been developed to measure velocity and translational temperature in the plume of a 1-kW-class arcjet thruster operating on hydrogen. Laser-induced fluorescence with a narrow-band cw laser is used to probe the Balmer alpha transition of excited atomic hydrogen. The velocity is determined from the Doppler shift of the fluorescence excitation spectrum, whereas the temperature is inferred from the lineshape. Analysis shows that although Doppler broadening is the only significant broadening mechanism, the fine structure of the transition must be taken into account. Near the exit plane, axial velocities vary from 4 to 14 km/s, radial velocities vary from 0 to 4 km/s, and swirl velocities are shown to be relatively small. Temperatures from 1000 to 5000 K indicate high dissociation fractions. PMID- 20856440 TI - Fiber-optic dual-cylindrical wave sensor for measurement of wall velocity gradient in a fluid flow. AB - A Young's fringe pattern created by two light waves emanating from a pair of slits has been used as the basis of a fiber-optic device for measuring the velocity gradients of flows near solid surfaces. This device is a variant of a dual-beam laser Doppler velocimeter, specialized to direct measurements of wall velocitygradients. A compact version of the device is described in which a fiber polishing technique is employedfor fabrication of a two-point optical source consisting of two fiber cores separated by 18 um. The light from this source is collimated and focused on two slits that are prepared through electron-beam lithography and that are 1 um wide and 10 um apart. Preliminary testing of the compact probe has been successful. PMID- 20856441 TI - Measurement of chromium content in dichromated gelatin by x-ray fluorescence. AB - X-ray fluorescence was applied to the determination of the chromium-ion content in developed dichromated gelatin after exposure. It was found that the Cr(3+) ions irreversibly linked to the gelatin molecules do not exceed one half of the original concentration of the ions. A similar study was carried out on the hardening of dichromated gelatin during dark reaction: as long as the degree of hardening of the gelatin allowed the chromium ions to migrate out of the film during development, the final Cr(3+) content was less than or equal to one half the original concentration. PMID- 20856442 TI - Optical correlation method for studying disperse media. AB - A new optical correlation method is developed for measuring the scattering particle size distribution function. The method is based on the transformation of the transverse coherence function of the scattered field that forms the scattering-particle images. A device for measuring the scattering-particle size distribution function is proposed that has a response time of about 10 s and can be applied to measure particles with sizes in the range of 3 to 500 um to within 10%. PMID- 20856443 TI - Transmission of a pulsed polarized light beam through thick turbid media: numerical results. AB - We present numerical results on the change in polarization state of light pulses transmitted through thick turbid media. These results were obtained with a modified version of a previous Monte Carlo code that takes into account depolarization introduced by multiple scattering. The results have shown that for scattered received power pulse shape, polarization and total received power mainly depend on the transport cross section, sigma(d), of the medium. The effect of the angular field of view of the receiver or of the distance between the diffusing medium and the receiver is shown, whereas the effect of the lateral displacement of the receiver elements proves to be of minor importance. An example of measurements showed a good agreement with numerical results, indicating the adequacy of our numerical code. PMID- 20856444 TI - Effects of asphericity on single-particle polarized light scattering. AB - Polarized light scattering from individual particles has been analyzed to determine the effects of particle shape. Flow cytometric techniques were used on samples of spherical microspheres and naturally occurring marine algae. An analog of the depolarization ratio was obtained by using crossed polarizers in the source and detector of the flow cytometer. Results suggest that differences between the polarized light scattering of spheres and aspherical particles are not discernible unless the scattered intensities are normalized to the forward scattering, which is roughly equivalent to particulate cross section. This research indicates that polarized light scattering, when normalized to particle size, may provide an indication of the extent of asphericity of hydrosols. PMID- 20856445 TI - Bridging the gap between the Rayleigh and Thomson limits for spheres and spheroids. AB - An exact transform of the scattering coefficients that removes the m-related refractive-index restrictions of the Rayleigh and Thomson approximations is presented. The resulting series is valid for all m and small x. A similar but approximate transform for spheroids also is presented. PMID- 20856446 TI - Two-dimensional temperature measurements in a technical combustor with laser Rayleigh scattering. AB - Application of the two-dimensional laser Rayleigh technique to the investigation of a large-scale industrial combustor is reported for the first time to our knowledge. Two-dimensional laser Rayleigh scattering was used to perform quantitative measurements of the temperature fields in different downstream positions of a 150-kW industrial, premixed, turbulent low-emission swirl combustor. Because of the possible interferences of the Rayleigh signal with Mie scattering and laser reflections of the burner components, some minor modifications of the design of the combustor and its gas supply were necessary. This was done without changing the basic characteristics of the burner. The quantitative and instantaneous character of the collected data allows calculation of ensemble-averaged temperature distributions and analysis of the flame structure in the turbulent combustion field. The measured temperature distribution confirms that the flame is stabilized by a central recirculation zone. PMID- 20856447 TI - Absorption and elastic scattering of light by particle aggregates. AB - Light scattering and absorption by spherical particles is extended to aggregates of spheres with arbitrary shape and size. We applied the theory of G6rardy and Ausloos [Phys. Rev. B 25, 4204-4229 (1082)] to compute the total extinction loss spectra of several aggregates of nanometer-sized silver spheres from the near IR to the near UV. Silver was best suited to provide quantitative comparison with experiments concerning the scattering and absorption in the visible spectral region. Additional resonant extinction was obtained besides the resonant extinction of the single silver sphere. The spectra were discussed in detail to give general results that are independent of the particle material. PMID- 20856448 TI - Polarization-dependent phase locking in stimulated Brillouin scattering systems. AB - Measurements of the mutual coherence of the output beams from a seeded, two-pump beam, stimulated Brillouin scattering system are reported. Mutual coherence depends on the relative polarizations of the pump beams and the seed beam. A seed beam can phase-lock the Stokes outputs even if the pump beams are orthogonally polarized. Four-wave mixing is responsible for this phase locking. PMID- 20856449 TI - Measurements of the refractive index of PbEuTe in the 3-10-um region of the infrared: errata. PMID- 20856451 TI - Patents. AB - 5,172,257; 5,191,216; 5,193,015; 5,202,744; 5,202,792; 5,204,516; 5,204,782; 5,208,701; 5,208,877; 5,210,400; 5,210,404; 5,210,409; 5,210,628; 5,210,646; 5,212,584; 5,212,593. PMID- 20856450 TI - From the editor in chief. PMID- 20856452 TI - Fabrication of refractive microlens arrays by excimer laser ablation of amorphous Teflon. AB - The fabrication of refractive microlens arrays by the technique of excimer laser ablation of doped amorphous Teflon combined with the subsequent annealing and melting of the produced polymer islands is described. The microlenses obtained are optically clear from the far UV (190 m) to the near IR (2000 nm) and are of good optical quality. They vary in size from 50 to 385 um in diameter with numerical apertures between 0.2 and 0.3. Utilization of these microlenses for material processingby excimer lasers at 193 nm is demonstrated, and possible applications are discussed. PMID- 20856453 TI - Telescopes of galileo. AB - The Florentine Istituto e Museo di Storia delta Scienza houses two complete telescopes and a single objective lens (reconstructed from several fragments) that can be attributed to Galileo. These optics have been partially dismantled and made available for optical testing with state-of-the-art equipment. The lenses were investigated individually; the focal length and the radii of curvature were measured, and the optical layout of the instruments was worked out. The optical quality of the surfaces and the overall performance of the two complete telescopes have been evaluated interferometrically at a wavelength of 633 nm (with a He-Ne laser source). It was found in particular that the optics of Galileo came close to attaining diffraction-limited operation. PMID- 20856454 TI - Detectors for scanning video imagers. AB - Detectors for scanning video (10-MHz) imagers should be chosen for their high quantum efficiency and internal gain. Because of the high bandwidth both photomultiplier tubes and avalanche photodiodes are limited by photon noise, so that dark noise is not the determining quantity. PMID- 20856455 TI - Artwork diagnostics with fiber-optic digital speckle pattern interferometry. AB - The possibility of employing a digital speckle pattern interferometer with optical fibers for nondestructive testing of artwork has been evaluated. A simple and accurate fiber-optic interferometer, able to perform real-time measurements in a hostile environment, has been realized with a minimum of optical components and a minimum of adjustments. As a result a deformation map of wooden panel paintings or mural frescoes under thermal stress may be depicted. Experimental results, obtained by the application of this interferometer both to laboratory models and to mural frescoes in situ, are presented. PMID- 20856456 TI - Three-wave lateral shearing interferometer. AB - The three-wave lateral shearing interferometer is an interferometer specially designed for optical testing. It determines three noncollinear phase gradients from one single-fringe pattern. From these quantities, two orthogonal derivatives and the measurement error are estimated, allowing the reconstruction of the aberrated wave front. This new interferometer has several benefits; among them is that its sensitivity and dynamics can be easily adjusted to the analyzed aberrations. PMID- 20856458 TI - Anastigmatic tilted Mangin mirror for long-focus imaging systems. AB - A tilted Mangin mirror can be designed to be free of coma and astigmatism and to cancel the chromatic aberrations of refracting components. PMID- 20856457 TI - Algorithm for phase-difference measurement in phase-shifting interferometry. AB - A phase-shifting algorithm is proposed and experimentally demonstrated for phase difference analysis. The method involves only three steps, the original and two equal in amount but unknown phase steps for each stage. Only six frames of data are thus sufficient for the phase-difference analysis between two stages. Real time holographic interferometry with a concentration change in a sugar-water solution in a test cell is presented for experimental verification. PMID- 20856459 TI - Automated spatially scanning ellipsometer for retardation measurements of transparent materials. AB - A highly sensitive and automated technique has been developed for measuring the birefringence in transparent optical materials. The spatially scanning modulated transmission ellipsometer maps the birefringence of a transparent material by probing it with a polarization-modulated He-Ne laser beam. Computer-controlled voltage biasing of a Pockels cell permits self-calibration and background subtraction of the system retardance. The technique is capable of resolving differential retardances as small as 0.1 nm (lambda/6328) through a range of +/ lambda/2, where lambda = 632.8 nm. Samples typically range in size from 50 um to 10 cm in diameter within the sample plane and as much as 400 mm along the optical axis. PMID- 20856460 TI - Computation, visualization, and animation of infrared Mueller matrix elements by scattering from surfaces that are absorbing and randomly rough. AB - Computation of Mueller matrix elements by infrared scattering from randomly rough two-dimensional surfaces and results of a method for graphic display of the data are presented. A full wave electromagnetic scattering model first generates raw data elements of the 4 * 4 Mueller matrix F(theta, nlambda, klambda, sigmas(2), ?h(2)?) in beam backscattering angle (theta) ranging from normal to oblique incidence, in refractive index of the beam scatterer (nlambda - iklambda) spanning the 9 <= lambda <= 12.5 um midinfrared band, and in mean-squared slope ((sigmaS(2)) and mean-squared height (?h(2)?) of the scattering surface. These data are next compressed into a graphics format file occupying considerably less computer storage space and mapped into color images of the Mueller elements as viewed on a high-resolution graphics terminal. The diagonal and two off-diagonal elements are animated in the lambda-theta plane according to varitions in sigmas(2) and ?h(2)?. Predicted elements for polarized IR beam energies on vibrational resonance of the surface molecules, and particularly the off-diagonal elements, show subtle properties of the scatterer as viewed in the animation sequences. PMID- 20856462 TI - Spectroscopic technique for measuring the temperature and pressure cycle of a pressure modulator radiometer. AB - Precise spectral line measurements of carbon monoxide in an operating pressure modulator cell permit independent determinations of the instantaneous gas temperature and pressure. PMID- 20856461 TI - Extremely achromatic f/1.0 all-spherical camera constructed for the high resolution echelle spectrometer of the Keck telescope. AB - We present a very large f/1.O prime focus, all-spherical, all-fused-silica catadioptric camera. It contains a two-element airspaced corrector, an f/0.76 primary mirror, and a singlet final element. It accommodates a chromatic range from 0.3 to 1.1um or more without refocus. It is optimized with an external entrance pupil but can be reoptimized for other pupil distances. In spite of its 30-in. (76.2-cm) focal length, it delivers 12.6-um (rms) average image diameters to a 3.6-in.- (9.1-cm-) diameter flat focal surface. It is thus well matched to the (7-15um) pixels and to the size of a (2 * 2) mosaic of today's largest available CCD's. PMID- 20856463 TI - Confocal image slicer. AB - A confocal image slicer for use in high-resolution spectrography in astrophysics is presented. The deviceimproves the light transmission of a high-resolution spectrograph by an (unprecedented) order of magnitude. The production of a prototype is described, and the first astronomical results obtained with the Anglo-Australian Telescope are presented. The confocal image slicer is being patented and may find useful applications in existing high-resolution spectrographs and in similar instruments planned for the new generation of very large astronomical telescopes. PMID- 20856464 TI - Multilayer-coated grating spectrometer operating in the extreme-ultraviolet region and based on the Seya-Namioka mount. AB - The performance of a spectrometer that uses a blazed multilayer-coated grating and that is based on the Seya-Namioka mount is analyzed. In the extreme-UV wavelength region, the efficiency of the grating is relatively high in a narrow bandpass that is defined by the reflectance of the multilayer coating. The bandpass can be shifted in wavelength by rotation of the grating, as is the case for the Seya-Namioka mount, for which the angle of incidence on the grating is near 35 degrees . It is shown that when the source is slightly off the Rowland circle, as occurs when the grating is rotated and the source-to-grating distance is fixed, one can maintain good focusing can be maintained by moving the detector over a small range of distance and angle. The multilayer coating can be designed so that the grating remains on-blaze in wavelength regions of interest and in particular orders as the grating is rotated. A spectrometer composed of a multilayer grating and a movable detector can have relatively high throughput and resolving power in the extreme-UV region. When the grating is rotated, the wavelength coverage is wider than is the case for incidence angles near normal. PMID- 20856465 TI - High-resolution imaging of laser-produced plasmas at a wavelength of 130 A by a normal-incidence multilayer-mirror microscope. AB - Laser-produced plasmas were imaged by a microscope consisting of spherical, primary, and secondary mirrors in a Cassegrain-type optical configuration. The mirrors were coated with 40 periods of Mo and Si and had a peak reflectance of ~60% at a wavelength of 130 A. Nb, Au, and Al targets were irradiated by as many as 24 beams of the Omega laser at the Laboratory for Laser Energetics at the University of Rochester. The images were recorded on Kodak 101 film, and the resolution was limited by the 10-um emulsion grain size. Two different secondary mirrors produced images with a magnification of 0.8 or 2.2, and a variety of plasma emission features were recorded with 5-um (0.6-arcsec) resolution in the target plane. The possibility of operating a similar microscope in the wavelength region of 34-50 A is discussed. PMID- 20856466 TI - Optical properties of sputter-deposited cerium oxyfluoride thin films. AB - CeO(x)F(y) films were made by reactive rf magnetron sputtering of Ce in Ar + O(2) + CF(4). Stoichiometries between CeO(2) and CeO(1.0)F(1.3) were obtained when the CF(4) content lay between 0% and 9%. For wavelengths lambda of > 0.4 um, the films were almost nonabsorbing, and the refractive index at lambda = 0.55 um went from 2.32 for CeO(2) to 1.62 at 9% CF4(4). At lambda < 0.4 um and <4% CF(4), the optical properties were consistent with an indirect band gap at 3.1-3.2 eV. CeO(2) films could serve as intercalation hosts for Li(+) ions. PMID- 20856467 TI - Optimization of interference filters with genetic algorithms applied to silver based heat mirrors. AB - In the optimization of multilayer stacks for various optical filtering purposes not only the thicknesses of the thin films are to be optimized, but also the sequence of materials. Materials with very different optical properties, such as metals and dielectrics, may be combined. A genetic algorithm is introduced to search for the optimal sequence of materials along with their optical thicknesses. This procedure is applied to a heat mirror in combination with a blackbody absorber for thermal solar energy applications at elevated temperatures (250 degrees C). The heat mirror is based on silver films with antireflective dielectric layers. Seven dielectrics have been considered. For a five-layer stack the sequence (TiO(2)/Ag/TiO(2)/Ag/Y(2)O(3)) is found to be optimal. PMID- 20856468 TI - X-ray focusing using cylindrical-channel capillary arrays. I. Theory. AB - A detailed analysis of the focusing and collimation of x rays by circular-pore microchannel plates (MCP's), or arrays of cylindrical capillaries, is presented. The focusing effect derives from external reflection of grazing-incidence rays at the interior surfaces of the hollow channels of the MCP and is similar to optical focusingby a spherical mirror. We give the point spread function of an MCP, taking into account surface roughness and misaligned channels. The calculation is based on multiply reflected rays and skew rays and is valid for a spherically curved MCP of any thickness. For comparison with experimental results the effects of a finite source and a detector aperture are also evaluated. This theory is compared with experiment. PMID- 20856469 TI - X-ray focusing using cylindrical-channel capillary arrays. II. Experiments. AB - A microchannel plate (MCP) detector blank has been used to focus x rays of 0.154 , 0.62-, and 0.84-nm wavelength generated by a microfocus x-ray tube and a laser produced plasma. The focusing effect of MCP's arises from total external reflection of x rays at the interior channel surfaces. Measurements of the intensity profiles of the images formed by the MCP have been made and compared with the predictions of a detailed model developed in Part I. [Appl. Opt. 32, 6316 (1993)]. It was found that the model gives a reliable description of the data. A consistent set of parameters was found from fits to the data at all three wavelengths. PMID- 20856470 TI - Empirical relations among scattering, roughness parameters, and thickness of aluminum films. AB - Experimental measurements of the angular distribution of scattering and scanning electron microscopy pictures of thin aluminum films were used to relate the total integrated scattering and the statistical parameters of the surface roughness to the film thickness. PMID- 20856471 TI - Linear quadratic Gaussian control of a deformable mirror adaptive optics system with time-delayed measurements. AB - We present a technique for controlling a ground-based deformable mirror adaptive optics telescope to compensate for optical wave-front phase distortion induced by a turbulent atmosphere. Specifically, a predictive linear quadratic Gaussian (LQG) controller is designed that generates commanded control voltages to the mirror actuators based on a set of time-delayed wave-front slope measurements from a Hartmann-type wave-front sensor. PMID- 20856472 TI - Modulation transfer functions of eyes implanted with intraocular lenses. AB - An experimental study of the retinal image quality in aged subjects after their eyes have been implanted with intraocular lenses (IOL's) has been performed. The method is based on recording in vivo the aerial image of a point test, after a double pass through the ocular media, and subsequent computation of the eye's modulation transfer function. The optical performance of three different types of bifocal IOL is compared with that of conventional monofocal IOL's. The results show that eyes implanted with bifocals exhibit a mean reduction in the modulation transfer function (contrast in the retinal image) of a factor of 2, while keeping a resolution similar to that of monofocal IOL's (which explains why visual acuities are also similar in these two cases). The mean retinal image modulation in eyes implanted with monofocal IOL's is ~2.5 times lower than that obtained with young emmetropic subjects, but it seems to be similar to that corresponding to # of persons of the same age (~60 years) normal eyes. PMID- 20856473 TI - Diffraction-free beams generated with programmable spatial light modulators. AB - Diffraction-free beams are generated by the use of diffractive optical elements written on a spatial light modulator (SLM). By alteration of the pattern placed on the SLM, the axis of propagation can be both shifted laterally and rotated. We present experimental results obtained by use of a magneto-optic SLM. PMID- 20856474 TI - Image sensing and processing by a bacteriorhodopsin-based artificial photoreceptor. AB - Sensing and processing of optical information have been conducted with a unique bioelectronic image sensor that immobilizes bacteriorhodopsin (bR) as a photosensitive retinal protein. A thin film of bR-containing purple membranes was coated on a two-dimensional pixel array of electrodes and was made into a junction with an electrolyte gel layer having a counterelectrode to form an artificial photoreceptor. Photocurrent signals from each pixel showed a differential responsivity to light intensity, intrinsic to this liquid-junction photocell. Images detected and processed by the bR-based artificial photoreceptor were simultaneously displayed on a light-emitting-diode monitor panel through parallel signal-transmission circuitry. The experiment revealed that the photoreceptor is, as a retina model, capable of selectively detecting motion of images in real time and of performing vectorial extraction of their edge components, similar to the visual processing function of biological photoreceptors. PMID- 20856475 TI - Precise method of determining systematic errors in phase-shifting interferometry on Fizeau interferences. AB - Fizeau phase-stepping interferometry permits multiple-beam interferences to be evaluated exactly with a resolution in the subnanometer range when a special four bucket algorithm is applied. The step width, which is set at 2pi/4 for the four bucket algorithm, has to be maintained precisely to avoid erroneousphase determination. A method is described by which deviations from the exact value of the step width can be quantitatively determined. In numerical calculations the phase dependence of the step-width error is determined and confirmed by accompanying experiments. Step-width errors recognized by the phase dependence of a difference measurement can be corrected by means of a general four-bucket algorithm. The topography of Fabry-Perot plates can therefore be measured with a high degree of accuracy, of lambda/200. PMID- 20856476 TI - In-plane displacement measurement configuration with twofold sensitivity. AB - An optical configuration is suggested that will achieve a twofold increase in sensitivity when one measures an in-plane displacement component of a deformation vector compared with the Leendertz two-beam illumination method. A theory and experimental demonstration of the method are presented. PMID- 20856477 TI - Determination of the optical function n(lambda) of vitreous silica by spectroscopic ellipsometry with an achromatic compensator. AB - Studies of dielectric materials by rotating-element spectroscopic ellipsometry (SE) are beset with a number of problems such as (1) low reflectance and hence low signal-to-noise ratio and (2) an almost zero (or 1800) change in the ellipsometric parameter A on reflection from the sample, which leads to significant errors in the measured parameters. These difficulties were overcome (1) by developing suitable procedures for correcting nonlinearity in the detection system and the deleterious effects of ambient light and (2) by incorporating an achromatic quarter-wave compensator in the SE system, respectively. A new rapid method of aligning and calibrating the compensator has also been developed. Test measurements with such an SE system on a vitreous silica sample revealed that the accuracy of measurements of Delta and Psi are 0.03 degrees and 0.015 degrees , respectively, over the spectral range of 300 700 nm. The SE data were then analyzed by standard procedures with linear regression analysis to determine the optical function n(lambda) (i.e., refractive index and its dispersion with wavelength) of vitreous silica and at the same time to characterize the microroughness of the surface layer of the sample. The refractive index of vitreous silica determined by this technique is within +/ 0.0004 of the best reported values in the literature over the spectral range of 300-700 nm. The SE data obtained on the vitreous silica sample revealed the presence of a 1.0-nm-thick microrough layer on the surface of the sample. PMID- 20856478 TI - Optical-fiber strain sensors with asymmetric etched structures. AB - Optical-fiber strain gauges with asymmetric etched structures have been analyzed, fabricated, and tested. These sensors are very sensitive with a gauge factor as high as 170 and a flat frequency response to at least 2.7 kHz. The gauge factor depends on the asymmetry of the etched structures and the number of etched sections. To understand the physical principles involved, researchers have used structural analysis programs based on a finite-element method to analyze fibers with asymmetric etched structures under tensile stress. The results show that lateral bends are induced on the etched fibers when they are stretched axially. To relate the lateral bending to the optical attenuation, we have also employed a ray-tracing technique to investigate the dependence of the attenuation on the structural deformation. Based on the structural analysis and the ray-tracing study parameters affecting the sensitivity have been studied. These results agree with the results of experimental investigations. PMID- 20856479 TI - From the editor in chief. PMID- 20856480 TI - Free-space optical mesh-connected bus networks using wavelength-division multiple access. AB - A novel optical free-space mesh-connected bus interconnect network architecture is proposed. A mesh-connected bus [IEEE Trans. Comput. C-30, 264-273 (1981)] is known to have the capability of interconnecting, with a three-stage switching, N nodes with a power distribution loss proportional to ?N and is therefore advantageous for networking a large number, say over 1000, of communicating ports. Based on conventional space-invariant optical components in a compact and efficient geometry, the proposed optical mesh-connected bus system concept can be used to build either free-space optical interconnect links for parallel processing applications or central switching systems for local or global lightwave communication networks. The proposed architecture lends itself to networking under both the wavelength-division multiple access and other multiple access environments. In this paper, based on the wavelength-division multiple access environment, various optical system implementation and performance issues are discused and parameters are analyzed. It was found that by use of a reasonably compact three-dimensional free-space volume, more than 100,000 dispersion-limited communication nodes at a uniform channel spacing of 0.75 nm can be linked with a moderate power distribution loss of 28 dB. Some preliminary optical wavelength-division multiple-access mesh-connected bus experiments based on a 27 * 27 panchromatic optical source array were performed to confirm the operational principle of the proposed concept. PMID- 20856481 TI - Mirror-folded free-space crossbars with holographic implementation. AB - Free-space optical crossbars that utilize elements such as beam splitters and holograms can in principle be folded by two parallel plane mirrors and implemented in a single plane, or even in a single line, parallel to the mirrors. Such crossbars, each performing either a processing or an interconnection function, can in turn be cascaded along a common plane or line between a single set of two mirrors to perform a large class of operations. By use of all possible inputs and outputs, novel power-conserving operations can also be performed. We report on the holographic implementation of a reconfigurable 2 * 2 mirror-folded generalized crossbar with a thermoplastic holographic camera; the bypass, the exchange, and the broadcast states are demonstrated. PMID- 20856482 TI - Spectral window of the acousto-optic folded spectrum analyzer. AB - I derive here the spectral window of the acousto-optic folded spectrum analyzer proposed by [K. Wagner and D. Psaltis, Proc. Soc. Photo-Opt. Instrum. Eng. 564, 209-223 (1985)]. This window function turns out to be quite informative. It clarifies important characteristics that distinguish this system from the more conventional digital spectrum analyzers, and it clarifies the relationships between various system design parameters and helps guide their selection. The spectral window of one specific implementation of a finer-resolution version of this analyzer (the super-fine-resolution variant suggested in the above reference) is also determined. Analysis shows that for certain narrow-frequency ranges this window has two main lobes separated by a large number of super-fine frequency-resolution bins. This characteristic makes it unacceptable in many applications. PMID- 20856483 TI - Copying holograms using light of reduced spatial and temporal coherence. AB - A reduced spatial and temporal coherence light from a halogen lamp is used to copy holographic optical elements, and a maximum diffraction efficiency of 80% is achieved. PMID- 20856484 TI - Material characterization with a simple laser scanning microscope. AB -

The design of a computer-controlled laser scanning microscope is described. It is capable of inspecting a 1 mm * 1 mm area in less than 1 s with an optical resolution of 2 um. Three applications of the laser scanning microscope are presented: the observation of the ferroelectric-domain structure of sodium nitrite layers, the observation of the spatial distribution of the photocurrent in polycrystalline solar cells, and the observation of the lateral distribution of thermoelectric currents in a thermal IR detector for the determination of the thermal properties of its absorber foil.

PACS: 0760P, 7240, 7780D.

PMID- 20856485 TI - Application of three-dimensional micro-optical components formed by lithography, electroforming, and plastic molding. AB - Micro-optics is usually associated with planar waveguides or integrated optical circuits. In this case the propagation of light is restricted to one or two dimensions, and the three-dimensional nature of light propagation is disregarded. We present a method of fabricating three-dimensional micro-optical components by the so-called LIGA process, a lithography, electroforming, and plastic molding process in which poly(methyl methacrylate) is structured by high-energy synchrotron radiation. We demonstrate an experimental system of image formation that uses microprisms and microlenses for a threedimensional microintegration of optical components. PMID- 20856486 TI - Holographic formation of a diode laser nondiffracting beam. AB - We report for the first time, to our knowledge, the characteristics of a so called nondiffracting beam produced by illumination of a binary-phase reflective holographic optical element with light from a diode laser. The Bessel beam has an intensity profile whose pattern changes little over distances of order 1 m and has a 1/e amplitude radius for the central lobe of ~100 um. This beam may have application for alignment of integrated optic elements in which unguided diffraction-free beams are used to align glass-slab elements containing interconnection holograms to a computer board. The aligning Bessel beam would be produced on reflection from a hologram on the glass-substrate interconnecting element. A single hologram may be used for different substrates having different lengths and functionality because of the large depth of field of the Bessel beam. PMID- 20856487 TI - Optoelectronic parallel computing system with optical image crossbar switch. AB - A novel architecture based on free-space optics is proposed for optoelectronic parallel computing systems. The main feature of the proposed architecture is its use of the optical image crossbar switch, a free-space optical switch that can directly switch images (two-dimensional optical signals) without any parallel-to serial conversion. To demonstrate the processing capability of the architecture, I investigate a fully parallel matrix multiplication algorithm for the proposed architecture. PMID- 20856488 TI - Design of space-multiplexed three-dimensional Omega networks and their optical implementation. AB - A method is described for arrangement of channels from different stages of a three-dimensional shuffle/exchange network so that only a single set of optics is needed to perform the two-dimensional shuffles. This arrangement is based on our earlier one-copy algorithm. It requires a feedback system and is an example of a space-multiplexed optical multistage network. We discuss the design issues and experimental results. PMID- 20856489 TI - Photoaddressed spatial light modulator using transmissive and highly photosensitive amorphous-silicon carbide film. AB - A novel photoaddressed spatial light modulator with a highly photosensitive hydrogenated amorphoussilicon carbide photoreceptor and a ferroelectric liquid crystal layer has been developed that operates in a transmission mode for visible light. The hydrogenated amorphous-silicon carbide photoreceptor shows a high photosensitivity comparable with that of hydrogenated amorphous silicon, which is prepared by a plasma chemical vapor deposition method with helium dilution of the source gases SiH(4) and C(2)H(2) An image is input to the photoacdressed spatial light modulator by blue or green light, and an output is read out by red light as a transmitted image. The photoaddressed spatial light modulator exhibits a response time of ~50 us and a contrast ratio of 30:1 under a write light (lambda = 565 nm) of 1.5 mW/cm(2) intensity and a resolution of 90 line pairs/mm. PMID- 20856490 TI - Polarization properties of photopolymers for use in holographic and coherent optical systems. AB - Some polarization properties of photopolymers are determined. Photopolymers on a Mylar substrate alter an incoming linearly polarized laser beam to an elliptical polarization. The extinction ratio is of the order of 10:1 for the samples tested. Polarization effects were found to change over different regions of each sample by approximately +/-10%. The Mylar substrate alone was found to distort the incoming polarization to a comparable degree. PMID- 20856491 TI - Modeling imager deterministic and statistical modulation transfer functions. AB - A unified two-step approach for evaluation of deterministic and statistical modulation transfer functions (MTF's) is applied to a time-delay-and-integration charge-coupled imager. The deterministic MTF's include the well-known spatial and temporal aperture MTF's, as well as the charge-coupled imager interpixel and intrapixel synchronism MTF's, which are derived here. These latter MTF's originate from nonsynchronous motion (velocity mismatch) between the image on the focal plane and the charge packets. The statistical evaluation results in phase and jitter MTF's. PMID- 20856492 TI - Parallel scheme of the iterative blind deconvolution method for stellar object reconstruction. AB - An algorithm for stellar object reconstruction without a reference star is described. The algorithm is based on parallel application of the iterative blind deconvolution method to several speckle frames, and it permits reconstruction of an object that satisfies the convolution relation in all the frames used. Computer simulations with noisy speckle images are carried out to demonstrate performances of the algorithm. The algorithm is applied to observational data of binary stars, and high-resolution images are clearly reconstructed. Binary parameters extracted from the images show good consistency with those obtained both with the power spectrum analysis and with the shift-and-add method. PMID- 20856493 TI - Multitarget detection using spatial synthesis joint transform correlation. AB - A spatial synthesis method that improves accuracy of detection for joint transform multitarget recognition is discussed. The reference function used for the conventional joint transform correlation is replaced by a synthesized function for sharpening correlation profiles without the use of a filter in the Fourier domain. It is shown that the synthesized function can be truncated spatially to fit multiplereference applications and that the effectiveness of this technique is not affected by the number of references. The implementation of the synthesized function, effects caused by noise disturbance, background cluttering, and spectral fringe binarization are investigated. PMID- 20856494 TI - General treatment of spatial light modulator dead-zone effects on optical correlation. I. Computer simulations. AB - In Part I we present an approximate mathematical analysis and exact computer simulations for optical correlation in correlators having pixellated spatial light modulators with transmissive (or reflective) dead zones in both the input and filter planes. We show that the correlation amplitude consists of four terms: a true correlation plus three different types of noise terms originating from the transmissive dead zones in both spatial light modulators; we describe the role that each of these terms plays in the correlation process. We calculate peak intensity, signal-to-noise ratio, and energy throughput efficiency as a function of dead-zone area in both spatial light modulators using either phase-only or matched filters. We utilize a dc block in the filter plane for noise reduction. We also use a filter reference image smaller than the input spatial light modulator size to reduce false correlation peaks. We discuss the effects of fabricating a filter from a filter reference image whose center has been offset rom optic axis. In Part II [Appl. Opt. 32,6536 (1993)] we present a general analytical treatment of our model that can justify the simulation results of Part I. This analysis is applicable even to mixed cases of opaque and transmissive dead zones. PMID- 20856495 TI - General treatment of spatial light modulator dead-zone effects on optical correlation. II. Mathematical analysis. AB - We present a general analytical treatment of optical correlation in correlators that use pixellated spatial light modulators with transmissive (or reflective) dead zones in both the input and filter planes. The active areas of the pixels modulate the light intensity while the dead zones transmit (or reflect) all of the light. Our model can predict the changes in the correlation peak and the signal-to-noise ratio with changes in dead zones, calculated in Part I [Appl. Opt. 32, 6527(1993)] from computer simulations. This model is also a general one: It applies to correlators in which one spatial light modulator contaions only opaque dead zones while the other contains only transmissive dead zones; it also applies to the case in which any one spatial light modulator contains both opaque and transmissive dead zones. PMID- 20856496 TI - Optical realization of the wavelet transform for two-dimensional objects. AB - Real-time wavelet transformations of two-dimensional objects are implemented by use of the conventional coherent correlator with a multireference matched filter. The different daughter wavelets are spatially multiplexed with different reference-beam directions. Two experiments are described, one of them with a spatial light modulator at the input plane in order to enable the real-time property. PMID- 20856497 TI - Investigation of substrate birefringence effects on optical-disk performance. AB - Substrates for magneto-optical disks are produced economically and efficiently by injection molding of polycarbonate plastics. Unfortunately, most plastics are birefringent, with different refractive indices in the plane of the disk (lateral birefringence) and perpendicular to the plane of the disk (vertical birefringence). One manifestation of media birefringence is the existence of a focus offset between the two distinct best-focus positions for data detection and tracking. This focus offset degrades overall system performance as the compromise focus position between the two best-focus points reduces the operating margin of the individual data and tracking channels. We present detailed numerical modeling results on the role of substrate birefringence in causing this focus offset. PMID- 20856498 TI - Hybrid implementation of a real-time Radon-space image-processing system. AB - A unique hybrid optical-digital image-processing system that functions at real time rates and performs analysis in Radon space is presented. This system functions by using the forward Radon transform (a mathematical tomographic transform of image data from two-dimensional image space to onedimensional Radon space), which is achieved by a front-end optical processor followed by a digital processing subsystem operating in Radon space. The system works by optically converting the two-dimensional image data into a series of one-dimensional projections. All further processing is performed digitally in Radon space on the one-dimensional projections. Using the system in transform space, we show that it can perform real-time detection of minimum-resolvable-temperature-difference measurement targets better than a human observer. Also, this paper discusses the potential of real-time object-moment analysis in Radon space. These object moments can be calculated in Radon space with significantly less image data and fewer digital processing operations than in image space. The optical front end is capable of performing 6.04 * 10(10) operations/s on the two-dimensional image data. PMID- 20856499 TI - From the editor in chief. PMID- 20856500 TI - Multipass optical system equipped with thin films for the study of the spectra of cryogenic solids: measurement of the infrared spectrum of solid H(2). AB - A multipass optical system external to the optical head of a cryostat has been designed for use with a Bruker IFS 120 HR interferometer. A White cell using mirrors with a focal length of 10 cm is the central feature of the system. Nearly all optical elements, including those in the cryostat, have been optimized with thin-film technology for maximum signal throughput in the 6000 to 7000 cm(-1) range. The extension of the path length of the sample, in a cell limited to 3.8 cm in length, is illustrated with spectra of solid para-H(2) at 12 K. The cell was limited to four passes in this application because of refraction of the infrared radiation at the sample surface. Twelve to 20 passes are possible for a sample with an index of refraction close to 1 and with smaller aperture settings. PMID- 20856501 TI - Azimuthal mode discrimination of annular resonators. AB - A diffraction formula for annular beam propagation is suggested. Significant computational savings are obtained without restriction to low azimuthal mode orders. Azimuthal mode discrimination is shown to exist in stable annular resonators. High-order azimuthal modes can suffer low diffraction losses with certain mirror parameters. These high-order modes are identified with azimuthal revolving rays that satisfy known geometric relations for multipass resonators. PMID- 20856502 TI - Dichromated gelatin holography: an investigation into laser-induced damage. AB - An investigation into the occurrence of laser-induced damage in a sealed dichromated gelatin hologram is presented. Our research shows that damage appears when the laser beam heats the gelatin above a certain critical temperature. As a way to relate this to the optical power, a model predicting the temperature profile generated by a Gaussian beam is developed and used to calculate the optical damage threshold of a dichromated gelatin hologram. PMID- 20856503 TI - Er:YAG, CO, and CO(2) laser delivery by ZnS-coated Ag hollow waveguides. AB - ZnS-coated Ag hollow waveguides for Er:YAG, CO, and CO(2) laser light are fabricated based on a sputtering and an electroplating technique. Three types of these waveguides with a 1-mm diameter and a 1-m length are fabricated. Two of them are designed to achieve the minimum loss at the wavelengths of Er:YAG and CO laser light, and the other is for all the lasers. Straight losses of 0.4, 0.5, and 0.25 dB/m are obtained for Er:YAG, CO, and CO(2) laser light, respectively. Because the waveguides are flexible and low loss, they are useful in delivery of mid-infrared lasers in industrial and medical applications. PMID- 20856504 TI - Frequency tuning of a distributed feedback dye laser with two transmission gratings. AB - Distributed feedback dye lasers, which use a holographic grating, present a very simple and reliable way to generate ultrashort pulses. We have developed a new technique for wavelength tuning of this type of laser by projecting the image of a second grating into the dye cell. Single-line operating and tuning was demonstrated with transform-limited output pulses on a picosecond time scale. PMID- 20856505 TI - Continuous-wave laser pump light sources: new concepts. AB - The relatively short lifetime of rare-gas discharge pump light sources for high power cw solid-state lasers is caused mainly by vaporized cathode emitter material reacting with the thermally highly loaded quartz wall. The introduction of new bipolar electrodes without special emitter materials mounted on hot-ended molybdenum-cup seals, together with 60-kHz ac operation, makes possible the application of a tungsten halide cleaning cycle within the lamp bulb. This new type of high-power rare-gas pump light source exhibits 20% better radiation efficiency, 20% lower Nd:YAG laser threshold, and considerably extended lifetime. PMID- 20856506 TI - Low-noise operation (-1 40 dB/Hz) in close-coupled Nd:YVO(4) second-harmonic lasers pumped by single-mode laser diodes. AB - Very-low-noise operation (as low as -140 dB/Hz) of close-coupled Nd:YVO(4) lasers is reported. This low noise level has been attained by controlling the spectra of the pumping laser diodes into the single longitudinal mode by suppressing mode hopping. The small-packaged second-harmonic laser (Phi12 * 16 mm) showed highly stabilized 530 nm/6 mW operations with a relative intensity noise of -140 dB/Hz. PMID- 20856508 TI - Interference fringes in the far field of short-external-cavity InGaAsP diode lasers: a method for longitudinal mode control. AB - Interference fringes in the far field of short-external-cavity InGaAsP diode lasers are discussed and explained. The interference occurs between light emitted from the front laser facet and light emitted from the rear laser facet that is reflected forward by the external mirror. The change in the relative phase of light emitted from each facet caused by a change in the longitudinal mode results in a shift of position of a portion of the fringes in the far field. This shift can be detected and processed to produce a discrimination signal that is used in a feedback control system to detect or prevent longitudinal mode hops. The control system has a response time as short as 15 ms and can prevent mode hops caused by drift, mechanical shock, or laser tuning; the technique permitted complete frequency tuning over the range of operation of the laser. The behavior of the control system was analyzed with the help of a model that can be used to optimize the control system. PMID- 20856507 TI - Subnanosecond pulse generation from diode-pumped acousto-optically Q-switched solid-state lasers. AB - Miniature diode-pumped acousto-optically Q-switched solid-state lasers deliver pulse durations as short as 600 ps at wavelengths near 1 um. Specifically, Nd:YVO(4) lasers operating at 1.064 um produce 600-ps/5-kW pulses at 1 kHz, 1.0 ns/2-kW pulses at 20 kHz, and 1.9-ns/0.5-kW pulses at 100 kHz. A Nd:YLF laser at 1.047 um generates 700-ps/15-kW pulses at 1 kHz, and 1.2-ns/4-kW pulses at 10 kHz. At 1.342 um, a Nd:YVO(4) laser produces 3.3-ns/0.8-0.6-kW pulses at 1-10 kHz. PMID- 20856509 TI - Position dispersion and optical limiting resulting from thermally induced nonlinearities in Chinese tea liquid. AB - We employ the z-scan method to distinguish thermally induced nonlinearities from others by varying the beam waist radius and to determine the thermo-optic coefficient of materials. One can attribute the origin of optical nonlinearities of Chinese tea liquid to laser-heating-induced nonlinear refraction while one irradiates the media with a cw He-Ne laser. We also analyze the influence of position dispersion on optical limiting. PMID- 20856510 TI - Multifrequency laser emission generated by two-color stimulated Raman effect using a single-frequency laser beam and a dye-Raman composite resonator. AB - A single-color circularly polarized laser beam is focused into pressurized hydrogen to generate rotational stimulated Raman emission. After being corrected to a linearly polarized beam, this two-color laser beam is passed through a dye amplifier and is focused into pressurized hydrogen, again to generate multifrequency laser emission by the two-color stimulated Raman effect. The laser beam is further confined in a resonator, which enhances intracavity intensity leading to increased efficiency. In these experiments, more than 11 rotational lines are generated simultaneously at 5 atm, and many additional vibrationally shifted rotational lines are generated at 9 atm. PMID- 20856511 TI - Efficient generation and heterodyne detection of 4.75-um light with second harmonic generation. AB - Second-harmonic generation energy conversion efficiencies of CO(2) laser radiation as high as 56% have been measured in 2-cm-long AgGaSe(2) crystals with 30-ns pulses. The value of the nonlinear coefficient d(36), which best fits the measured data, is (32 +/- 4) x 10(-12) m/V. Continuous-wave second-harmonic generation in tellurium generated up to 0.27 mW with an efficiency of 6.8(10)( 5). These pulsed and continuous beams were combined to demonstrate heterodyne detection at 4.75 um, which increased the signal strength of weak signals by at least a factor of 25 over direct detection. Simultaneous heterodyne detection of 5- and 10-um light is demonstrated by use of both the pump and second-harmonic beams from the cw laser as independent local oscillators. PMID- 20856512 TI - Raman or fluorescent scattering by active molecules or ions embedded in a single mode optical fiber. AB - By considering active molecules or ions as a collection of induced oscillating dipoles, we treat the problem of Raman or fluorescent scattering by the active molecules or ions embedded in a single-mode optical fiber theoretically. The analytical expressions and the numerical results for the scattering coefficients and the even-odd mode conversion coefficients of the guided modes are given, based on the method of dyadic Green's functions and on the expansions of the modal fields in terms of the vector cylindrical wave functions. We expect to incorporate the treatments into the analysis of a rare-earth-doped fiber amplifier or a fiber Raman amplifier. PMID- 20856513 TI - Design considerations of an infrared spectrometer based on difference-frequency generation in AgGaSe(2). AB - The availability of new nonlinear optical materials such as AgGaS(2) and AgGaSe(2) and improvements in compact, tunable, pulsed and continuous-wave (cw) solid-state pump lasers now make it possible to generate tunable, infrared narrow band coherent radiation over a wide wavelength range (4-18 um) by means of difference-frequency generation (DFG). This article describes the wavelength and outputpower characteristics of a tunable infrared source based on AgGaSe(2) and certain proven cw near-infrared pump sources for application to high-resolution spectroscopy. PMID- 20856514 TI - Dark spatial solitons in bacteriorhodopsin thin films. AB - We report on the observation of dark spatial solitons in thin solid films containing bacteriorhodopsin. Because of the high nonlinearity of the material, the dark spatial solutions can be easily observed even with a few milliwatts of power from a He-Ne laser. This result promises novel applications for optical switching and optical interconnects. PMID- 20856515 TI - Single-shot measurement of ultraviolet and visible femtosecond pulses using the optical Kerr effect. AB - We present a method that allows the single-shot measurement of femtosecond pulses in the ultraviolet as well as the visible spectral regions. The method is based on the optical Kerr shutter technique, and it provides the third-order intensity correlation function. PMID- 20856516 TI - Distributed loss and mode coupling and their effect on time-dependent propagation in multimode fibers. AB - A first-order solution to the transport equation for the total power propagating in each degenerate mode group of a multimode fiber is used to describe pulse propagation in multimode fibers. The basic transport equation is supplemented by models for Rayleigh-scattering-induced losses, mode coupling, and the modal group velocity function. Each of these models can be specified for a particular fiber from a standard set of near-field measurements and then incorporated into pulse propagation simulations, which closely matched the measured pulse response of test fibers. PMID- 20856518 TI - Densely spaced two-channel wavelength division demultiplexer with an S-shaped two coupler optical fiber ring resonator. AB - It is proposed that an S-shaped two-coupler single-mode optical fiber ring resonator be used as a densely spaced two-channel wavelength division demultiplexer. The dependence of the channel separation and the cross talk on the parameters of the couplers and the fiber, such as the intensity-coupling coefficients and the transmission coefficients of the couplers and the attenuation of the fiber, are studied theoretically. PMID- 20856517 TI - Pulse broadening in graded-index optical fibers: errata. PMID- 20856519 TI - Excimer-laser-induced spatially variant luminescence in pure-silica core fibers with fluorine-doped silica cladding. AB - Optical fibers with pure silica cores of both low and high water content and fluorine-doped silica claddings were irradiated with 248 nm (KrF) excimer-laser radiation. In addition to the differences in the spectra of luminescent emissions of the respective cores, spatial variance was observed in the luminescence behavior across cross sections of the cores. Photographic evidence of this phenomenon is presented along with the corresponding luminescence spectra. Spectral correlations of the spatial variances are made, and the defects that are responsible for the luminescence are discussed. PMID- 20856520 TI - Charge-to-photon transducers for particle detectors for the superconducting super collider. AB - The use of massive arrays of integrated optic intensity modulators is investigated for the purpose of transducing electrical charge to photons for transmission and further processing in the Superconducting Super-Collider. This involved the design of modulator arrays and packaging approaches that are scalable to the large quantities (millions) that are required for this application. A prototype was fabricated and evaluated. PMID- 20856521 TI - Investigation of directional coupler near-end cross talk by laser-induced refractive-index shifts. AB - The near-end cross talk of InGaAsP-InP waveguide directional couplers is investigated. It is shown that the cross-talk level is strongly dependent on the optical path difference between the two link-end arms of the coupler. By locally heating one of these arms with an argon laser beam this path difference, and hence the couplers' near-end cross talk, can be tuned. The ultimate limit for the near-end cross talk is determined by stray light and has therefore approximately the same level as the far-end cross talk. PMID- 20856523 TI - Calibration of an integrating sphere for determining the absorption coefficient of scattering suspensions. AB - Measuring the absolute absorption of suspensions of absorbing particles with unknown scattering characteristics is not possible in conventional spectrophotometers or in integrating spheres that have the sample located outside the sphere. A method for the calibration and use of an integrating sphere with a centrally located sample to measure absolute absorption coefficients of scattering suspensions is presented. Under the tested conditions the integrating sphere used in this study was insensitive to changes in the scattering coefficient of the sample but had a nonlinear response to increasing absorption of the sample, which could be corrected with an empirically derived function. This response was analyzed by using a Monte Carlo simulation, and results indicated that amplification of the absorption signal was primarily due to photons reflected from the sphere surface and the baffle reentering the cuvette. The calibration procedure described here may be generally applicable to spheres of different configurati n. An example of the use of the sphere for determining the absorption and scattering coefficients of marine phytoplankton samples is presented. PMID- 20856522 TI - Photoinduced diffraction in polymer waveguides. AB - We report on techniques for measuring photoinduced diffraction in prism-coupled slab polymer waveguides. Diffraction effects resulting from photochromic gratings in slab waveguides of Disperse Red 1 dye in polymethylmethacrylate were studied. Optical damage in the form of diffractive mode conversion was observed when we coupled in light with a wavelength slightly longer than the absorption edge of Disperse Red 1 dye. Slowly growing satellite beams in the outcoupled light were attributed to anisotropic scattering between the lowest-order TE mode and the lowest-order TM mode caused by self-diffraction from a grating produced through the photochromic effect. We have also investigated the effect of mode-coupling changes on the determination of diffraction efficiency and sensitivity in waveguide experiments. Diffraction efficiencies predicted by measurements of the modulation depth in the guide are found to overstate the actual diffraction efficiencies that could be observed in this geometry. Techniques for overc ming this limitation and for improving estimates of the energy density and interaction length in the guide are noted. PMID- 20856524 TI - Frequency translation of light waves by propagation around an optical ring circuit containing a frequency shifter: I. Experiment. AB - A technique for the external frequency translation of light waves is reported. The technique permits the stepwise sweeping of an optical frequency over a wide range with high linearity with respect to time. The frequency translator is composed of an optical pulse modulator and an optical ring circuit containing an acousto-optic frequency shifter and an optical amplifier. The pulse launched into the ring circuit undergoes a constant frequency shift for each circulation around the circuit and the frequency can be translated to a considerable degree from that of the original input pulse. We report a stepwise frequency translation over approximately 68 GHz for a 1.5-um light wave with a strictly constant frequency sweep rate and an approximately constant intensity. PMID- 20856525 TI - Measurement of (12)CO(2):(13)CO(2) ratios for medical diagnostics with 1.6-um distributed-feedback semiconductor diode lasers. AB - We have observed some of the absorption lines from the molecules (12)CO(2) and (13)CO(2)in the 1.6-um spectral region with the use of specially fabricated single-mode InGaAsP distributed-feedback semiconductor diode lasers. Using a 23.6 m-long multipass absorption cell in combination with radio-frequency modulation and detection techniques, we measured the (12)CO(2):(13)CO(2) isotopic ratio of two specific lines at 6253.73 and 6253.90 cm(-1) with sufficient precision for diagnostic medical tests that analyze CO(2) on human breath. PMID- 20856526 TI - Oceanic lidar: radiative transfer in the atmosphere at operating altitudes from 100 m to 100 km. AB - The feasibility of measuring water-column parameters of the sea with a fluorescence lidar under daylight conditions and at flight altitudes between 100 m and 100 km is studied by modeling the atmospheric radiative transfer. Parameters to be measured are fluorescence of gelbstoff and chlorophyll and Raman scattering of water molecules. A cloudless and stratified atmosphere with various conditions of near-surface visibility and ozone concentration is taken into consideration. Solar zenith angles are varied between 0 degrees and 60 degrees . Lidar specifications are set to 1 J output energy, 10 ns pulse duration, 0.1 mrad beam divergence, 0.1 mrad detection angle, and 400 cm(-1) detection bandwidth. Signal recovery is carried out over the effective pulse length of the returned signal, which is roughly 20-30 ns. Sensor zenith angles are set between 0 degrees and 60 degrees . As a result of the study the recommended range of excitation wavelengths for high altitudes should be chosen between 350 and 400 nm. Under these circumstances, and with the iven laser and sensor specifications, oceanic lidar measurements should also be possible at flight altitudes of up to 100 km under clear visibility conditions, even at noon. PMID- 20856527 TI - Correction for nonlinear photon-counting effects in lidar systems. AB - A useful analytic model describing the response of a photon-counting (PC) system has been developed. The model describes the nonlinear count loss and apparent count gain arising from the overlap of photomultiplier tube (PMT) pulses, taking into account the distribution in amplitude of the PMT output pulses and the effect of the pulse-height discrimination threshold. Comparisons between the model and Monte Carlo simulations show excellent agreement. The model has been applied to a PC lidar system with favorable results. Application of the model has permitted us to extend the linear operating range of the PC system and to quantify accurately the response of the system in its nonlinear operating regime, thus increasing the useful dynamic range of the system by 1 order of magnitude. PMID- 20856528 TI - Lidar-inversion technique based on total integrated backscatter calibrated curves. AB - The integrated backscatter signal from a smoke cloud contained in a chamber is studied as function of the measured concentration. An analysis based on the total backscattered signal leads to the determination of calibration curves specific to the material and to the lidar system. This procedure leads to a lidar inversion technique based on a calibrated total integrated backscatter curve. The limitation of the technique is discussed in terms of the maximum optical depth permitted for acceptable results. PMID- 20856529 TI - Radiometer for the measurement of water vapor in the upper atmosphere from space. AB - We describe the design, the development, and the calibration of a radiometer to measure water vapor abundance in the middle atmosphere, using the solar occultation technique from an orbiting platform. The use of gas cells containing water vapor and carbon dioxide leads to a relatively simple, but sensitive, design. This radiometer is shown to be capable of detecting water vapor in the mesosphere, where, because of dissociation by the Sun, the amounts are very small, of the order of 1 part per 10(6) or less. A flight version of the instrument will be launched in 1992 on board the European Retrievable Carrier space platform, and the data will be employed for a better understanding of the Earth's water budget. PMID- 20856530 TI - Backscattering and polarization ratio for cylindrical graphite fibers at CO(2) laser wavelengths. AB - Measurements are presented of backscattering from an artificial cloud composed of cylindrical graphite fibers at a distance of 730 m with a CO(2) lidar system at 20 wavelengths and two incident polarizations (horizontal and vertical). The backscatter measurements and the polarization ratio are in good agreement with single-scattering calculations for an infinitely long cylinder at normal incidence. The measurements give experimental evidence of the predominant orientation of graphite fibers with their long axes in a random position in the x y plane (i.e., parallel to the ground). PMID- 20856531 TI - Temporal pulse spreading of a return lidar signal. AB - Most spaceborne lidar applications use cross-track or conical scanning to ensure a global coverage of the investigated areas: the return signal of laser pulses shot at an angle with the nadir is biased by a slanting effect that induces a temporal spreading of the received signal as compared with the return signal of a nadir shot. This paper gives the basic formulas of the return signal for both a topographic target (laser range finders) and a diffuse target (atmospheric lidars). PMID- 20856532 TI - Lidar multiple scattering: improvement of Bissonnette's paraxial approximation. AB -

It is generally accepted that multiple scattering is important for evaluating backscatter lidar signals in the case of moderate or high optical depths and large receiver fields of view. On one hand, multiple scattering must be considered in inverting signals to obtain backscatter coefficients; on the other hand, it offers the opportunity to derive microphysical parameters of the scattering medium. Bissonnette developed a numerical code for the propagation of a continuous-wave laser beam through an atmosphere including multiple scattering. His model is also applicable to a backscatter lidar approximatively.

In this paper we investigate if the assumptions on which his backscatter lidar application is based are valid for typical atmospheric situations. It is found that for small and moderate optical depths, a prerequisite for the backscatter lidar application is fulfilled: second-order iterations of the solution to the radiative transfer equation can indeed be neglected as proposed by Bissonnette.

Furthermore, we propose an improvement of the simulation for limited fields of view that significantly alters the radial dependences of the backscattered signals. Essentially, on-axis backscattered signals are increased and the profiles tend to be somewhat narrower near the optical axis. The dependence of the radiative distribution on the phase function of the scattering medium, the optical depth, and on the field of view of the receiver is also changed. The modifications only slightly increase the computer time. Examples for typical atmospheric situations are shown, and proposals for intercomparisons with other models and measurements are made.

PMID- 20856533 TI - Integrating sphere depolarization at 10 um for a non-Lambertian wall surface: application to lidar calibration. AB - The relative Stokes vectors at the detector exit port of a sandblasted and gold plated integrating sphere are determined for four different polarizations incident on five unique surfaces. The results indicate in all cases that the integrating sphere is a depolarizer. These results validate assumptions used in hard-target calibration methodology for infrared lidars. PMID- 20856534 TI - Retrieval of atmospheric O(3), HNO(3), CFC-11, and CFC-12 profiles from MIPAS-B 89 limb emission spectra. AB - During the night from May 17 to May 18, 1989, the first of four flights of the Michelson Interferometer for Passive Atmospheric Sounding, Balloon-borne version (MIPAS-B) instrument took place from the Centre National d'Etudes Spatiales balloon-launching site at Aire-sur-l'Adour (France, 44 degrees N latitude). From approximately 33 km float altitude, stratospheric and tropospheric limb infrared emission spectra have been recorded by this novel type of fast-scanning interferometer. Although the measured spectra did not reach the expected quality and the a priori information on the corresponding viewing directions was coarse, the data were processed successfully with a retrieval algorithm specially adapted for application to noisydata. Mixingratio profiles of ozone, nitric acid, CFC-11, and CFC-12 havebeen retrieved from limb sequences of wide spectral intervals by nonlinear least-squares fitting in combination with a layer-bylayer onion-peeling approach. A rigorous error analysis has been carried out by means of Monte Carlo calculations. PMID- 20856535 TI - Laser-induced ion formation thresholds of aerosol particles in a vacuum. AB - Using a time-of-flight mass spectrometer, we have measured the threshold for producing ions from various aerosol particles in avacuum with laser radiation at 248 nm,308 nm, and 10.6um. In addition, a limited amount of similar data were taken at 193 and 337 nm. At 10.6 um, two thresholds were observed: one near 3 GW/cm(2), which corresponds to partial ionization, and another at 6 GW/cm(2), which we attribute to plasma formation. At 308 nm, the threshold for ion production is on the order of 200 MW/cm(2). Shorter wavelengths require even less energy, with < 100 MW/cm(2) yielding normal molecular-mass spectra and approximately 500 MW/cm(2) fragmenting the sample to atomic ions. PMID- 20856536 TI - Long-path absorption measurement of CO(2) with a Raman-shifted tunable dye laser. AB - A laser long-path absorption system was developed with a hydrogen Raman shifter pumped by a tunable dye laser. The absorption spectrum of CO(2) in the 2-um region was measured in the open air with a retroreflector or a hard target. The concentration of CO(2) was determined from the spectrum by the least-squares method. Noise in the system was analyzed, and the propagation of error to the obtained concentration was investigated. The statistical error in the concentration was estimated at approximately 1% for a single spectrum measurement. Comparison with the simultaneous measurements with a nondispersive infrared gas analyzer showed good agreement. PMID- 20856537 TI - Measurement of submicrometer A1(2)O(3) particles in plumes. AB - We made multiple-wavelength light transmission measurements at the edge of a plume from a small solid-propellant motor in order to determine the mean particle size and the in situ particle index of refraction. We retrieved the particle size distribution from the Sauter mean diameter and the geometrical standard deviation assuming a lognormal distribution. The good correlation of the data indicated the applicability of the technique with a relatively high confidence level and that submicrometer particles were dominantly present at the edge of the plume. This was confirmed by the size distribution of collected particles. The values measured for alumina particles in the edge of the plume were a Sauter mean diameter of 0.150 um +/- 4%, a geometrical standard deviation of 1.50 +/- 3%, and a real index of refraction of 1.63 +/- 8%. PMID- 20856538 TI - Optical properties of continental haze and cumulus and orographic clouds based on Space Shuttle polarimetric observations. AB - Digitized Space Shuttle imagery in the red, green, and blue spectral regions (0.600, 0.540, and 0.435 um, respectively) is used to characterize the mean radius and the index of refraction of droplets in cumulus and orographic clouds. The clouds are shown to consist concurrently of submicrometer and supermicrometer droplets, with the percent polarization indicative of the dominant sizes. Cloud development from haze as well as inhomogeneities in the cloud decks can be traced remotely. The absorption properties of clouds can also be determined remotely. An optical depth of continental haze in the same three spectral regions as the clouds is computed from the polarimetric and photometric contributions. Both Mie and Rayleigh scattering are included in the model. PMID- 20856539 TI - Effects of Raman scattering across the visible spectrum in clear ocean water: a Monte Carlo study. AB - Raman-scattering activity in clear ocean waters is documented for the visible spectrum from Monte Carlo simulations. The Raman-scattering activity has a significant effect on the upwelling irradiance value in air and on the submarine light field at the water surface across the visible spectrum. A reduction in Raman-scattering activity at 440 nm that is due to Fraunhofer lines at the Raman source wavelengths is also demonstrated. At wavelengths greater than 500 nm, Raman scattering makes a significant contribution to the in-water light field at depth. PMID- 20856540 TI - Diffuse reflectance of oceanic waters. II Bidirectional aspects. AB - For visible wavelengths and for most of the oceanic waters, the albedo for single scattering (?) is not high enough to generate within the upper layers of the ocean a completely diffuse regime, so that the upwelling radiances below the surface, as well as the water-leaving radiances, generally do not form an isotropic radiant field. The nonisotropic character and the resulting bidirectional reflectance are conveniently expressed by the Q factor, which relates a given upwelling radiance L(u) (theta',phi) to the upwelling irradiance E(u) (theta' is the nadir angle, phi is the azimuth angle, and Q = E(u)/L(u)); in addition the Q function is also dependent on the Sun's position. Another factor, denoted f, controls the magnitude of the global reflectance, R (= E(u) /E(d), where E(d) is the downwelling irradiance below the surface); f relates R to the backscattering and absorption coefficients of the water body (b(b) and a, respectively), according to R = f(b(b)/a). This f factor is also Sun angle dependent. By operating an azimuth-dependent Monte Carlo code, both these quantities, as well as their ratio (f/Q) have been studied as a function of the water optical characteristics, namely ? and eta; eta is the ratio of the molecular scattering to the total (molecular + particles) scattering. Realistic cases (including oceanic waters, with varying chlorophyll concentrations; several wavelengths involved in the remote sensing of ocean color and variable atmospheric turbidity) have been considered. Emphasis has been put on the geometrical conditions that would be typical of a satellite-based ocean color sensor, to derive and interpret the possible variations of the signal emerging from various oceanic waters, when seen from space under various angles and solar illumination conditions. PMID- 20856541 TI - Introduction to special issue of Applied Optics on soft-x-ray projection lithography. AB - This special issue contains a collection of papers describing results that were presented at the Second Topical Meeting on Soft-X-Ray Projection Lithography sponsored by the Optical Society of America and held 6-8 April 1992 in Monterey, California, along with several additional papers submitted after that meeting. These papers are being published in this collection to make them readily available to a larger audience than would normally occur with a proceedings and also to take advantage of the critical review process. PMID- 20856542 TI - X-ray production ~ 13 nm from laser-produced plasmas for projection x-ray lithography applications. AB - X-ray production in the region ~ 13 nm from laser-produced plasmas has been investigated as a source for projection x-ray lithography. The dependence of x ray conversion efficiency on target material, intensity, and pulse length has been studied by using a 0.53-um laser with a maximum of 0.3 J. A conversion efficiency of 1% into a 0.3-nm bandwidth has been demonstrated for Sn targets at intensities of ~ 10(11) W/cm(2) by using a 7.5-ns pulse. Intensity scaling suggests that laser spot size and two-dimensional expansion are important for optimizing x-ray production at these low-irradiation intensities. PMID- 20856543 TI - Characterization and control of laser plasma flux parameters for soft-x-ray projection lithography. AB - Laser plasmas are intrinsically an attractive soft-x-ray source for projection lithography. Compact, flexible, and small enough to be dedicated to a single installation, they offer an alternative to costly multi-installation synchrotron sources. For laser plasmas to provide ideal sources of soft x rays for projection lithography, their properties must be tuned to optimize several critical parameters. High x-ray conversion in the spectral band relevant to projection lithography is obviously required and has already received the attention of several studies. However, other features, such as the spectral content and direction of the x-ray emission, the plasma and particulate emission, the technology of the target, and efficient laser design, must also be optimized. No systematic study of all these features specifically for projection lithography has yet been made. It is our purpose to optimize these parameters in a coordinated approach, which leads to the design of a source that satisfies all the demanding requirements of an operating lithographic installation. We make an initial investigation of the plasma and particle emission of plasmas that have previously been shown to be good x-ray converters to the 13-nm band. The importance of the results reported may well force new approaches to the design of laser plasma soft-x-ray sources for projection lithography. PMID- 20856544 TI - X-ray plasma source design simulations. AB - The optimization of soft x-ray production from a laser-produced plasma for lithographic applications is discussed in the context of recent experiments by Kauffman et al. [Appl. Opt. 32, 6897 (1993)], which indicate that a conversion efficiency of 0.01 can be obtained with Sn targets at modest laser intensity. Computer simulations of the experiments delineate the critical phenomena underlying these high conversion efficiencies, especially the role of hydrodynamic expansion and radiative emission. Qualitative features of the experiments are reproduced, including the transition from one-dimensional to two dimensional flow. The quantitative discrepancy is ascribed to incorrect initiation of the ablating plasma and to inadequate atomic transition rate evaluation. PMID- 20856545 TI - Laser driver for soft-x-ray projection lithography. AB - A design of a diode-pumped Nd:YAG laser for use as the driver for a soft-x-ray projection lithography system is described. This laser will output up to 1 J per pulse with a 2- to 5-ns pulse duration and a 400-Hz pulse repetition rate. The design employs microchannel-cooled diode laser arrays, zigzag slab energy storage, a regenerative amplifier cavity that uses phase conjugator beam correction for near-diffraction-limited beam quality, and stimulated Brillouin scattering pulse compression to achieve the required pulse length. PMID- 20856546 TI - Synchrotron radiation sources and condensers for projection x-ray lithography. AB - The design requirements for a compact electron storage ring that could be used as a soft-x-ray source for projection lithography are discussed. The design concepts of the x-ray optics that are required for collecting and conditioning the radiation in divergence, uniformity, and direction to illuminate the mask correctly and the particular x-ray projection camera used are discussed. Preliminary designs for an entire soft-x-ray projection lithography system that uses an electron storage ring as a soft-x-ray source are presented. It is shown that, by combining the existing technology of storage rings with large collection angle condensers, a powerful and reliable source of 130-A photons for production line projection x-ray lithography is possible. PMID- 20856547 TI - Continuous emission source covering the 50-300-A band. AB - We have developed a continuous emission source for use in the soft-x-ray and extreme-UV spectral regions. The source and its characteristics are described. PMID- 20856548 TI - Prototype high-speed tape target transport for a laser plasma soft-x-ray projection lithography source. AB - A prototype high-speed tape target transport is constructed for use in a high repetition-rate laser plasma source. To reduce plasma debris, a 1000-5000-A-thick film of target material is supported by thin Mylar tape backing. Tape is transported to the laser focal volume at a maximum velocity of 356 cm/s, a rate sufficient to accommodate laser repetition rates of 1 kHz. The transport is fully vacuum compatible and can be retracted and then isolated from the laser plasma vacuum enclosure during tape reel replacement. The operating characteristics of the transport are described. PMID- 20856549 TI - Condenser optics, partial coherence, and imaging for soft-x-ray projection lithography. AB - A condenser system couples the radiation source to an imaging system, controlling the uniformity and partial coherence at the object, which ultimately affects the characteristics of the aerial image. A soft-x-ray projection lithography system based on a ring-field imaging system and a laser-produced plasma x-ray source places considerable constraints on the design of a condenser system. Two designs are proposed, critical illumination and Kohler illumination, each of which requires three mirrors and scanning for covering the entire ring field with the required uniformity and partial coherence. Images based on Hopkins' formulation of partially coherent imaging are simulated. PMID- 20856550 TI - Physical optics modeling in soft-x-ray projection lithography. AB - We develop a diffraction-based tool that can predict the image quality in projection lithography systems. The effects of partial coherence and source variations and imaging defects in both the condenser and the camera optics can all be determined. PMID- 20856551 TI - Multilayer mirror technology for soft-x-ray projection lithography. AB -

Recent advances in multilayer mirror technology meet many of the stringent demands of soft-x-ray projection lithography (SXPL). The maximum normal-incidence reflectivity achieved to date is 66% for Mo/Si multilayers at a soft-x-ray wavelength of 13.4 am, which is sufficient to satisfy the x-ray throughput requirements of SXPL. These high-performance coatings can be deposited on figured optics with layer thickness control of ~ 0.5%. Uniform multilayer coatings are required for SXPL imaging optics, for which maintaining the surface figure is critical to achieving diffraction-limited performance.

In contrast the coatings on the condenser optics will be graded to accommodate a large range of angles of incidence. Graded multilayer coatings can also be used to modify the figure of optical substrates without increasing the surface roughness. This offers a potential method for precise fabrication of aspheric imaging optics.

PMID- 20856552 TI - Masked deposition techniques for achieving multilayer period variations required for short-wavelength (68-A) soft-x-ray imaging optics. AB - Practical issues in the development of multilayer coatings for reflective imaging systems operating at lambda ~ 68 A are discussed. The 1% bandpass of Ru/B(4) C multilayers at this short wavelength imposes stringent tolerances with which the actual multilayer period variation across the curved surfaces must match the ideal period variation for a 20* demagnifying Schwarzschild objective. New deposition techniques that use masks to correct the period variation across the curved surfaces of each optic have been developed to ensure reflectance over the entire clear aperture. The narrow bandpass together with steep lateralperiod gradients and steeply curved surfaces requires improved metrology for an acceptable period variation to be obtained and the overlap of the reflectance peaks on the two mirrors to be verified. PMID- 20856553 TI - Ion-assisted sputter deposition of molybdenum-silicon multilayers. AB - X-ray multilayer (ML) structures that are fabricated by the use of magnetron sputter deposition exhibit a degradation in structural quality as the deposition pressure is increased. The observed change in morphology is attributed to a reduced mobility of surface adsorbed atoms, which inhibits the formation of smooth, continuous layers. The application of a negative substrate bias produces ion bombardment of the growing film surface by sputtering gas ions extracted from the plasma and permits direct control of the energy density supplied to the film surface during thin-film growth. The technique supplements the energy lost to thermalization in high-pressure deposition and permits the fabrication of high quality ML structures at elevated processing pressures. A threefold improvement in the soft-x-ray normal-incidence reflectance at 130 A results for substrate bias voltages of the order of ~ - 150 V for Mo-Si ML's deposited at 10-mTorr Ar. PMID- 20856554 TI - Silicide layer growth rates in Mo/Si multilayers. AB - The thermal stability of sputter-deposited Mo/Si multilayers was investigated by annealing studies at relatively low temperatures (~ 250-350 degrees C) for various times (0.5-3000 h). Two distinct stages of thermally activated Mo/Si interlayer growth were found: a primary surge, followed by a (slower) secondary steady-state growth in which the interdiffusion coefficient is constant. The interdiffusion coefficients for the interlayer formed by deposition of Mo-on-Si are higher than those of the interlayer formed by deposition of Si-on-Mo. Assuming that the activation energy is constant, an extrapolation of our results to ambient temperature finds that interlayer growth is negligible, suggesting long-term thermal stability in soft-x-ray projection lithography applications. PMID- 20856555 TI - Influence of electrical isolation on the structure and reflectivity of multilayer coatings deposited on dielectric substrates. AB - Multilayers prepared with electrically isolated or grounded surfaces during deposition are shown to have dramatically different hard-x-ray, soft-x-ray, and neutron reflectivity characteristics. The effect has been observed for (100) silicon wafers, fused silica, and borate glass substrates of different sizes and with different surface roughness and flatness for multilayer structures prepared by rf and dc magnetron sputtering. PMID- 20856556 TI - Tarnishing of Mo/Si multilayer x-ray mirrors. AB - Multilayer x-ray mirrors of molybdenum and silicon operating at normal incidence at energies just below the Si L(II,III) absorption edges are a key component in the development of soft-x-ray projection lithography. In this application high reflectivity is essential. Aging tests on such reflectors, with Mo as the last layer deposited, show that the structures decline in reflectivity with time when stored in air. Chemical analysis of a well-aged surface by photoelectron spectroscopy techniques reveals that the uppermost Mo layer eventually becomes completely oxidized to MoO(3) and MoO(2) and contaminated with carbonaceous materials. The oxidation can be prevented by storing the mirrors in an oxygen free atmosphere or by depositing the silicon as the top layer. The reflectivity of tarnished mirrors can be restored by removing the oxides by argon-ion etching or wet chemical methods. PMID- 20856557 TI - Radiation hardness of molybdenum silicon multilayers designed for use in a soft-x ray projection lithography system. AB - A molybdenum silicon multilayer is irradiated with 13.4-nm radiation to investigate changes in multilayer performance under simulated soft-x-ray projection lithography (SXPL) conditions. The wiggler-undulator at the Berlin electron storage ring BESSY is used as a quasi-monochromatic source of calculable spectral radiant intensity and is configured to simulate an incident SXPL x-ray spectrum. The test multilayer receives a radiant exposure of 240 J/mm(2) in an exposure lasting 8.9 h. The corresponding average incident power density is 7.5 mW/mm(2). The absorbed dose of 7.8 * 10(10) J/kg (7.8 * 10(12) rad) is equivalent to 1.2 times the dose that would be absorbed by a multilayer coating on the first imaging optic in a hypothetical SXPL system during 1 year of operation. Surface temperature increases do not exceed 2 degrees C during the exposure. Normal incidence reflectance measurements at lambda(0) = 13.4 nm performed before radiation exposure are in agreement with measurements performed after the exposure, indicating that no sign icant damage had occurred. PMID- 20856558 TI - Investigation of distortion and damage of molybdenum?silicon multilayer reflective coatings with high-intensity ultraviolet radiation. AB - Studies are performed to determine an upper limit on the optical damage threshold of a soft-x-ray molybdenum-silicon multilayer reflective coating by the use of a 308-nm, 15-ns pulse from a Xe-Cl excimer laser in order to simulate the potential damage induced by the x-ray flux from a pulsed laser-produced plasma. Experimental results yield a value of 0.26 J/cm(2) to produce visible signs of damage as determined by optical microscopy. Experiments are conducted first on silicon, as a reference point of a bulk material, and then applied to molybdenum silicon in an effort to facilitate a theoretical comparison between a simple and a more complicated material. Theoretical predictions are in reasonable agreement with experimental results, but suggest that a lower value of 0.085 J/cm(2) might cause significant thermal-induced damage. PMID- 20856559 TI - Mask technologies for soft-x-ray projection lithography at 13 nm. AB - We describe a variety of technologies for patterning transmissive and reflective soft x-ray projectionlithography masks containing features as small as 0.1 um. The transmission masks fabricated for use at 13 nm are of one type, a Ge absorbing layer patterned on a boron-doped Si membrane. Reflective masks were patterned by various methods that included absorbing layers formed on top of multilayer reflectors, multilayer-reflector-coating removal by reactive ion etching, and ion damage of multilayer regions by ion implantation. For the first time, we believe, a process for absorber repair that does not significantly damage the reflectance of the multilayer coating on the reflection mask is demonstrated. PMID- 20856560 TI - Reflection mask defect repair. AB - We developed a new technique for the repair of opaque defects on soft-x-ray projection lithography reflection masks by using ion-beam etching and a thin Si overcoat on the multilayer mirror. This technique clears the defect without damaging the multilayer mirror or introducing an absorptive element into the multilayer. Our procedure uses a beam of low atomic number ions (Si or Ar) of reduced beam energy and a thin Si overcoat to protect the multilayer mirror. PMID- 20856561 TI - Propagation errors in precision Fizeau interferometry. AB - A general analytical form of propagation errors in Fizeau interferometry is derived. The theory holds for any type of interferometry. The influence of the third-order aberrations is investigated as numerical examples. The experimental data agree with the theoretical prediction. PMID- 20856562 TI - Undulator radiation for at-wavelength interferometry of optics for extreme ultraviolet lithography. AB - Techniques are described for at-wavelength interferometry of multilayer coated optics designed for use in extreme-ultraviolet lithography. Broadly tunable undulator radiation, which covers the spectral region from 45 to 400 A, is described. The coherent power available at these wavelengths is described, and several types of interferometer that might be suitable at these short wavelengths are also described. PMID- 20856563 TI - Resist alternatives for sub-0.35-um lithography by using highly attenuated radiation. AB - The photoresist processes used for lithography at wavelengths from the deep UY to the soft x ray will need to accommodate the strong resist film absorbance inherent in this wavelength range. Already silylation processes have been demonstrated as manufacturable near-surface-imaged resists in the deep UV. In addition other chemistries are being developed that take advantage of near surface or at-the-surface imaging. Together these new approaches to imaging will provide not only greater wavelength flexibility but have potential for improved exposure and focus tolerances as well. These attributes will become important as device dimensions are reduced from 0.35 down to 0.1 um. PMID- 20856564 TI - Chemically amplified soft-x-ray resists: sensitivity, resolution, and molecular photodesorption. AB - The sensitivity, ion photodesorption, and lithographic performance of selected novolac-based chemically amplified resists have been studied at an exposure wavelength of 140 A. Flood exposures of the resits AZ PF514, AZ PN114, and SAL 601 yield D(0.9) values of 2.5-3.5 mJ/cm(2) for 0.25-um-thick films. Contrast values range from 3 for AZ PN114 to 5 for SAL 601. Photodesorption of fragment ions induced by 140-A radiation has been examined in AZ PN114 by using time-of flight mass spectrometry and compared with poly(methylmethacrylate) (PMMA). Mass integrated ion desorption yields from AZ PN114 are found to be ~ 90 times less per exposure than from PMMA. Soft-x-ray projection imaging in AZ PF514 and SAL 601 has been characterized by use of a multilayer-coated 20 * Schwarzschild objective and a transmissive Ge/Si mask illuminated by a laser plasma source. PMID- 20856566 TI - Front-end design issues in soft-x-ray projection lithography. AB - We present a protocol for the design of an illumination system (front end) for a soft-x-ray projection lithography tool. The protocol is illustrated by specific front-end designs. The most complete design analysis is for a laser-driven system. Other drivers; undulator, synchrotron orbital radiation, and plasma discharge, are also discussed. PMID- 20856565 TI - Characterization of AZ PN114 resist for soft-x-ray projection lithography. AB - Using 14-nm wavelength illumination, we have imaged 0.1-um-wide lines and spaces in single-layer thin films of the highy sensitive, negative, chemically amplified resist AZ PN114 by usingboth a Schwarzschild 20* camera and an Offner ring field 1* optical system. For soft-x-ray projection lithography the approximate 0.2-um absorption length in resists at 14-nm wavelength necessitates a multilayer resist system. To explore further the requirements of the imaging layer of such a system, we have transferred patterns, exposed by a high-resolution electron beam in a 60-nm-thick layer of AZ PN114, into the underlying layers of a trilevel structure. Significant pattern edge noise and resist granularity were found. It remains to be determined whether the observed noise is dominated by statistical fluctuations in dose or by resist chemistry. We also investigated pinhole densities in these films and found them to increase from 0.2 cm(-2) for 380-mm thick films to 15 cm(-2) for 50-nm-thick films. PMID- 20856567 TI - Schwarzschild microscope for carbon Kalpha radiation. AB - A Schwarzschild objective (magnification, *32; numerical aperture, 0.2), which has a 0.1-um resolution within 30 um of the object height, was designed and fabricated. We have developed new normalincidence multilayer mirrors for carbon Kalpha radiation (wavelength, 44.8 A), NiCr (80-20 wt. %)/C multilayers (thickness period, 22.5 A; number of layers, 50), which are deposited by ion-beam sputtering with the thickness distribution corrected by deposition masks. Magnified images were taken on photographic film with the Schwarzschild objective by using an electron impact carbon Kalpha radiation source, and a resolution of < 0.5 um was confirmed. PMID- 20856568 TI - Wavelength considerations in soft-x-ray projection lithography. AB - The choice of the operational wavelength for a soft-x-ray projection lithography system affects a wide variety of system parameters such as optical design, sources, resists, and multilayer mirrors. Several system constraints limit the choice for the operational wavelength. In particular, optical imaging requirements place an upper limit and throughput issues place a lower limit on the wavelength selection. We have determined that there are several discrete wavelength regions between 10 and 25 nm that satisfy the system-imposed constraints of high resolution, large depth of focus, and high throughput. PMID- 20856569 TI - Soft-x-ray projection lithography experiments using Schwarzschild imaging optics. AB - Soft-x-ray projection imaging is demonstrated by the use of 14-nm radiation from a laser plasma source and a single-surface multilayer-coated ellipsoidal condenser. Aberrations in the condenser and the Schwarzschild imaging objective are characterized and correlated with imaging performance. A new Schwarzschild housing, designed for improved alignment stability, is described. PMID- 20856570 TI - Soft-x-ray projection imaging with a 1:1 ring-field optic. AB - A molybdenum/silicon multilayer-coated 1:1 ring-field optic with a numerical aperture of 0.0835 is used to carry out soft-x-ray projection imaging with undulator radiation at 12.9 nm. An ideal optic of this type should be able to image 0.1-um features with a contrast exceeding 90% at this wavelength. The useful resolution of our ring-field optic is experimentally found to be approximately 0.2 um, probably because of the presence of substrate figuring errors. PMID- 20856571 TI - Large-area, high-resolution pattern replication by the use of a two-aspherical mirror system. AB - A soft-x-ray projection lithography system is developed by the use of multilayer mirrors. To determine the feasibility of a high throughput and a large exposure area, we developed a reduction system that consists of two-aspherical-mirror optics. The figure errors of aspherical mirrors are evaluated by a laser interferometer. The rms aspherical figure errors of concave and convex mirrors are 8.8 and 2.0 nm, respectively, which are not enough to yield a resolution of 0.1 um. The reduction optics is constructed by adjusting the mirror position to compensate for aberrations, and some trial replications are performed. An exposure area of larger than 10 mm * 0.6 mm with a fine pattern of less than a quarter micrometer is achieved. PMID- 20856572 TI - Possible damage mechanism of the dielectric coatings for a KrF laser. AB - We discuss the fracture of dielectric coatings during the irradiation of a high power (10(8-9) W/cm(2)) KrF laser by analyzing the thermal stress distribution within the coatings. It is shown that it is the compressive stresses perpendicular to the coating surface that make the optical coatings crack. PMID- 20856573 TI - Transverse color tolerances for visual optical systems. AB - We performed psychophysical experiments to determine the effects of transverse chromatic aberration on observer performance through a specially designed telescopic system that presents negligible monochromatic aberration. Our results provide the basis for assessing the performance of visually coupled lenses in detail. The effect of transverse color on contrast sensitivity is more severe than on resolution. Color effects are compared with those of astigmatism: It is shown how one may make detailed predictions of system performance in order to decide on the necessary balance of aberrations at the design stage. PMID- 20856574 TI - Hadamard spectroscopy with a two-dimensional detecting array. AB - In a conventional grating spectrograph consisting of a single entrance slit, a grating, and a multichannel (imaging) detector, considerable light throughput advantage can be realized by replacement of the single entrance slit with a mask. This replacement can yield a signal-to-noise ratio increase because of increased light collection over an extended area of the mask when compared with a single slit. The mask produces a spectrum on the detector, which is the convolution of the mask pattern and the spectral distribution of the light source. To retrieve the spectrum, the spectrum has to be inverted. In special cases in which emission spectra are superimposed on weak backgrounds, the signal-to-noise advantage is preserved through the inversion process. Thus this technique is valuable in the observation of light sources that are produced by atomic or molecular emissions such as aurora, airglow, some interstellar emission, or laboratory spectra. Considerable signal-to-noise advantages can also be realized when the background noise of the imaging detector is not negligible. The spectral mixing of the light from the mask on the detector causes high photon fluxes on the detector, which tend to swamp the detector noise. This is a particularly important advantage in the application of CCD's as detectors because they can have significant background noise. The technique was demonstrated by computer simulations and laboratory tests. PMID- 20856575 TI - Optical and crystalline properties of PbF(2) thin films. AB - The optical and crystalline properties of PbF(2) thin films as a function of the substrate temperature during deposition have been studied; the other evaporation conditions were kept as constant as possible. Channel spectra, guided modes, and ellipsometry techniques were used for the analysis of the optical properties of the films. X-ray diffraction was used for the analysis of the crystalline structure. PMID- 20856576 TI - Prototype fiber-optic-based pressure probe with built-in temperature compensation with signal recovery by coherence reading. AB - A prototype multimode fiber-based Fabry-Perot interferometric pressure probe utilizing a corrugated diaphragm with built-in temperature compensation, with signal recovery by coherence reading, has been constructed and demonstrated. A separate fiber-optic-based temperature sensor was incorporated into the pressure sensor to permit the pressure measurement to be corrected for the temperature dependence of the pressure probe. A measurement range to resolution of 3.6 * 10(4) - 1 and an overall measurement accuracy of +/-0.15% have been achieved. This system represents a practical approach for industrial use. PMID- 20856577 TI - Infrared collimator system. AB - A system of three spherical mirrors can be used as a replacement for an off-axis parabolic mirror collimator. The system is more compact and has ~2.5X larger diffractionlimited field of view. PMID- 20856578 TI - Rotational shearing interferometer. AB - An interferometer with 1800 rotational shear does not show rotationally symmetrical aberrations. The instrument, however, is suitable for aligning zooming laser optical systems, monitoring wavefront irregularities, and verifying beamsteering tilt directions. PMID- 20856579 TI - Accurate measurement of refractive indices. AB - A simple wedge measurement technique of optical refractive index is described. The procedure is more accurate and convenient than the usual minimum deviation method and is not limited to visible light. PMID- 20856580 TI - Fiber-coupled Laser Diode Mount for Interferometry. AB - One of the most difficult aspects of working with laser diodes in the laboratory is their sensitivity to optical feedback. This problem is particularly troublesome when trying to couple the laser light into an optical fiber for delivery to an interferometer or coherent fiber sensor. The generalpurpose laser diode mount described here avoids at least some of these difficulties by using an angle-polished fiber cable and an inexpensive coupler based on a small tip/tilt stage. The mount is very stable, can be used with a variety of lasers, and is inexpensive to make. PMID- 20856581 TI - Estimating secondary color. AB - Image quality of a refracting lens system often will be limited by residual secondary color. Information in this paper permits rapid determination of blur spot size, and resulting image quality degradation, due to secondary color for a refracting lens system that has been designed with normal optical glasses and is free of primary color (achromatic). Included here is a brief description of the basic theory involved and an example of how the plotted data are used. PMID- 20856582 TI - MetMap enables genome-scale Methyltyping for determining methylation states in populations. AB - The ability to assay genome-scale methylation patterns using high-throughput sequencing makes it possible to carry out association studies to determine the relationship between epigenetic variation and phenotype. While bisulfite sequencing can determine a methylome at high resolution, cost inhibits its use in comparative and population studies. MethylSeq, based on sequencing of fragment ends produced by a methylation-sensitive restriction enzyme, is a method for methyltyping (survey of methylation states) and is a site-specific and cost effective alternative to whole-genome bisulfite sequencing. Despite its advantages, the use of MethylSeq has been restricted by biases in MethylSeq data that complicate the determination of methyltypes. Here we introduce a statistical method, MetMap, that produces corrected site-specific methylation states from MethylSeq experiments and annotates unmethylated islands across the genome. MetMap integrates genome sequence information with experimental data, in a statistically sound and cohesive Bayesian Network. It infers the extent of methylation at individual CGs and across regions, and serves as a framework for comparative methylation analysis within and among species. We validated MetMap's inferences with direct bisulfite sequencing, showing that the methylation status of sites and islands is accurately inferred. We used MetMap to analyze MethylSeq data from four human neutrophil samples, identifying novel, highly unmethylated islands that are invisible to sequence-based annotation strategies. The combination of MethylSeq and MetMap is a powerful and cost-effective tool for determining genome-scale methyltypes suitable for comparative and association studies. PMID- 20856583 TI - Instantaneous non-linear processing by pulse-coupled threshold units. AB - Contemporary theory of spiking neuronal networks is based on the linear response of the integrate-and-fire neuron model derived in the diffusion limit. We find that for non-zero synaptic weights, the response to transient inputs differs qualitatively from this approximation. The response is instantaneous rather than exhibiting low-pass characteristics, non-linearly dependent on the input amplitude, asymmetric for excitation and inhibition, and is promoted by a characteristic level of synaptic background noise. We show that at threshold the probability density of the potential drops to zero within the range of one synaptic weight and explain how this shapes the response. The novel mechanism is exhibited on the network level and is a generic property of pulse-coupled networks of threshold units. PMID- 20856584 TI - Field assessment of a novel household-based water filtration device: a randomised, placebo-controlled trial in the Democratic Republic of Congo. AB - BACKGROUND: Household water treatment can improve the microbiological quality of drinking water and may prevent diarrheal diseases. However, current methods of treating water at home have certain shortcomings, and there is evidence of bias in the reported health impact of the intervention in open trial designs. METHODS AND FINDINGS: We undertook a randomised, double-blinded, placebo-controlled trial among 240 households (1,144 persons) in rural Democratic Republic of Congo to assess the field performance, use and effectiveness of a novel filtration device in preventing diarrhea. Households were followed up monthly for 12 months. Filters and placebos were monitored for longevity and for microbiological performance by comparing thermotolerant coliform (TTC) levels in influent and effluent water samples. Mean longitudinal prevalence of diarrhea was estimated among participants of all ages. Compliance was assessed through self-reported use and presence of water in the top vessel of the device at the time of visit. Over the 12-month follow-up period, data were collected for 11,236 person-weeks of observation (81.8% total possible). After adjusting for clustering within the household, the longitudinal prevalence ratio of diarrhoea was 0.85 (95% confidence interval: 0.61-1.20). The filters achieved a 2.98 log reduction in TTC levels while, for reasons that are unclear, the placebos achieved a 1.05 log reduction (p<0.0001). After 8 months, 68% of intervention households met the study's definition of current users, though most (73% of adults and 95% of children) also reported drinking untreated water the previous day. The filter maintained a constant flow rate over time, though 12.4% of filters were damaged during the course of the study. CONCLUSIONS: While the filter was effective in improving water quality, our results provide little evidence that it was protective against diarrhea. The moderate reduction observed nevertheless supports the need for larger studies that measure impact against a neutral placebo. TRIAL REGISTRATION: Current Controlled Trials ISRCTN03844341. PMID- 20856585 TI - Combined vitreous and cataract surgeries in highly hyperopic eye. AB - We report a case of a patient with a highly hyperopic eye who underwent cataract surgery combined with vitreous surgery to create a posterior vitreous detachment (PVD) to prevent choroidal neovascularization (CNV). A 78-year-old man noticed a decrease in his vision due to a cataract in his right eye. The patient had a severe visual loss in his left eye because of a CNV 2 years after a cataract surgery. His visual acuities were 20/30 OD and 20/600 OS, and funduscopic examination showed an orange-colored lesion OD and degenerative subretinal fibrosis OS. The posterior vitreous was attached to the retina in both eyes. The axial length was 18.9 mm OD and 19.0 mm OS. Cataract surgery combined with vitreous surgery to create PVD was performed on the right eye, and the vision improved to 20/20 with no signs of developing CNV after 5 years. We conclude that cataract surgery combined with vitreous surgery to create a PVD may prevent the development of CNV in highly hyperopic eyes. PMID- 20856586 TI - The digital aqueous humor outflow meter: an alternative tool for screening of the human eye outflow facility. AB - PURPOSE: To develop, characterize, and validate a prototype digital aqueous humor outflow tonographer (DAHOM). MATERIAL AND METHODS: The DAHOM was developed, characterized, and validated in three phases. Phase 1 involved construction of the sensor. This was broadly based on the fundamental design of a typical Schiotz tonographer with a series of improvements, including corneal indentation, which was converted to an electrical signal via a linear variable differential transducer, an analog signal which was converted to digital via ADC circuitry, and digital data acquisition and processing which was made possible by a serial port interface. Phase 2 comprised development of software for automated assessment of the outflow facility. Automated outflow facility assessment incorporated a series of fundamental improvements in comparison with traditional techniques, including software-based filtering of ripple noise and extreme variations, rigidity impact analysis, and evaluation of the impact of patient age, central corneal thickness, and ocular axial length. Phase 3 comprised characterization and validation of DAHOM, for which we developed an experimental setup using porcine cadaver eyes. DAHOM's repeatability was evaluated by means of Cronbach's alpha and intraclass correlation coefficient. The level of agreement with a standard Schiotz tonographer was evaluated by means of paired t-tests and Bland-Altman analysis in human eyes. RESULTS: The experimental setup provided the necessary data for the characterization of DAHOM. A fourth order polynomial equation provided excellent fit (R square >0.999). DAHOM demonstrated high repeatability (Cronbach's alpha >=0.997; intraclass correlation coefficient >=0.987) and an adequate level of agreement with a standard Schiotz tonographer. CONCLUSIONS: This study presents the development, characterization, and validation of a prototype digital tonographer. DAHOM demonstrates high repeatability and a sufficient level of agreement with a typical Schiotz tonographer, while its digital design remedies known vulnerabilities of conventional tonographers. PMID- 20856587 TI - Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity. AB - PURPOSE: To measure vitreous, aqueous, subretinal fluid and plasma levels of vascular endothelial growth factor in late stages of retinopathy of prematurity. METHODS: Interventional study. We enrolled patients with clinical diagnoses of bilateral stage V retinopathy of prematurity, confirmed by b-scan ultrasound and programmed for vitrectomy. During surgery we took samples from blood, aqueous, vitreous, and subretinal fluids. The vascular endothelial growth factor concentration in each sample was measured by ELISA reaction. A control sample of aqueous, vitreous and blood was taken from patients with congenital cataract programmed for phacoemulsification. For statistical analysis, a Mann-Whitney and a Wilcoxon W test was done with a significant P value of 0.05. RESULTS: We took samples of 16 consecutive patients who met the inclusion criteria. The vascular endothelial growth factor levels in the study group were: aqueous, 76.81 +/- 61.89 pg/mL; vitreous, 118.53 +/- 65.87 pg/mL; subretinal fluid, 1636.58 +/- 356.47 pg/mL; and plasma, 74.64 +/- 43.94 pg/mL. There was a statistical difference between the study and the control group (P < 0.001) in the aqueous and vitreous samples. CONCLUSION: Stage 5 retinopathy of prematurity has elevated intraocular levels of vascular endothelial growth factor, which remains high despite severe retinal lesion. There was no statistical difference in plasma levels of the molecule between the control and study group. PMID- 20856588 TI - A case of a retained intralenticular foreign body for two years. AB - We report a case of a missed metallic intraocular foreign body retained in the lens over a two-year period without causing inflammatory reaction, which presented with cataract later. A 24-year-old man presented with a progressive blurring of vision in the left eye for two years. He had had a history of metal on-metal activity two years before. He had pain for one day in left eye and it was healed by the following day. Biomicroscopic examination revealed cataract, an intralenticular foreign body, and a corneal scar at seven o'clock meridian of the cornea in the left eye. Best-corrected visual acuity was 20/200 in the left eye. Intralenticular foreign body removal, phacoemulsification, and an intraocular lens implantation was performed under local anesthesia. The intralenticular foreign body was metallic and its size was about 2 * 2 mm. Two weeks after the operation best corrected visual acuity was 20/20 in left eye. A retained foreign body should be considered in each patient with a history of penetrating ocular trauma and all efforts must be made to exclude presumptive diagnosis of intraocular foreign body. PMID- 20856589 TI - Success rates in the correction of astigmatism with toric and spherical soft contact lens fittings. AB - OBJECTIVES: To evaluate success rates in the correction of astigmatism with toric and spherical soft contact lens fitting. METHODS: 30 patients with soft toric lenses having more than 1.25 D of corneal astigmatism (25 eyes; Group A) or having 0.75-1.25 D of corneal astigmatism (22 eyes; Group B) and 30 patients with soft spheric lenses having 0.75-1.25 D of corneal astigmatism (28 eyes; Group C) or less than 0.75 D of corneal astigmatism (23 eyes; Group D) were included in the study. Corrected and uncorrected monocular visual acuity measurement with logMAR, biomicroscopic properties, autorefractometry and corneal topography were performed for all patients immediately before and at least 20 minutes after the application of contact lenses. Success of contact lens fitting was evaluated by three parameters: astigmatic neutralization, visual success, and retinal deviation. RESULTS: After soft toric lens application, spheric dioptres, cylindric and keratometric astigmatism, and retinal deviation decreased significantly in Groups A and B (P < 0.05). In Group C, spheric dioptres and retinal deviation decreased (P < 0.05), while cylindric and keratometric astigmatism did not change significantly (P > 0.05). In Group D, spheric dioptres, retinal deviation, and cylindric astigmatism decreased (P < 0.05). Keratometric astigmatism did not change significantly (P > 0.05) and astigmatic neutralization even increased. CONCLUSIONS: Visual acuity and residual spherical equivalent refraction remained between tolerable limits with the use of toric and spheric contact lenses. Spherical lenses failed to mask corneal toricity during topography, while toric lenses caused central neutralization and decrease in corneal cylinder in low and moderate astigmatic eyes. PMID- 20856590 TI - Tetracaine 0.5% eyedrops with or without lidocaine 2% gel in topical anesthesia for cataract surgery. AB - BACKGROUND AND OBJECTIVE: To evaluate the level of pain during phacoemulsification and foldable intraocular lens implantation under instillation of tetracaine 0.5% eyedrops versus a combination of lidocaine 2% gel and instillation of tetracaine eyedrops. METHODS: This prospective, randomized, controlled study included 51 patients undergoing phacoemulsification under topical anesthesia. They were randomized into two groups based on the topical anesthetic method they were to receive. Preoperatively all patients were asked to answer a questionnaire. One hour postoperatively, they were asked to grade their intraoperative and postoperative pain on a visual analog scale from 0 to 10. RESULTS: There were no statistically significant differences between the two methods of anesthesia. Gender and the presence of relatives or friends were independent factors playing a significant role in pain sensitivity. CONCLUSIONS: The combination of lidocaine 2% gel and tetracaine eyedrops does not have a better analgesic result than a single instillation of tetracaine 0.5% eyedrops. PMID- 20856591 TI - The role of clinical parapapillary atrophy evaluation in the diagnosis of open angle glaucoma. AB - PURPOSE: To determine if clinical evaluation of parapapillary atrophy (PPA) significantly improves the ability to distinguish open-angle glaucoma (OAG) patients from glaucoma suspects. METHODS: Patients in this study were under evaluation for glaucoma and had open angles, at least one reliable 24-2 SITA standard automatic perimetry, and digital stereophotographs of the optic disc. PPA was identified clinically as a parapapillary region of absent (betaPPA) or hyper/hypopigmented (alphaPPA) retinal pigment epithelium. A single masked observer evaluated photos for: vertical cup-to-disc ratio (CDR), clock hours of total and betaPPA, betaPPA as percentage width of the optic disc, presence or absence of betaPPA at each disc quadrant, and ordinal rating of total PPA. Generalized linear models were used to determine odds of an abnormal or borderline glaucoma hemifield test (GHT) as a function of PPA variables and covariates; model fit was assessed using the log-likelihood ratio test. RESULTS: Of 410 consecutive patients, 540 eyes (of 294 patients) met inclusion criteria. Mean age was greater among patients with abnormal compared with normal GHT (P < 0.001), but sex and race/ethnicity did not differ between groups (P >= 0.22). Age, central corneal thickness (CCT) and CDR (P <= 0.006), but not intraocular pressure (IOP) (P = 0.71), were significant univariable predictors of the odds of an abnormal GHT. All PPA parameters significantly predicted GHT (P <= 0.03), except presence of temporal betaPPA (P = 0.25). Adjustment for age, CCT, IOP, and CDR reduced the association between PPA and GHT, and model fit was not greatly improved by addition of PPA variables. CONCLUSIONS: Addition of most PPA parameters to a model already containing commonly assessed variables including age, CCT, IOP, and CDR does not significantly improve the ability to distinguish OAG patients from glaucoma suspects. PMID- 20856592 TI - A case of unilateral optic disc swelling with chronic active Epstein-Barr virus infection. AB - Ocular complications of chronic active Epstein-Barr virus (EBV) infection have rarely been reported and are usually associated with systemic symptoms. We described a 17-year-old boy with unilateral optic disc swelling without any systemic symptoms at the initial onset. Antibody titers to EBV were markedly elevated. Treatment with immunosuppressants and corticosteroids dramatically relieved all his symptoms, including unilateral optic swelling and visual field abnormalities. PMID- 20856593 TI - Erratum. AB - [This corrects the article on p. 59 in vol. 4, PMID: 20169050.]. PMID- 20856594 TI - Difluprednate ophthalmic emulsion 0.05% (Durezol) administered two times daily for managing ocular inflammation and pain following cataract surgery. AB - OBJECTIVE: To evaluate the efficacy and safety of twice-daily difluprednate ophthalmic emulsion 0.05% (Durezol((r))) versus placebo administered before surgery for managing inflammation and pain following cataract extraction. METHODS: Eligible subjects (N = 121) were randomized 2:1 to topical treatment with 1 drop difluprednate or placebo administered twice daily for 16 days, followed by a 14-day tapering period. Dosing was initiated 24 hours before unilateral ocular surgery. Clinical signs of inflammation (anterior chamber [AC] cell and flare grade, bulbar conjunctival injection, ciliary injection, corneal edema, and chemosis), ocular pain/discomfort, intraocular pressure (IOP), and adverse events were assessed. RESULTS: Clearing of inflammation on day 14 (primary endpoint), defined as an AC cell grade of 0 (<=5 cells) and a flare grade of 0 (complete absence), was achieved in a significantly greater percentage of subjects treated with difluprednate, compared with placebo (74.7% vs 42.5%; P = 0.0006). A significantly greater percentage of difluprednate-treated subjects were free of ocular pain/discomfort on day 14 than placebo-treated subjects (64.6% vs 30.0%; P = 0.0004). Three subjects (3.7%) in the difluprednate group had a clinically significant IOP rise (defined as >=21 mmHg and a change from baseline >=10 mmHg at same visit). CONCLUSIONS: Difluprednate, administered 2 times daily starting 24 hours before cataract surgery, was highly effective for managing ocular inflammation and relieving pain and discomfort postoperatively. Difluprednate was well tolerated and provides a convenient twice-daily option for managing postoperative ocular inflammation. PMID- 20856595 TI - Azelastine hydrochloride, a dual-acting anti-inflammatory ophthalmic solution, for treatment of allergic conjunctivitis. AB - Over 50% of patients who seek treatment for allergies present with ocular symptoms. Our current ability to control ocular allergic symptoms is greater than ever before. Newer dual-acting topical eyedrops attack multiple facets of the allergic cascade. Azelastine has antihistaminic effects providing immediate relief, mast cell stabilization providing early-phase intervention, and inhibition of expression and activation of anti-inflammatory mediators which characterize the late phase of the immune reaction. The ophthalmic eyedrop formulation is approved for treatment of allergic conjunctivitis in adults and children aged over 3 years. In clinical trials comparing azelastine with other dual-acting eyedrops, such as levocabastine and olopatadine, azelastine was reported to be slightly less efficacious and to sting briefly upon administration. Even so, many patients experienced the full benefit of symptom relief, and preferred azelastine. As a broad-spectrum drug, azelastine offers many desirable properties for management of ocular allergies. Because it can often produce maximal effect with just twice-daily dosing, azelastine is a particularly good choice for the allergic population in whom minimizing exposure to topical products and preservatives is a key concern. PMID- 20856596 TI - Suicidality: risk factors and the effects of antidepressants. The example of parallel reduction of suicidality and other depressive symptoms during treatment with the SNRI, milnacipran. AB - Suicidal behavior (SB) represents a major public health issue. Clinical and basic research suggests that SB is a specific entity in psychiatric nosology involving a combination of personality traits, genetic factors, childhood abuse and neuroanatomical abnormalities. The principal risk factor for suicide is depression. More than 60% of patients who complete suicide are depressed at the time of suicide, most of them untreated. There has been a controversy concerning a possible increased risk of SB in some depressed patients treated with antidepressants. Most recent evidence suggests, however, that treatment of depressed patients is associated with a favorable benefit-risk ratio. A recent study has determined the effects of 6 weeks of antidepressant treatment with the serotonin and norepinephrine reuptake inhibitor, milnacipran, on suicidality in a cohort of 30 patients with mild to moderate depression. At baseline, mild suicidal thoughts were present in 46.7% of patients. Suicidal thoughts decreased progressively throughout the study in parallel with other depressive symptoms and were essentially absent at the end of the study. At no time during treatment was there any indication of an increased suicidal risk. Retardation and psychic anxiety decreased in parallel possibly explaining the lack of any "activation syndrome" in this study. PMID- 20856597 TI - Milnacipran: a unique antidepressant? AB - Tricyclic antidepressants (TCAs) are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs) are better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and norepinephrine reuptake inhibitors (SNRIs). Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine), and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1). Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug-drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability. PMID- 20856598 TI - Leiter-R versus developmental quotient for estimating cognitive function in preschoolers with pervasive developmental disorders. AB - The utility of the developmental quotient (DQ) obtained with the Psychoeducational Profile Revised (PEP-R) was assessed as a means of estimating cognitive ability in young children with pervasive developmental disorders. Data from the PEP-R were analysed in a sample of 44 children aged from 2.0 to 5.9 years (mean 3.46 +/- 1), 13 with an autistic disorder and 31 with a pervasive developmental disorder not otherwise specified. DQ scores were compared with scores from the Leiter International Performance Scale Revised-Visualization and Reasoning Battery (Leiter-R) in the same 44 children. Overall and domain DQs on the PEP-R were significantly correlated with Leiter-R scores. This study suggests that DQ scores obtained from the PEP-R in preschool children with pervasive developmental disorders may be a viable alternative to the Leiter-R as an assessment tool. PMID- 20856600 TI - Disease-modifying therapies in relapsing-remitting multiple sclerosis. AB - CLINICAL QUESTION: What is the best current disease-modifying therapy for relapsing-remitting multiple sclerosis? RESULTS: The evidence shows that the most effective disease-modifying therapy for delaying short- to medium-term disability progression, prevention of relapses, reducing the area and activity of lesions on magnetic resonance imaging, with the least side effects, is high-dose, high frequency subcutaneous interferon-beta1a 44 MUg three times per week. IMPLEMENTATION: The pitfalls in treatment of MS can be avoided by remembering the following points: The most effective therapy to prevent or delay the appearance of permanent neurological disability with the fewest side effects should be chosen, and treatment should not be delayed.Adherence to treatment should be monitored closely, and needs comprehensive patient information and education to establish long-term adherence, which is a critical determinant of long-term outcome.The correct approach to the disease includes disease management, symptom management, and patient management. A combination of tools is necessary to ease the various symptoms, which fall into three broad categories, i.e. rehabilitation, pharmacological, and procedural.It is important to understand that no treatment modality should be used alone, unless it is in itself sufficient to remedy the particular symptom/problem. PMID- 20856601 TI - Faster return to work after psychiatric consultation for sicklisted employees with common mental disorders compared to care as usual. A randomized clinical trial. AB - INTRODUCTION: Return to work (RTW) of employees on sick leave for common mental disorders may require a multidisciplinary approach. This article aims to assess time to RTW after a psychiatric consultation providing treatment advice to the occupational physician (OP) for employees on sick leave for common mental disorders in the occupational health (OH) setting, compared to care as usual (CAU). METHODS: Cluster randomized clinical trial evaluating patients of 12 OPs receiving consultation by a psychiatrist, compared to CAU delivered by 12 OPs in the control group. 60 patients suffering from common mental disorders and >= six weeks sicklisted were included. Follow up three and six months after inclusion. Primary outcome measure was time to RTW. Intention- to-treat multilevel analysis and a survival analysis were performed to evaluate time to RTW in both groups. RESULTS: In CAU, referral was the main intervention. Both groups improved in terms of symptom severity and quality of life, but time to RTW was significantly shorter in the psychiatric consultation group. At three months follow up, 58% of the psychiatric consultation group had full RTW versus 44% of the control group, a significant finding (P = 0.0093). Survival analysis showed 68 days earlier RTW after intervention in the psychiatric consultation group (P = 0.078) compared to CAU. CONCLUSION: Psychiatric consultation for employees on sick leave in the OH setting improves time to RTW in patients with common mental disorders as compared to CAU. In further research, focus should be on early intervention in patients with common mental disorders on short sick leave duration. Psychiatric consultation might be particularly promising for improvement of RTW in those patients. TRIAL REGISTRATION NUMBER: ISRCTN: 86722376. PMID- 20856602 TI - The dual-gate lumen model of renal monoamine transport. AB - The three-phase response of urinary serotonin and dopamine in subjects simultaneously taking amino acid precursors of serotonin and dopamine has been defined.1,2 No model exists regarding the renal etiology of the three-phase response. This writing outlines a model explaining the origin of the three-phase response of urinary serotonin and dopamine. A "dual-gate lumen transporter model" for the basolateral monoamine transporters of the kidneys is proposed as being the etiology of the three-phase urinary serotonin and dopamine responses. PURPOSE: The purpose of this writing is to document the internal renal function model that has evolved in research during large-scale assay with phase interpretation of urinary serotonin and dopamine. PATIENTS AND METHODS: In excess of 75,000 urinary monoamine assays from more than 7,500 patients were analyzed. The serotonin and the dopamine phase were determined for specimens submitted in the competitive inhibition state. The phase determination findings were then correlated with peer-reviewed literature. RESULTS: The correlation between the three-phase response of urinary serotonin and dopamine with internal renal processes of the bilateral monoamine transporter and the apical monoamine transporter of the proximal convoluted renal tubule cells is defined. CONCLUSION: The phase of urinary serotonin and dopamine is dependent on the status of the serotonin gate, dopamine gate, and lumen of the basolateral monoamine transporter while in the competitive inhibition state. PMID- 20856599 TI - Getting the balance right: Established and emerging therapies for major depressive disorders. AB - Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising. PMID- 20856603 TI - Relationship between hair cortisol concentrations and depressive symptoms in patients with coronary artery disease. AB - OBJECTIVE: Concentrations of cortisol in hair, a novel marker of longer-term cortisol status, were compared in depressed versus nondepressed patients with coronary artery disease (CAD). METHODS: 20 mg hair samples of 3 cm length were collected from 121 patients attending a cardiac rehabilitation program, 34 of whom suffered from depressive symptoms. RESULTS: Controlling for age, gender, coronary artery bypass grafting, history of depression, and time since most recent acute coronary syndrome, cortisol concentrations (P = 0.162) did not predict severity of depression. Younger age (P = 0.003) was a significant predictor of depressive symptoms. Perceived stress was not associated with long term cortisol concentrations (P = 0.161). CONCLUSIONS: Cortisol concentrations in hair do not predict depressive symptoms in CAD patients attending cardiac rehabilitation. PMID- 20856605 TI - Reasons for reoperation after epilepsy surgery: a review based on a complex clinical case with three operations. AB - The results of surgical treatment of epileptic seizures have gradually improved in the past decade, approaching 60% to 90% seizure-free outcome in temporal lobe epilepsy and 45% to 66% in extratemporal lobe epilepsy. Unfortunately some patients continue with seizures after epilepsy surgery and the studies have shown that approximately the 3% to 15% of patients with a previous failed surgical procedure are reoperated. Selected patients may be candidates for further surgery, potentially leading to a significant decrease in the frequency and severity of seizures. In patients with intractable partial epilepsy there are many possible factors, alone or in combination, that could be related to the failure of resection. Some of the factors could be genetic or acquired predisposition to epileptogenicity. In this article we report a case with intractable epilepsy that required three interventions to render seizure free. We analyzed our specific case in the light of previous reports on reoperation and enumerate the potential reasons for reoperation that could apply to all patients with failure of an initial procedure. PMID- 20856604 TI - Overview of essential tremor. AB - Essential tremor (ET) is one of the most common movement disorders in the world. Despite this, only one medication (propranolol) is approved by the Food and Drug Administration (FDA) to treat it. Fortunately, recent studies have identified some additional medications as treatment of ET. Surgical procedures, such as deep brain stimulation of the ventral intermediate nucleus of the thalamus, offer treatment for refractory tremor. The epidemiology, pathogenesis, and medical and surgical treatment of ET will be discussed in this paper. PMID- 20856606 TI - Armodafinil in the treatment of sleep/wake disorders. AB - Excessive sleepiness (ES) is a major but underestimated public health concern associated with significant impairments in alertness/wakefulness and significant morbidity. The term ES has been used in the sleep medicine literature for years, but due to its nonspecific symptoms (ie tiredness or fatigue), it frequently goes unrecognized or is misdiagnosed in primary care. In some cases ES arises due to poor sleep habits or self-imposed sleep deprivation; however, ES is also a key component of a number of sleep/wake disorders and multiple medical and psychiatric disorders. Identification and treatment of ES is critical to improve the quality of life and well-being of patients and for the safety of the wider community. The inability of patients to recognize the nature, extent, and symptomatic profile of sleep/wake disorders requires vigilance on the part of healthcare professionals. Interventions to address ES and its associated impairments, treatment of the underlying sleep/wake disorder, and follow-up are a priority given the potential for serious consequences if left untreated. Wakefulness-promoting agents are available that treat ES associated with sleep/wake disorders. This review examines current approaches for managing this debilitating and potentially life-threatening condition, focusing on the place of armodafinil as a wakefulness-promoting agent. PMID- 20856608 TI - Short cognitive behavioral therapy and cognitive training for adults with ADHD - a randomized controlled pilot study. AB - In clinical practice, a growing need exists for effective non-pharmacological treatments of adult attention-deficit/hyperactivity disorder (ADHD). Here, we present the results of a pilot study of 10 adults with ADHD participating in short-term individual cognitive- behavioral therapy (CBT), 9 adults participating in cognitive training (CT), and 10 controls. Self-report questionnaires, independent evaluations, and computerized neurocognitive testing were collected before and after the treatments to evaluate change. There were distinctive pre hypotheses regarding the treatments, and therefore the statistical comparisons were conducted in pairs: CBT vs control, CT vs control, and CBT vs CT. In a combined ADHD symptom score based on self-reports, 6 participants in CBT, 2 in CT and 2 controls improved. Using independent evaluations, improvement was found in 7 of the CBT participants, 2 of CT participants and 3 controls. There was no treatment-related improvement in cognitive performance. Thus, in the CBT group, some encouraging improvement was seen, although not as clearly as in previous research with longer interventions. In the CT group, there was improvement in the trained tasks but no generalization of the improvement to the tasks of the neurocognitive testing, the self- report questionnaires, or the independent evaluations. These preliminary results warrant further studies with more participants and with more elaborate cognitive testing. PMID- 20856609 TI - Emerging treatments in the management of bipolar disorder - focus on risperidone long acting injection. AB - Bipolar disorder is a life-long psychiatric illness characterized by a high frequency of relapses and substantial societal costs. Almost half of the patients are prescribed second generation antipsychotics for treatment of manic states, or as the maintenance therapy. Risperidone long acting injection (RLAI) as a monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder was approved by Food and Drug Administration (FDA) in United States in May 2009. In this review we will consider the aspects of pharmacology, pharmacokinetics, metabolism, safety and tolerability, and clinical trials focusing on the efficacy of RLAI in bipolar disorder. The patients' perspective and attitudes to long-acting injections will also be discussed. PMID- 20856610 TI - Lacosamide for the prevention of partial onset seizures in epileptic adults. AB - Lacosamide is a newly registered antiepileptic drug with dual mechanisms of action. It selectively enhances slow inactivation of voltage-gated sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. It also binds to a collapsing-response mediator protein-2, CRMP2. Lacosamide has a favorable pharmacokinetic profile; is rapidly and completely absorbed, has a relatively long elimination half-life of 13 hours which allows twice-daily administration, linear pharmacokinetics, and has low potential for drug interactions and renal elimination. Both oral and intravenous formulations of lacosamide are being developed. In placebo-controlled clinical trials, lacosamide was effective in seizure reduction as adjunctive therapy in patients with uncontrolled partial-onset seizures. Lacosamide was generally well tolerated. The most frequently reported adverse events in placebo controlled trials were dizziness, headache, nausea, and diplopia. Intravenous lacosamide has a comparably good safety profile. PMID- 20856607 TI - Emerging role of sertindole in the management of schizophrenia. AB - The atypical antipsychotic sertindole is a phenylindole-derived compound that has affinity for and functions as an antagonist at a number of receptor systems, including dopamine D2 receptors, 5-HT(2A) and 5-HT(2C) receptors, and alpha-1 noradrenergic receptors. Although previous data suggested that sertindole was well tolerated and had good efficacy against both positive and negative symptom clusters, reports of QT prolongation with sertindole prompted its voluntary removal from the market in 1998. After further safety analyses, it recently regained approval and was reintroduced to the European market for the treatment of schizophrenia, where its role in therapy among available atypicals remains unclear. This article evaluates the preclinical and clinical data regarding sertindole's effectiveness and concludes that sertindole continues to demonstrate a number of strengths, including effective management of both positive and negative symptoms, well-tolerated side effects (including little or no sedation, weight gain, and extrapyramidal side effects), and a superior procognitive profile that is unique among atypical antipsychotics. However, minor concerns regarding its sexual side effects and the major consideration of QT prolongation suggest that additional comparative effectiveness studies are needed to determine the superiority of sertindole vs other atypical antipsychotics recently introduced. PMID- 20856611 TI - See you in chicago. PMID- 20856612 TI - Chemotherapy dosing strategies in the obese, elderly, and thin patient: results of a nationwide survey. AB - PURPOSE: Determining the optimal starting dose of chemotherapy (CHT) presents a considerable challenge when using body-surface area (BSA)-based dosing, particularly in obese, elderly, or thin patients. We sought to document the range of approaches employed when administering CHT to these patients. METHODS: A questionnaire was developed by a panel of oncologists and mailed to all members of the Medical Oncology Group of Australia. RESULTS: From 315 oncologists, 188 responded (response rate 59.7%). BSA-based dosing is standard practice for 176 (97.2%) of the responding oncologists. In the adjuvant disease setting, 23 (12.7%) use ideal rather than actual body weight (BW) to calculate BSA, or choose whichever is less. When treating obese patients, only 6.1% of respondents routinely use actual BW. Of the remainder, 69.5% either cap the dose at 2 m(2) or use ideal BW. In underweight patients, 95% (n = 171) routinely calculate BSA using actual BW. Forty one respondents (22.7%) routinely reduce dose in the fit elderly. CONCLUSION: This analysis of BSA-based CHT dosing methods demonstrates significant variability in practice. Based on evidence from adjuvant studies showing that actual BSA-based dosing is desirable, a substantial number of Australian patients are being underdosed. Further education, together with ongoing research, is required to optimize individualized dosing for efficacy and tolerability. PMID- 20856613 TI - Undertreatment of cancer patients with chemotherapy is a global concern. PMID- 20856614 TI - Charge capture: does your process ensure accuracy of the revenue cycle? PMID- 20856615 TI - The pros and cons of outsourcing information technology. PMID- 20856616 TI - Institute of medicine report: recognizing psychosocial health needs to treat the whole patient. PMID- 20856617 TI - Cancer care for the whole patient-a new institute of medicine report. PMID- 20856618 TI - Annual meeting track provides practical education. PMID- 20856619 TI - An interview with robert m. Langdon jr, MD. PMID- 20856620 TI - Collaboration between cooperative groups and industry. PMID- 20856621 TI - Conducting outreach programs. PMID- 20856622 TI - How I treat renal cell carcinoma. PMID- 20856623 TI - The debate in hospice care. PMID- 20856624 TI - Misdiagnosis: Disclosing a Colleague's Error. PMID- 20856625 TI - Two lists. PMID- 20856626 TI - Patient navigation through the cancer care continuum: an overview. AB - Technologic advances, medical specialization, novel payment structures, and an increased scientific knowledge base have resulted in a health care system requiring trained experts to deliver guidance as patients complete care plans: Enter the concept of patient navigation. PMID- 20856627 TI - Impact of irinotecan and oxaliplatin on overall survival in patients with metastatic colorectal cancer: a population-based study. AB - A look at the temporal impact of advancements in therapeutic options in the last 10 years-from fluorouracil to irinotecan and oxaliplatin-on overall survival in a population-based cohort. PMID- 20856628 TI - Are There Any Differences in the Clinical and Economic Outcomes Between US Cancer Patients Receiving Appropriate or Inappropriate Venous Thromboembolism Prophylaxis? AB - Prophylaxis is often underused and inappropriately prescribed. This study compares the efficacy and cost of appropriate and partial prophylaxis in cancer patients at risk for VTE. PMID- 20856629 TI - Preventing venous thromboembolism in cancer patients: can we do better? PMID- 20856631 TI - The truth, the whole truth, and the medical record. PMID- 20856630 TI - Poor documentation prevents adequate assessment of quality metrics in colorectal cancer. AB - To standardize oncology clinical practice and improve patient outcomes, multiple organizations have developed cancer-specific metrics on the basis of a systematic background review, expert guidance, and fundamental elements of cancer care staging and treatment. PMID- 20856632 TI - Electronic surveillance of testicular cancer: understanding patient perspectives on access to electronic medical records. AB - This study explores the basis for providing effective access to electronic medical record data as a reference source for patients with early-stage testicular cancer undergoing surveillance follow-up programs. PMID- 20856633 TI - Web portals and patient information-seeking behaviors. PMID- 20856634 TI - Survey of provider perspectives on patient assistance programs. AB - This survey attempts to quantify the costs of applying for patient assistance programs, which oncologists say too often involves weeks of paperwork, repeated telephone calls, and bureaucratic delays. PMID- 20856635 TI - Provider practice models in ambulatory oncology practice: analysis of productivity, revenue, and provider and patient satisfaction. AB - Physicians, nurse practitioners, and physician assistants often work in teams to deliver cancer care in ambulatory oncology practices. This is likely to become more prevalent as the demand for oncology services rises, and the number of providers increases only slightly. PMID- 20856636 TI - Withdrawing medically futile treatment. AB - Physicians confront clinical and ethical dilemmas when their patients wish to continue treatments they have deemed futile; they must consider ethical obligations in deciding whether treatment should be withdrawn and in transferring patients from futile treatment to supportive care. PMID- 20856637 TI - Increasing minority accrual onto clinical trials. AB - Selected winners of the ASCO 2008 Clinical Trials Participation Awards were asked to provide examples of how they increased minority accrual onto the clinical trials conducted by their practices. PMID- 20856638 TI - Clinical trials participation awards recognize community-based practices dedicated to research. PMID- 20856639 TI - Enhancing clinical trial awareness and outreach. PMID- 20856640 TI - ASCO Addresses the Rising Cost of Cancer Care. PMID- 20856642 TI - Role of radical prostatectomy for high-risk prostate cancer. AB - High-risk localized prostate cancer traditionally includes patients with clinical T3 disease but also includes those with apparently localized disease but with adverse prognostic factors such as a Gleason score of 8 to 10, prostate-specific antigen of more than 20 ng/ml, or extensive disease on biopsy. In the past, these patients were treated primarily with radiation therapy due to concerns that surgery was not likely to be curative and was associated with a high incidence of side-effects. In addition, the lack of randomized trials comparing curative treatments for high-risk prostate cancer makes treatment decisions in this patient population difficult. Several retrospective series have reported the long term efficacy of radical prostatectomy monotherapy in a high-risk population, showing that the 5-year cancer-specific survival rate was more than 80% and the 5 year biochemical recurrence-free survival rate was about 50%. In addition, comparisons of different treatment options by means of nonrandomized trials have shown improved outcomes with surgery compared with radiation therapy or observation. Thus, there is renewed interest in radical prostatectomy as the primary treatment for patients with high-risk prostate cancer. Here, we reviewed the outcomes of radical prostatectomy, with or without neoadjuvant or adjuvant therapies, in high-risk patients and what is known about the choice and timing of adjuvant therapies. PMID- 20856644 TI - Development and validation of the korean version of expanded prostate cancer index composite: questionnaire assessing health-related quality of life after prostate cancer treatment. AB - PURPOSE: Although the quality of life (QoL) of prostate cancer (PCa) patients is a major issue, there is no unified and useful methodology for assessing QoL. The Expanded Prostate Cancer Index Composite (EPIC) is a globally used tool to measure QoL after PCa treatment that comprises urinary, bowel, sexual, and hormonal domains. Acknowledging the need for such a tool applicable to Korean PCa patients, we translated EPIC into Korean and validated the new version. MATERIALS AND METHODS: The Korean version of EPIC was devised by translation, back translation, and reconciliation. Subsequently, we randomly selected 153 patients with localized PCa treated with radical perineal prostatectomy (67, 43.8%), radical retropubic prostatectomy (19, 12.4%), laparoscopic radical prostatectomy (12, 7.8%), robot-assisted laparoscopic radical prostatectomy (36, 23.5%), and high-intensity focused ultrasound ablation of the prostate (19, 12.4%) and asked them to complete EPIC. Reliability was assessed by test-retest correlation and Cronbach's alpha. Validity was assessed by factor analysis, interscale correlation, and correlation with Functional Assessment of Cancer Therapy Prostate (FACT-P). RESULTS: Test-retest correlation and Cronbach's alpha were high in each of the domains (0.92, 0.91, 0.76, 0.84 and 0.86, 0.84, 0.92, 0.83, p<0.0001). Interscale correlation among the domains was low (r<0.37), which indicated that EPIC is composed of proper domains. Interscale correlation between the function and bother subscales was high (0.94, 0.81, 0.84 and 0.80, p<0.0001). EPIC domains had low correlation with FACT-P, permitting complementary use. CONCLUSIONS: The Korean version of EPIC was developed by a proper process, as evident by its high reliability and validity. Therefore, it is a reliable, comprehensive, systematic method that evaluates QoL in Korean patients after PCa treatment. Furthermore, it can be adapted as an objective methodology for research globally. PMID- 20856643 TI - Comparison of Partial and Radical Nephrectomy for pT1b Renal Cell Carcinoma. AB - PURPOSE: Partial nephrectomy (PN) for patients with T1a renal cell carcinoma (RCC) has increasingly become accepted, although its role for patients with T1b RCC remains controversial. We retrospectively evaluated and then compared the oncologic and functional outcomes of patients with pT1b RCC who were treated with PN or radical nephrectomy (RN). MATERIALS AND METHODS: A total of 70 patients who were diagnosed with pT1bN0M0 RCC between January 1995 and December 2004 were included. The 5-year overall survival (OS), the 5-year recurrence-free survival (RFS), and the 5-year cancer-specific survival (CSS) were compared between the groups. Preoperative and postoperative serum creatinine and estimated glomerular filtration rate (GFR) levels were analyzed to assess renal function. RESULTS: The 5-year OS (92.3% vs. 87.8%, p=0.501), RFS (92.3% vs. 77.8%, p=0.175), and CSS (92.3% vs. 94.5%, p=0.936) of the PN and RN groups were not statistically different. The proportion of patients with decreased renal function was lower in the PN group than in the RN group (PN=0% vs. RN=11.5%). The postoperative change in serum creatinine and the GFR 1 year after nephrectomy was higher in the RN group than in the PN group (PN=0.2+/-0.2, 12.1+/-9.1 vs. RN=0.3+/-0.5, 18.1+/ 12.5), but there was no statistical difference. CONCLUSIONS: There were no statistically significant differences in prognosis or renal function between patients treated with PN and those treated with RN for pT1b RCC. PN may be a useful treatment modality for patients with pT1b RCC. PMID- 20856645 TI - Initial experience with laparoendoscopic single-site surgery by use of a homemade transumbilical port in urology. AB - PURPOSE: We present our initial experience with laparoendoscopic single-site surgery (LESS) by a single surgeon in the urologic field. MATERIALS AND METHODS: From May 2009 to April 2010, 30 consecutive patients underwent LESS including seven cases of nephrectomy, five cases of nephroureterectomy with bladder cuff excision, four cases of ureterolithotomy, eight cases of marsupialization, and six cases of varicocelectomy. We performed a retrospective analysis of the medical records of the above patients. The single port was made with a surgical glove and an Alexis(r) wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA). The wound retractor was put into the peritoneal space through an umbilical incision, and a laparoscopic triangle was secured by crossing both instruments. All operations were performed by the transperitoneal approach. RESULTS: Mean patient age was 54.8 years. Mean operative time was 171.2+/-109.1 minutes. Mean estimated blood loss was 265.0+/-395.5 ml. Mean incision length was 3.2+/-1.4 cm. Mean length of hospitalization was 5.2+/-2.9 days. There was one laparoscopic conversion and two open conversions. There were two cases of transient ileus that improved with conservative treatment. Mean visual analogue pain scales on the operative day and first postoperative day were 6.3/10 and 3.1/10, respectively. CONCLUSIONS: In our experience, LESS for urologic surgery is feasible, safe, and clinically applicable. We consider the homemade single port device to be a relatively cost-effective and convenient device. If surgical instruments for LESS and appropriate ports specified for LESS are developed, LESS would be a surgical treatment technique that could be used as an alternative to the conventional types of laparoscopic surgery. PMID- 20856646 TI - Holmium laser enucleation of the prostate for benign prostatic hyperplasia: effectiveness, safety, and overcoming of the learning curve. AB - PURPOSE: To examine the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) for the surgical treatment of benign prostatic hyperplasia and to estimate the time to overcome the learning curve. MATERIALS AND METHODS: From May 2008 to October 2009, 164 consecutive patients treated with HoLEP were enrolled in this study. International Prostate Symptom Score (IPSS), peak urinary flow rate (Qmax), and postvoid residual urine (PVR) were documented preoperatively and at 6 weeks and 3, 6, 12, and 18 months postoperatively. The 164 study subjects were divided into 3 groups (group 1 the first 50 patients treated, group 2 the second 50, and group 3 the third 64), and perioperative data and complications were analyzed in these groups to determine the learning curve. In addition, the inverse and upward techniques were compared in terms of the effects and the stability of morcellation. RESULTS: The mean patient age was 69 years, and the average operation time was 62 minutes (range, 20-208 minutes). Mean prostate volume was 54.2 ml and mean resected tissue weight was 18.6 g. Postoperatively, IPSS and PVR decreased and Qmax increased significantly. Postoperative complications were transient incontinence (8.5%), urinary retention (4.3%), hematuria (3.0%), urinary tract infection (1.2%), and urethral stricture (0.6%), and intraoperative complications were minor capsular perforation (4%) and bladder injury (8%). CONCLUSIONS: HoLEP was found to be effective and safe regardless of prostate size. We recommend that a systematic educational program be established to reduce the learning curve. PMID- 20856647 TI - Prevalence and treatment efficacy of genitourinary mycoplasmas in women with overactive bladder symptoms. AB - PURPOSE: To evaluate the incidence of genitourinary mycoplasmas and the efficacy of antibiotics in women with overactive bladder (OAB) symptoms. MATERIALS AND METHODS: Women with OAB symptoms (micturition >=8/24 hours and urgency >=1/24 hours) for >=3 months were screened for Mycoplasma hominis (M. hominis), Ureaplasma urealyticum (U. urealyticum), and Chlamydia trachomatis (C. trachomatis). Specimens from urethral and cervical vaginal swabs were examined for M. hominis and U. urealyticum by using the Mycoplasma IST2 kit and for C. trachomatis by using PCR. Women with positive results were treated with a 1 g dose of azithromycin. Persistent infection was treated with doxycycline. Changes in a 3-day bladder diary, Patient Perception of Bladder Condition (PPBC), and International Consultation on Incontinence Questionnaire-Female Lower Urinary Tract Symptoms (ICIQ-FLUTS) were evaluated 4 weeks after negative conversion. Patient satisfaction was assessed. RESULTS: Of 84 women screened, 42.8% were positive (U. urealyticum, 40.5%; M. hominis, 7.1%; C. trachomatis, 3.6%; two organisms, 8.3%). After treatment, 82.7% obtained negative conversion, and their median number of micturition episodes decreased from 10.6/24 hours to 8.1/24 hours (p=0.002). PPBC and domain scores of the ICIQ-FLUTS (filling and quality of life) significantly improved. About 87.5% women with negative conversion were satisfied with the treatment. CONCLUSIONS: Considering diagnostic tests and treatment for genitourinary mycoplasmas might be beneficial before invasive workup or treatment in women with OAB symptoms. PMID- 20856648 TI - Correlation between Metabolic Syndrome and Lower Urinary Tract Symptoms of Males and Females in the Aspect of Gender-Specific Medicine: A Single Institutional Study. AB - PURPOSE: We attempted to examine the correlation between metabolic syndrome and lower urinary tract symptoms (LUTS) in the aspect of gender-specific medicine. MATERIALS AND METHODS: A total of 922 patients participating in a health examination completed the International Prostate Symptom Score (IPSS) questionnaire and the Overactive Bladder Questionnaire Short Form (OABq-SF) symptom bother scale from March 2008 to July 2009. Metabolic syndrome was defined by using the National Cholesterol Education Program Adult Treatment Panel III criteria announced in 2001. We analyzed differences in lower urinary tract symptoms according to the presence of metabolic syndrome and the component elements of metabolic syndrome. RESULTS: The subjects were 538 males and 384 females with a mean age of 48.8+/-6.8 years. Among all patients, the number of patients with metabolic syndrome was 143 (15.5%); there were 110 males (20.4%) and 33 females (8.6%), showing a significant difference. There were no differences in scores on the IPSS or OABq-SF with respect to the presence or absence of metabolic syndrome in males. In females, however, there were significant differences in the IPSS and OABq-SF depending on the presence or absence of metabolic syndrome. In males and females, the IPSS total score was significantly correlated with age. Also, high-density lipoprotein (HDL) cholesterol in males and triglyceride in females was significantly correlated with the IPSS total score. CONCLUSIONS: There are sex differences in the morbidity rate of metabolic syndrome and its effect on lower urinary tract symptoms. Therefore, it is necessary to consider gender-specific medicine in the diagnosis and treatment of LUTS. PMID- 20856649 TI - Stent Position Is More Important than alpha-Blockers or Anticholinergics for Stent-Related Lower Urinary Tract Symptoms after Ureteroscopic Ureterolithotomy: A Prospective Randomized Study. AB - PURPOSE: To evaluate the clinical factors that impact ureteral stent-related lower urinary tract symptoms (LUTS) after ureteroscopic ureterolithotomy, including the stent position and medication. MATERIALS AND METHODS: Fifty-three patients who underwent ureteroscopic ureterolithotomy with indwelling a stent were distributed into three groups. On demand analgesics were given to the group 1 (n=18). Daily tamsulosin 0.2 mg was added for group 2 (n=15) and daily tamsulosin 0.2 mg and tolterodine 4 mg was added for group 3 (n=20). The patients were also subclassified into appropriate or inappropriate group according to stent position. All the patients completed a visual analogue scale (VAS) and International Prostate Symptom Score (IPSS) on the 1st and 7th postoperative days. The VAS and IPSS were analyzed according to the medication groups and the stent position. RESULTS: In the appropriate stent potion group, only the storage symptom scores of groups 2 and 3 on the 1st postoperative day were significantly lower than those of the group 1 (p=0.001). This medication effect on LUTS was not observed in the inappropriate stent position group. In this group, total IPSS (p=0.015) and storage symptom scores (p=0.002) were higher than in the appropriate stent position group on the 7th postoperative day. CONCLUSIONS: Correct placement of the stent was more important than medication for lessening stent-related storage symptoms. PMID- 20856650 TI - Is a 22 cm Ureteric Stent Appropriate for Korean Patients Smaller than 175 cm in Height? AB - PURPOSE: Determining the ideal length of a ureteric stent is important to avoid complications associated with stent placement. Clinically, most urologists usually choose the length of a ureteric stent according to the patient's height. On the basis of a Chinese population study, a 22 cm ureteric stent has been recommended for patients smaller than 175 cm. We evaluated the appropriateness of this recommendation in Korean patients. MATERIALS AND METHODS: A total of 70 patients who were smaller than 175 cm and who underwent ureteroscopic lithotripsy and ureteric stent insertion were studied. The appropriateness of the stent length was determined on the basis of plain film findings. Patient discomfort was measured by use of a visual analogue scale (VAS) before the removal of the ureteric stent. RESULTS: In 29 patients with a 22 cm ureteric stent, 21 patients (72.4%) had an appropriate ureteric stent length and the mean VAS was 4.1. In 36 patients with a 24 cm ureteric stent, 20 patients (55.6%) had an appropriate ureteric stent length and the mean VAS was 4.0. Among 5 patients with a 26 cm ureteric stent, 1 patient (20%) had an appropriate ureteric stent length and the mean VAS was 5.4. CONCLUSIONS: In Korean patients smaller than 175 cm in height, a 22 cm ureteric stent was an appropriate length. PMID- 20856651 TI - Efficacy and Safety of Tadalafil 5 mg Administered Once Daily in Korean Men with Erectile Dysfunction: A Prospective, Multicenter Study. AB - PURPOSE: The aim of this study was to evaluate the efficacy of a daily dose of tadalafil 5 mg as well as its safety for the cardiovascular system in men with erectile dysfunction. MATERIALS AND METHODS: This study included a total of 162 men who were administered a daily dose of tadalafil 5 mg between April and December of 2009. A total of 127 men completed the 8-week clinical trial. The International Index of Erectile Function (IIEF)-5, blood pressure, and heart rate were measured before treatment with tadalafil (V1) and 4 (V2) and 8 weeks (V3) after treatment with tadalafil. Adverse effects were assessed at V1, V2, and V3. In cases in which the International Prostate Symptom Score (IPSS) was >=8 at V1, maximal flow rate (Qmax) and postvoid residual volume (PVR) were measured. RESULTS: The IIEF-5 values were 11.25+/-3.18, 14.56+/-3.79, and 16.91+/-3.56 at V1, V2, and V3, respectively, with significant improvement (V1 vs. V2, p<0.001; V1 vs. V3, p<0.001). The IPSS values were 10.59+/-5.56, 9.07+/-6.06, and 8.15+/ 6.10 at V1, V2, and V3, respectively, and the differences were statistically significant (V1 vs. V2, p<0.001; V1 vs. V3, p<0.001). There were no significant differences in blood pressure or heart rate. Adverse effects were observed in 7 men (5.51%) at V2 and in 5 men (3.94%) at V3. CONCLUSIONS: Tadalafil 5 mg administered once-a-day may be effective in improving erectile function. Adverse effects on the cardiovascular system may be minimal. In addition, it is believed that this may also be effective in improving voiding symptoms. PMID- 20856652 TI - Management of severe bilateral ureteropelvic junction obstruction in neonates with prenatally diagnosed bilateral hydronephrosis. AB - PURPOSE: The management of prenatally detected bilateral ureteropelvic junction obstruction (UPJO) remains controversial. We attempted to develop a treatment plan for patients with severe bilateral UPJO. MATERIALS AND METHODS: We evaluated the records of 13 patients with prenatally diagnosed grade 3 or more bilateral hydronephrosis that led to the postnatal diagnosis of severe bilateral UPJO. Ultrasonography and (99m)technetium mercaptoacetyltriglycine ((99m)Tc-MAG3) renal scans were performed within 1 month. Four renal units had grade 3 and 22 had grade 4 hydronephrosis. All 13 patients were managed by unilateral pyeloplasty, and the patients' mean age was 3 months. At 1 month postoperatively, we decided whether delayed surgery in the opposite renal unit was necessary according to the findings of ultrasonography and (99m)Tc-MAG3 scans. RESULTS: Of 13 patients, 11 underwent initial pyeloplasty on renal units with more severe hydronephrosis or lower relative renal function (RRF) on (99m)Tc-MAG3 scans. The remaining 2 patients simultaneously underwent percutaneous nephrostomy on renal units with a lower RRF and initial pyeloplasty on renal units with a higher RRF. In 5 patients, contralateral hydronephrosis had spontaneously improved at 1 month postoperatively, and 8 patients underwent delayed contralateral pyeloplasty at 2 months postoperatively. CONCLUSIONS: In children with severe bilateral UPJO, the non-operated renal units with grade 3 and some with grade 4 hydronephrosis improved spontaneously after unilateral pyeloplasty. Therefore, delayed pyeloplasty of the opposite side should be considered at 1 month following initial pyeloplasty. PMID- 20856653 TI - Bilateral recurrent thigh abscesses for five years after a transobturator tape implantation for stress urinary incontinence. AB - The synthetic, tension-free midurethral sling procedure using transobturator tape (TOT) was introduced in 2001 and has become the most widely used procedure for the treatment of female urinary incontinence worldwide. However, infectious complications associated with erosions have occasionally been reported because of a foreign body reaction to the polypropylene mesh. We observed a case of a bilateral recurrent thigh abscess manifesting 5 years after a TOT sling procedure. The patient had recurrent thigh abscesses with repeated incisions and drainages in the past 1 year. Five months earlier, she had undergone a procedure to remove the eroded suburethral mesh, but incompletely. The right thigh abscess recurred, and ultimately the residual mesh was completely excised with abscess drainage. Complete mesh removal is very important to prevent abscess recurrence, and it is necessary for any urologist treating women who have undergone the TOT procedure to be aware of the possibility of abscesses occurring for a long time after the operation. PMID- 20856654 TI - Neovesical-urethral anastomotic stricture successfully treated by ureteral dilation balloon catheter. AB - Neovesical-urethral anastomotic stricture is a complication of orthotopic neobladder, with a reported incidence of 2.7% to 8.8%. Strictures of the neovesico-urethral anastomotic site can be treated with regular self-dilation, but high-grade strictures require a surgical procedure involving incision by electrocautery or cold knife. Here we describe a grade III neovesical-urethral anastomotic stricture after an orthotopic bladder substitution that was successfully treated by use of a ureteral dilation balloon catheter. PMID- 20856656 TI - Changes in Bypass Flow during Temporary Occlusion of Unused Branch of Superficial Temporal Artery. AB - OBJECTIVE: Some neurosurgeons intentionally ligate the branches of the superficial temporal artery (STA) that are not used in standard STA-to-middle cerebral artery (MCA) anastomosis for the purpose of improving the flow rate in the bypass graft. We investigated changes in bypass flow during temporary occlusion of such unused branches of the STA. METHODS: Bypass blood flow was measured by a quantitative microvascular ultrasonic flow probe before and after temporary occlusion of branches of the STA that were not used for anastomosis. We performed measurements on twelve subjects and statistically assessed changes in flow. We also examined all the patients with digital subtraction angiography in order to observe any post-operative changes in STA diameter. RESULTS: Initial STA flow ranged from 15 mL/min to 85 mL/min, and the flow did not change significantly during occlusion as compared with pre-occlusion flow. The occlusion time was extended by 30 minutes in all cases, but this did not contribute to any significant flow change. CONCLUSION: The amount of bypass flow in the STA seems to be influenced not by donor vessel status but by recipient vessel demand. Ligation of the unused STA branch after completion of anastomosis does not contribute to improvement in bypass flow immediately after surgery, and furthermore, carries some risk of skin necrosis. It is better to leave the unused branch of the STA intact for use in secondary operation and to prevent donor vessel occlusion. PMID- 20856655 TI - Impact of early enteral nutrition on in-hospital mortality in patients with hypertensive intracerebral hemorrhage. AB - OBJECTIVE: We conducted this study to evaluate the clinical impact of early enteral nutrition (EN) on in-hospital mortality and outcome in patients with critical hypertensive intracerebral hemorrhage (ICH). METHODS: We retrospectively analyzed 123 ICH patients with Glasgow Coma Scale (GCS) score of 3-12. We divided the subjects into two groups : early EN group (< 48 hours, n = 89) and delayed EN group (>= 48 hours, n = 34). Body weight, total intake and output, serum albumin, C-reactive protein, infectious complications, morbidity at discharge and in hospital mortality were compared with statistical analysis. RESULTS: The incidence of nosocomial pneumonia and length of intensive care unit stay were significantly lower in the early EN group than in the delayed EN group (p < 0.05). In-hospital mortality was less in the early EN group than in the delayed EN group (10.1% vs. 35.3%, respectively; p = 0.001). By multivariate analysis, early EN [odds ratio (OR) 0.229, 95% CI : 0.066-0.793], nosocomial pneumonia (OR = 5.381, 95% CI : 1.621-17.865) and initial GCS score (OR = 1.482 95% CI : 1.160 1.893) were independent predictors of in-hospital mortality in patients with critical hypertensive ICH. CONCLUSION: These findings indicate that early EN is an important predictor of outcome in patients with critical hypertensive ICH. PMID- 20856657 TI - Unruptured Intracranial Aneurysms with Oculomotor Nerve Palsy : Clinical Outcome between Surgical Clipping and Coil Embolization. AB - OBJECTIVE: To evaluate the clinical outcome of coil embolization for unruptured intracranial aneurysm (UIA) with oculomotor nerve palsy (ONP) compared with surgical clipping. METHODS: A total of 19 patients presented with ONP caused by UIAs between Jan 2004 and June 2008. Ten patients underwent coil embolization and nine patients surgical clipping. The following parameters were retrospectively analyzed to evaluate the differences in clinical outcome observed in both coil embolization and surgical clipping : 1) gender, 2) age, 3) location of the aneurysm, 4) duration of the symptom, and 5) degree of ONP. RESULTS: Following treatment, complete symptomatic recovery or partial relief from ONP was observed in 15 patients. Seven of the ten patients were treated by coil embolization, compared to eight of the nine patients treated by surgical clipping (p = 0.582). Patient's gender, age, location of the aneurysm, size of the aneurysm, duration of symptom, and degree of the ONP did not statistically correlate with recovery of symptoms between the two groups. No significant differences were observed in mean improvement time in either group (55 days in coil embolization and 60 days in surgical clipping). CONCLUSION: This study indicates that no significant differences were observed in the clinical outcome between coil embolization and surgical clipping techniques in the treatment of aneurysms causing ONP. Coil embolization seems to be more feasible and safe treatment modality for the relief and recovery of oculomotor nerve palsy. PMID- 20856658 TI - Intentional sparing of daughter sac from coil packing in the embolization of aneurysms causing the third cranial nerve palsy : initial clinical and radiological results. AB - OBJECTIVE: Cerebral aneurysms which cause oculomotor nerve [cranial nerve (CN) III] palsy, are frequently found with a daughter sac of the aneurysm dome. We assumed that CN III might be compressed by the daughter sac and it would be more helpful not to fill the daughter sac with coils than vice versa during endosaccular embolization for recovering from CN III palsy, because it may give a greater chance for the daughter sac to shrink by itself later. We reviewed the initial results of our experiences of such cases. METHODS: Among 9 aneurysms accompanied by CN III palsy, 7 (6 unruptured, 1 ruptured) showed a daughter sac. We tried to fill the main dome completely and spare the daughter sac from coil filling to increase the possibility of decompression. We evaluated the short-term effectiveness of this concept using medical records and angiograms. RESULTS: After initial embolization, all of CN III palsy caused by unruptured aneurysms (6/6) resolved completely after various periods (3-90 days) of time. No adverse effects were noted during and after the procedures except for one case of harmless coil stretching during coil filling using double microcatheter. CONCLUSION: During the coil embolization of the cerebral aneurysm causing CN III palsy, sparing the daughter sac from coil packing while tightly packing the main dome, can be helpful in increasing the effectiveness of decompression. However, a long-term follow-up will be required. PMID- 20856659 TI - Clinical features and treatments of upper lumbar disc herniations. AB - OBJECTIVE: Disc herniations at the L1-L2 and L2-L3 levels are different from those at lower levels of the lumbar spine with regard to clinical characteristics and surgical outcome. Spinal canals are narrower than those of lower levels, which may compromise multiple spinal nerve roots or conus medullaris. The aim of this study was to evaluate the clinical features and surgical outcomes of upper lumbar disc herniations. METHODS: We retrospectively reviewed the clinical features of 41 patients who had undergone surgery for single disc herniations at the L1-L2 and L2-3 levels from 1998 to 2007. The affected levels were L1-L2 in 14 patients and L2-L3 in 27 patients. Presenting symptoms and signs, patient characteristics, radiologic findings, operative methods, and surgical outcomes were investigated. RESULTS: The mean age of patients with upper lumbar disc was 55.5 years (ranged 31 to 78). The mean follow-up period was 16.6 months. Most patients complained of back and buttock pain (38 patients, 92%), and radiating pain in areas such as the anterior or anterolateral aspect of the thigh (32 patients, 78%). Weakness of lower extremities was observed in 16 patients (39%) and sensory disturbance was presented in 19 patients (46%). Only 6 patients (14%) had undergone previous lumbar disc surgery. Discectomy was performed using three methods : unilateral laminectomy in 27 cases, bilateral laminectomy in 3 cases, and the transdural approach in 11 cases, which were performed through total laminectomy in 10 cases and unilateral laminectomy in 1 case. With regard to surgical outcomes, preoperative symptoms improved significantly in 33 patients (80.5%), partially in 7 patients (17%), and were aggravated in 1 patient (2.5%). CONCLUSION: Clinical features of disc herniations at the L1-L2 and L2-L3 levels were variable, and localized sensory change or pain was rarely demonstrated. In most cases, the discectomy was performed successfully by conventional posterior laminectomy. On the other hand, in large central broad based disc herniation, when the neural elements are severely compromised, the posterior transdural approach could be an alternative. PMID- 20856660 TI - The proper volume and distribution of cement augmentation on percutaneous vertebroplasty. AB - OBJECTIVE: The purpose of this study was to determine the optimal volume of injected cement and its distribution when used to treat vertebral compression fractures, and to identify factors related to subsequent vertebral fractures. METHODS: A retrospective analysis of newly developing vertebral fractures after percutaneous vertebroplasty was done. The inclusion criteria were that the fracture was a single first onset fracture with exclusion of pathologic fractures. Forty-three patients were included in the study with a minimum follow up period of six months. Patients were dichotomized for the analysis by volume of cement, initial vertebral height loss, bone marrow density, and endplate-to endplate cement augmentation. RESULTS: None of the four study variables was found to be significantly associated with the occurrence of a subsequent vertebral compression fracture. In particular, and injected cement volume of more or less that 3.5 cc was not associated with occurrence (p = 0.2523). No relation was observed between initial vertebral height loss and bone marrow density (p = 0.1652, 0.2064). Furthermore, endplate-to-endplate cement augmentation was also not found to be significantly associated with a subsequent fracture (p = 0.2860) by Fisher's exact test. CONCLUSION: Neither volume of cement, initial vertebral height loss, bone marrow density, or endplate-to-endplate cement augmentation was found to be significantly related to the occurrence of a subsequent vertebral compression fracture. Our findings suggest that as much cement as possible without causing leakage should be used. PMID- 20856661 TI - C7 posterior fixation using intralaminar screws : early clinical and radiographic outcome. AB - OBJECTIVE: The use of segmental instrumentation technique using pedicle screw has been increasingly popular in recent years owing to its biomechanical stability. Recently, intralaminar screws have been used as a potentially safer alternative to traditional fusion constructs involving fixation of C2 and the cervicothoracic junction including C7. However, to date, there have been few clinical series of C7 laminar screw fixation in the literature. Thus, the purpose of this study is to report our clinical experiences using C7 laminar screw and the early clinical outcome of this rather new fixation technique. METHODS: Thirteen patients underwent C7 intralaminar fixation to treat lesions from trauma or degenerative disease. Seventeen intralaminar screws were placed at C7. The patients were assessed both clinically and radiographically with postoperative computed tomographic scans. RESULTS: There was no violation of the screw into the spinal canal during the procedure and no neurological worsening or vascular injury from screw placement. The mean clinical and radiographic follow up was about 19 months, at which time there were no cases of screw pull-out, screw fracture or non-union. Complications included two cases of dorsal breech of intralaminar screw and one case of postoperative infection. CONCLUSION: Intralaminar screws can be potentially safe alternative technique for C7 fixation. Even though this technique cannot be used in the cases of C7 laminar fracture, large margin of safety and the ease of screw placement create a niche for this technique in the armamentarium of spine surgeons. PMID- 20856662 TI - Outcome of pallidal deep brain stimulation in meige syndrome. AB - OBJECTIVE: Meige syndrome is the combination of blepharospasm and oromandibular dystonia. We assessed the surgical results of bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) in patients with medically refractory Meige syndrome. METHODS: Eleven patients were retrospectively analyzed with follow-ups of more than 12 months. The mean follow-up period was 23.1 +/- 6.4 months. The mean age at time of surgery was 58.0 +/- 7.8 years. The mean duration of symptoms was 8.7 +/- 7.6 years. DBS electrodes were placed under local anesthesia using microelectrode recording and stimulation. After 2.4 +/- 1.3 days of trial tests, the stimulation device was implanted under general anesthesia. Patients were evaluated using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). RESULTS: BFMDRS total movement scores improved by 59.8%, 63.5%, 74.1%, 74.5%, and 85.5% during the immediate postoperative period of test stimulation, 3, 6, 12, and 24 months (n = 5) after surgery, respectively. The BFMDRS total movement scores were reduced gradually and the results reached statistical significance in the postoperative period (test period, p < 0.001; 3 months, p < 0.001; 6 months, p = 0.003; 12 months, p < 0.001; 24 months, p = 0.042). There was no statistical difference between 12 months and 24 months. BFM subscores improved by 63.3% for the eyes, 80.9% for the mouth, 68.4% for speech/swallowing, and 87.9% for the neck at 12 months after surgery. The adverse effects were insignificant. CONCLUSION: The bilateral GPi-DBS can be effective for the treatment of intractable Meige syndrome without significant side effects. PMID- 20856664 TI - Epidemiology of primary brain and central nervous system tumors in Korea. AB - OBJECTIVE: The aim of this report is to provide accurate nationwide epidemiologic data on primary central nervous system (CNS) tumors in Korea. Despite its importance, there are no accurate statistics on primary CNS tumors in Korea. We analyzed primary CNS tumors diagnosed in 2005 from the nationwide registry. METHODS: Data on primary CNS tumors diagnosed in 2005 were collected from the Korean Central Cancer Registry and the Korean Brain Tumor Society. Crude and age standardized rates were calculated in terms of gender, age, and histological type. Tumors of uncertain histology were investigated individually at the corresponding hospitals and had their diagnoses confirmed. RESULTS: A total of 5,692 patients diagnosed with primary CNS tumors in 2005 were included in this study. CNS tumors occurred in females more often than in males (female to male, 1.43 : 1). The most common tumor was meningioma (31.2%). Glioblastoma accounted for 30.7% of all gliomas, and 19.3% of all malignant primary CNS tumors. In children under 19 years of age, both germ cell tumor and embryonal/primitive/medulloblastoma were the most common tumors. CONCLUSION: This article is the first nationwide primary CNS tumor epidemiology report in Korea. Data from this study should provide valuable information regarding the understanding of primary CNS tumors epidemiology in Korea. PMID- 20856663 TI - Tailored surgical approaches for benign craniovertebral junction tumors. AB - OBJECTIVE: We report our surgical experience in the treatment of 16 consecutive patients with benign craniovertebral junction (CVJ) tumor, observed from 2003 to 2008 at our department. METHODS: We had treated 6 foramen magnum meningiomas, 6 cervicomedullary hemangioblastomas, 1 accessory nerve schwannoma, 1 hypoglossal nerve schwannoma, 1 C2 root schwannoma, and 1 cavernous hemangioma. Clinical results were evaluated by Karnofsky Performance Scale (KPS) and all patients underwent preoperative neuroradiological evaluation with computed tomography (CT) and magnetic resonance image (MRI). Angiography was performed in 15 patients and preoperative embolization was done in 2 patients. RESULTS: Five far-lateral, 1 supracondylar and 10 midline suboccipital approaches were performed. Gross total removal was achieved in 15 cases (94%) and subtotal removal in 1 patient (6%). None of the patients required occipitocervical fusion. Radiological follow-up showed no recurrence in cases totally removed. Postoperative decrease of KPS scores was recorded in only 1 patient. The treatment of cervicomedullary solid hemangioblastoma presented particular issues : by preoperative embolization, we removed tumor totally without an excessive bleeding or brainstem injury. In one of foramen magnum meningioma, we carried out subtotal removal due to hard tumor consistency and encasement of neurovascular structures. CONCLUSION: : The choice of surgical approaches and the extent of bone resection should be defined according to the location and size of individual tumors. Moreover, we emphasize that preoperative neuroradiological evaluations on presumptive tumor type could be helpful to the surgeon in tailoring the technique and providing the required exposure for different lesions, without unnecessary surgical steps. PMID- 20856665 TI - Clear cell ependymoma occurring in the cauda equina. AB - The authors present a rare case of clear cell ependymoma that developed in the cauda equina. A 54-year-old man was admitted to hospital with intermittent lower back pain. A neurological examination conducted on admission revealed no sensory or motor disturbance. Deep tendon reflexes in both lower extremities were normal. Magnetic resonance images demonstrated a 1.0 cm-sized intradural mass at the filum terminale. Gross total resection was performed via total laminectomy of L1 and L2. The tumor was confirmed to be clear cell ependymoma by histopathologic examination. His symptom was relieved after surgery. PMID- 20856666 TI - Primary spinal cord melanoma. AB - Primary central nervous system (CNS) melanoma is a rare condition that accounts for only 1% of all melanomas. A 34-year-old Korean female presented with a two month history of progressive weakness in both legs. Spinal magnetic resonance image (MRI) revealed a spinal cord tumor at the level of T4, which was hyperintense on T1-weighted imaging and hypointense on T2-weighted imaging. The intradural and extramedullary tumor was completely resected and diagnosed as melanoma. There were no metastatic lesions. At three years after surgery, the patient is still alive, with no evidence of tumor recurrence. We present the details of this case along with a comprehensive review of spinal cord melanoma. PMID- 20856667 TI - Two separate episodes of intramedullary spinal cord metastasis in a single patient with breast cancer. AB - Intramedullary spinal cord metastases are very rare. Patients with breast cancer as the primary source of intramedullary spinal cord metastases tend to do better than other types of cancer. We report the very unusual case of a woman with breast cancer who had two separate episodes of intramedullary spinal cord metastasis. PMID- 20856668 TI - Spontaneous intracranial epidural hematoma originating from dural metastasis of hepatocellular carcinoma. AB - Spontaneous intracranial epidural hematoma (EDH) due to dural metastasis of hepatocellular carcinoma is very rare. A 53-year-old male patient with hepatocellular carcinoma, who was admitted to the department of oncology, was referred to department of neurosurgery because of sudden mental deterioration to semicoma with papillary anisocoria and decerebrate rigidity after transarterial chemoembolization for hepatoma. Brain computed tomography (CT) revealed large amount of acute EDH with severe midline shifting. An emergent craniotomy and evacuation of EDH was performed. Active bleeding from middle cranial fossa floor was identified. There showed osteolytic change on the middle fossa floor with friable mass-like lesion spreading on the overlying dura suggesting metastasis. Pathological examination revealed anaplastic cells with sinusoidal arrangement which probably led to spontaneous hemorrhage and formation of EDH. As a rare cause of spontaneous EDH, dural metastasis from malignancy should be considered. PMID- 20856669 TI - Benign osteoblastoma located in the parietal bone. AB - Benign osteoblastoma is an uncommon primary bone tumor, extremely rare in calvarium. We present a case of a 25-year-old female with an osteoblastoma of parietal bone which was totally resected. The authors discussed the clinical presentation, radiographic finding, differential diagnosis and management of the benign calvarial osteoblastoma with a review of the literature. PMID- 20856670 TI - Undetermined fibrous tumor with calcification in the cerebellopontine angle. AB - In this report, we introduce an undetermined fibrous tumor with calcification occurring in the cerebellopontine angle (CPA). A 51-year-old woman was admitted with a short history of dizziness. Computed tomography and magnetic resonance images revealed a 2*2*2 cm sized mass at the left CPA which was round and calcified. There was no dura or internal auditory canal involvement. At surgery, the tumor was located at the exit of 7th and 8th cranial nerve complex. It was very firm, bright yellow and well encapsulated. Histologic findings revealed that the tumor was predominantly composed of fibrous component, scant spindle cells and dystrophic calcification. Immunohistochemical staining demonstrated positive for vimentin and negative for epithelial membrane antigen (EMA), S-100 protein, CD34, factor XIIIa and smooth muscle actin. The diagnosis was not compatible with meningioma, schwannoma, metastatic brain tumors, and other fibrous tumors. Although the tumor was resected in total, long term follow-up monitoring is necessary due to the possibility of recurrence. PMID- 20856671 TI - Giant serpentine aneurysm of the middle cerebral artery. AB - Giant serpentine aneurysms are rare and have distinct angiographic findings. The rarity, large size, complex anatomy and hemodynamic characteristics of giant serpentine aneurysms make treatment difficult. We report a case of a giant serpentine aneurysm of the right middle cerebral artery (MCA) that presented as headache. Treatment involved a superficial temporal artery (STA)-MCA bypass followed by aneurysm resection. The patient was discharged without neurological deficits, and early and late follow-up angiography disclosed successful removal of the aneurysm and a patent bypass graft. We conclude that STA-MCA bypass and aneurysm excision is a successful treatment method for a giant serpentine aneurysm. PMID- 20856672 TI - Idiopathic hypertrophic cranial pachymeningitis misdiagnosed as acute subtentorial hematoma. AB - A case of idiopathic hypertrophic cranial pachymeningitis (IHCP) misdiagnosed as an acute subdural hematoma is reported. A 37-year-old male patient presented with headache following head trauma 2 weeks earlier. Computerized tomography showed a diffuse high-density lesion along the left tentorium and falx cerebri. Initial chest X-rays revealed a small mass in the right upper lobe with right lower pleural thickening, which suggested lung cancer, such as an adenoma or mediastinal metastasis. During conservative treatment under the diagnosis of a subdural hematoma, left cranial nerve palsies were developed (3rd and 6th), followed by scleritis and uveitis involving both eyes. Magnetic resonance imaging (MRI) revealed an unusual tentorium-falx enhancement on gadolinium-enhanced T1 weighted images. Non-specific chronic inflammation of the pachymeninges was noticed on histopathologic examination following an open biopsy. Systemic steroid treatment was initiated, resulting in dramatic improvement of symptoms. A follow up brain MRI showed total resolution of the lesion 2 months after steroid treatment. IHCP should be included in the differential diagnosis of subtentorial enhancing lesions. PMID- 20856673 TI - A painful glomus tumor on the pulp of the distal phalanx. AB - A 52-year-old female patient presented with an 8-year history of progressively intense pain, cold sensitivity, and severe tenderness to palpation of the ulnar side of the tip of her right little finger. Subsequent diagnostic evaluation with ultrasonographic imaging revealed the presence of a glomus tumor in the tender area. Glomus tumors are benign, occurring in the vascular hamartomatous tubercles of the glomus body, which is a myoarterial apparatus typically found in the reticular dermis of the skin. Distal glomus tumors are relatively uncommon, and account for approximately 1% of all hand tumors. Most of them are located in the subungual area because of its high concentration of glomus bodies. We report a case of a glomus tumor with a typical triad of symptoms, yet with a rare location : on the pulp of the ulnar aspect of the distal phalanx of the right little finger. PMID- 20856674 TI - Erratum: surgical experience of neglected lower cervical spine fracture in patient with ankylosing spondylitis. AB - [This corrects the article on p. 66 in vol. 48, PMID: 20717515.]. PMID- 20856675 TI - Mutations in Wnt2 alter presynaptic motor neuron morphology and presynaptic protein localization at the Drosophila neuromuscular junction. AB - Wnt proteins are secreted proteins involved in a number of developmental processes including neural development and synaptogenesis. We sought to determine the role of the Drosophila Wnt7b ortholog, Wnt2, using the neuromuscular junction (NMJ). Mutations in wnt2 produce an increase in the number of presynaptic branches and a reduction in immunolabeling of the active zone proteins, Bruchpilot and synaptobrevin, at the NMJ. There was no change, however, in immunolabeling for the presynaptic proteins cysteine-string protein (CSP) and synaptotagmin, nor the postsynaptic proteins GluRIIA and DLG at the NMJ. Consistent with the presynaptic defects, wnt2 mutants exhibit approximately a 50% reduction in evoked excitatory junctional currents. Rescue, RNAi, and tissue specific qRT-PCR experiments indicate that Wnt2 is expressed by the postsynaptic cell where it may serve as a retrograde signal that regulates presynaptic morphology and the localization of presynaptic proteins. PMID- 20856678 TI - Predictive power of air travel and socio-economic data for early pandemic spread. AB - BACKGROUND: Controlling the pandemic spread of newly emerging diseases requires rapid, targeted allocation of limited resources among nations. Critical, early control steps would be greatly enhanced if the key risk factors can be identified that accurately predict early disease spread immediately after emergence. METHODOLOGY/PRINCIPAL FINDINGS: Here, we examine the role of travel, trade, and national healthcare resources in predicting the emergence and initial spread of 2009 A/H1N1 influenza. We find that incorporating national healthcare resource data into our analyses allowed a much greater capacity to predict the international spread of this virus. In countries with lower healthcare resources, the reporting of 2009 A/H1N1 cases was significantly delayed, likely reflecting a lower capacity for testing and reporting, as well as other socio-political issues. We also report substantial international trade in live swine and poultry in the decade preceding the pandemic which may have contributed to the emergence and mixed genotype of this pandemic strain. However, the lack of knowledge of recent evolution of each H1N1 viral gene segment precludes the use of this approach to determine viral origins. CONCLUSIONS/SIGNIFICANCE: We conclude that strategies to prevent pandemic influenza virus emergence and spread in the future should include: 1) enhanced surveillance for strains resulting from reassortment in traded livestock; 2) rapid deployment of control measures in the initial spreading phase to countries where travel data predict the pathogen will reach and to countries where lower healthcare resources will likely cause delays in reporting. Our results highlight the benefits, for all parties, when higher income countries provide additional healthcare resources for lower income countries, particularly those that have high air traffic volumes. In particular, international authorities should prioritize aid to those poorest countries where both the risk of emerging infectious diseases and air traffic volume is highest. This strategy will result in earlier detection of pathogens and a reduction in the impact of future pandemics. PMID- 20856676 TI - Condensed mitotic chromosome structure at nanometer resolution using PALM and EGFP- histones. AB - Photoactivated localization microscopy (PALM) and related fluorescent biological imaging methods are capable of providing very high spatial resolutions (up to 20 nm). Two major demands limit its widespread use on biological samples: requirements for photoactivatable/photoconvertible fluorescent molecules, which are sometimes difficult to incorporate, and high background signals from autofluorescence or fluorophores in adjacent focal planes in three-dimensional imaging which reduces PALM resolution significantly. We present here a high resolution PALM method utilizing conventional EGFP as the photoconvertible fluorophore, improved algorithms to deal with high levels of biological background noise, and apply this to imaging higher order chromatin structure. We found that the emission wavelength of EGFP is efficiently converted from green to red when exposed to blue light in the presence of reduced riboflavin. The photon yield of red-converted EGFP using riboflavin is comparable to other bright photoconvertible fluorescent proteins that allow <20 nm resolution. We further found that image pre-processing using a combination of denoising and deconvolution of the raw PALM images substantially improved the spatial resolution of the reconstruction from noisy images. Performing PALM on Drosophila mitotic chromosomes labeled with H2AvD-EGFP, a histone H2A variant, revealed filamentous components of ~70 nm. This is the first observation of fine chromatin filaments specific for one histone variant at a resolution approximating that of conventional electron microscope images (10-30 nm). As demonstrated by modeling and experiments on a challenging specimen, the techniques described here facilitate super-resolution fluorescent imaging with common biological samples. PMID- 20856677 TI - Induction of ER stress in macrophages of tuberculosis granulomas. AB - BACKGROUND: The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection. PRINCIPAL FINDINGS: Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1alpha) and eukaryotic initiation factor 2 alpha (eIF2alpha), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation. CONCLUSIONS: In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection. PMID- 20856679 TI - Novel photosensitizers trigger rapid death of malignant human cells and rodent tumor transplants via lipid photodamage and membrane permeabilization. AB - BACKGROUND: Apoptotic cascades may frequently be impaired in tumor cells; therefore, the approaches to circumvent these obstacles emerge as important therapeutic modalities. METHODOLOGY/PRINCIPAL FINDINGS: Our novel derivatives of chlorin e(6), that is, its amide (compound 2) and boronated amide (compound 5) evoked no dark toxicity and demonstrated a significantly higher photosensitizing efficacy than chlorin e(6) against transplanted aggressive tumors such as B16 melanoma and M-1 sarcoma. Compound 5 showed superior therapeutic potency. Illumination with red light of mammalian tumor cells loaded with 0.1 uM of 5 caused rapid (within the initial minutes) necrosis as determined by propidium iodide staining. The laser confocal microscopy-assisted analysis of cell death revealed the following order of events: prior to illumination, 5 accumulated in Golgi cysternae, endoplasmic reticulum and in some (but not all) lysosomes. In response to light, the reactive oxygen species burst was concomitant with the drop of mitochondrial transmembrane electric potential, the dramatic changes of mitochondrial shape and the loss of integrity of mitochondria and lysosomes. Within 3-4 min post illumination, the plasma membrane became permeable for propidium iodide. Compounds 2 and 5 were one order of magnitude more potent than chlorin e(6) in photodamage of artificial liposomes monitored in a dye release assay. The latter effect depended on the content of non-saturated lipids; in liposomes consisting of saturated lipids no photodamage was detectable. The increased therapeutic efficacy of 5 compared with 2 was attributed to a striking difference in the ability of these photosensitizers to permeate through hydrophobic membrane interior as evidenced by measurements of voltage jump induced relaxation of transmembrane current on planar lipid bilayers. CONCLUSIONS/SIGNIFICANCE: The multimembrane photodestruction and cell necrosis induced by photoactivation of 2 and 5 are directly associated with membrane permeabilization caused by lipid photodamage. PMID- 20856681 TI - Correlation of random urine protein creatinine (P-C) ratio with 24-hour urine protein and P-C ratio, based on physical activity: a pilot study. AB - Quantification of proteinuria is usually predicated upon 24-hour urine collection. Multiple factors influence urine collection and the rate of protein and creatinine excretion. Urine collection is often incomplete, and therefore creatinine and protein excretion rates are underestimated. A random urine protein creatinine (P-C) ratio has been shown over the years to be a reliable alternative to the 24-hour collection for detection and follow up of proteinuria. However, urine protein excretion may be influenced by physical activity. We studied 48 patients with proteinuria and varying levels of physical activity to determine the correlation between the measures of urine protein excretion. The correlation coefficient (r) between 24-hour urine total protein and random urine P-C ratio was 0.75 (P < 0.01) in the overall study population, but varied according to the level of proteinuria and physical activity in a stratified analysis: r = 0.99 (P < 0.001) and r = 0.95 (P < 0.01) in bedridden patients; r = 0.44 (P = not significant [NS]) and r = 0.54 (P = NS) in semiactive patients; and r = 0.44 (P = NS) and r = 0.58 (P < 0.05) in active patients with nephrotic- (>3500 mg/day) and non-nephrotic (<3500 mg/day) range proteinuria, respectively. The correlation appeared to be stronger between random urine and 24-hour urine P-C ratio for the overall study population (r = 0.84; P < 0.001), and when stratified according to the level of proteinuria and physical activity: r = 0.99 (P < 0.001) and r = 0.92 (P < 0.01) in bedridden patients; r = 0.61 (P = NS) and r = 0.54 (P = NS) in semiactive patients; and r = 0.64 (P < 0.02) and r = 0.52 (P < 0.05) in active patients with nephrotic and non-nephrotic range proteinuria, respectively. We conclude that the random urine P-C ratio is a reliable and practical way of estimating and following proteinuria, but its precision and accuracy may be affected by the level of patient physical activity. PMID- 20856680 TI - Schistosomiasis coinfection in children influences acquired immune response against Plasmodium falciparum malaria antigens. AB - BACKGROUND: Malaria and schistosomiasis coinfection frequently occurs in tropical countries. This study evaluates the influence of Schistosoma haematobium infection on specific antibody responses and cytokine production to recombinant merozoite surface protein-1-19 (MSP1-(19)) and schizont extract of Plasmodium falciparum in malaria-infected children. METHODOLOGY: Specific IgG1 to MSP1-(19), as well as IgG1 and IgG3 to schizont extract were significantly increased in coinfected children compared to P. falciparum mono-infected children. Stimulation with MSP1-(19) lead to a specific production of both interleukin-10 (IL-10) and interferon-gamma (IFN-gamma), whereas the stimulation with schizont extract produced an IL-10 response only in the coinfected group. CONCLUSIONS: Our study suggests that schistosomiasis coinfection favours anti-malarial protective antibody responses, which could be associated with the regulation of IL-10 and IFN-gamma production and seems to be antigen-dependent. This study demonstrates the importance of infectious status of the population in the evaluation of acquired immunity against malaria and highlights the consequences of a multiple infection environment during clinical trials of anti-malaria vaccine candidates. PMID- 20856682 TI - Adult patients with pulmonary arterial hypertension due to congenital heart disease: a review on advanced medical treatment with bosentan. AB - Pulmonary arterial hypertension (PAH) is a progressive disease with poor survival outcome. PAH is classified by the 2009 updated clinical classification of pulmonary hypertension and a major subgroup is PAH due to congenital heart disease (CHD) with systemic-to-pulmonary shunt. CHD-PAH is a result of systemic to-pulmonary shunting and chronic increased flow that ultimately results in adaptations of pulmonary vasculature and endothelial dysfunction. The advanced stage is called Eisenmenger syndrome which forms a small percentage (1%) of all CHD patients. Therapies targeted on PAH symptoms are called primary therapy for PAH, but most CHD-PAH patients progress to advanced therapy which is directed at the PAH itself. In CHD-PAH, advanced therapies are extensively investigated for all three major pathways: endothelin-1 receptor antagonists such as bosentan, prostanoids such as epoprostenol and phosphodiesterase 5 inhibitors such as sildenafil. Endpoints in most trials were catheterization hemodynamics, World Health Organization functional class, six-minute walking distance and patient focused outcomes, based on quality of life questionnaires and Borg dyspnea index. The BREATHE-5 and EARLY study were two important randomized controlled trials showing efficacy of bosentan at short follow-up. Moreover in patients with Eisenmenger syndrome, one recent survival retrospective study with majority of patients on bosentan showed strong survival benefit over conservative therapy. A diversity of prospective cohort and retrospective studies were performed but all with limited data, due to small numbers and heterogeneity of underlying CHD diagnoses. Further larger studies are needed to determine optimal treatment for adults with CHD-PAH. This review focuses on bosentan in CHD-PAH. In particular, we discuss outcome of various clinical trials and compare efficacy and safety of bosentan to other advanced therapies. PMID- 20856683 TI - Current and emerging treatments for the management of osteogenesis imperfecta. AB - Osteogenesis imperfecta (OI) is the most common bone genetic disorder and it is characterized by bone brittleness and various degrees of growth disorder. Clinical severity varies widely; nowadays eight types are distinguished and two new forms have been recently described although not yet classified. The approach to such a variable and heterogeneous disease should be global and therefore multidisciplinary. For simplicity, the objectives of treatment can be reduced to three typical situations: the lethal perinatal form (type II), in which the problem is survival at birth; the severe and moderate forms (types III-IX), in which the objective is 'autonomy'; and the mild form (type I), in which the aim is to reach 'normal life'. Three types of treatment are available: non-surgical management (physical therapy, rehabilitation, bracing and splinting), surgical management (intramedullary rod positioning, spinal and basilar impression surgery) and medical-pharmacological management (drugs to increase the strength of bone and decrease the number of fractures as bisphosphonates or growth hormone, depending on the type of OI). Suggestions and guidelines for a therapeutic approach are indicated and updated with the most recent findings in OI diagnosis and treatment. PMID- 20856684 TI - Molecular mechanisms and treatment strategies for Dupuytren's disease. AB - Dupuytren's disease (DD) is a common disease of the hand and is characterized by thickening of the palmar fascia and formation of tight collagenous disease cords. At present, the disease is incurable and the molecular pathophysiology of DD is unknown. Surgery remains the most commonly used treatment for DD, but this requires extensive postoperative therapy and is associated with high rates of recurrence. Over the past decades, more indepth exploration of the molecular basis of DD has raised the hopes of developing new treatment modalities. This paper reviews the clinical presentation and molecular pathophysiology of this disease, as well as current and emerging treatment. It also explores the implications of new findings in the laboratory for future treatment. PMID- 20856685 TI - Emerging oral treatments in multiple sclerosis - clinical utility of cladribine tablets. AB - Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) that represents one of the first causes of neurological disability in young adults. Although the pathogenesis of MS is still unclear, an autoimmune mechanism has been demonstrated. According to this evidence in the last 15 years different treatments acting on the immune system have been developed. Current disease-modifying drugs (DMDs) for MS require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Moreover the clinical efficacy of these disease-modifying drugs is suboptimal. Thus, there is an important need for the development of new therapeutic strategies. Several oral therapies (fingolimod, fumaric acid, teriflunomide, laquinimod) are in development; Among these cladribine is the only therapy with the potential for short-course dosing. Cladribine is an immunosuppressant that offers sustained regulation of the immune system through a preferential lymphocyte depleting action. Cladribine has a well-characterized and well-known safety profile, derived from more than 15 years of use of the parenteral formulation both in the oncology field and in MS. This paper reviews the new oral emerging treatments and presents the available data about the use of cladribine in MS and the future perspective of its clinical use. PMID- 20856686 TI - Selecting GLP-1 agonists in the management of type 2 diabetes: differential pharmacology and therapeutic benefits of liraglutide and exenatide. AB - Failure of secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) plays a prominent role in type 2 diabetes, and restoration of GLP-1 action is an important therapeutic objective. Although the short duration of action of GLP-1 renders it unsuited to therapeutic use, 2 long-acting GLP-1 receptor agonists, exenatide and liraglutide, represent a significant advance in treatment. In controlled trials, both produce short-term glucose-lowering effects, with the reduction in hemoglobin A(1c) of up to 1.3%. These responses are often superior to those observed with additional oral agents. However, unlike sulfonylureas, thiazolidinediones, or insulin, all of which lead to significant weight gain, GLP 1 receptor agonists uniquely result in long-term weight loss of around 5 kg, and higher doses may enhance this further. Reduction in blood pressure of 2-7 mm Hg also has been observed. Both drugs produce transient mild gastrointestinal side effects; although mild hypoglycemia can occur, this is usually in combination with other hypoglycemic therapies. However, serious hypoglycemia and acute pancreatitis are rare. The once-daily dosage of liraglutide makes it more convenient than twice-daily dosage of prandial exenatide, and a superior glucose lowering effect was observed in the only head-to-head comparison reported so far. Besides cost, these considerations currently favor liraglutide over exenatide. Further studies are needed to confirm long-term safety, and most importantly, that short-term benefits translate into long-term reductions of diabetes-related cardiovascular events and other complications. PMID- 20856687 TI - Growth hormone deficiency and cerebral palsy. AB - Cerebral palsy (CP) is a catastrophic acquired disease, occurring during development of the fetal or infant brain. It mainly affects the motor control centres of the developing brain, but can also affect cognitive functions, and is usually accompanied by a cohort of symptoms including lack of communication, epilepsy, and alterations in behavior. Most children with cerebral palsy exhibit a short stature, progressively declining from birth to puberty. We tested here whether this lack of normal growth might be due to an impaired or deficient growth hormone (GH) secretion. Our study sample comprised 46 CP children, of which 28 were male and 18 were female, aged between 3 and 11 years. Data obtained show that 70% of these children lack normal GH secretion. We conclude that GH replacement therapy should be implemented early for CP children, not only to allow them to achieve a normal height, but also because of the known neurotrophic effects of the hormone, perhaps allowing for the correction of some of the common disabilities experienced by CP children. PMID- 20856691 TI - Predictors of Reading Comprehension for Struggling Readers: The Case of Spanish speaking Language Minority Learners. AB - This longitudinal study examined the process of English reading comprehension at age 11 for 173 low achieving Spanish-speaking children. The influence of growth rates, from early childhood (age 4.5) to pre-adolescence (age 11), in vocabulary and word reading skills on this complex process were evaluated using structural equation modeling. Standardized measures of word reading accuracy and productive vocabulary were administered annually, in English and Spanish, and English reading comprehension measures were administered at age 11. Latent growth curve analyses revealed that English skills accounted for all unique variance in English reading comprehension outcomes. Further, expected developmental shifts in the influence of word reading and vocabulary skills over time were not shown, likely on account of students' below grade level reading comprehension achievement. This work underscores the need for theoretical models of comprehension to account for students' skill profiles and abilities. PMID- 20856688 TI - Antibiotic optimization in the difficult-to-treat patient with complicated intra abdominal or complicated skin and skin structure infections: focus on tigecycline. AB - Complicated intra-abdominal and skin and skin structure infections are widely varied in presentation. These infections very often lead to an increase in length of hospital stay, with a resulting increase in costs and mortality. In addition, these infections may be caused by a wide variety of bacteria and are often polymicrobial with the possibility of the presence of antimicrobial-resistant strains, such as methicillin-resistant Staphylococcus aureus, vancomycin resistant enterococci, extended-spectrum beta-lactamase strains (Escherichia coli, Klebsiella pneumoniae), and K. pneumoniae carbapenemase-producing strains. In combination with patients' immunosuppression or comorbidities, the treatment and management options for initial therapy success are few. Tigecycline, a new glycylcyline antimicrobial from the tetracycline drug class, represents a viable option for the successful treatment of these infections. It has been shown to have activity against a wide variety of bacteria, including the antimicrobial resistant strains. As with all tetracycline drugs, it is not recommended for pregnant or nursing women. The potential side effects are those typical of tetracycline drugs: nausea, vomiting, and headaches. Drug-drug interactions are not expected, and renal function monitoring is not necessary. PMID- 20856692 TI - Structural Survey of Zinc Containing Proteins and the Development of the Zinc AMBER Force Field (ZAFF). AB - Currently the Protein Data Bank (PDB) contains over 18,000 structures that contain a metal ion including Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Pd, Ag, Cd, Ir, Pt, Au, and Hg. In general, carrying out classical molecular dynamics (MD) simulations of metalloproteins is a convoluted and time consuming process. Herein, we describe MCPB (Metal Center Parameter Builder), which allows one, to conveniently and rapidly incorporate metal ions using the bonded plus electrostatics model (Hoops et al., J. Am. Chem. Soc. 1991, 113, 8262-8270) into the AMBER Force Field (FF). MCPB was used to develop a Zinc FF, ZAFF, which is compatible with the existing AMBER FFs. The PDB was mined for all Zn containing structures with most being tetrahedrally bound. The most abundant primary shell ligand combinations were extracted and FFs were created. These include Zn bound to CCCC, CCCH, CCHH, CHHH, HHHH, HHHO, HHOO, HOOO, HHHD, and HHDD (O = water and the remaining are 1 letter amino acid codes). Bond and angle force constants and RESP charges were obtained from B3LYP/6-31G* calculations of model structures from the various primary shell combinations. MCPB and ZAFF can be used to create FFs for MD simulations of metalloproteins to study enzyme catalysis, drug design and metalloprotein crystal refinement. PMID- 20856694 TI - A photochemically initiated chemistry for coupling underivatized carbohydrates to gold nanoparticles. AB - The sensitive optoelectronic properties of metal nanoparticles make nanoparticle based materials a powerful tool to study fundamental biorecognition processes. Here we present a new and versatile method for coupling underivatized carbohydrates to gold nanoparticles (Au NPs) via the photochemically induced reaction of perfluorophenylazide (PFPA). A one-pot procedure was developed where Au NPs were synthesized and functionalized with PFPA by a ligand-exchange reaction. Carbohydrates were subsequently immobilized on the NPs by a fast light activation. The coupling reaction was efficient, resulting in high coupling yield as well as high ligand surface coverage. A colorimetric system based on the carbohydrate-modified Au NPs was used for the sensitive detection of carbohydrate protein interactions. Binding and cross-reactivity studies were carried out between carbohydrate-functionalized Au NPs and lectins. Results showed that the surface-bound carbohydrates not only retained their binding affinities towards the corresponding lectin, but also exhibited affinity ranking consistent with that of the free ligands in solution. PMID- 20856695 TI - Women's empowerment revisited: a case study from Bangladesh. AB - This article explores the changing dimensions of women's empowerment over time in three Bangladesh villages where one of the authors has been conducting research since 1991. The article discusses theoretical issues related to the measurement of women's empowerment, and describes findings from a recent study in the villages exploring the current salience of indicators developed for a 1992 survey. In the article we discuss the types of social, economic, and political change that affect the measurement of women's empowerment; propose and explain a new set of indicators for the rural Bangladesh setting; and discuss implications for measuring women's empowerment in other settings. PMID- 20856697 TI - Journal of oncology practice in transition. PMID- 20856693 TI - Estimating and disclosing the risk of developing Alzheimer's disease: challenges, controversies and future directions. AB - With Alzheimer's disease increasing in prevalence and public awareness, more people are becoming interested in learning their chances of developing this condition. Disclosing Alzheimer's disease risk has been discouraged because of the limited predictive value of available tests, lack of prevention and treatment options, and concerns regarding potential psychological and social harms. However, challenges to this status quo include the availability of direct-to consumer health risk information (e.g., genetic susceptibility tests), as well as a growing literature suggesting that people seeking risk information for Alzheimer's disease through formal education and counseling protocols generally find it useful and do not experience adverse effects. This paper reviews current and potential methods of risk assessment for Alzheimer's disease, discusses the process and impact of disclosing risk to interested patients and consumers, and considers the practical and ethical challenges in this emerging area. Anticipated future directions are addressed. PMID- 20856698 TI - Integrating genetic risk assessment into practice. AB - Genetic risk assessment is quickly becoming an expectation in oncology care, but providing these services requires time, money, resources, and education. Providing genetic evaluation services requires continued education to stay abreast of advances in the field. ASCO and other organizations provide detailed educational resources for those interested in beginning or expanding a genetic assessment program. PMID- 20856699 TI - Office-based intraperitoneal chemotherapy for ovarian cancer. AB - The challenges and opportunities when implementing an office-based intraperitoneal chemotherapy program. PMID- 20856700 TI - Ethical and legal implications of cancer genetic testing: do physicians have a duty to warn patients' relatives about possible genetic risks? AB - This vignette raises questions about the extent of physicians' obligations to warn relatives of a patient about a hereditary cancer risk. PMID- 20856701 TI - Refocusing the debate: evidence-based clinical cancer research versus marketplace reality. AB - The continued development and licensing of modestly beneficial high-priced treatments, and the potential for widening disparities in cancer care, warrant a renewed focus on how we measure and define benefits and cost. PMID- 20856702 TI - Let's Focus on Value. PMID- 20856703 TI - Good clinical practice research guidelines reviewed, emphasis given to responsibilities of investigators: second article in a series. AB - Investigators should be aware of the importance of Good Clinical Practice guideline compliance. PMID- 20856705 TI - Billing challenges for residents of skilled nursing facilities. AB - Consolidated billing is a commonly used but little understood form of reimbursement for medical services provided in skilled nursing facilities. PMID- 20856704 TI - ASCO Clinical Practice Guidelines: Past, Present and Future. PMID- 20856706 TI - Transition. PMID- 20856707 TI - Tobacco cessation and quality cancer care. AB - Oncologists are critical to tobacco cessation efforts by providing education and resources to patients to help them quit. ASCO is working to strengthen its tobacco control advocacy and promote better funding for tobacco-related cancer prevention research. PMID- 20856708 TI - Smoking behaviors among cancer survivors: an observational clinical study. AB - PURPOSE: Smoking is a well-recognized risk factor for several cancers including cancers of the lung, bladder, and head and neck. Studies have shown that smoking can adversely affect the outcomes of different modalities of cancer treatment. This study examines smoking behaviors among cancer survivors to collect information necessary to create successful smoking cessation interventions. METHODS: For this observational clinical study, questionnaires were sent to 1,000 randomly selected patients diagnosed with cancer between 2003 and 2007 in one cancer center. Data were statistically analyzed to determine the likelihood of a patient quitting smoking after being diagnosed with cancer. RESULTS: We received 187 responses from the 1,000 surveys sent (18.7%). Of these, 166 were usable for analysis. The mean age of respondents was 64 (+/- 13) years. Men were more likely than women to be past smokers (55% of men and 32% of women respectively, P = .003). Fifty-two percent of respondents reported having a history of smoking. However, only 20% of patients reported having been active smokers at the time they were diagnosed with cancer. Furthermore, only 44% of these reported having quit smoking after their diagnosis with cancer. Only 62% of all respondents reported that they had been informed of the dangers of smoking by their health care provider during cancer treatment. CONCLUSION: In our study sample, less than one half (44%) of smoking cancer patients quit smoking after their cancer diagnosis, and only 62% of smoking cancer patients received smoking cessation counseling from their physicians. Intervention programs are needed to help cancer survivors to quit smoking. Prospective clinical trials may help identify the ideal intervention for smoking cessation. PMID- 20856709 TI - Recent developments in medicare coverage of off-label cancer therapies. AB - Centers for Medicare & Medicaid Services has implemented a number of important changes during the last 18 months regarding use of the compendia and journals for determining medically accepted off-label indications. PMID- 20856710 TI - Global tobacco problem getting worse, not better. AB - Tobacco use is declining in most industrialized countries but that does not mean the tobacco problem is going away. Unless aggressive steps are taken to change consumption trends, current tobacco-related cancer deaths will increase dramatically in the next few decades. PMID- 20856711 TI - Medical errors: physician and institutional responsibilities. AB - When it comes to medical errors, honesty is always the best practice for your practice. PMID- 20856712 TI - Community oncology research award winners use awards to enhance quality of their practices. AB - The 2009 Community Oncology Research Award (CORA) winners say they plan to improve practice research management, increase minority participation in clinical trials, improve communication, and invest in staff training and certification. PMID- 20856713 TI - Tobacco use in the pediatric and adolescent cancer survivor. AB - Oncologists and other clinicians can do more to tackle the difficult issue of tobacco use among adolescent cancer survivors by learning more about available resources for these patients and by supporting more research efforts in this area. PMID- 20856715 TI - Exemplary attributes: how to prepare for an audit. AB - Experts discuss one of the biggest challenges to any research site implementing a clinical trial program: the audit process. PMID- 20856714 TI - Clinical trials participation award winners using innovative technology to support clinical research. AB - Examples show how selected winners of ASCO's Clinical Trials Participation Awards are using new technologies to support their clinical research programs. PMID- 20856716 TI - Current Issues Regarding ASCO Guideline Implementation. PMID- 20856717 TI - Medicare's Seasons. PMID- 20856718 TI - Physician-related factors involved in patient decisions to enroll onto cancer clinical trials. AB - The development of new cancer therapies requires additional, and more complex, clinical trials. But only approximately 3% to 5% of adult cancer patients participate in cancer clinical trials. This study seeks to identify and understand the attitudes of the public and cancer survivors toward health-related decisions and cancer clinical trials to identify the key factors that must be addressed to increase that percentage. PMID- 20856719 TI - Examining telephone calls in ambulatory oncology. AB - A large component of ambulatory oncology practice is management of telephone calls placed to and from the practice between outpatient appointments, but they are not a reimbursable service, they require staff resources, and they place an unpredictable demand on workload. In this study, telephone calls were examined at a private medical oncology practice to define telephone call volume and distribution in an active ambulatory oncology practice, describe the callers and reasons for calls, and examine any differences in call volume by practice characteristics. PMID- 20856720 TI - Telephone Triage in Today's Oncology Practice. PMID- 20856721 TI - Oncology Workforce: Results of the ASCO 2007 Program Directors Survey. AB - The supply of oncologists is projected to increase by 14%, but the demand for oncology visits is projected to increase by 48% because of a growing aging population and an increase in the number of cancer survivors. Multiple strategies must be implemented to ensure continued access to quality cancer care, such as increasing the number of oncology training positions. PMID- 20856722 TI - Quality of life predicts progression-free survival in patients with metastatic renal cell carcinoma treated with sunitinib versus interferon alfa. AB - In a randomized phase III trial, sunitinib was associated with significantly superior progression-free survival when compared with interferon alfa as first line therapy in patients with metastatic renal cell carcinoma. This article investigates whether baseline quality of life and demographic and clinical variables were predictive for progression-free survival. PMID- 20856723 TI - ASCO Provisional Clinical Opinion: KRAS, Cetuximab, and Panitumumab-Clinical Implications in Colorectal Cancer. AB - ASCO's Provisional Clinical Opinion alerts oncologists to emerging information from recent clinical trials that can assist them in treatment selection. Evidence suggests that cetuximab and panitumumab are ineffective in patients with KRAS mutations at codon 12 or 13. Thus, patients with colorectal cancer with these mutations should be spared the toxicity and cost of an ineffective therapy. PMID- 20856724 TI - Provisional clinical opinion. PMID- 20856725 TI - When is standard treatment sufficiently active to make use of a placebo controlled trial unethical? AB - Research has demonstrated that double blinding can lessen the potential for bias in study outcomes, such as perceiving a drug as more effective in the experimental arm of a study. Effective double-blinding techniques minimize the influence of investigator and patient expectations. PMID- 20856726 TI - Cost-neutral clinical research enterprise. AB - The fifth in the Exemplary Attributes series looks at cost-neutral clinical research enterprise in light of two attributes of an exemplary clinical trial site: diversification of trial mix and high accrual activity. PMID- 20856727 TI - Comparative effectiveness: its origin, evolution, and influence on health care. AB - Comparative effectiveness, the evaluation of multiple treatments for one condition to find the best option, is essential to evidence-based medicine and coverage with evidence development. This article outlines comparative effectiveness and the changes it has undergone in recent decades. PMID- 20856728 TI - Access, quality, and cost. PMID- 20856729 TI - ASCO Task Force on the Cost of Cancer Care. AB - The United States leads the world in cancer care outcomes, but the cost is extremely high-and growing rapidly. New proposals for health reform emphasize one clear and immediate need: to control runaway cost. PMID- 20856730 TI - Three Changes for Affordable Care: One Payer's Wish List. AB - The oncology cost trend is approximately two times higher than that of medicine overall. Patients with cancer once had amnesty in the cost debate, but this is no longer the case. How do we cut cost and still provide quality care? PMID- 20856731 TI - Penny wise, dollar foolish approach to antiemetic use may compromise patient care. AB - A recent coverage determination by National Government Services threatens to compromise the ability of patients to achieve complete control of chemotherapy induced nausea and vomiting by limiting oncologist discretion in prescribing antiemetics. PMID- 20856732 TI - 2009 national practice benchmark: report on 2008 data. AB - Many oncology practices have responded to rising supply costs and decreasing reimbursements by examining their operational processes and working to reduce costs and enhance practice efficiency. PMID- 20856734 TI - Commentary: practice patterns and potential impact on quality measures for a practicing physician. PMID- 20856733 TI - Longitudinal patterns of chemotherapy use in metastatic colorectal cancer. AB - Multiple agents and combination therapies available to patients with advanced colorectal cancer have significantly improved survival and provided an opportunity for individualization of care, allowing clinicians and patients to prioritize risks and benefits of comparable regimens. PMID- 20856735 TI - Patterns of care in community-based oncology practices for anemia associated with myelosuppressive chemotherapy. AB - Use of erythropoiesis-stimulating agents in the treatment of myelosuppresive chemotherapy-induced anemia has been shown to increase hemoglobin levels and reduce the need for transfusions in patients with cancer. PMID- 20856736 TI - Commentary: do guidelines influence physician practice behavior? The experience with erythropoiesis-stimulating agents. PMID- 20856737 TI - Safe handling of parenteral cytotoxics: recommendations for ontario. AB - In caring for patients with cancer, health care workers may be exposed to cytotoxic agents. Recommendations are needed to mitigate potential risks for cancer and adverse reproductive outcomes associated with exposure. PMID- 20856739 TI - Working with your institutional review board. PMID- 20856738 TI - Can physicians refuse treatment to patients who smoke? AB - Irrespective of the "rightness" of smoking behavior, physicians have a duty to offer all patients appropriate anticancer therapy and supportive care and to help their patients become tobacco free. PMID- 20856740 TI - The health insurance portability and accountability act privacy rule and its impact on cancer research. PMID- 20856742 TI - Cancer quality alliance proceedings: caring beyond cancer. PMID- 20856741 TI - Patient navigators: a different viewpoint. PMID- 20856743 TI - Surviving. PMID- 20856745 TI - Treatment plan and summary templates: the experience of one practice. AB - Using a formal treatment plan template enables clearer and more fruitful discussions between physician and patient and among physicians within a practice. Treatment plans are vital to formal chemotherapy teaching sessions for patients beginning therapy, regardless of disease histology or treatment intent. PMID- 20856744 TI - Quality of care and cancer survivorship: the challenge of implementing the institute of medicine recommendations. AB - As the population ages, maintaining the quality of care for new patients with cancer will be challenged by an anticipated shortage of health professionals to care for the increased number of newly diagnosed and surviving patients with cancer. PMID- 20856746 TI - Treatment summaries in radiation oncology and their role in improving patients' quality of care: past, present, and future. AB - Through treatment summaries, radiation oncologists can build upon past efforts and improve the future quality of care for all patients receiving treatment with radiation. This article looks at what treatment summaries should contain and how they might be improved. PMID- 20856747 TI - Passport for care: implementing the survivorship care plan. AB - Approximately 12,000 children in the United States are diagnosed with cancer each year, and roughly 75% of these patients become long-term survivors. The Passport for Care was developed to support these survivors and their health care providers. PMID- 20856748 TI - The cancer survivorship care plan: health care in the context of cancer. AB - A 6-year cancer survivor shares how participating in the development of his cancer survivorship care plan yielded physical and emotional benefits, and laments that such plans are not more readily available. PMID- 20856749 TI - Cancer care and survivorship planning: promises and challenges. AB - Although we have made some progress in understanding long-term effects of some cancer treatments, there is still much more to learn about the impact of our treatments on our patients. PMID- 20856750 TI - Cancer care and cancer survivorship care in the United States: will we be able to care for these patients in the future? AB - The combination of a shortfall in oncologists and primary care physicians and an increased number of patients using more health care resources raises concerns about our health care system's ability to accommodate future patients with cancer and cancer survivors. PMID- 20856751 TI - Ethical issues related to patient use of complementary and alternative medicine. AB - It is important for physicians to set aside their personal opinions and establish open lines of communication with patients about alternatives to conventional medical treatment. PMID- 20856752 TI - Medicare advantage: reforms needed to ensure access to clinical trials. AB - A Clinton administration Executive Memorandum authorized Medicare payment for routine costs associated with clinical trials and recognized the role of clinical trials in patient care. However, a loophole in Medicare Advantage regulations has created a disparity in the way clinical trial services are covered for these enrollees. PMID- 20856753 TI - Make the commitment to quality care. PMID- 20856754 TI - Join ASCO in Welcoming Dr John Cox As Editor-in-Chief. PMID- 20856755 TI - Continued regulatory actions affecting the use of erythropoiesis-stimulating agents. AB - The FDA sent a "Complete Response and Safety Labeling Change Order" to the sponsors of ESAs on July 30, ordering changes to ESA labels in three important ways. For the first time, the FDA used its statutory authority to order a sponsor to make revisions to a product label. PMID- 20856757 TI - American society of clinical oncology 2008 clinical practice guideline update summary: use of chemotherapy and radiation therapy protectants. PMID- 20856756 TI - Chemotherapy treatments for metastatic colorectal cancer: is evidence-based medicine in practice? AB - Treatment options for colorectal cancer have expanded to include multiple oxaliplatin- and irinotecan-based regimens and more biological/targeted therapies. PMID- 20856758 TI - Quality assurance and educational standards for clinical trial sites. PMID- 20856759 TI - Clinical trial participation award process and 2008 winners. PMID- 20856760 TI - Patient-centered medical home: renewing primary care. PMID- 20856761 TI - Blue Cross Blue Shield of Michigan First Health Plan to Provide Reimbursement for Participation in QOPI. PMID- 20856762 TI - Future supply of and demand for oncologists. PMID- 20856763 TI - Hospice referral: an important responsibility of the oncologist. PMID- 20856764 TI - The time has come for national insurance cards. PMID- 20856765 TI - Barriers to enrollment of elderly adults in early-phase cancer clinical trials. AB - Potential strategies to overcome barriers to enrollment of seniors into early phase trials. PMID- 20856767 TI - Clinical pharmacists in oncology practice. AB - The collaboration between oncologists and clinical pharmacists seems destined to grow. PMID- 20856766 TI - Overturning barriers will take heavy lifting. PMID- 20856768 TI - Increased use of oral chemotherapy drugs spurs increased attention to patient compliance. AB - Ensuring that patients with breast cancer are taking the oral aromatase inhibitors prescribed as follow-up treatment to surgery is an ongoing concern for oncologists. PMID- 20856770 TI - ASCO Outlines Minimum Standards and Exemplary Attributes for Research Sites: Previews Tools to Be Provided. AB - Encouraging community oncologists to consider how to enhance their research programs and also to give practitioners not already involved in research a clearer understanding of what it involves. PMID- 20856769 TI - The 2007 national practice benchmark: results of a national survey of oncology practices. AB - Long-term trends in the cost of pharmaceutical goods purchased by community oncology practices seem to have dramatically changed in 2007, potentially ending an era of practice growth built on the economic engine of in-office chemotherapy provision. PMID- 20856771 TI - Geriatric oncology: past, present, future. AB - Efforts to integrate geriatric oncology principles in the training of all medical oncologists are underway. PMID- 20856772 TI - Caring for the elderly cancer patient: training the next generation of oncologists. PMID- 20856773 TI - Personal health records: an emerging trend. AB - While today PHRs seem far from the world of working oncology offices, that may change soon. PMID- 20856774 TI - When doctors and patients disagree about medical futility. AB - Factors that may help physicians determine when additional treatment is medically futile, and what physicians can do to encourage patients to explore more appropriate care options. PMID- 20856775 TI - Including Oncological Image Data From CD-ROMs into the Normal Workflow. PMID- 20856777 TI - Strengths, weaknesses, opportunities, and threats. PMID- 20856778 TI - Communication at the end of life. PMID- 20856779 TI - Targeting Lymph Node Retrieval and Assessment in Stage II Colon Cancer: A Quality Outcome Community-Based Cancer Center Study. AB - PURPOSE: Adequate lymph node evaluation is required for the proper staging of colon cancer. The current recommended number of lymph nodes that should be retrieved and assessed is 12. METHODS: The multidisciplinary Gastrointestinal Tumor Board at the Derrick L. Davis Forsyth Regional Cancer Center reviewed and recommended that a minimum of 12 lymph nodes be examined in all cases of colon cancer to ensure proper staging. This recommendation occurred at the end of the first quarter of 2005. To ensure this new standard was being followed, an outcomes study looking at the number of lymph nodes evaluated in stage II colon cancer was initiated. All patients with stage II colon cancer diagnosed between 2004 and 2006 were reviewed. RESULTS: There was a statistically significant improvement in the number of stage II colon cancer patients with 12 or more lymph nodes evaluated. Before the Gastrointestinal Tumor Board's recommendation, 49% (40 out of 82 patients) had 12 or more lymph nodes sampled. The median number of lymph nodes evaluated was 11. After the Gastrointestinal Tumor Board's recommendation, 79% (70 out of 88 patients) had 12 or more lymph nodes sampled. The median number of lymph nodes was 16. CONCLUSION: Multidisciplinary tumor boards can impact the quality of care of patients as demonstrated in this study. Although we do not yet have survival data on these patients, based on the previous literature referenced in this article, we would expect to see an improvement in survival rates in patients with 12 or more nodes retrieved and assessed. PMID- 20856781 TI - An interview with peter g. Ellis, MD. PMID- 20856780 TI - Effect of pretreatment distress on daily fatigue after chemotherapy for breast cancer. AB - PURPOSE: Fatigue is one of the most frequently reported and adverse effects of cancer chemotherapy. The present study tested the hypothesis that women's levels of emotional distress at the time of their initial outpatient chemotherapy treatment would predict the severity of their postinfusion fatigue. METHODS: Sixty stage I (32.6%) and II (67.4%) patients with breast cancer (mean age, 44.5 years) who were receiving standard outpatient chemotherapy participated. The independent variable, emotional distress, was assessed for "last night," "this morning," and "right now" with a visual analog scale (0 to 100). The dependent variable, post-treatment fatigue (PTF), was assessed (0 to 100) over each of the subsequent 6 days using end-of-day diaries, which also included assessments of distress and nausea (0 to 100). For the statistical analyses, post-treatment fatigue was divided into three phases with means calculated for days 1 through 2 (phase 1), 3 to 4 (phase 2), and 5 to 6 (phase 3). RESULTS: Consistent with the study hypothesis, patients' pretreatment distress level in the clinic was a significant (P < .001) predictor of PTF. There was also a significant (P < .025) interaction with phase, with distress becoming a predictor of PTF after phase 1. Multivariate analysis indicated that prior levels of distress were not independent predictors of PTF. CONCLUSIONS: This study is the first to demonstrate time-specific effects of pretreatment distress on PTF. Possible mechanisms of these effects now warrant investigation, as do possible benefits of brief interventions to reduce patient distress immediately before treatment. PMID- 20856783 TI - The southwest oncology group: new processes to coordinate increasingly complex clinical trials. PMID- 20856782 TI - Hospital-physician relationships: taking a proactive approach to building mutually successful relationships. PMID- 20856784 TI - Making research dollars stretch for community practices. PMID- 20856785 TI - Ensuring patient safety and scientific credibility in clinical trials. PMID- 20856786 TI - Apheresis in the office setting. PMID- 20856787 TI - Genetic counseling: an indispensable step in the genetic testing process. PMID- 20856788 TI - Making the decision to not attempt resuscitation. PMID- 20856789 TI - Reproductive health issues in women with cancer. PMID- 20856790 TI - Epigenetic approaches in the treatment of myelodysplastic syndromes: clinical utility of azacitidine. AB - Myelodysplastic syndromes (MDS) are a varied group of diseases leading to significant morbidity and mortality. Therapy of MDS has been difficult, with supportive cares used to ameliorate symptoms, and hematopoietic stem cell transplantation the only curative option. Agents, such as the cytidine analog azacitidine, exert an effect on DNA methyltransferase leading to a reduction in DNA methylation, a process thought to be key to the pathogenesis of MDS. Recently, azacitidine has been shown to prolong survival and improve quality of life in patients with MDS, while maintaining a favorable adverse effect profile. This review highlights the scientific rationale for the use of azacitidine in addition to its application in current clinical practice for patients with MDS. PMID- 20856791 TI - Temsirolimus in the treatment of relapsed or refractory mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is a rare and aggressive subtype of lymphoma associated with a poor prognosis. Chemotherapy is the mainstay of frontline treatment for patients with this disease. Despite high response rates to combination chemotherapy regimens, the majority of patients relapse within a few years of treatment. Therefore, finding efficacious treatments for relapsed or refractory disease has become a growing area of clinical research. The mammalian target of rapamycin (mTOR) is responsible for integrating cell signals from growth factors, hormones, and nutrients and communicating energy status. Scientific research on aberrant molecular pathways in cancer has revealed that several proteins along the mTOR pathway may be upregulated in this and other types of lymphoma. Temsirolimus is the first mTOR inhibitor that has shown clinical efficacy in treating MCL that has relapsed after frontline treatments. PMID- 20856792 TI - Social network sensors for early detection of contagious outbreaks. AB - Current methods for the detection of contagious outbreaks give contemporaneous information about the course of an epidemic at best. It is known that individuals near the center of a social network are likely to be infected sooner during the course of an outbreak, on average, than those at the periphery. Unfortunately, mapping a whole network to identify central individuals who might be monitored for infection is typically very difficult. We propose an alternative strategy that does not require ascertainment of global network structure, namely, simply monitoring the friends of randomly selected individuals. Such individuals are known to be more central. To evaluate whether such a friend group could indeed provide early detection, we studied a flu outbreak at Harvard College in late 2009. We followed 744 students who were either members of a group of randomly chosen individuals or a group of their friends. Based on clinical diagnoses, the progression of the epidemic in the friend group occurred 13.9 days (95% C.I. 9.9 16.6) in advance of the randomly chosen group (i.e., the population as a whole). The friend group also showed a significant lead time (p<0.05) on day 16 of the epidemic, a full 46 days before the peak in daily incidence in the population as a whole. This sensor method could provide significant additional time to react to epidemics in small or large populations under surveillance. The amount of lead time will depend on features of the outbreak and the network at hand. The method could in principle be generalized to other biological, psychological, informational, or behavioral contagions that spread in networks. PMID- 20856793 TI - Epidemiology of HIV infection in large urban areas in the United States. AB - BACKGROUND: While the U.S. HIV epidemic continues to be primarily concentrated in urban area, local epidemiologic profiles may differ and require different approaches in prevention and treatment efforts. We describe the epidemiology of HIV in large urban areas with the highest HIV burden. METHODS/PRINCIPAL FINDINGS: We used data from national HIV surveillance for 12 metropolitan statistical areas (MSAs) to determine disparities in HIV diagnoses and prevalence and changes over time. Overall, 0.3% to 1% of the MSA populations were living with HIV at the end of 2007. In each MSA, prevalence was >1% among blacks; prevalence was >2% in Miami, New York, and Baltimore. Among Hispanics, prevalence was >1% in New York and Philadelphia. The relative percentage differences in 2007 HIV diagnosis rates, compared to whites, ranged from 239 (San Francisco) to 1239 (Baltimore) for blacks and from 15 (Miami) to 413 (Philadelphia) for Hispanics. The epidemic remains concentrated, with more than 50% of HIV diagnoses in 2007 attributed to male-to-male sexual contact in 7 of the 12 MSAs; heterosexual transmission surpassed or equaled male-to-male sexual transmission in Baltimore, Philadelphia, and Washington, DC. Yet in several MSAs, including Baltimore and Washington, DC, AIDS diagnoses increased among men-who-have sex with men in recent years. CONCLUSIONS/SIGNIFICANCE: These data are useful to identify local drivers of the epidemic and to tailor public health efforts for treatment and prevention services for people living with HIV. PMID- 20856794 TI - Novel GLP-1 fusion chimera as potent long acting GLP-1 receptor agonist. AB - GLP-1 has a variety of anti-diabetic effects. However, native GLP-1 is not suitable for therapy of diabetes due to its short half-life (t1/2<2 min). To circumvent this, we developed a long-lasting GLP-1 receptor agonist by the fusion of GLP-1 with human IgG2 Fc (GLP-1/hIgG2). ELISA-based receptor binding assay demonstrated that GLP-1/hIgG2 had high binding affinity to the GLP-1R in INS-1 cells (Kd = 13.90+/-1.52 nM). Upon binding, GLP-1/hIgG2 was rapidly internalized by INS-1 cells in a dynamin-dependent manner. Insulin RIA showed that GLP-1/IgG2 dose-dependently stimulated insulin secretion from INS-1 cells. Pharmacokinetic studies in CD1 mice showed that with intraperitoneal injection (i.p.), the GLP 1/hIgG2 peaked at 30 minutes in circulation and maintained a plateau for >168 h. Intraperitoneal glucose tolerance test (IPGTT) in mice showed that GLP-1/hIgG2 significantly decreased glucose excursion. Furthermore, IPGTT performed on mice one week after a single drug-injection also displayed significantly reduced glucose excursion, indicating that GLP-1/hIgG2 fusion protein has long-lasting effects on the modulation of glucose homeostasis. GLP-1/hIgG2 was found to be effective in reducing the incidence of diabetes in multiple-low-dose streptozotocin-induced type 1 diabetes in mice. Together, the long-lasting bioactive GLP-1/hIgG2 retains native GLP-1 activities and thus may serve as a potent GLP-1 receptor agonist. PMID- 20856795 TI - Development of social variation in reproductive schedules: a study from an English urban area. AB - BACKGROUND: There is striking social variation in the timing of the onset of childbearing in contemporary England, with the mean age at first motherhood about 8 years earlier in the most deprived compared to the least deprived neighbourhoods. However, relatively little is known about how these social differences in reproductive schedule develop in childhood. METHODOLOGY/PRINCIPAL FINDINGS: We studied the development of differences in reproductive schedules, using a cross-sectional survey over 1000 school students aged 9-15 in the metropolitan borough of North Tyneside. Students from more deprived neighbourhoods had earlier ideal ages for parenthood than those from more affluent ones, and these differences were fully apparent by age 11. We found evidence consistent with three mechanisms playing a role in maintaining the socioeconomic gradient. These were: vertical intergenerational transmission (students whose own parents were younger at their birth wanted children younger); oblique intergenerational transmission (students in neighbourhoods where parents were younger in general wanted children earlier); and low parental investment (students who did not feel emotionally supported by their own parents wanted children at a younger age). CONCLUSIONS/SIGNIFICANCE: Our results shed some light on the proximate factors which may be involved in maintaining early childbearing in disadvantaged communities. They help understand why educational initiatives aimed at adolescents tend to have no effect, whereas improving the well-being of poor families with young children may do so. Our results also suggest that there will be considerable intergenerational inertia in the response of reproductive schedules to changing socioecological conditions. PMID- 20856796 TI - Neutralisation of uPA with a monoclonal antibody reduces plasmin formation and delays skin wound healing in tPA-deficient mice. AB - BACKGROUND: Proteolytic degradation by plasmin and metalloproteinases is essential for epidermal regeneration in skin wound healing. Plasminogen deficient mice have severely delayed wound closure as have mice simultaneously lacking the two plasminogen activators, urokinase-type plasminogen activator (uPA) and tissue type plasminogen activator (tPA). In contrast, individual genetic deficiencies in either uPA or tPA lead to wound healing kinetics with no or only slightly delayed closure of skin wounds. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the therapeutic potential in vivo of a murine neutralizing antibody directed against mouse uPA we investigated the efficacy in skin wound healing of tPA-deficient mice. Systemic administration of the anti-mouse uPA monoclonal antibody, mU1, to tPA-deficient mice caused a dose-dependent delay of skin wound closure almost similar to the delayed kinetics observed in uPA;tPA double-deficient mice. Analysis of wound extracts showed diminished levels of plasmin in the mU1-treated tPA-deficient mice. Immunohistochemistry revealed that fibrin accumulated in the wounds of such mU1-treated tPA-deficient mice and that keratinocyte tongues were aberrant. Together these abnormalities lead to compromised epidermal closure. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that inhibition of uPA activity with a monoclonal antibody in adult tPA-deficient mice mimics the effect of simultaneous genetic ablation of uPA and tPA. Thus, application of the murine inhibitory mU1 antibody provides a new and highly versatile tool to interfere with uPA-activity in vivo in mouse models of disease. PMID- 20856797 TI - Distribution of class 1 integrons with IS26-mediated deletions in their 3' conserved segments in Escherichia coli of human and animal origin. AB - Class 1 integrons play a role in the emergence of multi-resistant bacteria by facilitating the recruitment of gene cassettes encoding antibiotic resistance genes. 512 E. coli strains sourced from humans (n = 202), animals (n = 304) and the environment (n = 6) were screened for the presence of the intI1 gene. In 31/79 integron positive E. coli strains, the gene cassette regions could not be PCR amplified using standard primers. DNA sequence analysis of 6 serologically diverse strains revealed atypical integrons harboured the dfrA5 cassette gene and only 24 bp of the integron 3'-conserved segment (CS) remained, due to the insertion of IS26. PCR targeting intI1 and IS26 followed by restriction fragment length polymorphism (RFLP) analysis identified the integron-dfrA5-IS26 element in 27 E. coli strains of bovine origin and 4 strains of human origin. Southern hybridization and transformation studies revealed the integron-dfrA5-IS26 gene arrangement was either chromosomally located or plasmid borne. Plasmid location in 4/9 E. coli strains and PCR linkage of Tn21 transposition genes with the intI1 gene in 20/31 strains, suggests this element is readily disseminated by horizontal transfer. PMID- 20856798 TI - Rapid emergence of free-riding behavior in new pediatric immunization programs. AB - BACKGROUND: Mathematical models have formalized how free-rider effects can threaten the stability of high vaccine coverage levels under established voluntary vaccination programs. However, little research has addressed the question of when free-riding begins to develop when a new vaccine is first introduced in a population. METHODOLOGY/PRINCIPAL FINDINGS: Here, we combine a game theoretical model of vaccinating behavior with an age-structured compartmental model to analyze rational vaccinating behavior in the first years of a universal immunization program, where a new vaccine is free to all children of a specified age. The model captures how successive birth cohorts face different epidemiological landscapes that have been shaped by the vaccinating decisions of previous birth cohorts, resulting in a strategic interaction between individuals in different birth cohorts. The model predicts a Nash equilibrium coverage level of for the first few birth cohorts under the new program. However, free-riding behavior emerges very quickly, with the Nash equilibrium vaccine coverage dropping significantly within 2-5 years after program initiation. Subsequently, a rich set of coupled dynamics between infection prevalence and vaccinating behaviors is possible, ranging from relatively stable (but reduced) coverage in later birth cohorts to wide fluctuations in vaccine coverage from one birth cohort to the next. Individual tolerance for vaccine risk also starts out at relatively high levels before dropping significantly within a few years. CONCLUSIONS/SIGNIFICANCE: These results suggest that even relatively new immunization programs can be vulnerable to drops in vaccine coverage caused by vaccine scares and exacerbated by herd immunity effects, necessitating vigilance from the start. PMID- 20856799 TI - The nonstructural proteins of Nipah virus play a key role in pathogenicity in experimentally infected animals. AB - Nipah virus (NiV) P gene encodes P protein and three accessory proteins (V, C and W). It has been reported that all four P gene products have IFN antagonist activity when the proteins were transiently expressed. However, the role of those accessory proteins in natural infection with NiV remains unknown. We generated recombinant NiVs lacking V, C or W protein, rNiV(V-), rNiV(C-), and rNiV(W-), respectively, to analyze the functions of these proteins in infected cells and the implications in in vivo pathogenicity. All the recombinants grew well in cell culture, although the maximum titers of rNiV(V-) and rNiV(C-) were lower than the other recombinants. The rNiV(V-), rNiV(C-) and rNiV(W-) suppressed the IFN response as well as the parental rNiV, thereby indicating that the lack of each accessory protein does not significantly affect the inhibition of IFN signaling in infected cells. In experimentally infected golden hamsters, rNiV(V-) and rNiV(C-) but not the rNiV(W-) virus showed a significant reduction in virulence. These results suggest that V and C proteins play key roles in NiV pathogenicity, and the roles are independent of their IFN-antagonist activity. This is the first report that identifies the molecular determinants of NiV in pathogenicity in vivo. PMID- 20856800 TI - Tactical voting in plurality elections. AB - How often will elections end in landslides? What is the probability for a head-to head race? Analyzing ballot results from several large countries rather anomalous and yet unexplained distributions have been observed. We identify tactical voting as the driving ingredient for the anomalies and introduce a model to study its effect on plurality elections, characterized by the relative strength of the feedback from polls and the pairwise interaction between individuals in the society. With this model it becomes possible to explain the polarization of votes between two candidates, understand the small margin of victories frequently observed for different elections, and analyze the polls' impact in American, Canadian, and Brazilian ballots. Moreover, the model reproduces, quantitatively, the distribution of votes obtained in the Brazilian mayor elections with two, three, and four candidates. PMID- 20856801 TI - Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. AB - BACKGROUND: Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: Mice were treated with an acute dose of either doxorubicin (DOX) (15 mg/kg) or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) (25 mg/kg). DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO). Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted. CONCLUSIONS/SIGNIFICANCE: These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these events probably account for the heart damage. PMID- 20856802 TI - Modulation of cell signaling networks after CTLA4 blockade in patients with metastatic melanoma. AB - BACKGROUND: The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma. METHODOLOGY/PRINCIPAL: Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. CONCLUSIONS/SIGNIFICANCE: The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887. PMID- 20856803 TI - Cardiovascular risk associated with interactions among polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems. AB - BACKGROUND: Vascular fibrinolytic balance is maintained primarily by interplay of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1). Previous research has shown that polymorphisms in genes from the renin angiotensin (RA), bradykinin, and fibrinolytic systems affect plasma concentrations of both t-PA and PAI-1 through a set of gene-gene interactions. In the present study, we extend this finding by exploring the effects of polymorphisms in genes from these systems on incident cardiovascular disease, explicitly examining two-way interactions in a large population-based study. METHODOLOGY/PRINCIPAL FINDINGS: Data from the population-based PREVEND study in Groningen, The Netherlands (n = 8,138) were analyzed. The effects of the polymorphisms and their interactions on cardiovascular events were analyzed via Cox proportional hazards models. There was no association between five of the six polymorphisms singly and risk of cardiovascular disease. There was a significant main effect for the ACE I/D polymorphism for both dominant and additive coding schemes. There were significant interactions between the following polymorphism pairs even after adjustment for known risk factors: ACE I/D & PAI-1 4G/5G (p = 0.012), BDKRB2 C181T & ACE I/D (p = 0.016), BDKRB2 C58T & ACE I/D (p = 0.025), BDKRB2 exon 1 I/D & AT1R A1166C (p = 0.017), and BDKRB2 C58T & AT1R A1166C (p = 0.015). CONCLUSIONS/SIGNIFICANCE: This study suggests possible interactions between genes from the RA, bradykinin, and fibrinolytic systems on the risk of cardiovascular disease, extending previous research that has demonstrated that interactions among genes from these systems influence plasma concentrations of both t-PA and PAI-1. Further explorations of these interactions are needed. PMID- 20856804 TI - Bioprospecting finds the toughest biological material: extraordinary silk from a giant riverine orb spider. AB - BACKGROUND: Combining high strength and elasticity, spider silks are exceptionally tough, i.e., able to absorb massive kinetic energy before breaking. Spider silk is therefore a model polymer for development of high performance biomimetic fibers. There are over 41,000 described species of spiders, most spinning multiple types of silk. Thus we have available some 200,000+ unique silks that may cover an amazing breadth of material properties. To date, however, silks from only a few tens of species have been characterized, most chosen haphazardly as model organisms (Nephila) or simply from researchers' backyards. Are we limited to 'blindly fishing' in efforts to discover extraordinary silks? Or, could scientists use ecology to predict which species are likely to spin silks exhibiting exceptional performance properties? METHODOLOGY: We examined the biomechanical properties of silk produced by the remarkable Malagasy 'Darwin's bark spider' (Caerostris darwini), which we predicted would produce exceptional silk based upon its amazing web. The spider constructs its giant orb web (up to 2.8 m(2)) suspended above streams, rivers, and lakes. It attaches the web to substrates on each riverbank by anchor threads as long as 25 meters. Dragline silk from both Caerostris webs and forcibly pulled silk, exhibits an extraordinary combination of high tensile strength and elasticity previously unknown for spider silk. The toughness of forcibly silked fibers averages 350 MJ/m(3), with some samples reaching 520 MJ/m(3). Thus, C. darwini silk is more than twice tougher than any previously described silk, and over 10 times better than Kevlar(r). Caerostris capture spiral silk is similarly exceptionally tough. CONCLUSIONS: Caerostris darwini produces the toughest known biomaterial. We hypothesize that this extraordinary toughness coevolved with the unusual ecology and web architecture of these spiders, decreasing the likelihood of bridgelines breaking and collapsing the web into the river. This hypothesis predicts that rapid change in material properties of silk co-occurred with ecological shifts within the genus, and can thus be tested by combining material science, behavioral observations, and phylogenetics. Our findings highlight the potential benefits of natural history-informed bioprospecting to discover silks, as well as other materials, with novel and exceptional properties to serve as models in biomimicry. PMID- 20856806 TI - Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity. AB - BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. CONCLUSION/SIGNIFICANCE: In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion. PMID- 20856805 TI - Queen conch (Strombus gigas) testis regresses during the reproductive season at nearshore sites in the Florida Keys. AB - BACKGROUND: Queen conch (Strombus gigas) reproduction is inhibited in nearshore areas of the Florida Keys, relative to the offshore environment where conchs reproduce successfully. Nearshore reproductive failure is possibly a result of exposure to environmental factors, including heavy metals, which are likely to accumulate close to shore. Metals such as Cu and Zn are detrimental to reproduction in many mollusks. METHODOLOGY/PRINCIPAL FINDINGS: Histology shows gonadal atrophy in nearshore conchs as compared to reproductively healthy offshore conchs. In order to determine molecular mechanisms leading to tissue changes and reproductive failure, a microarray was developed. A normalized cDNA library for queen conch was constructed and sequenced using the 454 Life Sciences GS-FLX pyrosequencer, producing 27,723 assembled contigs and 7,740 annotated transcript sequences. The resulting sequences were used to design the microarray. Microarray analysis of conch testis indicated differential regulation of 255 genes (p<0.01) in nearshore conch, relative to offshore. Changes in expression for three of four transcripts of interest were confirmed using real-time reverse transcription polymerase chain reaction. Gene Ontology enrichment analysis indicated changes in biological processes: respiratory chain (GO:0015992), spermatogenesis (GO:0007283), small GTPase-mediated signal transduction (GO:0007264), and others. Inductively coupled plasma-mass spectrometry analysis indicated that Zn and possibly Cu were elevated in some nearshore conch tissues. CONCLUSIONS/SIGNIFICANCE: Congruence between testis histology and microarray data suggests that nearshore conch testes regress during the reproductive season, while offshore conch testes develop normally. Possible mechanisms underlying the testis regression observed in queen conch in the nearshore Florida Keys include a disruption of small GTPase (Ras)-mediated signaling in testis development. Additionally, elevated tissue levels of Cu (34.77 ng/mg in testis) and Zn (831.85 ng/mg in digestive gland, 83.96 ng/mg in testis) nearshore are similar to reported levels resulting in reproductive inhibition in other gastropods, indicating that these metals possibly contribute to NS conch reproductive failure. PMID- 20856807 TI - Systematic characterizations of text similarity in full text biomedical publications. AB - BACKGROUND: Computational methods have been used to find duplicate biomedical publications in MEDLINE. Full text articles are becoming increasingly available, yet the similarities among them have not been systematically studied. Here, we quantitatively investigated the full text similarity of biomedical publications in PubMed Central. METHODOLOGY/PRINCIPAL FINDINGS: 72,011 full text articles from PubMed Central (PMC) were parsed to generate three different datasets: full texts, sections, and paragraphs. Text similarity comparisons were performed on these datasets using the text similarity algorithm eTBLAST. We measured the frequency of similar text pairs and compared it among different datasets. We found that high abstract similarity can be used to predict high full text similarity with a specificity of 20.1% (95% CI [17.3%, 23.1%]) and sensitivity of 99.999%. Abstract similarity and full text similarity have a moderate correlation (Pearson correlation coefficient: -0.423) when the similarity ratio is above 0.4. Among pairs of articles in PMC, method sections are found to be the most repetitive (frequency of similar pairs, methods: 0.029, introduction: 0.0076, results: 0.0043). In contrast, among a set of manually verified duplicate articles, results are the most repetitive sections (frequency of similar pairs, results: 0.94, methods: 0.89, introduction: 0.82). Repetition of introduction and methods sections is more likely to be committed by the same authors (odds of a highly similar pair having at least one shared author, introduction: 2.31, methods: 1.83, results: 1.03). There is also significantly more similarity in pairs of review articles than in pairs containing one review and one nonreview paper (frequency of similar pairs: 0.0167 and 0.0023, respectively). CONCLUSION/SIGNIFICANCE: While quantifying abstract similarity is an effective approach for finding duplicate citations, a comprehensive full text analysis is necessary to uncover all potential duplicate citations in the scientific literature and is helpful when establishing ethical guidelines for scientific publications. PMID- 20856808 TI - In silico identification of carboxylate clamp type tetratricopeptide repeat proteins in Arabidopsis and rice as putative co-chaperones of Hsp90/Hsp70. AB - The essential eukaryotic molecular chaperone Hsp90 operates with the help of different co-chaperones, which regulate its ATPase activity and serve as adaptors to recruit client proteins and other molecular chaperones, such as Hsp70, to the Hsp90 complex. Several Hsp90 and Hsp70 co-chaperones contain the tetratricopeptide repeat (TPR) domain, which interacts with the highly conserved EEVD motif at the C-terminal ends of Hsp90 and Hsp70. The acidic side chains in EEVD interact with a subset of basic residues in the TPR binding pocket called a 'carboxylate clamp'. Since the carboxylate clamp residues are conserved in the TPR domains of known Hsp90/Hsp70 co-chaperones, we carried out an in silico search for TPR proteins in Arabidopsis and rice comprising of at least one three motif TPR domain with conserved amino acid residues required for Hsp90/Hsp70 binding. This approach identified in Arabidopsis a total of 36 carboxylate clamp (CC)-TPR proteins, including 24 novel proteins, with potential to interact with Hsp90/Hsp70. The newly identified CC-TPR proteins in Arabidopsis and rice contain additional protein domains such as ankyrin, SET, octicosapeptide/Phox/Bem1p (Phox/PB1), DnaJ-like, thioredoxin, FBD and F-box, and protein kinase and U-box, indicating varied functions for these proteins. To provide proof-of-concept of the newly identified CC-TPR proteins for interaction with Hsp90, we demonstrated interaction of AtTPR1 and AtTPR2 with AtHsp90 in yeast two-hybrid and in vitro pull down assays. These findings indicate that the in silico approach used here successfully identified in a genome-wide context CC-TPR proteins with potential to interact with Hsp90/Hsp70, and further suggest that the Hsp90/Hsp70 system relies on TPR co-chaperones more than it was previously realized. PMID- 20856810 TI - The complete chloroplast genome sequence of date palm (Phoenix dactylifera L.). AB - BACKGROUND: Date palm (Phoenix dactylifera L.), a member of Arecaceae family, is one of the three major economically important woody palms--the two other palms being oil palm and coconut tree--and its fruit is a staple food among Middle East and North African nations, as well as many other tropical and subtropical regions. Here we report a complete sequence of the data palm chloroplast (cp) genome based on pyrosequencing. METHODOLOGY/PRINCIPAL FINDINGS: After extracting 369,022 cp sequencing reads from our whole-genome-shotgun data, we put together an assembly and validated it with intensive PCR-based verification, coupled with PCR product sequencing. The date palm cp genome is 158,462 bp in length and has a typical quadripartite structure of the large (LSC, 86,198 bp) and small single copy (SSC, 17,712 bp) regions separated by a pair of inverted repeats (IRs, 27,276 bp). Similar to what has been found among most angiosperms, the date palm cp genome harbors 112 unique genes and 19 duplicated fragments in the IR regions. The junctions between LSC/IRs and SSC/IRs show different features of sequence expansion in evolution. We identified 78 SNPs as major intravarietal polymorphisms within the population of a specific cp genome, most of which were located in genes with vital functions. Based on RNA-sequencing data, we also found 18 polycistronic transcription units and three highly expression-biased genes--atpF, trnA-UGC, and rrn23. CONCLUSIONS: Unlike most monocots, date palm has a typical cp genome similar to that of tobacco--with little rearrangement and gene loss or gain. High-throughput sequencing technology facilitates the identification of intravarietal variations in cp genomes among different cultivars. Moreover, transcriptomic analysis of cp genes provides clues for uncovering regulatory mechanisms of transcription and translation in chloroplasts. PMID- 20856809 TI - Fine-mapping resolves Eae23 into two QTLs and implicates ZEB1 as a candidate gene regulating experimental neuroinflammation in rat. AB - BACKGROUND: To elucidate mechanisms involved in multiple sclerosis (MS), we studied genetic regulation of experimental autoimmune encephalomyelitis (EAE) in rats, assuming a conservation of pathogenic pathways. In this study, we focused on Eae23, originally identified to regulate EAE in a (LEW.1AV1xPVG.1AV1)F2 cross. Our aim was to determine whether one or more genes within the 67 Mb region regulate EAE and to define candidate risk genes. METHODOLOGY/PRINCIPAL FINDINGS: We used high resolution quantitative trait loci (QTL) analysis in the 10th generation (G10) of an advanced intercross line (AIL) to resolve Eae23 into two QTLs that independently regulate EAE, namely Eae23a and Eae23b. We established a congenic strain to validate the effect of this region on disease. PVG alleles in Eae23 resulted in significant protection from EAE and attenuated CNS inflammation/demyelination. Disease amelioration was accompanied with increased levels of Foxp3(+) cells in the CNS of the congenic strain compared to DA. We then focused on candidate gene investigation in Eae23b, a 9 Mb region linked to all clinical phenotypes. Affymetrix exon arrays were used to study expression of the genes in Eae23b in the parental strains, where none showed differential expression. However, we found lower expression of exon 4 of ZEB1, which is specific for splice-variant Zfhep1. ZEB1 is an interleukin 2 (IL2) repressor involved in T cell development. The splice-specific variance prompted us to next analyze the expression of ZEB1 and its two splice variants, Zfhep1 and Zfhep2, in both lymph node and spleen. We demonstrated that ZEB1 splice-variants are differentially expressed; severity of EAE and higher IL2 levels were associated with down-regulation of Zfhep1 and up-regulation of Zfhep2. CONCLUSIONS/SIGNIFICANCE: We speculate that the balance between splice-variants of ZEB1 could influence the regulation of EAE. Further functional studies of ZEB1 and the splice-variants may unravel novel pathways contributing to MS pathogenesis and inflammation in general. PMID- 20856811 TI - Long-term memory for pavlovian fear conditioning requires dopamine in the nucleus accumbens and basolateral amygdala. AB - The neurotransmitter dopamine (DA) is essential for learning in a pavlovian fear conditioning paradigm known as fear-potentiated startle (FPS). Mice lacking the ability to synthesize DA fail to learn the association between the conditioned stimulus and the fear-inducing footshock. Previously, we demonstrated that restoration of DA synthesis to neurons of the ventral tegmental area (VTA) was sufficient to restore FPS. Here, we used a target-selective viral restoration approach to determine which mesocorticolimbic brain regions receiving DA signaling from the VTA require DA for FPS. We demonstrate that restoration of DA synthesis to both the basolateral amygdala (BLA) and nucleus accumbens (NAc) is required for long-term memory of FPS. These data provide crucial insight into the dopamine-dependent circuitry involved in the formation of fear-related memory. PMID- 20856812 TI - Classification of protein kinases on the basis of both kinase and non-kinase regions. AB - BACKGROUND: Protein phosphorylation is a generic way to regulate signal transduction pathways in all kingdoms of life. In many organisms, it is achieved by the large family of Ser/Thr/Tyr protein kinases which are traditionally classified into groups and subfamilies on the basis of the amino acid sequence of their catalytic domains. Many protein kinases are multi-domain in nature but the diversity of the accessory domains and their organization are usually not taken into account while classifying kinases into groups or subfamilies. METHODOLOGY: Here, we present an approach which considers amino acid sequences of complete gene products, in order to suggest refinements in sets of pre-classified sequences. The strategy is based on alignment-free similarity scores and iterative Area Under the Curve (AUC) computation. Similarity scores are computed by detecting common patterns between two sequences and scoring them using a substitution matrix, with a consistent normalization scheme. This allows us to handle full-length sequences, and implicitly takes into account domain diversity and domain shuffling. We quantitatively validate our approach on a subset of 212 human protein kinases. We then employ it on the complete repertoire of human protein kinases and suggest few qualitative refinements in the subfamily assignment stored in the KinG database, which is based on catalytic domains only. Based on our new measure, we delineate 37 cases of potential hybrid kinases: sequences for which classical classification based entirely on catalytic domains is inconsistent with the full-length similarity scores computed here, which implicitly consider multi-domain nature and regions outside the catalytic kinase domain. We also provide some examples of hybrid kinases of the protozoan parasite Entamoeba histolytica. CONCLUSIONS: The implicit consideration of multi-domain architectures is a valuable inclusion to complement other classification schemes. The proposed algorithm may also be employed to classify other families of enzymes with multi-domain architecture. PMID- 20856813 TI - Akt deficiency attenuates muscle size and function but not the response to ActRIIB inhibition. AB - BACKGROUND: Akt is a critical mediator of developmental skeletal muscle growth. Treatment with a soluble ActRIIB fusion protein (ActRIIB-mFc) increases skeletal muscle mass and strength by inhibiting myostatin and related peptides. Recent in vitro studies have suggested that Akt signaling is necessary for the ability of ActRIIB inhibition to induce muscle hypertrophy. Thus, we hypothesized that mice deficient in either Akt1 or Akt2 would not respond to in vivo inhibition of ActRIIB with ActRIIB-mFc treatment. METHODOLOGY AND PRINCIPAL FINDINGS: We analyzed body composition and muscle parameters in wild-type C57BL/6J and Akt1 and Akt2 knockout mice, and compared the responses to blockade of ActRIIB signaling via ActRIIB-mFc treatment. Mice lacking Akt1 or Akt2 had reduced muscle mass, grip strength and contractile force. However, deficiency of Akt1 or Akt2 did not prevent the ability of ActRIIB-mFc treatment to induce muscle hypertrophy, or increase grip strength and contractile force. Akt1 and Akt2 deficient mice responded similarly as wild type mice to ActRIIB-mFc treatment by increasing fiber size. CONCLUSIONS AND SIGNIFICANCE: Akt1 and Akt2 are important for the regulation of skeletal muscle mass and function. However, these Akt isoforms are not essential for the ability of ActRIIB inhibition to regulate muscle size, fiber type, strength or contractile force. PMID- 20856814 TI - Loss of STOP protein impairs peripheral olfactory neurogenesis. AB - BACKGROUND: STOP (Stable Tubulin-Only Polypeptide) null mice show behavioral deficits, impaired synaptic plasticity, decrease in synaptic vesicular pools and disturbances in dopaminergic transmission, and are considered a neurodevelopmental model of schizophrenia. Olfactory neurons highly express STOP protein and are continually generated throughout life. Experimentally-induced loss of olfactory neurons leads to epithelial regeneration within two months, providing a useful model to evaluate the role played by STOP protein in adult olfactory neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Immunocytochemistry and electron microscopy were used to study the structure of the glomerulus in the main olfactory bulb and neurogenesis in the neurosensorial epithelia. In STOP null mice, olfactory neurons showed presynaptic swellings with tubulovesicular profiles and autophagic-like structures. In olfactory and vomeronasal epithelia, there was an increase in neurons turnover, as shown by the increase in number of proliferating, apoptotic and immature cells with no changes in the number of mature neurons. Similar alterations in peripheral olfactory neurogenesis have been previously described in schizophrenia patients. In STOP null mice, regeneration of the olfactory epithelium did not modify these anomalies; moreover, regeneration resulted in abnormal organisation of olfactory terminals within the olfactory glomeruli in STOP null mice. CONCLUSIONS/SIGNIFICANCE: In conclusion, STOP protein seems to be involved in the establishment of synapses in the olfactory glomerulus. Our results indicate that the olfactory system of STOP null mice is a well-suited experimental model (1) for the study of the mechanism of action of STOP protein in synaptic function/plasticity and (2) for pathophysiological studies of the mechanisms of altered neuronal connections in schizophrenia. PMID- 20856815 TI - New views on strand asymmetry in insect mitochondrial genomes. AB - Strand asymmetry in nucleotide composition is a remarkable feature of animal mitochondrial genomes. Understanding the mutation processes that shape strand asymmetry is essential for comprehensive knowledge of genome evolution, demographical population history and accurate phylogenetic inference. Previous studies found that the relative contributions of different substitution types to strand asymmetry are associated with replication alone or both replication and transcription. However, the relative contributions of replication and transcription to strand asymmetry remain unclear. Here we conducted a broad survey of strand asymmetry across 120 insect mitochondrial genomes, with special reference to the correlation between the signs of skew values and replication orientation/gene direction. The results show that the sign of GC skew on entire mitochondrial genomes is reversed in all species of three distantly related families of insects, Philopteridae (Phthiraptera), Aleyrodidae (Hemiptera) and Braconidae (Hymenoptera); the replication-related elements in the A+T-rich regions of these species are inverted, confirming that reversal of strand asymmetry (GC skew) was caused by inversion of replication origin; and finally, the sign of GC skew value is associated with replication orientation but not with gene direction, while that of AT skew value varies with gene direction, replication and codon positions used in analyses. These findings show that deaminations during replication and other mutations contribute more than selection on amino acid sequences to strand compositions of G and C, and that the replication process has a stronger affect on A and T content than does transcription. Our results may contribute to genome-wide studies of replication and transcription mechanisms. PMID- 20856816 TI - SH3 domain-peptide binding energy calculations based on structural ensemble and multiple peptide templates. AB - SH3 domains mediate signal transduction by recognizing short peptides. Understanding of the driving forces in peptide recognitions will help us to predict the binding specificity of the domain-peptide recognition and to understand the molecular interaction networks of cells. However, accurate calculation of the binding energy is a tough challenge. In this study, we propose three ideas for improving our ability to predict the binding energy between SH3 domains and peptides: (1) utilizing the structural ensembles sampled from a molecular dynamics simulation trajectory, (2) utilizing multiple peptide templates, and (3) optimizing the sequence-structure mapping. We tested these three ideas on ten previously studied SH3 domains for which SPOT analysis data were available. The results indicate that calculating binding energy using the structural ensemble was most effective, clearly increasing the prediction accuracy, while the second and third ideas tended to give better binding energy predictions. We applied our method to the five SH3 targets in DREAM4 Challenge and selected the best performing method. PMID- 20856817 TI - Regulation of thromboxane receptor signaling at multiple levels by oxidative stress-induced stabilization, relocation and enhanced responsiveness. AB - BACKGROUND: Thromboxane A(2) (TxA(2)) is a major, unstable arachidonic acid metabolite, and plays a key role in normal physiology and control of vascular tone. The human thromboxane receptor (TPbeta), expressed in COS-7 cells, is located predominantly in the endoplasmic reticulum (ER). Brief hydrogen peroxide exposure increases the efficiency of translocation of TPbeta from the ER into the Golgi complex, inducing maturation and stabilization of TPbeta. However, the ultimate fate of this post-ER TPbeta pool is not known, nor is its capacity to initiate signal transduction. Here we specifically assessed if functional TPbeta was transported to the plasma membrane following H(2)O(2) exposure. RESULTS: We demonstrate, by biotinylation and confocal microscopy, that exposure to H(2)O(2) results in rapid delivery of a cohort of TPbeta to the cell surface, which is stable for at least eight hours. Surface delivery is brefeldin A-sensitive, indicating that translocation of this receptor cohort is from internal pools and via the Golgi complex. H(2)O(2) treatment results in potentiation of the increase to intracellular calcium concentrations in response to TPbeta agonists U46619 and 8-iso PGF(2alpha) and also in the loss of ligand-dependent receptor internalization. Further there is increased responsiveness to a second application of the agonist. Finally we demonstrate that the effect of H(2)O(2) on stimulating surface delivery is shared with the FP prostanoid receptor but not the EP3 or EP4 receptors. CONCLUSIONS/SIGNIFICANCE: In summary, brief exposure to H(2)O(2) results in an immediate and sustained increase in the surface pool of thromboxane receptor that is capable of mediating a persistent hyper responsiveness of the cell and suggests a highly sophisticated mechanism for rapidly regulating thromboxane signaling. PMID- 20856818 TI - Mammalian Otolin: a multimeric glycoprotein specific to the inner ear that interacts with otoconial matrix protein Otoconin-90 and Cerebellin-1. AB - BACKGROUND: The mammalian otoconial membrane is a dense extracellular matrix containing bio-mineralized otoconia. This structure provides the mechanical stimulus necessary for hair cells of the vestibular maculae to respond to linear accelerations and gravity. In teleosts, Otolin is required for the proper anchoring of otolith crystals to the sensory maculae. Otoconia detachment and subsequent entrapment in the semicircular canals can result in benign paroxysmal positional vertigo (BPPV), a common form of vertigo for which the molecular basis is unknown. Several cDNAs encoding protein components of the mammalian otoconia and otoconial membrane have recently been identified, and mutations in these genes result in abnormal otoconia formation and balance deficits. PRINCIPAL FINDINGS: Here we describe the cloning and characterization of mammalian Otolin, a protein constituent of otoconia and the otoconial membrane. Otolin is a secreted glycoprotein of ~70 kDa, with a C-terminal globular domain that is homologous to the immune complement C1q, and contains extensive posttranslational modifications including hydroxylated prolines and glycosylated lysines. Like all C1q/TNF family members, Otolin multimerizes into higher order oligomeric complexes. The expression of otolin mRNA is restricted to the inner ear, and immunohistochemical analysis identified Otolin protein in support cells of the vestibular maculae and semi-circular canal cristae. Additionally, Otolin forms protein complexes with Cerebellin-1 and Otoconin-90, two protein constituents of the otoconia, when expressed in vitro. Otolin was also found in subsets of support cells and non-sensory cells of the cochlea, suggesting that Otolin is also a component of the tectorial membrane. CONCLUSION: Given the importance of Otolin in lower organisms, the molecular cloning and biochemical characterization of the mammalian Otolin protein may lead to a better understanding of otoconial development and vestibular dysfunction. PMID- 20856819 TI - Deficiency of the metalloproteinase-disintegrin ADAM8 is associated with thymic hyper-cellularity. AB - BACKGROUND: Thymopoiesis requires thymocyte-stroma interactions and proteases that promote cell migration by degrading extracellular matrix and releasing essential cytokines and chemokines. A role for several members of the A Disintegrin and Metalloprotease (ADAM) family in T cell development has been reported in the past. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present data indicating that the family member ADAM8 plays a role in thymic T cell development. We used qrtPCR on FACS sorted thymic subsets together with immunofluorescence to analyze thymic ADAM8 expression. We found that ADAM8 was expressed in murine thymic stromal cells and at lower levels in thymocytes where its expression increased as cell matured, suggesting involvement of ADAM8 in thymopoiesis. Further flow cytometry analysis revealed that ADAM8 deficient mice showed normal development and expansion of immature thymocyte subsets. There was however an intrathymic accumulation of single positive CD4 and CD8 T cells which was most noticeable in the late mature T cell subsets. Accumulation of single positive T cells coincided with changes in the thymic architecture manifest in a decreased cortex/medulla ratio and an increase in medullary epithelial cells as determined by histology and flow cytometry. The increase in single positive T cells was thymus-intrinsic, independent of progenitor homing to the thymus or thymic exit rate of mature T cells. Chemotaxis assays revealed that ADAM8 deficiency was associated with reduced migration of single positive thymocytes towards CCL21. CONCLUSIONS/SIGNIFICANCE: Our results show that ADAM8 is involved in T cell maturation in the medulla and suggest a role for this protease in fine tuning maturation of thymocytes in the medulla. In contrast to ADAM10 and ADAM17 lack of ADAM8 appears to have a relatively minor impact on T cell development, which was unexpected given that maturation of thymocytes is dependent on proper localization and timing of migration. PMID- 20856820 TI - Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl) and sour (citric acid) tastants. AB - BACKGROUND: The gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved. METHODOLOGY/PRINCIPAL FINDINGS: Using immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants. CONCLUSIONS/SIGNIFICANCE: These findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity. PMID- 20856821 TI - Economic outcomes of patients receiving antiretroviral therapy for HIV/AIDS in South Africa are sustained through three years on treatment. AB - BACKGROUND: Although the medical outcomes of antiretroviral therapy (ART) for HIV/AIDS are well described, less is known about how ART affects patients' economic activities and quality of life, especially after the first year on ART. We assessed symptom prevalence, general health, ability to perform normal activities, and employment status among adult antiretroviral therapy patients in South Africa over three full years following ART initiation. METHODOLOGY/PRINCIPAL FINDINGS: A cohort of 855 adult pre-ART patients and patients on ART for <6 months was enrolled and interviewed an average of 4.4 times each during routine clinic visits for up to three years after treatment initiation using an instrument designed for the study. The probability of pain in the previous week fell from 74% before ART initiation to 32% after three years on ART, fatigue from 66% to 12%, nausea from 28% to 4%, and skin problems from 55% to 10%. The probability of not feeling well physically yesterday fell from 46% to 23%. Before starting ART, 39% of subjects reported not being able to perform their normal activities sometime during the previous week; after three years, this proportion fell to 10%. Employment rose from 27% to 42% of the cohort. Improvement in all outcomes was sustained over 3 years and for some outcomes increased in the second and third year. CONCLUSIONS/SIGNIFICANCE: Improvements in adult ART patients' symptom prevalence, general health, ability to perform normal activities, and employment status were large and were sustained through the first three years on treatment. These results suggest that some of the positive economic and social externalities anticipated as a result of large-scale treatment provision, such as increases in workforce participation and productivity and the ability of patients to carry on normal lives, may indeed be accruing. PMID- 20856822 TI - IL-2 mediates CD4+ T cell help in the breakdown of memory-like CD8+ T cell tolerance under lymphopenic conditions. AB - BACKGROUND: Lymphopenia results in the proliferation and differentiation of naive T cells into memory-like cells in the apparent absence of antigenic stimulation. This response, at least in part due to a greater availability of cytokines, is thought to promote anti-self responses. Although potentially autoreactive memory like CD8(+) T cells generated in a lymphopenic environment are subject to the mechanisms of peripheral tolerance, they can induce autoimmunity in the presence of antigen-specific memory-like CD4(+) T helper cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied the mechanisms underlying CD4 help under lymphopenic conditions in transgenic mice expressing a model antigen in the beta cells of the pancreas. Surprisingly, we found that the self-reactivity mediated by the cooperation of memory-like CD8(+) and CD4(+) T cells was not abrogated by CD40L blockade. In contrast, treatment with anti-IL-2 antibodies inhibited the onset of autoimmunity. IL-2 neutralization prevented the CD4-mediated differentiation of memory-like CD8(+) T cells into pathogenic effectors in response to self-antigen cross-presentation. Furthermore, in the absence of helper cells, induction of IL 2 signaling by an IL-2 immune complex was sufficient to promote memory-like CD8(+) T cell self-reactivity. CONCLUSIONS/SIGNIFICANCE: IL-2 mediates the cooperation of memory-like CD4(+) and CD8(+) T cells in the breakdown of cross tolerance, resulting in effector cytotoxic T lymphocyte differentiation and the induction of autoimmune disease. PMID- 20856823 TI - CRY2 is associated with rapid cycling in bipolar disorder patients. AB - BACKGROUND: Bipolar disorder patients often display abnormalities in circadian rhythm, and they are sensitive to irregular diurnal rhythms. CRY2 participates in the core clock that generates circadian rhythms. CRY2 mRNA expression in blood mononuclear cells was recently shown to display a marked diurnal variation and to respond to total sleep deprivation in healthy human volunteers. It was also shown that bipolar patients in a depressive state had lower CRY2 mRNA levels, nonresponsive to total sleep deprivation, compared to healthy controls, and that CRY2 gene variation was associated with winter depression in both Swedish and Finnish cohorts. PRINCIPAL FINDINGS: Four CRY2 SNPs spanning from intron 2 to downstream 3'UTR were analyzed for association to bipolar disorder type 1 (n = 497), bipolar disorder type 2 (n = 60) and bipolar disorder with the feature rapid cycling (n = 155) versus blood donors (n = 1044) in Sweden. Also, the rapid cycling cases were compared with bipolar disorder cases without rapid cycling (n = 422). The haplotype GGAC was underrepresented among rapid cycling cases versus controls and versus bipolar disorder cases without rapid cycling (OR = 0.7, P = 0.006-0.02), whereas overrepresentation among rapid cycling cases was seen for AAAC (OR = 1.3-1.4, P = 0.03-0.04) and AGGA (OR = 1.5, P = 0.05). The risk and protective CRY2 haplotypes and their effect sizes were similar to those recently suggested to be associated with winter depression in Swedes. CONCLUSIONS: We propose that the circadian gene CRY2 is associated with rapid cycling in bipolar disorder. This is the first time a clock gene is implicated in rapid cycling, and one of few findings showing a molecular discrimination between rapid cycling and other forms of bipolar disorder. PMID- 20856824 TI - Parallel evolution in Pseudomonas aeruginosa over 39,000 generations in vivo. AB - The Gram-negative bacterium Pseudomonas aeruginosa is a common cause of chronic airway infections in individuals with the heritable disease cystic fibrosis (CF). After prolonged colonization of the CF lung, P. aeruginosa becomes highly resistant to host clearance and antibiotic treatment; therefore, understanding how this bacterium evolves during chronic infection is important for identifying beneficial adaptations that could be targeted therapeutically. To identify potential adaptive traits of P. aeruginosa during chronic infection, we carried out global transcriptomic profiling of chronological clonal isolates obtained from 3 individuals with CF. Isolates were collected sequentially over periods ranging from 3 months to 8 years, representing up to 39,000 in vivo generations. We identified 24 genes that were commonly regulated by all 3 P. aeruginosa lineages, including several genes encoding traits previously shown to be important for in vivo growth. Our results reveal that parallel evolution occurs in the CF lung and that at least a proportion of the traits identified are beneficial for P. aeruginosa chronic colonization of the CF lung. PMID- 20856825 TI - COPD and cognitive impairment: the role of hypoxemia and oxygen therapy. AB - BACKGROUND: several studies have shown an association between chronic obstructive pulmonary disease (COPD) and cognitive impairment. These studies have been limited by methodological issues such as diagnostic uncertainty, cross-sectional design, small sample size, or lack of appropriate referent group. This study aimed to elucidate the association between COPD and the risk of cognitive impairment compared to referent subjects without COPD. In patients with established COPD, we evaluated the impact of disease severity and impairment of respiratory physiology on cognitive impairment and the potential mitigating role of oxygen therapy. METHODS: we used the Function, Living, Outcomes and Work (FLOW) cohort study of adults with COPD (n = 1202) and referent subjects matched by age, sex, and race (n = 302) to study the potential risk factors for cognitive impairment among subjects with COPD. Cognitive impairment was defined as a Mini Mental State Exam score of <24 points. Disease severity was using Forced Expiratory Volume in one second (FEV(1)); the validated COPD Severity Score; and the BMI (Body Mass Index), Obstruction, Dyspnea, Exercise Capacity (BODE) Index. Multivariable analysis was used to control for confounding by age, sex, race, educational attainment, and cigarette smoking. RESULTS: COPD was associated with a substantive risk of cognitive impairment compared to referent subjects (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.043-6.64). Among COPD patients, none of the COPD severity measures were associated with the risk of cognitive impairment (P > 0.20 in all cases). Low baseline oxygen saturation was related to increased risk of cognitive impairment (OR for oxygen saturation <=88% (OR 5.45; 95% CI 1.014-29.2; P = 0.048). Conversely, regular use of supplemental oxygen therapy decreased the risk for cognitive impairment (OR 0.14; 95% CI 0.07-0.27; P < 0.0001). CONCLUSION: COPD is a major risk factor for cognitive impairment. Among patients with COPD, hypoxemia is a major contributor and regular use of home oxygen is protective. Health care providers should consider screening their COPD patients for cognitive impairment. PMID- 20856826 TI - A validated disease specific prediction equation for resting metabolic rate in underweight patients with COPD. AB - Malnutrition is a serious condition in chronic obstructive pulmonary disease (COPD). Successful dietary intervention calls for calculations of resting metabolic rate (RMR). One disease-specific prediction equation for RMR exists based on mainly male patients. To construct a disease-specific equation for RMR based on measurements in underweight or weight-losing women and men with COPD, RMR was measured by indirect calorimetry in 30 women and 11 men with a diagnosis of COPD and body mass index <21 kg/m(2). The following variables, possibly influencing RMR were measured: length, weight, middle upper arm circumference, triceps skinfold, body composition by dual energy x-ray absorptiometry and bioelectrical impedance, lung function, and markers of inflammation. Relations between RMR and measured variables were studied using univariate analysis according to Pearson. Gender and variables that were associated with RMR with a P value <0.15 were included in a forward multiple regression analysis. The best-fit multiple regression equation included only fat-free mass (FFM): RMR (kJ/day) = 1856 + 76.0 FFM (kg). To conclude, FFM is the dominating factor influencing RMR. The developed equation can be used for prediction of RMR in underweight COPD patients. PMID- 20856827 TI - Tiotropium bromide inhibits TGF-beta-induced MMP production from lung fibroblasts by interfering with Smad and MAPK pathways in vitro. AB - BACKGROUND: chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and structural alterations (ie, tissue remodeling) throughout the conducting airways, parenchyma, and pulmonary vasculature. Matrix metalloproteinases (MMPs) are extracellular degrading enzymes that play a critical role in inflammatory cell infiltration and tissue remodeling, but the influence of the agents that are used for the treatment of COPD on the production of MMPs is not well understood. PURPOSE: the present study aimed to examine the influence of tiotropium bromide hydrate (TBH) on the production of MMPs from lung fibroblasts (LFs) induced by transforming growth factor (TGF)-beta in vitro. METHODS: LFs, at a concentration of 5 * 10(5) cells.mL(-1), were stimulated with TGF-beta in the presence of various concentrations of TBH. MMP-1 and MMP-2 levels in culture supernatants were examined by enzyme-linked immunosorbent assay (ELISA), and MMP messenger ribonucleic acid (mRNA) expression was examined by real-time polymerase chain reaction (RT-PCR). The influence of TBH on TGF-beta signaling pathways was also analyzed by examining Smad activation and signaling protein phosphorylation by ELISA. RESULTS: TBH at more than 15 pg.mL(-1) inhibited the production of MMP-1 and MMP-2, but not tissue inhibitor of matrix metalloproteinase (TIMP)-1 and TIMP-2, from LFs, after TGF-beta stimulation. TBH also suppressed MMP mRNA expression through the inhibition of Smad activation and signaling protein, extracellular-signal-regulated kinase (ERK) 1 and 2, and c-Jun N-terminal kinase (JNK), phosphorylation. CONCLUSION: These results may suggest that TBH suppresses MMP production from LFs, through interference of TGF-beta mediated signaling pathways and results in favorable modification of the clinical status of COPD. PMID- 20856828 TI - Pulmonary function tests, sputum induction, and bronchial provocation tests: diagnostic tools in the challenge of distinguishing asthma and COPD phenotypes in clinical practice. AB - BACKGROUND: despite a number of important differences in the pathogenesis, course, and prognosis, asthma and chronic obstructive pulmonary disease (COPD) have many features in common. Furthermore, smoking induces considerable overlap in pathogenesis and clinical features between these conditions. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, including overlap phenotypes of asthma and COPD, and to evaluate the correlation with airway reversibility and hyperreactivity in these overlapping conditions. METHODS: a total of 110 patients (17 healthy subjects; 16 "healthy" smokers; 46 asthma patients: 24 smokers and 22 non-smokers; and 31 COPD patients: 10 COPD patients with reversibility and 21 without) participated in the study. Induced sputum, reversibility testing, methacholine and adenosine 5'monophosphate (AMP) provocation challenges, and skin prick testing were performed. Airways inflammation was assessed by differential cell counts, and cytokines (interleukin 8 [IL-8] and tumor necrosis factor-alpha [TNF-alpha]) were measured in induced sputum by enzyme-linked immunosorbent assay (ELISA). RESULTS: COPD patients with reversibility had increased sputum neutrophils, IL-8, and TNF-alpha levels compared to smoking asthmatics. No difference was found in inflammatory cells and cytokines between COPD subgroups. Sputum neutrophilia was inversely correlated with the change in forced expiratory volume in one second (DeltaFEV(1)) in smoking asthmatic patients (r = -0.563, P = 0.036). No correlation was found between airway hyperresponsiveness (AHR), either with methacholine or AMP, and inflammation in asthmatic patients, regardless of smoking. Reversibility was not correlated with inflammation in COPD patients. However, the response to AMP challenge was correlated with sputum neutrophils (r = 0.844, P = 0.001). CONCLUSION: although overlaps exist in the disease characteristics of asthma and COPD, the combination of lung function testing, sputum induction, and AHR reveals information that facilitates the distinction between these diseases, allowing clinicians to better tailor their therapy. PMID- 20856829 TI - Glucocorticoid insensitivity as a future target of therapy for chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is characterized by an abnormal and chronic inflammatory response in the lung that underlies the chronic airflow obstruction of the small airways, the inexorable decline of lung function, and the severity of the disease. The control of this inflammation remains a key strategy for treating the disease; however, there are no current anti inflammatory treatments that are effective. Although glucocorticoids (GCs) effectively control inflammation in many diseases such as asthma, they are less effective in COPD. The molecular mechanisms that contribute to the development of this relative GC-insensitive inflammation in the lung of patients with COPD remain unclear. However, recent studies have indicated novel mechanisms and possible therapeutic strategies. One of the major mechanisms proposed is an oxidant-mediated alteration in the signaling pathways in the inflammatory cells in the lung, which may result in the impairment of repressor proteins used by the GC receptor to inhibit the transcription of proinflammatory genes. Although these studies have described mechanisms and targets by which GC function can be restored in cells from patients with COPD, more work is needed to completely elucidate these and other pathways that may be involved in order to allow for more confident therapeutic targeting. Given the relative GC-insensitive nature of the inflammation in COPD, a combination of therapies in addition to a restoration of GC function, including effective alternative anti-inflammatory targets, antioxidants, and proresolving therapeutic strategies, is likely to provide better targeting and improvement in the management of the disease. PMID- 20856830 TI - Onset of action of indacaterol in patients with COPD: comparison with salbutamol and salmeterol-fluticasone. AB - BACKGROUND: indacaterol is a novel, inhaled once-daily ultra-long-acting beta(2) agonist for the treatment of chronic obstructive pulmonary disease (COPD). OBJECTIVES: this study compared the onset of action of single doses of indacaterol 150 and 300 MUg with salbutamol 200 MUg, salmeterol-fluticasone 50/500 MUg, and placebo in moderate-to-severe COPD patients. METHODS: this was a multicenter, randomized, double-blind, placebo-controlled crossover study. The primary variable was forced expiratory volume in one second (FEV(1)) at five minutes postdose. RESULTS: out of 89 patients randomized (mean age 62 years), 86 completed the study. At five minutes postdose, both indacaterol doses were statistically and clinically superior to placebo (P < 0.001), with treatment placebo differences in FEV(1) of 100 (95% confidence interval [CI] 70-130) mL and 120 (95% CI 90-150) mL for indacaterol 150 and 300 MUg, respectively. FEV(1) at five minutes postdose with both indacaterol doses was numerically higher than for salbutamol (10 and 30 mL for indacaterol 150 and 300 MUg, respectively) and significantly higher than for salmeterol-fluticasone (50 mL, P = 0.003; 70 mL, P < 0.001, respectively). Moreover, both indacaterol doses showed significantly higher FEV(1) than placebo (P < 0.001) at all postdose time points. The numbers of patients with an FEV(1) increase of at least 12% and 200 mL at five minutes postdose were 16 (18.8%), 24 (27.6%), 20 (23.3%), 8 (9.1%), and 3 (3.4%) for indacaterol 150 and 300 MUg, salbutamol 200 MUg, salmeterol-fluticasone 50/500 MUg, and placebo, respectively. CONCLUSIONS: single doses of indacaterol 150 and 300 MUg demonstrated a fast onset of action similar to that for salbutamol and faster than that for salmeterol-fluticasone. PMID- 20856831 TI - Preparation, characterization and relative bioavailability of oral elemene o/w microemulsion. AB - The objective was to develop an elemene oil/water (o/w) microemulsion and evaluate its characteristics and oral relative bioavailability in rats. Elemene was used as the oil phase and drug, polysorbate 80 as a surfactant along with ethanol, propylene glycol, and glycerol as the cosurfactants. The microemulsion was prepared by mixing method, or ultrasonication method in an ultrasonic bath. Its three-dimensional response surface diagram was drawn by Mathcad software. The microemulsion was characterized by visual observation, cross-polarized microscopy, size, zeta potential, acidity, viscosity, and surface tension measurement. The drug content and entrapment efficiency were determined by ultra fast liquid chromatography (UFLC) and liquid surface method. Blood was drawn from rats at different time points after oral administration of an elemene microemulsion or a commercial elemene emulsion for measurement of the drug in plasma by UFLC to establish the pharmacokinetic parameters and relative bioavailability. The elemene microemulsion as a clarified and isotropic system containing 1% elemene (w/v), 5% ethanol (v/v), 15% propylene glycol (v/v), 15% glycerol (v/v), and 5% polysorbate 80 (w/v), was characterized as (57.7 +/- 2.8) nm in size, 0.485 +/- 0.032 in polydispersity index, (3.2 +/- 0.4) mv in zeta potential, (5.19 +/- 0.08) in pH, 6 mpa.s in viscosity, (31.8 +/- 0.3) mN.m(-1) in surface tension, (8.273 +/- 0.018) mg.mL(-1) in content of beta-elemene, and (99.81 +/- 0.24)% in average entrapment efficiency. The area under the concentration-time curves from 0 h to 24 h (AUC(0->24h)) of the elemene microemulsion and commercial elemene emulsion were integrated to be 3.092 mg.h.L( 1) and 1.896 mg.h.L(-1) respectively, yielding a relative bioavailability of 163.1%. The present study demonstrates the elemene microemulsion as a new formulation with ease of preparation, high entrapment efficiency, excellent clarity, good stability, and improved bioavailability. PMID- 20856832 TI - Silver/poly (lactic acid) nanocomposites: preparation, characterization, and antibacterial activity. AB - In this study, antibacterial characteristic of silver/poly (lactic acid) nanocomposite (Ag/PLA-NC) films was investigated, while silver nanoparticles (Ag NPs) were synthesized into biodegradable PLA via chemical reduction method in diphase solvent. Silver nitrate and sodium borohydride were respectively used as a silver precursor and reducing agent in the PLA, which acted as a polymeric matrix and stabilizer. Meanwhile, the properties of Ag/PLA-NCs were studied as a function of the Ag-NP weight percentages (8, 16, and 32 wt% respectively), in relation to the use of PLA. The morphology of the Ag/PLA-NC films and the distribution of the Ag-NPs were also characterized. The silver ions released from the Ag/PLA-NC films and their antibacterial activities were scrutinized. The antibacterial activities of the Ag/PLA-NC films were examined against Gram negative bacteria (Escherichia coli and Vibrio parahaemolyticus) and Gram positive bacteria (Staphylococcus aureus) by diffusion method using Muller-Hinton agar. The results indicated that Ag/PLA-NC films possessed a strong antibacterial activity with the increase in the percentage of Ag-NPs in the PLA. Thus, Ag/PLA NC films can be used as an antibacterial scaffold for tissue engineering and medical application. PMID- 20856833 TI - The use of PEGylated liposomes in the development of drug delivery applications for the treatment of hemophilia. AB - Hemophilia A is a rare X-linked bleeding disorder caused by lack or dysfunction of coagulation factor VIII (FVIII). Hemophilia A is treated with replacement therapy, but frequent injections of the missing FVIII often lead to the formation of inhibitory antibodies. Patients who develop high levels of inhibitors must be treated with bypassing agents such as activated FVII (FVIIa). Both FVIII and FVIIa have short half-lives and require multiple injections. Long-acting forms of these proteins would therefore reduce the frequency of injections, improve patient compliance and reduce complications. In this article we present a new platform technology that produces long-acting forms of FVIII and FVIIa and improves the efficacy of hemophilia treatment. This technology is based on the binding of proteins/peptides to the outer surface of PEGylated liposomes (PEGLip). Binding is dependent on an amino acid consensus sequence within the proteins and is highly specific. At the same time, binding is non-covalent and does not require any modification of the therapeutic agent or its production process. Association of proteins with PEGLip results in substantial enhancements in their pharmacodynamic properties following administration. These improvements seem to arise from the association of formulated proteins with platelets prior to induction of coagulation. PMID- 20856834 TI - The effect of magnetic nanoparticles of Fe(3)O(4) on immune function in normal ICR mice. AB - We investigated the effect of magnetic nanoparticles of Fe(3)O(4) (Fe(3)O(4) MNPs) on the mice immune system. Imprinting control region (ICR) mice were assigned randomly into four groups and treated with normal saline or low, medium, or high doses of Fe(3)O(4)-MNPs, respectively. After intravenous administration of Fe(3)O(4)-MNPs for 72 hours, the peripheral T cells and the induction of primary immune responses in mice were investigated by flow cytometry and determined using enzyme-linked immunosorbent assay, respectively. The results showed that the ratio of spleen to body weight was not different between the experimental groups and control group (P > 0.05). The lymphocyte transformation rates in the suspension of spleen were higher in low-dose group than those in the control group (P < 0.05), while the proliferation of splenocytes was low in the medium and high groups when compared to the control group (P < 0.05). In peripheral blood, both the proportions of subset CD4(+) and CD8(+) T lymphocytes in the low-dose group were higher than those in the control group, whereas there was no difference in the number of CD4(+) T cells between the medium- and low dose groups. Interestingly, the Fe(3)O(4)-MNPs enhanced the production of interleukin-2 (IL-2), interferon-gamma, and IL-10 but did not affect the production of IL-4 in peripheral blood. It is concluded that Fe(3)O(4)-MNPs could influence immune functions of normal ICR mice in a dose-dependent manner. PMID- 20856835 TI - Nano rare-earth oxides induced size-dependent vacuolization: an independent pathway from autophagy. AB - Four rare earth oxides have been shown to induce autophagy. Interestingly, we often noticed plentiful vacuolization, which was not always involved in this autophagic process. In this study, we investigated three other rare-earth elements, including Yttrium (Y), Ytterbium (Yb), and Lanthanum (La). Autophagic effect could be induced by all of them but only Y(2)O(3) and Yb(2)O(3) could cause massive vacuolization. Y(2)O(3) and Yb(2)O(3) treated by sonication or centrifugation to reduce particle size were used to test vacuolization level in HeLa cell lines. The results showed that rare earth oxides-induced vacuolization is size-dependent and differs from autophagic pathway. To further clarify the characteristics of this autophagic process, we used MEF Atg-5 (autophagy associated gene 5) knockout cell line, and the result showed that the autophagic process induced by rare earth oxides is Atg-5-dependent and the observed vacuolization was independent from autophagy. Similar results could also be observed in our tests on 3-methyladenine(3-MA), a well-known autophagy inhibitor. In conclusion, for the first time, we clarified the relationship between massive vacuolization and autophagic process induced by rare earth oxides and pointed out the size effect of rare earth oxides on the formation of vacuoles, which give clues to further investigation on the mechanisms underlying their biological effects. PMID- 20856836 TI - Preparation and characterization of solid lipid nanoparticles containing cyclosporine by the emulsification-diffusion method. AB - Solid lipid nanoparticles (SLNs) have been used for carrying different therapeutic agents because they improve absorption and bioavailability. The aim of the study was to prepare lipidic nanoparticles containing cyclosporine (CyA) by the emulsification-diffusion method and to study their physicochemical stability. Glyceryl behenate (Compritol((r)) ATO 888) and lauroyl macrogolglycerides (Gelucire((r)) 44/14) were used as carrier materials. Nanoparticles with good stability were obtained with Gelucire((r)), while it was difficult to obtain stable systems with Compritol((r)). Systems with Gelucire((r)) were characterized by particle size, Z-potential, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), entrapment efficiency and in vitro release. Particle size and Z-potential were evaluated for at least three months. With a high CyA content (>=60 mg) in Gelucire((r)) SLNs, variations in size were greater and particle size also increased over time in all batches; this effect may have been caused by a probable expulsion of the drug due to the lipid's partial rearrangement. While the Z-potential decreased 10 mV after three months, this effect may be explained by the superficial properties of the drug that make the molecules to be preferably oriented at the solid-liquid interface, causing a change in the net charge of the particle. SEM confirmed size and shape of the nanoparticles. DSC studies evidenced that CyA affects the lipid structure by a mechanism still unknown. The entrapment efficiency was higher than 92%, and CyA release from SLNs was relatively fast (99.60% in 45 min). PMID- 20856837 TI - Development of biodegradable polymer based tamoxifen citrate loaded nanoparticles and effect of some manufacturing process parameters on them: a physicochemical and in-vitro evaluation. AB - The aim of the present study was to develop nanoparticles of tamoxifen citrate, a non-steroidal antiestrogenic drug used for the treatment of breast cancer. Biodegradable poly (D, L- lactide-co-glycolide)-85:15 (PLGA) was used to develop nanoparticles of tamoxifen citrate by multiple emulsification (w/o/w) and solvent evaporation technique. Drug-polymer ratio, polyvinyl alcohol concentrations, and homogenizing speeds were varied at different stages of preparation to optimize the desired size and release profile of drug. The characterization of particle morphology and shape was performed by field emission scanning electron microscope (FE-SEM) and particle size distribution patterns were studied by direct light scattering method using zeta sizer. In vitro drug release study showed that release profile of tamoxifen from biodegradable nanoparticles varied due to the change in speed of centrifugation for separation. Drug loading efficiency varied from 18.60% to 71.98%. The FE-SEM study showed that biodegradable nanoparticles were smooth and spherical in shape. The stability studies of tamoxifen citrate in the experimental nanoparticles showed the structural integrity of tamoxifen citrate in PLGA nanoparticles up to 60 degrees C in the tested temperatures. Nanoparticles containing tamoxifen citrate could be useful for the controlled delivery of the drug for a prolonged period. PMID- 20856838 TI - Visualization of gold and platinum nanoparticles interacting with Salmonella enteritidis and Listeria monocytogenes. AB - PURPOSE: Rapid development of nanotechnology has recently brought significant attention to the extraordinary biological features of nanomaterials. The objective of the present investigation was to evaluate morphological characteristics of the assembles of gold and platinum nanoparticles (nano-Au and nano-Pt respectively), with Salmonella Enteritidis (Gram-negative) and Listeria monocytogenes (Gram-positive), to reveal possibilities of constructing bacteria nanoparticle vehicles. METHODS: Hydrocolloids of nano-Au or nano-Pt were added to two bacteria suspensions in the following order: nano-Au + Salmonella Enteritidis; nano-Au + Listeria monocytogenes; nano-Pt + Salmonella Enteritidis; nano-Pt + Listeria monocytogenes. Samples were inspected by transmission electron microscope. RESULTS: Visualization of morphological interaction between nano-Au and Salmonella Enteritidis and Listeria monocytogenes, showed that nano-Au were aggregated within flagella or biofilm network and did not penetrate the bacterial cell. The analysis of morphological effects of interaction of nano-Pt with bacteria revealed that nano-Pt entered cells of Listeria monocytogenes and were removed from the cells. In the case of Salmonella Enteritidis, nano-Pt were seen inside bacteria cells, probably bound to DNA and partly left bacterial cells. After washing and centrifugation, some of the nano-Pt-DNA complexes were observed within Salmonella Enteritidis. CONCLUSION: The results indicate that the bacteria could be used as a vehicle to deliver nano-Pt to specific points in the body. PMID- 20856839 TI - Organic functionalization of single-walled carbon nanotubes (SWCNTs) with some chemotherapeutic agents as a potential method for drug delivery. AB - The grafting of drugs to the single-walled carbon nanotube (SWCNT) was attained by the initial conversion of carboxylic groups in SWCNT to corresponding acyl chlorides. The active acyl chlorides in SWCNT were subsequently mixed with chemotherapeutic agents having NH, NH2, and OH functional groups to afford the formation of relevant amide and ester, respectively. The covalently grafted drugs to SWCNT were identified by infrared and UV-visible spectroscopy and transmission electron microscopy methods. From a clinical aspect, the grafting of drugs to the SWCNT can be used as a new tool and useful method for potential drug delivery in patients. PMID- 20856840 TI - Greater osteoblast and endothelial cell adhesion on nanostructured polyethylene and titanium. AB - Mostly due to desirable mechanical properties (such as high durability and low wear), certain synthetic polymers (such as polyethylene) and metals (such as titanium) have found numerous applications in the medical device arena from orthopedics to the vasculature, yet frequently, they do not proactively encourage desirable cell responses. In an effort to improve the efficacy of such traditional materials for various implant applications, this study used electron beam evaporation to create nanostructured surface features that mimic those of natural tissue on polyethylene and titanium. For other materials, it has been shown that the creation of nanorough surfaces increases surface energy leading to greater select protein (such as vitronectin and fibronectin) interactions to increase specific cell adhesion. Here, osteoblast (bone forming cells) and endothelial cell (cells that line the vasculature) adhesion was determined on nanostructured compared to conventional, nano-smooth polyethylene and titanium. Results demonstrated that nanorough surfaces created by electron beam evaporation increased the adhesion of both cells markedly better than conventional smooth surfaces. In summary, this study provided evidence that electron beam evaporation can modify implant surfaces (specifically, polyethylene and titanium) to have nanostructured surface features to improve osteoblast and endothelial cell adhesion. Since the adhesion of anchorage dependent cells (such as osteoblasts and endothelial cells) is a prerequisite for their long-term functions, this study suggests that electron beam evaporation should be further studied for improving materials for various biomedical applications. PMID- 20856841 TI - Iodine-125 radiolabeling of silver nanoparticles for in vivo SPECT imaging. AB - Silver nanoparticles are increasingly finding applications in medicine; however, little is known about their in vivo tissue distribution. Here, we have developed a rapid method for radiolabeling of silver nanoparticles with iodine-125 in order to track in vivo tissue uptake of silver nanoparticles after systemic administration by biodistribution analysis and single-photon emission computerized tomography (SPECT) imaging. Poly(N-vinyl-2 -pyrrolidone)-capped silver nanoparticles with an average size of 12 nm were labeled by chemisorption of iodine-125 with a > 80% yield of radiolabeling efficiency. Radiolabeled silver nanoparticles were intravenously injected in Balb/c mice, and the in vivo distribution pattern of these nanoparticles was evaluated by noninvasive whole body SPECT imaging, which revealed uptake of the nanoparticles in the liver and spleen. Biodistribution analysis confirmed predominant accumulation of the silver nanoparticles in the spleen (41.5%ID/g) and liver (24.5%ID/g) at 24 h. Extensive uptake in the tissues of the reticuloendothelial system suggests that further investigation of silver nanoparticle interaction with hepatic and splenic tissues at the cellular level is critical for evaluation of the in vivo effects and potential toxicity of silver nanoparticles. This method enables rapid iodine-125 radiolabeling of silver nanoparticles with a specific activity sufficient for in vivo imaging and biodistribution analysis. PMID- 20856842 TI - Detection of label-free cancer biomarkers using nickel nanoislands and quartz crystal microbalance. AB - We present a technique for the label-free detection and recognition of cancer biomarkers using metal nanoislands intended to be integrated in a novel type of nanobiosensor. His-tagged (scFv)-F7N1N2 is the antibody fragment which is directly immobilized, by coordinative bonds, onto ~5 nm nickel islands, then deposited on the surface of a quartz crystal of a quartz crystal microbalance (QCM) to validate the technique. Biomarker GTPase RhoA was investigated because it has been found to be overexpressed in various tumors and because we have recently isolated and characterized a new conformational scFv which selectively recognizes the active form of RhoA. We implemented a surface chemistry involving an antibiofouling coating of polyethylene glycol silane (PEG-silane) (<2 nm thick) and Ni nanoislands to reach a label-free detection of the active antigen conformation of RhoA, at various concentrations. The methodology proposed here proves the viability of the concept by using Ni nanoislands as an anchoring surface layer enabling the detection of a specific conformation of a protein, identified as a potential cancer biomarker. Hence, this novel methodology can be transferred to a nanobiosensor to detect, at lower time consumption and with high sensitivity, specific biomolecules. PMID- 20856843 TI - A once-daily dose of tadalafil for erectile dysfunction: compliance and efficacy. AB - Selective phosphodiesterase type 5 inhibitors (PDE5Is) have revolutionized the treatment of erectile dysfunction (ED) in men. As an on-demand treatment, PDE5Is have excellent efficacy and safety in the treatment of ED due to a broad spectrum of etiologies. Nevertheless, these drugs do have side-effect profiles that are troublesome to some patients, eg, headache, dyspepsia, myalgia, etc. Furthermore, many patients and their partners dislike the necessity of on-demand treatment for ED, citing a desire for greater spontaneity with sexual interactions. In 2008, approximately 10 years after the release of the first commercially available PDE5I, a paradigm shift in the management of ED occurred with the approval of once-daily dose of tadalafil by the US Food and Drug Administration for the management of ED. The prolonged half-life of tadalafil lends itself well to this dosing regimen and conveys the advantage of separating medication from sexual interactions; lower dose therapy also carries the theoretical benefit of lower incidence of side effects. In this study, we review the current state of the art with respect to this new management strategy for ED, highlighting published reports of the efficacy and tolerability of the daily dose tadalafil regimen. PMID- 20856844 TI - Development of QSAR model for immunomodulatory activity of natural coumarinolignoids. AB - Immunomodulation is the process of alteration in immune response due to foreign intrusion of molecules inside the body. Along with the available drugs, a large number of herbal drugs are promoted in traditional Indian treatments, for their immunomodulating activity. Natural coumarinolignoids isolated from the seeds of Cleome viscose have been recognized as having hepatoprotective action and have recently been tested preclinically for their immunomodulatory activity affecting both cell-mediated and humoral immune response. To explore the immunomodulatory compound from derivatives of coumarinolignoids, a quantitative structure activity relationship (QSAR) and molecular docking studies were performed. Theoretical results are in accord with the in vivo experimental data studied on Swiss albino mice. Immunostimulatory activity was predicted through QSAR model, developed by forward feed multiple linear regression method with leave-one-out approach. Relationship correlating measure of QSAR model was 99% (R(2) = 0.99) and predictive accuracy was 96% (RCV(2) = 0.96). QSAR studies indicate that dipole moment, steric energy, amide group count, lambda max (UV-visible), and molar refractivity correlates well with biological activity, while decrease in dipole moment, steric energy, and molar refractivity has negative correlation. Docking studies also showed strong binding affinity to immunomodulatory receptors. PMID- 20856845 TI - Emerging treatments in the management of schizophrenia - focus on sertindole. AB - The antipsychotic treatment of schizophrenia is still marked by poor compliance, and drug discontinuation; the development of more effective and safer drugs still remains a challenge. Sertindole is a second-generation antipsychotic with high affinity for dopamine D(2), serotonin 5-HT(2A), 5-HT(2C), and alpha(1)-adrenergic receptors, and low affinity for other receptors. Sertindole undergoes extensive hepatic metabolism by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4 and has an elimination half-life of approximately three days. In controlled clinical trials sertindole was more effective than placebo in reducing positive and negative symptoms, whereas it was as effective as haloperidol and risperidone against the positive symptoms of schizophrenia. The effective dose-range of sertindole is 12 20 mg, administered orally once daily. The most common adverse events are headache, insomnia, rhinitis/nasal congestion, male sexual dysfunction, and moderate weight gain, with few extrapyramidal symptoms and metabolic changes. Sertindole is associated with corrected QT interval prolongation, with subsequent risk of serious arrythmias. Due to cardiovascular safety concerns, sertindole is available as a second-line choice for patients intolerant to at least one other antipsychotic agent. Further clinical studies, mainly direct "head-to-head" comparisons with other second-generation antipsychotic agents, are needed to define the role of sertindole in the treatment of schizophrenia. PMID- 20856846 TI - Antithrombotic strategies in patients undergoing percutaneous coronary intervention for acute coronary syndrome. AB - In patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS), both periprocedural acute myocardial infarction and bleeding complications have been shown to be associated with early and late mortality. Current standard antithrombotic therapy after coronary stent implantation consists of lifelong aspirin and clopidogrel for a variable period depending in part on the stent type. Despite its well-established efficacy in reducing cardiac-related death, myocardial infarction, and stroke, dual antiplatelet therapy with aspirin and clopidogrel is not without shortcomings. While clopidogrel may be of little beneficial effect if administered immediately prior to PCI and may even increase major bleeding risk if coronary artery bypass grafting is anticipated, early discontinuation of the drug may result in insufficient antiplatelet coverage with thrombotic complications. Optimal and rapid inhibition of platelet activity to suppress ischemic and thrombotic events while minimizing bleeding complications is an important therapeutic goal in the management of patients undergoing percutaneous coronary intervention. In this article we present an overview of the literature on clinical trials evaluating the different aspects of antithrombotic therapy in patients undergoing PCI and discuss the emerging role of these agents in the contemporary era of early invasive coronary intervention. Clinical trial acronyms and their full names are provided in Table 1. PMID- 20856848 TI - Dynamic changes to survivin subcellular localization are initiated by DNA damage. AB - Subcellular distribution of the apoptosis inhibitor survivin and its ability to relocalize as a result of cell cycle phase or therapeutic insult has led to the hypothesis that these subcellular pools may coincide with different survivin functions. The PIK kinases (ATM, ATR and DNA-PK) phosphorylate a variety of effector substrates that propagate DNA damage signals, resulting in various biological outputs. Here we demonstrate that subcellular repartitioning of survivin in MCF-7 cells as a result of UV light-mediated DNA damage is dependent upon DNA damage-sensing proteins as treatment with the pan PIK kinase inhibitor wortmannin repartitioned survivin in the mitochondria and diminished it from the cytosol and nucleus. Mitochondrial redistribution of survivin, such as was recorded after wortmannin treatment, occurred in cells lacking any one of the three DNA damage sensing protein kinases: DNA-PK, ATM or ATR. However, failed survivin redistribution from the mitochondria in response to low-dose UV occurred only in the cells lacking ATM, implying that ATM may be the primary kinase involved in this process. Taken together, this data implicates survivian's subcellular distribution is a dynamic physiological process that appears responsive to UV light-initiated DNA damage and that its distribution may be responsible for its multifunctionality. PMID- 20856847 TI - Current and emerging therapies for the treatment of pancreatic cancer. AB - Pancreatic adenocarcinoma carries a dismal prognosis and remains a significant cause of cancer morbidity and mortality. Most patients survive less than 1 year; chemotherapeutic options prolong life minimally. The best chance for long-term survival is complete resection, which offers a 3-year survival of only 15%. Most patients who do undergo resection will go on to die of their disease. Research in chemotherapy for metastatic disease has made only modest progress and the standard of care remains the purine analog gemcitabine. For resectable pancreatic cancer, presumed micrometastases provide the rationale for adjuvant chemotherapy and chemoradiation (CRT) to supplement surgical management. Numerous randomized control trials, none definitive, of adjuvant chemotherapy and CRT have been conducted and are summarized in this review, along with recent developments in how unresectable disease can be subcategorized according to the potential for eventual curative resection. This review will also emphasize palliative care and discuss some avenues of research that show early promise. PMID- 20856849 TI - Temozolomide in malignant glioma. AB - Glioblastoma multiforme WHO grade IV (GBM) is the most aggressive malignant glioma and the most frequent primary tumor of the central nervous system. The median survival of newly diagnosed GBM patients was between 9 to 12 months prior to treatment with temozolomide being introduced. Primary resection that is as complete as possible is recommended for malignant glioma. Conventional fractionated irradiation 55 to 60 gy with concomitant temozolomide followed by standard temozolomide 6 cycles (5/28) (EORTC/NCIC-regime published by R Stupp in 2005) is the standard of care for newly diagnosed GBM after surgery, independent of the methylation status of the MGM-T gene promoter. Age is no contraindication for treatment with temozolomide, although comorbidity and performance status have to be considered. For temozolomide naive GBM and astrocytoma grade III patients with disease progression, temozolomide is still the treatment of choice outside of clinical studies. A general consensus regarding the schedule of choice has not yet been achieved; so far the 5 out of 28 days regimen (5/28) is the standard of care in most countries. Patients with disease progression after standard temozolomide (5/28) are candidates for clinical studies. Outside of clinical studies, dose-dense (7/7), prolonged (21/28), or metronomic (28/28) temozolomide, or alternatively a nitrosourea-based regimen can be an option. The excellent toxicity profile of temozolomide allows for various combinations with antitumor agents. None of these combinations, however, have been demonstrated to be statistically significantly superior compared to temozolomide alone. The role of lower dosed, dose-dense, or continuous regimen with or without drug combination and the role of temozolomide for newly diagnosed astrocytoma grade III and low grade glioma still has to be determined. PMID- 20856850 TI - Balancing detection and eradication for control of epidemics: sudden oak death in mixed-species stands. AB - Culling of infected individuals is a widely used measure for the control of several plant and animal pathogens but culling first requires detection of often cryptically-infected hosts. In this paper, we address the problem of how to allocate resources between detection and culling when the budget for disease management is limited. The results are generic but we motivate the problem for the control of a botanical epidemic in a natural ecosystem: sudden oak death in mixed evergreen forests in coastal California, in which species composition is generally dominated by a spreader species (bay laurel) and a second host species (coast live oak) that is an epidemiological dead-end in that it does not transmit infection but which is frequently a target for preservation. Using a combination of an epidemiological model for two host species with a common pathogen together with optimal control theory we address the problem of how to balance the allocation of resources for detection and epidemic control in order to preserve both host species in the ecosystem. Contrary to simple expectations our results show that an intermediate level of detection is optimal. Low levels of detection, characteristic of low effort expended on searching and detection of diseased trees, and high detection levels, exemplified by the deployment of large amounts of resources to identify diseased trees, fail to bring the epidemic under control. Importantly, we show that a slight change in the balance between the resources allocated to detection and those allocated to control may lead to drastic inefficiencies in control strategies. The results hold when quarantine is introduced to reduce the ingress of infected material into the region of interest. PMID- 20856851 TI - Viability and burden of Leishmania in extralesional sites during human dermal leishmaniasis. AB - BACKGROUND: The clinical and epidemiological significance of Leishmania DNA in extralesional sites is obscured by uncertainty of whether the DNA derives from viable parasites. To examine dissemination of Leishmania during active disease and the potential participation of human infection in transmission, Leishmania 7SLRNA was exploited to establish viability and estimate parasite burden in extralesional sites of dermal leishmaniasis patients. METHODS: The feasibility of discriminating parasite viability by PCR of Leishmania 7SLRNA was evaluated in relation with luciferase activity of luc transfected intracellular amastigotes in dose-response assays of Glucantime cytotoxicity. Monocytes, tonsil swabs, aspirates of normal skin and lesions of 28 cutaneous and 2 mucocutaneous leishmaniasis patients were screened by kDNA amplification/Southern blot. Positive samples were analyzed by quantitative PCR of Leishmania 7SLRNA genes and transcripts. RESULTS: 7SLRNA amplification coincided with luciferase activity, confirming discrimination of parasite viability. Of 22 patients presenting kDNA in extralesional samples, Leishmania 7SLRNA genes or transcripts were detected in one or more kDNA positive samples in 100% and 73% of patients, respectively. Gene and transcript copy number amplified from extralesional tissues were comparable to lesions. 7SLRNA transcripts were detected in 13/19 (68%) monocyte samples, 5/12 (42%) tonsil swabs, 4/11 (36%) normal skin aspirates, and 22/25 (88%) lesions; genes were quantifiable in 15/19 (79%) monocyte samples, 12/13 (92%) tonsil swabs, 8/11 (73%) normal skin aspirates. CONCLUSION: Viable parasites are present in extralesional sites, including blood monocytes, tonsils and normal skin of dermal leishmaniasis patients. Leishmania 7SLRNA is an informative target for clinical and epidemiologic investigations of human leishmaniasis. PMID- 20856852 TI - Impact of increased economic burden due to human echinococcosis in an underdeveloped rural community of the People's Republic of China. AB - BACKGROUND: Ningxia is located in western People's Republic of China, which is hyperendemic for human cystic echinococcosis (CE) throughout the entire area with alveolar echinococcosis (AE) hyperendemic in the south. This is in part due to its underdeveloped economy. Despite the recent rapid growth in P.R. China's economy, medical expenditure for hospitalization of echinococcosis cases has become one of the major poverty generators in rural Ningxia, resulting in a significant social problem. METHODOLOGY/PRINCIPAL FINDINGS: We reviewed the 2000 inpatient records with liver CE in surgical departments of hospitals from north, central and south Ningxia for the period 1996-2002. We carried out an analysis of health care expenditure of inpatient treatment in public hospitals, and examined the financial inequalities relating to human echinococcosis and the variation in per capita income between various socioeconomic groups with different levels of gross domestic product for different years. Hospital charges for Yinchuan, NHAR's capital city in the north, increased approximately 35-fold more than the annual income of rural farmers with the result that they preferred to seek health care in local county hospitals, despite higher quality and more efficient treatment and diagnosis available in the city. Household income levels thus strongly influenced the choice of health care provider and the additional expense impeded access of poor people to better quality treatment. CONCLUSIONS/SIGNIFICANCE: Information on socioeconomic problems arising from echinococcosis, which adds considerably to the burden on patient families and communities, needs to be collected as a prerequisite for developing policies to tackle the disease in rural Ningxia. PMID- 20856853 TI - Negative effects of paternal age on children's neurocognitive outcomes can be explained by maternal education and number of siblings. AB - BACKGROUND: Recent findings suggest advanced paternal age may be associated with impaired child outcomes, in particular, neurocognitive skills. Such patterns are worrisome given relatively universal trends in advanced countries toward delayed nuptiality and fertility. But nature and nurture are both important for child outcomes, and it is important to control for both when drawing inferences about either pathway. METHODS AND FINDINGS: We examined cross-sectional patterns in six developmental outcome measures among children in the U.S. Collaborative Perinatal Project (n = 31,346). Many of these outcomes at 8 mo, 4 y, and 7 y of age (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart Block Sort Test, Wechsler Intelligence Scale for Children, Wide Range Achievement Test) are negatively correlated with paternal age when important family characteristics such as maternal education and number of siblings are not included as covariates. But controlling for family characteristics in general and mother's education in particular renders the effect of paternal age statistically insignificant for most developmental measures. CONCLUSIONS: Assortative mating produces interesting relationships between maternal and paternal characteristics that can inject spurious correlation into observational studies via omitted variable bias. Controlling for both nature and nurture reveals little residual evidence of a link between child neurocognitive outcomes and paternal age in these data. Results suggest that benefits associated with the upward trend in maternal education may offset any negative effects of advancing paternal age. PMID- 20856854 TI - Priming the semantic neighbourhood during the attentional blink. AB - BACKGROUND: When two targets are presented in close temporal proximity amongst a rapid serial visual stream of distractors, a period of disrupted attention and attenuated awareness lasting 200-500 ms follows identification of the first target (T1). This phenomenon is known as the "attentional blink" (AB) and is generally attributed to a failure to consolidate information in visual short-term memory due to depleted or disrupted attentional resources. Previous research has shown that items presented during the AB that fail to reach conscious awareness are still processed to relatively high levels, including the level of meaning. For example, missed word stimuli have been shown to prime later targets that are closely associated words. Although these findings have been interpreted as evidence for semantic processing during the AB, closely associated words (e.g., day-night) may also rely on specific, well-worn, lexical associative links which enhance attention to the relevant target. METHODOLOGY/PRINCIPAL FINDINGS: We used a measure of semantic distance to create prime-target pairs that are conceptually close, but have low word associations (e.g., wagon and van) and investigated priming from a distractor stimulus presented during the AB to a subsequent target (T2). The stimuli were words (concrete nouns) in Experiment 1 and the corresponding pictures of objects in Experiment 2. In both experiments, report of T2 was facilitated when this item was preceded by a semantically-related distractor. CONCLUSIONS/SIGNIFICANCE: This study is the first to show conclusively that conceptual information is extracted from distractor stimuli presented during a period of attenuated awareness and that this information spreads to neighbouring concepts within a semantic network. PMID- 20856855 TI - A novel histone deacetylase inhibitor exhibits antitumor activity via apoptosis induction, F-actin disruption and gene acetylation in lung cancer. AB - BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferative mechanisms of OSU-HDAC 44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. CONCLUSIONS/SIGNIFICANCE: OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy. PMID- 20856856 TI - Design, development and evaluation of rK28-based point-of-care tests for improving rapid diagnosis of visceral leishmaniasis. AB - BACKGROUND: Visceral leishmaniasis (VL) is diagnosed by microscopic confirmation of the parasite in bone marrow, spleen or lymph node aspirates. These procedures are unsuitable for rapid diagnosis of VL in field settings. The development of rK39-based rapid diagnostic tests (RDT) revolutionized diagnosis of VL by offering high sensitivity and specificity in detecting disease in the Indian subcontinent; however, these tests have been less reliable in the African subcontinent (sensitivity range of 75-85%, specificity of 70-92%). We have addressed limitations of the rK39 with a new synthetic polyprotein, rK28, followed by development and evaluation of two new rK28-based RDT prototype platforms. METHODOLOGY/PRINCIPAL FINDINGS: Evaluation of 62 VL-confirmed sera from Sudan provided sensitivities of 96.8% and 93.6% (95% CI = K28: 88.83-99.61%; K39: 84.30-98.21%) and specificities of 96.2% and 92.4% (95% CI = K28: 90.53 98.95%; K39: 85.54-96.65%) for rK28 and rK39, respectively. Of greater interest was the observation that individual VL sera with low rK39 reactivity often had much higher rK28 reactivity. This characteristic of the fusion protein was exploited in the development of rK28 rapid tests, which may prove to be crucial in detecting VL among patients with low rK39 antibody levels. Evaluation of two prototype lateral flow-based rK28 rapid tests on 53 VL patients in Sudan and 73 VL patients in Bangladesh provided promisingly high sensitivities (95.9% [95% CI = 88.46-99.1 in Sudan and 98.1% [95% CI = 89.93-99.95%] in Bangladesh) compared to the rK39 RDT (sensitivities of 86.3% [95% CI = 76.25-93.23%] in Sudan and 88.7% [95% CI = 76.97-95.73%] in Bangladesh). CONCLUSIONS/SIGNIFICANCE: Our study compares the diagnostic accuracy of rK39 and rK28 in detecting active VL cases and our findings indicate that rK28 polyprotein has great potential as a serodiagnostic tool. A new rK28-based RDT will prove to be a valuable asset in simplifying VL disease confirmation at the point-of-care. PMID- 20856857 TI - Extracellular production and degradation of superoxide in the coral Stylophora pistillata and cultured Symbiodinium. AB - BACKGROUND: Reactive oxygen species (ROS) are thought to play a major role in cell death pathways and bleaching in scleractinian corals. Direct measurements of ROS in corals are conspicuously in short supply, partly due to inherent problems with ROS quantification in cellular systems. METHODOLOGY/PRINCIPAL FINDINGS: In this study we characterized the dynamics of the reactive oxygen species superoxide anion radical (O(2)(-)) in the external milieu of the coral Stylophora pistillata. Using a sensitive, rapid and selective chemiluminescence-based technique, we measured extracellular superoxide production and detoxification activity of symbiont (non-bleached) and aposymbiont (bleached) corals, and of cultured Symbiodinium (from clades A and C). Bleached and non-bleached Stylophora fragments were found to produce superoxide at comparable rates of 10(-11)-10(-9) mol O(2)(-) mg protein(-1) min(-1) in the dark. In the light, a two-fold enhancement in O(2)(-) production rates was observed in non-bleached corals, but not in bleached corals. Cultured Symbiodinium produced superoxide in the dark at a rate of . Light was found to markedly enhance O(2)(-) production. The NADPH Oxidase inhibitor Diphenyleneiodonium chloride (DPI) strongly inhibited O(2)(-) production by corals (and more moderately by algae), possibly suggesting an involvement of NADPH Oxidase in the process. An extracellular O(2)(-) detoxifying activity was found for bleached and non-bleached Stylophora but not for Symbiodinium. The O(2)(-) detoxifying activity was partially characterized and found to resemble that of the enzyme superoxide dismutase (SOD). CONCLUSIONS/SIGNIFICANCE: The findings of substantial extracellular O(2)(-) production as well as extracellular O(2)(-) detoxifying activity may shed light on the chemical interactions between the symbiont and its host and between the coral and its environment. Superoxide production by Symbiodinium possibly implies that algal bearing corals are more susceptible to an internal build-up of O(2)( ), which may in turn be linked to oxidative stress mediated bleaching. PMID- 20856859 TI - Application and validation of PFGE for serovar identification of Leptospira clinical isolates. AB - Serovar identification of clinical isolates of Leptospira is generally not performed on a routine basis, yet the identity of an infecting serovar is valuable from both epidemiologic and public health standpoints. Only a small number of reference laboratories worldwide have the capability to perform the cross agglutinin absorption test (CAAT), the reference method for serovar identification. Pulsed-field gel electrophoresis (PFGE) is an alternative method to CAAT that facilitates rapid identification of leptospires to the serovar level. We employed PFGE to evaluate 175 isolates obtained from humans and animals submitted to the Centers for Disease Control and Prevention (CDC) between 1993 and 2007. PFGE patterns for each isolate were generated using the NotI restriction enzyme and compared to a reference database consisting of more than 200 reference strains. Of the 175 clinical isolates evaluated, 136 (78%) were identified to the serovar level by the database, and an additional 27 isolates (15%) have been identified as probable new serovars. The remaining isolates yet to be identified are either not represented in the database or require further study to determine whether or not they also represent new serovars. PFGE proved to be a useful tool for serovar identification of clinical isolates of known serovars from different geographic regions and a variety of different hosts and for recognizing potential new serovars. PMID- 20856858 TI - Tick-borne rickettsioses, neglected emerging diseases in rural Senegal. AB - BACKGROUND: Rickettsioses are one of the most important causes of systemic febrile illness among travelers from developed countries, but little is known about their incidence in indigenous populations, especially in West Africa. METHODOLOGY/PRINCIPAL FINDINGS: Overall seroprevalence evaluated by immunofluorescence using six rickettsial antigens (spotted fever and typhus group) in rural populations of two villages of the Sine-Saloum region of Senegal was found to be 21.4% and 51% for spotted fever group rickettsiae for Dielmo and Ndiop villages, respectively. We investigated the role of tick-borne rickettsiae as the cause of acute non-malarial febrile diseases in the same villages. The incidence of rickettsial DNA in 204 blood samples from 134 (62M and 72F) febrile patients negative for malaria was studied. DNA extracted from whole blood was tested by two qPCR systems. Rickettsial DNA was found in nine patients, eight with Rickettsia felis (separately reported). For the first time in West Africa, Rickettsia conorii was diagnosed in one patient. We also tested 2,767 Ixodid ticks collected in two regions of Senegal (Niakhar and Sine-Saloum) from domestic animals (cows, sheep, goats, donkeys and horses) by qPCR and identified five different pathogenic rickettsiae. We found the following: Rickettsia aeschlimannii in Hyalomma marginatum rufipes (51.3% and 44.8% in Niakhar and Sine Saloum region, respectively), in Hyalomma truncatum (6% and 6.8%) and in Rhipicephalus evertsi evertsi (0.5%, only in Niakhar); R. c. conorii in Rh. e. evertsi (0.4%, only in Sine-Saloum); Rickettsia massiliae in Rhipicephalus guilhoni (22.4%, only in Niakhar); Rickettsia sibirica mongolitimonae in Hyalomma truncatum (13.5%, only in Sine-Saloum); and Rickettsia africae in Rhipicephalus evertsi evertsi (0.7% and 0.4% in Niakhar and Sine-Saloum region, respectively) as well as in Rhipicephalus annulatus (20%, only in Sine-Saloum). We isolated two rickettsial strains from H. truncatum: R. s. mongolitimonae and R. aeschlimannii. CONCLUSIONS/SIGNIFICANCE: We believe that together with our previous data on the high prevalence of R. africae in Amblyomma ticks and R. felis infection in patients, the presented results on the distribution of pathogenic rickettsiae in ticks and the first R. conorii case in West Africa show that the rural population of Senegal is at risk for other tick-borne rickettsioses, which are significant causes of febrile disease in this area. PMID- 20856860 TI - A new method for the characterization of strain-specific conformational stability of protease-sensitive and protease-resistant PrPSc. AB - Although proteinacious in nature, prions exist as strains with specific self perpetuating biological properties. Prion strains are thought to be associated with different conformers of PrP(Sc), a disease-associated isoform of the host encoded cellular protein (PrP(C)). Molecular strain typing approaches have been developed which rely on the characterization of protease-resistant PrP(Sc). However, PrP(Sc) is composed not only of protease-resistant but also of protease sensitive isoforms. The aim of this work was to develop a protocol for the molecular characterization of both, protease-resistant and protease-sensitive PrP(Sc) aggregates. We first set up experimental conditions which allowed the most advantageous separation of PrP(C) and PrP(Sc) by means of differential centrifugation. The conformational solubility and stability assay (CSSA) was then developed by measuring PrP(Sc) solubility as a function of increased exposure to GdnHCl. Brain homogenates from voles infected with human and sheep prion isolates were analysed by CSSA and showed strain-specific conformational stabilities, with mean [GdnHCl](1/2) values ranging from 1.6 M for MM2 sCJD to 2.1 for scrapie and to 2.8 M for MM1/MV1 sCJD and E200K gCJD. Interestingly, the rank order of [GdnHCl](1/2) values observed in the human and sheep isolates used as inocula closely matched those found following transmission in voles, being MM1 sCJD the most resistant (3.3 M), followed by sheep scrapie (2.2 M) and by MM2 sCJD (1.6 M). In order to test the ability of CSSA to characterise protease-sensitive PrP(Sc), we analysed sheep isolates of Nor98 and compared them to classical scrapie isolates. In Nor98, insoluble PrP(Sc) aggregates were mainly protease sensitive and showed a conformational stability much lower than in classical scrapie. Our results show that CSSA is able to reveal strain-specified PrP(Sc) conformational stabilities of protease-resistant and protease-sensitive PrP(Sc) and that it is a valuable tool for strain typing in natural hosts, such as humans and sheep. PMID- 20856861 TI - MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes. AB - Senescence is a state of growth arrest resulting mainly from telomere attrition and oxidative stress. It ultimately leads to cell death. We have previously shown that, in keratinocytes, senescence is induced by NF-kappaB activation, MnSOD upregulation and H(2)O(2) overproduction. We have also shown that senescent keratinocytes do not die by apoptosis but as a result of high macroautophagic activity that targets the primary vital cell components. Here, we investigated the mechanisms that activate this autophagic cell death program. We show that corpses occurring at the senescence plateau display oxidatively-damaged mitochondria and nucleus that colocalize with autophagic vacuoles. The occurrence of such corpses was decreased by specifically reducing the H(2)O(2) level with catalase, and, conversely, reproduced by overexpressing MnSOD or applying subtoxic doses of H(2)O(2). This H(2)O(2)-induced cell death did occur through autophagy since it was accompanied by an accumulation of autophagic vesicles as evidenced by Lysotracker staining, LC3 vesiculation and transmission electron microscopy. Most importantly, it was partly abolished by 3-methyladenine, the specific inhibitor of autophagosome formation, and by anti-Atg5 siRNAs. Taken together these results suggest that autophagic cell death is activated in senescent keratinocytes because of the upregulation of MnSOD and the resulting accumulation of oxidative damages to nucleus and mitochondria. PMID- 20856862 TI - Molecular evidence for high frequency of multiple paternity in a freshwater shrimp species Caridina ensifera. AB - BACKGROUND: Molecular genetic analyses of parentage provide insights into mating systems. Although there are 22,000 members in Malacostraca, not much has been known about mating systems in Malacostraca. The freshwater shrimp Caridina ensifera blue, is a new species belonging to Malacostraca which was discovered recently in Sulawesi, Indonesia. Due to its small body size and low fecundity, this species is an ideal species to study the occurrence and frequency of multiple paternity and to understand of how the low fecundity species persist and evolve. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we developed four polymorphic microsatellites from C. ensifera and applied them to investigate the occurrence and frequency of multiple paternity in 20 C. ensifera broods caught from Lake Matano, Sulawesi. By genotyping the mother and all offspring from each brood we discovered multiple paternity in all 20 broods. In most of the 20 broods, fathers contributed skewed numbers of offspring and there was an apparent inverse correlation between reproductive success of sires and their relatedness to mothers. CONCLUSIONS/SIGNIFICANCE: Our results in combination with recent reports on multiple paternity in crayfish, crab and lobster species suggests that multiple paternity is common in Malacostraca. Skewed contribution of fathers to the numbers of offspring and inverse correlation between reproductive success of sires and their relatedness to mothers suggest that sperm competition occurred and/or pre- and postcopulatory female choice happen, which may be important for avoiding the occurrence of inbreeding and optimize genetic variation in offspring and for persistence and evolution of low fecundity species. PMID- 20856863 TI - Comparative genome analysis reveals an absence of leucine-rich repeat pattern recognition receptor proteins in the kingdom Fungi. AB - BACKGROUND: In plants and animals innate immunity is the first line of defence against attack by microbial pathogens. Specific molecular features of bacteria and fungi are recognised by pattern recognition receptors that have extracellular domains containing leucine rich repeats. Recognition of microbes by these receptors induces defence responses that protect hosts against potential microbial attack. METHODOLOGY/PRINCIPAL FINDINGS: A survey of genome sequences from 101 species, representing a broad cross-section of the eukaryotic phylogenetic tree, reveals an absence of leucine rich repeat-domain containing receptors in the fungal kingdom. Uniquely, however, fungi possess adenylate cyclases that contain distinct leucine rich repeat-domains, which have been demonstrated to act as an alternative means of perceiving the presence of bacteria by at least one fungal species. Interestingly, the morphologically similar osmotrophic oomycetes, which are taxonomically distant members of the stramenopiles, possess pattern recognition receptors with similar domain structures to those found in plants. CONCLUSIONS: The absence of pattern recognition receptors suggests that fungi may possess novel classes of pattern recognition receptor, such as the modified adenylate cyclase, or instead rely on secretion of anti-microbial secondary metabolites for protection from microbial attack. The absence of pattern recognition receptors in fungi, coupled with their abundance in oomycetes, suggests this may be a unique characteristic of the fungal kingdom rather than a consequence of the osmotrophic growth form. PMID- 20856864 TI - Epigenetic mechanisms regulate stem cell expressed genes Pou5f1 and Gfra1 in a male germ cell line. AB - Male fertility is declining and an underlying cause may be due to environment epigenetic interactions in developing sperm, yet nothing is known of how the epigenome controls gene expression in sperm development. Histone methylation and acetylation are dynamically regulated in spermatogenesis and are sensitive to the environment. Our objectives were to determine how histone H3 methylation and acetylation contribute to the regulation of key genes in spermatogenesis. A germ cell line, GC-1, was exposed to either the control, or the chromatin modifying drugs tranylcypromine (T), an inhibitor of the histone H3 demethylase KDM1 (lysine specific demethylase 1), or trichostatin (TSA), an inhibitor of histone deacetylases, (HDAC). Quantitative PCR (qPCR) was used to identify genes that were sensitive to treatment. As a control for specificity the Myod1 (myogenic differentiation 1) gene was analyzed. Chromatin immunoprecipitation (ChIP) followed by qPCR was used to measure histone H3 methylation and acetylation at the promoters of target genes and the control, Myod1. Remarkably, the chromatin modifying treatment specifically induced the expression of spermatogonia expressed genes Pou5f1 and Gfra1. ChIP-qPCR revealed that induction of gene expression was associated with a gain in gene activating histone H3 methylation and acetylation in Pou5f1 and Gfra1 promoters, whereas CpG DNA methylation was not affected. Our data implicate a critical role for histone H3 methylation and acetylation in the regulation of genes expressed by spermatogonia--here, predominantly mediated by HDAC-containing protein complexes. PMID- 20856865 TI - Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. AB - BACKGROUND: The presence of Lewy bodies and Lewy neurites (LN) has been demonstrated in the enteric nervous system (ENS) of Parkinson's disease (PD) patients. The aims of the present research were to use routine colonoscopy biopsies (1) to analyze, in depth, enteric pathology throughout the colonic submucosal plexus (SMP), and (2) to correlate the pathological burden with neurological and gastrointestinal (GI) symptoms. METHODOLOGY/PRINCIPAL FINDINGS: A total of 10 control and 29 PD patients divided into 3 groups according to disease duration were included. PD and GI symptoms were assessed using the Unified Parkinson's Disease Rating Scale part III and the Rome III questionnaire, respectively. Four biopsies were taken from the ascending and descending colon during the course of a total colonoscopy. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha-synuclein, neurofilaments NF 220 kDa (NF) and tyrosine hydroxylase (TH). The density of LN, labeled by anti phosphorylated alpha-synuclein antibodies, was evaluated using a quantitative rating score. Lewy pathology was apparent in the colonic biopsies from 21 patients and in none of the controls. A decreased number of NF-immunoreactive neurons per ganglion was observed in the SMP of PD patients compared to controls. The amount of LN in the ENS was inversely correlated with neuronal count and positively correlated with levodopa-unresponsive features and constipation. CONCLUSION/SIGNIFICANCE: Analysis of the ENS by routine colonoscopy biopsies is a useful tool for pre-mortem neuropathological diagnosis of PD, and also provides insight into the progression of motor and non-motor symptoms. PMID- 20856866 TI - Dynamic analysis of vascular morphogenesis using transgenic quail embryos. AB - BACKGROUND: One of the least understood and most central questions confronting biologists is how initially simple clusters or sheet-like cell collectives can assemble into highly complex three-dimensional functional tissues and organs. Due to the limits of oxygen diffusion, blood vessels are an essential and ubiquitous presence in all amniote tissues and organs. Vasculogenesis, the de novo self assembly of endothelial cell (EC) precursors into endothelial tubes, is the first step in blood vessel formation. Static imaging and in vitro models are wholly inadequate to capture many aspects of vascular pattern formation in vivo, because vasculogenesis involves dynamic changes of the endothelial cells and of the forming blood vessels, in an embryo that is changing size and shape. METHODOLOGY/PRINCIPAL FINDINGS: We have generated Tie1 transgenic quail lines Tg(tie1:H2B-eYFP) that express H2B-eYFP in all of their endothelial cells which permit investigations into early embryonic vascular morphogenesis with unprecedented clarity and insight. By combining the power of molecular genetics with the elegance of dynamic imaging, we follow the precise patterning of endothelial cells in space and time. We show that during vasculogenesis within the vascular plexus, ECs move independently to form the rudiments of blood vessels, all while collectively moving with gastrulating tissues that flow toward the embryo midline. The aortae are a composite of somatic derived ECs forming its dorsal regions and the splanchnic derived ECs forming its ventral region. The ECs in the dorsal regions of the forming aortae exhibit variable mediolateral motions as they move rostrally; those in more ventral regions show significant lateral-to medial movement as they course rostrally. CONCLUSIONS/SIGNIFICANCE: The present results offer a powerful approach to the major challenge of studying the relative role(s) of the mechanical, molecular, and cellular mechanisms of vascular development. In past studies, the advantages of the molecular genetic tools available in mouse were counterbalanced by the limited experimental accessibility needed for imaging and perturbation studies. Avian embryos provide the needed accessibility, but few genetic resources. The creation of transgenic quail with labeled endothelia builds upon the important roles that avian embryos have played in previous studies of vascular development. PMID- 20856867 TI - Identification of CD8+ T cell epitopes in the West Nile virus polyprotein by reverse-immunology using NetCTL. AB - BACKGROUND: West Nile virus (WNV) is a growing threat to public health and a greater understanding of the immune response raised against WNV is important for the development of prophylactic and therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: In a reverse-immunology approach, we used bioinformatics methods to predict WNV-specific CD8(+) T cell epitopes and selected a set of peptides that constitutes maximum coverage of 20 fully-sequenced WNV strains. We then tested these putative epitopes for cellular reactivity in a cohort of WNV-infected patients. We identified 26 new CD8(+) T cell epitopes, which we propose are restricted by 11 different HLA class I alleles. Aiming for optimal coverage of human populations, we suggest that 11 of these new WNV epitopes would be sufficient to cover from 48% to 93% of ethnic populations in various areas of the World. CONCLUSIONS/SIGNIFICANCE: The 26 identified CD8(+) T cell epitopes contribute to our knowledge of the immune response against WNV infection and greatly extend the list of known WNV CD8(+) T cell epitopes. A polytope incorporating these and other epitopes could possibly serve as the basis for a WNV vaccine. PMID- 20856868 TI - In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi. AB - BACKGROUND: Cruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease. METHODOLOGY/PRINCIPAL FINDINGS: WRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR 483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported. CONCLUSIONS: We demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease. PMID- 20856869 TI - Role of CD45 signaling pathway in galactoxylomannan-induced T cell damage. AB - Previously, we reported that Galactoxylomannan (GalXM) activates the extrinsic and intrinsic apoptotic pathways through an interaction with the glycoreceptors on T cells. In this study we establish the role of the glycoreceptor CD45 in GalXM-induced T cell apoptosis, using CD45(+/+) and CD45(-/-) cell lines, derived from BW5147 murine T cell lymphoma. Our results show that whereas CD45 expression is not required for GalXM association by the cells, it is essential for apoptosis induction. In CD45(+/+) cells, CD45 triggering by GalXM reduces the activation of Lck, ZAP70 and Erk1/2. Conversely, in CD45(-/-) cells, Lck was hyperphosphorylated and did not show any modulation after GalXM stimulation. On the whole, our findings provide evidence that the negative regulation of Lck activation occurs via CD45 engagement. This appears to be related to the capacity of GalXM to antagonize T cell activation and induce T cell death. Overall this mechanism may be responsible for the immune paralysis that follows GalXM administration and could explain the powerful immunosuppression that accompanies cryptococcosis. PMID- 20856871 TI - Gingival fibroblasts as a promising source of induced pluripotent stem cells. AB - BACKGROUND: Induced pluripotent stem (iPS) cells efficiently generated from accessible tissues have the potential for clinical applications. Oral gingiva, which is often resected during general dental treatments and treated as biomedical waste, is an easily obtainable tissue, and cells can be isolated from patients with minimal discomfort. METHODOLOGY/PRINCIPAL FINDINGS: We herein demonstrate iPS cell generation from adult wild-type mouse gingival fibroblasts (GFs) via introduction of four factors (Oct3/4, Sox2, Klf4 and c-Myc; GF-iPS-4F cells) or three factors (the same as GF-iPS-4F cells, but without the c-Myc oncogene; GF-iPS-3F cells) without drug selection. iPS cells were also generated from primary human gingival fibroblasts via four-factor transduction. These cells exhibited the morphology and growth properties of embryonic stem (ES) cells and expressed ES cell marker genes, with a decreased CpG methylation ratio in promoter regions of Nanog and Oct3/4. Additionally, teratoma formation assays showed ES cell-like derivation of cells and tissues representative of all three germ layers. In comparison to mouse GF-iPS-4F cells, GF-iPS-3F cells showed consistently more ES cell-like characteristics in terms of DNA methylation status and gene expression, although the reprogramming process was substantially delayed and the overall efficiency was also reduced. When transplanted into blastocysts, GF-iPS-3F cells gave rise to chimeras and contributed to the development of the germline. Notably, the four-factor reprogramming efficiency of mouse GFs was more than 7-fold higher than that of fibroblasts from tail-tips, possibly because of their high proliferative capacity. CONCLUSIONS/SIGNIFICANCE: These results suggest that GFs from the easily obtainable gingival tissues can be readily reprogrammed into iPS cells, thus making them a promising cell source for investigating the basis of cellular reprogramming and pluripotency for future clinical applications. In addition, high-quality iPS cells were generated from mouse GFs without Myc transduction or a specific system for reprogrammed cell selection. PMID- 20856870 TI - Nephrocystin-1 forms a complex with polycystin-1 via a polyproline motif/SH3 domain interaction and regulates the apoptotic response in mammals. AB - Mutations in PKD1, the gene encoding for the receptor Polycystin-1 (PC-1), cause autosomal dominant polycystic kidney disease (ADPKD). The cytoplasmic C-terminus of PC-1 contains a coiled-coil domain that mediates an interaction with the PKD2 gene product, Polycystin-2 (PC-2). Here we identify a novel domain in the PC-1 C terminal tail, a polyproline motif mediating an interaction with Src homology domain 3 (SH3). A screen for interactions using the PC-1 C-terminal tail identified the SH3 domain of nephrocystin-1 (NPHP1) as a potential binding partner of PC-1. NPHP1 is the product of a gene that is mutated in a different form of renal cystic disease, nephronophthisis (NPHP). We show that in vitro pull down assays and NMR structural studies confirmed the interaction between the PC-1 polyproline motif and the NPHP1 SH3 domain. Furthermore, the two full-length proteins interact through these domains; using a recently generated model system allowing us to track endogenous PC-1, we confirm the interaction between the endogenous proteins. Finally, we show that NPHP1 trafficking to cilia does not require PC-1 and that PC-1 may require NPHP1 to regulate resistance to apoptosis, but not to regulate cell cycle progression. In line with this, we find high levels of apoptosis in renal specimens of NPHP patients. Our data uncover a link between two different ciliopathies, ADPKD and NPHP, supporting the notion that common pathogenetic defects, possibly involving de-regulated apoptosis, underlie renal cyst formation. PMID- 20856872 TI - The unfolded protein response is not necessary for the G1/S transition, but it is required for chromosome maintenance in Saccharomyces cerevisiae. AB - BACKGROUND: The unfolded protein response (UPR) is a eukaryotic signaling pathway, from the endoplasmic reticulum (ER) to the nucleus. Protein misfolding in the ER triggers the UPR. Accumulating evidence links the UPR in diverse aspects of cellular homeostasis. The UPR responds to the overall protein synthesis capacity and metabolic fluxes of the cell. Because the coupling of metabolism with cell division governs when cells start dividing, here we examined the role of UPR signaling in the timing of initiation of cell division and cell cycle progression, in the yeast Saccharomyces cerevisiae. METHODOLOGY/PRINCIPAL FINDINGS: We report that cells lacking the ER-resident stress sensor Ire1p, which cannot trigger the UPR, nonetheless completed the G1/S transition on time. Furthermore, loss of UPR signaling neither affected the nutrient and growth rate dependence of the G1/S transition, nor the metabolic oscillations that yeast cells display in defined steady-state conditions. Remarkably, however, loss of UPR signaling led to hypersensitivity to genotoxic stress and a ten-fold increase in chromosome loss. CONCLUSIONS/SIGNIFICANCE: Taken together, our results strongly suggest that UPR signaling is not necessary for the normal coupling of metabolism with cell division, but it has a role in genome maintenance. These results add to previous work that linked the UPR with cytokinesis in yeast. UPR signaling is conserved in all eukaryotes, and it malfunctions in a variety of diseases, including cancer. Therefore, our findings may be relevant to other systems, including humans. PMID- 20856874 TI - Prohibitins are required for cancer cell proliferation and adhesion. AB - Prohibitin 1 (PHB1) is a highly conserved protein that together with its homologue prohibitin 2 (PHB2) mainly localizes to the inner mitochondrial membrane. Although it was originally identified by its ability to inhibit G1/S progression in human fibroblasts, its role as tumor suppressor is debated. To determine the function of prohibitins in maintaining cell homeostasis, we generated cancer cell lines expressing prohibitin-directed shRNAs. We show that prohibitin proteins are necessary for the proliferation of cancer cells. Down regulation of prohibitin expression drastically reduced the rate of cell division. Furthermore, mitochondrial morphology was not affected, but loss of prohibitins did lead to the degradation of the fusion protein OPA1 and, in certain cancer cell lines, to a reduced capability to exhibit anchorage independent growth. These cancer cells also exhibited reduced adhesion to the extracellular matrix. Taken together, these observations suggest prohibitins play a crucial role in adhesion processes in the cell and thereby sustaining cancer cell propagation and survival. PMID- 20856873 TI - Phylogeny and classification of the trapdoor spider genus Myrmekiaphila: an integrative approach to evaluating taxonomic hypotheses. AB - BACKGROUND: Revised by Bond and Platnick in 2007, the trapdoor spider genus Myrmekiaphila comprises 11 species. Species delimitation and placement within one of three species groups was based on modifications of the male copulatory device. Because a phylogeny of the group was not available these species groups might not represent monophyletic lineages; species definitions likewise were untested hypotheses. The purpose of this study is to reconstruct the phylogeny of Myrmekiaphila species using molecular data to formally test the delimitation of species and species-groups. We seek to refine a set of established systematic hypotheses by integrating across molecular and morphological data sets. METHODS AND FINDINGS: Phylogenetic analyses comprising Bayesian searches were conducted for a mtDNA matrix composed of contiguous 12S rRNA, tRNA-val, and 16S rRNA genes and a nuclear DNA matrix comprising the glutamyl and prolyl tRNA synthetase gene each consisting of 1348 and 481 bp, respectively. Separate analyses of the mitochondrial and nuclear genome data and a concatenated data set yield M. torreya and M. millerae paraphyletic with respect to M. coreyi and M. howelli and polyphyletic fluviatilis and foliata species groups. CONCLUSIONS: Despite the perception that molecular data present a solution to a crisis in taxonomy, studies like this demonstrate the efficacy of an approach that considers data from multiple sources. A DNA barcoding approach during the species discovery process would fail to recognize at least two species (M. coreyi and M. howelli) whereas a combined approach more accurately assesses species diversity and illuminates speciation pattern and process. Concomitantly these data also demonstrate that morphological characters likewise fail in their ability to recover monophyletic species groups and result in an unnatural classification. Optimizations of these characters demonstrate a pattern of "Dollo evolution" wherein a complex character evolves only once but is lost multiple times throughout the group's history. PMID- 20856875 TI - The crystal structure of Toxoplasma gondii pyruvate kinase 1. AB - BACKGROUND: Pyruvate kinase (PK), which catalyzes the final step in glycolysis converting phosphoenolpyruvate to pyruvate, is a central metabolic regulator in most organisms. Consequently PK represents an attractive therapeutic target in cancer and human pathogens, like Apicomplexans. The phylum Aplicomplexa, a group of exclusively parasitic organisms, includes the genera Plasmodium, Cryptosporidium and Toxoplasma, the etiological agents of malaria, cryptosporidiosis and toxoplasmosis respectively. Toxoplasma gondii infection causes a mild illness and is a very common infection affecting nearly one third of the world's population. METHODOLOGY/PRINCIPAL FINDINGS: We have determined the crystal structure of the PK1 enzyme from T. gondii, with the B domain in the open and closed conformations. We have also characterized its enzymatic activity and confirmed glucose-6-phosphate as its allosteric activator. This is the first description of a PK enzyme in a closed inactive conformation without any bound substrate. Comparison of the two tetrameric TgPK1 structures indicates a reorientation of the monomers with a concomitant change in the buried surface among adjacent monomers. The change in the buried surface was associated with significant B domain movements in one of the interacting monomers. CONCLUSIONS: We hypothesize that a loop in the interface between the A and B domains plays an important role linking the position of the B domain to the buried surface among monomers through two alpha-helices. The proposed model links the catalytic cycle of the enzyme with its domain movements and highlights the contribution of the interface between adjacent subunits. In addition, an unusual ordered conformation was observed in one of the allosteric binding domains and it is related to a specific apicomplexan insertion. The sequence and structural particularity would explain the atypical activation by a mono-phosphorylated sugar. The sum of peculiarities raises this enzyme as an emerging target for drug discovery. PMID- 20856876 TI - Facilitation of male sexual behavior in Syrian hamsters by the combined action of dihydrotestosterone and testosterone. AB - BACKGROUND: Testosterone (T) controls male Syrian hamster sexual behavior, however, neither of T's primary metabolites, dihydrotestosterone (DHT) and estradiol (E(2)), even in highly supraphysiological doses, fully restores sexual behavior in castrated hamsters. DHT and T apparently interact with androgen receptors differentially to control male sexual behavior (MSB), but whether these two hormones act synergistically or antagonistically to control MSB has received scant experimental attention and is addressed in the present study. METHODOLOGY/PRINCIPAL FINDINGS: Sexually experienced male Syrian hamsters were gonadectomized and monitored 5 weeks later to confirm elimination of the ejaculatory reflex (week 0), at which time they received subcutaneous DHT-filled or empty capsules that remained in situ for the duration of the experiment. Daily injections of a physiological dose of 25 ug T or vehicle commenced two weeks after capsule implantation. MSB was tested 2, 4 and 5 weeks after T treatment began. DHT capsules were no more effective than control treatment for long-term restoration of ejaculation. Combined DHT + T treatment, however, restored the ejaculatory reflex more effectively than T alone, as evidenced by more rapid recovery of ejaculatory behavior, shorter ejaculation latencies, and a greater number of ejaculations in 30 minute tests. CONCLUSIONS/SIGNIFICANCE: DHT and T administered together restored sexual behavior to pre-castration levels more rapidly than did T alone, whereas DHT and vehicle were largely ineffective. The additive actions of DHT and T on MSB are discussed in relation to different effects of these androgens on androgen receptors in the male hamster brain mating circuit. PMID- 20856877 TI - Myosin Va participates in acrosomal formation and nuclear morphogenesis during spermatogenesis of Chinese mitten crab Eriocheir sinensis. AB - BACKGROUND: The Chinese mitten crab Eriocheir sinensis belongs to the Class Crustacea, Decapoda, Brachyura. The spermatozoon of this species is of aflagellated type, it has a spherical acrosome surrounded by the cup-shaped nucleus, which are unique to brachyurans. For the past several decades, studies on the spermatogenesis of the mitten crab mainly focus on the morphology. Compared with the extensive study of molecular mechanism of spermatogenesis in mammals, relatively less information is available in crustacean species. Myosin Va, a member of Class V myosin, has been implicated in acrosome biogenesis and vesicle transport during spermatogenesis in mammals. In the present study we demonstrate the expression and cellular localization of myosin Va during spermatogenesis in E. sinensis. METHODOLOGY/PRINCIPAL FINDINGS: Western blot demonstrated that myosin Va is expressed during spermatogenesis. Immunocytochemical and ultrastructural analyses showed that myosin Va mainly localizes in the cytoplasm in spermatocytes. At the early stage of spermiogenesis, myosin Va binds to the endoplasmic reticulum vesicle (EV) and proacrosomal granule (PG). Subsequently, myosin Va localizes within the proacrosomal vesicle (PV) formed by PG and EV fusion and locates in the membrane complex (MC) at the mid spermatid stage. At the late spermatid stage, myosin Va is associated with the shaping nucleus and mitochondria. In mature spermatozoon, myosin Va predominates in acrosomal tubule (AT) and nucleus. CONCLUSIONS/SIGNIFICANCE: Our study demonstrates that myosin Va may be involved in acrosome biogenesis and nuclear morphogenesis during spermatogenesis in E. sinensis. Considering the distribution and molecular characteristics of myosin Va, we also propose a hypothesis of AT formation in this species. It is the first time to uncover the role of myosin Va in crustacean spermatogenesis. PMID- 20856878 TI - The chaperone ClpX stimulates expression of Staphylococcus aureus protein A by Rot dependent and independent pathways. AB - The Clp ATPases (Hsp100) constitute a family of closely related proteins that have protein reactivating and remodelling activities typical of molecular chaperones. In Staphylococcus aureus the ClpX chaperone is essential for virulence and for transcription of spa encoding Protein A. The present study was undertaken to elucidate the mechanism by which ClpX stimulates expression of Protein A. For this purpose, we prepared antibodies directed against Rot, an activator of spa transcription, and demonstrated that cells devoid of ClpX contain three-fold less Rot than wild-type cells. By varying Rot expression from an inducible promoter we showed that expression of Protein A requires a threshold level of Rot. In the absence of ClpX the Rot content is reduced below this threshold level, hence, explaining the substantially reduced Protein A expression in the clpX mutant. Experiments addressed at pinpointing the role of ClpX in Rot synthesis revealed that ClpX is required for translation of Rot. Interestingly, translation of the spa mRNA was, like the rot mRNA, enhanced by ClpX. These data demonstrate that ClpX performs dual roles in regulating Protein A expression, as ClpX stimulates transcription of spa by enhancing translation of Rot, and that ClpX additionally is required for full translation of the spa mRNA. The current findings emphasize that ClpX has a central role in fine-tuning virulence regulation in S. aureus. PMID- 20856879 TI - Active site conformational dynamics in human uridine phosphorylase 1. AB - Uridine phosphorylase (UPP) is a central enzyme in the pyrimidine salvage pathway, catalyzing the reversible phosphorolysis of uridine to uracil and ribose 1-phosphate. Human UPP activity has been a focus of cancer research due to its role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5 fluorouracil (5-FU) and capecitabine. Additionally, specific molecular inhibitors of this enzyme have been found to raise endogenous uridine concentrations, which can produce a cytoprotective effect on normal tissues exposed to these drugs. Here we report the structure of hUPP1 bound to 5-FU at 2.3 A resolution. Analysis of this structure reveals new insights as to the conformational motions the enzyme undergoes in the course of substrate binding and catalysis. The dimeric enzyme is capable of a large hinge motion between its two domains, facilitating ligand exchange and explaining observed cooperativity between the two active sites in binding phosphate-bearing substrates. Further, a loop toward the back end of the uracil binding pocket is shown to flexibly adjust to the varying chemistry of different compounds through an "induced-fit" association mechanism that was not observed in earlier hUPP1 structures. The details surrounding these dynamic aspects of hUPP1 structure and function provide unexplored avenues to develop novel inhibitors of this protein with improved specificity and increased affinity. Given the recent emergence of new roles for uridine as a neuron protective compound in ischemia and degenerative diseases, such as Alzheimer's and Parkinson's, inhibitors of hUPP1 with greater efficacy, which are able to boost cellular uridine levels without adverse side-effects, may have a wide range of therapeutic applications. PMID- 20856880 TI - MPF governs the assembly and contraction of actomyosin rings by activating RhoA and MAPK during chemical-induced cytokinesis of goat oocytes. AB - The interplay between maturation-promoting factor (MPF), mitogen-activated protein kinase (MAPK) and Rho GTPase during actin-myosin interactions has yet to be determined. The mechanism by which microtubule disrupters induce the formation of ooplasmic protrusion during chemical-assisted enucleation of mammalian oocytes is unknown. Moreover, a suitable model is urgently needed for the study of cytokinesis. We have established a model of chemical-induced cytokinesis and have studied the signaling events leading to cytokinesis using this model. The results suggested that microtubule inhibitors activated MPF, which induced actomyosin assembly (formation of ooplasmic protrusion) by activating RhoA and thus MAPK. While MAPK controlled actin recruitment on its own, MPF promoted myosin enrichment by activating RhoA and MAPK. A further chemical treatment of oocytes with protrusions induced constriction of the actomyosin ring by inactivating MPF while activating RhoA. In conclusion, the present data suggested that the assembly and contraction of the actomyosin ring were two separable steps: while an increase in MPF activity promoted the assembly through RhoA-mediated activation of MAPK, a decrease in MPF activity triggered contraction of the ring by activating RhoA. PMID- 20856882 TI - Chemical and physical environmental conditions underneath mat- and canopy-forming macroalgae, and their effects on understorey corals. AB - Disturbed coral reefs are often dominated by dense mat- or canopy-forming assemblages of macroalgae. This study investigated how such dense macroalgal assemblages change the chemical and physical microenvironment for understorey corals, and how the altered environmental conditions affect the physiological performance of corals. Field measurements were conducted on macroalgal-dominated inshore reefs in the Great Barrier Reef in quadrats with macroalgal biomass ranging from 235 to 1029 g DW m(-2) dry weight. Underneath mat-forming assemblages, the mean concentration of dissolved oxygen was reduced by 26% and irradiance by 96% compared with conditions above the mat, while concentrations of dissolved organic carbon and soluble reactive phosphorous increased by 26% and 267%, respectively. The difference was significant but less pronounced under canopy-forming assemblages. Dissolved oxygen declined and dissolved inorganic carbon and alkalinity increased with increasing algal biomass underneath mat forming but not under canopy-forming assemblages. The responses of corals to conditions similar to those found underneath algal assemblages were investigated in an aquarium experiment. Coral nubbins of the species Acropora millepora showed reduced photosynthetic yields and increased RNA/DNA ratios when exposed to conditions simulating those underneath assemblages (pre-incubating seawater with macroalgae, and shading). The magnitude of these stress responses increased with increasing proportion of pre-incubated algal water. Our study shows that mat forming and, to a lesser extent, canopy-forming macroalgal assemblages alter the physical and chemical microenvironment sufficiently to directly and detrimentally affect the metabolism of corals, potentially impeding reef recovery from algal to coral-dominated states after disturbance. Macroalgal dominance on coral reefs therefore simultaneously represents a consequence and cause of coral reef degradation. PMID- 20856881 TI - Complex I-associated hydrogen peroxide production is decreased and electron transport chain enzyme activities are altered in n-3 enriched fat-1 mice. AB - The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate mitochondrial reactive oxygen species (ROS) production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6:n-3 ratio on liver mitochondrial H(2)O(2) production and electron transport chain (ETC) activity. There was an increase in n-3 fatty acids and a decrease in the n-6:n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p<0.05) in the activity of ETC complex I and increases (p<0.05) in the activities of complexes III and IV. Mitochondrial H(2)O(2) production with either succinate or succinate/glutamate/malate substrates was also decreased (p<0.05) in the fat-1 mice. This change in H(2)O(2) production was due to a decrease in ROS production from ETC complex I in the fat 1 animals. These results indicate that the fatty acid changes in fat-1 liver mitochondria may at least partially oppose oxidative stress by limiting ROS production from ETC complex I. PMID- 20856883 TI - Involvement of the melanocortin-1 receptor in acute pain and pain of inflammatory but not neuropathic origin. AB - BACKGROUND: Response to painful stimuli is susceptible to genetic variation. Numerous loci have been identified which contribute to this variation, one of which, MC1R, is better known as a gene involved in mammalian hair colour. MC1R is a G protein-coupled receptor expressed in melanocytes and elsewhere and mice lacking MC1R have yellow hair, whilst humans with variant MC1R protein have red hair. Previous work has found differences in acute pain perception, and response to analgesia in mice and humans with mutations or variants in MC1R. METHODOLOGY AND PRINCIPAL FINDINGS: We have tested responses to noxious and non-noxious stimuli in mutant mice which lack MC1R, or which overexpress an endogenous antagonist of the receptor, as well as controls. We have also examined the response of these mice to inflammatory pain, assessing the hyperalgesia and allodynia associated with persistent inflammation, and their response to neuropathic pain. Finally we tested by a paired preference paradigm their aversion to oral administration of capsaicin, which activates the noxious heat receptor TRPV1. Female mice lacking MC1R showed increased tolerance to noxious heat and no alteration in their response to non-noxious mechanical stimuli. MC1R mutant females, and females overexpressing the endogenous MC1R antagonist, agouti signalling protein, had a reduced formalin-induced inflammatory pain response, and a delayed development of inflammation-induced hyperalgesia and allodynia. In addition they had a decreased aversion to capsaicin at moderate concentrations. Male mutant mice showed no difference from their respective controls. Mice of either sex did not show any effect of mutant genotype on neuropathic pain. CONCLUSIONS: We demonstrate a sex-specific role for MC1R in acute noxious thermal responses and pain of inflammatory origin. PMID- 20856884 TI - Bacterial flagellin triggers cardiac innate immune responses and acute contractile dysfunction. AB - BACKGROUND: Myocardial contractile failure in septic shock may develop following direct interactions, within the heart itself, between molecular motifs released by pathogens and their specific receptors, notably those belonging to the toll like receptor (TLR) family. Here, we determined the ability of bacterial flagellin, the ligand of mammalian TLR5, to trigger myocardial inflammation and contractile dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: TLR5 expression was determined in H9c2 cardiac myoblasts, in primary rat cardiomyocytes, and in whole heart extracts from rodents and humans. The ability of flagellin to activate pro inflammatory signaling pathways (NF-kappaB and MAP kinases) and the expression of inflammatory cytokines was investigated in H9c2 cells, and, in part, in primary cardiomyocytes, as well as in the mouse myocardium in vivo. The influence of flagellin on left ventricular function was evaluated in mice by a conductance pressure-volume catheter. Cardiomyocytes and intact myocardium disclosed significant TLR5 expression. In vitro, flagellin activated NF-kappaB, MAP kinases, and the transcription of inflammatory genes. In vivo, flagellin induced cardiac activation of NF-kappaB, expression of inflammatory cytokines (TNF alpha, IL-1 beta, IL-6, MIP-2 and MCP-1), and provoked a state of reversible myocardial dysfunction, characterized by cardiac dilation, reduced ejection fraction, and decreased end-systolic elastance. CONCLUSION/SIGNIFICANCE: These results are the first to indicate that flagellin has the ability to trigger cardiac innate immune responses and to acutely depress myocardial contractility. PMID- 20856885 TI - Human activities on the deep seafloor in the North East Atlantic: an assessment of spatial extent. AB - BACKGROUND: Environmental impacts of human activities on the deep seafloor are of increasing concern. While activities within waters shallower than 200 m have been the focus of previous assessments of anthropogenic impacts, no study has quantified the extent of individual activities or determined the relative severity of each type of impact in the deep sea. METHODOLOGY: The OSPAR maritime area of the North East Atlantic was chosen for the study because it is considered to be one of the most heavily impacted by human activities. In addition, it was assumed data would be accessible and comprehensive. Using the available data we map and estimate the spatial extent of five major human activities in the North East Atlantic that impact the deep seafloor: submarine communication cables, marine scientific research, oil and gas industry, bottom trawling and the historical dumping of radioactive waste, munitions and chemical weapons. It was not possible to map military activities. The extent of each activity has been quantified for a single year, 2005. PRINCIPAL FINDINGS: Human activities on the deep seafloor of the OSPAR area of the North Atlantic are significant but their footprints vary. Some activities have an immediate impact after which seafloor communities could re-establish, while others can continue to make an impact for many years and the impact could extend far beyond the physical disturbance. The spatial extent of waste disposal, telecommunication cables, the hydrocarbon industry and marine research activities is relatively small. The extent of bottom trawling is very significant and, even on the lowest possible estimates, is an order of magnitude greater than the total extent of all the other activities. CONCLUSIONS/SIGNIFICANCE: To meet future ecosystem-based management and governance objectives for the deep sea significant improvements are required in data collection and availability as well as a greater awareness of the relative impact of each human activity. PMID- 20856887 TI - The cercal organ may provide singing tettigoniids a backup sensory system for the detection of eavesdropping bats. AB - Conspicuous signals, such as the calling songs of tettigoniids, are intended to attract mates but may also unintentionally attract predators. Among them bats that listen to prey-generated sounds constitute a predation pressure for many acoustically communicating insects as well as frogs. As an adaptation to protect against bat predation many insect species evolved auditory sensitivity to bat emitted echolocation signals. Recently, the European mouse-eared bat species Myotis myotis and M. blythii oxygnathus were found to eavesdrop on calling songs of the tettigoniid Tettigonia cantans. These gleaning bats emit rather faint echolocation signals when approaching prey and singing insects may have difficulty detecting acoustic predator-related signals. The aim of this study was to determine (1) if loud self-generated sound produced by European tettigoniids impairs the detection of pulsed ultrasound and (2) if wind-sensors on the cercal organ function as a sensory backup system for bat detection in tettigoniids. We addressed these questions by combining a behavioral approach to study the response of two European tettigoniid species to pulsed ultrasound, together with an electrophysiological approach to record the activity of wind-sensitive interneurons during real attacks of the European mouse-eared bat species Myotis myotis. Results showed that singing T. cantans males did not respond to sequences of ultrasound pulses, whereas singing T. viridissima did respond with predominantly brief song pauses when ultrasound pulses fell into silent intervals or were coincident with the production of soft hemi-syllables. This result, however, strongly depended on ambient temperature with a lower probability for song interruption observable at 21 degrees C compared to 28 degrees C. Using extracellular recordings, dorsal giant interneurons of tettigoniids were shown to fire regular bursts in response to attacking bats. Between the first response of wind-sensitive interneurons and contact, a mean time lag of 860 ms was found. This time interval corresponds to a bat-to-prey distance of ca. 72 cm. This result demonstrates the efficiency of the cercal system of tettigoniids in detecting attacking bats and suggests this sensory system to be particularly valuable for singing insects that are targeted by eavesdropping bats. PMID- 20856886 TI - Estimating the impact of plasma HIV-1 RNA reductions on heterosexual HIV-1 transmission risk. AB - BACKGROUND: The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy (ART), therapeutic vaccines, and other non-ART interventions. METHODOLOGY/PRINCIPAL FINDINGS: We use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log(10) plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log(10) copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1 related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels >=4 log(10) copies/mL. CONCLUSIONS/SIGNIFICANCE: This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels. PMID- 20856888 TI - Result publication of Chinese trials in World Health Organization primary registries. AB - BACKGROUND: Result publication is the key step to improve the transparency of clinical trials. OBJECTIVE: To investigate the result publication rate of Chinese trials registered in World Health Organization (WHO) primary registries. METHOD: We searched 11 WHO primary registries for Chinese trials records. The progress of each trial was analyzed. We searched for the full texts of result publications cited in the registration records. For completed trials without citations, we searched PubMed, Embase, Chinese Biomedical Literature Database (Chinese), China Knowledge Resource Integrated Database, and Chinese Science and Technology Periodicals Database for result publications. The search was conducted on July 14, 2009. We also called the investigators of completed trials to ask about results publication. RESULTS: We identified 1294 Chinese trials records (428 in ChiCTR,743 in clinicaltrials.gov,55 in ISRCTN, 21 in ACTRN). A total of 443 trials had been completed. The publication rate of the Chinese trials in WHO primary registries is 35.2% (156/443).The publication rate of Chinese trials in clinicaltrials.gov, ChiCTR, ISRCTN, and ACRTN was 36.5% (53/145), 36.3% (89/245), 26.0% (9/44), and 55.6% (5/9), respectively. The publication rate of trials sponsored by industry (23.8%) was lower than that of sponsored by central and local government (31.7%), hospital (35.1%), and universities (40.7%). The publication rate for randomized trials was higher than that of cohort study and case-control study (33.2% versus 16.7%, 22.2%). The publication rate for interventional studies and observational studies was similar (33.4% versus 33.3%). CONCLUSION: The publication rate of the registered Chinese trials was low, with no significant difference between ChiCTR and clinicaltrials.gov. An effective mechanism is needed to promote publication of results for registered trials in China. PMID- 20856892 TI - Thymic alterations in GM2 gangliosidoses model mice. AB - BACKGROUND: Sandhoff disease is a lysosomal storage disorder characterized by the absence of beta-hexosaminidase and storage of GM2 ganglioside and related glycolipids. We have previously found that the progressive neurologic disease induced in Hexb(-/-) mice, an animal model for Sandhoff disease, is associated with the production of pathogenic anti-glycolipid autoantibodies. METHODOLOGY/PRINCIPAL FINDINGS: In our current study, we report on the alterations in the thymus during the development of mild to severe progressive neurologic disease. The thymus from Hexb(-/-) mice of greater than 15 weeks of age showed a marked decrease in the percentage of immature CD4(+)/CD8(+) T cells and a significantly increased number of CD4(+)/CD8(-) T cells. During involution, the levels of both apoptotic thymic cells and IgG deposits to T cells were found to have increased, whilst swollen macrophages were prominently observed, particularly in the cortex. We employed cDNA microarray analysis to monitor gene expression during the involution process and found that genes associated with the immune responses were upregulated, particularly those expressed in macrophages. CXCL13 was one of these upregulated genes and is expressed specifically in the thymus. B1 cells were also found to have increased in the thy mus. It is significant that these alterations in the thymus were reduced in FcRgamma additionally disrupted Hexb(-/-) mice. CONCLUSIONS/SIGNIFICANCE: These results suggest that the FcRgamma chain may render the usually poorly immunogenic thymus into an organ prone to autoimmune responses, including the chemotaxis of B1 cells toward CXCL13. PMID- 20856893 TI - Renal Dnase1 enzyme activity and protein expression is selectively shut down in murine and human membranoproliferative lupus nephritis. AB - BACKGROUND: Deposition of chromatin-IgG complexes within glomerular membranes is a key event in the pathogenesis of lupus nephritis. We recently reported an acquired loss of renal Dnase1 expression linked to transformation from mild to severe membranoproliferative lupus nephritis in (NZBxNZW)F1 mice. As this may represent a basic mechanism in the progression of lupus nephritis, several aspects of Dnase1 expression in lupus nephritis were analyzed. METHODOLOGY/PRINCIPAL FINDINGS: Total nuclease activity and Dnase1 expression and activity was evaluated using in situ and in vitro analyses of kidneys and sera from (NZBxNZW)F1 mice of different ages, and from age-matched healthy controls. Immunofluorescence staining for Dnase1 was performed on kidney biopsies from (NZBxNZW)F1 mice as well as from human SLE patients and controls. Reduced serum Dnase1 activity was observed in both mesangial and end-stage lupus nephritis. A selective reduction in renal Dnase1 activity was seen in mice with massive deposition of chromatin-containing immune complexes in glomerular capillary walls. Mice with mild mesangial nephritis showed normal renal Dnase1 activity. Similar differences were seen when comparing human kidneys with severe and mild lupus nephritis. Dnase1 was diffusely expressed within the kidney in normal and mildly affected kidneys, whereas upon progression towards end-stage renal disease, Dnase1 was down-regulated in all renal compartments. This demonstrates that the changes associated with development of severe nephritis in the murine model are also relevant to human lupus nephritis. CONCLUSIONS/SIGNIFICANCE: Reduction in renal Dnase1 expression and activity is limited to mice and SLE patients with signs of membranoproliferative nephritis, and may be a critical event in the development of severe forms of lupus nephritis. Reduced Dnase1 activity reflects loss in the expression of the protein and not inhibition of enzyme activity. PMID- 20856894 TI - Low CD10 mRNA expression identifies high-risk ductal carcinoma in situ (DCIS). AB - PURPOSE: Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS. EXPERIMENTAL DESIGN: CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154). RESULTS: CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; [95CI:1.30-2.70], p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; [95%CI:1.24-4.09], p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; [95%CI:1.23-3.35], p = 0.006). CONCLUSION: The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management. PMID- 20856895 TI - A sub-cellular viscoelastic model for cell population mechanics. AB - Understanding the biomechanical properties and the effect of biomechanical force on epithelial cells is key to understanding how epithelial cells form uniquely shaped structures in two or three-dimensional space. Nevertheless, with the limitations and challenges posed by biological experiments at this scale, it becomes advantageous to use mathematical and 'in silico' (computational) models as an alternate solution. This paper introduces a single-cell-based model representing the cross section of a typical tissue. Each cell in this model is an individual unit containing several sub-cellular elements, such as the elastic plasma membrane, enclosed viscoelastic elements that play the role of cytoskeleton, and the viscoelastic elements of the cell nucleus. The cell membrane is divided into segments where each segment (or point) incorporates the cell's interaction and communication with other cells and its environment. The model is capable of simulating how cells cooperate and contribute to the overall structure and function of a particular tissue; it mimics many aspects of cellular behavior such as cell growth, division, apoptosis and polarization. The model allows for investigation of the biomechanical properties of cells, cell-cell interactions, effect of environment on cellular clusters, and how individual cells work together and contribute to the structure and function of a particular tissue. To evaluate the current approach in modeling different topologies of growing tissues in distinct biochemical conditions of the surrounding media, we model several key cellular phenomena, namely monolayer cell culture, effects of adhesion intensity, growth of epithelial cell through interaction with extra cellular matrix (ECM), effects of a gap in the ECM, tensegrity and tissue morphogenesis and formation of hollow epithelial acini. The proposed computational model enables one to isolate the effects of biomechanical properties of individual cells and the communication between cells and their microenvironment while simultaneously allowing for the formation of clusters or sheets of cells that act together as one complex tissue. PMID- 20856896 TI - beta1-syntrophin modulation by miR-222 in mdx mice. AB - BACKGROUND: In mdx mice, the absence of dystrophin leads to the deficiency of other components of the dystrophin-glycoprotein complex (DAPC), making skeletal muscle fibers more susceptible to necrosis. The mechanisms involved in the disappearance of the DAPC are not completely understood. The muscles of mdx mice express normal amounts of mRNA for the DAPC components, thus suggesting post transcriptional regulation. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the hypothesis that DAPC reduction could be associated with the microRNA system. Among the possible microRNAs (miRs) found to be upregulated in the skeletal muscle tissue of mdx compared to wt mice, we demonstrated that miR-222 specifically binds to the 3'-UTR of beta1-syntrophin and participates in the downregulation of beta1-syntrophin. In addition, we documented an altered regulation of the 3'-UTR of beta1-syntrophin in muscle tissue from dystrophic mice. CONCLUSION/SIGNIFICANCE: These results show the importance of the microRNA system in the regulation of DAPC components in dystrophic muscle, and suggest a potential role of miRs in the pathophysiology of dystrophy. PMID- 20856898 TI - Diversity of meiofauna from the 9 degrees 50'N East Pacific rise across a gradient of hydrothermal fluid emissions. AB - BACKGROUND: We studied the meiofauna community at deep-sea hydrothermal vents along a gradient of vent fluid emissions in the axial summit trought (AST) of the East Pacific Rise 9 degrees 50'N region. The gradient ranged from extreme high temperatures, high sulfide concentrations, and low pH at sulfide chimneys to ambient deep-sea water conditions on bare basalt. We explore meiofauna diversity and abundance, and discuss its possible underlying ecological and evolutionary processes. METHODOLOGY/PRINCIPAL FINDINGS: After sampling in five physico chemically different habitats, the meiofauna was sorted, counted and classified. Abundances were low at all sites. A total of 52 species were identified at vent habitats. The vent community was dominated by hard substrate generalists that also lived on bare basalt at ambient deep-sea temperature in the axial summit trough (AST generalists). Some vent species were restricted to a specific vent habitat (vent specialists), but others occurred over a wide range of physico chemical conditions (vent generalists). Additionally, 35 species were only found on cold bare basalt (basalt specialists). At vent sites, species richness and diversity clearly increased with decreasing influence of vent fluid emissions from extreme flow sulfide chimney (no fauna), high flow pompei worm (S: 4-7, H'(loge): 0.11-0.45), vigorous flow tubeworm (S: 8-23; H'(loge): 0.44-2.00) to low flow mussel habitats (S: 28-31; H'(loge): 2.34-2.60). CONCLUSIONS/SIGNIFICANCE: Our data suggest that with increasing temperature and toxic hydrogen sulfide concentrations and increasing amplitude of variation of these factors, fewer species are able to cope with these extreme conditions. This results in less diverse communities in more extreme habitats. The finding of many species being present at sites with and without vent fluid emissions points to a non endemic deep-sea hydrothermal vent meiofaunal community. This is in contrast to a mostly endemic macrofauna but similar to what is known for meiofauna from shallow-water vents. PMID- 20856897 TI - Who gets prompt access to artemisinin-based combination therapy? A prospective community-based study in children from rural Kilosa, Tanzania. AB - BACKGROUND: Effective and timely case management remains one of the fundamental pillars for control of malaria. Tanzania introduced artemisinin-combination therapy [ACT] for uncomplicated malaria; however, the policy change is challenged by limited availability of ACTs due to high cost. This study aimed to determine factors influencing prompt access to ACTs among febrile children in rural Kilosa, Tanzania. METHODS AND FINDINGS: In a community-based study, 1,235 randomly selected children under five were followed up weekly for six months, in 2008. Using a structured questionnaire, children's caretakers were asked about the child's febrile history in the last seven days, and treatment actions including timing, medicines used and source of care. Caretakers' knowledge about malaria and socioeconomic and demographic data were also obtained. About half of followed up children had at least one episode of fever. Less than half (44.8%) of febrile children were taken to government facilities. Almost one-third (37.6%; 95% CI 33.1-42.1) of febrile children had prompt access to ACT. Care-seeking from a government facility was the overriding factor, increasing the likelihood of prompt access to an ACT 18 times (OR 17.7; 95% CI 10.55-29.54; adjusted OR 16.9; 95% CI 10.06-28.28). Caretakers from the better-off household (3rd-5th quintiles) were more likely to seek care from government facilities (OR 3.66; 95% CI 2.56 5.24; adjusted OR 1.80; 95% CI 1.18-2.76). The majority of antimalarials accessed by the poor were ineffective [86.0%; 295/343], however, they paid more for them (median Tsh 500) compared to the better-offs (median Tsh 0). CONCLUSIONS: Prompt access to ACT among febrile children was unacceptably low, due mainly to limited availability of subsidised ACT at the location where most caretakers sought care. There is urgent need to accelerate implementation of strategies that will ensure availability of ACT at an affordable price in remote rural areas, where the burden of malaria is highest. PMID- 20856899 TI - Examining the "urban advantage" in maternal health care in developing countries. PMID- 20856900 TI - Combined impact of lifestyle-related factors on total and cause-specific mortality among Chinese women: prospective cohort study. AB - BACKGROUND: Although cigarette smoking, excessive alcohol drinking, obesity, and several other well-studied unhealthy lifestyle-related factors each have been linked to the risk of multiple chronic diseases and premature death, little is known about the combined impact on mortality outcomes, in particular among Chinese and other non-Western populations. The objective of this study was to quantify the overall impact of lifestyle-related factors beyond that of active cigarette smoking and alcohol consumption on all-cause and cause-specific mortality in Chinese women. METHODS AND FINDINGS: We used data from the Shanghai Women's Health Study, an ongoing population-based prospective cohort study in China. Participants included 71,243 women aged 40 to 70 years enrolled during 1996-2000 who never smoked or drank alcohol regularly. A healthy lifestyle score was created on the basis of five lifestyle-related factors shown to be independently associated with mortality outcomes (normal weight, lower waist-hip ratio, daily exercise, never exposed to spouse's smoking, higher daily fruit and vegetable intake). The score ranged from zero (least healthy) to five (most healthy) points. During an average follow-up of 9 years, 2,860 deaths occurred, including 775 from cardiovascular disease (CVD) and 1,351 from cancer. Adjusted hazard ratios for mortality decreased progressively with an increasing number of healthy lifestyle factors. Compared to women with a score of zero, hazard ratios (95% confidence intervals) for women with four to five factors were 0.57 (0.44 0.74) for total mortality, 0.29 (0.16-0.54) for CVD mortality, and 0.76 (0.54 1.06) for cancer mortality. The inverse association between the healthy lifestyle score and mortality was seen consistently regardless of chronic disease status at baseline. The population attributable risks for not having 4-5 healthy lifestyle factors were 33% for total deaths, 59% for CVD deaths, and 19% for cancer deaths. CONCLUSIONS: In this first study, to our knowledge, to quantify the combined impact of lifestyle-related factors on mortality outcomes in Chinese women, a healthier lifestyle pattern-including being of normal weight, lower central adiposity, participation in physical activity, nonexposure to spousal smoking, and higher fruit and vegetable intake-was associated with reductions in total and cause-specific mortality among lifetime nonsmoking and nondrinking women, supporting the importance of overall lifestyle modification in disease prevention. Please see later in the article for the Editors' Summary. PMID- 20856901 TI - The Goldilocks model for TCR-too much attraction might not be best for vaccine design. PMID- 20856902 TI - Polymorphic cis- and trans-regulation of human gene expression. AB - Expression levels of human genes vary extensively among individuals. This variation facilitates analyses of expression levels as quantitative phenotypes in genetic studies where the entire genome can be scanned for regulators without prior knowledge of the regulatory mechanisms, thus enabling the identification of unknown regulatory relationships. Here, we carried out such genetic analyses with a large sample size and identified cis- and trans-acting polymorphic regulators for about 1,000 human genes. We validated the cis-acting regulators by demonstrating differential allelic expression with sequencing of transcriptomes (RNA-Seq) and the trans-regulators by gene knockdown, metabolic assays, and chromosome conformation capture analysis. The majority of the regulators act in trans to the target (regulated) genes. Most of these trans-regulators were not known to play a role in gene expression regulation. The identification of these regulators enabled the characterization of polymorphic regulation of human gene expression at a resolution that was unattainable in the past. PMID- 20856903 TI - Attenuated T cell responses to a high-potency ligand in vivo. AB - alphabeta T cell receptor (TCR) recognition of foreign peptides bound to major histocompatibility complex (pMHC) molecules on the surface of antigen presenting cells is a key event in the initiation of adaptive cellular immunity. In vitro, high-affinity binding and/or long-lived interactions between TCRs and pMHC correlate with high-potency T cell activation. However, less is known about the influence of TCR/pMHC interaction parameters on T cell responses in vivo. We studied the influence of TCR/pMHC binding characteristics on in vivo T cell immunity by tracking CD4(+) T cell activation, effector, and memory responses to immunization with peptides exhibiting a range of TCR/pMHC half-lives and in vitro T cell activation potencies. Contrary to predictions from in vitro studies, we found that optimal in vivo T cell responses occur to ligands with intermediate TCR/pMHC half-lives. The diminished in vivo responses we observed to the ligand exhibiting the longest TCR/pMHC half-life were associated with attenuation of intracellular signaling, expansion, and function over a broad range of time points. Our results reveal a level of control over T cell activation in vivo not recapitulated in in vitro assays and highlight the importance of considering in vivo efficacy of TCR ligands as part of vaccine design. PMID- 20856904 TI - Bringing the tiger back from the brink-the six percent solution. PMID- 20856905 TI - Complete structural model of Escherichia coli RNA polymerase from a hybrid approach. AB - The Escherichia coli transcription system is the best characterized from a biochemical and genetic point of view and has served as a model system. Nevertheless, a molecular understanding of the details of E. coli transcription and its regulation, and therefore its full exploitation as a model system, has been hampered by the absence of high-resolution structural information on E. coli RNA polymerase (RNAP). We use a combination of approaches, including high resolution X-ray crystallography, ab initio structural prediction, homology modeling, and single-particle cryo-electron microscopy, to generate complete atomic models of E. coli core RNAP and an E. coli RNAP ternary elongation complex. The detailed and comprehensive structural descriptions can be used to help interpret previous biochemical and genetic data in a new light and provide a structural framework for designing experiments to understand the function of the E. coli lineage-specific insertions and their role in the E. coli transcription program. PMID- 20856906 TI - A mixture of "cheats" and "co-operators" can enable maximal group benefit. AB - Is a group best off if everyone co-operates? Theory often considers this to be so (e.g. the "conspiracy of doves"), this understanding underpinning social and economic policy. We observe, however, that after competition between "cheat" and "co-operator" strains of yeast, population fitness is maximized under co existence. To address whether this might just be a peculiarity of our experimental system or a result with broader applicability, we assemble, benchmark, dissect, and test a systems model. This reveals the conditions necessary to recover the unexpected result. These are 3-fold: (a) that resources are used inefficiently when they are abundant, (b) that the amount of co operation needed cannot be accurately assessed, and (c) the population is structured, such that co-operators receive more of the resource than the cheats. Relaxing any of the assumptions can lead to population fitness being maximized when cheats are absent, which we experimentally demonstrate. These three conditions will often be relevant, and hence in order to understand the trajectory of social interactions, understanding the dynamics of the efficiency of resource utilization and accuracy of information will be necessary. PMID- 20856907 TI - Does it matter who writes medical news stories? PMID- 20856908 TI - The upside of slackers. PMID- 20856910 TI - Depressive and adjustment disorders - some questions about the differential diagnosis: case studies. AB - BACKGROUND: Diagnosis and treatment of mood disorders in youth are still problematic because in this age the clinical presentation is atypical, and the diagnostic tools and the therapies are the same as that used for the adults. Mood disorders are categorically divided into unipolar disorders (major depressive disorder and dysthymic disorder) and bipolar disorder in Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision), but mood symptoms are also comprised in the diagnostic criteria of the adjustment disorder (AD), which occur in many different psychiatric disorders, and may also be found in some physical conditions. The differential diagnosis is not much addressed in the midst of clinical investigation and so remains the major problem in the clinical practice. AIMS: The associations between some variables and the depressive disorder and AD were analyzed to make considerations about differential diagnosis. PATIENTS AND METHODS: We reported a retrospective study of 60 patients affected by depressive disorder and AD. The analysis has evaluated the association between some variables and the single diagnostic categories. We have considered 10 variables, of which 6 are specific to the disorders, and 4 have been considered related problems. RESULTS: The statistical analysis showed significant results for the associations of 3 variables (prevalent symptoms, treatment, and family history) with the single diagnostic categories. CONCLUSION: The discriminate analysis resulted in statistically significant differences between patients with depressive disorders and those with AD on 3 variables, of which 2 are specific to the disorders, and 1 is included in the related problems. The other variables were weakly associated with the single diagnostic categories without any statistically significant differences. The 3 variables that were associated with the single diagnostic categories support the distinct construct validity of the 2 diagnostic categories, but, to date, it is difficult to establish if these variables can be considered diagnostic predictors. On the other hand, the other variables did not support the distinct construct validity of the 2 diagnostic categories, which suggest an overlapping and dimensional concept. The spectrum approach could unify categorical classification that is essential with a dimensional view. Combination of dimensional and categorical principles for classifying mood disorders may help to reduce the problems of underdiagnosis and undertreatment. PMID- 20856909 TI - Analysis of complex patterns of human exposure and immunity to Schistosomiasis mansoni: the influence of age, sex, ethnicity and IgE. AB - BACKGROUND: Numerous factors may influence Schistosoma infection intensity and prevalence within endemic communities, including exposure-related factors such as local environment and behaviour, and factors relating to susceptibility to infection such as immunology and genetics. While animal studies performed in the laboratory can be tightly controlled, human populations are highly heterogeneous, varying according to demographic characteristics, genetic background and exposure to infection. The heterogeneous nature of human water contact behaviour in particular makes it difficult to distinguish between a lack of cercarial exposure and reduced susceptibility to infection as the cause for low levels of infection in the field. METHODS AND PRINCIPAL FINDINGS: In this study we investigate risk factors for Schistosoma mansoni infection in a rural Ugandan fishing community receiving treatment as part of a multi-disciplinary longitudinal reinfection study. More specifically, we examine the influence that age, sex and ethnic background have on susceptibility to reinfection after anti-helminth drug treatment, but use individual estimates of cercarial exposure and multivariable methods in an attempt to remove noise created by environmental and behavioural heterogeneities. We then investigate whether schistosome-specific IgE immune responses could account for any remaining variations in susceptibility to reinfection. Our findings suggest that observed ethnic- and sex-related variations in S. mansoni reinfection were due to variations in cercarial exposure, as opposed to biological differences in susceptibility to infection. Age-related differences in reinfection were not explained by exposure, however, and appeared linked to the balance of IgE and IgG(4) to the tegumental antigen SmTAL1 (formerly Sm22.6), which itself was significantly related to resistance to reinfection. CONCLUSIONS: This study highlights the benefit of taking a multidisciplinary approach in complex field settings; it allows the ecology of a population to be understood and thus more robust conclusions to be made. PMID- 20856911 TI - Therapeutic interventions and adjustments in the management of Parkinson disease: role of combined carbidopa/levodopa/entacapone (Stalevo). AB - Parkinson disease (PD) is a neurodegenerative disorder characterized by 3 cardinal motor symptoms: resting tremor, rigidity, and bradykinesia. Since its introduction 40 years ago, levodopa has represented the gold standard for dopaminergic stimulation therapy in patients with PD. Levodopa is routinely combined with a dopa-decarboxylase inhibitor (DDCI) to prevent the conversion of levodopa into dopamine in peripheral circulation. However, up to 80% of patients treated with continuous levodopa manifest the onset of disabling motor complications capable of producing an adverse effect on quality of life as the disease progresses. In recent years, a new, safe, and efficacious armamentarium of treatment options has been provided by the marketing of the catechol-O methyltransferase (COMT) inhibitor, entacapone, a peripheral blocker of dopa to 3 0-methyldopa metabolism, which increments levodopa brain availability. When administered with levodopa, entacapone conjugates the rapid onset of levodopa induced effects with a protracted efficiency, thus providing additional benefits to classic levodopa treatment by increasing "on" time in fluctuating PD patients, and theoretically providing a more continuous and physiological-like stimulation of dopamine receptors implying a reduced risk of motor complications. In this context, the use of a single administration of combined carbidopa/ levodopa/entacapone (Stalevo((r))) in the treatment of PD affords clinical improvements similar to those obtained by 2 separate tablets (ie, levodopa/DDCI and entacapone), although the former produces a more positive effect on quality of life than the latter. Additionally, the STalevo Reduction In Dyskinesia Evaluation (STRIDE-PD) study was designed with the aim of demonstrating that the combination of levodopa, carbidopa, and entacapone, used as initial levodopa therapy, significantly delays the onset of dyskinesias compared with the conventional levodopa/carbidopa formulation. Unfortunately, STRIDEPD failed to prove the benefit of continuous dopaminergic stimulation with triple therapy in a clinical setting. Recently, the effect of combined COMT inhibitor with levodopa administration in reducing homocysteine synthesis has been described. To this regard, clear evidence has been presented indicating homocysteine as a risk factor for vascular diseases, cognitive impairment, and dementia. Several studies have discussed the potential of entacapone as adjunct to levodopa/ DDCI in reducing plasma homocysteine levels with contrasting results. PMID- 20856913 TI - Effects of quetiapine on sleep architecture in patients with unipolar or bipolar depression. AB - OBJECTIVE: To determine the effect of adjunctive quetiapine therapy on the sleep architecture of patients with bipolar or unipolar depression. METHODS: This is a prospective, single-blind, repeated measures polysomnographic study. Sleep architecture was analyzed by overnight polysomnography, and subjective sleep quality was measured using the Pittsburgh Sleep Quality Index. The Hamilton Rating Scale for Depression, Montgomery Asberg Depression Rating Scale, Young Mania Rating Scale, and Clinical Global Impression-Severity Scale were employed to quantify changes in illness severity with adjunctive quetiapine treatment. Polysomnographs and clinical measures were administered at baseline, after 2-4 days of treatment, and after 21-28 days of quetiapine treatment. The average dose of quetiapine was 155 mg, ranging from 100-200 mg. RESULTS: Adjunctive quetiapine therapy did not significantly alter sleep efficiency, sleep continuity, or Pittsburgh Sleep Quality Index scores. Respiratory Disturbance Index and percentage of total time in rapid eye movement (REM) sleep significantly decreased and the percentage of total time in non-REM sleep, and duration of Stage 2 and non-REM sleep significantly increased after 2-4 days of quetiapine treatment. Illness severity significantly decreased over time. CONCLUSIONS: Adjunctive quetiapine treatment alters sleep architecture in patients with major depressive disorder or bipolar disorder, which may partially explain its early antidepressant properties. Changes in sleep architecture are more robust and significant within two to four days of starting treatment. PMID- 20856912 TI - Current and emerging treatment options in the management of Friedreich ataxia. AB - Friedreich ataxia (FRDA) is the most common autosomal recessive ataxia. Oxidative damage within the mitochondria seems to have a key role in the disease phenotype. Therefore, FRDA treatment options have been mostly directed at antioxidant protection against mitochondrial damage. Available evidence seems to suggest that patients with FRDA should be treated with idebenone, because it is well tolerated and may reduce cardiac hypertrophy and, at higher doses, also improve neurological function, but large controlled clinical trials are still needed. Alternatively, gene-based strategies for the treatment of FRDA may involve the development of small-molecules increasing frataxin gene transcription. Animal and human studies are strongly needed to assess whether any of the potential new treatment strategies, such as iron-chelating therapies or treatment with erythropoietin or histone deacetylase inhibitors and other gene-based strategies, may translate into an effective therapy for this devastating disorder. In this review, we try to provide an answer to some questions related to current and emerging treatment options in the management of FRDA. PMID- 20856914 TI - Distinguishing between attention-deficit hyperactivity and fetal alcohol spectrum disorders in children: clinical guidelines. AB - Fetal alcohol spectrum disorders (FASD) are the physical and neurodevelopmental outcomes of fetal alcohol exposure. The behavioral phenotype of children with FASD includes difficulties with executive function, memory, planning, processing speed, and attention. Although attention deficit hyperactivity disorder (ADHD) is diagnosed in up to 94% of individuals with heavy prenatal alcohol exposure, the exact relationship between FASD and ADHD is unclear. There is some evidence that ADHD in FASD may be a specific clinical subtype and thus may require a different treatment approach. Although traditional behavioral observation scales may not distinguish between the two groups, there is evidence that children with FASD have a different profile on the four-factor model of attention than children with ADHD who do not have FASD. There is a paucity of good scientific evidence on effective interventions for individuals with ADHD and FASD. There is weak evidence that children with FASD and ADHD may have a better response to dexamphetamine than methylphenidate. There is a strong need for larger, high quality studies to examine the relationship between ADHD and FASD and identify effective treatments because management of inattention and hyperactivity may improve learning and ameliorate the common secondary disabilities associated with FASD. PMID- 20856916 TI - Polyclonal light chains in cerebrovascular disease. AB - Altered membrane permeability is a hallmark of inflammation and ischemia with systemic spreading. Renal dysfunction is a risk factor for cardiovascular, cerebrovascular, and metabolic diseases. The aim of the present study was to assess proteinuria and urinary polyclonal light chains in acute stroke and chronic cerebrovascular disease compared with other neurologic diseases. Our results showed significantly increased levels of urinary polyclonal light chains in cerebrovascular disease compared with other neurologic diseases. The highest values of urinary polyclonal kappa chains were found in acute stroke compared with chronic cerebrovascular disease and other neurologic diseases, while the level of lambda chains was mainly increased in chronic cerebrovascular diseases. The shift to chronic renal failure seems to be signaled by a decreased polyclonal light chain/creatinemia ratio. The absence of a significant correlation with blood pressure and other seric parameters suggests that polyclonal light chains are an early marker of reversible vascular impairment with renal dysfunction before progression to irreversible renal failure and need for dialysis and/or intensive care. PMID- 20856915 TI - Tailoring therapeutic strategies for treating posttraumatic stress disorder symptom clusters. AB - According to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, posttraumatic stress disorder (PTSD) is characterized by three major symptom clusters following an event that elicited fear, helplessness, or horror. This review will examine each symptom cluster of PTSD separately, giving case study examples of patients who exhibit a preponderance of a given symptom domain. We use a translational approach in describing the underlying neurobiology that is relevant to particular symptoms and treatment options, thus showing how clinical practice can benefit from current research. By focusing on symptom clusters, we provide a more specific view of individual patient's clinical presentations, in order to better address treatment needs. Finally, the review will also address potential genetic approaches to treatment as another form of individualized treatment. PMID- 20856917 TI - Management of depression in elderly stroke patients. AB - Poststroke depression (PSD) in elderly patients has been considered the most common neuropsychiatric consequence of stroke up to 6-24 months after stroke onset. When depression appears within days after stroke onset, it is likely to remit, whereas depression at 3 months is likely to be sustained for 1 year. One of the major problems posed by elderly stroke patients is how to identify and optimally manage PSD. This review provides insight to identification and management of depression in elderly stroke patients. Depression following stroke is less likely to include dysphoria and more likely characterized by vegetative signs and symptoms compared with other forms of late-life depression, and clinicians should rely more on nonsomatic symptoms rather than somatic symptoms. Evaluation and diagnosis of depression among elderly stroke patients are more complex due to vague symptoms of depression, overlapping signs and symptoms of stroke and depression, lack of properly trained health care personnel, and insufficient assessment tools for proper diagnosis. Major goals of treatment are to reduce depressive symptoms, improve mood and quality of life, and reduce the risk of medical complications including relapse. Antidepressants (ADs) are generally not indicated in mild forms because the balance of benefit and risk is not satisfactory in elderly stroke patients. Selective serotonin reuptake inhibitors are the first choice of PSD treatment in elderly patients due to their lower potential for drug interaction and side effects, which are more common with tricyclic ADs. Recently, stimulant medications have emerged as promising new therapeutic interventions for PSD and are now the subject of rigorous clinical trials. Cognitive behavioral therapy can also be useful, and electroconvulsive therapy is available for patients with severe refractory PSD. PMID- 20856918 TI - Fitting the pieces together: current research on the genetic basis of attention deficit/hyperactivity disorder (ADHD). AB - Attention-deficit/hyperactivity disorder (ADHD) is a highly disruptive childhood onset disorder that often persists into adolescence and adulthood. Comorbidity with other problems, such as autism, dyslexia and conduct disorder (CD) is very common. Although little is known about the pathophysiology of ADHD, family, twin and adoption studies have shown that it is highly heritable. Whole genome linkage studies suggest there are no common susceptibility genes of moderate effect size. Most published research has been based on functional candidate gene studies. The most consistent evidence for association with ADHD relates to a dopamine D4 receptor (DRD4) gene variable number tandem repeat (VNTR), a dopamine D5 receptor (DRD5) gene microsatellite and a dopamine transporter (DAT1) gene VNTR. In addition, the catechol-O-methyltransferase (COMT) val158/108 met variant has been shown to increase risk for associated antisocial behavior. The first genome-wide association studies (GWAS) of ADHD have been completed and although larger studies are still required to detect common risk variants, novel risk pathways are being suggested for ADHD. Further research on the contribution of rare variants, larger genome-wide association and sequencing studies and ADHD phenotype refinement is now needed. PMID- 20856919 TI - Once-monthly paliperidone injection for the treatment of schizophrenia. AB - Paliperidone palmitate is a new long-acting antipsychotic injection for the treatment of acute and maintenance therapy in schizophrenia. Paliperidone (9 hydroxyrisperidone) is the major active metabolite of risperidone and acts at dopamine D(2) and serotonin 5HT(2A) receptors. As with other atypical antipsychotics, it exhibits a high 5HT(2A):D(2) affinity ratio. It also has binding activity as an antagonist at alpha(1)-and alpha(2) adrenergic receptors and H(1) histaminergic receptors, but has virtually no affinity for cholinergic receptors. Paliperidone palmitate has been shown to be effective in reducing Positive and Negative Syndrome Scale total scores in four short-term trials in acute schizophrenia. It was also effective as maintenance therapy in a long-term trial in which time to recurrence of symptoms was significantly longer in paliperidone-treated patients compared with placebo. In addition, paliperidone was shown to be noninferior to risperidone long-acting injection in one study, but this noninferiority was not established in another longer study comparing the two drugs. Treatment should be initiated with 234 mg on day 1 and 156 mg on day 8, followed by a recommended monthly maintenance dose of 39-234 mg based on efficacy and tolerability. Paliperidone palmitate is generally well tolerated, although it can cause weight gain and a rise in prolactin levels, which is generally greater in women than in men. Overall, paliperidone palmitate may have advantages over other currently available long-acting injections, and therefore may be a useful alternative for the treatment of schizophrenia, although further long-term trials comparing it with active treatments are warranted. PMID- 20856920 TI - Profile of olanzapine long-acting injection for the maintenance treatment of adult patients with schizophrenia. AB - Olanzapine long-acting injection (OLAI) is a crystalline salt composed of olanzapine and pamoic acid, which permits a depot intramuscular formulation of olanzapine. The half-life of olanzapine pamoate is 30 days, and its steady state is reached approximately at 12 weeks. Oral supplementation of olanzapine is not required during OLAI initiation, according to Eli Lilly recommendations, although a study indicated that >=60% of D(2) receptor occupancy was reached only by the fifth injection cycle. To date, a short-term, placebo-controlled study of 8 weeks in acutely ill patients and a long-term, controlled trial of 24 weeks in stabilized patients have been conducted. In both the studies, efficacy and safety were similar to those of oral olanzapine, with the exception of an acute adverse effect, the so-called inadvertent intravascular injection event, which occurred 1 3 hours after the injection with an incidence rate of 0.07% per injection. It consisted of symptoms that are similar to those reported in cases of oral olanzapine overdose. The most significant studies published to date, on the use of olanzapine pamoate in schizophrenia, are reviewed in this article. The pharmacodynamic and pharmacokinetic profile and related side effects of OLAI are reported. PMID- 20856921 TI - Brief assessment of negative dysmorphic signs. AB - Body dysmorphic disorder is a body image dysperception, characterized either by an excessive preoccupation with a presumed or minimal flaw in appearance, or by unrecognition, denial, or even neglect regarding an obvious defect. These features are evaluated by a novel questionnaire, the Brief Assessment of Negative Dysmorphic Signs (BANDS). Moreover, the temperament and character background is examined. The relationship with addictive mentality/behavior and schizoaffectivity is also highlighted. Lastly, the potential shift toward cognitive impairment and dementia is considered. PMID- 20856922 TI - Not all partial dopamine D(2) receptor agonists are the same in treating schizophrenia. Exploring the effects of bifeprunox and aripiprazole using a computer model of a primate striatal dopaminergic synapse. AB - Species differences in physiology and unique active human metabolites contribute to the limited predictive value of preclinical rodent models for many central nervous system (CNS) drugs. In order to explore possible drivers for this translational disconnect, we developed a computer model of a dopaminergic synapse that simulates the competition among three agents and their binding to pre- and postsynaptic receptors, based on the affinities for their targets and their actual concentrations. The model includes presynaptic autoreceptor effects on neurotransmitter release and modulation by presynaptic firing frequency and is calibrated with actual experimental data on free dopamine levels in the striatum of the rodent and the primate. Using this model, we simulated the postsynaptic dopamine D(2) receptor activation levels of bifeprunox and aripiprazole, two relatively similar dopamine D(2) receptor agonists. The results indicate a substantial difference in dose-response for the two compounds when applying primate calibration parameters as opposed to rodent calibration parameters. In addition, when introducing the major human and rodent metabolites of aripiprazole with their specific pharmacological activities, the model predicts that while bifeprunox would result in a higher postsynaptic D(2) receptor antagonism in the rodent, aripiprazole would result in a higher D(2) receptor antagonism in the primate model. Furthermore, only the highest dose of aripiprazole, but not bifeprunox, reaches postsynaptic functional D(2) receptor antagonism similar to 4 mg haloperidol in the primate model. The model further identifies a limited optimal window of functionality for dopamine D(2) receptor partial agonists. These results suggest that computer modeling of key CNS processes, using well validated calibration paradigms, can increase the predictive value in the clinical setting of preclinical animal model outcomes. PMID- 20856923 TI - Brain amyloid beta protein and memory disruption in Alzheimer's disease. AB - The development of amyloid-containing neuritic plaques is an invariable characteristic of Alzheimer's diseases (AD). The conversion from monomeric amyloid beta protein (Abeta) to oligomeric Abeta and finally neuritic plaques is highly dynamic. The specific Abeta species that is correlated with disease severity remains to be discovered. Oligomeric Abeta has been detected in cultured cells, rodent and human brains, as well as human cerebrospinal fluid. Synthetic, cell, and brain derived Abeta oligomers have been found to inhibit hippocampal long-term potentiation (LTP) and this effect can be suppressed by the blockage of Abeta oligomer formation. A large body of evidence suggests that Abeta oligomers inhibit N-methyl-D-aspartate receptor dependent LTP; additional receptors have also been found to elicit downstream pathways upon binding to Abeta oligomers. Amyloid antibodies and small molecular compounds that reduce brain Abeta levels and block Abeta oligomer formation are capable of reversing synaptic dysfunction and these approaches hold a promising therapeutic potential to rescue memory disruption. PMID- 20856924 TI - Epigenetic drugs can stimulate metastasis through enhanced expression of the pro metastatic Ezrin gene. AB - Ezrin has been reported to be upregulated in many tumors and to participate in metastatic progression. No study has addressed epigenetic modification in the regulation of Ezrin gene expression, the importance of which is unknown. Here, we report that highly metastatic rhabdomyosarcoma (RMS) cells with high levels of Ezrin have elevated acetyl-H3-K9 and tri-methyl-H3-K4 as well as reduced DNA methylation at the Ezrin gene promoter. Conversely, poorly metastatic RMS cells with low levels of Ezrin have reduced acetyl-H3-K9 and elevated methylation. Thus epigenetic covalent modifications to histones within nucleosomes of the Ezrin gene promoter are linked to Ezrin expression, which in fact can be regulated by epigenetic mechanisms. Notably, treatment with histone deacetylase (HDAC) inhibitors or DNA demethylating agents could restore Ezrin expression and stimulate the metastatic potential of poorly metastatic RMS cells characterized by low Ezrin levels. However, the ability of epigenetic drugs to stimulate metastasis in RMS cells was inhibited by expression of an Ezrin-specific shRNA. Our data demonstrate the potential risk associated with clinical application of broadly acting covalent epigenetic modifiers, and highlight the value of combination therapies that include agents specifically targeting potent pro metastatic genes. PMID- 20856925 TI - Evidence of transfer by conjugation of type IV secretion system genes between Bartonella species and Rhizobium radiobacter in amoeba. AB - BACKGROUND: Bartonella species cospeciate with mammals and live within erythrocytes. Even in these specific niches, it has been recently suggested by bioinformatic analysis of full genome sequences that Lateral Gene Transfer (LGT) may occur but this has never been demonstrated biologically. Here we describe the sequence of the B. rattaustraliani (AUST/NH4(T)) circular plasmid (pNH4) that encodes the tra cluster of the Type IV secretion system (T4SS) and we eventually provide evidence that Bartonella species may conjugate and exchange this plasmid inside amoeba. PRINCIPAL FINDINGS: The T4SS of pNH4 is critical for intracellular viability of bacterial pathogens, exhibits bioinformatic evidence of LGT among bacteria living in phagocytic protists. For instance, 3 out of 4 T4SS encoding genes from pNH4 appear to be closely related to Rhizobiales, suggesting that gene exchange occurs between intracellular bacteria from mammals (bartonellae) and plants (Rhizobiales). We show that B. rattaustraliani and Rhizobium radiobacter both survived within the amoeba Acanthamoeba polyphaga and can conjugate together. Our findings further support the hypothesis that tra genes might also move into and out of bacterial communities by conjugation, which might be the primary means of genomic evolution for intracellular adaptation by cross-talk of interchangeable genes between Bartonella species and plant pathogens. CONCLUSIONS: Based on this, we speculate that amoeba favor the transfer of genes as phagocytic protists, which allows for intraphagocytic survival and, as a consequence, promotes the creation of potential pathogenic organisms. PMID- 20856926 TI - CXCL10 can inhibit endothelial cell proliferation independently of CXCR3. AB - CXCL10 (or Interferon-inducible protein of 10 kDa, IP-10) is an interferon inducible chemokine with potent chemotactic activity on activated effector T cells and other leukocytes expressing its high affinity G protein-coupled receptor CXCR3. CXCL10 is also active on other cell types, including endothelial cells and fibroblasts. The mechanisms through which CXCL10 mediates its effects on non-leukocytes is not fully understood. In this study, we focus on the anti proliferative effect of CXCL10 on endothelial cells, and demonstrate that CXCL10 can inhibit endothelial cell proliferation in vitro independently of CXCR3. Four main findings support this conclusion. First, primary mouse endothelial cells isolated from CXCR3-deficient mice were inhibited by CXCL10 as efficiently as wildtype endothelial cells. We also note that the proposed alternative splice form CXCR3-B, which is thought to mediate CXCL10's angiostatic activity, does not exist in mice based on published mouse CXCR3 genomic sequences as an in-frame stop codon would terminate the proposed CXCR3-B splice variant in mice. Second, we demonstrate that human umbilical vein endothelial cells and human lung microvascular endothelial cells that were inhibited by CXL10 did not express CXCR3 by FACS analysis. Third, two different neutralizing CXCR3 antibodies did not inhibit the anti-proliferative effect of CXCL10. Finally, fourth, utilizing a panel of CXCL10 mutants, we show that the ability to inhibit endothelial cell proliferation correlates with CXCL10's glycosaminoglycan binding affinity and not with its CXCR3 binding and signaling. Thus, using a very defined system, we show that CXCL10 can inhibit endothelial cell proliferation through a CXCR3 independent mechanism. PMID- 20856927 TI - Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia. AB - BACKGROUND: Inflammation has been proposed to be important in the pathogenesis of diabetic retinopathy. An early feature of inflammation is the release of cytokines leading to increased expression of endothelial activation markers such as vascular cellular adhesion molecule-1 (VCAM-1). Here we investigated the impact of diabetes and dyslipidemia on VCAM-1 expression in mouse retinal vessels, as well as the potential role of tumor necrosis factor-alpha (TNFalpha). METHODOLOGY/PRINCIPAL FINDINGS: Expression of VCAM-1 was examined by confocal immunofluorescence microscopy in vessels of wild type (wt), hyperlipidemic (ApoE( /-)) and TNFalpha deficient (TNFalpha(-/-), ApoE(-/-)/TNFalpha(-/-)) mice. Eight weeks of streptozotocin-induced diabetes resulted in increased VCAM-1 in wt mice, predominantly in small vessels (<10 um). Diabetic wt mice had higher total retinal TNFalpha, IL-6 and IL-1beta mRNA than controls; as well as higher soluble VCAM-1 (sVCAM-1) in plasma. Lack of TNFalpha increased higher basal VCAM-1 protein and sVCAM-1, but failed to up-regulate IL-6 and IL-1beta mRNA and VCAM-1 protein in response to diabetes. Basal VCAM-1 expression was higher in ApoE(-/-) than in wt mice and both VCAM-1 mRNA and protein levels were further increased by high fat diet. These changes correlated to plasma cholesterol, LDL- and HDL cholesterol, but not to triglycerides levels. Diabetes, despite further increasing plasma cholesterol in ApoE(-/-) mice, had no effects on VCAM-1 protein expression or on sVCAM-1. However, it increased ICAM-1 mRNA expression in retinal vessels, which correlated to plasma triglycerides. CONCLUSIONS/SIGNIFICANCE: Hyperglycemia triggers an inflammatory response in the retina of normolipidemic mice and up-regulation of VCAM-1 in retinal vessels. Hypercholesterolemia effectively promotes VCAM-1 expression without evident stimulation of inflammation. Diabetes-induced endothelial activation in ApoE(-/-) mice seems driven by elevated plasma triglycerides but not by cholesterol. Results also suggest a complex role for TNFalpha in the regulation of VCAM-1 expression, being protective under basal conditions but pro-inflammatory in response to diabetes. PMID- 20856928 TI - Microparticles carrying Sonic hedgehog favor neovascularization through the activation of nitric oxide pathway in mice. AB - BACKGROUND: Microparticles (MPs) are vesicles released from plasma membrane upon cell activation and during apoptosis. Human T lymphocytes undergoing activation and apoptosis generate MPs bearing morphogen Shh (MPs(Shh+)) that are able to regulate in vitro angiogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here, we investigated the ability of MPs(Shh+) to modulate neovascularization in a model of mouse hind limb ischemia. Mice were treated in vivo for 21 days with vehicle, MPs(Shh+), MPs(Shh+) plus cyclopamine or cyclopamine alone, an inhibitor of Shh signalling. Laser doppler analysis revealed that the recovery of the blood flow was 1.4 fold higher in MPs(Shh+)-treated mice than in controls, and this was associated with an activation of Shh pathway in muscles and an increase in NO production in both aorta and muscles. MPs(Shh+)-mediated effects on flow recovery and NO production were completely prevented when Shh signalling was inhibited by cyclopamine. In aorta, MPs(Shh+) increased activation of eNOS/Akt pathway, and VEGF expression, being inhibited by cyclopamine. By contrast, in muscles, MPs(Shh+) enhanced eNOS expression and phosphorylation and decreased caveolin-1 expression, but cyclopamine prevented only the effects of MPs(Shh+) on eNOS pathway. Quantitative RT-PCR revealed that MPs(Shh+) treatment increased FGF5, FGF2, VEGF A and C mRNA levels and decreased those of alpha5-integrin, FLT-4, HGF, IGF-1, KDR, MCP-1, MT1-MMP, MMP-2, TGFbeta1, TGFbeta2, TSP-1 and VCAM-1, in ischemic muscles. CONCLUSIONS/SIGNIFICANCE: These findings suggest that MPs(Shh+) may contribute to reparative neovascularization after ischemic injury by regulating NO pathway and genes involved in angiogenesis. PMID- 20856929 TI - In vivo structure of the E. coli FtsZ-ring revealed by photoactivated localization microscopy (PALM). AB - The FtsZ protein, a tubulin-like GTPase, plays a pivotal role in prokaryotic cell division. In vivo it localizes to the midcell and assembles into a ring-like structure-the Z-ring. The Z-ring serves as an essential scaffold to recruit all other division proteins and generates contractile force for cytokinesis, but its supramolecular structure remains unknown. Electron microscopy (EM) has been unsuccessful in detecting the Z-ring due to the dense cytoplasm of bacterial cells, and conventional fluorescence light microscopy (FLM) has only provided images with limited spatial resolution (200-300 nm) due to the diffraction of light. Hence, given the small sizes of bacteria cells, identifying the in vivo structure of the Z-ring presents a substantial challenge. Here, we used photoactivated localization microscopy (PALM), a single molecule-based super resolution imaging technique, to characterize the in vivo structure of the Z-ring in E. coli. We achieved a spatial resolution of ~35 nm and discovered that in addition to the expected ring-like conformation, the Z-ring of E. coli adopts a novel compressed helical conformation with variable helical length and pitch. We measured the thickness of the Z-ring to be ~110 nm and the packing density of FtsZ molecules inside the Z-ring to be greater than what is expected for a single layered flat ribbon configuration. Our results strongly suggest that the Z-ring is composed of a loose bundle of FtsZ protofilaments that randomly overlap with each other in both longitudinal and radial directions of the cell. Our results provide significant insight into the spatial organization of the Z-ring and open the door for further investigations of structure-function relationships and cell cycle-dependent regulation of the Z-ring. PMID- 20856930 TI - Triage of women with minor cervical lesions: data suggesting a "test and treat" approach for HPV E6/E7 mRNA testing. AB - BACKGROUND: Human papillomavirus (HPV) testing is included in the cervical cancer screening program in the triage of women with equivocal (ASC-US) or low-grade (LSIL) cytological lesions. These women have an increased risk for developing high grade dysplasia and cancer (CIN2+) compared to women with normal cytology. However, in order to avoid unnecessary follow-up, as well as overtreatment, a high positive predictive value (PPV) of the triage test is important. METHODOLOGY/PRINCIPAL FINDINGS: The HPV test PreTect HPV-Proofer, detecting E6/E7 mRNA from the HPV types 16, 18, 31, 33 and 45, is used as triage test together with repeat cytology. PPV data for HPV E6/E7 mRNA testing during the period from January 2006 up to June 2009 are reported. In total, 406 of 2099 women (19.3%) had a positive HPV test result. Of the women with a positive test result and with a histological diagnosis (n = 347), 243 women had histological high-grade dysplasia or cancer (CIN2+), giving a PPV of 70.0% (95% confidence interval [CI], 65.2%-74.8%). For HPV 16 or HPV 33 positive women above 40 years of age, the PPV was 83.7% (95% CI, 73.3%-94.0%) and 84.6% (95% CI, 65.0%-100.0%) respectively. The PPV of test positive women with HSIL cytology was 94.2% (95% CI, 88.7% 99.7%). CONCLUSIONS: When the result in triage is HPV mRNA positive, our data suggest direct treatment for women above 40 years of age or for women with a concurrent cytological HSIL diagnosis, contributing to better clinical safety for these women. In addition, by decreasing the time to treatment, thereby reducing the number of recalls, the patient management algorithm will be considerably improved, in turn reducing follow-up costs as well as unnecessary psychological stress among patients. PMID- 20856932 TI - Lethality and developmental delay in Drosophila melanogaster larvae after ingestion of selected Pseudomonas fluorescens strains. AB - BACKGROUND: The fruit fly, Drosophila melanogaster, is a well-established model organism for probing the molecular and cellular basis of physiological and immune system responses of adults or late stage larvae to bacterial challenge. However, very little is known about the consequences of bacterial infections that occur in earlier stages of development. We have infected mid-second instar larvae with strains of Pseudomonas fluorescens to determine how infection alters the ability of larvae to survive and complete development. METHODOLOGY/PRINCIPAL FINDINGS: We mimicked natural routes of infection using a non-invasive feeding procedure to study the toxicity of the three sequenced P. fluorescens strains (Pf0-1, SBW25, and Pf-5) to Drosophila melanogaster. Larvae fed with the three strains of P. fluorescens showed distinct differences in developmental trajectory and survival. Treatment with SBW25 caused a subset of insects to die concomitant with a systemic melanization reaction at larval, pupal or adult stages. Larvae fed with Pf-5 died in a dose-dependent manner with adult survivors showing eye and wing morphological defects. In addition, larvae in the Pf-5 treatment groups showed a dose-dependent delay in the onset of metamorphosis relative to control-, Pf0-1-, and SBW25-treated larvae. A functional gacA gene is required for the toxic properties of wild-type Pf-5 bacteria. CONCLUSIONS/SIGNIFICANCE: These experiments are the first to demonstrate that ingestion of P. fluorescens bacteria by D. melanogaster larvae causes both lethal and non-lethal phenotypes, including delay in the onset of metamorphosis and morphological defects in surviving adult flies, which can be decoupled. PMID- 20856931 TI - Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. AB - BACKGROUND: We hypothesized that chronic inhibition of epidermal growth factor receptor (EGFR) by cetuximab, a monoclonal anti-EGFR antibody, induces up regulation of its ligands resulting in resistance and that microRNAs (miRs) play an important role in the ligand regulation in head and neck squamous cell carcinoma (HNSCC). METHODOLOGY/PRINCIPAL FINDINGS: Genome-wide changes in gene and miR expression were determined in cetuximab-sensitive cell line, SCC1, and its resistant derivative 1Cc8 using DNA microarrays and RT-PCR. The effects of differentially expressed EGFR ligands and miRs were examined by MTS, colony formation, ELISA, and western blot assays. Heparin-binding EGF-like growth factor (HB-EGF) and its regulator, miR-212, were differentially expressed with statistical significance when SCC1 and 1Cc8 were compared for gene and miR expression. Stimulation with HB-EGF induced cetuximab resistance in sensitive cell lines. Inhibition of HB-EGF and the addition of miR-212 mimic induced cetuximab sensitivity in resistant cell lines. MicroRNA-212 and HB-EGF expression were inversely correlated in an additional 33 HNSCC and keratinocyte cell lines. Six tumors and 46 plasma samples from HNSCC patients were examined for HB-EGF levels. HB-EGF plasma levels were lower in newly diagnosed HNSCC patients when compared to patients with recurrent disease. CONCLUSIONS/SIGNIFICANCE: Increased expression of HB-EGF due to down-regulation of miR-212 is a possible mechanism of cetuximab resistance. The combination of EGFR ligand inhibitors or miR modulators with cetuximab may improve the clinical outcome of cetuximab therapy in HNSCC. PMID- 20856933 TI - Correlation between male social status, testosterone levels, and parasitism in a dimorphic polygynous mammal. AB - Life history trade-offs have often been assumed to be the consequence of restrictions in the availability of critical resources such as energy and nutrients, which necessitate the differential allocation of resources to costly traits. Here, we examined endocrine (testosterone) and health (parasite burdens) parameters in territorial and non-territorial New Zealand fur seal males. We documented intra-sexual differences in sexual behaviours, testosterone levels, and parasitism that suggest a trade-off exists between reproductive success and physical health, particularly susceptibility to helminths and acanthocephalans, in males displaying different mating tactics (i.e., territorial and non territorial tactics). Levels of testosterone were higher in territorial males and correlated positively with reproductive effort (i.e., intra- and inter-sexual interactions). However, these territorial males also exhibited high levels of parasitic infection, which may impair survival in the long-term. Our study, while limited in sample size, provides preliminary evidence for a link between male mating tactics, testosterone levels and parasite loads, and potential effects on reproductive success and life history that should be explored further. PMID- 20856935 TI - Demographic and clinical features of dengue fever in Pakistan from 2003-2007: a retrospective cross-sectional study. AB - BACKGROUND: Demographic features of dengue fever have changed tremendously in Pakistan over the past two decades. Small scale studies from all over the country have reported different aspects of individual outbreaks during this time. However, there is scarcity of data looking at the overall trend of dengue virus infection in the country. In this study, we examined annual trends, seasonality, and clinical features of dengue fever in the Pakistani population. METHODS: Demographic information and dengue IgM status of all patients tested for dengue IgM antibody at Aga Khan University Hospital from January 2003 to December 2007 were analyzed to look for trends of IgM-positive cases in Pakistan. In addition, clinical and biochemical parameters were abstracted retrospectively from medical records of all patients hospitalized with IgM-proven dengue fever between January 2006 and December 2007. These patients were categorized into dengue fever and dengue hemorrhagic fever according to the WHO severity grading scale. RESULTS: Out of a total of 15,040 patients (63.2% male and 36.8% female), 3952 (26.3%) tested positive for dengue IgM antibody. 209 IgM proven dengue patients were hospitalized during the study period. During 2003, IgM positive cases were seen only during the months of July-December. In contrast, such cases were detected throughout the year from the 2004-2007. The median age of IgM positive patients decreased every year from 32.0 years in 2003 to 24.0 years in 2007 (p<0.001). Among hospitalized patients, nausea was the most common presenting feature found in 124/209 (59.3%) patients. Children presented with a higher median body temperature than adults (p = 0.010). In addition, neutropenia was seen more commonly in children while raised serum ALT levels were seen more commonly in adults (both p = 0.006). While a low total white cell count was more common in patients with dengue fever as compared to Dengue Hemorrhagic Fever (p = 0.020), neutropenia (p = 0.019), monocytosis (p = 0.001) and raised serum ALT level (p = 0.005) were observed more commonly in the latter group. CONCLUSIONS: Dengue virus is now endemic in Pakistan, circulating throughout the year with a peak incidence in the post monsoon period. Median age of dengue patients has decreased and younger patients may be more susceptible. Total and differential leukocyte counts may help identify patients at risk of hemorrhage. PMID- 20856934 TI - Wnt isoform-specific interactions with coreceptor specify inhibition or potentiation of signaling by LRP6 antibodies. AB - beta-Catenin-dependent Wnt signaling is initiated as Wnt binds to both the receptor FZD and coreceptor LRP5/6, which then assembles a multimeric complex at the cytoplasmic membrane face to recruit and inactivate the kinase GSK3. The large number and sequence diversity of Wnt isoforms suggest the possibility of domain-specific ligand-coreceptor interactions, and distinct binding sites on LRP6 for Wnt3a and Wnt9b have recently been identified in vitro. Whether mechanistically different interactions between Wnts and coreceptors might mediate signaling remains to be determined. It is also not clear whether coreceptor homodimerization induced extracellularly can activate Wnt signaling, as is the case for receptor tyrosine kinases. We generated monoclonal antibodies against LRP6 with the unexpected ability to inhibit signaling by some Wnt isoforms and potentiate signaling by other isoforms. In cell culture, two antibodies characterized further show reciprocal activities on most Wnts, with one antibody antagonizing and the other potentiating. We demonstrate that these antibodies bind to different regions of LRP6 protein, and inhibition of signaling results from blocking Wnt binding. Antibody-mediated dimerization of LRP6 can potentiate signaling only when a Wnt isoform is also able to bind the complex, presumably recruiting FZD. Endogenous autocrine Wnt signaling in different tumor cell lines can be either antagonized or enhanced by the LRP6 antibodies, indicating expression of different Wnt isoforms. As anticipated from the roles of Wnt signaling in cancer and bone development, antibody activities can also be observed in mice for inhibition of tumor growth and in organ culture for enhancement of bone mineral density. Collectively, our results indicate that separate binding sites for different subsets of Wnt isoforms determine the inhibition or potentiation of signaling conferred by LRP6 antibodies. This complexity of coreceptor-ligand interactions may allow for differential regulation of signaling by Wnt isoforms during development, and can be exploited with antibodies to differentially manipulate Wnt signaling in specific tissues or disease states. PMID- 20856936 TI - A unified 35-gene signature for both subtype classification and survival prediction in diffuse large B-cell lymphomas. AB - Cancer subtype classification and survival prediction both relate directly to patients' specific treatment plans, making them fundamental medical issues. Although the two factors are interrelated learning problems, most studies tackle each separately. In this paper, expression levels of genes are used for both cancer subtype classification and survival prediction. We considered 350 diffuse large B-cell lymphoma (DLBCL) subjects, taken from four groups of patients (activated B-cell-like subtype dead, activated B-cell-like subtype alive, germinal center B-cell-like subtype dead, and germinal center B-cell-like subtype alive). As classification features, we used 11,271 gene expression levels of each subject. The features were first ranked by mRMR (Maximum Relevance Minimum Redundancy) principle and further selected by IFS (Incremental Feature Selection) procedure. Thirty-five gene signatures were selected after the IFS procedure, and the patients were divided into the above mentioned four groups. These four groups were combined in different ways for subtype prediction and survival prediction, specifically, the activated versus the germinal center and the alive versus the dead. Subtype prediction accuracy of the 35-gene signature was 98.6%. We calculated cumulative survival time of high-risk group and low-risk groups by the Kaplan-Meier method. The log-rank test p-value was 5.98e-08. Our methodology provides a way to study subtype classification and survival prediction simultaneously. Our results suggest that for some diseases, especially cancer, subtype classification may be used to predict survival, and, conversely, survival prediction features may shed light on subtype features. PMID- 20856937 TI - Increase on the initial soluble heme levels in acidic conditions is an important mechanism for spontaneous heme crystallization in vitro. AB - BACKGROUND: Hemozoin (Hz) is a heme crystal that represents a vital pathway for heme disposal in several blood-feeding organisms. Recent evidence demonstrated that beta-hematin (betaH) (the synthetic counterpart of Hz) formation occurs under physiological conditions near synthetic or biological hydrophilic hydrophobic interfaces. This seems to require a heme dimer acting as a precursor of Hz crystals that would be formed spontaneously in the absence of the competing water molecules bound to the heme iron. Here, we aimed to investigate the role of medium polarity on spontaneous betaH formation in vitro. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the effect of water content on spontaneous betaH formation by using the aprotic solvent dimethylsulfoxide (DMSO) and a series of polyethyleneglycols (PEGs). We observed that both DMSO and PEGs (3.350, 6.000, 8.000, and 22.000) increased the levels of soluble heme under acidic conditions. These compounds were able to stimulate the production of betaH crystals in the absence of any biological sample. Interestingly, the effects of DMSO and PEGs on betaH formation were positively correlated with their capacity to promote previous heme solubilization in acidic conditions. Curiously, a short chain polyethyleneglycol (PEG 300) caused a significant reduction in both soluble heme levels and betaH formation. Finally, both heme solubilization and betaH formation strongly correlated with reduced medium water activity provided by increased DMSO concentrations. CONCLUSIONS: The data presented here support the notion that reduction of the water activity is an important mechanism to support spontaneous heme crystallization, which depends on the previous increase of soluble heme levels. PMID- 20856938 TI - Interaction of the TNFR-receptor associated factor TRAF1 with I-kappa B kinase-2 and TRAF2 indicates a regulatory function for NF-kappa B signaling. AB - BACKGROUND: I-kappa B kinase 2 (IKK2 or IKK-beta) is one of the most crucial signaling kinases for activation of NF-kappa B, a transcription factor that is important for inflammation, cell survival and differentiation. Since many NF kappa B activating pathways converge at the level of IKK2, molecular interactions of this kinase are pivotal for regulation of NF-kappa B signaling. METHODOLOGY/PRINCIPAL FINDINGS: We searched for proteins interacting with IKK2 using the C-terminal part (amino acids 466-756) as bait in a yeast two-hybrid system and identified the N-terminal part (amino acids 1-228) of the TNF-receptor associated factor TRAF1 as putative interaction partner. The interaction was confirmed in human cells by mammalian two-hybrid and coimmunoprecipitation experiments. The IKK2/TRAF1 interaction seemed weaker than the interaction between TRAF1 and TRAF2, an important activating adapter molecule of NF-kappa B signaling. Reporter gene and kinase assays using ectopic expression of TRAF1 indicated that it can both activate and inhibit IKK2 and NF-kappa B. Co expression of fluorescently tagged TRAF1 and TRAF2 at different ratios implied that TRAF1 can affect clustering and presumably the activating function of TRAF2 in a dose dependent manner. CONCLUSIONS/SIGNIFICANCE: The observation that TRAF1 can either activate or inhibit the NF-kappa B pathway and the fact that it influences the oligomerization of TRAF2 indicates that relative levels of IKK2, TRAF1 and TRAF2 may be important for regulation of NF-kappa B activity. Since TRAF1 is an NF-kappa B induced gene, it might act as a feedback effector molecule. PMID- 20856939 TI - Inhibition of melanoma growth by subcutaneous administration of hTERTC27 viral cocktail in C57BL/6 mice. AB - BACKGROUND: hTERTC27 is a 27 kDa C-terminal polypeptide of human telomerase reverse transcriptase that has previously been shown to reduce tumorigenicity of HeLa cells and suppress growth of xenografted glioblastoma in nude mice. Although ectopic expression of hTERTC27 upregulated genes that are involved in apoptosis, cell cycle, and immune response, the mechanism for hTERTC27-induced tumor suppression has not been completely elucidated. Since hTERT was identified as a universal tumor-associated antigen, we hypothesize that hTERTC27 inhibits tumor growth in vivo through activation of anti-tumor immune response. METHODOLOGY/PRINCIPAL FINDING: Immunocompetent C57BL/6 mice were used for mouse B16 melanoma model. Mice bearing B16 melanoma were administered rAAV-/rAdv viral cocktail expressing hTERTC27, and tumor growth was monitored after viral cocktail treatment. Blood and splenocytes were used to determine the level of cytokines and the activity of immune cells, respectively. B16 tumor growth was significantly inhibited by subcutaneous administration of a single dose of 1.5*10(11) vg rAAV-hTERTC27 and 2.5*10(9) pfu rAdv-hTERTC27 viral cocktail (rAAV /rAdv-hTERTC27). The population and cytotoxicity of NK cells in the mice were significantly augmented by rAAV-/rAdv-hTERTC27 treatment, and selective depletion of the NK cell population in mice by intraperitoneal injection of anti-GM1 antibody abrogated the growth suppression of melanoma induced by rAAV-/rAdv hTERTC27 administration. CONCLUSION: Activation of NK cells by administration of rAAV-/rAdv-hTERTC27 is critical for growth suppression of melanoma in mouse model. PMID- 20856940 TI - Tetrathiafulvalene diindolylquinoxaline: a dual signaling anion receptor with phosphate selectivity. AB - Incorporation of tetrathiafulvalene into the backbone of a known neutral phosphate receptor, diindolylquinoxaline, yields a dual optical-electrochemical chemosensor for dihydrogen phosphate that functions in dichloromethane. This system shows selectivity for dihydrogen phosphate over other small anions and can be used to detect the presence of this analyte via fluorescence quenching or cyclic voltammetry. PMID- 20856941 TI - Profiling small molecule inhibitors against helix-receptor interactions: the Bcl 2 family inhibitor BH3I-1 potently inhibits p53/hDM2. AB - We validate a practical methodology for the rapid profiling of small molecule inhibitors of protein-protein interactions. We find that a well known BH3 family inhibitor can potently inhibit the p53/hDM2 interaction. PMID- 20856942 TI - Tandem Achmatowicz-Knoevenagel protocol: diastereoselective synthesis and anticancer evaluation of cyclopenta[b]pyrane derivatives. AB - Synthesis of cyclopenta[b]pyrane derivatives via Achmatowicz oxidative cyclization of furanols followed by intramolecular Knoevenagel condensation of the beta-ketoester arm is examined. The extent of diastereoselectivity was dependent on the nature of the chiral atom within the tethering carbon of the pyrenone ring. In some cases, this process proceeds with a high degree of stereoselectivity after protection of the anomeric hydroxyl group. Furthermore, the cytotoxic activity of pyrazolone derivatives thereof was studied against HCT116 (human colorectal cancer cells), SK-N-SH (human Caucasian bone marrow neuroblastoma) cells and the non-tumorigenic cells (MCF10A). PMID- 20856943 TI - Novel fluorinated polysilsesquioxane hollow spheres: synthesis and application in drug release. AB - Fluorinated polysilsesquioxane (FPSQ) hollow spheres with a large empty interior were synthesized in an aqueous medium by using (trifluoropropyl)trimethoxysilane as the sole precursor. The drug release applications of these spheres were demonstrated, and the materials have great potential as fluorinated drug release carriers. PMID- 20856944 TI - Facile nucleophilic substitution at the C3a tertiary carbon of the 3a bromohexahydropyrrolo[2,3-b]indole scaffold. AB - The synthesis of 3a-substituted hexahydropyrrolo[2,3-b]indole derivatives via nucleophilic substitution at the C3a position is reported. Nitrogen-, oxygen-, sulfur-, fluoro- and carbon-based nucleophiles have been employed, using both conventional organic solvents and ionic liquids. The C3a-substituted derivatives were obtained in good to excellent yields. PMID- 20856945 TI - Reactivity of alkynylzirconates towards allyl bromides: selective formation of beta-allyl-zirconacyclopentadienes. AB - Reaction of alkynylzirconates with allyl bromides afforded beta-allyl zirconacyclopentadienes with high selectivity in unique reaction site. PMID- 20856946 TI - Tetranuclear organometallic complexes containing Mo2O4(2+) and allylmolybdenum(II) moieties. AB - Refluxing toluene solutions of [Mo(eta(3)-allyl)(O(2)CMe)(CO)(2)(pz*H)(2)] (pz*H = pzH, pyrazole, or dmpzH, 3,5-dimethylpyrazole) without exclusion of air, give the tetranuclear complexes [Mo(2)O(2)(O(2)CCH(3))(2){(MU(3)-O)(MU-pz*)Mo(eta(3) allyl)(CO)(2)(pz*H)}(2)], where two chelating acetato ligands and two "Mo(eta(3) allyl)(CO)(2)(pz*H)(MU-pz*)" fragments are bonded to a central Mo(2)O(4)(2+) moiety. PMID- 20856951 TI - Growth dynamics and kinetics of monolayer and multilayer graphene on a 6H SiC(0001) substrate. AB - Using Scanning Tunnelling Microscopy (STM), the transformation from the commonly known carbon-rich (6?3*6?3)R30 degrees reconstructed surface to graphene on the 6H-SiC(0001) substrate is systematically investigated with the aid of adsorbing cobalt (Co) which acts as a tracer to map the evolution of these surfaces. The formation of graphene is observed to begin from the step-edges as Si desorption occurs and the growth process continues akin to that of a step flow growth mode. Analysis of the surface step-height evolution at various stages of graphitization shows that as the initial (6?3*6?3)R30 degrees surface converts to form graphene, three Si-C bilayers beneath collapse to regenerate a C-rich structure which also has a (6?3*6?3)R30 degrees periodicity at the interface between graphene and the SiC bulk. Based on these observations, a structural mechanism for the growth of mono- and multilayer graphene is proposed. In addition, we also examine the rate at which the initial (6?3*6?3)R30 degrees surface coverts to graphene as a function of time and temperature. Kinetic analysis of the growth process reveals that the transformation occurs with an activation energy of 3.0 +/- 0.4 eV, a value close to the breaking of a Si-C bond. PMID- 20856952 TI - A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions. AB - A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups. PMID- 20856953 TI - Are the majority of a(2)-ions cyclic? AB - Detailed analysis of >18 400 high-mass accuracy tandem mass spectra resulting from higher energy collisional dissociation yields further evidence of the cyclic nature of a(2)-ions. PMID- 20856954 TI - Synthesis and characterization of a series of halide-bridged, multinuclear iron(II) and cobalt(II) diamido complexes and a dinuclear, high-spin cobalt(II) alkyl derivative. AB - The synthesis and structural characterization of four multinuclear, halide bridged iron(ii) and cobalt(ii) diamidosilylether complexes of the form{Fe(2)Br(2)[(tBu)NON]}(2) (1), {Co(2)Br(2)[(tBu)NON]}(2) (2), {Fe(2)Cl(2)[(tBu)NON]}(n) (3) and {Co(2)Cl(2)[(tBu)NON](LiCl).2THF}(2) (4) ([(tBu)NON](2-) = [Me(3)CN(SiMe(2))](2)O(2-)) are reported. Thus, reaction of one equivalent of Li(2)[(tBu)NON] with two equivalents of MX(2) (X = Cl or Br; M = Co or Fe) form 1-4, which structurally contain one diamido ligand bridging two metal centres. Each amido group interacts with both metal centres to yield binuclear M(2)X(2)[(tBu)NON] units which dimerize via bromide bridges to form tetranuclear {Fe(2)Br(2)[(tBu)NON]}(2) (1) and {Co(2)Br(2)[(tBu)NON]}(2) (2) or form an infinite 1D chain of chloride-bridged dinuclear clusters {Fe(2)Cl(2)[(tBu)NON]}(n) (3). Replacing bromide for chloride in 2 results in a tetranuclear "ate" complex {Co(2)Cl(2)[(tBu)NON](LiCl).2THF}(2) (4) in which the tetranuclear core is capped with one LiCl and two THF molecules on each side. The reaction of four equivalents of LiCH(2)SiMe(3) with 4 generated the high-spin cobalt(ii) alkyl complex {Co(2)(CH(2)SiMe(3))(2)[(tBu)NON]} (5), in which each amide in [(tBu)NON](2-) bridges two Co(ii) centres, but the silylether donor only binds to one metal; each Co(ii) centre has a terminal -CH(2)SiMe(3) unit bonded as well. Variable temperature (1.8-300 K) magnetic susceptibility data for 1-5 showed significant antiferromagnetic coupling between metal centres. PMID- 20856955 TI - Theoretical investigation of the conformation, acidity, basicity and hydrogen bonding ability of halogenated ethers. AB - MP2/6-311++G(d,p) calculations have been carried out to investigate the conformation, protonation and the hydrogen bonding interactions with water of several halogenated ethers (CH(3)OCH(2)Cl, CH(2)ClOCH(2)Cl, CH(3)OCHCl(2), CHFClOCHF(2)). The optimized geometries, nu(CH) harmonic vibrational frequencies and the SAPT decomposition of the interaction energies are studied. The interaction with one water molecule gives several stable structures characterized by O(w)H(w)...O and CH...O(w) hydrogen bonds or by O...Cl halogen bonding. The MP2/CBS calculated binding energies of different complexes between the halogenated ethers and water vary between 1.7 and 7.7 kcal mol(-1). The energies of these structures are discussed as a function of the proton affinity of the ethers and the deprotonation enthalpy of the CH bonds. The contraction of the CH bonds and blue shifts of the corresponding stretching vibrations in the O protonated ethers and their O...H(w)O(w) complexes are compared. A natural bond orbital analysis has revealed that substitution of the H atoms by one or several halogen atoms has a great influence on the hyperconjugative effects from the two non-equivalent O lone pairs to relevant antibonding orbitals, and the subsequent geometry of the hydrogen bonded complexes. PMID- 20856956 TI - Theoretical study on the effect of intramolecular hydrogen bonding on OH stretching overtone decay lifetime of ethylene glycol, 1,3-propanediol, and 1,4 butanediol. AB - It is well known that the existence of hydrogen bonds causes the vibrational spectra for the donor OH bond to broaden. Most times this broadening is attributed to inhomogeneous contributions, however in this paper, we studied the homogeneous contribution coming from the decay lifetime of the OH stretching excitation. Alkane diol, which possesses an OH(b)OH(f) (b and f stand for hydrogen bonded and free, respectively) intramolecular hydrogen bond, provides us with a controllable molecule to systematically study the effect of intramolecular hydrogen bond on the decay rate of the OH vibrational excitation. In the present study we performed local mode vibrational calculation of gas phase ethylene glycol (EG), 1-3 propanediol (PD), and 1-4 butanediol (BD) using the potential energy curves calculated using B3LYP/6-31+G(d,p), MPW1PW91/6-311+G(2d,p), M06 2X/6-311+G(2df,2p), and MP2/6-311++G(3df,3pd) methods. In addition, we studied the dynamics of OH overtone excited state (Deltav(OH) = 3, 4) for the two most stable conformers of the aforementioned diols using the direct dynamics calculation employing the B3LYP/6-31+G(d,p) method. From the trajectory simulations we showed that the decay lifetime from the donor OH(b) excitation decreases while that from the acceptor OH(f) excitation increases as we increase the intramolecular hydrogen bond strength in going from EG, PD, to BD. These results are consistent with the gas phase experimental results of Kjaergaard et al. where the OH(b) peaks, which are sharp for EG disappear for BD. From the detailed analysis on the trajectories, we observed that the decrease in decay lifetime for the OH(b) bond excitation originates from the increase in the energy flow to the OH(b)O torsion/bend motion, while the increase in lifetime for OH(f) bond is due to the fixing of the OH(f) geometry by accepting a donor hydrogen. Furthermore, by plotting the calculated red shift versus the decay lifetime we obtained the following relationship T(decay)(fs) = 343176(Deltaomega(cm(-1)))( 1.36). PMID- 20856957 TI - Double-resonance spectroscopy of the jet-cooled free base and Cu(II) complex of protoporphyrin IX. AB - The excited-state dynamics of porphyrins, and related compounds, impact on their applications as photosensitizers for tumor-targeting drugs and solar cells. Many researchers have examined the influence of non-planar distortions in the ground state geometry on the properties of photoexcited states. We have identified the added importance of conformational changes in the excited state, relative to the initial geometry, on the resulting decay pathways. The ground-state structure and photodynamics of free-base and Cu(ii) complexes of protoporphyrin IX, laser desorbed into a cold supersonic expansion, have been investigated using infrared ion-dip spectroscopy combined with density-functional theory calculations. The vibrational bands associated with the N-H stretching mode of the free base are broader in the first electronically excited state, accessed via the Q band of protoporphyrin IX, than the corresponding bands in the ground-electronic state. This is attributed to rapid intersystem crossing in the excited state promoted by extension of the N-H bonds. Our calculations show that the stretching modes are highly anharmonic, which suggests the likelihood that other conformational changes are also taking place in the excited state. PMID- 20856958 TI - A comparative analysis of the role of water in the binding pockets of ionotropic glutamate receptors. AB - The binding pockets within proteins often contain water molecules. The ligand binding core of ionotropic glutamate receptors represents an example where the binding pocket has many crystallographically reported waters, but the precise role remains unclear. It is also unclear to what extent the dynamic properties of these waters are conserved across the different receptor subtypes. In order to shed some light on these aspects we have performed multiple molecular dynamics simulations of the ligand binding core of four glutamate bound iGluR structures (GluA2, GluK1, GluK2, and GluN2A) and one apo structure (GluA2). We find that the water positions are reproduced from the simulations, but they also reveal that all but one water molecule in the binding site can be rearranged or replaced with water molecules from the bulk that enter the binding site through transient water channels. This one exception is not reported in the apo crystal structure but within 15 ns of simulation, a water molecule enters the site from the bulk suggesting that it is a favoured position regardless of the state of the protein. Further calculations demonstrate that whilst it is not needed in order to be able to predict the correct binding pose, it does contribute a large favourable interaction energy. We also find that one conserved water has a much stronger interaction with the protein in GluA2, GluK1 and GluK2 compared to the GluN2A receptor. The position of this water molecule is such that it can influence the dynamics of the proposed switch in the GluA2 and GluK1/2 receptors. PMID- 20856959 TI - Ion-size effect within the aqueous solution interface at the Pt(111) surface: molecular dynamics studies. AB - All-atom classical force-field based molecular dynamics simulations have been employed to investigate the structure and dynamics of interfacial water in systems of pure water, 1 M LiOH and 1 M KOH aqueous solutions at an uncharged Pt(111) surface. Results indicate that the ordering of water molecules is affected as far as 9 A from the Pt surface, corresponding to three layers of water molecules. Specific packing geometries of water in electrolyte solutions depend on the ionic radius, and both Li(+) and K(+) ions are found to adsorb directly onto the Pt surface. Significantly higher values of the water-dipole autocorrelation function in the adlayer are found for the system with Li(+) ions compared to the systems with K(+) ions or pure water. Also strongly reduced translational motion is observed in the case of Li(+), both in-plane and perpendicular to the surface. This result suggests a strong stabilizing role of Li(+) ions on water molecules. Decreased mobility of the water adlayer makes it difficult for other compounds in the aqueous solution to access the Pt surface. This implies that the reason for the reduced catalytic activity of Pt(111) surface in the presence of LiOH is due to the freezing effect Li(+) ions have on water. PMID- 20856960 TI - Gold(I)/Zn(II) catalyzed tandem hydroamination/annulation reaction of 4-yne nitriles. AB - The tandem hydroamination-annulation reaction of 4-pentyne-nitriles in the presence of amine nucleophiles and a cooperatively operating catalyst system, consisting of Ph(3)PAuCl and Zn(ClO(4))(2), provides an efficient route to 2 aminopyrroles. Two regioisomeric 2-aminopyrroles were formed in moderate to good yields. PMID- 20856961 TI - Direct arylations of electron-deficient (hetero)arenes with aryl or alkenyl tosylates and mesylates. AB - A palladium catalyst derived from the ligand X-Phos enabled generally applicable direct arylations of electron-deficient heteroarenes and arenes with aryl and alkenyl tosylates or mesylates. PMID- 20856962 TI - Highly diastereoselective synthesis of quaternary alpha-trifluoromethyl alpha amino acids from chiral imines of trifluoropyruvate. AB - An efficient method for highly diastereoselective synthesis of quaternary alpha trifluoromethyl alpha-amino acids was developed via indium mediated allylation of (R)-phenylglycinol methyl ether based imines of trifluoropyruvate in good yields with high diastereoselectivities at room temperature; to illustrate the application of this method in organic synthesis, 2-allyl-2-(trifluoromethyl) aziridine was prepared in an efficient manner. PMID- 20856963 TI - Synthesis, structural and magnetic studies of an isostructural family of mixed 3d/4f tetranuclear 'star' clusters. AB - DC magnetic studies on new 'star' clusters of formula [Mn(3)Ln(acac)(6)(tea)(2)][Mn(acac)(3)] (Ln = Gd (1) and Dy (2)) and [Fe(3)Ln(acac)(6)(tea)(2)] (Ln = Gd (3) and Dy (4)) show that all cases display weak coupling, with compounds 3 and 4 displaying ferromagnetic J(LnFe) coupling, 3 having a S = 11 ground state. PMID- 20856964 TI - Designable synthesis of nanocomposite hydrogels with excellent mechanical properties based on chemical cross-linked interactions. AB - A new type of nanocomposite hydrogels based on covalent cross-linked interactions with excellent mechanical properties and good stability has been prepared by using in situ free-radical polymerization; polystyrene nanoparticles with photo activity are used as the cross-linking agent. PMID- 20856965 TI - Study of the optical and magnetic properties of pyrimidine in water combining PCM and QM/MM methodologies. AB - The solvent effects on the low-lying absorption spectrum and on the (15)N chemical shielding of pyrimidine in water are calculated using the combined and sequential Monte Carlo simulation and quantum mechanical calculations. Special attention is devoted to the solute polarization. This is included by an iterative procedure previously developed where the solute is electrostatically equilibrated with the solvent. In addition, we verify the simple yet unexplored alternative of combining the polarizable continuum model (PCM) and the hybrid QM/MM method. We use PCM to obtain the average solute polarization and include this in the MM part of the sequential QM/MM methodology, PCM-MM/QM. These procedures are compared and further used in the discrete and the explicit solvent models. The use of the PCM polarization implemented in the MM part seems to generate a very good description of the average solute polarization leading to very good results for the n-pi* excitation energy and the (15)N nuclear chemical shield of pyrimidine in aqueous environment. The best results obtained here using the solute pyrimidine surrounded by 28 explicit water molecules embedded in the electrostatic field of the remaining 472 molecules give the statistically converged values for the low lying n-pi* absorption transition in water of 36 900 +/- 100 (PCM polarization) and 36 950 +/- 100 cm(-1) (iterative polarization), in excellent agreement among one another and with the experimental value observed with a band maximum at 36 900 cm(-1). For the nuclear shielding (15)N the corresponding gas-water chemical shift obtained using the solute pyrimidine surrounded by 9 explicit water molecules embedded in the electrostatic field of the remaining 491 molecules give the statistically converged values of 24.4 +/- 0.8 and 28.5 +/- 0.8 ppm, compared with the inferred experimental value of 19 +/- 2 ppm. Considering the simplicity of the PCM over the iterative polarization this is an important aspect and the computational savings point to the possibility of dealing with larger solute molecules. This PCM-MM/QM approach reconciles the simplicity of the PCM model with the reliability of the combined QM/MM approaches. PMID- 20856966 TI - On the origin of an unusual dependence of (bio)chemical reactivity of ferric hydroxides on nanoparticle size. AB - Application of in situ UV-Vis absorption spectroscopy and ex situ X-ray photoelectron spectroscopy (XPS) makes it possible to resolve the controversies about the electronic properties of hematite (alpha-Fe(2)O(3)) nanoparticles (NPs) and, on this basis, to rationalize the unusual dependence of aquatic (bio)chemistry of these NPs on NP size. 2-Line ferrihydrite (FH) is also included in the study as the end polymorph of the size-driven phase transformation of hematite NPs in aqueous media. It is shown that the absorption edge of all NPs studied is due to the direct O 2p-Fe 3d charge transfer (CT) process, while a manifold of weak bands superimposed onto two main p-d CT bands is attributed to the d-d ligand field transitions. The band gap decreases from 2.95 to 2.18 eV with increasing NP size from 7 nm to 120 nm. This effect is attributed to restoration of hematite lattice structure, which ultimately results in an increase in the O 2p-Fe 3d hybridization, stabilization of the valence band, and delocalization of valence electrons, as confirmed by XPS. Finally, we show that the optical effects such as the Mie resonance significantly distort absorption spectra of hematite NPs larger than ~120 nm. Possible impacts of these findings on (photo)catalytic and biochemical properties of ferric (hydr)oxide NPs are discussed. PMID- 20856967 TI - Functionalization vs. fragmentation: n-aldehyde oxidation mechanisms and secondary organic aerosol formation. AB - Because of their relatively well-understood chemistry and atmospheric relevance, aldehydes represent a good model system for carbon-carbon fragmentation reactions in organic-aerosol aging mechanisms. Small aldehydes such as ethanal and propanal react with OH radicals under high NO(x) conditions to form formaldehyde and ethanal, respectively, with nearly unit yield. CO(2) is formed as a coproduct. This path implies the formation of the C(n-1) aldehyde, or an aldehyde with one fewer methylene group than the parent. However, as the carbon number of the n aldehyde increases, reaction with the carbon backbone becomes more likely and the C(n-1) formation path becomes less important. In this work we oxidized n pentanal, n-octanal, n-undecanal and n-tridecanal with OH radicals at high NO(x). The C(n-1) aldehyde molar yields after the peroxyl radical + NO reaction were 69 +/- 15, 36 +/- 10, 16 +/- 5 and 4 +/- 1%, respectively. Complementary structure activity relationship calculations of important rate constants enable estimates of branching ratios between several intermediates of the C(n)n-aldehyde reaction with OH: C(n) peroxyacyl nitrate versus C(n) alkoxyacyl radical formation, C(n-1) alkyl nitrate versus C(n-1) alkoxy radical, and C(n-1) aldehyde formation versus isomerization products. We also measured SOA mass yields, which we compare with analogous n-alkanes to understand the effect of fragmentation on organic-aerosol formation. PMID- 20856968 TI - Pentaatomic planar tetracoordinate carbon molecules [XCAl(3)](q) [(X,q) = (B,-2), (C,-1), (N,0)] with C-X multiple bonding. AB - Among the fascinating planar tetracoordinate carbon (ptC) species, pentaatomic molecules belong to the smallest class, well-known as "pptC". It has been generally accepted that the planarity of pptC structure is realized via the "delocalization" of the p(z) lone pair at the central carbon and the ligand ligand bonding interaction. Although "localization" is as key driving force in organic chemistry as "delocalization", the "localization" concept has not been applied to the design of pptC molecules, to the best of our knowledge. In this paper, we apply the "localization" strategy to design computationally a series of new pptC. It is shown that the central carbon atom and one "electronegative" ligand atom X (compared to the Al ligand) effectively form a highly localized C-X multiple bond, converting the lone pair at the central carbon to a two-center two electron pi-bond. At the aug-cc-pVTZ-B3LYP, MP2 and CCSD(T) levels, the designed 18-valence-electron pptC species [XCAl(3)](q); [(X,q) = (B,-2), (C,-1), (N,0)] are found to each possess a stable ptC structure bearing a C-X double bond, indicated by the structural, molecular orbital, Wiberg bonding, potential energy surface and Born-Oppenheimer molecular dynamics (BOMD) analysis. Moreover, our OVGF calculations showed that the presently disclosed (yet previously unconsidered) pptC structure of [C(2)Al(3)](-) could well account for the observed photoelectron spectrum (previously only ascribed to a close-energy fan like structure). Therefore, [C(2)Al(3)](-) could be the first pptC that bears the highly localized C-X double bond that has been experimentally generated. Notably, the pptC structure is the respective global minimum point for [BCAl(3)](2-) and [NCAl(3)], and the counterion(s) would further stabilize [BCAl(3)](2-) and [C(2)Al(3)](-). Thus, these newly designed pptC species with interesting bonding structure should be viable for future experimental characterization. The presently applied "localization" approach complements well the previous "delocalization" one, indicating that the general "localization vs. delocalization" concept in organic chemistry can be effectively transplanted to exotic pptC chemistry. PMID- 20856969 TI - Characterization of large vacancy clusters in diamond from a generational algorithm using tight binding density functional theory. AB - Point defects and pores in diamond affect its optical and electrical properties. We generated and evaluated a large number of vacancy V(n) clusters representing nanosized voids in diamonds for n up to 65. Our generational algorithm spawns the new generation n + 1 from the list of the most stable structures in the previous generation n. With energy as the only criterion, we generate a large structural diversity that allows their unbiased analysis. Since pi-electron delocalization is important for carbon, we used quantum mechanical tight-binding density functional theory (TBDFT). Adamantane-like globular shapes are preferred for n up to ~22. Beginning around n~ 35, the most stable structures show overall oblate shapes with some irregularities. These novel structures have not been seen before because hitherto only highly regular structures were considered. We see local graphitization in these relaxed structures providing an atomistic justification for the widely used "slit pore" model. The preference for structures with minimum number of cut bonds diminishes as n increases. There are no particularly stable "magic" sizes for vacancy clusters larger than n = 22 indicating that these larger voids can easily incorporate small vacancies and vacancy clusters. Radial distribution analysis shows that unusual contact or bond distances in the 1.6 to 2.8 A range appear in the vicinity of the internal surfaces of the vacancy clusters. Extremely long C-C bonds emerge as a result of structural relaxation of the dangling bonds in the vicinity of the vacancy clusters that cannot be simply described by ordinary sp(2)/sp(3) hybridization. PMID- 20856970 TI - Multiple mode coupling in Cy3 molecules by impulsive coherent vibrational spectroscopy using a few-cycle laser pulse. AB - Multiple vibrational mode coupling that induces the missing mode effect and Duschinsky rotation on the potential energy surface of the S(1) state in the Cy3 molecule was clarified by real-time ultrafast spectroscopy with a few-cycle laser pulse. The contributions of homogeneous and inhomogeneous dephasing to the total dephasing time were found to be 55% and 45%, respectively. PMID- 20856971 TI - Orientation and mutual location of ions at the surface of ionic liquids. AB - The structure of the liquid-vacuum interface in room temperature ionic liquids (ILs) is investigated using angle-resolved X-ray photoelectron spectroscopy (ARXPS) and synchrotron X-ray photoelectron spectroscopy (SXPS). By varying the polar angle and comparing the results for the chosen ionic liquids, we identify the presence of a surface layer that is chemically different to the bulk. In particular, this layer: (i) is enriched by aliphatic carbon atoms from the saturated carbon chains of the anions and cations, and (ii) contains an unequal distribution of cations and anions in a direction normal to the surface. This unequal distribution creates a potential gradient which extends from the surface into the liquid. We show unequivocally that this layer is not due to the presence of impurities. PMID- 20856973 TI - Modeling of thermodiffusion in liquid metal alloys. AB - In this paper following the linear non-equilibrium thermodynamics approach, an expression is derived for the calculation of the thermodiffusion factor in binary liquid metal alloys. The expression is comprised of two terms; the first term accounts for the thermally driven interactions between metal ions, a phenomenon similar to that of the non-ionic binary mixtures, such as hydrocarbons; the second term is called the electronic contribution and is the mass diffusion due to an internal electric field that is induced as a result of the imposed thermal gradient. Both terms are formulated as functions of the net heats of transport. The ion-ion net heat of transport is simulated by the activation energy of viscous flow and the electronic net heat of transport is correlated with the force acting on the ions by the rearrangement of the conduction electrons and ions. A methodology is presented and used to estimate the liquid metal properties, such as the partial molar internal energies, enthalpies, volumes and the activity coefficients used for model validation. The prediction power of the proposed expression along with some other existing thermodiffusion models for liquid mixtures, such as the Haase, Kempers, Drickamer and Firoozabadi formulas are examined against available experimental data obtained on ground or in microgravity environment. The proposed model satisfactorily predicts the thermodiffusion data of mixtures that are composed of elements with comparable melting points. It is also potentially and qualitatively able to predict a sign change in thermodiffusion factor of Na-K liquid mixture. With some speculation, the sign change is attributed to an anomalous change in thermoelectric power of Na-K mixture with composition. PMID- 20856972 TI - The complexes of halothane with benzene: the temperature dependent direction of the complexation shift of the aliphatic C-H stretching. AB - The formation of C-H...pi bonded complexes of halothane with benzene(-d(6)) has been studied using infrared and Raman spectroscopy of solutions in liquid krypton, in supersonic jet expansions and in room temperature vapour phase. The formation of complexes with 1 ? 1 and 2 ? 1 stoichiometry was observed. The complexation enthalpy in liquid krypton for the 1 ? 1 complex was determined to be -9.8(2) kJ mol(-1) and the enthalpy for the addition of a second halothane molecule to the 1 ? 1 complex was determined at -7.0(3) kJ mol(-1). The stretching mode of the halothane C-H bond involved in the formation of the complex in the jets was observed to blue shift by 7.7(10) cm(-1). In contrast, for the solutions of liquid krypton and the room temperature measurements a small red shift was observed. Supported by ab initio calculations and Monte Carlo simulations, this shift was explained by the differences in thermal populations of the van der Waals vibrations of the complex in the different experiments. PMID- 20856974 TI - Stochastic approach to laser-induced ultrafast dynamics: the desorption of H(2)/D(2) from Ru(0001). AB - The desorption of molecular hydrogen and deuterium induced by femtosecond-laser pulses is studied theoretically for the so-called DIMET (Desorption Induced by Multiple Electronic Transitions) process. These investigations are based on nonadiabatic classical Monte Carlo trajectory (CMCT) simulations on a ground and an excited state potential energy surface, including up to all six adsorbate degrees of freedom. The focus is on the hot-electron mediated energy transfer from the surface to the molecule and back, and the energy partitioning between the different degrees of freedom of the desorbing molecules. We first validate for a two-mode model comprising the desorption mode and the internal vibrational coordinate, the classical Monte Carlo trajectory method by comparing with Monte Carlo wavepacket (MCWP) calculations arising from a fully quantum mechanical open system density matrix treatment. We then proceed by extending the CMCT calculations to include all six nuclear degrees of freedom of the desorbing molecule. This allows for a detailed comparison between theory and experiment concerning isotope effects, energy partitioning (translational, vibrational, and rotational energies and their distributions), and the dependence of these properties on the laser fluence. The most important findings are as follows. (i) CMCT agrees qualitative with the MCWP scheme. (ii) The basic experimental features such as the large isotope effect, the non-linear increase of yield with laser fluence, translationally hot products (in the order of several 1000 K) and non-equipartitioning of translational and internal energies (E(trans) > E(vib) > E(rot)) are well reproduced. (iii) Predictions concerning a strong angular dependence of translational energies at large observation angles are also made. PMID- 20856975 TI - The influence of dendron's architecture on the "rigid" and "flexible" behaviour in binding DNA--a modelling study. AB - "Flexibility/rigidity" and "architecture" are cited among the Critical Nanoscale Design Parameters (CNDPs) that control the behaviour of dendritic molecules. We compare two different families of dendrons to explore the role played by architecture in influencing the ability of these molecules to optimize their surface to bind DNA-an indicator of rigid/flexible behaviour. PMID- 20856976 TI - Forming Rb(+) snowballs in the center of He nanodroplets. AB - Helium nanodroplets doped with rubidium atoms are ionized by applying a resonant two-step ionization scheme. Subsequent immersion of rubidium ions is observed in time-of-flight mass spectra. While alkali-metal atoms usually desorb from the surface of a helium nanodroplet upon electronic excitation, rubidium in its excited 5(2)P(1/2) state provides an exception from this rule (Aubock et al., Phys. Rev. Lett., 2008, 101, 35301). In our new experiment, Rb atoms are selectively excited either to the 5(2)P(1/2) or to the 5(2)P(3/2) state. From there they are ionized by a laser pulse. Time-of-flight mass spectra of the ionization products reveal that the intermediate population of the 5(2)P(1/2) state does not only make the ionization process Rb-monomer selective, but also gives rise to a very high yield of Rb(+)-He(N) complexes. Ions with masses of up to several thousand amu have been monitored, which can be explained by an immersion of the single Rb ion into the He nanodroplet, where most likely a snowball is formed in the center of the He nanodroplet. As the most stable position for an ion is in the center of a He nanodroplet, our results agree well with theory. PMID- 20856977 TI - Probing interfacial solvation of incipient self-assembled monolayers. AB - Poor solvation of alkylthiols in a water-rich interfacial environment is shown to induce a dispersion of energetically-distinct states above a critical value of the hydrocarbon chain length, which depends on the hydrophilicity of the terminal group. Switching between single and dispersed states can be achieved by an adequate choice of the solvent composition. PMID- 20856978 TI - Butanolysis of 4-methylbenzenediazonium ions in binary n-BuOH/H(2)O mixtures and in n-BuOH/SDS/H(2)O reverse micelles. Effects of solvent composition, acidity and temperature on the switch between heterolytic and homolytic dediazoniation mechanisms. AB - We investigated the effects of solvent composition, acidity and temperature on the switch between heterolytic and homolytic mechanisms in the course of the butanolysis of 4-methylbenzenediazonium (4MBD) ions in binary BuOH/H(2)O mixtures and in reverse micelles, RMs, composed of n-BuOH, H(2)O and sodium dodecyl sulfate, SDS, by employing a combination of spectrometric (UV/vis) and chromatographic (HPLC) techniques. In reaction mixtures with high n-BuOH percentages, S-shaped variations of k(obs) with acidity, defined hereafter as log([HCl]), are obtained with rate enhancements of up to ~370-fold on going from log([HCl]) = 2 to 6, with inflection points at -log[HCl] ~ 4. HPLC analyses of the reaction mixtures show that the substitution product 4-cresol, ArOH and the reduction product toluene, ArH, are formed competitively. The variation of their yields with acidity is also S-shaped, so that at high acidities (-log[HCl] < 3) only traces of ArH are detected but on lowering the acidity, the reduction product ArH becomes predominant The largest variations of k(obs) and of the product yields with acidity are found in the -log[HCl] = 3-5 range, suggesting that a turnover in the dediazoniation mechanism takes place under acidic conditions. The results can be interpreted in terms of two competitive reaction pathways, one heterolytic, involving a rate-determining formation of an extremely reactive aryl cation that traps the nucleophiles available in its solvation shell leading to the formation of substitution products (D(N) + A(N) mechanism) and a second route where the BuOH reacts with 4MBD to yield an unstable O-adduct of the type Ar-N[double bond, length as m-dash]N-O-R (diazo ether) in a rapid pre equilibrium step that initiates a radical process leading to the formation of the reduction product ArH (O-coupling mechanism). The results illustrate how the heterolytic and homolytic mechanisms can be switched by just changing the acidity of the solution. Kinetic analyses of the variations of k(obs) with acidity at different temperatures allowed us to separate k(obs) into the components for the heterolytic pathway, k(HET), and that for the homolytic one, k(HOM), to determine relevant thermodynamic parameters for both reaction pathways and for the equilibrium constant K for the formation of the O-adduct Ar-N=N-O-R. PMID- 20856979 TI - Positional effects of phosphoserine on beta-hairpin stability. AB - A disruptive interaction of phosphoserine with tryptophan in peptides that autonomously fold into a beta-hairpin structure in aqueous solution was explored in a positional context within the hairpin structure. All the peptides presented here have a serine or phosphoserine directly cross strand from a tryptophan residue in the beta-hairpin structure. It was observed that positioning of phosphoserine-tryptophan had a less destabilizing effect if the phosphoserine was on the C-terminus as opposed to the N-terminus. Greater destabilization was observed when the phosphoserine was positioned closer to the nucleating turn sequence rather than the termini of the hairpin. Multiple phosphorylations in a hairpin designed with two cross-strand serine-tryptophan pairs resulted in a greater decrease in hairpin formation with additional incorporations of phosphoserine. The work presented here gives further insight to destabilizing phosphoserine-tryptophan interaction within the beta-hairpin model system. PMID- 20856980 TI - Direct infusion mass spectrometry or liquid chromatography mass spectrometry for human metabonomics? A serum metabonomic study of kidney cancer. AB - Serum samples from kidney cancer patients and healthy controls were analyzed by both direct infusion mass spectrometry (DIMS) and liquid chromatography-mass spectrometry (LC-MS) with a high resolution ESI-Q-TOFMS. The classification and biomarker discovery capacities of the two methods were compared, and MS/MS experiments were carried out to identify potential biomarkers. DIMS had comparable classification and prediction capabilities to LC-MS but consumed only ~5% of the analysis time. With regard to biomarker discovery, twenty-three variables were found as potential biomarkers by DIMS, and 48 variables were obtained by LC-MS. DIMS is recommended to be a fast diagnostic method for kidney cancer, while LC-MS is necessary when comprehensive screening of biomarkers is required. PMID- 20856981 TI - Ratiometric fluorescent detection of intracellular hydroxyl radicals based on a hybrid coumarin-cyanine platform. AB - The first ratiometric fluorescent probe for hydroxyl radical ratiometric imaging in living cells was rationally designed based on a hybrid coumarin-cyanine platform. PMID- 20856982 TI - Chain mechanism for exchange of D2 with a ruthenium hydride. AB - The ruthenium hydride of (Ar(4)CpOH)Ru(CO)(2)H exchanges cleanly and rapidly with D(2) at room temperature to generate the ruthenium deuteride. A chain mechanism is proposed to explain the much more rapid exchange of RuH/D(2) than RuCO exchange with (13)CO. PMID- 20856983 TI - Primary photodynamics of a biomimetic model of photoactive yellow protein (PYP). AB - The present work aims at characterizing the photophysical behavior of a first biomimetic cyclodextrin model (CD-PYP1) of the photoactive site of photoactive yellow protein (PYP). The hydrophobic cyclodextrin cavity in which the chromophore self-includes, mimics its local environment within the protein. The photoinduced behavior of deprotonated CD-PYP1 (dp-CD-PYP1) has been probed by femtosecond transient-absorption spectroscopy and compared to those of the free deprotonated chromophore (pCT(-)) and of wild-type PYP. The excited-state deactivation of dp-CD-PYP1 is found to be non-exponential, with slower time components and higher quantum yield of fluorescence than pCT(-). Like in PYP, the non-exponential decay is attributed to ground-state structural heterogeneities of the self-inclusion complexes. A long-lived photoproduct is observed in the transient spectra of dp-CD-PYP1 and identified as the cis isomer. The isomerization quantum yield of dp-CD-PYP1 is estimated to be about 4%, in contrast with the free chromophore in solution which does not photoisomerize at all. This demonstrates the active role of the cyclodextrin environment to promote the photoisomerization of the chromophore, as is thought to be the case for wild type PYP. The effects of chromophore inclusion in the cyclodextrin on the photoinduced processes are rationalized within the framework of recent theoretical calculations involving two competitive deactivation channels: (i) trans to cis isomerization and (ii) rotation of the phenolate group, leading to trans ground-state recovery. Inclusion is proposed to favor isomerization by hindering the rotation of the phenolate group. Optimizing the structure of this first model in order to better reproduce the primary photoresponse of PYP thus appears very promising. PMID- 20856984 TI - A microdroplet-based shift register. AB - A microfluidic device is presented for the serial formation, storage and retrieval of water microdroplets in oil. The principle of operation is similar to that of an electronic shift register. Droplets, considered as units of information, can be arrayed and serially shifted within the device, allowing the controllable positioning of the emulsions and the creation of interfaces between drops. Using this passive system, by exploiting the balance between hydrodynamic pressure and surface tension across a drop due to the device design, droplet networks can be readily arrayed in a series of elements and cascaded within the microchannels in an automatable and high throughput fashion. The results showed the suitability of the system to be used for the formation of artificial lipid bilayers and for the study of biological dynamic processes based on the diffusion of molecules through interfaces. PMID- 20856985 TI - Distance-independent quenching of quantum dots by nanoscale-graphene in self assembled sandwich immunoassay. AB - A promising one-step homogeneous fluoroimmunoassay based on nanoscale-graphene sheets as powerful fluorescence acceptors and CdTe quantum dots as vigorous donors was designed to detect trace biomarker protein with distance-independent quenching efficiency, which significantly broke the distance limit (100 A) in traditional fluorescent biosensors. PMID- 20856986 TI - Tuning-up and driving a redox-active rotor. AB - The dynamic bistable rotational behaviour of a copper(I) coordination environment can be rationally tuned with balancing the substituent size on the rotor. Such rotors are sensitive to weak interactions, and the rotation was driven by a redox reaction on a ferrocenyl moiety via reconstruction of the charge interaction between redox centres. PMID- 20856987 TI - Cyclen-hybrid compound captures copper to protect INS-1 cells from islet amyloid polypeptide cytotoxicity by inhibiting and lysing effects. AB - Human islet amyloid polypeptide (hIAPP) deposit is the hallmark of type 2 diabetes pathology. Here, we report that apo-cyclen, attached to a specific hIAPP recognition motif (NYGAIL), captured copper ions and became proteolytically active. This cyclen-NYGAIL-copper complex was able to interfere with hIAPP aggregation and cleave hIAPP. These activities rescued INS-1 cells from hIAPP induced cytotoxicity. PMID- 20856988 TI - Synthesis of C-6-substituted uridine phosphonates through aerobic ligand-free Suzuki-Miyaura cross-coupling. AB - An efficient protocol for the construction of C-6-(hetero)aryl-substituted uridine phosphonate analogues utilizing an aerobic, ligand-free Suzuki-Miyaura cross-coupling reaction of a 6-iodo-precursor in aqueous media has been established. The method presents a modular approach toward the target compounds as demonstrated by the synthesis of a small library comprising 14 novel nucleoside phosphonates. PMID- 20856989 TI - Carbene-carbanion equilibrium for tris(2-pyridylthio)methanido Fe(II) complexes. AB - A reaction of FeCl(2) with tris(2-pyridylthio)methane (tptmH) produced the carbanion complex [Fe(tptm)(CH(3)CN)(2)](FeCl(4)){(C(2)H(5))(3)NH}. When FeI(2) was used instead of FeCl(2), the carbene complex [FeI(pyt)(bptmd)] (pyt = 2 pyridinethiolate, bptmd = bis(2-pyridylthio)methylidene) was isolated. The carbene forms [FeX(pyt)(bptmd)](n+) (n = 1 for X = CH(3)CN, n = 0 for X = I) were observed for [Fe(tptm)(CH(3)CN)(2)](FeCl(4)){(C(2)H(5))(3)NH} and [FeI(pyt)(bptmd)] in chloroform, whereas the carbene-carbanion equilibrium was observed in acetonitrile by NMR measurements. The thermodynamic parameters were evaluated by variable temperature (1)H NMR measurements using the diamagnetic salt [Fe(tptm)(CH(3)CN)(2)]PF(6) for [Fe(tptm)(CH(3)CN)(2)](+)? [Fe(pyt)(bptmd)(CH(3)CN)](+) + CH(3)CN (DeltaH = 23 kJ mol(-1), DeltaS = 55 J mol(-1) K(-1)). PMID- 20856990 TI - Preparation of half-metallocenes of thiophene-fused and tetrahydroquinoline linked cyclopentadienyl ligands for ethylene/alpha-olefin copolymerization. AB - Directed ortho-lithiation of the lithium carbamates generated from tetrahydroquinoline or tetrahydroquinaldine enables one-step preparation of thiophene-fused and tetrahydroquinoline-linked cyclopentadienes [2-R(1)-3-R(2) 4,5-dimethyl-6-(2-R(3)-2,3,4,5-tetrahydroquinolin-8-yl)-4H-cyclopenta[b]thiophene (R(1), R(2), R(3) = H or methyl)], from which titanium(iv) and zirconium(iv) complexes are prepared. The molecular structures of Me(2)Ti-complexes (12, R(1) = R(2) = Me, R(3) = H; 14, R(1) = R(2) = R(3) = Me) and Cl(2)Zr-complex (17, R(1) = R(2) = Me, R(3) = H) are determined by X-ray crystallography. The Me(2)Ti complexes, 14 and 15 (R(1) = R(3) = Me, R(2) = H) show excellent activities (62 and 54 * 10(6) g/molTi.h) in ethylene/1-octene copolymerization, even when activated with small amount of MAO (Al/Ti = 1000). PMID- 20856991 TI - The unexpected mechanism of carbonyl hydrosilylation catalyzed by (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)). AB - Complex (Cp)(ArN[double bond, length as m-dash])Mo(H)(PMe(3)) (2, Ar = 2,6 diisopropylphenyl) catalyzes the hydrosilylation of carbonyls by an unexpected associative mechanism. Complex 2 also reacts with PhSiH(3) by a sigma-bond metathesis mechanism to give the silyl derivative (Cp)(ArN[double bond, length as m-dash])Mo(SiH(2)Ph)(PMe(3)). PMID- 20856992 TI - A DNA-templated catalyst: the preparation of metal-DNA nanohybrids and their application in organic reactions. AB - Different kinds of metal-DNA nanohybrids are synthesized from cheap natural DNA on a large scale. These air-stable M-DNA nanohybrids maintain the advantages of both DNA and the metal nanoparticles, which exhibit reversible solubility and high catalytic activities. Moreover, the M-DNA nanohybrids could be easily reused for several cycles. PMID- 20856993 TI - Fabrication of silica nanotubes by using self-assembled gels and their applications in environmental and biological fields. AB - This critical review focuses on the preparation methods of a variety of the silica nanotubes by self-assembled organogels and the recent development of silica-based organic-inorganic hybrid nanomaterials for use as chemosensors in environmental studies as well as adsorbents for inorganic guest molecules and in biological applications for delivery of organic guest molecules (127 references). PMID- 20856995 TI - Adhesive systems: important aspects related to their composition and clinical use. AB - This literature review article addresses the types and the main components of different etch-and-rinse and self-etch adhesive systems available in the market, and relates them to their function, possible chemical interactions and influence of handling characteristics. Scanning electron microscopy (SEM) images are presented to characterize the interface between adhesives and dentin. Adhesive systems have been recently classified according to their adhesion approaches in etch-and-rinse, self-etch and glass ionomer. The etch-and-rinse systems require a specific acid-etch procedure and may be performed in two or three steps. Self etch systems employ acidic monomers that demineralize and impregnate dental substrates almost at the same time. These systems are separated in one or two steps. Some advantages and deficiencies were noted for etch-and-rinse and self etch approaches, mainly for the simplified ones due to some chemical associations and interactions. The SEM micrographs illustrate different relationships between adhesive systems and dental structures, particularly dentin. The knowledge of composition, characteristics and mechanisms of adhesion of each adhesive system is of fundamental importance to permit the adoption of ideal bonding strategies under clinical conditions. PMID- 20856996 TI - Compliance improvement in periodontal maintenance. AB - OBJECTIVES: The aim of this study was to assess the influence of efforts applied to modify the patients' behavior towards periodontal maintenance. MATERIAL AND METHODS: Patients were classified into three groups: Complete Compliance (participation in all visits), Irregular Compliance (irregular participation, one or more missing appointments), and Noncompliance (abandoned or never returned to the program). Complete compliers received usual procedures of the maintenance visit. The irregular compliers and non-compliers received usual procedures and strategies such as reminding next visit, informing patients on both periodontal disease and importance of maintenance, motivating the patient who showed an improvement in compliance. Thus, 137 patients were observed for 12 months. RESULTS: The degree of compliance has increased significantly during this period (p=0.001). No association was detected between age or gender and compliance degree. CONCLUSIONS: The results have shown that the intervention applied had a favorable influence on the patients' compliance. PMID- 20856997 TI - Timing and sequence of primary tooth eruption in children with cleft lip and palate. AB - OBJECTIVE: To determine the timing and sequence of eruption of primary teeth in children with complete bilateral cleft lip and palate. MATERIAL AND METHODS: This cross-sectional study was conducted at the Hospital for Rehabilitation of Craniofacial Anomalies of the University of Sao Paulo, Bauru, SP, Brazil, with a sample of 395 children (128 girls and 267 boys) aged 0 to 48 months, with complete bilateral cleft lip and palate. RESULTS: Children with complete bilateral clefts presented a higher mean age of eruption of all primary teeth for both arches and both genders, compared to children without clefts. This difference was statistically significant for all teeth, except for the maxillary first molar. Mean age of eruption of most teeth was lower for girls compared to boys. The greatest delay was found for the maxillary lateral incisor, which was the eighth tooth of children with clefts of both genders. Analyzing by gender, the maxillary lateral incisor was the eighth tooth to erupt in girls and the last in boys. CONCLUSION: The results suggest an interference of the cleft on the timing and sequence of eruption of primary teeth. PMID- 20856998 TI - Machined and plastic copings in three-element prostheses with different types of implant-abutment joints: a strain gauge comparative analysis. AB - OBJECTIVE: Using strain gauge (SG) analysis, the aim of this in vitro study was quantify the strain development during the fixation of three-unit screw implant supported fixed partial dentures, varying the types of implant-abutment joints and the type of prosthetic coping. The hypotheses were that the type of hexagonal connection would generate different microstrains and the type of copings would produce similar microstrains after prosthetic screws had been tightened onto microunit abutments. MATERIALS AND METHODS: Three dental implants with external (EH) and internal (IH) hexagonal configurations were inserted into two polyurethane blocks. Microunit abutments were screwed onto their respective implant groups, applying a torque of 20 Ncm. Machined Co-Cr copings (M) and plastic prosthetic copings (P) were screwed onto the abutments, which received standard wax patterns. The wax patterns were cast in Co-Cr alloy (n=5), forming four groups: G1) EH/M; G2) EH/P; G3) IH/M and G4) IH/P. Four SGs were bonded onto the surface of the block tangentially to the implants, SG 1 mesially to implant 1, SG 2 and SG 3 mesially and distally to implant 2, respectively, and SG 4 distally to implant 3. The superstructure's occlusal screws were tightened onto microunit abutments with 10 Ncm torque using a manual torque driver. The magnitude of microstrain on each SG was recorded in units of microstrain (uepsilon). The data were analyzed statistically by ANOVA and Tukey's test (p<0.05). RESULTS: Microstrain values of each group were: G1= 338.1 +/- 223.0 uepsilon; G2= 363.9 +/- 190.9 uepsilon; G3= 415.1 +/- 53.5 IE; G4= 363.9 +/- 190.9 uepsilon. No statistically significant difference was found between EH and IH, regardless of the type of copings (p>0.05). The hypotheses were partially accepted. CONCLUSIONS: It was concluded that the type of hexagonal connection and coping presented similar mechanical behavior under tightening conditions. PMID- 20856999 TI - Validation of the multimedia version of the RDC/TMD axis II questionnaire in Portuguese. AB - OBJECTIVE: The aim of the study was to validate the multimedia version of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis II Questionnaire in Portuguese language. MATERIAL AND METHODS: The sample comprised 30 patients with signs and symptoms of temporomandibular disorders (TMD), evaluated at the Orofacial Pain Control Center of the Dental School of the University of Pernambuco, Brazil, between April and June 2006. Data collection was performed using the following instruments: Simplified Anamnestic Index (SAI) and RDC/TMD Axis II written version and multimedia version. The validation process consisted of analyzing the internal consistency of the scales. Concurrent and convergent validity were evaluated by the Spearman's rank correlation. In addition, test and analysis of reproducibility by the Kappa weighted statistical test and Spearman's rank correlation test were performed. RESULTS: The multimedia version of the RDC/TMD Axis II questionnaire in Portuguese was considered consistent (Crombrach alpha = 0.94), reproducible (Spearman 0.670 to 0.913, p<0.01) and valid (p<0.01). CONCLUSION: The questionnaire showed valid and reproducible results, and represents an instrument of practical application in epidemiological studies of TMD in the Brazilian population. PMID- 20857000 TI - Radiographic assessment of photodynamic therapy as an adjunctive treatment on induced periodontitis in immunosuppressed rats. AB - OBJECTIVE: The aim of this study was to assess radiographically the effect of photodynamic therapy (PDT) as an adjunctive treatment to scaling and root planing (SRP) on induced periodontitis in dexamethasone-induced immunosuppressed rats. MATERIAL AND METHODS: The animals were divided into 2 groups: ND group (n=60): saline treatment; D group (n=60): dexamethasone treatment. In both ND and D groups, periodontal disease was induced by the placement of a ligature in the left first mandibular molar. After 7 days, ligature was removed and all animals received SRP, being divided according to the following treatments: SRP: saline and PDT: phenothiazinium dye (TBO) plus laser irradiation. Ten animals per treatment were killed at 7, 15 and 30 days. The distance between the cementoenamel junction and the height of the alveolar bone crest in the mesial surface of the mandibular left first molars was determined in millimeters in each radiograph. he radiographic values were analyzed statistically by ANOVA and Tukey's test at a p value <0.05. RESULTS: Intragroup radiographic assessment (ND and D groups) showed that there was statistically significant less bone loss in the animals treated with PDT in all experimental periods compared to those submitted to SRP. Intergroup radiographic analysis (ND and D groups) demonstrated that there was greater bone loss in the ND group treated with SRP compared to the D group treated with PDT at 7 and 30 days. CONCLUSION: PDT was an effective adjunctive treatment to SRP on induced periodontitis in dexamethasone-induced immunosuppressed rats. PMID- 20857001 TI - Luting glass ceramic restorations using a self-adhesive resin cement under different dentin conditions. AB - OBJECTIVES: The aim of this study was to investigate the bond strength of ceramic restorations luted using a self-adhesive resin cement (RelyX Unicem, 3M ESPE) under different dentin conditions. MATERIAL AND METHODS: In the experimental groups, ceramic restorations were luted to bovine incisors with RelyX Unicem under the following conditions: [Dry dentin]: surface was dried using air stream for 15 s; [Moist dentin]: excess dentin moisture was removed with absorbent paper; [Bonding agent]: Clearfil SE Bond (Kuraray) self-etching adhesive system was previously applied to dentin. In the Control group, cementation was done using an etch-and-rinse adhesive (Excite DSC) and Variolink II resin cement (Ivoclar Vivadent). Photoactivation of the resin cements was performed with UltraLume LED 5 unit (Ultradent). The restorations (n=5 per group) were sectioned into beams and microtensile testing was carried out. Data were subjected to ANOVA and Tukey's test (p<0.05). Failure modes were classified under Scanning Electron Microscopic (SEM) (x120 magnification). RESULTS: The bond strength was dependent on the moisture status of the dentin. Bond strength in the "dry dentin group" was significantly lower than that of all other groups, which showed similar results. A predominance of mixed failures was detected for the control group, while a predominance of adhesive failures was observed for the "bonding agent" and "dry dentin" groups. The "moist dentin" group presented predominantly cohesive failures within the luting material. The previous application of a self-etching adhesive showed no significant effect. CONCLUSIONS: Only excess dentin moisture should be removed for the cementation of ceramic restorations with self-adhesive resin cements. PMID- 20857002 TI - Effect of staining solutions and repolishing on color stability of direct composites. AB - OBJECTIVES: The purpose of this study was to assess the color change of three types of composite resins exposed to coffee and cola drink, and the effect of repolishing on the color stability of these composites after staining. MATERIALS AND METHODS: Fifteen specimens (15 mm diameter and 2 mm thick) were fabricated from microhybrid (Esthet-X; Dentsply and Filtek Z-250; 3M ESPE) and high-density hybrid (Surefil; Dentsply) composites, and were finished and polished with aluminum oxide discs (Sof-Lex; 3M ESPE). Color of the specimens was measured according to the CIE L*a*b* system in a reflection spectrophotometer (PCB 6807; BYK Gardner). After baseline color measurements, 5 specimens of each resin were immersed in different staining solutions for 15 days: G1 - distilled water (control), G2 - coffee, G3 - cola soft drink. Afterwards, new color measurement was performed and the specimens were repolished and submitted to new color reading. Color stability was determined by the difference (DeltaE) between the coordinates L*, a*, and b* obtained from the specimens before and after immersion into the solutions and after repolishing. RESULTS: There was no statistically significant difference (ANOVA, Tukey's test; p>0.05) among the DeltaE values for the different types of composites after staining or repolishing. For all composite resins, coffee promoted more color change (DeltaE>3.3) than distilled water and the cola soft drink. After repolishing, the DeltaE values of the specimens immersed in coffee decreased to clinically acceptable values (DeltaE<3.3), but remained significantly higher than those of the other groups. CONCLUSIONS: No significant difference was found among composite resins or between color values before and after repolishing of specimens immersed in distilled water and cola. Immersing specimens in coffee caused greater color change in all types of composite resins tested in this study and repolishing contributed to decrease staining to clinically acceptable DeltaE values. PMID- 20857003 TI - Statistical results on restorative dentistry experiments: effect of the interaction between main variables. AB - Statistical analysis interpretation is a critical field in scientific research. When there is more than one main variable being studied in a research, the effect of the interaction between those variables is fundamental on experiments discussion. However, some doubts can occur when the p-value of the interaction is greater than the significance level. OBJECTIVE: To determine the most adequate interpretation for factorial experiments with p-values of the interaction nearly higher than the significance level. MATERIALS AND METHODS: The p-values of the interactions found in two restorative dentistry experiments (0.053 and 0.068) were interpreted in two distinct ways: considering the interaction as not significant and as significant. RESULTS: Different findings were observed between the two analyses, and studies results became more coherent when the significant interaction was used. CONCLUSION: The p-value of the interaction between main variables must be analyzed with caution because it can change the outcomes of research studies. Researchers are strongly advised to interpret carefully the results of their statistical analysis in order to discuss the findings of their experiments properly. PMID- 20857004 TI - Time- and concentration-dependent cytotoxicity of antibiotics used in endodontic therapy. AB - OBJECTIVE: New drugs have to be assessed in endodontic therapy due to the presence of microorganisms resistant to therapeutic procedures. Thus, this study evaluated the time- and concentration-dependent cytotoxicity of different antibiotics used in endodontic therapy. MATERIAL AND METHODS: Human gingival fibroblasts were treated and divided into the following experimental groups: Group I - control; Group II - ciprofloxacin hydrochloride; Group III - clyndamicin hydrochloride; and Group IV - metronidazole. Each drug was used at concentrations of 5, 50, 150, and 300 mg/L for 24, 48, 72, and 96 h. Cytotoxicity was evaluated by the MTT assay [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] and spectrophotometric reading of ELISA plates. The results were analyzed by BioEstat 4.0 software using Kruskal-Wallis and Dunn's tests at a significance level of 5%. Cell viability was assessed for the different concentrations and times. RESULTS: All drugs presented dose-dependent cytotoxicity. Concentrations of 5 and 50 mg/L produced viable fibroblasts at all experimental times in all groups. CONCLUSIONS: Cell viability at 24 h was greater than in the other experimental times. Comparison between the same concentrations of antibiotics at different times showed that metronidazole presented the highest cell viability at 72 and 96 h compared to the other antibiotics, whereas clyndamicin hydrochloride showed higher cell viability at 72 h than ciprofloxacin hydrochloride. PMID- 20857005 TI - Comparative evaluation among different materials to replace soft tissue in oral radiology studies. AB - OBJECTIVE: The aim of this study was to establish which materials afford better simulation of soft tissues in Oral Radiology studies. MATERIAL AND METHODS: The sample was composed of four materials in eleven different thicknesses to simulate the soft tissues of the face. The mean values of the relative amounts of radiographic contrast of the materials were determined and compared to a gold standard value, which was obtained from 20 patients who were referred to have periapical radiographs taken of the left mandibular molars. Data were subjected to statistical analysis with Dunnett's test (p<0.05). RESULTS: The mean value of the relative amounts of contrast encountered in the patients was 0.47, with a range between 0.36 and 0.64 for all 44 material/thickness combinations. The majority of the tested materials showed values close to those of the patients' tissues, without statistically significant differences among them. The values of only three materials/thickness combinations differed statistically from those of the patients' tissues. CONCLUSIONS: Based on the results of the present study, it may be concluded that except for utility wax (4 mm and 8 mm) and water (4 mm), all materials tested at different thickness could be used as soft tissue substitute materials in Oral Radiology studies. PMID- 20857006 TI - Hand and ultrasonic instrumentation for orthograde root canal treatment of permanent teeth. AB - Root canal treatment is a frequently performed dental procedure and is carried out on teeth in which irreversible pulpitis has led to necrosis of the dental pulp. Removal of the necrotic tissue remnants and cleaning and shaping of the root canal are important phases of root canal treatment. Treatment options include the use of hand and rotary instruments and methods using ultrasonic or sonic equipment. OBJECTIVES: The objectives of this systematic review of randomized controlled trials were to determine the relative clinical effectiveness of hand instrumentation versus ultrasonic instrumentation alone or in conjunction with hand instrumentation for orthograde root canal treatment of permanent teeth. MATERIAL AND METHODS: The search strategy retrieved 226 references from the Cochrane Oral Health Group Trials Register (7), the Cochrane Central Register of Controlled Trials (CENTRAL) (12), MEDLINE (192), EMBASE (8) and LILACS (7). No language restriction was applied. The last electronic search was conducted on December 13th, 2007. Screening of eligible studies was conducted in duplicate and independently. RESULTS: Results were to be expressed as fixed effect or random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. Heterogeneity was to be investigated including both clinical and methodological factors. No eligible randomized controlled trials were identified. CONCLUSIONS: This review illustrates the current lack of published or ongoing randomized controlled trials and the unavailability of high-level evidence based on clinically relevant outcomes referring to the effectiveness of ultrasonic instrumentation used alone or as an adjunct to hand instrumentation for orthograde root canal treatment. In the absence of reliable research-based evidence, clinicians should base their decisions on clinical experience, individual circumstances and in conjunction with patients' preferences where appropriate. Future randomized controlled trials might focus more closely on evaluating the effectiveness of combinations of these interventions with an emphasis on not only clinically relevant, but also patient-centered outcomes. PMID- 20857008 TI - Survival and quality of life of patients with oral and oropharyngeal cancer at 1 year follow-up of tumor resection. AB - OBJECTIVE: This study aimed to assess the survival and life quality evolution of patients subjected to surgical excision of oral and oropharyngeal squamous cell carcinoma. MATERIAL AND METHODS: Forty-seven patients treated at a Brazilian healthcare unit specialized in head and neck surgery between 2006 and 2007 were enrolled in the study. The gathering of data comprised reviewing hospital files and applying the University of Washington Quality of Life (UW-QOL) questionnaire previously and 1 year after the surgery. Comparative analysis used Poisson regression to assess factors associated with survival and a paired t-test to compare preoperative and 1-year postoperative QOL ratings. RESULTS: 1 year after surgery, 7 patients were not found (dropout of the cohort); 15 had died and 25 fulfilled the UW-QOL again. The risk of death was associated with having regional metastasis previously to surgery (relative risk=2.18; 95% confidence interval=1.09-5.17) and tumor size T3 or T4 (RR=2.30; 95%CI=1.05-5.04). Survivors presented significantly (p<0.05) poorer overall and domain-specific ratings of quality of life. Chewing presented the largest reduction: from 74.0 before surgery to 34.0 one year later. Anxiety was the only domain whose average rating increased (from 36.0 to 70.7). CONCLUSIONS: The prospective assessment of survival and quality of life may contribute to anticipate interventions aimed at reducing the incidence of functional limitations in patients with oral and oropharyngeal cancer. PMID- 20857007 TI - Subcutaneous tissue reaction to castor oil bean and calcium hydroxide in rats. AB - Castor oil bean cement (COB) is a new material that has been used as an endodontic sealer, and is a candidate material for direct pulp capping. OBJECTIVE: The purpose of this study was to evaluate the biocompatibility of a new formulation of COB compared to calcium hydroxide cement (CH) and a control group without any material, in the subcutaneous tissue of rats. MATERIAL AND METHODS: The materials were prepared, packed into polyethylene tubes, and implanted in the rat dorsal subcutaneous tissue. Animals were sacrificed at the 7th and 50th days after implantation. A quantitative analysis of inflammatory cells was performed and data were subjected to ANOVA and Tukey's tests at 5% significance level. RESULTS: Comparing the mean number of inflammatory cells between the two experimental groups (COB and CH) and the control group, statistically significant difference (p=0.0001) was observed at 7 and 50 days. There were no significant differences (p=0.111) between tissue reaction to CH (382 inflammatory cells) and COB (330 inflammatory cells) after 7 days. After 50 days, significantly more inflammatory cells (p=0.02) were observed in the CH group (404 inflammatory cells) than in the COB group (177 inflammatory cells). CONCLUSIONS: These results demonstrate that the COB cement induces less inflammatory response within long periods. PMID- 20857009 TI - Prevalence of alveolar bone loss in healthy children treated at private pediatric dentistry clinics. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence of alveolar bone loss (BL) in healthy children treated at private pediatric dentistry clinics in Brasilia, Brazil. MATERIAL AND METHODS: The research included 7,436 sites present in 885 radiographs from 450 children. The BL prevalence was estimated by measuring the distance from the cementoenamel junction (CEJ) to alveolar bone crest (ABC). Data were divided in groups: (I) No BL: distance from CEJ to ABC is <2 mm; (II) questionable BL (QBL): distance from CEJ to ABC is >2 and <3 mm; (III) definite BL (DBL): distance from CEJ to ABC >3 mm. Data were treated by the chi-square nonparametric test and Fisher's exact test (p<0.05). RESULTS: Among males, 89.31% were classified in group I, 9.82% were classified in group II and 0.85% in group III. Among females, 93.05%, 6.48% and 0.46% patients were classified in Group I, II and III, respectively. The differences between genders were not statistically significant (Chi-square test, p = 0.375). Group composition according to patients' age showed that 91.11% of individuals were classified as group I, 8.22% in group II and 0.67% in group III. The differences among the age ranges were not statistically significant (Chi-square test, p = 0.418). The mesial and distal sites showed a higher prevalence of BL in the jaw, QBL (89.80%) and DBL (79.40%), and no significant difference was observed in the distribution of QBL (Fisher's exact test p = 0.311) and DBL (Fisher's exact test p = 0.672) in the dental arches. The distal sites exhibited higher prevalence of both QBL (77.56%) and DBL (58.82%). CONCLUSIONS: The periodontal status of children should never be underestimated because BL occurs even in healthy populations, although in a lower frequency. PMID- 20857010 TI - In vivo efficacy of alkaline peroxide tablets and mouthwashes on Candida albicans in patients with denture stomatitis. AB - OBJECTIVE: Effective cleaning of dentures is important for the maintenance of good oral hygiene for denture stomatitis patients. The in vivo efficacy of three different brands of alkaline peroxide tablets (Polident, Efferdent, and Fittydent) and two mouthwashes (CloSYS II and Corsodyl) to eliminate Candida albicans on dentures was evaluated in this in vivo study. MATERIAL AND METHODS: Ninety denture wearers with clinical evidence of denture stomatitis were randomly divided into 5 test groups and 1 control group. Each group was further divided into three subgroups in which the dentures were subjected to 15-, 30-, and 60-min disinfection procedures. The dentures of each test group were treated with one of the cleaners, while those of the control group were treated with distilled water. Swab samples from the palatal surfaces (2 cm x 2 cm template delimited area) of the upper dentures were obtained before and after 15, 30, and 60 min periods of cleaner use and examined mycologically. RESULTS: The reduction in the number of colony-forming units (CFU) of C. albicans before, and after 15, 30, and 60 min of use of CloSYS II and Corsodyl was significantly greater than that of the control group (p<0.05). Moreover, there was no statistically significant difference (p>0.05) among Polident, Efferdent and the control group in any of the treatment periods. Dentures treated with Fittydent appeared to have a significantly greater reduction in the number of Candida spp. only after 60 min of treatment. CONCLUSIONS: The results of this study showed that the use of mouthwashes significantly reduced the number of microorganisms on dentures. PMID- 20857012 TI - Comparison between two tomographic sections in the diagnosis of external root resorption. AB - OBJECTIVES: To assess the accuracy of coronal and sagittal CT sections to detect cavities simulating root resorption. MATERIAL AND METHODS: 60 mandibular incisors were embedded in plaster bases, and cavities with 0.6, 1.2 or 1.8 mm in diameter and 0.3, 0.6 or 0.9 mm in depth (small, medium and large cavities) were drilled on the buccal surfaces with high-speed round burs with diameters of 0.6, 1.2 and 1.8 mm to simulate external inflammatory root resorption. Simulations in the cervical, middle and apical thirds of each tooth root were made randomly. The Dental Scan software was used to obtain 1-mm-thick axial images from direct scanning, which were reconstructed in the coronal and sagittal planes using 3D software (Syngo FastView). Each series was loaded into the software. Fourteen images of each tooth were reconstructed in the coronal plane and 14 in the sagittal plane. A total of 1,652 images were obtained for analysis. Series information, tooth number and the plane reconstructed were stored. The images generated were saved on a CD-ROM together with the visualization software (Syngo FastView). Images were analyzed by a previously calibrated blinded, radiologist. Cochran's Q test was conducted separately for each region analyzed followed by pair-wise comparison by the McNemar test (p=0.05). RESULTS: No statistically significant difference (p>0.05) was observed in the diagnosis of simulated resorption between the apical, middle, and coronal thirds. When the axial plane was assessed separately, diagnoses were statistically different (p<0.05) among the three root thirds. The apical third differed significantly (p<0.05) from the cervical and middle thirds. Diagnostic errors were more often observed in the apical third compared to the cervical and middle thirds. Mid-sized cavities revealed no statistically significant differences (p>0.05) between planes, irrespective of the third in which the resorptions were located. CONCLUSION: When tomographic sections are requested for the diagnosis of buccal or lingual external root resorption, sagittal sections afford the best image characterization of the resorption process. PMID- 20857011 TI - Periodontal parameters and BANA test in patients with chronic renal failure undergoing hemodialysis. AB - OBJECTIVES: The aim of this study was to analyze the periodontal parameters of patients with chronic renal failure. MATERIAL AND METHODS: The periodontal status of 16 Brazilian patients aged 29 to 53 (41.7 +/- 7.2) years with chronic renal failure (CRF) and another matched group of 14 healthy controls with periodontitis was assessed clinically and microbiologically. Probing pocket depth (PPD), gingival recession (GR), dental plaque index (PLI), gingival index (GI), and dental calculus index (CI) were the clinical parameters recorded for the entire dentition (at least 19 teeth), while the anaerobic periodontopathogen colonization in four sites with the highest PPD was evaluated using the BANA test ("PerioScan"; Oral B). RESULTS: The results for the CRF group and control group, respectively were: PPD: 1.77 +/- 0.32 and 2.65 +/- 0.53; GR: 0.58 +/- 0.56 and 0.51 +/- 0.36; PLI: 1.64 +/- 0.56 and 1.24 +/- 0.67; GI: 0.64 +/- 0.42 and 0.93 +/- 0.50; CI: 1.17 +/- 0.54 and 0.87 +/- 0.52. Comparison between groups using the "t" test revealed a significantly increased PPD (p<0.001) in the control group. Comparison of the other clinicial parameters by the Mann-Whitney test showed differences only for PLI, which was significantly higher (p<0.05) in the CRF group. Spearman's test applied to each group showed a positive correlation among all clinical parameters, except for GR (p<0.05). None of the groups showed any correlation between GR and GI, while a significant negative correlation between GR and PPD was observed for the CRF group. The percentage of BANA positive sites was 35.9% for the CRF group and 35.7% for the control group. The BANA test correlated positively with PPD only in the control group and with GR only in the CRF group. CONCLUSIONS: In spite of a higher PLI and dense anaerobic microbial population even in shallow PPD, patients with CRF exhibited better periodontal conditions than periodontitis patients, which is an evidence of altered response to local irritants. PMID- 20857013 TI - Maxillary protraction after surgically assisted maxillary expansion. AB - This case report describes the orthodontic treatment of a 32-year-old woman with a Class III malocclusion, whose chief compliant was her dentofacial esthetics. The pretreatment lateral cephalometric tracings showed the presence of a Class III dentoskeletal malocclusion with components of maxillary deficiency. After discussion with the patient, the treatment option included surgically assisted rapid maxillary expansion (SARME) followed by orthopedic protraction (Sky Hook) and Class III elastics. Patient compliance was excellent and satisfactory dentofacial esthetics was achieved after treatment completion. PMID- 20857014 TI - Physical activity and cardiovascular risk factors among rural and urban groups and rural-to-urban migrants in Peru: a cross-sectional study. AB - OBJECTIVE: To compare physical activity and sedentary behavior patterns of rural to-urban migrants in Peru versus lifetime rural and urban residents and to determine any associations between low physical activity and four cardiovascular risk factors: obesity (body mass index > 30 kg/m2), systolic and diastolic blood pressure, hypertension, and metabolic syndrome. METHODS: The PERU MIGRANT (PEru's Rural to Urban MIGRANTs) cross-sectional study was designed to measure physical activity among rural, urban, and rural-to-urban migrants with the International Physical Activity Questionnaire (IPAQ). RESULTS: The World Health Organization (WHO) age-standardized prevalence of low physical activity was 2.2% in lifetime rural residents, 32.2% in rural-to-urban migrants, and 39.2% in lifetime urban residents. The adjusted odds ratios for low physical activity were 21.43 and 32.98 for migrant and urban groups respectively compared to the rural group. The adjusted odds ratio for being obese was 1.94 for those with low physical activity. There was no evidence of an association between low physical activity and blood pressure levels, hypertension, or metabolic syndrome. CONCLUSIONS: People living in a rural area had much higher levels of physical activity and lower risk of being overweight and obese compared to those living in an urban area of Lima. Study participants from the same rural area who had migrated to Lima had levels of physical inactivity and obesity similar to those who had always lived in Lima. Interventions aimed at maintaining higher levels of physical activity among rural-to-urban migrants may help reduce the epidemic of obesity in urban cities. PMID- 20857015 TI - [Quality of life and associated factors in women with breast cancer in Antioquia, Colombia]. AB - OBJECTIVE: To determine the quality of life and some associated factors in women diagnosed with breast cancer enrolled in cancer treatment programs in a Colombian province. METHODS: In a cross-sectional study, the WHOQOL BREF domains related to the quality of life of 220 women with breast cancer who were in treatment were analyzed. First, a descriptive analysis was done of the sociodemographic variables included in the study. This was followed by an analysis of the quality of-life scores of the patients in terms of their demographic, clinical, and social characteristics. Finally, some characteristics were identified that, in combination, explained the patients' quality of life. RESULTS: The quality of life was better for women with more schooling, those who were beneficiaries of the contributory health system, those who received support from family members, those from high-income groups, and those whose personal beliefs (religious and spiritual) helped them cope with the disease. Belonging to a lower-income group and having a skeptical attitude constituted risk factors for obtaining lower quality-of-life scores. CONCLUSIONS: The quality of life of breast cancer patients was poorer, both in general and in the physical, psychological, social, and environmental domains, in those who came from more humble levels of society. Psychosocial intervention, through patient-centered methods, is proposed as a strategy that can improve patients' quality of life, especially that of lower income women. It is necessary to strengthen strategies that enable patients to cope with the disease, relying on the moral, social, and spiritual support of their environment as the main resource. PMID- 20857016 TI - Mosquito vector abundance immediately before and after tropical storms Alma and Arthur, northern Belize, 2008. AB - OBJECTIVE: To monitor adult mosquito abundance in northern Belize before/after the first tropical storm of the wet season to estimate the time required for development/recovery of potential vector populations; determine which species predominate post-storm; and compare the effectiveness of two types of mosquito traps-octenol-baited Mosquito Magnets(r) and U.S. Centers for Disease Control and Prevention (CDC) light traps (with/without octenol). METHODS: Field experiments were conducted in Orange Walk Town, Belize, 21 May to 3 June 2008. Incidence rate ratios and exact binomial 95% confidence intervals were reported and trap-nights calculated to compare species abundance pre- and post-storm as well as trap-type effectiveness. RESULTS: Twice as many species and three times more Anopheles spp. were trapped pre-storm versus post-storm. However, greater numbers of Aedes taeniorhynchus and Culex (Culex) spp. were trapped post-storm. Mosquito Magnets(r) were consistently more effective than the CDC traps, obtaining twice as many Anopheles spp. and four times as many culicine species as the octenol baited version (which collected 14 times more mosquitoes overall and 3.5 times more culicine species than the unbaited version). The unbaited CDC trap did not trap any Anopheles spp. during the study period. CONCLUSIONS: Results indicated octenol is an effective attractant for An. crucians in northern Belize; malaria risk in Belize declines immediately post-storm (i.e., mosquito abundance drops); and arboviral risk associated with the rapid increase in culicine mosquitoes post storm may represent a greater public health threat than malaria (although further research and active disease surveillance is necessary to validate this hypothesis). PMID- 20857017 TI - [Seroprevalence of Chagas disease in Aguarico canton in the Ecuadorian Amazon]. AB - OBJECTIVE: Determine the current seroprevalence of Chagas disease in the population of Aguarico canton, and compare the findings with data from other epidemiological studies. METHODS: From September 2008 to October 2009, 2 033 serum samples were collected from 36.6% of the total population in Aguarico canton. The Chagatest recombinant ELISA v.3.0 was used to determine positivity to Chagas disease. Cases that tested positive were confirmed by indirect hemagglutination and ELISA. RESULTS: Of the 2 033 serum samples obtained, 73 tested positive for Chagas disease (3.6%). Seroprevalence in communities with positive cases ranged from 1.4% to 13.3%, with 60.3% of the positive cases found in females. These findings are similar to the 1990 comparison studies. CONCLUSIONS: The data obtained confirm the existence of an indigenous focus of Chagas disease in the Ecuadorian Amazon, with a percentage higher that the average for the Amazon region. No acute clinical cases or chronic pathologies were detected. Implementation of a culturally appropriate Chagas control program for the region is urgently needed. PMID- 20857018 TI - [Overweight and obesity in children and adolescents: comparison of three classification criteria based on body mass index]. AB - OBJECTIVE: To describe and compare the nutritional status of children and adolescents using three body mass index (BMI)-based criteria; to analyze the agreement between these criteria in terms of frequency of excess weight; and to investigate if the factors associated with excess weight were similar for the three criteria. METHODS: The following criteria were investigated: 2000 International Obesity Task Force (IOTF), 2006 Conde and Monteiro, and 2007 World Health Organization (WHO). Weight, height, and physical fitness were measured in 525 students from urban and rural schools, with ages between 7 and 15 years (mean = 11.0 +/- 2.1). The McNemar test, kappa statistics, and Poisson regression were used to evaluate each objective, respectively. RESULTS: The overall prevalence of excess weight (overweight + obesity) was 28.4% with the IOTF, 35.1% with the WHO, and 35.8% with Conde and Monteiro. There were no differences between criteria concerning overall prevalence of excess weight in males and females. However, within each sex, different results were observed for specific age groups, especially between 7 and 9 years. Nevertheless, the agreement (kappa) between the criteria was satisfactory: 0.71 to 0.98, depending on sex and age. The factors associated with excess weight and the strength of associations were similar for the three criteria. CONCLUSIONS: The prevalence of excess weight obtained with the IOTF was 20% lower than that calculated with the other criteria. Despite the differences between sexes observed for some age groups, the agreement between the three criteria was relatively high, and the factors associated with excess weight were similar. Further studies employing similar methods are required to confirm the present results in different populations of children and adolescents. PMID- 20857019 TI - Comparison of the QuantiFERON(r)-TB Gold assay and tuberculin skin test to detect latent tuberculosis infection among target groups in Trinidad & Tobago. AB - OBJECTIVE: To compare the QuantiFERON(r)-TB Gold (QFT-G) assay and tuberculin skin test (TST) in screening/diagnosis of latent tuberculosis infection (LTBI) among individuals in Trinidad & Tobago at high risk for TB. METHODS: A total of 560 individuals (TB patient contacts, HIV patients, health care workers, prison inmates, and TB patients [controls]) were recruited for the study. Blood was drawn and processed using the QFT-G assay, followed by immediate administration of TST solution on subjects' forearm. Data were analyzed with Epi InfoTM 3.5.1 software. Results were compared across the target groups using the chi-square test (P < 0.05). RESULTS: The QFT-G assay detected LTBI in 51% of the subjects (with most positive results occurring among the control group) whereas the TST detected it in 39.4% (P = 0.001). Overall, the QFT-G assay detected LTBI more frequently than the TST among all subjects except the control group, where detection favored the TST. The QFT-G assay produced indeterminate and nonreactive results in some HIV patients but required less turnaround time than the TST (23.3 h versus 70.2 h; P < 0.0001). The TST cost less per subject than the QFT-G assay (US $3.70 versus US $18.60; P = 0.0008). CONCLUSIONS: The QFT-G assay cost more but had a higher detection rate among most target groups and required less turnaround time than the TST. However, its sensitivity was lower among immunocompromised subjects. Therefore, the QFT-G assay should be used with caution for LBTI screening/diagnosis in resource-poor, high-HIV prevalence settings such as Trinidad & Tobago. PMID- 20857020 TI - [The public health care system and rehabilitation actions in Brazil]. AB - OBJECTIVE: To produce a historical account of rehabilitation actions in the context of the Brazilian Unified Health Care System (SUS). METHODS: Search of SciELO, LILACS, and MEDLINE databases for literature published between 1980 and 2009. The following Portuguese search terms were used: Sistema Unico de Saude, reabilitacao, politicas de saude, assistencia medica, historia. The English terms "rehabilitation" and "public health" were also used. Federal laws and Ministry of Health manuals available at the city of Rio de Janeiro Coordinating Office for Rehabilitation Programs, Fundacao Instituto Oswaldo Cruz library, and in BIREME database were also surveyed. RESULTS: Only a small number of publications were recovered (four books, three Health Ministry manuals, four articles published in Brazil, one master's thesis, and one doctoral dissertation). Nevertheless, analysis of these materials revealed that since many municipalities are still incapable of ensuring the right to universal and comprehensive health care, rehabilitation actions are often carried out in a precarious manner, unsupported by an adequate and comprehensive policy. On the other hand, there have been real improvements in terms of expanding care to the population with special needs. CONCLUSIONS: There still are factors hindering the achievement of optimal results in the care to people with special needs. The challenge of action planning must be undertaken especially by municipal governments to ensure an adequate supply of services and thus equity of access and comprehensive health care. PMID- 20857022 TI - [Ethics and eHealth: reflections for a safe practice]. AB - The term eHealth (or telemedicine, telehealth) has been used to describe activities that employ information and telecommunication technologies to deliver health care. Distance is an important factor hindering the delivery of many important services, such as diagnosis, treatment, prevention, health promotion, and health research assessment. Although eHealth can provide interesting solutions such as a second specialist opinion in geographically isolated areas, a large number of ethical and legal issues must be considered. It is essential to discuss, among others, aspects relating to safety and confidentiality; professional accountability; technical standards relating to digital recording, storage, and transmission of clinical data; copyright; authorization from professional regulatory bodies; and licensing for the remote practice of medicine. In Brazil, the Federal Council of Medicine has already established rules for telemedicine; however, it is still necessary to further this discussion to involve the entire health care sector. Since there are many eHealth projects being developed in Brazil, there is an urgent need to design protocols and training programs for all professionals involved. PMID- 20857021 TI - Comparison of three methods for diabetes screening in a rural clinic in Honduras. AB - OBJECTIVE: To evaluate two alternatives to the fasting plasma glucose (FPG) test for diabetes screening in Latin America. METHODS: Eight hundred adults without diabetes were recruited in a primary care clinic in Honduras. An equation-based screening formula, incorporating a random capillary glucose test and other risk factors, was used for initial screening. All patients with a screening-based probability of diabetes > 20%, plus one-fifth of those with a probability < 20%, were asked to return for FPG and point-of-care hemoglobin A1c (POC-A1c) tests. An FPG > 126 milligrams per deciliter and a POC-A1c > 6.5% were used as gold standards to assess the performance of the screening equation. The association between the POC-A1c and the FPG tests was examined as were patient factors associated with failure to return for follow-up and variation in diabetes risk across subgroups. RESULTS: The screening equation had excellent test characteristics compared with FPG and POC-A1c. Using the FPG gold standard, the POC-A1c had a sensitivity of 77.8% and a specificity of 84.9%. With an A1c cutoff of 7%, POC-A1c specificity increased to 96.2%. Thirty-four percent of patients asked to return for follow-up testing failed to do so. Those who failed to return were more likely to be men and to have hypertension. CONCLUSIONS: Both the screening equation and POC-A1c are reasonable alternatives to an FPG test for identifying patients with diabetes. Given the barriers to currently recommended screening procedures, these options could have important public health benefits in Latin America. PMID- 20857023 TI - How to improve the health of undocumented Latino immigrants with HIV in New Orleans: an agenda for action. AB - Latino communities continue to grow in the United States. These communities are significantly affected by HIV infection. New Orleans is a city whose demographics have changed since Hurricane Katrina in 2005, as numerous Latinos/Hispanics came to the city to help rebuild it. This population might have a higher risk of HIV acquisition and problems with access to health care. Data on HIV infection in these populations are insufficient. Active community participation and commitment of key stakeholders are important for developing strategies to bring about change. Political and social support is also a major determinant of any potential change. The following were common ground points after meetings with key stakeholders: (1) to analyze and diagnose health situations in documented and undocumented communities with HIV/AIDS in the city of New Orleans; (2) to develop partnerships and networks among stakeholders with a significant presence in Latino/Hispanic communities in the city; (3) to strengthen research in Latino/Hispanic community issues among research centers, academicians, and health care services; (4) to investigate the development of prevention strategies and technical innovations; (5) to advocate strategies to improve health care access among documented and undocumented immigrants. This project will report additional findings soon. PMID- 20857025 TI - [Effect of submicroscopic or polyclonal Plasmodium falciparum infection on mother and gestation product: systematic review]. AB - BACKGROUND: Malaria in pregnancy causes substantial maternal and infant morbidity mortality, even at submicroscopic parasite levels. In addition, the presence of polyclonal infections secondary to high parasite genetic diversity is a common finding. OBJECTIVES: To determine the frequency of submicroscopic and/or polyclonal plasmodial infection during pregnancy and to establish their impact on clinical presentation, immunity acquisition, and consequences on mother and gestation product. METHODS: A search on Medline was performed using key words (MeSH): pregnancy, malaria, PCR, microscopy, genotype, and clones. Studies on plasmodial infection diagnosed by microscopy and PCR were selected. RESULTS: A total of 16 studies were included, all carried out in Africa. The weighted mean (WM) of submicroscopic infection was 36%. According to type of infection (microscopic, submicroscopic or negative), the WM of maternal anemia and low birth weight (LBW) were 51%, 42%, 33%, and 19%, 16%, 11%, respectively. Risks (OR), using the negative group as reference, were: a) for maternal anemia 2.12 in microscopic infection and 1.48 in submicroscopic; b) for LBW 1.89 in microscopic and 1.56 in submicroscopic infection. The WM of polyclonal infection was 75% and the mean number of clones by sample was three. CONCLUSIONS: Submicroscopic and polyclonal P. falciparum infections during pregnancy are very common, but have been little studied and their impact must be assessed in each specific region because they depend on malaria transmission intensity and stability, maternal age and parity, among other variables, which are influenced by environmental and socio-economic conditions of each region. PMID- 20857026 TI - [Physical inactivity and associated factors in adults, Sao Paulo, Brazil]. AB - OBJECTIVE: To analyze the prevalence of overall and leisure time physical inactivity and associated factors and types of exercises or sports modalities according to schooling in 2,050 adults from 18 to 59 years of age - state of Sao Paulo, Brazil. METHODS: Population-based cross-sectional study with a stratified sample of clusters performed in multiple stages. Physical inactivity was determined using the short version of the International Physical Activity Questionnaire - IPAQ and by a question on the regular practice of leisure time physical activity. Data analysis took the sample design into account. RESULTS: Prevalence of physical inactivity during leisure was higher among women. Poisson multiple regression model in man indicated that overall sedentarism was lower among single and separated men, students and without car in the household. Leisure physical inactivity was greater among men over forty years, among those with less schooling and full-time students. Overall physical inactivity was more prevalent among woman with more schooling, with less qualified occupations and widows. Leisure physical inactivity decreased with age and schooling. Among modalities practiced for leisure, walking was more prevalent among women and football was more prevalent among men. Most modalities were directly associated with schooling; approximately 25% of the individuals with more than 12 years of schooling practiced walking. CONCLUSIONS: These results suggest that interventions and public policies to promote physical activity should consider differences in gender and socioeconomic status as well as the preferences for different modalities and the context in which the physical activity is practiced. PMID- 20857027 TI - [Prevalence and factors associated with abdominal obesity and excess weight among adults from Maranhao, Brazil]. AB - OBJECTIVE: To determine the prevalence of excess body weight and abdominal obesity and assess the association with socioeconomic, demographic and behavioral factors among adults of Maranhao, Brazil. METHODS: Multistage cluster sample investigated through a household survey on 1,005 adults aged 20 to 59 years (393 men and 612 women). Anthropometric measures: weight, height and waist circumference (WC) were assessed. Abdominal obesity was defined as WC > 80 for women and WC > 94 for men. Body mass index (BMI), weight in kilograms divided by the square of height in meters, > 25 kg/m2 was considered excess body weight. The dependent variable was divided into four categories: normal BMI and WC, excess body weight only (EBW), abdominal obesity only (AO) and abdominal obesity with excess body weight (AOEBW). Multinomial logistic regression was used for statistical analysis and estimates took the complex sampling design into account. RESULTS: Among men the prevalence of AO was 1.3%, EBW 20.3% and AOEBW 27.5%. Among women 15.5% presented AO, 1.3% EBW and 42.0% AOEBW. There was a significant statistical difference among sexes (p value < 0.001). In the multivariable analysis, among men, schooling > 9 years and living with a partner were factors associated with higher prevalence of EBW. Age > 35 years, family income > two minimum wages and living with a partner were associated with higher prevalence of AOEBW. Among women, age > 35 and living with a partner were factors associated with AO. Age > 35 years, living with a partner and schooling < 9 years were associated with a higher prevalence of AOEBW. CONCLUSION: the prevalence of EBW was higher among men whereas AO prevailed among women. Factors associated with excess body weight, abdominal obesity and both excess body weight and abdominal obesity varied. PMID- 20857028 TI - [Development of a food frequency questionnaire for adults in a population-based sample in Cuiaba, Mid-Western Region of Brazil]. AB - OBJECTIVE: To describe the design of a Food Frequency Questionnaire (FFQ) to be used in studies on food intake of adults from Cuiaba, Mato Grosso State, Brazil. METHODS: A 24-hour dietary recall (24hR) was applied to a sub-sample of 104 men and women, randomly selected from a random population-based study sample. Based on the frequency of report and on the contribution to the intake of energy and nutrients in the 24hR, 81 food items and respective reference servings were selected to comprise the FFQ food list. Reference portions were defined based on the most reported portion sizes in the 24-hour dietary recalls. The FFQ list was associated to eight options of intake frequency. RESULTS: Sugar, coffee, beans, rice, beef, bread, and soda were cited by at least 50% of the interviewed group and the latter four foods were the ones that most contributed to energy intake. There were no differences among men and women related to the foods that provided most macro and micronutrients. CONCLUSION: The FFQ included the most relevant food items involved in the food habits of the adult population from Cuiaba, Mato Grosso. Once the validity and reproducibility of this tool are proven, it will be useful in epidemiologic and clinical investigations on the role of diet on disease development in the target population. PMID- 20857029 TI - Factors associated with overweight and central adiposity in urban workers covered by the Workers Food Program of the Brazilian Amazon Region. AB - OBJECTIVE: To investigate factors associated with overweight and abdominal obesity in male and female workers. METHODS: This is a cross-sectional population based study. A representative sample of 1,054 workers ranging from 18 to 74 years of age, selected among individuals covered by the Workers' Food Program living in the Metropolitan region of Belem, Northern Brazil. Health-related behavior and anthropometry were assessed. Fasting blood samples were collected. RESULTS: Overweight prevalence was 38.0% among women and 50.4% among men. Among overweight subjects, there were 6.1% obese women and 10.7% obese men. Multivariate analysis was used to identify social behavior and clinical-biochemical factors associated with increased body adiposity (BMI > 25 kg/m2 and increased waist circumference: > 80 cm for women and > 94 cm for men). Variables positively and significantly associated with overweight and abdominal obesity in men according to prevalence ratio (PR) values were: age (1.02), high family income (1.05), smoking (1.36), hypertension (systolic blood pressure, 1.41; diastolic blood pressure, 1.85) and hypertriglyceridemia (2.29). In women, the PR of increased body adiposity was associated with: age (1.02), alcohol intake (1.42), hypertriglyceridemia (1.44), diastolic blood pressure (1.65) and hyperglycemia (1.71). CONCLUSIONS: The association of overweight and abdominal obesity with social behavior variables should be corrected with preventive and educational measures. Furthermore, association of overweight and abdominal obesity with clinical and biochemical variables places the urban workers from the Amazon region assisted by the Workers' Food Program at a possible risk for morbidity and mortality from increased body adiposity. PMID- 20857030 TI - [Oral health status and nutritional deficit in noninstitutionalized older adults in Londrina, Brazil]. AB - OBJECTIVE: To examine the association between nutritional deficit and oral health problems in noninstitucionalized elderly adults in a Brazilian community. METHODS: In this cross-sectional study, data were obtained from 267 elderly adults (160 women, 107 men) with ages between 60 and 74 years, identified through a census in the area covered by the Family Health Program in Londrina, Brazil. The Mini Nutritional Assessment score < 24 points was used to identify nutritional deficit. Oral evaluation consisted of an oral exam, measurement of stimulated salivary flow rate, and use of the Geriatric Oral Health Assessment Index (GOHAI) for self-perception data. Multivariate analyses were adjusted by sociodemographic variables, depression, and drug consumption. RESULTS: Nutritional deficit was identified in 58 adults (21.7%). Among the dental conditions studied, absence of posterior occlusion (Odds Ratio, OR: 2.18; Confidence Interval, 95% CI: 1.06 - 4.45), stimulated salivary flow rate < 0.7 ml/minute (OR: 2.18, 95% CI: 1.06 - 4.50), advanced periodontal illness (OR: 6.54; 95% CI: 2.03 - 21.00), and negative self perception of oral health (OR: 3.41; 95% CI: 1.59 - 7.33) were associated with nutritional deficit regardless of sex, age, social class, education, smoking, depression, and drug consumption. CONCLUSIONS: Oral health impairment was associated with nutritional deficit and it requires a greater integration between dentistry and nutrition in the health promotion of older adults, especially in the prevention of tooth loss and in the posterior occlusal rehabilitation to avoid obstacles for an adequate diet. PMID- 20857031 TI - [Physical activity level among children and adolescents orphaned by AIDS]. AB - OBJECTIVE: To estimate the level of physical activity among children and adolescents orphaned by AIDS according to socio-demographic and orphanhood related characteristics. METHODS: A population-based study was carried out with 235 children and adolescents aged 7 to 14 years in the municipality of Sao Paulo, SP, in 2007. Children were classified as active and inactive. The cut-off point established was 300 minutes of weekly physical activity. All variables were compared between both groups and sexes. RESULTS: An overall prevalence of 42% of inactivity was found. Active commuting and child's play were the main physical activities for most of the children and adolescents. As for physical activity level, a significant difference was observed between sexes (p < 0.001). Boys were more active and played outdoors more than girls. CONCLUSIONS: There is a high prevalence of physical inactivity among children and adolescents orphaned by AIDS, especially girls. PMID- 20857032 TI - [Food intake and meal patterns of adolescents, Sao Paulo, Brazil]. AB - OBJECTIVE: To assess food intake and meal patterns in adolescents, a cross sectional study was conducted with 228 adolescents from a public school, SP, Brazil. METHODS: Total energy, macronutrients, calcium, iron, and vitamin A intakes were evaluated. The food pattern was compared with the eating patterns established by the Food Pyramid for adolescents. Meal frequency was assessed to identify meal skipping. Descriptive statistics and Chi Square were used. RESULTS: Mean energy intake was lower than estimated for 66% adolescents, carbohydrate intake was lower than estimated for 50% adolescents, fat intake was higher than estimated for 50% of adolescents, and protein intake was above the recommendation for 40% of adolescents. Among adolescents studied, 21% skipped breakfast and one third of them had snacks instead of lunch or dinner. CONCLUSION: The diet of adolescents had insufficient energy intake and deficient intake of fruits and vegetables. Meal patterns were satisfactory, but breakfast should be encouraged. PMID- 20857033 TI - [Association between physical inactivity and overweight among adolescents in Salvador, Bahia--Brazil]. AB - OBJECTIVE: To assess the association between physical inactivity and overweight in an adolescent 10-14 year-old population of students in Salvador (Bahia, Brazil). METHODS: Cross-sectional study assessing adolescents enrolled in state and municipal schools of the city of Salvador (Bahia, Brazil). Subjects' anthropometric status, level of physical activity, sexual maturation, and food consumption were investigated as well as their socioeconomic and environmental status. A BMI equal to or above the 85th percentile ranked an adolescent in the overweight category. Physical inactivity characterized the adolescent who practiced moderate or vigorous physical activity for less than 300 minutes per week. A multivariate logistic regression analysis was used to check the associations of interest. RESULTS: The prevalence of excess weight was 11.8%. A positive association was shown between physical inactivity and overweight/obesity (PR male: 2,263 95%CI: 1,132 - 4,258), only statistically significant for male subjects. CONCLUSIONS: Results suggest a positive association between physical inactivity and overweight only among male participants. The investigation of this gender difference is vital and the authors suggest studies with more appropriate designs to elucidate the relationship. PMID- 20857034 TI - [The association between common mental disorders and quality of life in adolescents with asthma]. AB - INTRODUCTION: Asthma is the most prevalent chronic disease among adolescents, not only affecting their quality of life but also bringing deep concern about their health. Having a chronic disease in this age group, in addition to the limits caused by the disease itself, increases vulnerability to emotional damage including common mental disorders (CMD). OBJECTIVE: to evaluate the association between CMD and quality of life in adolescents with asthma. METHODS: This cross sectional study investigated 210 asthmatic adolescents from 12 to 21 years old treated in an outpatient adolescent healthcare facility in Rio de Janeiro, Brazil. The Pediatrics Asthma Quality of Life Questionnaire (PAQLQ) and the General Health Questionnaire (GHQ-12) were used to assess QoL and common mental disorders (CMD) respectively. Total quality of life and its various dimensions were treated as dichotomous variables. A binomial log-rhythmic model was used to calculate raw and adjusted prevalence ratios. RESULTS: The prevalence of asthmatics with CMD was 32.4% while the prevalence of poor QoL among adolescents with CMD was 36.6%. The final adjusted models showed an association between CMD and poor total quality of life (PR = 1. 84 95% CI 1.19 - 2.86) as well as for areas related to emotions (PR = 1.77 95% CI 1.16 - 2.62) and symptoms (RP = 1.75 95% CI 1.14 - 2.70). For the physical activity domain, the association with CMD was only borderline (RP = 1.43 95% CI 0.97 - 2.72). CONCLUSION: The results of this study suggest that greater attention should be paid to the emotional needs of adolescents with chronic diseases, including more effective actions in the field of mental health in order to improve quality of life and overall treatment of young asthmatic patients. PMID- 20857035 TI - Item response theory applied to the Beck Depression Inventory. AB - The Beck Depression Inventory (BDI), a scale that measures the latent trait intensity of depression symptoms, can be assessed by the Item Response Theory (IRT). This study used the Graded-Response model (GRM) to assess the intensity of depressive symptoms in 4,025 individuals who responded to the BDI, in order to efficiently use the information available on different aspects enabled by the use of this methodology. The fit of this model was done in PARSCALE software. We identified 13 items of the BDI in which at least one response category was not more likely than others to be chosen, so that these items had to be categorized again. The items with greater power of discrimination were sadness, pessimism, feeling of failure, dissatisfaction, self-hatred, indecision, and difficulty of work. The most serious items were weight loss, suicidal ideas, and social withdrawal. The group of 202 individuals with the highest levels of depressive symptoms was comprised by 74% of women and almost 84% had a diagnosis of a psychiatric disorder. The results show gains resulting from use of IRT in the analysis of latent traits. PMID- 20857036 TI - [Prevalence of Burnout Syndrome and sociodemographic and work factors of elementary education teachers of the City of Joao Pessoa]. AB - The Burnout Syndrome has been considered a public health issue because of the physical and mental health implications on workers, with clear effect on the quality of life at work. Thus, this study aimed to evaluate the prevalence of the Burnout syndrome in elementary school teachers in the city of Joao Pessoa, PB, and its relationship with sociodemographic and labor variables. Results showed that 33.6% of teachers presented high levels of Emotional Exhaustion, 8.3% a high level of Depersonalization, and 43.4% a low level of Professional Achievement. Socio-demographic and labor variables were associated with the dimensions of Burnout. Results indicate the importance of understanding and acknowledging occupational diseases to include teachers in public policy measures for the health and well-being of the category. PMID- 20857037 TI - [Access of hypertension and/or diabetes patients to healthcare services in Baixada Santista]. AB - Arterial Hypertension (AH) and Diabetes Mellitus (DM) are considered a worldwide epidemics whose control poses a challenge to health care services. Within the National Health System, the Family Health Program currently has the dual role of being a system gateway and reference structure. Bearing in mind this scenario, this study assessed the access of AH and DM patients to health care and therapeutic drugs. A household survey was conducted in five municipalities with over 100,000 inhabitants in the Baixada Santista. A two-stage self-weighted probabilistic sample was used. Results estimated a prevalence of 26.3% for AH and of 8.8% for DM, AH being more prevalent among women. As to health care, 85.3% of the individuals with AH interviewed reported having had their arterial pressure checked, and 70.2% of those with DM reported having had their glucose blood serum level tested in the preceding six months. Drug treatment was prescribed to 99.4% of these patients, and 62.8% of AH patients purchased such drugs from private drugstores, and 57.9% of DM patients received drugs provided by health centers. Over 90% of the patients had no access to educational group activities, and 78% of AH and 92.5% of DM patients had no supervising home visits. These findings suggest the need for primary health care as the mainstay for the care provided to HA and DM. PMID- 20857039 TI - [Factors associated with hospital mortality in Rio Grande do Sul SUS network in 2005: application of a Multilevel Model]. AB - OBJECTIVE: To use a multilevel analysis methodology to evaluate hospital mortality from the data available in the Hospital Information System of the National Unified Health System. METHODS: Cross-sectional study with data obtained from Authorization Forms for Hospital Admissions in Rio Grande do Sul, Brazil in 2005. The modeling was performed using multilevel logistic regression, with variables from the individual level (hospital admissions) and the context level (hospital profile). The variability originated from individual variables was analyzed as well as the participation of the profile of hospitals in the rate of hospital mortality. RESULTS: The crude death rate calculated for all hospitals was 6.3%. The variables "Use of Intensive Care Unit" followed by "Patient Age" were the main predictors for hospital death at the individual level. The context variables that were related most closely to hospital death (outcome) were: size of hospital, legal nature, and average length of stay. The OR for deaths at large hospitals was 1.85 times the odds for small hospitals and the OR for medium hospitals was 1.69 times the odds for small ones. The chance of deaths in public hospitals was 67% higher than in private ones. CONCLUSIONS: The hospital profile has an important role in hospital mortality in the Hospital Information System of the National Unified Health System. Multilevel analysis should be used to estimate the contribution of the profile of mortality in hospitals. PMID- 20857040 TI - On the risk of introduction of an emerging infectious disease. PMID- 20857042 TI - B-type natriuretic peptide is predictive of postoperative events in orthopedic surgery. AB - BACKGROUND: [Corrected] Clinical assessment is not always sufficient to predict postoperative (PO) cardiac complications. B-type natriuretic peptide (BNP) has an important prognostic value in patients with heart failure. Its value as a predictor of events in orthopedic surgeries has not yet been tested. OBJECTIVE: To assess the value of BNP in predicting cardiac complications in the PO period of orthopedic surgeries. METHODS: A total of 208 patients undergoing surgical treatment of femur fracture and hip or knee arthroplasty were prospectively evaluated. Of these, 149 (71.6%) were women and the mean age was 72.6 +/- 8.8 years. In the preoperative period, the patients underwent conventional clinical assessment and their surgical risk was estimated according to the American Society of Anesthesiologists' (ASA) classification. BNP was determined in the preoperative period, and its ability to predict PO cardiac events (death; acute myocardial infarction; unstable angina; atrial fibrillation; ventricular tachycardia; or heart failure) was analyzed using multivariate logistic regression analysis. RESULTS: Seventeen patients (8.0%) experienced cardiac events. Median BNP was significantly higher in these patients in comparison to those without cardiac events (93 [interquartile range 73-424] vs 26.6 [13.2 53.1], p = 0.0001). BNP was the main independent predictor of events (p = 0.01). The ASA classification was not an independent predictor. Analysis of the ROC curve demonstrated that for a cut-off point of 60 pg/mL, BNP showed sensitivity of 76.0% and specificity of 79.0% in the prediction of events, with an area under the curve of 83.0%. CONCLUSION: BNP is an independent predictor of PO cardiac events in orthopedic surgeries. PMID- 20857043 TI - Relevance of the ventricular remodeling pattern in the model of myocardial infarction in rats. AB - BACKGROUND: The relevance of the remodeling pattern in the model of infarcted rats is not known. OBJECTIVE: To analyze the presence of different patterns of remodeling in this model and its functional implications. METHODS: Infarcted rats (n=47) have been divided according to the geometry pattern, analyzed by echocardiogram: normal (normal mass index and normal relative thickness), concentric remodeling (normal mass index and increased relative thickness), concentric hypertrophy (increased mass index and increased relative thickness) and eccentric hypertrophy (increased mass index and normal relative thickness). Data are median and interquartile range. RESULTS: Infarcted rats showed only two of the four geometric patterns: normal pattern (15%) and eccentric hypertrophy - EH (85%). Groups of normal pattern and EH showed no differences in the values of fractional area change (Normal = 32.1 - 28.8 to 50.7; EH = 31.3 - 26.5 to 36.7; p = 0.343). Out of the infarcted animals, 34 (74%) had systolic dysfunction, detected by fractional area change. Considering these two geometry patterns, 77% of animals with eccentric hypertrophy and 57% with normal geometry presented systolic dysfunction (p=0.355). The relative wall thickness, the geometric patterns and the body mass index were not predictors of ventricular dysfunction (p> 0.05). On the other hand, infarct size was a predictive factor for ventricular dysfunction in univariate analysis (p<0.001) and multivariate analysis (p = 0.004). CONCLUSION: Rats that underwent coronary occlusion showed two different patterns of remodeling, which do not constitute a predictor of ventricular dysfunction. PMID- 20857044 TI - Chronic and regular use of statin prevents atrial fibrillation in period after cardiac surgery. AB - BACKGROUND: [Corrected] Atrial fibrillation is a common complication after cardiac surgery. The previous use of statins may reduce the incidence of this arrhythmia. OBJECTIVE: To evaluate whether the chronic and regular use of statins, for a period of six months, prevents atrial fibrillation after elective cardiac surgery. METHODS: A study carried out with 107 patients that underwent cardiac surgery, including 66% of males and their mean age was 60.4 years (25 to 84). We evaluated the presence of atrial fibrillation among patients that used statins or not on a regular basis in the preoperative period. We excluded patients with urgent heart surgery, kidney failure, inflammatory diseases, previous atrial fibrillation, patients with thyroid disease and those using a permanent pacemaker. RESULTS: In the postoperative period, atrial fibrillation was present in 42 patients (39%) of the sample, including 11 (26%) people that had used statins on a regular basis in the preoperative period and 31 (74%) who had not. It was possible to observe that, in 22% of the patients that were using statin, there was no development of atrial fibrillation, while 45% of those who did not take statin had arrhythmia (rho = 0.02). In the isolated myocardial revascularization, 47% of the patients that did not take statin and 23% of those that took statin developed atrial fibrillation ( rho = 0.02). There was no statistically significant difference in the analysis of groups with or without statin for the presence of risk factors for the development of atrial fibrillation (rho = 0.34). CONCLUSION: The regular use of statin, for six months or more in the preoperative period, reduced the incidence of atrial fibrillation after elective cardiac surgery. PMID- 20857045 TI - Expiratory positive airway pressure in postoperative cardiac hemodynamics. AB - BACKGROUND: [Corrected] Expiratory positive airway pressure (EPAP) is used in after cardiac surgeries. However, its hemodynamic effects have not been clearly studied. OBJECTIVE: To evaluate the hemodynamic changes caused by EPAP in patients after cardiac surgery monitored by Swan-Ganz. METHODS: Patients at the first or second cardiac surgery postoperative period hemodynamically stable with a Swan-Ganz catheter were included in the study. They were assessed at rest and after using 10 cmH2O EPAP at random. The variables studied were: oxygen saturation, heart rate and respiratory rate, mean artery pressures and pulmonary artery mean pressures (MAP and PAMP), central venous pressure (CVP) and pulmonary capillary wedge pressure (PAOP), cardiac output and index, and systemic and pulmonary vascular resistances. Patients were divided into subgroups (with ejection fraction <; 50% or > 50%) and data were compared by t test and ANOVA. RESULTS: Twenty-eight patients were studied (22 men, aged 68 +/- 11 years). Comparing the period of rest versus EPAP, the changes observed were: PAOP (11.9 +/- 3.8 to 17.1 +/- 4.9 mmHg, p < 0.001), PVC (8.7 +/- 4.1 to 10.9 +/- 4.3 mmHg, p = 0.014), PAMP (21.5 +/- 4.2 to 26.5 +/- 5.8 mmHg, p < 0.001), MAP (76 +/- 10 for 80 +/- 10 mmHg, p = 0.035). The other variables showed no significant differences. CONCLUSION: EPAP was well tolerated by patients and the hemodynamic changes found showed an increase in pressure measurements of right and left ventricular filling, as well as mean arterial pressure. PMID- 20857046 TI - Two-dimensional strain in Takotsubo cardiomyopathy. AB - This report presents the late follow-up of a case of Takotsubo cardiomyopathy with good clinical outcome and improved left ventricular global systolic function. However, there was persistence of significant regional longitudinal systolic dysfunction evaluated using a new echocardiographic technique (speckle tracking), with corresponding measures of strain (S) and strain rate (SR). We emphasize the importance of this new method to monitoring this cardiomyopathy, since it identifies patients with persistent systolic dysfunction who will possibly benefit from maintenance of clinical therapy. PMID- 20857047 TI - Case 4--77-year-old female patient with heart failure, normal left ventricular systolic function and signs of restrictive cardiopathy. PMID- 20857048 TI - Atrial septal defect and pulmonary hypertension in professional soccer player. AB - This study reports a rare case of late diagnosis of atrial septal defect (ASD) with pulmonary hypertension (PH) through two-dimensional echocardiography (ECHO) in a professional soccer player who resumed high-performance sports activity after surgery. PMID- 20857049 TI - Diabetes mellitus classification. AB - The right classification for diabetes mellitus (DM) allows a more adequate treatment and comprises four categories: type 1 DM, type 2 DM, other types, and gestational diabetes. In some cases, there might be a superposition of situations, especially with regard to the DM that initiates in the young adult or is initially presented with diabetic ketoacidosis intermediately to type 1 and 2 DM. Thus, additions to the classic classification system have been proposed as assessing the presence of autoimmunity (antibody) and b cell function (C-peptide) to precisely define the subtypes. The aim of this literature review was to analyze these diagnostic indexes' performance in the DM classification and to describe subtypes with details. The antibodies against pancreas confirm autoimmunity, and the antibody against insulin is more accurate before 5 years old, while the anti-glutamic acid decarboxylase is more accurate after 20 years old, a test which remains positive for a longer period. The measurement of C peptide evaluates the pancreatic insulin reserve, and the most largely used methods of stimulation are the measurement after meals or after intravenous glucagon. C-peptide values < 1.5 ng/ml define a patient with absent pancreatic function and, above this value, patients with preserved function. When the presence of antibodies (A+) directed to the pancreas is combined to its insulin secretion capability (beta+), it is possible to subdivide DM's classification in type 1A (A+beta-) and 1B (A+beta-); and type 2A (A+beta+) and 2B (A-beta+), which allows a more precise classification and treatment besides opening horizons for the understanding of DM pathogenesis. PMID- 20857050 TI - Maintaining the classic approach and innovating in valvulopathy clinics: the balance through bioethics. PMID- 20857051 TI - Change the Qualis criteria! PMID- 20857054 TI - [Rise high the roof beam, carpenters]. PMID- 20857052 TI - Experimental atherosclerosis in rabbits. AB - Many researches have been conducted in experimental models in order to study the development of atherosclerosis from hyperlipidemia-inducing diets. Since rabbits are very sensitive to cholesterol-rich diets and accumulate large amounts of cholesterol in their plasma, their use as experimental models to evaluate the development of atherosclerosis is highly relevant and brings information on factors that contribute to the progression and regression of this condition that can be applied to humans. As such, this review includes studies on the atherogenic function of cholesterol based on rabbits as the experimental model, since they have become the most largely used experimental model of atherosclerosis. PMID- 20857055 TI - [Endothelial dysfunction in diabetes mellitus and insulin resistance states: role of oxidative stress and potential therapeutic opportunities]. PMID- 20857056 TI - [Recent progress and novel perspectives on obesity pharmacotherapy]. AB - Obesity prevalence has risen dramatically over the past decades, which poses a great number of patients at risk of metabolic and cardiovascular complications. Long-term efficacy of lifestyle modification isolated has shown to be modest which, therefore, urges the need of more aggressive interventions such as adjuvant pharmacotherapy or the more radical surgical approach. Bariatric surgery has proven to date to be the most effective treatment, although it may be associated with nutritional and metabolic complications not yet completely recognized. By contrast, there is limited availability of antiobesity agents currently in the market, as well as historical facts involving the suspension of previously existing medications due to safety concerns. This article aims to present recent data on clinical trials of novel weight-loss drugs with short perspective to enter the market, if approved by the regulatory agencies. This review will discuss the efficacy and safety of these compounds, which include lorcaserin (selective serotonin 5-HT2c agonist), tesofensine (triple monoamine reuptake inhibitor), liraglutide (GLP-1 analogue) and cetilistat (gastrointestinal lipase inhibitor), as well as the combination therapies of bupropion/naltrexone, bupropion/zonisamide, phentermine/topiramate and pramlintide/metreleptin. PMID- 20857057 TI - Oxidative stress is not associated with vascular dysfunction in a model of alloxan-induced diabetic rats. AB - OBJECTIVES: To verify if an experimental model of alloxan-diabetic rats promotes oxidative stress, reduces nitric oxide bioavailability and causes vascular dysfunction, and to evaluate the effect of N-acetylcysteine (NAC) on these parameters. METHODS: Alloxan-diabetic rats were treated or not with NAC for four weeks. Plasmatic levels of malondialdehyde (MDA) and nitrite/nitrate (NOx), the endothelial and inducible nitric oxide synthase (eNOS and iNOS) immunostaining and the vascular reactivity of aorta were compared among diabetic (D), treated diabetic (TD) and control (C) rats. RESULTS: MDA levels increased in D and TD. NOx levels did not differ among groups. Endothelial eNOS immunostaining reduced and adventitial iNOS increased in D and TD. The responsiveness of rings to acetylcholine, sodium nitroprusside, and phenylephrine did not differ among groups. CONCLUSIONS: NAC had no effect on the evaluated parameters and this experimental model did not promote vascular dysfunction despite the development of oxidative stress. PMID- 20857058 TI - Nitric oxide enhancement and blood pressure decrease in patients with metabolic syndrome using soy protein or fish oil. AB - OBJECTIVE: To verify the effects of fish oil and soy on nitric oxide (NO) and blood pressure in patients with metabolic syndrome (MS). SUBJECTS AND METHODS: Sixty women with MS were investigated in a parallel randomized design study. The first group maintained their usual diet; the second group received 25 g/day of soy; the third group received 3 g/day of n-3 fatty acids, and the fourth group the same amount previously cited of n-3 fatty acids and soy. RESULTS: Serum nitric oxide metabolites showed significant increase after 90 days in the fish oil and soy groups. Systolic pressure reduced after 45 days of treatment with fish oil, whereas diastolic pressure decreased significantly throughout the study in the soy group. CONCLUSIONS: NO increase and blood pressure reduction with fish oil or soy protein reinforce the importance of the influence of NO on blood pressure in patients with MS. PMID- 20857059 TI - Biochemical acromegaly in patients with prolactinoma during treatment with dopaminergic agonists. AB - OBJECTIVE: To evaluate the frequency of subclinical acromegaly (in the absence of clinical phenotype but biochemically uncontrolled) in patients with prolactinoma during treatment with dopaminergic agonists. SUBJECTS AND METHODS: One hundred twenty one patients without a phenotype suggestive of acromegaly were studied. RESULTS: Initially, the laboratory diagnosis of acromegaly was unequivocal (elevated IGF-1 for gender and age with nadir GH > 1 MUg/L) in two patients, and likely (elevated IGF-1 with nadir GH > cut-off but < 1 MUg/L) in another patient. In two other patients, this diagnosis was possible (normal IGF-1 with nadir GH > 1 MUg/L). Repetition of the tests 6 months after withdrawal of the dopaminergic agonist confirmed the diagnosis of subclinical acromegaly (elevated IGF-1 for gender and age with nadir GH > 1 MUg/L) in these 5 patients. False-positive results were excluded in all cases. CONCLUSION: In patients with prolactinomas, acromegaly should be investigated not only in cases with a clinical phenotype. PMID- 20857060 TI - Thyroglobulin measurements in washout of fine needle aspirates in cervical lymph nodes for detection of papillary thyroid cancer metastases. AB - OBJECTIVE: The aim of this study was to evaluate the accuracy of the measurement of thyroglobulin in washout needle aspiration biopsy (FNAB-Tg) to detect papillary thyroid cancer (PTC) metastases. SUBJECTS AND METHODS: Forty-three patients (51.4 +/- 14.6 years) with PTC diagnosis and evidence of enlarged cervical lymph nodes (LN) were included. An ultrasound-guided fine-needle aspiration of suspicious LN was performed, for both cytological examination and measurement of FNAB-Tg. RESULTS: The median values of FNAB-Tg in patients with metastatic LN (n = 5) was 3,419 ng/mL (11.1-25,538), while patients without LN metastasis (n = 38) showed levels of 3.7 ng/mL (0.8-7.4). Considering a 10 ng/mL cutoff value for FNAB-Tg, the sensitivity and specificity was 100%. There were no differences on the median of FNAB-Tg measurements between those on (TSH 0.07 mUI/mL) or off levothyroxine (TSH 97.4 mUI/mL) therapy (3.3 vs. 3.8 ng/mL, respectively; P = 0.2). CONCLUSION: The results show that evaluation of FNAB-Tg in cervical LN is a valuable diagnostic tool for PTC metastases that can be used independent of the thyroid status. PMID- 20857061 TI - Mutations in the gene encoding paired box domain (PAX8) are not a frequent cause of congenital hypothyroidism (CH) in Iranian patients with thyroid dysgenesis. AB - OBJECTIVE: Congenital hypothyroidism (CH) may be caused by defects in the thyroid or in one of the stages in the synthesis of thyroid hormones. Thyroid dysgenesis may be associated with mutation in the paired box transcription factor 8 (PAX8) gene. We attempted to screen PAX8 gene mutation in 50 CH patients with thyroid dysgenesis. SUBJECTS AND METHODS: The patients were classified in two groups as agenesis and ectopic based on biochemical and para clinical tests. By employing PCR, Single Strand Conformation Polymorphism (SSCP) and sequencing, exons 3 to 12 of PAX8 gene with their exon-intron boundaries were studied. RESULTS: No mutation was found in these patients in any of the exons. CONCLUSION: Our results, once again, indicate that the PAX8 mutation rate is very low and can only explain a minority of the cases. Therefore, it is highly needed to further investigate the genes controlling development and function of thyroid. PMID- 20857062 TI - [Prevalence of diabetes and associated factors in an urban adult population of low educational level and income from the Brazilian Northeast wilderness]. AB - BACKGROUND: Diabetes mellitus (DM) is a public health problem in Brazil. The objective of this study was to investigate the prevalence of DM and its relation with socio-demographic features and other cardiovascular risk factors in a adult population from the wilderness of Pernambuco, Brazil. SUBJECTS AND METHODS: In 2008/2009 a cross-sectional study in the adult urban population of Canaa district, city of Triunfo, in the wilderness of Pernambuco/Brazil was conducted. A representative sample of 198 individuals, with average age of 57.7 years, 80% with primary education and 81.3% with a monthly income of less than 1 minimum wage was randomly selected. RESULTS: A prevalence of diabetes of 13.6% and 7.6% of disglycemia (6.6% of impaired fasting glycemia, and 1.0% of impaired glucose tolerance) was found. Among those with diabetes, 24% had no prior diagnosis. Among diabetics, metabolic syndrome (MS) and arterial hypertension (AH) were diagnosed in 87.5% and 68%, respectively. Besides these, there was a positive and significant association between DM and BMI, and between DM and MS. CONCLUSION: These data demonstrate a high prevalence of DM in the adult urban population from the wilderness of Pernambuco/Brazil. These results as well as their association with obesity and MS, indicate that more effective interventions are necessary for the prevention of these diseases also outside principal urban centers. PMID- 20857063 TI - Polymorphism of the estrogen receptor beta gene is related to infertility and infertility-associated endometriosis. AB - OBJECTIVE: To determine the frequency of the estrogen receptor b gene (ERbeta) +1730 G/A polymorphism in infertile women with and without endometriosis and controls. SUBJECTS AND METHODS: Case-control study that included 136 women with endometriosis, 69 women without endometriosis and 209 fertile women as controls. The ERbeta gene + 1730 G/A polymorphism was identified by RFLP-PCR (Restriction Fragment Length Polymorphism - Polymerase Chain Reaction). RESULTS: Genotypes GG, GA and AA of the ERbeta gene presented frequencies of 60.3%, 38.2% and 1.5%, respectively, in the women with endometriosis (p < 0.0022). Of the infertile women without endometriosis, 63.8% presented the normal homozygous genotype GG, 30.4% the GA heterozygous genotype, and 5.8% the homozygous mutated genotype AA (p < 0.0275). In the control group, 77.5% presented the normal homozygous genotype GG, 21.1% the heterozygous genotype GA, and 1.4% the homozygous mutated genotype AA. CONCLUSION: The data suggest that the estrogen receptor beta gene (ERbeta) +1730 G/A polymorphism can be associated with risk of infertility and endometriosis-associated infertility. PMID- 20857064 TI - [Graves disease and IgA deficiency as manifestations of 22q11.2 deletion syndrome]. AB - The 22q11.2 deletion syndrome (22q11.2DS) is related to a high phenotypic variability including the velocardiofacial/DiGeorge spectrum. Autoimmune, endocrine and immunodeficiency manifestations have been reportedly associated with the syndrome. The objective of this study was to report a case of 22q11.2DS associated with IgA deficiency and Graves disease and review literature in order to verify the frequency of syndrome alterations. Autoimmune disorders have been increasingly related to 22q11.2DS, and new phenotypes are being incorporated in the clinical spectrum of this syndrome. In our study we found that Graves disease in association with 22q11.2DS was reported in only sixteen patients, and fifteen cases were described in the last 13 years. Based on the incidence and on the amplitude of this recognized spectrum, we reinforce the findings of literature that Graves disease should be included on the 22q11.2DS manifestations, which would lead us to seek it with 22q11.2 deletion patients. PMID- 20857065 TI - Primary hyperparathyroidism and incidental multifocal metastatic papillary thyroid carcinoma in a man. AB - Co-existence of primary hyperparathyroidism (PHPT) and non-medullary thyroid carcinoma has been previously reported in sporadic case reports and some surgical series, but the majority of cases concerned women with occult papillary carcinomas without cervical lymph node involvement. We present a 71-year man with PHPT and multinodular goiter who was subjected to surgery for single parathyroid adenoma and was found to have synchronous multifocal papillary thyroid carcinoma (PTC) with cervical lymph node involvement. Review of the literature retrieved only a few similar cases. Ultrasonography of both thyroid and parathyroid glands might be considered in patients with hyperparathyroidism. Given that there are no specific guidelines for the management of patients with synchronous PHPT and PTC, they should be managed like the cases of single PTC. PMID- 20857066 TI - Prevalence and determinant factors to lipid abnormalities among HIV-infected patients: a cross-sectional study of 812 patients. PMID- 20857067 TI - [Hepatic fatty acid profile of rats with AIN-93 diet-induced steatosis attenuated by the partial substitution of soybean oil by diheptanoin and triheptanoin]. PMID- 20857068 TI - Renewing a partnership to further research and improve oral health. PMID- 20857069 TI - Contributing to ultimately offering quality oral health care to all Brazilians. PMID- 20857070 TI - Fluoride: its role in dentistry. AB - In spite of decades of research on fluoride and the recognition of its role as the cornerstone of dental caries reduction in the last fifty years, questions still arise on its use at community, self-applied and professional application levels. Which method of fluoride delivery should be used? How and when should it be used? How can its benefits be maximized and still reduce the risks associated with its use? These are only some of the challenging questions facing us daily. The aim of this paper is to present scientific background to understand the importance of each method of fluoride use considering the current caries epidemiological scenario, and to discuss how individual or combined methods can be used based on the best evidence available. PMID- 20857071 TI - Health promotion and dental caries. AB - The central idea of the Brazilian health system is to prevent the establishment of disease or detect it as early as possible. Prevention and treatment of dental caries are related to behavioral factors, including dietary and oral hygiene habits, which are related to many chronic diseases. Dental health promotion therefore should be fully integrated into broadly based health-promoting strategies and actions such as food and health policies, and general hygiene (including oral hygiene), among others. For decades, a linear relationship between sugar consumption and caries has been observed. Recent data has indicated that this relationship is not as strong as it used to be before the widespread use of fluoride. However, diet is still a key factor acting in the carious process. Oral hygiene is a major aspect when it comes to caries, since dental biofilm is its etiological factor. Oral hygiene procedures are effective in controlling dental caries, especially if plaque removal is performed adequately and associated with fluoride. An alternative to a more efficient biofilm control in occlusal areas is the use of dental sealants, which are only indicated for caries-active individuals. If a cavity is formed as a consequence of the metabolic activity of the biofilm, a restorative material or a sealant can be placed to block access of the biofilm to the oral environment in order to prevent caries progress. The prevention of dental caries based on common risk-factor strategies (diet and hygiene) should be supplemented by more disease-specific policies such as rational use of fluoride, and evidence-based dental health care. PMID- 20857072 TI - Financing national policy on oral health in Brazil in the context of the Unified Health System. AB - This article discusses the model of oral health care implemented in the Unified Health System of Brazil in the last decade. This model was conceived as a sub sector policy that, over the years, has sought to improve the quality of life of the Brazilian population. Through a chronological line, the study presents the National Policy on Oral Health as a counter-hegemonic patient care model for the dentistry practices existing in the country before this policy was implemented. The reorganization of the levels of oral health care, the creation of reference facilities for secondary and tertiary care, through Centers of Dental Specialties and Regional Dental Prosthesis Laboratories, and the differential funding and decentralized management of financial resources were able to expand the actions of oral health for more than 90 million inhabitants. The evolution shown after the deployment of the National Oral Health Policy, as of 2004, demonstrates the greater integration of oral health care under the Unified Health System and provides feedback information to help this policy to continue to be prioritized by the Federal Government and receive more support from the state and local levels in the coming years. PMID- 20857073 TI - Proposal for the teaching of the chemical control of supragingival biofilm. AB - The mechanical control of supragingival biofilm is accepted as one of the most important measures to treat and prevent dental caries and periodontal diseases. Nevertheless, maintaining dental surfaces biofilm-free is not an easy task. In this regard, chemical agents, mainly in the form of mouthwashes, have been studied to help overcome the difficulties involved in the mechanical control of biofilm. The aim of this paper was to discuss proposals for the teaching of supragingival chemical control (SCC) in order to improve dentists' knowledge regarding this clinical issue. Firstly, the literature regarding the efficacy of antiseptics is presented, clearly showing that chemical agents are clinically effective in the reduction of biofilm and gingival inflammation when used as adjuvant agents to mechanical control. Thus, it is suggested that the content related to SCC be included in the curricular grid of dental schools. Secondly, some essential topics are recommended to be included in the teaching of SCC as follows: skills and competencies expected of a graduate dentist regarding SCC; how to include this content in the curricular grid; teaching-learning tools and techniques to be employed; and program content. PMID- 20857074 TI - Oral cancer public policies: is there any evidence of impact? AB - Investigation in oral cancer comprises many different fields such as epidemiology, risk factors, biological markers, diagnostic testing, screening, treatment and prognosis. Although many researchers have dealt with the oral cancer problem, it is unknown if any public policy is capable of reducing its incidence around the world under the scrutiny of the scientific method. This paper aims to briefly review and discuss the literature regarding oral cancer public policies and to screen the evidence of controlled implementations of oral health policies that have been able to diminish oral cancer incidence around the globe. PMID- 20857075 TI - Self-performed supragingival biofilm control: qualitative analysis, scientific basis and oral-health implications. AB - Patients frequently fail to achieve an optimal mechanical plaque control. However, many patients are not confident about using mouthrinses, and many professionals refuse to prescribe them for regular daily use. Aiming at achieving a better understanding of the use and prescription of mouthrinses in periodontics, 24 dentists with different dental educational levels were purposively chosen and interviewed in a qualitative research. Partial data was presented at the 15th Congress of the Brazilian Association for Oral Health Promotion (ABOPREV), and full data was presented at the 88th General Session and Exhibition of the International Association for Dental Research (IADR). The professionals' answers were confirmed or rejected through scientific data analysis. Additionally, scientifically supported answers were provided for the interviewees' most frequent unanswered questions. Around half of the participants (46%) reported that they recommended the use of mouthrinses, although a high percentage (64%) of the dentists answered that they knew very little about the efficacy of mouthrinses and also about the oral benefits (54%) provided by them. All interviewees reported that they were aware of the fact that their patients, and themselves, failed to floss and, less frequently, to brush their teeth, and all of them believed that oral health impacts overall systemic health. Seventy five percent answered that using mouthrinses was safe. Most participants (55%) did not declare themselves as mouthrinse users. We concluded that dentists with different levels of dental education have only partial knowledge related to mouthrinse use in periodontics. The use of effective mouthrinses on a daily basis is justified and can help patients achieve or maintain a healthier mouth. A healthier mouth will positively impact patients' quality of life and could also benefit their overall systemic health. PMID- 20857076 TI - Promotion of Oral Health in the public and private context. PMID- 20857077 TI - Main branch stent deformation following difficult side branch rewiring and balloon dilatation. Rare complication of provisional T stenting. AB - Coronary artery bifurcations are one of the largest challenges in interventional cardiology. Presented is the case of a patient in whom restenosis of a drug eluting stent (DES) occurred as a consequence of guide wire re-crossing between the main vessel stent struts and the vessel wall in the proximal part of DES, and consequential balloon crushing of the proximal portion of the DES. Initially, the complication was not recognized because of a good angiographic result and absence of intravascular ultrasound (IVUS) guidance during the procedure. During the second procedure, IVUS analysis explained the mechanism of the DES failure. The problem was solved with the implantation of a new DES. PMID- 20857078 TI - Papillary fibroelastoma prolapsing into the left ventricular outflow tract: diagnosis using three-dimensional TEE. AB - A 72-year-old woman was admitted to our hospital with exertional dyspnea and atrial tachycardia due to atypical atrial flutter. Comprehensive three dimensional transesophageal echocardiography (3D-TEE) with offline reconstruction of the dataset (Siemens Foursight TEE, Erlangen, Germany) allowed visualization of the origin of the tumor and gave important additional information about the tumor: the tumor surface was floppy, it had the appearance of a "sea anemone", and it was attached to the endocardium of the head of the papillary muscle by a short stalk. The tumor was assessed to be 1.9 * 1.4 * 0.9 cm, and a prolapsing of the tumor into the left ventricular outflow tract during systole was demonstrated.A tumor size of 8 * 10 mm and an infiltration of the head of the anterior papillary muscle were found during surgery. The histopathological findings were typical for a papillary fibroelastoma (PFE) with involvement of the head of the papillary muscle.Our case indicates that a PFE might be difficult to distinguish from myxoma by echocardiography. Thus, the multimodal imaging approach and the three-dimensional visualization of the surface, the localization, and the attachment of the tumor to the head of a papillary muscle were very helpful for the identification of a fibroelastoma in this particular case. PMID- 20857079 TI - Transradial access in percutaneous coronary interventions: technique and procedure. AB - After showing significantly lower complication rates in diagnostic coronary angiography, the radial artery access was successfully introduced as a useful vascular access site for transradial percutaneous coronary intervention in order to enhance patients' comfort and reduce hospital workload and costs. Moreover, due to the reduced need for antiplatelet therapy cessation as a result of lower bleeding complications, patients treated with transradial access showed a significantly better cardiac outcome in randomized interventional acute coronary syndrome studies.Procedural success and postprocedural radial arteritis or radial occlusions are closely related to anatomical circumstances (e.g., anomalous radial branching patterns, tortuosity, e.g., radial loops and small radial artery diameters), or risk factors for radial spasms (e.g. smoking, anxiety, vessel diameter, age, gender) which can effectively be reduced by the use of smaller catheters (4-5 Fr) and the administration of an adjuvant pharmacological therapy before (3000 U heparin, verapamil, nitroglycerine) and after (ibuprofen) the intervention.For successful radial sheath access and transradial catheterization, it is important to use dedicated radial access needles <= 21-gauge and steel wires <= 0.018 in. In order to pass the brachiocephalic trunk without difficulties or complications and access the ascending aorta, the use of inspiration maneuvers is of central importance. PMID- 20857081 TI - [Oncological surgery of the small pelvis]. PMID- 20857080 TI - Potential impact of a 32-channel receiving head coil technology on the results of a functional MRI paradigm. AB - PURPOSE: The authors investigated the potential of a 32-channel (32ch) receiving head coil for functional magnetic resonance imaging (fMRI) compared to a standard eight-channel (8ch) coil using a motor task. MATERIAL AND METHODS: Brain activation was analyzed in 14 healthy right-handed subjects performing finger tapping with the right index finger (block design) during two experimental sessions, one with the 8ch and one with the 32ch coil (applied in a pseudorandomized order). Additionally, a phantom study was performed to compare signal-to-noise ratios (SNRs) of both coils. RESULTS: During both fMRI sessions, analysis of motor conditions resulted in an activation of the left "hand knob" (precentral gyrus). Application of the 32ch coil obtained additional activation clusters in the right cerebellum, left superior frontal gyrus (SMA), left supramarginal gyrus, and left postcentral gyrus. The phantom study revealed a significantly higher SNR for the 32ch coil compared to the 8ch coil in superficial cortical areas located near the surface of the brain. CONCLUSION: The 32ch technology has a potential impact on fMRI studies, especially in paradigms that result in activation of cortical areas located near the surface of the brain. PMID- 20857082 TI - Mapping QTL main and interaction influences on milling quality in elite US rice germplasm. AB - Rice (Oryza sativa L.) head-rice yield (HR) is a key export and domestic quality trait whose genetic control is poorly understood. With the goal of identifying genomic regions influencing HR, quantitative-trait-locus (QTL) mapping was carried out for quality-related traits in recombinant inbred lines (RILs) derived from crosses of common parent Cypress, a high-HR US japonica cultivar, with RT0034, a low-HR indica line (129 RILs) and LaGrue, a low-HR japonica cultivar (298 RILs), grown in two US locations in 2005-2007. Early heading increased HR in the Louisiana (LA) but not the Arkansas (AR) location. Fitting QTL-mapping models to separate QTL main and QTL * environment interaction (QEI) effects and identify epistatic interactions revealed six main-effect HR QTLs in the two crosses, at four of which Cypress contributed the increasing allele. Multi-QTL models accounted for 0.36 of genetic and 0.21 of genetic * environment interaction of HR in MY1, and corresponding proportions of 0.25 and 0.37 in MY2. The greater HR advantage of Cypress in LA than in AR corresponded to a genomewide pattern of opposition of HR-increasing QTL effects by AR-specific effects, suggesting a selection strategy for improving this cultivar for AR. Treating year-location combinations as independent environments resulted in underestimation of QEI effects, evidently owing to lower variation among years within location than between location. Identification of robust HR QTLs in elite long-grain germplasm is suggested to require more detailed attention to the interaction of plant and grain development parameters with environmental conditions than has been given to date. PMID- 20857083 TI - Genetic mapping of stem rust resistance gene Sr13 in tetraploid wheat (Triticum turgidum ssp. durum L.). AB - Wheat stem rust caused by Puccinia graminis f. sp. tritici, can cause significant yield losses. To combat the disease, breeders have deployed resistance genes both individually and in combinations to increase resistance durability. A new race, TTKSK (Ug99), identified in Uganda in 1999 is virulent on most of the resistance genes currently deployed, and is rapidly spreading to other regions of the world. It is therefore important to identify, map, and deploy resistance genes that are still effective against TTKSK. One of these resistance genes, Sr13, was previously assigned to the long arm of chromosome 6A, but its precise map location was not known. In this study, the genome location of Sr13 was determined in four tetraploid wheat (T. turgidum ssp. durum) mapping populations involving the TTKSK resistant varieties Kronos, Kofa, Medora and Sceptre. Our results showed that resistance was linked to common molecular markers in all four populations, suggesting that these durum lines carry the same resistance gene. Based on its chromosome location and infection types against different races of stem rust, this gene is postulated to be Sr13. Sr13 was mapped within a 1.2-2.8 cM interval (depending on the mapping population) between EST markers CD926040 and BE471213, which corresponds to a 285-kb region in rice chromosome 2, and a 3.1-Mb region in Brachypodium chromosome 3. These maps will be the foundation for developing high-density maps, identifying diagnostic markers, and positional cloning of Sr13. PMID- 20857084 TI - Genetic evidence of the programming of beta cell mass and function by glucocorticoids in mice. AB - AIMS/HYPOTHESIS: Prenatal exposure to excess glucocorticoids associates with low birthweight in rodents, primates and humans and its involvement in programming glucose homeostasis is suspected. Our aim was to further dissect the role of glucocorticoids on beta cell development and function in mice. METHODS: Using the model of maternal general food restriction during the last week of pregnancy, we thoroughly studied in the CD1 mouse-mothers and fetal and adult offspring--the pancreatic, metabolic and molecular consequences of maternal undernutrition associated with excess glucocorticoids. The specific involvement of the glucocorticoid receptor (GR) was studied in mutant fetuses lacking GR in pancreatic precursors or mature beta cells. RESULTS: Maternal general food restriction in the mouse is associated with decreased maternal glucose and increased corticosterone levels. Fetuses from underfed dams had increased corticosterone levels, decreased pancreatic endocrine gene expression but increased exocrine gene expression and a lower beta cell mass. The offspring of these dams had a low birthweight, permanent postnatal growth retardation and, as adults, impaired glucose tolerance, decreased beta cell mass (-50%) and massively reduced islet expression (-80%) of most of the genes involved in beta cell function (e.g. Pdx1, Sur1 [also known as Abcc8], insulin). Moreover, using mutant fetuses lacking GR in pancreatic precursors or beta cells we show that the deleterious effect of undernutrition on fetal beta cell development requires the presence of the GR in pancreatic precursor cells. CONCLUSIONS/INTERPRETATION: These results demonstrate the crucial role of excess fetal glucocorticoids and the importance of GR signalling in progenitor cells to programme beta cell mass and dysfunction. PMID- 20857085 TI - The effect of risky alcohol use and smoking on suicide risk: findings from the German MONICA/KORA-Augsburg Cohort Study. AB - BACKGROUND: Smoking and heavy alcohol use predicts suicidal behaviour. Whether the simultaneous presentation of both conditions induces an amplified effect on risk prediction has not been investigated so far. METHODS: In a community-based cohort study, a total of 12,888 subjects (6,456 men, 6,432 women; age range of 25 74 years at assessment) from three independent population-based cross-sectional MONICA surveys (conducted in 1984/85, 1989/90, and 1994/95), representative for the Southern German population, was followed up until 31 December 2002. Standardized mortality ratios (SMR) for deaths from suicide using German population rates were calculated for smoking and high alcohol consumption. RESULTS: After a mean follow-up time of 12.0 (SD 4.4) years and 154,275 person years at risk, a total of 1,449 persons had died from all causes and 38 of them from suicide. Compared to the general population, mortality from suicide was increased for risky alcohol consumption (SMR = 2.37; 95% CI 1.14-4.37) and for smoking (SMR = 2.30; 95% CI 1.36-3.63). A substantial increase in suicide mortality (SMR = 4.80; 95% CI 2.07-9.46) was observed for smokers with risky alcohol consumption. CONCLUSIONS: The approximately fourfold increased relative risk for completed suicide in subjects with smoking and risky alcohol consumption indicates a synergistic effect which deserves an increased alertness. PMID- 20857086 TI - Knee arthroscopy routines and practice. AB - PURPOSE: Knee arthroscopy is one of most commonly performed day-case orthopaedic procedures, thus consuming huge medical resources. The aim of the present questionnaire survey was to study knee arthroscopy routines and practice. METHODS: An electronic web-based survey including questions around pre-, per- and postoperative routines for elective knee arthroscopy was send to all orthopaedic units associated to the Swedish Arthroscopic Society (n = 60). RESULTS: Responses covering 37 centres out of 60 (response rate 62%) were returned. Preoperative radiograph routines varied considerable between centres; conventional radiograph varied between 5 and 100% and preoperative MRI between 5 and 80% of patients. General anaesthesia was the preferred intra-operative technique used in all centres (median 79% of patients), local anaesthesia with or without light sedation was used in all 28 out of the 37 centres responding (median 10% of cases) and spinal anaesthesia was used in 15 centres (median 5% of cases). Intra articular local anaesthesia was provided in all but one of centres. Perioperative administration of oral NSAIDs was common (31 out 37), 6 centres (all teaching hospitals) did not routinely give pre- or postoperative NSAID. Analgesic prescription was provided on a regular base in 18 (49%) of centres; an NSAID being the most commonly prescribed. All but one centre provided written information and instruction at discharge. Referral to physiotherapy, prescribed sick leave and scheduled follow-up in the outpatient clinic diverged considerably. CONCLUSION: Routines and practice associated to elective knee arthroscopy differed; however, no clear differences in practice were seen between teaching centres, general or local hospitals apart from a lower usage of NSAID for perioperative analgesia. There is an obvious room for further standardisation in the routine handling of patients undergoing elective arthroscopy of the knee. PMID- 20857087 TI - The original versus a modified inside-out transobturator procedure: 1-year results of a prospective randomized trial. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study is to compare a modified inside-out transobturator procedure with its original counterpart [inside-out transobturator (TVT-O)] for the treatment of female stress urinary incontinence (SUI). METHODS: A prospective, randomized trial in women suffering from SUI was used. The modified procedure consisted of a shorter tape whilst the scissors or guide no longer perforated the obturator membrane. The primary outcome was the resolution of subjective and objective SUI at 1 year. Secondary outcome measures included adverse events, quality of life measures, and groin pain. RESULTS: One hundred seventy-five patients were randomized. No intraoperative complications were recorded. The SUI cure rate was 91.7% versus 90.7% (original versus modified, respectively; p = 0.824). Incidence and intensity of groin pain was higher in the original TVT-O group on day 0 and 1 (p < 0.05), requiring more analgesics (p = 0.015) but not thereafter. CONCLUSIONS: At 1 year follow-up, the modified inside-out transobturator tape procedure was as efficient and safe as the original technique but associated with less immediate postoperative groin pain. PMID- 20857089 TI - In vitro study of P-glycoprotein induction as an antidotal pathway to prevent cytotoxicity in Caco-2 cells. AB - The Caco-2 cell line is a reliable in vitro model for predicting drug intestinal absorption and P-glycoprotein (P-gp)-mediated excretion in humans. Recent in vivo studies suggested the induction of P-gp as a cellular protection tool against paraquat poisoning, through the increase in its pulmonary and intestinal excretion. Thus, the aim of the present work was to evaluate P-gp expression and activity in Caco-2 cells exposed to doxorubicin (a known P-gp inducer) and to correlate these changes with paraquat toxic effects. Cytotoxicity of doxorubicin (0-100 MUM) and paraquat (0-1,000 MUM) was evaluated for a maximum period of 96 h. In doxorubicin-exposed cells, P-gp expression and transport activity were evaluated by flow cytometry, using a fluorescein isothiocyanate-conjugated antibody and the P-gp fluorescent subtract rhodamine 123, respectively. A significant increase in P-gp expression was observed as soon as 6 h after exposure to 5 MUM doxorubicin. P-gp activity also increased after 6 h, but only at higher doxorubicin concentrations (over 50 MUM). Paraquat (0-5,000 MUM) cytotoxicity was then evaluated with or without previous exposure of the cells to doxorubicin (5-100 MUM, a concentration range causing both an increase in P-gp expression and activity). Under P-gp induction, a significant reduction in paraquat cytotoxicity was observed. Furthermore, when these cells were incubated with a specific P-gp inhibitor (UIC2 antibody) the doxorubicin protective effects were blocked, confirming the involvement of P-gp in the reduction in paraquat cytotoxicity. In conclusion, the human Caco-2 cell line model can be used for the study of P-gp induction as an antidotal pathway against substrates of this transporter system. PMID- 20857088 TI - Delftia sp. JD2: a potential Cr(VI)-reducing agent with plant growth-promoting activity. AB - A chromium (Cr)-resistant bacterium isolated from soil containing 6,000 mg/kg of Cr was identified based on 16S rRNA gene sequence analysis as Delftia, and designated as JD2. Growth of JD2 was accompanied with reduction of Cr(VI) to Cr(III) in liquid medium initially containing 100 mg/L Cr(VI), the maximum concentration allowing growth. JD2 showed NADH/NADPH-dependent reductase activity associated with the soluble fraction of cells. The results suggest that JD2 might be a good candidate for the treatment of highly Cr(VI)-contaminated water and/or industrial effluents. The isolate produced indole-3-acetic acid in the presence and absence of Cr(VI) and showed free-living nitrogen-fixing activity possibly attributable to a V-nitrogenase. JD2 did not counteract the harmful effect of Cr(VI) during leguminous plant growth and nodulation by rhizobial strains but functioned as a "helper" bacterium to enhance the performance of rhizobial inoculant strains during inoculation of alfalfa and clover (used as model plants to study plant growth-promoting activity) in the absence of Cr(VI). PMID- 20857090 TI - Functional alpha-1B adrenergic receptors on human epicardial coronary artery endothelial cells. AB - Alpha-1-adrenergic receptors (alpha1-ARs) regulate coronary arterial blood flow by binding catecholamines, norepinephrine (NE), and epinephrine (EPI), causing vasoconstriction when the endothelium is disrupted. Among the three alpha1-AR subtypes (alpha1A, alpha1B, and alpha1D), the alpha1D subtype predominates in human epicardial coronary arteries and is functional in human coronary smooth muscle cells (SMCs). However, the presence or function of alpha1-ARs on human coronary endothelial cells (ECs) is unknown. Here we tested the hypothesis that human epicardial coronary ECs express functional alpha1-ARs. Cultured human epicardial coronary artery ECs were studied using quantitative real-time reverse transcription polymerase chain reaction, radioligand binding, immunoblot, and (3)H-thymidine incorporation. The alpha1B-subtype messenger ribonucleic acid (mRNA) was predominant in cultured human epicardial coronary ECs (90-95% of total alpha1-AR mRNA), and total alpha1-AR binding density in ECs was twice that in coronary SMCs. Functionally, NE and EPI through the alpha1B subtype activated extracellular signal-regulated kinase (ERK) in ECs, stimulated phosphorylation of EC endothelial nitric oxide synthase (eNOS), and increased deoxyribonucleic acid (DNA) synthesis. These results are the first to demonstrate alpha1-ARs on human coronary ECs and indicate that the alpha1B subtype is predominant. Our findings provide another potential mechanism for adverse cardiac effects of drug antagonists that nonselectively inhibit all three alpha1-AR subtypes. PMID- 20857091 TI - Advancing age alters the influence of eye position on sound localization. AB - Vision and audition provide spatial information about the environment to guide natural behavior. Because the eyes move in the head while the ears remain head fixed, input conveying eye position in the head is required to maintain audiovisual congruence. Human perception of auditory space was previously shown to shift with changes in eye position, regardless of the target's frequency content and spatial cues underlying horizontal and vertical localization. In this study, we examined whether this interaction is altered by advancing age. Head restrained young (18-44 yo), middle-aged (45-64 yo), and elderly (65-81 yo) human subjects localized noise bursts under conditions of transient and sustained ocular deflection. All three age groups demonstrated a time-dependent shift of auditory space in the direction of eye position. Moreover, this adaptation showed a clear decline with advancing age, but only for peripheral auditory space (beyond +/-10 degrees from midline). Alternatively, adaptation in the periphery may occur, but is more sluggish than in the central field and therefore not fully observed in this experiment. The age-dependent effect cannot be readily explained by senescent peripheral hearing loss, suggesting a change in central processing of auditory space in relation to the control of gaze. PMID- 20857092 TI - Prescription writing: a lost art? PMID- 20857093 TI - Effect of the inhibition of CYP3A4 or CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. AB - PURPOSE: The main metabolic pathways of oxycodone, a potent opioid analgetic, are N-demethylation (CYP3A4) to inactive noroxycodone and O-demethylation (CYP2D6) to active oxymorphone. We performed a three-way, placebo-controlled, double-blind cross-over study to assess the pharmacokinetic and pharmacodynamic consequences of drug interactions with oxycodone. METHODS: The 12 participants (CYP2D6 extensive metabolizers) were pre-treated with placebo, ketoconazole or paroxetine before oral oxycodone ingestion (0.2 mg/kg). RESULTS: Pre-treatment with ketoconazole increased the AUC for oxycodone 2- to 3-fold compared with placebo or paroxetine. In combination with placebo, oxycodone induced the expected decrease in pupil diameter. This decrease was accentuated in the presence of ketoconazole, but blunted by paroxetine. In comparison to pre-treatment with placebo, ketoconazole increased nausea, drowsiness, and pruritus associated with oxycodone. In contrast, the effect of pre-treatment with paroxetine on the above mentioned adverse events was not different from that of placebo. Ketoconazole increased the analgetic effect of oxycodone, whereas paroxetine was not different from placebo. CONCLUSIONS: Inhibition of CYP3A4 by ketoconazole increases the exposure and some pharmacodynamic effects of oxycodone. Paroxetine pretreatment inhibits CYP2D6 without inducing relevant changes in oxycodone exposure, and partially blunts the pharmacodynamic effects of oxycodone due to intrinsic pharmacological activities. Pharmacodynamic changes associated with CYP3A4 inhibition may be clinically important in patients treated with oxycodone. PMID- 20857094 TI - Comparative efficacy and overall safety of different doses of consensus interferon for treatment of chronic HCV infection: a systematic review and meta analysis. AB - BACKGROUND: About one-half of patients with hepatitis C genotype 1 and one-third with genotype 2/3 have treatment failure with peginterferon alpha and ribavirin. Consensus interferon (CIFN) is an option for retreatment of these patients. OBJECTIVE: To summarize comparative safety and efficacy of different regimens of CIFN for the treatment of patients with chronic hepatitis C infection. DATA SOURCE: Medline, Scopus, ISI, and Cochran Central Register of Clinical Trials were used. STUDY ELIGIBILITY CRITERIA: Randomized clinical trials (RCTs) were eligible for inclusion in the study. PARTICIPANTS: HIV and HBV seronegative patients with positive HCV-RNA during the 6 months before the start of the study were eligible for inclusion. INTERVENTIONS: Different regimens of CIFN were studied. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were appraised based on methods of random sequence generation, allocation concealment, and blinding. The random effects model of DerSimonian and Laird was employed to run the meta analysis. The end-point was sustained virological response (SVR). RESULTS: Data of 10 RCTs including 1,600 subjects were extracted. High daily induction dose regimen of CIFN did not yield a higher rate of SVR than low daily induction dose treatment regimen, RR = 0.83 (95% CI 0.58-1.17). A dose of 9 MUg thrice weekly (tiw) was associated with a significantly higher rate of SVR compared with 3 MUg [RR = 3.14 (95% CI 1.68-5.58)][Symbol: see text]. Withdrawal rate was similar [RR = 1.28 (95% CI 0.65-2.50)] but dose modification was higher in 9 MUg [RR = 3.22 (95% CI 1.08-9.60)]. A dose of 18/15 MUg tiw was not more effective than 9 MUg over a similar treatment duration [RR = 1.02 (95% CI 0. 87-1.19)]. LIMITATIONS: Limitations include inadequate reporting of methodological information and side effects, lack of publication bias assessment due to the small number of studies in each analysis. CONCLUSIONS: High dose daily induction therapy with CIFN is not superior to low dose therapy in terms of SVR. It seems that 9 MUg tiw is the optimal treatment dose of CIFN for treatment of HCV infection. Optimal duration and safety profile of CIFN therapy have yet been elucidated. PMID- 20857095 TI - Alterations in vitamin A and E levels in liver and testis of wild ungulates from a lead mining area. AB - In animals, exposure to metal pollution can induce oxidative stress via several mechanisms. This stress might then cause adverse effects on functions such as male reproductive capacity. Antioxidant vitamins A and E play an important role in maintaining organism functions under stressed conditions. This study assessed the effect of different metals and metalloids on levels of vitamins A and E in livers and testis (n = 67 and 36) of red deer and in livers (n = 22) of wild boar. The study compared animals residing within and outside a polluted mining area. Red deer from mined areas showed significant reductions in liver retinyl docosahexaenoate and retinyl docosapentaenoate. Free retinol, alpha-tocopherol, and retinyl palmitate in the testis were also lower. This might indicate that increased internal usage of these antioxidants is occurring as deer try to maintain the integrity and function of reproductive tissue. Wild boar from mined areas also showed significant reductions in liver retinyl stearate but increased free retinol levels. This might suggest that vitamin A is being mobilized to a greater degree to cope with the induced oxidative stress caused by exposure to metal pollution. Additionally, a significant negative relationship between liver alpha-tocopherol and bone lead (Pb) in boar might indicate some long-term effects of Pb on antioxidant levels. Results suggest that vitamin A and E status can be altered as a consequence of exposure to Pb pollution and that complex differences in this response probably exist between species. PMID- 20857096 TI - The genetic diversity of culturable nitrogen-fixing bacteria in the rhizosphere of wheat. AB - A total of 17 culturable nitrogen-fixing bacterial strains associated with the roots of wheat growing in different regions of Greece were isolated and characterized for plant-growth-promoting traits such as auxin production and phosphate solubilization. The phylogenetic position of the isolates was first assessed by the analysis of the PCR-amplified 16S rRNA gene. The comparative sequence analysis and phylogenetic analysis based on 16S rRNA gene sequences show that the isolates recovered in this study are grouped with Azospirillum brasilense, Azospirillum zeae, and Pseudomonas stutzeri. The diazotrophic nature of all isolates was confirmed by amplification of partial nifH gene sequences. The phylogenetic tree based on nifH gene sequences is consistent with 16S rRNA gene phylogeny. The isolates belonging to Azospirillum species were further characterized by examining the partial dnaK gene phylogenetic tree. Furthermore, it was demonstrated that the ipdC gene was present in all Azospirillum isolates, suggesting that auxin is mainly synthesized via the indole-3-pyruvate pathway. Although members of P. stutzeri and A. zeae are known diazotrophic bacteria, to the best of our knowledge, this is the first report of isolation and characterization of strains belonging to these bacterial genera associated with wheat. PMID- 20857097 TI - HLA-Cw group 1 ligands for KIR increase susceptibility to invasive cervical cancer. AB - Inherited genetic polymorphisms within immune response genes have been shown to associate with risk of invasive cervical cancer (ICC) and its immediate precursor, cervical intraepithelial neoplasia grade 3. Here, we used the transmission/disequilibrium test to detect disease-liability alleles and investigate haplotype transmission of KIR and HLA class I polymorphisms in a large family-based population of women with cervical cancer and their biological parents (359 trios). The effect of distinct human papillomavirus types was also explored. HLA-Cw group 1 (HLA-Cw alleles with asparagine at position 80), which serves as ligand for certain killer immunoglobulin-like receptors (KIR), was significantly overtransmitted in women with ICC (P = 0.04), and particularly in the subgroup of women infected with high risk HPV16 or 18 subtypes (P = 0.008). These data support the involvement of the HLA-C locus in modulating the risk of cervical neoplasia perhaps through its function as ligands for KIR, but functional studies are essential to confirm this hypothesis. PMID- 20857098 TI - FDG uptake in vaginal tampons is caused by urinary contamination and related to tampon position. AB - PURPOSE: The aim of the study was to determine the aetiology of FDG uptake in vaginal tampons (VT), a known artefact in premenopausal women evaluated by PET/CT. METHODS: This Institutional Review Board approved study consisted of retrospective and prospective parts. The retrospective analysis included 685 women examined between January 2008 and December 2009 regarding VT presence. PET/CT images were analysed to determine the localization and the standardized uptake value (SUV) of VTs. We prospectively recruited 24 women (20-48 years old) referred for staging or follow-up in an oncology setting between February and April 2010, who were provided a commercial VT to be used during the entire examination after obtaining written informed consent. After image acquisition, VTs were individually analysed for creatinine concentration and blood traces. Statistical significance was tested with the Mann-Whitney U test. RESULTS: In the retrospective part, 38 of 685 women were found to have a VT of which 17 (45%) were FDG positive. A statistically significant correlation was found between FDG activity and VT position below the pubococcygeal line (PCL) (13 +/- 11.2 mm). In the prospective study, 7 of 24 (29%) women had increased FDG activity in their VTs (SUV 18.8 +/- 11 g/ml) but were not menstruating. FDG-positive VTs were significantly lower in position (14.6 +/- 11.4 mm,below the PCL) than FDG negative VTs (p = 0.039). The creatinine concentration was significantly increased in all seven positive VTs (931 +/- 615 MUmol/l). CONCLUSION: FDG uptake in VTs is caused by urine contamination, which is likely related to localization below the PCL resulting in contact with urine during voiding. PMID- 20857099 TI - PET imaging of alphavbeta3 integrin expression in tumours with 68Ga-labelled mono , di- and tetrameric RGD peptides. AB - PURPOSE: Due to the restricted expression of alpha(v)beta(3) in tumours, alpha(v)beta(3) is considered a suitable receptor for tumour targeting. In this study the alpha(v)beta(3)-binding characteristics of (68)Ga-labelled monomeric, dimeric and tetrameric RGD peptides were determined and compared with their (111)In-labelled counterparts. METHODS: A monomeric (E-c(RGDfK)), a dimeric (E [c(RGDfK)](2)) and a tetrameric (E{E[c(RGDfK)](2)}(2)) RGD peptide were synthesised, conjugated with DOTA and radiolabelled with (68)Ga. In vitro alpha(v)beta(3)-binding characteristics were determined in a competitive binding assay. In vivo alpha(v)beta(3)-targeting characteristics of the compounds were assessed in mice with subcutaneously growing SK-RC-52 xenografts. In addition, microPET images were acquired using a microPET/CT scanner. RESULTS: The IC(50) values for the Ga(III)-labelled DOTA-E-c(RGDfK), DOTA-E-[c(RGDfK)](2) and DOTA E{E[c(RGDfK)](2)}(2) were 23.9 +/- 1.22, 8.99 +/- 1.20 and 1.74 +/- 1.18 nM, respectively, and were similar to those of the In(III)-labelled mono-, di- and tetrameric RGD peptides (26.6 +/- 1.15, 3.34 +/- 1.16 and 1.80 +/- 1.37 nM, respectively). At 2 h post-injection, tumour uptake of the (68)Ga-labelled mono-, di- and tetrameric RGD peptides (3.30 +/- 0.30, 5.24 +/- 0.27 and 7.11 +/- 0.67%ID/g, respectively) was comparable to that of their (111)In-labelled counterparts (2.70 +/- 0.29, 5.61 +/- 0.85 and 7.32 +/- 2.45%ID/g, respectively). PET scans were in line with the biodistribution data. On all PET scans, the tumour could be clearly visualised. CONCLUSION: The integrin affinity and the tumour uptake followed the order of DOTA-tetramer > DOTA-dimer > DOTA-monomer. The (68)Ga-labelled tetrameric RGD peptide has excellent characteristics for imaging of alpha(v)beta(3) expression with PET. PMID- 20857100 TI - Fludarabine modulates composition and function of the T cell pool in patients with chronic lymphocytic leukaemia. AB - The combination of cytotoxic treatment with strategies for immune activation represents an attractive strategy for tumour therapy. Following reduction of high tumour burden by effective cytotoxic agents, two major immune-stimulating approaches are being pursued. First, innate immunity can be activated by monoclonal antibodies triggering antibody-dependent cellular cytotoxicity. Second, tumour-specific T cell responses can be generated by immunization of patients with peptides derived from tumour antigens and infused in soluble form or loaded onto dendritic cells. The choice of cytotoxic agents for such combinatory regimens is crucial since most substances such as fludarabine are considered immunosuppressive while others such as cyclophosphamide can have immunostimulatory activity. We tested in this study whether fludarabine and/or cyclophosphamide, which represent a very effective treatment regimen for chronic lymphocytic leukaemia, would interfere with a therapeutic strategy of T cell activation. Analysis of peripheral blood samples from patients prior and during fludarabine/cyclophosphamide therapy revealed rapid and sustained reduction of tumour cells but also of CD4(+) and CD8(+) T cells. This correlated with a significant cytotoxic activity of fludarabine/cyclophosphamide on T cells in vitro. Unexpectedly, T cells surviving fludarabine/cyclophosphamide treatment in vitro had a more mature phenotype, while fludarabine-treated T cells were significantly more responsive to mitogenic stimulation than their untreated counterparts and showed a shift towards T(H)1 cytokine secretion. In conclusion, fludarabine/cyclophosphamide therapy though inducing significant and relevant T cell depletion seems to generate a micromilieu suitable for subsequent T cell activation. PMID- 20857101 TI - MAGE-A3 and MAGE-A4 specific CD4(+) T cells in head and neck cancer patients: detection of naturally acquired responses and identification of new epitopes. AB - Frequent expression of cancer testis antigens (CTA) has been consistently observed in head and neck squamous cell carcinomas (HNSCC). For instance, in 52 HNSCC patients, MAGE-A3 and -A4 CTA were expressed in over 75% of tumors, regardless of the sites of primary tumors such as oral cavity or hypopharynx. Yet, T-cell responses against these CTA in tumor-bearing patients have not been investigated in detail. In this study, we assessed the naturally acquired T-cell response against MAGE-A3 and -A4 in nonvaccinated HNSCC patients. Autologous antigen-presenting cells pulsed with overlapping peptide pools were used to detect and isolate MAGE-A3 and MAGE-A4 specific CD4(+) T cells from healthy donors and seven head and neck cancer patients. CD4(+) T-cell clones were characterized by cytokine secretion. We could detect and isolate MAGE-A3 and MAGE A4 specific CD4(+) T cells from 7/7 cancer patients analyzed. Moreover, we identified six previously described and three new epitopes for MAGE-A3. Among them, the MAGE-A3(111-125) and MAGE-A3(161-175) epitopes were shown to be naturally processed and presented by DC in association with HLA-DP and DR, respectively. All of the detected MAGE-A4 responses were specific for new helper epitopes. These data suggest that naturally acquired CD4(+) T-cell responses against CT antigens often occur in vivo in HNSCC cancer patients and provide a rationale for the development of active immunotherapeutic approaches in this type of tumor. PMID- 20857103 TI - Two-stage breast cancer screening in the developing world. PMID- 20857104 TI - Adjuvant S-1 chemotherapy for gastric cancer and peritoneal wash. PMID- 20857105 TI - Metachronous cancer in the stomach remnant. PMID- 20857106 TI - Chest wall resection for adult soft tissue sarcomas and chondrosarcomas: analysis of prognostic factors. AB - BACKGROUND: Wide resection with tumor-free margins is necessary in soft-tissue sarcomas to minimize local recurrence and to contribute to long-term survival. Information about treatment outcome and prognostic factors of adult sarcoma requiring chest wall resection (CWR) is limited. METHODS: Sixty consecutive patients were retrospectively studied for overall survival (OS), local recurrence free survival (LRFS), and disease-free survival (DFS). Twenty-one prognostic factors regarding survival were analyzed by univariate analysis using the Kaplan Meier method and the log-rank test. RESULTS: With a median survival of 2.5 years, the OS was 46% (33%) at 5 (10) years. The LRFS was 64% at 5 and 10 years, and the DFS was 30% and 25% at 5 and 10 years. At the end of the study period, 26 patients (43%) were alive, of which 20 patients (33%) had no evidence of disease and 40 patients (67%) had no chest wall recurrence. In the group of 9 patients with a radiation-induced soft-tissue sarcoma, the median survival was 8 months. Favorable outcome in univariate analysis in OS and LRFS applied for the low-grade sarcoma, bone invasion, and sternal resection. For OS only, age below 60 years and no radiotherapy were significant factors contributing to an improved survival. CWR was considered radical (R0) at the pathological examination in 43 patients. There were 52 patients with an uneventful recovery. There was one postoperative death. CONCLUSIONS: CWR for soft-tissue sarcoma is a safe surgical procedure with low morbidity and a mortality rate of less than 1%. With proper patient selection acceptable survival can be reached in a large group of patients. Care must be given to patients with radiation-induced soft-tissue sarcoma who have a significantly worse prognosis. PMID- 20857107 TI - Is resection of Crohn's disease a procedure of the past? PMID- 20857108 TI - Uterine fibroid embolisation for symptomatic uterine fibroids: a survey of clinical practice in Europe. AB - PURPOSE: To assess current uterine fibroid embolisation (UFE) practice in European countries and determine the clinical environment for UFE in different hospitals. MATERIAL AND METHODS: In May 2009, an invitation for an online survey was sent by e-mail to all members of the Cardiovascular and Interventional Radiologic Society of Europe, representing a total number of 1,250 different candidate European treatment centres. The survey covered 21 questions concerning local UFE practice. RESULTS: A total of 282 respondents completed the questionnaire. Fifteen questionnaires were excluded because they were doubles from centres that had already returned a questionnaire. The response rate was 267 of 1,250 centres (21.4%). Ninety-four respondents (33%) did not perform UFE and were excluded, and six centres were excluded because demographic data were missing. The remaining 167 respondents from different UFE centres were included in the study. Twenty-six percent of the respondents were from the United Kingdom (n = 43); 16% were from Germany (n = 27); 11% were from France (n = 18); and the remaining 47% (n = 79) were from other European countries. Most centres (48%, n = 80) had 5 to 10 years experience with UFE and performed 10 to 50 procedures annually (53% [n = 88]) of respondents). Additional demographic data, as well as specific data on referral of patients, UFE techniques used, and periprocedural and postprocedural, care will be provided. CONCLUSION: Although UFE as an alternative treatment for hysterectomy or myomectomy is widespread in Europe, its impact on the management of the patient with symptomatic fibroids seems, according to the overall numbers of UFE procedures, somewhat disappointing. Multiple factors might be responsible for this observation. PMID- 20857110 TI - Endovascular management of visceral artery pseudoaneurysms: transcatheter coil embolization using the isolation technique. AB - PURPOSE: To describe our experiences with treatment of visceral artery pseudoaneurysms (VAPA) by transcatheter coil embolization using an isolation technique and to propose indications for treating VAPA with this method. MATERIALS AND METHODS: We treated 37 patients with VAPA endovascularly: There were 15 pancreaticoduodenal arcade, 10 hepatic, 5 renal, 3 splenic, and 1 each left gastric, gastroepiploic, adrenal, and superior mesenteric artery pseudoaneurysms. Preprocedure computed tomography (CT) and/or angiographic studies confirmed the presence of VAPA in all 37 patients. Using the isolation technique, we embolized vessels at sites distal and proximal to the pseudoaneurysm. RESULTS: Transcatheter coil embolization with the isolation technique was technically successful in 33 (89%) of 37 patients, and angiogram confirmed the complete disappearance of the VAPA in 32 patients. No major complications occurred during the procedures. In a patient with a pancreaticoduodenal arcade artery pseudoaneurysm, we were unable to control hemorrhage. In 30 of 32 patients who recovered after transcatheter coil embolization using the isolation technique, follow-up CT scan showed no flow in VAPA; they survived without rebleeding. Two of the 32 patients (6%) with confirmed complete disappearance of VAPA on angiogram and CT scan obtained the day after the procedure manifested rebleeding during follow-up. CONCLUSION: Transcatheter coil embolization using the isolation technique is an effective alternative treatment in patients with VAPA. In combination with coil embolization, the isolation technique is particularly useful in patients whose pseudoaneurysms present surgical difficulties. PMID- 20857109 TI - Previous PICC placement may be associated with catheter-related infections in hemodialysis patients. AB - BACKGROUND: Catheter-related infections (CRIs) are a significant source of morbidity and mortality in hemodialysis patients. The identification of novel, modifiable risk factors for CRIs may lead to improved outcomes in this population. Peripherally inserted central catheters (PICCs) have been hypothesized to compromise vascular access due to vascular damage and venous thrombosis, whereas venous thrombosis has been linked to the development of CRIs. Here we examine the association between PICC placement and CRIs. METHODS: A retrospective review was performed of all chronic hemodialysis catheter placements and exchanges performed at a large university hospital from September 2003 to September 2008. History of PICC line use was determined by examining hospital radiologic records from December 1993 to September 2008. Catheter related complications were assessed and correlated with PICC line history. RESULTS: One hundred eighty-five patients with 713 chronic tunneled hemodialysis catheter placements were identified. Thirty-eight of those patients (20.5%) had a history of PICC placement; these patients were more likely to have CRIs (odds ratio = 2.46, 95% confidence interval = 1.71-3.53, p < .001) compared with patients without a history of PICC placement. There was no difference between the two groups in age or number of catheters placed. CONCLUSION: Previous PICC placement may be associated with catheter-related infections in hemodialysis patients. PMID- 20857111 TI - Acute megakaryoblastic leukemia AML FAB-M7 in a patient 15 years after kidney transplantation. PMID- 20857112 TI - Lenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment. AB - Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CLCr) was normal in 94 patients (CLCr>=80 ml/min), while RI was observed in 73 patients, including 40 patients with mild RI (50<=CLCr<80 ml/min) and 33 patients with moderate or severe RI (CLCr<50 ml/min). Response rates declined depending on the severity of RI, being 67% among patients with normal kidney function, 60% among patients with mild RI and 49% among patients with moderate or severe RI. Time to progression (TTP) was significantly reduced in patients with severe RI and in case of >2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previous treatment lines (2 vs. <2) and the use of novel agents like bortezomib or thalidomide prior to lenalidomide plus dexamethasone therapy had a more adverse effect on OS. In conclusion, lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with MM complicated by RI with manageable toxicity. PMID- 20857113 TI - Gemtuzumab ozogamicin, mitoxantrone, and etoposide in newly diagnosed acute myeloid leukemia patients with persistent leukemia after a course of induction therapy. PMID- 20857115 TI - Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis. AB - BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Mitomycin C is a drug often used in this clinical setting. The surgical and clinical factors that may influence the pharmacokinetics of hyperthermic intraperitoneal chemotherapy should be further elucidated. MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after single intraperitoneal bolus administration with mitomycin C was determined. RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C showed a 27 times greater exposure to peritoneal surfaces when compared to plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62% was retained in the body, and 9% was excreted in the urine. The extent of peritonectomy increased the clearance of mitomycin C from the peritoneal space (p = 0.051). A major resection of visceral peritoneal surface and a contracted peritoneal space reduced drug clearance. A contracted peritoneal space significantly reduced (p = 0.0001) drug concentrations in the plasma. CONCLUSIONS: Surgical and clinical factors may require modifications of drug dose or timing of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is an important determinant of mitomycin C pharmacokinetics. PMID- 20857114 TI - Multimodal therapy for liver cirrhosis patients with advanced hepatocellular carcinoma. AB - PURPOSE: We have previously shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced hepatocellular carcinoma (aHCC) in patients with HCV-related liver cirrhosis (C-LC) or alcoholic liver cirrhosis (A-LC) than in patients with HBV-related LC (B-LC). However, it is still unknown whether IACC actually improves the prognosis of aHCC patients with liver cirrhosis (LC), because it is difficult to perform a randomized controlled trial for patients with a poor prognosis. The aim of this study was to retrospectively assess the influence of IACC on the prognosis of aHCC. METHODS: Fifty-eight adult Japanese patients who had aHCC and LC underwent repeated trans arterial chemoembolization (TACE) without IACC between 1990 and 1997 at our hospital (group T), while 43 patients with aHCC and LC received IACC between 2000 and 2008 after undergoing several TACE sessions (group R). The Japan Integrated Staging score (JIS score) of each patient was >= 3 at the time of presentation, except for patients with tumor thrombi involving the first or subsequent portal vein branches or those with tumor invasion of the inferior vena cava. The same IACC regimen was repeated for as long as possible in group R. RESULTS: In group T, 13 patients had B-LC, 37 patients had C-LC, and 8 patients had A-LC, while the respective numbers were 14, 21, and 8 in group R. The median survival time (MST) was 248 days for patients with C-LC in group T and 708 days for those in group R, while it was 253 days for patients with A-LC in group T and 593 days for those in group R. There were significant differences of survival between the two groups. However, MST was 369 days for patients with B-LC in group T and 782 days for those in group R, without a significant difference. In group R, a complete or partial response was achieved after 4 weeks of chemotherapy in 14.3% of patients with B-LC versus 42.9% of patients with C-LC and 37.5% of patients with A-LC. CONCLUSIONS: In LC patients with a JIS score > 3 at diagnosis, multimodal therapy with IACC after TACE prolongs the MST of C-LC or A-LC patients compared with TACE alone, although it does not improve the MST of patients with B-LC. PMID- 20857116 TI - Suramab, a novel antiangiogenic agent, reduces tumor growth and corneal neovascularization. AB - PURPOSE: Oncological and ophthalmological diseases are increasingly treated with antiangiogenic agents. These agents have different intensities and duration of effects that should be considered to choose the most suitable therapy. Our purpose was to evaluate the synergistic effect of two drugs, jointly administered as a pharmaceutical compound, in two animal models. METHODS: Corneal neovascularization was induced in three groups of nine white New Zealand rabbits, applying a filter paper disk soaked in 1 M NaOH on the central cornea (Ormerod et al., Invest Ophthalmol Vis Sci 30:2148-2153, 1989). Group one was treated immediately after injury with intravenous Suramab, compound of Bevacizumab + Suramin, and group two with intravenous Bevacizumab. A third group of non-treated rabbits was included as control group. Digital photographs were taken at days 9, 15, 21, and 35. Neovessel index (NVI) was calculated using the Image J Program. Neovessels formation was quantified and given a score from 0 to 4 to each quadrant according to the centripetal growth of the longest vessel. Colorectal animal model: 6- to 8-week-old male BALB/c mice were inoculated with cancer cells. Seven days after tumor inoculation, four groups of BALB/c mice were treated with intravenous Bevacizumab (n = 9); intravenous Suramin (n = 10); intravenous Suramab (n = 10); and intravenous saline solution (n = 4). Tumor growth was assessed twice weekly by caliper measurement. RESULTS: The NVI was remarkably inferior in the group of rabbits treated with intravenous Suramab compared with controls after 35 days of follow-up. A greater inhibitory effect was obtained with Suramab compared to that obtained with Bevacizumab. Suramab significantly reduced tumor volume and prolonged survival of mice compared to controls. CONCLUSIONS: Suramab strongly reduced neovascularization in a rabbit model of corneal angiogenesis and induced a potent antitumoral effect in mice. PMID- 20857117 TI - Cerebral blood volume imaging by flat detector computed tomography in comparison to conventional multislice perfusion CT. AB - OBJECTIVE: We tested the hypothesis that Flat Detector computed tomography (FD CT) with intravenous contrast medium would allow the calculation of whole brain cerebral blood volume (CBV) mapping (FD-CBV) and would correlate with multislice Perfusion CT (PCT). METHODS: Twenty five patients were investigated with FD-CBV and PCT. Correlation of the CBV maps of both techniques was carried out with measurements from six anatomical regions from both sides of the brain. Mean values of each region and the correlation coefficient were calculated. Bland Altman analysis was performed to compare the two different imaging techniques. RESULTS: The image and data quality of both PCT and FD-CBV were suitable for evaluation in all patients. The mean CBV values of FD-CBV and PCT showed only minimal differences with overlapping standard deviation. The correlation coefficient was 0.79 (p < 0.01). Bland-Altman analysis showed a mean difference of -0.077 +/- 0.48 ml/100 g between FD-CBV and PCT CBV measurements, indicating that FD-CBV values were only slightly lower than those of PCT. CONCLUSION: CBV mapping with intravenous contrast medium using Flat Detector CT compared favourably with multislice PCT. The ability to assess cerebral perfusion within the angiographic suite may improve the management of ischaemic stroke and evaluation of the efficacy of dedicated therapies. PMID- 20857118 TI - Analysing the response in R2* relaxation rate of intracranial tumours to hyperoxic and hypercapnic respiratory challenges: initial results. AB - OBJECTIVE: To investigate the response in R2* relaxation rate of human intracranial tumours during hyperoxic and hypercapnic respiratory challenges. METHODS: In seven patients with different intracranial tumours, cerebral R2* changes during carbogen and CO(2)/air inhalation were monitored at 3 T using a dynamic multigradient-echo sequence of high temporal and spatial resolution. The R2* time series of each voxel was tested for significant change. Regions of interest were analysed with respect to response amplitude and velocity. RESULTS: The tumours showed heterogeneous R2* responses with large interindividual variability. In the 'contrast-enhancing' area of five patients and in the 'non tumoral' tissue most voxels showed a decrease in R2* for carbogen. For the 'contrast-enhancing' area of two patients hardly any responses were found. In areas of 'necrosis' and perifocal 'oedema' typically voxels with R2* increase and no response were found for both gases. For tissue responding to CO(2)/air, the R2* changes were of the same order of magnitude as those for carbogen. The response kinetic was generally attenuated in tumoral tissue. CONCLUSION: The spatially resolved determination of R2* changes reveals the individual heterogeneous response characteristic of intracranial human tumours during hyperoxic and hypercapnic respiratory challenges. PMID- 20857119 TI - Auditory fovea and Doppler shift compensation: adaptations for flutter detection in echolocating bats using CF-FM signals. AB - Rhythmical modulations in insect echoes caused by the moving wings of fluttering insects are behaviourally relevant information for bats emitting CF-FM signals with a high duty cycle. Transmitter and receiver of the echolocation system in flutter detecting foragers are especially adapted for the processing of flutter information. The adaptations of the transmitter are indicated by a flutter induced increase in duty cycle, and by Doppler shift compensation (DSC) that keeps the carrier frequency of the insect echoes near a reference frequency. An adaptation of the receiver is the auditory fovea on the basilar membrane, a highly expanded frequency representation centred to the reference frequency. The afferent projections from the fovea lead to foveal areas with an overrepresentation of sharply tuned neurons with best frequencies near the reference frequency throughout the entire auditory pathway. These foveal neurons are very sensitive to stimuli with natural and simulated flutter information. The frequency range of the foveal areas with their flutter processing neurons overlaps exactly with the frequency range where DS compensating bats most likely receive echoes from fluttering insects. This tight match indicates that auditory fovea and DSC are adaptations for the detection and evaluation of insects flying in clutter. PMID- 20857121 TI - The lumbosacral angle does not reflect progressive tethered cord syndrome in children with spinal dysraphism. AB - PURPOSE: Our goal was to validate the hypothesis that the lumbosacral angle (LSA) increases in children with spinal dysraphism who present with progressive symptoms and signs of tethered cord syndrome (TCS), and if so, to determine for which different types and/or levels the LSA would be a valid indicator of progressive TCS. Moreover, we studied the influence of surgical untethering and eventual retethering on the LSA. METHODS: We retrospectively analyzed the data of 33 children with spinal dysraphism and 33 controls with medulloblastoma. We measured the LSA at different moments during follow-up and correlated this with progression in symptomatology. RESULTS: LSA measurements had an acceptable intra- and interobserver variability, however, some children with severe deformity of the caudal part of the spinal column, and for obvious reasons those with caudal regression syndrome were excluded. LSA measurements in children with spinal dysraphism were significantly different from the control group (mean LSA change, 21.0 degrees and 3.1 degrees respectively). However, both groups were not age matched, and when dividing both groups into comparable age categories, we no longer observed a significant difference. Moreover, we did not observe a significant difference between 26 children with progressive TCS as opposed to seven children with stable TCS (mean LSA change, 20.6 degrees and 22.4 degrees respectively). CONCLUSIONS: We did not observe significant differences in LSA measurements for children with clinically progressive TCS as opposed to clinically stable TCS. Therefore, the LSA does not help the clinician to determine if there is significant spinal cord tethering, nor if surgical untethering is needed. PMID- 20857120 TI - Life-saving decompressive craniectomy for diffuse cerebral edema during an episode of new-onset diabetic ketoacidosis: case report and review of the literature. AB - PURPOSE: Diabetic ketoacidosis (DKA), a well-known complication of diabetes mellitus, is associated with severe diffuse cerebral edema leading to brain herniation and death. Survival from an episode of symptomatic cerebral edema has been associated with debilitating neurological sequelae, including motor deficits, visual impairment, memory loss, seizures, and persistent vegetative states. A review of the literature reveals scant information regarding the potential surgical options for these cases. The authors present their case in which they used a craniectomy to treat this life-threatening condition. METHODS: After reportedly suffering nausea and vomiting, a 12-year-old male presented to the emergency room with lethargy and was diagnosed with acute DKA. After appropriate treatment, the patient became comatose. A CT scan revealed diffuse cerebral edema. To decrease intracranial pressure and prevent further progression of brain herniation, a bifrontal decompressive craniectomy with duraplasty was performed. RESULTS: The patient's neurological function gradually improved, and he returned to school and his regular activities with only minimal cognitive deficits. CONCLUSION: Given the high mortality and morbidity associated with DKA related edema, we believe decompressive craniectomy should be considered for malignant cerebral edema and herniation syndrome. PMID- 20857122 TI - Electrocorticography and seizure outcomes in children with lesional epilepsy. AB - PURPOSE: The use of electrocorticographically (ECoG)-guided cortical resection in children with lesional epilepsy is controversial. Given the important developmental issues associated with recurrent childhood seizures, sustained seizure control is a key therapeutic goal. We therefore evaluated the effect of the decision to perform lesionectomy or ECoG-guided cortical resection on seizure outcome and surgical morbidity in the pediatric population. METHODS: We retrospectively analyzed seizure outcomes in 67 patients between the ages of 3 months and 16 years who underwent surgery for lesional epilepsy at British Columbia Children's Hospital. Thirty-four patients underwent ECoG, and 33 patients had lesionectomy without ECoG. RESULTS: One year post-operatively, 80% of patients who had ECoG-guided cortical resection or lesionectomy were seizure free. However, there was a trend toward improved seizure freedom in patients who had ECoG at most recent follow-up (79% patients with ECoG seizure free, vs. 61% with lesionectomy only; mean follow-up time 5.8 year, P=0.078). There was no increase in neurological morbidity in patients who had ECoG-guided cortical resection, and these patients were less likely to experience repeat epilepsy surgery. CONCLUSIONS: Overall, using ECoG to guide additional cortical resection may lead to more robust seizure freedom in children with lesional epilepsy without increasing their risk of surgical morbidity. PMID- 20857124 TI - Reversible complete heart block in ANCA-associated vasculitis. PMID- 20857123 TI - Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: findings from the Heart and Soul Study. AB - BACKGROUND: Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD). METHODS: We studied the relationship between HRV and CRP, IL-6, and fibrinogen in 862 outpatients with CHD. All participants provided fasting blood samples and underwent 24-h ambulatory monitoring to assess time-domain measures of HRV (MeanNN, SDNN, SDANN, and RMSSD). Regression analyses were adjusted for age, sex, ethnicity, body mass index, smoking, diabetes, beta blocker use, and cardiopulmonary history. RESULTS: MeanNN, SDNN, and SDANN were significantly and inversely associated with CRP and IL-6 levels in age-adjusted models and after adjustment for all covariates (p <= 0.02). MeanNN, SDNN, and SDANN were also inversely associated with fibrinogen levels in age-adjusted models (p < 0.03), but not significantly so in multivariable-adjusted models. Reduced vagal modulation of heart rate (RMSSD) was not significantly associated with any inflammatory measures. CONCLUSIONS: Reduced cardiac autonomic control is associated with increased systemic inflammation in patients with stable CHD. This relationship was largely independent of important covariates. PMID- 20857125 TI - Direct admission versus transfer of AMI patients for primary PCI. AB - BACKGROUND: Guidelines for the treatment of patients with ST-elevation myocardial infarction (STEMI) recommend primary PCI as first choice therapy. This recommendation has been linked to defined time limits achievable in a logistic network for the treatment of ACS. In the present study we analyzed the difference in 6 months outcome between STEMI patients who were admitted directly to a PCI center and those requiring transfer for primary PCI. RESULTS: 2,034 consecutive patients were included in the Bad Nauheim ACS registry. Admission diagnosis was STEMI in 1,057 (52%) patients (71% male, aged 63 +/- 13). 637 (60%) patients were directly admitted for primary PCI with a time delay from first medical contact until admission in the PCI center of 64 min (IQR 45-90) at median and door-to balloon time (DTB) at median 29 min (IQR 20-41). 420 (40%) patients were transferred from peripheral hospitals. In this subgroup time delay was 135 min (IQR 69-285) and DTB at median 31 min (IQR 22-49). 178 (16.8%) patients were at high risk (CPR or cardiogenic shock). Patients, who were admitted directly had a better outcome as transferral patients (log rank 6.1; p = 0.013 for 6 months mortality). However, Kaplan-Meier survival analysis (log rank 4.25; p = 0.039) and Cox regression analysis (95% CI 1.08-3.17; p = 0.026) revealed that this difference in outcome was restricted to high-risk patients. CONCLUSION: A network for the treatment of STEMI provides the logistic basis for the initiation of primary PCI according to current guidelines. However, transferral patients do not meet the defined time limits. Mortality rates for high-risk transferral patients appear to be higher as those of patients taken directly to the center by the EMS. PMID- 20857126 TI - The renin inhibitor aliskiren upregulates pro-angiogenic cells and reduces atherogenesis in mice. AB - Sca-1 and VEGFR-2 positive pro-angiogenic cells (PAC) predict outcome of patients with vascular disease. Activation of the renin-angiotensin-aldosterone system impairs PAC function. The effects of the direct renin inhibitor aliskiren on PAC numbers and function are not known. Treatment of C57Bl/6 mice and Apo E(-/-) mice on high-cholesterol diet with aliskiren, 25 mg/kg/day s.c. for 3-6 weeks, reduced systolic and diastolic blood pressure by -11.5 and -13.7% compared to vehicle. Aliskiren increased Sca-1/VEGFR-2 positive PAC in the blood (159 +/- 14%) and spleen-derived DiLDL/lectin positive PAC (180 +/- 21%). Migratory capacity of PAC was increased to 165 +/- 16%. In cultured human PAC, aliskiren dose-dependently increased the number of colony forming units to 152 +/- 9% (1 MUmol/l) and 187 +/ 7% (10 MUmol/l), which was prevented by the eNOS inhibitor LNMA. H2O2-induced apoptosis of cultured human PAC was reduced to 77 +/- 23%. In Apo E(-/-) mice, aliskiren reduced atherosclerotic plaque area in the aortic sinus by 58 +/- 4%. Circulating Sca-1/VEGFR-2 positive PAC were upregulated to 180 +/- 25% and migratory capacity of PAC was increased to 127 +/- 7%. Aliskiren reduced vascular NADPH oxidase activity to 41.6 +/- 6.7%. Despite similar blood pressure lowering, treatment with hydralazine (25 mg/kg/day) did not significantly influence atherogenesis or PAC. Treatment of C57Bl/6 mice with a lower dose of aliskiren (15 mg/kg/day) did not affect blood pressure but increased cultured DiLDL/lectin positive PAC to 229 +/- 30% and their migratory capacity to 214 +/- 24%. Aliskiren increased number and function of PAC in mice and prevented atherosclerotic lesion formation. The effects were observed independent of blood pressure lowering. PMID- 20857127 TI - Biomechanical testing of rectangular humeral shaft prosthesis: higher torsional stability without increased fracture risk. AB - BACKGROUND: Rectangular cementless femur shaft prostheses have a higher primary stability than round shafts. A novel rectangular humeral shaft design was tested with two questions: does the rectangular design cause a higher fracture risk during implantation than round designs, and does it increase the torsional stiffness? MATERIALS AND METHODS: Two series with six paired human humeri (total 24) were tested on one side with the rectangular shaft and on the contralateral side with a round shaft. In the first series, the shaft implantation was carried out with a constant speed of 100 mm/min and the maximum force was measured when the fracture occurred. In the second series, the implants were preloaded with 50 N and then rotated at 2 degrees per second with monitoring of the torsional torque. RESULTS: The maximum force at fracture showed no significant difference for the two designs (p = 0.34). Higher age and low bone density reduced the force required for fracture. The rectangular shaft showed significant higher torsional moments (p < 0.05). CONCLUSIONS: In biomechanical testing, the rectangular shaft had a significantly higher primary torsional stability than the round shaft without a higher risk of fracture during cementless implantation. Fracture risk and torsional stability are influenced by age and bone density. PMID- 20857128 TI - A novel splice-site mutation of ATP2A2 gene in a Chinese family with Darier disease. AB - Darier disease (DD; OMIM 124200) is a rare, autosomal dominant hereditary skin disorder characterized by abnormal keratinization and acantholysis. The causes of DD are defects in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 (SERCA2). The aim of this study was to report a novel splice-site mutation and to examine the relative quantity expression of ATP2A2 gene in a Chinese family with DD. Polymerase chain reaction (PCR) was carried out to amplify the exons and flanking intron boundaries of the ATP2A2 gene followed by direct sequencing. A novel splice-site mutation (IVS20-6T>A) was found in the family, which was confirmed by creating a novel HinfI (NEB Inc) recognition site and RT-PCR. Real-time quantitative PCR showed approximately 53 and 52% reduction of ATP2A2 expression of the proband and his father, respectively. The results support the proposition that haploinsufficiency is a common mechanism for the dominant inheritance of DD. PMID- 20857129 TI - Definition of treatment goals for moderate to severe psoriasis: a European consensus. AB - Patients with moderate to severe psoriasis are undertreated. To solve this persistent problem, the consensus programme was performed to define goals for treatment of plaque psoriasis with systemic therapy and to improve patient care. An expert consensus meeting and a collaborative Delphi procedure were carried out. Nineteen dermatologists from different European countries met for a face-to face discussion and defined items through a four-round Delphi process. Severity of plaque psoriasis was graded into mild and moderate to severe disease. Mild disease was defined as body surface area (BSA) <=10 and psoriasis area and severity index (PASI) <=10 and dermatology life quality index (DLQI) <=10 and moderate to severe psoriasis as (BSA > 10 or PASI > 10) and DLQI > 10. Special clinical situations may change mild psoriasis to moderate to severe including involvement of visible areas or severe nail involvement. For systemic therapy of plaque psoriasis two treatment phases were defined: (1) induction phase as the treatment period until week 16; however, depending on the type of drug and dose regimen used, this phase may be extended until week 24 and (2) maintenance phase for all drugs was defined as the treatment period after the induction phase. For the definition of treatment goals in plaque psoriasis, the change of PASI from baseline until the time of evaluation (DeltaPASI) and the absolute DLQI were used. After induction and during maintenance therapy, treatment can be continued if reduction in PASI is >=75%. The treatment regimen should be modified if improvement of PASI is <50%. In a situation where the therapeutic response improved >=50% but <75%, as assessed by PASI, therapy should be modified if the DLQI is >5 but can be continued if the DLQI is <=5. This programme defines the severity of plaque psoriasis for the first time using a formal consensus of 19 European experts. In addition, treatment goals for moderate to severe disease were established. Implementation of treatment goals in the daily management of psoriasis will improve patient care and mitigate the problem of undertreatment. It is planned to evaluate the implementation of these treatment goals in a subsequent programme involving patients and physicians. PMID- 20857130 TI - Deep neck abscesses: the Singapore experience. AB - This study aims to review our experience with deep neck abscesses, identify key trends, and improve the management of this condition. This is a retrospective chart review of patients diagnosed with deep neck abscesses in the Department of ENT (Otorhinolaryngology) at Tan Tock Seng Hospital, Singapore between 2004 and 2009. Patient demographics, etiology, bacteriology, systemic disease, radiology, treatment, complications, duration of hospitalization, and outcomes were reviewed. 131 patients were included (64.9% male, 35.1% female) with a median age of 51.0 years. 54 (41.2%) patients had diabetes mellitus. The parapharyngeal space (23.7%) was the most commonly involved space. Odontogenic and upper airway infections were the leading causes of deep neck abscesses (28.0% each). Klebsiella pneumoniae (27.1%) was the most commonly cultured organism in this study and among the diabetic patients (50.0%). 108 (82.4%) patients underwent surgical drainage. 42 patients suffered complications. All 19 patients, who had upper airway obstruction, had either a tracheostomy or intubation. Patients with multi-space abscesses, diabetes mellitus, and complications had prolonged hospitalizations. Old age and diabetes are risk factors for developing deep neck abscesses and their sequelae. The empiric choice of antibiotics should recognize that a dental source is likely, and that Klebsiella is most common in diabetics. Surgical drainage and adequate antibiotic coverage remains the cornerstone of treatment of deep neck abscesses. Therapeutic needle aspiration may successfully replace surgical drainage, if the abscesses are small and no complications are imminent. Airway obstruction should be anticipated in multi-space and floor of mouth abscesses. PMID- 20857131 TI - Surgical measurement to sphenoid sinus for the Chinese in Asia based on CT using sagittal reconstruction images. AB - The objective this study was to measure the changes of sphenoid sinusin the Chinese in AsiausingCT sagittal thin-slice reconstruction images, and to clarify the three-dimensional anatomical features of sphenoid sinus with its surrounding structures, relevant to the performing of the endoscopic sphenoidotomy. The sagittal reconstruction images were obtained from 178 CT images of 89 cases of normal adult participants (54 males and 35 females) with sphenoid sinus. We took the high-resolution axial CT images, from all the subjects, of the thickness by 0.625 mm, and reconstructed 1-mm-thick gapless sagittal CT images to measure the distance of all the sellar and pre-sellar types on the three-dimensional reconstructable sagittal plane under the bone window (4,000 at its width, and 400 at its level) in the CT images. The length of mean vertical line from the center of sphenoid ostium to the roof of sphenoid sinus of Non Onodi cell type is 10.6 +/- 1.5 mm, and of Onodi cell type is 3.3 +/- 1.5 mm. The length of vertical line from the center of sphenoid ostium to the lowest level of the bottom of sphenoid sinus is 12 mm +/- 3.7 mm. The length of mean horizontal line from the sphenoid ostium to the posterior wall of sphenoid sinus is 18 +/- 1.5 mm or 28 +/- 2.5 mm. The mean horizontal line from the lowest point of the sella to the anterior wall of sphenoid sinus is 17.5 +/- 1.3 mm in length. The mean horizontal distance from anterior wall to posterior wall of sphenoid sinus of Non Onodi cell type lining skull base is 10.1 +/- 1.0 mm, and of Onodi cell type, is 5.2 +/- 4.3 mm. The longest horizontal distance from the anterior wall to the posterior wall of sphenoid sinus is 22.0 +/- 7.7 mm. The present study provides atomical information about sphenoid sinus of the Chinese in Asia with some surgical distance measured between the sphenoid ostium and the surrounding structures, which is essential to avoid the complications during surgery. PMID- 20857132 TI - Pedigree likelihood ratio for lineage markers. AB - Lineage-based haplotype markers (e.g., Y chromosome STRs and mitochondrial DNA sequences) are important adjunct tools to the autosomal markers for kinship analysis and for specialized kinship applications such as database searching. Traditionally, the prosecution or kinship hypothesis considers the haplotypes in the same lineage and the probability of genotype data given the lineage hypothesis is simply set at 1 if the number of mismatched loci or nucleotides between the questioned person and the references is less than a predefined threshold. In this study, a kinship hypothesis based on a fixed relationship of the questioned person in the reference family is introduced. A graphical model is proposed to calculate the probability of the genotype data given the kinship hypothesis, which is the product of haplotype frequency of the founder in the pedigree and the transmission probability from the founder to all descendants. Proper mutation models are suggested for Y chromosome STRs and mitochondrial DNA sequence variants (i.e., SNPs) to calculate the transmission probability. The methods to infer the genotypes of the untyped individuals in the pedigree and the computational complexity of handling these untyped individuals are also addressed. Lastly, numerical examples of the applications are given to demonstrate the kinship hypothesis and the algorithms. PMID- 20857133 TI - A novel GJB1 frameshift mutation produces a transient CNS symptom of X-linked Charcot-Marie-Tooth disease. AB - X-linked Charcot-Marie-Tooth disease (CMT1X) is the second most common variant of CMT and is caused by mutations in the GJB1 gene encoding connexin 32. Some CMT1X patients with GJB1 missense mutations have shown transient central nervous system (CNS) symptoms with abnormal brain magnetic resonance imaging (MRI). Herein we report the first case with a novel GJB1 frameshift mutation that associates with a transient CNS symptom. The patient noticed high-arched feet and limited ankle dorsiflexion in early childhood; he transiently developed numbness and paresis of left face and arm, and dysphagia, with abnormal brain MRI. Although the CNS symptoms recovered within several hours without treatment, intravenous immunoglobulin (IVIg) therapy ameliorated progressing symptoms such as those of toe extensor muscles. His mother had been diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP), and repetitive IVIg treatments had relieved the symptoms. Therefore, inflammation might be involved in the pathophysiology of CMT1X with the GJB1 mutation, while molecular analysis revealed that the mutant GJB1 was more rapidly degraded by the proteasome pathway known as endoplasmic reticulum (ER)-associated degradation. PMID- 20857134 TI - Post infectious CNS disorders: towards a unified approach. AB - The spectrum of post infectious (PI) central nervous system (CNS) conditions includes a range of grey and white-matter disorders which can occur after viral or bacterial infections or in response to vaccinations. The clinical, radiological and immunological phenomenology raises a number of issues regarding the nature of immune-mediated CNS abnormalities, their etiology, pathogenesis and therapy. Here we focus on crucial issues pertaining to pathogenesis and aim to identify where current knowledge is insufficient in order to suggest future avenues of clinical and experimental research that may help to devise optimal therapy for these conditions. PMID- 20857135 TI - Tonic-clonic seizure following combined treatment of mycophenolate mofetil and acyclovir. PMID- 20857136 TI - The validity of clinical feature profiles for cytomegaloviral anterior segment infection. AB - BACKGROUND: Anterior segment cytomegalovirus (CMV) infection, which can be presented as anterior uveitis and corneal endotheliitis, has recently been reported in immunocompetent patients. We would like to access the validity of two presumed characteristic clinical profiles: profile 1, non-herpes simplex virus (HSV)/varicella zoster virus (VZV) corticosteroid-recalcitrant inflammatory ocular hypertensive syndrome (IOHS), and profile 2, corneal endotheliitis with specific coin-shaped keratic precipitates (KPs), that could be helpful in identifying CMV anterior segment intraocular infection. METHODS: Patients with either profile 1 or profile 2 or both were enrolled consecutively from the uveitis service in Chang Gung Memorial Hospital, Taoyuan, between January 1, 2006 and May 31, 2010. Diagnostic anterior chamber tapping was performed and followed by real-time quantitative polymerase chain reaction (PCR) to detect herpesviridae DNA including HSV I and II, VZV, CMV, and Epstein-Barr virus. RESULTS: Thirty-one eyes of 30 patients (21 males and nine females) were enrolled in this study. CMV DNA PCR was positive in 29 eyes of 28 patients (20 males and eight females). Nineteen of 20 eyes (19 patients) in profile 1 had positive CMV PCR. Ten of 11 eyes (11 patients) in profile 2 had positive CMV PCR. The positive predictive value of profile 1 and profile 2 was 94.7% and 90.9%, respectively. The positive predictive value of combining the two profiles was 93.3%. CONCLUSIONS: Non HSV/ZVZ corticosteroid-recalcitrant IOHS and corneal endotheliitis with specific coin-shaped KPs could be used as the screening tool for CMV anterior segment intraocular infection. PMID- 20857137 TI - Speeding of VO2 kinetics in response to endurance-training in older and young women. AB - The goal of this study was to examine the time-course of changes in oxygen uptake kinetics (tauVO(2p)) during step-transitions from 20 W to moderate-intensity cycling in response to endurance-training in older (O) and young (Y) women. Six O (69 +/- 7 years) and 8 Y (25 +/- 5 years) were tested pre-training, and at 3, 6, 9, and 12 weeks of training. VO(2p) was measured breath-by-breath using a mass spectrometer. Changes in deoxygenated-hemoglobin concentration of the vastus lateralis (?[HHb]) were measured by near-infrared spectroscopy in Y (but this was not possible in O). VO(2p) and ?[HHb] were modeled with a mono-exponential. Training was performed on a cycle-ergometer three times per week for 45 min at ~70% of VO(2 peak). Pre-training tauVO(2p) was greater (p < 0.05) in O (55 +/- 16 s) than Y (31 +/- 8 s). After 3 weeks training, tauVO(2p) decreased (p < 0.05) in both O (35 +/- 12 s) and Y (22 +/- 4 s). A pre-training "overshoot" in the normalized ?[HHb]/VO(2p) ratio relative to the subsequent steady-state level (interpreted as a mismatch of local O(2) delivery to muscle VO(2)) was observed in Y. Three weeks of training resulted in that "overshoot" being abolished. Thus there was a training-induced speeding of VO(2) kinetics in O and Y. In the Y this appeared to be the result of improved matching of local O(2) delivery to muscle VO(2). In O, inadequate systemic O(2) distribution (as indirectly expressed by the arterial-venous O(2) difference/VO(2p) ratio) seemed to play a role for the initial slower rate of adjustment in VO(2p). PMID- 20857138 TI - Estrogen-induced effects on the neuro-mechanics of hopping in humans. AB - Estrogen receptors in skeletal muscle suggest a tissue-based mechanism for influencing neuromuscular control. This has important physiological implications for both eumenorrheic women with fluctuating estrogen levels and those with constant and attenuated estrogen levels, i.e., women using the monophasic oral contraceptive pill (MOCP). This study examined the effects of endogenous plasma estrogen levels on leg stiffness (K (LEG)) and foot center of pressure (COP) during hopping. Nineteen females (Age = 28.0 +/- 4.2 years, Ht = 1.67 +/- 0.07 m, Mass = 61.6 +/- 6.8 kg) who had been using the MOCP for at least 12 months together with 19 matched, female, non-MOCP users (Age = 31.9 +/- 7.3 years, Ht = 1.63 +/- 0.05 m, Mass = 62.5 +/- 5.9 kg) participated. Non-MOCP users were tested at the time of lowest (menstruation) and highest (~ ovulation) estrogen whilst MOCP users were tested at Day 1 and Day 14 of their cycle. At each test session, K (LEG) (N m(-1) kg(-1)) and foot COP path length (mm) and path velocity (mm s( 1)) were determined from ground reaction force data as participants hopped at 2.2 Hz on a force plate. Statistical analysis revealed no significant (p < 0.05) differences for K (LEG). In contrast, significantly higher COP path length (30%) and COP path velocity (25%) were identified at ~ ovulation compared to menstruation in the non-MOCP users. Whilst there was no evidence of an estrogen induced effect on K (LEG); significantly elevated estrogen at ~ ovulation presumably increased extensibility of connective tissue and/or diminished neuromuscular control. Consistent lower limb dynamics of MOCP users demands less reliance on acutely modified neuromuscular control strategies during dynamic tasks and may explain the lower rate of lower limb musculoskeletal injuries in this population compared to non-MOCP users. PMID- 20857139 TI - Gravity, the hydrostatic indifference concept and the cardiovascular system. AB - Gravity, like any acceleration, causes a hydrostatic pressure gradient in fluid filled bodily compartments. At a force of 1G, this pressure gradient amounts to 10 kPa/m. Postural changes alter the distribution of hydrostatic pressure patterns according to the body's alignment to the acceleration field. At a certain location--referred to as hydrostatically indifferent--within any given fluid compartment, pressure remains constant during a given change of position relative to the acceleration force acting upon the body. At this specific location, there is probably little change in vessel volume, wall tension, and the balance of Starling forces after a positional manoeuvre. In terms of cardiac function, this is important because arterial and venous hydrostatic indifference locations determine postural cardiac preload and afterload changes. Baroreceptors pick up pressure signals that depend on their respective distance to hydrostatic indifference locations with any change of body position. Vascular shape, filling volume, and compliance, as well as temperature, nervous and endocrine factors, drugs, and time all influence hydrostatic indifference locations. This paper reviews the physiology of pressure gradients in the cardiovascular system that are operational in a gravitational/acceleration field, offers a broadened hydrostatic indifference concept, and discusses implications that are relevant in physiological and clinical terms. PMID- 20857140 TI - Surgical treatment of pancreatic endocrine tumours in Italy: results of a prospective multicentre study of 262 cases. AB - BACKGROUND: Information on the treatment of pancreatic endocrine tumours (PETs) comes mostly from small, retrospective, uncontrolled studies. METHODS: Newly diagnosed, histologically proven PETs, observed from June 2004 to March 2007 in 24 Italian centres, were included in a specific dataset. RESULTS: Three-hundred and ten patients (mean age 57.6 years, females 46.6%) were analysed. At the time of recruitment, 262 (84.5%) underwent surgery. The percentage of operated patients was 91.9% and 62.0% in surgical and non-surgical centres, respectively. A curative resection was carried out in 83.6% (n = 219) of cases, a palliative resection (debulking) in 10.7% (n = 28), an exploratory laparotomy in 4.6% (n = 12), and a bypass procedure in 1.1% (n = 3). Laparoscopy was performed in 8.0% (n = 21) of cases. Resection consisted of a pancreatoduodenectomy in 46 cases (21.0%), a distal pancreatectomy in 95 (43.4%), an enucleation in 50 (22.8%), a middle pancreatectomy in 16 (7.3%) and a total pancreatectomy in 12 (5.5%). Liver resection was associated with pancreatic resection in 26 cases (9.9%). Post operative mortality was 1.5% and morbidity 39.7%, respectively. A curative resection was performed more frequently in asymptomatic, small, non-metastatic, benign and at uncertain behaviour tumours, with low Ki67 values. CONCLUSIONS: This study strongly indicates the fact that surgical resection represents the cornerstone treatment of PETs. PMID- 20857141 TI - Integrin-linked kinase (ILK) in pulmonary fibrosis. AB - Pulmonary fibrosis is a common feature of a large group of lung diseases. The molecular mechanisms underlying pulmonary fibrosis and the key macromolecules involved are not fully understood yet. In an effort to better understand aspects of pulmonary fibrosis, the established bleomycin injection model in mice was used and the focus of the present study was on integrin-linked kinase (ILK) expression. ILK is an intracellular protein involved in the regulation of integrin-mediated processes. In fibrosis, ILK has been examined in the kidney and in the liver where it mediates epithelial to mesenchymal transition (EMT) and hepatic stellate cell activation, respectively. However, information on ILK's involvement in lung fibrosis is missing. In order to examine ILK's role in pulmonary fibrosis, we used both an in vivo and an in vitro approach. In vivo, the bleomycin model was used in order to examine ILK's expression and localization in the fibrotic lung. In vitro, transforming growth factor-beta1 was used to induce fibrotic characteristics and EMT in alveolar epithelial cells. ILK's role in alveolar EMT was studied by siRNA. Our results demonstrate that in the animal model used, ILK exhibits a decrease in expression at early stages of the fibrotic process and that a specific subset of fibroblasts is expressing ILK. The in vitro experiments suggested that ILK is not directly involved in E cadherin downregulation and initiation of EMT (as is the case in renal fibrosis) but is involved in upregulation of vimentin. These results suggest that ILK is involved in lung fibrosis in a tissue-specific manner and raise the possibility to use it as a specific therapeutic target for lung fibrosis in the future. PMID- 20857142 TI - TLE1 expression in malignant mesothelioma. AB - Malignant mesothelioma, an aggressive and often lethal tumor commonly associated with asbestos exposure, has been morphologically classified into epithelial, biphasic, and sarcomatoid subtypes. Histological distinction between biphasic or sarcomatoid mesothelioma and synovial sarcoma may be problematic in certain circumstances of intrathoracic location because of their similar clinicopathologic features, including not only their morphology but also occasional positive immunoreaction of mesothelioma markers. TLE1, which plays an important role in Wnt pathway, has been shown to be a specific marker for synovial sarcoma and diagnostically is useful; however, TLE1 expression in malignant mesotheliomas has not been fully evaluated. We immunohistochemically examined the expression of TLE1, factors related to the Wnt pathway including beta-catenin and cyclin D1, and mesothelioma markers including calretinin, HBME 1, cytokeratin 5/6, and thrombomodulin in 29 malignant mesotheliomas. TLE1 was variably expressed in 28 malignant mesotheliomas regardless of histomorphological subtype with >25% of positive cells in 20 cases (69.0%). There was no evidence of association of TLE1 expression with immunoreactivity to other markers. Our study showed no or limited value of the immunohistochemical TLE1 expression in distinguishing malignant mesothelioma and synovial sarcoma. PMID- 20857143 TI - Murine immune response induced by Leishmania major during the implantation of paraffin tablets. AB - We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL 10 mRNA expression than controls with very little expression of IFN-gamma. In contrast, both IFN-gamma and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP 1alpha was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation. PMID- 20857144 TI - Parental reports of adverse events following simultaneously given dT-IPV and MMR vaccines in healthy 9-year-old children. AB - In the Netherlands, children at 9 years of age receive a booster dT-IPV together with their second measles, mumps, and rubella (MMR) vaccination within the national immunization program. Safety is monitored continuously by enhanced passive surveillance. This population-based study was conducted to obtain more information on adverse events after vaccination at 9 years of age. Questionnaires on local and systemic reactions were distributed 1 and 3 weeks after vaccination, respectively, to parents of 1,250 healthy children who received their MMR and diphtheria, tetanus, and inactivated poliovirus injection (dT-IPV) vaccination as scheduled. Response to the questionnaires was 57.0% and 46.5%, respectively. Local reactions occurred in 86.5% of the children within 7 days after vaccination, more often at the dT-IPV (83.4%) than at the MMR site (32.7%). Pain was the most reported symptom (80.8% at the dT-IPV site; 29.1% at the MMR site). Systemic events occurred in 33.4% children within 7 days after vaccination, with headache as the most frequently reported (20.8%). Systemic events occurred in 20.8% children 8-21 days after vaccination. Children with local reactions at only the dT-IPV site had significantly more systemic events (19.3%) than those without local reactions (3.4%, p < 0.01). Such difference was not found for the MMR site. No serious adverse events were reported. Medical intervention was applied to 133 children (130 used analgesics and for three children the GP was consulted by phone). In conclusion, the frequency of reported local reactions is high, especially at the dT-IPV site, but all symptoms were transient. However, the use of reduced antigen content vaccines in association with the occurrence of adverse events is meaningful to explore. Furthermore, the overall rates are useful for monitoring variations in adverse events rates in the general population. PMID- 20857145 TI - Swine influenza A (H1N1) virus infection in infants. AB - There are few reports on pandemic swine influenza A (H1N1) virus infection in very young infants. We aimed to discuss the clinical characteristics and management of the H1N1 influenza infection in very young infants. Clinical characteristics of ten infants diagnosed with H1N1 influenza virus infection during the 2009 outbreak season in a tertiary neonatal intensive care unit were evaluated. The diagnosis was confirmed by testing of respiratory samples with pandemic H1N1 influenza specific real-time PCR assay. Of the 46 patients with fever or respiratory problems, ten (22%) were diagnosed with H1N1 influenza virus infection during the 2009 (October-December) peak outbreak season. All infants including the preterms were admitted from home, seven (70%) were full-term and three (30%) were preterm. Median age of the patients at admission was 24.5 days. Fever and cough were the most common symptoms. Apnea was the initial symptoms in three patients. Two patients required oxygen support, one of which, a preterm baby, had been mechanically ventilated for 2 days. Mean duration of hospitalization was 7.8 +/- 4.9 days. Chest radiography revealed radio-opacities on both lung fields in six patients. In addition, two patients had co-infection. All patients with proven infection were given oseltamivir medication. Recovery was achieved in all patients with no residual deficits or side effects from the antiviral oseltamivir treatment. The H1N1 influenza virus infection in very young infants appears to be mild to moderate in severity. The outcomes of the infants may be influenced by antiviral therapy. Treatment with antiviral oseltamivir appears to have no major adverse effects. PMID- 20857146 TI - Beyond immunity: quantifying the effects of host anti-parasite behavior on parasite transmission. AB - A host's first line of defense in response to the threat of parasitic infection is behavior, yet the efficacy of anti-parasite behaviors in reducing infection are rarely quantified relative to immunological defense mechanisms. Larval amphibians developing in aquatic habitats are at risk of infection from a diverse assemblage of pathogens, some of which cause substantial morbidity and mortality, suggesting that behavioral avoidance and resistance could be significant defensive strategies. To quantify the importance of anti-parasite behaviors in reducing infection, we exposed larval Pacific chorus frogs (Pseudacris regilla) to pathogenic trematodes (Ribeiroia and Echinostoma) in one of two experimental conditions: behaviorally active (unmanipulated) or behaviorally impaired (anesthetized). By quantifying both the number of successful and unsuccessful parasites, we show that host behavior reduces infection prevalence and intensity for both parasites. Anesthetized hosts were 20-39% more likely to become infected and, when infected, supported 2.8-fold more parasitic cysts. Echinostoma had a 60% lower infection success relative to the more deadly Ribeiroia and was also more vulnerable to behaviorally mediated reductions in transmission. For Ribeiroia, increases in host mass enhanced infection success, consistent with epidemiological theory, but this relationship was eroded among active hosts. Our results underscore the importance of host behavior in mitigating disease risk and suggest that, in some systems, anti-parasite behaviors can be as or more effective than immune-mediated defenses in reducing infection. Considering the severe pathologies induced by these and other pathogens of amphibians, we emphasize the value of a broader understanding of anti-parasite behaviors and how co-occurring stressors affect them. PMID- 20857148 TI - Significance of serum microRNAs in pre-diabetes and newly diagnosed type 2 diabetes: a clinical study. AB - To explore the clinical significance of seven diabetes-related serum microRNAs (miR-9, miR-29a, miR-30d, miR34a, miR-124a, miR146a and miR375) during the pathogenesis of type 2 diabetes (T2D), 56 subjects were recruited to this study: 18 cases of newly diagnosed T2D (n-T2D) patients, 19 cases of pre-diabetes individuals (impaired glucose tolerance [IGT] and/or impaired fasting glucose [IFG]) and 19 cases of T2D-susceptible individuals with normal glucose tolerance (s-NGT). Serum miRNAs were determined by real-time RT-PCR. Expression levels of single miRNAs and the expression signatures of miRNAs as a panel were analysed among the three groups. In n-T2D, all 7 miRNAs were significantly up-regulated compared with s-NGT and five were significantly up-regulated compared with pre diabetes, while miRNA expression was not significantly different between s-NGT and pre-diabetes. By Canonical discriminant analysis, 70.6% of n-T2D subjects (12/17) were recognized by canonical discriminant function, while s-NGT and pre diabetes subjects could not be discriminated from each other. Similar results were found in Hierarchical Clustering analysis based on the expression levels of all seven miRNAs. In different statistical analysis, miR-34a always showed the most significant differences. We conclude that the expression levels of seven diabetes-related miRNAs in serum were significantly elevated in n-T2D compared with pre-diabetes and/or s-NGT, and the latter two groups featured similar expression patterns of these miRNAs, suggesting that during the pathogenesis of T2D, the peripheral diabetes-related miRNAs have not changed significantly from s NGT at pre-diabetic stage. PMID- 20857147 TI - Transcript levels of major MMPs and ADAMTS-4 in relation to the clinicopathological profile of patients with lumbar disc herniation. AB - The involvement of matrix metalloproteinases (MMPs) in both the pathogenesis of intervertebral disc (ID) herniation and the spontaneous regression of herniated ID fragments remains only partially elucidated. The purpose of the present study was to simultaneously examine the transcript levels of a large number of MMPs ( 1, -3, -8, -9, -13 and -14) and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs) and to investigate their correlation with the clinicopathologic profile of patients suffering from symptomatic lumbar ID herniation. mRNA expression levels were determined by means of the real-time polymerase chain reaction in 63 herniated and 10 control ID specimens. Our results showed multiple positive correlations among all MMPs and ADAMTS-4 mRNA in herniated samples, indicating their possible synergistic effect in ID herniation. MMP-9 and -13 mRNA levels were significantly elevated in patients with chronic pain, presumably as a consequence of neovascularization and chronic inflammation. Smoking habits were found to have a negative dose-dependent effect on the transcript levels of MMP-3 and MMP-13 and a positive correlation with pain intensity, suggesting an unfavorable role for smoking in the regression process of herniated disc fragments. Our findings provide evidence of the molecular portrait of MMPs and ADAMTS-4 in lumbar ID herniation, as well as of its association with the clinicopathological profile of the patients included in this study, reinforcing the hypothesis of MMPs involvement in the natural history of ID herniation. However, further studies are necessary to elucidate the exact role of MMPs in the resorption process of herniated lumbar discs. PMID- 20857149 TI - Diabetes mellitus and its impact on long-term outcomes after coronary artery bypass graft surgery. AB - Diabetes mellitus (DM) is an important risk factor for accelerated atherosclerosis and increases cardiovascular disease. Several studies found a higher mortality rate in postoperative diabetic patients than in non-diabetic patients. However, other studies found conflicting evidence on bypass graft dysfunction in patients with diabetes mellitus. We therefore investigated the influence of diabetes mellitus on the long-term outcome after coronary artery bypass surgery (CABG). In this prospective study, 936 consecutive CABG patients were included. These patients were divided into three groups: patients without diabetes mellitus, patients with diabetes mellitus using oral drugs (non-insulin treated DM) and patients with diabetes mellitus using insulin (insulin-treated DM). The three groups were compared for mortality and (angiographic) bypass graft dysfunction. Of the 936 included patients, 720 (76.8%) patients were non diabetics, 138 (14.7%) were non-insulin-treated DM, and 78 (8.3%) patients were insulin-treated DM. Follow-up was achieved in all patients, at a mean of 33 months. Mortality was significantly higher in patients with insulin-treated DM, compared with non-insulin-treated DM or non-diabetic patients (P = 0.003). Fourteen (1.5%) patients suffered a myocardial infarction after CABG. A coronary angiography was performed in 77 (8.2%) patients during follow-up, proven bypass graft dysfunction was found in 41 (53.2%) patients. There was no significant difference in bypass graft dysfunction between the three groups. Diabetes mellitus has a significant impact on long-term follow-up after coronary surgery. Particularly insulin dependency is related to an increased mortality. However, diabetes has no influence on angiographically proven bypass graft dysfunction. PMID- 20857151 TI - Studies on the assembly of a leucine zipper antibacterial peptide and its analogs onto mammalian cells and bacteria. AB - Membrane-interaction and assembly of a leucine zipper peptide (LZP), and its single (SASA) and double (DASA) alanine-substituted analog onto mammalian, hRBCs and 3T3 cells and bacteria, Escherichia coli and Staphylococcus aureus were studied as a model system to understand the plausible role of assembly on their contrasting cytotoxic but similar bactericidal activities. Peptides' ability to depolarize and damage the membrane organization of hRBC and 3T3 cells decreased from LZP to SASA and to DASA which may be related to their decrease in assembly onto these mammalian live cells and oligomerization states in the presence of these cell membranes or zwitterionic PC/Chol lipid vesicles. However, LZP and its analogs showed appreciable similarities in damaging or depolarizing the E. coli or S. aureus cells, which further matched with their comparable assembly and oligomerization either onto these live cells or the cell membranes or in the presence of negatively charged PC/PG lipid vesicles. PMID- 20857152 TI - Prevalence of premenstrual syndrome and premenstrual dysphoric disorder in Japanese high school students. AB - To determine the prevalence and the impact of premenstrual symptoms among Japanese adolescent girls, a total of 618 high school students were assessed. Of them, 64.6% were found to suffer from premenstrual symptoms, which is lower than that in adult women. On the other hand, the rates of prevalence of moderate to severe PMS and PMDD in girls were higher than those in adult women. Premenstrual symptoms could have significant consequences by interfering with the daily functioning of adolescent girls. PMID- 20857150 TI - Arsenite treatment induces oxidative stress, upregulates antioxidant system, and causes phytochelatin synthesis in rice seedlings. AB - The effects of arsenite treatment on generation of reactive oxygen species, induction of oxidative stress, response of antioxidative system, and synthesis of phytochelatins were investigated in two indica rice (Oryza sativa L.) cvs. Malviya-36 and Pant-12 grown in sand cultures for a period of 5-20 days. Arsenite (As(2)O(3); 25 and 50 MUM) treatment resulted in increased formation of superoxide anion (O (2) (.-) ), elevated levels of H(2)O(2) and thiobarbituric acid reactive substances, showing enhanced lipid peroxidation. An enhanced level of ascorbate (AA) and glutathione (GSH) was observed irrespective of the variation in the level of dehydroascorbate (DHA) and oxidized glutathione (GSSG) which in turn influenced redox ratios AA/DHA and GSH/GSSG. With progressive arsenite treatment, synthesis of total acid soluble thiols and phytochelatins (PC) increased in the seedlings. Among antioxidative enzymes, the activities of superoxide dismutase (EC 1.15.1.1), catalase (EC 1.11.1.6), total ascorbate peroxidase (APX, EC 1.11.1.11), chloroplastic ascorbate peroxidase, guaiacol peroxidase (EC 1.11.1.7), monodehydroascorbate reductase (EC 1.6.5.4), and glutathione reductase (EC 1.6.4.2) increased in arsenite treated seedlings, while dehyroascorbate reductase (EC 1.8.5.1) activity declined initially during 5-10 days and increased thereafter. Results suggest that arsenite treatment causes oxidative stress in rice seedlings, increases the levels of many enzymatic and non-enzymatic antioxidants, and induces synthesis of thiols and PCs, which may serve as important components in mitigating arsenite-induced oxidative damage. PMID- 20857154 TI - Abdominal wall hernia repair with a composite ePTFE/polypropylene mesh: clinical outcome and quality of life in 152 patients. AB - PURPOSE: No consensus has yet been reached regarding the optimal mesh for the repair of small ventral hernias. A composite polytetrafluoroethylene/polypropylene mesh (Ventralex((r))) is designed for this purpose, and this paper reports its use in a larger series of patients. METHODS: Open repair for a small ventral hernia was undertaken in 152 patients between April 2006 and June 2008. Data from medical files were gathered, and follow-up questionnaires were retrieved. Patients were asked about pain, intake of analgesics and various physical capabilities. Patients with postoperative complaints were offered a follow-up visit. Ultrasonography was performed if recurrence was suspected. RESULTS: Median surgery time was 39 min (range 16-129 min). Junior surgeons performed 63% of the operations. Questionnaires were returned by 81.6% with a mean follow-up of 15.6 months. Eighteen patients (11.8%) had complications. Pain score was significantly lower and the physical capabilities of the patients were significantly enhanced after the operation. Recurrent hernia was reported in four patients (2.6%). Five patients (3.3%) had the mesh removed due to deep infection, chronic pain or early recurrence. The training level of the surgeon had no influence on the incidence of complications. A 93.8% majority of the patients would recommend this specific procedure to others. CONCLUSIONS: The intraperitoneal placement of this composite mesh is associated with a high level of patient satisfaction as well as low rates of both recurrence and infection. PMID- 20857153 TI - Brainstorming: weighted voting prediction of inhibitors for protein targets. AB - The "Brainstorming" approach presented in this paper is a weighted voting method that can improve the quality of predictions generated by several machine learning (ML) methods. First, an ensemble of heterogeneous ML algorithms is trained on available experimental data, then all solutions are gathered and a consensus is built between them. The final prediction is performed using a voting procedure, whereby the vote of each method is weighted according to a quality coefficient calculated using multivariable linear regression (MLR). The MLR optimization procedure is very fast, therefore no additional computational cost is introduced by using this jury approach. Here, brainstorming is applied to selecting actives from large collections of compounds relating to five diverse biological targets of medicinal interest, namely HIV-reverse transcriptase, cyclooxygenase-2, dihydrofolate reductase, estrogen receptor, and thrombin. The MDL Drug Data Report (MDDR) database was used for selecting known inhibitors for these protein targets, and experimental data was then used to train a set of machine learning methods. The benchmark dataset (available at http://bio.icm.edu.pl/~darman/chemoinfo/benchmark.tar.gz ) can be used for further testing of various clustering and machine learning methods when predicting the biological activity of compounds. Depending on the protein target, the overall recall value is raised by at least 20% in comparison to any single machine learning method (including ensemble methods like random forest) and unweighted simple majority voting procedures. PMID- 20857155 TI - Radiographic study on the pattern of wrist joint destruction in rheumatoid arthritis. AB - When planning therapy for rheumatoid arthritis (RA) in the wrist joint, knowing the pattern of joint destruction is important. There were a few studies using the Larsen and modified Larsen method to evaluate RA wrist joint destruction. However, these methods are inadequate for thoroughly assessing the severity of joint destruction because joint bone erosion and joint space narrowing could not be evaluated individually in these methods. To clarify the pattern of RA wrist joint destruction in the different zones of the wrist, we conducted a large-scale radiographic study. We modified the van der Heijde/Sharp method to assess radiographic images. Subjects were 191 RA patients (22 men and 169 women; mean age 57.0 years) who were examined at our center between 2001 and 2003 and underwent plain X-ray of both wrist joints (n = 382). Using X-ray images of the wrist joint, classification was performed based on the severity of wrist joint surface bone erosion and joint space narrowing at different zones, and the results were statistically analyzed. The results showed that joint space narrowing in the midcarpal joint (MCJ) advanced faster than in the radiocarpal joint (RCJ). Conversely, bone erosion in the RCJ advanced faster than in the MCJ. In X-ray diagnosis of RA wrist joint disorders, knowing the pattern of destruction is useful for assessing the presence or absence of early joint destruction and in planning therapy. PMID- 20857156 TI - Gender influence on ocular manifestations and their outcome in Behcet's Disease. A long-term follow-up of up to 20 years. AB - It is of general belief that males are prone to more frequent, more severe manifestations, and less favorable outcome. We evaluated this hypothesis in ophthalmological manifestations (OM) of Behcet's Disease (BD). Visual acuity (VA), anterior uveitis, posterior uveitis (PU), and retinal vasculitis (RV) were checked, according to Ben Ezra, in 1,515 patients with eye lesions. The data at baseline and last visit were compared. Male/female ratio was 1.2 in the BD registry (6,500 patients) and 1.51 for OM patients (Chi(2) = 98.962, p < 0.0001). The patients-year-follow-up was 4,987. All parameters improved significantly from the baseline. Mean VA improved from 4.87 to 5.35 for males (p < 0.0001) and from 5.20 to 5.74 for females (p < 0.0001). Difference between males/females at baseline was not significant (p = 0.60). The mean improvement for males/females was statistically non-significant (p = 0.58). Percent improvement of eyes for males/females was 47.1%/48.8% (p = 0.41). Mean PU improved from 1.83 to 0.71 for males (p < 0.0001) and from 1.66 to 0.49 for females (p < 0.0001). Difference between males/females at baseline was significant (p = 0.01). The mean improvement for males/females was statistically non-significant (p = 0.45). Percent improvement of eyes for males/females was 75.4%/81.0% (p = 0.004). Mean RV improved from 2.05 to 1.16 for males (p < 0.0001) and from 1.97 to 0.99 for females (p < 0.0001). Difference between males/females at baseline was not significant (p = 0.42). The mean improvement for males/females was statistically non-significant (p = 0.47). Percent improvement of eyes for males/females was 62%/64.4% (p = 0.33). Male gender is more prone to ocular manifestations. The severity of lesions at baseline was the same for VA and RV. For PU, the difference was statistically significant, but was not clinically relevant. The therapeutic outcome (mean improvement and percent of improved eyes) was the same for all parameters. PMID- 20857157 TI - Synovial fluid beta-endorphin level in avascular necrosis, rheumatoid arthritis, and osteoarthritis of the femoral head and knee. A controlled pilot study. AB - The goal of this study is to determine and compare the beta-endorphin levels in the synovial fluid of patients with different joint disorders (avascular necrosis, AVN; osteoarthritis, OA; and rheumatoid arthritis, RA of the hip or knee). Eighty-seven patients were involved in our study with an average age of 62 years. Thirty-three patients had AVN (18 hips, 15 knees). Twenty-three patients were diagnosed with OA (14 hips, 9 knees), and 31 patients suffered from RA (12 hips, 19 knees). We measured the beta-endorphin levels of the synovial fluids harvested from surgery-with radioimmunoassay. No significant difference was found in the beta-endorphin levels of the synovial fluid from AVN comparing to OA and RA, however beta-endorphin level was significantly higher in RA group than among patients with OA (p = 0.01). Synovial beta-endorphin level was slightly lower in knee comparing to hip joint p = (0.06). When examining the different joints separately in compliance with diagnoses, we concluded that the synovial beta endorphin level from AVN was between the values of OA and RA without significant difference, whereas it was significantly higher in the knee of RA, than of OA groups (p = 0.05 knee, p = 0.2 hip). Our results confirmed those experiments which stated that there is a significant increase in synovial beta-endorphin level in patients with inflammatory autoimmune diseases (e.g., RA), comparing to the level measured in degenerative conditions (e.g., OA). PMID- 20857158 TI - Polymyositis associated with hypothyroidism or hyperthyroidism: two cases and review of the literature. AB - Studies confirming a possible relationship of polymyositis within thyroid dysfunction, either hypothyroidism or hyperthyroidism, are hardly available. To define the association, identify clinical, laboratory, electromyographic, and pathologic features in polymyositis (PM) patients with hypothyroidism or hyperthyroidism, we conducted a MEDLINE and Chinese biomedicine database search to identify relevant literature published in the past 25 years. Seventeen cases were included. All patients were female (10 hypothyroidism patients, seven hyperthyroidism patients). The mean (SD) age of PM, hypothyroidism, and hyperthyroidism at diagnosis was 54.8 (16.7), 55.5 (16.5), and 32.7 years (10.2), respectively. PM diagnosis can precede or parallel hypothyroidism while PM may occur following the diagnosis of hyperthyroidism. The most common comorbidities were malignant tumors in these disorders, including thymoma, colon cancer, and thyroid cancer. Muscle weakness was described in 100% of patients. Other common manifestations included muscles' atrophy and pain, deep tendon reflexes, polyarthralgia, and dysphagia. Most patients had markedly elevated creatine kinase and the presence of anti-Sjogren's syndrome A (SSA) antibodies was also found in two cases. Malignancy associated with PM may more frequently occur in hypothyroidism than in hyperthyroidism. The abnormalities on electromyography and biopsy did not differ from those findings of PM. Therapy consisting of corticosteroids, thyroid hormone, or anti-thyroid drugs was administrated; however, poor prognosis seemed to be associated with malignant tumors as well as older age and the presence of anti-SSA antibodies. It is reasonable to suggest that those patients should be routinely evaluated for thyroid function, especially in older female and patients suffering from cancers. PMID- 20857159 TI - Primary extensive pyomyositis in an immunocompetent patient: case report and literature review. AB - Pyomyositis is a suppurative infection of the skeletal muscle; it mainly occurs in immunocompromised patients or, exceptionally, in immunocompetent patients in tropical or other areas. We present a 24-year-old immunocompetent lady with bilateral thigh myalgia and fever. Upon investigation, extensive multifocal bilateral fluid collections involving the extensor muscles of both thighs were demonstrated. Pus aspirate from the involved muscles proved the presence of Staphylococcus aureus. Incision and drainage of the involved muscles were performed with successful and complete recovery. PMID- 20857160 TI - Patients with rheumatoid arthritis who have failed everything else may respond to abatacept. PMID- 20857161 TI - Angiographically proven cervical venous engorgement: a possible concurrent cause in the pathophysiology of Hirayama's myelopathy. AB - The objective of this study is to discuss the possible role of cervical posterior epidural plexus engorgement during cervical flexion in the pathogenesis of Hirayama myelopathy. In Hirayama disease, MRI during neck flexion often shows that the posterior dura detaches from the posterior arches compressing the spinal cord. Autopsies demonstrated asymmetric changes in the anterior horns consistent with chronic ischemic damage, attributed to arterial insufficiency during flexion or to microcirculatory changes due to compression by the tight dura. In a 15-year old patient with 5-year history of distal upper limbs weakness, MRI demonstrated marked venous engorgement of the posterior epidural plexus in cervical flexion, confirmed by angiography. Laminectomy from C3 to C6 with duraplasty was performed. At one-year follow-up, the clinical condition of the patient remained stable. In Hirayama myelopathy, compression of the spinal cord by the tight dura is probably the most important pathogenetic factor. However, venous congestion in flexion might play an additional role in determining spinal cord ischemic changes. PMID- 20857162 TI - First report of an Iraqi Kurdish CADASIL patient. PMID- 20857163 TI - Warfarin therapy and incidence of cerebrovascular complications in left-sided native valve endocarditis. AB - Anticoagulant therapy has been anticipated to increase the risk of cerebrovascular complications (CVC) in native valve endocarditis (NVE). This study investigates the relationship between ongoing oral anticoagulant therapy and the incidence of symptomatic CVC in left-sided NVE. In a prospective cohort study, the CVC incidence was compared between NVE patients with and without ongoing warfarin. Among 587 NVE episodes, 48 (8%) occurred in patients on warfarin. A symptomatic CVC was seen in 144 (25%) patients, with only three on warfarin. CVC were significantly less frequent in patients on warfarin (6% vs. 26%, odds ratio [OR] 0.20, 95% confidence interval [CI] 0.06-0.6, p = 0.006). No increase in haemorrhagic lesions was detected in patients on warfarin. Staphylococcus aureus aetiology (adjusted OR [aOR] 6.3, 95% CI 3.8-10.4) and vegetation length (aOR 1.04, 96% CI 1.01-1.07) were risk factors for CVC, while warfarin on admission (aOR 0.26, 95% CI 0.07-0.94), history of congestive heart failure (adjusted OR 0.22, 95% CI 0.1-0.52) and previous endocarditis (aOR 0.1, 95% CI 0.01-0.79) correlated with lower CVC frequency. PMID- 20857164 TI - Long-term follow-up of patients with candiduria. AB - Candiduria is commonly encountered in hospitalized patients, particularly those with indwelling urinary catheters. While risk factors and therapy are well described in previous studies, little is known about long-term outcomes and recurrence rates of candiduria. We studied 188 patients with candiduria in a retrospective chart review at a single institution from January 1999 to December 2000. Data were collected regarding risk factors and underlying disease, therapy, follow-up cultures until December 2003, and mortality. Ninety-one patients with at least one follow-up culture >1 month after the initial culture (range 2-48) were available for further study. In this group, patients receiving antifungal therapy for asymptomatic candiduria were paradoxically more likely to have subsequent positive urine cultures than patients who never received antifungal therapy. Six patients developed candidemia during follow-up, although in none was this considered to represent a consequence of candiduria. Mortality rate at the end of the follow-up period (mean of 18 months) was 43%, including one death attributed to candidemia. Therapy for candiduria does not appear to reduce candiduria recurrence rates through 48 months of follow-up and little evidence of treatment benefit was identified. PMID- 20857165 TI - Optimization of patient dose and image quality with z-axis dose modulation for computed tomography (CT) head in acute head trauma and stroke. AB - The purpose of this study is to retrospectively analyze the effect of z-axis modulation for CT head protocols on patient dose and image quality in patients with acute head trauma and stroke. The study was approved by the Institutional Review Board. We retrospectively evaluated the effect of dose modulation on unenhanced CT head examinations in patients with acute head trauma and stroke. Two series of 100 consecutive studies were reviewed: 100 studies performed without dose modulation, 100 studies performed with z-axis dose modulation. Multidetector 16-section CT was performed sequentially and axial 5-mm-thick slices were obtained from base of skull to vertex. With z-axis dose modulation, the same tube current range was maintained, but a computer algorithm altered the tube current applied to each CT section. For each examination, the weighted volume CT dose index (CTDI (vol)) and dose-length product (DLP) were recorded and noise was measured. Each study was also reviewed for image quality by two independent, blinded readers. The variables (CTDI (vol) and DLP, image quality, and noise) in the two groups were compared by using student t test and Wilcoxon rank-sum test. For unenhanced CT head examinations, the CTDI (vol) and DLP, respectively, were reduced by 35.8% and 35.2%, respectively, by using z-axis dose modulation. Image quality and noise were unaffected by the use of this dose modulation technique (P < 0.004). Utilization of z-axis modulation technique for CT head examination in patients with acute head trauma and stroke offers significant radiation dose reduction while image quality is optimally maintained. PMID- 20857166 TI - Accuracy of CBCT measurements of a human skull. AB - The purpose of this study is to assess the accuracy and reproducibility of cone beam computed tomography (CBCT) measurements of a human dry skull by comparing them to direct digital caliper measurements. Heated gutta-percha was used to mark 13 specific distances on a human skull, and the distances were directly measured using a digital caliper and on CBCT images obtained with Iluma (3M Imtec, OK, USA) and 3D Accuitomo 170 (3D Accuitomo; J Morita Mfg. Corp., Kyoto, Japan) CBCT imaging systems. Iluma images were obtained at 120 kVp and 3.8 mA and reconstructed using voxel sizes of 0.2 and 0.3 mm(3). Accuitomo images were obtained at 60 kVp and 2 mA and a voxel size of 0.250 mm(3). In addition, 3-D reconstructions were produced from images obtained from both systems. All measurements were made independently by three trained observers and were repeated after an interval of 1 week. Agreement between observers and image type was assessed by calculating Pearson correlation coefficients, with a level of significance set at p < 0.05. Pearson correlation coefficients between readings ranged from 0.995 to 1 for all image types. Correlations among observers were also very high, ranging from 0.992 to 1 for the first reading and from 0.992 to 1 for the second reading for the different image types. All CBCT image measurements were identical and highly correlated with digital caliper measurements. Accuracy of measurements of various distances on a human skull obtained from different CBCT units and image types is comparable to that of digital caliper measurements. PMID- 20857167 TI - Understanding uncoupling in the multiredox centre P450 3A4-BMR model system. AB - Understanding the uncoupling at the haem active site and/or at the level of multidomain electron transfer is an important element in cytochrome P450 chemistry. Here a chimeric model system consisting of human cytochrome P450 3A4 and the soluble reductase domain of CYP102A1 from Bacillus megaterium (BMR) is used to study the relationship between electron transfer and the coupling efficiency in substrate monoxygenation. Several regulatory features were considered. FAD and FMN added to apoenzyme in oversaturating concentrations influence neither formaldehyde production nor coupling efficiency. The optimal conditions of coupling efficiency depended only on the NADPH concentration. The pH (8.0) and ionic strength (50 mM potassium phosphate) were found to modulate the level of coupling, indicating an influence over the formation of a productive interaction between the BMR and the haem domain. Overall, uncoupling is found to be an intrinsic property of the haem domain, and the covalent linkage of the reductase in a single polypeptide chain has little influence over the activity coupled to product formation. PMID- 20857168 TI - N-terminal myristoylation alters the calcium binding pathways in neuronal calcium sensor-1. AB - Neuronal calcium sensor-1 (NCS-1) interacts with many membranes and cytosolic proteins, both in a Ca(2+)-dependent and in a Ca(2+)-independent manner, and its physiological role is governed by its N-terminal myristoylation. To understand the role of myristoylation in altering Ca(2+) response and other basic biophysical properties, we have characterized the Ca(2+) filling pathways in both myristoylated (myr) and non-myristoylated (non-myr) forms of NCS-1. We have observed that Ca(2+) binds simultaneously to all three active EF-hands in non-myr NCS-1, whereas in the case of myr NCS-1, the process is sequential, where the second EF-hand is filled first, followed by the third and fourth EF-hands. In the case of myr NCS-1, the observed sequential Ca(2+) binding process becomes more prominent in the presence of Mg(2+). Besides, the analysis of (15)N-relaxation data reveals that non-myr NCS-1 is more dynamic than myr NCS-1. The overall molecular tumbling correlation time increases by approximately 20% upon myristoylation. Comparing the apo forms of non-myr NCS-1 and myr NCS-1, we found the possibility of existence of some substates, which are structurally closer to the holo form of the protein. There are more such substates in the case of non myr NCS-1 than in the case of the myr NCS-1, suggesting that the former accesses larger volumes of conformational substates compared with the latter. Further, the study reveals that the possibility of Ca(2+) binding simultaneously to different parts of the protein is more favourable in non-myr NCS-1 than in myr NCS-1. PMID- 20857169 TI - Coexpression of bile salt hydrolase gene and catalase gene remarkably improves oxidative stress and bile salt resistance in Lactobacillus casei. AB - Lactic acid bacteria (LAB) encounter various types of stress during industrial processes and gastrointestinal transit. Catalase (CAT) and bile salt hydrolase (BSH) can protect bacteria from oxidative stress or damage caused by bile salts by decomposing hydrogen peroxide (H(2)O(2)) or deconjugating the bile salts, respectively. Lactobacillus casei is a valuable probiotic strain and is often deficient in both CAT and BSH. In order to improve the resistance of L. casei to both oxidative and bile salts stress, the catalase gene katA from L. sakei and the bile salt hydrolase gene bsh1 from L. plantarum were coexpressed in L. casei HX01. The enzyme activities of CAT and BSH were 2.41 MUmol H(2)O(2)/min/10(8) colony-forming units (CFU) and 2.11 MUmol glycine/min/ml in the recombinant L. casei CB, respectively. After incubation with 8 mM H(2)O(2), survival ratio of L. casei CB was 40-fold higher than that of L. casei CK. Treatment of L. casei CB with various concentrations of sodium glycodeoxycholate (GDCA) showed that ~10(5) CFU/ml cells survived after incubation with 0.5% GDCA, whereas almost all the L. casei CK cells were killed when treaded with 0.4% GDCA. These results indicate that the coexpression of CAT and BSH confers high-level resistance to both oxidative and bile salts stress conditions in L. casei HX01. PMID- 20857170 TI - Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors. AB - BACKGROUND: To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. METHODS: Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types. RESULTS: A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure. CONCLUSIONS: Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction". PMID- 20857172 TI - Depiction of the vitreous pocket by optical coherence tomography. AB - The reported shape and size of the vitreous pocket vary depending on the method of visualization. We used spectral domain optical coherence tomography (SD-OCT) to clarify the structure of the normal vitreous pocket. The macular retina of 20 consecutive non-highly myopic eyes of 10 healthy young adults (aged 22-27 years) was examined using spectral SD-OCT. The premacular vitreous pocket and the pre papillary Cloquet's canal were observed in a scan area 9 mm in transverse diameter and 6 mm in longitudinal diameter. On SD-OCT, the vitreous pocket was observed in all the eyes, anterior to the macula as a flat dish-like structure measuring 7.5 +/- 0.6 mm in transverse diameter, 5.2 +/- 0.3 mm in longitudinal diameter, and 0.3 +/- 0.5 mm in thickness. The boundary of the vitreous pocket was clear, the central portion was thin, and the peripheral portion protruded anteriorly. The posterior wall of the vitreous pocket which can be observed at the macular region was a thin layer of vitreous cortex. Mildly reflective dots were observed inside the vitreous pocket. A thin wall was observed between the vitreous pocket and the pre-papillary Cloquet's canal. On SD-OCT, the vitreous pocket of healthy young adults was visualized as a liquefied lacuna with a clear boundary measuring approximately 7.5 * 5.2 * 0.3 mm, with the posterior wall composed of a layer of vitreous cortex and separated from the pre-papillary Cloquet's canal by a thin wall. PMID- 20857171 TI - Phase I study of oral irinotecan as a single-agent and given sequentially with capecitabine. AB - PURPOSE: To assess the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of orally administered irinotecan in the semi-solid matrix (SSM) formulation, both as a single agent and in sequential combination with capecitabine, in patients with advanced solid tumors. PATIENTS AND METHODS: Forty three patients were treated with irinotecan given as a single oral daily dose on days 1-5 every three weeks. An additional forty patients were treated with sequential oral irinotecan given daily on days 1-5 followed by capecitabine given orally as a divided dose twice daily on days 6-14 of each three week cycle. RESULTS: The MTD of single-agent oral irinotecan was estimated to be 60 mg/m(2)/day, and DLT included diarrhea, nausea, and neutropenia. In an initial group of patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, the MTD of sequential oral irinotecan/capecitabine was estimated to be 40/1600 mg/m(2)/day with DLT of delayed diarrhea. In a subsequent group of patients with ECOG PS of 0 or 1, the MTD for the sequential combination was 50/2000 mg/m(2)/day. The most common adverse events were fatigue, diarrhea, nausea/vomiting and dehydration. Pharmacokinetic (PK) evaluation showed that oral irinotecan was rapidly absorbed and effectively converted to the active metabolite, SN-38, achieving approximately 50% of the SN-38 systemic exposure resulting from an equivalent IV dose. CONCLUSIONS: Oral irinotecan can be safely administered as a single agent or in sequential combination with capecitabine. The efficacy of oral irinotecan should be explored further as a potentially convenient alternative to IV chemotherapy. PMID- 20857173 TI - Bilateral total cataract as the presenting feature of celiac disease. AB - An 18-year-old male presented to the ophthalmology department with bilateral total subluxated cataract. On systemic examination, he was found to have grossly short stature, multiple severe bony deformities, hypogonadism and partial adontia. Detailed work-up revealed a biochemical and radiologic picture consistent with osteomalacia, which had resulted from malabsorption secondary to celiac disease, confirmed histopathologically. To the best of our knowledge, this is the first reported case of bilateral cataract as the presenting feature of celiac disease. Malabsorption leading to hypocalcemia along with chronic diarrhea itself may have contributed to the development of bilateral cataract. PMID- 20857174 TI - Eyelashes on an extruding porous polyethylene orbital implant. AB - This photo essay describes a patient with eyelashes perpendicular to the extruding part of a porous polyethylene orbital implant. The upright position of these eyelashes created the impression of growth on the extruding implant, but they are lost eyelashes that became entrapped in the pores of the implant. PMID- 20857175 TI - Clinical features and prognosis of herpetic anterior uveitis: a retrospective study of 111 cases. AB - To describe the clinical features and outcomes in patients with herpetic anterior uveitis. We reviewed the records of 111 patients with a clinical diagnosis of herpetic anterior uveitis seen at the Department of Ophthalmology, Istanbul Faculty of Medicine, from January 1996 to December 2006. Demographic and clinical features, recurrence rate, and visual outcome were analyzed. Fifty patients were male, 61 were female. Mean age at presentation was 39.2 +/- 16.5 (6-74) years. Three atopic patients had bilateral involvement. Twelve patients had active or a past episode of herpes zoster ophthalmicus. Ocular findings were granulamatous anterior uveitis (93%), active keratitis or corneal scars (57%), elevated intraocular pressure (51%), iris atrophy (48%), distorted pupil (25%), and posterior synechiae (26%). Secondary glaucoma developed in two patients. None of the patients had posterior segment complications. The recurrence rate was 0.45/person-year. Topical corticosteroids and oral antiviral therapy were administered to all patients during active episodes. Long-term prophylactic oral acyclovir was used in 13%. Final visual acuity was worse than 0.5 in 17% of the involved eyes and was due to corneal scarring or cataract formation. Patients with iridocyclitis only had no permanent visual loss. Herpetic anterior uveitis is a recurrent granulomatous disease commonly associated with corneal involvement, iris atrophy, and transient intraocular pressure rise. Visual prognosis is good, especially in patients who have only anterior uveitis without corneal disease. PMID- 20857176 TI - Application of the white rot fungus Phanerochaete chrysosporium in biotreatment of bagasse effluent. AB - Biotreatment of bagasse effluent using Phanerochaete chrysosporium (white rot fungus) is investigated. This study confirmed that lignin is the major pollutant component in this effluent followed by different carbohydrates. The treatment conditions must be very proper, especially in terms of biomass culture to achieve a successful treatment. The best conditions of temperature, biomass concentration, pH and duration for biotreatment of this effluent were 35 degrees C, 552 mg l(-1), 6 and 5 to 9 days, respectively. Under these conditions, a 9 days long treatment reduced by 98.7% the original biochemical oxygen demand (of 2,780 mg l(-1)) and by 98.5% the dissolved chemical oxygen demand (initial 4,200 mg l(-1)). Moreover, fungal treatment reduced total dissolved solids from 3,950 to 575 mg l(-1) and color from 560 mg l(-1) PtCo to 111 mg l(-1) PtCo. PMID- 20857177 TI - Depression in Swedish women: relationship to factors at birth. AB - Depression is a common and serious disorder that may have developmental origins. Birth-related factors have been related to childhood and adult occurrence of somatic as well as psychiatric disorders, but studies on the relationship between birth-related factors and depression are few and show mixed results. In addition, varying methods have been used to assess depression. Standardized clinical criteria to diagnose depression, combined with birth data collected from midwife records have not been used in most studies. Participants in the Prospective Population Study of Women in Sweden (803 women), born 1914, 1918, 1922 and 1930, provide information on birth factors and depression. Women participated from 1968 at mid-life ages of 38-60 years, to 2000, when they were age 78-92 years. Original birth records containing birth weight, length, head circumference, and gestational time, as well as social factors were obtained. Lifetime depression was diagnosed via multiple information sources. Symptoms were assessed using the Comprehensive Psychopathological Rating Scale and diagnoses were based on DSM-III R criteria. Over their lifetime, 44.6% of women in this sample experienced depression. Birth weights <= 3500 g [odds ratio (OR), age-adjusted = 1.72; 95% CI 1.29-2.28, P < 0.001] and shorter gestational time (OR, age-adjusted = 1.13; 95% CI 1.04-1.24, P = 0.005) were independently associated with a higher odds of lifetime depression in a logistic regression model adjusted for age. Lower than median birth weights and shorter gestational time were related to lifetime depression in women. Both neurodevelopmental and environmental contributions to lifetime depression may be considered. PMID- 20857178 TI - Suprachoroidal drug delivery to the back of the eye using hollow microneedles. AB - PURPOSE: In this work, we tested the hypothesis that microneedles provide a minimally invasive method to inject particles into the suprachoroidal space for drug delivery to the back of the eye. METHODS: A single, hollow microneedle was inserted into the sclera, and infused nanoparticle and microparticle suspensions into the suprachoroidal space. Experiments were performed on whole rabbit, pig, and human eyes ex vivo. Particle delivery was imaged using brightfield and fluorescence microscopy as well as microcomputed tomography. RESULTS: Microneedles were shown to deliver sulforhodamine B as well as nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig, and human eyes. Volumes up to 35 MUL were administered consistently. Optimization of the delivery device parameters showed that microneedle length, pressure, and particle size played an important role in determining successful delivery into the suprachoroidal space. Needle lengths of 800-1,000 MUm and applied pressures of 250-300 kPa provided most reliable delivery. CONCLUSIONS: Microneedles were shown for the first time to deliver nanoparticle and microparticle suspensions into the suprachoroidal space of rabbit, pig and human eyes. This shows that microneedles may provide a minimally invasive method for controlled drug delivery to the back of the eye. PMID- 20857179 TI - Hyaluronic acid/chitosan-g-poly(ethylene glycol) nanoparticles for gene therapy: an application for pDNA and siRNA delivery. AB - PURPOSE: To design hyaluronic acid (HA) and chitosan-g-poly(ethylene glycol) (CS g-PEG) nanoparticles intended for a broad range of gene delivery applications. METHODS: Nanoparticles formulated at different HA/CS-g-PEG mass ratios were developed to associate either pDNA or siRNA. The physico-chemical characteristics, morphology, association efficiency and nuclease protection ability of the nanocarriers were compared for these two molecules. Their biological performance, including transfection effciency, nanoparticle cellular uptake and citotoxicity, was assesed. RESULTS: The resulting nanoparticles showed an adequate size (between 130 and 180 nm), and their surface charge could be modulated according to the nanoparticle composition (from +30 mV to -20 mV). All prototypes exhibited a greater association efficiency and nuclease protection for pDNA than for siRNA. However, cell culture experiments evidenced that HA/CS-g-PEG nanoparticles were effective carriers for the delivery of both, siRNA and pDNA, eliciting a biological response with minimal cytotoxicity. Moreover, experiments performed in the HEK-EGFP-Snail1 cell line showed the potential of the HA/CS-g PEG nanoparticles to silence the expression of the Snail1 transcription factor, an important mediator in tumor progression. CONCLUSIONS: HA/CS-g-PEG nanoparticles can be easily modulated for the delivery of different types of gene molecules, offering great potential for gene therapy applications, as evidenced by their biological performance. PMID- 20857180 TI - Increase of MT1-MMP, TIMP-2 and Ki-67 proteins in the odontogenic region of the rat incisor post-shortening procedure. AB - MT1-MMP and TIMP-2 are well known for their roles in remodelling of extracellular matrix components. However, reports are emerging on the involvement of these molecules in cell kinetics. In the rat incisor tooth, a shortening treatment increases the eruption and cell proliferation rates. However, the role of MT1-MMP and TIMP-2 proteins in these processes is still to be evaluated. Male Wistar rats were divided in two groups. In the normofunctional group (NF) the lower teeth of the rats remained in a normal eruption process. In the hypofunctional group (HP) rats their lower left incisor tooth was shortened every 2 days during 12 days. The eruption rate was estimated during the shortening period and MT1-MMP, TIMP-2 and Ki-67 protein expression from the odontogenic region was measured after the treatment. In HP groups an increase in eruption rate, and in MT1-MMP/TIMP-2 and Ki-67 expression were observed. We conclude that there is a relationship between the increase in eruption rate, and in levels of MT1-MMP, TIMP-2 and Ki-67 in the HP group. This suggests that MT1-MMP and TIMP-2 may have some role in cell proliferation during the eruption of the rat incisor tooth. PMID- 20857182 TI - Coping with guilt and shame after gambling loss. AB - In this study we examined the relations between guilt and shame and coping strategies in response to gambling loss. Based on H.B. Lewis's (Shame & guilt in neurosis. New York: International Universities Press, 1971) account of guilt and shame, we proposed that unlike guilt, the experience of shame involves the attribution of gambling loss to stable and global internal factors (i.e., self devaluation). We hypothesized that problem gambling severity would be more strongly associated with the intensity of shame than with the intensity of guilt following gambling loss. Further, we hypothesized that the intensity of shame would be positively associated with the use of avoidant coping strategies following gambling loss. Finally, we hypothesized that the intensity of shame would mediate the association between problem gambling severity and the use of avoidant coping. These hypotheses were supported by a retrospective survey of recent gambling losses. Our finding suggests that the experience of shame and the use of avoidant coping strategies to deal with this emotion are central to problem gambling severity. PMID- 20857181 TI - Expression of GDF-9, BMP-15 and their receptors in mammalian ovary follicles. AB - The synergetic process of folliculogenesis is mainly regulated by GDF-9 and BMP 15 as well as their receptors, such as BMPR2, TbetaR1 and BMPR1B. Expressions of these factors and the receptors are significant different among species. This study was designed to detect expression of GDF-9, BMP-15 and their receptors in mouse, porcine and human healthy follicles by immunohistochemistry. Three ages of human ovary were studied according to ovarian developmental schedule, i.e. gestational week (GW) 16, puberty (14 year-old) and adult (40 year-old). The results showed that both GDF-9 and BMP-15 were detectable in oocytes from primary follicles onward, besides, BMP-15 also presented in granulosa cells (GCs) and follicular follicle of mature follicles in mouse. However, they were maintained in oocytes and GCs from primordial to mature follicles in porcine except that GDF 9 was undetectable in GCs of mature follicles. For human ovary, GDF-9 presented in oocytes of primordial follicles in all samples, whereas BMP-15 was only observed in primordial follicle of adult ovary. Receptors, BMPR2, TbetaR1 and BMPR1B were found in oocytes and GCs of all follicles in mouse and porcine. In human, they were stained in oocytes from primordial follices but BMPR1B was not expressed in pubertal primordial follicles. Furthermore, we found that GDF-9, BMP 15 and three receptors distributed in adult corpus lutea. Collectively, our studies suggested that GDF-9, BMP-15 and their receptors might correlate with primordial follicular recruitment in pig and human. Positive expression of the receptors (BMPR2, TbetaR1 and BMPR1B)in primordial follicles of mouse ovaries indicated that these receptors might interact with others ligands besides GDF-9 and BMP-15 to regulate primordial follicular activity in mouse. Moreover, presence of GDF-9 in oocytes and BMP-15 in oocytes and GCs of mature follicles from mice and porcine elucidated coordinated roles of GDF-9 and BMP-15 in cumulus oophorus expansion. Additionally, expression of these factors in adult human corpus lutea suggested they play roles in corpus luteum activity. PMID- 20857183 TI - Mechanism of gemini disulfide detergent mediated oxidative refolding of lysozyme in a new artificial chaperone system. AB - Gemini surfactants are a new class of surfactants that consist of two hydrophilic head groups and two hydrophobic tails separated by a spacer group. As the properties of geminis are different to their monomeric counterparts, a large number of applications have been investigated. Here we report on the use of a new class of gemini detergents containing a disulfide bond in the spacer (Det-SS-Det) for protein refolding. Using lysozyme as a model protein we could demonstrate that the disulfide gemini detergents allow oxidative refolding of the protein in the absence of any external redox system in an "artificial chaperone system". Refolding kinetics using gemini disulfide detergents differing in their hydrophobicity were analysed to determine the folding and aggregation rate constants. The results point to an important role of the transiently formed mixed disulfides between the protein and the detergent (Prot-SS-Det) in the oxidative refolding process of lysozyme. PMID- 20857185 TI - Physiological and subjective sexual arousal in self-identified asexual women. AB - Asexuality can be defined as a lifelong lack of sexual attraction. Empirical research on asexuality reveals significantly lower self-reported sexual desire and arousal and lower rates of sexual activity; however, the speculation that there may also be an impaired psychophysiological sexual arousal response has never been tested. The aim of this study was to compare genital (vaginal pulse amplitude; VPA) and subjective sexual arousal in asexual and non-asexual women. Thirty-eight women between the ages of 19 and 55 years (10 heterosexual, 10 bisexual, 11 homosexual, and 7 asexual) viewed neutral and erotic audiovisual stimuli while VPA and self-reported sexual arousal and affect were measured. There were no significant group differences in the increased VPA and self reported sexual arousal response to the erotic film between the groups. Asexuals showed significantly less positive affect, sensuality-sexual attraction, and self reported autonomic arousal to the erotic film compared to the other groups; however, there were no group differences in negative affect or anxiety. Genital subjective sexual arousal concordance was significantly positive for the asexual women and non-significant for the other three groups, suggesting higher levels of interoceptive awareness among asexuals. Taken together, the findings suggest normal subjective and physiological sexual arousal capacity in asexual women and challenge the view that asexuality should be characterized as a sexual dysfunction. PMID- 20857184 TI - Influence of the albumin concentration and temperature on the lysis of human erythrocytes by sodium dodecyl sulfate. AB - The stability of human erythrocytes to sodium dodecyl sulfate (SDS) was assessed spectrophotometrically in the presence of different concentrations of bovine serum albumin (BSA) and at different temperatures (27-45 degrees C). The absorbance at 540 nm (A540) was correlated with the SDS concentration by sigmoidal regression based on the Boltzmann equation. Erythrocyte stability was characterized on the basis of the SDS concentration that induces hemolysis in 50% of the cells (D50). Progressive increases in the albumin concentration led to increases in the D50 value. The protective effect of BSA against SDS-induced hemolysis was attributed to the binding of the surfactant to the hydrophobic binding sites of this protein. The D50 values decreased sigmoidally with an increase in the temperature. This trend, which could not be explained by changes in the spectral properties of hemoglobin, maybe due to heterogeneity in the erythrocyte population. PMID- 20857186 TI - Health behavior modification after electron beam computed tomography and physician consultation. AB - This study aimed to determine whether participants reported altering health behaviors (physical activity, diet, and alcohol consumption) after seeing results from an electron-beam computed tomography (EBCT) scan for coronary artery calcium and reviewing these results with a physician. Clinicians attempt to motivate patients to control cardiovascular risk factors by adopting healthy behaviors and reducing harmful actions. Asymptomatic patients (N = 510) were evaluated by EBCT for the extent of coronary artery calcium. Information pertaining to demographics, health history, and lifestyle/health behaviors was obtained from each participant at the time of the EBCT scan. Patients were given their numerical calcium score, shown images of their coronary arteries, and counseled by a physician for lifestyle and medical risk modification based on their coronary artery calcium score. Approximately 6 years after the scan, participants completed a follow-up questionnaire related to lifestyle modifications. In multivariable analysis, the presence and extent of coronary artery calcium was significantly associated with beneficial health behavior modifications. Specifically, the greater a patient's coronary artery calcium score, the more likely they were to report increasing exercise (odds ratio = 1.34, P = 0.02), changing diet (odds ratio = 1.40, P < 0.01), and changing alcohol intake (odds ratio = 1.46, P = 0.05). This study suggests that seeing and being counseled on the presence and extent of coronary artery calcium is significantly associated with behavior change. PMID- 20857187 TI - Neurocognitive impairment and medication adherence in HIV patients with and without cocaine dependence. AB - Cocaine abuse among HIV patients is associated with faster disease progression and mortality. This study examined the relationship between neurocognitive functioning and medication adherence in HIV patients with (n = 25) and without (n = 39) current cocaine dependence. Active users had greater neurocognitive impairment (mean T-score = 35.16 vs. 40.97, p < .05) and worse medication adherence (mean z-score = -0.44 vs. 0.27, p < .001). In a multiple regression model, neurocognitive functioning (beta = .33, p < .01) and cocaine dependence (beta = -.36, p < .01) were predictive of poorer adherence. There was a significant indirect effect of cocaine dependence on medication adherence through neurocognitive impairment (estimate = -0.15, p < .05), suggesting that neurocognitive impairment partially mediated the relationship between cocaine dependence and poorer adherence. These results confirm that cocaine users are at high risk for poor HIV outcomes and underscore the importance of treating both neurocognitive impairment and cocaine dependence among HIV patients. PMID- 20857189 TI - Somatic items in the assessment of depressive symptoms in pediatric patients with diabetes. AB - Depression inventories contain somatic items which may be related to disease rather than to depression in individuals with chronic illness. Adolescents with type 1 diabetes (n = 151) and medically well controls (n = 68) completed the Center for Epidemiological Studies-Depression Scale (CES-D) which includes somatic and cognitive/affective symptoms. Diabetes patients reported higher levels of all depressive symptoms than controls; the discrepancy was equivalent for somatic and cognitive/affective symptoms. For diabetes patients, somatic and cognitive/affective symptoms did not correlate with indices of disease control except for number of diabetes-related hospitalizations, where the correlations were equivalent. In participants with diabetes and in controls, somatic and cognitive/affective symptoms were strongly correlated with each other. These findings were not moderated by level of depressive symptoms. Our study suggests that the somatic items on the CES-D do not confound the measurement of depressive symptoms in young people with type 1 diabetes. PMID- 20857191 TI - Ground water quality in the Kathmandu valley of Nepal. AB - A study was undertaken to assess the quality of groundwaters in the Kathmandu Valley, Nepal. The groundwater samples were randomly collected from shallow well, tube well, and deep-tube wells located at different places of Kathmandu, Lalitpur, and Bhaktapur districts in the Kathmandu valley. Physical, chemical, and microbiological parameters of the samples were evaluated to estimate the groundwater quality for drinking water. It was found that the groundwater in the valley is vulnerable to drink due to presence of iron and coliform bacteria. Iron was estimated to be much higher then the acceptable limit of World Health Organization (WHO) drinking-water quality guidelines (1.9 mg/L). Total coliform bacteria enumerated in groundwaters significantly exceeded the drinking-water quality standard and observed maximum coliform (267 CFU/100 mL) in shallow wells. The electrical conductivity and turbidity were found to be 875 MUS/cm and 55 NTU, respectively, which are above the WHO recommendations for drinking water guidelines. However, pH value was measured within the acceptable limit. Arsenic, chloride, fluoride, and hardness concentrations were found to be in agreement with the recommendations of WHO drinking-water quality guidelines. PMID- 20857188 TI - A randomized clinical trial of a coping improvement group intervention for HIV infected older adults. AB - This research tested if a 12-session coping improvement group intervention (n = 104) reduced depressive symptoms in HIV-infected older adults compared to an interpersonal support group intervention (n = 105) and an individual therapy upon request (ITUR) control condition (n = 86). Participants were 295 HIV-infected men and women 50-plus years of age living in New York City, Cincinnati, OH, and Columbus, OH. Using A-CASI assessment methodology, participants provided data on their depressive symptoms using the Geriatric Depression Screening Scale (GDS) at pre-intervention, post-intervention, and 4- and 8-month follow-up. Whether conducted with all participants (N = 295) or only a subset of participants diagnosed with mild, moderate, or severe depressive symptoms (N = 171), mixed models analyses of repeated measures found that both coping improvement and interpersonal support group intervention participants reported fewer depressive symptoms than ITUR controls at post-intervention, 4-month follow-up, and 8-month follow-up. The effect sizes of the differences between the two active interventions and the control group were greater when outcome analyses were limited to those participants with mild, moderate, or severe depressive symptoms. At no assessment period did coping improvement and interpersonal support group intervention participants differ in depressive symptoms. PMID- 20857192 TI - Sampling state and process variables on coral reefs. AB - Contemporary coral reefs are forced to survive through and recover from disturbances at a variety of spatial and temporal scales. Understanding disturbances in the context of ecological processes may lead to accurate predictive models of population trajectories. Most coral-reef studies and monitoring programs examine state variables, which include the percentage coverage of major benthic organisms, but few studies examine the key ecological processes that drive the state variables. Here we outline a sampling strategy that captures both state and process variables, at a spatial scale of tens of kilometers. Specifically, we are interested in (1) examining spatial and temporal patterns in coral population size-frequency distributions, (2) determining major population processes, including rates of recruitment and mortality, and (3) examining relationships between processes and state variables. Our effective sampling units are randomly selected 75 * 25 m stations, spaced approximately 250 500 m apart, representing a 10(3) m spatial scale. Stations are nested within sites, spaced approximately 2 km apart, representing a 10(4) m spatial scale. Three randomly selected 16 m(2) quadrats placed in each station and marked for relocation are used to assess processes across time, while random belt-transects, re-randomized at each sampling event, are used to sample state variables. Both quadrats and belt-transects are effectively sub-samples from which we will derive estimates of means for each station at each sampling event. This nested sampling strategy allows us to determine critical stages in populations, examine population performance, and compare processes through disturbance events and across regions. PMID- 20857193 TI - Mangrove vulnerability modelling in parts of Western Niger Delta, Nigeria using satellite images, GIS techniques and Spatial Multi-Criteria Analysis (SMCA). AB - Mangroves are known for their global environmental and socioeconomic value. Despite their importance, mangrove like other ecosystems is now being threatened by natural and human-induced processes that damage them at alarming rates, thereby diminishing the limited number of existing mangrove vegetation. The development of a spatial vulnerability assessment model that takes into consideration environmental and socioeconomic criteria, in spatial and non spatial formats has been attempted in this study. According to the model, 11 different input parameters are required in modelling mangrove vulnerability. These parameters and their effects on mangrove vulnerability were selected and weighted by experts in the related fields. Criteria identification and selection were mainly based on effects of environmental and socioeconomic changes associated with mangrove survival. The results obtained revealed the dominance of socioeconomic criteria such as population pressure and deforestation, with high vulnerability index of 0.75. The environmental criteria was broadly dispersed in the study area and represents vulnerability indices ranging from 0.00-0.75. This category reflects the greater influence of pollutant input from oil wells and pipelines and minimal contribution from climatic factors. This project has integrated spatial management framework for mangrove vulnerability assessment that utilises information technology in conjunction with expert knowledge and multi-criteria analysis to aid planners and policy/ decision makers in the protection of this very fragile ecosystem. PMID- 20857194 TI - Benthic macroinvertebrate assemblages in remediated wetlands around Sydney, Australia. AB - To investigate potential high organisational level impacts of persistent organic pollution in the wetlands in the Sydney Olympic Park (SOP) remediated site, the benthic macroinvertebrate assemblages of seven wetlands within SOP and two off site reference wetlands were examined. Sediment cores were collected, stained and preserved from each study site and the macroinvertebrates identified to the appropriate taxonomic level (Class, Order, Family, Subfamily). Data were analysed for taxon richness and macroinvertebrate abundance and multivariate techniques were used to identify chemical/physical characteristics of the sediment, which were important influences on the differences in the assemblage between study sites. Macroinvertebrate abundance was highly variable between study sites and taxon richness was low across all sites. Oligochaetes, nematodes, ostracods and chironomids were the most common taxa found and were the most important in influencing differences between the macroinvertebrate assemblages among the study sites. Sediment grain size and chemical characteristics of the sediments (SigmaPAH, SigmaPCB, TCDDeq and heavy metal concentrations) were important in separating the study sites based on taxon richness and abundance. Canonical correspondence analysis separated the macroinvertebrate assemblages at newly two created wetlands from those at other study sites including the urban reference sites. Increased sediment POP contamination (particularly as measured TCDDeq and SigmaDDT concentrations) is a likely contributor in excluding pollution sensitive taxa and, therefore, alterations to benthic macroinvertebrate assemblages. Further, the influence of TOC suggests the significance of catchment inputs in contributing to changes in macroinvertebrate assemblage. The SOP remediation led to the establishment of wetlands with benthic communities representative of those expected in urban wetlands. PMID- 20857195 TI - Synthesis of bis-peptides attached on poly[n]norbornene molecular scaffolds with well-defined relative positions and distances. AB - This article describes novel synthetic approaches to polynorbornene molecular scaffolds substituted with peptides at various, well-defined positions. A library of norbornene building blocks with attached peptides was prepared. Alkene cyclobutane epoxide (ACE) coupling method was used as a key step reaction for the connection of two norbornene building blocks into bis-peptide scaffolds. Photodimerization of cyclobutene diesters offers an alternative route to polynorbornene bis-peptides. Pyrrolo-peptides were used for preparation of peptide-substituted 7-aza norbornenes. Asymmetrical bis-peptide scaffolds were prepared by ACE coupling of peptide-norbornane epoxide with another norbornene peptide block. Chemical elaboration of bridgehead dimethyl esters of ACE products or epoxide ACE reagents was also used for peptide attachment. PMID- 20857196 TI - Age-related oxidative decline of mitochondrial functions in rat brain is prevented by long term oral antioxidant supplementation. AB - A combination of antioxidants (N-acetyl cysteine, alpha-lipoic acid, and alpha tocopherol) was selected for long term oral supplementation study in rats for protective effects on age-related mitochondrial alterations in the brain. Four groups of rats were chosen: young control (6-7 months); aged rats (22-24 months); aged rats (22-24 months) on daily antioxidant supplementation from 18 month onwards and young rats (6-7 months) on daily antioxidant supplementation from 2 month onwards. The brain mitochondrial functional parameters, status of antioxidant enzymes and accumulation of oxidative damage markers were measured in the four groups of rats. A significant decrease in complex IV activity and a loss of transmembrane potential and phosphorylation capacity along with an increased accumulation of oxidative damage markers and compromised antioxidant enzyme status were noticed in aged rat brain mitochondria as compared to that in young controls, but in aged rats supplemented with oral antioxidants the mitochondrial alterations were largely prevented. Antioxidant supplementation in young rats had no effect on mitochondrial parameters investigated in this study. The results have implications in biochemical and functional deficits of brain during aging as well as in neurodegenerative disorders. PMID- 20857197 TI - Conventional narrow-band imaging has good correlation with histopathological severity of Helicobacter pylori gastritis. AB - BACKGROUND AND AIM: Narrow-band imaging (NBI) is an optical image enhancement technique that enhances the vessels and patterns of gastric mucosal surface. Here we aim to test the diagnostic role of conventional NBI (C-NBI) in identifying Helicobacter pylori (HP) infection, severity of gastritis, and gastric atrophy. METHODS: Initially, the endoscopic records of 300 patients were retrospectively searched for specific C-NBI gastric mucosal patterns, where five different C-NBI mucosal patterns were identified. In a second step, 20 patients with different C NBI mucosal patterns were subjected to gastric mucosal biopsy for HP testing and histopathological assessment. RESULTS: Five different histopathological grades of HP gastritis, in terms of grade of gastric atrophy, intestinal metaplasia, infiltration by inflammatory cells, and density of HP infection, were recognized among the different C-NBI mucosal patterns. CONCLUSIONS: C-NBI seems to be a promising method for HP infection identification and gastric cancer risk stratification of patients. PMID- 20857198 TI - The safety of same-day endoscopy and percutaneous liver biopsy. AB - BACKGROUND AND AIMS: The aim of this study was to review our experience with same day endoscopy (SDE) plus percutaneous liver biopsy (PLB) and to evaluate its safety compared to PLB alone. METHODS: We retrospectively examined records of all patients who underwent PLB between January 2003 and September 2009 and identified those who underwent SDE and matched these patients to those undergoing PLB alone. Serious adverse events (SAEs) were analyzed using our endoscopic database (EndoPro, Pentax) and were divided into those occurring immediately post procedure and those occurring after discharge. RESULTS: In the study, 479 patients underwent 507 PLBs and 52 patients (11%) were identified as having SDE. No statistical differences were apparent in terms of sex, age, baseline laboratory values, medical comorbidities, cirrhosis, or liver lesions. The most common indication for PLB was chronic hepatitis C (HCV). A total of 15 patients underwent upper endoscopy (EGD); 37 patients underwent colonoscopy (most for colorectal cancer screening). One (1.9%) SAE occurred in the SDE and PLB group. This patient experienced microperforation of the hepatic flexure secondary to abnormal anatomy and underwent immediate laparoscopic repair with an unremarkable post-op course. Four (0.88%) SAEs occurred with PLB alone, mostly prolonged pain from subcapsular hematoma, with no transfusions or surgery required. CONCLUSIONS: At our institution, SDE with PLB is often performed and appears to be a safe method of practice. We believe that performance of EGD or colonoscopy on the same day as PLB optimizes medical resources and results in patient satisfaction without sacrificing safety. PMID- 20857199 TI - Arterial supply of the sinoatrial node: a CT coronary angiographic study. AB - We aimed to investigate the variances in especially the origin, course and termination of the sinoatrial node (SAN) artery in this study, using coronary CT angiography. The coronary CT angiography images of 251 patients (190 men and 61 women; age range, 20-82 years; mean age, 54.4 +/- 13.6 years) were retrospectively analyzed. The SAN artery (arteries) in each case was named according to a special nomenclature with regard to their origin, course and termination. The sinoatrial node was being vascularized by a single artery in 241 (96%) cases and by two arteries in 10 (4%) cases. It was arising from RCA in 139 (55.4%) cases, from LCX in 99 (39.4%) cases, from the aorta in 2 (0.8%) cases, and from the bronchial artery in 1 (0.4%) case. The mean diameter of the SAN arteries was 2.3 mm. The mean distance between the origin of the SAN artery from RCA and the RCA ostium was 16.2 mm, from LCX and the origin of LCX was 19.3 mm. Frequency of the atrial branch was 35.9%. S-shaped SAN artery is determined in 51 (20.3%) cases. Coronary CT angiography is considerably effective in depicting the various vascularization types of SAN. PMID- 20857201 TI - A case of transient left ventricular apical ballooning syndrome in a child: clinical features and imaging findings. AB - Transient left ventricular apical ballooning syndrome (TLVABS) is an acute cardiac disease that is characterized by transient left ventricular systolic dysfunction involving the apical region. The symptoms and electrocardiographic changes of TLVABS mimic those observed in acute myocardial infarction while obstructive coronary arterial lesions are not seen in patients with TLVABS. TLVABS usually occurs in elderly women after physical or emotional stress. However, it is very rare in children and so it not well known to pediatricians. Accordingly, TLVABS in children can be misdiagnosed as myocarditis or cardiomyopathy. We report here on a case of child who showed the typical findings of TLVABS in association with pericarditis. He presented with dyspnea and pericardial effusion, which required pericardiocentesis. After pericardiocentesis, he showed the typical echocardiographic and electrocardiographic findings of TLVABS. The MRI findings at 14 days after the initial symptoms showed normal coronary arteries and normal left ventricular function without any wall motion abnormalities. In addition, no delayed hyper enhancement was found on delayed-enhanced (DE)-MRI. We also reviewed the other reported cases of TLVABS in patients who were under the age of 40. PMID- 20857200 TI - Diagnostic accuracy of first generation dual-source computed tomography in the assessment of coronary artery disease: a meta-analysis from 24 studies. AB - The objective of this study is to evaluate the diagnostic accuracy of the first generation dual-source computed tomography (DSCT) in the diagnosis of coronary artery disease (CAD). We selected articles from four databases (Pubmed, Embase, the Cochrane central register of controlled trials (CENTRAL) and Chinese biomedical literature database. The strict study selection was made, and two reviewers independently extracted data back-to-back from included studies. Meta Disc version 1.4 was used to obtain the pooled results. 24 studies were included in meta-analysis. A cut off point of >=50% stenosis was used in all the studies to define significant coronary artery stenosis. In patient-based analysis (n = 801), pooled sensitivity was 0.980 [95% confidence interval (CI):0.970-0.990], specificity 0.870 (95% CI: 0.830-0.900), median positive predictive value (PPV) across studies 0.876 (range from 0.741 to 0.943) and negative predictive value (NPV) 0.964 (range from 0.900 to 1.000). In vessel-based analysis (n = 3,620) DSCT pooled sensitivity was 0.957 (95% CI: 0.943-0.969), specificity 0.930 (95% CI: 0.910-0.940), median PPV across studies 0.838 (range from 0.534 to 0.964) and NPV 0.973 (range from 0.885 to 0.996). In segment-based analysis (n = 6,177) DSCT pooled sensitivity was 0.915 (95% CI: 0.901-0.928), specificity 0.959 (95% CI: 0.956-0.963), median PPV 0.782 (range from 0.320 to 0.927) and NPV 0.985 (range from 0.929 to 0.999). In subgroups analysis, pooled sensitivity and specificity in segment based analysis were 93.1 and 92.3% when heart rate (HR) is beyond 70 bpm; when HR was below 70 bpm, the sensitivity was similar (93%), but specificity increased a little from 92.3 to 94%. When analysed based on segment with a cut off calcium score of 400, the sensitivity was slightly higher in the subgroup with a score over 400 than in the subgroup with a score below 400 (94 vs. 91%), while the specificity was much lower in the subgroup with the high calcium score than the subgroup with the low calcium score (85 vs. 96%). For subgroups with heart rate beyond and below 65 bpm in patient-based analysis, sensitivities were 0.95 (95% CI: 0.86-0.99) and 0.98 (95% CI 0.91-1.00), respectively, while the specificities were 0.88 (95% CI 0.81-0.94) and 0.85 (95% CI 0.77-0.91), respectively. The area under the receiver operating characteristic curve (AUC) in the two subgroups were 0.9608 and 0.9786, respectively. DSCT is highly sensitive for patient-based analysis of CAD and has high specificity and NPV for segment based analysis of CAD. First generation DSCT may have a role in the evaluation of patients with chest pain as a simple non-invasive examination because of its ability to diagnose or exclude significant CAD. PMID- 20857202 TI - BRAF V600E mutation and resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer: a meta-analysis. AB - Epidemiologic studies have evaluated the association between BRAF mutations and resistance to the treatment of anti-EGFR monoclonal antibodies (MoAb) in patients with metastatic colorectal cancer (mCRC). However, the results are still inconclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. A total of 11 studies were included in the final meta-analysis. There were seven studies for unselected mCRC patients and four studies for patients with wild type KRAS mCRC. Among unselected mCRC patients, BRAF V600E mutation was detected in 48 of 546 primary tumors (8.8%). The objective response rate (ORR) of patients with mutant BRAF was 29.2% (14/48), whereas the ORR of patients with wild-type BRAF was 33.5% (158/472).The overall RR for ORR of mutant BRAF patients over wild-type BRAF patients was 0.86 (95% CI=0.57-1.30; P=0.48). For patients with KRAS wild-type mCRC, BRAF V600E mutation was detected in 40 of 376 primary tumors (10.6%). The ORR of patients with mutant BRAF was 0.0% (0/40), whereas the ORR of patients with wild-type BRAF was 36.3% (122/336). The pooled RR of mutant BRAF patients over wild-type BRAF patients was 0.14 (95% CI=0.04-0.53; P=0.004). In conclusion, this meta-analysis provides evidence that BRAF V600E mutation is associated with lack of response in wild type KRAS mCRC treated with anti-EGFR MoAbs. BRAF mutation may be used as an additional biomarker for the selection of mCRC patients who might benefit from anti-EGFR MoAbs therapy. PMID- 20857203 TI - The evolutionary history of PDR in Brachypodium distachyon polyploids. AB - The ATP-binding cassette transporter genes include the pleiotropic drug resistance (PDR) family found only in fungi and plants. These transporters transport toxic compounds across biological membranes. Here, we investigated the evolution of the PDR1 gene in Brachypodium distachyon, a widely distributed temperate grass species that belongs to the Poaceae (Gramineae) family, which also contains the domesticated cereal crops. Because this species has multiple ploidy levels, investigating PDR1 evolution in B. distachyon will offer insights into the formation and evolution of polyploidy. From 23 B. distachyon ecotypes, 39 PDR1 homologs were identified. All ecotypes had either one or two PDR1 copies. Based on restriction site analysis, the PDR1 homologs were classified as E or H type. All but one diploid and tetraploid ecotypes had only a single H type PDR1. All but one hexaploid ecotypes had both an E and a H type PDR1. Phylogenetic analysis revealed that each type formed a well-supported cluster. The two PDR1 types appeared to evolve differently. These different evolutionary patterns could indicate a difference in age between the two types or might indicate different mutation rates or selection pressures on the two types. The phylogenetic analysis also revealed that the hexaploid ecotypes shared a genomic origin for their E type PDR1, but there were multiple origins for hexaploid H type PDR1 homologs. Overall, the results suggest that tetraploid and hexaploid might be misnomers in B. distachyon and suggest a complex polyploidization history during B. distachyon evolution. PMID- 20857204 TI - Association between IGF-IR, m-calpain and UCP-3 gene polymorphisms and growth traits in Nanyang cattle. AB - The objective of this study was to estimate the allele and genotype frequencies of the IGF-IR/TaqI, m-calpain/HhaI, and UCP-3/BglI polymorphisms and to determine associations between these polymorphisms and growth traits in Chinese indigenous cattle breeds. Genotyping was performed on 321 animals including 135 Nanyang, 80 Qinchuan, and 106 Jiaxian cattle. No significant differences in growth traits were observed between the genotypes of IGF-IR/TaqI polymorphism in Nanyang cattle. The m-calpain/HhaI, and UCP-3/BglI polymorphisms were associated with body weight, withers height, and body length of 6 months (P < 0.05 or P < 0.01), body length of 18 months (P < 0.05), and body length and heart girth of 24 months (P < 0.01) in Nanyang cattle. In addition, Nanyang cattle aged 12 months with AB genotype of m-calpain/HhaI polymorphism had higher body length and heart girth than those with BB genotype (P < 0.01). The withers height were greater (P < 0.01) in Nanyang cattle aged 12 months with genotype AB of UCP-3/BglI polymorphism than those with genotype BB. The Nanyang cattle aged 24 months with genotype AA had higher withers height than those with genotype BB (P < 0.05). In conclusion, the m-calpain/HhaI and UCP-3/BglI polymorphisms may be used as DNA markers for selection in the breeding process of Nanyang cattle. PMID- 20857205 TI - Molecular characterization and expression analysis of elongation factors 1A and 2 from the Pacific white shrimp, Litopenaeus vannamei. AB - Elongation factors (EF) are abundant cell proteins that play important roles in the metabolism of all multicellular organisms. Here we describe a functional analysis of elongation factor 1-alpha (EF1A) and elongation factor 2 (EF2), from the Pacific white shrimp, Litopenaeus vannamei. Full-length cDNAs of genes corresponding to EF1A and EF2 were obtained that were 1547 and 2729 bp long, with open reading frames encoding 461 and 846 amino acids, respectively. The deduced amino acid sequences of L. vannamei EF1A and EF2 showed high similarity with those from mice, humans, chickens and other shrimps. RT-PCR analysis indicated that mRNA transcripts of EF1A and EF2 are strongly (but differentially) expressed in haemocytes and gill tissue, and at varying levels in other examined tissues, of the shrimps. Levels of both EF1A and EF2 transcripts increased when shrimps were challenged by pH and cadmium stress, but reached maximal levels after different exposure periods. These results indicate that EF1A and EF2 may play distinct, essential roles in the repair of cellular damage induced by pH and cadmium stress. PMID- 20857206 TI - Oct4 regulates the miR-302 cluster in P19 mouse embryonic carcinoma cells. AB - Oct4 is a transcription factor that is required for pluripotency during early embryogenesis and the maintenance of embryonic stem (ES) cell and pluripotent cell identity. miR-302, a cluster of eight microRNAs (miRNAs) that are expressed specifically in ES cells and pluripotent cells, is crucial for normal pluripotent cell self-renewal and pluripotency. But, the mechanism by which miR-302 participates in the core regulatory circuitry that controls self-renewal and pluripotency in P19 embryonic carcinoma cells has not been established. Here, we show that Oct4 is required for the expression and transcriptional activation of miR-302 and that Oct4 binds to the putative promoter of miR-302, suggesting that Oct4 activates the primary miR-302 transcript in P19 cells. This study proposes that the miR-302 cluster acts downstream of the Oct4 regulation network in P19 cells. PMID- 20857208 TI - Pigment epithelium-derived factor plays an inhibitory role in proliferation and migration of HaCaT cells. AB - The normal vasculature is maintained by a balance between angiogenic factors and anti-angiogenic factors. Recent studies have shown that pigment epithelium derived factor (PEDF) can induce differentiation and inhibit angiogenesis of tumors. This study was designed to investigate the expression of PEDF and its roles in proliferation, adhesion and migration of HaCaT cells, a human keratinocyte cell line. Our results have shown that PEDF is expressed in HaCaT cells at both mRNA and protein levels determined by RT-PCR and Western blot, separately. PEDF signal mainly localizes in the cytoplasm of HaCaT cell, as determined by immunofluorescence. Furthermore, expression of PEDF is decreased by 50 ng/ml of VEGF(165). Proliferation and migration of HaCaT cells are decreased by PEDF, while adhesion of HaCaT cells is upregulated approximately by 29%. PEDF also induce the S phase accumulation of HaCaT cells. In addition, phosphorylation of ERK1/2, not JNK and p38, is decreased by PEDF. These results indicate that PEDF may play an inhibitory role on growth and migration of HaCaT cells through dephosphorylation of ERK1/2. PMID- 20857207 TI - Pattern of expression of the CREG gene and CREG protein in the mouse embryo. AB - The cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that inhibits cell proliferation and/or enhances differentiation. CREG is widely expressed in adult tissues such as the brain, heart, lungs, liver, intestines and kidneys in mice. We investigated the level of CREG expression during mouse embryogenesis and its distribution at 18.5 days post coitus (dpc) using immunohistochemical staining with diaminobenzidine, western blotting and reverse transcription-polymerase chain reaction. CREG expression was first detected in mouse embryos at 4.5 dpc. It was expressed at almost all stages up to 18.5 dpc. The level of CREG was found to increase gradually and was highest at 18.5 dpc. Western blotting showed that the CREG protein was expressed at higher levels in the brain, heart, intestines and kidneys than in the lungs and liver at 18.5 dpc. In 9.5 dpc embryos, CREG was expressed only in the endothelial cells of blood vessels, after the vascular lumen had formed. With advanced differentiation, vascular smooth muscle cells developed in the embryonic vascular structures; the expression of smooth muscle alpha-actin protein and CREG were positive and increased gradually in 10.5 dpc embryonic vessels. CREG expression in the embryonic blood vessels peaked at 15.5 dpc and was reduced slightly at 18.5 dpc. These results indicate that CREG is expressed during mouse embryogenesis and might participate in the differentiation of these organs during embryogenesis. PMID- 20857210 TI - Molecular cloning, characterization and expression analysis of adenylosuccinate lyase gene in grass carp (Ctenopharyngodon idella). AB - Adenylosuccinate lyase (ADSL) is a bifunctional enzyme acting in de novo purine synthesis and purine nucleotide recycling. In the present study, we have constructed a grass carp (Ctenopharyngodon idella) intestinal cDNA library that has over 2.3 * 10(5) primary clones. An expressed sequence tag (EST) of grass carp adenylosuccinate lyase (gcADSL) gene was screened from this library. Both 5' RACE and 3'-RACE were carried out in order to obtain the complete cDNA sequence, which contains a 1,446 bp open reading frame encoding 482 amino acids about 54.552 kDa. The deduced amino acid sequence shares high homology with its vertebrate counterparts, which shares 94% similarity with zebrafish, 81% with African clawed frog as well as chicken, 77% with human and 76% with mouse. This gcADSL genomic sequence, consisted of 13 exons and 12 introns, is 8,557 bp in size. Real-time quantitative PCR analysis revealed that the highest expression level of gcADSL was detected in muscle and the lowest in gill. In western blotting analysis, His(6)-tagged gcADSL protein expressed in Escherichia coli could be recognized not only by an anti-His(6)-tag monoclonal antibody but also by an anti-human ADSL polyclonal antibody, indicating immunological crossreactivity occurs between grass carp and human ADSL protein. 1,082 bp 5' flanking region sequence was cloned and analyzed. PMID- 20857209 TI - Soluble expression, purification, and characterization of recombinant human flotillin-2 (reggie-1) in Escherichia coli. AB - Large scale production of recombinant human flotillin-2 (reggie-1) is desirable for structural and biochemical studies. However, as the major lipid rafts specific hydrophobic protein, flotillin-2 was difficult to be expressed as soluble and functional form in prokaryotic system. In this study, we first cloned and expressed human flotillin-2 in Escherichia coli with five different fusion tags: poly-histidine, glutathione S-transferase (GST), thioredoxin (TRX), N Utilization substance (NusA) and maltose binding protein (MBP). We screened the expression level and solubility of the five flotillin-2 fusion proteins, the best MBP tagged flotillin-2 was then large scale produced. The optimized purification procedure included two steps of chromatography: Ni-NTA affinity chromatography and anion exchange chromatography. The typical yield was 36.0 mg soluble and functional recombinant flotillin-2 from 1 L of culture medium with purity above 97%. The activity of recombinant flotillin-2 was verified by pull-down assay with flotillin-1, showing that the purified recombinant flotillin-2 can specifically interact with flotillin-1. The circular dichroism (CD) spectroscopy showed that recombinant flotillin-2 had a very stable secondary structure dominated by alpha helix, beta-turn and random structure. PMID- 20857211 TI - Accumulation of beta-catenin by lithium chloride in porcine myoblast cultures accelerates cell differentiation. AB - The Wnt/beta-catenin signaling pathway regulates cell proliferation and differentiation to determine cell fate during embryogenesis. Lithium chloride (LiCl) is known to activate canonical Wnt signaling by inhibiting glycogen synthetase kinase-3beta and consequently stabilizing free cytosolic beta-catenin. To understand the role of the Wnt/beta-catenin pathway in the regulation of porcine myoblast differentiation, we studied the effects of LiCl on cultured porcine myoblasts and beta-catenin expression. A supplementation of 25 mM LiCl induced myoblast differentiation into myotubes over 3 days of culture. By semi quantitative RT-PCR analyses, levels of mRNA encoding MyoD, Myogenin, Myf5 and several Wnt-responsive genes in the cultured myoblast cells were significantly increased after LiCl treatment. Using Western blotting and immunofluorescence analysis, we found that the protein levels of beta-catenin were consistently increased by LiCl. Meanwhile, phosphorylated GSK-3beta at Ser9 levels were also increased as an indicator of GSK-3beta inactivation. Additionally, the nuclear staining of endogenous beta-catenin was also significantly increased in porcine myoblasts 48 h after LiCl treatment. These results provided additional evidence that Wnt/beta-catenin is a significant pathway that regulates myogenic differentiation. An enhanced level of beta-catenin plays a positive role in porcine myoblast differentiation. PMID- 20857212 TI - Cloning, expression and characterization of the putative nuclear transport factor 2 (NTF2) gene from moss Conocephalum conicum(L.) Dum. AB - Biomacromolecules import into the nucleus is a complex progress which requires the participation of several cytosolic factors, and nuclear transport factor 2 (NTF2) is one of essential components in nuclear trafficking. Its main role is to transport RanGDP from cytoplasm to nucleus by interacting with FxFG nucleoporin repeats. In the study a putative new gene, designated as CcNTF2, was obtained from the moss (Conocephalum conicum) cDNA library we have constructed. The full length cDNA sequence is 913 bp in size contains a 372 bp open reading frame (ORF) flanked by a 195 bp 5'-untranslated sequence and a long 346 bp 3'-non-coding region, encoding 123 amino acids of 13,575.3 Da. Part of the genomic sequence was also cloned and sequenced, which is 1,602 bp long and possesses two exons and one intron. Alignment analysis showed that the CcNTF2 protein is high conserved among plant NTF2 and shares 81% similarity with the ones from Arabidopsis thaliana and Brassica rapa. The expression of wild-type CcNTF2 was detected by immunoblotting of extraction of C. conicum and it indicated the putative protein is integral. Through functional expression of CcNTF2-green fluorescent protein (GFP) in tobacco, it was demonstrated that CcNTF2 can accumulate at the nuclear rim. Site directed mutagenesis analysis confirmed CcNTF2 P71K has influence on the protein import into nucleus. In addition, overexpression of CcNTF2 P71K was observed to be deleterious for the plant cell. It is the first illumination of NTF2 in moss, and our study established the primary foundation for further research on moss NTF2. PMID- 20857214 TI - Molecular characterization of a thioredoxin h gene (HbTRX1) from Hevea brasiliensis showing differential expression in latex between self-rooting juvenile clones and donor clones. AB - The cDNA code of thioredoxin h, designated as HbTRX1, was isolated from Hevea brasiliensis by rapid amplification of cDNA ends. HbTRX1 contained a 542-bp open reading frame encoding 123 amino acids. The deduced HbTRX1 protein showing high identity to thioredoxin h of other plant species was predicted to possess the conserved catalytic site WCXPC. Semiquantitative reverse transcription-polymerase chain reaction analysis revealed that HbTRX1 was constitutively expressed in all tested tissues. HbTRX1 transcripts accumulated at relatively low levels in the flower, somatic embryo, and leaves, while HbTRX1 transcripts accumulated at relatively high levels in the callus and latex. The HbTRX1 transcript was expressed at different levels, with higher levels in self-rooting juvenile clones than in their donor clones. HbTRX1 was expressed in Escherichia coli, and its activity was demonstrated using the dithiothreitol-dependent insulin assay. This work provides a basis for studying the biological function of thioredoxin h in rubber tree. PMID- 20857213 TI - Complete mitochondrial DNA sequences of the Nile tilapia (Oreochromis niloticus) and Blue tilapia (Oreochromis aureus): genome characterization and phylogeny applications. AB - Cichlid fishes have played an important role in evolutionary biology and aquaculture industry. Nile tilapia (Oreochromis niloticus), blue tilapia (Oreochromis aureus) and Mozambique tilapia (Oreochromis mossambicus), the useful models in studying evolutionary biology within Cichlid fishes, are also mainly cultured species in aquaculture with great economic importance. In this paper, the complete nucleotide sequence of the mitochondrial genome for O. niloticus and O. aureus were determined and phylogenetic analyses from mitochondrial protein coding genes were conducted to explore their phylogenetic relationship within Cichlids. The mitogenome is 16,625 bp for O. niloticus and 16,628 bp for O. aureus, containing the same gene order and an identical number of genes or regions with the other Cichlid fishes, including 13 protein-coding genes, two rRNA genes, 22 tRNA genes and one putative control region. Phylogenetic analyses using three different computational algorithms (maximum parsimony, maximum likelihood and Bayesian method) show O. niloticus and O. mossambicus are closely related, and O. aureus has remotely phylogenetic relationship from above two fishes. PMID- 20857216 TI - Molecular cloning and characterization of a phenylalanine ammonia-lyase gene (LrPAL) from Lycoris radiata. AB - LrPAL is a novel full-length cDNA isolated from Lycoris radiata by degenerate oligonucleotide primer PCR (DOP-PCR), 3'- and 5'-RACE approaches, harbours an open reading frame (ORF) encoding a 708 amino acid product. Sequence alignment showed that the deduced amino acid sequence of LrPAL shared more than 80% identity with other PAL sequences reported in Arabidopsis thaliana and other plants. RT-PCR revealed that LrPAL transcripts were higher in bud flowers and wilting flowers (5 days after blooming) than in blooming flowers. The transcript levels of LrPAL in leaves were significantly induced by methyl jasmonate (MJ) and nitric oxide (NO), and salicylic acid (SA). Similarly, HPLC analysis showed that galantamine (GAL) content was also higher in bud flowers and wilting flowers than in blooming flowers. The GAL content in leaves was significantly induced by MJ and NO, and inhibited by SA. This study enables us to further elucidate the role of LrPAL in the biosynthesis of GAL in Lycoris radiata at a molecular level. PMID- 20857215 TI - Vascular endothelial growth factor 1498C/T, 936C/T polymorphisms associated with increased risk of colorectal adenoma: a Chinese case-control study. AB - Single nucleotide polymorphisms in vascular endothelial growth factor gene VEGF, 1498C/T and 936 C/T are associated with colorectal cancer. We sought to determine whether such genetic variability in VEGF contributes to susceptibility of colorectal adenoma (CRA), a presumably precancerous state of colorectal cancer. In this research, two aforementioned polymorphisms were investigated for CRA susceptibility in a Chinese case-control study. The epidemiological risk factors were collected through questionnaire. The plasma VEGF levels were measured via enzyme-linked immunosorbent assay (ELISA). The Taqman-Probe assay was used to determine genotypes in 224 CRA patients and 200 CRA-free controls. The clinicopathological data of each sample were collected for further correlation analysis. According to data analysis males, cigarette smokers, patients who carry metabolic syndrome or familial antecedent of adenomas were significantly associated with CRA risk. Plasma VEGF levels of CRA patients were higher than those of controls (P = 0.003). This difference is independent of genotypes. The carriers with 936CT and CT+TT had higher risk of CRA in comparison with controls (CT vs. CC, OR 2.00, 95% CI 1.23-3.25, P = 0.006; CT+TT vs. CC, OR 2.04, 95% CI 1.28-3.26, P = 0.003). 936-T allele was associated with increased risk of CRA (OR 1.91, 95% CI 1.25-2.91, P = 0.003). Both CRA and control show no difference in the genotype of 1498C/T and the allele frequency of C-/T-. CRA patients with haplotype 1498T+936T presented significantly higher risk than those with wild type 1498T+936C. Moreover, patients carrying 936CT+TT and 936-T allele demonstrated a tendency for villous adenoma. CRA patients have elevated plasma VEGF levels. The VEGF 936C/T polymorphism and 1498T+936T haplotype were found to be associated with increased CRA susceptibility. PMID- 20857217 TI - Molecular characteristics and expression profiles of glycerol-3-phosphate dehydrogenase 1 (GPD1) gene in pig. AB - The cytosolic activity of glycerol-3-phosphate dehydrogenase 1 (GPD1, EC 1.1.1.8) plays an important role in the synthesis of triacylglycerol and in the transport of reducing equivalents from the cytosol to mitochondria. Here we report the full length genomic sequence of porcine GPD1 gene including promoter region. Porcine GPD1 gene contains eight exons and seven introns. Using the ImpRH, the GPD1 gene was mapped on chromosome 5. Sub-cellular localization of the pig GPD1 was localized in cytoplasm by GFP reporter gene. The full-length CDS of porcine GPD1 gene comprises 1050 nucleotides and it encodes 349 amino acids. Using the CDS sequences of 17 species, we built the phylogeny tree of GPD1 gene. We investigated the expression level of the gene in 13 different tissues and time course from birth to postnatal day 28 in longissinus doris muscle (LD) and in cerebrum. The result shows that porcine GPD1 gene is expressed in almost all tissues we tested but its levels of expression varies widely over 2 orders of magnitude. LD and the cerebrum have similar expression pattern that is at a low level at birth and increasing with aging to the highest level at postnatal day 8 in LD and postnatal day 14 in cerebrum. But weaning decreased the expression level of the GPD1 gene. This may partially explains the effects of weaning on energy metabolism. PMID- 20857218 TI - Isolation and characterization of a novel BcMF14 gene from Brassica campestris ssp. chinensis. AB - A putative RALF (rapid alkalinization factor)-like gene (GenBank accession number EF523517), named BcMF14, was isolated from Chinese cabbage (Brassica campestris L. ssp. chinensis Makino, syn. B. rapa ssp. chinensis) by rapid amplification of cDNA ends (RACE) based on a cDNA-AFLP differential fragment exclusively expressed in fertile line. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) discovered that BcMF14 was prominently expressed in stage four and five flower buds of fertile line, no expression in vegetative structures or in sterility line. Detailed RT-PCR illuminated its strong expression in stamens. Successful suppression of BcMF14 gene expression greatly reduced the normal pollen grains. The frequency of abnormal pollen grains was 48.95% in the mutant with many shriveled pollen grains with irregular shape and some larger ones with deep hollows along the germination ditch. Pollen germination was stopped because of the severely twisted pollen tubes. These results demonstrate a potential role of the BcMF14 gene in the development of male gametogenesis in Chinese cabbage. PMID- 20857220 TI - Mitochondrial DNA diversity and PCR-based sex determination of Irrawaddy dolphin (Orcaella brevirostris) from Chilika Lagoon, India. AB - Of the only known two Lagoon populations of Irrawaddy dolphins (Orcaella) in the world, one is residing in the Chilika Lagoon in Orissa state, India. In addition to accidental deaths in gill net fishery and mechanized boat operations, there has been exploitation of the species for their oil. Extreme patchy distribution and vulnerability to becoming entangled in fishing gear has made it a focus of conservation concern. Information on genetic diversity of populations has considerable potential for informing conservation plans. The present paper reports the first genetic study of O. brevirostris from Chilika Lagoon based on mtDNA sequencing and PCR-based sex identification from 11 individuals. Control region sequence comparison showed two haplotypes and cytochrome b a single haplotype in the Chilika population of the species. Phylogenetic analysis indicated distinct clades within the Asian samples, with the Indian population showing closest genetic proximity to the haplotypes from Thailand. Sex of the animal was determined by PCR-based method. It is important to continue to examine the population discreteness and genetic variation of Irrawaddy dolphin in Chilika Lagoon vis-a-vis its global geographic distribution for formulating the conservation plans of the species. PMID- 20857219 TI - Calreticulin expression levels and endoplasmic reticulum during late oogenesis and early embryogenesis of Rhodnius prolixus Stahl. AB - This study reports the cloning, expression analysis and localization of calreticulin (CRT) in the endoplasmic reticulum (ER) during late oogenesis and early embryogenesis of the insect Rhodnius prolixus. CRT was cloned and sequenced from cDNA extracted from unfertilized eggs. Real-time PCR showed that CRT expression remains at lower levels during late oogenesis when compared to vitellogenic oocytes or day 0 laid fertilized eggs. Immunofluorescence microscopy showed that this protein is located in the periphery of the egg, in a differential peripheral ooplasm surrounding the yolk-rich internal ooplasm, only identified by transmission electron microscopy (TEM) of thin sections. Using immunogold electron microscopy, the ER ultrastructure (CRT labeled) was identified in the peripheral ooplasm as dispersed lamellae, randomly distributed in the peripheral ooplasm. No massive alterations of ER ultrastructure were found before or right after (30 min) fertilization, but an increase in CRT expression levels and assembly of typical rough ER (parallel cisternae with associated ribosomes) were observed 18-24 h after oviposition. The lack of ER assembly at fertilization and the later formation of rough ER together with the increase in CRT expression levels, suggest that the major functions of ER might be of great importance during the early events of development. The possible involvement of ER in the early steps of embryogenesis will be discussed. PMID- 20857221 TI - Trans-chalcone: a novel small molecule inhibitor of mammalian alpha-amylase. AB - Trans-chalcone (1,3-diphenyl-2-propen-1-one), a biphenolic core structure of flavonoids precursor was tested for inhibitory activity toward alpha-amylase. Porcine pancreatic alpha-amylase was observed to be effectively inhibited by this compound, which showed competitive behavior with a K(i) of 48 MUM. Soluble starch (the natural substrate of the enzyme) was used in this study in order to obtain more realistic results. The possible binding mode of the compound was assessed in silico, and the two residues Trp59, and Tyr62 were proposed as main interacting residues with trans-chalcone. In conclusion, this compound could be used to design effective inhibitors of alpha-amylase. PMID- 20857222 TI - Ascorbic acid contents in transgenic potato plants overexpressing two dehydroascorbate reductase genes. AB - Ascorbic acid (AsA, vitamin C) is one of the most important nutritional quality factors in many horticultural crops and has many biological activities in the human body. Dehydroascorbate reductase (EC 1.8.5.1; DHAR) plays an important role in maintaining the normal level of ascorbic acid (AsA) by recycling oxidized ascorbic acid. To increase AsA content of potato, we isolated and characterized the cDNAs encoding two isoform DHARs localized in cytosol and chloroplast from potato, and developed two types of transgenic potato plants overexpressing cytosolic DHAR gene and chloroplastic DHAR, respectively. Incorporation of the transgene in the genome of potato was confirmed by PCR and real time RT-PCR. The overexpression of cytosolic DHAR significantly increased DHAR activities and AsA contents in potato leaves and tubers, whereas chloroplastic DHAR overexpression only increased DHAR activities and AsA contents in leaves, and did not change them in tubers. These results indicated that AsA content of potato can be elevated by enhancing recycling ascorbate via DHAR overexpression, moreover, cytosolic DHAR might play main important roles in improving the AsA contents of potato tubers. PMID- 20857223 TI - ISBT 128 coding and labeling for cellular therapy products. AB - This paper describes the development of the ISBT 128 coding and labeling for cellular therapy products. It is published on behalf of the international Cellular Therapy Coding and Labeling Advisory Group (see www.ICCBBA.org ). PMID- 20857225 TI - Prognostic impact of inferior mesenteric artery lymph node metastasis in colorectal cancer. AB - AIM: The aims of this study are to identify the natural course of inferior mesenteric artery (IMA) lymph node metastasis, and to evaluate the prognostic impact of IMA lymph node metastasis in the sigmoid colon and rectal cancer. PATIENTS AND METHODS: From our prospectively collected database, a total of 625 patients who underwent resection with curative intent for stage III adenocarcinoma of the sigmoid colon and rectal cancer between June 1995 and June 2007 were selected. Patients were divided into the IMA-positive group (n = 33) and the IMA-negative group (n = 592) according to IMA lymph node metastasis status. Clinicopathological features, recurrence patterns, and 5-year disease free survival rates were compared between the two groups. RESULTS: Following curative resection, 5-year disease-free survival rate was 31.9% in the IMA positive group and 69.4% in the IMA-negative group (p < 0.001). Cox regression analysis revealed that rectal cancer, pathologic stage, and presence of IMA lymph node metastasis were independently associated with disease-free survival. Systemic recurrence rate was significantly higher in the IMA-positive group than in the IMA-negative group (48.5 vs. 20.8%, respectively, p = 0.001). Para-aortic nodal recurrence showed significant association with presence of IMA lymph node metastasis on multivariate analysis (hazard ratio 11.8; 95% confidence interval 2.7-52.2, p = 0.001). CONCLUSION: Presence of IMA lymph node metastasis should be considered as a predictive factor for high systemic recurrence, and should be treated and followed up with caution for para-aortic nodal recurrence. PMID- 20857224 TI - Sharing genetic risk with next generation: mutation-positive parents' communication with their offspring in Lynch Syndrome. AB - Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention. The responsibility of informing offspring about genetic risk often falls to the parents. We systematically investigated how parents with Lynch Syndrome share knowledge of genetic risk with their offspring, challenges in the communication process and wish for professional support. Of all known mutation carriers over age 40 (n = 337) in 102 Finnish Lynch Syndrome families, 86% completed a self-reported questionnaire; 248 of them (86%) had children. Of the 248 parents, 87% reported disclosure and 13% nondisclosure. Reasons for nondisclosure were mainly the young age of offspring, socially distant relationships, or feeling of difficulty in discussing the topic. Men reported significantly more often disclosure with a support person (spouse etc.) (P < 0.001). The most difficult communication aspect was discussing children's cancer risk. Of the 191 firstborn adult children informed, 69% had taken the predictive genetic test. Every third parent suggested that health professionals should be involved in passing on the information and that a family appointment at the genetic clinic should be organized at the time of disclosure. Nearly all parents had informed their adult offspring about the genetic risk and possibility of genetic testing, but almost one-third were unsure of how their offspring had used the information. The challenge is to improve the communication processes, so that all offspring would get the information important for their health care, and parents would get the professional support desired at disclosure. PMID- 20857226 TI - Two new glycosides from Viburnum plicatum Thunb. ex Murray var. plicatum f. plicatum. AB - Two new glycosides, named plicatumoside A (1) and (+)-neomedioresinol 4,4'-di-O beta-D: -glucopyranoside (2), together with 13 known compounds, were isolated from the leaves of Viburnum plicatum Thunb. ex Murray var. plicatum f. plicatum. Their structures were established on the basis of NMR, MS, and chemical data. PMID- 20857227 TI - Physical activity and health-related quality of life in young adult cancer survivors: a Canadian provincial survey. AB - OBJECTIVES: Physical activity (PA) improves health-related quality of life (HRQL) in several cancer survivor groups but no studies have focused on young adult cancer survivors (YACS). This study determined the prevalence of PA in YACS and examined dose-response associations with HRQL. METHODS: A random sample of 2,000 YACS between the ages of 20-44 were identified through a Canadian provincial cancer registry and mailed a survey that included the Leisure-Time Exercise Questionnaire, the Medical Outcomes Study 36-Item Short Form (SF36) survey, and several validated psychosocial scales. The primary endpoint was the physical component summary (PCS) of the SF36. RESULTS: Completed questionnaires were received from 588 YACS. In terms of PA prevalence, 23% were completely sedentary, 25% were insufficiently active, 22% were active within public health guidelines, and 29% were active above public health guidelines. Analysis of covariance adjusted for important medical and demographic covariates showed a statistically significant and clinically meaningful dose-response association between PA and the PCS that spanned 6.3 points (95% confidence interval [CI] 3.7 to 8.8; p < 0.001) from completely sedentary to within guidelines. Similar associations were found for the mental component summary scale (p = 0.002), depression (p < 0.001), stress (p < 0.001) and self-esteem (p < 0.001). Associations between PA and HRQL were stronger for YACS that had previously received chemotherapy. CONCLUSIONS: PA is strongly associated with HRQL in YACS but only half of YACS are meeting public health guidelines and almost a quarter are completely sedentary. Randomized controlled trials examining intervention strategies to increase PA and improve health outcomes in this understudied patient population are warranted. PMID- 20857228 TI - Crystal structure of the protein L-isoaspartyl methyltransferase from Escherichia coli. AB - Among the known covalent damages that can occur spontaneously to proteins, the formation of isoaspartyl linkages through deamidation of asparagines and isomerization of aspartates may be one of the most rapid forms under conditions of physiological pH and temperature. The protein L-isoaspartyl methyltransferase (PIMT) is thought to recognize L-isoaspartyl residues and repair this kind of damaged proteins. Curiously, there is a potential functional difference between bacterial and mammalian PIMTs. Herein, we present the crystal structure of Escherichia coli PIMT (EcPIMT) at a resolution of 1.8 A. The enzyme we investigated was able to remain bound to its product S-adenosylhomocysteine (SAH) during crystallization. Analysis indicates that the high affinity of EcPIMT for SAH might lead to the lower activity of the enzyme. PMID- 20857230 TI - The slope method: a tool for analyzing semi-continuous data. AB - The MixAlco process is a biorefinery that converts lignocellulose into useful chemicals and hydrocarbon fuels via mixed-acid fermentation. For a semi continuous-staged fermentation train, during each transfer, discrete amounts of material are moved between fermentors and data are tabulated. Because of natural day-to-day variations, the data are inherently noisy. To calculate performance parameters (e.g., yield, conversion, selectivity, productivity), the average flowrate of each stream component must be determined. To minimize error associated with noise, three data analysis methods were compared: Average, Accumulation, and Slope. The Average method determines the flowrate by averaging the amounts moved each transfer. The Accumulation method stores the solids and liquids that exit the fermentation train in separate vessels. After an extended time period, the mass in each storage vessel is measured so the average flowrate can be calculated. The Slope method calculates the flowrate of material in each stream from the slope of the moving cumulative sum with respect to time. For all three methods, the measured rates were virtually identical; thus accuracy was not affected by the method. However, for the examples presented, the Average method had >40% error and the Slope method <4% error; thus, precision was significantly affected by the method. The Accumulation method calculated the flowrate with a single data point so it is not possible to determine the statistical error. PMID- 20857229 TI - Plantlet regeneration from callus cultures of selected genotype of Aloe vera L.- an ancient plant for modern herbal industries. AB - Aloe vera L., a member of Liliaceae, is a medicinal plant and has a number of curative properties. We describe here the development of tissue culture method for high-frequency plantlet regeneration from inflorescence axis-derived callus cultures of sweet aloe genotype. Competent callus cultures were established on 0.8% agar-gelled Murashige and Skoog's (MS) basal medium supplemented with 6.0 mg l-1 of 2,4-dichlorophenoxyacetic acid (2,4-D) and 100.0 mg l-1 of activated charcoal and additives (100 mg l-1 of ascorbic acid, 50.0 mg l-1 each of citric acid and polyvinylpyrrolidone, and 25.0 mg l-1 each of L-arginine and adenine sulfate). The callus cultures were cultured on MS medium containing 1.5 mg l-1 of 2,4-D, 0.25 mg l-1 of Kinetin (Kin), and additives with 4% carbohydrate source for multiplication and long-term maintenance of regenerative callus cultures. Callus cultures organized, differentiated, and produced globular embryogenic structures on MS medium with 1.0 mg l-1 of 2,4-D, 0.25 mg l-1 of Kin, and additives (50.0 mg l-1 of ascorbic acid and 25.0 mg l-1 each of citric acid, L arginine, and adenine sulfate). These globular structures subsequently produced shoot buds and then complete plantlets on MS medium containing 1.0 mg l-1 of 6 benzylaminopurine and additives. A hundred percent regenerated plantlets were hardened in the greenhouse and stored under an agro-net house/nursery. The regeneration system defined could be a useful tool not only for mass-scale propagation of selected genotype of A. vera, but also for genetic improvement of plant species through genetic transformation. PMID- 20857231 TI - Induction and purification by three-phase partitioning of aryl alcohol oxidase (AAO) from Pleurotus ostreatus. AB - Aryl alcohol oxidase (AAO) is an extracellular flavoenzyme involved in lignin degradation by white rot fungi. Screening of lignolytic and AAO activity from twenty different fungal species were carried out. Among them, seven species showed lignolytic activity and three of them (Pleurotus ostreatus, Pleurotus eous, and Pleurotus platypus) were found to be AAO positive. Maximal AAO activity was observed in batch cultures of P. ostreatus and was found to be induced by aromatic amino acids and aryl alcohols up to a level of 289 U/l. Purification of AAO was carried out by three-phase partitioning (TPP). The 67 kDa enzyme was purified up to 10.19-fold by TPP with an overall recovery of 10.95%. Optimum pH and temperature for P. ostreatus AAO activity was found to be around 6 and 40 degrees C, respectively. From the LB plot, K (m) value of AAO for oxidizing veratryl alcohol was determined to be 0.6 mM. Results of the study indicate that P. ostreatus is the best producers of AAO, and they could be employed as promising fungal species for biotechnological applications. PMID- 20857232 TI - Traumatic brain injury elicits similar alterations in alpha7 nicotinic receptor density in two different experimental models. AB - Traumatic brain injury (TBI) is a major cause of death and disability worldwide, especially in children and young adults. Previous studies have shown alterations in the central cholinergic neurotransmission after TBI. We therefore determined alpha7 nicotinic acetylcholine receptor (nAChR) densities in newborn piglets and adult rats after experimental TBI. Thirteen newborn piglets (post-TBI survival time: 6 h) underwent fluid percussion (FP) injury (n = 7) or sham operation (n = 6). Furthermore, adult rats randomized into three groups of post-TBI survival times (2, 24, 72 h) received controlled cortical impact injury (CCI, n = 8) or sham operation (n = 8). Brains were frozen, sagittally cut and incubated with the alpha7-specific radioligand [(125)I]alpha-bungarotoxin for autoradiography. In injured newborn piglets, decreased alpha7 receptor densities were observed in the hippocampus (-38%), the hippocampus CA1 (-40%), thalamus (-30%) and colliculus superior (-30%). In adult rats, CCI decreased the receptor densities (between -16 and -47%) in almost any brain region within 2 and 24 h. In conclusion, widespread and significantly lowered alpha7 nAChR densities were demonstrated in both TBI models. Our results suggest that a nearly similar TBI-induced decrease in the alpha7 density in the brain of immature and adult animals is found, even with the differences in species, age and experimental procedures. The alterations make the alpha7 nAChR a suitable target for drug development and neuroimaging after TBI. PMID- 20857233 TI - BrainKnowledge: a human brain function mapping knowledge-base system. AB - Associating fMRI image datasets with the available literature is crucial for the analysis and interpretation of fMRI data. Here, we present a human brain function mapping knowledge-base system (BrainKnowledge) that associates fMRI data analysis and literature search functions. BrainKnowledge not only contains indexed literature, but also provides the ability to compare experimental data with those derived from the literature. BrainKnowledge provides three major functions: (1) to search for brain activation models by selecting a particular brain function; (2) to query functions by brain structure; (3) to compare the fMRI data with data extracted from the literature. All these functions are based on our literature extraction and mining module developed earlier (Hsiao, Chen, Chen. Journal of Biomedical Informatics 42, 912-922, 2009), which automatically downloads and extracts information from a vast amount of fMRI literature and generates co occurrence models and brain association patterns to illustrate the relevance of brain structures and functions. BrainKnowledge currently provides three co occurrence models: (1) a structure-to-function co-occurrence model; (2) a function-to-structure co-occurrence model; and (3) a brain structure co occurrence model. Each model has been generated from over 15,000 extracted Medline abstracts. In this study, we illustrate the capabilities of BrainKnowledge and provide an application example with the studies of affect. BrainKnowledge, which combines fMRI experimental results with Medline abstracts, may be of great assistance to scientists not only by freeing up resources and valuable time, but also by providing a powerful tool that collects and organizes over ten thousand abstracts into readily usable and relevant sources of information for researchers. PMID- 20857234 TI - Code generation: a strategy for neural network simulators. AB - We demonstrate a technique for the design of neural network simulation software, runtime code generation. This technique can be used to give the user complete flexibility in specifying the mathematical model for their simulation in a high level way, along with the speed of code written in a low level language such as C+ +. It can also be used to write code only once but target different hardware platforms, including inexpensive high performance graphics processing units (GPUs). Code generation can be naturally combined with computer algebra systems to provide further simplification and optimisation of the generated code. The technique is quite general and could be applied to any simulation package. We demonstrate it with the 'Brian' simulator ( http://www.briansimulator.org ). PMID- 20857235 TI - Sudden death due to adrenal neuroblastoma: child abuse mimic? AB - Neuroblastoma is one of the most common malignancies in children. It is a tumor that can clinically present with varied symptoms that can mimic other entities, including child abuse. It is important that forensic pathologists are aware of the diseases that can masquerade as child abuse. A case of sudden, unexpected death in a 2-year-old due to previously undiagnosed neuroblastoma is presented. At initial presentation of the child in the emergency department, child abuse was considered as a possible explanation for the sudden demise. Death occurred before a full clinical workup could be completed and an autopsy was performed which unveiled the cause of death. PMID- 20857236 TI - Sudden death from ruptured intracranial vascular malformation. AB - Central nervous system (CNS) vascular malformations are well-known entities that may cause sudden death from rupture and intracranial hemorrhage. Despite this, relatively few papers deal with these lesions in the forensic literature. Here, we present four cases of sudden, non-traumatic death caused by ruptured CNS vascular malformations. In all four cases, the definitive source of bleeding was not identified grossly, being diagnosed only after relatively extensive histologic examination. When a source of intracranial hemorrhage is not readily identified at autopsy, it is common for forensic pathologists to rule the cause of death in such cases as "spontaneous intracerebral hemorrhage" or "spontaneous subarachnoid hemorrhage," depending on the location of the hemorrhage. Whether or not histologic evaluation is performed in such cases depends on pathologist preference or office policy, and may be influenced by limited available funding for such studies. Because vascular malformations are not always grossly visible at autopsy when accompanied by intracranial hemorrhage, we contend that it is important to thoroughly investigate the underlying cause of such hemorrhage through a meticulous gross examination as well as histologic examination. Such examination will lead to a more accurate assignment of the cause of death, which may have important implications for surviving family members, and will lead to a better understanding of the natural history of these intracranial lesions. A brief discussion of the histologic classification of CNS vascular malformations is provided. PMID- 20857238 TI - Symptoms and reflux in infants: Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R)--utility for symptom tracking and diagnosis. AB - Answering a need for a thoroughly validated infant gastroesophageal reflux questionnaire, the Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ R) was designed, refined, and validated using state-of-the-art psychometric methods. Diagnostic and evaluative (tracking) validity was identified. However, perplexing results of some clinical trials using the I-GERQ-R for diagnosis prompted analysis of possible reasons, including ambiguities in defining symptomatic gastroesophageal reflux disease (GERD) and aspects of the validation process. Symptomatic GERD is defined by "troublesomeness" of symptoms and attribution of their causation to reflux--two crucial issues. Methods of quantifying symptom-reflux associations are described and their limitations identified. The location of "symptomatic esophageal GERD" in the continuum of erosive GERD, histologic GERD, and nonerosive reflux disease is indicated, with the last including "suberosive," "premicroscopic," and "functional heartburn" subcategories. Another category is defined solely by surrogate measures of propensity to GERD (e.g., acid exposure thresholds defined on esophageal pH monitoring). During diagnostic validation of the Infant Gastroesophageal Reflux Questionnaire (I-GERQ) instruments, asymptomatic normals were contrasted with symptomatic GERD infants (who also tested positive with esophageal histology and esophageal pH monitoring). However, the diagnostic validation did not attempt to distinguish symptomatic GERD infants from symptomatic infants without GERD. The I GERQ-R is thus adequately sensitive to be used diagnostically to screen infants for symptom burden, but should probably be supplemented by other, perhaps invasive, testing to assure appropriate specificity. The I-GERQ-R's validation for evaluative properties, however, supports its use for tracking symptoms within clinical trials. PMID- 20857237 TI - Vascular endothelial function and hypertension: insights and directions. AB - Hypertension contributes significantly to worldwide cardiovascular morbidity and mortality. Hypertension appears to have a complex association with endothelial dysfunction, a phenotypical alteration of the vascular endothelium that precedes the development of adverse cardiovascular events and portends future cardiovascular risk. This review concentrates on recent findings with respect to the mechanisms of hypertension-associated endothelial dysfunction, the interrelationship between these two entities, and the relationship of the efficacy of antihypertensive therapies to improvements in vascular homeostasis beyond blood pressure reduction. Current evidence suggests that hypertension and endothelial dysfunction are integrally related with respect to pathophysiologic mechanisms. Future studies will need to identify the key connections between hypertension and endothelial dysfunction to allow novel interventions to be designed and promulgated. PMID- 20857239 TI - Clinical trial report: Eradication of Helicobacter pylori reduces the risk for subsequent gastric cancer. PMID- 20857241 TI - pYEMF, a pUC18-derived XcmI T-vector for efficient cloning of PCR products. AB - A 1330-bp DNA sequence with two XcmI cassettes was inserted into pUC18 to construct an efficient XcmI T-vector parent plasmid, pYEMF. The large size of the inserted DNA fragment improved T-vector cleavage efficiency, and guaranteed good separation of the molecular components after restriction digestion. The pYEMF-T vector generated from parent plasmid pYEMF permits blue/white colony screening; cloning efficiency analysis showed that most white colonies (>75%) were putative transformants which carried the cloning product. The sequence analysis and design approach presented here will facilitate applications in the fields of molecular biology and genetic engineering. PMID- 20857240 TI - Cardiac assessment in duchenne and becker muscular dystrophies. AB - Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies. In addition to muscle disease, there nearly always is an associated cardiomyopathy in Duchenne or Becker muscular dystrophy. In these muscular dystrophies, the severity of cardiomyopathy and congestive heart failure may not parallel the severity of skeletal muscle disease. Loss of normal dystrophin function in the heart produces four-chamber dilation and reduction in left ventricular function that develop after the onset of muscle weakness. Arrhythmias affecting both atrial and ventricular rhythms occur and may be life threatening. The degree to which hypoventilation and pulmonary dysfunction are present also directly affect cardiac function in muscular dystrophy. Care guidelines recently were issued to outline surveillance and treatment strategies for the younger patient with Duchenne muscular dystrophy. Herein, we review those guidelines, and additionally, provide recommendations for monitoring and treating cardiac disease in the populations of advanced Duchenne and Becker muscular dystrophies. PMID- 20857242 TI - Giant cell arteritis: epidemiology, diagnosis, and management. AB - Giant cell arteritis (GCA), also called temporal arteritis, is a vasculitis that affects large and middle-sized blood vessels--with predisposition to the involvement of cranial arteries derived from the carotid artery--in individuals older than 50 years of age. Familial aggregation of GCA has been observed. Incidence of GCA is higher in white individuals than those of other ethnicities, particularly those of Scandinavian background. A temporal artery biopsy is the gold standard test for the diagnosis of GCA. Several imaging modalities, in particular ultrasonography, are useful in the diagnosis of GCA. Corticosteroids are the cornerstone of treatment in GCA. Alternative, steroid-sparing drugs, particularly methotrexate, should be considered in GCA patients with severe corticosteroid-related side effects and/or in those who require prolonged corticosteroid therapy due to relapses of the disease. PMID- 20857243 TI - The role of quantitative sensory testing in the evaluation of musculoskeletal pain conditions. AB - Quantitative sensory testing (QST) is a noninvasive method of assessing sensory and pain perception that has been used in the past 30 years primarily for analysis of cutaneous and mucosal perception. In recent years, several published studies have demonstrated that QST may be useful in the analysis of painful musculoskeletal disorders as well. Based on the results of these studies, it can be postulated that QST may be useful in the analysis of the pathogenesis, classification, and differential diagnosis of musculoskeletal disorders. However, due to the diverse ethiopathogenetic basis of these disorders, a broad range of QST test batteries may be necessary to analyze the various musculoskeletal disease entities. This review analyzes published studies on this subject and summarizes current information on altered sensory and pain perception available for some of the most common musculoskeletal disorders. At present, QST remains primarily a research tool but may be useful in differential diagnosis in indicating the presence of central sensitization and for clinical monitoring of disease progression or treatment response. PMID- 20857245 TI - Ectopic thyroid presenting as a submandibular mass. AB - Although extremely rare, the presence of ectopic thyroid tissue in the submandibular region should be considered in the differential diagnosis of tissue masses in the cervical region. Diagnosis is confirmed by fine-needle aspiration biopsy and exclusion of malignancy should be confirmed by histopathologic analysis of the lesion. In general, surgery is the treatment of choice. A rare case of ectopic thyroid in the right submandibular region is reported; it was diagnosed after total thyroidectomy and successfully treated through surgery. PMID- 20857244 TI - Variations in brain gray matter associated with chronic pain. AB - Variations in brain gray matter volume and density have been reported in association with a variety of disorders characterized by chronic pain, including chronic low back pain, fibromyalgia, and irritable bowel syndrome. Correlation analyses have demonstrated relationships between morphometric and clinical variables. However, conclusions regarding the nature of these relationships are problematic given that currently available data are derived exclusively from cross-sectional studies. Further efforts to determine the relationship between chronic pain and variations in brain morphometry will depend in part on longitudinal studies of patients at various stages of illness, as well as those at risk of the development of chronic pain. Interpretation of findings from morphometric studies also must take into account genetic and experiential factors that recently have been demonstrated to influence brain morphometry and the risk of developing chronic pain. PMID- 20857247 TI - The development and evaluation of the subaxial injury classification scoring system for cervical spine trauma. AB - BACKGROUND: Fractures and dislocations of the subaxial cervical spine may give rise to devastating consequences. Previous algorithms for describing cervical trauma largely depend on retrospective reconstructions of injury mechanism and utilize nonspecific terminology which thus diminish their clinical relevance add to the difficulty of educating doctors and performing prospective research. QUESTIONS/PURPOSES: We characterized the potential benefits of the Subaxial Injury Classification (SLIC) scale which considers three major variables that influence spinal stability: morphology, integrity of the discoligamentous complex, and neurologic status. Each category was assigned a certain number of points based on the severity of the injury which are added together to generate a total score; this value provides prognostic information and may also be useful for directing subsequent management (ie, nonoperative treatment versus operative intervention). METHODS: We examined the individual components that comprise the SLIC paradigm and reviewed the manner in which cervical injuries are scored and stratified. We also critically assessed the preliminary data comparing the SLIC scheme to preexisting classification systems. RESULTS: The results of a preliminary analysis demonstrate that the intraclass coefficients (ICC) for the three primary components range between 0.49 and 0.90, suggesting that the overall reliability of the SLIC system appears to be at least as good as that of other conventional schemes for classifying subaxial cervical spine trauma (ICC between 0.41 and 0.53). CONCLUSIONS: This scheme will hopefully facilitate the development of evidence-based guidelines that may influence other aspects of the therapeutic decision-making process (eg, which operative approach is most appropriate for a particular injury). We anticipate its accuracy and reproducibility will increase over time as surgeons become more familiar with the protocol. PMID- 20857246 TI - Inter-observer agreement in laryngeal pre-neoplastic lesions. AB - In this series, laryngeal preneoplastic lesions were evaluated by the classifications of the World Health Organization (WHOC), Ljubljana (LC) and squamous intraepithelial neoplasia (SINC) by multiple observers. The inter observer agreement (IA) by WHOC for laryngeal lesions had been previously evaluated, but to the best of our knowledge, there are no data for LC and SINC. H&E stained slides from 42 laryngeal biopsies were evaluated by fourteen participants according to WHOC and LC, and SINC was additionally applied by 6. The results were analyzed statistically. The diagnoses which were favored by most participants for each case, according to WHOC, were as follows: squamous cell hyperplasia (n = 5; 12%), mild dysplasia (n = 11; 26.2%), moderate dysplasia (n = 12; 28.6%), severe dysplasia (n = 7; 16.7%), carcinoma in situ (n = 5; 12%), and invasive squamous cell carcinoma (n = 2; 4.8%). There was a significant difference between the participants for all three classifications; some participants gave lower or higher scores than the others. The mean correlation coefficients (MCC) of the participants were higher for WHOC compared to LC (0.55 +/- 0.15 and 0.48 +/- 0.14, respectively). The mean linear-weighted kappa (wKappa) values of participants were not significantly different (0.42 +/- 0.10, 0.41 +/- 0.12 and 0.37 +/- 0.07 for WHOC, LC and SINC, respectively). The kappa values in this series are in agreement with those in previous literature for WHOC, and the similar results obtained for LC and SINC are novel findings. Although the MCC of WHOC was higher, as the wkappa was not significantly different, the findings in this series are not in favor of any of the classifications for better IA for pre-neoplastic laryngeal lesions. PMID- 20857248 TI - Incidence of postthrombotic syndrome in patients undergoing primary total hip arthroplasty for osteoarthritis. AB - BACKGROUND: Postthrombotic syndrome (PTS) is a chronic condition in the lower extremity that develops after deep vein thrombosis (DVT). The incidence of PTS after total hip arthroplasty (THA) is not well established. QUESTIONS/PURPOSES: We (1) determined the incidence of PTS after DVT in patients undergoing primary THA for osteoarthritis; and (2) determined whether the incidence of PTS was greater in patients with DVT than without. METHODS: We retrospectively reviewed records of all 1037 patients who underwent primary THA for osteoarthritis during a 4-year period. All patients underwent postoperative screening ultrasound. We identified 21 (2%) patients with a DVT by ultrasound of whom 14 had a minimum 1 year followup (mean, 3.4 years; range, 1.0-6.0 years). PTS was diagnosed if any two of the six clinical signs were documented. RESULTS: Three of 14 patients with DVT had at least two signs consistent with PTS; two of these had a DVT proximal to the soleal arch. Three of 91 randomly matched patients undergoing THA without DVT had at least two signs of PTS. The incidence of developing PTS after THA appeared higher in patients with DVT than in patients without DVT. CONCLUSIONS: While we observed a difference between the incidence of PTS after THA in patients with and without DVT, that incidence was based on only three of 1037 patients with DVT after THA. PTS does not appear to be a major complication after DVT in patients undergoing THA. LEVEL OF EVIDENCE: Level III, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20857249 TI - The epidemiology of nonaccidental trauma in children. AB - BACKGROUND: Abuse of children is abhorrent in Western society and, yet, is not uncommon. Nonaccidental trauma (NAT) is the result of a complex sociopathology. Not all of the causative factors of NAT are known, many are incompletely described, not all function in each case, and many are secondary to preexisting pathology in other areas. QUESTIONS/PURPOSES: We therefore addressed the following questions in this review: (1) what is the general incidence of NAT; (2) what factors are intrinsic to the abused child, family, and society; and (3) what orthopaedic injuries are common in NAT? METHODS: We searched Medline, Medline In Process & Other Non-Indexed Citations, and Embase using OVID. Only one article fit our inclusion criteria; therefore, this is a descriptive generalized review of the epidemiology of NAT. RESULTS: The general incidence of NAT ranges from 0.47 per 100,000 to 2000 per 100,000. Younger children are at greater risk of NAT than older children. Parents are often the perpetrators of the abuse. Rib fractures are highly indicative of NAT in young children. CONCLUSIONS: It is important to consider child, family, and societal factors when confronted with suspicions of child abuse. Our review demonstrates the currently limited information on the true incidence of NAT. To determine a much more accurate incidence of NAT, there needs to be a population-based surveillance program conducted through primary care providers. PMID- 20857250 TI - Recurrent giant cell tumor of long bones: analysis of surgical management. AB - BACKGROUND: Treatment of giant cell tumor of bone (GCT) often is complicated by local recurrence. Intralesional curettage is the standard of care for primary GCTs. However, there is controversy whether intralesional curettage should be preferred over wide resection in recurrent GCTs. QUESTIONS/PURPOSES: We investigated the rerecurrence-free survival after surgical treatment of recurrent GCTs to determine the influence of the surgical approach, adjuvant treatment, local tumor presentation, and demographic factors on the risk of further recurrence. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 46 patients with recurrent GCTs of long bones treated with wide resection or intralesional curettage and compared these cohorts. Recurrence rates, risk factors for recurrence, and the development of pulmonary metastases were determined. The minimum followup was 37 months (mean, 134 months; range, 37-337 months). RESULTS: The rate of rerecurrence after wide resection was 6%. Intralesional curettage showed an overall rerecurrence rate of 32%. Implantation of polymethylmethacrylate (PMMA) instead of bone grafting was associated with a lower risk of subsequent recurrence in intralesional procedures (14% versus 50%). Extracompartmental disease did not increase the risk of rerecurrence. Pulmonary metastases occurred in seven patients and appeared independent of the surgical treatment modality chosen. CONCLUSIONS: Intralesional curettage with methylmethacrylate for recurrent GCT provided equivalent tumor control compared with resection in this retrospective study. If joint salvage is possible, we advocate this treatment over resection in recurrent GCTs to preserve the native joint articulation. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20857251 TI - Does a cemented cage improve revision THA for severe acetabular defects? AB - BACKGROUND: Evidence suggests a growing incidence of revision total hip arthroplasty (THA) including a subset with large acetabular defects. Revision THA for severe acetabular bone loss is associated with a relatively high rate of mechanical failure. QUESTIONS/PURPOSES: We questioned whether cementing a cage to the reconstructed acetabular defect and pelvis would improve the rate of mechanical failure for patients with Type 3 defects (Paprosky et al.) with and without pelvic discontinuity in comparison to historical controls. METHODS: We retrospectively collected data on 33 patients who underwent 35 revision THAs using an acetabular reconstruction cage cemented to morselized allograft and either structural allograft or trabecular metal augmentation for Type 3 defects in the presence (n = 13) and absence (n = 22) of pelvic discontinuity at a mean followup of 59 months (range, 24-92 months). The primary outcome was mechanical failure, defined as revision of the acetabular reconstruction for aseptic loosening. RESULTS: Revision surgery for mechanical failure occurred in four of the 13 patients with pelvic discontinuity and two of the 22 patients without discontinuity. Radiographic loosening occurred in one patient with and one patient without pelvic discontinuity. Seven of the 35 revisions were subsequently revised for deep infection all in patients who were immunocompromised. CONCLUSIONS: Cementing the cage to the pelvis can offer an advantage for treating severe acetabular defects. Trabecular metal augmentation appears to provide better initial mechanical stability than a structural allograft, but successful allograft reconstruction may restore bone stock. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 20857252 TI - Modeling disease progression in acute stroke using clinical assessment scales. AB - This article demonstrates techniques for describing and predicting disease progression in acute stroke by modeling scores measured using clinical assessment scales, accommodating dropout as an additional source of information. Scores assessed using the National Institutes of Health Stroke Scale and the Barthel Index in acute stroke patients were used to model the time course of disease progression. Simultaneous continuous and probabilistic models for describing the nature and magnitude of score changes were developed, and used to model the trajectory of disease progression using scale scores. The models described the observed data well, and exhibited good simulation properties. Applications include longitudinal analysis of stroke scale data, clinical trial simulation, and prognostic forecasting. Based upon experience in other areas, it is likely that application of this modeling methodology will enable reductions in the number of patients needed to carry out clinical studies of treatments for acute stroke. PMID- 20857254 TI - International Standards for a Safe Practice of Anesthesia 2010. PMID- 20857253 TI - Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. AB - Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited form of cardiomyopathy with low penetrance and variable expressivity. Dominant mutations and rare polymorphisms in desmosome genes are frequently identified. We reasoned that individuals with earlier onset disease would have more frequent desmosome gene mutations and rare polymorphisms. Three groups were compared: Young with symptoms attributable to ARVD/C or a diagnosis of ARVD/C at age of 21 years or earlier, Middle with first symptoms or diagnosis age of 22-49 years, and Late with first symptoms or diagnosis at age of 50 or more years. deoxyribonucleic acid (DNA) sequence analysis was performed on five cardiac desmosome genes, and the presence of mutations and rare missense polymorphisms was compared among the three groups. In the entire Young cohort, 20 (67%) had one or more cardiac desmosome gene mutations. The prevalence of cardiac desmosome gene mutations was similar in the Middle (48%) and Late (53%) cohorts (P = 0.23). Similar numbers of individuals in each cohort had more than one desmosome gene mutation, although the numbers are too small for statistical comparisons. The prevalence of certain rare missense DNA variants was not different among the cohorts (P = 0.71), yet these rare missense alleles were more prevalent in the overall study cohort of 112 ARVD/C participants compared to 100 race-matched controls (P = 0.027). The presence of these variants did not associate with the age of onset of ARVD/C or ventricular tachycardia. These findings highlight the complex interplay of environmental and genetic factors contributing to this condition. PMID- 20857255 TI - An iterative process of global quality improvement: the International Standards for a Safe Practice of Anesthesia 2010. AB - PURPOSE: To enhance patient safety through contemporaneous and comprehensive standards for a safe practice of anesthesia that augment, enhance, and support similar standards already published by various countries and that provide a resource for countries that have yet to formulate such standards. STANDARDS DEVELOPMENT: The Safe Anesthesia Working Group of the World Health Organization's "Safe Surgery Saves Lives" global initiative updated the 1992 International Standards for the Safe Practice of Anaesthesia (Standards) through an iterative process of literature review, consultation, debate, drafting, and refinement. These Standards address, in detail, the organization, support, practices, and infrastructure for anesthesia care. The Standards are grounded in the fundamental principle of safety in anesthesia, i.e., the continuous presence of an appropriately trained, vigilant anesthesia professional. In effect, the use of pulse oximetry during anesthesia is now considered mandatory, with acknowledgement that compromise may be unavoidable in emergencies. At the World Congress of Anaesthesiologists in 2008, drafts were presented for comment, further refinements were made, and the Revised Standards were adopted by the World Federation of Societies of Anaesthesiologists (WFSA). These Revised Standards were posted on the WFSA website for further feedback, and minor revisions followed. The International Standards for a Safe Practice of Anesthesia 2010 were endorsed by the Executive Committee of the WFSA in March 2010. Ongoing periodic revision is planned. CONCLUSION: While they are universally applicable, the 2010 Standards primarily target lesser-resourced areas. They are designed particularly for regions that have yet to formulate or adopt their own standards so as to promote optimum patient outcomes in every anesthetizing location in the world. PMID- 20857256 TI - [Faster double-lumen tube intubation with the videolaryngoscope than with a standard laryngoscope]. AB - PURPOSE: This study was designed to compare videolaryngoscopy with direct laryngoscopy with respect to ease of intubation when inserting a double lumen tube (DLT). METHODS: In this prospective randomized study 68 patients American Society of Anesthesiologists (ASA) physical status I and II were included. Patients with criteria indicating possible difficult intubation were excluded. The patients were randomized into two groups, depending on the tool used to facilitate intubation: videolaryngoscope (VL group) or direct laryngoscopy (DL group). The time required for intubation was the primary endpoint. Cormack and Lehane glottic visualization (CL) scores, the need for external laryngeal maneuvers and the number of attempts were measured. RESULTS: Glottic visualization was better in the VL group than in the DL group. The CL scores were I, II and III in 24, eight and two patients, respectively, in the VL group compared with 13, 11 and eight in the DL group (P = 0.025). Patients in the VL group required fewer attempts than the DL group (P = 0.019). Intubation time was 39.9 +/- 4.4 sec in the VL group and 47.9 +/- 5.4 sec in the DL group (P < 0.001). No intubation failure was noted in group VL compared with two in the DL group (not significant). CONCLUSION: The use of a videolaryngoscope reduces the time required for intubation with a DLT compared with the direct laryngoscopy in elective thoracic surgery. PMID- 20857257 TI - The clinical management of acetaminophen poisoning in a community hospital system: factors associated with hospital length of stay. AB - Acetaminophen (APAP) overdose is the most common pharmaceutical poisoning. The objective of this study was to examine the management of patients admitted for treatment of APAP overdose. Factors impacting hospital length of stay (LOS) were of particular interest. This was a retrospective cohort study of patients admitted to Kaiser Permanente Northern California hospitals for APAP overdose from July 2003 through December 2007. Medical records were abstracted for patient demographic data, key factors of overdose, California Poison Control System (CPCS) contact, data regarding hospital course, transfer for liver transplantation, and death. Four hundred thirty-five patients were included. The mean hospital LOS was 66.5 h (95% CI 62.1, 71.0). Four patients (0.9%) died. Eight patients (1.8%) were transferred for liver transplantation, but all of these patients later recovered without transplant. Of 289 cases eligible for placement on the Rumack-Matthew nomogram (acute ingestion with known time of ingestion <24 h and normal liver enzymes), 161 (55.7%) had APAP levels above the "200" line and 77 (26.6%) fell below the "150" line. CPCS was contacted in 295 cases (67.8%). Mean LOS in cases with CPCS consultation was 61.9 h (95% CI 57.2, 66.5 h) versus 76.3 h (95% CI 66.6, 86.0 h) in those without. LOS in cases treated with IV NAC was 67.1 h (95% CI 57.7, 76.5 h) versus 66.4 h (95% CI 61.2, 71.5 h) in cases treated with oral NAC. Many patients admitted for APAP overdose had serum APAP levels below the minimum toxicity level. Use of IV NAC did not impact hospital LOS. CPCS consultation appeared to decrease mean hospital LOS. PMID- 20857258 TI - MicroRNA-dependent regulation of PTEN after arsenic trioxide treatment in bladder cancer cell line T24. AB - Arsenic trioxide has shown remarkable biological activity against bladder cancer in some clinical studies. However, the mechanism of its action is unknown. Our aim was to find the relationship between miRNAs and arsenic trioxide treatment by using T24 human bladder carcinoma cells. By performing microRNA microarray and quantitative real-time PCR after ATO treatment, we found that expression levels of several miRNAs, in particular, miRNA-19a, were significantly decreased in T24 cell line. Furthermore, cell proliferation assay, flow cytometry analysis, prediction of miRNA targets, Western blot analysis, and luciferase reporter assay were performed to determine the role of mir-19a in affecting the biological behaviors of T24 cells. Several miRNAs were up-regulated or down-regulated in T24 cells treated with arsenic trioxide compared to their controls. If only changes above two folds were considered, two miRNAs were identified, miRNA-19a was down regulated, while miRNA-222* was up-regulated. Among them, knockdown of miRNA-19a by anti-miRNA-19a transfection showed a positive therapeutic effect in bladder cancer cells by inhibiting cell growth and inducing cell apoptosis targeting PTEN through the PTEN/Akt pathway. Besides this, a synergy effect was detected between knockdown of miRNA-19a and arsenic trioxide. Arsenic trioxide altered miRNA expression profile in T24 cells. It seems miRNA-19a plays a critical role in the mechanism of arsenic trioxide treatment in bladder cancer. The synergy effect between miRNA-19a and arsenic trioxide that advocates targeting the mir-19a may represent a potential approach to enhance the efficacy and safety of ATO to treat bladder cancer by a decrease in dose. PMID- 20857259 TI - Non-targeted effects of ionising radiation and radiotherapy. AB - Modern radiobiology is undergoing rapid change due to new discoveries contradicting the target concept which is currently used to predict dose-response relationships. Thus relatively recently discovered radiation-induced bystander effects (RIBEs), that include additional death, mutation and radio-adaptation in non-irradiated cells, change our understanding of the target concept and broadens its boundaries. This can be significant from a radioprotection point of view and also has the potential to reassess radiation damage models currently used in radiotherapy. This article reviews briefly the general concepts of RIBEs such as the proposed underlying mechanisms of signal induction and propagation, experimental approaches and biological end points used to investigate these phenomena. It also summarises several mathematical models currently proposed in an attempt to quantify RIBE. The main emphasis of this article is to review and highlight the potential impact of the bystander phenomena in radiotherapy. PMID- 20857260 TI - Role of platelets in placentation. AB - In the human placenta, embryo-derived trophoblasts aggressively invade maternal spiral arteries and transform the arteries to low-resistance large-caliber vessels. This process, which ensures adequate placental perfusion, is called maternal vascular remodeling. Histological examination showed deposition of maternal platelets in the trophoblast aggregates formed in the spiral arteries. Several lines of evidence suggest that these platelets are activated. Soluble factors released from the activated platelets, as a whole, enhanced invasive capacity of isolated trophoblasts in vitro. These findings suggest the importance of nonhemostatic platelet function in maternal vascular remodeling. In contrast, gene knockout studies suggest that maternal platelet defects are compatible with successful pregnancy in mice. Moreover, pregnant women with severe platelet defects usually accomplish an uneventful pregnancy. Thus, promotion of endovascular trophoblast infiltration by maternal platelets might not be the only mechanism that regulates maternal vascular remodeling. The maternal vascular remodeling is an essential component of human reproduction and should be secured by several complementary mechanisms. Future studies should aim to elucidate other mechanisms that could regulate endovascular trophoblast infiltration. PMID- 20857261 TI - Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7alpha-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis. AB - To examine the mRNA expression of hepatobiliary transporters in primary biliary cirrhosis (PBC) patients and to compare bile acid absorption, synthesis, and efflux in patients with non-end-stage and end-stage PBC, we obtained liver samples from PBC patients by percutaneous needle biopsy. End-stage PBC was defined as follows: histological stage IV; cirrhosis; serum total bilirubin, >=4.0 mg/dl; and Child-Pugh Class C. The mRNA expression levels of sodium taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), and hepatic cholesterol 7alpha-hydroxylase (CYP7A1) were significantly higher in the PBC patients than in the controls (P < 0.01). The mRNA levels of NTCP and BSEP were significantly higher in the end-stage PBC patients than in the controls (P < 0.01). However, hepatic CYP7A1 mRNA expression decreased significantly (by 70%) in the patients with end-stage PBC as compared to the controls and the patients with non-end-stage PBC (P < 0.01). The hepatic expression of transporters mediating bile acid influx and efflux showed sustained elevation, whereas that of the rate-limiting enzyme for bile acid biosynthesis was attenuated in the end stage PBC patients. Thus, mechanisms may be present preventing the accumulation of toxic bile acids in the hepatocytes of end-stage PBC patients. PMID- 20857262 TI - Basic study of retinal stem/progenitor cell separation from mouse iris tissue. AB - We described the possibility of retinal regeneration using a novel and efficient technique for culturing and separating retinal stem/progenitor cells from iris tissue. Immunohistochemical staining of adult agouti mouse iris tissue revealed the presence of nestin/low-affinity neurotrophin receptor p75 (p75(NTR))-positive cells on the endothelium camerae anterioris side. Cultured mouse iris-derived cells contained little or no melanin and were found to be positive for nestin. Most nestin-positive cells were analyzed for the coexpression of p75(NTR) as a cell membrane protein. When the p75(NTR) was used as a marker to sort the cells, we obtained a dense population of nestin-positive cells. Furthermore, the nestin/p75(NTR)-positive cells were able to differentiate into neural retina cells. Thus, this culture and separation technique is useful for obtaining retinal stem/progenitor cells from adult mouse iris tissue and for the efficient production of neural retina cells. PMID- 20857263 TI - Novel cis-active structures in the coding region mediate CRM1-dependent nuclear export of IFN-alpha 1 mRNA. AB - We recently reported the chromosome region maintenance 1 (CRM1)-dependent nuclear export of intron-less human interferon-alpha1 (IFN-alpha1) mRNA, which encodes a main effecter of host innate immunity. We show that the coding region of IFN alpha1 mRNA forms novel secondary structures that are responsible for the CRM1 dependent export of the transcript. Deletion-mutagenesis, in vivo export assays, and computer analyses of the folding potentials of export-competent fragments revealed the presence of a domain, termed the conserved secondary structure (CSS), comprising two adjacent putative stable stem-loop structures (nt 208-452). Internal deletion-mutagenesis and constitutive export assays of each stem-loop structure demonstrated that subregions 308-322 and 352-434 act as a core element by conferring the export function on the CSS. Leptomycin B (LMB) inhibition of the CRM1 pathway decreased the export of core element RNA, implying that the principal site of CRM1 action for exporting IFN-alpha1 mRNA resides within the core element. An RNPS1 (RNA-binding protein S1, serine-rich domain) cDNA was isolated by yeast three-hybrid screening, using bait containing two CSS regions. We showed that RNPS1 might recognize IFN-alpha1 mRNP that includes CRM1. The data demonstrate that interaction between RNA structures in the coding region and CRM1 affects the nucleocytoplasmic translocation of IFN-alpha1 mRNA. PMID- 20857264 TI - Detection of characteristic distributions of phospholipid head groups and fatty acids on neurite surface by time-of-flight secondary ion mass spectrometry. AB - Neurons have a large surface because of their long and thin neurites. This surface is composed of a lipid bilayer. Lipids have not been actively investigated so far because of some technical difficulties, although evidence from cell biology is emerging that lipids contain valuable information about their roles in the central nervous system. Recent progress in techniques, e.g., mass spectrometry, opens a new epoch of lipid research. We show herein the characteristic localization of phospholipid components in neurites by means of time-of-flight secondary ion mass spectrometry. We used explant cultures of mouse superior cervical ganglia, which are widely used by neurite investigation research. In a positive-ion detection mode, phospholipid head group molecules were predominantly detected. The ions of m/z 206.1 [phosphocholine, a common component of phosphatidylcholine (PC) and sphingomyelin (SM)] were evenly distributed throughout the neurites, whereas the ions of m/z 224.1, 246.1 (glycerophosphocholine, a part of PC, but not SM) showed relatively strong intensity on neurites adjacent to soma. In a negative-ion detection mode, fatty acids such as oleic and palmitic acids were mainly detected, showing high intensity on neurites adjacent to soma. Our results suggest that lipid components on the neuritic surface show characteristic distributions depending on neurite region. PMID- 20857265 TI - Immunohistochemical application of D2-40 as basal cell marker in evaluating atypical small acinar proliferation of initial routine prostatic needle biopsy materials. AB - D2-40 has been recently discovered as a lymphatic endothelial cell marker, and some investigators have found that D2-40 is also expressed in myoepithelial cells of salivary gland or breast. In this study, we evaluated D2-40 expression of basal cells and applied D2-40 immunohistochemistry in the combination of P504S, cytokeratin 5, and p63 for ten lesions with atypical small acinar proliferation (ASAP) in initial prostatic needle biopsy. As a result, D2-40 was expressed in basal cells, lymphatic endothelial cells, and some stromal fibroblasts of normal prostatic tissue. Among ten ASAP lesions, the final diagnosis of seven lesions was resolved by combination immunohistochemistry. D2-40 was comparable to cytokeratin 5 and p63 as a basal cell marker, and there were no lesions that failed to provide an accurate final diagnosis using only D2-40 immunohistochemistry without cytokeratin 5 or p63. However, we found some D2-40 positive stromal fibroblasts or D2-40-positive lumen-collapsed lymphatic vessels neighboring atypical glands. Pathologists should pay attention to avoid recognizing these cells as basal cells. In conclusion, the combination of immunohistochemistry of P504S, cytokeratin 5, p63, and D2-40 may contribute to the accurate diagnosis of ASAP in the initial prostatic needle biopsy. PMID- 20857266 TI - Lymphoepithelioma-like carcinoma of the stomach associated with adenosquamous carcinoma. AB - Lymphoepithelioma-like carcinoma and adenosquamous carcinoma of the stomach are relatively rare tumors. To date, there are no reports on lymphoepithelioma-like carcinoma of the stomach associated with adenosquamous carcinoma. We report herein the first case of such a tumor. A 67-year-old Japanese man presented with dull epigastralgia. The gastric endoscopy revealed an ulcerative cancerous lesion of the upper portion. Histological examination of the gastric tumor showed the coexistence of lymphoepithelioma-like carcinoma and adenosquamous carcinoma. The former showed a positive reaction for Epstein-Barr virus-encoded RNA (EBER). Neoplastic cells of the latter were immunoreactive for p63 and keratin 903, and Alcian blue stain detected acid mucin in glandular lumens. This pattern resembled mucoepidermoid carcinoma in the salivary gland. Finally, this is the first case of gastric lymphoepithelioma-like carcinoma associated with adenosquamous carcinoma, and clinicians and pathologists should recognize the presence of such a tumor. PMID- 20857267 TI - A duodenal follicular lymphoma associated with the lesion mimicking MALT lymphoma in terminal ileum and Bauhin valve. AB - This is a case report of a 66-year-old woman who consulted us with a 1-week history of postprandial epigastric discomfort and dyspepsia. Upper and lower gastrointestinal endoscopy and double-balloon enteroscopy revealed lesions in three parts: a swelling with a shallow depression in the ampulla of Vater, flat and rough nodules in the jejunum, and a mixture of lymphoid polyposis and rough surface of follicular lymphoma of the terminal ileum and Bauhin valve. The histological, immunophenotypic, and molecular findings of the duodenal lesion confirmed the diagnosis of follicular lymphoma. We initially diagnosed the ileal lesion as MALT lymphoma immunohistochemically. However, Southern blot hybridization analysis for immunoglobulin heavy chain gene rearrangement showed identical monoclonal bands in both the duodenal and ileal lesions. The molecular cytogenetic studies were also positive for the 14;18 translocation in both lesions. Therefore, the true diagnosis of this ileal lesion should be a follicular lymphoma with marginal zone differentiation. Primary follicular lymphomas of gastrointestinal tract were suggested to have intermediate features between nodal follicular lymphoma and MALT lymphoma. This case is an important clue to prove the similarity of follicular lymphoma of gastrointestinal tract to MALT lymphoma and will be crucial in considering the therapeutic strategy. PMID- 20857268 TI - Low-grade salivary duct carcinoma of the parotid gland: report of a case with immunohistochemical analysis. AB - Salivary duct carcinoma (SDC) is a highly aggressive malignancy of the salivary glands. However, one type of SDC, which shows minimal invasion and better prognosis, is known as low-grade SDC (LG-SDC). This report presents an additional case of LG-SDC of the parotid gland. The patient was a 38-year-old Japanese woman who noticed painless swelling of the left parotid region. Grossly, the cut surface of the tumor was cystic. Microscopically, the tumor showed a multicystic pattern, which was lined by eosinophilic to clear atypical cells with cribriform or Roman bridge patterns. An immunohistochemical examination revealed the tumor was positive for cytokeratin (CK) 7 and epithelial membrane antigen, partially positive for androgen receptor and gross cystic disease fluid protein-15, and diffusely positive for Her-2/Neu, progesterone, and estrogen receptors. The cancer cells showed focal immunopositivity for S-100 protein. Immunostaining for p63, CK14, and calponin showed an in situ pattern in most areas of this tumor, whereas the tumor showed minimal invasion. The cancer cells were diffusely positive for MUC1 and MUC6 and focally positive for MUC2 and MUC4. Finally, the tumor was diagnosed to be LG-SDC. The differential diagnosis and the mucin pattern were evaluated. PMID- 20857269 TI - A successfully treated inflammatory myofibroblastic tumor of the mandible with long-term follow-up and review of the literature. AB - Inflammatory myofibroblastic tumor (IMT) of the oral cavity is an extremely rare clinical and pathological disease entity. It was originally described in the lung but has recently been reported in various anatomic sites. We report such a case of inflammatory myofibroblastic tumor of the mandible in a 14-year-old girl. The patient presented with an aggressive ulcerative soft tissue mass of 3 months duration in the mandibular molar gingiva. Histologically, the lesion was composed of fibroblastic or myofibroblastic spindle cell proliferations with infiltrative margins in an inflammatory background. Immunohistochemically, the fibroblastic or myofibroblastic spindle cells were positive for vimentin, alpha-smooth muscle actin, and Ki-67 (MIB-1) but negative for desmin, pan-cytokeratin, S-100 protein, CD34, CD68, CD99, bcl-2, beta-catenin, estrogen receptor, progesterone receptor, ALK-1, and p53. These spindle cells were focally and weakly Ki-67- (MIB-1-) positive. The MIB-1 labeling index was 5%. The results of in situ hybridization for Epstein-Barr virus-encoded-RNA were negative. The ratio of IgG4+/IgG+ plasma cells was about 10%. A pathological diagnosis of inflammatory myofibroblastic tumor was made. The postoperative course was uneventful, and the patient has had no recurrence in the 10-year follow-up period. Although no evidence of oral inflammatory myofibroblastic tumor recurrence or malignant transformation has been reported, it has been observed that in inflammatory myofibroblastic tumors of other regions, a prolonged follow-up is necessary after surgical resection. No other case of an IMT patient under 20 years of age has appeared in either the English or the Japanese literature. PMID- 20857270 TI - Specialized chromatin patterns in the control of inflammatory gene expression. AB - Inflammatory responses to microbial and non-microbial stimuli involve coordinate changes in the expression of hundreds of genes. The inflammatory gene expression programs display two important features: first, alternative stimuli affect both a large set of common genes and a variable number of stimulus-specific genes. Second, different genes are activated with different kinetics over several hours after the initial stimulus. Mechanistically, these features reflect the interplay between two main groups of determinants: the combinatorial control of transcription by multiple transcription factors, with NF-kappaB and the IRFs playing a central and essential role in the induction of a large fraction of inflammatory genes; and the presence of well-defined, in part cell-type specific, patterns of chromatin organization at cis-regulatory regions of inflammatory genes. Recent advancements in this field are providing paradigms of general value explaining how inducible responses to environmental stimuli are controlled. PMID- 20857271 TI - NF-kappaB in liver cancer: the plot thickens. AB - The role of the NF-kappaB signaling pathway in liver cancer is complex. While some evidence suggests that in the liver, like in many other organ systems, NF kappaB is oncogenic, there is strong evidence showing that in certain liver cancer models NF-kappaB suppresses tumorigenesis. These contrasting findings cannot be dismissed on technicalities and are likely due to the complex nature of the NF-kappaB response. Similar contrasting findings regarding NF-kappaB activity are revealed in skin cancer models. Thus, it is possible that the contradictory role of NF-kappaB in tumorigenesis is a general phenomenon and not an oddity related solely to the liver. Further studies are indicated to decipher the underlying molecular mechanisms. Revealing these mechanisms may facilitate the identification of patient subgroups and specific situations in which NF-kappaB inhibition will be a preferred therapeutic option. Moreover, it is possible that specific interventions could boost the tumor suppressor functions of NF-kappaB in tumors that harbor mutations that render this pathway constitutively active. PMID- 20857272 TI - [Emotional status, cognitive performance and quality of life in HIV-infected patients. Results of an exploratory study]. AB - BACKGROUND: Due to the change of HIV disease from an acute life-threatening disease to a chronic infection, it is more psychosocial rather than therapeutic aspects that have become of interest in scientific investigations. The purpose of this exploratory study was to evaluate emotional distress, health-related quality of life (HRQoL) and cognitive performance. The diagnosis of HIV was considered a life event that may lead to post-traumatic stress syndrome. METHOD: We recruited 37 HIV-positive outpatients and assessed the frequency of depressive (BDI) and post-traumatic stress symptoms (PTSS) due to the diagnosis of HIV (IES), HRQoL (SF-36) and cognitive performance (SKT). Further, the new diagnostic concept of adjustment disorder as a stress response syndrome according to Maercker was considered. RESULTS: Of the 37 Patients, 67.6% (n=25) of the sample had a post traumatic stress syndrome. The HIV-related PTSS was considered adjustment disorder using the concept proposed by Maercker. Fourteen patients (37.8%) suffered from a depressive syndrome, and 27% (n=10) showed cognitive deficits (minimal: n=8; mild: n=1; moderate: n =1). HIV-positive patients with PTSS had significantly unfavourable values in the SF-36 domains general health (p=0.003), vitality (p=0.007), social functioning (p=0.000), role-emotional (p=0.016) and mental health (p=0.000). CONCLUSION: HIV-infected patients may face a major risk of HIV-related PTSS in the sense of adjustment disorder according to Maercker, depression and cognitive dysfunction. The presence of emotional distress is associated with impairments in quality of life. We therefore suggest an early and comprehensive bio-psycho-social assessment and therapy of HIV-infected patients. PMID- 20857273 TI - [Psychotherapy of Asperger syndrome in adults]. AB - There is an increase in awareness in professionals that the Asperger syndrome (AS) in adulthood is associated with specific problems and burdens which may well differ from those in childhood and adolescence. The core symptoms of AS generally persist into adulthood, however in contrast to childhood and adolescence there is no specific support system for adults in Germany. Also the environment of the afflicted patient changes thus producing different challenges and problems. In addition a subgroup of patients with high functioning AS primarily presents in adulthood generally due to secondary psychosocial problems, depression or anxiety. Difficulties in social interaction, problems with modified daily routines and unforeseen situations cause severe frustration for the majority of the patients. While several therapy programs have been developed and implemented for children and adolescents, for adults there are none. Also there is a lack of comprehensive concepts addressing the specific needs of adult patients with AS. From an economic perspective this is particularly unfortunate since affected people often have good or excellent partial abilities and might be very valuable employees. In this article existing therapeutic concepts for AS are summarized and a newly designed group therapy program for adult patients with Asperger syndrome in Freiburg is introduced (Freiburg Asperger-spezifische Therapie fur Erwachsene, FASTER) which specifically addresses the needs and problems of adult patients with AS. PMID- 20857274 TI - [Long-term course of patients in neurological rehabilitation Phase B. Results of the 6-year follow-up in a multicenter study]. AB - BACKGROUND: After conclusion of emergency care for severe neurological diseases patients in Germany are admitted at an early stage to so-called Phase B rehabilitation. No studies have been carried out on the long-term course of these patients. PATIENTS AND METHODS: In a prospective study in 2002 patients in Phase B from 9 centers were included and follow-up investigations were carried out after 5 and 6 years. Assessment instruments used were the Barthel index, the Rankin scale and the EQ-5D. Factors for the risk of a poor outcome and the chances for a good outcome were evaluated using multivariate logistic regression. RESULTS: A total of 1,280 patients were included in the study. A high age increased the risk of dying with a hazard quotient (HQ) of 1.05 (95% CI: 1.04 1.06) and high point counts in the coma remission scale (HQ 0.93; 95% CI: 0.92 0.96) and Barthel index (HQ 0.97; 95% CI: 0.97-0.98) on discharge reduced the risk of dying after 5 years. The factors swallowing impairment (OR 3.1; 95% CI: 1.7-5.5) and obligatory surveillance at the end of rehabilitation (OR 3.2; 95% CI: 1.2-8.6) increased the risk of a poor result in the Rankin scale 2-4 and the factors communication disorder (OR 5.0; 95% CI: 2.0-12.8) and PEG (percutaneous endoscopic gastrostomy) (OR 19.7; 95% CI: 2.7-144.4) on discharge increased the risk of a reduced health-related quality of life (defined as EQ-5D VAS <70) after 6 years. CONCLUSIONS: If support for bodily functions can be successfully reduced during Phase B rehabilitation, the patients will have a good outcome with respect to 5-year survival. If this is not successful the outcome is unfavorable with respect to survival and with respect to achieving self-sufficiency and health related quality of life after 6 years. PMID- 20857277 TI - [Neuroimaging in Parkinson's disease]. PMID- 20857275 TI - [Autism in adults with intellectual disabilities]. AB - According to the World Health Organization (WHO) the estimated prevalence of intellectual disabilities (ID) is about 1-3% and 1 out of 4 individuals with ID suffer from an additional autistic spectrum disorder (ASD) (arithmetic mean 24.6%, 19 studies, n=9,675) whereby the prevalence increases with the severity of ID (IQ 50-70: 9.9%, IQ<50: 31.7%). Therefore, it is of particular importance for physicians treating individuals with ID who have psychiatric disorders or behavioral problems to take ASD into account as a differential diagnosis so that appropriate treatment can be initiated.Irrespective of the IQ the diagnosis is based on an impairment of social interaction and communication and restricted repetitive interests presenting before the age of 3 (infantile or Kanner autism). ASD can be diagnosed as a separate disorder in adults with ID, however, the social and communicative abilities in respect of the cognitive and developmental level have to be considered.Due to reduced verbal capacity, high prevalence of physical and mental disorders, difficulties in taking the past medical history and presentation of atypical symptoms, the diagnostic assessment for autism in adults with ID is challenging.This article describes the typical symptoms, diagnostic approach, frequent comorbidities, differential diagnoses treatment options and their limitations for adults with ID suspected of having ASD. PMID- 20857276 TI - [Differential diagnosis of parkinsonian syndromes using MRI]. AB - The differential diagnosis of parkinsonian syndromes is considered one of the most challenging in clinical neurology. Despite published consensus operational criteria for the diagnosis of Parkinson's disease (PD) and the various atypical parkinsonian disorders (APD), such as progressive supranuclear palsy (PSP), multiple system atrophy (MSA) and corticobasal degeneration (CBD), the clinical separation of APDs from PD carries a high rate of misdiagnosis. However, the early differentiation between APD and PD, each characterized by a very different natural history, is crucial for determining the prognosis and choosing a treatment strategy. Despite limitations the various modern magnetic resonance imaging (MRI) techniques have undoubtedly added to the differential diagnosis of neurodegenerative parkinsonism. In clinical practice conventional MRI with visual assessment of T2 and T1-weighted imaging is a well established method for the exclusion of symptomatic parkinsonism due to other pathologies and may also point to the diagnosis of APD. Furthermore, advances in MRI techniques, such as diffusion-weighted imaging (DWI), have enabled abnormalities in the basal ganglia and infratentorial brain structures in APD to be quantitatively illustrated. PMID- 20857278 TI - Noninvasive high frequency oscillatory ventilation through nasal prongs: bench evaluation of efficacy and mechanics. AB - BACKGROUND: Noninvasive high frequency oscillatory ventilation through nasal prongs (nHFOV) has been proposed as a new respiratory support in neonatology. We studied the effect of ventilation parameters and nasal prongs on nHFOV efficacy and mechanics. METHODS: Customized sealed circuits connecting a SM3100A oscillator to a neonatal lung model were developed to evaluate the effect of applying HFOV via two different sized nasal prongs on delivered tidal volume and pressure. Measurements were made across a range of frequencies and pressures; amplitude was set to obtain visible lung oscillation. RESULTS: Volume delivered by peak-to-peak oscillation, ventilation, and pressure significantly differed among the interfaces, being higher for large cannulae and the control circuit (p < 0.0001). The interposition of a large or small nasal prong reduced volume to 56 and 26%, ventilation to 32 and 9%, and mean pressure to 83 and 79%, respectively, of the values measured for the direct connection of the oscillator to the test lung. Volume and ventilation were inversely related to frequency, which was particularly evident with larger diameter circuits due to higher delivered tidal volume (R (2) > 0.9). Increasing ventilation was associated with larger tidal volume and nasal prong diameter (adjusted R (2) = 0.97). CONCLUSIONS: nHFOV using common nasal prongs is technically possible. Efficiency of tidal volume delivery is significantly affected by prong diameter. PMID- 20857279 TI - Regional distribution of blood volume within the preterm infant thorax during synchronised mechanical ventilation. AB - PURPOSE: Perfusion in healthy adults is gravity-dependent. Little is known about lung perfusion in the preterm infant. The aim of this study was to describe the regional distribution of blood volume within the thorax in preterm infants receiving synchronised volume-targeted mechanical ventilation (SIPPV + TTV) and to compare this to regional distribution of tidal ventilation using electrical impedance tomography (EIT). METHODS: Stable supine ventilated preterm infants (<32-week gestation) were studied. Three sets of artefact-free 30-s EIT recordings of the right hemithorax were filtered in the cardiac and respiratory frequency domains to differentiate impedance change due to blood (DeltaZ (c)) and gas volume (DeltaZ (v)). The distribution of DeltaZ (c) and DeltaZ (v) in the anterior-to-posterior regions of the right chest were compared. Infants were subdivided by age (<= 7, >7 days) and oxygen requirement. RESULTS: A total of 5,471 beats were analysed from 26 infants (78 recordings); mean (standard deviation (SD)) gestational age was 26 (2) weeks and mean (SD) postnatal age was 9 (10) days. The median (interquartile range) DeltaZ (c) in the anterior half of the hemithorax was 1.41-fold (0.88-2.11) greater than that in the posterior half. The geometric centre of DeltaZ (c) was located at 46.7% of the anterior-posterior thoracic distance, compared to a more centrally located DeltaZ (v) (49.6%; p < 0.0001). The DeltaZ (v)/DeltaZ (c) ratio was 1.7 in the anterior third of the chest and 2.2 in the posterior (p < 0.0001). The area under the curve (AUC) analysis showed that DeltaZ (c) was more evenly distributed in infants >7 days of age and not influenced by oxygen requirement. CONCLUSIONS: There are gravity dependent differences in the distribution of blood volume and ventilation in the ventilated preterm chest. PMID- 20857280 TI - Peripherally inserted central venous catheters and central venous catheters related thrombosis in post-critical patients. AB - BACKGROUND: Peripherally inserted central venous catheters (PICC) have been proposed as an alternative to central venous catheters (CVC). The aim of this study was to determine the thrombosis rate in relation to PICC placement in patients discharged from the intensive care unit (ICU). METHODS: Data of patients admitted to the ICU (Careggi Teaching Hospital, Florence, Italy; January-August 2008) and discharged with a central venous device were sequentially studied. During the first 4 months, CVCs were used (CVC group), whereas during the last 4 months, PICCs were used (PICC group). Demographic/clinical and catheter-related data were collected. Intensivists performed Doppler examination at ICU discharge and 7, 15, and 30 days after placement. RESULTS: Data of 239 patients were analyzed (125 of CVC group, 114 of PICC group). A total of 2,747 CVC-days and 4,024 PICC-days of observation were included. Patient characteristics were comparable between groups. Patients with PICC had a significantly higher incidence rate of deep venous thrombosis (DVT) than patients with CVC (27.2 vs. 9.6%, P = 0.0012). The rate of DVT/1,000 catheter days was 4.4 for CVCs and 7.7 for PICCs. Eighty percent of DVTs occurred within 2 weeks after insertion. Binary logistic analysis showed a two-fold increased risk for women and a three-fold increased risk when using the left basilic vein in the PICC group. CONCLUSIONS: In our post-critically ill population, PICCs were associated with a higher rate of DVT complications than CVCs. Routine ultrasound surveillance for the first 2 weeks after patient discharge from the ICU with a PICC and preferential use of CVC for these patients may be warranted. PMID- 20857282 TI - Focus on bioanalysis. PMID- 20857283 TI - Robust classification of low-grade cervical cytology following analysis with ATR FTIR spectroscopy and subsequent application of self-learning classifier eClass. AB - Although the UK cervical screening programme has reduced mortality associated with invasive disease, advancement from a high-throughput predictive methodology that is cost-effective and robust could greatly support the current system. We combined analysis by attenuated total reflection Fourier-transform infrared spectroscopy of cervical cytology with self-learning classifier eClass. This predictive algorithm can cope with vast amounts of multidimensional data with variable characteristics. Using a characterised dataset [set A: consisting of UK cervical specimens designated as normal (n = 60), low-grade (n = 60) or high grade (n = 60)] and one further dataset (set B) consisting of n = 30 low-grade samples, we set out to determine whether this approach could be robustly predictive. Variously extending the training set consisting of set A with set B data produced good classification rates with three two-class cascade classifiers. However, a single three-class classifier was equally efficient, producing a user friendly, applicable methodology with improved interpretability (i.e., better classification with only one set of fuzzy rules). As data from set B were added incrementally to the training set, the model learned and evolved. Additionally, monitoring of results of the set B low-grade specimens (known to be low-grade cervical cytology specimens) provided the opportunity to explore the possibility of distinguishing patients likely to progress towards invasive disease. eClass exhibited a remarkably robust predictive power in a user-friendly fashion (i.e., high throughput, ease of use) compared to other classifiers (k-nearest neighbours, support vector machines, artificial neural networks). Development of eClass to classify such datasets for applications such as screening exhibits robustness in identifying a dichotomous marker of invasive disease progression. PMID- 20857281 TI - Smaller, weaker, and less stiff bones evolve from changes in subsistence strategy. AB - We propose a computational model with which to examine the evolution of bone. Our results indicate that changes in subsistence strategy have influenced the evolution of bone growth and mechanoregulation, and predict that bone size, stiffness, and structural strength may decrease in future generations, bringing increased risk of fracture and prevalence of osteoporosis. INTRODUCTION: Archeological data suggest that bone size and strength have decreased over evolution. We hypothesize that changing evolutionary pressures and levels of physical activity, both arising from changes in subsistence strategy, have affected the evolution of bone. We propose a computational model with which to examine the evolution of bone growth and mechanoregulation due to the transitions from hunter-gatherer to agricultural to modern lifestyles. METHODS: The evolution of genes governing growth and mechanoregulation in a population of bones is simulated, where each individual is represented by a 2-D bone cross-section. Genetic variability is assumed to modulate growth through mechanoregulatory factors that direct periosteal expansion, endosteal expansion/infilling, and ash content accretion in response to strains incurred during walking. RESULTS: The model predicts decreases in cortical area and section modulus (a measure of structural strength) and increases in maximum compressive strain over the course of the simulation, meaning evolution of smaller, less strong, and less stiff bones is predicted for the population average. The model predicts small but continued decreases in size, strength, and stiffness in modern populations, despite the absence of a strong evolutionary advantage to efficient bones during this phase. CONCLUSION: In conclusion, our results show that changing loading regimes and evolutionary pressures may have influenced the evolution of bone growth and mechanoregulation, and predict that bone size and strength may continue to decrease in future generations, bringing increased risk of fracture and prevalence of osteoporosis. PMID- 20857284 TI - Measurements of diagnostic examination performance and correlation analysis using microvascular leakage, cerebral blood volume, and blood flow derived from 3T dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging in glial tumor grading. AB - INTRODUCTION: To assess the diagnostic accuracy of microvascular leakage (MVL), cerebral blood volume (CBV) and blood flow (CBF) values derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging (DSC-MR imaging) for grading of cerebral glial tumors, and to estimate the correlation between vascular permeability/perfusion parameters and tumor grades. METHODS: A prospective study of 79 patients with cerebral glial tumors underwent DSC-MR imaging. Normalized relative CBV (rCBV) and relative CBF (rCBF) from tumoral (rCBVt and rCBFt), peri-enhancing region (rCBVe and rCBFe), and the value in the tumor divided by the value in the peri-enhancing region (rCBVt/e and rCBFt/e), as well as MVL, expressed as the leakage coefficient K(2) were calculated. Hemodynamic variables and tumor grades were analyzed statistically and with Pearson correlations. Receiver operating characteristic (ROC) curve analyses were also performed for each of the variables. RESULTS: The differences in rCBVt and the maximum MVL (MVL(max)) values were statistically significant among all tumor grades. Correlation analysis using Pearson was as follows: rCBVt and tumor grade, r = 0.774; rCBFt and tumor grade, r = 0.417; MVL(max) and tumor grade, r = 0.559; MVL(max) and rCBVt, r = 0.440; MVL(max) and rCBFt, r = 0.192; and rCBVt and rCBFt, r = 0.605. According to ROC analyses for distinguishing tumor grade, rCBVt showed the largest areas under ROC curve (AUC), except for grade III from IV. CONCLUSION: Both rCBVt and MVL(max) showed good discriminative power in distinguishing all tumor grades. rCBVt correlated strongly with tumor grade; the correlation between MVL(max) and tumor grade was moderate. PMID- 20857285 TI - Glioma grade assessment by using histogram analysis of diffusion tensor imaging derived maps. AB - INTRODUCTION: Current endeavors in neuro-oncology include morphological validation of imaging methods by histology, including molecular and immunohistochemical techniques. Diffusion tensor imaging (DTI) is an up-to-date methodology of intracranial diagnostics that has gained importance in studies of neoplasia. Our aim was to assess the feasibility of discriminant analysis applied to histograms of preoperative diffusion tensor imaging-derived images for the prediction of glioma grade validated by histomorphology. METHODS: Tumors of 40 consecutive patients included 13 grade II astrocytomas, seven oligoastrocytomas, six grade II oligodendrogliomas, three grade III oligoastrocytomas, and 11 glioblastoma multiformes. Preoperative DTI data comprised: unweighted (B (0)) images, fractional anisotropy, longitudinal and radial diffusivity maps, directionally averaged diffusion-weighted imaging, and trace images. Sampling consisted of generating histograms for gross tumor volumes; 25 histogram bins per scalar map were calculated. The histogram bins that allowed the most precise determination of low-grade (LG) or high-grade (HG) classification were selected by multivariate discriminant analysis. Accuracy of the model was defined by the success rate of the leave-one-out cross-validation. RESULTS: Statistical descriptors of voxel value distribution did not differ between LG and HG tumors and did not allow classification. The histogram model had 88.5% specificity and 85.7% sensitivity in the separation of LG and HG gliomas; specificity was improved when cases with oligodendroglial components were omitted. CONCLUSION: Constructing histograms of preoperative radiological images over the tumor volume allows representation of the grade and enables discrimination of LG and HG gliomas which has been confirmed by histopathology. PMID- 20857286 TI - Coenzyme Q(10) production directly from precursors by free and gel-entrapped Sphingomonas sp. ZUTE03 in a water-organic solvent, two-phase conversion system. AB - In a water-organic solvent, two-phase conversion system, CoQ(10) could be produced directly from solanesol and para-hydroxybenzoic acid (PHB) by free cells of Sphingomonas sp. ZUTE03 and CoQ(10) concentration in the organic solvent phase was significantly higher than that in the cell. CoQ(10) yield reached a maximal value of 60.8 mg l(-1) in the organic phase and 40.6 mg g(-1)-DCW after 8 h. CoQ(10) also could be produced by gel-entrapped cells in the two-phase conversion system. Soybean oil and hexane were found to be key substances for CoQ(10) production by gel-entrapped cells of Sphingomonas sp. ZUTE03. Soybean oil might improve the release of CoQ10 from the gel-entrapped cells while hexane was the suitable solvent to extract CoQ(10) from the mixed phase of aqueous and organic. The gel-entrapped cells could be re-used to produce CoQ(10) by a repeated-batch culture. After 15 repeats, the yield of CoQ(10) kept at a high level of more than 40 mg l(-1). After 8 h conversion under optimized precursor's concentration, CoQ(10) yield of gel-trapped cells reached 52.2 mg l(-1) with a molar conversion rate of 91% and 89.6% (on PHB and solanesol, respectively). This is the first report on enhanced production of CoQ(10) in a two-phase conversion system by gel entrapped cells of Sphingomonas sp. ZUTE03. PMID- 20857287 TI - Nitroreductase activity of ferredoxin reductase BphA4 from Dyella ginsengisoli LA 4 by catalytic and structural properties analysis. AB - Ferredoxin reductase BphA4 was well known as a component of biphenyl dioxygenase. However, there was little information about whether it could utilize nonphysiological oxidants as electron acceptors. In the present study, we reported the novel nitroreductase activity of BphA4(LA)-4. The homology model of ferredoxin reductase BphA4 from Dyella ginsengisoli LA-4 was constructed. According to the alignment of three-dimensional structures, it was supposed that BphA4(LA)-4 could function as nitroreductase. Recombinant His-tagged BphA4(LA)-4 was purified with a molecular mass of 49.6 +/- 1 kDa. Biochemical characterization of purified BphA4(LA)-4 possessed the nitroreductase activity with the optimal temperature 50 degrees C and pH 8.0. The substrate spectrum and kinetics indicated BphA4(LA)-4 could reduce several nitroaromatics with different apparent K(m) values: m-dinitrobenzene (560 MUM), o-dinitrobenzene (1,060 MUM), o nitroaniline (1,570 MUM), m-nitrobenzoic acid (1,300 MUM) and m-nitrophenol (67 MUM). The nitroreductase activity was further explained by docking studies, which was indicated that Arg 288 should play an important role in binding nitroaromatics. Moreover, there existed a good linear correlation between lnK(m) and calculated binding energy. PMID- 20857288 TI - Improvement of L-lactic acid production by osmotic-tolerant mutant of Lactobacillus casei at high temperature. AB - L-Lactic acid production by Lactobacillus casei was used as a model to study the mechanism of substrate inhibition and the strategy for enhancing L-lactic acid production. It was found that the concentration of cell growth and L-lactate decreased with the increase of glucose concentration and fermentation temperature. To enhance the osmotic stress resistance of the strain at high temperature, a mutant G-03 was screened and selected with 360 g/L glucose at 45 degrees C as the selective criterion. To further increase the cell growth for lactic acid production, 3 g/L of biotin was supplemented to the medium. As a result, L: -lactate concentration by the mutant G-03 reached 198.2 g/L (productivity of 5.5 g L(-1) h(-1)) at 41 degrees C in a 7-L fermentor with 210 g/L glucose as carbon source. L: -Lactate concentration and productivity of mutant G-03 were 115.2% and 97.8% higher than those of the parent strain, respectively. The strategy for enhancing L: -lactic acid production by increasing osmotic stress resistance at high temperature may provide an alternative approach to enhance organic acid production with other strains. PMID- 20857289 TI - Recombinant antimicrobial peptide hPAB-beta expressed in Pichia pastoris, a potential agent active against methicillin-resistant Staphylococcus aureus. AB - As a potential therapeutic agent, antimicrobial peptide has received increased attention in recent years. However, high-level expression of a small peptide with antimicrobial activity is still a challenging task. In this study, the coding sequence of antimicrobial peptide hPAB-beta, a variant derived from human beta defensin 2, was cloned into pPIC9K vector and transformed into Pichia pastoris. P. pastoris transformants harbored with multi-copy plasmids were screened by G418 selection. When the transformed cells were induced by methanol, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, Western blot, and matrix-assisted laser desorption ionization-time of flight mass spectrometry revealed recombinant hPAB-beta products consisting of three protein species of 4,680.4, 4,485.3, and 4,881.9 Da at proportions of 58%, 36%, and 6%, respectively, which may be due to the incomplete processing of the fusion signal peptide of alpha-factor by the STE13 protease. Expressed hPAB-beta was secreted into the culture medium at a level of 241.2 +/- 29.5 mg/L. Purified hPAB-beta with 95% homogeneity was obtained by 10 kDa membrane filtration followed by cation ion-exchange chromatography with a SP-Sepharose XL column. The two major protein species separated through a SOURCE 30RPC reverse phase chromatography column showed definite antimicrobial activities against Staphylococcus aureus. All 22 methicillin-resistant S. aureus (MRSA) isolates with multidrug resistance phenotype were sensitive to the recombinant hPAB-beta with minimal inhibitory concentrations of 8-64 MUg/ml. Our results show that the methylotrophic yeast inducible system is suitable for high-level expression of active hPAB-beta, and that expressed hPAB-beta in P. pastoris may be a potential antimicrobial agent against MRSA infection. PMID- 20857290 TI - Enhanced production of 2-hydroxyphenazine in Pseudomonas chlororaphis GP72. AB - Pseudomonas chlororaphis GP72 is a root-colonizing biocontrol strain isolated from the green pepper rhizosphere that synthesizes two phenazine derivatives: phenazine-1-carboxylic acid (PCA) and 2-hydroxyphenazine (2-OH-PHZ). The 2-OH-PHZ derivative shows somewhat stronger broad-spectrum antifungal activity than PCA, but its conversion mechanism has not yet been clearly revealed. The aim of this study was to clone and analyze the phenazine biosynthesis gene cluster in this newly found strain and to improve the production of 2-OH-PHZ by gene disruption and precursor addition. The conserved phenazine biosynthesis core operon in GP72 was cloned by PCR, and the unknown sequences located upstream and downstream of the core operon were detected by random PCR gene walking. This led to a complete isolation of the phenazine biosynthesis gene cluster phzIRABCDEFG and phzO in GP72. Gene rpeA and phzO were insertionally mutated to construct GP72AN and GP72ON, respectively, and GP72ANON collectively. The inactivation of rpeA resulted in a fivefold increase in the production of PCA, as well as 2-OH-PHZ. The addition of exogenous precursor PCA to the broth culture, to determine the conversion efficiency of PCA to 2-OH-PHZ under current culture conditions, revealed that PCA had a positive feedback effect on its own accumulation, leading to enhanced synthesis of both PCA and 2-OH-PHZ. The production of 2-OH-PHZ by GP72AN increased to about 170 MUg ml(-1), compared with just 5 MUg ml(-1) for the wild type. The hypothesis of biosynthetic pathway for 2-OH-PHZ from PCA was confirmed by identification of 2-hydroxyphenazine-1-carboxylic acid as an intermediate in the culture medium of the high-phenazine producing GP72AN mutant. PMID- 20857291 TI - Nocardioides sp. strain WSN05-2, isolated from a wheat field, degrades deoxynivalenol, producing the novel intermediate 3-epi-deoxynivalenol. AB - The mycotoxin deoxynivalenol (DON) causes serious problems worldwide in the production of crops such as wheat and barley because of its toxicity toward humans and livestock. A bacterial culture capable of degrading DON was obtained from soil samples collected in wheat fields using an enrichment culture procedure. The isolated bacterium, designated strain WSN05-2, completely removed 1,000 MUg/mL of DON from the culture medium after incubation for 10 days. On the basis of phylogenetic studies, WSN05-2 was classified as a bacterium belonging to the genus Nocardioides. WSN05-2 showed significant growth in culture medium with DON as the sole carbon source. High-performance liquid chromatography analysis indicated the presence of a major initial metabolite of DON in the culture supernatant. The metabolite was identified as 3-epi-deoxynivalenol (3-epi-DON) by mass spectrometry and (1)H and (13)C nuclear magnetic resonance analysis. The amount of DON on wheat grain was reduced by about 90% at 7 days after inoculation with WSN05-2. This is the first report of a Nocardioides sp. strain able to degrade DON and of the yet unknown 3-epi-DON as an intermediate in the degradation of DON by a microorganism. PMID- 20857293 TI - Infundibular dilation: an anatomical variant or a pre-aneurysm? Advantages of assessment with three-dimensional rotational angiography. AB - PURPOSE: Whether an infundibular dilation (ID) is an anatomical variant or a pre aneurysm has not been clearly determined. The aim of the present study was to evaluate the anatomical change of IDs by use of three-dimensional rotational angiography (3DRA) with volume rendering (VR). METHODS: One-hundred thirty-eight patients with known or suspected aneurysms, treated consecutively, underwent both two-dimensional digital subtraction angiography (2DDSA) and 3DRA with VR. Two readers evaluated the IDs or aneurysms blindly, using 2DDSA and 3DRA, according to the same diagnostic criteria. A 5-point scale of observer confidence was used to determine the presence of IDs or aneurysms. For 3DRA with VR, the relationship between IDs and aneurysms was classified as one of the three types: type I, protrusion or bulge from side wall of IDs; type II, aneurysms involving or enclosing IDs; or type III, aneurysms and IDs coexisting near each other but with some distance between them. RESULTS: The number of IDs found by 2DDSA and 3DRA with VR was 41 and 48, respectively. Five anterior choroidal arteries and two posterior communicating arteries IDs were missed by 2DDSA. According to 3DRA with VR, there were five IDs of type I, nine of type II, and 22 of type III. CONCLUSIONS: The 3DRA with VR appears superior to 2DRA for both diagnosing IDs and displaying the anatomical relationship between IDs and aneurysms. The findings also suggest that some IDs might progress to aneurysms or become a part of them, which should be carefully evaluated prior to operation. PMID- 20857294 TI - MHC presentation via autophagy and how viruses escape from it. AB - T cells detect infected and transformed cells via antigen presentation by major histocompatibility complex (MHC) molecules on the cell surface. For T cell stimulation, these MHC molecules present fragments of proteins that are expressed or taken up by the cell. These fragments are generated by distinct proteolytic mechanisms for presentation on MHC class I molecules to cytotoxic CD8(+) and on MHC class II molecules to helper CD4(+) T cells. Proteasomes are primarily involved in MHC class I ligand and lysosomes, in MHC class II ligand generation. Autophagy delivers cytoplasmic material to lysosomes and, therefore, contributes to cytoplasmic antigen presentation by MHC class II molecules. In addition, it has been recently realized that this process also supports extracellular antigen processing for MHC class II presentation and cross-presentation on MHC class I molecules. Although the exact mechanisms for the regulation of these antigen processing pathways by autophagy are still unknown, recent studies, summarized in this review, suggest that they contribute to immune responses against infections and to maintain tolerance. Moreover, they are targeted by viruses for immune escape and could maybe be harnessed for immunotherapy. PMID- 20857295 TI - Upper and lower extremity nerve injuries in pediatric missile wounds: a selective approach to management. AB - PURPOSE: Nerve injuries from missile and gunshot wounds often produce significant disability, and their management is controversial. The role of the surgeon in cases of missile wounds with neurologic deficits is not well defined. Enhancing the trauma team's ability to recognize treatable nerve injuries will lead to improved outcomes. Further, raising awareness of the time-sensitive nature of these injuries will also improve results in these cases. METHODS: We reviewed a consecutive series of 17 pediatric patients with peripheral nerve injuries caused by missile and gunshot wounds in a tertiary care children's hospital. We examined the indications for surgery, presence of associated injuries, mechanisms of injury, demographic characteristics and clinical outcomes. RESULTS: Urban victims were significantly more likely to have been intentionally assaulted than rural or suburban victims and they were also less likely to have completed follow-up care. High-energy weapons were more likely to require surgery compared with low-energy weapons. Patients presenting with tendon injuries were more likely to have a high grade nerve injury requiring surgery. CONCLUSIONS: Patients presenting with tendon lacerations or high-energy mechanisms were significantly more likely to require surgery. Early exploration should be undertaken in cases where transection is likely to have occurred. Early decompression of common entrapment sites distal to repairs or injuries should be performed. Because follow-up is poor in this population, treatment should be prompt and thorough. PMID- 20857296 TI - Thoraco-pelvic orthosis: a portable and removable bassinet for secure patient immobilization after primary bladder exstrophy closure. AB - A portable and removable thoraco-pelvic orthosis for patient immobilization after neonatal primary bladder exstrophy closure is described. The device is made of a polyethylene shell, moulded at 170 degrees C, coated inside with a 5 mm pad of plastazote and works applying a constant gentle pressure on the hips. PMID- 20857297 TI - Study of pelvic floor and sphincter muscles in congenital pouch colon with the help of three-dimensional CT scan. AB - INTRODUCTION: Congenital pouch colon (CPC) is a pouch-like dilatation of shortened colon associated with anorectal malformation (ARM). The disease is prevalent in northern India. Postoperatively, the continence results are not as good as in other ARMs and there is higher incidence of incontinence and perineal soiling in these patients. The present study aimed to evaluate the pelvic floor and sphincter muscle characteristics in patients of CPC with the help of 64-slice computerized tomography with three-dimensional (3D) volumetric reconstructions of images, thus, to know the overall quality of these muscles in the patients. MATERIALS AND METHODS: The study was conducted in patients admitted over a period of July 2007 to November 2008 in our department. Totally, eight patients of CPC were subjected to 64-slice CT with three-dimensional reconstructions of images and different parameters such as quality of pelvic floor muscles, configuration of vertical and parasagittal fibres, shape and thickness of sphincter muscle complex, attenuation values of sphincters were studied. RESULTS: The 3D reconstructed images of pelvis in patients of CPC showed a well-developed pelvic floor and sphincter muscle complex. The length of the parasagittal fibres, transverse width of the vertical fibres and CT attenuation values of these structures with overall muscle quality were found to be good in these patients. CONCLUSION: In cases of CPC, the pelvic floor muscles including striated muscle complex (vertical and parasagittal fibres) are well developed. Higher rates of incontinence and soiling in CPC are not because of poorly developed pelvic floor and sphincter muscles. Three-dimensional CT can also provide important anatomical information that can help the operating surgeon while performing surgery. PMID- 20857299 TI - A long-term survival case of tracheal agenesis: management for tracheoesophageal fistula and esophageal reconstruction. AB - Tracheal agenesis is a very rare disorder which leads to severe respiratory disorders immediately after birth. Reports are very limited on long-term survival cases. We report here a long-term survival case with Floyd's type I tracheal agenesis. During the neonatal stage, the patient underwent abdominal esophageal banding to substitute esophagus for trachea and transection at the cervical esophagus with esophagostomy. Subsequently, airway management was difficult due to a fragile tracheoesophageal fistula, but the fistula was conservatively treated and stabilized with the patient's growth. This patient is a very rare case in whom oral feeding was achieved after esophageal reconstruction using a gastric tube. For this case, we describe mainly (1) the management method of the tracheoesophageal fistula and (2) esophageal reconstruction without thoracotomy. PMID- 20857298 TI - Prenatal treatment with retinoic acid activates parathyroid hormone-related protein signaling in the nitrofen-induced hypoplastic lung. AB - PURPOSE: Prenatal treatment with retinoic acid (RA) has been reported to stimulate alveologenesis in hypoplastic lungs (HL) in the nitrofen model of congenital diaphragmatic hernia (CDH). Parathyroid hormone-related protein (PTHrP) promotes alveolar maturation by stimulating surfactant production, regulated by PTHrP receptor (PTHrP-R). PTHrP knockout and PTHrP-R null mice both exhibit pulmonary hypoplasia. We have recently reported that nitrofen inhibits PTHrP signaling in the nitrofen-induced HL. Because both PTHrP and PTHrP-R genes have RA-inducible element, we hypothesized that prenatal administration of RA upregulates pulmonary gene expression of PTHrP and PTHrP-R in the nitrofen induced HL. METHODS: Pregnant rats were exposed to either olive oil or nitrofen on day 9 of gestation (D9). RA was given on days D18, D19 and D20. Fetal lungs were obtained on D21 and divided into four groups: control, control + RA, nitrofen, nitrofen + RA. RT-PCR and Immunohistochemistry were performed to investigate the pulmonary PTHrP and PTHrP-R gene and protein expression in each group, respectively. RESULTS: The pulmonary gene expression levels of PTHrP and PTHrP-R were significantly increased in nitrofen + RA group compared to nitrofen group (p < 0.05). Immunoreactivity of PTHrP and PTHrP-R was also remarkably increased in nitrofen + RA group compared to nitrofen group. CONCLUSIONS: Upregulation of PTHrP and PTHrP-R genes after prenatal treatment with RA in the nitrofen-induced HL suggests that RA may have a therapeutic potential in reverting lung hypoplasia in CDH, by stimulating surfactant production and alveolar maturation. PMID- 20857300 TI - Bone marrow mononuclear stem cell infusion improves biochemical parameters and scintigraphy in infants with biliary atresia. AB - PURPOSE: To evaluate early postoperative results in a case controlled study following clinical use of stem cells in extrahepatic biliary atresia (EHBA). METHODS: From July 2005 to March 2008, 30 cases of suspected EHBA were divided in two groups in an intervention study. Group A received autologous mononuclear bone marrow stem cells at the time of Kasai or after Kasai. In Group B, only Kasai was performed. Liver function tests on postoperative day 7 were compared. Serum bilirubin, clinical status, hepatic scintigraphy and survival at 6 months and 1 year were compared. RESULTS: Mean age was 136 (74-275) days in Group A and 99.7 (56-172) days in Group B. Preoperative values of serum bilirubin (SB), aspartate aminotransferase (AST), alanine aminotransferase and alkaline phosphatase (ALP) were comparable between the groups though there was significant difference in postoperative SB, AST and ALP (p = 0.014, 0.0041, 0.0005), with and without the use of stem cells. The median post stem cell SB was 6.9 (0.5-11.6) mg/dl in Group A versus 10.1 (5.6-26.3) mg/dl in Group B. Median SB at 6 months follow-up was 0.6 (0.5-5.4) mg/dl in Group A versus 7.6 (0.8-9.2) mg/dl in Group B (p = 0.028). There was a significant difference in episodes of cholangitis at 6 months postoperatively between the two groups (p = 0.024). Hepatic scans done at <3 months; >3 months follow-up showed prompt excretion in 80% (4/5); 85.7% (6/7) in Group A versus 20% (1/5); 50% (1/2) in Group B. Survival at 6; 12 months' follow up was 45.5%; 27.3% in Group A versus 33.3%; 6.7% in Group B. Median postoperative survival was 181 (139,223) days in Group A versus 123 (65,181) days in Group B. CONCLUSION: Significant biochemical and scintigraphic improvement was noted following stem cell therapy in biliary atresia, probably attributable to anti-inflammatory action of stem cells. PMID- 20857301 TI - Neuronal migration disorders in microcephalic osteodysplastic primordial dwarfism type I/III. AB - Microcephalic osteodysplastic primordial dwarfism (MOPD) is a rare microlissencephaly syndrome, with at least two distinct phenotypic and genetic types. MOPD type II is caused by pericentrin mutations, while types I and III appear to represent a distinct entity (MOPD I/III) with variably penetrant phenotypes and unknown genetic basis. The neuropathology of MOPD I/III is little understood, especially in comparison to other forms of lissencephaly. Here, we report postmortem brain findings in an 11-month-old female infant with MOPD I/III. The cerebral cortex was diffusely pachygyric, with a right parietal porencephalic lesion. Histologically, the cortex was abnormally thick and disorganized. Distinct malformations were observed in different cerebral lobes, as characterized using layer-specific neuronal markers. Frontal cortex was severely disorganized and coated with extensive leptomeningeal glioneuronal heterotopia. Temporal cortex had a relatively normal 6-layered pattern, despite cortical thickening. Occipital cortex was variably affected. The corpus callosum was extremely hypoplastic. Brainstem and cerebellar malformations were also present, as well as old necrotic foci. Findings in this case suggest that the cortical malformation in MOPD I/III is distinct from other forms of pachygyria lissencephaly. PMID- 20857302 TI - Drosophila melanogaster heterochromatin protein HP1b plays important roles in transcriptional activation and development. AB - The condensed heterochromatic domains are known to be associated with transcriptional repression and cell differentiation. Here, we investigate the function of heterochromatin protein HP1b, a member of the HP1 family in Drosophila melanogaster, in transcription and development. Both knockdown and overexpression of HP1b resulted in partial lethality, indicating that HP1b is essential for the normal development. In contrast to the positive role of HP1a in heterochromatin formation, overexpression of HP1b decondensed the pericentromeric heterochromatin and reduced the association of HP1a and H3K9me2 with it, both known markers of pericentric heterochromatin. Interestingly, the structure of the heterochromatic fourth chromosome appeared not to be affected. Further experiments showed that the presence of HP1a partially rescued the lethality caused by HP1b overexpression in males, and it fully rescued the lethality in females. Consistent with this observation, the defective transcription of heterochromatic genes was also partially restored in the presence of HP1a. Overall, this study argues that HP1b counteracts HP1a function both in heterochromatin formation and in the transcriptional regulation of euchromatic genes. PMID- 20857303 TI - Precise localization of the voltage-gated potassium channel subunits Kv3.1b and Kv3.3 revealed in the molecular layer of the rat cerebellar cortex by a pre embedding immunogold method. AB - A proper motor activity relies on a correct cerebellar function. The Kv3.1 and Kv3.3 voltage-gated potassium channels are key proteins involved in cerebellar function and dysfunction, as the lack of these causes severe motor deficits. Both channel subunits are coexpressed in granule cells and are rapidly activated at relatively positive potentials to support the generation of fast action potentials. However, the contribution of each subunit to the molecular architecture of the parallel fibers, the granule cell axons, is so far unknown. The goal of this study was to elucidate the relative distribution of Kv3.1b and Kv3.3 in specific compartments of the rat parallel fibers by using a pre embedding immunocytochemical method for electron microscopy. Numerous Kv3.1b and Kv3.3 silver-intensified gold particles were associated with membranes of parallel fiber synaptic terminals and their intervaricose segments. Kv3.1b was found in about 85% of parallel fiber synaptic terminals and in about 47% of their intervaricose portions. However, only 28% of intervaricosities and 23% of parallel fiber presynaptic boutons were Kv3.3 immunopositive. The analysis also revealed that 54% of Purkinje cell dendritic spines localized Kv3.3. Although both potassium channel subunits share localization in the same presynaptic parallel fiber compartments, the present results with the method used indicate that there are a higher percentage of parallel fibers labeled for Kv3.1b than for Kv3.3, and that the labeling intensity for each subunit is higher in specific subcompartments analyzed than in others. PMID- 20857304 TI - Phosphoinositide 3-kinase-dependent regulation of Na+/H+ exchanger in dendritic cells. AB - Dendritic cells (DCs), antigen-presenting cells that are able to initiate primary immune responses and to establish immunological memory, are activated by exposure to bacterial lipopolysaccharides (LPS), which leads to cell swelling, triggering ROS formation and stimulating migration. The function of DCs is regulated by the phosphoinositide 3 (PI3) kinase pathway. On the other hand, PI3 kinase is an important regulator of diverse transporters including the Na(+)/H(+) exchanger (NHE). The present study was performed to elucidate the role of PI3 kinase in NHE activity, cell volume, ROS formation, and migration. To this end, DCs were isolated from murine bone marrow, cytosolic pH (pH(i)) determined utilizing 2',7' bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein fluorescence, Na(+)/H(+) exchanger activity from the Na(+)-dependent realkalinization after an ammonium pulse, cell volume from forward scatter in fluorescence-activated cell sorter analysis, ROS production from 2',7'-dichlorodihydrofluorescein diacetate fluorescence, and migration utilizing transwell migration assays. Exposure of DCs to LPS led within 4 h to a gradual cytosolic acidification paralleled by a transient time- and dose-dependent increase of Na(+)/H(+) exchanger activity, cell swelling, enhanced ROS production, and stimulation of migration. The PI3K inhibitors Wortmannin (1 MUM) or LY294002 (10 MUM) significantly blunted the effects of LPS on NHE activity, cell volume, ROS production, and migration. The present observations disclose a critical role of PI3K signaling in the regulation of DC function following exposure to LPS. PMID- 20857305 TI - Functional significance of the intermediate conductance Ca2+-activated K+ channel for the short-term survival of injured erythrocytes. AB - Increased cytosolic Ca(2+) concentrations activate Gardos K(+) channels in human erythrocytes with membrane hyperpolarization, efflux of K(+), Cl-, and osmotically obliged H2O resulting in cell shrinkage, a phenomenon referred to as Gardos effect. We tested whether the Gardos effect delays colloid osmotic hemolysis of injured erythrocytes from mice lacking the Ca(2+)-activated K(+) channel K(Ca)3.1. To this end, we applied patch clamp and flow cytometry and determined in vitro as well as in vivo hemolysis. As a result, erythrocytes from K(Ca)3.1-deficient (K(Ca)3.1(-/-)) mice lacked Gardos channel activity and the Gardos effect. Blood parameters, reticulocyte count, or osmotic erythrocyte resistance, however, did not differ between K(Ca)3.1(-/-) mice and their wild type littermates, suggesting low or absent Gardos channel activity in unstressed erythrocytes. Oxidative stress-induced Ca(2+) entry and phospholipid scrambling were significantly less pronounced in K(Ca)3.1(-/-) than in wild-type erythrocytes. Moreover, in vitro treatment with alpha-toxin from Staphylococcus aureus, which forms pores in the cellular membrane, resulted in significantly stronger hemolysis of K(Ca)3.1(-/-) than of wild-type erythrocytes. Intravenous injection of alpha-toxin induced more profound hemolysis in K(Ca)3.1(-/-) than in wild-type mice. Similarly, intra-peritoneal application of the redox-active substance phenylhydrazine, an agent for the induction of hemolytic anemia, was followed by a significantly stronger decrease of hematocrit in K(Ca)3.1(-/-) than in wild-type mice. Finally, malaria infection triggered the activation of K(Ca)3.1 and transient shrinkage of the infected erythrocytes. In conclusion, K(Ca)3.1 channel activity and Gardos effect counteract hemolysis of injured erythrocytes, thus decreasing hemoglobin release into circulating blood. PMID- 20857307 TI - Early-season warning of soybean rust regional epidemics using El Nino Southern/Oscillation information. AB - Soybean rust (SBR) is a disease of significant impact to Brazilian soybean production. Twenty-four locations in a major growing region in southern Brazil, where long-term (30 years) weather information was available, were selected to estimate the risk of SBR epidemics and identify potential predictors derived from El Nino 3.4 region. A rainfall-based model was used to predict SBR severity in an "epidemic development window" (the months of February and March for the studied region) in the time series. Twenty-eight daily simulations for each year-location (n = 720) were performed considering each day after 31 January as a hypothetical detection date (HDD) to estimate a severity index (SBRindex). The mean SBRindex in a single year was defined as the 'growing season severity index' (GSSI) for that year. A probabilistic risk assessment related GSSI and sea surface temperatures (SST) at the El Nino 3.4. region (here categorized as warm, cold or neutral phase) in October-November-December (OND) of the same growing season. Overall, the median GSSI across location-years was 34.5%. The risk of GSSI exceeding 60% was generally low and ranged from 0 to 20 percentage points, with the higher values found in the northern regions of the state when compared to the central-western. During a warm OND-SST phase, the probability of GSSI exceeding its overall mean (locations pooled) increased significantly by around 25 percentage points compared to neutral and cold SST phases, especially over the central western region. This study demonstrates the potential to use El Nino/Southern Oscillation information to anticipate the risk of SBR epidemics up to 1 month in advance at a regional scale. PMID- 20857306 TI - Non-steady-state calcium handling in failing hearts from the spontaneously hypertensive rat. AB - It is generally agreed that changes in Ca(2+) cycling are often associated with heart failure, yet the impact of these changes on a beat-to-beat basis remains unclear. Measurements of isometric force and [Ca(2+)](i) were made at 37 degrees C in left ventricular trabeculae from failing spontaneously hypertensive rat (SHR) hearts, and their normotensive Wistar-Kyoto (WKY) controls. At 1 Hz, peak stress was reduced in SHR (14.5 +/- 2.4 mN mm(-2) versus 22.5 +/- 6.7 mN mm-2 for WKY), although the Ca(2+) transients were bigger (peak [Ca(2+)](i) 0.60 +/- 0.08 MUM versus 0.38 +/- 0.03 MUM for WKY) with a slower decay of fluorescence (time constant 0.105 +/- 0.005 s versus 0.093 +/- 0.002 s for WKY). To probe dynamic Ca(2+) cycling, two experimental protocols were used to potentiate force: (1) an interval of 30 s rest, and (2) a 30-s train of paired-pulses, and the recirculation fraction (RF) calculated for recovery to steady-state. No difference was found between rat strains for RF calculated from either peak force or Ca(2+), although the RF was dependent on potentiation protocol. Since SR uptake is slower in SHR, the lack of change in RF must be due to a parallel decrease in trans-sarcolemmal Ca(2+) extrusion. This view was supported by a slower decay of caffeine-induced Ca(2+) transients in SHR trabeculae. Confocal analysis of LV free wall showed t-tubules were distorted in SHR myocytes, with reduced intensity of NCX and SERCA2a labelling in comparison to WKY. PMID- 20857308 TI - Complete nucleotide sequence of Velvet tobacco mottle virus isolate K1. AB - Velvet tobacco mottle virus (VTMoV) infects the native Australian plant Nicotiana velutina, which is endemic to central Australia. This virus is included in the genus Sobemovirus based on virion morphology and serological relationships. We report here the full genome sequence of VTMoV, attained using a genome-walking strategy with both degenerate and specific primers. This sequence confirms that VTMoV is a sobemovirus, with the same open reading frame (ORF) organisation as other described sobemoviruses. The VTMoV sequence is closest to those sobemoviruses isolated from monocotyledonous plants, although the narrow host range of VTMoV is limited to dicotyledonous plants. PMID- 20857310 TI - Partial SPAST and DPY30 deletions in a Japanese spastic paraplegia type 4 family. AB - Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale-Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree. PMID- 20857309 TI - Accuracy of templates for navigated implantation made by rapid prototyping with DICOM datasets of cone beam computer tomography (CBCT). AB - The aim of this study is to evaluate the accuracy of a surgical template-aided implant placement produced by rapid prototyping using a DICOM dataset from cone beam computer tomography (CBCT). On the basis of CBCT scans (Sirona(r) Galileos), a total of ten models were produced using a rapid-prototyping three-dimensional printer. On the same patients, impressions were performed to compare fitting accuracy of both methods. From the models made by impression, templates were produced and accuracy was compared and analyzed with the rapid-prototyping model. Whereas templates made by conventional procedure had an excellent accuracy, the fitting accuracy of those produced by DICOM datasets was not sufficient. Deviations ranged between 2.0 and 3.5 mm, after modification of models between 1.4 and 3.1 mm. The findings of this study suggest that the accuracy of the low dose Sirona Galileos(r) DICOM dataset seems to show a high deviation, which is not useable for accurate surgical transfer for example in implant surgery. PMID- 20857311 TI - Lipovitellin is a non-self recognition receptor with opsonic activity. AB - Lipovitellin (Lv), a glycolipoprotein, is a major component of the egg yolk, which is usually regarded as an energy reserve of nutrients essential for growth and development. We have purified Lv from ovulated eggs of the rosy barb Puntius conchonius by two-step chromatography and characterized it by staining with periodic acid/Schiff reagent and Sudan black B, amino acid composition analysis, and peptide mass fingerprinting. The results of ligand and bacterial binding assays, an enzyme-linked immunosorbent assay (ELISA), and the phagocytosis test revealed, for the first time, that the purified native form of P. conchonius Lv acts as a pattern recognition molecule with multiple specificities capable of identifying pathogen-associated molecular patterns (PAMPs), including those of lipopolysaccharide, lipoteichoic acid, and peptidoglycan, rather than self components and that it can bind Gram-negative and -positive bacteria, such as Escherichia coli and Staphylococcus aureus. These tests also showed that the P. conchonius Lv functions as an opsonin capable of enhancing macrophage phagocytosis. Taken together, these characteristics suggest that in developing embryos/larvae of P. conchonius, the native form of Lv may be physiologically involved in the sensing of invading pathogens via interaction with PAMPs and in the recruitment of the primitive macrophages that appear in early embryos to phagocytose and digest the pathogens, thereby protecting them from pathogenic attacks. PMID- 20857312 TI - Turning hand hygiene into a habit: the need is obvious. PMID- 20857313 TI - One-year follow-up of patients of the ongoing Dutch Q fever outbreak: clinical, serological and echocardiographic findings. AB - PURPOSE: In 2007, a large goat-farming-associated Q fever outbreak occurred in the Netherlands. Data on the clinical outcome of Dutch Q fever patients are lacking. The current advocated follow-up strategy includes serological follow-up to detect evolution to chronic disease and cardiac screening at baseline to identify and prophylactically treat Q fever patients in case of valvulopathy. However, serological follow-up using commercially available tests is complicated by the lack of validated cut-off values. Furthermore, cardiac screening in the setting of a large outbreak has not been implemented previously. Therefore, we report here the clinical outcome, serological follow-up and cardiac screening data of the Q fever patients of the current ongoing outbreak. METHODS: The implementation of a protocol including clinical and serological follow-up at baseline and 3, 6 and 12 months after acute Q fever and screening echocardiography at baseline. RESULTS: Eighty-five patients with acute Q fever were identified (male 62%, female 38%). An aspecific, flu-like illness was the most common clinical presentation. Persistent symptoms after acute Q fever were reported by 59% of patients at 6 months and 30% at 12 months follow-up. We observed a typical serological response to Coxiella burnetii infection in both anti-phase I and anti-phase II IgG antibodies, with an increase in antibody titres up to 3 months and a subsequent decrease in the following 9 months. Screening echocardiography was available for 66 (78%) out of 85 Q fever patients. Cardiac valvulopathy was present in 39 (59%) patients. None of the 85 patients developed chronic Q fever. CONCLUSIONS: Clinical, serological and echocardiographic data of the current ongoing Dutch Q fever outbreak cohort are presented. Screening echocardiography is no longer part of the standard work-up of Q fever patients in the Netherlands. PMID- 20857314 TI - Educating healthcare workers to optimal hand hygiene practices: addressing the need. AB - The education of healthcare workers is essential to improve practices and is an integral part of hand hygiene promotional strategies. According to the evidence reviewed here, healthcare worker education has a positive impact on improving hand hygiene and reducing healthcare-associated infection. Detailed practical guidance on steps for the organization of education programmes in healthcare facilities and teaching-learning strategies are provided using the World Health Organization (WHO) Guidelines for Hand Hygiene in Health Care as the basis for recommendations. Several key elements for a successful educational programme are also identified. A particular emphasis is placed on concepts included in the tools developed by WHO for education, monitoring and performance feedback. PMID- 20857318 TI - Desmoplastic non-infantile ganglioglioma in late adulthood. AB - Desmoplastic infantile ganglioglioma (DIG) is an uncommon supratentorial neuroepithelial brain tumor that typically occurs in infants younger than 24 months. Desmoplastic non-infantile ganglioglioma (DNIG) is a rare variant of this intracranial neoplasm. There are only 16 DNIG cases reported in the literature, with all patients under the age of 25 at the time of presentation. These DIG and DNIG cases were radiologically and histologically similar, with good outcome after treatment. Despite the size and high mitotic index for patients with DNIG, the prognosis is generally favorable and gross total resection is sufficient. We present a case of a 59-year-old woman with a DNIG. To the best of our knowledge, this is the first case reported of DNIG in late adulthood. Clinical presentation, histological and radiological findings are discussed. PMID- 20857319 TI - Quantitative analysis of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation in patients with low-grade gliomas. AB - Methylation of the MGMT promoter is supposed to be a predictive and prognostic factor in glioblastoma. Whether MGMT promoter methylation correlates with tumor response to temozolomide in low-grade gliomas is less clear. Therefore, we analyzed MGMT promoter methylation by a quantitative methylation-specific PCR in 22 patients with histologically verified low-grade gliomas (WHO grade II) who were treated with temozolomide (TMZ) for tumor progression. Objective tumor response, toxicity, and LOH of microsatellite markers on chromosomes 1p and 19q were analyzed. Histological classification revealed ten oligodendrogliomas, seven oligoastrocytomas, and five astrocytomas. All patients were treated with TMZ 200 mg/m2 on days 1-5 in a 4 week cycle. The median progression-free survival was 32 months. Combined LOH 1p and 19q was found in 14 patients; one patient had LOH 1p alone and one patient LOH 19q alone. The LOH status could not be determined in two patients and was normal in the remaining four. LOH 1p and/or 19q correlated with longer time to progression but not with radiological response to TMZ. MGMT promoter methylation was detectable in 20 patients by conventional PCR and quantitative analysis revealed the methylation status was between 12 and 100%. The volumetric response to chemotherapy analyzed by MRI and time to progression correlated with the level of MGMT promoter methylation. Therefore, our retrospective case series suggests that quantitative methylation-specific PCR of the MGMT promoter predicts radiological response to chemotherapy with TMZ in WHO grade II gliomas. PMID- 20857320 TI - Probabilistic characteristics of random damage events and their quantification in acrylic bone cement. AB - The failure of brittle and quasi-brittle polymers can be attributed to a multitude of random microscopic damage modes, such as fibril breakage, crazing, and microfracture. As the load increases, new damage modes appear, and existing ones can transition into others. In the example polymer used in this study--a commercially available acrylic bone cement--these modes, as revealed by scanning electron microscopy of fracture surfaces, include nucleation of voids, cracking, and local detachment of the beads from the matrix. Here, we made acoustic measurements of the randomly generated microscopic events (RGME) that occurred in the material under pure tension and under three-point bending, and characterized the severity of the damage by the entropy (s) of the probability distribution of the observed acoustic signal amplitudes. We correlated s with the applied stress (sigma) by establishing an empirical s-sigma relationship, which quantifies the activities of RGME under Mode I stress. It reveals the state of random damage modes: when ds/dsigma > 0, the number of damage modes present increases with increasing stress, whereas it decreases when ds/dsigma < 0. When ds/dsigma ~ 0, no new random damage modes occur. In the s-sigma curve, there exists a transition zone, with the stress at the "knee point" in this zone (center of the zone) corresponding to ~30 and ~35% of the cement's tensile and bending strengths, respectively. This finding explains the effects of RGME on material fatigue performance and may be used to approximate fatigue limit. PMID- 20857322 TI - Static and dynamic cultivation of bone marrow stromal cells on biphasic calcium phosphate scaffolds derived from an indirect rapid prototyping technique. AB - The adequate regeneration of large bone defects is still a major problem in orthopaedic surgery. Synthetic bone substitute materials have to be biocompatible, biodegradable, osteoconductive and processable into macroporous scaffolds tailored to the patient specific defect. Hydroxyapatite (HA) and tricalcium phosphate (TCP) as well as mixtures of both phases, biphasic calcium phosphate ceramics (BCP), meet all these requirements and are considered to be optimal synthetic bone substitute materials. Rapid prototyping (RP) can be applied to manufacture scaffolds, meeting the criteria required to ensure bone ingrowth such as high porosity and defined pore characteristics. Such scaffolds can be used for bone tissue engineering (BTE), a concept based on the cultivation of osteogenic cells on osteoconductive scaffolds. In this study, scaffolds with interconnecting macroporosity were manufactured from HA, TCP and BCP (60 wt% HA) using an indirect rapid prototyping technique involving wax ink-jet printing. ST 2 bone marrow stromal cells (BMSCs) were seeded onto the scaffolds and cultivated for 17 days under either static or dynamic culture conditions and osteogenic stimulation. While cell number within the scaffold pore system decreased in case of static conditions, dynamic cultivation allowed homogeneous cell growth even within deep pores of large (1,440 mm(3)) scaffolds. Osteogenic cell differentiation was most advanced on BCP scaffolds in both culture systems, while cells cultured under perfusion conditions were generally more differentiated after 17 days. Therefore, scaffolds manufactured from BCP ceramic and seeded with BMSCs using a dynamic culture system are the method of choice for bone tissue engineering. PMID- 20857321 TI - Surface immobilized zoledronate improves screw fixation in rat bone: a new method for the coating of metal implants. AB - Previous studies show that surface immobilized bisphosphonates improve the fixation of stainless steel screws in rat tibia after 2-8 weeks of implantation. We report here about the immobilization of a potent bisphosphonate, zoledronate, to crosslinked fibrinogen by the use of another technique, i.e. ethyl-dimethyl aminopropylcarbodiimide (EDC)/imidazole immobilization. Bone fixation of zoledronate-coated screws was compared to screws coated with crosslinked fibrinogen only and ditto with EDC/N-hydroxy-succinimide immobilized pamidronate. Fixation in rat tibia was evaluated by a pull-out test at either 2 or 6 weeks after implantation. Both bisphosphonate coatings increased the pull-out force at both time points, and zoledronate showed a significantly higher pull-out force than pamidronate. To further evaluate the new coating technique we also performed a morphometric study, focusing on the area surrounding the implant. The zoledronate coating resulted in an increased bone density around the screws compared to controls. No pronounced increase was seen around the pamidronate coated screws. Together, the results demonstrate the possibility of obtaining a significant local therapeutic effect with minute amounts of surface immobilized zoledronate. PMID- 20857323 TI - Osteoclastic cell behaviors affected by the alpha-tricalcium phosphate based bone cements. AB - Calcium phosphate cements (CPCs) have recently gained great interest as injectable bone substitutes for use in dentistry and orthopedics. alpha tricalcium phosphate (alpha-TCP) is a popularly used precursor powder for CPCs. When mixed with appropriate content of liquid and kept under aqueous conditions, alpha-TCP dissolves to form a calcium-deficient hydroxyapatite and then hardens to cement. In this study, alpha-TCP based cement (CP) and its composite cement with chitosan (Ch-CP) were prepared and the osteoclastic responses to the cements and their elution products were evaluated. Preliminary evaluation of the cements revealed that the CP and Ch-CP hardened within ~10 min at an appropriate powder to-liquid ratio (PL) of 3.0. In addition, CP and Ch-CP were transformed into an apatite phase following immersion in a saline solution. Moreover, the osteoblastic cells were viable on the cements for up to 10 days. Mouse-derived bone marrow cells were isolated and activated with osteoclastic differentiation medium, and the effects of the CP and Ch-CP substrates and their ionic eluants on the osteoclastic activity were investigated. Osteoclastic cells were viable for up to 14 days on both types of cements, maintaining a higher cell growth level than the control culture dish. Multi-nucleated osteoclastic cells that were tartrate-resistant acid phosphatase (TRAP)-positive were clearly observed when cultured on the cement substrates as well as treated with the cement eluants. The TRAP activity was found to be significantly higher in cells influenced by the cement substrates and their eluants with respect to the control culture dish (Ch CP > CP ? control). Overall, the osteoclastic differentiation was highly stimulated by the alpha-TCP based experimental cements in terms of both the substrate interaction and their elution products. PMID- 20857324 TI - Self-assembled micellar aggregates based monomethoxyl poly(ethylene glycol)-b poly(epsilon-caprolactone)-b-poly(aminoethyl methacrylate) triblock copolymers as efficient gene delivery vectors. AB - Amphiphilic triblock copolymers monomethoxyl poly(ethylene glycol) (mPEG)-b poly(epsilon-caprolactone) (PCL)-b-poly(aminoethyl methacrylate)s (PAMAs) (mPECAs) were synthesized as gene delivery vectors. They exhibited lower cytotoxicity and higher transfection efficiency in COS-7 cells in presence of serum compared to 25 kDa bPEI. The influence of mPEG and PCL segments in mPECAs was evaluated by comparing with corresponding diblock copolymers. The studies showed the incorporation of the hydrophobic PCL segment in triblock copolymers affected the binding capability to pDNA and surface charges of complexes due to the formation of micelles increasing the local charges. The presence of mPEG segment in gene vector decreased the surface charges of the complexes and increased the stability of the complexes in serum because of the steric hindrance effect. It was also found that the combination of PEG and PCL segments into one macromolecule might lead to synergistic effect for better transfection efficiency in serum. PMID- 20857325 TI - A study on agent-based secure scheme for electronic medical record system. AB - Patient records, including doctors' diagnoses of diseases, trace of treatments and patients' conditions, nursing actions, and examination results from allied health profession departments, are the most important medical records of patients in medical systems. With patient records, medical staff can instantly understand the entire medical information of a patient so that, according to the patient's conditions, more accurate diagnoses and more appropriate in-depth treatments can be provided. Nevertheless, in such a modern society with booming information technologies, traditional paper-based patient records have faced a lot of problems, such as lack of uniform formats, low data mobility, slow data transfer, illegible handwritings, enormous and insufficient storage space, difficulty of conservation, being easily damaged, and low transferability. To improve such drawbacks, reduce medical costs, and advance medical quality, paper-based patient records are modified into electronic medical records and reformed into electronic patient records. However, since electronic patient records used in various hospitals are diverse and different, in consideration of cost, it is rather difficult to establish a compatible and complete integrated electronic patient records system to unify patient records from heterogeneous systems in hospitals. Moreover, as the booming of the Internet, it is no longer necessary to build an integrated system. Instead, doctors can instantly look up patients' complete information through the Internet access to electronic patient records as well as avoid the above difficulties. Nonetheless, the major problem of accessing to electronic patient records cross-hospital systems exists in the security of transmitting and accessing to the records in case of unauthorized medical personnels intercepting or stealing the information. This study applies the Mobile Agent scheme to cope with the problem. Since a Mobile Agent is a program, which can move among hosts and automatically disperse arithmetic processes, and moves from one host to another in heterogeneous network systems with the characteristics of autonomy and mobility, decreasing network traffic, reducing transfer lag, encapsulating protocol, availability on heterogeneous platforms, fault-tolerance, high flexibility, and personalization. However, since a Mobile Agent contacts and exchanges information with other hosts or agents on the Internet for rapid exchange and access to medical information, the security is threatened. In order to solve the problem, this study proposes a key management scheme based on Lagrange interpolation formulas and hierarchical management structure to make Mobile Agents a more secure and efficient access control scheme for electronic patient record systems when applied to the access of patients' personal electronic patient records cross hospitals. Meanwhile, with the comparison of security and efficacy analyses being the feasibility of validation scheme and the basis of better efficiency, the security of Mobile Agents in the process of operation can be guaranteed, key management efficacy can be advanced, and the security of the Mobile Agent system can be protected. PMID- 20857326 TI - Ventricular fibrillation associated with early repolarization in a patient with thyroid storm. AB - We present a case of a 69-year-old male who was hospitalized for the treatment of thyroid storm due to Grave's disease, who presented with unexpected ventricular fibrillation (VF). The possible etiology was early repolarization (ER), characterized by J-point elevation in inferior and posterolateral leads, unmasked by the attenuation of beta-adrenergic effect with normalization of thyroid hormones and following the administration of a beta-blocker. Our case focuses attention on the occurrence of VF in a patient with ER during the treatment of hyperthyroidism, which to our knowledge is the first such report. PMID- 20857327 TI - Understanding Sarason's concepts of school cultures and change: joining a community in school improvement efforts. AB - This paper describes an evolving transformative partnership between a large comprehensive university, an urban school system and a predominantly African American, low-income neighborhood. The partnership's originating intent was to apply an array of university, civic and local resources to improve the academic performance of a neighborhood's schools and the health, welfare and economic well being of its residents. The extent to which that partnership would precipitate transactional (Sameroff and Fiese, Handbook of early childhood intervention, Cambridge University Press, Cambridge, pp. 119-149 in 1990) synergies among the partners was unanticipated; the long-term implications for each of the partners of such unfamiliar interactional processes remain unclear but are being systematically monitored over time. Evident at this point, however, it that a process has been initiated that has impacted how the university community, the local public school system, city government and the target neighborhood relate to each other, collaborate with each other and are changing each other. The pace of that process has varied over the years and challenged each partners' expectations and assumptions about the nature and consequences of their involvement. With time and perseverance, however, it appears that all are moving toward a sense of mutual learning and trust and toward extending to each other the benefit of the doubt. This paper discusses the evolution of that process and its implications for university-school-community collaborations. PMID- 20857328 TI - Alcohol availability and violence among inner-city adolescents: A multi-level analysis of the role of alcohol outlet density. AB - Researchers recognize that the connection between alcohol and peer violence may relate to community level ecological factors, such as the location of businesses that sell alcohol. Building on previous research among adults, this study examines the relationship between alcohol outlet density and violent behaviors among adolescents, taking into account demographic characteristics, individual alcohol use, and neighborhood level socioeconomic indicators. Data drawn from a diverse Emergency Department based sample of 1,050 urban adolescents, combined with tract level data from the state liquor control commission and U.S. Census, were analyzed. Results of multivariate multi-level regression analysis indicate that alcohol outlet density is significantly related to adolescents' violent behaviors, controlling for demographic characteristics and individual alcohol use. Census tract level socioeconomic indicators were not significantly associated with youth violence. Findings suggest that alcohol outlet density regulation should be considered as part of broader violence prevention strategies for urban adolescents. PMID- 20857329 TI - Neighborhood environment, sexual risk behaviors and acquisition of sexually transmitted infections among adolescents diagnosed with psychological disorders. AB - The association between neighborhood environment and prevalence of STIs, sexual partner variables and condom use among adolescents with psychological disorders was examined. Cross-sectional data in three urban areas of the US (Southeast, Northeast and Midwest) were obtained from 384 sexually active male and female participants who provided urine samples for laboratory-confirmed testing of Neisseria gonorrhoeae, Chlamydia trachomatis and Trichomonas vaginalis. A total of 15.4% of participants tested positive for one of the three STIs. Results indicated that relative to adolescents living in low risk neighborhood environments, those living in high risk environments were significantly more likely to have a STI and to report having casual partners. Findings suggest that in high risk neighborhoods, STI acquisition may be less dependent on condom use and more dependent on other contextual factors. The importance of expanding public health research to include assessment of neighborhood context as a determinant of sexual risk-taking is emphasized. PMID- 20857330 TI - Interdisciplinary knowledge translation: lessons learned from a mental health: fire service collaboration. AB - Collaborative approaches are being increasingly advocated for addressing a variety of health, mental health and social needs for children, youth and families. Factors important for effective knowledge translation of collaborative approaches of service delivery across disciplines, however, have not been rigorously examined. TAPP-C: The Arson Prevention Program for Children is an intervention program for child and adolescent firesetters provided collaboratively by fire service and mental health professionals. The present study examined the adopter, innovation, and dissemination characteristics associated with TAPP-C implementation, protocol adherence and extent of collaboration by 241 community-based fire service professionals from communities across Ontario. Results revealed that dissemination factors are particularly important for understanding program implementation, adherence and cross discipline collaboration. Moreover, the findings of this study show significant benefits to both within discipline (intra-disciplinary) and across discipline (interdisciplinary) knowledge translation strategies. PMID- 20857331 TI - Promoting healing and restoring trust: policy recommendations for improving behavioral health care for American Indian/Alaska Native adolescents. AB - American Indian/Alaska Native youth represent the strength and continued survival of many Nations and Tribes. However, they currently experience numerous health disparities and challenges, including the highest rate of suicide among 15-24 year-olds in the United States. Our comprehensive review of the literature on the mental health of AI/AN youth highlighted seven focal causes of behavioral health disparities: (1) high levels of violence and trauma exposure and traumatic loss, (2) past and current oppression, racism, and discrimination, (3) underfunded systems of care, (4) disregard for effective indigenous practices in service provision, policy, and funding, (5) overreliance on evidence-based practices, (6) lack of cultural competence among systems of care and providers, and (7) barriers to care. Seven policy recommendations that recognize the importance of moving beyond exclusive reliance on western models of care and that seek to foster transformation of individuals, families, communities, behavioral health service systems of care, and social structures are presented, supported, and discussed. PMID- 20857332 TI - Self-efficacy in service-learning community action research: theory, research, and practice. AB - The purpose of this article is threefold: In the first section, an overview of research and theory on the self-efficacy construct is provided, and the central role of self-efficacy in service-learning community action research is demonstrated. The second section reviews over 10 years of research validating the Community Service Self-Efficacy Scale (CSSES), which measures the individual's confidence in his or her own ability to make clinically (meaningfully) significant contributions to the community through service. Within the context of this review, recent (previously unpublished) validation research is also reviewed. Alternate versions of the CSSES, each of which was developed for a specific purpose, are presented. The third section provides recommendations for further research focused on (a) validating the CSSES and (b) examining self efficacy as an outcome, moderator, and mediating variable in service-learning community action research. PMID- 20857333 TI - Pursuing Franklin's dream: Philosophical and historical roots of service learning. AB - Two decades ago service-learning as an innovation lingered on the periphery of the academy. Today, service-learning has spread across American higher education. Few educational innovations have achieved such relatively rapid success. This article describes the historical and philosophical underpinnings of service learning. It notes some of the significant debates that have occurred among its practitioners. The authors draw from experience at their university, the University of Pennsylvania, to describe the importance of connecting service learning to the core educational and civic missions of a college or university, as well as to provide a case study of how that connection might be made. PMID- 20857334 TI - The interaction between the mu opioid receptor and filamin A. AB - Our laboratory embarked on research to discover proteins the interaction of which with the mu opioid receptor (MOPr) is required for its function and regulation. We performed yeast two-hybrid screens, using the carboxy tail of the human MOPr as bait and a human brain library. This yielded a number of proteins that seemed to bind to the MOPr C-tail. The one we chose to study in detail was filamin A (FLNA). Evidence was obtained that there was indeed protein-protein binding between the C-tail of MOPr and FLNA. A human melanoma cell line (M2) lacking the gene for FLNA and a control cell line (A7) which differed from M2 only in having been transfected with the gene for FLNA and expressing the FLNA protein were made available to us. We transfected these cell lines with the gene for MOPr and used them in our studies. The absence of FLNA strongly reduced MOPr downregulation as well as desensitization of adenylyl cyclase inhibition and G protein activation. A recent finding, published here for the first time, is that FLNA is required for the activation by mu opioid agonists of the MAP kinase p38. Deletion studies indicated that the MOPr binding site on FLNA is in the 24th repeat, close to its C-terminal. It was further found that FLNA lacking the N-terminal actin binding domain is as capable as full length FLNA to restore cells to control status, suggesting that actin binding is not required. A surprising finding was that upregulation of MOPr by morphine and some agonist analogs occurs in M2 cells lacking FLNA, whereas normal receptor downregulation takes place in A7 cells. PMID- 20857335 TI - Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. AB - Several unrelated disorders can lead to 5-methyltetrahydrofolate (5MTHF) depletion in the cerobrospinal fluid (CSF), including primary genetic disorders in folate-related pathways or those causing defective transport across the blood CSF barrier. We report a case of cerebral folate transport deficiency due to a novel homozygous mutation in the FOLR1 gene, in an effort to clarify phenotype genotype correlation in this newly identified neurometabolic disorder. A previously healthy infant developed an ataxic syndrome in the second year of life, followed by choreic movements and progressive myoclonic epilepsy. At the age of 26 months, we analyzed CSF 5MTHF by HPLC with fluorescence detection and conducted magnetic resonance (MR) imaging and spectroscopy studies. Finally, we performed mutational screening in the coding region of the FOLR1 gene. MR showed a diffuse abnormal signal of the cerebral white matter, cerebellar atrophy and a reduced peak of choline in spectroscopy. A profound deficiency of CSF 5MTHF (2 nmol/L; NV 48-127) with reduced CSF/plasma folate ratio (0.4; NV 1.5-3.5) was highly suggestive of defective brain folate-specific transport across the blood CSF/brain barrier. Mutation screening of FOLR1 revealed a new homozygous missense mutation (p.Cys105Arg) that is predicted to abolish a disulfide bond, probably necessary for the correct folding of the protein. Both parents were heterozygous carriers of the same variant. Mutation screening in the FOLR1 gene is advisable in children with profound 5MTHF deficiency and decreased CSF/serum folate ratio. Progressive ataxia and myoclonic epilepsy, together with impaired brain myelination, are clinical hallmarks of the disease. PMID- 20857336 TI - Smoking habits and health-related quality of life in a rural Japanese population. AB - PURPOSE: To investigate the association between smoking and health-related quality of life (HRQOL) in a rural Japanese population. METHODS: A cross sectional study of data from 823 subjects in Iwaki area of Hirosaki City, Japan. SF-36 scores between non-smokers and smokers were compared. To test the sensitivity of SF-36 scores in detecting health deterioration, effects of having diseases and having deviations from normal thresholds in health check-up were analyzed by adding them into covariates in ANCOVA. RESULTS: There was no significant difference in SF-36 scores between non-smokers and smokers. Presence of diseases significantly decreased the physical components of SF-36 scores while the results of health check-up had no significant influence on SF-36 scores. CONCLUSIONS: The results suggested the possibility that in Japan, where smoking prevalence is still relatively high, smokers may be less sensitive to sub clinical deterioration in their own health status than smokers in Western countries that already have experienced the major decline in their smoking rate. The importance of having the smoker become more sensitive to the sub-clinical adverse effects of cigarette smoking should be stressed for the success of smoking control programs. PMID- 20857337 TI - Comparison of the short-term health-related quality of life in patients with esophageal cancer with different routes of gastric tube reconstruction after minimally invasive esophagectomy. AB - OBJECTIVE: To compare the short-term health-related quality of life (HRQL) between the two different routes of gastric tube reconstruction after minimally invasive esophagectomy (MIE). METHODS: From January 2007 to June 2009, 97 patients who underwent three-incision subtotal MIE were enrolled in this retrospective study. Among them, 49 patients followed prevertebral route and 48 patients followed retrosternal route. The questionnaires (EORTC QLQ C-30 and OES 18) were applied to assess the HRQL of the patients before and 2, 4, 12, 24 weeks after operation. RESULTS: All the patients underwent operation with no mortality. No statistical difference was found in age, gender, serum albumin level, the level of growth in the esophagus, pathological diagnosis, tumor stage, operation time, blood loss or ICU stay between the two groups. The perioperative complication rate was 35.4% in retrosternal group and 32.7% in prevertebral group (P = 0.774). However, the rate of cervical anastomotic leak in the retrosternal group was much higher (20.8 vs. 6.1%, P = 0.033). But the rate of cardiac or pulmonary complication in the retrosternal group seemed to be lower (10.4 vs. 22.4%, P = 0.110). Besides, the rate of anastomotic stricture was similar (6.3 vs. 10.2%, P = 0.735). And all HRQL measures did not show major differences between the two groups before operation. However, at the time of 2 weeks after operation, the dysphagia and eating problem questionnaires scores were higher in retrosternal group than in prevertebral group, which meant that the patients in retrosternal group suffered more severe problems; meanwhile, the scores of global quality scale in retrosternal group was also lower, which indicated that the patients had a worse global quality of life. Whereas, at the time of 12 and 24 weeks after operation, the dyspnoea and reflux symptom questionnaire scores were lower in retrosternal group than in prevertebral group, which revealed that there were less problems in the patients of retrosternal group; meanwhile, the score of global quality scale in retrosternal group was higher conversely, which suggested that the patients gain a better status in global quality of life. CONCLUSION: Our results suggest that retrosternal route may be a good alternative choice for MIE in view of better HRQL after operation, although it has higher risk of anastomotic leak that might lead to worse HRQL in early period. PMID- 20857338 TI - Night-to-night repeatability of measurements of nocturnal breathing disorders in clinically stable chronic heart failure patients. AB - BACKGROUND: Portable sleep apnea monitors are often used to screen for sleep disordered breathing in chronic heart failure patients (CHF), but night-to-night repeatability of obtained measurements of nocturnal breathing disorders has not been fully assessed. METHODS: Fifty-six stable, moderate-to-severe CHF patients [male, 87%; age, 57 +/- 9 years; NYHA class, 2.6 +/- 0.6; left ventricular ejection fraction (LVEF), 32% +/- 9%] underwent an unattended in-hospital cardiorespiratory recording using a portable sleep apnea monitor during two consecutive nights. The apnea/hypopnea index (AHI), apnea index (AI), oxygen desaturation index (ODI), and periodic breathing (PB) duration were computed. Intra-subject night-to-night variability was assessed by the 95% limits of random variation (LoV). We also estimated the contribution of intra-rater variability to the overall intra-subject variability. Dichotomizing the AHI and PB duration according to conventional cutoffs of, respectively, >=5 events per hour, >=15 events per hour, and >=120 min, the percentage of patients concordantly classified by the two measurements was finally computed. RESULTS: The 95% LoV were +/-10.6, +/-7.7, +/-11.3 events per hour for AHI, AI and ODI, and +/-63.2 min for PB duration, respectively. The contribution of intra-rater variability to total intra-subject variability was 1.7%, 1.4%, 2.5%, and 1.3% for AHI, AI, ODI, and PB duration, respectively. Most patients (85%, 82%, and 95% for AHI >= 5, AHI >= 15, and PB duration, respectively) were classified concordantly by the two measurements. CONCLUSIONS: In patients with heart failure, measurements of severity of sleep-disordered breathing derived from portable sleep apnea monitors show significant night-to-night intra-subject variation with a negligible contribution from intra-rater variability; however, using the same measurements for classification purposes, as commonly performed in clinical practice to screen patients for sleep-disordered breathing, very stable results are obtained. PMID- 20857339 TI - Understanding equivalence and noninferiority testing. AB - Increasingly, the goal of many studies is to determine if new therapies have equivalent or noninferior efficacies to the ones currently in use. These studies are called equivalence/noninferiority studies, and the statistical methods for their analysis require only simple modifications to the traditional hypotheses testing framework. Nevertheless, important and subtle issues arise with the application of such methods. This article describes the concepts and statistical methods involved in testing equivalence/noninferiority. The aim is to enable the clinician to understand and critically assess the growing number of articles utilizing such methods. PMID- 20857340 TI - Patient-provider language concordance and colorectal cancer screening. AB - BACKGROUND AND OBJECTIVE: Patient-provider language barriers may play a role in health-care disparities, including obtaining colorectal cancer (CRC) screening. Professional interpreters and language-concordant providers may mitigate these disparities. DESIGN, SUBJECTS, AND MAIN MEASURES: We performed a retrospective cohort study of individuals age 50 years and older who were categorized as English-Concordant (spoke English at home, n = 21,594); Other Language-Concordant (did not speak English at home but someone at their provider's office spoke their language, n = 1,463); or Other Language-Discordant (did not speak English at home and no one at their provider's spoke their language, n = 240). Multivariate logistic regression assessed the association of language concordance with colorectal cancer screening. KEY RESULTS: Compared to English speakers, non English speakers had lower use of colorectal cancer screening (30.7% vs 50.8%; OR, 0.63; 95% CI, 0.51-0.76). Compared to the English-Concordant group, the Language-Discordant group had similar screening (adjusted OR, 0.84; 95% CI, 0.58 1.21), while the Language-Concordant group had lower screening (adjusted OR, 0.57; 95% CI, 0.46-0.71). CONCLUSIONS: Rates of CRC screening are lower in individuals who do not speak English at home compared to those who do. However, the Language-Discordant cohort had similar rates to those with English concordance, while the Language-Concordant cohort had lower rates of CRC screening. This may be due to unmeasured differences among the cohorts in patient, provider, and health care system characteristics. These results suggest that providers should especially promote the importance of CRC screening to non English speaking patients, but that language barriers do not fully account for CRC screening rate disparities in these populations. PMID- 20857341 TI - Chromium and manganese levels in biological samples of normal and night blindness children of age groups (3-7) and (8-12) years. AB - This study was designed to compare the levels of chromium (Cr) and manganese (Mn) in scalp hair, blood, and urine of night blindness in children age ranged (3-7) and (8-12) years of both genders, comparing them to sex- and age-matched controls. A microwave-assisted wet acid digestion procedure, was developed as a sample pretreatment, for the determination of Cr and Mn in biological samples of night blindness children. The proposed method was validated by using conventional wet digestion and certified reference samples of hair, blood and urine. The digests of all biological samples were analyzed for Cr and Mn by electrothermal atomic absorption spectrometry. The results indicated significantly higher levels of Cr, whilst low level of Mn in the biological samples (blood and scalp hair) of male and female night blindness children, compared with control subjects of both genders. These data present guidance to clinicians and other professional investigating deficiency of Mn and excessive level of Cr in biological samples (scalp hair and blood) of night blindness children. PMID- 20857342 TI - In situ solvent formation microextraction in the presence of ionic liquid for preconcentration and speciation of arsenic in saline samples and total arsenic in biological samples by electrothermal atomic absorption spectrometry. AB - In this modality, the extraction phase is formed in situ while simultaneously extracting analytes. First, a water-miscible ionic liquid (IL) ([Hmim][BF(4)]), capable of complete dissolving in the aqueous solution, was added to the sample. Then, an ion-exchange reagent (NaPF(6)) was added to obtain the hydrophobic IL ([Hmim][PF(6)]) that acted as the analyte extractant to form the cloudy homogeneous solution for the preconcentration and speciation of trace amounts of As (III) and As (V) with electrothermal atomic absorption spectrometry (ETAAS) detection. In situ solvent formation microextraction is a simple and rapid method for extraction and preconcentration of metal ions from sample solutions containing high concentration of salt. Some effective factors that influence the microextraction efficiency were investigated and optimized. Under the optimum experimental conditions, the limit of detection (3 sigma) and the enrichment factor were 6 ng L(-1) and 198, respectively. The obtained relative standard deviation was 4.78%. The proposed method was successfully applied for the determination of As (III) and As (V) in water samples, food salts, and total As in biological samples. PMID- 20857343 TI - The influence of oral magnesium sulfate on skin microvasculature blood flow in diabetic rats. AB - Microvascular disease is a major feature of type1 diabetes and results from long standing structural and functional changes especially in the skin microvasculature. Magnesium (Mg) deficiency has recently been proposed as a novel factor implicated in the pathogenesis of diabetes complications such as vascular disturbance, but its mechanism of action is not completely elucidated. The present study was designed to determine whether chronic magnesium sulfate administration could control streptozocin-induced diabetes and improve endothelium-dependent and endothelium-independent dilatation, and identify its probable mechanism in the skin microvasculature of diabetic rats. Fifty male Wistar rats (220 +/- 10 g) were divided into two diabetic and one control groups. One subgroup of diabetic received magnesium sulfate (10 g/l) in their drinking water, while two other groups had only tap water. Laser Doppler flow meter with iontophoresis was used to measure the relative changes in skin blood flow. We used acetylcholine (Ach), sodium nitroprusside (SNP), and N (w)-nitro-L-arginine (LNNA; NO synthase inhibitor) with magnesium sulfate (0.1 M) in control and experimental animal by microsyringe pump microinjection. SNP- and Ach-induced cutaneous perfusion increased significantly by Mg treatment in the diabetic groups, and local microinjection of magnesium sulfate (0.1 M) increased cutaneous blood flow in all groups (p < 0.01). However, the administration of LNNA prior to magnesium sulfate attenuated (p < 0.05) but not abolished the increase in cutaneous blood flow in diabetic and normal rats. From the results of this study, it may be concluded that Mg could improve skin microvasculature of diabetic rats with potentiation of nitric oxide pathway. PMID- 20857344 TI - Cortical 5HT 2A receptor function under hypoxia in neonatal rats: role of glucose, oxygen, and epinephrine resuscitation. AB - Neonatal hypoxia induces brain injury through alterations in neurotransmitters and its receptors. Molecular processes regulating serotonergic receptors play an important role in the control of respiration under hypoxia. The present study evaluates the serotonergic regulation of neonatal hypoxia and its resuscitation methods. Receptor binding assays and gene expression studies were done to evaluate the changes in 5HT(2A) receptors and its transporter in the cerebral cortex of hypoxic neonatal rats and hypoxic rats resuscitated with glucose, oxygen, and epinephrine. Hypoxic stress increased total 5HT and 5HT(2A) receptor number along with an upregulation of 5HT(2A) receptor and 5HT transporter gene in the cortex. The enhanced cortical 5HT(2A) receptors may act as a modulator of ventilatory response to hypoxia. These alterations were reversed to near control by glucose supplementation. Glucose supplementation helped in managing the serotonergic functional alterations. Hypoxia-induced adenosine triphosphate depletion causes a reduction in blood glucose levels which can be encountered by glucose administration, and oxygenation helps in overcoming the anaerobic condition. The adverse effect of immediate oxygenation and epinephrine supplementation was also reported. This has immense clinical significance in establishing a proper resuscitation for the management of neonatal hypoxia. PMID- 20857345 TI - RNA interference targeting mutant p53 inhibits growth and induces apoptosis in DU145 human prostate cancer cells. AB - p53 is the most frequently mutated tumor suppressor gene in human cancer. Recent studies have indicated that p53 mutants not only lose tumor suppression activity but also gain novel oncogenic functions that contribute to tumor malignancy. In this study, we explored mutant p53 as a target for novel anti-cancer treatment in prostate cancer. Using the DU145 human androgen-independent prostate cancer cell line, we show that silencing of mutant p53 gene by RNA interference led to significant inhibition of cell viability and growth, which was associated with cell cycle arrest at G1 and G2/M phase, and ultimately induced massive apoptosis. Mechanistically, p53-siRNA inhibited phosphatidylinositol 3'-kinase/Akt signaling pathway, which might be responsible for the reduced proliferation and apoptosis induction. These findings suggest that RNA interference targeting mutant p53 may serve as a novel therapeutic strategy for the treatment of androgen-independent prostate cancer. PMID- 20857346 TI - Predictors of mammography use in older women with disability: the patients' perspectives. AB - To determine the factors associated with mammography use among Medicare beneficiaries and reasons for nonuse. Cohort of 4610 community-dwelling Medicare beneficiaries >= 65 years included in the 2004-2005 Medicare Current Beneficiary Survey. Regression models evaluated the association of disability with mammography use. Reasons for underuse are described. Women with disability were more likely than women with no disability to report lower mammography use (unadjusted, moderate disability OR = 0.76; 95% CI = 0.64, 0.91; severe disability OR = 0.46; 95% CI = 0.40, 0.54). Lower use was significant for women with severe disability (adjusted, OR = 0.67; 95% CI = 0.54, 0.83) and women with fair-poor self-rated health, no HMO enrollment and >= 3 comorbidities. No physician recommendation, no need, dislike/pain during the test and forget it were reasons for underutilization. Mammography use decreases with increasing level of disability. Common reasons for underutilization are no physician recommendation, no need, dislike/pain during the test and forgot it. Screening guidelines should be used to target women with disabilities who can benefit from mammography. PMID- 20857347 TI - The bipolar spectrum: myth or reality? AB - The idea of a "bipolar spectrum" is controversial due to 1) lack of widely accepted definitions, 2) concern that spectrum definitions might subsume cases with non-bipolar disorders, 3) worry that "diagnostic creep" may lead practitioners to overdiagnose bipolar disorder in marginal cases, and 4) worry that more diagnosis of bipolar spectrum may increase aggressive pharmacotherapy. These concerns are weighed against theoretical and empiric evidence converging in support of the bipolar spectrum as having prognostic and prescriptive validity. Practitioners can use inexpensive and practical strategies to incorporate the spectrum concept into their work while minimizing risks of overdiagnosis or unnecessary medication exposure. PMID- 20857348 TI - Neurophysiologic markers of abnormal brain activity in schizophrenia. AB - Cortical electrophysiologic event-related potentials are multidimensional measures of information processing that are well-suited for efficiently parsing automatic and controlled components of cognition that span the range of deficits evidenced in schizophrenia patients. These information processes are key cognitive measures that are recognized as informative and valid targets for understanding the neurobiology of schizophrenia. These measures may be used in concert with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) neurocognitive measures in the development of novel treatments for schizophrenia and related neuropsychiatric disorders. The employment of novel event-related potential paradigms designed to carefully characterize the early spectrum of perceptual and cognitive information processing allows investigators to identify the neurophysiologic basis of cognitive dysfunction in schizophrenia and to examine the associated clinical and functional impairments. PMID- 20857350 TI - Study of polymorphs of progesterone by novel melt sonocrystallization technique: a technical note. AB - A large number of pharmaceuticals exhibit polymorphism; 23% steroids, 60% sulfonamides, and 70% of barbiturates have shown this property. In this study, we have investigated and compared a new technique termed as melt sonocrystallization (MSC) with melt and sonocrystallization (SC) for induction of polymorphism in progesterone (PRG). Polymorphs were characterized by DSC, XRD, FT-IR, and FT Raman spectroscopy. Melt sonocrystallized progesterone (MSC-PRG) contained both the polymorphs, more soluble form II along with less soluble form I, whereas melt progesterone (M-PRG) and sonocrystallized progesterone (SC-PRG) contained only form I. Improvement in dissolution characteristics of both the polymorphs were compared and form II was found to be more readily soluble than form I in deionized water. Reduction in mean particle size of PRG during SC was also determined using laser diffractometer. During stability testing (40 degrees C/75% RH) for 1 month, metastable form II of MSC-PRG was found to be transformed into its more stable state. MSC technique was thus found as a useful tool for induction of polymorphism. PMID- 20857349 TI - Denosumab for the treatment of osteoporosis. AB - Being a connective tissue, bone can increase or decrease its mass through the process of remodeling. Using a discovery in the mid-1980s-that tumor necrosis factor (TNF) could dramatically increase formation of osteoclasts (the cells that break down bone)-researchers at Amgen (Thousand Oaks, CA) discovered a TNF-like molecule that regulated bone resorption. Elevations in the expression of this molecule, receptor activator of nuclear factor-kappaB ligand (RANKL), can cause excessive bone destruction. A blocking antibody to RANKL named denosumab inhibits osteoclast formation and bone degradation. In a large multicenter clinical trial, known as the FREEDOM trial (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months), the effects of denosumab were tested in 60- to 90 year-old women over 3 years. Statistically significant reductions in fracture risk at the vertebral column, hip, and nonvertebral sites were associated with increases in bone mineral density (BMD) and reciprocal decreases in markers of bone resorption. However, the FREEDOM trial did not test the most beneficial use of a resorption blocking drug-to target the rapid bone loss that occurs in late perimenopause and early postmenopause. One adverse effect from denosumab is cellulitis, and research in animals suggests that RANKL/RANK interaction is needed for Langerhans cell (LC) survival in the skin. Further mechanistic and clinical studies on the role of RANKL in the skin are needed. PMID- 20857351 TI - Dysinnervated but viable myocardium in ischemic heart disease. PMID- 20857353 TI - The expanding world of small molecule microarrays. AB - Speed and throughput are vital ingredients for discovery-driven, "-omics" research. The small molecule microarray is one such platform, which delivers phenomenal screening throughput and capabilities. The concept at the heart of the technology is elegant, yet simple: by presenting large collections of molecules at a high density on a flat surface, one is able to interrogate them quickly and conveniently, evaluating all possible interactions in a single step. SMMs have, over the last decade, been established as a robust platform for screening, lead discovery, and molecular characterization. In this chapter, we describe the ways in which microarrays have been constructed and applied, focusing on the practical challenges faced when designing and performing SMM experiments. This is written as an introduction for new readers to the field, explaining the key principles and laying the foundation for the chapters that follow. PMID- 20857352 TI - Consumer beware: a systematic assessment of potential bias in the lay electronic media to examine the portrayal of "PARP" inhibitors for cancer treatment. AB - This study examined how the lay electronic media covers poly-ADP-ribose polymerase, or "PARP," inhibitors, a class of cancer agents currently under clinical investigation. Of 771 internet links, 51 targeted the lay public. Independent review by two investigators yielded the following categorizations: 36 (71%) were "overly positive", 15 (29%) "neutral", and none "overly negative". "Overly positive" articles used: (l) overstated benefit, (2) included quotations from enthusiastic scientists, and (3) discussed single or small patient subsets. They used such phrases as "the holy grail of cancer research", "the most exciting development in cancer research in a decade or more.... it could save thousands of lives", and "we were surprised and delighted.... it's the kind of thing you don't really think will happen". Healthcare providers should be aware of the foregoing when discussing PARP inhibitors-and perhaps other novel therapies-with cancer patients. PMID- 20857354 TI - Construction of photo-cross-linked microarrays of small molecules. AB - Small molecule microarrays are one of the most promising approaches to screen ligand molecules for individual proteins of interest. However, their potential has not been fully realized due to the limited number of methods to introduce small molecules onto the solid surfaces. To expand the compatibility of small molecule microarrays, we have developed a unique photo-cross-linking approach for immobilizing various small molecules, including natural products, on glass slides. PMID- 20857355 TI - Small molecule microarray: functional-group specific immobilization of small molecules. AB - Proteomic screening with small molecule microarrays can be a powerful tool in conjunction with various forward chemical genetics screening and high-throughput phenotype assays. Small molecule microarray screening can provide high quality information from the direct binding interaction between proteins of interest and a collection of small molecules in a high-throughput fashion. To realize this potential of small molecule microarray in the postgenomic era, the immobilization of small molecules on the surface of microscope glass slides has been a critical step, to apply small molecule library in protein screening assays and dissecting the protein network. In this chapter, we would like to focus on the protocol for the systematic immobilization of synthetic drug-like small molecules containing either specific functional handles or common functional groups. PMID- 20857357 TI - A method for small molecule microarray-based screening for the rapid discovery of affinity-based probes. AB - We describe herein a new method for the high-throughput identification of affinity-based probes (AfBPs) using a small molecule microarray (SMM) approach. A hydroxylethylene-based small molecule library was first generated by solid-phase combinatorial synthesis. The library was tagged with biotin to facilitate immobilization on avidin-coated slides. Preliminary screening with gamma secretase (both the recombinantly purified protein as well as cellular lysates overexpressing the enzyme) was carried out, in order to identify potential small molecule binders, which were subsequently redesigned into AfBPs. Several specific and potent probes for gamma-secretase were thus identified through the binding profiles observed on the SMMs. The SMM platform was able to sensitively and conveniently report activity-based binding interactions between aspartic proteases and their small molecule inhibitors. This new approach thus provides a potentially more rapid and efficient method for developing AfBPs using SMMs. PMID- 20857356 TI - Detecting protein-small molecule interactions using fluorous small-molecule microarrays. AB - General binding assays involving microarrays of small molecules can be used to identify small molecule ligands for nearly any protein, even in the absence of knowledge about protein structure or function. Several suitable methods for manufacturing small molecule microarrays (SMMs) exist and different immobilization methods may be more or less preferable for any given application. Here, we describe a protocol for noncovalent and homogenous capture of small molecules using fluorous interactions between small molecules containing fluorocarbon tags and fluorocarbon-coated glass surfaces. These arrays are especially useful for applications that require display of compounds in a specific orientation such as screening biased libraries. PMID- 20857358 TI - Nanodroplet chemical microarrays and label-free assays. AB - The microarraying of chemicals or biomolecules on a glass surface allows for dense storage and miniaturized screening experiments and can be deployed in chemical-biology research or drug discovery. Microarraying allows the production of scores of replicate slides. Small molecule libraries are typically stored as 10 mM DMSO stock solutions, whereas libraries of biomolecules are typically stored in high percentages of glycerol. Thus, a method is required to print such libraries on microarrays, and then assay them against biological targets. By printing either small molecule libraries or biomolecule libraries in an aqueous solvent containing glycerol, each adherent nanodroplet remains fixed at a position on the microarray by surface tension without the use of wells, without evaporating, and without the need for chemically linking the compound to the surface. Importantly, glycerol is a high boiling point solvent that is fully miscible with DMSO and water and has the additional property of stabilizing various enzymes. The nanoliter volume of the droplet forms the reaction compartment once additional reagents are metered onto the microarray, either by aerosol spray deposition or by addressable acoustic dispensing. Incubation of the nanodroplet microarray in a high humidity environment controls the final water content of the reaction. This platform has been validated for fluorescent HTS assays of protease and kinases as well as for fluorogenic substrate profiling of proteases. Label-free HTS is also possible by running nanoliter HTS reactions on a MALDI target for mass spectrometry (MS) analysis without the need for desalting of the samples. A method is described for running nanoliter-scale multicomponent homogeneous reactions followed by label-free MALDI MS spectrometry analysis of the reactions. PMID- 20857359 TI - Nanodroplet microarrays for high-throughput enzyme screening. AB - We describe here a method for the continuous assessment of enzymatic activity using microarrays. By uniformly coating fluorogenic substrates on slides, we generated surfaces capable of detecting enzymatic activity. The enzymes were deposited on the arrays in segregated droplets using standard microarrayers. Surfaces were developed for assessing the activities of both proteases and phosphatases, hence capitalizing on microarray technology to perform miniaturized high-throughput screens for these, as well as potentially any other, classes of enzyme. This offers an unprecedented ability for performing solution-phase enzymatic assays in nanoliter volumes on microarrays, in contrast to microliter volumes typically required in microplate-based assays, thereby reducing the amounts of reagent(s) required by anywhere from a hundred to a thousand-fold. This new approach thus provides a potentially more cost-effective, label-free enzyme screening technique. A single slide is able to accommodate several thousand assays, facilitating the assessment of both dose and time-dependent inhibition parameters in a single run. PMID- 20857360 TI - The application of the chemical array for biological study. AB - The identification of specific interactions between small molecules and human proteins of interest is a fundamental step in chemical biology and drug development. The small molecules that bind to specific proteins can be used as tools to study the functions of proteins and biological processes in cells. We have developed an efficient method to obtain novel binding ligands of human proteins by a chemical array approach. Our method includes the use of cell lysates that express proteins of interest fused with red fluorescent protein (RFP) and high-throughput screening by merged display analysis, which removes false positive signals from array experiments. To demonstrate large-scale ligand screening for various human proteins of interest, the gene library GLORIA (Gene Library of Osada Laboratory at RIKEN for chemical array analysis) has been established. Using the systematic platform, we detected novel inhibitors of carbonic anhydrase II. We also have shown that this screening method is useful not merely for ligand screening of proteins of interest, but also for gaining insight into structure-affinity relationships (SARs) and for studies of "fragment based approach."Traditional fragment-based ligand discoveries have been demonstrated by using several technologies, such as NMR spectroscopy and X-ray crystallography and mass spectrometry. We present initial studies of fragment based approach to binding assay by using the chemical array format. PMID- 20857361 TI - Peptide arrays with a chip. AB - Today, lithographic methods enable combinatorial synthesis of >50,000 oligonucleotides per cm(2), an advance that has revolutionized the whole field of genomics. A similar development is expected for the field of proteomics, provided that affordable, very high-density peptide arrays are available. However, peptide arrays lag behind oligonucleotide arrays. This is mainly due to the monomer-by monomer repeated consecutive coupling of 20 different amino acids associated with lithography, which adds up to an excessive number of coupling cycles. A combinatorial synthesis based on electrically charged solid amino acid particles resolves this problem. A computer chip consecutively addresses the different charged particles to a solid support, where, when completed, the whole layer of solid amino acid particles is melted at once. This frees hitherto immobilized amino acids to couple all 20 different amino acids in one single coupling reaction to the support. The method should allow for the translation of entire genomes into a set of overlapping peptides to be used in proteome research. PMID- 20857362 TI - In situ chemical modification of peptide microarrays: characterization by desorption/ionization on silicon nanowires. AB - Peptide microarrays are useful devices for the high throughput study of biomolecular or peptide-cell interactions. Whereas the synthesis of unmodified peptide libraries is an easy task and can be performed at reasonable cost, the synthesis of libraries of modified peptides remains expensive and time consuming. This bottleneck led us to examine the possibility to produce modified peptide microspots by in situ chemical modification of unmodified peptide microspots. The great advantage would be the preparation of a series of complex microarrays (daughter microarrays) starting from an easy-to-make and cost-effective unmodified peptide microarray (parent microarray). One step toward this goal has been presented in the accompanying chapter dealing with the in situ methylation methodology for studying the specificity of antibodies directed toward methylated epitopes. Here we describe the development of a novel desorption/ionization on silicon nanowires mass spectrometry (DIOSiNWs-MS) technique for characterizing the in situ chemical modification of peptides. PMID- 20857363 TI - In situ chemical modification of peptide microarrays: application to the study of the antibody responses to methylated antigens. AB - Peptide microarrays are useful tools for characterizing the humoral response against methylated antigens. They are usually prepared by printing unmodified and methylated peptides on substrates such as functionalized microscope glass slides. The preferential capture of antibodies by methylated peptides suggests the specific recognition of methylated epitopes. However, unmodified peptide epitopes can be masked due to their interaction with the substrate. The accessibility of unmodified peptides and thus the specificity of the recognition of methylated peptide epitopes can be probed using the in situ methylation procedure described here. Alternately, the in situ methylation of peptide microarrays allows probing the presence of antibodies directed toward methylated epitopes starting from easy to-make and cost-effective unmodified peptide libraries. In situ methylation was performed using formaldehyde in the presence of sodium cyanoborohydride and nickel chloride. This chemical procedure converts lysine residues into mono- or dimethyl lysines. PMID- 20857364 TI - Peptide microarrays on coated silicon slides for highly sensitive antibody detection. AB - Peptides, with their well-established chemistry and fully automated synthesis, provide an invaluable tool for the screening of protein ligands, for epitope mapping, and for antibody diagnostics on the microarray format.The method described in this chapter shows that the sensitivity of a peptide-based microimmunoassay is greatly improved by using a new, specifically developed substrate made of silicon coated by an optimized layer of silicon oxide. A set of six peptides corresponding to the sequences of human and rat acetylcholine receptor subunits was immobilized on glass and silicon slides coated by a copolymer of N,N-dimethylacrylamide, N-acryloyloxysuccinimide, and 3 (trimethoxysilyl) propyl methacrylate, copoly(DMA-NAS-MAPS). The spotted probes were incubated with rabbit anti-sera and with purified antibodies raised against the corresponding peptides. The coated silicon slides, in comparison against the glass substrates, showed a five- to tenfold enhancement of the fluorescence signals, leading to the specific detection of the full set of antibodies down to a concentration of 0.5-1 ng/mL in serum. The sensitivity provided by the test allows its use for the diagnosis of antibodies in clinical samples. PMID- 20857365 TI - Antibody signatures defined by high-content peptide microarray analysis. AB - Circulating antibodies are highly selective binding reagents directed to a vast repertoire of antigens. Candidate antigens displayed as overlapping peptides on microarrays can be used to screen for recognition by serum antibodies from clinically well-defined patient populations. The methodology is robust and enables unbiased visualization of antigen-specific B-cell responses. Additionally, autoantibody signatures of diagnostic value could be detected using microarrays displaying thousands of human peptides. PMID- 20857366 TI - High density peptide microarrays for proteome-wide fingerprinting of kinase activities in cell lysates. AB - Protein function is highly regulated in pathways that are responsible for complex biochemical mechanisms such as growth, metabolism, and signal transduction. One of the most important mechanisms is posttranslational modification (PTM) changing protein surfaces by phosphorylation, sulfation, acetylation, methylation, glycosylation, and sumoylation resulting in a more than 100-fold higher complexity (Geiss-Friedlander and Melchior, Nat Rev Mol Cell Biol 8, 947-956, 2007; Hunter, Mol Cell 28, 730-738, 2007). This chapter presents a very efficient way to detect potential phosphorylation sites in protein families using overlapping peptides covering the complete primary structures (peptide scans) immobilized on glass slides. Results of kinase activity fingerprinting of cell lysates using peptide microarrays displaying peptide scans through all human peptidyl-prolyl-cis/trans-isomerases are shown. PMID- 20857367 TI - A peptide microarray for detecting protein kinase activity in cell lysates. AB - Protein kinases (PKs) are widely recognized as valuable targets for disease diagnosis and drug discovery. For this reason, we have developed a sensitive peptide microarray for detecting intracellular PK activity. Peptides are immobilized on a glutaraldehyde-premodified high-amino terminal glass slide, by spotting 2 nL volumes of substrate peptide solutions with an automated microarray spotter. After the peptides are phosphorylated by cell lysates, phosphorylation is specifically recognized by a fluorescence-labeled antiphosphotyrosine antibody for tyrosine kinases, or Phos-tag biotin (a biotinylated phosphate-specific ligand based on Zn(2+) complex), which is subsequently bound with fluorescence labeled streptavidin, for serine/threonine kinases. The fluorescence signal is then detected by an automatic microarray scanner. The peptide microarray system involves simple peptide immobilization, requires low sample volumes and provides a high density array. Importantly, it provides high sensitivity for detecting PK activities in cell lysates. Thus, the peptide microarray system is expected to be useful for a high-throughput kinase assay to investigate intracellular kinase activity and has potential applications in disease diagnosis and drug discovery. PMID- 20857368 TI - Chemical microarrays constructed by selective attachment of hydrazide-conjugated substances to epoxide surfaces and their applications. AB - Microarray technology has received considerable attention for rapid analysis of biomolecular interactions and high-throughput screening to identify binding partners. An efficient and selective immobilization technique of substances on the surface is essential for successful construction of microarrays. Although a variety of immobilization methods have been exploited to prepare microarrays over the past decade, a superior technique needs to be developed for diverse applications. Recently, an efficient and simple method that relies on selective reactions between the hydrazide conjugated to substances and the epoxide derivatized on the solid surface was developed to fabricate chemical microarrays. Reactions between hydrazides with epoxides are highly selective in that they take place even in the presence of other potent nucleophiles such as amines and thiols. This technique is utilized to immobilize various substances such as small molecules, carbohydrates, and peptides to glass surfaces. The microarrays constructed by this immobilization method are used to evaluate protein binding to carbohydrates, peptides, and small molecules. In addition, the microarrays are also employed to determine binding affinities between proteins and binding partners as well as profiling of enzyme activities. PMID- 20857369 TI - A microarray-based method to perform nucleic acid selections. AB - This method describes a microarray-based platform to perform nucleic acid selections. Chemical ligands to which a nucleic acid binder is desired are immobilized onto an agarose microarray surface; the array is then incubated with an RNA library. Bound RNA library members are harvested directly from the array surface via gel excision at the position on the array where a ligand was immobilized. The RNA is then amplified via RT-PCR, cloned, and sequenced. This method has the following advantages over traditional resin-based Systematic Evolution of Ligands by Exponential Enrichment (SELEX): (1) multiple selections can be completed in parallel on a single microarray surface; (2) kinetic biases in the selections are mitigated since all RNA binders are harvested from an array via gel excision; (3) the amount of chemical ligand needed to perform a selection is minimized; (4) selections do not require expensive resins or equipment; and (5) the matrix used for selections is inexpensive and easy to prepare. Although this protocol was demonstrated for RNA selections, it should be applicable for any nucleic acid selection. PMID- 20857370 TI - [Influence of floor disinfection on microbial and particulate burden measured under low turbulance air flow in ophthalmological operation theatres]. AB - AIM: The necessity for routine disinfection of floors between two surgical procedures or disinfection only after visible contamination was assessed in two identical ophthalmological operating theatres equipped with laminar air flow ventilation. METHOD: Over a period of four weeks, one of the two tested operating rooms was disinfected after every surgical procedure, and the other only in the case of visible contamination. This regimen was inverted every week. To compare the air quality, particle count and total bacteria count were measured inside and outside the laminar air flow. Additionally, bacteria count was measured in the operating field, consisting of the operating table and the instrument tray. Patients were monitored for surgical site infection over a period of one year after operation. RESULTS: No difference in particle count or number of viable bacteria was found between the two investigated procedures. Also, no wound infections were observed after one year of surveillance for surgical site infection. CONCLUSION: It appears that frequent cleaning disinfection of floors is not necessary if a laminar air flow ventilation system is installed. Under these conditions, targeted disinfection of visibly soiled surfaces appears to be sufficient. Generally, the duration of surgical procedures should be kept as short as possible. PMID- 20857371 TI - Use of surface acoustic waves to reduce pain and discomfort related to indwelling nasogastric tube. AB - BACKGROUND AND STUDY AIMS: Nasogastric intubation, one of the most widely utilized therapeutic procedures in medical practice, is associated with trauma, pain, and discomfort, which can occur both at insertion and during the indwelling phase. Although lubricating jelly is useful during the insertion phase, insertion can still cause great discomfort. Furthermore, the jelly is rapidly absorbed and therefore is unable to decrease the friction between the tissues and the tube during the indwelling phase of the nasogastric tube. The aim of this study was to test a device, the NG-Shield, that generates surface acoustic waves on the surfaces of the nasogastric tube to reduce contact time and thus friction between the nasogastric tube and body tissues. PATIENT AND METHODS: Twenty-four healthy volunteers were enrolled in a single-center, crossover, blinded study, in which a nasogastric tube was inserted and left indwelling for 6 hours. Throughout the indwelling period the device was activated and deactivated alternately every hour, and the volunteers were questioned every hour about their pain and discomfort levels as well as grading pain and discomfort upon insertion and removal of the nasogastric tube. Pain and discomfort levels were compared between active and nonactive phases of the device. RESULTS: The activated NG-Shield was found to reduce both pain and discomfort significantly in both the nose and throat throughout the indwelling phase. CONCLUSIONS: The NG-Shield is a safe and effective device for reducing pain and discomfort associated with an indwelling nasogastric tube. PMID- 20857372 TI - Endoscopic radiofrequency ablation for Barrett's esophagus: 5-year outcomes from a prospective multicenter trial. AB - BACKGROUND AND STUDY AIMS: The AIM-II Trial included patients with nondysplastic Barrett's esophagus (NDBE) treated with radiofrequency ablation (RFA). Complete eradication of NDBE (complete response-intestinal metaplasia [CR-IM]) was achieved in 98.4 % of patients at 2.5 years. We report the proportion of patients demonstrating CR-IM at 5-year follow-up. PATIENTS AND METHODS: Prospective, multicenter US trial (NCT00489268). After endoscopic RFA of NDBE up to 6 cm, patients with CR-IM at 2.5 years were eligible for longer-term follow-up. At 5 years, we obtained four-quadrant biopsies from every 1 cm of the original extent of Barrett's esophagus. All specimens were reviewed by one expert gastrointestinal pathologist, followed by focal RFA and repeat biopsy if NDBE was identified. Primary outcomes were (i) proportion of patients demonstrating CR-IM at 5-year biopsy, and (ii) proportion of patients demonstrating CR-IM at 5-year biopsy or after the single-session focal RFA. RESULTS: Of 60 eligible patients, 50 consented to participate. Of 1473 esophageal specimens obtained at 5 years 85 % contained lamina propria or deeper tissue (per patient, mean 30 , standard deviation [SD] 13). CR-IM was demonstrated in 92 % (46 / 50) of patients, while 8 % (4 / 50) had focal NDBE; focal RFA converted all these to CR-IM. There were no buried glands, dysplasia, strictures, or serious adverse events. Kaplan-Meier CR IM survival analysis showed probability of maintaining CR-IM for at least 4 years after first durable CR-IM was 0.91 (95 % confidence interval [CI] 0.77 - 0.97) and mean duration of CR-IM was 4.22 years (standard error [SE] 0.12). CONCLUSIONS: In patients with NDBE treated with RFA, CR-IM was demonstrated in the majority of patients (92 %) at 5-year follow-up, biopsy depth was adequate to detect recurrence, and all failures (4 / 4, 100 %) were converted to CR-IM with single-session focal RFA. PMID- 20857373 TI - Volume changes of corpus striatum, thalamus, hippocampus and lateral ventricles in posttraumatic stress disorder (PTSD) patients suffering from headaches and without therapy. AB - BACKGROUND AND AIM: In the present study, we have hypothesized that volume changes of the caudate nucleus, putamen, globus pallidus, hippocampus, thalamus, and lateral ventricle in newly-diagnosed, male PTSD patients without therapy are more pronounced in those with headaches. To confirm or reject our hypothesis, we have undertaken an extensive study of forty-nine PTSD patients. PATIENTS AND METHODS: To confirm or reject our hypothesis, we have undertaken an extensive study of forty-nine PTSD male patients that underwent MRI scanning immediately upon admittance for the treatment. Based on headache frequency, they were classified into three groups: group 1 included patients with headaches at least twice a week; group 2 consisted of patients with headaches less than twice a week; and group 3 consisted of patients without headaches. All MRI scans underwent software-based volume compute and statistical processing. RESULTS: 39 out of 49 patients with PTSD suffered from headaches. Bilaterally, volume decreases were noted in groups 1 and 2 compared to group 3 for the caudate nucleus, putamen, hippocampus and lateral ventricle. Differences in globus pallidus and thalamus among groups appeared to be insignificant. CONCLUSION: The present study revealed a bilateral volume decrease of the caudate nucleus, putamen and hippocampus in PTSD male subjects without therapy. Intensity of volume alterations correlated with Hamilton's depression rating score; regression analysis uncovered correlated changes in the caudate nucleus, putamen and hippocampus, and an inverse correlation with the volume of the lateral ventricle in the PTSD patients. PMID- 20857374 TI - [Tracheostomy in the intensive care unit]. AB - Indication, timing and technique of tracheostomy have undergone considerable changes during the past years. Percutaneous tracheostomy has become a standard procedure in modern intensive care. It can be performed by the intensive medicine specialists themselves with low complication rates. Advantages are less stomal infections, better cosmetic results and cost savings in comparison to the surgical technique. Exact knowledge of the anatomic details, careful attention to contraindications and bronchoscopic supervision throughout the procedure are essential for optimal results. Exchange of the tracheostomy tube requires adequate preparation and training. If contraindications exist or permanent mechanical ventilation can be anticipated, surgical tracheostomy is indicated. The optimal timing of tracheostomy remains controversial. PMID- 20857375 TI - Early embryonic lethality in gene trap mice with disruption of the Arfgef2 gene. AB - The switching of ADP-ribosylation factors from the inactive form to the active form is catalyzed by ARF-GEF (ADP ribosylation factor--guanine nucleotide exchange protein) proteins containing a Sec7 domain. The murine Arfgef2 gene encoding the BIG2 protein belongs to the class of high molecular mass (>100 kDa) ARF-GEF proteins. BIG2 is believed to be associated with the trans-Golgi network and the recycling endosomes. In humans, mutations in the ARFGEF2 gene cause autosomal recessive periventricular heterotopia with microcephaly. To elucidate the function of BIG2 in mouse we studied a gene-trap mouse line with a functional disruption of the Arfgef2 gene. Heterozygous mutants did not reveal phenotypic abnormalities and were fertile. However, no homozygous embryos were obtained from breeding heterozygous females and males. To explore the reason for embryonic lethality, we analysed the pattern of expression of Arfgef2. Arfgef2 transcripts were detected in several adult tissues. Interestingly, Arfgef2 undergoes alternative splicing and the splicing pattern differs among tissues from adult animals. Moreover, the LacZ reporter gene of the gene-trap construct was used to reveal the expression of Arfgef2 during embryonic development. Here, we show that Arfgef2 mRNA is stored in the oocyte and is likely translated during the first embryonic divisions. SNP (Single Nucleotide Polymorphism) markers were used to demonstrate that the embryonic Arfgef2 gene is activated first at the 4-cell stage, suggesting an important role for embryonic development. This assumption is supported by the failure of Arfgef2-deficient oocytes fertilized with Arfgef2 deficient sperm to develop into 4-cell stage embryos. Our results indicate that murine BIG2 is essential for early embryonic development. PMID- 20857376 TI - Neurogenic differentiation of human conjunctiva mesenchymal stem cells on a nanofibrous scaffold. AB - The selection of a good quality scaffold is an essential strategy for tissue engineering. Ideally, the scaffold should be a functional and structural biomimetic of the native extracellular matrix and support multiple tissue morphogenesis. However, investigators have previously shown that three dimensional nanofibrous scaffolds are capable of influencing cellular behavior. In this study, we experimented with a three-dimensional nanofibrous scaffold fabricated from aligned-poly L-lactic acid (PLLA) for its ability to support neurogenic and hinder dopaminergic differentiation of conjunctiva mesenchymal stem cells (CJMSCs) in vitro. In this work, CJMSCs were seeded onto nanofibrous scaffolds, and were induced to differentiate along neurogenic lineages by culturing in specific differentiation media. Scanning electron microscopy imaging, RT-PCR and immunocytochemistry were used to analyze cultivated CJMSCs on scaffold and their expression of neurogenic-specific markers. We found a lack of expression of dopaminergic genes in CJMSCs seeded on align PLLA scaffold, while neurocyte-cell markers including Nestin, NSE, MAP-2 and beta-Tubulin III were expressed in these cells. On the basis of these experimental results, we conclude that the nanofibrous PLLA scaffold reported herein could be used as a potential cell carrier in neural tissue engineering and that these scaffolds could be useful for the partial inhibition of the dopaminergic differentiation of CJMSCs. PMID- 20857377 TI - Preliminary report of transfrontier disease surveillance in free-ranging buffalo in the Caprivi Strip, Namibia. AB - A capture operation to ascertain the health status of free-ranging buffalo (Syncerus caffer) from six areas in the Caprivi Strip in the north-east corner of Namibia is described. In-depth reports on buffalo capture operations and their cost, with detailed descriptions of diseases for research purposes, sampling techniques, field processing of samples and laboratory-related costs are still lacking in the literature. This paper describes materials, methods and the related costs of a disease surveillance operation conducted among buffalo in Namibia. The survey attempted to provide information designed to improve the control of infectious diseases in the Caprivi Strip, a key area bordering Angola, Zambia, Botswana and Zimbabwe. PMID- 20857378 TI - Prevalence of bacteria and parasites in White Ibis in Egypt. AB - A field survey was conducted to evaluate the prevalence of bacterial infections among free-living White Ibis (Nipponia nippon) in which 92 bacterial isolates were recovered from 193 different internal organs of 55 apparently healthy Ibis. Escherichia coli and Salmonella spp. were isolated at rates of 43.6% and 14.5%, respectively. The other bacterial pathogens isolated were Shigella spp. (34.5%), Enterobacter spp. (21.8%) Citrobacter spp. (18.1%), Klebsiella pneumonia (16.3), Staphylococcus aureus (10.9%) and Proteus mirabilis (7.2%). The antibiogram indicated that all isolates were highly sensitive to ciprofloxacin, enrofloxacin, trimethoprim and penicillin. Penicillin was most effective against S. aureus. An examination of the gastrointestinal tract revealed the presence of a nematode, Ascaris (Porroceacum ensicaudatum), and three trematodes (Echinochasmus perfoliatus, Apatemon aracilis and Patagifer bilobus). Other trematodes were detected in enlarged gall bladder and kidney lesions. Histopathological examination showed signs of hepatitis. The gall bladder had cholangitis, cholicystitis which may have been caused by trematode infestation. The kidneys also showed multiple parasitic cysts of trematodes and non-suppurative interstitial nephritis. This study suggests the possible role of the White Ibis, when living near poultry populations, in transmitting certain pathogens to poultry. PMID- 20857379 TI - The egg consumption of the average household in Italy. AB - A survey was conducted over a one-year period by means of telephone interviews with 7 991 Italian households to establish the domestic consumption of eggs, the distribution by source of supply, seasonal variations and storage and preparation methods used. Eggs are mainly purchased from large retailers (53%), followed by small retailers (25.2%), direct purchase from producers (16%), and local or itinerant markets (5.8%). It was found that 69.9% of households buy packaged eggs; 92% of households store them in the refrigerator, although this percentage varies considerably, according to the type of presentation (packaged or loose) and the number of eggs bought. Italian households mainly eat eggs cooked (48.9%), followed by partly cooked (35.0%) and raw (16.1%). PMID- 20857380 TI - Evaluation of peste des petits ruminants cell culture vaccine in sheep and goats in Pakistan. AB - The authors study the antibody response of a locally prepared live-attenuated peste des petits ruminants (PPR) cell culture vaccine in sheep and goats. Antibodies were measured using the competitive enzyme-linked immunosorbent assay. The vaccine was found to be safe and produced high serological titres within 21 days post vaccination. The serological titres remained high for one year post vaccination. PMID- 20857381 TI - Koch's postulate of Arcanobacterium pyogenes and its immunogenicity in local and imported Saanen goats. AB - The aim of this survey was to study Koch's postulate of Arcanobacterium pyogenes recovered from the necrotic lung of a kid and to compare the immunogenicity of this isolate in local and imported Saanen goats. The disease was successfully reproduced in intrathoracically challenged hamsters which showed lung congestion and liver abscesses, while hamsters that were intraperitoneally challenged showed only the formation of intestinal abscesses. The percentage of histopathologic legions in 12 observed microscopic fields per lung of three groups of hamsters (unchallenged controls, challenged intrathoracically and challenged intraperitoneally) showed a significant increase in lung necrosis of the intrathoracically challenged group, followed by intraperitoneally challenged hamsters, in comparison to unchallenged controls (p<0.05). In addition, the frequency of mucus accumulation in alveolar ducts followed the same respective pattern (p>0.05), while there was no significant difference in the frequency of neutrophil infiltration (p>0.05). The isolate was successfully recovered from the lungs and livers of hamsters challenged by both routes. Saanen does showed significant seroconversion using the indirect haemagglutination (HA) test and slide agglutination test (SAT) and at three weeks following priming and boosting with A. pyogenes antigens (p<0.05); however, only SAT showed significant seroconversion in local does at three weeks post booster (p<0.05). The possible causes and impact of the greater immunogenicity to A. pyogenes antigens in Saanen goats compared to local does are discussed. PMID- 20857382 TI - Effect of ferrous sulphate on haematological, biochemical and immunological parameters in neonatal calves. AB - The effect of oral administration of iron on haematological, biochemical and immunological parameters in neonatal calves was studied. Ten calves from a private farm in Gharbia Governorate were used. Calves were separated from their dams immediately after birth and received colostrum during the first hours after calving and twice daily for 48 h. Thereafter, they received whole milk. Calves were divided into two equal groups. The first group was kept as controls. Calves of the second group were given ferrous sulphate at a dose of 250 mg/calf daily, beginning at one day of age; this was continued for 28 days. Three blood samples were collected from each calf in all groups at 14, 21, 28 and 35 days of age. Iron administration produced a significant increase in red blood cell count, haemoglobin, packed cell volume and blood indices, in addition to non-significant changes in total and differential leukocyte counts. The administration of iron resulted in a significant increase in serum iron, total proteins, globulins, thyroid hormones, lymphocyte stimulation index, phagocytosis, body weight and body gain. The administration of iron is suggested as routine practice in calf producing farms due to its advantageous effects on the parameters tested. PMID- 20857383 TI - Detection of antibodies specific to Campylobacter fetus subsp. venerealis in the vaginal mucus of Nigerian breeding cows. AB - The presence of bovine venereal campylobacteriosis in the Lake Chad Basin of Nigeria was investigated using an enzyme-linked immunosorbent assay (ELISA) for the detection of IgA antibodies specific to Campylobacter fetus subsp. venerealis in vaginal mucus (n = 66). IgA antibodies specific to C. fetus subsp. venerealis were detected in 7 (11%) vaginal mucus samples. All but one of the IgA-positive samples originated from cows belonging to herds with a history of abortion and infertility which suggested an association between antibody detection and poor herd fertility. It was concluded that bovine venereal campylobacteriosis is prevalent in the Lake Chad Basin of Nigeria and its contribution to reduced reproductive performance in cattle herds may be grossly underestimated in this part of the world. PMID- 20857384 TI - Effects on some immunological traits after crossing three rabbit breeds in Egypt. AB - The authors evaluate the effect of crossing three purebred rabbit breeds in a complete 3 * 3 diallel crossbreeding experiment (New Zealand White, V-line and Gabali) on certain immunological traits, including IgG titre. Sheep red blood cells (SRBCs) were administered at 8 weeks of age and boosted at 10 weeks of age. V-line/Gabali crossbreeds gave the highest significant (p<0.05) level of serum total protein at 8 and 12 weeks of age (4.71 and 7.70 g/dl, respectively). Its reciprocal crossbreed Gabali/V-line resulted in the highest estimate of serum globulin at 8 weeks of age (2.07 g/dl). V-line/Gabali crossbreeds showed the highest positive heterosis percentage (H%) of total protein, albumin and globulin at 8 weeks of age (27.98, 30.28 and 25.00, respectively). However, its reciprocal crossbreeds, Gabali/V-line, revealed negative estimates for total protein and albumin at the same age (-4.07 and -29.80). V-line/Gabali crossbreeds gave the highest titre (3.167) and positive H% (0.69) of IgG to the second dose of SRBCs. On the contrary, the highest negative estimate to the second dose was recorded in Gabali/New Zealand White crossbreeds (-2.49). Using the Gabali breed as the female line gave superior results for most immunological parameters. PMID- 20857385 TI - Monitoring of ichthyic fauna in artificial reefs along the Adriatic coast of the Abruzzi Region of Italy. AB - With the support of European Community funds, three submerged artificial reefs composed of concrete cubes, bell-shaped modules and natural rocks were deployed along the Adriatic coast of the Abruzzi Region to increase the fish population and to prevent illegal trawling. The Provincial governments of Teramo and Pescara requested the Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' to monitor nectobenthic populations. Three sampling operations were conducted each year for each artificial reef. The authors present the results of a study conducted between 2005 and 2007, comparing the catches from the artificial reefs with those from the control sites using several diversity indexes. Artificial reef areas revealed greater species diversity and richness than the control sites. This study demonstrates the value of artificial reefs in response to the problem of low income, non-commercial fisheries as well as to the issue of over-exploitation of halieutic resources. In addition, the authors suggest that artificial reefs may be capable of activating habitat diversification processes that will increase biodiversity. PMID- 20857386 TI - Monitoring of herbal mixtures potentially containing synthetic cannabinoids as psychoactive compounds. AB - Herbal mixtures like 'Spice' with potentially bioactive ingredients were available in many European countries since 2004 and are still widely used as a substitute for cannabis, although merchandized as 'herbal incense'. After gaining a high degree of popularity in 2008, big quantities of these drugs were sold. In December 2008, synthetic cannabinoids were identified in the mixtures which were not declared as ingredients: the C(8) homolog of the non-classical cannabinoid CP 47,497 (CP-47,497-C8) and a cannabimimetic aminoalkylindole called JWH-018. In February 2009, a few weeks after the German legislation put these compounds and further pharmacologically active homologs of CP-47,497 under control, another cannabinoid appeared in 'incense' products: the aminoalkylindole JWH-073. In this paper, the results of monitoring of commercially available 'incense' products from June 2008 to September 2009 are presented. In this period of time, more than 140 samples of herbal mixtures were analyzed for bioactive ingredients and synthetic cannabimimetic substances in particular. The results show that the composition of many products changed repeatedly over time as a reaction to prohibition and prosecution of resellers. Therefore neither the reseller nor the consumer of these mixtures can predict the actual content of the 'incense' products. As long as there is no possibility of generic definitions in the controlled substances legislation, further designer cannabinoids will appear on the market as soon as the next legal step has been taken. This is affirmed by the recent identification of the aminoalkylindoles JWH-250 and JWH-398. As further cannabinoids can be expected to occur in the near future, a continuous monitoring of these herbal mixtures is required. The identification of the synthetic opioid O-desmethyltramadol in a herbal mixture declared to contain 'kratom' proves that the concept of selling apparently natural products spiked with potentially dangerous synthetic chemicals/pharmaceuticals is a continuing trend on the market of 'legal highs'. PMID- 20857387 TI - Electrode-assisted desorption electrospray ionization mass spectrometry. AB - A new ion source has been developed for rapid, noncontact analysis of materials at ambient conditions. The method provides desorption of analytes under ambient conditions directly from different surfaces with little or no sample preparation. The new method, termed electrode-assisted desorption electrospray ionization (EADESI), is on the basis of the ionization of molecules on different surfaces by highly charged droplets produced on a sharp-edged high voltage tip, and ions produced are introduced into the mass spectrometer through a capillary. The EADESI technique can be applied to various samples including amino acids, peptides, proteins, drugs and human fluids such as urine and blood. EADESI is promising for routine analyses in different fields such as forensic, environmental and material sciences. EADESI interface can be fit to a conventional ion-trap mass spectrometer. It can be used for various types of samples with a broad mass range. EADESI can also provide real-time analysis which is very valuable for biomedical applications. PMID- 20857389 TI - Barrier properties of gastrointestinal mucus to nanoparticle transport. AB - Gastrointestinal mucus, a complex network of highly branched glycoproteins and macromolecules, is the first barrier through which orally delivered drug and gene vectors must traverse. The diffusion of such vectors can be restricted by the high adhesivity and viscoelasticity of mucus. In this investigation, the barrier properties of gastrointestinal mucus to particle transport were explored using real-time multiple particle tracking. The influence of surface chemistry on particle transport rates was examined using amine-, carboxylate-, and sulfate modified polystyrene nanoparticles. A strong dependence of particle mobility in gastrointestinal mucus on surface charge was observed, with anionic particles diffusing 20-30 times faster than cationic particles. Comparison of diffusion coefficients calculated for gastrointestinal mucus with significantly varying values previously reported in the literature for other mucus sources, including cervicovaginal mucus and cystic fibrosis sputum, highlight the dependence of mucus barrier properties on the anatomical source. A significant degree of transport rate heterogeneity was also observed in native gastrointestinal mucus, suggesting a highly heterogeneous distribution of pore sizes. Furthermore, the suitability of purified mucin as a model system for transport studies was assessed by comparing particle transport rates between native intestinal mucus and purified porcine gastric mucin. Particle transport rates were approximately threefold lower in native mucus compared to purified mucin for anionic particles, yet comparable for cationic particles. Differences between barrier properties of the purified mucin preparation and native mucus depended on specific carrier properties, indicating that the purified mucin preparation does not provide an accurate model system for native mucus. PMID- 20857390 TI - Post-plasma grafting of AEMA as a versatile tool to biofunctionalise polyesters for tissue engineering. AB - In the last decade, substantial research in the field of post-plasma grafting surface modification has focussed on the introduction of carboxylic acids on surfaces by grafting acrylic acid (AAc). In the present work, we report on an alternative approach for biomaterial surface functionalisation. Thin poly-epsilon caprolactone (PCL) films were subjected to a dielectric barrier discharge Ar plasma followed by the grafting of 2-aminoethyl methacrylate (AEMA) under UV irradiation. X-ray photoelectron spectroscopy (XPS) confirmed the presence of nitrogen. The ninhydrin assay demonstrated, both quantitatively and qualitatively, the presence of free amines on the surface. Confocal fluorescence microscopy (CFM), atomic force microscopy (AFM) and scanning electron microscopy (SEM) were used to visualise the grafted surfaces, indicating the presence of pAEMA. Static contact angle (SCA) measurements indicated a permanent increase in hydrophilicity. Furthermore, the AEMA grafted surfaces were applied for comparing the physisorption and covalent immobilisation of gelatin. CFM demonstrated that only the covalent immobilisation lead to a complete coverage of the surface. Those gelatin-coated surfaces obtained were further coated using fibronectin. Osteosarcoma cells demonstrated better cell-adhesion and cell-viability on the modified surfaces, compared to the pure PCL films. PMID- 20857388 TI - Multifunctional hybrid three-dimensionally woven scaffolds for cartilage tissue engineering. AB - The successful replacement of large-scale cartilage defects or osteoarthritic lesions using tissue-engineering approaches will likely require composite biomaterial scaffolds that have biomimetic mechanical properties and can provide cell-instructive cues to control the growth and differentiation of embedded stem or progenitor cells. This study describes a novel method of constructing multifunctional scaffolds for cartilage tissue engineering that can provide both mechanical support and biological stimulation to seeded progenitor cells. 3-D woven PCL scaffolds were infiltrated with a slurry of homogenized CDM of porcine origin, seeded with human ASCs, and cultured for up to 42 d under standard growth conditions. These constructs were compared to scaffolds derived solely from CDM as well as 3-D woven PCL fabric without CDM. While all scaffolds promoted a chondrogenic phenotype of the ASCs, CDM scaffolds showed low compressive and shear moduli and contracted significantly during culture. Fiber-reinforced CDM scaffolds and 3-D woven PCL scaffolds maintained their mechanical properties throughout the culture period, while supporting the accumulation of a cartilaginous extracellular matrix. These findings show that fiber-reinforced hybrid scaffolds can be produced with biomimetic mechanical properties as well as the ability to promote ASC differentiation and chondrogenesis in vitro. PMID- 20857393 TI - Instructive materials for functional tissue engineering. PMID- 20857392 TI - Construction of an artificial glutathione peroxidase active site on copolymer vesicles. AB - To construct an efficient GPx mimic, a novel method for preparing polymer-based vesicles carrying GPx-active sites was developed. A series of block copolymers loaded with recognition and catalytic sites were synthesized based on polystyrene block-poly[tri(ethylene glycol) methyl ether acrylate]s (PS-PMEO(3) MAs). By altering the molar ratio of the functional copolymers, vesicles with GPx activity were obtained by self-assembly of these functional copolymers through blending. The optimum GPx mimic constructed by the blending process exhibited high catalytic activity and acted as a real catalyst with typical saturation kinetics behavior. The method may be of benefit for designing other enzyme mimics and may cast a light on constructing other biologically related functional nanoparticles. PMID- 20857391 TI - Bioactive scaffolds for engineering vascularized cardiac tissues. AB - Functional vascularization is a key requirement for the development and function of most tissues, and most critically cardiac muscle. Rapid and irreversible loss of cardiomyocytes during cardiac infarction directly results from the lack of blood supply. Contractile cardiac grafts, engineered using cardiovascular cells in conjunction with biomaterial scaffolds, are an actively studied method for cardiac repair. In this article, we focus on biomaterial scaffolds designed to mediate the development and maturation of vascular networks, by immobilized growth factors. The interactive effects of multiple vasculogenic factors are discussed in the context of cardiac tissue engineering. PMID- 20857394 TI - Crystal structure prediction and isostructurality of three small molecules. AB - A crystal structure prediction (CSP) study of three small, rigid and structurally related organic compounds (differing only in the position and number of methyl groups) is presented. A tailor-made force field (TMFF; a non-transferable force field specific for each molecule) was constructed with the aid of a dispersion corrected density functional theory method (the hybrid method). Parameters for all energy terms in each TMFF were fitted to reference data generated by the hybrid method. Each force field was then employed during structure generation. The experimentally observed crystal structures of two of the three molecules were found as the most stable crystal packings in the lists of their force-field optimised structures. A number of the most stable crystal structures were re optimised with the hybrid method. One experimental crystal structure was still calculated to be the most stable structure, whereas for another compound the experimental structure became the third most stable structure according to the hybrid method. For the third molecule, the experimentally observed polymorph, which was found to be the fourth most stable form using its TMFF, became the second most stable form. Good geometrical agreements were observed between the experimental structures and those calculated by both methods. The average structural deviation achieved by the TMFFs was almost twice that obtained with the hybrid method. The TMFF approach was extended by exploring the accuracy of a more general TMFF (GTMFF), which involved fitting the force-field parameters to the reference data for all three molecules simultaneously. This GTMFF was slightly less accurate than the individual TMFFs but still of sufficient accuracy to be used in CSP. A study of the isostructural relationships between these molecules and their crystal lattices revealed a potential polymorph of one of the compounds that has not been observed experimentally and that may be accessible in a thorough polymorph screen, through seeding, or through the use of a suitable tailor-made additive. PMID- 20857395 TI - Synthesis and conformational analysis of salivary proline-rich peptide P-B. AB - The 57-amino acid human salivary polypeptide P-B has been synthesized by the solid-phase method using 9-fluorenylmethoxycarbonyl (Fmoc) strategy. The circular dichroism (CD) spectroscopy, Fourier-transform infrared spectroscopy (FTIR) and molecular modeling methods have been used for conformational studies of P-B. Examination of the CD spectra of P-B showed the content of the secondary structure to be independent of temperature over the range 0-60 degrees C at pH = 7 as well as over the pH range of 2-12 at 37 degrees C. P-B adopts predominantly unordered structure with locally appearing beta-turns. The cumulative results obtained using the CD and FTIR spectroscopic techniques indicate the percentage of the polyproline type-II (PPII) helix being as low as about 10%. Similarly, the molecular dynamics (MD) simulations reveal only a short PPII helix in the C terminal fragment of the peptide (Pro(51)-Pro(54)), which constitutes 7%. PMID- 20857396 TI - Fine-needle aspiration cytology diagnosis of non-Hodgkins lymphoma in a resource challenged environment. AB - To establish the role of fine-needle aspiration cytology (FNAC) as a diagnostic tool for non-Hodgkins lymphoma in a resource challenged environment. This study was conducted on patients with lymphadenopathy, attending various clinics over a period of 18 months. FNAC of the enlarged lymph nodes was performed and biopsy, special stains and immunohistochemical staining was done in selected cases. Out of the total 275 cases, 42 cases (16%) were primary lymphoproliferative disorders. Non-Hodgkin lymphoma comprised of 32 cases (76.2% of all lymphomas), Hodgkin lymphoma-10 cases and the rest were metastatic carcinoma. The diagnostic accuracy for non-Hodgkin Lymphoma was 93.3%, sensitivity 95.4%, and specificity 87.5%. FNAC is a rapid, safe, easy, and nonexpensive diagnostic technique which can be used for early diagnosis of non-Hodgkins lymphoma. PMID- 20857397 TI - Cushing's syndrome and nocardiosis associated with a pulmonary carcinoid tumor: report of a case and review of the literature. AB - Ectopic hormone production is an uncommon complication of neoplastic lung disease. Rarely, patients may present with signs and symptoms of systemic endocrine dysfunction related to a hormone-secreting tumor. Bronchopulmonary carcinoids are the most common neoplasm implicated in ectopic ACTH-dependent Cushing's syndrome. Persistent hypercortisolism, such as that which occurs in Cushing's syndrome, causes immunosuppression and makes patients vulnerable to opportunistic infections. We present a case of a 42-year-old woman diagnosed with ACTH-dependent Cushing's syndrome which was originally thought to stem from a pituitary lesion as interpreted on magnetic resonance imaging. Her symptoms persisted after undergoing hypophysectomy, and further work-up involving a fine needle aspiration of the left lung revealed an ACTH-producing carcinoid tumor. Before treatment could be administered, the patient developed several new suspicious nodules in the left lung that were shown by fine needle aspiration to be infectious in nature. A Gram stain revealed numerous Gram positive branching organisms, and culture of the specimen grew Nocardia asteroides. Her pulmonary infection was treated with antibiotics and she underwent successful ablation of the carcinoid tumor. PMID- 20857398 TI - A pitfall of using 2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2 enylidene]malononitrile as a matrix in MALDI TOF MS: chemical adduction of matrix to analyte amino groups. AB - 2-[(2E)-3-(4-tert-Butylphenyl)-2-methylprop-2-enylidene]malononitrile (DCTB) has been considered as an excellent matrix for matrix-assisted laser desorption/ionization (MALDI) of many types of synthetic compounds. However, it might provide troublesome results for compounds containing aliphatic primary or secondary amino groups. For these compounds, strong extra ion peaks with a mass difference of 184.1 Da were usually observed, which might falsely indicate the presence of some unknown impurities that were not detected by other matrices. On the basis of the possible mechanisms proposed, these extra ions are the products of nucleophilic reactions between analyte amino groups and DCTB molecules or radical cations. In these reactions, an amino group replaces the dicyanomethylene group of DCTB forming a matrix adduct via a -C=N-bond. An aliphatic primary amine could react easily with DCTB and the reaction could start once they are mixed in a MALDI solution. For an aliphatic secondary amine, on the other hand, the reaction most likely occurs in the gas phase. Protonation of amino groups by adding acid seems to be a useful way to stop DCTB adduction for compounds with one single amino group, but not for compounds with multiple amino groups. Unlike aliphatic primary or secondary amines, aliphatic tertiary amines and aromatic amines do not yield DCTB adducts. This is because tertiary amines do not have the required transferrable H-(N) atom to form an extra -C=N-bond, while aromatic amines are not sufficiently nucleophilic to attack DCTB. In view of the possible matrix adduction, care should be taken in MALDI time-of-flight mass spectrometry (TOF MS) when DCTB is used as the matrix for compounds containing amino group(s). PMID- 20857399 TI - Pharmacokinetic properties of N-nitrosofenfluramine after its administration to rats. AB - N-nitrosofenfluramine (N-Fen), a synthetic adulterant in Chinese herbal diet products, is believed to cause hepatotoxicity in people who use these products. N Fen is a relatively new compound, and thus pharmacological and toxicological studies are insufficient. The aim of this work was to (1) define N-Fen's plasma pharmacokinetics and tissue distribution after single intraperitoneal (i.p.) administration of 25 mg/kg to rats; (2) define its bioavailability; and (3) identify fenfluramine (Fen) and norfenfluramine (Norf) as N-Fen metabolites. N Fen rapidly appeared in the circulation and was distributed to all tissues. Norf was found to be the primary metabolite and not Fen. Plasma and tissue levels of N Fen and Norf were low with bioavailability of N-Fen after i.p. administration was <3%. The AUC(0) (-t) of N-Fen in the liver and kidney were 6.6 and 12.1 times, respectively, greater than the brain, and 17.8 and 32.6 times, respectively, greater than the plasma. In conclusion, N-Fen did not show local accumulation in the liver, the site of toxicity, with concentrations represented as percentage of the total dose ranging from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation. PMID- 20857400 TI - Comparative genomics of NAD(P) biosynthesis and novel antibiotic drug targets. AB - NAD(P) is an indispensable cofactor for all organisms and its biosynthetic pathways are proposed as promising novel antibiotics targets against pathogens such as Mycobacterium tuberculosis. Six NAD(P) biosynthetic pathways were reconstructed by comparative genomics: de novo pathway (Asp), de novo pathway (Try), NmR pathway I (RNK-dependent), NmR pathway II (RNK-independent), Niacin salvage, and Niacin recycling. Three enzymes pivotal to the key reactions of NAD(P) biosynthesis are shared by almost all organisms, that is, NMN/NaMN adenylyltransferase (NMN/NaMNAT), NAD synthetase (NADS), and NAD kinase (NADK). They might serve as ideal broad spectrum antibiotic targets. Studies in M. tuberculosis have in part tested such hypothesis. Three regulatory factors NadR, NiaR, and NrtR, which regulate NAD biosynthesis, have been identified. M. tuberculosis NAD(P) metabolism and regulation thereof, potential drug targets and drug development are summarized in this paper. PMID- 20857401 TI - Dual regulation of hepatocyte apoptosis by reactive oxygen species: Increases in transcriptional expression and decreases in proteasomal degradation of BimEL. AB - Reactive oxygen species (ROS) have a fundamental role in intracellular signaling transduction. We show here that time-dependent extracellular signal-regulated kinase (ERK) activation due to inactivation of protein tyrosine phosphatases was closely linked to hepatocyte apoptosis under sustained exposure to ROS, which is produced through inhibition of ROS-scavenging enzymes. We found, for the first time, that active ERK transcriptionally increased BimEL expression among seven proteins of the Bcl-2 family. Transfection of Bim siRNA inhibited BimEL expression and hepatocyte apoptosis. Although ERK activation also elicited BimEL phosphorylation and subsequent ubiquitination, exposure to ROS for 9 h decreased proteasome activity. Collectively, the amount of BimEL was elevated by its increased expression and decreased degradation, leading to apoptosis. Exposure to ROS for 6 h caused neither reduction of proteasome activity nor hepatocyte apoptosis. These results indicate that the duration of exposure to ROS determines the fate of cells, that is, survival or death, in addition to the species, amounts, and generation sites of ROS. PMID- 20857403 TI - Artefactual effects of oxygen on cell culture models of cellular senescence and stem cell biology. AB - In life sciences, modelling of the in vivo conditions using in vitro models is an important tool to generate knowledge. Although aerobic organisms including mammals depend on accurate oxygen tension, mimicking physiological conditions in cell culture experiments is not very common. Due to the need for simple technical and experimental design, the requirement for simulating the in vivo oxygen tension parameters has been neglected over long time. Fortunately, due to increasing knowledge in recent years the attention has shifted towards this scientific demand. In this short review, we summarize data substantiating the necessity to adequately mimic physiological oxygen tension using cell culture models in life science research. PMID- 20857402 TI - Homocysteine induces smooth muscle cell proliferation through differential regulation of cyclins A and D1 expression. AB - The mechanism of homocysteine-induced cell proliferation in human vascular smooth muscle cells (SMCs) remains unclear. We investigated the molecular mechanisms by which homocysteine affects the expression of cyclins A and D1 in human umbilical artery SMCs (HUASMCs). Homocysteine treatment induced proliferation of HUASMCs and increased the expression levels of cyclins A and D1. Knocking down either cyclin A or cyclin D1 by small interfering RNA (siRNA) inhibited homocysteine induced cell proliferation. Furthermore, treatment with extracellular signal related kinase (ERK) inhibitor (PD98059) and dominant negative Ras (RasN17) abolished homocysteine-induced cyclin A expression; and treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) and mammalian target of rapamycin (mTOR) inhibitor (rapamycin) attenuated the homocysteine-induced cyclin D1 expression. Homocysteine also induced transient phosphorylation of ERK, Akt, and p70 ribosomal S6 kinase (p70S6K). Neutralizing antibody and siRNA for beta1 integrin blocked cell proliferation, expression of cyclins A and D1, and phosphorylation of ERK and Akt. In conclusion, homocysteine-induced differential activation of Ras/ERK and PI3K/Akt/p70S6K signaling pathways and consequent expression of cyclins A and D1 are dependent on beta1 integrin. Homocysteine may accelerate progression of atherosclerotic lesions by promoting SMC proliferation. PMID- 20857404 TI - Assembly of the fluorescent acrosomal matrix and its fate in fertilization in the water strider, Aquarius remigis. AB - Animal sperm show remarkable diversity in both morphology and molecular composition. Here we provide the first report of intense intrinsic fluorescence in an animal sperm. The sperm from a semi-aquatic insect, the water strider, Aquarius remigis, contains an intrinsically fluorescent molecule with properties consistent with those of flavin adenine dinucleotide (FAD), which appears first in the acrosomal vesicle of round spermatids and persists in the acrosome throughout spermiogenesis. Fluorescence recovery after photobleaching reveals that the fluorescent molecule exhibits unrestricted mobility in the acrosomal vesicle of round spermatids but is completely immobile in the acrosome of mature sperm. Fluorescence polarization microscopy shows a net alignment of the fluorescent molecules in the acrosome of the mature sperm but not in the acrosomal vesicle of round spermatids. These results suggest that acrosomal molecules are rearranged in the elongating acrosome and FAD is incorporated into the acrosomal matrix during its formation. Further, we followed the fate of the acrosomal matrix in fertilization utilizing the intrinsic fluorescence. The fluorescent acrosomal matrix was observed inside the fertilized egg and remained structurally intact even after gastrulation started. This observation suggests that FAD is not released from the acrosomal matrix during the fertilization process or early development and supports an idea that FAD is involved in the formation of the acrosomal matrix. The intrinsic fluorescence of the A. remigis acrosome will be a useful marker for following spermatogenesis and fertilization. PMID- 20857405 TI - Developmentally regulated inhibition of cell cycle progression by glucocorticoids through repression of cyclin A transcription in primary osteoblast cultures. AB - Synthetic glucocorticoids (GCs) like dexamethasone (DEX) are effective immunosuppressants indicated for autoimmune and inflammatory diseases. However, they often promote osteoporosis and bone fractures. Here, we investigated the anti-mitogenic effect of GCs in primary osteoblast cultures. DEX did not affect cell cycle progression in confluent (day 2), or early post-confluent cultures. Starting on day 5, however, DEX strongly inhibited the G1/S cell cycle transition. Day 5 also marked the beginning of a ~2-day commitment stage, during which cultures acquired resistance to the inhibitory effect of DEX on mineralization. Considering the importance of Wnt signaling in osteoblast development, we analyzed the effect of DEX on the Wnt pathway. DEX treatment did not inhibit the TOPGAL Wnt reporter before, but only during and after the commitment stage. However, this inhibition was not associated with repression of neither cyclin D1 nor c-Myc mRNA, well-established Wnt targets regulating cell cycle progression. On the other hand, acute (24-h) and chronic (7 days) DEX treatment significantly reduced both the mRNA and protein levels of cyclin A, another cell cycle regulator. Moreover, cyclin A repression by DEX was not observed before, but only during and after the commitment stage. Using gel shift and reporter assays, we identified an ATF/CREB-binding site critical for the DEX mediated repression of cyclin A transcription. Furthermore, and similar to cyclin A, Atf4 expression was repressed by DEX only during and after commitment. Our data suggest that GCs attenuate cell cycle progression in osteoblasts in a developmental stage-specific manner by repressing Atf4-dependent cyclin A gene expression. PMID- 20857406 TI - Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells. AB - A population of tumorigenic, chemoresistant, and radioresistant cancer stem cells is postulated to contribute to the aggressive and fatal clinical course of glioblastomas. Activation of the Hedgehog (HH) pathway and increased expression of its downstream effector GLI1 are driving factors of glioma tumorigenicity and glioma stem cell (GSC) biology. In this study, we describe a dependence of insulin-like growth factor (IGF) signaling on active HH/GLI1 in GSCs. Insulin receptor substrate 1 (IRS1) was identified as a target of the GLI1 transcription factor and inhibition of GLI1 was sufficient to obstruct IRS1 protein expression and IGF-I induced mitogen-activated protein kinase (MAPK) activation. Suppression of GLI1 activity decreased the responsiveness of GSCs to IGF-I stimulation and constrained IGF-I dependent GSC proliferation, clonogenicity, invasion, and angiogenesis. In addition, blockade of the HH/GLI1 and IGF pathways countered the intrinsic and acquired resistance of GSCs to temozolomide. These results provide further insight into the oncogenic mechanisms of the HH pathway in glioblastoma and demonstrate a cooperative signaling axis between the HH/GLI1 and IGF pathways to propagate malignant GSC phenotypes. PMID- 20857407 TI - Voltage-gated K+ channels play a role in cAMP-stimulated neuritogenesis in mouse neuroblastoma N2A cells. AB - Neuritogenesis is essential in establishing the neuronal circuitry. An important intracellular signal causing neuritogenesis is cAMP. In this report, we showed that an increase in intracellular cAMP stimulated neuritogenesis in neuroblastoma N2A cells via a PKA-dependent pathway. Two voltage-gated K(+) (Kv) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), inhibited cAMP stimulated neuritogenesis in N2A cells in a concentration-dependent manner that remarkably matched their ability to inhibit Kv currents in these cells. Consistently, siRNA knock down of Kv1.1, Kv1.4, and Kv2.1 expression reduced Kv currents and inhibited cAMP-stimulated neuritogenesis. Kv1.1, Kv1.4, and Kv2.1 channels were expressed in the cell bodies and neurites as shown by immunohistochemistry. Microfluorimetric imaging of intracellular [K(+)] demonstrated that [K(+)] in neurites was lower than that in the cell body. We also showed that cAMP-stimulated neuritogenesis may not involve voltage-gated Ca(2+) or Na(+) channels. Taken together, the results suggest a role of Kv channels and enhanced K(+) efflux in cAMP/PKA-stimulated neuritogenesis in N2A cells. PMID- 20857408 TI - PP2A interaction with Rb2/p130 mediates translocation of Rb2/p130 into the nucleus in all-trans retinoic acid-treated ovarian carcinoma cells. AB - One of the mechanisms by which all-trans retinoic acid (ATRA) has been shown to suppress the growth of CAOV3 ovarian carcinoma cells involves an increase in the accumulation of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. This increase in accumulation of RB2/p130 by ATRA results from increased stability of Rb2/p130 protein as a result of an increase in dephosphorylation of the protein by the serine/threonine phosphatase PP2A. We show that upon ATRA treatment, PP2A interacts with the Rb2/p130 C-terminus and specifically dephosphorylates two residues (S1080 and T1097) adjacent to NLS1 and NLS2 of Rb2/p130. Moreover, co-immunoprecipitation studies reveal that Rb2/p130 can form a complex with the nuclear transport proteins, importin alpha and importin beta, binding to the same dephosphorylated NLS1 and NLS2 sites. Finally, mutation of S1080 and T1097 results in retension of Rb2/p130 in the cytoplasm. Our studies suggest that one mechanism by which ATRA treatment of CAOV3 cells induces G0/G1 arrest involves the recruitment of PP2A to the C-terminus of Rb2/p130, resulting in the dephosphorylation of the S1080 and T1097 adjacent to the NLS and the subsequent interaction of Rb2/p130 with importins leading to transport of the Rb2/p130 to the nucleus where it inhibits cell-cycle progression. PMID- 20857409 TI - KIT receptor activation by autocrine and paracrine stem cell factor stimulates growth of merkel cell carcinoma in vitro. AB - The co-expression of KIT receptor and its ligand stem cell factor (SCF) has been reported in biopsy specimens of Merkel cell carcinoma (MCC). However, the functional role of SCF/KIT in the pathogenesis of this aggressive tumor has not been elucidated. The present study reports expression and effects of SCF and KIT in the Merkel cell carcinoma cell line MCC-1 in vitro. SCF and KIT were endogenously co-expressed in MCC-1 cells. Exogenous soluble SCF modulated KIT receptor mRNA and protein expression, stimulated growth of MCC-1 cells, upregulated endogenous activation of KIT, AKT, and of extracellular signal regulated kinase (ERK) 1/2 signaling pathway. On the contrary, an inhibitory antibody that neutralized the KIT ligand binding site, reduced growth of MCC-1 cells, as did high doses of the KIT kinase inhibitors imatinib and nilotinib. Also, inhibitors of KIT downstream effectors, U0126 that blocks MEK1/2 as well as wortmannin and LY294002 that inhibit phosphatidylinositol 3-kinase-dependent AKT phosphorylation, inhibited the proliferation of MCC-1 cells. These data support the hypothesis that KIT is activatable by paracrine or autocrine tumor cell derived SCF and stimulates growth of Merkel cell carcinoma in vitro. Blockade of KIT and the downstream signaling cascade at various levels results in inhibition of Merkel cell carcinoma growth in vitro, suggesting targets for therapy of this cancer. PMID- 20857410 TI - NAD(P)H oxidase participates in the palmitate-induced superoxide production and insulin secretion by rat pancreatic islets. AB - Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase complex has been shown to be involved in the process of glucose-stimulated insulin secretion (GSIS). In this study, we examined the effect of palmitic acid on superoxide production and insulin secretion by rat pancreatic islets and the mechanism involved. Rat pancreatic islets were incubated during 1 h with 1 mM palmitate, 1% fatty acid free-albumin, 5.6 or 10 mM glucose and in the presence of inhibitors of NAD(P)H oxidase (DPI--diphenyleneiodonium), PKC (calphostin C) and carnitine palmitoyl transferase-I (CPT-I) (etomoxir). Superoxide content was determined by hydroethidine assays. Palmitate increased superoxide production in the presence of 5.6 and 10 mM glucose. This effect was dependent on activation of PKC and NAD(P)H oxidase. Palmitic acid oxidation was demonstrated to contribute for the fatty acid induction of superoxide production in the presence of 5.6 mM glucose. In fact, palmitate caused p47(PHOX) translocation to plasma membrane, as shown by immunohistochemistry. Exposure to palmitate for 1 h up-regulated the protein content of p47(PHOX) and the mRNA levels of p22(PHOX), gp91(PHOX), p47(PHOX), proinsulin and the G protein-coupled receptor 40 (GPR40). Fatty acid stimulation of insulin secretion in the presence of high glucose concentration was reduced by inhibition of NAD(P)H oxidase activity. In conclusion, NAD(P)H oxidase is an important source of superoxide in pancreatic islets and the activity of NAD(P)H oxidase is involved in the control of insulin secretion by palmitate. PMID- 20857411 TI - Relationship between the lung function and anthropometric measures and indexes in adolescents from Cordoba, Argentina. AB - OBJECTIVES: The objectives of this study were to determine the degrees of association between the Forced Vital Capacity (FVC) with four anthropometric variables: height, sitting height, surface, and body volume, and two somatometrics indexes: Body Mass Index (BMI) and Cormic index, and to confront the values of FVC obtained with the predicted ones by the method of Polgar. METHODS: One sample of 54 boys and 31 girls was selected. All of them were 11-18 years of age, and were students of the National School of Monserrat (Cordoba, Argentina). The FVC was determined through computerized spirometer and the data were analyzed applying General Linear Models. The values of FVC were confronted with the predicted ones by the method of Polgar. RESULTS: The results indicate the existence of direct relation, with different values from the regression coefficient, between the FVC and the somatometrics variables, with statistically significant differences between sexes. The association of the FVC with the sitting height and the Cormic index demonstrates an increased differential based on sex. The values obtained from FVC in women, similar to those predicted by the method of Polgar; do not occur in masculine sex. CONCLUSIONS: we emphasize the observed intersexual difference when we used the Cormic index and sitting height for predicting the FVC; in contrast with the BMI, which has little explanatory power for the FVC. Finally, we also want to emphasize the necessity of counting on local reference tables for spirometric values. PMID- 20857412 TI - Tyrosine phosphorylation modulates store-operated calcium entry in cultured rat epididymal basal cells. AB - Store-operated calcium entry (SOCE) is essential for many cellular processes. In this study, we investigated modulation of SOCE by tyrosine phosphorylation in rat epididymal basal cells. The intracellular Ca(2+) ([Ca(2+)]i) measurement showed that SOCE occurred in rat epididymal basal cells by pretreating the cells with thapsigargin (Tg), the inhibitor of sarco-endoplasmic reticulum Ca(2+)-ATPase. To identify the role of Ca(2+) channels in this response, we examined the effects of transient receptor potential canonical channel blockers 2-aminoethoxydiphenyl borate (2-APB), 1-[beta-[3-(4-methoxyphenyl)pro-poxy]-4-methoxyphenethyl]-1H imidazole hydrochloride(SKF96365), Gd(3+), and non-selective cation channel blocker Ni(2+) respectively on SOCE and found that these blockers could inhibit the Ca(2+) influx to different extent. Furthermore, we studied the regulation of SOCE by tyrosine kinase pathway. The inhibitor of tyrosine kinase genistein remarkably suppressed the SOCE response, whereas sodium orthovanadate, the inhibitor of tyrosine phosphatase, greatly enhanced it. The results suggest that tyrosine kinase pathway plays a significant role in the initiation of SOCE and positively modulates SOCE in epididymal basal cells. PMID- 20857413 TI - Acetylcholine inhibits hypoxia-induced tumor necrosis factor-alpha production via regulation of MAPKs phosphorylation in cardiomyocytes. AB - Recent findings have reported that up-regulation of tumor necrosis factor-alpha (TNF-alpha) induced by myocardial hypoxia aggravates cardiomyocyte injury. Acetylcholine (ACh), the principle vagal neurotransmitter, protects cardiomyocytes against hypoxia by inhibiting apoptosis. However, it is still unclear whether ACh regulates TNF-alpha production in cardiomyocytes after hypoxia. The concentration of extracellular TNF-alpha was increased in a time dependent manner during hypoxia. Furthermore, ACh treatment also inhibited hypoxia-induced TNF-alpha mRNA and protein expression, caspase-3 activation, cell death and the production of reactive oxygen species (ROS) in cardiomyocytes. ACh treatment prevented the hypoxia-induced increase in p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) phosphorylation, and increased extracellular signal-regulated kinase (ERK) phosphorylation. Co-treatment with atropine, a non-selective muscarinic acetylcholine receptor antagonist, or methoctramine, a selective type-2 muscarinic acetylcholine (M(2) ) receptor antagonist, abrogated the effects of ACh treatment in hypoxic cardiomyocytes. Co treatment with hexamethonium, a non-selective nicotinic receptor antagonist, and methyllycaconitine, a selective alpha7-nicotinic acetylcholine receptor antagonist, had no effect on ACh-treated hypoxic cardiomyocytes. In conclusion, these results demonstrate that ACh activates the M(2) receptor, leading to regulation of MAPKs phosphorylation and, subsequently, down-regulation of TNF alpha production. We have identified a novel pathway by which ACh mediates cardioprotection against hypoxic injury in cardiomyocytes. PMID- 20857414 TI - 3D imaging of telomeres and nuclear architecture: An emerging tool of 3D nano morphology-based diagnosis. AB - Patient samples are evaluated by experienced pathologists whose diagnosis guides treating physicians. Pathological diagnoses are complex and often assisted by the application of specific tissue markers. However, cases still exist where pathologists cannot distinguish between closely related entities or determine the aggressiveness of the disease they identify under the microscope. This is due to the absence of reliable markers that define diagnostic subgroups in several cancers. Three-dimensional (3D) imaging of nuclear telomere signatures is emerging as a new tool that may change this situation offering new opportunities to the patients. This article will review current and future avenues in the assessment of diagnostic patient samples. PMID- 20857415 TI - Blockade of TNFR1 signaling: A role of oscillatory fluid shear stress in osteoblasts. AB - Fluid shear stress protects cells from TNF-alpha-induced apoptosis. Oscillatory fluid shear stress (OFSS) is generally perceived as physiologically relevant biophysical signal for bone cells. Here we identify several cellular mechanisms responsible for mediating the protective effects of OFSS against TNF-alpha induced apoptosis in vitro. We found that exposure of MC3T3-E1 osteoblast-like cells to as little as 5 min of OFSS suppressed TNF-alpha-induced activation of caspase-3, cleavage of PARP and phosphorylation of histone. In contrast, H(2)O(2) induced apoptosis was not inhibited by OFSS suggesting that OFSS might not be protecting cells from TNF-alpha-induced apoptosis via stimulation of global pro survival signaling pathways. In support of this speculation, OFSS inhibition of TNF-alpha-induced apoptosis was unaffected by inhibitors of several pro-survival signaling pathways including pI3-kinase (LY294002), MAPK/ERK kinase (PD98059 or U0126), intracellular Ca2+ release (U73122), NO production (L-NAME), or protein synthesis (cycloheximide) that were applied to cells during exposure to OFSS and during TNF-alpha treatment. However, TNF-alpha-induced phosphorylation and degradation of IkappaBalpha was blocked by pre-exposure of cells to OFSS suggesting a more specific effect of OFSS on TNF-alpha signaling. We therefore focused on the mechanism of OFSS regulation of TNF-receptor 1 (TNFR1) signaling and found that OFSS (1) reduced the amount of receptor on the cell surface, (2) prevented the association of ubiquitinated RIP in TNFR1 complexes with TRADD and TRAF2, and (3) reduced TNF-alpha-induced IL-8 promoter activity in the nucleus. We conclude that the anti-apoptotic effect of OFSS is not mediated by activation of universal pro-survival signaling pathways. Rather, OFSS inhibits TNF-alpha induced pro-apoptotic signaling which can be explained by the down-regulation of TNFR1 on the cell surface and blockade of TNFR1 downstream signaling by OFSS. PMID- 20857416 TI - RARgamma is required for correct deposition and removal of Suz12 and H2A.Z in embryonic stem cells. AB - Retinoic acid (RA) induces embryonic stem cell differentiation. The effects of RA are mediated by retinoic acid receptors (RARs) that promote epigenetic changes controlling gene transcription. We show here that RARgamma, in the absence of the ligand RA, is required for deposition of the histone variant H2A.Z and the polycomb group protein Suz12 at RA target genes, and that in embryonic stem cells both RARgamma and Suz12 exist in a multi-protein complex in the absence of ligand. Addition of RA causes removal of H2A.Z and Suz12 from RARgamma target genes when the genes are transcriptionally activated. PMID- 20857417 TI - Public attitudes toward sex offenders and their relationship to personality traits and demographic characteristics. AB - The present study examined public attitudes toward the sentencing, treatment, management, and perceived dangerousness of sex offenders. Seventy-eight university undergraduates completed a 25-item attitude toward sex offenders survey developed for the present study, along with a five-factor measure of personality (NEO Personality Inventory - Revised), a demographic questionnaire, and the Paulhus Deception Scale, to control for social desirability. While participants most frequently endorsed the belief that sentences were not sufficiently severe, they tended to espouse treatment and risk management alternatives to longer sentences and eschewed exceptionally severe punishments (e.g., surgical castration). Participants estimated high rates of sexual recidivism (59%), although they also estimated significantly lower recidivism rates for treated offenders. Results of a principle components analysis suggested that participant attitudes comprised two broad domains: systems attitudes (e.g., law enforcement, corrections, justice) and rehabilitative attitudes. Although few demographic differences emerged in participant attitudes, 'openness to experience' and 'agreeableness' each significantly predicted more rehabilitative attitudes, while contrary to expectations, 'extraversion' was significantly associated with more negative systems-related attitudes. The results provide support that personality traits may be linked to important social attitudes, including those toward sex offenders. PMID- 20857418 TI - Protein kinase D1 promotes anchorage-independent growth, invasion, and angiogenesis by human pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases. Novel molecularly targeted therapies are urgently needed. Here, we extended our studies on the role of protein kinase D1 (PKD1) in PDAC cell lines. Given that Panc-1 express moderate levels of PKD1, we used retroviral-mediated gene transfer to create a Panc-1 derivative that stably over-expresses PKD1 (Panc-1-PKD1). Reciprocally, we used shRNA targeting PKD1 in Panc-28 to produce a PKD1 under expressing Panc-28 derivative (Panc-28-shPKD1). Our results demonstrate that Panc 1-PKD1 cells exhibit significantly increased anchorage-independent growth in soft agar and increased in vitro invasion compared with Panc-1-mock. Reciprocally, Panc-28-shPKD1 cells show a significant decrease in anchorage-independent growth and invasiveness, as compared with Panc-28-mock cells. The selective PKD family inhibitor CRT0066101 markedly decreased colony-forming ability and invasiveness by either Panc-1-PKD1 or Panc-28-mock cells. Secretion of the pro-angiogenic factors vascular endothelial growth factor (VEGF) and CXC chemokines (CXCL8) was significantly elevated by PKD1 over-expression in Panc-1 cells and reduced either by depletion of PKD1 via shRNA in Panc-28 cells or by addition of CRT0066101 to either Panc-1-PKD1 or Panc-28-mock cells. Furthermore, human umbilical vein endothelial cell (HUVEC) tube formation was significantly enhanced by co-culture with Panc-1-PKD1 compared with Panc-1-mock in an angiogenesis assay in vitro. Conversely, PKD1 depletion in Panc-28 cells decreased their ability to induce endotube formation by HUVECs. PDAC-induced angiogenesis in vitro and in vivo was markedly inhibited by CRT0066101. Our results lend further support to the hypothesis that PKD family members provide a novel target for PDAC therapy. PMID- 20857419 TI - MicroRNA-26a is a novel regulator of vascular smooth muscle cell function. AB - Aberrant smooth muscle cell (SMC) plasticity has been implicated in a variety of vascular disorders including atherosclerosis, restenosis, and abdominal aortic aneurysm (AAA) formation. While the pathways governing this process remain unclear, epigenetic regulation by specific microRNAs (miRNAs) has been demonstrated in SMCs. We hypothesized that additional miRNAs might play an important role in determining vascular SMC phenotype. Microarray analysis of miRNAs was performed on human aortic SMCs undergoing phenotypic switching in response to serum withdrawal, and identified 31 significantly regulated entities. We chose the highly conserved candidate miRNA-26a for additional studies. Inhibition of miRNA-26a accelerated SMC differentiation, and also promoted apoptosis, while inhibiting proliferation and migration. Overexpression of miRNA 26a blunted differentiation. As a potential mechanism, we investigated whether miRNA-26a influences TGF-beta-pathway signaling. Dual-luciferase reporter assays demonstrated enhanced SMAD signaling with miRNA-26a inhibition, and the opposite effect with miRNA-26a overexpression in transfected human cells. Furthermore, inhibition of miRNA-26a increased gene expression of SMAD-1 and SMAD-4, while overexpression inhibited SMAD-1. MicroRNA-26a was also found to be downregulated in two mouse models of AAA formation (2.5- to 3.8-fold decrease, P < 0.02) in which enhanced switching from contractile to synthetic phenotype occurs. In summary, miRNA-26a promotes vascular SMC proliferation while inhibiting cellular differentiation and apoptosis, and alters TGF-beta pathway signaling. MicroRNA 26a represents an important new regulator of SMC biology and a potential therapeutic target in AAA disease. PMID- 20857420 TI - Thrombin induces expression of twist and cell motility via the hypoxia-inducible factor-1alpha translational pathway in colorectal cancer cells. AB - Deep vein thrombosis associated with advanced cancer is known as Trousseau's syndrome. We hypothesized that thrombin, an activator of protease-activated receptor (PAR)-1 and PAR-4 contributes to tumor metastasis. In this study, we demonstrated that thrombin and the PAR-1 activating peptide (AP) SFLLRN, but not the PAR-4 AP GYPGKF, induced HIF-1alpha activities, protein expression, and cell motility in colorectal cancer cells, and these actions were significantly inhibited by the PAR-1 antagonist SCH79797. Moreover, thrombin-induced HIF-1alpha activity and cell motility were blocked by inhibiting important mediators of signaling transduction, including the ERK, PI3K, and mTOR pathways. These results showed that thrombin induced HIF-1alpha protein expression through PAR-1 and HIF 1alpha translational de novo protein synthesis. Twist can regulate epithelial mesenchymal transition (EMT) and increase tumor metastasis. However, we observed that thrombin-induced HIF-1alpha increased Twist mRNA and its protein level was mediated by the modulation of PAR-1 activation and the HIF-1alpha translational pathway. In addition, Twist could increase N-cadherin but not E-cadherin to promote tumor metastasis. Overexpression of dominant-negative HIF-1alpha reversed thrombin-mediated Twist and Twist-induced N-cadherin expression. Moreover, siTwist inhibited Twist-induced N-cadherin and Thrombin-induced cell motility. In conclusion, our study showed that thrombin-induced HIF-1alpha upregulated Twist at the transcriptional level to enhance cell motility. These findings show that thrombin upregulates Twist via HIF-1alpha to make tumor cells malignant and also establish a link between the coagulation disorder and cancer metastasis. PMID- 20857421 TI - Sphingosine 1-phosphate mediates chemotaxis of human primary fibroblasts via the S1P-receptor subtypes S1P1 and S1P3 and Smad-signalling. AB - The sphingolipid sphingosine 1-phosphate (S1P) induces chemotaxis of primary fibroblasts. Thus, S1P exhibited a chemotactic effect in a concentration dependent manner from 10-6 to 10-9 M; higher concentrations resulted in a loss of migration, and lower amounts were ineffective to evoke movement toward a concentration gradient of S1P. In congruence with the migratory response, S1P caused an extension of lamellipodia at the cell periphery of human fibroblasts and a rearrangement of the cytoskeleton. These effects were visible by phalloidin staining of actin filaments as well as focal adhesion turnover. As the molecular mechanism of S1P-mediated migration of fibroblasts has not been well characterized, we investigated whether S1P-receptors are involved in the chemotactic response. Indeed, inhibition of G(i) signalling markedly reduced motility towards S1P, suggesting an involvement of S1P-receptor subtypes. Moreover, downregulation of S1P1 and S1P3 indicated that these S1P-receptor subtypes are responsible for the chemotactic action of the bioactive sphingolipid. After having identified a crosstalk between Smad-proteins and S1P signalling, we investigated whether Smad-activation is involved in the chemotactic response induced by S1P. Indeed S1P caused a Smad-activation via the S1P receptor subtypes S1P1 and S1P3. Moreover, downregulation of Smad3 diminished the ability of S1P to mediate a chemotactic response in fibroblasts, indicating a crosstalk between TGF-beta- and S1P-signalling. PMID- 20857422 TI - Internal pilots for observational studies. AB - Study planning often involves selecting an appropriate sample size. Power calculations require specifying an effect size and estimating "nuisance" parameters, e.g. the overall incidence of the outcome. For observational studies, an additional source of randomness must be estimated: the rate of the exposure. A poor estimate of any of these parameters will produce an erroneous sample size. Internal pilot (IP) designs reduce the risk of this error - leading to better resource utilization - by using revised estimates of the nuisance parameters at an interim stage to adjust the final sample size. In the clinical trials setting, where allocation to treatment groups is pre-determined, IP designs have been shown to achieve the targeted power without introducing substantial inflation of the type I error rate. It has not been demonstrated whether the same general conclusions hold in observational studies, where exposure-group membership cannot be controlled by the investigator. We extend the IP to observational settings. We demonstrate through simulations that implementing an IP, in which prevalence of the exposure can be re-estimated at an interim stage, helps ensure optimal power for observational research with little inflation of the type I error associated with the final data analysis. PMID- 20857423 TI - Inducing the liver: understanding the signals that promote murine liver budding. AB - The endoderm emerges as an epithelial sheet that covers the surface of the developing murine embryo. This tissue will produce the entire gut tube as well as associated digestive and respiratory organs including the thyroid, thymus, lung, liver, and pancreas. The emergence of each endodermal organ occurs in a temporally distinct manner that is dependant upon reciprocal inductive interactions between the endoderm and the underlying mesoderm. The emergence of the hepatic endoderm, which occurs using a morphological process termed liver budding, initiates during early somitogenesis in the mouse at approximately 8.25 days post-coitum (dpc). Explant and transplant studies performed in chicken and mouse have demonstrated that secreted signals from adjacent mesodermal tissues initiate the hepatic gene program from ventral-fated endoderm. Here, we review the data in support of the roles of members of the fibroblast growth factor (FGF), bone morphogenetic protein (BMP), and Wnt signaling pathways in liver budding and discover that little is known about the precise endogenous signals involved in the molecular and morphological induction of liver budding in the mouse. PMID- 20857425 TI - Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva. AB - Human gingiva plays an important role in the maintenance of oral health and shows unique fetal-like scarless healing process after wounding. Here we isolate and characterize mesenchymal stem cells from human normal and hyperplastic gingival tissues (N-GMSC and H-GMSC, respectively). Immunocytochemical staining indicated that gingival lamina propria contained Stro-1 and SSEA-4 positive cells, implying existence of putative gingival MSC. Under attachment-based isolating and culturing condition, gingival MSC displayed highly clonogenic and long-term proliferative capability. By using single colony isolation and expansion approaches, we found both N-GMSC and H-GMSC possessed self-renewal and multipotent differentiation properties. N-GMSC and H-GMSC showed distinct immunoregulatory functions in a murine skin allograft setting via up-regulation of putative systemic regulatory T cells (Tregs). N-GMSC and H-GMSC were capable of regenerating collagenous tissue following in vivo transplantation, in which H GMSC exhibited more robust regenerative capability. These findings suggest that gingival tissue contains tissue-specific mesenchymal stem cell population and is an ideal resource for immunoregulatory therapy due to its substantial availability and accessibility. In addition, gingival MSC over-activation may contribute to gingival hyperplastic phenotype. PMID- 20857424 TI - Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. AB - Adipose tissue is composed of lipid-filled mature adipocytes and a heterogeneous stromal vascular fraction (SVF) population of cells. Similarly, the bone marrow (BM) is composed of multiple cell types including adipocytes, hematopoietic, osteoprogenitor, and stromal cells necessary to support hematopoiesis. Both adipose and BM contain a population of mesenchymal stromal/stem cells with the potential to differentiate into multiple lineages, including adipogenic, chondrogenic, and osteogenic cells, depending on the culture conditions. In this study we have shown that human adipose-derived stem cells (ASCs) and bone marrow mesenchymal stem cells (BMSCs) populations display a common expression profile for many surface antigens, including CD29, CD49c, CD147, CD166, and HLA-abc. Nevertheless, significant differences were noted in the expression of CD34 and its related protein, PODXL, CD36, CD 49f, CD106, and CD146. Furthermore, ASCs displayed more pronounced adipogenic differentiation capability relative to BMSC based on Oil Red staining (7-fold vs. 2.85-fold induction). In contrast, no difference between the stem cell types was detected for osteogenic differentiation based on Alizarin Red staining. Analysis by RT-PCR demonstrated that both the ASC and BMSC differentiated adipocytes and osteoblast displayed a significant upregulation of lineage-specific mRNAs relative to the undifferentiated cell populations; no significant differences in fold mRNA induction was noted between ASCs and BMSCs. In conclusion, these results demonstrate human ASCs and BMSCs display distinct immunophenotypes based on surface positivity and expression intensity as well as differences in adipogenic differentiation. The findings support the use of both human ASCs and BMSCs for clinical regenerative medicine. PMID- 20857426 TI - Preclinical testing of the Akt inhibitor triciribine in T-cell acute lymphoblastic leukemia. AB - Over the past 20 years, survival rates of T-cell acute lymphoblastic leukemia (T ALL) patients have improved, mainly because of advances in polychemotherapy protocols. Despite these improvements, we still need novel and less toxic treatment strategies targeting aberrantly activated signaling networks which increase proliferation, survival, and drug resistance of T-ALL cells. One such network is represented by the phosphatidylinositol 3-kinase (PI3K)/Akt axis. PI3K inhibitors have displayed some promising effects in preclinical models of T-ALL. Here, we have analyzed the therapeutic potential of the Akt inhibitor, triciribine, in T-ALL cell lines. Triciribine caused cell cycle arrest and caspase-dependent apoptosis. Western blots demonstrated a dose-dependent dephosphorylation of Akt1/Akt2, and of mammalian target of rapamycin complex 1 downstream targets in response to triciribine. Triciribine induced autophagy, which could be interpreted as a defensive mechanism, because an autophagy inhibitor (chloroquine) increased triciribine-induced apoptosis. Triciribine synergized with vincristine, a chemotherapeutic drug employed for treating T-ALL patients, and targeted the side population of T-ALL cell lines, which might correspond to leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, may serve as an efficient treatment towards T-ALL cells requiring upregulation of this signaling pathway for their proliferation and survival. PMID- 20857427 TI - Fibroblast growth factor-2 stimulates directed migration of periodontal ligament cells via PI3K/AKT signaling and CD44/hyaluronan interaction. AB - Fibroblast growth factor-2 (FGF-2) regulates a variety of functions of the periodontal ligament (PDL) cell, which is a key player during tissue regeneration following periodontal tissue breakdown by periodontal disease. In this study, we investigated the effects of FGF-2 on the cell migration and related signaling pathways of MPDL22, a mouse PDL cell clone. FGF-2 activated the migration of MPDL22 cells and phosphorylation of phosphatidylinositol 3-kinase (PI3K) and akt. The P13K inhibitors, Wortmannin and LY294002, suppressed both cell migration and akt activation in MPDL22, suggesting that the PI3K/akt pathway is involved in FGF 2-stimulated migration of MPDL22 cells. Moreover, in response to FGF-2, MPDL22 showed increased CD44 expression, avidity to hyaluronan (HA) partly via CD44, HA production and mRNA expression of HA synthase (Has)-1, 2, and 3. However, the distribution of HA molecular mass produced by MPDL22 was not altered by FGF-2 stimulation. Treatment of transwell membrane with HA facilitated the migration of MPDL22 cells and an anti-CD44 neutralizing antibody inhibited it. Interestingly, the expression of CD44 was colocalized with HA on the migrating cells when stimulated with FGF-2. Furthermore, an anti-CD44 antibody and small interfering RNA for CD44 significantly decreased the FGF-2-induced migration of MPDL22 cells. Taken together, PI3K/akt and CD44/HA signaling pathways are responsible for FGF-2 mediated cell motility of PDL cells, suggesting that FGF-2 accelerates periodontal regeneration by regulating the cellular functions including migration, proliferation and modulation of extracellular matrix production. PMID- 20857429 TI - T cell suppression by osteoclasts in vitro. AB - T cells are critical regulators of osteoclast differentiation and function in bone, but whether osteoclasts can, in turn, regulate T cell homing, and response to stimuli is unclear. To investigate whether osteoclasts are immune competent cells, the expression of HLA Class II and costimulatory receptors was evaluated by RT-PCR and immunohistochemistry by comparing osteoclast precursors and mature osteoclasts. T-cell-attracting chemokines were measured in the supernatants of confluent cultures of osteoclasts and compared with mesenchymal stromal cells and osteoblasts. T cell proliferation, cytokine production, and apoptosis were assayed in co-cultures with osteoclasts in the presence or absence of mitogenic stimuli. To define the mechanism of action of osteoclasts, cytokine-blocking experiments were performed. Our findings revealed that mature osteoclasts constitutively expressed Class II HLA in the membrane and upregulate the expression of CD40 and CD80 during differentiation. Osteoclasts secreted high levels of most T cell chemoattractants and effectively retained T cells in adhesion assays. Moreover, the osteoclasts potently blunted T cell response to PHA and CD3/CD28 stimulation, thus inhibiting proliferation, suppressing T cell TNFalpha and IFNgamma production and decreasing T cell apoptosis by a mostly cell contact independent mechanism. In conclusion, osteoclasts are immune-competent cells which can retain T cells and suppress in vitro T cell response to proliferative stimuli. PMID- 20857428 TI - Relationships of lipocalin 2 with breast tumorigenesis and metastasis. AB - Breast cancer is one of the most common cancers in women worldwide and accounts for one-sixth of cancer deaths in the United States. Breast cancer consists of a heterogeneous group of tumours classified into five types, in which the HER2/neu positive and the basal type (most are ER and HER2 negative) have the worst clinical prognosis. In recent years, prognostic/predictive markers such as ER/PR or HER2/neu have been widely used in the selection of the optimal breast cancer treatments for individual patients, which have been proven to be very effective in disease control. These results suggest that further examination of the molecular mechanisms underlying the breast tumorigenesis and identification of the potential biomarkers in different types of breast cancers will greatly benefit clinical diagnosis and facilitate the design of more effective personalized therapies to increase patient survival. This review aims to summarize recent research findings on lipocalin 2 (LCN2), a newly identified biomarker and a potential therapeutic target for breast cancer, and the possible mechanisms underlying its role in tumorigenesis and metastasis. PMID- 20857430 TI - Identification of spathulenol in Salvia mirzayanii and the immunomodulatory effects. AB - The methanol extract of Salvia mirzayanii has shown an immunomodulatory effect on peripheral blood lymphocytes. Bioassay-guided fractionation using a lymphocyte proliferation assay on Salvia mirzayanii was performed in order to purify and identify the active compounds. Fractionation of the methanol extract and purification of the components using normal column chromatography and preparative thin layer chromatography resulted in identification of the bioactive compound, spathulenol, with an immunoinhibitory effect. Identification of this compound was performed by 1D and 2D NMR methods and HRMS. Treatment of activated lymphocytes with a concentrated fraction containing 62% of spathulenol (SP) showed a decrease in the proliferation of lymphocytes with an IC(50) of 85.4 +/- 11.08 ug/mL. Flow cytometry analysis using annexin V and propidium iodide staining of the stimulated peripheral blood lymphocytes in the presence of SP demonstrated a dose dependent increase in the percentage of apoptotic cells (IC(50) ; 77.2 +/- 5.31 ug/mL). No significant increase in caspase 3 activity in a 20 h treatment of stimulated lymphocytes compared with the control was observed. In conclusion, this study identified the possible activity of spathulenol as one of the immunomodulatory compounds present in Salvia mirzayanii. SP showed the capacity to inhibit proliferation in the lymphocytes and to induce apoptosis in these cells possibly through a caspase-3 independent pathway. PMID- 20857431 TI - Role of alpha class glutathione transferases (GSTs) in chemoprevention: GSTA1 and A4 overexpressing human leukemia (HL60) cells resist sulforaphane and curcumin induced toxicity. AB - Alpha-class glutathione transferases (alpha-GSTs) have been shown to protect cells from the harmful effects of reactive oxygen species (ROS) induced lipid peroxidation (LPO) during oxidative stress caused by various physico-chemical agents. While GSTA1-1/A2-2 isozymes exhibit high activity towards lipid and fatty acid hydroperoxides through their selenium independent glutathione peroxidase (GPx) activity, the GSTA4-4 isozyme efficiently metabolizes the LPO product 4 hydroxynonenal (4-HNE) by conjugating it with glutathione (GSH). Because of the fact that ROS generated by the chemopreventive agents, sulforaphane (SFN) and curcumin (Cur), are implicated in the mechanisms of cancer cell killing, the present studies were designed to investigate the contribution of ROS induced LPO in the cytotoxic effects of these agents and the role of alpha-class GSTs in modulating their toxicity. Human erythroleukemic (HL60) cells were stably transfected with the cDNA encoding the hGSTA1-1 and mGsta4-4 isozymes. After analysing the expression and activities of the respective GST isozymes, the effects of SFN and Cur on the extent of LPO, cytotoxicity and apoptosis were compared in empty vector (VT), hGSTA1-1 and mGsta4-4 expressing HL60 cells. These studies demonstrate that when compared with SFN, Cur was relatively more cytotoxic to HL60 cells. The ectopic expression of hGSTA1-1 and mGsta4-4 isozymes provided resistance to SFN and Cur induced cytotoxicity and apoptosis through a significant suppression of LPO in these cells. Overall, the results suggest that the expression of alpha-class GSTs in cancer cells can modulate the therapeutic efficacy of chemopreventive agents. PMID- 20857432 TI - Hydrolysates of citrus plants stimulate melanogenesis protecting against UV induced dermal damage. AB - The sun-tanning process occurs as a spontaneous response to ultraviolet (UV) irradiation. UV will induce tanning and DNA damage, processes that can lead to photoaging and skin disorders such as hyperpigmentation and cancer. The pigment melanin protects skin from UV damage; therefore, an efficient melanin-promoting suntan lotion could be highly beneficial. In this study, a process was developed to increase the content of naringenin in citrus extracts and to determine whether a higher naringenin content of citrus would induce melanogenesis. Melanin content and tyrosinase expression in mouse B16 melanoma cells were assayed after treatment with citrus plant extracts and their hydrolysates. The results indicate that hydrolysis increased the naringenin content in citrus extracts and that citrus preparations stimulated cellular melanogenesis and tyrosinase expression. It is suggested that this method is applicable to the industrial production of melanin-promoting suntan lotions with antiphotocarcinogenic properties derived from citrus rind and citrus products. PMID- 20857433 TI - The in vivo Pig-a gene mutation assay, a potential tool for regulatory safety assessment. AB - The Pig-a (phosphatidylinositol glycan, Class A) gene codes for a catalytic subunit of the N-acetylglucosamine transferase complex involved in an early step of glycosylphosphatidyl inositol (GPI) cell surface anchor synthesis. Pig-a is the only gene involved in GPI anchor synthesis that is on the X-chromosome, and research into the origins of an acquired genetic disease involving GPI anchor deficiency (paroxysmal nocturnal hemoglobinuria) indicates that cells lacking GPI anchors, or GPI-anchored cell surface proteins, almost always have mutations in the Pig-a gene. These properties of the Pig-a gene and the GPI anchor system have been exploited in a series of assays for measuring in vivo gene mutation in blood cells from humans, rats, mice, and monkeys. In rats, flow cytometric measurement of Pig-a mutation in red blood cells requires microliter volumes of blood and data can be generated in hours. Spontaneous mutant frequencies are relatively low (<5 * 10(-6)) and rats treated with multiple doses of the potent mutagen, N-ethyl N-nitrosourea, display Pig-a mutant frequencies that are close to the sum of the frequencies produced by the individual exposures. A general observation is that induced mutant frequencies are manifested earlier in reticulocytes (about 2 weeks after treatment) than in total red blood cells (about 2 months after exposure). Based on data from a limited number of test agents, the assay shows promise for regulatory applications, including integration of gene mutation measurement into repeat-dose toxicology studies. PMID- 20857434 TI - Blood pressure lowering, cardiovascular inhibitory and bronchodilatory actions of Achillea millefolium. AB - Achillea millefolium Linn. (Asteraceae) is used in folk medicine for the treatment of overactive cardiovascular and respiratory ailments. This study describes its hypotensive, cardio-depressant, vasodilatory and bronchodilatory activities. The crude extract of Achillea millefolium (Am.Cr) caused a dose dependent (1-100 mg/kg) fall in arterial blood pressure of rats under anaesthesia. In spontaneously beating guinea-pig atrial tissues, Am.Cr exhibited negative inotropic and chronotropic effects. In isolated rabbit aortic rings, Am.Cr at 0.3-10 mg/mL relaxed phenylephrine (PE, 1 um) and high K(+) (80 mm) induced contractions, as well as suppressed the PE (1 um) control peaks obtained in Ca(++) -free medium, like that caused by verapamil. The vasodilator effect of Am.Cr was partially blocked by N(omega) -nitro-l-arginine methyl ester in endothelium intact preparations. In guinea-pig tracheal strips, Am.Cr inhibited carbachol (CCh, 1 um) and K(+) -induced contractions. These results indicate that Achillea millefolium exhibits hypotensive, cardiovascular inhibitory and bronchodilatory effects, thus explaining its medicinal use in hyperactive cardiovascular and airway disorders, such as hypertension and asthma. PMID- 20857435 TI - The 40th anniversary of the Environmental Mutagen Society. PMID- 20857436 TI - Repeat-pulse 13CO2 labeling of canola and field pea: implications for soil organic matter studies. AB - Both the quantity and quality of plant residues can impact soil properties and processes. Isotopic tracers can be used to trace plant residue decomposition if the tracer is homogeneously distributed throughout the plant. Continuous labeling will homogeneously label plants but is not widely accessible because elaborate equipment is needed. In order to determine if the more accessible repeat-pulse labeling method could be used to trace plant residue decomposition, this labeling procedure was employed using (13)CO(2) to enrich field pea and canola plants in a controlled environment. Plants were exposed weekly to pulses of 33 atom% (13)CO(2) and grown to maturity. The distribution of the label throughout the plant parts (roots, stem, leaves, and pod) and biochemical fractions (ADF and ADL) was determined. The label was not homogeneously distributed throughout the plant; in particular, the pod fractions were less enriched than other fractions indicating the importance of continuing labeling well into plant maturity for pod producing plants. The ADL fraction was also less enriched than the ADF fraction. Because of the heterogeneity of the label throughout the plant, caution should be applied when using the repeat-pulse method to trace the fate of (13)C-labeled residues in the soil. However, root contributions to below-ground C were successfully determined from the repeat-pulse labeled root material, as was (13)C enrichment of soil within the top 15 cm. Canola contributed more above- and below ground residue C than field pea; however, canola was also higher in ADF and ADL fractions indicating a more recalcitrant residue. PMID- 20857437 TI - Continuous flow infrared matrix-assisted laser desorption electrospray ionization mass spectrometry. AB - Continuous flow infrared matrix-assisted laser desorption electrospray ionization (CF IR MALDESI) mass spectrometry was demonstrated for the on-line analysis of liquid samples. Samples in aqueous solution were flowed through a 50 um i.d. fused-silica capillary at a flow rate of 1-6 uL/min. As analyte aqueous solution flowed through the capillary, a liquid sample bead formed at the capillary tip. A pulsed infrared optical parametric oscillator (OPO) laser with wavelength of 2.94 um and a 20 Hz repetition rate was focused onto the capillary tip for sample desorption and ablation. The plume of ejected sample was entrained in an electrospray to form ions by MALDESI. The resulting ions were sampled into an ion trap mass spectrometer for analysis. Using CF IR MALDESI, several chemical and biochemical reactions were monitored on-line: the chelation of 1,10 phenanthroline with iron(II), insulin denaturation with 1,4-dithiothreitol, and tryptic digestion of cytochrome c. PMID- 20857438 TI - Thermally induced intramolecular oxygen migration of N-oxides in atmospheric pressure chemical ionization mass spectrometry. AB - N-Oxides are known to undergo three main thermal degradation reactions, namely deoxygenation, Cope elimination (for N-oxides containing a beta-hydrogen) and Meisenheimer rearrangement, in atmospheric pressure chemical ionization mass spectrometry (APCI-MS). The ions corresponding to these thermal degradants observed in the ensuing APCI mass spectra have been used to identify N-oxides as well as to determine the N-oxidation site when the analyte contains multiple tertiary amine groups. In this paper, we report a thermally induced oxygen migration from one N-oxide amine to another tert-amine group present in the same molecule through a six-membered ring transition state during APCI-MS analysis. The observed intramolecular oxygen migration resulted in the formation of a new isomeric N-oxide, rendering the results of the APCI-MS analysis more difficult to interpret and potentially misleading. In addition, we observed novel degradation behavior that happened after the Meisenheimer rearrangement of the newly formed N oxide: a homolytic cleavage of the N-O bond instead of elimination of an aldehyde or a ketone that usually follows the rearrangement. Understanding of these unusual degradation pathways, which have not been reported previously, should facilitate structural elucidation of N-oxides using APCI-MS analysis. PMID- 20857439 TI - Sulfur isotope analysis of cinnabar from Roman wall paintings by elemental analysis/isotope ratio mass spectrometry--tracking the origin of archaeological red pigments and their authenticity. AB - The most valuable pigment of the Roman wall paintings was the red color obtained from powdered cinnabar (Minium Cinnabaris pigment), the red mercury sulfide (HgS), which was brought from mercury (Hg) deposits in the Roman Empire. To address the question of whether sulfur isotope signatures can serve as a rapid method to establish the provenance of the red pigment in Roman frescoes, we have measured the sulfur isotope composition (delta(34)S value in 0/00 VCDT) in samples of wall painting from the Roman city Aventicum (Avenches, Vaud, Switzerland) and compared them with values from cinnabar from European mercury deposits (Almaden in Spain, Idria in Slovenia, Monte Amiata in Italy, Moschellandsberg in Germany, and Genepy in France). Our study shows that the delta(34)S values of cinnabar from the studied Roman wall paintings fall within or near to the composition of Almaden cinnabar; thus, the provenance of the raw material may be deduced. This approach may provide information on provenance and authenticity in archaeological, restoration and forensic studies of Roman and Greek frescoes. PMID- 20857440 TI - Intramolecular stable carbon isotopic analysis of archaeal glycosyl tetraether lipids. AB - Glycolipids are prominent constituents in the membranes of cells from all domains of life. For example, diglycosyl-glycerol dibiphytanyl glycerol tetraethers (2Gly GDGTs) are associated with methanotrophic ANME-1 archaea and heterotrophic benthic archaea, two archaeal groups of global biogeochemical importance. The hydrophobic biphytane moieties of 2Gly-GDGTs from these two uncultivated archaeal groups exhibit distinct carbon isotopic compositions. To explore whether the isotopic compositions of the sugar headgroups provide additional information on the metabolism of their producers, we developed a procedure to analyze the delta(13)C values of glycosidic headgroups. Successful determination was achieved by (1) monitoring the contamination from free sugars during lipid extraction and preparation, (2) optimizing the hydrolytic conditions for glycolipids, and (3) derivatizing the resulting sugars into aldononitrile acetate derivatives, which are stable enough to withstand a subsequent column purification step. First results of delta(13)C values of sugars cleaved from 2Gly-GDGTs in two marine sediment samples, one containing predominantly ANME-1 archaea and the other benthic archaea, were obtained and compared with the delta(13)C values of the corresponding biphytanes. In both samples the dominant sugar headgroups were enriched in (13)C relative to the corresponding major biphytane. This (13)C enrichment was significantly larger in the putative major glycolipids from ANME-1 archaea (~150/00) than in those from benthic archaea (<70/00). This method opens a new analytical window for the examination of carbon isotopic relationships between sugars and lipids in uncultivated organisms. PMID- 20857441 TI - In vacuo reduction of silver orthophosphate with graphite for high-precision oxygen isotope analysis. AB - The reduction of silver phosphate with graphite under vacuum conditions was studied at final reaction temperatures varying from 430 to 915 degrees C to determine: (i) the CO(2) extraction yield, and (ii) the oxygen isotopic composition of CO(2). The CO(2) yield and oxygen isotopic composition were determined on a calibrated dual inlet and triple collector isotope ratio mass spectrometer. We observed the following three stages of the reduction process. (1) At temperatures below 590 degrees C only CO(2) is formed, while silver orthophosphate decays to pyrophosphate. (2) At higher temperatures, 590-830 degrees C, predominantly CO is formed from silver pyrophosphate which decays to metaphosphate; this CO was always converted into CO(2) by the glow discharge method. (3) At temperatures above 830 degrees C the noticeable sublimation of silver orthophosphate occurs. This observation was accompanied by the oxygen isotope analysis of the obtained CO(2). The measured delta(18)O value varied from -11.930/00 (at the lowest temperature) to -20.320/00 (at the highest temperature). The optimum reduction temperature range was found to be 780-830 degrees C. In this temperature range the oxygen isotopic composition of CO(2) is nearly constant and the reaction efficiency is relatively high. The determined difference between the delta(18)O value of oxygen in silver phosphate and that in CO(2) extracted from this phosphate is +0.700/00. PMID- 20857442 TI - Novel software for data analysis of Fourier transform ion cyclotron resonance mass spectra applied to natural organic matter. AB - Natural organic matter (NOM) occurs as an extremely complex mixture of large, charged molecules that are formed by secondary synthesis reactions. Due to their nature, their full characterization is an important challenge to scientists specializing in NOM as well as analytical chemistry. Ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) analysis enables the identification of thousands of masses in a single measurement. A major challenge in the data analysis process of NOM using the FT-ICR MS technique is the need to sort the entire data set and to present it in an accessible mode. Here we present a simple targeted algorithm called the David Mass Sort (DMS) algorithm which facilitates the detection and counting of consecutive series of masses correlated to any selected mass spacing. This program searches for specific mass differences among all of the masses in a single spectrum against all of the masses in the same spectrum. As a representative case, the current study focuses on the analysis of the well-characterized Suwannee River humic and fulvic acid (SRHA and SRFA, respectively). By applying this algorithm, we were able to find and assess the amount of singly and doubly charged molecules. In addition we present the capabilities of the program to detect any series of consecutive masses correlated to specific mass spacing, e.g. COO, H(2), OCH(2) and O(2). Under several limitations, these mass spacings may be correlated to both chemical and biochemical changes which occur simultaneously during the formation and/or degradation of large mixtures of compounds. PMID- 20857443 TI - Evading metal adduct formation during desorption-ionization mass spectrometry. AB - An investigation into the propensity of metal adduct formation in the recently developed Desorption Ionization by Charge Exchange (DICE) mass spectrometric technique has demonstrated that this method could be utilized to minimize spectral complications caused by metal adducts. For example, peaks for sodium and other metal adducts were not observed in the mass spectra acquired by the ambient pressure DICE technique from samples deposited on a solid surface, even after the salt content of samples was deliberately increased. A mass spectrum recorded from a urine sample by this technique showed peaks only for the proton adducts of urea and creatinine. This technique employs a nebulized spray of charged toluene droplets for analyte desorption. Because of the non-polar nature of the spray reagent, it neither contains any appreciable amount of cations nor provides any favored 'pickup' of metal cations from the sample matrix. Consequently, peaks for metal adducts that are commonly observed with other desorption techniques are minimal or absent in the spectra recorded by the DICE method. PMID- 20857444 TI - A preliminary matrix-assisted laser desorption/ionization time-of-flight approach for the characterization of Italian lentil varieties. AB - Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) was used in this study to obtain protein fingerprints of seven different lentil varieties, to characterize their differences and similarities. Two different matrices have been tested in order to obtain reproducible and significant mass spectra. Extraction with water containing 0.1% of trifluoroacetic acid has been used as preparative step to obtain hydrophilic protein samples of lentil seeds. The obtained MALDI protein profiles identified clear differences between the seven studied lentil varieties. Moreover, considering the high complexity of the obtained MALDI spectra, multivariate techniques of data analysis were employed to find further classification details. These multivariate analyses confirmed the possibility of a clear classification of the seven lentil varieties, indicating that the proposed procedure can be a valid taxonomic tool, and a method to certify the origin of lentils, useful for high added value lentils (Italian lentils). PMID- 20857445 TI - Essential methodological improvements in the oxygen isotope ratio analysis of N containing organic compounds. AB - The quantitative conversion of organically bound oxygen into CO, a prerequisite for the (18)O/(16)O analysis of organic compounds, is generally performed by high temperature conversion in the presence of carbon at ~1450 degrees C. Since this high-temperature procedure demands complicated and expensive equipment, a lower temperature method that could be utilized on standard elemental analyzers was evaluated. By substituting glassy carbon with carbon black, the conversion temperature could be reduced to 1170 degrees C. However, regardless of the temperature, N-containing compounds yielded incorrect results, despite quantitative conversion of the bound oxygen into CO. We believe that the problems were partially caused by interfering gases produced by a secondary decomposition of N- and C-containing polymers formed during the decomposition of the analyte. In order to overcome the interference, we replaced the gas chromatographic (GC) separation of CO and N(2) by reversible CO adsorption, yielding the possibility of collecting and purifying the CO more efficiently. After CO collection, the interfering gases were vented by means of a specific stream diverter, thus preventing them from entering the trap and the mass spectrometer. Simultaneously, a make-up He flow was used to purge the gas-specific trap before the desorption of the CO and its subsequent mass spectrometric analysis. Furthermore, the formation of interfering gases was reduced by the use of polyethylene as an additive for analytes with a N:O ratio greater than 1. These methodological modifications to the thermal conversion of N-containing analytes, depending on their structure or O:N ratio, led to satisfactory results and showed that it was possible to optimize the conditions for their individual oxygen isotope ratio analysis, even at 1170 degrees C. With these methodological modifications, correct and precise delta(18)O results were obtained on N-containing analytes even at 1170 degrees C. Differences from the expected standard values were below +/-10/00 with standard deviations of the analysis <0.20/00. PMID- 20857446 TI - Simultaneous selective detection of organophosphate and phthalate esters using gas chromatography with positive ion chemical ionization tandem mass spectrometry and its application to indoor air and dust. AB - A selective and sensitive method for the simultaneous determination of 14 organophosphate and six phthalate esters using gas chromatography (GC) and mass spectrometry (MS) is presented. Both of these compound classes are frequently found in the indoor environment due to their use as bulk additives in numerous polymers, consumer products and building materials. GC/MS utilizing positive ion chemical ionisation (PICI) in selected reaction monitoring (SRM) mode with isobutane as the reagent gas was found to be the best of the tested methods; it proved superior to electron ionisation (EI) in selected ion monitoring (SIM) mode and to PICI using methane as the reagent gas. The method was applied to indoor air samples collected by active air sampling using solid-phase extraction (SPE) cartridges. Organophosphates and phthalates were simultaneously determined with method detection limits (MDLs) in the range of 0.1-47 ng m(-3). For most compounds the MDLs were <=0.2 ng m(-3), but due to the presence of some of these ubiquitous indoor air pollutants in the blanks, significantly higher MDLs were observed for a few compounds. Finally, the method was also applied in the screening of a much more complex sample matrix, indoor dust. PMID- 20857447 TI - Fluorous derivatization combined with liquid chromatography/tandem mass spectrometry: a method for the selective and sensitive determination of sialic acids in biological samples. AB - We have developed a novel method for selective and sensitive analysis of sialic acids (N-acetylneuraminic, N-glycolylneuraminic, and 2-keto-3-deoxy-D-glycero-D galactonononic acid) utilizing liquid chromatography/tandem mass spectrometry (LC/MS/MS) combined with a fluorous derivatization technique. In this method, the carboxylic groups in the sialic acids are derivatized via amidation with heptadecafluoroundecylamine, a commercially available perfluoroalkylamine reagent. This reaction proceeds rapidly and readily at room temperature in the presence of a condensation reagent. Subsequently, the derivatives are retained specifically on an LC column with a perfluoroalkyl stationary phase by means of a fluorophilic or 'fluorous' interaction, and detected by positive electrospray ionization MS/MS. The detection limits of the examined sialic acids are in the range of 60-750 amol on column. We show that the proposed method can be used to analyze trace amounts of sialic acids in biological samples. PMID- 20857449 TI - Characterization of a peptide family from the skin secretion of the Middle East tree frog Hyla savignyi by composition-based de novo sequencing. AB - A new tryptophyllin-like peptide family was found in the skin secretion of the tree frog Hyla savignyi. Peptides were characterized by database-independent sequencing strategies and specific ion fragmentation features were investigated. Skin secretions from specimens of Hyla savignyi were collected by mild electrical stimulation. Peptides were separated by reversed-phase nano-high-performance liquid chromatography (nanoHPLC) and mass spectra were acquired online by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Peptides were characterized by manual de novo sequencing and by composition-based sequencing (CBS), appearing mostly as C-terminal free acids and as their acid amide analogs. Amide peptides yielded lower intensities of y-type ions after collision-induced dissociation (CID) than their acid analogs. A mechanism of internal b-ion formation (positive ion mode) and of CO(2) elimination (negative ion mode) is proposed. We also exemplified phenomena such as the proline effect and formation of non-direct sequence ions after sequence rearrangements. The occurrence of rearrangement products, of internal ions and of the proline effect made the CID spectra highly complex. CBS analysis nevertheless resulted in successful and highly reliable sequence analysis. PMID- 20857450 TI - Ability of N-acetylcarnosine to protect lens crystallins from oxidation and oxidative damage by radical probe mass spectrometry (RP-MS). AB - The application of Radical Probe Mass Spectrometry based on protein footprinting studies is described to investigate the effectiveness of the antioxidant N acetylcarnosine (NAC) in preventing oxidative damage to lens crystallins present in the eye of mammals. Despite separate clinical trials which have reported the benefit of administering NAC to the eye as a 1% topical solution for the treatment of human cataract, no evidence was found to suggest that the antioxidant had any significant direct effect on reducing the levels of oxidation within the most abundant lens crystallins, alpha and beta-crystallin, at the molecular level at increasing concentrations of NAC. The results of this laboratory study suggest that the therapeutic benefit demonstrated in clinical trials is associated with the nature or formulation of the topical solution and/or that the mode of action of NAC as an antioxidant is not a direct one. PMID- 20857448 TI - Liquid chromatography/tandem mass spectrometry assay for the absolute quantification of the expected circulating apelin peptides in human plasma. AB - Apelin peptides are of great interest owing to their involvement in physiological and pathological processes and they have been proposed as novel biomarkers for heart failure. The plasma concentrations of bioactive peptides of 12 (apelin-12), 13 (apelin-13) and pyroglutamyl apelin-13 (apelin-p13), 17 (apelin-17) and 36 (apelin-36) amino acids are reported to range from 20 to 4000 pg/mL in healthy subjects. As standard immunoassays cannot specifically quantify each apelin peptide, we have developed a sensitive and targeted multiplexed liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for each plasma apelin fragment. The approach was based on a cation-exchange extraction step of apelin forms present in human plasma. Apelin-12, -13, -p13, -17 and -36 were quantified using a triple quadrupole mass spectrometer operating in the multiple reaction monitoring mode. Stable isotope-labeled internal standards were used for quantification. Following assay validation, apelin peptide stability in plasma was investigated. Ten plasma samples from healthy donors were analyzed both with a standard immunoassay and with our LC/MS/MS method. The immunoassay results for the ten healthy donors showed immunoreactive plasma apelin concentrations ranging from 208 to 466 pg/mL. The lower limits of detection of our LC/MS/MS assay ranged from 10 to 50 pg/mL for apelin-12, -13, -p13, -17, and -36. Surprisingly, none of the five expected circulating forms of apelin was detected. These results question the nature and/or the concentration of circulating apelin peptides as well as the specificity of the immunoassays that have hitherto been used for clinical applications. PMID- 20857451 TI - Photochemical degradation of natural organic sulfur compounds (CHOS) from iron rich mine pit lake pore waters--an initial understanding from evaluation of single-elemental formulae using ultra-high-resolution mass spectrometry. AB - In order to better understand the chemical diversity of dissolved organic matter (DOM) in iron-rich mine waters, a variety of sediment pore waters was analysed by means of ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FTICRMS). A considerable number of the DOM elemental formulae were found to contain sulfur. In a rather simplified experiment, DOM was exposed to sunlight in the presence of dissolved ferric iron, which is common in the oxygenated acidified epilimnetic waters of mine pit lakes. The photochemical alteration of the CHOS (carbon-, hydrogen-, oxygen- and sulfur-containing) compounds was then categorised by following the changes in signal intensity of mass peaks. Nearly 20,000 elemental compositions were identified and sorted into the following categories: totally degraded, partially degraded, not significantly degraded, minor new photoproducts, and newly formed photoproducts. A large proportion of the CHOS compounds were found to be entirely degraded; the degradation ratios exceeded those of the CHO compounds. The pools of totally degraded compounds and those of newly formed products were contrasted with respect to photochemically relevant mass differences. These results indicate that photochemical loss of sulfur-containing low molecular weight compounds can be considered likely. One feasible explanation is the photodegradation of sulfonic acids within the CHOS pool eventually leading to the release of sulfate. PMID- 20857452 TI - A validated interpretation of the collision-induced dissociation of protonated 5' methylthioadenosine through selected A+1 and A+2 isotope fragmentations by tandem mass spectrometry. PMID- 20857453 TI - Sleep after mobile phone exposure in subjects with mobile phone-related symptoms. AB - Several studies show increases in activity for certain frequency bands (10-14 Hz) and visually scored parameters during sleep after exposure to radiofrequency electromagnetic fields. A shortened REM latency has also been reported. We investigated the effects of a double-blind radiofrequency exposure (884 MHz, GSM signaling standard including non-DTX and DTX mode, time-averaged 10 g psSAR of 1.4 W/kg) on self-evaluated sleepiness and objective EEG measures during sleep. Forty-eight subjects (mean age 28 years) underwent 3 h of controlled exposure (7:30-10:30 PM; active or sham) prior to sleep, followed by a full-night polysomnographic recording in a sleep laboratory. The results demonstrated that following exposure, time in Stages 3 and 4 sleep (SWS, slow-wave sleep) decreased by 9.5 min (12%) out of a total of 78.6 min, and time in Stage 2 sleep increased by 8.3 min (4%) out of a total of 196.3 min compared to sham. The latency to Stage 3 sleep was also prolonged by 4.8 min after exposure. Power density analysis indicated an enhanced activation in the frequency ranges 0.5-1.5 and 5.75-10.5 Hz during the first 30 min of Stage 2 sleep, with 7.5-11.75 Hz being elevated within the first hour of Stage 2 sleep, and bands 4.75-8.25 Hz elevated during the second hour of Stage 2 sleep. No pronounced power changes were observed in SWS or for the third hour of scored Stage 2 sleep. No differences were found between controls and subjects with prior complaints of mobile phone related symptoms. The results confirm previous findings that RF exposure increased the EEG alpha range in the sleep EEG, and indicated moderate impairment of SWS. Furthermore, reported differences in sensitivity to mobile phone use were not reflected in sleep parameters. PMID- 20857454 TI - Confirmation studies of Soviet research on immunological effects of microwaves: Russian immunology results. AB - This paper presents the results of a replication study performed to investigate earlier Soviet studies conducted between 1974 and 1991 that showed immunological and reproductive effects of long-term low-level exposure of rats to radiofrequency (RF) electromagnetic fields. The early studies were used, in part, for developing exposure standards for the USSR population and thus it was necessary to confirm the Russian findings. In the present study, the conditions of RF exposure were made as similar as possible to those in the earlier experiments: Wistar rats were exposed in the far field to 2450 MHz continuous wave RF fields with an incident power density in the cages of 5 W/m2 for 7 h/day, 5 days/week for a total of 30 days, resulting in a whole-body SAR of 0.16 W/kg. Effects of the exposure on immunological parameters in the brain and liver of rats were evaluated using the complement fixation test (CFT), as in the original studies, and an additional test, the more modern ELISA test. Our results, using CFT and ELISA, partly confirmed the findings of the early studies and indicated possible effects from non-thermal RF exposure on autoimmune processes. The RF exposure resulted in minor increases in formation of antibodies in brain tissue extract and the exposure did not appear to be pathological. In addition, a study was conducted to replicate a previous Soviet study on effects from the injection of blood serum from RF-exposed rats on pregnancy and foetal and offspring development of rats, using a similar animal model and protocol. Our results showed the same general trends as the earlier study, suggesting possible adverse effects of the blood serum from exposed rats on pregnancy and foetal development of intact rats, however, application of these results in developing exposure standards is limited. PMID- 20857455 TI - Therapeutic effects of acrobatic exercise and magnetic field exposure on functional recovery after spinal cord injury in mice. AB - The effects of acrobatic exercise and magnetic stimulation (MS) in mice applied either separately or in combination while on recovery after spinal cord injury have been investigated. This progress has been compared in six groups of animals. The first two groups consisted of non-injured and injured animals, respectively, which were not exposed to any treatment. The third group included injured animals that participated in an acrobatic exercise and were exposed to MS applied at the frequency of 1 Hz. The animals in the fourth group were exposed to the MS (1 Hz) only, without performing any acrobatic exercises. While the mice in the fifth group participated in the acrobatic exercise and were exposed to MS at 15 Hz, the animals in group six received an acrobatic exercise without exposure to MS. The effects of the treatment were evaluated with the Basso Mouse Scale, the Horizontal Ladder Scale, and the Abnormal Posture Scale. While all groups showed improvement at the end of the study period, the animals that received exercise combined with 1 Hz MS demonstrated the best functional improvement. The animals exposed to the MS applied at a frequency of 15 Hz combined with acrobatic exercise, and those animals that were engaged in exercise and were not exposed to the MS, performed the worst. The area of the spared white matter at the lesion center correlated well with functional recovery and was greatest in the animals that received MS (1 Hz) combined with exercise. PMID- 20857456 TI - An evaluation of self-reported mobile phone use compared to billing records among a group of engineers and scientists. AB - Most epidemiologic studies of potential health impacts of mobile phones rely on self-reported information, which can lead to exposure misclassification. We compared self-reported questionnaire data among 60 participants, and phone billing records over a 3-year period (2002-2004). Phone usage information was compared by the calculation of the mean and median number of calls and duration of use, as well as correlation coefficients and associated P-values. Average call duration from self-reports was slightly lower than billing records (2.1 min vs. 2.8 min, P = 0.01). Participants reported a higher number of average daily calls than billing records (7.9 vs. 4.1, P = 0.002). Correlation coefficients for average minutes per day of mobile phone use and average number of calls per day were relatively high (R = 0.71 and 0.69, respectively, P < 0.001). Information reported at the monthly level tended to be more accurate than estimates of weekly or daily use. Our findings of modest correlations between self-reported mobile phone usage and billing records and substantial variability in recall are consistent with previous studies. However, the direction of over- and under reporting was not consistent with previous research. We did not observe increased variability over longer periods of recall or a pattern of lower accuracy among older age groups compared with younger groups. Study limitations included a relatively small sample size, low participation rates, and potential limited generalizability. The variability within studies and non-uniformity across studies indicates that estimation of the frequency and duration of phone use by questionnaires should be supplemented with subscriber records whenever practical. PMID- 20857458 TI - Metformin induces Rab4 through AMPK and modulates GLUT4 translocation in skeletal muscle cells. AB - Metformin is a major oral anti-diabetic drug and is known as an insulin sensitizer. However, the mechanism by which metformin acts is unclear. In this study, we found that AICAR, an AMPK activator, and metformin increased the expression of Rab4 mRNA and protein levels in skeletal muscle C2C12 cells. The promoter activity of Rab4 was increased by metformin in an AMPK-dependent manner. Metformin stimulated the phosphorylation of AS160, Akt substrate, and Rab GTPase activating protein (GAP), and also increased the phosphorylation of PKC-zeta, which is a critical molecule for glucose uptake. Knockdown of AMPK blocked the metformin-induced phosphorylation of AS160/PKC-zeta. In addition, a colorimetric absorbance assay showed that insulin-induced translocation of GLUT4 was suppressed in Rab4 knockdown cells. Moreover, Rab4 interacted with PKC-zeta but not with GLUT4. The C-terminal-deleted Rab4 mutant, Rab4DeltaCT, showed diffuse sub-cellular localization, while wild-type Rab4 localized exclusively to the perinuclear membrane. Unlike Rab4DeltaCT, wild-type Rab4 co-localized with PKC zeta. Together, these results demonstrate that metformin induces Rab4 expression via AMPK-AS160-PKC-zeta and modulates insulin-mediated GLUT4 translocation. PMID- 20857459 TI - Left main coronary artery aneurysm in a patient with Takayasu arteritis: parellel images from aortography, computed tomography, and magnetic resonance tomography. PMID- 20857460 TI - An unexplored O2-involved pathway for the decarboxylation of saturated carboxylic acids by TiO2 photocatalysis: an isotopic probe study. AB - The aerobic decarboxylation of saturated carboxylic acids (from C(2) to C(5)) in water by TiO(2) photocatalysis was systematically investigated in this work. It was found that the split of C(1)-C(2) bond of the acids to release CO(2) proceeds sequentially (that is, a C(5) acid sequentially forms C(4) products, then C(3) and so forth). As a model reaction, the decarboxylation of propionic acid to produce acetic acid was tracked by using isotopic-labeled H(2)(18)O. As much as ~42% of oxygen atoms of the produced acetic acids were from dioxygen ((16)O(2)). Through diffuse reflectance FTIR measurements (DRIFTS), we confirmed that an intermediate pyruvic acid was generated prior to the cut-off of the initial carboxyl group; this intermediate was evidenced by the appearance of an absorption peak at 1772 cm(-1) (attributed to C=O stretch of alpha-keto group of pyruvic acid) and the shift of this peak to 1726 cm(-1) when H(2)(16)O was replaced by H(2)(18)O. Consequently, pyruvic acid was chosen as another model molecule to observe how its decarboxylation occurs in H(2)(16)O under an atmosphere of (18)O(2). With the alpha-keto oxygen of pyruvic acid preserved in the carboxyl group of acetic acid, ~24% new oxygen atoms of the produced acetic acid were from molecular oxygen at near 100% conversion of pyruvic acid. The other ~76% oxygen atoms were provided by H(2)O through hole/OH radical oxidation. In the presence of conduction band electrons, O(2) can independently accomplish such C(1)-C(2) bond cleavage of pyruvic acid to generate acetic acid with ~100% selectivity, as confirmed by an electrochemical experiment carried out in the dark. More importantly, the ratio of O(2) participation in decarboxylation increased along with the increase of pyruvic acid conversion, indicating the differences between non-substituted acids and alpha-keto acids. This also suggests that the O(2)-dependent decarboxylation competes with hole/OH-radical promoted decarboxylation and depends on TiO(2) surface defects at which Ti(4c) sites are available for the simultaneous coordination of substrates and O(2). PMID- 20857461 TI - Dimeric self-assembly of pyridyl guanidinium carboxylates in polar solvents. AB - A series of pyridyl guanidinium-carboxylates has been prepared and the dimeric self-assembly of these studied in H(2)O/DMSO mixtures, principally using dilution isothermal calorimetry. Compounds 5 and 6, incorporating an aromatic ring in the "tethering" region between the guanidinium and carboxylate groups, demonstrate the strongest dimerisation in neat DMSO. X-ray crystal structures of 5 and 6 reveal two different dimerisation architectures in the solid-state, but both involve carboxylate-guanidinium salt bridges as anticipated, and pi-pi interactions. Compounds 10-16 incorporating peptidic fragments between the guanidinium and carboxylate groups, showed reduced dimerisation strength with increased amino acid content, but also sustained dimerisation under increasingly aqueous conditions, up to 50% H(2)O/DMSO in the case of 14 and 15. The extent of our study in H(2)O/DMSO mixtures was determined by substrate solubility of 10-16, and not the limit of self-assembly. PMID- 20857463 TI - Highly efficient N-heterocyclic carbene/pyridine-based ruthenium sensitizers: complexes for dye-sensitized solar cells. PMID- 20857464 TI - One-pot synthesis of menthol catalyzed by a highly diastereoselective Au/MgF2 catalyst. PMID- 20857465 TI - Probing the active site of an O2-tolerant NAD+-reducing [NiFe]-hydrogenase from Ralstonia eutropha H16 by in situ EPR and FTIR spectroscopy. PMID- 20857462 TI - Noninvasive imaging of dendrimer-type N-glycan clusters: in vivo dynamics dependence on oligosaccharide structure. PMID- 20857467 TI - Switching of a single boryl center in pi-conjugated photochromic polyboryl compounds and its impact on fluorescence quenching. PMID- 20857466 TI - Catalytic organometallic reactions of ammonia. AB - Until recently, ammonia had rarely succumbed to catalytic transformations with homogeneous catalysts, and the development of such reactions that are selective for the formation of single products under mild conditions has encountered numerous challenges. However, recently developed catalysts have allowed several classes of reactions to create products with nitrogen-containing functional groups from ammonia. These reactions include hydroaminomethylation, reductive amination, alkylation, allylic substitution, hydroamination, and cross-coupling. This Minireview describes examples of these processes and the factors that control catalyst activity and selectivity. PMID- 20857468 TI - Intermediates in the catalytic cycle of methyl coenzyme M reductase: isotope exchange is consistent with formation of a sigma-alkane-nickel complex. PMID- 20857470 TI - Small-molecule sensing: a direct enzyme-linked immunosorbent assay for the monosaccharide Kdo. PMID- 20857469 TI - Relocation of Aurora B and survivin from centromeres to the central spindle impaired by a kinesin-specific MKLP-2 inhibitor. PMID- 20857471 TI - Enantioselective and Z/E-selective conjugate addition of alpha-substituted cyanoacetates to acetylenic esters catalyzed by bifunctional ruthenium and iridium complexes. PMID- 20857472 TI - Readily accessible bicyclononynes for bioorthogonal labeling and three dimensional imaging of living cells. PMID- 20857473 TI - Solid-state conversion of the solvated dimer [{tBuZn(MU-OtBu)(thf)}2] into a long overlooked trimeric [{tBuZnOtBu}3] species. PMID- 20857474 TI - Click syntheses of 1,2,3-triazolylbiferrocenyl dendrimers and the selective roles of the inner and outer ferrocenyl groups in the redox recognition of ATP2- and Pd2+. PMID- 20857475 TI - Photoinduced catalytic reaction by a fluorescent active cryptand containing an anthracene fragment. PMID- 20857476 TI - Layered cobalt hydroxide nanocones: microwave-assisted synthesis, exfoliation, and structural modification. PMID- 20857477 TI - Rhodium-catalyzed asymmetric conjugate addition of arylboroxines to borylalkenes: asymmetric synthesis of beta-arylalkylboranes. PMID- 20857479 TI - Catalysis of mononuclear aquaruthenium complexes in oxygen evolution from water: a new radical coupling path using hydroxocerium(IV) species. AB - The mechanism of O(2) evolution from water catalyzed by a series of mononuclear aquaruthenium complexes, [Ru(terpy)(bpy)(OH(2))](2+), [Ru(tmtacn)(R(2)bpy)(OH(2))](2+) (R=H, Me, and OMe; R(2)bpy=4,4'-disubstituted 2,2'-bipyridines), and [Ru(tpzm)(R(2)bpy)(OH(2))](2+) (R=H, Me, and OMe), is investigated, where terpy=2,2':6',2''-terpyridine, bpy=2,2'-bipyridine, tmtacn=1,4,7-trimethyl-1,4,7-triazacyclononane, and tpzm=tris(1 pyrazolyl)methane. The kinetics of O(2) evolution is investigated as a function of either the catalyst concentration or the oxidant concentration by employing Ce(NH(4))(2)(NO(3))(6) as an oxidant; these catalysts can be classified into two groups that have different rate laws for O(2) evolution. In one class, the rate of O(2) evolution is linear to both the catalyst and Ce(4+) concentrations, as briefly reported for [Ru(terpy)(bpy)(OH(2))](2+) (S. Masaoka, K. Sakai, Chem. Lett. 2009, 38, 182). For the other class, [Ru(tmtacn)(R(2)bpy)(OH(2))](2+), the rate of O(2) evolution is quadratic to the catalyst concentration and independent of the Ce(4+) concentration. Moreover, the singlet biradical character of the hydroxocerium(IV) ion was realized by experimental and DFT investigations. These results indicate that the radical coupling between the oxygen atoms of a Ru(V)=O species and a hydroxocerium(IV) ion is the key step for the catalysis of [Ru(terpy)(bpy)(OH(2))](2+) and [Ru(tpzm)(R(2)bpy)(OH(2))](2+), while the well known oxo-oxo radical coupling among two Ru(V)=O species proceeds in the catalysis of [Ru(tmtacn)(R(2)bpy)(OH(2))](2+). This is the first report demonstrating that the radical character provided by the hydroxocerium(IV) ion plays a crucial role in the catalysis of such ruthenium complexes in the evolution of O(2) from water. PMID- 20857480 TI - Synthetic glycolysis. PMID- 20857481 TI - MYBL2, a link between proliferation and differentiation in maturing colon epithelial cells. AB - Multiple signals, controlling both proliferation and differentiation, must be integrated in the reprogramming of intestinal epithelial cells during maturation along the crypt-luminal axis. The v-myb family member Mybl2, a molecule implicated in the development and maintenance of the stem cell phenotype, has been suggested to play an important role in proliferation and differentiation of several cell types and is a gene we have found is commonly regulated in several systems of colon cell maturation both in vitro and in vivo. Here we show that siRNA silencing of Mybl2 in proliferating Caco-2 cells increases expression of the cell-cycle regulators cdk2, cyclin D2, and c-myc and decreases expression of cdc25B and cyclin B2 with a consequent 10% increase of cells in G2/M and a complementary 10% decrease in G1. Mybl2 occupies sequences upstream of transcriptional start sites of cyclin D2, c-myc, cyclin B2, and cdc25B and regulates reporter activity driven by upstream regions of cdk2, cyclin D2, and c myc. These data suggest that Mybl2 plays a subtle but key role in linking specific aspects of cell-cycle progression with generation of signals for differentiation and may therefore be fundamental in commitment of intestinal epithelial cells to differentiation pathways during their maturation. PMID- 20857482 TI - pH control mechanisms of tumor survival and growth. AB - A distinguishing phenotype of solid tumors is the presence of an alkaline cellular feature despite the surrounding acidic microenvironment. This phenotypic characteristic of tumors, originally described by Otto Warburg, arises due to alterations in metabolism of solid tumors. Hypoxic regions of solid tumors develop due to poor vascularization and in turn regulate the expression of numerous genes via the transcription factor HIF-1. Ultimately, the tumor microenvironment directs the development of tumor cells adapted to survive in an acidic surrounding where normal cells perish. The provision of unique pH characteristics in tumor cells provides a defining trait that has led to the pursuit of treatments that target metabolism, hypoxia, and pH-related mechanisms to selectively kill cancer cells. Numerous studies over the past decade involving the cancer-specific carbonic anhydrase IX have re-kindled an interest in pH disruption-based therapies. Although an acidification of the intracellular compartment is established as a means to induce normal cell death, the defining role of acid-base disturbances in tumor physiology and survival remains unclear. The aim of this review is to summarize recent data relating to the specific role of pH regulation in tumor cell survival. We focus on membrane transport and enzyme studies in an attempt to elucidate their respective functions regarding tumor cell pH regulation. These data are discussed in the context of future directions for the field of tumor cell acid-base-related research. PMID- 20857483 TI - TNF-alpha increases alphavbeta3 integrin expression and migration in human chondrosarcoma cells. AB - Chondrosarcoma is a type of highly malignant tumour with a potent capacity to invade locally and cause distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Tumour necrosis factor (TNF)-alpha is a key cytokine involved in inflammation, immunity, cellular homeostasis and tumour progression. Integrins are the major adhesive molecules in mammalian cells and have been associated with metastasis of cancer cells. However, the effects of TNF-alpha in migration and integrin expression in chondrosarcoma cells are largely unknown. In this study, we found that TNF-alpha increased the migration and the expression of alphavbeta3 integrin in human chondrosarcoma cells. Activations of MAPK kinase (MEK), extracellular signal-regulating kinase (ERK) and nuclear factor-kappaB (NF kappaB) pathways after TNF-alpha treatment were demonstrated, and TNF-alpha induced expression of integrin and migration activity was inhibited by the specific inhibitor and mutant of MEK, ERK and NF-kappaB cascades. Taken together, our results indicated that TNF-alpha enhances the migration of chondrosarcoma cells by increasing alphavbeta3 integrin expression through the MEK/ERK/NF-kappaB signal transduction pathway. PMID- 20857484 TI - Expression pattern of receptor activator of NFkappaB (RANK) in a series of primary solid tumors and related bone metastases. AB - Receptor activator of NFkappaB ligand (RANKL), RANK, and osteoprotegerin (OPG) represent the key regulators of bone metabolism both in normal and pathological conditions, including bone metastases. To our knowledge, no previous studies investigated and compared RANK expression in primary tumors and in bone metastases from the same patient. We retrospectively examined RANK expression by immunohistochemistry in 74 bone metastases tissues from solid tumors, mostly breast, colorectal, renal, lung, and prostate cancer. For 40 cases, tissue from the corresponding primary tumor was also analyzed. Sixty-six (89%) of the 74 bone metastases were RANK-positive and, among these, 40 (59.5%) showed more than 50% of positive tumor cells. The median percentage of RANK-positive cells was 60% in primary tumors and metastases, without any statistically significant difference between the two groups (P=0.194). The same percentage was obtained by considering only cases with availability of samples both from primary and metastasis. Our study shows that RANK is expressed by solid tumors, with high concordance between bone metastasis and corresponding primary tumor. These data highlight the central role of RANK/RANKL/OPG pathway as potential therapeutic target not only in bone metastasis management, but also in the adjuvant setting. PMID- 20857485 TI - Lateral entorhinal neurons are not spatially selective in cue-rich environments. AB - The hippocampus is a brain region that is critical for spatial learning, context dependent memory, and episodic memory. It receives major inputs from the medial entorhinal cortex (MEC) and the lateral EC (LEC). MEC neurons show much greater spatial firing than LEC neurons in a recording chamber with a single, salient landmark. The MEC cells are thought to derive their spatial tuning through path integration, which permits spatially selective firing in such a cue-deprived environment. In accordance with theories that postulate two spatial mapping systems that provide input to the hippocampus-an internal, path-integration system and an external, landmark-based system-it was possible that LEC neurons can also convey a spatial signal, but that the signal requires multiple landmarks to define locations, rather than movement integration. To test this hypothesis, neurons from the MEC and LEC were recorded as rats foraged for food in cue-rich environments. In both environments, LEC neurons showed little spatial specificity, whereas many MEC neurons showed a robust spatial signal. These data strongly support the notion that the MEC and LEC convey fundamentally different types of information to the hippocampus, in terms of their spatial firing characteristics, under various environmental and behavioral conditions. PMID- 20857487 TI - Detailed descriptions of routes traveled, but not map-like knowledge, correlates with tests of hippocampal function in older adults. AB - We examined hippocampal contribution to remote spatial memory in older adults by correlating their performance on tests sensitive to hippocampal damage with their description of routes they traversed many times or only once, and with their map like knowledge of downtown Toronto. We found that performance on table-top tests of spatial location (Smith and Milner (1981) Neuropsychologia 19:781-793) and on paired-associate learning, and the number of Internal Details on the Autobiographical Interview (Levine et al., (2002) Psychol Aging 17:677-689), all correlated significantly with the number and type of perceptual details used in describing routes one has traversed, but not with map-like knowledge of Toronto. No significant correlations were found with performance on tests of frontal function (WCST, phonemic fluency, and backward digit span). We conclude that the hippocampus is implicated in vivid re-experiencing of a familiar route, but not with map-like knowledge of a large-scale environment. These findings are interpreted as consistent with Multiple Trace Theory's prediction that it is the degree of detail of a retrieved memory that is crucially dependent on the hippocampus. PMID- 20857488 TI - Spatial learning deficits in mice lacking A-type K(+) channel subunits. AB - Kv4.2-mediated A-type K(+) channels in dendrites act to dampen back-propagating action potentials, constrain coincidence detection, and modify synaptic properties. Because of naturally high concentrations in the hippocampus, genetic deletion of this protein results in enhanced CA1 dendritic excitability and a broader signal integration time window with potential implications for spatial learning. In this investigation, we tested Kv4.2 knockout mice in the Morris water maze to assess their spatial reference acquisition and recall abilities. These mice demonstrated prolonged latencies and pathlength to reach a hidden platform during learning trials that was correlated to a decreased use of spatial search strategies in favor of repetitive looping. Knockout mice also showed no preference for target areas in recall-based probe trials but were less impaired by a switch in the platform location at the start of reversal learning. We discuss the possibility that these behavior discrepancies may be attributable to an enhancement in synaptic plasticity and loss of selectivity among synaptic pathways bearing different information into the CA1 region. (c) 2010 Wiley Periodicals, Inc. PMID- 20857486 TI - How hippocampus and cortex contribute to recognition memory: revisiting the complementary learning systems model. AB - We describe how the Complementary Learning Systems neural network model of recognition memory (Norman and O'Reilly (2003) Psychol Rev 104:611-646) can shed light on current debates regarding hippocampal and cortical contributions to recognition memory. We review simulation results illustrating three critical differences in how (according to the model) hippocampus and cortex contribute to recognition memory, all of which derive from the hippocampus' use of pattern separated representations. Pattern separation makes the hippocampus especially well-suited for discriminating between studied items and related lures; it makes the hippocampus especially poorly suited for computing global match; and it imbues the hippocampal ROC curve with a Y-intercept > 0. We also describe a key boundary condition on these differences: When the average level of similarity between items in an experiment is very high, hippocampal pattern separation can fail, at which point the hippocampal model will start to behave like the cortical model. We describe the implications of these simulation results for extant debates over how to describe hippocampal versus cortical contributions and how to measure these contributions. PMID- 20857489 TI - Effect of posterior tibial slope on knee biomechanics during functional activity. AB - Treatment of medial compartment knee osteoarthritis with high tibial osteotomy can produce an unintended change in the slope of the tibial plateau in the sagittal plane. The effect of changing posterior tibial slope (PTS) on cruciate ligament forces has not been quantified for knee loading in activities of daily living. The purpose of this study was to determine how changes in PTS affect tibial shear force, anterior tibial translation (ATT), and knee-ligament loading during daily physical activity. We hypothesized that tibial shear force, ATT, and ACL force all increase as PTS increases. A previously validated computer model was used to calculate ATT, tibial shear force, and cruciate-ligament forces for the normal knee during three common load-bearing tasks: standing, squatting, and walking. The model calculations were repeated with PTS altered in 1 degrees increments up to a maximum change in tibial slope of 10 degrees . Tibial shear force and ATT increased as PTS was increased. For standing and walking, ACL force increased as tibial slope was increased; for squatting, PCL force decreased as tibial slope was increased. The effect of changing PTS on ACL force was greatest for walking. The true effect of changing tibial slope on knee-joint biomechanics may only be evident under physiologic loading conditions which include muscle forces. PMID- 20857490 TI - Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. AB - Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and loss of viability. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells. PMID- 20857491 TI - CD8+ Foxp3+ tumor infiltrating lymphocytes accumulate in the context of an effective anti-tumor response. AB - The composition of tumor infiltrating lymphocytes (TIL) is heterogeneous. In addition, the ratio of various subpopulations in the tumor microenvironment is highly dependent on the nature of the host's immune response. Here, we characterize Foxp3-expressing CD8(+) T cells in the tumor that demonstrate effector function and accumulate in the context of an effective anti-tumor response. CD8(+) Foxp3(+) T cells are induced in TIL in regressing tumors of FVB/N mice treated with a GM-CSF secreting HER-2/neu targeted whole cell vaccine. Foxp3 expression in tumor antigen-specific CD8 T cells is restricted to the tumor microenvironment and influenced by cues in the tumor. Interestingly, Foxp3(+) and Foxp3(-) CD8(+) T cells have similar IFN-gamma production and antigen-specific degranulation after stimulation with RNEU(420-429) , the immunodominant HER-2/neu (neu) epitope in this model. Adoptive transfer studies, using RNEU((420-429)) specific effector T cells into neu-N mice (a model that results in immune tolerance to neu), confirm that CD8(+) Foxp3(+) T cells are present in tumors only if there is an existing pool of tumor-rejecting effector T cells. CD8(+) Foxp3(+) TILs mark the presence of tumor-rejecting antigen-specific T cells and their accumulation serves as a marker for an effective T cell response. PMID- 20857493 TI - Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells. AB - Circulating tumor cells (CTC) are an independent prognostic factor in metastatic breast cancer patients (MBC). However, CTC are undetectable in one third of patients. The aim of this study was to assess the prognostic factors in MBC patients without detectable CTC. This retrospective study included 292 MBC patients evaluated between January 2004 and December 2007. CTC were enumerated before patients started a new line of treatment using the CellSearchTM. Overall survival (OS) was calculated from the date of CTC measurement and estimated by the Kaplan-Meier product limit method. CTC were not detected in 35.96% patients, whereas 40.75% patients had CTC >= 5. Undetectable CTC status was positively correlated with presence of brain metastasis (OR: 6.17, 95%CI = 2.14-17.79; p = 0.001), and inversely correlated with bone metastasis (OR: 0.47; 95%CI = 0.27 0.80; p = 0.01). In multivariate analysis, hormone receptors, number of metastatic sites and lines of therapy were independent prognostic factors for OS in patients without detectable CTC. Patients without detectable CTC before starting of a new line of therapy comprise a heterogeneous group with substantially different prognosis. We showed that some important metastatic disease characteristics are predictive of undetectable CTC status in MBC. PMID- 20857492 TI - Biologic markers of sun exposure and melanoma risk in women: pooled case-control analysis. AB - A model has been proposed whereby melanomas arise through two distinct pathways dependent on the relative influence of host susceptibility and sun exposure. Such pathways may explain site-specific patterns of melanoma occurrence. To explore this model, we investigated the relationship between melanoma risk and general markers of acute (recalled sunburns) and chronic (prevalent solar keratoses) sun exposure, stratified by anatomic site and host phenotype. Our working hypothesis was that head and neck melanomas have stronger associations with solar keratoses and weaker associations with sunburn than trunk melanomas. We conducted a collaborative analysis using original data from women subjects of 11 case-control studies of melanoma (2,575 cases, 3,241 controls). We adjusted for potential confounding effects of sunlamp use and sunbathing. The magnitude of sunburn associations did not differ significantly by melanoma site, nevus count or histologic subtype of melanoma. Across all sites, relative risk of melanoma increased with an increasing number of reported lifetime "painful" sunburns, lifetime "severe" sunburns and "severe" sunburns in youth (p(trend) < 0.001), with pooled odds ratios (pORs) for the highest category of sunburns versus no sunburns of 3.22 [95% confidence interval (CI) 2.04-5.09] for lifetime "painful" sunburns, 2.10 (95%CI 1.30-3.38) for lifetime "severe" sunburns and 2.43 (95%CI 1.61-3.65) for "severe" sunburns in youth. Solar keratoses strongly increased the risk of head and neck melanoma (pOR 4.91, 95%CI 2.10-11.46), but data were insufficient to assess risk for other sites. Reported sunburn is strongly associated with melanoma on all major body sites. PMID- 20857494 TI - LAPTM4B overexpression is a novel predictor of epithelial ovarian carcinoma metastasis. AB - LAPTM4B is a novel tumor-associated gene. To date, there have been no published data regarding the role of LAPTM4B expression in epithelial ovarian carcinoma metastasis. Therefore, this study was performed to determine whether LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis. LAPTM4B expression was evaluated in 22 normal ovarian specimens and 139 ovarian carcinomas by western blotting analyses and immunohistochemistry. Univariate and multivariate analyses were used to determine the association between LAPTM4B expression and epithelial ovarian carcinoma metastasis. Western blotting analysis demonstrated that LAPTM4B was overexpressed in metastatic tissues from patients with ovarian cancers, and immunohistochemistry results revealed that among 59 patients with LAPTM4B overexpression, 57 (96.6%) presented intraperitoneal metastasis and 31 (52.5%) had lymph node metastasis. The results of the univariate and multivariate analyses demonstrated that LAPTM4B overexpression correlated with metastasis. The odds ratio of high-to-low expression for intraperitoneal metastasis was 11.410 (95% CI: 2.357, 55.239) and that for lymph node metastasis was 6.332 (95% CI: 2.533, 15.831). For intraperitoneal metastasis, the sensitivity and specificity of LAPTM4B overexpression were 48.7% and 90.9%; for lymph node metastasis, they were 73.8%% and 71.1%, respectively. LAPTM4B overexpression is a new predictor of epithelial ovarian carcinoma metastasis and an important potential biomarker for the early diagnosis of ovarian carcinoma. PMID- 20857495 TI - Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression. AB - Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox 2(-/-) mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2(-/-) and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2(-/-) mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2(-/-) vs. ZS:Cox-2(-/-) forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-kappaB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end products (RAGE), NF-kappaB p65, and cyclin D1, in ZD:Cox-2(-/-) forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2(-/-) mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy. PMID- 20857496 TI - Long-term survival of photoreceptors transplanted into the adult murine neural retina requires immune modulation. AB - Stem cell therapy presents an opportunity to replace photoreceptors that are lost as a result of inherited and age-related degenerative disease. We have previously shown that murine postmitotic rod photoreceptor precursor cells, identified by expression of the rod-specific transcription factor Nrl, are able to migrate into and integrate within the adult murine neural retina. However, their long-term survival has yet to be determined. Here, we found that integrated Nrl.gfp(+ve) photoreceptors were present up to 12 months post-transplantation, albeit in significantly reduced numbers. Surviving cells had rod-like morphology, including inner/outer segments and spherule synapses. In a minority of eyes, we observed an early, marked reduction in integrated photoreceptors within 1 month post transplantation, which correlated with increased numbers of amoeboid macrophages, indicating acute loss of transplanted cells due to an inflammatory response. In the majority of transplants, similar numbers of integrated cells were observed between 1 and 2 months post-transplantation. By 4 months, however, we observed a significant decrease in integrated cell survival. Macrophages and T cells were present around the transplantation site, indicating a chronic immune response. Immune suppression of recipients significantly increased transplanted photoreceptor survival, indicating that the loss observed in unsuppressed recipients resulted from T cell-mediated host immune responses. Thus, if immune responses are modulated, correctly integrated transplanted photoreceptors can survive for extended periods of time in hosts with partially mismatched H-2 haplotypes. These findings suggest that autologous donor cells are optimal for therapeutic approaches to repair the neural retina, though with immune suppression nonautologous donors may be effective. PMID- 20857497 TI - Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells. AB - The molecular signaling pathways orchestrating the biology of cancer stem-like cells (CSLCs), including glioblastoma, remain to be elucidated. We investigated in this study the role of the MEK/extracellular signal-regulated kinase (ERK) pathway in the control of self-renewal and tumorigenicity of glioblastoma CSLCs, particularly in relation to the PI3K/mTOR (mammalian target of rapamycin) pathway. Targeted inactivation of MEK alone using pharmacological inhibitors or siRNAs resulted in reduced sphere formation of both cell line- and patient derived glioblastoma CSLCs, accompanied by their differentiation into neuronal and glial lineages. Interestingly, this effect of MEK inactivation was apparently augmented in the presence of NVP-BEZ235, a dual inhibitor of PI3K and mTOR. As a potential explanation for this observed synergy, we found that inactivation of either the MEK/ERK or PI3K/mTOR pathway triggered activation of the other, suggesting that there may be mutually inhibitory crosstalk between these two pathways. Significantly, inactivation of either pathway led to the reduced activation of p70S6K, and siRNA-mediated knockdown of p70S6K resulted in the activation of both pathways, which no longer maintained the cross-inhibitory relationship. Finally, combinational blockade of both pathways in glioblastoma CSLCs suppressed their tumorigenicity, whether transplanted subcutaneously or intracranially, more efficiently than blockade of either alone. Our findings suggest that there is p70S6K-mediated, cross-inhibitory regulation between the MEK/ERK and PI3K/mTOR pathways, in which each contribute to the maintenance of the self-renewal and tumorigenic capacity of glioblastoma CSLCs. Thus, combinational disruption of these pathways would be a rational and effective strategy in the treatment of glioblastoma. PMID- 20857499 TI - Early asymmetries in maternal transcript distribution associated with a cortical microtubule network and a polar body in the beetle Tribolium castaneum. AB - The localization of maternal mRNAs during oogenesis plays a central role in axial specification in some insects. Here we describe a polar body-associated asymmetry in maternal transcript distribution in pre-blastoderm eggs of the beetle Tribolium castaneum. Since the position of the polar body marks the future dorsal side of the embryo, we have investigated whether this asymmetry in mRNA distribution plays a role in dorsal-ventral axis specification. Whilst our results suggest polar body-associated transcripts do not play a significant role in specifying the DV axis, at least during early embryogenesis, we do find that the polar body is closely associated with a cortical microtubule network (CMN), which may play a role in the localization of transcripts during oogenesis. Transcripts of the gene T.c.pangolin co-localize with the CMN at the time of their anterior localization during oogenesis and their anterior localization is disrupted by the microtubule-depolymerizing agent colcemid. PMID- 20857498 TI - Human pyruvate kinase M2: a multifunctional protein. AB - Glycolysis, a central metabolic pathway, harbors evolutionary conserved enzymes that modulate and potentially shift the cellular metabolism on requirement. Pyruvate kinase, which catalyzes the last but rate-limiting step of glycolysis, is expressed in four isozymic forms, depending on the tissue requirement. M2 isoform (PKM2) is exclusively expressed in embryonic and adult dividing/tumor cells. This tetrameric allosterically regulated isoform is intrinsically designed to downregulate its activity by subunit dissociation (into dimer), which results in partial inhibition of glycolysis at the last step. This accumulates all upstream glycolytic intermediates as an anabolic feed for synthesis of lipids and nucleic acids, whereas reassociation of PKM2 into active tetramer replenishes the normal catabolism as a feedback after cell division. In addition, involvement of this enzyme in a variety of pathways, protein-protein interactions, and nuclear transport suggests its potential to perform multiple nonglycolytic functions with diverse implications, although multidimensional role of this protein is as yet not fully explored. This review aims to provide an overview of the involvement of PKM2 in various physiological pathways with possible functional implications. PMID- 20857500 TI - The actions of in ovo cortisol on egg fertility, embryo development and the expression of growth-related genes in rainbow trout embryos, and the growth performance of juveniles. AB - Rainbow trout (Oncorhynchus mykiss) oocytes were incubated for 3 hr in ovarian fluid alone (CC), or cortisol-enriched ovarian fluid [100 or 1,000 ng ml(-1) (CL and CH, respectively)], after which they were fertilized; the growth and development of the embryos reared from these oocytes was monitored until first feed, and the juveniles were monitored for 9 months. The hatching rates of the CH group were significantly reduced, but the overall survival as measured at 40-week post-fertilization was similar in the three treatment groups. In addition, significant apparently biphasic changes relative to the CC group were found in the expression of some key growth-related genes in the CL and CH treatment groups, particularly IGF-1, IGF-2, GH1, GH2, GH receptors, and thyroid hormone receptors (TRalpha and TRbeta). Moreover, the juveniles of the CL (but not the CH treatment group) exhibited enhanced growth; the enhanced growth could not be explained on the basis of increased feed conversion efficiency or changes in serum GH levels at the juvenile stage. Additionally, relative growth rates from the three treatment groups were similar, suggesting that the biphasic growth enhancing effects of cortisol occurred very early in embryogenesis. PMID- 20857501 TI - How factors secreted from astrocytes impact myelin repair. AB - Over a century ago, hypertrophy of astrocytes was noted as a pathology of multiple sclerosis (MS) and was hypothesized to play an important role in this disease, yet the contribution of astrocytes has been largely underemphasized in the pathophysiology of CNS demyelination. Astrocytes perform many homeostatic functions within the developing and adult CNS, including enhancing formation and maintenance of the blood-brain barrier, moderating neuronal connections through the tripartite synapse, and perhaps even offering intercellular communication independently of neurons. Although there is a significant body of literature characterizing different types of MS lesions, the inflammatory demyelination in an active MS lesion is accompanied by the presence of macrophages, lymphocytes, and large reactive astrocytes. The astrocyte has long been viewed as a cell that promotes inflammation and demyelination, while also forming the glial scar, thus hindering remyelination and axon growth. Renewed interest in the astrocyte has been brought about by recent studies demonstrating that astrocytes can also function as cellular mediators of CNS myelination by promoting oligodendrocyte progenitor migration, proliferation, and differentiation. Thus, refining our knowledge of astrocytic functions in the regulation of CNS myelination may help us to better understand why remyelination fails in MS. PMID- 20857502 TI - Reduced expression and activation of voltage-gated sodium channels contributes to blunted baroreflex sensitivity in heart failure rats. AB - Voltage-gated sodium (Na(v)) channels are responsible for initiation and propagation of action potential in the neurons. To explore the mechanisms of chronic heart failure (CHF)-induced baroreflex dysfunction, we measured the expression and current density of Na(v) channel subunits (Na(v)1.7, Na(v)1.8, and Na(v)1.9) in the aortic baroreceptor neurons and investigated the role of Na(v) channels in aortic baroreceptor neuron excitability and baroreflex sensitivity in sham and CHF rats. CHF was induced by left coronary artery ligation. The development of CHF (6-8 weeks after the coronary ligation) was confirmed by hemodynamic and morphological characteristics. Immunofluorescent data indicated that Na(v)1.7 was expressed in A-type (myelinated) and C-type (unmyelinated) nodose neurons, but Na(v)1.8 and Na(v)1.9 were expressed only in C-type nodose neurons. Real-time RT-PCR and Western blot data showed that CHF reduced mRNA and protein expression levels of Na(v) channels in nodose neurons. In addition, using the whole-cell patch-clamp technique, we found that Na(v) current density and cell excitability of the aortic baroreceptor neurons were lower in CHF rats than that in sham rats. Aortic baroreflex sensitivity was blunted in anesthetized CHF rats, compared with that in sham rats. Furthermore, Na(v) channel activator (rATX II, 100 nM) significantly enhanced Na(v) current density and cell excitability of aortic baroreceptor neurons and improved aortic baroreflex sensitivity in CHF rats. These results suggest that reduced expression and activation of the Na(v) channels are involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in CHF state. PMID- 20857503 TI - Dystroglycan modulates the ability of insulin-like growth factor-1 to promote oligodendrocyte differentiation. AB - The adhesion receptor dystroglycan positively regulates terminal differentiation of oligodendrocytes, but the mechanism by which this occurs remains unclear. Using primary oligodendrocyte cultures, we identified and examined a connection between dystroglycan and the ability of insulin-like growth factor-1 (IGF-1) to promote oligodendrocyte differentiation. Consistent with previous reports, treatment with exogenous IGF-1 caused an increase in MBP protein that was preceded by activation of PI3K (AKT) and MAPK (ERK) signaling pathways. The extracellular matrix protein laminin was further shown to potentiate the effect of IGF-1 on oligodendrocyte differentiation. Depletion of the laminin receptor dystroglycan using siRNA, however, blocked the ability of IGF-1 to promote oligodendrocyte differentiation of cells grown on laminin, suggesting a role for dystroglycan in IGF-1-mediated differentiation. Indeed, loss of dystroglycan led to a reduction in the ability of IGF-1 to activate MAPK, but not PI3K, signaling pathways. Pharmacological inhibition of MAPK signaling also prevented IGF-1 induced increases in myelin basic protein (MBP), indicating that MAPK signaling was necessary to drive IGF-1-mediated enhancement of oligodendrocyte differentiation. Using immunoprecipitation, we found that dystroglycan, the adaptor protein Grb2, and insulin receptor substrate-1 (IRS-1), were associated in a protein complex. Taken together, our results suggest that the positive regulatory effect of laminin on oligodendrocyte differentiation may be attributed, at least in part, to dystroglycan's ability to promote IGF-1-induced differentiation. PMID- 20857505 TI - Stabilization of oligomeric structure of alpha-crystallin by Zn+2 through intersubunit bridging. AB - alpha-Crystallin, the major protein of mammalian eye lens, is a member of the small heat shock protein family and is a molecular chaperone. We previously reported that its molecular chaperone function as well as stability increased in presence of Zn+2. Despite the effect of Zn+2 on the structure and function of alpha-crystallin, evidence for direct interaction between them remained elusive. We now present the MALDI mass spectrometric data that shows direct evidence of Zn+2 binding to recombinant alphaA- and alphaB-crystallin. The binding stoichiometry was over three Zn+2 per subunit of alpha-crystallin at zinc/protein molar ratio of 20. Observation of multiple Zn+2 binding is consistent with the large increase in thermodynamic stability. Sequence-based analysis of alphaA- and alphaB-crystallin predicted both proteins to be nonzinc binding proteins. Our dynamic light scattering data shows that Zn+2 stabilizes the oligomeric structure of alpha-crystallin by bridging neighboring subunits in multiple centers. Despite the low affinity binding, the intersubunit bridging by multiple Zn+2 makes the oligomer so stable that oligomer breakdown does not occur even at 6M urea. The subunit bridging has been supported by our FRET data that showed absence of subunit exchange in presence of zinc. MALDI data also showed that the interaction of alpha-crystallin with Zn+2 is quite different from other bivalent metal ions. Bound Zn+2 could be easily removed by dialysis of the complex. The relevance of such weak interaction on the stability of the oligomeric structure of alpha crystallin and its function in the eye lens has been discussed. PMID- 20857504 TI - Diterpenoid biopolymers: new directions for renewable materials engineering. AB - Most types of ambers are naturally occurring, relatively hard, durable resinite polymers derived from the exudates of trees. This resource has been coveted for thousands of years due to its numerous useful properties in industrial processes, beauty, and purported medicinal properties. Labdane diterpenoid-based ambers represent the most abundant and important resinites on earth. These resinites are a dwindling nonrenewable natural resource, so a new source of such materials needs to be established. Recent advances in sequencing technologies and biochemical engineering are rapidly accelerating the rate of identifying and assigning function to genes involved in terpenoid biosynthesis, as well as producing industrial-scale quantities of desired small-molecules in bacteria and yeast. This has provided new tools for engineering metabolic pathways capable of producing diterpenoid monomers that will enable the production of custom-tailored resinite-like polymers. Furthermore, this biosynthetic toolbox is continuously expanding, providing new possibilities for renewing dwindling stocks of naturally occurring resinite materials and engineering new materials for future applications. PMID- 20857506 TI - Conformational plasticity of the calcium-binding pocket in the Burkholderia glumae lipase: remodeling induced by mutation of calcium coordinating residues. AB - Most bacterial lipases bind one or more Ca2+ atoms at different locations and are a suitable case of study for investigating structural effects related to calcium binding, depletion, or mutation of calcium-binding sites. Generally Ca2+ in microbial lipases can play a crucial role in the stabilization of the whole three dimensional structure by mediating long-range effects. It has been recently demonstrated that calcium binding influences thermal stability of Burkholderia glumae lipase (BGL) through the restriction of conformational plasticity of specific regions. Moreover, calcium depletion results in a highly cooperative protein unfolding, eliciting protein aggregation. To further shed light on molecular mechanisms and structural features connected to calcium binding in microbial lipases, we present a molecular dynamics investigation, based on multiple-replica approach at different temperatures, of BGL mutants targeting the calcium-binding site. It turns out that additional acidic residues, which are conserved in other microbial lipases, help in overcoming effects induced by mutation of D241 Ca2+-coordinating residue, upon rearrangements induced in the calcium binding site. PMID- 20857507 TI - Hypoxic-ischemic brain injury exacerbates neuronal apoptosis and precipitates spontaneous seizures in glucose transporter isoform 3 heterozygous null mice. AB - We examined the effects of 45-min hypoxia (FiO(2) 0.08; Hx) vs. normoxia (FiO(2) 0.21; Nx) on the ipsilateral (Ipsi) and contralateral (Ctrl) sides of the brain in neuronal glucose transporter isoform 3 (Glut3) heterozygous null mice (glut3(+/-)) and their wild-type littermates (WT), undergoing unilateral carotid artery ligation. Glut3(+/-) mice, under Nx, demonstrated a compensatory increase in blood-brain barrier/glial Glut1 protein concentration and a concomitant increase in neuronal nitric oxide synthase (nNOS) enzyme activity and Bax protein, with a decrease in procaspase 3 protein (P < 0.05 each). After Hx, reoxygenation in FiO(2) of 0.21 led to no comparable adaptive up-regulation of the ipsilateral brain Glut3 or Glut1 protein at 4 hr and Glut1 at 24 hr in glut3(+/-) vs. WT. These brain Glut changes in glut3(+/-) but not WT mice were associated with an increase in proapoptotic Bax protein and caspase-3 enzyme activity (P < 0.01 each) and a decline in the antiapoptotic Bcl-2 and procaspase 3 proteins (P < 0.05 each). Glut3(+/-) mice after Hx demonstrated TUNEL-positive neurons with nuclear pyknosis in most ipsilateral (hypoxic-ischemia) brain regions. A subset (~55%) of glut3(+/-) mice developed spontaneous seizures after hypoxic-ischemia, confirmed by electroencephalography, but the WT mice remained seizure-free. Pentylenetetrazole testing demonstrated an increased occurrence of longer lasting clinical seizures at a lower threshold in glut3(+/-) vs. WT mice, with no detectable differences in monamine neurotransmitters. We conclude that hypoxic-ischemic brain injury in glut3(+/-) mice exacerbates cellular apoptosis and necrosis and precipitates spontaneous seizures. PMID- 20857508 TI - Accumulation of protein carbonyls within cerebellar astrocytes in murine experimental autoimmune encephalomyelitis. AB - Recent work from our laboratory has implicated protein carbonylation in the pathophysiology of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). The present study was designed to determine the changes in protein carbonylation during disease progression and to identify the target cells and modified proteins in the cerebellum of EAE animals, prepared by active immunization of C57/BL6 mice with MOG(35-55) peptide. In this model, protein carbonylation was maximal at the peak of the disease (acute phase), to decrease thereafter (chronic phase). Double-immunofluorescence microscopy of affected cerebella showed that carbonyls accumulate in white matter astrocytes and to a lesser extent in microglia/macrophages, in both the acute and the chronic phase. Surprisingly, T cells, oligodendrocytes, and neurons were barely stained. By 2D oxyblot and mass spectrometry, beta-actin, beta-tubulin, GFAP, and HSC-71 were identified as the major targets of carbonylation throughout the disease. Using a pull-down/Western blot method, we found a significant increase in the proportion of carbonylated beta-actin, beta-tubulin, and GFAP in the chronic phase but not in the acute phase. These results suggest that as disease progresses from the inflammatory to the neurodegenerative phase there may be an inappropriate removal of oxidized cytoskeletal proteins. Additionally, the extensive accumulation of carbonylated GFAP in the chronic phase of EAE may be responsible for the abnormal shape of astrocytes observed at this stage. PMID- 20857509 TI - Simvastatin interferes with process outgrowth and branching of oligodendrocytes. AB - Statins have attracted interest as a treatment option for multiple sclerosis (MS) because of their pleiotropic antiinflammatory and immunomodulatory effects. However, contradictory results have been described when they are applied to oligodendrocytes (OLGs), the cell type predominantly affected in MS. In this study we focus on the in vitro effect of statins on process outgrowth in OLN-93 cells, a well-characterized OLG-derived cell line, and primary cultures of neonatal rat OLGs. Application of the lipophilic simvastatin, as low as 0.1-1 MUM, disturbs process formation of both cell types, leading to less ramified cells. We show that both protein isoprenylation and cholesterol synthesis are required for the normal differentiation of OLGs. It is further demonstrated that the expression of 2',3'-cyclic-nucleotide-3' phosphodiesterase (CNP) and tubulin is lowered, concomitant with a reduction of membrane-bound CNP as well as tubulin. Therefore, we propose that lack of isoprenylation of CNP could help to explain the altered morphological and biochemical differentiation state of treated OLGs. Moreover, expression of specific myelin markers, such as myelin basic protein, myelin-associated glycoprotein, and myelin oligodendrocyte glycoprotein, was compromised after treatment. We conclude that simvastatin treatment has detrimental effects on OLG process outgrowth, the prior step in (re)myelination, thereby mortgaging long-term healing of MS lesions. PMID- 20857510 TI - Distribution and classification of aggrecan-based extracellular matrix in the thalamus of the rat. AB - Extracellular matrix molecules take part in functional isolation and stabilization of neuronal compartments but form a vivid interface between neuronal elements at the same time. Previous studies have shown that the accumulation of extracellular matrix, especially its typical phenotypic form, termed perineuronal nets, correlates not only with the functional properties of the single neuron but also with the functional properties of the whole brain area. In contrast to recent advances in investigating neocortex, the present study mapped the occurrence and phenotypic appearance of aggrecan-based matrix accumulation throughout the rat thalamus. Results showed that divisions of thalamus that relay information to cortical fields known rather for their plastic properties exibit a poor matrix immunoreactivity, whereas matrix accumulation is more enhanced in nuclei connected to primary cortical regions. In addition to perineuronal nets, extracellular matrix condensed in another peculiar form, in 2 5-MUm, large, round or oval structures, as described by Bruckner et al. ([ 2008] Neuroscience 151:489-504) as axonal coats (ACs). Multiple labelling experiments showed that specific excitatory afferents were not ensheathed with these structures. At the same time, inhibitory endings were occasionally enwrapped in ACs. Electron microscopic analysis showed that aggrecan-immunoreactive profiles were present mostly around inhibitory terminals but also in all neuronal compartments. We suggest that aggrecan-based extracellular matrix is formed by both pre- and postsynaptic elements and is preferably associated with inhibitory terminals in the extracellular space. PMID- 20857511 TI - Silent synapses in neuromuscular junction development. AB - In the last few years, evidence has been found to suggest that some synaptic contacts become silent but can be functionally recruited before they completely retract during postnatal synapse elimination in muscle. The physiological mechanism of developmental synapse elimination may be better understood by studying this synapse recruitment. This Mini-Review collects previously published data and new results to propose a molecular mechanism for axonal disconnection. The mechanism is based on protein kinase C (PKC)-dependent inhibition of acetylcholine (ACh) release. PKC activity may be stimulated by a methoctramine sensitive M2-type muscarinic receptor and by calcium inflow though P/Q- and L type voltage-dependent calcium channels. In addition, tropomyosin-related tyrosine kinase B (trkB) receptor-mediated brain-derived neurotrophic factor (BDNF) activity may oppose the PKC-mediated ACh release depression. Thus, a balance between trkB and muscarinic pathways may contribute to the final functional suppression of some neuromuscular synapses during development. PMID- 20857512 TI - Cerebrolysin enhances neurogenesis in the ischemic brain and improves functional outcome after stroke. AB - Cerebrolysin is a peptide preparation mimicking the action of neurotrophic factors and has beneficial effects on neurodegenerative diseases and stroke. The present study investigated the effect of Cerebrolysin on neurogenesis in a rat model of embolic middle cerebral artery occlusion (MCAo). Treatment with Cerebrolysin at doses of 2.5 and 5 ml/kg significantly increased the number of bromodeoxyuridine-positive (BrdU(+)) subventricular zone (SVZ) neural progenitor cells and doublecortin (DCX) immunoreactivity (migrating neuroblasts) in the ipsilateral SVZ and striatal ischemic boundary 28 days after stroke when the treatment was initiated 24 hr after stroke. The treatment also reduced TUNEL(+) cells by ~50% in the ischemic boundary. However, treatment with Cerebrolysin at a dose of 2.5 ml/kg initiated at 24 and 48 hr did not significantly reduce infarct volume but substantially improved neurological outcomes measured by an array of behavioral tests 21 and 28 days after stroke. Incubation of SVZ neural progenitor cells from ischemic rats with Cerebrolysin dose dependently augmented BrdU(+) cells and increased the number of Tuj1(+) cells (a marker of immature neurons). Blockage of the PI3K/Akt pathway abolished Cerebrolysin-increased BrdU(+) cells. Moreover, Cerebrolysin treatment promoted neural progenitor cell migration. Collectively, these data indicate that Cerebrolysin treatment when initiated 24 and 48 hr after stroke enhances neurogenesis in the ischemic brain and improves functional outcome and that Cerebrolysin-augmented proliferation, differentiation, and migration of adult SVZ neural progenitor cells contribute to Cerebrolysin-induced neurogenesis, which may be related to improvement of neurological outcome. The PI3K/Akt pathway mediates Cerebrolysin-induced progenitor cell proliferation. PMID- 20857513 TI - Crush stenting with drug-eluting stents: relevance of coronary bifurcation lesion location on angiographic and clinical outcomes. AB - BACKGROUND: Data on the relevance of the location of coronary bifurcation lesions treated by crush stenting with outcomes were limited. HYPOTHESIS: We hypothesized that the location of the bifurcation lesion correlated with clinical outcome. METHOD: A total of 212 patients with 230 true bifurcation lesions treated by crush stenting with drug-eluting stents (DES) were assessed prospectively. Surveillance quantitative angiographies were indexed at 8 months after procedure. Primary endpoint was major adverse cardiac events (MACE), defined as cardiac death, myocardial infarction, and target lesion revascularization (TLR). RESULTS: Patients in the distal right coronary artery (RCAd) group were characterized by higher proportions of prior myocardial infarction and very tortuous lesions. However, lesions in the RCAd group, compared to those of other groups, had the lowest late lumen loss, with resultant lowest incidence of MACE at a mean follow up of 268+/-35 days. Independent predictors of MACE included unsatisfied kissing (KUS; hazard ratio [HR]: 12.14, 95% confidence interval [CI]: 4.01-12.10, P = .001) and non-RCA lesion (HR: 20.69, 95% CI: 5.05-22.38, P = .001), while those of TLR were KUS (HR: 10.21, 95% CI: 0.01-0.34, P = .002), bifurcation angle (HR: 4.728, 95% CI: 2.541-4.109, P = .001), and non-RCA lesion (HR: 16.05, 95%CI: 1.01 4.83, P = .001). CONCLUSIONS: Classical crush stenting with drug-eluting stents is associated with significantly better outcomes in RCAd. Quality of kissing inflation is mandatory to improve outcome. PMID- 20857514 TI - Homozygous inactivation of the LGI1 gene results in hypomyelination in the peripheral and central nervous systems. AB - Mutations in the LGI1 gene in humans predispose to the development of autosomal dominant partial epilepsy with auditory features (ADPEAF). Homozygous inactivation of the Lgi1 gene in mice results in an epilepsy phenotype characterized by clonic seizures within 2-3 weeks after birth. Before onset of seizures, the 2-3-week-old null mutant mice show poor locomotor activity and neuromuscular strength. EM analysis of the sciatic nerve demonstrates impaired myelination of axons in the peripheral nervous system. Although heterozygous mutant mice do not show any locomotor phenotypes, they also demonstrate an intermediate level of hypomyelination compared with the wild-type mice. Hypomyelination was also observed in the central nervous system, which, although relatively mild, was still significantly different from that of the wild-type mice. These data suggest a role for LGI1 in the myelination functions of Schwann cells and oligodendrocytes. PMID- 20857515 TI - Overexpression of Wld(S) or Nmnat2 in mauthner cells by single-cell electroporation delays axon degeneration in live zebrafish. AB - Axon degeneration is supposed to be a therapeutic target for treating neurodegenerative diseases. Mauthner cells (M-cells) are ideal for studying axons in vivo because of their limited numbers, large size, and long axons. In this study, we labeled M-cells by single-cell electroporation with plasmids expressing DsRed2 or EGFP. Injury-induced axon degeneration in labeled M-cell was imaged under a confocal microscope, and we found that the Mauthner axons started to degenerate about 24 hr after lesion. The Wld(S) protein containing full-length Nmnat1 is well-known for its axon-protective function in many systems. Overexpression of Wld(S) in M-cells also greatly delayed axon degeneration in live zebrafish. Nmnat2 is the only Nmnat highly expressed in brain. Here we demonstrated that overexpression of Nmnat2 in M-cells significantly delayed axon degeneration in vivo, and disruption of the NAD synthesis activity of Nmnat2 markedly attenuated its axon-protective function. All these data show that injury induced axon degeneration of M-cell has a mechanism similar to that in mammalians and would be a valuable model for studying axon degeneration in vivo. PMID- 20857516 TI - Glial cell line-derived neurotrophic factor enhances in vitro differentiation of mid-/hindbrain neural progenitor cells to dopaminergic-like neurons. AB - Parkinson's disease (PD) affects the motor system through the degeneration of the dopaminergic neurons of the substantia nigra. The use of human embryonic stem cell (hESC)-derived human neural progenitor (hNP) cells provides a potential cell source for cell therapies and drug screens for future treatments. Glial cell line derived neurotrophic factor (GDNF) is a known dopaminergic neuroprotectant agent; however, its potential role in neural differentiation remains largely unknown. Addition of 25 ng/ml GDNF to hNP cell differentiation media, over a 21-day period, induced a significantly (P < 0.05) greater portion of hNP cells to differentiate into dopaminergic neurons than non-GDNF cultures, 50% compared with 2.9% of cells expressing tyrosine hydroxylase (TH), respectively. The hNP cells exposed to GDNF selectively expressed dopamine receptors 1, 4, and 5 and were evoked to release dopamine with KCl. This is the first report of GDNF and leukemia inhibitory factor enriching hESC-derived hNP cells toward dopaminergic like neurons. PMID- 20857517 TI - Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells. AB - Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI, profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may affect neural development. In the present study, we investigated the effects of fluoxetine on the process of differentiation from ES cells into neural cells using the stromal cell-derived inducing activity (SDIA) method. Fluoxetine treatment was found to enhance the expression of glial marker genes following neural differentiation, as observed by immunocytochemical analysis or quantitative RT-PCR. The promoter activity of glial marker genes was also significantly enhanced when cells were treated with fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of mouse ES cells into glial cell lineage, which may affect fetal neural development. PMID- 20857518 TI - Clinical implications of accessory pancreatic duct. AB - The accessory pancreatic duct (APD) is the main drainage duct of the dorsal pancreatic bud in the embryo, entering the duodenum at the minor duodenal papilla (MIP). With the growth, the duct of the dorsal bud undergoes varying degrees of atrophy at the duodenal end. Patency of the APD in 291 control cases was 43% as determined by dye-injection endoscopic retrograde pancreatography. Patency of the APD in 46 patients with acute pancreatitis was only 17%, which was significantly lower than in control cases (P < 0.01). The terminal shape of the APD was correlated with APD patency. Based on the data about correlation between the terminal shape of the APD and its patency, the estimated APD patency in 167 patients with acute pancreatitis was 21%, which was significantly lower than in control cases (P < 0.01). A patent APD may function as a second drainage system for the main pancreatic duct to reduce the pressure in the main pancreatic duct and prevent acute pancreatitis. Pancreatographic findings of 91 patients with pancreaticobiliary maljunction (PBM) were divided into a normal duct group (80 patients) and a dorsal pancreatic duct (DPD) dominant group (11 patients). While 48 patients (60%) with biliary carcinoma (gallbladder carcinoma, n = 42; bile duct carcinoma, n = 6) were identified in PBM with a normal pancreatic duct system, only two cases of gallbladder carcinoma (18%) occurred in DPD-dominant patients (P < 0.05). Concentration of amylase in the bile of DPD dominance was significantly lower than that of normal pancreatic duct system (75 403.5 +/- 82 015.4 IU/L vs 278 157.0 +/- 207 395.0 IU/L, P < 0.05). In PBM with DPD dominance, most pancreatic juice in the upper DPD is drained into the duodenum via the MIP, and reflux of pancreatic juice to the biliary tract might be reduced, resulting in less frequency of associated biliary carcinoma. PMID- 20857519 TI - A review of the efficacy of traditional Iranian medicine for inflammatory bowel disease. AB - The etiology of inflammatory bowel disease (IBD) is not yet known, but many factors such as defects in the immune system, oxidative stress, microbial content in the gastrointestinal tract, nuclear factor (NF)-kappaB, nitric oxide (NO), cyclooxygenase-2 (Cox-2), and leukotriene B4 (LB4) are thought to play a role in its pathogenesis. In traditional Iranian medicine (TIM), several medicinal plants are thought to be effective for the treatment of IBD. In this study, information on all of these remedies were derived from all available old sources such as documents or notes and books and were added to the information derived from modern medical databases covering all in vitro, in vivo and clinical trials. For some of these plants, only one or two mechanisms of action have been found such as in Cassia fistula, Lepidium sativum, and Bunium persicum. However, for some plants various mechanisms of action are known. For example, Commiphora mukul is effective in IBD due to its immunomodulatory, antioxidant, and antibacterial properties and it decreases NF-kappaB, NO and Cox-2. Another herb, Plantago ovata, has immunomodulatory, antioxidant, anti-inflammatory and wound healing activities and decreases NO and LB4. Considering the mechanisms of action of these plants, the combination of some of them may be useful because of their many mechanisms of action such as Pistacia lentiscus, Bunium persicum, Solanum nigrum, Plantago ovata, Boswellia, Solanum nigrum, Plantago ovata and Commiphora mukul. For some of the herbal products used in TIM such as oleogum resin from Commiphora myrrha, seeds of Ocimum basilicum, seeds of Linum usitatissimum, gum resin of Dracaena cinnabari, seeds of Plantago major, seeds of Lallementia royleana, and seeds of Allium porrum, there is no or not enough studies to confirm their benefits in IBD. It is suggested that an evaluation of the effects of these plants on different aspects of IBD should be performed. PMID- 20857520 TI - Diagnosis and management of pancreatic neuroendocrine tumor in von Hippel-Lindau disease. AB - The pancreatic manifestations seen in patients with von Hippel-Lindau (VHL) disease are subdivided into 2 categories: pancreatic neuroendocrine tumors (NET), and cystic lesions, including simple cyst and serous cystadenoma. The VHL associated cystic lesions are generally asymptomatic and do not require any treatment, unless they are indistinguishable from other cystic tumor types with malignant potential. Because pancreatic NET in VHL disease are non-functioning and have malignant potential, it is of clinical importance to find and diagnose these as early as possible. It will be recommended that comprehensive surveillance using dynamic computed tomography for abdominal manifestations, including pancreatic NET, should start from the age of 15 years in VHL patients. Unlike sporadic non-functioning NET without VHL disease, in which surgical resection is generally recommended, VHL patients at lower metastatic risk of pancreatic NET should be spared the risks of operative resection. PMID- 20857521 TI - Recent standardization of treatment strategy for pancreatic neuroendocrine tumors. AB - Recent advances in localization techniques, such as the selective arterial secretagogue injection test (SASI test) and somatostatin receptor scintigraphy have promoted curative resection surgery for patients with pancreatic neuroendocrine tumors (PNET). For patients with sporadic functioning PNET, curative resection surgery has been established by localization with the SASI test using secretin or calcium. For curative resection of functioning PNET associated with multiple endocrine neoplasia type 1 (MEN 1) which are usually multiple and sometimes numerous, resection surgery of the pancreas and/or the duodenum has to be performed based on localization by the SASI test. As resection surgery of PNET has increased, several important pathological features of PNET have been revealed. For example, in patients with Zollinger-Ellison syndrome (ZES), duodenal gastrinoma has been detected more frequently than pancreatic gastrinoma, and in patients with MEN 1 and ZES, gastrinomas have been located mostly in the duodenum, and pancreatic gastrinoma has been found to co-exist in 13% of patients. Nonfunctioning PNET in patients with MEN 1 becomes metastatic to the liver when it is more than 1 cm in diameter and should be resected after careful observation. The most important prognostic factor in patients with PNET is the development of hepatic metastases. The treatment strategy for hepatic metastases of PNET has not been established and aggressive resection with chemotherapy and trans-arterial chemoembolization have been performed with significant benefit. The usefulness of octreotide treatment and other molecular targeting agents are currently being assessed. PMID- 20857522 TI - Liver disease and erythropoietic protoporphyria: a concise review. AB - The porphyries are a group of metabolic disorders characterized by deficiencies in the activity of enzymes involved in the biosynthesis of heme. In erythropoietic protoporphyria (EPP), in the majority of cases an autosomal dominant disease, there is a mutation of the gene that encodes ferrochelatase (FECH). FECH deficiency is associated with increased concentrations of protoporphyrin in erythrocytes, plasma, skin and liver. The prevalence of this inherited disorder oscillates between 1:75 000 and 1:200 000. Clinical manifestations of EPP appear in early infancy upon first exposure to the sun. Nevertheless, approximately 5%-20% of patients with EPP develop liver manifestations. Retention of protoporphyrin in the liver is associated with cholestatic phenomena and oxidative stress that predisposes to hepatobiliary disease of varying degrees of severity, such as cholelithiasis, mild parenchymal liver disease, progressive hepatocellular disease with end-stage liver disease and acute liver failure. Liver damage is the major risk in EPP patients, so surveillance and frequent clinical and biochemical liver follow-up is mandatory. The diagnostic approach consists in detecting increased levels of protoporphyrin, decreased activity of FECH and genetic analysis of the FECH gene. A variety of non-surgical therapeutic approaches have been adopted for the management of EPP associated with liver disease, but none of these has been shown to be unequivocally efficacious. Nevertheless, some may have a place in preparing patients for liver transplantation. Liver transplantation does not correct the constitutional deficiency of FECH. Consequently, there is a risk of recurrence of liver disease after liver transplantation as a result of continuing overproduction of protoporphyrin. Some authors recommend that bone marrow transplantation should be considered in liver allograft recipients to prevent recurrence of hepatic disease. PMID- 20857523 TI - Association of symptoms with gastrointestinal microbiota in irritable bowel syndrome. AB - AIM: To investigate the correlations between self-reported symptoms of irritable bowel syndrome (IBS) and the gastrointestinal (GI) microbiota composition. METHODS: Fecal samples were collected from a total of 44 subjects diagnosed with IBS. Their symptoms were monitored with a validated inflammatory bowel disease questionnaire adjusted for IBS patients. Thirteen quantitative real-time polymerase chain reaction assays were applied to evaluate the GI microbiota composition. Eubacteria and GI bacterial genera (Bifidobacterium, Lactobacillus and Veillonella), groups (Clostridium coccoides/Eubacterium rectale, Desulfovibrio desulfuricans) and distinct bacterial phylotypes [closest 16S rDNA sequence resemblance to species Bifidobacterium catenulatum, Clostridium cocleatum, Collinsella aerofaciens (C. aerofaciens), Coprococcus eutactus (C. eutactus), Ruminococcus torques and Streptococcus bovis] with a suspected association with IBS were quantified. Correlations between quantities or presence/absence data of selected bacterial groups or phylotypes and various IBS related symptoms were investigated. RESULTS: Associations were observed between subjects' self-reported symptoms and the presence or quantities of certain GI bacteria. A Ruminococcus torques (R. torques)-like (94% similarity in 16S rRNA gene sequence) phylotype was associated with severity of bowel symptoms. Furthermore, among IBS subjects with R. torques 94% detected, the amounts of C. cocleatum 88%, C. aerofaciens-like and C. eutactus 97% phylotypes were significantly reduced. Interesting observations were also made concerning the effect of a subject's weight on GI microbiota with regard to C. aerofaciens-like phylotype, Bifidobacterium spp. and Lactobacillus spp. CONCLUSION: Bacteria seemingly affecting the symptom scores are unlikely to be the underlying cause or cure of IBS, but they may serve as biomarkers of the condition. PMID- 20857524 TI - Lowered HGK expression inhibits cell invasion and adhesion in hepatocellular carcinoma cell line HepG2. AB - AIM: To investigate the effects of RNA interference targeting hepatocyte progenitor kinase-like kinase (HGK) in the invasion and adhesion of hepatocellular carcinoma (HCC) cell line HepG2. METHODS: Three paired insert DNA fragments specific to HGK gene and one negative control DNA fragment were synthesized and inserted into RNAi-Ready pSIREN-RetroQ-ZsGreen vector. Western blotting assay and real-time reverse transcriptase polymerase chain reaction (RT PCR) were used to screen the vector with a highest inhibitory rate. The vector was used to generate recombinant retrovirus specific to HGK. 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2h-tetrazolium bromide (MTT) assay was used to examine cell growth; wound closure assay and cell adhesion assay were employed to investigate cell migration and adhesion respectively; and transwell assay and three-dimensional culture invasion assay were used to detect cell invasion. The expressions of matrix metalloproteinase (MMP)-2, MMP-9 and nuclear factor (NF) kappaB were detected by Western blotting assay. RESULTS: The real time RT-PCR and Western blotting assay showed that cells transfected with retrovirus mediating RNAi targeting of HGK (RV-shHGK)-1 vector had the strongest inhibition of HGK protein, with an inhibition rate of 76%, and this vector was used to generate recombinant retrovirus RV-shHGK-1. Cell adhesion assay and MTT assay found that cell adhesion and growth of the cells infected with RV-shHGK-1 were significantly lower than those of the control cells (P < 0.05). Wound closure assay, transwell assay and three-dimensional culture invasion assay showed that the cell invasiveness was significantly less in HGK knockdown cells than in the control cells (P < 0.05). The expressions of MMP-2, MMP-9 and NF-kappaB were inhibited in HepG2 cells infected with RV-shHGK-1. CONCLUSION: Down-regulation of HGK can obviously inhibit the migration and invasion of HepG2 cells in vitro. HGK may be a new therapeutic target for treatment of HCC. PMID- 20857525 TI - Infantile hepatic hemangioendothelioma: a clinicopathologic study in a Chinese population. AB - AIM: To investigate whether the clinicopathologic features of infantile hemangioendothelioma (IHE) of the liver in a Chinese population are similar to the features observed in other races. METHODS: The clinical data, radiological findings, histopathological changes and outcome of 12 cases of IHE diagnosed by the Department of Pathology, West China Hospital over the last 10 years were analyzed retrospectively. Immunohistochemical studies were carried out using antibodies against CD31, CD34, Factor VIII, cytokeratin 8 and cytokeratin 18. RESULTS: The 12 patients were aged from fetal to 5 years (three males and nine females). The tumor was presented with different clinical manifestations, mainly as an asymptomatic, palpable, upper abdominal mass, except for the two fetuses who were detected antenatally by ultrasound. In one patient, this presentation was accompanied by an initial severe pneumothorax. No symptoms of congestive heart failure were present and neither congenital abnormalities nor vascular tumors in the skin or other organs were found. Laboratory abnormalities included leukocytosis (40%), anemia (60%), thrombocytosis (60%), hyperbilirubinemia (16.7%), abnormal liver function (50%) and increased alpha-fetoprotein (80%). Based on radiological findings and gross specimens, the tumor presented as a solitary lesion or a multifocal space-occupying lesion. The tumor size ranged from 5.0 cm * 3.5 cm * 2.0 cm to 13.8 cm * 9.0 cm * 7.7 cm, and the 0.2-1.1 cm nodules were diffusely distributed within the multifocal tumor. Seven cases were surgically resected, three cases underwent biopsy and the two fetuses were aborted. Histologically, nine cases were classified as type I and three as type II, presenting aggressive morphologic features, immature vessels, active mitosis and necrosis. An inflammatory component, predominantly eosinophilic granulocytes, sometimes obscured the nature of the tumor. Ten patients are alive after a follow up of 1-9 years. Based on immunohistochemistry, the endothelial cells in all cases were positive for CD31, CD34 and polyclonal factor VIII antigen, whereas the scattered hyperplasia bile ducts were positive for cytokeratin 8 and cytokeratin 18. CONCLUSION: The clinical manifestations of IHE are non-specific. There is no significant correlation between histological type and prognosis. The clinicopathologic features of IHE in Chinese patients may provide a clue to further evidence-based studies. PMID- 20857526 TI - High prevalence of viable Mycobacterium avium subspecies paratuberculosis in Crohn's disease. AB - AIM: To examine the detection rate of viable Mycobacterium avium subspecies paratuberculosis (MAP) in patients with inflammatory bowel disease [Crohn's disease (CD) and ulcerative colitis (UC)]. METHODS: Thirty patients with CD (15 with at least one NOD2/CARD15 mutation), 29 with UC, and 10 with no inflammatory bowel disease (IBD). were tested for MAP by polymerase chain reaction (specific IS900 fragment) and blood culture. RESULTS: MAP DNA was detected in all original blood samples and 8-wk blood cultures (CD, UC and non-IBD). Positive MAP DNA status was confirmed by dot blot assays. All 69 cultures were negative by acid fast Ziehl-Neelsen staining. Viable MAP, in spheroplast form, was isolated from the 18-mo blood cultures of all 30 CD patients, one UC patient, and none of the non-IBD controls. No association was found between positive MAP cultures and use of immunosuppressive drugs or CD-associated single nucleotide polymorphisms. CONCLUSION: MAP is widely present in our area and MAP DNA can be recovered from the blood of CD, UC and non-IBD patients. However, MAP spheroplasts were only found in CD patients. PMID- 20857527 TI - Risk factors associated with the development of ischemic colitis. AB - AIM: To ascertain the role of cardiovascular risk factors, cardiovascular diseases, standard treatments and other diseases in the development of ischemic colitis (IC). METHODS: A retrospective, case-control study was designed, using matched data and covering 161 incident cases of IC who required admission to our hospital from 1998 through 2003. IC was diagnosed on the basis of endoscopic findings and diagnostic or compatible histology. Controls were randomly chosen from a cohort of patients who were admitted in the same period and required a colonoscopy, excluding those with diagnosis of colitis. Cases were matched with controls (ratio 1:2), by age and sex. A conditional logistic regression was performed. RESULTS: A total of 483 patients (161 cases, 322 controls) were included; mean age 75.67 +/- 10.03 years, 55.9% women. The principal indications for colonoscopy in the control group were lower gastrointestinal hemorrhage (35.4%), anemia (33.9%), abdominal pain (19.9%) and diarrhea (9.6%). The endoscopic findings in this group were hemorrhoids (25.5%), diverticular disease (30.4%), polyps (19.9%) and colorectal cancer (10.2%). The following variables were associated with IC in the univariate analysis: arterial hypertension (P = 0.033); dyslipidemia (P < 0.001); diabetes mellitus (P = 0.025); peripheral arterial disease (P = 0.004); heart failure (P = 0.026); treatment with hypotensive drugs (P = 0.023); angiotensin-converting enzyme inhibitors; (P = 0.018); calcium channel antagonists (P = 0.028); and acetylsalicylic acid (ASA) (P < 0.001). Finally, the following variables were independently associated with the development of IC: diabetes mellitus [odds ratio (OR) 1.76, 95% confidence interval (CI): 1.001-3.077, P = 0.046]; dyslipidemia (OR 2.12, 95% CI: 1.26-3.57, P = 0.004); heart failure (OR 3.17, 95% CI: 1.31-7.68, P = 0.01); peripheral arterial disease (OR 4.1, 95% CI: 1.32-12.72, P = 0.015); treatment with digoxin (digitalis) (OR 0.27, 95% CI: 0.084-0.857, P = 0.026); and ASA (OR 1.97, 95% CI: 1.16-3.36, P = 0.012). CONCLUSION: The development of an episode of IC was independently associated with diabetes, dyslipidemia, presence of heart failure, peripheral arterial disease and treatment with digoxin or ASA. PMID- 20857528 TI - Recurrent abscess after primary successful endo-sponge treatment of anastomotic leakage following rectal surgery. AB - AIM: To assess long-term efficacy of initially successful endo-sponge assisted therapy. METHODS: Between 2006 and 2009, consecutive patients who had undergone primary successful endo-sponge treatment of anastomotic leakage following rectal cancer surgery were enrolled in the study. Patients were recruited from 6 surgical departments in Vienna. Clinical and oncologic outcomes were assessed through routine endoscopic and radiologic follow-up examination. RESULTS: Twenty patients (7 female, 13 male) were included. The indications for endo-sponge treatment were anastomotic leakage (n = 17) and insufficiency of a rectal stump after Hartmann's procedure (n = 3). All patients were primarily operated for rectal cancer. The overall mortality rate was 25%. The median follow-up duration was 17 mo (range 1.5-29.8 mo). Five patients (25%) developed a recurrent abscess. Median time between last day of endo-sponge therapy and occurrence of recurrent abscess was 255 d (range 21-733 d). One of these patients was treated by computed tomography-guided drainage and in 3 patients Hartmann's procedure had to be performed. Two patients (10%) developed a local tumor recurrence and subsequently died. CONCLUSION: Despite successful primary outcome, patients who receive endo sponge therapy should be closely monitored in the first 2 years, since recurrence might occur. PMID- 20857529 TI - A predictive factor for the response to S-1 plus cisplatin in gastric cancer. AB - AIM: To prove that the protein expression level of thymidylate synthase is a predictive factor for the response to S-1/cisplatin (CDDP) chemotherapy in gastric cancer. METHODS: We measured the protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT) in advanced gastric cancer. Before S-1/CDDP chemotherapy, tumor specimens from primary sites were obtained by endoscopic biopsy and analyzed by enzyme-linked immunosorbent assay. The chemotherapeutic effects on the primary sites were evaluated by endoscopic biopsy performed more than once after S-1/CDDP chemotherapy. The effects are a predictive factor for the response to S-1/CDDP chemotherapy in patients with advanced gastric cancer, as evaluated by endoscopic biopsy over time. RESULTS: The protein expression level of TS was significantly higher (P < 0.05) in the tumor than in the normal tissue, and significantly lower (P < 0.05) in the responders than in the non responders. We were able to evaluate the correlation between changes in the protein expression levels of TS, DPD and OPRT and chemotherapeutic responses in 7 patients by assessing tumor tissues more than twice. In the responders, the protein expression level of TS was < 40 ng/mg protein. However, there were significant increases in the protein expression levels of TS (P < 0.01) and DPD (P < 0.05) after chemotherapy in 3 patients. In these cases, the patient assessment changed from "responder" to "non-responder". In the non-responders, the protein expression level of TS was > 40 ng/mg protein. CONCLUSION: We have confirmed that the protein expression level of TS is a predictive factor for the response to S-1/CDDP chemotherapy in patients with advanced gastric cancer. PMID- 20857530 TI - Clinicopathological evaluation of duodenal well-differentiated endocrine tumors. AB - AIM: To assess the clinicopathological characteristics of duodenal well differentiated endocrine tumors. METHODS: We examined clinicopathological characteristics in 11 consecutive patients with duodenal well-differentiated endocrine tumors treated by endoscopic therapy or surgery in our hospital from 1992 through 2007. Patients with well-differentiated endocrine tumors of the papilla of Vater or with gastrinoma were excluded. RESULTS: Three patients received endoscopic treatment, and 8 underwent surgery. In patients who received endoscopic treatment, the tumor diameter was less than 1.0 cm, with no histopathological evidence of lymphovascular invasion or invasion of the muscularis. There were no complications such as late bleeding or perforation after treatment. Among 8 patients with tumors less than 1.0 cm in diameter, 3 underwent partial resection, and 2 underwent radical surgery. Three patients had lymphovascular invasion, 1 had invasion of the muscularis, and 1 had proximal lymph node metastasis. Among 3 patients with tumors 1.0 cm or more in diameter, 1 underwent partial resection, and 2 underwent radical surgery. One patient had lymphovascular invasion, with no lymph node metastasis. After treatment, all patients are alive and have remained free of metastasis and recurrence. CONCLUSION: Duodenal well-differentiated endocrine tumors less than 1.0 cm in diameter have a risk of lymphovascular invasion, invasion of the muscularis, and lymph node metastasis, irrespective of procedural problems. PMID- 20857531 TI - Endoscopic removal of gastric ectopic pancreas: an initial experience with endoscopic submucosal dissection. AB - AIM: To evaluate the therapeutic usefulness and safety of endoscopic resection in patients with gastric ectopic pancreas. METHODS: A total of eight patients with ectopic pancreas were included. All of them underwent endoscopic ultrasonography before endoscopic resection. Endoscopic resection was performed by two methods: endoscopic mucosal resection (EMR) by the injection-and-cut technique or endoscopic mucosal dissection (ESD). RESULTS: We planned to perform EMR in all eight cases but EMR was successful in only four cases. In the other four cases, saline spread into surrounding normal tissues and the lesions became flattened, which made it impossible to remove them by EMR. In those four cases, we performed ESD and removed the lesions without any complications. CONCLUSION: If conventional EMR is difficult to remove gastric ectopic pancreas, ESD is a feasible alternative method for successful removal. PMID- 20857532 TI - Double balloon endoscopy increases the ERCP success rate in patients with a history of Billroth II gastrectomy. AB - AIM: To evaluate the effect of double balloon endoscope (DBE) on the endoscopic retrograde cholangiopancreatography (ERCP) success rate in patients with a history of Billroth II (B II) gastrectomy. METHODS: From April 2006 to March 2007, 32 patients with a B II gastrectomy underwent 34 ERCP attempts. In all cases, the ERCP procedures were started using a duodenoscope. If intubation of the afferent loop or reaching the papilla failed, we changed to DBE for the ERCP procedure (DBE-ERCP). We assessed the success rate of afferent loop intubation, reaching the major papilla, selective cannulation, possibility of therapeutic approaches, procedure-related complications, and the overall success rate. RESULTS: Among the 32 patients with a history of B II gastrectomy, the duodenoscope was successfully passed up to the papilla in 22 patients (69%), and cannulation was successfully performed in 20 patients (63%). Six patients (2 with failure in afferent loop intubation and 4 with failure in reaching the papilla) underwent DBE-ERCP. The DBE reached the papilla in all the 6 patients (100%) and selective cannulation was successful in 5 patients (83%). Four patients (67%) who had common bile duct stones were successfully treated. One patient underwent diagnostic ERCP only and the other one, in whom selective cannulation failed, was diagnosed with papilla cancer proven by biopsy. There were no complications related to the DBE. The overall ERCP success rate increased to 88% (28/32). CONCLUSION: The overall ERCP success rate increases with DBE in patients with a previous B II gastrectomy. PMID- 20857534 TI - Laparoscopic low anterior resection for rectal carcinoma: complications and management in 132 consecutive patients. AB - AIM: To analyze the clinical manifestations and risk factors of complications in laparoscopic low anterior resection (LAR) for rectal cancer patients. METHODS: A series of 132 consecutive patients who received laparoscopic LAR for rectal cancer in our center were included. The etiology, diagnosis, treatment and prevention of rectal cancer were studied among the patients with surgery-related complications using both univariate and multivariate regression analysis. RESULTS: No conversion to open surgery was observed and 5 cases converted to hand assisted laparoscopic operation. The overall morbidity rate was 20.5%. Complications occurred during the operation in 7 patients (5.3%), within 30 postoperative days in 24 patients (18.2%), and within 3 mo in 2 patients (1.5%). The most significant complications were anastomotic leakage (9.1%) and anastomotic hemorrhage (5.3%). Size and location of tumor, pathological staging and preoperative nutrition were significant factors associated with LAR complications, while gender, age and pathological type showed no relevance. Binary logistics regression showed that the size and location of tumor, and pathological staging were independent factors of laparoscopic LAR. All the complications were treated during their onset of clinical manifestations by interventional or conservative therapy. CONCLUSION: Anastomotic leakage is a major complication in laparoscopic LAR. The complications may be associated with tumor size and site, and pathological stage. Interventional therapies are of value in the management of laparoscopic LAR complications. PMID- 20857533 TI - Plasma miR-216a as a potential marker of pancreatic injury in a rat model of acute pancreatitis. AB - AIM: To study the potential value and specificity of plasma miR-216a as a marker for pancreatic injury. METHODS: Two rat models were applied in this article: L arginine-induced acute pancreatitis was used as one model to explore the potential value of plasma miR-216a for detection of pancreatic injury; nonlethal sepsis induced in rats by single puncture cecal ligation and puncture (CLP) was used as the other model to evaluate the specificity of plasma miR-216a compared with two commonly used markers (amylase and lipase) for acute pancreatitis. Plasmas were sampled from rats at indicated time points and total RNA was isolated. Real-Time Quantitative reverse transcriptase-polymerase chain reaction was used to quantify miR-216a in plasmas. RESULTS: In the acute pancreatitis model, among five time points at which plasmas were sampled, miR-216a concentrations were significantly elevated 24 h after arginine administration and remained significantly increased until 48 h after operation (compared with 0 h time point, P < 0.01, Kruskal-Wallis Test). In the CLP model, plasma amylase and lipase, two commonly used biomarkers for acute pancreatitis, were significantly elevated 24 h after operation (compared with 0 h time point, P < 0.01 and 0.05 respectively, Pairwise Bonferroni corrected t-tests), while miR-216a remained undetectable among four tested time points. CONCLUSION: Our article showed for the first time that plasma miR-216a might serve as a candidate marker of pancreatic injury with novel specificity. PMID- 20857535 TI - High expression level of EDIL3 in HCC predicts poor prognosis of HCC patients. AB - AIM: To determine the role of epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) in pathogenesis of hepatocellular carcinoma (HCC) by investigating the EDIL3 expression in HCC and its prognostic value for HCC. METHODS: EDIL3 expression was detected in 101 HCC surgical tissue samples with immunohistochemistry method, and its relation with clinicopathologic features and prognosis of HCC patients was analyzed. RESULTS: EDIL3 was highly expressed in 48.5% of the HCC patients. Although the EDIL3 expression level did not correlate with any clinicopathological parameters, Kaplan-Meier survival analysis showed that high expression level of EDIL3 resulted in a significantly poor prognosis of HCC patients (log-rank test, P = 0.010). Multivariate Cox's analysis showed that the EDIL3 expression level was a significant and independent prognostic parameter for the overall survival rate of HCC patients (hazard ratio = 1.978, 95% confidence interval = 1.139-3.435, P = 0.015). CONCLUSION: High expression level of EDIL3 predicts poor prognosis of HCC patients. EDIL3 may be a potential target of antiangiogenic therapy for HCC. PMID- 20857536 TI - Clinicopathological features of gastric glomus tumor. AB - AIM: To study the clinicopathological features of gastric glomus tumor and review the related Chinese literature published in 1990-2010. METHODS: A case of gastric glomus tumor was reported. Clinicopathological findings in 56 cases of gastric glomus tumor were analyzed. RESULTS: Gastric glomus tumor was far more common in women than in men with a female to male ratio of 1.6:1. The median age of the patients was 45 years (range 28-79 years). The patients often complained of epigastric pain and bloody stool. The tumor was located in antrum of the stomach. The greatest diameter of the tumor was 0.8-11 cm. Histologically, the tumor was comprised of nests of glomus cells surrounding the capillaries. Glomus cells were small, uniform and round. Vimentin, smooth muscle actin and actin were expressed in the tumor. Other markers, including S-100 protein, CD34, CD117, desmin, CD56, synaptophysin, chromogranin A, neuron specific enolase and cytokeratin were all negative. CONCLUSION: Gastric glomus tumor is a rare benign mesenchymal neoplasm. Its diagnosis depends on pathologic examination. Differential diagnosis includes gastrointestinal stromal tumor, paraganglioma and carcinoid tumor. PMID- 20857537 TI - Complete resection of isolated pancreatic metastatic melanoma: a case report and review of the literature. AB - Isolated metastatic melanoma of the pancreas is very rare. Currently, there is very limited experience with surgical resection of pancreatic metastasis. The potential benefit of metastasectomy can improve the quality of life and survival time of patients. We present a case of a 39-year-old Chinese male with a solitary pancreatic tumor which was considered a cystic benign lesion for years. Pathology and immunohistochemistry showed that the tumor in pancreatic tail was a metastasis from a malignant melanoma of the eyeball. No other metastastic foci were found in abdomen. The tumor was completely resected with combined distal pancreatectomy and splenectomy. The patient has survived 25 mo without any signs of local recurrence or other metastatic lesions after operation, indicating that complete surgical resection of a solitary metastatic melanoma of the pancreas can prolong the survival time of patients. PMID- 20857538 TI - Abnormal colonic cholinergic and nitrergic activities in relation to elastosis in uncomplicated diverticular disease. AB - I read with interest the review on the pathogenesis of diverticular disease by Commane et al in World J Gastroenterol 2009; 15(20): 2479-2488. However, I would like to discuss several important errors that the authors made whilst citing information from previously published work on the neuromuscular dysfunction in the disease. PMID- 20857539 TI - [HIV status and recurrent tuberculosis]. PMID- 20857540 TI - [Podoconiosis]. PMID- 20857542 TI - Images in clinical medicine. Gottron's papules and dermatomyositis. PMID- 20857541 TI - Oleanane-type triterpene glucuronides from the roots of Glycyrrhiza uralensis Fischer. AB - Investigation of characteristic constituents of the roots of Glycyrrhiza uralensis Fischer led to isolation of four new triterpene glucuronides, namely uralsaponins C-F (1-4), an artificial product, namely the methyl ester of glycyrrhizin (5), as well as six known triterpene glucuronides (6-11). These new compounds were identified by 1D and 2D NMR spectroscopic analysis. The cytotoxicity of the selected compounds and their aglycones were evaluated against HeLa and MCF-7 cancer cell lines, and the preliminary structure-activity relationship was also elucidated. PMID- 20857543 TI - Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. PMID- 20857544 TI - Pediatric mental health care dysfunction disorder? PMID- 20857545 TI - Pediatric mental health care dysfunction disorder? PMID- 20857546 TI - Africa faces an uphill struggle to reach the MDGs. PMID- 20857547 TI - Rwanda: an injection of hope. PMID- 20857548 TI - The MDG decade: looking back and conditional optimism for 2015. PMID- 20857549 TI - Letter from Renato V. Iozzo. Matrix Biology. PMID- 20857550 TI - Moving past sleight of hand. PMID- 20857551 TI - Core muscle activation during Swiss ball and traditional abdominal exercises. PMID- 20857552 TI - Congenital isolated biventricular diverticula evaluated by cardiac computed tomography and magnetic resonance imaging. PMID- 20857553 TI - [The significance of individual sensitivity to hypoxia for the duration of severe compression trauma]. AB - In the experiments on rats was shown that individual differences in sensitivity to hypoxia were significant for subsequences of long-term immobilization stress and severe compression trauma. In these conditions, low resistant rats were more sensitive to hypoxia compared with high resistant animals. The low resistant rats had got more significant changes of the main functional systems and acid-alkaline buffer state. PMID- 20857555 TI - [Clinical and diagnostic value of heart rate variabilities in workers exposed to noise and vibration]. AB - Noise and vibration cause disorders of vegetative regulation of cardiovascular system. Daily ECG monitoring with heart rate variabilities analysis enables quanitative evaluation of disordered vegetative control over heart rate and diagnosis of cardioneuropathy caused by long occupational exposure to noise and vibration. PMID- 20857554 TI - [Redistribution of gastrointestinal ammonia into blood in alcohol coma rat: the role in lethal outcome]. AB - At 3 h after the intragastral administration of ethanol (446 mmol/kg) the blood ammonia concentration in v. portae increased 1.4 times, in v. cava inf. caudally of vv. renales inflow - 2.2 times, cranially of vv. hepaticae - 2.5 times, and in blood obtained by decapitation - by 65%7. The rate of ammonia accumulation in 'avage medium injected intraperitoneally was triple as that in intact rats. The exposure to atmospheric ammoniac (0.84-1.07 mg/l) for 3 h resuited in increasing blood ammonia concentration 2.4 times compared with the isolated ethanol action. The ammonia inhalation promoted the lethal action of ethanol with a dose alteration factor of 0.81 and suppressed gas-exchange. The promotion of the ethanol lethal action by the non-lethal ammonium acetate dosage has been observed. These data suggest that in rat, the coma-inducing ethanol ingestion promotes the translocation of intestinal ammonia into the common bloodstream, which has a detrimental effect on the outcome of alcohol coma. PMID- 20857556 TI - [Osteoporosis as a problem of industrial hygiene (clinical and X-ray aspects of diagnosis)]. AB - The article was aimed to evaluate locomotory system state in mental and physical workers. The study covered 232 patients. The investigation revealed peculiarities concerning course of destructive and degenerative diseases of locomotory system in the workers examined. PMID- 20857557 TI - [Novelties of re-entrance for the world's invalids]. PMID- 20857558 TI - [Therapeutic education for all concerned patients]. PMID- 20857559 TI - [Reorientation of politics with regard to the struggle against HIV]. PMID- 20857560 TI - [Nursing profession in France: return to the year 1900]. PMID- 20857561 TI - [Physiopathology and treatment of chronic respiratory insufficiency]. PMID- 20857562 TI - Spatial justice and the translation of European strategic planning ideas in the urban sub-region of south Yorkshire. AB - This paper analyses urban planning practices in South Yorkshire to reveal how EU strategic spatial ideas and values are reproduced. Specifically, the paper examines how the notion of spatial justice was interpreted as the organising concepts within the European Spatial Development Perspective became situated within a territory severely affected by deindustrialisation in the 1980s, but subsequently a major beneficiary of EU Structural Fund programmes. The analysis reveals how policy-making at this scale used a construct of polycentric urban development that reasserted a model of economic growth based on the indigenous assets held in city centres at the expense of more redistributive measures targeted at the former coal-mining communities in the sub-region. PMID- 20857563 TI - Comparing the capitalisation benefits of light-rail transit and overlay zoning for single-family houses and condos by neighbourhood type in metropolitan Phoenix, Arizona. AB - Light rail transit (LRT) is increasingly accompanied by overlay zoning which specifies the density and type of future development to encourage landscapes conducive to transit use. Neighbourhood type (based on land use mix) is used to partition data and investigate how pre-existing land use, treatment with a park and-ride (PAR) versus walk-and-ride (WAR) station and overlay zoning interrelate. Hedonic models estimate capitalisation effects of LRT-related accessibility and overlay zoning on single-family houses and condos in different neighbourhoods for the system in metropolitan Phoenix, Arizona. Impacts differ by housing and neighbourhood type. Amenity-dominated mixed-use neighbourhoods-predominantly WAR communities-experience premiums of 6 per cent for single-family houses and over 20 per cent for condos, the latter boosted an additional 37 per cent by overlay zoning. Residential neighbourhoods-predominantly PAR communities-experience no capitalisation benefits for single-family houses and a discount for condos. The results suggest that land use mix is an important variable to select comparable neighbourhoods. PMID- 20857565 TI - Contested identities: gendered politics, gendered religion in Pakistan. AB - In Pakistan, the self-serving use of Islam by more secular elements alongside politico-religious ones facilitated the latter's increasing influence and the conflation and intricate interweaving of Islam and Pakistani nationhood. A paradigm shift under Zia's martial law revamped society as much as state laws, producing both religiously defined militias and aligned civil society groups. Examining the impact on women of fusing religion and politics, this paper argues that women become symbolic markers of appropriated territory in the pursuit of state power, and that the impact of such fusing, different for differently situated women, needs to be gauged in societal terms as well as in terms of state dynamics. Questioning the positing of civil society as a self-evident progressive desideratum, the paper concludes that gender equality projects seeking reconfigurations of power cannot be effective without vigorously competing in the creation of knowledge, culture and identity. PMID- 20857564 TI - The unhappy marriage of religion and politics: problems and pitfalls for gender equality. AB - This article explores how religion as a political force shapes and deflects the struggle for gender equality in contexts marked by different histories of nation building and challenges of ethnic diversity, different state-society relations (from the more authoritarian to the more democratic), and different relations between state power and religion (especially in the domain of marriage, family and personal laws). It shows how 'private' issues, related to the family, sexuality and reproduction, have become sites of intense public contestation between conservative religious actors wishing to regulate them based on some transcendent moral principle, and feminist and other human rights advocates basing their claims on pluralist and time- and context-specific solutions. Not only are claims of 'divine truth' justifying discriminatory practices against women hard to challenge, but the struggle for gender equality is further complicated by the manner in which it is closely tied up with, and inseparable from, struggles for social and economic justice, ethnic/racial recognition, and national self-determination vis--vis imperial/global domination. PMID- 20857566 TI - Religion, politics and gender equality in Turkey: implications of a democratic paradox? AB - This article examines the gendered implications of the intertwining of Islam and politics that took shape after the process of democratisation in Turkey had brought a political party with an Islamist background to power. This development revived the spectre of restrictive sex roles for women. The country is thus confronted with a democratic paradox: the expansion of religious freedoms accompanying potential and/or real threats to gender equality. The ban on the Islamic headscarf in universities has been the most visible terrain of public controversy on Islam. However, the paper argues that a more threatening development is the propagation of patriarchal religious values, sanctioning secondary roles for women through the public bureaucracy as well as through the educational system and civil society organisations. PMID- 20857567 TI - Islamic politics and women's quest for gender equality in Iran. AB - The unification of a strong and authoritarian state with religious laws and institutions after the 1979 revolution in Iran has resulted in the creation of a dualistic state structure in which non-elected and non-accountable state authorities and institutions-the majority of whom have not accepted either the primacy of democracy nor the premise of equality between men and women (or Muslims and non-Muslims)-are able to oversee the elected authorities and institutions. The central question posed by this paper is whether a religious state would be capable of democratising society and delivering gender equality. By analysing the regime's gender policies and political development, the paper suggests that, at least in the case of Iran and Shi'ism, the larger obstacle to gender (and minorities') equality has more to do with the undemocratic state society relations that persist in Iran and less to do with the actual or potential compatibility (or lack thereof) of religious traditions or practices with democratic principles. PMID- 20857568 TI - Between universal feminism and particular nationalism: politics, religion and gender (in)equality in Israel. AB - This article argues that one of the many "idiosyncrasies" of the Israeli case, namely Israel's continuing, violent conflict with its Arab neighbours, is of highly influential relevance to the issue of gender relations. Viewed by many Israeli Jews as a struggle for the very existence of the Jewish state, the Arab Israeli conflict has overshadowed most other civil and social issues, rendering them "secondary" to the primary concern of securing the safe existence of the state. This has pushed such pressing issues as gender equality and women's rights aside, thus allowing for the perpetuation of discriminatory, sometimes rather repressive treatment of women in Israel. The most blatant expression of this is the turning of the struggle for civil marriage and divorce into a non-issue. Following a short introduction of the relevant political context, we discuss women's positivist and legal status, then conclude with an analysis of the women's movement, highlighting the emergence of religious feminism. PMID- 20857569 TI - On the bodies of women: the common ground between Islam and Christianity in Nigeria. AB - This article explores the common ideological ground between Islam and Christianity in Nigeria, in the ways in which gender and sexuality are configured in relation to women's bodies. The latter constitute key sites for the inscription of social norms and practices inherent in particular interpretations of religion. We proceed by examining the interplay between religion and politics in historical context and in specific concrete instances. While the religious right among Muslims and Christians share the view that women's bodies are sexually corrupting and therefore in need of control, this perspective is also found in secular institutions. At the same time Christians and Muslims are strongly opposed to controls on women's bodies that may lead to either religious group being identified as 'the other'. The linkage made between women's bodies and 'public morality' produces diverse forms of gender inequality. The moralising of political economy that these processes entail complicates the terrain on which challenges to the politicisation of religion and its gender politics need to be sustained. PMID- 20857570 TI - Gender, religion and democratic politics in India. AB - This article examines the impact of identity politics on gender equality. More specifically it explores the paradoxical and complex relationship of religion and politics in a multi-religious society and the complicated ways in which women's activism has both reinforced and challenged their gender identities. Contrary to the argument that religious politics does not always negate gender equality, the article argues that the Hindu religious politics and women's activism associated with it provides a compelling example of the instrumentalisation of women to accomplish the political goals of the Hindu right. It also examines the approach and strategies of influential political parties, women's organisations and Muslim women's groups towards legal reform and the contested issue of a uniform civil code. Against those who argue that, in the current communal conjuncture, reform within Muslim personal laws or Islamic feminism is the best strategy for enhancing the scope of Muslim women's rights, the article argues that such an approach tends to freeze identities within religious boundaries. It shows how women's and minority rights are used within the politics of religion to sideline the agenda of women's rights. PMID- 20857571 TI - Religion, politics and gender in the context of nation-state formation: the case of Serbia. AB - This article argues that nationalism has connected religion with secular politics in Serbia but that their rapprochement has been a gradual process. In order to demonstrate the transition from a limited influence of religion on politics to a much tighter relationship between the two, this article discusses the abortion legislation reform and the introduction of religious education in public schools, respectively. It argues that, while illustrative of different types of connection between religion and politics, these two issues had similar implications for gender equality-they produced discourses that recreated and justified patriarchal social norms. After religion gained access to public institutions, its (patriarchal) discourses on gender were considerably empowered. The article points to some tangible evidence of a re-traditionalisation and re patriarchalisation of gender roles within the domestic realm in Serbia. PMID- 20857572 TI - Democracy in the country but not in the home? Religion, politics and women's rights in Chile. AB - This article explores the influence of religious actors on the elaboration of two public policies that are key to the advancement of women's rights and have long formed part of the women's movement's agenda in Chile: the introduction of sexual education in secondary schools in the 1990s and the distribution of emergency contraception in the 2000s. Our analysis of how different actors-from a variety of ideological and power positions-have influenced the two policy debates suggests that their discourses and strategies are highly contingent on the political environment. While conservative religious forces retain an enormous capacity to hinder policy making and implementation in the arena of family and sexuality, the government's determination to confront such interference seems to have grown in a context of fewer authoritarian enclaves, a more pluralist society and a strong sexual and reproductive rights movement. The diversification of religious positions on issues of family and sexuality has also affected the room for manoeuvre in the policy arena. PMID- 20857573 TI - Politics, religion and gender equality in contemporary Mexico: women's sexuality and reproductive rights in a contested secular state. AB - This article explores the complexities of the interaction between politics, religion and gender equality in contemporary Mexico, by analysing recent developments in public debate, legal changes and implementation of government policies in two areas: 1) the inclusion of emergency contraception in public health services in 2004; and 2) the decriminalisation of abortion in Mexico City in 2008, which was followed by a massive campaign to re-criminalise abortion in the federal states. Three main findings emerge from our analysis: first, that women's sexual and reproductive autonomy has become an issue of intense public debate that is being addressed by both state-public policy and society; second, that the gradual democratisation of the Mexican political system and society is forcing the Catholic Church to play by the rules of democracy; and third, that the character and nature of the Mexican (secular) state has become an arena of intense struggle within which traditional political boundaries and ideologies are being reconfigured. PMID- 20857574 TI - Reproductive rights in Poland: when politicians fear the wrath of the Church. AB - The historical prestige of the Polish Catholic Church is the result of its presence as a national symbol of resistance, both under foreign occupation and during the communist regime. In the post-communist era the power of the Church within the political arena has significantly increased, through the Concordat that was signed with the state as well as through formal and informal ties with political parties. Catholicism is the de facto religion of the state, even if Poland remains a nominally secular country. This was illustrated by the adoption, in 1993, of a total abortion ban. Although the relation of Poles to the Catholic dogma on sexuality and reproductive rights tends to be weak, fearing criticism from Church authorities, most politicians avoid controversial topics and express their commitment to Catholic dogma. Thus women's groups have encountered serious difficulties in their efforts to defend women's rights to sexual and reproductive autonomy. Although accession to the European Union has put Poland in an awkward position with respect to equality of rights between women and men, it has not fundamentally altered the real situation with respect to the controversial topic of abortion. PMID- 20857575 TI - Sex, secularism and religious influence in US politics. AB - Through an analysis of alliances between secular and religious actors in US politics and a specific case study on anti-trafficking policy, we show that the intertwining of religion and politics in the US comes from two sources: 1) the secular political and cultural institutions of American public life that have developed historically out of Protestantism, and which predominantly operate by presuming Protestant norms and values; and 2) the direct influence on US politics of religious groups and organisations, particularly in the past quarter-century of lobby groups and political action committees identified with conservative evangelical Christianity. The sources of policies that promote gender and sexual inequality in the US are both secular and religious and we conclude that it is inaccurate to assume that religious influence in politics is necessarily conservative or that more secular politics will necessarily be more progressive than the religious varieties. PMID- 20857576 TI - Europe, the final solution and the dynamics of intent. AB - The scale and scope of the "final solution" of the "Jewish question" were extreme even in the horrific annals of genocide. Bloxham attempts to shed light on the pattern of mass murder in its expansion and contraction by viewing the Holocaust in a set of temporally and culturally specific contexts. It places the Holocaust into a broader European framework of violent ethnopolitics and geopolitics from the late nineteenth century through the mid-twentieth century. The Holocaust is depicted as an only partially discrete part of a continental process of traumatic flux, and a part, furthermore, that can itself be partially disaggregated into national and regional components. Bloxham moves from a general consideration of patterns of ethnic violence in the period to a closer causal explanation that shows the different valences of Nazi policy towards Jews in the lands directly ruled by Germany and those of Germany's allies respectively. He shows that the peculiarly extensive ambitions of the "final solution" at its most expansive can only be explained when wider geopolitical and strategic contextual terms are factored in along with consideration of Nazi ideology and the internal dynamics of some of the key institutions of the perpetrator state. PMID- 20857577 TI - The forest behind the bar charts: bridging quantitative and qualitative research on Roma/Tigani in contemporary Romania. AB - Rughinis discusses three controversial issues with regard to surveys of the Romani population: ethnonym use, self-identification versus hetero-attribution of Romani ethnicity, and the use of variables in reference to Romani settlements. She uses data sets from ten surveys of Romanian Roma between 2000 and 2008 as well as the 2002 Romanian Census to compare two types of samples, and to explore the consequences of several research choices for the quality of the data. In addition to specific methodological issues, Rughinis addresses the relevance to such surveys of qualitative research in Romani communities. PMID- 20857578 TI - Reading Mustafa Kemal Ataturk on the Armenian genocide of 1915. AB - The debate on where Mustafa Kemal Atatrk, the founder of modern Turkey and universally known as the "Father of the Turks," stood in regard to the colossal violence committed against Armenians during the First World War has become a fiercely contested part of the Turkish-Armenian reconciliation process, especially within the past few years. Ulgen aims to clear away the clouds of dust surrounding Kemal by delving into his texts and examining his role in the reification of Turkish denial of the destruction of Ottoman Armenians. Based on a textual analysis of his entire corpus, including Nutuk-the Great Speech of 1927 and the master-narrative of modern Turkish history and national identity-her article examines and documents how his charismatic leadership helped to consolidate both the myth of "murderous Armenians" and that of the Turks as an "oppressed nation" (mazlum millet), monumentalizing both in official Turkish historiography. Ulgen argues that Kemal's portrayal of Armenians and the Armenian Question was generally consistent across the years and in various political documents, as well as being consistent with contemporary Turkish representations of the events of 1915. What really tips the balance towards Turkish innocence in Kemal's representation of the conflict is not his framing of the issue per se but the stark difference in the rhetoric he deploys in depicting Armenian and Turkish atrocities and, hence, Armenians and Turks. The undeniable authority of this discursive regime is central to the resilience of Turkish denial today. PMID- 20857583 TI - Experimental encounters: Filipino and Hawaiian bodies in the U.S. imperial invention of odontoclasia, 1928-1946. AB - Through extensive dietary and dental surveys among infants and children living in Hawai'i starting in the late 1920s, medical researchers transformed immigrant and indigenous children's mouths into objects of pathological comparison, establishing sites of alternative empirical and epistemological contact that are endemic to U.S. Pacific empire. These studies resulted in the extension of odontoclasia, a veterinary diagnosis, from dogs to humans. As a dietary antidote, researchers recommended the wider consumption of poi, a starchy Hawaiian staple. Although this appears to be a novel endorsement of indigenous foodways predating contemporary activist efforts to reinstate traditional food cultures to support indigenous health, narrow technocratic specificity and the biomedical emphasis on the cultural rather than structural etiology of odontoclasia marginalized Hawaiian health by reducing morbidity to failures to conform to U.S. imperial modernity, which included industrial medical surveillance on plantations. Conversely, doctors credited plantations for saving Filipinos through successful imperial and hygienic assimilation. PMID- 20857585 TI - Transnational indigenous exchange: rethinking global interactions of indigenous peoples at the 1904 St. Louis Exposition. AB - When the St. Louis Exposition opened in 1904 it became host to the largest gathering of the world's Indigenous peoples to that date. However, questions about how Native peoples understood these transnational Indigenous interactions have remained largely out of the realm of academic inquiry-a fact often attributed to the "absence" of primary sources. This article counters such assertions by providing a rereading that interrogates colonial assumptions embedded in both archival materials and contemporary scholarly interpretations. By analyzing a candid photograph of two Native women-one Tzoneca, the other Ainu taken at the fair by Jessie Tarbox Beals and utilizing Frederick Starr's journal, this article ultimately questions whether the Exposition's celebration of empire may have inadvertently served anti-colonial purposes. Namely, by presenting Indigenous participants with opportunities to forge relationships across the globe, a fact that may have served to inform the late 20th century emergence of a global Indigenous consciousness. PMID- 20857586 TI - "Sowing death in our women's wombs": modernization and indigenous nationalism in the 1960s Peace Corps and Jorge Sanjines' "Yawar Mallku". AB - This paper explores the centrality of gender and sexual politics to both 1960s modernization discourses and anti-imperialist cultural nationalist ideologies through an analysis of Jorge Sanjines' 1969 radical neorealist film Yawar Mallku, the text that led to the Peace Corps' expulsion from Bolivia. After outlining the development discourse that explicitly guided both the Peace Corps and the Revolutionary Nationalist (MNR) government of Bolivia and exploring the relationship of this discourse to the Bolivian radical and indigenous movements of the late 1960s, this paper reads Yawar Mallku in the context of these movements to arrive at an understanding how cultural nationalism in Bolivia became directed towards the developmentalist ideal of a masculine utopia whose construction would entail controlling women's bodies. Finally, the paper attempts to understand how indigenous women in Bolivia have articulated radical political visions within and in response to U.S. modernizing forces and indigenous cultural nationalism. PMID- 20857587 TI - "A fascinating interracial experiment station": remapping the Orient-occident divide in Hawai'i. PMID- 20857588 TI - Care for the "racially careless": Indian hospitals in the Canadian West, 1920 1950s. AB - In the 1930s, sanatorium directors and medical bureaucrats warned of the threat to Canadian society of "Indian tuberculosis." Long-standing government policy aimed to isolate Aboriginal people on reserves and in residential schools, while their access to medical care was limited by government parsimony and community prejudice. Characterized as "racially careless" concerning their own health, Aboriginal bodies were seen as a menace to their neighbours and a danger to the nation. By the 1940s state-run racially segregated Indian hospitals institutionalized Aboriginal people who were not welcome in provincial sanatoria or in the modernizing community hospitals. The opening of the Charles Camsell Indian Hospital in Edmonton in 1946, one of the first acts of the newly created department of National Health and Welfare, was a very public demonstration of the state's commitment to define and promote "national health" by isolating and institutionalizing Aboriginal people. PMID- 20857589 TI - War's long shadow: masculinity, medicine, and the gendered politics of trauma, 1914-1939. AB - War is an inherently traumatizing experience, and during the First World War more than 15,000 Canadian soldiers were diagnosed with some form of war-related psychological wounds. Many more went unrecognized. Yet the very act of seeking an escape from the battlefield or applying for a postwar pension for psychological traumas transgressed masculine norms that required men to be aggressive, self reliant, and un-emotional. Using newly available archival records, contemporary medical periodicals, doctors' notes, and patient interview transcripts, this paper examines two crises that arose from this conflict between idealized masculinity and the emotional reality of war trauma. The first came on the battlefield in 1916 when, in some cases, almost half the soldiers evacuated from the front were said to be suffering from emotional breakdowns. The second came later, during the Great Depression, when a significant number of veterans began to seek compensation for their psychological injuries. In both crises, doctors working in the service of the state constructed trauma as evidence of deviance, in order to parry a larger challenge to masculine ideals. In creating this link between war trauma and deviance, they reinforced a residual conception of welfare that used tests of morals and means to determine who was deserving or undeserving of state assistance. At a time when the Canadian welfare state was being transformed in response to the needs of veterans and their families, doctors' denial that "real men" could legitimately exhibit psychosomatic symptoms in combat meant that thousands of legitimately traumatized veterans were left uncompensated by the state and were constructed as inferior, feminized men. PMID- 20857590 TI - The first welfare case: money, sex, marriage, and white supremacy in Selma, 1966: a reproductive justice analysis. AB - King v. Smith, the first welfare case heard by the U.S. Supreme Court, overturned the Alabama substitute father law. Such laws directed or allowed welfare officials to use the sexual behavior and reproductive capacity of poor African American women to alienate this population from "cash-money"; to reassert political and bureaucratic control over the intimate relationships of African Americans, demonstrating that this population was unprepared for civil rights and full citizenship; and to shore up white supremacy in the civil rights era. The context for this case which originated in Selma, Alabama in 1966 illustrates that even if poor African American women had had access to contraception and legal abortion at that time, they would still have lacked reproductive autonomy and dignity as the state surveilled their sexual behavior and enforced laws making sex, itself, as well as reproduction, and the right to define their own intimate relationships and families, a race and class privilege. PMID- 20857591 TI - "Reclaiming the white daughter's purity": Afrikaner nationalism, racialized sexuality, and the 1975 Abortion and Sterilization Act in apartheid South Africa. AB - This article examines the struggle over abortion law reform that preceded the enactment in 1975 of the first statutory law on abortion in South Africa. The ruling National Party government produced legislation intended to eliminate access to doctors willing to procure abortions in an attempt to prevent young, unmarried white women from engaging in premarital (hetero) sexual activity. It was also aimed at strictly regulating the medical profession's actions with regards to abortion. The production of the abortion legislation was directly influenced by international struggles for accessible abortion and, more broadly, sexual liberation. The regime believed South Africa was being infiltrated by Western "immorality" and the abortion law was an attempt to buttress racist heteropatriarchal apartheid culture. Examining the abortion controversy highlights the global circulation of ideas about reproduction in the twentieth century and foregrounds a neglected dimension of the history of sexual regulation in apartheid South Africa: the disciplining and regulation of white female reproductive sexuality. PMID- 20857592 TI - Bodies of evidence: activists, patients, and the FDA regulation of Depo-Provera. AB - In January 1983, the FDA held one of only two scientific "Public Boards of Inquiry" in the history of the administration to determine whether to approve Depo-Provera for use as a contraceptive in the United States. At the hearing, ideas about gender and power played a central role in negotiations between scientists, doctors, patients, and women's health activists. The nature of the Depo-Provera Public Board of Inquiry lends itself to analysis of the interaction between and among these groups, each of which had a vested interest in the outcome of the FDA decision. The stories and strategies emerging from the actors involved in the Public Board of Inquiry reveal the enormous complexity of regulating reproduction in the late twentieth century. PMID- 20857593 TI - From breakthrough to bust: the brief life of Norplant, the contraceptive implant. AB - This essay examines the history of Norplant from its development in the 1960s, to its approval by the FDA in 1990, through its tumultuous reception in American society, to its removal from the market in 2000. The rejection of Norplant by women was influenced by the social and political climate of the 1990s, in which a feminist health agenda, a consumerist ideology in health care, a growing tendency toward class action litigation, and increasing distrust of the pharmaceutical industry worked together to empower women to take charge of their reproductive decision making. The rhetoric of population control in the 1960s, when the pill and IUD were introduced, was very different from the language of individual choice that dominated in the 1990s, the era of Norplant. This investigation of Norplant extends the historical analysis of reproductive politics to the very end of the twentieth century. PMID- 20857594 TI - Clear and pregnant danger: the making of prenatal psychology in mid-twentieth century America. AB - Despite shaky evidence, American medical literature in the twenty-first century includes assumptions about the ability of expectant women's psyche to impact their pregnancy. This essay argues that such notions are rooted in "prenatal psychology," a discursive hybrid constructed by renowned psychiatrists in the 1940s and 1950s. Benefiting from the popularity of Freudianism and from women's social status after the war, doctors like Karl Menninger, William Menninger, Helene Deutsch, and Flanders Dunbar fused traditional ideas about the power of women's emotions to influence pregnancy with trendy ego psychology and psychosomatic theories. They argued that women who experienced difficult pregnancies, threw up excessively or miscarried, suffered from a problem that had a name: neurosis. Several leading obstetricians and gynecologists embraced these ideas and helped spread them in the professional literature, urging their colleagues to use talk therapy in the care of pregnant women. PMID- 20857595 TI - "All this that has happened to me shouldn't happen to nobody else": Loretta Ross and the Women of Color Reproductive Freedom Movement of the 1980s. AB - Loretta Ross exemplifies women of color feminist participation in and transformation of the women's health movement of the 1970s and 1980s. Ross helped build a women's health movement that by the late 1980s made the demands of women of color central. This movement was attractive to many women of color who had rejected the collapse of a broader women's health movement into the abortion rights movement as too narrowly focused. Many women of color activists, including Ross, argued that the emphasis on abortion rights and choice failed to address the linked socioeconomic and community health issues confronted by many women of color and poor women. Ross's work spurred coalition building among white women and women of color that focused on expanding reproductive justice and women's health beyond legal abortion. By the 1990s these efforts had produced a vibrant and engaged feminist reproductive justice movement that promoted the socioeconomics of good health for all women. PMID- 20857596 TI - Rethinking the mantra that abortion should be "safe, legal, and rare". PMID- 20857597 TI - Film as the medium; reproduction, sex, and power as the message. PMID- 20857599 TI - Ties that bind: ethnic and religious factors in the marriage choices of Irish American Catholics on the Dakota frontier. PMID- 20857600 TI - An economic and ethical approach to charity and to charity endowments. AB - We examine how and why donors divide gifts between people in the present (across distance) and between the present and future (across time). US donors tend to give less to charities that benefit the poor and more to charities that benefit the non-poor (such as museums, universities, and arts organizations). Many of these wealthier charities have created endowments that benefit not only present persons, but also future persons. We develop a shorthand framework for linking time to distance in charitable allocations that incorporates a "proximity preference," i.e., charity that prefers those who are nearer to us whether by reason of physical distance, psychic-identity, or temporal distance. Even though ethical considerations suggest that recipients' level of need should be the dominant factor in allocating gifts, donors also express preferences, ceteris paribus, for benefits arriving sooner rather than later, and for recipients who are ''closer'' rather than farther away. PMID- 20857601 TI - Spatial practice, conceived space and lived space: Hong Kong's "Piers saga" through the Lefebvrian lens. AB - By applying the Lefebvrian lens, this paper tries to understand why unlike previous similar cases, the latest removal of the Star Ferry and Queen's Pier was so controversial. To Lefebvre, embedded in "spatial practices" that "secrete" a place are two contradicting spaces: "conceived spaces" produced by planners to create exchange values and "lived spaces" appropriated by citizens for use values. Applying Lefebvre's framework to examine the "Piers saga", it is found that the pre-Second World War (WWII) piers were "conceived" by spatial practices of a colonial and racially segregated trading enclave. The public space in the commercial heart that housed the previous generations of piers was not accessible to the Chinese community, thus denying them opportunities to appropriate them and turn them into "lived" spaces. It was only after WWII when the Government carried out further reclamation to meet the needs of an industrializing economy that inclusive public spaces were conceived in the commercial heart, enabling the general public to "appropriate" them as "lived" space. When the Government planned to remove this very first "lived" space in the political and economic heart of the city to conceive further reclamation for the restructuring economy, the more enlightened citizens were determined to defend it. PMID- 20857602 TI - The Illinois Forest Preserve District Act of 1913 and the emergence of metropolitan park system planning in the USA. AB - In 1913, the Illinois Legislature enacted the Forest Preserve District Act. After adoption of the Act by voters in Cook County, the Chicago metropolitan area became among the first in the USA to establish a park system with an outer ring of nature preserves. This article chronicles the story of how the Cook County Forest Preserve District was established, its historical context and its influence on planning practice. It contends that although Chicago was not the originator of the idea of outer parks, it added significantly to development of the concept of comprehensive park system planning. The article contends that the paradigm of park management changed from conservation of the native landscape to multiple use management during the 20-year struggle to establish the district, and that passage of the Act was largely the result of the efforts of two individuals - Dwight Perkins and Jens Jensen. PMID- 20857603 TI - "This villa life": town planning, suburbs and the "new social order" in early twentieth-century Sydney. AB - In Australia, social reformers approached the new century and post-First World War reconstruction with the hope of establishing a "new social order" based on national efficiency and class harmony. This was to be delivered through the new science of town planning. The would-be reformers posited themselves as an intellectual vanguard which would provide leadership and assist in establishing an enlightened bureaucracy of professional public servants who would also lead the way to social betterment. Their project, however, had collapsed by the end of the war. Lacking collective political clout, the nascent planning professionals' influence declined as the political environment became more conservative in the 1920s. Reformist and radical features of town planning were stripped from suburban agendas. Suburbs, once held up as the cradle of the 'new social order', were to become places for quarantining class and reinvigorating liberalism. PMID- 20857604 TI - The limits of scientific planning: Doxiadis and the Tehran Action Plan. AB - Tehran after the Second World War experienced a modernization drive and rapid population growth. In 1972, the Greek planner, Constantinos Doxiadis, who had already undertaken major housing and planning projects in Iran, was invited to prepare an action plan for the city, to guide the future investment for easing the city's problems. Doxiadis saw cities as nightmares, but advocated that a holistic scientific analysis and a naturalist approach to urban growth management could address their problems. In applying his ideas to Tehran, however, the limits of his ideas of scientific planning became evident, not only through contextual pressures, such as lack of time and data, but also through the planning consultant's approach, in which commercial considerations and the application of readymade solutions could shape the outcome. Rather than working with the context, Doxiadis followed the modernist tenet of breaking with the past, proposing the creation of West Tehran, an alternative to the city where all future growth should take place on a utopian basis. The radical nature of his proposals, his death, and a turbulent revolution aborted the impact of his action plan on Tehran, while faith in modernist scientific planning was widely being abandoned. PMID- 20857605 TI - Brazilian city planners, American city planning? New perspectives on urban planning in Rio de Janeiro, 1930-1945. AB - This article analyses the connections between the ideas and principles of American city planning from 1920 with those articulated by Brazilian city planners in the 1930s and implemented by the administration of the City of Rio de Janeiro, then the capital of Brazil, notably during the period of the Estado Novo [The New State] from 1937 to 1945. In a period characterized by the centralization of political power and the concentration of decision-making in the hands of the president and the state, the City of Rio de Janeiro undertook a series of restructuring projects which utilized new forms of administration and organization. This article explores the links between urban planning in Brazil and the USA that were a notable feature of these projects. It examines particular requirements set down in city plans, city planning commissions and funding for urban activities, such as 'excess condemnation', by focusing upon articles and books written by four Brazilian engineers and proposals put forward by the American City Planning Institute, detailed in the proceedings of the National Conference on City Planning, in the periodical, City Planning and works by affiliated authors. PMID- 20857606 TI - Experiences of collective trauma and political activism: a study of women "agents of memory" in post-Soviet Lithuania. PMID- 20857607 TI - Varieties of second modernity: the cosmopolitan turn in social and political theory and research. AB - The theme of this special issue is the necessity of a cosmopolitan turn in social and political theory. The question at the heart of this introductory chapter takes the challenge of 'methodological cosmopolitanism', already addressed in a Special Issue on Cosmopolitan Sociology in this journal (Beck and Sznaider 2006), an important step further: How can social and political theory be opened up, theoretically as well as methodologically and normatively, to a historically new, entangled Modernity which threatens its own foundations? How can it account for the fundamental fragility, the mutability of societal dynamics (of unintended side effects, domination and power), shaped by the globalization of capital and risks at the beginning of the twenty-first century? What theoretical and methodological problems arise and how can they be addressed in empirical research? In the following, we will develop this 'cosmopolitan turn' in four steps: firstly, we present the major conceptual tools for a theory of cosmopolitan modernities; secondly, we de-construct Western modernity by using examples taken from research on individualization and risk; thirdly, we address the key problem of methodological cosmopolitanism, namely the problem of defining the appropriate unit of analysis; and finally,we discuss normative questions, perspectives, and dilemmas of a theory of cosmopolitan modernities, in particular problems of political agency and prospects of political realization. PMID- 20857608 TI - Supervised neglect - Again! PMID- 20857609 TI - Retraction. The search for the discipline of nursing. PMID- 20857610 TI - Laboratory research facilities and hospitals: an anachronism in 21st century Australia? PMID- 20857611 TI - Surgical complications: car crashes and the credit crunch. PMID- 20857612 TI - Radio-frequency ablation for the treatment of Morton's neuroma. PMID- 20857613 TI - Inflammatory pseudotumour of the spleen: the findings on F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). PMID- 20857614 TI - Periurethral abscess: an unusual source of sepsis. PMID- 20857615 TI - University clinical, education, and research associates (UCERA). PMID- 20857616 TI - Prothrombin fragments in cardiovascular disease. AB - Prothrombin fragment 1+2 (F1+2), which comes from in vivo cleavage of prothrombin by factor Xa, is considered to be useful for diagnosis of thrombosis. Recognition of the central role of thrombosis in the pathogenesis ofcardiovascular disease has prompted growing interest in the association o F1+2 with cardiovascular clinical syndromes. Increased F1+2 levels have reported in venous thromboembolism, inflammation, cancer, sepsis, acute coronary syndromes, stroke, peripheral arterial disease, atrial fibrillation and during the postoperative period. However, a clear relationship with the appearance of thrombosis has not always been consistently demonstrated. Besides its potential prognostic and diagnostic value, it could also be usefu in assessing the impact of various therapies. However, it should be kept in mind that measurement of hemostasis activation markers has several important biological and methodological disadvantages. Activation markers reflect the presence of thrombosis in any vascular bed, so they are not specific. Furthermore, elevations occur not only in the presence of overt thrombosis but also during the hypercoagulable state. The cutoff level to be used for the definition of elevations is still largely unknown due to the use of different analytical methods, none of which have been standardized until know. Finally, the prognostic value of F1+2 and other markers of coagulation activation remains to be fully defined in future studies. PMID- 20857617 TI - Carbamylated LDL. AB - Nonenzymatic modification of protein by cyanate, that is, carbamylation, has received new attention due to its apparent relevance in atherosclerosis. For example, carbamylation of low-density lipoprotein (LDL) is an important mechanism that potentially impacts high-risk atherosclerotic individuals with increased urea (renal insufficiency) or thiocyanate (tobacco smoking). Carbamylated LDL (cLDL) is increased in patients with end-stage kidney disease, especially those with atherosclerosis. In addition, cLDL exhibits distinct cytotoxic effects when tested in vitro on endothelial cells, induces the expression of adhesion molecules, and aggravates the monocyte adhesion to endothelial cells. It also facilitates the proliferation of vascular smooth-muscle cell (VSMC). Studies of potential pharmacological interruption of these processes in vivo may lead to discoveries of novel therapies for atherosclerosis. PMID- 20857618 TI - Cocaine in acute myocardial infarction. AB - Cocaine, a crystalline tropane alkaloid which is obtained from the leaves of the coca plant, acts a powerfully addictive stimulant that directly targets the central nervous system. The effects of the drug appear almost immediately after a single dose (intravenous, intranasal, or inhaled), and disappear within a few minutes or hours. Although the free commercialization of the drug is illicit and severely penalized in virtually all countries, its use remains widespread in many social, cultural, and personal settings. There is a variety of well-recognized side effects of cocaine abuse, which involve virtually every organ system. There is also emerging evidence, however, that cocaine abuse might trigger a variety of cardiac disorders, ranging from arrhythmias to acute myocardial infarction (AMI), heart failure and even sudden cardiac death, especially in relatively young male patients (e.g., those in the mid-1930s), in those who concomitantly use tobacco and alcohol, in those having experienced a trauma or a car accident and lack traditional risk factors for atherosclerosis. Since the use of cocaine may influence the treatment strategies of patients being evaluated for possible acute coronary syndrome (ACS) as well as the prognosis of an AMI, it might be advisable to introduce cocaine screening in patients admitted with chest pain at the emergence department, especially in high-risk patients (i.e., young males with concurrent use of tobacco or alcohol, suffering from a recent accident and with no traditional atherosclerotic risk factors), or in those who are unresponsive and unreliable. This strategy might be helpful to adopt the best therapeutic approach for reducing the risks associated with cardiovascular disease in these patients, and also to deter relapse. PMID- 20857619 TI - EGFR and KRAS in colorectal cancer. AB - The epidermal growth factor receptor (EGFR) is recognized as an important player in colorectal cancer (CRC) initiation and progression. This membrane-bound receptor tyrosine kinase (RTK) has therefore become a key target of therapeutic strategies designed to treat metastatic CRC, in particular with monoclonal antibodies (mAbs) against the extracellular domain of the receptor. KRAS is an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus. Activating mutations in KRAS are recognized as a strong predictor of resistance to EGFR-targeted mAbs. Routine testing of all patients with CRC for KRAS mutations is now recommended; only those harboring wild-type (WT) KRAS should be candidates for such therapies, thus improving outcomes, and minimizing unnecessary toxicity and cost. Even though the identification of the importance of KRAS status has marked a turning point in the treatment of metastatic CRC (mCRC), it is becoming apparent that other critical elements in the complex signaling pathways related to EGFR may also contribute vital information that will aid in treatment decisions and ultimately benefit patients. PMID- 20857620 TI - Prostaglandin EP receptors and their roles in mucosal protection and ulcer healing in the gastrointestinal tract. AB - Endogenous prostaglandins (PGs) play an important role in modulating the mucosal integrity and various functions of the alimentary tract, and E type PGs are most effective in these actions. PGE2 protects against acid reflux esophagitis and affords gastric cytoprotection against ethanol and indomethacin. These effects are mimicked by EP1 agonists and attenuated by an EP1 antagonist. Adaptive cytoprotection induced by mild irritants is also attenuated by the EP1 antagonist as well as indomethacin. PGs contribute to capsaicin-induced gastric cytoprotection, yet this effect is mitigated by indomethacin and sensory deafferentation but not the EP1 antagonist. Similarly, PGE2 does not exhibit gastric cytoprotection in EP1-receptor knockout mice, while capsaicin-induced protection is observed in animals lacking either EP1 receptors but disappears in IP-receptor knockout mice. In the duodenum, acid perfusion produces damage in animals lacking EP3 receptors. The protective effect of PGE2 on indomethacin induced small intestinal damage is mimicked by both EP3 and EP4 agonists. PGE2 also shows a healing-promoting effect on gastric ulcers as well as intestinal lesions via the activation of EP4 receptors. The underlying mechanisms of these actions of PGE2 in the stomach, duodenum, or small intestine are related to inhibition of stomach contraction (EP1), stimulation of duodenal HCO3- secretion (EP3/EP4), or suppression of bacterial invasion due to inhibition of intestinal contraction (EP4) and stimulation of mucus secretion (EP3/EP4) respectively, although the mechanisms related to the esophageal protection remain unknown. Furthermore, the healing-promoting effect is associated with the stimulation of angiogenesis via an increase in VEGF expression (EP4). PMID- 20857621 TI - Advances in pancreatic cancer detection. AB - Pancreatic cancer represents a major challenge for research studies and clinical management. No specific tumor marker for the diagnosis of pancreatic cancer exists. Therefore, extensive genomic, transcriptomic, and proteomic studies are being developed to identify candidate markers for use in high-throughput systems capable of large cohort screening. Understandably, the complex pathophysiology of pancreatic cancer requires sensitive and specific biomarkers that can improve both early diagnosis and therapeutic monitoring. The lack of a single diagnostic marker makes it likely that only a panel of biomarkers is capable of providing the appropriate combination of high sensitivity and specificity. Biomarker discovery using novel technology can improve prognostic upgrading and pinpoint new molecular targets for innovative therapy. PMID- 20857622 TI - Urine peptidomics for clinical biomarker discovery. AB - Urine-based proteomic profiling is a novel approach that may result in the discovery of noninvasive biomarkers for diagnosing patients with different diseases, with the aim to ultimately improve clinical outcomes. Given new and emerging analytical technologies and data mining algorithms, the urine peptidome has become a rich resource to uncover naturally occurring peptide biomarkers for both systemic and renal diseases. However, significant analytical hurdles remain in sample collection and storage, experimental design, data analysis, and statistical inference. This study summarizes, focusing on our experiences and perspectives, the progress in addressing these challenges to enable high throughput urine peptidomics-based biomarker discovery. PMID- 20857623 TI - [Sensitization to Blomia tropicalis and Dermatophagoides pteronyssinus, farinae and siboney prevalence in patients with rhinitis, allergic asthma, or both, in a population of a metropolitan area of Mexico City]. AB - BACKGROUND: The increased prevalence of asthma has been associated with an increase in atopic sensitization, and it is parallel with similar increases in other allergic diseases. In United States, Blomia tropicalis has the fourth place between the most known types of house dust mites, and is the most common in the southern subtropical states. In Mexico there have been few studies to investigate sensitization to this mite. OBJECTIVE: To identify the prevalence of sensitization to Blomia tropicalis and Dermatophagoides in patients with rhinitis and/or allergic bronchial asthma in a population of the metropolitan area of Mexico. PATIENTS AND METHOD: We selected 334 patients with a diagnosis of rhinitis and/or bronchial asthma, 149 men and 185 women, aged between 3 and 74 years, of which 189 had positive skin tests to at least one of the mites (Dermatophagoides and/or Blomia tropicalis). We measured the wheal area and compared the averages of the surface of the wheal and correlations were made of the results using the Pearson correlation coefficient. RESULTS: The total number of patients who presented positive skin test to Blomia tropicalis in association with other mites was 53 (28.0%) and the total number of patients who presented positive skin test to only Blomia tropicalis was 23 (12.1%). Correlations of r = 0.45, 0.45 and 0.68 (statistically significant, p < 0.05) were found between the three species of Dermatophagoides, while there was no correlation between positive dermoreactions of Blomia tropicalis with those of Dermatophagoides. CONCLUSIONS: In the metropolitan area of Mexico City, while not having a tropical or sub-tropical weather, it is important to include Blomia tropicalis in diagnostic panels of allergens. PMID- 20857624 TI - [Sensitization to Ficus benjamina prevalence in adult patients with moderate severe allergic rhinitis]. AB - BACKGROUND: Allergic rhinitis can be caused by allergens such as house dust mites, pollen, fungi, and animals. A less common cause is allergy to Ficus benjamina. OBJECTIVES: To determine the prevalence of sensitization to Ficus benjamina on patients with moderate-severe allergic rhinitis, and to describe the epidemiologic factors associated to Ficus benjamina sensitization. PATIENTS AND METHOD: It is an observational, transversal, prospective study; patients with persistent moderate-severe allergic rhinitis diagnosis were included; skin tests to the most frequent aeroallergens and to Ficus benjamina were applied to these patients, as well as a questionnaire in order to investigate the degree of exposure to Ficus benjamina. RESULTS: 89 patients with persistent moderate-severe allergic rhinitis were included. 59% had a Ficus benjamina plant at home or at work, 97% were located outdoors. Nine patients (10.1%) were sensitized to Ficus benjamina. A statistically significant association was found between sensitization to Ficus benjamina and to Felix domesticus, Canis familiaris, and Periplaneta. CONCLUSIONS: Prevalence of sensitization to Ficus benjamina was similar to that reported in the literature, and it is associated to three or more indoor allergens. Patients with allergic rhinitis should avoid contact with Ficus benjamina because of the risk of acquiring sensitization. PMID- 20857626 TI - Consumption of camel's milk by patients intolerant to lactose. A preliminary study. AB - OBJECTIVE: To determine whether camel's milk can be consumed by patients intolerant to lactose without undesirable reactions. PATIENTS AND METHOD: Twenty five patients with clinical and laboratorial diagnosis of lactose intolerance underwent provocation tests with growing amounts of cow's milk and subsequently with camel's milk. RESULTS: Except for two patients, who had mild reactions to the maximum dosage of camel's milk (250 mL), the acceptance was excellent. Pasteurization of camel's milk did not affect tolerance. Also, most of the patients showed significant clinical reactions when drinking very low amounts of cow's milk. CONCLUSION: Camel's milk can be considered an option for the individuals intolerant to lactose who present symptoms when ingesting cow's milk. PMID- 20857625 TI - [Risk factors related to allergic diseases at Mexico City]. AB - BACKGROUND: Several studies suggest that the prevalence of allergic diseases has been increasing worldwide in recent years; then it is very important to identify some risk factors that could be related. OBJECTIVE: To know some hereditary and environmental risk factors that could be related to the development of allergic diseases in open population from Mexico City. PATIENTS AND METHOD: It was an open population, cross-sectional trial, in two phases with a random sample size of 4272 individuals in 214 public health centers. A questionnaire was applied by health workers. Statistical analysis was made with Excel 97-2004 using the Mann Whitney U test for continuous variables and chi-square-test for discrete variables. p < 0.001 was considered statistically significant. RESULTS: The prevalence of allergic diseases in Mexico City was 42.6%, allergic rhinitis was the most frequent. The most important risk factors for allergic diseases were: family history of atopy in first and second degree; early consumption of cow's milk; early weaning with cereal, egg, beef, fish and pulses; living with some animals, indoor plants, active and passive smoking, to keep stuffed toys in the rooms, as well as living in dwellings with dust, cold temperatures, wall saltpeter and with dampness (mold growth). CONCLUSION: Because genetic factors can not be modified, it is important to identify environmental factors related to the development of allergic diseases in order to promote preventive measures. PMID- 20857627 TI - [Etoposide desensitization. A case report]. AB - All chemotherapeutic agents have the potential to induce hypersensitivity reactions and the repeated administration of such drugs during a cancer treatment enhances specific sensitization. Epipodophyllotoxins (etoposide and teniposide) are commonly used to treat lung, testicular, central nervous system and hematologic cancers. Hypersensitivity reactions to epipodophyllotoxins are not the most common but they have been reported. We present a case of an eight-year old male patient, diagnosed with high risk acute lymphoblastic leukemia who received treatment with etoposide among other drugs (St. Jude XIIIB). During the first course of treatment he needed premedication to etoposide administration because of mild hypersensitivity reactions. At the beginning of a second treatment the patient presented two severe hypersensitivity reactions (acute urticaria, angioedema and hypotension) despite the use of premedication and slow infusion. We initiated a twelve steps desensitization protocol for etoposide with success in the second round allowing the administration of further doses in an ambulatory unit without hypersensitivity reactions. PMID- 20857628 TI - [Prevalence of reactions secundary to mosquito bites Aedes aegypti at en el Regional Center of Allergy and Clinical Immunology, University Hospital, de Monterrey, Nuevo Leon]. AB - BACKGROUND: although systemic reactions resulting from hymenoptera stings have been studied extensively, the prevalence of allergic reactions to mosquitoes is unknown. OBJECTIVE: to investigate the prevalence of allergic reactions to Aedes aegypti bites in patients seeking treatment at the Allergy and Clinical Immunology Regional Center of Jose E Gonzalez University Hospital in Monterrey, Mexico. MATERIAL AND METHOD: we carried out a cross-sectional, descriptive study that included patients receiving skin tests for aeroallergens; skin sensitivity to mosquito bites was also tested. A questionnaire was used to obtain information about previous allergic reactions to mosquito bites. RESULTS: a total of 482 patients between 2 and 60 years of age were included; 53% were female, 407 (84.4%) had a history of local reactions to mosquito bites. Twelve patients (2.4%) stated a history of large local reaction; three (0.6%) of them with a positive skin prick test, one (0.2%) of those had systemic reaction history to mosquito. Eighty five (17.6%) patients had a positive mosquito skin test and 307 (63.6%) had a positive skin test for at least one aeroallergen. Seventy-eight (91.7%) of the 85 patients with a positive mosquito skin test had a history of local skin reactions to mosquito bite (odds ratio: 2.303 [confidence interval (CI) 1.037-5.10]. There was no statistically significance association between allergic diseases and mosquito allergy. CONCLUSIONS: adverse reactions and allergic reactions to mosquito bites occur frequently. However mosquito allergy is low. Further studies are required to determine the prevalence of mosquito allergy in the general population. PMID- 20857629 TI - [Validation of a knowledge-questionnaire about asthma applied to teachers of elementary school of Monterrey, Mexico]. AB - BACKGROUND: asthma is one of the most common chronic childhood diseases; is increasing in prevalence and an important cause of school absenteeism. Previous studies have failed to evaluate knowledge about asthma among elementary school teachers worldwide because of the lack of validated questionnaires. OBJECTIVE: to validate a questionnaire about asthma knowledge for elementary school teachers in Monterrey, Nuevo Leon. MATERIAL AND METHODS: an observational, cross sectional, descriptive study, from February to December 2004, by applying a questionnaire to a group of elementary school teachers in Monterrey, Nuevo Leon. The questionnaire is a translation and adaptation to the questionnaire of 13 questions used to assess the knowledge about asthma among parents, according to the National Asthma Education Program of US. RESULTS: a total of 179 questionnaires were applied, in which 6 of the 13 questions were answered correctly by more than 90% of the teachers. The internal consistency reliability was adequate with a Cronbach a coefficient of 0.75. CONCLUSIONS: in order to obtain reliable data using questionnaires, these must undergo a validation process. Our questionnaire got validation because of the reliability shown according to the internal consistency analysis. PMID- 20857630 TI - [Sensitization to aeroallergens in subjects with allergic rhinitis who live in the metropolitan zone of Guadalajara, Jalisco]. AB - BACKGROUND: allergic rhinitis is the most common allergic disease worldwide. Aeroallergens are compromise in its presentation and its prevalence varies in different parts of the world. Aeroallergen sensitization in the Guadalajara metropolitan area is not yet documented. OBJECTIVE: to determine by means of skin prick test the sensitization prevalence to aeroallergens in patients with allergic rhinitis. PATIENTS AND METHODS: We retrospective evaluated the results of skin prick test to different aeroallergens and their prevalence by age group in patients with allergic rhinitis referred to our allergy department. RESULTS: the complete data of 965 subjects were available, 78% of these had positive skin prick tests, the age range of the patients was 16 to 78 years, 74.9% of which were women; 9% were sensitized to one allergen and 11.5% had more than 15 positive skin prick test. The most frequent interior allergens were house dust mites and outdoor allergens Quercus sp and Fraxinus sp. Males showed the highest reaction frequency to aeroallergens. The age range from 21 to 40 years presented the highest frequency of positive skin prick test. CONCLUSION: our data demonstrate that house dust mites followed by tree pollens are the most frequent aeroallergens in patient with allergic rhinitis. Positive skin prick test frequency was age associated. PMID- 20857631 TI - [Immunotherapy in patients allergic to bee venom]. AB - OBJECTIVE: to review the main features about honey-bee venom desensitization in patients with adverse reactions to honey-bee stings. METHOD: a non-systematic search was performed in the main internet medical data base looking for relevant papers related to honeybee venom allergy, patients' selection for honey-bee venom immunotherapy (HBVIT), the most effective immunotherapy, the time of application and the protection obtained by HBVIT. RESULTS: of a total of 1,656 articles found, 18 documents were selected and revised, with the following findings: the HBVIT is indicated in patients with a clinical history and diagnostic confirmatory tests of allergy to bee venom and with the knowledge of the natural history of the disease. The protection against systemic reactions caused by new bee stings using HBVIT is over 90%. It is advisible to apply HBVIT for continuos periods of 5 years in order to develop a long-lasting immunologic tolerance. CONCLUSIONS: HBVIT has well defined clinical indications, and its adequate application offers protection in the long term against new bee stings. PMID- 20857632 TI - [A report of a family with chronic granulomatous disease with a gp91phox disorder]. AB - The chronic granulomatous disease is a primary immunodeficiency with a defect of the phagocytosis process; its main alteration resides in the incapacity of the NADPH oxidase system to produce reactive oxygen species capable of destruct pathogenic organisms such as bacteria, fungus and mycobacteria. Patients are susceptible to severe and mild infections, mainly pneumonias, linfadenitis and gastroenteritis that tend to be repetitive; in addition, they presented granulomatous inflammation and autoimmunity. We presented the case of two brothers with X-linked chronic granulomatous disease with alteration in the sub unit gp91Phox; heredofamilial background was endogamy and consanguinity. Both patients suffered severe infections, frequent abscesses and a poor growth. Diagnosis was confirmed with nitroblue tetrazolium test. During their evolution, the patients presented also BCGitis, BCGosis and septic shock. They began prophylactic treatment with trimetoprim sulfametoxazole and itraconazole, as well as gamma interferon, with favorable response, presenting a lower amount of infectious episodes, as well as a recovery of their weight and height. The early diagnosis of the patients has improved their prognosis. PMID- 20857633 TI - [Who is looking out for the children? Reflections on pediatric postanesthetic recovery care]. PMID- 20857634 TI - [Regional anesthesia in children]. PMID- 20857636 TI - [Local and regional analgesia after pediatric surgery: study in 116 patients]. AB - OBJECTIVES: Pain control is essential to patient comfort and reduced stress response, morbidity, and mortality after pediatric anesthesia. We assessed analgesic quality and the incidence of complications of regional blocks in combination with general anesthesia. MATERIAL AND METHODS: Prospective study of 116 patients under 3 years of age who underwent surgery in our hospital over a period of 2 years. The studied patients were classified in 3 groups according to whether they received general anesthesia only, a regional block by single injection, or a caudal nerve block via catheter. We recorded demographic and intraoperative variables, postoperative analgesic requirements, and the time the first postoperative analgesic dose was needed. RESULTS: Analgesia was significantly more effective in the patients who received either type of regional block. The patients who received general anesthesia alone needed supplemental analgesia earlier than the others (P < .001); patients with nerve blocks required fewer doses of rescue analgesics (P < .001). The incidence of complications was low and all were minor. No case of caudal catheter contamination occurred. CONCLUSIONS: Regional nerve blocks combined with general anesthesia in children are effective and safe. Advantages of providing nerve blocks include hemodynamic stability, prolonged postoperative analgesia, lower consumption of analgesics, and few complications. PMID- 20857635 TI - [Monitoring oxygen consumption in energy metabolism in pediatric anesthesia: clinical utility]. AB - OBJECTIVES: To determine changes in oxygen consumption as a marker of energy metabolism during general inhaled anesthesia in pediatric patients and to identify factors that might influence consumption. MATERIAL AND METHODS: Prospective, observational, double-blind study in children under inhaled anesthesia in spontaneous ventilation. We monitored heart rate electrocardiogram, noninvasive blood pressure, respiratory frequency, carbon dioxide (CO2) end expiratory pressure, oxygen saturation by pulse oximetry, state entropy, response entropy, esophageal temperature, and (by indirect calorimetry) oxygen consumption and the respiratory quotient. Capillary blood was extracted every 5 minutes to determine lactate concentration. RESULTS: Thirty-six patients (ASA 1-2) between 5 and 11 years old were included. Mean (SD) oxygen consumption was 0.6 (0.12) mL x kg(-1)min(-1) at baseline, 5.3 (03) mL x kg(-1) min(-1) during maintenance of anesthesia, and 8.1 (1.1) mL x kg(-1) min(-1) on awakening. A progressive increase was detected in lactic acid concentration, from a baseline mean of 0.8 (0.1) mmol/L to 2.2 (0.9) mmol/L half an hour later; the change was unrelated to oxygen consumption. After correcting the flow of normal saline solution to 0.9%, a significant increase in oxygen consumption (P < .05) was detected. Factors that were significantly correlated (P < 0.1 and r of +/- 0.95) were temperature (oxygen consumption decreased > 10% for each degree centigrade decrease), inspired oxygen fraction > 0.8; sharp changes in the expired CO2 fraction exceeding 2 standard deviations (+/- 6), use of nitrous oxide in the gas mix (inspired nitrous oxide fraction > 20%), the length of the sampling line, and increased respiratory frequency. A model with 3 factors was constructed to explain the kinetics of oxygen consumption during anesthesia. CONCLUSIONS: Oxygen consumption monitoring may provide an indirect indicator of homeostatic changes during surgery. The ideal system for carrying out such monitoring during anesthesia remains to be found, and the values to guide the anesthesiologist in deciding whether or not to intervene immediately still need to be determined. PMID- 20857637 TI - [Inhaled anesthesia through a device for noninvasive continuous positive airway pressure ventilation for upper digestive endoscopy in pediatric patients]. AB - OBJECTIVE: The demand for sedation for pediatric diagnostic procedures performed outside operating rooms has increased considerably, but the ideal method to choose has been the subject of debate. The aim of this study was to assess the efficacy of using a device for continuous positive airway pressure, connected to a Mapleson D circuit and a nasopharyngeal tube as the interface, in order to ventilate and administer sevoflurane for upper digestive tract endoscopy in children. MATERIAL AND METHODS: Prospective cohort study of children undergoing upper digestive tract endoscopy. We recorded epidemiologic variables, heart rate, mean arterial pressure, arterial oxygen saturation and procedure-related adverse events before, during and 10 minutes after the procedure. Time spent in the recovery room was also recorded. The endoscopist asked the patients about their level of satisfaction and whether they had noticed any irritating smell or gas smell. RESULTS: Data was collected on 29 patients (17 boys, 12 girls) with a mean (SD) age of 4.2 (3.9) years. The mean duration of endoscopy was 15 (7) minutes. Arterial oxygen saturation below 92% during the procedure did not occur and the endoscopic exploration was completed satisfactorily with this technique in 28 patients (96%). All were discharged from the recovery room within 30 minutes. The endoscopist reported that the technique was considered satisfactory in all cases, although 2 children noted an anesthetic "gas" smell. CONCLUSIONS: A modified Mapleson D circuit and nasopharyngeal tube can be used effectively as an interface for noninvasive ventilation and administration of sevoflurane during upper digestive endoscopy in pediatric patients. PMID- 20857638 TI - [Perioperative treatment of a man receiving a left-lung transplant combined with coronary revascularization without use of extracorporeal circulation: with a brief review of pathophysiology and the literature]. AB - Patients with significant coronary artery disease were once traditionally rejected as candidates for lung transplants because of higher risk of morbidity and mortality. We report the case of a man who received a left lung transplant and coronary revascularization without extracorporeal circulation in a combined surgical procedure after being diagnosed with significant coronary disease during the preoperative study for acceptance as a candidate for lung transplantation. We review the history of such combination procedures, which are changing clinicians' attitudes as to appropriate therapeutic approaches to take for complex patients. We also discuss the possible advantages of performing surgery without extracorporeal circulation. To our knowledge, this is the first report of a combined procedure that took place in a Spanish hospital. PMID- 20857639 TI - [Perioperative considerations in vagal nerve stimulator implantation]. AB - Vagal nerve stimulation has become an a important tool in the treatment of refractory epilepsy, which continues to be the main indication for this technique. Other therapeutic indications are emerging, however, and vagal nerve stimulation has now been approved for major depression. Additional possible uses under study include morbid obesity, Alzheimer disease, chronic pain syndromes, and certain neuropsychologic disorders. This review considers perioperative aspects relevant to using this therapeutic procedure with a view to facilitating better and more integrated management of its application. PMID- 20857640 TI - [Recommendations for managing the difficult airway using supraglottic devices in the adult patient undergoing ambulatory surgery]. PMID- 20857641 TI - [Esmolol to control hemodynamic response during removal of a bilateral pheochromocytoma from a 10-year-old girl]. AB - Pheochromocytomas, which derive from chromaffin cells, can secrete catecholamines in large amounts. The incidence of these tumors is low at 2 to 8 cases per million population and only 10% of cases occur in children. A thorough understanding of the pathophysiology of these tumors and the consequent effect of drugs will be necessary for treating these patients during the perioperative period. A great deal has been published on drugs that can be used in this setting, but only a small portion of the information is relevant to children. Esmolol, a short-action beta-blocker, figures among the drugs that have been developed in recent years. We report a case in which esmolol was used during surgery in a 10-year-old girl undergoing scheduled removal of a bilateral pheochromocytoma. PMID- 20857642 TI - [Thromboprophylaxis in cardiac surgery: comment on the article "General aspects of perioperative thromboprophylaxis"]. PMID- 20857643 TI - [Anesthesia for surgical correction of encephalocele in a neonate]. PMID- 20857644 TI - [Ultrasound-guided extraction of a foreign body]. PMID- 20857645 TI - [True knot in an umbilical cord]. PMID- 20857646 TI - [Megaesophagus in a man with advanced achalasia]. PMID- 20857647 TI - Vaccines to antibodies: grow up! AB - Through a process called affinity maturation, all of the HIV-specific antibodies identified so far have accumulated multiple mutations, some of which are required for them to bind to and neutralize HIV. Researchers are now beginning to grapple with what this means for vaccine design. PMID- 20857648 TI - Microbicides finally gel, securing spotlight at the International AIDS Conference. AB - The efficacy of a microbicide candidate was the definitive bright spot at this year's conference, while the lingering economic slowdown and its impact on HIV/AIDS funding were dark clouds on the horizon PMID- 20857649 TI - A systems approach to understanding vaccines. AB - Researchers are starting to apply the tools of systems biology to better understand human immune responses to vaccination, including HIV vaccine candidates. PMID- 20857650 TI - 3-D structure of dendritic cell-T cell virological synapses revealed. PMID- 20857651 TI - First U.S. national AIDS strategy aims to cut new infections and optimize care. PMID- 20857652 TI - Vaccine candidate targeting dendritic cells enters clinical trial. PMID- 20857653 TI - Why person affected by leprosy did not look after their plantar ulcer? Experience from Pakokku zone, Myanmar. AB - A cross-sectional study was carried out to identify methods of caring plantar ulcers in leprosy patients and the underlying causes of poor plantar ulcer care during January and February 2008. This was conducted in Pakokku zone as it was one of the "9 selected townships of the Disabilities survey, i.e., Basic Health Staff project 2003/4", which was funded by Japan International Cooperation Agency. After getting consent, all available leprosy cases, i.e., 101 cases with foot disability grade 2 were interviewed with the pre-tested questionnaire. Among 101 cases, 13 cases who took care of their ulcer poorly and 20 who did none of the recommended measures were recruited for in-depth interview (IDI). The subjects were largely old people, males and people with no marriage partner. The majority had earned money by doing sedentary job. Prolongation of ulcers was observed in 78 cases. Most had been suffering from ulcers for years. When asking face-to-face interview, all the recommended care measures were not reported. Among these recommended measures, a large number of respondents reported about soaking measure. However, these reported measures were contradicted to the preventive methods which they disclosed in IDI. Plantar ulcer care seemed to be an individualised practice. The individual ways of performing were related to their view of ulcer, the environment, and occupation, and custom, communication with family and health staff. The findings identified the actual practice of plantar ulcer care in study areas. It is suggested that the current performance of planar ulcer care is inadequate and more attention should be given to achieve the target set by the programme as a recommendation. PMID- 20857654 TI - History and characteristics of isolates maintained at the leprosy research center. AB - The origin, history, sensitivity to anti-leprosy drugs and genotypic characteristics for 27 strains maintained at the Leprosy Research Center in Tokyo are described. Strains are isolated and passaged in nude mouse footpads, and frozen bacillary suspensions with different generations are also maintained. The Leprosy Research Center provides bacillary materials as experimental resources at researchers' request. PMID- 20857655 TI - [Novel method for simple detection of mutations conferring drug resistance in Mycobacterium leprae, based on a DNA microarray, and its applicability in developing countries]. AB - The simple method to detect mutations conferring resistant to dapsone, rifampicin, and quinolone was exploited in Mycobacterium. leprae on the basis of reverse DNA hybridization with capture probe fixed to the glass slide. Mutations were discriminated by a series of oligonucleotide probes corresponding to each mutation in the folP1, rpoB, and gyrA genes of M. leprae. The method was transferred to two laboratories in developing countries. The results obtained with the kit at those laboratories were highly concordant with results of sequencing. The method is feasible for the testing by local person in areas with high prevalence of leprosy. PMID- 20857656 TI - [International cooperation for prosthetics and orthotics in Myanmar]. AB - "Effectiveness of the sole protection and the plantar ulcer treatment of Micro Cellular Rubber (MCR) sandals" was investigated as a part of research enterprise "Research concerning the diagnosis, treatment, and the prevention of disability of an effective Leprosy in Myanmar" of the international medical treatment cooperation for three years since 2007. Furthermore "Introduction of Orthotics for the footdrop" was recently attempted through those activities. We participated for two research items from 2007, and reported on the research content and the result. We discussed the ideal way of international technical support for the developing countries in the future. Conclusively we recognized further expected works in this field 1) to train more numbers of orthotic practitioners for MCR sandals; 2) to make them skillful; 3) to train Prosthetists and Orthotists (PO) in Myanmar leaders; and 4) to organize helpers in Japan including preparation for publishing guidelines for PO workers. PMID- 20857657 TI - [International collaboration of the NGO for Hansen's disease in China]. PMID- 20857658 TI - [Activities of co-medical staffs in Myanmar JICA project on leprosy control and basic health services project (2000-2005)]. PMID- 20857659 TI - [Thalidomide--coverage by health insurance when used for treatment of ENL]. PMID- 20857660 TI - [Preoperative evaluation, preparation and outcome prediction. II: preface and comments]. AB - In this special issue, essential points in preoperative evaluation are presented on the basis of up-to-date information. Myasthenia gravis should be evaluated according to individual severity. Muscular dystrophies may lead to rhabdomyolysis perioperatively. Schizophrenia is predisposed to developing torsade de pointes. Depression could be a risk factor of acute myocardial infarction. Infants may be influenced by anesthesia with respect to brain development. Elderly patients should be evaluated on the basis of age, physiological states, coexisting diseases and the type of surgery. Difficult airway management can be predicted by Mallanpati classification and thyromental distance. Jehovah's Witness of ages below 15 should be informed about the policy of life-saving blood transfusion. Oral contraceptive is associated with a fivefold-increased risk of perioperative venous thromboembolism. PMID- 20857661 TI - [Preparation before anesthesia for patients with myasthenia gravis]. AB - Myasthenia gravis (MG) is an autoimmune disease resulting from the production of antibodies against the acetylcholine receptors of the neuromuscular synapse, and is the disease characterized by weakness and fatigability of the skeletal muscle, with improvement following rest. Adequate preoperative evaluation of the MG patients must be carried out. Especially, the preoperative evaluation of respiratory muscle strength is very important. Although several general anesthetic techniques have been proposed, none has been proven to be superior to the others. It is necessary to evaluate anesthetic management of MG patients according to the severity of the individual patient. But the use of regional anesthesia seems to be warranted whenever possible. Based on the preoperative severity, operative procedure and perioperative management, extubation should be carried out carefully in all MG patients. MG is a disease with many pitfalls in the safe administration of anesthesia. PMID- 20857662 TI - [Anesthesia preoperative preparation of muscular dystrophy]. AB - The muscular dystrophies are inherited myogenic disorders characterized by progressive muscle wasting and weakness of variable distribution and severity. They can be subdivided into several groups, including congenital forms, in accordance with the distribution of predominant muscle weakness: Duchenne/Becker; limb-girdle; Fukuyama type congenital muscular dystrophy; Emery-Dreifus; facioscapulohumeral; oculopharyngeal; myotonic dystrophy, et al. Muscular dystrophies are susceptible to perioperative respiratory, cardiac and other complications, such as rhabdomyolysis. Halogenated inhalational anesthetic agents have been implicated as a cause of acute rhabdomyolysis that resembles malignant hyperthermia. Depolarizing neuromuscular blocking drugs that cause rhabdomyolysis are contraindicated in these patients. Recommendations are proposed for the safe anesthetic management of these patients. PMID- 20857663 TI - [Perioperative management of epileptic patients]. AB - The number of epileptic patients scheduled to receive anesthesia and operation is not small. The management of anesthesia for epileptic patients requires caution and prudence. It is necessary to continue their anticonvulsant therapy to avoid perioperative seizures. Anesthesiologists should consider the side effects of anticonvulsants such as liver dysfunction, renal dysfunction, anemia, and gingival hyperplasia. Drug interactions of anticonvulsants and muscle relaxants or opioids and other drugs are also to be considered. Volatile anesthetics and intravenous anesthetics have both anticonvulsant and convulsive properties, although the convulsive properties of clinical doses of these anesthetics are permissible. PMID- 20857664 TI - [Anesthesia for patients with neurological diseases]. AB - Several surgical treatments can be employed for the patients with neurological disorders, such as multiple sclerosis, Guillain-Barre syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer disease and spinal cord injury. It is possible that anesthesia related complications are induced in these neurologically complicated patients in the perioperative period. Respiratory dysfunction and autonomic nervous system dysfunction are most common in this population. Respiratory muscle weakness and bulbar palsy may cause aspiration pneumonia. Sometimes, postoperative ventilatory support is mandatory in these patients. Autonomic nervous system dysfunction may cause hypotension secondary to postural changes, blood loss, or positive airway pressure. Some therapeutic agents prescribed for neurological symptoms have drug interaction with anesthetic agents. Patients with motor neuron disease should be considered to be vulnerable to hyperkalemia in response to a depolarizing muscle relaxant. Although perioperative treatment guideline for most neurologic disorders has not been reported to lessen perioperative morbidity, knowledge of the clinical features and the interaction of common anesthetics with the drug therapy is important in planning intraoperative and postoperative management. PMID- 20857665 TI - [Preoperative assessment, preparation and prospect of prognosis in schizophrenic patients]. AB - Schizophrenic patients are at increased risk for perioperative complications such as hypotension and hypothermia during anesthesia, postoperative ileus, confusion and pneumonia. In addition, schizophrenic patients are predisposed to developing pulmonary thromboembolism, torsade de pointes, water intoxication and rhabdomyolysis. The increased complications are associated with physical disorders, antipsychotic agents, hazardous health behaviors, and interactions between antipsychotic agents and anesthetic drugs. Increased cortisol, norepinephrine and cytokine concentrations are considered as possible cause of postoperative confusion and ileus. Anesthesia with ketamine, propofol and fentanyl decreased the frequency of the postoperative confusion in schizophrenic patients. Epidural anesthesia with local anesthesia in schizophrenic patients undergoing abdominal surgery minimized postoperative ileus. Antipsychotic drugs administrated to schizophrenic patients should be continued before anesthesia for decreasing postoperative confusion. Thus, anesthesiologists must not only be aware of the perioperative problems of these patients but must also learn how to manage their perioperative course. PMID- 20857666 TI - [Preoperative evaluation, preparation and prognosis in depressed patients]. AB - Depressed patients have some problems before, during and after anesthesia such as hypotension, and torsade de pointes during anesthesia, postoperative confusion, serotonin toxicity, increased intraoperative bleeding by selective serotonin reuptake inhibitors. Depressed patients treated by antidepressants have decreased plasma cortisol and interleukin-6 response to surgery and are more at risk for developing postoperative confusion, that is associated with abnormal cortisol response to surgery and more frequent in patients discontinued antidepressants 72 hours before surgery. Depressed patients treated by antidepressants have high postoperative pain score, that depend on their depressed state. A small-dose of ketamine improves postoperative depressive state and relieves postoperative pain in depressed patients and is a suitable anesthetic for depressed patients. As the anesthetic management in depressed patients is becoming increasingly, anesthesiologists should be familiar with medical illness, abnormal response to surgery in depressed patients and must learn their perioperative management. PMID- 20857667 TI - [Preanesthetic evaluation of pediatric patients]. AB - Preoperative evaluation of pediatric patients undergoing anesthesia requires specific consideration. Upper respiratory infection and fever are common problems encountered in the otherwise healthy children who are scheduled for minor surgery. Considerations for the preanesthetic evaluation of the patients with asthma or ex-preterm infants are discussed. It is important to provide less stressful environment to patients and to fulfill patients' satisfaction. Fasting time should be minimum. If patients are extremely anxious and feel fear for separation from their parents, anxiolytic medication might be helpful. Parents present at induction may be another option for smooth induction of anesthesia. Children may have received vaccines. Surgery should be planned in accordance with the vaccination program. Several laboratory examinations can be omitted after careful physical examination and interview. Blood count, ECG, or chest X-ray seldom affect the preoperative preparation or anesthetic method for the patients who do not have any particular findings in physical examination. Such examination is not only unnecessary, but gives stress to those patients. In recent years, there have been some reports that anesthesia during infancy affect the development of the brain and causes learning disability or emotional complication. These findings are mainly based on the results of animal experiments and the effect of anesthetics on the developing brain has not been thoroughly confirmed yet in the clinical settings. We need to keep our eyes on the forthcoming research. PMID- 20857668 TI - [Preoperative evaluation, management and outcome in the elderly patient]. AB - Two principles should be kept in mind when performing preoperative evaluation of the elderly patient. First, we should suspect the disease processes commonly associated with aging. Second, we should assess the degree of functional reserve of specific, pertinent organ systems. Preoperative risk assessment is focused on detailed review from anamnesis and physical examination together with the assessment of functional status. Especially, it is important to examine the cardiovascular and respiratory functions in the elderly patient. Further, this also includes assessment of consumed drugs, physiological function, cognitive function, competency, availability of social support, and sign of depression. Surgical risk and outcome in the elderly patient depend primarily on four factors: age, the patient's physiological status and coexisting disease, whether the surgery is elective or urgent, and the type of procedures. PMID- 20857669 TI - [Preoperative management of malignant hyperthermia]. AB - Malignant hyperthermia (MH) is a potentially fatal complication of general anesthesia following exposure to a depolarizing muscle relaxant and/or volatile anesthetics. MH is inherited as autosomal dominant and is thought to result from disordered Ca2+ regulation by the sarcoplasmic reticulum of the skeletal muscle. The mortality is still approximately 15% in Japan. It is difficult to diagnose by usual examinations preoperatively. Therefore, early detection, prompt treatment, discontinuation of triggering agents, and sufficient administration of dantrolene are needed. PMID- 20857670 TI - [Management of the difficult airway]. AB - Difficult airway management (DAM) including cannot intubate and cannot ventilate (CICV), and difficult mask ventilation is a life threatening issue during anesthesia care. Although American Society of Anesthesiologists (ASA) has presented the guideline for this purpose, it is still not available in this country. We as a specialist for airway management should be prepared this trouble any time by equipping a laryngoscope, fiberoptic bronchoscope, and novel devices such as Airway Scope and Airtraq. PMID- 20857671 TI - [Preoperative evaluation and perioperative prevention of infectious diseases]. AB - Preoperative evaluation of infectious diseases in patients for elective and non elective surgery is important for the anesthesiologists not only to rule out the patient's state of illness, but also to prevent transmission of infectious diseases in healthcare settings. To prevent transmission of infectious diseases in healthcare settings, Center for Disease Control published guidelines that consist of standard precaution and transmission-based precautions. In the face of exposure to known infectious diseases, certain post exposure prophylaxis has been established, especially against exposure to human immunodeficiency virus and hepatitis B virus. There are also growing interests in perioperative prevention of surgical site infection, since World Health Organization has published surgical safety checklist with the slogan "Safe surgery saves life". Anesthesiologists need to have knowledge on the prevention of surgical site infection especially on antibiotic prophylaxis, because it starts in the operating room. PMID- 20857672 TI - [Jehovah's Witness patients]. AB - There are still legal and ethical problems relating to the refusal of blood transfusion due to religious belief of Jehovah's Witness patients. Since general consensus about the anesthetic management of these patients has not been established, the "Guidelines for refusal of blood transfusion on religious grounds" was proposed by the joint committee including Japanese Society of Anesthesiologists in February 2008. The principle of the guideline is that if a patient, who refuses blood transfusion even at cost of life, is 18 years old or above and competent to understand the medical treatment and the adverse effects due to bloodless medicine, doctors may plan and complete bloodless surgery. The same policy is allowed if the patient is 15 years old or above and he/she as well as all the parental authorities refuse blood transfusion. In other cases, the policy of life-saving blood transfusion should be explained to the patients. If a bloodless surgery is planned, precise perioperative strategies to avoid blood loss have to be carried out with the cooperation of all the physicians who care the patient. Anesthesiologists should be carefully prepared for the possible law suits that might lead to unexpected outcomes. PMID- 20857673 TI - [Antihypertensive drugs]. AB - Lately, treatment for hypertension has changed in Japan, according to Japanese Society of Hypertension Guideline 2000 (JSH 2000). We present the characteristics of antihypertensive drugs, and directions for their preoperative use. PMID- 20857674 TI - [Steroids]. AB - We sometimes encounter preoperative patients with steroid treatment. These patients require steroid cover around the operative period because their adrenal cortical function is suppressed. Steroid supplementing therapy has changed since a generation ago. Therefore, steroid treatment is one of the items that anesthegiologists must study immediately. PMID- 20857675 TI - [Anticoagulant or antiplatelet drugs and anesthesia]. AB - An increasing number of preoperative patients are receiving therapy with an oral anticoagulant (warfarin) or antiplatelet drugs to prevent thromboembolic complications. Because of its irreversible inhibition on hepatic synthesis of vitamin K-dependent coagulation factors, warfarin must be stopped 3 to 4 (ideally 4 to 5) days prior to the planned major operation. Normal PT-INR is mandatory prior for neuraxial block. Rapid reversal of warfarin in emergency settings with FFP rather than vitamin K is advocated. More reliable and prompt reversal is possible with PCCs and rFVIIa, but this approach is off-label use in Japan as well as in the US. Antiplatelet drugs have different mechanisms to suppress platelet aggregation. Ticlopidine and clopidogrel should be stopped 7 days prior to the major surgery because of their irreversible inhibition on ADP receptors of platelets. Although it is recommended to stop aspirin 7 days prior to the planned major surgery in some guidelines, low dose oral aspirin (75-300 mg day(-1)) alone is accepted in another guideline because it does not create a level of risk that will interfere with the performance of neuraxial blocks. PMID- 20857676 TI - [Oral contraceptive and anesthesia]. AB - Current oral contraceptive (OCs) use is associated with a fivefold increased risk of perioperative venous thromboembolism (VTE). Although the absolute number of patient who develops perioperative VTE when taking OCs is small (15-25 per 100,000 person-years), the newer OC contains desogestrel as progestogen (the third generation OC) is found to have slightly greater risk of VTE than the older OCs. "WHO criteria for the use of oral contraceptive, third edition (2004)" classifies only the major surgery with prolonged immobilization as "Category 4" where oral contraceptive is not to be used. On the contrary, Japanese Ministry of Health, Labour and Welfare prohibits OCs in all kinds of surgery. Although the restraint of perioperative OCs administration is invalid, it would be prudent to halt perioperative OCs in Japan. PMID- 20857677 TI - [The direction and the position of epidural catheter tips inserted 5 cm or 7 cm cephalad did not differ]. AB - BACKGROUND: Epidural catheter insertion is a common procedure in gynecological surgeries. At a previous study, we investigated the catheter's direction and position, inserted 7cm cephalad from T12-L1, with postoperative plain X-P using picture archiving communication system (PACS). 74% of the catheters advanced in cephalad direction and 71.4% of the catheter tips stayed within one vertebra from the puncture level. We estimated that the catheters were too long to advance straight. Then, we planned another prospective study to compare the catheter advanced 7 cm or 5 cm regarding its direction and tip position. METHODS: Fifty one female patients receiving gynecological surgery were enrolled. Epidural catheters were inserted from T12-L1 intervertebral space in cephalad direction for the length of 5 cm confirmed with postoperative plain X-P using PACS. The catheter's direction, the length, and the position were verified and compared with the result of the previous study. RESULTS: The catheters going cephalad appeared more frequently among 5 cm group than 7 cm group. Those going caudalad appeared more frequently among 7 cm group than 5 cm group. However, the catheter tip final position and the length from the puncture levels were not significantly different between the groups. CONCLUSIONS: The direction and the position of epidural catheter inserted 5 cm or 7 cm cephalad did not differ. PMID- 20857678 TI - [Landiolol infusion attenuates increase in heart rate, but does not prevent increase in blood pressure in response to emergence from anesthesia and tracheal extubation]. AB - BACKGROUND: Tracheal extubation and emergence procedures induce abrupt changes in hemodynamics and humoral responses. The purpose of this study was to examine the effects of different doses of landiolol on hemodynamics during emergence from anesthesia. METHODS: All patients undergoing general anesthesia were enrolled in this study. Immediately after the end of the surgery, all anesthetics were discontinued. Thereafter, during emergence from anesthesia, all patients were ventilated with 100% oxygen and landiolol infusion was started in all but the control group patients. In the normal dose group, landiolol infusion was started at a rate of 0.125 mg x kg(-1) x min(-1) for 1 min, decreasing it to 0.04 mg x kg(-1) x min(-1) until the time of extubation. In the low dose group, landiolol infusion was given at a rate of 0.06 mg x kg(-1) x min(-1) for 1 min and then continuously infused at the rate of 0.02 mg x kg(-1) x min(-1) until extubation. RESULTS: Systolic and diastolic pressure increased during the emergence period in all 3 groups, there being no significant differences in systolic and diastolic pressure between the 3 groups during the observation period. Heart rate increased during the emergence period in the control group. In contrast, heart rate in both normal and low dose groups did not increase during the observation period. CONCLUSIONS: Landiolol could prevent the increase in heart rate but not blood pressure during emergence from anesthesia. Effects on the changes in heart rate between 0.125 and 0.06 landiolol groups were not significantly different. PMID- 20857679 TI - [The effect of transversus abdominis plane block for pediatric patients receiving bone graft to the alveolar cleft]. AB - BACKGROUND: Transversus abdominis plane block (TAP block) is useful for lower abdominal operations. Recently, ultrasound guided nerve block has been performed with ultrasound scanning. METHODS: We investigated the effectiveness of TAP block in 64 pediatric patients (aged 5-12 years, F/M = 21/43) receiving bone graft from the ilium to the alveolar cleft. We compared the dosages for postoperative analgesics between the groups of TAP block and non-TAP block. RESULTS: In the TAP block group, the frequency of using the postoperative analgesics was lower compared with non TAP block group (P < 0.05). CONCLUSIONS: We concluded that TAP block was effective in pediatric patients receiving bone graft to the alveolar cleft. PMID- 20857680 TI - [Alteration of the planned surgical procedure by intraoperative transesophageal echocardiography in two cases of emergency operations]. AB - We report alteration of the planned surgical procedures in two cases during emergency operations. Both patients were urgently scheduled for off-pump coronary artery bypass grafting surgery supported by an intraaortic balloon pump. Intraoperative transesophageal echocardiography (TEE) demonstrated the findings which had not been diagnosed preoperatively and the operative procedure was altered in both cases. Information provided by TEE can be helpful especially in emergency cases where preoperative assessment may be inadequate. We have demonstrated the important role of intraoperative TEE. PMID- 20857681 TI - [A man with severe dilated cardiomyopathy with implantable cardioverter defibrillator who underwent sigmoidectomy]. AB - We report a man with severe dilated cardiomyopathy with an implantable cardioverter-defibrillator (ICD) who underwent sigmoidectomy. During the operation, the defibrillation function of the ICD has been stopped to prevent malfunction caused by electrocautery artifacts, and the electrodes of the external defibrillator were placed on the chest wall. Pulmonary artery catheter was inserted under X-ray imaging to prevent the interference between ICD leads and the catheter. Anesthesia was maintained with combined general and thoracic epidural anesthesia. In order to prevent the afterload increase, both milrinone and carperitide were administered. Fluid resuscitation was also performed to maintain circulating blood volume. As a result of the management, patient has not exhibited any heart failure. PMID- 20857682 TI - [Spinal anesthesia in a patient with SMON disease]. AB - We report a patient with subacute myelo-optico-neuropathy (SMON) in whom spinal anesthesia was employed to treat fracture of the femur neck. An 87-year-old woman was diagnosed as having SMON at the age of 45. The patient was admitted to our hospital with fracture of the femur neck. Aspiration pneumonia was also suspected with shadow in the right lung on the chest X-P The percutaneous oxygen saturation (Spo2) with room air was 77%. Spinal anesthesia with 5 mg of 0.5% hyperbaric bupivacaine and 20 mcg of fentanyl was performed at L3-4. The level of anesthesia was T4. During surgery, no severe pain in the lower limbs was observed. Three hours after the end of surgery, the level of anesthesia was T9. On the day after surgery, the extent of dysesthesia and reflex were similar to those before surgery. General anesthesia has been chosen in SMON patients, because there was a report of severe pain of the lower limbs after spinal anesthesia with dibucaine. In our patient, general anesthesia was considered inappropriate due to hypoxemia. We used a mixture of bupivacaine and fentanyl for spinal anesthesia, because the neurotoxicity of bupivacaine is weaker than that of dibucaine. PMID- 20857683 TI - [Disease and epigenome analysis]. PMID- 20857684 TI - [E3 ubiquitin ligase family for MHC molecules]. PMID- 20857685 TI - [Beyond antibody using phage display: molecular targeting by novel designed molecule]. PMID- 20857686 TI - [Sodium-dependent phosphate transporters and cardiovascular disease]. PMID- 20857687 TI - [Re-examination of starch-statolith hypothesis, a model for gravity sensing mechanism in plants]. PMID- 20857688 TI - [Regulation and function of sialic acid modifications in B lymphocytes]. PMID- 20857689 TI - [Liquid chromatography/multiple-stage mass spectrometry in structural analysis of glycoproteins]. PMID- 20857690 TI - [Manipulation of Th17-mediated autoimmunity by targeting nuclear receptors]. PMID- 20857691 TI - [Structure and function of glycoconjugates involved in dengue virus infection]. PMID- 20857692 TI - [Update on epigenetic regulation in pathophysiologies of stress-induced psychiatric disorders]. AB - Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene transcription without altering the DNA code, could play a critical role in the pathophysiology of psychiatric disorders. The present review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in several psychiatric disorders such as depression, schizophrenia and Rett syndrome. The gene transcriptions of the key molecules such as brain-derived neurotrophic factor (BDNF) or Reelin that play a role in on psychiatric disorders are regulated with histone modification or DNA methylation. Furthermore, one potential mechanism whereby stress can disrupt prenatal and/or neonatal development is through epigenetics, because the key issue of epigenetics is its long-term influence. In addition, we also found in the recent research that the epigenetic mechanism of gene regulation, especially histonedeacetylase, in the brain may be involved in the development of emotional resistance to stress stimuli. A better understanding of epigenetic regulation might provide new therapeutic avenues for disorders such as depression, schizophrenia, Rett syndrome and neurodevelopmental diseases. PMID- 20857693 TI - [Therapeutic strategies for Alzheimer disease based on endoplasmic reticulum stress]. AB - The endoplasmic reticulum (ER) stress response is a defense system for dealing with the accumulation of unfolded proteins in the ER lumen. Recent reports have shown that ER stress is involved in the pathology of Alzheimer disease and some neurodegenerative diseases. In a screen for compounds that induce the ER-mediated chaperone BiP/GRP78 (BiP), we identified BiP inducer X (BIX). BIX preferentially induced BiP with slight inductions of GRP94, calreticulin, and CHOP. The induction of BiP mRNA by BIX was mediated by activation of ER stress response elements (ERSEs) upstream of the BiP gene, through the ATF6 pathway. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice, good in vivo models of ER stress. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Considering these results together, it appears that BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for Alzheimer disease and some neurodegerenerative diseases caused by ER stress. PMID- 20857694 TI - [Surrogate marker for ABeta42]. AB - Currently, therapeutic intervention for Alzheimer disease (AD) after the disease onset is not very effective because progressive neuronal death precedes clinical symptoms. Available medicines such as AchE inhibitors transiently slow the progression of the symptoms, but they do not inhibit the pathological process. On the other hand, most of the next generation anti-AD drugs under development in pharmaceutical companies are to function to inhibit the progress of the pathological process and, thus, establishment of highly probable prediction of AD onset is necessary. AD is diagnosed using clinical criteria coupled with brain imaging systems such as SPECT and PET. To diagnose AD cases before the onset, it will be necessary to develop methods for detecting the pathological accumulation of proteins (e.g., Abeta in the brain, or develop biomarkers for predicting Abeta/tau accumulation in the brain. Our recent discovery of APL1beta28, a possible biomarker of AD, may contribute to early detection of AD. PMID- 20857695 TI - [Immunotherapy and Alzheimer's disease]. AB - Recent progress in biological studies on Alzheimer's disease (AD) could lead to a new strategy for its treatment. One of the representative and leading therapies is passive and active immunotherapy. The first active immunotherapy using the full length of Abeta protein was stopped due to the serious side-effect of encephalitis. Currently, a new revised immunotherapy using humanized mouse monoclonal antiserum against a part of Abeta protein is under clinical trials. Here, future advance concerning AD treatment as well as the present situation will be reviewed. PMID- 20857696 TI - [Drug development for tauopathy and Alzheimer's disease]. AB - Neurofibrillary tangles (NFTs), which consist of a fibrillar aggregate of hyperphosphorylated tau, are commonly seen in aging brains and those with Alzheimer's disease. Based on Braak staging of NFTs, NFTs are first observed in the entorhinal cortex. Then, NFTs spread from the entorhinal cortex to the limbic and neocortex. NFT the formation in the entorhinal cortex may be correlated with memory loss in brain aging, because entorhinal cortex is involved in memory formation, and NFTs in the limbic and neocortex may cause dementia in AD, because the limbic and neocortex serve higher order brain functions. These suggest that regional development of NFTs is correlated with decline of brain functions in aging and AD. Recent reports suggested that the process of NFT formation, but not NFT itself, is involved in neuronal dysfunction. We found that there are three tau aggregation forms, soluble tau oligomer, granular tau, and fibrilar tau, before NFT formation. From the analysis of tau Tg mice, it was indicated that soluble oligomer tau may be involved in synapse loss, and insoluble granular tau aggregates may play a role in neuronal death. Therefore, inhibition of oligomer tau, and granular tau aggregation is expected to block the progression of AD symptoms by preventing synapse loss and neuronal loss. PMID- 20857697 TI - [Image of the month. Renal involvement with lymphoma]. PMID- 20857698 TI - [How I treat...lower extremity deep vein thrombosis]. AB - Venous thromboembolism is a widespread and sometimes life-threatening disease. It is still often unadequately managed, however. This article aims at summing up the most recent national and international guidelines and points out usual pitfalls although some therapeutic uncertainties persist. PMID- 20857699 TI - [Clinical case of the month. Bilateral optic neuropathy secondary to biphosphonate therapy]. AB - Ocular side effects associated with biphosphonates have been described. Conjunctivitis, uveitis and scleritis are the most common adverse events. We report a case of bilateral toxic optic neuropathy with optic dies edema occurring soon after a pamidronate intravenous infusion in a patient who previously presented both a conjunctivitis and an uveitis of moderate intensity associated with alendronate therapy. PMID- 20857700 TI - [Sexual abuse: a cause for psychosomatic illnesses]. AB - A human being is a psychosomatic entity, an inseparable mind/body unit. Psychosomatic illness is caused by a break of this vulnerable internal equilibrium from important emotional perturbations provoked by experiences of abuse. Patients rarely consult their physician for abuse they suffered, and they often keep it a lifetime secret. Moreover, since there is a latency period between the abuse and the emergence of physical symptoms, neither the physician nor the patient realize how past abuse and present symptoms are related. Symptomatic treatment cannot treat the root pathologies and thus, psychosomatic illnesses most commonly become chronic. PMID- 20857701 TI - [Perioperative tobacco cessation: potential benefits and principles of management]. AB - Thirty percent of surgical patients undergoing routine surgery are smokers, and smoking is an additional risk for these patients. During the perioperative period, smokers are more prone than non smokers to present either systemic complications interesting the cardiovascular and pulmonary functions or specific complications related to the surgical procedure, such as infections, wound problems and delayed osteosynthesis. Therefore, coming-off from smoking addiction is an obvious prerequisite in these patients. Diagnosing smoking habit, evaluating its severity and its systemic repercussions on vital functions, as well as proposing an efficacious and appropriate help to smokers before surgery become one essential objective of pre-anesthetic assessment. PMID- 20857702 TI - [Fungi at the beach]. AB - Fungi responsible for dermatomycoses survive in a resting phase inside diverse parts of the environment. Sand in the wet, partly wet and dry portions of the beaches frequently contains dermatophytes, yeasts and moulds. These microorganisms possibly infect skin and nails during summertime. PMID- 20857703 TI - [Medullary thyroid cancer: surgical results and prognostic factors]. AB - Medullary thyroid carcinoma is a rare tumour (5 to 10% of all thyroid cancers). A number of factors influencing prognosis have been suggested, but their relative significance is not clear. This retrospective study was performed on 44 consecutive patients treated from 1965 to 2003. The aim of the study was to identify prognostic factors, and to assess the results of treatment and associated complications. Mean age was 53.8 years. 5 patients were stage I, 15 in stage II, 22 in stage III and 2 in stage IV. Total thyroidectomy was performed in all cases and 33 also underwent neck dissection. No postoperative complications were observed in 36 patients. Overall survival was 76% at 5 years and 57% at 10 years. In univariate analysis, the factors which were significant predictors of survival were stage III and IV, metastases at presentation, cervical lymph node dissection, postoperative external beam radiotherapy and elevated postoperative calcitonin. In the multivariate analysis, stage IV, metastases at presentation and persistent postoperative elevated calcitonin were significant predictors of survival. PMID- 20857704 TI - [Critical reflections concerning euthanasia for persons with dementia]. AB - In the public debate on the extension of euthanasia for people with dementia, in addition to ethical considerations and arguments, other issues have to be kept in mind. The diagnosis of dementia is difficult and the clinical picture is very fluctuating. The assessment and especially the operationalization of legal capacity and the use of advance directives are complex problems. The discussion should be conducted against the backdrop of a cultural framework in which the interpretation and development of palliative care is crucial. The development of a framework like advance care planning creates opportunities. The question remains whether the legal issues can be clarified and whether a legal approach generates solutions for the problems described. PMID- 20857705 TI - [A rare cause of acute renal failure, acute tubulo-interstitial nephritis]. AB - We report the case of an acute renal failure due to an acute interstitial nephropathy (ATIN) induced by non steroidal anti-inflammatory drugs (NSAID). Even though this pathology is a rare cause of acute renal failure, it still requires special attention in view of the fact that it induces a high risk of acute morbidity but it also can evolve into chronic renal failure. Its differential diagnosis with other causes of acute renal failure becomes essential because of the different therapeutic care. In this article, we are going to briefly sum up the reasoning to adopt in order to diagnose an acute renal failure. PMID- 20857706 TI - [Liraglutide (Victoza): human glucagon-like peptide-1 used in once daily injection for the treatment of type 2 diabetes]. AB - Liraglutide (Victoza) is a peptide produced by DNA recombinant technology, which presents 97% homology with human glucagon-like peptide-1 (GLP-1) but is resistant to dipeptidylpeptidase-4, the enzyme that degrades the natural hormone. It actives the GLP-1 receptor and exerts an incretin mimetic effect during at least 24 hours after a single subcutaneous injection. Besides a glucose-dependent stimulatory effect of insulin secretion, liraglutide inhibits glucagon secretion and retards gastric emptying. In patients with type 2 diabetes, it reduces glycated haemoglobin by at least 1%, without inducing hypoglycaemia. It also induces a moderate weight loss and a mild reduction in blood pressure. Gastrointestinal adverse events (nausea, vomiting) may occur during the initial phase of treatment, but rarely impose the interruption of the medication and usually diminish with time.Although indicated in combination with other glucose lowering agents, liraglutide is currently reimbursed in Belgium only if administered in patients with type 2 diabetes not sufficiently controlled with a combination of metformin plus sulfonylurea or metformin plus a thiazolidinedione. Victoza is presented in prefilled pens and is injected subcutaneously once a day. Treatment will be initiated with 0.6 mg to improve digestive tolerance and the daily dose will be increased to 1.2 mg (usual dose) after at least one week, and up to 1.8 mg (maximal dose) if necessary. PMID- 20857707 TI - [Medication of the month. Exforge HCT: combination of amlodipine besylate, valsartan and hydrochlorothiazide in a single tablet]. AB - Because of the multifactorial nature of hypertension, most patients require combination therapy to achieve blood pressure control. Very often the antihypertensive regimen includes a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic. Currently, several associations combining two antihypertensive agents with complementary mechanisms of action are available. These combination therapies are more efficient to control blood pressure through synergistic and additive effects, can reach target blood pressure more quickly, are likely to attenuate the side effects of each molecule, and could improve patient adherence. Exforge HCT is the first fixed-dose combination of three antihypertensive drugs including amlodipine besylate, valsartan and hydrochlorothiazide (HCTZ) in a single pill. The association of these three drugs improves, with an equal tolerance, blood pressure control compared to dual therapies (valsartan/HCTZ, amlodipine/valsartan, or HCTZ/amlodipine). This triple therapy attenuates the diuretic-induced hypokalemia. The benefits of triple therapy over dual therapy are observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic blood pressure. Exforge HCT is currently indicated for the treatment of essential hypertension, as replacement therapy for adult patients whose blood pressure is adequately controlled by the combination of amlodipine, valsartan and HCTZ. PMID- 20857708 TI - [A patient with cardiovascular risk factors and comorbidities: integration of indications and contra-indications in pharmacotherapy]. AB - A patient with abdominal obesity, type 2 diabetes, arterial hypertension and dyslipidaemia is exposed to a high risk of coronary artery disease, congestive heart failure and/or renal insufficiency. The management of such a patient requires different medications, which should be prescribed by taking into account both (relative and absolute) indications and contra-indications to improve overall prognosis. The present clinical case report illustrates the therapeutic reasoning leading to an appropriate pharmacological polytherapy, combined with life-style changes. PMID- 20857709 TI - Discovery and characterization of field resistance to Bt maize: Spodoptera frugiperda (Lepidoptera: Noctuidae) in Puerto Rico. AB - Transgenic maize, Zea mays L., event TC1507 produces the Cry1F protein to provide protection from feeding by several important lepidopteran pests, including Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae). Reports of reduced field performance against this species in Puerto Rico were investigated, and laboratory bioassays showed that S. frugiperda collected from the affected area exhibited lower sensitivity to the Cry1F protein compared with typical colonies from other regions. The resistance was shown to be autosomally inherited and highly recessive. The Puerto Rico colony was shown to be moderately less sensitive than susceptible laboratory strains to Cry1Ab and Cry1Ac, but the differences in sensitivity were dramatically smaller than for Cry1F. Potential contributory factors to the emergence of resistance to Cry1F in Puerto Rico populations of S. frugiperda include the tropical island geography, unusually large population sizes in 2006, and drought conditions reducing the availability of alternative hosts. In response to this resistance incident, the technology providers have stopped commercial sales of TC1507 maize in Puerto Rico pending potential reversion to susceptibility. PMID- 20857710 TI - Practical sampling plans for Varroa destructor (Acari: Varroidae) in Apis mellifera (Hymenoptera: Apidae) colonies and apiaries. AB - The parasitic mite Varroa destructor Anderson & Trueman (Acari: Varroidae) is arguably the most detrimental pest of the European-derived honey bee, Apis mellifera L. Unfortunately, beekeepers lack a standardized sampling plan to make informed treatment decisions. Based on data from 31 commercial apiaries, we developed sampling plans for use by beekeepers and researchers to estimate the density of mites in individual colonies or whole apiaries. Beekeepers can estimate a colony's mite density with chosen level of precision by dislodging mites from approximately to 300 adult bees taken from one brood box frame in the colony, and they can extrapolate to mite density on a colony's adults and pupae combined by doubling the number of mites on adults. For sampling whole apiaries, beekeepers can repeat the process in each of n = 8 colonies, regardless of apiary size. Researchers desiring greater precision can estimate mite density in an individual colony by examining three, 300-bee sample units. Extrapolation to density on adults and pupae may require independent estimates of numbers of adults, of pupae, and of their respective mite densities. Researchers can estimate apiary-level mite density by taking one 300-bee sample unit per colony, but should do so from a variable number of colonies, depending on apiary size. These practical sampling plans will allow beekeepers and researchers to quantify mite infestation levels and enhance understanding and management of V. destructor. PMID- 20857711 TI - Distribution of glassy-winged sharpshooter and threecornered alfalfa hopper on plant hosts in the San Joaquin Valley, California. AB - Homalodisca vitripennis (Germar) and Spissistilus festinus (Say) populations were surveyed bimonthly for 14 mo in Kern County, CA, at five agricultural sites made up of a variety of potential host plants. In addition, S. festinus populations were surveyed in four alfalfa, Medicago sativa L., fields in Kern and Tulare counties. Insects were collected by beats-sweeps and sticky traps. Data on host plant condition and phenology, and ground cover presence and composition were collected at the five agricultural sites, whereas data on mowing and insecticide use were collected at the four alfalfa sites. Populations of both insects persisted at the five agricultural locations despite insecticide applications applied as part of a H. vitripennis areawide management program and standard commercial operations. Plants colonized by H. vitripennis included eucalyptus (Eucalyptus L'Her.), jojoba [Simmondsia chinensis (Link) C. K. Schneid.], and citrus (Citrus spp.). Populations of S. festinus were much greater in collections from alfalfa fields than from the five agricultural sites. Insects collected from the five mixed agricultural sites were negative for presence of X. fastidiosa. In laboratory tests, S. festinus did not acquire or transmit X. fastidiosa in tests with infected grape (Vitis spp.) as an acquisition source and grape, almond [Prunus dulcis (Mill.) D.A.Webb], and alfalfa as inoculation hosts. Recommendations for vector control, vegetation management, and targeted monitoring to reduce insect populations and inoculum potential are discussed. PMID- 20857712 TI - Association of "Candidatus Liberibacter solanacearum" with the psyllid, Trioza apicalis (Hemiptera: Triozidae) in Europe. AB - The psyllid Trioza apicalis Forster (Hemiptera: Triozidae) is a serious pest of carrots, Daucus carota L., in Europe. Carrots exhibiting symptoms of psyllid damage were observed in commercial fields in southern Finland in 2008. Symptoms in affected plants included leaf curling, yellow and purple discoloration of leaves, stunted growth of shoots and roots, and proliferation of secondary roots. Mechanisms by which T. apicalis induces symptoms in plants are not understood, and no plant pathogens have yet been associated with this insect. Given recent association of liberibacter with several crops affected by psyllids, an investigation on whether this bacterium is associated with T. apicalis was conducted. Polymerase chain reaction (PCR) primer pairs OA2/OI2c and LsoF/OI2c, specific for 16S rRNA gene from "Candidatus Liberibacter solanacearum," generated amplicons of 1,168 bp and 1,173 bp, respectively, from DNA extracted from field collected psyllids (61 and 36.6%, respectively), laboratory-reared psyllids (70 and 33.3%, respectively), field-collected petioles from symptomatic carrots (80 and 55%, respectively), and laboratory-grown carrots (100% for both primer pairs). In contrast, no PCR products were detected in DNA extracted from insect free plants. The DNA sequences of amplicons of the genes encoding liberibacter 16S rRNA from psyllids and carrots were identical. DNA of the 16S rRNA gene sequences determined from carrots and psyllids were 99.9% identical to analogous sequences of "Ca. L. solanacearum" amplified from several solanaceous crops and the psyllid Bactericera cockerelli (Sulc), a vector of this bacterium. This is the first report of a plant pathogen associated with T. apicalis and the second known psyllid species associated with "Ca. L. solanacearum". PMID- 20857713 TI - Interspecific hybridization as a source of novel genetic markers for the sterile insect technique in Bactrocera tryoni (Diptera: Tephritidae). AB - Bactrocera tryoni (Froggatt) (Diptera: Tephritidae) or "Qfly," is the most serious horticultural pest in Australia, with a bioclimatic range that extends from the tropical north to the temperate south. Various Australian horticultural exports depend on certification that they originated from B. tryoni-free areas. To eliminate, rather than suppress, B. tryoni in production areas, a sterile insect technique (SIT) campaign directed at B. tryoni has been in operation in southeastern Australia since 1997. Like many other SIT programs around the world, the B. tryoni SIT program relies on fluorescent dust to mark the sterile insects. However, fluorescent dust marking does not provide 100% accuracy in the identification of sterile insects, as required where the aim is to declare regions completely free of fruit fly. Here, we show that novel mitochondrial markers can be introduced into a strain of B. tryoni by interspecies hybridization between B. tryoni and a related but well-differentiated species, Bactrocera jarvisi (Tryon), followed by backcrossing of the hybrid strain with the parental B. tryoni strain. These novel markers do not affect the viability of the strain as measured by pupation and eclosion rates. A simple polymerase chain reaction-based test is described that distinguishes the marked B. tryoni from wild B. tryoni. As required in practice, the test was shown to work reliably on DNA extracted from dead flies that had remained in field traps for up to two weeks. PMID- 20857714 TI - Suitability and accessibility of immature Agrilus planipennis (Coleoptera: Buprestidae) stages to Tetrastichus planipennisi (Hymenoptera: Eulophidae). AB - Tetrastichus planipennisi Yang (Hymenoptera: Eulophidae), a gregarious larval endo-parasitoid, is one of three biocontrol agents from Asia currently being released in the United States to combat the invasive emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae). The current protocol for rearing T. planipennisi involves presenting the wasps with artificially infested ash sticks made by placing field-collected larvae into shallow grooves beneath flaps of bark. Although third and fourth instars are readily accepted by T. planipennisi in these exposures, the suitability of younger or older developmental stages, which are often more readily available in the field, has not been tested. In this study, we used both artificially infested ash sticks and naturally infested ash logs to test which emerald ash borer developmental stages (second to fourth instars, J larvae [preprepupae], prepupae, and pupae) are most suitable for rearing T. planipennisi. T. planipennisi parasitized all stages except for pupae, but parasitized fewer J larvae and prepupae in naturally infested logs than in artificially infested ash sticks. This is probably because, in naturally infested ash logs, these stages were confined to pupal chambers excavated in the sapwood and may have been largely beyond the reach of ovipositing T. planipennisi. The number of T. planipennisi progeny produced was positively correlated (logarithmic) with host weight, but this relationship was stronger when J larvae and prepupae were excluded from the data set. Fourth instars yielded the most parasitoid progeny, followed by, in approximately equal numbers, J larvae, prepupae, and third instars. Second instars yielded too few parasitoid progeny to benefit rearing efforts. PMID- 20857715 TI - Incorporation of intraguild predation into a pest management decision-making tool: the case of thrips and two pollen-feeding predators in strawberry. AB - Action thresholds are traditionally based on the density of pests and the economic damage they cause to crops. Pest damage assessments are usually made in a "sterile" environment, devoid of extenuating factors such as predators, parasitoids, and alternative food sources. Recently, the effects of a predator or parasitoid species have been considered. However, interactions between natural enemy species (intraguild predation and interference), which are common in agricultural fields, have not been incorporated yet into decision-making tools. We conducted a series of leaf disc and potted plant trials to evaluate the effects of two predator species, the anthocorid Orius laevigatus (Fieber) and the phytoseiid Neoseiulus cucumeris (Oudemans) on the density of and fruit damage inflicted by western flower thrips, Frankliniella occidentalis (Pergande). We then used the obtained results to develop a pest management decision-making tool for the control of western flower thrips. Because strawberries (Fragaria x ananassa Duchesne) flower in cycles, pollen, a food source for both predators and the pest, is periodically available in the system and has also been incorporated in our decision-making tool. The developed new management tool would allow the relaxation of the economic threshold (ET) for western flower thrips in strawberry flowers. The presence of an average of a single O. laevigatus per flower for example, may allow that relaxation of the ET by 40% (from 10 to 14 western flower thrips per flower) when pollen is available during the winter. Because field monitoring shows that O. laevigatus populations in Israeli strawberry often reach mean densities of three to four per flower, the new approach promises to drastically reduce the employment of toxic insecticides. PMID- 20857716 TI - Beauveria bassiana infection alters colony development and defensive secretions of the beetles Tribolium castaneum and Ulomoides dermestoides (Coleoptera: Tenebrionidae). AB - We studied the effect of the entomopathogenic fungus Beauveria bassiana strain GHA on a) colony development of the beetles Tribolium castaneum (Herbst) and Ulomoides dermestoides (Fairmaire) (Coleoptera: Tenebrionidae) under laboratory conditions; and 2) the volatile blend released by both beetles, containing defensive pheromones, by using the solid phase microextraction technique. Colony development of both species was strongly altered 3 mo after treatment with B. bassiana, showing a significant reduction in progeny of 37.5% for T. castaneum and 50.0% for U. dermestoides. We also showed that the volatiles released by T. castaneum diminished close to 20% compared with those of healthy beetles, whereas in U. dermestoides secretions dramatically dropped to 5%, 7 d after immersion in 1 x 10(9) conidia per ml. These results suggest that after infection events take place, fungus-induced diminished secretion of the defensive pheromones may be a physiologic clue for behavioral changes in infected beetles. PMID- 20857717 TI - Risk of introducing exotic fruit flies, Ceratitis capitata, Ceratitis cosyra, and Ceratitis rosa (Diptera: Tephritidae), into southern China. AB - Exotic fruit flies (Ceratitis spp.) are often serious agricultural pests. Here, we used, pathway analysis and Monte Carlo simulations to assess the risk of introduction of Ceratitis capitata (Wiedemann), Ceratitis cosyra (Walker), and Ceratitis rosa Karsch, into southern China with fruit consignments and incoming travelers. Historical data, expert opinions, relevant literature, and archives were used to set appropriate parameters in the pathway analysis. Based on the ongoing quarantine/ inspection strategies of China, as well as the interception records, we estimated the annual number of each fruit fly species entering Guangdong province undetected with commercially imported fruit, and the associated risk. We also estimated the gross number of pests arriving at Guangdong ports with incoming travelers and the associated risk. Sensitivity analysis also was performed to test the impact of parameter changes and to assess how the risk could be reduced. Results showed that the risk of introduction of the three fruit fly species into southern China with fruit consignments, which are mostly transported by ship, exists but is relatively low. In contrast, the risk of introduction with incoming travelers is high and hence deserves intensive attention. Sensitivity analysis indicated that either ensuring all shipments meet current phytosanitary requirements or increasing the proportion of fruit imports sampled for inspection could substantially reduce the risk associated with commercial imports. Sensitivity analysis also provided justification for banning importation of fresh fruit by international travelers. Thus, inspection and quarantine in conjunction with intensive detection were important mitigation measures to reduce the risk of Ceratitis spp. introduced into China. PMID- 20857718 TI - Developing a systems approach for Thaumatotibia leucotreta (Lepidoptera: Tortricidae) on 'Hass' avocado in South Africa. AB - Thaumatotibia leucotreta (Meyrick) (Lepidoptera: Tortricidae) is pest of the avocado, Persea americana (Mill.) (Lauraceae), in South Africa and is regarded as a phytosanitary threat. The objective of this study was to develop a systems approach for T. leucotreta on 'Hass' avocado that will mitigate the pest risk. T. leucotreta males were monitored with pheromone traps, and numbers declined during the winter. Field studies indicated that most of eggs were laid during January in the Deerpark area, and during harvest, only 0.029 lesions produced live larvae. Survival of larvae in fruit infested on the tree and left to develop after harvest varied and depended on the time of infestation before harvest. Fruit firmness was measured and fifth instars were only present in soft fruit. Fenpropathrin and a granulovirus were effective in reducing the infestation levels. Bags used to cover fruit also reduced infestation levels. Lesions caused by T. leucotreta were visible from two weeks after infestation and fruit with lesions can be sorted. The mean infestation rate per orchard was 0.003 lesions per fruit which makes T. leucotreta on Hass amenable to the alternative treatment efficacy approach and maximum pest limit. In the case of T. leucotreta on Hass, poor host status, production, preharvest and postharvest measures were studied and low infestation levels were observed; all these elements would make a systems approach an option. Furthermore, inspection and certification as well as shipping and distribution measures could be added. PMID- 20857719 TI - Ionizing radiation as a phytosanitary treatment against fruit flies (Diptera: Tephritidae): efficacy in naturally versus artificially infested fruit. AB - Some phytosanitary irradiation treatment research against tephritid fruit flies (Diptera: Tephritidae) has used artificially infested fruit with the unstated and untested assumption that the method adequately simulated a natural situation. We compare grapefruit, Citrus paradisi Macfayden, naturally infested by Mexican fruit fly, Anastrepha ludens (Loew), via oviposition until larvae reached the late third instar versus insertion of diet-reared third instars into holes made in grapefruits 24 h before irradiation; the latter technique has been used in other studies. Both infestation techniques resulted in statistically indistinguishable results, indicating that insertion of diet-reared third instar Mexican fruit fly into holes bored into grapefruit and subsequently sealed 24 h before irradiation would adequately represent natural infestation and could be used to develop a radiation phytosanitary treatment of the insect in grapefruit when prevention of adult emergence is used as the measure of efficacy. Nevertheless, it may not be advisable to extend this conclusion to other fruit fly/fruit combinations without doing appropriate comparison studies. Dissection of puparia from nonirradiated control insects that failed to emerge as adults showed a relatively even distribution of mortality among the developmental stages within the puparium. In contrast, dissection of puparia from irradiated third instars that did not emerge as adults revealed a sharp attenuation in development from cryptocephalic to phanerocephalic pupae demonstrating this transition to be the developmental step most affected by radiation. PMID- 20857720 TI - Acoustic detection of Oryctes rhinoceros (Coleoptera: Scarabaeidae: Dynastinae) and Nasutitermes luzonicus (Isoptera: Termitidae) in palm trees in urban Guam. AB - Adult and larval Oryctes rhinoceros (L.) (Coleoptera: Scarabaeidae: Dynastinae) were acoustically detected in live and dead palm trees and logs in recently invaded areas of Guam, along with Nasutitermes luzonicus Oshima (Isoptera: Termitidae), and other small, sound-producing invertebrates and invertebrates. The low-frequency, long-duration sound-impulse trains produced by large, active O. rhinoceros and the higher frequency, shorter impulse trains produced by feeding N. luzonicus had distinctive spectral and temporal patterns that facilitated their identification and discrimination from background noise, as well as from roaches, earwigs, and other small sound-producing organisms present in the trees and logs. The distinctiveness of the O. rhinoceros sounds enables current usage of acoustic detection as a tactic in Guam's ongoing O. rhinoceros eradication program. PMID- 20857721 TI - Effect of mass rearing on life history traits and inbreeding depression in the sweetpotato weevil (Coleoptera: Brentidae). AB - Inadvertent selection is an important genetic process that frequently occurs during laboratory culture and maintenance of biological control agents and other beneficial organisms used in procedures such as the sterile insect technique (SIT). We investigated effects of mass rearing and inbreeding depression on life history traits (number of progeny emerging from host plants, body weight, developmental period, and starvation tolerance) in the sweetpotato weevil, Cylas formicarius elegantulus (Summers) (Coleoptera: Brentidae). The effect of inbreeding was measured by comparing the results obtained from the full-sib crosses with those obtained from nonkin crosses in both wild and mass-reared strains. The mass-reared strain had more progeny than the wild strain. The developmental period of mass-reared strain was shorter than that of the wild strain. Other traits did not differ significantly between strains. We detected inbreeding depression effects on numbers of progeny, and the effects were more pronounced in the mass-reared strain. Hence, laboratory adaptation to mass rearing can produce changes in important biological attributes of sweetpotato weevils. PMID- 20857723 TI - Temperature-dependent development and emergence pattern of Hypothenemus hampei (Coleoptera: Curculionidae: Scolytinae) from coffee berries. AB - The coffee berry borer, Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae: Scolytinae), is the most important constrain for coffee production throughout the world. Knowledge on the emergence pattern of H. hampei females to infest new berries is crucial to effectively plan control measures. In this laboratory study, we assessed the development of immature stages and the emergence pattern of H. hampei females from the berries by exposing them to temperatures that are typical for high-altitude plantations (> or = 1,700 m above sea level [masl] ) or when coffee is grown under shade trees (20-22 degrees C), and optimum altitude plantations (1,200-1,600 masl) or nonshaded coffee (25-30 degrees C). Fecundity and emergence pattern of H. hampei females from coffee berries varied with temperature. Temperature played a crucial role determining the rate of H. hampei development and therefore the emergence of the females to start a new infestation cycle. The emergence and colonization phases of new colonizing females in coffee plantations with mean temperatures of 20, 25, or 30 degrees C would take place at different moments in the development of the coffee berries, and in some cases more than once. The implications of our findings for an improved, site-specific timing of control interventions against H. hampei are discussed. PMID- 20857722 TI - Biology and feeding requirements of larval hunter flies Coenosia attenuata (Diptera: Muscidae) reared on larvae of the fungus gnat Bradysia impatiens (Diptera: Sciaridae). AB - The larval feeding requirements and biology of the generalist predatory muscid hunter fly Coenosia attenuata Stein 1903 (Diptera: Muscidae) were investigated at 25 degrees C. Larval C. attenuata were fed second-, third, and fourth-instar (L2, L3, and L4) larvae of the fungus gnat Bradysia impatiens (Johannsen) (Diptera: Sciaridae) at variable rates to determine minimum and optimum numbers of these prey required for normal development. The proportion of C. attenuata larvae surviving to pupation differed significantly as a function of L2 and L3 prey numbers. When the number of prey/d was increased from 10 to 15 L2 and from 5 to 7 L3 per day, the respective percentages of pupation increased from 0 to 77% and from 0 to 48%. In contrast, all numbers of L4 prey (1-7 prey per d) supported pupation, and the pupation rate did not vary with prey number. At the highest prey numbers tested, mortalities of C. attenuata larvae fed L2, L3, and L4 fungus gnat larvae were 7, 30, and 75%, respectively. The higher mortality of larvae fed L4 prey was clearly the result of lethal wounds inflicted by the fungus gnat larvae in defensive strikes against the predators. At prey numbers supporting maximum rates of adult emergence, larval development required 12-14 d, and duration of the pupal stage was approximately 10 d. C. attenuata larvae killed large numbers of prey during their development (means of up to 232 L2, 144 L3, or 87 L4 fungus gnats), and larvae provided with marginally inadequate numbers of prey survived for long periods (mean 14-22 d, maximum 34 d) before succumbing to apparent starvation. These are favorable attributes with respect to use of C. attenuata as a biological control agent, suggesting a strong potential to substantially impact high-density pest populations and to survive in low-density pest populations. PMID- 20857724 TI - Resistance of cultivated rice varieties to Cnaphalocrocis medinalis (Lepidoptera: Pyralidae). AB - Cnaphalocrocis medinalis Guenee (Lepidoptera: Pyralidae) is a major pest in rice, Oryza sativa L. (Graminales: Poaceae), in Asia. The current study investigated the resistance of 17 rice varieties or lines to C. medinalis and behavioral responses of the insect to varieties of different corrected damage ratings (CDRs) and damaged leaves scales (DLSs). The results showed that most varieties (or lines) commonly cultured in rice production were susceptible (DLS 3 and 5) to damage caused by C. medinalis; Yangjing 9538, 91SP, and TN1 were the most susceptible (DLS 7 and 9). A significant positive correlation was observed between CDR and leaf width and chlorophyll content in rice leaves, whereas no significant correlations between resistance and plant height and leaf length were found. The number of eggs laid by C. medinalis adult females significantly increased with CDR. There was a significant difference in the number of eggs laid for varieties of different DLSs. The number laid on varieties of DLS 9 was 44.4, 134.5, and 466.7% greater than DLS 7, 5 and 3, respectively; the number laid on varieties of DLS 7 was 65.5% greater than DLS 5 and 300% greater than DLS 3; and the number laid on those of DLS 5 was 141.7% greater than DLS 3. Developmental duration (day) of larvae, the body length of fifth instar larvae and pupae weight also significantly increased with CDR. A significant difference of to excised leaves was also found among different DLSs with a higher proportion of both first and third instars settled on the leaves of high DLS. Dispersal experiments of larvae on excised leaves showed that the number of first instars that remained settled gradually increased with DLSs. These findings suggested that rice of higher DLS are more suitable for feeding and settling of larvae. PMID- 20857725 TI - Phoretic dispersal of armored scale crawlers (Hemiptera: Diaspididae). AB - Dispersal and colonization of new areas by armored scale insects (Hemiptera: Diaspididae) is achieved by mobile first-instar nymphs, called crawlers. Few studies have considered the actual mechanisms by which crawlers disperse, and although crawlers are capable of actively wandering over short distances (generally < 1 m), their dispersal over longer distances has been thought to be wind-mediated. Here, we present evidence of a potentially more important means of dispersal over longer distances (> 1 m). We first confirmed that crawlers of four species of Diaspididae [Abgrallaspis aguacatae Evans, Watson & Miller; Hemiberlesia lataniae (Signoret); Aspidiotus nerii Bouche; and Diaspidiotus perniciosus (Comstock)] have four hairs on the end of each of their legs and that each of these hairs ends in a suction cup-like structure, reminiscent of the attachment structures possessed by phoretic mites. In a controlled environment, using crawlers of A. nerii, we then showed that the crawlers use these structures to attach themselves to three different insect species [Musca domestica L., Cryptolaemus montrouzieri Mulsant and Linepithema humile (Mayr)] and can effectively be moved phoretically by these insects. Crawlers can remain attached to flying insects for considerable periods of time, suggesting that this may be an important means of dispersal for armored scale insects. The importance of phoresy for diaspidid dispersal in the field remains to be determined. PMID- 20857726 TI - Mexican rice borer (Lepidoptera: Crambidae) oviposition site selection stimuli on sugarcane, and potential field applications. AB - The Mexican rice borer, Eoreuma loftini (Dyar) (Lepidoptera: Crambidae), a key pest of sugarcane (Saccharum spp.) and rice, Oryza sativa L., in Texas, has not been controlled with chemical insecticides or biological agents, but some sugarcane varieties have shown degrees of resistance. Assessment of selected sugarcane leaf characteristics indicate that preference for oviposition sites is mostly determined by the presence of a leaf fold and secondarily by the availability of dry leaf tissue, both of which are antixenotic nonchemical stimuli. We suggest that breeding sugarcane lines bearing leaves that do not fold on drying could provide substantial antixenotic resistance against the Mexican rice borer. Previously identified antixenotic chemical stimuli, i.e., low quantities or absence of important nutrients in green leaf tissue, only become apparent when resistant and susceptible sugarcane varieties are compared. Varietal differences in oviposition preference, however, were not observed on excised dry leaf tissue, indicating that expression of resistance in terms of chemical stimuli requires detection of biochemicals in nearby living leaf tissue. Excised dry sugarcane leaves retain the two dominant nonchemical oviposition preference stimuli for Mexican rice borers, and the leaves effectively trapped eggs away from intact plants when dry leaves were used as "mulch" at the bottom of greenhouse cages. Under commercial sugarcane field conditions, bundled dry leaves also collected Mexican rice borer eggs. Possible applications of dry sugarcane leaf substrate for egg scouting and for trapping eggs are discussed. PMID- 20857727 TI - Species composition, seasonal activity, and semiochemical response of native and exotic bark and ambrosia beetles (Coleoptera: Curculionidae: Scolytinae) in northeastern Ohio. AB - In 2007, we surveyed the alien and endemic scolytine (bark and ambrosia beetles) fauna of northeastern Ohio, and for the most abundant species, we characterized their seasonal activity and response to three semiochemical baits. In total ,5,339 scolytine beetles represented by 47 species and 29 genera were caught in Lindgren funnel traps. Three species constituted 57% of the total catch, including Xylosandrus germanus (Blandford), Tomicus piniperda (L.), and Dryocoetes autographus (Ratzeburg). Of the total captured, 32% of the species and approximately 60% of the individuals were exotic, suggesting that exotic species numerically dominate the scolytine fauna in some urban areas. More native and exotic species were caught in traps baited with ethanol alone than in traps baited with other lures. However, significantly more individuals, especially of T. piniperda, D. autographus, Gnathotrichus materiarius (Fitch), and Ips grandicollis (Eichhoff), and species were caught in traps baited with ethanol plus alpha-pinene than in traps baited with ethanol alone or the exotic Ips lure. This suggests that among these baits, the ethanol plus alpha-pinene baits may be useful in maximizing scolytine beetle catches of these species within this region. Species diversity and richness for both native and exotic beetles was greatest in traps baited with ethanol alone. The period of peak trap capture varied depending upon species: X. germanus was most abundant in traps in mid-May and early-August; T. piniperda in mid-May; D. autographus in early June, mid July, and mid-September; Anisandrus sayi Hopkins and G. materiarius in mid-May, mid-July, and early September; and I. grandicollis in early April, mid-July, and late September. PMID- 20857728 TI - Plum curculio (Coleoptera: Curculionidae) adult mortality and associated fruit injury after exposure to field-aged insecticides on tart cherry branches. AB - Plum curculio, Conotrachelus nenuphar (Herbst) (Coleoptera: Curculionidae), adults were exposed to field-aged residues of thiamethoxam, acetamiprid, thiacloprid, indoxacarb, or azinphos-methyl on tart cherry, Prunus cerasus L. variety Montmorency. At 1, 3, 7, and 14 d postapplication, fruit were sampled for chemical residues, and bioassays were used to assess beetle mortality and plant tissue injury. Azinphos-methyl had lethal activity within 1 d of exposure at all postapplication intervals and significant fruit protection extended to 14 d postapplication. All of the neonicotinoids had lethal activity at 3 d posttreatment, with acetamiprid activity extending to 7 d. Antifeedant and oviposition deterrent effects were seen with thiamethoxam and thiacloprid; damage incidence was significantly reduced in the absence of significant beetle mortality or intoxication. Thiamethoxam and acetamiprid penetrated into leaf and fruit tissue and were detected in the interior tissues at 14 d postapplication, but interior thiacloprid residues were not detected after day 1. Indoxacarb provided some fruit protection out to 7 d postapplication, and 14-d-old residues intoxicated beetles, but the slow action of this compound allowed significant damage to occur before beetles were incapacitated. Indoxacarb was only detected as a surface residue after the first day postapplication. These data on the plant insect-chemistry interactions will support use and management decisions as compounds with acute contact activity are phased out. PMID- 20857729 TI - Potential impact of differential production of the Cry2Ab and Cry1Ac proteins in transgenic cotton in response to cold stress. AB - Transgenic Bollgard II cotton, Gossypium hirsutum L., expresses Cry1Ac and Cry2Ab proteins that provide control of lepidopteran larvae, including Helicoverpa and Heliothis species (Lepidoptera: Noctuidae) worldwide. Experiments conducted at Katherine, Northern Territory, Australia evaluated the impact of night minimum temperatures on Cry1Ac and Cry2Ab protein levels in Bollgard II cotton. In both 2003 and 2004, potted plants were either grown outside continuously or protected from cold in a glasshouse each night. In 2003, bulked samples of leaves were taken after two periods of low minimum temperature and used to determine a cold stress threshold and critical period. In 2004, replicated samples were taken on 10 dates spanning five periods of low minimum temperature, allowing analysis of seasonal variation in Cry protein levels. The protein level was markedly higher for Cry2Ab than for Cry1Ac. Cry1Ac protein level peaked midseason and was not adversely affected by minimum temperatures down to 2.6 degrees C. The Cry2Ab protein level remained approximately constant but was reduced by low minimum temperatures (threshold, approximately 14 degrees C) for up to 6 d after each chill. The rate of Cry2Ab protein loss was 1.15 and 1.01% per chilling day-degree below threshold in 2003 and 2004, respectively. Impact would seem to be negligible on both the overall efficacy against lepidopteran larvae in-crop and on the current pyramided genes/high-dose/refuge Bt resistance-management strategies because the cold-stress effect is transient, a high level of Cry2Ab protein is still expressed, and there is no impact of chilling on Cry1Ac protein level. PMID- 20857730 TI - (3Z,6Z,9Z,12Z,15Z) -pentacosapentaene and (Z) -11-hexadecenyl acetate: sex attractant blend for Dioryctria amatella (Lepidoptera: Pyralidae). AB - In 2006-2008, we tested (3Z,6Z,9Z,12Z,15Z)-pentacosapentaene (pentaene) with the pheromone components (Z)-11-hexadecenyl acetate (Z11-16:Ac) and (Z)-9 tetradecenyl acetate (Z9-14:Ac), as sex attractants for four sympatric species of coneworms, Dioryctria Zeller (Lepidoptera: Pyralidae) in slash (Pinus elliottii Engelm.) and loblolly pine (Pinus taeda L.) seed orchards in Georgia and Louisiana, respectively. The addition ofpentaene increased catches of male southern pine coneworm, Dioryctria amatella (Hulst), in wing traps baited with Z11-16:Ac, whereas catches of Dioryctria disclusa Heinrich in traps baited with Z9-14:Ac were unaffected by the addition of pentaene. The effect of pentaene on male Dioryctria merkeli Mutuura & Munroe was inconsistent. In 2006, pentaene seemed to inhibit attraction of D. merkeli to traps baited with Z9-14:Ac, whereas in a subsequent trial in 2008, moths were equally attracted to Z9-14:Ac with or without the pentaene. We caught too few Dioryctria clarioralis (Walker) in any experiment for meaningful analyses. Our field results with pentaene and the unresolved complexity of the taxonomy, ecology, and management of southern coneworms support the need for a comprehensive examination of the chemical ecology of Dioryctria spp. PMID- 20857731 TI - Lethal and sublethal effects of imidacloprid on hemlock woolly adelgid (Hemiptera: Adelgidae) and two introduced predator species. AB - Eastern hemlock, Tsuga canadensis (L.) Carriere, branchlets were systemically treated with imidacloprid and bioassayed with hemlock woolly adelgid, Adelges tsugae (Annand) (Hemiptera: Adelgidae), and predators. After 10 d, two hemlock woolly adelgid predators, Laricobius nigrinus Fender (Coleoptera: Derodontidae) and Sasajiscymnus tsugae Sasaji & McClure (Coleoptera: Coccinellidae), were allowed to feed on remaining hemlock woolly adelgid for 20 d on branches systemically treated with 1, 10, or 100 ppm imidacloprid. Every 5 d, mortality, mobility (measured as flip time), number of hemlock woolly adelgid consumed, and degree of intoxication of each individual beetle were recorded. Liquid chromatography-mass spectrometry was used to quantify imidacloprid and some of its major metabolites in hemlock wood tissues and in the predator beetles postmortem. Probit analysis of hemlock woolly adelgid mortality and imidacloprid concentrations recovered from branch wood tissues determined the 30 d LC50 to be 242 ppb. A topical application of imidacloprid to the ventral abdomen of individual beetles resulted in a 6 d LD50 value of 1.8 and 0.71 ng imidacloprid per beetle for L. nigrinus and S. tsugae, respectively. In no-choice tests, L. nigrinus mortality was significantly higher on hemlock branchlets treated with 100 ppm imidacloprid than on controls, but S. tsugae mortality was not. S. tsugae consumed the same number of adelgids on treated branchlets as on controls, but L. nigrinus consumed fewer adelgids from the 100 ppm branchlets than on controls. In choice tests, beetle mortality and flip times were generally not significantly different from controls. At times, both beetle species displayed intoxication symptoms after feeding on adelgids from treated branchlets and imidacloprid was recovered from both beetle species postmortem. These results suggest that systemic imidacloprid displayed both lethal and sublethal effects on these two nontarget predators of the hemlock woolly adelgid. PMID- 20857732 TI - Optimization of trap color for emerald ash borer (Coleoptera: Buprestidae). AB - Field assays were performed to determine the optimal color for Agrilus planipennis Fairmaire (Coleoptera: Buprestidae) traps. Previous studies have found that more A. planipennis are caught on purple or green traps than traps of other colors. In three studies, we evaluated various shades of purple, wavelengths of green (500-570 nm), and greens of different reflectance (from 9 to 66%). In all tests, traps of corrugated plastic in standard, commercially available purple (currently used to survey A. planipennis) and a customized green color were used as bases for comparison. Among purple traps, a paint color previously shown to be generally attractive to buprestids caught significantly more A. planipennis adults than traps coated with paints containing more blue or red, or traps constructed of the standard purple plastic. Among traps with maximum reflectance at varying green wavelengths, those ranging in wavelength from 525 to 540 nm caught significantly more adult A. planipennis than traps of other wavelengths. In the 530-540 nm range of the electromagnetic spectrum, there was no significant difference among traps in the 23-66% reflectance range, but traps painted with a peak reflectance of 49% caught more beetles than purple or the custom green plastic traps. Male to female ratio was highest on green traps. PMID- 20857733 TI - Recapture of codling moth (Lepidoptera: Tortricidae) males: influence of lure type and pheromone background. AB - Recapture of marked male codling moths, Cydia pomonella (L.) (Lepidoptera: Tortricidae), released four distances from traps was measured in experiments comparing either lure type or mating disruption. Experiment 1 assessed recapture by 0.1, 1, and 10 mg of codlemone lures. Experiments 2 and 3 assessed moth recapture in orchard plots with 0, 500, or 1,000 Isomate C Plus dispensers per ha. Moths were released 1, 3, 10, and 30 m downwind of the trap in experiments 1 and 2, and 3, 10, 30, and 45 m in experiment 3. Lure type did not affect recapture, however, significantly more moths were recaptured at 3 m compared with 10 or 30 m. Most moths recaptured < or = 10 m of the trap were recaptured by day 3, whereas most of the moths recaptured > or = 10 m were recaptured after day 3. Thus, 0.1-, 1-, and 10-mg lures, have an attractive range of between 10 and 30 m in orchards lacking mating disruption. Both mating disruption rates greatly reduced moth recapture, and moths recaptured under a 1,000 dispenser per ha rate were recaptured from < or = 10 m and within the first 2 d after release. Similar results were observed when release points were expanded to 45 m. Thus, results suggest that pheromone dispenser technologies and placement strategies that maximize disruption of males that arise within 10 m of a female are needed to markedly improve mating disruption. PMID- 20857734 TI - Variable development rate and survival of navel orangeworm (Lepidoptera: Pyralidae) on wheat bran diet and almonds. AB - A series of laboratory and field studies were conducted using three lines of navel orangeworm, Amyelois transitella (Walker) (Lepidoptera: Pyralidae), reared on wheat bran diet and almonds, Prunus dulcis (Mill.) D.A.Webb, at constant and fluctuating temperature. The duration of development on wheat bran diet at constant temperature differed significantly among the three lines. Development was as much as 40% faster at constant temperature than at fluctuating temperatures, consequently the developmental duration determined at constant temperature was not an absolute measure. When the maximum temperature in fluctuating regimes exceeded 43 degrees C, survival decreased by 50% compared with the constant temperature control. In almonds held at constant temperature, the developmental rate on new-crop nuts was variety-dependent and was fastest on 'Nonpareil' almonds and slowest on the experimental selection '23-122'. Development and survival were also variety-dependent on unharvested (mummy) almonds, and navel orangeworm average emergence was earliest from Nonpareil and latest from 'Carmel' nuts, differing by 529 degree-days, whereas survival was the highest on 'Butte', 35.7%, and the lowest on Carmel nuts, 7.2%. In our trials, both the speed of development and survival depended on host age, variety and quality, indicating that almonds were a dynamic rather than a static nutrient source for navel orangeworm. Identifying the factors responsible for variation in development and survival will give insight into improving control strategies. PMID- 20857735 TI - Evaluation of emergence traps for monitoring blueberry gall midge (Diptera: Cecidomyiidae) adults and within field distribution of midge infestation. AB - The blueberry gall midge, Dasineura oxycoccana (Johnson) (Diptera: Cecidomyiidae), is a key pest of rabbiteye blueberry, Vaccinium virgatum Aiton, in the southeastern United States, but it has not been studied extensively and little is known about its ecology and management. Studies were conducted to develop an improved method for monitoring D. oxycoccana adults and to determine the within-field distribution of infestation. Four emergence traps were evaluated in an organic rabbiteye blueberry planting for their effectiveness in capturing D. oxycoccana adults early in the season. These traps included a jar trap, wheat blossom midge trap, petri dish trap, and bucket trap. The petri dish and bucket traps captured the highest numbers of adults in 2007 and 2008, respectively. Both traps had a clear plastic panel coated with adhesive. Adult midges emerging from the soil beneath the traps were caught in the adhesive as they flew up toward the light. Emergence traps are useful for detecting the presence of adults early in the season before larval infestation is apparent in the flower buds. To determine the pattern of midge infestation, flower buds were collected weekly from January to March in 2006 from rabbiteye blueberry plants located in a plot at the southwest border of an existing blueberry planting. There were no differences found in the number of larvae collected from various distances within blueberry rows. However, when flower buds were collected from an isolated rabbiteye plot in 2007 and 2008, D. oxycoccana infestation was not uniform. In both years, the southern border row had a significantly higher number of midge larvae per bud compared with the other rows. PMID- 20857736 TI - Survey of wireworms (Coleoptera: Elateridae) in North Carolina sweetpotato fields and seasonal abundance of Conoderus vespertinus. AB - Adult and larval wireworm (Coleoptera: Elateridae) populations were surveyed in North Carolina sweetpotato, Ipomoea batatas (L.) Lam., fields during 2005 and 2006 by using yellow sticky traps and larvalbaits. Eight species of larvae and nine species of adult wireworms were identified. Conoderus vespertinus (F.) was the most prevalent wireworm species, making up 65.9% of the larvae and 62.9% of the adults captured. Adult C. vespertinus were most abundant in July, and larvae were smaller and more abundant after 15 July than earlier in the season, indicating an early summer generation turnover and oviposition in fields planted to sweetpotato. A significant positive relationship was observed between late season abundance of C. vespertinus and the incidence of wireworm damage. Other wireworm species encountered were Conoderus amplicollis (Gyllenhal), Conoderus bellus (Say), Conoderus falli (Lane), Conoderus lividus (Degeer), Conoderus scissus (Schaeffer), Glyphonyx bimarginatus (Schaeffer), and Melanotus communis (Gyllenhal). PMID- 20857737 TI - Toxicity and residual efficacy of chlorantraniliprole, spinetoram, and emamectin benzoate to obliquebanded leafroller (Lepidoptera: Tortricidae). AB - Studies were conducted to determine the residual toxicity of spinetoram, chlorantraniliprole, and emamectin benzoate to obliquebanded leafroller, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae). Larvae were exposed to apple (Malus spp.) foliage collected at different intervals after an airblast sprayer application at the manufacturer-recommended field rate and half the field rate. A mortality of 100% was recorded at field rate applications of spinetoram, chlorantraniliprole, and emamectin benzoate through 59, 38, and 10 d after treatment (DAT), respectively. Significantly less foliage was consumed by C. rosaceana larvae surviving in the emamectin, chlorantraniliprole, and spinetoram treatments compared with those exposed to untreated foliage. Third-instar C. rosaceana exposed to fresh residues on terminal foliage showed 100% mortality after 5-d exposure to spinetoram residues and after 10-d exposure to chlorantraniliprole and emamectin benzoate. The effects of larval movement from foliage with fresh residues was examined by transferring neonate larvae from foliage treated with spinetoram, chlorantraniliprole, or emamectin benzoate to untreated foliage after various exposure intervals. An exposure of 1, 3, and 6 d was required for spinetoram, chlorantraniliprole, and emamectin benzoate to cause 100% mortality at the field rate, respectively. The higher the concentration of chlorantraniliprole and emamectin benzoate, the less exposure time was necessary to cause high levels of mortality in C. rosaceana neonates. Our results indicate that these novel insecticides are highly toxic to C. rosaceana larvae. Implications of these results for C. rosaceana management programs are discussed. PMID- 20857738 TI - Chemical and sensory comparison of tomatoes pollinated by bees and by a pollination wand. AB - Tomato flowers (Solanum lycopersicum L.) in greenhouses require assisted pollination. Compared with pollination using a vibration wand, pollination by buzz pollinating bees results in improved seed set and consequently, higher fruit weight. We investigated whether there are further chemical and sensory differences between bee- and wand-pollinated cherry tomatoes, Solanum lycopersicum variety Conchita. The pollination method did not result in significant differences in concentration of soluble solids and titratable acidity. However, the concentration of soluble solids was significantly positively correlated with seed number. We suggest that an increase in the amount of soluble solids in the locular area, due to increased seed numbers, is counteracted by the effects of seed numbers on the growth of the walls, which occurs through cell elongation. In the sensory part of this study, a large, untrained panel significantly preferred bee-pollinated over wand-pollinated tomatoes and classified bee-pollinated tomatoes as having more depth of flavor than wand-pollinated tomatoes. Thus, bee-pollinated tomatoes taste better than wand-pollinated tomatoes, and it is likely that the sensory differences between the two groups of tomatoes are mediated through effects of pollination treatment on seed numbers. Future chemical and sensory studies of fresh tomatoes should take into account the effects of seed numbers and their possible effect on the distribution of chemical compounds within tomatoes. PMID- 20857739 TI - Toxicity of plant essential oils to acaricide-susceptible and -resistant Tetranychus urticae (Acari: Tetranychidae) and Neoseiulus californicus (Acari: Phytoseiidae). AB - The toxicity of 10 plant essential oils to adults of acaricide-susceptible, chlorfenapyr-resistant (CRT-53), fenpropathrin-resistant (FRT-53), pyridaben resistant (PRT-53), and abamectin-resistant (ART-53) strains of Tetranychus urticae Koch (Acari: Tetranychidae) and to female Neoseiulus californicus McGregor (Acari: Phytoseiidae) was examined using spray or vapor-phase mortality bioassays. In bioassay with the susceptible adults, lemon eucalyptus (19.3 microg/cm3) was the most toxic oil, followed by peppermint, citronella Java, thyme red, caraway seed, clove leaf, and pennyroyal oils (LC50, 20.6-23.7 microg/cm3). The toxicity of these oils was almost identical against adults from either of the susceptible and resistant strains, even though CRT-53, FRT-53, PRT 53, and ART-53 adults exhibited high levels of resistance to chlorfenapyr (resistance ratio [RR], > 9,140), fenpropathrin (RR, 94), pyridaben (RR, > 390), and abamectin (RR, 85), respectively. Against female N. californicus, lemon eucalyptus (LC50, 21.4 microg/cm3) was the most toxic oil, whereas the LC50 values of the other nine oils ranged from 23.2 to 72.6 microg/cm3. N. californicus was 1-2 times more tolerant than T. urticae to the test essential oils. Thus, these essential oils merit further study as potential acaricides for the control of acaricide-resistant T. urticae populations as fumigants. PMID- 20857740 TI - Effect of varying dispenser point source density on mating disruption of Grapholita molesta (Lepidoptera: Tortricidae). AB - Hand-applied dispensers are successfully used in mating disruption programs, but cost of labor to apply these dispensers limits their adoption. Creating hand applied dispensers that release larger amounts of pheromone and that can be applied at lower densities per hectare could reduce the cost of mating disruption and increase its use. The effect of reducing the number of point sources per hectare while keeping the amount of pheromone applied per hectare constant on the success of Grapholita molesta (Busck) (Lepidoptera: Tortricidae) mating disruption was investigated with Confuse-OFM, paraffin disk, and Isomate-M Rosso dispensers. For all dispensers, as point source density decreased, numbers of moths captured increased, percentage of orientation disruption to traps decreased, and variability in these measures increased. Decreasing point source density, even while keeping the amount of pheromone applied per hectare constant is not a viable option for reducing the cost of G. molesta mating disruption with hand-applied dispensers. Puffers (aerosol dispensers) are applied at 2.5-5 dispensers per ha for G. molesta control. However, hand-applied dispensers fail when clumped at such low numbers of release sites. Potential explanations for the success of Puffers and the failure of hand-applied dispensers at very low point source densities are presented. The utility of paraffin disk dispensers as experimental devices also is discussed. PMID- 20857741 TI - Reducing tuber damage by potato tuberworm (Lepidoptera: Gelechiidae) with cultural practices and insecticides. AB - Cultural practices and insecticide treatments and combinations were evaluated for effect on tuber damage by potato tuberworm, Phthorimaea operculella (Zeller) (Lepidoptera: Gelechiidae) in the Columbia basin of eastern Oregon and Washington. A range of intervals between initial application of several insecticides and vine-kill were tested to determine how early to implement a program to control potato tuberworm tuber damage. Esfenvalerate, methamidophos, and methomyl were applied at recommended intervals, with programs beginning from 28 to 5 d before vine-kill. All insecticide treatments significantly reduced tuber damage compared with the untreated control, but there was no apparent advantage to beginning control efforts earlier than later in the season. Esfenvalerate and indoxacarb at two rates and a combination of the two insecticides were applied weekly beginning 4 wk before and at vine-kill, and indoxacarb was applied at and 1 wk postvine-kill as chemigation treatments. Application of insecticides at and after vine-kill also reduced tuberworm infestation. 'Russet Norkotah' and 'Russet Burbank' plants were allowed to naturally senesce or were chemically defoliated. They received either no irrigation or were irrigated by center-pivot with 0.25 cm water daily from vine kill until harvest 2 wk later. Daily irrigation after vine-kill reduced tuber damage, and chemical vine-kill tended to reduce tuber damage compared with natural senescence. Covering hills with soil provides good protection but must be done by vine-kill. Data from these trials indicate that the most critical time for initiation of control methods is immediately before and at vine-kill. PMID- 20857742 TI - DNA identification confirms pecan weevil (Coleoptera: Curculionidae) infestation of Carpathian walnut. AB - Larvae found infesting fruit from a Carpathian walnut, Juglans regia L., tree in Missouri were confirmed by DNA analysis to be those of pecan weevil, Curculio caryae (Horn) (Coleoptera: Curculionidae). The infested walnut tree occurs in the midst of pecan weevil-infested pecans, Carya illinoinensis (Wang.) K. Koch; the larval haplotypes were found to be identical to pecan weevil larvae from the region, indicating that the walnut infestation arose by association with infested pecan. This is the first confirmed DNA analysis showing pecan weevil attacks J. regia and the second report that J. regia may be at risk of infestation by pecan weevil. Further study indicates this infestation on walnut is established and ongoing. The pecan weevil is a key pest of pecan and seems capable of inflicting similar damage to walnut if spread to commercial areas that produce J. regia. PMID- 20857743 TI - Impact of insecticide efficacy on developing action thresholds for pest management: a case study of onion thrips (Thysanoptera: Thripidae) on onion. AB - An action threshold (AT) is one of the most important decision-making elements in integrated pest management. Unlike economic thresholds, ATs are not typically derived from an economic injury level model, but they are more commonly used. ATs may be identified from research-based, pest-crop relationships, but they also may be based on experience. ATs may be adjusted depending on, e.g., weather and plant variety, but modifying ATs to accommodate differences in insecticide efficacy has received little attention. To examine this point, several combinations of ATs and insecticides were evaluated against onion thrips, Thrips tabaci Lindeman (Thysanoptera: Thripidae), a major pest of onion (Allium cepa L.). Studies were conducted in New York onion fields from 2006 to 2008 by using registered insecticides for T. tabaci on onions. We hypothesized that the most efficacious insecticides would provide acceptable control of thrips populations regardless of AT (one, three, and five thrips per leaf), whereas less effective products would only control populations using the lowest AT (one thrips per leaf). Results indicated that T. tabaci infestations were managed effectively when spinetoram was applied after a three larvae per leaf threshold, but not when using lambda cyhalothrin, methomyl or formetanate hydrochloride. However, T. tabaci infestations were managed well when methomyl and formetanate hydrochloride were applied after a one larva per leaf threshold. T. tabaci infestations were never controlled using lambda-cyhalothrin, regardless of the AT used. None of the products reduced T. tabaci populations to an acceptable level when applied at a five larvae per leaf threshold. Implications of adjusting ATs based on efficacy of different insecticides are discussed. PMID- 20857744 TI - Apparent synergy among defense mechanisms in subterranean termites (Rhinotermitidae) against epizootic events: limits and potential for biological control. AB - The use of entomopathogens for biological control of subterranean termites (Rhinotermitidae) has attracted attention in the past four decades, and several laboratory studies have shown promising results with fungal agents. This approach was based on the concept of classical biological control with the use of a virulent agent that can self-replicate in a termite nest and be transmitted among individuals, resulting in an epizootic to kill the entire colony. However, the absence of positive results in field studies challenged the potential of fungal pathogens as a realistic approach for subterranean termite control, and the relationship between fungi and subterranean termites remains poorly understood. A multimodal approach of the currently identified defense mechanisms allowed us to show that subterranean termites have the ability to prevent an epizootic from occurring. The defense mechanisms involved in such resistance are reviewed and documented. Finally, the interactions among three major defense mechanisms (grooming, cellular encapsulation, and gut antifungal activity) were analyzed, and it is suggested that these mechanisms act synergistically to produce an efficient defense against the infection of the fungus at the individual and group level so as to protect the colony from epizootics. PMID- 20857745 TI - Spatial association of marine dockage with land-borne infestations of invasive termites (Isoptera: Rhinotermitidae: Coptotermes) in urban south Florida. AB - Marine vessels have been implicated in the anthropogenic dispersal of invasive termites for the past 500 yr. It has long been suspected that two invasive termites, the Formosan subterranean termite, Coptotermes formosanus Shiraki, and Coptotermes gestroi (Wasmann) (Isoptera: Rhinotermitidae), were introduced to and dispersed throughout South Florida by sailboats and yachts. We compared the distances between 190 terrestrial point records for Formosan subterranean termite, 177 records for C. gestroi, and random locations with the nearest marine dockage by using spatial analysis. Results show that the median distance to nearest docks associated with C. gestroi is significantly smaller than for the random points. Results also reveal that the median distance to nearest docks associated with Formosan subterranean termite is significantly smaller than for the random points. These results support the hypothesis that C. gestroi and Formosan subterranean termite are significantly closer to potential infested boat locations, i.e., marine docks, than random points in these urban areas. The results of our study suggest yet another source of aggregation in the context of exotic species, namely, hubs for pleasure boating. PMID- 20857746 TI - Induction and transmission of tolerance to the synthetic pesticide emamectin benzoate in field and laboratory populations of diamondback moth. AB - Field surveys of pest insect pest populations in agroecosystems reveal low but significant levels of tolerance to synthetic and biological pesticides but fail to uncover resistance alleles in test crosses. To study the potential of inducible mechanisms to generate tolerance to synthetic pesticides, we performed baseline susceptibility studies in field and laboratory populations of diamondback moth, Plutella xylostella (L.), to commercial formulations of emamectin benzoate. Pesticide exposure in the field caused elevated levels of tolerance, which decreased in field-collected populations after maintaining insects with pesticide-free diet in the laboratory. Because no significant resistance alleles were identified in back-crossed individuals, the observed increase in tolerance was probably not based on preexisting recessive resistance mechanisms in the population. Instead, the genetic analysis after five and 12 generations is compatible with a transient up-regulation of an immune and metabolic status in tolerant insects that can be transmitted to offspring by a maternal effect. Although the epigenetic effects contributed to incremental increases in tolerance in the first five generations, other resistance mechanisms that are transmitted genetically predominate after 12 generations of increased exposure to the pesticide. PMID- 20857747 TI - Identification of a dieldrin resistance-associated mutation in Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - The southern cattle tick, Rhipicephalus (Boophilus) microplus (Canestrini) (Acari: Ixodidae), is a major vector of tick fever organisms affecting cattle in many parts of the world, including Australia, Africa, and South America. Control of the southern cattle tick through acaricide use is an important approach in disease management. Resistance has emerged to many of the acaricides currently and previously used, including the cyclodienes. Although cyclodiene resistance mechanisms have been characterized in many insect species, this report is the first to identify mutations associated with dieldrin resistance in the cattle tick. A novel two base pair mutation in the GABA-gated chloride channel gene has been identified at position 868-9 and causes a codon change from threonine to leucine. Analysis of a small number of field-collected samples resistant to dieldrin shows this mutation has been maintained without selection pressure since the withdrawal of dieldrin in Australia > 20 yr ago. The mutation is not found in other laboratory-maintained strains of R. microplus that were subject to selection pressure with various acaricides. PMID- 20857748 TI - Laboratory evaluation of verbutin as a synergist of acaricides against larvae of Rhipicephalus (Boophilus) microplus (Acari: Ixodidae). AB - Synergistic effects of verbutin, a member of aryl alkynyl derivatives, to three commonly used acaricides were evaluated with the modified Food and Agricultural Organization Larval Packet Test (FAO-LPT) against both susceptible and resistant strains of the southern cattle tick, Rhipicephalus (Boophilus) microplus (Canestrini) (Acari: Ixodidae). These tick strains demonstrated various levels of resistance to coumaphos (2.5-8.2x), permethrin (57.9-711.7x), and amitraz (3.5 177.5x). Verbutin alone was more toxic to tick larvae than piperonyl butoxide (PBO), a conventional pesticide synergist. With synergism ratios (SRs) ranging from 1.5 to 6.0, verbutin was more potent than PBO (SR = 0.9-1.6) in synergizing coumaphos toxicity to resistant tick larvae. Similarly, verbutin (SR = 1.8-15) was also found to be more potent than PBO (SR = 0.9-2.5) in synergizing amitraz in resistant tick strains. Both verbutin and PBO significantly increased permethrin toxicity to larvae of all tick strains tested, and there was no significant difference between the two synergists. SRs ranged from 2.1 to 4.4 and from 2.1 to 3.6 for PBO and verbutin, respectively. PMID- 20857749 TI - Insecticide resistance status of Colorado potato beetle (Coleoptera: Chrysomelidae) adults in northern Xinjiang Uygur autonomous region. AB - Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), has become the economically most important insect defoliator of potatoes, Solanum tuberosum L., in northern Xinjiang Uygur autonomous region in China. Currently, control of Colorado potato beetle relies mainly on chemical insecticides. And this may result in insecticide resistance. In this study, LD50 values were measured by a topical bioassay for 14 conventional insecticides in seven local populations from Urumqi, Changji, Tacheng, Nilka, Gongliu, Qapqal, and Tekes counties (cities). The Tekes field population was the most susceptible population and was selected as a reference strain. Compared with the Tekes strain, the Changji, Qapqal, Nilka, Tacheng, and Gongliu populations exhibited moderate to very high levels of resistance to cyhalothrin. The Qapqal and Changji populations showed a moderate and a very high resistance to deltamethrin, respectively. And the Changji population developed a high resistance against alpha-cypermethrin. Moreover, the Qapqal population had a moderate resistance to carbofuran, and the Urumqi population reached high level of resistance to endosulfan. Possible resistance mechanisms of the Changji and Qapqal populations were determined using three enzyme inhibitors. Triphenyl phosphate (TPP), diethylmeleate, and piperonyl butoxide (PBO) had little synergism to cyhalothrin in the two populations. In contrast, PBO and TPP exhibited some synergistic effects to carbofuran in the Qapqal population, indicating the involvement of monooxygenases and esterases in conferring carbofuran resistance. It seems that additional mechanisms, such as target site insensitivity, should play an important role in Colorado potato beetle resistances to cyhalothrin and carbofuran in northern Xinjiang local populations. PMID- 20857750 TI - Assessment of the contact toxicity of methyl palmitate on Tetranychus viennensis (Acari: Tetranychidae). AB - Previous work demonstrated that methyl palmitate possesses acaricidal activity against Tetranychus viennensis Boisduval (Acari: Tetranychidae) via an unknown mechanism. Here, the symptoms of methyl palmitate toxicity to T. viennensi were studied to determine the acaricidal mechanism of action of this fatty acid methyl ester. Methyl palmitate caused concentration-dependent mortality of T. viennensis, with a moderate concentration (5 mg/ml) eliciting excitement and premature oviposition without spinning shortly after exposure. Tremors of the appendages were subsequently observed, followed by quiescence after approximately 5 h. Mites developed dorsal fluid exosmosis at 15-20 h posttreatment with reduced egg production, followed shortly thereafter by death. Some typical neurotoxic symptoms such as excitement and convulsions were observed in methyl palmitate exposed mites, suggesting that methyl palmitate may be a neurotoxin. Compared with other neurotoxic acaricides, methyl palmitate poisoning is a slow process in mites. Transmission electron microscopy revealed serious ultrastructural damage in response to 5 mg/ml methyl palmitate exposure. Autolysis of membranous structures was also observed, especially in the mitochondria, suggesting a novel mode of action for methyl palmitate-induced toxicity. PMID- 20857751 TI - Assessment of resistance risk in obliquebanded leafroller (Lepidoptera: Tortricidae) to the reduced-risk insecticides chlorantraniliprole and spinetoram. AB - Obliquebanded leafroller, Choristoneura rosaceana (Harris) (Lepidoptera: Tortricidae), is a major pest of pome fruit in Washington. The use of broad spectrum insecticides for decades has led to the development of insecticide resistance in C. rosaceana. Recently registered insecticides with novel modes of action, such as chlorantraniliprole and spinetoram, have provided effective C. rosaceana control, but resistance remains a threat. The risk of insecticide resistance development in a pest can be assessed by artificial selection in the laboratory. Subsequently, this information can be valuable in developing strategies to retain susceptibility in the field. A laboratory population of C. rosaceana was selected after repeated exposure to chlorantraniliprole and spinetoram to determine the risk of resistance evolution. After six generations of selection, 6.58- and 3.64-fold increases in LC50 were recorded for chlorantraniliprole and spinetoram, respectively. The realized heritability (h2) of resistance was estimated as 0.17 for chlorantraniliprole and 0.18 for spinetoram by using threshold trait analysis. The rates of resistance development were compared using the response quotient (Q), which was estimated as 0.11 and 0.07 for chlorantraniliprole and spinetoram, respectively. Projected rates of resistance evolution indicated that if h2 = 0.2 and 80% of the population was killed at each generation, then a 10-fold increase in LC50 would be expected in less than six generations for chlorantraniliprole and 10 generations for spinetoram. These results indicate that the risk of resistance development in C. rosaceana exists to both of these insecticides but that resistance development in C. rosaceana would be slower against spinetoram than chlorantraniliprole. PMID- 20857752 TI - Fitness costs of Cry1Ab resistance in a field-derived strain of Ostrinia nubilalis (Lepidoptera: Crambidae). AB - The study of fitness costs associated with resistance to toxins from Bacillus thuringiensis Berliner (Bt) in Ostrinia nubilalis (Hubner) (Lepidoptera: Crambidae) is important for understanding resistance evolution and for evaluating resistance management practices that prevent or mitigate resistance to transgenic corn, Zea mays L. Resistant individuals identified from a field collection in Kandiyohi, MN, were used to generate a Cry1Ab-resistant strain. We used susceptible and resistant strains with similar genetic background to establish crosses and estimate dominance of fitness costs by measuring fitness components and population parameters determined by fertility life tables. Spermatophore volume and mating frequency also were compared to identify potential effects of resistance on fertility. Inheritance of fitness costs in O. nubilalis varied from recessive to incompletely recessive among the parameters evaluated. Selection for resistance to Cry1Ab significantly reduced the fitness of O. nubilalis. Resistant insects exhibited reduced pupal weight and increased developmental time compared with susceptible and F1 larvae derived from reciprocal crosses of resistant and susceptible parents. In addition, it was observed that resistant insects exhibited a higher proportion of unsuccessful matings and lower fertility than the susceptible strain. Despite the differences observed in resistant insects, our results did not indicate strong evidence of fitness costs in the F1 progeny. PMID- 20857753 TI - Planting patterns of in-field refuges observed for Bt maize in Minnesota. AB - The U.S. Environmental Protection Agency (USEPA) requires the use of nontransgenic refuges to slow the evolution of insect resistance to transgenic crops. In-field refuges, or refuges that are planted within the same field as the transgenic crop, are allowed; however, these refuges are required to be at least four rows wide. We described in-field planting patterns used by growers for both CrylAb [against Ostrinia nubilalis (Hubner)] and Cry3Bb (against Diabrotica virgifera virgifera LeConte) maize, Zea mays L. Maize fields known to contain Cry1Ab, Cry3Bb, or both were sampled in southwestern Minnesota during late June and early September 2005. Rows were sampled to describe the pattern of in-field refuges in the entire field. Most in-field refuges contained > 20% Cry seed (79% of Cry1Ab and 84% of Cry3Bb). However, only 5% of Cry1Ab fields and 2% of Cry3Bb fields with in-field refuges were in compliance with USEPA requirements because the Cry- seed was not in wide enough strips or blocks. Most growers had planted their fields with either finely mixed refuges or with strips that were too narrow. There was a high diversity in planting patterns, and the occurrence of Cry seed was in random rows. Growers may have been rushed while planting and not noticed which seed was going into which rows. Resistance failures have not been documented for either O. nubilalis or D. virgifera virgifera, so better education programs will need to be undertaken to encourage growers to plant in-field refuges properly. PMID- 20857754 TI - Chlorpyrifos bioassay and resistance monitoring of San Joaquin Valley California citricola scale populations. AB - The responses to chlorpyrifos of six populations of citricola scale, Coccus pseudomagnoliarum (Kuwana) (Hemiptera: Coccidae), were tested using a leaf dip bioassay, and two- to nine-fold resistances were found. LC50 responses of nymphs ranged from 7.5 to 68.9 ppm and LC90 responses ranged from 20 to 222 ppm chlorpyrifos. A population tested monthly during August-October showed up to 3.5 fold differences in LC50 responses but no differences in LC90 responses as scale size increased. A diagnostic concentration of 178 ppm chlorpyrifos was used to test 93 populations from throughout the San Joaquin Valley California during 2006 2009 by using a leaf dip bioassay. Of the populations tested, 41% showed > 20% survival after exposure to the diagnostic concentration of chlorpyrifos, indicating resistance problems. Research is needed to relate the level of survival of the scales in the bioassay to the field efficacy of the insecticide. Tulare County citrus growers applied a higher number of organophosphate and carbamate insecticides during the 15-yr period from 1994 to 2008, and these orchards showed a higher average scale survival of chlorpyrifos and a higher number of locations with resistant scale compared with the other San Joaquin Valley counties. Chlorpyrifos resistance is a significant issue for citricola scale management because biological control is ineffective in the San Joaquin Valley and the alternative neonicotinoid and insect growth regulator (IGR) insecticides require more frequent application. PMID- 20857755 TI - Categorizing the resistance of soybean genotypes to the soybean aphid (Hemiptera: Aphididae). AB - We evaluated selected soybean, Glycine max (L.) Merr., genotypes during their reproductive stages for resistance to the soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), under greenhouse conditions and documented the categories of aphid-resistant soybean. Two screening studies were performed to assess the level of resistance to the soybean aphid on six soybean genotypes during the reproductive stages of development. Significant differences in aphid damage ratings were detected among the soybean evaluated in the screening studies. Three genotypes (KS4202, K-1639-2, and K1621) were considered moderately resistant based on the assessed damage ratings. Two of these genotypes (K-1639-2 and KS4202), along with a commercial variety ('Asgrow 2703') were used in a follow-up greenhouse study to test for antibiosis and tolerance. For the antibiosis evaluation, KS4202 had significantly more nymphs than Asgrow 2703 and K-1639-2. In fact, KS4202 had a threefold difference in the number of nymphs compared with Asgrow 2703 (81.8 +/- 14.7 and 26.2 +/- 13.9 nymphs, respectively) and a fivefold difference compared with K-1639-2 (15.6 +/- 13.9). Although not significant, Asgrow 2703 had more nymphs than K-1639-2. The lower aphid numbers on infested K 1639-2 plants compared with aphid numbers on Asgrow 2703 and KS4202 plants indicates antibiosis for this genotype. No significant differences in average seed weight, number of seeds per pod, or plant damage were observed between infested and control KS4202 plants; however, significant differences in biomass, total seed weight, number of pods per plant, and number of seeds per plant were detected. PMID- 20857756 TI - Silicon-mediated rice plant resistance to the Asiatic rice borer (Lepidoptera: Crambidae): effects of silicon amendment and rice varietal resistance. AB - The Asiatic rice borer, Chilo suppressalis (Walker) (Lepidoptera: Crambidae), is one of the most destructive pests in rice, Oryza sativa L., throughout Asian countries. The aim of this study was to investigate the potential of applied silicon in mediating rice plant resistance to C. suppressalis in a susceptible (Shanyou63) and a moderately resistant (Yanfeng47) rice cultivar. Silicon-treated plants showed significant increases in silicon content compared with the control. Silicon addition significantly decreased borer penetration, weight gain, and stem damage, and it prolonged penetration duration and larval development; some of the effects were manifested more strongly in the susceptible rice cultivar compared with the moderately resistant cultivar. Therefore, silicon amendment may contribute to the suppression of C. suppressalis directly through reduced feeding damage and performance and indirectly through increased exposure time of young larvae to natural enemies and control measures. PMID- 20857757 TI - Evaluation of potential resistance in seeds of different soybean cultivars to Helicoverpa armigera (Lepidoptera: Noctuidae) using demographic parameters and nutritional indices. AB - The use of resistant cultivars is a key component of any integrated pest management (IPM) program. Here, we assess the resistance status of 10 different soybean cultivar seeds according to their effects on demographic and nutritional indices of Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) when incorporated into artificial diets. All experiments were conducted at 25 +/- 1 degrees C, 60 +/- 5% RH, and a photoperiod of 16:8 (L:D) h. Life table, reproduction, development, adult longevity, and nutritional indices of H. armigera were significantly affected by the cultivars examined. Mean developmental time of across all immature stages varied from 57 d on 'L17' to 32 d on 'Clark'. Efficiency of conversion of digested food (ECD) for old larvae ranged from 36.4% on 'Sari' to 14.8% on 'Sahar'. The adults that emerged from these larvae had very different rates of reproduction; the highest and lowest values for net reproductive rate (Ro) were 270 and 17 on Clark and L17, respectively. The most important demographic parameter, intrinsic rate of increase (rm), ranged from 0.114 on Sari to 0.09 on L17. H. armigera did not perform well on Sahar, L17, 'Gorgan3', and 'M4'. These cultivars show antibiosis resistance compared with other tested cultivars and are key candidates for field tests to determine usefulness in an IPM system. PMID- 20857758 TI - Categorizing sugarcane cultivar resistance to the sugarcane aphid and yellow sugarcane aphid (Hemiptera: Aphididae). AB - Sugarcane (Saccharum spp.) in Louisiana is colonized by two aphid species, the sugarcane aphid, Melanaphis sacchari (Zehntner), and the yellow sugarcane aphid, Sipha flava (Forbes) (Hemiptera: Aphididae). The main problem associated with M. sacchari is transmission of sugarcane yellow leaf virus, a casual agent of yellow leaf disease whose absence has been added to certification standards for micropropagated sugarcane in Louisiana. Greenhouse studies were conducted to categorize dominant commercial sugarcane cultivars for their ability to tolerate aphid injury and to express antixenotic or antibiotic effects on both aphid species. Antixenosis tests showed no preference among cultivars by either aphid species. Loss of chlorophyll content in tolerance tests also did not show differences among cultivars for both aphid species. However, antibiosis tests revealed that life history parameters such as the duration of the reproductive period and fecundity of both aphid species were negatively affected on 'HoCP 91 555' compared with 'L 97-128'. Estimation of demographic statistics indicated that both aphid species exhibited a significantly lower intrinsic rate of increase (1.8-2.8-fold) and longer doubling time (1.7-3.1-fold) on HoCP 91-555 relative to L 97-128. From these tests, cultivars in the current study can be ranked from most to the least susceptible as L 97-128 > 'LCP 85-384' > 'HoCP 96 540' > 'Ho 95-988' > HoCP 91-555 for M. sacchari and L 97-128 > LCP 85-384 > HoCP 91-555 for S. flava. Therefore, antibiosis is an important category of resistance in sugarcane to both aphid species, and HoCP 91-555 might provide useful germplasm for developing aphid resistant cultivars. PMID- 20857759 TI - Leaf alkaloids, phenolics, and coffee resistance to the leaf miner Leucoptera coffeella (Lepidoptera: Lyonetiidae). AB - Coffee (Coffea spp.) alkaloids (caffeine and related methylxanthines) and phenolics (caffeic and chlorogenic acids) have recognized pestistatic/pesticidal activity and mediate insect-plant interactions. The present investigation assessed the resistance of 12 coffee genotypes to the leaf miner Leucoptera (= Perileucoptera) coffeella (Guerin-Meneville & Perrottet) (Lepidoptera: Lyonetiidae) and correlated such results with the leaf content of coffee alkaloids and phenolics that probably play a role in the interaction between coffee and this leaf miner. The levels of chlorogenic and caffeic acid, caffeine, and related methylxanthines were measured and quantified in leaf extracts of these genotypes before and 7 d after their infestation by the leaf miner. Some coffee genotypes (Coffea canephora L. and Coffea racemosa Lour. and its hybrids with Coffea arabica L.) exhibited high pesticidal activity (100% mortality) toward the L. coffeella, indicating their antibiosis resistance. However, there was no correlation between this activity and the leaf levels of coffee alkaloids and phenolics. Curiously, infestation by L. coffeella leads to a nearly four-fold decline in the leaf levels of chlorogenic acid, which does not affect this pest species but may affect other generalist species. Indeed, chlorogenic acid sprayed on coffee leaves stimulated locomotory activity of the green scale Coccus viridis (Green) (Hemiptera: Coccidae), thus minimizing their feeding in contrast with the absence of this polyphenol. Therefore, reduction of chlorogenic acid levels in coffee leaves due to leaf miner infestation seems to also favor infestation by generalist insects, such as the green scale. PMID- 20857760 TI - Transgenic rice plants expressing a fused protein of Cry1Ab/Vip3H has resistance to rice stem borers under laboratory and field conditions. AB - Six transgenic rice, Oryza sativa L., lines (G6H1, G6H2, G6H3, G6H4, G6H5, and G6H6) expressing a fused Cry1Ab/Vip3H protein, were evaluated for resistance against the Asiatic rice borer, Chilo suppressalis (Walker) (Lepidoptera: Crambidae), and the stem borer Sesamia inferens (Walker) (Lepidoptera: Noctuidae) in the laboratory and field. The bioassay results indicated that the mortality of Asiatic rice borer and S. inferens neonate larvae on six transgenic lines from seedling to filling stage was up to 100% at 168 h after infestation. The cumulative feeding area by Asiatic rice borer neonate larvae on all transgenic lines was significantly reduced compared with the untransformed parental 'Xiushui 110' rice. A 2-yr field evaluation showed that damage during the vegetative stage (deadheart) or during the reproductive stage (whitehead) caused by Asiatic rice borer and S. inferens for transgenic lines was much lower than the control. For three lines (G6H1, G6H2, and G6H6), no damage was found during the entire growing period. Estimation of fused Cry1Ab/Vip3H protein concentrations using PathoScreen kit for Bt-Cry1Ab/1Ac protein indicated that the expression levels of Cry1Ab protein both in main stems (within the average range of 0.006-0.073% of total soluble protein) and their flag leaves (within the average range of 0.001-0.038% of total soluble protein) were significantly different among six transgenic lines at different developmental stages. Both laboratory and field researches suggested that the transgenic rice lines have considerable potential for protecting rice from attack by both stem borers. PMID- 20857761 TI - Biotypic diversity in greenbug (Hemiptera: Aphididae): microsatellite-based regional divergence and host-adapted differentiation. AB - Nineteen isolates of the cereal aphid pest greenbug, Schizaphis graminum (Rondani) (Hemiptera: Aphididae), were collected from wheat, Triticum aestivum L.; barley, Hordeum vulgare L.; or noncultivated grass hosts in five locations from Colorado and Wyoming. Parthenogenetic colonies were established. Biotypic profiles of the 19 isolates were determined based on their abilities to damage a set of host plant differentials, and 13 new biotypes were identified. Genetic diversity among the 19 isolates and five previously designated greenbug biotypes (E, G, H, I, and K) was examined with 31 cross-species transferable microsatellite (simple sequence repeat) markers. Neighbor-joining clustering analysis of marker data revealed host-adapted genetic divergence as well as regional differentiation of greenbug populations. Host associated biotypic variation seems to be more obvious in "agricultural biotypes," whereas isolates collected from noncultivated grasses tend to show more geographic divergence. It seems that the biotype sharing the most similar biotypic profiles and the same geographic region with current prevailing one may have the greatest potential to become the new prevailing biotype. Close monitoring of greenbug population dynamics especially biotypic variation on both crop plants and noncultivated grasses in small grain production areas may be a useful strategy for detecting potentially new prevailing virulent biotypes of the greenbug. PMID- 20857762 TI - A novel method for estimating soybean herbivory in western corn rootworm (Coleoptera: Chrysomelidae). AB - The western corn rootworm, Diabrotica virgifera virgifera LeConte (Coleoptera: Chrysomelidae), is the key pest of corn, Zea mays L., in North America. The western corn rootworm variant is a strain found in some parts of the United States that oviposits in soybean, Glycine max (L.) Merr., thereby circumventing crop rotation. Soybean herbivory is closely associated with oviposition; therefore, evidence of herbivory could serve as a proxy for rotation resistance. A digital image analysis method based on the characteristic green abdominal coloration of rootworm adults with soybean foliage in their guts was developed to estimate soybean herbivory rates of adult females. Image analysis software was used to develop and apply threshold limits that allowed only colors within the range that is characteristic of soybean herbivory to be displayed. When this method was applied to adult females swept from soybean fields in an area with high levels of rotation resistance, 54.3 +/- 2.1% were estimated to have fed on soybean. This is similar to a previously reported estimate of 54.8%. Results when laboratory-generated negative controls were analyzed showed an acceptably low frequency of false positives. This method could be developed into a management tool if user-friendly software were developed for its implementation. In addition, researchers may find the method useful as a rapid, standardized screen for measuring frequencies of soybean herbivory. PMID- 20857763 TI - Development of a binomial sampling plan for the carob moth (Lepidoptera: Pyralidae), a pest of California dates. AB - The seasonal density fluctuations of the carob moth, Ectomyelois ceratoniae (Zeller) (Lepidoptera: Pyralidae), were determined in a commercial date, Phoenix dactylifera L. garden. Four fruit categories (axil, ground, abscised green, and abscised brown) were sampled, and two carob moth life stages, eggs and immatures (larvae and pupae combined), were evaluated on these fruits. Based on the relative consistency of these eight sampling units (four fruit categories and two carob moth stages), four were used for the development of a binomial sampling plan. The average number of carob moth eggs and immatures on ground and abscised brown fruit was estimated from the proportion of infested fruit, and these binomial models were evaluated for model fitness and precision. These analyses suggested that the best sampling plan should consist of abscised brown dates and carob moth immatures by using a sample size of 100 dates. The performance of this binomial plan was evaluated further using a resampling protocol with 25 independent data sets at action thresholds of 7, 10, and 15% to represent light, medium and severe infestations, respectively. Results from the resampling program suggested that increasing sample size from 100 to 150 dates improved the precision of the binomial sampling plan. Use of this sampling plan will be the cornerstone of an integrated pest management program for carob moth in dates. PMID- 20857764 TI - Development and validation of node-based sample units for estimating soybean aphid (Hemiptera: Aphididae) densities in field cage experiments. AB - The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is currently the most important insect threat to soybean, Clycine max (L.) Merr., production in the North Central United States. Field cage studies are a key tool in investigating the potential of natural enemies and host plant resistance to control this pest. However, a major constraint in the use of cage studies is the limited number of treatments and replicates that can be used as aphid densities frequently become so large as to limit the number of experimental units that can be quantified. One way to overcome this limitation is to develop methods that estimate whole-plant aphid densities based on a reduced sampling plan. Here, we extend an existing method, node-sampling, used for estimating aphid populations in open field conditions and apply it to caged populations. We show that parameters calculated under open field conditions are inappropriate to estimate caged populations. In contrast, using four independent data sets of caged populations and a cross-validation technique, we demonstrate that a three-node sampling unit and a weighted formula provide accurate and robust estimates of whole-plant aphid density. This method reduced the number of aphids counted per plant by and average of 60%, with greater reductions at higher aphid densities. We further demonstrate that nearly identical statistical results were obtained when whole-plant or node-sampling estimates were used in the analysis of two case studies. The reduced sample unit method developed here saves time without sacrificing efficiency so that more plants, replications, or studies can be conducted that will lead to improved soybean aphid management. PMID- 20857765 TI - Toxicity of seven Bacillus thuringiensis Cry proteins against Cylas puncticollis and Cylas brunneus (Coleoptera: Brentidae) using a novel artificial diet. AB - "Sweetpotato weevils" Cylas puncticollis (Boheman) and Cylas brunneus F. (Coleoptera: Brentidae) are the most important biological threat to sweetpotato, Ipomoea batatas L. (Lam), productivity in sub-Saharan Africa. Sweetpotato weevil control is difficult due to their cryptic feeding behavior. Expression of Cylas active Bacillus thuringiensis (Bt) Cry proteins in sweetpotato could provide an effective control strategy. Unfortunately, Bt Cry proteins with relatively high toxicity against Cylas spp. have not been identified, partly because no published methodology for screening Bt Cry proteins against Cylas spp. in artificial diet exists. Therefore, the initial aim of this study was to develop an artificial diet for conducting bioassays with Cylas spp. and then to determine Bt Cry protein efficacy against C. puncticollis and C. brunneus by using this artificial diet. Five diets varying in their composition were evaluated. The highest survival rates for sweetpotato weevil larvae were observed for diet E that contained the highest amount of sweetpotato powder and supported weevil development from first instar to adulthood, similar to sweetpotato storage roots. Seven coleopteran-active Bt Cry proteins were incorporated into diet E and toxicity data were generated against neonate C. puncticollis and second-instar C. brunneus. All Bt Cry proteins tested had toxicity greater than the untreated control. Cry7Aa1, ET33/34, and Cry3Ca1 had LC50 values below 1 microg/g diet against both species. This study demonstrates the feasibility of using an artificial diet bioassay for screening Bt Cry proteins against sweetpotato weevil larvae and identifies candidate Bt Cry proteins for use in transforming sweetpotato varieties potentially conferring field resistance against these pests. PMID- 20857766 TI - A computer model for simulating population development of the Indianmeal moth (Lepidoptera: Pyralidae) in stored corn. AB - The Indianmeal moth, Plodia interpunctella (Hubner) (Lepidoptera: Pyralidae), is a common pest of stored corn, Zea mays L. We developed a computer model to simulate population development of the Indianmeal moth in stored corn by using previously published data describing immature developmental times and survivorship, and adult longevity and fecundity. The model accurately simulated population development of Indianmeal moths in corn stored during fall and into winter of three separate storage seasons in South Carolina. This is the period when the Indianmeal moth is a pest in stored corn in South Carolina. The model predicted that populations would increase after winter as grain temperatures rose, but observed populations in the grain bins never increased after winter. Despite this, the model should be useful from a management perspective because the corn is being sold off or used up after winter, and the observed Indianmeal moth populations never reached damaging levels after winter. PMID- 20857767 TI - Susceptibility of various life stages of Rhyzopertha dominica (Coleoptera: Bostrichidae) to flameless catalytic infrared radiation. AB - In laboratory experiments, a flameless catalytic infrared emitter, fueled by propane, was used to disinfest hard red winter wheat, Triticum aestivum L., containing different life stages of the lesser grain borer, Rhyzopertha dominica (F.), an economically important insect species associated with stored wheat in Kansas. The emitter generates infrared radiation in the 3-7-microm range. The life stages of R. dominica exposed to infrared radiation included eggs, larvae in different stages of development, pupae, and 2-wk-old adults. A noncontact infrared thermometer measured grain temperatures continuously during exposures of infested wheat to infrared radiation. The grain temperatures attained were influenced by wheat quantity; distance from the emitter; and exposure time, which in turn influenced effectiveness against various life stages of H. dominica. In general, higher grain temperatures were attained in 113.5 g of wheat as opposed to 227.0 g, and at 8.0 cm from the emitter surface rather than at 12.7 cm, and during a 60-s exposure compared with a 45-s exposure. Logistic regression indicated the probability of death of various life stages of R. dominica was temperature dependent. The log odds ratios showed old larvae were less susceptible to infrared radiation than young larvae. Approximately > or = 94% mortality of all R. dominica life stages occurred when using 113.5 g of wheat, exposed for 60 s at a distance of 8.0 cm from the emitter, resulting in mean +/- SE wheat temperatures that ranged between 107.6 +/- 1.4 and 113.5 +/- 0.5 degrees C. Our results with small grain quantities show flameless catalytic infrared technology to be a promising tool for disinfestation of stored wheat. PMID- 20857768 TI - The NBNA: transforming nursing practice to meet the challenges of health-care reform. PMID- 20857769 TI - Where have all my sisters and brothers gone? A look at the HIV/AIDS epidemic among African-Americans. PMID- 20857770 TI - Cultural comparison of chronic conditions, functional status, and acceptance in older African-American and White adults. AB - Acceptance of functional decline accompanying chronic illness is challenging for all elders, and even more so for African-American elders. This study examined functional status and the number, types, and acceptance of chronic conditions in 16 African-American and 46 White elders. African-American elders reported better functioning but resembled Whites in number of chronic conditions and acceptance. All African-Americans reported hypertension; 76% of Whites reported arthritis. Greater acceptance was correlated with fewer chronic conditions (r = -.23, p < .05) and better functioning (r = -.59, p < .01). Poorer functioning (i.e., functional disability) was correlated with more chronic conditions (r = .27, p < .05). Culturally sensitive interventions are needed to enhance elders' acceptance of chronic conditions and to improve their functioning. PMID- 20857771 TI - Educating ethnic minority students for the nursing workforce: facilitators and barriers to success. AB - The number of ethnic minorities graduating from nursing programs does not meet the number of ethnic minority nurses that are needed for patient care. In order to identify the facilitators and barriers to success, a survey was sent to current students and to those who graduated within 2 years. There were 314 responses, which was an overall response rate of 39.6%. Among the 4 facilitator factors, only the general academic support factor was perceived as more helpful by African-American students (p = 0.001). Among the 5 barrier factors, African American students and Other Ethnic Minority students perceived program workload and pace (African-Americans p < 0.005; Other multicultural groups p < 0.02), computer access (African-Americans p < 0.05; Other multicultural groups p < 0.05) and technology competence (African-Americans p < 0.02) to be barriers. Any student, regardless of ethnicity, who worked at a job 13 to 40 hours a week, perceived family and financial concerns as a barrier. Results indicated that curriculum content should include technology basics and testing for competence. Financial support for students must be expanded through loans and scholarships so workload and pace become more manageable. PMID- 20857772 TI - Exploring effects of therapeutic massage and patient teaching in the practice of diaphragmatic breathing on blood pressure, stress, and anxiety in hypertensive African-American women: an intervention study. AB - The problem of hypertension among African-Americans is one of the major areas of health disparities. The American Heart Association (2009) noted that the prevalence of hypertension among African-Americans is perhaps among the highest in the world and this is particularly so among African-American women (44.0%). The purpose of this study was to determine how therapeutic chair massage and patient teaching in diaphragmatic breathing affected African-American women's blood pressure, stress, and anxiety levels over one week or six weeks time periods. A Modified Stress, Coping, and Adaptation Model (Roy, 1976; Lazarus, 1966), Descriptives, T-tests, Pearson Product Moment Correlations, Multivariate analysis of variance (MANOVA), and Multivariate analysis of variance with covariate (MANCOVA) were used. Descriptive statistics indicated a significance for decreased systolic blood pressure levels for the one week post massage intervention measurement with p = .01, diastolic blood pressure level significance for the same group p = .02, significance for this group's State Trait Anxiety Inventory (STAI) Y2 Scale score p = .01, and Roy's Largest Root p = .03. PMID- 20857774 TI - Individual interviews with African-American women regarding condom use: a pilot study. AB - African-American women between 25 and 34 years of age are disproportionately affected by HIV/AIDS. Current prevention techniques, including education, have not had a significant influence on decreasing the rates of HIV and increasing safer sexual practices among some African-American women. This pilot study is one step towards increasing the understanding of this serious problem and developing effective interventions to stem the tide of HIV infection in African-American women. A grounded theory approach was used to address the process that unmarried, heterosexual, African-American women used to negotiate condom use with their sexual partner. Major concepts, connections between the categories, and theoretical codes are identified in this study and can be used to predict, speculate, explain, and understand the reported behavior of African-American women in negotiating condom use with their sexual partner. PMID- 20857773 TI - What women in the United States Virgin Islands still want and need to know about HPV, cervical cancer, and condom use. AB - Cervical cancer is an infection-related cancer caused primarily by the human papilloma virus. Sexual behavior is a primary risk factor for contracting the genital type of the HPV. While studies have shown that vertical transmission, horizontal transmission, and transmission of the HPV following contact with infected secretions without sexual intercourse are possible, they are not common. The incidence of cervical cancer in the Caribbean is the third highest in the world. This report describes the outcomes of a cross-sectional, mixed methods, exploratory study undertaken to examine questions and concerns about HPV transmission, physical examination, cervical cancer screening, and HPV/cervical cancer risk management among a targeted group of single, unmarried women in the U.S. Virgin Islands. Analysis of the data revealed that the women had many questions and concerns about the origin of HPV infection and cervical cancer, HPV and cervical cancer risk factors, HPV and cervical cancer screening, and HPV and cervical cancer prevention and risk management. Results of the study are used to suggest opportunities for nurses to respond to the questions and concerns posed by the women through the University of the Virgin Islands and within community based settings. PMID- 20857775 TI - Physical inactivity in female African-American adolescents: consequences, costs, & care. AB - Physical inactivity is a major public health problem and there is a higher prevalence of physical inactivity in female African-American adolescents. Physical inactivity is an independent risk factor for many chronic diseases such as heart disease, hypertension, diabetes, and obesity, which are associated with increased morbidity and mortality. Therefore, addressing physical inactivity during adolescence may be a key to reducing health disparities and to improving the health of female African-American adolescents both now and in their future womanhood. This paper presents an overview of the substantial health and economic consequences that are associated with physical inactivity. In addition, family focused, community-oriented, and church-based strategies that are aimed at increasing physical activity in female African-American adolescents are discussed. PMID- 20857776 TI - Nurses collaborating with cross disciplinary networks: starting to integrate genomics into practice. AB - Nurses and other health-care providers are poised to include genetic discoveries into practice settings and to translate such knowledge for consumer benefit within culturally appropriate contexts. Nurses must seek collaboration with multi disciplinary networks both locally and internationally. They must also capitalize on the expertise of other seasoned researchers in order to gain national and international exposure, recognition, and funding. Scholarly tailgating is using network relationships to achieve one's professional goals, and capitalizing on expert knowledge from seasoned researchers, educators, and practitioners from diverse international groups. By using scholarly tailgating principles, nurses can become important agents of change for multi-disciplinary networks, and thereby assist in decreasing health disparities. The purpose of this document is to encourage and inspire nurses to seek collaborative multi-disciplinary networks to enable genomic integration into health-care practice and education. Strategies for integrating genomics into practice settings are discussed. PMID- 20857778 TI - Causes and prevalence of ocular morbidity among primary school children in Ilorin, Nigeria. AB - OBJECTIVE: To determine the causes and prevalence of ocular morbidity among primary school children in Ilorin, Nigeria. MATERIALS AND METHODS: A cross sectional survey of primary school children in 10 randomly selected primary schools within Ilorin, Nigeria was carried out between July 2005 and January 2006. Relevant ocular history and basic ocular examinations were carried out on the children that were selected from a multi-stage sampling process. RESULTS: One thousand three hundred and ninety three pupils were surveyed. There were 689 (49.4%) boys and 704 (50.6%) girls. The age range was between 4 and 15 years. The mean and modal ages were 10.16 SD 2.5 and 10 respectively. Two hundred and seventy seven pupils had ocular pathology giving a prevalence of 19.9%. The two most common ocular disorders found among the pupils were refractive errors and vernal conjunctivitis with prevalence of 6.9% and 6.7% respectively. Others included genetic / congenital / developmental ocular disorders 39 (2.8%), glaucoma / glaucoma suspect 20 (1.4%), ocular infections 18 (1.3%), and ocular trauma 11 (0.8%). More than three-quarters (86.7%) of the causes of visual impairment and blindness among the pupils were avoidable (preventable or treatable). CONCLUSION: The sheer magnitude of avoidable causes of visual impairment and blindness in the study underscores the need for effective school eye-health programmes in developing countries. PMID- 20857777 TI - Evaluation of the effect of duration of diabetes mellitus on peripheral neuropathy using the United Kingdom screening test scoring system, bio thesiometry and aesthesiometry. AB - BACKGROUND AND OBJECTIVES: Risk factors predisposing to foot ulceration in diabetic subjects are multiple. Long duration of diabetes mellitus is a major risk factor, likewise peripheral neuropathy (PN), which globally, is recognized as the commonest risk factor for foot disease in diabetic subjects. OBJECTIVES: To evaluate the effect of duration of diabetes mellitus on peripheral neuropathy using the United Kingdom Screening Test (UKST) Scoring System, Bio-thesiometry and Aesthesiometry, in Nigerian diabetic subjects without current or previous foot ulceration. SUBJECTS AND METHODS: One hundred and twenty (120) diabetes mellitus (DM) subjects with and without symptoms of peripheral neuropathy receiving care at the medical outpatient department (MOPD) and the diabetic clinic of the Nnamdi Azikiwe University Teaching Hospital Nnewi, Nigeria, were recruited consecutively as they presented. Data collected included subjects age (years), gender, age at first diagnosis of DM, duration of DM (years) and baseline fasting venous plasma glucose. The United Kingdom Screening Test (UKST) symptom score was used to separate the participants into two groups those with symptoms of PN and those without and the subjects further assessed by three methods the UKST Signs score, Bio-thesiometry and Aesthesiometry to determine the presence . of PN. RESULTS: Among the 120 diabetic participants, 83(69.2%) had neuropathic symptoms (the symptomatic participants) while 37 (30.8%) were asymptomatic (the asymptomatic participants). The different methods of diagnosing PN increasingly detected PN with increasing duration of diabetes. For the symptomatic group, the UKST method detected PN least in those with duration of DM <5 years (73.9%) and 100.0% in those with duration of DM >15 years while for the asymptomatic group, it detected PN in 25.0% of those with duration of DM <5 years, and 100.0% for those with duration of DM >15 years. For the symptomatic group, Aesthesiometry detected PN in 65.2% of those with duration of DM <5 years and 91.7% in those with duration of DM >15 years. For the asymptomatic group, it detected PN in 29.2% of those with duration of DM <5 years and 100.0% in those with duration of DM >15 years. Likewise, for the symptomatic group, Bio thesiometry detected PN in 47.8% of those with duration of DM <5 years and 100.0% in those with duration of DM >15 years. For the asymptomatic group, it detected PN in 16.7% of those with duration of DM <5 years and 100.0% in those with duration of DM >15 years. CONCLUSION: Long duration of diabetes mellitus and peripheral neuropathy are risk factors for foot complication in Nigerians with diabetes mellitus. Diabetic subjects with long duration of diabetes (>10 years) almost always have associated peripheral neuropathy, and should be recognized as a special group at high risk for foot disease from DM. Specific preventive programs should target this group to reduce the rate of avoidable loss of limbs to diabetes. PMID- 20857779 TI - Comparing the level of CD4 T lymphocytes, to pulmonary features of tuberculosis in HIV patients in a local hospital. AB - AIM: This study is to assess the effect of CD4 T lymphocytes, on features of pulmonary tuberculosis on HIV positive patients with co-existing tuberculosis attending clinic in university of Benin Teaching Hospital Benin Nigeria. SETTING: University of Benin Teaching Hospital Benin, Nigeria. METHOD: This study was carried out on 200 patients who had laboratory confirmation of HIV, CD4 T lymphocytes measured, with tuberculosis co-infection, and control group of 100 patients, who were HIV negative, but positive for tuberculosis infection, between 1st July, 2003 and 30th May, 2004, were further examined with chest radiography, in the hospital. The standard procedures of chest radiography were used, with minor adjustment to allow good image quality on the radiograph. Two Radiologists analyzed these on standard image viewing box. RESULTS: The average CD4 T lymphocyte count in the study group (HIV sero-positive) was 173.90 cells/nl and median of 172 cells/nl. 128 (64%) subjects had CD4 T lymphocyte counts less than 200 cell/nl while 72(36%) subjects had CD, lymphocyte count above or equal to 200 cells/nl. 111 (86.72%) subjects with a CD4 T lymphocyte count less than 200 cells/nl and 31 (43.1%) subjects with CD4 T lymphocyte count 200cells/nl or more had an atypical chest radiographic pattern of primary pulmonary tuberculosis. Atypical chest radiogra phic pattern was more frequent among patients with CD4 T lymphocyte count less than 200 cell/nl (86.72%) compared with patients with CD4 T lymphocyte count greaterthan 200 cells/nl (43.1%) (P < 0.001). CONCLUSION: There is significant relationship and correlation between immune status of HIV positive patient and pulmonary pattern of tuberculosis. The variation on pulmonary pattern of tuberculosis noted also collaborated well with the level of CD4 T lymphocyte in the patients. PMID- 20857780 TI - Indications for oesophagogastroduodenoscopy in Ilorin, Nigeria--a 30 month review. AB - BACKGROUND: Oesophagogastroduodenoscopy is one of the most commonly performed endoscopic procedures. Properly performed, it provides valuable information in patients with upper gastrointestinal conditions. Oesophagogastroduodenoscopy is a visual examination of the upper intestinal tract using a lighted, flexible fibreoptic endoscope or videoscope. Oesophagogastroduodenoscopy is generally indicated for evaluating upper abdominal symptoms such as dysphagia or odynophagia, oesophageal reflux symptoms, gastroduodenal or oesophageal ulcer, upper tract stricture or obstruction, gastrointestinal bleeding, persistent vomiting of unknown cause etc. This study is therefore to review the indications for oesophagogastroduodenoscopy in Ilorin, Nigeria. AIM: To review the indications for oesophagogastroduodenoscopy in Ilorin, Nigeria. METHODOLOGY: A review of the indications for oesophagogastroduodenoscopy was undertaken to cover a thirty-month period from June 2006 to November 2008. The endoscopy register of the operating theatre was examined over this period. The biodata of the patients who underwent the procedure over this period was reviewed. RESULTS: A total of 206 patients had oesophagogastroduodenoscopy done on them during the period under review. 124 of the patients were males (60.2%) while 82 were females (39.8%). The indications for oesophagogastroduodenoscopy were dyspepsia, 94 patients (45.6%); upper gastrointestinal tract bleed, 54 patients (26.2%); gastric outlet obstruction, 12 patients (5.8%); gastric cancer, 11 patients (5.3%); dysphagia, 9 patients (4.3%); acute exacerbation of peptic ulcer disease, 8 patients (3.8%); gastro-oesophageal reflux disease, 7 patients (3.4%); recurrent vomiting, 3 patients (1.5%); bloody stool, 2 patients (1.0%); epigastric mass, 2 patients (1.0%); 1 patient (0.5%) each on account of excessive salivation, foreign body ingestion, ingestion of corrosive, and recurrent anaemia. CONCLUSION: The commonest indication for oesophagogastroduodenoscopy in Ilorin is dyspepsia. PMID- 20857781 TI - The pattern of hysterosalpingographic findings in women being investigated for infertility in Nnewi, Nigeria. AB - BACKGROUND: Tubal occlusion is the commonest cause of female infertility in the developing societies. Hysterosalpingography remains a vital method of assessing tubal patency especially in resource limited settings such as ours. OBJECTIVE: To review the pattern of hysterosalpingographic findings among women being investigated for infertility in Nnamdi Azikiwe University Teaching Hospital Nnewi, Nigeria over a period of five years (2001-2005). METHOD: The data obtained from the request forms and radiologists' reports were analyzed using SPSS version 11. The level of statistical significance was set at p < 0.05. RESULTS: Of the 320 studied, 230 were found suitable for analysis. Their ages ranged from 20 to 44 years (mean 32.8 +/- 5.8 years). The indications were primary infertility in 103 (44.8%), secondary infertility in 88(38.3%), while in 39 (16.9%) patients the type of infertility was not specified. The reports revealed that 67 (29.1%) had normal HSG Cervical abnormalities were found in 34 (14.8%), uterine cavity abnormalities in 108 (47.0%). Tubal pathologies were seen in 100 (43.5%) with bilateral tubal occlusion in 43 (18.7%) and bilateral hydrosalpinges in 6 (2.6%) patients. CONCLUSION: Tubal pathology remains a major contributor to female infertility in this part of the world. PMID- 20857782 TI - Prevalence of pin tract infection: the role of combined silver sulphadiazine and chlorhexidine dressing. AB - OBJECTIVE: Infection at the pin tract is a common complication of external fixation. This study was done to compare the rate of pin site infection following combined 1% silver sulphadiazine and 5 % chlorbexidine dressing with 5% chlorhexidine dressing alone. METHOD: This was a prospective controlled study which compared the results of pin site dressing using a combination of chlorhexidine and silver sulphadiazine cream (Study group) with dressing using chlorhexidine alone. Eligible patients had external fixation in the treatment of open fractures or orthopaedic conditions. Pin-tract infection was deemed to be present iferythema, cellulitis or purulent discharge occurred around a pin site. We did not distinguish between deep and superficial infection. RESULTS: The study group had one hundred and seventy pin sites while the control group had one hundred and sixty-four pin sites. Thirty-eight patients, in whom thirty-seven uniplanar external fixators and one Ilizarov ring fixator were used, made up both groups. Three patients (7.9%) had pin tract infection in the study group while nine patients (23.7%) had pin tract infection in the control group. CONCLUSION: There was a significantly lower prevalence of pin-tract infection amongst patients whose external fixation pins were dressed with 1% silver sulphadiazine and 5% chlorhexidine than in those dressed with chlorhexidine alone (P = 0.03). Therefore, we advocate the use of a combination of silver sulphadiazine and chlorhexidine for pin site dressing. PMID- 20857783 TI - A study of extracranial aneurysms at UNTH in Enugu, Nigeria. AB - BACKGROUND: Previous studies on aneurysms in Nigeria have either been case reports or studies of peripheral aneurysms. No study has comprehensively evaluated all aspects of this disease as an entity among Nigerians. The need therefore arises to re-evaluate this lesion so as to make deductions on incidence, sex ratio, aetiology and management. STUDY DESIGN: This is a retrospective descriptive study of arterial aneurysms at the University of Nigeria Teaching Hospital (UNTH), Enugu. Those treated between January 1993 and December 2002 were included for the study. Data were obtained from medical records for all patients admitted with aneurysms over the study period. RESULTS: Atotal of 26 patients were admitted during the period, but 24 case notes were analysed. The age range was 10-75 years with male: female ratio of 1.4:1. Traumatic pseudo aneurysms accounted for 16 cases (67.0%) while true aneurysms comprised the remaining. Of all the aneurysms, femoral artery with most of the pseudo aneurysms had 8 out of 24 (33.0%). This is followed by the infra-renal abdominal aorta (5/24, 21.0%) and other sites (11/24, 46.0%). Diagnoses were made clinically in most cases and by abdominal ultrasonography in abdominal aortic aneurysms. Twenty-one patients had surgical intervention with 9.5% operative mortality. CONCLUSION: The incidence of aneurysm is low in our locality (2.6/year) based on the rate of diagnosis. Abdominal aorta harbours most of the true aneurysms with diameter ranging from 8.0-15.0 cm without rupture. Untreated, all will eventually rupture with catastrophic consequences. Treatment involved excision with graft interposition. This is not only expensive but the graft is often not readily available. As a solution, grafts should be stocked with drug revolving fund. PMID- 20857784 TI - Aetiological patterns and management outcome of paediatric head trauma: one-year prospective study. AB - BACKGROUND: Trauma is the most common cause ofpaediatric deaths. In 75% ofpaediatric trauma deaths, head injury is responsible, and most are from falls. Recent reports from Nigeria, however, appear to indicate a predominance of road traffic accidents, instead of falls. OBJECTIVE: To evaluate the aetiology of paediatric head trauma, management protocols and outcome from our Centre, in order to acquire a baseline data base and recommend measures to reduce childhood trauma. PATIENTS AND METHODS: A prospective study of all paediatric head trauma cases presenting to Nnamdi Azikiwe University Teaching Hospital, Nnewi, for 12months from April 21, 2006 to April 20, 2007, was done and collated data subsequently analyzed. The paediatric age group was taken as = 15 years, and grading of head injury was with the Glasgow Coma Scale (3-15) and the modified scale for non-verbal children; while outcome was measured with the Glasgow Outcome Scale (1-5). RESULTS: Out of 334 patients treated within the period of study, 210 were head trauma cases. Of these, 52 were paediatric head trauma, representing 24.8% of all head trauma cases; and 19.2% (10 of 52) of them were aged 0-2 years. About 62% (32 of 52) were males. Falls and RTA were each responsible in 25 (48.1%) cases. Mild head injury occurred in 31 (59.6%), and 49 (94.2%) patients were evaluated by plain radiography. Treatment was conservative in 39 (75%) cases; with satisfactory outcome in 36 (69.2%), and a mortality rate of 15.4%. CONCLUSIONS: Road traffic injury, mostly from motorcycles, has become the major cause of morbidity and mortality amongst the paediatric age group, especially the male gender, and outcome from management is mostly satisfactory. PMID- 20857785 TI - Appropriateness of ophthalmic cases presenting to a Nigerian tertiary health facility: implications for service delivery in a developing country. AB - OBJECTIVE: To assess whether the ophthalmic cases presenting at a Nigerian tertiary eye unit are appropriate for such level of care and also draw necessary implications for service delivery. METHODS: Data on 1321 consecutive new patients that presented at the ophthalmic clinic of the University of Teaching Hospital, Ilorin, Nigeria between February and July 2005 were reviewed on demographics, referral routes, and reasons for patronage, diagnoses and disease categories. Information on the general situation of health infrastructures prevailing at the surrounding health facilities was collected from key-informants. RESULTS: One thousand and ninety-one (82.6%) presented without any referral and 1095 (82.9%) patronized in order to access perceived good quality of eye care service being rendered. However, only a small proportion of their ailments (191, 14.5%) actually required attention at the tertiary level of eye care. The key informants painted a picture of severely-challenged general and health infrastructures particularly at the primary health care facility level. CONCLUSION: An overwhelming majority of ophthalmic patients directly accessed eye care at the tertiary level, even though most of their ailments could have been satisfactorily treated at the lower facilities of health care were the latter to be functioning optimally. A better coordinated and strengthened health care system, particularly at the primary and secondary health care facilities would ease the burden of inappropriate presentations on tertiary health facilities in Nigeria. PMID- 20857786 TI - Quantification of human immunodeficiency virus-1 viral load using nucleic acid sequence-based amplification (NASBA) in north central Nigeria. AB - BACKGROUND: Viral load (VL) quantification is considered an integral part of the standard care in human immunodeficiency virus (HIV) infected individuals but in Nigeria as in most of sub-Saharan Africa, this has not reached the majority ofpatients. METHODS: We report the first field application of the NucliSens EasyQ HIV-1 platform for the real time quantification of HIV-1 VL combining NASBA amplification and real time detection with molecular beacons among HIV-1 infected individuals in north central Nigeria where the predominant HIV-1 subtypes are CRF02_AG and G. CD4+ counts were enumerated using a fluorescence-activated cell sorter system. RESULTS: Of one hundred and forty nine (n=149) plasma sample from patients with mean age of 32 years and made up of 77 males and 72 females, fifty {n=50 (37.9%); 28 males and 22 females} had VLs below the lower detection limit (LDL=25 IU/ml) set by the assay while eighty-two {n=82 (62.1%); 39 males and 43 females} had VL levels above the LDL. Furthermore, 13 of 82 (15.9%) patients with viral loads above the LDL had VLs between 26-1000 IU/ml while 69 (84.1%) had VLs of 1001-2,400,000 IU/ml. 17 (11.4%) of the samples could not be analyzed due to poor viral amplification. Among individuals with both CD4+ and VL results (n=56), those with CD4+ of 1-418 cell/microl presented with higher VL usually above 45,000 IU/ml when compared with those with CD4+ of over 500 cell/microl. CONCLUSION: Our findings highlight the pattern, usefulness and feasibility ofVL quantification by NucliSens EasyQ in monitoring HIV-1 patients in Nigeria. PMID- 20857788 TI - Patients' preference for number of embryos transferred during IVF/ICSI: a Nigerian experience. AB - BACKGROUND: The Human Fertilization and Embryology Authority is considering limiting the number of embryos that can be transferred to single embryo per cycle as has been done in several European countries, with the aim of reducing the rate of multiple pregnancies and its attendant complications following in vitro fertilization (IVF) / Intracytoplasmic sperm injection (ICSI). OBJECTIVE: To determine the number of embryos patients' attending a fertility clinic in Nigeria, would prefer transferred during IVF/ICSI. MATERIALS AND METHODS: Fifty four consecutive female patients who underwent IVF/ICSI procedures between May 2006 and April 2007 at the Port Harcourt Fertility Centre, Rivers State were interviewed using structured questionnaires. They were informed of all the obstetric and perinatal complications of multiple pregnancies and the advantages and trend towards single embryo transfer and then asked to choose the number of embryos (one, two or three) they would prefer transferred assuming similar implantation rates. Each respondent was allowed to give reason(s) for their choice. DESIGN: Prospective, descriptive study. RESULTS: Fifty one (94.4%) of the respondents preferred the transfer of multiple (2 or 3) embryos. Only three (5.6%) patients opted for single embryo transfer. Majority of the patients (31 or 60.8%) preferred multiple embryo transfer because of their desire for twins while twenty (39.2%) cited cost of IVF as their reason. Fifteen (29.4%) patients saw multiple pregnancies as a compensation for their long periods of infertility. CONCLUSION: With the desire for twins and high poverty level in Nigeria, a policy of single embryo transfer might be difficult to implement. Health economic studies would be required to determine if the accumulative cost of taking care of twins/triplets is less, equal or outweighs the cost of several single embryo transfers. PMID- 20857787 TI - Some behavioural risk factors for intestinal helminthiasis in nursery and primary school children in Enugu, south eastern Nigeria. AB - The objective of this study was to determine some common behavioural risk factors for intestinal helminthiasis in nursery and primary school children in Enugu. DESIGN: A cross-sectional survey on 460 children attending nursery and primary schools in Enugu was carried out in 2003 with a view to determine some behavioural risk factors for intestinal helminthiasis. SETTING: This study was carried out in the research laboratory of the Federal Ministry of Health, National Arbovirus and Vector Research Centre, Enugu. METHOD: Intestinal helminthiasis was diagnosed using the kato-katz method in analysing fresh stool samples collected from nursery and primary school children in Enugu. These fresh stool samples were collected into appropriately labeled clean containers. Questionnaires were administered by the researchers to obtain data from the children and their parents or guardians as regards some behavioural risk factors for intestinal helminthiasis. RESULTS: The results from this study showed that the prevalence of intestinal helminthiasis was significantly affected by various behavioural risk factors. The rate of helminthic infection varied significantly with hand washing habits after defeacation (chi2 = 75.77; df= 2; p = 0.001) and with different habits of washing fruits before eating (chi2 = 52.79; df=2; p = 0.001) among the pupils. Also, the rate ofhelminthic infection varied significantly with the source of drinking water (chi2 = 55.12; df = 3; p = 0.01), water boiling habits (chi2 = 40.89; df = 2; p = 0.001), use of footwear after school hours (chi2 = 30.72; df = 2; p = 0.001). Sites utilized for defeacation by the pupils (chi2 = 80.25; df=3; p = 0.001) also significantly influenced the rate ofhelminthic infection. CONCLUSION: Various behavioural factors which significantly affect the rate of helminthic infection abound in children living in Enugu. The government should give attention to the control of these behavioural risk factors. A lot of health education will be needed to curb the poor personal hygienic habits which are obvious risk factors for intestinal helminthiasis. PMID- 20857789 TI - Thyroid cancers in nodular goiters in Kano, Nigeria. AB - BACKGROUND: Cancer is an occasional incidental finding in nodular goiter, but there has been no formal study on this disease in our locality. AIMS AND OBJECTIVES: To determine the occurrence of histologically diagnosed malignancy in patients who present with nodular goiters. METHODOLOGY: This is a 7-year (2000 2006) retrospective study of all histologically diagnosed malignancies within nodular goiters at Aminu Kano Teaching Hospital, Kano. RESULTS: There were 160 multinodular goiters during the study period, out of which 24 (15.0%) had histologically diagnosed cancer, and 1 out of the thirteen patients with solitary thyroid nodule (7.6%) had carcinoma. The ages of the patients with carcinoma ranged from 16 to 65 years, with a mean age of 38.8 years. Eighteen (72%) were females, and 7 (28%) were males. Six out of the 25 cases of carcinoma were detected preoperatively by fine needle aspiration cytology. Well differentiated follicular carcinoma was the predominant histological type in 13 (52%) cases, followed by papillary in 10 (40%), medullary carcinoma in 1 (4%) and anaplastic carcinoma in 1 (4%) patient. CONCLUSION: One-seventh of nodular goiters in our center harboured malignancy, and follicular carcinoma was the prevalent histological type. This is consistent with the findings elsewhere in endemic goitrous regions. Ultrasound guided fine needle aspiration would improve preoperative diagnosis and guide appropriate surgical management. PMID- 20857790 TI - Grandmultiparity: experience at Awka, Nigeria. AB - BACKGROUND/AIM: The grandmultiparae have basically been regarded as high risk obstetric patients. This study was undertaken to estimate the prevalence in this area as well as evaluate the problems, associated factors and ways of reducing the burden. METHODOLOGY: This was a retrospective study of the problems of grandmultiparity (five or more previous viable babies) at Amaku General Hospital, Awka over a three year period, January 2006 to December 2008. One hundred and thirty five (135) grandmultiparous women (study group) were matched with a similar number of women of lower parity (Para 2 and 3), who attended and delivered in the hospital during the same period. The problems seen in both groups during pregnancy and labour, mode of delivery, birth weight, perinatal and maternal mortalities were compared. The soccio-demographic characteristics were also compared. RESULTS: The incidence of grandmultiparae was 7.53%. Twenty nine (21.5%) of the grandmultiparae were unbooked compared to 6 (4.4%) of the control group. Ninety four (69.7%) of the study group belonged to the low social class IV and V compared to 27 (20%) of the control. Anaemia in pregnancy was commoner in study than in the control group (49 (36.3%) versus 12 (8.9%). There was a high caesarean section rate in the study group compared to the control (31 (23.0%) versus 6 (4.4%). The maternal mortality rate in the study group was 22.2/1000. There was no maternal death in the control. CONCLUSION: Improving the socio economic standard of our women and increased awareness in the importance of family planning will reduce the incidence and complications of grandmultiparity. PMID- 20857792 TI - Delays in presentation and treatment of breast cancer in Enugu, Nigeria. AB - OBJECTIVE: To assess the delays and define the causes of delay in presentation and treatment of breast cancer patients in Enugu, Nigeria. DESIGN: A cross sectional survey of breast cancer patients using a semi structured questionnaire. SETTING: Surgical Oncology unit, University of Nigeria Teaching Hospital Enugu, (UNTH-E), Nigeria. SUBJECTS: 164 consecutively presenting breast cancer patients seen between June 1999 and May 2005. RESULTS: Most of the patients (82.3%) reported for initial evaluation at a modern health facility while 17.5% reported first to alternative practitioners. Forty six patients (26.4%) presented within a month of noticing the symptoms while 72 (45.3%) delayed more than 3 months. In contrast, 18 (17%) were seen at the site of definitive treatment within one month of seeking help at the initial hospital while 73.4% had a delay of more than 3 months after the initial hospital contact. Institutional or physician induced delays were present in 46.2% of the cases while patient related delays were present in 79.2% of cases. Only use of alternative practitioners for initial treatment was significantly related to delays of more than three months before presentation (p = 0.017). CONCLUSION: For breast cancer prevention programs in Nigeria to succeed, they must in addition to breast awareness and screening programs, address the institutional bottlenecks, the dearth of knowledge among primary care physicians and improve referrals from alternative practitioners and prayer houses. PMID- 20857791 TI - Gastrointestinal stromal tumours at the University of Nigeria Teaching Hospital Enugu, Nigeria: an immunohistochemical study of GIT mesenchymal tumours. AB - Mesenchymal tumours of the gastrointestinal tract (GIT) are uncommon. Recent progress in the understanding of the biology and origin of these tumours has led to their reclassification. A new subclass designated Gastrointestinal Stromal Tumours (GIST) is diagnosed based on the presence of a mutational over expression of c-kit protein that is thought to be critical in the pathogenesis of these tumours. This new class oftumours may form the majority of gastrointestinal mesenchymal tumours. Even though the diagnosis of GIST is mainly based on positive staining with CD117, a minority of tumours with histological characteristics of GIST are CD117 negative and are classified as CD117 negative GIST. In this first review of mesenchymal GIT tumours from Nigeria, we present 11 cases ofmesenchymal tumours of the gastrointestinal tract seen within a six-year period at our centre. Immunohistochemistry was performed on 7 of them in which histological appearances suggested GIST. Only two cases had all the criteria defined in the consensus conference on the diagnosis of GIST. Our findings, albeit in a very small sample, contrasts with what obtains in developed countries in the proportion of GIT mesenchymal tumours that are truly GIST. This raises a question to be answered on the true nature and proportion of gastrointestinal strumal tumours among GIT tumours in Nigerian patients. PMID- 20857793 TI - Demographic and sociocultural characteristics of sickle anaemia children with positive hepatitis B surface antigenaemia in a tertiary health facility in Enugu. AB - BACKGROUND: Hepatitis B virus) infection is contracted through contact with body fluid of infected persons. Patients with sickle cell anaemia (SCA), a common haematological disorder in Nigeria, have tendencies to visit traditional healers who administer scarifications and ritual marks that may expose them to HBV infection. OBJECTIVE: To determine the demographic and socio-cultural characteristics of children with SCA infected with HBV at the University of Nigeria Teaching Hospital Enugu. SUBJECTS AND METHOD: Two hundred and twenty one children aged 6 months to 17 years with SCA were recruited consecutively from October 2004 to April 2005. They were screened for HBsAg using ELISA method. RESULTS: There was no statistically difference in hepatitis B surface antigenaemia among different age group (P = 0.907). Social class did not significantly influence the prevalence of HBsAg among subjects (p = 0.887). Socio cultural practices like circumcision and scarification did not influence the prevalence of HBsAg, (p = 0.636) (p = 0.771) respectively. Significantly higher number of people from lowest socioeconomic class practice scarification (p = 0.0001). CONCLUSION: Demographic and sociocultural factors do not appear to influence the prevalence of HBsAg among children with SCA in Enugu, Nigeria. PMID- 20857794 TI - A 4 year review of neonatal outcome at the University of Benin Teaching Hospital, Benin City. AB - BACKGROUND: Neonatal morbidity and mortality rates reflect a nation's socio economic status, the efficiency and effectiveness of health care services. This important indicator is useful in planning for improved healthcare delivery. A four year review of neonatal outcome was therefore conducted in the special care baby Unit (SCBU) of University of Benin Teaching Hospital (UBTH). METHODS AND SUBJECTS: The study was done between 2003 and 2006 and sought to review the morbidity, mortality, salvage rate of low birth weight babies and outcome of all inborn and outborn babies admitted into the SCBU of UBTH. The biodata, birth weight, sex, APGAR scores and reasons for admissions and outcome were abstracted from case notes/admission records. RESULT: A total of 3075 babies were admitted to the unit during the period under review. 2602 (84.6%) were inborn while 473 (15.4%) were out-born. There were more males 1676 (54.6%). There were 855 (27.8%) preterm babies of which 803 (26.1%) were low birth weight babies. Neonatal sepsis, severe birth asphyxia, pre-maturity and neonatal tetanus were the most common morbidities suffered by the neonates. Mortality was recorded amongst 625 (20.3%) babies. Mortality rate was significantly higher amongst the out-born than in born babies, P value < 0.0001. CONCLUSION: The neonatal mortality rate in this study is high. The morbidity profile observed in the study is attributable to preventable causes. Of note is the contribution ofNNT to morbidity and mortality. Strengthening of linkages in perinatal care, improving maternal emergency obstetric care and neonatal resuscitation skills are proposed measures to reduce neonatal mortality. PMID- 20857795 TI - Review of obstetrics genito-urinary fistulae in the University of Calabar Teaching Hospital Calabar, Nigeria. AB - BACKGROUND: Obstetric fistulae with Urinary incontinence are one of the most distressing maternal morbidities. It is associated with physical and social deprivation such as wife abandonment and violent reactions against the victims particularly in the developing countries of the world. AIMS AND OBJECTIVES: To study the demographic and reproductive profiles as well as management of patients with obstetric fistulae in UCTH, Calabar, Nigeria. PATIENTS AND METHOD: A five year retrospective study of case records of 37 patients managed in Maternity Annex of University of Calabar Teaching Hospital, Calabar Nigeria for obstetric genito-urinary fistulae was carried out. RESULTS: One in every 122 parturients during the period had fistula. Eleven (29.7%) were teenagers. Many patients were married (54.1%), nulliparous (59.4%), come from low socioeconomic class (72.9%) and did not utilize modern obstetric facilities properly. Many cases resulted from prolonged obstructed labour (51.4%) and 70.2% presented with total incontinence of urine. Eighteen (48.7%) were diagnosed within 6 month of delivery. The main types encountered included were vesico-vaginal (34.4%) or complex (10.8%) fistulae who were manage conservatively (21.6%) or with bladder repairs. Majority (29.7%) were referred for further treatment. CONCLUSION: Parturient in Calabar still suffer from this age long obstetric morbidity mainly due to poor utilization of modern obstetric care facilities. Results of treatment are largely unsatisfactory; therefore resources should be channeled towards prevention. PMID- 20857796 TI - Safety, efficacy and acceptability of implanon a single rod implantable contraceptive (etonogestrel) in University of Benin Teaching Hospital. AB - OBJECTIVE: The study evaluated the safety, efficacy and acceptability of Implanon (etonogestrel) subdermal implant contraceptive amongst its acceptors. STUDY DESIGN: This was part of an on going prospective longitudinal study that involved 32 women out of 46 sexually active healthy informed volunteers recruited from our family planning clinic between February and March 2007. All the subjects received the single rod subdermal implant Implanon which contains 68 mg etonogestrel. Data on socio-demographic characteristics, menstrual pattern, haematological indices, weight, blood pressure, side effects and user's satisfaction were collected and analysed. The subjects served as their own control. RESULTS: The mean age and parity were 33.9 +/- 5.2 years and 3.1 +/- 1.7 respectively. The mean weight was 71.4 +/- 12.0 kg at pre-insertion. At 6 months the weight reduced to a non significant (p < 0.13) mean value of 70.0 +/- 10.5 kg and increased to a non significant (p < 0.88) mean value of 71.5 +/- 11.6 kg at 12 months. The mean systolic and diastolic blood pressures did not show statistical significant changes at 6 months follow up (p < 0.17/0.64). However at 12 months there were significant but within normal reductions (p < 0.003/0.05) in the systolic and diastolic blood pressures. The side effects were menstrual abnormalities. Eighteen (56.3%), 1 (3.1%) and 13 (40.6%) reported reduced, increased and combinations of bleeding patterns respectively. No participant had normal cycle. Other experiences were headache, 4 (12.5%) and reduced libido 3 (9.4%). The mean packed and white blood cell concentrations did not show statistical significant changes at 6 and 12 months follow up. At 12 months there was statistical significant increase (p < 0.04) in the mean +/- SD platelet count (205312.5 +/- 75694.8 per ul) when compared with the pre-insertion mean value (176343.8 +/- 52945.3 per ul). One acceptor had thrombocytopenia without any untoward effect. Two subjects discontinued method on account of menorrhagia and headache. The efficacy and continuation rate were 100% and 93.8% respectively. All the clients received adequate information about the method and most of them were satisfied with it at follow up. CONCLUSION: Implanon was an effective, safe and acceptable method of contraception amongst its acceptors. Menstrual abnormalities were the major side effects which most of the subjects found tolerable with adequate counseling. The reduced platelet concentration of the one acceptor would require follow up to ascertain the trend. PMID- 20857797 TI - Krukenberg tumour simulating uterine fibroids and pelvic inflammatory disease. AB - OBJECTIVE: To report a case of cancer of the colon which presented as secondaries to the ovaries. METHOD: Case report. SUMMARY: The case presented is that of a 39 year-old female who presented with lower abdominal pain and a multinodular pelvic mass which led to an initial diagnosis of multiple uterine fibroids and pelvic inflammatory disease. The presence of a colonic mass was first suggested by ultrasound. Laparotomy revealed carcinoma of the colon with bilateral krukenberg's tumour and an insignificant fibroleiomyoma. CONCLUSION: This case is reported to alert practitioners that all multinodular pelvic masses should not be assumed to be multiple fibroids. PMID- 20857798 TI - Congenital orbital teratoma. AB - Congenital orbital teratoma though rare is available in this environment. This is a case report of a baby with a protruding orbital mass in the left eye with all classical clinical features of teratoma. Though the histopathological report fell short of confirming the diagnosis the clinical features and outcome of management strongly suggest that the lesion is a teratoma. Multidisciplinary approach to the management not only saved the life of the baby in question but also enhanced the outcome of treatment. Good and compliant follow up for six months was experienced. Cytological test is mandatory for any suspected cases ofteratoma. PMID- 20857799 TI - Sarcoma botyroides of the cervix in a HIV positive 45-year-old woman: a case report. AB - Embryonal rhabdomyosarcomas (Sarcoma botyroides) are malignancies of connective tissue with abnormal cells which are thought to arise from skeletal muscle progenitors. It is a rare childhood malignant solid tumour and occurs in children mostly less than 10 years. It can occur at any age but two commonest peaks are 1 5 years (when approximately 66.6% occur) and 15-19 years accounting for the rest. Sarcoma botyroides which usually occurs in the vagina in childhood is rare in the female reproductive tract of adult women especially those over the age of 40. We report here a case of a 45-year-old HIV-positive woman who presented with profuse bleeding from the vagina with severe anaemia. Macroscopically, a cauliflower polypoid growth was seen protruding from the cervix into the vagina. Histopathological studies confirmed a diagnosis of sarcoma botyroides. CONCLUSION: The need for a high index of suspicion of sarcoma botyroides of the cervix must be borne in mind when making a diagnosis on all cervical polypoidal masses. Also the importance of looking out for lesions and malignancies on all HIV positive patients cannot be over-emphasized. PMID- 20857800 TI - Successful repair of iatrogenic cyclical menouria: a case report. PMID- 20857801 TI - Neurobrucellosis--a case report and review of literature. AB - Neurobrucellosis is a rare form of systemic brucellosis, a disease acquired through ingestion of unpasteurized dairy products, which may manifest as stroke, encephalitis, meningitis, or psychiatric disorders. Presently there is no known report ofneurobrucellosis in Nigeria, although consumption of unpasteurized dairy products is not uncommon in this country. In this report we present a 28 year old spinster with history of significant ingestion of unpasteurized cow milk and brucellosis of the brain diagnosed in our centre through brain magnetic resonance imagining (MRI) and brucella antigen agglutination test. Because of the indolent nature of brucellosis infection, it should be suspected in individuals with pyrexia of unknown origin so that early detection and treatment could prevent long-term sequelae such as focal neurologic deficits, hydrocephalus and psychiatric illness. PMID- 20857802 TI - Aggressive behaviour and mental illness: a study of in-patients at Aro Neuropsychiatric Hospital, Abeokuta. AB - OBJECTIVES: To determine the magnitude and pattern of aggressive behaviour among psychiatric in-patients and identity associated socio-demographic and clinical factors. METHOD: The study was cross-sectional in design. Among patients admitted to the Neuro-psychiatric Hospital, Aro (and its Lantoro annex), Abeokuta between January 1 to December 31, 2005, those who manifested aggressive behaviour were identified. Each was evaluated by the medical team, and a questionnaire detailing socio-demographic and clinic variables was administered on them. RESULTS: A total of 305 patients comprising 213 (69.8%) males and 92 (30.2%) females were managed as inpatients during the period of the survey. Out of these, 43 patients manifested aggressive behaviour representing a rate of 13.8%. The aggressive patients consisted of 26 males and 17 females, representing rates of 12.2 and 18.5 percent for the sexes respectively. Of the 11 diagnoses entered for all the patients, only 3 were associated with aggressive behaviour. These included schizophrenia, 21 patients (48.8%); bipolar manic illness, 12 patients (27.9%) and co-morbid substance use (mainly cannabis) and mental disorder, 10 patients (22.3%). Nursing personnel constituted the majority of target of aggression. Unemployment was the only socio demographic variable observed with significant positive relationship with aggressive behaviour. In addition, the commonest probable precipitants of aggressive behaviour included hallucinations, clamouring for discharge and attempting to abscond, reaction to confrontational interview, impulsivity and reaction to unmet demands. CONCLUSION: Mental health practitioners (especially nurses) should be equipped with necessary skills in managing aggressive and potentially aggressive patients. The present observations may be useful in raising the suspicion of care providers on potentially aggressive patients for preventive purpose. PMID- 20857803 TI - The specialty of general medical practice/family medicine: the need for development in Nigeria. PMID- 20857804 TI - [ISKRA guidelines for antimicrobial prophylaxis in surgery--Croatian National Guidelines]. AB - Summary. The development of the Guidelines for perioperative prophylactic use of antimicrobial agents (further on Guidelines) was initiated by the Interdisciplinary Section for Antibiotic Resistance Control (ISKRA) of the Croatian Ministry of Health and Social Welfare in accordance with the principles of AGREE (Appraisal of Guidelines for Research and Evaluation) methodology which means that the guidelines are the result of a consensus between all involved professional societies. Guidelines were composed in order to improve antibiotic use in surgical professions. Data obtained from observational studies have shown that the use of antimicrobials in surgical professions is unsatisfactory, and since around 50% of all prescribed drugs in surgical professions refer to perioperative prophylaxis, such guidelines could significantly improve current negative trend and reduce the occurrence of infections in surgical patients as well as slow down the selection of resistant bacteria. In the introductory part of the guidelines, principles of perioperative prophylaxis are presented. The advantages and risks of prophylaxis are listed as well as factors that determine prophylaxis effectiveness. For easier orientation, surgical professions have been divided into basic surgical fields. In each field, the specificity of the field has been described followed by uniform structured tables and with every listed surgical procedure there is the most probable cause of infection, the drug of choice for prophylaxis, alternative drug, remark for particular surgical procedure and finally the grade of recommendation. The Guidelines do not cover perioperative prophylaxis in immunocompromised patients nor perioperative prophylaxis in children. The Guidelines do not cover all possible surgical interventions, but can be used as a basis for most surgical procedures performed in our hospitals. At the very end of these Guidelines, a comprehensive list of references enables all those interested to find further information and details about this topic. The revision of the Guidelines is planned in three years' time. PMID- 20857805 TI - [Attitudes of health personnel in a university hospital toward evidence-based medicine]. AB - Over the last few years the concepts and methods of the evidence-based medicine (EBM) have been increasingly recognized and applied in the Croatian medical community. Central Medical Library at Zagreb university Medical School has been developing a web-based service aimed to help practitioners find best evidence for solving specific clinical problems. Therefore, the health personnel affiliated to a teaching hospital were surveyed. The questionnaire included 18 questions evaluating attitudes towards EBM. It was displayed by the library's information desk. There were 204 respondents, 62% of them clinical specialists. Most respondents agreed that EBM is useful in clinical decision making (57.4%) as well as in improving patient care (55.4%). Lack of personal time (60.8%) and insufficient skills (60.3%) were percieved as the main barriers to practising EBM. The vast majority of respondents (96.6%) reported never having received EBM training. The study results show that medical librarians can play an expanded role in saving the practitioners' time by searching EBM resources and assessing the quality of the information. PMID- 20857806 TI - [Frequency and characteristics of dyspepsia in coronary artery disease patients]. AB - The aim of the study was to determine the frequency of functional and organic dyspepsia and possible predictors for organic dyspepsia in coronary artery disease (CAD) patients. The 150 patients (109 men; mean age 62.61 +/- 10.23 yr) undergoing coronary artery by-pass grafting because of stable pectoral angina due to significant CAD were enrolled in the study. Dyspepsia was determined by the existence of epigastralgy, heartburn, nausea and vomiting. Dyspepsia with endoscopic lesions was defined as organic, and dyspepsia with normal endoscopy was defined as functional. Multivariate analysis (logistic regression) was used to estimate predictive values of some independent clinical and demographic variables in relation to organic dyspepsia (dependent variable). One hundred thirty-five (90%) patients had at least one symptom of dyspepsia. Eighty five patients (63%) had organic dyspepsia, and 50 (37%) patients had functional dyspepsia (P < 0.001). Patients with organic dyspepsia had more dyspeptic symptoms than patients with functional dyspepsia (1.92 +/- 0.88 vs. 1.38 +/- 0.87, P < 0.001). More dyspeptic symptoms correlated with heavy GD lesions (r = 0.267; P < 0.0001). Multivariate analysis revealed independent correlation of consuming low-dose aspirin (standardized coefficient beta = 11.701, P = 0.004), diabetes (beta = 2.921, P = 0.027), cigarette smoking (beta = 2.910, P = 0.037) and nausea (beta = 3.620, P = 0.015) with organic dyspepsia. The study showed high frequency of dyspepsia, especially organic dyspepsia, in CAD patients. Three or more dyspeptic symptoms, low-dose aspirin, cigarette smoking, diabetes and nausea, increased the probability of organic dyspepsia. Therefore, for patients with combination of dyspeptic symptoms and present risk factors the endoscopic examination should be considered. PMID- 20857807 TI - [Frequency of recurrent convulsions after a first febrile seizure: two-year observation results]. AB - Febrile convulsions are the most frequent neurological disorder of early childhood. One third of children with febrile convulsions will have a recurrence, and only a small number will develop afebrile convulsions with epilepsy variation. The aim of the work was to establish the frequency of convulsion recurrence through the retrospective study with regard to age, type of recurrence, and applied prophylaxis in children in Tuzla Canton in a two-year period after the first febrile convulsion. Amongst 716 patients, 21.9% had a recurrence. Recurrence of simple febrile convulsions occurred in 124 (78.9%), complex in 18 (11.5%), and 14 (9.8%) patients had afebrile convulsions. There was no statistically significant difference in recurrence appearance between patients who received continuous and intermittent prophylaxis or different type of continuous prophylaxis. Knowledge of recurrence frequency according to age groups opens the possibility of recurrence prevention with adequate therapeutic measures, especially in home care conditions. Good parent education would represent the first step in recurrence prevention. PMID- 20857808 TI - [Haemosiderosis bulbi in a patient with myelodysplastic syndrome (MDS RAEB-1)]. AB - Haemosiderosis bulbi is a degenerative condition of the eye bulb caused by the toxic effects of an intracellular accumulation of haemosiderin. Haemosiderin is a product of the decomposition of haemoglobin. The most common and severe damage takes place in the epithelial cells of the eye tissues. Haemosiderosis bulbi is a complication of the long existing haemophthalmus, the intravitreal bleeding, which is neither spontaneously resorbed nor operatively removed. The condition is characterized by the loss of light perception and the reddish colour of the intrabulbar tissues. The cause of the haemophthalmus in our patient is protracted anaemia due to pre-existing myelodysplastic syndrome (MDS RAEB-1). PMID- 20857809 TI - [Laparoscopic partial pericystectomy of hepatic hydatid cysts --Papadimitriou operation: a case report]. AB - Operative treatment of hepatic hydatid cyst is technically demanding procedure. The method of choice is conservative treatment with Albendazolum followed by surgery. Open laparotomy or laparoscopic operation can be performed. We prefere laparoscopic exploration followed by laparoscopic total pericystectomy or laparoscopic partial pericystectomy. If laparoscopic operation is not possible due to technical reasons and patient safety, conversion to an open operation should be done, followed by total or partial pericystectomy. The case and our detailed technique of laparoscopic partial pericystectomy with biliostasis and omentoplasty is described. Laparoscopic operation is equally safe for the patient, yet with minor trauma and better aesthetic effect. PMID- 20857810 TI - [Arthroscopy of the elbow]. AB - Elbow arthroscopy has become an indispensable method of surgical care of injuries and their consequences and damages that affect the elbow. The advantages of elbow arthroscopy in comparison to classical open surgery are multiple. Primarily, arthroscopy allows an excellent view of intra-articular structures and thus a detailed overview of the entire joint which enables us to perform complete surgery without opening the joint. Furthermore, morbidity is significantly smaller, rehabilitation is faster, and return to daily activities is also faster. Basic requirements for successful application of elbow arthroscopy are careful planning of the procedure, very good knowledge of regional anatomy of the elbow, strictly following the rules of performing the procedure, good technique and an experienced surgeon. Pathologies that can currently be addressed arthroscopically include osteochondritis dissecans of elbow, lateral epicondylitis, synovial plica syndrome, elbow osteoarthritis, elbow contracture, as well as the diseases where the synovectomy is needed, such as rheumatoid arthritis, pigmented villonodular synovitis, synovial chondromatosis and hemophiliac synovitis. PMID- 20857811 TI - [Systemic therapy in the treatment of psoriasis: drugs of prebiological era]. AB - Psoriasis is a chronic, recurrent skin disease that lasts a whole life. A quarter of adults are suffering from severe forms of psoriasis that requires the application of the systemic treatment. Despite the development of new groups of medicines, traditional therapy is still of great importance. Methotrexate, cyclosporine and acitretin are cost-effective and provide excellent disease control. Methotrexate and acitretin are good choice in terms of maintenance therapy, whereas cyclosporin would ideally be used as intermittent therapy. Fear of serious side effects of traditional drugs can be avoided by setting individualized plan for each patient and careful monitoring. PMID- 20857812 TI - [Standardisation of optotypes]. AB - Optotypes are signs of different sizes, systematically placed on the visual acuity chart. The human eye has a spatial resolution of 1' of arc (Snellen). Optotypes in the basic row on all charts subtend 5' of arc and their detail 1' of arc, from the testing distance. The disadvantage of all classical charts is the irregular progresssion of optotype sizes in adjacent rows. This was solved by logMAR (Bailey-Lovie) chart in 1976. The chart was made with optotype sizes in steps with a constant ratio 1:1.2589 (geometric progression). This chart has become the standard for visual acuity testing worldwide. It has been recommended by the following bodies: International Council of Ophthalmology (ICO), 1984 and 2002; World Health Organisation (WHO), 2003; International Organisation for Standardisation (ISO) 1996, and Croatian Standard Institute homologised the ISO standard as nHRN EN ISO 8596:1996. For normative, medical and practical reasons it is advised that all school medicine, occupational health and ophthalmology departments adopt the logMAR charts system. PMID- 20857813 TI - [Hinko Lehner--the first Croatian logoped]. AB - In his career, somewhat longer than 22 years, Lehner was frequently transferred from place to place. Beside working as municipal and county physician he worked also as a spa doctor. Very much interested in the stuttering treatment, his own problem that he had solved during his student period in Vienna, he kept trying to sensitize his fellow-doctors, teachers, but also the Croatian authorities for this problem. He lectured and published on this topic in the professional medical journal, but also in the newspapers. About stuttering he published, at his own expenses, first a booklet (1895) and then a book (1912). Therefore it is justified to consider him a pioneer of logopedy in Croatia albeit, regrettably, forgotten. In order to improve the health situation in Croatia as well as the social status of his profession, he wrote about the health system and the position of doctor in the society. PMID- 20857814 TI - [On (internal) propedeutics /2/]. PMID- 20857815 TI - A direct measurement for LDL-cholesterol increases hypercholesterolemia prevalence: comparison with Friedewald calculation. AB - Direct measurement by homogenous assays has recently been applied to measuring low-density lipoprotein-cholesterol (LDL-C) and has replaced the Friedewald calculation in Japan, but it remains unclear how direct measurement compares with the Friedewald calculation in evaluating hypercholesterolemia. The aim of this study was to determine the effect of the two methods on the diagnosis of hypercholesterolemia. In a total of 1655 workers from our institution (1451 men, 43.6 +/- 10.2 years; 204 women, 38.3 +/- 10.4 years), we investigated the LDL-C levels by the direct and Friedewald methods. In this study, we excluded workers whose triglyceride levels exceeded 400 mg/dl (n=18). Direct LDL-C showed a significantly positive correlation with Friedewald LDL-C (R2 = 0.975, P < 0.0001). On the other hand, the mean direct LDL-C was 5.9 mg/dl higher than the mean Friedewald LDL-C (126.7 +/- 30.6 mg/dl vs. 120.8 +/- 30.5 mg/dl, P < 0.0001), and direct LDL-C was higher in 89.1% of the study population. The frequency of study subjects diagnosed with hypercholesterolemia, defined as LDL-C > or =140 mg/dl, was significantly higher in the direct measurement than in the Friedewald calculation (31.7% vs. 25.1%, P < 0.0001). In conclusion, we demonstrated that the direct measurement showed a higher rate of hypercholesterolemia prevalence than the Friedewald calculation indicated. This result suggests that we have to give careful consideration to the method for measuring LDL-C in the clinical diagnosis and management decisions of hypercholesterolemia. PMID- 20857816 TI - Genetic polymorphisms and oral cancer. AB - Oral cancer, a disease associated with major morbidity and mortality, represents a significant worldwide health problem. It is clear that the major etiological factors for oral cancer are tobacco and alcohol exposure. It has been shown that metabolic activation is associated with cancer susceptibility. Various carcinogens and carcinogenic precursors, such as benzopyrene and nitrosamine, have been identified in tobacco smoke, and those are activated or detoxified by two types of metabolic enzymes, phase I and phase II. There are some polymorphisms for these enzyme genes, the functions of which are modified by the types of polymorphisms. On the other hand, there are some genes besides these enzyme genes related to cancer susceptibility. In this review, we discuss the relationships between polymorphisms concerned with oral cancer. Although there are many reports on the polymorphisms related to oral cancer, the results of these reports are controversial. Further studies are needed to evaluate the interactions between carcinogens and the genetic polymorphisms. PMID- 20857817 TI - [Results of surgical resection for patients with pulmonary cryptococcosis]. AB - Pulmonary cryptococcosis is a fungal infection caused by inhalation of Cryptococcus neoformans. Pulmonary cryptococcal infections tend to occur in immunocompromised individuals, although they can occasionally develop even in immunocompetent hosts. This report presents a retrospective clinical study of 8 patients who underwent a surgical resection for pulmonary cryptococcosis between 1999 and 2008. The age of the patients ranged from 49 to 85 years old (mean 62.6). There were 4 male and 4 female patients. All patients except for 1 had no symptoms. Two patients were immuno-compromised hosts undergoing corticosteroid therapy due to myasthenia gravis and rheumatoid arthritis, respectively. There were 7 patients with a single nodule and 1 patient with multiple nodules. The tumors ranged from 9 to 21 mm in diameter. None of the patients were definitely diagnosed prior to the surgical resection. The surgical procedures included 5 partial resections, 1 segmentectomy and 2 lobectomies. It is often difficult to make a differential diagnosis between lung cancer and pulmonary cyptococosis, because pulmonary cyptococosis shows similar imaging findings in CT. Therefore, a surgical resection is recommended if an observation of the pulmonary nodes is required to make a differential diagnosis of malignant tumors. All of the patients in the current series showed a good outcome without any relapse including cryptococcal meningitis after a surgical resection. PMID- 20857818 TI - [Characteristics of indoor gaseous air pollutants in winter]. AB - There are many gaseous air pollutants found in indoor air. It is very important to precisely measure the concentration of these compounds in order to evaluate the risk to human health and to reduce their concentrations. A diffusive sampling device is suitable for measurement of indoor air, because these are small, light, and can be used without a power supply for the pump. In this study, representative gaseous air pollutants in winter indoor and outdoor air were measured using diffusive sampling devices. Furthermore, the relationship between gaseous air pollutants, secondary formation mechanism, and the outbreak source were examined. The indoor concentrations of aldehydes, nitrogen dioxide and ammonia were higher than outdoor concentrations. By contrast, indoor concentrations of ozone were lower than outdoor concentrations. The indoor concentrations of nitrogen dioxide in 43% houses exceeded the maximum limit stated by environmental law (60 ppb). It was suggested that the main emission sources of nitrogen dioxide are kerosene and gas stoves. In addition, it was suggested that carbonyl compounds are formed by interactions between volatile organic compounds (VOCs) and ozone from outdoor air. Formic acid was estimated to be formed by the oxidation of formaldehyde with ozone, because a positive correlation between formaldehyde and formic acid, and an inverse correlation between formaldehyde and ozone, were observed in indoor air. PMID- 20857819 TI - [Experience in treating patients with malignant pleural mesothelioma]. AB - The objective of this study was to analyze the outcome of patients with malignant pleural mesothelioma who were treated from 1993 to 2009. We analyzed a total of 28 patients with malignant pleural mesothelioma. All the patients were males, except for two females and the mean age was 64.5 years old. Twelve and 16 of the patients underwent an extrapleural pneumonectomy and a pleural biopsy, respectively. The histological types included 14 epithelial type, 8 biphasic type, and 6 sarcomatoid type. Three patients were classified as stage I, 8 as stage II, 9 as stage III, and 8 as stage IV. Fourteen and eight of the patients underwent systemic chemotherapy and radiotherapy, respectively. The 2-year survival rate of all the patients was 25.7%, and the 2-year survival of the patients with at least one more modalities of the treatments with chemotherapy, radiotherapy and extrapleural pneumonectomy were much higher than those without. We should therefore consider selecting a multimodality treatment for such patients because the administration of either systemic chemotherapy or radiotherapy was found to be associated with a favorable prognosis. PMID- 20857820 TI - [Current state of research on occupational stress of psychiatric nurses and insight into its future]. AB - In this report, we surveyed the occupational stress of psychiatric department nurses who said that the burnout rate was high and the turnover rate of nurses who quit shortly after being hired. Insight into the future of such research is described. In previous research, the occupational stress of psychiatric department nurses varied by each ward function, such as the wards of psychiatric department acute period, the psychiatric department recuperation period and the psychiatric department geriatric period, in which much research concerning the stress of psychiatric department nurses has been reported. However, at present, many of the questionnaire investigations used to measure and evaluate the occupational stress of psychiatric department nurses have not used a standard set up based on knowledge concerning the occupational stress of psychiatric department nurses. Hereafter, in research on the stress of psychiatric department nurses, standards with enough reliability and validity to measure and evaluate the occupational stress of psychiatric department nurses are still being searched for. Also, the development of mental health care in the psychiatric department ward according to these standards is expected. PMID- 20857821 TI - [An autopsy case of microscopic polyangiitis associated with bacterial endocarditis]. AB - The patient was an 87-year-old man whose initial symptom was general fatigue and inappetence. His laboratory data revealed a rise in C-reactive protein (CRP) and white blood cell count (WBC), and CT scan showed suspicious pneumonia. Antibiotics were given to the patient, but his fever and laboratory data were sustained. Follow up examination revealed a high titer (107 U/ml) of myeloperoxidase specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA). He was diagnosed with MPO-ANCA associated vasculitis. Steroid pulse therapy was started. The patient's clinical symptoms and laboratory data thereafter significantly improved, but after one week the patient's symptom was aggravated and he died. An autopsy was performed, and necrotizing arteritis of the interlobular arteries were found in the kidneys. We found bacterial infective vegetation attached to the aortic valve. Infected thromboembolus and microabscesses were also found in many organs. We report a case of subacute microscopic polyangiitis associated with bacterial endocarditis. PMID- 20857823 TI - Nasty people. Some folks just don't play nice. PMID- 20857822 TI - [Effect of the occupational health practical training course offered by the Occupational Health Training Center]. AB - The Occupational Health Training Center offers the Occupational Health Practical Training Course (PTC) as a part of the postgraduate education of the University of Occupational and Environmental Health (UOEH). In this study, we evaluated the effect of the PTC on its trainees by signed questionnaires handed out before and after the course. Three PTCs are offered annually, and the curriculum consists of 4 divisions: General Health Management, Health Care and Promotion, Work Conditions and Ergonomics, and Work Environment Control. There was an significant affirmative difference in "General interest in Occupational Health Practice (OHP)" between before and after the PTC, but not in "Interest in OHP related to one's clinical specialty". This result implies that, in some clinical fields, it may be difficult to realize a common subject with OHP. We confirmed the presence of significant affirmative differences between before and after the PTC on all questions categorized in both "Acquisition of Knowledge and Skill Related to OHP" and "Awareness of Occupational Physicians' Mission". The results suggested that the PTC had a positive effect on the subjects. PMID- 20857824 TI - Down in the mouth. Sipping a soda has unintended consequences for an unwary picnicker. PMID- 20857825 TI - Build a safety net. It's prudent, professional and practical. PMID- 20857826 TI - Some estrogen with that? The protective and therapeutic effects of female sex hormones. Interview by John Erich. PMID- 20857827 TI - Part 8: Commitment to excellence. PMID- 20857828 TI - An economic education. It is possible to develop educational in-service programs that are comprehensive, cost-effective and high quality. PMID- 20857829 TI - Policy development. Developing well-researched, legally sound policies with true applicability to your EMS agency is paramount. PMID- 20857830 TI - Jumpsuits & pinstripes. Providing care for the incarcerated patient can be challenging from both a logistical and medical perspective. PMID- 20857831 TI - Hospice and DNR care. What EMS providers need to know about do-not-resuscitate orders. PMID- 20857832 TI - Quality improvement part 2: Concurrent review. EMS agencies must embrace continuous quality improvement as part of their daily operations. PMID- 20857833 TI - Past imperfect. Over time, we find some of our interventions may not be all we hoped. PMID- 20857834 TI - Obesity and insulin resistance: adding pieces to the puzzle. PMID- 20857835 TI - Effect of HMB supplementation on body composition, fitness, hormonal profile and muscle damage indices. AB - There is a huge market for ergogenic supplements for athletes. However, only a few products have been proven to have ergogenic effects and to be effective at improving muscle strength and body composition. One such supplement is beta hydroxy beta-methylbutyrate (HMB). Derived from the amino acid leucine and its keto acid alpha-ketoisocaproate (KIC), HMB has been well documented as an oral ergogenic supplement commonly used by athletes. Several studies have shown that combining exercise training with HMB supplementation leads to increased muscle mass and strength, and there is some anecdotal evidence of aerobic improvement. However, HMB supplementation has been found to be effective mainly for untrained individuals. While previous reviews have emphasized three main pathways for HMB's mode of action: 1) enhancement of sarcolemmal integrity via cytosolic cholesterol, 2) inhibition of protein degradation via proteasomes, and 3) increased protein synthesis via the mTOR pathway, more recent studies have suggested additional possible mechanisms for its physiological effects. These include decreased cell apoptosis and enhanced cell survival, increased proliferation, differentiation and fusion via the MAPK/ERK and PI3K/Akt pathways, and enhanced IGF-I transcription. These are described here, and hormonal interactions are discussed, along with HMB dosage and safety issues. PMID- 20857836 TI - Intrauterine treatment of an infant with fetal goitre. PMID- 20857837 TI - The involvement of insulin receptor genotypes in pre- and co-obese acanthosis Nigricans children and adolescent. AB - Acanthosis nigricans (AN) is most commonly related to obesity as a manifestation of cutaneous insulin resistance in children and adolescents, while the interaction and time course between AN and obesity and detailed mechanism for the pre- and co-obese appearance of AN (PCOAN) in child are unclear. In this study, the involvement of insulin receptor in child PCOAN was investigated via studying the association of polymorphisms of INSR gene with PCOAN. In total, 99 children with PCOAN and 100 healthy controls recruited were genotyped and analyzed by PCR RFLP method. Significantly different distributions were found in the frequency of the INSR His1085His genotypes, but not in other INSR genotypes, between the two groups. Our results provide not only the evidence that the T allele of INSR His1085His is correlated with the appearance of PCOAN but revealed that the insulin receptor pathway may play an important role in this PCOAN. PMID- 20857839 TI - Late effects of childhood ALL treatment on body mass index and serum leptin levels. AB - BACKGROUND: It is well known that survivors of acute lymphoblastic leukemia (ALL) show a tendency to become overweight. Cranial irradiation (CRT), is considered to be the primary risk factor for development of obesity. AIMS: The aim of our study was to evaluate body mass index (BMI) and serum leptin levels in survivors of childhood ALL. METHODS: Subjects (Group I) consisted of 93 survivors of childhood ALL (53 males > or = 9 years old, 40 females > or = 8 years old) diagnosed between January 1975 and December 2002 in the Hematology-Oncology Division in Cerrahpasa Medical Faculty, Istanbul University after a follow up 10.21 +/- 4.90 (mean +/- SD) years. Fifty healthy individuals of similar chronological age were taken as controls (29 males, 21 females). Seventy-four subjects had received radiotherapy (Group IA) and 19 had not (Group I B). RESULTS: In Group I, BMI was significantly higher than in Group II (21.65 +/- 4.02 vs 20.31 +/- 3.49, p = 0.04). However, BMI was significantly higher only in Group I A (21.83 +/- 4.27) than in Group II (p = 0.032). Leptin levels were significantly higher in Group I A females than in Group II females. There was a significant correlation between BMI-SDS and serum leptin levels in group IA females. CONCLUSIONS: Leukemia treatment leads to obesity. Higher leptin levels in girls may suggest that sex may be a differentiating factor for this late effect. PMID- 20857838 TI - Arterial stiffness, lipoprotein particle size, and lipoprotein particle concentration in children with type 1 diabetes. AB - OBJECTIVE: To determine if lipoprotein particle abnormalities correlate with arterial stiffness in children with type 1 diabetes (T1D). STUDY DESIGN: In this case-control study, we evaluated 70 children, 35 with T1D and 35 controls, ages 10-18 years, matched for age, sex, race, and BMI. Arterial stiffness was assessed by radial tonometry (AI75) and blood was collected for lipoprotein subclass analysis. RESULTS: T1D subjects had increased AI75, decreased small LDL particle concentration (P = 0.0067), increased large LDL particle concentration (P = 0.007), increased large HDL particle concentration (P = 0.0012), increased mean LDL particle size (P = 0.0028), and increased mean HDL particle size (P < 0.0001) compared to controls. No significant correlations were found between lipoprotein subclasses and arterial stiffness in T1D subjects. CONCLUSIONS: T1D subjects have increased arterial stiffness when compared to controls, despite a less pro atherogenic lipoprotein profile, indicating the need to identify other risk factors that correlate with arterial stiffness in T1D youth. PMID- 20857840 TI - The clinical characteristics of vitamin D deficiency in childhood: a systematic literature review of Japanese patients. AB - To describe the characteristics of children with vitamin D deficiency, we reviewed the reports of vitamin D deficiency among Japanese children that were published between 1989 and 2008. We identified 25 patients with vitamin D deficiency in 9 published studies and evaluated their clinical characteristics together with those of 3 patients we recently treated. The patients were distributed in two distinct age groups at diagnosis: < 1 year old and > or = 1 year old. The main symptom of the < 1 year old age group was hypocalcemic convulsions and that of the > or = 1 year old age group was bowed legs. Serum calcium, intact PTH, and 1,25(OH)2D levels were significantly lower in the < 1 year age group than in the > or = 1 year age group. It would be useful to find and make early interventions in cases of children at a high-risk of vitamin D deficiency. PMID- 20857841 TI - The rising incidence of type 1 diabetes mellitus and the role of environmental factors--three decade experience in a primary care health center in Saudi Arabia. AB - BACKGROUND: The incidence of type 1 diabetes has been increasing all over the world including Saudi Arabia and environmental factors have been suggested to play an important role in its etiology. OBJECTIVE: The aim of this study was to evaluate if there are any contributory roles of various environmental factors in the rising incidence of type 1 diabetes in children in the Eastern Province of Saudi Arabia. METHODS: We conducted a retrospective study of Saudi Arab subjects (n = 119) diagnosed between 1980 and 2009 with type 1 diabetes and these subjects were classified to six groups on the basis of the onset of diabetes. RESULTS: 119 subjects (61 boys and 58 girls) with confirmed diagnosis of type 1 diabetes met the study eligibility criteria. 89 children (74%) presented with ketoacidosis. The mean age of onset was 4 3/4 years for Group II and age of onset increased to above 8 years on subsequent years. Excessive weight gain was noted in all study groups. No etiological influences of maternal age at birth, birth order, birth weight, early introduction of cow's milk and cereals, infections and vaccines as well as nitrate levels in drinking water were noted in any of the groups. The predicted doubling of diabetes in young children below 5 years as in previous studies was not found in our study. CONCLUSIONS: The rising incidence of type 1 diabetes over the last 30 years is not proved to have been influenced by various environmental factors. PMID- 20857843 TI - Down-regulation of Kir6.2 affects calcium influx and insulin secretion in HIT-T15 cells. AB - In pancreatic beta cells, ATP-sensitive potassium (K(ATP)) channels are metabolic sensors that couple cell metabolism to electrical activity, and therefore K(ATP) channels regulate insulin secretion. We assume that down-regulating the expression of Kir6.2 subunits of K(ATP) channels may change calcium influx induced by glucose and insulin secretion regulated by K(ATP) channels. In our study, we employ Kir6.2-shRNA plasmid to downregulate Kir6.2 expression in HIT T15 cells. Then, we research the effect of downregulation of Kir6.2 on K(ATP) current, cytoplasmic free Ca2+ concentration and insulin secretion. All results illustrate that downregulation of Kir6.2 subunits of K(ATP) channels in HIT-T15 cells affects K(ATP) current and insulin secretion, and fails to promote calcium influx. The results demonstrate the function of Kir6.2 subunits in electrophysiology characteristic, insulin secretion and calcium influx, and RNA interference provides a feasible alternative to study the function of Kir6.2 subunits in K(ATP) channels in different kinds of diabetes. PMID- 20857842 TI - Decreased bone turnover in children and adolescents with well controlled type 1 diabetes. AB - AIM: Osteoporosis is a common long-term complication of type 1 diabetes (T1DM). We aimed to determine whether bone mineral density (BMD) and turnover are already altered during childhood. PATIENTS AND METHODS: We recruited 27 T1DM children and 32 controls (age 10.5 +/- 2.5 yr.) and measured BMD (dual-energy x-ray absorptiometry); bone biomarkers levels (osteocalcin: OC; procollagen type 1 propeptides amino-terminal: PINP; crosslinking telopeptides of type 1 collagen C terminal: CTX), glycated hemoglobin (HbA1c), dietary intake and physical activity. RESULTS: Patients with T1DM had lower levels of OC (70.3 +/- 3.3 vs 105.3 +/- 6.8), PINP (556.4 +/- 47.6 vs 716.3 +/- 53.8), CTX(0.97 +/- 0.07 vs 1.20 +/- 0.08), physical activity, and calcium intake. Biomarkers were negatively correlated with HbA1c. Though, BMD was similar among groups and not related to HbA1c, disease duration, physical activity or dietary intakes. CONCLUSIONS: Bone turnover is altered in T1DM children, whereas BMD remains normal during growth. Physical activity and optimal calcium intakes may improve bone metabolism and delay osteoporosis. PMID- 20857844 TI - Anemia and neutropenic fever with high dose diazoxide treatment in a case with hyperinsulinism due to Munchausen by proxy. AB - BACKGROUND: The etiology of hyperinsulinemic hypoglycemia in adolescents is similar to that of adults. Patients resistant to medical treatment may undergo pancreatectomy. Diazoxide is the mainstay of medical treatment. Rarely bone marrow suppression is reported due to diazoxide. PATIENT: An adolescent with severe hyperinsulinemic hypoglycemia was referred for pancreatectomy after she was treated with high doses of diazoxide, octreotide and glucose. She developed anemia and febrile neutropenia in the course of diazoxide treatment that resolved with cessation of medication. The cause of the hyperinsulinemia proved to be classical Munchausen by proxy. CONCLUSION: This is the first report of bone marrow suppression involving erythroid series by diazoxide. Follow-up of blood count may be considered in patients on high dosages since anemia may be dose dependent. Munchausen by proxy poses a serious threat to children with significant morbidity and mortality. Awareness and a high index of suspicion in clinical settings with unusual causes are the mainstay for the diagnosis. PMID- 20857845 TI - Six year old with autoimmune polyglandular syndrome: can genetics tell us the story? AB - Children who have diabetes mellitus type 1 (DMT1) are at increased risk of developing other autoimmune diseases. These associated diseases include Hashimoto's thyroiditis, Graves' disease, Celiac disease, and Addison's disease. Since Addison's disease is potentially fatal if undiagnosed and untreated, it would be prudent to effectively screen individuals to determine if they are at risk of developing this disease. We present a case of a 6 year old male with a history of DMT1, who presented in adrenal crisis and was subsequently diagnosed with Addison's disease. HLA-DRB1 404/DR4 is one of the genes involved in the development of Addison's disease in children with DMT1. Our patient later tested positive for this haplotype. Genetic testing is not routinely done in patients with (DMT1) to determine if they will potentially develop other associated conditions. We propose using genetic testing of associated HLA haplotypes to screen children with DMT1 for Addison's disease. PMID- 20857846 TI - Testicular adrenal rest tumor in a patient with 11beta-hydroxylase deficient congenital adrenal hyperplasia. AB - In patients with congenital adrenal hyperplasia, testicular adrenal hyperplasia and tumors can develop. A three-year-old boy was admitted to our hospital with complaints of enlarged penis and development of pubic hair. 11beta-hydroxylase deficient congenital adrenal hyperplasia was diagnosed and hydrocortisone treatment was started. His family did not accept treatment well and did not come for check-ups regularly, which is why his metabolic control was poor. In ultrasonographic evaluation, a hypoechoic mass, 10x10 mm in size, was detected in his left testis at 15 years of age and steroid dose was increased. Almost two years later the tumor completely disappeared with high dose steroid treatment. In conclusion, the monitoring of congenital adrenal hyperplasia with ultrasonography is recommended, especially in puberty, because it is important that testicular adrenal rest hyperplasia should be determined before testicular adrenal rest tumors develop. In this case we observed that small testicular adrenal rest tumors disappeared completely with high dose steroid treatment in nearly two years. PMID- 20857847 TI - Two unrelated Chinese patients with hyperinsulinism /hyperammonemia (HI/HA) syndrome due to mutations in glutamate dehydrogenase gene. AB - BACKGROUND: Hyperinsulinism/ hyperammonemia (HI/HA) syndrome is caused by excessive activity of glutamate dehydrogenase (GDH) encoded by GLUD1 gene, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver. So GDH is important in normal glucose homeostasis. Mutations of GDH result in HI/ HA syndrome. METHODS: We have performed protein (leucine) and fat loading test on one patient. We detected the level of serum glucose, insulin and blood ammonia. Genomic DNA of the two patients and their parents is isolated from blood and the exons of GLUD1 gene are amplified by polymerase chain reaction (PCR) for direct sequencing. RESULTS: The leucine diet can evocate hypoglycemia obviously. Two heterozygous mutations c.978G>A (R269H) and c.1506C>T (S445L) are identified, respectively. These are both de novo. For one patient, a better blood glucose level can be gained from leucine-restriction diet, and without diazoxide while, for the other patient, diazoxide is necessary. CONCLUSIONS: The heterozygous mutations in GLUD1 gene can cause HI/HA syndrome, it is sensitive to the leucine. The diazoxide and leucine-restriction diet do well in controlling the blood glucose level. PMID- 20857848 TI - The "intraendothelial canalicular formation": the route for lymphocyte diapedesis at the level of peripheral and mucosa-associated lymphoid tissue HEVs. AB - How the lymphocyte crosses the blood endothelium during transendothelial migration is demonstrated through the study of serial sections of high endothelial venules (HEVs) of peripheral (mesenteric lymph nodes) and mucosa associated lymphoid tissue (Peyer's patches, vermiform appendix) during normal lymphocyte homing and experimental intestinal inflammation. The sequence of serial ultrastructural features of lymphocytes englobed in the endothelial wall at different moments of transmigration made it possible to bring out that their transendothelial migration toward the extracellular matrix of lymphoid tissues occurs through an intraendothelial canalicular formation constituted by two adjacent endothelial cells that have closed interendothelial junctions. This intraendothelial canalicular formation, morphologically unlike the transcellular and paracellular migratory pathways, is an innovative model of migratory route for lymphocyte diapedesis that does not compromise the continuity of the endothelial wall. The increased presence of lymphocytes and intraendothelial canalicular formations during experimental inflammation and the metabolic hyperactivity of the spring/summer months compared to the lethargic fast in Chiropters underscores an influence on lymphocyte traffic through the HEVs of the peripheral and mucosa-associated lymphoid tissue. PMID- 20857849 TI - The ideation of movement is supported by fronto-temporal cortical regions involved in the retrieval of semantic knowledge. AB - BACKGROUND AND AIM OF THE WORK: The neurofunctional correlates of movement ideation, which should be distinguished from motor imagery, have not been fully investigated. This functional Magnetic Resonance Imaging (fMRI) experiment revealed the brain activation patterns associated with different motor processes, including ideation. METHODS: Fifteen healthy participants underwent fMRI and performed three tasks using the right index finger: 1. execution of a simple prespecified movement; 2. execution of a simple voluntary movement; 3. ideation of a simple voluntary movement without execution. A number of t-test comparisons across conditions were carried out. RESULTS: The execution ofa simple prespecified finger movement activated the right inferior parietal cortex and substantia nigra, the left middle frontal gyrus, and thalamus, and bilaterally the post-central gyri, the superior parietal lobule and the cerebellum. Execution of a simple voluntary movement activated the left anterior cingulate cortex. The ideation of a voluntary simple movement activated the left inferior, middle and superior temporal gyri and the inferior frontal gyri bilaterally. CONCLUSIONS: The execution of a prespecified action involves structures within the somatosensory cortex, such as the post-central gyrus. The execution of a voluntary action is achieved with the support of the anterior cingulate cortex, a structure active when resolution of conflict is required. The ideation of a voluntary action requires the contribution of associative areas of the left frontal and temporal lobes, which support the retrieval of semantic knowledge necessary in the planning of a voluntary act. PMID- 20857850 TI - Defense mechanisms and symptom severity in panic disorder. AB - BACKGROUND AND AIM OF THE WORK: Whether the use of maladaptive defense style is a trait or a state phenomenon in panic disorder (PD) is still an open question. The aim of the study was to verify whether PD patients used a different defense style than healthy subjects, after controlling for the effect of symptoms severity. METHODS: Therefore, 61 PD patients and 64 healthy controls participated in the study. All subjects were evaluated with SCID-IV, SCL-90, Ham-A, Ham-D and the Defence Style Questionnaire-40 items (DSQ-40). RESULTS: PD patients showed higher Ham-A, Ham-D and SCL-90 scores than controls and they used more neurotic and immature defences. The differences in defense style disappeared after controlling for the effect of symptom severity, whereas the differences in symptom severity persisted after controlling for the effect of defense style. CONCLUSIONS: This finding suggests that the use of less mature defenses in PD was explained by the severity of anxious symptoms, whereas the contrary was not true. Therefore, the use of less mature defense style might be supposed to be a state phenomenon in PD. PMID- 20857851 TI - Type 1 diabetes (T1DM) in children and adolescents of immigrated families in Emilia-Romagna (Italy). AB - BACKGROUND AND AIM OF THE WORK: The etiology and natural history of T1DM are still unknown but certainly both genetics and environmental factors contribute to the development of the disease. Migration studies are an important tool to better understand the role of the environment. The aim of this study was to investigate some variables in diabetic children of immigrant families living in Emilia Romagna compared with Italian diabetic children living in the same region. METHODS: We recruited 73 diabetic children from immigrant families and 707 Italian diabetic children. All children were cared by Pediatric Diabetes Units of Emilia-Romagna (10 centers). The investigated variables were: gender, current age, place of birth, parents' country of origin, age at diagnosis, HbA1c and insulin regimen. RESULTS: No significant difference with reference to gender neither among the two ethnic groups, nor in the current mean age was observed. Mean age at diagnosis in the Italian children was lower than in immigrant patients born outside Italy--group A- (7.4 vs. 9.6, p < 0.000) and higher compared to those born in Italy--group B- (7.4 vs. 5.7 p < 0.003; A vs. B p < 0.000). The immigrant patients showed higher mean HbA1c than Italian patients (8.8 vs. 8.2, p < 0.009). CONCLUSIONS: A younger age at diagnosis of T1DM in immigrant children, born in Italy compared with those born in the country of origin, and with Italian patients, suggests the existence of some environmental determinants acquired with a more westernised lifestyle. Immigrant children have significantly poorer metabolic control compared with western patients. (www.actabiomedica.it) PMID- 20857852 TI - Detection of enteroviruses from urban sewage in Parma. AB - BACKGROUND AND AIM OF THE WORK: The human enteroviruses (EV) are the most common and widespread human viruses in the world. They have bowel as their natural habitat and they can spread in the environment through the faecal excretion. In the continental climate Regions these viruses may cause epidemic outbreaks in summer and fall, while in the tropical Regions the EV infections present a high incidence during all year. The symptoms can be minor or subclinic, but they can be also associated to rare and serious diseases. The aim of this study was to evaluate the environmental circulation of polioviruses and non-polio enteroviruses (NPEV) using standard methods of urban wastewater surveillance recommended by the WHO. METHODS: A total of 188 wastewater samples were collected between February 2005 and December 2008 from two sewage treatment plants in Parma. The sampling was carried out twice a month. Environmental variables were collected for each day of sampling. RESULTS: Out of the 188 examined wastewater samples, 78.7% were positive to the enterovirus research. One out of the 148 positive samples was identified as poliovirus Sabin-like type 3. The remaining 147 positive samples were enteroviruses non polio: Coxsakieviruses and Echoviruses. All Coxsakieviruses isolated were of type B. CONCLUSIONS: The proposed method has shown high sensibility, also in presence of very low expected prevalence of vaccine poliovirus. It allows to verify the kind and relative frequency of enteric viruses circulating in the country, whose characteristics (virulence and pathogenicity) may vary with reference to a different epidemiologic and demographic structure of the resident population. PMID- 20857853 TI - Training program for community health workers in remote areas in Senegal. First experience. AB - BACKGROUND: In some countries, community health workers (CHWs) act as a bridge between the health care delivery system and the community, and ensure primary health care. It is essential to improve health worker education and training; however, in remote areas such as rural Senegal villages, these CHWs are often unable to leave their home community for training and education. We set out to perform a training program in a village in Senegal and to evaluate its effectiveness in that village. METHODS: We prepared a training program to be based on face-to-face lessons and practical exercises; a nurse from the university of Parma carried out the training of the CHW in loco for a period of four weeks. After six months, the nurse with an anthropologist returned to the village to verify the results of the training program. RESULTS: The CHW had retained most of what she had been taught, but her opinion about the training program was not altogether positive, given that the absence of a working health centre in the village and an insufficient period of practical experience in a hospital. The village community did not understand the role of the CHW and was not informed that there was a training program to help increase her technical know-how. CONCLUSIONS: This experience confirmed the important role of the CHW in rural areas in a poor region in Senegal, in the absence of other professional healthcare figures readily accessible to the population. Nonetheless, in order to properly carry out the role of CHWs, an adequate theoretical and practical training is necessary. PMID- 20857854 TI - Life-threatening asthma after heroin inhalation. A case report and a review of the literature. AB - Heroin addiction may increase the risk of pulmonary involvement. We describe the case of a 23 year-old woman who was admitted to our unit for severe asthma attack non responsive to beta-2-agonists and acute respiratory failure, soon after heroin inhalation. The patient was successfully treated with non invasive positive pressure ventilation. Opiate inhalation can be an asthma trigger and should be considered in the care of patients with poorly controlled asthma and life-threatening asthmatic attacks. PMID- 20857855 TI - Dermatomyositis as first clinical appearance for a thymic epidermoid cell carcinoma. AB - Primary thymic carcinoma is a rare and heterogeneous group of tumours of the anterior mediastinum that includes different histological types. Frequently, it first comes to clinical attention through paraneoplastic syndromes such as dermatomyositis. We report the case of a 54-year-old woman with several episodes of fever and chest pain in the previous 5 months. The patient was admitted to the Rheumatology Department with a peri-ungual erythema and papular lesions on both sides of each hand and alteration at biochemistry tests. A left deltoid muscle biopsy specimen showed a histological pattern compatible with the diagnosis of dermatomyositis. A computed tomography of the chest, abdomen and pelvis, showed a solid mass in the upper anterior mediastinal area and a mediastinoscopy with mass biopsy was performed. Only the immunohistochemical staining technique allowed a definitive histological diagnosis. We report the diagnostic challenge and the therapeutic approach of thymic neoplasia. PMID- 20857856 TI - Sleep homeostasis: finding Odysseus among the mnesteres. PMID- 20857857 TI - Metabolic disease in sleep disordered breathing: puberty! puberty! PMID- 20857858 TI - Short sleep duration promoting overconsumption of food: A reward-driven eating behavior? PMID- 20857859 TI - Short sleep duration in prevalent and persistent psychological distress in young adults: the DRIVE study. AB - OBJECTIVES: Young people are sleeping less. Short sleep duration has a range of negative consequences including a hypothesized link with psychological distress, which has yet to be studied DESIGN: Prospective cohort study SETTING: Community based sample from Australia PARTICIPANTS: Twenty thousand (20,822) young adults (aged 17-24) identified through the state vehicle licensing authority. A random sample (n = 5000) was approached for follow-up 12-18 months later, with 2837 providing full data. MAIN OUTCOME MEASURE: Psychological distress, determined by a Kessler 10 score > 21, at baseline; and as both onset and persistence of distress at follow-up. RESULTS: Shorter sleep duration was linearly associated with prevalent psychological distress: relative risk (RR) 1.14 (95% CI 1.12 to 1.15). Only the very short (< 5 h) sleepers among those not distressed at baseline had an increased risk for onset of psychological distress (RR 3.25 [95% CI 1.84, 5.75]). Of 945 cohort participants reporting psychological distress at baseline, 419 (44%) were distressed at follow-up. Each hour less of sleep increased the risk of psychological distress persisting after adjustment for potential confounding variables: RR 1.05 (95% CI 1.01 to 1.10). Long sleep duration showed no association with distress at any time point. CONCLUSIONS: Self reported shorter sleep duration is linearly associated with prevalent and persistent psychological distress in young adults. In contrast, only the very short sleepers had a raised risk of new onset of distress. Different approaches to sleep duration measurement yield different results and should guide any interventions to improve subjective sleep duration in young adults. PMID- 20857860 TI - Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis. AB - STUDY OBJECTIVES: The sleep-deprivation-induced changes in delta power, an electroencephalographical correlate of sleep need, and brain transcriptome profiles have importantly contributed to current hypotheses on sleep function. Because sleep deprivation also induces stress, we here determined the contribution of the corticosterone component of the stress response to the electrophysiological and molecular markers of sleep need in mice. DESIGN: N/A SETTINGS: Mouse sleep facility. PARTICIPANTS: C57BL/6J, AKR/J, DBA/2J mice. INTERVENTIONS: Sleep deprivation, adrenalectomy (ADX). MEASUREMENTS AND RESULTS: Sleep deprivation elevated corticosterone levels in 3 inbred strains, but this increase was larger in DBA/2J mice; i.e., the strain for which the rebound in delta power after sleep deprivation failed to reach significance. Elimination of the sleep-deprivation-associated corticosterone surge through ADX in DBA/2J mice did not, however, rescue the delta power rebound but did greatly reduce the number of transcripts affected by sleep deprivation. Genes no longer affected by sleep deprivation cover pathways previously implicated in sleep homeostasis, such as lipid, cholesterol (e.g., Ldlr, Hmgcs1, Dhcr7, -24, Fkbp5), energy and carbohydrate metabolism (e.g., Eno3, G6pc3, Mpdu1, Ugdh, Man1b1), protein biosynthesis (e.g., Sgk1, Alad, Fads3, Eif2c2, -3, Mat2a), and some circadian genes (Per1, -3), whereas others, such as Homer1a, remained unchanged. Moreover, several microRNAs were affected both by sleep deprivation and ADX. CONCLUSIONS: Our findings indicate that corticosterone contributes to the sleep-deprivation induced changes in brain transcriptome that have been attributed to wakefulness per se. The study identified 78 transcripts that respond to sleep loss independent of corticosterone and time of day, among which genes involved in neuroprotection prominently feature, pointing to a molecular pathway directly relevant for sleep function. PMID- 20857861 TI - Insomnia with short sleep duration and mortality: the Penn State cohort. AB - STUDY OBJECTIVES: Because insomnia with objective short sleep duration is associated with increased morbidity, we examined the effects of this insomnia subtype on all-cause mortality. DESIGN: Longitudinal. SETTING: Sleep laboratory. PARTICIPANTS: 1,741 men and women randomly selected from Central Pennsylvania. MEASUREMENTS: Participants were studied in the sleep laboratory and were followed up for 14 years (men) and 10 years (women). "Insomnia" was defined by a complaint of insomnia with duration > or = 1 year. "Normal sleeping" was defined as absence of insomnia. Polysomnographic sleep duration was classified into two categories: the "normal sleep duration group" subjects who slept > or = 6 h and the "short sleep duration group" subjects who slept < 6 h. We adjusted for age, race, education, body mass index, smoking, alcohol, depression, sleep disordered breathing, and sampling weight. RESULTS: The mortality rate was 21% for men and 5% for women. In men, mortality risk was significantly increased in insomniacs who slept less than 6 hours compared to the "normal sleep duration, no insomnia" group, (OR = 4.00, CI 1.14-13.99) after adjusting for diabetes, hypertension, and other confounders. Furthermore, there was a marginally significant trend (P = 0.15) towards higher mortality risk from insomnia and short sleep in patients with diabetes or hypertension (OR = 7.17, 95% CI 1.41-36.62) than in those without these comorbid conditions (OR = 1.45, 95% CI 0.13-16.14). In women, mortality was not associated with insomnia and short sleep duration. CONCLUSIONS: Insomnia with objective short sleep duration in men is associated with increased mortality, a risk that has been underestimated. PMID- 20857862 TI - Determining sleep quality in children with sleep disordered breathing: EEG spectral analysis compared with conventional polysomnography. AB - STUDY OBJECTIVES: To identify the extent of sleep disruption in children with various severities of sleep disordered breathing (SDB) using both conventional visually scored assessment of sleep stages and arousal indices together with EEG power spectral analysis. DESIGN: Sleep stages and power spectral analysis of the sleep EEG in children with varying severities of SDB with matched control subjects with no history of snoring were compared across the whole night, across sequential hours from sleep onset, and across sleep stages. MEASUREMENTS: Overnight polysomnography was performed on 90 children (49M/41F) aged 7-12 y with SDB and 30 age-matched healthy controls (13M/17F). Sleep stages were visually scored and the EEG spectra were analyzed in 5-s epochs. RESULTS: Conventional visual scoring indicated that, although sleep duration was reduced in severely affected children, sleep quality during the essential stages of SWS and REM was preserved, as evidenced by the lack of any significant decrease in their duration in SDB severity groups. This finding was supported by the lack of substantial differences in EEG spectral power between the groups over the whole night, within specific hours, and in individual sleep stages. CONCLUSIONS: Both conventional scoring and EEG spectral analysis indicated only minor disruptions to sleep quality in children with SDB when assessed across the night, in any specific hour of the night, or in any specific sleep stage. These results suggest that reduced daytime functioning previously reported in children with SDB may not be due to sleep disruption. We speculate that in children, in contrast to adults, a stronger sleep drive may preserve sleep quality even in severe SDB. PMID- 20857863 TI - The relative impact of obstructive sleep apnea and hypertension on the structural and functional changes of the thoracic aorta. AB - BACKGROUND: Recent studies suggest that obstructive sleep apnea (OSA) causes thoracic aortic dilatation; but it is well accepted that hypertension can cause aortic dilatation, and hypertension is a common finding in patients with OSA. We aimed to investigate the relative impact of OSA and hypertension on the structural and functional changes of the thoracic aorta. METHODS: This was an echocardiography substudy of our prospective OSA study in patients with acute myocardial infarction (AMI). Ninety-four male patients who completed both echocardiography and polysomnography were recruited. OSA was defined as an apnea hypopnea index (AHI) > or = 15/hour. RESULTS: The patients' mean age was 53 +/- 10 years, and mean body mass index (BMI) was 24.6 +/- 3 kg/m2. Sixty-four (68.1%) patients had OSA; of these, 39 (41.5%) had severe OSA. Thirty-three (52.6%) of the OSA cohort had hypertension. There was no correlation between any of the echocardiographic parameters and thoracic aortic size. Stepwise multivariate regression showed that BMI (P = 0.024), older age (P = 0.044), and hypertension (P = 0.025) were the only determinants. There was no significant independent relationship between OSA/AHI and thoracic aortic size. Systolic blood pressure but notAHI correlated significantly with aortic distensibility and compliance (r = -0.40 and -0.26, P < 0.001 and 0.022, respectively). CONCLUSIONS: Hypertension is a common finding in male AMI patients with OSA. In these patients, increased afterload from systemic hypertension rather than mechanical stress on the aortic wall determines the thoracic aortic size and abnormalities in aortic functional indices. BMI and age were also independent predictors of thoracic aortic dilatation. PMID- 20857864 TI - Obstructive sleep apnea and aging effects on macrovascular and microcirculatory function. AB - STUDY OBJECTIVES: Many patients with obstructive sleep apnea (OSA) are obese, and whether obesity itself explains the increased prevalence of cardiovascular disease in OSA is unknown. We hypothesize that OSA, independent of obesity, contributes to abnormal vascular function. DESIGN: Physiology study. SETTING: Academic medical centers. PATIENTS: Obese subjects, free of known comorbidities, were enrolled. MEASUREMENTS AND RESULTS: Vascular function was assessed with brachial artery ultrasound for flow-mediated dilation (FMD) and in skin microcirculation by laser Doppler flowmetry. Arterial stiffness was measured by arterial tonometry. Seventy-two subjects (43/72 women, 38/72 with OSA) were studied. FMD was impaired in patients with OSA, compared with control subjects (5.7% +/- 3.8% vs 8.3% +/- 4.1%, P = 0.005). In step-forward regression analysis inclusive of age, sex, and body mass index, age (P = 0.013) was a significant independent predictor of FMD. In a subgroup of subjects younger than 50 years of age (n = 59), however, OSA was the only independent predictor of FMD (P = 0.04), adjusted for known covariates. OSA did not significantly influence vascular function in the skin microcirculation. The augmentation index, a measure of arterial stiffness, was similar between the OSA and control groups (16.2% +/- 11.4% vs 20.4% +/- 10.1%, respectively, P = 0.10). In step-forward regression analysis of younger men (< or = 50 years old, 23 subjects), OSA independently predicted the augmentation index in men only (P = 0.001). CONCLUSIONS: In obesity, both OSA and aging impair endothelial function and increase arterial stiffness. The influence of OSA on vascular function is most pronounced in young subjects. OSA, therefore, may be associated with functional impairment ("a premature aging effect") on the endothelium and on arterial stiffness (in men), although skin microcirculatory function appears preserved. PMID- 20857865 TI - Catecholamines, adiponectin, and insulin resistance as measured by HOMA in children with obstructive sleep apnea. AB - INTRODUCTION: Obstructive sleep apnea (OSA) has been implicated in the pathophysiology of metabolic syndrome. Its contribution to insulin resistance is complicated by obesity and puberty. We hypothesized that OSA is associated with worse insulin resistance and lower adiponectin after adjustment for obesity and puberty and that catecholamines might mediate these changes. METHODS: Normal controls and children with suspected OSA were recruited and categorized as pubertal or prepubertal. Overnight polysomnography (PSG) was performed. Subjects were categorized as OSA for total apnea hypopnea index (Total-AHI) > or = 1.5 events/h. Fasting blood glucose, insulin, adiponectin, and 24-hour urinary catecholamines were obtained. Homeostatic model assessment of insulin resistance (HOMA) was calculated. The independent effects of OSA upon HOMA, adiponectin, and urinary catecholamines following adjustment for body mass index (BMI) were determined. RESULTS (median; min, max): Subjects (n = 98, 42F; 11 +/- 4 years, 37 prepubertal) were generally overweight (BMI-Z = 2.1; -3, 4.1) and had wide ranging insulin sensitivities (HOMA = 2.7; 0.5, 27) and PSG parameters (Total-AHI = 1.6; 0, 185). The risks of elevated insulin (P = 0.04) and HOMA (P = 0.05) were higher in OSA vs non OSA obese pubertal children. Polysomnographic markers of OSA, including Total-AHI (P = 0.001, R2 = 0.32), were negatively associated with adiponectin in pubertal children. Total-AHI and oxygen desaturation were associated with higher urinary normetanephrine and norepinephrine. CONCLUSIONS: In obese pubertal children, OSA was associated with worse insulin resistance. Worsening OSA was associated with lower adiponectin and increasing urinary catecholamines. Whether OSA directly lowers adiponectin and aggravates a predisposition to insulin resistance is unknown, but these preliminary findings highlight the importance of further studying pediatric OSA. PMID- 20857866 TI - Consequences of comorbid sleep apnea in the metabolic syndrome--implications for cardiovascular risk. AB - STUDY OBJECTIVES: Metabolic syndrome (MetSyn) increases overall cardiovascular risk. MetSyn is also strongly associated with obstructive sleep apnea (OSA), and these 2 conditions share similar comorbidities. Whether OSA increases cardiovascular risk in patients with the MetSyn has not been investigated. We examined how the presence of OSA in patients with MetSyn affected hemodynamic and autonomic variables associated with poor cardiovascular outcome. DESIGN: Prospective clinical study. PARTICIPANTS: We studied 36 patients with MetSyn (ATP III) divided into 2 groups matched for age and sex: (1) MetSyn+OSA (n = 18) and (2) MetSyn-OSA (n = 18). MEASUREMENTS: OSA was defined by an apnea-hypopnea index (AHI) > 15 events/hour by polysomnography. We recorded muscle sympathetic nerve activity (MSNA - microneurography), heart rate (HR), and blood pressure (BP - Finapres). Baroreflex sensitivity (BRS) was analyzed by spontaneous BP and HR fluctuations. RESULTS: MSNA (34 +/- 2 vs 28 +/- 1 bursts/min, P = 0.02) and mean BP (111 +/- 3 vs. 99 +/- 2 mm Hg, P = 0.003) were higher in patients with MetSyn+OSA versus patients with MetSyn-OSA. Patients with MetSyn+OSA had lower spontaneous BRS for increases (7.6 +/- 0.6 vs 12.2 +/- 1.2 msec/mm Hg, P = 0.003) and decreases (7.2 +/- 0.6 vs 11.9 +/- 1.6 msec/mm Hg, P = 0.01) in BP. MSNAwas correlated with AHI (r = 0.48; P = 0.009) and minimum nocturnal oxygen saturation (r = -0.38, P = 0.04). CONCLUSION: Patients with MetSyn and comorbid OSA have higher BP, higher sympathetic drive, and diminished BRS, compared with patients with MetSyn without OSA. These adverse cardiovascular and autonomic consequences of OSA may be associated with poorer outcomes in these patients. Moreover, increased BP and sympathetic drive in patients with MetSyn+OSA may be linked, in part, to impairment of baroreflex gain. PMID- 20857867 TI - The association of sleep duration with adolescents' fat and carbohydrate consumption. AB - STUDY OBJECTIVES: To investigate the relation between sleep duration and energy consumption in an adolescent cohort. DESIGN: Cross-sectional. SETTING: Free living environment. PARTICIPANTS: Two hundred forty adolescents (mean age 17.7 +/ 0.4 years). MEASUREMENTS AND RESULTS: Daily 24-hour food-recall questionnaires and wrist-actigraphy measurements of sleep duration were employed to test the hypothesis that shorter weekday sleep duration (< 8 h) is associated with altered nutrient intake. Nutrition parameters included total calories, calories from meals and snacks, and proportions of caloric intake from fat and carbohydrates. Compared with adolescents sleeping 8 or more hours on average on weekdays, those sleeping less than 8 hours consumed a higher proportion of calories from fats (35.9% +/- 6.7% vs 33.2% +/- 6.9%; mean +/- SD; P = 0.004) and a lower proportion of calories from carbohydrates (49.6% +/- 8.2% vs 53.3% +/- 8.3%; P = 0.001). After adjusting for potential confounders, shorter sleep duration was significantly associated with an average daily increase of calories consumed from fat of 2.2 percentage points and an average daily decrease in percentage of calories from carbohydrates of 3.0 percentage points. In unadjusted analyses, shorter sleep duration was also associated with a 2.1-fold increased odds (95% confidence interval: 1.03, 4.44) of daily consuming 475 or more kcal from snacks. CONCLUSION: Quantitative measures of macronutrient intake in adolescents were associated with objectively measured sleep duration. Short sleep duration may increase obesity risk by causing small changes in eating patterns that cumulatively alter energy balance. PMID- 20857868 TI - Insomnia symptoms and daytime function in stable heart failure. AB - OBJECTIVES: To evaluate insomnia symptoms and the extent to which they are associated with clinical and demographic patient characteristics, daytime symptoms, and functional performance in patients with stable heart failure (HF). DESIGN: Cross-sectional, observational. SETTING: Five structured HF disease management programs in the Northeastern U.S. PARTICIPANTS: 173 stable chronic HF patients INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Full polysomnography was obtained for one night in participants' homes. Participants completed the six minute walk test, Medical Outcomes Study SF-36, Epworth Sleepiness Scale, Pittsburgh Sleep Quality Index, Multi-Dimensional Assessment of Fatigue Scale, Centers for the Epidemiological Studies of Depression Scale, and questionnaire items eliciting insomnia symptoms (self-reported difficulty initiating and maintaining sleep and waking too early in the morning). Over half of HF patients reported insomnia symptoms. These were associated with increased daytime symptoms (depression, fatigue), excessive daytime sleepiness, and functional performance in models that statistically controlled for clinical and demographic covariates. These relationships were not explained by sleep disordered breathing. CONCLUSIONS: Insomnia symptoms are common in patients with stable heart failure and are associated with daytime symptoms and decrements in functional performance. PMID- 20857869 TI - Enhancing slow wave sleep with sodium oxybate reduces the behavioral and physiological impact of sleep loss. AB - STUDY OBJECTIVES: To investigate whether enhancement of slow wave sleep (SWS) with sodium oxybate reduces the impact of sleep deprivation. DESIGN: Double blind, parallel group, placebo-controlled design SETTING: Sleep research laboratory PARTICIPANTS: Fifty-eight healthy adults (28 placebo, 30 sodium oxybate), ages 18-50 years. INTERVENTIONS: A 5-day protocol included 2 screening/baseline nights and days, 2 sleep deprivation nights, each followed by a 3-h daytime (08:00-11:00) sleep opportunity and a recovery night. Sodium oxybate or placebo was administered prior to each daytime sleep period. Multiple sleep latency test (MSLT), psychomotor vigilance test (PVT), Karolinska Sleepiness Scale (KSS), and Profile of Mood States were administered during waking hours. MEASUREMENTS AND RESULTS: During daytime sleep, the sodium oxybate group had more SWS, more EEG spectral power in the 1-9 Hz range, and less REM. Mean MSLT latency was longer for the sodium oxybate group on the night following the first daytime sleep period and on the day following the second day sleep period. Median PVT reaction time was faster in the sodium oxybate group following the second day sleep period. The change from baseline in SWS was positively correlated with the change in MSLT and KSS. During recovery sleep the sodium oxybate group had less TST, SWS, REM, and slow wave activity (SWA) than the placebo group. CONCLUSIONS: Pharmacological enhancement of SWS with sodium oxybate resulted in a reduced response to sleep loss on measures of alertness and attention. In addition, SWS enhancement during sleep restriction appears to result in a reduced homeostatic response to sleep loss. PMID- 20857870 TI - Energy expenditure is affected by rate of accumulation of sleep deficit in rats. AB - STUDY OBJECTIVES: Short sleep is a putative risk factor for obesity. However, prolonged total sleep deprivation (TSD) leads to negative energy balance and weight loss in rodents, whereas sleep-restricted humans tend to gain weight. We hypothesized that energy expenditure (VO2) is influenced by the rate of accumulation of sleep deficit in rats. DESIGN AND INTERVENTION: Six Sprague Dawley rats underwent chronic sleep-restriction (CSR, 6-h sleep opportunity at ZT0-6 for 10 days) and stimulus-control protocols (CON, 12-h sleep opportunity for 10 days, matched number of stimuli) in a balanced cross-over design. Four additional rats underwent TSD (4 days). Sleep was manipulated using a motor driven walking wheel. MEASUREMENTS AND RESULTS: Electroencephalography, electromyography, and body temperature were measured by telemetry, and VO2, by respirometry. Total sleep deficits of 55.1 +/- 6.4 hours, 31.8 +/- 6.8 hours, and 38.2 +/- 2.3 hours accumulated over the CSR, CON, and TSD protocols, respectively. Responses to TSD confirmed previous reports of elevated VO2 and body temperature. These responses were attenuated in CSR, despite a greater cumulative sleep deficit. Rate of rise of VO2 was strongly correlated with rate of accumulation of sleep deficit, above a threshold deficit of 3.6 h x day(-1). CONCLUSION: The change in VO2 is affected by rate of accumulation of sleep deficit and not the total sleep loss accrued. Negative energy balance, observed during TSD, is strongly attenuated when brief daily sleep opportunities are available to rats (CSR), despite greater accumulated sleep deficit. PMID- 20857871 TI - The injection of hypocretin-1 into the nucleus pontis oralis induces either active sleep or wakefulness depending on the behavioral state when it is administered. AB - STUDY OBJECTIVES: We previously reported that the microinjection of hypocretin (orexin) into the nucleus pontis oralis (NPO) induces a behavioral state that is comparable to naturally occurring active (rapid eye movement) sleep. However, other laboratories have found that wakefulness occurs following injections of hypocretin into the NPO. The present study tested the hypothesis that the discrepancy in behavioral state responses to hypocretin injections is due to the fact that hypocretin was not administered during the same states of sleep or wakefulness. DESIGN: Adult cats were implanted with electrodes to record sleep and waking states. Hypocretin-1 (0.25 microL, 500microM) was microinjected into the NPO while the animals were awake or in quiet (non-rapid eye movement) sleep. MEASUREMENTS AND RESULTS: When hyprocretin-1 was microinjected into the NPO during quiet sleep, active sleep occurred with a short latency. In addition, there was a significant increase in the time spent in active sleep and in the number of episodes of this state. On the other hand, the injection of hyprocretin 1 during wakefulness resulted not only in a significant increase in wakefulness, but also in a decrease in the percentage and frequency of episodes of active sleep. CONCLUSIONS: The present data demonstrate that the behavioral state of the animal dictates whether active sleep or wakefulness is induced following the injection of hypocretin. Therefore, we suggest that hypocretin-1 enhances ongoing states of wakefulness and their accompanying patterns of physiologic activity and that hypocretin-1 is also capable of promoting active sleep and the changes in various processes that occur during this state. PMID- 20857872 TI - Increased disease activity is associated with altered sleep architecture in an experimental model of systemic lupus erythematosus. AB - STUDY OBJECTIVES: The aim of this study was to evaluate sleep patterns during the course of the disease in (NZB/NZW)F1 mice, an experimental model of systemic lupus erythematosus (SLE). DESIGN: Female mice were implanted with electrodes for chronic recording of sleep-wake cycles during the entire experimental phase (9, 19, and 29 weeks of age). The disease course was also assessed. At each time point, blood samples were collected from the orbital plexus to evaluate serum antinuclear antibodies (ANA), which are important serologic parameters of disease evolution. Pain perception was also evaluated. MEASUREMENTS AND RESULTS: During the dark phase, (NZB/NZW)F, mice aged 19 weeks spent more time in sleep, and, as a consequence, the total waking time was lower when compared with earlier periods. An augmented number of sleep-stage transitions and microarousals were observed at the 29th week of life in both light and dark phases. At this same time-point, the mice showed lower pain thresholds than they had at 9 weeks of life. The disease status was confirmed; the entire group of mice at 29 weeks of life showed positive ANA with high titer levels. CONCLUSIONS: The sleep-recording data showed that, during the progress and severe phases of the disease (19 and 29 wks of age, respectively), sleep architecture is altered. According to these results, increased sleep fragmentation, disease activity, and pain sensitivity are features observed in these mice, similar to symptoms of SLE. PMID- 20857873 TI - Relationship between surface facial dimensions and upper airway structures in obstructive sleep apnea. AB - STUDY OBJECTIVES: We hypothesized that the facial phenotype is closely linked to upper airway anatomy. The aim of this study was to investigate the relationship between surface facial dimensions and upper airway structures using magnetic resonance imaging (MRI) in subjects with obstructive sleep apnea (OSA). DESIGN: Cohort study. SETTING: Sleep investigation unit. PATIENTS: Sixty-nine patients (apnea-hypopnea index > or = 10/h) underwent MRI as part of a study of upper airway anatomy in oral appliance therapy. INTERVENTIONS: Measurements of a range of surface facial dimensions and upper airway soft tissue volumes were performed on the MR images using image-analysis software. Pearson correlation analyses were performed. MEASUREMENTS AND RESULTS: Significant correlations were identified between a number of surface facial dimensions and neck circumference. Significant positive correlations were demonstrated between surface facial dimensions (including facial widths, facial heights, nose width, interocular and intercanthal widths) and upper airway structures. The strongest associations were between the tongue volume and the midface width (r = 0.70, P < 0.001), and lower face width (r = 0.60, P <0.001). Surface facial dimensions in combination were also strong determinants for tongue volume (r2 = 0.69). Correlations between surface soft tissue thickness and upper airway soft tissue volumes occurred at the level of the midface but not at the level of the lower face. CONCLUSIONS: This study demonstrates that there is a relationship between surface facial dimensions and upper airway structures in subjects with OSA. These findings support the potential role of surface facial measurements in anatomic phenotyping for OSA. PMID- 20857875 TI - Residential care and treatment. PMID- 20857874 TI - Assessing the prioritization of primary care referrals for polysomnograms. AB - STUDY OBJECTIVE: The mortality attributed to obstructive sleep apnea (OSA) is comparable to that of breast cancer and colon cancer. We sought to determine if patients at high risk for OSA were less likely to be referred by their primary care physician for polysomnograms (PSG) than mammograms or endoscopies. DESIGN: Prospective cohort study; patients were recruited between January 2007 and April 2007. SETTING: Academic public hospital system PATIENTS: 395 patients waiting for family or internal medicine primary care appointments were administered the Berlin questionnaire. Chart abstraction or interview determined demographics; insurance and employment status; body mass index (BMI); comorbidities; and prior PSG, mammography, or endoscopy referrals. RESULTS: Mean BMI was 30 +/- 7.4 kg/m2; 187 (47%) patients had high-risk Berlin scores. Overall, 19% of patients with high-risk Berlin scores were referred for PSG, compared to 63% of those eligible for mammograms and 80% of those eligible for endoscopies. Women (OR = 2.9, P = 0.02), COPD (OR = 4.6, P = 0.03), high-risk Berlin scores (OR = 3.4, P = 0.009), and higher BMI (OR = 1.1, P < 0.001) were positively associated with PSG referrals. Privately insured patients were less likely to be referred than uninsured patients (OR = 0.3, P = 0.04). There was no significant difference in referrals among those with other forms of insurance. Race was not associated with PSG referrals. CONCLUSION: In a public hospital, primary care patients were less likely to be referred for PSG compared to mammogram and endoscopy. Uninsured patients were more likely to be referred for PSG than those with private insurance. Further studies are needed to address the low PSG referral rates in high-risk populations. PMID- 20857876 TI - Residential care and treatment. PMID- 20857877 TI - Commentary on residential group care. PMID- 20857878 TI - The Building Bridges Initiative: residential and community-based providers, families, and youth coming together to improve outcomes. AB - The Building Bridges Initiative (BBI) provides a framework for achieving positive outcomes for youth and families served in residential and community programs. Founded on core principles, an emerging evidence base, and acknowledged best practices, the BBI emphasizes collaboration and coordination between providers, families, youth, advocates, and policymakers to achieve its aims. Examples are presented of successful state, community, and provider practice changes, and available tools and resources to support all constituencies in achieving positive outcomes. PMID- 20857879 TI - Performance-based contracting in residential care and treatment: driving policy and practice change through public-private partnership in Illinois. AB - The National Quality Improvement Center on the Privatization of Child Welfare Services selected Illinois as a demonstration site in 2007 to evaluate performance-based contracting in residential treatment services. This article discusses the first two years of project implementation including developing residential treatment performance indicators, adjusting those indicators for risk at the provider level, and setting agency-specific benchmarks, as well as the project's fiscal foundation and related systemic improvements to support policy and practice change resulting from this initiative. PMID- 20857880 TI - National child and youth care practitioner professional certification: promoting competent care for children and youth. AB - This article provides an overview of the history, development, and conceptual framework guiding a national certification initiative for child and youth care workers. Summarized are descriptions of three certification assessment measures (supervisor assessment, situational judgment certification exam, and portfolio assessment), integrated with results from an international pilot validation study. The certification program is the first national effort to identify and assess underlying child and youth work competencies that transcend work setting (community-based to out-of-home care), population characteristics (diagnosed mental health concerns, experiencing child abuse, etc.), and age of the child/youth (early childhood through adolescence). The authors assert, building on a seven-year collaborative effort to establish the certification program, that it is time to transform the child and youth serving workforce crisis into an opportunity to bring together the varied child- and youth-caring fields into a united profession that has a rich knowledge and skill base of international scope. PMID- 20857881 TI - Innovations in implementation of trauma-informed care practices in youth residential treatment: a curriculum for organizational change. AB - Children in the child welfare system frequently experience trauma within the caregiving relationship. These traumatic experiences may be compounded by system trauma and place these children at high risk of emotional disorders and placement in out-of-home (OOH) mental health treatment programs. This article reviews the literature on trauma and children in the child welfare system and discusses a study of trauma-informed practices in OOH treatment programs and the curriculum Creating Trauma-Informed Care Environments, which resulted from study findings. PMID- 20857882 TI - A social pedagogy approach to residential care: balancing education and placement in the development of an innovative child welfare residential program in Ontario, Canada. AB - This paper chronicles the exploration and development of a residential program of the child welfare authority of Renfrew County in Ontario, Canada. Recognizing that virtually its entire population of youth in care was failing to achieve positive outcomes in education, Renfrew County Family and Children Services embarked on a program development process that included many unique elements within the Ontario child welfare context. This process introduced the theoretical framework of social pedagogy to the provision of residential care, and it replaced the idea of psychotherapy as the primary agent of change for youth with the concept of living and learning. The result is a template for the Ottawa River Academy, a living and learning program for youth in care that exemplifies the possibilities embedded in creative thought, attention to research and evidence, and a preparedness to transcend traditional assumptions with respect to service designs and business models for residential care in child welfare. PMID- 20857883 TI - Modernizing residential treatment centers for children and youth--an informed approach to improve long-term outcomes: the Damar pilot. AB - Much controversy exists regarding the effectiveness of residential treatment. Recently, emerging research has demonstrated that community-based residential treatment has more positive long-term outcomes for youth. This article describes a community-based program that was implemented at a residential treatment agency serving youth. Targeted recidivism variables that were used to guide the study are described. Results demonstrated significant behavioral improvements, as well as improved post-discharge status. Conclusions and recommendations are also provided. PMID- 20857884 TI - Children and residential experiences: a comprehensive strategy for implementing a research-informed program model for residential care. AB - This paper describes an effort to bridge research and practice in residential care through implementing a program model titled Children and Residential Experiences (CARE). The strategy involves consulting at all levels of the organization to guide personnel to incorporate CARE evidence-based principles into daily practice, and fostering an organizational culture and climate that sustains the integration of CARE principles. CARE aims to promote residential care programs that serve the best interests of children. PMID- 20857885 TI - Psychotropic medication management in a residential group care program. AB - This article presents a psychotropic medication management approach that is used within a residential care program. The approach is used to assess medications at youths' times of entry and to facilitate decision making during care. Data from a typical case study have indicated that by making medication management decisions slowly, systematically, and based on behavioral data, it is possible to make changes to psychotropic treatment that have a positive effect on youth behavior and psychological well-being. PMID- 20857886 TI - Restraint use in residential programs: why are best practices ignored? AB - Several states and providers have embarked on initiatives to reduce using restraint and seclusion in residential programs. Restraint and seclusion are associated with harm to youth and staff, significant costs, reduced quality of care, and less engagement of youth and families. Successful reduction/prevention strategies have been identified, implemented, and reported. Both states and residential providers have implemented prevention approaches, made significant changes, reduced restraint/seclusion use, and offered their experience and positive outcomes. PMID- 20857887 TI - Academic and behavioral characteristics of students at a secondary residential school. AB - This study examined academic and behavioral characteristics of 423 adolescents who had attended a residential school over a seven-year period. Students represented diverse demographic backgrounds. Student academic achievement was examined at admissions and over time in reading, mathematics, written language, and fluency. Findings are discussed with respect to present and future programming for youth enrolled in residential schools. PMID- 20857888 TI - Young people's satisfaction with residential care: identifying strengths and weaknesses in service delivery. AB - This paper presents findings from a landmark Australian study investigating the experiences and perspectives of young people in residential care. Data from a representative sample are analyzed to identify young people's satisfaction with various aspects of their residential care experience: their sense of safety, normality, support, comfort in general living environment, participation in decision-making, and improvements in well-being. Findings point to strengths and weaknesses in current service delivery. The vast majority of respondents felt safe and well-treated and satisfied with the care and support provided by staff. Respondents were less commonly satisfied with the care and support provided by caseworkers, their participation in higher order decision-making, their sense of normality, and the amount of contact with their families. Compared with older respondents, younger respondents less commonly expressed satisfaction with various aspects of their care. Similarly, those reporting more placements were less satisfied with their care and support than those reporting fewer placements. PMID- 20857889 TI - Comparing three years of well-being outcomes for youth in group care and nonkinship foster care. AB - Using three waves of data from the National Survey of Child and Adolescent Well Being, this study examines differences in cognitive, academic, and affective well being of youth first placed in nonkinship foster care (N = 259) and youth first placed in group care (N = 89). To compare nonrandomized groups, propensity score matching was used. Results from hierarchical linear modeling suggest that both groups of youth show improved behavior and below-average academics over time. PMID- 20857890 TI - Lessons learned from 14 years of outcomes: the need for collaboration, utilization, and projection. AB - In 1995, the Indiana Association of Residential Child Care Agencies (IARCCA), an association of children and family services, responded to a request to demonstrate effectiveness of residential care. The organization developed a vision for evaluating outcomes that incorporated collaboration with others, use of data and projection toward the future. This guiding vision led to an ongoing project for IARCCA member agencies across Indiana. This article shares lessons learned from this 15-year process, including developing benchmarks to establish best practices for serving youth. PMID- 20857891 TI - The relative safety of pooled whole-blood-derived platelets prepared by the buffy coat method versus single-donor (apheresis) platelets. AB - Conversion to a single-donor (apheresis) platelet inventory in Western Europe and other countries that provide similar health care to the US but rely on buffy-coat pooled whole-blood-derived platelets will confer the benefit of a > or = 2-fold reduction in the risk of all emerging transfusion-transmitted infections (TTIs). In Europe, this benefit will include a > or = 2-fold reduction in the risk of acquiring variant Creutzfeldt-Jakob disease (vCJD) from platelet transfusion. In countries that use buffy coats from first-time donors to produce platelet pools, there will also be a > or = 2-fold reduction in the risk of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus infections. Conversion to a single-donor inventory collected from male donors (or female donors without a history of pregnancy or shown not to have white-blood-cell antibodies) should also reduce the risk of transfusion-related acute lung injury, although this prediction is based on theory and may not materialize or prove hard to document. Because conversion to a single-donor inventory can effect a > or = 2 fold reduction in the risk of all TTIs without incurring any risk, it is a more advantageous risk-reduction strategy for emerging TTIs compared with the introduction of pathogen-reduction systems for platelets. The latter cannot protect from vCJD and potentially also from some other emerging TTIs; moreover, they have recently been associated with an increased risk of bleeding. PMID- 20857892 TI - Multi-center evaluation of the hepatitis B surface antigen (HBsAg) assay and HbsAg confirmatory assay for the family of Access immunoassay systems. AB - BACKGROUND: Accurate detection of Hepatitis B Surface Antigen (HBsAg) is an important aid in the diagnosis of patients infected with the hepatitis B virus (HBV). A multi-center study was conducted to characterize the performance of the HBsAg assay on the family of Access immunoassay systems from Beckman Coulter. METHODS: The Access HBsAg assay was characterized in a multi-center study and compared to the Abbott AxSYM* and PRISM* HBsAg assays. The bioMerieux VIDAS* assay was used to resolve discrepant results. Reproducibility studies (intra assay, inter-assay and inter-lot) were performed with pooled serum samples (negative sample, close to cut off, low, medium and high positive samples). Analytical sensitivity, subtype and genotype detection were studied with various commercial panels (SFTS panel, WHO 80/549, WHO 00/588, Teragenix HBV Genotype panel). A panel of recombinant HBsAg mutant proteins was tested to investigate reactivity towards genetic mutations. Clinical sensitivity was verified with seroconversion panels and samples from subjects with known HBV infection. Analytical specificity was studied with samples from patients with potential cross-reactive infections. Clinical specificity was validated among blood donors and a hospitalized population. RESULTS: The imprecision was < 10%. Analytical sensitivity was < or = 0.1 ng/mL (SFTS panel), 0.020 PEI Units/mL (ad panel), 0.024 PEI Units/mL (ay panel), 0.092 IU/mL with WHO 80/549 and 0.056 IU/mL with WHO 00/588. All genotype samples and HBsAg mutants were reactive with the Access HBsAg assay. Seroconversion panels tested showed no significant difference with the reference method. Sensitivity for subjects with known HBV infection was 100%. No interference with potentially cross-reactive infections was observed after confirmatory testing. Specificity was 99.96% (100% after confirmatory testing) in a blood donor population and 99.5% (100% after confirmatory testing) in a hospitalized population. Excellent separation of positive and negative populations was observed. CONCLUSIONS: The Access HBsAg and HBsAg Confirmatory assays meet all clinical and analytical performance requirements of assays for the detection of HBsAg. PMID- 20857893 TI - Simvastatin and asymmetric dimethylarginine-homocysteine metabolic pathways in patients with newly detected severe hypercholesterolemia. AB - BACKGROUND: The idea that statin therapy decreases asymmetric dimethylarginine through lowering low-density lipoprotein cholesterol levels seems logic. However, controversy exists in the literature concerning this issue. This study compares the effect of moderate (40 mg) to high (80 mg) simvastatin doses on asymmetric dimethylarginine levels in patients with newly detected severe hypercholesterolemia (after targeted LDL levels of < or = 2.6 mmol/L are reached). METHODS: The study included 120 adult patients with newly detected severe hypercholesterolemia (total cholesterol > or = 7.5 mmol/L and low-density lipoprotein cholesterol > or = 4.9 mmol/L). Asymmetric dimethylarginine levels were determined by enzyme-linked immunosorbent assay, total homocystein by the high performance liquid chromatography method. RESULTS: A statistically significant decrease exists in total cholesterol, triglycerides, low-density lipoprotein cholesterol and apolipoprotein-B levels as well as apolipoprotein B/apolipoprotein-A1 index following one month of 40 mg simvastatin therapy (P < 0.001). Asymmetric dimethylarginine and total homocystein levels were also decreased but the difference was not significant (p = 0.571; p = 0.569). A dose dependent effect was established comparing the influence of moderate (40 mg) to high (80 mg) simvastatin doses on the tested atherogenic biomarkers (lipid profile, apolipoprotein-A1, apolipoprotein-B). Asymmetric dimethylarginine and total homocystein levels showed a statistically significant decrease with 80 mg simvastatin (p < 0.001; p = 0.038). In the group of 40 patients, who had reached LDL-cholesterol target levels on 80 mg simvastatin, a reduction in ADMA levels demonstrated a statistically significant correlation with the reduction of LDL cholesterol (r(xy) = 0.355; p < 0.01) and of Apo-B (r(xy) = 0.508; p < 0.001). The backward selection process selected percent ApoB-change as the most important statistically significant factor related to percent ADMA-change (F = 21.127; p = 0.001; R2 = 0.265). CONCLUSIONS: Optimizing the target values of low-density lipoprotein cholesterol to the moderate dose (40 mg) of simvastatin has no effect on asymmetric dimethylarginine and total homocysteine in contrast to high dose (80 mg) after targeted LDL of < or = 2.6 mmol/L levels are reached in patients with newly detected severe hypercholesterolemia. PMID- 20857894 TI - Comparison of long-term prognostic value of N-terminal-proBNP and midregional-pro adrenomedullin in patients with acute myocardial infarction. AB - BACKGROUND: N-terminal-proBNP (NT-proBNP) and Midregional-pro-Adrenomedullin (MR proADM) predict mortality of patients with acute myocardial infarction (AMI). Comparison of the prognostic values of NT-proBNP and MR-proADM to predict long term adverse clinical events (AE) after AMI has not been evaluated yet. METHODS: 30 patients with AMI were enrolled into this prospective study. Measurements of NT-proBNP and MR-proADM were performed at initial presentation, two or three days and four months after AMI. Long-term AE defined as recurrent AMI, need for repeated percutaneous transluminal angioplasty or coronary bypass graft surgery, congestive heart failure, cardiopulmonary resuscitation, cardiogenic shock, syncope, and death were documented during a follow-up period of ten months. RESULTS: At initial presentation, NT-proBNP values were significantly higher in patients with AE compared to patients without AE (p < 0.05). The area under the ROC curve (AUC) indicated good predictive performance of NT-proBNP (AUC 0.78, 95% CI 0.59-0.91, p = 0.003) and MR-proADM (AUC 0.71, 95% CI 0.51-0.86, p = 0.046) regarding AE. Comparing both AUC revealed no differences between NT-proBNP and MR proADM as predictors of AE (p = 0.59). Patients with NT-proBNP levels > or = 370 pg/mL were more likely to suffer from AE than patients with lower levels (relative risk 6.7, 95% CI 1.0-46, p = 0.018). With this cutoff, NT-proBNP could exclude AE with a negative predictive value of 92% being similar to MR-proADM (negative predictive value 76%, relative risk 2.8, 95% CI 1.2-6.9, p = 0.042). CONCLUSIONS: Early measurements of NT-proBNP or MR-proADM during the acute phase of AMI may allow the risk of a long-term AE to be excluded, based on the comparable test characteristics,. PMID- 20857895 TI - Prevalence of CYP450 gene variations in patients with type 2 diabetes. AB - BACKGROUND: Drug degradation in the human organism is driven by detoxification mechanisms that can be affected in their efficiency by genetic mutations. The purpose of this pilot investigation was to investigate whether Type 2 diabetes is associated with mutations in prominent members of the CYP 450 isoenzyme family. METHODS: Genomic DNA was isolated from EDTA blood samples of 203 Caucasian subjects (101 patients with Type 2 diabetes and 102 non-diabetic subjects, age (mean +/- STD): 49 +/- 16 years) was analyzed. Genomic DNA was isolated from EDTA blood. Mutation analysis for CYP2C8 (*2/*3/*4), CYP2C9 (*2/*3), CYP2C19 (*2/*3), CYP2D6 (*3/*4/*5/*6) and PPARgamma (P12A) was performed by means of real-time PCR methods (Light-Cycler, Roche Diagnostics, Indianapolis, IN, USA). RESULTS: The genotyping revealed the following allele frequency distributions for the two investigated groups: CYP2C8: *2 (type 2 diabetes 3% vs. 1%, n.s.), *3 (16% vs. 3%, n.s.), *4 (15% vs. 2%, p < 0.05), CYP2C9: *2 (20% vs. 24%, n.s.), *3 (22% vs. 21%, n.s.), CYP2C19: *2 (23% s. 33%, n.s.), *3 (0% vs. 0%, n.s.), CYP2D6: *3 (3% vs. 4%, n.s.), *4 (40% vs. 37%, n.s.), *5 (3% vs. 2%, n.s.), *6 (0% vs. 0%, n.s.), PPARgamma P12A (15% vs. 21%, n.s.), i.e. all but one mutation (CYP2C8*4) were found with equal prevalence in the two cohorts. CONCLUSIONS: In this pilot investigation, we found an increased prevalence of the CYP2C8*4 mutation in the Type 2 diabetic patient group. This may result in a modification of drug degradation and drug efficacy in these patients and may have an influence, e.g. on the choice of anti-diabetic drugs. However, further trials are necessary in order to confirm our findings. PMID- 20857896 TI - Comparison of two different methods for CA19-9 antigen determination. AB - BACKGROUND: This study was designed to investigate the clinical performance of the Access GI Monitor (Beckman Coulter) on the UniCel DxI 800, a method for CA19 9 antigen determination, and to compare with CA19-9 assay on the AxSYM system (Abbott). METHODS: 1,063 serum samples from unselected patients with different underlying diagnoses were tested with both methods. Passing-Bablok regression analysis and Bland Altman analysis was performed. In addition, using ROC analysis, the distribution of Access GI Monitor and AxSYM CA19-9 antigen levels was tested in patients with pancreatic cancer (n = 50), acute inflammatory disease (n = 20), and with chronic inflammation of the pancreatic gland (n = 18). Furthermore, four patients with pancreatic cancer were monitored individually in their courses of the disease (before, during, and after therapeutic procedures) to compare their CA19-9 values with regard to inter-method concordance. RESULTS: Passing-Bablok analysis showed a systematic difference with R = 0.93, slope 0.75, and intercept -1.0. Bland Altman analysis showed a wide scatter of relative differences between both methods, especially in the low end measuring range. In the selected group of patients with pancreatic diseases the analysis of concordance revealed 95.5 % agreement between both methods with a comparable area under the ROC curves (0.73 vs. 0.76). A clear concordance was found for all four selected patients. CONCLUSIONS: Although we found significant systematic measuring variations in the global analysis, the two different automated methods for the quantitative determination of CA19-9 antigen were comparable with respect to their clinical accuracy and applicability to support decision making in the management of pancreatic cancer. PMID- 20857897 TI - Comparison of four direct homogeneous methods for the measurement of low-density lipoprotein cholesterol. AB - BACKGROUND: The primary lipoprotein risk factor is low-density lipoprotein cholesterol (LDL-C), and medication is targeted at lowering LDL-C values. To clarify the usefulness of direct homogeneous assays for LDL-C measurement, we compared the values obtained by various reagents to those obtained by the Friedewald equation and analyzed different reactivity to IDL/VLDL and LDL. METHODS: Serum samples were collected from 55 patients with hypercholesterolemia. The LDL-C concentrations were determined by four direct homogeneous assays using reagent A (Kyowa Medex), B (Sekisui Medical), C (Denka Seiken), and D (Sysmex), which are commercially available. RESULTS: Significant correlation was observed in LDL-C values obtained by the homogeneous assays and the Friedewald equation. However, there were two discrepancies in reagents B and C, respectively. These assays showed 40% and 55% lower LDL-C values than those calculated by the Friedewald equation, respectively. Reactivity to the IDL fraction in reagents B and C was lower than in reagents A and D. CONCLUSIONS: Direct homogeneous assays for LDL-C are suitable for routine laboratory examination. However, it was shown that attention should be given to the different reactivity to IDL and LDL among reagents in some clinical samples. PMID- 20857898 TI - Absence of anti-pendrin auto-antibodies in the sera of Tunisian patients with autoimmune thyroid diseases. AB - BACKGROUND: We previously demonstrated that the PDS gene is involved in the genetic susceptibility to autoimmune thyroid diseases (AITD) in Tunisia. In the same population, we now investigated the presence of anti-pendrin auto-antibodies (aAbs) in AITD patients' sera. METHODS: Thirty seven Tunisian AITD patients and 19 healthy subjects from families previously linked to the PDS gene, 75 unrelated patients and 20 healthy unrelated subjects were included in our study. The detection of anti-pendrin aAbs in patients' sera was performed by ELISA using membrane protein extracts of CHO cells expressing pendrin (CHO-hPDS) and by immunofluorescence using transient COS-7 cells expressing a GFP tagged pendrin. CHO cells transfected with human TPO in the same ELISA conditions were used as positive control. RESULTS: The majority of AITD patients' sera were positive for the presence of anti-TPO aAbs. In contrast, no reactivity was detected with CHO hPDS membrane protein extracts. Likewise, no significant immunostaining was found on transfected COS-7cells upon exposure to patients' and controls' sera. CONCLUSIONS: Our data point to the absence of anti-pendrin aAbs in Tunisian AITD patients' sera. PMID- 20857899 TI - Reliability of mycophenolic acid monitoring by an enzyme multiplied immunoassay technique. AB - BACKGROUND: For mycophenolic acid (MPA), substantial inter- and intra-individual variability and drug interactions have been observed and therapeutic drug monitoring is now recommended. In this study, a MPA commercial Enzyme Multiplied Immunoassay Technique (EMIT) was evaluated and compared with the HPLC-UV reference method which is easily practicable in a routine laboratory. METHODS: Plasma samples (n = 117) were collected from adult renal graft patients treated by mycophenolate in combination with either cyclosporin A (CyA) (n = 32) or tacrolimus (n = 85). RESULTS: Considering all samples, correlation was excellent (p < 0.0001). However, significant MPA overestimation was observed with EMIT in the early post-transplant period (30%, n = 32) or when combined with cyclosporin (45%). CONCLUSIONS: In the early post-transplant period, or in cases where CyA is used in combination with MPA, the EMIT cannot be recommended. HPLC or LC/MS are here the method of choice. PMID- 20857900 TI - Conference on clinical use of troponin T high sensitive (TnThs) on September 8, 2009 at the airport conference center, Frankfurt/Main. AB - With the redefinition of myocardial infarction in 2000, cardiology associations ESC and ACC require the use of the 99th percentile of a healthy population at a coefficient of variation (CV) of less than 10 % for Troponin values in diagnosing myocardial infarction. With a new Troponin T high sensitive (TnThs) assay as an advancement, it is now possible to fulfill these requirements. A panel of experts from laboratories and cardiologists discussed how to use this new assay in daily routine. Their experience confirms the excellent correlation between the upper measuring range of the new, highly sensitive Troponin T high sensitive test and the values obtained for Troponin T (4th generation). The Troponin T high sensitive test will identify more patients with myocardial infarction when using Troponin Ths above the 99t percentile (14 pg/mL). To diagnose myocardial infarction, one Troponin T value above the 99th percentile, a rise or fall within hours, and symptoms of ischemia need to be applied. Patients with elevated Troponin T levels but without myocardial infarction are supposed to have myocardial damage due to other reasons and have a rather poor prognosis. Is one of the criteria is not fulfilled, a myocardial infarction is less probable and differential diagnosis needs to be conducted. PMID- 20857901 TI - Proteomic molecular portrait of interface zone in breast cancer. AB - Surgical tumor margins are intended to encompass residual tumor cells but may not always accurately delineate the boundary between tumor and normal tissue. Efforts to define tumor margins based on molecular analysis have achieved limited success. Furthermore, no clinical trials have addressed the scope of the tumor microenvironment. Here, we considered the tumor cell population and surrounding microenvironment in delineating tumor margins, classifying breast cancer into tumor and normal zones, and introducing the concept of an interface zone, the region between the invading tumor front and normal tissue, which develops during tumor invasion and metastasis through remodeling of the tumor microenvironment. Pathological signatures of invasion markers in tumor tissues are most dynamic within the invading tumor front. We compared protein profiles of tumor, normal, and interface zones using MALDI-MS. Proteins upregulated in the interface zone were identified by peptide mass fingerprinting and confirmed by database searching with chemically assisted MALDI-PSD spectra. Upregulation was confirmed for RhoGDIalpha, CAPG, WDR1, and CK8 by Western and immunohistochemical analyses. Our results demonstrate that the molecular profile of the interface zone is unique and suggest that upregulation of proteins here may be related to progression and metastasis of breast carcinomas. PMID- 20857903 TI - Photochemical microcontact printing by thiol-ene and thiol-yne click chemistry. AB - This article describes the microstructured immobilization of functional thiols on alkene- and alkyne-terminated self-assembled monolayers on silicon oxide substrates by photochemical microcontact printing. A photochemical thiol-ene or thiol-yne "click" reaction was locally induced in the area of contact between stamp and substrate by irradiation with UV light (365 nm). The immobilization reaction by photochemical microcontact printing was verified by contact angle measurements, X-ray photoelectron spectroscopy, atomic force microscopy, and time of-flight secondary ion mass spectrometry. The reaction rate of photochemical microcontact printing by thiol-ene chemistry was studied using time dependent contact angle measurements. The selective binding of lectins to galactoside microarrays prepared by photochemical microcontact printing was also demonstrated. It was found that photochemical microcontact printing results in a high surface coverage of functional thiols within 30 s of printing even for dilute (mM) ink solutions. PMID- 20857902 TI - Fabrication of a planar zwitterionic lipid bilayer on titanium oxide. AB - There is great demand to fabricate planar phospholipid bilayers on biocompatible materials. The preferred method of forming bilayers on these substrates is the spontaneous adsorption and rupture of phospholipid vesicles. However, in the case of titanium oxide, model vesicles composed solely of zwitterionic phospholipids do not follow this self-assembly pathway under physiological conditions, prompting the use of complex bilayer materials and less-facile methods. Herein, we report a novel pH-based strategy for fabricating zwitterionic bilayers on titanium oxide in a simple and robust manner. Depending on the pH conditions under which lipid vesicles adsorb onto titanium oxide, quartz crystal microbalance-dissipation (QCM-D) monitoring demonstrated that the self-assembly pathway can in fact result in planar bilayer formation. The pH of the solution could then be adjusted to physiological levels with no effect on the mass and viscoelastic properties of the bilayer. Moreover, fluorescence recovery after photobleaching (FRAP) measurements indicated a high degree of lateral lipid diffusivity within the bilayer at physiological pH, commensurate with its role as a cell membrane mimic. Compared to existing protocols, this strategy permits the fabrication of a more diverse array of planar bilayers on titanium oxide by tuning the self-assembly pathway of lipid vesicle adsorption onto solid substrates. PMID- 20857904 TI - China embarking on development of its own national water quality criteria system. PMID- 20857905 TI - Label-free prehybridization DNA microarray imaging using photonic crystals for quantitative spot quality analysis. AB - Technical variability during DNA capture probe printing remains an important obstacle to obtaining high quality data from microarray experiments. While methods that use fluorescent labels for visualizing printed arrays prior to hybridization have been presented, the ability to measure spot density using label-free techniques would provide valuable information on spot quality without altering standard microarray protocols. In this study, we present the use of a photonic crystal biosensor surface and a high resolution label-free imaging detection instrument to generate prehybridization images of spotted oligonucleotide microarrays. Spot intensity, size, level of saturation, and local background intensity were measured from these images. This information was used for the automated identification of missed spots (due to mechanical failure or sample depletion) as well as the assignment of a score that reflected the quality of each printed feature. Missed spots were identified with >95% sensitivity. Furthermore, filtering based on spot quality scores increased pairwise correlation of posthybridization spot intensity between replicate arrays, demonstrating that label-free spot quality scores captured the variability in the microarray data. This imaging modality can be applied for the quality control of printed cDNA, oligonucleotide, and protein microarrays. PMID- 20857906 TI - Interaction between vine pesticides and bovine serum albumin studied by nuclear spin relaxation data. AB - Pesticides are chemicals usually used in agriculture to prevent possible diseases to crops, such as grapes, caused by parasites. Even if most of the pesticides are degraded during the wine process, residual levels remain in the final product. The most commonly used pesticides in vine belong to several classes of chemical compounds; among them, triazoles and anilinopyrimidines have been commercially used since the 1970s and 1990s, respectively. In this work, we investigated the interaction between three of the most used fungicides belonging to the chemical classes mentioned above (myclobutanil, triadimenol, and pyrimethanil) and bovine serum albumin (BSA) by nuclear spin relaxation analysis. We found that all of the pesticides were able to form a complex with BSA; nevertheless, there were strong differences in their affinity toward the plasma protein. The nuclear magnetic resonance approach used on the basis of the analysis of selective relaxation rate enhancements of pesticide protons in the presence of BSA allowed for the calculation of the affinity indexes and the equilibrium constants of the three systems. Myclobutanil showed the highest affinity toward BSA, whereas triadimenol gave the weakest interaction with the protein. The differences in the capacity of the three pesticides to bind to albumin highlighted the existence of different binding strengths on the protein. These results indicate that myclobutanil and triadimenol, despite their structure similarity, may have very different residence times in the plasma and rates of clearance. PMID- 20857907 TI - Addressable terminally linked DNA-CNT nanowires. AB - Despite many advances in carbon nanotube (CNT) research, several issues continue to plague the field with regard to the construction of well-defined hybrid CNT materials. Regiospecific covalent functionalization, nonspecific surface absorption, and carbon nanotube aggregation/bundling present major difficulties when working with these materials. In this communication, we circumvent these problems and report a new addressable hybrid material composed of single-walled carbon nanotubes terminally linked by oligonucleotides into a nanowire motif. We show that the oligonucleotide junctions are addressable and can be targeted by gold nanoparticles. PMID- 20857908 TI - Four-coordinate, trigonal pyramidal Pt(II) and Pd(II) complexes. AB - We report herein the characterization of electrophilic, trigonal bipyramidal {[SiP(3)(R)]Pt(L)}(+) cations ([SiP(3)(R)] = [(2-R(2)PC(6)H(4))(3)Si]; R = Ph, (i)Pr) that feature weakly coordinated ligands including CH(2)Cl(2), Et(2)O, toluene, and H(2). A cationic toluene adduct that shows a close platinum aryl C-H sigma-contact is perhaps most noteworthy in this context. For the isopropyl substituted ligand, [SiP(3)(iPr)], it has proven possible to exclude the fifth axial donor to afford the rigorously four-coordinate, trigonal pyramidal (TP) complex {[SiP(3)(iPr)]Pt}(+). An isostructural TP palladium complex {[SiP(3)(iPr)]Pd}(+) is also accessible. Prototypical four-coordinate d(8) platinum and palladium complexes are square planar. The TP d(8) cations described herein are hence geometrically distinct. PMID- 20857909 TI - Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha(1) adrenoceptors. AB - A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors-Bogeso pharmacophore model for dopamine D(2) and alpha(1)-adrenoceptor antagonists, with the aim of obtaining selective alpha(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central alpha(1)-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1 methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10,11 dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4 methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl)methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to alpha(1a), alpha(1b), and alpha(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) receptors, respectively. PMID- 20857910 TI - Label-free high-throughput screening assay for inhibitors of Alzheimer's amyloid beta peptide aggregation based on MALDI MS. AB - Aggregation of amyloid-beta (Abeta) peptides is causatively linked to Alzheimer's disease (AD); thus, suppression of this process by small molecule inhibitors is a widely accepted therapeutic and preventive strategy for AD. Screening of the inhibitors of Abeta aggregation deserves much attention; however, despite intensive efforts, there are only a few high-throughput screening methods available, all of them having drawbacks related to the application of external fluorescent probes or artificial Abeta derivatives. We have developed a label free MALDI MS-based screening test for inhibitors of Abeta42 fibrillization that exhibits high sensitivity, speed, and automation possibilities suitable for high throughput screening. The test was evaluated by transmission electron microscopy and compared with a fluorimetric thioflavin-based assay, where interference of a number of tested compounds with thioflavin T binding and/or fluorescence caused false-positive results. The MALDI MS-based method can significantly speed up in vitro screening of compound libraries for inhibitors of Abeta42 fibrillization. PMID- 20857911 TI - Synthesis and biological activities of transition metal complexes based on acetylsalicylic acid as neo-anticancer agents. AB - [(MU(4)-eta(2))-(Prop-2-ynyl)-2-acetoxybenzoate]dicobalthexacarbonyl (Co-ASS), a derivative of aspirin (ASS), demonstrated high growth-inhibitory potential against various tumor cells with interference in the arachidonic acid cascade as probable mode of action. The significance of the kind of metal and cluster was verified in this structure-activity study: Co(2)(CO)(6) was respectively exchanged by a tetrameric cobalt-, trimeric ruthenium-, or trimeric ironcarbonyl cluster. Furthermore, the metal binding motif was changed from alkyne to 1,3 butadiene. Compounds were evaluated for growth inhibition, antiproliferative effects, and apoptosis induction in breast (MCF-7, MDA-MB 231) and colon cancer (HT-29) cell lines and for COX-1/2 inhibitory effects at isolated isoenzymes. Additionally, the major COX metabolite prostaglandin E2 (PGE(2)) was quantified in arachidonic acid-stimulated MDA-MB 231 breast tumor cells. It was demonstrated that the metal cluster was of minor importance for effects on cellular activity if an alkyne was used as ligand. Generally, no correlation existed between growth inhibition and COX activity. Cellular growth inhibition and antiproliferative activity at higher concentrations of the most active compounds Prop-ASS-Co(4) and Prop-ASS-Ru(3) correlated well with apoptosis induction. PMID- 20857912 TI - Structure-activity relationship study of first selective inhibitor of excitatory amino acid transporter subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl) 5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101). AB - The excitatory amino acid transporters (EAATs) are expressed throughout the central nervous system, where they are responsible for the reuptake of the excitatory neurotransmitter (S)-glutamate (Glu). (1) Recently, we have reported the discovery of the first subtype selective EAAT1 inhibitor 2-amino-4-(4 methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3 carbonitrile (UCPH-101) (1b) and presented an introductory structure-activity relationship (SAR) study. (2) Here, we present a detailed SAR by the design, synthesis, and pharmacological evaluation of analogues 1g-1t. By comparison of potencies of 1b, 1h, and 1i versus 1j, it is evident that potency is largely influenced by the chemical nature of the R(1) substituent. The study also demonstrates that any chemical change of the functional groups or a change to the parental scaffold results in the complete loss of inhibitory activity of the compounds at EAAT1. Finally, a bioavailability study of UCPH-101 determined the half-life to be 30 min in serum (rats) but also that it was not able to penetrate the blood-brain barrier to any significant degree. PMID- 20857913 TI - Chemoselectivity diversity in the reaction of LiNC6F5SiMe3 with nitriles and the synthesis, structure, and reactivity of zirconium mono- and tris[2-(2 pyridyl)tetrafluorobenzimidazolate] complexes. AB - Unlike the reaction of LiNTMS(2).TMEDA (TMS = SiMe(3); TMEDA = tetramethylethylenediamine) with 2-cyanopyridine, which results in the nearly exclusive formation of the amidinate, (Me(3)SiNC(6)F(5))Li.TMEDA (1) reacts with 2-cyanopyridine in toluene to yield quantitatively the lithium pyridyltetrafluorobenzimidazolate complex [C(6)F(4)N(2)C(2-C(5)H(4)N)]Li.TMEDA (3). In this work, the reactivity of complex 1 toward aromatic nitriles Ar-CN (Ar = Ph, o-OMeC(6)H(4), C(6)F(5), 2-pyridyl) was examined. Whereas complex 1 fails to react with o-methoxybenzonitrile, its reaction with benzonitrile or pentafluorobenzonitrile gives triphenyl-1,3,5-triazine (4) or the hexacoordinate lithium polymer [LiN(4-NCC(6)F(4))(C(6)F(5)).THF.TMEDA](n) (7), respectively. When 1 is reacted with 2-cyanopyridine in tetrahydrofuran (THF), the benzimidazolate coordination polymer {[C(6)F(4)N(2)C(2-C(5)H(4)N)]Li.THF}(n) (5) is obtained. Herein we discuss how this diverse chemoselectivity in the reaction of the examined lithium N-silylated amides LiNRTMS.TMEDA (R = TMS, C(6)F(5)) with nitriles is influenced by the electronic properties of the nitrile or amide substituents and by the ability of these substituents to interact with the lithium or silicon atoms. Further, we present the syntheses and structures of zirconium tris(pyridyltetrafluorobenzimidazolate) chloride (10) and zirconium bis(dimethylamido)(pyridyltetrafluorobenzimidazolate) chloride.THF (11) complexes. These complexes, the first prepared zirconium mono- and tris(benzimidazolate)s, were crystallographically characterized and examined in the polymerization of propylene with methyl aluminoxane (1:1000 Zr/Al molar ratio). PMID- 20857914 TI - Design and synthesis of prolylcarboxypeptidase (PrCP) inhibitors to validate PrCP as a potential target for obesity. AB - Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 MUM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice. PMID- 20857915 TI - Synthesis, crystal structure, and photoluminescent properties of ternary Cd(II)/triazolate/chloride system. AB - Solvothermal reactions of cadmium chloride and 1,2,4-triazole (Htrz) in different solvent mediums have successfully synthesized five ternary Cd(II)/trz/Cl(-) complexes, [Cd(trz)Cl].H(2)O (1.H(2)O), [Cd(4)(trz)(5)Cl(3)(H(2)O)].(THF)(1.25).(H(2)O)(2.5) (2.1.25THF.2.5H(2)O), [Cd(3)(trz)(2)Cl(MeCN)] (3), [Cd(3)(trz)(4)Cl(2)].(H(2)O)(0.5) (4.0.5H(2)O), and [Cd(4)(trz)(6)Cl(2)(H(2)O)(0.5)].(H(2)O)(3.5) (5.3.5H(2)O). All of these five coordination polymers have three-dimensional (3-D) structural features, which are constructed by distinct substructures including clusters, chains, rings, and even 3-D frameworks. In all cases, 1,2,4-triazolate adopts a MU(1,2,4) bridging mode, and chloride ions display a MU(2), MU(3), MU(4) bridging mode, respectively, which makes the structural diversity in the assembling system, for example, MU(4) Cl and cadmium triazolate, build up an unprecedented tetranuclear cluster [Cd(4)(trz)(8)Cl](-) in 2. All of the materials exhibit intense blue fluorescent emission and high thermal stability, wherein 1 presents an interesting guest responsive photoluminescent property. PMID- 20857916 TI - Low-potential photoelectrochemical biosensing using porphyrin-functionalized TiO2 nanoparticles. AB - A novel photoelectrochemical biosensing platform for the detection of biomolecules at relatively low applied potentials was constructed using porphyrin functionalized TiO2 nanoparticles. The functional TiO2 nanoparticles were prepared by dentate binding of TiO2 with sulfonic groups of water-soluble [meso tetrakis(4-sulfonatophenyl)porphyrin] iron(III) monochloride (FeTPPS) and characterized by transmission electron microscopy; contact angle measurement; and Raman, X-ray photoelectron, and ultraviolet-visible absorption spectroscopies. The functional nanoparticles showed good dispersion in water and on indium tin oxide (ITO) surface. The resulting FeTPPS-TiO2-modified ITO electrode showed a photocurrent response at +0.2 V to a light excitation at 380 nm, which could be further sensitized through an oxidation process of biomolecules by the hole injected FeTPPS. Using glutathione as a model, a methodology for sensitive photoelectrochemical biosensing at low potential was thus developed. Under optimal conditions, the proposed photoelectrochemical method could detect glutathione ranging from 0.05 to 2.4 mmol L-1 with a detection limit of 0.03 mmol L-1 at a signal-to-noise ratio of 3. The photoelectrochemical biosensor had an excellent specificity against anticancer drugs and could be successfully applied to the detection of reduced glutathione in gluthion injection, showing a promising application in photoelectrochemical biosensing. PMID- 20857917 TI - Enantioselective synthesis of alpha-methyl carboxylic acids from readily available starting materials via chemoenzymatic dynamic kinetic resolution. AB - An enantioselective method for the synthesis of alpha-methyl carboxylic acids starting from trans-cinnamaldehyde, a readily available and inexpensive compound, has been developed. Allylic alcohol 1 was obtained via a standard Grignard addition to trans-cinnamaldehyde. Dynamic kinetic resolution was applied to allylic alcohol 1 utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important alpha methyl substituted carboxylic acids in high ee and overall yields of up to 76%. PMID- 20857918 TI - Organocatalytic asymmetric tandem Michael addition-hemiacetalization: a route to chiral dihydrocoumarins, chromanes, and 4H-chromenes. AB - Asymmetric tandem Michael addition-hemiacetalization between aliphatic aldehydes and (E)-2-(2-nitrovinyl)phenols was investigated for constructing benzopyran backbones. Interestingly, the diastereo- and enantioselectivities changed markedly when the reaction was mediated by different types of secondary amine catalysts. The diphenylprolinol silyl ether 7 promoted the reaction with excellent enantioselectivities (up to 99% ee) but with moderate diastereoselectivities (2.8:1 to 10:1). Prolylprolinols are another type of efficient catalyst. Among them, l,l-prolylprolinol 5c is identified as the optimal species, showing high catalytic activity, good enantioselectivities (up to 89% ee), and excellent diasereoselectivities (up to 50:1 dr). Various aliphatic aldehydes and substituted (E)-2-(2-nitrovinyl)phenols were proven to be well tolerated in this tandem reaction. In addition, the chroman-2-ols 3 yielded in the above reactions could be conveniently transformed to synthetically and biologically significant chiral dihydrocoumarin, chroman, and 4H-chromene derivatives. PMID- 20857919 TI - High-energy MnO2 nanowire/graphene and graphene asymmetric electrochemical capacitors. AB - In order to achieve high energy and power densities, we developed a high-voltage asymmetric electrochemical capacitor (EC) based on graphene as negative electrode and a MnO(2) nanowire/graphene composite (MGC) as positive electrode in a neutral aqueous Na(2)SO(4) solution as electrolyte. MGC was prepared by solution-phase assembly of graphene sheets and alpha-MnO(2) nanowires. Such aqueous electrolyte based asymmetric ECs can be cycled reversibly in the high-voltage region of 0-2.0 V and exhibit a superior energy density of 30.4 Wh kg(-1), which is much higher than those of symmetric ECs based on graphene//graphene (2.8 Wh kg(-1)) and MGC//MGC (5.2 Wh kg(-1)). Moreover, they present a high power density (5000 W kg( 1) at 7.0 Wh kg(-1)) and acceptable cycling performance of ~79% retention after 1000 cycles. These findings open up the possibility of graphene-based composites for applications in safe aqueous electrolyte-based high-voltage asymmetric ECs with high energy and power densities. PMID- 20857920 TI - Approaches for the synthesis of functionalized cryptophycins. AB - The first syntheses of bioactive cryptophycins functionalized at unit D were accomplished in a one-pot Staudinger reduction/cyclization step. An azido precursor for the lower part of the backbone was introduced to minimize protective group chemistry and enable a very convenient synthesis of cryptophycin 52 and unit D cryptophycin analogues containing an ester or a free carboxylic acid for bioconjugations. Both new cryptophycin derivatives show high biological activity in cytotoxicity assays. PMID- 20857921 TI - Surface-enhanced Raman spectroscopy of graphene. AB - Surface-enhanced Raman scattering (SERS) exploits surface plasmons induced by the incident field in metallic nanostructures to significantly increase the Raman intensity. Graphene provides the ideal prototype two-dimensional (2d) test material to investigate SERS. Its Raman spectrum is well-known, graphene samples are entirely reproducible, height controllable down to the atomic scale, and can be made virtually defect-free. We report SERS from graphene, by depositing arrays of Au particles of well-defined dimensions on a graphene/SiO(2) (300 nm)/Si system. We detect significant enhancements at 633 nm. To elucidate the physics of SERS, we develop a quantitative analytical and numerical theory. The 2d nature of graphene allows for a closed-form description of the Raman enhancement, in agreement with experiments. We show that this scales with the nanoparticle cross section, the fourth power of the Mie enhancement, and is inversely proportional to the tenth power of the separation between graphene and the center of the nanoparticle. One important consequence is that metallic nanodisks are an ideal embodiment for SERS in 2d. PMID- 20857922 TI - Chemoselective esterification and amidation of carboxylic acids with imidazole carbamates and ureas. AB - Imidazole carbamates and ureas were found to be chemoselective esterification and amidation reagents. A wide variety of carboxylic acids were converted to their ester or amide analogues by a simple synthetic procedure in high yields. PMID- 20857923 TI - Coulometric detection of components in liquid plugs by microfabricated flow channel and electrode structures. AB - Coulometry has been demonstrated to be effective for determining the analyte in a liquid plug on the nanoliter-scale confined in a flow channel. A plug prepared in a rhombus structure of an auxiliary flow channel was placed on a thin-film three electrode system, and hydrogen peroxide was detected as a model analyte. Under a fixed potential, the current decayed rapidly, particularly in shallow flow channels, thus making reproducible amperometric detection difficult. On the other hand, the increasing charge during coulometry facilitated the measurements. A constricted flow channel structure with an array of platinum strips for the working electrode was effective at efficiently consuming the analyte to improve the sensitivity and lower the detection limit. Compared to the case of a single short working electrode with the same area, a 4-fold increase in sensitivity was observed for the best combination of flow channel height and interstrip distance. With an increase in the generated current while maintaining the background at a low level, the detection limit was lowered from 1.3 MUM to 410 nM using working electrodes with the same area. Furthermore, the processing of solutions containing L-glutamate or L-glutamate oxidase and the detection of L-glutamate were demonstrated. PMID- 20857924 TI - Synthesis, crystal structure, and magnetic properties of the copper selenite chloride Cu5(SeO3)4Cl2. AB - A new copper selenite chloride Cu(5)(SeO(3))(4)Cl(2) has been prepared by chemical vapor transport reactions. Its crystal structure was determined by single-crystal X-ray diffraction. The title compound crystallizes in the monoclinic space group P2(1)/c with the unit cell parameters a = 10.9104(8) A, b = 8.3134(6) A, c = 7.5490(6) A, beta = 90.715(6) degrees , Z = 2, and R(1) = 0.0383. Bond valence sum calculations indicate that the cations have the oxidation state Cu(II) and Se(IV), respectively. Three crystallographic different copper atoms, having different coordination polyhedra, [CuO(5)], [CuO(6)], and [CuO(3)Cl(2)], are connected by corner and edge sharing to form a framework that can be described as metal-oxygen slabs connected by Cl atoms via edge sharing [CuO(3)Cl(2)] polyhedra. The two crystallographic different selenium atoms both have [SeO(3)E] coordination, where E is the 4s(2) lone pair on Se(IV); they are isolated from each other and do bond to the Cu-coordination polyhedra only. The magnetic properties of the Cu(2+) ions with effective spin S = 1/2 moments are dominated by antiferromagnetic interactions. For temperatures T < T(c) ~45 K, Neel magnetic ordering is observed with small ferromagnetic canted moments. We attribute these to antisymmetric Dzyaloshinskii-Moriya (DM) spin exchange which is allowed by the low symmetry spin exchange paths along the distorted transition metal oxyhalide coordinations. PMID- 20857925 TI - Aging induced Ag nanoparticle rearrangement under ambient atmosphere and consequences for nanoparticle-enhanced DNA biosensing. AB - Localized surface plasmons of metallic nanoparticles can strongly amplify the magnitude of the surrounding electric field. This in turn enhances fluorescence from nearby fluorophores. However, little is known regarding how time-dependent changes in nanoparticle structure due to exposure to the ambient environment affect their behavior in plasmonic devices. Here, we report the interesting finding that the aging of a nanostructured Ag substrate in ambient atmosphere markedly improves the fluorescence signal of a plasmonic-based DNA detection system. The effect can be observed with an exposure time as short as two days, and a nearly 17-fold signal enhancement can be achieved with 30 days of aging. Analysis of substrate surface topography by atomic force microscopy (AFM) reveals a substantial change in nanoparticle morphology as the substrates age despite being covalently attached to a solid dry substrate. Nanoparticle morphological changes also manifest in extinction spectra. This process can be further accelerated by light. Together, our findings address the important question of Ag nanoparticle stability over time and its potential ramifications for plasmon enabled sensors. They also imply that nanoparticle aging may be used strategically to tune nanoparticle size and geometry and plasmon spectrum, which may be beneficial for studies on plasmonics as well as sensor optimization. PMID- 20857926 TI - Zinc binding drives sheet formation by the SAM domain of diacylglycerol kinase delta. AB - The diacylglycerol kinase (DGK) family of enzymes plays critical roles in lipid signaling pathways by converting diacylglycerol to phosphatidic acid, thereby downregulating signaling by the former and upregulating signaling by the latter second messenger. Ten DGK family isozymes have been identified to date, which possess different interaction motifs imparting distinct temporal and spatial control of DGK activity to each isozyme. Two DGK family members, delta and eta, contain a sterile alpha motif (SAM) domain. The SAM domain of DGKdelta1 forms helical polymers that are important for retaining the enzyme in cytoplasmic puncta, thereby inhibiting activity at the plasma membrane until pathway activation. Because zinc was found to be important for stabilizing the similar SAM polymers of the scaffolding protein Shank-3, we investigated the potential role of zinc in DGKdelta SAM domain (DGKdeltaSAM) assembly. We find that DGKdeltaSAM binds zinc at multiple sites, driving the organization of the DGKdeltaSAM into large sheets of polymers. Moreover, a mutant DGKdelta containing a SAM domain refractory to zinc binding diminishes the formation of cytoplasmic puncta, shows partially impaired regulation of transport to the plasma membrane, and lacks the ability to inhibit the formation of CopII coated vesicles. These results suggest that zinc may play an important role in the assembly and physiology of the DGKdelta isozyme. PMID- 20857927 TI - In vitro and in vivo characterization of novel 18F-labeled bombesin analogues for targeting GRPR-positive tumors. AB - The gastrin-releasing peptide receptor (GRPR) is overexpressed on a number of human tumors and has been targeted with radiolabeled bombesin analogues for the diagnosis and therapy of these cancers. Seven bombesin analogues containing various linkers and peptide sequences were designed, synthesized, radiolabeled with (18)F, and characterized in vitro and in vivo as potential PET imaging agents. Binding studies displayed nanomolar binding affinities toward human GRPR for all synthesized bombesin analogues. Two high-affinity peptide candidates 6b (K(i) = 0.7 nM) and 7b (K(i) = 0.1 nM) were chosen for further in vivo evaluation. Both tracers revealed specific uptake in GRPR-expressing PC-3 tumors and the pancreas. Compared to [(18)F]6b, compound [(18)F]7b was characterized by superior tumor uptake, higher specificity of tracer uptake, and more favorable tumor-to-nontarget ratios. In vivo PET imaging allowed for the visualization of PC-3 tumor in nude mice suggesting that [(18)F]7b is a promising PET tracer candidate for the diagnosis of GRPR-positive tumors in humans. PMID- 20857928 TI - Dendritic polyglycerols with oligoamine shells show low toxicity and high siRNA transfection efficiency in vitro. AB - RNA interference provides great opportunities for treating diseases from genetic disorders, infection, and cancer. The successful application of small interference RNA (siRNA) in cells with high transfection efficiency and low cytotoxicity is, however, a major challenge in gene-mediated therapy. Several pH responsive core shell architectures have been designed that contain a nitrogen shell motif and a polyglycerol core, which has been prepared by a two-step protocol involving the activation of primary and secondary hydroxyl groups by phenyl chloroformate and amine substitution. Each polymer was analyzed by particle size and zeta potential measurements, whereas the respective polyplex formation was determined by ethidium bromide displacement assay, atomic force microscopy (AFM), and surface charge analysis. The in vitro gene silencing properties of the different polymers were evaluated by using a human epithelial carcinoma cell (HeLaS3) line with different proteins (Lamin, CDC2, MAPK2). Polyplexes yielded similar knockdown efficiencies as HiPerFect controls, with comparably low cytotoxicity. Therefore, these efficient and highly biocompatible dendritic polyamines are promising candidates for siRNA delivery in vivo. PMID- 20857929 TI - A framework for evaluating the contribution of transformation products to chemical persistence in the environment. AB - The REACH legislation of the EU requires that transformation products be included in chemicals assessment for chemicals produced or imported in amounts exceeding 100 tones/year. However, including transformation products in assessments could be considered an intractable problem, particularly given the paucity of available data and the difficulty of predicting the most likely transformation route from the many possible products of a complex parent chemical (the so-called "combinatorial explosion" problem). Here, we present a scheme for identifying transformation products that substantially contribute to the joint persistence of a parent chemical and its substance family. Our scheme integrates methods for the prediction of biodegradation products, the estimation of physicochemical properties and degradation half-lives, and the calculation of a persistence metric, the joint persistence. We compare results from our scheme to 22 test cases with known transformation products. Our results highlight that the "combinatorial explosion" problem can be managed but that there is a serious need for better data for environmental half-lives of chemicals. PMID- 20857930 TI - Untying knots in proteins. AB - A shoelace can be readily untied by pulling its ends rather than its loops. Attempting to untie a native knot in a protein can also succeed or fail depending on where one pulls. However, thermal fluctuations induced by the surrounding water affect conformations stochastically and may add to the uncertainty of the outcome. When the protein is pulled by the termini, the knot can only get tightened, and any attempt at untying results in failure. We show that, by pulling specific amino acids, one may easily retract a terminal segment of the backbone from the knotting loop and untangle the knot. At still other amino acids, the outcome of pulling can go either way. We study the dependence of the untying probability on the way the protein is grasped, the pulling speed, and the temperature. Elucidation of the mechanisms underlying this dependence is critical for a successful experimental realization of protein knot untying. PMID- 20857932 TI - High-yield singlet fission in a zeaxanthin aggregate observed by picosecond resonance Raman spectroscopy. AB - We report high-yield triplet generation by singlet fission upon photoexcitation of a new aggregate of the carotenoid all-trans 3R,3'R-zeaxanthin. The yield is determined by picosecond time-resolved resonance Raman spectroscopy, which allows direct characterization and quantification of triplet excited-state signatures and ground-state depletion. The technique and analysis reveals that triplets form within picoseconds. A quantum yield of 90-200% is derived with the assumption of weak exciton-coupling in the zeaxanthin aggregate. PMID- 20857931 TI - Microfluidic measurement of antibody-antigen binding kinetics from low-abundance samples and single cells. AB - We present a simple microfluidic fluorescence bead assay for accurately measuring antibody-antigen binding kinetics with a standard inverted fluorescent microscope. We measured association and dissociation rate constants from antibody antigen interactions spanning nearly 4 orders of magnitude in equilibrium binding affinity (30 pM-100 nM). Two versions of this assay are presented, which allow for dissociation rate measurements either directly, by use of fluorescently labeled antigen, or indirectly, by use of unlabeled antigen. We also demonstrate simultaneous, multiplexed binding measurements of multiple antibody-antigen interactions using a combination of spectral separation and spatial localization. Complete antibody-antigen binding kinetics were measured for as little as 8 * 104 antibody molecules (~132 zeptomoles) immobilized on a single bead and less than 2 * 106 antibodies (~3 attomoles) loaded into the microfluidic device, a reduction in detection limit and sample consumption of 4 orders of magnitude when compared to surface plasmon resonance (SPR) spectroscopy and alternative measurement techniques. We show that the microfluidic bead assay, when combined with small volume compartmentalization, enables direct measurement of antigen binding kinetics of antibodies secreted from single hybridoma cells. We anticipate that this assay will be useful as a routine analytical tool for studying molecular interactions as well as for screening primary antibody-secreting plasma cells isolated from immunized animals. PMID- 20857933 TI - Synthesis of poly(3-alkylthiophene)-block-poly(arylisocyanide): two sequential, mechanistically distinct polymerizations using a single catalyst. AB - Block copolymers of poly(3-hexylthiophene) and a poly(arylisocyanide) were synthesized in a single pot via the addition of 2-bromo-3-hexyl-5 chloromagnesiothiophene followed by n-decyl 4-isocyanobenzoate to a solution of Ni(1,3-bis(diphenylphosphino)propane)Cl(2). The respective mechanistically distinct polymerizations proceeded in a controlled fashion and afforded well defined block copolymers with tunable molecular weights and compositions. The block copolymers exhibited microphase separation characteristics in the solid state. PMID- 20857934 TI - Simple flow injection analysis system for simultaneous determination of phenolic antioxidants with multiple pulse amperometric detection at a boron-doped diamond electrode. AB - A method for simultaneous determination of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) in food was developed that uses multiple pulse amperometry (MPA) with flow injection analysis (FIA). Determination of these phenolic antioxidants was carried out with a cathodically pretreated boron-doped diamond electrode and an aqueous ethanolic (30% ethanol, v/v) 10 mmol L-1 KNO3 solution (pH(cond) = 1.5) as supporting electrolyte. A dual-potential waveform, at E(det1) = 850 mV/200 ms and E(det2) = 1150 mV/200 ms versus Ag/AgCl (3.0 mol L 1 KCl), was employed. The use of E(det1) or E(det2) caused the oxidation of BHA or of BHA and BHT, respectively; hence, concentration subtraction could be used to determine both species. The respective analytical curves presented good linearity in the investigated concentration range (0.050-3.0 MUmol L-1 for BHA and 0.70-70 MUmol L-1 for BHT), and the detection limits were 0.030 MUmol L-1 for BHA and 0.40 MUmol L-1 for BHT. The proposed method, which is simple, quick, and presents good precision and accuracy, was successfully applied in the simultaneous determination of BHA and BHT in commercial mayonnaise samples, with results similar to those obtained by HPLC, at a 95% confidence level. PMID- 20857935 TI - Total synthesis of (+)-perophoramidine and determination of the absolute configuration. AB - The first asymmetric total synthesis of (+)-perophoramidine has been achieved in 17 steps with ~11% overall yield. The key step relies on an asymmetric biomimetic Diels-Alder reaction between the in situ-generated chiral diene T-24 and the substituted tryptamine 23 to assemble the core structure 27a in a highly efficient way. An acid-catalyzed thermodynamic equilibrium results in C?N double bond migration of the amidine moiety in 37, which guarantees a regioselective methylation on N(1) at the end of the synthesis. The absolute configuration of (+)-perophoramidine was determined by X-ray crystallographic analysis of the chiral intermediate 32 and comparison of the rotation of synthetic (+) perophoramidine with that of the natural product. PMID- 20857936 TI - Palladium-catalyzed conversion of aryl and vinyl triflates to bromides and chlorides. AB - The palladium-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) has been developed using dialkylbiaryl phosphine ligands. A variety of aryl, heteroaryl, and vinyl halides can be prepared via this method in good to excellent yields. PMID- 20857937 TI - Characterization of photoelectric properties and composition effect of TiO(2)/ZnO/Fe(2)O(3) composite by combinatorial methodology. AB - On the basis of combinatorial methodology and the idea of an equilateral ingredient triangle, the TiO(2)/ZnO/Fe(2)O(3) composite system including 66 ingredient points was designed. The photocurrents under different light sources and bias voltages were measured, and the photocurrent amplitude at 300 s was chosen as a parameter to evaluate the photoelectric response of the composite. To appraise the composition effect of the composite compared with pure materials, the quantitative formula of the composition effect has been provided for the first time in this paper. We found that not all the ingredient points demonstrated the enhanced composition effect in the as-designed ingredient triangle material library. The reasons of different composition effect for different ingredient points have been discussed in detail. X-ray diffraction (XRD) and field emission scanning electron microscopy (FE-SEM) were used to investigate the phase structure and the grain morphology of the composite. PMID- 20857938 TI - Application of nonparametric multivariate analyses to the authentication of wild and farmed European sea bass (Dicentrarchus labrax). Results of a survey on fish sampled in the retail trade. AB - The aim of this study was to apply biometric measurements and analyses of proximate composition, fatty acid composition, and ratios of stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N) in muscle tissue to reliably differentiate between wild and farmed European sea bass (Dicentrarchus labrax). Farmed (n = 20) and wild (n = 19) European sea bass were purchased between March and May 2008 and used as standard samples. In the same months, a survey was conducted to evaluate the truthfulness of the statements on the labels of European sea bass sold in retail markets (declared farmed n = 34 and declared wild n = 33). In addition, data from the literature (reference) were employed to build the profile type of wild and farmed European sea bass. Primarily, an exploration and comparison of the analytical data of the standard data set based on principal component analysis and permutation test were performed. Afterward, an inferential statistical approach based on nonparametric combination test methodology (NPC) was applied on standard samples to check its suitability in discriminating the production method. This multivariate statistical analysis selected 30 variables on a total of 36 available. The validation of standard fish data set was accomplished by a novel nonparametric rank-based method according to profile type (just 1 misclassification over 39 samples). Both the NPC test and nonparametric rank-based method were then applied to survey fishes using the selected variables with the aim to classify the individual European sea bass as "true farmed" or "true wild". The former test segregated 10 fishes over 33 declared wild, whereas the results obtained by the nonparametric rank-based method showed that 11 of 33 declared wild European sea bass samples could be unquestionably attributed to the wild cluster. Moreover, considering the comparative contribution of profile type, a few surveyed farmed samples were ascribed to the wild cluster. PMID- 20857939 TI - Light-induced covalent immobilization of monolayers of magnetic nanoparticles on hydrogen-terminated silicon. AB - Specifically tailored omega-alkenyl-1-carboxylic acids were synthesized for use as surfactants in the single-step preparation of manganese ferrite (MnFe2O4) nanoparticles (NPs). Monodisperse manganese ferrite NPs terminated with omega alkenyl moieties were prepared via a one-pot reaction at high temperature without the need of ligand exchange. Using this approach, simple adjustment of the rate of heating allowed precise tuning of the size of the nanoparticles, which were characterized in bulk form by transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD). These surfactant-coated magnetic nanoparticles were then deposited onto hydrogen terminated silicon(111) wafers and covalently anchored to the surface by UV initiated covalent bonding. Analysis by scanning electron microscopy (SEM) and X ray photoelectron spectroscopy (XPS) confirmed that the UV treatment led to covalent immobilization of the NPs on the silicon surface with a consistent packing density across the surface. The magnetic properties of the stable, surface-bound nanoparticle arrays were characterized using a superconducting quantum interference device (SQUID) magnetometer. The materials and methods described here are being developed for use in bit-patterned ultrahigh density magnetic recording media and nanoscale biomagnetic sensing. PMID- 20857940 TI - Iron(II) and ruthenium(II) complexes containing P, N, and H ligands: structure, spectroscopy, electrochemistry, and reactivity. AB - The purpose of this work was to explore the possibility of using iron(II) hydrides in CO(2) reduction and to compare their reactivity to that of their ruthenium analogues. Fe(bpy)(P(OEt)(3))(3)H(+) and Ru(bpy)(P(OEt)(3))(3)H(+) do not react with CO(2) in acetonitrile, but the one-electron-reduction products of Ru(bpy)(P(OEt)(3))(3)H(+) and Ru(bpy)(2)(P(OEt)(3))H(+) and the two-electron reduction product of Fe(bpy)(P(OEt)(3))(3)H(+) do. Ru(bpy)(2)(P(OEt)(3))H(+) also reacts slowly with CO(2) to give a formate complex [as reported previously by Albertin et al. (Inorg. Chem. 2004, 43, 1336)] with a second-order rate constant of ~4 * 10(-3) M(-1) s(-1) in methanol. The structures for the hydride complexes [Fe(bpy)(P(OEt)(3))(3)H](+) and [Ru(bpy)(2)(P(OEt)(3))H](+) and for the (eta(5) Cp)bis- and -tris-PTA complexes (PTA = 1,3,5-triaza-7 phosphatricyclo[3.3.1.13.7]decane) of iron(II) are reported. These and the CpFe(CO)(bpy)(+) and Fe(II)PNNP compounds have been subjected to electrochemical and UV-vis spectroscopic characterization. Fe(bpy)(P(OEt)(3))(3)H(+) exhibits a quasi-reversible oxidation at +0.42 V vs AgCl/Ag in acetonitrile; Ru(bpy)(P(OEt)(3))(3)H(+) and Ru(bpy)(2)(P(OEt)(3))H(+) are oxidized irreversibly at +0.90 and +0.55 V, respectively, vs AgCl/Ag. The reduction site for Fe(bpy)(P(OEt)(3))(3)H(+) and Fe(bpy)(P(OEt)(3))(3)(CH(3)CN)(2+) appears to be the metal and gives rise to a two-electron process. The bpy-centered reductions are negatively shifted in the ruthenium(II) hydride complexes, compared to the acetonitrile complexes. The results of attempts to prepare other iron(II) hydrides are summarized. PMID- 20857941 TI - Highly strained compliant optical metamaterials with large frequency tunability. AB - Metamaterial designs are typically limited to operation over a narrow bandwidth dictated by the resonant line width. Here we report a compliant metamaterial with tunability of Deltalambda ~ 400 nm, greater than the resonant line width at optical frequencies, using high-strain mechanical deformation of an elastomeric substrate to controllably modify the distance between the resonant elements. Using this compliant platform, we demonstrate dynamic surface-enhanced infrared absorption by tuning the metamaterial resonant frequency through a CH stretch vibrational mode, enhancing the reflection signal by a factor of 180. Manipulation of resonator components is also used to tune and modulate the Fano resonance of a coupled system. PMID- 20857942 TI - Reaction of trimethylsilylacetylenes with antimony pentafluoride under matrix isolation conditions: experimental and computational study. AB - Reaction of trimethylsilylacetylenes Me(3)SiC=CR with SbF(5) in the solid state was investigated using matrix isolation infrared spectroscopy and quantum mechanical calculations. Two reaction pathways were detected. Replacement of the trimethylsilyl group with SbF(4) produces neutral antimony acetylides F(4)SbC=CR. Acetylenic bond protonation produces silyl cation 6-R, fully bridged for R = H and SiMe(3). High total charges on the bridging SiMe(3) group and low Me(3)Si-C bond orders to acetylenic moiety, both calculated at the MP4(SDQ)/6-311G(d,p) level of theory, indicate high silyl cation character of these species. PMID- 20857943 TI - Effect of surface chemistry on electronic properties of carbon nanotube network thin film transistors. AB - Thin films of single-walled carbon nanotubes (SWNTs) are a viable nanomaterial for next generation sensors, transistors, and electrodes for solar cells and displays. Despite their remarkable properties, challenges in synthesis and processing have hindered integration in current electronics. Challenges include the inability to precisely assemble and control the deposition of SWNT films on a variety of surfaces and the lack of understanding of the transport properties of these films. Here, we utilize an optimized "dry transfer" technique that facilitates the complete intact transfer of SWNT films between different surfaces. We then show the effect of surface chemistry on the electronic properties of SWNT films. By isolating the effect of the surface, we gain insight into the fundamental transport properties of SWNTs on surfaces with different chemical functionalities. Thin film transistor (TFT) characteristics, corroborated with MU-Raman spectroscopy, show that by using different surface chemical functionalities it is possible to alter the electronic properties of SWNT films. This opens up another route to tune the electronic properties of integrated SWNT films. PMID- 20857944 TI - Cooperative catalysis with metal and secondary amine: synthesis of 2-substituted quinolines via addition/cycloisomerization cascade. AB - A cooperative catalytic system, consisting of CuI and pyrrolidine, has been developed for an efficient synthesis of 2-substituted quinolines. A combination of both the catalysts is necessary; the use of either catalyst alone does not give the product. PMID- 20857945 TI - Probing exciton localization in single-walled carbon nanotubes using high resolution near-field microscopy. AB - We observe localization of excitons in semiconducting single-walled carbon nanotubes at room temperature using high-resolution near-field photoluminescence (PL) microscopy. Localization is the result of spatially confined exciton energy minima with depths of more than 15 meV connected to lateral energy gradients exceeding 2 meV/nm as evidenced by energy-resolved PL imaging. Simulations of exciton diffusion in the presence of energy variations support this interpretation predicting strongly enhanced PL at local energy minima. PMID- 20857946 TI - Visualizing light-triggered release of molecules inside living cells. AB - The light-triggered release of deoxyribonucleic acid (DNA) from gold nanoparticle based, plasmon resonant vectors, such as nanoshells, shows great promise for gene delivery in living cells. Here we show that intracellular light-triggered release can be performed on molecules that associate with the DNA in a DNA host-guest complex bound to nanoshells. DAPI (4',6-diamidino-2-phenylindole), a bright blue fluorescent molecule that binds reversibly to double-stranded DNA, was chosen to visualize this intracellular light-induced release process. Illumination of nanoshell-dsDNA-DAPI complexes at their plasmon resonance wavelength dehybridizes the DNA, releasing the DAPI molecules within living cells, where they diffuse to the nucleus and associate with the cell's endogenous DNA. The low laser power and irradiation times required for molecular release do not compromise cell viability. This highly controlled co-release of nonbiological molecules accompanying the oligonucleotides could have broad applications in the study of cellular processes and in the development of intracellular targeted therapies. PMID- 20857947 TI - General route toward patterning of graphene oxide by a combination of wettability modulation and spin-coating. AB - A general route was demonstrated to realize the patterning of reduced graphene oxide sheets (RGOs) on a variety of substrates by a combination of modulating the solution wettability of the substrates and spin-coating process. By virtue of usual surface treatment technique or application of mixed solvent, the GO solution wettability can be controlled precisely. The wettability modulation combined with spin-coating and reducing process brings on patterning of RGOs. This simple but effective, general, and low-cost approach holds great promise for numerous potential applications in organic electronics, flexible transparent conducting thin films, and flexible semi-transparent sensors. PMID- 20857948 TI - A colorimetric proton sponge. AB - 1,8-Bis(dimethylamino)naphthalene ("Proton Sponge") and bromomaleic anhydride react quickly at room temperature, generating 3-(4,5-bis(dimethylamino)napthalen 1-yl)furan-2,5-dione (4-maleicanhydridoproton sponge or "MAPS"). MAPS is a deep purple solid that exhibits positive solvatochromism in solution. It is a weaker base than Proton Sponge. When protonated in solution, MAPS loses its color, but the color change can be reversed by deprotonation with a stronger base. MAPS thus acts as a colorimetric version of a proton sponge. PMID- 20857949 TI - Enhanced capacity and rate capability of carbon nanotube based anodes with titanium contacts for lithium ion batteries. AB - Carbon nanotubes are being considered for adoption in lithium ion batteries as both a current collector support for high-capacity active materials (replacing traditional metal foils) and as free-standing electrodes where they simultaneously store lithium ions. The necessity to establish good electrical contact to these novel electrode designs is critical for success. In this work, application of nickel and titanium as both separable and thin film electrical contacts to free-standing single-wall carbon nanotube (SWCNT) electrodes is shown to dramatically enhance both the reversible lithium ion capacity and rate capability in comparison with stainless steel. Scanning electron microscopy showed that evaporation of Ni and Ti can effectively coat the SWCNT bundles in a bulk electrode which is capable of providing an improved electrical contact. A thin film of titanium emerged as the preferred electrical contact promoting the highest capacity ever measured for a SWCNT free-standing electrode of 1250 mAh/g. In addition, the titanium contacting approach demonstrated a 5-fold improvement in lithium ion capacity at extraction rates greater than 1C for a high-energy density Ge-SWCNT electrode. The overall performance improvement with Ti contacts is attributed to a lower contact resistance, nanoscale "wetting" of SWCNT bundles to improve contact uniformity, and effective electron coupling between Ti and SWCNTs due to work function-energy level alignment. The experimental results provide the basis for a Ragone analysis (power vs energy parameters), whereby Ge SWCNT-Ti anodes paired with a LiFePO(4) cathode can lead to a 60% improvement over conventional graphite anodes in both power and energy density for a complete battery. PMID- 20857950 TI - Micellar shape driven counterion binding. Small-angle neutron scattering study of AOT micelle. AB - Sodium dioctylsulfosuccinate (AOT) micelle has a special counterion binding behavior in aqueous electrolyte medium, viz., the counterion binding constant (beta) abruptly increases by 2-fold at about 0.015 mol dm(-3) NaCl concentration (c*), but not in sodium salicylate (NaSa) solution. Since counterions affect the structure and performance of ionic surfactants, ascertaining the cause for the sudden shift in the beta value of AOT micelle is of fundamental importance. In this study the special counterion binding behavior of AOT micelle has been ascertained at 40 degrees C by carrying out surface tension, zeta potential, and fluorescence emission (pyrene probe) measurements. The results of the small-angle neutron scattering experiment carried out at 40 degrees C showed that at c* the shape of AOT micelle changes from prolate spheroid to rodlike in NaCl solution, but not in NaSa solution, thus establishing micellar shape change as responsible for the abrupt change in beta value. The absence of sudden shift in beta of AOT micelle in NaSa solution is attributed to the binding of salicylate coanion to AOT micelle through hydrophobic interaction. PMID- 20857951 TI - Tetraquinanes via [4 + 4] photocycloaddition/transannular ring closure. AB - Intramolecular [4 + 4] photocycloaddition of a furan and a cyclopentane-annulated 2-pyridone yields a cyclooctadiene product with four new stereogenic centers. Transannular ring closure produces the 5-5-5-5 fused ring system of the crinipellins, including three contiguous quaternary carbons, with the correct absolute stereochemistry derived from (-)-carvone. PMID- 20857954 TI - Charge-coupled transient model for electrowetting. AB - Electrowetting is widely used as a means to increase the wettability of droplets on a substrate covered by a dielectric. Although static or quasi-static models of the triple-line movement already exist, little research has been published on transient modeling coupled to the charge transient. This work describes a model of two differential equations coupling the charging to the movement taking into account friction. The model results are validated by comparison to published experimental results. The model focuses on applications, and hence the time to respond, the power consumption, and the energy and its breakdown into components are calculated. Moreover, the use of a generalized voltage source allows us to model successfully the results of a "corona charge" experiment as a means to increase wettability without contact between the electrode and the liquid sample. Finally, the model is extended to an ideal "charge-driven mode" electrowetting proposal resulting in better controllability of the speed and transient time between two contact angle values with applications to lab-on-a chip or displays. PMID- 20857953 TI - Stereocontrolled synthesis of contiguous C(sp3)-C(aryl) bonds by lanthanide(III) catalyzed domino aryl-Claisen [3,3]-sigmatropic rearrangements. AB - A domino [3,3]-sigmatropic aryl-Claisen rearrangement of cyclic and acyclic bisaryloxy-substituted alkenes can be performed in high yield by using Ln(fod)(3) catalysis to obtain bisphenolic products incorporating two contiguous aryl C(sp(3)) bonds. Stereospecific rearrangement was observed for cyclic substrates. The precursor diaryl ethers were typically synthesized from the corresponding diols by double arylation procedures using either copper catalyzed coupling of aryltrifluoroborate salts or by S(N)Ar reaction. PMID- 20857952 TI - Free-standing and reactive thin films fabricated by covalent layer-by-layer assembly and subsequent lift-off of azlactone-containing polymer multilayers. AB - We report an approach to the fabrication of free-standing and amine-reactive thin films that is based on the reactive layer-by-layer assembly and subsequent lift off of azlactone-containing polymer multilayers. We demonstrate that covalently cross-linked multilayers fabricated using the azlactone-functionalized polymer poly(2-vinyl-4,4-dimethylazlactone) (PVDMA) and a primary amine-containing polymer [poly(ethyleneimine) (PEI)] can be delaminated from planar glass and silicon surfaces by immersion in mildly acidic aqueous environments to yield flexible freestanding membranes. These free-standing membranes are robust and can withstand exposure to strong acid, strong base, or incubation in high ionic strength solutions that typically lead to the disruption and erosion of polymer multilayers assembled by reversible weak interactions (e.g., "polyelectrolyte multilayers" assembled by electrostatic interactions or hydrogen bonding). We demonstrate further that these PEI/PVDMA assemblies contain residual reactive azlactone functionality that can be exploited to chemically modify the films (either directly after fabrication or after they have been lifted off of the substrates on which they were fabricated) using a variety of amine-functionalized small molecules. These free-standing membranes can also be transferred readily onto other objects (for example, onto the surfaces of planar substrates containing holes or pores) to fabricate suspended polymer membranes and other film-functionalized interfaces. In addition to planar, two-dimensional free standing films, this approach can be used to fabricate and isolate three dimensional free-standing membranes (e.g., curved films or tubes) by layer-by layer assembly on, and subsequent lift-off from, the surfaces of topologically complex substrates (e.g., the curved ends of glass tubing, etc.). The results of this investigation, when combined, suggest the basis of methods for the fabrication of stable, chemically reactive, and flexible polymer thin films and membranes of potential utility in a variety of fundamental and applied contexts. PMID- 20857955 TI - Chiral phosphoric acid-catalyzed enantioselective transfer hydrogenation of ortho hydroxyaryl alkyl N-H ketimines. AB - The first enantioselective chiral phosphoric acid-catalyzed transfer hydrogenation of unprotected ortho-hydroxyaryl alkyl N-H ketimines using Hantszch di-tert-butyl ester as a reductant is reported. A variety of ortho hydroxybenzylamines were obtained in good to excellent yields and enantiomeric excesses. PMID- 20857956 TI - Hydrolysis of p-nitrophenyl esters promoted by semifluorinated quaternary ammonium polymer latexes and films. AB - Semifluorinated polymer latexes were prepared by emulsion polymerization of 2.5 25% of a fluoroalkyl methacrylate, 25% chloromethylstyrene, 1% styrylmethyl(trimethyl)ammonium chloride, and the remainder 2-ethylhexyl methacrylate under surfactant-free conditions. The chloromethylstyrene units were converted to quaternary ammonium ions with trimethylamine. In aqueous dispersions at particle concentrations of less than 1 mg mL(-1) the quaternary ammonium ion latexes promoted hydrolyses of p-nitrophenyl hexanoate (PNPH) in pH 9.4 borate buffer and of diethyl p-nitrophenyl phosphate (Paraoxon) in 0.1 M NaOH at 30 degrees C with half-lives of less than 10 min. Thin 0.7-2 MUm films of the latexes on glass promoted fast hydrolysis of Paraoxon but not of PNPH under the same conditions. Even after annealing the quaternary ammonium ion polymer films at temperatures well above their glass transition temperatures, AFM images of the film surfaces had textures of particles. Contact angle measurements of the annealed films against water and against hexadecane showed that the surfaces were not highly fluorinated. PMID- 20857958 TI - Asymmetric synthesis of indolines by catalytic enantioselective reduction of 3H indoles. AB - A highly enantioselective metal-free reduction of 3H-indoles has been developed. This Bronsted acid catalyzed transfer hydrogenation of indole derivatives with Hantzsch dihydropyridine as the hydrogen source constitutes an efficient method for the synthesis of various optically active indolines with high enantioselectivities. PMID- 20857957 TI - Surface orientation of magainin 2: molecular dynamics simulation and sum frequency generation vibrational spectroscopic studies. AB - We combined molecular dynamics based free energy calculations with sum frequency generation (SFG) spectroscopy to study the orientational distribution of solvated peptides near hydrophobic surfaces. Using a simplified atomistic model of the polystyrene (PS) surface, molecular dynamics simulations have been applied to compute the orientational probability of an alpha-helical peptide, magainin 2, with respect to the PS/water interface. Free energy calculations revealed that the preferred (horizontal) peptide orientation was driven by the favorable interactions between the hydrophobic PS surface and the hydrophobic residues on the helix, and additional simulations examined the importance of small aggregate formation. Concentration-dependent measurements obtained via SFG vibrational spectroscopy suggest that, at very low peptide concentrations, magainin molecules tend to lie down at the PS/solution interface, which correlates well with the simulation results. When the concentration is increased, peptides exhibit behavior not captured by MD simulations using single helical peptides. A combination of simulations and experiments was shown to yield more reliable results with molecular-level insights into interaction between peptides and polymer surfaces. PMID- 20857959 TI - Antiviral activity of various 1-(2'-deoxy-beta-D-lyxofuranosyl), 1-(2'-fluoro beta-D-xylofuranosyl), 1-(3'-fluoro-beta-D-arabinofuranosyl), and 2'-fluoro-2',3' didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues against duck hepatitis B virus (DHBV) and human hepatitis B virus (HBV) replication. AB - Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2'-fluoroxylofuranosyl, 3'-fluoroarabinofuranosyl, and 2'-fluoro 2',3'-didehydro-2',3'-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy beta-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-beta-d-lyxofuranosyl)-5 trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-beta-d-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-beta-d-xylofuranosyl)thymine (39), 2',3'-dideoxy-2',3' didehydro-2'-fluorothymidine (48), and 2',3'-dideoxy-2',3'-didehydro-2'-fluoro-5 ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC(50) values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 MUM, respectively. Compounds 23, 25, 39, 48, and 49 (EC(50) = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 MUM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC(50) of 4.1 MUM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 MUM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested. PMID- 20857960 TI - Structural inhomogeneity of water by complex network analysis. AB - There is still an open debate regarding the structure forming capabilities of water at ambient conditions. To probe the presence of such inhomogeneities, we apply complex network analysis methods to a molecular dynamics simulation at room temperature. This study provides both a structural and quantitative characterization of kinetically homogeneous substates present in bulk water. We find that the conformation-space network is highly modular, and that structural properties of water molecules are spatially correlated over at least two solvation shells. From a kinetic point of view, the free energy surface is characterized by multiple heterogeneous metastable regions with different populations and marginal barriers separating them. The typical time scale of hopping between them is 200-400 fs. A scanning in temperature reveals that those substates can be stabilized either entropically or enthalpically. The latter resembles an icelike domain that extends for at least two solvation shells. PMID- 20857961 TI - Influence of cyclosporine A on molecular interactions in lyotropic reverse hexagonal liquid crystals. AB - We present a dielectric study of H(II) mesophases (H(II)) based on a GMO/tricaprylin/phosphatidylcholine/water system seeded with the peptide Cyclosporine A (CSA). The study covers a frequency range 0.01 Hz to 1 MHz and a temperature range of 293 to 319 K, with a 3 K temperature step. Three dielectric relaxation processes are observed and discussed. This picture is further elucidated by comparison with a dielectric study of the empty H(II) mesophase system, previously published, where the same three processes were involved. A complex picture emerges whereby the CSA is intercalated between the surfactant tails yet protrudes into the interface as well. Whereas the CSA remains hydrophobic, it still influences the relaxation behavior of the GMO head and counterion movement along the interface in a nontrivial manner. The third dipolar species, the tricaprylin molecule, is also influenced by the presence of CSA. A critical temperature T(0) = 307 K is recognized and identified as the dehydration temperature of the surfactant heads. This induces a conformal transition in the CSA, drastically changing its effect on the three dielectric processes evident in the raw data. The implications of this behavior are discussed in detail. PMID- 20857962 TI - Facile fabrication of superhydrophobic octadecylamine-functionalized graphite oxide film. AB - We demonstrated a facile strategy of producing superhydrophobic octadecylamine (ODA)-functionalized graphite oxide (GO) films. ODA was chemically grafted on GO sheets by the nucleophilic substitution reaction of amine groups with epoxy groups. The long hydrocarbon chain in ODA reduces the surface energy of the GO sheet. The fabricated ODA-functionalized GO film exhibited a high contact angle (163.2 degrees ) and low hysteresis (3.1 degrees ). This method is promising in terms of low-cost and large-scale superhydrophobic coatings and has potential applications for surface modification of GO paper or other GO-based composite materials. PMID- 20857963 TI - Coverage and aggregation of gold nanoparticles on silanized glasses. AB - We study the dynamics of the coverage and aggregation of gold nanoparticles over organosilanized glass substrates for different sizes of nanoparticles. We present measurements of extinction spectra and nanoparticle counting statistics and demonstrate that both methods are equivalent describing those processes. We introduce models that describe the mentioned dynamics, which are characterized by an exponential-like function with two relevant parameters: a saturation value and a characteristic time. The electrostatic repulsion plays a significant role in both processes. The aggregation is dominated by the mobility of the isolated nanoparticles, which first join in dimers and, further in time, in clusters of higher number of nanoparticles. PMID- 20857964 TI - Peptide-conjugated PAMAM for targeted doxorubicin delivery to transferrin receptor overexpressed tumors. AB - The purpose of this work was to evaluate the potential of HAIYPRH (T7) peptide as a ligand for constructing tumor-targeting drug delivery systems. T7 could target to transferrin-receptor (TfR) through a cavity on the surface of TfR and then transport into cells via endocytosis with the help of transferrin (Tf). In this study, T7-conjugated poly(ethylene glycol) (PEG)-modified polyamidoamine dendrimer (PAMAM) (PAMAM-PEG-T7) was successfully synthesized and further loaded with doxorubicin (DOX), formulating PAMAM-PEG-T7/DOX nanoparticles (NPs). In vitro, almost 100% of DOX was released during 2 h in pH 5.5, while only 55% of DOX was released over 48 h in pH 7.4. The cellular uptake of DOX could be significantly enhanced when treated with T7-modified NPs in the presence of Tf. Also, the in vitro antitumor effect was enhanced markedly. The IC(50) of PAMAM PEG-T7/DOX NPs with Tf was 231.5 nM, while that of NPs without Tf was 676.7 nM. T7-modified NPs could significantly enhance DOX accumulation in the tumor by approximately 1.7-fold compared to that of unmodified ones and by approximately 5.3-fold compared to that of free DOX. For in vivo antitumor studies, tumor growth of mice treated with PAMAM-PEG-T7/DOX NPs was significantly inhibited compared to that of mice treated with PAMAM-PEG/DOX NPs and saline. The study provides evidence that PAMAM-PEG-T7 can be applied as a potential tumor-targeting drug delivery system. T7 may be a promising ligand for targeted drug delivery to the tumor. PMID- 20857965 TI - Hairy carbon nanotube@nano-Pd heterostructures: design, characterization, and application in Suzuki C-C coupling reaction. AB - Poly(glycidyl methacrylate), PGMA, was prepared via ATRP in bulk solution, and its epoxy groups were further acid-hydrolyzed in order to obtain a polymer with glycerol moieties (noted POH). The POH chain end C-Br bonds were subjected to a nucleophilic attack by NaN(3), resulting in azide-terminated POH (POH-N(3)). The CNTs were modified by in-situ-generated alkynylated diazonium cations from the para-alkynylated aniline of the formulas H(2)N-C(6)H(4)-C=C-H, yielding CNT C(6)H(4)-C=C-H nanotubes. The azide-functionalized polymer POH-N(3) was clicked to the alkynyl-modified CNTs giving CNT@POH hybrids, which were further subjected to an oxidation resulting in carboxylated polymer-modified CNTs (noted CNT@PCOOH). The as-designed hairy CNTs served as efficient platforms for the in situ synthesis and massive loading of 3 nm sized palladium nanoparticles (NPs). The CNT@PCOOH@Pd heterostructures prepared so far exhibited an efficient catalytic effect in the C-C Suzuki coupling reaction and were regenerated up to four times without any significant loss of catalytic activity. PMID- 20857966 TI - Metal cation complexation with natural organic matter in aqueous solutions: molecular dynamics simulations and potentials of mean force. AB - Natural organic matter (NOM, or humic substance) has a known tendency to form colloidal aggregates in aqueous environments, with the composition and concentration of cationic species in solution, pH, temperature, and the composition of the NOM itself playing important roles. Strong interaction of carboxylic groups of NOM with dissolved metal cations is thought to be the leading chemical interaction in NOM supramolecular aggregation. Computational molecular dynamics (MD) study of the interactions of Na(+), Mg(2+), and Ca(2+) with the carboxylic groups of a model NOM fragment and acetate anions in aqueous solutions provides new quantitative insight into the structure, energetics, and dynamics of the interactions of carboxylic groups with metal cations, their association, and the effects of cations on the colloidal aggregation of NOM molecules. Potentials of mean force and the equilibrium constants describing overall ion association and the distribution of metal cations between contact ion pairs and solvent-separated ions pairs were computed from free MD simulations and restrained umbrella sampling calculations. The results provide insight into the local structural environments of metal-carboxylate association and the dynamics of exchange among these sites. All three cations prefer contact ion pair to solvent-separated ion pair coordination, and Na(+) and Ca(2+) show a strong preference for bidentate contact ion pair formation. The average residence time of a Ca(2+) ion in a contact ion pair with the carboxylic groups is of the order of 0.5 ns, whereas the corresponding residence time of a Na(+) ion is only between 0.02 and 0.05 ns. The average residence times of a Ca(2+) ion in a bidentate coordinated contact ion pair vs a monodentate coordinated contact ion pair are about 0.5 and 0.08 ns, respectively. On the 10 ns time scale of our simulations, aggregation of the NOM molecules occurs in the presence of Ca(2+) but not Na(+) or Mg(2+). These results agree with previous experimental observations and are explained by both Ca(2+) ion bridging between NOM molecules and decreased repulsion between the NOM molecules due to the reduced net charge of the NOM-metal complexes. Simulations on a larger scale are needed to further explore the relative importance of the different aggregation mechanisms and the stability of NOM aggregates. PMID- 20857967 TI - Interplay between dewetting and layer inversion in poly(4 vinylpyridine)/polystyrene bilayers. AB - We investigated the morphology and dynamics of the dewetting of metastable poly(4 vinylpyridine) (P4VP) thin films situated on top of polystyrene (PS) thin films as a function of the molecular weight and thickness of both films. We focused on the competition between the dewetting process, occurring as a result of unfavorable intermolecular interactions at the P4VP/PS interface, and layer inversion due to the lower surface energy of PS. By means of optical and atomic force microscopy (AFM), we observed how both the dynamics of the instability and the morphology of the emerging patterns depend on the ratio of the molecular weights of the polymer films. When the bottom PS layer was less viscous than the top P4VP layer (liquid-liquid dewetting), nucleated holes in the P4VP film typically stopped growing at long annealing times because of a combination of viscous dissipation in the bottom layer and partial layer inversion. Full layer inversion was achieved when the viscosity of the top P4VP layer was significantly greater (>104) than the viscosity of the PS layer underneath, which is attributed to strongly different mobilities of the two layers. The density of holes produced by nucleation dewetting was observed for the first time to depend on the thickness of the top film as well as the polymer molecular weight. The final (completely dewetted) morphology of isolated droplets could be achieved only if the time frame of layer inversion was significantly slower than that of dewetting, which was characteristic of high-viscosity PS underlayers that allowed dewetting to fall into a liquid-solid regime. Assuming a simple reptation model for layer inversion occurring at the dewetting front, the observed surface morphologies could be predicted on the basis of the relative rates of dewetting and layer inversion. PMID- 20857968 TI - Molecular understanding of conformational dynamics of a fibronectin module on rutile (110) surface. AB - The conformational dynamics of the 10th type-III module of fibronectin (FN III(10)) adsorbed on the perfect and three reduced rutile TiO(2)(110) surfaces with different types of defects was investigated by molecular dynamics (MD) simulations. Stable protein-surface complexes were presented in the four simulated models and were derived from the contributions of direct and indirect interactions of various functional groups in FN-III(10) with the metal oxide layers. A detailed analysis to characterize the overall structural stability of the adsorbed FN-III(10) molecule suggests that the bonding strength and the loss of protein secondary structure vary widely, depending on the topology of the substrate surface. The additional adsorption sites exhibiting higher activity, provided by the reduced surfaces, are responsible for the stronger FN-III(10) TiO(2) interactions, but too high an interaction energy will cause a severe conformational deformation and therefore a significant loss of bioactivity of the adsorbed protein. PMID- 20857969 TI - A {Fe(NO)3}10 trinitrosyliron complex stabilized by an n-heterocyclic carbene and the cationic and neutral {Fe(NO)2}(9/10) products of its NO release. AB - In contrast to the instability of XFe(NO)(3) and [R(3)PFe(NO)(3)](+), the N heterocyclic carbene (NHC)-containing trinitrosyliron complex (TNIC) [(IMes)Fe(NO)(3)][BF(4)] (1) [IMes =1,3-bis(2,4,6-trimethylphenyl)imidazol-2 ylidene] can be readily isolated and manipulated in solution under ambient conditions. Nevertheless, in the presence of thiolates (SR(-)), this EPR-silent TNIC (denoted {Fe(NO)(3)}(10) in the Enemark-Feltham notation) releases gaseous NO, affording in the case of SR(-) = SPh(-) the EPR-active, neutral dinitrosyliron complex (DNIC) (IMes)Fe(SPh)(NO)(2) (3, {Fe(NO)(2)}(9)). Carbon monoxide enforces a bimolecular reductive elimination of PhSSPh from 3, yielding (IMes)(CO)Fe(NO)(2) (2), a reduced {Fe(NO)(2)}(10) DNIC. The NO released from TNIC 1 in the presence of SPh(-) could be taken up by the NO-trapping agent [(bme dach)Fe](2) [bme-dach = N,N'-bis(2-mercaptoethyl)-1,4-diazacycloheptane] to form the mononitrosyliron complex (MNIC) (bme-dach)Fe(NO). In the absence of SPh(-), direct mixing of [(bme-dach)Fe](2) with 1 releases both NO and the NHC with formation of a spin-coupled, diamagnetic {Fe(NO)}(7)-{Fe(NO)(2)}(9) complex, [(NO)Fe(bme-dach)Fe(NO)(2)][BF(4)] (4). In 4, the MNIC serves as a bidentate metallodithiolate ligand of Fe(NO)(2), forming a butterfly complex in which the Fe-Fe distance is 2.7857(8) A. Thus, 1 is found to be a reliable synthon for [{Fe(NO)(2)}(9)](+). The solid-state molecular structures of complexes 1-3 show that all three complexes have a tetrahedral geometry in which the bulky mesitylene substituents of the carbene ligand appear to umbrella the Fe(NO)(2)L [L = NO (1), CO (2), SPh (3)] motif. PMID- 20857970 TI - A versatile photochromic dithienylethene-containing beta-diketonate ligand: near infrared photochromic behavior and photoswitchable luminescence properties upon incorporation of a boron(III) center. AB - A versatile dithienylethene-containing beta-diketonate ligand and its boron(III) compounds have been successfully synthesized. Upon photocyclization, the ligand shows a new absorption band at 630 nm with good fatigue resistance and high thermal stability. Incorporation of the boron center has been demonstrated to shift the photochromic behavior to the NIR region. PMID- 20857971 TI - Effect of gastric conditions on beta-lactoglobulin interfacial networks: influence of the oil phase on protein structure. AB - Understanding the effects of digestion conditions on the structure of interfacial protein networks is important in order to rationally design food emulsions which can moderate lipid digestion. This study compares the effect of gastric conditions (pH, temperature, and ionic strength) on beta-lactoglobulin films at different fluid interfaces: air-water, tetradecane-water, and olive oil-water. The experiments have been designed to simulate the passage into the stomach media. Hence, preformed interfacial protein (beta-lactoglobulin) networks have been exposed to gastric conditions in order to establish generic aspects of the digestion process. The results show that the presence of an oil phase affects both the unfolding of the protein at the interface on adsorption and the subsequent interprotein associations responsible for network formation at the interface. Furthermore, the effects of the physiological conditions characteristic of the stomach also altered differently the preformed protein layer at different fluid interfaces. Initially, the effects of temperature, acid pH, and ionic strength on the dilatational modulus of beta-lactoglobulin adsorbed layers at tetradecane-water and olive oil-water interfaces were studied in isolation. The presence of salt was found to have a major effect on the dilatational response at the oil-water interface in contrast to the observations at the air-water interface: it enhanced intermolecular association, hence increasing the packing at the interface causing it to become more elastic. Exposure to acid pH (2.5) also increased the elasticity of the interface, possibly due to the fact that strong electrostatic interactions acting at the interface compensated for the reduced level of intermolecular association. However, the increase in dilatational modulus at the oil-water interface was less noticeable upon exposure to combined changes in acid pH and ionic strength, as would occur in the stomach. This is consistent with previously reported observations at the air-water interface. The quantitative differences in the response of the protein networks to gastric media at different fluid interfaces are discussed in terms of the conformation of beta-lactoglobulin within the networks formed at each interface based on detailed theoretical modeling of adsorption data. PMID- 20857972 TI - Facile proton conduction via ordered water molecules in a phosphonate metal organic framework. AB - A new phosphonate metal-organic framework (MOF) with a layered motif but not that of the classical hybrid inorganic-organic solid is presented. Zn(3)(L)(H(2)O)(2).2H(2)O (L = [1,3,5-benzenetriphosphonate](6-)), henceforth denoted as PCMOF-3, contains a polar interlayer lined with Zn-ligated water molecules and phosphonate oxygen atoms. These groups serve to anchor free water molecules into ordered chains, as observed by X-ray crystallography. The potential for proton conduction via the well-defined interlayer was studied by (2)H solid-state NMR spectroscopy and AC impedance spectroscopy. The proton conductivity in H(2) was measured as 3.5 * 10(-5) S cm(-1) at 25 degrees C and 98% relative humidity. More interestingly, an Arrhenius plot gave a low activation energy of 0.17 eV for proton transfer, corroborating the solid-state NMR data that showed exchange between all deuterium sites in the D(2)O analogue of PCMOF-3, even at -20 degrees C. PMID- 20857973 TI - Predominant (6,5) single-walled carbon nanotube growth on a copper-promoted iron catalyst. AB - We have developed a magnesia (MgO)-supported iron-copper (FeCu) catalyst to accomplish the growth of single-walled carbon nanotubes (SWNTs) using carbon monoxide (CO) as the carbon source at ambient pressure. The FeCu catalyst system facilitates the growth of small-diameter SWNTs with a narrow diameter distribution. UV-vis-NIR optical absorption spectra and photoluminescence excitation (PLE) mapping were used to evaluate the relative quantities of the different (n,m) species. We have also demonstrated that the addition of Cu to the Fe catalyst can also cause a remarkable increase in the yield of SWNTs. Finally, a growth mechanism for the FeCu-catalyzed synthesis of SWNTs has been proposed. PMID- 20857974 TI - SufD and SufC ATPase activity are required for iron acquisition during in vivo Fe S cluster formation on SufB. AB - In vivo biogenesis of Fe-S cluster cofactors requires complex biosynthetic machinery to limit release of iron and sulfide, to protect the Fe-S cluster from oxidation, and to target the Fe-S cluster to the correct apoenzyme. The SufABCDSE pathway for Fe-S cluster assembly in Escherichia coli accomplishes these tasks under iron starvation and oxidative stress conditions that disrupt Fe-S cluster metabolism. Although SufB, SufC, and SufD are all required for in vivo Suf function, their exact roles are unclear. Here we show that SufB, SufC, and SufD, coexpressed with the SufS-SufE sulfur transfer pair, purify as two distinct complexes (SufBC(2)D and SufB(2)C(2)) that contain Fe-S clusters and FADH(2). These studies also show that SufC and SufD are required for in vivo Fe-S cluster formation on SufB. Furthermore, while SufD is dispensable for in vivo sulfur transfer, it is absolutely required for in vivo iron acquisition. Finally, we demonstrate for the first time that the ATPase activity of SufC is necessary for in vivo iron acquisition during Fe-S cluster assembly. PMID- 20857975 TI - Phosphonoxins III: synthesis of alpha-aminophosphonate analogs of antifungal polyoxins with anti-Giardia activity. AB - A synthesis of alpha-aminophosphonate analogs of polyoxins, termed phosphonoxin C1, C2, and C3, has been achieved. The key step was the addition of lithium dimethyl phosphite to the aldehyde of a protected threose derivative. alpha Hydroxyphosphonate analogs C4 and C5 were also obtained by taking advantage of an unprecedented conversion of an azide to hydroxyl during treatment with hydrogen on palladium on carbon. The resulting phosphonoxin C5 inhibited the growth of an intestinal protozoan, Giardia lamblia, at low micromolar concentration. PMID- 20857977 TI - One-pot syntheses of chromeno[3,4-c]pyrrole-3,4-diones via Ugi-4CR and intramolecular Michael addition. AB - One-pot and diastereoselective syntheses of diverse chromeno[3,4-c]pyrrole-3,4 diones from readily available starting materials were achieved via sequential Ugi 4CR and intramolecular Michael addition. PMID- 20857976 TI - Insights into the surface complexation of dimethylarsinic acid on iron (oxyhydr)oxides from ATR-FTIR studies and quantum chemical calculations. AB - The surface chemistry of methylated arsenicals with ubiquitous geosorbents and industrial catalysts is poorly understood. These arsenic compounds pose both a health and an environmental risk in addition to being a challenge to the energy industry. We report herein a detailed spectroscopic analysis of the surface structure of dimethylarsinic acid (DMA) adsorbed on hematite and goethite using attenuated total internal reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Spectra of adsorbed DMA, DMA(ads), were collected in situ as a function of pH and ionic strength, using both H(2)O and D(2)O at 298 K in flow mode. Experimental data were complemented with DFT calculations of geometries and frequencies of hydrated DMA-iron oxide clusters. Results indicate the simultaneous formation of inner- and outer-sphere complexes with distinct spectral components. Desorption behavior of DMA due to chloride and phosphate was studied as a function of time from the decrease in the absorbance of apparent spectral features. The impact of our studies on the environmental fate of DMA in geochemical environments and the design of technologies to reduce arsenic content in fuels are discussed. PMID- 20857978 TI - Charge transfer enhancement in the SERS of a single molecule. AB - We measured the surface-enhanced Raman scattering (SERS) of individual gold nanoparticle-4-aminobenzenethiol (ABT)-gold film junctions to investigate the charge-transfer (CT) enhancement of the SERS signals. Despite the mild electromagnetic field enhancement (~10(5)) and high surface density of the ABT molecules (~240 molecules/hotspot) at the junctions, we observed the clear spectral and temporal signatures of CT-enhanced single-molecule SERS (SM-SERS). The result reveals that only a small fraction of the molecules at the junction has a significant CT-enhancement of 10(1)~10(3), whereas the rest of the molecules are nearly CT-inactive. Furthermore, the result also proves that overall (charge-transfer and electromagnetic) enhancement of 10(6)~10(8) is sufficient to observe the SM-SERS of an electronically off-resonant molecule, which disproves the widespread belief that a minimum enhancement of ~10(14) is required for SM-SERS. PMID- 20857980 TI - Elucidation of the 1,3-sulfanylalcohol oxidation mechanism: an unusual identification of the disulfide of 3-sulfanylhexanol in sauternes botrytized wines. AB - A four-step purification method was developed to isolate a citrus odorant detected by gas chromatography-olfactometry (GC-O), which was apparently specific to Sauternes botrytized wines. A fragmentation pattern of the odorant was obtained by multidimensional gas chromatography-mass spectrometry-olfactometry (MDGC-MS-O). The exact mass measurement was used to determine its elemental formula as C(6)H(12)OS. On the basis of these data, the unusual structure of 3 propyl-1,2-oxathiolane was synthesized and characterized for the first time. This confirmed its identification. Its occurrence in Sauternes wine extracts was demonstrated to result from the thermal oxidative degradation of 3 sulfanylhexanol disulfide (3,3'-disulfanediyldihexan-1-ol) in the GC injector. This disulfide was synthesized and then firmly identified for the first time in Sauternes wine. Although the presence of 3-sulfanylhexanol oxidation products had previously been reported in natural extracts (but not wine), the full oxidation pathway from 3-sulfanylhexanol to 3-propyl-gamma-sultine via 3,3' disulfanediyldihexan-1-ol was clearly established for the first time. Because the disulfide has mainly been detected in Sauternes botrytized wines, this finding suggested a singular reactivity of 3-sulfanylhexanol in botrytized wines, thus opening up a wide range of new opportunities in wine chemistry. PMID- 20857979 TI - Quantitative nanostructure-activity relationship modeling. AB - Evaluation of biological effects, both desired and undesired, caused by manufactured nanoparticles (MNPs) is of critical importance for nanotechnology. Experimental studies, especially toxicological, are time-consuming, costly, and often impractical, calling for the development of efficient computational approaches capable of predicting biological effects of MNPs. To this end, we have investigated the potential of cheminformatics methods such as quantitative structure-activity relationship (QSAR) modeling to establish statistically significant relationships between measured biological activity profiles of MNPs and their physical, chemical, and geometrical properties, either measured experimentally or computed from the structure of MNPs. To reflect the context of the study, we termed our approach quantitative nanostructure-activity relationship (QNAR) modeling. We have employed two representative sets of MNPs studied recently using in vitro cell-based assays: (i) 51 various MNPs with diverse metal cores (Proc. Natl. Acad. Sci. 2008, 105, 7387-7392) and (ii) 109 MNPs with similar core but diverse surface modifiers (Nat. Biotechnol. 2005, 23, 1418-1423). We have generated QNAR models using machine learning approaches such as support vector machine (SVM)-based classification and k nearest neighbors (kNN)-based regression; their external prediction power was shown to be as high as 73% for classification modeling and having an R(2) of 0.72 for regression modeling. Our results suggest that QNAR models can be employed for: (i) predicting biological activity profiles of novel nanomaterials, and (ii) prioritizing the design and manufacturing of nanomaterials toward better and safer products. PMID- 20857981 TI - Multiple release kinetics of targeted drug from gold nanorod embedded polyelectrolyte conjugates induced by near-infrared laser irradiation. AB - The conjugates of gold nanorods and the model drug, fluorescein isothiocyanate (FITC), embedded inside polyelectrolytes (GNRs/FITC@PLE) were synthesized to study the release kinetics of FITC under femtosecond near-infrared (NIR) laser irradiation. The optical and structural properties of GNRs/FITC@PLE conjugates before and after laser treatments were examined using UV-vis spectroscopy, confocal microscopy, and transmission electron microscopy (TEM). The release of FITC from the conjugates was induced by the heat generated from gold nanorods under laser irradiation. The concentration of released FITC was measured as the time of continuous and periodic laser irradiation was varied. Within 5 min of the laser exposure, the release rates of FITC exhibited zero-order and first-order kinetics under continuous and periodic irradiation, respectively. Furthermore, a drug release system was designed based on the conjugates of gold nanorods and the anticancer drug, paclitaxel (PTX), embedded inside polyelectrolytes (GNRs/PTX@PLE). The conjugates were applied for in vitro studies with breast cancer cells. The release of PTX from the conjugates was triggered by NIR laser irradiation, and the inhibition rates of the cells showed strong dependencies on the irradiation modes and time. The results suggested that the multiple releases of PTX from the conjugates can be controlled by laser irradiation within a long period of time. Our system holds great potential for future therapeutic applications on breast cancers. PMID- 20857982 TI - Planar to linear structural transition in small boron-carbon mixed clusters: C(x)B(5-x)- (x = 1-5). AB - Bulk carbon and boron form very different materials, which are also reflected in their clusters. Small carbon clusters form linear structures, whereas boron clusters are planar. For example, it is known that the B(5)(-) cluster possesses a C(2v) planar structure and C(5)(-) is a linear chain. Here we study B/C mixed clusters containing five atoms, C(x)B(5-x)(-) (x = 1-5), which are expected to exhibit a planar to linear structural transition as a function of the C content. The C(x)B(5-x)(-) (x = 1-5) clusters were produced and studied by photoelectron spectroscopy; their geometric and electronic structures were investigated using a variety of theoretical methods. We found that the planar-to-linear transition occurs between x = 2 and 3: the global minimum structures of the B-rich clusters, CB(4)(-) and C(2)B(3)(-), are planar, similar to B(5)(-), and those of the C-rich clusters, C(3)B(2)(-) and C(4)B(-), are linear, similar to C(5)(-). PMID- 20857984 TI - A density functional study of the structural and electronic properties of silicon monoxide clusters. AB - By use of density functional theory, a systemic theoretical study was conducted on the structural and electronic properties of ground-state silicon monoxide clusters ((SiO)(n), where n = 1-26). In our calculations, the most energetically favorable geometry for each cluster size was found to undergo a structural change from one dimension (linear) to three dimensions at cluster size n = 4, with the buckled structure as the favorable one. The sp(3) silicon containing structures are favorable for n = 5-13, and the Si-cored structures are energetically favorable at n = 14 and larger. Furthermore, for the lowest-energy structures obtained, the energy gaps between the highest occupied and lowest unoccupied molecular orbital, binding energies, ionization potentials, and electron affinities were calculated and analyzed to understand the evolutions in geometries and to identify any particularly stable species. PMID- 20857983 TI - Caterpillar- and salivary-specific modification of plant proteins. AB - Though there is overlap, plant responses to caterpillar herbivory show distinct variations from mechanical wounding. In particular, effectors in caterpillar oral secretions modify wound-associated plant responses. Previous studies have focused on transcriptional and protein abundance differences in response to caterpillar herbivory. This study investigated Spodoptera exigua caterpillar-specific post translational modification of Arabidopsis thaliana soluble leaf proteins by liquid chromatography/electrospray ionization/mass spectroscopy/mass spectroscopy (LC/ESI/MS/MS). Given that caterpillar labial saliva contains oxidoreductases, such as glucose oxidase, particular attention was paid to redox-associated modifications, such as the oxidation of protein cysteine residues. Caterpillar- and saliva-specific protein modifications were observed. Differential phosphorylation of the jasmonic acid biosynthetic enzyme, lipoxygenase 2, and a chaperonin protein is seen in plants fed upon by caterpillars with intact salivary secretions compared to herbivory by larvae with impaired labial salivary secretions. Often a systemic suppression of photosynthesis is associated with caterpillar herbivory. Of the five proteins modified in a caterpillar-specific manner (a transcription repressor, a DNA-repair enzyme, PS I P700, Rubisco and Rubisco activase), three are associated with photosynthesis. Oxidative modifications are observed, such as caterpillar-specific denitrosylation of Rubisco activase and chaperonin, cysteine oxidation of Rubisco, DNA-repair enzyme, and chaperonin and caterpillar-specific 4-oxo-2-nonenal modification of the DNA-repair enzyme. PMID- 20857985 TI - Photobehavior of the geometrical isomers of two 1,4-distyrylbenzene analogues with side groups of different electron donor/acceptor character. AB - The photobehavior of two 1,4-distyrylbenzene analogues where the central benzene ring is asymmetrically substituted with a pyrid-4-ylethenyl group at one side and thien-2-ylethenyl or a p-nitrostyryl group at the other side, has been studied in two solvents at room temperature. The four geometrical isomers (EE, ZE, EZ, and ZZ) of each compound were separated by the combined use of HPLC and spectrophotometric techniques. The radiative/reactive competition in their excited state relaxation was particularly examined: the diabatic/adiabatic contributions were estimated and a reasonable interpretation of the photoisomerization mechanism was proposed. The role of the conformational isomers was also investigated by measured and computed spectral data. Since the different electron donor/acceptor character of the side groups of these molecules can induce charge transfer phenomena that can affect the relaxation pathways of their excited states, the photobehavior was compared in inert and polar solvents to clarify the role of the intramolecular charge transfer. The latter was found to affect markedly the relaxation properties and to induce interesting fluorosolvatochromic effects, particularly in the p-nitro derivative. The participation of the triplet state in the reaction mechanism of the latter was also investigated by flash photolysis and sensitized experiments. PMID- 20857987 TI - Formation and characterization of magnesium bisozonide and carbonyl complexes in solid argon. AB - The reactions of magnesium atoms with dioxygen and dioxygen/carbon monoxide mixture have been investigated by matrix isolation infrared absorption spectroscopy. Magnesium atoms react with dioxygen in solid argon to form the inserted MgO(2) molecules under UV excitation, which were previously characterized. Annealing allows the dioxygen molecules to diffuse and to react with MgO(2) and form the magnesium bisozonide complex, Mg(O(3))(2), which is proposed to be coordinated by two argon atoms in solid argon matrix. The Mg(O(3))(2)(Ar)(2) complex is characterized to have two equivalent side-on bonded ozonide ligands with a D(2h) symmetry. The coordinated argon atoms can be replaced by carbon monoxide to give the magnesium bisozonide dicarbonyl complex, Mg(O(3))(2)(CO)(2), a neutral magnesium carbonyl complex with CO binding to the Mg(2+) center. PMID- 20857986 TI - Raman spectroscopic study of the vapor phase of 1-methylimidazolium ethanoate, a protic ionic liquid. AB - The gas phase over the ionic liquid 1-methylimidazolium ethanoate, [Hmim][O(2)CCH(3)], was studied by means of Raman spectroscopy. Raman spectra are presented, the species in the gas phase are identified, and their bands are assigned. The results are interpreted using ab initio quantum mechanical calculations that also predict vibrational spectra. The obtained data reinforce a previous interpretation, based on FT-ICR mass spectrometric data, that the vapor phase over [Hmim][O(2)CCH(3)] consists predominantly of two neutral molecules, monomeric ethanoic acid and 1-methylimidazole. PMID- 20857988 TI - Total synthesis of (+)-isatisine A. AB - The asymmetric total synthesis of (+)-isatisine A has been accomplished commencing with a Lewis acid-catalyzed cyclization of homochiral (S) vinylcyclopropane diester and N-tosylindole-2-carboxaldehyde to construct the tetrahydrofuran ring. A palladium-catalyzed oxidative decarboxylation was utilized to obtain the dihydrofuran required for the subsequent dihydroxylation reaction to install the diol present on the tetrahydrofuran ring. The total synthesis was completed by an indole oxidation and electrophilic aromatic substitution sequence to construct isatisine A acetonide, which was then carried forward to the antipode of the natural product. The absolute configuration of the natural enantiomer (-)-isatisine A was determined to be C2(S), C9(R), C10(S), C12(R), and C13(R). PMID- 20857989 TI - Palladium-catalyzed C-H functionalization of heteroarenes with aryl bromides and chlorides. AB - Palladium-catalyzed C-H arylation of electron-enriched heteroarenes with aryl bromides and aryl chlorides proceeds in the presence of LiO-t-Bu as a base. The reaction allows one-pot synthesis of differently substituted 2,5-diarylthiazole with the same catalyst system by switching the solvent and the amount of base. PMID- 20857990 TI - Determination of structure and dynamics of the solvated bisulfide (HS-) ion by ab initio QMCF molecular dynamics. AB - The hydration structure of the bisulfide (HS(-)) ion in dilute aqueous solution was characterized by means of an ab initio quantum mechanical charge field (QMCF) molecular dynamics simulation at the Hartree-Fock level employing Dunning double zeta plus polarization function (DZP) basis sets. An average H-S bond distance of 1.35 A resulted from the simulation and a hydration shell located at 2.42 A S(HS( ))...H(w) and 3.97 A HS(-) distances, respectively. At the sulfur site, the average coordination number is 5.9 +/- 1.1, while the value for the hydrogen site is 9.2 +/- 1.6. The calculated H(HS(-))-S(HS(-)) stretching frequency of 2752 cm( 1) obtained from the QMCF MD simulation is in good agreement with that reported from the Raman spectrum (2570 cm(-1)) only if a scaling factor of 0.89 is applied. The stability of the nondissociated HS(-) structure is reflected by the force constants of 436.1 and 4.5 N/m determined for the H(HS(-))-S(HS(-)) and H(HS(-))...O(w) bonds, respectively. A weak structure-making effect of the hydrated HS(-) ion results from the mean residence times of 1.5 and 2.1 ps of coordinated water molecules at the sulfur and hydrogen sites of the HS(-) ion, respectively. PMID- 20857991 TI - Oligo(FcDC-co-CholDEA) with ferrocene in the main chain and cholesterol as a pendant group-preparation and unusual properties. AB - With ever-increasing need for thin, flexible, and functional materials in electrochemical systems, various techniques have been explored for creating materials used in fuel cells, batteries, electrochromic devices, solar cells, and sensors. In the present study, a novel ferrocene (Fc) and cholesterol (Chol) containing oligomer, oligo(FcDC-co-CholDEA), was specially designed and prepared by putting Fc in the main chain and Chol as a side group. MALDI-TOF MS and freezing point depression measurements revealed that in average each oligomer contains three Fc units and three Chol units. Cyclic voltammetric measurements revealed that the oligomer displays superior electrochemical stability if compared with other Fc derivatives containing only one Fc unit and one or two Chol unit and with poly(ferrocenylsilane) with Fc in the main chain. In particular, the Fc-containing oligomer possesses an unusual oxidation center, of which the oxidation potential could be as high as 1.81 V. The oligomer is also superior in self-assembly, as demonstrated by forming an LB film of layered structures. Furthermore, supramolecular films with high mechanical strength in the wet state can be prepared by employing a simple solution casting method. This finding demonstrates that self-assembly is a simple but effective way to create films of potential uses in real-life applications provided proper building blocks are designed and employed. PMID- 20857992 TI - DFT-based simulations of IR amide I' spectra for a small protein in solution. Comparison of explicit and empirical solvent models. AB - Infrared (IR) amide I' spectra are widely used for investigations of the structural properties of proteins in aqueous solution. For analysis of the experimental data, it is necessary to separate the spectral features due to the backbone conformation from those arising from other factors, in particular the interaction with solvent. We investigate the effects of solvation on amide I' spectra for a small 40-residue helix-turn-helix protein by theoretical simulations based on density functional theory (DFT). The vibrational force fields and intensity parameters for the protein amide backbone are constructed by transfer from smaller heptaamide fragments; the side chains are neglected in the DFT calculations. Solvent is modeled at two different levels: first as explicit water hydrogen bonded to the surface amide groups, treated at the same DFT level, and, second, using the electrostatic map approach combined with molecular dynamics (MD) simulation. Motional narrowing of the spectral band shapes due to averaging over the fast solvent fluctuation is introduced by use of the time averaging approximation (TAA). The simulations are compared with the experimental amide I', including two (13)C isotopically edited spectra, corrected for the side chain signals. Both solvent models are consistent with the asymmetric experimental band shape, which arises from the differential solvation of the amide backbone. However, the effects of (13)C isotopic labeling are best captured by the gas-phase calculations. The limitations of the solvent models and implications for the theoretical simulations of protein amide vibrational spectra are discussed. PMID- 20857993 TI - Stereoselective synthesis of 2-carbamoyl-2-cyanocyclopropanecarboxylates by tandem oxidative cyclization and neighboring group-assisted decarboxylation. AB - In this paper, we report a facile synthesis of 2-carbamoyl-2 cyanocyclopropanecarboxylates through a tandem iodosobenzene/tetrabutylammonium iodide-induced oxidative cyclization and a subsequent neighboring group-assisted decarboxylation of the Michael adducts of 2-cyanoacetamides with alpha,beta unsaturated malonates. This method affords the desired highly functionalized cyclopropanes in moderate to good yields and with excellent diastereoselectivities. In addition, the reaction proceeds smoothly under mild conditions and with good functional group tolerance. PMID- 20857994 TI - Intercalation of 3-phenyl-1-proponal into OTS SAMs on silica nanoasperities to create self-repairing interfaces for MEMS lubrication. AB - Self-assembled monolayers (SAMs) have been widely studied as potential lubricants for microelectromechanical system (MEMS) devices. However, these single-layer films have nominally been found to be insufficient for mitigating wear in sliding contacts because of their rapid breakdown under the high pressures found within the nanoasperity junctions at such interfaces. As such, there is a critical need to explore approaches beyond simple, single-component SAMs toward films that introduce additional lubricant molecules into the system. Because alcohol vapors have previously been shown to reduce wear in MEMS devices, here we have investigated a mixed monolayer consisting of an octadecyltrichlorosilane (OTS) SAM infused with 3-phenyl-1-propanol (3P1P), assembled on silica nanoparticle films. A combination of atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), thermal gravimetric analysis (TGA), and FTIR spectroscopy was employed to investigate the structural and frictional properties of the mixed monolayers and to evaluate surface wear as a function of time. The nanoparticle film/AFM tip junction provides a ready mimic for the asperity-asperity contacts found in MEMS devices. Here it was found that for a mixed monolayer of OTS with ca. 15% 3P1P, the surfaces showed dramatically reduced friction and no wear under the same load conditions as surfaces with an OTS SAM alone. Moreover, the multicomponent film also displayed no increase in friction and exhibited no wear even after 14 h of shearing contact in an AFM at loads that would break down the OTS layer. The ability of the OTS SAM to trap short-chain alcohols, such as 3P1P, and to release them under load suggests a simple MEMS lubrication scheme that could be readily integrated into MEMS device architectures. PMID- 20857995 TI - Synthesis and structure of a 3D porous network containing aromatic 1D chains of Li(6) rings: experimental and computational studies. AB - A bimetallic 3D network containing 1D chains of Li(6) unit rings has been synthesized by using a molybdenum containing metalloligand and the DFT calculations reveal that the rings are aromatic in behavior and resemble the corresponding hydrocarbon analogues. PMID- 20857996 TI - Magneto-structural correlation studies and theoretical calculations of a unique family of single end-to-end azide-bridged Ni(II)4 cyclic clusters. AB - The work in this paper aims to portray a complete structural, magnetic, and theoretical description of two original end-to-end (EE) MU(1,3)-azide-bridged, cyclic tetranuclear Ni(II) clusters, [{Ni(II)(L(1))(MU(1,3)-N(3))(H(2)O)}(4)] (1) and [{Ni(II)(L(2))(MU(1,3)-N(3))(H(2)O)}(4)] (2), where the ligands used to achieve these species, HL(1) and HL(2), are the tridentate Schiff base ligands obtained from [1 + 1] condensations of salicylaldehyde with 1-(2-aminoethyl) piperidine and 4-(2-aminoethyl)-morpholine, respectively. The title compounds, 1 and 2, crystallize in a monoclinic P2(1) space group. Overall, both species can be described in a similar way; where all Ni(II) centers within each molecule are hexacoordinated and bound to [L(1)](-) or [L(2)](-) through the phenoxo oxygen, imine nitrogen, and piperidine/morpholine nitrogen atoms of the corresponding ligand. The remaining coordination sites are satisfied by one molecule of H(2)O and two nitrogen atoms from N(3)(-) anions. The latest act as bridges between Ni(II) ions, and eventually, only four azido groups are linked to the same number of Ni(II) centers resulting in the formation of cyclic Ni(II)(4) systems. Interestingly, compounds 1 and 2 are the two sole examples of tetranuclear clusters generated exclusively by EE azide-bridging ligands to date. All the N(azide)-Ni-N(azide) moieties are almost linear in 1 and 2 indicating trans arrangement of the azido ligand. Variable-temperature (2-300 K) magnetic susceptibilities of 1 and 2 have been measured under magnetic fields of 0.04 T (from 2 to 30 K) and 0.7 T (from 30 to 300 K), and magneto-structural correlations have been performed. Despite the presence of both ferromagnetic and antiferromagnetic interactions in both compounds, significant differences have been observed in their magnetic behaviors directly related to the arrangement of the bridging azido ligands. Hence, compound 1 has an overall moderate antiferromagnetic behavior due to the presence of an exchange pathway with an unprecedented Ni-N...N-Ni torsion angle close to 0 degrees , meanwhile complex 2 exhibits a predominant ferromagnetic behavior, with torsion angles between 50 and 90 degrees . Density functional theory calculations have been performed to provide more insight into the magnetic nature of this new family of Ni(II)-azido complexes and also to corroborate the fitting of the data. PMID- 20857997 TI - Magnetic properties of largest-spin single molecule magnets: Mn17 complexes--a density functional theory approach. AB - The exchange coupling constants of two Mn(17) complexes have been analyzed; one of them has the second largest ground-state spin value reported up to now, being the largest-spin single-molecule magnet. The two complexes show a two-edge sharing supertetrahedra structural motif, Mn(II)(6)Mn(III)(11), and similar ligands, but they show different total spin values. One of them has the highest possible, S = 37, while for the second complex, the S value is lower and equal to 28 +/- 1. The calculated J values using DFT methods for both systems indicate the predominance of the ferromagnetic interactions consistent with the S = 37 total spin. The analysis of similar Mn(19) complexes with the two supertetrahedra sharing one vertex gives similar results, pointing out the preponderance of the ferromagnetic couplings. PMID- 20857998 TI - Spectroscopic and computational studies of an end-on bound superoxo-Cu(II) complex: geometric and electronic factors that determine the ground state. AB - A variety of techniques including absorption, magnetic circular dichroism (MCD), variable-temperature, variable-field MCD (VTVH-MCD), and resonance Raman (rR) spectroscopies are combined with density functional theory (DFT) calculations to elucidate the electronic structure of the end-on (eta(1)) bound superoxo-Cu(II) complex [TMG(3)trenCuO(2)](+) (where TMG(3)tren is 1,1,1-tris[2-[N(2)-(1,1,3,3 tetramethylguanidino)]ethyl]amine). The spectral features of [TMG(3)trenCuO(2)](+) are assigned, including the first definitive assignment of a superoxo intraligand transition in a metal-superoxo complex, and a detailed description of end-on superoxo-Cu(II) bonding is developed. The lack of overlap between the two magnetic orbitals of [TMG(3)trenCuO(2)](+) eliminates antiferromagnetic coupling between the copper(II) and the superoxide, while the significant superoxo pi*(sigma) character of the copper dz(2) orbital leads to its ferromagnetically coupled, triplet, ground state. PMID- 20857999 TI - Poly(methyl vinyl ether-co-maleic acid)-polyethylene glycol nanocomposites cross linked in situ with cellulose nanowhiskers. AB - Nanocomposites were developed by cross-linking cellulose nanowhiskers with poly(methyl vinyl ether-co-maleic acid) and polyethylene glycol. Nuclear magnetic resonance (NMR) studies showed cross-linking occurs between the matrix and cellulose nanowhiskers via an esterification reaction. Proton NMR T(2) relaxation experiments provided information on the mobility of the polymer chains within the matrix, which can be related to the structure of the cross-linked nanocomposite. The nanocomposite was found to consist of mobile chain portions between cross linked junction points and immobilized chain segments near or at those junction points, whose relative fraction increased upon further incorporation of cellulose nanowhiskers. Atomic force microscopy images showed a homogeneous dispersion of nanowhiskers in the matrix even at high nanowhisker content, which can be attributed to cross-linking of the nanowhiskers in the matrix. Relative humidity conditions were found to affect the mechanical properties of the composites negatively while the nanowhiskers content had a positive effect. It is expected that the cross-links between the matrix and the cellulose nanowhiskers trap the nanowhiskers in the cross-linked network, preventing nanowhisker aggregation subsequently producing cellulose nanocomposites with unique mechanical behaviors. The results show that in situ cross-linking of cellulose nanowhiskers with a matrix polymer is a promising route to obtain nanocomposites with well dispersed nanowhiskers, tailored nanostructure, and mechanical performance. PMID- 20858000 TI - Dielectric relaxation spectroscopy of hydrated and dehydrated silk fibroin cast from aqueous solution. AB - The dynamics of silk protein in the presence and absence of water has been investigated by dielectric relaxation spectroscopy (DRS). The silk fibroin film cast from its water solution contains 4-7 wt % bound water molecules, which can be removed by dehydration at 165 degrees C. Temperature and frequency scans were performed on the hydrated and dehydrated samples over the temperature range from 100 to 280 degrees C, and frequency range from 20 to 1 MHz. Temperature scans of hydrated samples show three relaxation peaks, including beta- and alpha relaxations, related to bound water and to the glass transition. A new third peak, denoted as alpha', was seen in hydrated sample at around 60 degrees C, and its intensity increases with decreasing frequency. On the other hand, in the completely dehydrated sample, the beta- and alpha'-relaxation peaks both disappeared, which reveals their origin from bound water molecules. The alpha' process is attributed to the removal of bound water, after which the glass transition of dehydrated silk appears at higher temperature as the alpha process. Real-time DRS has also been performed to monitor isothermal crystallization. Both the dielectric constant, epsilon', and conductivity, sigma, decrease gradually as the crystallization proceeds. Analysis of dielectric modulus shows that both conductivity and the alpha-relaxation are observed at the beginning of crystallization. As the crystal grows, the alpha-relaxation starts gradually to diminish both in strength and in rate. Before crystallization, alpha-helices and random coils with dipole moments are the major components in silk fibroin. During crystallization, alpha-helices can be transformed into antiparallel beta-sheets, which possess no dipole moment, causing the decreasing trend in the dielectric parameters as crystallization proceeds. PMID- 20858001 TI - IR fingerprints of U(VI) nitrate monoamides complexes: a joint experimental and theoretical study. AB - Infrared spectra of 0.5 mol.L(-1) uranium(VI) nitrate monoamide complexes in toluene have been recorded and compared with infrared spectra calculated by DFT. The investigated monoamides were N,N-dimethylformamide (DMF), N,N dibutylformamide (DBF), and N,N-dicyclohexylformamide (DcHF). The validity of DFT calculations for describing uranium nitrate monoamide complexes has been confirmed as a fair agreement between experimental and calculated spectra was obtained. Furthermore, a topological analysis of the electron density has been carried out to characterize monoamide-uranium interactions. From this work, it appears that the increase of stability of uranylmonoamide complexes may be directly linked to the degree of polarization of the ligands in interaction with uranylnitrate. Among the investigated monoamides, the most stable complex is UO(2)(NO(3))(2).2DcHF. This complex is characterized by a high positive charge delocalization in the outer part of the ligand molecule, which leads to a more concentrated positive charge close to the uranyl cation (UO(2)(2+)), thus strengthening the electrostatic interaction between the metal and the ligand. PMID- 20858002 TI - Uranium(VI) removal by nanoscale zerovalent iron in anoxic batch systems. AB - This study investigated the influences of pH, bicarbonate, and calcium on U(VI) removal and reduction by synthetic nanoscale zerovalent iron (nanoFe(0)) particles under anoxic conditions. The results showed that the rates of U(VI) removal and reduction by nanoFe(0) varied significantly with pH and concentrations of bicarbonate and/or calcium. For instance, at pH 6.92 the pseudo first-order rate constants of U(VI) removal decreased by 78.5% and 81.3%, and U(VI) reduction decreased by 90.3% and 89.3%, when bicarbonate and calcium concentrations were increased from 0 to 1 mM, respectively. X-ray photoelectron spectroscopy (XPS) analysis confirmed the formation of UO(2) and iron (hydr)oxides as a result of the redox interactions between U(VI) and nanoFe(0). The study demonstrated the potential of using nanoFe(0) for U(VI)-contaminated site remediation and highlighted the impacts of pH, bicarbonate, and calcium on the U(VI) removal and reduction processes. PMID- 20858003 TI - A diarylethene cocrystal that converts light into mechanical work. AB - The photomechancial effect of a rectangular plate two-component cocrystal composed of a photochromic diarylethene derivative, 1,2-bis(2-methyl-5-(1 naphthyl)-3-thienyl)perfluorocyclopentene (1o), and perfluoronaphthalene (FN) has been examined. The crystal of 1o.FN with the size of 1-5 mm in length exhibits reversible bending motion upon alternate irradiation with ultraviolet (UV) and visible light. The reversible bending could be repeated over 250 times. In situ X ray crystallographic analysis revealed that the deformation of the crystal is due to the elongation of the b-axis of the unit cell, which corresponds to the long axis of the plate crystal, induced by the shape change of component diarylethene molecules upon photocyclization. The bending motion was observed even at 4.7 K, and dynamic measurement of the bending proved that the anisotropic expansion of the crystal takes place in the microsecond time scale at the low temperature. Molecular crystal cantilevers made of 1o.FN can lift metal balls, the weight of which is 200-600 times heavier than the weight of the crystal, upon UV irradiation. The maximum stress generated by UV irradiation was estimated to be 44 MPa, which is 100 times larger than that of muscles (~0.3 MPa) and comparable to that of piezoelectric crystals, such as lead zirconate titanate (PZT) (~50 MPa). PMID- 20858004 TI - Sequential one-pot combination of multireactions through multicatalysis: a general approach to rapid assembly of functionalized push-pull olefins, phenols, and 2-methyl-2H-chromenes. AB - A general, sustainable and practical process for the sequential cascade one-pot synthesis of library of highly substituted push-pull olefins, phenols and 2 methyl-2H-chromenes was reported through multicatalysis cascade (MCC) reactions. Direct sequential one-pot combination of amine- or amino acid-catalyzed cascade Knoevenagel/Michael/aldol condensation/decarboxylation with other reactions like amine- or amino acid-catalyzed cascade Claisen-Schmidt/iso-aromatization, Claisen Schmidt/isomerization, Claisen-Schmidt/iso-aromatization/isomerization, Michael addition, Claisen-Schmidt/Michael, ruthenium-base-silica-catalyzed ring closing metathesis/base-induced ring-opening/benzylic oxidation/[1,7]-sigmatropic hydrogen shift, or ruthenium-base-heat-catalyzed ring closing metathesis/base induced ring-opening/[1,7]-sigmatropic hydrogen shift reactions of alkyl acetoacetates, a variety of aldehydes and alkyl halides furnished the highly functionalized push-pull olefins, phenols and 2-methyl-2H-chromenes with high yields. The yields and regioselectivities were good to excellent. Evidence for a new reaction pathway involving in situ formation of novel push-pull dienamines under amine- or amino acid-catalysis is presented along with examples demonstrating the amenability of the process to MCC chemistry. PMID- 20858005 TI - Complete enantioseparation through supramolecular complex formation between tris(1,3-diaminopropane)cobalt(III) phosphate and beta-cyclodextrin, [Co(tn)3]PO4.beta-CDX. AB - The supramolecular complex [Co(tn)(3)]PO(4).beta-CDX (tn = 1,3-diaminopropane; beta-CDX = beta-cyclodextrin) was prepared through beta-CDX, rac [Co(tn)(3)]Cl(3), and Na(3)PO(4) in a mole ratio of 1:2:2. After one recrystallization process, the circular dichroism spectrum confirmed that complete enantioseparation of [Co(tn)(3)]PO(4) is achieved in this system. X-ray crystal structure analysis reveals the presence of the only Lambda-enantiomer in the unit cell and the head-to-head chiral discrimination structure of this system. Thus, we found that the present diastereomer formation with beta-CDX affords the very convenient and effective optical resolution procedure of [Co(tn)(3)](3+). PMID- 20858008 TI - Tuning electron transfer rates via systematic shifts in the acceptor state density using size-selected ZnO colloids. AB - We report direct measurements of the influence of the available density of acceptor states on the rate of near-barrierless electron transfer between a dye sensitizer and an oxide semiconductor. The electron donor was the excited state of a zinc porphyrin, and the acceptors were a series of size-selected ZnO nanocrystals. The available density of states was tuned by controlling the relative position of the ZnO band edge using quantum confinement. The resulting change in the rate was consistent with a simple model of the state density as a function of energy above the ZnO band edge. PMID- 20858006 TI - Bimetallic reductive elimination from dinuclear Pd(III) complexes. AB - In 2009, we reported C-halogen reductive elimination reactions from dinuclear Pd(III) complexes and implicated dinuclear intermediates in Pd(OAc)(2)-catalyzed C-H oxidation chemistry. Herein, we report results of a thorough experimental and theoretical investigation of the mechanism of reductive elimination from such dinuclear Pd(III) complexes, which establish the role of each metal during reductive elimination. Our results implicate reductive elimination from a complex in which the dinuclear core is intact and suggest that redox synergy between the two metals is responsible for the facile reductive elimination reactions observed. PMID- 20858009 TI - A new palladium precatalyst allows for the fast Suzuki-Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids. AB - Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki-Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow. With this precatalyst, Suzuki-Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2 thiophene, and 2-pyrroleboronic acids and their analogues proceed at room temperature or 40 degrees C in short reaction times to give the desired products in excellent yields. PMID- 20858010 TI - Simple reagents for direct halonium-induced polyene cyclizations. AB - Although there are many reagent combinations that can initiate polyene cyclizations, simple electrophilic halogen sources have not yet proven broadly effective as promoters of such processes. Herein is described a readily prepared and stable class of reagents capable of effecting such transformations for a wide range of electron-rich and -deficient terpenes derived from geraniol, farnesol, and nerol, thereby enabling the effective synthesis of a diverse array of complex chlorine-, bromine-, and iodine-containing polycyclic frameworks. Efforts to date have led to the first racemic laboratory total synthesis and structural revision of the anti-HIV natural product peyssonol A as well as an efficient and concise inaugural total synthesis of peyssonoic acid A. They have also permitted formal racemic total syntheses of aplysin-20, loliolide, K-76, and stemodin to be achieved through routes that are typically shorter, higher-yielding, and more environmentally conscious than previous efforts. Preliminary attempts to use chiral forms of the reagent class for enantioselective alkene halogenation are also described. PMID- 20858011 TI - A highly selective and general palladium catalyst for the oxidative Heck reaction of electronically nonbiased olefins. AB - A general, highly selective oxidative Heck reaction is reported. The reaction is high-yielding under mild conditions without the need for base or high temperatures, and the selectivity is excellent, without the requirement for electronically biased olefins or other specific directing groups. A preliminary mechanistic investigation suggests that the unusually high selectivity may be due to the catalyst's sensitivity to C-H bond strength in the selectivity-determining beta-hydride elimination step. PMID- 20858012 TI - Synthesis of heterocycles via Pd-ligand controlled cyclization of 2-chloro-N-(2 vinyl)aniline: preparation of carbazoles, indoles, dibenzazepines, and acridines. AB - The Pd-catalyzed condensation of 2-bromostyrene and 2-chloroaniline derivatives yields stable diphenylamine intermediates, which are selectively converted to five-, six-, or seven-membered heteroaromatics (indoles, carbazoles, acridines, and dibenzazepines). The selectivity of these intramolecular transformations is uniquely ligand-controlled and offers efficient routes to four important classes of heterocycles from a common precursor. PMID- 20858013 TI - C-H bond activation of benzene by unsaturated eta2-cyclopropene and eta2-benzyne complexes of niobium. AB - We report the synthesis of a niobium cyclopropyl complex, Tp(Me2)NbMe(c C(3)H(5))(MeCCMe), and show that thermal loss of methane from this compound generates an intermediate that is capable of activating both aliphatic and aromatic C-H bonds. Isotopic labeling, trapping studies, a detailed kinetic analysis, and density functional theory all suggest that the active intermediate is an eta(2)-cyclopropene complex formed via beta-hydrogen abstraction rather than an isomeric cyclopropylidene species. C-H activation chemistry of this type represents a rather unusual reactivity pattern for eta(2)-alkene complexes but is favored in this case by the strain in the C(3) ring which prevents the decomposition of the key intermediate via loss of cyclopropene. PMID- 20858014 TI - Sialylated Lewis x antigen bearing glycoproteins in human plasma. AB - Recent studies have shown that antibodies targeting Lewis x (Le(x)) antigen are a valuable tool in the isolation and identification of glycoproteins in plasma. A focus of this study was to determine whether sialylated Lewis x (sLe(x)) antigen carrying glycoproteins occur in human plasma and whether an antibody targeting this antigen could be used to isolate and identify glycoproteins bearing this antigen. An additional objective was to determine the degree to which proteins conjugated to Le(x) and sLe(x) antigens are similar in structure. A specific anti sLe(x) antibody (anti-sLe(x)Ab), CHO-131, immobilized in an immunoaffinity column was used to select a set of specific sLe(x) bearing proteins from human plasma, after which they were identified by either of two analytical strategies. One approach was to further resolve the affinity selected proteins by reversed phase chromatography (RPC), tryptic digest the RPC fractions, and identify peptide fragments by MALDI-MS/MS. The second was to tryptic digest the affinity selected protein fraction, further resolve the tryptic fragments by RPC, and identify peptides from RPC fractions by MALDI-MS/MS. Histidine-rich glycoprotein, plasminogen, apolipoprotein A-I, vitronectin, proteoglycan-4, clusterin, Ig gamma 2 chain C region, Ig mu chain C region, and interalpha-trypsin inhibitor heavy chain H4 were found to change three folds or more in association with breast cancer. Fifty percent of the glycoproteins carrying either sLe(x) antigen from CHO-131 selection, Le(x) antigen from selection with TG-1 antibody, or both were found to be changed three folds or more in concentration in breast cancer plasma relative to controls. PMID- 20858016 TI - Proteomic identification of paclitaxel-resistance associated hnRNP A2 and GDI 2 proteins in human ovarian cancer cells. AB - Ovarian cancer is a gynecological malignancy with the highest mortality. Chemoresistance is an important subject for the treatment of ovarian cancer, because obtaining significant drug resistance to the first line chemotherapy, paclitaxel, causes major therapeutic obstacles. It is essential to improve the survival rate of ovarian cancer patients by mining the biomarkers indicating the drug resistance and prognosis, and by further understanding underlying mechanisms of drug resistance. In the present study, we established paclitaxel-resistant subline (SKpac) from human epithelial ovarian cancer cell line, SKOV3, and performed comparative analysis of whole proteomes between paclitaxel-resistant SKpac sublines and paclitaxel-sensitive parental SKOV3 cells to identify differentially expressed proteins and useful biomarkers indicating chemoresistance. Proteins related to chemoresistant process were identified by two-dimensional gel electrophoresis (2DE) with mass spectrometry (MALDI-TOF and LC-MS/MS). Eighteen spots were differentially expressed and were identified in SKpac chemoresistant cells compared to SKOV3. The expressions of ALDH 1A1, annexin A1, hnRNP A2, and GDI 2 proteins were validated by Western blot, which was consistent with proteomic analysis. Among the selected proteins, downregulation of hnRNP A2 and GDI 2 was found to be the most significant finding in SKpac cells and chemoresistant ovarian cancer tissues. Our results suggest that hnRNP A2 and GDI 2 may represent potential biomarkers of the paclitaxel resistant ovarian cancers for tailored cancer therapy. PMID- 20858017 TI - Understanding rural practice: implications for occupational therapy education in Canada. AB - INTRODUCTION: Currently Canadians living in rural communities tend to have a poorer health status than those living in urban settings. This is contributed to by the shortage of health professionals choosing work in rural and remote areas. Over the past decade there has been much research into the recruitment and retention of rural health professionals. However little has been done to identify the actual nature of rural practice and whether graduates have been adequately prepared for the diversity of rural work. The present study sought to identify the rewards and challenges of rural occupational therapy practice in western Canada. Participants' were also asked about their preparedness for rural practice after graduation, and specifically about the usefulness of course work and practical skills taught as undergraduates. METHODS: Participants were occupational therapists working in rural communities in the Canadian provinces of Alberta and Saskatchewan. The quantitative approach employed a self-administered survey with closed- and open-ended questions. Data were entered into SPSS v14 (http://www.spss.com.au) for frequency data and percentages. RESULTS: The participants (n = 59) worked mainly in full-time community healthcare positions with clients who had physical health issues. More than half worked in sole therapy positions. The average length of time in their current position was 5 years. Most participants reported that they were receiving informal professional support, with some receiving a formal support as well. Participants more frequently identified the rewards of rural practice (n = 214) than its challenges (n = 112). Perceived rewards included team work, autonomy, diversity and flexible work schedule, increased client contact, job satisfaction, experiences gained and the rural lifestyle. The most frequently mentioned challenges included staff shortages, the generalist nature of rural occupational therapy practice, excess time spent travelling, coping with inappropriate referrals and the need for more professional support. Regarding participants' perceptions about the course work and practical skills taught during their training that best prepared them for actual practice, some highlighted additional valuable resources such as actual hands-on experience during rural fieldwork placement, personal characteristics, working in an urban setting prior to embarking on a rural career, coming from a rural background and locating a mentor prior to working rurally. Some recommended increasing management and organisational skills content in the curriculum because these were considered essential skills for effective rural practice. The return of unanswered questionnaires by participants who did not consider themselves to be rural therapists because of access to online and telehealth resources suggests further research is warranted into the changing nature of rural practice. CONCLUSION: Characteristics of current rural occupational therapy practice in western Canada were identified. Overall, rural occupational therapy practice appeared to be rewarding, and few had difficulty in accessing professional support. While on the whole the participants believed their training prepared them adequately for rural practice, the acquisition of increased management and organisational skills during training was seen as necessary to effectively manage their typically large and diverse caseloads. Participants' access to online and telehealth resources appears to have markedly changed the nature of rural practice and further research is recommended to determine the impact of such technologies. PMID- 20858015 TI - Human common salivary protein 1 (CSP-1) promotes binding of Streptococcus mutans to experimental salivary pellicle and glucans formed on hydroxyapatite surface. AB - The saliva proteome includes host defense factors and specific bacterial-binding proteins that modulate microbial growth and colonization of the tooth surface in the oral cavity. A multidimensional mass spectrometry approach identified the major host-derived salivary proteins that interacted with Streptococcus mutans (strain UA159), the primary microorganism associated with the pathogenesis of dental caries. Two abundant host proteins were found to tightly bind to S. mutans cells, common salivary protein-1 (CSP-1) and deleted in malignant brain tumor 1 (DMBT1, also known as salivary agglutinin or gp340). In contrast to gp340, limited functional information is available on CSP-1. The sequence of CSP-1 shares 38.1% similarity with rat CSP-1. Recombinant CSP-1 (rCSP-1) protein did not cause aggregation of S. mutans cells and was devoid of any significant biocidal activity (2.5 to 10 MUg/mL). However, S. mutans cells exposed to rCSP-1 (10 MUg/mL) in saliva displayed enhanced adherence to experimental salivary pellicle and to glucans in the pellicle formed on hydroxyapatite surfaces. Thus, our data demonstrate that the host salivary protein CSP-1 binds to S. mutans cells and may influence the initial colonization of this pathogenic bacterium onto the tooth surface. PMID- 20858018 TI - Is small beautiful? Student performance and perceptions of their experience at larger and smaller sites in rural and remote longitudinal integrated clerkships in the Rural Clinical School of Western Australia. AB - INTRODUCTION: The Rural Clinical School of Western Australia (RCSWA) provides 25% of Western Australia's medical students in their first full clinical year with a longitudinal integrated clerkship in rural and remote areas. They live and work in 10 different sites in groups of 3 to 10 members. This study aimed to discover if students at the smaller sites were disadvantaged by the reduced number of student colleagues, and also by a smaller population catchment area potentially providing a smaller number of clinical presentations. METHOD: Data were collected from 2003 until 2007 from a variety of sources including annual comparisons of end of year results, annual mid-year interviews of all students and staff, and the Dundee Ready Education Environment Measure (DREEM) Survey. RESULTS: There was no difference in end of year results between smaller sites and larger sites and both had slightly higher marks (and statistically significantly better) than their metropolitan colleagues. Mid-year interviews were shown to correlate significantly with the findings from the DREEM questionnaire in terms of student perceptions. Students at small sites were more satisfied with their educational experience than those at the larger sites. CONCLUSION: With good infrastructure, clarity about learning objectives and a structured academic approach to the complexities of the first full clinical year's curriculum, students need not be disadvantaged by being sent in small numbers to small and/or remote sites for their clinical education. This was established both academically in terms of end of year marks, and also by their subjective experiences. PMID- 20858019 TI - Qualitative evaluation of a physical activity-based chronic disease prevention program in a low-income, rural South African setting. AB - INTRODUCTION: Chronic diseases, an increasing global concern, are prevalent in the low-income communities of South Africa, where rural health systems bear the double burden of infectious and chronic diseases. The Discovery Healthy Lifestyle Programme (DHLP) is a physical activity-based chronic disease prevention program that has been implemented in a low-income, rural setting in South Africa. The DHLP consists of both school- and primary healthcare clinic-based interventions for learners (Healthnutz) and adults (Live it Up), facilitated by teachers, nurses and community volunteers. The aim of this evaluation was to qualitatively assess the process by which the DHLP was implemented, identifying enabling factors and barriers. METHODS: Data were collected in target communities at schools and clinics from semi-structured focus groups of program leaders and members, teachers and community members (n = 45), situational analyses of the school physical activity environment, informal community observations and informal interviews with program coordinators. RESULTS: The target communities faced socioeconomic and health inequalities and remained under-resourced and under-served. In spite of these and other challenges, the DHLP was well received by community members and stakeholders. It was valued by respondents for its health and psychosocial outcomes, evidenced by increased knowledge and awareness of the importance of physical activity and healthy lifestyles, and positively altered perceptions of physical activity. Program implementers believed the Live it Up component was growing, and this suggested the sustainability of the program. There were, however, some concerns about the fidelity of the Healthnutz intervention, due to timetabling difficulties. Despite this, teachers were positive about the program and its value for their learners, staff and school. The community characteristics of being under-resourced and under-served appeared to positively influence DHLP implementation. Local government involvement in the DHLP resulted in greater ownership of the program, which enabled successful implementation. CONCLUSIONS: This study presents a unique opportunity to assess the implementation and sustainability requirements of programs in environments of limited resources, considerable burden of infectious and chronic diseases and extensive socioeconomic challenges. The findings suggest that through enhancement of knowledge, transfer of appropriate skills and the provision of an enabling environment, participation in physical activity can be effectively promoted in a low-income, rural setting. Physical activity interventions that promote the participation and empowerment of rural communities can be feasible and accessible, thereby assisting in addressing the growing burden of chronic diseases in low-income. PMID- 20858020 TI - Improving the skills of rural and remote generalists to manage mental health emergencies. AB - CONTEXT: People living in rural and remote areas have been found to suffer higher rates of mental illness and psychological distress than their urban counterparts. However, rural and remote Australians also suffer from a lack of specialist mental health services. Mental health consumers are concerned about the lack of access to specialist mental health care and report poor service quality and stigmatizing staff attitudes when presenting with mental health emergencies at acute care facilities. Standards for the Mental Health Workforce released in 2002 promote respect for the individual, their family and carers; best practice in the assessment, early detection and management of acute illness; promotion of mental health and safety; and the prevention of relapse. These standards are for generalists providing care to mentally ill patients; their family and carers in the acute care setting; as well as specialist mental health professionals. Up skilling generalists in rural and remote areas to respectfully and effectively manage mental health emergency care is a priority. ISSUES: A short course, 'Managing Mental Health Emergencies' was developed by the Australian Rural Nurses and Midwives in 2002. Almost 750 participants had completed the course at the time of the evaluation. The objectives of the course were to: develop an increased knowledge of mental health presentations and gain confidence in managing and assessing mental health clients; gain an understanding of the referral processes in the local environment; gain an insight into the impact of mental health emergencies on individuals, their family and carers; and identify strategies to minimise the impact of managing mental health emergencies on the healthcare team. The model of training matched what is known to be best practice in rural and remote health practitioner development in emergency care, being local, interdisciplinary, and engaging local expert service providers while being overseen by a national steering committee. The evaluation consisted of a pre- (n=456) and post-course (n=163) survey, and follow-up interviews with participants between 3 and 6 months post-course (n=44). LESSONS LEARNED: The pre- and post-survey identified that, as a result of the course, participants had improved confidence in seeking information about suicide ideation, were significantly more able to differentiate between substance intoxication and psychosis (chi(2)[df=1, n=619] =140.9, p<.000); and between dementia and delirium (chi(2)[df=3, n=619] =126.5, p<.000). The follow-up interview notes were analysed using thematic analysis. Three themes were used: changing attitudes; changing clinical practice; and communication. Participants had reflected on their attitudes following the course and recognized how these had been stigmatizing. Many participants reported putting their new skills into practice and reported better recognition of non-verbal cues and better information seeking from family members, past history and police. The Managing Mental Health Emergencies course is a valuable addition to the emergency courses available to rural and remote healthcare providers. PMID- 20858021 TI - The changing world of G protein-coupled receptors. PMID- 20858022 TI - International Workshop at the Nobel Forum, Karolinska Institutet on G protein coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached? AB - A meeting was held May 19, 2010 at the Karolinski Institute on Nomenclature in Pharmacology. This meeting occurred in conjunction with the Symposium The Changing World of G Protein Coupled Receptors: From Monomers to Dimers and Receptor Mosaics (Higher-order Oligomers) held the previous day at the Royal Swedish Academy of Science. Two broad topics of nomenclature were discussed; ligand nomenclature and the definition of 'receptor-receptor' interactions. This paper summarizes discussions on these topics along with a consensus definition of the term 'receptor-receptor' interaction. PMID- 20858023 TI - G protein coupled receptors as allosteric proteins and the role of allosteric modulators. AB - Seven transmembrane receptors (7TMRs) are proteins that convey signals through changes in conformation. These conformations are stabilized by external molecules (i.e. agonists, antagonists, modulators) and act upon other bodies (termed 'guests') which can be other molecules in the extracellular space, or proteins along the plane of the membrane (receptor oligomerization) or signaling proteins in the cytosol (i.e. G protein, beta-arrestin). These elements comprise allosteric systems and a great deal of 7TMR pharmacology can be considered in terms of allosteric behavior. Allosteric ligands acting on 7TMRs possess four unique behaviors that can be valuable therapeutically; (1) the ability to alter the interaction of very large proteins, (2) probe dependence, (3) saturable effect, and (4) induction of separate changes in affinity and efficacy of other ligands. Two of these behaviors (namely probe dependence for CCR5-based HIV-1 entry inhibitors and functional selectivity for biased agonism) will be highlighted with examples. PMID- 20858024 TI - NF-kappaB as a potential therapeutic target in myelodysplastic syndromes and acute myeloid leukemia. AB - IMPORTANCE OF THE FIELD: The inactive NF-kappaB-inhibitor of NF-kappaB (IkappaB) complex is activated by stimuli including pro-inflammatory cytokines, mitogens, growth factors and stress-inducing agents. The release of NF-kappaB facilitates its translocation to the nucleus, where it promotes cell survival by initiating transcription of genes encoding stress-response enzymes, cell-adhesion molecules, pro-inflammatory cytokines and anti-apoptotic proteins. NF-kappaB and associated regulatory factors (IkappaB kinase subunits and bcl-3) are implicated in hematological and solid tumour malignancies. NF-kappaB appears to be involved in cell proliferation control, apoptosis control, angiogenesis promotion and possibly regulation of diffusion of metastases. There are several reports that inhibition of NF-kappaB as a therapeutic target may have a role in tumour cell death or growth inhibition. AREA COVERED IN THIS REVIEW: We review data about inhibition of NF-kappaB in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We describe the molecular mechanisms underlying NF-kappaB deregulation in these haematological malignancies. WHAT THE READER WILL GAIN: Constitutive activation of NF-kappaB in the nucleus has been reported in some varieties of MDS/AML. The in vitro and in vivo results of NF-kappaB inhibition in myeloid malignancies are highlighted. TAKE HOME MESSAGE: NF-kappaB selective inhibitory drugs may be useful, either as single agents or associated with conventional chemotherapy. PMID- 20858025 TI - Speech intelligibility and perceptions of communication effectiveness by speakers with dysarthria following traumatic brain injury and their communication partners. AB - PRIMARY OBJECTIVE: This study examined differences in perceived communicative effectiveness between a group of eight participants with chronic dysarthria following TBI and their nominated communication partners (TBIP). The relationship between communicative effectiveness and listener ratings of speech intelligibility was also examined. RESEARCH DESIGN: Group comparison design. METHODS AND PROCEDURES: The Communicative Effectiveness Survey was completed by the participants with TBI and their communication partner. Speech intelligibility of the eight adults with dysarthria was rated by nine naive listeners using direct magnitude estimation. MAIN OUTCOMES AND RESULTS: The participants with TBI tended to rate their communicative effectiveness higher than their TBIP; however, this trend was not significant. No significant differences were noted between the TBI and TBIP groups in ratings of communicative effectiveness in various communication settings. No significant relationship was found between conversation level intelligibility and perceptions of communicative effectiveness, as rated by individuals with TBI and TBIP. CONCLUSIONS: The findings of this study highlight the need for collaborative participation in the therapeutic process by all stakeholders. The lack of correlation between speech intelligibility and perceived communicative effectiveness highlights the need for careful examination of activity and participation during assessment and goal setting. PMID- 20858026 TI - Blood glucose dysregulation and cognitive outcome in ARDS survivors. AB - OBJECTIVE: Hyperglycaemia is common in critically ill patients and may contribute to increased mortality and morbidity. This study assessed the impact of blood glucose on cognitive outcome in acute respiratory distress syndrome (ARDS) patients' 1 year post-hospital discharge. DESIGN: Retrospective data for 74 ARDS survivors who were enrolled in a prospective mechanical ventilation randomized clinical trial. A standard protocol was used to manage blood glucose. The highest, lowest, mean and standard deviation glucose values were examined, as well as duration of hypoxemia and other clinical data. Standardized neuropsychological tests were administered to identify cognitive sequelae. Logistic regression models were used to assess risk factors for cognitive sequelae. MEASUREMENTS AND RESULTS: There was a significant relationship between the blood glucose and cognitive sequelae. Greater duration of mechanical ventilation and highest blood glucose predicted cognitive sequelae. CONCLUSIONS: Blood glucose dysregulation, specifically moderate hyperglycaemia and ICU length of stay, predicted adverse cognitive sequelae in ARDS patients. PMID- 20858027 TI - Isokinetic strength training of lower limb muscles following acquired brain injury. AB - PRIMARY OBJECTIVE: To investigate the effectiveness of isokinetic strength training of ankle and knee muscles in adults with chronic acquired brain injury (ABI). RESEARCH DESIGN: Series of single case studies. METHODS: Twelve people with ABI participated in a 2.5-week baseline, 12-week intervention and a 4-week follow-up phase. INTERVENTION: Concentric isokinetic exercise, twice a week, for plantarflexors (PFs), dorsiflexors (DFs), knee flexors (KFs) and knee extensors (KEs). OUTCOMES: Peak torque and power at 60 and 90 degrees s-1, PFs and KFs tone at 60 degrees s-1, gait speed and timed chair rises. RESULTS: For single case analyses strength improvements were noted in 11/12 participants' PFs, 5/12 participants' DFs and 7/12 participants' KEs and KFs. Gait speed improved in 8/12 participants and chair rise time improved in 7/12 participants. PFs tone increased in three participants, KFs tone increased in six participants and three participants reported knee pain. For group analyses, peak torque of PFs and KEs, fast gait speed and timed chair rises demonstrated improvement (p < 0.05). CONCLUSIONS: Isokinetic strength training may be effective to improve lower limb muscle strength; however, care needs to be taken in selecting suitable candidates as some individuals reported knee pain with this intensive programme. PMID- 20858028 TI - Seasonal and regional variations of asthma and association with osteoporosis: possible role of vitamin D in asthma. AB - BACKGROUND: Based on the evidence that vitamin D is involved in the development of immune system and vitamin D receptor gene is associated with asthma, we supposed that vitamin D is related to the development of asthma. METHODS: Asthma patients were identified from the Swedish Hospital Discharge Register and the hospitalization rate was examined by different seasons and regions. Standardized incidence ratios (SIRs) for asthma were examined among patients hospitalized for osteoporosis compared with the general population. RESULTS: A total of 172,384 patients were hospitalized for asthma in Sweden during 1965-2007. More patients were hospitalized in winter and North Sweden than in summer and South Sweden. The risk of asthma after osteoporosis was significantly increased, giving an overall SIR of 2.93. The risk was higher in male patients when compared with female subjects. Patients hospitalized for osteoporosis at age younger than 55 showed a high risk. Reversing the analyses and examining the risk of osteoporosis after hospitalization of asthma, SIR was significantly increased (3.54). CONCLUSION: Our study suggests that vitamin D, as indicated by the high risk of asthma after osteoporosis and the seasonal and regional variations of hospitalization, could play an important role for the development of asthma. PMID- 20858029 TI - A problem-solving intervention for children with persistent asthma: a pilot of a randomized trial at a pediatric summer camp. AB - BACKGROUND: Pediatric summer camps are emerging as a means to increase social support and improve children's attitudes about their chronic illness. Because of the high rate of camp attendance, it may be feasible to implement interventions within that setting; however, it has yet to be determined what components of camp are beneficial. OBJECTIVE: The objective of this pilot study was to determine the efficacy of a problem-solving intervention targeting disease management in improving psychosocial functioning of children with persistent asthma, over and above the benefits of participation in a pediatric summer camp. METHODS: Fifty campers were randomly assigned to receive camp plus a nightly problem-solving intervention activity or camp as usual. Changes in self-reported asthma knowledge and problem-solving skills and self- and parent-reported child self- and social competence health-related quality of life were assessed thrice: before camp, on the last day of camp, and 3-months post-camp. RESULTS: There were no significant differences between the problem-solving intervention group and the camp as usual group in change across psychosocial variables from before camp to last day of camp or before camp to 3-months post-camp. Increases in asthma knowledge and problem-solving were found 3-months post-camp when groups were combined. CONCLUSIONS: Although support was found for improvements in disease knowledge and problem-solving skills after camp participation, there were no identified benefits to the problem-solving intervention. Children with asthma who participated in camp were functioning at a high level in terms of knowledge, problem-solving, and social and self-competence, suggesting that interventions may be more effective if targeted to patients with identified problems with disease management. PMID- 20858030 TI - 'We are the forgotten victims': Perspectives of adult siblings of persons with traumatic brain injury. AB - PRIMARY OBJECTIVE: This study determined how the lives of a cross-national sample of adult siblings had changed since their brothers and sisters incurred a traumatic brain injury. RESEARCH DESIGN: A total of 272 participants provided responses to the question, 'How is your life different since your sibling had a TBI?' Responses were analysed through the constant comparative method of textual analysis. METHODS AND PROCEDURES: Responses were collected through a mailed survey. The analysed question appeared at the end of a 243-item quantitatively based survey containing five open-ended questions. OUTCOMES AND RESULTS: Three themes emerged: (1) 'Family impacts' such as growing up with a sibling with TBI and impact on family closeness; (2) 'Caring' including caring for and about the family member; and (3) 'Making sense of the experience' through adjustment and personal development. CONCLUSIONS: The study demonstrates that having a sibling with a TBI can result in profound and enduring negative and positive life changes for non-injured siblings. Professionals need to attend to the needs of siblings for support and guidance and should be considered as key informants about their injured family members during intake and service planning. PMID- 20858031 TI - Sustained vertebral antifracture efficacy of oral anti-osteoporotic therapies in postmenopausal osteoporosis. AB - OBJECTIVE: Vertebral fractures are common in women with postmenopausal osteoporosis, a chronic condition requiring long-term treatment with anti osteoporotic treatments. Therefore, it is important to assess sustainability of antifracture efficacy. METHODS: A review of the literature to determine pivotal vertebral fracture studies for oral bisphosphonates (ibandronate, risedronate and alendronate), strontium ranelate, and raloxifene and to evaluate vertebral antifracture efficacy over time. RESULTS: Data from the BONE trial showed that ibandronate sustained vertebral antifracture efficacy over time (58% vertebral fracture risk reduction in first year p = 0.0561, increased to 62% for years 0-3; p < 0.001). The Vertebral Efficacy with Risedronate Therapy-North America (VERT NA) and VERT-multi-national (VERT-MN) studies demonstrated that the relative risk reduction (RRR) with risedronate versus placebo decreased over time (VERT-NA: 65% for first year to 41% for years 0-3; VERT-MN: 61% for first year to 49% for years 0-3). Data from the Fracture Intervention Trial (FIT) I trial with alendronate showed that the RRR in the cumulative incidence of new vertebral fractures versus placebo decreased from 62% for years 0-2 to 47% for years 0-3. Similar decreases in RRR over time were reported with strontium ranelate in the Spinal Osteoporosis Therapeutic Intervention study (SOTI; 49% for first year to 33% for years 0-4) and Treatment of Peripheral Osteoporosis Study (TROPOS; 45% for first year to 24% for years 0-5). No clear trend exists for sustained efficacy over time with raloxifene. CONCLUSIONS: Vertebral fracture protection could be interpreted to decrease over time with alendronate, risedronate and strontium ranelate, and may be due to multiple factors. Ibandronate sustained vertebral antifracture efficacy over time. PMID- 20858032 TI - N-aryl pyrazoles, indazoles and azaindazoles as antagonists of CC chemokine receptor 1: patent cooperation treaty applications WO2010/036632, WO2009/134666 and WO2009/137338. AB - BACKGROUND: CC chemokine receptor 1 (CCR1) is a GPCR involved in the migration and activation of leukocytes. A number of studies have highlighted a role for CCR1 in preclinical animal models of inflammatory diseases, including MS and rheumatoid arthritis. OBJECTIVE: This review examines three reports on a new series of CCR1 antagonists. METHODS: The compounds of the title inventions are put in the context of earlier work in the area of CCR1 antagonism. The structure activity relationships disclosed in the inventions are also discussed. CONCLUSIONS: Several of the compounds disclosed in patent cooperation treaty applications WO 2010/036632, WO 2009/134666 and WO 2009/137338 are sub-nanomolar antagonists of MIP-1alpha-induced calcium flux in CCR1-bearing cells. Further preclinical studies are required with these new CCR1 antagonists in order to understand their potential for ameliorating human inflammatory diseases. PMID- 20858033 TI - Haplotypes on 9p21 modify the risk for coronary artery disease among Indians. AB - The chromosomal region 9p21 has been reported to be associated with myocardial infarction, coronary artery disease (CAD), diabetes, and many other related multifactorial diseases in humans. Although the genome-wide association studies have identified a limited number of single-nucleotide polymorphisms (SNPs) at 9p21 for CAD risk, the role of flanking SNPs has not been studied so far. Therefore, in the present work, we studied the role of flanking SNPs with respect to that of the previously identified SNPs rs10757278 and rs2383207 at 9p21 among the Indian subjects found to have CAD (n = 414) along with age- and sex-matched control subjects (n = 408). Our study replicated the association of genome-wide association studies that had identified SNPs rs2383207 (p = 4.7 * 10(-5)) and rs10757278 (p = 5.5 * 10(-5)) among Indians with CAD. Further, we evaluated nine additional SNPs, of which two SNPs flanking rs2383207 (rs1537375 [p = 2.4 * 10( 5)] and rs1537374 [p = 5.6 * 10(-5)]) were also strongly associated with CAD. The haplotypes constructed using four risk SNPs revealed that the haplotypes with combinations of rs10757278 showed CAD risks, whereas the minor alleles of rs2383207, rs1537375, and rs1537374 in combinations reduce the CAD risks substantially. Our study demonstrates that the variation in the chromosomal region 9p21 is involved in modifying progression toward CAD among Indians and the risk may be variable, contributed by the SNPs that are flanking previously identified SNPs. PMID- 20858034 TI - Intraurethral instillation of ketamine for male rigid cystoscopy. AB - PURPOSE: This study was conducted to examine the efficacy of ketamine along with lidocaine gel for instillation in the male urethra for easiness of outpatient rigid cystoscopy, as compared with only using lidocaine gel. PATIENTS AND METHODS: A total of 60 consecutive men who were scheduled to undergo rigid cystoscopy were randomly assigned to receive either 10 mL of 2% lidocaine gel combined with 2 mL normal saline, or 10 mL of 2% lidocaine gel combined with 2 mL ketamine (100 mg). Hemodynamic changes and the level of pain perception of patients at the beginning, during, and after every procedure in both groups were recorded by using the visual analogue scale. RESULTS: There were no significant differences in hemodynamic changes between the two groups; however, the perception of pain was significantly decreased when lidocaine was used in conjunction with ketamine, most notably during the first 5 minutes of cystoscopy. CONCLUSIONS: Instillation of lidocaine gel in conjunction with ketamine in the urethra could decrease pain perception and make men undergoing outpatient rigid cystoscopy more comfortable during the procedure. PMID- 20858035 TI - Endoscopic stented ureterocystostomy. AB - BACKGROUND AND PURPOSE: Fibrotic or neoplastic obstruction of the terminal ureter and ureterovesical junction can preclude internal drainage with a Double-J catheter. Some minimally invasive alternatives are described in the literature to avoid a percutaneous nephrostomy. We present a pure endourologic technique. PATIENTS AND METHODS: In six patients with an obstructed upper urinary tract, after the introduction of iodine contrast, the ureter was punctured with a needle to introduce a guidewire in the urinary tract under cystoscopic and fluoroscopic control. The alternative path between the bladder and ureter was then dilated up 10F to facilitate the Double-J catheter introduction. RESULTS: All six patients had their obstructed urinary tract drained with a Double-J catheter inserted above the level of obstruction. No complication was verified. CONCLUSION: Internal urinary tract drainage with a Double-J catheter was accomplished using endourologic principles in six patients, avoiding a percutaneous nephrostomy or other more invasive procedures. PMID- 20858036 TI - Role of echinocandins in the management of fungal infections in neonates. AB - As the incidence rates of neonatal systemic fungal infections (SFI) have been increasing over the last years, research efforts have been addressed towards identifying both effective preventative strategies, and efficacious and well tolerated antifungal drugs. Historically, the first options in treatment of neonatal SFI have been – and currently are – fluconazole and amphotericin B. However, these two drugs carry limitations both in efficacy and in putative toxicity. Recently, new therapeutic alternatives have drawn the neonatologists' attention. Echinocandins are a new class of antifungal drugs with characteristics that might better meet the needs of this particular population of patients. Caspofungin (CSP), micafungin (MICA), and anidulafungin have inherent good activities both against biofilms, and against natively fluconazole-resistant strains of Candida spp, thus overcoming two of the major weaknesses of the commonly used antifungal drugs in nurseries. CSP and MICA have been recently studied in neonatal populations. The kinetics and appropriate dosing of this agent in premature and term infants have been described, but ongoing further studies are needed to better address this area. Case-report series show clinical efficacy and tolerability in critical neonatal patients given CSP and MICA. In addition, extrapolation of data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both CSP and MICA are effective and well tolerated also in neonates. Further studies properly designed for neonatal populations will better address long-term safety and ecological issues related to echinocandin use in neonates. PMID- 20858037 TI - Attitudes of psychiatrists in South Australia towards research degrees. AB - OBJECTIVE: The aim of this paper was to identify attitudes towards higher degrees by research (PhDs and Masters) among psychiatrists in South Australia, with the objective of identifying possible ways to increase the uptake of higher degrees in that population. METHOD: A survey questionnaire was designed, piloted and sent to all members of the Royal Australian and New Zealand College of Psychiatrists in South Australia. RESULTS: The response rate was 54.9% (n = 179). The sample included 99 individuals who had completed or considered completing a higher degree and 80 individuals who had not considered this. Responses to items were collated separately according to these two groups. Qualitative data were analysed thematically across the sample. Service demands, financial pressures and time constraints, along with a number of other factors including a lack of mentors and role models, were identified as issues in both quantitative and qualitative data. CONCLUSIONS: A number of positive attitudes were expressed regarding higher degrees by research, but a number of negative opinions were also expressed. The study achieved its aim of identifying attitudes, but ways in which to increase higher degrees by research for psychiatrists remains an area for further exploration. PMID- 20858038 TI - Comparison between two defibrillation waveforms. AB - Two defibrillation waveforms, the chopped biphasic pulses and the constant current pulses, were assessed and compared. Two indices are introduced. The first one is the ratio between the delivered energy W and the energy W(0) of a rectangular pulse with the same duration and electric charge. The second index eta(C) = W(0)/W(C0) stands for the level of utilizing the initially loaded capacitor energy W(C0). Some design considerations are also discussed. Another aspect of the study is the choice of appropriate capacitor for pulse generation. The results obtained show that there is no outstanding optimal waveform. The W/W(0) ratio is higher for the known constant current shapes but specifically with a patient resistance lower than 80 Omega. On the other hand, the implementation of these shapes would face several difficulties. The chopped biphasic waveforms are obtained by relatively simple technical solutions leading to very small in size and weight portable instruments. PMID- 20858039 TI - A novel intraoperative sensor for soft tissue balancing in total knee arthroplasty. AB - Ligament balancing during total knee arthroplasty (TKA) is a controllable and critical procedure necessary for the longevity of the prosthesis. Intraoperative knowledge of the magnitude and location of tibiofemoral forces, can guide the surgeon to an accurate balancing throughout the operation. We developed a novel sensor device in order to monitor tibiofemoral forces during TKA ligament balancing procedure. The device predicts loads with an error of +/- 1.5%, following a linear trend of slope = 0.9933 and R(2) = 0.9987; while the location of load is predicted with a practically acceptable error of +/- 0.5 mm. The device was subjected to a surgical validation with in situ application during simulated TKAs on composite and cadaveric knees, with a very satisfactory outcome and no operative time elongation. The device can be a useful intraoperative instrument for accurate TKA ligament balancing procedures based on objective and graphically demonstrated and recorded evidence. PMID- 20858040 TI - Cutoff score of the sexual interest and desire inventory-female for diagnosis of hypoactive sexual desire disorder. AB - OBJECTIVE: To determine the most appropriate cutoff value for the Sexual Interest and Desire Inventory-Female (SIDI-F) score to discriminate between women with hypoactive sexual desire disorder (HSDD) and those with no female sexual dysfunction (FSD). The SIDI-F is a clinician-rated instrument consisting of 13 items designed to assess HSDD severity in women. The total score ranges from 0 to 51, with higher scores indicating better sexual function. METHODS: Data from patients enrolled in a North American nontreatment study and a European nontreatment study were analyzed. Both studies were 4-week, prospective, multicenter trials designed to assess the reliability and validity of the SIDI-F. Only patients with HSDD or no FSD were included in this analysis. Receiver operating characteristics (ROC) analysis was used to determine the ability of the SIDI-F to differentiate between patients with HSDD and those with no FSD at baseline. RESULTS: A total of 428 women were included in this analysis: 174 from North America (HSDD 113, no FSD 61) and 254 from Europe (HSDD 130, no FSD 124). In the North American study, a SIDI-F cutoff score of 33 minimized the difference between sensitivity (94.7%) and specificity (93.4%). In the European study, SIDI F cutoff scores of both 33 and 34 minimized the difference between sensitivity (95.2%) and specificity (94.4%). CONCLUSIONS: In appropriately screened women, a SIDI-F score of <=33 indicates the presence of HSDD. PMID- 20858041 TI - Primary ovarian echinococcosis mimicking an ovarian carcinoma: an uncommon masquerade even in the developing world. PMID- 20858042 TI - Enantioselective production of benzoin from benzoin acetate via kinetic resolution and deracemization using Rhizopus oryzae. AB - In this study, the production of enantiopure benzoin from rac-benzoin acetate was achieved by lipase catalyzed kinetic resolution combined with deracemization using Rhizopus oryzae (CBS111718). The growth cells were pretreated with 20 kHz and 30 kHz ultrasound irradiation and mechanical homogenization. Approximately 100% conversion and 96% enantiomeric excess of the product (S-benzoin) were obtained by applying 20 kHz ultrasound irradiation at pH 6. The deracemization process involves new and important processes that allow for the transformation of a racemate into a single stereoisomeric product in 100% theoretical yields. Moreover, the application of ultrasound increases the conversion rate by reducing mass transfer limitation. PMID- 20858043 TI - Is it time to consider cognitive behavioral therapy for persons with epilepsy? Clues from pathophysiology, treatment and functional neuroimaging. AB - Depression is common in neurological conditions. Patients with epilepsy are significantly more likely to have depression than the general population. However, no published studies have examined the effects of antidepressants and psychotherapy on the brain in patients with epilepsy. A systematic review of 34 relevant neuroimaging articles was conducted on temporal lobe epilepsy (with and without depression), depression (with and without epilepsy), and cognitive behavioral therapy (CBT) and antidepressants through PET, functional MRI, SPECT or proton spectroscopic imaging. Results indicate hypoactivity in the frontal cortex and hippocampus, and hyperactivity in the left dorsomedial prefrontal cortex for depression (with and without epilepsy). Hypoactivity was consistently found in the frontal cortex and temporal region in temporal lobe epilepsy (with and without depression). Studies of nonepilepsy groups suggest that CBT impacts the frontal cortex, prefrontal cortex, temporal lobe, thalamus and hippocampus- all of these areas are dysfunctional in temporal lobe epilepsy with depression. The findings suggest that patients with epilepsy may benefit from CBT. More research is needed to establish CBT as evidence-based practice for epilepsy with depression. PMID- 20858044 TI - Assessment of cellular toxicity of TiO2 nanoparticles for cardiac tissue engineering applications. AB - Because of the increased use of titanium dioxide (TiO2) nanoparticles (NPs) in tissue engineering (TE), and in new constructs for cardiac TE, their effect was studied on three relevant cell types: Adult rat ventricular cardiomyocytes, human embryonic stem cell-derived cardiomyocytes (hESC-CM) and fibroblasts. For adult rat myocytes, 10 MUg/mL TiO2 NPs showed no significant effect on myocyte survival over 24 h or acute myocyte contractility. Increasing the concentration to 100 MUg/mL was seen to reduce contraction amplitude (p < 0.05). For hESC-CM, 10 MUg/mL TiO2 reduced the beating rate significantly by 24 h. No arrhythmias or cessation of beating were observed in either cell type. Culturing fibroblasts in 5-150 MUg/mL TiO2 significantly reduced cell proliferation at day 4 and increased cell death. We conclude that there may be modest but potentially adverse effects of TiO2 NPs if used in fast degrading polymers for myocardial tissue engineering (MTE) applications. PMID- 20858045 TI - Physico-chemical features of engineered nanoparticles relevant to their toxicity. AB - Nanotoxicology studies require investigations of several physico-chemical aspects of the particle/body fluid interaction, here described by reviewing recent literature in the light of new experimental data. Current characterization mostly covers morphology and metric-related characteristics (form, chemical composition, specific surface area, primary particle size and size distribution), and is mandatory in any experimental study. To unveil toxicity mechanisms, several other physico-chemical properties relevant to (geno) toxicity need to be assessed, typically the release or quenching of radical/ROS (Reactive Oxygen Species), the presence of active metal ions, evidence of structural defects. Major tasks for physical chemists working on nanoparticles-induced genotoxicity are described with some examples: (i), Tailored preparation of the same material in different sizes; (ii) particle modification changing a single property at a time; and (iii) identification of appropriate reference materials. Phenomena occurring during the contact between nanoparticles and cellular media or biological fluids (dispersion, agglomeration/aggregation, protein adsorption) are discussed in relation to the surface properties of the nanoparticles considered. PMID- 20858046 TI - Industry self regulation of television food advertising: responsible or responsive? AB - INTRODUCTION: This study evaluated the impact of the Australian Food and Grocery Council (AFGC) self-regulatory initiative on unhealthy food marketing to children, introduced in January 2009. The study compared patterns of food advertising by AFGC and non-AFGC signatory companies in 2009, 2007 and 2006 on three Sydney commercial free-to-air television channels. METHODS: Data were collected across seven days in May 2006 and 2007, and four days in May 2009. Advertised foods were coded as core, non-core and miscellaneous. Regression for counts analyses was used to examine change in rates of advertisements across the sampled periods and differential change between AFGC-signatory or non-signatory companies between 2007 and 2009. RESULTS: Of 36 food companies that advertised during the 2009 sample period, 14 were AFGC signatories. The average number of food advertisements decreased significantly from 7.0 per hour in 2007 to 5.9 in 2009. There was a significant reduction in non-core food advertising from 2007 to 2009 by AFGC signatories compared with non-signatory companies overall and during peak times, when the largest numbers of children were viewing. There was no reduction in the rate of non-core food advertisements by all companies, and these advertisements continue to comprise the majority during peak viewing times. DISCUSSION: While some companies have responded to pressures to reduce unhealthy food advertising on television, the impact of the self-regulatory code is limited by the extent of uptake by food companies. The continued advertising of unhealthy foods indicates that this self-regulatory code does not adequately protect children. PMID- 20858047 TI - Angiotensin receptor blockers and cancer - Relationship dismissed by VALUE data while waiting for EMA and FDA reports. PMID- 20858048 TI - Simultaneous detection of multiple single-nucleotide polymorphisms by a simple membrane chip. AB - Technologies that screen multiple single-nucleotide polymorphisms (SNPs) could be very valuable in predicting patients' susceptibilities to diseases or responses to therapeutic interventions. In this study, we developed a chip that can accurately detect four SNPs at same time. This chip is cost-effective and user friendly because it uses a detection protocol analogous to dot blotting and does not require sophisticated instruments. To establish this chip, we designed and blotted onto a nylon membrane SNP-specific oligonucleotide probes for human angiotensinogen, cholesteryl ester transfer protein, and apolipoprotein E. This chip detected the corresponding SNPs harbored within the angiotensinogen, cholesteryl ester transfer protein, and apolipoprotein E sequences from 20 donors. Importantly, the SNPs detected by our chip matched exactly with the direct sequencing results, thereby highlighting the accuracy of this chip. In conclusion, our chip is a robust tool for multiple SNP screening and holds the potential to future refinement in detecting diseases-associating genes in patients. PMID- 20858049 TI - Analysis of educational materials and destruction/opt-out initiatives for storage and use of residual newborn screening samples. AB - In recent years, the storage and use of residual newborn screening (NBS) samples has gained attention. To inform ongoing policy discussions, this article provides an update of previous work on new policies, educational materials, and parental options regarding the storage and use of residual NBS samples. A review of state NBS Web sites was conducted for information related to the storage and use of residual NBS samples in January 2010. In addition, a review of current statutes and bills introduced between 2005 and 2009 regarding storage and/or use of residual NBS samples was conducted. Fourteen states currently provide information about the storage and/or use of residual NBS samples. Nine states provide parents the option to request destruction of the residual NBS sample after the required storage period or the option to exclude the sample for research uses. In the coming years, it is anticipated that more states will consider policies to address parental concerns about the storage and use of residual NBS samples. Development of new policies regarding storage and use of residual NBS samples will require careful consideration of impact on NBS programs, parent and provider educational materials, and respect for parents among other issues. PMID- 20858050 TI - A one-step prescreening for point mutations and large rearrangement in BRCA1 and BRCA2 genes using quantitative polymerase chain reaction and high-resolution melting curve analysis. AB - High-resolution melting (HRM) of DNA is a versatile method for mutation scanning that monitors the fluorescence of double-strand DNA with saturating dye. Performing HRM on a real-time thermocycler enables semiquantitative analysis (quantitative polymerase chain reaction, qPCR) to be associated to HRM analysis for detection of both large gene rearrangements and point mutations (qPCR-HRM). We evaluated this method of mutation screening for the two major breast and ovarian cancer susceptibility genes BRCA1 and BRCA2. Screening of these two genes is time-consuming and must include exploration of large rearrangements that represent 5% to 15% of the alterations observed in these genes. To assess the reliability of the HRM technology, 201 known nucleotide variations scattered over all amplicons were tested. The sensitivity of qPCR was evaluated by analyzing seven large rearrangements. All previously identified variants tested were detected by qPCR-HRM. A retrospective study was done with 45 patients: qPCR-HRM allowed all the variants previously tested by denaturing high-performance liquid chromatography to be identified. qPCR analysis showed three cases of allele dropout (due to a 104-bp deletion, SNP primer mismatch, and an Alu insertion). A prospective study was done with 165 patients allowing 22 deleterious mutations, 16 unclassified variants, and 2 rearrangements to be detected. qPCR-HRM is a simple, sensitive, and fast method that does not require modified PCR primers. Thus, this method allows in one step the detection of point mutation, gene rearrangements, and prevention of missing a mutation due to primer mismatch. PMID- 20858051 TI - ROCK inhibition facilitates the generation of human-induced pluripotent stem cells in a defined, feeder-, and serum-free system. AB - Human-induced pluripotent stem cells (iPSCs) generated from human adult somatic cells through reprogramming hold great promises for future regenerative medicine. However, exposure of human iPSCs to animal feeder and serum in the process of their generation and maintenance imposes risk of transmitting animal pathogens to human subjects, thus hindering the potential therapeutic applications. Here, we report the successful generation of human iPSCs in a feeder-independent culture system with defined factors. Two stable human iPSC lines were established from primary human dermal fibroblasts of two healthy volunteers. These human iPSCs expressed a panel of pluripotency markers including stage-specific embryonic antigen (SSEA)-4, tumor-rejection antigen (TRA)-1-60, TRA-1-81, and alkaline phosphatase, while maintaining normal karyotypes and the exogenous reprogramming factors being silenced. In addition, these human iPSCs can differentiate along lineages representative of the three embryonic germ layers upon formation of embryoid bodies, indicating their pluripotency. Furthermore, subcutaneous transplantation of these cells into immunodeficient mice resulted in teratoma formation in 6 to 8 weeks. Our findings are an important step toward generating patient-specific iPSCs in a more clinically compliant manner by eliminating the need of animal feeder cells and animal serum. PMID- 20858052 TI - Continuing robotically? The completion of a robot-assisted radical prostatectomy after laparotomy. AB - The laparoscopic management of difficult adhesions can be quite challenging for even the most experienced of laparoscopic surgeons. We describe a case of managing a suspected enterotomy with a laparotomy during a robot-assisted radical prostatectomy and the surgical options after repair. The case was complicated by a Meckel's diverticulum fused and continuous with a urachal cyst, itself a rare occurrence. After the excision of the Meckel's diverticulum-urachal complex, the laparotomy incision was closed, and the prostatectomy was performed robotically. We discuss the controversies regarding continuation of a planned robotic procedure after a midline laparotomy. PMID- 20858053 TI - A simple allele-specific polymerase chain reaction method to detect the Gly143Glu polymorphism in the human carboxylesterase 1 gene: importance of genotyping for pharmacogenetic treatment. AB - Human carboxylesterases 1 and 2 (CES1 and CES2) catalyze the hydrolysis of many exogenous compounds. Alterations in CES sequences could lead to variability in both the inactivation of drugs and the activation of prodrugs. The human CES1 gene encodes for the enzyme carboxylesterase 1, a serine esterase governing both metabolic deactivation and activation of numerous therapeutic agents. Some of theses drugs are the antiviral oseltamivir used to treat some types of influenza infections and the methylphenidate employed in the treatment of patients with attention deficit. The Gly143Glu polymorphism in CES1 gene has been shown to reduce enzyme activity. The aim of the present study was to develop an easy and cheap method to detect this polymorphism. For this, we studied a group of people from Cordoba, a Mediterranean area from Argentina. Our results show that our methodology could detect the presence of this polymorphism with a frequency around 1.8%, only in the heterozygote form. These results could be relevant to patients before the treatment with some drugs where the CES1 enzyme is involved. PMID- 20858054 TI - A predictive nuclear translocation assay for spliced x-box-binding protein 1 identifies compounds with known organ toxicities. AB - Compound toxicity is still the main cause of attrition, emphasizing the need for novel predictive assays to identify toxic compounds early during drug development. Endoplasmic reticulum (ER) stress has recently been discovered as a molecular event that links cellular dysfunction to drug-induced organ toxicity in humans. Among higher organisms the inositol-requiring transmembrane kinase/endoribonuclease pathway plays a major role in mediating the ER stress response. Inositol-requiring transmembrane kinase/endoribonuclease achieves this through its endoribonuclease activity causing a frameshift in the translation of the X-box-binding protein 1 (XBP1) to produce spliced XBP1 (XBP1s), which translocates into the nucleus, where it initiates transcription of ER stress response genes. Based on this biology, we have designed a novel beta galactosidase-based XBP1s-enzyme fragment complementation assay, which enables identification of compound-induced ER stress in human U2OS cells. The XBP1s enzyme fragment complementation assay was established in a 384-well format and validated using a library of 1280 pharmacologically active compounds. Importantly, the library of pharmacologically active compounds screen identified both well-established ER stress inducers and several compounds that are known organ toxicants but not previously reported to induce ER stress. Implementation of this assay to assess compound-induced ER stress will facilitate decision making for compound selection and we believe that it will significantly increase the ability to reduce toxicity of preclinical drug candidates. PMID- 20858055 TI - From access to engagement: measuring retention in outpatient HIV clinical care. AB - Engagement in HIV care is increasingly recognized as a crucial step in maximizing individual patient outcomes. The recently updated HIV Medicine Association primary HIV care guidelines include a new recommendation highlighting the importance of extending adherence beyond antiretroviral medications to include adherence to clinical care. Beyond individual health, emphasis on a "test and treat" approach to HIV prevention highlights the public health importance of engagement in clinical care as an essential intermediary between the putative benefits of universal HIV testing ("test") followed by ubiquitous antiretroviral treatment ("treat"). One challenge to administrators, researchers and clinicians who want to systematically evaluate HIV clinical engagement is deciding on how to measure retention in care. Measuring retention is complex as this process includes multiple clinic visits (repeated measures) occurring longitudinally over time. This article provides a synthesis of five commonly used measures of retention in HIV care, highlighting their methodological and conceptual strengths and limitations, and suggesting situations where certain measures may be preferred over others. The five measures are missed visits, appointment adherence, visit constancy, gaps in care, and the Human Resources and Services Administration HIV/AIDS Bureau (HRSA HAB) performance measure for retention in HIV care. As has been noted for antiretroviral medication adherence, there is no gold standard to measure retention in care, and consideration of the advantages and limitations of each measure, particularly in the context of the desired application, should guide selection of a retention measure. PMID- 20858056 TI - Do brief screening questions or provider perception accurately identify persons with low health literacy in the HIV primary care setting? AB - Rapid and accurate health literacy screening tools could assist interventions to improve care in the HIV clinic setting. Prior studies described brief screening questions for identification of persons with low health literacy, but the performance of these questions in HIV clinics is unknown. We examined the accuracy of provider perception and previously described brief screening questions for identification of low health literacy among 147 persons attending two HIV specialty clinics. Mean age was 41 and 48% were African American. Using the short Test of Functional Health Literacy in Adults (S-TOFHLA) as reference measure, the combined prevalence of marginal and inadequate health literacy (low health literacy) was 16%. Sensitivity and specificity of provider perception for identifying persons with low health literacy were 0.47 and 0.79. The screening question "How confident are you filling out medical forms by yourself?" had an area under the receiver operator characteristic curve (AUROC) of 0.67. Response of "somewhat" to this question had sensitivity 0.30, specificity 0.91, positive likelihood ratio 3.4 (95% confidence interval [CI] 1.8-6.4) and negative likelihood ratio 0.76 (95% CI 0.4-1.4). Educational attainment was a more sensitive but less specific measure of low health literacy (sensitivity 0.90, specificity 0.61 for completed high school or fewer years education), but was overall a more accurate discriminator of health literacy than either provider perception or screening questions (AUROC 0.79; p<0.05 for comparison of AUROCs). HIV providers often misjudge patients' health literacy. In the absence of rapid and accurate health literacy screening tools, clinics caring for persons with HIV/AIDS should implement clinic-wide interventions to improve health communication. PMID- 20858057 TI - Quantitative structure-activity relationship analysis of 4(3H)-quinazolone derivatives as tyrosine kinase inhibitors by multiple linear regression. AB - Computational chemistry is playing an increasingly important role in drug design and discovery, structural biology, and quantitative structure-activity relationship studies. A series of 4(3H)-quinozolone derivatives were screened for two-dimensional quantitative structure-activity relationship studies and subsequently their absorption, distribution, metabolism, and excretion (ADME) properties with the use of soft modeling techniques after selecting suitable descriptors for molecular structure. Multiple linear regression analysis was performed for this study. The final quantitative structure-property relationship mathematical models were found as follows: Equation [Y= log (1MIC)] [symbol: see the text] pMIC= 1. 0:2165kappa(1) - 2.082chi(3) - 0.3235MUT - 0.2185MUx - 100.6qN - 35.42. 2. 0:2185kappa(1) - 2.1575chi(3) - 0.3622MUT - 0.2142MUx - 100.4qN - 31.25. 3. 0:0015omega - 2.0822chi(3) - 0.1252MUT - 0.2180MUx - 112.9qN - 36.05. 4. 2:108chi(3) - 0.0035ET - 0.2033MUx - 3.489qesp - 92.60qN - 33.20. 5. 0:2140kappa(1) - 2.186chi(3) - 0.0036Oxxx - 0.0016Oxyy - 78.02qN - 31.52. PMID- 20858058 TI - Allergic contact dermatitis caused by farnesol: clinical relevance. AB - CONTEXT: The fragrance material farnesol is cited as an infrequent but important cause of allergic contact dermatitis (ACD). It is included in the fragrance mix II patch series and requires labeling in the European Union if it is used in a consumer product. OBJECTIVE: To review the existing literature to determine the causative role of farnesol in clinical contact allergy. MATERIALS AND METHODS: Survey of the literature on farnesol studies; predictive and clinical elicitation tests in case reports, reviews, and abstracts. RESULTS: Predictive animal studies demonstrated in most cases that farnesol was a nonsensitizer. However, 2 local lymph node assays (LLNAs) indicated strong sensitization potential. Predictive human test data indicated a low potential, if any, for sensitization in human tests with farnesol at 10% or 12%. A few clinical reports indicated low-level allergy or questionable reactions to farnesol, with 5% being the most commonly used. There were also reports in which no reactions were seen. DISCUSSION: Predictive testing on farnesol in animals shows conflicting results depending on the study methodology used. Human predictive patch-test data also had gaps that prevented it from being definitive in pointing to a causative relationship between farnesol and contact dermatitis. The real sensitizing potential of a material can best be determined by evaluating the clinical and epidemiological data so as to help resolve the conflicting animal and human predictive test data. CONCLUSIONS: This literature and scoring exercise showed that predictive and clinical elicitation data do not document a clear causative determination that farnesol is a frequent contact allergen. Detailed clinical relevance and patient studies should clarify the clinical problem farnesol represents. PMID- 20858060 TI - Young caregivers in the end-of-life setting: a population-based profile of an emerging group. AB - PURPOSE: Little is known about young caregivers of people with advanced life limiting illness. Better understanding of the needs and characteristics of these young caregivers can inform development of palliative care and other support services. METHODS: A population-based analysis of caregivers was performed from piloted questions included in the 2001-2007 face-to-face annual health surveys of 23,706 South Australians on the death of a loved one, caregiving provided, and characteristics of the deceased individual and caregiver. The survey was representative of the population by age, gender, and region of residence. FINDINGS: Most active care was provided by older, close family members, but large numbers of young people (ages 15-29) also provided assistance to individuals with advanced life-limiting illness. They comprised 14.4% of those undertaking "hands on" care on a daily or intermittent basis, whom we grouped together as active caregivers. Almost as many young males as females participate in active caregiving (men represent 46%); most provide care while being employed, including 38% who work full-time. Over half of those engaged in hands-on care indicated the experience to be worse or much worse than expected, with young people more frequently reporting dissatisfaction thereof. Young caregivers also exhibited an increased perception of the need for assistance with grief. CONCLUSION: Young people can be integral to end-of-life care, and represent a significant cohort of active caregivers with unique needs and experiences. They may have a more negative experience as caregivers, and increased needs for grief counseling services compared to other age cohorts of caregivers. PMID- 20858059 TI - Product development issues for PEGylated proteins. AB - Covalent attachment of poly(ethylene) glycol (PEG) groups to proteins, a process commonly called PEGylation, is often used to improve the performance of a protein in vivo. To date, at least eight such PEGylated peptide and protein conjugates have been approved as therapeutic agents and many more have undergone clinical trials. This review examines PEGylation from the perspective of developing a commercially viable drug product. The first section focuses on obtaining a pure and well-characterized drug substance. The latter section discusses formulation and manufacturing issues, with an emphasis on analytical methodology that provides the most detailed description of the purity and stability of PEGylated proteins. PMID- 20858061 TI - Women front and center: the opportunities of involving women in participatory health research worldwide. AB - Participatory research involving communities, especially women, is increasingly recognized as a valuable and scientifically sound approach to improve the relevance of a study, the accuracy of data collection and interpretation, the adherence to study procedures, and the likelihood of adopting any resulting intervention. This approach has interdisciplinary roots dating back more than half a century. Although widely used in community-based conservation and development projects worldwide, international public health research has yet to fully embrace this inclusive approach, which requires the sharing of power with research participants and a more involved relationship building process with communities. In return, the gap between publication and public action can be narrowed because ownership of the research process by an empowered community can lay the foundation for an accelerated implementation of interventions tailored to community needs and based on research results. This article draws on the professional experiences of the authors as well as published examples of international participatory health research with women. Factors critical for the success of participatory research are discussed, including attention to initial planning, early community involvement, conceptual clarity, defined community benefits, and joint interpretation of results, as well as translation to action. It includes common challenges and strategies to overcome them, such as conflict resolution and data ownership. PMID- 20858062 TI - Systematic review and meta-analysis of percutaneous nephrolithotomy for patients in the supine versus prone position. AB - PURPOSE: To evaluate the efficacy and safety of percutaneous nephrolithotomy (PCNL) for patients in the supine position vs prone position. MATERIALS AND METHODS: Eligible studies were identified from electronic databases (Cochrane CENTRAL, Medline and EMBASE). The database search, quality assessment, and data extraction were independently performed by two reviewers. Efficacy (stone-free rate, operative time) and safety (complication, such as fever and transfusion rate) were explored by using Review Manager 5.0. Sensitivity analysis was performed to explore the influence of low-quality studies. RESULTS: Two randomized controlled trials and two case-control studies including 389 patients met the inclusion criteria. Meta-analysis of extractable data showed that PCNL in the supine position was associated with a significantly shorter operative time than PCNL in the prone position (mean difference: -24.84; 95% confidence interval [CI]: -34.45 to -15.23; P < 0.00001). There was no difference between the positions with regard to success rate (odds ratio [OR]: 1.16; 95% CI: 0.68-1.48; P = 0.59), complication (OR: 1.09; 95% CI: 0.67-1.80; P = 0.72), transfusion rate (OR: 2.19; 95% CI: 0.93-5.13; P = 0.07), and fever rate (OR: 0.39; 95% CI: 0.13 1.16; P = 0.09). CONCLUSION: PCNL in the supine position took a shorter operative time than the prone position, but both positions appeared to be equivalent with regard to the stone-free rate and complication rate, transfusion rate, and fever rate. In brief, PCNL in the supine position is as effective and safe as PCNL in the prone position and was an alternate option for removal of renal calculi in PCNL. PMID- 20858063 TI - Monitoring of thermal dose during ablation therapy using quantum dot-mediated fluorescence thermometry. AB - PURPOSE: The objective of this study was to demonstrate the feasibility of quantum dot (QD)-mediated fluorescence thermometry to monitor thermal dose in an in-vitro thermal ablation zone generated by laser-heated gold nanoshells (LGNS). MATERIALS AND METHODS: Hyperthermic cell death of human prostate cancer cell line (PC-3) was determined after various heating settings and correlated to the thermal conditions using an Arrhenius model prior to LGNS ablation. PC-3 cells with gold nanoshells (GNS) and QDs were exposed to a near-infrared laser and QD excitation light. When the cells were heated by GNS, local temperature was measured using the temperature-dependent fluorescence intensity of QDs. Using the predetermined Arrhenius model, the thermal dose (i.e., cell death of PC-3 cells) by LGNS was estimated with local temperatures measured with QD-mediated thermometry. The estimated thermal dose was confirmed with calcein-acetoxy methylester viability assay. RESULTS: For PC-3 cell line, the activation energy and frequency factor of the Arrhenius model were 86.78 kcal/mol and 6.35 * 10(55) Hz, respectively. During LGNS ablation of PC-3 cells, QD-mediated temperature measurement showed that the temperature of the laser spot increased rapidly to ~58 degrees C +/- 4 degrees C. The estimated thermal dose showed that cell death reached to ~90% in 120 seconds. The death cell zone observed after staining corresponded to a peak area of the temperature profile generated after analysis of the QD fluorescence intensity. CONCLUSIONS: This study shows that the QD fluorescence thermometry can accurately monitor the PC-3 cell death by LGNS ablation. This approach holds promises for a better monitoring of thermal ablation procedures in clinical practice. PMID- 20858064 TI - A technique for the management of a large median lobe in robot-assisted laparoscopic radical prostatectomy. AB - An enlarged median lobe is encountered 8% to 18% of the time during robot assisted laparoscopic prostatectomy. A large intravesical lobe can obscure the anatomy of the bladder neck and generate a large bladder neck, necessitating reconstruction. In addition, it may increase the likelihood of ureteral injury, positive surgical margin, and residual prostate tissue. When encountering this anatomic variant, a clear surgical plan is required. We describe our approach to the large median lobe and highlight a specific technique that may be beneficial in managing this anatomic variant. PMID- 20858065 TI - The mRNA level of Charcot-Leyden crystal protein/galectin-10 is a marker for CRTH2 activation in human whole blood in vitro. AB - CRTH2 is one of the prostaglandin D2 receptors and plays a proinflammatory role in allergic diseases. Gene expression markers in whole blood induced by CRTH2 activation have not previously been reported. Using microarray analyses of 54 675 genes, we revealed modest gene expression changes in human whole blood stimulated in vitro by a selective CRTH2 agonist, DK-PGD2. Five genes were found to exhibit 1.5- to 2.6-fold changes in expression. The expression of Charcot-Leyden crystal protein/galectin-10 (CLC/Gal-10) in particular was consistently enhanced in human whole blood stimulated by DK-PGD2, as confirmed by quantitative real-time polymerase chain reaction analyses. DK-PGD(2)-induced increases in blood CLC/Gal 10 mRNA levels were largely attenuated by the CRTH2 antagonist CAY10471.Thus, the DK-PGD2-induced CLC/Gal-10 mRNA level can serve as a potential marker for monitoring pharmacodynamic effects of blood exposure to CRTH2 modulating agents. PMID- 20858067 TI - Application of proteomic technologies for prostate cancer detection, prognosis, and tailored therapy. AB - Prostate cancer affects 3 in 10 men over the age of 50 years, and, unfortunately, the clinical course of the disease is poorly predicted. At present, there is no means that can distinguish indolent from aggressive/metastatic tumors. Thus, a personalized clinical approach could be helpful in diagnosing clinically relevant disease and guiding appropriate patient therapy. Individualized medicine requires a deep knowledge of the molecular mechanisms underpinning prostate cancer carcinogenesis. Proteomics may be the most powerful way to uncover biomarkers of detection, prognosis, and prediction, as proteins do the work of the cell and represent the majority of the diagnostic markers and drug targets today. Proteomic technologies are rapidly advancing beyond the two-dimensional gel separation techniques of the past to new types of mass spectrometry and protein microarray analyses. Biological fluids and tissue-cell proteomes from men with prostate cancer are being explored to identify diagnostic and prognostic biomarkers and therapeutic targets using these new proteomic approaches. Traditional and novel proteomic technology and their application to prostate cancer studies in translational research will be presented and discussed in this review. Proteomics coupled with powerful nanotechnology-based biomarker discovery approaches may provide a new and exciting opportunity for body fluid-borne biomarker discovery and characterization. While innovative mass spectrometry technology and nanotrap could be applied to improve the discovery and measurement of biomarkers for the early detection of prostate cancer, the use of tissue proteomic tools such as the reverse-phase protein microarray may provide new approaches for personalization of therapies tailored to each tumor's unique pathway activation network. PMID- 20858066 TI - Transdermal permeation of novel n-acetyl-glucosamine/NSAIDs mutual prodrugs. AB - The current investigation reports skin permeation of three novel mutual prodrugs (MP) which couple n-acetyl-glucosamine with an NSAID, either ketoprofen or ibuprofen. They were evaluated for transdermal permeation using shed snakeskin, and to our knowledge represent the first MPs synthesized for this purpose, although they also could be used for subcutaneous delivery. MPs are defined as two active drug compounds usually connected by an ester linkage. Glucosamine administration has been linked to damaged cartilage repair, and pain relief in joints afflicted with osteoarthritis. NSAIDs are commonly used orally in transdermal creams or gels for joint pain relief. Two novel compounds we report (MP1 and MP2) covalently link ibuprofen and ketoprofen directly to the amide nitrogen of n-acetyl-glucosamine (NAG); the other compound (MP3) covalently links ibuprofen to the amide nitrogen, using a short chain acetyl linker. Permeability studies show that the ketoprofen mutual prodrug (MP2) permeates shed snakeskin more than three times greater than either ibuprofen derivative, while ethanol markedly increases the permeation for all three. The ketoprofen mutual prodrug appears the most likely candidate for transdermal administration; all three mutual prodrugs may be candidates for subcutaneous injection. PMID- 20858068 TI - Heat shock proteins in prostate cancer: from tumorigenesis to the clinic. AB - The heat shock proteins (HSP) constitute a superfamily of chaperone proteins present in all cells and in all cell compartments, operating in a complex interplay with synergistic/overlapping multiplicity of functions, even though the common effect is cell protection. Several reasons explain the need for investigating HSP in prostate cancer: (1) these molecules function as chaperones of tumorigenesis accompanying the emergence of prostate cancer cells, (2) they appear as useful molecular markers associated with disease aggressiveness and with resistance to anticancer therapies including hormone therapy, radiotherapy, chemotherapy and hyperthermia, and (3) they can be used as targets for therapies. The latter can be accomplished by: (i) interrupting the interaction of HSP (mainly HSPC1) with various client proteins that are protected from degradation when chaperoned by the HSP; (ii) using the chaperone and adjuvant capabilities of certain HSP to present antigenic peptides to the immune system, so this system can recognise the prostate tumour cells as foreign to mount an effective antitumoral response; and (iii) using treatment planning models taking into account the HSP expression levels to obtain more effective therapies. In summary, the study of the HSP during tumorigenesis as well as during cancer progression, and the inclusion of treatment designs targeting HSP combined with other treatment modalities, should improve prostate cancer survival in the near future. PMID- 20858072 TI - Patient with AIDS and acute circinate skin eruptions. PMID- 20858069 TI - Nanoparticle-mediated thermal therapy: evolving strategies for prostate cancer therapy. AB - PURPOSE: Recent advances in nanotechnology have resulted in the manufacture of a plethora of nanoparticles of different sizes, shapes, core physicochemical properties and surface modifications that are being investigated for potential medical applications, particularly for the treatment of cancer. This review focuses on the therapeutic use of customised gold nanoparticles, magnetic nanoparticles and carbon nanotubes that efficiently generate heat upon electromagnetic (light and magnetic fields) stimulation after direct injection into tumours or preferential accumulation in tumours following systemic administration. This review will also focus on the evolving strategies to improve the therapeutic index of prostate cancer treatment using nanoparticle-mediated hyperthermia. CONCLUSIONS: Nanoparticle-mediated thermal therapy is a new and minimally invasive tool in the armamentarium for the treatment of cancers. Unique challenges posed by this form of hyperthermia include the non-target biodistribution of nanoparticles in the reticuloendothelial system when administered systemically, the inability to visualise or quantify the global concentration and spatial distribution of these particles within tumours, the lack of standardised thermal modelling and dosimetry algorithms, and the concerns regarding their biocompatibility. Nevertheless, novel particle compositions, geometries, activation strategies, targeting techniques, payload delivery strategies, and radiation dose enhancement concepts are unique attributes of this form of hyperthermia that warrant further exploration. Capitalising on these opportunities and overcoming these challenges offers the possibility of seamless and logical translation of this nanoparticle-mediated hyperthermia paradigm from the bench to the bedside. PMID- 20858074 TI - Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. PMID- 20858075 TI - Concerns regarding a randomized study of the timing of antiretroviral therapy in zimbabweans with AIDS and acute cryptococcal meningitis. PMID- 20858076 TI - Safety, censoring, and intent-to-treat analysis: dangers to generalizability. PMID- 20858077 TI - Should antiretroviral therapy be delayed for 10 weeks for patients treated with fluconazole for cryptococcal meningitis? PMID- 20858080 TI - Decreasing the probability of creatine phosphokinase elevations: clinical considerations for daptomycin dosing in obese patients. PMID- 20858081 TI - Coronary aging in HIV-infected patients. PMID- 20858082 TI - Fatal cases of pandemic (H1N1) 2009 influenza despite their early antiviral treatment in Japan. PMID- 20858083 TI - Measurement and mathematical modeling of thermally induced injury and heat shock protein expression kinetics in normal and cancerous prostate cells. AB - PURPOSE: Hyperthermia can induce heat shock protein (HSP) expression in tumours, which will cause enhanced tumour viability and increased resistance to additional thermal, chemotherapy, and radiation treatments. The study objective was to determine the relationship of hyperthermia protocols with HSP expression kinetics and cell death and develop corresponding computational predictive models of normal and cancerous prostate cell response. METHODS: HSP expression kinetics and cell viability were measured in PC3 prostate cancer and RWPE-1 normal prostate cells subjected to hyperthermia protocols of 44 degrees to 60 degrees C for 1 to 30 min. Hsp27, Hsp60, and Hsp70 expression kinetics were determined by western blotting and visualised with immunofluorescence and confocal microscopy. Based on measured HSP expression data, a mathematical model was developed for predicting thermally induced HSP expression. Cell viability was measured with propidium iodide staining and flow cytometry to quantify the injury parameters necessary for predicting cell death following hyperthermia. RESULTS: Significant Hsp27 and Hsp70 levels were induced in both cell types with maximum HSP expression occurring at 16 h post-heating, and diminishing substantially after 72 h. PC3 cells were slightly more sensitive to thermal stress than RWPE-1 cells. Arrhenius analysis of injury data suggested a transition between injury mechanisms at 54 degrees C. HSP expression and injury models were effective at predicting cellular response to hyperthermia. CONCLUSION: Measurement of thermally induced HSP expression kinetics and cell viability associated with hyperthermia enabled development of thermal dosimetry guidelines and predictive models for HSP expression and cell injury as a function of thermal stress to investigate and design more effective hyperthermia therapies. PMID- 20858084 TI - Deep regional hyperthermia for the whole thoracic region using 8 MHz radiofrequency-capacitive heating device: relationship between the radiofrequency output power and the intra-oesophageal temperature and predictive factors for a good heating in 59 patients. AB - PURPOSE: To assess the relationship between the radiofrequency (RF) output power and the intra-oesophageal temperature for hyperthermia of the whole thoracic region, and also to evaluate the patients' characteristics associated with adequate heating. MATERIALS AND METHODS: Fifty-nine patients with thoracic cancer treated with radiotherapy plus hyperthermia were retrospectively analysed. The 8 MHz RF capacitive heating device was applied, both the upper and lower electrodes were 300 mm in diameter, placed on opposite sides of the whole thoracic region. All the patients also underwent intra-oesophageal temperature measurements. RESULTS: All thermal parameters, T(min), T(max), T(ave), and %T >= 41 degrees C, of the intra-oesophageal temperature highly correlated with the median RF output power (p < 0.0001), and the relations were independent in the multivariable analyses including clinical characteristics (p < 0.01). The performance status showed a statistically significant association on T(max), T(ave) and %T >= 41 degrees C (p < 0.05). The patient age and subcutaneous fat at some levels were inversely correlated with the thermal parameters (p < 0.05). CONCLUSION: The RF output power was significantly correlated with the intra-oesophageal temperature; it could be used as a promising parameter to assess the efficacy of hyperthermia for the whole thoracic region. Higher intra-oesophageal temperature may be achieved in patients with good performance status, younger age and thinner subcutaneous fat. PMID- 20858088 TI - The regimen of gemcitabine and cisplatin combined with radio frequency hyperthermia for advanced non-small cell lung cancer: a phase II study. AB - PURPOSE: This phase II randomised trial was designed to evaluate the therapeutic efficacy and feasibility of radio frequency regional hyperthermia in combination with chemotherapy for patients with advanced non-small lung cancer (NSCLC). METHODS: Eighty patients with pathologically proven advanced NSCLC, were enrolled and divided into two groups. Group A patients were treated by radio frequency regional hyperthermia in combination with the regimen of gemcitabine and cisplatin (GP). Group B patients were treated with the GP regimen alone. RESULTS: In group A, one patient achieved a complete response (CR), 18 achieved a partial response (PR), 18 achieved a stable disease and three experienced a progression of the disease. Thirty-three patients had a positive Clinical Benefit Response (CBR). In group B, no patient achieved CR, 17 achieved PR, 19 achieved a stable disease and four experienced a progression of the disease. Nineteen patients had a positive CBR. Significant differences between the two groups were observed for the CBR (P < 0.05), but not for RR. Major toxicities included bone marrow depression, nausea, vomiting, without significant differences between the two groups (P > 0.05). CONCLUSIONS: Radio-frequency regional hyperthermia in combination with chemotherapy (GP) is a safe, well tolerated, and effective therapeutic modality for patients with advanced NSCLC. The addition of hyperthermia improved quality of life. PMID- 20858089 TI - Acquired Robertsonian translocation is not always suggestive of poor prognosis: a case of acquired Rob(13;14) in Philadelphia chromosome-negative cells of chronic myelogenous leukemia. PMID- 20858090 TI - Missing mismatch repair: a key to T cell immortality. PMID- 20858091 TI - Conditional inactivation of MLH1 in thymic and naive T-cells in mice leads to a limited incidence of lymphoblastic T-cell lymphomas. AB - Defects in the mismatch repair system (MMR) underlie hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and also a significant number of sporadic colorectal cancers. Mice carrying a null allele for the MMR gene Mlh1 are preferentially prone to the development of lymphomas of B- and T-cell origin and to a lesser extent gastrointestinal tumors. Consistent with these findings in mice, MMR defects have also been observed in sporadic and hereditary hematological malignancies. To study the role of MLH1 for lymphomagenesis in more detail, we generated a new mouse model carrying a conditional Mlh1 allele (Mlh1(flox/flox)). Mating of these mice with EIIa-Cre recombinase transgenic mice allowed the constitutive inactivation of MLH1, and the resulting Mlh1(Deltaex4/Deltaex4) mouse line displays complete MMR deficiency and a cancer predisposition phenotype similar to Mlh1-/- mice. For T-cell specific MMR inactivation we combined the Mlh1(flox/flox) allele with the Lck-Cre transgene. In the resulting Mlh1(TDeltaex4/TDeltaex4) mice, MLH1 inactivation is limited to DP/SP thymocytes and naive peripheral T-cells. The development of T-cell lymphomas in Mlh1(TDeltaex4/TDeltaex4) mice is significantly reduced compared to Mlh1-/- mice, implying that MMR functions either at very early stages during T cell development or even earlier in lymphoid precursor cells to suppress lymphomagenesis. PMID- 20858092 TI - Quality of life of long-term survivors with Hodgkin lymphoma after high-dose chemotherapy, autologous stem cell transplantation, and conventional chemotherapy. AB - In this study, we investigated the quality of life (QoL) of long-term survivors with Hodgkin lymphoma who received high-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT). QoL of this group was compared with QoL of patients who were treated with conventional chemotherapy and with QoL of the healthy German population. Two standardized questionnaires, the EORTC QLQ-C30 and the EQ-5D, including the visual analogue scale (VAS) were applied. A total of 98 patients were included in the study, all of them treated in our institution. Thirty-seven patients who received HDCT with PBSCT between 1986 and 2007 were compared with 61 patients treated with conventional chemotherapy and supplementary radiation between 1998 and 2009. The median follow up for the HDCT group was 11 years. Statistical analysis with the one-sample t test shows a reduced QoL of both groups of patients compared to the healthy population. Compared to the group of patients who received conventional chemotherapy, there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea, which was worse in the group that was treated with BCNU containing high dose protocols. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long-term survivors with Hodgkin lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies. PMID- 20858093 TI - Dasatinib is effective against optic nerve infiltration of Philadelphia chromosome-positive acute lymphoblastic leukemia. PMID- 20858094 TI - Therapy-related myeloid sarcoma with an NPM1 mutation. PMID- 20858095 TI - The Hammersmith Hospital hematopathology case of the month: paraspinal B lymphoblastic lymphoma – problems in diagnosis and initial indolent behavior. AB - We describe a young man who presented with neurological signs and symptoms, and with a paraspinal soft tissue mass involving the vertebral body at T4. The patient was treated with dexamethasone prior to neurosurgical decompression and debulking. Biopsy showed features of a small B-cell lymphoma possibly of follicle center cell origin. The patient achieved complete remission with radiotherapy. However, he experienced relapse 10 months later with a soft tissue mass close to and involving the posteroinferior aspect of the sternum. Biopsy of the recurrent lesion showed features of B lymphoblastic leukemia/lymphoma. The first biopsy was revisited to demonstrate the lymphoblastic immunophenotype of the lesional cells. The 'indolent' appearance of the cells in the first biopsy was attributable to treatment with dexamethasone prior to the biopsy. PMID- 20858096 TI - High expression levels of the mammalian target of rapamycin inhibitor DEPTOR are predictive of response to thalidomide in myeloma. PMID- 20858097 TI - Somatic mutations altering Tyr641 of EZH2 are rare in primary central nervous system lymphoma. PMID- 20858098 TI - Association of number of follow-up providers with outcomes in survivors of hematologic malignancies. AB - Studies examining follow-up care among cancer survivors have increased in number, and are mostly focused on who best provides care. It is not known whether having single or multiple physicians as follow-up providers has outcome implications. We prospectively studied the association between number of follow-up providers among survivors of hematologic malignancies and serious medical utilization (defined as emergency room visits or hospitalizations) within a 6-month period. Patients completing treatment (n = 314) were included. Patients seeing multiple follow-up providers were more likely to be younger, to reside farther away from the university hospital, to have prescription drug insurance, to have received prior cancer treatment, to have multiple myeloma, and to have undergone hematopoietic cell transplant as a part of cancer treatment. Multivariate analysis showed that the number of follow-up providers was not associated with serious medical utilization (odds ratio 1.29, 95% confidence interval 0.68–2.48, p = 0.44) after adjusting for patient factors. Our study showed that among survivors of hematologic malignancies, outcomes were not different for survivors who were seen by single or multiple follow-up providers. PMID- 20858099 TI - Influenza in patients with hematologic disease: an ounce of prevention is worth a pound of cure. PMID- 20858100 TI - Cell-mediated immunity in chronic lymphocytic leukemia. PMID- 20858101 TI - Therapy-related myelodysplasia and fludarabine combination therapy - do the benefits justify the risk? PMID- 20858102 TI - Azacytidine as a novel agent in the treatment of acute lymphoblastic leukemia. PMID- 20858103 TI - Diagnosis and treatment of a patient with primary gastric extranodal natural killer/T-cell lymphoma, nasal type. PMID- 20858104 TI - Intracavity hyperthermia in nasopharyngeal cancer: a phase III clinical study. AB - PURPOSE: To compare the local tumour control, survival, and acute mucous toxicity of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy (RT) combined with intracavity hyperthermia versus conventional RT alone. METHODS AND MATERIALS: Previously untreated NPC patients were assigned randomly into the conventional RT group and the hyperthermia group. In addition to curative RT, hyperthermia group patients received intracavity hyperthermia before or after RT; T90 was 42.5 degrees -43 degrees C for 50 min twice a week for 7 weeks. RESULTS: From August 2001 to July 2006, 180 eligible patients with NPC were enrolled in this study. The complete response (CR) rate in the two arms (RT plus hyperthermia versus conventional RT) was 95.6% and 81.1%, respectively (p = 0.003, chi2 test). CR rates for T2 and T3 patients in the hyperthermia group were 97.1% and 96.9%, respectively, while in the conventional RT group they were 79.5% and 76.7%, respectively. The difference between the two groups was statistically significant (p = 0.03 and p = 0.024, respectively). The 5-year local control rate was 91.1% and 78.9% for the two arms, respectively (p = 0.022). Oral mucous toxicity in both arms was comparable. The 5-year PFS and 5-year OS rate for the hyperthermia arm vs. the conventional arm were 72.7% versus 63.1% (p = 0.039) and 78.2% versus 70.3% (p = 0.14), respectively. CONCLUSIONS: Conventional RT treatment followed by intracavity hyperthermia was well tolerated by the NPC patients. The addition of hyperthermia improved the local tumour control, and our results indicated a positive impact on PFS of NPC patients. PMID- 20858106 TI - Expression of interleukin-17 in autoimmune dacryoadenitis in MRL/lpr mice. AB - PURPOSE: Th-cytokines play important roles in dacryoadenitis associated with Sjogren's syndrome (SS). The aims of this study were to (i) investigate whether interleukin (IL)-17, a newly identified Th-cytokine, participates in autoimmune dacryoadenitis of MRL/lpr mice and (ii) examine the relationships among IL-17, IL 4, and interferon (IFN)-gamma in these mice. METHODS: Three-month-old MRL/lpr mice with lacrimal gland inflammation and 3-month-old control BALB/c mice were used. Frozen sections of lacrimal glands and submandibular lymph nodes were stained with monoclonal antibodies to cytokines IL-17, IL-4, and IFN-gamma. Concentrations of IL-17 in serum and 48-h splenocyte culture supernatants were detected by ELISA. RESULTS: Marked lacrimal gland inflammation was observed in all MRL/lpr mice but not in any BALB/c control mice. In the lacrimal glands of MRL/lpr mice, the proportions of cells that stained were 5 +/- 3% for IL-17, 32 +/- 14% for IL-4, and 4 +/- 2% for IFN-gamma. In the submandibular lymph nodes of MRL/lpr mice, expression of IL-17 and IL-4 was significantly higher than that of IFN-gamma, and all three cytokines were significantly higher in MRL/lpr mice than in BALB/c mice. Concentrations of IL-17 in both serum and splenocyte culture supernatants of MRL/lpr mice were elevated compared to BALB/c controls. CONCLUSIONS: Since expression of IL-17 is elevated in 3-month-old MRL/lpr mice, we suggest that it plays a role in the pathophysiology of autoimmune dacryoadenitis in these mice. PMID- 20858107 TI - The corneal expression of antimicrobial peptides during experimental fungal keratitis. AB - PURPOSE/AIM OF STUDY: To investigate the expression of endogenous antimicrobial peptides within the murine cornea during the onset and progression of posttraumatic keratomycosis caused by Candida albicans. MATERIALS AND METHODS: Scarified corneas of BALB/c mice were topically inoculated with C. albicans and monitored for one week. A murine gene microarray compared the relative expression of 36 antimicrobial peptide genes in infected corneas to controls. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) determined gene expression levels for murine cathelicidin and beta-defensins in normal corneas, scarified corneas, and C. albicans-infected corneas. Immunofluorescent staining localized the expression of cathelicidin in corneal sections. RESULTS: Traumatized eyes exposed to C. albicans developed progressive corneal inflammation, with a fungal inoculum of 10(6) colony-forming units (CFU) bringing about significantly (P < 0.05) more severe corneal inflammatory disease than a 10(5) CFU inoculum. Camp, encoding a murine cathelicidin-related antimicrobial peptide, was significantly upregulated 45-fold by microarray (P = 0.0007) and 36 fold by real-time RT-PCR (P = 0.0009). Camp increased significantly (P = 0.002) more in corneas receiving the higher than the lower fungal inoculum. Cathelicidin was preferentially expressed within the stroma on the first day after fungal inoculation, and Camp expression progressively declined over one week as the amount of recoverable fungi decreased. The genetic expression of beta-defensin 1 and beta-defensin 2 was initially downregulated (P <= 0.01) at the onset of fungal keratitis then returned toward normal levels. CONCLUSIONS: The antimicrobial peptide cathelicidin rapidly increases within the inflamed murine corneal stroma after the initiation of fungal keratitis and may play a role in the host responses that follow corneal trauma and infection. PMID- 20858108 TI - Correlating patient-reported response to hydroxypropyl cellulose ophthalmic insert (LACRISERT(r)) therapy with clinical outcomes: tools for predicting response. AB - BACKGROUND/AIMS: To determine whether patient-reported improvement in symptoms of dry eye syndrome, activities of daily living, and other quality-of-life measures after treatment with hydroxypropyl cellulose ophthalmic inserts correlates significantly with physician assessment of clinical outcomes. METHODS: Patient registry of those treated for 1 month with inserts as monotherapy or in combination with existing treatments for moderate-to-severe dry eye syndrome. A total of 520 participants were enrolled. Of those, 418 patients completed the study. Results of this registry were evaluated and correlations were calculated to determine whether patient-reported symptoms, quality of life, and changes in disease severity based on the Ocular Surface Disease Index, and activities of daily living outcomes are predictive of physician assessment of clinical signs, symptoms, and adherence to therapy. RESULTS: Most patients reported overall improvement in their condition. Patient-reported improvements in the symptoms of dry eye syndrome and activities of daily living were significant predictors of physician assessment of compliance with insert therapy, improvement in symptoms and clinical signs, effectiveness of therapy, and acceptance of use as adjunctive therapy. CONCLUSIONS: Patient-reported symptoms and activities of daily living are predictors of patient compliance and treatment success with the use of inserts, as reported by treating physicians. The benefits were additive to the standard of care that was continued during the course of the study. These predictors, along with clinical diagnostic tests, can be used by eye care professionals to assess the efficacy of treatment for moderate-to-severe dry eye syndrome quickly and reliably. PMID- 20858109 TI - Effects of postural variation on anterior chamber depth in pseudoexfoliative eyes with normal intraocular pressure. AB - PURPOSE: Pseudoexfoliation (PEX) is a condition characterized by widespread intraocular and systemic production and deposition of an abnormal fibrillar extracellular material. Zonular instability is frequently associated with PEX. Anterior chamber depth (ACD) and intraocular pressure (IOP) changes in normotensive eyes with PEX after prone position was investigated in this study. METHODS: Thirty subjects with normotensive pseudoexfoliative eyes and 30 healthy control subjects were enrolled. None of the eyes had cataract or posterior synechia. Central ACD, axial length (AL), and IOP were measured 5 min after supine and prone positions by using A-scan ultrasonography and TonoPen. RESULTS: Mean ACD decreased from 2.89 +/- 0.27 mm to 2.71 +/- 0.23 mm in eyes with PEX and from 2.94 +/- 0.25 mm to 2.84 +/- 0.30 mm in normal eyes with postural change. The ACD decreased significantly in both group of eyes in prone position (p < 0.001 in PEX group, p = 0.005 in normal group), but the decrease in ACD in eyes with PEX was significantly greater than the decrease in normal control eyes (p = 0.03). Mean IOP was 16.9 +/- 2.1 mmHg after supine position and 17.1 +/- 2.04 mmHg after prone position in eyes with PEX, 16.1 +/- 2.7 mmHg after supine position and 16.3 +/- 2.6 mmHg after prone position in normal eyes. Postural changes in IOP and AL were not statistically significant in both groups of eyes (p = 0.096 in the PEX group and p = 0.484 in the normal group for IOP; p = 0.177 in the PEX group and p = 0.276 in the normal group for AL). CONCLUSION: The lens is more mobile in pseudoexfoliative eyes than normal eyes after supine to prone position. Although the ACD of pseuodoexfoliative eyes decreased statistically significantly after 5 min of prone position, IOP did not change significantly. PMID- 20858111 TI - Enhanced characterization of serum autoantibody reactivity following HSP 60 immunization in a rat model of experimental autoimmune glaucoma. AB - PURPOSE: Antibodies against heat shock proteins have been identified in sera of human glaucoma patients in several studies and immunization with heat shock protein 60 (HSP 60) causes retinal ganglion cell (RGC) loss in an animal model of experimental autoimmune glaucoma. The aim of this study was to observe the time course of increased anti-retina antibody appearance in the serum and characterize the identification of prominent autoantibodies that accompany HSP 60 immunization in a rat model of experimental autoimmune glaucoma. METHODS: Eight weeks after immunization with HSP 60 retinal flatmounts were prepared and RGCs were counted in eight predefined areas and compared to controls. Serum collected before, as well as four and eight weeks after, immunization was used to detect antibody patterns against bovine retinal antigens using Western blotting techniques. These patterns were analyzed by multivariate statistical methods. Autoantibodies that were prominently increased were further identified through mass spectrometry. Intraocular pressure was measured throughout the study. RESULTS: After eight weeks, animals immunized with HSP 60 showed significant RGC loss of retinal flatmounts (P = 0.02), which was intraocular pressure independent. Early changes in antibody profiles, many of them significant upregulations, were detected. Antigens with significantly upregulated antibody reactivity after four weeks were identified as histone H2B type 1, S-arrestin, glial fibrillary acidic protein, vimentin, and heat shock protein 60. These upregulated autoantibodies returned to normal levels four weeks following their initial upregulation. Antibodies against retinaldehyde binding protein 1 on the other hand became upregulated after eight weeks. CONCLUSION: This is the first study to identify the appearance and disappearance of retinal autoantibodies in the serum of rats at several time points following their initial upregulation in response to HSP 60 immunization in a model of experimental autoimmune glaucoma. PMID- 20858110 TI - Inhibitory effects of oral disulfiram on endotoxin-induced uveitis in rats. AB - PURPOSE: Disulfiram (DSF) exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the effect of oral DSF on endotoxin induced uveitis (EIU) in rats. METHODS: We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO), and prostaglandin E2 (PGE2) in the anterior chamber. Some eyes were enucleated for histologic examination and immunohistochemical analysis. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour before the LPS injection, either 250, 500, or 750 mg/kg DSF was administered orally. Twenty-four hours later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF alpha, NO, and PGE2 were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis in the iris ciliary body (ICB) cells was performed to determine the expression of activated nuclear factor kappa B (NF-kappaB), inducible-nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). RESULTS: The oral administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of TNF-alpha, NO, and PGE2 in the aqueous humor and improved the histiologic status of the ocular tissue. The expression of activated NF-kappaB-positive cells in the ICB was significantly inhibited by oral administrated with DSF 3 hr after the LPS injection. The LPS-induced increased expressions of iNOS and COX-2 proteins in the ICB were also inhibited by oral DSF 24 hr after LPS injection. CONCLUSIONS: The present results indicate that oral DSF suppresses the inflammation in EIU by inhibiting the NF-kappaB-dependent pathway and the subsequent production of pro inflammatory mediators. PMID- 20858113 TI - Development of biodegradable controlled release scleral systems of triamcinolone acetonide. AB - PURPOSE: To develop scleral controlled-release-systems of triamcinolone acetonide (TA) based on biodegradable poly(lactide) (PLA). MATERIALS AND METHODS: (1) PLA microspheres containing TA were prepared by a single or double emulsification solvent evaporation method. Morphology, size, effect of drug input and method of microsphere preparation on drug loading, and in vitro TA release of the microspheres were investigated. (2) Mini-tablets consisting of blank PLA microspheres and TA (weight ratios of 1:1, 2:1, and 4:1, respectively) were developed and their release profile in vitro was evaluated. (3) The in vitro transscleral diffusion profile was evaluated by placing a PLA-TA (1:1) tablet in a donor chamber and measuring the TA concentration in a receptor chamber. Donor and receptor chambers were separated by rabbit sclera. (4) Two cadaver rabbit eyes received a 1:1 PLA-TA tablet episclerally, which was covered by a scleral patch. TA aqueous humor and vitreous concentrations were measured 5, 10, and 20 days post implantation. RESULTS: (1) Microsphere average size was 2 MUm. The double emulsification method and increasing drug input led to an increase in drug loading and encapsulation. Sustained release of TA over several days from the microspheres in vitro was observed, with the rate of release being affected by their TA content. (2) TA exhibited sustained release profile from the PLA-TA tablets, with the rate of release being affected by the PLA:TA ratio. (3) TA could slowly cross the sclera tissue in vitro, with approximately 21% of the drug loaded in the donor compartment being diffused through the sclera in 45 days. (4) Following scleral administration of the PLA-TA mini-tablets, TA accumulated in the vitreous and aqueous humor of cadaver eyes. CONCLUSIONS: The PLA-TA microspheres and mini-tablets appear promising for the controlled transscleral delivery of TA and justify further investigation. PMID- 20858112 TI - Characterization of a stabilized form of microplasmin for the induction of posterior vitreous detachment. AB - PURPOSE: To investigate the stability and safety of a diluted acidified form of microplasmin and its ability to induce a posterior vitreous detachment (PVD) following intravitreal injection in post-mortem porcine eyes. METHODS: Microplasmin diluted in normal saline (NS) and balanced salt solution (BSS+) was assayed for residual activity by hydrolysis of the chromogenic substrate Glu-Phe Lys-pNA. Residual activity on vitreous was determined by injecting aliquots of microplasmin reconstituted in balanced salt solution (BSS+) or normal saline (NS) kept at room temperature (RT) for up to 1 hr, then injected in aliquots of porcine vitreous and incubated for 2 hr at 37 degrees C. The breakdown products were submitted to SDS Page electrophoresis and compared to determine the level of enzymatic activity. Pig eyes were incubated with graded concentrations of microplasmin 0.625, 1.25, or 2.50 mg/mL reconstituted in BBS+ or NS. Morphologic alterations and the ability to induce a PVD was assessed by light and electron microscopy. RESULTS: Microplasmin's enzymatic activity in an in vitro assay in BSS+ was 70% of its baseline value after 30 min, and about 50% after 60 min at RT. The corresponding effect on degradation of vitreous gel was 60 and 40% baseline at 30 and 60 min. There was no loss of activity in the microplasmin diluted in normal saline over this time period. Dilution of acidified microplasmin in normal saline did not lead to structural changes within the retina. A dose dependent PVD was observed in eyes treated with microplasmin diluted in NS. CONCLUSIONS: Acidified (stabilized) microplasmin has the same intraocular activity profile as microplasmin at a neutral pH. Better retention of activity at room temperature makes it a better candidate for use in clinical practice. PMID- 20858114 TI - A comparison of three different intravitreal treatment modalities of macular edema due to branch retinal vein occlusion. AB - PURPOSE: To compare the efficacy of intravitreal injection of triamcinolone, bevacizumab, and a combination of triamcinolone-bevacizumab for the management of macular edema due to branch retinal vein occlusion. METHODS: Fifty-two eyes of 52 patients (29 male, 23 female) with branch retinal vein occlusion and macular edema were included. Patients received one of the following intravitreal treatments: 4 mg triamcinolone acetonide monotherapy (n=17), 1.25 mg bevacizumab monotherapy (n=14) or a combination of 2 mg triamcinolone acetonide and 1.25 mg bevacizumab (n=21). Measurements of Snellen visual acuity and central macular thickness with optical coherence tomography were done at baseline, and at months one, three, and six. RESULTS: At baseline, the three groups did not differ in age (P=0.12), duration of macular edema (P=0.24), visual acuity (P=0.62), central macular thickness (P=0.16), and intraocular pressure (P=0.15). All study groups showed significant reduction of central macular thickness (P=0.02, P=0.02, and P=0.001, respectively) and improvement in visual acuity (P=0.02, P= 0.02 and P=0.02, respectively) one month after injection. At six months, there was a significant reduction in central macular thickness (P=0.02, P=0.02, and P=0.04, respectively) while only bevacizumab monotherapy group demonstrated significant improvement in visual acuity (P=0.01). CONCLUSION: Intravitreal injection of triamcinolone, bevacizumab or combination of triamcinolone-bevacizumab appears to have similar therapeutic effects on macular edema due to branch retinal vein occlusion at one month. Intravitreal injection of bevacizumab yielded better results of visual acuity than the others at six months. PMID- 20858115 TI - Protective effects of caffeic acid phenethyl ester on retinal ischemia/reperfusion injury in rats. AB - PURPOSE: To investigate whether caffeic acid phenethyl ester (CAPE) has a protective effect on retinal ischemia/reperfusion (I/R) injury in rats, and to determine the possible antioxidant mechanisms. METHODS: Seventy-six female Wistar rats were randomized evenly into Sham, I/R injury model (M group), model plus vehicle (MV), and model plus CAPE (MC) groups. Retinal ischemia/reperfusion injury was induced by increasing the intraocular pressure to 110 mmHg for 60 min. Rats in the MV and MC groups were injected with vehicle and CAPE (10 umol/kg i.p.), respectively, before reperfusion and once a day for one or seven days after I/R. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) in the retinal tissues were determined 24 hr after I/R. Retinal cells apoptosis was detected 24 hr after I/R injury by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick end labeling staining. On day 7 after reperfusion, the electroretinogram (ERG) was recorded, and the retinal histology was examined and quantified using light microscopy. RESULTS: CAPE significantly decreased the MDA levels and increased the activities of SOD, GSH-Px, and CAT in the retina compared with the ischemia group (p< 0.05). CAPE attenuated the I/R-induced apoptosis of retinal cells in the inner nuclear and ganglion cells of the rat retina. CAPE also suppressed the I/R-induced reduction in the a- and b-wave amplitudes of the ERG (p<0.05). The thickness of the entire retina, inner nuclear layer, and inner plexiform layer and the number of cells in the ganglion cell layer in the MC group were significantly greater than those in the M group (p<0.05). CONCLUSIONS: CAPE can protect the rat retina from I/R injury by enhancing the antioxidation ability and inhibiting the apoptosis of retinal cells, which suggests that CAPE is potentially useful for treating I/R-induced eye disorders. PMID- 20858116 TI - Mesopic pupil size and refractive error. PMID- 20858121 TI - Combining coma score and serum biomarker levels to predict unfavorable outcome following childhood brain trauma. AB - This study aims to determine if pairing the Glasgow Coma Scale (GCS) with serum biomarker levels may achieve higher outcome predictive values than using either the GCS or biomarker levels alone in childhood brain trauma. Twenty-eight critically ill children with isolated accidental brain trauma were studied in a prospective observational study. The GCS was recorded at various time points post injury. Enzyme-linked immunosorbent assay (ELISA) was used to quantify eight different serum biomarker levels (S100b, NSE, IL-6, IL-8, IL-10, L-selectin, SICAM, and endothelin) on day 1 post injury. The Glasgow Outcome Score (GOS) was used to assess global outcome at 6 months post injury. Outcome predictive values of the GCS, individual biomarker levels, and paired combinations of the GCS and biomarkers were compared using receiver operator characteristic (ROC) curve analysis and its multivariate extension, multivariate ROC curve (MultiROC). When using either the GCS or individual biomarker levels alone to predict unfavorable outcome, only the PICU discharge summated GCS achieved an area under the ROC curve (AUC) of more than 0.95. This high degree of outcome predictability was also achieved by pairing the GCS with a single biomarker level. The most pronounced improvement in outcome prediction was observed by pairing the post resuscitation summated GCS with the day-1 serum IL-8 level, which increased the AUC from 0.78 to 0.98 and the sensitivity and specificity from 75% to 100% and 96% respectively. Paired combinations of the GCS and serum biomarker levels greatly enhanced the accuracy of post-traumatic unfavorable outcome prediction than may be achieved using either the GCS or individual biomarker levels alone. PMID- 20858125 TI - Robust observer-based tracking control of hodgkin-huxley neuron systems under environmental disturbances. AB - A nervous system consists of a large number of highly interconnected nerve cells. Nerve cells communicate by generation and transmission of short electrical pulses (action potential). In addition, membrane voltage is the only measurable state in nervous systems. A robust observer-based model reference tracking control is proposed for Hodgkin-Huxley (HH) neuron systems to generate a desired reference response in spite of environmental noises, uncertain initial values, and diffusion currents from other interconnected nerve cells. In order to simplify the robust tracking control design of nonlinear stochastic HH neuron systems, a fuzzy interpolation method is employed to interpolate several linear stochastic systems to approximate a nonlinear stochastic HH neuron system so that the nonlinear robust tracking control problem can be solved by the linear matrix inequality (LMI) technique with the help of Robust Control Toolbox in Matlab. The proposed robust observer-based tracking control scheme can provide new methods for desired action potential generation, suppression of oscillations, and blockage of action potential transmission under environmental noise and diffusion currents. These new methods are useful for patients with different neuron system dysfunctions. Finally, three simulation examples of tracking control of nervous systems are given to illustrate the design procedure and confirm the tracking performance of the proposed method. PMID- 20858122 TI - The hormone ghrelin prevents traumatic brain injury induced intestinal dysfunction. AB - Intestinal barrier breakdown following traumatic brain injury (TBI) is characterized by increased intestinal permeability, leading to bacterial translocation, and inflammation. The hormone ghrelin may prevent intestinal injury and have anti-inflammatory properties. We hypothesized that exogenous ghrelin prevents intestinal injury following TBI. A weight-drop model created severe TBI in three groups of anesthetized Balb/c mice. Group TBI: animals underwent TBI only; Group TBI/ghrelin: animals were given 10 MUg of ghrelin intraperitoneally prior and 1 h following TBI; Group sham: no TBI or ghrelin injection. Intestinal permeability was measured 6 h following TBI by detecting serum levels of FITC-Dextran after injection into the intact ileum. The terminal ileum was harvested for histology, expression of the tight junction protein MLCK and inflammatory cytokine TNF-alpha. Permeability increased in the TBI group compared to the sham group (109.7 +/- 21.8 MUg/mL vs. 32.2 +/- 10.1 MUg/mL; p < 0.002). Ghrelin prevented TBI-induced permeability (28.3 +/- 4.2 MUg/mL vs. 109.7 +/- 21.8 MUg/mL; p < 0.001). The intestines of the TBI group showed blunting and necrosis of villi compared to the sham group, while ghrelin injection preserved intestinal architecture. Intestinal MLCK increased 73% compared to the sham group (p < 0.03). Ghrelin prevented TBI-induced MLCK expression to sham levels. Intestinal TNF-alpha increased following TBI compared to the sham group (46.2 +/- 7.1 pg/mL vs. 24.4 +/- 2.2 pg/mL p < 0.001). Ghrelin reduced TNF-alpha to sham levels (29.2 +/- 5.0 pg/mL; p = NS). We therefore conclude that ghrelin prevents TBI-induced injury, as determined by intestinal permeability, histology, and intestinal levels of TNF-alpha. The mechanism for ghrelin mediating intestinal protection is likely multifactorial, and further studies are needed to delineate these possibilities. PMID- 20858126 TI - Internal-time temporal difference model for neural value-based decision making. AB - The temporal difference (TD) learning framework is a major paradigm for understanding value-based decision making and related neural activities (e.g., dopamine activity). The representation of time in neural processes modeled by a TD framework, however, is poorly understood. To address this issue, we propose a TD formulation that separates the time of the operator (neural valuation processes), which we refer to as internal time, from the time of the observer (experiment), which we refer to as conventional time. We provide the formulation and theoretical characteristics of this TD model based on internal time, called internal-time TD, and explore the possible consequences of the use of this model in neural value-based decision making. Due to the separation of the two times, internal-time TD computations, such as TD error, are expressed differently, depending on both the time frame and time unit. We examine this operator-observer problem in relation to the time representation used in previous TD models. An internal time TD value function exhibits the co-appearance of exponential and hyperbolic discounting at different delays in intertemporal choice tasks. We further examine the effects of internal time noise on TD error, the dynamic construction of internal time, and the modulation of internal time with the internal time hypothesis of serotonin function. We also relate the internal TD formulation to research on interval timing and subjective time. PMID- 20858127 TI - Psychophysically tuned divisive normalization approximately factorizes the PDF of natural images. AB - The conventional approach in computational neuroscience in favor of the efficient coding hypothesis goes from image statistics to perception. It has been argued that the behavior of the early stages of biological visual processing (e.g., spatial frequency analyzers and their nonlinearities) may be obtained from image samples and the efficient coding hypothesis using no psychophysical or physiological information. In this work we address the same issue in the opposite direction: from perception to image statistics. We show that psychophysically fitted image representation in V1 has appealing statistical properties, for example, approximate PDF factorization and substantial mutual information reduction, even though no statistical information is used to fit the V1 model. These results are complementary evidence in favor of the efficient coding hypothesis. PMID- 20858128 TI - Neural decoding with hierarchical generative models. AB - Recent research has shown that reconstruction of perceived images based on hemodynamic response as measured with functional magnetic resonance imaging (fMRI) is starting to become feasible. In this letter, we explore reconstruction based on a learned hierarchy of features by employing a hierarchical generative model that consists of conditional restricted Boltzmann machines. In an unsupervised phase, we learn a hierarchy of features from data, and in a supervised phase, we learn how brain activity predicts the states of those features. Reconstruction is achieved by sampling from the model, conditioned on brain activity. We show that by using the hierarchical generative model, we can obtain good-quality reconstructions of visual images of handwritten digits presented during an fMRI scanning session. PMID- 20858129 TI - A theoretical basis for emergent pattern discrimination in neural systems through slow feature extraction. AB - Neurons in the brain are able to detect and discriminate salient spatiotemporal patterns in the firing activity of presynaptic neurons. It is open how they can learn to achieve this, especially without the help of a supervisor. We show that a well-known unsupervised learning algorithm for linear neurons, slow feature analysis (SFA), is able to acquire the discrimination capability of one of the best algorithms for supervised linear discrimination learning, the Fisher linear discriminant (FLD), given suitable input statistics. We demonstrate the power of this principle by showing that it enables readout neurons from simulated cortical microcircuits to learn without any supervision to discriminate between spoken digits and to detect repeated firing patterns that are embedded into a stream of noise spike trains with the same firing statistics. Both these computer simulations and our theoretical analysis show that slow feature extraction enables neurons to extract and collect information that is spread out over a trajectory of firing states that lasts several hundred ms. In addition, it enables neurons to learn without supervision to keep track of time (relative to a stimulus onset, or the initiation of a motor response). Hence, these results elucidate how the brain could compute with trajectories of firing states rather than only with fixed point attractors. It also provides a theoretical basis for understanding recent experimental results on the emergence of view- and position invariant classification of visual objects in inferior temporal cortex. PMID- 20858130 TI - Change-based inference in attractor nets: linear analysis. AB - One standard interpretation of networks of cortical neurons is that they form dynamical attractors. Computations such as stimulus estimation are performed by mapping inputs to points on the networks' attractive manifolds. These points represent population codes for the stimulus values. However, this standard interpretation is hard to reconcile with the observation that the firing rates of such neurons constantly change following presentation of stimuli. We have recently suggested an alternative interpretation according to which computations are realized by systematic changes in the states of such networks over time. This way of performing computations is fast, accurate, readily learnable, and robust to various forms of noise. Here we analyze the computation of stimulus discrimination in this change-based setting, relating it directly to the computation of stimulus estimation in the conventional attractor-based view. We use a common linear approximation to compare the two methods and show that perfect performance at estimation implies chance performance at discrimination. PMID- 20858131 TI - Deep, big, simple neural nets for handwritten digit recognition. AB - Good old online backpropagation for plain multilayer perceptrons yields a very low 0.35% error rate on the MNIST handwritten digits benchmark. All we need to achieve this best result so far are many hidden layers, many neurons per layer, numerous deformed training images to avoid overfitting, and graphics cards to greatly speed up learning. PMID- 20858132 TI - Assessing the impact of prehospital intubation on survival in out-of-hospital cardiac arrest. AB - There is a developing body of literature documenting adverse survival outcome of out-of-hospital endotracheal intubation for critical multiple trauma and head injury patients. OBJECTIVE: To compare the rates of survival to hospital admission and discharge of nontraumatic out-of-hospital cardiac arrest (OHCA) patients who received successful out-of-hospital endotracheal intubation and those who were not intubated. METHODS: We conducted a retrospective analysis from an ongoing database of OHCA patients brought to a large suburban tertiary care emergency department by paramedic services between 1995 and 2006. We dichotomized patients by whether they were successfully endotracheally intubated or not prior to hospital arrival. Utstein style cardiac arrest variables were abstracted for all cases. All survivors to hospital admission were reviewed to exclude those patients in whom intubation was not attempted or unnecessary, such as those who had successful first-shock recovery of spontaneous circulation. We used chi square and logistic regression techniques for analysis, using survival to discharge as the primary outcome and survival to admission as a secondary outcome. RESULTS: There were 1,515 total cases with 33 early survivors excluded. Overall, 1,220 (86.2%) were intubated; of those intubated, 270 (20.2%) survived to admission and 93 (7.0%) survived to discharge. Upon univariate analysis, there was no difference in survival between intubated and non intubated groups (6.5% vs 10.0%, OR = 0.63, 95% CI 0.37,1.08). For patients initially in ventricular fibrillation/ventricular tachycardia (VT/VF), in a multivariate Logit model, intubation significantly decreased survival to discharge, adjusted odds ratio (OR) = 0.52 (95% confidence interval 0.27, 0.998). Intubated non-VF patients were more likely to survive to admission, adjusted OR 2.96 (1.04, 8.43), but not to discharge (1.8% vs. 1.0%, p = 1.0). CONCLUSION: This observational study in an unselected population shows that patients in VF/VT arrest who underwent out-of hospital intubation were less likely to survive to discharge than those not intubated. Out-of-hospital intubation of patients with non-VF arrest was associated with an increased rate of survival to admission, but not survival to discharge. Future prospective studies are needed to define the role of out-of hospital endotracheal intubation in cardiac arrest patients. PMID- 20858133 TI - Latency and loss of pulse oximetry signal with the use of digital probes during prehospital rapid-sequence intubation. AB - BACKGROUND: Prehospital personnel rely on timely and accurate pulse oximetry data when performing critical skills, such as rapid-sequence intubation (RSI). However, loss of signal may be a frequent occurrence in patients with poor peripheral perfusion. In addition, a delay or latency period in the timeliness of pulse oximetry data may exist with probes placed on the fingers. OBJECTIVE: To define the incidence of pulse oximetry signal loss or a latent period during prehospital RSI. METHODS: Patients with severe traumatic brain injury (TBI) (Glasgow Coma Scale score [GCS] 3-8) undergoing prehospital RSI by air medical crews were enrolled. Data from hand-held oximetry-capnometry units were analyzed for either the loss of a pulse oximetry tracing (>= 30 seconds) during the RSI procedure or the presence of a latent period, defined by the saturation of peripheral oxygen (SpO(2)) nadir occurring after intubation in patients undergoing desaturation (SpO(2) <= 93%) during the procedure. RESULTS: A total of 98 of 124 patients (79%, 95% confidence interval [CI] 71-85%) had pulse oximetry failure during critical points in the RSI procedure. In the 49 patients with a desaturation during RSI, a latent period was observed in 27 patients (55%, 95% CI 41-68%). CONCLUSIONS: A high incidence of pulse oximetry failure was observed with the use of a digital pulse oximetry probe during prehospital RSI. In addition, a latent period appears to exist in the majority of patients undergoing desaturation. PMID- 20858134 TI - Tactical medicine--competency-based guidelines. AB - BACKGROUND: Tactical emergency medical support (TEMS) is a rapidly growing area within the field of prehospital medicine. As TEMS has grown, multiple training programs have emerged. A review of the existing programs demonstrated a lack of competency-based education. OBJECTIVE: To develop educational competencies for TEMS as a first step toward enhancing accountability. METHODS: As an initial attempt to establish accepted outcome-based competencies, the National Tactical Officers Association (NTOA) convened a working group of subject matter experts. RESULTS: This working group drafted a competency-based educational matrix consisting of 18 educational domains. Each domain included competencies for four educational target audiences (operator, medic, team commander, and medical director). The matrix was presented to the American College of Emergency Physicians (ACEP) Tactical Emergency Medicine Section members. A modified Delphi technique was utilized for the NTOA and ACEP groups, which allowed for additional expert input and consensus development. CONCLUSION: The resultant matrix can serve as the basic educational standard around which TEMS training organizations can design programs of study for the four target audiences. PMID- 20858135 TI - Long-term effects of presurgical infant orthopedics in patients with cleft lip and palate: a systematic review. AB - OBJECTIVE: This study aimed to assess the scientific evidence on the efficiency of presurgical infant orthopedic appliances in patients with cleft lip and palate to shed light on a specific, contemporary discussion of whether the appliances have long-term advantages with respect to treatment outcomes. DESIGN: A systematic review. METHODS: Two literature surveys from the five electronic databases were performed with a 1-month interval. Randomized controlled trials and controlled clinical trials (controls had no presurgical infant orthopedics) that had follow-up periods of a minimum of 6 years were included in the study. The exceptions to the follow-up limit were studies related to feeding and parent satisfaction. RESULTS: Of the 319 articles retrieved in the literature surveys, 12 were qualified for the final analysis. The level of evidence of these articles ranged from 1b to 4. Eight randomized controlled trials and four controlled clinical trials were available on eight treatment outcomes. The longest follow-up period of the randomized controlled trials was 6 years. No randomized controlled trials were found on active presurgical infant orthopedic appliances and on nasoalveolar molding appliances. CONCLUSIONS: Based on the results, presurgical infant orthopedic appliances have no long-term positive effects on seven of the eight studied treatment outcomes in patients with cleft lip and palate. More randomized controlled trials need to be done to have evidence regarding the effects of presurgical infant orthopedics in different surgical protocols. Also, the encouraging results about the effect of nasolaveolar molding appliances on nasal symmetry have to be supported by future randomized controlled trials. PMID- 20858138 TI - The influence of gender and of AIDS on the immunity of autopsied patients' esophagus. AB - Previous studies have shown that males who have AIDS are more frequently affected by infectious diseases than females. The esophagus is the organ in the digestive tube that is more commonly affected by opportunistic infections during the syndrome. The aim of this study was to assess the influence of AIDS and of gender on local immunity of the esophageal epithelium. Fragments of the esophagus from 29 autopsied women and 37 autopsied men were collected at a university hospital from 1980 to 2009 and were divided in groups with and without AIDS. The IgA-, IgG , and IgM-positive cells and Langerhans cells (LCs) were immunostained, respectively, with anti-IgA, anti-IgG, anti-IgM, and anti-S100. The software Image J was used to measure the esophageal epithelium and to count the epithelium cellular layers. Patients with AIDS, apart from gender, showed an increase in IgA , IgG-, and IgM-positive cells and a reduction of Langerhans cells, in thickness and in number of cellular layers in the esophageal epithelium. However, among individuals with AIDS, men presented lower secretory expression of IgA-, IgG-, and IgM-positive cells than women and more intense reduction of LCs. Women have naturally presented better local esophageal immunity than men. Although AIDS possibly causes immunological and morphological alterations in the esophageal epithelium in both genders, women have better esophageal immunity, which may explain a greater frequency of hospital admissions due to infection of men with AIDS when compared with women. PMID- 20858137 TI - alpha-Galactosidase A expressed in the salivary glands partially corrects organ biochemical deficits in the fabry mouse through endocrine trafficking. AB - Fabry disease is caused by an X-linked deficiency of the lysosomal enzyme alpha galactosidase A (GLA) and has been treated successfully with enzyme replacement therapy (ERT). Gene therapy has been proposed as an alternative to ERT due to the presumed advantages of continuous, endogenous production of the therapeutic enzyme. GLA production in the liver and its therapeutic efficacy in the Fabry mouse have been demonstrated previously with various viral vector systems. In consideration of the potential advantages of using the salivary glands as endogenous GLA biosynthesis sites, we explored the feasibility of this approach in the Fabry mouse. GLA -/0 or -/- mice received an adenoviral vector (2 * 10(10) or 1 * 10(9) viral particles) expressing GLA to the right submandibular gland via oral cannulation of the submandibular duct. Four days later, animals were sacrificed; saliva, plasma, kidney, liver, and brain were collected and assayed using ELISA, Western blot, and a GLA enzymatic activity assay using both traditional fluorescence methods and isotope dilution mass spectrometry by following the U.S. EPA Method 6800. GLA activity was significantly elevated in the serum and liver of both treatment groups, and improvement in the kidney was marginally significant (P < 0.069) in the high-dose group. Notably, we found that liver and salivary gland produce different glycoforms of the GLA transgene. Only small numbers of adenoviral genomes were observed in the livers of treated animals, but in four of 14 in the high-dose groups, liver levels of adenovirus exceeded 20 copies/MUg, indicating that the sequestration in the salivary gland was imperfect at high doses. Taken together, these results indicate that the salivary gland-based gene therapy for Fabry disease is promising, and further studies with advanced viral vector gene delivery systems (e.g., adeno-associated virus) for long-term treatment appear to be warranted. PMID- 20858139 TI - Incidence and prevalence of juvenile idiopathic arthritis in Catalonia (Spain). AB - OBJECTIVE: To ascertain the incidence and prevalence of juvenile idiopathic arthritis (JIA) in Catalonia (autonomous region in northeast Spain), examined according to the currently established disease subtypes. METHODS: Before initiating the study, we conducted an educational programme on paediatric rheumatology, addressed to all general paediatricians in Catalonia. A 2-year (2004-2006), prospective, population-based study was then carried out to determine the incidence of JIA. Prospective and retrospective data retrieval was performed to calculate prevalence. The International League of Associations for Rheumatology (ILAR, Edmonton revision) classification criteria were applied. RESULTS: Over the study period, 145 new cases of JIA were diagnosed. The mean annual incidence was 6.9/105 children aged less than 16 years (range 5.8-8.1 years; 9.0 years for girls and 4.8 years for boys). On separate analysis of patients <= 6 and > 6 years, the distribution in younger children was found to be similar for both girls and boys, whereas in older children, most girls belonged to the oligoarthritis and polyarthritis subgroups, and boys to the enthesitis related arthritis and undifferentiated subgroups. The calculated prevalence of JIA (31 October 2006) was 39.7 (36.1-43.7)/105 children younger than 16. The relative risk of girls having JIA was 2.1 [95% confidence interval (CI) 1.7-2.7, p < 0.001]. In 70% of patients, the diagnosis was established before the age of 7. Subgroup distribution of prevalent cases mirrored that of incident cases. CONCLUSION: This is the first population-based study on the epidemiology of JIA in Catalonia. Incidence and prevalence rates are lower than those reported for several areas in Nordic countries of Europe. Oligoarthritis was the most common subtype. PMID- 20858140 TI - A case of IgG4-positive multiorgan lymphoproliferative syndrome: dramatic perturbations of the CD8-positive T-cell repertoire in peripheral blood. PMID- 20858141 TI - Pheochromocytoma in a patient with a preliminary diagnosis of Raynaud's phenomenon. PMID- 20858142 TI - Association of cigarette smoking with organ damage in primary systemic vasculitis. AB - OBJECTIVES: To study the association between late organ damage in patients with primary systemic vasculitis (PSV) and cigarette smoking. PSV included Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS), and polyarteritis nodosa (PAN). METHODS: The pattern and extent of organ damage according to the Vasculitis Damage Index (VDI) were analysed for 86 prevalent cases with PSV retrieved from a geographically defined population in southern Sweden (46 WG, 27 MPA, four CSS, and nine PAN). Data on clinical findings, laboratory tests, and smoking habits were collected from case records from the time of diagnosis. The patients were stratified into two main groups according to their smoking habits: smokers (subdivided into active and ex smokers) and non-smokers (patients who had never smoked). RESULTS: Data on smoking habits were available for 77 patients (90%). Thirty-three (38%) patients were categorized as smokers and 44 (51%) were non-smokers. Smoking was more common in men (61.5% vs. 23.6% in women, p = 0.001). There were no differences in smoking habits between the main diagnostic groups (WG 40% smokers, MPA 45%). Ear, nose, and throat (ENT) damage was significantly more prevalent in non-smokers (p = 0.001). Myocardial infarction (MI) and end-stage renal disease (ESRD) were more common in the current smokers (p = 0.04) than in the non-smokers. CONCLUSIONS: We found ENT damage to be significantly less prevalent in smokers. This is the first report of a possible modifying effect of cigarette smoking on the development of organ damage in PSV, but more studies are needed before any firm conclusions can be made. PMID- 20858143 TI - Hereditary isolated metatarsophalangeal arthritis. AB - OBJECTIVE: To describe a family with 13 members in four generations affected by early-onset isolated painful arthritis limited to the first metatarsophalangeal (MTP) joint but without evidence of generalized joint disease at follow-up. METHODS: A complete family pedigree was constructed and radiographs from the affected family members and their offspring were taken. Laboratory tests including serum measurements of C-reactive protein (CRP), urate, and rheumatoid factor (RF) were performed to exclude gout and rheumatoid arthritis from the diagnosis. RESULTS: The age at onset of first MTP joint symptoms varied from 12 to 51 years. Both females and males were affected in the four successive generations, including male-to-male transmission as well as maternal inheritance. The affected patients were often treated surgically with good pain-relieving results. CONCLUSION: To our knowledge, this is the first report of early-onset isolated foot metatarsal arthritis with apparent autosomal dominant inheritance. PMID- 20858144 TI - Malignancies in patients with rheumatoid arthritis. PMID- 20858145 TI - 99mTechnetium nanocolloid scintigraphy in prognostication of early RA. PMID- 20858146 TI - Survival in patients with pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre: prognosis still poor and prediction difficult. AB - OBJECTIVES: To describe the survival rate in a cohort of systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) and to evaluate possible predictors for SSc-PAH in a cohort of SSc patients. METHODS: Thirty patients with SSc-PAH and 150 SSc patients without PAH were included. Survival and survival on therapy were calculated. Clinical features at baseline were correlated to the risk for development of PAH during follow-up. RESULTS: The 1-, 2-, 3-, and 4-year survival rates were 86, 59, 39, and 22%, respectively, from diagnosis of PAH. The hazard ratio for total mortality in the SSc-PAH group was 3.2 [95% confidence interval (CI) 1.8-5.7] compared to SSc without PAH (p < 0.001). Risk factors at baseline for the development of PAH were: limited skin involvement, low diffusing capacity of the lung for carbon monoxide (DL(CO)), high N-terminal pro-brain natriuretic peptide (NTProBNP), increased estimated systolic pulmonary arterial pressure (ESPAP), and the presence of teleangiectases. Severe peripheral vascular disease requiring iloprost treatment during follow-up was associated with an eightfold increased risk of PAH. CONCLUSION: Despite modern treatment and yearly screening by echocardiography, the survival in SSc-PAH is still low in our cohort. The identified risk factors should be assessed to select patients eligible for right heart catheterization (RHC) to make an earlier diagnosis. PMID- 20858147 TI - Post-approval trials of new medicines: widening use or deepening knowledge? Analysis of 10 years of etanercept. AB - OBJECTIVE: To investigate the main aims of the post-approval randomized controlled trials (RCTs) on etanercept and the extent to which they were designed to gain more comparative information. METHODS: A search of the literature (Medline, Embase), trial registries (Clinical Trials.gov, Controlled Trials.com), and market authorization reports from the Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) was carried out to identify all RCTs. A comparison of trial data identified unpublished trials and multiple publications relating to the same study. All RCTs completed and/or published after initial market approval was regarded as post-approval. RESULTS: Up until 2008, we found 84 post-approval trials, 11 (13%) trials on approved extensions of indication, another 30 (36%) trials on the approved indications, and 43 (51%) trials on indications not (yet) approved. Nearly half of the studies on indications not yet approved were initiated and funded by independent sponsors. After the initial approval of etanercept, six head-to-head trials were conducted on the approved indications. Overall, the main objectives of post-approval trials with etanercept were found to confirm efficacy and safety in new indications, and to gather additional information for optimal use on the approved indications. CONCLUSION: Post-approval RCTs on etanercept focus more on studies searching for new indications than on deepening knowledge about use. Ten years after the market entry of etanercept, one of the reasonable demands of clinical practice, for more comparative information, still remains unanswered. PMID- 20858148 TI - Changes with time in skin temperature of the shoulders in healthy controls and a patient with shoulder-hand syndrome. AB - BACKGROUND: Abnormal skin temperature in the shoulder is caused by various diseases. A thermography is unable to capture temperature changes over time. In contrast, a Thermocron is an effective measuring device to monitor temperature changes over time. PURPOSES: The purposes of this study employing a Thermocron were to measure shoulder skin temperature over time in healthy subjects and to detect shoulder skin temperature abnormalities in a patient with shoulder-hand syndrome. SUBJECTS AND METHODS: Subjects comprised 10 healthy volunteers (20 shoulders; 4 men and 6 women, mean age 54 years). For measurements, a Thermocron was attached on both shoulders. Measurements were made from 21.00 to 07.00 the following morning at 15-minute intervals. RESULTS: Gradual difference in right and left shoulder skin temperature was observed with the timing of measurements but no significant difference was apparent, i.e. dominant side 34.9 +/- 0.8 degrees C, non-dominant side 34.9 +/- 0.9 degrees C (P = 0.28). Presentation of a case with shoulder-hand syndrome. A 54-year-old woman with the diagnosis of rotator cuff tear underwent surgical treatment of rotator cuff repair, but the pain of the operated shoulder persisted due to phase 1 shoulder-hand syndrome. In postoperative week 3, skin temperature measurement using Thermocrons demonstrated a significant decrease in temperature on the operated side (affected side 34.3 +/ 0.4 degrees C, healthy side 35.2 +/- 0.3 degrees C; P < 0.05). CONCLUSION: The changing of the skin temperature during night-time was successfully recorded both in the healthy subjects and a case with shoulder-hand syndrome using a Thermocron. PMID- 20858149 TI - Early weight loss and outcome at one year in obese adolescents treated with orlistat or placebo. AB - BACKGROUND: Pharmacotherapy, associated with a comprehensive weight loss intervention, has emerged as a promising therapeutic approach in adolescents. Identification of subjects who best respond to a pharmacological intervention remains difficult. OBJECTIVE: To compare the value of early weight loss after 12 weeks of treatment with placebo or orlistat (120 mg three times a day) in predicting treatment outcome after 52 weeks. METHODS: Secondary analysis of a randomized control trial in 182 placebo-treated and 357 orlistat-treated obese adolescents (Body mass index [BMI] >= 2 kg/m(2) above the 95(th) percentile). RESULTS: Percent weight change at 12 weeks was positively correlated with percent change in weight (r(2) >= 0.41), BMI (r(2) >= 0.33) and waist circumference (r(2) >= 0.20) at 52 weeks in both the placebo and orlistat groups (P < 0.001). A weight loss >= 5% of baseline weight at 12 weeks was associated with a mean weight loss of 8.1% (95% CI: 6.4 to 9.7) at the study end that was independent of treatment. Subjects in the orlistat group were 2.44 times (95% CI: 1.34 to 4.46) more likely to experience a weight loss >= 5% after 12 weeks than subjects in the placebo group (P = 0.0028). CONCLUSIONS: Early weight loss predicts a favourable outcome in both placebo-treated and orlistat-treated subjects but is more than 2 times more likely to occur in the orlistat group. Addition of orlistat should be considered as part of a weight loss intervention but reevaluated after 3 months of treatment. PMID- 20858150 TI - Baseline predictors of placebo response in exercise-induced bronchoconstriction (EIB): pooled regression analysis >from three studies of montelukast in EIB. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB) can be variable in its presentation and severity. Evaluating patterns of placebo response and patient related factors driving placebo response could facilitate more efficient clinical trials for EIB. METHODS: Data were pooled from three randomized, double-blind, crossover trials evaluating single-dose montelukast 10 mg or placebo in patients (N = 160) 15-45 years of age with EIB, defined as maximum % fall in forced expiratory volume in one second (FEV1) >=20% after two screening exercise challenges. Serial exercise challenges were performed at 2, 8.5-12, and 24 h postdose. The authors evaluated the distribution and variability of placebo response. They also evaluated possible drivers of response, analyzing all baseline patient demographic and prerandomization screening visit pulmonary function data as single covariates in a simple univariate regression model for maximum % fall in FEV1 while on placebo at 2 h postdose. All covariates with p values <.1 were entered into both stepwise forward and backward regression procedures to select the "best" model. RESULTS: Placebo response was variable, and showed a significant non-normal distribution (p < .001). Significant predictors of a greater response to placebo included: higher screening FEV1 % predicted (p <.001), smaller maximum % fall in FEV1 in screening (p < .001), shorter time to recovery in screening (p = .007), more asthma-related health care visits in the previous year (p = .004), older age (p = .001), less frequent asthma awakenings in the previous month (p = .003), and less frequent asthma symptoms in the past year (p = .011). CONCLUSION: Predictors of a larger placebo response were generally markers of less severe asthma and/or EIB. This may be related to EIB variability, spontaneous improvement, or the extent of placebo response relative to the outcomes in less severe patients. PMID- 20858151 TI - The role of GSTP1 polymorphisms and tobacco smoke exposure in children with acute asthma. AB - BACKGROUND: The glutathione S-transferase enzymes (GSTs) play an important role in the detoxification of environmental tobacco smoke (ETS), which contributes to airway inflammation, a key component of asthma. Genetic variation in GST genes may influence individuals' ability to detoxify environmental pollutants. OBJECTIVE: To examine the role of polymorphisms in GSTP1 (Ile105Val and Ala114Val), alone and in combination with ETS exposure, on atopy and asthma severity. METHODS: GSTP1 Ile105Val and Ala114Val were genotyped and ETS exposure was assessed by parental questionnaire, which was validated by urinary cotinine measurements. Associations between ETS exposure, GSTP1 polymorphisms, and their interaction on atopy and asthma severity were investigated. RESULTS: For the functional GSTP1 105 SNP, those with the Ile/Ile genotype had odds for atopy of 2.77 (p = .054) when assessed by genotype alone, which increased to 9.02 (p = .050) when ETS was included, relative to individuals with other genotypes. Likewise, compared to children with other GSTP1 114 genotypes, those with Ala/Ala genotype had a 5.47-fold (p = .002) increased risk of atopy (p = .020) when assessed by genotype alone, increasing to 9.17-fold when ETS was included. The 105 Ile/Ile individuals all had the AA (105 Ile/Ile and 114 Ala/Ala) haplotype group; therefore, the odds for atopy were the same. Individuals without any *C haplotype (105 Val and 114 Val allele) who were exposed to ETS had a 9.17-fold increased risk of atopy when compared with individuals with at least one *C haplotype and not exposed to ETS (p = .020). CONCLUSION: There were significant interactions between GSTP1 SNPs, atopy, and ETS exposure in this cohort. PMID- 20858152 TI - A subgroup analysis of the MONICA study: a 12-month, open-label study of add-on montelukast treatment in asthma patients. AB - OBJECTIVE: We evaluated montelukast, a leukotriene receptor antagonist (LTRA), added to inhaled corticosteroids (ICS) or ICS+long-acting beta2 agonist (LABA) regimens over a period of 1 year to explore the therapeutic effects on asthma patients in patient subgroups. METHODS: The majority of patients enrolled in this 12-month, open-label study were >=18 years of age (n = 1681) with mild to moderate asthma insufficiently controlled by ICS or ICS+LABA. Patients received montelukast 10 mg qd as add-on therapy and were evaluated at Months 3, 6, 9, and 12. Asthma Control Test (ACT) score in the overall population was the primary endpoint; ACT score categories range from <16 (uncontrolled) to 25 (completely controlled). A post hoc secondary analysis of the following subgroups was conducted. age (< 30 years, 30-50 years, >50 years), gender, presence of allergic rhinitis, duration of asthma (< 5 years, >=5 years), and the use of ICS or ICS+LABA. RESULTS: Over 12 months of therapy, mean ACT scores improved by 5.7 units (p < .0001); at baseline, the mean (SD) ACT score for all patients was 14.6 (4.6) and at Month 12, the mean (SD) ACT score was 20.3 (4.2). The subgroups of patients who had allergic rhinitis and those who were <30 years of age demonstrated numerically better ACT scores compared with those who did not have allergic rhinitis or who were >30 years of age. Additional evaluation of the ACT score categories also demonstrated better control among patients who had duration of asthma <5 years and were treated with ICS without LABA. CONCLUSION: Add-on montelukast demonstrated significant improvement in asthma symptoms over 12 months in all patients in the study. Asthma control was improved in all patient subgroups, but comorbid allergic rhinitis, younger age, shorter duration of asthma, and treatment with only ICS and not ICS+LABA were indicators of better control with add-on montelukast. These observations may likely be shared with other antiasthmatic medications and should be further explored. PMID- 20858153 TI - The differences of eosinophil- and neutrophil-related inflammation in elderly allergic and non-allergic chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common disease in the elderly population and is characterized by airway inflammation. Whether it is a progressive condition resulting from allergic inflammation or a distinct condition involving a pathogen-induced reaction remains unclear. OBJECTIVES: To determine the role of allergic inflammation in the pathogenesis of elderly COPD. METHODS: A total of 63 elderly adults (21 mite-allergic COPD patients, 29 non allergic COPD patients, and 13 normal controls) were recruited in this study. The serum-specific IgE for mites, level of interleukin-5 (IL-5), IL-8, leptin, adiponectin, regulated upon activation normal T cell expressed and secreted (RANTES), growth-related oncogene-alpha (GRO-alpha), vitamin E, and glutathione (GSH) were determined. RESULTS: The serum levels of GRO-alpha in patients with COPD were higher in comparison to normal controls (105.8 +/- 32.7 vs. 7.5 +/- 7.5 pg/mL, p= .021). Compared to patients with non-allergic COPD, patients with mite allergies had a higher serum level of IL-8 (63.2 +/- 12.6 vs. 35.0 +/- 8.2 pg/mL, p= .022). Although both IL-5 and RANTES levels were increased in COPD patients, there were no significant differences between allergic and non-allergic COPD. There were also no differences in serum levels of leptin, adiponectin, vitamin E, and GSH between COPD patients and normal controls. CONCLUSIONS: The increased serum levels of GRO-alpha indicate that it may have potential as a candidate biomarker for elderly COPD patients. There was no difference of eosinophils related chemokines in allergic and non-allergic COPD. These results indicated that both adipokines and eosinophil-related chemokines only play trivial roles in the pathogenesis of COPD. PMID- 20858155 TI - An assessment of dietary flavonoid intake in the UK and Ireland. AB - Accurate estimates of flavonoid intake are important for public health studies and potential policies related to these phytochemicals. As an alternative to studies involving population samples and individual food consumption surveys, the international FAO Food Balance Sheets (FBS) were used in the current study to estimate flavonoid consumption among the populations of the UK and Republic of Ireland. A supplemented USDA database was prepared for flavonoid analyses of the foods reported in the FBS. Twenty-three flavonoids from five groups (anthocyanidins, flavonols, flavanols, flavanones, and flavones) were analyzed. Estimated per-capita daily flavonoid intake (all five groups) was 182 mg and 177 mg for the UK and Ireland, respectively. In both cases, anthocyanidins and flavanols accounted for about 65% of total consumption. Combined intake of flavones, flavanones, and flavonols was 60 mg/day in the UK and 69 mg/day in Ireland. These flavonoid intake values are compared with those previously reported for the UK and other countries. Overall, these novel results contribute to establishing accurate reference points for national flavonoid intakes. PMID- 20858156 TI - Optimization conditions for anthocyanin and phenolic content extraction form purple sweet potato using response surface methodology. AB - Purple sweet potato flour could be used to enhance the bioactive components such as phenolic compounds and anthocyanin content that might be used as nutraceutical ingredients for formulated foods. Optimization of anthocyanin and phenolic contents of purple sweet potato were investigated using response surface methodology. A face-centered cube design was used to investigate the effects of three independent variables: namely, drying temperature 55-65 degrees C, citric acid concentration 1-3% w/v and soaking time 1-3 min. The optimal conditions for anthocyanin and phenolic contents were 62.91 degrees C, 1.38%, 2.53 min and 60.94 degrees C, 1.04% and 2.24 min, respectively. However, optimal conditions of anthocyanin content were not apparent. The experimental value of anthocyanin content was 19.78 mg/100 g and total phenolic content was 61.55 mg/g. These data showed that the experimental responses were reasonably close to the predicted responses. Therefore, the results showed that treated flours could be used to enhance the antioxidant activities of functional foods. PMID- 20858157 TI - Association of breast-feeding and feeding on demand with child weight status up to 4 years. AB - OBJECTIVES: The mechanisms underlying the protective effect of breast-feeding on the development of childhood overweight are unclear. This study examines the association of breast-feeding with weight gain in the first year, and body mass index (BMI) and overweight up to 4 years. In addition, we examine possible mechanisms of this effect (i.e., feeding pattern, eating style, unhealthy snacking behavior). METHODS: Data originated from the KOALA Birth Cohort Study (N = 2 834). Questionnaires assessed breast-feeding duration up to 12 months, feeding pattern (i.e., feeding on demand or feeding to schedule) at 3 months, BMI at 1, 2 and 4 years, eating style (e.g., slow eating) at age 1, and unhealthy snacking at age 2. Linear and logistic regression analyses were used to examine the association of breast-feeding and feeding pattern with eating style, unhealthy snacking, BMI z-scores and overweight. RESULTS: Each additional month of breast-feeding was associated with less weight gain in the first year (regression coefficient B = -37.6 g, p < 0.001), a lower BMI z-score at age 1 (B = -0.02, p < 0.01), and a lower odds of being overweight at age 1 (odds ratio = 0.96, p < 0.05). Breast-feeding was associated with fewer unhealthy snacking occasions per week at age 2 (B = -0.19 for each month of breast-feeding, p < 0.001), but was unrelated to eating style. Feeding pattern was unrelated to all outcome variables after adjustment for breast-feeding duration. CONCLUSIONS: The study showed a short-term protective effect of breast-feeding against overweight development. Possible mechanisms through which breast-feeding may protect against overweight include less unhealthy snacking behavior, but not feeding pattern or child's eating style. PMID- 20858158 TI - Effects of bisoprolol and cilazapril on the central retinal artery blood flow in patients with essential hypertension--preliminary results. AB - BACKGROUND: A growing body of evidence suggests that effective blood pressure reduction may inhibit the progression of microvascular damage in patients with essential arterial hypertension. However, the potential influence of anti hypertensive drugs on ocular circulation has not been studied sufficiently. PURPOSE: The aim of our study was to evaluate the effects of anti-hypertensive therapy on blood flow in the central retinal artery in patients with systemic arterial hypertension. MATERIAL AND METHODS: Twenty patients with essential arterial hypertension, aged 32-46 years, were examined with Doppler ultrasonography (10 MHz ultrasound probe). Blood flow velocities, pulsatility, and vascular resistance were determined before and 3 hours after systemic application of either bisoprolol 5 mg or cilazapril 2.5 mg. RESULTS: Administered bisoprolol significantly decreased maximum (9.8 +/- 0.5 cm/s versus 8.5 +/- 0.6 cm/s; P < 0.05) and minimum (2.75 +/- 0.19 cm/s versus 1.75 +/- 0.27 cm/s; P < 0.02) velocity, increased the Pourcellot's index (0.71 to 0.79; P < 0.05) in central retinal artery. There were no statistically significant changes in central retinal artery blood flow after administration of cilazapril. CONCLUSION: Systemic application of beta-blockers may unfavourably disturb the ocular blood flow. PMID- 20858161 TI - Subacute osteomyelitis masquerading as primary bone sarcoma: report of six cases. AB - BACKGROUND: We report a series of six immunocompetent patients who were believed initially to have primary bone sarcomas, but turned out to have subacute osteomyelitis. METHODS: Case report and review of relevant literature. RESULTS: All our patients were treated with antibiotics and recovered fully from the infection. Only one patient had a recurrence with the same offending microorganism, which resolved after a longer period of intravenous antibiotic. CONCLUSIONS: Subacute osteomyelitis and bone tumors can be similar in presentation, and the key to proper diagnosis is histopathological and microbiological confirmation in biopsy specimens. PMID- 20858164 TI - Adherence monitoring in drug delivery. AB - Adherence monitoring is an important issue in inhaled drug delivery. Adherence is commonly found to be low and poor adherence is associated with increased mortality and morbidity and increased use of health services. Improving adherence is essential to maintaining disease and symptom control for patients and decreasing health costs. Feedback on actual adherence has been shown to increase subsequent adherence. In addition, education programs, reminder systems and increased patient-clinician interaction can also improve adherence. However, improved adherence is not sufficient if inhalation devices are being used incorrectly; the emphasis must be on devices being used in accordance with both the prescribed regimen and the instructions for use. As a result of technological advancements, drug delivery devices that both monitor adherence and address poor inhaler technique are now available. These devices combine monitoring systems with various feedback mechanisms in order to 'coach' the patient to use the device correctly. Some devices also incorporate connectivity to communicate accurate adherence and inhaler technique data to the clinician. This editorial considers current and future adherence monitoring devices and the impact that such technology could have on improving the patient's adherence and inhaler technique. PMID- 20858162 TI - Post-esophagectomy pseudomembranous inflammation of the interposed colon. AB - BACKGROUND: Pseudomembranous colitis (PMC) usually is caused by antibiotic related changes in colonic anaerobic microflora, leading to Clostridium difficile overgrowth and overproduction of toxins. We present the first reported case of PMC affecting the intrathoracic, interposed colon of an esophagectomy patient in the absence of inflammation of the in situ colon. METHODS: Case report and review of pertinent English-language literature. CASE REPORT: A 47 year-old male developed Clostridium difficile-related colitis after in Ivor-Lewis esophagectomy for carcinoma of the esophagus, and rendered asymptomatic after 10 days of therapy with oral vancomycin. Postoperatively, the patient developed a broncho esophageal fistula, and was reconstructed with a two-stage colonic esophageal colonic interposition three months after the fistula was closed surgically. On postoperative day nine, the patient developed symptomatic PMC of the interposed colon segment, whereas the in situ colon was spared. Therapy with oral vancomycin for three weeks eradicated the infection. CONCLUSIONS: Pseudomembranous colitismay develop in the interposed colon after a esophageal colonic interposition, even absent inflammation of the in situ colon. Previous infection with C. difficile may have increased the risk in this patient. PMID- 20858165 TI - Bicontinuous cubic liquid crystals as sustained delivery systems for peptides and proteins. AB - IMPORTANCE OF THE FIELD: Self-assembling lipid-based liquid crystalline systems are a broad and active area of research. Of these mesophases, the cubic phase with its highly twisted bilayer and two non-intersecting water channels has been investigated extensively for drug delivery. The cubic phase has been shown to accommodate and control the release of drugs with varying physicochemical properties. Also, the lipids used to prepare these delivery systems are generally cheap, safe and biodegradable, making these systems highly attractive. Early research investigating the potential of cubic phases as delivery systems showed that several peptides or proteins entrapped within these gel-based systems showed retarded release. Furthermore, entrapment within the cubic phase protected the selected peptide or protein from chemical and physical degradation with its native confirmation and bioactivity retained. AREAS COVERED IN THIS REVIEW: In this review, the literature pertaining to the delivery of various bioactives from cubic liquid crystalline phases is examined, with a particular focus on peptides and proteins. The scope and limitations of the cubic phases in this respect and the future of cubic liquid crystalline systems as sustained delivery systems are highlighted. WHAT THE READER WILL GAIN: The reader will be able to gain an understanding of the properties of the bicontinuous cubic phase and how its structural attributes make these systems desirable for sustained delivery of bioactives, in particular peptides and proteins, but also how these same structural properties have hindered progress towards clinical applications. Current strategies to overcome these issues will also be discussed. TAKE HOME MESSAGE: The bicontinuous cubic phase offers great potential in the field of peptide and protein delivery, but limited research in this area precludes definite conclusions to its future in this respect. PMID- 20858166 TI - Using liposomes to target infection and inflammation induced by foreign body injuries or medical implants. AB - IMPORTANCE OF THE FIELD: Foreign body (FB) injuries occur under many circumstances: at work, when practising a hobby, in car accidents, or in violence afflicted zones. Owing to the nature of these injuries, they are not restricted to a certain part of the body and may affect several organs simultaneously. In general, an FB will be surgically removed when it is a cause of pain or infection or when jeopardizing a critical biological function. However, in many cases removing the FB is not possible owing to risk of harming adjacent delicate tissue. Furthermore, often when surgically removing the FB, microscopic fragments or debris remain at the site of invasion, becoming a cause of pain and recurring infection and inflammation. FB-related complications can also originate from micro- or nanoparticles released by degradation of medical implants. The use of advanced drug delivery technologies to target the tissue surrounding the FB, or the FB itself, may be of therapeutic benefit. Liposomes, vesicles with an aqueous core entrapped in one or more lipid bilayers, are widely used as drug delivery systems. Previous studies show that nanoliposomes can effectively target infected and inflamed tissue. The working hypothesis of this paper is that nanoliposomes, of specific lipid composition, may be used to target FB under conditions of inflammation. AREAS COVERED IN THIS REVIEW: A comprehensive literature review regarding the use of liposomes for targeting and treating infection and inflammation, as well as a prospective on conjugates that can improve FB targeting in vivo. WHAT THE READER WILL GAIN: The article aims to assess whether nanoliposomes loaded with a therapeutic compound may be advantageous for treating FB-related pathologies. TAKE HOME MESSAGE: Nanoliposomes are promising candidates for targeting FB-induced infection and inflammation. Certain properties, related to the micro-anatomy and physiology of inflammation as well as to the liposome physicochemical properties, make possible 'passive' targeting of the FB region. Conjugating specific ligands to the surface of the liposomes can improve their efficacy by adding an element of 'active' targeting. Despite the great clinical need, the use of nano-based technologies to target and treat FB-induced infection, inflammation and pain has not been exploited yet. The use of drug loaded nanoliposomes for this application seems to be most promising and should be evaluated with high priority. PMID- 20858167 TI - HIV-1 RT-associated RNase H function inhibitors: Recent advances in drug development. AB - The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV 1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action. PMID- 20858168 TI - Ribonucleotide reductase: a mechanistic portrait of substrate analogues inhibitors. AB - Ribonucleotide reductase (RNR) is the key enzyme in the biosynthesis of deoxyribonucleotides. Several different strategies for inactivation of RNRs have been reported, including the use of substrate analogues as mechanism-based inhibitors. This article undergoes a critical analysis on the current status of ribonucleotide reductase inhibitory mechanisms by substrate analogues highlighting experimental and theoretical/computational approaches. We have summarized a general portrait of the inhibitory mechanisms and classified the nucleoside analogue inhibitors in three main classes. The critical analysis undertaken will contribute in finding new and more effective ways of inhibiting RNR. PMID- 20858169 TI - Using small molecule GSK3beta inhibitors to treat inflammation. AB - Glycogen Synthase Kinase 3 beta (GSK3beta) is a serine-threonine kinase originally identified for its role in the conversion of glucose to glycogen. Pharmacological inhibition can be achieved by drug binding to ATP or magnesium binding sites on the enzyme. Pharmaceutical companies have developed several small molecule GSK3beta inhibitors for diabetes research. Additionally, GSK3beta inhibitors are being clinically tested as therapeutics for neurological diseases, however, the mechanisms of involvement are unclear. Several studies have shown that the therapeutic effect of GSK3beta inhibition is associated with the inhibition of inflammation. Similarly, the mechanisms underlying the anti inflammatory function of GSK3beta inhibition are not well understood. GSK3beta inhibition attenuates activation of the pro-inflammatory transcription factor NFkappaB, and activates the immuno-modulatory transcription factor beta-catenin. GSK3beta inhibition has also been shown to induce secretion of the anti inflammatory cytokine IL-10. In addition, pharmacological inhibition of GSK3beta suppressed alloreactive T-cell responses. The combined anti-proliferative and anti-inflammatory properties of small molecule inhibitors of GSK3beta make them an attractive treatment modality towards the control of inflammation. PMID- 20858171 TI - Regulators of platelet cAMP levels: clinical and therapeutic implications. AB - Platelets are indispensable for primary haemostasis, but their function needs to be tightly regulated to prevent excessive platelet activity, possibly leading to atherothrombotic events. An important mediator of the platelet activity is cyclic AMP (cAMP), which inhibits platelet aggregation. Intracellular cAMP levels are regulated via the Gs and Gi alpha subunits of heterotrimeric G proteins, which couple to adenylyl cyclase to respectively stimulate or inhibit cAMP production. Binding of a ligand to its G protein-coupled seven-transmembrane receptor activates these G proteins. In this review, we discuss a Gs-coupled receptor on platelets, VPAC1, and 2 important Gi-coupled receptors, the ADP receptor P2Y(12) and the prostaglandin E(2) receptor EP3. The regulation of platelet cAMP levels at the level of the receptors themselves or the G proteins coupled to them is analyzed. Alterations in Gsalpha and Gialpha function are associated with altered platelet reactivity. An increase in Gs function, or alternatively a defective Gi signaling, can be a risk factor for bleeding, while a loss of Gs function can result in a prothrombotic state. Regulator of G protein signaling (RGS) proteins accelerate the rate of inactivation of G protein-mediated signaling. One of the RGS proteins, RGS2, inhibits Gs signaling by interacting directly with adenylyl cyclase. The thienopyridine class of antiplatelet agents is based on cAMP mediated regulation of platelet function through modification of the P2Y(12) receptor. Clopidogrel and some other novel cAMP regulators are discussed. Secondly, we review the use of prostacyclin derivatives to treat pulmonary arterial hypertension. PMID- 20858170 TI - Use of Kv1.3 blockers for inflammatory skin conditions. AB - Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1-family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders. PMID- 20858172 TI - Drug target identification for neuronal apoptosis through a genome scale screening. AB - During normal nervous system development, physiologically appropriate neuronal apoptosis contributes to a sculpting process that removes approximately one-half of all neurons born during neurogenesis. However, neuronal apoptosis subsequent to this developmental window is physiologically inappropriate for most systems and can contribute to neurodegenerative diseases. Neuronal apoptosis is characterized by specific morphological events and requires the activation of an intrinsic transcriptional program. With the completion of genome sequencing in humans and model organisms, and the advent of DNA microarray technology, the transcriptional cascades and networks regulating neuronal apoptosis are being elucidated providing new potential pharmacological targets. This review will introduce the reader to this genomic approach and illustrate with a few examples a methodological strategy for the rational selection of pharmacological targets and the development of neuroprotective agents. PMID- 20858173 TI - Sirtuin family: a link to metabolic signaling and senescence. AB - A vast collection of data obtained during the last decade supports the view on sirtuins as sensors of actual cellular metabolic state being involved in cell cycle progression, apoptosis/survival decision making, longevity, inflammation etc. Moreover, sirtuins themselves can control metabolism through their ability to consume NAD(+). In turn, cellular NAD parameters may affect the generation of ATP, a main cellular currency of energy. Therefore, sirtuins became recognized as critical affectors of cellular metabolism which participate in fat mobilization, gluconeogenesis, caloric restriction etc. Cellular senescence is viewed as a mechanism to restrict excessive cell growth when it is unnecessary or harmful. It is therefore necessary to understand the mechanism of senescence to design new approaches to combat cancer. Growth in turn depends on metabolism as it requires energy. Therefore, in this review, we address the connection of sirtuins to senescence through their participation in the regulation of metabolic and biochemical parameters and related signaling. PMID- 20858174 TI - What is known about the antiviral agents active against bovine viral diarrhea virus (BVDV)? AB - Viruses belonging to the Flaviviridae family cause clinically significant diseases in humans and animals. This family includes three genera: Pestivirus [including bovine viral diarrhea virus (BVDV)], Flavivirus [including yellow fever virus (YFV), dengue virus, and West Nile virus (WNV)], and Hepacivirus [including hepatitis C virus (HCV)]. BVDV is responsible for major losses in cattle, causing a range of clinical manifestations, and is also a problematic contaminant in the laboratory. Noncytopathic BVDV infection can remain unnoticed and infect laboratory cell lines through its presence in contaminated bovine serum used in cell culture. BVDV is considered to be a valuable surrogate virus model for identifying and characterizing antiviral agents to be used against HCV. In some aspects of viral replication, BVDV is more advantageous than the currently used HCV replicon systems. In this review, we report the design, synthesis, and activity against BVDV of a series of compounds assayed until now. PMID- 20858175 TI - Infrared-spectroscopy: a non-invasive tool for medical diagnostics and drug analysis. AB - Constant development enabled Infrared (IR) spectroscopy to become a widely used, non-invasive tool for fast sample analyses with less to no pre-preparation. Furthermore, computational data handling is no more a limiting factor and hence, IR measurements are predestined for clinical diagnostics and drug analysis. Within this review the focus was put on clinical topics of high interest. One example is Alzheimer's disease, where the exact metabolism is still not clarified, or blood glucose monitoring for high throughput screening of patients without taking any drop of blood. The second section of this manuscript was focused on the analysis of drugs. The detection of physico-chemical parameters in pharmaceutics and the improvement of industrial proceedings allowed a dramatic increase of quality of produced medicine. In pharmaceutical industries problems with the equable allocation of agents occurs especially in scaling up processes. IR-analyzing-techniques serve as fast and precise indicators for the detection of active components and their distribution in tablets. In combination with statistical factors and medical investigations pharmaceuticals can be improved from their development until their application, and every step can be easily controlled by IR spectroscopy. PMID- 20858176 TI - Use of the adamantane structure in medicinal chemistry. AB - This review summarizes the importance and recent discoveries of the use of adamantane derivatives in Medicinal Chemistry. We have organized the article in 4 sections: 1) Absorption, Distribution, Metabolism, or Excretion (ADME) properties 2) Hydrophobic Effects 3) Ion Channels and 4) Rigid scaffold. Within each section, we have provided examples of how the adamantane group changes the properties of known drugs or provides a important pharmacophore for the design of new drugs. PMID- 20858177 TI - Materials degradation in PVC medical devices, DEHP leaching and neonatal outcomes. AB - Polymeric materials play a key role in the production of medical and clinical devices thanks to their special features such as flexibility, easy processing and good price/performance ratio. Among the different polymeric matrixes, one of the most used is Poly(vinyl chloride) (PVC). At room temperature PVC is hard and brittle, thus great amounts (40-50%) of phthalate esters that act as plasticizers are added to the polymer to make it flexible and appropriate for medical use. Di (2-ethylhexyl)-phthalate (DEHP) is the most widely used plasticizer in PVC medical devices. However, DEHP is not chemically bound to PVC and migrates from medical devices with time and use. The potential for DEHP to produce adverse effects in humans has been the subject of considerable discussion and debate in the scientific community. In particular, newborns in the new environment have to be considered at particularly increased risk, because of their small body size and the multiple medical device-related to the DEHP exposure. The major factors determining the degree to which DEHP migrates from medical devices are temperature, amount of DEHP in the device, storage time, shaking of the device while in contact with the medical solutions and degree of PVC degradation. PMID- 20858178 TI - The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review. AB - OBJECTIVE: This review focuses on the efficacy and safety of effective herbal medicines in the management of hyperlipidemia in human. METHODS: PubMed, Scopus, Google Scholar, Web of Science, and IranMedex databases were searched up to 11th May 2010. The search terms were "hyperlipidemia" and ("herbal medicine" or "medicine traditional", "extract plant") without narrowing or limiting search elements. All of the human studies on the effects of herbs with the key outcome of change in lipid profiles were included. RESULTS: Fifty three relevant clinical trials were reviewed for efficacy of plants. This study showed significant decrease in total cholesterol and LDL cholesterol after treatment with Daming capsule (DMC), chunghyul-dan, Glycyrrhiza glabra, garlic powder (Allicor), black tea, green tea, soy drink enriched with plant sterols, licorice, Satureja khuzestanica, Monascus purpureus Went rice, Fenugreek, Commiphora mukul (guggul), Achillea wilhelmsii C. Koch, Ningzhi capsule (NZC), cherry, compositie salviae dropping pill (CSDP), shanzha xiaozhi capsule, Ba-wei-wan (hachimijiogan), rhubarb stalk, Silybum marianum, Rheum Ribes and Jingmingdan granule (primrose oil). Conflicting data exist for red yeast rice, garlic and guggul. No significant adverse effect or mortality were observed except in studies with DMC, guggul, and Terminalia belerica, Terminalia chebula, Emblica officinalis, ginger, and garlic powder (Allium sativum). CONCLUSION: Amongst reviewed studies, 22 natural products were found effective in the treatment of hyperlipidemia that deserve further works to isolate and characterization of their constituents to reach novel therapeutic and more effective agents. PMID- 20858179 TI - Antithrombotic therapy in cardiovascular and haematological diseases: new perspectives. PMID- 20858180 TI - Current therapeutic strategies and future perspectives for the prevention of arterial thromboembolism: focus on atrial fibrillation. AB - Arterial thromboembolism is a sudden obstruction of arterial blood flow caused by dislodgment of a blood clot from the site of its formation. Atrial fibrillation (AF) is the most common cardiac arrhythmia and a major risk factor for arterial thromboembolism in clinical practice. Most of AF-related arterial thromboembolic events affect the cerebral circulation, leading to increased mortality or long term disability from stroke. In the setting of AF, stroke is more likely to be fatal or associated with longer hospitalization, greater disability and higher rates of recurrence. Anticoagulant therapy reduces the risk of stroke, and the greatest benefit is achieved in patients at highest absolute risk. Aspirin is a less effective option, and should not be considered as an equivalent alternative for AF patients with a moderate stroke risk, who are eligible for oral anticoagulation. Nonetheless, anticoagulant therapy remains underused in AF patients with high stroke risk, particularly in the elderly, whilst it might perhaps be overused in the low risk patients. This could also be related to limitations in current risk stratification schemas for stroke and bleeding complications of anticoagulant therapy in AF patients in contemporary clinical practice. In this review article, we present an overview of current therapeutic strategies, new developments and future perspectives for the prevention of arterial thromboembolism in the context of AF and thromboembolism. We also discuss risk factors for stroke and bleeding complications, current risk stratification issues and emerging strategies for more accurate identification of AF patients who should be anticoagulated. PMID- 20858181 TI - Current therapeutic strategies and future perspectives for the treatment of venous thromboembolism. AB - Pulmonary embolism (PE) and deep vein thrombosis (DVT) are widely regarded as manifestations of a single disease, venous thromboembolism (VTE). An evidence based approach to the treatment of acute VTE will be reviewed here. Currently available therapeutic options will be emphasized; possible future treatment approaches will be discussed briefly. The chronic management of VTE involves assessment of the risks and benefits of prolonged anticoagulation and is discussed in more detail elsewhere in this issue. PMID- 20858183 TI - Further issues with new oral anticoagulants. AB - In recent years new oral anticoagulants have been evaluated in the prevention of venous thromboembolism (VTE) after elective hip or knee arthroplasty, atrial fibrillation to prevent ischemic stroke and in the treatment of acute VTE. While two oral anticoagulants, dabigatran and rivaroxaban, have become available for the prevention of VTE in orthopaedic surgery, other indications still are under evaluation or await approval. There are also areas where these novel drugs have not yet been evaluated. These include patients with acute VTE and cancer, pregnant patients with acute VTE and patient with either rheumatic heart valve disease or artificial heart valves. Finally, in acute care settings, where anticoagulant reversibility is critical, such as during and after coronary artery bypass surgery or acute PCI setting in patients with high bleeding risk, novel intravenous anticoagulant drugs with either short half life or specific antidotes may have added value. This article will focus on these unresolved issues. PMID- 20858182 TI - Residual vein thrombosis and D-dimer for optimizing duration of anticoagulation in idiopathic deep vein thrombosis. AB - Long-term anticoagulant treatment is highly effective in preventing recurrent Venous Thrombo-Embolism (VTE) in patients with idiopathic Deep Vein Thrombosis (DVT) of the lower limbs, though associated with an increased risk for major bleeding that may offset the benefits of anticoagulation. Accordingly to recent guidelines, patients with idiopathic DVT should be treated for at least 3 months and then should be evaluated for the risk-benefit ratio of long-term therapy. However, such 'time for decision' is often unclear and the optimal duration of VKA remains debatable. In recent studies, markers for the assessment of the individual risk for recurrent thrombosis have been proposed, which can be of help to establish the optimal duration of VKA treatment; among them, the D-dimer (D-d) assay and the Residual Vein Thrombosis (RVT) assessment by Compression Ultra Sonography (CUS) were shown to be the most suitable. Studies' results showed that negative results of these parameters after 3 to 6 months of therapy, identify a group of patients at low-risk for recurrent thrombosis in whom VKA treatment can be withheld. In the present review we will discuss advantages and potential limits of using these individual markers for the management of patients with a first episode of DVT of the lower limbs. PMID- 20858184 TI - New anticoagulants for the prevention of thromboembolism. AB - The traditional agents used for thromboprophylaxis are effective and safe but have limitations particularly related to ease of administration. Newer agents targeting single coagulation factors such as the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban have demonstrated efficacy and safety for thromboembolism prophylaxis in the orthopedic population and have the additional benefit of oral administration and predictable pharmacokinetics. Pharmacology of the new anticoagulants and published data on the use of these agents in total knee and hip replacement patients will be reviewed in this article. PMID- 20858185 TI - Pharmacologic properties of the new oral anticoagulants: a clinician-oriented review with a focus on perioperative management. AB - The past decade has witnessed an explosion in the clinical development of new orally-administered anticoagulant drugs aimed at complementing vitamin K antagonists and heparins for the prevention and treatment of venous thromboembolism, for the prevention of stroke in patients with chronic atrial fibrillation, and for treatment of acute coronary syndromes. This review will focus on those new oral anticoagulants that are most relevant to the practicing clinician. These drugs consist of dabigatran, a direct thrombin inhibitor and rivaroxaban, a factor Xa inhibitor, both of which have been recently approved for clinical use. In addition, apixaban will be reviewed, which is another factor Xa inhibitor that is in the final stages of clinical development. The objectives of this review are: 1) to provide a clinician-oriented overview of the key pharmacokinetic and pharmacodynamic properties of dabigatran, rivaroxaban and apixaban; 2) to consider the implications of these drugs' pharmacologic properties in the perioperative setting for patients who require elective or urgent surgery, focusing on pre- and post-operative dosing, laboratory monitoring and reversal of anticoagulant effect. PMID- 20858187 TI - Protrhombotic effects of contraceptives. AB - The use of oral contraceptives first became widespread some 40 years ago, and reports of an excess risk of cardiovascular disease among women who used these agents soon followed. Few drugs have been the object of such intensive epidemiological research, the outcome of which has provided clinicians with detailed information about risks not only of specific thrombotic diseases but also important non-contraceptive benefits from the pill. Recently, oral contraceptives have been classified by some according to "generation" (first, second, third, and most recently, fourth generation): first-generation formulations containing lynestrenol or norethindrone, second-generation formulations containing levonorgestrel, third-generation formulations containing desogestrel or gestodene, and oral contraceptives containing an estrogen and other progestagens (cyproterone or norgestimate) or a progestagen alone. The results of several study was that the use of the older high-dose oral contraceptives increased the risk of cardiovascular disease by modifying the Low density lipoprotein and High-Density lipoprotein cholesterol level, increasing triglyceride serum level, reducing glucose tolerance, raising blood pressure, and promoting clotting mechanisms. In this review we investigate the mechanism of the oral contraceptives and performed a risk assessment of every generation. PMID- 20858186 TI - Managing bleeding complications in patients treated with the old and the new anticoagulants. AB - An increasing number of patients receive anticoagulant therapy to prevent and treat arterial or venous thromboembolism. The major complication of anticoagulant therapy is the increase of the individual bleeding risk. All anticoagulant drugs can cause haemorrhages, that can sometimes be life-threatening. Although heparins and the vitamin K antagonists have been the most widely used anticoagulants for decades, the correct management of bleeding complications associated with these agents has been poorly studied. More recently, new anticoagulant drugs, both parenteral and oral, have been approved for clinical use. Currently, none of these new agents has a specific antidote, and little advise can be given on how to manage a major bleeding event. The aim of this article is to describe the haemorrhagic risk and the management of bleeding complications associated with the principal anticoagulant drugs. PMID- 20858188 TI - Endothelial dysfunction: methods of assessment & implications for cardiovascular diseases. AB - The endothelium is a thin monocellular layer lining the entire human vascular system, separating blood from interstitium. It plays a core role in the vascular tone by releasing a variety of vasoactive substances, such as nitric oxide (NO) and endothelin. In addition to regulating vasomotion, the healthy endothelium also has anti-thrombotic (through prostacyclins), anti-inflammatory (through developmental endothelial locus-1{Del-1}) and anti-proliferative (through NO and prostaglandin I2) properties. All such mechanisms are regulated by a strict balance amongst several agonist and antagonist biochemical substances secreted by the endothelium. Endothelial dysfunction (ED) is a systemic process in which the endothelium loses the ability/capacity to maintain vascular equilibrium. ED is strongly associated with cardiovascular risk factors/diseases and can be assessed by a number of invasive and non invasive methods. Strict physiological and/or pharmacological management of cardiovascular risk factors improves the functional status of the endothelium and reduces the risk of future cardiac events. This review will provide an overview of the modern perception of endothelial biology, the methods of its assessment and interaction of the endothelium with cardiovascular risk factors and prognosis. PMID- 20858189 TI - Patent foramen ovale and thromboembolic complications. AB - The foramen ovale, an atrial septal defect which is essential in the fetal circulation, remains patent through adulthood in approximately 25% of the general population and so it represents the most common persistent abnormality of fetal origin. Patent foramen ovale (PFO) allows interatrial right-to-left blood shunting during those periods of the cardiac cycle in which the right atrial pressure exceeds the left one. An increasing number of pathological manifestations of PFO has been recently identified; among these, paradoxical systemic embolism, refractory hypoxemia in patients with right ventricular myocardium infarction or severe pulmonary disease, orthostatic oxygen desaturation in the rare platypnea-orthodeoxia syndrome, neurological decompression illness in divers, high altitude pilots and astronauts, and finally, migraine headache with aura. Nowadays many techniques allow to detect a PFO. In this study we investigated each of them, assessing their potential diagnostic role even in comparison with the main features of the other methods. PMID- 20858190 TI - Recent patents on nano flavor preparation and its application. AB - Nano flavor preparation and its application have been reviewed in this paper. Nano flavor could be prepared by physical methods such as spray drying with microfluidization and ultrasonication, physical adsorption and so on, chemical methods such as complex formation, nano-sized self-structured liquid, and nano emulsification and so on. Different preparation technology could produce nano particles with different physical properties, thus they could be used in different occasions such as food, drug, cosmetics and so on. The article presents some promising patents on nano flavor preparation and its application. PMID- 20858191 TI - Use of osmotic dehydration to improve fruits and vegetables quality during processing. AB - Osmotic treatment describes a preparation step to further processing of foods involving simultaneous transient moisture loss and solids gain when immersing in osmotic solutions, resulting in partial drying and improving the overall quality of food products. The different aspects of the osmotic dehydration (OD) technology namely the solutes employed, solutions characteristics used, process variables influence, as well as, the quality characteristics of the osmodehydrated products will be discussed in this review. As the process is carried out at mild temperatures and the moisture is removed by a liquid diffusion process, phase change that would be present in the other drying processes will be avoided, resulting in high quality products and may also lead to substantial energy savings. To optimize this process, modeling of the mass transfer phenomenon can improve high product quality. Several techniques such as microwave heating, vacuum, high pressure, pulsed electric field, etc. may be employed during or after osmotic treatment to enhance performance of the osmotic dehydration. Moreover new technologies used in osmotic dehydration will be discussed. Patents on osmotic dehydration of fruits and vegetables are also discussed in this article. PMID- 20858192 TI - Recent applications of peanut phytoalexins. AB - The search for natural alternatives to synthetic antioxidants and antimicrobials is growing tremendously as consumers become concerned with currently used compounds. Peanut phytoalexins may become a viable source of these compounds. Recent developments have shown compounds derived from peanuts possess both high antioxidant activity and antimicrobial capabilities. Some of these compounds have been identified as stilbenes and other low molecular weight phenolic compounds. Patents have been awarded for increasing the amounts of these compounds in peanut plants and in the peanut seeds. Increasing phytoalexins in peanut seeds may provide a method to increase dietary consumption of these compounds. In addition to their use as antioxidants and antimicrobials, peanut phytoalexins may possess beneficial health effects. Studies have shown these compounds to have anti diabetic, anticancer, and vasodilatory effects. Many of the recent patents concerning peanut phytoalexins focus on this area with patents being submitted for synergistic effects with chemotherapy drugs and treatment of diabetes and hepatitis B. Peanut phytoalexins may not only be able to replace synthetic food ingredients, but may also treat diseases that currently plague the human population. PMID- 20858193 TI - Food applications for flaxseed and its components: products and processing. AB - Flaxseed is the richest plant source of omega-3 fatty acid (alpha-linolenic acid) and the phytohormone lignans. It is also an essential source of high-quality protein and dietary fiber. Additionally, flaxseed has potential to be a source of phenolic compounds. Because of the beneficial physiological effects of its components, this seed is considered a functional food. It can contribute to the reduction of several diseases such as diabetes mellitus, arteriosclerosis and cancer. Food products and processing with regards to flaxseed are presented in this article. The article also presents some promising patents on food applications for flaxseed and its components. In addition, some potential opportunity areas are also discussed along with the impact of the use of this seed and its components in foods. PMID- 20858194 TI - Present and potential industrial applications of macro- and microalgae. AB - This review provides a complete overview over a spectrum of areas where value added applications of algae are in sight, from conventional food, feed, dietary supplement, and cosmetics to novel technologies for environmental and biofuel applications. In most cases macro- and microalgae are discussed separately due to their inherent differences from cultivation. Comparison of various cultivation systems are made in relation to specific value-added products. The potential uses of algal biomeal, the sizable waste stream generated after extraction of targeted compounds such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from the biomass of cultivated microalgae, are also discussed based on the concept of waste-recovery and biorefinery. The article presents some promising patents on potential industrial applications of macro- and microalgae. PMID- 20858195 TI - Edible plants, their secondary metabolites and antiobesogenic potential. AB - Obesity is a current public health issue and is considered as a disease when excessive accumulation of visceral fat leads to a chronic low-grade inflammatory state associated with high circulating levels of inflammatory markers, such as cytokines and acute-phase proteins, insulin resistance and cardiovascular diseases. Diet is the source of basic nutrients for life maintenance and other phytochemicals known as bioactive compounds (present both in vegetal and animal products) that are associated with health promotion and disease prevention. This review examines the most representative phytochemicals such as phytosterols, saponins, phenolic compounds and alkaloids in edible plants associated with obesity prevention/ treatment, the biological mechanisms associated with this process as well as the development of products for human health improvement and maintenance. The article presents some promising patents on edible plants, their secondary metabolites and antiobesogenic potential. PMID- 20858196 TI - Drug screening for Huntington's disease and other neurodegenerative disorders. AB - Devising therapies for neurodegenerative diseases remains a major challenge due to the complex etiology, prolonged disease course and the paucity of validated targets. These factors make it difficult to model neurodegenerative diseases in a manner amenable to large-scale screening. However recent developments in automation, combinatorial chemistry and high-throughput phenotypic assays have presented new opportunities for discovering small molecule therapeutics for neurodegenerative diseases. This review focuses on novel in vitro and phenotypic screens for Huntington's disease and a few other neurodegenerative diseases. The lessons learned from these screens and the potential of the small molecules identified as therapeutic leads are discussed. PMID- 20858198 TI - Study on the Langmuir aggregation of sodium octanesulfonate on human serum albumin. AB - The microphase adsorption-spectral correction (MPASC) technique was described and applied to the study of the interactions of sodium octanesulfonate (SOS) with human serum albumin (HSA). The aggregation SOS obeys the Langmuir monolayer adsorption. The results show the adsorption ratio of sodium octanesulfonate to HSA is SOS:HSA=18:1.The adsorption constant is K(SOS-HSA)=4.03 * 10(2). The detection limit is 0.036MUmol/L. FT-IR spectra proved the binding changed the conformation of HSA. PMID- 20858199 TI - The phosphorylation of lipid transfer protein CaMBP10. AB - Calmodulin-binding protein-10 (CaMBP10) was isolated previously from Chinese cabbage and identified as a member of the lipid transfer protein family. In this study, we found that CaMBP10 was phosphorylated in a calcium(Ca(2+))-dependent manner, and the phosphorylation was inhibited by calmodulin (CaM) antagonists. In gel kinase assay revealed that the phosphorylation of CaMBP10 was catalyzed by a 45 kDa protein kinase, which underwent autophosphorylation in the presence of Ca(2+). Immunoblotting assay further identified this kinase as a calcium dependent protein kinase (CDPK). In addition, the phosphorylation site was mapped to the C-terminal region of CaMBP10, where the CaM-binding domain resides. These results provide novel insights into the molecular mechanisms that regulate CaMBP10 functions. PMID- 20858197 TI - Biological activities of natural and engineered cyclotides, a novel molecular scaffold for peptide-based therapeutics. AB - Cyclotides are a growing family of large plant-derived backbone-cyclized polypeptides (~30 amino acids long) that share a disulfide-stabilized core characterized by an unusual knotted structure. Their unique circular backbone topology and knotted arrangement of three disulfide bonds makes them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size. Currently more than 100 sequences of different cyclotides have been characterized and the number is expected to increase dramatically in the coming years. Considering their stability, biological activities and ability to cross the cell membrane, cyclotides can be exploited to develop new peptide-based drugs with high potential for success. The cyclotide scaffold can be engineered or evolved using molecular evolution to inhibit protein-protein interactions implicated in cancer and other human diseases, or design new antimicrobial. The present review reports the biological diversity and therapeutic potential of natural and engineered cyclotides. PMID- 20858200 TI - Roles of L5-7 loop in the structure and chaperone function of SsHSP14.1. AB - The small heat shock protein SsHSP14.1 from the hyper-thermophilic archeaon, Sulfolobus solfataricus (S. solfataricus) was able to protect proteins from thermal aggregation and prevent enzymes from heat induced inactivation. According to the 3D (dimensional) structural model of SsHSP14.1 developed by us before, the region L5-7 (beta5-beta7, 68-82 residues) plays an important role for the oligomerization of SsHSP14.1 and its chaperone function. Here, to validate the findings, an in-depth investigation was conducted of both the wild type SsHSP14.1 and its deletion mutant DEL75-79. With E. coli proteins and bromelain as substrate, the deletion mutant DEL75-79 can protect them from thermo-aggregating as effective as the wild protein. Interestingly, unlike the wild protein, DEL75 79 was unable to prevent bromelain and EcoRI from thermo-inactivating. Results of size exclusion HPLC showed that the oligomerization state was changed in mutant protein. This was in accordance with the changed structure and lower hydrophobicity of DEL75-79. These outcomes proved that the L5-7 loop did play a role for the oligomerizing SsHSP14.1, and that the residues 75-79 were indispensable for its function of prevent enzymes from thermo-inactivating. PMID- 20858201 TI - Construction, expression and functional characterization of the beta-lactamase with alphav integrin ligands. AB - Antibody-directed enzyme prodrug therapy (ADEPT) delivers chemotherapeutic agents at high concentration to tumor tissues while minimizing systemic drug exposure. beta-Lactamases are particularly useful enzymes for ADEPT systems due to their unique substrate specificity, which allows the activation of a variety of lactam based prodrugs with minimal interference from mammalian enzymes. This study used integrin alpha(v)beta(3) as a target for tumor-specific delivery of beta Lactamase. beta-Lactamase was fused with ACDCRGDCFCG peptide (RGD4C) by recombinant DNA technology. Likewise, this study cloned a fused cDNA and successfully expressed active recombinant protein in E. coli purified with Ni-NTA resin. After purification, beta-Lactamase moiety showed the expected size of 42 kDa on Tricine-SDS-PAGE, and was further confirmed by Western blotting. Based on flow cytometric analysis, the purified protein was found to be active for specificity in breast cancer cell line, MCF-7, which supports the utility of the protein as an agent for ADEPT. PMID- 20858202 TI - Study of the nucleotide-binding domain 1 of the human transporter protein MRP6. AB - Multidrug-resistance-associated protein 6 (MRP6/ABCC6) is a protein belonging to the ABC transporter family. Proteins in this family share many characteristic structural features, including two membrane-spanning domains and two nucleotide binding domains (NBD1 and NBD2), that function cooperatively but not equally bind and hydrolyze ATP. The MRP6 protein is structurally and functionally poorly characterized. Previously, we showed, by NMR spectroscopy, that a fragment of MRP6-NBD1 presents helical structure and fluorescence experiments demonstrated that peptide binds ATP. These data suggested that the study on selected regions could be a valid approach to define the structure of MRP6 . In the present study, to better characterize MRP6-NBD1, we report data of CD spectroscopy, nucleotide binding and ATP hydrolysis on two different polypeptides, one corresponding to the full-length NBD1 domain (residues from Asp-627 to Leu-851) and the other is a shorter polypeptide (residues from Arg-648 to Thr-805) without some key residues. We report that both polypeptides are highly structured in aqueous buffer and in 20% trifluoroethanol showing considerable helical and beta-structure content. The ATP hydrolysis activity is exhibited only by the full-length NBD1 domain. Comparison between our findings and the structurally well characterized MRP1-NBD1 supports the role of H-loop for the ATP hydrolysis and of A-loop in stabilizing the ATP binding. PMID- 20858203 TI - Predicting caspase substrate cleavage sites based on a hybrid SVM-PSSM method. AB - Caspases play an important role in many critical non-apoptosis processes by cleaving relevant substrates at cleavage sites. Identification of caspase substrate cleavage sites is the key to understand these processes. This paper proposes a hybrid method using support vector machine (SVM) in conjunction with position specific scoring matrices (PSSM) for caspase substrate cleavage sites prediction. Three encoding schemes including orthonormal binary encoding, BLOSUM62 matrix profile and PSSM profile of neighborhood surrounding the substrate cleavage sites were regarded as the input of SVM. The 10-fold cross validation results demonstrate that the SVM-PSSM method performs well with an overall accuracy of 97.619% on a larger dataset. PMID- 20858204 TI - Myoglobin as a new fluorescence probe to sense H2S. AB - A new, fast, simple and cost-effective sensing device for monitoring H(2)S has been developed. Proof-of-principle results showing that a commercial and cheap Myoglobin (Mb) can be successfully used as a biological probe for a fluorescence biosensor for H(2)S detection are reported. The two different commercial labels Cy3 and Atto620 were selected for this study. A high selectivity for detecting H(2)S against other thiols was found. The applicability of the proposed sensing system was successfully explored not only in solution but also when applied in the form of a solid state device. PMID- 20858206 TI - Spontaneous adjustment mechanism in an RNA-binding protein: cooperation between energetic stabilization and target search enhancement. AB - We propose a novel concept associated with the relationship between structure and function in biomolecular systems. We performed a 75 nanoseconds molecular dynamics (MD) simulation for an RNA-binding protein, neuro-oncological ventral antigen (NOVA), and examined its physico-chemical properties. NOVA dissociated from the NOVA-RNA complex showed a large conformational change: formation of intra-molecular hydrogen bonds between the C-terminal region and the loop structure located at the middle of amino acid sequence. The free energy analysis suggests that the deformed structure is more stabilized in macromolecular crowding environment where the dielectric constant is smaller than 5. The solvent accessible surface area (SASA) analysis indicates that NOVA enhances the efficiency of association with RNA by changing the relative SASA for the target sequence in RNA molecules. Based on the obtained results, we propose a novel concept of spontaneous adjustment mechanism to explain the structural and energetic changes observed for NOVA in the free state. PMID- 20858205 TI - Anti-tuberculosis activity of alpha-helical antimicrobial peptides: de novo designed L- and D-enantiomers versus L- and D-LL-37. AB - With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis (Mtb), a new class of antimycobacterial agents with very different modes of action compared to classical antibiotics, are urgently needed. In this study, a series of 26-residue, amphipathic, alpha helical antimicrobial peptides consisting of all D-amino acid residues and synthetic human L-LL37 (L-enantiomer) and D-LL37 (D-enantiomer) were investigated against M. tuberculosis susceptible strain (H37Rv) and a clinical multi-drug resistant strain (Vertulo). Minimal inhibitory concentrations (MICs) were determined through a peptide killing assay. D5, the most active analog against M. tuberculosis had a MIC value of 11.2 MUM (35.2 MUg/ml) against H37Rv strain and 15.6 MUM (49 MUg/ml) against the MDR strain. Peptide D1 had similar activity as D5 against the MDR strain (57 MUg/mL), a 9-fold improvement in hemolytic activity and a 7.4-fold better therapeutic index compared to D5. Surprisingly, LL37 enantiomers showed little to no activity compared to the de-novo designed alpha helical antimicrobial peptides. PMID- 20858207 TI - Characterization of the non-fibrillar alpha-synuclein oligomers. AB - Under certain in vitro conditions, alpha-Synuclein is an abundant 14 kDa presynaptic intrinsically disordered protein, involved in the pathogenesis of Parkinson's disease (PD) forms amyloid fibrils which resemble those found in Lewy bodies of PD patients. However, a substantial fraction of alpha-synuclein molecules (10-20 %) does not form fibrils during fibrillation and exists in a form of soluble oligomers. In this study, we examined these soluble oligomers by a variety of biophysical techniques including atomic force microscopy (AFM), circular dichroism, Fourier-transform infrared spectroscopy and thioflavin T fluorescence. We observed that the fibrillation kinetics is affected by the variation in salt and protein concentrations. Although both high salt and high protein concentrations noticeably accelerated alpha-synuclein fibrillation, the amount of non-fibrillar oligomers is independent of the salt content. The oligomers formed at low salt concentration adopt more beta-sheet structure and are smaller in size than those formed at high salt concentration. AFM analysis shows that the low salt oligomers represent a mixture of small oligomers and some amorphous aggregates, whereas oligomers formed at high salt concentrations are noticeably larger, more homogenous, and are mostly spherical in shape. All the late stage non-fibrillar oligomers do not form fibrils even when seeded with pre formed fibrils, are characterized by negligible rates of dissociation, likely due to their intertwined structure, and are able to disrupt the integrity of the biological membrane. These findings suggest that these soluble oligomers are important players in the multi-pathway aggregation of alpha-synuclein and should be taken into account in studies on the molecular mechanisms of this protein fibrillation. PMID- 20858208 TI - Conformational variation revealed by the crystal structure of RNase U2A complexed with Ca ion and 2'-adenylic acid at 1.03 A resolution. AB - Asparagine can be non-enzymatically deamidated and isomerized via succinimide to isoaspartate. This post-translational modification can potentially alter the physical properties or the function of the parent protein. Asn32 of ribonuclease U2A from Ustilago sphaerogena is known to rapidly deamidate and isomerize in alkaline conditions. The crystal structure of ribonuclease U2A complexed with 2' adenylic acid and calcium ions was determined at 1.03 A resolution. In this structure, the region from Asp29 to Asp37 winds around a calcium ion, and the main-chain of Asn32-Gly33 adopts an extended conformation. Rotation of the side chain of Asn32 could bring Asn32C(gamma) into close proximity to Gly33N, in a conformation suitable for succinimide formation. The structure suggests that in solution the region around Asn32-Gly33 is likely to be in equilibrium between multiple conformers, with the deamidation of Asn32 proceeding when the region adopts an extended conformation. PMID- 20858209 TI - The relaxin peptide family--structure, function and clinical applications. AB - The relaxin peptide family in humans consists of seven members, relaxin-1, -2 and -3 and insulin-like (INSL) peptides 3, 4, 5 and 6. It is an offshoot of the large insulin superfamily. Each member consists of two chains, commonly referred to as A and B, which are held together by two inter-chain disulfide bonds and another intra-chain disulfide bond present within the A chain. The cysteine residues present in each chain, together with the distinctive disulfide bonding pattern, are conserved across all members of the superfamily. The chemical synthesis of these complex peptides poses a significant challenge. In the past, random combination of the two synthetic S-reduced chains under oxidizing conditions was utilized to form the three disulfide bonds. Nowadays, with the aid of highly efficient solid phase peptide synthesis methodologies, in conjunction with selective S-thiol-protecting groups, combination of individual A- and B- chains by sequential chemical formation of each of the three disulfide bonds is now possible resulting in good yields of these peptides. The relaxin peptide family members bind to G-protein coupled receptors (GPCRs) which have been classified as relaxin family peptide (RXFP) receptors. The various unique receptor-ligand interactions are outlined in this review, together with the physiological roles of the relaxin peptide family members and lastly their past and present clinical applications. PMID- 20858210 TI - Monoclonal antibodies in the treatment of asthma. PMID- 20858211 TI - Modulation of photosensitization processes for an improved targeted photodynamic therapy. AB - Photodynamic therapy (PDT) is a cancer treatment modality involving the combination of light, a photosensitizer (PS) and molecular oxygen, which results in the production of cytotoxic reactive oxygen species (ROS). Singlet oxygen ((1)O(2)) is one of the most important of these ROS. Because the lifetime and diffusion of (1)O(2) is very limited, a controllable singlet oxygen generation with high selectivity and localization would lead to more efficient and reliable PDT. The lack of selective accumulation of the PS within tumour tissue is a major problem in PDT. Targeted PDT would offer the advantage to enhance photodynamic efficiency by directly targeting diseased cells or tissues. Many attempts have been made to either selectively deliver light to diseased tissues or increase the uptake of the photoactive compounds by the target cells. The review will survey the literature regarding the multi-level control of (1)O(2) production for PDT applications. The mechanisms of ROS formation are described. The different strategies leading to targeted formation of (1)O(2) are developed. Some active PDT agents have been based on energy transfer between PS by control of the aggregation/ disaggregation. The concept of molecular beacon based on quenching dequenching upon protease cleavage is capable of precise control of (1)O(2) by responding to specific cancer-associated biomarkers. PMID- 20858212 TI - Effects of the novel non-peptidyl low molecular weight radical scavenger IAC in different models of inflammation: a new perspective in anti- inflammatory therapy. AB - The bis (1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)-decandioate called IAC, is a new non-peptidyl low molecular weight radical scavenger able to give a fast reaction with the majority of radical species involved in the oxidative stress. This intrinsic property might be of particular interest in all the processes where it presents an over production of reactive oxygen/nitrogen species (ROS/RNS) such as inflammation. Indeed, it is well known that systemic inflammatory response is associated with the production of ROS, nitric oxide (NO), which in turn deplete the endogenous GSH, mediating cytotoxicity. It has been shown that IAC through its antioxidant activity, exerted a protective effect in vitro in islets isolated from type-2 diabetic patients, and in vivo in a non obese diabetic mouse model and in DNBS-induced colitis in rats. The ability of IAC to protect brain from ischemia, suggests a possible use of the compound in broad range of inflammatory- related diseases. It is well known that the use of non steroidal anti-inflammatory drugs (NSAIDs) is associated with a broad spectrum of untoward side-effects such as gastrointestinal ulceration. The major pathogenetic element in the development of these effects is the depletion of prostaglandins (PGs) through inhibition of cyclooxygenase. The evidence that IAC protects gastric mucosa in an animal model of indomethacin-induced ulcer, through local increase of PGE2 levels and antioxidant activity, candidates this compound as a novel, promising, anti-inflammatory compound avoiding the major common untoward side-effects elicited by NSAID's. PMID- 20858213 TI - Squalamine as an example of a new potent antimicrobial agents class: a critical review. AB - An important strategy to circumvent the problem of antimicrobial resistance is to search for new compounds with antimicrobial activity. In this context, aminosterols, which include squalamine-like compounds and ceragenins, have gained interest due to their wide spectrum of antibacterial and antifungal properties. In light of recently reported data, we decided to analyze the mechanism of action of these compounds as well as their antimicrobial properties. Aminosterols are active against both bacterial reference strains and multidrug-resistant antibiotics as they disrupt the integrity of the bacterial membrane. Thus, these compounds could be useful in the development of new topical decontaminants or disinfecting agents. PMID- 20858214 TI - Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists. AB - The prodrug design is a versatile, powerful method that can be applied to a wide range of parent drug molecules, administration routes, and formulations. Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing lipophilicity, or by improving aqueous solubility. Prodrug design may improve the bioavailability of parent molecule, and thus can be integrated into the iterative process of lead optimization, rather than employing it as a post-hoc approach. The purpose of this review is to provide an update of advances and progress in the knowledge of current strategic approaches of prodrug design, along with their real-world utility in drug discovery and development. The review covers the type of prodrugs and functional groups that are amenable to prodrug design. Various prodrug approaches for improving oral drug delivery are discussed, with numerous examples of marketed prodrugs, including improved aqueous solubility, improved lipophilicity, transporter mediated absorption, and prodrug design to achieve site-specific delivery. Tools employed for prodrug screening, and specific challenges in prodrug research and development are also elaborated. This article is intended to encourage discovery scientists to be creative and consider a rationally designed prodrug approach during the lead optimization phase of drug discovery programs, when the structure activity relationship (SAR) for the drug target is incompatible with pharmacokinetic or biopharmaceutical objectives. PMID- 20858215 TI - Use of enzymes in the production of semi-synthetic penicillins and cephalosporins: drawbacks and perspectives. AB - Semi-synthetic beta-lactamic antibiotics are the most used anti-bacteria agents, produced in hundreds tons/year scale. It may be assumed that this situation will even increase during the next years, with new beta-lactamic antibiotics under development. They are usually produced by the hydrolysis of natural antibiotics (penicillin G or cephalosporin C) and the further amidation of natural or modified antibiotic nuclei with different carboxylic acyl donor chains. Due to the contaminant reagents used in conventional chemical route, as well as the high energetic consumption, biocatalytic approaches have been studied for both steps in the production of these very interesting medicaments during the last decades. Recent successes in some of these methodologies may produce some significant advances in the antibiotics industry. In fact, the hydrolysis of penicillin G to produce 6-APA catalyzed by penicillin G acylase is one of the most successful historical examples of the enzymatic biocatalysis, and much effort has been devoted to find enzymatic routes to hydrolyze cephalosporin C. Initially this could be accomplished in a quite complex system, using a two enzyme system (D amino acid oxidase plus glutaryl acylase), but very recently an efficient cephalosporin acylase has been designed by genetic tools. Other strategies, including metabolic engineering to produce other antibiotic nuclei, have been also reported. Regarding the amidation step, much effort has been devoted to the improvement of penicillin acylases for these reactions since 1960. New reaction strategies, continuous product extraction or new penicillin acylases with better properties have proven to be the key to have competitive biocatalytic processes. In this review, a critical discussion of these very interesting advances in the application of enzymes for the industrial synthesis of semi-synthetic antibiotics will be presented. PMID- 20858216 TI - Emerging roles for riboflavin in functional rescue of mitochondrial beta oxidation flavoenzymes. AB - Riboflavin, commonly known as vitamin B2, is the precursor of flavin cofactors. It is present in our typical diet, and inside the cells it is metabolized to FMN and FAD. As a result of their rather unique and flexible chemical properties these flavins are among the most important redox cofactors present in a large series of different enzymes. A problem in riboflavin metabolism or a low intake of this vitamin will have consequences on the level of FAD and FMN in the cell, resulting in disorders associated with riboflavin deficiency. In a few number of cases, riboflavin deficiency is associated with impaired oxidative folding, cell damage and impaired heme biosynthesis. More relevant are several studies referring reduced activity of enzymes such as dehydrogenases involved in oxidative reactions, respiratory complexes and enzymes from the fatty acid beta oxidation pathway. The role of this vitamin in mitochondrial metabolism, and in particular in fatty acid oxidation, will be discussed in this review. The basic aspects concerning riboflavin and flavin metabolism and deficiency will be addressed, as well as an overview of the role of the different flavoenzymes and flavin chemistry in fatty acid beta-oxidation, merging clinical, cellular and biochemical perspectives. A number of recent studies shedding new light on the cellular processes and biological effects of riboflavin supplementation in metabolic disease will also be overviewed. Overall, a deeper understanding of these emerging roles of riboflavin intake is essential to design better therapies. PMID- 20858217 TI - Oxidative stress and endothelial dysfunction in cardiovascular disease: mitochondria-targeted therapeutics. AB - Functional impairment of endothelial activity (endothelial dysfunction) precedes the development of cardiovascular diseases (CVD). This condition is a result of a reduced bioavailability of nitric oxide (NO), a well known vasodilator, which is mainly due to increased NO degradation caused by its reaction with reactive oxygen species (ROS). Although there are several conditions that contribute independently to endothelial dysfunction, such as hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia, increased oxidative stress seems to play a key role. In addition to their original pharmacological properties, drugs used clinically at present, including anti-hypertension reagents, angiotensin receptor blockers and anti-hyperlipidemic reagents such as statins, protect various organs via anti-oxidative stress mechanisms. Moreover, some substances with antioxidant properties, such as vitamin C or vitamin E, have been used to eradicate the oxidative stress associated with CVD. The results of the clinical trials employing anti-oxidative stress reagents in patients with CVD are contradictory, which could be a result of inadequate study design or selected targets. This review considers the process of endothelial dysfunction and CVD from a mitochondrial perspective and evaluates strategies currently under development for the targeted delivery of antioxidants or NO to mitochondria. It endorses the idea that selectively targeting specific antioxidants and NO donors to mitochondria is an effective strategy for modulating mitochondrial respiration and ROS production and protecting mitochondria against oxidative stress. PMID- 20858218 TI - NS5B RNA dependent RNA polymerase inhibitors: the promising approach to treat hepatitis C virus infections. AB - Hepatitis C virus (HCV), a causative agent for non-A and non-B hepatitis, has infected approximately 3% of world's population. The current treatment option of ribavirin in combination with pegylated interferon possesses lower sustained virological response rates, and has serious disadvantages. Unfortunately, no prophylactic vaccine has been approved yet. Therefore, there is an unmet clinical need for more effective and safe anti-HCV drugs. HCV NS5B RNA dependent RNA polymerase is currently pursued as the most popular target to develop safe anti HCV agents, as it is not expressed in uninfected cells. More than 25 pharmaceutical companies and some research groups have developed ~50 structurally diverse scaffolds to inhibit NS5B. Here we provide comprehensive account of the drug development process of these scaffolds. NS5B polymerase inhibitors have been broadly classified in nucleoside and non nucleoside inhibitors and are sub classified according to their mechanism of action and structural diversities. With some additional considerations about the inhibitor bound NS5B enzyme X-ray crystal structure information and pharmacological aspects of the inhibitors, this review summarizes the lead identification, structure activity relationship (SAR) studies leading to the most potent NS5B inhibitors with subgenomic replicon activity. PMID- 20858219 TI - Selective COX-1 inhibition: A therapeutic target to be reconsidered. AB - Since cyclooxygenase (COX) isozymes discovery, many papers and reviews have been published to describe the structural bases of COX inhibition, and to debate on the therapeutic and adverse effects of worldwide clinically used nonsteroidal anti-inflammatory drugs (NSAIDs), included COX-2 selective inhibitors (well known as Coxibs). COX-2 inhibition has been widely investigated, whereas the role of COX-1 in human pathophysiology is mostly not yet well ascertained. As time goes on, the cliche that the constitutively expressed isoform COX-1 is only involved in normal physiological functions, such as platelet aggregation, gastric mucosa protection and renal electrolyte homeostasis is going to be shattered. Low-dose aspirin, behaving as a preferential inhibitor of platelet COX-1, allowed to enlighten the role exerted by this isoenzyme in many mammalian cell types. This review would elucidate the most recent findings on selective COX-1 inhibition and their relevance to human pathology such as cancer, neuro-inflammation, cardioprotection, fever and pain. It would also focus on the design and development of new highly selective COX-1 inhibitors, useful tools in pharmacological studies aimed at gaining a deeper insight of the role of COX-1 in human health and disease. Among the traditional NSAIDs, other then aspirin and indomethacin, only few examples of selective COX-1 inhibitors (SC-560, FR122047, mofezolac, P6 and TFAP) have been so far identified. This review has also the scope to stimulate the development of novel drugs, which activity is COX-1 mediated. PMID- 20858220 TI - Human platelets express and are activated by galectin-8. AB - Gals (galectins) are proteins with glycan affinity that are emerging as mediators of atherosclerosis. Despite the similarities in structure and sequence, different Gals exert distinct effects on their target cells. We have shown that Gal-1 triggers platelet activation, suggesting a role for Gals in thrombus formation. Since Gal-8 is expressed upon endothelial activation and also contributes to inflammation, to understand further the role of these lectins in haemostasis, we evaluated the effect of Gal-8 on human platelets. Gal-8 bound specific glycans in the platelet membrane and triggered spreading, calcium mobilization and fibrinogen binding. It also promoted aggregation, thromboxane generation, P selectin expression and granule secretion. GP (glycoprotein) alphaIIb and Ib-V were identified as putative Gal-8 counter-receptors by MS. Studies performed using platelets from Glanzmann's thromboasthenia and Bernard-Soulier syndrome patients confirmed that GPIb is essential for transducing Gal-8 signalling. Accordingly, Src, PLC2gamma (phospholipase C2gamma), ERK (extracellular-signal regulated kinase) and PI3K (phosphoinositide 3-kinase)/Akt downstream molecules were involved in the Gal-8 signalling pathway. Gal-8 fragments containing either the N- or C-terminal carbohydrate-recognition domains showed that activation is exerted through the N-terminus. Western blotting and cytometry showed that platelets not only contain Gal-8, but also expose Gal-8 after thrombin activation. These findings reveal Gal-8 as a potent platelet activator, supporting a role for this lectin in thrombosis and inflammation. PMID- 20858221 TI - Saccharomyces cerevisiae glucose signalling regulator Mth1p regulates the organellar Na+/H+ exchanger Nhx1p. AB - Organelle-localized NHEs (Na+/H+ exchangers) are found in cells from yeast to humans and contribute to organellar pH regulation by exporting H+ from the lumen to the cytosol coupled to an H+ gradient established by vacuolar H+-ATPase. The mechanisms underlying the regulation of organellar NHEs are largely unknown. In the present study, a yeast two-hybrid assay identified Mth1p as a new binding protein for Nhx1p, an organellar NHE in Saccharomyces cerevisiae. It was shown by an in vitro pull-down assay that Mth1p bound to the hydrophilic C-terminal half of Nhx1p, especially to the central portion of this region. Mth1p is known to bind to the cytoplasmic domain of the glucose sensor Snf3p/Rgt2p and also functions as a negative transcriptional regulator. Mth1p was expressed in cells grown in a medium containing galactose, but was lost (possibly degraded) when cells were grown in medium containing glucose as the sole carbon source. Deletion of the MTH1 gene increased cell growth compared with the wild-type when cells were grown in a medium containing galactose and with hygromycin or at an acidic pH. This resistance to hygromycin or acidic conditions was not observed for cells grown with glucose as the sole carbon source. Gene knockout of NHX1 increased the sensitivity to hygromycin and acidic pH. The increased resistance to hygromycin was reproduced by truncation of the Mth1p-binding region in Nhx1p. These results implicate Mth1p as a novel regulator of Nhx1p that responds to specific extracellular carbon sources. PMID- 20858222 TI - Lack of DNA helicase Pif1 disrupts zinc and iron homoeostasis in yeast. AB - The Saccharomyces cerevisiae gene PIF1 encodes a conserved eukaryotic DNA helicase required for both mitochondrial and nuclear DNA integrity. Our previous work revealed that a pif1Delta strain is tolerant to zinc overload. In the present study we demonstrate that this effect is independent of the Pif1 helicase activity and is only observed when the protein is absent from the mitochondria. pif1Delta cells accumulate abnormal amounts of mitochondrial zinc and iron. Transcriptional profiling reveals that pif1Delta cells under standard growth conditions overexpress aconitase-related genes. When exposed to zinc, pif1Delta cells show lower induction of genes encoding iron (siderophores) transporters and higher expression of genes related to oxidative stress responses than wild-type cells. Coincidently, pif1Delta mutants are less prone to zinc-induced oxidative stress and display a higher reduced/oxidized glutathione ratio. Strikingly, although pif1Delta cells contain normal amounts of the Aco1 (yeast aconitase) protein, they completely lack aconitase activity. Loss of Aco1 activity is also observed when the cell expresses a non-mitochondrially targeted form of Pif1. We postulate that lack of Pif1 forces aconitase to play its DNA protective role as a nucleoid protein and that this triggers a domino effect on iron homoeostasis resulting in increased zinc tolerance. PMID- 20858223 TI - Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity. AB - DENV (dengue virus) induces UPR (unfolded protein response) in the host cell, which strikes a balance between pro-survival and pro-apoptotic signals. We previously showed that Salubrinal, a drug that targets the UPR, inhibits DENV replication. Here, we examine the impact on UPR after direct or ADE (antibody dependent enhanced) infection of cells with DENV clinical isolates. THP-1 cells in the presence of subneutralizing concentration of humanized antibody 4G2 (cross reactive with flavivirus envelope protein) or HEK-293 cells (human embryonic kidney 293 cells) were infected with DENV-1-4 serotypes. UPR gene expression was monitored under these infection conditions using real-time RT-PCR (reverse transcription-PCR) and Western blots to analyse serotype-dependent variations. Subsequently, in a blinded study, strain-specific differences were compared between DENV-2 clinical isolates obtained from a single epidemic. Results showed that THP-1 cells were infected efficiently and equally by DENV-1-4 in the ADE mode. At 48 hpi (h post infection), DENV-1 and -3 showed a higher replication rate and induced higher expression of several UPR genes such as BiP (immunoglobulin heavy-chain-binding protein), GADD34 (growth arrest DNA damage inducible protein 34) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein]. The ADE infection of THP-1 cells with epidemic DENV-2 high-UPR-gene expressing strains appears to correlate with severe disease; however, no such correlation could be made when the same viruses were used to infect HEK-293 cells. Our finding that UPR gene expression in THP-1 cells during ADE infection correlates with dengue disease severity is consistent with a previous study [Morens, Marchette, Chu and Halstead (1991) Am. J. Trop. Med. Hyg. 45, 644-651] that showed that the growth of DENV 2 isolates in human peripheral blood leucocytes correlated with severe and mild dengue diseases. PMID- 20858224 TI - Modulation of TGF-beta/BMP-6 expression and increased levels of circulating smooth muscle progenitor cells in a type I diabetes mouse model. AB - BACKGROUND: Diabetic patients experience exaggerated intimal hyperplasia after endovascular procedures. Recently it has been shown that circulating smooth muscle progenitor cells (SPC) contribute to intimal hyperplasia. We hypothesized that SPC differentiation would be increased in diabetes and focused on modulation of TGF-beta/BMP-6 signaling as potential underlying mechanism. METHODS: We isolated SPC from C57Bl/6 mice with streptozotocin-induced diabetes and controls. SPC differentiation was evaluated by immunofluorescent staining for alphaSMA and collagen Type I. SPC mRNA expression of TGF-beta and BMP-6 was quantified using real-time PCR. Intima formation was assessed in cuffed femoral arteries. Homing of bone marrow derived cells to cuffed arterial segments was evaluated in animals transplanted with bone marrow from GFP-transgenic mice. RESULTS: We observed that SPC differentiation was accelerated and numeric outgrowth increased in diabetic animals (24.6 +/- 8.8 vs 8.3 +/- 1.9 per HPF after 10 days, p < 0.05). Quantitative real-time PCR showed increased expression of TGF-beta and decreased expression of the BMP-6 in diabetic SPC. SPC were MAC-3 positive, indicative of monocytic lineage. Intima formation in cuffed arterial segments was increased in diabetic mice (intima/media ratio 0.68 +/- 0.15 vs 0.29 +/- 0.06, p < 0.05). In GFP-chimeric mice, bone marrow derived cells were observed in the neointima (4.4 +/- 3.3 cells per section) and particularly in the adventitia (43.6 +/- 9.3 cells per section). GFP-positive cells were in part MAC-3 positive, but rarely expressed alpha-SMA. CONCLUSIONS: In conclusion, in a diabetic mouse model, SPC levels are increased and SPC TGF-beta/BMP-6 expression is modulated. Altered TGF beta/BMP-6 expression is known to regulate smooth muscle cell differentiation and may facilitate SPC differentiation. This may contribute to exaggerated intimal hyperplasia in diabetes as bone marrow derived cells home to sites of neointima formation. PMID- 20858225 TI - The spatial context of clinic-reported sexually transmitted infection in Hong Kong. AB - BACKGROUND: The incidence and prevalence of sexually transmitted infection (STI) in China has been on the rise in the past decade. Delineation of epidemiologic pattern is often hampered by its uneven distribution. Spatial distribution is often a neglected aspect of STI research, the description of which may enhance epidemiologic surveillance and inform service development. METHODS: Over a one month-period, all first time attendees of 6 public STI clinics in Hong Kong were interviewed before clinical consultation using a standard questionnaire to assess their demographic, clinical and behavioural characteristics. A GIS (geographic information system)-based approach was adopted with mapping performed. The cases attending the clinics in different locations were profiled. A comparison was made between neighbourhood cases (patients living near a clinic) and distant cases (those farther off), by calculating the odds ratio for demographic, behavioural and geographic characteristics. RESULTS: Of the 1142 STI patients evaluated, the residence locations of 1029 (90.1%) could be geocoded, of which 95.6% were ethnic Chinese and 63.4% male. Geographically only about a quarter lived in the same district as the clinic. STI patients aged 55 or above were more likely to be living in the vicinity of the clinic, located in the same or adjacent tertiary planning unit (a small geographic unit below district level). A majority of patients came from locations a few kilometers from the clinic, the distance of which varies between clinics. Overall, more syphilis cases were reported in patients residing in the same or adjacent tertiary planning unit, while distant cases tended to give a higher risk of inconsistent condom use. There were otherwise no significant clinical and epidemiologic differences between neighbourhood and distant STI cases. CONCLUSIONS: There was no specific relationship between STI and the residence location of patients as regards their clinical and epidemiologic characteristics in the territory of Hong Kong. Older STI patients were however more inclined to attend the nearby STI clinics. Most patients have travelled a variable distance to access the STI service. The relationship between STI clinic cases and distance could be a complex issue intertwined between psychosocial characteristics and STI service coverage. PMID- 20858226 TI - Does tiotropium lower exacerbation and hospitalization frequency in COPD patients: results of a meta-analysis. AB - BACKGROUND: International guidelines recommend long-acting bronchodilators in patients who remain symptomatic despite adequate treatment with short-acting bronchodilators. The purpose of this study is to estimate the effect of tiotropium, a long-acting anticholinergic inhalant, on exacerbation and hospitalisation frequency. METHODS: Electronic databases (Medline, Embase, INAHTA, CRD databases, and the Cochrane Library) were searched for randomised controlled trials, comparing tiotropium to placebo, or other bronchodilators. Outcomes were the exacerbation frequency and hospitalisation frequency. Data were pooled using the generic inverse variance method for continuous outcomes. RESULTS: Nine studies reported comparisons with placebo (n = 8), ipratropium (short-acting anticholinergic inhalant, n = 1), and salmeterol (long-acting beta2 agonist inhalant, n = 1). Only two studies reported adequate concealment of allocation. Tiotropium reduces the number of exacerbations per patient year by 0.31 (95% CI 0.46- 0.17) compared to placebo, and by 0.23 (95% CI 0.31- 0.15) compared to ipratropium. A significant difference in exacerbation frequency between tiotropium and salmeterol was found (-0.16; 95% CI -0.29 - -0.03) based on approximations of the results of one study.The number of hospitalisations is reduced by 0.04 (95% CI 0.08- 0.01) per patient year compared to placebo and by 0.06 (95% CI -0.09 - -0.03) per patient year compared to ipratropium. CONCLUSIONS: Statistically significant but clinically small effects were found for tiotropium compared to placebo and ipratropium. The comparison with salmeterol is significant for exacerbation frequency but not for hospitalisation frequency. Publication bias may be present. PMID- 20858227 TI - Proteomic characterization of vanA-containing Enterococcus recovered from Seagulls at the Berlengas Natural Reserve, W Portugal. AB - BACKGROUND: Enterococci have emerged as the third most common cause of nosocomial infections, requiring bactericidal antimicrobial therapy. Although vancomycin resistance is a major problem in clinics and has emerged in an important extend in farm animals, few studies have examined it in wild animals. To determine the prevalence of vanA-containing Enterococcus strains among faecal samples of Seagulls (Larus cachinnans) of Berlengas Natural Reserve of Portugal, we developed a proteomic approach integrated with genomic data. The purpose was to detect the maximum number of proteins that vary in different enterococci species which are thought to be connected in some, as yet unknown, way to antibiotic resistance. RESULTS: From the 57 seagull samples, 54 faecal samples showed the presence of Enterococcus isolates (94.7%). For the enterococci, E. faecium was the most prevalent species in seagulls (50%), followed by E. faecalis and E. durans (10.4%), and E. hirae (6.3%). VanA-containing enterococcal strains were detected in 10.5% of the 57 seagull faecal samples studied. Four of the vanA containing enterococci were identified as E. faecium and two as E. durans. The tet(M) gene was found in all five tetracycline-resistant vanA strains. The erm(B) gene was demonstrated in all six erythromycin-resistant vanA strains. The hyl virulence gene was detected in all four vanA-containing E. faecium isolates in this study, and two of them harboured the purK1 allele. In addition these strains also showed ampicillin and ciprofoxacin resistance. The whole-cell proteomic profile of vanA-containing Enterococcus strains was applied to evaluate the discriminatory power of this technique for their identification. The major differences among species-specific profiles were found in the positions corresponding to 97-45 kDa. Sixty individualized protein spots for each vanA isolate was identified and suitable for peptide mass fingerprinting measures by spectrometry measuring (MALDI/TOF MS) and their identification through bioinformatic databases query. The proteins were classified in different groups according to their biological function: protein biosynthesis, ATP synthesis, glycolysis, conjugation and antibiotic resistance. Taking into account the origin of these strains and its relation to infectious processes in humans and animals, it is important to explore the proteome of new strains which might serve as protein biomarkers for biological activity. CONCLUSIONS: The comprehensive description of proteins isolated from vancomycin-resistant Enterococcus faecium and E. durans may provide new targets for development of antimicrobial agents. This knowledge may help to identify new biomarkers of antibiotic resistance and virulence factors. PMID- 20858228 TI - The association between blood glucose and oxidized lipoprotein(a) in healthy young women. AB - BACKGROUND: Oxidized lipoproteins play important roles in the atherosclerotic processes. Oxidized lipoprotein(a) (oxLp(a)) may be more potent in atherosclerotic pathophysiology than native Lp(a), a cardiovascular disease relevant lipoprotein. Increased blood glucose concentrations can induce oxidative modification of lipoproteins. The aim of this study was to investigate the association between circulating oxLp(a) and cardiometabolic variables including blood glucose in healthy volunteers within the normal range of blood glucose. METHODS: Several cardiometabolic variables and serum oxLp(a) (using an ELISA system) were measured among 70 healthy females (mean age, 22 years). RESULTS: Lp(a) and glucose were significantly and positively correlated with oxLp(a) in simple correlation test. Furthermore, a multiple linear regression analysis showed oxLp(a) to have a weakly, but significantly positive and independent correlation with only blood glucose (beta = 0.269, P < 0.05). CONCLUSIONS: These results suggest that increased glucose may enhance the oxidization of Lp(a) even at normal glucose levels. PMID- 20858230 TI - Randomised primary health center based interventions to improve the diagnosis and treatment of undifferentiated fever and dengue in Vietnam. AB - BACKGROUND: Fever is a common reason for attending primary health facilities in Vietnam. Response of health care providers to patients with fever commonly consists of making a presumptive diagnosis and proposing corresponding treatment. In Vietnam, where malaria was brought under control, viral infections, notably dengue, are the main causes of undifferentiated fever but they are often misdiagnosed and inappropriately treated with antibiotics.This study investigate if educating primary health center (PHC) staff or introducing rapid diagnostic tests (RDTs) improve diagnostic resolution and accuracy for acute undifferentiated fever (AUF) and reduce prescription of antibiotics and costs for patients. METHODS: In a PHC randomized intervention study in southern Vietnam, the presumptive diagnoses for AUF patients were recorded and confirmed by serology on paired (acute and convalescence) sera. After one year, PHCs were randomized to four intervention arms: training on infectious diseases (A), the provision of RDTs (B), the combination (AB) and control (C). The intervention lasted from 2002 until 2006. RESULTS: The frequency of the non-etiologic diagnosis "undifferentiated fever" decreased in group AB, and - with some delay- also in group B. The diagnosis "dengue" increased in group AB, but only temporarily, although dengue was the most common cause of fever. A correct diagnosis for dengue initially increased in groups AB and B but only for AB this was sustained. Antibiotics prescriptions increased in group C. During intervention it initially declined in AB with a tendency to increase afterwards; in B it gradually declined. There was a substantial increase of patients' costs in B. CONCLUSIONS: The introduction of RDTs for infectious diseases such as dengue, through free market principles, does improve the quality of the diagnosis and decreases the prescription of antibiotics at the PHC level. However, the effect is more sustainable in combination with training; without it RDTs lead to an excess of costs. PMID- 20858229 TI - Fragile X and autism: Intertwined at the molecular level leading to targeted treatments. AB - Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and gamma aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism. PMID- 20858231 TI - Protective effect of aqueous extract from Spirulina platensis against cell death induced by free radicals. AB - BACKGROUND: Spirulina is a commercial alga well known to contain various antioxidants, especially phycocyanin. Apart from being sold as a nutraceutical, Spirulina is incorporated as a functional ingredient in food products and beverages. Most of the previous reports on antioxidant activity of Spirulina were based on chemical rather than cell-based assays. The primary objective of this study was to assess the antioxidant activity of aqueous extract from Spirulina based on its protective effect against cell death induced by free radicals. METHODS: The antioxidant activity of the cold water extract from food-grade Spirulina platensis was assessed using both chemical and cell-based assays. In the cell-based assay, mouse fibroblast cells (3T3) cells were incubated for 1 h in medium containing aqueous extract of Spirulina or vitamin C (positive control) at 25, 125 and 250 MUg/mL before the addition of 50 MUM 1,1-diphenyl-2 picrylhydrazyl (DPPH) or 3-ethylbenzothiazoline-6-sulfonic acid (ABTS). The cells were incubated for another 24 h before being assessed for cell death due to apoptosis using the Cell Death Detection ELISA Kit. Spectrophotometric assays based on DPPH and ABTS were also used to assess the antioxidant activity of the extract compared to vitamin C and vitamin E (positive controls). RESULTS: Spirulina extract did not cause cytotoxic effect on 3T3 cells within the range of concentrations tested (0 - 250 MUg/mL). The extract reduced significantly (p < 0.05) apoptotic cell death due to DPPH and ABTS by 4 to 5-fold although the activity was less than vitamin C. Based on the DPPH assay, the radical scavenging activity of the extract was higher than phycocyanin and was at least 50% of vitamin C and vitamin E. Based on the ABTS assay, the antioxidant activity of the extract at 50 MUmug/mL was as good as vitamin C and vitamin E. CONCLUSIONS: The results showed that aqueous extract of Spirulina has a protective effect against apoptotic cell death due to free radicals. The potential application of incorporating Spirulina into food products and beverages to enhance their antioxidant capacity is worth exploring. PMID- 20858232 TI - A statistical approach for detecting genomic aberrations in heterogeneous tumor samples from single nucleotide polymorphism genotyping data. AB - We describe a statistical method for the characterization of genomic aberrations in single nucleotide polymorphism microarray data acquired from cancer genomes. Our approach allows us to model the joint effect of polyploidy, normal DNA contamination and intra-tumour heterogeneity within a single unified Bayesian framework. We demonstrate the efficacy of our method on numerous datasets including laboratory generated mixtures of normal-cancer cell lines and real primary tumours. PMID- 20858233 TI - Development of infectious cDNA clones of Salmonid alphavirus subtype 3. AB - BACKGROUND: Salmonid alphavirus (SAV) is a widespread pathogen in European aquaculture of salmonid fish. Distinct viral subtypes have been suggested based on sequence comparisons and some of these have different geographical distributions. In Norway, only SAV subtype 3 have so far been identified. Little is known about viral mechanisms important for pathogenesis and transmission. Tools for detailed exploration of SAV genomes are therefore needed. RESULTS: Infectious cDNA clones in which a genome of subtype 3 SAV is under the control of a CMV promoter were constructed. The clones were designed to express proteins that are putatively identical to those previously reported for the SAVH20/03 strain. A polyclonal antiserum was raised against a part of the E2 glycoprotein in order to detect expression of the subgenomic open reading frame (ORF) encoding structural viral proteins. Transfection of the cDNA clone revealed the expression of the E2 protein by IFAT, and in serial passages of the supernatant the presence of infectious recombinant virus was confirmed through RT-PCR, IFAT and the development of a cytopathic effect similar to that seen during infection with wild type SAV. Confirmation that the recovered virus originated from the infectious plasmid was done by sequence identification of an introduced genetic tag. The recombinant virus was infectious also when an additional ORF encoding an EGFP reporter gene under the control of a second subgenomic alphavirus promoter was added. Finally, we used the system to study the effect of selected point mutations on infectivity in Chinook salmon embryo cells. While introduced mutations in nsP2197, nsP3263 and nsP3323 severely reduced infectivity, a serine to proline mutation in E2206 appeared to enhance the virus titer production. CONCLUSION: We have constructed infectious clones for SAV based on a subtype 3 genome. The clones may serve as a platform for further functional studies. PMID- 20858234 TI - The need for nursing instruction in patients receiving steroid pulse therapy for the treatment of autoimmune diseases and the effect of instruction on patient knowledge. AB - BACKGROUND: Many patients who receive steroid pulse therapy go home the same day or the day after steroid administration. Nursing instructions are important for improving patient knowledge related to their diseases and treatments, but the short hospital stay often prevents complete education and guidance regarding the given therapy. The purpose of this study was to investigate the need for nursing instruction in patients receiving steroid pulse therapy for the treatment of autoimmune diseases and the effect of instruction on patient knowledge of their disease and treatment. METHODS: Patients with systemic lupus erythematosus (SLE) and systemic sclerosis receiving steroid pulse therapy (N = 63) were recruited from a medical center in Taipei. A structured questionnaire was used for data collection before and after nursing instruction, and 1 week as well as 2 weeks after therapy. The need for nursing instruction and knowledge levels were validated using Cronbach's alpha reliability test. RESULTS: There was a significant difference (P < 0.001) in the need for nursing instruction among the 4 time points. There was a positive correlation between the need for nursing instruction and body weight change, frequency of treatment, and distress, but there was a negative correlation with knowledge level (beta = -0.012, P = 0.003) regarding symptoms. The knowledge level of subjects after nursing instruction was significantly higher than before nursing instruction (80 +/- 14.31 vs. 70.06 +/- 17.23, P < 0.001). CONCLUSIONS: This study indicates that nursing instruction is needed by patients receiving steroid pulse therapy, and that by designing and administering nursing instructions according to the priority of patient symptoms, nurses can improve patient knowledge related to their diseases and treatments. In addition, the need for nursing instruction can be affected by patient characteristics. PMID- 20858235 TI - Coinfection with EBV/CMV and other respiratory agents in children with suspected infectious mononucleosis. AB - BACKGROUND: Numerous studies have shown that Epstein-Barr virus (EBV) and cytomegalovirus (CMV) can infect immunocompetent patients simultaneously with other agents. Nonetheless, multiple infections with other agents in EBV/CMV infected children have received little attention. We conducted a retrospective study of children with suspected infectious mononucleosis. Peripheral blood samples were analyzed by indirect immunofluorescence to detect EBV, CMV and other respiratory agents including respiratory syncytial virus; adenovirus; influenza virus types A and B; parainfluenza virus types 1, 2 and 3; Chlamydia pneumoniae and Mycoplasma pneumoniae. A medical history was collected for each child. RESULTS: The occurrence of multipathogen infections was 68.9%, 81.3% and 63.6% in the children with primary EBV, CMV or EBV/CMV, respectively, which was significantly higher than that in the past-infected group or the uninfected group (p < 0.001). Of the multipathogen-infected patients, the incidence of C. pneumoniae in children with primary infection was as high as 50%, significantly higher than in the other groups (p < 0.001). In the patients with multipathogen infection and EBV/CMV primary infection, fever, rash, lymphadenopathy, hepatomegaly, splenomegaly, atypical lymphocytes and abnormal liver function were more frequent and the length of hospital stay and duration of fever were longer than in other patients. CONCLUSION: Our study suggests that there is a high incidence of multipathogen infections in children admitted with EBV/CMV primary infection and that the distribution of these pathogens is not random. PMID- 20858236 TI - Establishing a follow-up of the Swiss MONICA participants (1984-1993): record linkage with census and mortality data. AB - BACKGROUND: To assess the feasibility and quality of an anonymous linkage of 1) MONICA (MONItoring of trends and determinants in CArdiovscular disease, three waves between 1984 and 1993) data with 2) census and mortality records of the Swiss National Cohort in order to establish a mortality follow-up until 2008. Many countries feature the defect of lacking general population cohorts because they have missed to provide for follow-up information of health surveys. METHODS: Record linkage procedures were used in a multi-step approach. Kaplan-Meier curves from our data were contrasted with the survival probabilities expected from life tables for the general population, age-standardized mortality rates from our data with those derived from official cross-sectional mortality data. Cox regression models were fit to investigate the influence of covariates on survival. RESULTS: 97.8% of the eligible 10,160 participants (25-74y at baseline) could be linked to a census (1990: 9,737; 2000: 8,749), mortality (1,526, 1984-2008) and/or emigration record (320, 1990-2008). Linkage success did not differ by any key study characteristic. Results of survival analyses were robust to linkage step or certainty of a correct link. Loss to follow-up between 1990 and 2000 amounted to 4.7%. MONICA participants had lower mortality than the general population, but similar mortality patterns, (e.g. variation by educational level, marital status or region). CONCLUSIONS: Using anonymized census and death records allowed an almost complete mortality follow-up of MONICA study participants of up to 25 years. Lower mortality compared to the general population was in line with a presumable 'healthy participant' selection in the original MONICA study. Apart from that, the derived data set reproduced known mortality patterns and showed only negligible potential for selection bias introduced by the linkage process. Anonymous record linkage was feasible and provided robust results. It can thus provide valuable information, when no cohort study is available. PMID- 20858237 TI - MIQE precis: Practical implementation of minimum standard guidelines for fluorescence-based quantitative real-time PCR experiments. AB - The conclusions of thousands of peer-reviewed publications rely on data obtained using fluorescence-based quantitative real-time PCR technology. However, the inadequate reporting of experimental detail, combined with the frequent use of flawed protocols is leading to the publication of papers that may not be technically appropriate. We take the view that this problem requires the delineation of a more transparent and comprehensive reporting policy from scientific journals. This editorial aims to provide practical guidance for the incorporation of absolute minimum standards encompassing the key assay parameters for accurate design, documentation and reporting of qPCR experiments (MIQE precis) and guidance on the publication of pure 'reference gene' articles. PMID- 20858238 TI - Genome-wide analysis of mRNA decay patterns during early Drosophila development. AB - BACKGROUND: The modulation of mRNA levels across tissues and time is key for the establishment and operation of the developmental programs that transform the fertilized egg into a fully formed embryo. Although the developmental mechanisms leading to differential mRNA synthesis are heavily investigated, comparatively little attention is given to the processes of mRNA degradation and how these relate to the molecular programs controlling development. RESULTS: Here we combine timed collection of Drosophila embryos and unfertilized eggs with genome wide microarray technology to determine the degradation patterns of all mRNAs present during early fruit fly development. Our work studies the kinetics of mRNA decay, the contributions of maternally and zygotically encoded factors to mRNA degradation, and the ways in which mRNA decay profiles relate to gene function, mRNA localization patterns, translation rates and protein turnover. We also detect cis-regulatory sequences enriched in transcripts with common degradation patterns and propose several proteins and microRNAs as developmental regulators of mRNA decay during early fruit fly development. Finally, we experimentally validate the effects of a subset of cis-regulatory sequences and trans-regulators in vivo. CONCLUSIONS: Our work advances the current understanding of the processes controlling mRNA degradation during early Drosophila development, taking us one step closer to the understanding of mRNA decay processes in all animals. Our data also provide a valuable resource for further experimental and computational studies investigating the process of mRNA decay. PMID- 20858241 TI - IHE cross-enterprise document sharing for imaging: interoperability testing software. AB - BACKGROUND: With the deployments of Electronic Health Records (EHR), interoperability testing in healthcare is becoming crucial. EHR enables access to prior diagnostic information in order to assist in health decisions. It is a virtual system that results from the cooperation of several heterogeneous distributed systems. Interoperability between peers is therefore essential. Achieving interoperability requires various types of testing. Implementations need to be tested using software that simulates communication partners, and that provides test data and test plans. RESULTS: In this paper we describe a software that is used to test systems that are involved in sharing medical images within the EHR. Our software is used as part of the Integrating the Healthcare Enterprise (IHE) testing process to test the Cross Enterprise Document Sharing for imaging (XDS-I) integration profile. We describe its architecture and functionalities; we also expose the challenges encountered and discuss the elected design solutions. CONCLUSIONS: EHR is being deployed in several countries. The EHR infrastructure will be continuously evolving to embrace advances in the information technology domain. Our software is built on a web framework to allow for an easy evolution with web technology. The testing software is publicly available; it can be used by system implementers to test their implementations. It can also be used by site integrators to verify and test the interoperability of systems, or by developers to understand specifications ambiguities, or to resolve implementations difficulties. PMID- 20858240 TI - Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers. AB - BACKGROUND: Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1-/- mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. RESULTS: In wildtype mice we found that polymodal C-fibers (CPMs) lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs) were not sensitized following inflammation. However, results suggested that some of these fibers may have gained mechanical sensitivity and that some previous silent fibers gained heat sensitivity. In mice lacking TRPV1, inflammation only decreased heat threshold of CPMs but did not sensitize their responses to the heat ramp. No CH fibers could be identified in naive nor inflamed TRPV1-/- mice. CONCLUSIONS: Results obtained here suggest that increased heat sensitivity in TRPV1-negative CPM fibers alone following inflammation is insufficient for the induction of heat hyperalgesia. On the other hand, TRPV1-positive CH fibers appear to play an essential role in this process that may include both afferent and efferent functions. PMID- 20858242 TI - Development of a primary care-based complex care management intervention for chronically ill patients at high risk for hospitalization: a study protocol. AB - BACKGROUND: Complex care management is seen as an approach to face the challenges of an ageing society with increasing numbers of patients with complex care needs. The Medical Research Council in the United Kingdom has proposed a framework for the development and evaluation of complex interventions that will be used to develop and evaluate a primary care-based complex care management program for chronically ill patients at high risk for future hospitalization in Germany. METHODS AND DESIGN: We present a multi-method procedure to develop a complex care management program to implement interventions aimed at reducing potentially avoidable hospitalizations for primary care patients with type 2 diabetes mellitus, chronic obstructive pulmonary disease, or chronic heart failure and a high likelihood of hospitalization. The procedure will start with reflection about underlying precipitating factors of hospitalizations and how they may be targeted by the planned intervention (pre-clinical phase). An intervention model will then be developed (phase I) based on theory, literature, and exploratory studies (phase II). Exploratory studies are planned that entail the recruitment of 200 patients from 10 general practices. Eligible patients will be identified using two ways of 'case finding': software based predictive modelling and physicians' proposal of patients based on clinical experience. The resulting subpopulations will be compared regarding healthcare utilization, care needs and resources using insurance claims data, a patient survey, and chart review. Qualitative studies with healthcare professionals and patients will be undertaken to identify potential barriers and enablers for optimal performance of the complex care management program. DISCUSSION: This multi-method procedure will support the development of a primary care-based care management program enabling the implementation of interventions that will potentially reduce avoidable hospitalizations. PMID- 20858243 TI - Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia. AB - BACKGROUND: Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis. METHODS: As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations. RESULTS: Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 * 10(-3)). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019). CONCLUSIONS: Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation. PMID- 20858244 TI - Is the association between optimistic cardiovascular risk perceptions and lower rates of cardiovascular disease mortality explained by biomarkers of systemic inflammation or endothelial function? A case-cohort study. AB - BACKGROUND: More optimistic perceptions of cardiovascular disease risk are associated with substantively lower rates of cardiovascular death among men. It remains unknown whether this association represents causality (i.e. perception leads to actions/conditions that influence cardiovascular disease occurrence) or residual confounding by unmeasured factors that associate with risk perceptions and with physiological processes that promote cardiovascular disease (i.e. inflammation or endothelial dysfunction). PURPOSE: To evaluate whether previously unmeasured biological markers of inflammation or endothelial dysregulation confound the observed association between cardiovascular disease risk perceptions and cardiovascular disease outcomes; METHODS: We conducted a nested case-cohort study among community-dwelling men from Southeastern New England (USA) who were interviewed between 1989 and 1990 as part of the Pawtucket Heart Health Program. We measured C-reactive protein (CRP) and Vascular Endothelial Growth Factor (VEGF) levels from stored sera for a random sample of the parent cohort (control sample, n = 127) and all cases of cardiovascular death observed through 2005 (case sample, n = 44). We evaluated potential confounding using stratified analyses and logistic regression modeling. RESULTS: Optimistic ratings of risk associated with lower odds of dying from cardiovascular causes among men (OR = 0.39, 95% CI = 0.17, 0.91). Neither CRP nor VEGF confounded these findings. CONCLUSIONS: The strong cardio-protective association between optimistic ratings of cardiovascular disease risk and lower rates of cardiovascular mortality among men is not confounded by baseline biomarkers of systemic inflammation or endothelial dysfunction. PMID- 20858239 TI - Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. AB - INTRODUCTION: Pulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care. METHODS: A systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method. RESULTS: Clinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy. CONCLUSIONS: This systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed. PMID- 20858245 TI - Hospital admissions for asthma, diabetes and COPD: is there an association with practice nurse staffing? A cross sectional study using routinely collected data. AB - BACKGROUND: Delivering good quality primary care for patients with chronic conditions has the potential to reduce non-elective hospital admissions. Practice nurse staffing levels in England have been linked to attainment of general practice performance targets for some chronic conditions. The aim of this study was to examine whether practice nurse staffing level is similarly associated with non-elective hospital admissions in three clinical areas: asthma, Chronic Obstructive Pulmonary Disease (COPD) and diabetes. METHODS: This observational study used cross sectional analysis of routinely collected data. Hospital admissions data for the period 2005-2006 (for asthma, COPD and diabetes) were linked with a database of practice characteristics, nurse staffing data and data on population characteristics for the same period. Statistical modelling explored the relationship between non-elective hospital admission rates for the three conditions and the list size per full time equivalent (FTE) practice nurse. RESULTS: Higher practice nurse staffing levels were significantly associated with lower rates of admission for asthma (p < 0.001) and COPD (p < 0.001). A similar association was seen for patients with two or more admissions (p < 0.05 for asthma and p < 0.001 for COPD). For diabetes, higher practice nurse staffing level was significantly associated with higher admission rates (p < 0.05), but this association was not significant in case of patients with two or more admissions. Across all models, increasing deprivation was associated with higher admission rates for all conditions. CONCLUSIONS: The inconsistent relationship between nurse staffing and patient outcomes across the different conditions and the fact that for diabetes the relationship between staffing and outcomes was in a different direction from the association between staffing and care quality, highlights the need to avoid making a simple causal interpretation of these findings and reduces the possible confidence in such conclusions. There is a need for more research into the organisation and delivery of diabetes care services in general practice, preferably using patient level data; in order to better understand the impact of the different staffing configurations on patient outcomes. PMID- 20858246 TI - Selective gene silencing by viral delivery of short hairpin RNA. AB - RNA interference (RNAi) technology has not only become a powerful tool for functional genomics, but also allows rapid drug target discovery and in vitro validation of these targets in cell culture. Furthermore, RNAi represents a promising novel therapeutic option for treating human diseases, in particular cancer. Selective gene silencing by RNAi can be achieved essentially by two nucleic acid based methods: i) cytoplasmic delivery of short double-stranded (ds) interfering RNA oligonucleotides (siRNA), where the gene silencing effect is only transient in nature, and possibly not suitable for all applications; or ii) nuclear delivery of gene expression cassettes that express short hairpin RNA (shRNA), which are processed like endogenous interfering RNA and lead to stable gene down-regulation. Both processes involve the use of nucleic acid based drugs, which are highly charged and do not cross cell membranes by free diffusion. Therefore, in vivo delivery of RNAi therapeutics must use technology that enables the RNAi therapeutic to traverse biological membrane barriers in vivo. Viruses and the vectors derived from them carry out precisely this task and have become a major delivery system for shRNA. Here, we summarize and compare different currently used viral delivery systems, give examples of in vivo applications, and indicate trends for new developments, such as replicating viruses for shRNA delivery to cancer cells. PMID- 20858248 TI - Health care providers underestimate symptom intensities of cancer patients: a multicenter European study. AB - BACKGROUND: Many patients with advanced cancer depend upon health care providers for symptom assessment. The extent of agreement between patient and provider symptom assessments and the association of agreement with demographic- and disease-related factors was examined. METHODS: This cross-sectional study included 1933 patient-health care provider dyads, from 11 European countries. Patients reported symptoms by using the four-point scales of the European Organization of Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) version 3, and providers used corresponding four point categorical scales. Level of agreement was addressed at the group level (Wilcoxon Signed-Rank test), by difference scores (provider score minus patient score), at the individual level (Intraclass Correlation Coefficients, ICCs) and visually by Bland-Altman plots. Absolute numbers and chi-square tests were used to investigate the relationship between agreement and demographic-, as well as disease-related factors. RESULTS: The prevalence of symptoms assessed as moderate or severe by patients and providers, respectively, were for pain (67 vs.47%), fatigue (71 vs. 54%), generalized weakness (65 vs. 47%), anorexia (47 vs. 25%), depression (31 vs. 17%), constipation (45 vs. 30%), poor sleep (32 vs. 21%), dyspnea (30 vs. 16%), nausea (27 vs. 14%), vomiting (14 vs. 6%) and diarrhea (14 vs. 6%). Symptom scores were identical or differed by only one response category in the majority of patient-provider assessment pairs (79-93%). Providers underestimated the symptom in approximately one of ten patients and overestimated in 1% of patients. Agreement at the individual level was moderate (ICC 0.38 to 0.59). Patients with low Karnofsky Performance Status, high Mini Mental State score, hospitalized, recently diagnosed or undergoing opioid titration were at increased risk of symptom underestimation by providers (all p < 0.001). Also, the agreement was significantly associated with drug abuse (p = 0.024), provider profession (p < 0.001), cancer diagnosis (p < 0.001) and country (p < 0.001). CONCLUSIONS: Considerable numbers of health care providers underestimated symptom intensities. Clinicians in cancer care should be aware of the factors characterizing patients at risk of symptom underestimation. PMID- 20858247 TI - Effective population management practices in diabetes care - an observational study. AB - BACKGROUND: Ensuring that evidence based medicine reaches patients with diabetes in the US and internationally is challenging. The chronic care model includes evidence based management practices which support evidence based care. However, despite numerous studies, it is unclear which practices are most effective. Few studies assess the effect of simultaneous practices implemented to varying degrees. The present study evaluates the effect of fifteen practices applied concurrently and takes variation in implementation levels into account while assessing the impact of diabetes care management practices on glycemic and lipid monitoring. METHODS: Fifteen management practices were identified. Implementation levels of the practices in 41 medical centres caring for 553,556 adults with diabetes were assessed from structured interviews with key informants. Stepwise logistic regression models with management practices as explanatory variables and glycemic and lipid monitoring as outcome variables were used to identify the diabetes care practices most associated with high performance. RESULTS: Of the 15 practices studied, only provider alerts were significantly associated with higher glycemic and lipid monitoring rates. The odds ratio for glycemic monitoring was 4.07 (p < 0.00001); the odds ratio for lipid monitoring was 1.63 (p < 0.006). Weaker associations were found between action plans and glycemic monitoring (odds ratio = 1.44; p < 0.03) and between guideline distribution and training and lipid monitoring (odds ratio = 1.46; p < 0.03). The covariates of gender, age, cardiac disease and depression significantly affected monitoring rates. CONCLUSIONS: Of fifteen diabetes care management practices, our data indicate that high performance is most associated with provider alerts and more weakly associated with action plans and with guideline distribution and training. Lack of convergence in the literature on effective care management practices suggests that factors contributing to high performance may be highly context-dependent or that the factors involved may be too numerous or their implementation too nuanced to be reliably identified in observational studies. PMID- 20858249 TI - Evolution of mantis shrimps (Stomatopoda, Malacostraca) in the light of new Mesozoic fossils. AB - BACKGROUND: We describe new specimens of Mesozoic mantis shrimps (Stomatopoda, Malacostraca) that exhibit morphological and developmental information previously unknown. RESULTS: Specimens assigned to the taxon Sculda exhibit preserved pleopods, thoracopods including all four raptorial limbs as well as details of antennae and antennulae. The pleopods and the antennulae resemble those of the modern mantis shrimps, but the raptorial limbs are not as differentiated as in the modern species. In some specimens, the first raptorial limb (second thoracopod) is not significantly larger than the similar-sized posterior three pairs (as in extant species), but instead these appendages become progressively smaller along the series. In this respect they resemble certain Palaeozoic stomatopods. Another specimen, most likely belonging to another species, has one pair of large anterior raptorial thoracopods, a median-sized pair and two more pairs of small-sized raptorial appendages and, thus, shows a new, previously unknown type of morphology. A single specimen of Pseudosculda laevis also exhibits the size of the raptorial limbs; they are differentiated as in modern species, one large pair and three small pairs. Furthermore, we report additional larval specimens and show also post-larval changes, e.g., of the tail fan. CONCLUSIONS: These new data are used to reconsider the phylogeny of Stomatopoda. We still need a strict taxonomical revision of the Mesozoic mantis shrimps, but this first examination already demonstrates the importance of these fossils for understanding mantis shrimp evolution and the interpretation of evolutionary pathways of particular features. PMID- 20858251 TI - Fed-batch process for the psychrotolerant marine bacterium Pseudoalteromonas haloplanktis. AB - BACKGROUND: Pseudoalteromonas haloplanktis is a cold-adapted gamma proteobacterium isolated from Antarctic sea ice. It is characterized by remarkably high growth rates at low temperatures. P. haloplanktis is one of the model organisms of cold-adapted bacteria and has been suggested as an alternative host for the soluble overproduction of heterologous proteins which tend to form inclusion bodies in established expression hosts. Despite the progress in establishing P. haloplanktis as an alternative expression host the cell densities obtained with this organism, which is unable to use glucose as a carbon source, are still low. Here we present the first fed-batch cultivation strategy for this auspicious alternative expression host. RESULTS: The key for the fed-batch cultivation of P. haloplanktis was the replacement of peptone by casamino acids, which have a much higher solubility and allow a better growth control. In contrast to the peptone medium, on which P. haloplanktis showed different growth phases, on a casamino acids-containing, phosphate-buffered medium P. haloplanktis grew exponentially with a constant growth rate until the stationary phase. A fed batch process was established by feeding of casamino acids with a constant rate resulting in a cell dry weight of about 11 g l-1 (OD540 = 28) which is a twofold increase of the highest densities which have been obtained with P. haloplanktis so far and an eightfold increase of the density obtained in standard shake flask cultures. The cell density was limited in the fed-batch cultivation by the relatively low solubility of casamino acids (about 100 g l-1), which was proven by pulse addition of casamino acid powder which increased the cell density to about 20 g l-1 (OD540 = 55). CONCLUSION: The growth of P. haloplanktis to higher cell densities on complex medium is possible. A first fed-batch fermentation strategy could be established which is feasible to be used in lab-scale or for industrial purposes. The substrate concentration of the feeding solution was found to influence the maximal biomass yield considerably. The bottleneck for growing P. haloplanktis to high cell densities still remains the availability of a highly concentrated substrate and the reduction of the substrate complexity. However, our results indicate glutamic acid as a major carbon source, which provides a good basis for further improvement of the fed-batch process. PMID- 20858250 TI - Ovalbumin sensitization and challenge increases the number of lung cells possessing a mesenchymal stromal cell phenotype. AB - BACKGROUND: Recent studies have indicated the presence of multipotent mesenchymal stromal cells (MSCs) in human lung diseases. Excess airway smooth muscle, myofibroblasts and activated fibroblasts have each been noted in asthma, suggesting that mesenchymal progenitor cells play a role in asthma pathogenesis. We therefore sought to determine whether MSCs are present in the lungs of ovalbumin (OVA)-sensitized and challenged mice, a model of allergic airways disease. METHODS: Balb/c mice were sensitized and challenged with PBS or OVA over a 25 day period. Flow cytometry as well as colony forming and differentiation potential were used to analyze the emergence of MSCs along with gene expression studies using immunochemical analyses, quantitative polymerase chain reaction (qPCR), and gene expression beadchips. RESULTS: A CD45-negative subset of cells expressed Stro-1, Sca-1, CD73 and CD105. Selection for these markers and negative selection against CD45 yielded a population of cells capable of adipogenic, osteogenic and chondrogenic differentiation. Lungs from OVA-treated mice demonstrated a greater average colony forming unit-fibroblast (CFU-F) than control mice. Sorted cells differed from unsorted lung adherent cells, exhibiting a pattern of gene expression nearly identical to bone marrow-derived sorted cells. Finally, cells isolated from the bronchoalveolar lavage of a human asthma patient showed identical patterns of cell surface markers and differentiation potential. CONCLUSIONS: In summary, allergen sensitization and challenge is accompanied by an increase of MSCs resident in the lungs that may regulate inflammatory and fibrotic responses. PMID- 20858252 TI - Motif prediction to distinguish LPS-stimulated pro-inflammatory vs. antibacterial macrophage genes. AB - BACKGROUND: Innate immunity is the first line of defence offered by host cells to infections. Macrophage cells involved in innate immunity are stimulated by lipopolysaccharide (LPS), found on bacterial cell surface, to express a complex array of gene products. Persistent LPS stimulation makes a macrophage tolerant to LPS with down regulation of inflammatory genes ("pro-inflammatory") while continually expressing genes to fight the bacterial infection ("antibacterial"). Interactions of transcription factors (TF) at their cognate TF binding sites (TFBS) on the expressed genes are important in transcriptional regulatory networks that control these pro-inflammatory and antibacterial expression paradigms involved in LPS stimulation. RESULTS: We used differential expression patterns in a public domain microarray data set from LPS-stimulated macrophages to identify 228 pro-inflammatory and 18 antibacterial genes. Employing three different motif search tools, we predicted respectively four and one statistically significant TF-TFBS interactions from the pro-inflammatory and antibacterial gene sets. The biological literature was utilized to identify target genes for the four pro-inflammatory profile TFs predicted from the three tools, and 18 of these target genes were observed to follow the pro-inflammatory expression pattern in the original microarray data. CONCLUSIONS: Our analysis distinguished pro-inflammatory vs. antibacterial transcriptomic signatures that classified their respective gene expression patterns and the corresponding TF TFBS interactions in LPS-stimulated macrophages. By doing so, this study has attempted to characterize the temporal differences in gene expression associated with LPS tolerance, a major immune phenomenon implicated in various pathological disorders. PMID- 20858253 TI - Direct microscopy versus sputum cytology analysis and bleach sedimentation for diagnosis of tuberculosis: a prospective diagnostic study. AB - BACKGROUND: Diagnostic options for pulmonary tuberculosis in resource-poor settings are commonly limited to smear microscopy. We investigated whether bleach concentration by sedimentation and sputum cytology analysis (SCA) increased the positivity rate of smear microscopy for smear-positive tuberculosis. METHODS: We did a prospective diagnostic study in a Medecins Sans Frontieres-supported hospital in Mindouli, Republic of Congo. Three sputum samples were obtained from 280 consecutive pulmonary tuberculosis suspects, and were processed according to WHO guidelines for direct smear microscopy. The remainder of each sputum sample was homogenised with 2.6% bleach, sedimented overnight, smeared, and examined blinded to the direct smear result for acid-fast bacilli (AFB). All direct smears were assessed for quality by SCA. If a patient produced fewer than three good quality sputum samples, further samples were requested. Sediment smear examination was performed independently of SCA result on the corresponding direct smear. Positivity rates were compared using McNemar's test. RESULTS: Excluding SCA, 43.2% of all patients were diagnosed as positive on direct microscopy of up to three samples. 47.9% were diagnosed on sediment microscopy, with 48.2% being diagnosed on direct microscopy, sediment microscopy, or both. The positivity rate increased from 43.2% to 47.9% with a case definition of one positive smear (>=1 AFB/100 high power fields) of three, and from 42.1% to 43.9% with two positive smears. SCA resulted in 87.9% of patients producing at least two good-quality sputum samples, with 75.7% producing three or more. Using a case definition of one positive smear, the incremental yield of bleach sedimentation was 14/121, or 11.6% (95% CI 6.5-18.6, p = 0.001) and in combination with SCA was 15/121, or 12.4% (95% CI 7.1-19.6, p = 0.002). Incremental yields with two positive smears were 5/118, or 4.2% (95% CI 1.4-9.6, p = 0.062) and 7/118, or 5.9% (95% CI 2.4 11.8, p = 0.016), respectively. CONCLUSIONS: The combination of bleach sedimentation and SCA resulted in significantly increased microscopy positivity rates with a case definition of either one or two positive smears. Implementation of bleach sedimentation led to a significant increase in the diagnosis of smear positive patients. Implementation of SCA did not result in significantly increased diagnosis of tuberculosis, but did result in improved sample quality. Requesting extra sputum samples based on SCA results, combined with bleach sedimentation, could significantly increase the detection of smear-positive patients if routinely implemented in resource-limited settings where gold standard techniques are not available. We recommend that a pilot phase is undertaken before routine implementation to determine the impact in a particular context. PMID- 20858254 TI - A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice. AB - BACKGROUND: In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F2 population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals. RESULTS: This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations. CONCLUSIONS: It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed. PMID- 20858255 TI - Educational climate seems unrelated to leadership skills of clinical consultants responsible of postgraduate medical education in clinical departments. AB - BACKGROUND: The educational climate is crucial in postgraduate medical education. Although leaders are in the position to influence the educational climate, the relationship between leadership skills and educational climate is unknown. This study investigates the relationship between the educational climate in clinical departments and the leadership skills of clinical consultants responsible for education. METHODS: The study was a trans-sectional correlation study. The educational climate was investigated by a survey among all doctors (specialists and trainees) in the departments. Leadership skills of the consultants responsible for education were measured by multi-source feedback scores from heads of departments, peer consultants, and trainees. RESULTS: Doctors from 42 clinical departments representing 21 specialties participated. The response rate of the educational climate investigation was moderate 52% (420/811), Response rate was high in the multisource-feedback process 84.3% (420/498). The educational climate was scored quite high mean 3.9 (SD 0.3) on a five-point Likert scale. Likewise the leadership skills of the clinical consultants responsible for education were considered good, mean 5.4 (SD 0.6) on a seven point Likert scale. There was no significant correlation between the scores concerning the educational climate and the scores on leadership skills, r = 0.17 (p = 0.29). CONCLUSIONS: This study found no relation between the educational climate and the leadership skills of the clinical consultants responsible for postgraduate medical education in clinical departments with the instruments used. Our results indicate that consultants responsible for education are in a weak position to influence the educational climate in the clinical department. Further studies are needed to explore, how heads of departments and other factors related to the clinical organisation could influence the educational climate. PMID- 20858256 TI - Improving long-term care provision: towards demand-based care by means of modularity. AB - BACKGROUND: As in most fields of health care, societal and political changes encourage suppliers of long-term care to put their clients at the center of care and service provision and become more responsive towards client needs and requirements. However, the diverse, multiple and dynamic nature of demand for long-term care complicates the movement towards demand-based care provision. This paper aims to advance long-term care practice and, to that end, examines the application of modularity. This concept is recognized in a wide range of product and service settings for its ability to design demand-based products and processes. METHODS: Starting from the basic dimensions of modularity, we use qualitative research to explore the use and application of modularity principles in the current working practices and processes of four organizations in the field of long-term care for the elderly. In-depth semi-structured interviews were conducted with 38 key informants and triangulated with document research and observation. Data was analyzed thematically by means of coding and subsequent exploration of patterns. Data analysis was facilitated by qualitative analysis software. RESULTS: Our data suggest that a modular setup of supply is employed in the arrangement of care and service supply and assists providers of long-term care in providing their clients with choice options and variation. In addition, modularization of the needs assessment and package specification process allows the case organizations to manage client involvement but still provide customized packages of care and services. CONCLUSION: The adequate setup of an organization's supply and its specification phase activities are indispensible for long-term care providers who aim to do better in terms of quality and efficiency. Moreover, long-term care providers could benefit from joint provision of care and services by means of modular working teams. Based upon our findings, we are able to elaborate on how to further enable demand-based provision of long term care by means of modularity. PMID- 20858257 TI - GPFrontend and GPGraphics: graphical analysis tools for genetic association studies. AB - BACKGROUND: Most software packages for whole genome association studies are non graphical, purely text based programs originally designed to run with UNIX-like operating systems. Graphical output is often not intended or supposed to be performed with other command line tools, e.g. gnuplot. RESULTS: Using the Microsoft .NET 2.0 platform and Visual Studio 2005, we have created a graphical software package to analyze data from microarray whole genome association studies, both for a DNA-pooling based approach as well as regular single sample data. Part of this package was made to integrate with GenePool 0.8.2, a previously existing software suite for GNU/Linux systems, which we have modified to run in a Microsoft Windows environment. Further modifications cause it to generate some additional data. This enables GenePool to interact with the .NET parts created by us. The programs we developed are GPFrontend, a graphical user interface and frontend to use GenePool and create metadata files for it, and GPGraphics, a program to further analyze and graphically evaluate output of different WGA analysis programs, among them also GenePool. CONCLUSIONS: Our programs enable regular MS Windows users without much experience in bioinformatics to easily visualize whole genome data from a variety of sources. PMID- 20858258 TI - Persistence of low drug treatment coverage for injection drug users in large US metropolitan areas. AB - OBJECTIVES: Injection drug users (IDUs) are at high risk for HIV, hepatitis, overdose and other harms. Greater drug treatment availability has been shown to reduce these harms among IDUs. Yet, little is known about changes in drug treatment availability for IDUs in the U.S. This paper investigates change in drug treatment coverage for IDUs in 90 metropolitan statistical areas (MSAs) during 1993-2002. METHODS: We define treatment coverage as the percent of IDUs who are in treatment. The number of IDUs in drug treatment is calculated from treatment entry data and treatment census data acquired from the Substance Abuse and Mental Health Service Administration, divided by our estimated number of IDUs in each MSA. RESULTS: Treatment coverage was low in 1993 (mean 6.7%; median 6.0%) and only increased to a mean of 8.3% and median of 8.0% coverage in 2002. CONCLUSIONS: Although some MSAs experienced increases in treatment coverage over time, overall levels of coverage were low. The persistence of low drug treatment coverage for IDUs represents a failure by the U.S. health care system to prevent avoidable harms and unnecessary deaths in this population. Policy makers should expand drug treatment for IDUs to reduce blood-borne infections and community harms associated with untreated injection drug use. PMID- 20858259 TI - Does Chinese culture influence psychosocial factors for heroin use among young adolescents in China? A cross-sectional study. AB - BACKGROUND: Little empirical research has examined how cultural factors influence psychosocial factors for heroin drug use. The objectives of the study were to investigate the levels of individualism and collectivism among young adolescents and how cultural differences were associated with the constructs of the Theory of Planned Behavior and other psychosocial factors for heroin drug use. METHODS: A cross-sectional study was conducted among young adolescents in an HIV and heroin stricken area in China. The Individualism-Collectivism Interpersonal Assessment Inventory (ICIAI) was used to measure cultural norms and values in the context of three social groups: family members, close friends, and classmates. RESULTS: A total of 220 boys and 241 girls were recruited and participated in an interview. Compared to boys, girls reported higher levels of the three specific-relationship ICIAIs, as well as higher levels of perceived behavioral control for heroin use, perceived peer control, and communication with parent about heroin use, but a lower level of favorable attitude towards heroin use. The levels of descriptive and subjective norms of heroin use were low in both girls and boys. Among boys, family ICIAI was positively associated with perceived behavioral control, and friend ICIAI was positively associated with perceived peer control and communication with parent. Among girls, family ICIAI was positively associated with perceived behavioral control and communication with parents about heroin use, but negatively with favorable attitudes to heroin use; friend ICIAI was positively associated with perceived peer control, and classmate ICIAI was negatively associated with favorable attitudes toward heroin use. CONCLUSIONS: This study documents that collectivistic aspects of Chinese culture may influence psychosocial factors for heroin use, although the patterns are varied by gender. Findings provide an empirical basis for the development of culturally competent intervention programs for heroin use intervention and prevention. PMID- 20858261 TI - A de novo marker chromosome derived from 9p in a patient with 9p partial duplication syndrome and autism features: genotype-phenotype correlation. AB - BACKGROUND: Previous studies focusing on candidate genes and chromosomal regions identified several copy number variations (CNVs) associated with increased risk of autism or autism spectrum disorders (ASD). CASE PRESENTATION: We describe a 17 year-old girl with autism, severe mental retardation, epilepsy, and partial 9p duplication syndrome features in whom GTG-banded chromosome analysis revealed a female karyotype with a marker chromosome in 69% of analyzed metaphases. Array CGH analysis showed that the marker chromosome originated from 9p24.3 to 9p13.1 with a gain of 38.9 Mb. This mosaic 9p duplication was detected only in the proband and not in the parents, her four unaffected siblings, or 258 ethnic controls. Apart from the marker chromosome, no other copy number variations (CNVs) were detected in the patient or her family. Detailed analysis of the duplicated region revealed: i) an area extending from 9p22.3 to 9p22.2 that was previously identified as a critical region for the 9p duplication syndrome; ii) a region extending from 9p22.1 to 9p13.1 that was previously reported to be duplicated in a normal individual; and iii) a potential ASD locus extending from 9p24.3 to 9p23. The ASD candidate locus contained 34 genes that may contribute to the autistic features in this patient. CONCLUSION: We identified a potential ASD locus (9p24.3 to 9p23) that may encompass gene(s) contributing to autism or ASD. PMID- 20858260 TI - Roles of Sema4D and Plexin-B1 in tumor progression. AB - Sema4D, also known as CD100, is a protein belonging to class IV semaphorin. Its physiologic roles in the immune and nervous systems have been extensively explored. However, the roles of Sema4D have extended beyond these traditionally studied territories. Via interaction with its high affinity receptor Plexin-B1, Sema4D-Plexin-B1 involvement in tumor progression is strongly implied. Here, we critically review and delineate the Sema4D-Plexin-B1 interaction in many facets of tumor progression: tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth. We correlate the in vitro and in vivo experimental data with the clinical study outcomes, and present a molecular mechanistic basis accounting for the intriguingly contradicting results from these recent studies. PMID- 20858262 TI - Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity. AB - BACKGROUND: Tumour growth and metastatic infiltration are favoured by several components of the tumour microenvironment. Bone marrow-derived multipotent mesenchymal stromal cells (MSC) are known to contribute to the tumour stroma. When isolated from healthy bone marrow, MSC exert potent antiproliferative effects on immune effector cells. Due to phenotypic and morphological similarities of MSC and tumour stromal cells (TStrC), we speculated that immunotherapeutic approaches may be hampered if TStrC may still exhibit immunomodulatory properties of MSC. METHODS: In order to compare immunomodulatory properties of MSC and tumour stromal cells (TStrC), we established and analyzed TStrC cultures from eleven paediatric tumours and MSC preparations from bone marrow aspirates. Immunophenotyping, proliferation assays and NK cell cytotoxicity assays were employed to address the issue. RESULTS: While TStrC differed from MSC in terms of plasticity, they shared surface expression of CD105, CD73 and other markers used for MSC characterization. Furthermore, TStrC displayed a strong antiproliferative effect on peripheral blood mononuclear cells (PBMC) in coculture experiments similar to MSC. NK cell cytotoxicity was significantly impaired after co-culture with TStrC and expression of the activating NK cell receptors NKp44 and NKp46 was reduced. CONCLUSIONS: Our data show that TStrC and MSC share important phenotypic and functional characteristics. The inhibitory effect of TStrC on PBMC and especially on NK cells may facilitate the immune evasion of paediatric tumours. PMID- 20858263 TI - Rationale and design of EXPLORE: a randomized, prospective, multicenter trial investigating the impact of recanalization of a chronic total occlusion on left ventricular function in patients after primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. AB - BACKGROUND: In the setting of primary percutaneous coronary intervention, patients with a chronic total occlusion in a non-infarct related artery were recently identified as a high-risk subgroup. It is unclear whether ST-elevation myocardial infarction patients with a chronic total occlusion in a non-infarct related artery should undergo additional percutaneous coronary intervention of the chronic total occlusion on top of optimal medical therapy shortly after primary percutaneous coronary intervention. Possible beneficial effects include reduction in adverse left ventricular remodeling and preservation of global left ventricular function and improved clinical outcome during future coronary events. METHODS/DESIGN: The Evaluating Xience V and left ventricular function in Percutaneous coronary intervention on occLusiOns afteR ST-Elevation myocardial infarction (EXPLORE) trial is a randomized, prospective, multicenter, two-arm trial with blinded evaluation of endpoints. Three hundred patients after primary percutaneous coronary intervention for ST-elevation myocardial infarction with a chronic total occlusion in a non-infarct related artery are randomized to either elective percutaneous coronary intervention of the chronic total occlusion within seven days or standard medical treatment. When assigned to the invasive arm, an everolimus-eluting coronary stent is used. Primary endpoints are left ventricular ejection fraction and left ventricular end-diastolic volume assessed by cardiac Magnetic Resonance Imaging at four months. Clinical follow-up will continue until five years. DISCUSSION: The ongoing EXPLORE trial is the first randomized clinical trial powered to investigate whether recanalization of a chronic total occlusion in a non-infarct related artery after primary percutaneous coronary intervention for ST-elevation myocardial infarction results in a better preserved residual left ventricular ejection fraction, reduced end-diastolic volume and enhanced clinical outcome. TRIAL REGISTRATION: trialregister.nl NTR1108. PMID- 20858265 TI - Profile and professional expectations of medical students in Mozambique: a longitudinal study. AB - INTRODUCTION: This paper compares the socioeconomic profile of medical students registered at the Faculty of Medicine of Universidade Eduardo Mondlane (FM-UEM), Maputo, for the years 1998/99 and 2007/08. CASE STUDY: The objective is to describe the medical students' social and geographical origins, expectations and perceived difficulties regarding their education and professional future. Data were collected through questionnaires administered to all medical students. DISCUSSION AND EVALUATION: The response rate in 1998/99 was 51% (227/441) and 50% in 2007/08 (484/968).The main results reflect a doubling of the number of students enrolled for medical studies at the FM-UEM, associated with improved student performance (as reflected by failure rates). Nevertheless, satisfaction with the training received remains low and, now as before, students still identify lack of access to books or learning technology and inadequate teacher preparedness as major problems. CONCLUSIONS: There is a high level of commitment to public sector service. However, students, as future doctors, have very high salary expectations that will not be met by current public sector salary scales. This is reflected in an increasing degree of orientation to double sector employment after graduation. PMID- 20858264 TI - A proteomic view of Caenorhabditis elegans caused by short-term hypoxic stress. AB - BACKGROUND: The nematode Caenorhabditis elegans is both sensitive and tolerant to hypoxic stress, particularly when the evolutionarily conserved hypoxia response pathway HIF-1/EGL-9/VHL is involved. Hypoxia-induced changes in the expression of a number of genes have been analyzed using whole genome microarrays in C. elegans, but the changes at the protein level in response to hypoxic stress still remain unclear. RESULTS: Here, we utilized a quantitative proteomic approach to evaluate changes in the expression patterns of proteins during the early response to hypoxia in C. elegans. Two-dimensional difference gel electrophoresis (2D DIGE) was used to compare the proteomic maps of wild type C. elegans strain N2 under a 4-h hypoxia treatment (0.2% oxygen) and under normoxia (control). A subsequent analysis by MALDI-TOF-TOF-MS revealed nineteen protein spots that were differentially expressed. Nine of the protein spots were significantly upregulated, and ten were downregulated upon hypoxic stress. Three of the upregulated proteins were involved in cytoskeletal function (LEV-11, MLC-1, ACT 4), while another three upregulated (ATP-2, ATP-5, VHA-8) were ATP synthases functionally related to energy metabolism. Four ribosomal proteins (RPL-7, RPL-8, RPL-21, RPS-8) were downregulated, indicating a decrease in the level of protein translation upon hypoxic stress. The overexpression of tropomyosin (LEV-11) was further validated by Western blot. In addition, the mutant strain of lev-11(x12) also showed a hypoxia-sensitive phenotype in subsequent analyses, confirming the proteomic findings. CONCLUSIONS: Taken together, our data suggest that altered protein expression, structural protein remodeling, and the reduction of translation might play important roles in the early response to oxygen deprivation in C. elegans, and this information will help broaden our knowledge on the mechanism of hypoxia response. PMID- 20858266 TI - Characterization of volatile compounds of Daucus crinitus Desf. Headspace Solid Phase Microextraction as alternative technique to Hydrodistillation. AB - BACKGROUND: Traditionally, the essential oil of aromatic herbs is obtained using hydrodistillation (HD). Because the emitted volatile fraction plays a fundamental role in a plant's life, various novel techniques have been developed for its extraction from plants. Among these, headspace solid phase microextraction (HS SPME) can be used to obtain a rapid fingerprint of a plant's headspace. Daucus crinitus Desf. is a wild plant that grows along the west coast of Algeria. Only a single study has dealt with the chemical composition of the aerial part oils of Algerian D. crinitus, in which isochavicol isobutyrate (39.0%), octyl acetate (12.3%), and beta-caryophyllene (5.4%) were identified. Using GC-RI and GC-MS analysis, the essential oils and the volatiles extracted from separated organs of D. crinitus Desf. were studied using HS-SPME. RESULTS: GC-RI and GC-MS analysis identified 72 and 79 components in oils extracted using HD and in the volatile fractions extracted using SPME, respectively. Two types of essential oils were produced by the plant: the root oils had aliphatic compounds as the main component (87.0%-90.1%), and the aerial part oils had phenylpropanoids as the main component (43.1%-88.6%). HS-SPME analysis showed a more precise distribution of compounds in the organs studied: oxygenated aliphatic compounds were well represented in the roots (44.3%-84.0%), hydrocarbon aliphatic compounds were in the leaves and stems (22.2%-87.9%), and phenylpropanoids were in the flowers and umbels (47.9%-64.2%). Moreover, HS-SPME allowed the occurrence of isochavicol (29.6 - 34.7%) as main component in D. crinitus leaves, but it was not detected in the oils, probably because of its solubility in water. CONCLUSIONS: This study demonstrates that HD and HS-SPME modes could be complimentary extraction techniques in order to obtain the complete characterization of plant volatiles. PMID- 20858267 TI - Spindle assembly checkpoint genes reveal distinct as well as overlapping expression that implicates MDF-2/Mad2 in postembryonic seam cell proliferation in Caenorhabditis elegans. AB - BACKGROUND: The spindle assembly checkpoint (SAC) delays anaphase onset by inhibiting the activity of the anaphase promoting complex/cyclosome (APC/C) until all of the kinetochores have properly attached to the spindle. The importance of SAC genes for genome stability is well established; however, the roles these genes play, during postembryonic development of a multicellular organism, remain largely unexplored. RESULTS: We have used GFP fusions of 5' upstream intergenic regulatory sequences to assay spatiotemporal expression patterns of eight conserved genes implicated in the spindle assembly checkpoint function in Caenorhabditis elegans. We have shown that regulatory sequences for all of the SAC genes drive ubiquitous GFP expression during early embryonic development. However, postembryonic spatial analysis revealed distinct, tissue-specific expression of SAC genes with striking co-expression in seam cells, as well as in the gut. Additionally, we show that the absence of MDF-2/Mad2 (one of the checkpoint genes) leads to aberrant number and alignment of seam cell nuclei, defects mainly attributed to abnormal postembryonic cell proliferation. Furthermore, we show that these defects are completely rescued by fzy 1(h1983)/CDC20, suggesting that regulation of the APC/CCDC20 by the SAC component MDF-2 is important for proper postembryonic cell proliferation. CONCLUSION: Our results indicate that SAC genes display different tissue-specific expression patterns during postembryonic development in C. elegans with significant co expression in hypodermal seam cells and gut cells, suggesting that these genes have distinct as well as overlapping roles in postembryonic development that may or may not be related to their established roles in mitosis. Furthermore, we provide evidence, by monitoring seam cell lineage, that one of the checkpoint genes is required for proper postembryonic cell proliferation. Importantly, our research provides the first evidence that postembryonic cell division is more sensitive to SAC loss, in particular MDF-2 loss, than embryonic cell division. PMID- 20858268 TI - A prospective study of dietary selenium intake and risk of type 2 diabetes. AB - BACKGROUND: Growing evidence raises concern about possible associations of high selenium exposure with diabetes in selenium-replete populations such as the US. In countries with lower selenium status, such as Italy, there is little epidemiological evidence on the association between selenium and diabetes. This study examined the prospective association between dietary selenium intake and risk of type 2 diabetes. METHODS: The ORDET cohort study comprised a large sample of women from Northern Italy (n = 7,182). Incident type 2 diabetes was defined as a self-report of a physician diagnosis, use of antidiabetic medication, or a hospitalization discharge. Dietary selenium intake was measured by a semi quantitative food-frequency questionnaire at the baseline examination (1987 1992). Participants were divided in quintiles based on their baseline dietary selenium intake. RESULTS: Average selenium intake at baseline was 55.7 MUg/day. After a median follow-up of 16 years, 253 women developed diabetes. In multivariate logistic regression analyses, the odds ratio for diabetes comparing the highest to the lowest quintile of selenium intake was 2.39, (95% CI: 1.32, 4.32; P for linear trend = 0.005). The odds ratio for diabetes associated with a 10 MUg/d increase in selenium intake was 1.29 (95% CI: 1.10, 1.52). CONCLUSIONS: In this population, increased dietary selenium intake was associated with an increased risk of type 2 diabetes. These findings raise additional concerns about the association of selenium intake above the Recommended Dietary Allowance (55 MUg/day) with diabetes risk. PMID- 20858270 TI - Brace technology thematic series: the dynamic derotation brace. AB - BACKGROUND: The dynamic derotation brace (DDB) was designed in Greece in 1982, as a modification of the Boston brace. It is a custom-made, underarm spinal orthosis featuring aluminium blades set to produce derotating and anti-rotating effects on the thorax and trunk of patients with scoliosis. It is indicated for the non operative correction of most curves, barring the very high thoracic ones, (when the apex vertebra is T5 or above). The purpose of this article is to familiarize physicians with the DDB, analyze the rationale behind its design, and present the published results of its application. DESCRIPTION & PRINCIPLES: The key feature of the DDB is the addition of the aluminium-made derotating blades posteriorly. These function as a force couple, which is added to the side forces exerted by the brace itself. Corrective forces are also directed through pads. One or more of previously proposed pathomechanical models of scoliosis may underline the corrective function of the DDB: it may act directly on the apical intervertebral disc, effecting correction through the Heuter-Volkman principle; the blades may produce an anti-rotatory element against the deforming "spiral composite muscle trunk rotator"; or it may alter the neuro-motor response by constantly providing new somatosensory input to the patient. RESULTS: Based on measurements of the Cobb and Perdriolle angles, up to 82% of patients remained stable or improved with the use of the DDB. Results have varied, though, depending on the type/location of the deformity. The overall results showed that 35% of the curves improved, 46% remained stable and 18% became worse, as assessed by measuring the Cobb angle. The DDB has also been shown to improve cosmesis (except for right thoracic curves) and leave several aspects of patient quality of life unaffected during use. CONCLUSION: Conservative treatment of idiopathic scoliosis using the DDB has shown favorable results. Thoracic curves appear more resistant to both angular and rotatory correction. The published outcome data on the DDB support our belief that the incorporation of aluminium blades to other orthoses would likely improve their efficacy. PMID- 20858269 TI - MicroRNA roles in beta-catenin pathway. AB - beta-catenin, a key factor in the Wnt signaling pathway, has essential functions in the regulation of cell growth and differentiation. Aberrant beta-catenin signaling has been linked to various disease pathologies, including an important role in tumorigenesis. Here, we review the regulation of the Wnt signaling pathway as it relates to beta-catenin signaling in tumorigenesis, with particular focus on the role of microRNAs. Finally, we discuss the potential of beta-catenin targeted therapeutics for cancer treatment. PMID- 20858271 TI - EMG1 is essential for mouse pre-implantation embryo development. AB - BACKGROUND: Essential for mitotic growth 1 (EMG1) is a highly conserved nucleolar protein identified in yeast to have a critical function in ribosome biogenesis. A mutation in the human EMG1 homolog causes Bowen-Conradi syndrome (BCS), a developmental disorder characterized by severe growth failure and psychomotor retardation leading to death in early childhood. To begin to understand the role of EMG1 in mammalian development, and how its deficiency could lead to Bowen Conradi syndrome, we have used mouse as a model. The expression of Emg1 during mouse development was examined and mice carrying a null mutation for Emg1 were generated and characterized. RESULTS: Our studies indicated that Emg1 is broadly expressed during early mouse embryonic development. However, in late embryonic stages and during postnatal development, Emg1 exhibited specific expression patterns. To assess a developmental role for EMG1 in vivo, we exploited a mouse gene-targeting approach. Loss of EMG1 function in mice arrested embryonic development prior to the blastocyst stage. The arrested Emg1-/- embryos exhibited defects in early cell lineage-specification as well as in nucleologenesis. Further, loss of p53, which has been shown to rescue some phenotypes resulting from defects in ribosome biogenesis, failed to rescue the Emg1-/- pre implantation lethality. CONCLUSION: Our data demonstrate that Emg1 is highly expressed during mouse embryonic development, and essential for mouse pre implantation development. The absolute requirement for EMG1 in early embryonic development is consistent with its essential role in yeast. Further, our findings also lend support to the previous study that showed Bowen-Conradi syndrome results from a partial EMG1 deficiency. A complete deficiency would not be expected to be compatible with a live birth. PMID- 20858272 TI - Validation of the Rasch-based Depression Screening in a large scale German general population sample. AB - BACKGROUND: The study aimed at presenting normative data for both parallel forms of the "Rasch-based Depression Screening (DESC)", to examine its Rasch model conformity and convergent and divergent validity based on a representative sample of the German general population. METHODS: The sample was selected with the assistance of a demographic consulting company applying a face to face interview (N = 2509; mean age = 49.4, SD = 18.2; 55.8% women). Adherence to Rasch model assumptions was determined with analysis of Rasch model fit (infit and outfit), unidimensionality, local independence (principal component factor analysis of the residuals, PCFAR) and differential item functioning (DIF) with regard to participants' age and gender. Norm values were calculated. Convergent and divergent validity was determined through intercorrelations with the depression and anxiety subscales of the Hospital Anxiety and Depression Scale (HADS-D and HADS-A). RESULTS: Fit statistics were below critical values (< 1.3). There were no signs of DIF. The PCFAR revealed that the Rasch dimension "depression" explained 68.5% (DESC-I) and 69.3% (DESC-II) of the variance, respectively which suggests unidimensionality and local independence of the DESC. Correlations with HADS-D were rDESC-I = .61 and rDESC-II = .60, whereas correlations with HADS-A were rDESC-I = .62 and rDESC-II = .60. CONCLUSIONS: This study provided further support for the psychometric quality of the DESC. Both forms of the DESC adhered to Rasch model assumptions and showed intercorrelations with HADS subscales that are in line with the literature. The presented normative data offer important advancements for the interpretation of the questionnaire scores and enhance its usefulness for clinical and research applications. PMID- 20858273 TI - Preventing disease through opportunistic, rapid engagement by primary care teams using behaviour change counselling (PRE-EMPT): protocol for a general practice based cluster randomised trial. AB - BACKGROUND: Smoking, excessive alcohol consumption, lack of exercise and an unhealthy diet are the key modifiable factors contributing to premature morbidity and mortality in the developed world. Brief interventions in health care consultations can be effective in changing single health behaviours. General Practice holds considerable potential for primary prevention through modifying patients' multiple risk behaviours, but feasible, acceptable and effective interventions are poorly developed, and uptake by practitioners is low. Through a process of theoretical development, modeling and exploratory trials, we have developed an intervention called Behaviour Change Counselling (BCC) derived from Motivational Interviewing (MI). This paper describes the protocol for an evaluation of a training intervention (the Talking Lifestyles Programme) which will enable practitioners to routinely use BCC during consultations for the above four risk behaviours. METHODS/DESIGN: This cluster randomised controlled efficacy trial (RCT) will evaluate the outcomes and costs of this training intervention for General Practitioners (GPs) and nurses. Training methods will include: a practice-based seminar, online self-directed learning, and reflecting on video recorded and simulated consultations. The intervention will be evaluated in 29 practices in Wales, UK; two clinicians will take part (one GP and one nurse) from each practice. In intervention practices both clinicians will receive training. The aim is to recruit 2000 patients into the study with an expected 30% drop out. The primary outcome will be the proportion of patients making changes in one or more of the four behaviours at three months. Results will be compared for patients seeing clinicians trained in BCC with patients seeing non-BCC trained clinicians. Economic and process evaluations will also be conducted. DISCUSSION: Opportunistic engagement by health professionals potentially represents a cost effective medical intervention. This study integrates an existing, innovative intervention method with an innovative training model to enable clinicians to routinely use BCC, providing them with new tools to encourage and support people to make healthier choices. This trial will evaluate effectiveness in primary care and determine costs of the intervention. PMID- 20858274 TI - Survivors of war in the Northern Kosovo (II): baseline clinical and functional assessment and lasting effects on the health of a vulnerable population. AB - BACKGROUND: This study documents torture and injury experience and investigates emotional well-being of victims of massive violence identified during a household survey in Mitrovice district in Kosovo. Their physical health indicators such as body mass index (BMI), handgrip strength and standing balance were also measured. A further aim is to suggest approaches for developing and monitoring rehabilitation programmes. METHODS: A detailed assessment was carried out on 63 male and 62 female victims. Interviews and physical examination provided information about traumatic exposure, injuries, and intensity and frequency of pain. Emotional well-being was assessed using the "WHO-5 Well-Being" score. Height, weight, handgrip strength and standing balance performance were measured. RESULTS: Around 50% of victims had experienced at least two types of torture methods and reported at least two injury locations; 70% had moderate or severe pain and 92% reported constant or periodic pain within the previous two weeks. Only 10% of the victims were in paid employment. Nearly 90% of victims had experienced at least four types of emotional disturbances within the previous two weeks, and many had low scores for emotional well-being. This was found to be associated with severe pain, higher exposure to violence and human rights violations and with a low educational level, unemployment and the absence of political or social involvement.Over two thirds of victims were overweight or obese. They showed marked decline in handgrip strength and only 19 victims managed to maintain standing balance. Those who were employed or had a higher education level, who did not take anti-depressant or anxiety drugs and had better emotional well-being or no pain complaints showed better handgrip strength and standing balance. CONCLUSIONS: The victims reported a high prevalence of severe pain and emotional disturbance. They showed high BMI and a reduced level of physical fitness. Education, employment, political and social participation were associated with emotional well-being. Interventions to promote physical activity and social participation are recommended. The results indicate that the rapid assessment procedure used here offers an adequate tool for collecting data for the monitoring of health interventions among the most vulnerable groups of a population exposed to violence. PMID- 20858275 TI - Zinc status in HIV infected Ugandan children aged 1-5 years: a cross sectional baseline survey. AB - BACKGROUND: Low concentrations of serum zinc have been reported in HIV infected adults and are associated with disease progression and an increased risk of death. Few studies have been conducted in HIV infected children in Africa. We determined serum zinc levels and factors associated with zinc deficiency in HIV infected Ugandan children. METHODS: We measured the baseline zinc status of 247 children aged 1-5 years enrolled in a randomised trial for multiple micronutrient supplementation at paediatric HIV clinics in Uganda (http://ClinicalTrials.gov NCT00122941). Zinc status was determined using inductively coupled atomic emission spectrophotometry (ICP-AES). Clinical and laboratory characteristics were compared among zinc deficient (zinc < 10.0 MUmol/L) and non deficient children. Logistic regression was used to determine predictors of low serum zinc. RESULTS: Of the 247 children, 134 (54.3%) had low serum zinc (< 10.0 MUmol/L). Of the 44 children on highly active antiretroviral therapy (HAART), 13 (29.5%) had low zinc compared to 121/203 (59.6%) who were not on HAART. Overall, independent predictors of low zinc were fever (OR 2.2; 95%CI 1.1-4.6) and not taking HAART (OR 3.7; 95%CI 1.8-7.6). CONCLUSION: Almost two thirds of HAART naive and a third of HAART treated HIV infected children were zinc deficient. Increased access to HAART among HIV infected children living in Uganda might reduce the prevalence of zinc deficiency. PMID- 20858276 TI - Dysregulated miR-183 inhibits migration in breast cancer cells. AB - BACKGROUND: The involvement of miRNAs in the regulation of fundamental cellular functions has placed them at the fore of ongoing investigations into the processes underlying carcinogenesis. MiRNA expression patterns have been shown to be dysregulated in numerous human malignancies, including breast cancer, suggesting their probable involvement as novel classes of oncogenes or tumour suppressor genes. The identification of differentially expressed miRNAs and elucidation of their functional roles may provide insight into the complex and diverse molecular mechanisms of tumorigenesis. MiR-183 is located on chromosome 7q32 and is part of a miRNA family which are dysregulated in numerous cancers. The aims of this study were to further examine the expression and functional role of miR-183 in breast cancer. METHODS: MiR-183 expression was quantitated in primary breast tumours, tumour associated normal tissue and breast cancer cell lines using RQ-PCR. Gain of function analysis was performed in breast cancer cells using pre-miR-183 and the effect of miR-183 overexpression on cell viability, proliferation, apoptosis and migration was examined. Customized Taqman Low Density Arrays (TLDA) were used to identify dysregulated genes in breast cancer cells transfected with pre-miR-183. RESULTS: We demonstrate that miR-183 is dysregulated in breast cancer and expression correlates with estrogen receptor and HER2/neu receptor expression. Induced overexpression of miR-183 inhibited migration of breast cancer cells. This finding was substantiated by RQ-PCR of mRNA from cells overexpressing miR-183 which showed dysregulation of several migration and invasion related genes. Specifically, the VIL2-coding protein Ezrin was confirmed as a target of miR-183 and downregulation of this protein was confirmed with immunocytochemistry. CONCLUSIONS: These findings indicate that miR 183 targets VIL2 and may play a central role in the regulation of migration and metastasis in breast cancer. Consequently, this miRNA may present an attractive target for therapeutic intervention. PMID- 20858277 TI - Collybistin and gephyrin are novel components of the eukaryotic translation initiation factor 3 complex. AB - BACKGROUND: Collybistin (CB), a neuron-specific guanine nucleotide exchange factor, has been implicated in targeting gephyrin-GABAA receptors clusters to inhibitory postsynaptic sites. However, little is known about additional CB partners and functions. FINDINGS: Here, we identified the p40 subunit of the eukaryotic translation initiation factor 3 (eIF3H) as a novel binding partner of CB, documenting the interaction in yeast, non-neuronal cell lines, and the brain. In addition, we demonstrated that gephyrin also interacts with eIF3H in non neuronal cells and forms a complex with eIF3 in the brain. CONCLUSIONS: Together, our results suggest, for the first time, that CB and gephyrin associate with the translation initiation machinery, and lend further support to the previous evidence that gephyrin may act as a regulator of synaptic protein synthesis. PMID- 20858278 TI - Beta-arrestin inhibits CAMKKbeta-dependent AMPK activation downstream of protease activated-receptor-2. AB - BACKGROUND: Proteinase-activated-receptor-2 (PAR2) is a seven transmembrane receptor that can activate two separate signaling arms: one through Galphaq and Ca2+ mobilization, and a second through recruitment of beta-arrestin scaffolds. In some cases downstream targets of the Galphaq/Ca2+ signaling arm are directly inhibited by beta-arrestins, while in other cases the two pathways are synergistic; thus beta-arrestins act as molecular switches capable of modifying the signal generated by the receptor. RESULTS: Here we demonstrate that PAR2 can activate adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy balance, through Ca2+-dependent Kinase Kinase beta (CAMKKbeta), while inhibiting AMPK through interaction with beta-arrestins. The ultimate outcome of PAR2 activation depended on the cell type studied; in cultured fibroblasts with low endogenous beta-arrestins, PAR2 activated AMPK; however, in primary fat and liver, PAR2 only activated AMPK in beta-arrestin-2-/- mice. beta-arrestin-2 could be co-immunoprecipitated with AMPK and CAMKKbeta under baseline conditions from both cultured fibroblasts and primary fat, and its association with both proteins was increased by PAR2 activation. Addition of recombinant beta-arrestin-2 to in vitro kinase assays directly inhibited phosphorylation of AMPK by CAMKKbeta on Thr172. CONCLUSIONS: Studies have shown that decreased AMPK activity is associated with obesity and Type II Diabetes, while AMPK activity is increased with metabolically favorable conditions and cholesterol lowering drugs. These results suggest a role for beta-arrestin in the inhibition of AMPK signaling, raising the possibility that beta-arrestin dependent PAR2 signaling may act as a molecular switch turning a positive signal to AMPK into an inhibitory one. PMID- 20858279 TI - Time-to-pregnancy and pregnancy outcomes in a South African population. AB - BACKGROUND: Time-to-pregnancy (TTP) has never been studied in an African setting and there are no data on the rates of adverse pregnancy outcomes in South Africa. The study objectives were to measure TTP and the rates of adverse pregnancy outcomes in South Africa, and to determine the reliability of the questionnaire tool. METHODS: The study was cross-sectional and applied systematic stratified sampling to obtain a representative sample of reproductive age women for a South African population. Data on socio-demographic, work, health and reproductive variables were collected on 1121 women using a standardized questionnaire. A small number (n = 73) of randomly selected questionnaires was repeated to determine reliability of the questionnaire. Data was described using simple summary statistics while Kappa and intra-class correlation statistics were calculated for reliability. RESULTS: Of the 1121 women, 47 (4.2%) had never been pregnant. Mean gravidity was 2.3 while mean parity was 2.0 There were a total of 2467 pregnancies; most (87%) resulted in live births, 9.5% in spontaneous abortion and 2.2% in still births. The proportion of planned pregnancies was 39% and the median TTP was 6 months. The reliability of the questionnaire for TTP data was good; 63% for all participants and 97% when censored at 14 months. Overall reliability of reporting adverse pregnancy outcomes was very high, ranging from 90 - 98% for most outcomes. CONCLUSION: This is the first comprehensive population-based reproductive health study in South Africa, to describe the biologic fertility of the population, and provides rates for planned pregnancies and adverse pregnancy outcomes. The reliability of the study questionnaire was substantial, with most outcomes within 70 - 100% reliability index. The study provides important public information for health practitioners and researchers in reproductive health. It also highlights the need for public health intervention programmes and epidemiological research on biologic fertility and adverse pregnancy outcomes in the population. PMID- 20858280 TI - Impact of repeated four-monthly anthelmintic treatment on Plasmodium infection in preschool children: a double-blind placebo-controlled randomized trial. AB - BACKGROUND: Helminth infections can alter susceptibility to malaria. Studies need to determine whether or not deworming programs can impact on Plasmodium infections in preschool children. METHODS: A double-blind placebo-controlled randomised trial was conducted to investigate the impact of anthelmintic treatment on Plasmodium infection in children aged 12-59 months. Children were randomly assigned to receive either albendazole or placebo every four months for 12 months with a follow-up at 14 months. RESULTS: 320 Children (out of 1228, 26.1%) complied with all the follow-up assessments. Plasmodium prevalence and mean Plasmodium parasite density was significantly higher in the treatment group (44.9% and 2319 +/- SE 511) compared to the placebo group (33.3% and 1471 +/- 341) at baseline. The odds of having Plasmodium infection increased over time for children in both the placebo and treatment groups, however this increase was significantly slower for children in the treatment group (P = 0.002). By month 14, mean Plasmodium density had increased by 156% in the placebo group and 98% in the treatment group but the rate of change in Plasmodium density was not significantly different between the groups. The change from baseline in haemoglobin had a steeper increase among children in the treatment group when compared to the placebo group but this was not statistically significant. CONCLUSIONS: Repeated four-monthly anthelminthic treatments for 14 months resulted in a significantly lower increase in the prevalence of Plasmodium infection in preschool children which coincided with a reduction in both the prevalence and intensity of A. lumbricoides infections. TRIAL REGISTRATION: Current controlled trials ISRCTN44215995. PMID- 20858281 TI - Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. AB - BACKGROUND: Trop2 is a cell-surface glycoprotein overexpressed by a variety of epithelial carcinomas with reported low to restricted expression in normal tissues. Expression of Trop2 has been associated with increased tumor aggressiveness, metastasis and decreased patient survival, but the signaling mechanisms mediated by Trop2 are still unknown. Here, we studied the effects murine Trop2 (mTrop2) exerted on tumor cellular functions and some of the signaling mechanisms activated by this oncogene. RESULTS: mTrop2 expression significantly increased tumor cell proliferation at low serum concentration, migration, foci formation and anchorage-independent growth. These in vitro characteristics translated to increased tumor growth in both subcutaneous and orthotopic pancreatic cancer murine models and also led to increased liver metastasis. mTrop2 expression also increased the levels of phosphorylated ERK1/2 mediating cell cycle progression by increasing the levels of cyclin D1 and cyclin E as well as downregulating p27. The activation of ERK was also observed in human pancreatic ductal epithelial cells and colorectal adenocarcinoma cells overexpressing human Trop2. CONCLUSIONS: These findings demonstrate some of the pathogenic effects mediated by mTrop2 expression on cancer cells and the importance of targeting this cell surface glycoprotein. This study also provides the first indication of a molecular signaling pathway activated by Trop2 which has important implications for cancer cell growth and survival. PMID- 20858282 TI - Stress-induced glucocorticoid receptor activation determines functional recovery following ischemic stroke. AB - BACKGROUND: A major consequence of stroke is permanent motor disturbance, such as postural imbalance and loss of skilled movement. The degree of neuronal and functional loss and subsequent recovery after stroke is influenced by hypothalamic-pituitary-adrenal axis activation and the response to glucocorticoid hormones. This study investigated if recovery after stroke is related to glucocorticoid receptor (GR) activation in a rat model of stroke. METHODS: Adult male rats were pre-trained and tested in a skilled reaching task and received a focal ischemic motor cortex lesion. One group of animals received daily restraint stress starting one week pre-lesion up to three weeks post-lesion. Immuno histochemical analysis of GR expression was performed to determine receptor activation. RESULTS: Stress reduced reaching success in naive animals and diminished recovery of limb use. Exaggerated functional loss in stressed rats was related to increased GR activation in the lesion hemisphere as indicated by nuclear GR location. CONCLUSION: These findings provide a mechanistic link between stress-induced motor disability and GR activation in a rat model of stroke. The elevated receptor activation proposes synergistic effects of stress and stroke to modulate the impact of glucocorticoids on motor system function at the genomic level. The modulation of GR biosynthesis may alter responsiveness to stroke treatment and compromise recovery. PMID- 20858283 TI - Solitary neurofibroma of the gingiva with prominent differentiation of Meissner bodies: a case report. AB - BACKGROUND: Oral neurofibromas are peripheral nerve sheath tumors, similar to schwannomas. Histological variations in oral neurofibromas are relatively uncommon. CASE PRESENTATION: Here, we present a case of unique variation in the observed characteristics of a neurofibroma, with no relation to neurofibromatosis type-1 or von Recklinghausen disease of the skin. The neurofibroma was observed in the right mandibular gingiva of a 32-year-old Japanese woman. Histologically, it differed from conventional neurofibromas in that the tumor was composed of a mixture of fine fibrillary collagen in sheets and/or cords of neoplastic Schwann cells containing numerous clusters of Meissner bodies. Histologically, these bodies were in contact with neoplastic Schwann cells. The Meissner bodies were immunopositive for S-100 protein, neuron-specific enolase, and vimentin, but were negative for calretinin. CD34-positive spindle cells were observed around the Meissner bodies. No recurrence or signs of other tumors have been observed in the patient for 5 years after tumor resection. CONCLUSION: To the best of our knowledge, no formal descriptions of sporadic, solitary neurofibromas containing numerous Meissner bodies occurring in the oral cavity are available in literature. We believe that an uncommon proliferation of Meissner bodies, as seen in the present case, may result from aberrant differentiation of neoplastic Schwann cells. PMID- 20858285 TI - The evaluation of "Safe Motherhood" program on maternal care utilization in rural western China: a difference in difference approach. AB - BACKGROUND: Maternal care is an important strategy for protection and promotion of maternal and children's health by reducing maternal mortality and improving the quality of birth. However, the status of maternal care is quite weak in the less developed rural areas in western China. It is found that the maternal mortality rates in some western areas of China were 5.8 times higher than those of their eastern costal counterparts. In order to reduce the maternal mortality rates and to improve maternal care in western rural areas of China, the Chinese Ministry of Health (MOH) and the United Nations Children's Fund (UNICEF) sponsored a program named "Safe Motherhood" in ten western provinces of China from 2001 through 2005. This study mainly aims to evaluate the effects of "Safe Motherhood" program on maternal care utilization. METHODS: 32 counties were included in both surveys conducted in 2001 and 2005, respectively. Ten counties of which implemented comprehensive community-based intervention were used as intervention groups, while 22 counties were used as control groups. Stratified 3 stage probability-proportion-to-size sampling method was used to select participating women. Two cross-sectional surveys were conducted with questionnaires about the prenatal care utilization in 2001 and 2005, respectively. Difference in difference estimation was used to assess the effect of intervention on the maternal care utilization while controlling for socio economic characteristics of women. RESULTS: After the intervention, the proportion of pregnant women who had their first prenatal visit in the first trimester was increased from 38.9% to 76.1%. The proportion of prenatal visits increased from 82.6% to 98.3%. The proportion of women mobilized to deliver in hospitals increased from 62.7% to 94.5%. Hospital delivery was improved greatly from 31.1% to 87.3%. The maternal mortality rate was lowered by 34.9% from 91.76 to 59.74 per 100,000 live births. The community-based intervention had increased prenatal visits rate by 5.2%, first prenatal visit in first trimester rate by 12.0% and hospital delivery rate by 22.5%, respectively. No effect was found on rate of women being mobilized to hospital delivery compared with that of the control group. CONCLUSION: The intervention program seemed to have improved the prenatal care utilization in rural western China. PMID- 20858284 TI - Isolation of detergent resistant microdomains from cultured neurons: detergent dependent alterations in protein composition. AB - BACKGROUND: Membrane rafts are small highly dynamic sterol- and sphingolipid enriched membrane domains that have received considerable attention due to their role in diverse cellular functions. More recently the involvement of membrane rafts in neuronal processes has been highlighted since these specialized membrane domains have been shown to be involved in synapse formation, neuronal polarity and neurodegeneration. Detergent resistance followed by gradient centrifugation is often used as first step in screening putative membrane raft components. Traditional methods of raft isolation employed the nonionic detergent Triton X100. However successful separation of raft from non-raft domains in cells is dependent on matching the detergent used for raft isolation to the specific tissue under investigation. RESULTS: We report here the isolation of membrane rafts from primary neuronal culture using a panel of different detergents that gave rise to membrane fractions that differed in respect to cholesterol and protein content. In addition, proteomic profiling of neuronal membrane rafts isolated with different detergents, Triton X100 and CHAPSO, revealed heterogeneity in their protein content. CONCLUSIONS: These data demonstrate that appropriate selection of detergent for raft isolation is an important consideration for investigating raft protein composition of cultured neurons. PMID- 20858286 TI - Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children. AB - BACKGROUND: Fat-mass and obesity-associated (FTO) gene is a gene located in chromosome region 16q12.2. Genetic variants in FTO are associated with the obesity phenotype in European and Hispanic populations. However, this association still remains controversial in Asian population. We aimed to test the association of FTO genetic variants with obesity and obesity-related metabolic traits among children living in Beijing, China. METHODS: We genotyped FTO variants rs9939609 in 670 children (332 girls and 338 boys) aged 8-11 years living in Beijing, and analyzed its association with obesity and obesity-related metabolic traits. Overweight and obesity were defined by age- and sex-specific BMI reference for Chinese children. Obesity-related metabolic traits included fasting plasma glucose, lipid profiles, leptin, ghrelin, adiponectin and blood pressures. RESULTS: The frequency of rs9939609 A allele was 12.2%, which was 21.9% for the heterozygote and 1.2% for the homozygote of the A allele. The obesity prevalence among the carriers of AA/AT genotypes was significantly higher than that among those with TT genotype (36.4% vs. 22.6%, P=0.004). Compared to the carrier of TT genotype, the likelihood of obesity was 1.79 (95% confidence interval (95% CI) 1.20-2.67, P=0.004) for the carrier of AA/AT genotype, after adjustment of sex, age and puberty stages. The BMI Z-score of children with AA/AT genotype were significantly higher than that of their counterparts with the TT genotype (1.1+/ 0.1 vs. 0.8+/-0.1, P=0.02). The concentration of triglyceride was 1.03+/-0.52 mmol/L among TT carrier and 1.13+/-0.68 mmol/L among AA/AT carrier (P=0.045). While, the concentrations of adiponectin were 18.0+/-0.4 MUg/ml among carriers of TT and 16.2+/-0.7 MUg/ml among subjects with AA/AT genotype (P=0.03). The level of glucose marginally increased in the AA/AT genotype subjects (4.67+/-0.40 mmol/L vs. 4.60+/-0.35 mmol/L, P=0.08). The evidence of association was reduced after adjustment for BMI (P=0.38 for triglyceride, P=0.20 for adiponectin and glucose). There was weak evidence of association between rs9939609 and other obesity-related metabolic traits including total cholesterol (3.92+/-0.03 mmol/L vs. 4.02+/-0.05 mmol/L, P=0.10), insulin (2.69+/-1.77 ng/ml vs. 3.12+/-2.91 ng/ml, P=0.14), and insulin resistance (HOMA-IR 0.56+/-0.03 vs. 0.66+/-0.05, P=0.10). CONCLUSIONS: Genetic variation in the FTO gene associates with obesity in Chinese children. PMID- 20858287 TI - Transcriptome and expression profiling analysis revealed changes of multiple signaling pathways involved in immunity in the large yellow croaker during Aeromonas hydrophila infection. AB - BACKGROUND: The large yellow croaker (Pseudosciaena crocea) is an economically important marine fish in China suffering from severe outbreaks of infectious disease caused by marine bacteria such as Aeromonas hydrophila (A. hydrophila), resulting in great economic losses. However, the mechanisms involved in the immune response of this fish to bacterial infection are not fully understood. To understand the molecular mechanisms underlying the immune response to such pathogenic bacteria, we used high-throughput deep sequencing technology to investigate the transcriptome and comparative expression profiles of the large yellow croaker infected with A. hydrophila. RESULTS: A total of 13,611,340 reads were obtained and assembled into 26,313 scaffolds in transcriptional responses of the A. hydrophila-infected large yellow croaker. Via annotation to the NCBI database, we obtained 8216 identified unigenes. In total, 5590 (68%) unigenes were classified into Gene Ontology, and 3094 unigenes were found in 20 KEGG categories. These genes included representatives from almost all functional categories. By using Solexa/Illumina's DeepSAGE, 1996 differentially expressed genes (P value < 0.05) were detected in comparative analysis of the expression profiles between A. hydrophila-infected fish and control fish, including 727 remarkably upregulated genes and 489 remarkably downregulated genes. Dramatic differences were observed in genes involved in the inflammatory response. Bacterial infection affected the gene expression of many components of signaling cascades, including the Toll-like receptor, JAK-STAT, and MAPK pathways. Genes encoding factors involved in T cell receptor (TCR) signaling were also revealed to be regulated by infection in these fish. CONCLUSION: Based on our results, we conclude that the inflammatory response may play an important role in the early stages of infection. The signaling cascades such as the Toll-like receptor, JAK STAT, and MAPK pathways are regulated by A. hydrophila infection. Interestingly, genes encoding factors involved in TCR signaling were revealed to be downregulated by infection, indicating that TCR signaling was suppressed at this early period. These results revealed changes of multiple signaling pathways involved in immunity during A. hydrophila infection, which will facilitate our comprehensive understanding of the mechanisms involved in the immune response to bacterial infection in the large yellow croaker. PMID- 20858288 TI - High cell density and latent membrane protein 1 expression induce cleavage of the mixed lineage leukemia gene at 11q23 in nasopharyngeal carcinoma cell line. AB - BACKGROUND: Nasopharyngeal carcinoma (NPC) is commonly found in Southern China and South East Asia. Epstein-Barr virus (EBV) infection is well associated with NPC and has been implicated in its pathogenesis. Moreover, various chromosome rearrangements were reported in NPC. However, the underlying mechanism of chromosome rearrangement remains unclear. Furthermore, the relationship between EBV and chromosome rearrangement with respect to the pathogenesis of NPC has not been established. We hypothesize that during virus- or stress-induced apoptosis, chromosomes are initially cleaved at the base of the chromatin loop domain structure. Upon DNA repair, cell may survive with rearranged chromosomes. METHODS: In this study, cells were seeded at various densities to induce apoptosis. Genomic DNA extracted was processed for Southern hybridization. In order to investigate the role of EBV, especially the latent membrane protein 1 (LMP1), LMP1 gene was overexpressed in NPC cells and chromosome breaks were analyzed by inverse polymerase chain (IPCR) reaction. RESULTS: Southern analysis revealed that high cell density resulted in cleavage of the mixed lineage leukemia (MLL) gene within the breakpoint cluster region (bcr). This high cell density-induced cleavage was significantly reduced by caspase inhibitor, Z-DEVD FMK. Similarly, IPCR analysis showed that LMP1 expression enhanced cleavage of the MLL bcr. Breakpoint analysis revealed that these breaks occurred within the matrix attachment region/scaffold attachment region (MAR/SAR). CONCLUSIONS: Since MLL locates at 11q23, a common deletion site in NPC, our results suggest a possibility of stress- or virus-induced apoptosis in the initiation of chromosome rearrangements at 11q23. The breakpoint analysis results also support the role of chromatin structure in defining the site of chromosome rearrangement. PMID- 20858289 TI - Similar patterns of rDNA evolution in synthetic and recently formed natural populations of Tragopogon (Asteraceae) allotetraploids. AB - BACKGROUND: Tragopogon mirus and T. miscellus are allotetraploids (2n = 24) that formed repeatedly during the past 80 years in eastern Washington and adjacent Idaho (USA) following the introduction of the diploids T. dubius, T. porrifolius, and T. pratensis (2n = 12) from Europe. In most natural populations of T. mirus and T. miscellus, there are far fewer 35S rRNA genes (rDNA) of T. dubius than there are of the other diploid parent (T. porrifolius or T. pratensis). We studied the inheritance of parental rDNA loci in allotetraploids resynthesized from diploid accessions. We investigate the dynamics and directionality of these rDNA losses, as well as the contribution of gene copy number variation in the parental diploids to rDNA variation in the derived tetraploids. RESULTS: Using Southern blot hybridization and fluorescent in situ hybridization (FISH), we analyzed copy numbers and distribution of these highly reiterated genes in seven lines of synthetic T. mirus (110 individuals) and four lines of synthetic T. miscellus (71 individuals). Variation among diploid parents accounted for most of the observed gene imbalances detected in F1 hybrids but cannot explain frequent deviations from repeat additivity seen in the allotetraploid lines. Polyploid lineages involving the same diploid parents differed in rDNA genotype, indicating that conditions immediately following genome doubling are crucial for rDNA changes. About 19% of the resynthesized allotetraploid individuals had equal rDNA contributions from the diploid parents, 74% were skewed towards either T. porrifolius or T. pratensis-type units, and only 7% had more rDNA copies of T. dubius-origin compared to the other two parents. Similar genotype frequencies were observed among natural populations. Despite directional reduction of units, the additivity of 35S rDNA locus number is maintained in 82% of the synthetic lines and in all natural allotetraploids. CONCLUSIONS: Uniparental reductions of homeologous rRNA gene copies occurred in both synthetic and natural populations of Tragopogon allopolyploids. The extent of these rDNA changes was generally higher in natural populations than in the synthetic lines. We hypothesize that locus-specific and chromosomal changes in early generations of allopolyploids may influence patterns of rDNA evolution in later generations. PMID- 20858290 TI - Persistent transmission of malaria in Garo hills of Meghalaya bordering Bangladesh, north-east India. AB - BACKGROUND: Malaria is endemic in Garo hills of Meghalaya, and death cases are reported annually. Plasmodium falciparum is the major parasite, and is solely responsible for each malaria-attributable death case. Garo hills are categorized high-risk for drug-resistant malaria; however, there exists no data on malaria transmitting mosquitoes prevalent in the region. Included in this report are entomological observations with particular reference to vector biology characteristics for devising situation specific intervention strategies for disease transmission reduction. METHODS: The epidemiological data of the West Garo hills have been reviewed retrospectively for 2001-2009 to ascertain the disease transmission profile given the existing interventions. Point prevalence study was conducted in Dalu Community Health Centre that lies in close proximity to international border with Bangladesh to ascertain the true prevalence of malaria, and parasite species. Mosquito collections were made in human dwellings of malaria endemic villages aiming at vector incrimination, and to study relative abundance, resting and feeding preferences, and their present susceptibility status to DDT. RESULTS: Investigations revealed that the West Garo hill district is co-endemic for Plasmodium falciparum and Plasmodium vivax, but P. falciparum was the predominant infection (> 82%). Malaria transmission was perennial and persistent with seasonal peak during May-July corresponding to months of high rainfall. Entomological collections revealed that Anopheles minimus was the predominant species that was incriminated by detection of sporozoites in salivary glands (infection rate 2.27%), and was ascertained to be fully susceptible to DDT. CONCLUSION: For the control of malaria, improved diagnosis and sustained supply of drugs for artemisinin-based combination therapy are strongly advocated, which should be enforced for treatment of every single case of P. falciparum. Greater political commitment is called for organized vector control operations along border/high-risk areas to contain the spread of drug-resistant malaria, and averting impending disease outbreaks. PMID- 20858291 TI - Identification and characterization of a virus-specific continuous B-cell epitope on the PrM/M protein of Japanese Encephalitis Virus: potential application in the detection of antibodies to distinguish Japanese Encephalitis Virus infection from West Nile Virus and Dengue Virus infections. AB - BACKGROUND: Differential diagnose of Japanese encephalitis virus (JEV) infection from other flavivirus especially West Nile virus (WNV) and Dengue virus (DV) infection was greatly hindered for the serological cross-reactive. Virus specific epitopes could benefit for developing JEV specific antibodies detection methods. To identify the JEV specific epitopes, we fully mapped and characterized the continuous B-cell epitope of the PrM/M protein of JEV. RESULTS: To map the epitopes on the PrM/M protein, we designed a set of 20 partially overlapping fragments spanning the whole PrM, fused them with GST, and expressed them in an expression vector. Linear epitope M14 (105VNKKEAWLDSTKATRY120) was detected by enzyme-linked immunosorbent assay (ELISA). By removing amino acid residues individually from the carboxy and amino terminal of peptide M14, we confirmed that the minimal unit of the linear epitope of PrM/M was M14-13 (108KEAWLDSTKAT118). This epitope was highly conserved across different JEV strains. Moreover, this epitope did not cross-react with WNV-positive and DENV positive sera. CONCLUSION: Epitope M14-13 was a JEV specific lineal B-cell epitpe. The results may provide a useful basis for the development of epitope based virus specific diagnostic clinical techniques. PMID- 20858292 TI - PeptideMine--a webserver for the design of peptides for protein-peptide binding studies derived from protein-protein interactomes. AB - BACKGROUND: Signal transduction events often involve transient, yet specific, interactions between structurally conserved protein domains and polypeptide sequences in target proteins. The identification and validation of these associating domains is crucial to understand signal transduction pathways that modulate different cellular or developmental processes. Bioinformatics strategies to extract and integrate information from diverse sources have been shown to facilitate the experimental design to understand complex biological events. These methods, primarily based on information from high-throughput experiments, have also led to the identification of new connections thus providing hypothetical models for cellular events. Such models, in turn, provide a framework for directing experimental efforts for validating the predicted molecular rationale for complex cellular processes. In this context, it is envisaged that the rational design of peptides for protein-peptide binding studies could substantially facilitate the experimental strategies to evaluate a predicted interaction. This rational design procedure involves the integration of protein protein interaction data, gene ontology, physico-chemical calculations, domain domain interaction data and information on functional sites or critical residues. RESULTS: Here we describe an integrated approach called "PeptideMine" for the identification of peptides based on specific functional patterns present in the sequence of an interacting protein. This approach based on sequence searches in the interacting sequence space has been developed into a webserver, which can be used for the identification and analysis of peptides, peptide homologues or functional patterns from the interacting sequence space of a protein. To further facilitate experimental validation, the PeptideMine webserver also provides a list of physico-chemical parameters corresponding to the peptide to determine the feasibility of using the peptide for in vitro biochemical or biophysical studies. CONCLUSIONS: The strategy described here involves the integration of data and tools to identify potential interacting partners for a protein and design criteria for peptides based on desired biochemical properties. Alongside the search for interacting protein sequences using three different search programs, the server also provides the biochemical characteristics of candidate peptides to prune peptide sequences based on features that are most suited for a given experiment. The PeptideMine server is available at the URL: http://caps.ncbs.res.in/peptidemine. PMID- 20858294 TI - [A boy with a swelling on the chest]. AB - A 15-year-old boy presented with a swelling on the right side of his thorax based on an isolated bifid rib, which was diagnosed by reconstruction CT-scanning. PMID- 20858293 TI - Educational inequalities in mortality and associated risk factors: German--versus French-speaking Switzerland. AB - BACKGROUND: Between the French- and German-speaking areas of Switzerland, there are distinct differences in mortality, similar to those between Germany and France. Assessing corresponding inequalities may elucidate variations in mortality and risk factors, thereby uncovering public health potential. Our aim was to analyze educational inequalities in all-cause and cause-specific mortality in the two Swiss regions and to compare this with inequalities in behavioural risk factors and self-rated health. METHODS: The Swiss National Cohort, a longitudinal census-based record linkage study, provided mortality and survival time data (3.5 million individuals, 40-79 years, 261,314 deaths, 1990-2000). The Swiss Health Survey 1992/93 provided cross-sectional data on risk factors. Inequalities were calculated as percentage of change in mortality rate (survival time, hazard ratio) or risk factor prevalence (odds ratio) per year of additional education using multivariable Cox and logistic regression. RESULTS: Significant inequalities in mortality were found for all causes of death in men and for most causes in women. Inequalities were largest in men for causes related to smoking and alcohol use and in women for circulatory diseases. Gradients in all-cause mortality were more pronounced in younger and middle-aged men, especially in German-speaking Switzerland. Mortality inequalities tended to be larger in German speaking Switzerland whereas inequalities in associated risk factors were generally more pronounced in French-speaking Switzerland. CONCLUSIONS: With respect to inequalities in mortality and associated risk factors, we found characteristic differences between German- and French-speaking Switzerland, some of which followed gradients described in Europe. These differences only partially reflected inequalities in associated risk factors. PMID- 20858295 TI - [Rendu-Osler-Weber syndrome and cerebral infarction]. AB - A 30 year old man with a history of migraine presented at the neurology outpatient clinic with hypesthesia of the left side of his body during a migraine attack, which was unusual for him. His family history was positive for Rendu Osler-Weber syndrome. MRI and magnetic resonance angiography (MRA) of the brain showed multiple small infarcts, without vascular malformations. CT angiography revealed an arteriovenous fistula in the lung. Rendu-Osler-Weber syndrome (or hereditary haemorrhagic telangiectasia, HHT) is an autosomal dominant condition affecting the blood vessels. It is estimated that about 60-80% of the patients with a pulmonary arteriovenous malformation (AVM) have HHT. Neurological complications include cerebral infarction and brain abscess. Also, there is a higher prevalence of migraine in patients with HHT, although the role that HHT plays in the pathogenesis of migraine is unclear. The treatment of choice of pulmonary AVM is endovascular treatment, with a success rate of 75% in the long term. PMID- 20858296 TI - [Endoscopic vein-graft harvesting for coronary bypass grafting: good results in patients at risk for surgical site infection]. AB - OBJECTIVE: To determine the clinical impact of endoscopic vein-graft harvesting in patients undergoing coronary artery bypass grafting (CABG) who are at risk for surgical site infection. DESIGN: Retrospective cohort study. METHOD: Of patients undergoing elective CABG between March 1st 2006 and March 1st 2007, 335 were eligible for analysis. The results of endoscopic vein-graft harvesting were compared with traditional open vein-graft harvesting. Medical records of all patients were reviewed and data collection was completed by means of a telephone survey. The primary outcome measure was the incidence of surgical site infections. Secondary outcome measures were duration of hospital stay, patient satisfaction and quality of life. RESULTS: Among the 335 patients included the incidence of surgical site infection was 2.5% following open harvesting (n = 236) and 2.0% following endoscopic harvesting (n = 99; p = 0.08). Patients in the endoscopic harvesting group had more risk factors for surgical site infection (diabetes, peripheral artery disease, obesity). Surgical site infection after open harvesting resulted in a prolonged hospital stay and a higher number of patients undergoing open wound treatment, re-admittance and additional surgical procedures. Total mean hospital stay in the open harvesting group was 7.9 days and 6.1 days in the endoscopic harvesting group (p < 0.05). Patients were more satisfied with the surgical wound after endoscopic harvesting compared with open harvesting (patient satisfaction score: 8.6 versus 7.8; p < 0.001). CONCLUSION: Endoscopic vein-graft harvesting resulted in a - statistically non-significant - lower incidence of surgical site infection than open harvesting, although the patients had a higher risk for infections. Infections in the endoscopic harvesting group were less severe. The hospital stay was shorter and the patient satisfaction was higher than in the open harvesting group. PMID- 20858297 TI - [The endo-exo prosthesis for patients with a problematic amputation stump]. AB - Following lower limb amputation, quality of life is highly related to the ability to use a prosthetic limb. The conventional way to attach a prosthetic limb to the body is with a socket. Many patients experience serious discomfort wearing a conventional prosthesis because of pain, instability during walking, pressure sores, bad smell or skin irritation. In addition, sitting is uncomfortable and pelvic and lower back pain due to unstable gait is often seen in these patients. The main disadvantage of the current prosthesis is the attachment of a rigid prosthesis socket to a soft and variable body. The socket must fit tightly for stability during walking but should also be comfortable for sitting. The implantation of an osseointegrated, intramedullary, transcutaneously conducted prosthesis is a new procedure for attaching a limb prosthesis to the human body without the disadvantages of the conventional prosthesis. The intramedullary prosthesis is designed with a rough surface resembling cancellous bone to enable a secure solid integration with the long bone. We treated two patients with this new prosthesis, a 44-year-old man after a transfemoral amputation, and a 32-year old woman after a lower leg amputation; both amputations were necessary because of trauma. Those two patients are now, more than one year after the operation, showing excellent functional results without infectious complications. We assume that endo-exo prosthesis may be a promising option for selected patients unable to use a conventional prosthesis because of a problematic amputation stump. PMID- 20858298 TI - [Treatment of complex biliary stones by cholangioscopy laser lithotripsy in 10 patients]. AB - OBJECTIVE: To describe the efficacy and safety of laser lithotripsy during peroral cholangioscopy for the treatment of complex biliary stones. DESIGN: Prospective, descriptive study. METHODS: Data were prospectively collected on all patients referred over a period of two years for peroral cholangioscopic laser lithotripsy following failure of endoscopic retrograde cholangiopancreatography (ERCP). The efficacy and safety of the treatment were studied. RESULTS: Eleven patients were treated. ERCP with stone removal and mechanical lithotripsy had been undertaken previously in these patients, but was unsuccessful. In one patient, lithotripsy was not performed because the endoscope could not be positioned satisfactorily. This patient was operated. Ten patients were treated with laser lithotripsy. In 9 of the 10 patients lithotripsy led to complete removal of all stone. In one patient the stone extraction partially failed. One complication occurred, a rupture of the common bile duct which could be managed conservatively by a stent. CONCLUSION: Peroral cholangioscopy guided laser lithotripsy of biliary stones appears to be a safe and effective treatment in patients in whom initial ERCP and mechanical lithotripsy is unsuccessful. PMID- 20858299 TI - [Medical research in children: should the rules be eased?]. AB - 'Non-therapeutic research' in children, i.e. research that will not directly benefit the patients involved, is indispensable for improving the quality of paediatric care. However, as children cannot give consent, such research is strictly limited. According to the Dutch Medical Research Involving Human Subjects Act (WMO) non-therapeutic studies with children are only allowed if the risks are negligible and the burdens are minimal. A Dutch expert committee ('committee Doek') investigating whether the WMO should be made less rigid, recently recommended discouraging the use of the distinction between 'therapeutic' and 'non-therapeutic' research and maintaining the absolute limit regarding risks and burdens only for observational studies in children younger than 12 years. This paper discusses these recommendations and argues that in principle, the risks and burdens of all research that has no direct benefit for the subjects should be kept to a minimum. PMID- 20858300 TI - [Medical research in children: the pros and cons of extending the legal boundaries]. AB - The Dutch Medical Research Involving Human Subjects Act (WMO) limits non therapeutic research in children by means of the absolute requirement of negligible risk and minimal burden. The European Clinical Trials Directive, however, allows clinical research with medicinal products in children when, among other requirements, the investigation has any direct benefit for the group of patients involved. In addition, pain, discomfort, fear and other anticipated risks should be minimised. This European Directive has been implemented in the WMO, but the Dutch restriction on non-therapeutic research with children was not adjusted. An expert committee has now advised the Dutch government to bring the WMO in line with the Clinical Directive for all forms of medical interventional and observational research involving children, except for observational studies in children younger than 12 years. In these children, the strict limits of minimal risk and burden should be maintained. PMID- 20858301 TI - [Diagnosis of fetal alcohol spectrum disorders]. AB - Prenatal alcohol exposure may cause decreased growth of the child, congenital abnormalities, specific facial characteristics, and, most importantly, mental retardation and behavioural disorders, all known as fetal alcohol spectrum disorders (FASD). A significant number of pregnant women in the Netherlands drink alcohol, but the prevalence of FASD in our country is unknown. Repeated and high peak blood alcohol concentrations, for example in the case of binge drinking by the mother, result in more severe abnormalities; a safe limit for alcohol consumption in pregnancy cannot be defined. In 2007 and 2008, Dutch paediatricians reported a total of 56 diagnosed cases of FASD, mostly adopted and foster children. Possibly the condition has not always been diagnosed. Use of international guidelines for diagnosis by the medical profession may improve detection. The guidelines of the Canadian Public Health Agency provide a useful and generally accepted classification, with strict cut-off points to avoid overdiagnosis; attention should always be paid to the broad differential diagnosis. PMID- 20858302 TI - [Outcomes of 16 years of oesophageal surgery: low postoperative mortality and improved long-term survival]. AB - OBJECTIVE: To assess trends in patient characteristics and treatment outcomes in a large cohort of patients who underwent oesophagectomy for oesophageal carcinoma in a tertiary referral centre over a period of 16 years. DESIGN: Retrospective cohort study. METHODS: We carried out a trend analysis on collected data on demographic and clinico-pathological characteristics, complications and survival of patients who underwent oesophagectomy between January 1993 and December 2008 at the Academic Medical Center in Amsterdam (AMC), the Netherlands. Patients were subsequently divided into three comparably-sized groups according to the year of operation: group 1 (1993-1998; n = 332), group 2 (1999-2004; n = 312), and group 3 (2005-2008; n = 296). RESULTS: A total of 940 patients underwent oesophagectomy during the total study period. Transhiatal oesophagectomy was performed more often during the first two time periods (65 and 64%, respectively), while the transthoracic approach was used more often in the third period (53%). The proportion of patients who underwent a microscopically radical resection increased significantly over the three periods of time. In-hospital mortality in all three periods was low, between 3.2%-3.4%. The three-year survival rate improved significantly over the three periods (p = 0.018), from 42% and 48% to 53% in the most recent period. CONCLUSION: Over the past 16 years in-hospital mortality in patients undergoing oesophagectomy for a potentially curable oesophageal carcinoma at the AMC, has been stably low. The total number of complications increased during these periods. Long-term survival improved during this time to a three-year overall survival of more than 50% in the most recent period. PMID- 20858303 TI - [A woman with chest pain]. AB - A 62-year-old Turkish woman presented at the emergency department with severe chest pain caused by a large, submucosal oesophageal haematoma. PMID- 20858304 TI - [Acute lymphoblastic leukaemia in children and adolescents: chance of cure now higher than 80%]. AB - Acute lymphoblastic leukaemia (ALL) is the most prevalent type of cancer in patients under the age of 18 years. Treatment of ALL consists of chemotherapy for a period of 2 years. Bone marrow transplantation and radiotherapy are indicated in only very few patients. The most important chemotherapeutic agents for the treatment of ALL are glucocorticoids (dexamethasone, prednisone), vincristine, asparaginase, methotrexate and 6-mercaptopurine. The cure rate of patients under the age of 18 years has increased from almost zero to > 80% in the past 40 years. Prognostically important factors are age at diagnosis, genetic abnormalities in the leukaemic cells and initial response to therapy. Adolescents with ALL have a much better prognosis when treated according to the protocol for children with ALL rather than the protocol for adults. It is anticipated that genomic research will lead to better classification and to more personalized therapy for individual patients. PMID- 20858305 TI - [Improved treatment results in hilar cholangiocarcinoma after transition to more extensive procedure: 20 years experience AMC]. AB - OBJECTIVE: To determine the result of surgical treatment of patients with hilar cholangiocarcinoma (HCCA) before and after the transition from predominantly local bile duct resections to more extensive resections including partial liver resection in order to achieve complete tumour resection in the Academic Medical Center, Amsterdam (The Netherlands). DESIGN: Retrospective and descriptive. METHODS: In the period 1988-2003, 117 consecutive patients underwent resection due to suspected HCCA. Preoperative work-up included staging laparoscopy, preoperative biliary drainage and short-course radiation therapy (3 x 3.5 Gy) to prevent seeding metastases. A more extended multidisciplinary surgical approach combining bile duct resection with partial liver resection was applied as of 1998. Outcomes of resection including 5-year survival were assessed in patients who had undergone resection before (1988-1997; period 1) and after (1998-2003; period 2) this change in surgical approach. RESULTS: In 18 patients (15.3%) a benign lesion was found in the resection specimen. Among the other 99 patients with microscopically confirmed HCCA, 21 (72%) of 29 patients had undergone bile duct resection in combination with partial liver resection in period 2 as compared to 17 (24%) of 70 patients in period 1. The margin tumour free resection rate increased from 20% in period 1 to 59% in period 2. Five-year survival increased from 20% (SE: 5) in period 1, to 33% (SE: 9) in period 2. Morbidity and mortality in period 2 were 69% and 10%, respectively, as compared to 64% and 17% in period 1. CONCLUSION: More extensive resection of HCCA in combination with partial liver resection in the setting of a multidisciplinary approach led to a higher rate of margin free resections and improved 5-year survival. PMID- 20858306 TI - [Thrombocytopenia in two newborn babies. Unexpected serious complications in full term babies]. AB - Thrombocytopenia usually has a moderate course in full-term babies. Here, however, we describe two newborns with serious complications due to neonatal alloimmune thrombocytopenia. One patient was transferred to the paediatrician because of pallor, a swelling on the head and petechiae. He had a subgaleal hemorrhage. Following a platelet transfusion he made a complete recovery. The other presented with thrombocytopenia and petechiae and was treated with intravenous immunoglobulin. Several days later the patient started vomiting. Cranial ultrasound showed hydrocephalus most probably arising from an intraventricular haemorrhage following the thrombocytopenia, for which he received a ventriculoperitoneal drain. After this he made a successful recovery. Although neonatal alloimmune thrombocytopenia is a rare condition it can have serious consequences for the newborn and for subsequent pregnancies. It is important that treatment be started early and that cranial ultrasound always be performed. PMID- 20858307 TI - [Coronary artery dissection in young adults]. AB - Two young patients, a 23-year-old man and a 30-year-old woman, without any risk factors for coronary artery disease, apart from the woman being a smoker, were admitted to our hospital because of acute myocardial infarction (MI) due to spontaneous dissection of a coronary artery (SDCA). The first patient developed acute chest pain while playing soccer. The second patient had unspecific chest pain in the preceding four weeks and was admitted after successful resuscitation with ventricular fibrillation. Both patients were treated with primary percutaneous coronary intervention. SDCA is a rare cause of MI and sudden cardiac death with an indistinguishable presentation due to plaque rupture. The majority of cases occur in young women. It is associated with various pathophysiological mechanisms and can manifest during pregnancy, in the postpartum period, in collagen diseases, cocaine abuse, severe hypertension, smoking, oral contraceptives, heavy exercise, or vasospasm. Treatment, pharmacological or with revascularization, is based on the severity of the dissection. Patients who survive the acute phase have good long-term prognoses. PMID- 20858308 TI - [Clinical relevance of retrospective observations]. AB - Many retrospective observational studies have been published in the recent literature. In the current issue of this journal two papers deal with retrospective analysis of observations after different surgical interventions: one concerns surgery for hilar cholangiocarcinoma, the other surgery for oesophageal carcinoma. Studies of this design are hard to interpret due to a number of methodological issues: (a) cohort effects: both the patient population and diagnostic procedures may have changed over time; (b) the learning curve of the healthcare provider, in this case the surgeon; and (c) confounding by indication: the data studied is biased by medical decision-making. However, the results of these studies inform healthcare providers and patients about survival and complication rates, among other things. Although they are not properly designed according to basic evidence-based medicine guidelines, these studies still provide us with clinically relevant information about current experience of medical interventions. PMID- 20858309 TI - [A toddler with vomiting and abnormal eye movements]. AB - A 1,5-year old girl was admitted to the hospital with vomiting and developed abnormal eye movements. MRI of the brain revealed a subdural hematoma associated with an arachnoid cyst. PMID- 20858310 TI - [Substitution of dexamethasone for dexamphetamine due to their written and spoken similarity]. AB - We present a 15-year-old girl and an 11-year-old boy who were prescribed dexamphetamine for treatment of Attention Deficit Hyperactivity Disorder (ADHD), and who subsequently presented with symptoms indicative of Cushing's syndrome. It turned out that both children had taken high doses of dexamethasone instead of dexamphetamine due to an error made by the pharmacist. The diagnosis of exogenous Cushing's syndrome is easily made. However, it is a serious condition with possibly severe and persistent complications. The substitution of dexamethasone for dexamphetamine has been described before. Both doctors and pharmacists should be aware of this possible error. PMID- 20858311 TI - [Progesterone for prevention of preterm delivery: only in trial setting]. AB - Since the discovery of progesterone researchers have studied whether administration of exogenous progesterone can prevent preterm birth. Two trials were published in 2003 that showed a positive effect of progesterone with regard to the prevention of recurrent preterm birth. However, more recent data do not support these findings. In multiple pregnancies the use of progesterone does not seem to reduce the number of preterm births. The results in pregnant women with asymptomatic shortening of the cervix are promising, although more research is needed in this group. PMID- 20858313 TI - [Requirements regarding compounded pharmaceutical preparation]. AB - Picking the wrong container with raw material in making compounded pharmaceutical preparation is one of the threats to patient safety. The question is whether there still is a place for this type of medication in pharmacotherapy. This case raises three questions: is there a therapeutic rationale for this therapeutic agent, how far should we go in individualizing pharmacotherapy and what are the pharmaceutical prerequisites for this kind of compounding? Once there is an agreement about the need for this product, the focus is on the need for implementation of Good Manufacturing Practice (GMP) rules in community pharmacies. Alternatively, this type of individualized therapy should be stopped. PMID- 20858312 TI - [Fluorodeoxyglucose F18(FDG)-probe guided biopsy]. AB - Although positron emission tomography-computed tomography (PET-CT) has improved the diagnosis of malignant and inflammatory abnormalities, histopathological examination is often required to supplement imaging examination in order to make a definite diagnosis. In some cases a lesion is not visible using conventional imaging techniques but is visible on a PET scan with fluorodeoxyglucose F18 (FDG). In other cases a lesion cannot be approached percutanuously because of localisation or size of the lesion. In these cases the surgeon can now perform an FDG-probe guided biopsy or resection. Using this technique the surgeon can peroperatively detect lesions that have taken up radioactive FDG - so-called FDG avid lesions - and excise these for histopathological examination. This technique reduces the inadvertent excision of non-representative tissue and can be of value for localising FDG-avid lesions for total resections. FDG-probe guided surgery can potentially increase the sensitivity of diagnostic resections. PMID- 20858315 TI - [Variations in Dutch National Medical Registration hardly affect the hospital standardised mortality rate (HSMR)]. AB - OBJECTIVE: To analyse the variation in the registration of hospital admissions across Dutch hospitals and determine how this variation affects the Hospital Standardised Mortality Rate (HSMR). DESIGN: Retrospective, descriptive. METHOD: We used data from the National Medical Registration (LMR), covering the records of all hospital admissions in 2005 in Dutch hospitals, to analyse the variation between hospitals in 3 variables: the number of secondary diagnoses, the percentage of unplanned admissions, and the percentage of non-specified diagnoses ('other diagnoses'). The impact of this variation on the HSMR was analysed by calculating the correlation between the HSMR and each of the variables. The correlation between the original HSMR and the HSMR without adjustment for these variables was also calculated. RESULTS: The variation in the percentages of unplanned admissions and admissions with a non-specified diagnosis was low. The variation in these two variables had a small or no effect on the HSMR. There was a considerable variation in the mean number of secondary diagnoses per hospital. This variation had a limited but statistically significant effect on the HSMR. The HSMR calculated without adjustments for secondary diagnoses correlated strongly with the original HSMR. CONCLUSION: This analysis does not support the view that the HSMR is strongly affected by variation in the registration of hospital admissions and is therefore not reliable. Therefore, there is no need for restraint with regard to publication of the Dutch HSMR. PMID- 20858316 TI - [Unusual use of nutmeg]. AB - A 20-year-old woman with borderline personality disorder was referred to the emergency department by a psychiatric clinic. After taking 10 g of nutmeg she complained of stomach ache and dizziness. A physical examination showed mild hypothermia and sinus tachycardia. She was admitted for observation and discharged after 24 h to the psychiatric clinic without sequelae. Nutmeg is a spice. Relatively unknown are the hallucinogenic and euphoric effects for which it is used by drug abusers and students. Symptoms appear 6 h after ingestion of at least 10 g of nutmeg and are related to its effects on the central nervous system. Use of the drug can lead to anxiety and feelings of doom and even to psychosis. Dry mouth, nausea and dizziness may also occur. A physical examination may show hypothermia, tachycardia or hypertension or, in rarer cases, hypotension and shock. Symptoms disappear without sequelae after 24-48 h. Treatment consists of supportive measures. In the event of haemodynamic instability, cardiovascular monitoring is indicated. PMID- 20858317 TI - [Atrial fibrillation: a growing problem in clinical practice]. AB - The first revision of the the practice guideline 'Atrial fibrillation' from the Dutch College of General Practitioners has provided an important document. Atrial fibrillation is a growing problem in clinical practice. Harmonization of general practice with cardiological guidelines will undoubtedly have favourable results, with as consequences improvement of the diagnostic outcome and state of the art treatment at an earlier moment. It can be expected, that the revised version of the Dutch College of General Practitioners' practice guideline will greatly contribute to the dialogue between cardiologist and general practitioner and may perhaps lead to joint research. PMID- 20858318 TI - [A man with a swelling next to his nose]. AB - A 61-year old male presented himself at the department of dermatology with an asymptomatic node next to the nose, which appeared to be a first manifestation of sarcoidosis. PMID- 20858319 TI - [Medullary thyroid cancer, a tumour with many appearances]. AB - Medullary thyroid cancer (MTC) has a variable clinical presentation. We present 3 patients with this endocrine tumour. The first patient, a 41-year-old woman complaining of diarrhoea, a painful abdomen, weight loss and sensibility disorders in both legs, had metastases of MTC in the spine, with little progression during 2 years of follow-up. The second patient, a 64-year-old woman suffering from a painful nodule in the neck and a painful shoulder, was diagnosed with MTC and liver, lung and bone metastases. She died after 14 months due to progressive disease. The third patient, an 81-year-old woman with hyperparathyroidism, was coincidentally diagnosed with MTC after goitre surgery at the age of 67. When she was evaluated for rising calcitonin levels, a pheochromocytoma was found. RET mutation analysis confirmed a MEN2A syndrome. Current diagnostic procedures of MTC may include positron emission tomography with 18F-deoxyglucose (FDG-PET) and 18F-diphenylalanine (DOPA-PET). MTC is usually treated surgically. Tyrosine kinase inhibitors appear to offer potential new therapeutic possibilities. PMID- 20858320 TI - [Hypoxaemia and bradycardia in children during guillotine adenotonsillectomy without intubation]. AB - OBJECTIVE: To study the incidence of hypoxaemia and bradycardia in children who undergo guillotine adenotonsillectomy in a sitting position, without intubation and under inhalation anaesthesia. DESIGN: Retrospective study. METHOD: Analysis of age, weight, sex, oxygen saturation, heart rate and subsequent bleeding in all children up to the age of 11 years who underwent guillotine adenotonsillectomy in the period December 1999 to December 2007. Hypoxaemia was defined as oxygen saturation of less than 85% for longer than 60 s. Bradycardia was defined as a heart rate of less than 60/min for longer than 30 s. RESULTS: We analysed data from 2963 patients. The mean age was 4.7 years and mean weight 18.8 kg. There was no significant relationship between age, weight and the onset of incidental desaturation or bradycardia. A total of 132 patients (4.5%) had hypoxaemia and 280 patients (9.4%) had bradycardia. Twenty-five patients had both hypoxaemia and bradycardia, of whom 3 (0.1%) had bradycardia immediately following hypoxaemia. In none of the recorded episodes of hypoxaemia and bradycardia did this lead to peri- or postoperative complications. CONCLUSION: Hypoxaemia and bradycardia occurred during guillotine adenotonsillectomy in non-intubated children in a sitting position under inhalation anaesthesia. The simultaneous onset of hypoxaemia and bradycardia is rare, however, and does not lead to perioperative complications. A further study is required using adenotonsillectomy with a large number of intubated and non-intubated children in order to compare the incidence of hypoxaemia and bradycardia and the occurrence of complications. PMID- 20858322 TI - [Anabolic androgenic steroids in amateur sports in the Netherlands]. AB - In the Netherlands an estimated 20,000 people use anabolic androgenic steroids (AAS). The use of AAS is particularly common in regular visitors to gyms and fitness centres. AAS are usually synthetic derivatives of testosterone with both an anabolic and an androgenic effect. AAS have many side effects like liver damage (oral use) or infections (intramuscular use), which can be explained partly by the androgenic effect and partly by the manner of use. Many of these side effects are only reported in case studies and have not been systematically investigated. PMID- 20858323 TI - [Carbapenem-resistant Klebsiella pneumoniae following foreign travel]. AB - This is the first report of 3 patients in whom carbapenemase-producing Klebsiella pneumoniae was identified in the Netherlands following foreign travel. They were a 55-year-old man who had undergone chemotherapy for lung cancer metastases, a 66 year-old woman and a 30-year-old man. The first patient was transferred from a Greek hospital; his isolate belonged to an epidemic clone (multilocus sequence type 258) with a KPC-2 carbapenemase gene. The patient died from pneumonia. The other two patients, who had been travelling around in India, were found to be colonised in the gasto-intestinal tract with different multiresistant K. pneumoniae isolates containing a New Delhi metallo-carbapenemase gene (NDM-1). The rapid emergence and dissemination of Enterobacteriaceae resistant to carbapenems such as imipenem and meropenem poses a considerable threat to clinical patient care and public health. Carbapenemase-producing strains are characterized by resistance to nearly all available beta-lactam antibiotics including cephalosporins and carbapenems. These strains are often also resistant to other classes of antibiotics. Invasive infections by these strains are associated with high morbidity and mortality rates. Adequate microbiological laboratory detection and infection control measures in hospital are pivotal to preventing dissemination in the Dutch healthcare setting. PMID- 20858324 TI - [Antibiotic resistance: measures urgently needed]. AB - Antimicrobial resistance is increasing rapidly and there are hardly any new antimicrobial agents to be expected in the coming years. The number of patients affected by extended spectrum beta-lactamase producing organisms (ESBLs) is rising and there are strong indications that this is caused in part by the use of antimicrobial agents in animal husbandry. There are many arguments against the widespread use of antimicrobial agents in food-production animals, but this has not resulted in decreased usage so far. The current situation is critical and requires immediate action. In human healthcare the prescription of 'rescue' antibiotics, e.g. carbapenems, has to be restricted and controlled. In animal husbandry the use of antibiotics has to be reduced dramatically and a more sustainable approach to food production has to be supported by government and consumers. PMID- 20858325 TI - [Laboratory diagnosis of acute Q fever]. AB - In the Netherlands an increasing number of laboratories are involved in diagnosing acute Q-fever. More uniformity in diagnostics and interpretation is desirable. To enable this, a working group on diagnostics of acute Q-fever was created on the initiative of the National Institute for Public Health and the Environment (RIVM) and the Dutch Association for Medical Microbiology (NVMM). The diagnostics of acute Q-fever includes a diagnostic flow chart (algorithm) consisting of tests for DNA and for antibodies against the antigens that appear in the successive stages of the disease. Reporting of both confirmed and suspected cases of acute Q-fever is obligatory. PMID- 20858326 TI - [The environment: a challenge for health]. PMID- 20858327 TI - [Introduction. The environment and public health]. PMID- 20858328 TI - [Is environmental health the future of public health?]. AB - In France, the field of public health and public health training have developed over recent decades in parallel to the emergence of environmental health; however, these two fields are grounded in conceptual and methodological underpinnings that often differ. The authors of this article try to analyse the differences between these two approaches which both have prevention as their main purpose. Both approaches use epidemiology as a tool, but they are distinguished by their uniquely different definitions of environment. Unifying both approaches around a common basis is possible, but in order to do this, public health must evolve to expand and integrate new disciplines other than epidemiology. Supported by its close ties to societal issues of concern and recent scientific developments, the environmental health boom can and should revive public health values and contribute to the development of public health training in France. PMID- 20858329 TI - [Research, impact and adaptation in public health for the new climate of Quebec]. AB - After its modest beginnings focusing on arctic Quebec in 1999, the Quebec research programme on health and climate change became interested in the remainder of the province around 2002. The European heat wave in 2003 accelerated the pace of this programme and prompted the Quebec health sector's participation in the Ouranos Research Consortium. The research findings from the 2003-2006 period have directly fed into the health component of the Quebec government's climate change action plan (2006-2012), financed through the first carbon tax in the Americas. This component is planning for a series of adaptations to the health network and to some other public networks, which will apply to construction, the built environment and outdoor developments, clinical management methods and practices, public health surveillance as well as emergency preparedness. In this article, the authors describe how research is supporting action and implementation, while also preparing for the future, and how this interaction has progressively established itself over the last 10 years. PMID- 20858330 TI - [The adventures of "Sick Building Syndrome"]. AB - The Sick Building syndrome concept is used to describe a variety of minor symptoms that afflict groups of people in the workplace or in public buildings. In theory, the sick building syndrome is characterized by an unspecified etiology: it underlines a multiplicity of possible causes, environmental or psychosocial, which produce various effects. In practice, the concept is often misused as a synonym of the psychogenic syndrome. The paper explores this "etiological reduction" and highlights some of the problematic consequences. The authors advocate for the recognition of uncertainty, which is in their opinion, a source and driver of renewed reflection in the public health area. PMID- 20858331 TI - [General practitioners mobilize to confront a cancer cluster]. AB - With a view to respond to the growing concerns of a neighborhood population where a cluster of cancer was observed in 2002, public health authorities organized monitoring and surveillance activities by mobilizing local general practitioners (GPs). The monitoring activity has been carried out in the form of a free annual prevention consultation available at some local GPs' offices. Five years after the initiation of this monitoring activity, it was deemed interesting and necessary to make a review of the activity to take stock of the procedures established. Various data sources have been analyzed: anonymous records and files completed by GPs, answers to satisfaction enquiries sent out to the beneficiaries of the action in 2008, and the compilation of feedback and reactions of participating GPs during the annual meetings with the team responsible for monitoring. In 5 years, 29% of the population concerned went to one consultation at least. The percentage of participants gradually decreased to 2% at the fifth visit. The follow-up consultation was considered to be satisfactory by the surveyed population, and GP volunteers confirmed their interest in this approach. The positive atmosphere in which the follow-up and the monitoring took place is noteworthy and corroborates the role that health professionals can play in the management of a cancer cluster. PMID- 20858332 TI - [Do pharmaceutical waste and drug residue pose a risk to public health?]. AB - Recently, awareness has developed of the environmental consequences of drug waste and disposal. These residues are identified as coming from either diffuse sources, the most significant of which is via the discharge of these residues in urine and feces, and thus the sewage system and water contains these drug remnants and their metabolites, or from point sources, sometimes with very high levels of concentration in waste from chemical and pharmaceutical industries, health care settings, but also from intensive livestock farming and aquaculture. Depending on their physical chemistry properties, these substances are more or less naturally biodegradable and easily treated in sewage purification plants. The effectiveness of these treatment processes is highly random and unpredictable, but is overall around 60%, nevertheless with variations of 2-99% according to the molecules. The silt from these treatment plants, sometimes very rich in lipophilic substances is on occasion reused for agricultural application as fertilizer, paving the way for a possible contamination of crops. Furthermore, the use of veterinary drugs in animals can lead to soil contamination either directly or through manure and slurry. The contamination can equally reach and affect surface water, groundwater and sometimes the water intended for human consumption. The National academy of Pharmacy has established some general recommendations on the proper use of drugs, environmental monitoring and surveillance, risk assessment for humans and the environment, prevention and the need for prevention. Several categories of drugs are more worrying: cancer treatments, antibiotics as well as transfers of anti-bio-resistance, and hormonal derivatives which has been previously demonstrated to contribute, along with other molecules, to detrimental effects on endocrines. PMID- 20858333 TI - [Health and environment: the 2nd public health revolution.]. AB - As of the mid-19th century, most infectious disease epidemics have been fought and slowed down by taking action on the environment (water, housing, waste) and education. This constitutes the 1st public health revolution paradigm. As we face the current epidemic of chronic diseases and the failure of the dominant biomedical model to stop them, a 2nd public health revolution is needed. The vision for this 2nd public health revolution requires a new paradigm built upon an eco-systemic definition of health and the recognition of the legitimacy for citizen participation based on the precautionary principle. PMID- 20858335 TI - [Assessing the potential impact of public policies on health: the stars are aligned!]. PMID- 20858336 TI - [Nosocomial infection control in France: a socio-historical approach]. AB - This article argues that the emergence of nosocomial infections as a public health issue is the result of specific socio-cultural processes. An analysis of the French periodical Revue d'Hygiene et de Medecine Sociale over the period 1953 1988 and of the discourse of national actors in the fight against hospital acquired infections demonstrates that the recognition of nosocomial infections as a public health issue occurred almost independently of objective criteria related to frequency or severity. It is suggested that professional and societal factors provide a better explanation of the emergence of nosocomial infections as a public health issue. Nosocomial infections essentially rescued ?Hygiene', a discipline threatened by the reorganization of the university-hospital system following the 1958 reform. Having entered hospitals, hygienists have had to compete with microbiologists also involved in a subject that has attracted an increasing number of actors from a range of fields. Beyond the development of a public health issue, a battlefield of symbolic fights is thus emerging. PMID- 20858337 TI - [Blood donation in foreign populations in Marseille]. AB - Blood donations by populations from the Maghreb and Sub-Saharan Africa are a public health necessity for reasons of genetic polymorphism. This article aims to determine whether blood donors' social characteristics ? i.e. greater socio economic integration and a strong sense of citizenship ? constitute deterrents to blood donation among foreign populations. Results show that donors from the Maghreb and Sub-Saharan Africa are not better integrated than non-donors from the same areas. However, blood donors express a significantly greater sense of citizenship than non-donors. Donors from the Maghreb and Sub-Saharan Africa feel a greater sense of citizenship than non-donors from the same areas. The study of blood donation in these categories of population has two major implications. In biological terms, blood donation by foreign populations constitutes a response to transfusion needs. In cultural terms, blood donation is used by populations from the Maghreb and Sub-Saharan Africa as an active means of expressing their sense of citizenship. PMID- 20858338 TI - [Management and follow-up of patients treated with antiretroviral prophylaxis: an evaluation of professional practices]. AB - The care management of patients treated for cases of sexual or blood exposure requires stringent clinical and biological follow-up procedures. Despite the provision of information about the importance of regular follow-up, the number of patients dropping out of screening consultations at the Hospital Lariboisiere Fernand Widal (Assistance Publique-Hopitaux de Paris) has increased. The main purpose of this study is to improve follow-up for patients treated with anti retroviral prophylaxis following a known sexual or blood exposure. An investigation based on 5 markers of a targeted clinical audit form ("drop-outs" or lost to follow-up, conduct of HIV serology tests, traceability of clinical, biological and compliance monitoring) was carried out. A review of practices was conducted on the basis of an analysis of patient cases over a six-month period, followed by the implementation and evaluation of corrective measures over a two year period. A significant decline in the number of patients lost to follow-up was observed. The study shows a significant improvement in other markers: serological follow-up, compliance traceability, and clinical and biological monitoring. These results were observed between 2005 and 2007. Two distinctive effects were identified: improvement in patient care management and the quality of care, and the empowerment of actors, thereby ensuring a certain continuity of action. The decline in the rate of lost to follow-up patients and improved monitoring of compliance and iatrogenic risks confirm these effects. The overall approach is incorporated into an evaluation of professional practices. PMID- 20858339 TI - [An economic evaluation of intimate partner violence in France]. AB - This study aims to carry out an economic evaluation of intimate partner violence in France. Using published data, institutional sources, field studies and expert opinions, the cost of intimate partner violence is estimated in terms of the overall cost to society. A range of different economic approaches are used (micro economic, meso-economic and macro-economic approaches). The total cost of intimate partner violence in France is estimated at 2.5 billion Euros per year (between 1.7 and 3.5 billion Euros). The total cost of intimate partner violence includes healthcare costs (483 ? million), social and justice services (355 ? million), production losses as a result of deaths, imprisonments and absenteeism (1099 ? million), and the human costs of rape and prejudice (535 ? million). By increasing the budget allocated to the prevention of domestic violence by one euro, it is estimated that the state, health insurance and local authorities could make savings of up to 87 Euros of social spending, including 30 Euros of direct expenses. PMID- 20858340 TI - [Physical activity and consumption of fruits and vegetables: social representations in relation to age]. AB - The aim of this paper is to carry out a survey and comparative analysis of social representations of physical activity and fruit and vegetables in a sample of young, adult and elderly subjects. Four "urban" areas and four "rural" areas were selected for the purposes of the investigation. The samples used to assess social representations of fruit and vegetables and physical activity included 132 and 153 participants respectively. Verbal association was used and a factorial correspondence analysis was applied to the data. The prevention messages delivered as part of the second national program of nutrition and health were integrated by adult participants. A very limited awareness of the benefits of eating fruit and vegetable was observed in the young population. This study underlines the importance of implementing regular measures for the purposes of qualitative local evaluations that consider the specific characteristics of every age group in order to assess the psychological impact of prevention campaigns. PMID- 20858341 TI - [Assessment of the quality of response to the 2008 cholera outbreak in Contonou (Benin)]. AB - To assess the quality of the response to the 2008 outbreak of cholera in Cotonou (Benin), this retrospective study focused on the health professionals managing the response, community leaders, cases of cholera found in homes and health service documents. The terms of reference used for the purposes of this assessment included the WHO recommendations and the rules set out in the national plan for the fight against epidemics. The resources and method used in this study complied with the norms specified in the plan, as did the epidemiologic follow up. Community and family interventions concerned only a limited number of households in comparison with the total number of cases. Of the 402 cases diagnosed between July 28th and October 16th 2008, 384 cases were given treatment complying with the specified protocols, and just one death was recorded (hospital lethality 0.25%). The mean length of hospitalization was 2.43 days +/- 1.16. Compliance with standard response procedures resulted in good quality care and very low lethality. The national plan of response to epidemics is therefore validated. An improved management of outbreaks requires national multi-sector coordination. Authorities in the following areas need to be involved: healthcare, environment, education, public administration and local communities. PMID- 20858342 TI - [Decreased hospital spending as a result of antibiotic prescriptions dispensed in community pharmacies. Results from the Midi-Pyrenees region.]. AB - A contract between French hospitals and national health authorities was signed in early 2006 to improve the rational use of antibiotics in hospitals. The contract offers a financial reward in the event of decreased spending as a result of hospital prescriptions dispensed in community pharmacies compared to the previous year. The article describes the limitations relating to the financial rewards defined by the contract, particularly those concerning the measurement and relevance of the chosen indicator. Since no national data are currently available, quantitative results drawn from the Midi-Pyrenees region are used to illustrate the analysis. PMID- 20858343 TI - [Proposal for a framework for the evaluation process in health education]. AB - The article outlines a proposal for a framework of evaluation as part of a project for the prevention of tobacco addiction. Though not glaringly self evident, this type of evaluation is a response to a pressing need in view of the wide range of partners involved, the available conventions and different temporalities among actors. The conceptual and methodological approach draws from the sociology of organizations and political science, but also from the perceptions and experiences of a wide range of actors. Far from being exclusive, the concepts and analytical tools used to assess the project may yet serve to restore the fundamental meaning of a system of relations within a project or, better yet, to direct emerging projects on the basis of future relations anticipated between the different partners. PMID- 20858344 TI - [An urban health workgroup in northern Marseille: the experiment of a health and living environment network]. AB - The reseau sante cadre de vie (health and living environment network) was created in 2007 by the Atelier Sante Ville (Urban Health Workgroup) with the support of the CUCS in a run-down residential area of Marseille. Its aim is to improve the health of residents living in the private jointly-owned property of Kalliste by acting on factors determining lifestyle practices and the living environment. With the help of associations and institutions involved in the local network, a range of activities targeting local residents have been developed to promote access to healthcare and prevention and improve the living environment. The success of the project can be largely attributed to the involvement of the local social centre and institutional support. The development and continuity of cooperation (particularly between housing professionals and healthcare professionals) remain significant challenges in the effort to ensure the coherence and efficiency of the project. PMID- 20858345 TI - [Community-based intervention to reduce birth asphyxia mortality in Mali]. AB - Approximately one million newborn babies die every year as a result of birth asphyxia in developing countries. The objectives of this study are to develop the management of birth asphyxia and to establish a community-based surveillance system of vital events in rural areas of Ouelessebougou, Mali. Traditional birth attendants, female leaders of village associations and village health workers were trained to carry out communication activities designed to change behaviours in the management of birth asphyxia. The study has improved health facility-based delivery (from 80 to 93%) and the identification of birth asphyxia (11 to 12% new born babies have been resuscitated). As a result of training and supervising community actors, the quality of delivery is improved and neonatal mortality is reduced. PMID- 20858355 TI - Measurement of fetal biparietal diameter in owl monkeys (Aotus nancymaae). AB - Owl monkeys are New World primates frequently used in biomedical research. Despite the historical difficulty of breeding owl monkeys in captivity, several productive owl monkey breeding colonies exist currently. The animals in the colony we describe here are not timed-pregnant, and determination of gestational age is an important factor in prenatal care. Gestational age of human fetuses is often determined by using transabdominal measurements of fetal biparietal diameter. The purpose of this study was to correlate biparietal diameter measurements with gestational age in owl monkeys. We found that biparietal diameter can be used to accurately predict gestational age in owl monkeys. PMID- 20858356 TI - Treatment and eradication of murine fur mites: I. Toxicologic evaluation of ivermectin-compounded feed. AB - Fur mite outbreaks remain a persistent problem in laboratory mouse colonies. All currently published treatment methods are labor-intensive, expensive, or unreliable. During a recent outbreak with Myobia musculi and Myocoptes musculinus in a large colony (approximately 30,000 cages), we developed a feed-based treatment regime in which ivermectin was the active ingredient. Rodent feed was compounded with 3 different concentrations of ivermectin (12, 24, and 48 ppm) and gamma-irradiated. Postcompounding analysis revealed loss of ivermectin during manufacturing, but the remaining drug was stable for at least 6 mo. In an 8-wk toxicity study in a C57BL/6NTac mouse breeding colony, ad-libitum feeding of the 3 diets yielded estimated doses of 1.3, 2.7, and 5.4 mg/kg. Adult mice lacked adverse clinical effects, except that 1 of the 144 mice in the 48-ppm group developed tremors and ataxia and was euthanized. No significant differences between doses were revealed by CBC, serum chemistry, body weight, or gross necropsy. Plasma drug concentrations plateaued at a dose-dependent level 7 to 10 d after initiation of treatment and decreased to undetectable levels 6 to 9 d after its discontinuation. Fertility of the P0 generation was unaffected. Pup mortality was higher in the 24- and 48-ppm groups, reaching 100% at the higher dose. Animals exposed to ivermectin as neonates had normal weaning weights, but mice receiving 24-ppm feed had lower adult weights. Our results indicate that using feed containing 12 ppm ivermectin (estimated ingested dose, 1.3 mg/kg) was safe in a C57BL/6NTac breeding colony. PMID- 20858357 TI - Multidimensional cost-benefit analysis to guide evidence-based environmental enrichment: providing bedding and foraging substrate to pen-housed monkeys. AB - Refinement of animal care and housing is an important shared goal-and challenge of the team of research, veterinary, and animal care personnel charged with ensuring the wellbeing of laboratory animals. This study addresses 2 issues central to decision-making and implementation of environmental enhancement: methods for useful and comprehensive cost analysis and evaluation of engineering, husbandry, and facilities considerations. The study was undertaken to analyze the feasibility and cost of providing wood shavings as a floor cover for pen-housed monkeys. The beneficial effects of bedding for the welfare of laboratory-housed animals have long been validated. Our study illustrates a workable team-based procedure for comprehensive cost analysis of an important environmental enhancement and demonstrates that the animal welfare benefit is accompanied by decreased husbandry costs. An engineering solution to the potential challenge that wood shavings pose in terms of clogging water pipes was successful. Another successful outcome was the reduction in water (estimated at 192,000 gal annually) and chemicals used to clean housing areas. Emphasis on rigorous evaluation and objective measures of cost and benefit, as well as inclusion of the many factors and teams involved in animal research, holds strong potential for building a better foundation from which to contribute effective changes and improvements in laboratory animal welfare. Taken together, the findings of this study demonstrate that team-based, integrative, and scientific evaluation of environmental enhancement is an effective approach to guide selection of strategies with maximal potential for improving animal welfare. PMID- 20858358 TI - Operation of an air filtration device results in morbidity and mortality in growing chickens (Gallus gallus domesticus). AB - Environmental conditions may influence experimental outcomes in laboratory animals. In this study, we measured the effects of a vortex air-filtration device (AFD) on growth rate, morbidity, mortality, behavior, and gross pathology in P2a Leghorn chickens (Gallus gallus domesticus) raised from hatchlings to 6 wk of age. Growth rate was reduced in the group exposed to the operating AFD ('AFD on' group) compared with the 2 control groups ('AFD off' and 'Historical' groups). Similarly, 6-wk survival probability and body weight were decreased in the AFD-on group compared with controls. Splenic and cardiac weight indices were lower in the AFD-on and AFD-off groups compared with the Historical group. A progressive increase in the ambient sound level (Historical, 53.5 +/- 1.7 dBA; AFD off, 63.6 +/- 0.5 dBA; AFD on, 71.8 +/- 0.8 dBA) was the only variable found to correlate with the physiologic differences observed across the 3 groups of growing chickens. These findings indicate that experimental outcomes with growing chickens are negatively affected by vortex air-filtration devices. PMID- 20858359 TI - Treatment and eradication of murine fur mites: II. Diagnostic considerations. AB - Fur mites are a persistent problem in contemporary laboratory mouse colonies. We conducted several studies to evaluate fur mite diagnostic methodologies and interpretation of results. Retrospective analysis of test results from sentinel mice exposed to soiled bedding collected from colonies infested with Myobia musculi and Myocoptes musculinus revealed the skin scrape test to be more reliable than pelt examination, provided that both the head and dorsal thoracolumbar regions were sampled. To assess their diagnostic accuracy, 3 commercial laboratories were sent positive control slides containing mites, mite parts, or eggs in sets of slides containing diagnostic skin scrapings in varying ratios. Laboratory B correctly identified the positive control slide. Laboratory A identified 1 of 3 positive control slides, whereas laboratory C failed to identify both positive control slides submitted. To determine the time required for a mouse to shed its entire hair coat, fur of Crl:CD1(ICR), BALB/cAnNCrl, and Crl:CFW(SW) albino mice was dyed black and the presence of dyed fur evaluated monthly for 8 mo. Limited dyed hair was still present at 8 mo; therefore, finding eggs or egg casings many months after treatment cessation does not necessarily imply treatment failure. To evaluate the effectiveness of soiled bedding sentinels for detection of fur mites in a mite-infested colony, we exposed naive mice to varying amounts (100%, 50%, 25%, 2.5%, and 0%) of soiled bedding in clean bedding. As little as 2.5% soiled bedding resulted in detection of a positive sentinel within a 2-mo period. PMID- 20858360 TI - Resident bacterial flora in the skin of C57BL/6 mice housed under SPF conditions. AB - Research in cutaneous biology frequently involves models that use mice housed in SPF conditions. Little information is available concerning the species of bacteria that normally inhabit the skin of these mice. The aim of this study was to characterize the bacterial skin flora of mice housed under SPF conditions. Skin biopsies from C57BL/6 mice under normal and surgically prepped conditions were both cultured and analyzed by using DNA extraction and sequencing. The species isolated most commonly from culture were staphylococci. Coagulase negative staphylococci were isolated more frequently than was Staphylococcus aureus. Molecular sequencing yielded several additional organisms not found by culture. Overall, culturing of isolates yielded 14 species of bacteria, and molecular sequencing identified another 6 species. Investigators conducting cutaneous research in mouse models should aware of the cutaneous bacterial flora present on these mice. PMID- 20858361 TI - Noise in a laboratory animal facility from the human and mouse perspectives. AB - The current study was performed to understand the level of sound produced by ventilated racks, animal transfer stations, and construction equipment that mice in ventilated cages hear relative to what humans would hear in the same environment. Although the ventilated rack and animal transfer station both produced sound pressure levels above the ambient level within the human hearing range, the sound pressure levels within the mouse hearing range did not increase above ambient noise from either noise source. When various types of construction equipment were used 3 ft from the ventilated rack, the sound pressure level within the mouse hearing range was increased but to a lesser degree for each implement than were the sound pressure levels within the human hearing range. At more distant locations within the animal facility, sound pressure levels from the large jackhammer within the mouse hearing range decreased much more rapidly than did those in the human hearing range, indicating that less of the sound is perceived by mice than by humans. The relatively high proportion of low-frequency sound produced by the shot blaster, used without the metal shot that it normally uses to clean concrete, increased the sound pressure level above the ambient level for humans but did not increase sound pressure levels above ambient noise for mice at locations greater than 3 ft from inside of the cage, where sound was measured. This study demonstrates that sound clearly audible to humans in the animal facility may be perceived to a lesser degree or not at all by mice, because of the frequency content of the sound. PMID- 20858362 TI - Population genetic statistics from rhesus macaques (Macaca mulatta) in three different housing configurations at the California National Primate Research Center. AB - This study analyzed the genetic composition of 3382 genetically characterized and pedigreed animals currently maintained under 3 different housing configurations at the California National Primate Research Center, including the indoor colony, outdoor 'corn cribs,' and half-acre field cages. Summary statistics based on 15 short tandem repeats strongly suggest significant effects of genetic drift, including the loss of allele diversity, among the enclosures within the housing facilities even though gene flow among the different housing units is actively promoted by colony management. Management methods of selectively harvesting female macaques to prevent overrepresentation of one or only a few matrilines and cross-fostering 1-wk-old infants among breeding cages and corn cribs have been insufficient to prevent genetic subdivisions among the cages and corn cribs and to evenly distribute genetic diversity throughout the colony. In addition to promoting several colony management strategies recommended herein to effectively curb inbreeding and genetic differentiation, current attempts of infant cross fostering and minimizing matriline fragmentation should be expanded. The inclusion of inbred or highly genetically homogeneous animals with diminished allele diversity in linkage and association studies will likely compromise the potential for identifying allele-disease associations, whereas the inclusion of macaques from different geographic origins or their hybrids (or both) in experimental research confounds interpretations of phenotypic differences, due to inflation of the genetic contribution to phenotypic variance. PMID- 20858363 TI - Assessment of carprofen and buprenorphine on recovery of mice after surgical removal of the mammary fat pad. AB - The purpose of this study was to determine the level of pain elicited by mammary fat pad removal surgery and the effects of postoperative analgesics on recovery. Female FVB mice were anesthetized, and mammary fat pad removal was performed. After surgery, mice received carprofen, buprenorphine, a combination of carprofen and buprenorphine, or saline treatment. Additional mice received anesthesia but no surgery or treatment. Food and water intake, body weight, wheel running activity, and a visual assessment score were recorded daily for 4 d after surgery and compared with presurgical findings. Corticosterone metabolites in fecal samples were analyzed at 12 and 24 h postsurgically and compared with baseline values. All surgical groups had significantly decreased food intake at 24 h, with a return to baseline by 48 h. The combination treatment resulted in a significantly decreased water intake and body weight at 24 h. All surgical groups had significantly decreased wheel running activity at 24 h only. The visual assessment scores indicated mild pain for all surgical groups, with the buprenorphine treated mice showing the highest pain index scores, as compared with nonsurgical controls. Fecal corticosterone metabolite levels did not differ significantly between any of the groups or across time. The parameters used in this study did not indicate that administration of these analgesic regimens improved recovery as compared with that of saline-treated mice. Care should be taken when using visual assessment scores to evaluate pain in mice, given that analgesics may have side effects that inadvertently elevate the score. PMID- 20858364 TI - Comparison of buprenorphine and meloxicam for postsurgical analgesia in rats: effects on body weight, locomotor activity, and hemodynamic parameters. AB - Buprenorphine is administered to humans and animals for postoperative pain management, although its use is associated with complications. Alternative analgesics, including the nonsteroidal antiinflammatory meloxicam, are available, but information on their postoperative effects is limited. The objective of the present study was to compare buprenorphine (0.03 mg/kg SC twice daily for 3 d) with meloxicam (2 mg/kg SC initial dose followed by 1 mg/kg SC once daily for 2 d) by assessing parameters relating to postsurgical recovery in rats that underwent surgical implantation of radiotelemetric transducers. Rats treated after surgery with buprenorphine showed greater reductions in body weight, food consumption, locomotor activity, and nighttime heart rates than did meloxicam treated rats. Buprenorphine and meloxicam treatments both had stimulatory effects on mean arterial pressure and daytime heart rate measurements, although effects on nighttime mean arterial pressure were greater in the buprenorphine-treated rats. In summary, the lesser physiologic changes associated with meloxicam, as compared with buprenorphine, suggest that meloxicam offers advantages for use as a postoperative analgesic after laparotomy and radiotelemetric transducer implantation in rats. PMID- 20858365 TI - A comprehensive laboratory animal facility pandemic response plan. AB - The potential of a severe influenza pandemic necessitates the development of an organized, rational plan for continued laboratory animal facility operation without compromise of the welfare of animals. A comprehensive laboratory animal program pandemic response plan was integrated into a university-wide plan. Preparation involved input from all levels of organizational hierarchy including the IACUC. Many contingencies and operational scenarios were considered based on the severity and duration of the influenza pandemic. Trigger points for systematic action steps were based on the World Health Organization's phase alert criteria. One extreme scenario requires hibernation of research operations and maintenance of reduced numbers of laboratory animal colonies for a period of up to 6 mo. This plan includes active recruitment and cross-training of volunteers for essential personnel positions, protective measures for employee and family health, logistical arrangements for delivery and storage of food and bedding, the removal of waste, and the potential for euthanasia. Strategies such as encouraging and subsidizing cryopreservation of unique strains were undertaken to protect valuable research assets and intellectual property. Elements of this plan were put into practice after escalation of the pandemic alerts due to influenza A (H1N1) in April 2009. PMID- 20858366 TI - Treatment and eradication of murine fur mites: III. Treatment of a large mouse colony with ivermectin-compounded feed. AB - We determined the efficacy of ivermectin-compounded feed against fur mites in mice and describe its use to eradicate mites in vivaria holding approximately 30,000 cages. C57BL/6NCrl mice infested with Myobia musculi and Myocoptes musculinus were treated with ivermectin-compounded feed (approximate ingested dose, 1.3 mg/kg) for 1, 4, or 8 consecutive weeks. Regardless of treatment duration, all treated mice, as well as contact sentinels, remained free of fur mites for as long as 21 wk after treatment. No adverse effects were observed. Subsequently, facility-wide treatment was implemented in an attempt to eradicate fur mites from 3 vivaria housing approximately 120,000 mice. Medicated feed was provided for 8 wk to ensure that all cages and mice were treated. A single investigative group reported adverse effects in their colony 4 wk after treatment was initiated; mortality was attributed to ivermectin toxicity after an intracranial injection at 1 d of age. Naive pups were unaffected. No other adverse effects were noted. Approximately 14,500 skin scrape samples were evaluated during the 12-mo posttreatment surveillance period. All samples were negative for mites. To our knowledge, this is the first report of successful eradication of fur mites from a mouse colony of this large size. PMID- 20858367 TI - Microchip-associated sarcoma in a shrew (Suncus murinus). AB - A 16-mo-old female house musk shrew (Suncus murinus) with a 1-wk history of a rapidly growing subcutaneous mass in the interscapsular region was euthanized and submitted for necropsy. Macroscopic examination identified an irregular, well demarcated, solid, tan-white subcutaneous mass. A small cavity containing a microchip device was present at the center of the mass. In addition, massive splenomegaly was evident grossly. Histologically, the subcutaneous mass comprised spindle cells arranged in a storiform pattern of interweaving bundles, consistent with a high-grade soft tissue sarcoma with multifocal necrosis. Immunohistochemical investigation suggested that the neoplastic cells were positive for neuron-specific enolase and (rarely) alpha-smooth muscle actin and negative for cytokeratin, desmin, S100, and vimentin. In light of the mesenchymal histopathologic phenotype and the lack of specific immunoreactivity pattern, the mass was considered to be most consistent with a poorly differentiated sarcoma. To our knowledge, this is the first report of a microchip-associated soft tissue sarcoma in a shrew. PMID- 20858368 TI - Pulmonary idiopathic alveolar ossification in a raccoon (Procyon lotor). AB - Here we describe gross and histopathologic findings in a laboratory-confined adult male raccoon (Procyon lotor) with microscopic ossified areas in pulmonary alveoli. At the time of necropsy, gross lesions were present in the kidneys and in one thyroid gland. Noteworthy microscopic findings included multifocal foci of osseous tissue within the alveoli of the lungs, bilateral thyroid adenomas, pancreatic islet cell amyloidosis, cortical kidney infarcts, cystic adenomatous hyperplasia of urinary bladder, and mineralizations (psommama bodies) of small blood vessels of meninges and choroid plexus. Pulmonary ossification in raccoons has not been reported previously. The other histopathologic lesions have been documented to occur as incidental findings in raccoons and do not appear to have any apparent association with the formation of osseous foci in the lungs of the animal described. PMID- 20858369 TI - Presumed mycobacteriosis in laboratory zebra finch (Taeniopygia guttata). AB - Husbandry staff noticed a research-naive, young-adult, female finch tossing its head back intermittently. A second finch exhibiting similar signs was reported a few days later. Postmortem necropsy and histopathology with hematoxylin and eosin and acid-fast staining on the first finch revealed the presence of acid-fast organisms in several organs. After presumptive diagnosis of mycobacteriosis, all remaining finches housed in the same room as the first underwent necropsy and histology. Three additional finches were positive for Mycobacterium-like acid fast organisms. Incidental findings of megabacteriosis were noted histopathologically on 2 other finches. PMID- 20858370 TI - Nonsurgical repair of a pseudoaneurysm in a cynomolgus macaque (Macaca fascicularis). AB - A cynomolgus macaque presented with an ecchymotic and edematous left leg approximately 1 wk after a blood sample had been collected from the left femoral vein. Ecchymosis was noted in the femoral triangle, prepuce, and scrotum. The animal was not febrile or exhibiting signs of pain or distress. Duplex Doppler ultrasound imaging was used to evaluate the area. An arteriovenous fistula between the femoral artery and vein, accompanied by a pseudoaneurysm arising from the femoral artery, was identified. Various invasive and noninvasive treatment options for the pseudoaneurysm, including surgical repair, thrombin injection, stent placement, and ultrasound-guided compression repair (UGCR), were considered. UGCR was chosen as the first option for treatment. After a total of 20 min of UGCR at the neck of the pseudoaneurysm, complete thrombosis was achieved. Subsequent imaging of the lesion revealed resolution of the pseudoaneurysm. Because of the risks involved with invasive management techniques for this vascular lesion, UGCR is a valuable noninvasive treatment option for the repair of pseudoaneurysms. PMID- 20858371 TI - How many hours should a surgical resident work? PMID- 20858372 TI - In-hospital mortality following hip fracture care in southern Ontario. AB - BACKGROUND: The incidence of hip fractures is increasing within the aging population. We investigated the overall rate of in-hospital mortality following hip fracture and how this mortality rate compares across academic and community hospitals. METHODS: We reviewed prospectively collected data from 17 hospitals in southern Ontario as part of a project to evaluate a new streamlined clinical care pathway developed for acute care of elderly patients with hip fractures. We collected demographic data, prefracture living status, acute care mortality and time to surgery, and we compared these data between community and academic hospitals. RESULTS: Between March 2007 and February 2008, 2178 consecutive patients were admitted with a hip fracture to 13 community and 4 academic hospitals. The mean age was 79 years and 72% were women. The overall in-hospital mortality rate was 5.0%, with no difference between patients treated in academic versus community hospitals (p = 0.56). We found a greater rate of acute care in hospital mortality for patients admitted from dependent-living facilities compared with those who were living independently (risk ratio 0.63, 95% confidence interval 0.42-0.96). CONCLUSION: Acute care in-hospital mortality following hip fractures remains high and is consistent across academic and community hospitals. With the rising incidence of hip fractures, we need to improve the models of care for these patients to reduce mortality and to maximize functional outcomes while maintaining efficient use of limited health care resources. PMID- 20858373 TI - Treatment of complex perianal fistulas in Crohn disease: infliximab, surgery or combined approach. AB - BACKGROUND: The aim of this study was to compare the outcomes of the management of perianal fistulas in Crohn disease between infliximab, surgery or a combination of surgery and infliximab. METHODS: We prospectively subdivided 35 consecutive patients with Crohn disease with complex perianal fistulas into 3 groups: 11 patients received infliximab (5 mg/kg intravenously at 0, 2 and 6 wk; group A), 10 underwent surgery (group B) and 14 received a combination of surgery and postoperative infliximab (group C). We evaluated the rate and time of healing of perianal fistulas, the rate of recurrences and time to relapse at a median follow-up of 18.8 (standard deviation [SD] 10.8, range 8-38) months. RESULTS: The time to healing of fistulas was significantly shorter among patients who received surgery and infliximab than among those who received surgery alone (p < 0.05) and was close to statistically shorter among those who received both treatments than among those who received infliximab alone (p = 0.06). Patients who received surgery and infliximab had a significantly longer mean time to relapse (p < 0.05) than those who received infliximab (mean 2.6 [SD 0.7] mo) or surgery alone (mean 3.6 [SD 0.5] mo). CONCLUSION: We found better outcomes among patients who received a combination of surgery and infliximab therapy. These patients experienced a short time to healing of fistulas and significantly longer mean time to relapse of complex fistulas. PMID- 20858374 TI - Technical factors, surgeon case volume and positive margin rates after breast conservation surgery for early-stage breast cancer. AB - BACKGROUND: For patients with breast cancer, a negative surgical margin at first breast-conserving surgery (BCS) minimizes the need for reoperation and likely reduces postoperative anxiety. We assessed technical factors, surgeon and hospital case volume and margin status after BCS in early-stage breast cancer. METHODS: We performed a retrospective cohort study using a regional cancer centre database of patients who underwent BCS for breast cancer from 2000 to 2002. We considered the influence of patient, tumour and technical factors (e.g., size of specimen and preoperative diagnosis of cancer available) and surgeon and hospital case volume on margin status at first and final operation. We performed univariate and multivariate regression analyses. RESULTS: We reviewed 489 cases. There were no differences in patient or tumour characteristics among the low-, medium- and high-volume surgeon groups. High-volume surgeons were significantly more likely than other surgeons to operate with a confirmed preoperative diagnosis and to resect a larger volume of tissue. In our univariate analysis and at first operation, the rates of positive margins were 16.4%, 32.9% and 29.1% for high-, medium- and low-volume surgeons, respectively (p = 0.002). In the multivariate analysis, tumour factors (palpability, size, histology), presence of a confirmed preoperative diagnosis and size of resection specimen significantly predicted negative margins. However, when we controlled for these and other factors, high surgeon volume was not a predictor of negative margins at first surgery (odds ratio 1.8, 95% confidence interval 0.9-3.8, p = 0.09). Increased hospital volume was not associated with a lower rate of positive margins at first surgery. CONCLUSION: Various tumour and technical factors were associated with negative margins at first BCS, whereas surgeon and hospital volume status were not. Technical steps that are under the control of the operating surgeon are likely effective targets for quality initiatives in breast cancer surgery. PMID- 20858375 TI - Melatonin ameliorates liver fibrosis induced by bile-duct ligation in rats. AB - BACKGROUND: Hepatic stellate cells, the main mediators in the pathogenesis of fibrosis, are triggered by free radicals and produce collagen. Melatonin is a powerful physiologic scavenger of hydroxyl radicals. It is also involved in the inhibitory regulation of the collagen content in tissue. There is no effective treatment available for liver fibrosis. Our objective was to evaluate the effects of melatonin on liver fibrosis induced by bile-duct ligation (BDL) in rats. METHODS: We divided male Wistar rats (n = 32) into 4 groups. Two groups received BDL and 2 groups received sham operations. One of the BDL groups and one of the sham groups were administered melatonin (100 mg/kg/day via intraperitoneal injection), and the controls were given vehicle only. After 1 month, we biochemically evaluated the changes in hepatic fibrosis by measuring tissue collagen levels and histopathologic examination. We evaluated the levels of malondialdehyde (MDA), glutathione (GSH), luminal and lucigenin in tissue homogenates, and we studied proinflammatory cytokines in serum using commercially available kits. RESULTS: Bile-duct ligation caused hepatic fibrotic changes, whereas melatonin suppressed these changes in 5 of 8 rats (p < 0.001). Bile-duct ligation resulted in increased collagen, MDA, luminal and lucigenin levels and decreased GSH levels, whereas melatonin reversed these effects. CONCLUSION: We found that melatonin functions as an effective fibrosuppressant and antioxidant, and the results suggest that it can be used as a therapeutic option. PMID- 20858376 TI - A 7-year review of men's and women's ice hockey injuries in the NCAA. AB - BACKGROUND: Ice hockey is a high-speed collision sport with recognized injury potential. Body checking, identified as a primary cause of injury, is allowed in men's hockey but is not allowed at any level for female players. The injury patterns in collegiate hockey should reflect this fundamental difference in how the game is played. In this study, we reviewed the injuries sustained by National Collegiate Athletic Association (NCAA) hockey players over a 7-year period. METHODS: We conducted a retrospective database review of injuries and exposures reported to the Injury Surveillance System to determine rates of injury or differences in the pattern of injury between the sexes. RESULTS: The rate of injury during games for men (18.69/1000 athlete-exposures [AEs]) and women (12.10/1000 AEs) was significantly higher than the rate of injury during practice. The rate of concussion was 0.72/1000 AEs for men and 0.82/1000AEs for women, and the rate remained stable over the study period. Player contact was the cause of concussions in game situations for 41% of women and 72% of men. CONCLUSION: Both men and women had increased rates of practice-related injuries that resulted in time loss during the study period. In addition, there were high rates of concussions from player contact. The concussion rate in women was higher than expected. A more detailed examination with focused data collection may impact these findings. PMID- 20858377 TI - Intraoperative spinal cord and nerve root monitoring: a survey of Canadian spine surgeons. AB - BACKGROUND: Intraoperative spinal cord and nerve root monitoring is used to identify an insult to the neural elements with the goal of preventing injury. There are 2 major categories of monitoring: evoked potentials (somatosensory evoked potentials and motor evoked potentials) and electromyography. The availability of intraoperative neuromonitoring and the indications for use vary widely. In this study, we aimed to document the current practices and opinions of Canadian spine surgeons with regards to intraoperative spinal monitoring. METHODS: We surveyed members of the Canadian Spine Society about the availability and use of various types of intraoperative neuromonitoring modalities for surgical procedures. RESULTS: We distributed 105 surveys and received 95 responses (90%). Somatosensory evoked potentials were the most commonly available form of intraoperative neuromonitoring, although it was available to only 65.3% of respondents. Surgeons in either full-time or part-time academic practice used monitoring more frequently than those in private practice (p < 0.001), but this association was not based on surgeon preference after controlling for availability. Years of practice and training background (orthopedic or neurosurgical) did not influence the use of monitoring. Canadian spine surgeons overwhelmingly reported that they use intraoperative neuromonitoring to reduce the risk of adverse operative events, rather than because of liability concerns. Most respondents believed that monitoring should be used in the correction of major deformity and scoliosis. CONCLUSION: The availability of spinal monitoring in Canada is variable. Most surgeons believe that it is an important adjunct to improve patient safety. PMID- 20858378 TI - Current thinking about acute compartment syndrome of the lower extremity. AB - Acute compartment syndrome of the lower extremity is a clinical condition that, although uncommon, is seen fairly regularly in modern orthopedic practice. The pathophysiology of the disorder has been extensively described and is well known to physicians who care for patients with musculoskeletal injuries. The diagnosis, however, is often difficult to make. In this article, we review the clinical risk factors of acute compartment syndrome of the lower extremity, identify the current concepts of diagnosis and discuss appropriate treatment plans. We also describe the Canadian medicolegal environment in regard to compartment syndrome of the lower extremity. PMID- 20858380 TI - CAGS and ACS Evidence Based Reviews in Surgery. 34: effects of beta-blockers in patients undergoing noncardiac surgery. AB - QUESTION: Do beta-blockers have an effect on the 30-day risk of major cardiovascular events in patients with or at risk of atherosclerotic disease undergoing noncardiac surgery? DESIGN: Randomized controlled trial. SETTING: Multicentre trial in 190 hospitals in 23 countries. PATIENTS: In total, 8351 patients with or at risk of atherosclerotic disease undergoing noncardiac surgery. INTERVENTION: Patients were randomly assigned by a computerized 24-hour phone service to receive extended-release metoprolol succinate 200 mg (n = 4174) or placebo (n = 4177). Treatment was started 2-4 hours before surgery and continued for 30 days. MAIN OUTCOME: Cardiovascular death, nonfatal myocardial infarction (MI) and nonfatal cardiac arrest. RESULTS: Of those randomized, 8331 (99.8%) patients completed the 30-day follow-up. Fewer patients in the metoprolol group than in the placebo group had an MI (176 [4.2%] v. 239 [5.7%] patients; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.60-0.089, p = 0.0017). However, there were more deaths in the metoprolol group than in the placebo group (129 [3.1%] v. 97 [2.3%] patients; HR 1.33, 95% CI 1.03-1.74, p = 0.0317). More patients in the metoprolol group than in the placebo group had a stroke (41 [1.0%] v. 19 [0.5%] patients; HR 2.17, 95% CI 1.26-3.74, p = 0.0053). CONCLUSION: A perioperative beta-blocker regimen results in fewer MIs but is associated with an increased risk of stroke and perioperative death in patients with or at risk for atherosclerotic disease undergoing noncardiac surgery. Patients are unlikely to accept the risks associated with perioperative extended-release metoprolol use. PMID- 20858381 TI - Practical tips for surgical research: blinding: who, what, when, why, how? PMID- 20858379 TI - Dramatic innovations in modern surgical subspecialties. AB - Innovation is defined as the introduction of something new, whether an idea, method or device. In this article, we describe the most important and innovative concepts and techniques that have advanced patient care within modern surgical subspecialties. We performed a systematic literature review and consulted academic subspecialty experts to evaluate recent changes in practice. The identified innovations included reduced blood loss and improved training in hepatobiliary surgery, total mesorectal excision and neoadjuvant therapies in colorectal surgery, prosthetic mesh in outpatient surgery, sentinel lymph node theory in surgical oncology, endovascular and wire-based skills in vascular and cardiovascular surgery, and the acceptance of abnormal anatomy through damage control procedures in trauma and critical care. The common denominator among all subspecialties is an improvement in patient care manifested as a decrease in morbidity and mortality. Surgeons must continue to pursue innovative thinking, technological advances, improved training and systematic research. PMID- 20858383 TI - [Skin as material and medium for artistic creation]. PMID- 20858382 TI - Case series: splenectomy: does it still play a role in the management of thrombotic thrombocytopenic purpura? PMID- 20858384 TI - [Psoriatic arthritis: what the dermatologist needs to know, part 1]. AB - Psoriatic arthritis is defined as inflammatory arthritis occurring in patients with psoriasis and is classified as a seronegative spondyloarthropathy associated with human leukocyte antigen B27. Between 25 and 35% of patients with psoriasis go on to develop psoriatic arthritis during the course of their disease. Given that the skin is affected before the joints in most cases, the dermatologist must be able to recognize the signs and symptoms in order to make a diagnosis and start the most appropriate treatment. This review aims to cover key aspects of the initial diagnostic workup and clinical evaluation. It examines the epidemiology, pathogenesis, and manifestations of psoriatic arthritis, as well as the complementary tests and diagnostic tools the dermatologist should be aware of in order to make the correct diagnosis. PMID- 20858385 TI - [Lipid nutrition and the epidermal barrier: The connection between immune mediated inflammatory diseases and peroxisome proliferator-activated receptors, a new therapeutic target in psoriasis and atopic dermatitis]. AB - The authors describe peroxisome proliferator-activated receptor (PPAR) transcription factors as connectors between the enzymatic mechanisms of the epidermal barrier and the abnormal immune and inflammatory responses that characterize atopic dermatitis and psoriasis. Also described is a new connection between lipid metabolism and the epidermal barrier. A suggestion that emerges is that atopic dermatitis and psoriasis share at least 2 pathogenic mechanisms namely, deficient expression of PPAR-#a and impaired production of interleukin-10 and interferon-gamma-in spite of differences in causes and manifestations. A standardized olive oil formulation with powerful bactericidal and fungicidal effects also has the ability to increase serum levels of these 2 cytokines and regulate serum levels of high-density lipoprotein cholesterol in patients at high risk for inflammatory and cardiovascular disease, suggesting that these may be among the mechanisms responsible for the benefits observed following oral and/or topical administration in patients with atopic dermatitis or psoriasis. PMID- 20858386 TI - [Guidelines on the use of methotrexate in psoriasis]. AB - Psoriasis, a chronic multifactorial inflammatory disease that develops in genetically predisposed individuals, affects approximately 1.5% of the Spanish population. This disease has a negative impact on patients' quality of life, and long-term therapy is often required to control the symptoms. In addition to the classical systemic treatments (methotrexate, acitretin, cyclosporine, and ultraviolet light), the group of drugs known as biologics (etanercept, infliximab, adalimumab, and ustekinumab) provides the dermatologist with an expanded therapeutic armamentarium, thereby improving the likelihood of controlling psoriasis in patients with severe and/or extensive disease. Methotrexate, a classic antipsoriatic drug, is still very useful either as single drug therapy or in combination with other systemic drugs, particularly as a rescue therapy or combined with biologics. This article aims to establish the role of methotrexate in the treatment of psoriasis. We considered it of interest to develop guidelines for using methotrexate in the management of psoriasis with a view to ensuring the safe and proper use of this drug in the management of psoriasis. This document was developed by consensus among members of the Psoriasis Group of the Spanish Academy of Dermatology and Venereology. PMID- 20858387 TI - [Botulinum toxin type A for the treatment of primary hyperhidrosis: a prospective study of 52 patients]. AB - BACKGROUND AND OBJECTIVES: Primary hyperhidrosis is characterized by excessive sweating in a defined region of the body. It should not be considered a purely cosmetic problem as it has a significant impact on the social and professional relationships of affected individuals. The aim of this study was to determine the clinical profile of patients with primary hyperhidrosis and assess the results obtained with the use of botulinum toxin type A (BTX-A) in clinical practice. MATERIAL AND METHODS: The study included 52 patients (39 women and 13 men) with a diagnosis of primary hyperhidrosis treated for the first time with BTX-A. All patients completed a questionnaire that included the following information: age; sex; profession; age at onset, family history, and site of hyperhidrosis; accompanying signs and symptoms, and previous treatment; time to effect of BTX-A; local or systemic side effects; and severity of hyperhidrosis before and after BTX-A treatment. RESULTS AND CONCLUSIONS: Primary hyperhidrosis began during puberty in 61.5% of the patients included in the study, 75% were women, and the mean age was 29.9 years. In 36.5% of patients, first-degree relatives also had primary hyperhidrosis. Hyperhidrosis was classified as palmar in 61.5% of cases, plantar in 53.8%, and axillary in 59.6%. Other sites were affected less frequently. The most common accompanying symptoms were facial erythema (32.7%), palpitations (30.7%), muscle tension (28.8%), shivering (23%), and headache (17.3%). Treatment with BTX-A was well tolerated and there was a highly significant reduction in the severity of hyperhidrosis 2 months after performing the treatment (P<0.001). PMID- 20858388 TI - [Cost analysis of Mohs micrographic surgery in high-risk facial basal cell carcinoma]. AB - INTRODUCTION: Mohs micrographic surgery (MMS) is the treatment of choice for high risk facial basal cell carcinoma (BCC) as it offers the greatest chance of cure with maximum preservation of healthy tissue. Its use in Spanish public health care hospitals is still limited, however, due to the controversy surrounding its cost. OBJECTIVES: To determine the cost of MMS with fresh tissue to treat high risk facial BCC and compare this to the estimated cost of conventional surgery in a Spanish public hospital. A secondary objective was to identify cost optimization strategies for MMS. MATERIAL AND METHODS: Cross-sectional study of a consecutive series of patients with high-risk facial BCC who underwent MMS at the Department of Dermatology at Hospital Costa del Sol in Malaga, Spain between July 2006 and December 2007. We performed a descriptive analysis of the clinical characteristics of the patients and surgical factors. We calculated the total and mean cost of MMS and compared the results to the estimated costs of conventional surgery using patients as their own controls. Differences were analyzed according to tumor site and size, histologic subtype, and recurrence. RESULTS: Seventy-nine patients (mean age, 62 years) with 81 high-risk facial BCCs, 97.5% of which were primary tumors, underwent MMS. The most common tumor site was the nose (57%) followed by the orbital region (25%). Histology showed that 64% of the tumors were infiltrative or micronodular carcinomas. Tumor-free margins were achieved in all patients, with no more than 2 stages required in 88% of the cases. The most common surgical reconstruction techniques were direct closure (21%) and closure with a local skin flap or graft (71%); the corresponding estimates for conventional surgery were 2% and 89%, respectively. The total and mean cost of MMS was e106,129.07 and e1325.80, respectively (compared to e97 700 and e1208.70 for conventional surgery). The difference in mean costs between MMS and conventional surgery was not significant (P=0.534). CONCLUSIONS: MMS is a viable, effective technique that does not generate significantly higher costs than conventional surgery in selected patients with high-risk facial BCC. Certain technical and organizational strategies could contribute to optimizing the cost of MMS. PMID- 20858390 TI - [New mutation in the Birt Hogg Dube gene]. AB - Patients with Birt-Hogg-Dube syndrome have an increased risk of developing hamartomas of the pilosebaceous unit, renal tumors of various types, lung cysts, and spontaneous pneumothorax. We present the case of a 54-year-old woman with a long history of whitish papules in the central region of the face and a family history of similar lesions. Biopsy and genetic study revealed a new mutation of the gene involved in Birt-Hogg-Dube syndrome. PMID- 20858389 TI - [Clinical management of psoriatic arthritis in Spain: the CALIPSO study]. AB - OBJECTIVE: To describe the clinical management of psoriatic arthritis for patients being treated by dermatologists and rheumatologists in Spain. METHODS: Multicenter, retrospective, naturalistic observational study in which demographic and clinical variables were recorded for patients diagnosed with psoriatic arthritis. Data referred to the previous 12 months and were collected during a single visit with the physician. RESULTS: A total of 266 patients were enrolled; 78.1% were being treated by rheumatologists and 21.9% by dermatologists. The data covered 1138 visits. The main reason for consulting a physician was to monitor psoriatic arthritis (82.7% of the visits). The most widely used examination was to determine the tender- and swollen-joint count (73.1%). The tests most frequently ordered were acute-phase reactants: erythrocyte sedimentation rate (79.8%) and C reactive protein level (74.5%). Affected body surface area and the Psoriasis Area and Severity Index were the main assessments used by dermatologists. Rheumatologists tended to examine the joints and record biochemical markers. A disease-modifying antirheumatic drug was prescribed for 71.1% of the patients; 51.8% were prescribed a biologic agent (61.5% in combination with another treatment). Treatment approach differed by specialty and was modified if response was nil or partial (the rationale for 45.1% of all changes). CONCLUSION: Differences in the management of psoriatic arthritis in dermatology and rheumatology were evident in both diagnostic and treatment approaches. These 2 specialties should cooperate to establish common practice guidelines for use in Spain. PMID- 20858391 TI - [Cold, erythematous-violaceous macules on both breasts of a 66-year-old woman]. PMID- 20858392 TI - [Episodes of flushing and blistering]. PMID- 20858393 TI - [Relieving the pain associated with plantar warts]. PMID- 20858394 TI - [Facial granulomatous dermatoses]. PMID- 20858395 TI - Linear basal cell carcinoma. PMID- 20858396 TI - [Perifollicular palpable purpura as the initial manifestation of HIV infection]. PMID- 20858397 TI - [Pachydermodactyly: a rare form of acquired digital fibromatosis]. PMID- 20858398 TI - [Subungual squamous cell carcinoma. Presentation of two cases]. PMID- 20858399 TI - [Positron emission tomography (PET): fundamentals and technological limitations]. PMID- 20858400 TI - [Evaluation of the effect of bimatoprost/timolol fixed combination on ocular blood flow in patients with ocular hypertension using colour Doppler imaging. Preliminary study]. AB - PURPOSE: To investigate the effects of topical bimatoprost (0.3 mg/ml)/timolol maleate (5 mg/ ml) fixed combination on retrobulbar blood flow in patients with ocular hypertension (OHT). PATIENTS AND METHODS: Twenty consecutive patients with OHT were prospectively randomised to either bimatoprost/timolol or placebo during a 12 weeks double masked treatment trial. Examinations were performed at baseline and after 12 weeks of treatment. Visual acuity, intraocular pressure (IOP), slit lamp examination, automated static perimetry, systemic blood pressure and heart rate were all recorded. Retrobulbar blood flow measurements of the ophthalmic artery (AO) and central retinal artery (CRA) were measured by colour Doppler imaging. RESULTS: IOP was significantly decreased by bimatoprost/timolol fixed combination (p < 0.0001). Bimatoprost/timolol fixed combination therapy resulted in a significant increase in end diastolic velocity (EDV) of the CRA (p = 0.03). In patients treated with bimatoprost/timolol a statistically significant correlation between IOP and EDV was observed after 12 weeks of treatment (r = 0.511, p = 0.045). The systolic (p = 0.54) and diastolic (p = 0.67) blood pressures and heart rate (p = 0.10) did not show statistically significant differences during the study period. CONCLUSIONS: Topical bimatoprost/timolol fixed combination significantly reduced IOP in patients with OHT. However, the only significant change observed in retrobulbar haemodynamics was an increase in EDV of the CRA, probably associated with a reduction in IOP. PMID- 20858401 TI - [Ability of Heidelberg Retina Tomograph III to predict progression in patients with early glaucoma or suspected primary open-angle glaucoma]. AB - PURPOSE: To study the ability of Heidelberg Retina Tomography III (HRT 3) measurements to predict perimetry changes in patients with early glaucoma or suspected primary open-angle glaucoma. MATERIAL AND METHODS: One hundred and thirty two eyes with early glaucoma or suspected glaucoma with no changes in basal perimetry were prospectively selected and periodically evaluated over five years. The eyes were divided in two groups depending on the presence or absence of progression (changes in glaucoma perimetry). The association between morphometric parameters and baseline HRT 3 indices, glaucoma probability score (GPS) and Moorefield's Regression Analysis (MRA), and perimetry progression were studied using Cox multivariate regression analyses. Kaplan-Meier curves were used to illustrate the results. RESULTS: Forty-eight eyes (36.36%) showed perimetry progression. Perimetry progression showed higher correlations with the disc area (p = 0.001), the cup area (p = 0.002) and the vertical cup disc area (p = 0.001). Multivariate regression analyses showed that eyes with baseline MRA or baseline GPA changes were at a higher risk of having perimetry abnormalities and a faster progression. CONCLUSIONS: MRA and GPA indices are useful to predict perimetry progression in patients with early primary open-angle glaucoma or suspected glaucoma. These indices can be used as risk markers of functional progression in glaucoma. PMID- 20858402 TI - [Influence of axial length in refractive outcome after cataract surgery]. AB - PURPOSE: To analyse the influence of axial length (AL) and age on refractive outcome after cataract surgery in terms of uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA) and subjective refraction. METHODS: A retrospective review of 171 consecutive cases of uncomplicated cataract surgery was done. The refractive outcome was analysed (UCVA, BCVA and postoperative retraction) according AL before surgery (AL < 22 mm, between 22 and 25 mm and AL > 25 mm) and age (< 40, between 40-60 years and > 60 years). RESULTS: After surgery mean UCVA was 0.6 +/- 0.33 Diopters (D) and mean BCVA was 0.93 +/- 0.23 D. Mean refractive outcome was 0.89 +/- 0.78 D. There were no significant differences in post-operative UCVA, BCVA and refraction between the three age groups. There were statistically significant differences (p = 0.004) in UCVA between the three AL groups. The group with AL between 22 and 25 mm had better UCVA. Mean refractive outcome was -0.95 +/- 1.91 D in the group with AL < 22 mm, 0.36 +/- 0.88 D in the group with AL between 22 and 25 mm and 0.23 +/- 1.15 D in the group with AL > 25 mm. CONCLUSIONS: AL influences refractive outcome and UCVA after cataract surgery. Eyes with AL < 22 mm have a worse refractive outcome. PMID- 20858403 TI - [Intravitreal ranibizumab (Lucentis(r)) in the treatment of choroidal neovascular membrane secondary to punctate inner choroidopathy]. AB - CLINIC CASE: A 25 year old patient with high myopia diagnosed of metachronic choroidal neovascularisation in both eyes secondary to punctate inner choroidopathy leading to visual impairment and metamorphopsia. First eye was treated with four injections of ranibizumab after photodynamic therapy and the second eye only with charge dose of ranibizumab, reaching inactivity with good final visual acuity in both eyes. DISCUSSION: Ranibizumab is useful in the treatment of this illness. Prospective studies are needed to investigate the usefulness of a combination with adjuvant therapies such as photodynamic therapy. PMID- 20858405 TI - [Hemifacial microsomia (oculo-auriculo-vertebral spectrum) in Pre-Hispanic Tumaco La Tolita ceramic culture (300 b.C. to 600 a.C.)]. PMID- 20858406 TI - [Luigi Preziosi (Malta, 1888-1965)]. PMID- 20858409 TI - Nonessential sites improve phosphorylation switch. AB - Multisite phosphorylation is a common form of posttranslational protein regulation which has been used to increase the switchlike behavior of the protein response to increasing kinase concentrations. In this letter, we show that the switchlike response of multisite phosphoproteins is strongly enhanced by nonessential phosphorylation sites, a mechanism that is robust to parameter changes and easily implemented in nature. We obtained analytic estimates for the Hill exponent (or coefficient) of the switchlike response, and we observed that a tradeoff exists between the switch and the kinase threshold for activation. This also suggests a possible evolutionary mechanism for the relatively large numbers of phosphorylation sites found in various proteins. PMID- 20858411 TI - Fluorescence anisotropy of protein complexes in living cells. PMID- 20858410 TI - Lipid bilayer domain fluctuations as a probe of membrane viscosity. AB - We argue that membrane viscosity, eta(m), plays a prominent role in the thermal fluctuation dynamics of micron-scale lipid domains. A theoretical expression is presented for the timescales of domain shape relaxation, which reduces to the well-known eta(m) = 0 result of Stone and McConnell in the limit of large domain sizes. Experimental measurements of domain dynamics on the surface of ternary phospholipid and cholesterol vesicles confirm the theoretical results and suggest domain flicker spectroscopy as a convenient means to simultaneously measure both the line tension, sigma, and the membrane viscosity, eta(m), governing the behavior of individual lipid domains. PMID- 20858412 TI - The biophysical origin of traveling-wave dispersion in the cochlea. AB - Sound processing begins at the peripheral auditory system, where it undergoes a highly complex transformation and spatial separation of the frequency components inside the cochlea. This sensory signal processing constitutes a neurophysiological basis for psychoacoustics. Wave propagation in the cochlea, as shown by measurements of basilar membrane velocity and auditory nerve responses to sound, has demonstrated significant frequency modulation (dispersion), in addition to tonotopic gain and active amplification. The physiological and physical basis for this dispersion remains elusive. In this article, a simple analytical model is presented, along with experimental validation using physiological measurements from guinea pigs, to identify the origin of traveling wave dispersion in the cochlea. We show that dispersion throughout the cochlea is fundamentally due to the coupled fluid-structure interaction between the basilar membrane and the scala fluids. It is further influenced by the variation in physical and geometrical properties of the basilar membrane, the sensitivity or gain of the hearing organ, and the relative dominance of the compression mode at about one-third octave beyond the best frequency. PMID- 20858413 TI - Coordination of the nuclear and cytoplasmic activities of p53 in response to DNA damage. AB - The tumor suppressor p53 plays a key role in the cellular response to various stresses. Most previous studies have focused on either the nuclear or cytoplasmic proapoptotic functions of p53, ignoring the combination of both functions. To explore how the two functions of p53 are coordinated in the DNA damage response via computer simulation, we construct a model for the p53 network comprising coupled positive and negative feedback loops involving p53, Mdm2, and Akt, as well as PUMA and Bax. In our model p53 is stabilized and accumulates in the nucleus and cytoplasm upon DNA damage. Nuclear p53 induces expression of Mdm2, PTEN, PUMA, and Bax. Cytoplasmic p53 is then released from the p53.Bcl-xL complex by PUMA to activate Bax directly. We find that the switching between low and high protein levels underlies the decision between cell survival and death. Moreover, a balance between the nuclear and cytoplasmic p53 levels and appropriate levels of Akt and PUMA are required for reliable cell fate decision. Our results indicate that coordination of the transcription-dependent and -independent activities of p53 is important in determining cellular outcomes. These findings advance our understanding of the mechanism for p53-mediated cellular responses and provide clues to p53-based cancer therapy. PMID- 20858414 TI - Fluorescence anisotropy reveals order and disorder of protein domains in the nuclear pore complex. AB - We present a new approach for studying individual protein domains within the nuclear pore complex (NPC) using fluorescence polarization microscopy. The NPC is a large macromolecular complex, the size and complexity of which presents experimental challenges. Using fluorescence anisotropy and exploiting the symmetry of the NPC and its organization in the nuclear envelope, we have resolved order and disorder of individual protein domains. Fluorescently tagging specific domains of individual nucleoporins revealed both rigid and flexible domains: the tips of the FG domains are disordered, whereas the NPC-anchored domains are ordered. Our technique allows the collection of structural information in vivo, providing the ability to probe the organization of protein domains within the NPC. This has particular relevance for the FG domain nucleoporins, which are crucial for nucleocytoplasmic transport. PMID- 20858415 TI - Membrane potential depolarization as a triggering mechanism for Vpu-mediated HIV 1 release. AB - Vpu, a component unique to HIV-1, greatly enhances the efficiency of viral particle release by unclear mechanisms. This Vpu function is intrinsically linked to its channel-like structure, which enables it to interfere with homologous transmembrane structures in infected cells. Because Vpu interacts destructively with host background K(+) channels that set the cell resting potential, we hypothesized that Vpu might trigger viral release by destabilizing the electric field across a budding membrane. Here, we found that the efficiency of Vpu mediated viral release is inversely correlated with membrane potential polarization. By inhibiting the background K(+) currents, Vpu dissipates the voltage constraint on viral particle discharge. As a proof of concept, we show that HIV-1 release can be accelerated by externally imposed depolarization alone. Our findings identify the trigger of Vpu-mediated release as a manifestation of the general principle of depolarization-stimulated exocytosis. PMID- 20858416 TI - Cell blebbing and membrane area homeostasis in spreading and retracting cells. AB - Cells remodel their plasma membrane and cytoskeleton during numerous physiological processes, including spreading and motility. Morphological changes require the cell to adjust its membrane tension on different timescales. While it is known that endo- and exocytosis regulate the cell membrane area in a timescale of 1 h, faster processes, such as abrupt cell detachment, require faster regulation of the plasma membrane tension. In this article, we demonstrate that cell blebbing plays a critical role in the global mechanical homeostasis of the cell through regulation of membrane tension. Abrupt cell detachment leads to pronounced blebbing (which slow detachment does not), and blebbing decreases with time in a dynamin-dependent fashion. Cells only start spreading after a lag period whose duration depends on the cell's blebbing activity. Our model quantitatively reproduces the monotonic decay of the blebbing activity and accounts for the lag phase in the spreading of blebbing cells. PMID- 20858417 TI - Synthetic chloride-selective carbon nanotubes examined by using molecular and stochastic dynamics. AB - Synthetic channels, such as nanotubes, offer the possibility of ion-selective nanoscale pores which can broadly mimic the functions of various biological ion channels, and may one day be used as antimicrobial agents, or for treatment of cystic fibrosis. We have designed a carbon nanotube that is selectively permeable to anions. The virtual nanotubes are constructed from a hexagonal array of carbon atoms (graphene) rolled up to form a tubular structure, with an effective radius of 4.53 A and length of 34 A. The pore ends are terminated with polar carbonyl groups. The nanotube thus formed is embedded in a lipid bilayer and a reservoir containing ionic solutions is added at each end of the pore. The conductance properties of these synthetic channels are then examined with molecular and stochastic dynamics simulations. Profiles of the potential of mean force at 0 mM reveal that a cation moving across the pore encounters an insurmountable free energy barrier of ~25 kT in height. In contrast, for anions, there are two energy wells of ~12 kT near each end of the tube, separated by a central free energy barrier of 4 kT. The conductance of the pore, with symmetrical 500 mM solutions in the reservoirs, is 72 pS at 100 mV. The current saturates with an increasing ionic concentration, obeying a Michaelis-Menten relationship. The pore is normally occupied by two ions, and the rate-limiting step in conduction is the time taken for the resident ion near the exit gate to move out of the energy well. PMID- 20858418 TI - Kinetic and energetic analysis of thermally activated TRPV1 channels. AB - Thermal TRP channels are important for thermal sensation and nociception, but their gating mechanisms have remained elusive. With optically generated submillisecond temperature steps from 22 degrees C to >60 degrees C, we have directly measured the activation and deactivation kinetics of TRPV1 channels, and from the measurements we determined the energetics of thermal gating. We show that activation by temperature follows single exponential time courses. It occurs in a few milliseconds and is significantly faster than activation by agonists. The gating has characteristics of a melting process involving large compensatory enthalpy (>100 kcal/mol) and entropy changes with little free energy change. The reaction path is asymmetrical with temperature mainly driving the opening while the closing has nominal but negative temperature dependence (i.e., sensitivity to cold). Both voltage and agonists alter the slope of the temperature-dependent gating curve as well as shifting the midpoint. However, compared to the energetic effect of temperature on gating, the effect of voltage is small. Our data on the interdependence between voltage and direct temperature responses are not fit to a model involving independent stimuli but instead support a temperature-sensing mechanism that is coupled to charge movement or agonist binding. PMID- 20858419 TI - Cytochrome c-lipid interactions: new insights from resonance energy transfer. AB - Resonance energy transfer (RET) from anthrylvinyl-labeled phosphatidylcholine (AV PC) or cardiolipin (AV-CL) to cytochrome c (cyt c) heme moiety was employed to assess the molecular-level details of protein interactions with lipid bilayers composed of PC with 2.5 (CL2.5), 5 (CL5), 10 (CL10), or 20 (CL20) mol % CL under conditions of varying ionic strength and lipid/protein molar ratio. Monte Carlo analysis of multiple data sets revealed a subtle interplay between 1), exchange of the neutral and acidic lipid in the protein-lipid interaction zone; 2), CL transition into the extended conformation; and 3), formation of the hexagonal phase. The switch between these states was found to be controlled by CL content and salt concentration. At ionic strengths >= 40 mM, lipid bilayers with CL fraction not exceeding 5 mol % exhibited the tendency to transform from lamellar to hexagonal phase upon cyt c adsorption, whereas at higher contents of CL, transition into the extended conformation seems to become thermodynamically favorable. At lower ionic strengths, deviations from homogeneous lipid distributions were observed only for model membranes containing 2.5 mol % CL, suggesting the existence of a certain surface potential critical for assembly of lipid lateral domains in protein-lipid systems that may subsequently undergo morphological transformations depending on ambient conditions. These characteristics of cyt c-CL interaction are of great interest, not only from the viewpoint of regulating cyt c electron transfer and apoptotic propensities, but also to elucidate the general mechanisms by which membrane functional activities can be modulated by protein-lipid interactions. PMID- 20858420 TI - Structural role of the conserved cysteines in the dimerization of the viral transmembrane oncoprotein E5. AB - The E5 oncoprotein is the major transforming protein of bovine papillomavirus type 1. This 44-residue transmembrane protein can interact with the platelet derived growth factor receptor beta, leading to ligand-independent activation and cell transformation. For productive interaction, E5 needs to dimerize via a C terminal pair of cysteines, though a recent study suggested that its truncated transmembrane segment can dimerize on its own. To analyze the structure of the full protein in a membrane environment and elucidate the role of the Cys-Ser-Cys motif, we produced recombinantly the wild-type protein and four cysteine mutants. Comparison by circular dichroism in detergent micelles and lipid vesicular dispersion and by NMR in trifluoroethanol demonstrates that the absence of one or both cysteines does not influence the highly alpha-helical secondary structure, nor does it impair the ability of E5 to dimerize, observations that are further supported by sodium dodecylsulfate polyacrylamide gel electrophoresis. We also observed assemblies of higher order. Oriented circular dichroism in lipid bilayers shows that E5 is aligned as a transmembrane helix with a slight tilt angle, and that this membrane alignment is also independent of any cysteines. We conclude that the Cys-containing motif represents a disordered region of the protein that serves as an extra covalent connection for stabilization. PMID- 20858421 TI - Lipid polymorphism induced by surfactant peptide SP-B(1-25). AB - Pulmonary surfactant protein B (SP-B) is an essential protein for lowering surface tension in the alveoli. SP-B(1-25), a peptide comprised of the N-terminal 25 amino-acid residues of SP-B, is known to retain much of the biological activity of SP-B. Circular dichroism has shown that when SP-B(1-25) interacts with negatively charged lipid vesicles, it contains significant helical structure for the lipid compositions and peptide/lipid ratios studied here. The effect of SP-B(1-25) on lipid organization and polymorphisms was investigated via DSC, dynamic light scattering, transmission electron microscopy, and solid-state NMR spectroscopy. At 1-3 mol% peptide and physiologic temperature, SP-B(1-25) partitions at the interface of negatively charged PC/PG lipid bilayers. In lipid mixtures containing 1-5 mol% peptide, the structure of SP-B(1-25) remains constant, but (2)H and (31)P NMR spectra show the presence of an isotropic lipid phase in exchange with the lamellar phase below the T(m) of the lipids. This behavior is observed for both DPPC/POPG and POPC/POPG lipid mixtures as well as for both the PC and PG components of the mixtures. For 1-3 mol% SP-B(1-25), a return to a single lamellar phase above the lipid mixture T(m) is observed, but for 5 mol% SP-B(1-25) a significant isotropic component is observed at physiologic temperatures for DPPC and exchange broadening is observed in (2)H and (31)P NMR spectra of the other lipid components in the two mixtures. DLS and TEM rule out the formation of micellar structures and suggest that SP-B(1-25) promotes the formation of a fluid isotropic phase. The ability of SP-B(1-25) to fuse lipid lamellae via this mechanism, particularly those enriched in DPPC, suggests a specific role for the highly conserved N-terminus of SP-B in the packing of lipid lamellae into surfactant lamellar bodies or in stabilizing multilayer structures at the air-liquid interface. Importantly, this behavior has not been seen for the other SP-B fragments of SP-B(8-25) and SP-B(59-80), indicating a critical role for the proline rich first seven amino acids in this protein. PMID- 20858422 TI - Water under the BAR. AB - Many cellular processes require the generation of highly curved regions of cell membranes by interfacial membrane proteins. A number of such proteins are now known, and several mechanisms of curvature generation have been suggested, but so far a quantitative understanding of the importance of the various potential mechanisms remains elusive. Following previous theoretical work, we consider the electrostatic attraction that underlies the scaffold mechanism of membrane bending in the context of the N-BAR domain of amphiphysin. Analysis of atomistic molecular dynamics simulations reveals considerable water between the membrane and the positively charged concave face of the BAR, even when it is tightly bound to highly curved membranes. This results in significant screening of electrostatic interactions, suggesting that electrostatic attraction is not the main driving force behind curvature sensing, supporting recent experimental work. These results also emphasize the need for care when building coarse-grained models of protein-membrane interactions. These results are emphasized by simulations of oligomerized amphiphysin N-BARs at the atomistic and coarse grained level. In the coarse-grained simulations, we find a strong dependence of the induced curvature on the dielectric screening. PMID- 20858423 TI - Fluctuations and the rate-limiting step of peptide-induced membrane leakage. AB - Peptide-induced vesicle leakage is a common experimental test for the membrane perturbing activity of antimicrobial peptides. The leakage kinetics is usually very slow, requiring minutes to hours for complete release of vesicle contents, and exhibits a biphasic behavior. We report here that, in the case of the peptaibol trichogin GA IV, all processes involved in peptide-membrane interaction, such as peptide-membrane association, peptide aggregation, and peptide translocation, take place on a timescale much shorter than the leakage kinetics. On the basis of these findings, we propose a stochastic model in which the leakage kinetics is determined by the discrete nature of a vesicle suspension: peptides are continuously exchanging among vesicles, producing significant fluctuations over time in the number of peptide molecules bound to each vesicle, and in the formation of pores. According to this model, the fast initial leakage is caused by vesicles that contain at least one pore after the peptides are randomly distributed among the liposomes, whereas the slower release is associated with the time needed to occasionally reach in an intact vesicle the critical number of bound peptides necessary for pore formation. Fluctuations due to peptide exchange among vesicles therefore represent the rate-limiting step of such a slow mechanism. PMID- 20858424 TI - Anesthetic binding in a pentameric ligand-gated ion channel: GLIC. AB - Cys-loop receptors are molecular targets of general anesthetics, but the knowledge of anesthetic binding to these proteins remains limited. Here we investigate anesthetic binding to the bacterial Gloeobacter violaceus pentameric ligand-gated ion channel (GLIC), a structural homolog of cys-loop receptors, using an experimental and computational hybrid approach. Tryptophan fluorescence quenching experiments showed halothane and thiopental binding at three tryptophan associated sites in the extracellular (EC) domain, transmembrane (TM) domain, and EC-TM interface of GLIC. An additional binding site at the EC-TM interface was predicted by docking analysis and validated by quenching experiments on the N200W GLIC mutant. The binding affinities (K(D)) of 2.3 +/- 0.1 mM and 0.10 +/- 0.01 mM were derived from the fluorescence quenching data of halothane and thiopental, respectively. Docking these anesthetics to the original GLIC crystal structure and the structures relaxed by molecular dynamics simulations revealed intrasubunit sites for most halothane binding and intersubunit sites for thiopental binding. Tryptophans were within reach of both intra- and intersubunit binding sites. Multiple molecular dynamics simulations on GLIC in the presence of halothane at different sites suggested that anesthetic binding at the EC-TM interface disrupted the critical interactions for channel gating, altered motion of the TM23 linker, and destabilized the open-channel conformation that can lead to inhibition of GLIC channel current. The study has not only provided insights into anesthetic binding in GLIC, but also demonstrated a successful fusion of experiments and computations for understanding anesthetic actions in complex proteins. PMID- 20858426 TI - The stepping pattern of myosin X is adapted for processive motility on bundled actin. AB - Myosin X is a molecular motor that is adapted to select bundled actin filaments over single actin filaments for processive motility. Its unique form of motility suggests that myosin X's stepping mechanism takes advantage of the arrangement of actin filaments and the additional target binding sites found within a bundle. Here we use fluorescence imaging with one-nanometer accuracy to show that myosin X takes steps of ~18 nm along a fascin-actin bundle. This step-size is well short of the 36-nm step-size observed in myosin V and myosin VI that corresponds to the actin pseudohelical repeat distance. Myosin X is able to walk along bundles with this step-size if it straddles two actin filaments, but would be quickly forced to spiral into the constrained interior of the bundle if it were to use only a single actin filament. We also demonstrate that myosin X takes many sideways steps as it walks along a bundle, suggesting that it can switch actin filament pairs within the bundle as it walks. Sideways steps to the left or the right occur on bundles with equal frequency, suggesting a degree of lateral flexibility such that the motor's working stroke does not bias it to the left or to the right. On single actin filaments, we find a broad mixture of 10-20-nm steps, which again falls short of the 36-nm actin repeat. Moreover, the motor leans to the right as it walks along single filaments, which may require myosin X to adopt strained configurations. As a control, we also tracked myosin V stepping along actin filaments and fascin-actin bundles. We find that myosin V follows a narrower path on both structures, walking primarily along one surface of an actin filament and following a single filament within a bundle while occasionally switching to neighboring filaments. Together, these results delineate some of the structural features of the motor and the track that allow myosin X to recognize actin filament bundles. PMID- 20858425 TI - Assembly of the m2 tetramer is strongly modulated by lipid chain length. AB - The influenza virus matrix protein 2 (M2) assembles into a tetramer in the host membrane during viral uncoating and maturation. It has been used as a model system to understand the relative contributions of protein-lipid and protein protein interactions to membrane protein structure and association. Here we investigate the effect of lipid chain length on the association of the M2 transmembrane domain into tetramers using Forster resonance energy transfer. We observe that the interactions between the M2 helices are much stronger in 1,2 dilauroyl-sn-glycero-3-phosphocholine than in 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine bilayers. Thus, lipid chain length and bilayer thickness not only modulate peptide interactions, but could also be a major determinant of the association of transmembrane helices into functional membrane protein oligomers. PMID- 20858427 TI - Myosin heads contribute to the maintenance of filament order in relaxed rabbit muscle. AB - Raising the temperature of rabbit skeletal muscle from ~0 degrees C to ~20 degrees C has been shown to enhance the helical organization of the myosin heads and to change the intensities of the 10 and 11 equatorial reflections. We show here by time-resolved x-ray diffraction combined with temperature jump that the movement of the heads to enhance the organized myosin helix occurs at the same fast rate as the change in the intensities of the equatorial reflections. However, model calculations indicate that the change in the equatorials cannot be explained simply in terms of the movement of myosin heads. Analysis of electron micrographs of transverse sections of relaxed muscle fibers cryofixed at ~5 degrees C and ~35 degrees C shows that in addition to the reorganization of the heads the thin and thick filaments are less constrained to their positions in the hexagonal filament lattice in the warm muscle than in the cold. Incorporating the changes in filament order in model calculations reconciles these with the observed changes in equatorial reflections. We suggest the thin filaments in the cold muscle are boxed into their positions by the thermal movement of the disordered myosin heads. In the warmer muscle, the packed-down heads leave the thin filaments more room to diffuse laterally. PMID- 20858428 TI - Kinesin recycling in stationary membrane tubes. AB - Collections of motors dynamically organize to extract membrane tubes. These tubes grow but often pause or change direction as they traverse an underlying microtubule (MT) network. In vitro, membrane tubes also stall: they stop growing in length despite a large group of motors available at the tip to pull them forward. In these stationary membrane tubes in vitro, we find that clusters of processive kinesin motors form and reach the tip of the tube at regular time intervals. The average times between cluster arrivals depends on the time over which motors depart from the tip, suggesting that motors are recycled toward the tip. Numerical simulations of the motor dynamics in the membrane tube and on the MTs show that the presence of cooperative binding between motors quantitatively accounts for the clustering observed experimentally. Cooperative binding along the length of the MT and a nucleation point at a distance behind the tip define the recycling period. Based on comparison of the numerical results and experimental data, we estimate a cooperative binding probability and concentration regime where the recycling phenomenon occurs. PMID- 20858429 TI - Second harmonic generation microscopy probes different states of motor protein interaction in myofibrils. AB - The second harmonic generation (SHG) signal intensity sourced from skeletal muscle myosin II strongly depends on the polarization of the incident laser beam relative to the muscle fiber axis. This dependence is related to the second-order susceptibility chi((2)), which can be described by a single component ratio gamma under generally assumed symmetries. We precisely extracted gamma from SHG polarization dependence curves with an extended focal field model. In murine myofibrillar preparations, we have found two distinct polarization dependencies: With the actomyosin system in the rigor state, gamma(rig) has a mean value of gamma(rig) = 0.52 (SD = 0.04, n = 55); in a relaxed state where myosin is not bound to actin, gamma(rel) has a mean value of gamma(rel) = 0.24 (SD = 0.07, n = 70). We observed a similar value in an activated state where the myosin power stroke was pharmacologically inhibited using N-benzyl-p-toluene sulfonamide. In summary, different actomyosin states can be visualized noninvasively with SHG microscopy. Specifically, SHG even allows us to distinguish different actin-bound states of myosin II using gamma as a parameter. PMID- 20858430 TI - Origin of twist-bend coupling in actin filaments. AB - Actin filaments are semiflexible polymers that display large-scale conformational twisting and bending motions. Modulation of filament bending and twisting dynamics has been linked to regulatory actin-binding protein function, filament assembly and fragmentation, and overall cell motility. The relationship between actin filament bending and twisting dynamics has not been evaluated. The numerical and analytical experiments presented here reveal that actin filaments have a strong intrinsic twist-bend coupling that obligates the reciprocal interconversion of bending energy and twisting stress. We developed a mesoscopic model of actin filaments that captures key documented features, including the subunit dimensions, interaction energies, helicity, and geometrical constraints coming from the double-stranded structure. The filament bending and torsional rigidities predicted by the model are comparable to experimental values, demonstrating the capacity of the model to assess the mechanical properties of actin filaments, including the coupling between twisting and bending motions. The predicted actin filament twist-bend coupling is strong, with a persistence length of 0.15-0.4 MUm depending on the actin-bound nucleotide. Twist-bend coupling is an emergent property that introduces local asymmetry to actin filaments and contributes to their overall elasticity. Up to 60% of the filament subunit elastic free energy originates from twist-bend coupling, with the largest contributions resulting under relatively small deformations. A comparison of filaments with different architectures indicates that twist-bend coupling in actin filaments originates from their double protofilament and helical structure. PMID- 20858431 TI - Phosphorylation of caldesmon at sites between residues 627 and 642 attenuates inhibitory activity and contributes to a reduction in Ca2+-calmodulin affinity. AB - Caldesmon is an actin- and myosin-binding protein found in smooth muscle that inhibits actin activation of myosin ATPase activity. The activity of caldesmon is controlled by phosphorylation and by binding to Ca(2+)-calmodulin. We investigated the effects of phosphorylation by p(21)-activated kinase 3 (PAK) and calmodulin on the 22 kDa C-terminal fragment of caldesmon (CaD22). We substituted the major PAK sites, Ser-672 and Ser-702, with either alanine or aspartic acid to mimic nonphosphorylated and constitutively phosphorylated states of caldesmon, respectively. The aspartic acid mutation of CaD22 weakened Ca(2+)-calmodulin binding but had no effect on inhibition of ATPase activity. Phosphorylation of the aspartic acid mutant with PAK resulted in the slow phosphorylation of Thr 627, Ser-631, Ser-635, and Ser-642. Phosphorylation at these sites weakened Ca(2+)-calmodulin binding further and reduced the inhibitory activity of CaD22 in the absence of Ca(2+)-calmodulin. Phosphorylation of these sites of the alanine mutant of CaD22 had no effect on Ca(2+)-calmodulin binding but did reduce inhibition of ATPase activity. Thus, the region between residues 627 and 642 may contribute to the overall regulation of caldesmon's activity. PMID- 20858432 TI - Significant impact on muscle mechanics of small nonlinearities in myofilament elasticity. AB - Important mechanisms in muscle contraction have recently been reevaluated based on analyses that rely on the assumption of linear myofilament elasticity. However, the present theoretical study shows that nonlinearity of this elasticity, even when so minor that it may be difficult to detect in experimental data, could have great impact on the interpretation of muscle mechanical experiments. This is illustrated by using simulated stiffness and strain-versus force data for muscle fibers shortening at different constant velocities. There is substantial quantitative agreement, for this condition, between models with distributed myofilament compliance and models where the compliance of the myofilaments and the actomyosin cross-bridges are lumped together into two separate elastic elements acting in series. The data thus support the usefulness of the latter, simpler, type of model in the analysis. However, most importantly, the data emphasize the importance of caution before reevaluating fundamental mechanisms of muscle contraction based on analyses relying on the assumption of linear myofilament elasticity. PMID- 20858433 TI - Toward a consensus view of duplex RNA flexibility. AB - The structure and flexibility of the RNA duplex has been studied using extended molecular dynamics simulations on four diverse 18-mer oligonucleotides designed to contain many copies of the 10 unique dinucleotide steps in different sequence environments. Simulations were performed using the two most popular force fields for nucleic acids simulations (AMBER and CHARMM) in their latest versions, trying to arrive to a consensus picture of the RNA flexibility. Contrary to what was found for DNA duplex (DNA(2)), no clear convergence is found for the RNA duplex (RNA(2)), but one of the force field seems to agree better with experimental data. MD simulations performed with this force field were used to fully characterize, for the first time to our knowledge, the sequence-dependent elastic properties of RNA duplexes at different levels of resolutions. The flexibility pattern of RNA(2) shows similarities with DNA(2), but also surprising differences, which help us to understand the different biological functions of both molecules. A full mesoscopic model of RNA duplex at different resolution levels is derived to be used for genome-wide description of the flexibility of double-helical fragments of RNA. PMID- 20858434 TI - Salt concentration effects on equilibrium melting curves from DNA microarrays. AB - DNA microarrays find applications in an increasing number of domains where more quantitative results are required. DNA being a charged polymer, the repulsive interactions between the surface of the microarray and the targets in solution are increasing upon hybridization. Such electrostatic penalty is generally reduced by increasing the salt concentration. In this article, we present equilibrium-melting curves obtained from dedicated physicochemical experiments on DNA microarrays in order to get a better understanding of the electrostatic penalty incurred during the hybridization reaction at the surface. Various salt concentrations have been considered and deviations from the commonly used Langmuir adsorption model are experimentally quantified for the first time in agreement with theoretical predictions. PMID- 20858435 TI - Electrostatic origin of salt-induced nucleosome array compaction. AB - The physical mechanism of the folding and unfolding of chromatin is fundamentally related to transcription but is incompletely characterized and not fully understood. We experimentally and theoretically studied chromatin compaction by investigating the salt-mediated folding of an array made of 12 positioning nucleosomes with 177 bp repeat length. Sedimentation velocity measurements were performed to monitor the folding provoked by addition of cations Na(+), K(+), Mg(2+), Ca(2+), spermidine(3+), Co(NH(3))(6)(3+), and spermine(4+). We found typical polyelectrolyte behavior, with the critical concentration of cation needed to bring about maximal folding covering a range of almost five orders of magnitude (from 2 MUM for spermine(4+) to 100 mM for Na(+)). A coarse-grained model of the nucleosome array based on a continuum dielectric description and including the explicit presence of mobile ions and charged flexible histone tails was used in computer simulations to investigate the cation-mediated compaction. The results of the simulations with explicit ions are in general agreement with the experimental data, whereas simple Debye-Huckel models are intrinsically incapable of describing chromatin array folding by multivalent cations. We conclude that the theoretical description of the salt-induced chromatin folding must incorporate explicit mobile ions that include ion correlation and ion competition effects. PMID- 20858436 TI - Control of the flow properties of DNA by topoisomerase II and its targeting inhibitor. AB - The flow properties of DNA are important for understanding cell division and, indirectly, cancer therapy. DNA topology controlling enzymes such as topoisomerase II are thought to play an essential role. We report experiments showing how double-strand passage facilitated by topoisomerase II controls DNA rheology. For this purpose, we have measured the elastic storage and viscous loss moduli of a model system comprising bacteriophage lambda-DNA and human topoisomerase IIalpha using video tracking of the Brownian motion of colloidal probe particles. We found that the rheology is critically dependent on the formation of temporal entanglements among the DNA molecules with a relaxation time of ~1 s. We observed that topoisomerase II effectively removes these entanglements and transforms the solution from an elastic physical gel to a viscous fluid depending on the consumption of ATP. A second aspect of this study is the effect of the generic topoisomerase II inhibitor adenylyl-imidodiphosphate (AMP-PNP). In mixtures of AMP-PNP and ATP, the double-strand passage reaction gets blocked and progressively fewer entanglements are relaxed. A total replacement of ATP by AMP-PNP results in a temporal increase in elasticity at higher frequencies, but no transition to an elastic gel with fixed cross-links. PMID- 20858437 TI - Effect of single-strand break on branch migration and folding dynamics of Holliday junctions. AB - The Holliday junction (HJ), or four-way junction, is a central intermediate state of DNA for homologous genetic recombination and other genetic processes such as replication and repair. Branch migration is the process by which the exchange of homologous DNA regions occurs, and it can be spontaneous or driven by proteins. Unfolding of the HJ is required for branch migration. Our previous single molecule fluorescence studies led to a model according to which branch migration is a stepwise process consisting of consecutive migration and folding steps. Folding of the HJ in one of the folded conformations terminates the branch migration phase. At the same time, in the unfolded state HJ rapidly migrates over entire homology region of the HJ in one hop. This process can be affected by irregularities in the DNA double helical structure, so mismatches almost terminate a spontaneous branch migration. Single-stranded breaks or nicks are the most ubiquitous defects in the DNA helix; however, to date, their effect on the HJ branch migration has not been studied. In addition, although nicked HJs are specific substrates for a number of enzymes involved in DNA recombination and repair, the role of this substrate specificity remains unclear. Our main goal in this work was to study the effect of nicks on the efficiency of HJ branch migration and the dynamics of the HJ. To accomplish this goal, we applied two single-molecule methods: atomic force microscopy and fluorescence resonance energy transfer. The atomic force microscopy data show that the nick does not prevent branch migration, but it does decrease the probability that the HJ will pass the DNA lesion. The single-molecule fluorescence resonance energy transfer approaches were instrumental in detailing the effects of nicks. These studies reveal a dramatic change of the HJ dynamics. The nick changes the structure and conformational dynamics of the junctions, leading to conformations with geometries that are different from those for the intact HJ. On the basis of these data, we propose a model of branch migration in which the propensity of the junction to unfold decreases the lifetimes of folded states, thereby increasing the frequency of junction fluctuations between the folded states. PMID- 20858438 TI - Laser-assisted single-molecule refolding (LASR). AB - To assemble into functional structures, biopolymers search for global minima through their folding potential energy surfaces to find the native conformation. However, this process can be hindered by the presence of kinetic traps. Here, we present a new single-molecule technique, termed laser-assisted single-molecule refolding (LASR), to characterize kinetic traps at the single-molecule level. LASR combines temperature-jump kinetics and single-molecule spectroscopy. We demonstrate the use of LASR to measure single-molecule DNA melting curves with ~1 degrees C accuracy and to determine the activation barrier of a model kinetic trap. We also show how LASR, in combination with mutagenesis, can be used to estimate the yields of competing pathways, as well as to generate and characterize transient, unstable complexes. PMID- 20858439 TI - Solid-state NMR characterization of gas vesicle structure. AB - Gas vesicles are gas-filled buoyancy organelles with walls that consist almost exclusively of gas vesicle protein A (GvpA). Intact, collapsed gas vesicles from the cyanobacterium Anabaena flos-aquae were studied by solid-state NMR spectroscopy, and most of the GvpA sequence was assigned. Chemical shift analysis indicates a coil-alpha-beta-beta-alpha-coil peptide backbone, consistent with secondary-structure-prediction algorithms, and complementary information about mobility and solvent exposure yields a picture of the overall topology of the vesicle subunit that is consistent with its role in stabilizing an air-water interface. PMID- 20858440 TI - Neutron reflectometry study of the conformation of HIV Nef bound to lipid membranes. AB - Nef is an HIV-1 accessory protein that directly contributes to AIDS progression. Nef is myristoylated on the N-terminus, associates with membranes, and may undergo a transition from a solution conformation to a membrane-associated conformation. It has been hypothesized that conformational rearrangement enables membrane-associated Nef to interact with cellular proteins. Despite its medical relevance, to our knowledge there is no direct information about the conformation of membrane-bound Nef. In this work, we used neutron reflection to reveal what we believe are the first details of the conformation of membrane-bound Nef. The conformation of Nef was probed upon binding to Langmuir monolayers through the interaction of an N-terminal His tag with a synthetic metal-chelating lipid, which models one of the possible limiting cases for myr-Nef. The data indicate that residues are inserted into the lipid headgroups during interaction, and that the core domain lies directly against the lipid headgroups, with a thickness of ~40 A. Binding of Nef through the N-terminal His tag apparently facilitates insertion of residues, as no insertion occurred upon binding of Nef through weak electrostatic interactions in the absence of the specific interaction through the His tag. PMID- 20858441 TI - Mapping conformational ensembles of abeta oligomers in molecular dynamics simulations. AB - Although the oligomers formed by Abeta peptides appear to be the primary cytotoxic species in Alzheimer's disease, detailed information about their structures appears to be lacking. In this article, we use exhaustive replica exchange molecular dynamics and an implicit solvent united-atom model to study the structural properties of Abeta monomers, dimers, and tetramers. Our analysis suggests that the conformational ensembles of Abeta dimers and tetramers are very similar, but sharply distinct from those sampled by the monomers. The key conformational difference between monomers and oligomers is the formation of beta structure in the oligomers occurring together with the loss of intrapeptide interactions and helix structure. Our simulations indicate that, independent of oligomer order, the Abeta aggregation interface is largely confined to the sequence region 10-23, which forms the bulk of interpeptide interactions. We show that the fractions of beta structure computed in our simulations and measured experimentally are in good agreement. PMID- 20858442 TI - Order statistics theory of unfolding of multimeric proteins. AB - Dynamic force spectroscopy has become indispensable for the exploration of the mechanical properties of proteins. In force-ramp experiments, performed by utilizing a time-dependent pulling force, the peak forces for unfolding transitions in a multimeric protein (D)(N) are used to map the free energy landscape for unfolding for a protein domain D. We show that theoretical modeling of unfolding transitions based on combining the observed first (f(1)), second (f(2)), ..., N(th) (f(N)) unfolding forces for a protein tandem of fixed length N, and pooling the force data for tandems of different length, n(1) >10 nm average hydrodynamic radius) assemblies of codiffusing, membrane-attached Abeta molecules appear on the cell membrane together with a near-monomeric species. When the extracellular concentration is 150 nM, the membrane contains only the smaller species, but with a similar degree of attachment. At both concentrations, the extracellular solution contains only small (~2.3 nm average hydrodynamic radius) Abeta oligomers or monomers. We conclude that at near-physiological concentrations only the small oligomeric Abeta species are relevant, they are capable of attaching to the cell membrane, and they assemble in situ to form much larger complexes. PMID- 20858444 TI - Free heme and the polymerization of sickle cell hemoglobin. AB - In search of novel control parameters for the polymerization of sickle cell hemoglobin (HbS), the primary pathogenic event of sickle cell anemia, we explore the role of free heme, which may be excessively released in sickle erythrocytes. We show that the concentration of free heme in HbS solutions typically used in the laboratory is 0.02-0.04 mole heme/mole HbS. We show that dialysis of small molecules out of HbS solutions arrests HbS polymerization. The addition of 100 260 MUM of free heme to dialyzed HbS solutions leads to rates of nucleation and polymer fiber growth faster by two orders of magnitude than before dialysis. Toward an understanding of the mechanism of nucleation enhancement by heme, we show that free heme at a concentration of 66 MUM increases by two orders of magnitude the volume of the metastable clusters of dense HbS liquid, the locations where HbS polymer nuclei form. These results suggest that spikes of the free heme concentration in the erythrocytes of sickle cell anemia patients may be a significant factor in the complexity of the clinical manifestations of sickle cell anemia. The prevention of free heme accumulation in the erythrocyte cytosol may be a novel avenue to sickle cell therapy. PMID- 20858445 TI - In vitro fracture testing of submicron diameter collagen fibril specimens. AB - Mechanical testing of collagenous tissues at different length scales will provide improved understanding of the mechanical behavior of structures such as skin, tendon, and bone, and also guide the development of multiscale mechanical models. Using a microelectromechanical-systems (MEMS) platform, stress-strain response curves up to failure of type I collagen fibril specimens isolated from the dermis of sea cucumbers were obtained in vitro. A majority of the fibril specimens showed brittle fracture. Some displayed linear behavior up to failure, while others displayed some nonlinearity. The fibril specimens showed an elastic modulus of 470 +/- 410 MPa, a fracture strength of 230 +/- 160 MPa, and a fracture strain of 80% +/- 44%. The fibril specimens displayed significantly lower elastic modulus in vitro than previously measured in air. Fracture strength/strain obtained in vitro and in air are both significantly larger than those obtained in vacuo, indicating that the difference arises from the lack of intrafibrillar water molecules produced by vacuum drying. Furthermore, fracture strength/strain of fibril specimens were different from those reported for collagenous tissues of higher hierarchical levels, indicating the importance of obtaining these properties at the fibrillar level for multiscale modeling. PMID- 20858446 TI - Multi-image colocalization and its statistical significance. AB - Accurately localizing molecules within the cell is one of main tasks of modern biology, and colocalization analysis is one of its principal and most often used tools. Despite this popularity, interpretation is often uncertain because colocalization between two or more images is rarely analyzed to determine whether the observed values could have occurred by chance. To address this, we have developed a robust methodology, based on Monte Carlo randomization, to measure the statistical significance of a colocalization. The method works with voxel based, intensity-based, object-based, and nearest-neighbor metrics. We extend all of these to measure colocalization in images with three colors. We also introduce three new metrics; blob colocalization, where the blob consists of a local maximum surrounded by a three-dimensional group of voxels; cluster diameter, to measure the clustering of fluorophores in three or more images; and the intercluster distance to measure the distance between these clusters. The robustness of these metrics was tested by varying the image thresholds over a broad range, which produced no change in the statistical significance of the colocalizations. A comparison of blob colocalization with voxel and Manders colocalization metrics shows that the different measures produce consistent results with similar values for significance and nonsignificance. Using our methodology, we are able to determine not only whether the labeled molecules colocalize with a probability greater than chance, but also whether they are sequestrated into different compartments. The program, written in C++, is freely available as source, as well as in a Linux version. PMID- 20858447 TI - Monitoring photosynthesis in individual cells of Synechocystis sp. PCC 6803 on a picosecond timescale. AB - Picosecond fluorescence kinetics of wild-type (WT) and mutant cells of Synechocystis sp. PCC 6803, were studied at the ensemble level with a streak camera and at the cell level using fluorescence-lifetime-imaging microscopy (FLIM). The FLIM measurements are in good agreement with the ensemble measurements, but they (can) unveil variations between and within cells. The BE mutant cells, devoid of photosystem II (PSII) and of the light-harvesting phycobilisomes, allowed the study of photosystem I (PSI) in vivo for the first time, and the observed 6-ps equilibration process and 25-ps trapping process are the same as found previously for isolated PSI. No major differences are detected between different cells. The PAL mutant cells, devoid of phycobilisomes, show four lifetimes: ~20 ps (PSI and PSII), ~80 ps, ~440 ps, and 2.8 ns (all due to PSII), but not all cells are identical and variations in the kinetics are traced back to differences in the PSI/PSII ratio. Finally, FLIM measurements on WT cells reveal that in some cells or parts of cells, phycobilisomes are disconnected from PSI/PSII. It is argued that the FLIM setup used can become instrumental in unraveling photosynthetic regulation mechanisms in the future. PMID- 20858448 TI - The vitamin E-binding protein afamin is altered significantly in the peritoneal fluid of women with endometriosis. AB - The objective of this case-control study of 242 reproductive-age women was to determine the concentration of afamin in the serum and peritoneal fluid of women with and without endometriosis and to test afamin as a diagnostic marker of endometriosis. Afamin levels were altered significantly in the peritoneal fluid of women with endometriosis compared with disease-free controls, correlated with vitamin E levels, and are consistent with increased oxidative stress in the peritoneal cavity of women with endometriosis. PMID- 20858449 TI - Circulating regulatory T cells (CD4+CD25+FOXP3+) decrease in breast cancer patients after vaccination with a modified MHC class II HER2/neu (AE37) peptide. AB - Regulatory T cells (T(Reg)), CD4(+)CD25(+)FOXP3(+), are implicated in suppressing tumor immune responses. We analyzed peripheral blood lymphocytes (PBL) from breast cancer patients receiving a modified HLA class II HER2/neu peptide (AE37) vaccine for T(Reg) cells and correlated their levels with vaccine-specific immune responses. The mean CD4(+)CD25(+)FOXP3(+) T(Reg) cells decreased in patients with vaccination with no significant difference in serum TGF-beta levels. IFN-gamma ELISPOT and DTH increased after vaccination with a good correlation between T(Reg) cell reduction and size of DTH to AE37. The T(Reg) cell reduction and associated immune response suggest that AE37 may be clinically useful. PMID- 20858450 TI - GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. AB - Mucosal immunization with a killed whole-cell pneumococcal vaccine, given with enterotoxin-related adjuvants, has been shown to confer multi-serotype protection against colonization of the nasopharynx and middle ear in mice. However, because novel mucosal immunization strategies may be difficult to implement, here we evaluated subcutaneous injection. Strain RM200 was engineered to be capsule negative, autolysin-negative, and to express a non-toxic mutant pneumolysoid. Liter-scale and 60-l Good Manufacturing Practice (GMP) cultures were grown in bovine-free soy-based medium, killed with chloroform or beta-propiolactone, and injected into C57Bl/6 mice without or with aluminum adjuvant. The adjuvant Al(OH)(3) strongly increased responses, particularly if pre-treated with phosphate. Protection was found in several tested model infections: nasal colonization with a serotype 6B strain and fatal aspiration-sepsis with strains of serotype 3 and 5. Protection against colonization was mechanistically dependent on the presence of CD4+ T cells at the time of challenge; in contrast, in the type 3 aspiration-sepsis model, CD4+ T cells were not required for protection at the time of challenge, suggesting that antibody alone was sufficient to protect against death in this model. Rabbits receiving sequential intramuscular injections in a pilot toxicity study displayed local reactogenicity at injection sites but no clinical signs. The rabbit antiserum thus produced was active in an in vitro phagocytic killing assay and passively protected mice in the type 3 aspiration-sepsis model. Approval is being sought for human trials of this vaccine. PMID- 20858451 TI - Genetic analysis of ticks belonging to the Rhipicephalus sanguineus group in Latin America. AB - Phylogenetic analyses based on mitochondrial 16S rDNA sequences were generated from Rhipicephalus sanguineus group specimens collected in 29 localities among 9 Latin-American countries, plus ticks collected in South Africa, Spain, and Italy. Sequences from Latin America generated six different haplotypes (A, B, C, D, E, and F). Phylogenetic analyses generated trees that segregated our tick sequences into two distinct clades: one is represented by haplotypes A-C, and South African R. sanguineus and Rhipicephalus turanicus ticks; the second clade is represented by haplotypes D-F, and European R. sanguineus and R. turanicus ticks. When haplotypes A-F are plotted in the Latin America map according to their geographical coordinates, it is clearly seen that haplotypes D-F are restricted to the southern portion of this continent, whereas haplotypes A-C are distributed in areas between northern Mexico and Brazil (except for the extreme south of this last country, where haplotype E was present). Hence, our phylogenetic analyses separated New World specimens of R. sanguineus into two distinct clades, one represented by tropical and subtropical populations (haplotypes A-C), here designated as the 'tropical' species. On the other hand, haplotypes D-F are here designated as the 'temperate' species because of their distribution in the southern portion of South America. Until recently, it was assumed that the R. sanguineus group was represented by a single species in the New World, namely R. sanguineus. While the present results coupled with recent studies support the presence of at least two species under the taxon R. sanguineus in the New World, they also show that even in the Old World, the taxon R. sanguineus might be represented by more than one species, since our phylogenetic analysis segregated European and South African R. sanguineus ticks into two distinct clades. The same can be applied for Spanish and South African R. turanicus. PMID- 20858452 TI - Western blotting method (TESAcruzi) as a supplemental test for confirming the presence of anti-Trypanosoma cruzi antibodies in finger prick blood samples from children aged 0-5 years in Brazil. AB - Some Latin American countries have plans for total control and/or eradication of Chagas disease by the main vector (Triatoma infestans) and by blood transfusion. To achieve this, patients with Chagas disease must be identified. A Western blotting test, TESAcruzi, is described as a supplemental test for diagnosis of Chagas disease using samples collected from children <5 years living in different states of Brazil. Blood samples collected by finger prick on filter paper were sent to the test laboratory by a central laboratory to confirm results obtained previously. Ten percent of negative samples, all doubtful and all positive samples were received. Commercial reagents, IgG indirect immunofluorescence, enzyme immunoassay, and a recently introduced TESAcruzi test were used. From 8788 samples, 163 (1.85%) were reactive by IgG-ELISA and 312 (3.55%) by IgG IIF. From these, 77 (0.87%) were reactive in the TESAcruzi test. The results had high clinical value to identify those truly infected. PMID- 20858453 TI - Molecular characterization of human and animal Echinococcus granulosus isolates in Isfahan, Iran. AB - Cystic hydatid disease (CHD) is one of the most important zoonotic diseases in different parts of Iran. While it causes major health problem, there is limited information about its transmission cycles and reservoirs of human infection. Therefore we aimed to characterize the existence Echinococcus granulosus cysts in humans and animals in the province of Isfahan, central region of Iran. We collected hydatid cysts from the liver and lungs of patients who underwent surgery procedure and also cysts were obtained from domestic animals at slaughterhouses. DNA was extracted from the protoscoleces and examined by polymerase chain reaction (PCR) of rDNA internal transcribed spacer1 (ITS1-PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP). In addition, fragments of the genes coding for mitochondrial cytochrome c oxidase subunit 1 (CO1) and NADH dehydrogenase 1 (ND1) were sequenced. Among the two different identified strains/genotypes (sheep and camel), the sheep strain was shown to be the most common genotype of E. granulosus affecting humans, sheep, cattle, goats and occasionally camels. Nine out of 26 camel samples were infected with sheep strain. However the camel genotype was observed in humans, camels and cattle. Seventeen out of 26 camel isolates, 6 out of 31 human and 5 out of 14 cattle samples were infected with the camel genotype. The camel genotypes had PCR and RFLP patterns which were different from the PCR and RFLP patterns of the rest of isolates (sheep strain). The results of this study showed that the 'camel' strain was actual source of infection to humans which circulates between intermediate hosts including camels and cattle, and it confirms the camel-dog transmission cycle in Isfahan. PMID- 20858454 TI - Characterization of insecticide resistance in Trinidadian strains of Aedes aegypti mosquitoes. AB - Bioassays and biochemical assays were conducted on eight Trinidadian strains of Aedes aegypti larvae to determine the involvement of biochemical mechanisms in resistance to insecticides. Larval strains were assayed to dichlorodiphenyltrichloroethane (DDT), bendiocarb, temephos and permethrin, using the Centers for Disease Control and Prevention (CDC) time-mortality bioassay method. A Resistance Threshold (RT) was calculated for each insecticide in relation to the CAREC reference susceptible Ae. aegypti strain and larval strains with <80% mortality were considered to be resistant. Biochemical assays were performed to determine the activities of nonspecific esterases (alpha- and beta ), PNPA-esterases, mixed function oxidases (MFO), glutathione-S-transferases (GST) and acetylcholinesterase (AChE) enzymes which are involved in insecticide resistance in mosquitoes. Enzyme profiles of each strain were compared with those of the CAREC reference susceptible strain by Kruskal-Wallis and Dunn's multiple comparison tests (p<0.05). The CAREC 99th percentile was calculated for each enzyme and the percentage of individuals with enzyme activities above that of the CAREC 99th percentile was calculated. Activities were classified as unaltered (<50%), incipiently altered (15-50%) or altered (>50%) for each strain. The established RTs for permethrin and bendiocarb were 30 and 75 min, respectively; and 120 min for DDT and temephos. All strains were resistant to DDT (1.00-40.25% mortality) and temephos (11.50-74.50% mortality) while six strains were resistant to bendiocarb (51.50-78.50% mortality) and five to permethrin (6.50-42.50% mortality). Biochemical assays revealed that the median activity levels for all enzymes varied significantly (p<0.05). The Curepe strain had incipiently altered levels of alpha-esterase while the other seven strains had altered activity with five of them registering 100%. The St Clair strain showed altered activity levels of beta-esterase while three strains had incipiently altered levels. The majority of strains had altered activity of MFO enzymes but only the St Clair strain showed altered activity of GST. PNPA-esterases activity was unaltered in all strains and only the Haleland Park strain showed altered remaining AChE activity in the presence of propoxur. Elevated levels of enzymes (incipiently altered or altered), except in the case of PNPA-esterases, show that biochemical resistance may play an important role in the manifestation of insecticide resistance in Trinidadian populations of Ae. aegypti. It is therefore important for insecticide resistance surveillance to be ongoing as the detection of resistance before it spreads throughout an entire population makes it possible for early intervention. PMID- 20858455 TI - Isolation and characterization of Acanthamoeba spp. from air-conditioners in Kuala Lumpur, Malaysia. AB - During a study on the quality of the indoor environment, Acanthamoeba spp. were detected in 20 out of 87 dust samples collected from air-conditioners installed in a four-story campus building located in Kuala Lumpur, Malaysia. Twenty-one cloned Acanthamoeba isolates designated as IMU1 to IMU21 were established from the positive primary cultures. Five species were identified from the 16 isolates according to the morphological criteria of Pussard and Pons; i.e. A. castellanii, A. culbertsoni, A. griffini, A. hatchetti and A. polyphaga. Species identities for the remaining five isolates (IMU4, IMU5, IMU15, IMU20 and IMU21), however, could not be determined morphologically. At genotypic characterization, these isolates were placed into T3 (IMU14); T5 (IMU16 and IMU17) and T4 (all the remaining isolates). To predict the potential pathogenicity of these Acanthamoeba isolates, thermo- and osmotolerance tests were employed; many isolates were predicted as potential human pathogens based on the outcome of these tests. This is the first time potentially pathogenic Acanthamoeba have been isolated from air conditioners in Malaysia. PMID- 20858456 TI - Structural analysis of the receptor binding domain of botulinum neurotoxin serotype D. AB - Botulinum neurotoxins (BoNTs) are the most toxic proteins known. The mechanism for entry into neuronal cells for serotypes A, B, E, F, and G involves a well understood dual receptor (protein and ganglioside) process, however, the mechanism of entry for serotypes C and D remains unclear. To provide structural insights into how BoNT/D enters neuronal cells, the crystal structure of the receptor binding domain (S863-E1276) for this serotype (BoNT/D-HCR) was determined at 1.65A resolution. While BoNT/D-HCR adopts an overall fold similar to that observed in other known BoNT HCRs, several major structural differences are present. These structural differences are located at, or near, putative receptor binding sites and may be responsible for BoNT/D host preferences. Two loops, S1195-I1204 and K1236-N1244, located on both sides of the putative protein receptor binding pocket, are displaced >10A relative to the corresponding residues in the crystal structures of BoNT/B and G. Obvious clashes were observed in the putative protein receptor binding site when the BoNT/B protein receptor synaptotagmin II was modeled into the BoNT/D-HCR structure. Although a ganglioside binding site has never been unambiguously identified in BoNT/D-HCR, a shallow cavity in an analogous location to the other BoNT serotypes HCR domains is observed in BoNT/D-HCR that has features compatible with membrane binding. A portion of a loop near the putative receptor binding site, K1236-N1244, is hydrophobic and solvent-exposed and may directly bind membrane lipids. Liposome binding experiments with BoNT/D-HCR demonstrate that this membrane lipid may be phosphatidylethanolamine. PMID- 20858457 TI - Crystal structure of the N-terminal region of human Topoisomerase IIbeta binding protein 1. AB - Human DNA Topoisomerase IIbeta binding protein 1 (TopBP1) is a modulating protein that plays an essential role in the response to DNA damage. The N-terminal region of TopBP1, which contains predicted BRCA1-carboxy terminal (BRCT) domains 1 and 2, binds to Rad9, a component of the cell cycle checkpoint clamp Rad9-Hus1-Rad1 complex. Here, we report the crystal structure of the TopBP1N-terminal region (residues 1-290) at 2.4A resolution. Interestingly, in addition to the predicted tandem BRCT1-2 repeats (residues 103-284), residues 7-98 form a previously unreported BRCT domain (here, BRCT0). In contrast to both BRCT1 and BRCT2, which possess the conventional phosphopeptide binding residues within a surface pocket, the corresponding pocket in BRCT0 is largely hydrophobic. Structural comparisons together with peptide binding studies indicate that the tandem BRCT1-2 domains are the binding region for phosphorylated Ser387 in Rad9. PMID- 20858459 TI - Depletion of the cellular levels of Bag-1 proteins attenuates phorbol ester induced downregulation of IkappaBalpha and nuclear accumulation of NF-kappaB. AB - Bag-1 consists in humans of four isoforms generated from the same RNA by alternative translation. Overexpression of single Bag-1 isoforms has identified Bag-1 as a negative regulator of action of many proteins including the glucocorticoid receptor (GR). Here we have analysed the ability of Bag-1 to regulate the transrepression function of the GR. Silencing Bag-1 expression only marginally affects the transrepression action of the GR but decreased the action of the transcription factor NF-kappaB. Furthermore phosphorylation and degradation of the inhibitor protein IkappaBalpha and nuclear accumulation of p65 and p50 NF-kappaB proteins in response to phorbol ester was attenuated following Bag-1 depletion in HeLa cells. Reconstitution of Bag-1 in depleted cells partially restored IkappaBalpha and NF-kappaB activation. Knock-down of Bag-1 expression also did not significantly alter GR-mediated transactivation but affected the basal transcription of some of the target genes. Thus Bag-1 proteins function as regulators of the action of selective transcription factors. PMID- 20858460 TI - Echinophilic proteins stomatin, sorcin, and synexin locate outside gangliosideM1 (GM1) patches in the erythrocyte membrane. AB - The detergent (Triton X-100, 4 degrees C)-resistant membrane (DRM)-associated membrane proteins stomatin, sorcin, and synexin (anexin VII) exposed on the cytoplasmic side of membrane were investigated for their lateral distribution in relation to induced ganglioside(M1) (GM1) raft patches in flat (discocytic) and curved (echinocytic) human erythrocyte membrane. In discocytes, no accumulation of stomatin, sorcin, and synexin in cholera toxin subunit B (CTB) plus anti-CTB induced GM1 patches was detected by fluorescence microscopy. In echinocytes, stomatin, sorcin, and synexin showed a similar curvature-dependent lateral distribution as GM1 patches by accumulating to spiculae induced by ionophore A23187 plus calcium. Stomatin was partly and synexin and sorcin were fully recruited to the spiculae. However, the DRM-associated proteins only partially co localized with GM1 and were frequently distributed into different spiculae than GM1. The study indicates that stomatin, sorcin, and synexin are echinophilic membrane components that mainly locate outside GM1 rafts in the human erythrocyte membrane. Echinophilicity is suggested to contribute to the DRM association of a membrane component in general. PMID- 20858458 TI - The obesity-associated Fto gene is a transcriptional coactivator. AB - The fat mass and obesity associated, FTO, gene has been shown to be associated with obesity in human in several genome-wide association scans. In vitro studies suggest that Fto may function as a single-stranded DNA demethylase. In addition, homologous recombination-targeted knockout of Fto in mice resulted in growth retardation, loss of white adipose tissue, and increase energy metabolism and systemic sympathetic activation. Despite these intense investigations, the exact function of Fto remains unclear. We show here that Fto is a transcriptional coactivator that enhances the transactivation potential of the CCAAT/enhancer binding proteins (C/EBPs) from unmethylated as well as methylation-inhibited gene promoters. Fto also exhibits nuclease activity. We showed further that Fto enhances the binding C/EBP to unmethylated and methylated DNA. The coactivator role of FTO in modulating the transcriptional regulation of adipogenesis by C/EBPs is consistent with the temporal progressive loss of adipose tissue in the Fto-deficient mice, thus suggesting a role for Fto in the epigenetic regulation of the development and maintenance of fat tissue. How FTO reactivates transcription from methyl-repressed gene needs to be further investigated. PMID- 20858461 TI - An essential role for phospholipase D in the recruitment of vesicle amine transport protein-1 to membranes in human neutrophils. AB - Although phosphatidic acid (PA) regulates a wide variety of physiological processes, its targets remain poorly characterized in human neutrophils. By co sedimentation with PA-containing vesicles we identified several PA-binding proteins including vesicle amine transport protein-1 (VAT-1), Annexin A3 (ANXA3), Rac2, Cdc42 and RhoG in neutrophil cytosol. Except for ANXA3, protein binding to PA-containing liposomes was calcium-independent. Cdc42 and RhoG preferentially interacted with PA whereas VAT-1 bound to PA or phosphatidylserine with the same affinity. VAT-1 translocated to neutrophil membranes upon N-formyl-methionyl leucyl-phenylalanine (fMLF) stimulation. Inhibition of fMLF-induced PLD activity with the Src kinase inhibitor PP2, the selective inhibitor of PLD FIPI, or of PA formation with primary alcohols reduced VAT-1 translocation. In contrast, inhibition of PA hydrolysis with propranolol enhanced fMLF-mediated VAT-1 recruitment to membranes. PMA also redistributed VAT-1 to membranes in a PKC- and PLD-dependent manner. Though fMLF and PMA increased VAT-1 phosphorylation, different kinases appear to be involved. Cell fractionation revealed that a pool of VAT-1 was co-localized with primary, secondary and tertiary granules and plasma membrane markers in resting neutrophils. Stimulation with fMLF enhanced VAT-1 co-localization with CD32a, a plasma membrane marker. Confocal microscopy revealed that VAT-1 decorates granular structures at the cell periphery and double labeling with VAT-1/lactoferrin antibodies showed a partial co localization with secondary granules in control and fMLF-stimulated cells. Characterization of these putative PA-binding proteins constitutes another step forward for a better understanding of the role of PLD-derived PA in neutrophil physiology. PMID- 20858462 TI - Sensitization of melanoma cells for death ligand-induced apoptosis by an indirubin derivative--Enhancement of both extrinsic and intrinsic apoptosis pathways. AB - Until today effective therapies are lacking for metastatic melanoma. The death ligand TRAIL appears as promising in cancer treatment; however, melanoma cells reveal both preexisting and inducible TRAIL resistance. Here, we present evidence that the recently described indirubin derivative 8-Rha-beta enhances melanoma cell sensitivity for death ligands and overcomes resistance to TRAIL and CD95 agonists. Indirubin is known from traditional Chinese medicine and is a potent kinase inhibitor. Unraveling of apoptotic signaling pathways revealed that TRAIL resulted in a quick (within 8h) downregulation of both agonistic TRAIL receptors DR4 and DR5, in a kind of negative feed-back loop. Treatment with indirubin, however, mediated upregulation of both receptors, thus compensating this negative feed-back loop by TRAIL. Furthermore, indirubin activated intrinsic apoptosis pathways, seen in loss of mitochondrial membrane potential and release of cytochrome c. The mitochondrial response appeared as related to upregulation of Bax and Bad and to downregulation of Mcl-1. Remarkably, indirubin in combination with TRAIL was also able to overcome apoptosis resistance due to ectopic Bcl-2 overexpression. The tumor suppressor p53 appeared as master regulator of these propapoptotic changes and is the transactivator of proapoptotic proteins which was upregulated by indirubin. Taking into account the physiological role of death ligands in immune surveillance, sensitization of melanoma cells for death ligands may be supportive for an anti-tumor immune response. Furthermore, combinations with kinase inhibitors, such as indirubin 8-Rha-beta may help for a breakthrough of TRAIL-mediated strategies in melanoma. PMID- 20858463 TI - Moderate exercise changes synaptic and cytoskeletal proteins in motor regions of the rat brain. AB - Physical exercise is known to enhance brain function in several aspects. We evaluated the acute effects of a moderate forced exercise protocol on synaptic proteins, namely synapsin I (SYN) and synaptophysin (SYP), and structural proteins (neurofilaments, NFs) in rat brain regions related to motor function and often affected by neurodegenerative disorders. Immunohistochemistry, Western blotting and real-time PCR were used to analyze the expression of those proteins after 3, 7 and 15days of exercise (EX3, EX7 and EX15). In the cerebellum, increase of SYN was observed at EX7 and EX15 and of NF68 at EX3. In the substantia nigra, increases of protein levels were observed for NF68 and NF160 at EX3. In the striatum, there was an increase of SYN at EX3 and EX7, of SYP at EX7 and of NF68 at EX3. In the cortex, decreased levels of NF68 and NF160 were observed at EX3, followed by an increase of NF68 at EX15. In the reticular formation, all NF proteins were increased at EX15. The mRNA data for each time point and region also revealed significant exercise-related changes of SYN, SYP and NF expression. These results suggest that moderate physical exercise modulates synaptic and structural proteins in motor brain areas, which may play an important role in the exercise-dependent brain plasticity. PMID- 20858464 TI - Anatomy of the kisspeptin neural network in mammals. AB - Kisspeptin has been recognized as a key regulator of GnRH secretion during puberty and adulthood, conveying the feedback influence of endogenous gonadal steroids onto the GnRH system. Understanding the functional roles of this peptide depends on knowledge of the anatomical framework in which it acts, including the location of kisspeptin-expressing cells in the brain and their connections. In this paper, we review current data on the anatomy of the kisspeptin neuronal network, including its colocalization with gonadal steroid hormone receptors, anatomical sites of interaction with the GnRH system, and recent evidence of neurochemical heterogeneity among different kisspeptin neuronal populations. Evidence to date suggests that kisspeptin cells in mammals comprise an interconnected network, with reciprocal connections both within and between separate cell populations, and with GnRH neurons. At the same time, there is more functional and anatomical heterogeneity in this system than originally thought, and many unanswered questions remain concerning anatomical relationships of kisspeptin neurons with other neuroendocrine and neural systems in the brain. PMID- 20858465 TI - Reduced GABAA receptors and benzodiazepine binding sites in the posterior cingulate cortex and fusiform gyrus in autism. AB - Individuals with autism display deficits in the social domain including the proper recognition of faces and interpretations of facial expressions. There is an extensive network of brain regions involved in face processing including the fusiform gyrus (FFG) and posterior cingulate cortex (PCC). Functional imaging studies have found that controls have increased activity in the PCC and FFG during face recognition tasks, and the FFG has differential responsiveness in autism when viewing faces. Multiple lines of evidence have suggested that the GABAergic system is disrupted in the brains of individuals with autism and it is likely that altered inhibition within the network influences the ability to perceive emotional expressions. On-the-slide ligand binding autoradiography was used to determine if there were alterations in GABA(A) and/or benzodiazepine binding sites in the brain in autism. Using (3)H-muscimol and (3)H-flunitrazepam we could determine whether the number (B(max)), binding affinity (K(d)), and/or distribution of GABA(A) receptors and benzodiazepine binding sites (BZD) differed from controls in the FFG and PCC. Significant reductions were found in the number of GABA(A) receptors and BZD binding sites in the superficial layers of the PCC and FFG, and in the number of BZD binding sites in the deep layers of the FFG. In addition, the autism group had a higher binding affinity in the superficial layers of the GABA(A) study. Taken together, these findings suggest that the disruption in inhibitory control in the cortex may contribute to the core disturbances of socio-emotional behaviors in autism. PMID- 20858467 TI - Kisspeptin antagonists: unraveling the role of kisspeptin in reproductive physiology. AB - Kisspeptin has recently been identified as a key neuroendocrine gatekeeper of reproduction and is essential for the initiation of human puberty and maintenance of adult reproduction. Kisspeptin neurons appear to be integrative sensors, as they respond to changes in numerous internal and external factors including nutrient and fat status, stress and sex steroids, thus providing a link between these factors and reproduction. We have pioneered the development of kisspeptin antagonists as powerful tools for interrogating the role of kisspeptin in reproductive physiology and pathology, and as potential treatments for hormone dependent disease. This article summarizes their development and key findings to date. These demonstrate an essential role for kisspeptin in GnRH neuron firing, GnRH pulsatile secretion, negative feedback by gonadal steroids, the onset of puberty, and the ovulatory LH surge. These studies establish that kisspeptin antagonists are powerful investigative tools and set the scene for more extensive physiological and pathophysiological studies as well as therapeutic intervention. PMID- 20858466 TI - Toward a technology of treatment individualization for young children with autism spectrum disorders. AB - Although the etiology of autism spectrum disorders (ASD) and early development of the ASD are not yet well understood, recent research in the field of autism has heavily emphasized the importance of early intervention (i.e. treatment before the age of 4 years). Currently, several methods have been demonstrated to be efficacious with some children however no treatment completely ameliorates the symptoms of ASD or works for all children with the disorder. The heterogeneity and developmental nature of the disorder make it unlikely that one specific treatment will be best for all children, or will work for any one child throughout his or her educational career. Thus, this paper examines early research validating different technologies for individualizing treatment. A discussion of current research on pre-treatment characteristics associated with differential outcomes in treatment, including child, family, and practitioner variables; and how specific intervention techniques address each of those pre treatment characteristics is provided. The ultimate goal of this line of research is to enable practitioners to prospectively tailor treatments to specific children and increase the overall rate of positives outcomes for children with autism. Research that furthers understanding of how to match clients with efficacious treatments will decrease the outcome variability that characterizes early intervention research at present, and provide for the most efficient allocation of resources during the critical early intervention time-period. This type of research is in its infancy, but is imperative if we are to determine a priori which treatment method will be most effective for a specific child. PMID- 20858468 TI - Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. AB - Activation of nucleus factor-kappaB (NF-kappaB) in the dorsal root ganglia (DRG) is critical for development of neuropathic pain. The underlying mechanisms, however, are largely unknown. In the present work we tested if the activation of NF-kappaB is required for re-expression of Nav1.3, which is important for development of neuropathic pain, in uninjured DRG neurons. We found that intrathecal injection of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, completely blocked the mechanical allodynia induced by L5 ventral root transection (L5-VRT), when applied 30 min before or 8h after operation, but at 7d after L5-VRT the same manipulation had no effect on established allodynia. Pre treatment with PDTC also prevented the re-expression of Nav1.3 induced by L5-VRT. As our previous work has shown that up-regulation of tumor necrosis factor-alpha (TNF-alpha) in DRG is responsible for the re-expression of Nav1.3 in uninjured DRG neurons following L5 ventral root injury, we investigated whether activation of NF-kappaB is essential for the up-regulation of Nav1.3 by TNF-alpha. Results showed that application of rat recombinant TNF-alpha (rrTNF) into the cultured normal adult rat DRG neurons increased the immunoreactive (IR) of Nav1.3 localized mainly around the cell membrane and pre-treatment with PDTC blocked the change dose-dependently. The data suggested that injury to ventral root might lead to neuropathic pain and the re-expression of Nav1.3 in primary sensory neurons by activation of NF-kappaB. PMID- 20858469 TI - The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxic-ischemic injury in fetal lambs. AB - The aim of the present work was to evaluate in an early time point the effect of the cannabinoid agonist WIN 55,212-2 after hypoxic-ischemic (HI) brain injury induced by partial occlusion of the umbilical cord of premature fetal lambs. Lambs were assigned to three experimental groups: one SHAM group: non-injured animals, and two hypoxic-ischemic groups that received a dose of 0.01MUg/kg WIN 55,212-2 (HI+WIN group) or not (HI+VEH) after 60min of a hypoxic-ischemic event. All animals were managed on mechanical ventilation for 3h and then sacrificed. Brains were perfusion-fixed and different regions separated for regional cerebral blood flow measurement, apoptosis quantification by TUNEL method and S-100 protein analysis by flow cytometry. The number of apoptotic cells was lower in the HI+WIN group in all regions studied. Moreover, animals treated with the cannabinoid agonist showed higher values in the percentage of S-100 positive cells in all regions, except in the cortex. In both studies we obtained similar values between SHAM group and HI+WIN group. Our results suggest that the administration of the cannabinoid agonist WIN 55,212-2 after hypoxic-ischemic brain injury in preterm lambs decreases brain injury reducing the delayed cell death and glial damage. PMID- 20858470 TI - Parent-assisted group treatment for friendship problems of children with autism spectrum disorders. AB - Children with Asperger's Disorder or High Functioning Autism are included in regular education classes but find themselves excluded from the social lives of their classmates. This paper briefly reviews studies which attempt to provide them with training to overcome their social difficulties. These interventions have had limited success and have not systematically incorporated the child's parents into the intervention. Children's Friendship Training is a manualized parent-assisted group treatment which teaches social skill through learning and practicing sets of rules of etiquette for key social situations. The treatment approach has been demonstrated to have success in improving friendships of children with autism spectrum disorders. The content of Children's Friendship Training is briefly described and results of controlled studies are reviewed. Limitations of previous research and future directions are also described. PMID- 20858471 TI - Fluoxetine prevents LPS-induced degeneration of nigral dopaminergic neurons by inhibiting microglia-mediated oxidative stress. AB - Lipopolysaccharide (LPS)-induced microglial activation causes degeneration of nigral dopaminergic (DA) neurons. Here, we examined whether fluoxetine prevents LPS-induced degeneration of DA in the rat substantia nigra (SN) in vivo. Seven days after LPS injection into the SN, immunostaining for tyrosine hydroxylase (TH) revealed a significant loss of nigral DA neurons. Parallel activation of microglia (visualized by OX-42 and ED1 immunohistochemistry), production of reactive oxygen species (ROS) (assessed by hydroethidine histochemistry), and degeneration of nigral DA neurons were also observed in the SN. Western blot analyses and double-label immunohistochemistry showed an increase in the expression of inducible nitric oxide synthase (iNOS) within activated microglia. LPS also induced translocation of p67(phox), the cytosolic component of NADPH oxidase, to the membrane of SN microglia, indicating activation of NADPH oxidase. The LPS-induced loss of nigral DA neurons was partially inhibited by fluoxetine, and the observed neuroprotective effects were associated with fluoxetine-mediated suppression of microglial NADPH oxidase activation and iNOS upregulation, and decreased ROS generation and oxidative stress. These results suggest that fluoxetine and analogs thereof may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglia derived oxidative damage. PMID- 20858472 TI - Altered white matter fractional anisotropy and social impairment in children with autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) have severe difficulties in social interaction and communication, as well as restricted and/or stereotyped patterns of behavior. Previous studies have suggested that abnormal neural connectivity might be associated with higher information processing dysfunction involving social impairment. However, the white matter structure in ASD is poorly understood. To explore this, we conducted a voxel-based, whole-brain diffusion tensor imaging (DTI) analysis to determine fractional anisotropy (FA), lambda(1), lambda(2) and lambda(3) in high-functioning children with ASD compared with age-, gender-, and handedness-matched healthy control participants. We then investigated whether DTI parameters were associated with behaviorally measured social function. We found that FA and lambda(1) were significantly lower in the ASD group than in the control group in the white matter around left dorsolateral prefrontal cortex (DLPFC), posterior superior temporal sulcus/temporo-parietal junction, right temporal pole, amygdala, superior longitudinal fasciculus, occipitofrontal fasciculus, mid- and left anterior corpus callosum, and mid- and right anterior cingulate cortex. The FA value in the left DLPFC was negatively correlated with the degree of social impairment in children with ASD. Higher lambda(1) values were observed in the cerebellar vermis lobules in the ASD group. The white matter alterations in children with ASD were around cortical regions that play important roles in social cognition and information integration. These DTI results and their relationship to social impairment add to evidence of cerebral and cerebellar white matter structural abnormalities in ASD. PMID- 20858473 TI - Pediatric reference intervals for lymphocyte vitamin C (ascorbic acid). AB - OBJECTIVE: To establish pediatric reference intervals for lymphocyte vitamin C. DESIGN AND METHODS: This was a prospective study of 194 well children aged 0-7 years old of mixed ethnicity who had blood drawn for the purpose of this study. Blood was collected during elective surgery under general anesthesia and lymphocytes isolated and stored as frozen ascorbic acid lymphocyte lysates for later HPLC analysis by previously described methodology. Reference intervals were established according to the Clinical and Laboratory Standards Institute (CLSI) and the International Federation of Clinical Chemistry (IFCC) guidelines (C28 A3). Horn-Pesce robust method was used to estimate the 95% confidence interval and 95% reference interval. RESULTS: Reference intervals were independent of age or gender and shown to be 12.9-52.8 MUg/10(8) cells (lymphocytes). CONCLUSION: We have defined pediatric reference ranges for lymphocyte vitamin C in healthy, fasted children at a relevant age group (0-7 years). The new reference interval can now be used to more reliably explore possible implications of variation of vitamin C levels on bleeding and other clinical signs. PMID- 20858474 TI - WITHDRAWN: Focused factories and boutique laboratories. The truth might lie in between. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.clinbiochem.2010.09.001. The duplicate article has therefore been withdrawn. PMID- 20858475 TI - Effect of centrifugation and sugar supplementation on the semen cryopreservation of captive collared peccaries (Tayassu tajacu). AB - The present study is aimed at evaluating the effect of centrifugation for seminal plasma removal and the supplementation of fructose or glucose to the Tris-based extender on the kinematic patterns of the motility parameters of frozen-thawed semen obtained from captive collared peccaries (Tayassu tajacu). Semen samples (n = 14) were collected from 10 sexually mature male collared peccaries by electroejaculation. These samples were further evaluated for parameters such as motility, vigor, sperm viability, membrane integrity, and sperm morphology. The samples were divided into four aliquots, and only two of these aliquots were centrifuged. The semen aliquots (centrifuged and raw semen samples) were diluted in Tris-based extenders supplemented with fructose or glucose. Egg yolk (20%) and glycerol (3%) were added to all the samples which were cryopreserved in liquid nitrogen and thawed at 37 degrees C/1 min. The frozen-thawed semen was evaluated for the same parameters described for the fresh semen. On the other hand, the kinematic motility patterns were evaluated by a computer-aided system. After thawing, it was observed that the values for the total sperm motility were around 30% for all the samples. A negative effect of centrifugation was verified for parameters such as sperm morphology, linearity, straightness, and beat cross frequency (P < 0.05). However, no differences between fructose and glucose were verified for any semen end point (P > 0.05). In conclusion, it is not recommended to centrifuge the ejaculates from collared peccaries prior to conducting the cryopreservative procedures using a Tris-based extender supplemented with fructose or glucose. PMID- 20858477 TI - Glybenclamide: an antidiabetic with in vivo antithrombotic activity. AB - While proper platelet function is a vital component of hemostasis, their inappropriate activation contributes to thrombotic disorders. One pathway for platelet activation involves their synthesis of the lipid mediator thromboxane A2 (TXA2). Although TXA2 acts by binding to a seven-transmembrane receptor (i.e., the prostanoid TP receptor) that participates in the genesis of thrombosis, currently, there are no antagonists available for clinical use. Since the only available drug targeting this pathway (aspirin) is associated with inherent limitations/serious side effects, developing prostanoid TP receptor antagonists is clearly warranted. To this end, we have previously employed the "repurposing old drugs for new uses" approach to identify prostanoid TP receptor antagonists and showed that the antidiabetic agent glybenclamide selectively inhibited human platelet prostanoid TP receptors (in vitro). On this basis, we hypothesized that glybenclamide exhibits in vivo antiplatelet potential, and therefore, may protect against thrombosis development. Using murine platelets, it was found that glybenclamide injections: 1) inhibited platelet aggregation induced by the prostanoid TP receptor agonist U46619 and the TXA2 precursor arachidonic acid, under ex vivo experimental settings, concentration-dependently; 2) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 3) impaired hemostasis by prolonging tail bleeding time; and 4) delayed the development of occlusive thrombi in a carotid artery injury model. Taken together, these findings indicate that glybenclamide does indeed exert, ex vivo and in vivo, prostanoid TP receptor-dependent inhibitory effects on platelet function. Thus, glybenclamide has the potential to be applied in the management of thromboembolic disorders. PMID- 20858476 TI - Zebrafish Nkd1 promotes Dvl degradation and is required for left-right patterning. AB - The establishment of the left-right (LR) axis in zebrafish embryos relies on signals from the dorsal forerunner cells (DFC) and the Kupffer's vesicle (KV). While the Wnt signaling network influences many aspects of embryonic development, its precise role in LR patterning is still unclear. One branch of the Wnt network leads to stabilization of beta-catenin and activation of downstream target genes. Other Wnt ligands appear to act independently of beta-catenin to modulate calcium release and influence cell polarity. Central to regulation of beta-catenin and coordination of convergent extension (CE) movements is Dishevelled (Dvl). Naked Cuticle (Nkd) binds Dvl and modulates beta-catenin-dependent and independent Wnt signaling. Here, we analyze the expression patterns of three zebrafish Nkd homologs and find enriched expression of nkd1 in DFCs and KV. Dvl is degraded upon Nkd1 overexpression in zebrafish. Knockdown of Nkd1 specifically in the DFC results in beta-catenin nuclear localization and transcriptional activation as well as alterations to DFC migration, KV formation, ciliogenesis and LR patterning. Furthermore, we identify asymmetric expression of the Nodal antagonist charon around the KV and show that Nkd1 knockdown impacts asymmetric charon expression. Our findings show that Nkd1 acts as a beta-catenin antagonist in the DFCs necessary for LR patterning. PMID- 20858478 TI - The flavonoid quercetin induces cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer (HeLa) cells through p53 induction and NF kappaB inhibition. AB - With increasing use of plant-derived cancer chemotherapeutic agents, exploring the antiproliferative effects of phytochemicals has gained increasing momentum for anticancer drug design. The dietary phytochemical quercetin, modulates several signal transduction pathways associated with cell proliferation and apoptosis. The present study was undertaken to examine the effect of quercetin on cell viability, and to determine the molecular mechanism of quercetin-induced cell death by investigating the expression of Bcl-2 family proteins (Bcl-2, Bcl xL, Mcl1, Bax, Bad, p-Bad), cytochrome C, Apaf-1, caspases, and survivin as well as the cell cycle regulatory proteins (p53, p21, cyclin D1), and NF-kappaB family members (p50, p65, IkappaB, p-IkappaB-alpha, IKKbeta and ubiquitin ligase) in human cervical cancer (HeLa) cells. The results demonstrate that quercetin suppressed the viability of HeLa cells in a dose-dependent manner by inducing G2/M phase cell cycle arrest and mitochondrial apoptosis through a p53-dependent mechanism. This involved characteristic changes in nuclear morphology, phosphatidylserine externalization, mitochondrial membrane depolarization, modulation of cell cycle regulatory proteins and NF-kappaB family members, upregulation of proapoptotic Bcl-2 family proteins, cytochrome C, Apaf-1 and caspases, and downregulation of antiapoptotic Bcl-2 proteins and survivin. Quercetin that exerts opposing effects on different signaling networks to inhibit cancer progression is a classic candidate for anticancer drug design. PMID- 20858479 TI - C-Phycocyanin inhibits MDR1 through reactive oxygen species and cyclooxygenase-2 mediated pathways in human hepatocellular carcinoma cell line. AB - The effects of C-Phycocyanin (C-PC), a biliprotein from Spirulina platensis on the regulation of multidrug resistance-1 (MDR1), a poly glycoprotein in human hepatocarcinoma cell line, HepG2 were reported. The results revealed that a significant down regulation of MDR1 expression in C-PC treated HepG2 cells was through reactive oxygen species and cyclooxygenase-2 (COX-2) mediated pathways. C PC in a concentration dependent manner increased the accumulation of doxorubicin in HepG2 cells and enhanced sensitivity of the cells to doxorubicin by 5 folds. The induction of MDR1 expression by PGE2 and its down regulation by C-PC and DPI (Diphenylene iodonium, NADPH oxidase inhibitor) or by COX-2 knockdown suggest that the enhanced sensitivity of HepG2 cells to doxorubicin by C-PC is mediated by the down regulation of MDR1 expression. Further studies reveal the involvement of NF-kappaB and AP-1 in the C-PC induced down regulation of MDR1. Also the inactivation of the signal transduction pathways involving Akt, ERK, JNK and p38 by C-PC was observed. The present study thus demonstrates the efficacy of C-PC in overcoming the MDR1 mediated drug resistance in HepG2 cells by the down regulation of reactive oxygen species and COX-2 pathways via the involvement of NF-kappaB and AP-1. PMID- 20858480 TI - Effects of piclozotan (SUN N4057), a partial serotonin 1A receptor agonist, on motor complications induced by repeated administration of levodopa in parkinsonian rats. AB - Serotonin 1A receptor agonists have attracted much interest recently as potential therapeutic agents for levodopa-induced motor complications, such as dyskinesia and motor fluctuations. The effects of piclozotan (SUN N4057) on a rat model of advanced Parkinson's disease were investigated. Parkinsonian rats, unilaterally 6 hydroxydopamine-lesioned rats, were administered levodopa for 8 to 9 weeks. Based on the results of rotational behavior and forelimb hyperkinesia in Week 5, the rats were allocated to three treatment groups (saline and two dosing rates of piclozotan set at 0.018 and 0.036 mg/kg/h). Piclozotan was administered via continuous subcutaneous infusion using an osmotic pump for 3 to 4 weeks. At Week 7 of repeated levodopa dosing, the effects of piclozotan on levodopa-induced behavior were evaluated. In addition, extracellular levels of levodopa-derived dopamine in the striatum were measured using microdialysis in Weeks 8 to 9 after completion of the respective behavioral studies. Chronic treatment with levodopa induced forelimb hyperkinesia and shortened the duration of rotational behavior. Piclozotan (0.018 and 0.036 mg/kg/h, plasma concentrations 5.3+/-0.7 and 14.3+/ 2.9 ng/ml) reduced levodopa-induced forelimb hyperkinesia by 55% and 69%, respectively, at 1h relative to the control. Piclozotan (0.036 mg/kg/h) significantly lengthened the duration of rotational behavior by 26% versus the control and attenuated the increase in striatal levodopa-derived extracellular dopamine levels. These findings suggest that piclozotan, a serotonin 1A agonist, can improve motor complications in patients with advanced Parkinson's disease. PMID- 20858481 TI - Simvastatin attenuates cardiopulmonary bypass-induced myocardial inflammatory injury in rats by activating peroxisome proliferator-activated receptor gamma. AB - Statins have been shown to downregulate the systemic inflammatory response after cardiopulmonary bypass. However, the role of statins as anti-inflammatory agents in heart tissue remains unknown. The aim of this study was to test whether statin pretreatment attenuates local inflammatory cytokines production in heart and to explore whether the underlying mechanism involves peroxisome proliferator activated receptor (PPAR) gamma. A rat model of cardiopulmonary bypass was established. The animals were pretreated with simvastatin 5 mg/kg/day or 10 mg/kg/day for 7 days before operation. The serum concentration and myocardial level of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1 was evaluated by enzyme linked immunosorbent assay. The polymorphonuclear neutrophils accumulation in heart tissue was determined by myeloperoxidase activity assay. The activity of nuclear factor (NF) kappaB and PPARgamma in the heart was determined by electrophoretic mobility shift assay. The myocardial PPARgamma expression was also examined by immunohistochemistry. The systemic and local TNF-alpha, IL-6 and MCP-1 were all significantly elevated after cardiopulmonary bypass. In contrast, simvastatin pretreatment significantly decreases the serum and myocardial expression level of above cytokines, myocardial myeloperoxidase activity and myocardial NF-kappaB activity. However, there was an evident increase in the activity and expression of PPARgamma. In conclusion, simvastatin pretreatment not only attenuates acute systemic and local inflammatory response induced by cardiopulmonary bypass. The anti-inflammatory effect of simvastatin in myocardium may be partly related to the activation of PPARgamma and inhibition of NF-kappaB. PMID- 20858482 TI - Effects of S(+)-efonidipine on the rabbit sinus node action potential and calcium channel subunits Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1. AB - The effect of S(+)-efonidipine on sinus node action potential and calcium channel alpha-subunits was examined. The slope of the phase 4 depolarization of isolated rabbit sinus node tissue was significantly reduced by S(+)-efonidipine (1 MUM), slightly reduced by nifedipine (1 MUM), but was not affected by R(-)-efonidipine. S(+)-efonidipine (1 MUM), inhibited the expressed Ca(V)1.2, Ca(V)1.3 and Ca(V)3.1 channel currents by 75.7%, 75.3% and 94.0%, nifedipine 84.0%, 43.2% and 14.9%, and R(-)-efonidipine 30.0%, 19.6% and 92.8%, respectively. Thus, the prolongation of the phase 4 depolarization of the rabbit sinus node by S(+)-efonidipine may be explained by blockade of the Ca(V)1.3 channel current. PMID- 20858483 TI - Coenzyme Q10: a novel gastroprotective effect via modulation of vascular permeability, prostaglandin E2, nitric oxide and redox status in indomethacin induced gastric ulcer model. AB - Coenzyme Q10 is an essential cofactor in the mitochondrial electron transport pathway, and is endowed for its potent antioxidant capacity; characters that endorse its implication in several clinical practices and as a food supplement. Nevertheless, its potential gastro-protective effect, in acute models, has never been assessed, which is the objective of this study. Since indomethacin mediated gastropathy is multifaceted, including mitochondrial dysfunction and generation of reactive oxygen species, thus, the indomethacin-induced gastric injury serves as a convenient animal model for this work. Rats treated with indomethacin revealed mucosal hemorrhagic lesions, increased microvascular permeability and inhibited prostaglandin E2 and mucus content. Redox imbalance was reflected by decreased mucosal glutathione (GSH), nitric oxide and glutathione peroxidase contents/activity, along with elevated lipid peroxides. Pretreatment with CoQ10 caused discernible decrease in indomethacin-induced gastric lesions, vascular permeability and lipid peroxide content. In addition, prostaglandin E2 and GSH levels were restored, while those of nitric oxide and glutathione peroxidase were elevated significantly above normal; however, mucus formation was not altered significantly. The positive effects were comparable to those of sucralfate, the standard drug used herein, except for the mucus and prostaglandin E2 levels that were increased above normal by sucralfate. CoQ10-mediated gastroprotective effect involves preservation of microvascular permeability, elevation of prostaglandin E2, improvement of redox status, as well as boosting of nitric oxide. Nevertheless, maintaining gastric mucus content is ruled out. PMID- 20858485 TI - Detection of EBV in nasopharyngeal carcinoma by quantum dot fluorescent in situ hybridization. AB - AIMS: Nasopharyngeal carcinoma (NPC) is a common cancer in Southeast Asia and is frequently associated with Epstein-Barr virus (EBV) infection. The primary aim of this study was to improve the method of EBV detection by exploring quantum dots in FISH detection, and compare QD-based FISH with conventional ISH. MATERIALS AND METHODS: Biopsy specimens were retrospectively retrieved from 35 NPC patients as paraffin-embedded tissue blocks. QD-FISH was developed to detect the presence of EBV encoded small RNA (EBER) using biotin-labeled EBER oligonucleotide probe indirectly labeled with streptavidin-conjugated quantum dots. Conventional ISH was also performed using a commercial kit to assess concordance between the two methods. RESULTS: All the 35 NPC cases were nonkeratinizing carcinoma (7 differentiated and 28 undifferentiated subtypes). EBER-positive signals were detected in 91.43% (32/35) and 80% (28/35) cases by QD-FISH and ISH, respectively. There was no significant difference in the number of EBER-positive cases by the two methods. A moderate concordance was found between QD-FISH and ISH for EBER status (kappa=0.55). Four EBER-negative cases by ISH showed EBER positive signals when detected by QD-FISH. CONCLUSIONS: EBV is closely associated with NPC in Chinese patients. QD-FISH is a novel effective method for EBER detection, and has a moderate concordance with conventional ISH. PMID- 20858484 TI - Harmine inhibits tumour specific neo-vessel formation by regulating VEGF, MMP, TIMP and pro-inflammatory mediators both in vivo and in vitro. AB - Harmine is a beta-carboline alkaloid present in medicinal plants such as Peganum harmala that have been used as folk medicine in anticancer therapy. In this study, we demonstrated the anti-angiogenic activity of harmine using in vivo and in vitro assay systems. In vivo anti-angiogenic activity was studied using B16F 10 melanoma cells which induced capillary formation in C57BL/6 mice. Intraperitoneal administration of harmine at 10 mg/kg body weight significantly decreased tumour directed capillary formation. A drastic elevation in serum pro angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO) and pro-inflammatory cytokines in angiogenesis induced animals was significantly decreased by harmine treatment. At the same time harmine increased anti-tumour factors like interleukin-2 (IL-2) and tissue inhibitor metalloprotease (TIMP). Moreover nuclear factor (NF)-kappaB and other transcription factors like CREB, ATF-2 involved in tumour development and angiogenesis were also inhibited by harmine. Various in vitro assays also supported the anti-angiogenic activity of harmine. It reduced proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVEC). Direct treatment of the harmine also inhibited microvessel outgrowth from the rat aortic ring. Production of other factors by tumour cells which are involved in angiogenesis like cyclooxygenase (COX-2), inducible nitric oxide synthase (iNOS) and matrix metalloproteases (MMPs) were also decrease by the treatment with harmine. Our data suggest that harmine may be a strong angiogenic inhibitor with the ability to decrease the proliferation of vascular endothelial cells and to reduce expression of various pro-angiogenic factors. PMID- 20858486 TI - Hypoxia, hypoxia-inducible factor-1alpha and vascular endothelial growth factor in a murine model of Schistosoma mansoni infection. AB - Schistosomiasis mansoni is a chronic parasitic disease where much of the symptomatology is attributed to granuloma formation, an immunopathological reaction against Schistosoma eggs. To more clearly understand the immunopathology of schistosomiasis, the tissue microenvironment generated by S. mansoni infected mice was investigated. Using the hypoxia marker pimonidazole, we provide immunohistochemical evidence that hypoxia occurred in inflammatory cells infiltrated around the eggs and cells surrounding granulomas in the liver, intestine, spleen and lungs of infected mice. Hypoxia-inducible factor-1alpha (HIF-1alpha) was mainly expressed in inflammatory cells surrounding the eggs and in hepatocytes surrounding cellular and fibrocellular granulomas in infected mouse liver. HIF-1alpha expression was also verified in granulomas in the other tissues tested (intestine, spleen and lungs). Vascular endothelial growth factor (VEGF) expression was observed in the extracellular space surrounding inflammatory cells in liver granuloma. The VEGF expression pattern verified in infected mouse liver was very similar to that observed in the other tissues tested. A strong positive correlation occurred between pimonidazole binding and HIF-1alpha and VEGF expression in the tissues tested, except for lung. This work is the first evidence that infection by a helminth parasite, S. mansoni, produces a hypoxic tissue microenvironment and induces HIF-1alpha and VEGF expression. PMID- 20858487 TI - In vivo inhibition of epidermal growth factor receptor autophosphorylation prevents receptor internalization. AB - The question whether epidermal growth factor (EGF)-induced receptor endocytosis requires the prior autophosphorylation via the EGF receptor (EGFR) kinase domain has been a matter of long-standing debate. In the airway epithelial cell line NCI H292, the EGFR kinase domain inhibitor BIBW 2948 BS was found to inhibit both autophosphorylation and subsequent internalization of the endogenous EGFR with similar IC50 values. Applying an ex vivo EGFR internalization assay in a clinical study, the in vivo effect of inhalatively administered BIBW 2948 BS was determined directly at the targeted receptor in airway tissues from COPD patients. In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF-induced internalization of EGFR. PMID- 20858488 TI - Recent advances in the pathophysiology of Parkinson's disease: evidence from fMRI and TMS studies. PMID- 20858489 TI - Video capsule colonoscopy: where will we be in 2015? PMID- 20858491 TI - Mechanical properties of the esophagus in eosinophilic esophagitis. AB - BACKGROUND & AIMS: This study aimed to analyze the mechanical properties of the esophagus in eosinophilic esophagitis (EoE) using the functional luminal imaging probe (EndoFLIP; Crospon Medical Devices, Galway, Ireland). METHODS: Thirty-three EoE patients (22 male; age range, 23-67 years) and 15 controls (6 male; age range, 21-68 years) were included. Subjects were evaluated during endoscopy with the EndoFLIP probe, comprised of a compliant cylindrical bag (maximal diameter 25 mm) with 16 impedance planimetry segments. Stepwise bag distensions from 2 to 40 mL were conducted and the associated intrabag pressure and intraluminal geometry were analyzed. RESULTS: The EndoFLIP clearly displayed the tubular esophageal geometry and detected esophageal narrowing and localized strictures. Stepwise distension progressively opened the esophageal lumen until a distension plateau was reached such that the narrowest cross-sectional area (CSA) of the esophagus maximized despite further increases in intra-bag pressure. The esophageal distensibility (CSA vs pressure) was reduced in EoE patients (P = .02) with the distension plateau of EoE patients substantially lower than that of controls (median: CSA 267 mm(2) vs 438 mm(2); P < .01). Mucosal eosinophil count, age, sex, and current proton pump inhibitor treatment did not predict this limiting caliber of the esophagus (P >= 0.20). CONCLUSIONS: Esophageal distensibility, defined by the change in the narrowest measurable CSA within the distal esophagus vs intraluminal pressure was significantly reduced in EoE patients compared with controls. Measuring esophageal distensibility may be an important adjunct to the management of EoE, as it is capable of providing an objective means to measure the outcomes of medical or dilation therapy. PMID- 20858492 TI - Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. AB - BACKGROUND & AIMS: Prevalence of nonalcoholic fatty liver disease (NAFLD) has not been well established. The purpose of this study was to prospectively define the prevalence of both NAFLD and nonalcoholic steatohepatitis (NASH). METHODS: Outpatients 18 to 70 years old were recruited from Brooke Army Medical Center. All patients completed a baseline questionnaire and ultrasound. If fatty liver was identified, then laboratory data and a liver biopsy were obtained. RESULTS: Four hundred patients were enrolled. Three hundred and twenty-eight patients completed the questionnaire and ultrasound. Mean age (range, 28-70 years) was 54.6 years (7.35); 62.5% Caucasian, 22% Hispanic, and 11.3% African American; 50.9% female; mean body mass index (BMI) (calculated as kg/m(2)) was 29.8 (5.64); and diabetes and hypertension prevalence 16.5% and 49.7%, respectively. Prevalence of NAFLD was 46%. NASH was confirmed in 40 patients (12.2% of total cohort, 29.9% of ultrasound positive patients). Hispanics had the highest prevalence of NAFLD (58.3%), then Caucasians (44.4%) and African Americans (35.1%). NAFLD patients were more likely to be male (58.9%), older (P = .004), hypertensive (P < .00005), and diabetic (P < .00005). They had a higher BMI (P < .0005), ate fast food more often (P = .049), and exercised less (P = 0.02) than their non-NAFLD counterparts. Hispanics had a higher prevalence of NASH compared with Caucasians (19.4% vs 9.8%; P = .03). Alanine aminotransferase, aspartate aminotransferase, BMI, insulin, Quantitative Insulin-Sensitivity Check Index, and cytokeratin-18 correlated with NASH. Among the 54 diabetic patients, NAFLD was found in 74% and NASH in 22.2%. CONCLUSION: Prevalence of NAFLD and NASH is higher than estimated previously. Hispanics and patients with diabetes are at greatest risk for both NAFLD and NASH. PMID- 20858494 TI - Genetic testing for hereditary colorectal cancer: challenges in identifying, counseling, and managing high-risk patients. PMID- 20858497 TI - Growth differences and differential expression analysis of pituitary adenylate cyclase activating polypeptide (PACAP) and growth hormone-releasing hormone (GHRH) between the sexes in half-smooth tongue sole Cynoglossus semilaevis. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) and growth hormone releasing hormone (GHRH) are regulators of growth hormone secretion. In this article, we examined the difference in growth and mRNA expression of PACAP and GHRH between the sexes in half-smooth tongue sole, an important cultured fish species indicating sexually growth dimorphism in China. Firstly, a significant body weight difference between females and males was first observed at 7 months (P<0.05) and at 18 onths the mean body weight of the females (771.0+/-44.3 g) was as much as 4.9 times higher than that of males (130.6+/-6.0 g). As a result, half smooth tongue sole, Cynoglossus semilaevis, is a good model to investigate the effects of growth-related genes expression on sexual growth dimorphism. Secondly, the cDNAs encoding PRP/PACAP and GHRH were isolated. Two differently processed mRNA transcripts of PRP/PACAP (PRP-encoding and PRP splice variant) were found. PACAP and GHRH mRNA was highly abundant in brain and less abundant in other tissues. However, PACAP mRNA was expressed in most brain regions, and was lower in the cerebellum. GHRH mRNA was predominantly expressed in the hypothalamus and weakly expressed in all areas of the brain examined. Ontogenetic expression analysis indicated that PACAP and GHRH mRNA was detected in the early stages of embryogenesis. Finally, differential expression showed that there was no significant difference of the expression level of PACAP or GHRH between the sexes before 8 months of age. However, between 9 and 12 months of age, the GHRH mRNA expression level in males was significantly higher than in females (P<0.05), which might be associated with GH deficiency in males. In contrast, the male PACAP mRNA expression level was not significantly higher than that in females even at 9 and 12 months of age. The present results provide important clues for understanding the sexual growth dimorphism mechanisms in half-smooth tongue sole. PMID- 20858498 TI - Whole genome re-sequencing identifies a mutation in an ABC transporter (mdr2) in a Plasmodium chabaudi clone with altered susceptibility to antifolate drugs. AB - In malaria parasites, mutations in two genes of folate biosynthesis encoding dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) modify responses to antifolate therapies which target these enzymes. However, the involvement of other genes which modify the availability of exogenous folate, for example, has been proposed. Here, we used short-read whole-genome re-sequencing to determine the mutations in a clone of the rodent malaria parasite, Plasmodium chabaudi, which has altered susceptibility to both sulphadoxine and pyrimethamine. This clone bears a previously identified S106N mutation in dhfr and no mutation in dhps. Instead, three additional point mutations in genes on chromosomes 2, 13 and 14 were identified. The mutated gene on chromosome 13 (mdr2 K392Q) encodes an ABC transporter. Because Quantitative Trait Locus analysis previously indicated an association of genetic markers on chromosome 13 with responses to individual and combined antifolates, MDR2 is proposed to modulate antifolate responses, possibly mediated by the transport of folate intermediates. PMID- 20858499 TI - T cell stimulator cells, an efficient and versatile cellular system to assess the role of costimulatory ligands in the activation of human T cells. AB - It is well established that full activation of T cells requires the interaction of the TCR complex with the peptide-MHC complex (Signal 1) and additional signals (Signal 2). These second signals are generated by the interaction of costimulatory ligands expressed on antigen presenting cells with activating receptors on T cells. In addition, T cell responses are negatively regulated by inhibitory costimulatory pathways. Since professional antigen presenting cells (APC) harbour a plethora of stimulating and inhibitory surface molecules, the contribution of individual costimulatory molecules is difficult to assess on these cells. We have developed a system of stimulator cells that can give signal 1 to human T cells via a membrane bound anti-CD3 antibody fragment. By expressing human costimulatory ligands on these cells, their role in T cell activation processes can readily be analyzed. We demonstrate that T cell stimulator cells are excellent tools to study various aspects of human T cell costimulation, including the effects of immunomodulatory drugs or how costimulatory signals contribute to the in vitro expansion of T cells. T cell stimulator cells are especially suited for the functional evaluation of ligands that are implicated in costimulatory processes. In this study we have evaluated the role of the CD2 family member CD150 (SLAM) and the TNF family member TL1A (TNFSF15) in the activation of human T cells. Whereas our results do not point to a significant role of CD150 in T cell activation we found TL1A to potently costimulate human T cells. Taken together our results demonstrate that T cell stimulator cells are excellent tools to study various aspects of costimulatory processes. PMID- 20858500 TI - Celecoxib blocks cardiac Kv1.5, Kv4.3 and Kv7.1 (KCNQ1) channels: effects on cardiac action potentials. AB - Celecoxib is a COX-2 inhibitor that has been related to an increased cardiovascular risk and that exerts several actions on different targets. The aim of this study was to analyze the effects of this drug on human cardiac voltage gated potassium channels (Kv) involved on cardiac repolarization Kv1.5 (I(Kur)), Kv4.3+KChIP2 (I(to1)) and Kv7.1+KCNE1 (I(Ks)) and to compare with another COX-2 inhibitor, rofecoxib. Currents were recorded in transfected mammalian cells by whole-cell patch-clamp. Celecoxib blocked all the Kv channels analyzed and rofecoxib was always less potent, except on Kv4.3+KChIP2 channels. Kv1.5 block increased in the voltage range of channel activation, decreasing at potentials positive to 0 mV. The drug modified the activation curve of the channels that became biphasic. Block was frequency-dependent, increasing at fastest frequencies. Celecoxib effects were not altered by TEA(out) in R487Y mutant Kv1.5 channels but the kinetics of block were slower and the degree of block was smaller with TEA(in), indicating that celecoxib acts from the cytosolic side. We confirmed the blocking properties of celecoxib on native Kv currents from rat vascular cells, where Kv1.5 are the main contributors (IC(50)~ 7 MUM). Finally, we demonstrate that celecoxib prolongs the action potential duration in mouse cardiac myocytes and shortens it in guinea pig cardiac myocytes, suggesting that Kv block induced by celecoxib may be of clinical relevance. PMID- 20858502 TI - Protein folding disorders: toward a basic biological paradigm. AB - Mechanistic 'physics' models of protein folding fail to account for the observed spectrum and rate of protein folding and aggregation disorders in human populations, showing that more appropriately in vivo paradigms reflecting biological and other embedding contexts are needed for understanding the etiology, prevention, and treatment of these diseases. Here, a topological rate distortion analysis is applied to the problem that is analogous to Tlusty (2007) elegant exploration of the genetic code. A 'developmental' perspective sees the rate distortion function as a temperature analog in a spontaneous symmetry breaking argument, and permits incorporation of external factors as catalysts, driving the system to different possible outcomes via a nonequilibrium empirical Onsager treatment, viewed as a kind of dynamic regression equation. The formalism produces large-scale, quasi-equilibrium 'resilience' states representing normal and pathological protein folding. Generalization to long times produces diffusion models of protein folding disorders in which epigenetic or life history factors determine the rate of onset of dysfunction. PMID- 20858501 TI - Nix Nought Nothing: fairy tale or real deal. AB - Nix was first described in the heart as the protein product of a differentially expressed mRNA detected by hybridization to a partial cDNA sequence tag on an RNA expression array. Over the subsequent 8 years Nix has become the prototypical transcriptionally-regulated cardiac myocyte "suicide" gene and has been used as a model to interrogate mechanisms of programmed cardiomyocyte death in hypertrophy and heart failure. Nix stimulates conventional apoptosis mediated via the intrinsic mitochondrial pathway, but emerging evidence indicates that Nix also controls programmed necrosis dependent upon sarcoplasmic reticular-mitochondrial tethering, calcium cross-talk, and the mitochondrial permeability transition. Recent studies have also described Nix labeling of senescent cardiomyocyte mitochondria for autophagic elimination, elucidated a physiological mitochondrial quality control Nix function; so-called "mitochondrial pruning". This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure." PMID- 20858503 TI - Co-evolution of learning complexity and social foraging strategies. AB - Variation in learning abilities within populations suggests that complex learning may not necessarily be more adaptive than simple learning. Yet, the high cost of complex learning cannot fully explain this variation without some understanding of why complex learning is too costly for some individuals but not for others. Here we propose that different social foraging strategies can favor different learning strategies (that learn the environment with high or low resolution), thereby maintaining variable learning abilities within populations. Using a genetic algorithm in an agent-based evolutionary simulation of a social foraging game (the producer-scrounger game) we demonstrate how an association evolves between a strategy based on independent search for food (playing a producer) and a complex (high resolution) learning rule, while a strategy that combines independent search and following others (playing a scrounger) evolves an association with a simple (low resolution) learning rule. The reason for these associations is that for complex learning to have an advantage, a large number of learning steps, normally not achieved by scroungers, are necessary. These results offer a general explanation for persistent variation in cognitive abilities that is based on co-evolution of learning rules and social foraging strategies. PMID- 20858505 TI - A folding "framework structure" of Tetrahymena group I intron. AB - We have published the dynamic extended folding (DEF) method, which is a RNA secondary structure prediction approach-to simulate the in vivo RNA co transcriptional folding process. In order to verify the reliability of the method, we selected the X-ray-determined Tetrahymena group I intron as a sample to construct the framework of its folding secondary structure. Our prediction coincides well with the secondary structure predicted by T.R. Cech and the X-ray diffraction crystal structure determined by Lehnert V. Our results show that the DEF framework structure of Tetrahymena group I intron reflects its function sites in a concise and straightforward manner, and the scope of the simulation was expanded. PMID- 20858504 TI - Persistent random motion: uncovering cell migration dynamics. AB - In this paper we study analytically the stick-slip models recently introduced to explain the stochastic migration of free cells. We show that persistent motion of cells of many different types is compatible with stochastic reorientation models which admit an analytical mesoscopic treatment. This is proved by examining and discussing experimental data compiled from different sources in the literature, and by fitting some of these results too. We are able to explain many of the 'apparently complex' migration patterns obtained recently from cell tracking data, like power-law dependences in the mean square displacement or non-Gaussian behavior for the kurtosis and the velocity distributions, which depart from the predictions of the classical Ornstein-Uhlenbeck process. PMID- 20858506 TI - Coexistence in a fluctuating environment by the effect of relative nonlinearity: a minimal model. AB - The minimal model of the "relative nonlinearity" type fluctuation-maintained coexistence is investigated. The competing populations are affected by an environmental white noise. With quadratic density dependence, the long-term growth rates of the populations are determined by the average and the variance of the (fluctuating) total density. At most two species can coexist on these two "regulating" variables; competitive exclusion would ensue in a constant environment. A numerical study of the expected time until extinction of any of the two species reveals that the criterion of mutual invasibility predicts the parameter range of long-term coexistence correctly in the limit of zero extinction threshold. However, any extinction threshold consistent with a realistic population size will allow only short-term coexistence. Therefore, our simulations question the biological relevance of mutual invasibility, as a sufficient condition of coexistence, for large density fluctuations. We calculate the average and the variance of the fluctuating density of the coexisting populations analytically via the moment-closure approximation; the results are reasonably close to the simulated behavior. Based on this treatment, robustness of coexistence is studied in the limit of infinite population size. We interpret the results of this analysis in the context of necessity of niche segregation with respect to the regulating variables using a framework theory published earlier. PMID- 20858507 TI - Visualization of microvascular blood flow in mouse kidney and spleen by quantum dot injection with "in vivo cryotechnique". AB - The "in vivo cryotechnique" (IVCT) is a powerful tool to instantly capture blood flow, and all plasma components are well kept in tissue samples. In this study, we injected glutathione (GSH)-coated quantum dots (QDs), which emit a 650-nm fluorescent signal with an ultraviolet excitation, into anesthetized mouse left ventricles, and IVCT was performed for kidneys, spleens and livers at 2, 5, 10, 15, 30s or 24h after the QD injection. The frozen tissues were processed to freeze-substitution fixation (FS). Then, some specimens were embedded in paraffin wax for tissue sectioning, and some were cut with a razor blade and directly mounted on glass slides. They were observed in fluorescence or confocal laser scanning microscope (CLSM). In the renal cortex, QD distribution was detected mostly in glomerular blood capillaries at 2second, and extended to peritubular blood capillaries at 5s. Distribution of horseradish peroxidase (HRP) in renal cortex at 30s after the injection was compared by the simultaneous injection with QDs. HRP was detected by a diaminobenzidin reaction in interstitium in addition to blood vessels, whereas QDs were localized only inside blood vessels. Three dimensional reconstruction with CLSM demonstrated the capillary networks in the whole renal glomerulus. In the spleens, QDs were detected in splenic cords entering from sheathed capillaries at 10s, and extended to deeper splenic cords and also into splenic sinuses at 15s. Thus, strict time-dependent visualization of blood flow in tissue sections became possible within seconds by the new technical combination of IVCT and injection of QDs into animal organs. PMID- 20858508 TI - Bisphenol-A rapidly promotes dynamic changes in hippocampal dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDA receptor subunit NR2B. AB - Bisphenol-A (BPA) is known to be a potent endocrine disrupter. Evidence is emerging that estrogen exerts a rapid influence on hippocampal synaptic plasticity and the dendritic spine density, which requires activation of NMDA receptors. In the present study, we investigated the effects of BPA (ranging from 1 to 1000 nM), focusing on the rapid dynamic changes in dendritic filopodia and the expressions of estrogen receptor (ER) beta and NMDA receptor, as well as the phosphorylation of NMDA receptor subunit NR2B in the cultured hippocampal neurons. A specific ER antagonist ICI 182,780 was used to examine the potential involvement of ERs. The results demonstrated that exposure to BPA (ranging from 10 to 1000 nM) for 30 min rapidly enhanced the motility and the density of dendritic filopodia in the cultured hippocampal neurons, as well as the phosphorylation of NR2B (pNR2B), though the expressions of NMDA receptor subunits NR1, NR2B, and ERbeta were not changed. The antagonist of ERs completely inhibited the BPA-induced increases in the filopodial motility and the number of filopodia extending from dendrites. The increased pNR2B induced by BPA (100 nM) was also completely eliminated. Furthermore, BPA attenuated the effects of 17beta estradiol (17beta-E2) on the dendritic filopodia outgrowth and the expression of pNR2B when BPA was co-treated with 17beta-E2. The present results suggest that BPA, like 17beta-E2, rapidly results in the enhanced motility and density of dendritic filopodia in the cultured hippocampal neurons with the concomitant activation of NMDA receptor subunit NR2B via an ER-mediated signaling pathway. Meanwhile, BPA suppressed the enhancement effects of 17beta-E2 when it coexists with 17beta-E2. These results provided important evidence suggesting the neurotoxicity of the low levels of BPA during the early postnatal development of the brain. PMID- 20858509 TI - Toxicological studies of Karlodinium micrum (Dinophyceae) isolated from East China Sea. AB - Karlodinium micrum (Strain NMBjah047) was isolated from the water samples of East China Sea (ECS). The hemolytic, ichthyotoxic, and cytotoxic activities of the algae was characterized. Embryotoxicity of both intra and extracellular extracts were also tested on a local sea urchin species. The algal intracellular hemolytic toxicity averaged about 87.5% at different algal growth phases. However, extracellular hemolytic activity depended on the population growth phase. The toxicity increased with the increase in the population size, reaching the highest hemolytic activity during the stationary phase, and maintained a relatively high activity even when the population declined. Time and density dependent ichthyotoxicity to Lateolabrax maculates juveniles was also detected. The LD(50) in 24 h was 1.1 * 10(5) cells/mL. Inhibition of the fertilized egg hatching was also observed and estimated the IC(50) in 40 h with 3.5 * 10(4) cells/mL. Extracellular extracts of K. micrum dense culture also showed significant cytotoxic activity on HUVEC (IC(50) = 70.8 MUg/mL). A dose dependent acute toxicity to embryos of sea urchin was also determined. The algal intracellular and extracellular extracts delayed or even restricted the embryological development of the sea urchin, illustrating the potential toxicity of K. micrum not only to vertebrates, but also to marine invertebrates. The hemolytic compounds in the ECS strain were extracted and analyzed. At least two fractions had significant hemolytic activities. A lipid-like compound, named Digalactosyldiacylglycerol (DGDG), was suggested to be responsible for the hemolytic activity in one of these fractions. From the results of the present studies, this strain of K. micrum isolated from the East China Sea might be considered a toxic strain with hemolytic activity, ichthyotoxicity, cytotoxicity and embryotoxicity. PMID- 20858510 TI - A metanalysis of the effect of the Muller-Lyer illusion on saccadic eye movements: no general support for a dissociation of perception and oculomotor action. AB - Milner and Goodale's (1995) proposal of a functional division of labor between vision-for-perception and vision-for-action is supported by neuropsychological, brain-imaging, and psychophysical evidence. However, there remains considerable debate as to whether, as their proposal would predict, the effect of contextual illusions on vision-for-action can be dissociated from that on vision-for perception. Meta-analytical efforts examining the effect of the Muller-Lyer (ML) illusion on pointing (Bruno, Bernardis, & Gentilucci, 2008) or grasping (Bruno & Franz, 2009) have been conducted to resolve the controversy. To complement this work, here we re-analyzed 17 papers detailing 21 independent studies investigating primary saccades to target locations that were perceptually biased by the ML illusion. Using a corrected percent illusion effect measure to compare across different studies and across experimental conditions within studies, we find that saccadic eye movements are always strongly biased by the illusion although the size of this effect can be reduced by factors such as display duration and between-trials variability in display length and orientation, possibly due to a process of saccadic adaptation. In contrast to some reports, we find no general support for differences between voluntary and reflexive saccades or between saccades performed in conjunction with a pointing movement and saccades performed without pointing. We conclude that studies on the effect of the Muller-Lyer illusion do not provide evidence for a functional dissociation between primary saccades and perception. PMID- 20858511 TI - Using the Utah Population Database to assess familial risk of primary open angle glaucoma. AB - PURPOSE: Primary open angle glaucoma (POAG) is a leading cause of irreversible blindness in the elderly. Previous epidemiological studies have identified family history, ethnic origin, age, high intraocular pressure and diabetes mellitus as risk factors. However, it is difficult to assess the extent family history plays in this disease process. The Utah Population Database (UPDB), created by the University of Utah, has recently become a resource for which greater than 9 million records are available for use. The UPDB is divided into two major data sets from which family members can be identified, namely 1.6 million genealogy records and 2 million Utah birth certificates. This study utilizes these resources to assess the familial risk of POAG within the Utah Population. METHODS: The University of Utah's hospital and clinic records were searched for patients with primary and chronic open angle glaucoma (ICD9 codes 365.04 and 365.11) between the years 1995 and 2005. A case-control analysis was then performed with specialized UPDB software that was modified to constrain the control and pedigree populations to over 1 million University of Utah-UPDB linked records. Controls were matched to cases by gender and birth year (+/-2.5years) with only one control being used per case. Population-attributable risk (PAR) to familial factors and relative risk (RR) were computed using conditional logistic regression (CLR). RESULTS: From the original 1.5 million medical records, 6198 patients with glaucoma were identified. Of these, 3391 met the inclusion criteria, which required patients to have at least one parent or one child in the UPDB. The PAR in this population was found to be 0.20, indicating 20% of the risk for glaucoma is attributable to genetic factors. CLR computations also showed a significantly increased relative risk (p<0.05) in first cousins (RR=1.45 (95% confidence interval (CI) 1.16-1.8)), second cousins (RR=1.19 (95% CI 1.08-1.32)), siblings (RR=3.76 (95% CI 2.66-5.31)), parents (RR=6.25 (95% CI 3.94-9.9)) and children (RR=6.77 (95% CI 3.39-13.5)). CONCLUSIONS: Based on these familial data, there is a significantly higher prevalence of glaucoma in both first and second generation relatives of those affected as compared to relatives in the control group. When compared with other epidemiologic studies, such as an analysis of first-degree relatives of patients from the Rotterdam study, which showed a PAR of 16%, our study actually demonstrates a greater familial contribution to glaucoma. The UPDB is a valuable and unique resource providing a large population from which to analyze the familial risk of glaucoma. PMID- 20858512 TI - Learning by doing: action performance facilitates affordance perception. AB - We investigated the effect of action performance on perceptual judgments by evaluating accuracy in judging whether doorways allowed passage. Participants made judgments either before or after walking through doorways of varying widths. Participants in the action-first group benefited from action feedback and made more accurate judgments compared to a perception-first group that judged doorways before walking through them. Action feedback aided perceptual judgments by facilitating scaling to body dimensions: Judgments in the action-first group were strongly related to height, weight, and torso size, whereas judgments in the perception-first group were not. PMID- 20858513 TI - Detecting contrast changes in invisible patterns during binocular rivalry. AB - When dissimilar images are presented to the two eyes, the human visual system lapses into binocular rivalry, a unique perceptual state characterized by stochastic alternations in dominance of one of the two source images over the other. Probe targets delivered to an eye during suppression phases are more difficult to detect than probes delivered during dominance phases. Nearly all probe studies have involved presenting new stimulation (e.g., a spot of light) either superimposed on or replacing the suppressed stimulus. Here, we ask whether observers can detect a reduction in the contrast of the suppressed stimulus itself. In other words, can observers detect a probe that should make an already invisible stimulus even weaker? Specifically, we compared observers' ability to detect contrast increments and contrast decrements introduced within a rival pattern during dominance and suppression. Contrast increment thresholds were elevated across all pedestal contrasts when the increment was introduced during suppression compared to during dominance, replicating previous results. Contrast decrement thresholds measured during suppression were elevated to an even greater extent, but the fact that they were obtained at all establishes that observers were able to detect probes that should make an already invisible target even more difficult to perceive. In a second experiment, we found a similar pattern of results for contrast change detection in complex images of faces as well. Based on the resulting threshold-vs.-contrast functions, we suggest that, regardless of the complexity of the image, rivalry suppression modulates the neural contrast response function through a mixture of reduced overall response gain and a shift in the contrast gain. PMID- 20858514 TI - Lightness, brightness and transparency: a quarter century of new ideas, captivating demonstrations and unrelenting controversy. AB - The past quarter century has witnessed considerable advances in our understanding of Lightness (perceived reflectance), Brightness (perceived luminance) and perceived Transparency (LBT). This review poses eight major conceptual questions that have engaged researchers during this period, and considers to what extent they have been answered. The questions concern 1. the relationship between lightness, brightness and perceived non-uniform illumination, 2. the brain site for lightness and brightness perception, 3 the effects of context on lightness and brightness, 4. the relationship between brightness and contrast for simple patch-background stimuli, 5. brightness "filling-in", 6. lightness anchoring, 7. the conditions for perceptual transparency, and 8. the perceptual representation of transparency. The discussion of progress on major conceptual questions inevitably requires an evaluation of which approaches to LBT are likely and which are unlikely to bear fruit in the long term, and which issues remain unresolved. It is concluded that the most promising developments in LBT are (a) models of brightness coding based on multi-scale filtering combined with contrast normalization, (b) the idea that the visual system decomposes the image into "layers" of reflectance, illumination and transparency, (c) that an understanding of image statistics is important to an understanding of lightness errors, (d) Whittle's logW metric for contrast-brightness, (e) the idea that "filling-in" is mediated by low spatial frequencies rather than neural spreading, and (f) that there exist multiple cues for identifying non-uniform illumination and transparency. Unresolved issues include how relative lightness values are anchored to produce absolute lightness values, and the perceptual representation of transparency. Bridging the gap between multi-scale filtering and layer decomposition approaches to LBT is a major task for future research. PMID- 20858515 TI - Molecular remodeling of potassium channels in fibroblasts from centenarians: a marker of longevity? AB - Aging is a complex process resulting from, among other, dynamic non-linear interactions between genetics and environment. Centenarians are the best example of successful aging in humans, as they escaped from, or largely postponed, major age-related diseases. Ionic fluxes changes play a key role in several patho physiological cellular processes, but their relation to human aging is largely unexplored. In the present study we have compared patch-clamp potassium (K(+)) current recordings from dermal fibroblasts (DF) obtained from young, elderly and centenarian donors. We found that in DF from elderly donors, but not from centenarians, K(+) current amplitude is significantly smaller with respect to DF from young donors. Moreover, cell membrane capacitance of DF from elderly donors is smaller with respect to young donors and centenarians. We also observed that the voltage-gated Shaker Kv1.1 channel is expressed in higher percentage of elderly's and centenarian's DF than young's, whereas the large-conductance calcium-activated K(+) (BK(Ca)) channel beta1 subunit is expressed in lower percentage of centenarian's DF than in elderly's and young's. The maintenance of "young" K(+) currents and the peculiar age-related remodeling of K(+) channel subtypes in centenarian's DF is likely associated with successful aging and might provide a predictive marker of longevity. PMID- 20858516 TI - A cohort study of leisure time physical activity and depression. AB - OBJECTIVE: The objective of the study was to examine the role of leisure time physical activity on the risk of developing depression in a large longitudinal setting. METHODS: A prospective cohort study was used, comprising three updated measures of leisure time physical activity and covariates and 26 years of follow up data on 18,146 individuals from the Copenhagen City Heart Study, Denmark. The study population was linked to two Danish hospital registers for information on depression. Data were collected in three rounds, namely, 1976-1978, 1981-1983, and 1991-1994, and analyses were conducted in 2010. RESULTS: Compared to women with a high physical activity level, women with a moderate level had a hazard ratio of 1.07 (95% confidence interval: 0.80-1.44) for developing depression while women with a low level had a hazard ratio of 1.80 (95% confidence interval: 1.29-2.51). Compared to men with a high physical activity level, men with a moderate level had a hazard ratio of 1.11 (95% confidence interval: 0.73-1.68) for developing depression, while men with a low level had a hazard ratio of 1.39 (95% confidence interval: 0.83-2.34). CONCLUSION: Among women, a low level of physical activity was significantly associated with a greater risk of depression. PMID- 20858518 TI - Subjective and model-estimated reward prediction: association with the feedback related negativity (FRN) and reward prediction error in a reinforcement learning task. AB - In this study, we examined whether the feedback-related negativity (FRN) is associated with both subjective and objective (model-estimated) reward prediction errors (RPE) per trial in a reinforcement learning task in healthy adults (n=25). The level of RPE was assessed by 1) subjective ratings per trial and by 2) a computational model of reinforcement learning. As results, model-estimated RPE was highly correlated with subjective RPE (r=.82), and the grand-averaged ERP waves based on the trials with high and low model-estimated RPE showed the significant difference only in the time period of the FRN component (p<.05). Regardless of the time course of learning, FRN was associated with both subjective and model-estimated RPEs within subject (r=.47, p<.001; r=.40, p<.05) and between subjects (r=.33, p<.05; r=.41, p<.005) only in the Learnable condition where the internal reward prediction varied enough with a behavior reward contingency. PMID- 20858517 TI - HIV-1 Vpu targets cell surface markers CD4 and BST-2 through distinct mechanisms. AB - Vpu is a small integral membrane protein encoded by HIV-1 and some SIV isolates. The protein is known to induce degradation of the viral receptor molecule CD4 and to enhance the release of newly formed virions from the cell surface. Vpu accomplishes these two functions through two distinct mechanisms. In the case of CD4, Vpu acts as a molecular adaptor to connect CD4 to an E3 ubiquitin ligase complex resulting in CD4 degradation by cellular proteasomes. This requires signals located in Vpu's cytoplasmic domain. Enhancement of virus release on the other hand involves the neutralization of a cellular host factor, BST-2 (also known as CD317, HM1.24, or tetherin) and requires Vpu's TM domain. The current review discusses recent advances on the role of Vpu in controlling degradation of CD4 and in regulating virus release. PMID- 20858519 TI - Molecular function of microtubule-associated protein 2 for filial imprinting in domestic chicks (Gallus gallus domesticus). AB - RNA interference (RNAi)-mediated gene-silencing can be a tool for elucidating the role of genes in the neural basis of behavioral plasticity. Previously, we reported that exogenous DNA could be successfully delivered into newly-hatched chick brains via electroporation. Here, we used this in vivo gene-transfer technique and showed that transfected microRNA vectors preferentially silence exogenous DNA expression in neuronal cells. Using this system, the up-regulation of microtubule-associated protein 2 (MAP2) accompanying filial imprinting was suppressed in vivo, which impaired the filial imprinting in chicks. In addition, the phosphorylation of MAP2 was found to increase in parallel with filial imprinting, and lithium chloride, an inhibitor of glycogen synthase kinase 3 (GSK3), was found to impair filial imprinting. Our results suggest that the regulation of MAP2 expression and its phosphorylation are required for filial imprinting and may modify microtubule stability, thereby leading to cytoskeletal reorganization during imprinting. This in vivo RNAi-mediated gene-silencing system will facilitate the analysis of gene function in the living chick brain and provides further clues regarding the molecular mechanisms underpinning avian learning. PMID- 20858521 TI - Genetic and diabetic auto-antibody markers in Saudi children with type 1 diabetes. AB - Human leukocyte antigen DRB1 and DQB1 contribute to the genetic susceptibility of type 1 diabetes (T1DM), and they are involved in the induction of the autoimmune destruction of pancreatic beta cells precipitating the disease. The objective of this study was to examine diabetic auto-antibodies (ICA-512, GAD65) and the HLA DR/DQ genotype among T1DM Saudi children in a cross-sectional study conducted at King Khalid University and National Guard Hospitals, Riyadh. Subjects included in this study were 103 Saudi patients and 180 healthy controls. In all, 41% of patients were positive for ICA512 73.3% positive for GAD65, and 27.3% had both antibodies. The risk alleles were DRB1*0301 (odds ratio [OR] = 11.1); DRB1*0405 (OR = 6.02); DRB1*0401 (OR = 5.8); DQB1*0201 (OR, 17.69) and DQB1*0302 (OR = 3.77). In addition, the DRB1*03/04-DQB1*02/0302 (OR = 123.4) is positively associated with T1DM. However, DRB1*0403 (OR = 0.27), DRB1*1101 (OR = 0.049), DRB1*1307 (OR = 0.28), DRB1*1501 (OR = 0.12), DQB1*0301 (OR = 0.03), DQB1*0401 (OR = 0.04), and DQB1*0602 (OR = 0.16) were protective. Among GAD-positive patients, 81% were DRB1*0301, 68.75% were DQB1*0201, 62.5% were DRB1*0405, 43.75% were DQB1*0302, and 43.7% were DRB1*03/04. Among ICA512-positive patients, all were DRB1*0301, 66.6% were DQB1*0201, 55% were DRB1*0405, 33.3% were DQB1*0302, and 55% were DRB1*03/04. In conclusion, these results show a strong association of HLA-DQB1*0201/0302 and DRB1*03/04 with T1DM. Thus, combining genetic markers with autoantibody is useful in a screening program for early detection of T1DM among Saudi children. PMID- 20858522 TI - Inactivation of a functional HLA-A gene: a 4-kb deletion turns HLA-A*24 into a pseudogene. AB - An unusual haplotype without a detectable human leukocyte antigen (HLA)-A allele by serologic or molecular typing methods segregates in a Caucasian family. Microsatellite analysis and fluorescence in situ hybridization implicated that the deletion encompasses a narrow region. To identify the deleted region, five different fragments in close proximity to HLA-A, known to be highly polymorphic, were amplified and sequenced. The presence of heterozygous sequences in all five fragments of the individuals carrying the haplotype with the HLA-A deletion, indicates that the fragments are not involved in the deletion. Therefore, the 5' primer from the fragment closest to the centromeric side of HLA-A was combined with the 3' primer closest to the telomeric side encompassing an 11-kb region. Sequencing revealed that a deletion of 4089 bp was present, located upstream of HLA-A, including exons and introns 1-3 of the HLA gene. Sequence information of the 3' part of HLA-A, downstream the deletion, identified that the deleted allele originates from an A*24 allele. Although different repeat sequences are present in the region both inside and outside the deletion, no evidence points to a retrotransposon mechanism. The detected partial deletion of HLA-A turns this functional gene into a pseudogene. PMID- 20858523 TI - Science based guidance for the assessment of endocrine disrupting properties of chemicals. AB - The European legislation on plant protection products (Regulation (EC) No. 1107/2009) and biocides (Directive 98/8/EC), as well as the regulation concerning chemicals (Regulation (EC) No. 1907/2006 'REACH') only support the marketing and use of chemical products on the basis that they do not induce endocrine disruption in humans or non-target species. However, there is currently no agreed guidance on how to identify and evaluate endocrine activity and disruption. Consequently, an ECETOC task force was formed to provide scientific criteria that may be used within the context of these three legislative documents. Specific scientific criteria for the determination of endocrine disrupting properties that integrate information from both regulatory (eco)toxicity studies and mechanistic/screening studies are proposed. These criteria combine the nature of the adverse effects detected in studies which give concern for endocrine toxicity with an understanding of the mode of action of toxicity so that adverse effects can be explained scientifically. The criteria developed are presented in the form of flow charts for assessing relevant effects for both humans and wildlife species. In addition, since not all chemicals with endocrine disrupting properties are of equal hazard, assessment of potency is also proposed to discriminate chemicals of high concern from those of lower concern. The guidance presented in this paper includes refinements made to an initial proposal following discussion of the criteria at a workshop of invited regulatory, academic and industry scientists. PMID- 20858524 TI - Therapeutic efficacies of Coriandrum sativum aqueous extract against metronidazole-induced genotoxicity in Channa punctatus peripheral erythrocytes. AB - Metronidazole (MTZ), a nitroimidazole drug, is primarily used as an anti protozoan or an anti-bacterial agent in humans, although its genotoxic and carcinogenic effects have been widely reported, particularly in aquatic organisms. MTZ may induce DNA damages through single-strand breaks, modification of bases, DNA-DNA and DNA-protein cross-links, ultimately leading to apoptosis or necrosis. Here, we have assessed the genotoxicity of MTZ in the peripheral erythrocytes of Channa punctatus, using micronucleation (MN) and binucleation (BN) as genotoxicity markers. The therapeutic potential of aqueous extract of Coriandrum sativum against MTZ-induced genotoxicity has also been examined. The results show significant (P<0.05) increase in both MN and BN formation due to MTZ treatment. Such aberrations were higher in smaller fish samples for a particular dosage of MTZ, as established by correlation analysis between fish body weight and MN/BN count at P<0.05. However, such degenerative damages were found to be alleviated by a great extent due to treatment with C. sativum leaf extract. Hence, we establish that MTZ can produce considerable degrees of micronucleus and binucleus formation in peripheral erythrocytes of C. punctatus, and such deleterious effect of MTZ treatment can be mitigated by aqueous extract of C. sativum leaves. PMID- 20858525 TI - Electrical neuroimaging reveals intensity-dependent activation of human cortical gustatory and somatosensory areas by electric taste. AB - To analyze the neural basis of electric taste we performed electrical neuroimaging analyses of event-related potentials (ERPs) recorded while participants received electrical pulses to the tongue. Pulses were presented at individual taste threshold to excite gustatory fibers selectively without concomitant excitation of trigeminal fibers and at high intensity evoking a prickling and, thus, activating trigeminal fibers. Sour, salty and metallic tastes were reported at both intensities while clear prickling was reported at high intensity only. ERPs exhibited augmented amplitudes and shorter latencies for high intensity. First activations of gustatory areas (bilateral anterior insula, medial orbitofrontal cortex) were observed at 70-80ms. Common somatosensory regions were more strongly, but not exclusively, activated at high intensity. Our data provide a comprehensive view on the dynamics of cortical processing of the gustatory and trigeminal portions of electric taste and suggest that gustatory and trigeminal afferents project to overlapping cortical areas. PMID- 20858526 TI - Cognitive and emotional conflicts of counter-conformity choice in purchasing books online: an event-related potentials study. AB - Using event-related potentials (ERPs), this study investigated the neural substrates of the conflicts in counter-conformity choices in purchasing books online. For each trial, a participant decided whether to buy a book according to the title keyword, as well as the numbers of positive and negative reviews on the book. A participant's choice was termed conformity if she/he decided to buy the book under the condition of consistently positive reviews, or not to buy the book under the condition of consistently negative reviews, whereas the case was counter-conformity if a participant did the opposite. In the time window 300 600ms after the stimulus onset, a strong negative deflection of ERP (N500) was recorded when participants made counter-conformity choices. The topographic distribution of the N500 (N400-like) is not typical of the semantic N400. The N500 might be evoked by the cognitive and emotional conflicts faced by participants in counter-conformity choices. The present findings provide evidence that the N400 can be elicited by non-semantic conflicts. PMID- 20858520 TI - Development and applications of photo-triggered theranostic agents. AB - Theranostics, the fusion of therapy and diagnostics for optimizing efficacy and safety of therapeutic regimes, is a growing field that is paving the way towards the goal of personalized medicine for the benefit of patients. The use of light as a remote-activation mechanism for drug delivery has received increased attention due to its advantages in highly specific spatial and temporal control of compound release. Photo-triggered theranostic constructs could facilitate an entirely new category of clinical solutions which permit early recognition of the disease by enhancing contrast in various imaging modalities followed by the tailored guidance of therapy. Finally, such theranostic agents could aid imaging modalities in monitoring response to therapy. This article reviews recent developments in the use of light-triggered theranostic agents for simultaneous imaging and photoactivation of therapeutic agents. Specifically, we discuss recent developments in the use of theranostic agents for photodynamic-, photothermal- or photo-triggered chemotherapy for several diseases. PMID- 20858527 TI - A delay model for quorum sensing of Pseudomonas putida. AB - The bacterial strain Pseudomonas putida IsoF, isolated from a tomato rhizosphere, possesses a quorum sensing regulation system, which allows the bacteria to recognise aspects of their environment or to communicate with each other by the so-called autoinducer molecules. In an experimental study, the time series of the autoinducer production did not show the expected behaviour, as it was observed for other bacterial species by indirect measurements. The modelling approach introduced here allows an explanation of the behaviour, supporting the hypothesis of the existence of a further (not yet detected) enzyme, which degrades the autoinducer into an inactive form. Especially the properties of the considered delay differential system allow for the description of the time series. For example the appearance of a first small maximum in the initial phase can be explained by a delay differential equation. PMID- 20858528 TI - Structure and dynamics of the 'protein folding code' inferred using Tlusty's topological rate distortion approach. AB - Tlusty's topological rate distortion analysis of the genetic code is applied to protein symmetries and protein folding rates. Unlike the genetic case, numerous thermodynamically accessible 'protein folding codes' can be identified from empirical classifications. Folding rates follow from a topologically driven rate distortion argument, a model that can, in principle, be extended to intrinsically disordered proteins. The elaborate cellular regulatory machinery of the endoplasmic reticulum and heat shock proteins is needed to prevent transition between the various thermodynamically 'natural' sets of hydrophobic-core protein conformations, and its corrosion by aging would account for the subsequent onset of many protein folding disorders. These results imply markedly different evolutionary trajectories for the genetic and protein folding codes, and suggest that the 'protein folding code' is really a complicated composite, distributed across protein production and a cellular, or higher, regulatory apparatus acting as a canalizing catalyst that drives the system to converge on particular transitive components within a significantly larger 'protein folding groupoid'. PMID- 20858529 TI - The course of olfactory deficits in patients with Parkinson's disease--a study based on psychophysical and electrophysiological measures. AB - OBJECTIVES: Patients with Parkinson's disease (PD) commonly show olfactory deficits in the early stages of the disease. These deficits can be verified psychophysically or electrophysiologically using olfactory event-related potentials (OERP). While psychophysical olfactory function in PD patients can improve over time, the course of OERPs in PD has not yet been investigated. METHODS: Olfactory function was investigated twice in 19 patients at 5-year intervals. Psychophysical tests included the "Sniffin' Sticks" test battery. In addition, OERPs were recorded in response to two odors on each side (phenyl-ethyl alcohol: 40% (v/v), H(2)S, 6ppm). OERPs were evaluated regarding existence (yes/no). Average disease duration at follow-up was 9.0 years and the average Hoehn and Yahr score (disease stage) was 2.2. RESULTS: Psychophysically, 1 patient was normosmic, 14 were hyposmic, and 4 were functionally anosmic at the initial visit. Re-examination revealed 1 normosmic, 9 hyposmic, and 8 functionally anosmic patients. Mean olfactory function decreased significantly in all patients. OERPs were initially existent in 3 out of 19 patients. At follow up, OERPs were no longer present in these patients, but were detectable in 3 other patients. CONCLUSIONS: Overall, mean olfactory function decreased, although improvements were observed at the individual level. We confirmed previous findings regarding psychophysical follow-up results. Electrophysiological measures showed a pattern of fluctuation in olfactory function comparable to that of the psychophysical results. These fluctuations do not seem to predict the course of the disease. PMID- 20858530 TI - Plasticity in the synaptic number associated with neuropathic pain in the rat spinal dorsal horn: A stereological study. AB - This study aimed to determine whether neuropathic pain is associated with a plasticity change in the number of synapses in the spinal dorsal horn. 12 normal adult SD rats were randomly divided into two groups: 7 animals were subjected to unilateral loose ligation (to induce chronic constriction injury) of the sciatic nerve (CCI group) and 5 animals subjected to unilateral sham-operation (sham operated group). 28 days after operation, the L4-L6 segment of the spinal cord was removed, and paraffin-embedded sections were prepared and stained with Nissl's method and synaptophysin immunohistochemistry. The numbers of neurons and synapses in the spinal dorsal horn were estimated using a contemporary stereological technique-the optical disector. An 86% increase in the number (per unit length of the spinal cord) of synapses or 98% increase in the ratio between the numbers of synapses and neurons in the spinal dorsal horn was found in the middle tissue block but not in both the rostral and caudal tissue blokes cut from L4-L6 segment of the spinal cord. The results suggest that neuropathic pain, as established by the CCI model, is associated with a plasticity change in the spinal dorsal horn: increase in the number of synapses. PMID- 20858531 TI - Reduced visual P300 amplitudes in individuals at ultra-high risk for psychosis and first-episode schizophrenia. AB - The purpose of this study was to investigate whether individuals at ultra-high risk (UHR) for psychosis and patients experiencing first-episode schizophrenia had impairments in visual information processing as indexed by the visual P300 event-related potential. Sixteen UHR individuals, 21 first-episode schizophrenia patients, and 16 healthy controls were included. Participants were asked to perform a visuospatial oddball task while undergoing an electroencephalogram. The UHR and first-episode groups showed reduced P300 amplitudes in comparison to healthy controls. P300 amplitudes were negatively correlated with severity of negative symptoms in both the UHR and first-episode groups. These results suggest that the visual P300 may be a neurobiological vulnerability marker, reflecting neurophysiological abnormalities associated with enduring negative symptoms in schizophrenia. PMID- 20858532 TI - Influence of muscle activity on brain oxygenation during verbal fluency assessed with functional near-infrared spectroscopy. AB - A large part of the literature of functional near-infrared spectroscopy (fNIRS) deals with overt verbal fluency. It has been claimed that fNIRS has a low susceptibility to movement related artefacts as, for example, associated with overt speech. However, so far, no study has investigated this assumption in an experimental design. Therefore, we examined a group of 16 healthy subjects during performance of two verbal fluency tasks (experiment 1: phonological fluency; experiment 2: semantical fluency, paced answers, pronouncing vs. writing). We measured changes of oxygenated (O(2)Hb) and deoxygenated haemoglobin (HHb) over fronto-temporal (brain) areas via fNIRS, while temporalis muscle activity was simultaneously assessed by means of electromyography (EMG). Statistical analyses indicated comparable word production, higher increases of O(2)Hb and higher decreases of HHb over fronto-temporal areas during word fluency in contrast to the control task weekday reciting. This fNIRS pattern indicates fluency related activation and was found for pronouncing and for writing in both experiments. Regarding the EMG data, fluency related activity was only found for pronouncing, not for writing. Thus, muscle activity cannot account for fluency related fNIRS activity during writing. Additionally, correlation analyses showed no systematic associations of fNIRS and EMG signals. In conclusion, we found arguments that fNIRS actually allows for the measurement of brain activity over fronto-temporal areas during verbal fluency. Nonetheless, further studies should evaluate more direct associations between fNIRS and EMG signals by specific experimental manipulations and data analysing approaches that allow dealing fNIRS and EMG raw data simultaneously. PMID- 20858533 TI - Effect of pentylenetetrazole and sound stimulation induced single and repeated convulsive seizures on the MDA, GSH and NO levels, and SOD activities in rat liver and kidney tissues. AB - OBJECTIVES: the aim of our study was to evaluate the activity of superoxide dismutase (SOD) and the levels of glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) in liver and kidney tissues in a rat model of convulsive seizure induced by single and repeated doses of pentylenetetrazole (PTZ) and sound stimulation with key ringing. MATERIALS AND METHODS: male Wistar adult rats (n=48), were used in the experiment. The animals were divided into six groups: (1) Single Seizure Control Group (SS-Control; n=8), (2) Repeated Seizures Control Group (RS-Control; n=8), (3) PTZ induced Single Seizure Group (SS-PTZ Group; n=8), (4) PTZ induced Repeated Seizures Group (RS- PTZ Group; n=8), (5) Key Ringing Induced Single Seizure Group (SS-KEY Group; n=8), (6) Key-Ringing Induced Repeated Seizures Group (RS-KEY Group; n=8). Following injections rats were observed for seizure activity for 30 min. Animals were sacrificed 24h after induced seizure (single or last seizure) or saline administration. MDA, NO, GSH levels and SOD activities were determined in liver and kidney tissues. RESULTS: there was no significant difference between SS-Control and RS-Control groups, SS PTZ and SS-KEY groups, and RS-PTZ and RS-KEY groups (p>0.05) in none of the examined 4 parameters in liver and kidney tissues. The liver and kidney levels of MDA and NO in SS-PTZ group were found to be significantly higher than the SS Control group (p<0.05). In SS-KEY group, the liver and kidney levels of MDA and NO were found to be significantly higher and GSH levels were significantly lower than the SS-Control group (p<0.05). While liver and kidney levels of MDA in RS PTZ group and RS-KEY group were found to be significantly higher than the RS Control group (p<0.05), liver and kidney GSH levels were significantly lower (p<0.05). The liver levels of NO in RS-PTZ group and RS-KEY group were found to be significantly higher than the RS-Control group (p<0.05). Kidney SOD activities in RS-PTZ group and RS-KEY group were found to be significantly lower than the RS Control group (p<0.05). When RS-PTZ group is compared with the SS-PTZ group, the liver SOD activity and kidney NO level were found to be significantly lower in the RS-PTZ group (p<0.05). While the liver NO level and GSH level in RS-KEY group were significantly higher than the SS-KEY group, SOD activity was significantly lower in the RS-KEY group (p<0.05). When RS-KEY group was compared with SS-KEY group, the kidney NO level and SOD activity were found to be significantly lower in the RS-KEY group (p<0.05). CONCLUSION: in conclusion, key-ringing or PTZ induced single and repeated seizures result in increased oxidative damage and lipid peroxidation, and decreased antioxidant defense mechanisms. PMID- 20858534 TI - Inhibitory components from the buds of clove (Syzygium aromaticum) on melanin formation in B16 melanoma cells. AB - In the course to find a new whitening agent, we evaluated the methanol extract from bud of clove (Syzygium aromaticum) on melanin formation in B16 melanoma cells. Eugenol and eugenol acetate were isolated as the active compounds and showed melanin inhibition of 60% and 40% in B16 melanoma cell with less cytotoxicity at the concentration of 100 and 200 MUg/mL, respectively. Furthermore, an essential oil prepared from the bud of clove, which contain eugenol and eugenol acetate as dominant components, showed melanin inhibition of 50% and 80% in B16 melanoma cells at the concentration of 100 and 200 MUg/mL, respectively. PMID- 20858535 TI - Comparative analysis of the chemical constituents of two varieties of Pueraria candollei. AB - A high-performance liquid chromatography (HPLC) method was developed to determine the contents of miroestrol and deoxymiroestrol in the tubers of Pueraria candollei var. mirifica and P. candollei var. candollei. The linear detection ranges were 0.78-25.00 MUg/mL for miroestrol and 1.56-25.00 MUg/mL for deoxymiroestrol. The limit of detection (LOD) and limit of quantification (LOQ) were 0.2 and 0.78 MUg/mL, respectively, for miroestrol and 0.78 and 1.56 MUg/mL, respectively, for deoxymiroestrol. Our results suggest that both varieties of P. candollei can produce miroestrol and deoxymiroestrol and that the developed HPLC method can be applied for quality control of plants and their products. PMID- 20858536 TI - Nine new tropane alkaloids from Datura stramonium L. identified by GC/MS. AB - Sixty seven tropane alkaloids were identified in the organs of Datura stramonium L. by GC/MS. Nine new tropane alkaloids, 3,7-dihydroxy-6-propionyloxytropane, 6,7 dehydro-3-tigloyloxytropane, 3-tigloyloxy-6,7-epoxytropane, 3,7-dihydroxy-6-(2' methylbutyryloxy)tropane, 6,7-dehydroapoatropine, 3-(3' methoxytropoyloxy)tropane, 3-tigloyloxy-6-isobutyryloxy-7-hydroxytropane, 3 tropoyloxy-6-isobutyryloxytropane, 3beta-tropoyloxy-6beta-isovaleroyloxytropane were tentatively identified. The alkaloids cyclotropine, dihydroaposcopolamine, 6,7-dehydrohyoscyamine and 4'-hydroxylittorine are reported for the first time for the genus Datura and 6,7-dehydrotropine for the family Solanaceae. Hyoscyamine and scopolamine figure as the major tropane alkaloids in the plant organs. PMID- 20858537 TI - The TFIIS and TFIIS-like genes from Medicago truncatula are involved in oxidative stress response. AB - The cDNA sequence coding for a novel putative TFIIS (transcription elongation factor II-S), hereby named MtTFIIS-like, was isolated from barrel medic (Medicago truncatula Gaertn.) by reverse transcriptase-polymerase chain reaction. The nucleotide sequence contains an open reading frame of 1074 bp, predicting a 40.0 kDa protein, conserved among plant species. The N-terminal region of the MtTFIIS like protein includes a LW motif, characterized by highly conserved leucine (L) and tryptophan (W) residues, also found in the canonical TFIIS protein, elongin A (transcription elongation factor S-III) and CRSP70 (cofactor required for Sp1 activation), while a proline-rich region is present in the C-terminal domain. The expression profiles of the MtTFIIS-like gene were evaluated by quantitative real time PCR (QRT-PCR) in barrel medic plantlets grown in vitro under oxidative stress conditions induced by copper (CuCl(2) 0.05, 0.1 and 0.2mM) and polyethylene glycol (PEG6000 50, 100 and 150 g/L), respectively. Both stress agents caused ROS (reactive oxygen species) accumulation. Moreover, EPR spectra of leaves from plantlets exposed to toxic copper doses confirmed that the heavy metal is translocated from roots to the aerial parts, where it is found predominantly in the Cu(2+) redox state. The MtTFIIS-like gene expression was significantly enhanced (up to 2.9-fold) in aerial parts of copper-treated plants, and in roots (up to 4.4-fold) in response to PEG treatments. The expression profiles of the MtTFIIS-like gene were compared to those of the MtTFIIS gene, encoding the canonical TFIIS protein, which was similarly up-regulated in response to both stresses. Interestingly, the MtTFIIS-like and MtTFIIS genes were significantly up-regulated (up to 3.2- and 4.3-fold, respectively) during seed imbibition, a physiological process which requires active DNA repair. Based on the reported data, the possible roles played in planta by the novel MtTFIIS-like gene are discussed. PMID- 20858538 TI - Designing HPMC matrices with improved resistance to dissolved sugar. AB - High concentrations of dissolved sugars can accelerate in vitro drug release in certain hydroxypropyl methylcellulose (HPMC) matrices (Williams et al., 2009). This study investigated the potential for common formulation variables to modulate sucrose sensitivity, and explored if more resistant formulations could be designed. In a model matrix containing 30% HPMC (MethocelTM K4M), the inclusion of sugar as a tablet diluent was a key factor. Lactose:microcrystalline cellulose mixtures, dextrose and d-xylose all produced highly swollen, erodible matrices in 0.7M sucrose (37 degrees C), which collapsed and rapidly released remaining drug after 1-4h. This suggests internal and external sugars combine to disrupt the diffusion barrier properties of the gel layer. In contrast, matrices containing microcrystalline cellulose as the sole diluent provided extended release for 10h. Small particle size (<63MUm) and high or low viscosity HPMC (MethocelTM K100M or K100LV) also improved sugar resistance. Knowledge of these variables allowed a significantly more resistant HPMC matrix to be designed which provided extended release for >16h in 0.9M sucrose. By judicious selection of excipient properties, the tolerance of HPMC matrices to high sucrose environments can be significantly improved. PMID- 20858539 TI - Development, evaluation and clinical studies of Acitretin loaded nanostructured lipid carriers for topical treatment of psoriasis. AB - The objective of the present study was to formulate and characterize Acitretin loaded Nanostructured Lipid Carriers (ActNLCs), to understand in vitro drug release and clinically evaluate the role of the developed gel in the topical treatment of psoriasis. ActNLCs were prepared by solvent diffusion technique using 3(2) full factorial design. The mean diameter and surface morphology of ActNLC was evaluated. ActNLCs were lyophilized and crystallinity of NLC was characterized by Differential Scanning Calorimtery (DSC) and powder X-Ray Diffraction (XRD). The NLCs were incorporated in 1% w/w Carbopol 934 P gel base and in vitro skin deposition studies in Human Cadaver Skin and double-blind clinical studies in psoriatic patients were conducted. The optimized ActNLCs were spherical in shape, with average particle size of 223(+/-8.92)nm, zeta potential of -26.4 (+/-0.86) mV and EE of 63.0(+/-1.54)%. DSC and XRD data confirmed the formation of NLCs. Significantly higher deposition of Acitretin was found in human cadaver skin from ActNLC gel (81.38 +/-1.23%) as compared to Act plain gel (47.28+/-1.02%). Clinical studies demonstrated significant improvement in therapeutic response and reduction in local side effects with ActNLCs loaded gel indicated its effectiveness in the topical treatment of Psoriasis. PMID- 20858540 TI - Evaluation of a cationic calix[4]arene: Solubilization and self-aggregation ability. AB - Water-soluble calixarenes are promising macrocyclic compounds which have found numerous applications in chemistry and biology. However, these compounds have been less studied in regard to their behavior in aqueous solutions and mechanisms of drug solubilization. The present work is devoted to the evaluation of the solubilizing properties and estimation of self-aggregation ability of positively charged 5,11,17,23-tetrakis(trimethylammoniomethyl)-25,26,27,28-tetrapropoxy calix[4]arene tetrachloride (aminocalix), including comparisons with a series of pharmaceutically relevant cyclodextrins. Phase-solubility measurements of the drugs with aminocalix and various cyclodextrins were carried out. Aminocalix showed a solubilizing ability comparable to the cyclodextrins. The drug solubility enhancement caused by the aminocalix was studied and was found to be maximal for steroid drugs. An attempt to understand the solubilizing mechanism of aminocalix was undertaken based on correlation analysis between physical and physico-chemical properties of the drugs from one side and the solubilizing ability of aminocalix from the other. Correlation analysis supports the supposition that the solubilizing effect of aminocalix is based on interaction of the drug with aminocalix aggregates rather than on inclusion complexation. UV absorbance, osmolality and surface tension concentration dependences of aminocalix showed an inflection at 1% (w/v) which was initially related to the transition from monomers to micelles. However, dynamic light scattering and transmission electron microscopy measurements revealed that likely vesicles of diverse size exist at 0.1% (w/v) concentration. Thus the 1% (w/v) inflection point was interpreted to be spontaneous reordering of the vesicles between two different size populations. PMID- 20858541 TI - Characterization, anti-oxidative and anti-inflammatory effects of Costa Rican noni juice (Morinda citrifolia L.). AB - AIM OF THE STUDY: Noni fruit (Morinda citrifolia L.) juice has been used for more than 2000 years in Polynesia as a traditional folk medicine. The aim of the present study was to finely characterize noni juice from Costa Rica and to evaluate its anti-oxidative and anti-inflammatory activities. MATERIALS AND METHODS: A microfiltrated noni juice was prepared with Costarican nonis. HPLC-DAD and Electro Spray Ionization Mass Spectrometric detection (HPLC-ESI-MS) were used to identify phenolic compounds and iridoids. The anti-oxidative activity of noni juice was measured in vitro by both Oxygen Radical Absorbance Capacity (ORAC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging methods. The anti inflammatory effects of noni juice were investigated in vitro by: measuring its effect on nitric oxide and prostaglandin E2 production by activated macrophages, evaluating its inhibitory activities on cyclooxygenase (COX)-1 and -2 and in vivo on a carrageenan-induced paw oedema model in rats. RESULTS: Several polyphenols belonging to the coumarin, flavonoid and phenolic acid groups, and two iridoids were identified. Noni juice demonstrated a mean range free radical scavenging capacity. Furthermore, it also reduced carrageenan-induced paw oedema, directly inhibited cyclooxygenase COX-1 and COX-2 activities and inhibited the production of nitric oxide (NO) and prostaglandins E(2) (PGE(2)) in activated J774 cells, in a dose dependent manner. CONCLUSIONS: This study showed that noni's biological effects include: (1) anti-oxidant properties probably associated with phenolic compounds, iridoids and ascorbic acid and (2) anti-inflammatory action through NO and PGE(2) pathways that might also be strengthened by anti-oxidant effects. PMID- 20858543 TI - Large-scale production of a disulfide-stabilized constitutively active mutant opsin. AB - Previous studies of constitutively activated mutants of opsin in the absence of chromophore were carried out in crude cell membranes because such mutants could not be recovered in a detergent-solubilized form in the active state. We employed a strategy in which a stabilizing disulfide bond allowed for successful purification of a constitutively activated mutant opsin, N2C/E113Q/M257Y/D282C, solubilized in nonionic detergent from mammalian cell culture. The purified mutant opsin is able to activate transducin to a higher degree than opsin and may prove useful for future structural studies of the active state of GPCRs. PMID- 20858542 TI - Conserved proximal promoter elements control repulsive guidance molecule c/hemojuvelin (Hfe2) gene transcription in skeletal muscle. AB - Repulsive guidance molecule c (RGMc; gene symbol: Hfe2) plays a critical role in iron metabolism. Inactivating mutations cause juvenile hemochromatosis, a severe iron overload disorder. Understanding mechanisms controlling RGMc biosynthesis has been hampered by minimal information about the RGMc gene. Here we define the structure, examine the evolution, and establish mechanisms of regulation of the mouse RGMc gene. RGMc is a 4-exon gene that undergoes alternative RNA splicing to yield 3 mRNAs with 5' different untranslated regions. Gene transcription is induced during myoblast differentiation, producing all 3 mRNAs. We identify 3 critical promoter elements responsible for transcriptional activation in skeletal muscle, comprising paired E-boxes, a putative Stat and/or Ets element, and a MEF2 site, and muscle transcription factors myogenin and MEF2C stimulate RGMc promoter function in non-muscle cells. As these elements are conserved in RGMc genes from multiple species, our results suggest that RGMc has been a muscle-enriched gene throughout its evolutionary history. PMID- 20858544 TI - FMRI investigation of cross-modal interactions in beat perception: audition primes vision, but not vice versa. AB - How we measure time and integrate temporal cues from different sensory modalities are fundamental questions in neuroscience. Sensitivity to a "beat" (such as that routinely perceived in music) differs substantially between auditory and visual modalities. Here we examined beat sensitivity in each modality, and examined cross-modal influences, using functional magnetic resonance imaging (fMRI) to characterize brain activity during perception of auditory and visual rhythms. In separate fMRI sessions, participants listened to auditory sequences or watched visual sequences. The order of auditory and visual sequence presentation was counterbalanced so that cross-modal order effects could be investigated. Participants judged whether sequences were speeding up or slowing down, and the pattern of tempo judgments was used to derive a measure of sensitivity to an implied beat. As expected, participants were less sensitive to an implied beat in visual sequences than in auditory sequences. However, visual sequences produced a stronger sense of beat when preceded by auditory sequences with identical temporal structure. Moreover, increases in brain activity were observed in the bilateral putamen for visual sequences preceded by auditory sequences when compared to visual sequences without prior auditory exposure. No such order dependent differences (behavioral or neural) were found for the auditory sequences. The results provide further evidence for the role of the basal ganglia in internal generation of the beat and suggest that an internal auditory rhythm representation may be activated during visual rhythm perception. PMID- 20858545 TI - High-speed vascular dynamics of the hemodynamic response. AB - While a range of cellular mechanisms have been proposed to underlie control of neurovascular coupling, a comprehensive, reconciliatory model has yet to be determined. To fit with such a model, it is essential that candidate mechanisms exhibit reaction times, spatial ranges, and speeds of propagation that are consistent with the vascular manifestations of the 'hemodynamic response'. Understanding these vascular dynamics is therefore a critical step towards developing a robust model of neurovascular coupling. In this study, we utilize high-speed optical imaging of exposed rodent somatosensory cortex to explore and characterize the spatiotemporal dynamics of surface vessels during functional hyperemia. Our high-speed, high-resolution optical imaging approach allows us to study the hemodynamic response independently in individual vessels, and in discrete regions of the parenchyma with enough resolution to precisely characterize subtle spatial and temporal features of the response. Specifically, we explore when and where the first hemodynamic changes occur in response to stimuli, the direction and speed at which these changes propagate in arterioles and regions of the parenchyma, and the relative timing at which each of these compartments returns to its original baseline state. From these results, we are able to conclude that the hemodynamic response appears to initiate in the parenchyma and then spreads rapidly to surface arterioles. Following the initial onset we find evidence that the response spreads spatially outwards via the dilation of targeted arterioles. This propagation of vasodilation is independent of the direction of blood flow within each arteriole. We also find evidence of a decay phase that acts with a more uniform spatial dependence, rather than along targeted vessels, causing the periphery of the responding region to return to baseline first. We hypothesize that different underlying cellular mechanisms/signaling pathways are responsible for the response initiation and the response decay. Our results advance the fundamental understanding of the hemodynamic response, as well as our ability to evaluate potential cellular mechanisms for their involvement in neurovascular coupling. PMID- 20858546 TI - Dimensionality estimation for optimal detection of functional networks in BOLD fMRI data. AB - Estimation of the intrinsic dimensionality of fMRI data is an important part of data analysis that helps to separate the signal of interest from noise. We have studied multiple methods of dimensionality estimation proposed in the literature and used these estimates to select a subset of principal components that was subsequently processed by linear discriminant analysis (LDA). Using simulated multivariate Gaussian data, we show that the dimensionality that optimizes signal detection (in terms of the receiver operating characteristic (ROC) metric) goes through a transition from many dimensions to a single dimension as a function of the signal-to-noise ratio. This transition happens when the loci of activation are organized into a spatial network and the variance of the networked, task related signals is high enough for the signal to be easily detected in the data. We show that reproducibility of activation maps is a metric that captures this switch in intrinsic dimensionality. Except for reproducibility, all of the methods of dimensionality estimation we considered failed to capture this transition: optimization of Bayesian evidence, minimum description length, supervised and unsupervised LDA prediction, and Stein's unbiased risk estimator. This failure results in sub-optimal ROC performance of LDA in the presence of a spatially distributed network, and may have caused LDA to underperform in many of the reported comparisons in the literature. Using real fMRI data sets, including multi-subject group and within-subject longitudinal analysis we demonstrate the existence of these dimensionality transitions in real data. PMID- 20858547 TI - Phylogeny and biogeography of the Asian trogons (Aves: Trogoniformes) inferred from nuclear and mitochondrial DNA sequences. AB - We present the first species-level molecular phylogenetic hypothesis for the Asian trogons, using DNA sequences of multiple mitochondrial and nuclear loci, and Bayesian and maximum likelihood tree reconstruction methods. The two genera of Asian trogons, Harpactes and Apalharpactes, are distantly related to each other. Within the widespread Southeast Asian genus Harpactes, we recovered three species groups: (1) H. oreskios; (2) H. orrhophaeus and H. duvaucelii; and (3) a clade of the seven large-bodied species. Short internal branch lengths link species in the large-bodied group, suggesting rapid diversification. Apalharpactes, which is currently restricted to the montane forests of Sumatra and Java, appears to be a relictual lineage distantly related to all other trogons. Bayesian and maximum likelihood analyses indicate Apalharpactes is sister to the African genus Apaloderma, although this result was not strongly supported. Overall, the extant Asian trogon species appear to have diversified prior to the Pleistocene, based on large pair-wise mitochondrial divergences between taxa. PMID- 20858548 TI - Dispersals of Hyoscyameae and Mandragoreae (Solanaceae) from the New World to Eurasia in the early Miocene and their biogeographic diversification within Eurasia. AB - The cosmopolitan Solanaceae contains 21 tribes and has the greatest diversity in South America. Hyoscyameae and Mandragoreae are the only tribes of this family distributed exclusively in Eurasia with two centers of diversity: the Mediterranean-Turanian (MT) region and the Tibetan Plateau (TP). In this study, we examined the origins and biogeographical diversifications of the two tribes based on the phylogenetic framework and chronogram inferred from a combined data set of six plastid DNA regions (the atpB gene, the ndhF gene, the rps16-trnK intergenic spacer, the rbcL gene, the trnC-psbM region and the psbA-trnH intergenic spacer) with two fossil calibration points. Our data suggest that Hyoscyameae and Mandragoreae each forms a monophyletic group independently derived from different New World lineages in the early Miocene. Phylogenetic relationships within both tribes are generally well resolved. All genera of Hyoscyameae are found to be monophyletic and they diversified in middle to late Miocene. At nearly the same time, Mandragoreae split into two clades, corresponding to the MT region and the TP region, respectively. Both the phylogenetic relationships and the estimated ages of Hyoscyameae and Mandragoreae support two independent dispersal events of their ancestors from the New World into Eurasia. After their arrivals in Eurasia, the two tribes diversified primarily in the MT region and in the TP region via multiple biogeographic processes including vicariance, dispersal, recolonization or being preserved as relicts, from the mid Miocene to the late Quaternary. PMID- 20858549 TI - Is complement alternative pathway disregulation involved in veno-occlusive disease of the liver? PMID- 20858550 TI - Rainbow trout (Oncorhynchus mykiss) possess two hormone-sensitive lipase-encoding mRNAs that are differentially expressed and independently regulated by nutritional state. AB - Teleost fish store lipids among several tissues primarily as triacylglycerol (TG). Upon metabolic demand, stored TGs are hydrolyzed by hormone-sensitive lipase (HSL). In this study, two distinct cDNAs encoding HSL were isolated, cloned, and sequenced from adipose tissue of rainbow trout. The full-length cDNAs, designated HSL1 and HSL2, were 2562-bp and 2887-bp in length, respectively, and share 82% nucleotide identity. Phylogenetic analysis suggests that the two HSLs derive from paralogous genes that may have arisen during a teleost-specific genome duplication event. Quantitative real-time PCR revealed that HSL1 and HSL2 were differentially expressed, both in terms of distribution among tissues as well as in terms of abundance within selected tissues of juvenile trout. HSL1 and HSL2 mRNAs were detected in the brain, spleen, pancreas, kidney, gill, intestine, heart, and white muscle, but were most abundant in the red muscle, liver, and adipose tissue. HSL1 mRNA was more abundant than HSL2 mRNA in the adipose tissue, whereas HSL2 mRNA was more abundant than HSL1 mRNA in the liver. Short term fasting (4 weeks) increased HSL1 and HSL2 mRNA expression in the adipose tissue, but only HSL1 mRNA levels increased in the liver and the red muscle. During a prolonged fast (6 weeks), there was continued elevation of HSL1 and HSL2 mRNA levels in the liver and muscle; HSL mRNA expression in mesenteric fat declined, coincident with depletion of mesenteric fat mass. Refeeding fish reduced HSL expression to levels seen in continuously fed fish. These findings indicate that the pattern of HSL expression is consistent with the diverse lipid storage pattern of fish and suggest that distinct mechanisms serve to regulate differential expression of the two HSLs in tissues and during a progressive fast. PMID- 20858551 TI - A seasonal difference of daily energy expenditure in a free-living subterranean rodent, the silvery mole-rat (Heliophobius argenteocinereus; Bathyergidae). AB - In seasonal climatic regimes, animals have to deal with changing environmental conditions. It is reasonable to expect that seasonal changes are reflected in animal overall energetics. The relation between daily energy expenditure (DEE) and seasonally variable ecological determinants has been studied in many free living small mammals; however with inconsistent results. Subterranean mammals, i.e. fossorial (burrowing) mammals which live and forage underground, live in a seasonally and diurnally thermally stable environment and represent a suitable model to test seasonality in DEE in respect to seasonal changes, particularly those in soil characteristics and access to food supply. Both factors are affected by seasonal rainfall and are supposed to fundamentally determine activity of belowground dwellers. These ecological constraints are pronounced in some tropical regions, where two distinct periods, dry and rainy seasons, regularly alternate. To explore how a tropical mammal responds to an abrupt environmental change, we determined DEE, resting metabolic rate (RMR) and sustained metabolic scope (SusMS) in a solitary subterranean rodent, the silvery mole-rat, at the end of dry season and the onset of rainy season. Whereas RMR did not differ between both periods, mole-rats had 1.4 times higher DEE and SusMS after the first heavy rains. These findings suggest that rainfall is an important environmental factor responsible for higher energy expenditure in mole-rats, probably due to increased burrowing activity. SusMS in the silvery mole-rat is comparable to values in other bathyergids and all bathyergid values rank among the lowest SusMS found in endothermic vertebrates. PMID- 20858553 TI - Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application. AB - OBJECTIVES: To describe the feasibility and safety of subcutaneous immunoglobulin (SCIg) in polymyositis (PM) and dermatomyositis (DM). METHODS: Since 2009, we used SCIg to treat patients with severe idiopathic myositis (4 with DM, 3 with PM), diagnosed according to the Bohan and Peter's criteria. SCIg (Vivaglobin(r); CSL Behring) was administered by a programmable pump at the patient's usual IVIg monthly dose fractioned into equal doses given subcutaneously at weekly intervals. A standardized protocol was used to evaluate patients and to assess disease activity, treatment response and quality of life. RESULTS: Seven female patients were studied. All were Caucasians, with a median age of 53 years and a median disease duration of 72 months. The median follow-up period was 14+/-4 months. During treatment period, no relapse of the disease occurred. All patients showed a favourable clinical response and reported a good tolerance to the treatment with an improved quality of life. CK serum levels decreased over time with a concomitant improvement in MRC and Rankin modified scores. Three patients were able to discontinue the immunosuppressant and all to reduce the daily maintenance prednisone dose. CONCLUSIONS: Our experience demonstrates the beneficial effect and the safety of SCIg administration in active and refractory inflammatory myopathies. PMID- 20858552 TI - Visfatin-induced lipid raft redox signaling platforms and dysfunction in glomerular endothelial cells. AB - Adipokines have been reported to contribute to glomerular injury during obesity or diabetes mellitus. However, the mechanisms mediating the actions of various adipokines on the kidney remained elusive. The present study was performed to determine whether acid sphingomyelinase (ASM)-ceramide associated lipid raft (LR) clustering is involved in local oxidative stress in glomerular endothelial cells (GECs) induced by adipokines such as visfatin and adiponectin. Using confocal microscopy, visfatin but not adiponectin was found to increase LRs clustering in the membrane of GECs in a dose and time dependent manner. Upon visfatin stimulation ASMase activity was increased, and an aggregation of ASMase product, ceramide and NADPH oxidase subunits, gp91(phox) and p47(phox) was observed in the LR clusters, forming a LR redox signaling platform. The formation of this signaling platform was blocked by prior treatment with LR disruptor filipin, ASMase inhibitor amitriptyline, ASMase siRNA, gp91(phox) siRNA and adiponectin. Corresponding to LR clustering and aggregation of NADPH subunits, superoxide (O(2)(-)) production was significantly increased (2.7 folds) upon visfatin stimulation, as measured by electron spin resonance (ESR) spectrometry. Functionally, visfatin significantly increased the permeability of GEC layer in culture and disrupted microtubular networks, which were blocked by inhibition of LR redox signaling platform formation. In conclusion, the injurious effect of visfatin, but not adiponectin on the glomerular endothelium is associated with the formation of LR redox signaling platforms via LR clustering, which produces local oxidative stress resulting in the disruption of microtubular networks in GECs and increases the glomerular permeability. PMID- 20858554 TI - Predicting microstructure development during casting of drug-eluting coatings. AB - We have devised a novel diffuse interface formulation to model the development of chemical and physical inhomogeneities, i.e. microstructure, during the process of casting drug-eluting coatings. These inhomogeneities, which depend on the coating constituents and manufacturing conditions, can have a profound affect on the rate and extent of drug release, and therefore the ability of coated medical devices to function successfully. By deriving the model equations in a time-dependent reference frame, we find that it is computationally viable to probe a wide, physically relevant range of material and process quantities. To illustrate the application of the model, we have evaluated the impact of manufacturing solvent, coating thickness and evaporation rate on microstructure development. Our results suggest that modifying these process conditions can have a strong and nearly discontinuous effect on coating microstructure, and therefore on drug release. Further, we demonstrate that the model can be applied to processes that involve the incremental application of the coating in layers or passes. This new model formulation, which can also be used to predict the kinetics of drug release, provides a tool to elucidate and quantify the relationships between process variables, microstructure and performance. Establishing these relationships can reduce empiricism in materials selection and process design, providing a facile and efficient means to tailor the underlying microstructure and achieve a desired drug-release behavior. PMID- 20858555 TI - Alginate-PEGAc: a new mucoadhesive polymer. AB - We have synthesized a novel mucoadhesive polymer, alginate-polyethylenglycol acrylate (alginate-PEGAc), in which an alginate backbone carries acrylated polyethylenglycol. This polymer combines the strength, simplicity and gelation ability of alginate with the mucoadhesion properties arising from the characteristics and acrylate functionality of PEG. The strong bonding to the mucus results from a combination of PEG's ability to interpenetrate the mucus surface and a Michael-type addition reaction between an acrylate end group on a polymer and the sulfide end group of the mucin-type glycoprotein. We have synthesized alginate-PEGAc, verified the formation of the desired product by nuclear magnetic resonance, demonstrated the lack of cytotoxicity, and evaluated the ability of this polymer to function as a novel mucoadhesive material for controlled drug release. Based on our findings we believe that modifying other polymers with PEG-acrylate can open the way for the development of many other multifunctional biomaterials for a variety of biotechnological and biomedical applications. PMID- 20858556 TI - Dual effect of adipose tissue on bone health during growth. AB - Recent studies suggest association between body fat and childhood bone health, although conflicting findings have also been reported. The aim of the present study was to examine the association between body fat content and areal BMD, volumetric BMD, bone turnover markers, and calcitropic factors in apparently healthy children and adolescents. The study was carried out as a school based cross-sectional cohort study with 186 subjects (61% girls) aged from 7 to 19 years. Background characteristics, including medical history and lifestyle factors, were collected. Anthropometry, BMD and body composition measurements with DXA and pQCT, a fasting blood sample and a second morning void urine sample were obtained. The subjects were divided into three groups, representing low, intermediate and high adiposity, based on age and gender specific fat percentage Z-scores. Multivariate analysis was performed to all bone variables using lean body mass, pubertal development, dietary intake of calcium and intensity of physical activity as covariates. In pQCT, a significant difference between the groups was observed in cortical BMD (MANOVA; p=0.02) in proximal radius, the intermediate group having the highest values. Similarly, DXA-derived LS and WB BMD Z-scores differed significantly between the groups (MANOVA; p=0.026 and p=0.036, respectively), with highest values in the intermediate group. High body fat content associated also with low bone turnover markers, low PTH, high S-Ca and high urinary calcium excretion. The differences in biochemical markers explain our and others' findings of bone health in children and adolescents with different body fat content. These findings suggest that normal body fat content is beneficial for bone health in growing children and adolescents while both low and high body fat content have adverse skeletal effects. PMID- 20858557 TI - Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening. AB - Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n=56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 MUg /kg/day), an extreme dose of alendronate (200 MUg/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening. PMID- 20858559 TI - Migraine and stroke. AB - An association between migraine and ischemic stroke has been observed for many years but exact mechanisms by which migraine can lead to stroke are currently still under investigation. Migraine is related to stroke in several ways. First, ischemic stroke can develop as a complication of an attack of migraine with aura (so called migraineous infarction). Second, epidemiological studies suggest that migraine with aura is a risk factor for ischemic stroke. Third, a patent foramen ovale (PFO) is a well known risk factor for stroke and on the other hand, seems to be associated with migraine with aura. The purpose of this review is to summarize the current literature linking the two neurological diseases: migraine and stroke. For many years, migraine and cerebral ischemic stroke have been linked together. The association between these two diseases is multidimensional and rather complex. PMID- 20858558 TI - Paget's disease of bone: the skeletal distribution, complications and quality of life as perceived by patients. AB - CONTEXT: Paget's disease of bone (PDB) is a focal disorder of bone metabolism with overgrowth of affected bone resulting in the skeletal complications of this disease. OBJECTIVE: This study examines what patients know about the skeletal distribution of their PDB, and correlates this with their reports of complications and quality of life. DESIGN: The New England Registry for PDB (NRPD) is a voluntary registry with a questionnaire linked to a radiographic database. Data were collected by mail beginning in 2001. SETTING: Ambulatory population. PATIENTS: Any patient with PDB living in New England was eligible to enroll; 285 elected to participate, mean age 73.2 years. MAIN OUTCOME MEASURES: Patients were asked what bones were affected by PDB, and whether they suffered complications from PDB. Radiographic studies were sought to corroborate their responses. An SF-12 was administered. RESULTS: Compared to the general population, they reported substantially lower levels of physical health (Physical Component Score (PCS) mean=40), and slightly better mental health (Mental Component Score (MCS) mean=52). There were more instances of agreement on disease presence and fewer instances on disagreement (p=0.001). Radiographic studies supported the presence of a complication from PDB when deformity, fracture and joint replacement had occurred, but were less correlative when headache or hearing loss was reported. CONCLUSIONS: Most patients with PDB are aware of the skeletal distribution of their disease; there is a reasonable correlate between complications ascribed to PDB and the presence of PDB on the radiograph except when headache or hearing loss is reported. PMID- 20858560 TI - Zebra mussel (Dreissena polymorpha) parasites: potentially useful bioindicators of freshwater quality? AB - In environmental quality bioassessment studies, analysis of host-parasite interactions may well be a valuable alternative to classical macroinvertebrate sampling approaches. Herein, we investigated whether zebra mussel (Dreissena polymorpha) parasites could be useful biomonitoring tools. Mussel populations were sampled twice at two sites in northeastern France representing different levels of contamination and were characterized for parasite infection following standard histological methods. Our results indicated that sites of different environmental quality (i.e. chemical contamination) exhibited different parasite communities characterized by different trematode species and parasite associations. An additional significant finding was the positive correlation established between the prevalence of Rickettsiales-like organisms and metal contamination. Multivariate analyses were valuable in examining parasite communities. PMID- 20858561 TI - A review of the environmental corrosion, fate and bioavailability of munitions grade depleted uranium. AB - Depleted uranium (DU) is a by-product of nuclear fuel enrichment and is used in antitank penetrators due to its high density, self-sharpening, and pyrophoric properties. Military activities have left a legacy of DU waste in terrestrial and marine environments, and there have been only limited attempts to clean up affected environments. Ten years ago, very little information was available on the dispersion of DU as penetrators hit their targets or the fate of DU penetrators left behind in environmental systems. However, the marked increase in research since then has improved our knowledge of the environmental impact of firing DU and the factors that control the corrosion of DU and its subsequent migration through the environment. In this paper, the literature is reviewed and consolidated to provide a detailed overview of the current understanding of the environmental behaviour of DU and to highlight areas that need further consideration. PMID- 20858562 TI - The life cycle impact assessment applied to the Domingo Rubio tidal system by the study of seasonal variations of the aquatic eutrophication potential. AB - The innovative technique of Life Cycle Impact Assessment (LCIA) applied to dynamic environmental systems has been recently developed. In this work we investigate a complex system, the Domingo Rubio tideland (Huelva, Spain), where a tidal marsh and a continental lagoon converge. This wetland, catalogued as Natural Park by the Andalusia government, is subjected to a high eutrophicant pressures related to the strawberry culture and the inputs coming from industrial wastes. NO(2)(-), NO(3)(-) and PO(4)(3-) were analyzed in 41 water samples, obtaining values up to 100mg L(-1) Sigma(NO(2)(-), NO(3)(-)) and 18.5mg L(-1) PO(4)(3-). All these values exceed the accepted levels by the European Environment Agency. N/P ratios and the Aquatic Eutrophication Potentials (AEP) for N and P showed a constant imbalance of the system. During one tidal cycle, the tidal channel can have both N and P as limiting nutrient (P is the limiting nutrient during low tide and N is during high tide) and there exists an alternation of AEP domination too between N and P in the continental area, what points to an excess of both nutrients all over the study area, and to the necessity of diminishing the nutrient inputs and a higher control on these pollution sources as well. PMID- 20858563 TI - Fluorescent properties of organic carbon in cave dripwaters: effects of filtration, temperature and pH. AB - For the first time the specific fluorescent characteristics of organic carbon (OC) in sequentially filtered cave dripwater samples have been studied and the proportions of organic carbon in each size fraction quantified. We examined the effects of pH, temperature and filtration on the fluorescent properties of OC sampled from four drip points in different seasons. Dripwaters were sampled from both normal (pH 7.5-8.5) and hyper-alkaline (pH 9-13) drip points in Poole's Cavern, Buxton, UK, which provides a model system for understanding the effects of pH on the chemical properties of OC. At high-pH values, charge stabilisation of OC is greatly enhanced, resulting in 10-20 times more coarse colloidal and particulate (>100 nm) organic carbon than in lower pH dripwaters; indicating that destabilisation (e.g. charge shielding) of colloidal OC is an important process control on the transmission of OC in cave dripwaters at near-neutral pH. OC fluorescence in high-pH dripwaters exhibited a high degree of pH sensitivity between pH 10 and 12, consistent with substantial changes in the coordination or neighbouring environment of fluorescent acidic functional groups. Inner-filter effects (IFE) associated with the coarse colloidal and particulate fraction of OM mask the true fluorescent signal, so that size fractionation is necessary to obtain a signal which is correlated with the concentration of organic carbon. Fluorescence intensities in the samples studied were best correlated with organic carbon with a dimension <100 nm. These results have important implications for the use of fluorescence as a tracer in hydrogeological studies. PMID- 20858564 TI - The use of micropatterning to control smooth muscle myosin heavy chain expression and limit the response to transforming growth factor beta1 in vascular smooth muscle cells. AB - In the healthy artery, contractile vascular smooth muscle cells (VSMCs) have an elongated shape and are highly aligned but transition to a synthetic phenotype in culture, while additionally becoming well spread and randomly organized. Thus, controlling VSMC phenotype is a challenge in tissue engineering. In this study, we investigated the effects of micropatterning on contractile protein expression in VSMCs at low and high passage and in the presence of transforming growth factor beta 1 (TGFbeta1). Micropatterning led to significantly decreased cell area, increased elongation, and increased alignment compared to non-patterned VSMCs independent of passage number. In the presence of serum, micropatterning led to increased smooth muscle myosin heavy chain (SM-MHC) and alpha-actin expression in low passage VSMCs, but had no effect on high passage VSMCs. Micropatterning was as effective as TGFbeta1 in up-regulating SM-MHC at low passage; however, micropatterning limited VSMC response to TGFbeta1 at both low and high passage. Investigation of TGFbeta receptor 1 revealed higher expression in non-patterned VSMCs compared to patterned at high passage. Our studies demonstrate that micropatterning is an important regulator of SM-MHC expression in contractile VSMCs and that it may provide a mechanism for phenotype stabilization in the presence of growth factors. PMID- 20858565 TI - Child Mania Rating Scale-Parent Version: a valid measure of symptom change due to pharmacotherapy. AB - BACKGROUND: The development of valid parent-report measures of symptom change in pediatric bipolar disorder (PBD) is imperative to evaluate the effectiveness of different treatment approaches; yet, few studies have tested the sensitivity of symptom measures. The current study evaluated the sensitivity of the Child Mania Rating Scale (CMRS-P) to detect symptom change over time in a treatment study for PBD. METHODS: Data on symptom change were drawn from a prospective six-week, double-blind, placebo-controlled, randomized outpatient medication treatment trial of risperidone versus divalproex. The sample included 66 children with Bipolar type I disorder. Measures were administered every week for six weeks of treatment. RESULTS: The CMRS-P demonstrated statistically (p <= .05) and clinically significant change in symptom report from pre to post-test. Growth curve modeling indicated that the CMRS-P demonstrated overall similarity to the YMRS in the magnitude and trajectory of change over time. Finally, results indicate that the CMRS-P is able to detect response rates with moderate levels of agreement with other measures. LIMITATIONS: Limitations of this study include a relatively small sample size and uncertain generalizability beyond treatment trials. CONCLUSIONS: The CMRS-P is short, easy to administer, and represents parent's report of symptoms, all strengths which make it a compelling treatment outcome tool. This preliminary evidence of its validity as a treatment outcome measure makes it applicable in other research settings and suggests its potential use in clinical settings. PMID- 20858566 TI - Physical treatments for bipolar disorder: a review of electroconvulsive therapy, stereotactic surgery and other brain stimulation techniques. AB - BACKGROUND: Despite pharmacological advances, bipolar disorder continues to be difficult to treat. This article reviews the evidence base for the use of electroconvulsive therapy (ECT) and other brain stimulation therapies in bipolar disorder. METHODS: The evidence base for the efficacy of ECT and transcranial magnetic stimulation in the treatment of mania, bipolar depression and mixed affective states was reviewed. Reports on the use of vagus nerve stimulation, stereotaxic surgery, deep brain stimulation, magnetic seizure therapy and transcranial direct current stimulation in treating depression, as well as bipolar disorder were also reviewed. Studies were identified from Medline and Embase database searches. RESULTS: There are a few randomized controlled trials of ECT in mania and bipolar depression, and none in mixed affective states. Nevertheless, such studies consistently reported clinically meaningful efficacy, with a majority of pharmacotherapy resistant patients responding to ECT. Evidence for the use of other brain stimulation therapies in treating bipolar mood states is preliminary and limited. CONCLUSIONS: ECT is an effective treatment for acute mania, bipolar depression and mixed affective states and has useful efficacy even in pharmacotherapy-resistant patients. Other brain stimulation techniques may have potential for the treatment of bipolar disorder and should be further researched. PMID- 20858567 TI - Interconnection between biological abnormalities in borderline personality disorder: use of the Bayesian networks model. AB - There is agreement in that strengthening the sets of neurobiological data would reinforce the diagnostic objectivity of many psychiatric entities. This article attempts to use this approach in borderline personality disorder (BPD). Assuming that most of the biological findings in BPD reflect common underlying pathophysiological processes we hypothesized that most of the data involved in the findings would be statistically interconnected and interdependent, indicating biological consistency for this diagnosis. Prospectively obtained data on scalp and sleep electroencephalography (EEG), clinical neurologic soft signs, the dexamethasone suppression and thyrotropin-releasing hormone stimulation tests of 20 consecutive BPD patients were used to generate a Bayesian network model, an artificial intelligence paradigm that visually illustrates eventual associations (or inter-dependencies) between otherwise seemingly unrelated variables. The Bayesian network model identified relationships among most of the variables. EEG and TSH were the variables that influence most of the others, especially sleep parameters. Neurological soft signs were linked with EEG, TSH, and sleep parameters. The results suggest the possibility of using objective neurobiological variables to strengthen the validity of future diagnostic criteria and nosological characterization of BPD. PMID- 20858568 TI - Optimal timing for surgical revascularization in survivors of acute coronary syndromes eligible for elective coronary artery bypass graft surgery. AB - BACKGROUND: Several patients with acute coronary syndrome (ACS) are discharged home after the acute phase of ACS and are suitable for elective coronary artery bypass graft (CABG) surgery. The aim of the study was to assess the optimal timing for surgical revascularization and its effect on 12-month outcome in patients discharged from hospital after ACS and referred for elective CABG surgery. METHODS: The analysis involved 2028 patients enrolled into the ongoing Polish Registry of Acute Coronary Syndromes (PL-ACS) who were discharged from hospital with the intention to undergo elective CABG surgery. CONCLUSIONS: Among 2028 patients 1216 (60.0%) underwent surgery during 12months of follow-up. Patients who underwent surgical revascularization had a lower prevalence of mortality (5.7% vs 11.5%, p<0.0001). Patients who underwent surgery within the first month had a significantly higher prevalence of mortality than those who did not undergo surgery (5.7% vs 1.6%, p<0.0001). By the third month, the two cumulative mortalities were similar (4.2% vs 4.6%, p=0.65). From the beginning of the fourth month, the cumulative mortality was significantly higher among patients who did not undergo surgery. PMID- 20858569 TI - Effect of chicken meat environment on gene expression of Campylobacter jejuni and its relevance to survival in food. AB - Poultry meat is the major food source responsible for gastrointestinal infections caused by the human pathogen Campylobacter jejuni. Even though C. jejuni does not grow below 30 degrees C, the bacterium survives on raw meat surfaces at refrigerated temperatures and thus poses a risk to the consumer. Previously, we have shown that chicken meat juice prolongs survival of C. jejuni at 5 degrees C compared to laboratory medium, suggesting that compounds present in meat juice influence adaptation to low temperatures. In the present study we have used chicken meat juice to identify C. jejuni genes that are differentially expressed in a typical chicken meat environment encountered by consumers. The analysis showed that chicken meat juice increased expression of luxS involved in quorum sensing, as well as a gene involved in O-linked flagellin glycosylation in C. jejuni, while expression of haemin uptake and the peroxide stress response genes were reduced. Furthermore, we propose that LuxS may play a key role in adaptation to the chicken meat juice environment, as lack of the luxS gene reduces the ability of C. jejuni to survive in chicken meat juice at low temperature. Finally, our data suggest that part of an ABC transport system is induced and we speculate that uptake of cryoprotectants may be important for C. jejuni to adapt to low temperature. In summary, we found that C. jejuni has a specific but limited transcriptional response to chicken meat juice and that luxS has an impact on the prolonged survival of C. jejuni in this important environment in the food chain. PMID- 20858570 TI - On the modeling of inactivation kinetics by UV irradiation. PMID- 20858572 TI - Nuclear Health Just in Time Lectures and Nuclear Health Supercourse: http://www.pitt.edu/~super1/lecture/lec37401/index.htm. PMID- 20858573 TI - Neck motion patterns in whiplash-associated disorders: quantifying variability and spontaneity of movement. AB - BACKGROUND: whiplash-associated disorders have usually been explored by analyzing changes in the cervical motor system function by means of static variables such as the range of motion, whereas other behavioural features such as speed, variability or smoothness of movement have aroused less interest. METHODS: whiplash patients (n=30), control subjects (n=29) and a group of people faking the symptoms of whiplash-associated-disorders (Simulators, n=30) performed a cyclical flexion-extension movement. This movement was recorded by means of video photogrammetry. The computed variables were: range of motion, maxima angular velocity and acceleration, and two additional variables that quantify the repeatability of a motion and its spontaneity. Two comparisons were made: Control vs. Patients and Patients vs. Simulators. At each comparison we used ANOVA to detect differences between groups and discriminant analysis to evaluate the ability of these variables to classify individuals. FINDINGS: comparison between Controls and Patients showed significant reductions in the range of motion, and both the maximum of angular velocity and acceleration in the Patients. The most efficient discriminant model only included the range of motion and maximum angular velocity. Comparison between Patients and Simulators showed a significant reduction in all measured variables in the Simulators. The best classification model was obtained with maximum angular velocity, spontaneity and repeatability of motion. INTERPRETATION: our results suggest that the pathological patterns differ from those of Controls in amplitude and speed of motion, but not in repeatability or spontaneity of movement. These variables are especially useful for detecting abnormal movement patterns. PMID- 20858571 TI - Chocolate consumption is inversely associated with prevalent coronary heart disease: the National Heart, Lung, and Blood Institute Family Heart Study. AB - BACKGROUND & AIMS: Epidemiologic studies have suggested beneficial effects of flavonoids on cardiovascular disease. Cocoa and particularly dark chocolate are rich in flavonoids and recent studies have demonstrated blood pressure lowering effects of dark chocolate. However, limited data are available on the association of chocolate consumption and the risk of coronary heart disease (CHD). We sought to examine the association between chocolate consumption and prevalent CHD. METHODS: We studied in a cross-sectional design 4970 participants aged 25-93 years who participated in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Chocolate intake was assessed through a semi-quantitative food frequency questionnaire. We used generalized estimating equations to estimate adjusted odds ratios. RESULTS: Compared to subjects who did not report any chocolate intake, odds ratios (95% CI) for CHD were 1.01 (0.76-1.37), 0.74 (0.56-0.98), and 0.43 (0.28-0.67) for subjects consuming 1-3 times/month, 1-4 times/week, and 5+ times/week, respectively (p for trend <0.0001) adjusting for age, sex, family CHD risk group, energy intake, education, non-chocolate candy intake, linolenic acid intake, smoking, alcohol intake, exercise, and fruit and vegetables. Consumption of non-chocolate candy was associated with a 49% higher prevalence of CHD comparing 5+/week vs. 0/week [OR = 1.49 (0.96-2.32)]. CONCLUSIONS: These data suggest that consumption of chocolate is inversely related with prevalent CHD in a general United States population. PMID- 20858574 TI - Bilateral total knee replacement in a congenital amputee with bilateral fibular deficiency. AB - We present the first ever reported case of bilateral total knee replacements in a congenital amputee with bilateral fibular deficiency. A 60 year old woman with bilateral fibular hemimelia presented with advanced osteoarthritis in both her knees for which bilateral total knee replacements was performed. The left knee replacement was followed up at 12 months and the right knee at 7 years. Oxford knee scores improved from 14 to 40 for the left knee and were 37 for the right knee. She was able to walk independently to a distance beyond 400 m. Modification in the surgical procedure and postoperative rehabilitation is discussed. Mid-term follow-up of 7 years reaffirms total knee replacement as a viable option for below knee amputees with knee osteoarthritis. PMID- 20858575 TI - Driver drowsiness classification using fuzzy wavelet-packet-based feature extraction algorithm. AB - Driver drowsiness and loss of vigilance are a major cause of road accidents. Monitoring physiological signals while driving provides the possibility of detecting and warning of drowsiness and fatigue. The aim of this paper is to maximize the amount of drowsiness-related information extracted from a set of electroencephalogram (EEG), electrooculogram (EOG), and electrocardiogram (ECG) signals during a simulation driving test. Specifically, we develop an efficient fuzzy mutual-information (MI)- based wavelet packet transform (FMIWPT) feature extraction method for classifying the driver drowsiness state into one of predefined drowsiness levels. The proposed method estimates the required MI using a novel approach based on fuzzy memberships providing an accurate-information content-estimation measure. The quality of the extracted features was assessed on datasets collected from 31 drivers on a simulation test. The experimental results proved the significance of FMIWPT in extracting features that highly correlate with the different drowsiness levels achieving a classification accuracy of 95%-- 97% on an average across all subjects. PMID- 20858576 TI - Approximation-based adaptive tracking control of pure-feedback nonlinear systems with multiple unknown time-varying delays. AB - This paper presents adaptive neural tracking control for a class of non-affine pure-feedback systems with multiple unknown state time-varying delays. To overcome the design difficulty from non-affine structure of pure-feedback system, mean value theorem is exploited to deduce affine appearance of state variables x(i) as virtual controls alpha(i), and of the actual control u. The separation technique is introduced to decompose unknown functions of all time-varying delayed states into a series of continuous functions of each delayed state. The novel Lyapunov-Krasovskii functionals are employed to compensate for the unknown functions of current delayed state, which is effectively free from any restriction on unknown time-delay functions and overcomes the circular construction of controller caused by the neural approximation of a function of u and [Formula: see text] . Novel continuous functions are introduced to overcome the design difficulty deduced from the use of one adaptive parameter. To achieve uniformly ultimate boundedness of all the signals in the closed-loop system and tracking performance, control gains are effectively modified as a dynamic form with a class of even function, which makes stability analysis be carried out at the present of multiple time-varying delays. Simulation studies are provided to demonstrate the effectiveness of the proposed scheme. PMID- 20858577 TI - Neural network learning without backpropagation. AB - The method introduced in this paper allows for training arbitrarily connected neural networks, therefore, more powerful neural network architectures with connections across layers can be efficiently trained. The proposed method also simplifies neural network training, by using the forward-only computation instead of the traditionally used forward and backward computation. PMID- 20858578 TI - High-performance reconfigurable hardware architecture for restricted Boltzmann machines. AB - Despite the popularity and success of neural networks in research, the number of resulting commercial or industrial applications has been limited. A primary cause for this lack of adoption is that neural networks are usually implemented as software running on general-purpose processors. Hence, a hardware implementation that can exploit the inherent parallelism in neural networks is desired. This paper investigates how the restricted Boltzmann machine (RBM), which is a popular type of neural network, can be mapped to a high-performance hardware architecture on field-programmable gate array (FPGA) platforms. The proposed modular framework is designed to reduce the time complexity of the computations through heavily customized hardware engines. A method to partition large RBMs into smaller congruent components is also presented, allowing the distribution of one RBM across multiple FPGA resources. The framework is tested on a platform of four Xilinx Virtex II-Pro XC2VP70 FPGAs running at 100 MHz through a variety of different configurations. The maximum performance was obtained by instantiating an RBM of 256 * 256 nodes distributed across four FPGAs, which resulted in a computational speed of 3.13 billion connection-updates-per-second and a speedup of 145-fold over an optimized C program running on a 2.8-GHz Intel processor. PMID- 20858579 TI - Self-organizing multilayer perceptron. AB - In this paper, we propose an extension of a self-organizing map called self organizing multilayer perceptron (SOMLP) whose purpose is to achieve quantization of spaces of functions. Based on the use of multilayer perceptron networks, SOMLP comprises the unsupervised as well as supervised learning algorithms. We demonstrate that it is possible to use the commonly used vector quantization algorithms (LVQ algorithms) to build new algorithms called functional quantization algorithms (LFQ algorithms). The SOMLP can be used to model nonlinear and/or nonstationary complex dynamic processes, such as speech signals. While most of the functional data analysis (FDA) research is based on B-spline or similar univariate functions, the SOMLP algorithm allows quantization of function with high dimensional input space. As a consequence, classical FDA methods can be outperformed by increasing the dimensionality of the input space of the functions under analysis. Experiments on artificial and real world examples are presented which illustrate the potential of this approach. PMID- 20858580 TI - Proto-object based rate control for JPEG2000: an approach to content-based scalability. AB - The JPEG2000 system provides scalability with respect to quality, resolution and color component in the transfer of images. However, scalability with respect to semantic content is still lacking. We propose a biologically plausible salient region based bit allocation mechanism within the JPEG2000 codec for the purpose of augmenting scalability with respect to semantic content. First, an input image is segmented into several salient proto-objects (a region that possibly contains a semantically meaningful physical object) and background regions (a region that contains no object of interest) by modeling visual focus of attention on salient proto-objects. Then, a novel rate control scheme distributes a target bit rate to each individual region according to its saliency, and constructs quality layers of proto-objects for the purpose of more precise truncation comparable to original quality layers in the standard. Empirical results show that the suggested approach adds to the JPEG2000 system scalability with respect to content as well as the functionality of selectively encoding, decoding, and manipulation of each individual proto-object in the image, with only some slightly trivial modifications to the JPEG2000 standard. Furthermore, the proposed rate control approach efficiently reduces the computational complexity and memory usage, as well as maintains the high quality of the image to a level comparable to the conventional post-compression rate distortion (PCRD) optimum truncation algorithm for JPEG2000. PMID- 20858581 TI - A geometric method for optimal design of color filter arrays. AB - A color filter array (CFA) used in a digital camera is a mosaic of spectrally selective filters, which allows only one color component to be sensed at each pixel. The missing two components of each pixel have to be estimated by methods known as demosaicking. The demosaicking algorithm and the CFA design are crucial for the quality of the output images. In this paper, we present a CFA design methodology in the frequency domain. The frequency structure, which is shown to be just the symbolic DFT of the CFA pattern (one period of the CFA), is introduced to represent images sampled with any rectangular CFAs in the frequency domain. Based on the frequency structure, the CFA design involves the solution of a constrained optimization problem that aims at minimizing the demosaicking error. To decrease the number of parameters and speed up the parameter searching, the optimization problem is reformulated as the selection of geometric points on the boundary of a convex polygon or the surface of a convex polyhedron. Using our methodology, several new CFA patterns are found, which outperform the currently commercialized and published ones. Experiments demonstrate the effectiveness of our CFA design methodology and the superiority of our new CFA patterns. PMID- 20858582 TI - Fuzzy random impulse noise removal from color image sequences. AB - In this paper, a new fuzzy filter for the removal of random impulse noise in color video is presented. By working with different successive filtering steps, a very good tradeoff between detail preservation and noise removal is obtained. One strong filtering step that should remove all noise at once would inevitably also remove a considerable amount of detail. Therefore, the noise is filtered step by step. In each step, noisy pixels are detected by the help of fuzzy rules, which are very useful for the processing of human knowledge where linguistic variables are used. Pixels that are detected as noisy are filtered, the others remain unchanged. Filtering of detected pixels is done by blockmatching based on a noise adaptive mean absolute difference. The experiments show that the proposed method outperforms other state-of-the-art filters both visually and in terms of objective quality measures such as the mean absolute error (MAE), the peak-signal to-noise ratio (PSNR) and the normalized color difference (NCD). PMID- 20858583 TI - On a derivative-free fan-beam reconstruction formula. AB - We clarify that the derivative-free fan-beam reconstruction formula [IEEE Trans. Image Process. 2, 543-547, 1993] only allows exact reconstruction of an object for a circular trajectory or at the origin of the coordinate system for a radially symmetric noncircular trajectory. PMID- 20858584 TI - Robust adaptive controller design for a class of uncertain nonlinear systems using online T-S fuzzy-neural modeling approach. AB - This paper proposes a novel method of online modeling and control via the Takagi Sugeno (T-S) fuzzy-neural model for a class of uncertain nonlinear systems with some kinds of outputs. Although studies about adaptive T-S fuzzy-neural controllers have been made on some nonaffine nonlinear systems, little is known about the more complicated uncertain nonlinear systems. Because the nonlinear functions of the systems are uncertain, traditional T-S fuzzy control methods can model and control them only with great difficulty, if at all. Instead of modeling these uncertain functions directly, we propose that a T-S fuzzy-neural model approximates a so-called virtual linearized system (VLS) of the system, which includes modeling errors and external disturbances. We also propose an online identification algorithm for the VLS and put significant emphasis on robust tracking controller design using an adaptive scheme for the uncertain systems. Moreover, the stability of the closed-loop systems is proven by using strictly positive real Lyapunov theory. The proposed overall scheme guarantees that the outputs of the closed-loop systems asymptotically track the desired output trajectories. To illustrate the effectiveness and applicability of the proposed method, simulation results are given in this paper. PMID- 20858585 TI - Full-angle fluorescence diffuse optical tomography with spatially coded parallel excitation. AB - Challenges remain in imaging fast biological activities through whole small animal using fluorescence diffuse optical tomography (FDOT). In this study, a novel full-angle FDOT with spatially coded parallel excitation (SC-FDOT) is proposed, which provides much better image qualities than our previous FDOT with multiple-points illumination (MP-FDOT) while maintaining comparable temporal resolution. Singular-value analysis and numerical simulations are used to obtain the key experimental parameters including the optimal point sources number and the optimal projections number, and to compare the performances of SC-FDOT, MP FDOT and the conventional FDOT with single-point illumination. Results demonstrate that SC-FDOT has the best spatial-temporal performances in imaging fast biological activities through whole body. Physical phantom experiments are performed to evaluate the spatial performance of SC-FDOT in practical experimental applications. Utilizing the proposed system, a nude mouse implanted with a small fluorescent inclusion is also imaged. The preliminary result demonstrates the feasibility of SC-FDOT in in vivo applications. PMID- 20858586 TI - Do we need time adjusted mean platelet volume measurements? AB - Mean platelet volume (MPV) is associated with various diseases. Several authors reported anticoagulant and time dependency. Therefore, standardized laboratory methods are essential. The aim of this study was to standardize the MPV measurement. Blood was collected in potassium-ethylenediaminetetra-acid (EDTA) and sodium-citrate tubes. First, MPV and platelet count were determined every half hour for 4 hours in 20 healthy volunteers. The same parameters were acquired from a second group of 100 healthy donors. We measured at the point of highest stability determined in the first step and aimed to determine a reference range. Citrate samples revealed significantly smaller MPV (7.0 fL +/- 0.69 standard deviation [SD]) than EDTA (8.0 fL +/- 0.8 SD). Platelets swell until 120 minutes in EDTA and until 60 minutes in citrate. Mean platelet count changed significantly in citrate. In the second group, no inverse correlation between MPV and platelet count was seen. A reference range was calculated (EDTA, 7.2-10.8 fL; citrate, 6.1-9.5 fL). Platelets stored in citrate are significantly smaller compared to those stored in EDTA. Timing is important when measuring platelet volume. Optimal measuring time should be 120 minutes after venipuncture. For this we depicted a reference range. Platelet count is most stable in EDTA. There was no inverse relation between MPV and platelet count. PMID- 20858587 TI - A practical approach to the flow cytometric detection and diagnosis of T-cell lymphoproliferative disorders. AB - The flow cytometric analysis of T-cell malignancies is difficult due to the heterogeneity of T-cells and the lack of convenient methods to detect T-cell clonality. Neoplastic T-cells are most often detected by their altered level of surface antigen expression, and detection requires an extensive knowledge of the phenotype of normal T-lymphocytes. This review focuses on the methods to distinguish malignant T-cells from their normal counterparts and the phenotypic features of the T-cell lymphoproliferative disorders. PMID- 20858588 TI - Review: Stem cells and gene therapy. AB - Both stem cell and gene therapy research are currently the focus of intense research in institutions and companies around the world. Both approaches hold great promise by offering radical new and successful ways of treating debilitating and incurable diseases effectively. Gene therapy is an approach to treat, cure, or ultimately prevent disease by changing the pattern of gene expression. It is mostly experimental, but a number of clinical human trials have already been conducted. Gene therapy can be targeted to somatic or germ cells; the most common vectors are viruses. Scientists manipulate the viral genome and thus introduce therapeutic genes to the target organ. Viruses, in this context, can cause adverse events such as toxicity, immune and inflammatory responses, as well as gene control and targeting issues. Alternative modalities being considered are complexes of DNA with lipids and proteins. Stem cells are primitive cells that have the capacity to self renew as well as to differentiate into 1 or more mature cell types. Pluripotent embryonic stem cells derived from the inner cell mass can develop into more than 200 different cells and differentiate into cells of the 3 germ cell layers. Because of their capacity of unlimited expansion and pluripotency, they are useful in regenerative medicine. Tissue or adult stem cells produce cells specific to the tissue in which they are found. They are relatively unspecialized and predetermined to give rise to specific cell types when they differentiate. The current review provides a summary of our current knowledge of stem cells and gene therapy as well as their clinical implications and related therapeutic options. PMID- 20858590 TI - A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance--part 12. PMID- 20858591 TI - Did backcrossing contribute to the origin of hybrid edible bananas? AB - BACKGROUND: Bananas and plantains (Musa spp.) provide a staple food for many millions of people living in the humid tropics. The cultivated varieties (cultivars) are seedless parthenocarpic clones of which the origin remains unclear. Many are believed to be diploid and polyploid hybrids involving the A genome diploid M. acuminata and the B genome M. balbisiana, with the hybrid genomes consisting of a simple combination of the parental ones. Thus the genomic constitution of the diploids has been classified as AB, and that of the triploids as AAB or ABB. However, the morphology of many accessions is biased towards either the A or B phenotype and does not conform to predictions based on these genomic formulae. SCOPE: On the basis of published cytotypes (mitochondrial and chloroplast genomes), we speculate here that the hybrid banana genomes are unbalanced with respect to the parental ones, and/or that inter-genome translocation chromosomes are relatively common. We hypothesize that the evolution under domestication of cultivated banana hybrids is more likely to have passed through an intermediate hybrid, which was then involved in a variety of backcrossing events. We present experimental data supporting our hypothesis and we propose a set of experimental approaches to test it, thereby indicating other possibilities for explaining some of the unbalanced genome expressions. Progress in this area would not only throw more light on the origin of one of the most important crops, but provide data of general relevance for the evolution under domestication of many other important clonal crops. At the same time, a complex origin of the cultivated banana hybrids would imply a reconsideration of current breeding strategies. PMID- 20858592 TI - The uneven phylogeny and biogeography of Erodium (Geraniaceae): radiations in the Mediterranean and recent recurrent intercontinental colonization. AB - BACKGROUND AND AIMS: The genus Erodium is a common feature of Mediterranean-type climates throughout the world, but the Mediterranean Basin has significantly higher diversity than other areas. The aim here is to reveal the biogeographical history of the genus and the causes behind the evolution of the uneven distribution. METHODS: Seventy-eight new nrITS sequences were incorporated with existing plastid data to explore the phylogenetic relationships and biogeography of Erodium using several reconstruction methods. Divergence times for major clades were calculated and contrasted with other previously published information. Furthermore, topological and temporal diversification rate shift analyses were employed using these data. KEY RESULTS: Phylogenetic relationships among species are widely congruent with previous plastid reconstructions, which refute the classical taxonomical classification. Biogeographical reconstructions point to Asia as the ancestral area of Erodium, arising approx. 18 MYA. Four incidences of intercontinental dispersal from the Mediterranean Basin to similar climates are demonstrated. Increases in diversification were present in two independent Erodium lineages concurrently. Two bursts of diversification (3 MYA and 0.69 MYA) were detected only in the Mediterranean flora. CONCLUSIONS: Two lineages diverged early in the evolution of the genus Erodium: (1) subgenus Erodium plus subgenus Barbata subsection Absinthioidea and (2) the remainder of subgenus Barbata. Dispersal across major water bodies, although uncommon, has had a major influence on the distribution of this genus and is likely to have played as significant role as in other, more easily dispersed, genera. Establishment of Mediterranean climates has facilitated the spread of the genus and been crucial in its diversification. Two, independent, rapid radiations in response to the onset of drought and glacial climate change indicate putative adaptive radiations in the genus. PMID- 20858593 TI - Cardiolipin: characterization of distinct oxidized molecular species. AB - Cardiolipin (CL) is a phospholipid predominantly found in the mitochondrial inner membrane and is associated structurally with individual complexes of the electron transport chain (ETC). Because the ETC is the major mitochondrial reactive oxygen species (ROS)-generating site, the proximity to the ETC and bisallylic methylenes of the PUFA chains of CL make it a likely target of ROS in the mitochondrial inner membrane. Oxidized cellular CL products, uniquely derived from ROS-induced autoxidation, could serve as biomarkers for the presence of the ROS and could help in the understanding of the mechanism of oxidative stress. Because major CL species have four unsaturated acyl chains, whereas other phospholipids usually have only one in the sn-2 position, characterization of oxidized CL is highly challenging. In the current study, we exposed CL, under aerobic conditions, to singlet oxygen (1O2), the radical initiator 2,2'-azobis(2-methylpropionamidine) dihydrochloride, or room air, and the oxidized CL species were characterized by HPLC-tandem mass spectrometry (MS/MS). Our reverse-phase ion-pair HPLC-MS/MS method can characterize the major and minor oxidized CL species by detecting distinctive fragment ions associated with specific oxidized species. The HPLC MS/MS results show that monohydroperoxides and bis monohydroperoxides were generated under all three conditions. However, significant amounts of CL dihydroperoxides were produced only by 1O2-mediated oxidation. These products were barely detectable from radical oxidation either in a liposome bilayer or in thin film. These observations are only possible due to the chromatographic separation of the different oxidized species. PMID- 20858594 TI - Small insertions and deletions (INDELs) in human genomes. AB - In this review, we focus on progress that has been made with detecting small insertions and deletions (INDELs) in human genomes. Over the past decade, several million small INDELs have been discovered in human populations and personal genomes. The amount of genetic variation that is caused by these small INDELs is substantial. The number of INDELs in human genomes is second only to the number of single nucleotide polymorphisms (SNPs), and, in terms of base pairs of variation, INDELs cause similar levels of variation as SNPs. Many of these INDELs map to functionally important sites within human genes, and thus, are likely to influence human traits and diseases. Therefore, small INDEL variation will play a prominent role in personalized medicine. PMID- 20858595 TI - A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice. AB - Autosomal dominant centronuclear myopathy (AD-CNM) is due to mutations in the gene encoding dynamin 2 (DNM2) involved in endocytosis and intracellular membrane trafficking. To understand the pathomechanisms resulting from a DNM2 mutation, we generated a knock-in mouse model expressing the most frequent AD-CNM mutation (KI Dnm2(R465W)). Heterozygous (HTZ) mice developed a myopathy showing a specific spatial and temporal muscle involvement. In the primarily and prominently affected tibialis anterior muscle, impairment of the contractile properties was evidenced at weaning and was progressively associated with atrophy and histopathological abnormalities mainly affecting mitochondria and reticular network. Expression of genes involved in ubiquitin-proteosome and autophagy pathways was up-regulated during DNM2-induced atrophy. In isolated muscle fibers from wild-type and HTZ mice, Dnm2 localized in regions of intense membrane trafficking (I-band and perinuclear region), emphasizing the pathophysiological hypothesis in which DNM2-dependent trafficking would be altered. In addition, HTZ fibers showed an increased calcium concentration as well as an intracellular Dnm2 and dysferlin accumulation. A similar dysferlin retention, never reported so far in congenital myopathies, was also demonstrated in biopsies from DNM2-CNM patients and can be considered as a new marker to orientate direct genetic testing. Homozygous (HMZ) mice died during the first hours of life. Impairment of clathrin-mediated endocytosis, demonstrated in HMZ embryonic fibroblasts, could be the cause of lethality. Overall, this first mouse model of DNM2-related myopathy shows the crucial role of DNM2 in muscle homeostasis and will be a precious tool to study DNM2 functions in muscle, pathomechanisms of DNM2-CNM and developing therapeutic strategies. PMID- 20858596 TI - Molecular networks implicated in speech-related disorders: FOXP2 regulates the SRPX2/uPAR complex. AB - It is a challenge to identify the molecular networks contributing to the neural basis of human speech. Mutations in transcription factor FOXP2 cause difficulties mastering fluent speech (developmental verbal dyspraxia, DVD), whereas mutations of sushi-repeat protein SRPX2 lead to epilepsy of the rolandic (sylvian) speech areas, with DVD or with bilateral perisylvian polymicrogyria. Pathophysiological mechanisms driven by SRPX2 involve modified interaction with the plasminogen activator receptor (uPAR). Independent chromatin-immunoprecipitation microarray screening has identified the uPAR gene promoter as a potential target site bound by FOXP2. Here, we directly tested for the existence of a transcriptional regulatory network between human FOXP2 and the SRPX2/uPAR complex. In silico searches followed by gel retardation assays identified specific efficient FOXP2 binding sites in each of the promoter regions of SRPX2 and uPAR. In FOXP2 transfected cells, significant decreases were observed in the amounts of both SRPX2 (43.6%) and uPAR (38.6%) native transcripts. Luciferase reporter assays demonstrated that FOXP2 expression yielded a marked inhibition of SRPX2 (80.2%) and uPAR (77.5%) promoter activity. A mutant FOXP2 that causes DVD (p.R553H) failed to bind to SRPX2 and uPAR target sites and showed impaired down-regulation of SRPX2 and uPAR promoter activity. In a patient with polymicrogyria of the left rolandic operculum, a novel FOXP2 mutation (p.M406T) was found in the leucine zipper (dimerization) domain. p.M406T partially impaired the FOXP2 regulation of SRPX2 promoter activity, whereas that of the uPAR promoter remained unchanged. Together with recently described FOXP2-CNTNAP2 and SRPX2/uPAR links, the FOXP2 SRPX2/uPAR network provides exciting insights into molecular pathways underlying speech-related disorders. PMID- 20858597 TI - Differences in RDS trafficking, assembly and function in cones versus rods: insights from studies of C150S-RDS. AB - Cysteine 150 of retinal degeneration slow protein (RDS) mediates the intermolecular disulfide bonding necessary for large RDS complex assembly and morphogenesis of the rim region of photoreceptor outer segments. Previously, we showed that cones have a different requirement for RDS than rods, but the nature of that difference was unclear. Here, we express oligomerization-incompetent RDS (C150S-RDS) in the cone-dominant nrl(-/-) mouse. Expression of C150S-RDS leads to dominant functional abnormalities, ultrastructural changes, biochemical anomalies and protein mislocalization in cones. These data suggest that RDS complexes in cones are more susceptible to disruption than those in rods, possibly due to structural or microenvironmental differences in the two cell types. Furthermore, our results suggest that RDS intermolecular disulfide bonding may be part of RDS inner-segment assembly in cones but not in rods. These data highlight significant differences in assembly, trafficking and function of RDS in rods versus cones. PMID- 20858598 TI - Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart. AB - Heart formation requires a highly balanced network of transcriptional activation of genes. The homeodomain transcription factor, Shox2, is essential for the formation of the sinoatrial valves and for the development of the pacemaking system. The elucidation of molecular mechanisms underlying the development of pacemaker tissue has gained clinical interest as defects in its patterning can be related to atrial arrhythmias. We have analyzed putative targets of Shox2 and identified the Bmp4 gene as a direct target. Shox2 interacts directly with the Bmp4 promoter in chromatin immunoprecipitation assays and activates transcription in luciferase-reporter assays. In addition, ectopic expression of Shox2 in Xenopus embryos stimulates transcription of the Bmp4 gene, and silencing of Shox2 in cardiomyocytes leads to a reduction in the expression of Bmp4. In Tbx5(del/+) mice, a model for Holt-Oram syndrome, and Shox2(-/-) mice, we show that the T-box transcription factor Tbx5 is a regulator of Shox2 expression in the inflow tract and that Bmp4 is regulated by Shox2 in this compartment of the embryonic heart. In addition, we could show that Tbx5 acts cooperatively with Nkx2.5 to regulate the expression of Shox2 and Bmp4. This work establishes a link between Tbx5, Shox2 and Bmp4 in the pacemaker region of the developing heart and thus contributes to the unraveling of the intricate interplay between the heart specific transcriptional machinery and developmental signaling pathways. PMID- 20858600 TI - A window into third-generation sequencing. AB - First- and second-generation sequencing technologies have led the way in revolutionizing the field of genomics and beyond, motivating an astonishing number of scientific advances, including enabling a more complete understanding of whole genome sequences and the information encoded therein, a more complete characterization of the methylome and transcriptome and a better understanding of interactions between proteins and DNA. Nevertheless, there are sequencing applications and aspects of genome biology that are presently beyond the reach of current sequencing technologies, leaving fertile ground for additional innovation in this space. In this review, we describe a new generation of single-molecule sequencing technologies (third-generation sequencing) that is emerging to fill this space, with the potential for dramatically longer read lengths, shorter time to result and lower overall cost. PMID- 20858599 TI - FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. AB - Complex I is the first and largest enzyme in the respiratory chain and is located in the inner mitochondrial membrane. Complex I deficiency is the most commonly reported mitochondrial disorder presenting in childhood, but the molecular basis of most cases remains elusive. We describe a patient with complex I deficiency caused by mutation of the molecular chaperone FOXRED1. A combined homozygosity mapping and bioinformatics approach in a consanguineous Iranian-Jewish pedigree led to the identification of a homozygous mutation in FOXRED1 in a child who presented with infantile-onset encephalomyopathy. Silencing of FOXRED1 in human fibroblasts resulted in reduced complex I steady-state levels and activity, while lentiviral-mediated FOXRED1 transgene expression rescued complex I deficiency in the patient fibroblasts. This FAD-dependent oxidoreductase, which has never previously been associated with human disease, is now shown to be a complex I specific molecular chaperone. The discovery of the c.1054C>T; p.R352W mutation in the FOXRED1 gene is a further contribution towards resolving the complex puzzle of the genetic basis of human mitochondrial disease. PMID- 20858601 TI - Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. AB - Lafora disease (LD) is an autosomal recessive progressive myoclonic epilepsy characterized by the presence of intracellular polyglucosan inclusions commonly known as Lafora bodies in many tissues, including the brain, liver and skin. The disease is caused by mutations in either EPM2A gene, encoding the protein phosphatase, laforin, or EPM2B gene, encoding the ubiquitin ligase, malin. But how mutations in these two genes cause disease pathogenesis is poorly understood. In this study, we show that the Lafora bodies in the axillary skin and brain stain positively for the ubiquitin, the 20S proteasome and the molecular chaperones Hsp70/Hsc70. Interestingly, mutant malins that are misfolded also frequently colocalizes with Lafora bodies in the skin biopsy sample of the respective LD patient. The expression of disease-causing mutations of malin in Cos-7 cells results in the formation of the profuse cytoplasmic aggregates that colocalize with the Hsp70/Hsc70 chaperones and the 20S proteasome. The mutant malin expressing cells also exhibit proteasomal dysfunction and cell death. Overexpression of Hsp70 decreases the frequency of the mutant malin aggregation and protects from mutant malin-induced cell death. These findings suggest that Lafora bodies consist of abnormal proteins, including mutant malin, targeted by the chaperones or the proteasome for their refolding or clearance, and failure of these quality control systems could lead to LD pathogenesis. Our data also indicate that the Hsp70 chaperone could be a potential therapeutic target of LD. PMID- 20858602 TI - Oligodendrocyte progenitor cell numbers and migration are regulated by the zebrafish orthologs of the NF1 tumor suppressor gene. AB - Neurofibromatosis type 1 is the most commonly inherited human cancer predisposition syndrome. Neurofibromin (NF1) gene mutations lead to increased risk of neurofibromas, schwannomas, low grade, pilocytic optic pathway gliomas, as well as malignant peripheral nerve sheath tumors and glioblastomas. Despite the evidence for NF1 tumor suppressor function in glial cell tumors, the mechanisms underlying transformation remain poorly understood. In this report, we used morpholinos to knockdown the two nf1 orthologs in zebrafish and show that oligodendrocyte progenitor cell (OPC) numbers are increased in the developing spinal cord, whereas neurons are unaffected. The increased OPC numbers in nf1 morphants resulted from increased proliferation, as detected by increased BrdU labeling, whereas TUNEL staining for apoptotic cells was unaffected. This phenotype could be rescued by the forced expression of the GTPase-activating protein (GAP)-related domain of human NF1. In addition, the in vivo analysis of OPC migration following nf1 loss using time-lapse microscopy demonstrated that olig2-EGFP(+) OPCs exhibit enhanced cell migration within the developing spinal cord. OPCs pause intermittently as they migrate, and in nf1 knockdown animals, they covered greater distances due to a decrease in average pause duration, rather than an increase in velocity while in motion. Interestingly, nf1 knockdown also leads to an increase in ERK signaling, principally in the neurons of the spinal cord. Together, these results show that negative regulation of the Ras pathway through the GAP activity of NF1 limits OPC proliferation and motility during development, providing insight into the oncogenic mechanisms through which NF1 loss contributes to human glial tumors. PMID- 20858603 TI - A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Maori, case and control sample sets. AB - Genetic variation in ABCG2 (rs2231142, Q141K), encoding a uric acid transporter, is associated with gout in diverse populations. The aim of this study was to examine a role for ABCG2 in gout susceptibility in New Zealand Maori, Pacific Island and Caucasian samples. Patients (n = 185, 173 and 214, for Maori, Pacific Island and Caucasian, respectively) satisfied the American College of Rheumatology gout classification criteria. The comparison samples comprised 284, 129 and 562 individuals, respectively, without gout. rs2231142 was genotyped and stratification accounted for using genomic control markers. Association of the minor allele of rs2231142 with gout was observed in the Pacific Island samples (OR = 2.80, P(STRAT) < 0.001 after accounting for effects of population structure), but not in the Maori samples (OR = 1.08, P(STRAT)= 0.70), with heterogeneity in association evident between the Maori and Pacific Island datasets (P(HET) = 0.001). A similar dichotomy in association was observed when samples were stratified into Western (Tonga, Samoa, Niue, Tokelau) versus Eastern Polynesian (Maori, Cook Island) origin (OR = 2.59, P(STRAT) < 0.001; OR = 1.12, P(STRAT)= 0.48, respectively; P(HET) = 0.005). Association with gout was observed in the Caucasian samples (OR = 2.20, P = 3.2 * 10(-8)). Unlike SLC2A9, which is a strong risk factor for gout in both Maori and Pacific Island people, ABCG2 rs2231142 has a strong effect only in people of Western Polynesian ancestry. Our results emphasize the need to account for sub-population differences when undertaking biomedical genetic research in a group defined by a geographical region and shared ancestry but characterized by migratory events that create bottlenecks and altered genetic structure in the founder populations. PMID- 20858604 TI - Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease. AB - The copy number variation in beta-defensin genes on human chromosome 8 has been proposed to underlie susceptibility to inflammatory disorders, but presents considerable challenges for accurate typing on the scale required for adequately powered case-control studies. In this work, we have used accurate methods of copy number typing based on the paralogue ratio test (PRT) to assess beta-defensin copy number in more than 1500 UK DNA samples including more than 1000 cases of Crohn's disease. A subset of 625 samples was typed using both PRT-based methods and standard real-time PCR methods, from which direct comparisons highlight potentially serious shortcomings of a real-time PCR assay for typing this variant. Comparing our PRT-based results with two previous studies based only on real-time PCR, we find no evidence to support the reported association of Crohn's disease with either low or high beta-defensin copy number; furthermore, it is noteworthy that there are disagreements between different studies on the observed frequency distribution of copy number states among European controls. We suggest safeguards to be adopted in assessing and reporting the accuracy of copy number measurement, with particular emphasis on integer clustering of results, to avoid reporting of spurious associations in future case-control studies. PMID- 20858606 TI - Contemporary management of carotid bifurcation atherosclerosis for stroke prevention: endarterectomy or stent? PMID- 20858605 TI - The human deafness-associated connexin 30 T5M mutation causes mild hearing loss and reduces biochemical coupling among cochlear non-sensory cells in knock-in mice. AB - Mutations in the GJB2 and GJB6 genes, respectively, coding for connexin26 (Cx26) and connexin30 (Cx30) proteins, are the most common cause for prelingual non syndromic deafness in humans. In the inner ear, Cx26 and Cx30 are expressed in different non-sensory cell types, where they largely co-localize and may form heteromeric gap junction channels. Here, we describe the generation and characterization of a mouse model for human bilateral middle/high-frequency hearing loss based on the substitution of an evolutionarily conserved threonine by a methionine residue at position 5 near the N-terminus of Cx30 (Cx30T5M). The mutation was inserted in the mouse genome by homologous recombination in mouse embryonic stem cells. Expression of the mutated Cx30T5M protein in these transgenic mice is under the control of the endogenous Cx30 promoter and was analysed via activation of the lacZ reporter gene. When probed by auditory brainstem recordings, Cx30(T5M/T5M) mice exhibited a mild, but significant increase in their hearing thresholds of about 15 dB at all frequencies. Immunolabelling with antibodies to Cx26 or Cx30 suggested normal location of these proteins in the adult inner ear, but western blot analysis showed significantly down-regulated the expression levels of Cx26 and Cx30. In the developing cochlea, electrical coupling, probed by dual patch-clamp recordings, was normal. However, transfer of the fluorescent tracer calcein between cochlear non-sensory cells was reduced, as was intercellular Ca(2+) signalling due to spontaneous ATP release from connexin hemichannels. Our findings link hearing loss to decreased biochemical coupling due to the point-mutated Cx30 in mice. PMID- 20858607 TI - Managing patients with symptomatic coronary and carotid artery disease. AB - The management of patients with concurrent carotid and cardiac disease remains enduringly controversial. National and international guidelines provide no real consensus, and there is poor-quality natural history data to inform the debate. Systematic reviews suggest that coronary artery bypass grafting (CABG) plus either staged or synchronous carotid endarterectomy (CEA) or carotid artery stenting (CAS) are associated with a 9% risk of procedural stroke or death. Given that about 90% of these procedures are performed in asymptomatic individuals, it is questionable whether any benefit is actually being conferred to the patient. A few contemporary studies have now shown that the risk of stroke in neurologically asymptomatic patients with a unilateral 70% to 99% stenosis undergoing an isolated CABG is extremely low. These data, therefore, challenge current practice and mandate a radical review of evidence and guidelines. PMID- 20858608 TI - Commentary on "Managing patients with symptomatic coronary and carotid disease". PMID- 20858609 TI - Trials in progress. AB - Nine completed randomized clinical trials (RCTs) failed to show any advantage of carotid angioplasty and stenting (CAS) over carotid surgery, whereas a number of larger trials were recently developed and are still ongoing or have just released interim data analysis. These new RCTs, giving emphasis to CAS carried out with appropriate credentialing and updated technology should be appropriately powered. According to last published data, carotid revascularization performed by highly qualified surgeons and interventionalists might be safe and effective; nevertheless, stroke is more likely after carotid stenting, whereas myocardial infarction is more likely after surgery, and the 2 risks need to be balanced in selecting the indication for treatment in specific patients. It is hoped that ongoing RCTs will clarify a couple of other issues: (1) the benefit of CAS in "asymptomatic" patients with respect not only to surgery but also to medical therapy alone and (2) which subgroups of patients at "average risk" would benefit more from CAS. Final results from pending RCTs are eagerly awaited to manage the common practice with CAS. PMID- 20858610 TI - Commentary on "Trials in progress". PMID- 20858611 TI - Carotid stenting trials: what have they taught us? AB - Carotid artery occlusion is one of the most frequently identified and one of the most treatable causes of ischemic strokes. Although carotid endarterectomy (CEA) is recognized as the gold standard for treating symptomatic, severe carotid stenosis, the development of carotid angioplasty and stenting (CAS) has encouraged investigations to demonstrate its safety and efficacy as a viable alternative to surgical management. Recent findings have emphasized patient selection as the key to the judicious application of CAS as well as CEA. More than proving CAS as a noninferior alternative to a surgical gold standard, trials exploring the relationship of various factors to patient outcomes may show that endovascular procedures will complement and improve on surgical techniques for treating a wide spectrum of patients suffering from carotid disease. PMID- 20858612 TI - Commentary on "Lessons learned from carotid stenting trials: patient selection is the key". PMID- 20858613 TI - Minimizing the complications of carotid endarterectomy. AB - As a primarily prophylactic operation, the efficacy of carotid endarterectomy (CEA) depends on attaining a complication rate as low as possible. Complications can be classified by time period (periprocedural and late) or type (local and systemic). The authors' purpose is to describe the incidence of complications associated with CEA, identify causative factors, and suggest steps that can be taken to minimize their occurrence. PMID- 20858614 TI - Commentary on "Minimizing the complications of carotid endarterctomy". PMID- 20858615 TI - Minimizing complications of carotid stenting. AB - Results of carotid artery stenting (CAS) are directly related to the experience and skills of the operator. The most dreadful complication of CAS is stroke. Analyzing the complications during the authors' own procedures, they came to the conclusion that most, if not all, of the complications are preventable. Attention to details is crucial, and it involves having the appropriate wires, catheters, balloons, stents, and cerebral protection devices readily available. PMID- 20858616 TI - Commentary on "making carotid stenting safer: look before you leap". PMID- 20858617 TI - Carotid endarterectomy or carotid artery stenting? Matching the patient to the intervention. AB - Extracranial carotid disease accounts for approximately 25% of ischemic strokes. Although carotid endarterectomy (CEA) is the established gold standard for carotid revascularization, carotid artery angioplasty and stenting (CAS) is continually developing into a safer and more efficacious method of stroke prevention and has gained popularity as an alternative to CEA. Recent trials have reported clinical equipoise between CEA and CAS. There are certain patient characteristics that can increase the risk of adverse outcomes for both CEA and CAS. Proper patient selection is the key to successful outcomes when deciding the optimal treatment for carotid stenosis. Patients must be individualized, and a specific risk-benefit ratio must be formulated for CEA, CAS, and best-medical therapy (BMT). Ultimately, optimizing medical therapy and using CEA and CAS as complementary therapies rather than competing ones will likely achieve the best patient outcomes. PMID- 20858618 TI - Commentary on "Carotid endarterectomy or carotid stenting? Matching the patient to the intervention". PMID- 20858619 TI - Clinical efficacy and safety of sunitinib after imatinib failure in Japanese patients with gastrointestinal stromal tumor. AB - BACKGROUND: Imatinib used to be the only effective treatment for advanced gastrointestinal stromal tumor. However, early clinical reports have shown that sunitinib has substantial anticancer activity in patients with advanced gastrointestinal stromal tumor after failure of imatinib. METHODS: Eighteen Japanese patients with advanced gastrointestinal stromal tumor who were resistant or intolerant to previous treatment with imatinib were entered into this study. These patients were given sunitinib orally, once daily at a 50-mg starting dose, in 6-week cycles with 4 weeks on and 2 weeks off treatment. Tumor response and drug safety were then evaluated. RESULTS: Median time-to-treatment failure was 207 days. Overall, 5.6% (1/18) of patients achieved partial response, 38.9% (7/18) had stable disease and 44.4% (8/18) had progressive disease. The common adverse events were hand-foot syndrome, liver dysfunction, fatigue, anorexia and hypertension. Mild anemia, leukocytopenia and neutropenia were also noted. Nine patients required dose reduction or cessation because of adverse events. CONCLUSIONS: This study demonstrates that sunitinib may be an effective agent for advanced gastrointestinal stromal tumor after failure of imatinib in clinical practice. PMID- 20858620 TI - Clinical and radiographic outcomes of image-based computer-assisted total knee arthroplasty: an evidence-based evaluation. AB - Conventional instrumentation systems have limited accuracy in determining the crucial landmarks needed for alignment in total knee arthroplasty (TKA). Given this, the image-based navigation system was introduced to improve the accuracy of implantation of components into the femur and tibia. PubMed, EMBASE, Web of Science, and Evidence-Based Medicine databases were electronically searched to identify eligible studies published until October 2008. A systematic review and meta-analysis of 6 randomized/quasi-randomized controlled trials that compared image-based navigation and conventional techniques was conducted. The operative time was longer in the navigation group in 3 studies. Moreover, there was a higher rate of achieving mechanical leg axis within the range of 3 degrees deviation in patients undergoing navigated TKA. However, all studies between the 2 groups were similar in range of motion, knee scores, and postoperative complication rates at the last follow-up. Overall, these short-term follow-up trials show that there were similar early clinical outcomes between image-based navigation and conventional techniques. PMID- 20858621 TI - Neutralisation of Dkk-1 protects from systemic bone loss during inflammation and reduces sclerostin expression. AB - Introduction Inflammation is a major risk factor for systemic bone loss. Proinflammatory cytokines like tumour necrosis factor (TNF) affect bone homeostasis and induce bone loss. It was hypothesised that impaired bone formation is a key component in inflammatory bone loss and that Dkk-1, a Wnt antagonist, is a strong inhibitor of osteoblast-mediated bone formation. METHODS: TNF transgenic (hTNFtg) mice were treated with neutralising antibodies against TNF, Dkk-1 or a combination of both agents. Systemic bone architecture was analysed by bone histomorphometry. The expression of beta-catenin, osteoprotegerin and osteocalcin was analysed. In vitro, primary osteoblasts were stimulated with TNF and analysed for their metabolic activity and expression of Dkk-1 and sclerostin. Sclerostin expression and osteocyte death upon Dkk-1 blockade were analysed in vivo. RESULTS: Neutralisation of Dkk-1 completely protected hTNFtg mice from inflammatory bone loss by preventing TNF-mediated impaired osteoblast function and enhanced osteoclast activity. These findings were accompanied by enhanced skeletal expression of beta-catenin, osteocalcin and osteoprotegerin. In vitro, TNF rapidly increased Dkk-1 expression in primary osteoblasts and effectively blocked osteoblast differentiation. Moreover, blockade of Dkk-1 not only rescued impaired osteoblastogenesis but also neutralised TNF-mediated sclerostin expression in fully differentiated osteoblasts in vitro and in vivo. CONCLUSIONS: These findings indicate that low bone formation and expression of Dkk-1 trigger inflammatory bone loss. Dkk-1 blocks osteoblast differentiation, induces sclerostin expression and leads to osteocyte death. Inhibition of Dkk-1 may thus be considered as a potent strategy to protect bone from inflammatory damage. PMID- 20858622 TI - Rheumatoid arthritis and herpes zoster: risk and prevention in those treated with anti-tumour necrosis factor therapy. PMID- 20858623 TI - Hyperuricaemia and gout: state of the art and future perspectives. AB - Major progress has been made in the past decade in understanding the pathogenesis and treatment of gout. These advances include identification of the genetic and environmental risk factors for gout, recognition that gout is an important risk factor for cardiovascular disease, elucidation of the pathways regulating the acute gout attack and the development of novel therapeutic agents to treat both the acute and chronic phases of the disease. This review summarises these advances and highlights the research agenda for the next decade. PMID- 20858625 TI - Variant CJD: where has it gone, or has it? PMID- 20858626 TI - Tourette's syndrome and other tic disorders. AB - Tourette's syndrome is a neuropsychiatric disorder characterised by motor and phonic tics. Although tics are common in children, only about 1% of those affected meet the criteria for Tourette's syndrome, and many are not disabled by it. Associated problems such as attention deficit hyperactivity disorder and obsessive-compulsive disorders can often be more disabling than the tics themselves. People with Tourette's tend to be worst in their teenage years but improve in adulthood. The cause is unknown but there are strong genetic factors. Treatment should be aimed at minimising disability and includes social, psychological and biological approaches. PMID- 20858627 TI - Which antibody and which cancer in which paraneoplastic syndromes? AB - Paraneoplastic neurological syndromes can be associated with the presence of onconeural antibodies. These antibodies are the result of an immune response against a tumour that is ectopically expressing a neuronal antigen. The 'classical' onconeural antibodies (anti-Hu, Yo, Ma2, CRMP-5, amphiphysin and Ri) are directed against intracellular antigens and are strongly associated with underlying malignancy. By contrast, onconeural antibodies directed against cell surface antigens (eg, anti-NMDA, VGKC, AChR) have a weaker tumour association. This article gives a practical overview of the tumour associations, and the neurological associations, of the onconeural antibodies. There is also guidance on how to investigate occult malignancy in antibody positive cases. PMID- 20858628 TI - When confronted by a patient with the radiologically isolated syndrome. AB - As MRI becomes ever easier to access, it is clear that there is a group of patients, scanned for a wide range of symptoms, where the imaging looks inflammatory, despite the discordance with the clinical presentation. This is the so-called radiologically isolated syndrome, which can be a source of anxiety and difficulty for both patient and clinician. The evidence for its relationship to the clinically isolated syndrome and therefore to multiple sclerosis is presented, and I will describe a pragmatic approach to managing the situation. PMID- 20858629 TI - Reading epilepsy. AB - Reading epilepsy is a rare epilepsy syndrome triggered by language related activity, in particular reading. Here we describe a patient with reflex seizures brought on specifically by reading in Arabic. The types of reading epilepsy, their typical clinical features, probable pathophysiology and management are discussed. PMID- 20858630 TI - Coming into contact with the right people. PMID- 20858631 TI - Whither grand rounds? PMID- 20858633 TI - Ethiopia. PMID- 20858632 TI - The dark night. PMID- 20858634 TI - Sleep disorders in neurology. PMID- 20858635 TI - Conditions causing gemcitabine crystallization. AB - INTRODUCTION: Intravesical delivery of chemotherapy agents is used very commonly for the treatment of superficial bladder cancer. We recently completed a phase II study of intravesical gemcitabine in which an alkaline adjusted gemcitabine preparation was used initially, based on very early phase I studies. However, crystallization was noted in some of the pre-prepared syringes, which prompted us to investigate the conditions under which gemcitabine crystallized. METHODS: Gemcitabine was prepared in syringes in triplicate and conditions were varied with respect to pH, temperature, and duration. Samples were observed for up to 48 h for the development of crystallization. High-performance liquid chromatography analysis of gemcitabine concentrations was undertaken for all samples. RESULTS: Crystallization of gemcitabine was favored under conditions of bicarbonate treatment and lowering of temperature. However, the process was reversible, as demonstrated by recovery of gemcitabine concentrations in samples brought back to room temperature. Crystallization resulted in reduction of gemcitabine concentrations in the pre-prepared syringes. CONCLUSIONS: Gemcitabine solutions may be associated with crystallization if the native pH is increased with the addition of sodium bicarbonate, and samples are stored in a cold environment. PMID- 20858636 TI - Pregnancy a short time after multimodal therapy for bilateral breast cancer: a case report and review of literature. AB - Pregnancy occurring after multimodal therapy in a woman with breast cancer with a 1-year follow-up period is a relatively rare condition and has been defined as pregnancy-associated breast cancer. A patient can become pregnant after chemotherapy for breast cancer while she is on tamoxifen. However, the effects of tamoxifen on fetus and on the course of the pregnancy are still unknown. Here, we present a 39-year-old woman treated with chemotherapy and radiotherapy for bilateral breast cancer, and who became pregnant while taking tamoxifen. PMID- 20858637 TI - Regional landfills methane emission inventory in Malaysia. AB - The decomposition of municipal solid waste (MSW) in landfills under anaerobic conditions produces landfill gas (LFG) containing approximately 50-60% methane (CH(4)) and 30-40% carbon dioxide (CO(2)) by volume. CH(4) has a global warming potential 21 times greater than CO(2); thus, it poses a serious environmental problem. As landfills are the main method for waste disposal in Malaysia, the major aim of this study was to estimate the total CH(4) emissions from landfills in all Malaysian regions and states for the year 2009 using the IPCC, 1996 first order decay (FOD) model focusing on clean development mechanism (CDM) project applications to initiate emission reductions. Furthermore, the authors attempted to assess, in quantitative terms, the amount of CH(4) that would be emitted from landfills in the period from 1981-2024 using the IPCC 2006 FOD model. The total CH(4) emission using the IPCC 1996 model was estimated to be 318.8 Gg in 2009. The Northern region had the highest CH(4) emission inventory, with 128.8 Gg, whereas the Borneo region had the lowest, with 24.2 Gg. It was estimated that Pulau Penang state produced the highest CH(4) emission, 77.6 Gg, followed by the remaining states with emission values ranging from 38.5 to 1.5 Gg. Based on the IPCC 1996 FOD model, the total Malaysian CH( 4) emission was forecast to be 397.7 Gg by 2020. The IPCC 2006 FOD model estimated a 201 Gg CH(4) emission in 2009, and estimates ranged from 98 Gg in 1981 to 263 Gg in 2024. PMID- 20858638 TI - Towards zero waste: a case study in the City of Tshwane. AB - Tshwane is presently landfilling all of its municipal solid waste (MSW) with no pre-processing or minimization efforts. This is a result of the available capacity of its existing landfills, thought to be able to satisfy the city's needs for, at most, the next 10 years. It is possible that the authorities will not wake up to the problem before it is too late. This study addresses these challenges. This study first identified and evaluated technologies available in developed countries for processing the various components of the MSW stream, appropriate to local conditions, as an alternative to landfilling, to ensure that these components will be either reused, recycled or rendered harmless to the environment before disposal. Then most appropriate technologies for Tshwane were selected and assembled into an optimal configuration to achieve a zero waste situation in Tshwane within a decade or two. This represents a significant change in MSW management in Tshwane, from total landfill to zero waste to landfill. Although the study focused on Tshwane, it can be argued that the findings can be implemented in any other South African municipality, and even implemented in other emerging countries. PMID- 20858639 TI - Globalisation and antibiotic resistance. PMID- 20858642 TI - A new professional code in sports medicine. PMID- 20858640 TI - UN chief urges world leaders to put development goals back on track. PMID- 20858643 TI - Global elimination of mother to child HIV transmission is now achievable, say agencies. PMID- 20858644 TI - Allowing migrant health workers to work back home would help offset "brain drain". PMID- 20858645 TI - European Union leads way on e-health, but obstacles remain. PMID- 20858646 TI - Acute toxicity and mutagenesis of three metabolites mixture of nitrobenzene in mice. AB - Nitrobenzene is a synthetic compound, more than 95% of which is used in the production of aniline. Nitrobenzene has been demonstrated to be substantially metabolized to p-Nitrophenol, p-Aminophenol and p-Nitroaniline in food animals (e.g., bovines, fowls). There have been no studies on the acute toxicity and the mutagenesis of the mixture of the three metabolites mentioned above. The aim of the present study is to testify the acute toxicity and the mutagenesis of the three metabolites mixture. Seventy Kunming mice (half male, half female) received an intragastric administration exposure to metabolites-containing suspension of 750, 638, 542, 461, 392, 333 mg kg(-1) body weight and 0.5% sodium carboxymethyl cellulose (control), followed by a 14-day observation. The medial lethal dose (LD(50)) concentration for nitrobenzene metabolites mixture in this study was 499.92 mg/kg. Their mutagenic toxicology was studied through micronucleus and sperm abnormality test. Kunming mice were twice intragastrically exposed to 1/5 LD(50), 1/10 LD(50), 1/20 LD(50) mg kg(-1) nitrobenzene metabolites-containing suspension spaced 24-h apart. Cyclophosphamide, pure water and sodium carboxymethyl cellulose served as doses of the positive group, the negative group and the solvent control group, respectively. The incidence of micronucleus and sperm abnormality increased significantly in the 1/5 LD(50) and 1/10 LD(50) group compared with the negative and solvent control group. A dose-related increase in the incidence of micronucleus and sperm abnormality was noted. In conclusion, the three metabolites mixture of nitrobenzene was secondary toxicity and mutagenic substances in mice. PMID- 20858647 TI - Effects of light smoking on extra-high-frequency auditory thresholds in young adults. AB - There have been few reports showing a correlation between hearing levels and life style in young people. In this study, we succeeded in sensitively evaluating hearing levels in 51 young male adults of 21-23 years in age by 12 k Hz extra high-frequency auditory thresholds, which cannot be measured by usual audiometry devices for clinical use. Noise exposure, alcohol consumption and sleeping time did not affect hearing levels in young adults. Auditory thresholds of 12 kHz frequency in smokers were significantly (p < 0.05) higher than those in non smokers, while there were no differences in 1 kHz, 4 kHz and 8 kHz frequencies of hearing levels between smokers and non-smokers. Since the Brinkman Index (BI; cigarettes/day multiplied by number of years) of smokers in this study was from 12 to 60, our results suggest that even light smoking of less than 20 cigarettes/day for 3 years can result in the development of hearing loss of 12 kHz frequency in young adults. Binary logistic regression analysis again showed a correlation between hearing loss (>= 40 dB of auditory thresholds in 12 kHz frequency) and light smoking (12 <= BI <= 60). Thus, this study showed that auditory threshold at 12 kHz frequency could be a sensitive marker for hearing in young adults. More importantly, we for the first time provided epidemiological evidence that light smoking might affect hearing level at 12 kHz frequency and revealed a new risk of light smoking. PMID- 20858648 TI - Effects of Melissa officinalis L. on oxidative status and DNA damage in subjects exposed to long-term low-dose ionizing radiation. AB - The aim of this study was to determine the capability of Melissa officinalis L. (Lemon balm) infusion on improvement of oxidative stress status in radiology staff that were exposed to persistent low-dose radiation during work. The study was a before-after clinical trial performed on 55 radiology staff. They were asked to drink Lemon balm infusion which was prepared like a tea bag twice daily (1.5 g/100 mL) for 30 days. In the plasma, lipid peroxidation, DNA damage, catalase, superoxide dismutase, myeloperoxidase, and glutathione peroxidase activity were measured before and after using Lemon balm infusion.Use of Lemon balm infusion in radiology unit workers resulted in a significant improvement in plasma levels of catalase, superoxide dismutase, and glutathione peroxidase and a marked reduction in plasma DNA damage, myeloperoxidase, and lipid peroxidation. It is concluded that infusion of Lemon balm markedly improve oxidative stress condition and DNA damage in radiology staff when used as a dietary supplement for radiation protection. PMID- 20858649 TI - Oxidative stress response in Nile tilapia (Oreochromis niloticus) exposed to textile mill effluent. AB - Textile mill effluent is an important pollution factor because of its organic and inorganic substances content. In this study, toxic effects of textile mill effluent on fish Oreochromis niloticus were investigated by using antioxidant enzymes and lipid peroxidation (LPO) responses. Superoxide dismutase (SOD), catalase (CAT) enzyme activities and lipid peroxidation by means of thiobarbituric reactive substances (TBARS) level were measured in liver and gill tissues of fish. The fish were exposed to non-lethal concentrations (0.1%, 1% and 10%) of textile mill effluent for 15, 30 and 45 days. In control group, fish were left in aquariums containing tap water without chlorine. As a result, the activities of SOD, CAT enzymes and level of TBARS in the liver and gill increased in 15, 30 and 45 days after 1% and 10% doses application. PMID- 20858650 TI - Factors affecting exhaled carbon monoxide levels in coffeehouses in the Western Black Sea region of Turkey. AB - The aim of this study was to evaluate indoor air quality and factors affecting expired carbon monoxide (CO) levels in a coffeehouse environment. This cross sectional study was conducted at 16 randomly selected coffeehouses in Duzce, Turkey, during November 2007 to March 2008. A total of 547 people, average age 46.72 +/- 17.03 (19-82) years, participated. The selected coffeehouses were divided into four groups: (1) smoking, (2) nonsmoking, (3) old-style and (iv) new style coffeehouses. Prior to entering the coffeehouse, exhaled CO levels in smokers (mean 21.17 +/- 6.73 parts per million [ppm]) were significantly higher than those for nonsmokers (6.51 +/- 4.56 ppm; p < 0.001). Measurements taken after 2 hours in the coffeehouse also showed significantly higher CO concentrations for smokers (22.72 +/- 5.31 ppm), compared to nonsmokers (6.51 +/- 4.56 ppm; p < 0.001). It was determined that CO levels inside coffee shops were above the WHO guidelines. Exhaled CO levels in nonsmokers are influenced by the ambient CO levels as a result of the use of cigarettes in coffeehouses in addition to the structure of coffeehouses. PMID- 20858651 TI - Patterns of cognitive decline, conversion rates, and predictive validity for 3 models of MCI. AB - Our objective was to compare the predictive ability of different models of mild cognitive impairment (MCI) as a marker of incipient dementia in a longitudinal population-based Canadian sample. We examined the use of existing, well documented MCI criteria using data from persons who underwent a clinical examination in the second wave of the Canadian Study of Health and Aging (CSHA). Demographic characteristics, average neuropsychological test performance, and sample frequencies and conversion rates were calculated for each classification. Receiver operating characteristic (ROC) analyses were employed to assess the predictive power of each cognitive classification. The highest sample frequencies and conversion rates were associated with case definitions of multiple-domain MCI. The only diagnostic criteria to significantly predict dementia 5 years later was the cognitive impairment no dementia (CIND)-2 case definition. More restrictive MCI case definitions fail to address the varying temporal increases in decline across different cognitive domains in the progression from normal cognitive functioning and dementia. PMID- 20858653 TI - Aggressive tumoral calcinosis in an infant thoracotomy scar. AB - The authors report a case of tumoral calcinosis (TC) in a six-month-old infant, which developed within the thoracotomy scar from previous aortic coarctation repair. After initial resection of the lesion, the child returned with a large mass of TC restricting movement of the left shoulder. Repeated total resection was successful with no recurrence in 12 months' follow-up. This is the first report of TC that developed in a postoperative scar and is unusual in its recurrence and aggressive growth. Pathogenesis, diagnosis and treatment of this rare event is discussed. PMID- 20858654 TI - The use of video-assisted thoracic surgery in the management of Pancoast tumors. AB - We describe our experience using video-assisted thoracic surgery (VATS) as an adjunct to the surgical management of Pancoast tumors. Between March 2004 and November 2009, 13 patients with Pancoast tumors were included in this study. Surgery was performed by positioning the patient to allow either an anterior or a posterior thoracotomy. VATS was employed to explore the pleural cavity, to optimize the surgical access and as an assistance during surgical resection. Three patients with pleural carcinosis at thoracoscopy did not undergo further surgery. Seven lobectomies and three wedge resections were performed with an en bloc chest-wall resection and mediastinal lymphadenectomy. The surgical approaches were a transmanubrial L-shaped incision (n=1), a posterior thoracotomy (n=8), and a combined transmanubrial and posterior thoracotomy (n=1) which were dictated by the thoracoscopic findings. The average operative time was 200 min (range: 185-280 min); the average blood loss was 325 ml (range: 250-1200 ml). The average hospitalization was nine days (range: 8-30 days). Our study indicates that VATS may be an effective and safe adjunct to standard surgical resection in patients with Pancoast tumors. It reduces the magnitude of surgery, either by sparing the patient a useless thoracotomy or, by optimizing the site of the thoracotomy. It may also have a significant educational role. PMID- 20858652 TI - Review: disruption of the postsynaptic density in Alzheimer's disease and other neurodegenerative dementias. AB - The most common causes of neurodegenerative dementia include Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). We believe that, in all 3, aggregates of pathogenic proteins are pathological substrates which are associated with a loss of synaptic function/plasticity. The synaptic plasticity relies on the normal integration of glutamate receptors at the postsynaptic density (PSD). The PSD organizes synaptic proteins to mediate the functional and structural plasticity of the excitatory synapse and to maintain synaptic homeostasis. Here, we will discuss the relevant disruption of the protein network at the PSD in these dementias and the accumulation of the pathological changes at the PSD years before clinical symptoms. We suggest that the functional and structural plasticity changes of the PSD may contribute to the loss of molecular homeostasis within the synapse (and contribute to early symptoms) in these dementias. PMID- 20858655 TI - Intra-cardiac metastasis from testicular non-seminoma germ cell tumour; to resect or not to resect. AB - Metastatic heart tumours are rare. Most arise from lung, breast and renal cancerous primaries, soft-tissue sarcoma and malignant melanoma. We report the case of a 32-year-old policeman who presented to the emergency department very short of breath with a five-week history of weight loss and malaise. He was noted to have a mass in his right testicle, numerous 2-3 cm round shadows on chest X ray (CXR) and a large mass within the right ventricular cavity. After much informed debate, the patient was treated solely with chemotherapy with the expectation of cure. We set out this argument and recommendations for future patients with this unusual problem. PMID- 20858656 TI - Extended resections for primary lung cancer with oncological principles. PMID- 20858657 TI - Re: Primary cardiac synovial sarcoma. PMID- 20858658 TI - One more case of spontaneous bleeding from the ascending aorta during vacuum assisted closure treatment. PMID- 20858659 TI - Antithrombotic therapy in patients with left ventricular assist devices: a critical view of the data and lessons from the past. PMID- 20858660 TI - Left atrial function assessed by trans-thoracic echocardiography in patients treated by ablation for a lone paroxysmal atrial fibrillation. AB - AIMS: Atrial fibrillation (AF) may induce three kinds of atrial remodelling: morphological, contractile, and electrical. Maintain of sinus rhythm is usually associated with left atrial (LA) volume decrease, but little is known about the evolution of its mechanical properties. We sought to explore LA mechanical and morphological remodelling in patients with lone paroxysmal-AF treated by catheter ablation (CA). METHODS AND RESULTS: We prospectively included 31 patients (56.4 +/- 10 years). We also followed 15 age- and gender-matched controls to get normal values. Each patient had a complete echocardiography at baseline and at 3-month and 1-year follow-up. LA-anatomical reverse remodelling was documented: indexed LA volume decreased from 39 mL/m(2) at baseline to 31 mL/m(2) at 1 year (P < 0.001). However, it remained larger than controls (31 vs. 23 mL/m(2), P = 0.001). LA compliance improved (LA lateral systolic peaks of strain = 50 vs. 31%, P < 0.05) without reaching controls values as estimated by 50 vs. 81%, P < 0.05). LA contractility increased as highlighted by A'-peak velocity (10 cm/s at 1Y-F/up vs. 7.5 at baseline, P = 0.01) and LA late diastolic peaks of strain rate (septal: -3 vs. -1 s(-1), lateral: -3 vs. -1.4 s(-1), P < 0.05). We show a functional remodelling at 1 year, with most contractile parameters being comparable to controls, whereas LA compliance remains significantly altered. CONCLUSION: AF-CA could reverse LA anatomical and functional remodelling. Despite improvement, LA compliance remains altered after 1 year, probably reflecting irreversible fibrosis. PMID- 20858661 TI - Overstaging of cartilage invasion by multidetector CT scan for laryngeal cancer and its potential effect on the use of organ preservation with chemoradiation. AB - OBJECTIVE: The two currently acceptable treatment options for locally advanced laryngeal cancer are total laryngectomy and organ preservation using chemoradiation. To facilitate therapeutic decision making, the accurate pre treatment evaluation of cartilage invasion is of paramount importance. The purpose of this study was to evaluate the positive predictive value (PPV) and negative predictive value (NPV) of detecting neoplastic cartilage invasion in laryngeal cancer patients using fast-speed multidetector CT (MDCT). METHODS: 61 consecutive patients with clinically staged T3 or T4 squamous cell carcinoma of the larynx or hypopharynx who underwent total laryngectomy were analysed. All patients had MDCT of the neck within 2 weeks prior to surgery. Central radiographic and pathological review was performed in an attempt to correlate findings. MDCT invasion of cartilage was graded based on objective criteria. RESULTS: MDCT scan was found to have a PPV of 78% and an NPV of 100% for detection of invasion through cartilage, with sensitivity being 100% and specificity 96%. For detection of any cartilage invasion (minor, major or through cartilage invasion), PPV and NPV were 63% and 92%, respectively. The sensitivity was 85% and specificity was 75%. For the detection of tumour invasion through cartilage or major cartilage invasion, MDCT scan had a PPV of 53% and an NPV of 95%. 47% (9/19) patients were down-staged from T4 to T3 after central pathology review. CONCLUSION: The low PPV for cartilage destruction using MDCT suggests that a significant proportion of patients who were treated by total laryngectomy could have been appropriately offered organ preservation if more accurately staged at initial diagnosis. PMID- 20858662 TI - Development, implementation and evaluation of a dedicated metal artefact reduction method for interventional flat-detector CT. AB - The purpose of this study was to develop, implement and evaluate a dedicated metal artefact reduction (MAR) method for flat-detector CT (FDCT). The algorithm uses the multidimensional raw data space to calculate surrogate attenuation values for the original metal traces in the raw data domain. The metal traces are detected automatically by a three-dimensional, threshold-based segmentation algorithm in an initial reconstructed image volume, based on twofold histogram information for calculating appropriate metal thresholds. These thresholds are combined with constrained morphological operations in the projection domain. A subsequent reconstruction of the modified raw data yields an artefact-reduced image volume that is further processed by a combining procedure that reinserts the missing metal information. For image quality assessment, measurements on semi anthropomorphic phantoms containing metallic inserts were evaluated in terms of CT value accuracy, image noise and spatial resolution before and after correction. Measurements of the same phantoms without prostheses were used as ground truth for comparison. Cadaver measurements were performed on complex and realistic cases and to determine the influences of our correction method on the tissue surrounding the prostheses. The results showed a significant reduction of metal-induced streak artefacts (CT value differences were reduced to below 22 HU and image noise reduction of up to 200%). The cadaver measurements showed excellent results for imaging areas close to the implant and exceptional artefact suppression in these areas. Furthermore, measurements in the knee and spine regions confirmed the superiority of our method to standard one-dimensional, linear interpolation. PMID- 20858663 TI - Pre-operative evaluation of peritoneal deposits using multidetector computed tomography in ovarian cancer. AB - OBJECTIVE: In the management of epithelial ovarian cancer (EOC), the identification of peritoneal deposits is the most important prognostic factor. We conducted a prospective study to evaluate the role of multidetector CT (MDCT) in identifying peritoneal deposits pre-operatively. METHODS: 38 previously untreated patients (median age 50 years; range 26-70 years) were evaluated with contrast enhanced MDCT of the abdomen and pelvis. All CT scans were performed on a four slice MDCT scanner with thin-slice image acquisition. Multiplanar coronal, sagittal or oblique images were constructed and all images were reviewed by at least two radiologists. The extent of disease was determined and mapped for all areas of the abdomen and pelvis. CT scans were reviewed and compared with surgical findings. Peritoneal deposits and thickening were separately noted for each of the nine segments of the abdomen and pelvis (i.e. bilateral hypochondria, bilateral lumbar, bilateral iliac fossa, epigastrium, umbilical region and hypogastrium) and were mainly used to determine the accuracy of MDCT in the depiction of peritoneal carcinomatosis. RESULTS: Sensitivity, specificity, positive and negative predictive values and accuracy of CT in the detection of peritoneal deposits were similar to those reported in the literature. The most common anatomical sites to have peritoneal deposits were the pouch of Douglas (18 cases) and the right subdiaphragmatic region (18 cases). CONCLUSION: Despite the improved scanning technology, image reconstruction and viewing ability of MDCT, its overall accuracy for the detection of peritoneal deposits is not significantly improved when compared with conventional CT; however, MDCT is useful in the assessment of disease at specific locations in the abdomen and pelvis. PMID- 20858664 TI - Comparison of the helical tomotherapy against the multileaf collimator-based intensity-modulated radiotherapy and 3D conformal radiation modalities in lung cancer radiotherapy. AB - OBJECTIVES: The aim of this study was to compare three-dimensional (3D) conformal radiotherapy and the two different forms of IMRT in lung cancer radiotherapy. METHODS: Cases of four lung cancer patients were investigated by developing a 3D conformal treatment plan, a linac MLC-based step-and-shoot IMRT plan and an HT plan for each case. With the use of the complication-free tumour control probability (P(+)) index and the uniform dose concept as the common prescription point of the plans, the different treatment plans were compared based on radiobiological measures. RESULTS: The applied plan evaluation method shows the MLC-based IMRT and the HT treatment plans are almost equivalent over the clinically useful dose prescription range; however, the 3D conformal plan inferior. At the optimal dose levels, the 3D conformal treatment plans give an average P(+) of 48.1% for a effective uniform dose to the internal target volume (ITV) of 62.4 Gy, whereas the corresponding MLC-based IMRT treatment plans are more effective by an average DeltaP(+) of 27.0% for a Delta effective uniform dose of 16.3 Gy. Similarly, the HT treatment plans are more effective than the 3D conformal plans by an average DeltaP(+) of 23.8% for a Delta effective uniform dose of 11.6 Gy. CONCLUSION: A radiobiological treatment plan evaluation can provide a closer association of the delivered treatment with the clinical outcome by taking into account the dose-response relations of the irradiated tumours and normal tissues. The use of P - effective uniform dose diagrams can complement the traditional tools of evaluation to compare and effectively evaluate different treatment plans. PMID- 20858666 TI - Contributing to an important debate or increasing the news/death ratio? PMID- 20858665 TI - Intensity-modulated radiotherapy increases dose to the brachial plexus compared with conventional radiotherapy for head and neck cancer. AB - OBJECTIVE: The preferential use of intensity-modulated radiotherapy (IMRT) over conventional radiotherapy (CRT) in the treatment of head and neck cancer has raised concerns regarding dose to non-target tissue. The purpose of this study was to compare dose-volume characteristics with the brachial plexus between treatment plans generated by IMRT and CRT using several common treatment scenarios. METHOD: The brachial plexus was delineated on radiation treatment planning CT scans from 10 patients undergoing IMRT for locally advanced head and neck cancer using a Radiation Therapy Oncology Group-endorsed atlas. No brachial plexus constraint was used. For each patient, a conventional three-field shrinking-field plan was generated and the dose-volume histogram (DVH) for the brachial plexus was compared with that of the IMRT plan. RESULTS: The mean irradiated volumes of the brachial plexus using the IMRT vs the CRT plan, respectively, were as follows: V50 (18+/-5 ml) vs (11+/-6 ml), p = 0.01; V60 (6+/ 4 ml) vs (3+/-3 ml), p = 0.02; V66 (3+/-1 ml) vs (1+/-1 ml), p = 0.04, V70 (0+/-1 ml) vs (0+/-1 ml), p = 0.68. The maximum point dose to the brachial plexus was 68.9 Gy (range 62.3-78.7 Gy) and 66.1 Gy (range 60.2-75.6 Gy) for the IMRT and CRT plans, respectively (p = 0.01). CONCLUSION: Dose to the brachial plexus is significantly increased among patients undergoing IMRT compared with CRT for head and neck cancer. Preliminary studies on brachial plexus-sparing IMRT are in progress. PMID- 20858667 TI - What should public health research focus on? Comments from a decision analytic perspective. PMID- 20858668 TI - Moderate pandemic, not many dead--learning the right lessons in Europe from the 2009 pandemic. PMID- 20858669 TI - Potential for greater coherence in EUROPEAN influenza surveillance. PMID- 20858671 TI - Anticoagulation for atrial fibrillation: should warfarin be temporarily stopped or continued after acute cardioembolic stroke? AB - Despite anticoagulation for atrial fibrillation, some patients still suffer an ischaemic stroke. The issue of whether to stop or continue warfarin, or possibly to reverse the anticoagulation is an area of uncertainty. Continued anticoagulation may, however, increase haemorrhagic transformation of the infarct. In this article we review the published evidence in an attempt to quantify the risks and benefits of each treatment strategy and identify areas for further research. PMID- 20858672 TI - Examining three frailty conceptualizations in their ability to predict negative outcomes for home-care clients. PMID- 20858674 TI - In situ measurements of thoron exhalation rate in Okinawa, Japan. AB - Thoron exhalation rates from the ground surface were measured at 57 sites on Okinawa Island, Japan, using a ZnS(Ag) scintillation detector equipped with photomultiplier. The arithmetic means +/- SD, median +/- SD, minimum and maximum of the rates (unit: Bq m(-2) s(-1)) were estimated to be 1.9 +/- 1.4, 1.6 +/- 0.3, 0.04 and 6.2, respectively. The soils distributed on the island are generally classified into dark red soils, residual regosols, as well as red and yellow soils. While it was assumed that the soils were originated from the bedrock, recent studies suggested that the main material of dark red soils is the East Asian eolian dust. In the dark red soils area, the exhalation rate is relatively higher than that in the other areas. This suggested that the eolian dust was an enhancer for the environmental thoron concentration on Okinawa Island. PMID- 20858675 TI - Anomalous results with the widely used NRPB/SSI-type passive radon dosemeter. AB - In an industrial hall, with large variations of radon concentration within minutes, simultaneous measurements were done with two types of passive radon detectors and an active radon measuring device. The widely used passive radon detector of the National Radiological Protection Board (NRPB) [Health Protection Agency (former NRPB) (HPA)]/Statens stralskyddsinstitut (Swedish Radiation Protection Institute) (SSI) type produced anomalous results, seemingly uncorrelated to the radon concentration which was in the order of hundreds of becquerels per metre, usually underestimating but occasionally overestimating. We tried to reproduce similar exposure characteristics in our laboratory, but failed to reproduce the anomalous readings. We suspected, but could not prove, that the anomalous results were due to the combination of high radon concentration gradients, with pressure-driven air exchange between the inside of the detector holder and the outside atmosphere. Moreover, this theory was at least partly contradicted when we drilled holes in the detector holder. Although of interest, this effect is not likely to have substantially influenced any radon surveys, given the unusual nature of the exposure that caused the effect. PMID- 20858676 TI - The HMGU thoron experimental house: a new tool for exposure assessment. AB - A thoron experimental house was constructed in a laboratory room of Helmholtz Zentrum Munchen to perform exposure studies of thoron and its decay products under controlled conditions. The single room house (7.1 m(3)) was built from unfired clay stones and clay plaster. For the plaster of the inner side, the clay was mixed with granite powder enriched with (232)Th. The thoron inventory increased by this means to about 1700 Bq and the progeny potential alpha energy to 130 uJ inside the room. The instrumentation of the experimental house includes active and passive devices for thoron and thoron decay product measurement including attached and unattached progeny, for aerosol particle number and size measurement and characterisation of the climatic conditions. Various parameters as ventilation rate and aerosol concentration can be adjusted. Experiments performed in the experimental house demonstrate the experimental power of this new tool for indoor thoron exposure assessment. PMID- 20858677 TI - An overview of thoron and its progeny in the indoor environment. AB - An account is given of the behaviour of thoron and its progeny in the indoor environment. Emphasis is placed on the spatial distribution of these radionuclides in room air and on their interactions with indoor aerosols. How these aspects of thoron and progeny behaviour give rise to special problems for measuring them and assessing their radiological impact are described. Descriptions and comparisons are given of a range of thoron and progeny measurement techniques both passive and active. Recent progress in thoron dosimetry is described as well as compared with radon dosimetry. The results of some indoor thoron and progeny surveys carried out in different countries in recent years are given. As an example of this a summary account is presented of a recently concluded survey of thoron and its airborne progeny in over 200 houses in Ireland. PMID- 20858678 TI - Assessment of radiological hazards of clay bricks fabricated in the Punjab province of Pakistan. AB - The Punjab is the most populous among the four provinces of Pakistan, which has around 72 million of people and 205 344 km(2) of land. The majority of the population of this province lives in houses made of clay bricks that contain variable amounts of naturally occurring radioactive material (NORM). The concentration level of NORM in clay bricks used to construct dwellings may pose health hazards to inhabitants if it exceeds the permissible limits. For radiological surveillance, activity concentrations of the primordial radionuclides (40)K, (226)Ra and (232)Th were measured in 140 brick samples collected from 35 districts of the Punjab province. A high-purity germanium gamma ray detector coupled with a personal computer-based multichannel analyzer was employed for the measurement of activity concentrations of primordial radionuclides in the brick samples. The province-wide average activity concentrations and the range (given in parenthesis) of (40)K, (226)Ra and (232)Th were found to be 624 +/- 133 (299-918), 35 +/- 7 (21-47) and 42 +/- 8 (22-58) Bq kg(-1), respectively. The values lie within the range of activity concentration values for clay bricks of some countries of Asia. Potential radiological constraint was checked in the form of hazard indices calculated from the measured activity concentrations; the indices were found to be less than their limiting values. Indoor external dose was calculated for a standard size room made of clay bricks, and the dose rate was 159 +/- 30 (83-219) nGy h(-1). The average value of the dose rate is comparable to that of Asian countries and is about twice the worldwide average value. Annual effective dose E(ff) in the bricks-made room was calculated and the average value of the dose was 0.80 mSv y(-1), which is about twice the worldwide background value of 0.41 mSv y(-1). PMID- 20858679 TI - Terrestrial outdoor exposures in the south-west Caspian region. AB - Natural radionuclides (40)K, (232)Th and (238)U present in soil and anthropogenic (137)Cs a fission product released to the environment mainly through atmospheric testing of nuclear arms and accidents in nuclear installations are the major contributors to terrestrial outdoor exposures. As part of a comprehensive study of environmental radioactivity in the south Caspian region, soil inventories of these radionuclides have been measured in more than 50 locations throughout Guilan, a northern province of Iran with the highest population density. In the case of natural radionuclides, outdoor absorbed dose rates in air have been inferred from concentrations of radionuclides in soil on the basis of which annual effective dose values have been estimated using the method described in UNSCEAR 2000. Calculation of (137)Cs contribution to dose has been performed by considering its soil inventory profiles and associated numerically estimated photon fluxes at 1 m above the ground. Maps representing the contribution of natural and anthropogenic radionuclides to annual effective dose in the study area have been produced using relevant geostatistical technique. Combined annual effective dose equivalent ranges from 33.1 +/- 4.9 to 91.9 +/- 16.5 MUSv . y(-1) with a mean value of 64.7 +/- 15.2 MUSv . y(-1). PMID- 20858680 TI - Dosimetric data and radiation risk analysis for new procedures in interventional cardiology. AB - The purpose of this study was to evaluate radiation doses to the patients and operators during interventional cardiology procedures, with a particular focus on the transcatheter aortic valve implantation (TAVI). Patient doses for 5549 diagnostic and therapeutic procedures and 76 TAVI were examined, as well as occupational doses to Cardiology Department operators. The average patient dose for TAVI was double that of PTCA and six times higher than a simple CA; statistically significant differences were shown in the average patient dose for both transfemoral and transapical access; the measurements show a corresponding increase in the average occupational dose for the cardiologist. Interventional cardiology could increase the collective dose and occupationally exposed worker doses; this increase could be significant if the use of certain procedures is extended to younger people; particular attention in the choice of procedure, optimisation and staff education and organisation is therefore suggested. PMID- 20858681 TI - A new technique for beta attenuation studies in neutron activation foils using 4pibeta-gamma coincidence system. AB - Foil activation method is an accurate method for neutron fluence rate measurements. In this, the inactive foils are activated and the induced activity is then measured and correlated to the neutron fluence rate through the cross section for the reaction, number of atoms and time of irradiation. To evaluate this induced activity, gamma-ray spectrometers are generally used. If the neutron fluence rate is very low of the order of 1-10(3) n cm(-2) s(-1), a 4pibeta flow type proportional counter with 100 % efficiency is the most suitable detector for measuring the low induced activity. But this method poses a serious problem of beta self-attenuation in the foils. A detailed investigation of the beta attenuation of different activation foils such as gold, manganese, cobalt, magnesium and aluminium by empirical equations as well as with a new experimental method using 4pibeta-gamma coincidence counter and 4pibeta flow-type proportional counter is discussed in this paper. PMID- 20858682 TI - Standardisation of radiation portal monitor controls and readouts. AB - There is an urgent need to standardise the numbering configuration of radiation portal monitor sensing panels. Currently, manufacturers use conflicting numbering schemes that may confuse operators of these varied systems. There is a similar problem encountered with the varied choices of coloured indicator lights and coloured print lines designated for gamma and neutron alarms. In addition, second party software that changes the alarm colour scheme may also have been installed. Furthermore, no provision exists for the colour blind or to provide work stations with only black ink on alarm printouts. These inconsistencies and confusing set ups could inadvertently cause a misinterpretation of the alarm, resulting in the potential release of a radiological hazard into a sovereign country. These issues are discussed, and a proposed solution is offered. PMID- 20858684 TI - Adipose tissue dysfunction signals progression of hepatic steatosis towards nonalcoholic steatohepatitis in C57BL/6 mice. AB - OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here, we aimed to investigate the interaction between adipose tissue and liver in NAFLD and identify potential early plasma markers that predict nonalcoholic steatohepatitis (NASH). RESEARCH DESIGN AND METHODS: C57Bl/6 mice were chronically fed a high-fat diet to induce NAFLD and compared with mice fed a low-fat diet. Extensive histological and phenotypical analyses coupled with a time course study of plasma proteins using multiplex assay were performed. RESULTS: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into four subgroups: low-fat low (LFL) responders displaying normal liver morphology, low-fat high (LFH) responders showing benign hepatic steatosis, high-fat low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and high fat high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared with HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodeling. Plasma haptoglobin, IL-1beta, TIMP-1, adiponectin, and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP 1alpha early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL 18, IL-1beta, MIP-1gamma, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers. CONCLUSIONS: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. PMID- 20858685 TI - Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). AB - OBJECTIVE: To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies. RESEARCH DESIGN AND METHODS: Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3-6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5' noncoding region, detecting essentially all enterovirus serotypes. RESULTS: Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found. CONCLUSIONS: This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood. PMID- 20858683 TI - Common variants at 10 genomic loci influence hemoglobin A1(C) levels via glycemic and nonglycemic pathways. AB - OBJECTIVE: Glycated hemoglobin (HbA1(c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1(c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1(c) levels. RESEARCH DESIGN AND METHODS: We studied associations with HbA1(c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1(c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS: Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 * 10-26), HFE (rs1800562/P = 2.6 * 10-20), TMPRSS6 (rs855791/P = 2.7 * 10-14), ANK1 (rs4737009/P = 6.1 * 10-12), SPTA1 (rs2779116/P = 2.8 * 10-9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 * 10-9), and four known HbA1(c) loci: HK1 (rs16926246/P = 3.1 * 10-54), MTNR1B (rs1387153/P = 4.0 * 10-11), GCK (rs1799884/P = 1.5 * 10-20) and G6PC2/ABCB11 (rs552976/P = 8.2 * 10-18). We show that associations with HbA1(c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1(c)) difference between the extreme 10% tails of the risk score, and would reclassify ~2% of a general white population screened for diabetes with HbA1(c). CONCLUSIONS: GWAS identified 10 genetic loci reproducibly associated with HbA1(c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1(c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1(c). PMID- 20858686 TI - Basal and insulin mediated VLDL-triglyceride kinetics in type 2 diabetic men. AB - OBJECTIVE: Increased very-low-density lipoprotein triglycerides (VLDL-TG) concentration is a central feature of diabetic dyslipidemia. The objective was to compare basal and insulin mediated VLDL-TG kinetics, oxidation, and adipose tissue storage in type 2 diabetic and healthy (nondiabetic) men. RESEARCH DESIGN AND METHODS: Eleven type 2 diabetic and 11 healthy men, matched for BMI and age, were included. Ex vivo-labeled VLDL-TG tracers, blood and breath samples, fat biopsies, indirect calorimetry, and body composition measures were applied to determine VLDL-TG kinetics, VLDL-TG fatty acids (FA) oxidation, and storage in regional adipose tissue before and during a hyperinsulinemic euglycaemic clamp. RESULTS: VLDL-TG secretion was significantly greater in diabetic compared with healthy men (basal: 86.9 [31.0] vs. 61.9 [30.0] MUmol/min, P = 0.03; clamp: 60.0 [26.2] vs. 34.2 [17.9] MUmol . min-1, P = 0.01). The insulin mediated suppression of VLDL-TG secretion was significant in both groups. VLDL-TG clearance was lower in diabetic men (basal: 84.6 [32.7] vs. 115.4 [44.3] ml . min-1, P = 0.08; clamp: 76.3 [30.6] vs. 119.0 [50.2] ml . min-1, P = 0.03). During hyperinsulinemia fractional VLDL-TG FA oxidation was comparable, but in percentage of energy expenditure (EE), significantly higher in diabetic men. Basal VLDL-TG storage was similar, but significantly greater in abdominal compared with leg fat. CONCLUSIONS: Increased VLDL-TG in type 2 diabetic men is caused by greater VLDL TG secretion and less so by lower VLDL-TG clearance. The ability of hyperinsulinemia to suppress VLDL-TG secretion appears preserved. During hyperinsulinemia VLDL-TG FA oxidation is significantly increased in proportion of EE in type 2 diabetic men. Greater basal abdominal VLDL-TG storage may help explain the accumulation of upper-body fat in insulin-resistant individuals. PMID- 20858687 TI - In vivo antibacterial activity of nemonoxacin, a novel non-fluorinated quinolone. AB - OBJECTIVES: To evaluate the in vivo antibacterial efficacy of nemonoxacin, a novel C8-methoxy non-fluorinated quinolone in murine systemic and local infection models. METHODS: The efficacy of nemonoxacin in systemic infections was evaluated in mouse peritonitis models using isolates of methicillin-susceptible Staphylococcus aureus (MSSA, n=1), methicillin-resistant S. aureus (MRSA, n=1), methicillin- and levofloxacin-resistant Staphylococcus capitis (levofloxacin resistant MRSC, n=1), penicillin-intermediate Streptococcus pneumoniae (PISP, n=1), penicillin-resistant S. pneumoniae (PRSP, n=2), Enterococcus faecalis (n=2, including 1 vancomycin-resistant Enterococcus, VRE) and Escherichia coli (n=3). The local infections included mouse pulmonary infections caused by PRSP (n=1), Klebsiella pneumoniae (n=1) and mouse ascending urinary tract infection caused by E. coli (n=1). RESULTS: In the mouse systemic infection model, nemonoxacin demonstrated potent activity against MSSA (ED(50) =2.08 mg/kg), MRSA (ED(50) =2.59 mg/kg), levofloxacin-resistant MRSC (ED(50) =2.52 mg/kg), PISP (ED(50) =5.47 mg/kg), PRSP (ED(50) =3.68-5.28 mg/kg) and E. coli (ED(50) =3.13-5.28 mg/kg), and moderate activity towards E. faecalis infection (ED(50) =8.48-15.16 mg/kg). The therapeutic efficacy of nemonoxacin was significantly higher (P<0.01) than that of levofloxacin in infections caused by Gram-positive isolates (MSSA, MRSA, levofloxacin-resistant MRSC, PISP, PRSP and E. faecalis), but less potent than that of levofloxacin against E. coli infection (P<0.01). Nemonoxacin in vivo efficacy results with Gram-positive isolates (2- to 5-fold ED(50) advantage over levofloxacin) are consistent with the MIC data (4- to 16-fold MIC advantage of nemonoxacin over levofloxacin). In the mouse pulmonary infection model, nemonoxacin showed potent activity towards PRSP (higher than levofloxacin) and K. pneumoniae (lower than levofloxacin) infections. In the mouse ascending urinary tract infection model, nemonoxacin exhibited potent activity against E. coli infection (lower than levofloxacin). CONCLUSIONS: The results validated the potent efficacy of nemonoxacin in vivo. The higher efficacy of nemonoxacin than of levofloxacin towards infections caused by Gram-positive cocci (especially MRSA, levofloxacin-resistant MRSC, PRSP and VRE) warrants investigation of its clinical use. PMID- 20858688 TI - Efficacy of doripenem in the treatment of Pseudomonas aeruginosa experimental pneumonia versus imipenem and meropenem. AB - OBJECTIVES: The aim of this study was to compare doripenem with imipenem and meropenem in an experimental rabbit model of Pseudomonas aeruginosa pneumonia and then to compare different doripenem doses and methods of intravenous administration. METHODS: Using a rabbit experimental model of pneumonia, efficacy was assessed following 2 days of treatment by colony counts of different tissues (lung, spleen and blood culture). RESULTS: Mean pulmonary bacterial loads were 3.17 +/- 0.53, 3.42 +/- 0.61 and 2.75 +/- 0.59 log(10) cfu/g for imipenem, doripenem (0.5 g three times daily) and meropenem, respectively, compared with 7.57 +/- 0.99 cfu/g for control animals. At a higher dose (1 g three times daily), doripenem showed significantly better efficacy (2.70 +/- 0.65 log(10) cfu/g) than the standard regimen of doripenem. Sterilization of spleen cultures was achieved with standard regimens of imipenem (1 g three times daily) and a higher dose of doripenem. CONCLUSIONS: In this model of P. aeruginosa pneumonia, doripenem had an efficacy equivalent to that of meropenem and imipenem at a high dose of 1 g three times a day and lower efficacy at a standard dose (0.5 g three times daily) than the other two agents in terms of bacteria cultivated from spleens. Doripenem is a new drug that offers new therapeutic options, especially for difficult-to-treat infections such as pneumonia due to non-fermenting Gram negative bacteria. PMID- 20858689 TI - Statistical approaches to analyse patient-reported outcomes as response variables: an application to health-related quality of life. AB - Patient-reported outcomes (PRO) are used as primary endpoints in medical research and their statistical analysis is an important methodological issue. Theoretical assumptions of the selected methodology and interpretation of its results are issues to take into account when selecting an appropriate statistical technique to analyse data. We present eight methods of analysis of a popular PRO tool under different assumptions that lead to different interpretations of the results. All methods were applied to responses obtained from two of the health dimensions of the SF-36 Health Survey. The proposed methods are: multiple linear regression (MLR), with least square and bootstrap estimations, tobit regression, ordinal logistic and probit regressions, beta-binomial regression (BBR), binomial-logit normal regression (BLNR) and coarsening. Selection of an appropriate model depends not only on its distributional assumptions but also on the continuous or ordinal features of the response and the fact that they are constrained to a bounded interval. The BBR approach renders satisfactory results in a broad number of situations. MLR is not recommended, especially with skewed outcomes. Ordinal methods are only appropriate for outcomes with a few number of categories. Tobit regression is an acceptable option under normality assumptions and in the presence of moderate ceiling or floor effect. The BLNR and coarsening proposals are also acceptable, but only under certain distributional assumptions that are difficult to test a priori. Interpretation of the results is more convenient when using the BBR, BLNR and ordinal logistic regression approaches. PMID- 20858690 TI - Relapsing demyelinating CNS disease in a Korean pediatric population: multiple sclerosis versus neuromyelitis optica. AB - BACKGROUND AND OBJECTIVE: Our objective was to characterize the clinical and radiologic features of Korean pediatric patients with relapsing central nervous system (CNS) demyelination disease. METHODS: Twenty-one patients with relapsing CNS demyelinating events were classified as having multiple sclerosis (MS, 18 patients) or neuromyelitis optica (NMO, three patients) according to the international consensus definitions. Retrospective analysis of clinical and radiologic features was conducted. Anti-aquaporin-4 antibody (AQP4 Ab) test was performed in six patients (including three NMO patients) who showed selective involvement of optic nerve and spinal cord. RESULTS: Median age at the initial episode in patients with MS was 7.0 years (range, 4.4-13.6 years). Three of 18 MS patients (3/18, 17%) showed selective involvement of the optic nerve and spinal cord during the clinical course. Five patients (31%) at the initial episode and nine patients (50%) at relapse met the McDonald magnetic resonance imaging criteria for dissemination in space. Oligoclonal bands detected with a silver staining method were positive in only one patient of 16 patients tested. Two NMO patients positive for AQP4 Ab showed frequent relapses and early disabilities that were unresponsive to interferon treatment. CONCLUSIONS: We conclude that Korean pediatric patients with relapsing CNS demyelination disease were characterized by preferential involvement of the optic nerve or spinal cord. The AQP4 Ab test seems to be useful for predicting clinical courses in the setting of heterogeneous opticospinal presentations. PMID- 20858691 TI - Idiopathic acute transverse myelitis in children: an analysis and discussion of MRI findings. AB - BACKGROUND: There is lack of reported magnetic resonance imaging (MRI) studies of idiopathic acute transverse myelitis (ATM) in children. OBJECTIVE: To describe the imaging features of idiopathic ATM in children. METHODS: We retrospectively analyzed the spinal MRI findings of children diagnosed with ATM. The anatomic regions, vertebral segmental length, gray or white matter involvement, cord expansion and gadolinium enhancement were examined. RESULTS: A total of 27 children were diagnosed with isolated monophasic ATM with a mean follow-up of 5.2 years. Two children later diagnosed with neuromyelitis optica were excluded from the pediatric ATM cohort. None of the patients had a subsequent diagnosis of multiple sclerosis. The mean age of onset was 9.5 years (0.5-16.9 years). Spinal MRIs were abnormal in 21 (78%). The mean interval between symptom onset and the MRI was 1.7 days (0-19 days). Central cord hyperintensity involving gray matter was seen in all patients. A majority (67%) of the patients demonstrated long segment lesions with a mean segment length of 6.4. CONCLUSIONS: We conclude that central cord inflammation extending over three or more segments is the most common finding of idiopathic monophasic transverse myelitis in children. The risk of multiple sclerosis in children who experience isolated transverse myelitis as a first demyelinating event is low. PMID- 20858693 TI - Demonstration of a right ventricular substrate of ventricular tachycardia after myocardial infarction. AB - A 57-year-old man with prior anteroseptal myocardial infarction underwent catheter ablation of ventricular tachycardia (VT) exhibiting a left bundle branch block QRS morphology. After failed left ventricular ablation, catheter ablation from the right ventricle (RV) eliminated the VT. An RV voltage map demonstrated an area of low voltage around the successful ablation site that likely allowed for a VT substrate. PMID- 20858692 TI - An information aid for newly diagnosed multiple sclerosis patients improves disease knowledge and satisfaction with care. AB - BACKGROUND: Patients report information deficits in the period surrounding diagnosis of multiple sclerosis (MS). We assessed the effectiveness of an add-on information aid for newly diagnosed MS patients. METHODS: We randomly assigned 120 newly diagnosed MS patients from five Italian centres to diagnosis disclosure (current practice at the centre) or current practice plus information aid (ISRCTN81072971). The information aid consisted of a personal interview with a physician using a navigable compact disc and a take-home booklet. The primary composite endpoint was score in the highest tertile of MS knowledge and satisfaction with care questionnaires. Other endpoints were safety; treatment adherence; extra contacts/consultations; switching of care centre; and changes in Hospital Anxiety and Depression Scale and Control Preference Scale scores. RESULTS: At 1 month, 30/60 intervention and 8/60 control patients achieved the primary endpoint (odds ratio [OR] 6.5, 95% CI 2.6-16.0; p < 0.001; number needed to treat [NNT] 3). Figures at 6 months were 26/60 intervention and 11/60 control patients (OR 3.4, 95% CI 1.5-7.8; p = 0.04; NNT 4). There were no adverse events. No significant treatment effects were seen on secondary outcomes. CONCLUSION: The information aid was safe and significantly associated with attainment of the primary outcome at 1 and 6 months. PMID- 20858694 TI - Alcohol ablation at the posterior papillary muscle prevents ventricular fibrillation in swine without affecting mitral valve function. AB - AIMS: Radiofrequency ablation at the posterior papillary muscle (PM) significantly reduced ventricular fibrillation (VF) inducibility in rabbits and dogs, suggesting that PM may be involved in the generation of VF. However, the effect of ablation at the PM on VF inducibility remains unknown in normal intact swine hearts because in this species radiofrequency energy delivered at PM provoked incessant VF. METHODS AND RESULTS: Twelve anesthetized swine underwent median sternotomy. Under the ultrasonographic guidance, chemical ablation was performed via injection of dehydrated alcohol into the base of the posterior PM (group PM, n = 6) or anterior wall (control group, n = 6) in the left ventricle. Ventricular fibrillation inducibility and mitral valve function were measured pre and post-ablation. Hearts were explanted and the ablated myocardium was stained with haematoxylin and eosin. Ventricular fibrillation inducibility was significantly decreased from 100 +/- 0% pre-ablation to 11.9 +/- 7.8% post ablation in group PM (P = 0.001), whereas it was not statistically different in the control group (100 +/- 0 vs. 92.9 +/- 7.1%, pre-ablation vs. post-ablation). Haemorrhage and cellular necrosis was observed in the centre of ablated myocardium and no significant mitral regurgitation was observed following ablation at the posterior PM. CONCLUSION: Alcohol ablation of the left posterior PM reduced VF inducibility in normal intact swine hearts, with no significant mitral regurgitation. This suggests that the posterior PM may be involved in the generation of VF, and the recurrence of VF may be prevented by chemical ablation at the posterior PM. PMID- 20858695 TI - The pregnancy outcome of retrieved excess eggs collected during selective follicular reduction from patients with three or more preovulatory follicles undergoing controlled ovarian stimulation and IUI. PMID- 20858696 TI - Aberrant expression of regulators of cell-fate found in eutopic endometrium is found in matched ectopic endometrium among women and in a baboon model of endometriosis. AB - BACKGROUND: We have recently shown that women with endometriosis express an increased amount of telomerase and nucleolin, with concomitant loss of gamma-H2AX in eutopic endometrium. To further examine these selected factors that regulate cell fate, in the pathogenesis of endometriosis, we studied the expression of telomerase, nucleolin, proliferating cell nuclear antigen and gamma-H2AX in ectopic endometriotic deposits from women, and in matched eutopic and ectopic endometrial tissue from a baboon model of endometriosis. METHODS: Ectopic active peritoneal endometriotic lesions were collected from seven symptomatic women. Endometriosis was induced in six baboons by intra-peritoneal autologous inoculation of menstrual endometrium. Eutopic and matched ectopic endometrial tissues were collected prior to and 6, 12 and 15 months after the induction of endometriosis as previously described. Eutopic endometrium was also obtained from eight healthy fertile control baboons. Immunohistochemistry was performed as previously described, and telomerase activity was confirmed using the telomeric repeat amplification protocol assay. RESULTS: All active human endometriotic lesions expressed the proliferative markers but showed weak or absent staining for gamma-H2AX. A similar expression pattern of these markers was seen in the ectopic lesions of the baboons with induced disease. In these baboons, the eutopic endometrium also showed intense immunoreactivity for all proliferative markers 6-12 months after induction with a parallel loss of gamma-H2AX. The opposite staining pattern was seen in eutopic endometrium of healthy animals and in pre-induction endometrium of animals with induced disease. CONCLUSIONS: Endometriotic lesions have excess proliferative potential; in baboons, these were present within 12 months of the initiation of the disease. In eutopic tissue, these changes appear to be induced by the development of endometriosis. PMID- 20858697 TI - Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial. AB - BACKGROUND: Clomiphene citrate (CC) is the first-line therapy for the induction of ovulation in infertile women with polycystic ovary syndrome (PCOS), but ~20% of patients are unresponsive. The aim of the current study was to test the hypothesis that a 6-week intervention that consisted of structured exercise training (SET) and hypocaloric diet increases the probability of ovulation after CC in overweight and obese CC-resistant PCOS patients. METHODS: A cohort of 96 overweight and obese CC-resistant PCOS patients was enrolled consecutively in a three-arm randomized, parallel, controlled, assessor-blinded clinical trial. The three interventions were: SET plus hypocaloric diet for 6 weeks (Group A); 2 weeks of observation followed by one cycle of CC therapy (Group B); and SET plus hypocaloric diet for 6 weeks, with one cycle of CC after the first 2 weeks (Group C). The primary end-point was the ovulation rate. Other reproductive data, as well as anthropometric, hormonal and metabolic data, were also collected and considered as secondary end points. RESULTS: After 6 weeks of SET plus hypocaloric diet, the ovulation rate was significantly (P =0.008) higher in Group C [12/32 (37.5%)] than in Groups A [4/32 (12.5%)] and B [3/32 (9.4%)] with relative risks of 3.9 [95% confidence interval (CI) 1.1-8.3; P = 0.035] and 4.0 (95% CI 1.2-12.8; P = 0.020) compared with Groups A and B, respectively. Compared with baseline, in Groups A and C, a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes was observed. In the same two groups, the insulin sensitivity index was significantly (P < 0.05) better than that in Group B. CONCLUSIONS: In overweight and obese CC-resistant PCOS patients, a 6-week intervention of SET and a hypocaloric diet was effective in increasing the probability of ovulation under CC treatment. The study was registered at Clinicaltrials.gov:NCT0100468. PMID- 20858698 TI - Mild ovarian stimulation for IVF: 10 years later. AB - Ovarian stimulation to achieve multiple follicle development has been an integral part of IVF treatment. In the context of improved laboratory performance, the need for a large number of oocytes as an integral part of a successful IVF programme may be questioned. The aim of the current debate is to summarize the studies performed during the last decade to develop the concept of mild stimulation aiming to obtain fewer than eight oocytes. Here we examine the balance between IVF success and patient discomfort, and complications and cost, and how these might improve by simpler ovarian stimulation protocols aimed at retrieving fewer oocytes. We intend to analyse why progress has been rather slow and why there is much resistance to mild stimulation. Finally, presumed useful directions for future research will be discussed. PMID- 20858699 TI - Men's experiences of infertility and infertility treatment 5 years after diagnosis of male factor infertility: a retrospective cohort study. AB - BACKGROUND: The aim of this study was to describe the perceptions of infertile men regarding the impact of infertility on their intimate relationships, their experience of treatment and their sources of information and support. METHODS: A cross-sectional survey of a consecutive cohort of men diagnosed 5 years earlier as infertile at Melbourne IVF and the Royal Women's Hospital Reproductive Services, Melbourne was conducted. Study-specific questions assessed the impact of male factor infertility on the intimate relationships, their perceived quality of infertility-related health care and their preferred sources of infertility related information and personal support and the effectiveness of these. RESULTS: The response rate was 41% (112/276). Male factor infertility was reported to have had a negative impact on the intimate partner relationship by 25% of men, and 32% reported a negative effect on their sexual satisfaction. Satisfaction with medical care and clinic information was high and not influenced by the outcome of the treatment. Clinic-provided information and discussion with clinic staff were the most strongly preferred sources of information, and the partner and clinic staff were the most valued sources of personal support. Very few men found support groups useful and less than half confided in friends. CONCLUSIONS: The findings suggest that for a significant subgroup of men, male factor infertility affects their intimate relationship negatively. Wider sources of social support are not used by infertile men as they rely predominantly on clinic-provided information and support. This indicates that psychologically informed supportive clinical care is particularly important for men diagnosed as infertile. PMID- 20858701 TI - What's in a name? Generics and the persistence of the pharmaceutical brand in American medicine. AB - This paper explores the complex role that brand names have played in the maintenance of therapeutic standards within twentieth-century American medicine. What made a generic drug generic in the second half of the twentieth century--and by extension, what made a nonproprietary drug not proprietary in the first half- was dependent on changing drug branding practices and evolving standards of evidence attached to claims of therapeutic efficacy and safety. This article maps three eras of shifting oppositions between branded and unbranded pharmaceuticals. First, an era of "ethical marketing," extending from before the Pure Food and Drug Act of 1906 into roughly the 1930s, which pitted nonproprietary or "ethical" pharmaceuticals against proprietary or patent medicines; second, an era of ascendant brand-name prescribing from the 1930s until roughly the 1960s, as manufacturers of innovative and patent-protected "specialty" drugs depicted generic production as a form of counterfeiting; and finally, an era of generic backlash from the 1960s onwards, which assumed the interchangeability of branded and generic drugs. This article uses clinical, popular, policy, and trade literatures to explore the enduring roles of brand-logic in the face of generic competition in the American drug market. PMID- 20858700 TI - Melanoma differentiation associated gene-7/interleukin-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by endoplasmic reticulum stress. AB - Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensively characterized. Treatment with recombinant GST-MDA-7/IL-24 potently induced apoptosis in diverse myeloid leukemia cell types including U937, HL60, MV4-11, EOL-1, and MLL/ENL cells. MDA-7/IL-24 also markedly induced apoptosis in and suppressed the colony-forming capacity of primary AML blasts but exerted minimal toxicity toward normal CD34(+) hematopoietic progenitor cells. MDA-7/IL 24 lethality was associated with pronounced endoplasmic reticulum (ER) stress induction in leukemia cell lines and primary AML blasts, manifested by the accumulation of growth arrest and DNA damage-inducible protein 34 (GADD34), 78 kDa glucose-regulated protein (GRP78)/BiP, inositol-requiring enzyme 1alpha (IRE1alpha), and eukaryotic initiation factor 2alpha phosphorylation. It is noteworthy that short hairpin RNA (shRNA) knockdown of IRE1alpha, GADD34, or GRP78/BiP significantly enhanced MDA-7/IL-24-mediated apoptosis, indicating a protective role for these molecules against MDA-7/IL-24 lethality. MDA-7/IL-24 also down-regulated the antiapoptotic protein Mcl-1 and sharply increased expression of the proapoptotic proteins Bim and Noxa. Ectopic Mcl-1 expression or shRNA knockdown of Bim or Noxa significantly attenuated MDA-7/IL-24-mediated leukemia cell death. Finally, knockdown of Bax or Bak significantly reduced MDA 7/IL-24 lethality. Together, these findings indicate that MDA-7/IL-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by ER stress induction, Mcl-1 down-regulation, and Bim and Noxa up-regulation. They also suggest that MDA-7/IL-24 warrants further investigation in myeloid leukemia. PMID- 20858702 TI - GH and IGF1 levels are positively associated with musculotendinous collagen expression: experiments in acromegalic and GH deficiency patients. AB - OBJECTIVE: Disproportionate growth of musculoskeletal tissue is a major cause of morbidity in both acromegalic (ACRO) and GH-deficient (GHD) patients. GH/IGF1 is likely to play an important role in the regulation of tendon and muscle collagen. We hypothesized that the local production of collagen is associated with the level of GH/IGF1. DESIGN AND METHODS: As primary outcomes, collagen mRNA expression and collagen protein fractional synthesis rate (FSR) were determined locally in skeletal muscle and tendon in nine ACRO and nine GHD patients. Moreover, muscle myofibrillar protein synthesis and tendon collagen morphology were determined. RESULTS AND CONCLUSIONS: Muscle collagen I and III mRNA expression was higher in ACRO patients versus GHD patients (P<0.05), whereas collagen protein FSR did not differ significantly between ACRO and GHD patients in muscle (P=0.21) and tendon (P=0.15). IGF1Ea and IGF1Ec mRNA expression in muscle was higher in ACRO patients versus GHD patients (P<0.01). Muscle IGF1Ea mRNA expression correlated positively with collagen I mRNA expression (P<0.01). Tendon collagen fibrillar area tended to be higher in GHD patients relative to ACRO patients (P=0.07). Thus, we observed a higher expression for collagen and IGF1 mRNA in local musculotendinous tissue in ACRO patients relative to GHD patients. Moreover, there was a tendency towards a higher collagen protein FSR and a smaller collagen fibril diameter in ACRO patients relative to GHD patients. The results indicate a collagen-stimulating role of local IGF1 in human connective tissue and add to the understanding of musculoskeletal pathology in patients with either high or low GH/IGF1 axis activity. PMID- 20858703 TI - Hand-touch method for detection of neonatal hypothermia in Nepal. AB - Neonatal hypothermia is the fourth leading causes of neonatal death in Nepal. Thus, it is the caregivers' responsibility to identify the hypothermia by using valid and less time consuming method like hand-touch method. Therefore, we examined the diagnostic validity of hand-touch method against low-reading mercury (LRM) thermometer for detecting neonatal hypothermia. We assessed neonate's temperature first by hand-touch method, then by LRM thermometer and tympanic thermometer among 100 full-term neonates, delivered within 24 h in Maternity Ward of Tribhuvan University Teaching Hospital, Nepal. We used World Health Organization (1997) criteria for classification of neonatal hypothermia. The sensitivity and specificity of the hand-touch method for detection of neonatal hypothermia were 95.6% and 70.1% against LRM thermometer and 76.6% and 83% against the tympanic thermometer, respectively. Touching method is practical and therefore has a good diagnostic validity; it can be introduced in essential newborn care package after giving adequate training to caregivers. PMID- 20858704 TI - Woods and trees. PMID- 20858705 TI - The cardiorenal anaemia syndrome in systolic heart failure: prevalence, clinical correlates, and long-term survival. AB - AIMS: We sought to assess the prevalence and clinical correlates of cardiorenal anaemia (CRA) syndrome in systolic heart failure and the relationship between renal dysfunction and anaemia on hard clinical outcomes. METHODS AND RESULTS: We studied 951 patients with chronic heart failure (CHF) and systolic dysfunction. The primary outcome was all-cause mortality and urgent heart transplantation (UHT). Cox's regression analyses were used to assess the relation of the variables to the primary outcome. Hazard ratios (HRs) with 95% confidence intervals (CI) were calculated. The prevalence of CRA syndrome was 21.1%. Age (P < 0.001), body mass index (P< 0.001), diabetes (P =< 0.001), ischaemic aetiology (P< 0.006), left ventricular ejection fraction (P= 0.018), and treatment with renin-angiotensin system inhibitors (P< 0.001) were independently related to CRA syndrome. During a median follow-up of 3.7 years, the primary outcome occurred in 404 patients (42.5%). Compared with patients with preserved renal function and normal haemoglobin (Hb) levels, those with CRA syndrome had a significantly increased risk for the primary outcome; the univariate and multivariate-adjusted HRs were 4.04 (CI: 3.11-5.24; P< 0.0001) and 2.22 (CI: 1.64-2.98; P< 0.0001), respectively. Three-year UHT-free survival was 86 and 47%, respectively. Among patients with renal dysfunction, the adjusted HR for the primary outcome increased by 17% (CI: 8-26; P= 0.0001) for each 1g/dL decrease below an Hb value of 13.0 g/dL. CONCLUSION: Heart failure, renal dysfunction, and anaemia are a fatal combination. Despite a relatively low prevalence, the CRA syndrome contributes to considerable mortality due to CHF. PMID- 20858706 TI - Interaction of 5-HT2A and 5-HT2C receptors in R(-)-2,5-dimethoxy-4 iodoamphetamine-elicited head twitch behavior in mice. AB - Drug-elicited head-twitch behavior is a useful model for studying hallucinogen activity at 5-HT(2A) receptors in the mouse. Chemically diverse compounds active in this assay yield biphasic dose-effect curves, but there is no compelling explanation for the "descending" portion of these functions. A set of experiments was designed to test the hypothesis that the induction of head-twitch behavior is mediated by agonist actions at 5-HT(2A) receptors, whereas the inhibition of head twitch behavior observed at higher doses results from competing agonist activity at 5-HT(2C) receptors. The effects of the phenethylamine hallucinogen R(-)-2,5 dimethoxy-4-iodoamphetamine (DOI) on head-twitch behavior were studied over a range of doses in the mouse, generating a characteristic biphasic dose-response curve. Pretreatment with the selective 5-HT(2A) antagonist (+)-(2,3 dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (M100907) shifted only the ascending limb of the DOI dose-effect function, whereas pretreatment with the nonselective 5-HT(2A/2C) antagonist 3-{2-[4-(4 fluorobenzoyl)piperidin-1-yl]ethyl}quinazoline-2,4(1H,3H)-dione (ketanserin) produced a parallel shift to the right in the DOI dose-response curve. Administration of the 5-HT(2C) agonist S-2-(chloro-5-fluoro-indol-l-yl)-1 methylethylamine (Ro 60-0175) noncompetitively inhibited DOI-elicited head-twitch behavior across the entire dose-effect function. Finally, pretreatment with the selective 5-HT(2C) antagonists 6-chloro-5-methyl-1-[(2-[2-methylpyrid-3 yloxy]pyrid-5yl)carbamoyl]indoline (SB242084) or 8-[5-(2,4-dimethoxy-5-(4 trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane 2,4-dione hydrochloride (RS 102221) did not alter DOI-elicited head-twitch behavior on the ascending limb of the dose-response curve but shifted the descending limb of the DOI dose-response function to the right. The results of these experiments provide strong evidence that DOI-elicited head-twitch behavior is a 5-HT(2A) agonist-mediated effect, with subsequent inhibition of head-twitch behavior being driven by competing 5-HT(2C) agonist activity. PMID- 20858707 TI - Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. AB - The plasma membrane monoamine transporter (PMAT) and organic cation transporter 3 (OCT3) are the two most prominent low-affinity, high-capacity (i.e., uptake(2)) transporters for endogenous biogenic amines. Using the Flp-in system, we expressed human PMAT (hPMAT) and human OCT3 (hOCT3) at similar levels in human embryonic kidney 293 cells. Parallel and detailed kinetics analysis revealed distinct and seemingly complementary patterns for the two transporters in transporting monoamine neurotransmitters. hPMAT is highly selective toward serotonin (5-HT) and dopamine, with the rank order of transport efficiency (V(max)/K(m)) being: dopamine, 5-HT ? histamine, norepinephrine, epinephrine. The substrate preference of hPMAT toward these amines is substantially driven by large (up to 15-fold) distinctions in its apparent binding affinities (K(m)). In contrast, hOCT3 is less selective than hPMAT toward the monoamines, and the V(max)/K(m) rank order for hOCT3 is: histamine > norepinephrine, epinephrine > dopamine >5-HT. It is noteworthy that hOCT3 demonstrated comparable (<=2-fold difference) K(m) toward all amines, and distinctions in V(max) played an important role in determining its differential transport efficiency toward the monoamines. Real-time reverse transcription-polymerase chain reaction revealed that hPMAT is expressed at much higher levels than hOCT3 in most human brain areas, whereas hOCT3 is selectively and highly expressed in adrenal gland and skeletal muscle. Our results suggest that hOCT3 represents a major uptake(2) transporter for histamine, epinephrine, and norepinephrine. hPMAT, on the other hand, is a major uptake(2) transporter for 5-HT and dopamine and may play a more important role in transporting these two neurotransmitters in the central nervous system. PMID- 20858710 TI - Reductionism in medical science and practice. PMID- 20858709 TI - Anti-inflammatory and analgesic effect of plumbagin through inhibition of nuclear factor-kappaB activation. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) (PL) is a naturally occurring yellow pigment found in the plants of the Plumbaginaceae, Droseraceae, Ancistrocladaceae, and Dioncophyllaceae families. It has been reported that PL exhibits anticarcinogenic, anti-inflammatory, and analgesic activities. However, the mechanism underlying its anti-inflammatory action remains unknown. In the current study, we investigated and characterized the anti-inflammatory and analgesic effects of PL orally administrated in a range of dosages from 5 to 20 mg/kg. We also examined the role of nuclear factor kappaB (NF-kappaB) and proinflammatory cytokines and mediators in this effect. The results showed that PL significantly and dose-dependently suppressed the paw edema of rats induced by carrageenan and various proinflammatory mediators, including histamine, serotonin, bradykinin, and prostaglandin E(2). PL reduced the number of writhing episodes of mice induced by the intraperitoneal injection of acetic acid, but it did not reduce the writhing episode numbers induced by MgSO(4) in mice or prolong the tail-flick reaction time of rats to noxious thermal pain. Mechanistic studies showed that PL effectively decreased the production of the proinflammatory cytokines interleukin 1beta, interleukin 6, and tumor necrosis factor alpha. It also inhibited the expression of the proinflammatory mediators inducible nitric oxide synthase and cyclooxygenase 2, whereas it did not inhibit the expression of cyclooxygenase 1. Further studies demonstrated that PL suppressed inhibitor of kappaBalpha phosphorylation and degradation, thus inhibiting the phosphorylation of the p65 subunit of NF-kappaB. This study suggests that PL has a potential to be developed into an anti-inflammatory agent for treating inflammatory diseases. PMID- 20858708 TI - A novel family of negative and positive allosteric modulators of NMDA receptors. AB - The N-methyl-D-aspartate (NMDA) receptor family regulates various central nervous system functions, such as synaptic plasticity. However, hypo- or hyperactivation of NMDA receptors is critically involved in many neurological and psychiatric conditions, such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Consequently, subtype-selective positive and negative modulators of NMDA receptor function have many potential therapeutic applications not addressed by currently available compounds. We have identified allosteric modulators with several novel patterns of NMDA receptor subtype selectivity that have a novel mechanism of action. In a series of carboxylated naphthalene and phenanthrene derivatives, compounds were identified that selectively potentiate responses at GluN1/GluN2A [e.g., 9-iodophenanthrene-3-carboxylic acid (UBP512)]; GluN1/GluN2A and GluN1/GluN2B [9-cyclopropylphenanthrene-3-carboxylic acid (UBP710)]; GluN1/GluN2D [3,5-dihydroxynaphthalene-2-carboxylic acid (UBP551)]; or GluN1/GluN2C and GluN1/GluN2D receptors [6-, 7-, 8-, and 9-nitro isomers of naphth[1,2-c][1,2,5]oxadiazole-5-sulfonic acid (NSC339614)] and have no effect or inhibit responses at the other NMDA receptors. Selective inhibition was also observed; UBP512 inhibits only GluN1/GluN2C and GluN1/GluN2D receptors, whereas 6 bromo-2-oxo-2H-chromene-3-carboxylic acid (UBP608) inhibits GluN1/GluN2A receptors with a 23-fold selectivity compared with GluN1/GluN2D receptors. The actions of these compounds were not competitive with the agonists L-glutamate or glycine and were not voltage-dependent. Whereas the N-terminal regulatory domain was not necessary for activity of either potentiators or inhibitors, segment 2 of the agonist ligand-binding domain was important for potentiating activity, whereas subtype-specific inhibitory activity was dependent upon segment 1. In terms of chemical structure, activity profile, and mechanism of action, these modulators represent a new class of pharmacological agents for the study of NMDA receptor subtype function and provide novel lead compounds for a variety of neurological disorders. PMID- 20858711 TI - Epistasis contributes to the genetic buffering of plasma HDL cholesterol in mice. AB - Stressful environmental factors, such as a high-fat diet, can induce responses in the expression of genes that act to maintain physiological homeostasis. We observed variation in plasma concentrations of high-density lipoprotein (HDL) cholesterol across inbred mouse strains in response to high dietary fat intake. Several strains, including C57BL/6J, have stable levels of plasma HDL independent of diet, whereas other strains, including DBA2/J, show marked changes in plasma HDL. To explore this phenomenon further, we used publicly available data from a C57BL/6J * DBA/2J intercross to identify genetic factors that associate with HDL under high-fat diet conditions. Our analysis identified an epistatic interaction that plays a role in the buffering of HDL levels in C57BL/6J mice, and we have identified Arl4d as a candidate gene that mediates this effect. Structural modeling further elucidates the interaction of genetic factors that contribute to the robustness of HDL in response to high-fat diet in the C57BL/6J strain. PMID- 20858712 TI - Functional analysis of two single nucleotide polymorphisms in SLC30A2 (ZnT2): implications for mammary gland function and breast disease in women. AB - Zinc transporter 2 (ZnT2) plays a major role in zinc (Zn) export from the mammary gland. Recently, we determined that ZnT2 is associated with secretory vesicles reflecting its role in Zn secretion during lactation. Herein, we identified two distinct single nucleotide polymorphisms (SNPs) in SLC30A2, which encodes ZnT2. SNP1 (rs35235055) results in a leucine-to-proline substitution (Leu(23)Pro), while SNP2 (rs35623192) results in an arginine-to-cysteine substitution (Arg(340)Cys). We examined the localization and function of each SNP in cells generated to express these polymorphic variants. SNP1 was mislocalized to lysosomes, while SNP2 was mislocalized to the Golgi apparatus. FluoZin-3 fluorescence illustrated increased lysosomal accumulation of Zn in cells expressing SNP1 concomitant with the abrogation of Zn secretion. In contrast, ectopic expression of SNP2 was associated with the expansion of cytoplasmic Zn pools, elevated reactive oxygen species, and increased Zn efflux. Taken together, our data indicate that polymorphic variants in ZnT2 distinctly alter mammary cell Zn metabolism. We speculate that these SNPs may compromise mammary cell function, which may have important implications in human health and breast disease. PMID- 20858713 TI - Electrical signals affect the cardiomyocyte transcriptome independently of contraction. AB - Cardiomyocytes in vivo are continuously subjected to electrical signals that evoke contractions and instigate drastic changes in the cells' morphology and function. Studies on how electrical stimulation affects the cardiac transcriptome have remained limited to a small number of heart-specific genes. Furthermore, these studies have ignored the interplay between the electrical excitation and the subsequent contractions. We carried out a genomewide assessment of the effects of electrical signaling on gene expression, while distinguishing between the effects deriving from the electrical pulses themselves and the effects instigated by the evoked contractions. Changes in gene expression in primary cultures of neonatal ventricular cardiomyocytes from Lewis Rattus norvegicus were investigated with microarrays and RT-quantitative PCR (QPCR). A series of experiments was included in which the culture medium was supplemented with the contraction inhibitor blebbistatin to allow for electrical stimulation in the absence of contraction. Electrical stimulation was shown to directly enhance calcium handling and induce cardiomyocyte differentiation by arresting cell division and activating key cardiac transcription factors as well as additional differentiation mechanisms such as wnt signaling. Several genes involved in metabolism were also directly activated by electrical stimulation. Furthermore, our data suggest that contraction exerts negative feedback on the transcription of various genes. Together, these observations indicate that intercellular electric currents between adjacent cardiomyocytes have an important role in cardiomyocyte development. They act at least partially through a pulse-specific gene expression program that is activated independently from the evoked contractions. PMID- 20858714 TI - Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis. PMID- 20858716 TI - PALB2/FANCN: recombining cancer and Fanconi anemia. AB - Partner and localizer of BRCA2 (PALB2) was originally identified as a BRCA2 interacting protein that is crucial for key BRCA2 genome caretaker functions. It subsequently became clear that PALB2 was another Fanconi anemia (FA) gene (FANCN), and that monoallelic PALB2 mutations are associated with increased risk of breast and pancreatic cancer. Mutations in PALB2 have been identified in breast cancer families worldwide, and recent studies have shown that PALB2 also interacts with BRCA1. Here, we summarize the molecular functions and clinical phenotypes of this key DNA repair pathway component and discuss how its discovery has advanced our knowledge of both FA and adult cancer predisposition. PMID- 20858715 TI - AXL is an essential factor and therapeutic target for metastatic ovarian cancer. AB - The receptor tyrosine kinase AXL is thought to play a role in metastasis; however, the therapeutic efficacy of an AXL-targeting agent remains largely untested in metastatic disease. In this study, we defined AXL as a therapeutic target for metastatic ovarian cancer. AXL is primarily expressed in metastases and advanced-stage human ovarian tumors but not in normal ovarian epithelium. Genetic inhibition of AXL in human metastatic ovarian tumor cells is sufficient to prevent the initiation of metastatic disease in vivo. Mechanistically, inhibition of AXL signaling in animals with metastatic disease results in decreased invasion and matrix metalloproteinase activity. Most importantly, soluble human AXL receptors that imposed a specific blockade of the GAS6/AXL pathway had a profound inhibitory effect on progression of established metastatic ovarian cancer without normal tissue toxicity. These results offer the first genetic validation of GAS6/AXL targeting as an effective strategy for inhibition of metastatic tumor progression in vivo. Furthermore, this study defines the soluble AXL receptor as a therapeutic candidate agent for treatment of metastatic ovarian cancer, for which current therapies are ineffective. PMID- 20858717 TI - E-cadherin/p120-catenin and tetraspanin Co-029 cooperate for cell motility control in human colon carcinoma. AB - Tumor invasion and metastasis are major obstacles to clinical treatment that rely on cell migration. Here, we elucidate a mechanism of colon carcinoma cell migration that is supported by the cell surface tetraspanin Co-029 (tspan8), which is known to favor tumor progression and metastasis. This mechanism is unmasked by silencing of E-cadherin or its associated adapter molecule p120 catenin (p120ctn), and it involves a switch in signaling between the collagen binding integrins alpha(1)beta(1) and alpha(2)beta(1). Direct interaction between E-cadherin and Co-029 was documented by chemical cross-linking and immunohistologic analysis of colon carcinomas. High expression of Co-029 and cytoplasmic delocalization of p120ctn were each associated with poor prognosis. Cell motility was reduced severely by antibody-mediated disruption of Co-029 only when p120ctn was silenced, suggesting that tumor progression may be hindered by Co-029 targeting. Our findings define a function for tetraspanin Co-029 as a modifier of cancer cell motility and reveal an adhesion signaling network implicated in progression and metastasis. PMID- 20858718 TI - Liver cancer protease activity profiles support therapeutic options with matrix metalloproteinase-activatable oncolytic measles virus. AB - Primary and secondary cancers of the liver are a significant health problem with limited treatment options. We sought here to develop an oncolytic measles virus (MV) preferentially activated in liver tumor tissue, thus reducing infection and destruction of healthy tissue. We documented that in primary tumor tissue, urokinase-type plasminogen activator and especially matrix metalloproteinase-2 (MMP-2) are significantly more active than in adjacent nontumorous tissue. We then generated variants of the MV fusion protein by inserting different MMP substrate motifs at the protease cleavage site and identified the motif PQGLYA as the most efficient cleavage site as determined by syncytia formation on protease positive tumor cells. The corresponding MMP-activatable oncolytic MV-MMPA1 virus was rescued and shown to be strongly restricted on primary human hepatocytes and healthy human liver tissue, while remaining as effective as the parental MV in the tumor tissue sections. Our findings underline the clinical potency of the MMP activation concept as a strategy to generate safer oncolytic viruses for the treatment of primary and secondary cancers of the liver. PMID- 20858720 TI - Epidermal growth factor receptor expression identifies functionally and molecularly distinct tumor-initiating cells in human glioblastoma multiforme and is required for gliomagenesis. AB - Epidermal growth factor receptor (EGFR) is a known diagnostic and, although controversial, prognostic marker of human glioblastoma multiforme (GBM). However, its functional role and biological significance in GBM remain elusive. Here, we show that multiple GBM cell subpopulations could be purified from the specimens of patients with GBM and from cancer stem cell (CSC) lines based on the expression of EGFR and of other putative CSC markers. All these subpopulations are molecularly and functionally distinct, are tumorigenic, and need to express EGFR to promote experimental tumorigenesis. Among them, EGFR-expressing tumor initiating cells (TIC) display the most malignant functional and molecular phenotype. Accordingly, modulation of EGFR expression by gain-of-function and loss-of-function strategies in GBM CSC lines enhances and reduces their tumorigenic ability, respectively, suggesting that EGFR plays a fundamental role in gliomagenesis. These findings open up the possibility of new therapeutically relevant scenarios, as the presence of functionally heterogeneous EGFR(pos) and EGFR(neg) TIC subpopulations within the same tumor might affect clinical response to treatment. PMID- 20858719 TI - Hyperpolarized 13C spectroscopic imaging informs on hypoxia-inducible factor-1 and myc activity downstream of platelet-derived growth factor receptor. AB - The recent development of hyperpolarized (13)C magnetic resonance spectroscopic imaging provides a novel method for in vivo metabolic imaging with potential applications for detection of cancer and response to treatment. Chemotherapy induced apoptosis was shown to decrease the flux of hyperpolarized (13)C label from pyruvate to lactate due to depletion of NADH, the coenzyme of lactate dehydrogenase. In contrast, we show here that in PC-3MM2 tumors, inhibition of platelet-derived growth factor receptor with imatinib reduces the conversion of hyperpolarized pyruvate to lactate by lowering the expression of lactate dehydrogenase itself. This was accompanied by reduced expression of vascular endothelial growth factor and glutaminase, and is likely mediated by reduced expression of their transcriptional factors hypoxia-inducible factor-1 and c-Myc. Our results indicate that hyperpolarized (13)C MRSI could potentially detect the molecular effect of various cell signaling inhibitors, thus providing a radiation free method to predict tumor response. PMID- 20858721 TI - MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. AB - The variants c.306+5G>A and c.1865T>A (p.Leu622His) of the DNA repair gene MLH1 occur frequently in Spanish Lynch syndrome families. To understand their ancestral history and clinical effect, we performed functional assays and a penetrance analysis and studied their genetic and geographic origins. Detailed family histories were taken from 29 carrier families. Functional analysis included in silico and in vitro assays at the RNA and protein levels. Penetrance was calculated using a modified segregation analysis adjusted for ascertainment. Founder effects were evaluated by haplotype analysis. The identified MLH1 c.306+5G>A and c.1865T>A (p.Leu622His) variants are absent in control populations and segregate with the disease. Tumors from carriers of both variants show microsatellite instability and loss of expression of the MLH1 protein. The c.306+5G>A variant is a pathogenic mutation affecting mRNA processing. The c.1865T>A (p.Leu622His) variant causes defects in MLH1 expression and stability. For both mutations, the estimated penetrance is moderate (age-cumulative colorectal cancer risk by age 70 of 20.1% and 14.1% for c.306+5G>A and of 6.8% and 7.3% for c.1865T>A in men and women carriers, respectively) in the lower range of variability estimated for other pathogenic Spanish MLH1 mutations. A common haplotype was associated with each of the identified mutations, confirming their founder origin. The ages of c.306+5G>A and c.1865T>A mutations were estimated to be 53 to 122 and 12 to 22 generations, respectively. Our results confirm the pathogenicity, moderate penetrance, and founder origin of the MLH1 c.306+5G>A and c.1865T>A mutations. These findings have important implications for genetic counseling and molecular diagnosis of Lynch syndrome. PMID- 20858722 TI - Automated grading for diabetic retinopathy: a large-scale audit using arbitration by clinical experts. AB - BACKGROUND/AIMS: Automated grading software has the potential to reduce the manual grading workload within diabetic retinopathy screening programmes. This audit was undertaken at the request of Scotland's National Diabetic Retinopathy Screening Collaborative to assess whether the introduction of automated grading software into the national screening programme would be safe, robust and effective. METHODS: Automated grading, performed by software for image quality assessment and for microaneurysm/dot haemorrhage detection, was carried out on 78,601 images, obtained from 33,535 consecutive patients, which had been manually graded at one of two regional diabetic retinopathy screening programmes. Cases where the automated grading software assessment indicated gradable images with no disease but the screening programme indicated ungradable images or disease more severe than mild retinopathy were arbitrated by seven senior ophthalmologists. RESULTS: 100% (180/180) of patients with proliferative retinopathy, 100% (324/324) with referable background retinopathy, 100% (193/193) with observable background retinopathy, 97.3% (1099/1130) with referable maculopathy, 99.2% (384/387) with observable maculopathy and 99.8% (1824/1827) with ungradable images were detected by the software. CONCLUSION: The automated grading software operated to previously published results when applied to a large, unselected population attending two regional screening programmes. Manual grading workload reduction would be 36.3%. PMID- 20858723 TI - Targeted delivery of saporin toxin by monoclonal antibody to the transcobalamin receptor, TCblR/CD320. AB - Cellular uptake of cobalamin (Cbl) occurs by endocytosis of transcobalamin saturated with Cbl by the transcobalamin receptor (TCblR/CD320). The cell cycle associated overexpression of this receptor in many cancer cells provides a suitable target for delivering chemotherapeutic drugs and cytotoxic molecules to these cells while minimizing the effect on the normal cell population. We have used monoclonal antibodies to the extracellular domain of TCblR to deliver saporin-conjugated secondary antibody to various cell lines propagating in culture. A molar ratio of 2.5:10 nmol/L of primary:secondary antibody concentration was identified as the lowest concentration needed to produce the optimum cytotoxic effect. The effect was more pronounced when cells were seeded at lower density, suggesting lack of cell division in a fraction of the cells at higher density as the likely explanation. Cells in suspension culture, such as K562 and U266 cells, were more severely affected than adherent cultures, such as SW48 and KB cells. This differential effect of the anti-TCblR-saporin antibody conjugate and the ability of an anti-TCblR antibody to target proliferating cells were further evident by the virtual lack of any effect on primary skin fibroblasts and minimal effect on bone marrow cells. These results indicate that preferential targeting of some cancer cells could be accomplished through the TCblR. PMID- 20858724 TI - Antitumor effect of temsirolimus against oral squamous cell carcinoma associated with bone destruction. AB - The mammalian target of rapamycin (mTOR) is engaged in the molecular pathogenesis of oral squamous cell carcinoma, which frequently invades the maxilla or the mandible. However, the effects of a mTOR inhibitor on bone destruction associated with oral squamous cell carcinoma are still unclear. In this study, we investigated the antitumor effect of temsirolimus-mediated mTOR inhibition against advanced oral squamous cell carcinoma. Temsirolimus inhibited the proliferation and migration of HSC-2 oral squamous cell carcinoma cells in vitro and suppressed the growth of oral squamous cell carcinoma xenografts in vivo. Significantly, we clearly show that temsirolimus inhibited osteoclast formation both in vitro and in vivo. Reverse transcriptase-PCR analysis showed that temsirolimus decreased the mRNA expression of receptor activator for nuclear factor-kappaB ligand, known as an osteoclast differentiation factor in bone stromal ST2 cells. Moreover, temsirolimus normalized blood-free calcium concentration in mouse models for humoral hypercalcemia. These findings suggest that mTOR signaling is a potential target of oral squamous cell carcinoma associated with bone destruction, and hence we describe the efficacy of temsirolimus for the treatment of advanced oral squamous carcinoma. PMID- 20858725 TI - The use of one-bead one-compound combinatorial library technology to discover high-affinity alphavbeta3 integrin and cancer targeting arginine-glycine-aspartic acid ligands with a built-in handle. AB - The alphavbeta3 integrin, expressed on the surface of various normal and cancer cells, is involved in numerous physiologic processes such as angiogenesis, apoptosis, and bone resorption. Because this integrin plays a key role in angiogenesis and metastasis of human tumors, alphavbeta3 integrin ligands are of great interest to advances in targeted therapy and cancer imaging. In this report, one-bead one-compound (OBOC) combinatorial libraries containing the arginine-glycine-aspartic acid (RGD) motif were designed and screened against K562 myeloid leukemia cells that had been transfected with the human alphavbeta3 integrin gene. Cyclic peptide LXW7 was identified as a leading ligand with a built-in handle that binds specifically to alphavbeta3 and showed comparable binding affinity (IC(50) = 0.68 +/- 0.08 MUmol/L) to some of the well-known RGD "head-to-tail" cyclic pentapeptide ligands reported in the literature. The biotinylated form of LXW7 ligand showed similar binding strength as LXW7 against alphavbeta3 integrin, whereas biotinylated RGD cyclopentapeptide ligands revealed a 2- to 8-fold weaker binding affinity than their free forms. LXW7 was able to bind to both U-87MG glioblastoma and A375M melanoma cell lines, both of which express high levels of alphavbeta3 integrin. In vivo and ex vivo optical imaging studies with the biotinylated ligand/streptavidin-Cy5.5 complex in nude mice bearing U-87MG or A375M xenografts revealed preferential uptake of biotinylated LXW7 in tumor. When compared with biotinylated RGD cyclopentapeptide ligands, biotinylated LXW7 showed higher tumor uptake but lower liver uptake. PMID- 20858726 TI - Monitoring molecular-specific pharmacodynamics of rapamycin in vivo with inducible Gal4->Fluc transgenic reporter mice. AB - Rapamycin (Rap), a small-molecule inhibitor of mTOR, is an immunosuppressant, and several Rap analogues are cancer chemotherapeutics. Further pharmacologic development will be significantly facilitated if in vivo reporter models are available to enable monitoring of molecular-specific pharmacodynamic actions of Rap and its analogues. Herein we present the use of a Gal4->Fluc reporter mouse for the study of Rap-induced mTOR/FKBP12 protein-protein interactions in vivo with the use of a mouse two-hybrid transactivation strategy, a derivative of the yeast two-hybrid system applied to live mice. Upon treatment with Rap, a bipartite transactivator was reconstituted, and transcription of a genomic firefly luciferase reporter was activated in a concentration-dependent (K(d) = 2.3 nmol/L) and FK506-competitive (K(i) = 17.1 nmol/L) manner in cellulo, as well as in a temporal and specific manner in vivo. In particular, after a single dose of Rap (4.5 mg/kg, i.p.), peak Rap-induced protein-protein interactions were observed in the liver at 24 hours post treatment, with photon flux signals 600 fold over baseline, which correlated temporally with suppression of p70S6 kinase activity, a downstream effector of mTOR. The Gal4->Fluc reporter mouse provides an intact physiologic system to interrogate protein-protein interactions and molecular-specific pharmacodynamics during drug discovery and lead characterization. Imaging protein interactions and functional proteomics in whole animals in vivo may serve as a basic tool for screening and mechanism-based analysis of small molecules targeting specific protein-protein interactions in human diseases. PMID- 20858727 TI - Genetically engineered oncolytic Newcastle disease virus effectively induces sustained remission of malignant pleural mesothelioma. AB - Malignant pleural mesothelioma is a highly aggressive tumor. Alternative treatment strategies such as oncolytic viral therapy may offer promising treatment options in the future. In this study, the oncolytic efficacy and induction of tumor remission by a genetically engineered Newcastle disease virus [NDV; NDV(F3aa)-GFP; GFP, green fluorescent protein] in malignant pleural mesothelioma is tested and monitored by bioluminescent tumor imaging. The efficacy of NDV(F3aa)-GFP was tested against several mesothelioma cell lines in vitro. Firefly luciferase-transduced MSTO-211H* orthotopic pleural mesothelioma tumor-bearing animals were treated with either single or multiple doses of NDV(F3aa)-GFP at different time points (days 1 and 10) after tumor implantation. Tumor burden was assessed by bioluminescence imaging. Mesothelioma cell lines exhibited dose-dependent susceptibility to NDV lysis in the following order of sensitivity: MSTO-211H > MSTO-211H* > H-2452 > VAMT > JMN. In vivo studies with MSTO-211H* cells showed complete response to viral therapy in 65% of the animals within 14 days after treatment initiation. Long-term survival in all of these animals was >50 days after tumor installation (control animals, <23 d). Multiple treatment compared with single treatment showed a significantly better response (P = 0.005). NDV seems to be an efficient viral oncolytic agent in the therapy of malignant pleural mesothelioma in an orthotopic pleural mesothelioma tumor model. PMID- 20858728 TI - Global proteomics reveal an atypical strategy for carbon/nitrogen assimilation by a cyanobacterium under diverse environmental perturbations. AB - Cyanobacteria, the only prokaryotes capable of oxygenic photosynthesis, are present in diverse ecological niches and play crucial roles in global carbon and nitrogen cycles. To proliferate in nature, cyanobacteria utilize a host of stress responses to accommodate periodic changes in environmental conditions. A detailed knowledge of the composition of, as well as the dynamic changes in, the proteome is necessary to gain fundamental insights into such stress responses. Toward this goal, we have performed a large-scale proteomic analysis of the widely studied model cyanobacterium Synechocystis sp. PCC 6803 under 33 different environmental conditions. The resulting high-quality dataset consists of 22,318 unique peptides corresponding to 1955 proteins, a coverage of 53% of the predicted proteome. Quantitative determination of protein abundances has led to the identification of 1198 differentially regulated proteins. Notably, our analysis revealed that a common stress response under various environmental perturbations, irrespective of amplitude and duration, is the activation of atypical pathways for the acquisition of carbon and nitrogen from urea and arginine. In particular, arginine is catabolized via putrescine to produce succinate and glutamate, sources of carbon and nitrogen, respectively. This study provides the most comprehensive functional and quantitative analysis of the Synechocystis proteome to date, and shows that a significant stress response of cyanobacteria involves an uncommon mode of acquisition of carbon and nitrogen. PMID- 20858729 TI - Microstructured elastomeric surfaces with reversible adhesion and examples of their use in deterministic assembly by transfer printing. AB - Reversible control of adhesion is an important feature of many desired, existing, and potential systems, including climbing robots, medical tapes, and stamps for transfer printing. We present experimental and theoretical studies of pressure modulated adhesion between flat, stiff objects and elastomeric surfaces with sharp features of surface relief in optimized geometries. Here, the strength of nonspecific adhesion can be switched by more than three orders of magnitude, from strong to weak, in a reversible fashion. Implementing these concepts in advanced stamps for transfer printing enables versatile modes for deterministic assembly of solid materials in micro/nanostructured forms. Demonstrations in printed two- and three-dimensional collections of silicon platelets and membranes illustrate some capabilities. An unusual type of transistor that incorporates a printed gate electrode, an air gap dielectric, and an aligned array of single walled carbon nanotubes provides a device example. PMID- 20858730 TI - Electrochemical and homogeneous electron transfers to the Alzheimer amyloid-beta copper complex follow a preorganization mechanism. AB - Deciphering the electron transfer reactivity characteristics of amyloid beta peptide copper complexes is an important task in connection with the role they are assumed to play in Alzheimer's disease. A systematic analysis of this question with the example of the amyloid beta-peptide copper complex by means of its electrochemical current-potential responses and of its homogenous reactions with electrogenerated fast electron exchanging osmium complexes revealed a quite peculiar mechanism: The reaction proceeds through a small fraction of the complex molecules in which the peptide complex is "preorganized" so as the distances and angles in the coordination sphere to vary minimally upon electron transfer, thus involving a remarkably small reorganization energy (0.3 eV). This preorganization mechanism and its consequences on the reactivity should be taken into account for reactions involving dioxygen and hydrogen peroxide that are considered to be important in Alzheimer's disease through the production of harmful reactive oxygen species. PMID- 20858731 TI - The C-MYB story--is it definitive? PMID- 20858732 TI - PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts. AB - A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explant-derived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrbeta, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rho-associated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish. PMID- 20858733 TI - Structural insights into the pH-controlled targeting of plant cell-wall invertase by a specific inhibitor protein. AB - Invertases are highly regulated enzymes with essential functions in carbohydrate partitioning, sugar signaling, and plant development. Here we present the 2.6 A crystal structure of Arabidopsis cell-wall invertase 1 (INV1) in complex with a protein inhibitor (CIF, or cell-wall inhibitor of beta-fructosidase) from tobacco. The structure identifies a small amino acid motif in CIF that directly targets the invertase active site. The activity of INV1 and its interaction with CIF are strictly pH-dependent with a maximum at about pH 4.5. At this pH, isothermal titration calorimetry reveals that CIF tightly binds its target with nanomolar affinity. CIF competes with sucrose (Suc) for the same binding site, suggesting that both the extracellular Suc concentration and the pH changes regulate association of the complex. A conserved glutamate residue in the complex interface was previously identified as an important quantitative trait locus affecting fruit quality, which implicates the invertase-inhibitor complex as a main regulator of carbon partitioning in plants. Comparison of the CIF/INV1 structure with the complex between the structurally CIF-related pectin methylesterase inhibitor (PMEI) and pectin methylesterase indicates a common targeting mechanism in PMEI and CIF. However, CIF and PMEI use distinct surface areas to selectively inhibit very different enzymatic scaffolds. PMID- 20858734 TI - ATP synthase: from sequence to ring size to the P/O ratio. PMID- 20858735 TI - Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. AB - ErbB4 is unusual among receptor tyrosine kinases because some isoforms can be efficiently cleaved at the plasma membrane to release a soluble intracellular domain. The cleavage product has high kinase activity and homes to the nucleus. A screen for proteins that associate with the ErbB4 intracellular domain identified candidate interactors including ITCH, WWP2, Nucleolin, and Krab-associated protein 1 (Kap1). Kap1 binds to multiple isoforms of ErbB4 but does not require ErbB4 kinase activity for binding, nor is it an ErbB4 substrate. Kap1 reduces ERBB4 transcription and either directly or indirectly modulates the expression of genes that are themselves regulated by ErbB4. Upregulation of ErbB4 and suppression of MDM2 jointly enhance and accelerate the accumulation of p21(CIP1) in response to DNA damage. Overall, these findings further substantiate the role of ErbB4 in conjoint regulation of growth factor signaling and DNA damage responses. PMID- 20858736 TI - Hsp27 protects adenocarcinoma cells from UV-induced apoptosis by Akt and p21 dependent pathways of survival. AB - Transcriptional activation of p53 target genes, due to DNA damage, causes either apoptosis or survival by cell cycle arrest and DNA repair. However, the regulators of the choice between cell death and survival signaling have not been completely elucidated. Here, we report that human adenocarcinoma cells (MCF-7) survive UV-induced DNA damage by heat shock protein 27 (Hsp27)-assisted Akt/p21 phosphorylation/translocation. Protein levels of the p53 target genes, such as p21, Bcl-2, p38MAPK, and Akt, showed a positive correlation to Hsp27 level during 48 hours postirradiation, whereas p53 expression increased initially but started decreasing after 12 hours. Hsp27 prevented the G(1)-S phase cell cycle arrest, observed after 8 hours of post-UV irradiation, and PARP-1 cleavage was inhibited. Conversely, silencing Hsp27 enhanced G(1)-S arrest and cell death. Moreover, use of either Hsp27 or Akt small interference RNA reduced p21 phosphorylation and enhanced its retention in nuclei even after 48 hours postirradiation, resulting in enhanced cell death. Our results showed that Hsp27 expression and its direct chaperoning interaction increases Akt stability, and p21 phosphorylation and nuclear-to-cytoplasm translocation, both essential effects for the survival of UV induced DNA-damaged cells. We conclude that the role of Hsp27 in cancer is not only for enhanced p53 proteolysis per se, rather it is also a critical determinant in p21 phosphorylation and translocation. PMID- 20858737 TI - Prostaglandin E receptor EP1 suppresses breast cancer metastasis and is linked to survival differences and cancer disparities. AB - Cyclooxygenase-2 is frequently overexpressed and associated with poor prognosis in breast cancer. The cyclooxygenase-2 product prostaglandin E(2) elicits cellular responses through four G-protein-coupled receptors, designated EP1 to EP4, coupled to distinct intracellular signaling pathways. EP4, expressed on malignant breast cells, promotes metastasis; however, a role for EP1 in metastasis has not been investigated. Using a murine model of metastatic breast cancer, we now show that pharmacologic antagonism of EP1 with SC19220 or AH6809 promoted lung colonization of mammary tumor cells by 3.7- to 5.4-fold. Likewise, reducing EP1 gene expression by shRNA also increased metastatic capacity relative to cells transfected with nonsilencing vector but did not affect the size of transplanted tumors. Examination of invasive ductal carcinomas by immunohistochemistry shows that EP1 was detected in both the cytoplasm and nucleus of benign ducts as well as malignant cells in some samples, but was absent or limited to either the nucleus or cytoplasm in other malignant samples. Overall survival for women with tumors that were negative for nuclear EP1 was significantly worse than for women with EP1 expression (P = 0.008). There was no difference in survival for women with differences in cytoplasmic EP1 expression (P = 0.46). Comparing EP1 mRNA in breast tumors from African American and European American women revealed that many more African American breast tumors lacked detectable EP1 mRNA (P = 0.04). These studies support the hypothesis that EP1 functions as a metastasis suppressor and that loss of nuclear EP1 is associated with poorer overall survival and may contribute to disparities in outcome in different populations. PMID- 20858738 TI - Computational analysis of miRNA targets in plants: current status and challenges. AB - Plant microRNAs (miRNA) target recognition mechanism was once thought to be simple and straightforward, i.e. through perfect reverse complementary matching; therefore, very few target prediction tools and algorithms were developed for plants as compared to those for animals. However, the discovery of transcription suppression and the more recent observation of widespread translational regulation by miRNAs highlight the enormous diversity and complexity of gene regulation in plant systems. This, in turn, necessitates the need for advanced computational tools/algorithms for comprehensive miRNA target analysis to help understand miRNA regulatory mechanisms. Yet, advanced/comprehensive plant miRNA target analysis tools are still lacking despite the desirability and importance of such tools, especially the ability of predicting translational inhibition and integrating transcriptome data. This review focuses on recent progress in plant miRNA target recognition mechanism, principles of target prediction based on these understandings, comparison of current prediction tools and algorithms for plant miRNA target analysis and the outlook for future directions in the development of plant miRNA target tools and algorithms. PMID- 20858740 TI - Lesion development and replication kinetics during early infection in cattle inoculated with Vesicular stomatitis New Jersey virus via scarification and black fly (Simulium vittatum) bite. AB - Vesicular stomatitis viruses are the causative agents of vesicular stomatitis, an economically important contagious disease of livestock that occurs in North, Central, and South America. Little is known regarding the early stages of infection in natural hosts. Twelve adult Holstein steers were inoculated with Vesicular stomatitis New Jersey virus (VSNJV) on the coronary bands (CB) of the feet via scarification (SC) or by VSNJV-infected black fly (Simulium vittatum) bite (FB). Three additional animals were inoculated on the neck skin using FB. Clinical disease and lesion development were assessed daily, and animals were euthanatized from 12 hours post inoculation (HPI) through 120 HPI. The animals inoculated in the neck failed to develop any clinical signs or gross lesions, and VSNJV was detected neither by in situ hybridization (ISH) nor by immunohistochemistry (IHC). Lesions on the CB were more severe in the animals infected by FB than by SC. In both groups, peak VSNJV replication occurred between 24 and 48 HPI in keratinocytes of the CB, as evidenced by ISH and IHC. There was evidence of viral replication limited to the first 24 HPI in the local draining lymph nodes, as seen through ISH. Successful infection via FB required logarithmically less virus than with the SC technique, suggesting that components in black fly saliva may facilitate VSNJV transmission and infection in cattle. The lack of lesion development in the neck with the same method of inoculation used in the CB suggests that specific characteristics of the CB epithelium may facilitate VSNJV infection. PMID- 20858741 TI - Immunohistochemical identification of canine melanocytic neoplasms with antibodies to melanocytic antigen PNL2 and tyrosinase: comparison with Melan A. AB - The immunoreactivity of PNL2 and antityrosinase in formalin-fixed, paraffin embedded canine melanocytic neoplasms (n = 101) was compared with that of Melan A. Of the 113 samples overall, 106 were positive for PNL2, 101 for Melan A, and 90 for tyrosinase. Six melanomas that were positive for PNL2 were negative for Melan A; 1 melanoma that was negative for PNL2 was positive for Melan A. Eighty tumors were positive for all 3 markers; 111 reacted with at least 1 the 3 antibodies. Decalcification with formic acid for up to 1 week did not affect immunoreactivity of any of the markers; however, decalcification with HCl for 1 day or 1 week notably decreased or completely abrogated immunoreactivity for Melan A and PNL2. There was only minor loss of immunoreactivity for tyrosinase in tissues decalcified with HCl for 1 week. Prolonged fixation (up to 2 months) did not affect PNL2 or tyrosinase immunoreactivity; however, Melan A immunoreactivity was reduced after 1 month of fixation. PNL2 was not expressed in 120 nonmelanocytic tumors (carcinomas, sarcomas, steroid-producing tumors, and leukocytic tumors). In summary, antibody PNL2 is slightly more sensitive than Melan A and more sensitive than tyrosinase in the identification of canine melanocytic neoplasms. Furthermore, PNL2 does not appear to cross-react with nonmelanocytic neoplasms. PNL2 is resistant to prolonged fixation but sensitive to strong decalcification. Results indicate that PNL2 is an excellent marker in the identification of canine melanomas and that the sensitivity is close to 100% when used in conjunction with Melan A and tyrosinase. PMID- 20858742 TI - Proliferative peritonitis with larval and cystic parasitic stages in a dog. AB - A six year old Labrador mix dog, born in Spain, was imported to Germany in young age. After a period of vague abdominal pain and negative laboratory results, the dog was referred to a local veterinary clinic for laparotomy, where the tentative diagnosis of echinococcus alveolaris was made and the dog was euthanized. At necropsy, many cystic structures and a massive proliferative peritonitis were visible. Furthermore a few solid larval cestodal stages were found in the peritoneal and chest cavity. Histological the cysts contained a small eosinophillic tegument, a cell poor stroma, basophilic somatic nuclei and a variable amount of amorphous bodies. The solid cestodes exhibited a quite similar composition with neither scolices nor any head structures. Histological features of the parasitic stages resembled cysts and asexual stages of Sparganum proliferum. Distinctions to other larval cestode infestations in body cavities were discussed. PMID- 20858739 TI - Oestrogen receptor beta ligand: a novel treatment to enhance endogenous functional remyelination. AB - Demyelinating diseases, such as multiple sclerosis, are characterized by inflammatory demyelination and neurodegeneration of the central nervous system. Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future therapy of multiple sclerosis. Oestrogens and oestrogen receptor ligands are promising treatments to prevent multiple sclerosis-induced neurodegeneration. In the present study we investigated the capacity of oestrogen receptor beta ligand treatment to affect callosal axon demyelination and stimulate endogenous myelination in chronic experimental autoimmune encephalomyelitis using electrophysiology, electron microscopy, immunohistochemistry and tract-tracing methods. Oestrogen receptor beta ligand treatment of experimental autoimmune encephalomyelitis mice prevented both histopathological and functional abnormalities of callosal axons despite the presence of inflammation. Specifically, there were fewer demyelinated, damaged axons and more myelinated axons with intact nodes of Ranvier in oestrogen receptor beta ligand-treated mice. In addition, oestrogen receptor beta ligand treatment caused an increase in mature oligodendrocyte numbers, a significant increase in myelin sheath thickness and axon transport. Functional analysis of callosal axon conduction showed a significant improvement in compound action potential amplitudes, latency and in axon refractoriness. These findings show a direct neuroprotective effect of oestrogen receptor beta ligand treatment on oligodendrocyte differentiation, myelination and axon conduction during experimental autoimmune encephalomyelitis. PMID- 20858743 TI - Anthropometric factors in adulthood and risk of colorectal adenomas: The French E3N-EPIC prospective cohort. AB - Anthropometric factors have been associated with colorectal cancer and adenomas but with conflicting results in women or regarding adenoma characteristics. The authors aimed to explore associations between anthropometric factors (height, weight, body mass index, waist and hip circumferences, and weight changes) and adenoma risk. They analyzed the 17,391 women of the French Etude epidemiologique des femmes de la Mutuelle Generale de l'Education Nationale (E3N)-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort who underwent a colonoscopy during follow-up (1993-2002), including 1,408 who developed a first colorectal adenoma. In Cox multivariate proportional hazard regression models, obesity was associated with an increased colorectal adenoma risk (hazard ratio = 1.53, 95% confidence interval: 1.21, 1.94). This association was restricted to left colon adenomas (P(homogeneity) = 0.05 and 0.01 for colon vs. rectum and right vs. left colon, respectively), with a dose-effect relation observed from 22 kg/m2. A high waist circumference was also associated with left colon adenoma risk (hazard ratio = 1.81, 95% confidence interval: 1.36, 2.41). Mean weight gain over 0.5 kg/year was associated with a 23% increased colorectal adenoma risk. Associations did not differ between advanced and nonadvanced adenomas. In conclusion, study findings suggest that obesity and weight gain are associated with early colorectal carcinogenesis in women, and specifically regarding the distal colon. PMID- 20858744 TI - Familial aggregation of glioma: a pooled analysis. AB - In genome-wide association studies, inherited risk of glioma has been demonstrated for rare familial syndromes and with common variants from 3-5 chromosomal regions. To assess the degree of familial aggregation of glioma, the authors performed a pooled analysis of data from 2 large glioma case-control studies in the United States (MD Anderson Cancer Center, Houston, Texas (1994 2006) and University of California, San Francisco (1991-2004)) and from the Swedish Cancer Registry (1958-2006) to measure excess cases of cancer among first degree relatives of glioma probands. This analysis included 20,377 probands with glioma and 52,714 first-degree relatives. No overall increase was found in the expected number of cancers among family members; however, there were 77% more gliomas than expected. There were also significantly more sarcoma and melanoma cases than expected, which is supported by evidence in the literature, whereas there were significantly fewer-than-expected cases of leukemia, non-Hodgkin lymphoma, and bladder, lung, pancreatic, prostate, and uterine cancers. This large pooled analysis provided sufficient numbers of related family members to examine the genetic mechanisms involved in the aggregation of glioma with other cancers in these families. However, misclassification due to unvalidated cancers among family members could account for the differences seen by study site. PMID- 20858745 TI - A population-based case-control study of fetal growth, gestational age, and maternal breast cancer. AB - Fetal growth or gestational age in a woman's pregnancies may modify pregnancy related breast cancer risk, yet studies of these exposures are few. The authors conducted a population-based case-control study among parous Michigan women aged <=50 years using linked Michigan Cancer Registry (1985-2004) and Michigan livebirth records (1978-2004). Breast cancer cases (n = 7,591) were matched 1:4 to controls (n = 28,382) on maternal birth year and race. Using conditional logistic regression, the authors examined the associations of gestational age (in weeks) and fetal growth (defined using birth weight percentiles for gestational age) in first and last births with breast cancer risk. Having a small-for gestational-age or large-for-gestational-age infant at a maternal first or last birth was not associated with breast cancer risk, but having a small-for gestational-age infant at a last birth at >=30 years modestly reduced risk: odds ratio = 0.82 (95% confidence interval: 0.68, 0.98). First delivery at <32 or >41 weeks also modestly reduced risk: odds ratio = 0.80 (95% confidence interval: 0.62, 1.04) or 0.92 (95% confidence interval: 0.85, 0.99), respectively. In the largest case-control study to date, fetal growth was not associated with overall breast cancer risk in women aged <=50, and there was some evidence for reduced breast cancer risk for early or late gestational age in first births only. PMID- 20858746 TI - Dynamics of nasal irritation from pulsed homologous alcohols. AB - Relatively, few studies have focused on how nasal irritation changes over time. To simulate the rhythm of natural respiration, subjects received 3-s pulses of volatile organic compounds interspersed with 3-s pulses of clean air. Each trial, subjects received 9 pulses of a chemical vapor over about 1 min. Subjects rated nasal irritation from each pulse using magnitude estimation. Within a trial, compound and concentration were fixed. Compound (ethanol, n-butanol, or n hexanol) and concentration (4 levels for each compound) varied across trials. For all stimuli, rated irritation decreased over time (adaptation). Plots of log rated intensity versus elapsed time were approximately linear (intensity decreased by a fixed ratio per unit time). Interestingly, the slopes of intensity versus time functions differed very little: Regardless of concentration and compound, rated irritation decreased by about 32% over the 9 pulses. The basic mechanism of short-term adaptation may be the same for the 3 alcohols studied. Regardless, these data suggest that very simple models might be able to describe some aspects of perceptual dynamics quite well. PMID- 20858747 TI - Subcellular localization-dependent decrements in skeletal muscle glycogen and mitochondria content following short-term disuse in young and old men. AB - Previous studies have shown that skeletal muscle glycogen and mitochondria are distributed in distinct subcellular localizations, but the role and regulation of these subcellular localizations are unclear. In the present study, we used transmission electron microscopy to investigate the effect of disuse and aging on human skeletal muscle glycogen and mitochondria content in subsarcolemmal (SS), intermyofibrillar (IMF), and intramyofibrillar (intra) localizations. Five young (~23 yr) and five old (~66 yr) recreationally active men had their quadriceps muscle immobilized for 2 wk by whole leg casting. Biopsies were obtained from m. vastus lateralis before and after the immobilization period. Immobilization induced a decrement of intra glycogen content by 54% (P < 0.001) in both age groups and in two ultrastructurally distinct fiber types, whereas the content of IMF and SS glycogen remained unchanged. A localization-dependent decrease (P = 0.03) in mitochondria content following immobilization was found in both age groups, where SS mitochondria decreased by 33% (P = 0.02), superficial IMF mitochondria decreased by 20% (P = 0.05), and central IMF mitochondria remained unchanged. In conclusion, our findings demonstrate a localization-dependent adaptation to immobilization in glycogen and mitochondria content of skeletal muscles of both young and old individuals. Specifically, this suggests that short term disuse preferentially affects glycogen particles located inside the myofibrils and that mitochondria volume plasticity can be dependent on the distance to the fiber border. PMID- 20858748 TI - Signaling and cytotoxic functions of 4-hydroxyalkenals. AB - The peroxidation of n-3 and n-6 polyunsaturated fatty acids (PUFAs) and of their hydroperoxy metabolites is a complex process. It is initiated by free oxygen radical-induced abstraction of a hydrogen atom from the lipid molecule followed by a series of nonenzymatic reactions that ultimately generate the reactive aldehyde species 4-hydroxyalkenals. The molecule 4-hydroxy-2E-hexenal (4-HHE) is generated by peroxidation of n-3 PUFAs, such as linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid. The aldehyde product 4-hydroxy-2E-nonenal (4-HNE) is the peroxidation product of n-6 PUFAs, such as arachidonic and linoleic acids and their 15-lipoxygenase metabolites, namely 15-hydroperoxyeicosatetraenoic acid (15-HpETE) and 13-hydroperoxyoctadecadienoic acid (13-HpODE). Another reactive peroxidation product is 4-hydroxy-2E,6Z-dodecadienal (4-HDDE), which is derived from 12-hydroperoxyeicosatetraenoic acid (12-HpETE), the 12-lipoxygenase metabolite of arachidonic acid. Hydroxyalkenals, notably 4-HNE, have been implicated in various pathophysiological interactions due to their chemical reactivity and the formation of covalent adducts with macromolecules. The progressive accumulation of these adducts alters normal cell functions that can lead to cell death. The lipophilicity of these aldehydes positively correlates to their chemical reactivity. Nonetheless, at low and noncytotoxic concentrations, these molecules may function as signaling molecules in cells. This has been shown mostly for 4-HNE and to some extent for 4-HHE. The capacity of 4-HDDE to generate such "mixed signals" in cells has received less attention. This review addresses the origin and cellular functions of 4-hydroxyalkernals. PMID- 20858749 TI - Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia. AB - Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 MUmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 +/- 32.23 vs. 119.50 +/- 37.68 MUmol/l and 1.43 +/- 0.46 vs. 1.73 +/- 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 +/- 0.49 vs. 3.09 +/- 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part. PMID- 20858750 TI - MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic beta-cell proliferation in islets from early lactating mothers. AB - Maternal pancreatic islets undergo a robust increase of mass and proliferation during pregnancy, which allows a compensation of gestational insulin resistance. Studies have described that this adaptation switches to a low proliferative status after the delivery. The mechanisms underlying this reversal are unknown, but the action of glucocorticoids (GCs) is believed to play an important role because GCs counteract the pregnancy-like effects of PRL on isolated pancreatic islets maintained in cell culture. Here, we demonstrate that ERK1/2 phosphorylation (phospho-ERK1/2) is increased in maternal rat islets isolated on the 19th day of pregnancy. Phospho-ERK1/2 status on the 3rd day after delivery (L3) rapidly turns to values lower than that found in virgin control rats (CTL). MKP-1, a protein phosphatase able to dephosphorylate ERK1/2, is increased in islets from L3 rats. Chromatin immunoprecipitation assay revealed that binding of glucocorticoid receptor (GR) to MKP-1 promoter is also increased in islets from L3 rats. In addition, dexamethasone (DEX) reduced phospho-ERK1/2 and increased MKP-1 expression in RINm5F and MIN-6 cells. Inhibition of transduction with cycloheximide and inhibition of phosphatases with orthovanadate efficiently blocked DEX-induced downregulation of phospho-ERK1/2. In addition, specific knockdown of MKP-1 with siRNA suppressed the downregulation of phospho-ERK1/2 and the reduction of proliferation induced by DEX. Altogether, our results indicate that downregulation of phospho-ERK1/2 is associated with reduction in proliferation found in islets of early lactating mothers. This mechanism is probably mediated by GC-induced MKP-1 expression. PMID- 20858751 TI - Intraspecies disparity in growth rate is associated with differences in expression of local growth plate regulators. AB - Disparities in longitudinal growth within a species can be partly explained by endocrinological differences. We hypothesized that regulatory networks acting locally in the growth plate may also be important. We tested this hypothesis by evaluating the IGF/IGFBP expression, the vitamin D pathway, and the PTHrP-Indian hedgehog (IHH) feedback loop in rib growth plates from 10- and 21-wk-old small- (Miniature Poodles, MP) and large-breed dogs (Great Danes, GD) using immunohistochemistry and quantitative (q)PCR. The rib growth plates of GD were 1.7 times thicker compared with those of MP, with larger proliferative (in absolute terms) and larger hypertrophic (in absolute and relative terms) zones. IGF/IGFBP gene expression profiling of the growth plates revealed decreased gene expression of igfbp2, -4, and -6 and an unaltered expression of igf-I and igf-II and their respective receptors in GD vs. MP. Immunohistochemistry and qPCR findings showed that the vitamin D pathway was more active in GD than in MP. Staining for 1alpha- and 24-hydroxylase was more abundant and intense in GD and the gene expressions of 1alpha-hydroxylase and the vitamin D receptor-driven 24 hydroxylase were six- and eightfold higher in GD vs. MP, respectively. Consistent with the immunohistochemistry findings, the expression of mRNA for components of the parathyroid hormone-related peptide (PTHrP)-IHH loop was different in GD compared with MP, with there being a relative threefold downregulation of Pthrp and a tenfold upregulation of Ihh in GD vs MP. These differences suggest that the effects of IHH in the regulation of chondrocyte proliferation and hypertrophy, both independently of PTHrP, can become more dominant during rapid growth rates. In conclusion, our data suggest that, in addition to modest endocrine differences, more pronounced changes in the expression of locally acting regulatory networks, such as the IGF system, vitamin D pathway, and PTHrP-IHH feedback loop are important contributors to within-species disparities in growth rates. PMID- 20858752 TI - Prepubertal urinary estrogen excretion and its relationship with pubertal timing. AB - Whether prepubertal estrogen production impacts on the timing of puberty is not clear. We aimed to investigate prepubertal 24-h estrogen excretion levels and their association with early and late pubertal markers. Daily urinary excretion rates of estrogens of 132 healthy children, who provided 24-h urine samples 1 and 2 yr before the start of the pubertal growth spurt [age at takeoff (ATO)], were quantified by stable isotope dilution/GC-MS. E-sum3 (estrone + estradiol + estriol) was used as a marker for potentially bioactive estrogen metabolites and E-sum5 (E-sum3 + 16-epiestriol + 16-ketoestradiol) for total estrogen production. Pubertal outcomes were ATO, age at peak height velocity (APHV), duration of pubertal growth acceleration (APHV-ATO), age at Tanner stage 2 for pubic hair (PH2), genital (G2, boys) and breast (B2, girls) development, and age at menarche. Prepubertal urinary estrogen excretions (E-sum3 and E-sum5) were not associated with ATO, APHV, and age at PH2 but with duration of pubertal growth acceleration (P < 0.01) in both sexes. Girls with higher E-sum3 reached B2 0.9 yr (P = 0.04) and menarche 0.3 yr earlier (P = 0.04) than girls with lower E-sum3. E sum3 was not associated with age at G2 in boys (P = 0.6). For most pubertal variables, the associations with E-sum3 were stronger than with E-sum5. In conclusion, prepubertal estrogens may not be critical for the onset of the pubertal growth spurt but are correlated with its duration in both boys and girls. Prepubertal estrogen levels may already predict the timing of girls' menstruation and breast development but do not appear to affect sexual maturation in boys. PMID- 20858753 TI - Plasma lipoproteins are required for both basal and stress-induced adrenal glucocorticoid synthesis and protection against endotoxemia in mice. AB - Lipoprotein-associated cholesterol has been suggested to make a significant contribution to adrenal steroidogenesis in vivo. To determine whether lipoproteins indeed contribute to optimal adrenal steroidogenesis in mice, in the current study we have determined the effect of relative lipoprotein deficiency on adrenal steroidogenesis in C57BL/6 wild-type mice. Feeding C57BL/6 mice the lipid lowering drug probucol (0.25% wt/wt) for 2 wk induced a 90% decrease in plasma high-density lipoprotein (HDL) cholesterol levels and a 77% reduction in low density lipoprotein (LDL) cholesterol levels. Neutral lipid stores were depleted upon probucol treatment specifically in the glucocorticoid-producing zona fasciculata of the adrenal, leading to a 44% decreased plasma corticosterone level under basal conditions. Exposure to lipopolysaccharide (LPS) induced a 37% increase in the adrenal uptake of HDL cholesteryl esters. Probucol-treated mice could induce only a relatively minor corticosterone response upon a LPS challenge compared with controls, which coincided with an approximately twofold increased hepatic expression level of interleukin-6 and tumor necrosis factor (TNF)alpha and an 89% higher TNFalpha response in plasma. Furthermore, a compensatory two- to fivefold upregulation of LDL receptor (cholesterol uptake) and HMG-CoA reductase (cholesterol synthesis) expression was noticed in the adrenals of probucol-treated mice. In conclusion, we have shown that lipoprotein deficiency in mice as a result of probucol feeding is associated with decreased adrenal cortex cholesterol levels, a lower basal and stress-induced plasma glucocorticoid level, and an increased susceptibility to LPS-induced inflammation. Therefore, it is suggested that plasma lipoproteins are required for optimal adrenal steroidogenesis and protection against endotoxemia in mice. PMID- 20858754 TI - Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams. AB - Exposure to excess testosterone (T) during fetal life has a profound impact on the metabolic and reproductive functions in the female's postnatal life. However, less is known about the effects of excess testosterone in males. The aim of the present study was to evaluate the impact (consequences) of an excess of T during fetal development on mature male testis. The testicular evaluation was by histological analysis and by determination of mRNA expression of the FSH receptor (FSH-R), transforming growth factor-beta type I receptor (TbetaR-I), and two members of the TGF-beta superfamily, transforming growth factor-beta3 (TGFbeta3) and anti-Mullerian hormone (AMH) in males born to mothers receiving an excess of T during pregnancy. At 42 wk of age, postpubertal males born to mothers treated with 30 mg of T propionate twice weekly from day 30 to 90, followed by 40 mg of T propionate from day 90 to 120 of pregnancy (T males), showed higher concentrations of FSH in response to a GnRH analog, a higher number of Sertoli cells/seminiferous tubule cross-section, and a lower number of germ cells/tubules (P < 0.05) than control males (C males) born to mothers treated with the vehicle. The mRNA expression of FSH-R and of TbetaR-I was higher in T males compared with C males (P < 0.05). Moreover, in T males, AMH expression level correlated negatively with the expression level of TGFbeta3. In C males, this latter correlation was not observed. These results suggest that prenatal exposure to an excess of T can negatively modify some histological and molecular characteristics of the mature testis. PMID- 20858755 TI - Maintenance of the thyroid axis during diet-induced obesity in rodents is controlled at the central level. AB - The hypothalamic-pituitary-thyroid (HPT) axis is a major contributor in maintaining energy expenditure and body weight, and the adipocyte hormone leptin regulates this axis by increasing TRH levels in the fed state. Leptin stimulates TRH directly in the hypothalamic paraventricular nucleus (PVN; direct pathway) and indirectly by regulating proopiomelnocortin neurons in the hypothalamic arcuate nucleus (ARC; indirect pathway). Whereas the indirect pathway is fully functional in lean animals, it is inactive during diet-induced obesity (DIO) because of the establishment of leptin resistance. Despite this, the HPT axis activity in obese humans and rodents remains within the normal levels or slightly higher. Therefore, in this study, we aimed to determine the mechanism(s) by which the HPT axis is still active despite leptin resistance. With a combination of using the Sprague-Dawley rat physiological model and the Zuker rat that bears a mutation in the leptin receptor, we were able to demonstrate that under DIO conditions the HPT axis is regulated at the central level, but only through the direct pathway of leptin action on TRH neurons. Deiodinase enzymes, which are present in many tissues and responsible for converting thyroid hormones, were not statistically different between lean and DIO animals. These data suggest that the increase in T(4/3) seen in obese animals is due mostly to central leptin action. We also found that T(3) feedback inhibition on the prepro-TRH gene is controlled partially by leptin-induced pSTAT3 signaling via the TRH promoter. This interactive relationship between T(3) and pSTAT3 signaling appears essential to maintain the HPT axis at normal levels in conditions such as obesity. PMID- 20858756 TI - alpha-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. AB - alpha-Synuclein has been studied in numerous cell types often associated with secretory processes. In pancreatic beta-cells, alpha-synuclein might therefore play a similar role by interacting with organelles involved in insulin secretion. We tested for alpha-synuclein localizing to insulin-secretory granules and characterized its role in glucose-stimulated insulin secretion. Immunohistochemistry and fluorescent sulfonylureas were used to test for alpha synuclein localization to insulin granules in beta-cells, immunoprecipitation with Western blot analysis for interaction between alpha-synuclein and K(ATP) channels, and ELISA assays for the effect of altering alpha-synuclein expression up or down on insulin secretion in INS1 cells or mouse islets, respectively. Differences in cellular phenotype between alpha-synuclein knockout and wild-type beta-cells were found by using confocal microscopy to image the fluorescent insulin biosensor Ins-C-emGFP and by using transmission electron microscopy. The results show that anti-alpha-synuclein antibodies labeled secretory organelles within beta-cells. Anti-alpha-synuclein antibodies colocalized with K(ATP) channel, anti-insulin, and anti-C-peptide antibodies. alpha-Synuclein coimmunoprecipitated in complexes with K(ATP) channels. Expression of alpha synuclein downregulated insulin secretion at 2.8 mM glucose with little effect following 16.7 mM glucose stimulation. alpha-Synuclein knockout islets upregulated insulin secretion at 2.8 and 8.4 mM but not 16.7 mM glucose, consistent with the depleted insulin granule density at the beta-cell surface membranes observed in these islets. These findings demonstrate that alpha synuclein interacts with K(ATP) channels and insulin-secretory granules and functionally acts as a brake on secretion that glucose stimulation can override. alpha-Synuclein might play similar roles in diabetes as it does in other degenerative diseases, including Alzheimer's and Parkinson's diseases. PMID- 20858757 TI - Decidual PTEN expression is required for trophoblast invasion in the mouse. AB - Trophoblast invasion likely depends on complex cross talk between the fetal and maternal tissues and may involve the modulation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling activity in maternal decidual cells. In this report, we studied implantation in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice, which lack the PI3K signaling antagonist gene Pten in myometrial and stromal/decidual cells. Primiparous Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice were found to be subfertile because of increased fetal mortality at e11.5. Histopathological analyses revealed a failure of decidual regression in these mice, accompanied by reduced or absent invasion of fetal trophoblast glycogen cells and giant cells, abnormal development of the placental labyrinth, and frequent apparent intrauterine fetal growth restriction. Unexpectedly, the loss of phosphate and tensin homolog deleted on chromosome 10 (PTEN) expression in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) decidual cells was not accompanied by a detectable increase in AKT phosphorylation or altered expression or activation of PI3K/AKT downstream effectors such as mammalian target of rapamycin or glycogen synthase kinase-3beta. Terminal deoxynucleotidyl transferase-mediated nick end labeling and bromodeoxyuridine incorporation analyses attributed to the lack of decidual regression mainly to decreased apoptosis in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) decidual cells, rather than to increased proliferation. Remodeling of the maternal vasculature was delayed in Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) uteri at e11.5, as evidenced by persistence of vascular smooth muscle and decreased infiltration of uterine natural killer cells. In addition, thickening of the myometrium and disorganization of the muscle fibers were observed before and throughout gestation. Almost all Pten(tm1Hwu/tm1Hwu);Amhr2(tm3(cre)Bhr/+) mice failed to carry a second litter to term, apparently attributable to endometrial hyperplasia and uterine infections. Together, these data demonstrate novel roles of PTEN in the mammalian uterus and its requirement for proper trophoblast invasion and decidual regression. PMID- 20858758 TI - Molecular conversations and the development of the hair follicle and basal cell carcinoma. AB - The understanding of the anatomy and development of fetal and adult hair follicles and the molecular study of the major embryonic pathways that regulate the hair follicle have led to exciting discoveries concerning the development of basal cell carcinoma (BCC). These studies have shed light on the major roles of Sonic hedgehog (Shh) signaling and its interactions with the insulin-like growth factor (IGF) axis in BCC development. New work, for example, explores a link between Shh signaling and IGF binding protein-2 (IGFBP-2) in the hair follicle as it transforms into BCC. IGFBP-2 was overexpressed in specific hair follicle cells of mice with ectopically activated Shh signaling [keratin 14 (K14)-Cre: patched homologue 1 (Cre: Ptch1)(lox/lox) mice]. Ptch1 deletion resulted in both an expansion of the stem cell niche and inhibition of cell differentiation. In transformed hair follicles, IGFBP-2 mediates epidermal progenitor cell expansion. Evidence also indicated that IGFBP-2 is expressed in human BCC. PMID- 20858759 TI - Genetic variations in the sonic hedgehog pathway affect clinical outcomes in non muscle-invasive bladder cancer. AB - Sonic hedgehog (Shh) pathway genetic variations may affect bladder cancer risk and clinical outcomes. Therefore, we genotyped 177 single-nucleotide polymorphisms (SNP) in 11 Shh pathway genes in a study including 803 bladder cancer cases and 803 controls. We assessed SNP associations with cancer risk and clinical outcomes in 419 cases of non-muscle-invasive bladder cancer (NMIBC) and 318 cases of muscle-invasive and metastatic bladder cancer (MiMBC). Only three SNPs (GLI3 rs3823720, rs3735361, and rs10951671) reached nominal significance in association with risk (P <= 0.05), which became nonsignificant after adjusting for multiple comparisons. Nine SNPs reached a nominally significant individual association with recurrence of NMIBC in patients who received transurethral resection (TUR) only (P <= 0.05), of which two (SHH rs1233560 and GLI2 rs11685068) were replicated independently in 356 TUR-only NMIBC patients, with P values of 1.0 * 10(-3) (SHH rs1233560) and 1.3 * 10(-3) (GLI2 rs11685068). Nine SNPs also reached a nominally significant individual association with clinical outcome of NMIBC patients who received Bacillus Calmette-Guerin (BCG; P <= 0.05), of which two, the independent GLI3 variants rs6463089 and rs3801192, remained significant after adjusting for multiple comparisons (P = 2 * 10(-4) and 9 * 10( 4), respectively). The wild-type genotype of either of these SNPs was associated with a lower recurrence rate and longer recurrence-free survival (versus the variants). Although three SNPs (GLI2 rs735557, GLI2 rs4848632, and SHH rs208684) showed nominal significance in association with overall survival in MiMBC patients (P <= 0.05), none remained significant after multiple-comparison adjustments. Germ-line genetic variations in the Shh pathway predicted clinical outcomes of TUR and BCG for NMIBC patients. PMID- 20858760 TI - Association between C-peptide concentration and prostate cancer incidence in the CLUE II cohort study. AB - Diabetes, characterized by perturbations in insulin production and signaling, is inversely associated with prostate cancer risk irrespective of stage. Obesity, a diabetes risk factor, is inversely associated with localized disease but positively associated with advanced disease. To understand the complex association between hyperinsulinemia and prostate cancer, we evaluated the association of plasma C-peptide, an insulin secretion marker, with prostate cancer risk in a case-control study nested in a prospective community cohort. Prostate cancer cases (n = 264) and matched controls (n = 264) were identified in the CLUE II cohort between 1989 (baseline) and 2002. C-peptide concentration was measured in baseline plasma by ELISA. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression, adjusting for being overweight or obese and family history. Median C-peptide concentration was lower in cases (1,180 pmol/L) than in controls (1,365 pmol/L; P = 0.03). Men in the highest (versus lowest) fourth of C-peptide had a lower risk for prostate cancer (OR, 0.65; 95% CI, 0.37-1.14; P-trend = 0.08), primarily localized disease (OR, 0.44; 95% CI, 0.19-1.03; P-trend = 0.04). Associations were similar to overall, when excluding cases diagnosed during the first 5 years of follow-up, men with diabetes, or men who had not had a prostate-specific antigen test. C-peptide concentration was inversely associated with subsequent diagnosis of prostate cancer, primarily localized disease, similar to the association for obesity. However, we cannot rule out detection bias that might result if men with higher C-peptide have lower prostate-specific antigen irrespective of whether prostate cancer is present or not. PMID- 20858761 TI - Patched1 inhibits epidermal progenitor cell expansion and basal cell carcinoma formation by limiting Igfbp2 activity. AB - Basal cell carcinoma (BCC) of the skin is the most common form of cancer, with the majority being caused by mutations in the Patched1 (Ptch1) gene, leading to activation of the Hedgehog (Hh) signaling pathway. Hh signaling is implicated in many tumor types; thus, defining the mechanisms by which Ptch1 regulates tissue proliferation is of paramount importance. Here, we show that the key role of Ptch1 in the skin is to limit the size of the epidermal stem/progenitor compartment and allow hair follicle differentiation. Specifically, loss of Ptch1 leads to the promotion of progenitor cell fate by increasing basal cell proliferation and limiting the progression of basal cells into differentiated hair follicle cell types. Our data indicate that BCCs likely result from hair follicle progenitor cells that, due to Hh signal activation, cannot progress through normal hair follicle differentiation. These data confirm the role of Ptch1 as a negative regulator of epidermal progenitor turnover and also show for the first time that Ptch1 plays a role in the differentiation of the hair follicle lineage. In addition, we show that insulin-like growth factor binding protein 2 (Igfbp2) is upregulated in both murine and human BCCs and that blocking Igfbp2 activity reduces the Hh-mediated expansion of epidermal progenitor cells. We propose that Igfbp2 mediates epidermal progenitor cell expansion and therefore represents an epidermal progenitor cell-specific target of Hh signaling that promotes BCC development. PMID- 20858762 TI - Skin deep and deeper: multiple pathways in basal cell carcinogenesis. AB - This perspective places the report by Villani et al. that appears in this issue of the journal (beginning on page 1222) in the context of recent work showing an intersection between two important developmental pathways implicated in oncogenesis: the hedgehog and insulin-like growth factor (IGF) pathways. Villani et al. define a key role for the IGF regulatory protein Igfbp2 in a genetic model of basal cell carcinogenesis driven by targeted constitutive activation of hedgehog signaling. Placed in the framework of other recently published work, the observations of Villani et al. both raise questions about the cell of origin for basal cell cancers and define additional putative therapeutic and preventive targets for this disease. PMID- 20858764 TI - Adult day-case renal biopsy: a single-centre experience. AB - BACKGROUND: Despite improvements in safety seen over the last 20 years, percutaneous renal biopsy is still associated with haemorrhagic complications. Due to concerns over delayed bleeding, most nephrologists would advocate overnight observation. Recent evidence in both adult and paediatric populations suggest that in some groups, this is unnecessary. Since 1991, we have provided a day-case renal biopsy service performing 70 such procedures per year. In this study, we present a retrospective analysis of this practice. METHODS: A total of 192 patients over a consecutive 3-year period were analysed retrospectively. Patients were selected according to standardized criteria, and biopsy was performed using a modern technique (automated biopsy needles under ultrasound guidance). Complications were identified by examination of case notes and local hospital admission databases, and by telephone interview. Our pathology database was examined for sample adequacy and diagnosis. RESULTS: There were no delayed complications in the study group with 187 patients (97.4%) being discharged home on the same day. Major complications occurred in five patients (2.6%), all related to bleeding. Of these, two needed radiological intervention to achieve haemostasis. Sufficient tissue for diagnosis was achieved in 97% of cases, with a mean of 47 +/- 23 glomeruli obtained per patient. Most biopsies were obtained with <= 2 passes (84%). CONCLUSIONS: Our findings show that in selected adult patients, renal biopsy can be performed as a day-case procedure. Given the benefits of day-case strategies in terms of patient and healthcare costs, we advocate increased utilization of this technique. PMID- 20858763 TI - Dietary vitamin D exposure prevents obesity-induced increase in endometrial cancer in Pten+/- mice. AB - The possibility that dietary vitamin D(3) (VD(3)) exposure inhibits endometrial carcinogenesis in an animal model and modifies the enhanced risk of endometrial carcinoma associated with obesity was investigated. At 4 weeks of age, Pten(+/-) and wild-type mice were each divided into four treatment groups and fed AIN93G control diet, or AIN93G-based diet containing either 25,000 international units of VD(3) per kilogram of diet, 58% fat to induce obesity (high fat), or high fat and 25,000 international units of VD(3) per kilogram of diet. Mice were kept on these diets until they were sacrificed at week 28. Although VD(3) did not affect endometrial cancer risk, it inhibited obesity-induced increase in endometrial lesions. Specifically, high-fat diet increased focal glandular hyperplasia with atypia and malignant lesions from 58% in the control diet-fed Pten(+/-) mice to 78% in obese mice. Dietary VD(3) decreased the incidence of endometrial pathology in obese Pten(+/-) mice to 25% (P < 0.001). VD(3) altered the endometrial expression of 25-hydroxylase, 1alpha-hydroxylase, and vitamin D receptor in the wild-type and Pten(+/-) mice. Estrogen receptor-alpha mRNA levels were higher (P < 0.014) and progesterone receptor protein levels in the luminal epithelium were lower (P < 0.04) in the endometrium of control diet-fed Pten(+/-) than wild-type mice, but the expression of these receptors was not affected by the dietary exposures. VD(3) reversed the obesity-induced increase in osteopontin (P < 0.001) and significantly increased E-cadherin expression (P < 0.019) in the endometrium of obese Pten(+/-) mice. Our data confirm the known association between obesity and endometrial cancer risk. Dietary exposure to VD(3) inhibited the carcinogenic effect of obesity on the endometrium. This protective effect was linked to a reduction in the expression of osteopontin and increase in E-cadherin. PMID- 20858766 TI - Renal injury due to hepatic hydatid disease. PMID- 20858765 TI - HIV infection and renal transplantation. AB - BACKGROUND: Some aspects of kidney transplant outcome in human immunodeficiency virus (HIV)-infected patients are still controversial. Besides, published experience is scarce in Europe. METHODS: A multicentre case-control study was designed to analyse the outcome of renal transplant in HIV + patients in Spain. Twenty HIV + patients were compared with a matched cohort of 40 HIV - recipients. RESULTS: Post-transplant follow-up period was 39.98 +/- 36.51 months. Pre transplant dialysis duration and the incidence of pre-transplant opportunistic infections were significantly higher for HIV + patients. Following transplantation, HIV + recipients presented lower incidence of immediate renal function and more acute rejection. Graft survival was lower although the difference was not significant (1 year: 85 vs 97.5%; 5 years: 74.4 vs 91%; log rank P = 0.058). There was no difference in patient survival rates. Eight patients in each group presented hepatitis C (HCV) infection. Coinfected patients were compared with HIV +/HCV - and HIV -/HCV + recipients. Coinfected patients presented more time on dialysis, greater duration of delayed graft function and lower graft survival (HIV +/HCV + vs HIV +/HCV -: log-rank P = 0.009; HIV +/HCV + vs HIV -/HCV +: log-rank P = 0.02). Conversely, when excluding HCV + patients in both groups, graft survival in HIV + and HIV - patients was similar. CONCLUSIONS: The outcome was good, particularly in non-coinfected patients. Coinfected patients constitute an especially high-risk group for kidney transplantation. PMID- 20858767 TI - First it's rickets, then it's not the sodium-phosphate transporter 2a knockout mystery. PMID- 20858768 TI - Lack of adrenomedullin in the central nervous system results in apparently paradoxical alterations on pain sensitivity. AB - Adrenomedullin (AM) is a regulatory peptide, coded by the adm gene, which is involved in numerous physiological processes, including pain sensitivity. Previous studies have shown that intrathecal injection of AM induced hyperalgesia in the rat. Here, we explore pain sensitivity in a mouse conditional knockout for adm in neurons of the central nervous system, including the spinal cord and dorsal root ganglia. Double immunofluorescence in wild-type (WT) animals shows that AM immunoreactivity is found in calcitonin gene-related peptide-positive neurons of the dorsal root ganglia but not in neurons that bind isolectin B4. Mice lacking adm had modified expression of canonical sensorial neuropeptides, having significantly more calcitonin gene-related peptide and less substance P and enkephalin than their WT littermates. Furthermore, the spinal cord of adm knockout mice expressed higher levels of the AM receptor components, suggesting a compensation attempt to deal with the lack of afferent AM signaling. Behavioral nociceptive tests also found differences between genotypes. In the tail-flick test, which measures mostly spinal reflexes, the adm-null animals had a longer latency than their WT counterparts. On the other hand, in the hotplate test, which requires encephalic processing, mice lacking adm had shorter latencies than normal littermates. These results suggest that AM acts as a nociceptive modulator in spinal reflexes, whereas it may have an analgesic function at higher cognitive levels. This study confirms the important role of AM in pain sensitivity processing but unveils a more complex scenario than previously surmised. PMID- 20858769 TI - After the injury: initial evaluation of a web-based intervention for parents of injured children. AB - The purpose of this study was to survey parent knowledge of child injury reactions (including post-traumatic stress symptoms) and to evaluate parent satisfaction and learning outcomes following a video- or web-based intervention. Fifty parents of children ages 6-17 years who were injured within the past 2 months were recruited from emergency and inpatient settings. A repeated-measures experimental design was employed in which participants were assigned to either a web-based or video intervention. Parent knowledge was assessed pre- and post intervention. Learning outcomes and satisfaction were evaluated post intervention. Parents showed high levels (~70% accuracy) of knowledge about potential psychological injury reactions at baseline and post-intervention. In addition, post-intervention parents were able to generate new positive strategies to help their child recover and became more specific about types of reactions to monitor (e.g. avoidance). Participants reported high levels of satisfaction with both web and video interventions. While parents possess high levels of basic knowledge about child recovery from injury, the Web site and video tools provided concrete guidance that was useful in enhancing parent understanding of specific traumatic stress reactions to monitor in children post-injury. PMID- 20858770 TI - Alvimopan use in laparoscopic and open bowel resections: clinical results in a large community hospital system. AB - BACKGROUND: Alvimopan has received Food and Drug Administration approval to accelerate the time to upper and lower gastrointestinal recovery following partial large or small bowel resection with primary anastomosis. OBJECTIVE: To assess the efficacy, safety, and economic benefit of alvimopan in patients undergoing open or laparoscopic bowel resection in a community hospital system setting. METHODS: This 6-month, open-label, multi-hospital, prospective study combined with a retrospective chart review compared postoperative length of stay and postoperative ileus-related morbidity (nasogastric tube insertion, hospital readmission) for patients undergoing open or laparoscopic bowel resection who received alvimopan 12 mg (n = 108) versus historical control bowel resection patients (n = 91) who would have been eligible to receive alvimopan. Multivariate analysis assessed the effects of age and surgery type on postoperative length of stay. Additional-day hospital costs were estimated using ordinary least-squares regression to calculate costs based on length of stay in the control cohort. RESULTS: Compared with historical controls, patients receiving alvimopan had a mean 1.8-day shorter postoperative length of stay (p = 0.01) and lower rates of nasogastric tube insertion (2% vs 15%, p < 0.001). Multivariate analysis revealed a statistically significant reduction in postoperative length of stay in the alvimopan group of approximately 1.2 days (p = 0.01), regardless of age or surgery type, with an even larger difference (3.2 days) observed in patients >=70 years old. Mean cost savings associated with alvimopan use ranged from $531 (laparoscopic bowel resection) to $997 (open bowel resection) per patient. CONCLUSIONS: Consistent with clinical trial data, alvimopan use resulted in an approximately 1 day shorter postoperative length of stay and was associated with substantial cost savings. PMID- 20858771 TI - Joint estimation of the basic reproduction number and generation time parameters for infectious disease outbreaks. AB - The basic reproduction number is a key parameter determining whether an infectious disease will persist. Its counterpart over time, the effective reproduction number, is of value in assessing in real time whether interventions have brought an outbreak under control. In this paper, we use theoretical arguments and simulation to understand the relationship between estimation of the reproduction number based on a full continuous time epidemic model and 2 other recently developed estimators. All these methods make use of "epidemic curve" data and require assumptions about the generation time distribution. The 2 simplest estimators do not require information about the-often difficult to obtain-population size. The simplest estimator is shown to require further assumptions that are rarely valid in practical settings and to produce severely biased estimates compared to the others. Furthermore, we show that in general the parameters of the generation time distribution and the reproduction number are non-identified in the early stages of an incomplete outbreak. On the basis of these results, we recommend that, wherever possible, estimation of the basic and effective reproduction numbers should be based on a well-defined epidemic model; moreover, if external information is available then it should be incorporated in a Bayesian analysis. PMID- 20858773 TI - Degradation of 10-methacryloyloxydecyl dihydrogen phosphate. AB - To understand the mechanism of 10-methacryloyloxydecyl dihydrogen phosphate (MDP) hydrolysis, we investigated the degradation of 2-methacryloyloxyethyl dihydrogen phosphate (MEP), because the MEP molecule has the methacryloxy and phosphate ester portions of MDP but, unlike the latter, is water-soluble. The MEP-N methcryloyl glycine (NMGly), MDP-NMGly, and MDP-2-hydroxyethyl methacrylate (HEMA) primers were designed, stored for different periods, and then analyzed. Our null hypotheses were that (1) the mechanism of MDP hydrolysis differs from that of MEP and (2) the type of hydrophilic monomer--NMGly or HEMA--has no effect on the MDP hydrolysis rate. Similar to the production of methacrylic acid (MA) and 2-hydroxyethyl dihydrogen phosphate (HEP) during MEP hydrolysis, MDP produced MA and 10-hydroxydecyl dihydrogen phosphate (HDP) during hydrolysis. However, the rate of MDP hydrolysis depended on the type of hydrophilic monomer: Compared with HEMA, NMGly significantly increased the rate of MDP hydrolysis. PMID- 20858772 TI - Accurate genome-scale percentage DNA methylation estimates from microarray data. AB - DNA methylation is a key regulator of gene function in a multitude of both normal and abnormal biological processes, but tools to elucidate its roles on a genome wide scale are still in their infancy. Methylation sensitive restriction enzymes and microarrays provide a potential high-throughput, low-cost platform to allow methylation profiling. However, accurate absolute methylation estimates have been elusive due to systematic errors and unwanted variability. Previous microarray preprocessing procedures, mostly developed for expression arrays, fail to adequately normalize methylation-related data since they rely on key assumptions that are violated in the case of DNA methylation. We develop a normalization strategy tailored to DNA methylation data and an empirical Bayes percentage methylation estimator that together yield accurate absolute methylation estimates that can be compared across samples. We illustrate the method on data generated to detect methylation differences between tissues and between normal and tumor colon samples. PMID- 20858774 TI - Defining the contribution of genetics in the etiology of dental caries. PMID- 20858775 TI - Measuring the color of maxillofacial prosthetic material. AB - Color information from different color-measuring systems varies during color matching in maxillofacial prosthetics. We studied the hypothesis that a non contact measuring system and 4 contact color-measuring instruments perform comparably in accuracy and precision on measurements of pigmented maxillofacial elastomer specimens having human skin colors. Measurement comparisons in accuracy on opaque standard color patches were made in Phase I. In Phase II, the system with the best accuracy was used as the reference instrument, and comparisons in accuracy and precision on elastomer specimens were made. The CIEDE2000 color difference formula was used. Repeated-measures ANOVA with Tukey testing and linear regression analysis for CIELAB and color differences among the instruments were performed. The contact measuring systems perform differently in accuracy, possibly due to edge loss and other factors, but performed comparably in precision with the non-contact measuring instrument. This non-contact system is recommended for color measurement of maxillofacial prosthetic materials. PMID- 20858776 TI - Effect of glass-ionomer cement on the progression of proximal caries. AB - Although effective preventive strategies exist for pit and fissure caries, prevention of proximal caries remains a significant challenge. This split-mouth study was designed to investigate the effect of glass-ionomer cement (GIC) on the progression of initial proximal caries in posterior teeth, testing the hypothesis that local application of fluoride-releasing GIC would reduce this progression. GIC was applied to 41 pairs of posterior teeth after elastic band separation in 7 to 19-year-old individuals. Follow-up bitewing radiographs were taken at 6 and 12 months. Differences in Delta mean lesion depth at 6 and 12 months between test and control groups were significant (p < 0.05, p < 0.000). Lesions treated with GIC were more likely to remain in or regress to the outer half of enamel (OR = 6.3; 95%CI, 1.3-30.9). GIC provides an effective approach to the clinical management of incipient proximal caries. PMID- 20858777 TI - Taste genes associated with dental caries. AB - Dental caries is influenced by a complex interplay of genetic and environmental factors, including dietary habits. Previous reports have characterized the influence of genetic variation on taste preferences and dietary habits. We therefore hypothesized that genetic variation in taste pathway genes (TAS2R38, TAS1R2, GNAT3) may be associated with dental caries risk and/or protection. Families were recruited by the Center for Oral Health Research in Appalachia (COHRA) for collection of biological samples, demographic data, and clinical assessment of oral health, including caries scores. Multiple single-nucleotide polymorphism (SNP) assays for each gene were performed and analyzed by transmission disequilibrium test (TDT) analysis (FBAT software) for three dentition groups: primary, mixed, and permanent. Statistically significant associations were seen in TAS2R38 and TAS1R2 for caries risk and/or protection. PMID- 20858778 TI - Tea catechin EGCg suppresses the mgl gene associated with halitosis. AB - Epigallocatechin gallate (EGCg), the main antimicrobial tea catechin, has been reported to inhibit growth and virulence factors of oral pathogens in vitro. Although the mechanism is unclear, the potential of EGCg in reducing halitosis caused by volatile sulfur compounds (VSCs) has been suggested. This study tested the hypothesis that EGCg reduces VSCs by suppressing mgl, the gene encoding L methionine-alpha-deamino-gamma-mercaptomethane-lyase, responsible for methyl mercaptan (CH3SH) production by oral anaerobes. In this study, the effect of EGCg on in vitro growth, CH3SH production, and mgl gene expression in P. gingivalis W83 was investigated. EGCg inhibited growth of P. gingivalis W83 (MIC = 97.5 ug/mL) and was bactericidal (MBC = 187.5 ug/mL). At sub-MIC levels, EGCg inhibited CH3SH production, and mgl mRNA and protein expression (p < 0.05). We conclude that EGCg may represent a natural and alternative agent to the antimicrobial chemicals currently available for halitosis control. PMID- 20858780 TI - Diet and caries-associated bacteria in severe early childhood caries. AB - Frequent consumption of cariogenic foods and bacterial infection are risk factors for early childhood caries (ECC). This study hypothesized that a short diet survey focused on frequency of foods, categorized by putative cariogenicity, would differentiate severe ECC (S-ECC) from caries-free children. Children's diets were obtained by survey and plaque bacteria detected by PCR from 72 S-ECC and 38 caries-free children. S-ECC children had higher scores for between-meal juice (p < 0.01), solid-retentive foods (p < 0.001), eating frequency (p < 0.005), and estimated food cariogenicity (p < 0.0001) than caries-free children. S-ECC children with lesion recurrence ate fewer putative caries-protective foods than children without new lesions. Streptococcus mutans (p < 0.005), Streptococcus sobrinus (p < 0.005), and Bifidobacteria (p < 0.0001) were associated with S-ECC, and S. mutans with S. sobrinus was associated with lesion recurrence (p < 0.05). S. mutans-positive children had higher food cariogenicity scores. Food frequency, putative cariogenicity, and S. mutans were associated with S-ECC individually and in combination. PMID- 20858779 TI - Application of polychromatic uCT for mineral density determination. AB - Accurate assessment of mineral density (MD) provides information critical to the understanding of mineralization processes of calcified tissues, including bones and teeth. High-resolution three-dimensional assessment of the MD of teeth has been demonstrated by relatively inaccessible synchrotron radiation microcomputed tomography (SRuCT). While conventional desktop uCT (CuCT) technology is widely available, polychromatic source and cone-shaped beam geometry confound MD assessment. Recently, considerable attention has been given to optimizing quantitative data from CuCT systems with polychromatic x-ray sources. In this review, we focus on the approaches that minimize inaccuracies arising from beam hardening, in particular, beam filtration during the scan, beam-hardening correction during reconstruction, and mineral density calibration. Filtration along with lowest possible source voltage results in a narrow and near-single peak spectrum, favoring high contrast and minimal beam-hardening artifacts. More effective beam monochromatization approaches are described. We also examine the significance of beam-hardening correction in determining the accuracy of mineral density estimation. In addition, standards for the calibration of reconstructed grey-scale attenuation values against MD, including K(2)PHO(4) liquid phantom, and polymer-hydroxyapatite (HA) and solid hydroxyapatite (HA) phantoms, are discussed. PMID- 20858781 TI - The long-term effects of water fluoridation on the human skeleton. AB - Municipal water fluoridation has notably reduced the incidence of dental caries and is widely considered a public health success. However, ingested fluoride is sequestered into bone, as well as teeth, and data on the long-term effect of exposure to these very low doses of fluoride remain inconclusive. Epidemiological studies suggest that effects of fluoride on bone are minimal. We hypothesized that the direct measurement of bone tissue from individuals residing in municipalities with and without fluoridated water would reveal a relationship between fluoride content and structural or mechanical properties of bone. However, consonant with the epidemiological data, only a weak relationship among fluoride exposure, accumulated fluoride, and the physical characteristics of bone was observed. Analysis of our data suggests that the variability in heterogenous urban populations may be too high for the effects, if any, of low-level fluoride administration on skeletal tissue to be discerned. PMID- 20858782 TI - Accuracy of NHANES periodontal examination protocols. AB - This study evaluates the accuracy of periodontitis prevalence determined by the National Health and Nutrition Examination Survey (NHANES) partial-mouth periodontal examination protocols. True periodontitis prevalence was determined in a new convenience sample of 454 adults >= 35 years old, by a full-mouth "gold standard" periodontal examination. This actual prevalence was compared with prevalence resulting from analysis of the data according to the protocols of NHANES III and NHANES 2001-2004, respectively. Both NHANES protocols substantially underestimated the prevalence of periodontitis by 50% or more, depending on the periodontitis case definition used, and thus performed below threshold levels for moderate-to-high levels of validity for surveillance. Adding measurements from lingual or interproximal sites to the NHANES 2001-2004 protocol did not improve the accuracy sufficiently to reach acceptable sensitivity thresholds. These findings suggest that NHANES protocols produce high levels of misclassification of periodontitis cases and thus have low validity for surveillance and research. PMID- 20858784 TI - Executive dysfunction in school-age children with ADHD. AB - OBJECTIVE: The study examined executive function deficits (EFD) in school-age children (7 to 14 years) with ADHD. METHOD: A clinical sample of children diagnosed with ADHD (n = 49) was compared to a population sample (n = 196) on eight executive function (EF) measures. Then, the prevalence of EFD in clinical and non-clinical children was examined at the individual level according to three methods previously applied to define EFD, and a fourth method was included to control for the effect of age on performance. RESULTS: Children with ADHD were significantly more impaired on measures of EF than children without ADHD at the group level. However, only about 50% of children with ADHD were found to have EFD at the individual level, and results appeared relatively robust across methods applied to define EFD. CONCLUSION: As a group, children with ADHD displayed more problems on neuropsychological measures of EF than non-clinical children; at the individual level, there appeared to be heterogeneity in EF impairment. PMID- 20858783 TI - Does incomplete caries removal reduce strength of restored teeth? AB - Little information is available about whether the presence of residual caries beneath an occlusal restoration affects fracture strength of the tooth. This in vitro study tested the hypothesis that restored teeth after incomplete excavation have lower fracture strengths than restored teeth after complete excavation. Fourteen pairs of molars were randomly assigned to an experimental (incomplete excavation) or to a control group (complete excavation) and loaded vertically (after cyclic loading). Failure load and fracture mode were recorded. Restored teeth in the incomplete excavation group resulted in reduced fracture strength (p < 0.001) of the tooth-restoration complex (1276 N +/- 626 N) compared with the control group (2768 N +/- 710 N). Teeth in the complete excavation group all fractured vertically, while in the experimental group, cracks in the restoration were observed, characterized as 'ice-cracks'. The fracture strength of teeth restored over incomplete caries excavation was significantly reduced, possibly resulting in long-term clinical failure. PMID- 20858785 TI - A 12-month prospective, observational study of treatment regimen and quality of life associated with ADHD in central and eastern europe and eastern Asia. AB - OBJECTIVES: This prospective, observational, non-randomized study aimed to describe the relationship between treatment regimen prescribed and the quality of life (QoL) of ADHD patients in countries of Central and Eastern Europe (CEE) and Eastern Asia over 12 months. METHODS: 977 Male and female patients aged 6-17 years seeking treatment for symptoms of ADHD were assessed using the Child and Adolescent Symptom Inventory-4 Parent Checklists, and the Clinical Global Impressions-ADHD-Severity scale. QoL was assessed using the Child Health and Illness Profile-Child Edition parent report form. Patients were grouped according to whether they were prescribed psycho- and/or pharmacotherapy (treatment) or not (no/'other' treatment). RESULTS: No statistically significant differences were observed between cohorts (treatment vs. no/'other' treatment) in terms of change in QoL, although there was improvement over 12 months, with a greater improvement experienced by patients in the treatment cohort in both study regions (CEE and Eastern Asia). Psychoeducation/counselling and methylphenidate were the predominant ADHD treatments prescribed. CONCLUSIONS: Although both treatment and no/'other' treatment cohorts showed improvements in mean QoL over 12 months, the difference was small and not statistically significant. A major limitation was the higher than anticipated number of patients switching treatments, predominantly from the no/'other' treatment cohort. PMID- 20858786 TI - Changes in emotions related to medication used to treat ADHD. Part II: clinical approaches. AB - ADHD is one of the most common neurobehavioral disorders of childhood, and FDA approved medications offer an efficacious treatment option. However, case reports and anecdotal sources suggest that children can have emotional responses, both salutary and detrimental, to these agents. We have previously conducted a comprehensive literature review and found very few research studies systematically examining changes in emotional expression (EE) associated with ADHD medication use. In addition, no empirical data pertaining to the management of these responses could be found. Although few methodologically stringent data are available for changes in EE, such changes should be recognized and measured to determine appropriate responses by clinicians and to maximize treatment benefits and reduce side effects. In this companion report, we draw on available research evidence and clinical experience to explore typical clinical manifestations, differential diagnosis, scales for monitoring, and management approaches of EE observed with pharmacologic treatment of ADHD. In the future, controlled clinical trials of ADHD pharmacotherapy should employ standardized ratings of EE at baseline, during and after treatment. In addition, future research studies should examine various management approaches of these EE changes, to ensure maximal treatment benefits and minimal risks to patients with ADHD who are treated with medication. PMID- 20858787 TI - Imaging of hematuria. AB - OBJECTIVE: In this article, we will discuss the current status of imaging in patients with hematuria of urologic origin. Issues impacting evaluation of these patients with radiography, excretory urography, retrograde pyelography, and sonography will be discussed. CONCLUSION: Conventional radiography has no role in the detection of renal or urothelial carcinoma. Low-dose CT offers much greater sensitivities for the detection of urinary tract calculi than radiography at doses equivalent to conventional radiography. Ultrasound alone is insufficient for imaging of hematuria. Using ultrasound alone, it is often difficult to differentiate renal transitional cell carcinoma from other causes of filling defects of the renal collecting system such as blood clots, sloughed papillae, or fungus balls. The prominence of the role of excretory urography in the evaluation of patients with hematuria has diminished, and MDCT urography is now preferred to excretory urography in most cases. PMID- 20858788 TI - Diagnostic performance of diffusion-weighted MRI in the detection of nonpalpable undescended testes: comparison with conventional MRI and surgical findings. AB - OBJECTIVE: The aim of this feasibility study was to evaluate the role of diffusion-weighted MRI in the evaluation of nonpalpable undescended testes. MATERIALS AND METHODS: Thirty-six boys with undescended testes underwent preoperative abdominal and pelvic MRI to identify the location of the testes. MRI included free-breathing diffusion-weighted imaging (DWI) with b values of 50, 400, and 800 s/mm(2), a T1-weighted turbo spin-echo sequence, and a T2-weighted fat-suppressed turbo spin-echo sequence. After laparoscopic examinations, two observers independently reviewed the preoperative images. The DW images alone were reviewed first, followed by the conventional MR images alone and the conventional MR and the DW images together. The laparoscopic and MRI findings were compared. Sensitivity, specificity, and accuracy in the identification of nonpalpable undescended testes were calculated for DWI, conventional MRI, and the combination of DWI and conventional MRI. RESULTS: The combination of DWI and conventional MRI was the most sensitive and most accurate technique. Observer 1 found 31 undescended testes, and observer 2, 30 testes with this technique. Sensitivity was 0.91 and 0.88 for observers 1 and 2, and accuracy was 0.92 and 0.86. With DWI alone, observer 1 located 30 testes, and observer 2, 28 testes (sensitivity, 0.88 and 0.82; accuracy, 0.86 and 0.81). Using conventional MRI alone, both observers located 29 testes (sensitivity, 0.85; accuracy, 0.86 and 0.84). The accuracy of locating testes was superior with the combination of DWI and conventional MRI for both observers (accuracy, 0.92 and 0.86). An intraabdominal atrophic testis managed by laparoscopic orchiectomy was found by neither observer with DWI or with conventional MRI. CONCLUSION: Use of DWI with a high b value yields information that complements conventional MRI findings, improving identification and location of nonpalpable undescended testes. We recommend the use of conventional MRI in addition to DWI to increase the preoperative sensitivity and accuracy of identifying and locating nonpalpable testes. PMID- 20858789 TI - Adult extragonadal germ cell tumors. AB - OBJECTIVE: The purpose of this article is to describe the key imaging features of primary and metastatic extragonadal germ cell tumors in adults. CONCLUSION: Extragonadal germ cell tumors primarily affect men during the third and fourth decades of life. Their imaging characteristics are nonspecific, and extragonadal germ cell tumors should always be included in the differential diagnosis of a midline anterior mediastinal or retroperitoneal mass. Levels of human chorionic gonadotropin or alpha-fetoprotein or both may be elevated, depending on the histologic subtype. PMID- 20858790 TI - Assessment of scaphoid viability with MRI: a reassessment of findings on unenhanced MR images. AB - OBJECTIVE: The purpose of this article is to evaluate the accuracy of unenhanced T1-weighted MR images in predicting the vascular status of the proximal pole of the scaphoid in patients with chronic scaphoid fracture nonunions. MATERIALS AND METHODS: A database search identified 29 patients with chronic scaphoid nonunions who underwent a preoperative MRI examination and intraoperative assessment of scaphoid viability from 2004 to 2009. T1-weighted MR images were evaluated by two musculoskeletal radiologists. If the proximal pole demonstrated diffusely decreased T1-weighted signal (less than or equal to that of skeletal muscle), the patient was placed in a moderate-to-high risk for avascular necrosis (AVN) category. Otherwise, the patient was placed in a viable-to-low risk for AVN category. Scaphoid viability or necrosis was diagnosed intraoperatively depending on whether punctate bleeding was present. After the patients were classified according to the T1-weighted appearance, the appearance on STIR images was recorded. RESULTS: There were 29 patients (25 male) with a mean age of 21 years. When we compared the MRI results, using only the T1-weighted images, with the surgical findings, unenhanced MRI had a sensitivity, specificity, and accuracy of 55%, 94%, and 79%, respectively, for diagnosing AVN. Increased proximal pole STIR signal was noted with similar frequencies in patients with and without AVN. CONCLUSION: T1-weighted unenhanced MRI is an acceptable alternative to delayed contrast-enhanced MRI in the preoperative assessment of the vascular status of the proximal pole of the scaphoid in patients with chronic fracture nonunions. STIR images were not beneficial in determining proximal pole viability. PMID- 20858791 TI - Contrast-enhanced whole-body joint MRI in patients with unclassified arthritis who develop early rheumatoid arthritis within 2 years: feasibility study and correlation with MRI findings of the hands. AB - OBJECTIVE: The purpose of this article is to examine the feasibility of whole body joint MRI for detecting systemic joint synovitis and for analyzing the relationship between the hands and systemic joint involvement in patients with unclassified arthritis who later develop early rheumatoid arthritis (RA). MATERIALS AND METHODS: The study included 17 patients (five men and 12 women; median age, 65 years [range, 38-77 years]; median symptom duration, 3 months [range, 1-6 months]). MRI of the systemic joints was performed for patients with unclassified arthritis without radiographic evidence of RA and who were diagnosed as having RA according to 1987 revised classification criteria within 2 years. RESULTS: The chosen 4-point scale for image quality was moderate to excellent. MRI findings of systemic joints were in accordance with joint swelling and tenderness (chi-square test, p < 0.0001). Sixty percent (45/75) of hand joints and 67% (12/18) of systemic joints other than hands showed MR synovitis without swelling. With regard to the correlation of MRI findings between hands and joints other than hands, there was a statistically significant positive correlation in the joint count (r = 0.5514 and p = 0.0218) and semiquantitative value of hand synovitis (r = 0.5382 and p = 0.0258). CONCLUSION: Whole-body joint MRI in early RA is feasible in terms of image quality and agreement with the results of clinical examination. MRI may be more sensitive for depicting synovitis-positive joints than clinical examination. Estimation of the systemic burden of synovitis detected by MRI may be possible via MRI of the hands. PMID- 20858792 TI - Thermal ablation of spinal osteoid osteomas close to neural elements: technical considerations. AB - OBJECTIVE: The purpose of this study was to evaluate experience with and determine the efficacy and safety of thermal ablation in the management of spinal osteoid osteomas close to neural elements. MATERIALS AND METHODS: The records of all patients with osteoid osteomas of the spine managed with thermal ablation at two academic centers from 1993 to 2008 were reviewed. RESULTS: Seventeen patients (13 male patients, four female patients; mean age, 25.9 years) had lesions in the lumbar (seven patients), thoracic (six patients), cervical (three patients), and sacral (one patient) regions of the spine. Two lesions were in the vertebral body, one was within the dens, and the others were in the posterior elements. The mean lesion diameter was 8.8 mm, and the mean distance between the lesion and the closest neural element was 4.3 mm. The lesions were managed with laser (13 lesions) or radiofrequency (four lesions) ablation. Special thermal protection techniques involving the epidural injection of gas or cooled fluid were used. Pain levels were assessed immediately before the procedure and on the day after the procedure. Long-term follow-up findings were available for 11 patients. No complications were encountered, and all patients reported relief of pain. The 11 patients who participated in long-term follow-up reported continued relief of pain. CONCLUSION: Percutaneous thermal ablation can be used to manage spinal osteoid osteomas close to the neural elements. Special thermal protection techniques may add a margin of safety. PMID- 20858793 TI - Image Gently, Step Lightly: promoting radiation safety in pediatric interventional radiology. AB - OBJECTIVE: The Image Gently, Step Lightly campaign is an education and awareness campaign focusing on radiation safety in pediatric interventional radiology. To promote radiation safety by standardizing workflow and encouraging team responsibility, the campaign Website includes a procedural checklist that the medical team may use to review radiation safety steps before each pediatric interventional procedure. CONCLUSION: Use of this checklist can be an effective tool in the ongoing effort to maximize radiation safety during interventional procedures. PMID- 20858794 TI - Discriminative role of CT in exudative and transudative pleural effusions. PMID- 20858795 TI - Mobile telephone-based remote orthopedic consultation. PMID- 20858796 TI - CT characteristics of lung nodules present at diagnosis of extrapulmonary malignancy in children. PMID- 20858797 TI - Fulminant evolution of Behcet disease. PMID- 20858798 TI - Tree-in-bud pattern: spectrum of cause. PMID- 20858799 TI - MDCT of the abdomen: missed diagnoses due to satisfaction of search. PMID- 20858800 TI - Swine-origin influenza A (H1N1) viral infection: small airways disease. PMID- 20858801 TI - Time to change the philosophy of medicine. PMID- 20858802 TI - Memorial-Melvin M. Figley. PMID- 20858803 TI - American Board of Radiology certifying examination: oral versus computer-based format. AB - OBJECTIVE: This pilot study of a computer-based examination for primary certification by the American Board of Radiology was designed to acquire comparative data on candidates that were measures of individual performance on the oral examination compared with the computer-based examination. MATERIALS AND METHODS: The pilot computer-based pediatric radiology examination was designed by experienced oral board examiners and the pediatric subspecialty trustees. Images were chosen from the examination repository of the American Board of Radiology. The 20-minute examination was designed to include 8-10 cases with 26-31 scorable units covering all aspects of pediatric radiology. RESULTS: Among the 1,317 candidates taking the oral board examination, 1,048 candidates (79.6%) participated in the voluntary pilot examination. The scores of the two examinations were subjected to statistical analysis. The sensitivity and specificity of the pilot examination were 94.5% and 45.7%. The overall accuracy was 92.8%. Seventy-five candidates (7.2%) who participated in this study received different verdicts on the pilot examination and the pediatric radiology category of the oral examination. Fifty-six of these candidates (5.3%) failed the pilot examination but passed in the oral pediatric radiology category; 19 of the candidates (1.8%) passed the pilot examination but failed the oral pediatric radiology test. Pilot examination scores were higher for candidates who passed the oral pediatric radiology category (median score, 80; interquartile range, 74.1-85.2) than for candidates who failed (median score, 65.4; interquartile range, 58.6-71.0) (p < 0.0001). CONCLUSION: The pediatric pilot examination was useful for differentiating passing candidates from failing candidates when the score in the pediatric radiology category of the oral examination was used as the reference standard. The overall accuracy was 92.8%. PMID- 20858804 TI - Prospective study of access site complications of automated contrast injection with peripheral venous access in MDCT. AB - OBJECTIVE: The purpose of this article is to prospectively assess the frequency and type of IV injection site complications associated with high-flow power injection of nonionic contrast medium in MDCT. SUBJECTS AND METHODS: Contrast enhanced (300-370 mg iodine/mL) MDCT examinations with high flow rates (up to 8 mL/s) using automatic CT injectors were performed according to standardized MDCT protocols. The location, type, and size (16-24 gauge) of IV catheters and volumes, iodine concentration, and flow rates of contrast medium were documented. Patients were questioned about associated discomfort, IV catheter sites were checked, and adverse effects were recorded. RESULTS: Prospectively, 4,457 patients were studied. The injection rate ranged from 1-2.9 mL/s (group 1; n = 1,140) to 3-4.9 mL/s (group 2; n = 2,536) to 5-8 mL/s (group 3; n = 781); 1.2% of the patients experienced extravasations (n = 52). Contrast medium iodine concentration, flow rates, and volumes were not related to the frequency of extravasation. The extravasation rate was highest with 22-gauge IV catheters (2.2%; p < 0.05) independently of the anatomic location. For 20-gauge IV catheters, extravasation rates were significantly higher in the dorsum of the hand than in the antecubital fossa (1.8% vs 0.8%; p = 0.018). Extravasation rates were higher in older patients (>= 50 vs < 50 years, 0.6% vs 1.4%; p = 0.019). Different iodine concentrations did not trigger significant differences in contrast material reactions (p = 0.782). CONCLUSION: Automated IV contrast injection applying high flow rates (i.e., up to 8 mL/s) is performed without increased risk of extravasation. The overall extravasation rate was 1.2% and showed no correlation with iodine concentration, flow rates, or contrast material reactions. Performing high flow rates with low-diameter IV catheters (e.g., 22 gauge catheters) and a location of IV catheter in the hand is associated with a higher extravasation rate. PMID- 20858805 TI - High-intensity focused ultrasound to treat primary hyperparathyroidism: a feasibility study in four patients. AB - OBJECTIVE: Many patients with primary hyperparathyroidism either decline or are not candidates for surgical parathyroidectomy. There are drawbacks to medical therapy as well as percutaneous ethanol injection as alternative therapies for primary hyperparathyroidism. Therefore, in this pilot study, our aim was to test the feasibility, safety, and efficacy of a newly developed noninvasive high intensity focused ultrasound (HIFU) technique for the nonsurgical management of primary hyperparathyroidism. SUBJECTS AND METHODS: We treated four menopausal women with biochemical, sonographic, and cytologic evidence of benign primary hyperparathyroidism. HIFU treatment was performed in two sessions using TH-One under sonographic guidance and with the patient under conscious sedation. Parathyroid volume and function were evaluated at baseline and repeatedly until 12 months after the second HIFU session. RESULTS: Serum parathyroid hormone levels decreased in all four patients and normalized 1 and 8 months after the second HIFU session in two patients. Serum calcium levels decreased in all patients and normalized in three patients. Three of four parathyroid tumors had decreased in size by 11%, 43%, and 79%, respectively, 12 months after the second HIFU session. All adverse events related to HIFU were transient: mild subcutaneous edema in three patients and impaired vocal cord mobility in one patient that resolved 40 days later. CONCLUSION: HIFU is a promising procedure for patients with primary hyperparathyroidism that may become an alternative to established options, especially in elderly patients with comorbidities, or in patients who decline surgery. Large-scale long-term studies including patients with secondary and tertiary hyperparathyroidism are warranted. PMID- 20858806 TI - More than a procedure. PMID- 20858807 TI - PAVM embolization: an update. AB - OBJECTIVE: Pulmonary arteriovenous malformations (PAVMs) are most often associated with hereditary hemorrhagic telangiectasia. Untreated, they represent a serious threat due to paradoxical embolization that may manifest as stroke or brain abscess. PAVM treatment is challenging even in the most experienced hands. CONCLUSION: Fortunately, new tools and techniques are emerging that may improve the outcomes associated with embolization and reduce some of the risks associated with treating these high-flow lesions. New trends in overall PAVM management are also developing. PMID- 20858808 TI - Incidence of infectious complications after an ultrasound-guided intervention. AB - OBJECTIVE: The objective of our study was to determine the incidence of infectious complications of common ultrasound-guided procedures including fine needle aspiration (FNA), drain placement, biopsy, pseudoaneurysm thrombin injection, thoracentesis, and paracentesis. SUBJECTS AND METHODS: The infection prevention and control (IPAC) committee at the Mayo Clinic, Rochester, MN, conducts surveillance of selected infections including radiology procedures. When a positive culture, hospital admission, or operating room visit for infection is identified, the patient's electronic records are thoroughly reviewed by an infection control practitioner looking for information about prior interventions. Similarly, the department of radiology prospectively follows all patients who have undergone ultrasound-guided hepatic, renal, and pancreatic biopsies for complications 24 hours, 3 months, and 12 months after biopsy. We reviewed 2 years of these data to determine the incidence of infections after common ultrasound guided procedures. RESULTS: We performed 13,534 ultrasound-guided procedures from January 2006 to December 2007. There were 11 likely and three possible procedure related infections for an overall incidence of 0.1% (14/13,534). The infections consisted of five abscesses, four bloodstream infections, four cases of peritonitis, and one urinary tract infection. The highest incidence of infections occurred after ultrasound-guided biopsy (0.2%, 10/5,487), with biopsy of a hepatic transplant having the highest incidence (1.0%, 2/192). No infections occurred after thoracentesis and FNA despite the large number of procedures performed (2,489 and 2,340, respectively). Nearly all patients improved on antibiotics. One patient died 5 days after paracentesis; however, death was likely due to multiorgan failure in the setting of fulminant liver failure with hepatorenal syndrome. CONCLUSION: The incidence of a serious infectious complication after ultrasoundguided intervention is low. Radiologists can use these data to provide more accurate information to patients when asking for consent before procedures and to reassure their patients. PMID- 20858809 TI - Percutaneous biliary drainage in patients with nondilated intrahepatic bile ducts compared with patients with dilated intrahepatic bile ducts. AB - OBJECTIVE: The purpose of this article is to compare the technical success and guidance of percutaneous transhepatic biliary drainage (PTBD) in patients with nondilated and dilated bile duct systems using different techniques to supplement the conventional approach. MATERIALS AND METHODS: Between 2006 and 2008, 71 patients (mean age, 66.6 years) underwent PTBD with 97 interventions. According to sonographic evaluation of bile duct morphology, patients were divided into two groups: 50 patients with dilated and 21 patients with nondilated bile ducts. In a retrospective analysis, both groups were compared for technical success, fluoroscopy time, complications, and medical indications. The use of interventional guidance (deviations from the standard protocol) in patients with nondilated bile ducts was recorded. RESULTS: The technical success rate was 90% in patients with dilated bile ducts versus 81% in patients with nondilated ducts, with no significant difference (p = 0.36). The greater complexity of the intervention in patients with nondilated bile ducts resulted in longer fluoroscopy times (p = 0.04). Complication rates were not different between the two groups. The main indication for PTBD was relief of a compressed biliary system in patients with dilated ducts and postoperative management of complications or prevention of tumor-associated bile duct obstruction in patients with nondilated ducts. T-drainage, additional CT-guided puncture, and temporary gallbladder drainage were performed in 16 of 21 interventions for patients with nondilated bile ducts, resulting in a 100% success rate, versus a success rate of 60% in the five PTBDs of nondilated ducts performed in the conventional manner. CONCLUSION: T-drainage, additional CT-guided puncture, and temporary gallbladder drainage improve the technical success of PTBD when used in patients with nondilated bile ducts. With these measures, technical success and complication rates in patients with nondilated ducts are comparable to those for PTBD of dilated bile ducts. PMID- 20858810 TI - Time-resolved and bolus-chase MR angiography of the leg: branching pattern analysis and identification of septocutaneous perforators. AB - OBJECTIVE: The goal of this study was to compare time-resolved MR angiography (MRA) and bolus-chase MRA in the identification of peroneal artery septocutaneous perforators and for classification of the branching pattern of the arterial tree in the leg in a cohort of candidates for fibular free flap transfer operations. MATERIALS AND METHODS: Retrospective analysis was performed on imaging data from 53 legs of 27 patients (age range, 27-88 years) who underwent time-resolved MRA (FLASH; TR/TE, 2.5/1.0; flip angle, 22 degrees ; voxel dimensions, 1.54 * 1.25 * 1.5 mm; acquisition time, 2.27 s/frame) and bolus-chase MRA (FLASH; 3.2/1.2; flip angle, 25 degrees ; voxel dimensions, 0.94 * 0.89 * 1 mm) at 3 T with gadobenate dimeglumine administered at 0.05 and 0.10 mmol/kg, respectively. The branching pattern was analyzed; the total number of septocutaneous perforators for each leg was calculated from the time-resolved and bolus-chase MRA data; and the results were combined. The total and average number of septocutaneous perforators per leg and the frequency of various branching patterns were calculated. The techniques were compared in terms of branching pattern and number of visible septocutaneous perforators. RESULTS: A total of 84 septocutaneous perforators (1.58 +/- 1.05 [SD] per leg) were identified. Pattern 1A was found in 42 legs; 1B, two legs; 2A, one leg; 2B, one; 3A, four; 3B, one; and 3D, two legs. Classification with time resolved MRA was successful for 53 legs and with boluschase MRA for 51 legs (Z = 0.713, p = 0.24, one-tailed, not significant). Twenty-two septocutaneous perforators were identified with time-resolved MRA and 82 with bolus-chase MRA. CONCLUSION: MRA of the leg can be used to investigate the branching pattern and identify septocutaneous perforators in a single step. With the imaging parameters and contrast dose used in this study, septocutaneous perforators can be better identified with boluschase MRA, although this result may be partially related to the higher gadolinium dose used in this technique. PMID- 20858811 TI - MRI may be sufficient for noninvasive assessment of great vessel stents: an in vitro comparison of MRI, CT, and conventional angiography. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of MRI and CT assessment of great vessel stents in an in vitro model. MATERIALS AND METHODS: Three contemporary great vessel stent materials (nitinol, platinum iridium, and stainless steel) were assessed with three luminal conditions: no stenosis, internal stenosis, and external stenosis. Stents of the same material were implanted into an aorta model that was attached to an animal bypass pump with pulsatile flow. Each stent was imaged with conventional angiography as reference standard, 10 different MRI sequences, and CT. The sensitivity and specificity for the identification of stent stenosis was determined and stent lumen measurements compared. RESULTS: Of the investigated MRI sequences, three had the highest overall sensitivity and specificity for the identification of stent stenosis in all studied materials: through-plane gradientrecalled echo (GRE) with 75 degrees flip angle (100% and 95%, respectively), in- and through plane steady-state free precession (SSFP) (99% and 90%) and MR angiography (MRA) with 75 degrees flip angle (93% and 85%). Comparable sensitivity and specificity were achieved with CT (98% and 93%). GRE, SSFP, and MRA sequences tended to underestimate stent lumen diameter in externally nonstenosed stents and overestimate diameter in internally stenosed stents (p < 0.05). CT slightly underestimated external stenoses in all stent types (p < 0.05). CONCLUSION: Defined MRI sequences are feasible to assess nitinol, platinum-iridium, and stainless steel great vessel stents with diagnostic performance comparable with CT. PMID- 20858812 TI - Combined assessment of aortic root anatomy and aortoiliac vasculature with dual source CT as a screening tool in patients evaluated for transcatheter aortic valve implantation. AB - OBJECTIVE: The objective of our study was to investigate the feasibility, image quality, and clinical implications of a combined dual-source CT angiography (CTA) protocol to assess aortic root anatomy and aortoiliac vasculature in patients with severe aortic stenosis evaluated for transcatheter aortic valve implantation. SUBJECTS AND METHODS: Eighty consecutive patients (47 women and 33 men; mean age, 82.3 +/- 7.8 [SD] years) with severe aortic stenosis evaluated for transcatheter aortic valve implantation underwent a combined single-dose contrast enhanced dual-source CTA protocol (body weight < 70 kg, 110 mL of contrast medium; >= 70 kg, 130 mL) consisting of ECG-gated dual-source CTA of the chest with integrated cardiac CT and ungated CTA of the abdomen and pelvis. Two independent observers measured the dimensions of the aortic root and the aortoiliac vasculature and rated image quality semiquantitatively. Vessel attenuation was assessed. Amenability to transfemoral access was evaluated on the basis of vessel diameter (> 7 mm), anatomy, and the presence of vascular disease. RESULTS: Image quality of the aortic root was diagnostic in all 80 patients, and image quality of the aortoiliac vasculature was diagnostic in 79 patients. Vascular attenuation was greater than 200 HU at any vessel level. The mean diameter of the aortic annulus was 24.1 +/- 2.9 (SD) mm. Inter- and intraobserver correlations for aortic root and aortoiliac measurements were high (r = 0.93 0.99). Aortic root dimensions were suitable for transcatheter aortic valve implantation in 65 patients (81%). Thirty-eight patients (48%) were deemed amenable to instant transfemoral access without another vasculature intervention. CONCLUSION: The dimensions of the aortic root and the aortoiliac vasculature can be assessed with a combined single-dose contrast-enhanced dual-source CTA protocol, thereby allowing determination of patient eligibility for transcatheter aortic valve implantation, prosthesis sizing, and evaluation of the access route in one examination. PMID- 20858813 TI - Detection of hepatocellular carcinoma: comparison of angiographic C-arm CT and MDCT. AB - OBJECTIVE: The aim of this study was to compare the accuracy, sensitivity, and positive predictive value of C-arm CT with those of MDCT in the detection of hepatocellular carcinoma. MATERIALS AND METHODS: We retrospectively evaluated the cases of 50 patients with nodules of hepatocellular carcinoma who underwent biphasic MDCT and selective C-arm CT with flat-detector angiographic systems. We evaluated arterial phase C-arm CT images and the corresponding biphasic MDCT images of 59 hepatic areas in 50 patients. Three independent blinded observers rated both sets of images using a detection confidence scale. The diagnostic accuracy of the two techniques was compared on the basis of area under alternative free-response receiver operating characteristic curve (A(1)). Focal accumulation of iodized oil was the reference standard. RESULTS: Accuracy was significantly higher for C-arm CT (A(1) = 0.830) than for MDCT (A(1)= 0.618) for lesions smaller than 10 mm in diameter (p < 0.001), but the accuracy of the two techniques did not differ significantly for lesions measuring 10 mm or larger. C arm CT was significantly more sensitive than MDCT in the detection of lesions 20 mm or smaller (74.1% vs 34.0% for lesions < 10 mm [p < 0.001]; 94.7% vs 77.1% for lesions 10-20 mm [p < 0.001]). The positive predictive values of the two techniques did not differ significantly irrespective of lesion size. CONCLUSION: Compared with biphasic MDCT, C-arm CT depicted hepatocellular carcinoma lesions smaller than 10 mm with more accuracy and those 20 mm and smaller with more sensitivity. The two techniques were equally accurate in the detection of hepatocellular carcinoma lesions 10 mm in diameter and larger. PMID- 20858814 TI - CT fluoroscopy-assisted cervical transforaminal steroid injection: tips, traps, and use of contrast material. AB - OBJECTIVE: CT fluoroscopy-assisted cervical transforaminal steroid injection is an effective therapeutic option for cervical radiculopathy, yet it is approached with trepidation by some interventionalists. CT fluoroscopy is superior to conventional fluoroscopy for delineating complex anatomic relations in the neck but must be combined with careful technique to avoid rare but serious complications. We describe the anatomy of the neural foramen, our technique of CT fluoroscopy-assisted cervical transforaminal steroid injection, and the CT appearance of appropriate and inappropriate needle positions. CONCLUSION: Understanding anatomy will help to avoid complications and optimize the therapeutic potential of cervical transforaminal steroid injection. Use of contrast material for CT fluoroscopic guidance facilitates appropriate needle positioning and reduces the risk of complications. PMID- 20858815 TI - Diagnostic value of cardiac CT in the evaluation of bicuspid aortic stenosis: comparison with echocardiography and operative findings. AB - OBJECTIVE: This study was conducted to assess the diagnostic value of cardiac CT for the evaluation of patients with bicuspid aortic valve disease. MATERIALS AND METHODS: Fifty consecutive patients with aortic stenosis who underwent surgical valve repair between September 2005 and November 2006 were examined by ECG-gated CT and echocardiography. A 64-MDCT scanner was used. The image findings regarding the number of leaflets (bicuspid or tricuspid) were compared against the intraoperative findings and were statistically analyzed by one-way univariate analysis of variance. The aortic valve area (AVA) was also measured by CT and echocardiography, and the measured values were statistically compared by use of the paired Student's t test. RESULTS: Seventeen patients had a bicuspid aortic valve, and 33 had a tricuspid aortic valve. In 10 of the 50 patients, echocardiography was unable to depict the type of aortic valve because of extensive calcification. The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of a bicuspid aortic valve were 76.5%, 60.6%, 68.4%, and 95.2%, respectively, for echocardiography and 94.1%, 100%, 100%, and 97.1%, respectively, for CT. The CT findings were not significantly different from the intraoperative findings (p = 0.99), but the echocardiographic findings were (p < 0.05). The AVA measurements obtained by CT and echocardiography were 0.940 +/- 0.44 cm(2) and 0.659 +/- 0.234 cm(2), respectively, showing a significant difference (p < 0.05). CONCLUSION: ECG-gated cardiac CT is useful for the accurate morphologic assessment of bicuspid aortic stenosis, especially in patients with severe valve calcification. PMID- 20858816 TI - Cardiac CT for the differentiation of bicuspid and tricuspid aortic valves: comparison with echocardiography and surgery. AB - OBJECTIVE: The purpose of this study is to evaluate the diagnostic performance of CT, compared with that of echocardiography and surgery, for differentiating between bicuspid and tricuspid aortic valves. MATERIALS AND METHODS: Forty-seven patients with bicuspid valve and 47 patients with tricuspid aortic valve underwent retrospectively ECG-gated dual-source CT and echocardiography. Thirty four (72%) of the 47 patients with bicuspid aortic valve underwent valve surgery. Two independent blinded observers assessed the CT image quality of the aortic valve during diastole and systole on a 4-point scale, determined which phase allowed the differentiation of valve type, distinguished between tricuspid and bicuspid aortic valves, and assessed for the presence of a raphe. Diagnostic performance of CT was determined using echocardiography and surgery as the reference standard. RESULTS: According to echocardiography and surgery, seven (15%) of the 47 bicuspid aortic valves had no raphe, and 40 (85%) had a raphe. CT image quality was diagnostic (i.e., scores of 1-3) in all 94 patients in both diastole and systole. Among patients with bicuspid aortic valve and no raphe, differentiation between tricuspid and bicuspid aortic valves could be performed in diastole in 100% (7/7) of cases. Among patients with bicuspid aortic valve and raphe, differentiation was possible only in systole in 5% (2/40) of cases and when combining diastole and systole in 95% (38/40) of cases. In three bicuspid aortic valves with raphe, the valve was misclassified by CT as tricuspid aortic valve. Overall sensitivity and specificity of CT for the diagnosis of bicuspid aortic valve were 94% and 100%. CONCLUSION: CT is highly accurate for differentiation between bicuspid and tricuspid aortic valves. For bicuspid aortic valves without raphe, diastolic reconstructions are sufficient, whereas in those with a raphe, additional reconstructions in systole are required. PMID- 20858817 TI - Assessment of right ventricular function in acute pulmonary embolism using ECG synchronized MDCT. AB - OBJECTIVE: The purpose of this article is to determine the independent predictors of right ventricular (RV) dysfunction in patients with acute pulmonary embolism (PE) and to assess the relationship between RV ejection fraction (EF) and PE load. SUBJECTS AND METHODS: Breath-hold CT of the chest was performed for 64 patients with PE (33 men and 31 women; mean [+/- SD] age, 58.6 +/- 16.5 years). In addition, ECG-synchronized cardiac CT was performed to determine the RV and left ventricular (LV) EFs. PE load was determined using the Qanadli obstruction index. Multivariable regression analysis was performed to determine independent predictors of RV dysfunction (defined as EF < 35%). In addition, the relationship between RV EF and PE load was assessed by receiver operating characteristic (ROC) curves. RESULTS: RV dysfunction was independently predicted by a PE load greater than 50% (odds ratio, 40.17; 95% CI, 4.22-382.67) and an LV EF less than 45% (odds ratio, 31.18; 95% CI, 2.00-487.09; p < 0.05 for both). Curve analysis revealed that a PE load greater than 50% had a sensitivity of 82% and a specificity of 85% to identify an RV EF less than 35%. Conversely, an RV EF less than 35% had a sensitivity of 93% and a specificity of 67% to predict a PE load greater than 50%. CONCLUSION: RV dysfunction (defined as RV EF < 35%) in patients with acute PE is highly sensitive to define a PE load greater than 50%. Furthermore, RV dysfunction is independently predicted by an obstruction index greater than 50% or an LV EF less than 45%. Assessment of RV function by ECG synchronized CT may become useful for guiding therapy. PMID- 20858818 TI - Cryptogenic organizing pneumonia: serial high-resolution CT findings in 22 patients. AB - OBJECTIVE: We conducted a review of serial high-resolution CT (HRCT) findings of cryptogenic organizing pneumonia (COP). MATERIALS AND METHODS: Over the course of 14 years, we saw 32 patients with biopsy-confirmed COP. Serial HRCT scans were available for only 22 patients (seven men and 15 women; mean age, 52 years; median follow-up period, 8 months; range, 5-135 months). Serial CT scans were evaluated by two chest radiologists who reached a conclusion by consensus. Overall changes in disease extent were classified as cured, improved (i.e., >= 10% decrease in extent), not changed, or progressed (i.e., >= 10% increase in extent). When there were remaining abnormalities, the final follow-up CT images were analyzed to express observers' ideas regarding what type of interstitial lung disease the images most likely suggested. RESULTS: The two most common patterns of lung abnormality on initial scans were ground-glass opacification (86% of patients [19/22]) and consolidation (77% of patients [17/22]), distributed along the bronchovascular bundles or subpleural lungs in 13 patients (59%). In six patients (27%), the disease disappeared completely; in 15 patients (68%), the disease was decreased in extent; and in one patient (5%), no change in extent was detected on follow-up CT. When lesions remained, the final follow-up CT findings were reminiscent of fibrotic nonspecific interstitial pneumonia in 10 of 16 patients (63%). CONCLUSION: Although COP is a disease with a generally good prognosis, most patients (73%) with COP have some remaining disease seen on follow-up CT scans, and, in such cases, the lesions generally resemble a fibrotic nonspecific interstitial pneumonia pattern. PMID- 20858819 TI - Negative ECG-gated cardiac CT in patients with low-to-moderate risk chest pain in the emergency department: 1-year follow-up. AB - OBJECTIVE: The purpose of this article is to determine the frequency of adverse cardiac events during the year following a negative cardiac CT angiogram in a population of patients presenting to the emergency department with low-to moderate risk chest pain. SUBJECTS AND METHODS: Eighty-one consecutive patients who had standard of care evaluation for low-to-moderate risk chest pain in the emergency department were enrolled and consented to have a cardiac CT angiogram added to their workup and to have follow-up for 1 year. Eleven patients were excluded, six because their cardiac CT examinations were unsuccessful, four because of a positive cardiac CT angiogram result, and one was lost to follow-up. Seventy patients with negative cardiac CT angiographic results (< 50% stenosis) were included and were interviewed in detail at 3, 6, and 12 months about intervening cardiac events, diagnostic testing, and therapy. Electronic medical records were also reviewed at each time point. RESULTS: None of the 70 patients reported an adverse cardiac event over the 12-month follow-up period. At 1 year, the cause of chest pain was unknown in 49 patients, gastrointestinal in nine patients, anxiety in seven patients, musculoskeletal in three patients, and other in two patients. Three of four patients with 50% or greater stenosis on their cardiac CT had subsequent cardiac catheterization and stent placement. CONCLUSION: In patients with low-to-moderate risk chest pain evaluated in the emergency department, adverse cardiac events may be rare during the 12 months following a negative cardiac CT angiogram. PMID- 20858820 TI - CT angiography of coronary artery aneurysms: detection, definition, causes, and treatment. AB - OBJECTIVE: This article reviews the predisposing conditions, diagnostic criteria, CT appearances, and potential complications of coronary artery aneurysms. CONCLUSION: With the increasing use of MDCT to image the coronary arteries, aneurysms will be identified more frequently. Coronary artery aneurysms arise from a variety of causes, with CT appearance, management, and clinical course depending on the cause. PMID- 20858821 TI - MRI of nonischemic cardiomyopathy. AB - OBJECTIVE: The purpose of this article is to present current clinical and research issues in MRI evaluation of nonischemic cardiomyopathy, a diverse set of diseases, many of which have a genetic basis. CONCLUSION: Cardiac cine MRI along with delayed myocardial enhancement MRI and other MRI techniques can provide information beyond echocardiography for tissue characterization. MRI is increasingly being used for evaluation of genetically positive, phenotypically negative patients as well as for risk stratification. PMID- 20858822 TI - Hepatic hemangioma and metastasis: differentiation with gadoxetate disodium enhanced 3-T MRI. AB - OBJECTIVE: The purpose of this study was to evaluate the gadoxetate disodium enhanced MRI findings of hepatic hemangioma and to investigate the diagnostic performance in differentiating hepatic hemangioma and metastasis. MATERIALS AND METHODS: Images of 32 hepatic hemangiomas in 25 patients and of 29 hepatic metastatic lesions in 20 patients were retrospectively reviewed. Two independent readers interpreted hepatobiliary phase images alone, dynamic extracellular phase images alone, and combined hepatobiliary and dynamic extracellular phase images. MRI findings and performance with respect to the differential diagnosis of hemangioma and metastasis were assessed. RESULTS: During the hepatic arterial phase, 11 of the 32 hemangiomas (34%) exhibited early total enhancement, and nine (28%) exhibited peripheral nodular enhancement. A bright dot sign or minimal peripheral enhancement during the late dynamic phase was observed for a small number of lesions (6% and 28%, respectively). Twenty-three of the 29 metastatic lesions (79%) exhibited ring enhancement during the hepatic arterial phase. Twenty-nine hemangiomas (91%) and all of the metastatic lesions exhibited homogeneous or heterogeneous hypointensity during the hepatobiliary phase. The sensitivity, specificity, and area under the receiver operating characteristic curve for the detection of hemangioma were 76%, 81%, and 0.87 for the hepatobiliary phase alone; 97%, 88%, and 0.97 for the dynamic extracellular phase alone; and 97%, 88%, and 0.98 for the combination. Five nodules smaller than 1 cm (four hemangiomas, one metastatic lesion) that exhibited no enhancement during the arterial phase and minimal enhancement during the late dynamic phase were not differentiated. CONCLUSION: Gadoxetate disodium-enhanced MRI was found useful for differentiating hepatic hemangiomas and metastatic lesions, especially during the dynamic extracellular phase. Only a limited number of lesions smaller than 1 cm in diameter, which exhibited minimal enhancement on late dynamic phase images, were difficult to diagnose. PMID- 20858823 TI - Comparison of MRI and endoscopic ultrasound in the characterization of pancreatic cystic lesions. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of MRI and endoscopic ultrasound (EUS) for the characterization of cystic pancreatic lesions and prediction of malignancy. MATERIALS AND METHODS: Fifty patients (24 women and 26 men; average age, 57 years) underwent both MRI and EUS. All pancreatic lesions (21 cystic and 29 solid lesions) were proven by histopathologic analysis. Two radiologists retrospectively examined MR images, and a single gastroenterologist reviewed EUS images. The MRI and EUS characterizations of morphologic features of the cystic lesions and predictions of malignancy were evaluated. The prediction of malignancy was done by receiver operating characteristic (ROC) curve analysis. RESULTS: There was no difference between the ability of MRI and EUS to correctly classify lesions as cystic or solid (accuracy, 90-98% vs 88%; p > 0.05). There was no difference between the sensitivity of MRI and EUS for the characterization of septa (94.4% for MRI vs 77.8% for EUS), mural nodule (66.7-58.3% for MRI vs 58.3% for EUS), main pancreatic duct dilatation (92.9-85.7% for MRI vs 85.7% for EUS), and communication with main pancreatic duct (100% for MRI vs 88.9% for EUS). The area under ROC curve values for predicting malignancy showed no statistical significance (0.755-0.774 for MRI vs 0.769 for EUS; p > 0.894). CONCLUSION: MRI and EUS are comparable in the characterization of cystic pancreatic lesions and prediction of malignancy. PMID- 20858824 TI - Stone-targeted dual-energy CT: a new diagnostic approach to urinary calculosis. AB - OBJECTIVE: The objective of our study was to assess a stone-targeted low-dose protocol for the detection and characterization of urinary tract stones using a dual-energy CT scanner. SUBJECTS AND METHODS: Thirty-nine patients (20 men, 19 women; age range, 22-87 years; average age, 47 years) with suspected renal colic in which ureteral stones were shown at low-dose unenhanced CT were enrolled in the study. Stone composition could be established in 24 patients, and these patients represent our study population regarding the CT characterization of stones. All examinations were performed with a preliminary low-dose unenhanced CT acquisition of the whole urinary system that was immediately followed by a limited (scanning length, 5 cm) dual-energy acquisition of the region containing the ureteral stone. Stone characterization was assessed using a dual-energy software tool available on the system. Two experienced radiologists who were blinded to the chemical composition of the stones retrospectively reviewed images and analyzed data to determine the composition of the stones. Their results were compared with the biochemical analysis results obtained by stereomicroscopy and infrared spectrometry. RESULTS: Based on in vitro-measured data, our combined protocol reduced dose by up to 50% compared with a full dual-energy acquisition; in addition, the calculated radiation doses of our protocol in patients are comparable to those of low-dose single- and dual-energy protocols. In 24 patients, 24 ureteral stones considered to be responsible for symptoms and detected at low-dose unenhanced CT were also shown at dual-energy CT. Correct chemical composition was obtained by dual-energy analysis in all 24 ureteral calculi regarding the characterization of uric acid (n = 3), calcium salt (n = 18), and combined uric acid-calcium salt (n = 3) stones. CONCLUSION: The use of dual-energy CT attenuation values made it possible to characterize all ureteral calculi, discriminating uric acid stones from calcium salt stones. The increment in radiation exposure due to contemporary scanning with two tubes at different energy levels can be substantially reduced using a limited stone-targeted dual energy protocol. PMID- 20858825 TI - Significance of upper urinary tract urothelial thickening and filling defect seen on MDCT urography in patients with a history of urothelial neoplasms. AB - OBJECTIVE: The purpose of this article is to assess the ability of CT urography to depict urothelial tumors in the upper renal collecting systems, compared with ureteroscopy and pathologic analysis, and to describe the relative implication of the radiologic signs of urothelial thickening and endoluminal filling defects. MATERIALS AND METHODS: We conducted a retrospective study to evaluate 326 consecutive CT urography examinations (using the split-bolus technique) performed at our institution between February 2006 and May 2009 in 188 patients (145 men and 43 women; median age, 65.5 years; range, 32.4-90.2 years) undergoing surveillance because of a history of urothelial tumor. Initial CT urography reports from multiple board-certified body imaging radiologists were reviewed for upper tract lesions and were classified by radiologic sign (filling defect or urothelial wall thickening) and lesion location (pelvicalyceal or ureteral) by one of the authors. The reference standard for comparison was pathologic analysis or visualization of tumor on ureteroscopy. Sensitivity and positive predictive values (PPVs) were calculated for upper tract tumors. RESULTS: Thirty-eight lesions were reported on initial CT urography examinations, 24 of which were subsequently confirmed to be tumors (PPV, 63.2%). Urothelial thickening was reported in 14 lesions, nine of which were tumors (PPV, 64%). Endoluminal filling defects were seen in 24 lesions, 15 of which were tumors (PPV, 62.5%). When stratified by location, urothelial thickening was more predictive of tumor in the pelvicalyceal system (PPV, 87.5% [7/8]) than in the ureter (PPV, 33.3% [2/6]). In contrast, filling defects were more predictive in the ureter (PPV, 87.5% [7/8]) than in the pelvicalyceal system (PPV, 50% [8/16]). CT urography failed to depict four tumors. CONCLUSION: Our data confirm that CT urography has utility in the surveillance of upper tract tumors. Urothelial thickening is an important radiologic sign of tumor, especially in the pelvicalyceal system. PMID- 20858826 TI - Masters of radiology panel discussion: who is accountable for the appropriateness of studies--the radiologist, the referring physician, or both? PMID- 20858827 TI - A survey of radiology chairpersons' perceptions of the relative importance of education of medical students, residents, and fellows. AB - OBJECTIVE: The purpose of the study was twofold: to assess radiology chairpersons' perceptions about the value of education of medical students, residents, and fellows with respect to the achievement of department success and to uncover their personal involvement in instructional activities. MATERIALS AND METHODS: A questionnaire was sent to all American members of the Society of Chairmen in Academic Radiology (SCARD) requesting their opinions about 21 putative responsibilities of their job including student, resident, and fellow education. The survey also asked the respondents to list the size of their trainee complement, both residents and fellows. The data were assessed in toto and after disaggregation by program size as indicated by the number of trainees and by the percentage of fellows versus all trainees. RESULTS: Sixty-nine of 108 chairpersons responded with contributory responses for a response rate of 63.9%. Resident training was the fourth most frequently affirmatively cited component of their perceptions of a department's success at 86% positive. Slightly more than half indicated that they were personally involved in resident instruction but less than a third participated in student or in fellow training. Disaggregation by the size of the department with respect to the number of trainees revealed that resident teaching as a critical factor decreased in estimation of importance from 100% to 64% (p < 0.001) as programs increased in size. Fellowship training correspondingly increased from 18% to 45% (p = 0.054) from small to large departments. CONCLUSION: Resident education as a valued activity and as a specific chair function varies inversely with both program size and the percentage of fellows among all trainees. PMID- 20858828 TI - Measurement accuracy and reproducibility of semiautomated metric and volumetric lymph node analysis in MDCT. AB - OBJECTIVE: The purpose of this study was to assess the measurement accuracy and reproducibility of semiautomated metric and volumetric lymph node analysis in MDCT. MATERIALS AND METHODS: Whole-body CT with IV contrast administration was performed on 112 patients. Peripheral (cervical, axillary, and inguinal), abdominal, and thoracic lymph nodes were evaluated independently by two radiologists both manually and with semiautomated segmentation software. Long axis diameter, short-axis diameter, and volume were measured. Agreement between the semiautomated and manual measurements (measurement error), need for manual correction, and relative interobserver differences were determined. Statistical analysis encompassed the variance inhomogeneity test, intraclass correlation coefficients, and Bland-Altman plots. RESULTS: In total, 742 peripheral (cervical, axillary, and inguinal), abdominal, and thoracic lymph nodes (mean diameter, 13.2 +/- 4.3 mm; range, 4-37 mm) were evaluated. Semiautomatic segmentation without need for further correction was possible for 480 of 742 lymph nodes (64.7%). Calculation of intraclass correlation coefficients revealed high correlation between manual and semiautomatic measurements (r = 0.70-0.81) with a slight trend toward size overestimation for semiautomatic short-axis diameter (14.3%; limits of agreement, -34.3%, 62.9%) and long-axis diameter (11.7%; limits of agreement, -25.2%, 48.5%). Bland-Altman plots showed significantly (p < 0.0001) lower interobserver differences for semiautomated short-axis diameter (1.2%; 95% CI, -39.9% to 42.3%) compared with the manual measurement (7.6%; 95% CI, -38.7% to 53.9%). Among all locations, the relative interobserver difference for semiautomatic volume (2.9%; 95% CI, -31.4% to 37.3%) was significantly lower than that for manual short-axis diameter (p < 0.0001), manual long-axis diameter (0.0178), and semiautomatic short-axis diameter (p < 0.0001). CONCLUSION: Semiautomatic short-axis diameter, particularly volume measurements, of lymph nodes are, irrespective of location, precise in terms of reproducibility and appear to be considerably more reliable than manual lymph node assessment. PMID- 20858829 TI - Improvement of image quality of low radiation dose abdominal CT by increasing contrast enhancement. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of noise index and contrast material dose on radiation dose, contrast enhancement, image noise, and image quality in abdominal CT. SUBJECTS AND METHODS: Contrast-enhanced abdominal CT with tube current modulation was performed on 195 patients. The patients were prospectively randomized into three groups of equal size (protocol A, noise index of 12 HU and 521 mg I/kg; protocol B, 15 HU and 521 mg I/kg; protocol C, 15 HU and 600 mg I/kg). Scanning was initiated 5 and 45 seconds after aortic enhancement reached 100 HU. Attenuation was measured in the aorta, portal vein, and liver. Transverse CT images were qualitatively graded for diagnostic acceptability and image noise. Arterial phase volume-rendered and multiplanar reformatted (MPR) images and portal venous phase MPR CT angiograms were qualitatively graded for depiction of vessels. Contrast enhancement, objective image noise, radiation dose, and qualitative grades were analyzed and compared among the three groups. RESULTS: The contrast enhancement values of the aorta, portal vein, and liver were higher in protocol C than in protocols A and B (p < 0.05). Objective image noise was greater in protocols B and C than in protocol A (p < 0.05). The radiation dose in protocols B and C was 31-32% lower than in protocol A (p < 0.001). Depiction of vessels, diagnostic acceptability, and subjective image noise were comparable in protocols A and C. CONCLUSION: Use of higher contrast enhancement can compensate for the degradation of image quality resulting from use of a low radiation dose for CT. PMID- 20858830 TI - High hamstring tendinopathy: MRI and ultrasound imaging and therapeutic efficacy of percutaneous corticosteroid injection. AB - OBJECTIVE: The goals of this study were to review the MRI and sonographic findings in patients diagnosed clinically with high hamstring tendinopathy and to evaluate the efficacy of ultrasound-guided corticosteroid injections in providing symptomatic relief. CONCLUSION: MRI is more sensitive than ultrasound in detecting peritendinous edema and tendinopathy at the proximal hamstring origin. Fifty percent of patients had symptomatic improvement lasting longer than 1 month after percutaneous corticosteroid injection, and 24% of patients had symptom relief for more than 6 months. PMID- 20858831 TI - CT mucosal window settings: a novel approach to evaluating early T-stage head and neck carcinoma. AB - OBJECTIVE: The purpose of this study is to evaluate the CT densities of small head and neck mucosal cancers as a means of deriving a CT mucosal window display of narrower window width and higher window level to better detect and delineate head and neck carcinomas. MATERIALS AND METHODS: We retrospectively studied 19 subjects with T1-2 head and neck carcinomas. The density of tumor and adjacent normal mucosa on CT were measured. CT scans for the 19 patients with tumors and 35 subjects without mucosal tumors were anonymized and interpreted by two readers using standard soft-tissue windows and were reviewed again 1 week later with the addition of mucosal windows. RESULTS: The mean (+/- SD) attenuation of 17 visible tumors was 85.5 +/- 18.3 Hounsfield units (HU) and that of the surrounding normal mucosa was 55.3 +/- 15.2 HU (p < 0.0001). From our data, we derived guideline mucosal window settings-a window width of 120 HU and a window level of 60 HU. On blinded review, reader A detected 12 tumors with the addition of mucosal windows (sensitivity, 63%; specificity, 82%) and nine tumors on soft-tissue windows alone (sensitivity, 47%; specificity, 94%). Reader B detected nine tumors with use of mucosal windows (sensitivity, 47%; specificity, 71%) and eight tumors on soft tissue windows alone (sensitivity, 42%; specificity, 74%). CONCLUSION: Early T stage tumors have higher CT density than normal mucosa. Their conspicuity can be amplified using display windows with narrower window width and higher window level. The potential clinical applications are for the improved detection of unknown primary tumors and delineation of a known mucosal tumor. PMID- 20858832 TI - High-resolution susceptibility-weighted imaging at 3 T with a 32-channel head coil: technique and clinical applications. AB - OBJECTIVE: The purpose of this article is to illustrate the utility of susceptibility-weighted imaging (SWI) as an adjunct to routine MRI of the brain in neurologic disorders. CONCLUSION: SWI is a 3D spoiled gradient-echo sequence that combines phase and magnitude information to provide a high sensitivity for the detection of blood degradation products, calcifications, and iron deposits. PMID- 20858833 TI - Optimization of kVp and mAs for pediatric low-dose simulated abdominal CT: is it best to base parameter selection on object circumference? AB - OBJECTIVE: The objective of our study was to determine the effect of mAs and kVp reduction on pediatric phantoms based on patient circumference to optimize dose reduction and maintain image quality for abdominal CT. SUBJECTS AND METHODS: Three polymethylmethacrylate right cylindric CT dose index (CTDI) phantoms with diameters of 10, 16, and 32 cm simulated the abdomen of an infant, child, and adolescent, respectively. Using a National Institute of Standards & Technology ion chamber and Victoreen 660 electrometer, doses at centerline were recorded on a 16-MDCT scanner. Measurements were obtained in incremental steps from 50 to 400 mAs and from 80 to 140 kVp. Noise was calibrated to clinical images through a calibration factor. RESULTS: For phantoms of all circumferences, doses increased linearly with an increase in mAs and by the power function of kVp(n) for increases in kVp. There was an associated decrease in noise for all circumferences and a sharp decrease at lower doses with a plateau at higher doses. Using a noise threshold of 20 HU and a dose threshold of 2.5 cGy, a range of imaging parameters was established for each circumference from which technique optimization curves were created to determine optimal mAs and kVp pairs. The mean measured dose was 2.435 +/- 0.019 cGy. The mean measured noise was 29.35 +/- 1.45 HU. CONCLUSION: For pediatric CT, the most accurate way to strike the balance between image quality and radiation dose is to adjust dose to abdominal circumference, not body weight or age. Our data support the use of technique optimization curves to optimize kVp and mAs. PMID- 20858834 TI - T2 relaxation time changes in distal femoral articular cartilage in children with juvenile idiopathic arthritis: a 3-year longitudinal study. AB - OBJECTIVE: Increased cartilage T2 relaxation time is thought to be an early marker of disease progression in juvenile idiopathic arthritis, because it can identify microstructural changes before damage becomes visible. The purpose of this study was to investigate longitudinal changes in T2 relaxation time mapping (i.e., T2 map) in children with early juvenile idiopathic arthritis and to compare with changes in clinical assessments. SUBJECTS AND METHODS: Twenty children (age range, 6.4-16 years) with early juvenile idiopathic arthritis completed at least four evaluations with T2 maps and clinical assessments: at enrollment, at 3 months, and at 1, 2, and 3 years. Sagittal T2 maps of distal femoral cartilage were generated, a region of interest was selected, and a T2 relaxation time profile was generated. The area under the curve from the T2 profile (i.e., T2 value) was correlated with patient age and sex and the following clinical assessments: total knee score, Childhood Health Assessment Questionnaire, physician global assessment, parent global assessment, and total number of active joints. RESULTS: There was a significant increase in mean T2 values from 3 months to 2 years (p < 0.05). There was a significant decrease in mean Childhood Health Assessment Questionnaire values between enrollment and 2 years (p < 0.05) and a significant decrease in parent global assessment, physician global assessment, total number of active joints, and total knee score values between enrollment and 1 year (p < 0.05). There were no statistically significant correlations between T2 values and patient age, sex, or clinical assessments. CONCLUSION: In patients with early juvenile idiopathic arthritis, T2 maps showed increased T2 values from the 3-month to 2-year follow-up, during which time the clinical assessments improved. This increase likely represents progressive microstructural changes, even though clinical symptoms improved with treatment. PMID- 20858835 TI - Synovial sarcoma in children: imaging features and common benign mimics. AB - OBJECTIVE: Synovial sarcoma is the most common malignant nonrhabdomyosarcoma soft tissue sarcoma in children. This article shows examples of synovial sarcoma in children and corresponding examples of benign mimics. CONCLUSION: It is important for radiologists to recognize the often nonaggressive appearance of synovial sarcoma in the pediatric population to guide surgical resection and expedite diagnosis before the development of locoregional spread or metastatic disease. PMID- 20858836 TI - Pseudoangiomatous stromal hyperplasia: imaging findings with pathologic and clinical correlation. AB - OBJECTIVE: The purpose of this article is to describe the imaging characteristics of pseudoangiomatous stromal hyperplasia, where the primary histologic component was pseudoangiomatous stromal hyperplasia. CONCLUSION: The tumoral form of pseudoangiomatous stromal hyperplasia is rare. The most common mammographic and sonographic finding is a circumscribed mass. Its appearance on MRI is nonspecific, but it may present as clumped nonmasslike persistent enhancement on contrast-enhanced imaging. Biopsy guided by MRI may be necessary to confirm the diagnosis. PMID- 20858837 TI - Hypoxia in models of lung cancer: implications for targeted therapeutics. AB - PURPOSE: To efficiently translate experimental methods from bench to bedside, it is imperative that laboratory models of cancer mimic human disease as closely as possible. In this study, we sought to compare patterns of hypoxia in several standard and emerging mouse models of lung cancer to establish the appropriateness of each for evaluating the role of oxygen in lung cancer progression and therapeutic response. EXPERIMENTAL DESIGN: Subcutaneous and orthotopic human A549 lung carcinomas growing in nude mice as well as spontaneous K-ras or Myc-induced lung tumors grown in situ or subcutaneously were studied using fluorodeoxyglucose and fluoroazomycin arabinoside positron emission tomography, and postmortem by immunohistochemical observation of the hypoxia marker pimonidazole. The response of these models to the hypoxia-activated cytotoxin PR-104 was also quantified by the formation of gammaH2AX foci in vitro and in vivo. Finally, our findings were compared with oxygen electrode measurements of human lung cancers. RESULTS: Minimal fluoroazomycin arabinoside and pimonidazole accumulation was seen in tumors growing within the lungs, whereas subcutaneous tumors showed substantial trapping of both hypoxia probes. These observations correlated with the response of these tumors to PR-104, and with the reduced incidence of hypoxia in human lung cancers relative to other solid tumor types. CONCLUSIONS: These findings suggest that in situ models of lung cancer in mice may be more reflective of the human disease, and encourage judicious selection of preclinical tumor models for the study of hypoxia imaging and antihypoxic cell therapies. PMID- 20858838 TI - Cisplatin-induced downregulation of OCTN2 affects carnitine wasting. AB - PURPOSE: Carnitine is an essential cofactor for mitochondrial fatty acid oxidation that is actively reabsorbed by the luminal transporter Octn2 (Slc22a5). Because the nephrotoxic agent cisplatin causes urinary loss of carnitine in humans, we hypothesized that cisplatin may affect Octn2 function. EXPERIMENTAL DESIGN: Excretion of carnitine and acetylcarnitine was measured in urine collected from mice with or without cisplatin administration. The transport of carnitine was assessed in cells that were transfected with OCT1 or OCT2. The effect of cisplatin treatment on gene expression was analyzed using a mouse GeneChip array and validated using quantitative reverse transcriptase-PCR. RESULTS: In wild-type mice, urinary carnitine excretion at baseline was ~3-fold higher than in mice lacking the basolateral cisplatin transporters Oct1 and Oct2 [Oct1/2(-/-) mice], indicating that carnitine itself undergoes basolateral uptake into the kidney. Transport of carnitine by OCT2, but not OCT1, was confirmed in transfected cells. We also found that cisplatin caused an increase in the urinary excretion of carnitine and acetylcarnitine in wild-type mice but not in Oct1/2(-/ ) mice, suggesting that tubular transport of cisplatin is a prerequisite for this phenomenon. Cisplatin did not directly inhibit the transport of carnitine by Octn2 but downregulated multiple target genes of the transcription factor peroxisome proliferator activated receptor alpha, including Slc22a5, in the kidney of wild-type mice that were absent in Oct1/2(-/-) mice. CONCLUSION: Our study shows a pivotal role of Oct1 and Oct2 in cisplatin-related disturbances in carnitine homeostasis. We postulate that this phenomenon is triggered by deactivation of peroxisome proliferator activated receptor alpha and leads to deregulation of carnitine-shuttle genes. PMID- 20858839 TI - Superior efficacy of tumor cell vaccines grown in physiologic oxygen. AB - PURPOSE: Atmospheric oxygen (~20% O(2)) has been the universal condition employed to culture tumor cells used as vaccine antigen. We tested the hypothesis that reducing oxygen tension would increase the efficacy of tumor cell lysate vaccines. EXPERIMENTAL DESIGN: GL261 glioma cells and EMT6 breast carcinoma cells were grown in 5% or 20% O(2). Syngeneic tumor-bearing mice were vaccinated with these tumor cell lysates mixed with CpG oligodeoxynucleotides as an adjuvant. Tumor infiltrating T cells and apoptotic GL261 cells were quantified by immunohistochemistry. Tumor-reactive immunoglobulin was detected by Western blot. Ovalbumin and gp100-derived peptides were mixed with GL261 lysates as marker antigens to detect changes in presentation of exogenous antigen on MHC class I in vitro, and in vivo following adoptive transfer of gp100-specific CD8(+) T cells. RESULTS: Mice bearing orthotopic glioma and breast carcinoma survived significantly longer when vaccinated with 5% O(2) lysates. Antigen-specific CTL activation was significantly enhanced following stimulation with lysates derived from GL261 cells grown in 5% O(2) versus 20% O(2) through a mechanism that involved enhanced cross-presentation of exogenous antigen on MHC I. Vaccination with 5% O(2) GL261 cell lysates caused a significant increase in CTL proliferation, tumoricidal function, and trafficking into brain tumor sites, whereas 20% O(2) lysate vaccines predominantly evoked an antibody response. CONCLUSIONS: Tissue culture oxygen functions as an "immunologic switch" by dictating the cellular and humoral immune responses elicited by tumor cell lysates. These results have profound implications for cancer vaccines that utilize tumor cells as the source of antigen. PMID- 20858840 TI - Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer. AB - In contrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel agents capable of treating advanced triple negative breast cancer (TNBC) are lacking. Poly(ADP-ribose) polymerase (PARP) inhibitors are emerging as one of the most promising "targeted" therapeutics to treat TNBC, with the intended "target" being DNA repair. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative breast cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer. PMID- 20858841 TI - Involvement of human herpesvirus-6 variant B in classic Hodgkin's lymphoma via DR7 oncoprotein. AB - PURPOSE: Hodgkin's lymphoma (HL) is associated with the presence of EBV in Reed Sternberg (RS) cells in ~40% of cases. Here, we studied the presence of human herpesvirus type 6 (HHV-6) variant B in RS cells of HL patients and correlated results with clinical parameters. We then examined the implication of HHV-6 DR7B protein in cell deregulation. EXPERIMENTAL DESIGN: HHV-6 DR7B protein was produced in a Semliki Forest virus system. Polyclonal antibodies were then generated and used for immunochemical HHV-6 localization in HL biopsies. Binding between DR7B and p53 was studied using a double-hybrid system. Transactivation of NFkappaB was observed after transient transfection using reporter gene assays. We looked for Id2 factor expression after stable transfection of the BJAB cell line by reverse transcription-PCR and Western blot analysis. RESULTS: HHV-6 was more common in nodular sclerosis subtype HL, and DR7B oncoprotein was detected in RS cells for 73.7% of EBV-negative patients. Colocalization of EBV and HHV-6 was observed in RS cells of doubly infected patients. DR7B protein bound to human p53 protein. p105-p50/p65 mRNA expression and activation of the NFkappaB complex were increased when DR7B was expressed. Stable expression of DR7B exhibited a strong and uniform expression of Id2. A slightly higher percentage of remission was observed in patients with RS cells testing positive for DR7B than in those testing negative. CONCLUSIONS: Collectively, these data provide evidence for the implication of a novel agent, HHV-6, in cases of nodular sclerosis HL. PMID- 20858842 TI - Location, location, location-makes all the difference for hypoxia in lung tumors. AB - Hypoxia is a clinically important component of the tumor microenvironment because it adversely affects progression, metastasis, response to chemoradiation therapy, and overall patient survival. Here, we describe how different animal tumor models of lung cancer can yield surprisingly different hypoxic profiles. PMID- 20858843 TI - Sequential cytarabine and alpha-particle immunotherapy with bismuth-213 lintuzumab (HuM195) for acute myeloid leukemia. AB - PURPOSE: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with beta-emitters, the alpha-particle-emitting radionuclide bismuth-213 ((213)Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of (213)Bi-lintuzumab, the first targeted alpha-emitter, after partially cytoreductive chemotherapy. EXPERIMENTAL DESIGN: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m(2)/d) for 5 days followed by (213)Bi-lintuzumab (18.5-46.25 MBq/kg). RESULTS: The MTD of (213)Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade <=2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by (213)Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. CONCLUSIONS: Sequential administration of cytarabine and (213)Bi-lintuzumab is tolerable and can produce remissions in patients with AML. PMID- 20858845 TI - Receptor for activated C-kinase 1 regulates the cell surface expression and function of ATP binding cassette G2. AB - In a previous report, we identified the receptor for activated C-kinase 1 (RACK1) as a positive regulator of the cellular localization and expression of ATP binding cassette B4, a phosphatidylcholine translocator expressed on the bile canalicular membrane. In the present study, we focused on the role of RACK1 on ATP-binding cassette G2 (ABCG2), which is responsible for the cellular extrusion of compounds including antitumor drugs. Protein expression of ABCG2 was up regulated by RACK1 overexpression, although mRNA expression of ABCG2 was not dependent on RACK1. The effect of RACK1 on the expression of ABCG2 on the cell surface was confirmed by the uptake of [(3)H]estrone sulfate, an ABCG2 substrate, into isolated membrane vesicles. The expression of RACK1 affected cellular resistance to mitoxantrone, an anticancer drug excreted by ABCG2, and this effect of RACK1 was abolished in the presence of fumitremorgin C, a selective ABCG2 inhibitor. These results suggest that RACK1 has functional significance as a regulatory cofactor of ABCG2 and is indispensable for the cell surface expression and excretion function of ABCG2. The precise mechanism for RACK1-dependent expression of ABCG2 remains to be clarified, because the results of N benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132) and chloroquine treatment and those of metabolic labeling experiments did not give us clear evidence whether the reduction of ABCG2 expression in RACK1-knocked down cells may be caused by the suppression of ABCG2 protein synthesis or by acceleration of its degradation. PMID- 20858846 TI - Cultural factors and social support related to breastfeeding among immigrant mothers in Taipei City, Taiwan. AB - The objectives of this study were to identify cultural factors (including acculturation and breastfeeding cultures in subjects' native countries and those in mainstream Taiwanese society) and social support related to breastfeeding among immigrant mothers in Taiwan. This study was a cross-sectional survey performed from October 2007 through January 2008. The study participants were 210 immigrant mothers living in Taipei City. The prevalence of exclusive and partial breastfeeding at 3 months postpartum was 59.0% and 14.3%, respectively. Logistic regression analysis revealed that breastfeeding experience among mothers-in-law and the perceived level of acceptance of breastfeeding in Taiwan were positively associated with breastfeeding at 3 months postpartum. Immigrant women with a higher level of household activity support were less likely to breastfeed. Immigrant mothers in Taiwan usually come from cultures with a higher acceptance level for breastfeeding; however, their breastfeeding practices are more likely to be influenced by the mainstream culture in Taiwan. PMID- 20858844 TI - Tissue-adapted invasion strategies of the rice blast fungus Magnaporthe oryzae. AB - Magnaporthe oryzae causes rice blast, the most serious foliar fungal disease of cultivated rice (Oryza sativa). During hemibiotrophic leaf infection, the pathogen simultaneously combines biotrophic and necrotrophic growth. Here, we provide cytological and molecular evidence that, in contrast to leaf tissue infection, the fungus adopts a uniquely biotrophic infection strategy in roots for a prolonged period and spreads without causing a loss of host cell viability. Consistent with a biotrophic lifestyle, intracellularly growing hyphae of M. oryzae are surrounded by a plant-derived membrane. Global, temporal gene expression analysis used to monitor rice responses to progressive root infection revealed a rapid but transient induction of basal defense-related gene transcripts, indicating perception of the pathogen by the rice root. Early defense gene induction was followed by suppression at the onset of intracellular fungal growth, consistent with the biotrophic nature of root invasion. By contrast, during foliar infection, the vast majority of these transcripts continued to accumulate or increased in abundance. Furthermore, induction of necrotrophy-associated genes during early tissue penetration, previously observed in infected leaves, was not seen in roots. Collectively, our results not only report a global characterization of transcriptional root responses to a biotrophic fungal pathogen but also provide initial evidence for tissue-adapted fungal infection strategies. PMID- 20858847 TI - Pediatric 99mTc-MDP bone SPECT with ordered subset expectation maximization iterative reconstruction with isotropic 3D resolution recovery. AB - PURPOSE: To perform a preliminary evaluation of the image quality of pediatric technetium 99m ((99m)Tc) methylene diphosphonate (MDP) bone single photon emission computed tomography (SPECT) by using iterative reconstruction-ordered subset expectation maximization with three-dimensional resolution recovery (OSEM 3D)-and to assess whether any improvements with use of this technique could lead to a reduction in patient dose or a shortening in imaging time. MATERIALS AND METHODS: Institutional advisory board approval was obtained for this investigation. Fifty (99m)Tc-MDP SPECT studies of the spine were evaluated (36 female and 14 male patients; mean age, 15.5 years). Each study was acquired by using a dual-detector camera, with each detector rotating 360 degrees . By using filtered back projection (FBP) and OSEM-3D, images were reconstructed from data generated by both detectors. Likewise, OSEM-3D was used to reconstruct data from a single detector simulating half the administered radiopharmaceutical activity. Two nuclear medicine physicians, blinded to the patient data, reviewed the images for image quality in four different categories by using a four-point scale: artifacts (category 1), lesions (category 2), noise (category 3), and image sharpness (category 4). RESULTS: Compared with FBP, images reconstructed by using OSEM-3D with one or two detectors showed significant improvement in image quality with regard to lesion detection, noise level, and image sharpness (P < .02, .01, and .001, respectively). With OSEM-3D, no significant differences were observed when either one or two detectors were used. CONCLUSION: Improved image quality of skeletal SPECT with either a 50% reduction in radiation dose or a 50% reduction in acquisition time or combination of the two can be achieved by using OSEM-3D. PMID- 20858848 TI - Dual-source parallel RF transmission for clinical MR imaging of the spine at 3.0 T: intraindividual comparison with conventional single-source transmission. AB - PURPOSE: To prospectively and intraindividually compare single-source radiofrequency (RF) excitation and dual-source parallel RF excitation in 3.0-T magnetic resonance (MR) imaging of the spine. MATERIALS AND METHODS: Institutional review board approval and written informed patient consent were obtained. The RF power of a 3.0-T MR imaging system was distributed to two ports of the body coil of the system by using independent RF transmit channels. The maximum B(1) field strength for dual-source parallel RF excitation was maintained, as compared with single-source RF excitation. The repetition time was reduced according to the revised RF setup with dual-source parallel RF excitation while maintaining specific energy absorption limitations. Thirty patients were examined with and without dual-source parallel RF excitation. Diagnostic quality was assessed independently by two radiologists according to a four-point grading system. Image contrast ratios (CRs) were calculated between reference tissues and vertebrae for single-source RF excitation and dual-source parallel RF excitation. RESULTS: The mean acceleration achieved with dual-source parallel RF excitation was 36% (range, 18%-50%). The total imaging duration of a three-station total spinal examination was reduced by one-third by using dual-source parallel RF transmission. For all cases investigated, diagnostic image quality without significant differences between the two methods and with a good interobserver agreement was achieved (Kendall tau-b, 0.50-0.84). The observed image contrast changes were predominantly small (<0.10 in 15 of 24 CRs), though they were significantly different (P < .05). CONCLUSION: While shortening examination times by approximately one-third, the dual-source parallel RF transmission mode in MR imaging of the spine yielded diagnostic image quality comparable to that with the conventional single-source RF transmission mode. PMID- 20858849 TI - Gray- and white-matter changes 1 year after first clinical episode of multiple sclerosis: MR imaging. AB - PURPOSE: To assess, by means of magnetic resonance (MR) imaging, the longitudinal changes in white matter (WM) and gray matter (GM) in a cohort of patients with clinically isolated syndrome (CIS) who were followed up for 1 year. MATERIALS AND METHODS: This prospective, HIPAA-compliant study was approved by the institutional review board. Written informed consent was obtained from all the participants. Changes in GM and WM integrity were respectively investigated by using three-dimensional T1-weighted and diffusion-tensor (DT) imaging sequences and by applying voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses. Thirty-four consecutive patients (21 women, 13 men; mean age, 32.8 years +/- 7.7 [standard deviation]) who had CIS were recruited. All the patients underwent a neurologic and an MR examination at baseline and 12 months later; the MR examination consisted of three-dimensional T1-weighted dual-echo turbo spin-echo DT imaging. VBM and TBSS were used to analyze GM volume and WM fractional anisotropy, respectively. RESULTS: After 1 year, multiple sclerosis (MS) was diagnosed in 33 (97%) of 34 patients with CIS. Longitudinal volumetric analysis revealed a significant (P < .001) reduction in global GM volume. The VBM analysis showed the development of regional GM atrophy involving several cortical and subcortical regions in both hemispheres (P < .05). No significant longitudinal change in global or regional WM fractional anisotropy was otherwise observed. CONCLUSION: WM damage was detectable early and involved most fiber tracts in patients with MS, but it did not worsen significantly during the 1st year after clinical onset. In contrast, GM damage was not detectable at the time of clinical onset, but a significant decrease in cortical and deep GM volume was observed at 1 year. PMID- 20858850 TI - Primary human breast adenocarcinoma: imaging and histologic correlates of intrinsic susceptibility-weighted MR imaging before and during chemotherapy. AB - PURPOSE: To investigate the histopathologic and dynamic magnetic resonance (MR) imaging correlates of intrinsic susceptibility-weighted (ISW) MR imaging in patients with primary human breast adenocarcinoma and to assess the relationship between baseline transverse relaxation rate (R2*) and T2* relaxivity change (DeltaR2*) and the response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Institutional ethics approval and informed consent were obtained. Between September 2001 and January 2008, 83 women (median age, 46 years; age range, 26-72 years) with breast cancer were recruited to undergo dynamic contrast medium-enhanced (DCE), dynamic susceptibility contrast-enhanced (DSC), and ISW MR imaging before and after two cycles of NAC. After excluding necrotic, infiltrating, and invasive lobular carcinomas, 31 patients were available for baseline assessment and 27 were available for response assessment. Transfer constant, leakage space, rate constant, initial area under the gadolinium concentration-time curve at 60 seconds, relative blood volume (rBV), relative blood flow (rBF), and R2* were calculated. Relationships between baseline R2* and histopathologic variables (tumor grade, estrogen receptor status, progesterone receptor status, human epidermal growth factor 2 status), tumor size, and dynamic MR imaging parameters were sought. Baseline adenocarcinoma R2* (n = 31) and DeltaR2* (n = 27) were correlated with final pathologic response. RESULTS: Inverse correlations between baseline R2* and rBV (rho = -0.48, P = .013) and rBF (rho = -0.44, P = .024) were found, but not after NAC. No relationships were observed between baseline R2* and other kinetic imaging parameters, histopathologic characteristics, or tumor size (P > .05). Baseline R2* values were lower in tumors than in normal breast tissue (31.8 sec(-1) vs 36.2 sec(-1), P = .017) but not after NAC. Increases in R2* were observed after treatment (31.1 sec(-1) vs 34.8 sec(-1), P = .006), with larger increases correlating with pathologic response. DeltaR2* was not as effective as DCE or DSC MR imaging parameters in the prediction of response. CONCLUSION: R2* is influenced by blood volume in untreated breast adenocarcinomas. Increases in R2* after two cycles of NAC correlate with pathologic response. Therapy-induced uncoupling of the relationship between R2* and rBV and rBF is consistent with responding tumors becoming hypoxic early during treatment. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100421/-/DC1. PMID- 20858852 TI - Unilateral subtalar coalition: contralateral sustentaculum tali morphology. AB - PURPOSE: To measure and compare the dimensions of the sustentaculum tali (ST) in pediatric patients with unilateral subtalar coalition to determine if the contralateral side has altered morphology. MATERIALS AND METHODS: The institutional review board approved this study, which was HIPAA compliant. Informed consent was waived. Radiology records were reviewed to identify 35 patients with unilateral subtalar coalition undergoing computed tomography (CT) (21 male, 14 female; mean age, 14.54 years) and 33 control patients with triplane fracture (21 male, 12 female; mean age, 13.48 years). CT images were reviewed, and reformatted images through the subtalar joint (on the side opposite the coalition) were created. Anteroposterior measurements of the middle facet (MF) and the ST were recorded by two observers with electronic calipers. The MF/ST ratio and the ST length extending posterior to the MF were calculated. Measurements between groups were compared by using Wald tests based on linear regressions. Inter- and intraobserver variabilities were determined by means of a component of variance model. RESULTS: The lengths of the MF and ST for the study and control groups were 12.86 and 16.82 mm (P < .001) and 23.83 and 22.06 mm (P = .053), respectively. Intra- and interobserver correlations for both measurements were 0.94 and 0.92 and 0.86 and 0.77, respectively. MF/ST ratio was 0.54 versus 0.76 (P < .001), and ST length extending posterior to the MF was 10.97 versus 5.24 mm (P < .001). CONCLUSION: The MF is smaller and the ST extends further beyond the MF in patients with a contralateral subtalar coalition than in control patients. The morphology of the ST may provide insight into the origins and development of coalitions. PMID- 20858851 TI - Do liposomal apoptotic enhancers increase tumor coagulation and end-point survival in percutaneous radiofrequency ablation of tumors in a rat tumor model? AB - PURPOSE: To characterize effects of combining radiofrequency (RF) ablation with proapoptotic intravenous liposome-encapsulated paclitaxel and doxorubicin on tumor destruction, apoptosis and heat-shock protein (HSP) production, intratumoral drug accumulation, and end-point survival. MATERIALS AND METHODS: R3230 mammary adenocarcinomas (n = 177) were implanted in 174 rats in this animal care committee-approved study. Tumors received (a) no treatment, (b) RF ablation, (c) paclitaxel, (d) RF ablation followed by paclitaxel (RF ablation-paclitaxel), (e) paclitaxel before RF ablation (paclitaxel-RF ablation), (f) RF ablation followed by doxorubicin (RF ablation-doxorubicin), (g) paclitaxel followed by doxorubicin without RF ablation (paclitaxel-doxorubicin), or (h) paclitaxel before RF ablation, followed by doxorubicin (paclitaxel-RF ablation-doxorubicin). Tumor coagulation area and diameter were compared at 24-96 hours after treatment. Intratumoral paclitaxel uptake with and without RF ablation were compared. Immunohistochemical staining revealed cleaved caspase-3 and 70-kDa HSP (HSP70) expression. Tumors were randomized into eight treatment arms for Kaplan-Meier analysis of defined survival end-point (3.0-cm diameter). RESULTS: Paclitaxel-RF ablation increased tumor coagulation over RF ablation or paclitaxel (mean, 14.0 mm +/- 0.9 [standard deviation], 6.7 mm +/- 0.6, 2.5 mm +/- 0.6, respectively; P < .001). Paclitaxel-RF ablation-doxorubicin had similar tumor coagulation (P < .05), compared with paclitaxel-RF ablation, at 24 and 96 hours. Mean intratumoral paclitaxel accumulation for paclitaxel-RF ablation (6.76 MUg/g +/- 0.35) and RF ablation-paclitaxel (9.28 MUg/g +/- 0.87) increased over that for paclitaxel (0.63 MUg/g +/- 0.25, P < .001). Paclitaxel substantially increased apoptosis and decreased HSP70 expression at coagulation margin. Mean end-point survival for paclitaxel-RF ablation-doxorubicin (56.8 days +/- 25.3) was greater, compared with that for paclitaxel-RF ablation or RF ablation-paclitaxel (17.6 days +/- 2.5), RF ablation-doxorubicin (30.3 days +/- 4.9, P < .002), or paclitaxel doxorubicin (27.9 days +/- 4.1, P < .001). CONCLUSION: Selecting adjuvant liposomal chemotherapies (paclitaxel, doxorubicin) to target cellular apoptosis and HSP production effectively increases RF ablation-induced tumor coagulation and end-point survival, and combined multidrug approach results in even better outcomes. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100500/-/DC1. PMID- 20858853 TI - An accompanying genetic severe deficiency of tissue factor protects mice with a protein C deficiency from lethal endotoxemia. AB - Mice with a severe genetic deficiency of protein C (PC), PC(-/-)PC(tg4), display enhanced susceptibility to lethal effects of gram-negative endotoxemia induced by lipopolysaccharide (LPS), whereas mice severely deficient in tissue factor (TF), TF(-/-)hTF(tg), are protected from LPS-mediated lethality. In this study, we show that a simultaneous severe deficiency of TF protected low-PC mice from LPS induced death, resulting in a survival profile similar to that experienced by wild-type (WT) mice. Plasma and whole blood coagulation assays, the latter measured by thromboelastography, demonstrated development of coagulopathies in LPS-treated mice, which were more severe in the case of the doubly deficient TF( /-)hTF(tg)/PC(-/-)PC(tg4) mice, mainly reflecting earlier signs of disseminated intravascular coagulation in this latter cohort. Markers of inflammation were also elevated in response to LPS in both groups of mice at times just preceding death. We conclude that whereas coagulopathies are more exacerbated in LPS treated TF(-/-)hTF(tg)/PC(-/-)PC(tg4) mice, the lowering of TF levels in mice with an accompanying severe PC deficiency confers protection against death compared with mice with a single severe PC deficiency. This suggests that proteases generated as a result of factor VIIa/TF-mediated thrombin generation play a mechanistic role in the enhanced lethality seen under very low PC conditions in an endotoxemia model in mice. PMID- 20858854 TI - Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia. AB - Adult T-cell leukemia (ATL), a heterogeneous disease, can be divided into smoldering, chronic, lymphoma, and acute types clinically. In addition to different clinical manifestations, different stages of ATL have different molecular signatures. Here, we demonstrated that smoldering/chronic ATL peripheral blood mononuclear cells spontaneously proliferated ex vivo in a cytokine (interleukin-12 [IL-12]/IL-9/IL-15)-dependent manner, while acute-type ATL peripheral blood mononuclear cells did not proliferate or proliferated independent of cytokines. Smoldering/chronic ATL cells produced IL-2 and IL-9 in 6-day ex vivo cultures. Interestingly, the addition of an anti-IL-2R-alpha monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/IL-9, and the downstream Janus kinase/signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment. PMID- 20858855 TI - Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells. AB - Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34(+) cells. Treatment of PMF CD34(+) cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-alpha led to the generation of greater numbers of CD34(+) chemokine (C-X-C motif) receptor (CXCR)4(+) cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F(+). Furthermore, sequential treatment of PMF CD34(+) cells but not normal CD34(+) cells with decitabine (5-aza-2'-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F(+) PMF CD34(+) cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rgamma(null) mice, the percentage of JAK2V617F/JAK2(total) in human CD45(+) marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F(+) and that JAK2V617F(+) HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC. PMID- 20858856 TI - Membrane-type MMPs are indispensable for placental labyrinth formation and development. AB - The membrane-type matrix metalloproteinases (MT-MMPs) are essential for pericellular matrix remodeling in late stages of development, as well as in growth and tissue homeostasis in postnatal life. Although early morphogenesis is perceived to involve substantial tissue remodeling, the roles of MT-MMPs in these processes are only partially characterized. Here we explore the functions of 2 prominently expressed MT-MMPs, MT1-MMP and MT2-MMP, and describe their roles in the process of placental morphogenesis. The fetal portion of the placenta, in particular the labyrinth (LA), displays strong overlapping expression of MT1-MMP and MT2-MMP, which is critical for syncytiotrophoblast formation and in turn for fetal vessels. Disruption of trophoblast syncytium formation consequently leads to developmental arrest with only a few poorly branched fetal vessels entering the LA causing embryonic death at embryonic day 11.5. Through knockdown of MMP expression, we demonstrate that either MT1-MMP or MT2-MMP is crucial specifically during development of the LA. In contrast, knockdown of MT-MMP activity after LA formation is compatible with development to term and postnatal life. Taken together these data identify essential but interchangeable roles for MT1-MMP or MT2-MMP in placental vasculogenesis and provide the first example of selective temporal and spatial MMP activity required for development of the mouse embryo. PMID- 20858857 TI - Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group. AB - Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid-based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapeutica en Hemopatia Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL. PMID- 20858859 TI - Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. AB - This study assessed the cumulative incidence of clinically significant cardiac disease in 1279 Hodgkin lymphoma patients treated with mediastinal irradiation and quantified the standard incidence ratios (SIRs) and absolute excess risks of cardiac procedures compared with a normal matched population. Cox regression analysis was used to explore factors associated with cardiac complications. Poisson regression analysis of SIRs was used to estimate the excess risk of cardiac interventions from mediastinal irradiation. After a median follow-up of 14.7 years, 187 patients experienced 636 cardiac events and 89 patients required a cardiac procedure. 5-, 10-, 15-, and 20-year cumulative incidence rates of cardiac events were 2.2%, 4.5%, 9.6%, and 16%. SIRs for cardiac procedures were increased for coronary artery bypass graft (3.19), percutaneous intervention (1.55), implantable cardioverter defibrillator or pacemaker placement (1.9), valve surgery (9.19), and pericardial surgery (12.91). Absolute excess risks were 18.2, 19.3, 9.4, 14.1, and 4.7 per 10 000 person-years, respectively. Older age at diagnosis and male sex were predictors for cardiac events. However, younger age at diagnosis was associated with excess risk specifically from radiation therapy compared with the general population. These results may help guideline development for both the types and timing of cardiac surveillance in survivors of Hodgkin lymphoma. PMID- 20858858 TI - Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease. AB - Hyperactivation of the transcription factor Stat5 leads to various leukemias. Stat5 activity is regulated by the protein phosphatase SHP-1 in a phospholipase C (PLC)-beta3-dependent manner. Thus, PLC-beta3-deficient mice develop myeloproliferative neoplasm, like Lyn (Src family kinase)- deficient mice. Here we show that Lyn/PLC-beta3 doubly deficient lyn(-/-);PLC-beta3(-/-) mice develop a Stat5-dependent, fatal myelodysplastic/myeloproliferative neoplasm, similar to human chronic myelomonocytic leukemia (CMML). In hematopoietic stem cells of lyn( /-);PLC-beta3(-/-) mice that cause the CMML-like disease, phosphorylation of SHP 1 at Tyr(536) and Tyr(564) is abrogated, resulting in reduced phosphatase activity and constitutive activation of Stat5. Furthermore, SHP-1 phosphorylation at Tyr(564) by Lyn is indispensable for maximal phosphatase activity and for suppression of the CMML-like disease in these mice. On the other hand, Tyr(536) in SHP-1 can be phosphorylated by Lyn and another kinase(s) and is necessary for efficient interaction with Stat5. Therefore, we identify a novel Lyn/PLC-beta3 mediated regulatory mechanism of SHP-1 and Stat5 activities. PMID- 20858860 TI - Adhesive epicardial corticosteroids prevent postoperative atrial fibrillation. AB - BACKGROUND: Postoperative atrial fibrillation remains a common cause of morbidity. Although epicardial drug delivery can increase efficacy and reduce side effects, it is impractical for postoperative atrial fibrillation because pericardial bleeding/effusion and drainage cause rapid drug elimination. Fibrin glue sprayed on the epicardium is vigorously adherent, allowing an admixed drug to remain in contact with the heart. The purpose of the present study was to evaluate a novel corticosteroid-fibrin glue mixture applied to the atrial epicardium at the time of surgery for prevention of postoperative atrial tachyarrhythmias. METHODS AND RESULTS: Talc was instilled into the pericardium in 15 dogs to simulate postoperative inflammation. Pacemakers were implanted to monitor arrhythmias. A mixture of triamcinolone and fibrin glue (Tisseel) was sprayed onto the atria of the treatment animals (n=9), whereas control animals (n=6) received Tisseel or nothing. After 1 week, pacemaker interrogation quantified postoperative atrial tachyarrhythmias (atrial rate >200 bpm) burden. Excised hearts underwent histological examination and tensile strength testing. postoperative atrial tachyarrhythmias occurred in 100% of control animals but only 33% of treatment animals (P=0.027). The median time (25th percentile, 75th percentile) in tachycardia was 5.5 hours (2.7, 12.6) per day in the control group, compared with 0 hours (0, 0.2) in the treatment group (P=0.001). Severe inflammation was present in 6 of 6 control animals and 1 of 9 treatment animals (P=0.001). The tensile strength of a healing left atriotomy was not significantly different between groups. Steroid levels at the time the animals were killed were very low (median of 0.22 MUg/dL [0.18, 0.23]). CONCLUSIONS: A mixture of triamcinolone and fibrin glue sprayed onto the atria reduced postoperative atrial tachyarrhythmias and reduced inflammatory cell infiltration. There was no change in the tensile strength of a healing atriotomy and plasma steroid levels were low. Clinical trials of this approach are warranted. PMID- 20858861 TI - Efficacy and risk of atrial fibrillation ablation before 45 years of age. AB - BACKGROUND: Young patients with atrial fibrillation (AF) tend to be more symptomatic and less willing to take long-term medications, yet catheter ablation remains recommended as second-line therapy for AF regardless of age. This study seeks to characterize the effectiveness and risk of AF ablation in the young. METHODS AND RESULTS: Consecutive (n=1548) patients who underwent 2038 AF ablation procedures were included. Major procedural complications and efficacy were analyzed on the basis of age at the initial procedure: <45 years (group 1), 45 to 54 years (group 2), 55 to 64 years (group 3), and >=65 years (group 4). AF control was defined as no or rare AF on or off antiarrhythmic drugs. The primary outcome of AF control was similar in all groups; it was achieved in 87% in group 1, 88% in group 2, 88% in group 3, and 82% in group 4 (P=0.06). However, more group 1 patients demonstrated freedom from AF off antiarrhythmic drugs (76%) compared with group 2 at 68%, group 3 at 65%, and group 4 at 53% (P<0.001). There were no major complications in group 1, 10 (1.7%) in group 2, 14 (1.4%) in group 3, and 10 (2.6%) in group 4 (P=0.01). CONCLUSIONS: In patients younger than 45 years, there is a lower major complication rate and a comparable efficacy rate, with a greater chance of being AF free without antiarrhythmic drugs. These findings suggest that it may be appropriate to consider ablative therapy as first line therapy in this age group. PMID- 20858862 TI - Pharmacodynamic effects of concomitant versus staggered clopidogrel and omeprazole intake: results of a prospective randomized crossover study. AB - BACKGROUND: A drug interaction between clopidogrel and omeprazole resulting in impaired platelet inhibition has been reported. It has been suggested that staggering administration of clopidogrel and omeprazole may overcome this pharmacodynamic (PD) interaction. METHODS AND RESULTS: This prospective, open label, 3-period, randomized crossover study was performed in 20 healthy volunteers. Subjects were randomly selected to receive omeprazole (40 mg daily) concomitantly (CONC) or staggered by 8 to 12 hours (STAG) for 1 week on a background of clopidogrel therapy in a crossover fashion, with a 2- to 4-week washout period between treatments. After another 2- to 4-week washout period, all subjects were treated for 1 week with clopidogrel alone. Clopidogrel was administered as a 600-mg loading dose followed by a 75-mg maintenance dose during all phases. PD effects were assessed by vasodilator-stimulated phosphoprotein phosphorylation assay, VerifyNow P2Y(12) system, and light transmittance aggregometry at baseline, 24 hours, and 1 week. The primary end point was the comparison of P2Y(12) reactivity index assessed by vasodilator-stimulated phosphoprotein phosphorylation assay at 1 week between CONC and STAG regimens. No significant difference in the primary end point was observed (least squares mean +/- SEM, 56.1 +/- 3.5% for CONC versus 61.6 +/- 3.4% for STAG; P = 0.08). P2Y(12) reactivity index values were significantly lower in the clopidogrel regimen (48.8 +/-3.4%) than in the CONC (P = 0.02) and STAG (P = 0.001) regimens. No PD differences were observed between regimens at baseline and 24 hours. Concordant results were obtained by P2Y(12)-specific assessments using VerifyNow but not with light transmittance aggregometry. CONCLUSIONS: Omeprazole impairs clopidogrel-induced antiplatelet effects in the maintenance phase of treatment irrespective of timing of their administration. PMID- 20858863 TI - A model for predicting mortality in acute ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention: results from the Assessment of Pexelizumab in Acute Myocardial Infarction Trial. AB - BACKGROUND: Accurate models to predict mortality are needed for risk stratification in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: We examined 5745 patients with STEMI undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction Trial within 6 hours of symptom onset. A Cox proportional hazards model incorporating regression splines to accommodate nonlinearity in the log hazard ratio (HR) scale was used to determine baseline independent predictors of 90-day mortality. At 90 days, 271 (4.7%) of 5745 patients died. Independent correlates of 90-day mortality were (in descending order of statistical significance) age (HR, 2.03/10-y increments; 95% CI, 1.80 to 2.29), systolic blood pressure (HR, 0.86/10-mm Hg increments; 95% CI, 0.82 to 0.90), Killip class (class 3 or 4 versus 1 or 2) (HR, 4.24; 95% CI, 2.97 to 6.08), heart rate (>70 beats per minute) (HR, 1.45/10-beat increments; 95% CI, 1.31 to 1.59), creatinine (HR, 1.23/10-MUmol/L increments >90 MUmol/L; 95% CI, 1.13 to 1.34), sum of ST-segment deviations (HR, 1.25/10-mm increments; 95% CI, 1.11 to 1.40), and anterior STEMI location (HR, 1.47; 95% CI, 1.12 to 1.93) (c index, 0.82). Internal validation with bootstrapping confirmed minimal overoptimism (c-index, 0.81). CONCLUSIONS: Our study provides a practical method to assess intermediate-term prognosis of patients with STEMI undergoing primary PCI, using baseline clinical and ECG variables. This model identifies key factors affecting prognosis and enables quantitative risk stratification that may be helpful in guiding clinical care and for risk adjustment for observational analyses. PMID- 20858864 TI - The association of patent foramen ovale morphology and stroke size in patients with paradoxical embolism. AB - BACKGROUND: Patent foramen ovale (PFO) has been implicated in the pathogenesis of cryptogenic stroke through paradoxical embolization to the cerebral circulation. This study evaluated the relationship between the morphological and functional size of the PFO by echocardiography compared with cerebral infarct volume identified on MRI. METHODS AND RESULTS: Patients who were referred to interventional cardiology with the diagnosis of cryptogenic stroke were included and had either a transesophageal echocardiogram or an intracardiac echo and a brain MRI at the time of stroke. Transesophageal echocardiogram or intracardiac echo was used to obtain PFO measurements. MRI of the brain with 3 sequences (T2, diffusion-weighted imaging, and fluid-attenuated inversion recovery) was used to diagnose acute stroke and measure the infarct volume. In the 72 patients studied, the median measured stroke volume was 4.3 cm(3) on diffusion-weighted imaging, 4.1 cm(3) on T2, and 3.5 cm(3) on fluid-attenuated inversion recovery. There was no significant correlation between the PFO height, length, septum secundum thickness, or echo bubble grade and the infarct volume measured from the 3 MRI sequences. There was a significant correlation between septal excursion distance and infarct volume (r=0.35; P=0.005), but the 12 patients with atrial septal aneurysm did not have the largest strokes. CONCLUSIONS: This analysis revealed that septal excursion distance correlates with stroke size by MRI. However, smaller PFO size without the presence of atrial septal aneurysm may still be associated with significant strokes. There was no significant association between PFO height, length by echo, or shunt grade by transcranial Doppler study and brain infarct volume. Therefore, PFO size or morphology should not be the only criteria to decide whether a PFO should be closed. PMID- 20858865 TI - The myelin brake: when enough is enough. AB - Myelination by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system is tightly regulated by interactions with axons. Various investigations have shed light on the signaling pathways that mediate the production of myelin, but an important question remains; that is, which signals determine when the cell stops myelinating. New studies demonstrate that in Schwann cells, this is controlled by the abundance of Dlg1, which acts to stop active myelination. PMID- 20858867 TI - Regulation of Ras localization by acylation enables a mode of intracellular signal propagation. AB - Growth factor stimulation generates transient H-Ras activity at the plasma membrane but sustained activity at the Golgi. Two overlapping regulatory networks control compartmentalized H-Ras activity: the guanosine diphosphate-guanosine triphosphate cycle and the acylation cycle, which constitutively traffics Ras isoforms that can be palmitoylated between intracellular membrane compartments. Quantitative imaging of H-Ras activity after decoupling of these networks revealed regulation of H-Ras activity at the plasma membrane but not at the Golgi. Nevertheless, upon stimulation with epidermal growth factor, Ras activity at the Golgi displayed a pulse-like profile similar to that at the plasma membrane but also remained high after the initial stimulus. A compartmental model that included the acylation cycle and H-Ras regulation at the plasma membrane accounted for the pulse-like profile of H-Ras activity at the Golgi but implied that sustained H-Ras activity at the Golgi required H-Ras activation at an additional compartment, which we experimentally determined to be the endoplasmic reticulum. Thus, in addition to maintaining the localization of Ras, the acylation cycle underlies a previously unknown form of signal propagation similar to radio transmission in its generation of a constitutive Ras "carrier wave" that transmits Ras activity between subcellular compartments. PMID- 20858868 TI - The cover. Moulting ducks. PMID- 20858866 TI - Synthetic lethal screen of an EGFR-centered network to improve targeted therapies. AB - Intrinsic and acquired cellular resistance factors limit the efficacy of most targeted cancer therapeutics. Synthetic lethal screens in lower eukaryotes suggest that networks of genes closely linked to therapeutic targets would be enriched for determinants of drug resistance. We developed a protein network centered on the epidermal growth factor receptor (EGFR), which is a validated cancer therapeutic target, and used small interfering RNA screening to comparatively probe this network for proteins that regulate the effectiveness of both EGFR-targeted agents and nonspecific cytotoxic agents. We identified subnetworks of proteins influencing resistance, with putative resistance determinants enriched among proteins that interacted with proteins at the core of the network. We found that clinically relevant drugs targeting proteins connected in the EGFR network, such as protein kinase C or Aurora kinase A, or the transcriptional regulator signal transducer and activator of transcription 3 (STAT3), synergized with EGFR antagonists to reduce cell viability and tumor size, suggesting the potential for a direct path to clinical exploitation. Such a focused approach can potentially improve the coherent design of combination cancer therapies. PMID- 20858869 TI - A piece of my mind. Healing hearts. PMID- 20858870 TI - Inconsistent results, inaccurate claims plague direct-to-consumer gene tests. PMID- 20858871 TI - Troubled by "stem cell tourism" claims, group launches web-based guidance. PMID- 20858872 TI - Salmonella cases traced to egg producers: findings trigger recall of more than 500 million eggs. PMID- 20858873 TI - Antibiotic therapy in patients hospitalized with acute chronic obstructive pulmonary disease. PMID- 20858874 TI - Antibiotic therapy in patients hospitalized with acute chronic obstructive pulmonary disease. PMID- 20858875 TI - Antibiotic therapy in patients hospitalized with acute chronic obstructive pulmonary disease. PMID- 20858876 TI - Distinguishing hemorrhagic stroke from ischemic stroke. PMID- 20858877 TI - Effect of binge drinking on the heart as assessed by cardiac magnetic resonance imaging. PMID- 20858878 TI - Self-management counseling in patients with heart failure: the heart failure adherence and retention randomized behavioral trial. AB - CONTEXT: Motivating patients with heart failure to adhere to medical advice has not translated into clinical benefit, but past trials have had methodological limitations. OBJECTIVE: To determine the value of self-management counseling plus heart failure education, compared with heart failure education alone, for the primary end point of death or heart failure hospitalization. DESIGN, SETTING, AND PATIENTS: The Heart Failure Adherence and Retention Trial (HART), a single center, multiple-hospital, partially blinded behavioral efficacy randomized controlled trial involving 902 patients with mild to moderate heart failure and reduced or preserved systolic function, randomized from the Chicago metropolitan area between October 2001 and October 2004 and undergoing follow-up for 2 to 3 subsequent years. INTERVENTIONS: All patients were offered 18 contacts and 18 heart failure educational tip sheets during the course of 1 year. Patients randomized to the education group received tip sheets in the mail and telephone calls to check comprehension. Patients randomized to the self-management group received tip sheets in groups and were taught self-management skills to implement the advice. MAIN OUTCOME MEASURE: Death or heart failure hospitalization during a median of 2.56 years of follow-up. RESULTS: Patients were representative of typical clinical populations (mean age, 63.6 years; 47% women, 40% racial/ethnic minority, 52% with annual family income less than $30,000, and 23% with preserved systolic function). The rate of the primary end point in the self-management group was no different from that in the education group (163 [40.1%)] vs 171 [41.2%], respectively; odds ratio, 0.95 [95% confidence interval, 0.72-1.26]). There were no significant differences on any secondary end points, including death, heart failure hospitalization, all-cause hospitalization, or quality of life. CONCLUSIONS: Compared with an enhanced educational intervention alone, the addition of self-management counseling did not reduce death or heart failure hospitalization in patients with mild to moderate heart failure. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00018005. PMID- 20858879 TI - Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. AB - CONTEXT: Critically short telomeres produce apoptosis, cell senescence, and chromosomal instability in tissue culture and animal models. Variations in telomere length have been reported in severe aplastic anemia but their clinical significance is unknown. OBJECTIVE: To investigate the relationship between telomere length and clinical outcomes in severe aplastic anemia. DESIGN, SETTING, AND PATIENTS: Single institution analysis of 183 patients with severe aplastic anemia who were treated in sequential prospective protocols at the National Institutes of Health from 2000 to 2008. The pretreatment leukocyte age-adjusted telomere length of patients with severe aplastic anemia consecutively enrolled in immunosuppression protocols with antithymocyte globulin plus cyclosporine for correlation with clinical outcomes were analyzed. MAIN OUTCOME MEASURES: Hematologic response, relapse, clonal evolution, and survival. RESULTS: There was no relationship between hematologic response and telomere length with response rates of 56.5% of 46 patients in the first, 54.3% of 46 in the second, 60% of 45 in the third, and 56.5% of 46 in the fourth quartiles. Multivariate analysis demonstrated that telomere length was associated with relapse, clonal evolution, and mortality. Evaluated as a continuous variable, telomere length inversely correlated with the probability of hematologic relapse (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.03-0.69; P = .01). The probability of clonal evolution was higher in patients in the first quartile (24.5%; 95% CI, 8.7% 37.5%) than in quartiles 2 through 4 (8.4%; 95% CI, 3.2%-13.3%; P = .009), and evolution to monosomy 7 or complex cytogenetics was more common in the first quartile (18.8%; 95% CI, 3.5%-31.6%) [corrected] than in quartiles 2 through 4 (4.5%; 95% CI, 0.5%-8.2%; P = .002) [corrected]. Survival between these 2 groups differed, with 66% (95% CI, 52.9%-82.5%) surviving 6 years in the first quartile compared with 83.8% (95% CI, 77.3%-90.9%) in quartiles 2 through 4 (P = .008). CONCLUSION: In a cohort of patients with severe aplastic anemia receiving immunosuppressive therapy, telomere length was unrelated to response but was associated with risk of relapse, clonal evolution, and overall survival. PMID- 20858881 TI - Rethinking rapid response teams. PMID- 20858882 TI - Role of state attorneys general in health policy. PMID- 20858883 TI - Putting the secure examination to the test. PMID- 20858880 TI - Subclinical hypothyroidism and the risk of coronary heart disease and mortality. AB - CONTEXT: Data regarding the association between subclinical hypothyroidism and cardiovascular disease outcomes are conflicting among large prospective cohort studies. This might reflect differences in participants' age, sex, thyroid stimulating hormone (TSH) levels, or preexisting cardiovascular disease. OBJECTIVE: To assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE and EMBASE (1950 to May 31, 2010) were searched without language restrictions for prospective cohort studies with baseline thyroid function and subsequent CHD events, CHD mortality, and total mortality. The reference lists of retrieved articles also were searched. DATA EXTRACTION: Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. Euthyroidism was defined as a TSH level of 0.50 to 4.49 mIU/L. Subclinical hypothyroidism was defined as a TSH level of 4.5 to 19.9 mIU/L with normal thyroxine concentrations. RESULTS: Among 55,287 adults, 3450 had subclinical hypothyroidism (6.2%) and 51,837 had euthyroidism. During follow-up, 9664 participants died (2168 of CHD), and 4470 participants had CHD events (among 7 studies). The risk of CHD events and CHD mortality increased with higher TSH concentrations. In age- and sex adjusted analyses, the hazard ratio (HR) for CHD events was 1.00 (95% confidence interval [CI], 0.86-1.18) for a TSH level of 4.5 to 6.9 mIU/L (20.3 vs 20.3/1000 person-years for participants with euthyroidism), 1.17 (95% CI, 0.96-1.43) for a TSH level of 7.0 to 9.9 mIU/L (23.8/1000 person-years), and 1.89 (95% CI, 1.28 2.80) for a TSH level of 10 to 19.9 mIU/L (n = 70 events/235; 38.4/1000 person years; P <.001 for trend). The corresponding HRs for CHD mortality were 1.09 (95% CI, 0.91-1.30; 5.3 vs 4.9/1000 person-years for participants with euthyroidism), 1.42 (95% CI, 1.03-1.95; 6.9/1000 person-years), and 1.58 (95% CI, 1.10-2.27, n = 28 deaths/333; 7.7/1000 person-years; P = .005 for trend). Total mortality was not increased among participants with subclinical hypothyroidism. Results were similar after further adjustment for traditional cardiovascular risk factors. Risks did not significantly differ by age, sex, or preexisting cardiovascular disease. CONCLUSIONS: Subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater. PMID- 20858884 TI - A national health agenda for Asian Americans and Pacific Islanders. PMID- 20858885 TI - Enlisting the help of the largest health care workforce--patients. PMID- 20858886 TI - JAMA patient page. Subclinical hypothyroidism. PMID- 20858888 TI - Helping each other grow: romantic partner support, self-improvement, and relationship quality. AB - This research tested whether and how partners' support of self-improvement efforts influences recipients' relationship evaluations and self-improvement success. Study 1 provided an initial test of predictions using self-reports (N = 150). Study 2 assessed support behavior exhibited in couples' (N = 47) discussions of self-improvement desires, and tracked relationship quality and self-improvement every 3 months for 1 year. More nurturing and action facilitating partner support was more helpful to recipients, whereas partners who criticized and invalidated recipients were less helpful. Receiving more help from the partner, in turn, predicted greater relationship quality and more self improvement. More negative support seeking also predicted lower self-improvement because recipients' behavior elicited less partner help. These effects were not attributable to partners' general warmth and understanding, global self or relationship evaluations, how much recipients desired or tried to change, or whether targeted attributes posed relationship problems. This research documents the powerful influence that partners' help has on recipients' personal growth. PMID- 20858887 TI - Therapy-induced senescence in cancer. AB - Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer. PMID- 20858889 TI - Staying alive: T cell costimulation, CD28, and Bcl-xL. PMID- 20858890 TI - CD28 costimulation can promote T cell survival by enhancing the expression of Bcl xL. Immunity. 1995. 3: 87-98. PMID- 20858891 TI - Antigen receptor allelic exclusion: an update and reappraisal. AB - Most lymphocytes express cell surface Ag receptor chains from single alleles of distinct Ig or TCR loci. Since the identification of Ag receptor allelic exclusion, the importance of this process and the precise molecular mechanisms by which it is achieved have remained enigmatic. This brief review summarizes current knowledge of the extent to which Ig and TCR loci are subject to allelic exclusion. Recent progress in studying and defining mechanistic steps and molecules that may control the monoallelic initiation and subsequent inhibition of V-to-(D)-J recombination is outlined using the mouse TCRbeta locus as a model with frequent comparisons to the mouse IgH and Igkappa loci. Potential consequences of defects in mechanisms that control Ag receptor allelic exclusion and a reappraisal of the physiologic relevance of this immunologic process also are discussed. PMID- 20858892 TI - Identification of two forms of Q{beta} replicase with different thermal stabilities but identical RNA replication activity. AB - The enzyme Qbeta replicase is an RNA-dependent RNA polymerase, which plays a central role in infection by the simple single-stranded RNA virus bacteriophage Qbeta. This enzyme has been used in a number of applications because of its unique activity in amplifying RNA from an RNA template. Determination of the thermal stability of Qbeta replicase is important to gain an understanding of its function and potential applications, but data reported to date have been contradictory. Here, we provide evidence that these previous inconsistencies were due to the heterogeneous forms of the replicase with different stabilities. We purified two forms of replicase expressed in Escherichia coli, which differed in their thermal stability but showed identical RNA replication activity. Furthermore, we found that the replicase undergoes conversion between these forms due to oxidation, and the Cys-533 residue in the catalytic beta subunit and Cys 82 residue in the EF-Tu subunit of the replicase are essential prerequisites for this conversion to occur. These results strongly suggest that the thermal stable replicase contains the intersubunit disulfide bond between these cysteines. The established strategies for isolating and purifying a thermally stable replicase should increase the usefulness of Qbeta replicase in various applications, and the data regarding thermal stability obtained in this study may yield insight into the precise mechanism of infection by bacteriophage Qbeta. PMID- 20858893 TI - The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase. AB - The TAZ transcription co-activator promotes cell proliferation and epithelial mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F box protein beta-TrCP and ubiquitylated by the SCF/CRL1(beta-TrCP) E3 ligase. The interaction between TAZ and beta-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1epsilon and subsequent binding by beta-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions. PMID- 20858894 TI - Ca2+ overload and sarcoplasmic reticulum instability in tric-a null skeletal muscle. AB - The sarcoplasmic reticulum (SR) of skeletal muscle contains K(+), Cl(-), and H(+) channels may facilitate charge neutralization during Ca(2+) release. Our recent studies have identified trimeric intracellular cation (TRIC) channels on SR as an essential counter-ion permeability pathway associated with rapid Ca(2+) release from intracellular stores. Skeletal muscle contains TRIC-A and TRIC-B isoforms as predominant and minor components, respectively. Here we test the physiological function of TRIC-A in skeletal muscle. Biochemical assay revealed abundant expression of TRIC-A relative to the skeletal muscle ryanodine receptor with a molar ratio of TRIC-A/ryanodine receptor ~5:1. Electron microscopy with the tric a(-/-) skeletal muscle showed Ca(2+) overload inside the SR with frequent formation of Ca(2+) deposits compared with the wild type muscle. This elevated SR Ca(2+) pool in the tric-a(-/-) muscle could be released by caffeine, whereas the elemental Ca(2+) release events, e.g. osmotic stress-induced Ca(2+) spark activities, were significantly reduced likely reflecting compromised counter-ion movement across the SR. Ex vivo physiological test identified the appearance of "alternan" behavior with isolated tric-a(-/-) skeletal muscle, i.e. transient and drastic increase in contractile force appeared within the decreasing force profile during repetitive fatigue stimulation. Inhibition of SR/endoplasmic reticulum Ca(2+ ATPase) function could lead to aggravation of the stress-induced alternans in the tric-a(-/-) muscle. Our data suggests that absence of TRIC-A may lead to Ca(2+) overload in SR, which in combination with the reduced counter-ion movement may lead to instability of Ca(2+) movement across the SR membrane. The observed alternan behavior with the tric-a(-/-) muscle may reflect a skeletal muscle version of store overload-induced Ca(2+) release that has been reported in the cardiac muscle under stress conditions. PMID- 20858896 TI - Activity of a C-terminal plant homeodomain (PHD) of Msc1 is essential for function. AB - Msc1, a member of the Jarid1 family of putative histone demethylases, is required for chromosome stability in fission yeast. Msc1 associates with the Swr1 complex that facilitates deposition of histone H2A.Z into chromatin. To assess the function of Msc1 in the Swr1 complex, domains of Msc1 necessary for interaction with Swr1 were identified. The C-terminal plant homeodomain (PHD) 2 and PHD3 of Msc1 are sufficient to confer association with Swr1 and allow Msc1 to function in the context of kinetochore mutants. On the other hand, a mutant with a single amino acid substitution in PHD2 within the full-length Msc1 protein retains the ability to bind to Swr1 but eliminates the function of Msc1 in combination with kinetochore mutants. Thus, Swr1 association is critical but not sufficient for Msc1 function. An activity of Msc1 that depends on the cysteine residue within PHD2 of Msc1 is likewise critical for function. On the basis of our observation that the PHDs of Msc1 act as E3 ubiquitin ligases and that mutations of cysteine residues within those domains abolish ligase activity, we speculate that the ability of Msc1 to facilitate ubiquitin transfer is critical for the function it mediates through its association with Swr1. PMID- 20858895 TI - Mutant huntingtin alters cell fate in response to microtubule depolymerization via the GEF-H1-RhoA-ERK pathway. AB - Cellular responses to drug treatment show tremendous variations. Elucidating mechanisms underlying these variations is critical for predicting therapeutic responses and developing personalized therapeutics. Using a small molecule screening approach, we discovered how a disease causing allele leads to opposing cell fates upon pharmacological perturbation. Diverse microtubule-depolymerizing agents protected mutant huntingtin-expressing cells from cell death, while being toxic to cells lacking mutant huntingtin or those expressing wild-type huntingtin. Additional neuronal cell lines and primary neurons from Huntington disease mice also showed altered survival upon microtubule depolymerization. Transcription profiling revealed that microtubule depolymerization induced the autocrine growth factor connective tissue growth factor and activated ERK survival signaling. The genotype-selective rescue was dependent upon increased RhoA protein levels in mutant huntingtin-expressing cells, because inhibition of RhoA, its downstream effector, Rho-associated kinase (ROCK), or a microtubule associated RhoA activator, guanine nucleotide exchange factor-H1 (GEF-H1), all attenuated the rescue. Conversely, RhoA overexpression in cells lacking mutant huntingtin conferred resistance to microtubule-depolymerizer toxicity. This study elucidates a novel pathway linking microtubule stability to cell survival and provides insight into how genetic context can dramatically alter cellular responses to pharmacological interventions. PMID- 20858897 TI - Requirement of TGFbeta signaling for SMO-mediated carcinogenesis. AB - Hedgehog (Hh) signaling, via the key signal transducer Smoothened (SMO) and Gli transcription factors, is essential for embryonic development and carcinogenesis. At present, the molecular mechanism of Hh signaling-mediated carcinogenesis is not completely understood. Using a mouse model (K14cre/R26SmoM2) of SMO-mediated basal cell carcinoma development, we identified TGFbeta2 as a major Hh-regulated gene. TGFbeta2 expression was high in the keratinocytes, with activated TGFbeta signaling (indicated by elevated expression of phosphorylated SMAD2/3) detected in both tumor and stroma. The significance of TGFbeta signaling for SMO function was demonstrated in two assays. Down-regulation of TGFbeta2 expression prevented Hh signaling-dependent osteoblast differentiation and motor neuron differentiation. Furthermore, inhibition of TGFbeta signaling by TGFbeta receptor I inhibitor SD208 significantly reduced tumor area in K14cre/R26SmoM2 mice. Tumor shrinkage in mice was associated with an increased number of lymphocytes, suggesting an immune suppression role of TGFbeta signaling. The relevance of our results to human cancer is reflected by the fact that human basal cell carcinomas, which almost always harbor activated Hh signaling, have activated TGFbeta signaling, as indicated by high levels of phosphorylated SMAD2 and SMAD3 in tumor and stroma. Together, our data indicate that TGFbeta signaling is critical for Hh signaling-mediated carcinogenesis. PMID- 20858898 TI - Hypoxia increases the dependence of glioma cells on glutathione. AB - Glutathione (GSH) is an essential antioxidant responsible for the maintenance of intracellular redox homeostasis. As tumors outgrow their blood supply and become hypoxic, their redox homeostasis is challenged by the production of nitric oxide and reactive oxygen species (ROS). In gliomas, the sustained import of L-cystine via the L-cystine/L-glutamate exchanger, system x(c)(-), is rate-limiting for the synthesis of GSH. We show that hypoxia causes a significant increase in NO and ROS but without affecting glioma cell growth. This is explained by a concomitant increase in the utilization of GSH, which is accompanied by an increase in the cell-surface expression of xCT, the catalytic subunit of system x(c)(-), and L cystine uptake. Growth was inhibited when GSH synthesis was blocked by buthionine sulfoximine (BSO), an inhibitor of the enzyme required for GSH synthesis, or when cells were deprived of L-cystine. These findings suggest that glioma cells show an increased requirement for GSH to maintain growth under hypoxic conditions. Therefore, approaches that limit GSH synthesis such as blocking system x(c)(-) may be considered as an adjuvant to radiation or chemotherapy. PMID- 20858899 TI - The protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2). AB - Axin is a negative regulator of Wnt/beta-catenin signaling via regulating the level of beta-catenin, which is a key effector molecule. Therefore, controlling the level of Axin is a critical step for the regulation of Wnt/beta-catenin signaling. It has been shown that ubiquitination-mediated proteasomal degradation may play a critical role in the regulation of Axin; however, the E3 ubiquitin ligase(s), which attaches ubiquitin to a target protein in combination with an E2 ubiquitin-conjugating enzyme, for Axin has not yet been identified. Here, we show that Smurf2 is an E3 ubiquitin ligase for Axin. Transient expression of Smurf2 down-regulated the level of Axin and increased the ubiquitination of Axin. Conversely, shRNA specific to Smurf2 blocked Axin ubiquitination. Essential domains of Axin responsible for Smurf2 interaction as well as Smurf2-mediated down-regulation and ubiquitination were identified. In vitro ubiquitination assays followed by analysis using mass spectroscopy revealed that Smurf2 specifically ubiquitinylated Lys(505) of Axin and that the Axin(K505R) mutant resisted degradation. Knockdown of endogenous Smurf2 increased the level of endogenous Axin and resulted in reduced beta-catenin/Tcf reporter activity. Overall, our data strongly suggest that Smurf2 is a genuine E3 ligase for Axin. PMID- 20858900 TI - Identification of the Drosophila ortholog of HSPB8: implication of HSPB8 loss of function in protein folding diseases. AB - Protein aggregation is a hallmark of many neuronal disorders, including the polyglutamine disorder spinocerebellar ataxia 3 and peripheral neuropathies associated with the K141E and K141N mutations in the small heat shock protein HSPB8. In cells, HSPB8 cooperates with BAG3 to stimulate autophagy in an eIF2alpha-dependent manner and facilitates the clearance of aggregate-prone proteins (Carra, S., Seguin, S. J., Lambert, H., and Landry, J. (2008) J. Biol. Chem. 283, 1437-1444; Carra, S., Brunsting, J. F., Lambert, H., Landry, J., and Kampinga, H. H. (2009) J. Biol. Chem. 284, 5523-5532). Here, we first identified Drosophila melanogaster HSP67Bc (Dm-HSP67Bc) as the closest functional ortholog of human HSPB8 and demonstrated that, like human HSPB8, Dm-HSP67Bc induces autophagy via the eIF2alpha pathway. In vitro, both Dm-HSP67Bc and human HSPB8 protected against mutated ataxin-3-mediated toxicity and decreased the aggregation of a mutated form of HSPB1 (P182L-HSPB1) associated with peripheral neuropathy. Up-regulation of both Dm-HSP67Bc and human HSPB8 protected and down regulation of endogenous Dm-HSP67Bc significantly worsened SCA3-mediated eye degeneration in flies. The K141E and K141N mutated forms of human HSPB8 that are associated with peripheral neuropathy were significantly less efficient than wild type HSPB8 in decreasing the aggregation of both mutated ataxin 3 and P182L HSPB1. Our current data further support the link between the HSPB8-BAG3 complex, autophagy, and folding diseases and demonstrate that impairment or loss of function of HSPB8 might accelerate the progression and/or severity of folding diseases. PMID- 20858901 TI - ARFGAP2 and ARFGAP3 are essential for COPI coat assembly on the Golgi membrane of living cells. AB - Coat protein complex I (COPI) vesicles play a central role in the recycling of proteins in the early secretory pathway and transport of proteins within the Golgi stack. Vesicle formation is initiated by the exchange of GDP for GTP on ARF1 (ADP-ribosylation factor 1), which, in turn, recruits the coat protein coatomer to the membrane for selection of cargo and membrane deformation. ARFGAP1 (ARF1 GTPase-activating protein 1) regulates the dynamic cycling of ARF1 on the membrane that results in both cargo concentration and uncoating for the generation of a fusion-competent vesicle. Two human orthologues of the yeast ARFGAP Glo3p, termed ARFGAP2 and ARFGAP3, have been demonstrated to be present on COPI vesicles generated in vitro in the presence of guanosine 5'-3-O (thio)triphosphate. Here, we investigate the function of these two proteins in living cells and compare it with that of ARFGAP1. We find that ARFGAP2 and ARFGAP3 follow the dynamic behavior of coatomer upon stimulation of vesicle budding in vivo more closely than does ARFGAP1. Electron microscopy of ARFGAP2 and ARFGAP3 knockdowns indicated Golgi unstacking and cisternal shortening similarly to conditions where vesicle uncoating was blocked. Furthermore, the knockdown of both ARFGAP2 and ARFGAP3 prevents proper assembly of the COPI coat lattice for which ARFGAP1 does not seem to play a major role. This suggests that ARFGAP2 and ARFGAP3 are key components of the COPI coat lattice and are necessary for proper vesicle formation. PMID- 20858902 TI - Internal initiation of influenza virus replication of viral RNA and complementary RNA in vitro. AB - Influenza virus transcription is a prototype of primer-dependent initiation. Its replication mechanism is thought to be primer-independent. The internal initiation and realignment model for influenza virus genome replication has been recently proposed (Deng, T., Vreede, F. T., and Brownlee, G. G. (2006) J. Virol. 80, 2337-2348). We obtained new results, which led us to propose a novel model for the initiation of viral RNA (vRNA) replication. In our study, we analyzed the initiation mechanisms of influenza virus vRNA and complementary RNA (cRNA) synthesis in vitro, using purified RNA polymerase (RdRp) and 84-nt model RNA templates. We found that, for vRNA -> cRNA ->, RdRp initiated replication from the second nucleotide of the 3'-end. Therefore, host RNA-specific ribonucleotidyltransferases are required to add one nucleotide (purine residues are preferred) to the 3'-end of vRNA to make the complete copy of vRNA. This hypothesis was experimentally proven using poly(A) polymerase. For cRNA -> vRNA, the dinucleotide primer AG was synthesized from UC (fourth and fifth from the 3' end) by RdRp pausing at the sixth U of UUU and realigning at the 3'-end of cRNA template; then RdRp was able to read through the entire template RNA. The RdRp initiation complex was not stable until it had read through the UUU of cRNA and the UUUU of vRNA at their respective 3'-ends. This was because primers overlapping with the first U of the clusters did not initiate transcription efficiently, and the initiation product of v84+G (the v84 template with an extra G at its 3'-end), AGC, realigned to the 3'-end. PMID- 20858903 TI - Nucleophosmin C-terminal leukemia-associated domain interacts with G-rich quadruplex forming DNA. AB - Nucleophosmin (NPM1) is a nucleocytoplasmic shuttling phosphoprotein, mainly localized at nucleoli, that plays a key role in ribogenesis, centrosome duplication, and response to stress stimuli. Mutations at the C-terminal domain of NPM1 are the most frequent genetic lesion in acute myeloid leukemia and cause the aberrant and stable translocation of the protein in the cytoplasm. The NPM1 C terminal domain was previously shown to bind nucleic acids. Here we further investigate the DNA binding properties of the NPM1 C-terminal domain both at the protein and nucleic acid levels; we investigate the domain boundaries and identify key residues for high affinity recognition. Furthermore, we demonstrate that the NPM1 C-terminal domain has a preference for G-quadruplex forming DNA regions and induces the formation of G-quadruplex structures in vitro. Finally we show that a specific sequence found at the SOD2 gene promoter, which was previously shown to be a target of NPM1 in vivo, is indeed folded as a G quadruplex in vitro under physiological conditions. Our data extend considerably present knowledge on the DNA binding properties of NPM1 and suggest a general role in the transcription of genes characterized by the presence of G-quadruplex forming regions at their promoters. PMID- 20858904 TI - Fine mapping of the insulin-induced gene 2 identifies a variant associated with LDL cholesterol and total apolipoprotein B levels. AB - BACKGROUND: In a whole-genome scan, a single nucleotide polymorphism (SNP) (rs7566605) upstream of the insulin-induced gene 2 (INSIG2) was shown to influence body mass index and obesity in the Framingham Heart Study, with replication of these results in an additional 4 of 5 studies. However, other studies could not replicate the association. Because INSIG2 plays an important role in cholesterol biosynthesis, we hypothesized that human INSIG2 variants might play a role in the regulation of plasma lipid and lipoprotein levels. METHODS AND RESULTS: We selected tagging SNPs spanning >100 kb of INSIG2 locus and sequenced 18 434 base pairs to discover novel SNPs. Thirty-two SNPs were genotyped in 645 individuals from the Quebec Family Study. Two SNPs (rs10490626 and rs12464355) were associated with plasma low-density lipoprotein cholesterol (LDL-C) (P<0.0015) and total apolipoprotein B (apoB) levels (P<0.014), whereas no association was found between any SNP and body mass index. We replicated the finding of rs10490626 for both LDL-C and total apoB in additional study samples, including 758 individuals from Saguenay-Lac St. Jean, Quebec (P=0.040 for LDL-C, P=0.044 for apoB), 3247 Europeans (P=0.028 for LDL-C, P=0.030 for apoB), and 1695 South Asians (P=0.0036 for LDL-C, P=0.034 for apoB) from the INTERHEART study (for LDL-C, the combined 2-sided P=6.2*10-5 and for total apoB, P=0.0011). Furthermore, we identified a variant in the human sorbin and SH(3)-domain containing-1 gene that was associated with INSIG2 mRNA levels, and this SNP was shown to act in combination with rs10490626 to affect LDL-C (P=0.022) in the Quebec Family Study and in INTERHEART South Asians (P=0.019) and Europeans (P=0.052). CONCLUSION: These results suggest that INSIG2 genetic variants may have a more direct role in lipid and lipoprotein metabolism than in obesity. PMID- 20858906 TI - Lactobacillus rhamnosus GR-1-induced IL-10 production in human placental trophoblast cells involves activation of JAK/STAT and MAPK pathways. AB - Intrauterine infection/inflammation complicates 25% to 40% of preterm births (PTB). The human vagina is normally populated by Lactobacillus species, some of which upregulate interleukin 10 (IL-10) output in lipopolysaccharide (LPS) treated human placental trophoblast cells. We hypothesize that a probiotic strain, L rhamnosus GR-1 exerts its anti-inflammatory effect through activation of the Janus Kinases/Signal Transducers and Activators of Transcription (JAK/STAT) and mitogen-activated protein kinase (MAPK) pathways. Placental trophoblasts from term healthy pregnancies were treated with LPS in the presence or absence of pretreatments with GR-1 supernatant and/or chemical inhibitors of the intracellular signaling pathways. Phosphorylation of STAT3 and p38 was measured by Western Blot analysis, and output of IL-10 was determined by enzyme linked immunosorbent assay (ELISA). Phosphorylation of STAT-3 and p38 was upregulated by GR-1 supernatant alone or in combination with LPS, while IL-10 output was inhibited by both JAK and p38 inhibitors. These data provide an underlying intracellular mechanism for cytokine regulation in the human placenta by L rhamnosus GR-1 and potential prevention of infection/inflammation-mediated PTB. PMID- 20858905 TI - Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease. AB - BACKGROUND: Genome-wide association studies have identified a locus on chromosome 9p21.3 to be strongly associated with myocardial infarction/coronary artery disease and ischemic stroke. To gain insights into the mechanisms underlying these associations, we hypothesized that single nucleotide polymorphisms (SNPs) in this region would be associated with platelet reactivity across multiple populations. METHODS AND RESULTS: Subjects in the initial population included 1402 asymptomatic Amish adults in whom we measured platelet reactivity (n=788) and coronary artery calcification (CAC) (n=939). Platelet reactivity on agonist stimulation was measured by impedance aggregometry, and CAC was measured by electron beam CT. Twenty-nine SNPs at the 9p21.3 locus were genotyped using the Affymetrix 500K array. Twelve correlated SNPs in the locus were significantly associated with platelet reactivity (all P<=0.001). The SNP most strongly associated with platelet reactivity, rs10965219 (P=0.0002), also was associated with CAC (P=0.002) along with 9 other SNPs (all P<0.004). Association of rs10965219 with platelet reactivity persisted after adjustment for CAC, a measure of underlying atherosclerotic burden known to affect platelet reactivity. We then tested rs10965219 for association with platelet function in 2364 subjects from the Framingham Heart Study and 1169 subjects from the Genetic Study of Aspirin Responsiveness. The rs10965219 G allele (frequency ~51% across all 3 populations) was significantly associated with higher platelet reactivity in the Framingham Heart Study (P=0.001) and trended toward higher reactivity in the Genetic Study of Aspirin Responsiveness (P=0.087); the combined P value for metaanalysis was 0.0002. CONCLUSIONS: These results suggest that risk alleles at 9p21.3 locus may have pleiotropic effects on myocardial infarction/coronary artery disease and stroke risk, possibly through their influence on platelet reactivity. PMID- 20858907 TI - Cone and rod photoreceptor transplantation in models of the childhood retinopathy Leber congenital amaurosis using flow-sorted Crx-positive donor cells. AB - Retinal degenerative disease causing loss of photoreceptor cells is the leading cause of untreatable blindness in the developed world, with inherited degeneration affecting 1 in 3000 people. Visual acuity deteriorates rapidly once the cone photoreceptors die, as these cells provide daylight and colour vision. Here, in proof-of-principle experiments, we demonstrate the feasibility of cone photoreceptor transplantation into the wild-type and degenerating retina of two genetic models of Leber congenital amaurosis, the Crb1(rd8/rd8) and Gucy2e(-/-) mouse. Crx-expressing cells were flow-sorted from the developing retina of CrxGFP transgenic mice and transplanted into adult recipient retinae; CrxGFP is a marker of cone and rod photoreceptor commitment. Only the embryonic-stage Crx-positive donor cells integrated within the outer nuclear layer of the recipient and differentiated into new cones, whereas postnatal cells generated a 10-fold higher number of rods compared with embryonic-stage donors. New cone photoreceptors displayed unambiguous morphological cone features and expressed mature cone markers. Importantly, we found that the adult environment influences the number of integrating cones and favours rod integration. New cones and rods were observed in ratios similar to that of the host retina (1:35) even when the transplanted population consisted primarily of cone precursors. Cone integration efficiency was highest in the cone-deficient Gucy2e(-/-) retina suggesting that cone depletion creates a more optimal environment for cone transplantation. This is the first comprehensive study demonstrating the feasibility of cone transplantation into the adult retina. We conclude that flow-sorted embryonic stage Crx-positive donor cells have the potential to replace lost cones, as well as rods, an important requirement for retinal disease therapy. PMID- 20858908 TI - Antipsychotics and the risk of venous thromboembolism. PMID- 20858909 TI - Antipsychotic drugs and risk of venous thromboembolism: nested case-control study. AB - OBJECTIVE: To determine whether antipsychotic drugs are associated with an increased risk of venous thromboembolism, and to examine risks by type of antipsychotic, potency, and dose. DESIGN: Population based nested case-control study. SETTING: The UK QResearch primary care database. PARTICIPANTS: Patients (cases) with a first ever record of venous thromboembolism between 1 January 1996 and 1 July 2007; each was matched with up to four controls by age, calendar time, sex, and practice. MAIN OUTCOME MEASURES: Odds ratios for venous thromboembolism associated with antipsychotic drugs adjusted for comorbidity; concomitant drug exposure. RESULTS: There were 25 532 eligible cases (15 975 with deep vein thrombosis and 9557 with pulmonary embolism) and 89 491 matched controls from a study population of 7 267 673. Individuals prescribed antipsychotic drugs in the previous 24 months had a 32% greater risk of venous thromboembolism than non users, despite adjustment for potential risk factors (odds ratio 1.32, 95% confidence interval 1.23 to 1.42). Patients who had started a new drug in the previous three months had about twice the risk (1.97, 1.66 to 2.33). The risk was greater for individuals prescribed atypical rather than conventional drugs (adjusted odds ratio 1.73, 1.37 to 2.17, for atypical drugs; 1.28, 1.18 to 1.38, for conventional drugs). It also tended to be greater for patients prescribed low rather than high potency drugs (1.99, 1.52 to 2.62, for low potency; 1.28, 1.18 to 1.38, for high potency). The estimated number of extra cases of venous thromboembolism per 10 000 patients treated over one year was 4 (3 to 5) in patients of all ages and 10 (7 to 13) for patients aged 65 and over. CONCLUSIONS: There is an association between use of antipsychotic drugs and risk of venous thromboembolism in a large primary care population. The increased risk was more marked among new users and those prescribed atypical antipsychotic drugs. PMID- 20858910 TI - A training paradigm to enhance motor recovery in contused rats: effects of staircase training. AB - BACKGROUND: Ambulating on stairs is an important aspect of daily activities for many individuals with incomplete spinal cord injury (SCI), and little is known about the effect of training for this specific task. OBJECTIVE: The goal of this study was to determine whether staircase ascent training enhances motor recovery in animals with contusion injury. METHODS: Rats received a midthoracic contusion lesion of moderate severity and were randomly divided into 2 groups, with one group receiving staircase ascent training for up to 8 weeks and the other receiving no training. To assess the direct effect of training, a task-specific staircase climbing test was performed. Open field test (BBB) and gait analysis (CatWalk) assessed overground recovery, and a grid test was used to assess improvement in sensorimotor tasks. Changes in muscle mass of the forelimb and hindlimb muscles were also measured, and the extent of spared white matter was determined for lesion verification and anatomical correlations. RESULTS: Staircase training improved the task-specific performance of ascent. Gait parameters, including base of support, stride length, regularity index (RI), and step sequence, also improved. Overground locomotion and the grid test, both showed a trend of improved performance. Finally, hindlimb muscle mass was maintained with training. CONCLUSIONS: Staircase ascent training after incomplete SCI has beneficial effects on task-specific as well as nonspecific motor and sensorimotor activities. PMID- 20858911 TI - Environmental sustainability in an aging society: a research agenda. AB - OBJECTIVE: This article presents the results of a multidisciplinary consensus conference held to recommend a research agenda on the relationship between aging and environmental sustainability and conservation. The intersection of these two topics has important implications for the health and well-being of older persons but it has thus far received little scientific attention. METHODS: The consensus conference was conducted with gerontological experts from various disciplines and environmental scientists. Using a structured methodology, participants achieved consensus on recommendations for a research agenda on aging and environmental sustainability. RESULTS: Eight major recommendations for research are detailed in this article as well as cross-cutting research themes affecting all areas, including racial and economic diversity, geographical region, cohort, and intergenerational linkages. DISCUSSION: Given the vulnerability of older persons to environmental threats detailed by the consensus conference, conferees recommended that research on these topics be urgently promoted, both by researchers and by funding agencies. PMID- 20858912 TI - Differences in self-reported oral health among community-dwelling black, Hispanic, and white elders. AB - OBJECTIVE: To compare differences in self-rated oral health among community dwelling Black, Hispanic, and White adults aged 60 and older. METHOD: A total of 4,859 participants in the National Health and Nutrition Examination Survey (1999 2004) provided self-report information on oral health. RESULTS: Blacks and Hispanics reported poorer self-rated oral health than Whites. In separate dentate and edentulous groups, socioeconomic status, social support, physical health, clinical oral health outcomes, and dental checkups accounted for much of the difference in self-rated oral health in Blacks, but significant differences remained for Hispanics. DISCUSSION: The study findings may have important implications for health policy and program development. Programs and services designed for minority populations should target treatments for dental diseases and include components that take into account subjective evaluations of oral health conditions and perceived dental needs of the individuals. PMID- 20858913 TI - Assessment of the accuracy of an ultrasound elastography liver scanning system using a PVA-cryogel phantom with optimal acoustic and mechanical properties. AB - The accuracy of a transient elastography liver-scanning ultrasound system was assessed using a novel application of PVA-cryogel as a tissue-mimicking material with acoustic and shear elasticity properties optimized to best represent those of liver tissue. Although the liver-scanning system has been shown to offer a safer alternative for diagnosing liver cirrhosis through stiffness measurement, as compared to the liver needle biopsy exam, the scanner's accuracy has not been fully established. Young's elastic modulus values of 5-6 wt% PVA-cryogel phantoms, also containing glycerol and 0.3 um Al(2)O(3) and 3 um Al(2)O(3), were measured using a 'gold standard' mechanical testing technique and transient elastography. The mechanically measured values and acoustic velocities of the phantoms ranged between 1.6 and 16.1 kPa and 1540 and 1570 m s(-1), respectively, mimicking those observed in liver tissue. The values reported by the transient elastography system overestimated Young's elastic modulus values representative of the progressive stages of liver fibrosis by up to 32%. These results were attributed to the relative rather than absolute nature of the measurement arising from the single-point acoustic velocity calibration of the system, rendering the measurements critically dependent on the speed of sound of the sample under investigation. Given the wide range of acoustic velocities which exist in the liver, spanning healthy tissue to cirrhotic pathology, coupled with the system's assumption that the liver is approximately elastic when it is rather highly viscoelastic, care should be exercised when interpreting the results from this system in patient groups. PMID- 20858914 TI - Characterizing early contrast uptake of ductal carcinoma in situ with high temporal resolution dynamic contrast-enhanced MRI of the breast: a pilot study. AB - Improvements in the reliable diagnosis of preinvasive ductal carcinoma in situ (DCIS) by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) are needed. In this study, we present a new characterization of early contrast kinetics of DCIS using high temporal resolution (HiT) DCE-MRI and compare it with other breast lesions and normal parenchyma. Forty patients with mammographic calcifications suspicious for DCIS were selected for HiT imaging using T(1) weighted DCE-MRI with ~7 s temporal resolution for 90 s post-contrast injection. Pixel-based and whole-lesion kinetic curves were fit to an empirical mathematical model (EMM) and several secondary kinetic parameters derived. Using the EMM parameterized and fitted concentration time curve for subsequent analysis allowed for calculation of kinetic parameters that were less susceptible to fluctuations due to noise. The parameters' initial area under the curve (iAUC) and contrast concentration at 1 min (C(1 min)) provided the highest diagnostic accuracy in the task of distinguishing pathologically proven DCIS from normal tissue. There was a trend for DCIS lesions with solid architectural pattern to exhibit a negative slope at 1 min (i.e. increased washout rate) compared to those with a cribriform pattern (p < 0.04). This pilot study demonstrates the feasibility of quantitative analysis of early contrast kinetics at high temporal resolution and points to the potential for such an analysis to improve the characterization of DCIS. PMID- 20858915 TI - Total body carbon and oxygen masses: evaluation of dual-energy x-ray absorptiometry estimation by in vivo neutron activation analysis. AB - Oxygen and carbon are the first and second abundant elements, respectively, in the human body by mass. Although many physiological and pathological processes are accompanied with alteration of total body oxygen (TBO) and carbon (TBC) masses, in vivo measurements of the two elements are limited. Up to now, almost all available information of TBC and TBO is based on in vivo neutron activation (IVNA) analysis which is very expensive and involves moderate radiation exposure. The aim of the present study was to develop and evaluate an alternative strategy for TBC and TBO estimation. Mechanistic models were derived for predicting TBC and TBO masses from dual-energy x-ray absorptiometry (DXA) and total body water (TBW). Twenty-eight adult subjects were studied. IVNA-measured TBC and TBO masses were used as the criterion. TBC masses predicted by DXA-alone and by DXA-TBW models were 20.8 +/- 7.1 kg and 20.6 +/- 6.8 kg, respectively, close to the IVNA measured value (19.5 +/- 6.3 kg). There were strong correlations (both with r > 0.95, P < 0.001) between the predicted and measured TBC masses. TBO masses predicted by DXA-alone and by DXA-TBW models were 46.0 +/- 9.8 kg and 46.5 +/- 9.9 kg, respectively, close to the IVNA-measured value (48.0 +/- 10.4 kg). Correlations (both with r > 0.97, P < 0.001) were strong between the predicted and measured TBO masses. Bland-Altman analysis validated the applicability of DXA based models to predict TBC and TBO masses. As both DXA and TBW dilutions are widely available, low-risk, low-cost techniques, the present study provides a safe and practical method for estimating elemental composition in vivo. PMID- 20858916 TI - Spherical cluster analysis for beam angle optimization in intensity-modulated radiation therapy treatment planning. AB - An intuitive heuristic to establish beam configurations for intensity-modulated radiation therapy is introduced as an extension of beam ensemble selection strategies applying scalar scoring functions. It is validated by treatment plan comparisons for three intra-cranial, pancreas, and prostate cases each. Based on a patient specific matrix listing the radiological quality of candidate beam directions individually for every target voxel, a set of locally ideal beam angles is generated. The spherical distribution of locally ideal beam angles is characteristic for every treatment site and patient: ideal beam angles typically cluster around distinct orientations. We interpret the cluster centroids, which are identified with a spherical K-means algorithm, as irradiation angles of an intensity-modulated radiation therapy treatment plan. The fluence profiles are subsequently optimized during a conventional inverse planning process. The average computation time for the pre-optimization of a beam ensemble is six minutes on a state-of-the-art work station. The treatment planning study demonstrates the potential benefit of the proposed beam angle optimization strategy. For the three prostate cases under investigation, the standard treatment plans applying nine coplanar equi-spaced beams and treatment plans applying an optimized non-coplanar nine-beam ensemble yield clinically comparable dose distributions. For symmetric patient geometries, the dose distribution formed by nine equi-spaced coplanar beams cannot be improved significantly. For the three pancreas and intra-cranial cases under investigation, the optimized non coplanar beam ensembles enable better sparing of organs at risk while guaranteeing equivalent target coverage. Beam angle optimization by spherical cluster analysis shows the biggest impact for target volumes located asymmetrically within the patient and close to organs at risk. PMID- 20858917 TI - The influence of the heel effect in cone-beam computed tomography: artifacts in standard and novel geometries and their correction. AB - For decades, the heel effect has been known to cause an angular dependence of the emitted spectrum of an x-ray tube. In radiography, artifacts were observed and attributed to the heel effect. However, no problems due to the heel effect were discerned in multi-slice computed tomography (MSCT) so far. With flat-detector CT (FDCT), involving larger cone angles and different system geometries, the heel effect might cause new artifacts. These artifacts were analyzed in this paper for system geometries different from the ones widely used nowadays. Simulations and measurements were performed. Simulations included symmetric as well as asymmetric detector layouts and different x-ray tube orientations with respect to the detector plane. The measurements were performed on a micro-CT system in an asymmetric detector layout. Furthermore, an analytical correction scheme is proposed to overcome heel effect artifacts. It was shown that the type of artifact greatly depends on the orientation of the x-ray tube and also on the type of detector alignment (i.e. symmetric or different types of asymmetric alignment). Certain combinations exhibited almost no significant artifact while others greatly influenced the quality of the reconstructed images. The proposed correction scheme showed good results that were further improved when also applying a scatter correction. When designing CT systems, care should be taken when placing the tube and the detector. Orientation of the x-ray tube like in most MSCT systems seems advisable in asymmetric detector layouts. However, a different type of tube orientation can be overcome with suitable correction schemes. PMID- 20858919 TI - A heat transfer model of skin tissue for the detection of lesions: sensitivity analysis. AB - In this paper, we study the transient thermal response of skin layers to determine to which extent the surface temperature distribution reflects the properties of subsurface structures, such as benign or malignant lesions. Specifically, we conduct a detailed sensitivity analysis to interpret the changes in the surface temperature distribution as a function of variations in thermophysical properties, blood perfusion rate, metabolic heat generation and thicknesses of skin layers, using a multilayer computational model. These properties can vary from individual to individual or depend on location, external and internal influences, and in certain situations accurate property data are not available in the literature. Therefore, the uncertainties in these data could potentially affect the accuracy of the interpretation/diagnosis of a lesion in a clinical setting. In this study, relevant parameters were varied within characteristic physiological ranges, and differences in the surface temperature response were quantified. It was observed that variations in these parameters have a small influence on the surface temperature distribution. Analysis using this multilayer model was further conducted to determine the sensitivity of transient thermal response to different lesion sizes. This work validates the idea of examining the transient thermal response obtained using a thermal imaging system with the objective of lesion identification. The modeling effort and the sensitivity analysis reported in this paper comprise a portion of a comprehensive research effort involving experimentation on a skin phantom model as well as measurements on patients in a clinical setting, that are currently underway. One of the preliminary results from the ongoing clinical trial is also included to demonstrate the feasibility of the proposed approach. PMID- 20858918 TI - Characterization of single-core magnetite nanoparticles for magnetic imaging by SQUID relaxometry. AB - Optimizing the sensitivity of SQUID (superconducting quantum interference device) relaxometry for detecting cell-targeted magnetic nanoparticles for in vivo diagnostics requires nanoparticles with a narrow particle size distribution to ensure that the Neel relaxation times fall within the measurement timescale (50 ms-2 s, in this work). To determine the optimum particle size, single-core magnetite nanoparticles (with nominal average diameters 20, 25, 30 and 35 nm) were characterized by SQUID relaxometry, transmission electron microscopy, SQUID susceptometry, dynamic light scattering and zeta potential analysis. The SQUID relaxometry signal (detected magnetic moment/kg) from both the 25 nm and 30 nm particles was an improvement over previously studied multi-core particles. However, the detected moments were an order of magnitude lower than predicted based on a simple model that takes into account the measured size distributions (but neglects dipolar interactions and polydispersity of the anisotropy energy density), indicating that improved control of several different nanoparticle properties (size, shape and coating thickness) will be required to achieve the highest detection sensitivity. Antibody conjugation and cell incubation experiments show that single-core particles enable a higher detected moment per cell, but also demonstrate the need for improved surface treatments to mitigate aggregation and improve specificity. PMID- 20858920 TI - Measurement of flow velocity fields in small vessel-mimic phantoms and vessels of small animals using micro ultrasonic particle image velocimetry (micro-EPIV). AB - Determining a multidimensional velocity field within microscale opaque fluid flows is needed in areas such as microfluidic devices, biofluid mechanics and hemodynamics research in animal studies. The ultrasonic particle image velocimetry (EchoPIV) technique is appropriate for measuring opaque flows by taking advantage of PIV and B-mode ultrasound contrast imaging. However, the use of clinical ultrasound systems for imaging flows in small structures or animals has limitations associated with spatial resolution. This paper reports on the development of a high-resolution EchoPIV technique (termed as micro-EPIV) and its application in measuring flows in small vessel-mimic phantoms and vessels of small animals. Phantom experiments demonstrate the validity of the technique, providing velocity estimates within 4.1% of the analytically derived values with regard to the flows in a small straight vessel-mimic phantom, and velocity estimates within 5.9% of the computationally simulated values with regard to the flows in a small stenotic vessel-mimic phantom. Animal studies concerning arterial and venous flows of living rats and rabbits show that the micro-EPIV measured peak velocities within several cardiac cycles are about 25% below the values measured by the ultrasonic spectral Doppler technique. The micro-EPIV technique is able to effectively measure the flow fields within microscale opaque fluid flows. PMID- 20858921 TI - Theoretical predictions for ionization cross sections of DNA nucleobases impacted by light ions. AB - Induction of DNA double strand breaks after irradiation is considered of prime importance for producing radio-induced cellular death or injury. However, up to now ion-induced collisions on DNA bases remain essentially experimentally approached and a theoretical model for cross section calculation is still lacking. Under these conditions, we here propose a quantum mechanical description of the ionization process induced by light bare ions on DNA bases. Theoretical predictions in terms of differential and total cross sections for proton, alpha particle and bare ion carbon beams impacting on adenine, cytosine, thymine and guanine bases are then reported in the 10 keV amu(-1)-10 MeV amu(-1) energy range. The calculations are performed within the first-order Born approximation (FBA) with biological targets described at the restricted Hartree-Fock level with geometry optimization. Comparisons to recent theoretical data for collisions between protons and cytosine point out huge discrepancies in terms of differential as well as total cross sections whereas very good agreement is shown with our previous classical predictions, especially at high impact energies (E(i) >= 100 keV amu(-1)). Finally, in comparison to the rare existing experimental data a systematic underestimation is observed in particular for adenine and thymine whereas a good agreement is reported for cytosine. Thus, further improvements appear as necessary, in particular by using higher order theories like the continuum-distorted-wave one in order to obtain a better understanding of the underlying physics involved in such ion-DNA reactions. PMID- 20858922 TI - Measuring solar UV radiation with EBT radiochromic film. AB - Ultraviolet radiation dosimetry has been performed with the use of a radiochromic film dosimeter called Gafchromic EBT for solar radiation exposure. The film changes from a clear colour to blue colour when exposed to ultraviolet radiation and results have shown that the colour change is reproducible within +/-10% at 5 kJ m(-2) UV exposure under various conditions of solar radiation. Parameters tested included changes in season (summer versus winter exposure), time of day, as well as sky conditions such as cloudy skies versus clear skies. As the radiochromic films' permanent colour change occurs in the visible wavelengths the film can be analysed with a desktop scanner with the most sensitive channel for analysis being the red component of the signal. Results showed that an exposure of 5 kJ m(-2) (approximately 1 h exposure in full sun during summer) produced an approximate 0.28 change in the net OD when analysed in reflection mode on the desktop scanner which is significant darkening. The main advantages of this film type, and thus the new EBT2 film which has replaced EBT for measurement of UV exposure, is the visible colour change and thus easy analysis using a desktop scanner, its uniformity in response and its robust physical strength for use in outside exposure situations. PMID- 20858923 TI - Radiosensitizer-eluting nanocoatings on gold fiducials for biological in-situ image-guided radio therapy (BIS-IGRT). AB - Image-guided radiation treatments (IGRT) routinely utilize radio-opaque implantable devices, such as fiducials or brachytherapy spacers, for improved spatial accuracy. The therapeutic efficiency of IGRT can be further enhanced by biological in situ dose painting (BIS-IGRT) of radiosensitizers through localized delivery within the tumor using gold fiducial markers that have been coated with nanoporous polymer matrices loaded with nanoparticles (NPs). In this work, two approaches were studied: (i) a free drug release system consisting of Doxorubicin (Dox), a hydrophilic drug, loaded into a non-degradable polymer poly(methyl methacrylate) (PMMA) coating and (ii) poly(d,l-lactic-co-glycolic acid) (PLGA) NPs loaded with fluorescent Coumarin-6, serving as a model for a hydrophobic drug, in a biodegradable chitosan matrix. Temporal release kinetics measurements in buffer were carried out using fluorescence spectroscopy. In the first case of free Dox release, an initial release within the first few hours was followed by a sustained release over the course of the next 3 months. In the second platform, release of NPs and the free drug was controlled by the degradation rate of the chitosan matrix and PLGA. The results show that dosage and rate of release of these radiosensitizers coated on gold fiducials for IGRT can be precisely tailored to achieve the desired release profile for radiation therapy of cancer. PMID- 20858924 TI - Does the 'P300' speller depend on eye gaze? AB - Many people affected by debilitating neuromuscular disorders such as amyotrophic lateral sclerosis, brainstem stroke or spinal cord injury are impaired in their ability to, or are even unable to, communicate. A brain-computer interface (BCI) uses brain signals, rather than muscles, to re-establish communication with the outside world. One particular BCI approach is the so-called 'P300 matrix speller' that was first described by Farwell and Donchin (1988 Electroencephalogr. Clin. Neurophysiol. 70 510-23). It has been widely assumed that this method does not depend on the ability to focus on the desired character, because it was thought that it relies primarily on the P300-evoked potential and minimally, if at all, on other EEG features such as the visual-evoked potential (VEP). This issue is highly relevant for the clinical application of this BCI method, because eye movements may be impaired or lost in the relevant user population. This study investigated the extent to which the performance in a 'P300' speller BCI depends on eye gaze. We evaluated the performance of 17 healthy subjects using a 'P300' matrix speller under two conditions. Under one condition ('letter'), the subjects focused their eye gaze on the intended letter, while under the second condition ('center'), the subjects focused their eye gaze on a fixation cross that was located in the center of the matrix. The results show that the performance of the 'P300' matrix speller in normal subjects depends in considerable measure on gaze direction. They thereby disprove a widespread assumption in BCI research, and suggest that this BCI might function more effectively for people who retain some eye-movement control. The applicability of these findings to people with severe neuromuscular disabilities (particularly in eye-movements) remains to be determined. PMID- 20858926 TI - Microstructural effects on the magnetic and magneto-transport properties of electrodeposited Ni nanowire arrays. AB - The magnetic and magneto-transport properties of Ni nanowire (NW) arrays, fabricated by electrodeposition in anodic-aluminum-oxide (AAO) templates, have been investigated. The AAO pores have diameters ranging from 35 to 75 nm, and the crystallinity of the Ni NW arrays could change from poly-crystalline to single crystalline with the [111] and [110] orientations based on the electrodeposition potential. Notably, double switching magnetization loops and double-peaked magnetoresistance curves were observed in [110]-oriented NWs. The crystalline orientation of the Ni NW arrays is found to influence the corresponding magnetic and magneto-transport properties significantly. These magnetic behaviors are dominated by the competition between the magneto-crystalline and shape anisotropy. PMID- 20858927 TI - Using liquid crystals to detect DNA hybridization on polymeric surfaces with continuous wavy features. AB - In this study, we examined the orientational behavior of thermotropic liquid crystals (LCs) supported on a film of DNA that was chemically immobilized on a nanostructure surface. The surface was comprised of gold film deposited onto a polymer substrate that had a sinusoidal distortion normal to the surface, leading to a parallel array of peaks and troughs. The sinusoidal structures were produced by treating a polydimethylsiloxane (PDMS) substrate with oxygen plasma and buckled on a cylindrical surface. This patterned PDMS was then used to create replicas of the associated relief structures on another polymer surface, poly(urethaneacrylate), where a film of gold was deposited. The gold films were functionalized with thiol-modified DNA, and then used as substrates for the hybridization of a complementary strand of DNA (cDNA). The orientation of nematic 4-cyano-4'-pentylbiphenyl (5CB) was found to be parallel to the plane of the surface-immobilized DNA before incubation with a solution of cDNA. However, the hybridization of DNA induced a random orientation of 5CB, indicating that the DNA complexes disturbed the sinusoidal structure of the surface. These results demonstrate that LC can be used to detect the hybridization of DNA by manipulating the response of LC to the DNA decorated surfaces. PMID- 20858928 TI - Using aggregates of gold nanorods in SER(R)S experiments: an empirical evaluation of some critical aspects. AB - An empirical evaluation of some critical aspects resulting from aggregation of gold nanorods (AuNRs) used as surface enhanced resonant Raman scattering (SERRS) active substrates was reported. Two types of AuNR substrates with longitudinal plasmon bands which either match (in-plasmon resonance) or not (off-plasmon resonance) the wavelength of the exciting laser source (lambda: 632.8 nm) were tested in resonant Raman detection of methylene blue (MB). The in-plasmon resonance condition proved to be significantly useful for detecting MB at very low concentration (less than 10(-10) M), whereas the off-plasmon resonance setup is more than enough for intermediate-low concentrations (down to 10(-8) M). Differently sized AuNR aggregates, obtained by sequential dilution of the AuNR solutions allowed us to investigate the dependence of for surface enhanced Raman scattering (SERS) intensity on the size of the aggregates, pointing out a simple strategy for preparing AuNR-based SERS substrates. PMID- 20858929 TI - Nonvolatile resistive switching in metal/La-doped BiFeO3/Pt sandwiches. AB - The resistive switching (RS) characteristics of a Bi(0.95)La(0.05)FeO(3) (La-BFO) film sandwiched between a Pt bottom electrode and top electrodes (TEs) made of Al, Ag, Cu, and Au have been studied. Devices with TEs made of Ag and Cu showed stable bipolar RS behaviors, whereas those with TEs made of Al and Au exhibited unstable bipolar RS. The Ag/La-BFO/Pt structure showed an on/off ratio of 10(2), a retention time > 10(5) s, and programming voltages < 1 V. The RS effect can be attributed to the formation/rupture of nanoscale metal filaments due to the diffusion of the TEs under a bias voltage. The maximum current before the reset process (on-to-off switching) was found to increase linearly with the current compliance applied during the set process (off-to-on switching). PMID- 20858925 TI - Dynamic single photon emission computed tomography--basic principles and cardiac applications. AB - The very nature of nuclear medicine, the visual representation of injected radiopharmaceuticals, implies imaging of dynamic processes such as the uptake and wash-out of radiotracers from body organs. For years, nuclear medicine has been touted as the modality of choice for evaluating function in health and disease. This evaluation is greatly enhanced using single photon emission computed tomography (SPECT), which permits three-dimensional (3D) visualization of tracer distributions in the body. However, to fully realize the potential of the technique requires the imaging of in vivo dynamic processes of flow and metabolism. Tissue motion and deformation must also be addressed. Absolute quantification of these dynamic processes in the body has the potential to improve diagnosis. This paper presents a review of advancements toward the realization of the potential of dynamic SPECT imaging and a brief history of the development of the instrumentation. A major portion of the paper is devoted to the review of special data processing methods that have been developed for extracting kinetics from dynamic cardiac SPECT data acquired using rotating detector heads that move as radiopharmaceuticals exchange between biological compartments. Recent developments in multi-resolution spatiotemporal methods enable one to estimate kinetic parameters of compartment models of dynamic processes using data acquired from a single camera head with slow gantry rotation. The estimation of kinetic parameters directly from projection measurements improves bias and variance over the conventional method of first reconstructing 3D dynamic images, generating time-activity curves from selected regions of interest and then estimating the kinetic parameters from the generated time-activity curves. Although the potential applications of SPECT for imaging dynamic processes have not been fully realized in the clinic, it is hoped that this review illuminates the potential of SPECT for dynamic imaging, especially in light of new developments that enable measurement of dynamic processes directly from projection measurements. PMID- 20858930 TI - Therapeutic application of metallic nanoparticles combined with particle-induced x-ray emission effect. AB - Metallic nanoparticles (MNP) are able to release localized x-rays when activated with a high energy proton beam by the particle-induced x-ray emission (PIXE) effect. The exploitation of this phenomenon in the therapeutic irradiation of tumors has been investigated. PIXE-based x-ray emission directed at CT26 tumor cells in vitro, when administered with either gold (average diameter 2 and 13 nm) or iron (average diameter 14 nm) nanoparticles (GNP or SNP), increased with MNP solution concentration over the range of 0.1-2 mg ml(-1). With irradiation by a 45 MeV proton therapy (PT) beam, higher concentrations had a decreased cell survival fraction. An in vivo study in CT26 mouse tumor models with tumor regression assay demonstrated significant tumor dose enhancement, thought to be a result of the PIXE effect when compared to conventional PT without MNP (radiation only group) using a 45 MeV proton beam (p < 0.02). Those receiving GNP or SNP injection doses of 300 mg kg(-1) body weight before proton beam therapy demonstrated 90% or 75% tumor volume reduction (TVR) in 20 days post-PT while the radiation-only group showed only 18% TVR and re-growth of tumor volume after 20 days. Higher complete tumor regression (CTR) was observed in 14-24 days after a single treatment of PT with an average rate of 33-65% for those receiving MNP compared with 25% for the radiation-only group. A lower bound of therapeutic effective MNP concentration range, in vivo, was estimated as 30-79 ug g(-1) tissue for both gold and iron nanoparticles. The tumor dose enhancement may compensate for an increase in entrance dose associated with conventional PT when treating large, solid tumors with a spread-out Bragg peak (SOBP) technique. The use of a combined high energy Bragg peak PT with PIXE generated by MNP, or PIXE alone, may result in new treatment options for infiltrative metastatic tumors and other diffuse inflammatory diseases. PMID- 20858932 TI - Hybrid nanowire-multilayer graphene film light-emitting sources. AB - We report a versatile hybrid device consisting of one-dimensional ZnS and Te doped ZnS (ZnS:Te) nanowires (NWs) upon two-dimensional multilayer graphene films (MGFs). Single-crystalline ZnS and ZnS:Te NWs were grown directly on a MGF without a catalyst, and exhibited blue-green and blue emission peaks of ~ 503 and ~ 440 nm. A field emission light emitter using ZnS:Te NWs on a MGF was demonstrated, and it indicates excellent contact properties between the NWs and MGFs. The resulting hybrid devices are promising candidates for potential applications as building blocks for the development of highly functional and efficient electroluminescent devices and field-emitting devices including flexible and/or transparent display devices. PMID- 20858931 TI - Improved cellular uptake of functionalized single-walled carbon nanotubes. AB - Single-walled carbon nanotubes (SWNTs) due to their unique structural and physicochemical properties, have been proposed as delivery systems for a variety of diagnostic and therapeutic agents. However, SWNTs have proven difficult to solubilize in aqueous solution, limiting their use in biological applications. In an attempt to improve SWNTs' solubility, biocompatibility, and to increase cell penetration we have thoroughly investigated the construction of carbon scaffolds coated with aliphatic carbon chains and phospholipids to obtain micelle-like structures. At first, oxidized SWNTs (2370 +/- 30 nmol mg(-1) of SWNTs) were covalently coupled with an alcoholic chain (stearyl alcohol, C(18)H(37)OH; 816 nmol mg(-1) of SWNTs). Subsequently, SWNTs-COOC(18)H(37) derivatives were coated with phosphatidylethanolamine (PE) or -serine (PS) phospholipids obtaining micelle-like structures. We found that cellular uptake of these constructs by phagocytic cells occurs via an endocytotic mechanism for constructs larger than 400 nm while occurs via diffusion through the cell membrane for constructs up to 400 nm. The material that enters the cell by phagocytosis is actively internalized by macrophages and localizes inside endocytotic vesicles. In contrast the material that enters the cells by diffusion is found in the cell cytosol. In conclusion, we have realized new biomimetic constructs based on alkylated SWNTs coated with phospholipids that are efficiently internalized by different cell types only if their size is lower than 400 nm. These constructs are not toxic to the cells and could now be explored as delivery systems for non permeant cargoes. PMID- 20858933 TI - Growth of single crystalline barium titanate nanowires from TiO2 seeds deposited on conducting glass. AB - A new synthetic method is reported for depositing BaTiO(3) nanowire film on conducting glass. First, a TiO(2) particle thin film is prepared by spray coating, and then transformed to single crystalline BaTiO(3) nanowires grown on the conducting glass by hydrothermal treatment using TiO(2) particles as seeds of nanowire growth. The BaTiO(3) nanowires are 50-100 nm in diameter and have a film thickness of 4 um. The capacitance of the BaTiO(3) one-dimensional (1D) nanowire array film was found to be 4.5 times higher than that of the nanoparticle film by measuring the impedance. The piezoelectric property of an individual BaTiO(3) nanowire was also demonstrated by piezoforce microscopy. PMID- 20858934 TI - Tailored antireflective biomimetic nanostructures for UV applications. AB - Antireflective surfaces composed of biomimetic sub-wavelength structures that employ the 'moth eye principle' for reflectance reduction are highly desirable in many optical applications such as solar cells, photodetectors and laser optics. We report an efficient approach for the fabrication of antireflective surfaces based on a two-step process consisting of gold nanoparticle mask generation by micellar block copolymer nanolithography and a multi-step reactive ion etching process. Depending on the RIE process parameters nanostructured surfaces with tailored antireflective properties can easily be fabricated that show optimum performance for specific applications. PMID- 20858935 TI - Characteristics of AgInSbTe-SiO2 nanocomposite thin film applied to nonvolatile floating gate memory devices. AB - Nanocomposite thin films containing AgInSbTe (AIST) particles embedded in an SiO(2) matrix was prepared by sputtering deposition and its feasibility for nonvolatile floating gate memory (NFGM) was investigated. The sample subjected to a 400 degrees C annealing exhibited a distinct hysteresis memory window (DeltaV(FB)) shift = 6.6 V and charge density = 5.2 * 10(12) cm(-2) after +/- 8 V gate voltage sweep. Electrical measurement revealed the current transport is via the Schottky emission in low applied field and the space-charge-limited conduction mechanism in high applied field in the samples, regardless of their thermal history. Transmission electron microscopy and x-ray photoelectron spectroscopy indicated that the metallic Sb(2)Te nanocrystals (NCs) with diameters about 5-7 nm dispersed in a nanocomposite layer may serve as the discrete charge-storage traps for nonvolatile memory. Analytical results illustrate the utilization of an AIST-SiO(2) nanocomposite layer as the core structure of NFGM devices is able to simplify the device structure and fabrication process. PMID- 20858936 TI - Photoelectronic characterization of IgG antibody molecule-quantum dot hybrid as biosensing probe. AB - Quantum dot (QD)-based biomolecule hybrids have recently attracted much attention in specifically identifying and labeling target proteins. In this study, QD encapsulated with immunoglobulin antibodies, as a labeling building block in biosensors, was investigated to clarify the most efficient configuration and photoluminescence behavior. Both the biological recognition capacity and photoluminescence emitting signal of the antibody-coupled nanocrystal were validated through a photoelectrical characterization procedure. Derivation of the optimum number of antibody molecules to be packed onto the QD surface yielded the highest binding capacity for the target antigen. During formation of the bioactive layer, the intrinsic photoluminescence response of the QDs significantly decreased due to photoinduced hole transfer according to their rearranged electronic structure. The thorough study of this assembly provides a validation approach for the careful titration of biosensor probes for optimal reaction kinetics. Furthermore, it contributes to the development of an effective tool for the application and interpretation of QD-based labeling techniques. PMID- 20858937 TI - Flexible, transparent single-walled carbon nanotube transistors with graphene electrodes. AB - This paper reports a mechanically flexible, transparent thin film transistor that uses graphene as a conducting electrode and single-walled carbon nanotubes (SWNTs) as a semiconducting channel. These SWNTs and graphene films were printed on flexible plastic substrates using a printing method. The resulting devices exhibited a mobility of ~ 2 cm(2) V(-1) s -1), On/Off ratio of ~ 10(2), transmittance of ~ 81% and excellent mechanical bendability. PMID- 20858938 TI - Monodispersed NiO nanoflowers with anomalous magnetic behavior. AB - Nickel oxide (NiO) nanoflowers, prepared by thermal decomposition, exhibit anomalous magnetic properties far below the blocking temperature, i.e., a cusp in both the zero-field-cooled and field-cooled curves at about 21 K. Detailed characterization discloses that the individual NiO nanoflower consists of porous crystals with holes (1.0-1.5 nm in size) inside. We believe that the low temperature magnetic feature observed here could be a new kind of spin transition for the uncompensated spins around the holes and will trigger more studies in other nanostructured antiferromagnetic materials. PMID- 20858939 TI - Development of a Spanish version of the "Backache Index". AB - INTRODUCTION: In routine clinical practice a physical examination should include an assessment of ability/function. The use of a scale or index in low back pain (LBP) is mainly used to categorize patients and to measure syndrome severity. For this reason we developed an easy and quick to perform standardised measuring procedure of impairment in patients with LBP without using inclinometers. The new "Backache Index" (BAI) is applied in order to help therapists, doctors, and surgeons perform physical examinations easily. The factor of presence or absence of pain with respect to different lumbar movements is elaborated for the patient with LBP, standing in an erect position. This resulted in outcome scores (0-3) for five impairment examinations of the trunk from which the sum of the scores gives the BAI (max. 15 points). OBJECTIVES: The purpose of this study was to develop the linguistic adaptation and to explore the reliability of this new Backache Index translated in a Spanish version called "indice de Dolor de Espalda" or IDE, which can fulfil the existing need for a reliable routine examination in the clinical environment for Spanish speaking clinicians and patients. METHODS: Two independent translations were made by two separate professional translators to Spanish. Both versions were compared and consensus resulted in a single translation. In a pain center patients were asked to participate in this project as volunteers. The exclusion criteria have been used in patients with LBP suffering of severe spinal pathology or having deseases. In total 46 patients (67% females, age = 52 +/- 13 years) underwent the physical examination at the first session (IDE-1) and were retested without any treatment after 3 days (IDE-2). RESULTS: The two translations submitted by respective experts were identical and the final IDE was used in futher clinical examinations. The test-retest after 3 days of the same group revailed that the reliability for the 5 outcome scores was good (ICC ? 0.73). No significant difference was found between IDE-1 (4.65 +/- 4.15 ) and IDE-2 (4.72 +/- 4.20) and the absolute reliability was perfect with an ICC=0.97. CONCLUSIONS: The IDE form facilitates a better diffusion under the Spanish speaking population, allowing it to maintain the degree of homogenenity and acceptance that the "Indice de Dolor de Espalda" or IDE has in clinical practice, helping to spread among the Hispanic world one of the objectives that the creator of this index raised when it was developed. PMID- 20858940 TI - Patient guided Piezo-electric Extracorporeal Shockwave Therapy as treatment for chronic severe patellar tendinopathy: A pilot study. AB - BACKGROUND AND PURPOSE: Patellar tendinopathy is a common overuse injury for which no evidence-based treatment guidelines exist. Extracorporeal Shock Wave Therapy (ESWT) seems to be an effective treatment for patellar tendinopathy but the most beneficial treatment strategies still need to be ascertained. Aim of this pilot study was to investigate if patient guided Piezo-electric, focused ESWT, without local anesthesia is a safe and well tolerated treatment which improves pain and function in patients with patellar tendinopathy. METHODS: Nineteen male athletes with severe chronic patellar tendinopathy received 3 patient guided focused medium to high energy ESWT treatments at a weekly interval. Before and after 3 months VISA-P and VAS (pain) scores were recorded. Data on side effects and complications of treatment were also collected. RESULTS: No serious complications were reported and patients tolerated the treatment well. Mean VISA-P score improved from 36.1 to 50.1 (p < 0.05), VAS decreased from to 7.2 to 3.7 (p < 0.05). CONCLUSION: Patient guided Piezo-electric ESWT without local anesthesia is a safe and well tolerated treatment which should be considered as a treatment for patients with patellar tendinopathy. PMID- 20858941 TI - Simulated malingering in the testing of cervical muscle isometric strength. AB - We sought to determine if simulated malingering trials of isometric cervical muscular strength in flexion, extension and right/left bending are substantially different from maximum effort trials in young, healthy subjects. A convenience sample of healthy, young adult subjects was used (M=9, F=9) who were free of neck pain. A uniaxial load cell was used to measure forces (N) produced by three trials of isometric flexion, extension and bilateral bending contractions of the head/neck muscles in two modes: comfortable maximum (MAX) and simulated (insincere) malingering (INSIN). An ANOVA model was created and tested post-hoc for paired differences within and between modes and genders. A separate ANOVA was conducted to test for differences in the ratio between flexion and extension (F/E ratio). In MAX mode, males were stronger in all ranges vs females; the expected F/E and bilateral ratios were demonstrated and good consistency of effort within and between trials was demonstrated by low CV's and high ICC's, respectively. In INSIN mode, all mean peak values were significantly lower in both genders; however, the difference between genders disappeared. Within-trial consistency was much poorer with significantly higher CV's while between-trial variability was good as demonstrated by high ICC's. The flexion/extension ratio was increased in INSIN vs MAX, with no difference between genders. It appears that simulated malingering trials produced consistent patterns of deviation from maximal effort trials: reduced peak values, increased flexion/extension ratio and increased variability of within-trial effort. These findings may provide a basis for valid indicators of insincere effort in neck pain patients. PMID- 20858942 TI - The correlation between craniovertebral angle, backpack weights, and disability due to neck pain in adolescents. AB - PURPOSES: To investigate the responses of the craniovertebral (CV) angle to backpack loadings in adolescents with and without neck pain and to explore the relationships between CV angle, relative backpack weight, neck pain and disability. METHODS: A cross-sectional single-blinded study was conducted on 60 adolescents (30 neck pain and 30 non-neck pain) aged from 13 to 18 years old. The verbal analog scale (VAS) and Chinese version of Northwick Park Neck Pain Questionnaire (NPQ) were used to assess neck pain severity and disability respectively. CV angle was measured in neutral and with backpack loadings of 5% to 30% of subject's body weight by using the Head Posture Spinal Curvature Instrument (HPSCI). RESULTS: In both groups, CV angles gradually decreased with increment of backpack loadings and the amount of decreases became significant from 10% body weight onwards (P < 0.05). Although the changes of CV angles did not show any significant differences at any point of comparison between the groups, the neck pain group showed a clinically significant decrease of CV angle (~ 5 degrees ) at 10% relative loading whereas non-neck pain group did it at 15% relative loading. Change of CV angles did not show significant correlations with relative backpack weight, cervical pain and disability (P > 0.05). CONCLUSIONS: Our findings suggested a safety limit of 10% relative backpack load for adolescents. The results showed the tendency that the ability of maintaining good head posture in response to backpack loadings by non-neck pain subjects might be better than those with neck pain. PMID- 20858943 TI - Relationship between learning strategies of patients and proper perception of the home exercise program with non-specific low back pain. AB - OBJECTIVES: This study explored how the effectiveness of prescription exercises for a home program for patients with non-specific low back pain by using the method with specified describing style in accordance with ATLAS (The Assessing the Learning Strategies of Adults) and traditional method that we often use in clinic. PATIENTS AND METHODS: Twenty-six patients with non-specific low-back pain were referred to the physical therapy department for exercise therapy. Subjects were randomly assigned to control group, and experimental group. The stability exercise procedures were considered for each group. For patients in control group, exercises procedures were demonstrated with wording that we often use in clinic. For patients in experimental group, it was done by using the method with specified describing style in accordance with ATLAS (The Assessing the Learning Strategies of Adults). An Exercise Assessment Scale was also developed to measure exercise performance for this study. RESULTS: All demographic parameters, functionality scores, and distribution of learning strategies were homogeneous in two groups. The correlation tests showed no significant relationship between personal factors and properly perception of the home exercise program in control and experimental group. Exercise Assessment Scale scores were compared in both groups which showed a significantly superiority in experimental group compared to the control group. CONCLUSIONS: The wording that we often use in clinic to describe home exercise program in patients with non-specific low back pain is not sufficient. While the method of specified describing style in accordance with ATLAS is more effective in understanding of exercises. PMID- 20858944 TI - Investigation of the relationship between wearing glasses and deep cervical flexor endurance in patients with non-specific neck pain. AB - AIMS: The aims of this study: 1) to determine postural changes according to wearing glasses and relationship between these changes and deep cervical flexor muscle group, 2) to investigate effectiveness of endurance training on postural changes and deep cervical flexor muscles. METHODS: Seventy-three patients who had neck pain participated in this study and divided into two groups according to wearing glasses or not. Before and after endurance training for 6 weeks, postural angles of cervical region were counted, deep cervical flexor endurance test was performed and score of pain and disability index were noted of all subjects. RESULTS: Before treatment endurance levels were lower and scores of disability index were higher in experimental group (p< 0.05). After treatment endurance levels were improved, and scores of disability index were decreased more significantly in control group (p< 0.05). There were no significant differences between gaze, head and neck angles in both groups after treatment (p> 0.05). CONCLUSION: As a result it was seen that wearing glasses affected endurance of deep neck flexor muscles negatively, and it was not found relationship between postural angles and endurance of deep cervical flexor muscles. Also it was observed that endurance training for 6 weeks hadn't affected postural angles but enhanced performance of deep cervical flexor muscles significantly. PMID- 20858945 TI - Treatment of chronic radiculopathy of the first sacral nerve root using neuromobilization techniques: A case study. AB - BACKGROUND AND OBJECTIVES: The engagement of the first sacral nerve root is one of the most common etiologies in Sciatic Pain Syndrome (SPS). Different interfering methods are used in the physical therapy of people with SPS including physical modalities, exercise therapy, traction, and joint and neuromobilization, depending on the symptoms and radiculopathy phase. The present case study attempts to describe neuromobilization methods in treating chronic radiculopathy of the first sacral nerve root, as well as its abnormal neurodynamic responses. THE CASE: The patient was a 36-year-old man with lower back pain during construction work 9 months before, and presenting with complaint of burning pain and tingling in his left Posterior part of the thigh and leg. Active extension, rotation, and lateral flexion of the trunk in standing position had a complete range with no pain. SLR and Slump neurodynamic tests revealed that with increasing sensitive elements, there appeared to be abnormal sciatic nerve tension, and complaint due to returning burn and tingling in the posterior part of the thigh and leg. MRI findings revealed intervertebral disc dehydrations at L3-4, L4-5, and L5-S1 levels, as well as postero-lateral protrusion in L5-S1 intervertebral disc. Following three routine physical therapy sessions, with no improvement, neuromobilization technique was used for 6 sessions. RESULTS: The usual routine physical therapy methods did have any visible impact in solving the patient's problems during daily-life activities and physical diagnosis findings, yet, following neuromobilization technique, the assessment at the beginning of the eleventh session and the patient's follow-ups two months later showed that his problems during daily-life activities and in neurodynamic tests were totally solved. DISCUSSION AND CONCLUSION: Abnormal neurodynamic responses and consequently symptoms in patients with chronic radiculopathy may be due to a pathomechanic problem and deficiency in neural adjustment for movement and tension transfer. Neuromobilization techniques can increasingly useful in treatment of abnormal neural tensions and removing chronic radiculopathy symptoms. PMID- 20858946 TI - Butterfly vertebra anomaly: A case report. AB - Butterfly vertebra is an uncommon congenital spinal anomaly. Only a small number of cases with butterfly vertebra have thus far been reported in the literature.We herewith describe a 32-year-old male admitted to our clinic with low back pain. He has been suffering from low back pain since early adolescence. Radiologic investigations confirmed presence of butterfly vertebra at Lumbar(L)2 level and L3-4, L4-5 posterior disc protrusion and slight osteoarthritic changes in lumbar spine which proved to be a coincidental finding along with nonspecific low back pain. Routine examination of the motor and sensory system was found to be normal. Hematologic evaluation was made to rule out pathologic causes of anterior wedging of the vertebra like infections and metastases in the spine. Butterfly vertebra anomaly is considered to be incidental and usually asymptomatic. Awareness of this anomaly is important for correct diagnosis, while its imaging features may be confused with traumatic compression fracture, or with a pathologic fracture. Also, this spinal anomaly may be associated with many syndromes. This taken into account, all the necessary investigations should be carried out for purposes of achieving a correct diagnosis. PMID- 20858947 TI - Correlation between cognitive impairment and CSF biomarkers in amnesic MCI, non amnesic MCI, and Alzheimer's disease. AB - Decreased delayed recall, decreased amyloid-beta peptides (Abeta1-42), and increased tau protein concentration in cerebrospinal fluid (CSF) are generally regarded to be valid neuropsychological and biological markers for Alzheimer's disease (AD). Previous studies failed to demonstrate clear-cut correlations between neuropsychological impairment and CSF markers. In this study we test recent models of disease progression, that propose that changes in CSF biomarkers already reach a plateau in a preclinical phase, before cognitive decline begins, that is, even before MCI can be diagnosed. We recruited 73 patients with probable AD (n=36) and mild cognitive impairment (MCI) (amnesic MCI=25; non-amnesic MCI=12). We used the CERAD-NP, a widely used neuropsychological battery with norms for different age and education groups, and additional neuropsychological tests for assessing the cognitive profile of these patient groups. We found a significant correlation between Abeta1-42 in the CSF and memory performance for amnesic MCI patients, but not for non-amnesic MCI and AD patients. All other correlations between cognitive tasks and Abeta1-42 were not significant. Tau protein concentration in the CSF was not correlated with any neuropsychological marker in any of the patients groups. We conclude that the decrease of Abeta1-42 in the CSF mirrors disease progression during the early stages up into AD and therefore is not restricted to the preclinical phase. The decrease of Abeta1-42 reaches a plateau only in the full blown demented syndrome and further functional disease progression is then related to neurodegeneration without further reduction of Abeta1-42 in the CSF. PMID- 20858948 TI - Neuron specific toxicity of oligomeric amyloid-beta: role for JUN-kinase and oxidative stress. AB - Recent studies have demonstrated a potential role for oligomeric forms of amyloid beta (Abeta) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Abeta. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose dependent increase in cell death following Abeta oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Abeta. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Abeta toxicity in neurons. These data indicate that oligomeric Abeta is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Abeta as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD. PMID- 20858949 TI - Cholinergic central system, Alzheimer's disease, and anesthetics liaison: a vicious circle? AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation and aggregation of amyloid-beta peptide and loss of forebrain cholinergic neurons, resulting in progressive loss of memory and irreversible impairment of higher cognitive functions. Several studies have accounted for the close relationship between AD and the central cholinergic system, suggesting that a dysfunction of acetylcholine containing neurons in the brain contributes significantly to the cognitive deficit of individuals with AD. The aim of the present review is to survey current literature on this topic in order to provide a clear understanding of the role of the cholinergic system in the development and neurodegenerative process of AD. The implications for anesthesia are also discussed. This knowledge could be valuable to improve anesthesia performance and patient safety. PMID- 20858950 TI - The speech and language FOXP2 gene modulates the phenotype of frontotemporal lobar degeneration. AB - The FOXP2 gene is mutated in a severe monogenic form of speech and language deficits, but no study on the influence of genetic variations within FOXP2 in neurological disorders characterized by language impairment is available yet. In the present study, we investigated the impact of common FOXP2 polymorphisms with regard to frontotemporal lobar degeneration (FTLD). Two-hundred ten FTLD patients underwent clinical and a wide standardized neuropsychological examination as well as brain imaging. In all patients, and in 200 age-matched healthy controls, four FOXP2 polymorphisms were evaluated, namely rs2396753, rs1456031, rs17137124 and rs1852469. SPECT images were analyzed by Statistical Parametric Mapping (SPM5). No significant differences of the four FOXP2 polymorphisms in genotype distribution and allele frequency between FTLD and controls were observed. A significant and specific association between rs1456031 TT and rs17137124 TT genotypes and verbal fluency scores was reported. The two polymorphisms showed an addictive effect. When the analysis was computed on the number of observations over time, and 391 assessments considered, comparable results were obtained. FTLD patients carrying at-risk polymorphisms showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus, and putamen, compared to the non-carriers (p < 0.005). Genetic variations within FOXP2 do not represent a genetic risk to FTLD per se, but modulate FTLD presentation when disease is overt, affecting language performances and leading to hypoperfusion in language associated brain areas. PMID- 20858951 TI - Does the combination of the MMSE and clock drawing test (mini-clock) improve the detection of mild Alzheimer's disease and mild cognitive impairment? AB - There is currently a need to develop tools to identify patients with mild AD and mild cognitive impairment (MCI). We determined the validity and reliability of a brief, easily administered cognitive screening battery consisting of fusion of two well-known brief tests (Mini-Mental Status Examination [MMSE] and Clock Drawing Test [CDT]) (Mini-clock) to differentiate between patients with mild AD, MCI, and healthy control subjects. 66 consecutive patients with mild AD, 21 with MCI, and 66 healthy controls seen in a memory clinic setting were compared. Receiver operating characteristic (ROC) curve analysis was used to calculate the cut-off value permitting discrimination between mild AD, MCI, and healthy control subjects. Interrater and test-retest reliability were also assessed. Mean cognitive scores for patients with AD, MCI, and control subjects on all two individual tests were significantly different (for each, p < 0.001). The mean area under the ROC curve for Mini-clock was higher than that obtained with MMSE or CDT in differentiating mild AD from controls (0.973 vs. 0.952 and 0.881, respectively) and MCI from controls (0.855 vs. 0.821 and 0.779, respectively). Test-retest reliability for the Mini-clock was 0.99, meanwhile interrater reliability was 0.87. The mean time to complete the test for all subjects was 8 min and 50 s. The Mini-clock is highly sensitive and specific in the detection of mild AD and reasonably accurate when attempting to separate MCI from health controls. It has a high interrater and test-retest reliability, can be quickly administered, and does not require major training. PMID- 20858952 TI - Comprehensive nuclear magnetic resonance studies on interactions of amyloid-beta with different molecular sized anesthetics. AB - Laboratory research on anesthetic-induced structural changes of amyloid beta (Abeta) peptide, from normal monomeric alpha-helix to the micro-aggregated form, has generated much interest in the scientific community as Abeta oligomerization is considered a key step in Alzheimer disease pathogenesis. A comprehensive review of the interactions of Abeta peptide with anesthetics of different molecular sizes is summarized as follows. Smaller sized anesthetics could access and perturb the cavity containing crucial amino acid residues G29, A30 and I31 of Abeta peptide leading to Abeta oligomerization. However, bulkier sized anesthetics are sterically hindered from accessing the cavity containing these crucial residues and do not initiate Abeta oligomerization. Notably, when a small sized anesthetic is co-administered with a larger sized one, the latter does not prevent access of the small sized anesthetic to the cavity. The results of these biophysical studies are supported by animal model studies which indicate that inhaled small molecular anesthetics induce enhanced Abeta plaque deposition in transgenic mice with AD pathology. In this review, a molecular pathway for the A$?beta $-anesthetic interaction at the atomic level is presented. PMID- 20858953 TI - Neprilysin activity in cerebrospinal fluid is associated with dementia and amyloid-beta42 levels in Lewy body disease. AB - Lewy body disease, defined by the occurrence of alpha-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer's disease (AD)-like pathology, in particular amyloid-beta (Abeta) plaques and lowered cerebrospinal fluid (CSF) Abeta42 levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Abeta pathology. Neprilysin (NEP) is an Abeta-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP activity levels may also be associated with dementia and lowered CSF Abeta42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Abeta42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2-81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2 87.2; p=0.004) and controls (21.5 pmol/ml*min, 0.15-413.4; p=0.02). In addition, CSF NEP activity levels correlated positively with CSF Abeta42 levels (Rho=0.28, p=0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Abeta pathway. PMID- 20858954 TI - Nutraceutical properties of Mediterranean diet and cognitive decline: possible underlying mechanisms. AB - Recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from mild cognitive impairment to Alzheimer's disease (AD), reduced risk of AD, and decreased mortality in AD patients. Furthermore, the Mediterranean diet (MeDi) combines several foods, micro- and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. At present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids, and polyunsaturated fatty acids (PUFA) (particularly, n-3 PUFA), and reduced risk of cognitive decline and dementia. Light to moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for vascular dementia, cognitive decline, and predementia syndromes, the current evidence is only suggestive of a protective effect. Finally, the limited epidemiological evidence available on fruit and vegetable consumption and cognition generally support a protective role of these macronutrients against cognitive decline, dementia, and AD. We reviewed evidence on the possible mechanisms underlying the suggested protective role of MeDi against age-related changes in cognitive function, predementia syndromes, and dementia, examining the possible role of macronutrients and food nutrients of the MeDi and their nutraceutical properties in modulating the risk of cognitive decline. Although vascular variables are likely to be in the causal pathway between MeDi and dementia syndromes and should be considered as possible mediators, other nonvascular biological mechanisms (i.e., metabolic, oxidative, and inflammatory) may be invoked to explain the complex epidemiological association between MeDi and cognitive decline. PMID- 20858955 TI - Amyloid-beta impairs, and ibuprofen restores, the cGMP pathway, synaptic expression of AMPA receptors and long-term potentiation in the hippocampus. AB - Amyloid-beta (Abeta) rapidly impairs hippocampal long-term potentiation (LTP) and cognitive function in rats. We hypothesized that: a) Abeta-induced impairment of LTP would be due to impairment of the nitric oxide (NO)-cGMP pathway and AMPA receptor translocation; and b) treatment with the anti-inflammatory drug ibuprofen would restore the NO-cGMP pathway and LTP. The aims of this work were to assess whether ibuprofen prevents and/or rescues Abeta-induced LTP impairments in hippocampal slices and to analyze the role of the altered NO-cGMP-protein kinase G pathway and AMPA receptor phosphorylation and synaptic expression in the mechanisms by which Abeta impairs and ibuprofen restores LTP. Abeta impairs tetanus-induced activation of guanylate cyclase and cGMP increase, preventing protein kinase G activation, phosphorylation of GluR1 in Ser845 and AMPA receptors translocation to synaptic membranes, which is responsible for LTP impairment by Abeta. Ibuprofen prevents LTP impairment by Abeta by restoring guanylate cyclase activation and increase in cGMP and, subsequently, activation of protein kinase G, phosphorylation of GluR1 in Ser845 and synaptic expression of AMPA receptors. Restoration of cGMP levels is enough to restore all this process as indicated by the fact that the cGMP analog 8-Br-cGMP also normalizes the function of this pathway and restores LTP in the presence of Abeta. These results indicate that Abeta impairs LTP by impairing the NO-cGMP pathway and that ibuprofen restores LTP by restoring this pathway. These data suggest that restoring cGMP levels may have therapeutic utility to improve cognitive function impaired by Abeta. PMID- 20858956 TI - The impact of general and regional anesthesia on the incidence of post-operative cognitive dysfunction and post-operative delirium: a systematic review with meta analysis. AB - Post-operative cognitive complications such as delirium have been consistently associated with poor short and long term outcomes, and the role of anesthesia, particularly the role of general versus regional anesthesia, remains unclear. The objective of this systematic review with meta-analysis was to compare the influence of general, regional, or a combination of anesthesia on the development of Post-Operative Cognitive Dysfunction (POCD) and Post-Operative Delirium (POD). Standard bibliographic databases were searched and complimented by hand searching of original and review article references. Included studies were randomized controlled trials comparing general to regional (spinal, epidural, or intravenous block) or a combination of these in a cohort who were pre-operatively cognitively normal and had an average age exceeding fifty. Where POD was the principle outcome, studies must have employed the DSM or ICD criteria. Where POCD was the principal outcome, this was defined as any objective cognitive impairment. Twenty one studies were considered suitable for inclusion. There was no effect of anesthesia type on the odds ratio of developing POD (0.88, 0.51-1.51 with 95% confidence) however general anesthesia was marginally non-significantly associated with POCD (odds ratio of 1.34, 0.93-1.95 with 95% confidence). There was no evidence of publication bias. In conclusion, it appears that general anesthesia, compared to others, may increase the risk of developing POCD; however this has not been shown for POD. Possible reasons for this finding have been explored. This data would advocate for the use of regional anesthesia wherever possible especially in people otherwise vulnerable to developing cognitive symptoms. PMID- 20858957 TI - Risk of incident dementia in drug-untreated arterial hypertension: a population based study. AB - Arterial hypertension in midlife may increase the risk of late-life dementia. Notably, there is conflicting data as to whether hypertension in the elderly (age 65 years and older) is a risk factor for dementia and Alzheimer's disease (AD). We determined whether drug-untreated hypertension was associated with a higher risk of incident dementia and AD. In a population-based study of older people in central Spain (NEDICES), non-demented participants were followed prospectively. Dementia at follow-up was diagnosed using DSM-IV criteria. Using Cox proportional hazards models, the risk of dementia was estimated in participants with drug untreated hypertension and in participants with drug-treated hypertension versus controls. The 3,824 participants had a mean duration of follow-up of 3.2 years. Sixty-two (3.3%) of 1,870 participants without baseline hypertension developed incident dementia versus 78 (4.7%) of 1,657 with drug-treated, baseline hypertension and 19 (12.0%) with drug-untreated, baseline hypertension. In an unadjusted Cox model, risk of dementia was increased in participants with drug untreated hypertension (relative risk [RR] =1.93, 95% confidence interval [CI]=1.15-3.23, p = 0.01) and in participants with drug-treated hypertension (RR =1.43, 95% CI= 1.02-2.0, p =0.035) versus participants without hypertension (reference group). In a fully adjusted Cox model, the risk of dementia remained increased in participants with drug-untreated hypertension (RR =2.38, 95% CI =1.32-4.29, p=0.004). Results were similar for risk of AD. Our results suggest that drug-untreated hypertension may be an independent risk factor for dementia and AD in the elderly. PMID- 20858959 TI - Plasma cystatin C and risk of developing Alzheimer's disease in subjects with mild cognitive impairment. AB - Recent years have witnessed an increasing interest in mild cognitive impairment (MCI), particularly as a possible prodromal stage of Alzheimer's disease (AD). Experimental and clinical data have suggested that cystatin C (CysC) is protective against the development of AD. In this study, we sought to cross sectionally and longitudinally investigate the changes in plasma CysC levels in patients with MCI and whether the levels of this molecule might serve as a biochemical predictor of cognitive decline in this patient group. Cross-sectional analysis of baseline data showed a borderline significant difference in plasma CysC levels among the three study groups (Controls, n=63; AD, n=63; MCI, n=59) (p =0.032) that disappeared after post hoc analysis. Plasma CysC levels did not differ at baseline (t1) and at follow-up (t2) both in MCI patients that converted to AD (n= 32) and those that did not convert (n=27). However, a significant independent association between CysC at t1 and CysC at t2 was found in non converters but not in converters MCI subjects. Moreover, when disease onset was evaluated in patients groups stratified on the basis of their CysC plasma levels, a significant anticipation of the conversion to dementia in MCI subjects with CysC levels below the median (CysC < 1067 ng/ml) (p =0.0011) was observed. Altogether, this work adds to the growing body of literature suggesting that CysC modulates the clinical expression of cognitive decline, and opens a new area of investigation of CysC as a therapeutic target for neurodegenerative disorders. PMID- 20858958 TI - Following activation of the amyloid cascade, apolipoprotein E4 drives the in vivo oligomerization of amyloid-beta resulting in neurodegeneration. AB - According to the amyloid hypothesis, the accumulation of oligomerized amyloid beta (Abeta) is a primary event in the pathogenesis of Alzheimer's disease (AD). The trigger of the amyloid cascade and of Abeta oligomerization in sporadic AD, the most prevalent form of the disease, remains elusive. Here, we examined the hypothesis that apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for AD, triggers the accumulation of intraneuronal oligomerized Abeta following activation of the amyloid cascade. We investigated the intracellular organelles that are targeted by these processes and govern their pathological consequences. This revealed that activation of the amyloid cascade in vivo by inhibition of the Abeta degrading enzyme neprilysin specifically results in accumulation of Abeta and oligomerized Abeta and of ApoE4 in the CA1 neurons of ApoE4 mice. This was accompanied by lysosomal and mitochondrial pathology and the co-localization of Abeta, oligomerized Abeta, and ApoE4 with enlarged lysosomes and of Abeta and oligomerized Abeta with mitochondria. The time course of the lysosomal effects paralleled that of the loss of CA1 neurons, whereas the mitochondrial effects reached an earlier plateau. These findings suggest that ApoE4 potentiates the pathological effects of Abeta and the amyloid cascade by triggering the oligomerization of Abeta, which in turn, impairs intraneuronal mitochondria and lysosomes and drives neurodegeneration. PMID- 20858960 TI - Alzheimer's disease: a general introduction and pathomechanism. AB - Alzheimer's disease (AD) is the most common form of dementia, which affects more than 35 million people worldwide with increasing tendency. Satisfying therapies and prevention are not available. Since the first description of the fatal progressive neurodegenerative disease in 1907, however, major findings on the molecular mechanisms have been reported. Current clinical trials target diverse aspects and principles of AD, such as the generation and aggregation of amyloid beta (Abeta). Extracellular amyloid plaques, predominantly consisting of Abeta, and intracellular neurofibrillar tangles, formed by hyperphosphorylated tau, are the major pathological hallmarks in the brain of AD patients. AD is consequently one of about 40 identified amyloidoses - protein misfolding diseases, which share as their main pathogenic mechanism the aberrant deposition of endogenous proteins as amyloid fibrils. This article aims principally to introduce AD and its identified key players, to summarize classic and recent publications on the complex molecular mechanisms underlying the disease, and to discuss challenges that need to be faced for the development of improved therapeutic strategies. PMID- 20858961 TI - Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer's disease. AB - Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain. PMID- 20858962 TI - Low serum progranulin predicts the presence of mutations: a prospective study. AB - Serum progranulin is decreased in frontotemporal dementia (FTD) patients with progranulin gene (PGRN) mutations. We investigate the utility of prospective serum screening as a surrogate diagnostic marker for progranulin mutations. A commercial ELISA was used to measure progranulin protein concentration in serum from 63 FTD patients and 32 normal controls, and DNA screening then performed. Four patients (2/17 behavioral variant, 2/8 corticobasal syndrome) had abnormally low progranulin levels with PGRN mutations confirmed on DNA testing. Surprisingly, elevated levels were found in 6/16 patients with progressive non fluent aphasia, the significance of which is unclear. Serum testing is an accurate and cost effective means of predicting PGRN mutations. PMID- 20858963 TI - EEG, activity, and sleep architecture in a transgenic AbetaPPswe/PSEN1A246E Alzheimer's disease mouse. AB - Since sleep and electroencephalogram (EEG) disturbances are endophenotypes of Alzheimer's disease (AD) patients alongside cognitive dysfunction, we here characterized these parameters in transgenic mice carrying transgenes for amyloid beta protein precursor (AbetaPPswe) and presenilin 1 (PSEN1A246E) at 5 (pre plaque) and 20 months, relative to PSEN1 and wild-type (WT) mice, using a novel wireless microchip device. While circadian rhythms were not affected, we obtained significantly higher overall activity at 5 months in the AbetaPP/PSEN1 strain (p < 0.001) compared to both PSEN1 and WT animals. Vigilance staging revealed that AbetaPP/PSEN1 animals present with an age-independent increase in wakefulness (p < 0.001) and a decrease in non rapid-eye movement (NREM) sleep (p < 0.01). These changes were age- and genotype-dependent only during the light phase, while dark phase activity pattern were equally affected at both ages. In all genotypes, the amount of REM sleep was lower at 20 months indicating a general age-related profile. Spectral power of qEEG changed in AbetaPP/PSEN1 mice at 5 months during wakefulness and REM sleep; during wakefulness hippocampal delta (0.5-5 Hz) was reduced and theta (5-9 Hz) power enhanced. By contrast, NREM EEG spectra were affected by age and genotype. Interestingly, PSEN1 animals also showed spectral EEG changes, these differed from both WT and AbetaPP/PSEN1 animals. Our results indicate that AbetaPP/PSEN1 mice exhibit abnormalities in activity and sleep architecture preceding amyloid plaque deposition as well as age-related changes in cortical EEG power. Though not fully recapitulating the profile of AD patients, this suggests activity and EEG recordings as sensitive and translational biomarkers in murine models. PMID- 20858965 TI - Anesthetics promoting in vitro AbetaPP metabolism and amyloid-beta toxicity. AB - At present, more than 35 million people worldwide have Alzheimer's disease (AD). With increasing incidence and a growing number of aged patients undergoing surgery, the relevance of a possible interaction between anesthetics and AD is growing as well. Below, we review in vitro studies investigating the effects of anesthetics on the metabolism of amyloid precursor protein and its metabolite amyloid-beta. PMID- 20858964 TI - Midlife alcohol consumption and later risk of cognitive impairment: a twin follow up study. AB - In this prospective follow-up study, we monitored the effects of midlife alcohol consumption and drinking patterns on cognitive impairment risks in late life. 1,486 subjects recruited from the Finnish Twin Cohort were included in the analyses. Alcohol consumption data was obtained with structured questionnaires in 1975 and 1981, and subjects were contacted between 1999 and 2007 to conduct a telephone interview evaluating cognitive function. The mean follow-up period was 22.8 years (standard deviation 2.1 years). Both abstainers and heavy drinkers were found to have an increased risk of cognitive impairment in comparison to light drinkers (relative risk ratios 1.44; 95% confidence interval: 1.02-2.10 and 1.94, 1.10-3.44, respectively. Also, binge drinking at least monthly in 1975 and 1981, as well as more than two pass-outs due to excess drinking in 1981 were associated with an increased risk of cognitive impairment (1.98, 1.08-3.64 and 3.85, 1.51-9.83, respectively), even when excluding abstainers and controlling for total alcohol consumption. Subgroup analyses based on apolipoprotein E epsilon4 status suggest that the increased risk of cognitive impairment associated with being an abstainer is limited to subjects without an epsilon4 allele. Our results add to the evidence that light to moderate alcohol use is associated with a lower risk of cognitive impairment compared with higher levels of consumption. In addition, binge drinking was found to be an independent risk factor for cognitive impairment. PMID- 20858966 TI - Expression of the ghrelin and neurotensin systems is altered in the temporal lobe of Alzheimer's disease patients. AB - Ghrelin and neurotensin (NTS) are neuroendocrine peptides that exert opposite effects on food intake and energy homeostasis, but share comparable actions in improving memory and learning. Ghrelin and NTS mediate their effects via receptors with high evolutionary identity: two ghrelin G-protein coupled receptors (GPCRs; GHS-R1a/1b) and three NTS-receptors, two GPCRs (NTSR1/2) and one non-GPCR (NTSR3). Because ghrelin and NTS systems are tightly linked to energy balance regulation and cognitive processes, they have been proposed to be altered in Alzheimer's disease (AD), a dementia syndrome markedly influenced by the metabolic status. Although it has been demonstrated that ghrelin and NTS can attenuate AD-related cognitive impairment, a comprehensive analysis of these systems in AD has not been conducted. Here, we used quantitative real time-RT-PCR to analyze expression of the ghrelin/NTS axis in one of the cortical regions most affected in AD, the temporal gyrus. Results unveiled a striking reduction of mRNA levels for ghrelin, and its newly discovered In2-ghrelin variant, as well as for the enzyme responsible for ghrelin acylation, ghrelin-O-acyltransferase and GHS R1a, while expression of GHS-R1b was markedly increased. In addition, expression levels of NTSR1 and NTSR2 were profoundly decreased in AD, whereas mRNA levels of NTS only declined slightly, and those of NTSR3 (which is involved in neuronal apoptosis) did not vary. Taken together, our results provide the first quantitative evidence showing that ghrelin/NTS systems are markedly altered in the brain of AD patients, thereby suggesting that these systems may contribute to the severe cognitive deficit observed in this pathology. PMID- 20858968 TI - Morphometric changes in the cortical microvascular network in Alzheimer's disease. AB - Alzheimer's disease (AD) pathology is accompanied by abnormalities of the microvasculature. Despite the potential importance of morphometric changes in the cortical capillary network on neuronal dysfunction and cognitive impairment, few autopsy studies have addressed this issue. In the present study, we investigated morphological microvascular changes and capillary length density (CLD) in ten well-characterized AD patients compared to ten age-matched controls using virtual isotropic hemispheres. The CLD in the temporal cortex was increased by 33% in AD patients compared to controls (p=0.04), whereas CLD in the occipital cortex was unchanged. An increase of CLD was correlated to a decrease of cortical diameter in the temporal cortex (Pearson's r -0.62, p=0.003), suggesting that the increase in temporal CLD results from, or contributes to cortical atrophy. In the occipital cortex, more string vessels, probably remnants of degenerated capillaries, were observed in AD patients than in controls (p=0.004). An exploratory analysis suggests co-localization of Abeta and string vessels. Our data indicate that morphometric changes in the cortical capillary network occur in AD in a region-specific manner and may be related to cortical atrophy in the affected regions. PMID- 20858967 TI - Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia. AB - Increasing evidence indicates that patients develop post-operative cognitive decline (POCD) following surgery. POCD is characterized by transient short-term decline in cognitive ability evident in the early post-operative period. This initial decline might be associated with increased risk of a delayed cognitive decline associated with dementia 3 to 5 years post-surgery. In some studies, the conversion rates to dementia are up to 70% in patients who are 65 years or older. The factors responsible for the increased risk of dementia are unclear; however, clinical studies investigating the prevalence of POCD and dementia following surgery do not show an association with the type of anesthesia or duration of surgery. Epidemiological studies from our group support this observation. The adjusted Hazard Ratios for developing dementia (or AD specifically) after prostate or hernia surgery were 0.65 (95% CI, 0.51 to 0.83, prostate) and 0.65 (95% CI, 0.49 to 0.85, hernia) for cohorts of subjects exposed to general anesthesia compared to those exposed only to local anesthesia. Animal studies suggest that prolonged exposure to some volatile-inhalational anesthetics increase production of amyloid-beta and vulnerability to neurodegeneration, but these results are weakened by the absence of clinical support. Inflammation and a maladaptive stress response might also contribute to the pathophysiology of this disorder. Future research needs to identify predisposing factors, and then strategies to protect against POCD and subsequent dementia. The field also needs to adopt a more rigorous approach to codifying the frequency and extent of early and delayed post-operative cognitive decline. PMID- 20858969 TI - Long-term post-operative cognitive decline in the elderly: the effects of anesthesia type, apolipoprotein E genotype, and clinical antecedents. AB - Cognitive dysfunction in the elderly commonly observed following anesthesia has been attributed to age-related neuronal changes exacerbated by pharmacotoxic effects. However, the extent to which these changes may persist following recovery from surgery is still largely unknown. This study investigates the long term effects of anesthesia on cognitive functioning after orthopedic surgery in 270 elderly patients over the age of 65 who completed a computerized cognitive battery before and 8 days, 4 and 13 months after surgery. Their performance was compared to those of 310 elderly controls who completed the same neuropsychiatric evaluation at baseline and one-year interval. Multivariate analyses adjusted for socio-demographic variables, depressive symptomatology, vascular pathology as well as baseline cognitive performance. We found early and transient post operative decline in reaction time and constructional praxis. With regard to long term changes we observed improvement compared to controls in most verbal tasks (probably due to learning effects). On the other hand, a clear dissociation effect was observed for several areas of visuospatial functioning which persisted up to the 13-month follow-up. This specific pattern of visuospatial deficit was found to be independent of apolipoprotein E genotype and closely resembles what has recently been termed vascular mild cognitive impairment, in turn associated with subtle sub-cortical vascular changes. The observation of only minor differences between persons operated by general and regional anesthesia makes it difficult to attribute these changes directly to the anesthetic agents themselves, suggesting that cognitive dysfunction may be attributable at least in part to peri-operative conditions, notably stress and glucocorticoid exposure. PMID- 20858970 TI - Anesthetics and tau protein: animal model studies. AB - Recent studies have suggested that general anesthesia may initiate or accelerate cognitive impairment and Alzheimer's disease (AD). To understand the possible underlying mechanisms, several studies have been carried out in animal models. In this review, we first briefly discuss the mechanisms leading to neurodegeneration and cognitive impairment in AD, with an emphasis on tau abnormalities in this pathological process. Subsequently, we review the role of anesthesia in inducing tau abnormalities and the possible mechanisms. Recent studies suggest that anesthesia may accelerate the development of AD by promoting abnormal hyperphosphorylation of tau. Further studies are certainly needed to understand the molecular mechanism by which anesthesia may initiate or accelerate cognitive impairment and AD. An understanding of the mechanism will help develop strategies for preventing or eliminating this adverse effect of anesthesia. PMID- 20858971 TI - Studies in animal models of the effects of anesthetics on behavior, biochemistry, and neuronal cell death. AB - Recent clinical studies have suggested that there is an increased risk of Alzheimer's disease (AD) in patients undergoing surgical interventions, but it is unknown whether this effect is related to anesthesia, cardiovascular complications of surgery, or associated conditions such as hypothermia. In addition, many patients, especially the elderly, present persistent post operative cognitive deterioration after anesthesia, without clear complications during surgery. Experimental studies in animals may be helpful to dissect the pathogenic role of the different factors involved in surgery. Here, we review studies on the effects of anesthesia on neuronal function performed in tissue culture and in experimental animals. Several studies have shown that a small inhalation of anesthetics induces activation of caspases and cell toxicity on glioma and pheochromocitoma cells in culture, which is prevented by treatment with the metal chelating agent clioquinol. Exposure of old rodents to anesthesia produced memory deficits and increased levels of amyloid-beta (Abeta) peptide and phosphorylated tau in brain. The effects of long term or short term repetitive exposure to small molecular weight anesthetics are more severe in transgenic AbetaPPswe than in wild type mice. In the former, low molecular weight increased the number of TUNEL(+) apoptotic cells and the ratio of pro-apoptotic proteins in hippocampus; reduced astroglial and increased microglial responses; increased Abeta aggregates and high molecular weight peptides; abnormal chaperone responses and reduced autophagy. In conclusion, anesthetic gases induce changes which may reproduce AD pathology in mice with mutations which produced AD. It would be interesting to know whether anesthetics are risky for subjects with special genetic risk factors. PMID- 20858972 TI - Cognitive dysfunction after cardiac surgery. AB - Both short and long term cognitive changes occur after cardiac surgery but the pathophysiology of these neurobehavioral changes remain incompletely understood. The cause of cognitive decline is most likely multifactorial and probably represents a complex interaction between cerebral microemboli, global cerebral hypoperfusion, inflammation, and genetic susceptibility. The problem of cognitive decline after cardiac surgery continues to increase as the surgical population becomes older and has more prevalent comorbid diseases. A better understanding of the etiology is essential to finding new preventive strategies as no definitive therapy exists for cognitive dysfunction. PMID- 20858973 TI - Anesthesia for the patient with dementia. AB - With a growing aging population, more patients suffering from dementia are expected to undergo surgery, thus being exposed to either general or regional anesthesia. This calls for specific attention ranging from the legal aspects of obtaining informed consent in demented patients to deciding on the use of premedication, choice of anesthetics, and management of postoperative pain. This review reflects on both general considerations concerning geriatric patients but also on the specific features of perioperatively used drugs and anesthetics that might have an impact on patients with Alzheimer's disease (AD). PMID- 20858974 TI - Increased cortical thickness and caudate volume precede atrophy in PSEN1 mutation carriers. AB - Neuroimaging studies of familial Alzheimer's disease allow investigation of the disease process before clinical onset. We performed semi-automated MRI analysis to evaluate cortical thickness (CTh), grey matter (GM) volumes, and GM diffusivity indexes in PSEN1 mutation carriers (MC). We recruited 11 MC from 4 families with PSEN1 mutations (L286P, M139T, K239N) and 6 familial and 12 non familial healthy controls. MC were classified as either asymptomatic (n=6) or symptomatic (n=5). Subjects underwent structural and diffusion-weighted 3-Tesla MRI scanning. CTh and GM volumes of subcortical structures and diffusivity indexes were calculated and group comparisons were performed. Structural images were reanalyzed with voxel-based morphometry methodology. Cerebrospinal fluid amyloid-beta1-42 levels (Abeta) were measured. We found that symptomatic MC presented widespread cortical thinning, especially in precuneus and parietotemporal areas (p<0.01) and increased mean diffusivity (MD) in these areas compared to controls. Unexpectedly, asymptomatic MC, 9.9 years prior to the predicted age of disease onset, presented increased CTh in the precuneus and parietotemporal areas (p<0.01), increased caudate volumes (p<0.01), and decreased MD (p<0.05) in these areas compared to HC. In MC, CTh correlated with adjusted age. Abeta values were within normal limits in AMC. In conclusion, at early preclinical stages, CTh in the precuneus and parietotemporal regions and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. The different trends in MD in asymptomatic and symptomatic MC suggest that different microstructural changes underlie the contrasting morphometric findings. Reactive neuronal hypertrophy or/and inflammation may account for increased CTh and decreased MD in asymptomatic MC. PMID- 20858975 TI - HPA axis dysregulation associated to apolipoprotein E4 genotype in Alzheimer's disease. AB - The present work investigated the involvement of cortisol and its receptors, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), in Alzheimer's disease (AD). Cortisol was measured in cerebrospinal fluid (CSF) samples from controls, mild cognitive impairment (MCI), progressive MCI evolving to AD, and AD. CSF cortisol levels do not seem to have a prognostic value, as increases in cortisol levels were found only in AD patients. GR expression was decreased while MR expression was increased in the frontal cortex of AD. When considering degeneration (ratio to synaptophysin and the post-synaptic marker PSD95), GR expression was similar between controls and AD, suggesting that GR loss was due to synaptic degeneration in AD. Increases in cortisol levels and MR expression were associated to an apolipoprotein E4 genotype. Cognitive status was negatively associated to CSF cortisol. In apolipoprotein E4 carriers, MR but not GR expression, negatively correlated to Mini-Mental Status Examination score and positively correlated to frontal cortex amyloid-beta levels. It is concluded that there is a dysregulation of the hypothalamus-pituitary-adrenal axis in AD that seems to be consequence rather than cause of AD. PMID- 20858976 TI - Amyloid-beta peptide fibrils induce nitro-oxidative stress in neuronal cells. AB - Different mechanisms including oxidative stress are proposed for amyloid-beta peptide (Abeta) neurotoxicity, and here we contribute to demonstrate that nitro oxidative stress is playing a key role. Yeasts are a well-known model for H2O2 toxicity. Interestingly, yeast cell wall prevents interaction of Abeta fibrils with membrane receptors or calcium channels and we found a significant viability reduction in yeasts when challenged with Abeta fibrils. Furthermore, iron and copper chelators, as well as the antioxidants glutathione and trolox, were neuroprotective on neuroblastoma cells and mouse hippocampal neurons challenged with Abeta fibrils. Glutathione prevents the oxidation, glycation and nitrotyrosination of cell proteins induced by Abeta. Trolox protected neurons in cell viability studies, maintaining the vesicular transport integrity and preventing the trigger of apoptotic mechanisms. Interestingly, we have also found that brain derived neuronal factor (BDNF) and neurotrophin-3 (NT-3) were able to protect mouse hippocampal and cortical neurons against H2O2 and Abeta fibrils. Considering that superoxide anion, produced by Abeta cell damage, and nitric oxide, whose production is altered in AD, react to form the highly reactive peroxynitrite anion, we studied the role of trolox to ameliorate the peroxynitrite cell damage. Finally, one of the major proteins to be nitrotyrosinated in AD, the triose phosphate isomerase (TPI) was assayed searching for a denitrase activity that could reverse intracellular nitrotyrosination. We have found that human neuroblastoma SH-SY5Y cells express a constitutive denitrase activity that partially denitrated nitro-TPI. Altogether, our results support a key role of nitro-oxidative stress in the neuronal damage induced by Abeta fibrils. PMID- 20858977 TI - Unawareness of memory deficit in amnestic MCI: FDG-PET findings. AB - To unveil the brain metabolic correlates of (un)awareness of memory deficit in subjects with amnestic mild cognitive impairment (aMCI), forty-two outpatients underwent brain 18F-FDG-PET. Awareness of memory deficit was assessed with the Memory Complaint Questionnaire (MAC-Q), identifying two groups: low (MCI/unaware; 17 patients) and good (MCI/aware; 25 patients) aMCI awareness. Twenty-nine age matched healthy subjects represented the control group. SPM2 was used to assess the correlation between brain metabolism and MAC-Q score, for comparisons between each patient group and controls, and between aMCI/unaware and aMCI/aware groups. The two aMCI groups were comparable in terms of age, gender, education, depression, and neuropsychological tests scores. In the whole 42-patient group, a positive correlation was found between MAC-Q score and metabolism in posterior cingulate cortex in both hemispheres and in inferior parietal lobule, middle cingulate cortex, precuneus and angular gyrus in the left hemisphere. Compared to controls, hypometabolism was found in aMCI/unaware in three large clusters, including precuneus, inferior parietal lobule and superior occipital gyrus, in the left hemisphere, and in inferior parietal lobule, angular gyrus and middle temporal gyrus in the right hemisphere. Smaller clusters of hypometabolism were found in bilateral temporal lobe in aMCI/aware. Hypometabolism in inferior parietal lobule, angular gyrus and superior temporal gyrus in the left hemisphere was highlighted in aMCI/unaware versus aMCI/aware. The significant correlation in all 42 aMCI patients points to posteromedial cortex as a key node of the network being involved in awareness of memory deficit. Patients with low awareness show a more severe hypometabolic pattern, typical of Alzheimer's disease and therefore could be more at risk of developing dementia. PMID- 20858978 TI - CSF levels of the histamine metabolite tele-methylhistamine are only slightly decreased in Alzheimer's disease. AB - Neuropathological studies have reported a strong neurofibrillary degeneration of the tuberomamillary nucleus, the region of origin of histamine neurons, in Alzheimer's disease (AD). Histaminergic neurons enhance cognition and memory, suggesting that their degeneration may contribute to the cognitive decline of AD. Besides neurons, the brain histaminergic system comprises mast cells and microglia that can also produce histamine. The level of activity of this histaminergic system in AD remained unknown. In the present study, we have measured the levels of the main histamine metabolite in brain, tele methylhistamine (t-MeHA), an index of histaminergic system activity, in the cerebrospinal fluid (CSF) of 97 non-AD (controls) and 91 AD patients, males or females. t-MeHA levels in CSF of controls tended to be higher, although non significantly, in females than in males. t-MeHA levels of controls and AD significantly increased with age (1.66 +/- 0.13, 2.04 +/- 0.12, and 2.76 +/- 0.12 pmol/ml at 40, 60 and 80 years, respectively). In spite of the strong degeneration of histamine neurons in the disease, t-MeHA levels in CSF were only slightly decreased in AD compared to controls (2.14 +/- 0.10 vs 2.76 +/- 0.13 pmol/ml, -22%, p < 0.01). This decrease was similar whatever the age, and was slightly higher in females than in males. The increase observed with age, and the limited magnitude of the decrease in AD even at late stages may result from the compensatory activation of spared neurons, as well as the neuroinflammation induced activation of microglia occurring in senescence and AD. PMID- 20858979 TI - Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. AB - Several studies have highlighted the close relationship between Alzheimer's disease (AD) and alterations in the bidirectional transport of amyloid-beta (Abeta) peptides across the blood-brain barrier (BBB). The brain capillary endothelial cells (BCECs) that compose the BBB express the receptors and transporters that enable this transport process. There is significant in vivo evidence to suggest that P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) restrict Abeta peptides entry into the brain, whereas the receptor for advanced glycation end-products (RAGE) seems to mediate apical-to-basolateral passage across the BBB. However, deciphering the molecular mechanisms underlying these in vivo processes requires further in vitro characterization. Using an in vitro BBB model and specific competition experiments against RAGE, we have observed a significant decrease in apical-to-basolateral (but not basolateral-to apical) transport of Abeta1-40 and Abeta1-42 peptides through BCECs. This transport is a caveolae-dependent process and fits with the apical location of RAGE observed in confocal microscopy experiments. Inhibition of P-gp and BCRP using different inhibitors increases transport of Abeta peptides suggesting that these efflux pumps are involved in Abeta peptide transport at the BCECs level. Taken as a whole, these results demonstrate the involvement of the caveolae dependent transcytosis of Abeta peptides through the BBB in a RAGE-mediated transport process, reinforcing the hypothesis whereby this receptor is a potential drug target in AD. PMID- 20858980 TI - Dissociation between controlled and automatic processes in the behavioral variant of fronto-temporal dementia. AB - A decline of cognitive functioning affecting several cognitive domains was frequently reported in patients with frontotemporal dementia. We were interested in determining if these deficits can be interpreted as reflecting an impairment of controlled cognitive processes by using an assessment tool specifically developed to explore the distinction between automatic and controlled processes, namely the process dissociation procedure (PDP) developed by Jacoby. The PDP was applied to a word stem completion task to determine the contribution of automatic and controlled processes to episodic memory performance and was administered to a group of 12 patients with the behavioral variant of frontotemporal dementia (bv FTD) and 20 control subjects (CS). Bv-FTD patients obtained a lower performance than CS for the estimates of controlled processes, but no group differences was observed for estimates of automatic processes. The between-groups comparison of the estimates of controlled and automatic processes showed a larger contribution of automatic processes to performance in bv-FTD, while a slightly more important contribution of controlled processes was observed in control subjects. These results are clearly indicative of an alteration of controlled memory processes in bv-FTD. PMID- 20858981 TI - Workplace violence. PMID- 20858982 TI - Corporate financial decision makers' perceptions of their company's safety performance, programs and personnel: Do company size and industry injury risk matter? AB - OBJECTIVE: Top-level managers make important decisions about safety-related issues, yet little research has been done involving these individuals. The current study explored corporate financial decisions makers' perceptions of their company's safety and their justifications for these perceptions. This study also explored whether their perceptions and justifications varied as a function of company size or industry injury risk. PARTICIPANTS: A total of 404 individuals who were the most senior managers responsible for making decisions about property and casualty risk at their companies participated in this study. METHODS: The participants took part in a telephone survey. RESULTS: The results suggest that corporate financial decision makers have positive views of safety at their companies relative to safety at other companies within their industries. Further, many believe their company's safety is influenced by the attention/emphasis placed on safety and the selection and training of safety personnel. Participants' perceptions varied somewhat based on the size of their company and the level of injury risk in their industry. CONCLUSIONS: While definitive conclusions about corporate financial decision makers' perceptions of safety cannot be reached as a result of this single study, this work does lay groundwork for future research aimed at better understanding the perceptions top-level managers. PMID- 20858983 TI - Subjective health complaints in relation to sickness absence. AB - OBJECTIVE: The Dutch population is healthy in terms of living and working conditions, but the levels of subjective health complaints (SHC) and sickness absence are high in the Dutch workforce. Are SHC related to sickness absence? PARTICIPANTS: The study population included the personnel of four companies: a library (n= 185), an administrative office (n=114), a cheese factory (n=201) and a company producing metal constructions (n=65). METHODS: The employees received the Basic Occupational Health Questionnaire including 22 common SHC. For each employee, the number and type of SHC but not their intensity was linked to the number of sickness absence episodes between January 2003 and December 2004. RESULTS: The questionnaires of 409 employees (72%) were suitable for statistical analysis. The prevalence of SHC in the study population was 78% between January and June 2003. Employees who reported > or = 5 SHC had higher rates of both short (1-7 days) and medium (8-42 days) sickness absence episodes. Long (> 42 days) episodes were strongly related to SHC amounting to a rate ratio (RR) of 4.2 with a 95% confidence interval [CI] 1.7 to 10.4 in workers reporting multiple SHC relative to those without complaints. Fatigue was associated with medium duration sickness absence (RR=1.6; 95% CI 1.1-2.2) and musculoskeletal complaints, particularly low back pain (RR= 1.8; 95% CI 1.2-2.8), with long episodes. CONCLUSIONS: The number of SHC was related to sickness absence. The 20% of participants reporting most SHC were responsible for about 40% of work days lost in the two-year period of study. PMID- 20858984 TI - Weight gain and work comp: A growing problem in the workers' compensation rehabilitation system. AB - OBJECTIVE: Obesity has become a major public health concern in the United States, and has ultimately affected occupational health, including Workers' Compensation. Obesity has been determined to contribute to work-related injury. This analysis examined weight change post-injury during the Workers' compensation rehabilitation process, and specifically how it relates to perceived mental health need, perceived dietary habits, food stamp usage, and the amount of time since the work injury. METHODS: Archival data analysis was conducted examining Workers' Compensation claimants over a four year period. PARTICIPANTS: Data was collected from 1,864 valid Workers' Compensation claims and analyzed using descriptive statistics and a backwards elimination multiple regression analysis to examine predictive relationships between the variables of interest. RESULTS: Approximately 2/3 of the sample reported weight gain post-injury, with the additional 1/3 reporting weight loss or no change. Both perceived benefit from mental health services and perceived healthy dietary habits were significantly predictive of weight gain. CONCLUSIONS: Clinical psychological distress, such as depression and anxiety, may be contributory factors to weight gain, and poor perceptions in food quality and caloric estimations may also relate to this problem. Suggestions for future research, including intervention studies, are also included. PMID- 20858985 TI - Perceived job-anxiety and general psychosomatic symptom load and perceived social support - Is there a relationship? AB - OBJECTIVE: Job-related distress has often been found to be related with low social support at work. The question is whether dimensions of social support outside work have a similar relation with job-anxiety or whether they are independent. PARTICIPANTS: A sample of 154 employed inpatients from a psychosomatic rehabilitation center (70% women) participated in this study. METHODS: Participants completed self-rating questionnaires on perceived symptom load in the domain of work (job-anxiety) and in general life (general psychosomatic symptom load), and on perceived social support at work and outside work. RESULTS: Job-anxiety showed moderate correlations with the perceived level of social support through colleagues. Thereby the social support dimensions of "consolation and encouragement" and "criticism, overload, rejection" were more strongly related to job-anxiety than the dimension of "practical support". There were no significant correlations between job-anxiety and social support through household members, leisure time partners or neighbors. CONCLUSIONS: Social support is in a specific way important in the context of work other than concerning general mental health outside the work-context. Job-anxiety is a domain-specific clinical phenomenon and independent from perceived social support outside the workplace. PMID- 20858986 TI - Health-selection mechanisms in the pathway towards a disability pension. AB - Studies emphasizing the disability pension (DP) process are rare. OBJECTIVE: To identify similarities and differences in work and health between persons who, prior to DP changed jobs due to health-reasons (health-selectors) to other disability pensioners. PARTICIPANTS: a retrospective cohort study was performed on a random sample of all individuals in three counties of Sweden who, in 1998, were under the age of 65 and had been granted DP. METHODS: A questionnaire was administered in 2000 (n=917, response rate 52%). The responses and register data on sickness absence in 1990-1998 and DP diagnoses were analysed. RESULTS: The health-selection group had lower self-perceived health; more partial sick-leave days during the eight years preceding DP, and DP diagnoses were more often musculoskeletal and psychiatric disorders, than the other disability pensioners. The groups did not differ regarding occupational affiliation before the last job. For subjects in the health-selection group, the job change did more often not involve a change of employer, and more had switched to jobs entailing less physical strain, particularly customer service work. Work history did not differ between the groups regarding the average level of physical work demands during the work career, however, disparities were found in the distribution of demands. CONCLUSIONS: The findings pinpoint the importance of studying disability pensioning as a process over time in order to identify and elucidate how exposure and selection interact and contribute to early exclusion from the labour market. PMID- 20858987 TI - Processes of task performance as measured by the Assessment of Motor and Process Skills (AMPS): A predictor of work-related outcomes for adults with schizophrenia? AB - OBJECTIVE: To determine whether the processes of task performance as measured by the Assessment of Motor and Process Skills (AMPS) would discriminate between the employment levels of adults with schizophrenia. PARTICIPANTS: Twenty adults with schizophrenia who were engaged either in competitive employment, supported employment, prevocational training, or non-vocational activities, participated in this exploratory study. METHODS: Each participant completed the AMPS, the Positive and Negative Syndrome Scale (PANSS), the Addiction Severity Index (ASI), and the Worker Role Interview (WRI) to gather data about their occupational performance, symptoms, drug / alcohol use, and psychosocial / environmental factors that might influence their work-related outcomes. RESULTS: Analysis revealed a moderate correlation between the level of employment and the global scores of the process skills scale in the AMPS. CONCLUSIONS: This should be seen as preliminary evidence that beyond the basic cognitive functions, processes of task performance may also be a predictor of work-related outcomes for this population. The results also highlighted the importance of considering personal causation and worker roles when assessing the work capacities of these clients. Finally, findings supported the four levels of employment used in this study, which appeared to form a continuum from non-vocational activities, prevocational training, supported employment, through to competitive employment. PMID- 20858988 TI - Outcome analysis of occupational therapy programme for persons with early psychosis. AB - OBJECTIVE: This study examined the vocational outcomes of young persons with early psychosis after their participation in an occupational therapy program, and identified clinical or process variables that are linked to the vocational outcomes. PARTICIPANTS: A total of 147 clients, aged between 15 and 25, with early psychosis or schizophrenia participated in this study. METHODS: A retrospective review of case management plans and outcomes was conducted. A survey form was designed to record demographic and clinical variables, and a follow-up telephone interview was conducted to monitor the vocational status of clients during the first three months after discharge. RESULTS: Although none of the clients had been engaged in work prior to participation in the programme, 53.7% could maintain a productive role in work (27.2%) or training/education (16.3%) in the three-month follow-up. Better mental condition and insight, stronger motivation for joining treatment, better social support, longer work history, and a shorter period of idleness before joining the programme, were significantly related to more favourable vocational outcomes. Older clients and those with more years of education were more likely to maintain a worker role. Parents were much more conservative about the future work plan than the clients themselves. CONCLUSIONS: Symptom management, work habit training, enrichment of the work experience, building social support and cultivation of insight into illness were important strategies related to the successful adoption of a productive role. PMID- 20858990 TI - Ergonomic and behavioral interventions as the primary treatment for work-related lateral epicondylitis. AB - OBJECTIVE: Work-related injuries (WRI) are costly to employers and the United States government due to missed days at work and medical expenses. This case report documents the results of using ergonomic and behavioral changes to address a client's symptoms due to a WRI. PARTICIPANT: The client worked as an administrative assistant at a small, private medical college and presented with lateral epicondylitis. METHOD: She received ergonomic and behavioral interventions to treat her injury that included modification to her work environment and education on modifying behaviors that would decrease stress and excessive work. RESULTS: The client reported decreased headaches with improved lighting and increased tolerance to typing with the addition of a keyboard tray, but not elimination of her chief complaints with the tray, floor mat, and behavioral changes. CONCLUSION: Some interventions that occurred at the client's desk resulted in decreased secondary symptoms. No improvements in the primary symptoms were found. PMID- 20858989 TI - Managerial leadership is associated with employee stress, health, and sickness absence independently of the demand-control-support model. AB - OBJECTIVES: Research on health effects of managerial leadership has only taken established work environment factors into account to a limited extent. We therefore investigated the associations between a measure of Attentive Managerial Leadership (AML), and perceived stress, age-relative self-rated health, and sickness absence due to overstrain/fatigue, adjusting for the dimensions of the Demand-Control-Support model. PARTICIPANTS: Blue- and white-collar workers from Finland, Germany and Sweden employed in a multi-national forest industry company (N=12,622). METHODS: Cross-sectional data on leadership and health from a company wide survey analysed with logistic regression in different subgroups. RESULTS: AML was associated with perceived stress, age-relative self-rated health, and sickness absence due to overstrain/fatigue after controlling for the Demand Control-Support model. Lack of AML was significantly associated with a high stress level in all subgroups (OR=1.68-2.67). Associations with age-relative self rated health and sickness absence due to overstrain/fatigue were weaker, but still significant, and in the expected direction for several of the subgroups studied, suggesting an association between lack of AML and negative health consequences. CONCLUSION: The study indicates that managerial leadership is associated with employee stress, health, and sickness absence independently of the Demand-Control-Support model and should be considered in future studies of health consequences for employees, and in work environment interventions. PMID- 20858991 TI - Informational ecology and care workers: Safety alarm systems in Finnish elderly care organizations. AB - OBJECTIVE: This article explores the use of information and communication technologies including safety alarm technologies and their impacts on elderly care organizations' informational ecology, or internal information environment. Results are reported from a case study on the use of safety telephones and high tech well-being wristbands that monitor vital signs in Finnish elderly-care organizations. PARTICIPANTS AND METHODS: Data collection involved human impact assessment methodologies including interviews and longer-term assessment processes among 78 care workers at 8 workplaces offering sheltered accommodation. The assessment results were analyzed qualitatively, also with the help of the concept of information quality. RESULTS AND CONCLUSIONS: Changes in the informational ecology were identified; informational ecology in a care unit is in many ways affected by technology use. The human impact assessment methodologies and the topic of information quality offered useful and novel points of view about daily care work in increasingly technological environments. PMID- 20858992 TI - Harassment among university hospital physicians in four European cities. Results from a cross-sectional study in Norway, Sweden, Iceland and Italy (the HOUPE study). AB - OBJECTIVES: The objective of this cross-national study was to identify work related factors related to the prevalence of harassment, and identify potential similarities and differences in harassment levels and appointed perpetrators within the same professional group across four European cities. PARTICIPANTS: 2078 physicians working in university hospitals in Trondheim, Stockholm, Reykjavik, and Padova participated in the study. METHODS: Questionnaire comprised items on direct and indirect experience of workplace harassment, appointed perpetrators, psychosocial work environment and basic socio-demographics. RESULTS: Harassment was found to be a relatively frequent work environment problem among physicians in all four European cities, with particular high levels in Padova. Role conflict, human resource primacy, empowerment leadership, and control over work pace were all found to be significantly related to workplace harassment. CONCLUSIONS: Differences in harassment prevalence and perpetrators indicated a cultural difference between the Italian and the Nordic hospitals. Harassment followed the line of command in Padova in contrast to being a horizontal phenomenon in the Scandinavian hospitals. This may be explained by national differences in organizational systems and traditions. In order to decrease harassment level and create a positive and productive work environment, each organization must employ different strategies in accordance with their harassment patterns. PMID- 20858993 TI - How to assess physical work-ability with Functional Capacity Evaluation methods in a more specific and efficient way? AB - OBJECTIVE: The objective of this paper is to propose a three-step procedure that can be used in the selection of functional tests from any full Functional Capacity Evaluation (FCE) method in order to assess efficiently physical work ability in workers with musculoskeletal complaints (MSC) and related functional limitations. METHODS: Recently, some authors have considered the selection of functional tests specific to particular jobs from within a full FCE method. In the present study, based on existing literature and on their own expertise on FCE methods, the authors develop in an analogous manner a conceptual framework for selecting functional tests specific to particular MSCs from within a full FCE method. RESULTS: The first step is to establish the worker's medical condition and to assign it to one or more defined MSC categories (upper extremity, back, lower extremity). The second step is to identify activities that are restricted by the medical condition (e.g., lifting and bending for MSC of the back). The third and final step is to select functional tests from a full FCE tests battery to permit measurement of the restricted activities identified in Step 2, striving to avoid redundancy by selecting a limited number of tests for each activity under investigation. CONCLUSIONS: The proposed three-step procedure is a new approach to enhance the efficiency and practicality of FCEs. PMID- 20858994 TI - A Hepatitis C virus-host interaction involved in viral replication: toward the identification of antiviral targets. AB - Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The current standard therapy for hepatitis C patients, which is based on a combination of pegylated interferons and ribavirin, results in viral clearance in about 50% of the treated individuals. Clinical trials of a variety of specific anti-HCV drugs, including several which target virus-encoded enzymes, are on going, and some of these studies have reported impressive reductions of HCV levels in patients. However, the development of antivirals with diverse mechanisms of action is still required to eliminate this life-threatening virus. Besides specific viral proteins, targeting host cellular factors that are key to efficient viral replication could lead to the development of novel treatment strategies. Therapies against host factors are generally considered to present a low risk of generating drug-resistant viruses. The current understanding of anti HCV drugs in clinical development and of virus-host interactions implicated in the regulation of HCV replication is summarized. PMID- 20858995 TI - A multiplex PCR-based molecular identification of five morphologically related, medically important subgenus Stegomyia mosquitoes from the genus Aedes (Diptera: Culicidae) found in the Ryukyu Archipelago, Japan. AB - Internal transcribed spacer regions of ribosomal DNA were sequenced, and new species-specific primers were designed to simplify the molecular identification of five morphologically related subgenus Stegomyia mosquito species--Aedes aegypti, Ae. albopictus, Ae. riversi, Ae. flavopictus, and Ae. daitensis--found in the Ryukyu Archipelago, Japan. Each newly designed primer was able to amplify a species-specific fragment with a different size. Conditions for multiplex PCR were optimized to identify all five species in a single PCR. This method is a convenient tool for entomological field surveys, particularly in arbovirus endemic/epidemic areas where some of these species coexist. PMID- 20858996 TI - Macrorestriction analysis and antimicrobial susceptibility profiling of Salmonella enterica at a University Teaching Hospital, Kuala Lumpur. AB - The genetic diversity and antimicrobial resistance rates of clinical Salmonella isolates (2007-2008) at the University of Malaya Medical Centre, Kuala Lumpur, were investigated and the genetic diversity of the isolates was determined by pulsed-field gel electrophoresis (PFGE) and repetitive extragenic palindromic (REP)-PCR. XbaI-PFGE analysis generated 57 profiles (Dice coefficient, F=0.08 1.00), whereas REP-PCR using the REP primer generated only 35 (F=0.34-1.00). PFGE was therefore the more discriminative and reproducible method for assessing the genetic diversity of salmonellae. The antibiograms of 78 Salmonella isolates were assessed against 19 antimicrobials using the disk diffusion method. Twenty serotypes were identified, with the most common being S. Enteritidis (18%) followed by S. Typhimurium (14%), S. Paratyphi B var Java (9%), S. Weltevreden (9%), and S. Corvallis (9%). A total of 38 resistant profiles were defined, with 53.8% of the isolates being resistant to three or more antimicrobials. The highest resistance rates were observed for cephalothin (55.1%), tetracycline (47.4%), and nalidixic acid (35.9%). The presence of multidrug-resistant Salmonella strains is a cause for concern as it may limit the treatment of severe salmonellosis. One multidrug-resistant S. Enteritidis strain was a putative extended-spectrum beta-lactamase producer, based on a double disk diffusion analysis, and was resistant to ceftriaxone (MIC>32 microg/mL). The data generated by this study will contribute towards epidemiological monitoring and investigations of Salmonella infections in Malaysia. PMID- 20858997 TI - Human rabies epidemiology in Shandong Province, China. AB - Rabies has reemerged in China. National rabies surveillance is centralized and based mainly on six provincial stations, including one in Shandong Province, which are selected and monitored by the China CDC. Data collection includes human rabies cases (diagnosed by local hospitals on the basis of signs or symptoms), documentation of post-exposure prophylaxis, primary laboratory diagnosis of suspect animal cases, and investigation of dog or other animal bites in viral transmission. Of the 408 human rabies cases reported during the period 2003-2007, most involved middle-aged male farmers bitten by their own unvaccinated dogs, with a seasonal peak in the autumn. These data provide key pointers regarding rabies prevention and control based upon an objective evidence-based framework. PMID- 20858998 TI - Onset and duration of symptoms and timing of disease transmission of 2009 influenza A (H1N1) in an outbreak in Fukuoka, Japan, June 2009. AB - The first confirmed case of 2009 influenza A (H1N1) in Fukuoka, Japan was reported in early-June 2009. The disease rapidly spread through this area, mainly in schools, until there were no new cases detected 3 weeks later. We describe herein the clinical characteristics of this novel infection that came to light through the investigation of this outbreak. The patient records at hospitals and local public health centers were reviewed, and we defined laboratory-confirmed cases as those of a person who had influenza-like symptoms, such as a fever of 37C or more, cough, sore throat, rhinorrhea, or headache. From May 19 to June 31, 2009, a total of 71 cases were identified. The median age was 11 years, and all the patient took neuraminidase inhibitors and fully recovered. The fevers lasted for 1 to 5 days (median, 2). Cough lasted for 2 to 11 days (median, 7), and in 10 cases (34.5%) cough started before the fever. The incubation period was 2 to 3 days. Infectors transmitted the disease to another person on the day of or the day before fever onset. The findings regarding the onset and duration of symptoms and the timing of disease transmission of 2009 influenza A (H1N1) may be useful for future response. PMID- 20858999 TI - Analysis of Candida glabrata strains with reduced sensitivity to micafungin in vitro isolated from a patient with persistent Candidemia. AB - We report the appearance of Candida glabrata strains with reduced sensitivity during treatment with the echinocandin drug micafungin (MCF). Four C. glabrata strains were isolated from sputum, gastric juice, and blood taken from a patient during hospitalization. Two of these strains, one of which was obtained after treatment with MCF for suspected Candida pneumonia and the other of which was obtained during MCF treatment for candidemia, were isolated from blood and found to have a reduced susceptibility to MCF. These two clinical isolates showed a high minimum inhibitory concentration (MIC) for MCF, with this change in MIC being unique for MCF among established antifungal drugs. To further investigate the mechanism underlying this reduced sensitivity, an in vivo mouse infection model and in vitro enzymatic analysis were performed. MCF had little effect in the mouse disseminated infection model and enzymatic analysis showed the low affinity of MCF to the 1,3-Beta-D-glucan synthase of the clinical isolates, although the enzymes of both clinical isolates and control strain were noncompetitively inhibited by MCF. Taken together, this low affinity of MCF for the enzymes is likely to cause the reduced sensitivities. These data further indicate that MCF could induce acquired MCF-resistant strains during clinical use. PMID- 20859000 TI - Cultivation for 21 days should be considered to isolate respiratory adenoviruses from samples containing small numbers of adenoviral genomes. AB - Adenovirus types 1, 2, and 3 can usually be isolated in only a short time, although occasionally it may take longer. This phenomenon has been explained empirically as being due to the viral load in the sample, although to date there has been no experimental confirmation of this. In this study we therefore tried to establish a correlation between the quantity of respiratory adenovirus genome in the clinical sample and the time required for its isolation. The correct choice of sensitive cell line is important for this purpose, thus we compared the sensitivity of three different cell lines (HeLa, A549, and RD), and found A549 to be the most sensitive to adenoviruses 1-3. Stored clinical samples (n=21) containing adenoviruses 1-3 were diluted to make solutions containing between 10 and 10(8) copies/microL of adenovirus genome (n=242). These diluted clinical samples were then inoculated into A549 cells, which were cultivated for 21 days and the results compared to the number of viral genomes in each cultivated sample. Adenoviruses could be isolated from all samples (41/41) containing >/=10(6) copies/microL within 6 days, whereas samples containing 10 and 10(2) copies/microL required cultivation for 12.6+/-3.8 and 11.2+/-3.8 days (mean+/ S.D.), respectively, before adenoviruses could be isolated. A cultivation time of 21 days should therefore be considered for the isolation of respiratory adenoviruses from samples containing <10(3) adenovirus genome copies/microL. PMID- 20859001 TI - The prevalence and distribution of Chlamydia trachomatis genotypes among sexually transmitted disease clinic patients in Guangzhou, China, 2005-2008. AB - This study was designed to determine the prevalence and distribution of Chlamydia trachomatis genotypes from clinical specimens in Guangzhou, China, obtained in the period 2005-2008. One hundred and ninety-four urogenital C. trachomatis samples were collected from sexually transmitted disease clinic patients, and the VS1-VS2 of OmpA gene was amplified by nested PCR and sequenced using an ABI-prism 3730 sequencer. Clinical C. trachomatis strains were genotyped and analyzed for a mutation with respect to the reference VS1-VS2 sequence. VS1-VS2 fragments with 453 bp were amplified from 194 clinical samples. Upon alignment with the sequences of the reference strains, 189 strains with discernible sequences were typed into 9 genotypes, while 5 with ambiguous sequences were considered to be mixed-serovar samples. The most prevalent genotypes were E (50, 26%), F (46, 24%), J (35, 19%), and D (24, 13%). There was no significant difference in the distribution of any of the genotypes detected during the study period, except for genotype K (P<0.01). A total of 16 (8%, 16/189) genetic variants of the OmpA VS1 VS2 of the reference strains were identified. Mutations occurred frequently for genotypes D (2/24, 8%), E (6/50, 12%), F (2/46, 4%), G (1/8, 13%), H (1/12, 8%), and K (4/11, 36%), with most of these being sense mutations that may result in amino acid substitution. Sequencing the OmpA VS1-VS2 enabled the genotype and sequence variations within each genotype to be analyzed. Genotypes E, F, J, and D continued to dominate among urogenital C. trachomatis, whereas genotype K increased significantly in Guangzhou between 2005 and 2008. PMID- 20859002 TI - Matrix metalloproteinase-9 (mmp-9) in children with dengue virus infection. AB - The purpose of this study was to investigate the role of matrix metalloproteinase 9 (MMP-9) in the pathogenesis of vascular leakage in patients with dengue virus infection. Serum samples from 24 children with serologically confirmed dengue virus infection (dengue fever [DF], 16; dengue hemorrhagic fever [DHF], 8; age, 9.5+/-2.4 years; 67% male] were analyzed for MMP-9 during the febrile and toxic stages and at follow-up. Serum samples obtained from 7 healthy children were used as controls. Serum MMP-9 levels in patients with dengue virus infection were found to be lower at the febrile (227.0+/-186.9 ng/ml) and toxic stages (150.9+/ 151.7 ng/ml) than at follow-up (424.5+/-227.8 ng/ml) or in the control group (393.3+/-125.9 ng/ml, P<0.001 by one-way ANOVA). There was no significant difference between MMP-9 levels in patients with DHF and those with DF at any stage of the disease. In conclusion, MMP-9 levels are reduced during the febrile and toxic stages of dengue virus infection. PMID- 20859003 TI - Detection of Anaplasma bovis DNA in the peripheral blood of domestic dogs in Japan. AB - The prevalence of Ehrlichia and Anaplasma in 1,427 dogs from 32 Japanese prefectures was evaluated by PCR and DNA nucleotide sequencing. PCR screening demonstrated that 18 dogs (1.3%) were positive for Anaplasmataceae. Sequence analysis revealed that 14 of the amplicons were most closely related to Wolbachia spp., symbionts of Dirofilaria immitis, whereas three were identified as Anaplasma bovis. The remaining amplicon could not be sequenced. Almost the entire sequence of 16S rRNA (1,452 bp) from one of the positive specimens was determined, and subsequent phylogenetic analysis confirmed that the detected sequence was that of A. bovis. This is the first detection of A. bovis DNA fragments in dogs. Species-specific nested PCR showed that 15 (1.1%) of the 1,427 dogs involved in this study were positive for A. bovis. The geographical distribution of these dogs ranged from Aomori Prefecture in northern Japan to Kagoshima Prefecture in the south. The relationship between A. bovis infection and clinical disease is not yet clearly understood. PMID- 20859004 TI - Molecular survey of rickettsial agents in feral raccoons (Procyon lotor) in Hokkaido, Japan. AB - Rickettsial infection in feral raccoons (Procyon lotor) in Hokkaido, Japan was analyzed by molecular methods. Genus-specific nested polymerase chain reaction (PCR) analysis based on the Rickettsia citrate synthase (gltA) gene showed that 13 of 699 raccoons (1.9%) examined were positive for Rickettsia. Twelve of the 13 partial gltA sequence amplicons were successfully analyzed. The nucleotide sequence of one amplicon was identical to both Rickettsia heilongjiangensis and R. japonica, one was identical to R. felis, and the rest to R. helvetica. This is the first report on the detection of rickettsial agents in peripheral blood of raccoons. PMID- 20859005 TI - Micafungin alters the expression of genes related to cell wall integrity in Candida albicans biofilms. AB - We investigated whether treating Candida biofilms with micafungin, an echinocandin that inhibits the synthesis of glucan in the fungal cell wall, alters the expression of genes related to chitin synthesis and degradation in response to cell wall stress. As expected, all four genes encoding chitin synthases--CHS1, CHS2, CHS3, and CHS8--were upregulated by micafungin treatment. Interestingly, of the four genes encoding chitinases, the expression of only CHT2 and CHT3 was markedly downregulated, that of CHT1 was upregulated, and that of CHT4 remained unaltered after micafungin treatment. Thus, the suppression of only two genes associated with chitin degradation, CHT2 and CHT3, may be involved in the tolerance to the cell wall stress caused by micafungin as well as the induction of chitin synthesis. Further, micafungin markedly increased UTR2, which is calcineurin dependent, and CRZ2, which is calcineurin independent. Therefore, gene regulation possibly includes calcineurin-dependent and independent stress responses, though the regulation of genes associated with cell wall chitin has not yet been completely clarified. Our results imply that cell wall stress can be exploited to enhance the efficacy of micafungin. PMID- 20859006 TI - Molecular epidemiology of rabies virus in Mongolia, 2005-2008. AB - The objective of this study was to determine the genetic diversity of rabies virus (RABV) in Mongolia based on the nucleotide sequences of viral N gene. A total of 24 rabies-positive samples from seven different domestic and wild animal species collected in western and central Mongolia between 2005 and 2008 were examined for their N gene sequences. The results showed that the endemic Mongolian RABVs could be divided into two different groups closely related to the Steppe-type and Arctic-like viruses isolated in Russia. PMID- 20859007 TI - Evaluation of spa typing for the classification of clinical methicillin-resistant Staphylococcus aureus isolates. AB - We evaluated the utility of typing the spa gene, which encodes protein A of Staphylococcus aureus, for analyzing methicillin-resistant S. aureus (MRSA) isolates from patients with health care-associated infections by comparing the results of spa typing with those of pulsed-field gel electrophoresis (PFGE) and multiple-locus variable-number tandem repeat analysis (MLVA). We analyzed 78 clinical MRSA isolates collected at our hospital over a period of 2 months. The clinical isolates were found to have 12 different spa types, with approximately 82% (64/78) of them being typed as t002. The same clinical MRSA isolates were classified into 15 and 19 types upon MLVA and PFGE analysis, respectively, and 19 and 28 types when spa typing was used in combination with MLVA and PFGE, respectively. The discriminatory ability of spa typing alone is low, and thus indicating that this technique is insufficient for performing the initial genotyping of MRSA in short-term epidemiological studies. Therefore, spa typing should be used in combination with MLVA or PFGE for further typing of MRSA isolates. PMID- 20859008 TI - Prevalence of multidrug and extensively drug-resistant tuberculosis in Beijing, China: a hospital-based retrospective study. AB - Tuberculosis (TB) is a disease of worldwide public-health concern. The development of resistance to an increasing number of second-line drugs and those used to treat multidrug-resistant (MDR) TB is rapidly becoming an emergency that could hinder the prevention and treatment of TB globally. This study describes the resistance profile of MDR and extensively drug-resistant (XDR) TB with a hospital-based survey in Beijing, China, conducted in the period 2007 to 2009. Drug-susceptibility tests performed on 967 Mycobacterium tuberculosis strains isolated from 967 patients showed that the rate of resistance to at least one first-line and at least one second-line drug was 70.1% and 60.7%, respectively. The overall MDR rate was 19.4%, and 14.9% of the MDR cases were XDR. In conclusion, MDR and XDR TB represent a significant number of total TB cases, therefore effective measures to manage these resistant strains are desperately needed. Development of a national TB policy in China might be a key method for solving the present problems of TB management. PMID- 20859010 TI - Chronological observation of shell domain of norovirus GII.4 major structural protein VP1. PMID- 20859009 TI - Surveillance of severe invasive group G streptococcal infections in Japan during 2002-2008. AB - Group G Streptococcus strains isolated from patients with severe invasive infections in the period 2002-2008 were surveyed and their prevalence compared with that observed in the period 1995-2001 in Japan. Strains with genotypes stg485, stg6792, stc36, stg6, and stg652 were isolated in both periods, whereas various new genotypes appeared in 2002-2008 and some genotypes found in 1995-2001 were not found subsequently, thus indicating a change in the prevalent genotyped strains causing severe invasive streptococcal infections. PMID- 20859011 TI - Sequencing and phylogenetic analyses of Saffold cardiovirus (SAFV) genotype 3 isolates from children with upper respiratory infection in Gunma, Japan. PMID- 20859012 TI - Isolation of Streptococcus pneumoniae serotypes 6C and 6D from the nasopharyngeal mucosa of healthy Japanese children. PMID- 20859013 TI - Paediatric trauma care. AB - BACKGROUND: Childhood trauma has become a major cause of mortality and morbidity, disability and socio-economic burden and it is expected by the World Health Organization (WHO) that by 2020 it will be the number 1 disease globally. The WHO and UNICEF have published their third World Report on Child Injury Prevention in December 2008. MATERIALS AND METHODS: A systematic review was performed on the history and magnitude of paediatric trauma worldwide. Additionally exciting developments and new trends were assessed and summarized. RESULTS: Paediatric trauma is a growing field of clinical expertise. New developments include total body digital imaging of children presenting with polytrauma; targeted management of head injuries; conservative management of abdominal injuries in children and diagnostic laparoscopy, including the laparoscopic management of complications following the conservative management of solid organ injuries. CONCLUSION: Paediatric trauma has long been neglected by the medical profession. In order to deal with it appropriately, it makes sense to adopt the public health approach, requiring that we view child injuries similarly to any other disease or health problem. The greatest gain in our clinical practice with dealing with child injuries will result from a strong focus on primary (preventing the injury), secondary (dealing with the injury in the most efficient manner) as well as tertiary prevention (making sure that children treated for trauma will be appropriately reintegrated within our society). By actively promoting child safety we will not only achieve a most welcome reduction in medical cost and disability, but also the ever-so-much desired decline of avoidable childhood misery and suffering. PMID- 20859014 TI - Challenges of anaesthesia in the management of the surgical neonates in Africa. AB - Africa has one of the highest neonatal mortalities in the world, for which the commonest causes do not include surgical conditions such as some congenital anomalies that are amenable to surgery but are not often operated on because of a number of challenges. These challenges include cultural beliefs and practices, dearth of human resource capacity, inadequate laboratory and imaging support and lack of consumables and intensive or high dependency care facilities. Some of these challenges will be examined and highlighted using the acronym "ASKS" in this article. PMID- 20859015 TI - Early management of mesenteric cyst prevents catastrophes: a single centre analysis of 17 cases. AB - BACKGROUND: Mesenteric cysts are rare intra-abdominal masses in the paediatric age group with varied presentation, ranging from an asymptomatic mass to acute abdomen. This study reviews our experience in the diagnosis and treatment of 17 mesenteric cysts in our centre, with especial reference to acute abdominal symptoms. PATIENTS AND METHODS: Seventeen patients (age less than 10 years) with mesenteric cysts were managed in our hospital. The age ranged from 15 days to 10 years. Patients were admitted with acute or chronic symptoms. They were evaluated with complete history, clinical examination, blood investigations and radiological investigations (x-ray abdomen erect, ultrasound abdomen (USG) and computed tomography (CT) scan in selected cases) to reach a provisional diagnosis. The diagnosis was proven on laparotomy and histologically confirmed. RESULTS: The main presenting symptoms were abdominal pain or lump. The most common mode of presentation was acute small intestinal obstruction. USG was not conclusive in all. Abdominal CT scan with intravenous contrast was diagnostic in nine patients. Five patients had volvulus on exploration. Cysts were located in small intestinal mesentery in 14 cases and three were in the sigmoid mesentery. Seven patients had complete excision, intestinal resection was required in four and marsupialisation with cauterisation of margins was done in six patients. Histologically, all were lymphangiomatous mesenteric cysts. CONCLUSION: The diagnosis of mesenteric cysts should be kept in mind in any patient presenting with acute abdominal symptoms. Small bowel volvulus with mesenteric cyst constituted a significant number in children with acute abdominal symptoms. Early diagnosis and treatment yields excellent outcome. PMID- 20859016 TI - Evaluation of early and late complications in patients with congenital lobar emphysema: a 12 year experience. AB - BACKGROUND: Congenital lobar emphysema (CLE) is characterised by over distension of one lobe and pressure on the adjacent lobe and mediastinum. In this study, we review the pathological results of our paediatric patients with CLE, highlighting the early and late complications that occurred in these patients. PATIENTS AND METHODS: In a prospective study from 1996 to 2008, we evaluated 30 patients with CLE diagnosis. Variables collected included sex, age at the time of diagnosis, radiological diagnostic method, type of treatment, pathological analysis, surgical findings and early postoperative complications. Parents were asked to refer to our clinic for follow-up and evaluation of late complications. RESULTS: Thirty patients and males accounted for majority of the study population (n = 20, 67%). The mean age of male and female patients (at admission) was 7.2 +/- 2.3 and 4.7 +/- 1.2 months respectively (P = not significant). The main diagnostic method was chest x-ray (CXR) in all patients. Abnormal bronchial cartilage was found in 71% of patients. The most affected lobe was left upper lobe (50%). Associated anomalies were seen in four patients. Early postoperative periodhadtwo cases of pneumothoraces. At six month follow up, five (25%) males and four females (40%) had delayed weight gain. Permanent oxygen dependency was seen in two patients. Twenty- six patients underwent thoracotomy. Mortality rate was 13%. Base deficit at the time of admission was greater in those patients who eventually died, (-8.6 +/- 1.2 versus -3.1 +/- 0.4) (P = 0.0003). There were two deaths in the bilobar involvement group and two in the unilobar involvement group (P = 0.07, near significant). CONCLUSION: This study confirms that the number of affected lobes and base deficit at the time of admission were associated with significantly increased mortality. PMID- 20859017 TI - Management of biliary perforation in children. AB - BACKGROUND: To study the aetiology, management and outcome of biliary perforations in paediatric age group. PATIENTS AND METHODS: In a retrospective study, the records of patients presented with biliary peritonitis due to biliary perforations, managed from March 2006 to July 2009, are reviewed. RESULTS: Eight male patients with biliary peritonitis due to biliary perforation were managed. These patients were divided in two groups, A and B. Group A, (n = 3) patients, had common bile duct (CBD) perforation, and Group B (n=5) patients had gallbladder perforation. The presenting features were abdominal pain, fever, abdominal distension, vomiting, constipation, jaundice and signs of peritonism. The management of CBD perforations in Group A was by draining the site of perforation and biliary diversion (tube cholecystostomy). In Group B, the gallbladder perforations were managed by tube cholecystostomy in four patients and cholecystectomy in one patient, however, one patient had to be re-explored and cholecystectomy performed due to complete necrosis of gall bladder. There was no mortality in our series. All patients were asymptomatic on regular follow-up. CONCLUSION: Early optimal management of biliary perforations remarkably improved the very high mortality and morbidity that characterised this condition in the past. PMID- 20859018 TI - Paediatric pancreatic problems: a five-year experience. AB - BACKGROUND: To analyse a tertiary care experience with various pancreatic problems in the paediatric age group and clarify the frequency of various pancreatic diseases in the same patient population as well as the role of surgical or conservative management in their treatment. PATIENTS AND METHODS: All patients with clinical suspicion of disease pertaining to the pancreas, substantiated by laboratory investigations or imaging modalities over a period of five years are included in our study. RESULTS: Of the total 228 patients with various pancreatic problems, who presented to us, mostly with acute pancreatitis and pancreatic trauma, 64 needed surgical interventions. The total mortality rate encountered was a meagre 3.5%. CONCLUSION: Paediatric pancreatic disorders are not so infrequent; and a high index of suspicion aided by the newer modalities of investigation greatly helps in the appropriate and timely management. PMID- 20859019 TI - Outcome of colostomy closure with different skin closure techniques in a developing country. AB - BACKGROUND: Colostomy site, which is a potentially contaminated wound, is traditionally closed with interrupted skin stitches and placement of intraperitoneal or parietal or both drains; often with poor cosmetic outcome in our country. This study aims at prospective evaluation of colostomy closure wounds by different techniques. PATIENTS AND METHODS: This study was carried out in all infants and children with colostomy (for different pathologies) admitted for colostomy closure in our institute from August 1, 2006 to February 29, 2008. Patients were divided into two groups: Group A with colostomy closure without any drain and subcuticular skin closure and Group B with colostomy closure with both intraperitoneal and parietal drain and interrupted skin closure. Patient's details, including age, sex, body weight, diagnosis, preoperative bowel preparation, peroperative antibiotics, postoperative wound infection, anastomotic leaks, duration of hospitalisation and postoperative follow-up for wound assessment, were recorded. By the end of February 2008, 151 cases of colostomy closure were recorded, 70 in Group A and 81 in Group B. RESULTS: Statistical analysis of the data showed no statistically significant difference in wound infection and anastomotic leak between the two groups. On postoperative follow up, wound assessment showed significantly better cosmesis in the no drain subcuticular group. CONCLUSION: This study shows that closing colostomies without any drain and subcuticular skin closure does not result in any increased incidence of wound infection and has better cosmetic results. PMID- 20859020 TI - Challenges and outcome of Wilms' tumour management in a resource-constrained setting. AB - BACKGROUND: To review the results of Wilms' tumour patients in a tertiary referral hospital in a developing country and to find ways of improving long-term survival. PATIENTS AND METHODS: Between January 1998 and May 2004, 40 patients with Wilms' tumour (WT) were admitted to Queen Elizabeth Central Hospital. Their files were reviewed and general physical condition on admission, pre-operative investigations, management and outcome were noted. RESULTS: The mean age of presentation was 4.2 years with an equal distribution between the sexes. The mean BMI was 15 kg/m2 and more than 80% of the patients were either mildly (PCV <33%) or severely anaemic (PCV <24%). All patients presented with abdominal distension. Half of them had additional complaints including abdominal pain, haematuria, dyspnoea, oedema and or weight loss. Thirty-nine out of the forty patients received pre-operative chemotherapy. Of the 36 patients that underwent surgery, 32 underwent total nephrectomy, one a partial nephrectomy, and in three the tumour was irresectable. There were no intra-operative tumour ruptures. Only 15% of the patients completed their post-operative course of chemotherapy. The 1-year survival lies between 25% and 53%. Fifteen of the 36 patients operated were known to have a recurrence. CONCLUSION: The patients presented in an advanced stage of the disease. Survival rates are disappointing and recurrence rates are high. Some improvement in outcome may be expected with the implementation of more aggressive treatment protocols but early diagnosis, completion of treatment regimens are needed. Pro-active follow-up is essential to measure outcome. PMID- 20859021 TI - Alvarado score as an admission criterion in children with pain in right iliac fossa. AB - BACKGROUND: Acute appendicitis is an important differential diagnosis in children with pain in the right iliac fossa. Some patients have equivocal signs that make the diagnosis difficult. Many patients with suspected acute appendicitis are admitted for observation and finally discharged because they did not have appendicitis. We decided to design this study to investigate whether the Alvarado score could be used by emergency room doctors as a criterion for admission to hospital. PATIENTS AND METHODS: This is a prospective study comprising 350 patients who attended the emergency department with suspected acute appendicitis in the period from May 2007 to April 2009. All patients were scored by Alvarado score in the emergency department before admission. The Alvarado score is based on three symptoms, three signs and two laboratory findings. The decision for admission and surgery was made independent of the score. The diagnosis of patients who underwent appendicectomy was confirmed by both operative findings and postoperative histopathology. RESULTS: We studied the Alvarado scores of 350 patients who presented to the emergency department with pain in the right iliac fossa; their age ranged from 8 to 14 years; 182 patients (52%) operated with the aim to treat acute appendicitis, 168 patients (48%) were discharged without surgical intervention and advised to attend the out-patient clinic after 24 hours for re-evaluation. we have found that patients with a low Alvarado score (less than 6) did not have acute appendicitis. CONCLUSION: Patients with equivocal signs can present a diagnostic challenge and are very often admitted to the surgical department for observation. The Alvarado score can be used as a scoring system that help in taking the decision for admission of cases with suspected acute appendicitis especially by primary healthcare providers. PMID- 20859022 TI - Hirschsprung's disease: management problem in a developing country. AB - BACKGROUND: The management of Hirschsprung's disease remains a problem in developing countries. Our aim is to identify the main epidemiological, clinical, and therapeutic characteristics of Hirschsprung's disease at the University Child Hospital Charles De Gaulle of Ouagadougou (CHUP-CDG). PATIENTS AND METHOD: It is a retrospective study carried out in the period from January 2001 to December 2007 in the Surgery Unit at CHUP-CDG, which is a reference centre for Paediatric Surgery in Burkina Faso. RESULTS: There were 52 patients (M: F=3.3:1). The annual incidence was seven cases. Age at presentation and diagnosis ranged from two days 10 years (median 20 months). Twenty five patients were from poor socio-economic conditions. Presentations were mainly intestinal obstruction, chronic constipation and enterocolitis. There were two cases of associated trisomy 21. Average age at operative intervention was 3.17 months. The rectosigmoidal form was the most frequently encountered. Over two-thirds (67.31%), with no complications at presentation, had benefited from nursing before their final treatment. A temporary colostomy was requested in case of complication. Swenson's technique was practiced for all the patients who underwent surgery operation. The assessment of functional results in eight patients after an average decrease of 3.5 years gave excellent results. Post-surgery complications were mainly enterocolitis in 12% of patients. Mortality rate was 16%. CONCLUSION: Management of Hirschsprung's disease is a problem in Burkina Faso. It is characterised by its late presentation and difficult diagnosis due to inaccessibility and the non availability of some investigation services (barium enema, histochemistry, and histology), resulting in high morbidity and mortality rates. Effective technical capacities, adequate staff training, and public education will be necessary to improve care quality. PMID- 20859023 TI - Treatment of acute appendicitis with one-port transumbilical laparoscopic assisted appendectomy: a six-year, single-centre experience. AB - BACKGROUND: Laparoscopic appendectomy is a feasible and safe alternative to open appendectomy for uncomplicated appendicitis. In the past decade several laparoscopic procedures have been described using one or more ports. We report our experience in treating acute appendicitis with one-port transumbilical laparoscopic-assisted appendectomy (TULAA). PATIENTS AND METHODS: We performed 231 TULAA on patients in the period from November 2001 to September 2007. We introduced an 11 mm Hasson's port using open technique; an operative channel with 10 mm telescope and an atraumatic grasper were used. After intra-abdominal laparoscopic dissection, the appendix was exteriorised through the umbilical access. The appendectomy was performed outside the abdomen as in the open procedure; the operation was completed using only one port in 227 patients (98%), two and three ports in two patients (1%) while conversion to open surgery was needed in two patients (1%). RESULTS: The average operating time was 38 minutes and the median time to discharge was three days. Four (1, 7%) early postoperative complications (two suppuration of the umbilical wound) with no major complications were observed. CONCLUSIONS: Our results demonstrate that TULAA, which combines the advantages of both open and laparoscopic procedures, is a valid alternative form of treating uncomplicated appendicitis. If appendectomy cannot be completed with only one port, insertion of one or more ports may be necessary to safely conclude the procedure. PMID- 20859024 TI - Cleft lip and palate surgery in children: anaesthetic considerations. AB - BACKGROUND: The Care of cleft patients is very challenging. Team cleft care is usually lacking in many developing countries due to shortage of qualified manpower. This study is aimed at highlighting anaesthetic challenges in the management of cleft in children. PATIENTS AND METHODS: This was a study of cleft lip and palate patients who were managed during team cleft care activities at University of Maiduguri Teaching Hospital and Federal Medical Centre Nguru both in north eastern Nigeria from January to June 2009. RESULTS: One hundred and six cleft patients presented for surgical repair under general or local anaesthesia. Fifteen (14%) patients all of whom children were unfit for general anaesthesia due to various medical reasons. Ninety-one (86%) cleft patients comprising 53(50%) children and 38(36%) adults had cleft repair under halothane general endotracheal anaesthesia and local anaesthesia, respectively. There was no anaesthetic complications recorded under local anaesthesia. Fifteen percent of children who received general endotracheal anaesthesia suffered various anaesthetic complications which included hypoxia (3.8%), laryngospasm (1.9%), kinking of endotracheal tube (5.7%), inadvertent extubation (1.9%) and pulmonary aspiration (1.9%). There was no mortality or anaesthesia-related morbidity at the time of discharge in all the cases. CONCLUSION: We conclude that anaesthesia for cleft lip and palate repair in hospital based team-cleft care activities in our environment is relatively safe. We recommend general anaesthesia with controlled ventilation for children and local anaesthesia for adult and older children who can cooperate. PMID- 20859025 TI - A 10-year audit of gynaecological surgeries performed in the paediatric age group at the Jos University Teaching Hospital. AB - BACKGROUND: Surgeries performed for gynaecological conditions in children and adolescents are not common in our environment. Adequate facilities and the skill to perform the required procedures may also be lacking. We were interested in reviewing the practice of paediatric gynaecological surgery in our facility. PATIENTS AND METHODS: A retrospective study of case files and theatre records of children below the age of 16 years who had surgeries at the Jos University Teaching Hospital over a 10 year period was undertaken. RESULTS: A total of 89 surgeries were performed in this age group during the period under review. Twenty eight (33.4%) of the patients were below the age of 11. The most common surgical procedure was for the management of septic abortion (21.3%). Correction of congenital malformations of the genital tract accounted for 21.4% (19) of the surgeries performed. Fourteen (15.7%) laparotomies were performed for ovarian cysts. CONCLUSION: Though the number of surgeries performed on children for gynaecologic reasons may appear small, the skills required to manage them should be enhanced and the requisite facilities provided. PMID- 20859026 TI - Correction of incomplete penoscrotal transposition by a modified Glenn-Anderson technique. AB - PURPOSE: Penoscrotal transposition may be partial or complete, resulting in variable degrees of positional exchanges between the penis and the scrotum. Repairs of penoscrotal transposition rely on the creation of rotational flaps to mobilise the scrotum downwards or transpose the penis to a neo hole created in the skin of the mons-pubis. All known techniques result in complete circular incision around the root of the penis, resulting in severe and massive oedema of the penile skin, which delays correction of the associated hypospadias and increases the incidence of complications, as the skin vascularity and lymphatics are impaired by the designed incision. A new design to prevent this post operative oedema, allowing early correction of the associated hypospadias and lowering the incidence of possible complications, had been used, whose results were compared with other methods of correction. MATERIALS AND METHODS: Ten patients with incomplete penoscrotal transposition had been corrected by designing rotational flaps that push the scrotum back while the penile skin remains attached by small strip to the skin of the mons-pubis. RESULTS: All patients showed an excellent cosmetic outcome. There was minimal post-operative oedema and no vascular compromise to the penile or scrotal skin. Correction of associated hypospadias can be performed in the same sitting or in another sitting, without or with minimal complications. CONCLUSION: This modification, which maintains the penile skin connected to the skin of the lower abdomen by a small strip of skin during correction of penoscrotal transposition, prevents post operative oedema and improves healing with excellent cosmetic appearance, allows one-stage repair with minimal complications and reduce post-operative complications such as urinary fistula and flap necrosis. PMID- 20859027 TI - Correction of incomplete cleft palate by u-shaped flap palatoplasty. AB - OBJECTIVES: During cleft palate repair, velopharyngeal sphincter reconstruction is still a challenge to plastic surgeons. To improve results of surgical treatment of cleft palate and secondary velopharyngeal incompetence, a carefully designed modified procedure for palatoplasty is presented. MATERIALS AND METHODS: Thirty patients with incomplete cleft palate corrected by this procedure from April 2003 to October 2007 were included. A u-shaped incision was made in the anterior palate to separate bipedicle flap based on the greater palatine arteries of both sides. After complete dissection of the nasal and palatal mucosa, palatal muscles were carefully dissected from the posterior edge of the bones of the hard palate, wherein the well-mobilised flap receded backward spontaneously and elongated the soft palate. After suturing the nasal mucosa in the midline, the dissected palatal muscles of both sides were sutured together in the anterior third of the soft palate. On suturing the nasal mucosa and the palatal muscles, the soft palate became elongated and the oral mucosa was seen receding backward spontaneously to cover the anterior part of the soft palate. RESULTS: All corrected patients showed good results, with no recurrence, no post-operative fistulae, with accepted speech pattern and no need for further pharyngoplasty. The line of the sutured nasal mucosa and the palatal muscles became covered by the healthy non-sutured oral mucosa and the soft palate became elongated, with narrowing of the vellopharyngeal isthmus after this technique. CONCLUSION: The designed flap allows covering of sutured nasal mucosa and palatal muscles with a healthy unsutured oral mucosa and elongates the soft palate. Thus, there was no incidence of post-operative fistula and no need for further pharyngoplasties. PMID- 20859028 TI - Spontaneous rupture of hepatocellular carcinoma in children. AB - Spontaneous rupture of hepatocellular carcinoma (HCC) with intraperitoneal haemorrhage is a life-threatening complication with a high mortality rate. The mechanism of spontaneous rupture of HCC is unknown. It may be related to venous congestion, haemorrhage, central necrosis, or trauma. Patients with ruptured tumours confirmed on computerised tomography (CT) scan underwent immediate cardiovascular resuscitation. Depending on the stage of the tumour as seen on the CT scan and the condition of the patient, stoppage of bleeding was accomplished by transcutaneous hepatic artery embolisation, selective hepatic artery ligation, or hepatic resection. Only clinically stable, small tumours were resected as an emergency procedure. We report the case of a 12-year-old child admitted with acute right upper quadrant abdominal pain and signs of hypovolaemia. Ultrasonography revealed free peritoneal fluid and left liver haematoma was suspected. CT scan showed a tumour on the left side of the liver and free peritoneal fluid. Emergency laparotomy revealed haemoperitoneum and a 5-cm diameter left liver tumour which was ulcerated and haemorrhagic. The tumour was completely resected. Histopathological examination confirmed a diagnosis of rupture of differentiated HCC. PMID- 20859029 TI - Persistent Mullerian duct syndrome: a case report and review of the literature. AB - Persistent Mullerian duct syndrome is a rare form of internal male pseudohermaphroditism, in which Mullerian duct derivatives (uterus and fallopian tubes) are present in a genotypic (46XY) and phenotypic male. Over 150 cases have been reported, mainly from outside the African setting. This article presents an unexpected case encountered in an African setting. Handicaps in the management were unavailability of necessary diagnostic tools as well as lack of finance to assess those available. Although a diagnosis was eventually arrived at and the parents thoroughly counseled, the patient has not represented for definitive surgery. PMID- 20859030 TI - Ultrasound-guided endoscopic transgastric drainage of a post-traumatic pancreatic pseudocyst in a child. AB - Despite of a number of techniques in the armentarium of the paediatric surgeon, the management of pancreatic pseudocysts remains a challenge. We report on a case of a 5-year-old child with a post-traumatic pancreatic pseudocyst who was successfully treated with endoscopic ultrasound-guided transgastric approach. Endoscopic ultrasound-guided transgastric drainage of a pancreatic pseudocyst is effective and safe in children. PMID- 20859031 TI - Emergency separation of a xipho-omphalopagus twin in a developing country. AB - Female conjoined twins (thoraco-omphalopagus) were delivered by emergency caesarean section in a private nursing home. On examination, one of the twins was dead and was threatening the survival of the surviving twin (twin A). An emergency separation was performed to salvage the surviving twin. PMID- 20859032 TI - Major complication after intrauterine vesico-amniotic shunting. AB - Bilateral foetal uropathy is the leading cause of chronic renal failure in childhood. Vesico-amniotic shunting (VAS) is a simple, feasible, and widely used procedure for decompressing the foetal urinary system. We report a case of a boy with bilateral foetal uropathy who underwent VAS at a gestational age of 29 weeks. Vesico-abdominal shunt dislodgement occurred and led to urinary ascites and anhydramnios. Postpartal laparotomy showed a shunt perforation between the urinary bladder and the peritoneal cavity. PMID- 20859033 TI - Duplication of cervical oesophagus: a case report and review of literatures. AB - Foregut duplication is commonly found in the posterior mediastinum. 10-20% of these anomalies are associated with oesophageal duplication. It can occur in all parts of oesophageal length. Although duplication of cervical oesophagus has been previously reported, but a majority of them were found in thoracic oesophagus. Infants with oesophageal duplication usually manifested by respiratory distress or asymptomatic thoracic mass, casually, detected in X-ray. A 7-month-old infant weighing about 7.5 kg, with the signboard of respiratory distress, fever and nutritional intolerance was admitted to our hospital. Physical examination showed dehydration, stridor, tachypnoea, intercostal retraction and neck stiffness. Plain chest radiogram showed dubious cystic mass in the distal neck. Cervical and chest computed tomography scan showed neck cystic lesion disseminated to posterior mediastinum, probably propagated to the respiratory system. Cystic lesion connected to oesophagus was partially resected, oesophagus was repaired and remaining mucous of a cyst was removed, then gastrostomy tube was applied. Although cervical oesophageal duplication cysts are rare, but they must be considered as one of the differential diagnoses of cervical mass with respiratory distress in infants. PMID- 20859034 TI - Blue rubber bleb naevus syndrome: a rare cause of gastrointestinal bleeding in an African child. AB - Blue rubber bleb naevus syndrome (BRBNS) is characterised by vascular malformations of the skin and gastrointestinal tract. We present the rare case of BRBNS in an African child. She presented with large-volume gastrointestinal bleeding and was managed by on-table colonoscopic identification and surgical excision, of all her enteric, vascular malformations. PMID- 20859035 TI - Adrenal masses associated with Beckwith Wiedemann syndrome in the newborn. AB - Adrenal cystic lesions are rare and may be associated with both complete and incomplete Beckwith syndrome (BWS). Because the adrenal gland often houses malignant lesions, differentiation between benign and malignant lesions of the gland, although usually difficult, is very necessary from the point of view of management. Here we present our experience in a case of incomplete BWS with adrenal cystic lesion and review of the literature. PMID- 20859036 TI - Sternal cleft repair: a report of two cases and review of literature. AB - A cleft sternum is a rare congenital anomaly often diagnosed as asymptomatic at birth. Clinical outcome may be unfavourable when an associated anomaly, particularly, an intra cardiac anomaly coexists with the defect. Primary repair should be employed in the neonatal period because the flexibility of the chest wall is maximal and thus the compression of underlying structures is minimal. However, patients with sternal cleft may even present late in the childhood or adolescence period. We herein report two cases of successful repair of sternal clefts with review of the available literature. PMID- 20859037 TI - A case of Burkitt's lymphoma presenting as suspected acute appendicitis. PMID- 20859038 TI - Impacted intranasal foreign body causing orbital cellulitis and mistaken for orbital pathology. PMID- 20859039 TI - Preparation for surgery in paediatric cases with swine flu: suggested procedure. PMID- 20859040 TI - Rural doctors course: Need and challenges. PMID- 20859041 TI - Routine immunization: opportunities, challenges. PMID- 20859042 TI - Seasonal variation in prevalence of hypertension: Implications for interpretation. AB - OBJECTIVES: to study seasonal variation in prevalence of hypertension. MATERIALS AND METHODS: the study was carried out in the year 2006, in Gokulpuri, an urban slum located in eastern part of Delhi. 275 females 18-40 years of age were examined in summer. Blood pressure was measured in two seasons, summer and winter. Nutritional status of each individual was assessed by BMI. RESULTS: the prevalence of hypertension based on SBP was 12.72% in summer which increased to 22.22% in winter. The prevalence of hypertension, using DBP criteria increased to more than double (summer vs. winter, 11.27% vs. 26.59%, P< 0.001). Overall prevalence of hypertension (SBP >= 140 or DBP >= 90 mm of Hg) was 1.9 times during winter compared to summer (P<0.001). Greater increase in prevalence of hypertension during winter among older females and underweight as well as normal females was observed. CONCLUSION: Significant increase in prevalence of hypertension during winter compared to summer indicates need for considering this factor while comparing prevalence reported in different studies as well as interpreting the surveillance data based on repeat surveys. PMID- 20859043 TI - Influenza pandemic preparedness and response: A review of legal frameworks in India. AB - BACKGROUND: the potential of pandemics to cause global destabilization calls for robust pandemic preparedness plans with supportive health legislation. Few international studies have investigated their national legal preparedness in case of a pandemic. This study reviews India's legal preparedness in the face of an epidemic. MATERIALS AND METHODS: this study reviewed and analyzed seminal publications pertinent to pandemic preparedness and relevant legal frameworks in India. The analyses are presented in matrix formats and reviewed by national experts. RESULTS: current legal frameworks are largely 'policing' in nature. These provisions seem to be adequate to deal with small scale emergencies but do not appear to be sufficient for large scale health crises during pandemics. CONCLUSION: india needs a critical mass of public health legislations to make impact and not police acts to control epidemics. This study aims to assist policy makers to create comprehensive pandemic preparedness plans, translating preparedness 'on paper' to 'in practice'. PMID- 20859044 TI - Study of needle stick injuries among health care workers at a tertiary care hospital. AB - A cross-sectional study was conducted among health care workers at a tertiary care hospital in Goa to study the problem of needle stick injuries. A structured questionnaire was used to interview the study participants at their work place. Participants were asked to recall needle stick injuries in the preceding 12 months. Factors such as work experience, type of procedure, action taken following injury etc were also studied. Statistical analysis was done with SPSS software. Around 34.8% (200/575) of the Health care workers had experienced a needle stick injury in the last one year. Needle stick injuries were equally distributed across different work experience periods. Hollow bore needles were responsible for 77.5% of needle stick injuries followed by suturing needles (19.2%). As far as use of personal protection was concerned only 58% of the health care workers were wearing gloves at the time of the injury. There is therefore an urgent need at the hospital level to have a uniform needle stick injuries policy covering safe work practices, safe disposal of sharps, procedures in event of needle stick injury, training including pre-employment training, monitoring and evaluation of needle stick injuries and procedures for reporting needle stick injuries. PMID- 20859045 TI - A study on factors influencing treatment outcome of failure patients receiving DOTS in a district of West Bengal. AB - Failure to primary treatment under RNTCP can be an enormous setback for the society. A record based retrospective cohort analysis of 212 patients failing primary treatment under Cat I or Cat III was done in Burdwan district of West Bengal to find the treatment outcome after re-registration under Cat II and its possible influencing factors. Retreatment of failed patients resulted in 24.06% chronicity. Important factors influencing the outcome of being failure were found to be Adolescence (AOR = 2.350; C.I. 0.660-8.281), Urban residence (AOR = 1.878; C.I. 0.705-5.002), primary categorization in Cat I versus Cat III (AOR = 5.036; C.I. 0.897-28.281), higher bacillary load at the beginning of retreatment regimen (AOR = 5.437; C.I. 0.787-37.562) and more than three weeks delay in instituting Cat II treatment (AOR = 3.550; C.I. 0.941- 13.393). 17.35% of such failed patients were still defaulters. Hence such factors may be looked into for more efficient control of Tuberculosis in our country. PMID- 20859046 TI - Safety and efficacy of vinyl bags in prevention of hypothermia of preterm neonates at birth. AB - The present study was planned to evaluate the safety and efficacy of vinyl bags in prevention of hypothermia during resuscitation at birth in very low birth weight neonates. Sixty neonates of gestational age <=32 weeks and birth weight <= 1500gm were randomised to either study group, or control group. Study group neonates were put in vinyl bags up to neck and the head was covered with a cap after drying immediately following delivery and resuscitated under radiant warmer. Control group neonates were resuscitated by conventional drying under radiant warmer. Mean axillary and rectal temperature recorded immediately after admission to NICU were significantly higher in the study group compared to control group. Temperature recorded after 1 hour of admission to NICU were however comparable between the two groups. As temperature maintenance in these VLBW neonates is of tremendous importance, it would make sense to recommend the use of vinyl bags during their resuscitation. PMID- 20859047 TI - A study on demographic and clinical profile of burn patients in an Apex Institute of West Bengal. AB - Burn injuries constitute a major public health problem. A hospital-based descriptive observational study was conducted among 83 burn patients admitted in the Institute of Post Graduate Medical Education and Research, Kolkata in 2008 to assess the demographic and clinical profile of burn patients and to study the medicolegal and social causes. Majority of patients were females (61.5%), literates (78.4%), hindus (79.5%) and in the age group of 20-39 years (56.6%). Occupation-wise housewives were 36.1% followed by students (16.8%).Majority of the cases (61.4%) were accidental whereas suicidal and homicidal cases were 18.1% and 20.5% respectively. According to the size 25.3% patients had 20% -39% of body surface burns and 21.7% had 80% or more burns. 53% of the cases were given blood transfusion and 23.5% died in the study period. PMID- 20859048 TI - Reproductive health of newly married women residing in a resettlement colony of Delhi: a longitudinal study. AB - During the period immediately after marriage, women are neither assessed for their reproductive health nor given any intervention for the same. A community based longitudinal study was done to assess the status of reproductive health of newly married women in which 71 newly married women were followed for 9 months. Mean age at marriage was 20.24 (19.74-20.74) years. 76.06% were anemic. With time, proportion reporting menstrual complaints and RTI symptoms increased significantly (P<0.05). 29 (40.85%) reported menstrual complaints and 22 (30.99%) RTI symptoms. Only 14 (19.72%) subjects used contraceptive methods. 79% conceived within 9 months of marriage. Only 25% pregnancies got registered in first trimester. Reproductive and nutritional status of the newly married women was unsatisfactory. PMID- 20859049 TI - Awareness and perception of mothers about functioning and different services of ICDS in two districts of West Bengal. AB - Integrated Child Development Services, a national programme of the Government of India has health, nutrition, and pre-school education components of services. To ascertain awareness, perception of mothers about functioning and different services of ICDS a cross-sectional community based study was conducted between June to September 2007 in Howrah and Purulia districts of West Bengal. A total of 1235 mothers were included as study subjects. As per opinion of the mothers 73% AWCs opened regularly, behaviour of the AWWs was friendly (71.6%) and 63% mothers opined that ICDS is beneficial to their children. 84.2% mothers were aware of any ICDS services. Quantity and quality of supplementary food was acceptable to 88% and 72.7% mothers respectively. 79.2% and 87.5% mothers did not receive any advice on child feeding and growth chart. Making beneficiaries aware about services by targeted interventions will ensure better utilization of ICDS. PMID- 20859050 TI - An application of Indian public health standard for evaluation of primary health centers of an EAG and a Non-EAG state. AB - National Rural Health Mission (NRHM) has provided the opportunities to develop a standard for Sub centers, PHCs and CHCs in the country, popularly known as Indian Public Health Standards (IPHS). The study was carried out to find out and compare to what extent the IPHS were followed by the PHCs in the selected districts of both the Empowered Action Group (EAG) state of Assam and non EAG state of Karnataka. It was a Cross sectional observational study conducted during September-October 2008 where the quality of care and services provided in the selected PHCs as per the IPHS norms was assessed. All the PHCs in both the studied districts were rendering the assured services of OPD, 24hrs general emergency service and referral services while 24 hour delivery services were being provided by 80% of the PHCs of the selected districts of both the states. Functional labor rooms were available only in 80% and 90% of the studied PHCs in Assam and Karnataka respectively. Basic laboratory facilities, for routine blood, urine and stool examination were available in 80% of the studied PHCs in the non EAG state of Karnataka while it was only in 20% of the studied PHCs of the EAG state of Assam. The findings of the present study revealed important deficiencies as per IPHS norms in the studied PHCs of both Assam and Karnataka. PMID- 20859051 TI - A survey of hospitals managing human rabies cases in India. AB - A survey of 23 infectious diseases (ID) hospitals/ID wards of general hospitals was done during 2008-09 to assess the facilities for and management of rabies patients. All were Government hospitals and 0.5% of total beds was earmarked for rabies cases. The hospitals were mostly run by medical colleges (47.8%) and ID hospitals (30.4%) and located outside city limits (52.2%). The patients were admitted to 'rooms (39.1%)' and 'wards (43.5%)'. The general conditions of rabies sections i.e. sanitation and linen (65%), space and toilet (52% and 56%) and bed (47.8%) require improvements. There is a need to improve staff availability, use of personal protective wears, preventive vaccination of care providers and medicinal supplies. It is recommended to encourage hospitalization of human rabies cases to ensure a 'painless and dignified death' and this must be considered as a 'human rights' issue. PMID- 20859052 TI - A study on care seeking behavior of chest symptomatics in a slum of Bankura, West Bengal. AB - A cross-sectional, community based study was undertaken in Patpur slum of Bankura to determine the prevalence of chest symptomatics, their health care seeking Behavior and its correlates. Prevalence of chest symptomatics (cough for 3 weeks or more) was found to be 5.5%, three fourths of whom sought relief from a health care provider. Among them, 70.8% did so within 2 weeks, median being 7 days. No preference for either government or private health care provider was seen in first visit, where the major reason for choosing facilities was advice by family & friends (43.8%). Most of the chest symptomatics (75%) were retained in the same facility. Shift from private to government facility for subsequent visits (33.3%) was higher than from government to private facility (16.7%). The main reason (50%) for changing health facility was expectation for better service. PMID- 20859053 TI - A paralytic disease with presentation of food poisoning affecting three members of a family at Khammam, Andhra-Pradesh. PMID- 20859054 TI - Seropositivity of HIV infection among armed forces attending integrated testing and counseling centre in a tertiary care hospital. PMID- 20859055 TI - Some observations on diabetes mellitus in Ludhiana, Punjab. PMID- 20859057 TI - Evaluation of the integrated disease surveillance project training at Kannur district of North Kerala. PMID- 20859056 TI - Prevalence of intestinal parasitic infections amongst food handlers in hotels and restaurants in Solapur city. PMID- 20859058 TI - p120-Catenin is essential for N-cadherin-mediated formation of proper junctional structure, thereby establishing cell polarity in epithelial cells. AB - The role of p120-catenin in the function of classical cadherins is still enigmatic despite various studies. To elucidate its role, we examined the effect of p120-catenin on the N-cadherin-mediated localization of junctional proteins in epithelial cells in this study. Cadherin-deficient MIA PaCa-2 epithelial cells did not show linear localization of tight junction proteins ZO-1 and occludin. When N-cadherin was expressed in these cells, however, the resultant transfectant cells revealed strong cell adhesion activity and linear localization of ZO-1, occludin, and N-cadherin in the lateral membrane. When the p120-catenin-binding site of N-cadherin was disrupted, the linear localization of ZO-1 and occludin disappeared, and the mutant N-cadherin became localized more diffusely in the transfectant, although the cell adhesion activity did not change much. Knockdown of p120-catenin also resulted in the very weak localization of ZO-1 and occludin. A similar effect of p120-catenin on the localization of junctional proteins was obtained under more dynamic conditions in a wound healing assay. Moreover, p120 catenin was essential for the regulation of centrosome orientation in this healing assay. Taken together, the present data indicate that p120-catenin is essential for N-cadherin-mediated formation of proper junctional structures and thereby the establishment of the cell polarity. Similar results were obtained when E-cadherin mutants comparable to those of N-cadherin were used, suggesting that p120-catenin plays the same role in the function of other classical cadherins. PMID- 20859059 TI - A review of the development of radical photopolymerization initiators used for designing light-curing dental adhesives and resin composites. AB - This paper reviews our recent studies on radical photopolymerization initiators, which are used in the design of light-curing dental adhesives and resin composites, by collating information of related studies from original scientific papers, reviews, and patent literature. The photopolymerization reactivities of acylphosphine oxide (APO) and bisacylphosphine oxide (BAPO) derivatives, and D,L camphorquinone (CQ)/tertiary amine were investigated, and no significant differences in degree of conversion (DC) were found between BAPO and CQ/amine system (p>0.05). In addition, a novel 7,7-dimethyl-2,3-dioxobicyclo[2.2.1]heptane 1-carbonyldiphenyl phosphine oxide (DOHC-DPPO=CQ-APO) was synthesized and its ultraviolet and visible (UV-VIS) spectral behavior was investigated. CQ-APO possessed two maximum absorption wavelengths (lambdamax) at 350-500 nm [372 nm (from APO group) and 475 nm (from CQ moiety)], and CQ-APO-containing resins exhibited good photopolymerization reactivity, excellent color tone, relaxed operation time, and high mechanical strength. It was also found that a newly synthesized, water-soluble photoinitiator (APO-Na) improved adhesion to ground dentin. PMID- 20859060 TI - Diffusion of GM primer and dentin adhesive into EDTA-conditioned dentin. AB - The aim of this study was to investigate the diffusion of red-stained experimental GM primer and blue-stained dentin bonding agent into EDTA conditioned dentin and the effect of GM priming on contraction gap formation. After GM priming at 0, 35, 70, or 100 vol%, marginal adaptation was evaluated by measuring the wall-to-wall contraction gap width of a light-activated resin composite (Palfique Estelite, Tokuyama Dental, Japan) mediated with a commercial dentin bonding agent (Clearfil Photo Bond, Kuraray Medical, Japan). Contraction gap formation was completely prevented when treated with 35 vol% GM primer. Moreover, after treatment with 35 vol% GM, the red and blue dyes of stained GM primer and dentin bonding agent diffused up to a depth of 40 um into the dentin surface. The diffusion of primer and bonding agent into EDTA-conditioned dentin was essential for bonding efficacy although SEM observation revealed an absence of hybrid layer formation. PMID- 20859061 TI - Clinical aspects and adrenal functions in eleven Japanese children with X-linked adrenoleukodystrophy. AB - X-linked adrenoleukodystrophy (X-ALD) is a genetic disease associated with demyelination of the central nervous system, adrenocortical insufficiency and accumulation of very long chain fatty acids. It is a clinically heterogeneous disorder ranging from a severe childhood cerebral form to an asymptomatic form. The incidence in Japan is estimated to be between 1:30,000 and 1:50,000 boys as determined by a nationwide retrospective survey between 1990 and 1999, which found no cases with Addison's form. We reviewed the medical records of eleven Japanese boys with X-ALD from 1990 to 2010 in our institute. Eight patients were detected by neuropsychological abnormalities, whereas a higher prevalence of unrecognized adrenocortical insufficiency (5/11: 45%) was observed than previously recognized. While no neurological abnormalities were demonstrated in two brothers, the elder brother had moderate Addison's disease at diagnosis and the presymptomatic younger brother progressed to Addison's disease six months after the diagnosis of X-ALD. Early detection of impaired adrenal function as well as early identification of neurologically presymptomatic patients by genetic analysis is essential for better prognosis. Addison's form might be overlooked in Japan; therefore, X-ALD should be suspected in patients with adrenocortical insufficiency. PMID- 20859063 TI - Current perspective on the role of the thrombin receptor in cerebral vasospasm after subarachnoid hemorrhage. AB - Cerebral vasospasm is a persistent arterial narrowing typically observed during the 3 - 14 days after subarachnoid hemorrhage (SAH). Vasospasm is frequently associated with ischemic neurological deficits or even death, resulting in a poor prognosis for patients with SAH. However, the mechanism underlying cerebral vasospasm remains elusive, and no effective therapeutic strategies have been established. A large amount of thrombin is produced during SAH. Recent investigations have uncovered a key role of the thrombin receptor in the pathogenesis of cerebral vasospasm. Thrombin has little contractile effect in the normal cerebral artery, but it induces an enhanced and prolonged contraction after SAH, owing to the up-regulation of thrombin receptor PAR(1) (proteinase activated receptor 1) and the impairment of receptor desensitization in arterial smooth muscle. Thrombin-mediated activation of PAR(1) is an irreversible process, as it is initiated by the proteolytic removal of the N-terminal region. Since the mechanism of receptor desensitization is impaired after SAH, the thrombin-induced contraction irreversibly persists even after terminating thrombin stimulation. Intrathecal administration of a PAR(1) antagonist prevents the PAR(1) up regulation and the increased reactivity to thrombin. PAR(1) is suggested to play a key role in cerebral vasospasm and may be useful as a therapeutic target for prevention and treatment of cerebral vasospasm. PMID- 20859062 TI - Computational analysis of the effects of antineoplastic agents on axonal transport. AB - Axonal transport plays a crucial role in neuronal morphogenesis, survival, and function. Despite its importance, however, the molecular mechanisms of axonal transport remain mostly unknown because a simple and quantitative assay system for axonal transport has been lacking. In order to better characterize the molecular mechanisms involved in axonal transport, we here developed a computer assisted monitoring system. Using lipophilic fluorochrome chloromethylbenzamido dialkylcarbocyanine (CM-DiI) as a labeling dye, we have successfully labeled membranous organelles in cultured chick dorsal root ganglia neurons. We confirmed that sodium azide, an ATPase inhibitor, and nocodazole, a microtubule destabilizing agent, markedly suppressed anterograde and retrograde axonal transport of CM-DiI-labeled particles. We further tested the effects of several anti-neoplastic drugs on axonal transport. Paclitaxel, vincristine, cisplatin, and oxaliplatin, all of which are known to be neurotoxic and to cause neurological symptoms, suppressed anterograde and retrograde axonal transport. Another series of anti-neoplastic drugs, including methotrexate and 5 fluorouracil, did not affect the axonal transport. This is the first report of an automated monitoring system for axonal transport. This system will be useful for toxicity assays, characterizing axonal transport, or screening drugs that may modify neuronal functions. PMID- 20859065 TI - Diabetes mellitus- and cooling-induced bladder contraction: an in vitro study. AB - The effects of diabetes mellitus during cooling on ACh- and KCl-induced responses were investigated in rat urinary bladder. Diabetes was induced in the rats by 50 mg/kg streptozotocin via an intraperitoneal injection. Rats' body and bladder weights were measured. The isometric tension to ACh (10(-9) - 3 * 10(-4) M) and KCl (5-100 mM) in strips of urinary detrusor muscle of diabetic and non-diabetic rats, in organ baths at 37 and 28oC were recorded. The body weights were significantly decreased and the bladder weights increased in STZ-induced diabetic group compared to the non-diabetic group. ACh and KCl caused concentration dependent contractions of urinary bladders from non-diabetic and STZ-induced diabetic rats. During cooling, the sensitivity and the maximal response were significantly higher than those during 37oC, both in non-diabetic and diabetic preparations. Cooling of detrusor muscle preparations induces a graded contraction inversely proportional to the temperature in diabetic rats. It may be assumed that the cooling response involves the same mechanisms in the diabetic and non-diabetic animals. PMID- 20859064 TI - Novel spliced variants of large-conductance Ca(2+)-activated K(+)-channel beta2 subunit in human and rodent pancreas. AB - Large-conductance Ca(2+)-activated K(+ )(BK) channel regulates action potential firing in pancreatic beta-cells. We cloned novel spliced variants of the BK channel beta(2)-subunit (BKbeta2b), which consisted of 36 amino acids including the N-terminal in the original human BKbeta2 (BKbeta2a), from human and rodent pancreas. Real-time PCR analysis showed the abundant expression of BKbeta2b transcripts in human and rodent pancreas and also in the RINm5f insulinoma cell line. In addition, up-regulation of both BK-channel alpha-subunit (BKalpha) and BKbeta2b transcripts was observed in pancreas tissues from diabetes mellitus patients. In HEK293 cells co-expressing BKalpha and BKbeta2b, the inactivation of BK-channel currents, which is typical for BKalpha + BKbeta2a, was not observed, and electrophysiological and pharmacological properties of BKalpha + BKbeta2b were almost identical to those of BKalpha alone. In HEK293 cells stably expressing BKalpha, the transient co-expression of yellow fluorescence protein (YFP)-tagged BKbeta2a proteins resulted in their distribution along the cell membrane. In contrast, the co-expression of YFP-tagged BKbeta2b with BKalpha showed diffusely distributed fluorescence signals throughout the cell body. Taken together, the predominant splicing of BKbeta2b versus that of BKbeta2a presumably enhances the contribution of BK channels to membrane potential and may possibly be a factor modulating insulin secretion in a suppressive manner in pancreatic beta-cells. PMID- 20859066 TI - Properties of acetylcholine-induced relaxation of smooth muscle isolated from the proximal colon of the guinea-pig. AB - The properties of mechanical responses elicited by stimulation with acetylcholine (ACh) were investigated in circular smooth muscle preparations isolated from the proximal colon of guinea-pig. Application of ACh (10(-8)-10(-6) M) for 3-5 min produced a biphasic response, with an initial contraction followed by a relaxation. Atropine inhibited the initial contraction, while N(omega)-nitro-L arginine (L-NA) inhibited the relaxation, suggesting that the former was produced by activation of muscarinic receptors while the latter was produced by an elevated production of nitric oxide (NO). In the presence of atropine, the ACh relaxation was attenuated by removal of the mucosa and abolished by removal of both submucosal and mucosal layers. The ACh-induced relaxation was also attenuated by either tetrodotoxin (TTX, 3 * 10(-7) M) or hexamethonium (10(-6) M). In the presence of atropine, transmural nerve stimulation (TNS) elicited a biphasic response, with an initial phasic contraction followed by a relaxation. The amplitude of TNS-induced relaxation was significantly reduced by hexamethonium or L-NA and was abolished by TTX. Both ACh and TNS produced relaxation in preparations isolated from the proximal colon, but not in those from the middle part of colon. Immunohistochemistry for neuronal nitric oxide synthase revealed no difference in the distribution of nitrergic nerves between the proximal and middle part of the colon, with nitrergic nerves in both the mucosal and submucosal layers as well as in the smooth muscle and myenteric layers. These results suggest that ACh induces NO production by excitation of postganglionic nerves distributed mainly in the mucosal and submucosal layers. In circular smooth muscle preparations isolated from the middle part of colon, ACh or TNS produced contractile responses alone, with no associated relaxation, suggesting that the ACh-activated postganglionic nitrergic nerves are distributed in the mucosal and submucosal layers of the proximal colon but not in the middle part of the colon. PMID- 20859068 TI - Induction of RhoA gene expression by interleukin-4 in cultured human bronchial smooth muscle cells. AB - RhoA, a small GTPase, is one of the key proteins of smooth muscle contraction. In allergic asthma, an upregulation of RhoA in bronchial smooth muscle has been suggested. However, the mechanism of its upregulation has not yet been clarified. In the present study, the effects of interleukin-4 (IL-4), one of the T-helper 2 cytokines, on RhoA mRNA expression and promoter activity of RhoA gene were examined in cultured human bronchial smooth muscle cells (hBSMCs). The quantitative real-time RT-PCR analyses revealed that incubation of hBSMCs with IL 4 (10, 30 and 100 ng/mL, for 24 hr) caused an increase in RhoA mRNA in a concentration-dependent manner. In luciferase reporter gene assay using hBSMCs that were transfected with luciferase constructs and were then stimulated with IL 4 (100 ng/mL), an importance of the most proximal STAT6 binding region (78-70 bp upstream of the transcription initiation site) was suggested. It is thus possible that IL-4 is capable of upregulating RhoA by promoting its transcription in hBSMCs. The proximal STAT6 binding region is required for the IL-4-induced increase in promoter activity of the human RhoA gene. PMID- 20859069 TI - The relationships among gait and mobility under single and dual task conditions in community-dwelling older adults. AB - AIMS: The purpose of this study was to examine relationships among gait and mobility under single and dual task conditions in older adults. METHODS: Community-dwelling older adults (n=41, mean age=75) completed mobility and gait tasks. Mobility was assessed with the Timed-Up-and-Go (TUG). Select gait parameters were examined while individuals walked at their preferred speed across the GAITRite electronic walkway. Two age groups were studied (younger age group=65-75; older age group=76+). Multiple linear regression analyses were used to examine the relationship between gait and mobility under single vs dual conditions. RESULTS: Older adults required more time to complete the TUG when concurrently performing a second cognitive task (10.84 sec vs 15.77 sec). In addition, one or more gait characteristic such as stride length, cadence and stance explained (a) a high percentage of variance in mobility performance under single task conditions (TUG 74%) and (b) a smaller portion of variance in mobility performance under dual task conditions (TUGc 25%). No salient age group differences were observed in TUG performance, but gait characteristics accounted for a larger portion of variance in TUGc performance (46%) for the older age group (mean age=81) than for the younger age group (mean age=69; TUGc 18%). PMID- 20859073 TI - Can physicians use selective debridement codes, 97597 and 97598, to bill Medicare? PMID- 20859074 TI - Combining acoustic pressure wound therapy with electrical stimulation for treatment of chronic lower-extremity ulcers: a case series. PMID- 20859067 TI - Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs. AB - PURPOSE: The objectives of this study were to compare the functional expression of muscarinic and purinergic receptors in the urinary bladder of 2 species, rat and guinea pig under comparable experimental conditions; and to test whether the receptors in males and females differ. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to identify gene expression profiles in bladder smooth muscle (total n=8 rats, 7 guinea pigs) and mechanical responses to nerve stimulation and applied acetylcholine (ACh) in the presence of specific antagonists were used to identify functional receptor sub-types (total n=12 rats, 16 guinea pigs). RESULTS: RT-PCR indicated that M2 and M3 were the predominant muscarinic receptor genes in both the male and female rat and guinea pig bladders. The phasic component of the nerve-induced contraction was greater in guinea pigs vs. rats. The tonic component and the ACh response were inhibited by the M3 receptor antagonist, darifenacin (10(-6) M, P<=0.05), but not by the M2 receptor antagonist, methoctramine (10(-5) M). The antipurinergic drug alpha, beta-methylene ATP (5 * (-5) M) caused a significant reduction in the amplitude of the phasic response to nerve stimulation in all groups, and this effect was significantly greater in male vs. female rats. mRNA for the purinergic P2X1, P2X2, P2X4, P2X5 and P2X7 receptors was detected in both male and female rats, whereas P2X3 and P2X6 were inconsistently detected in male rats. The P2X1 purinoceptor antagonist pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4', 8' disulphonate) (PPNDS), only inhibited nerve induced contractions at high concentrations (up to 10(-4) M). CONCLUSIONS: While only minor functional differences were documented in cholinergic and purinergic bladder contractile responses between male and female animals, and between rats and guinea pigs, data such as presented in this study are critical in determining how relative functional contributions may change in the diseased state, providing valuable information towards new treatment options. PMID- 20859075 TI - Iranian Diabetic Foot Research Network. PMID- 20859076 TI - The effect of various wound dressings on the activity of debriding enzymes. AB - OBJECTIVE: To understand the compatibility between the debriding enzymes collagenase and papain, and various wound dressings. DESIGN: The extracts from a silver dressing (Acticoat; Smith & Nephew, St Petersburg, Florida), iodine dressings (Iodoflex and Iodosorb; Smith & Nephew), a pigment-complexed polyvinyl alcohol (PVA) dressing (Hydrofera Blue; Healthpoint, Ltd, Fort Worth, Texas), and collagen dressings (Hydrofera Blue and FibraCol Plus; Systagenix Wound Management, Quincy, Massachusetts) were examined in vitro with collagenase and papain (papain was used in papain-urea debriding agents, no longer available on today's US market). SETTING: All testing was in vitro and performed at Healthpoint, Ltd. PATIENTS: Testing was not performed using human or animal subjects. All in vitro testing was conducted in the lab using artificial wound eschar substrate and other lab equipment. MAIN OUTCOME MEASURES: The main outcome measure was percent collagenase and papain activity lost when combined with each type of dressing tested. MAIN RESULTS: The results demonstrated that the pigment complexed polyvinyl alcohol dressing and the collagen dressing were compatible with collagenase, whereas the iodine dressings inhibit the activity of collagenase. The nanocrystal silver dressing (Acticoat) caused more than a 50% loss in activity when combined with collagenase. Papain displayed varying levels of inhibition with all dressings tested with the enzyme. The iodine dressings significantly inhibit papain activity, whereas the other dressings exhibited inhibitory activity ranging from 10% to 30%. CONCLUSION: Antimicrobial dressings are widely used for management of wound bioburden. Frequently, they are used in combination with other topical therapeutic drugs, such as enzymatic debriding agents for the removal of wound necrotic tissues. Such combined applications may have greater potential to achieve multiple healing activities simultaneously, including exudate and bioburden management, debridement, and tissue regeneration. Overall, the authors' testing found that collagenase was observed to be more tolerant when used with the dressings tested than papain. These findings merit further exploration in clinical wounds to confirm clinical validity. PMID- 20859077 TI - Development and implementation of a professional wound care training program for nurses in Taiwan. PMID- 20859079 TI - Checklist for differential diagnosis of lower-extremity ulcers. PMID- 20859080 TI - Perivascular hemophagocytosis: report of 2 cases and review of the literature. AB - Hemophagocytosis may be encountered in association with a variety of underlying conditions, including primary or familial disorders, and secondary forms induced by infections, malignancy, and metabolic disorders. It is usually observed in organs such as the spleen, lymph nodes, bone marrow, and central nervous system, but rarely in the skin. When hemophagocytosis coexists with a sepsis-like systemic disorder it is termed hemophagocytic syndrome or hemophagocytic lymphohistiocytosis. Recently, 2 cases with evidence of perivascular hemophagocytosis in skin biopsy specimens of patients without additional findings of hemophagocytic lymphohistiocytosis have been reported. We report 2 additional cases of patients with cutaneous lesions suggestive of leukocytoclastic vasculitis whose skin biopsies showed a perivascular and interstitial infiltrate of neutrophils with nuclear dust and extravasated erythrocytes, and the presence of histiocytes with phagocytized red blood cells and nuclear fragments. There was also evidence of fibrin in the walls of the venules. One patient presented with a sepsis-like clinical scenario, but an extensive work-up failed to demonstrate any underlying disease or infection. The second patient was asymptomatic at the time of presentation, but further work-up revealed an underlying B-cell lymphoma. Whether these histologic findings represent late lesions of leukocytoclastic vasculitis or an incomplete presentation as part of a hemophagocytic syndrome is debatable, because both are associated with activated immunity and cytokine release, which could account for the presence of hemophagocytosis. Although the histopathologic finding alone of hemophagocytosis is insufficient to label as a syndrome, it should incite the clinician for further systemic evaluation. PMID- 20859081 TI - Cutaneous myelofibrosis with JAK2 V617F mutation: metastasis, not merely extramedullary hematopoiesis! AB - Primary myelofibrosis (PMF) is a myeloproliferative neoplasm. There are 31 reported cases of cutaneous involvement by PMF, most of which have been described as "extramedullary hematopoiesis." We report a new case of cutaneous involvement by PMF and demonstrate mutation of the Janus kinase 2 gene in the cutaneous lesions. Extramedullary myelofibrosis is best considered a metastatic phenomenon. Reporting such cases as extramedullary hematopoiesis may cause confusion with reactive forms of extramedullary hematopoiesis. PMID- 20859082 TI - Spiradenoma with marked adenomyoepitheliomatous features. PMID- 20859083 TI - The impact of gender and anchor drugs on TDF renal toxicity. PMID- 20859084 TI - cART durability and causes for treatment switching or discontinuation in HIV positive patients older than 50 years of age. PMID- 20859085 TI - Preefficacy use and sharing of antiretroviral medications to prevent sexually transmitted HIV infection among US men who have sex with men. PMID- 20859086 TI - Self-examination behaviors for syphilis symptoms among HIV-infected men. PMID- 20859087 TI - Value-based nursing care. PMID- 20859088 TI - Nurses in the Boardroom. AB - This department highlights nursing leaders who have demonstrated the ability to inspire and lead change. This competency is seen in the ability to create, structure, and implement organizational change through strategic vision, risk taking, and effective communication. Each article showcases a project of a nurse leader who demonstrates change in a variety of environments ranging from acute care hospitals to home care and alternative practice settings. Included are several "lessons learned" applicable to multiple settings that provide insight for other nurses in executive practice. PMID- 20859089 TI - Instruments to assess organizational readiness for evidence-based practice. AB - In this department, Dr Newhouse highlights hot topics in nursing outcomes, research, and evidence-based practice relevant to the nurse administrator. The goal is to discuss the practical implications for nurse leaders in diverse healthcare settings. Content includes evidence-based projects and decision making, locating measurement tools for quality improvement and safety projects, using outcome measures to evaluate quality, practice implications of administrative research, and exemplars of projects that demonstrate innovative approaches to organizational problems. In this article, the author discusses the importance of assessing the readiness of the organization in accelerating evidence-based practice initiatives and provides a description and references of potential instruments to measure organizational readiness. PMID- 20859090 TI - The top 10 in 2010. PMID- 20859091 TI - Factors associated with success and breakdown of shared governance. AB - Shared governance (SG), a process for empowering nurses in practice settings, has been widely used for decades. However, despite enthusiasm for the concept, the process is not always successful or falters after successful initiation. To assist nursing leaders trying to implement or maintain SG processes, the author summarizes literature on both human and structural factors that contribute to the success or breakdown of SG practice models. Barriers to implementation and strategies to support implementation, as well as enculturation of SG, are discussed. PMID- 20859093 TI - A handoff report card for general nursing orientation. AB - While redesigning nursing orientation, a gap in the transmission of information from general hospital to unit orientation was identified: Unit managers were unaware of the strengths and weaknesses identified in the nursing orientation of newly hired experienced nurses and, therefore, could not tailor the unit orientation to meet the specific needs of these orientees. The authors discuss the development and implementation of a nursing orientation report card, consisting of a 100-point score containing a summary of skills, knowledge, and Benner level measuring clinical performance and critical thinking, to facilitate better exchange of performance data. PMID- 20859092 TI - Failure to rescue measure: validation of community- and hospital-acquired complications. AB - The inclusion of the failure to rescue (FTR) measure as one of the Centers for Medicare and Medicaid Services Inpatient Prospective Payment System measures has raised questions about the characteristics of FTR cases and their outcomes. In this study, we validated 75% of the identified FTR complications using medical record review (n = 461). Nearly half (49.5%) of the complications originated in the community and were present on admission. Acute renal failure, gastrointestinal hemorrhage, and sepsis most often originated in the community. Cardiac arrest/shock, pneumonia, and pulmonary embolism and deep vein thrombosis most often developed in the hospitals. These findings have important implications for practice as clinical leadership focuses on the prevention and aggressive management of complications to prevent death, increased length of stay, and possible reductions in Medicare diagnosis related groups' reimbursements. PMID- 20859094 TI - Transforming nursing workflow, part 2: the impact of technology on nurse activities. AB - OBJECTIVE: To assess the impact of new technology on nurse workflow, nurses at 2 hospitals were observed before and after implementation of an electronic medication charting system. In part 1 (September 2010 issue), we discussed the chaotic nature of nurse activities and its implications on transforming workflow. BACKGROUND: Numerous studies have documented the impact of technology on performance and satisfaction, but technology's impact on the frequency, duration, and pattern of activities is less understood. These patterns are important to the development of new care models. METHODS: Observers shadowed nurses at 2 hospitals before and after the implementation of an electronic medication charting system. A total of 196 hours of observation was recorded at one site, and 185 hours at the other site. RESULTS: Analysis of variance revealed a number of significant differences in the time spent on a variety of activities, but the duration and frequency of nurse activities were not drastically altered by the additional technology. CONCLUSIONS: Computer use increased; however, the impact was evenly distributed among other activities. More importantly, time with patients and verbal communication remained unchanged as nurses seemed to incorporate the new requirements into their normal routine. PMID- 20859095 TI - Predicting patient satisfaction with nurses' call light responsiveness in 4 US hospitals. AB - OBJECTIVE: This multihospital study determined the contributors to patient/family satisfaction levels with nurses' call light responsiveness and compared the reasons for call light usage as perceived by patients and nurses. BACKGROUND: Delayed responses to answering call lights may result in a patient falling and can affect patient satisfaction. METHODS: This cross-sectional survey study was conducted from September 2008 to November 2009 in 4 US hospitals; 1,253 patients/family participants and 988 nurses were surveyed. Descriptive and multiple regression analyses were conducted. RESULTS: Women, older patient/family participants, and those who perceived that nurses often answered call lights in person, that their problems were resolved after pushing the call light, and that their call lights less frequently involved safety issues were more satisfied with nurses' responsiveness. The top 5 reasons for using call lights were the same for patients and nurses. CONCLUSION: Nursing administrators should emphasize increasing staff's call light responsiveness. PMID- 20859096 TI - Closing wards during summer time and its effects on patients' outcomes. AB - Closure of wards (units) during the summer is a management practice introduced in some Italian hospitals to deal with the national nursing shortage and seasonal staffing patterns. The authors discuss a cross-sectional comparative study that they conducted to assess the effects of this management practice on patient outcomes. PMID- 20859097 TI - JONA certification supplement. PMID- 20859098 TI - Reliability testing of the National Database of Nursing Quality Indicators pressure ulcer indicator. AB - A criterion-referenced Web-based test was designed and administered to 256 individuals at 48 randomly sampled National Database of Nursing Quality Indicators (NDNQI) member hospitals to determine the reliability of the NDNQI pressure ulcer indicator. Overall kappa values for pressure ulcer identification, staging, and sourcing indicate moderate to near perfect reliability. Findings suggest that nurses can accurately differentiate pressure ulcers from other ulcerous wounds in Web-based photographs, reliably stage pressure ulcers, and reliably identify community versus nosocomial pressure ulcers. PMID- 20859099 TI - Certification and education: do they affect pressure ulcer knowledge in nursing? AB - OBJECTIVE: To determine whether wound care certification and education affect nursing knowledge. This study examined pressure ulcer knowledge among registered nurses who were (1) certified in wound care, (2) certified in specialty areas other than wound care, or (3) not certified in any specialty area. DESIGN: A convenience sample of 460 nurses, located in both urban and rural areas, provided demographic information and completed a standardized pressure ulcer knowledge test using (Pieper Pressure Ulcer Knowledge Tool). RESULTS: The mean standardized test score for the total sample was 78%, with nurses certified in wound care scoring 89%, nurses certified in specialties other than wound care scoring 78%, and nurses receiving no certification scoring 76.5%. CONCLUSION: Wound care certification and education significantly affect nursing knowledge. PMID- 20859100 TI - Effect of certification in oncology nursing on nursing-sensitive outcomes. AB - The study compared certified nurses with noncertified nurses for symptom management of nausea, vomiting, and pain; patient satisfaction; and nurse satisfaction to determine the effect of certification in oncology nursing on those nursing-sensitive outcomes. A total of 93 nurses-35 (38%) of them certified in oncology nursing-and 270 patients completed surveys. Chart audits provided additional data on symptom management. Certified nurses scored higher than noncertified nurses on the Nurses' Knowledge and Attitudes Survey Regarding Pain as well as the Nausea Management: Nurses' Knowledge and Attitudes Survey. The chart audits showed that certified nurses followed National Comprehensive Cancer Network guidelines for chemotherapy-induced nausea and vomiting (CINV) management more often than noncertified nurses. The study demonstrated that job satisfaction is fairly high for oncology nurses and patient satisfaction is high. In general, cancer pain and CINV were managed well but improvements can be made. Nurses and physicians continuously should be educated on evidence-based guidelines for symptom management of cancer pain and CINV, and a CINV knowledge and attitude assessment tool should be developed. PMID- 20859101 TI - Predictors of professional nursing practice behaviors in hospital settings. AB - BACKGROUND: Many hospital nurses perform isolated, routine tasks, rather than use their professional training, because they are subject to control by organizational and medical divisions of labor. The environment may interfere with a nurse's ability to practice autonomously and according to professional standards. OBJECTIVES: The purpose of the study was to explore how certain factors in the environment and personal characteristics interact to affect hospital nursing practice behaviors. METHODS: The study used a nonexperimental, comparative design. Surveys were sent to a random sample of 500 nurses throughout the state of Michigan. Three instruments,measuring structural empowerment, self efficacy for nursing practice, and professional practice behaviors,were included. Path analysis was used for statistical analysis. RESULTS: Three hundred sixty four nurses responded (73%), of whom 251 provided usable protocols for the final analysis. Environmental factors (structural empowerment) contributed both directly to professional practice behaviors as well as indirectly through self efficacy. Self-efficacy mainly exerted its effect as a mediator in the relationship between environmental factors and practice behaviors. Support for the proposed theoretical model was mixed, although the proposed model fit the data well (chi2 = 11.02 [(5, N = 251), p < .05, CFI = .999, NNFI = .991, RMSEA = .069]). An alternative model emerged from the data analysis. DISCUSSION: Nurses may practice more professionally when the environment provides opportunities and power through resources, support, and information. Self-efficacy may contribute to professional practice behaviors, especially in an environment that has the requisite factors that provide empowerment. PMID- 20859102 TI - Perceived effects of specialty nurse certification: a review of the literature. AB - Recent evidence suggests that specialty nurse education and certification may improve the quality of patient care. Specialty nurse certification also may improve nurses' job satisfaction and sense of empowerment, as well as positively affect collaboration with other health care team members. Despite the evidence that there are intrinsic rewards for specialty certification, the lack of extrinsic value to nurses makes it unlikely that greater numbers of nurses will be attracted to certification unless health care administrators increase opportunities for recognition and greater compensation. PMID- 20859103 TI - Perioperative nurses and patient outcomes: mortality, complications, and length of stay. AB - The purpose of the study described in this article was to identify the relationship between RN staffing factors in the OR and surgical patient outcomes. The study addressed two main questions: whether the level of RN staffing in the OR is related to postoperative complications, mortality, and length of stay (LOS) and whether certification, RN agency use, 24-hour staffing, and the performance of multi-disciplinary code drills are related to complication mortality, and LOS. According to this study, selected organizational factors in ORs had a significant influence on patient outcomes. PMID- 20859104 TI - Competence and certification of registered nurses and safety of patients in intensive care units. AB - BACKGROUND: Adverse events that place patients at risk for harm are common in intensive care units. Clinicians' level of knowledge and judgment appear to play a role in the prevention, mitigation, and creation of adverse advents. Research suggests a possible association between nurses' specialty certification and clinical expertise. The relationship between specialty certification and clinical competence of registered nurses and safety of patients is a relatively new area of inquiry in nursing. OBJECTIVE: To explore the relationship between the proportion of certified staff nurses in a unit and risk of harm to patients. METHODS: Hierarchical linear modeling was used in a secondary data analysis of 48 intensive care units from a random sample of 29 hospitals to examine the relationships between unit certification rates, organizational nursing characteristics(magnet status, staffing, education, and experience), and rates of medication administration errors, falls, skin breakdown,and 3 types of nosocomial infections. Medicare case mix index was used to adjust for patient risk. RESULTS: Unit proportion of certified staff registered nurses was inversely related to rate of falls, and total hours of nursing care was positively related to medication administration errors. The mean number of years of experience of registered nurses in the unit was inversely related to frequency of urinary tract infections; however, the small sample size requires that caution be exercised when interpreting results. CONCLUSIONS: Specialty certification and competence of registered nurses are related to patients' safety. Further research on this relationship is needed. PMID- 20859105 TI - Countering side effects. PMID- 20859106 TI - The adjunctive use of metformin to treat or prevent atypical antipsychotic induced weight gain: a review. AB - Patients with schizophrenia have a greater incidence of being overweight or obese compared with the general population. Such individuals are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidemia, and other metabolic derangements. As a result, frequent monitoring of weight and other metabolic parameters is recommended. In addition, several pharmacologic strategies to help prevent or reduce SGA-induced weight gain have been proposed. Despite this, clinicians often struggle to manage obesity and metabolic issues in such patients. Metformin has attracted attention as a potential treatment option because it is thought to result in weight reduction and improved glycemic control in obese patients with and without type 2 diabetes mellitus. This article focuses on relevant pharmacologic aspects of metformin and reviews currently available evidence on the use of metformin as an augmentation agent for the treatment or prevention of SGA-induced weight gain. PMID- 20859107 TI - Improving marital quality in women with medical illness: integration of evidence based programs into clinical practice. AB - Good marital quality (MQ) is associated with better outcomes in many medical illnesses, especially for women. However, improved outcome is only apparent when MQ is measured across a range of marital functioning and when it is statistically described as either good or poor functioning. This article describes the biological processes that have been shown to underlie this relationship and reviews the influence of MQ on patient outcomes in cardiovascular disease. Studies of interventions to improve MQ vary in level of sophistication, depending on the skill of the provider. This article describes successful evidence-based interventions and the skill sets associated with those interventions. In daily clinical practice, psychiatrists can assess MQ by using the Global Assessment of Relational Functioning (GARF) scale and by asking questions about several dimensions of functioning. Understanding how to apply findings from family research concerning outcomes of medical illness is especially important for psychiatrists who practice psychosomatic medicine. This article outlines how such findings can be applied in clinical practice. PMID- 20859108 TI - Strategies for addressing adherence problems in patients with serious and persistent mental illness: recommendations from the expert consensus guidelines. AB - Poor adherence to medication can have devastating consequences for patients with serious mental illness. The literature review and recommendations in this article are reprinted from The Expert Consensus Guideline Series: Adherence Problems in Patients with Serious and Persistent Mental Illness, published in 2009. The expert consensus survey (39 questions, 521 options) on adherence problems in schizophrenia and bipolar disorder was completed by 41 experts in 2008. This article first reviews the literature on interventions aimed at improving adherence. It then presents the experts' recommendations for targeting factors that can contribute to nonadherence and relates them to the literature. The following psychosocial/programmatic and pharmacologic interventions were rated first line for specific problems that can lead to nonadherence: ongoing symptom/ side-effect monitoring for persistent symptoms or side effects; services targeting logistic problems; medication monitoring/environmental supports (e.g., Cognitive Adaptation Training, assertive community treatment) for lack of routines or cognitive deficits; and adjusting the dose or switching to a different oral antipsychotic for persistent side effects (also high second-line for persistent symptoms). Among pharmacologic interventions, the experts gave high second-line ratings to switching to a long-acting antipsychotic when lack of insight, substance use, persistent symptoms, logistic problems, lack of routines, or lack of family/ social support interfere with adherence and to simplifying the treatment regimen when logistic problems, lack of routines, cognitive deficits, or lack of family/social support interfere with adherence. Psychosocial/programmatic interventions that received high second-line ratings in a number of situations included medication monitoring/environmental supports, patient psychoeducation, more frequent and/or longer visits if possible, cognitive behavioral therapy (CBT), family-focused therapy, and services targeting logistic problems. It is important to identify specific factors that may be contributing to a patient's adherence problems in order to customize interventions and to consider using a multifaceted approach since multiple problems may be involved. PMID- 20859109 TI - Clozapine treatment causes oxidation of proteins involved in energy metabolism in lymphoblastoid cells: a possible mechanism for antipsychotic-induced metabolic alterations. AB - There is increasing concern about the serious metabolic side effects and neurotoxicity caused by atypical (second-generation) antipsychotics. In a previous study by our group (Walss-Bass et al. Int J Neuropsychopharmacol 2008;11:1097-104), using a novel proteomic approach, we showed that clozapine treatment in SKNSH cells induces oxidation of proteins involved in energy metabolism, leading us to hypothesize that protein oxidation could be a mechanism by which atypical antipsychotics increase the risk for metabolic alterations. In this study, the same proteomic approach was used to identify specific proteins oxidized after clozapine treatment in lymphoblastoid cell lines from patients with schizophrenia and normal controls. Cells were treated with 0 and 20 MUM clozapine for 24 hours and protein extracts were labeled with 6-iodoacetamide fluorescein (6-IAF). The lack of incorporation of 6-IAF into the thiol group of cysteine residues is an indicator of protein oxidation. Labeled proteins were exposed to two dimensional electrophoresis, and differential protein labeling was assessed. Increased oxidation after clozapine treatment was observed in 9 protein spots (P<0.05). The following 7 proteins were identified by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) in those 9 spots: enolase, triosephosphate isomerase (TPI), glyceraldehyde 3-phosphate dehydrogenase (GAPD), Rho GDP dissociation inhibitor (GDI), cofilin, uridine monophosphate/ cytidine monophosphate (UMP-CMP) kinase, and translation elongation factor. Several of these proteins play important roles in energy metabolism and mitochondrial function. These results further support the hypothesis that oxidative stress may be a mechanism by which antipsychotics increase the risk of metabolic syndrome and diabetes. PMID- 20859110 TI - CNS drug development. Part I: The early period of CNS drugs. AB - This column begins a new series on central nervous system (CNS) drug development. This series will review developments up to the present day and end with a forward looking perspective on what to expect over the next 10-20 years. The goal of this series is to explain to practicing clinicians how drugs are developed and why CNS drug development is at an important juncture involving both significant challenges and opportunities. This column (Part 1) reviews the history of CNS drug development from the period before written history through the golden era (i.e., late 1940s-early 1960s) in which the first modern medications for anxiety, bipolar, depressive, and psychotic disorders were discovered by chance. It also describes the early era of rational drug development in which other agents (e.g., thioridazine, fluphenazine, haloperidol, imipramine) were developed based on those first agents. The blueprint laid down for development of antibiotics is reviewed in relation to its impact on CNS drug development. The impact of the blockbuster business model and modern marketing/sales approaches on CNS drug development is also discussed. PMID- 20859111 TI - Patients who shock us. AB - When psychiatrists talk with patients, they occasionally encounter a patient who shocks them with a point of view that is radically different from their own. It is a challenge to one's professional role and therapeutic intentions, and it may seem provocative. Using two hypothetical case examples, the author explores how one responds at the moment of encounter and in subsequent therapeutic work. Starting with addressing the prevailing affect and the importance of maintaining the therapeutic relationship, efforts to identify defenses and deeper concerns may then lead to insight, relief, and greater mastery. Throughout the clinical work run elements of transference and counter-transference, including the patient's multi-layered motivations for shocking the doctor. Consultation may be valuable in this situation. On the rare occasion of fundamental incompatibility, it may be best to refer the patient to another therapist. PMID- 20859113 TI - A biopsychosocial approach to improving quality of life in tardive dystonia. AB - Tardive dystonia is a potential side effect of antipsychotic medications and certain other dopamine antagonists. It is characterized by sustained muscle contractions that lead to abnormal postures and movements. It is generally a permanent side effect that has a significant impact on a patient's physical, psychological, and social well-being, decreasing overall quality of life. The authors present the case of a patient with severe tardive dystonia due to metoclopramide that illustrates the profound physical, psychological, and social impact of this condition. It is important for clinicians to be knowledgeable about tardive dystonia so that they can take active steps to prevent its development and have a positive impact on its prognosis when it does develop by recognizing the condition early. Treatment of tardive dystonia should follow a biopsychosocial approach that combines an array of treatment modalities, depending on the individual presentation. Incorporating a quality of life questionnaire specific to dystonia into clinical practice can help clinicians tailor care to the needs of the individual patient. PMID- 20859114 TI - Reducing seclusion and restraint: questionnaire for organizational assessment. AB - Mental health organizations that have successfully reduced or, in some cases, eliminated use of seclusion and restraint report that they have primarily focused on organizational factors to facilitate this process. The purpose of this paper is to describe the development of an instrument that measures staff perceptions of organizational activities to reduce seclusion and restraint as well as staff attitudes toward the use of these interventions. Consequently, the instrument can be used diagnostically to identify areas in need of improvement and can also be used as an outcome measure to assess shifts in staff perceptions reflective of organizational change. This article describes validation of the instrument, information on its administration, and analysis and use of data obtained with it. PMID- 20859115 TI - Epithelial tumors of the thymic gland are rare malignancies. Foreword. PMID- 20859116 TI - Epidemiology of thymoma and associated malignancies. AB - BACKGROUND: Thymoma is a rare malignancy of unknown etiology. METHODS: The author examined patterns in thymoma incidence in the US general population using data from Surveillance, Epidemiology, and End Results (SEER) cancer registries. Prior studies concerning the risk of additional malignancies in thymoma patients were reviewed. RESULTS: Based on cancer registry data, the overall incidence of thymoma in the US is 0.13 per 100,000 person-years. Thymoma is exceedingly uncommon in children and young adults, rises in incidence in middle age, and peaks in the seventh decade of life. Thymoma incidence is especially high among Asians and Pacific Islanders in the US. While several studies based at single treatment centers have suggested that thymoma patients have a broadly increased risk for other malignancies, follow up data from US cancer registries support a more limited spectrum of cancer risk. In particular, thymoma patients have a subsequently elevated risk for developing B-cell non-Hodgkin's lymphoma. Based on limited data, thymoma patients may also have an elevated risk for developing soft tissue sarcomas. DISCUSSION: Thymoma is a rare malignancy. The excess risk for non-Hodgkin's lymphoma is consistent with an effect of immune disturbance arising from the thymoma or its treatment. While descriptive epidemiologic data may yield clues to the etiology of thymoma, large multi-center case-control studies will be required to formally evaluate environmental and genetic risk factors. PMID- 20859117 TI - The autoimmune regulator AIRE in thymoma biology: autoimmunity and beyond. AB - Thymomas are tumors of thymic epithelial cells. They associate more often than any other human tumors with various autoimmune diseases; myasthenia gravis is the commonest, occurring in 10-50% of thymoma patients, depending on the World Health Organization-defined histologic subtype. Most thymomas generate many polyclonal maturing T lymphocytes but in disorganized microenvironments Failure to induce self-tolerance may be a key factor leading to the export of potentially autoreactive CD4 progeny, thus predisposing to autoimmune diseases. Normally, the master Autoimmune Regulator promotes expression of peripheral tissue-restricted antigens such as insulin by medullary thymic epithelial cells and induction of tolerance to them. The failure of approximately 95% of thymomas to express autoimmune regulator is another feature potentially contributing to autoimmunity. PMID- 20859118 TI - The thymus and the immune system: layered levels of control. AB - Control points of normal thymopoiesis may provide insights into strategies for interrupting cell interactions in thymomas which appear to maintain active T cell production. Thymus production of T cells represents one of two pathways by which peripheral T cell populations are maintained or, if lost, regenerated. The production of T cells by the thymus results from a series of thymus epithelial cell (TEC) - thymocyte interactions from entry of thymocyte precursors into the thymus to release of mature naive single positive T cells into the periphery. Within this series of interactions, certain control points have been identified, all of which act through TEC to modulate thymopoiesis. PMID- 20859119 TI - Caspr2 antibodies in patients with thymomas. AB - Myasthenia gravis is the best known autoimmune disease associated with thymomas, but other conditions can be found in patients with thymic tumors, including some that affect the central nervous system (CNS). We have become particularly interested in patients who have acquired neuromyotonia, the rare Morvan disease, or limbic encephalitis. Neuromyotonia mainly involves the peripheral nerves, Morvan disease affects both the peripheral nervous system and CNS, and limbic encephalitis is specific to the CNS. Many of these patients have voltage-gated potassium channel autoantibodies. All three conditions can be associated with thymomas and may respond to surgical removal of the underlying tumor together with immunotherapies and symptomatic treatments. Herein, we review the results of our recent studies that show that voltage-gated potassium channel autoantibodies are not principally directed against the potassium channels themselves but in some patients are directed against a protein that is complexed with potassium channels in both the peripheral nervous system and CNS, contactin-2 associated protein (Caspr2). These antibodies are common in the subgroup of patients with thymic malignancies. PMID- 20859120 TI - The role of fine needle aspiration cytology in the diagnosis and management of thymic neoplasia. AB - BACKGROUND: Fine needle aspiration biopsy is commonly used to document the metastasis to the mediastinum. It is less often used to make the primary diagnosis of tumors, particularly thymic neoplasms. This is due to fear of sampling error, rarity of thymic tumors, multiplicity of lesions in the mediastinum, and inexperience on the part of the cytopathologist. We show that needle aspiration sampling of thymic tumors, both thymoma and thymic carcinoma, is an accurate method of diagnosis. METHODS AND RESULTS: In our series of 22 thymic tumors aspirated preoperatively and compared with the subsequent surgical resection, the accuracy of a diagnosis of thymoma was 100%, and the accuracy of a diagnosis of carcinoma was 100%. Difficulties were encountered when vague terminology was used, and insufficient information was conveyed. Immunohistochemical stains can be applied to cytologic material to aid in the identification of the epithelial and lymphocytic components of thymoma. DISCUSSION: Correlation with clinical and radiographic information is necessary, and wording of the cytology report should be as complete and clear as possible. PMID- 20859121 TI - Thymoma and thymic carcinoma: molecular pathology and targeted therapy. AB - Thymomas and thymic carcinomas (TC) are rare epithelial tumors of the thymus. Although most thymomas have organotypic features (i.e., resemble the normal thymus), TC are morphologically undistinguishable from carcinomas in other organs. Apart from their different morphology, TC and thymomas differ also in functional terms (TC, in contrast to thymomas, have lost the capacity to promote the maturation of intratumorous lymphocytes), have different genetic features (discussed in this review), a different immunoprofile (most TC overexpress c-KIT, whereas thymomas are consistently negative), and different clinical features (TC, in contrast to thymomas, are not associated with paraneoplastic myasthenia gravis). Thus, although all the data suggest that the biology of thymomas and TC is different, in clinical practice, their therapeutic management up to now is identical. In the age of personalized medicine, the time may have come to think this over. We will briefly review the molecular genetics of malignant thymic tumors, summarize the current status of targeted therapies with an emphasis on the multitargeted kinase inhibitors sunitinib and sorafenib, and try to outline some future directions. PMID- 20859122 TI - Thymic tumors: relevant molecular data in the clinic. AB - INTRODUCTION: Thymic malignancies are rare intrathoracic tumors that may be aggressive and difficult to treat in advanced stage. Over the past years, significant efforts have been conducted to dissect the molecular pathways involved in the carcinogenesis of these tumors. Insights have been made following anecdotal clinical responses to targeted therapies, and large-scale genomic analyses have been conducted. METHODS: Review of the literature, 1990-2010. RESULTS: The Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in thymomas and thymic carcinomas, but EGFR mutations are exceptional, and this does not support the use of EGFR tyrosine kinase inhibitors. On the contrary, single observations of responses create a basis for further evaluation of cetuximab in thymomas. KIT-mutant thymic carcinomas represent a small molecular subset of thymic tumors. The clinical relevance of KIT mutations is more limited in thymic carcinoma than in GIST as KIT mutations are far less frequent (7% of thymic carcinomas) and are not correlated with KIT expression; furthermore, KIT mutants are not uniformly sensitive to imatinib. Beyond EGFR and KIT signaling pathways, other molecular alterations with potential prognostic or predictive relevance are emerging in thymic malignancies. CONCLUSIONS: Given the rarity of these tumors, translation of preclinical findings to the clinic may be quick and represents one of the most promising therapeutic approaches for advanced-stage thymic malignancies. PMID- 20859123 TI - Imaging thymoma. AB - Thymoma is a rare tumor, although it is the most common primary neoplasm of the anterior mediastinum. In the majority of thymoma patients, imaging is requested for investigation of symptoms related to their tumor, although an increasing number of asymptomatic patients are discovered incidentally due to the increased utilization of computed tomography for screening or for imaging of other unrelated diseases. This review will focus on the goals of imaging thymoma, the imaging features of thymoma, as well as the advantages and limitations of each imaging modality in establishing the diagnosis, staging, and prognosis of thymoma. PMID- 20859124 TI - Staging system of thymoma. AB - INTRODUCTION: Thirty years have gone by since the Masaoka staging system of thymoma was proposed in 1981. Although the Masaoka staging system has been accepted by many surgeons and pathologists, some proposals of revision and improvements have been suggested. At this time, I reinvestigated the Masaoka staging system based on the recent follow-up study of the thymomas resected at Nagoya City University. METHODS: Using the follow-up results of 211 thymomas in Nagoya, I analyzed the following aspects: (1) evaluation of the Masaoka staging system as a prognostic factor in the Nagoya series and (2) critical assessment of the proposals of revision to the Masaoka staging system. RESULTS: (1) Univariate analysis showed that Masaoka stages were significantly prognostic for overall survival (p < 0.0001). (2) The difference of survivals between stage I and II was not significant, but progression-free survival of stage I was 100% for up to 20 years, whereas one tumor death case in stage II was found. (3) Differences of survival between the cases with and without great vessel invasion in stage III were not significant. (4) Prognosis of N tumors was yet better defined. CONCLUSION: (1) The Masaoka staging system remains a valuable prognostic factor. (2) Combination of stage I with II and separation of stage III into subgroups are not recommended. (3) At the moment, it is better to include N tumors in stage IVb. PMID- 20859125 TI - The multidisciplinary approach to thymoma: combining molecular and clinical approaches. AB - Thymomas are rare epithelial tumors that display significant heterogeneity. Thymomas are usually indolent; however, thymic carcinomas are typically invasive with a high risk of relapse and death. Current treatment approaches are primarily based on clinical stage. Surgery is the mainstay for treatment of early stage disease, whereas multimodality therapy is required for advanced disease. The most important prognostic factors are stage and histology; however, increasing recognition of disease heterogeneity has led to recent exploration of underlying molecular mechanisms. Molecular characterization of thymic tumors may offer strategies to improve diagnosis, therapy, and prognosis. This article describes recently identified molecular characteristics of thymoma and thymic carcinoma that may potentially impact disease classification, targeted therapeutic decision making, and design of future clinical trials. PMID- 20859126 TI - Evaluation and treatment of stage I and II thymoma. AB - Thymomas are relatively uncommon. Nevertheless, an accumulation of studies (mostly retrospective, single-institution series) have made it important to approach this disease in a knowledgeable, evidence-based fashion. This begins with the approach to evaluation of a patient with an anterior mediastinal mass, in whom a reliable clinical diagnosis is usually possible in experienced centers. Surgical resection is the mainstay of treatment, and every effort must be made to achieve a complete resection. PMID- 20859127 TI - Induction therapy for locally advanced thymoma. AB - Thymomas are the most frequently encountered tumors of the mediastinum and often present with either localized or locally advanced disease. The prognosis in thymoma has been consistently shown to correspond to the invasiveness of the tumor (as represented by the Masaoka stage of the tumor) and the completeness of surgical resection. Because treatment with a variety of different chemotherapy regimens has demonstrated radiographic response rates greater than 50% in patients with advanced thymoma, a number of investigators have explored the use of preoperative (induction, neoadjuvant) therapy for patients with locally advanced thymoma. In this review, we summarize the published experience with preoperative therapy for thymoma and discuss ongoing clinical trials exploring multimodality therapy for treatment of locally advanced thymoma. PMID- 20859129 TI - Technical advances of radiation therapy for thymic malignancies. AB - Radiation therapy often plays a critical role in the treatment of thymic malignancies. However, because of the location of these tumors, historically patients have been at a significant risk for radiation-related toxicity such as pericardial effusions, radiation pneumonitis, long-term pulmonary fibrosis, and occasional long-term esophageal stricture, particularly for unresectable thymoma. Recent advancements in technology have provided the treating radiation oncologist with the ability to more accurately target the region at risk while sparing normal structures. In this review, we provide an overview of key advances in radiation techniques for thymoma over the past two decades. These techniques include 3D conformal therapy, intensity-modulated radiation therapy, 4D treatment planning, adaptive radiation therapy, and proton therapy. Each advancement has brought with it unique advantages in maintaining long-term disease control while improving quality of life in this manageable disease. PMID- 20859128 TI - Radiotherapy for thymic neoplasms. AB - The role of radiotherapy in the treatment of thymoma and thymic carcinoma has been evaluated by many investigators over the past two decades. The low incidence of these neoplasms has limited most published studies to small series spanning long time intervals or population-based studies. The exact indications and protocols for the use of radiotherapy as a part of the multidisciplinary approach to thymoma and thymic carcinoma are still unclear. However, a review of recent literature shows potential benefits for certain patients based on stage and grade of disease as well as the extent of surgical resection. PMID- 20859130 TI - Extended resections for thymic malignancies. AB - Almost all series reporting on the results of resection in thymic tumors indicate that the performance of a complete resection is probably the most important prognostic factor. This issue is not a factor in Masaoka stage I and II tumors that are almost always easily completely resected and have an excellent prognosis. Masaoka stage III tumors that invade the pericardium, lungs, or great vessels have relatively higher incomplete resection rates, significantly higher recurrence rates, and thus a worse prognosis. There are several small reports on the efficacy of resection of the great veins when involved by a thymic malignancy with low morbidity and meaningful long-term survival. Superior vena cava reconstruction is commonly performed by a polytetrafluroethylene, venous, or pericardial graft. These cases can usually be identified preoperatively and, thus, considered for induction therapy. Because these types of cases are almost always of marginal respectability in terms of obtaining a true en bloc resection, there is an increasing enthusiasm for offering induction therapy in an effort to enhance resectability. Preliminary results suggest increased R0 resection rates and improved survival with induction therapy for locally advanced tumors. The optimal induction treatment is unknown. The ultimate extended surgery for advanced thymic tumors is an extrapleural pneumonectomy performed for extensive pleural disease (Masaoka stage IVA). These rarely performed operations are done for IVA disease found at initial presentation and for recurrent disease as a salvage procedure. Again these advanced patients are probably best managed by induction chemotherapy followed by resection. PMID- 20859131 TI - Surgical treatment of recurrent thymomas. AB - Thymomas are neoplasms arising from the epithelial thymic cells, with a recurrence rate after complete resection ranging from 5 to 50%, according to the initial stage of disease. The pleura is the most frequent site of relapse, while distant metastases occur in less than 5% of the cases. Data in the literature show that recurrences can occur several years after the resection of a thymoma; unfortunately, few reports have analyzed the treatment of recurrences of thymoma. There is no standard treatment for the recurrent disease, and most of the treatments proposed by the authors are based more on their personal experience and individualized treatment than on an evidence-based method. Moreover, most series concerning surgery for recurrent thymomas suffer from a selection bias: patients with limited disease and better performance status are usually selected for surgery, with an anticipated survival advantage in the surgical group. Surgery for recurrent thymoma is indicated if complete resection is feasible, whereas in the case of predicted debulking surgery, it may be considered as part of a multidisciplinary protocol. In the literature, a few case reports of the surgical treatment of metachronous distant metastases to liver or brain from thymoma have been described, but they are really rare, and a decision about their treatment is always on a single patient basis. We can conclude that reoperation for thymoma recurrences is feasible and relatively safe, and it should always be considered because the other treatment modalities are not curative. PMID- 20859132 TI - Tumor-node metastasis staging system for thymic epithelial tumors. AB - BACKGROUND: The Masaoka clinical staging classification is the most widely accepted nowadays and is an excellent predictor for the prognosis of thymoma. Nevertheless, an update of this classification is desirable for it to be suitable for all thymic epithelial tumors including thymic carcinoma and carcinoid. The tumor-node metastasis (TNM) system classification and clinical staging system for thymic epithelial tumors have not been established yet. Until now, four TNM staging systems have been proposed: Yamakawa and Masaoka in 1991 (Y-M system), Tsuchiya et al. in National Cancer Center Hospital of Japan in 1994 (NCCHJ system), the World Health Organization Consensus Committee in 2004 (World Health Organization system), and Bedini et al. in National Cancer Institute of Italy in 2005 (NCII system). METHODS: In this study, we show survival curves of thymic epithelial tumors (n = 1320) including thymoma, thymic carcinoma, and carcinoid according to the Y-M system. RESULTS: The 5-year overall survival rates of stage I, II, III, IVA, and IVB thymic epithelial tumors were 94.2%, 91.2%, 70.5%, 56.3%, and 38.2%, respectively. Significant differences in survival rates were observed between stages II and III (p < 0.0001), stages III and IVA (p = 0.0205), and stages IVA and IVB (p = 0.0192). DISCUSSION: This TNM staging system is an excellent predictor for the prognosis of thymic epithelial tumors including thymic carcinoma. The N and/or M factors influence the prognosis more than T factor. For the subclassification of the N and/or M factors, large-scale studies including the resectable and unresectable tumors are necessary. PMID- 20859133 TI - The role of chemotherapy in advanced thymoma. AB - BACKGROUND: Thymoma and thymic carcinomas are rare malignancies. Most thymomas and about one-third of thymic carcinomas can be cured with local therapy. The remainder of will be candidates for systemic therapy. Numerous retrospective trials confirm objective responses to a variety of single-agent and combination chemotherapeutic regimens. METHODS: No prospective randomized comparison of regimens has been performed because of the rarity of the disease. This paper reviewed the literature of chemotherapy in advanced thymic malignancies. RESULTS: Existing data suggest that anthracycline plus cisplatin regimens seem to demonstrate higher response rates and perhaps longer median survival times compared with nonanthracycline-containing regimens. DISCUSSION: Thymic malignancies are sensitive to a broad spectrum of systemic agents. Thymic carcinoma has a distinct clinical presentation and worse therapeutic outcomes than thymoma. Despite reproducible high response rates in thymoma, durable complete remissions are rare. Thus, novel new therapeutic targets need to be identified and appropriate agents developed to have further impact on this disease. PMID- 20859134 TI - Targeted therapy for advanced thymic tumors. AB - The use of targeted therapies for the treatment of thymic malignancies is documented in the literature. However, only a few drugs have undergone evaluation in phase II trials. Most of the evidence for the benefit of biologic therapies for thymic malignancies is in the form of case reports and small case series. No major activity has been observed with any agent so far, likely due to the lack of selection of patients for targeted therapies and the small numbers studied. A better understanding of the biology of these tumors will be essential in furthering the field. PMID- 20859135 TI - International thymic malignancies interest group: a way forward. PMID- 20859136 TI - Nursing home report cards. PMID- 20859138 TI - Response to Nurse staffing and quality of care with direct measurement of inpatient staffing. PMID- 20859140 TI - Nuchal translucency quality monitoring: the transition from research to clinical care. PMID- 20859141 TI - Endometrial ablation: what counts? PMID- 20859142 TI - Tort reform: why is it so frequently unobtainable? PMID- 20859143 TI - Undermeasurement of nuchal translucencies: implications for screening. AB - OBJECTIVE: To analyze the maximum nuchal translucency from 327 centers to determine whether a more-than-expected number of centers had maximum nuchal translucency of 2.5 mm or less (approximately 4% of nuchal translucency values should be 2.5 mm or higher). METHODS: We analyzed data from 182,669 nuchal translucency cases at centers in which at least 100 nuchal translucency examinations were performed from July 2008 through June 2009 and investigated the appropriateness of the distribution of values. We then investigated the likelihood of the skewing of the distribution seen using a 100 simulations of such modeled data. RESULTS: Based on a binomial distribution, the chance that a center would have no nuchal translucency values above 2.5 mm is 1.7% for 100 patients per center, and 0.2% for 150 patients per center. Additionally, the median multiples of the median should shift by approximately 2.5% if all nuchal translucency values higher than 2.5 mm are excluded from the population. Our data show that 7.3% of centers had a maximum nuchal translucency of to 2.5 mm or less, and more than 20% have never reported an nuchal translucency of greater than 3 mm. The maximum nuchal translucency at a center correlated positively with its median multiple of the median. Centers with no nuchal translucency values greater than 2.5 mm also have nearly 50% of their ultrasonographers with excessive low nuchal translucency (greater than 10% of cases less than fifth percentile). CONCLUSION: Too many centers have a maximum nuchal translucency of 2.5 mm or lower, low median nuchal translucency, and excessive low nuchal translucency, indicating that data from these centers are not representative of the expected distribution of nuchal translucencies. Our data suggest a systematic undermeasurement of nuchal translucency. LEVEL OF EVIDENCE: III. PMID- 20859144 TI - Bipolar radiofrequency endometrial ablation compared with hydrothermablation for dysfunctional uterine bleeding: a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of two second-generation ablation techniques, bipolar radiofrequency impedance-controlled endometrial ablation and hydrothermablation, in the treatment of menorrhagia. METHODS: This study was a double-blind, randomized controlled trial, which took place in a large teaching hospital in The Netherlands with 500 beds. Women with menorrhagia were randomly allocated to bipolar radiofrequency ablation (bipolar group) and hydrothermablation (hydrotherm group). At follow-up, both women and observers remained unaware of the type of treatment that had been performed. The primary outcome was amenorrhea. Secondary outcome measures were patient satisfaction and reintervention. RESULTS: We included 160 women in the study, of which 82 were allocated to the bipolar group and 78 to the hydrotherm group. No complications occurred in either of the treatment groups. After 12 months, 87% (65 of 75) of the patients in the bipolar group were completely satisfied with the result of the treatment compared with 68% (48 of 71) in the hydrotherm group (relative risk 1.3, 95% confidence interval [CI] 1.03-1.6). The amenorrhea rates were 47% (35 of 75) in the bipolar group and 24% (17 of 71) in the hydrotherm group (relative risk 2.0, 95% CI 1.2-3.1). The relative risks for a reintervention in the bipolar group compared with the hydrotherm group was 0.29 (95% CI 0.12-0.67), whereas for hysterectomy, this was 0.49 (95% CI 0.15-1.5). CONCLUSION: In the treatment of menorrhagia, bipolar radiofrequency endometrial ablation system is superior to hydrothermablation. CLINICAL TRIAL REGISTRATION: ISRCTN Register, www.isrctn.org, ISRCTN23845359. LEVEL OF EVIDENCE: I. PMID- 20859145 TI - Screening for prenatal substance use: development of the Substance Use Risk Profile-Pregnancy scale. AB - OBJECTIVE: To report on the development of a questionnaire to screen for hazardous substance use in pregnant women and to compare the performance of the questionnaire with other drug and alcohol measures. METHODS: Pregnant women were administered a modified TWEAK (Tolerance, Worried, Eye-openers, Amnesia, K[C] Cut Down) questionnaire, the 4Ps Plus questionnaire, items from the Addiction Severity Index, and two questions about domestic violence (N=2,684). The sample was divided into "training" (n=1,610) and "validation" (n=1,074) subsamples. We applied recursive partitioning class analysis to the responses from individuals in the training subsample that resulted in a three-item Substance Use Risk Profile-Pregnancy scale. We examined sensitivity, specificity, and the fit of logistic regression models in the validation subsample to compare the performance of the Substance Use Risk Profile-Pregnancy scale with the modified TWEAK and various scoring algorithms of the 4Ps. RESULTS: The Substance Use Risk Profile Pregnancy scale is comprised of three informative questions that can be scored for high- or low-risk populations. The Substance Use Risk Profile-Pregnancy scale algorithm for low-risk populations was mostly highly predictive of substance use in the validation subsample (Akaike's Information Criterion=579.75, Nagelkerke R=0.27) with high sensitivity (91%) and adequate specificity (67%). The high-risk algorithm had lower sensitivity (57%) but higher specificity (88%). CONCLUSION: The Substance Use Risk Profile-Pregnancy scale is simple and flexible with good sensitivity and specificity. The Substance Use Risk Profile-Pregnancy scale can potentially detect a range of substances that may be abused. Clinicians need to further assess women with a positive screen to identify those who require treatment for alcohol or illicit substance use in pregnancy. LEVEL OF EVIDENCE: III. PMID- 20859146 TI - Effectiveness of timing strategies for delivery of individuals with placenta previa and accreta. AB - OBJECTIVE: To compare strategies for the timing of delivery in individuals with placenta previa and ultrasonographic evidence of placenta accreta, and to determine the optimal gestational age at which to deliver individuals. METHODS: A decision tree was designed comparing nine strategies for delivery timing in an individual with placenta previa and ultrasonographic evidence of placenta accreta. The strategies ranged from a scheduled delivery at 34, 35, 36, 37, 38, or 39 weeks of gestation to a scheduled delivery at 36, 37, or 38 weeks of gestation only after amniocentesis confirmation of fetal lung maturity. Outcomes factored into the model included maternal intensive care unit admission, perinatal mortality, infant mortality, respiratory distress syndrome, mental retardation, and cerebral palsy. RESULTS: A scheduled delivery at 34 weeks of gestation was the preferred strategy and resulted in the highest quality-adjusted life years under the base case assumptions. Strategies awaiting confirmation of fetal lung maturity failed to result in better outcome than strategies that delivered at the corresponding gestational age without amniocentesis. After sensitivity analyses, delivery at 37 weeks of gestation without amniocentesis was the preferred strategy in limited situations, and delivery at 39 weeks of gestation was the preferred strategy only in unlikely situations. CONCLUSION: This decision analysis suggests the preferred strategy for timing of delivery in individuals with ultrasonographic evidence of placenta previa and placenta accreta under a variety of circumstances is delivery at 34 weeks of gestation. At any given gestational age, incorporating amniocentesis for verification of fetal lung maturity does not assist in the management of such individuals. LEVEL OF EVIDENCE: III. PMID- 20859147 TI - Single umbilical artery risk factors and pregnancy outcomes. AB - OBJECTIVE: To identify risk factors for fetuses and neonates with single umbilical artery and isolated single umbilical artery (single umbilical artery in the absence of chromosomal abnormalities and structural abnormalities) and to assess whether there is an increased risk for complications during pregnancy, labor, and delivery, and for perinatal morbidity and mortality. METHODS: A population-based retrospective cohort analysis of deliveries in Nova Scotia, Canada, between 1980 and 2002 was conducted using the Nova Scotia Atlee Perinatal Database. Risk factors and outcomes for single umbilical artery and isolated single umbilical artery pregnancies were compared with three-vessel-cord pregnancies. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each outcome using multiple logistic regression to adjust for confounding factors. Separate models were run for single umbilical artery and isolated single umbilical artery. RESULTS: There were 203,240 fetuses and neonates available for analysis, with 885 (0.44%) having single umbilical artery and 725 (0.37%) having isolated single umbilical artery. Single umbilical artery fetuses and neonates had a 6.77 times greater risk of congenital anomalies and 15.35 times greater risk of chromosomal abnormalities. The most common congenital anomalies in chromosomally normal fetuses and neonates were genitourinary (6.48%), followed by cardiovascular (6.25%) and musculoskeletal (5.44%). For isolated single umbilical artery, placental abnormalities (OR 3.63, 95% CI 3.01-4.39), hydramnios (OR 2.80, 95% CI 1.42-5.49), and amniocentesis (OR 2.52, 95% CI 1.82-3.51) occurred more frequently than with three vessel cords. Neonates with single umbilical artery and isolated single umbilical artery had increased rates of prematurity, growth restriction, and adverse neonatal outcomes. CONCLUSION: Fetuses and neonates with single umbilical artery and isolated single umbilical artery are at increased risk for adverse outcomes. Identification of single umbilical artery is important for prenatal diagnosis of congenital anomalies and aneuploidy. Increased surveillance with isolated single umbilical artery may improve pregnancy outcomes. LEVEL OF EVIDENCE: II. PMID- 20859148 TI - Childhood cardiac function after severe maternal red cell isoimmunization. AB - OBJECTIVE: To estimate the long-term effects of anemia on the fetal heart by echocardiography of children who received intrauterine blood transfusions for red cell isoimmunization. METHODS: Surviving children who received intrauterine transfusions during the period from 1992 to 2003 were identified. Children matched for age and sex were chosen for the control group to create a 1:1 case control study design. A clinical interview, physical examination, and echocardiography assessment (corrected for body surface area) were performed. RESULTS: Twenty-five children were recruited for the case group and matched to 25 healthy children for the control group. Children in the case group had received a median of four intrauterine transfusion procedures (range 1-7), with a median gestation at initial intrauterine transfusion of 28 weeks (range 22-34 weeks). Hydrops was present in 32%. Median initial hemoglobin was 76 g/L (range 25-133 g/L). Median gestation at delivery was 36 weeks (range 29-38 weeks). The median age of children in the case group was 10.1 years (range 3.6-15.8 years) and of those in the control group was 10.5 years (range 3.8-16.4 years; P=.122). There was no difference in body surface area, baseline heart rate, systolic blood pressure, or diastolic blood pressure between children in the case group and those in the control group. Echocardiography demonstrated three main differences: children in the case group had 9% less left atrial area (95% confidence interval [CI] 2-16% less; P=.02), 10% less ventricular mass (95% CI 1-19% less; P=.039), and an average 11 ms less mitral valve atrial duration (95% CI 3-19 ms less; P=.009) than did those in the control group. These results did not alter when adjusted for isoimmunization severity. CONCLUSION: Fetal anemia secondary to red cell isoimmunization is associated with a reduction in left ventricular mass and left atrial area in childhood, although resting ventricular function is maintained. We speculate this may be secondary to the prenatal effects of anemia on cardiomyocyte proliferation and differentiation. LEVEL OF EVIDENCE: III. PMID- 20859149 TI - Maternal pregnancy-related hypertension and risk for hypertension in offspring later in life. AB - OBJECTIVE: To estimate the association between maternal pregnancy-related hypertension and offspring hypertension later in life in a birth cohort from New England. METHODS: Covariate and exposure data were collected between 1959 and 1966 through the Collaborative Perinatal Project. Follow-up information was obtained through the New England Family Study between 2001 and 2004, when study participants were between 34 and 44 years old. The study population consisted of 1,556 individuals. Participants who reported having hypertension diagnosed at least once were considered to have hypertension. Logistic regression was used to estimate the association between maternal pregnancy-related hypertension and offspring hypertension later in life. Results were adjusted for sex, maternal race, maternal body mass index, maternal socioeconomic status, maternal diabetes, and twin pregnancy. RESULTS: Maternal pregnancy-related hypertension was associated with an increased risk of being prescribed antihypertensives compared with never having hypertension diagnosed (from 8.8% to 17.4%; adjusted odds ratio 1.88, 95% confidence interval 1.00-3.55). The association was not attenuated after adjustment for birth weight or preterm delivery. After excluding offspring of women who reported hypertension during pregnancy only, this association increased to an adjusted odds ratio of 1.97 (95% confidence interval 1.04-3.72). CONCLUSION: In a birth cohort from New England, maternal pregnancy-related hypertension was associated with hypertension in offspring later in life. LEVEL OF EVIDENCE: II. PMID- 20859150 TI - Tranexamic acid treatment for heavy menstrual bleeding: a randomized controlled trial. AB - OBJECTIVE: To assess the efficacy and safety of an oral formulation of tranexamic acid for the treatment of heavy menstrual bleeding. METHODS: Adult women with heavy menstrual bleeding (mean menstrual blood loss 80 mL or more per cycle) were enrolled in a double-blind, placebo-controlled study. After two pretreatment menstrual cycles, women were randomized to receive tranexamic acid 3.9 g/d or placebo for up to 5 days per menstrual cycle through six cycles. To meet the prespecified three-component primary efficacy end point, mean reduction in menstrual blood loss from baseline with tranexamic acid treatment needed to be 1) significantly greater than placebo, 2) greater than 50 mL, and 3) greater than a predetermined meaningful threshold (36 mL or higher). Health-related quality of life was measured using a validated patient-reported outcome instrument. RESULTS: Women who received tranexamic acid (n=115) met all three primary efficacy end points: first, a significantly greater reduction in menstrual blood loss of -69.6 mL (40.4%) compared with -12.6 mL (8.2%) in the 72 women who received placebo (P<.001); reduction of menstrual blood loss exceeding a prespecified 50 mL; and last, reduction of menstrual blood loss considered meaningful to women. Compared with women receiving placebo, women treated with tranexamic acid experienced significant improvements in limitations in social or leisure and physical activities, work inside and outside the home, and self-perceived menstrual blood loss (P<.01). The majority of adverse events were mild to moderate in severity, and the incidence of gastrointestinal adverse events was comparable with placebo. CONCLUSION: In this study, a new oral tranexamic acid treatment was well tolerated and significantly improved both menstrual blood loss and health-related quality of life in women with heavy menstrual bleeding. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00386308. LEVEL OF EVIDENCE: I. PMID- 20859151 TI - Endometrial safety of ultra-low-dose estradiol vaginal tablets. AB - OBJECTIVE: To evaluate the endometrial hyperplasia and carcinoma rate after 52 week treatment with ultra-low-dose 10-microgram 17beta-estradiol vaginal tablets in postmenopausal women with vaginal atrophy. METHODS: Endometrial biopsy data from individuals using active treatment (n=205) in a randomized, double-blind, placebo-controlled trial were pooled with the data from an open-label endometrial safety trial (n=336). Patients received 10-microgram estradiol vaginal tablets for 52 weeks. All endometrial biopsy samples were histologically analyzed at baseline and at end of trial by the same laboratory in both trials. RESULTS: A total of 541 women using estradiol were included in the combined analysis of endometrial safety. A total of 456 women completed the trials, and 443 women had a biopsy performed at week 52: 85.6% were categorized as "atrophic endometrium," 12.6% had nonevaluable biopsy samples, 1.1% had polyps, and 0.2% were categorized as "weakly proliferative." One case of complex hyperplasia without atypia was reported in an individual exposed to trial drug for only 9 days. One woman's biopsy sample demonstrated endometrioid adenocarcinoma, grade 2, but the lack of an evaluable screening biopsy sample makes it uncertain whether the carcinoma was preexisting. In total, two events of hyperplasia and carcinoma were reported in 386 evaluable biopsy samples (incidence rate 0.52% per year). CONCLUSION: The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women is 0% to 1%. The results of this pooled analysis therefore support the endometrial safety of unopposed ultra-low-dose vaginal estrogen. There was no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram estradiol vaginal tablets for 1 year under study conditions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748). LEVEL OF EVIDENCE: II. PMID- 20859152 TI - Overexpression of karyopherin-2 in epithelial ovarian cancer and correlation with poor prognosis. AB - OBJECTIVES: To evaluate karyopherin 2 (KPNA2) as a biomarker for epithelial ovarian cancer. METHODS: A candidate oncogene, KPNA2, was identified in gene microarray assays of epithelial ovarian cancer tissues compared with normal human ovarian surface epithelial tissues. Differences in expression were further validated by real-time polymerase chain reaction and Western blotting. KPNA2 expression patterns in epithelial ovarian cancer tissues were determined using immunohistochemistry and were compared with specific clinicopathologic features of the patient specimens analyzed. Factors associated with patient survival were also statistically analyzed. RESULTS: KPNA2 was found to be upregulated approximately eightfold in epithelial ovarian cancer tissues compared with human ovarian surface epithelial tissues, and overexpression was detected at the level of both transcription and translation. Immunohistochemical assays detected positive KPNA2 expression (++ or +++) in 50 of 102 (49.0%) epithelial ovarian cancer specimens, whereas negative KPNA2 expression (- or +) was observed in all of the human ovarian surface epithelial tissues analyzed. KPNA2 overexpression was also found to be significantly associated with specific histologic type, an advanced stage, a high histologic grade, and tumor recurrence (P<.05). The 5-year overall survival rate for KPNA2-negative compared with KPNA2-positive patients was 73.1% and 60.5%, respectively (P<.05). CONCLUSION: KPNA2 may play an important role in the development, differentiation, and carcinogenesis of epithelial ovarian cancer and therefore could be an indicator of poor prognosis for patients with epithelial ovarian cancer. LEVEL OF EVIDENCE: II. PMID- 20859153 TI - Improving continuous wound infusion effectiveness for postoperative analgesia after cesarean delivery: a randomized controlled trial. AB - OBJECTIVE: To evaluate in which anatomical layer (above the fascia or below the fascia) continuous wound infusion of local anesthetic, combined with nonsteroidal antiinflammatory drugs, through a multiorifice catheter has the best effectiveness during the first 48 hours on postoperative pain intensity after elective cesarean delivery. METHODS: Fifty-six women undergoing elective cesarean delivery under spinal anesthesia were randomly allocated to receive 48-hour continuous wound infusion either above the fascia or below the fascia using ropivacaine and ketoprofene through a multiholed wound catheter. No other systemic analgesics were used, except for rescue patient-controlled intravenous morphine. Evaluation by a blinded investigator included visual analog scale scores at rest and at movement, morphine consumption, patient satisfaction, residual pain at 1 and 6 months, and undesirable side effects. RESULTS: Continuous wound infusion below the fascia resulted in significantly reduced pain at rest and total postoperative morphine consumption (15.7 mg, 95% confidence interval 9.7-20.7 mg) compared with wound administration above the fascia (26.4 mg, 95% confidence interval 18.1-34.7). No undesirable side effects or residual pain requiring treatment were recorded in both groups, whereas analgesia and satisfaction were excellent. CONCLUSION: After cesarean delivery, continuous wound infusion over 48 hours with ropivacaine and ketoprofene through a multiholed wound catheter inserted below the fascia results in better analgesia when compared with administration above the fascia. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01160913. LEVEL OF EVIDENCE: I. PMID- 20859154 TI - A multicenter interventional program to reduce the incidence of anal sphincter tears. AB - OBJECTIVE: In Norway, we have experienced a gradual increase in the incidence of obstetric anal sphincter injuries from under 1% in the late 1960s to 4.3% in 2004. This study was aimed to assess whether an interventional program causes a decrease in the frequency of anal sphincter tears. METHODS: In all, 40,152 vaginal deliveries between 2003 and 2009 were enrolled in the interventional cohort study from four Norwegian obstetric departments. The focus of the intervention was on manual assistance during the final part of the second stage of labor. Data were analyzed in relation to occurrence of obstetric anal sphincter tears. RESULTS: The proportion of parturients with anal sphincter tears decreased from 4-5% to 1-2% during the study period in all four hospitals (P<.001). The tears associated with both noninstrumental and instrumental deliveries decreased dramatically. The number of patients with grades 3 and 4 anal sphincter ruptures decreased significantly, and the reduction was most pronounced in grade 4 tears (-63.5%) and least in 3c tears (-47.5%) (both P<.001). The number of episiotomies increased in two hospitals but remained unchanged in the other two. The lowest proportion of tears at the end of the intervention (1.2% and 1.3%, respectively) was found in the two hospitals with an unchanged episiotomy rate. CONCLUSION: The multicenter intervention caused a highly significant decrease in obstetric anal sphincter injuries. LEVEL OF EVIDENCE: II. PMID- 20859155 TI - Effect of surgical volume on route of hysterectomy and short-term morbidity. AB - OBJECTIVE: To estimate whether a surgeon's case volume is related to route of hysterectomy and short-term morbidity. METHODS: This is a cross-sectional study collecting data on inpatient hysterectomies using the New York State Department of Health database from 2001 through 2006. An acute morbidity and mortality index was created. Surgeons' license numbers were used to generate an annual average number of hysterectomies performed. A multivariable logistic regression model assessing surgical volume on acute morbidity after controlling for known confounders was created. RESULTS: A total of 146,494 hysterectomies were performed in the state of New York. Of these, 103,181 (70.4%) were abdominal, 26,660 (18.2%) were vaginal, and 16,653 (11.4%) were laparoscopic-assisted. Twenty- six percent of hysterectomies are performed by physicians who perform, on average, fewer than 10 hysterectomies per year. The percentage of abdominal hysterectomies is 81% for surgeons performing fewer than 10 hysterectomies per year compared with 67% for surgeons performing at least 10 hysterectomies per year (P<.001). Postoperative morbidity and mortality were reported as 16.5% and 0.21%, respectively, for surgeons performing fewer than 10 hysterectomies per year as compared with 11.7% and 0.06%, respectively, for those performing at least 10 hysterectomies (P<.001). CONCLUSION: Surgeons who perform an average of 10 hysterectomies per year are more likely to perform minimally invasive hysterectomies. These surgeons also have a decrease in morbidity and mortality rates when compared with surgeons who perform fewer than 10 hysterectomies per year. LEVEL OF EVIDENCE: II. PMID- 20859156 TI - Birth outcomes among offspring of women exposed to the September 11, 2001, terrorist attacks. AB - OBJECTIVE: To evaluate the effects of the September 11, 2001, World Trade Center attacks on birth outcomes. METHODS: Live singleton births between September 11, 2001, and October 31, 2002, to women enrolled in a World Trade Center Health Registry (the Registry, n=446) were compared with births to women residing more than 5 miles from the World Trade Center (n=49,616). Birth weight, gestational age, low birth weight, and preterm delivery were evaluated using linear and logistic regression. Births before September 11, 2001, were analyzed to assess possible seasonal biases of associations with pregnancy trimester on September 11. Associations of birth outcomes with September 11-related psychologic stress and physical exposures were assessed among births to women within the Registry (n=499). RESULTS: Birth weight and gestational age distributions were similar for births to women enrolled in the Registry and comparison births. Although mean gestational age and birth weight varied with trimester on September 11, a similar association was found among births in previous years, consistent with a seasonal effect not related to exposure. Registry-linked births to mothers with probable posttraumatic stress disorder (n=61) had a higher odds of low birth weight (adjusted odds ratio [OR] 2.49, 95% confidence interval [CI] 1.02-6.08) and preterm delivery (adjusted OR 2.48, 95% CI 1.05-5.84) compared with births to women without posttraumatic stress disorder. CONCLUSION: Women who lived, worked, or were near the World Trade Center on or soon after September 11 had pregnancy outcomes similar to women residing more than 5 miles away. However, among exposed women, probable posttraumatic stress disorder was associated with low birth weight and preterm delivery. LEVEL OF EVIDENCE: II. PMID- 20859157 TI - Trends over time with commonly performed obstetric and gynecologic inpatient procedures. AB - OBJECTIVES: To estimate trends over time in inpatient obstetric and gynecologic surgical procedures, and to estimate commonly performed obstetric and gynecologic surgical procedures across a woman's lifespan. METHODS: Data were collected for procedures in adult women from 1979 to 2006 using the National Hospital Discharge Survey, a federal discharge dataset of U.S. inpatient hospitals, including patient and hospital demographics and International Classification of Diseases, 9th Revision, Clinical Modification procedure codes for adult women from 1979 to 2006. Age-adjusted rates per 1,000 women were created using 1990 U.S. Census data. Procedural trends over time were assessed. RESULTS: More than 137 million obstetric and gynecologic procedures were performed, comprising 26.5% of surgical procedures for adult women. Sixty-four percent were only obstetric and 29% were only gynecologic, with 7% of women undergoing both obstetric and gynecologic procedures during the same hospitalization. Obstetric and gynecologic procedures decreased from approximately 5,351,000 in 1979 to 4,949,000 in 2006. Both operative vaginal delivery and episiotomy rates decreased, whereas spontaneous vaginal delivery and cesarean delivery rates increased. All gynecologic procedure rates decreased during the study period, with the exception of incontinence procedures, which increased. Common procedures by age group differed across a woman's lifetime. CONCLUSION: Inpatient obstetric and gynecologic procedures rates decreased from 1979 to 2006. Inpatient obstetric and gynecologic procedure rates are decreasing over time but still comprise a large proportion of inpatient surgical procedures for U.S. women. LEVEL OF EVIDENCE: III. PMID- 20859158 TI - Prevalence and seroprevalence of high-risk human papillomavirus infection. AB - OBJECTIVE: To estimate the prevalence and seroprevalence of high-risk human papillomavirus (HPV) in Korean girls and women. METHODS: We estimated the seroprevalence of HPV subtypes 16 and 18 among 1,094 girls and women aged 9-59 years and the prevalence of genital high-risk HPV among 902 women aged 20-59 years who visited our institution for a medical checkup. Genital high-risk HPV DNA was measured using liquid hybridization and polymerase chain reaction assays. Serum antibodies to HPV subtypes 16 and 18 were measured using a multiplexed competitive luminex technique. RESULTS: The prevalence of genital high-risk HPV was 12.6% among Korean women aged 20-59 years. It reached a peak of 23.2% at 20 29 years of age, decreasing thereafter but increasing again to 12.4% at 50-59 years of age. Human papillomavirus 56 was the most common subtype followed by HPV 18, HPV 52, and HPV 16. The seroprevalence of HPV subtypes 16 and 18 was 8.7% among Korean girls and women aged 9-59 years. It reached its highest peak of 13.4% at 25-29 years of age and decreased thereafter. It then reached a second peak of 10.9% at 40-49 years of age and plateaued thereafter. The seroprevalences of HPV subtypes 16 and 18 were 7.4% and 2.7%, respectively. In multivariable analysis, the prevalence and seroprevalence of high-risk HPV were correlated only with the number of lifetime sexual partners. CONCLUSION: High-risk HPV infection is common among Korean women. Our epidemiological data on high-risk HPV infection will help to assess vaccine policy and to establish a baseline for estimating vaccine efficacy. LEVEL OF EVIDENCE: III. PMID- 20859159 TI - Changes in knowledge of cervical cancer prevention and human papillomavirus among women with human immunodeficiency virus. AB - OBJECTIVE: To estimate changes in high-risk women's knowledge of cervical cancer prevention, human papillomavirus (HPV), and HPV vaccination since introduction and marketing of HPV vaccines. METHODS: At study visits in 2007 and 2008-2009, women with the human immunodeficiency virus (HIV) and at-risk comparison women in a multicenter U.S. cohort study completed 44-item self-report questionnaires exploring their knowledge of cervical cancer prevention, HPV, and HPV vaccination. Results from 2007 were compared with those obtained in 2008-2009. Knowledge scores were correlated with demographic variables, measures of education and attention, and medical factors. Significant associations were assessed in multivariable models. RESULTS: HIV-seropositive women had higher knowledge scores than seronegative women at baseline (13.2 +/- 5.7 compared with 11.8 +/- 6.0, P < .001) and follow-up (14.1 +/- 5.3 compared with 13.2 +/- 5.5, P = .01), but the change in scores was similar (0.9 +/- 5.3 compared with 1.5 +/- 5.5, P = .13). Knowledge that cervical cancer is caused by a virus rose significantly (P = .005), but only to 24%. Belief that cervical cancer is preventable only rose from 52% to 55% (P = .04), but more than 90% of women in both periods believed regular Pap testing was important. In analysis of covariance models, higher baseline score, younger age, higher education level, higher income, and former- as opposed to never-drug users, but not HIV status, were associated with improved knowledge. CONCLUSION: High-risk women's understanding of cervical cancer and HPV has improved, but gaps remain. Improvement has been weakest for less educated and lower-income women. LEVEL OF EVIDENCE: II. PMID- 20859160 TI - Correlates of seasonal influenza vaccine coverage among pregnant women in Georgia and Rhode Island. AB - OBJECTIVE: To identify facilitators of and barriers to pregnant women being vaccinated against seasonal influenza by identifying factors associated with influenza vaccination during pregnancy among women who had recently given birth to a live infant. METHODS: We analyzed pooled data from Georgia (n=2,692) and Rhode Island (n=2,732) participants in the 2006 and 2007 surveys of the Pregnancy Risk Assessment and Monitoring System, which conducts cross-sectional surveys of women with live births. SUDAAN software was used for analysis to account for complex survey design. We estimated rates of seasonal influenza vaccination among pregnant women in Georgia and Rhode Island and identified factors associated with being vaccinated. RESULTS: The prevalence of immunization for seasonal influenza in 2006 and 2007 combined was 18.4% (95% confidence interval [CI]: 15.9-21.1) in Georgia and 31.9% (95% CI 29.8-34.0) in Rhode Island. Multivariable analyses showed that in Georgia, multiparous women were significantly less likely to have been vaccinated than primiparous women (adjusted odds ratio [OR] 0.60; 95% CI 0.40-0.89). In Georgia, among those not vaccinated, 43% indicated that their health care providers did not mention anything about the seasonal influenza vaccination. In Rhode Island, women whose health care provider encouraged them to be vaccinated (adjusted OR 56.62; 95% CI 37.43-85.63) and those who did not smoke cigarettes (adjusted OR 1.92; 95% CI 1.25-2.94) were significantly more likely to be vaccinated. CONCLUSION: Our findings indicate a need for strategies to promote seasonal influenza vaccine use among pregnant women. Health care providers can play a significant role in increasing influenza vaccination coverage rates among pregnant women by advising women to be vaccinated and by addressing their concerns about vaccine safety. LEVEL OF EVIDENCE: III. PMID- 20859161 TI - Risk of thromboembolic disease in patients undergoing laparoscopic gynecologic surgery. AB - OBJECTIVE: To estimate the incidence of venous thromboembolism among patients undergoing gynecologic laparoscopy and characterize the risk of venous thromboembolism among patients with gynecologic malignancy. METHODS: Data were collected for patients who underwent laparoscopic gynecologic surgery from January 2000 to January 2009. Incidence of deep vein thrombosis (DVT) or pulmonary embolism diagnosed within 6 weeks of surgery was estimated. Fisher's exact test was used to estimate the association between the presence of perioperative venous thromboembolism and categorical variables. RESULTS: Six (of 849) patients developed symptomatic venous thromboembolism (0.7%, 95% confidence interval: 0.024-1.44%). The median time to diagnosis of venous thromboembolism was postoperative day 15.5 (range, 1-41 days), median body mass index was 25.4 kg/m (range, 18.4-50 kg/m), median operative time was 176 minutes (range, 53-358 minutes), and median estimated blood loss was 125 mL (range, 10-250 mL). Five of 430 (1.2%) patients with a history of gynecologic malignancy developed postoperative thromboembolic events. Venous thromboembolism was diagnosed in three of 662 (0.5%) patients undergoing intermediate complexity procedures and three of 106 (2.8%) patients undergoing high-complexity procedures. Three patients with venous thromboembolism (50%) had a history of at least one previous modality of cancer treatment before laparoscopy. One patient (17%) had DVT only, four (67%) had pulmonary emboli without an identified DVT, and one (17%) had both. There were no associated mortalities. CONCLUSION: The incidence of thromboembolism in patients undergoing low- and intermediate-complexity, minimally invasive surgery was low, even among patients with a gynecologic malignancy. Patients undergoing high-complexity, minimally invasive procedures may benefit from postoperative anticoagulation. LEVEL OF EVIDENCE: II. PMID- 20859162 TI - Polypropylene vaginal mesh grafts in gynecology. AB - Basic concepts are presented for the use of polypropylene mesh in gynecology for prolapse and stress-incontinence repair. The vagina is a clean-contaminated environment, and it is not possible to insert polypropylene mesh devices without bacterial contamination, despite standard antibiotic usage. Once inserted, the host tissue immediately attaches to the polypropylene and attempts to defend it from bacterial invasion, but if the bacteria have already reached the surface of the device, then dislodgement is difficult. The devices with larger surface areas result in greater bacterial contamination, more polypropylene degradation, increased inflammatory response, fibrous tissue stimulation, and erosion. Noninert polypropylene degrades into potentially toxic compounds that would be expected to stimulate a greater inflammatory reaction leading to erosion. If the physician does not place the mesh below full-thickness vaginal epithelium, penetrates the epithelium during insertion, or if there is hematoma formation near the vaginal incision, then defective healing and erosion may result. Scar tissue causes contraction to less than 50% of the implanted size, which results in dyspareunia and tension on the pelvic mesh attachments. Such contraction may cause pelvic pain and subsequent erosion into adjacent organs. An individual response in fibrosis also exists, with some individuals being "high responders." Manufacturers need encouragement to develop meshes that are inert and incorporate without contraction along with routine clinical tests to detect "high responders" to avoid complications. Polypropylene is not inert within the human body. PMID- 20859163 TI - New insights on vaginal birth after cesarean: can it be predicted? AB - OBJECTIVE: To evaluate existing vaginal birth after cesarean (VBAC) screening tools and to identify additional factors that may predict VBAC or failed trial of labor. DATA SOURCES: Relevant studies were identified through MEDLINE, Database of Abstracts of Reviews of Effectiveness, and the Cochrane databases (1980 September 2009), and from recent systematic reviews, reference lists, reviews, editorials, web sites, and experts. METHODS OF STUDY SELECTION: Inclusion criteria limited studies to those of humans, written in English, studies conducted in the United States and developed countries, and those rated good or fair quality by the U.S. Preventive Services Task Force criteria. Studies of individual predictors were combined using a random effects model when the estimated odds ratios were comparable across included studies. TABULATION, INTEGRATION, AND RESULTS: We identified 3,134 citations and reviewed 963 papers, of which 203 met inclusion criteria and were quality-rated. Twenty-eight provided evidence on predictors of VBAC and 16 presented information on scored models for predicting VBAC (or failed trial of labor). Six of the 11 scored models for predicting VBAC (or failed trial of labor) were validated by separated dataset, cross-validation, or both. Whereas accuracy remained high across all models for predicting VBAC, with predictive values ranging from 88% to 95%, accuracy for predicting failed trial of labor was low, ranging from 33% to 58%. Individual predictors including Hispanic ethnicity, African-American race, advanced maternal age, no previous vaginal birth history, birth weight heavier than 4 kg, and use of either augmentation or induction were all associated with reduced likelihood of VBAC. CONCLUSION: Current scored models provide reasonable predictability for VBAC, but none provides consistent ability to identify women at risk for failed trial of labor. A scoring model is needed that incorporates known antepartum factors and can be adjusted for current obstetric factors and labor patterns if induction or augmentation is needed. This would allow women and clinicians to better determine individuals most likely to require repeat cesarean delivery. PMID- 20859166 TI - Special requirements of electronic medical record systems in obstetrics and gynecology. PMID- 20859164 TI - Painful, swollen hands in a young woman. PMID- 20859167 TI - The role of uterine closure in the risk of uterine rupture. PMID- 20859168 TI - Special requirements of electronic medical record systems in obstetrics and gynecology. PMID- 20859171 TI - The role of uterine closure in the risk of uterine rupture. PMID- 20859172 TI - Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss. PMID- 20859176 TI - ACOG Committee Opinion No. 468: Influenza vaccination during pregnancy. AB - Preventing influenza during pregnancy is an essential element of prenatal care, and the most effective strategy for preventing influenza is annual immunization. The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practice recommends influenza vaccination for all women who will be pregnant through the influenza season (October through May in the United States). The American College of Obstetricians and Gynecologists' Committee on Obstetric Practice supports this recommendation. No study to date has shown an adverse consequence of inactivated influenza vaccine in pregnant women or their offspring. Vaccination early in the season and regardless of gestational age is optimal, but unvaccinated pregnant women should be immunized at any time during influenza season as long as the vaccine supply lasts. PMID- 20859177 TI - ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. AB - Fragile X syndrome is the most common inherited form of mental retardation. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,000-6,000 females. Approximately 1 in 250 females carry the premutation. DNA-based molecular analysis is the preferred method of diagnosis for fragile X syndrome and its premutations. Prenatal testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation. Women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency are candidates for genetic counseling and fragile X premutation carrier screening. PMID- 20859178 TI - ACOG Committee Opinion No. 470: Challenges for overweight and obese urban women. AB - Overweight and obesity are epidemic in the United States. Obesity is a risk factor for numerous conditions, including diabetes, hypertension, high cholesterol, stroke, heart disease, certain types of cancer, and arthritis. More than one fourth of U.S. women are overweight and more than one third are obese. Women living in urban settings, irrespective of demographics or income, are particularly vulnerable to becoming overweight or obese because of limited resources for physical activity and healthy food choices. Therefore, there is a need for clinicians and public health officials to address not only individual behaviors but also environmental issues in their efforts to reduce the epidemic of obesity in this particular group of the population. PMID- 20859181 TI - Pediatric invasive aspergillosis. PMID- 20859182 TI - Caspofungin versus liposomal amphotericin B: are they really comparable? PMID- 20859183 TI - Safety and efficacy of fosamprenavir in human immunodeficiency virus-infected pregnant women. PMID- 20859185 TI - Vitamin D supplementation could reduce the risk of type A influenza infection and subsequent pneumonia. PMID- 20859187 TI - The neural bases of normal and deviant moral cognition and behavior. PMID- 20859189 TI - The role of neuroimaging in translational cognitive neuroscience. AB - Despite the current enthusiasm for neuroimaging as a key method in translational neuroscience, there is a lack of debate about the nosological framework within which neuroimaging measures should be related to diagnostic categories. Here, the aim was to stimulate a debate about the role of cognitive neuroscience and neuroimaging in mediating between molecular/genetic, clinical diagnostic, and symptom-based descriptions of neuropsychiatric disorders. The diagnostic role of neuroimaging in translational neuroscience is stressed, namely, to be combined with cognitive measures to define cognitive-anatomical syndromes as an intermediate diagnostic category that mediates between clinical diagnoses and psychoreactive as well as neurobiological etiologic factors. This multilevel approach will be illustrated by reviewing recent insights into the cognitive anatomical basis of inappropriate social behavior and social knowledge in frontotemporal dementia and by discussing its implications for the study of neuropsychiatric disorders such as major depressive disorder in which neuroanatomical abnormalities are more subtle. PMID- 20859188 TI - Functional MRI evidence for distinctive binding and consolidation pathways for face-name associations: analysis of activation maps and BOLD response amplitudes. AB - OBJECTIVE: Although some of the anatomical underpinnings of learning and memory systems have been identified, there remains little understanding of how the brain moves from acquiring new information to retaining it. This study was designed to further explore and elucidate the neural mechanisms underlying encoding and memory in a common real-life task, that is, face-name associations. One possible outcome is that the tasks will recruit different neural structures mediating these processes, which can be identified through contrast analysis of activations. Alternatively, it is possible that similar anatomical regions, such as the hippocampus and parahippocampal gyrus, may be involved in both tasks. In that case, analysis of blood oxygenation level dependent (BOLD) amplitude differences between the tasks in those common neural structures may be able to detect whether physiological activation differences occur in encoding versus memory. METHODS: Five healthy adult participants underwent high-field magnetic resonance imaging (MRI) while learning face-name pairs (encoding phase) and during a multiple-choice recognition task after a brief delay (memory phase). Average activation and BOLD response amplitudes in specific regions of interest and whole-brain activation maps were analyzed. RESULTS: Common activations were observed in the encoding and recognition memory tasks in several regions of interest encompassing the medial temporal and inferior occipital regions. However, higher BOLD response amplitudes occurred in the right fusiform gyrus and the right hippocampus during encoding. In contrast, higher amplitudes were detected in the lingual gyrus bilaterally during recognition memory. Encoding activated distributed prefrontal and temporal cortical regions bilaterally, which mediate attentional, executive, language, and memory systems. Recognition memory recruited a different network of regions encompassing convergence zones in the left prefrontal cortex and the parietal-occipital-temporal region bilaterally, where multimodal visual association, language, memory, and decision-making systems interact. CONCLUSIONS: Higher BOLD response amplitudes in the right fusiform gyrus and the right hippocampus during face-name encoding suggest a potentially specific binding pathway where disparate information might be neurally linked. In contrast, the increased BOLD response in the lingual gyrus during recognition memory may indicate a key neural substrate for memory consolidation and long-term knowledge of what is learned. Whole-brain activation maps revealed task-specific differences in areas of the prefrontal, temporal, and occipital-parietal-temporal junctions as well. Findings suggest that there are distinctive anatomical and physiological nodes for face-name learning and memory within large-scale cortical-subcortical networks. Hence, lesions in fairly widespread cerebral regions may potentially disrupt specific binding and/or memory consolidation processes. PMID- 20859190 TI - Is there evidence of brain white-matter abnormalities in obsessive-compulsive disorder?: a narrative review. AB - OBJECTIVE: Although several studies have confirmed the occurrence of gray-matter abnormalities in obsessive-compulsive disorder (OCD), the literature on white matter in OCD is more limited. In this study, we reviewed the role of white matter abnormalities in the pathophysiology of OCD. METHOD: We reviewed the PubMed studies investigating white-matter integrity in patients with OCD between 1980 and 2010. RESULTS: Case studies of patients who developed obsessive compulsive symptoms secondary to multiple sclerosis, cerebrovascular diseases, and paraneoplastic leucoencephalopathy and controlled studies of patients with OCD examined with neuroimaging techniques (eg, structural, diffusion, and spectroscopic magnetic resonance imaging) were all consistent with the existence of abnormalities in specific white-matter tracts (eg, internal capsule, cingulate bundle, and corpus callosum) of individuals with OCD. CONCLUSIONS: Our review emphasizes that the reported white-matter alterations in OCD complement the broader gray-matter abnormalities identified and may well suggest that OCD is associated with large-scale disruption in brain systems or networks, as opposed to being a consequence of disturbances in isolated brain regions. PMID- 20859191 TI - Assessing the impact of mass rape on the incidence of HIV in conflict-affected countries. AB - OBJECTIVES: To quantify the potential impact of mass rape on HIV incidence in seven conflict-afflicted countries (CACs), with severe HIV epidemics, in sub Saharan Africa. DESIGN: Uncertainty analysis of a risk equation model. METHODS: A mathematical model was used to evaluate the potential impact of mass rape on increasing HIV incidence in women and girls in Burundi, Democratic Republic of Congo (DRC), Rwanda, Sierra Leone, Somalia, southern Sudan and Uganda. The model was parameterized with data from UNAIDS/WHO and the US Census Bureau's International Database. Incidence data from UNAIDS/WHO were used for calibration. RESULTS: Mass rape could cause approximately five HIV infections per 100,000 females per year in the DRC, Sudan, Somalia and Sierra Leone, double the number in Burundi and Rwanda, and quadruple the number in Uganda. The number of females infected per year due to mass rape is likely to be relatively low in Somalia and Sierra Leone at 127 [median (interquartile range [IQR] 55-254)] and 156 [median (IQR 69-305)], respectively. Numbers could be high in the DRC and Uganda: 1120 [median (IQR 527-2360)] and 2172 [median (IQR 1031-4668)], respectively. In Burundi, Rwanda and Sudan, the numbers are likely to be intermediate. Under extreme conditions, 10,000 women and girls could be infected per year in the DRC and 20 000 women and girls could be infected per year in Uganda. Mass rape could increase annual incidence by approximately 7% [median (IQR 3-15)]. CONCLUSION: Interventions and treatment targeted to rape survivors during armed conflicts could reduce HIV incidence. Support should be provided both on the basis of human rights and public health. PMID- 20859192 TI - Fracture incidence in HIV-infected women: results from the Women's Interagency HIV Study. AB - BACKGROUND: The clinical importance of the association of HIV infection and antiretroviral therapy (ART) with low bone mineral density (BMD) in premenopausal women is uncertain because BMD stabilizes on established ART and fracture data are limited. METHODS: We measured time to first new fracture at any site with median follow-up of 5.4 years in 2391 (1728 HIV-infected, 663 HIV-uninfected) participants in the Women's Interagency HIV Study (WIHS). Self-report of fracture was recorded at semiannual visits. Proportional hazard models assessed predictors of incident fracture. RESULTS: At baseline, HIV-infected women were older (40 +/- 9 vs. 36 +/- 10 years, P < 0.0001), more likely to report postmenopausal status and be hepatitis C virus-infected, and weighed less than HIV-uninfected women. Among HIV-infected women, mean CD4(+) cell count was 482 cells/MUl; 66% were taking ART. Unadjusted incidence of fracture did not differ between HIV-infected and uninfected women (1.8 vs. 1.4/100 person-years, respectively, P = 0.18). In multivariate models, white (vs. African-American) race, hepatitis C virus infection, and higher serum creatinine, but not HIV serostatus, were statistically significant predictors of incident fracture. Among HIV-infected women, older age, white race, current cigarette use, and history of AIDS-defining illness were associated with incidence of new fracture. CONCLUSION: Among predominantly premenopausal women, there was little difference in fracture incidence rates by HIV status, rather traditional risk factors were important predictors. Further research is necessary to characterize fracture risk in HIV infected women during and after the menopausal transition. PMID- 20859195 TI - Second course of radiation for new primary head-and-neck cancer: population-based study of survival. AB - OBJECTIVES: To analyze patient and tumor characteristics, and survival of patients who received 2 courses of radiotherapy for different primary head and neck cancers (HNCs). METHODS: A total of 234 patients who underwent 2 courses of radiotherapy for different primary, localized, or regional HNCs registered in the population-based Surveillance, Epidemiology, and End Results database were identified. RESULTS: The latency between first and second irradiated HNCs ranged from 0.3 to 28.8 years (median, 6.3 years). Only 22% of first irradiated HNCs were node positive, and only 22% of second irradiated HNCs were node positive. After the diagnosis of the second irradiated HNC, the 1-, 2-, and 5-year overall survivals were 68%, 40%, and 17%, respectively. The variables of gender, race, latency, and stage of second cancer did not significantly impact survival. At the time of diagnosis of second irradiated HNC, younger age (P = 0.026), later year of diagnosis (P = 0.005), and cancer-directed surgery (P = 0.032) were favorable predictors of improved survival. With Cox regression analyses, younger age (P = 0.060) and cancer-directed surgery for the second irradiated HNC (HR = 0.75, 95% CI: 0.55-1.01, P = 0.062) were borderline significantly favorable risk factors, whereas year of diagnosis (P = 0.13) was not. CONCLUSIONS: From a population based analysis, patients undergoing a second course of radiation for HNC appear to benefit from cancer-directed surgery, although this did not reach statistical significance with Cox regression analyses. The improved outcome after resection is perhaps attributable to a therapeutic benefit from surgery and/or more indolent disease among those amenable to resection. PMID- 20859194 TI - The impact of tumor volume and radiotherapy dose on outcome in previously irradiated recurrent squamous cell carcinoma of the head and neck treated with stereotactic body radiation therapy. AB - PURPOSE: To assess the effect of stereotactic body radiotherapy (SBRT) dose and tumor volume on outcomes in patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: A total of 96 patients with recurrent, previously irradiated squamous cell carcinoma of the head and neck were treated with SBRT using Cyberknife and Trilogy-intensity modulated radiosurgery. Kaplan-Meier survival analyses were used to estimate locoregional control (LRC) and overall survival rates. Response was evaluated using positron emission tomography/computed tomography or computed tomography and detailed physical examination. RESULTS: The median follow-up for all patients was 14 months (2-39 months). The median dose of prior radiation was 68.4 Gy (32-170 Gy). Patients were divided into 4 SBRT dose groups: I (15-28 Gy/n = 29), II (30 36 Gy/n = 22), III (40 Gy/n = 18), and IV (44-50 Gy/n = 27). The median gross tumor volume (GTV) was 24.3(3) cm (2.5-162 cm). For GTV <=25 cm(3) (n = 50), complete response rates were 27.8%/30%/45.5%/45.5%, and for GTV >25 cm(3) (n = 46), complete response rates were 20%/25%/42.8%/50% for SBRT groups I-IV, respectively. The 1-/2-/3-year LRC rates for doses 40 to 50 Gy were 69.4%/57.8%/41.1%, respectively, whereas for 15 to 36 Gy, they were 51.9%/31.7%/15.9%, respectively (P = 0.02). The overall 1- and 2-year overall survival rates were 58.9% and 28.4%, respectively. Treatment was well tolerated with no grade 4/5 toxicities. CONCLUSIONS: Dose escalation up to 50 Gy in 5 fractions is feasible with SBRT for recurrent head and neck squamous cell carcinoma. Higher SBRT doses were associated with significantly higher LRC rates. Large tumor volume required higher SBRT doses to achieve optimal response rates compared with smaller tumor volume. PMID- 20859193 TI - Contemporary costs of HIV healthcare in the HAART era. AB - BACKGROUND: The delivery of HIV healthcare historically has been expensive. The most recent national data regarding HIV healthcare costs were from 1996-1998. We provide updated estimates of expenditures for HIV management. METHODS: We performed a cross-sectional review of medical records at 10 sites in the HIV Research Network, a consortium of high-volume HIV care providers across the United States. We assessed inpatient days, outpatient visits, and prescribed antiretroviral and opportunistic illness prophylaxis medications for 14 691 adult HIV-infected patients in primary HIV care in 2006. We estimated total care expenditures, stratified by the median CD4 cell count obtained in 2006 (<=50, 51 200, 201-350, 351-500, >500 cells/MUl). Per-unit costs of care were based on Healthcare Cost and Utilization Project (HCUP) data for inpatient care, discounted average wholesale prices for medications, and Medicare physician fees for outpatient care. RESULTS: Averaging over all CD4 strata, the mean annual total expenditures per person for HIV care in 2006 in three sites was US $19 912, with an interquartile range from US $11 045 to 22 626. Average annual per-person expenditures for care were greatest for those with CD4 cell counts 50 cell/MUl or less (US $40 678) and lowest for those with CD4 cell counts more than 500 cells/MUl (US $16 614). The majority of costs were attributable to medications, except for those with CD4 cell counts 50 cells/MUl or less, for whom inpatient costs were highest. CONCLUSION: HIV healthcare in the United States continues to be expensive, with the majority of expenditures attributable to medications. With improved HIV survival, costs may increase and should be monitored in the future. PMID- 20859196 TI - Impact of epidermal growth factor receptor expression on disease-free survival and rate of pelvic relapse in patients with advanced cancer of the cervix treated with chemoradiotherapy. AB - OBJECTIVES: To determine the impact of the expression of epidermal growth factor receptor (EGFR) on disease-free survival (DFS) and on pelvic relapse in patients with advanced cancer of the cervix receiving concurrent chemoradiotherapy. METHODS: In 112 consecutive patients with advanced cancer of the cervix (11 stage IB2-IIA, 25 IIB, 63 IIIB, 13 IVA) treated with chemoradiotherapy between December 1994 and September 2004, the expression of EGFR using histoimmunochemistry was measured and used in univariate and multivariate analysis, along with variables such as age, International Federation of Gynecology and Obstetrics Staging System for Epithelial Ovarian Cancer (FIGO) stage, histology, Eastern Cooperative Oncology Group (ECOG), tumor size, and ganglia involvement diagnosed with computerized axial tomography, treatment with cisplatin to evaluate its impact on DFS and pelvic relapse. RESULTS: Of the 112 biopsies, 32 (28.6%) were negative or slightly positive (EGFR+/-) and 80 (71.4%) were moderate or intensely positive (EGFR++/+++). The overexpression of EGFR (++/+++) was significantly associated with an epidermoid histology (P < 0.0001), with a higher rate of pelvis relapse and a decreased DFS (hazard ratio [HR]: 2.31 [1.08-4.96]; P = 0.03). Overall, treatment with cisplatin increased DFS (HR: 0.51 [0.26-0.97]; P = 0.04). CONCLUSIONS: Patients with tumors of the cervix and overexpression of the EGFR++/+++ show a higher probability of pelvic relapses and a decreased disease free survival. The poor prognosis of these tumors may be a consequence of an increase in radio-resistance. PMID- 20859198 TI - Clinical cancer genetics: Part I: Gastrointestinal. AB - There is an increasing recognition of the importance of genetic and familial cancer syndromes in routine clinical practice. Although most of gastrointestinal cancers are sporadic, a number of important cancer predisposition syndromes are now recognized and well characterized. In this review, we discuss some of the basic principles of clinical cancer genetics and clinically relevant aspects of the more common gastrointestinal cancer syndromes from the perspective of practicing radiation oncologists. PMID- 20859197 TI - Selective serotonin reuptake inhibitors, glioblastoma multiforme, and impact on toxicities and overall survival: the mayo clinic experience. AB - PURPOSE: The diagnoses of glioblastoma multiforme (GBM) and depression are often found to coexist. The impact of selective serotonin reuptake inhibitors (SSRI) on treatment-related toxicity and outcome in patients with GBM is unclear. METHODS AND MATERIALS: We retrospectively reviewed 160 patients with GBM who received treatment at our institution between 1999 and 2008. Those taking an SSRI during treatment for GBM were identified and toxicities were assessed. RESULTS: Median survival for the entire cohort was 1.05 years. A total of 35 patients (21.8%) took an SSRI during initial treatment for GBM. There was no statistical difference in the rate of >=grade 3 toxicity in patients taking an SSRI when compared with those who were not (11.4% vs. 13.6%, respectively; P = 1.00). Two year survival in the cohort of patients taking an SSRI was 32% versus 17% in those who were not (P = 0.18). After making adjustment for age, recursive partitioning analysis class, and extent of surgery, absence of an SSRI during treatment was associated with a hazard risk of 1.5 (95% confidence interval = 1.00-2.42; P = 0.05). CONCLUSIONS: This retrospective review suggests that concomitant use of an SSRI during treatment does not adversely affect survival. There was no increased toxicity with the use of SSRI concurrent with treatment of newly-diagnosed GBM. PMID- 20859199 TI - Tolerance to the rate-increasing and not rate-decreasing effects of pregnanolone in rats. AB - Chronic treatment with benzodiazepines, which positively modulate gamma aminobutyric acidA (GABAA) receptors, can lead to the development of tolerance. Similar effects might also occur during chronic treatment with positive modulators acting at other sites on GABAA receptors (e.g. neuroactive steroids). In this study, tolerance and cross tolerance were examined in seven rats treated daily with the neuroactive steroid pregnanolone (25.6 mg/kg/day) and responding under a fixed ratio 10 schedule of food presentation. Dose-effect curves were determined for positive GABAA modulators (pregnanolone, flunitrazepam, midazolam, and pentobarbital), and other drugs (ketamine and morphine) before, during, and after chronic treatment. Initially, daily pregnanolone administration increased responding; although tolerance developed to the rate-increasing effects after 14 weeks, tolerance did not develop to the rate-decreasing effects. The potencies of pregnanolone, midazolam, and morphine to decrease responding did not change during treatment, whereas flunitrazepam was more potent and pentobarbital and ketamine were less potent during treatment as compared to before treatment. Pregnanolone and midazolam were more potent after treatment than before treatment. The development of tolerance to the rate-increasing effects of pregnanolone indicates that neuroadaptations occur during chronic treatment; the fact that tolerance develops to only some effects suggests that the behavioral consequences of these neuroadaptations are limited. PMID- 20859200 TI - Relation between serum monocyte chemoattractant protein-1 and coronary collateral development. AB - BACKGROUND: The degree of coronary collateral development is not same in every patient with similar degree of coronary stenosis. In animal studies monocyte chemoattractant protein-1 (MCP-1) has been found to be related to collateral vessel development. In this study we investigated whether a higher serum MCP-1 level is related to better coronary collateral vessel development in patients with stable coronary artery disease. METHOD: Eighty-three patients with stable angina pectoris, who have at least one coronary stenosis equal to or greater than 70% at coronary angiography, were prospectively enrolled. Serum MCP-1 and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral development was graded according to the Rentrop method. Patients with grade 2-3 collateral developments were included in good collateral group and formed group I. The patients with grade 0-1 collateral developments were included in poor collateral group and formed group II. RESULTS: The serum MCP-1 level was significantly higher in good collateral group (288 +/- 277 pg/ml vs. 132 +/- 64 pg/ml; P<0.001). There was also a positive correlation between serum MCP-1 level and Rentrop score (r=0.39, P<0.001). The patients in the good collateral group also had a significantly higher number of coronary arteries with significant stenosis (1.7 +/- 0.7 vs. 1.4 +/- 0.6, P=0.049), and higher VEGF levels (322 +/- 147 pg/ml vs. 225 +/- 161 pg/ml, P=0.007). In multivariate analysis, only serum MCP-1 level (P=0.014, odds ratio: 1.01, 95% confidence interval: 1.002-1.019) was independently related to good coronary collateral development. CONCLUSION: Higher serum MCP-1 level is related to better coronary collateral development. PMID- 20859201 TI - The current state of recombinant allergens for immunotherapy. AB - PURPOSE OF REVIEW: Subcutaneous immunotherapy is a well documented treatment of allergic rhinitis and asthma. The majority of the disadvantages of the treatment are related to the poor quality of the natural allergen extracts which can contain varying amounts of individual allergens including allergens to which the patient may not be sensitized. Recombinant allergens offer a possibility to use well defined molecules with consistent pharmaceutical quality defined in mass units. The proof of concept of the clinical efficacy of recombinant allergens is based on two studies published as full articles. RECENT FINDINGS: One study applied a mixture of five Phleum pratense major allergens in a maximum dose of 40mcg protein. The clinical efficacy showed a significant efficacy with 40% reduction in disease severity. The second study compared a commercial birch extract with both recombinant Bet v 1 and purified Bet v 1 in dosages of 15mcg allergen. The clinical effect was 60% additional efficacy. Systemic side effects occurred more frequently with grass allergens. A third study used hypoallergenic fragments and a trimer of Bet v 1. The study did not show efficacy and a rather high frequency of systemic side effects. SUMMARY: The advantages of using recombinant allergens for immunotherapy are obvious but more studies on a large scale are needed before the overall value in terms of efficacy and safety can be assessed. Clinical trials are also necessary for new combined vaccines based on recombinant allergens that in experimental studies have shown greatly enhanced immunogenicity and low allergen-specific reactivity. PMID- 20859202 TI - Functional regulatory T cells and allergen immunotherapy. AB - PURPOSE OF REVIEW: Burgeoning literature ascribing roles for regulatory T cells (Treg) in controlling clinical allergy frequently relies on phenotypic markers rather than functional suppression assays. This review examines evidence for functional Treg in controlling immune responses to allergen with particular focus on allergen-specific immunotherapy. RECENT FINDINGS: Over the last year, use of recently identified Treg markers has facilitated more precise delineation and isolation of Treg subtypes. Advanced flow cytometry allows better discrimination and tracking of effector T cells (Teff) and Treg in co-culture assays for Treg function. These approaches enable critical appraisal of the evidence for Treg mediation of the observed changes in immune reactivity to allergen accompanying immunotherapy. Recent studies suggest that different mechanisms of immune regulation may occur at different times of immunotherapy, with Treg playing a more important role early in treatment. Additionally, advanced imaging techniques reveal increased Treg numbers in allergen-exposed mucosal tissue after therapy consistent with an enhanced local functional role. SUMMARY: These findings support a mechanistic role for Treg early in allergen immunotherapy. Research is required to clarify the precise Treg subsets involved, their specificity and how their activity can be enhanced during immunotherapy by appropriate allergen form, optimal site of administration and use of adjuvants and adjunct therapies. PMID- 20859203 TI - Chronic mucocutaneous candidiasis and congenital susceptibility to Candida. AB - PURPOSE OF REVIEW: To give an overview on the clinical spectrum and the molecular background of host defence against Candida. RECENT FINDINGS: For many decades the molecular causes and the pathogenesis for an increased susceptibility to Candida and fungal infections in general - have been elusive. In 2009 and 2010 interesting reports on the genetic background and the pathomechanisms involved in chronic mucocutaneous candidiasis (CMC) have been published. SUMMARY: The susceptibility to recurrent Candida infections can be a monogenetic Mendelian trait. The sensing of Candida cell wall components and the consecutive intracellular signalling in myeloid cells via CARD9, but also the role of Th17 cells and their cytokines take centre stage in the human host defence against Candida. PMID- 20859204 TI - The future of regenerating the myocardium. AB - PURPOSE OF REVIEW: Stem cell therapy for cardiac disease may be facing two major problems nowadays: although vasculogenesis likely occurs as a result of cell therapy, its clinical applications are limited and significant, integrated cardiomyogenesis has not demonstratively been shown to occur, even in the experimental setting, with any other source than embryonic or other pluripotent stem cells. RECENT FINDINGS: In this article, we highlight several factors that will need to be optimized if we are to achieve clinically effective cardiomyogenesis, such as the identification of optimal stem cell populations, and the ideal time and methods for cell transplantation. So far, educated attempts at achieving transplanted stem cell-induced myogenesis have largely failed outside of the embryonic stem cell realm, and we present the rationale for also considering acellular techniques, which may enhance the potential of endogenous progenitor populations. SUMMARY: In today's cardiovascular field, once a cardiomyocyte is lost it is lost for good, without any form of direct therapeutic option. For these reasons, cell therapy justifies our continued attention and efforts, and may constitute the holy grail of cardiovascular therapeutics. PMID- 20859205 TI - Consciousness revealed: new insights into the vegetative and minimally conscious states. AB - PURPOSE OF REVIEW: In recent years, the results of neuroimaging studies have fundamentally changed the way we think about the vegetative and minimally conscious states. RECENT FINDINGS: Functional MRI studies have demonstrated that some high-level cognitive functions, such as language comprehension and target detection, are preserved in a subset of patients with disorders of consciousness. Similar methods have even allowed a patient who was assumed to be in a vegetative state to communicate. PET has provided insights into similarities and differences in the ways in which pain is processed by this patient group, whereas electrophysiological methods have revealed further evidence of awareness as well as learning. SUMMARY: The prognostic and diagnostic information provided by these new approaches clearly argues for their future use alongside conventional assessment techniques. By demonstrating that a behaviourally unresponsive patient could communicate by means of his/her thoughts using functional MRI, these new techniques open up a new direction of research into the development of more sophisticated communication devices that may be used more generally by these patients. In our opinion, such devices, employing electroencephalograph among other techniques, may soon allow for patients who retain sufficient cognitive abilities to communicate, to do so outside of an MRI scanner. PMID- 20859206 TI - Novel insights into the management of brain metastases. AB - PURPOSE OF REVIEW: This review provides available clinical evidence regarding current therapies, discusses ongoing controversies, and introduces investigational approaches in the management of brain metastases. RECENT FINDINGS: Novel approaches to estimating prognosis of patients with brain metastases highlight the importance of tailoring treatment to each particular patient. In the setting of unfavorable prognosis, either hospice care, symptom management, or short-course whole-brain radiotherapy (WBRT) is a critical component of palliation. In the setting of favorable or intermediate prognosis, treatment options can include a slightly more prolonged course of WBRT, surgery, stereotactic radiosurgery, systemic therapy, or a combination. Selection of the appropriate treatment is influenced by the number of brain metastases, overall patient performance status and residual life expectancy, as well as an understanding of the benefits and toxicities of each modality. Recent clinical studies have shed novel insight on the temporal sequence of memory changes following WBRT. Innovative approaches to mitigating these radiation-induced memory effects are currently being investigated. SUMMARY: Evidence-based management of brain metastases represents an evolving field of active clinical research. Ongoing and future investigations focus on the preservation of cognition and quality of life, in addition to conventional outcomes such as intracranial tumor control and survival. PMID- 20859207 TI - New treatments for infant colic. AB - PURPOSE OF REVIEW: Infantile colic is a common problem within the first 3 months of life and causes considerable distress for parents and paediatricians. Despite 40 years of research, its pathogenesis is incompletely understood and treatment remains an open issue. This review will describe recent studies that have examined different kinds of interventions. RECENT FINDINGS: Important advances in understanding the aetiopathogenesis of infantile colic have been recently proposed and opened new perspectives in its management.The composition of intestinal microbiota, specially an inadequate amount of lactobacilli and an increased concentration of coliforms, might influence the pathogenesis of infantile colic. The benefit of supplementation with Lactobacillus reuteri has been recently reported and experimental data showed the effect of probiotics may be related to the influence on gut motility and pain perception. SUMMARY: Infantile colic is a clinical entity with a wide range of clinical presentations and outcome. Firstly, paediatricians have to exclude other underlying diseases with a medical examination and prevent feeding disorders. Then, considering the favourable clinical course of the disturbance, well tolerated strategies should be adopted. The findings highlighted in this review may promote the implementation of new researches and treatments to reduce abdominal pain related to infantile colic. PMID- 20859208 TI - Holoprosencephaly: recommendations for diagnosis and management. AB - PURPOSE OF REVIEW: This review presents recent advances in our understanding and clinical management of holoprosencephaly (HPE). HPE is the most common developmental disorder of the human forebrain and involves incomplete or failed separation of the cerebral hemispheres. The epidemiology, clinical features, causes, diagnostic approach, management, and outcomes of HPE are discussed. RECENT FINDINGS: Chromosomal abnormalities account for the most commonly identified cause of HPE. However, there are often unidentifiable causes in patients with nonsyndromic, nonchromosomal forms of HPE. The prevalence of HPE may be underestimated given that patients with mild forms often are not diagnosed until they present with severely affected children. Pregestational maternal diabetes mellitus is the most recognized risk factor for HPE, as supported by recent large-scale epidemiological studies. Genetic studies using microarray based comparative genomic hybridization technology have resulted in better characterization of important HPE loci. SUMMARY: HPE encompasses a wide spectrum of forebrain and midline defects, with an accompanying wide spectrum of clinical manifestations. A coordinated, multidisciplinary care team is required for clinical management of this complex disorder. Further research will enable us to better understand the pathogenesis and causes of HPE, and thus to improve the genetic counseling of patients and their families. PMID- 20859209 TI - Restless legs syndrome and periodic limb movements disorder in the pediatric population. AB - PURPOSE OF REVIEW: Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) are common neurological disorders in childhood which are usually underdiagnosed. As many pediatricians and pediatric pulmonologists with interest in sleep medicine will be encountering children with RLS and PLMS in their practice, we feel a comprehensive review of these disorders from a pediatric perspective would be very important in understanding basic pathophysiology, clinical features in early diagnosis, and effective management. RECENT FINDINGS: There has recently been increased awareness about these disorders in children, and the American Academy of Sleep Medicine has recently published pediatric specific diagnostic criteria. There have also been exciting discoveries into the basic pathophysiology of these conditions which have helped to better understand these disorders. Genetics plays a very important role in their development, and current management strategies have been very successful in treatment of these conditions. SUMMARY: RLS occurs in 1 out of 120 school-age children. In many children, diagnosis is not even suspected as these children present with atypical symptoms and associated comorbid conditions. In this review, we will discuss RLS and PLMS in the pediatric population and briefly review their pathophysiology, clinical presentation, risk factors, neurobehavioral consequences, and newer diagnostic criteria along with recent advances in their management. PMID- 20859211 TI - Basilar artery occlusion after multifactor coagulopathy including Rhizopus oryzae infection in burns. AB - The authors report a case of a 29-year-old male patient with severe burn injuries (54% TBSA) and inhalation injury. He developed a candidemia and a cutaneous zygomycotic superinfection with Rhizopus oryzae while he received burn intensive care. Despite aggressive surgery, sepsis persisted, and therapy was limited by uncontrollable coagulopathy and catecholamine refractory shock after 15 days. Autopsy revealed a thromboembolic occlusion of the basilar artery that resulted in liquefactive necrosis of the basal brain tissue and the brain stem. Because cerebral vessel occlusions after burn injuries are reported rarely, the current literature was reviewed, and possible pathophysiological aspects are discussed. PMID- 20859212 TI - Outdoor recreational fires: a review of 329 adult and pediatric patients. AB - Outdoor recreational fires are a frequent occurrence during the summer months and can be associated with burns resulting in significant morbidity. Both pediatric and adult populations can be affected, and their mechanism of injury is often different. Understanding these mechanisms is important when designing prevention programs. It is the goal of this study to review our experience with outdoor recreational fires. All patients who presented to Spectrum Health Blodgett Regional Burn Unit for burns secondary to an outdoor recreational fire over an 8 year period were reviewed. Demographic data, mechanism of injury, body area involved, TBSA burned, treatments undertaken, and subsequent complications were recorded. Pediatric patients (aged 16 years and younger) were analyzed independently, and risk factors were determined. A total of 329 patients suffered burns secondary to outdoor recreational fires over the length of the study. More than 35% required inpatient treatment, with an average length of stay of 4.8 days. Hands were the most frequently affected body part, with the mean TBSA involved being 3.5%. Ninety-four patients (28.6%) required split-thickness skin grafting. The most common mechanism of injury in both adult and pediatric populations was falling into an ongoing fire. Wound infection was the most common complication. Alcohol intoxication was associated with a higher burn severity and complication rate. Pediatric patients represented 39.8% of the sample. Burns secondary to outdoor recreational fires are associated with significant morbidity. Adult prevention programs should target awareness with respect to alcohol consumption and campfires secondary to the morbidity associated with these injuries. Pediatric patients are particularly susceptible, and parents should remain diligent about campfire safety and be educated about the inherent dangers of both active and extinguished fires. PMID- 20859210 TI - Sleep-disordered breathing and pregnancy: potential mechanisms and evidence for maternal and fetal morbidity. AB - PURPOSE OF REVIEW: This article reviews current data on pathophysiologic mechanisms by which sleep-disordered breathing during pregnancy may cause harm, and explores biological pathways for associated adverse maternal and fetal outcomes, especially pregnancy-induced hypertension and gestational diabetes. RECENT FINDINGS: Accumulating data indicate that snoring and sleep apnea during pregnancy are likely to increase the risk for gestational hypertension and preeclampsia. Several new studies have observed that sleep-disordered breathing and short sleep duration also increase the risk of gestational diabetes, similar to observations in the general population. There are varying levels of emerging evidence for potential mechanisms, including oxidative stress, increased sympathetic activity and inflammation, adipokine levels and insulin resistance, linking sleep-disordered breathing events during pregnancy to adverse outcomes. SUMMARY: Sleep-disordered breathing and adverse maternal-fetal outcomes such as preeclampsia and gestational diabetes share a number of mechanistic pathways, and growing data in pregnant women indicate that snoring and sleep apnea increase the risk of these and other complications for both the mother and the fetus. Nevertheless, direct evidence of the pathophysiologic mechanisms by which sleep disordered breathing during pregnancy exerts negative effects remains sparse. PMID- 20859213 TI - Risk factors for ophthalmic complications in patients with burns. AB - A retrospective study of patients admitted to MetroHealth Medical Center was performed to identify the risk factors for short- and long-term ophthalmologic complications related to burn injury. From 2000 to 2007, the authors identified 293 patients with the inclusion criteria of facial burns, TBSA >=20%, or smoke inhalation injury. Seventy (24%) developed ocular complications, and 16 (11%) developed long-term complications. Statistically significant risk factors identified for short-term complications were burn size, chemical burns, depth of facial burns, initial Glasgow Coma Scale, and need for mechanical ventilation/sedation. Risk factors for long-term complications included wound infection with Pseudomonas or Acinetobacter, third-degree burn size, hours to ophthalmology evaluation, LOS, time on mechanical ventilation, and need for STSG. In addition to facial burns, the requirement of mechanical ventilation, prolonged sedation, and presence of infection with Pseudomonas or Acinetobacter increase the risk of injury to the eye after burn injury, and these patients may benefit from serial eye examinations for early identification of ocular complications. PMID- 20859214 TI - Excellent reliability of the Sollerman hand function test for patients with burned hands. AB - The purpose of this study was to identify the minimal detectable change (MDC) of the Sollerman hand function test (SHT) for patients with burned hands. Twelve subjects were studied, giving a total of 21 burned hands (10 right hands and 11 left hands). Each subject received two sessions of SHT assessment, held at 7- to 10-day intervals. Three raters were recruited to observe and assign scores for the patients' performance during the tests. The MDC was calculated based on standard measurement error, and the intraclass correlation coefficient was applied to examine relative reliability. Results showed that both intra- and interrater MDCs were acceptable (6.7 and 6.9 points, respectively) and that both intra- and interrater relative reliabilities were excellent (intraclass correlation coefficients = 0.98). According to this study, the SHT was found to have appropriate MDC and relative reliability in monitoring changes over time for patients with burned hands. The MDCs of SHT calculated in this study are useful in determining whether any change in score is the result of more than random error. PMID- 20859215 TI - Methods and tools used for the measurement of burn scar contracture. AB - After burn injury, scar contracture can cause significant impairment and functional deficit. Many studies have investigated the treatment and prevention of burn scar contracture, but few studies have focused on the methods for measuring contracture. The purpose of this study was to determine whether consistent and objective methods of measurement are used to quantify scar contracture in the clinical evaluation of burn patients and in burn research. A survey was administered to 407 burn therapists to determine the methods and tools used clinically to measure scar contracture, while a review of recent burn literature was conducted to determine the methods and tools used in burn research. The results of the survey indicate that there is a lack of consensus in the methods and tools used for the measurement of scar contracture, both clinically and in research. Instead, a variety of measurement methods was reported, each with varying degrees of objectivity. Clinically, the methods are rarely checked for reliability or performance competency. In burn research, the methods and tools vary, and contracture data obtained are often reported in an inconsistent manner. If the measurement of scar contracture is not done objectively and consistently, then it is difficult to determine reliability, validity, and responsiveness of the measurement methods. Development of standard protocols with reliable measures of scar contracture would improve the quality of burn care and research. PMID- 20859217 TI - Effectiveness of mycophenolic acid in refractory pyoderma gangrenosum. PMID- 20859216 TI - Stem cells and burns: review and therapeutic implications. AB - Despite significant advances in burn resuscitation and wound care over the past 30 years, morbidity and mortality from thermal injury remain high. Limited donor skin in severely burned patients hinders effective wound excision and closure, leading to infectious complications and prolonged hospitalizations. Even with large-volume fluid resuscitation, the systemic inflammatory response syndrome compromises end-organ perfusion in burn patients, with resultant multiorgan failure. Stem cells, which enhance wound healing and counteract systemic inflammation, now offer potential therapies for these challenges. Through a review of the literature, this article seeks to illustrate applications of stem cell therapy to burn care and to highlight promising areas of research. PMID- 20859218 TI - Remission of incapacitating acute cutaneous lupus erythematosus in a patient with systemic lupus erythematosus by B cell-depletive therapy. PMID- 20859219 TI - Giant cell arteritis presenting as ageusia and lower extremity claudication. PMID- 20859220 TI - Patient perceptions of and experiences with inflammatory myositis. PMID- 20859221 TI - A patient with Henoch-Schonlein purpura manifesting unusual symptoms and clinical course. AB - We evaluated and treated a girl with Henoch-Schonlein purpura (HSP), who initially developed redness, swelling, and pain in all 4 limbs accompanied by Raynaud syndrome and then had convulsions and disturbance of consciousness. HSP was diagnosed based on later findings of purpura in both legs and a decrease in factor XIII activity not accompanied by thrombocytopenia. She was normotensive. A skin biopsy specimen showed small-vessel vasculitis accompanied by immunoglobulin A deposition. The cause of erythema and limb pain, convulsions, and disturbed consciousness presumably was vasculitis. The possibility of HSP should be considered in patients with limb pain despite initial absence of purpura and in patients with central nervous system symptoms such as convulsions. PMID- 20859222 TI - Cytomegalovirus as a trigger for systemic lupus erythematosus. AB - Cytomegalovirus (CMV) infections have been associated with exacerbations of systemic lupus erythematosus (SLE). Their role in triggering this disease, however, remains a subject of debate. We present a 43-year-old man with no history of systemic illness who developed persistent signs and symptoms of a CMV associated mononucleosis-like syndrome while fulfilling diagnostic criteria for previously undiagnosed SLE. The patient was admitted with persistent fever for 3 weeks, cervical lymphadenopathy, elevated liver function tests, and leukopenia. Further laboratory studies revealed positive antinuclear antibody, anti-dsDNA, anti-Sm/RNP, rheumatoid factor, and anticardiolipin antibodies along with decreased complement levels and proteinuria of 876 mg/dL. CMV immunoglobulin M was positive in the absence of CMV immunoglobulin G, supporting acute CMV infection. Symptoms improved with intravenous administration of methylprednisolone and ganciclovir therapy. Mechanisms by which CMV may trigger autoimmunity have been proposed, and this case could support CMV infection as a potential trigger for SLE in susceptible individuals. PMID- 20859223 TI - Abatacept therapy for rheumatoid arthritis in the setting of hepatitis C infection. AB - Chronic hepatitis C in the setting of rheumatoid arthritis may be an obstacle to optimal management because of potential hepatotoxicity and adverse effects from immune suppression in these patients with a chronic infection. There are no reports in the literature discussing the use of abatacept, a T-cell costimulatory blocker, in patients with chronic hepatitis C. This article is the first report to describe the use of abatacept in 2 patients with rheumatoid arthritis and concomitant hepatitis C with favorable outcome. PMID- 20859224 TI - Oral tuberculosis in a patient with rheumatoid arthritis after long treatment with methotrexate and adalimumab. AB - The treatment of rheumatoid arthritis (RA) with tumor necrosis factor alpha (TNF alpha) inhibitors has been associated with an increased risk of tuberculosis (TB). Most patients have extrapulmonary disease. We describe a case of tonsil TB in an RA patient treated with methotrexate for 23 years and adalimumab (TNF-alpha inhibitor) for the last 3 years after an initial negative PPD (purified protein derivative of tuberculin) skin test. Our patient presented with a tonsil ulcer. PPD skin test was now positive; biopsy result of the lesion revealed Mycobacterium tuberculosis on culture, and a granuloma typical of TB on histologic assessment. The patient received antituberculous treatment with complete resolution of the lesion. This case illustrates that oral TB can occur after long treatment with TNF-alpha inhibitor and that tuberculous granulomas can be formed in such patients. PMID- 20859225 TI - Rare cause of thoracic myelopathy: ossified ligamentum flavum. AB - Myelopathy due to ossification of ligamentum flavum was first described in 1938 by Anzai (J Jpn Orthop Assosc. 1938;13:305-316). This is a rare condition that has been described mostly in the far east, most commonly in Japan (Miyasaka et al, Am J Neuroradiol. 1983;4:629-632). Cases reported from the western hemisphere are rare, particularly in the African-American population (Wiseman et al, J Spinal Disord Tech. 2002;15:542-545). We report an African-American patient who presented with progressive back and chest pain of recent onset, numbness, tingling, and gait disturbance due to T3 paraplegia secondary to ossified ligamentum flavum resulting in thoracic spinal stenosis. On cross-sectional imaging, there was cord effacement at multiple levels, most pronounced at T10. The patient required emergency laminectomies, which allowed him to recover significant function. This case presentation should heighten physician awareness to this unusual clinical entity, since early diagnosis and timely surgical intervention can prevent permanent neurologic deficits. PMID- 20859226 TI - Sensorineural hearing loss: an underdiagnosed complication of Kawasaki disease. AB - BACKGROUND: Kawasaki disease (KD) is an acute systemic vasculitis of unknown etiology in which the main complication is coronary arteritis. Sensorineural hearing loss (SNHL) has also been described as a complication of this disorder. The objective of this study was to evaluate the prevalence of SNHL in patients with KD and to determine the possible causative abnormality, correlating the findings with the prevalence of cardiac complications, with the use of gammaglobulin, and with the results of laboratory tests. METHODS: A clinical cohort of 40 patients with KD seen between 2005 and 2007 was evaluated by acoustic immittance measurement and brainstem-evoked response audiometry that were performed within the first 30 days of disease and 6 months after the first evaluation. Patients with hearing disability after this period underwent further testing through otoacoustic emissions analysis. All patients were treated with intravenous administration of immunoglobulin. RESULTS: Ten (25%) of the 40 patients developed coronary aneurysm, and 22 (55%) disclosed hearing loss within the first 30 days, although this problem was noticed by the parents in only 3 children. In 12 (30%), the hearing loss persisted after 6 months. Ten (83.3%) of these 12 patients also showed thrombocytosis (platelets, >500,000), 8 (66%) had anemia (hemoglobin, <10 mg/dL), and all had high erythrocyte sedimentation rate (>50 mm/hr) persisting more than 30 days. CONCLUSION: SNHL was more prevalent than coronary complications. A significant association was found between persistent SNHL, although often not initially noted, with a prolonged presence of thrombocytosis, anemia, and high erythrocyte sedimentation rate and the delayed use of intravenous administration of immunoglobulin after the first 10 days of illness. PMID- 20859227 TI - The prevalence of rheumatoid arthritis in Argentina: a capture-recapture study in a city of Buenos Aires province. AB - OBJECTIVE: The objective of this study was to assess the prevalence of rheumatoid arthritis (RA) in the population of a city of 70,000 inhabitants located in Buenos Aires, Argentina. METHODS: Based on the hypothesis that RA is an underdiagnosed disease in Argentina, a capture-recapture method was applied. A local registry of RA patients of Lujan City was taken as the primary source; a telephone survey was specifically carried out as a secondary source of information. Patients suspected of having RA were referred to a local hospital to be examined by a team of 12 rheumatologists. Anamnesis and physical examination were followed by hand and foot radiography and erythrocyte sedimentation rate and rheumatoid factor measurements. RESULTS: According to the American College of Rheumatology criteria, a prevalence rate of 0.94% (95% confidence interval [CI], 0.86%-1.02%) was found in the surveyed population; in agreement with other studies, this prevalence was higher in women when compared with men (for female, 1.54% [95% CI, 1.40%-1.69%]; for male, 0.40% [95% CI, 0.32%-0.49%]). CONCLUSION: The prevalence of RA in a representative sample of the population of a city from the central region of Argentina seems to be close to 1%. PMID- 20859228 TI - Psychological status and patient-assessed health instruments in ankylosing spondylitis. AB - BACKGROUND: Determination of the relationships between disease and psychological status in ankylosing spondylitis (AS) is needed for clinical assessment and management, as well as selection and monitoring of AS patients for biological therapy. OBJECTIVE: The study aimed to describe associations between self reported health status and psychological factors in AS patients and to compare the Symptom Checklist 90-Revised (SCL-90-R) profiles of the AS patients and the control subjects. METHODS: Disease status was determined through the Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and the Bath AS Metrology Index (BASMI). Psychological status was measured using the SCL-90-R. RESULTS: BASDAI and BASFI scores correlated with somatization, anxiety, obsessive compulsive, depression, and hostility subscales of SCL-90-R (P <= 0.05). BASFI scores were significantly correlated with interpersonal sensitivity and phobic anxiety subscales of SCL-90-R (P < 0.05), whereas no correlation was observed between BASDAI and interpersonal sensitivity and phobic anxiety subscales. BASMI scores were significantly correlated with somatization and interpersonal sensitivity subscales (P < 0.05). After age and sex adjustments, a statistically significant difference was determined between the somatization scores of the AS patients and control subjects (P = 0.005). CONCLUSION: AS is a chronic disease, which causes deformities and workforce decline. This, in turn, might lead to psychological distress. There is a need to assess the mood of patients with AS. Completion of self-report assessment tools are potentially confounded by reporting biases that result from psychological factors. Some patients may overreport symptoms or disability because of a tendency to somatize. Thus, during interpretation of these tools, psychological status should be taken into account especially deciding the treatment regimen including biologic therapies. PMID- 20859229 TI - Antisynthetase syndrome presenting as rheumatoid-like polyarthritis. AB - BACKGROUND: The antisynthetase syndrome is a systemic inflammatory disease associated with anti-tRNA synthetase antibodies and consisting of the clinical features of inflammatory myopathy arthritis, interstitial lung disease (ILD), fever, Raynaud syndrome, and rash. It rarely presents with symmetric arthritis as the initial manifestation of the disease. OBJECTIVE: The aim of the study was to describe the clinical, laboratory, and radiographic characteristics of patients with antisynthetase syndrome who presented with symptoms of inflammatory arthritis, mimicking rheumatoid arthritis (RA) at the time of initial evaluation. METHODS: Six cases derived from a single university-based rheumatology clinic in Wisconsin are presented. The major clinical, laboratory, radiographic, and histopathologic data are described. RESULTS: All 6 patients demonstrated symmetric synovitis involving the hands. Five patients met the American College of Rheumatology classification criteria for RA. Three patients had nail-fold capillary abnormalities, and 4 patients were observed to have Raynaud phenomenon. Three patients demonstrated a cytoplasmic pattern when testing for antinuclear antibodies by immunofluorescent assay, and all had t-RNA synthetase antibodies. Two patients had positive rheumatoid factors, but none had strongly positive cyclic citrullinated peptide antibodies. None of the patients demonstrated radiographic erosions. All patients had evidence of ILD by imaging or pulmonary function testing. Prognosis was generally favorable, although disease severity and treatment varied considerably. CONCLUSION: In patients who present with features mimicking but atypical for RA, such as early ILD, nail-fold capillary abnormalities, Raynaud phenomenon, cytoplasmic antinuclear antibody pattern, negative cyclic citrullinated peptide antibody status, and nonerosive arthritis, the antisynthetase syndrome should be considered. PMID- 20859230 TI - Histology of a fusion mass augmented with demineralized bone matrix for congenital scoliosis. AB - The pseudarthrosis rate after a posterior spinal fusion for congenital scoliosis and kyphoscoliosis is high, between 9.1 and 46.1%. Autogenous iliac crest bone graft is the current gold standard graft material, but is associated with complications that include donor site pain and infection. Demineralized bone matrix (DBM) may be a cost effective, safe, and clinically effective alternative bone graft material. The medical records of a single patient with the diagnosis of congenital scoliosis who had undergone a posterior spinal fusion were reviewed under an institutional review board approved protocol. At 11 months after posterior spinal fusion, bone biopsies were obtained upon routine planned exploration of the spinal fusion site. These samples were sectioned and reviewed by an independent pathologist to assess for bone maturity and the presence of residual allograft bone graft material. The histological specimens that were obtained from the patient showed mature bone with no residual graft material evident in any of the samples. In conclusion, in this particular case, the DBM was fully incorporated into the fusion mass. Although a large clinical trial would be necessary to make generalized conclusions about the use of DBM in the congenital scoliosis population, this histological analysis adds evidence that DBM is incorporated and may aid in obtaining a solid spinal fusion in this difficult population. PMID- 20859231 TI - Phase I safety study of lenalidomide and dacarbazine in patients with metastatic melanoma previously untreated with systemic chemotherapy. AB - This phase I trial assessed the maximal tolerated dose (MTD) of dacarbazine in combination with lenalidomide in metastatic melanoma. Cohorts of three to six patients with metastatic melanoma without brain metastases were enrolled at each of three dose levels of dacarbazine: 600 mg/m2, 800 mg/m2, and 1000 mg/m2 administered intravenously every 3 weeks. Lenalidomide (25 mg/day) was administered orally for 14 days followed by a 7-day rest. Safety was assessed every 3 weeks, and tumor response was evaluated every 6 weeks. An additional 10 patients were enrolled in an expansion cohort at MTD level. Twenty-eight chemotherapy-naive patients were enrolled. The MTD was determined to be dose level 2 (800 mg/m2). Three patients experienced a grade 4 adverse reaction; two pulmonary emboli and one cerebral ischemia. Two patients had a deep venous thrombosis. Of 27 patients assessable for disease response, two experienced a complete response and four experienced a partial response. The median overall survival was 10.6 months (range 1.6-46.0+ months). One patient had a small brain lesion at the baseline; 10 additional patients developed brain metastasis at 0 10.8 months after completion of study therapy. The combination of dacarbazine and lenalidomide is safe and well tolerated in patients with metastatic melanoma. Clinical activity was seen at the MTD level. Additional measures to prevent brain metastasis are needed for patients who achieve a response. PMID- 20859232 TI - PET study on mice bearing human colon adenocarcinoma cells using [11C]GF120918, a dual radioligand for P-glycoprotein and breast cancer resistance protein. AB - OBJECTIVE: To evaluate the functions of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in human colon adenocarcinoma (Caco-2), we carried out an in-vitro study and a small animal positron emission tomography (PET) study using [C]GF120918 (elacridar). METHODS: [C]GF120918 was synthesized by reacting the desmethyl precursor with [C]CH3I. An in-vitro study using [C]GF120918 was carried out in Caco-2 and Madin-Darby canine kidney cells in the presence or absence of a transporter inhibitor (cyclosporine A and unlabeled GF120918). The biodistribution of radioactivity after the injection of [C]GF120918 was determined in Caco-2-bearing mice using a small animal PET scanner. RESULTS: In Caco-2 cells expressing Pgp and BCRP, coincubation with unlabeled GF120918 caused an approximately two-fold increase in [C]GF120918 uptake compared with that of the control ([C]GF120918 only). In Caco-2-bearing mice, PET results indicated that [C]GF120918 uptake in the tumor was low, but was significantly increased by treatment with unlabeled GF120918. In metabolite analysis, the radioactive component in the tumor almost corresponded to intact [C]GF120918. CONCLUSION: A PET study combining the administration of [C]GF120918 with unlabeled GF120918 may be a useful tool for evaluating the functions of Pgp and BCRP in tumors. PMID- 20859233 TI - Idiopathic orbital inflammation leading to unilateral blindness over a 2-day presentation in a child. AB - An 8-year-old boy developed vision loss to no light perception on the left side over a 2-day period. He initially presented with unilateral eyelid swelling, which progressed to bilateral edema and an eventual left-sided orbital apex syndrome. Orbital imaging revealed enlarged extraocular muscles, and biopsy confirmed idiopathic orbital inflammation. Despite subsequent orbital decompression, high-dose steroids, and additional steroid-sparing therapy, he did not regain vision after 9 months of follow up. PMID- 20859234 TI - Bilateral orbital subperiosteal hemorrhage following labor. AB - A 27-year-old woman presented with 13 days of bilateral periorbital swelling, discomfort, and visual loss, which developed immediately after labor. She had significant blood loss requiring blood transfusion. There was bilateral proptosis, left optic neuropathy, and a superior visual hemifield defect in the left eye. MRI of the orbits showed bilateral superior subperiosteal hematomas. She underwent bilateral orbitotomy and drainage of subperiosteal hematomas. Six months later, complete resolution of proptosis with normal ocular motility and visual acuity was observed; however, there was persistence of a left relative afferent pupillary defect with superior visual field loss. This case report highlights the need for a high index of diagnostic suspicion of subperiosteal hematoma arising in a nontraumatic setting, such as in the peripartum period, and consideration for emergent surgical management of optic neuropathy. PMID- 20859235 TI - Reply re: "Lacrimal canalicular transplantation with composite eyelid graft". PMID- 20859236 TI - A survey study of occupational pain and injury in ophthalmic plastic surgeons. AB - PURPOSE: To determine factors associated with pain/injury related to practicing ophthalmic plastic and reconstructive surgery. METHODS: A 29-question electronic survey was sent to the American Society of Ophthalmic Plastic and Reconstructive Surgery's listserv. The Chi-Squared Automatic Interaction Detector technique was used to generate a decision tree using SPSS software. The levels of dendograms were limited to 8. Significance was pre-established at alpha = 0.05. RESULTS: One hundred thirty surveys were completed, and 72.5% reported pain associated with operating, 80.9% reported use of loupe magnification, 68.7% reported use of a headlight, 42.5% reported modification of their operating room practice, and 9.2% reported stopping operating due to pain or spine injury. Most respondents regularly exercise, with 55.7% characterizing the amount of exercise as less than necessary; 60.8% and 57.3% agreed that loupe use and headlamp use, respectively, can lead to spine problems.Chi-Squared Automatic Interaction Detector analysis found that 62.7% (n = 47) with neck pain had modified their operating room practice, compared with 13.5% (n = 7) without pain (chi = 30.42; df = 1; p < 0.001); All surgeons that had to stop operating (n = 9) had tried modifying their operating room practice; over half (57.6%, n = 38) of practicing surgeons had changed their operating room practice (chi = 6.09; df = 1; p = 0.014). The majority who exercised 5 hours or less had modified their operating room practice (70.2%, n = 33), compared with 26.3% (n = 5) who exercised more. CONCLUSIONS: Many oculoplastic surgeons experience discomfort due to operating, and an alarming minority have stopped operating due to pain or neck injury. Participants identified loupe and headlamp use as a special concern. PMID- 20859237 TI - Histoplasmosis presenting as a cutaneous malignancy of the eyelid. AB - Cutaneous histoplasmosis is an uncommon infection and can occur as a primary infection. A manifestation imitating a cutaneous neoplasm is rare, and eyelid involvement is rarer still. The authors report a case of histoplasmosis that presented as an ulcerated lesion on the lower eyelid margin that clinically resembled a basal cell carcinoma. Given its worldwide distribution, it is important to include this disease in the differential diagnosis of nonhealing eyelid lesions. Biopsy and tissue culture are paramount to establishing the diagnosis. This case describes a rare presentation of histoplasmosis on the eyelid and highlights the importance of histopathologic evaluation. PMID- 20859238 TI - Adult-onset asthma and severe periocular xanthogranuloma: a case report. AB - A 55-year-old obese Mexican American male with a 3-year history of adult-onset asthma presented with a 10-year history of disfiguring eyelid edema. A biopsy revealed lymphoid aggregates consisting of reactive lymphoid follicles and Touton giant cells. He was diagnosed with adult-onset asthma associated with periocular xanthogranuloma and treated with systemic steroids. This case highlights an uncommon disease in its most severe presentation. PMID- 20859239 TI - Ptosis assessment spectacles: a new method of measuring lid position and movement in children. AB - PURPOSE: Accurate assessment of eyelid position and movement is vital in planning the surgical correction of ptosis. Conventional measurements taken using a millimeter ruler are considered the gold standard, although in young children this can be a difficult procedure. The authors have designed ptosis assessment spectacles with a measuring millimeter scale marked on the center of the lens to facilitate accurate assessment of eyelid position and function in children. The purpose of the study was to assess the accuracy and reproducibility of eyelid measurement using these ptosis assessment spectacles. METHODS: Fifty-two children aged 2-12 years were recruited in this study. Each child underwent 2 sets of measurements. The first was undertaken by an ophthalmologist in the conventional manner using a ruler, and the second set made with ptosis assessment spectacles. On each occasion the palpebral aperture, skin crease, and levator function were recorded in millimeters. A verbal analog scale was used to assess parent satisfaction with each method. RESULTS: Clinically acceptable reproducibility was shown with the ruler and the spectacles for all measurements: palpebral aperture, skin crease, and levator function. Parents significantly preferred the glasses for measurement, as compared with the ruler (p < 0.05). CONCLUSIONS: The spectacles are as accurate as conventional methods of measurement, but are easier to use. Children tolerate these spectacles well, and most parents preferred them to the ruler. PMID- 20859240 TI - Primary orbital manifestation of Hodgkin lymphoma in a 3-year-old child. AB - Hodgkin lymphoma is exceedingly rare in children, as is primary orbital manifestation of systemic Hodgkin lymphoma in any age category. The authors describe the clinicopathologic manifestations of a rare case of systemic Hodgkin lymphoma with primary orbital manifestation in a 3-year-old boy with histologically proven Hodgkin lymphoma with mixed cellularity. After an incisional biopsy and tumor debulking, followed by systemic workup, the diagnosis of stage IVA Hodgkin lymphoma was made. He underwent treatment with 4 cycles of adriamycin, bleomycin, vincristine, etopiside, prednisone, and cyclophosphamide, followed by involved field radiation. He has been followed at regular intervals for 6 years. Scans have shown resolution at all sites, and blood counts have remained normal. To the best of the authors' knowledge, this is the youngest patient with primary orbital manifestation of Hodgkin lymphoma reported in the English literature. PMID- 20859241 TI - A case of delayed oculocardiac reflex induced by an intraorbital foreign body. AB - A 56-year-old male presented with a history of left periorbital pain, nausea, vomiting, dyspnea, sweating, and pallor. His left eye was injured by a bomb explosion approximately 40 years ago. Evisceration was performed. There were no cardiopulmonary and gastroenterological findings except mild bradycardia (54/min). CT evaluation revealed a 4-cm-sized, sharp, metallic, intraorbital foreign body in the left orbit. After the removal of the foreign body, the symptoms completely resolved with a normal heart rate (69/min). The authors present a case of delayed oculocardiac reflex induced by an old intraorbital foreign body. PMID- 20859242 TI - Anticyclic-citrullinated protein antibodies in the diagnosis of ophthalmic inflammatory disease. AB - While rheumatoid factor (RF) testing has been previously used in the detection of rheumatoid arthritis (RA), its effectiveness has been limited by poor rates of sensitivity and specificity and its positivity in multiple other disease states. Given its enhanced specificity, quantification of anticyclic-citrullinated protein (anti-CCP) antibodies has emerged as a standard in molecular testing for RA. Despite the importance of this test in clinical rheumatology, we are unaware of any reports of its use in the detection of uveitis or orbital disease. In this report, we characterize the first use of anti-CCP in the diagnosis of orbital disease. PMID- 20859243 TI - Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. AB - OBJECTIVES: The goals of this study were to determine the role of organic cation transporter 3 (OCT3) in the pharmacological action of metformin and to identify and functionally characterize genetic variants of OCT3 with respect to the uptake of metformin and monoamines. METHODS: For pharmacological studies, we evaluated metformin-induced activation of AMP-activated protein kinase, a molecular target of metformin. We used quantitative PCR and immunostaining to localize the transporter and isotopic uptake studies in cells transfected with OCT3 and its nonsynonymous genetic variants for functional analyses. RESULTS: Quantitative PCR and immunostaining showed that OCT3 was expressed high on the plasma membrane of skeletal muscle and liver, target tissues for metformin action. Both the OCT inhibitor, cimetidine, and OCT3-specific short hairpin RNA significantly reduced the activating effect of metformin on AMP-activated protein kinase. To identify genetic variants in OCT3, we used recent data from the 1000 Genomes and the Pharmacogenomics of Membrane Transporters projects. Six novel missense variants were identified. In functional assays, using various monoamines and metformin, three variants, T44M (c.131C>T), T400I (c.1199C>T) and V423F (c.1267G>T) showed altered substrate specificity. Notably, in cells expressing T400I and V423F, the uptakes of metformin and catecholamines were significantly reduced, but the uptakes of metformin, 1-methyl-4-phenylpyridinium and histamine by T44M were significantly increased more than 50%. Structural modeling suggested that these two variants may be located in the pore lining (T400) or proximal (V423) membrane spanning helixes. CONCLUSION: Our study suggests that OCT3 plays a role in the therapeutic action of metformin and that genetic variants of OCT3 may modulate metformin and catecholamine action. PMID- 20859244 TI - Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease. AB - OBJECTIVE: Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD. METHODS: In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6 month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis. RESULTS: Thirty eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667). CONCLUSIONS: Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment. PMID- 20859245 TI - Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol. AB - BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments. OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol. METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia. CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects. PMID- 20859247 TI - A comparison of the adoption of electronic health records in North Carolina and South Carolina HIV systems. AB - BACKGROUND: The electronic exchange of health records has been a notable topic in recent years in the effort to improve the quality of healthcare delivery and reduce administrative burden. Interviews and documents from stakeholders in human immunodeficiency virus (HIV) care, and HIV information technology were collected between November 2004 through March 2005 to conduct a qualitative policy analysis on the adoption of an electronic health record (EHR) system among HIV care providers in North Carolina and South Carolina. METHOD: Interview data on the current state of EHR use were collected in February through June 2008. The case study analysis included description, categorical aggregation, and naturalistic generalization. RESULTS: Naturalistic generalizations that emerged were (1) state level policies can have a significant effect on successful adoption of EHRs; (2) state-level champions are integral to cross-sectoral, multi-institutional EHR adoption; (3) voluntary and mandatory adoption strategies can lead to successful cross-sectoral, multi-institutional EHR implementation. CONCLUSION: State health departments can play an integral part in the successful implementation of EHR systems. PMID- 20859246 TI - ABCB1 gene polymorphisms are associated with the severity of major depressive disorder and its response to escitalopram treatment. AB - OBJECTIVE: ATP-binding cassette, sub-family B (MDR/TAP), member 1 (ABCB1) is a drug transporter protein expressed on the epithelial cells of the intestine and the endothelial cells of the blood-brain barrier. Intestinal ABCB1 actively transports drugs from the cell membrane and prevents them from entering the blood stream whereas the blood-brain barrier ABCB1 prevents drugs from entering the central nervous system. In this study, we tested whether genetic polymorphisms within the ABCB1 gene are associated with the severity of depression and the effectiveness of the antidepressant, escitalopram (S-CIT), in treating major depressive disorder (MDD). METHODS: Twenty single nucleotide polymorphisms in the ABCB1 gene were selected and genotyped in 100 MDD patients who had undergone S CIT treatment continuously for 8 weeks. The serum concentrations of S-CIT and its metabolites (S-desmethylcitalopram and S-didesmethylcitalopram) were then measured at weeks 2, 4, and 8. RESULTS: The ABCB1 genotypes of rs1922242 (P=0.0028) and rs1202184 (P=0.0021) showed significant association with the severity of depressive symptoms as assessed by the Hamilton Rating Scale for Depression adjusted with Hamilton Rating Scale for Anxiety. The haplotype block, rs1882478-rs2235048-rs2235047-rs1045642-rs6949448 (from intron 27 to intron 26), of ABCB1 was found strongly associated with the remission rate (global P=0.003, d.f.=69) in which haplotype T-T-T-C-C was associated with a slower remission rate on S-CIT treatment (P=0.001). The haplotypes may not be indicators of the severity of depression or anxiety. CONCLUSION: Our findings suggest that single nucleotide polymorphisms in the ABCB1 gene may be indicators of the severity of depression and of the likely S-CIT treatment remission response in MDD. PMID- 20859248 TI - Acute bilateral ischemia of fingers: an unusual complication of temporal arteritis. AB - We describe the case of a patient with documented temporal arteritis, who presented two years into her course with acute digital ischemia, presumed secondary to small vessel vasculitis. To our knowledge, this complication of temporal arteritis has not been previously reported. PMID- 20859249 TI - Hiccups as a sign of chronic myocardial ischemia. AB - Chronic myocardial ischemia often presents with a fairly typical history, but patients can present with atypical chest pain or pain referred to a less-typical location like the jaw, stomach, or back. Sometimes patients describe symptoms usually not attributed to heart disease, like indigestion or feeling cold and clammy, in the presence or absence of chest pain. One important clue to underlying coronary artery disease is the appearance of symptoms that are induced by effort and relieved by rest. This paper describes two unusual presentations of myocardial ischemia in patients whose main symptom was hiccups, the first intractable hiccups over months and the second effort-induced hiccups. Both also described atypical chest pain. PMID- 20859250 TI - Asacol(r)-induced neutropenia resolution without the use of granulocyte colony stimulating factor. AB - We report a case of neutropenia and gram-negative septicemia in a 73-year-old male with ulcerative colitis. During the hospital course, medications were adjusted according to rare accounts of drug-induced neutropenia. While the substitution of propafenone for another antiarrhythmic brought about no change in the patient's absolute neutrophil count, the cessation of Asacol(r) (Warner Chilcott, Rockaway, NJ) was followed by a significant improvement in the neutropenic state. In fact, this neutrophil count continued to trend upward for months following. We thereby conclude that Asacol(r) carries the potential to induce neutropenia and that this reaction may be reversed in some patients solely by discontinuing the medication and without the aid of stimulating factors such as filgrastim. PMID- 20859251 TI - Giant melanoma: novel problem, same approach. AB - Thick melanomas are relatively common; however, melanomas greater than 10 cm in size are rarely encountered. Though the size may seem daunting, the work up and principles of wide surgical excision remain the same. Sentinel lymph node biopsy should also be considered in patients with no clinical evidence of metastatic disease. PMID- 20859252 TI - Novel markers in zero-hour kidney biopsies indicate graft quality and clinical outcome. AB - BACKGROUND: In renal transplantation, allograft biopsies provide valuable diagnostic information indicating adverse allograft outcome posttransplantation. To uncover novel candidate markers characteristic of subtle inflammation and immune activation present during the intraoperative period, we investigated messenger RNA (mRNA) gene expression profiles in renal zero biopsies. METHODS: Transcription profiles from deceased donors (n=63) and living donors (n=26) were investigated for inflammation-associated markers in zero-hour biopsies by real time reverse-transcriptase polymerase chain reaction. RESULTS: We observed a significant induction of the chemokine receptor 7 ligands [C-C motif] ligand 19/21 in the deceased donor group (P<0.001). Additionally, along with the induction of the activation marker CD69 (P<0.01), we further detected significant elevated mRNA levels of the inducible immunoproteasome subunits PSMB8, PSMB9, and PSMB10 (P<0.001, respectively). Candidate markers were further tested for posttransplantation clinical outcomes showing the potential to predict the development of delayed graft function, acute rejection, and renal function after 6 months. For instance, by combining mRNA gene expression profiles with clinical patient data, the analysis revealed high sensitivity (95%) and specificity (84%, area under the curve=0.93) for the prediction of acute rejection. CONCLUSIONS: Zero-hour biopsies of renal allografts may provide useful information on subclinical pathological changes in the grafted kidney. The identification of CCL19/21 or PSMB8/9/10 makes these molecules particularly suitable as potential candidate targets for therapeutic interventions. PMID- 20859253 TI - Hen1 is required for oocyte development and piRNA stability in zebrafish. AB - Piwi-interacting RNAs (piRNAs) are germ line-specific small RNA molecules that have a function in genome defence and germ cell development. They associate with a specific class of Argonaute proteins, named Piwi, and function through an RNA interference-like mechanism. piRNAs carry a 2'-O-methyl modification at their 3' end, which is added by the Hen1 enzyme. We show that zebrafish hen1 is specifically expressed in germ cells and is essential for maintaining a female germ line, whereas it is dispensable in the testis. Hen1 protein localizes to nuage through its C-terminal domain, but is not required for nuage formation. In hen1 mutant testes, piRNAs become uridylated and adenylated. Uridylation frequency is highest on retro-transposon-derived piRNAs and is accompanied by decreased piRNA levels and mild derepression of transposon transcripts. Altogether, our data suggest the existence of a uridylation-mediated 3'-5' exonuclease activity acting on piRNAs in zebrafish germ cells, which is counteracted by nuage-bound Hen1 protein. This system discriminates between piRNA targets and is required for ovary development and fully efficient transposon silencing. PMID- 20859255 TI - Polypyrimidine tract-binding protein stimulates the poliovirus IRES by modulating eIF4G binding. AB - Tethered hydroxyl-radical probing has been used to determine the orientation of binding of polypyrimidine tract-binding protein (PTB) to the poliovirus type 1 (Mahoney) (PV-1(M)) internal ribosome entry site/segment (IRES)-the question of which RNA-binding domain (RBD) binds to which sites on the IRES. The results show that under conditions in which PTB strongly stimulates IRES activity, a single PTB is binding to the IRES, a finding which was confirmed by mass spectrometry of PTB/IRES complexes. RBDs1 and 2 interact with the basal part of the Domain V irregular stem loop, very close to the binding site of eIF4G, and RBDs3 and 4 interact with the single-stranded regions flanking Domain V. The binding of PTB is subtly altered in the presence of the central domain (p50) of eIF4G, and p50 binding is likewise modified if PTB is present. This suggests that PTB stimulates PV-1(M) IRES activity by inducing eIF4G to bind in the optimal position and orientation to promote internal ribosome entry, which, in PV-1(M), is at an AUG triplet 30 nt downstream of the base of Domain V. PMID- 20859254 TI - Molecular organization and dynamics of the melatonin MT1 receptor/RGS20/G(i) protein complex reveal asymmetry of receptor dimers for RGS and G(i) coupling. AB - Functional asymmetry of G-protein-coupled receptor (GPCR) dimers has been reported for an increasing number of cases, but the molecular architecture of signalling units associated to these dimers remains unclear. Here, we characterized the molecular complex of the melatonin MT1 receptor, which directly and constitutively couples to G(i) proteins and the regulator of G-protein signalling (RGS) 20. The molecular organization of the ternary MT1/G(i)/RGS20 complex was monitored in its basal and activated state by bioluminescence resonance energy transfer between probes inserted at multiple sites of the complex. On the basis of the reported crystal structures of G(i) and the RGS domain, we propose a model wherein one G(i) and one RGS20 protein bind to separate protomers of MT1 dimers in a pre-associated complex that rearranges upon agonist activation. This model was further validated with MT1/MT2 heterodimers. Collectively, our data extend the concept of asymmetry within GPCR dimers, reinforce the notion of receptor specificity for RGS proteins and highlight the advantage of GPCRs organized as dimers in which each protomer fulfils its specific task by binding to different GPCR-interacting proteins. PMID- 20859256 TI - CBP/p300 double null cells reveal effect of coactivator level and diversity on CREB transactivation. AB - It remains uncertain how the DNA sequence of mammalian genes influences the transcriptional response to extracellular signals. Here, we show that the number of CREB-binding sites (CREs) affects whether the related histone acetyltransferases (HATs) CREB-binding protein (CBP) and p300 are required for endogenous gene transcription. Fibroblasts with both CBP and p300 knocked-out had strongly attenuated histone H4 acetylation at CREB-target genes in response to cyclic-AMP, yet transcription was not uniformly inhibited. Interestingly, dependence on CBP/p300 was often different between reporter plasmids and endogenous genes. Transcription in the absence of CBP/p300 correlated with endogenous genes having more CREs, more bound CREB, and more CRTC2 (a non-HAT coactivator of CREB). Indeed, CRTC2 rescued cAMP-inducible expression for certain genes in CBP/p300 null cells and contributed to the CBP/p300-independent expression of other targets. Thus, endogenous genes with a greater local concentration and diversity of coactivators tend to have more resilient-inducible expression. This model suggests how gene expression patterns could be tuned by altering coactivator availability rather than by changing signal input or transcription factor levels. PMID- 20859257 TI - Nanoparticles deliver triplex-forming PNAs for site-specific genomic recombination in CD34+ human hematopoietic progenitors. AB - Triplex-forming peptide nucleic acids (PNAs) are powerful gene therapy agents that can enhance recombination of short donor DNAs with genomic DNA, leading to targeted and specific correction of disease-causing genetic mutations. Therapeutic use of PNAs is severely limited, however, by challenges in intracellular delivery, particularly in clinically relevant targets such as hematopoietic stem and progenitor cells. Here, we demonstrate efficient and nontoxic PNA-mediated recombination in human CD34(+) cells using poly(lactic-co glycolic acid) (PLGA) nanoparticles for intracellular oligonucleotide delivery. Treatment of progenitor cells with nanoparticles loaded with PNAs and DNAs targeting the beta-globin locus led to levels of site-specific modification in the range of 0.5-1% in a single treatment, without detectable loss in cell viability, resulting in a 60-fold increase in modified and viable cells as compared to nucleofection. As well, the differentiation capacity of the progenitor cells treated with nanoparticles did not change relative to untreated progenitor cells, indicating that nanoparticles are safe and minimally disruptive delivery vectors for PNAs and DNAs to mediate gene modification in human primary cells. This is the first demonstration of the use of biodegradable nanoparticles to deliver genome-editing agents to human primary cells, and provides a strong rationale for systemic delivery of complex nucleic acid mixtures designed for gene correction. PMID- 20859258 TI - Gene therapy of canine leukocyte adhesion deficiency using lentiviral vectors with human CD11b and CD18 promoters driving canine CD18 expression. AB - To identify cellular promoters in a self-inactivating (SIN) lentiviral vector that might be beneficial in treating children with leukocyte adhesion deficiency type 1 (LAD-1), we tested lentiviral vectors with human CD11 and CD18 leukocyte integrin proximal promoter elements directing expression of canine CD18 in animals with canine LAD (CLAD). Lentiviral vectors with either the human CD11b (637 bp) proximal promoter or the human CD18 (1,060 bp) proximal promoter resulted in the highest percentages of CD18(+) CLAD CD34(+) cells in vitro. Subsequently, two CLAD dogs were infused with autologous CD34(+) cells transduced with the hCD11b (637 bp)-cCD18 vector, and two CLAD dogs were infused with autologous CD34(+) cells transduced with the hCD18 (1,060 bp)-cCD18 vector. Each dog received a nonmyeloablative dose of 200 cGy total body irradiation (TBI) before the infusion of transduced cells. The two CLAD dogs treated with the hCD18 (1,060 bp)-cCD18 vector, and one of the two dogs treated with the hCD11b (637 bp) cCD18 vector, had reversal of the CLAD phenotype. These studies using endogenous leukocyte integrin proximal promoters represent an important step in the development of gene therapy for children with LAD-1. PMID- 20859260 TI - Retraction to "Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system". PMID- 20859259 TI - Targeted gene-and-host progenitor cell therapy for nonunion bone fracture repair. AB - Nonunion fractures present a challenge to orthopedics with no optimal solution. In-vivo DNA electroporation is a gene-delivery technique that can potentially accelerate regenerative processes. We hypothesized that in vivo electroporation of an osteogenic gene in a nonunion radius bone defect site would induce fracture repair. Nonunion fracture was created in the radii of C3H/HeN mice, into which a collagen sponge was placed. To allow for recruitment of host progenitor cells (HPCs) into the implanted sponge, the mice were housed for 10 days before electroporation. Mice were electroporated with either bone morphogenetic protein 9 (BMP-9) plasmid, Luciferase plasmid or injected with BMP-9 plasmid but not electroporated. In vivo bioluminescent imaging indicated that gene expression was localized to the defect site. Microcomputed tomography (uCT) and histological analysis of murine radii electroporated with BMP-9 demonstrated bone formation bridging the bone gap, whereas in the control groups the defect remained unbridged. Population of the implanted collagen sponge by HPCs transfected with the injected plasmid following electroporation was noted. Our data indicate that regeneration of nonunion bone defect can be attained by performing in vivo electroporation with an osteogenic gene combined with recruitment of HPCs. This gene therapy approach may pave the way for regeneration of other skeletal tissues. PMID- 20859262 TI - Retraction to "Metabolic basis of sexual dimorphism in PKU mice after genome targeted PAH gene therapy". PMID- 20859261 TI - AAV4-mediated expression of IGF-1 and VEGF within cellular components of the ventricular system improves survival outcome in familial ALS mice. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron cell death in the cortex, brainstem, and spinal cord. Extensive efforts have been made to develop trophic factor-based therapies to enhance motor neuron survival; however, achievement of adequate therapeutic delivery to all regions of the corticospinal tract has remained a significant challenge. Here, we show that adeno-associated virus serotype 4 (AAV4)-mediated expression of insulin-like growth factor-1 (IGF-1) or vascular endothelial growth factor (VEGF)-165 in the cellular components of the ventricular system including the ependymal cell layer, choroid plexus [the primary cerebrospinal fluid (CSF) producing cells of the central nervous system (CNS)] and spinal cord central canal leads to trophic factor delivery throughout the CNS, delayed motor decline and a significant extension of survival in SOD1(G93A) transgenic mice. Interestingly, when IGF-1- and VEGF-165-expressing AAV4 vectors were given in combination, no additional benefit in efficacy was observed suggesting that these trophic factors are acting on similar signaling pathways to modestly slow disease progression. Consistent with these findings, experiments conducted in a recently described in vitro cell culture model of ALS led to a similar result, with both IGF-1 and VEGF-165 providing significant motor neuron protection but in a nonadditive fashion. These findings support the continued investigation of trophic factor-based therapies that target the CNS as a potential treatment of ALS. PMID- 20859264 TI - The Incidence and gastrointestinal infectious risk of functional gastrointestinal disorders in a healthy US adult population. AB - OBJECTIVES: Functional gastrointestinal disorders (FGDs) are recognized sequelae of infectious gastroenteritis (IGE). Within the active duty military population, a group with known high IGE rates, the population-based incidence, risk factors, and attributable burden of care referable to FGD after IGE are poorly defined. METHODS: Using electronic medical encounter data (1999-2007) on active duty US military, a matched, case-control study describing the epidemiology and risk determinants of FGD (irritable bowel syndrome (IBS), functional constipation (FC), functional diarrhea (FD), dyspepsia (D)) was conducted. Incidence rates and duration of FGD-related medical care were estimated, and conditional logistic regression was utilized to evaluate FGD risk after IGE. RESULTS: A total of 31,866 cases of FGD identified were distributed as follows: FC 55% (n=17,538), D 21.2% (n=6,750), FD 2.1% (n=674), IBS 28.5% (n=9,091). Previous IGE episodes were distributed as follows: specific bacterial pathogen (n=65, 1.2%), bacterial, with no pathogen specified (n=2155, 38.9%), protozoal (n=38, 0.7%), viral (n=3431, 61.9%). A significant association between IGE and all FGD (odds ratio (OR) 2.64; P<0.001) was seen, with highest risk for FD (OR 6.28, P<0.001) and IBS (OR 3.72, P<0.001), and moderate risk for FC (2.15, P<0.001) and D (OR 2.39, P<0.001). Risk generally increased with temporal proximity to, and bacterial etiology of, exposure. Duration of FGD-related care was prolonged with 22.7% having FGD associated medical encounters 5 years after diagnosis. CONCLUSIONS: FGD are common in this population at high risk for IGE. When considering effective countermeasures and mitigation strategies, attention directed toward prevention as well as the acute and chronic sequelae of these infections is needed. PMID- 20859263 TI - Gene therapy of mdx mice with large truncated dystrophins generated by recombination using rAAV6. AB - Recombinant adeno-associated viral (rAAV) vector-mediated gene transfer represents a promising approach for many diseases. However, the applicability of rAAV vectors has long been hindered by the small (~4.8 kb) DNA packaging capacity. This limitation can hamper the packaging and delivery of critical regulatory elements and/or larger coding sequences, such as the ~14-kb dystrophin complementary DNA (cDNA) that is of interest for gene therapy of Duchenne muscular dystrophy (DMD). Here, we have demonstrated reconstitution of an expression cassette (7.3 kb) encoding a highly functional "minidystrophin" protein (DeltaH2-R19, 222 kd) in vivo following intravascular co-delivery of two independent rAAV6 vectors sharing a central homologous recombinogenic region of 372 nucleotides. Similar to previously reported trans-splicing approaches, one rAAV vector provides the promoter with the ~1/2 initial portion of minidystrophin, while the second vector provides the remaining minidystrophin cDNA followed by the polyadenylation signal. Significantly, administering a modest dose [2 * 10(12) vector genomes (vg)] of the two minidystrophin-encoding rAAV vectors to dystrophic mice elicited an improvement of physiological performance indicative of prevention or amelioration of the disease state. These studies provide evidence that functional dystrophin transgenes larger than that typically carried by a single rAAV genome can be reconstituted in vivo by homologous recombination (HR) following intravascular co-delivery with rAAV6. PMID- 20859270 TI - Is electronic approval appropriate? Assurance should dictate. PMID- 20859271 TI - Is electronic approval appropriate? PMID- 20859272 TI - Is electronic approval appropriate? Quorum requires convened meeting. PMID- 20859273 TI - Is electronic approval appropriate? Convened meeting for approval. PMID- 20859274 TI - Is electronic approval appropriate? A word from OLAW and USDA. PMID- 20859275 TI - Epistaxis and nasal swelling in a cynomolgus macaque. PMID- 20859277 TI - Indirect blood pressure monitoring in small mammals. AB - Direct blood pressure monitoring is the most accurate cardiovascular monitoring technique, but it is challenging in small mammals, as well as time-consuming and costly. Therefore, indirect blood pressure monitoring is most commonly used in clinic and laboratory settings. This column discusses indirect blood pressure monitoring in small mammals. PMID- 20859278 TI - A technique for intracisternal collection and administration in a rhesus macaque. AB - Accessing the subarachnoid space via intrathecal needle placement can be done in nonhuman primates (NHPs) and other species to collect cerebral spinal fluid (CSF) or to deliver agents into the CSF. Researchers can use a variety of techniques for intrathecal collection and administration. Drawing on various published resources and previous experience with intracisternal CSF sampling, the authors sought to modify one collection technique to include CSF administration. Here, the authors describe how they collected CSF from the cisterna magna of rhesus macaques (Macaca mulatta) and administered substances through the cisterna magna into the CSF. They identify potential concerns that they had when developing the technique and describe how they alleviated those concerns. The authors found this technique, which relies heavily on teamwork, to be an effective method for intracisternal injection of an experimental compound. PMID- 20859279 TI - Using a cardiac anchor to refine myocardial infarction surgery in the rat. AB - Researchers have used the rat model of myocardial infarction for more than 20 y to successfully mimic the detrimental effects of coronary occlusion of the left anterior descending (LAD) coronary artery in humans. But researchers have published little about this surgery's intricacies or about the pathological progression of the disease after surgery. The authors describe a refined technique that uses a suture anchor at the apex of the heart, which allows easy and accurate placement of a ligature around the LAD. Furthermore, they detail the pathological timeline for the deposition of collagen in the injured left ventricle, a hallmark of myocardial infarction. Researchers can use this refined technique to easily create a rat myocardial infarction and use the pathophysiological markers described herein to follow disease progression. PMID- 20859280 TI - Refined induction of anesthesia with remifentanil after bolus propofol administration in Landrace/Large White swine. AB - The authors report a prospective randomized blind study in which they used a refined anesthetic technique in male Landrace/Large White swine (n = 125 pigs, 19 +/- 2 kg, 10-15 weeks old). The animals were first premedicated with ketamine, midazolam and atropine and then given a dose of 1, 2, 3, 4 or 5 MUg remifentanil per kg body weight (dose amounts were randomly assigned) after a bolus dose of propofol. The authors assessed the intubation conditions (e.g., jaw relaxation and other parameters) 20 min after premedication and then 5 min after anesthesia induction. All animals that received each of the different remifentanil dose amounts were successfully intubated in less than 30 s. No animal developed apnea during intubation or experienced substantial reductions in heart rate or blood pressure (> 25%) between the two time points (20 min after premedication and 5 min after anesthesia induction). Overall intubation conditions were significantly better in animals that received 5 MUg remifentanil per kg body weight than in animals that received other dose amounts (P < 0.001). The average time to intubation was significantly shorter for animals that received 5 MUg remifentanil per kg body weight than for animals that received any of the other dose amounts (P < 0.001). The authors concluded that for this study, 5 MUg remifentanil per kg body weight resulted in excellent intubating conditions in this swine breed. PMID- 20859281 TI - Benefits of providing nesting material as a form of environmental enrichment for mice. AB - Husbandry conditions in a laboratory environment can be barren and monotonous. Improving those conditions by providing opportunities for laboratory mice to engage in species-specific behavior can improve their mental and physical well being. Giving the animals choices and control over their environment is key to reducing stress. Nesting is a normal behavior of mice, and giving mice nesting opportunities allows them to choose how and where to create their nest and provides them a means of thermoregulation in their microenvironment. PMID- 20859282 TI - A passion for management. PMID- 20859283 TI - Drug resistance in metastatic castration-resistant prostate cancer. AB - Docetaxel in combination with prednisone is the standard of care in men with symptomatic castration-resistant prostate cancer (CRPC). However, a substantial proportion of men with CRPC do not benefit from docetaxel or other systemic therapy and those who do benefit invariably progress and die of (or with) prostate cancer. Resistance to chemotherapy in metastatic CRPC is a result of cellular mechanisms of drug resistance intrinsic to prostate cancer and general mechanisms common to different tumor types. Continued signaling from the androgen receptor, activation of oncogenic survival pathways by various receptor tyrosine kinases and crosstalk between the androgen receptor and these oncogenic survival pathways are hallmarks of progression of CRPC. General mechanisms of drug resistance include the existence of subpopulations of cancer cells with cellular mechanisms of resistance, resistance related to interactions between prostate cancer cells and their surrounding microenvironment and impaired drug delivery to the cancer cells. New therapeutics targeting these mechanisms are under evaluation in clinical trials. Drug resistance in metastatic CRPC is multifactorial and complex and development of new medical therapies remains challenging. PMID- 20859284 TI - A multi-analyte serum test for the detection of non-small cell lung cancer. AB - BACKGROUND: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. METHODS: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. RESULTS: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-alpha, CYFRA 21-1, interleukin 1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. CONCLUSIONS: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various 'high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions. PMID- 20859286 TI - Is GAPDH a relevant housekeeping gene for normalisation in colorectal cancer experiments? PMID- 20859285 TI - Relevance of BCAR4 in tamoxifen resistance and tumour aggressiveness of human breast cancer. AB - BACKGROUND: Breast cancer anti-oestrogen resistance 4 (BCAR4) was identified in a search for genes involved in anti-oestrogen resistance in breast cancer. We explored whether BCAR4 is predictive for tamoxifen resistance and prognostic for tumour aggressiveness, and studied its function. METHODS: BCAR4 mRNA levels were measured in primary breast tumours, and evaluated for association with progression-free survival (PFS) and clinical benefit in patients with oestrogen receptor (ERalpha)-positive tumours receiving tamoxifen as first-line monotherapy for advanced disease. In a separate cohort of patients with lymph node-negative, ERalpha-positive cancer, and not receiving systemic adjuvant therapy, BCAR4 levels were evaluated for association with distant metastasis-free survival (MFS). The function of BCAR4 was studied with immunoblotting and RNA interference in a cell model. RESULTS: Multivariate analyses established high BCAR4 mRNA levels as an independent predictive factor for poor PFS after start of tamoxifen therapy for recurrent disease. High BCAR4 mRNA levels were associated with poor MFS and overall survival, reflecting tumour aggressiveness. In BCAR4-expressing cells, phosphorylation of v-erb-b2 erythroblastic leukaemia viral oncogene homolog (ERBB)2, ERBB3, and their downstream mediators extracellular signal regulated kinase 1/2 and v-akt murine thymoma viral oncogene homolog (AKT) 1/2, was increased. Selective knockdown of ERBB2 or ERBB3 inhibited proliferation, confirming their role in BCAR4-induced tamoxifen resistance. CONCLUSION: BCAR4 may have clinical relevance for tumour aggressiveness and tamoxifen resistance. Our cell model suggests that BCAR4-positive breast tumours are driven by ERBB2/ERBB3 signalling. Patients with such tumours may benefit from ERBB-targeted therapy. PMID- 20859287 TI - Abnormal DNA content in oral epithelial dysplasia is associated with increased risk of progression to carcinoma. AB - BACKGROUND: Oral epithelial dysplasia (OED) is a histologically detectable lesion that may progress to carcinoma but there are no accurate markers that predict progression. This study examined the development of carcinoma from oral dysplastic lesions, and the association between abnormal DNA content and progression to carcinoma. METHODS: Epithelial dysplasias from the Oral Pathology Diagnostic Service were matched against the Ontario Cancer Registry database to identify cases that progressed to carcinoma. A case-control study was conducted to compare DNA image cytometry of dysplasias that progressed with those that have not progressed. For a subset of the progressed dysplasias, DNA content of the carcinoma was also analysed. RESULTS: A total of 8% of epithelial dysplasias progressed to carcinoma after 6-131 months. In all, 28 of 99 dysplasias showed abnormal DNA content by image cytometry. In multivariate analysis of time to progression, abnormal DNA content was a significant predictor with hazard ratio of 3.3 (95% confidence interval: 1.5-7.4) corrected for site and grade of dysplasia. Analysis of sequential samples of dysplasia and carcinoma suggested that epithelial cell populations with grossly abnormal DNA content were transient intermediates during oral cancer development. CONCLUSIONS: Abnormal DNA content is a significant biomarker of a subset of OED that progress to carcinoma. PMID- 20859288 TI - Role of human tissue kallikrein in gastrointestinal stromal tumour invasion. AB - BACKGROUND: Human tissue kallikrein (hK1) generates vasodilator kinins from kininogen and promotes angiogenesis by kinin-dependent and kinin-independent mechanisms. Here, we investigate the expression and functional relevance of hK1 in human gastrointestinal stromal tumour (GIST). METHODS: Vascularisation and hK1 expression of GIST samples were assessed by immunohistochemistry. In two GIST cell lines, hK1 expression was assessed by PCR, and hK1 protein levels and activity were measured by ELISA and an amidolytic assay, respectively. The effect of hK1 silencing, inhibition or overexpression on GIST cell proliferation, migration and paracrine induction of angiogenesis was studied. Finally, local and systemic levels of hK1 were assessed in mice injected with GIST cells. RESULTS: Human tissue kallikrein was detected in 19 out of 22 human GIST samples. Moreover, GIST cells express and secrete active hK1. Titration of hK1 demonstrated its involvement in GIST invasive behaviour, but not proliferation. Furthermore, hK1 released by GIST cells promoted endothelial cell migration and network formation through kinin-dependent mechanisms. Gastrointestinal stromal tumour implantation in nude mice resulted in local and systemic hK1 expression proportional to tumour dimension. CONCLUSIONS: Human tissue kallikrein is produced and released by GIST and participates in tumour invasion. Further studies are needed to validate hK1 as a diagnostic biomarker and therapeutic target in GIST. PMID- 20859289 TI - Melanoma sentinel node biopsy and prediction models for relapse and overall survival. AB - BACKGROUND: To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas. METHODS: A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illumina's DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced. RESULTS: Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 * 10-7), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%). CONCLUSION: Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients. PMID- 20859291 TI - Sinefungin VA and dehydrosinefungin V, new antitrypanosomal antibiotics produced by Streptomyces sp. K05-0178. AB - Two new nucleotide antibiotics, named sinefungin VA and dehydrosinefungin V, were separated by cation exchange column chromatography and purified by HPLC from the culture broth of Streptomyces sp. K05-0178, together with the known antibiotics, sinefungin, dehydrosinefungin and KSA-9342. The structures of the two novel sinefungin analogs were elucidated by spectroscopic studies, including various NMR and advanced peptide chemical methods. Sinefungin VA consists of adenosine and ornithylvalylalanine, whereas dehydrosinefungin V consists of 4',5' dehydroadenosine and ornithylvaline. Sinefungin VA showed potent antitrypanosomal activity with an IC(50) value of 0.0026 MUg ml(-1) in vitro without cytotoxicity against MRC-5 cells. Dehydrosinefungin V showed moderate antitrypanosomal activity (IC(50)=0.15 MUg ml(-1)). PMID- 20859290 TI - MicroRNA in lung cancer. AB - MicroRNAs (miRNAs) are small non-protein-coding RNAs that function as endogenous negative gene regulators. Dysfunctions of miRNAs are frequently found in malignancies, including lung cancer. In this review, we summarise the current understanding of miRNAs in lung cancer tumourigenesis, and highlight their potential in overcoming drug resistance, abetting histological sub-classification techniques, and serving as biomarkers for lung cancer risk stratification and outcome prediction. PMID- 20859292 TI - Reduced ischemic brain injury by partial rejuvenation of bone marrow cells in aged rats. AB - Circulating bone marrow-derived immature cells, including endothelial progenitor cells, have been implicated in homeostasis of the microvasculature. Decreased levels of circulating endothelial progenitor cells, associated with aging and/or cardiovascular risk factors, correlate with poor clinical outcomes in a range of cardiovascular diseases. Herein, we transplanted bone marrow cells from young stroke-prone spontaneously hypertensive rats (SHR-SP) into aged SHR-SP, the latter not exposed to radiation or chemotherapy. Analysis of recipient peripheral blood 28 days after transplantation revealed that 5% of circulating blood cells were of donor origin. Cerebral infarction was induced on day 30 posttransplantation. Animals transplanted with bone marrow from young SHR-SP displayed an increase in density of the microvasculature in the periinfarction zone, reduced ischemic brain damage and improved neurologic function. In vitro analysis revealed enhanced activation of endothelial nitric oxide synthase and reduced activation p38 microtubule-associated protein (MAP) kinase, the latter associated with endothelial apoptosis, in cultures exposed to bone marrow-derived mononuclear cells from young animals versus cells from aged counterparts. Our findings indicate that partial rejuvenation of bone marrow from aged rats with cells from young animals enhances the response to ischemic injury, potentially at the level of endothelial/vascular activation, providing insight into a novel approach ameliorate chronic vascular diseases. PMID- 20859293 TI - Two-photon NADH imaging exposes boundaries of oxygen diffusion in cortical vascular supply regions. AB - Oxygen transport imposes a possible constraint on the brain's ability to sustain variable metabolic demands, but oxygen diffusion in the cerebral cortex has not yet been observed directly. We show that concurrent two-photon fluorescence imaging of endogenous nicotinamide adenine dinucleotide (NADH) and the cortical microcirculation exposes well-defined boundaries of tissue oxygen diffusion in the mouse cortex. The NADH fluorescence increases rapidly over a narrow, very low pO(2) range with a p(50) of 3.4 +/- 0.6 mm Hg, thereby establishing a nearly binary reporter of significant, metabolically limiting hypoxia. The transient cortical tissue boundaries of NADH fluorescence exhibit remarkably delineated geometrical patterns, which define the limits of tissue oxygen diffusion from the cortical microcirculation and bear a striking resemblance to the ideal Krogh tissue cylinder. The visualization of microvessels and their regional contribution to oxygen delivery establishes penetrating arterioles as major oxygen sources in addition to the capillary network and confirms the existence of cortical oxygen fields with steep microregional oxygen gradients. Thus, two photon NADH imaging can be applied to expose vascular supply regions and to localize functionally relevant microregional cortical hypoxia with micrometer spatial resolution. PMID- 20859294 TI - Susceptibility of Tmax to tracer delay on perfusion analysis: quantitative evaluation of various deconvolution algorithms using digital phantoms. AB - The time-to-maximum of the tissue residue function (T(max)) perfusion index has proven very predictive of infarct growth in large clinical trials, yet its dependency on simple tracer delays remains unknown. Here, we determine the dependency of computed tomography (CT) perfusion (CTP) T(max) estimates on tracer delay using a range of deconvolution techniques and digital phantoms. Digital phantom data sets simulating the tracer delay were created from CTP data of six healthy individuals, in which time frames of the left cerebral hemisphere were shifted forward and backward by up to +/-5 seconds. These phantoms were postprocessed with three common singular value decomposition (SVD) deconvolution algorithms-standard SVD (sSVD), block-circulant SVD (bSVD), and delay-corrected SVD (dSVD)-with an arterial input function (AIF) obtained from the right middle cerebral artery (MCA). The T(max) values of the left hemisphere were compared among different tracer delays and algorithms by a region of interest-based analysis. The T(max) values by sSVD were positively correlated with 'positive shifts' but unchanged with 'negative shifts,' those by bSVD had an excellent positive linear correlation with both positive and negative shifts, and those by dSVD were relatively constant, although slightly increased with the positive shifts. The T(max) is a parameter highly dependent on tracer delays and deconvolution algorithm. PMID- 20859297 TI - Determinants of plasma alkylresorcinol concentration in Danish post-menopausal women. AB - BACKGROUND: Alkylresorcinols (AR), a group of phenolic lipids present in the outer parts of wheat and rye grain kernels, have been suggested as biomarkers of whole-grain wheat and rye intake. In this study, we investigated potential determinants of plasma AR concentration in a free-living population. SUBJECTS/METHODS: Non-fasting samples from post-menopausal women enrolled in the Danish Diet, Cancer and Health study (n = 360) were selected. Diet was assessed using a semi-quantitative food frequency questionnaires (FFQ) and the association between food items likely to contain AR and relevant non-dietary factors were studied by analysis of covariance models. RESULTS: The median AR concentration was 78 nmol/l (interquartile range = 106.9 nmol/l). Intake of rye bread, identified as the main determinant, was associated with 87% higher plasma total AR concentration per 100 g of bread (95% confidence interval = 46-139%). About 8 12% of the total variation (depending on the AR homologue) in plasma AR concentration was explained by the selected dietary variables. At a nutrient level, total dietary fiber and cereal fiber were significantly associated with plasma total AR concentration (P = 0.05), but only ~2% of the total plasma AR concentration was explained by the dietary fiber or cereal fiber intake. CONCLUSIONS: In the studied population, AR plasma concentration was mainly affected by rye bread intake among investigated determinants. PMID- 20859295 TI - Negative BOLD-fMRI signals in large cerebral veins. AB - Reductions in blood oxygenation level dependent (BOLD)-functional magnetic resonance imaging (fMRI) signals below baseline levels have been observed under several conditions as negative activation in task-activation studies or anticorrelation in resting-state experiments. Converging evidence suggests that negative BOLD signals (NBSs) can generally be explained by local reductions in neural activity. Here, we report on NBSs that accompany hemodynamic changes in regions devoid of neural tissue. The NBSs were investigated with high-resolution studies of the visual cortex (VC) at 7 T. Task-activation studies were performed to localize a task-positive area in the VC. During rest, robust negative correlation with the task-positive region was observed in focal regions near the ventricles and dispersed throughout the VC. Both positive and NBSs were dependent on behavioral condition. Comparison with high-resolution structural images showed that negatively correlated regions overlapped with larger pial and ependymal veins near sulcal and ventricular cerebrospinal fluid (CSF). Results from multiecho fMRI showed that NBSs were consistent with increases in local blood volume. These findings confirm theoretical predictions that tie neural activity to blood volume increases, which tend to counteract positive fMRI signal changes associated with increased blood oxygenation. This effect may be more salient in high-resolution studies, in which positive and NBS may be more often spatially distinct. PMID- 20859296 TI - NADPH oxidase mediates striatal neuronal injury after transient global cerebral ischemia. AB - Medium spiny neurons (MSNs) constitute most of the striatal neurons and are known to be vulnerable to ischemia; however, the mechanisms of the vulnerability remain unclear. Activated forms of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX), which require interaction between cytosolic and membrane-bound subunits, are among the major sources of superoxide in the central nervous system. Although increasing evidence suggests that NOX has important roles in neurodegenerative diseases, its roles in MSN injury after transient global cerebral ischemia (tGCI) have not been elucidated. To clarify this issue, C57BL/6 mice were subjected to tGCI by bilateral common carotid artery occlusion for 22 minutes. Western blot analysis revealed upregulation of NOX subunits and recruitment of cytosolic subunits to the cell membrane at early (3 to 6 hours) and late (72 hours) phases after tGCI. Taken together with immunofluorescent studies, this activation arose in MSNs and endothelial cells at the early phase, and in reactive microglia at the late phase. Pharmacological and genetic inhibition of NOX attenuated oxidative injury, microglial activation, and MSN death after tGCI. These findings suggest that NOX has pivotal roles in MSN injury after tGCI and could be a therapeutic target for brain ischemia. PMID- 20859298 TI - No efficacy of processed Fabuless (Olibra) in suppressing appetite or food intake. AB - BACKGROUND/OBJECTIVES: To investigate the feasibility of Fabuless (previously called Olibra and Reducal) as a food ingredient for food intake and appetite reduction, by assessing the effects of food processing on efficacy. SUBJECTS/METHODS: In total, 24 healthy volunteers (16 female, 8 male; age: 18-43 years; body mass index: 18-37 kg/m(2)) took part in a randomized, placebo controlled, double-blinded, cross-over trial. Yoghurt-based meal replacement drinks (containing processed or unprocessed Fabuless, or a control fat) were followed by an ad libitum lunch and evening meal (dinner). Key outcome measures were energy intake and self-reported appetite ratings. RESULTS: Compared with control, only unprocessed Fabuless reduced subsequent energy intake, although only during dinner (P < 0.01; control, processed and unprocessed: 4.3, 3.9 and 4.2 MJ, respectively) and not during lunch (3.6, 3.7 and 3.6 MJ). Self-reported appetite scores did not differ between treatments. CONCLUSIONS: Although modest effects of unprocessed Fabuless were seen on food intake, but not on appetite, the ingredient was not robust to common food-manufacturing processes (thermal and shear processing). Claims on reduced food intake and appetite relating to this ingredient in food products are, therefore, only valid if functionality has been demonstrated after all relevant processing and storage steps. PMID- 20859299 TI - Effects of supplementation with tocotrienol-rich fraction on immune response to tetanus toxoid immunization in normal healthy volunteers. AB - BACKGROUND/OBJECTIVES: Vitamin E is an essential fat-soluble vitamin that has been shown to induce favorable effects on animal and human immune systems. The objective of this study was to assess the effects of tocotrienol-rich fraction (TRF) supplementation on immune response following tetanus toxoid (TT) vaccine challenge in healthy female volunteers. SUBJECTS/METHODS: In this double-blinded, placebo-controlled clinical trial, participants were randomly assigned to receive either placebo (control group) or 400 mg of TRF (study group) supplementation daily. Over the 2-month period of the study, volunteers were asked to attend three clinical sessions (that is, on days 0, 28 and 56) and blood samples were obtained from the volunteers during the follow-up. On day 28, all volunteers were also vaccinated with the TT vaccine (20 Lf) intramuscularly. RESULTS: The results from the clinical trial showed that TRF supplementation significantly increased the total vitamin E level in the plasma of the TRF-supplemented volunteers compared with the placebo group, indicating overall compliance. Volunteers supplemented with TRF showed a significantly (P < 0.05) enhanced production of interferon-gamma and interleukin (IL)-4 by the mitogen or TT-stimulated leukocytes compared with the control group. Volunteers from the TRF group produced significantly (P < 0.05) lower amounts of IL-6 compared with the placebo group. Anti-TT IgG production was also significantly (P < 0.05) augmented in the TRF-supplemented group compared with the placebo group. CONCLUSIONS: We conclude that TRF has immunostimulatory effects and potential clinical benefits to enhance immune response to vaccines. PMID- 20859300 TI - Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study. AB - BACKGROUND/OBJECTIVES: The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels. SUBJECTS/METHODS: Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1lambdas (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score. RESULTS: Serum total IgG levels were negatively associated with serum 25OHD (adjusted R (2) = 0.376; beta = -0.02; P<0.001), supplemented vitamin D intake per kg bodyweight (adjusted R (2) = 0.375; beta = -0.82; P < 0.001) and total vitamin D intake per kg bodyweight (adjusted R (2) = 0.398; beta = -0.60; P = 0.002). Serum 25OHD was positively associated with FEV1 (adjusted R (2) = 0.308; beta = 0.0007; P = 0.025). CONCLUSIONS: Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies. PMID- 20859301 TI - Simple advice on lifestyle habits and long-term changes in biomarkers of inflammation and vascular adhesion in healthy middle-aged men. AB - BACKGROUND/OBJECTIVES: Lifestyle habits, vascular function and inflammation are components in the development of cardiovascular disease (CVD). We investigated whether simple advice on dietary and exercise habits given (at a single time point) to hypercholesterolemic men affects circulating biomarkers of inflammation and vascular adhesion. SUBJECTS/METHODS: In total, 157 men (age 46+/-5 years) with mild hypercholesterolemia were randomized to four intervention groups, diet (D, n=40), exercise (E, n=39), diet and exercise (DE, n=39) or controls (C, n=39) and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1) and soluble E-selectin (sE-selectin) were quantified at baseline and after a 6-month intervention period. RESULTS: The intervention applied in this study, that is, simple advice on lifestyle changes given at a single time point, had a modest effect on inflammatory biomarkers and soluble vascular adhesion molecules. The most apparent alterations were found for individuals in group DE, who responded with significant reductions in sICAM-1, 28 (-41 to -14 MUg/l) and sE-selectin, -3.6 (-6.9 to -0.3 MUg/l) after 6 months. None of the groups had altered their concentrations of sVCAM-1, CRP or IL-6 significantly after the intervention. In all individuals combined, we found changes in apolipoprotein B (apoB) to predict alterations in sICAM-1 (beta=0.21) and sE-selectin (beta=0.26), independently of changes in inflammation and other adhesion molecules. CONCLUSIONS: These observations indicate that even small efforts to improve diet and physical activity can influence biomarkers of vascular function in individuals at increased risk for CVD. ApoB was identified as an important determinant of this improvement, which adds further support to the notion of apoB as a critical target in cardiovascular prevention. PMID- 20859303 TI - [Public health and social justice]. PMID- 20859302 TI - Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. AB - Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings. PMID- 20859304 TI - [Record linkage between hospital discharge data and death records in the Puglia Region in 2001-2006 (Italy)]. AB - In order to correctly perform record linkage among databases and accurately determine outcome indicators using hospital discharge data and death records, the quality of data is fundamental. A deterministic record linkage method was use to link hospital discharge data with records from the Death Registry in the Puglia region (Italy) for the years 2001-2006. Thirty-five percent of hospital discharge records in which the recorded discharge modality was "death" were not in agreement with the corresponding death records. Furthermore, 40% of hospital discharge records where the date of death was the same as the date of discharge from hospital did not record "death" as the discharge modality. PMID- 20859305 TI - [Chemical and ecotoxicological evaluation of sludge from city and industrial waste-water treatment]. AB - The aim of this study was to evaluate the toxicity of sludge produced by wastewater treatment, by using both chemical and ecotoxicological evaluations. Samples of sludge from treatment of urban and industrial wastewater were analysed. Toxicity of sludge was evaluated by measuring Vibrio fischeri, polychlorobyphenyls, polycyclic aromatic hydrocarbons and metals. Results of chemical and ecotoxicological evaluations were found to be discordant. In all samples, contaminants were found to be below the accepted threshold levels; on the contrary, toxicological evaluations of sludge samples obtained from industrial wastewater found these samples to be toxic. These findings indicate that the evaluation of sludge to be used in agriculture should include an ecotoxicological evaluation, as suggested by the European Community in 1999. Furthermore, chemical evaluation of sludge should be performed by using a single method and the chosen method should have the most restrictive threshold levels of all methods currently in use in the EU. PMID- 20859306 TI - [Analysis of the association between socio-demographic variables and diagnosis related groups (DRGs) at high risk of inappropriateness in hospitals in Caltanisetta (Italy)]. AB - The aim of this study was to evaluate the association between socio-demographic variables and hospital admissions at high risk of inappropriateness. Hospital discharge data for patients admitted to hospitals in the province of Caltanissetta in the Sicily Region (Italy) in the years 2007-2008 was obtained from the healthcare system database of the Region. Only acute care admissions of > 1 day duration and regarding patients ? 1 year of age were considered. Data regarding gender, nationality, age, marital status was collected for each admission as well as name of the local health authority in which the patient was registered. Univariate and multivariate analyses were performed using Chi-square and multivariate logistical regression analysis (Hosmer e Lemeshow) Fourteen percent (8.220/58.561) of admissions were found to be at high risk of inappropriateness, which was associated with patient age [1-15 years and 46-65 years OR : 1,55 (I.C. 95%: 1,42-1,69) and 1,62 ( I.C. 95%: 1,53-1,72) respectively], marital status [married OR1,46 (I.C. 95%: 1,38-1,53)], place of residence [patients from the Caltanissetta local health authority OR: 1,22 (I.C. 95%: 1,15-1,30)] and nationality [Italian OR: 2,19 (I.C. 95%: 1,40-0,87) ]. PMID- 20859307 TI - [Analysis of the causes of death in the Umbria Region (Italy) 1994-2008]. AB - The leading causes of death in the Umbria Region (Italy) between 1994-2008 were analysed and a comparison was made between data from three five-year time periods: 1994-1998, 1999-2003 and 2004-2008. Standardized rates of Years of Potential Life Lost (YPLL) at 75 years, by gender and cause of death, were also measured. Mortality data was obtained from the Umbria Registry of causes of death; diagnoses were codified according to the International Classification of Diseases 10th revision (ICD10). Mortality trends over time were analysed by using standardized mortality rates with the 2001 Umbria census data as the reference population . The joinpoint regression program was used to analyze rates calculated by the SEER (Surveillance Epidemiology and End Results) software of the National Cancer Institute (USA). Mortality for all causes, standardised by age, show a significantly decreasing trend from 1994 to 2008 in both genders. Mortality rates for cardiovascular diseases and malignant tumours show a significant constant decline in both genders. Standardised rates of YPLL at 75 years declined by 32% in males and 29% in females between the five-year period 1994-1998 and the period 2004-2008. In conclusion, a generalised decline in mortality and a shift towards older age groups is observed with a consequent decline in YPLL, allowing a positive judgment to be given regarding the efficacy of preventive, therapeutic and rehabilitation interventions implemented by the regional health care system. PMID- 20859308 TI - [Evaluation of a rapid diagnostic test for influenza viruses A and B]. AB - This study analysed the performance of a rapid test for the diagnosis of human influenza A and B. Three-hundred nasopharyngeal samples were analysed using the BD Directigen Flu A+B test and real-time PCR, during the 2007-2008 and 2008-2009 flu seasons. Specificity of the BD Directigen Flu A+B test was 100% and sensitivity was fpund to be 67% for influenza B virus and 89% for the detection of influenza B virus. Results are comparable to those reported in the literature and by the Centers for Disease Control (CDC). PMID- 20859309 TI - [Observational Team work Assessment for Surgery as Quality and Safety improvement tool]. AB - As in high reliability systems , also in surgery the causes of adverse events are primarily correlated to deficiencies in Non Technical Skills (individual and social skills), that contribute with Technical Skills to a safe surgical procedure. Non Technical Skills are cognitive behavioural and interpersonal abilities, that are not specific to the expertise of one profession, but very important to guarantee the patient safety and to reduce risk of errors and adverse events. The Observational Teamwork Assessment for Surgery (OTAS) is an useful tool to assess teamwork of the whole surgical team (surgeons, anaesthetists, nurses) in real time and through the surgical procedure (pre-intra postoperative phases). OTAS consists of the two following parts: a) teamwork related task checklist to fill by a surgeon, b) teamwork-related behaviours rated by a psychologist/human factors expert. Back translation in Italian language of the eight task checklists and of the rating scales of the five behavioural areas was performed by two Italian surgeons with certified English language knowledge. The OTAS model in Italian language was applied in four surgical procedures : the test-retest reliability was found to be acceptable with K- Pearson index. The internal consistency of behavioural scales appeared sound using Cronbach ?. OTAS is an useful tool to assess the risk factors correlated to patient and team and to detect the vulnerability areas where changes to reduce errors and improve surgical outcomes might be introduced. PMID- 20859310 TI - [Regulations for the commercialization of new disinfectants: efficacy studies required for products to be used in foodstuffs, and in industrial, domestic and institutional areas]. AB - Regulations for the commercialization of new disinfectants in Europe are currently going through a transition phase. Up to the present time these were set down by each member State of the European Union while in May 2010 a single European set of regulations (Directive 98/8/CE) will become effective in all Member States, the main aspects of which are discussed in this paper. In particular, we discuss the main points regarding studies and other information to be submitted for obtaining approval of new active substances and for reviewing products already in the market. PMID- 20859311 TI - [Novel approaches for the prevention of influenza: the intradermal vaccination]. AB - Conventional non-adjuvanted influenza vaccines have shown suboptimal immunogenicity in subjects at high risk for complications, such as the elderly. Between the several strategies proposed to develop more immunogenic vaccines than the conventional ones, a promising option is represented by the administration of non-adjuvanted vaccine through the intradermal (ID) route. This paper summarizes and discusses the main results recently obtained in clinical trials investigating the safety, tolerability and immunogenicity of new ID influenza vaccines, containing standard or reduced antigen dosages, in different age-groups. PMID- 20859312 TI - Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. AB - The treatment of chronic pain, therapeutic opioid use and abuse, and the nonmedical use of prescription drugs have been topics of intense focus and debate. After the liberalization of laws governing opioid prescribing for the treatment of chronic non-cancer pain by state medical boards in the late 1990s, and with the introduction of new pain management standards implemented by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) in 2000, opioids, in general, and the most potent forms of opioids including Schedule II drugs, in particular, have dramatically increased. Despite the escalating use and abuse of therapeutic opioids, nearly 15 to 20 years later the scientific evidence for the effectiveness of opioids for chronic non-cancer pain remains unclear. Concerns continue regarding efficacy; problematic physiologic effects such as hyperalgesia, hypogonadism and sexual dysfunction; and adverse side effects - especially the potential for misuse and abuse - and the increase in opioid related deaths. Americans, constituting only 4.6% of the world's population, have been consuming 80% of the global opioid supply, and 99% of the global hydrocodone supply, as well as two-thirds of the world's illegal drugs. Retail sales of commonly used opioid medications (including methadone, oxycodone, fentanyl base, hydromorphone, hydrocodone, morphine, meperidine, and codeine) have increased from a total of 50.7 million grams in 1997 to 126.5 million grams in 2007. This is an overall increase of 149% with increases ranging from 222% for morphine, 280% for hydrocodone, 319% for hydromorphone, 525% for fentanyl base, 866% for oxycodone, to 1,293% for methadone. Average sales of opioids per person have increased from 74 milligrams in 1997 to 369 milligrams in 2007, a 402% increase. Surveys of nonprescription drug abuse, emergency department visits for prescription controlled drugs, unintentional deaths due to prescription controlled substances, therapeutic use of opioids, and opioid abuse have been steadily rising. This manuscript provides an updated 10-year perspective on therapeutic use, abuse, and non-medical use of opioids and their consequences. PMID- 20859313 TI - Comparative outcomes of a 2-year follow-up of cervical medial branch blocks in management of chronic neck pain: a randomized, double-blind controlled trial. AB - BACKGROUND: Cervical therapeutic intraarticular facet joint injections, therapeutic medial branch blocks, and radiofrequency neurotomy have been applied in managing chronic neck pain of cervical facet joint origin. However, the effectiveness of these modalities continues to be debated. The purpose of this study was to determine the clinical effectiveness of therapeutic cervical medial branch blocks with or without steroids. STUDY DESIGN: A randomized, double-blind, controlled trial. SETTING: An interventional pain management practice, a specialty referral center, a private practice setting in the United States. OBJECTIVE: To evaluate the clinical outcomes of therapeutic cervical medial branch blocks with local anesthetic with or without steroids in managing chronic neck pain of facet joint origin. METHODS: A total of 120 patients meeting inclusion criteria were included. All of the patients met the diagnostic criteria of cervical facet joint pain by means of comparative, controlled diagnostic blocks, with at least 80% relief. Group I consisted of cervical medial branch blocks with bupivacaine only and Group II consisted of cervical medial branch blocks with bupivacaine and steroid. Therapeutic cervical medial branch blocks with local anesthetic with or without steroids were administered. Main outcome measures included numeric pain scores, Neck Disability Index (NDI), opioid intake, and work status evaluated at baseline, 6, 12, 18, and 24 months. The one year results of outcomes were published in 2008. This manuscript describes the 2 year results. Significant improvement was defined as at least 50% improvement in pain relief and/or functional status improvement. OUTCOMES ASSESSMENT: Patient outcomes were measured at baseline, 3, 6, 12, 18, and 24 months post-treatment with the Numeric Rating Scale (NRS), the Neck Disability Index (NDI), employment status, and opioid intake. Decrease of >= 50% of NRS scores and Oswestry scores were considered significant. RESULTS: Eighty-five percent of patients in Group I and 93% of patients in Group II showed significant pain relief (>= 50%) at 2 years. The average number of treatments for 2 years was 5.7. The duration of average pain relief with each procedure was 17-19 weeks on average in both groups. Significant improvement of pain and function was demonstrated for 83 to 89 weeks over a period of 2 years. LIMITATIONS: The study limitations include the lack of a placebo group. CONCLUSIONS: In this study, therapeutic cervical medial branch blocks instituted after the diagnosis, with controlled comparative local anesthetic blocks with 80% concordant pain relief, repeated approximately 6 times over a period of 2 years, provided significant improvement over a period of 2 years. CLINICAL TRIAL: NCT00332722. PMID- 20859314 TI - A treatment option for post-injection sciatic neuropathy: transsacral block with methylprednisolone. AB - BACKGROUND: Accidental intraneural injection induced nerve injury is an iatrogenic tragedy and intramuscular injection (IM) is the most common injury mechanism affecting the sciatic nerve. The most frequent presentation of sciatic nerve injury includes radicular pain and paresthesia with almost immediate onset of variable motor and sensory deficit. OBJECTIVES: Intraneural injection is a common injury mechanism of the sciatic nerve and generates neuropathic pain with inflammatory neuritis. Steroids inhibit the production of inflammatory mediators and reduce ectopic discharges on damaged neural membranes. The results of transsacral steroid injection on neuropathic pain in 5 patients with accidental sciatic nerve injury due to intraneural injection were presented in this report. DESIGN: Report of 5 cases. DESCRIPTION OF CASES: Five patients, 32, 34, 45, 54 and 70 years old respectively, complaining of severe neuropathic pain, paresthesia and progressive weakness of the lower extremity with difficulty in walking secondary to gluteal injection were admitted to the clinic. The symptoms were resistant to drug therapies. Electromyography disclosed axonal damage of the sciatic nerve. The initial examination of the patients revealed a Numeric Rating Scale (NRS) of 10, 10, 9, 9, and 10 respectively. RESULTS: Diagnostic block was performed through the unilateral S1-S2-S3 sacral foramina with 22-G spinal needle by 5 mL 1% lidocaine into each foramen. NRS scores decreased to 1, 2, 2, 2 and 1, respectively. One week later, the patients were administered 80 mg methylprednisolone with 1% lidocaine in 15 mL solution shared equally in each foramen. The patients were checked one month after therapeutic block and a full recovery was achieved in all patients. CONCLUSION: The neuropathic pain due to accidental intraneural injection of the sciatic nerve would be an acceptable indication for transsacral nerve block with corticosteroids in the treatment of sciatic neuropathic pain symptoms. PMID- 20859315 TI - Oral versus topical Ibuprofen for chronic knee pain: a prospective randomized pilot study. AB - BACKGROUND: Topical ibuprofen provides an alternative treatment to oral ibuprofen for the treatment of chronic knee pain. OBJECTIVE: To compare the efficacy of topical versus oral ibuprofen in chronic knee pain treatment. STUDY DESIGN: Prospective, randomized, unblinded pilot study. SETTING: A private pain management practice. METHODS: Twenty patients received either ibuprofen tablets 3 times daily (2400 mg total) or 4% topical gel 4 times daily (320 mg total) for 2 weeks. Subjects completed the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index, the Medical Outcomes Study 12-Item Short Form (SF-12v2) Health Survey, and a satisfaction questionnaire. RESULTS: Comparison of WOMAC and SF-12v2 mean changes from baseline showed no differences between groups. Patient satisfaction and study treatment convenience were rated equivalently between groups. Within the topical group, significant improvements (P < 0.05) were experienced in the mean differences of WOMAC Pain scores from baseline to 2 weeks (-82.6, -158.3 to -6.8), WOMAC Stiffness scores from baseline to one week (-25.3, -50.0 to -0.6) and baseline to 2 weeks (-47.8, -95.7 to 0.1), WOMAC Physical Function scores from baseline to one week (-175.9, -348.6 to -3.2) and baseline to 2 weeks (-312.1, -580.5 to -43.7), and patient satisfaction scores from baseline to one week and baseline to 2 weeks. Within the oral group, significant improvements (P < 0.05) were experienced in mean differences of WOMAC Physical Function from baseline to one week (-342.6, -638.1 to -47.1) and baseline to 2 weeks (-323.2, -637.1 to -9.2). LIMITATIONS: As this was a preliminary investigation, the sample size of 20 subjects is a limitation in this study. CONCLUSION: Treatment of chronic knee pain with topical ibuprofen provided comparable clinical efficacy and patient satisfaction as oral ibuprofen in this pilot study. PMID- 20859316 TI - Differential treatment of nerve root compression pain caused by lumbar disc herniation applying nucleoplasty. AB - BACKGROUND: Nucleoplasty is a minimally invasive intervention use to perform disc decompression in cases of nerve root compression caused by disc herniation. It is important to find rational guidelines for choosing between nucleoplasty and microsurgery. OBJECTIVE: To analyze factors that may impact the results of nucleoplasty, and to validate the rational guidelines between minimally invasive treatment and open surgery. STUDY DESIGN: Prospective, non-randomized, cohort study with a minimal follow-up period of 18 months. METHODS: Patients were given a neurological examination, visual analogue scale and Oswestry disability questionnaire, obligatory MRI, optional RCT, and discography, only before nucleoplasty. Patients have been divided into the following groups: Group 1 - patients with a disc protrusion treated with nucleoplasty (n = 46), which has been divided into Subgroup 1A, those with a disc protrusion size <= 5 mm (n = 24), and Subgroup 1B, those with a disc protrusion size 6 - 9 mm (n = 22); Group 2 - patients with a disc extrusion treated with nucleoplasty (n = 27); Group 3 - patients with a disc extrusion or sequester treated with microdiscectomy (n = 65). OUTCOME MEASURES: Clinically significant outcomes were a 50% relief of pain intensity and a 40% decrease of Oswestry Disability Index (ODI). RESULTS: A decrease of pain intensity and disability was found in all groups of patients, P < 0.0001; SP (statistical power) = 99 - 100%. Subgroups 1A and 1B showed no clinically significant differences in outcome, P = 0.99; SP = 5.3. Clinically significant results: Group 1 - 78%; 95% CI (confidence interval) [66; 90%], Group 2 - 44%; 95% CI [25; 65%], Group 3 - 93%; 95% CI [85; 98%]. Total annulus disruption increases the rate of unsatisfactory results of nucleoplasty, OR (odds ratio) = 4.5; 95% CI [1.57; 12.87] (logistic regression model, P = 0.0034). Nucleoplasty performed in cases of uncontained disc herniation (disc extrusion) have a significantly higher rate of unsatisfactory results versus microdiscectomy, OR = 19.06; 95% CI [2.29; 68.73] (logistic regression model, P < 0.0001). LIMITATIONS: This study was limited by the small number of patients in each group. CONCLUSION: The size of the disc protrusion does not significantly affect the outcome of nucleoplasty. The rational guideline for choosing between the 2 types of surgery is the integrity of the annulus. PMID- 20859317 TI - Flushing following interlaminar lumbar epidural steroid injection with dexamethasone. AB - BACKGROUND: Epidural steroid injections are commonly used in managing radicular pain. Most complications related to epidural injections are minor and self limited. Flushing is considered as one such minor side effect. Flushing has been studied using various steroid preparations including methylprednisone, triamcinolone, and betamethasone but its frequency has never been studied using dexamethasone. OBJECTIVE: This study evaluates the frequency of flushing associated with fluoroscopy-guided lumbar epidural steroid injections using dexamethasone. STUDY DESIGN: Retrospective cohort design study. Patients presenting with low back pain were evaluated and offered a fluoroscopically guided lumbar epidural steroid injection using dexamethasone via an interlaminar approach as part of a conservative care treatment plan. SETTING: University-based Pain Management Center. INTERVENTION: All injections were performed consecutively over a 2-month period by one staff member using 16 mg (4 mg/mL) of dexamethasone. A staff physician specifically asked each participant about the presence of flushing following the procedure prior to discharge on the day of injection and again on follow-up within 48 hours after the injections. The answers were documented as "YES" or "NO." RESULTS: A total of 150 participants received fluoroscopically guided interlaminar epidural steroid injection. All participants received 16 mg (4 mg/mL) of dexamethasone with 2 mL of 0.2% ropiviciane. Overall incidence of flushing was 42 out of 150 cases (28%). Of the 42 participants who experienced flushing, 12 (28%) experienced the symptom prior to discharge following the procedure. Twenty-seven of the 42 (64%) were female (P < 0.05). All the participants who experienced flushing noted resolution by 48 hours. No other major side effects or complications were noted. LIMITATIONS: Follow-up data were solely based on subjective reports by patients via telecommunication. Follow-up time was limited to only 48 hours, which overlooks the possibility that more participants might have noted flushing after the 48 hour limit. CONCLUSIONS: Flushing is commonly reported following epidural steroid injections. With an incidence of 28%, injections using dexamethasone 16 mg by interlaminar epidural route appear to be associated with more flushing reaction than previously reported with other steroid preparations. Additionally, female participants are more likely to experience flushing though the reactions seem to be self-limiting with resolution by 48 hours. PMID- 20859318 TI - Scapuloplasty alleviates scapular pain resulting from lung cancer metastasis. AB - Osteoplasty, a highly effective minimally invasive procedure that alleviates the painful effects of metastatic bone disease by injecting bone cement to support weakened bones, provides immediate and substantial pain relief. However, it is rarely performed in non-weight bearing flat bones such as the scapula. Fractures of the body of the scapula are rarely treated surgically, except for cases of marked displacement of fragments that limit the function of the scapula. According to the reported incidences of operative treatment of different scapula fracture types, 99% of all isolated scapula body fractures are treated nonoperatively A 54-year-old man had been experiencing metastatic bone pain in the lateral border, medial border, and medial infraspinatus fossa of the left scapula for the past 2 months; this pain originated from adenocarcinoma of the right lung. He could not sleep on his back even after completion of radiation therapy. We decided to perform scapuloplasty. The patient was placed in the prone position on a radiolucent table with an inflatable adjustable axillary pillow. Three 13-gauge, 10-cm long bone biopsy needles were simultaneously inserted from the 3 different entry points to fill the osteolytic lesion with the bone cement with fluoroscopic guidance under local anesthesia and intravenous analgesia. After confirming needle placement and ensuring that no contrast medium was extravasated, a total of 8 mL of the cement was injected. Immediately after the operation, the patient could lie on his back without pain. Scapuloplasty is a new variant of osteoplasty used to alleviate the painful effects of metastatic bone disease. It may be an option of shoulder motion-preserving minimally invasive procedure for alleviating intractable pain induced by lying on the back. PMID- 20859319 TI - Clinical and histological effects of the intrathecal administration of methylprednisolone in dogs. AB - BACKGROUND: Methylprednisolone is one of the most commonly used steroids for management of chronic back pain via epidural injection. Its inadvertent injection into the intrathecal space is associated with complications such as adhesive arachnoiditis. OBJECTIVE: The present study aimed to assess the clinical and histological changes associated with the injection of methylprednisolone into the intrathecal space of dogs. STUDY DESIGN: A randomized, double blind, controlled animal trial. METHODS: After approval by the animal research ethics committee, 14 dogs were studied in a randomized double blind controlled trial. They were assigned to one of 2 groups: Group I received 1 mL of 0.9% normal saline; Group II received 1 mL (1.15mg/kg) of methylprednisolone into the intrathecal space. Animals were clinically evaluated for 21 days, and then sacrificed. The lumbar and sacral portions of their spinal cords were removed for histological examination. RESULTS: In Group I, there were no clinical or histological changes. All animals in Group II showed no clinical changes but all exhibited histological changes in the spinal cord. The main histological changes consisted of meningeal thickening and lymphocytic infiltrates in the blood vessels. In 3 animals, adhesion of pia, arachnoid, and dura matter was noted and the nerve roots were surrounded by fibrosis. In one animal, necrosis of the spinal cord was evident. LIMITATIONS: The limitations of the present study include: small sample of animals (n=14), relative short clinical follow-up (21 days), and use of a commercially available drug solution, which is not preservative free. CONCLUSION: The present study demonstrated that the intrathecal administration of commercially available methylprednisolone was responsible for causing histological changes in the spinal cord and meninges of the animals studied. PMID- 20859320 TI - Numerous studies show urine drug testing a critical tool in treatment of chronic noncancer pain. PMID- 20859322 TI - One door opens, one door closes - yielding path to bradykinin-induced pain. PMID- 20859323 TI - Gadolinium encephalopathy after intrathecal gadolinium injection. AB - BACKGROUND: Gadolinium-induced encephalopathy is a well documented complication due to the inadvertent entrance of a high dose of gadolinium into the intrathecal compartment. In lab animals, injecting gadolinium into the intrathecal compartment resulted in neurotoxicity and seizures. It is also well recognized that the presence of autologous blood in the intrathecal compartment can cause a broad range of neurological changes that can include seizures and mental status changes. At the time of writing this report, there were no references in the literature of simultaneous injection of gadolinium and blood into the subarachnoid space. CASE: We present a case of a patient who received a high dose of gadolinium in the epidural space for needle placement confirmation during a fluoroscopically-guided epidural steroid injection for the treatment of lumbar radiculopathy. The injection was complicated by a wet tap necessitating an epidural blood patch for post-dural puncture headache. Shortly after the injection of the autologous blood, the patient developed grand-mal seizures and mental status changes requiring endotracheal intubation and admission to an intensive care unit. We describe the clinical course and management, as well as brain MRI findings and cerebrospinal fluid (CSF) changes. The patient made a complete recovery and was discharged. CONCLUSION: This case reinforces the need for using a low dose of gadolinium for the confirmation of needle placement in the epidural space, especially in procedures that carry the risk of inadvertent intrathecal injection. We attribute these findings to inadvertent simultaneous intrathecal injection of high dose gadolinium and autologous blood. A literature review of the cases of gadolinium-induced encephalopathy is provided followed by discussion. PMID- 20859324 TI - Application of X STOP device in the treatment of lumbar spinal stenosis. AB - Low back pain is exceptionally ubiquitous, complex, and costly. Nevertheless, lumbar spinal stenosis (LSS) with neurogenic intermittent claudication (NIC) is a frequent cause of low back and lower extremity pain. Although the phenomena and pathophisiology of lumbar spinal stenosis has been described for decades, therapeutic treatment options remain considerably limited. Current care consists of conservative measures including physical therapy, rest, medications, and epidural steroid injection therapy or invasive surgical treatment including laminectomy with or without fusion. Despite standard of care intervention, many patients are often left inadequately treated and suffer from debilitating low back and lower extremity pain as a result of lumbar spinal stenosis. Interspinous process distraction (IPD) devices were originally described in the 1950s, but technological advances, which have contributed to improved safety and efficacy, have rekindled an interest in IPD implantation. By mimicking lumbar flexion at affected levels of stenosis, it is thought these devices decompress neural structures within the neural foramina and therefore provide pain relief. X-STOP is one such device that is currently approved in the United States for the treatment of mild to moderate NIC resulting from LSS. This manuscript presents a focused review of NIC and LSS and comprehensively presents literature related to the use of the X-STOP IPD device. PMID- 20859325 TI - Brain activity associated with chronic cancer pain. AB - BACKGROUND: The number of neuroimaging studies that examine chronic pain are relatively small, and it is clear that different chronic pain conditions activate diverse regions of the brain. OBJECTIVE: Cancer patients presenting for diagnostic positron emission tomography (PET) imaging were asked to rate their spontaneous baseline pain score. Twenty patients with either no pain (NRS = 0) or with moderate to severe pain (NRS = 4) were invited to participate in this study to determine the difference in brain activity in cancer patients with moderate to severe chronic pain versus no pain. STUDY DESIGN: Prospective, non-randomized, observational report. SETTING: Academic medical center. METHODS: Patients had a 2 D PET scan with the radionuclide 18F-fluoro-2-deoxyglucose (FDG) at a dose of approximately 20 mCi. Each individual raw PET scan was coregistered and normalized to standard stereotactic space. Differences in regional glucose metabolism were then statistically compared between patients with moderate-to severe pain and patients with no pain. RESULTS: The NRS pain score in the patients with moderate to severe pain (n = 11) was 4.5 [4.0-6.0] (median [interquartile range]) versus 0.0 [0.0-0.0] (p < 0.001) in the group with no pain (n = 9). Compared to patients with no pain, patients with moderate to severe pain had increased glucose metabolism bilaterally in the prefrontal cortex, BA 9-11. Unilateral activation was found in the right parietal precuneus cortex, BA 7. There were no areas of the brain in which there was decreased activity due to moderate to severe pain. CONCLUSIONS: Our results showing a preferential activation of the prefrontal cortex are consistent with results from studies showing that affective pain perception and negative emotions play an important part in the chronic pain experience. LIMITATIONS: This was not a randomized clinical trial. Patient medication was not controlled. PMID- 20859326 TI - Physical examination, diagnostic imaging, and medical errors. PMID- 20859327 TI - There is another approach to medical malpractice disputes. PMID- 20859329 TI - Pros and cons of outsourcing laboratory services. PMID- 20859328 TI - Study of medication errors on a community hospital oncology ward. AB - PURPOSE: Medication errors (MEs) have been a significant problem resulting in excessive patient morbidity and cost, especially for cancer chemotherapeutic agents. Although some progress has been made, ME measurement methods and prevention strategies remain important areas of research. METHODS: During a 2 year period (2003-2004), we conducted a prospective study on the oncology ward of a large community hospital, with the goals of (1) complete nurse reporting of observed medication administration errors (MAEs), (2) classifying observed MAEs, and (3) formulating improvement strategies. We also conducted a retrospective review of a randomly chosen sample of 200 chemotherapy orders to assess the appropriateness of ordering, dispensing, and administration. RESULTS: Our nurses reported 141 MAEs during the study period, for a reported rate of 0.04% of medication administrations. Twenty-one percent of these were order writing and transcribing errors, 38% were nurse or pharmacy dispensing errors, and 41% were nurse administration errors. Only three MAEs resulted in adverse drug events. Nurses were less likely to report MAEs that they felt were innocuous, especially late-arriving medications from the pharmacy. A retrospective review of 200 chemotherapy administrations found only one clear MAE, a miscalculated dose that should have been intercepted. CONCLUSIONS: Significant reported MAE rates on our ward (0.04% of drug administrations and 0.03 MAEs/patient admission) appear to be relatively low due to application of current safety guidelines. An emphasis on studying MAEs at individual institutions is likely to result in meaningful process changes, improved efficiency of MAE reporting, and other benefits. PMID- 20859330 TI - Oncologists and medical malpractice. PMID- 20859331 TI - An interview with ravindranath "ravi" patel, MD. PMID- 20859332 TI - Practices recognized for commitment to clinical trials. PMID- 20859333 TI - Cincinnati's HealthBridge: Bringing Results From Multiple Service Locations to One Record. PMID- 20859334 TI - What do cars and cancer care have in common? More than you might expect. PMID- 20859336 TI - Even more cost savings? PMID- 20859337 TI - Defining Quality: QOPI Is a Start. PMID- 20859338 TI - Preserving Evidence-Based Oncology: We Can't Jeopardize Clinical Trials. PMID- 20859340 TI - Providing Access to Oncology Care for Rural Patients via Telemedicine. PMID- 20859341 TI - Hematology in the United kingdom. AB - This article is the first in a series of features comparing and contrasting aspects of oncology care delivery in non-US settings. The Journal of Oncology Practice will occasionally publish similar pieces in anticipation of discovering best practices from international health care systems. Dr Prentice's contribution is based on his presentation to the Committee on Practice of the American Society of Hematology at their December 2005 meeting. PMID- 20859339 TI - Racial differences in patterns of care among medicaid-enrolled patients with breast cancer. AB - PURPOSE: Suboptimal care among minority and low-income patients may explain poorer survival. There is little information describing patterns of health care in Medicaid-insured women with breast cancer in the United States. Using a previously created and validated database linking Medicaid claims and state-wide tumor registry data, we describe patterns of breast cancer care within a low income population. METHODS: Sample characteristics were described by frequencies and means. Logistic regressions were used to determine predictors of type of surgery, use of radiation therapy after breast-conserving surgery (BCS), and use of adjuvant chemotherapy. RESULTS: The sample consisted of 974 women. The dataset included only white (58%) and black (42%) women. Sixty-seven percent were treated with mastectomy; 43% received adjuvant chemotherapy; and 67% of women receiving BCS received adjuvant radiation. In multivariate analysis, predictors of BCS were young age, black race, and smaller tumor size. Furthermore, there was a trend toward more black than white women with tumors 4 cm or larger having BCS (18% v 8%; P = .06). Race was not related to use of adjuvant radiation therapy after BCS or to use of adjuvant chemotherapy. CONCLUSION: In this group of patients with breast cancer enrolled in Medicaid, black women were more likely than white women to have BCS. Race was not associated with adjuvant radiation therapy or chemotherapy use. Factors affecting the quality of care delivered to low-income and minority patients are complex, and better care lies in exploring areas that need improvement. PMID- 20859342 TI - Disparities in cancer care.